PMID- 29473939 TI - Overuse of antimicrobial prophylaxis in low-risk patients undergoing transurethral resection of the prostate. AB - OBJECTIVE: To evaluate the current antimicrobial prophylaxis practices for low risk patients undergoing transurethral resection of the prostate (TURP) or photoselective vaporisation of the prostate (PVP) in comparison with the antimicrobial prophylaxis recommendations of the European Association of Urology (EAU), which have been shown to effectively reduce infectious complications and antimicrobial resistance rates. METHODS: In May 2017, we sent an anonymous online -survey to board-certified urologists in Germany, Austria and Switzerland, by use of the database directory of the respective urology associations. Besides demographical questions, urologists were asked about their sources of information on antimicrobial prophylaxis prescription and their prescribing patterns before, during and after surgery in patients without an indwelling catheter or significant bacteriuria undergoing TURP or PVP. RESULTS: Overall, 374 of 5825 urologists responded, of whom 76% (286/374) performed TURP and 16% (60/374) PVP. For TURP and PVP, respectively: (i) 42% (119/286) and 33% (20/60) reported routine use of preoperative antimicrobial prophylaxis, which does not conform to guideline recommendations; (ii) 43% (124/286) and 52% (31/60) reported prescribing non-recommended perioperative antimicrobial prophylaxis regimens; and (iii) 60% (172/286) and 65% (39/60) routinely extended antimicrobial prophylaxis after surgery for up to one week. In summary, of the urologists who responded to the questionnaire, 74% (211/286) reported nonadherence to guidelines on antimicrobial prophylaxis for TURP. CONCLUSION: A low adherence to guidelines for low-risk patients undergoing TURP or PVP was reported. Given these preliminary data, there is an urgent need to monitor adherence to antimicrobial prophylaxis guidelines in urology to reduce antimicrobial resistance rates. PMID- 29473940 TI - Delirium-A Framework to Improve Acute Care for Older Persons. AB - This article is based on the M. Powell Lawton Award Lecture that I delivered at the 2016 Gerontological Society of America Annual Meeting. I provide an overview of my journey in geriatric medicine and delirium research. I created new measures, including the Confusion Assessment Method, for identification of delirium; conceptualized a multifactorial risk model; and developed and tested intervention strategies for delirium prevention. The Hospital Elder Life Program arose from this work. In addition, like Dr. Lawton, I am working to apply my work to the policy arena. As the population ages, we face an unprecedented opportunity to realize the full benefit of aging in our society, an untapped resource. The field of aging is facing innumerable challenges in terms of continued stigma and funding shortfalls for clinical care and research. I issue a call to action to clinicians, researchers, and leaders in aging to seize this opportunity to use our know-how and expertise to transform the experience of aging for all. PMID- 29473941 TI - Targeted Geriatric Assessment for Fast-Paced Healthcare Settings: Development, Validity, and Reliability. AB - OBJECTIVES: To develop and examine the validity and reliability of a targeted geriatric assessment (TaGA) for busy healthcare settings. DESIGN: The TaGA was developed through the consensus of experts (Delphi technique), and we investigated its construct validity and reliability in a cross-sectional study. SETTING: Geriatric day hospital specializing in acute care in Brazil. PARTICIPANTS: Older adults (N = 534) aged 79.5 +/- 8.4, 63% female, consecutively admitted to the geriatric day hospital. MEASUREMENTS: The Frailty Index (FI), Physical Frailty Phenotype, and Identification of Seniors at Risk (ISAR) were used to explore the TaGA's validity. External scales were used to investigate the validity of each matched TaGA domain. The interrater reliability and time to complete the instrument were tested in a 53-person subsample. RESULTS: In 3 rounds of opinion, experts achieved consensus that the TaGA should include 10 domains (social support, recent hospital admissions, falls, number of medications, basic activities of daily living, cognitive performance, self-rated health, depressive symptoms, nutritional status, gait speed). They arrived at sufficient agreement on specific tools to assess each domain. A single numerical score from 0 to 1 expressed the cumulative deficits across the 10 domains. The TaGA score was highly correlated with the FI (Spearman coefficient = 0.79, 95% confidence interval (CI)=0.76-0.82) and discriminated between frail and nonfrail individuals better than the ISAR (area under the receiver operating characteristic curve 0.84 vs 0.72; P < .001). The TaGA score also had excellent interrater reliability (intraclass correlation coefficient = 0.92, 95% CI=0.87 0.95). Mean TaGA administration time was 9.5 +/- 2.2 minutes. CONCLUSION: The study presents evidence supporting the TaGA's validity and reliability. This instrument may be a practical and efficient approach to screening geriatric syndromes in fast-paced healthcare settings. Future research should investigate its predictive value and effect on care. PMID- 29473942 TI - Graphical Instructions for Administration and Scoring the Mini-Cog: Results of a Randomized Clinical Trial. AB - OBJECTIVES: To develop a novel set of graphical Mini-Cog instructions designed to aid clinicians previously untrained on the Mini-Cog in accurate administration and scoring and to determine whether use of these graphical instructions improved the speed and accuracy of deployment of this tool. DESIGN: Randomized clinical trial. SETTING: Testing was conducted in a simulated environment with a mock patient. PARTICIPANTS: Registered nurses working in inpatient or outpatient settings at a large academic medical center who had no prior exposure to or training with the Mini-Cog (N=92). MEASUREMENTS: Our primary outcome was the composite proportion of nurses who made errors in administration or scoring of the Mini-Cog. RESULTS: None of the nurses in the graphical instruction group and 28 (61%) in the standardized instructions group (15 (33%) made administration errors, 22 (48%) made scoring errors) made errors. Nurses randomly assigned to the graphical group were able to read (median 36 vs 54 seconds, P<.001), administer (46 vs 62 seconds, P<.001), and score (15 vs 84 seconds, P<.001) the Mini-Cog more quickly than those in the standardized instructions group. CONCLUSION: Graphical instructions increase the accuracy and speed of test administration in nurses without prior training in Mini-Cog administration. Further research is necessary to confirm these findings and evaluate the use of this method in other healthcare professionals and settings. PMID- 29473943 TI - Confusion and Bacteriuria in Long-Term Care Facility Residents. PMID- 29473944 TI - Non-endocannabinoid N-acylethanolamines and 2-monoacylglycerols in the intestine. AB - This review focuses on recent findings of the physiological and pharmacological role of non-endocannabinoid N-acylethanolamines (NAEs) and 2-monoacylglycerols (2 MAGs) in the intestine and their involvement in the gut-brain signalling. Dietary fat suppresses food intake, and much research concerns the known gut peptides, for example, glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK). NAEs and 2-MAGs represent another class of local gut signals most probably involved in the regulation of food intake. We discuss the putative biosynthetic pathways and targets of NAEs in the intestine as well as their anorectic role and changes in intestinal levels depending on the dietary status. NAEs can activate the transcription factor PPARalpha, but studies to evaluate the role of endogenous NAEs are generally lacking. Finally, we review the role of diet-derived 2-MAGs in the secretion of anorectic gut peptides via activation of GPR119. Both PPARalpha and GPR119 have potential as pharmacological targets for the treatment of obesity and the former for treatment of intestinal inflammation. PMID- 29473945 TI - Home-Based Primary Care: Beyond Extension of the Independence at Home Demonstration. AB - The Independence at Home (IAH) Demonstration Year 2 results confirmed that the first-year savings were 10 times as great as those of the pioneer accountable care organizations during their initial 2 years. We update projected savings from nationwide conversion of the IAH demonstration, incorporating Year 2 results and improving attribution of IAH-qualified (IAH-Q) Medicare beneficiaries to home based primary care (HBPC) practices. Applying IAH qualifying criteria to beneficiaries in the Medicare 5% claims file, the effect of expanding HBPC to the 2.4 million IAH-Q beneficiaries is projected using various growth rates. Total 10 year system-wide savings (accounting for IAH implementation but before excluding shared savings) range from $2.6 billion to $27.8 billion, depending on how many beneficiaries receive HBPC on conversion to a Medicare benefit, mix of clinical practice success, and growth rate of IAH practices. Net projected savings to the Centers for Medicare and Medicaid Services (CMS) after routine billing for IAH services and distribution of shared savings ranges from $1.8 billion to $10.9 billion. If aligning IAH with other advanced alternative payment models achieved at least 35% penetration of the eligible population in 10 years, CMS savings would exceed savings with the current IAH design and HBPC growth rate. If the demonstration were simply extended 2 years with a beneficiary cap of 50,000 instead of 15,000 (as currently proposed), CMS would save an additional $46 million. The recent extension of IAH, a promising person-centered CMS program for managing medically complex and frail elderly adults, offers the chance to evaluate modifications to promote more rapid HBPC growth. PMID- 29473946 TI - Can PET/CT help manage ground glass nodules? PMID- 29473947 TI - Quality of preoperative pelvic computed tomography (CT) and magnetic resonance imaging (MRI) for rectal cancer in a region in Ontario: A retrospective population-based study. AB - BACKGROUND AND OBJECTIVES: Treatment decisions for rectal cancer rely on preoperative staging with CT and MRI scans. We assessed the quality of such scans in a region of Ontario. METHODS: We retrospectively collected data for patients undergoing rectal cancer surgery between July 2011 and December 2014. We measured three aspects of quality: use; comprehensiveness of reporting T-category, N category, mesorectal fascia (MRF) status; and in non-radiated patients sensitivity and specificity of reports for relevant elements. RESULTS: A total of 559 patients underwent major rectal cancer surgery. Preoperative staging with CT and MRI was performed in 93% and 50% of patients. CT scan reports provided information on T-category, N-category, and MRF status in 41%, 92%, and 16% of cases. These same elements were reported on MRI in 88%, 93%, and 62% of cases. CT scan sensitivity and specificity was 80% and 80% for T-category, and 85% and 39% for N-category. MRI sensitivity and specificity was 75% and 81% for T-category, 79% and 37% for N-category, and 33% and 89% for MRF status. CONCLUSION: In this region of Ontario, pre-operative MRI was underutilized, CT reporting of MRF status was low, and when reported sensitivity and specificity of T- and N category were similar for CT and MRI. PMID- 29473948 TI - Facilitation of ischaemia-induced ventricular fibrillation by catecholamines is mediated by beta1 and beta2 agonism in the rat heart in vitro. AB - BACKGROUND AND PURPOSE: Antiarrhythmic beta-blockers are used in patients at risk of myocardial ischaemia, but the survival benefit and mechanisms are unclear. We hypothesized that beta-blockers do not prevent ventricular fibrillation (VF) but instead inhibit the ability of catecholamines to facilitate ischaemia-induced VF, limiting the scope of their usefulness. EXPERIMENTAL APPROACH: ECGs were analysed from ischaemic Langendorff-perfused rat hearts perfused with adrenoceptor antagonists and/or exogenous catecholamines (CATs: 313 nM noradrenaline + 75 nM adrenaline) in a blinded and randomized study. Ischaemic zone (IZ) size was deliberately made small or large. KEY RESULTS: In rat hearts with large IZs, ischaemia-induced VF incidence was high in controls. Atenolol, butoxamine and trimazosin did not affect VF at concentrations with beta1 -, beta2 - or alpha1 - adrenoceptor specificity and selectivity (confirmed in separate rat aortae myography experiments). In hearts with small IZs and low baseline incidence of ischaemia-induced VF, CATs, delivered to the uninvolved zone (UZ), increased ischaemia-induced VF incidence. This effect was not mimicked by atrial pacing, hence, not due to sinus tachycardia. However, the CATs-facilitated increase in ischaemia-induced VF was inhibited by atenolol and butoxamine (but not trimazosin), indicative of beta1 - and beta2 - but not alpha1 -adrenoceptor involvement (confirmed by immunoblot analysis of downstream phosphoproteins). CATs did not facilitate VF in low-flow globally ischaemic hearts, which have no UZ. CONCLUSIONS AND IMPLICATIONS: Catecholamines facilitated ischaemia-induced VF when risk was low, acting via beta1 - and beta2 - adrenoceptors located in the UZ. There was no scope for facilitation when VF risk was high (large IZ), which may explain why beta-blockers have equivocal effectiveness in humans. PMID- 29473949 TI - Design and Validation of a Radio-Frequency Identification-Based Device for Routinely Assessing Gait Speed in a Geriatrics Clinic. AB - OBJECTIVES: To evaluate the feasibility, acceptability, and validity of a radio frequency identification (RFID)-based system to measure gait speed in a clinical setting as a first step to using unobtrusive gait speed assessment in routine clinical care. DESIGN: Feasibility study comparing gait speed assessed using an RFID-based system with gait speed assessed using handheld stopwatch, the criterion standard. SETTING: Outpatient geriatrics clinic at a Connecticut-based academic medical center. PARTICIPANTS: Clinic attendees who could walk independently with or without an assistive device (N=50) and healthcare providers (N=9). MEASUREMENTS: Gait speed was measured in twice using 2 methods each time before participants entered an examination room. Participants walked at their usual pace while gait speed was recorded simultaneously using the RFID-based system and a handheld stopwatch operated by a trained study investigator. After 2 trials, participants completed a brief survey regarding their experience. At the end of the study period, clinic healthcare providers completed a separate survey. RESULTS: Test-retest reliability of the RFID-based system was high (intraclass correlation coefficient = 0.953). The mean difference +/- standard deviation in gait speed between the RFID-based system and the stopwatch was -0.003+/-0.035 m/s (p=.53) and did not differ significantly according to age, sex, or use of an assistive walking aid. Acceptability of the device was high, and 8 of 9 providers indicated that measuring gait speed using the RFID-based system should be a part of routine clinical care. CONCLUSION: RFID technology may offer a practical means of overcoming barriers to routine measurement of gait speed in real-world outpatient clinical settings. PMID- 29473950 TI - Serine proteinases in the turnover of the cartilage extracellular matrix in the joint: implications for therapeutics. AB - Cartilage destruction is a key characteristic of arthritic disease, a process now widely established to be mediated by metzincins such as MMPs. Despite showing promise in preclinical trials during the 1990s, MMP inhibitors for the blockade of extracellular matrix turnover in the treatment of cancer and arthritis failed clinically, primarily due to poor selectivity for target MMPs. In recent years, roles for serine proteinases in the proteolytic cascades leading to cartilage destruction have become increasingly apparent, renewing interest in the potential for new therapeutic strategies that utilize pharmacological inhibitors against this class of proteinases. Herein, we describe key serine proteinases with likely importance in arthritic disease and highlight recent advances in this field. LINKED ARTICLES: This article is part of a themed section on Translating the Matrix. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.1/issuetoc. PMID- 29473952 TI - Biophysical and structural insight into the USP8/14-3-3 interaction. AB - The ubiquitin-specific protease 8 (USP8)/14-3-3 protein-protein interaction has recently been shown to exert a significant role in the pathogenesis of Cushing's disease (CD). USP8 is a deubiquitinase that prevents epidermal growth factor receptor (EGFR) degradation. Impairment of 14-3-3 binding leads to a higher deubiquitination of EGFR and results in a higher EGFR signaling and an increased production of adrenocorticotropic hormone. Here we report the high-resolution crystal structure of the 14-3-3 binding motif of USP8 surrounding Ser718 in complex with 14-3-3zeta and characterize the interaction with fluorescence polarization and isothermal titration calorimetry. Furthermore, we analyze the effect of USP8 mutations identified in CD on binding to 14-3-3. PMID- 29473953 TI - LETTER TO THE EDITOR. PMID- 29473951 TI - 4-Hydroxynonenal-induced GPR109A (HCA2 receptor) activation elicits bipolar responses, Galphai -mediated anti-inflammatory effects and Gbetagamma -mediated cell death. AB - BACKGROUND AND PURPOSE: In this study, we examined the possibility that 4 hydroxynonenal (4-HNE) acting as a ligand for the HCA2 receptor (GPR109A) elicits both anti-inflammatory and cell death responses. EXPERIMENTAL APPROACH: Agonistic activity of 4-HNE was determined by observing the inhibition of cAMP generation in CHO-K1-GPR109A-Gi cell line, using surface plasmon resonance (SPR) binding and competition binding assays with [3 H]-niacin. 4-HNE-mediated signalling pathways and cellular responses were investigated in cells expressing GPR109A and those not expressing these receptors. KEY RESULTS: Agonistic activity of 4-HNE was stronger than that of niacin or 3-OHBA at inhibiting forskolin-induced cAMP production and SPR binding affinity. In ARPE-19 and CCD-841 cells, activation of GPR109A by high concentrations of the agonists 4-HNE (>=10 MUM), niacin (>=1000 MUM) and 3-OHBA (>=1000 MUM) induced apoptosis accompanied by elevated Ca2+ and superoxide levels. This 4-HNE-induced cell death was blocked by knockdown of GPR109A or NOX4 genes, or treatment with chemical inhibitors of Gbetagamma (gallein), intracellular Ca2+ (BAPTA-AM), NOX4 (VAS2870) and JNK (SP600125), but not by the cAMP analogue 8-CPT-cAMP. By contrast, low concentrations of 4-HNE, niacin and 3-OHBA down-regulated the expression of pro-inflammatory cytokines IL 6 and IL-8. These 4-HNE-induced inhibitory effects were blocked by a cAMP analogue but not by inhibitors of Gbetagamma -downstream signalling molecules. CONCLUSIONS AND IMPLICATIONS: These results revealed that 4-HNE is a strong agonist for GPR109A that induces Galphai -dependent anti-inflammatory and Gbetagamma -dependent cell death responses. Moreover, the findings indicate that specific intracellular signalling molecules, but not GPR109A, can serve as therapeutic targets to block 4-HNE-induced cell death. PMID- 29473955 TI - Growth Capacity of a Novel Potential Probiotic Lactobacillus paracasei K5 Strain Incorporated in Industrial White Brined Cheese as an Adjunct Culture. AB - : In this study, a novel potential probiotic strain Lactobacillus paracasei K5, previously isolated from traditional Greek Feta cheese and kefir grains, was evaluated as an adjunct culture for industrial white brined cheese production. Targeting industrial applications, apart from free cell cultures, a novel ready to-use freeze-dried immobilized biocatalyst was prepared. The biocatalyst composed of L. paracasei K5 cells immobilized on delignified wheat bran prebiotic carrier and was freeze-dried without cryoprotectants. The adjunct free or immobilized culture was added separately without prior adaptation during white brined cheese manufacture and the produced cheeses were compared with commercial white brined cheeses. Several parameters that affect the acceptability and quality of the cheeses, including microbial populations, physicochemical parameters, volatile by-products and organoleptic characteristics, were analyzed through 70 days of storage. Results showed that the viability of the adjunct culture added either free or immobilized remained in high levels (7 to 8 log cfu/g) during maturation and storage. In addition, all white brined cheeses with the adjunct probiotic culture showed a sharp decrease in spoilage and pathogenic microorganisms such as enterobacteria, salmonella, staphylococci and coliforms during cheese maturation, especially when compared with the commercial white brined cheeses. Finally, after maturation time exceeded, all cheeses were characterized as safe for human consumption. Cheeses volatile compounds were significantly enhanced by the incorporated immobilized biocatalysts. These findings indicate the potential industrial use of freeze-dried ready-to-use immobilized lactobacilli as reinforcement adjunct cultures for the production of good-quality functional cheese products. PRACTICAL APPLICATION: The launch on market of novel foods developed by the incorporation of functional ingredients provides potential benefits to consumers' diet and new business opportunities for producers. Probiotic food products are one significant category of functional foods. Thus, this study focused on the development of a novel ready-to-use freeze dried potential probiotic biocatalyst for functional white brined cheese production. The potential industrial application of such biocatalysts is highlighted by their incorporation as adjunct cultures that resulted in good quality functional cheeses. PMID- 29473954 TI - Converting a broad matrix metalloproteinase family inhibitor into a specific inhibitor of MMP-9 and MMP-14. AB - MMP-14 and MMP-9 are two well-established cancer targets for which no specific clinically relevant inhibitor is available. Using a powerful combination of computational design and yeast surface display technology, we engineered such an inhibitor starting from a nonspecific MMP inhibitor, N-TIMP2. The engineered purified N-TIMP2 variants showed enhanced specificity toward MMP-14 and MMP-9 relative to a panel of off-target MMPs. MMP-specific N-TIMP2 sequence signatures were obtained that could be understood from the structural perspective of MMP/N TIMP2 interactions. Our MMP-9 inhibitor exhibited 1000-fold preference for MMP-9 vs. MMP-14, which is likely to translate into significant differences under physiological conditions. Our results provide new insights regarding evolution of promiscuous proteins and optimization strategies for design of inhibitors with single-target specificities. PMID- 29473956 TI - Cardiac vagal flexibility and accurate personality impressions: Examining a physiological correlate of the good judge. AB - OBJECTIVE: Research has long sought to identify which individuals are best at accurately perceiving others' personalities or are good judges, yet consistent predictors of this ability have been difficult to find. In the current studies, we revisit this question by examining a novel physiological correlate of social sensitivity, cardiac vagal flexibility, which reflects dynamic modulation of cardiac vagal control. METHOD: We examined whether greater cardiac vagal flexibility was associated with forming more accurate personality impressions, defined as viewing targets more in line with their distinctive self-reported profile of traits, in two studies, including a thin-slice video perceptions study (N = 109) and a dyadic interaction study (N = 175). RESULTS: Across studies, we found that individuals higher in vagal flexibility formed significantly more accurate first impressions of others' more observable personality traits (e.g., extraversion, creativity, warmth). These associations held while including a range of relevant covariates, including cardiac vagal tone, sympathetic activation, and gender. CONCLUSION: In sum, social sensitivity as indexed by cardiac vagal flexibility is linked to forming more accurate impressions of others' observable traits, shedding light on a characteristic that may help to identify the elusive good judge and providing insight into its neurobiological underpinnings. PMID- 29473957 TI - Comparison of two novel staging systems with the TNM system in predicting stage III colon cancer survival. AB - BACKGROUND AND OBJECTIVES: Adaptations of the TNM staging system that incorporate the Lymph Node Ratio (LNR) have been proposed for stage III colon cancer. This study compared the concordance of two novel staging systems and the TNM system with observed survival outcomes in stage III patients. METHODS: A review of patients who underwent surgery for stage III colon cancer between January 2002 and April 2015 at a tertiary care centre was performed. The Kaplan-Meier method was used to estimate the 5-year overall (OS) and disease free survival (DFS) rates, and the concordance probability was calculated to evaluate the discriminatory power of the staging systems. RESULTS: Two hundred and sixty-one patients were identified. For TNM stages IIIA, IIIB, and IIIC, 5-year OS was 83.4%, 67.6%, and 38.3%, respectively (P < 0.001). All three staging systems were independently predictive of OS and DFS (P < 0.001). However, the novel staging system by Sugimoto et al18 was the most favourable prognostic tool, with a concordance of 0.646 for DFS and 0.659 for OS. CONCLUSIONS: The novel staging system by Sugimoto et al18 was superior to the TNM system. Incorporating LNR into staging models for node positive colon cancers may improve survival information available to patients and potentially aid treatment decisions. PMID- 29473958 TI - Is tissue still the issue? Lobectomy for suspicious lung nodules without confirmation of malignancy. AB - BACKGROUND: Histologic confirmation of malignancy has been indicated for a suspicious lung nodule prior to resection. The purpose of this study was to determine whether or not foregoing routine tissue biopsy increased the incidence of lobectomy for benign lesions. METHODS: Retrospective cohort of 256 patients who underwent thoracoscopic or open lobectomy for a confirmed or suspected pulmonary malignancy, with or without tissue diagnosis. Clinical, radiographic, and pathologic data were compared. RESULTS: Among 256 patients, 127 had attempted biopsy (group A) and 129 had no biopsy procedure (group B). There was no significant difference in the incidence of benign resections between the groups (Group A = 4 (3.2%) benign pathology vs group B = 9 (7.0%; P = 0.16). Group B had significantly lower operative time (127.1 vs 112.3 minutes; P = 0.004) and intraoperative complications (23 vs 37 patients; P = 0.03). There was a trend toward longer hospital stay and surgical waiting time in group A (6.6 vs 5.2 days, P = 0.24; 92.4 vs 66.2 days; P = 0.14, respectively). CONCLUSION: Foregoing biopsies and proceeding to lobectomy in selected patients with suspicious lung nodules is safe, did not increase the incidence of resected benign pathology, and may decrease surgical wait time. Patients should be carefully evaluated and counseled. PMID- 29473959 TI - Reconstruction using a constrained-type hip tumor prosthesis after resection of malignant periacetabular tumors: A study by the Japanese Musculoskeletal Oncology Group (JMOG). AB - BACKGROUND: We conducted a nationwide survey of prosthetic reconstruction using a constrained-type hip tumor prosthesis (C-THA) following resection of periacetabular tumors. METHODS: Eighty patients with periacetabular tumors underwent wide resection and prosthetic reconstruction using C-THA at JMOG affiliated institutions (39 males and 41 females; mean age, 46.7 years; mean follow-up period, 65 months). Primary bone or soft tissue sarcoma accounted for 75% of the cases. Adjuvant radiotherapy and chemotherapy were performed for 12 and 37 patients, respectively. RESULTS: There were 21 local recurrences (26%), necessitating amputation in 2 patients. Other postoperative complications included deep infection in 31 patients (39%), delayed wound healing in 25 (31%), and prosthesis-related complications requiring surgery in 7 (9%). Removal of the prosthesis was required in 23 patients (29%) (deep infection (n = 20), local recurrence resulting in amputation (n = 2), and outer cup displacement (n = 1). Patients whose abductor muscle was conserved or who underwent functional abductor muscle reconstruction showed significantly longer prosthesis survival. No postoperative wound complications occurred in three recent patients undergoing wound management with a RAM flap. The mean MSTS score was 43%. CONCLUSIONS: We analyzed the outcome of 80 patients with periacetabular tumors undergoing C-THA reconstruction. The rates of postoperative complication were still high, but comparable to those in previous studies. Our results suggest wound management using a RAM flap is useful for reducing wound complications. PMID- 29473960 TI - Breast-specific factors determine cosmetic outcome and patient satisfaction after breast-conserving therapy: Results from the randomized COBALT study. AB - BACKGROUND AND OBJECTIVES: To identify breast-specific factors and the role of tumor, treatment, and patient-related items in influencing patient opinion on cosmesis and satisfaction after breast-conserving therapy (BCT). METHODS: Data from the randomized COBALT study was used. At 3, 12, and 36 months, 128 patients with T1-T2 breast cancer completed a questionnaire on breast-specific factors and overall cosmetic outcome and patient satisfaction, using a 4-point Likert scale. RESULTS: There was a strong positive correlation between breast-specific factors, overall cosmetic outcome,and satisfaction at all time-points. Excellent/good cosmetic outcomes and satisfaction decreased during follow-up. A shift was noted in the degree of influence of the various breast-specific factors. At 3 years, symmetry factors such as size, shape, and nipple position largely determined a patient's opinion on the final cosmesis, followed by firmness. The risk of an unacceptable outcome was associated with young age and large excision volumes. CONCLUSION: A questionnaire including breast-specific questions provides important information on final cosmetic results and satisfaction after BCT. These outcomes can also be of great value as quality indicators and pre-operative counseling. The major influence of breast-specific factors on asymmetry underlines the importance of achieving an optimal excision volume at the initial procedure. PMID- 29473961 TI - Discounting: A practical guide to multilevel analysis of choice data. AB - Multilevel modeling provides the ability to simultaneously evaluate the discounting of individuals and groups by examining choices between smaller sooner and larger later rewards. A multilevel logistic regression approach is advocated in which sensitivity to relative reward magnitude and relative delay are considered as separate contributors to choice. Examples of how to fit choice data using multilevel logistic models are provided to help researchers in the adoption of these methods. PMID- 29473962 TI - Postoperative low hepatitis C virus load predicts long-term outcomes after hepatectomy for hepatocellular carcinoma. AB - BACKGROUND: Preoperative hepatitis C virus (HCV) viral load is known to predict long-term outcomes after hepatectomy for HCV-related hepatocellular carcinoma (HCC). This study sought to examine the hypothesis that postoperative and preoperative HCV viral-load have similar prognostic implications, as well as determine a target viral-load that will improve long-term postoperative outcomes. METHOD: One hundred and eighty-one patients who underwent curative hepatectomy for HCV-related HCC were divided into five groups according to time-weighted average viral load. The cumulative-recurrence curves of the five groups were compared to identify prognostic trends. The optimal cut-off viral load value related to recurrence was also investigated. RESULTS: The five cumulative recurrence curves were separated into two clusters according to viral load. Patients with a negative viral load had comparable recurrence curves to patients with the lowest viral-load (P = 0.907); both of these patient groups had more favorable outcomes than patients with a viral load categorized in the other groups (all P < 0.050). The optimal cut-off based on maximum HR method (> or <=4.0 log10 IU/mL) was a strong prognostic indicator of recurrence in multivariate analysis (HR 3.09; 95%CI 1.96-5.04; P < 0.001). CONCLUSION: Postoperative HCV viral load correlated with long-term surgical outcomes. A low viral load (<=4.0 log10 IU/mL) independently predicted better long-term outcomes. PMID- 29473963 TI - HEPATOFLUO: A prospective monocentric study assessing the benefits of indocyanine green (ICG) fluorescence for hepatic surgery. AB - BACKGROUND AND OBJECTIVES: Fluorescence imaging using indocyanine green (ICG) is undergoing extensive development. This study aimed to assess the merits of ICG in regard to hepatic surgery. METHODS: Patients with liver lesions that required a resection were eligible. They received an injection of ICG the day before the surgery. Step 1 allowed assessment of use of the medical device under surgical conditions. Steps 2 and 3 assessed the capacity of the MD to detect known tumorous lesions and to spot a predefined area of the liver following injection of ICG into the portal vein (ICGp). RESULTS: The 1st step allowed for validation of the MD use with three patients. Between 04-2013 and 04-2015, 45 pts were included (40 eligible) in steps 2 and 3. All of the tumorous lesions (95/119) exhibited fluorescence. Four new metastasis were detected in 3 pts, and two missing metastases in 1 pt. False positive were 22%. The maximal depth for detection by fluorescence was 13 mm. Injection of ICGp allowed the corresponding anatomical area to be identified in 16/20 patients. CONCLUSION: This study confirmed that intraoperative fluorescence is a helpful and relevant tool for the liver surgeon (NCT 01738217). PMID- 29473964 TI - Waking the neighbours: disruption of H-NS repression by overlapping transcription. AB - The histone-like nucleoid structuring (H-NS) protein and its analogues bind large stretches of horizontally acquired AT-rich DNA in a broad range of bacterial species. Binding by H-NS silences the promoters within such DNA that would otherwise deplete the cellular pool of RNA polymerase. Selective de-repression can occur when sequence-specific DNA-binding proteins locally disrupt H-NS function; this mechanism is important for the regulation of many virulence genes. In this issue of Molecular Microbiology, Rangarajan and Schnetz show that when transcription from a neighbouring region invades an H-NS-bound locus, it can disrupt local H-NS repression. Moreover, they show that de-repression occurs in a dose-dependent manner, and they demonstrate a natural example of this in Escherichia coli. This finding has important implications for H-NS function and its impact on genome evolution. PMID- 29473965 TI - Alternaria alternata challenge at the nasal mucosa results in eosinophilic inflammation and increased susceptibility to influenza virus infection. AB - BACKGROUND: Eosinophils in the nasal mucosa are an elemental feature of allergic rhinitis. OBJECTIVE: Our objective was to explore eosinophilic inflammation and its impact on respiratory virus infection at the nasal mucosa. METHODS: Inflammation in the nasal mucosae of mice was evaluated in response to repetitive stimulation with strict intranasal volumes of a filtrate of Alternaria alternata. Mice were then challenged with influenza virus. RESULTS: Repetitive stimulation with A. alternata resulted in eosinophil recruitment to the nasal passages in association with elevated levels of IL-5, IL-13 and eotaxin-1; eosinophil recruitment was diminished in eotaxin-1-/- mice, and abolished in Rag1-/- mice. A. alternata also resulted in elevated levels of nasal wash IgA in both wild-type and eosinophil-deficient ?dblGATA mice. Interestingly, A. alternata-treated mice responded to an influenza virus infection with profound weight loss and mortality compared to mice that received diluent alone (0% vs 100% survival, ***P < .001); the lethal response was blunted when A. alternata was heat-inactivated. Minimal differences in virus titre were detected, and eosinophils present in the nasal passages at the time of virus inoculation provided no protection against the lethal sequelae. Interestingly, nasal wash fluids from mice treated with A. alternata included more neutrophils and higher levels of pro-inflammatory mediators in response to virus challenge, among these, IL-6, a biomarker for disease severity in human influenza. CONCLUSIONS AND CLINICAL RELEVANCE: Repetitive administration of A. alternata resulted in inflammation of the nasal mucosae and unanticipated morbidity and mortality in response to subsequent challenge with influenza virus. Interestingly, and in contrast to findings in the lower airways, eosinophils recruited to the nasal passages provided no protection against lethal infection. As increased susceptibility to influenza virus among individuals with rhinitis has been the subject of several clinical reports, this model may be used for further exploration of these observations. PMID- 29473966 TI - Beyond Abstinence: Changes in Indices of Quality of Life with Time in Recovery in a Nationally Representative Sample of U.S. Adults. AB - BACKGROUND: Alcohol and other drug (AOD) treatment and recovery research typically have focused narrowly on changes in alcohol/drug use (e.g., "percent days abstinent") with little attention on changes in functioning or well-being. Furthermore, little is known about whether and when such changes may occur, and for whom, as people progress in recovery. Greater knowledge would improve understanding of recovery milestones and points of vulnerability and growth. METHODS: National, probability-based, cross-sectional sample of U.S. adults who screened positive to the question, "Did you used to have a problem with alcohol or drugs but no longer do?" (Response = 63.4% from 39,809; final weighted sample n = 2,002). Linear, spline, and quadratic regressions tested relationships between time in recovery and 5 measures of well-being: quality of life, happiness, self-esteem, recovery capital, and psychological distress, over 2 temporal horizons: the first 40 years and the first 5 years, after resolving an AOD problem and tested moderators (sex, race, primary substance) of effects. Locally Weighted Scatterplot Smoothing regression was used to explore turning points. RESULTS: In general, in the 40-year horizon there were initially steep increases in indices of well-being (and steep drops in distress), during the first 6 years, followed by shallower increases. In the 5-year horizon, significant drops in self-esteem and happiness were observed initially during the first year followed by increases. Moderator analyses examining primary substance found that compared to alcohol and cannabis, those with opioid or other drugs (e.g., stimulants) had substantially lower recovery capital in the early years; mixed race/native Americans tended to exhibit poorer well-being compared to White people; and women consistently reported lower indices of well-being over time than men. CONCLUSIONS: Recovery from AOD problems is associated with dynamic monotonic improvements in indices of well-being with the exception of the first year where self-esteem and happiness initially decrease, before improving. In early recovery, women, certain racial/ethnic groups, and those suffering from opioid and stimulant-related problems appear to face ongoing challenges that suggest a need for greater assistance. PMID- 29473967 TI - Importance of wide re-resection in adult spermatic cord sarcomas: Report on oncologic outcomes at a single institution. AB - BACKGROUND AND OBJECTIVES: We evaluated the effect of re-resection with wide margins (undertaken because initial resection performed elsewhere was incomplete) on survival in patients with spermatic cord sarcoma (SCS). METHODS: After excluding those with metastatic disease and those not undergoing surgical intervention, the records of 72 consecutive patients treated for SCS between 1981 and 2011 at Memorial Sloan Kettering Cancer Center were reviewed. Recurrence-free survival (RFS) and cancer-specific survival were calculated using the Kaplan Meier method for comparing between the 48 patients who underwent wide re resection (WRR) within 5 months of diagnosis and the 24 who did not. The relationship of age, tumor size, tumor histology, adjuvant radiation, and wide re resection with recurrence and death was assessed by univariate Cox regression. RESULTS: WRR significantly improved RFS (hazard ratio [HR] 0.16, 95%CI 0.07-0.37; P < 0.0001), despite the fact that patients receiving WRR had higher-grade disease. Tumor-positive margins upon WRR were strongly associated with both disease recurrence (HR 5.56; 95%CI 1.14-27.11, P = 0.034) and death from cancer (HR 6.16, 95%CI 1.25-30.29; P = 0.025). CONCLUSIONS: A WRR with negative margins is effective in the management of patients with SCS and leads to improved RFS. PMID- 29473968 TI - Safety and oncologic outcomes of robotic liver resections: A systematic review. AB - The robotic system has emerged as a new minimally invasive technology with promising results. We sought to systematically review the available literature on the safety and the oncologic outcomes of robotic liver surgery. A systematic review was conducted using Medline (PubMed), Embase and Cochrane library through November 12th, 2017. A robotic approach may be a safe and feasible surgical option for minor and major liver resections. PMID- 29473969 TI - Isolation and characterization of N2 -fixing bacteria from giant reed and switchgrass for plant growth promotion and nutrient uptake. AB - The aims of this study were to isolate and characterize N2 -fixing bacteria from giant reed and switchgrass and evaluate their plant growth promotion and nutrient uptake potential for use as biofertilizers. A total of 190 bacteria were obtained from rhizosphere soil and inside stems and roots of giant reed and switchgrass. All the isolates were confirmed to have nitrogenase activity, 96.9% produced auxin, and 85% produced siderophores. Then the top six strains, including Sphingomonas trueperi NNA-14, Sphingomonas trueperi NNA-19, Sphingomonas trueperi NNA-17, Sphingomonas trueperi NNA-20, Psychrobacillus psychrodurans NP-3, and Enterobacter oryzae NXU-38, based on nitrogenase activity, were inoculated on maize and wheat seeds in greenhouse tests to assess their potential benefits to plants. All the selected strains promoted plant growth by increasing at least one plant growth parameter or increasing the nutrient concentration of maize or wheat plants. NNA-14 outperformed others in promoting early growth and nutrient uptake by maize. Specifically, NNA-14 significantly increased root length, surface area, and fine roots of maize by 14%, 12%, and 17%, respectively, and enhanced N, Ca, S, B, Cu, and Zn in maize. NNA-19 and NXU-38 outperformed others in promoting both early growth and nutrient uptake by wheat. Specifically, NNA-19 significantly increased root dry weight and number of root tips of wheat by 25% and 96%, respectively, and enhanced Ca in wheat. NXU-38 significantly increased root length, surface area, and fine roots of wheat by 21%, 13%, and 26%, respectively, and enhanced levels of Ca and Mg in wheat. It is concluded that switchgrass and giant reed are colonized by N2 -fixing bacteria that have the potential to contribute to plant growth and nutrient uptake by agricultural crops. PMID- 29473970 TI - Feasibility of Activation Energy Prediction of Gas-Phase Reactions by Machine Learning. AB - Machine learning based on big data has emerged as a powerful solution in various chemical problems. We investigated the feasibility of machine learning models for the prediction of activation energies of gas-phase reactions. Six different models with three different types, including the artificial neural network, the support vector regression, and the tree boosting methods, were tested. We used the structural and thermodynamic properties of molecules and their differences as input features without resorting to specific reaction types so as to maintain the most general input form for broad applicability. The tree boosting method showed the best performance among others in terms of the coefficient of determination, mean absolute error, and root mean square error, the values of which were 0.89, 1.95, and 4.49 kcal mol-1 , respectively. Computation time for the prediction of activation energies for 2541 test reactions was about one second on a single computing node without using accelerators. PMID- 29473971 TI - PROTACs: An Emerging Targeting Technique for Protein Degradation in Drug Discovery. AB - Proteolysis-targeting chimeric molecules (PROTACs) represent an emerging technique that is receiving much attention for therapeutic intervention. The mechanism is based on the inhibition of protein function by hijacking a ubiquitin E3 ligase for protein degradation. The hetero-bifunctional PROTACs contain a ligand for recruiting an E3 ligase, a linker, and another ligand to bind with the protein targeted for degradation. Thus, PROTACs have profound potential to eliminate "undruggable" protein targets, such as transcription factors and non enzymatic proteins, which are not limited to physiological substrates of the ubiquitin-proteasome system. These findings indicate great prospects for PROTACs in the development of therapeutics. However, there are several limitations related to poor stability, biodistribution, and penetrability in vivo. This review provides an overview of the main PROTAC-based approaches that have been developed and discusses the promising opportunities and considerations for the application of this technology in therapies and drug discovery. PMID- 29473972 TI - Favorable response to mammalian target of rapamycin inhibition in a young patient with unresectable fibrolamellar carcinoma of the liver. PMID- 29473973 TI - Expression Quantitative Trait Locus Study of Bone Mineral Density GWAS Variants in Human Osteoclasts. AB - Osteoporosis is a complex disease with a strong genetic component. Genomewide association studies (GWAS) have been very successful at identifying common genetic variants associated with bone parameters. A recently published study documented the results of the largest GWAS for bone mineral density (BMD) performed to date (n = 142,487), identifying 307 conditionally independent single nucleotide polymorphisms (SNPs) as associated with estimated BMD (eBMD) at the genomewide significance level. The vast majority of these variants are non-coding SNPs. Expression quantitative trait locus (eQTL) studies using disease-specific cell types have increasingly been integrated with the results from GWAS to identify genes through which the observed GWAS associations are likely mediated. We generated a unique human osteoclast-specific eQTL data set using cells differentiated in vitro from 158 participants. We then used this resource to characterize the 307 recently identified BMD GWAS SNPs for association with nearby genes (+/-500 kb). After correction for multiple testing, 24 variants were found to be significantly associated with the expression of 32 genes in the osteoclast-like cells. Bioinformatics analysis suggested that these variants and those in strong linkage disequilibrium with them are enriched in regulatory regions. Several of the eQTL associations identified are relevant to genes that present strongly as having a role in bone, particularly IQGAP1, CYP19A1, CTNNB1, and COL6A3. Supporting evidence for many of the associations was obtained from publicly available eQTL data sets. We have also generated strong evidence for the presence of a regulatory region on chromosome 15q21.2 relevant to both the GLDN and CYP19A1 genes. In conclusion, we have generated a unique osteoclast-specific eQTL resource and have used this to identify 32 eQTL associations for recently identified BMD GWAS loci, which should inform functional studies of osteoclast biology. (c) 2018 American Society for Bone and Mineral Research. PMID- 29473974 TI - TFM classification and staging of oral submucous fibrosis: A new proposal. PMID- 29473975 TI - Elbasvir/grazoprevir and sofosbuvir for hepatitis C virus genotype 3 infection with compensated cirrhosis: A randomized trial. AB - : Many direct-acting antiviral regimens have reduced activity in people with hepatitis C virus (HCV) genotype (GT) 3 infection and cirrhosis. The C-ISLE study assessed the efficacy and safety of elbasvir/grazoprevir (EBR/GZR) plus sofosbuvir (SOF) with and without ribavirin (RBV) in compensated cirrhotic participants with GT3 infection. This was a phase 2, randomized, open-label study. Treatment-naive participants received EBR/GZR + SOF + RBV for 8 weeks or EBR/GZR + SOF for 12 weeks, and peginterferon/RBV treatment-experienced participants received EBR/GZR + SOF +/- RBV for 12 weeks or EBR/GZR + SOF for 16 weeks. The primary endpoint was HCV RNA <15 IU/mL 12 weeks after the end of treatment (sustained virologic response at 12 weeks [SVR12]). Among treatment naive participants, SVR12 was 91% (21/23) in those treated with RBV for 8 weeks and 96% (23/24) in those treated for 12 weeks. Among treatment-experienced participants, SVR12 was 94% (17/18) and 100% (17/17) in the 12-week arm, with and without RBV, respectively, and 94% (17/18) in the 16-week arm. Five participants failed to achieve SVR: 2 relapsed (both in the 8-week arm), 1 discontinued due to vomiting/cellulitis (16-week arm), and 2 discontinued (consent withdrawn/lost to follow-up). SVR12 was not affected by the presence of resistance-associated substitutions (RASs). There was no consistent change in insulin resistance, and 5 participants reported serious adverse events (pneumonia, chest pain, opiate overdose, cellulitis, decreased creatinine). High efficacy was demonstrated in participants with HCV GT3 infection and cirrhosis. Treatment beyond 12 weeks was not required, and efficacy was maintained regardless of baseline RASs. CONCLUSION: Data from this study support the use of EBR/GZR plus SOF for 12 weeks without RBV for treatment-naive and peginterferon/RBV-experienced people with GT3 infection and cirrhosis (ClinicalTrials.gov NCT02601573). (Hepatology 2018;67:2113-2126). PMID- 29473976 TI - Microencapsulation increases survival of the probiotic Lactobacillus plantarum IS 10506, but not Enterococcus faecium IS-27526 in a dynamic, computer-controlled in vitro model of the upper gastrointestinal tract. AB - AIM: To test the effect of microencapsulation on the survival of two probiotic strains isolated from Dadih, Indonesian fermented buffalo milk, in a dynamic, computer-controlled in vitro model of the upper gastrointestinal (GI) tract (TIM 1), simulating human adults. METHODS AND RESULTS: Free or microencapsulated probiotics, Lactobacillus plantarum IS-10506 or Enterococcus faecium IS-27526, resuspended in milk were studied for survival in the complete TIM-1 system (stomach + small intestine) or in the gastric compartment of TIM-1 only. Hourly samples collected after the ileal-caecal valve or after the pylorus were plated on MRS agar (for Lactobacillus) or S&B agar (for Enterococcus). Survival of the free cells after transit through the complete TIM-1 system was on average for the E. faecium and L. plantarum 15.0 and 18.5% respectively. Survival of the microencapsulated E. faecium and L. plantarum was 15.7 and 84.5% respectively. The free cells were further assessed in only the gastric compartment of TIM-1. E. faecium and L. plantarum showed an average survival of 39 and 32%, respectively, after gastric passage. CONCLUSION: There is similar sensitivity to gastric acid as well as survival after complete upper GI tract transit of free cells, but microencapsulation only protected L. plantarum. SIGNIFICANCE AND IMPACT OF STUDY: Survival of microencapsulated L. plantarum IS-10506 is increased compared to free cells in a validated in vitro model of the upper GI tract. It increases its use as an ingredient of functional foods. PMID- 29473977 TI - Elevated seawater temperature disrupts the microbiome of an ecologically important bioeroding sponge. AB - Bioeroding sponges break down calcium carbonate substratum, including coral skeleton, and their capacity for reef erosion is expected to increase in warmer and more acidic oceans. However, elevated temperature can disrupt the functionally important microbial symbionts of some sponge species, often with adverse consequences for host health. Here, we provide the first detailed description of the microbial community of the bioeroding sponge Cliona orientalis and assess how the community responds to seawater temperatures incrementally increasing from 23 degrees C to 32 degrees C. The microbiome, identified using 16S rRNA gene sequencing, was dominated by Alphaproteobacteria, including a single operational taxonomic unit (OTU; Rhodothalassium sp.) that represented 21% of all sequences. The "core" microbial community (taxa present in >80% of samples) included putative nitrogen fixers and ammonia oxidizers, suggesting that symbiotic nitrogen metabolism may be a key function of the C. orientalis holobiont. The C. orientalis microbiome was generally stable at temperatures up to 27 degrees C; however, a community shift occurred at 29 degrees C, including changes in the relative abundance and turnover of microbial OTUs. Notably, this microbial shift occurred at a lower temperature than the 32 degrees C threshold that induced sponge bleaching, indicating that changes in the microbiome may play a role in the destabilization of the C. orientalis holobiont. C. orientalis failed to regain Symbiodinium or restore its baseline microbial community following bleaching, suggesting that the sponge has limited ability to recover from extreme thermal exposure, at least under aquarium conditions. PMID- 29473978 TI - Distinction between rhinovirus-induced acute asthma and asthma-augmented influenza infection. AB - BACKGROUND: Rhinovirus (RV) is an established trigger of asthma attacks, whereas such a link is less consistent for influenza virus (IFV). OBJECTIVE: In the context of precision medicine, we hypothesized that IFV infection may cause a condition essentially different from RV, and we investigated this by evaluating clinical characteristics of RV/IFV-positive and -negative children with respiratory symptoms and/or fever. METHODS: One thousand two hundred and seven children, 6 months to 13 years old, hospitalized for flu-like illness were recruited in this cross-sectional study. Collected information included demographics, medical history, symptoms/physical findings/diagnosis at presentation and treatment. Nasal secretions were PCR-tested for IFV/RV. Associations were evaluated with adjusted logistic regression models. RESULTS: Rhinovirus positivity was associated with an asthma-like presentation, including increased wheeze/effort of breathing/diagnosis of acute asthma, and decreased fever/vomiting. Conversely, IFV+ children presented with less wheeze/effort of breathing/diagnosis of acute asthma, while they were more frequently febrile. In those with previous asthma history, both viruses induced wheeze; however, IFV was uniquely associated with a more generalised and severe presentation including fever, rales, intercostal muscle retractions and lymphadenopathy. These symptoms were not seen in RV+ asthmatics, who had fewer systemic signs and more cough. CONCLUSIONS AND CLINICAL RELEVANCE: In children with respiratory symptoms and/or fever, RV but not IFV is associated with wheeze and an asthma-like presentation. In those with an asthma history, IFV causes more generalised and severe disease that may be better described as "asthma-augmented influenza" rather than an "asthma attack." Differences in the acute conditions caused by these viruses should be considered in the design of epidemiological studies. PMID- 29473979 TI - A novel GLP-1/GIP/Gcg triagonist reduces cognitive deficits and pathology in the 3xTg mouse model of Alzheimer's disease. AB - Type 2 diabetes mellitus (T2DM) is an important risk factor for Alzheimer's disease (AD). Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have been identified to be effective in T2DM treatment and neuroprotection. In this study, we further explored the effects of a novel unimolecular GLP-1/GIP/Gcg triagonist on the cognitive behavior and cerebral pathology in the 7-month-old triple transgenic mouse model of AD (3xTg AD), and investigated its possible electrophysiological and molecular mechanisms. After chronic administration of the GLP-1/GIP/Gcg triagonist (10 nmol/kg bodyweight, once daily, i.p.) for 30 days, open field, Y maze and Morris water maze tests were performed, followed by in vivo electrophysiological recording, immunofluorescence and Western blotting experiments. We found that the chronic treatment with the triagonist could improve long-term spatial memory of 3xTg-AD mice in Morris water maze, as well as the working memory in Y maze task. The triagonist also alleviated the suppression of long-term potentiation (LTP) in the CA1 region of hippocampus. In addition, the triagonist significantly reduced hippocampal pathological damages, including amyloid-beta (Abeta) and phosphorylated tau aggregates, and upregulated the expression levels of S133 p CREB, T286 p-CAMKII and S9 p-GSK3beta in the hippocampus of the 3xTg-AD mice. These results demonstrate for the first time that the novel GLP-1/GIP/Gcg triagonist is efficacious in ameliorating cognitive deficits and pathological damages of 3xTg-AD mice, suggesting that the triagonist might be potentially beneficial in the treatment of AD. PMID- 29473980 TI - Low-dose T1W DCE-MRI for early time points perfusion measurement in patients with intracranial tumors: A pilot study applying the microsphere model to measure absolute cerebral blood flow. AB - BACKGROUND: Previous studies have measured cerebral blood flow (CBF) with DSC-MRI using an "early time points" (ET) method based on microsphere theory. PURPOSE: To develop and assess a new ET method for absolute CBF estimation using low-dose high-temporal (LDHT) T1W-DCE-MRI. STUDY TYPE: Retrospective cohort study. SUBJECTS: Seven patients with sporadic vestibular schwannoma (VS) who underwent test-retest imaging; one patient with glioblastoma multiforme (GBM) imaged pretreatment; and 12 neurofibromatosis type 2 (NF2) patients undergoing bevacizumab treatment, imaged pre- and 90 days posttreatment. FIELD STRENGTH/SEQUENCE: LDHT-DCE-MRI was performed at 1.5 and 3.0T, using 3D spoiled gradient echo with phase cycling. DSC-MRI performed in one patient, using 3D echo shifted multi-shot echo-planar imaging (PRESTO) at 3T. ASSESSMENT: Through Monte Carlo simulations, CBF estimation using three newly developed average contrast agent concentration (AC) -based methods (ACrPK, ACrMG, ACcomb), was compared against conventional maximum gradient (MG) approaches, at varying Rician noise levels. Reproducibility and applicability of the ACcomb method was assessed in our sporadic-VS/GBM/NF2 patient cohort, respectively. STATISTICAL TESTS: Reproducibility was measured using test-retest coefficient of variation (CoV). Pre- and posttreatment CBF values were compared using paired t-test with Bonferroni correction. RESULTS: Monte Carlo stimulations demonstrated that AC based methods, particularly ACcomb, offered superior accuracy to conventional MG approaches. Overall test-retest CoV using the ACcomb method was 5.76 in normal appearing white matter (NAWM). The new ACcomb method produced gray matter/white matter CBF estimates in the NF2 patient cohort of 55.9 +/- 13.9/25.8 +/- 3.5 on day 0; compared with 155.6 +/- 17.2/128.4 +/- 29.1 for the classical MG method. There was a moderate (10% using ACcomb and ACrPK) increase in CBF of NAWM 90 days post therapy (P = 0.03 and 0.005). DATA CONCLUSION: Our new AC-based method of CBF estimation offers excellent reproducibility, and displays more accuracy in both Monte Carlo analysis and clinical data application, than conventional MG based approaches. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 4 J. MAGN. RESON. IMAGING 2018;48:543-557. PMID- 29473981 TI - Theta frequency decreases throughout the hippocampal formation in a focal epilepsy model. AB - Mesial temporal lobe epilepsy is characterized by focal, recurrent spontaneous seizures, sclerosis and granule cell dispersion (GCD) in the hippocampal formation. Changes in theta rhythm properties have been correlated with the severity of hippocampal restructuring and were suggested as a cause of memory deficits accompanying epilepsy. For severe sclerosis, it has even been questioned whether theta band oscillations persist. We asked how theta oscillations change with graded restructuring along the longitudinal hippocampal axis and whether these changes correlate with the overall severity of temporal lobe epilepsy. We recorded local field potentials in the medial entorhinal cortex and along the septo-temporal axis of the dentate gyrus at sites with different degrees of GCD in freely behaving epileptic mice. Theta frequency was decreased at all recording positions throughout the dentate gyrus and in the medial entorhinal cortex, irrespective of the extent of GCD or the rate of severe epileptic events. The frequency reduction by up to 1.7 Hz, corresponding to 1/3 octaves within the theta range, was present during rest, exploration and running. Despite the frequency reduction, theta oscillations remained coherent across the hippocampal formation and were modulated by running speed as in controls. The reduction in theta frequency thus is likely not a consequence of the local restructuring but rather a global phenomenon affecting the hippocampal formation as a whole. PMID- 29473982 TI - Longitudinal changes in myocardial T1 and T2 relaxation times related to diffuse myocardial fibrosis in aortic stenosis; before and after aortic valve replacement. AB - BACKGROUND: Diffuse myocardial fibrosis is associated with adverse outcomes, although detection and quantification is challenging. Cardiac MR relaxation times mapping represents a promising imaging biomarker for diffuse myocardial fibrosis. PURPOSE: To investigate whether relaxation times can detect longitudinal changes in myocardial tissue composition associated with diffuse fibrosis in patients with severe aortic stenosis (AS) before and after aortic valve replacement (AVR). STUDY TYPE: Prospective longitudinal study. POPULATION/SUBJECTS/PHANTOM/SPECIMEN/ANIMAL MODEL: Fifteen patients with severe AS. FIELD STRENGTH/SEQUENCE: 3T / 3(3)3(3)5-MOLLI, T2 -GraSE, and 3D-QALAS. ASSESSMENT: Patients underwent MR examinations at three timepoints: before AVR, as well as 3 and 12 months after AVR. Data from each patient was analyzed in 16 myocardial segments. STATISTICAL TESTS: The segment-wise T1 and T2 data were analyzed over time after surgery using linear mixed models for repeated measures analysis. RESULTS: The results showed that T1 relaxation times were significantly (P < 0.05) shorter 3 and 12 months postoperative than preoperative and that the T2 relaxation times were significantly (P < 0.05) longer 3 and 12 months postoperative than preoperative for both 3D and 2D mapping methods. No significant changes were seen between 3 and 12 months postoperative for any of the methods (P = 0.06/0.19 for T1 with 3D-QALAS/MOLLI and P = 0.09/0.25 for T2 with 3D-QALAS/GraSE). DATA CONCLUSION: We demonstrated that changes in myocardial relaxation times and thus tissue characteristics can be observed within 3 months after AVR surgery. The significant changes in relaxation times from preoperative examinations to the follow-up may be interpreted as a reduction of interstitial fibrosis in the left ventricular wall. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018. PMID- 29473983 TI - Biofilm inhibitory efficiency of phytol in combination with cefotaxime against nosocomial pathogen Acinetobacter baumannii. AB - AIMS: This study aimed to evaluate the antibiofilm potential of phytol and cefotaxime combinations (PCCs) against Acinetobacter baumannii and to elucidate the molecular mechanism of their antibiofilm potential through the transcriptomic approach. METHODS AND RESULTS: Phytol and cefotaxime combination(s) (PCC(s) [160 MUg ml-1 + 8 MUg ml-1 for microbial type culture collection (MTCC) strain and 160 MUg ml-1 + 0.5 MUg ml-1 for clinical isolate] effectively inhibited the A. baumannii biofilm formation. Additionally, light, confocal laser scanning and scanning electron microscopic analyses validated the antibiofilm potential of PCCs. Furthermore, PCCs treated A. baumannii cells showed a decreased level of hydrophobicity index compared to their respective controls. Fourier-transform infrared (FT-IR) spectra of exopolysaccharide matrix extracted from PCCs-treated A. baumannii cells showed a visible decrease in absorbance of polysaccharides, nucleic acids and protein regions compared to the spectra of untreated controls. In the blood sensitivity assay, the PCCs-treated A. baumannii plates showed reduced a number of bacterial colonies compared to their control plates. Reduced level of catalase production was also observed in the PCCs treatment compared to their controls. Transcriptomic analysis revealed the downregulation of bfmR, bap, csuA/B, ompA, pgaA, pgaC and katE biofilm virulence genes in both the A. baumannii strains on treatment with PCCs. CONCLUSION: The obtained results of this study indicate that PCCs have potent antibiofilm activity and downregulate the biofilm-related virulence genes expression in A. baumannii. SIGNIFICANCE AND IMPACT OF THE STUDY: To the best of our knowledge, this is the pioneering study, which shows the antibiofilm effect of PCCs against A. baumannii along with their molecular mechanism. The antibiofilm effect of PCCs could be a successful strategy for eradicating infections related to A. baumannii biofilms in nosocomial settings. PMID- 29473984 TI - Dorsal hippocampus is necessary for visual categorization in rats. AB - The hippocampus may play a role in categorization because of the need to differentiate stimulus categories (pattern separation) and to recognize category membership of stimuli from partial information (pattern completion). We hypothesized that the hippocampus would be more crucial for categorization of low density (few relevant features) stimuli-due to the higher demand on pattern separation and pattern completion-than for categorization of high-density (many relevant features) stimuli. Using a touchscreen apparatus, rats were trained to categorize multiple abstract stimuli into two different categories. Each stimulus was a pentagonal configuration of five visual features; some of the visual features were relevant for defining the category whereas others were irrelevant. Two groups of rats were trained with either a high (dense, n = 8) or low (sparse, n = 8) number of category-relevant features. Upon reaching criterion discrimination (>=75% correct, on 2 consecutive days), bilateral cannulas were implanted in the dorsal hippocampus. The rats were then given either vehicle or muscimol infusions into the hippocampus just prior to various testing sessions. They were tested with: the previously trained stimuli (trained), novel stimuli involving new irrelevant features (novel), stimuli involving relocated features (relocation), and a single relevant feature (singleton). In training, the dense group reached criterion faster than the sparse group, indicating that the sparse task was more difficult than the dense task. In testing, accuracy of both groups was equally high for trained and novel stimuli. However, both groups showed impaired accuracy in the relocation and singleton conditions, with a greater deficit in the sparse group. The testing data indicate that rats encode both the relevant features and the spatial locations of the features. Hippocampal inactivation impaired visual categorization regardless of the density of the category-relevant features for the trained, novel, relocation, and singleton stimuli. Hippocampus-mediated pattern completion and pattern separation mechanisms may be necessary for visual categorization involving overlapping irrelevant features. PMID- 29473985 TI - Intracranial vessel wall lesions in patients with systematic lupus erythematosus. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is related to vasculitis, which causes brain infarctions; however, the pathology of large cerebral vessels has not been fully established. PURPOSE: To demonstrate the prevalence of vessel wall lesions (VWLs) in SLE patients using 3D vessel wall imaging and to assess the relationship between VWLs and brain infarctions. STUDY TYPE: Retrospective. SUBJECTS: Sixty SLE patients and 50 healthy subjects (HS). FIELD STRENGTH/SEQUENCE: Each subject underwent 3T MRI, which included 3D FSE PDWI (CUBE). ASSESSMENT: For each of the 33 segments of the intracranial artery (internal carotid artery ~ M3 segment of middle cerebral artery [MCA]), the VWLs were scored as either positive or negative, and the VWL score was calculated as the sum of the segments with VWLs. We also evaluated brain lesions on conventional MRI. STATISTICAL TESTS: We used logistic regression analyses to determine the clinical (serological test and cardiovascular risk factors) and imaging characteristics associated with infarctions in SLE patients. RESULTS: For the peripheral vessels such as MCA, VWLs were more common for SLE patients than for HS (43.3% versus 16.7% in M1 segment, 60.4% versus 16.7% in M2 segment, both P < 0.01). There were 21 infarctions in 13 patients (21.7%), and the median VWL score was larger in the patients with infarctions than in those without (13 versus 6, P < 0.01). Multivariate logistic regression analyses revealed a high VWL score ( >= 9) to be the only factor independently associated with the presence of infarctions (odds ratio: 10.1, 95% confidence interval: 1.01-101; P < 0.049). DATA CONCLUSION: We demonstrated a substantially high prevalence of VWLs among SLE patients, which were associated with brain infarctions. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1237 1246. PMID- 29473986 TI - Riboflavin induces Metarhizium spp. to produce conidia with elevated tolerance to UV-B, and upregulates photolyases, laccases and polyketide synthases genes. AB - AIMS: The effect of nutritional supplementation of two Metarhizium species with riboflavin (Rb) during production of conidia was evaluated on (i) conidial tolerance (based on germination) to UV-B radiation and on (ii) conidial expression following UV-B irradiation, of enzymes known to be active in photoreactivation, viz., photolyase (Phr), laccase (Lac) and polyketide synthase (Pks). METHODS AND RESULTS: Metarhizium acridum (ARSEF 324) and Metarhizium robertsii (ARSEF 2575) were grown either on (i) potato dextrose agar medium (PDA), (ii) PDA supplemented with 1% yeast extract (PDAY), (iii) PDA supplemented with Rb (PDA+Rb), or (iv) PDAY supplemented with Rb (PDAY+Rb). Resulting conidia were exposed to 866.7 mW m-2 of UV-B Quaite-weighted irradiance to total doses of 3.9 or 6.24 kJ m-2 . Some conidia also were exposed to 16 klux of white light (WL) after being irradiated, or not, with UV-B to investigate the role of possible photoreactivation. Relative germination of conidia produced on PDA+Rb (regardless Rb concentration) or on PDAY and exposed to UV-B was higher compared to conidia cultivated on PDA without Rb supplement, or to conidia suspended in Rb solution immediately prior to UV-B exposure. The expression of MaLac3 and MaPks2 for M. acridum, as well as MrPhr2, MrLac1, MrLac2 and MrLac3 for M. robertsii was higher when the isolates were cultivated on PDA+Rb and exposed to UV-B followed by exposure to WL, or exposed to WL only. CONCLUSIONS: Rb in culture medium increases the UV-B tolerance of M. robertsii and M. acridum conidia, and which may be related to increased expression of Phr, Lac and Pks genes in these conidia. SIGNIFICANCE AND IMPACT OF THE STUDY: The enhanced UV-B tolerance of Metarhizium spp. conidia produced on Rb-enriched media may improve the effectiveness of these fungi in biological control programs. PMID- 29473987 TI - Chemical composition of glandular secretions from a pair-living monogamous primate: Sex, age, and gland differences in captive and wild owl monkeys (Aotus spp.). AB - Broadening our knowledge of olfactory communication in strictly monogamous systems can inform our understanding of how chemosignals may facilitate social and reproductive behavior between the sexes. Compared to other social and mating systems, relatively little is known about olfactory communication in strictly monogamous non-human primates. Furthermore, platyrrhines are not well represented in chemical analyses of glandular secretions. We conducted semi-quantitative headspace gas chromatography with mass spectrometry to investigate the chemical components of glandular secretions from the subcaudal and pectoral glands of a strictly pair-living platyrrhine, the owl monkey (Aotus spp.). In this study, the first chemical analysis of a wild platyrrhine population, our goals were to (1) conduct a robust analysis of glandular secretions from both captive and wild owl monkey populations and (2) identify whether biologically relevant traits are present in glandular secretions. We also compared and contrasted the results between two Aotus species in different environmental contexts: wild Aotus azarae (N = 33) and captive A. nancymaae (N = 104). Our findings indicate that secretions from both populations encode sex, gland of origin, and possibly individual identity. These consistent patterns across species and contexts suggest that secretions may function as chemosignals. Our data also show that wild A. azarae individuals are chemically discriminated by age (adult or subadult). Among the captive A. nanycmaae, we found chemical differences associated with location, possibly caused by dietary differences. However, there was no noticeable effect of contraception on the chemical profiles of females, nor evidence that closely related individuals exhibit more similar chemical profiles in A. nancymaae. Overall, our data suggest that glandular secretions of both wild and captive Aotus convey specific information. Future studies should use behavioral bioassays to evaluate the ability of owl monkeys to detect signals, and consider whether odor may ultimately facilitate social and sexual relationships between male and female owl monkeys. PMID- 29473989 TI - Bacillus amyloliquefaciens alters gene expression, ROS production and lignin synthesis in cotton seedling roots. AB - AIMS: Previous research demonstrated that applying Bacillus amyloliquefaciens to cotton seeds promotes growth, alters root architecture and alleviates salt stress of cotton seedlings. This research was undertaken to further study the genetic responses elicited in cotton seedlings by this growth promoting bacterium. METHODS AND RESULTS: GeneChip microarrays and RT-qPCR were used to detect changes in gene expression in seedling roots inoculated with B. amyloliquefaciens. Roots were stained with 3'3-diaminobenzidine and phloroglucinol-HCl to determine whether treated seedlings had a greater accumulation of reactive oxygen species and lignin. Two hundred and fifty-two transcripts were differentially expressed in inoculated cotton seedling roots; 139 transcripts were up-regulated and 113 were down-regulated. Some up-regulated transcripts were related to nitrate assimilation, cell growth, hormones, transport, transcription factors and antioxidants. Five genes identified to be up-regulated using microarrays were determined to be up-regulated using RT-qPCR. Inoculated cotton seedling roots had a greater accumulation of reactive oxygen species and lignin. CONCLUSIONS: The differential expression of genes associated with diverse functions supports that B. amyloliquefaciens elicits a complex genetic response in seedling roots. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrated that beneficial bacteria can alter gene expression of cotton that leads to growth promotion. PMID- 29473990 TI - Insights into the mechanisms of desiccation resistance of the Patagonian PAH degrading strain Sphingobium sp. 22B. AB - AIM: To analyse the physiological response of Sphingobium sp. 22B to water stress. METHODS AND RESULTS: The strain was grown under excess of carbon source and then subjected to low (60RH) and high (18RH) water stress conditions for 96 h. Quantification of trehalose, glycogen, polyhydroxybutyrate (PHB) and transmission electron microscopy (TEM) was studied. Genes linked with desiccation were searched in Sphingobium sp. 22B and Sphingomonas 'sensu latu' genomes and their transcripts were quantified by real-time PCR. Results showed that, in the absence of water stress, strain 22B accumulated 4.76 +/- 1.41% of glycogen, 0.84 +/- 1.62% of trehalose and 44.9 +/- 6.4% of PHB per cellular dry weight. Glycogen and trehalose were mobilized under water stressed conditions, this mobilization was significantly higher in 60RH in comparison to 18RH. Gene treY was upregulated sixfold in 60RH relative to control condition. TEM and quantification of PHB revealed that PHB was mobilized under 60RH condition accompanied by the downregulation of the phbB gene. TEM images showed an extracellular amorphous matrix in 18RH and 60RH. Major differences were found in the presence of aqpZ and trehalose genes between strain 22B and Sphingomonas genomes. CONCLUSION: Strain 22B showed a carbon conservative metabolism capable of accumulation of three types of endogenous carbon sources. The strain responds to water stress by changing the expression pattern of genes related to desiccation, formation of an extracellular amorphous matrix and mobilization of the carbon sources according to the degree of water stress. Trehalose, glycogen and PHB may have multiple functions in different degrees of desiccation. The robust endowment of molecular responses to desiccation shown in Sphingobium sp. 22B could explain its survival in semi-arid soil. SIGNIFICANCE AND IMPACT OF THE STUDY: Understanding the physiology implicated in the toleration of the PAH-degrading strain Sphingobium sp 22B to environmental desiccation may improve the bioaugmentation technologies in semi-arid hydrocarbon-contaminated soils. PMID- 29473991 TI - An Amorphous Noble-Metal-Free Electrocatalyst that Enables Nitrogen Fixation under Ambient Conditions. AB - N2 fixation by the electrocatalytic nitrogen reduction reaction (NRR) under ambient conditions is regarded as a potential approach to achieve NH3 production, which still heavily relies on the Haber-Bosch process at the cost of huge energy and massive production of CO2 . A noble-metal-free Bi4 V2 O11 /CeO2 hybrid with an amorphous phase (BVC-A) is used as the cathode for electrocatalytic NRR. The amorphous Bi4 V2 O11 contains significant defects, which play a role as active sites. The CeO2 not only serves as a trigger to induce the amorphous structure, but also establishes band alignment with Bi4 V2 O11 for rapid interfacial charge transfer. Remarkably, BVC-A shows outstanding electrocatalytic NRR performance with high average yield (NH3 : 23.21 MUg h-1 mg-1cat. , Faradaic efficiency: 10.16 %) under ambient conditions, which is superior to the Bi4 V2 O11 /CeO2 hybrid with crystalline phase (BVC-C) counterpart. PMID- 29473992 TI - Radical prostatectomy and the effect of close surgical margins: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. AB - OBJECTIVE: To evaluate biochemical recurrence (BCR) patterns amongst men undergoing radical prostatectomy (RP) with specimens having negative (NSM), positive (PSM), and close surgical margins (CSM) from the Shared Equal Access Regional Cancer Hospital (SEARCH) cohort, as PSM after RP are a significant predictor of biochemical failure and possible disease progression, with CSM representing a diagnostic challenge for surgeons. PATIENTS AND METHODS: Men undergoing RP between 1988 and 2015 with known final pathological margin status were evaluated. The cohort was divided into three groups based on margin status; NSM, PSM, and CSM. CSM were defined by distance of tumour <=1 mm from the surgical margin. BCR was defined as a prostate-specific antigen (PSA) level of >0.2 ng/mL, two values at 0.2 ng/mL, or secondary treatment for an elevated PSA level. Predictors of BCR, metastases, and mortality were analysed using Cox proportional hazard models. RESULTS: Of 5515 men in the SEARCH database, 4337 (79%) men met criteria for inclusion in the analysis. Of these, 2063 (48%) had NSM, 1902 (44%) had PSM, and 372 (8%) had CSM. On multivariable analysis, relative to NSM, men with CSM had a higher risk of BCR (hazard ratio [HR] 1.51, 95% confidence interval [CI] 1.25-1.82; P < 0.001) but a decreased risk of BCR when compared to those men with PSM (HR 2.09, 95% CI 1.86-2.36; P < 0.001). Metastases, prostate cancer-specific mortality and all-cause mortality did not differ based on margin status alone. CONCLUSIONS: Management of men with CSM is a diagnostic challenge, with a disease course that is not entirely benign. The evaluation of other known risk factors probably provides greater prognostic value for these men and may ultimately better select those who may benefit from adjuvant therapy. PMID- 29473993 TI - Universal cell type identifier based on number theory. AB - Cell type classification and handling is a key issue for understanding biological systems. The advent of high multiplexing technologies increased the complexity of the classification process and new tools are needed to support the organization of this knowledge. I propose a classification based on both prime numbers and the fundamental theorem of arithmetic. As a not limiting example, I show the application of this method to unambiguously define any existing cell type using the CD nomenclature established by the Human Leukocyte Differentiation Antigens Workshops. This system allows for the unique identification of any possible combination of markers hence any cell population without previous knowledge and without the need to increment the system. This method can be the future basis of any database and ontology system dealing with cell types and beyond the biological field applies to the description of any entity characterized by a list of discrete qualities. (c) 2018 International Society for Advancement of Cytometry. PMID- 29473994 TI - Rapid Analysis of Cell-Nanoparticle Interactions using Single-Cell Raman Trapping Microscopy. AB - Iron oxide nanoparticles have been used in preclinical studies to label stem cells for non-invasive tracking and homing. The search continues for novel particle candidates that are suitable for clinical applications. Since standard analyses to investigate cell-particle interactions and safety are labor intensive, an efficient procedure is required to guide future particle development and to exclude adverse health effects. The application of combined Raman trapping microscopy with fluidic chips is reported for the analysis of single cells labeled with different types of aminated iron oxide particles. Multivariate data analysis revealed Raman signal differences that could be clearly assigned to cell-particle interactions and cytotoxicity, respectively. A validation dataset verified that more than 95 % of the spectra were correctly classified. Thus, our approach enables rapid discrimination of non-hazardous from cytotoxic nanoparticles as a prerequisite for safe clinical applications. PMID- 29473995 TI - Chronic inflammation in skeletal muscle impairs satellite cells function during regeneration: can physical exercise restore the satellite cell niche? AB - Chronic inflammation impairs skeletal muscle regeneration. Although many cells are involved in chronic inflammation, macrophages seem to play an important role in impaired muscle regeneration since these cells are associated with skeletal muscle stem cell (namely, satellite cells) activation and fibro-adipogenic progenitor cell (FAP) survival. Specifically, an imbalance of M1 and M2 macrophages seems to lead to impaired satellite cell activation, and these are the main cells that function during skeletal muscle regeneration, after muscle damage. Additionally, this imbalance leads to the accumulation of FAPs in skeletal muscle, with aberrant production of pro-fibrotic factors (e.g., extracellular matrix components), impairing the niche for proper satellite cell activation and differentiation. Treatments aiming to block the inflammatory pro fibrotic response are partially effective due to their side effects. Therefore, strategies reverting chronic inflammation into a pro-regenerative pattern are required. In this review, we first describe skeletal muscle resident macrophage ontogeny and homeostasis, and explain how macrophages are replenished after muscle injury. We next discuss the potential role of chronic physical activity and exercise in restoring the M1 and M2 macrophage balance and consequently, the satellite cell niche to improve skeletal muscle regeneration after injury. PMID- 29473996 TI - Octopamine modulates the activity of motoneurons related to calling behavior in the gypsy moth Lymantria dispar. AB - A morphofunctional investigation of the different neuronal subpopulations projecting through each of the nerves IV-VI emerging bilaterally from the terminal abdominal ganglion (TAG) was correlated with the octopaminergic activity in the ganglion that controls the ovipositor movements associated with calling behavior in the female gypsy moth Lymantria dispar. Tetramethylrodamine-dextran backfills from nerve stumps resulted in a relatively low number of TAG projections, ranging from 12 to 13 for nerve pair IV, 12 to 14 for nerve pair V, and 8 to 9 for nerve pair VI. Furthermore, as assessed by electrophysiological recordings, a number of fibers within each of these nerves displays spontaneous tonic activity, also when the ganglion is fully disconnected from the ventral nerve cord (VNC). Octopamine (OA) applications to the TAG strongly enhanced the activity of these nerves, either by increasing the firing rate of a number of spontaneously firing units or by recruiting new ones. This octopaminergic activity affected calling behavior, and specifically the muscle activity leading to cycling extensions of the intersegmental membrane (IM) between segments VIII and IX (ovipositor). Our results indicate that in the female gypsy moth the octopaminergic neural activity of the TAG is coupled with extensions and retractions of IM for the purpose of releasing pheromone, where motor units innervated by nerve pair IV appear antagonistic with respect to those innervated by nerve pair V. PMID- 29473997 TI - Extracellular bone morphogenetic protein modulator BMPER and twisted gastrulation homolog 1 preserve arterial-venous specification in zebrafish blood vessel development and regulate Notch signaling in endothelial cells. AB - The bone morphogenetic protein (BMP) signaling pathway plays a central role during vasculature development. Mutations or dysregulation of the BMP pathway members have been linked to arteriovenous malformations. In the present study, we investigated the effect of the BMP modulators bone morphogenetic protein endothelial precursor-derived regulator (BMPER) and twisted gastrulation protein homolog 1 (TWSG1) on arteriovenous specification during zebrafish development and analyzed downstream Notch signaling pathway in human endothelial cells. Silencing of bmper and twsg1b in zebrafish embryos by morpholinos resulted in a pronounced enhancement of venous ephrinB4a marker expression and concomitant dysregulated arterial ephrinb2a marker expression detected by in situ hybridization. As arteriovenous specification was disturbed, we assessed the impact of BMPER and TWSG1 protein stimulation on the Notch signaling pathway on endothelial cells from different origin. Quantitative real-time PCR (qRT-PCR) and western blot analysis showed increased expression of Notch target gene hairy and enhancer of split, HEY1/2 and EPHRINB2. Consistently, silencing of BMPER in endothelial cells by siRNAs decreased Notch signaling and downstream effectors. BMP receptor antagonist DMH1 abolished BMPER and BMP4 induced Notch signaling pathway activation. In conclusion, we found that in endothelial cells, BMPER and TWSG1 are necessary for regular Notch signaling activity and in zebrafish embryos BMPER and TWSG1 preserve arteriovenous specification to prevent malformations. PMID- 29473998 TI - Graphene oxide composites for magnetic solid-phase extraction of trace cytokinins in plant samples followed by liquid chromatography-tandem mass spectrometry. AB - In this work, an easy, effective, and sensitive method based on graphene oxide@silica@magnetite composites as adsorbent of magnetic solid-phase extraction combined with liquid chromatography and tandem mass spectrometry, was established and validated for the trace analysis of cytokinins in different plants. The prepared magnetic composite was characterized by infrared spectroscopy, transmission electron microscopy, Brunauer-Emmett-Teller analysis, and magnetic hysteresis. Under the optimized conditions, good linearities in the range of 0.5 100 ng/mL were obtained with the corresponding linear correlation coefficient >0.9989 for the investigated four cytokinins, and good sensitivity levels were achieved with low detection limits ranging from 93 to 120 pg/mL. The established magnetic solid-phase extraction with liquid chromatography and tandem mass spectrometry method has been validated in the separation and analysis of four cytokinins in plant samples with good recoveries between 78.9 and 97.3% for four cytokinins with the relative standard deviations lower than 13.5%. PMID- 29473999 TI - Melanoma cases demonstrate increased carrier frequency of phenylketonuria/hyperphenylalanemia mutations. AB - Identifying novel melanoma genetic risk factors informs screening and prevention efforts. Mutations in the phenylalanine hydroxylase gene (the causative gene in phenylketonuria) lead to reduced pigmentation in untreated phenylketonuria patients, and reduced pigmentation is associated with greater melanoma risk. Therefore, we sought to characterize the relationship between phenylketonuria carrier status and melanoma risk. Using National Newborn Screening Reports, we determined the United States phenylketonuria/hyperphenylalanemia carrier frequency in Caucasians to be 1.76%. We examined three publically available melanoma datasets for germline mutations in the phenylalanine hydroxylase gene associated with classic phenylketonuria and/or hyperphenylalanemia. Mutations were identified in 29/814 melanoma patients, with a carrier frequency of 3.56%. There was a twofold enrichment (p-value = 3.4 * 10-5 ) compared to the Caucasian frequency of hyperphenylalanemia/phenylketonuria carriers. These data demonstrate a novel association between phenylalanine hydroxylase carrier status and melanoma risk. Further, functional investigation is warranted to determine the link between phenylalanine hydroxylase mutations and melanomagenesis. PMID- 29474000 TI - Alternatives. PMID- 29474001 TI - Proteogenomic Analysis to Identify Missing Proteins from Haploid Cell Lines. AB - Chromosome-centric Human Proteome Project aims at identifying and characterizing protein products encoded from all human protein-coding genes. As of early 2017, 19 837 protein-coding genes have been annotated in the neXtProt database including 2691 missing proteins that have never been identified by mass spectrometry. Missing proteins may be low abundant in many cell types or expressed only in a few cell types in human body such as sperms in testis. In this study, we performed expression proteomics of two near-haploid cell types such as HAP1 and KBM-7 to hunt for missing proteins. Proteomes from the two haploid cell lines were analyzed on an LTQ Orbitrap Velos, producing a total of 200 raw mass spectrometry files. After applying 1% false discovery rates at both levels of peptide-spectrum matches and proteins, more than 10 000 proteins were identified from HAP1 and KBM-7, resulting in the identification of nine missing proteins. Next, unmatched spectra were searched against protein databases translated in three frames from noncoding RNAs derived from RNA-Seq data, resulting in six novel protein-coding regions after careful manual inspection. This study demonstrates that expression proteomics coupled to proteogenomic analysis can be employed to identify many annotated and unannotated missing proteins. PMID- 29474002 TI - Pathway Complexity Versus Hierarchical Self-Assembly in N-Annulated Perylenes: Structural Effects in Seeded Supramolecular Polymerization. AB - Studies were carried out on the hierarchical self-assembly versus pathway complexity of N-annulated perylenes 1-3, which differ only in the nature of the linking groups connecting the perylene core and the side alkoxy chains. Despite the structural similarity, compounds 1 and 2 exhibit noticeable differences in their self-assembly. Whereas 1 forms an off-pathway aggregate I that converts over time (or by addition of seeds) into the thermodynamic, on-pathway product, 2 undergoes a hierarchical process in which the kinetically trapped monomer species does not lead to a kinetically controlled supramolecular growth. Finally, compound 3, which lacks the amide groups, is unable to self-assemble under identical experimental conditions and highlights the key relevance of the amide groups and their position to govern the self-assembly pathways. PMID- 29474003 TI - The potent pro-oxidant activity of rhododendrol-eumelanin is enhanced by ultraviolet A radiation. AB - RS-4-(4-hydroxyphenyl)-2-butanol (rhododendrol, RD), a skin-whitening agent, is known to induce leukoderma in some consumers. To explore the mechanism underlying this effect, we previously showed that the oxidation of RD with mushroom or human tyrosinase produces cytotoxic quinone oxidation products and RD-eumelanin exerts a potent pro-oxidant activity. Cellular antioxidants were oxidized by RD eumelanin with a concomitant production of H2 O2 . In this study, we examined whether this pro-oxidant activity of RD-eumelanin is enhanced by ultraviolet A (UVA) radiation because most RD-induced leukoderma lesions are found in sun exposed areas. Exposure to a physiological level of UVA (3.5 mW/cm2 ) induced a two to fourfold increase in the rates of oxidation of GSH, cysteine, ascorbic acid, and NADH. This oxidation was oxygen-dependent and was accompanied by the production of H2 O2 . These results suggest that RD-eumelanin is cytotoxic to melanocytes through its potent pro-oxidant activity that is enhanced by UVA radiation. PMID- 29474004 TI - Image-guided surgery in cancer: A strategy to reduce incidence of positive surgical margins. AB - Primary treatment for many solid cancers includes surgical excision or radiation therapy, with or without the use of adjuvant therapy. This can include the addition of radiation and chemotherapy after primary surgical therapy, or the addition of chemotherapy and salvage surgery to primary radiation therapy. Both primary therapies, surgery and radiation, require precise anatomic localization of tumor. If tumor is not targeted adequately with initial treatment, disease recurrence may ensue, and if targeting is too broad, unnecessary morbidity may occur to nearby structures or remaining normal tissue. Fluorescence imaging using intraoperative contrast agents is a rapidly growing field for improving visualization in cancer surgery to facilitate resection in order to obtain negative margins. There are multiple strategies for tumor visualization based on antibodies against surface markers or ligands for receptors preferentially expressed in cancer. In this article, we review the incidence and clinical implications of positive surgical margins for some of the most common solid tumors. Within this context, we present the ongoing clinical and preclinical studies focused on the use of intraoperative contrast agents to improve surgical margins. This article is categorized under: Laboratory Methods and Technologies > Imaging. PMID- 29474006 TI - Why allometric variation in mammalian metabolism is curvilinear on the logarithmic scale. AB - Studies performed over the last 20 years have repeatedly documented a slight convex curvature (relative to the x-axis) in double-logarithmic plots of basal metabolic rate (BMR) versus body mass in mammals. This curvilinear pattern has usually been interpreted in the context of a simple, two-parameter power function on the arithmetic scale, y = a * xb , with the exponent in the equation supposedly increasing systematically with body size. An equation of this form has caused concern among ecologists because a variable exponent is inconsistent with an assumption underlying the metabolic theory of ecology (MTE). However, the appearance of an exponent that varies with body size is an artifact resulting from the widespread use of logarithmic transformations in allometric analyses. Curvature in the distribution on the logarithmic scale actually is caused by a requirement for an explicit, non-zero intercept-and not a variable exponent-in the model describing the distribution on the arithmetic scale. Thus, the MTE need not be revised to accommodate an exponent that varies with body size in the scaling of mammalian BMR, but the theory may need to be tweaked to accommodate an intercept in the allometric equation. In general, any bivariate dataset that is well described by a three-parameter power equation on the arithmetic scale will follow a curvilinear path when displayed on the logarithmic scale. Consequently, reports of curvilinearity in log domain (i.e., "complex allometry") need to be revisited because conclusions from those investigations are likely to be flawed. PMID- 29474005 TI - PharmGKB: A worldwide resource for pharmacogenomic information. AB - As precision medicine becomes increasingly relevant in healthcare, the field of pharmacogenomics (PGx) also continues to gain prominence in the clinical setting. Leading institutions have begun to implement PGx testing and the amount of published PGx literature increases yearly. The Pharmacogenomics Knowledgebase (PharmGKB; www.pharmgkb.org) is one of the foremost worldwide resources for PGx knowledge, and the organization has been adapting and refocusing its mission along with the current revolution in genomic medicine. The PharmGKB website provides a diverse array of PGx information, from annotations of the primary literature to guidelines for adjusting drug treatment based on genetic information. It is freely available and accessible to everyone from researchers to clinicians to everyday citizens. PharmGKB was found over 17 years ago, but continues to be a vital resource for the entire PGx community and the general public. This article is categorized under: Translational, Genomic, and Systems Medicine > Translational Medicine. PMID- 29474007 TI - Predictors and Moderators of Relapse in Children and Adolescents With Major Depressive Disorder. AB - OBJECTIVE: To identify predictors and moderators of relapse during continuation treatment among depressed youth randomly assigned to fluoxetine or placebo. METHODS: Potential predictors and moderators of relapse that were identified by a literature review were examined in 102 youth (aged 7-18 years), diagnosed with major depressive disorder as defined by DSM-IV criteria, who were considered responders after 12 weeks of fluoxetine treatment (acute phase). This randomized controlled trial was conducted from June 2000 through October 2005. Each candidate predictor and moderator was evaluated with a multiple logistic regression model to examine the main and interaction effects of 12 weeks of continuation treatment on relapse status (at week 24) while controlling for age, sex, and depression severity. Relapse was defined as a Children's Depression Rating Scale-Revised total score >= 40 with worsening of depressive symptoms for at least 2 weeks. RESULTS: Youth with comorbid dysthymia (adjusted odds ratio [OR] = 2.88, P = .03) and low levels of family leadership (adjusted OR = 1.39, P = .006) at baseline are more likely to relapse than their counterparts. Higher levels of depression (OR = 1.21, P = .003) and higher levels of residual sleep disturbance (insomnia) (OR = 6.74, P = .006) and irritability (OR = 7.40, P = .01) at the end of acute treatment (12 weeks) increased the odds of relapse. Higher levels of depressive symptoms at baseline in youth who remained on fluoxetine for continuation treatment were associated with increased odds of relapse (adjusted OR = 1.14, P = .03). Females who remained on fluoxetine for the duration of continuation treatment were almost 9 times more likely to relapse than males (adjusted OR = 8.86, P = .007). CONCLUSIONS: This is the first large continuation study for treatment of depression in youth to examine predictors and moderators of relapse. Youth with greater improvement by the end of 3 months of treatment were less likely to relapse than those with continued depressive symptoms. In addition, youth with comorbid dysthymia had 3 times greater risk of relapse that those without. Targeting residual symptoms, particularly sleep disturbance and irritability, earlier in treatment may reduce relapse rates. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00332787. PMID- 29474008 TI - An Inverse U-Shaped Curve of Resting-State Networks in Individuals at High Risk of Alzheimer's Disease. AB - OBJECTIVE: Higher functional connectivity (FC) in resting-state networks has been shown in individuals at risk of Alzheimer's disease (AD) by many studies. However, the longitudinal trajectories of the FC remain unknown. The present 35 month follow-up study aimed to explore longitudinal changes in higher FC in multiple resting-state networks in subjects with the apolipoprotein E epsilon4 allele (ApoE4) and/or amnestic mild cognitive impairment (aMCI). METHODS: Fifty one subjects with aMCI and 64 cognitively normal (CN) subjects underwent neuropsychological tests and resting-state functional magnetic resonance imaging (fMRI) scans twice from April 2011 to June 2015. Subjects were divided into 4 groups according to diagnosis and ApoE4 status. The CN non-ApoE4 group served as a control group, and other groups served as AD risk groups. The cross-sectional and longitudinal patterns of multiple resting-state networks, including default mode network, hippocampus network, executive control network, and salience network, were explored by comparing FC data between groups and between time points, respectively. RESULTS: At baseline, compared with the control group, the AD risk groups showed higher FC with 8 regions in multiple networks. At follow up, 6 of the regions displayed longitudinally decreased FC in AD risk groups. In contrast, the FC with all of these regions was maintained in the control group. Notably, among the 3 risk groups, most of the higher FC at baseline (5 of the 8 regions) and longitudinally decreased FC at follow-up (4 of the 6 regions) were shown in the aMCI ApoE4 group. CONCLUSIONS: Higher resting-state FC is followed by a decline in subjects at AD risk, and this inverse U-shaped trajectory is more notable in subjects with higher risk. PMID- 29474009 TI - Direct and Indirect Cost Burden and Change of Employment Status in Treatment Resistant Depression: A Matched-Cohort Study Using a US Commercial Claims Database. AB - BACKGROUND: Treatment-resistant depression (TRD) poses a substantial burden to health care payers including employers, costing an estimated $29 billion-$48 billion yearly in the United States. Furthermore, variation of burden across increasing levels of resistance and the potential impact of TRD on employment status remain largely unexplored. OBJECTIVE: To evaluate health care resource utilization (HRU) and costs, work loss, indirect costs, and employment status change in TRD. METHODS: A claims-based algorithm identified adults with TRD from a US claims database of privately insured employees and dependents (January 2010 March 2015). TRD patients were matched 1:1 on demographics to patients with major depressive disorder (MDD) (non-TRD MDD) and without MDD (non-MDD), who were identified using ICD-9-CM codes. Costs, HRU, and employment status change were compared over 2 years following the first antidepressant (randomly imputed date for non-MDD), adjusting for baseline comorbidity index and costs. RESULTS: TRD patients (N = 6,411) had more HRU than either matched control cohort, translating into higher per patient per year (PPPY) health care costs: $6,709 and $9,917 more than non-TRD MDD and non-MDD patients, respectively (P < .001 for both). TRD patients with work loss data (N = 1,908) had 35.8 work loss days PPPY (1.7 and 6.2 times the work loss rate in non-TRD MDD and non-MDD patients, respectively). Work loss-related costs in TRD patients were $1,811 higher than non-TRD MDD and $3,460 higher than in non-MDD patients (P < .001). TRD patients had 1.3-1.4 times the rate of employment status change versus control cohorts (all P < .05). CONCLUSIONS: TRD, even compared to MDD, poses a significant direct and indirect cost burden to US employers and may be associated with higher rates of employment status change. PMID- 29474010 TI - [[In process].] AB - The 'case' of Georg Friedrich NICOLAI, a Berlin physiologist and pacifist, who vehemently stood against a chauvi- nistic academic world in Germany in August 1914, is typical for the academic situation and the role of nationalistic professors as 'mandarines' at German universities and academies at the outbreak of the Great War. NICOLAI suffered a lot from his pacifist internationalism: he was brutally excluded from scientific community, and his academic career was destroyed. Had he not successfully escaped to Denmark, his physical existence would have been endangered as well. On the other hand his dignity was never endangered while NICOLAI successfully resisted military dictatorship and a kind of submissive chauvinism of a perishing Kaiserreich. PMID- 29474011 TI - [Not Available.] AB - At the beginning of the First World War, the numbers of members from French speaking countries in German Academies and the number of members from German speaking countries in French Academies were roughly the same, and equally high. For instance the French Academy of Sciences had 23 members belonging to German speaking countries, of which 17 from Germany. The Berlin Academy of sciences had 16 members from French speaking countries, the Gbttingen Academy 18 members, and the Bavarian Academy 13. The Leopoldina had also a great number of French members, as a result of a long-lasting policy. These data show that the relationships between France and Germany in the fields of natural and human sciences were traditionally very well developed. However, these relationships were so damaged by the First World War that they could revive only slowly after the Second World War. The sometimes vivid discussions, which took place within several Academies of the Institut de France regarding the mea- sures to be taken in the field of scientific cooperation against the Central Powers, will be commented in this paper. PMID- 29474012 TI - [Not Available.] AB - The German Academy of Sciences Leopoldina submitted at the outbreak of the First World War no public opinion - regardless of personal settings of the board and unlike many of its members. Public-meetings, however, were introduced only in 1924, making it the Leopoldina were no opportunities to academy speeches, in contrast to other scientific academies. But in their official bulletin with which they appeared in public, obituaries were published during the entire war period to researchers regardless of the nation, including in French and English scholars. It was only at the suggestion of a member from the July 1915 German war dead were honoured with a symbolic Iron Cross, as was common in German newspapers from the beginning of the war. An exclusion of members from the 'hostile' abroad was never considered. During the war, however, no foreigners were co-opted, but again only immediately after the war. The academy board then pleaded strongly for an international reconciliation of sciences. At the public propaganda war in the "battle of the minds" were also renowned Leopoldina members involved, as reflected in total war and its consequences in the Leopoldina members similar to the entire German population. The analysis of the signatories of various manifestos brings to light that the "Declaration of University Professors of Germany" only just over half of the scholars instead of "almost the whole teaching body" was signed, as previously generalized. PMID- 29474013 TI - The Great War as a Crucial Point in the History of Russian Science and Technology. AB - The paper is devoted to one of the most important and, at the same time, relatively unexplored phases in the history of Russian science and technology. The Great War coincided with the beginning of a heyday in science, engineering education, and technology in Russia. It was precisely the time in which Russia's era of "Big Science" was emer- ging. Many Russian and Soviet technical projects and scientific schools were rooted in the time of the Great War. The "engineerization" of science and a "physical-technical" way of thinking had already begun before the war. But it was precisely the war which encouraged a large proportion of the Russian academic community to take part in industrial projects. Academics also played a significant role in developing concepts and implementing strategic plans during the Great War. This article also discusses how the organization of science and the academic community was transformed during, and after, the Great War. And it looks at the impact that war had on Russia's participation in the international scientific community. PMID- 29474014 TI - TELL ME AGAIN, WHAT IS A COLLEGE?. PMID- 29474015 TI - DETERMINING DENTAL STUDENT COMPETENCE. AB - Almost 20 years ago dental education, including ancillary and residency training, made a fundamental shift to a competency model. Competency is the level of knowledge, skills, and values needed to begin independent practice. This replaced the older emphasis on process. It had formerly been assumed that if a student was exposed to good teaching for a set period of time, he or she must be ready for practice. The responsibility has been shifted from schools needing to demonstrate that they have done the traditional things well to requiring that they demonstrate that every graduate is in fact capable of independent performance as a dentist. This paper describes the nature of competency in predoctoral dental education and introduces some of the most common assessment methods schools use to ensure that each graduate is competent. PMID- 29474016 TI - EDUCATING THE DEVELOPING DENTAL STUDENT IN ETHICS AND PROFESSIONALISM. AB - Ethics education has been a required part of accreditation standards for dental and dental hygiene programs since the 19lJs. The dominant approach uses a combination of lectures and small, case-based seminars to teach ethical principles and provide practice in decision-making procedures to reason through dilemmas where there are several "right" ways to act. Detail is provided about three such programs. PMID- 29474017 TI - NEW ACCREDITTATION STANDARD FOR DENTAL EDUCATION PROGRAMS ON HUMANISTIC ENVIRONMENT. AB - Dental techniques and materials have changed dramatically in the past few decades, as have the expectations of patients, and the relationships among oral healthcare professionals and those they serve. The most current accreditation standards for dental education require that programs demonstrate success in preparing graduates for these relation- ships. The core approach emerging is that this part of dentistry should be built around humanism or respect for the dignity of all. This paper describes the new accreditation requirement, some of the historic need for change, the evolving environment of oral health care, and some programs that schools are developing to address these needs. PMID- 29474018 TI - INTERPROFESSIONAL EDUCATION AND COLLABORATIVE PRACTICE. A PATHWAY TO BETTER PATIENT CARE, IMPROVED HEALTH, AND LOWER COSTS. AB - Dentistry usually concerns itself with managing the scope of practice relationships with areas historically performed by dentists as solo practitioners. Many trends in health care-such as electronic records, Big Data, consolidated reimbursement systems, effective but expensive technology, the economies of group practice-are now overwhelming the boundaries of tasks performed in isolation. The Commission on Dental Accreditation has added a standard that dental education programs must prepare professionals to function in these new environments. PMID- 29474019 TI - EVIDENCE BASED DENTISTRY AND CODA REQUIREMENTS. AB - Most of us assume that what we do, and teach, is evidence-based. The challenge is to insure that this is indeed the case. More to the point, how can we readily find the credible evidence we need to guide practice and teaching? And, can we differentiate high-quality evidence from less trustworthy reports? This paper presents a basic, three-step process for querying the literature, identifying levels of evidence, evaluating the evidence, and summarizes the early experiences of three dental schools in developing a curriculum that incorporates EBD and critical thinking. PMID- 29474021 TI - EThICS ON OUR SLEEVE. PMID- 29474020 TI - ASSESSMENT OF DENTAL STUDENT COMPETENCY IN THE NEW MILLENNIUM. WHAT HAS CHANGED? AB - The major shift in dental education in the past couple of decades has been away from process-clock-hours and number of clinical procedures-to outcomes. In order to be accredited today, schools must document that their graduates have the skills, knowledge, 8nd values required to begin independent dental practice. There has been a corresponding change in assessment methods. Graduates must demonstrate independent competency in all aspects of dental practice, and schools must provide evidence that their programs function as claimed. PMID- 29474022 TI - WHAT DID WE JUST AGREE TO? ANALYSIS AND REWRITING OF THE DENTIST'S PLEDGE. PMID- 29474023 TI - ORAL PRIMING AND THE ACD BASIC RULE. AB - James Rest proposed a model of moral behavior with four components: sensitivity, reasoning, character, and courage (or action). Research has shown that moral character is a complex construct. Multiple moral self-concepts exist within each individual, and different context predispose various of these to become dominant in different settings. Moral priming is the practice of manipulating the environment to favor the use of appropriate moral self-concepts. A study is reported, demonstrating that dentists can be primed to express more moral views based entirely on context. The observed effect of priming was large. The ACD Rule for Moral Identity states that when there is conflict between professionalism and economic or other self-interests, professionalism takes precedence. PMID- 29474024 TI - ACOs continue to evolve. PMID- 29474025 TI - A new focus on coding quality audits. PMID- 29474026 TI - BCG vaccines: WHO position paper - February 2018. PMID- 29474027 TI - Rethinking denial management. Most organizations take an administrative approach to managing denials. Maybe that's why they're not collecting as much as they should. PMID- 29474029 TI - Top 10 reasons for EHRs to use middleware for connectivity. PMID- 29474028 TI - Switching your imaging solution: Is your imaging solution like a flip phone or smartphone? PMID- 29474030 TI - The patient-centric movement: What's driving it, what's ahead? PMID- 29474031 TI - How do your cybersecurity efforts stack up? Being prepared will make you less likely to become a soft target. PMID- 29474032 TI - 10 cybersecurity trends to watch in 2017: Will the hard-learned lessons of 2016 lay the foundation for healthcare security success in the future? PMID- 29474033 TI - Corrigendum. AB - [This corrects the article DOI: 10.1080/2162402X.2017.1376155.]. PMID- 29474035 TI - FDA issues warning for battery-powered mobile medical carts. PMID- 29474034 TI - How to achieve IT resilience in the healthcare industry. PMID- 29474036 TI - Enabling predictive healthcare analytics through better workflows. PMID- 29474037 TI - Tips for giving your organization a telehealth checkup. PMID- 29474038 TI - Beyond videoconferencing: Is your infrastructure ready for telemedicine? PMID- 29474039 TI - Improve your medical imaging TCO: An enterprise imaging strategy built around a true vendor neutral archive can deliver significant savings. PMID- 29474040 TI - EMRs and capture solutions: The total cost of system ownership. PMID- 29474041 TI - Business continuity helps protect reputation, brand, and data. PMID- 29474042 TI - Value-based care is here to stay. PMID- 29474043 TI - Achieving your FHIR share of interoperability. PMID- 29474044 TI - Rethinking healthcare data: Value-based imaging requires interoperability. PMID- 29474045 TI - Bringing genetic testing to the hospital lab. PMID- 29474046 TI - How docs get into the tech game: From health information exchanges to e prescribing to evidence-based medicine, sometimes a clinical perspective is just what the doctor ordered. PMID- 29474047 TI - Revenue integrity: A better reimbursement strategy. PMID- 29474048 TI - Look to tech to solve billing errors: End-to end software integration is the key to revenue cycle success. PMID- 29474049 TI - Empowering patients to pay: Tackle 'through the roof' AR while helping patients to take control. PMID- 29474050 TI - Four top trends in the RCM environment. PMID- 29474051 TI - Meeting the challenges of a value-based world. PMID- 29474052 TI - ACOs move from infancy to adolescence: But what will care models of the future look like? PMID- 29474053 TI - Head of the unexpected: Three overlooked HIPAA liabilities to get vigilante about. PMID- 29474054 TI - Healthcare IoT will deliver great benefits: The challenge will be mastering IoT security. PMID- 29474055 TI - Thriving under pressure: Lab information systems can reduce errors and automate workflow. PMID- 29474056 TI - Quantitative Prediction of Multivalent Ligand-Receptor Binding Affinities for Influenza, Cholera, and Anthrax Inhibition. AB - Multivalency achieves strong, yet reversible binding by the simultaneous formation of multiple weak bonds. It is a key interaction principle in biology and promising for the synthesis of high-affinity inhibitors of pathogens. We present a molecular model for the binding affinity of synthetic multivalent ligands onto multivalent receptors consisting of n receptor units arranged on a regular polygon. Ligands consist of a geometrically matching rigid polygonal core to which monovalent ligand units are attached via flexible linker polymers, closely mimicking existing experimental designs. The calculated binding affinities quantitatively agree with experimental studies for cholera toxin ( n = 5) and anthrax receptor ( n = 7) and allow to predict optimal core size and optimal linker length. Maximal binding affinity is achieved for a core that matches the receptor size and for linkers that have an equilibrium end-to-end distance that is slightly longer than the geometric separation between ligand core and receptor sites. Linkers that are longer than optimal are greatly preferable compared to shorter linkers. The angular steric restriction between ligand unit and linker polymer is shown to be a key parameter. We construct an enhancement diagram that quantifies the multivalent binding affinity compared to monovalent ligands. We conclude that multivalent ligands against influenza viral hemagglutinin ( n = 3), cholera toxin ( n = 5), and anthrax receptor ( n = 7) can outperform monovalent ligands only for a monovalent ligand affinity that exceeds a core-size dependent threshold value. Thus, multivalent drug design needs to balance core size, linker length, as well as monovalent ligand unit affinity. PMID- 29474057 TI - Microfluidic-Based Cell-Embedded Microgels Using Nonfluorinated Oil as a Model for the Gastrointestinal Niche. AB - Microfluidic-based cell encapsulation has promising potential in therapeutic applications. It also provides a unique approach for studying cellular dynamics and interactions, though this concept has not yet been fully explored. No in vitro model currently exists that allows us to study the interaction between crypt cells and Peyer's patch immune cells because of the difficulty in recreating, with sufficient control, the two different microenvironments in the intestine in which these cell types belong. However, we demonstrate that a microfluidic technique is able to provide such precise control and that these cells can proliferate inside microgels. Current microfluidic-based cell microencapsulation techniques primarily use fluorinated oils. Herein, we study the feasibility and biocompatibility of different nonfluorinated oils for application in gastrointestinal cell encapsulation and further introduce a model for studying intercellular chemical interactions with this approach. Our results demonstrate that cell viability is more affected by the solidification and purification processes that occur after droplet formation rather than the oil type used for the carrier phase. Specifically, a shorter polymer cross-linking time and consequently lower cell exposure to the harsh environment (e.g., acidic pH) results in a high cell viability of over 90% within the protected microgels. Using nonfluorinated oils, we propose a model system demonstrating the interplay between crypt and Peyer's patch cells using this microfluidic approach to separately encapsulate the cells inside distinct alginate/gelatin microgels, which allow for intercellular chemical communication. We observed that the coculture of crypt cells alongside Peyer's patch immune cells improves the growth of healthy organoids inside these microgels, which contain both differentiated and undifferentiated cells over 21 days of coculture. These results indicate the possibility of using droplet-based microfluidics for culturing organoids to expand their applicability in clinical research. PMID- 29474058 TI - Directed Evolution of Membrane Transport Using Synthetic Selections. AB - Understanding and engineering solute transporters is important for metabolic engineering and the development of therapeutics. However, limited available experimental data on membrane transporters makes sequence-function relationships complex to predict. Here we apply ligand-responsive biosensor systems that enable selective growth of E. coli cells only if they functionally express an importer that is specific to the biosensor ligand. Using this system in a directed evolution framework, we successfully engineer the specificity of nicotinamide riboside transporters, PnuC, to accept thiamine as a substrate. Our results provide insight into the molecular determinants of substrate recognition of the PnuC transporter family and demonstrate how synthetic biology can be deployed to engineer the substrate spectrum of small molecule transporters. PMID- 29474059 TI - A HaloTag-Based Multicolor Fluorogenic Sensor Visualizes and Quantifies Proteome Stress in Live Cells Using Solvatochromic and Molecular Rotor-Based Fluorophores. AB - Protein homeostasis, or proteostasis, is essential for cellular fitness and viability. Many environmental factors compromise proteostasis, induce global proteome stress, and cause diseases. The proteome stress sensor is a powerful tool for dissecting the mechanism of cellular stress and finding therapeutics that ameliorate these diseases. In this work, we present a multicolor HaloTag based sensor (named AgHalo) to visualize and quantify proteome stresses in live cells. The current AgHalo sensor is equipped with three fluorogenic probes that turn on fluorescence when the sensor forms either soluble oligomers or insoluble aggregates upon exposure to stress conditions, both in vitro and in cellulo. In addition, AgHalo probes can be combined with commercially available always fluorescent HaloTag ligands to enable two-color imaging, allowing for direct visualization of the AgHalo sensor both before and after cells are subjected to stress conditions. Finally, pulse-chase experiments can be performed to discern changes in the cellular proteome in live cells by first forming the AgHalo conjugate and then either applying or removing stress at any desired time point. In summary, the AgHalo sensor can be used to visualize and quantify proteome stress in live cells, a task that is difficult to accomplish using previous always-fluorescent methods. This sensor should be suited to evaluating cellular proteostasis under various exogenous stresses, including chemical toxins, drugs, and environmental factors. PMID- 29474060 TI - Probing DNA Translocations with Inplane Current Signals in a Graphene Nanoribbon with a Nanopore. AB - Many theoretical studies predict that DNA sequencing should be feasible by monitoring the transverse current through a graphene nanoribbon while a DNA molecule translocates through a nanopore in that ribbon. Such a readout would benefit from the special transport properties of graphene, provide ultimate spatial resolution because of the single-atom layer thickness of graphene, and facilitate high-bandwidth measurements. Previous experimental attempts to measure such transverse inplane signals were however dominated by a trivial capacitive response. Here, we explore the feasibility of the approach using a custom-made differential current amplifier that discriminates between the capacitive current signal and the resistive response in the graphene. We fabricate well-defined short and narrow (30 nm * 30 nm) nanoribbons with a 5 nm nanopore in graphene with a high-temperature scanning transmission electron microscope to retain the crystallinity and sensitivity of the graphene. We show that, indeed, resistive modulations can be observed in the graphene current due to DNA translocation through the nanopore, thus demonstrating that DNA sensing with inplane currents in graphene nanostructures is possible. The approach is however exceedingly challenging due to low yields in device fabrication connected to the complex multistep device layout. PMID- 29474061 TI - Improved Analysis of RNA Localization by Spatially Restricted Oxidation of RNA Protein Complexes. AB - Recent analysis of transcriptomes has revealed that RNAs perform a myriad of functions beyond encoding proteins. Critical to RNA function is its transport to unique subcellular locations. Despite the importance of RNA localization, it is still very challenging to study in an unbiased manner. We recently described the ability to tag RNA molecules within subcellular locations through spatially restricted nucleobase oxidation. Herein, we describe a dramatic improvement of this protocol through the localized oxidation and tagging of proteins. Isolation of RNA-protein complexes enabled the enrichment of challenging RNA targets on chromatin and presented a considerably optimized protocol for the analysis of RNA subcellular localization within living cells. PMID- 29474062 TI - Heating Rate of Light Absorbing Aerosols: Time-Resolved Measurements, the Role of Clouds, and Source Identification. AB - Light absorbing aerosols (LAA) absorb sunlight and heat the atmosphere. This work presents a novel methodology to experimentally quantify the heating rate (HR) induced by LAA into an atmospheric layer. Multiwavelength aerosol absorption measurements were coupled with spectral measurements of the direct, diffuse and surface reflected radiation to obtain highly time-resolved measurements of HR apportioned in the context of LAA species (black carbon, BC; brown carbon, BrC; dust), sources (fossil fuel, FF; biomass burning, BB), and as a function of cloudiness. One year of continuous and time-resolved measurements (5 min) of HR were performed in the Po Valley. We experimentally determined (1) the seasonal behavior of HR (winter 1.83 +/- 0.02 K day-1; summer 1.04 +/- 0.01 K day-1); (2) the daily cycle of HR (asymmetric, with higher values in the morning than in the afternoon); (3) the HR in different sky conditions (from 1.75 +/- 0.03 K day-1 in clear sky to 0.43 +/- 0.01 K day-1 in complete overcast); (4) the apportionment to different sources: HRFF (0.74 +/- 0.01 K day-1) and HRBB (0.46 +/- 0.01 K day 1); and (4) the HR of BrC (HRBrC: 0.15 +/- 0.01 K day-1, 12.5 +/- 0.6% of the total) and that of BC (HRBC: 1.05 +/- 0.02 K day-1; 87.5 +/- 0.6% of the total). PMID- 29474063 TI - Wicket: A Versatile Tool for the Integration and Optimization of Exogenous Pathways in Saccharomyces cerevisiae. AB - Yeast can be used as a microbial cell factory to produce valuable chemicals. However, introducing an exogenous pathway into particular or different chromosomal locations for stable expression is still a daunting task. To address this issue, we designed a DNA cassette called a "wicket", which can be integrated into the yeast genome at designated loci to accept exogenous DNA upon excision by a nuclease. Using this system, we demonstrated that, in strains with "wickets", we could achieve near 100% efficiency for integration of the beta-carotene pathway with no need for selective markers. Furthermore, it allowed independent and simultaneous integration of different genes in a pathway, resulting in a large variety of strains with variable copy numbers of each gene. This system could be a useful tool to modulate the integration of multiple copies of genes within a metabolic pathway and to optimize the yield of the target products. PMID- 29474064 TI - A Space Efficient Direct Access Data Compression Approach for Mass Spectrometry Imaging. AB - Advances in mass spectrometry imaging that improve both spatial and mass resolution are resulting in increasingly larger data files that are difficult to handle with current software. We have developed a novel near-lossless compression method with data entropy reduction that reduces the file size significantly. The reduction in data size can be set at four different levels (coarse, medium, fine, and superfine) prior to running the data compression. This can be applied to spectra or spectrum-by-spectrum, or it can be applied to transpose arrays or array-by-array, to efficiently read the data without decompressing the whole data set. The results show that a compression ratio of up to 5.9:1 was achieved for data from commercial mass spectrometry software programs and 55:1 for data from our in-house developed msIQuant program. Comparing the average signals from regions of interest, the maximum deviation was 0.2% between compressed and uncompressed data sets with coarse accuracy for the data entropy reduction. In addition, when accessing the compressed data by selecting a random m/ z value using msIQuant, the time to update an image on the computer screen was only slightly increased from 92 (+/-32) ms (uncompressed) to 114 (+/-13) ms (compressed). Furthermore, the compressed data can be stored on readily accessible servers for data evaluation without further data reprocessing. We have developed a space efficient, direct access data compression algorithm for mass spectrometry imaging, which can be used for various data-demanding mass spectrometry imaging applications. PMID- 29474065 TI - Programmed Protein Self-Assembly Driven by Genetically Encoded Intein-Mediated Native Chemical Ligation. AB - Harnessing and controlling self-assembly is an important step in developing proteins as novel biomaterials. With this goal, here we report the design of a general genetically programmed system that covalently concatenates multiple distinct protein domains into specific assembled arrays. It is driven by iterative intein-mediated native chemical ligation (NCL) under mild native conditions. The system uses a series of initially inert recombinant protein fusions that sandwich the protein modules to be ligated between one of a number of different affinity tags and an intein protein domain. Orthogonal activation at opposite termini of compatible protein fusions, via protease and intein cleavage, coupled with sequential mixing directs an irreversible and traceless stepwise assembly process. This gives total control over the composition and arrangement of component proteins within the final product, enabled the limits of the system reaction efficiency and yield-to be investigated, and led to the production of "functional" assemblies. PMID- 29474066 TI - Stairlike Aurivillius Phases in the Pseudobinary Bi5Nb3O15-ABi2Nb2O9 (A = Ba and Sr) System: A Comprehensive Analysis Using Superspace Group Formalism. AB - We report the possibility of extending the so-called stairlike Aurivilius phases in the pseudobinary Bi5Nb3O15-ABi2Nb2O9 (A = Ba and Sr) over a wide range of compositions. These phases are characterized by a discontinuous stacking of [Bi2O2] slabs and perovskite blocks, leading to long-period intergrowths stabilized as a single phase. When analyses from precession electron diffraction tomography and X-ray and neutron powder diffraction are combined, the monoclinic incommensurately modulated structure with q = alphaa* + gammac* previously proposed for the ABi7Nb5O24 composition could be generalized to the Bi5Nb3O15 ABi2Nb2O9 (A = Ba and Sr) compounds. Considering the compositions expressed as (A,Bi)1- xNb xO3-3 x, the stacking sequence associated with compositions ranging from x = 2/5 to 3/8 is governed by the component gamma of the modulation vector and can be predicted following a Farey tree hierarchy independently to the A cation. The length of the steps, characteristic of the stairlike nature, is controlled by the alpha component and depends on the substitution ratio A/Bi and the nature of A (A = Ba and Sr). This study highlights the compositional flexibility of stairlike Aurivillius phases. PMID- 29474067 TI - Palladium-Catalyzed Amide-Directed Enantioselective Hydrocarbofunctionalization of Unactivated Alkenes Using a Chiral Monodentate Oxazoline Ligand. AB - A Pd-catalyzed amide-directed enantioselective hydrocarbofunctionalization of unactivated alkenes with C-H nucleophiles has been developed using a chiral monodentate oxazoline (MOXin) ligand. Various indoles react at C3 position with aminoquinoline-coupled 3-alkenamides to give gamma addition products in good to excellent yield and enantioselectivity. This study represents an important advance of the development of chiral monodentate oxazoline ligands, which have been underexplored for asymmetric catalysis. PMID- 29474068 TI - Investigation of Rhizospheric Microbial Communities in Wheat, Barley, and Two Rice Varieties at the Seedling Stage. AB - The plant rhizosphere microbiota plays multiple roles in plant growth. We investigated the taxonomic and functional variations in the rhizosphere microbial community, examining both prokaryotes and eukaryotes, of four crops at the seedling stage: wheat, barley, and two rice varieties ( indica and japonica) seeded in paddy soil. The diversity of rhizosphere communities in these four species was determined. Results showed that wheat and barley had much stronger selection effects than rice for the rhizosphere microbial community. Functional metagenomic profiling indicated that a series of sequences related to glycan, limonene, and pinene degradation pathways as well as some relatively rare functions related to N or S metabolism were enriched in the rhizosphere soil. We conclude that the four tested crops induced the formation of the microbial community with specific features that may influence the plant growth but stochastic processes also appreciably influenced the functional selection. PMID- 29474069 TI - Discovery of a New Four-Leaf Clover-Like Ligand as a Potent c-MYC Transcription Inhibitor Specifically Targeting the Promoter G-Quadruplex. AB - Downregulating transcription of the oncogene c-MYC is a feasible strategy for cancer therapy. Stabilization of the G-quadruplex structure present in the c-MYC promoter can suppress c-MYC transcription. Thus, far, several ligands targeting this structure have been developed. However, most have shown no selectivity for the c-MYC G-quadruplex over other G-quadruplexes, leading to uncertain side effects. In this study, through structural modification of aryl-substituted imidazole/carbazole conjugates, a brand-new, four-leaf clover-like ligand called IZCZ-3 was found to preferentially bind and stabilize the c-MYC G-quadruplex. Further intracellular studies indicated that IZCZ-3 provoked cell cycle arrest and apoptosis and thus inhibited cell growth, primarily by blocking c-MYC transcription through specific targeting of the promoter G-quadruplex structure. Notably, IZCZ-3 effectively suppressed tumor growth in a mouse xenograft model. Accordingly, this work provides an encouraging example of a selective small molecule that can target one particular G-quadruplex structure, and the selective ligand might serve as an excellent anticancer agent. PMID- 29474070 TI - Molecular Mechanism, Dynamics, and Energetics of Protein-Mediated Dinucleotide Flipping in a Mismatched DNA: A Computational Study of the RAD4-DNA Complex. AB - DNA damage alters genetic information and adversely affects gene expression pathways leading to various complex genetic disorders and cancers. DNA repair proteins recognize and rectify DNA damage and mismatches with high fidelity. A critical molecular event that occurs during most protein-mediated DNA repair processes is the extrusion of orphaned bases at the damaged site facilitated by specific repairing enzymes. The molecular-level understanding of the mechanism, dynamics, and energetics of base extrusion is necessary to elucidate the molecular basis of protein-mediated DNA damage repair. The present article investigates the molecular mechanism of dinucleotide extrusion in a mismatched DNA (containing a stretch of three contiguous thymidine-thymidine base pairs) facilitated by Radiation sensitive 4 (RAD4), a key DNA repair protein, on an atom by-atom basis using molecular dynamics (MD) and umbrella-sampling (US) simulations. Using atomistic models of RAD4-free and RAD4-bound mismatched DNA, the free energy profiles associated with extrusion of mismatched partner bases are determined for both systems. The mismatched bases adopted the most stable intrahelical conformation, and their extrusion was unfavorable in RAD4-free mismatched DNA due to the presence of prohibitively high barriers (>12.0 kcal/mol) along the extrusion pathways. Upon binding of RAD4 to the DNA, the global free energy minimum is shifted to the extrahelical state indicating the key role of RAD4-DNA interactions in catalyzing the dinucleotide base extrusion in the DNA-RAD4 complex. The critical residues of RAD4 contributing to the conformational stability of the mismatched bases are identified, and the energetics of insertion of a beta-hairpin of RAD4 into the DNA duplex is examined. The conformational energy landscape-based mechanistic insight into RAD4 mediated base extrusion provided here may serve as a useful baseline to understand the molecular basis of xeroderma pigmentosum C (XPC)-mediated DNA damage repair in humans. PMID- 29474071 TI - Identification of Gibberellic Acid Derivatives That Deregulate Cholesterol Metabolism in Prostate Cancer Cells. AB - The naturally occurring pentacyclic diterpenoid gibberellic acid (1) was used in the generation of a drug-like amide library using parallel-solution-phase synthesis. Prior to the synthesis, a virtual library was generated and prioritized based on drug-like physicochemical parameters such as log P, hydrogen bond donor/acceptor counts, and molecular weight. The structures of the synthesized analogues (2-13) were elucidated following analysis of the NMR, MS, UV, and IR data. Compound 12 afforded crystalline material, and its structure was confirmed by X-ray crystallographic analysis. All compounds were evaluated in vitro for cytotoxicity and deregulation of lipid metabolism in LNCaP prostate cancer cells. While no cytotoxic activity was identified at the concentrations tested, synthesized analogues 3, 5, 7, 10, and 11 substantially reduced cellular uptake of free cholesterol in prostate cancer cells, suggesting a novel role of gibberellic acid derivatives in deregulating cholesterol metabolism. PMID- 29474072 TI - On-Surface Synthesis of Indenofluorene Polymers by Oxidative Five-Membered Ring Formation. AB - On-surface synthesis is a successful approach to the creation of carbon-based nanostructures that cannot be obtained via standard solution chemistry. In this framework, we have established a novel synthetic pathway to one-dimensional conjugated polymers composed of indenofluorene units. Our concept is based on the use of ortho-methyl groups on a poly( para-phenylene) backbone. In this situation, surface-assisted oxidative ring closure between a methyl and the neighboring aryl moiety gives rise to a five-membered ring. The atomically precise structures and electronic properties of the obtained indenofluorene polymers have been unambiguously characterized by STM, nc-AFM, and STS, supported by theoretical calculations. This unprecedented synthetic protocol can potentially be extended to other polyphenylenes and eventually graphene nanoribbons, to incorporate five-membered rings at desired positions for the fine tuning of electronic properties. PMID- 29474073 TI - Pt-Richcore/Sn-Richsubsurface/Ptskin Nanocubes As Highly Active and Stable Electrocatalysts for the Ethanol Oxidation Reaction. AB - Direct ethanol fuel cells are one of the most promising electrochemical energy conversion devices for portable, mobile and stationary power applications. However, more efficient and stable and less expensive electrocatalysts are still required. Interestingly, the electrochemical performance of the electrocatalysts toward the ethanol oxidation reaction can be remarkably enhanced by exploiting the benefits of structural and compositional sensitivity and control. Here, we describe the synthesis, characterization, and electrochemical behavior of cubic Pt-Sn nanoparticles. The electrochemical activity of the cubic Pt-Sn nanoparticles was found to be about three times higher than that obtained with unshaped Pt-Sn nanoparticles and six times higher than that of Pt nanocubes. In addition, stability tests indicated the electrocatalyst preserves its morphology and remains well-dispersed on the carbon support after 5000 potential cycles, while a cubic (pure) Pt catalyst exhibited severe agglomeration of the nanoparticles after a similar stability testing protocol. A detailed analysis of the elemental distribution in the nanoparticles by STEM-EELS indicated that Sn dissolves from the outer part of the shell after potential cycling, forming a ~0.5 nm Pt skin. This particular atomic composition profile having a Pt-rich core, a Sn-rich subsurface layer, and a Pt-skin surface structure is responsible for the high activity and stability. PMID- 29474074 TI - Geometric Energy Derivatives at the Complete Basis Set Limit: Application to the Equilibrium Structure and Molecular Force Field of Formaldehyde. AB - Geometric energy derivatives which rely on core-corrected focal-point energies extrapolated to the complete basis set (CBS) limit of coupled cluster theory with iterative and noniterative quadruple excitations, CCSDTQ and CCSDT(Q), are used as elements of molecular gradients and, in the case of CCSDT(Q), expansion coefficients of an anharmonic force field. These gradients are used to determine the CCSDTQ/CBS and CCSDT(Q)/CBS equilibrium structure of the S0 ground state of H2CO where excellent agreement is observed with previous work and experimentally derived results. A fourth-order expansion about this CCSDT(Q)/CBS reference geometry using the same level of theory produces an exceptional level of agreement to spectroscopically observed vibrational band origins with a MAE of 0.57 cm-1. Second-order vibrational perturbation theory (VPT2) and variational discrete variable representation (DVR) results are contrasted and discussed. Vibration-rotation, anharmonicity, and centrifugal distortion constants from the VPT2 analysis are reported and compared to previous work. Additionally, an initial application of a sum-over-states fourth-order vibrational perturbation theory (VPT4) formalism is employed herein, utilizing quintic and sextic derivatives obtained with a recursive algorithmic approach for response theory. PMID- 29474075 TI - Predicting the Conformational Variability of Abl Tyrosine Kinase using Molecular Dynamics Simulations and Markov State Models. AB - Understanding protein conformational variability remains a challenge in drug discovery. The issue arises in protein kinases, whose multiple conformational states can affect the binding of small-molecule inhibitors. To overcome this challenge, we propose a comprehensive computational framework based on Markov state models (MSMs). Our framework integrates the information from explicit solvent molecular dynamics simulations to accurately rank-order the accessible conformational variants of a target protein. We tested the methodology using Abl kinase with a reference and blind-test set. Only half of the Abl conformational variants discovered by our approach are present in the disclosed X-ray structures. The approach successfully identified a protein conformational state not previously observed in public structures but evident in a retrospective analysis of Lilly in-house structures: the X-ray structure of Abl with WHI-P154. Using a MSM-derived model, the free energy landscape and kinetic profile of Abl was analyzed in detail highlighting opportunities for targeting the unique metastable states. PMID- 29474076 TI - The Role of Semilabile Oxygen Atoms for Intercalation Chemistry of the Metal-Ion Battery Polyanion Cathodes. AB - Using the orthorhombic layered Na2FePO4F cathode material as a model system we identify the bonding of the alkali metal cations to the semilabile oxygen atoms as an important factor affecting electrochemical activity of alkali cations in polyanion structures. The semilabile oxygens, bonded to the P and alkali cations, but not included into the FeO4F2 octahedra, experience severe undercoordination upon alkali cation deintercalation, causing an energy penalty for removing the alkali cations located in the proximity of such semilabile oxygens. Desodiation of Na2FePO4F proceeds through a two-phase mechanism in the Na-ion cell with a formation of an intermediate monoclinic Na1.55FePO4F phase with coupled Na/vacancy and Fe2+/Fe3+ charge ordering at 50% state of charge. In contrast, desodiation of Na2FePO4F in the Li-ion cell demonstrates a sloping charge profile suggesting a solid solution mechanism without formation of a charge-ordered intermediate phase. A combination of a comprehensive crystallographic study and extensive DFT-based calculations demonstrates that the difference in electrochemical behavior of the alkali cation positions is largely related to the different number of the nearest neighbor semilabile oxygen atoms, influencing their desodiation potential and accessibility for the Na/Li chemical exchange, triggering coupled alkali cation-vacancy ordering and Fe2+/Fe3+ charge ordering, as well as switching between the "solid solution" and "two-phase" charging mechanistic regimes. PMID- 29474077 TI - Highly Diastereoselective Synthesis of Trifluoromethyl Indolines by Interceptive Benzylic Decarboxylative Cycloaddition of Nonvinyl, Trifluoromethyl Benzoxazinanones with Sulfur Ylides under Palladium Catalysis. AB - A highly diastereoselective synthesis of trifluoromethyl-substituted indolines under palladium catalysis is disclosed. The reaction proceeds by interceptive decarboxylative benzylic cycloaddition (IDBC) of nonvinyl, trifluoromethyl benzoxazinanones with sulfur ylides. The palladium-pi-benzyl zwitterionic intermediates are suggested for this transformation, and this would be the first example of an IDBC reaction. PMID- 29474078 TI - Palladium-Catalyzed C-O Cross-Coupling of Primary Alcohols. AB - Two catalyst systems are described, which together provide mild and general conditions for the Pd-catalyzed C-O cross-coupling of primary alcohols. For activated substrates, such as electron-deficient aryl halides, the commercially available ligand L2 promotes efficient coupling for a variety of alcohol nucleophiles. In the case of unactivated electrophiles, such as electron-rich aryl halides, the new ligand L8 was developed to improve these challenging C-O bond-forming reactions. PMID- 29474079 TI - Transformation of Substituted Glycals to Chiral Fused Aromatic Cores via Annulative pi-Extension Reactions with Arynes. AB - The Diels-Alder addition of arynes to appropriately substituted vinyl/aryl glycals followed by pi-extension via pyran ring opening smoothly furnished meta disubstituted fused aromatic cores containing a stereodefined orthogonally protected chiral side chain. The method is broad in terms of aryl homologation, affording benzene, naphthalene, and phenanthrene derivatives. Base-induced deprotonation followed by cleavage of the allylic C-O bond appear to be the crucial steps leading to the development of aromaticity, which is the driving force behind the annulative pi-extension process. The present protocol can be used for the synthesis of meta-disubstituted naphthalene aldehydes and substrates for aldolases. PMID- 29474080 TI - Strain Modulation of Graphene by Nanoscale Substrate Curvatures: A Molecular View. AB - Spatially nonuniform strain is important for engineering the pseudomagnetic field and band structure of graphene. Despite the wide interest in strain engineering, there is still a lack of control on device-compatible strain patterns due to the limited understanding of the structure-strain relationship. Here, we study the effect of substrate corrugation and curvature on the strain profiles of graphene via combined experimental and theoretical studies of a model system: graphene on closely packed SiO2 nanospheres with different diameters (20-200 nm). Experimentally, via quantitative Raman analysis, we observe partial adhesion and wrinkle features and find that smaller nanospheres induce larger tensile strain in graphene; theoretically, molecular dynamics simulations confirm the same microscopic structure and size dependence of strain and reveal that a larger strain is caused by a stronger, inhomogeneous interaction force between smaller nanospheres and graphene. This molecular-level understanding of the strain mechanism is important for strain engineering of graphene and other two dimensional materials. PMID- 29474081 TI - The Nature of the Dielectric Response of Methanol Revealed by the Terahertz Kerr Effect. AB - The dielectric response of liquids in the terahertz (THz) and sub-THz frequency range arises from low-energy collective molecular motions, which are often strongly influenced by intermolecular interactions. To shed light on the microscopic origin of the THz dielectric response of the simplest alcohol, methanol, we resonantly excite this liquid with an intense THz electric-field pulse and monitor the relaxation of the induced optical birefringence. We find a unipolar THz-Kerr-effect signal which, in contrast to aprotic polar liquids, shows a weak coupling between the THz electric field and the permanent molecular dipole moment of the liquid. We assign this weak coupling to the restricted translational rather than rotational nature of the excited mode. Our approach opens a new avenue to the assignment of the dielectric spectrum of liquids to a microscopic origin. PMID- 29474082 TI - Characterization of the Platinum-Hydrogen Bond by Surface-Sensitive Time-Resolved Infrared Spectroscopy. AB - The vibrational dynamics of Pt-H on a nanostructured platinum surface has been examined by ultrafast infrared spectroscopy. Three bands are observed at 1800, 2000, and 2090 cm-1, which are assigned to Pt-CO in a bridged and linear configuration and Pt-H, respectively. Lifetime analysis revealed a time constant of (0.8 +/- 0.1) ps for the Pt-H mode, considerably shorter than that of Pt-CO because of its stronger coupling to the metal substrate. Two-dimensional attenuated total reflection infrared spectroscopy provided additional evidence for the assignment based on the anharmonic shift, which is large in the case of Pt-H (90 cm-1), in agreement with the density functional theory calculations. The absorption cross section of Pt-H is smaller than that of the very strong Pt-CO vibration by only a modest factor of ~1.5-3. Because Pt-H is transiently involved in catalytic water splitting on Pt, the present spectroscopic characterization paves the way for in-operando kinetic studies of such reactions. PMID- 29474083 TI - Different Conformational Subensembles of the Intrinsically Disordered Protein alpha-Synuclein in Cells. AB - The intrinsically disordered protein alpha-synuclein (alphaS) is thought to play an important role in cellular membrane processes. Although in vitro experiments indicate that this initially disordered protein obtains structure upon membrane binding, NMR and EPR studies in cells could not single out any conformational subensemble. Here we microinjected small amounts of alphaS, labeled with a Forster resonance energy transfer (FRET) pair, into SH-SY5Y cells to investigate conformational changes upon membrane binding. Our FRET studies show a clear conformational difference between alphaS in the cytosol and when bound to small vesicles. The identification of these different conformational subensembles inside cells resolves the apparent contradiction between in vitro and in vivo experiments and shows that at least two different conformational subensembles of alphaS exist in cells. The existence of conformational subensembles supports the idea that alphaS can obtain different functions which can possibly be dynamically addressed with changing intracellular physicochemical conditions. PMID- 29474084 TI - Georatusin, a Specific Antiparasitic Polyketide-Peptide Hybrid from the Fungus Geomyces auratus. AB - Georatusin (1), featuring a highly reduced, methylated polyketide moiety fused to a tryptophan by an amide and ester bond forming a 13-membered ring, was produced by the soil fungus Geomyces auratus. An HMQC-COSY spectrum was measured to build up the connectivities despite the overlapping proton signals. DQF-COSY, HETLOC, J HMBC, and ROESY were implemented to determine the relative configuration of the flexible moiety. Georatusin (1) shows specific antiparasitic activities against Leishmania donovani and Plasmodium falciparum without obvious cytotoxicity. The biosynthesis of 1 was also proposed. PMID- 29474085 TI - RNA Control by Photoreversible Acylation. AB - External photocontrol over RNA function has emerged as a useful tool for studying nucleic acid biology. Most current methods rely on fully synthetic nucleic acids with photocaged nucleobases, limiting application to relatively short synthetic RNAs. Here we report a method to gain photocontrol over RNA by postsynthetic acylation of 2'-hydroxyls with photoprotecting groups. One-step introduction of these groups efficiently blocks hybridization, which is restored after light exposure. Polyacylation (termed cloaking) enables control over a hammerhead ribozyme, illustrating optical control of RNA catalytic function. Use of the new approach on a transcribed 237 nt RNA aptamer demonstrates the utility of this method to switch on RNA folding in a cellular context, and underlines the potential for application in biological studies. PMID- 29474086 TI - Thermal Transport in Quasi-1D van der Waals Crystal Ta2Pd3Se8 Nanowires: Size and Length Dependence. AB - Van der Waals (vdW) crystals with covalently bonded building blocks assembled together through vdW interactions have attracted tremendous attention recently because of their interesting properties and promising applications. Compared to the explosive research on two-dimensional (2D) vdW materials, quasi-one dimensional (quasi-1D) vdW crystals have received considerably less attention, while they also present rich physics and engineering implications. Here we report on the thermal conductivity of exfoliated quasi-1D Ta2Pd3Se8 vdW nanowires. Interestingly, even though the interatomic interactions along each molecular chain are much stronger than the interchain vdW interactions, the measured thermal conductivity still demonstrates a clear dependence on the cross-sectional size up to >110 nm. The results also reveal that partial ballistic phonon transport can persist over 13 MUm at room temperature along the molecular chain direction, the longest experimentally observed ballistic transport distance with observable effects on thermal conductivity so far. First-principles calculations suggest that the ultralong ballistic phonon transport arises from the highly focused longitudinal phonons propagating along the molecular chains. These data help to understand phonon transport through quasi-1D vdW crystals, facilitating various applications of this class of materials. PMID- 29474087 TI - Thiodigalactoside-Bovine Serum Albumin Conjugates as High-Potency Inhibitors of Galectin-3: An Outstanding Example of Multivalent Presentation of Small Molecule Inhibitors. AB - Galectin inhibitors are urgently needed to understand the mode of action and druggability of different galectins, but potent and selective agents still evade researchers. Small-sized inhibitors based on thiodigalactoside (TDG) have shown their potential while modifications at their C3 position indicated a strategy to improve selectivity and potency. Considering the role of galectins as glycoprotein traffic police, involved in multivalent bridging interactions, we aimed to create multivalent versions of the potent TDG inhibitors. We herein present for the first time the multivalent attachment of a TDG derivative using bovine serum albumin (BSA) as the scaffold. An efficient synthetic method is presented to obtain a novel type of neoglycosylated proteins loaded with different numbers of TDG moieties. A polyethylene glycol (PEG)-spacer is introduced between the TDG and the protein scaffold maintaining appropriate accessibility for an adequate galectin interaction. The novel conjugates were evaluated in galectin binding and inhibition studies in vitro. The conjugate with a moderate density of 19 conjugated TDGs was identified as one of the most potent multivalent Gal-3 inhibitors so far, with a clear demonstration of the benefit of a multivalent ligand presentation. The described method may facilitate the development of specific galectin inhibitors and their application in biomedical research. PMID- 29474088 TI - Synthesis, Characterization, and Reactivity of a High-Spin Iron(II) Hydrido Complex Supported by a PNP Pincer Ligand and Its Application as a Homogenous Catalyst for the Hydrogenation of Alkenes. AB - This study focused on the synthesis and characterization of a range of low valent, high-spin iron(II) complexes supported by a carbazole-based PNP pincer type ligand. The addition of the lithiated ligand (PNP)Li to FeCl2(THF)1.5 yielded the chlorido complex (PNP)FeCl (1), which could be readily converted to the four-coordinate iron(II) alkyl complexes (PNP)FeR [R = CH2SiMe3 (3a), Me (3b), CH2Ph (3c)]. These iron(II) complexes were fully characterized by X-ray analysis and a comprehensive, density-functional-theory-assisted study with complete assignment of their paramagnetic 1H and 13C NMR spectra. Treatment of 1 with KHBEt3 or the addition of molecular hydrogen to (PNP)FeR afforded a high spin iron(II) PNP hydrido complex, which was identified as the dimer [(PNP)Fe(MU H)]2 (4) with two bridging hydrido ligands between the iron centers. Exposing complexes 1 and 4 to carbon monoxide led to the corresponding six-coordinate, diamagnetic complexes (PNP)Fe(CO)2Cl (2) and (PNP)Fe(CO)2H (5), of which 2 was present as cis/trans isomers. Furthermore, 4 was found to be an active catalyst for the hydrogenation of alkenes. PMID- 29474089 TI - Phase Stability and Mechanisms of Transformation of La-Doped gamma-Alumina. AB - We report the phase stability of cubic gamma-Al2O3 with respect to lanthanum dopant amount and describe a complete phase transition sequence up to a temperature of 1800 degrees C, which proceeds from La-doped gamma-Al2O3 to LaAlO3/gamma-Al2O3 to LaAl11O18. For this purpose, lanthanum contents from 0.81 to 10.0 atom % were incorporated into Al2O3 powders. X-ray diffraction analyses show that only gamma-Al2O3 phase was present after heat treatment at 1000 degrees C for 2 h with 0.81, 1.68, 2.24, and 2.62 atom % lanthanum concentrations. The phase stabilization can be mainly attributed to the combined effects of small crystallite size of the Al2O3 powders and the presence of the lanthanum dopant, which occupies the Al2O3 octahedral sites. At compositions of 3.63, 5.00, 7.49, and 10.0 atom %, the amount of LaAlO3 phase formed by the solid phase reaction between Al2O3 and La3+ ions becomes detectable under X-ray diffraction. PMID- 29474090 TI - Syntheses of 2-Aroyl Benzofurans through Cascade Annulation on Arynes. AB - The highly efficient and expedient route for the syntheses of 2-aroyl benzofurans has been developed via the cascade [2+2] followed by a [4+1] annulation on arynes. The overall transformation proceeded through the formation of ortho quinone methide by the insertion of transient aryne into N, N-dimethylformamide and subsequent trapping with sulfur ylide. Moreover, this transformation has a broad range of substrate scope with a high functional-group tolerance. This new reaction was successfully utilized in the synthesis of the potent CYP19 aromatase inhibitor and late-stage functionalization on the bioactive complex estrone. PMID- 29474091 TI - Photodegradation of Dicloran in Freshwater and Seawater. AB - Dicloran appears to be a model pesticide for investigating photodegradation processes in surface waters. Photodegradation processes are particularly relevant to this compound as it is applied to crops grown in proximity to freshwater and marine ecosystems. The photodegradation of dicloran under simulated sunlight was measured in distilled water, artificial seawater, phosphate buffer, and filter sterilized estuarine water to determine its half-life, degradation rate, and photodegradation products. The half-life was approximately 7.5 h in all media. There was no significant difference in the rate of degradation between distilled water and artificial seawater for dicloran. For the intermediate products, a higher concentration of 2-chloro-1,4-benzoquinone was measured in artificial seawater versus distilled water, while a slightly higher concentration of 1,4 benzoquinone was measured in distilled water versus artificial seawater. The detection of chloride and nitrate ions after 2 h of light exposure suggests photonucleophilic substitution contributes to the degradation process. Differences in product distributions between water types suggest that salinity impacts on chemical degradation may need to be addressed in chemical exposure assessments. PMID- 29474092 TI - Enantioselective Organocatalyzed Direct alpha-Thiocyanation of Cyclic beta Ketoesters by N-Thiocyanatophthalimide. AB - A new electrophilic thiocyanation reagent, N-thiocyanatophthalimide, was synthesized and applied to the first example of catalytic asymmetric electrophilic alpha-thiocyanation of various cyclic beta-ketoesters by the bifunctional cinchona alkaloid catalysis. Thus, a variety of chiral alpha thiocyanato beta-ketoesters with a quaternary carbon center have been achieved in excellent yields (up to 99%) and high enantioselectivities (up to 94% ee) in a convenient manner. PMID- 29474093 TI - The Effect of Foot Reflexology on the Anxiety Levels of Women in Labor. AB - OBJECTIVES: This research was conducted to analyze the effect of foot reflexology on the anxiety levels of women during labor. DESIGN, SETTING AND SUBJECTS: The study was conducted as a semiexperimental study. It was conducted with 154 nulliparous pregnant women who applied to a maternity unit of a state hospital in the north-western part of Turkey to give birth. INTERVENTIONS: Foot reflexology was applied once to the pregnant women in the experimental group when cervical dilation was 3-4 cm. The treatment was applied to the right foot and left foot reflex points for 15 min, for a total of 30 min. The data in the study were collected using the "Pregnant Women Introductory Information Form" and the "Spielberger State-trait Anxiety Inventory" (STAI TX-1). In evaluating the data, number, percentage, Chi-square, independent samples t-test, and repeated measure analysis of variance test were used. MAIN OUTCOME MEASURES: The mean scores of the STAI TX-1 were used to analyze the results. RESULTS: The mean STAI TX-1 scores were measured before reflexology, in the latent and active phases of labor and early in postpartum period (four times in total). The mean STAI TX-1 scores were higher in the experimental group than in the control group (p < 0.001). The mean STAI TX-1 scores postreflexology application (when cervical dilation was 3-4 cm) and during the active phase of the labor (when cervical dilation was 6-8 cm) of the pregnant women in the experimental group were lower than those of the control group (respectively p = 0.010, p < 0.001). In the experimental group, there was no statistically significant difference between the mean STAI TX-1 scores pre- and postreflexology (p = 0.820). The mean STAI TX-1 scores in the early postpartum period were similar in the experimental and control groups (p = 0.080). CONCLUSION: Foot reflexology was found to have a positive effect in lowering the total anxiety scores of the pregnant women. Reflexology is a noninvasive and economical method, which may be used by health professionals to reduce problems during labor. A decrease in anxiety experienced at birth improves women's positive birth experiences, promotes a secure mother-infant attachment, and protects postpartum mental health. PMID- 29474094 TI - Natural History of Chronic Obstructive Pulmonary Disease Exacerbations in a General Practice-based Population with Chronic Obstructive Pulmonary Disease. AB - RATIONALE: Acute exacerbations of chronic obstructive pulmonary disease (AECOPDs) are important adverse events in the natural history of chronic obstructive pulmonary disease (COPD). OBJECTIVES: To investigate the natural history of AECOPDs over 10 years of follow-up. METHODS: We identified 99,574 patients with COPD from January 1, 2004, to March 31, 2015, from the UK Clinical Practice Research Datalink. We defined moderate AECOPDs as those managed outside hospital and severe as those requiring hospitalization. During the baseline period (first year of follow-up), patients were grouped according to the number and severity of AECOPDs and then followed for a maximum of 10 years (mean, 4.9 yr). We investigated the effect of baseline AECOPD number and severity on risk of further events and death. MEASUREMENTS AND MAIN RESULTS: Around one-quarter of the patients with COPD did not exacerbate during follow-up. Compared with no AECOPDs in the baseline period, AECOPD number predicted the future long-term rate of AECOPDs in a graduated fashion, ranging from hazard ratio (HR) of 1.71 (1.66 1.77) for one event to HR of 3.41 (3.27-3.56) for five or more events. Two or more moderate AECOPDs were also associated with an increased risk of death in a graduated fashion, ranging from HR of 1.10 (1.03-1.18) for two moderate AECOPDs to HR of 1.57 (1.45-1.70) for five or more moderate AECOPDs, compared with those with no AECOPDs at baseline. Severe AECOPDs were associated with an even higher risk of death (HR, 1.79; 1.65-1.94). CONCLUSIONS: A large proportion of patients with COPD do not exacerbate over a maximum 10 years of follow-up. AECOPD frequency in a single year predicts long-term AECOPD rate. Increasing frequency and severity of AECOPDs is associated with risk of death and highlights the importance of preventing AECOPDs. PMID- 29474095 TI - Cost Savings from Reducing Pain Through the Delivery of Integrative Medicine Program to Hospitalized Patients. AB - OBJECTIVES: An important task facing hospitals is improving pain management without raising costs. Integrative medicine (IM), a promising nonpharmacologic pain management strategy, is yet to be examined for its cost implications in an inpatient setting. This institution has had an inpatient IM department for over a decade. The purpose was to examine the relationship between changes in patients' pain, as a result of receiving IM therapy, and total cost of care during an inpatient hospital admission. DESIGN: In this retrospective analysis, data from an EPIC-based electronic health record (EHR) patient demographics, length of stay (LOS), and All Patient Refined Diagnosis Related Groups (APR-DRG) severity of illness measures were utilized. IM practitioners collected and entered patient reported pain scores into the EHR. The authors regressed the demographic, change in pain, LOS, and APR-DRG variables with changes in pain on total cost for the hospital admission. To estimate cost savings to the hospital, they computed the average reduction in cost associated with reduction in pain by multiplying the coefficient for change in pain by average total cost. SETTING/LOCATION: A large, tertiary care hospital in Minneapolis, MN. SUBJECTS: Adult inpatient admissions, 2730, during the study period where patients received IM for pain and met eligibility criteria. INTERVENTION: IM services provided to inpatients. OUTCOME MEASURES: Change in pain on an 11-point numeric rating scale before and after initial IM sessions; total costs for hospital admissions. RESULTS: Both LOS and age were found to increase cost, as did being white, male, married, and having APR-DRG severity coded as extreme. For patients receiving IM therapies, pain was reduced by an average of 2.05 points and this pain reduction was associated with a cost savings of $898 per hospital admission. CONCLUSIONS: For patients receiving IM therapies, pain was significantly reduced and costs were lowered by about 4%. PMID- 29474096 TI - Theranostic radiopharmaceuticals: established agents in current use. AB - Although use of the term "theranostic" is relatively recent, the concept goes back to the earliest days of nuclear medicine, with the use of radioiodine for diagnosis and therapy of benign and malignant thyroid disease being arguably the most successful molecular radiotherapy in history. A diagnostic scan with 123I-, 124I-, or a low activity of 131I-iodide is followed by therapy with high activity 131I-iodide. Similarly, adrenergic tumours such as phaeochromocytoma and neuroblastoma can be imaged with 123I-metaiodobenzylguanidine and treated with 131I-metaiodobenzylguanidine. Bone scintigraphy can be used to select patients with painful bone metastases from prostate cancer who may benefit from treatment with beta- or alpha-particle emitting bone seeking agents, the most recent and successful of which is 223Ra radium chloride. Anti-CD20 monoclonal antibodies can be used to image and treat non-Hodgkins lymphoma, though this has not been as commercially successful as initially predicted. More recently established theranostics include somatostatin receptor targeting peptides for diagnosis and treatment of neuroendocrine tumours with agents such as 68Ga-DOTATATE and 177Lu DOTATATE, respectively. Finally, agents which target prostate-specific membrane antigen are becoming increasingly widely available, despite the current lack of a commercial product. With the recent licensing of the somatostatin peptides and the rapid adoption of 68Ga- and 177Lu-labelled prostate-specific membrane antigen targeting agents, we have built upon the experience of radioiodine and are already seeing a great expansion in the availability of widely accepted theranostic radiopharmaceuticals. PMID- 29474097 TI - VIBE MRI: an alternative to CT in the imaging of sports-related osseous pathology? AB - MRI is an excellent diagnostic tool in the imaging of sports-related musculoskeletal pathology; however, standard slice thickness acquisitions can lack the spatial resolution to accurately define and characterise osseous abnormalities. Standard MRI sequences may be supplemented with CT to reduce diagnostic uncertainty. We provide a clinical perspective, in the form of pictorial review, on the potential applications of 3D MRI sequences, specifically using volumetric interpolated breath-hold examination in the characterisation of various musculoskeletal osseous pathologies. The potential to negate the requirement for CT in a young radiation sensitive cohort is a clinically significant concept and suggests the requirement for further studies comparing the performance of volumetric MRI to CT. PMID- 29474098 TI - Comparing four radiotherapy techniques for treating the chest wall plus levels III-IV draining nodes after breast reconstruction. AB - OBJECTIVE: To compare the dosimetric outcomes of four radiotherapy (RT) techniques for treating the chest wall plus draining nodes after mastectomy and breast reconstruction. METHODS: Three-dimensional conformal radiotherapy, linac based intensity modulated RT, helical tomotherapy (HT) and direct tomotherapy treatments were planned for 40 breast cancer patients. Dose prescription was 50 Gy. Plans were compared in terms of doses to the planning target volume, organs at risk and the homogeneity index. The non-parametric Friedman test for paired data and the Conover post hoc analysis were used for data analysis. RESULTS: HT provided the highest D90 and D98% and the lowest HI, V107% and D2%. HT was associated with the lowest D2% and V25 Gy to the heart in left-sided treatments but the mean cardiac dose was highest. HT provided the highest V5 Gy and V20 Gy to the ipsilateral lung, but the V30 Gy was lower. The contralateral breast and lung were more exposed with HT. CONCLUSION: The present dosimetric study together with daily use of CT-MV image guided RT have led us to opt for HT after mastectomy and breast reconstruction and to draw up a suitable protocol for treating the chest wall and levels III and IV draining nodes. Advances in knowledge: HT is a suitable for treating the chest wall and levels III and IV draining nodes. PMID- 29474099 TI - Beyond supervised learning: A multi-perspective approach to outpatient physical therapy mentoring. AB - BACKGROUND: Novice physical therapists face multiple challenges as they transition to autonomous, efficient, and seasoned therapists. Mentoring is known to facilitate growth among novice therapists; however, formalized mentoring programs within the outpatient setting are scarce or management-centered. This study sought to explore the most desired components of a formal mentoring program from multiple perspectives. METHODS: An inductive qualitative inquiry explored perceptions of participants (n = 35) from four populations. Interviews were conducted with students (n = 5) and novice therapists (n = 5), and survey data was collected from faculty (n = 7) and expert therapists (n = 18). Thematic content analysis was used for data analysis. RESULTS: Three primary themes emerged as program emphasis: 1) Program function; 2) novice therapists' needs; and 3) the making of a mentorship (including mentor/mentee characteristics and matching strategy). CONCLUSIONS: This study captured multiple perspectives as to the components of interest in development of a formalized mentoring program for novice therapists in the outpatient setting. As the profession continues to emphasize standards for guided learning, steps must be taken by individual employers to promote and facilitate the most effective practices. Findings provide depth and suggestions for developing an outpatient-mentoring program. PMID- 29474100 TI - Cervical myelopathy causing numbness and paresthesias in lower extremities: A case report identifying the cause of a false positive Sharp-Purser test. AB - INTRODUCTION: The patient was referred to an outpatient physical therapy clinic for lumbar radiculopathy by a primary care physician and subsequently referred for imaging due to suspicion of cervical myelopathy. The case highlights the clinical reasoning of the physical therapist differentiating between lumbar stenosis, cervical myelopathy, and upper cervical instability. To the author's knowledge, this is the only case report in the literature to describe the mechanism that could underpin a false positive Sharp-Purser test (SPT). The case also highlights the importance of interpreting the outcomes of special tests cautiously. CASE DESCRIPTION: A 55-year-old female was referred to outpatient physical therapy for lumbar radiculopathy. The patient's complaint was a one-year history of intermittent bilateral lower buttock paresthesias radiating to the bilateral posterior thighs. She reported a three-month history of bilateral anterior thigh numbness that would present after sitting for 30 minutes. Lumbar stenosis was initially suspected, however the patient's failure to improve but rather worsen with flexed postures suggested this diagnosis was improbable. The patient experienced bilateral anterior thigh numbness with active cervical flexion, and had a reduction in symptoms with the SPT. OUTCOMES: Magnetic resonance imaging revealed multi-focal disc-osteophyte complexes with central canal stenosis from C4-7. The patient underwent an anterior cervical discectomy and fusion with a good outcome. DISCUSSION: A large disc herniation causing central canal stenosis could underpin a false positive SPT. Special tests should always be used with caution, as they can lead to inaccurate diagnoses if there is a false positive. PMID- 29474101 TI - Efficacy of proprioceptive neuromuscular facilitation compared to other stretching modalities in range of motion gain in young healthy adults: A systematic review. AB - The objective of this study was to evaluate the efficacy of proprioceptive neuromuscular facilitation (PNF) on range of motion (ROM) gain in young healthy adults. We performed a systematic review of randomized controlled trials and quasi-randomized trials, including young healthy adults. The interventions were: PNF compared with different PNF techniques, control, other muscle stretching exercises and musculoskeletal manipulations. The outcome measures were: articular ROM and adverse effects. The final number of included studies was 46, involving 1,864 adults. There was difference on ROM comparing assisted hold-relax (HR) on diagonal plane to control, based on very low-quality evidence. There was also difference on ROM comparing assisted HR to self-HR; self-contract-relax (CR) to control; assisted CR contract to control; and assisted HR contract to control, based on low-quality evidence. Moderate-quality evidence shows that results differ between self HR and control (SMD: 0.95; 95%CI 0.03, 1.86; I249%; P = 0.16) in terms of ROM gain. When performing the other comparisons, the results were based on low or very low-quality evidence and do not allow to state if PNF is more or less effective than other stretches for improving ROM in healthy young adults. No adverse effects were mentioned. PMID- 29474102 TI - Defining the Elements of Early Palliative Care That Are Associated With Patient Reported Outcomes and the Delivery of End-of-Life Care. AB - Purpose We describe the key elements of early palliative care (PC) across the illness trajectory and examine whether visit content was associated with patient reported outcomes and end-of-life care. Methods We performed a secondary analysis of patients with newly diagnosed advanced lung or noncolorectal GI cancer (N = 171) who were randomly assigned to receive early PC. Participants attended at least monthly visits with board-certified PC physicians and advanced practice nurses at Massachusetts General Hospital. PC clinicians completed surveys documenting visit content after each encounter. Patients reported quality of life (Functional Assessment of Cancer Therapy-General) and mood (Hospital Anxiety and Depression Scale and Patient Health Questionnaire-9) at baseline and 24 weeks. End-of-life care data were abstracted from the electronic health record. We summarized visit content over time and used linear and logistic regression to identify whether the proportion of visits addressing a content area was associated with patient-reported outcomes and end-of-life care. Results We analyzed data from 2,921 PC visits, most of which addressed coping (64.2%) and symptom management (74.5%). By 24 weeks, patients who had a higher proportion of visits that addressed coping experienced improved quality of life ( P = .02) and depression symptoms (Depression subscale of the Hospital Anxiety and Depression Scale, P = .002; Patient Health Questionnaire-9, P = .004). Patients who had a higher proportion of visits address treatment decisions were less likely to initiate chemotherapy ( P = .02) or be hospitalized ( P = .005) in the 60 days before death. Patients who had a higher proportion of visits addressing advance care planning were more likely to use hospice ( P = .03). Conclusion PC clinicians' focus on coping, treatment decisions, and advance care planning is associated with improved patient outcomes. These data define the key elements of early PC to enable dissemination of the integrated care model. PMID- 29474104 TI - Recovering from provoked vestibulodynia: Experiences from encounters with somatocognitive therapy. AB - Although provoked vestibulodynia (PVD) represents a significant challenge for many young women in the Western world, little is known about how these women experience therapeutic efforts. The aim of this paper is to enhance our knowledge of the way that the therapeutic process is experienced by women with PVD undergoing somatocognitive therapy (SCT). The study enhances insight into this recently developed therapy through a detailed description of the physiotherapy approach. The empirical data are based on interviews with six women who participated in SCT. The empirical data analysis is guided by thematic analysis. Our findings demonstrate how the women experience SCT as a bodily process of wholeness. The process of wholeness relates to new experiences in the women's own bodies, awareness of muscular and mental tension and relaxation, breathing patterns, and perceptions focusing on pain. The findings are presented as three interrelated themes: 1) sensitizing the body as an interconnected unit; 2) incorporating the painful pubic region into the body; and 3) developing a new understanding of oneself. The women who participated in this study found that SCT contributed significantly to the process of their recovery from PVD. PMID- 29474103 TI - Hypolipidemic and Antidiabetic Effects of Functional Rice Cookies in High-Fat Diet-Fed ICR Mice and db/db Mice. AB - We have previously reported the lipid-lowering effects of a Korean rice cookie called dasik (RCD) in comparison with a western style cookie. In this study, Schisandra chinensis (Turcz.) Baill. (Chinese magnolia vine) fruit-supplemented RCD (SRCD) was added to a diet, and the hypolipidemic and antidiabetic effects of different diets were examined by using the ICR and db/db mouse models, respectively. ICR mice were fed the AIN-76 diet, or high-fat diet (HFD), or the RCD- or SRCD-supplemented HFD (10%, w/w) for 9 weeks (n = 7 per group). Compared with the RCD group, plasma and hepatic triglyceride and cholesterol concentrations were decreased in the SRCD group. Hepatic expressions for fatty acid and cholesterol synthesis were downregulated, whereas those for beta oxidation and cholesterol export were upregulated (P < .05). The antidiabetic effects of SRCD were tested in db/db mice for 10 weeks (n = 7 per group). Glucose tolerance was improved in the SRCD group through the regulation of gluconeogenic enzymes and biomarkers related to the insulin signaling pathway (P < .05). In addition, SRCD increased the expression levels of antioxidative enzymes, and decreased those of inflammatory cytokines (P < .05). Moreover, oxidative stress, leptin, and insulin levels were lower in the SRCD group than in the other groups (P < .05). In conclusion, the lipid-lowering and antidiabetic effects of SRCD were greater than those of RCD with respect to the suppression of lipid synthesis, oxidative stress, and inflammation and the improvement of glucose metabolism. PMID- 29474105 TI - Perspectives of Dutch Physiotherapists on Self-Management Support: A Q Methodology Study. AB - Self-management support programs are reported to have positive effects on the health and care of people with physical disabilities. It is unclear how physiotherapists (PTs) view self-management support. A cross-sectional study with mixed-methods design using Q-methodology was conducted to determine the perspectives of Dutch PTs on self-management support. PTs (n = 39) rank-ordered 37 validated statements about self-management support from "most disagree (-3)" to "most agree (+3)." Differences in perspectives on self-management support were explored in a by-person centroid factor analysis on the basis of the explained variance (R2). After having sorted the statements, PTs explained their ranking of -3 and +3 statements in semi-structured interviews. All PTs recognized self management support as intrinsic part of physiotherapy practice. Nevertheless, four particular perspectives could be identified: (1) the "externally driven educator" (R2 = 14%), (2) "internally driven educator" (R2 = 9%), (3) "client centered coach" (R2 = 13%), and (4) "client-initiated coach" perspective (R2 = 15%). Each perspective reflects particular goals and perceptions of self management support. Differences were identified with respect to the PTs' role perception (educating or coaching), drive (external or internal), and collaboration with the patient (as partner or not). The identified perspectives can be used in the physiotherapy education curriculum to create awareness about the various ways of practicing self-management support and the skills needed to be able to tailor support to patient needs and to switch between perspectives. PMID- 29474106 TI - Neighborhood environmental factors are related to health-enhancing physical activity and walking among community dwelling older adults in Nigeria. AB - INTRODUCTION: Health promotion strategies grounded by evidence-based determinants of physical activity constitute an important focus of physiotherapy practice in the twenty-first century. This study investigated associations between neighborhood environmental factors and health-related moderate-to-vigorous physical activity (MVPA) and walking for transportation and recreation among community dwelling Nigerian older adults. METHODS: A representative sample of 353 Nigerian older adults (age = 68.9 +/- 9.13 years) in a cross-sectional survey provided self-reported min/week of MVPA and walking for transportation and recreation and perceived neighborhood environmental factors. RESULTS: In multilevel linear regression analyses, proximity of destinations (beta = 3.291; CI = 0.392, 6.191), access to services and places (beta = 4.417; CI = 0.995, 7.838), esthetics (beta = 3.603; CI = 0.617, 6.590), traffic safety (beta = 5.685; CI = 3.334, 8.036), and safety from crime (beta = 1.717; CI = 0.466, 2.968) were related to more MVPA. Also, proximity of destinations (beta = 1.656; CI = 0.022, 3.291) and safety from crime (beta = 2.205; CI = 0.018, 4.579) were related to more transport walking. Access to services and places (beta = 2.086; CI = 0.713, 3.459) and walking infrastructure and safety (beta = 1.741; CI = 0.199, 3.282) were related to more recreational walking. CONCLUSIONS: Six of eight supportive environmental factors were associated with more physical activity among community dwelling older Nigerian adults. Policy makers including physiotherapists in this role can use the evidence to inform community-based physical activity and health promotion programs for older adults in Nigeria. PMID- 29474107 TI - A Systematic Review of Tools to Measure Respiratory Rate in Order to Identify Childhood Pneumonia. AB - Pneumonia is the leading infectious cause of death in children worldwide, with most deaths occurring in developing countries. Measuring respiratory rate is critical to the World Health Organization's guidelines for diagnosing childhood pneumonia in low-resource settings, yet it is difficult to accurately measure. We conducted a systematic review to landscape existing respiratory rate measurement technologies. We searched PubMed, Embase, and Compendex for studies published through September 2017 assessing the accuracy of respiratory rate measurement technologies in children. We identified 16 studies: 2 describing manual devices and 14 describing automated devices. Although both studies describing manual devices took place in low-resource settings, all studies describing automated devices were conducted in well-resourced settings. Direct comparison between studies was complicated by small sample size, absence of a consistent reference standard, and variations in comparison methodology. There is an urgent need for affordable and appropriate innovations that can reliably measure a child's respiratory rate in low-resource settings. Accelerating development or scale-up of these technologies could have the potential to advance childhood pneumonia diagnosis worldwide. PMID- 29474108 TI - Response to Verd re: "Academy of Breastfeeding Medicine's 2017 Position Statement on Informal Breast Milk Sharing for the Term Healthy Infant". PMID- 29474109 TI - Urinary Tract Infection: Cost Study. AB - A study of cost has been performed that considers cases and controls of healthcare-associated infections (HAI) regarding urinary tract infections (UTI) in a public hospital in the south of Chile. To perform the study, 10 cases of UTI were examined, considering the use of a urinary catheter as a risk factor. The study contributes to clarifying the costs of HAI, justifying the investments that can be made in order to prevent HAI in health centers. This study provides the basis to determine the importance not only in preventing infections, but also in the savings that the health system should consider when health centers prevent nosocomial infections. PMID- 29474110 TI - Chronic Azithromycin Use in Cystic Fibrosis and Risk of Treatment-Emergent Respiratory Pathogens. AB - RATIONALE: Azithromycin has been shown to improve lung function and reduce the number of pulmonary exacerbations in patients with cystic fibrosis. Concerns remain, however, regarding the potential emergence of treatment-related respiratory pathogens. OBJECTIVES: To determine whether chronic azithromycin use (defined as three-times weekly administration) is associated with increased rates of detection of eight specific respiratory pathogens. METHODS: We performed a new user, propensity score-matched retrospective cohort study utilizing data from the Cystic Fibrosis Foundation Patient Registry. Incident azithromycin users were propensity score matched 1:1 with contemporaneous nonusers. Kaplan-Meier curves and Cox proportional hazards regression were used to evaluate the association between chronic azithromycin use and incident respiratory pathogen detection. Analyses were performed separately for each pathogen, limited to patients among whom that pathogen had not been isolated in the 2 years before cohort entry. RESULTS: After propensity score matching, the mean age of the cohorts was approximately 12 years. Chronic azithromycin users had a significantly lower risk of detection of new methicillin-resistant Staphylococcus aureus, nontuberculous mycobacteria, and Burkholderia cepacia complex compared with nonusers. The risk of acquiring the remaining five pathogens was not significantly different between users and nonusers. CONCLUSIONS: Using an innovative new-user, propensity score matched study design to minimize indication and selection biases, we found in a predominantly pediatric cohort that chronic azithromycin users had a lower risk of acquiring several cystic fibrosis-related respiratory pathogens. These results may ease concerns that chronic azithromycin exposure increases the risk of acquiring new respiratory pathogens among pediatric patients with cystic fibrosis. PMID- 29474111 TI - In memory: Predicting preferences for memorializing lost loved ones. AB - People's preferences for memorializing loved ones vary and may depend on their personal attitudes and experiences with death. Participants (N = 145) completed the memorializing preferences checklist and measures of personal attitudes and life experiences with death. Factor analysis identified four memorializing preferences. In terms of predicting preferences, greater acknowledgment of death, and having experienced more losses, predicted preference for memorializing through societal tradition, community legacy, and continuing intimacy. Greater death resistance and less closeness to the deceased predicted preference for memorializing through confronting loss. Findings are discussed in terms of the range of preferences for and motivations behind memorializing. PMID- 29474112 TI - Three new species of Phylloporia (Hymenochaetales) with dimitic hyphal systems from tropical China. AB - Three new species of Phylloporia from tropical China are described in this study: P. manglietiae, P. pendula, and P. pseudopectinata. Phylloporia manglietiae is characterized by triquetrous to ungulate basidiomata, with 6-8 pores/mm, a monomitic to dimitic hyphal system, and broadly ellipsoidal basidiospores, 3-3.5 * 2-2.5 MUm. Phylloporia pendula has small, imbricate, and pendent basidiomata, with 7-9 pores/mm, a dimitic hyphal system, and broadly ellipsoidal basidiospores, 3.5-4 * 2.5-3 MUm. Phylloporia pseudopectinata differs from other species of Phylloporia by its applanate basidiomata, with 8-9 pores/mm, a dimitic hyphal system, and subglobose basidiospores, 3-3.5 * 2-3 MUm. Phylogenetic analyses, based on sequences from the D1-D2 domains of the 28S gene and the internal transcribed spacer (ITS) region (ITS1-5.8S-ITS2 = ITS) of the nuc rDNA, support the classification of the three new species in Phylloporia. PMID- 29474113 TI - Suicide assessment and treatment: Gaps between theory, research, and practice. AB - A considerable body of literature focuses on suicide risk assessment, treatment, and prevention. However, incorporation of these research and theoretical advances in routine care by practitioners has been largely unexamined. We examine the challenges-lack of training, fear, complexities of decision-making, practical barriers, lack of usage of assessment tools, and violations of psychometric principles by assessment tools-that confront practitioners when utilizing advances in the field. Identifying and addressing these barriers has implications to help bridge the gaps between theory, research, and practice to improve quality of care. Clinical, training, policy implications, and future research directions are reviewed. PMID- 29474114 TI - Effect of dry needling on radial tunnel syndrome: A case report. AB - This case report describes a 45-year-old male who presented with chronic right lateral elbow pain managed unsuccessfully with conservative treatment that included anti-inflammatory medication, injection, massage, exercise, bracing, taping, electro-physical agents, and manual therapy. Diagnosis of radial tunnel syndrome (RTS) was based on palpatory findings, range of motion testing, resisted isometrics, and a positive upper limb neural tension test 2b (radial nerve bias). Conventionally, the intervention for this entrapment has been surgical decompression, with successful outcomes. This is potentially a first-time report, describing the successful management of RTS with dry needling (DN) using a recently published DN grading system. Immediate improvements were noted in all the outcome measures after the first treatment, with complete pain-resolution maintained at a 6-month follow-up. A model is proposed describing the mechanism by which DN could be used to intervene for nerve entrapment interfaces. PMID- 29474115 TI - Dynamic MRI for bowel motility imaging-how fast and how long? AB - OBJECTIVE: Dynamic imaging of small intestinal motility is an increasingly common research method to examine bowel physiology in health and disease. However, limited data exist to guide imaging protocols with respect to quantitative analysis. The purpose of this study is to define the required temporal resolution and scan duration in dynamic MRI for small bowel motility assessment. METHODS: Six healthy volunteers underwent motility imaging with MR enterography using breath-hold protocol. A coronal two-dimensional balanced fast field echo sequence was used to acquire dynamic data at a high temporal resolution of 10 frames per second (fps). Motility was quantified by generating a registration-derived motility index for local and global regions of bowel. To evaluate temporal resolution and scan duration, the data were undersampled and the scan length was varied to determine the impact on motility index. RESULTS: The mean motility index stabilizes at a temporal resolution of 1 fps (median absolute percentage change 1.4% for global and 1.9% for local regions of interest). The mean motility index appears to stabilize for scan durations of 15 s or more in breath-hold (median absolute % change 2.8% for global and 1.7% for local regions of interest). CONCLUSION: A temporal resolution of at least 1 fps and a scan duration of at least 15 s is necessary in breath-hold scans for consistent motility observations. The majority of small bowel motility studies to date are in line with these requirements. Advances in knowledge: This study suggests the minimum temporal resolution and scan duration required in breath-hold scans to obtain robust measurements of small bowel motility from MRI. PMID- 29474116 TI - Brief report: Bereaved parents informing research design: The place of a pilot study. AB - BACKGROUND: Risk minimization in research with bereaved parents is important. However, little is known about which research methods balance the sensitivity required for bereaved research participants and the need for generalizable results. AIM: To explore parental experiences of participating in mixed method bereavement research via a pilot study. DESIGN: A convergent parallel mixed method design assessing bereaved parents' experience of research participation. SETTING/PARTICIPANTS: Eleven parents whose child was treated for cancer at The Royal Children's Hospital, Brisbane completed the questionnaire/interview being piloted (n = 8 mothers; n = 3 fathers; >6 months and <6 years bereaved). Of these, eight parents completed the pilot study evaluation questionnaire, providing feedback on their experience of participation. RESULTS: Participants acknowledged the importance of bereaved parents being central to research design and the development of bereavement programs. Sixty-three per cent (n = 5/8) of parents described completion of the questionnaire as 'not at all/a little bit' of a burden. Seventy-five per cent (n = 6/8) of parents opting into the telephone interview described participation as 'not at all/a little bit' of a burden. When considering the latest timeframes for participation in bereavement research 63% (n = 5/8) of parents indicated 'no endpoint.' Findings from the pilot study enabled important adjustments to be made to a large-scale future study. CONCLUSIONS: As a research method, pilot studies may be utilized to minimize harm and maximize the potential benefits for vulnerable research participants. A mixed method approach allows researchers to generalize findings to a broader population while also drawing on the depth of the lived experience. PMID- 29474117 TI - Improving Provider Communication about HPV Vaccines for Vaccine-Hesitant Parents Through the Use of Motivational Interviewing. AB - Human papillomavirus (HPV) vaccine uptake is below that of other routine adolescent vaccines. This is due in part to the fact that the HPV vaccine is often not routinely recommended by providers to all eligible adolescents. While providers' recommendations are crucial, even a strongly stated recommendation can be insufficient among HPV vaccine-hesitant parents. Providers must be prepared to respond to parental concerns following giving the recommendation for the HPV vaccine. This paper presents the analysis of implementation of an intervention aimed at improving provider communication with HPV vaccine-hesitant parents. Healthcare providers and staff at eight pediatric and family medicine clinics received communication training that included motivational interviewing (MI) techniques. Process evaluation in the form of serial surveys, as well as program evaluation in the form of focus groups with participating providers and staff, assessed the perceived efficacy of the intervention. Outcomes included time spent discussing the HPV vaccine during clinical visits, providers' self-efficacy for addressing parental HPV vaccine hesitancy, and their general perceptions of the effectiveness of MI techniques. Overall, findings indicate the intervention improved providers' communication with HPV vaccine-hesitant parents and providers reported the use of MI played a central role in improved HPV vaccine acceptance. Lessons learned and recommendations for future interventions are also discussed. PMID- 29474118 TI - Young people's experiences of living with epilepsy: The significance of family resilience. AB - OBJECTIVE: Young people with chronic illnesses, such as epilepsy, tend to have poorer psychosocial outcomes compared to their peers. Nevertheless, not all young people experience difficulties adapting to living with epilepsy. The aim of this study was to examine family processes, as little is known about their impact on young people's adaptation to the condition. METHOD: Semi-structured interviews were conducted with 15 young people, aged between 13 and 16 years old, to explore their experiences of living with epilepsy from the perspective of family resilience. RESULTS: Findings from these interviews provided in-depth descriptions of stressful circumstances encountered and family processes. These processes, which in turn promoted positive adaptation, included shared family beliefs, family connectedness, and communication processes that supported collaborative problem-solving. CONCLUSION: Practitioners who support young people living with chronic conditions, such as epilepsy, should consider interventions that promote family connectedness, as it allows young people to turn to their families for support in times of stress. Additionally, it is important to explore young people's beliefs, helping them and their families construct a new sense of normality if necessary. Supporting open communication between family members, where differing views were acknowledged, is likely to be important in facilitating resilience. PMID- 29474119 TI - Description and outcomes of a buprenorphine maintenance treatment program integrated within Prevention Point Philadelphia, an urban syringe exchange program. AB - BACKGROUND: Syringe exchange programs are uniquely positioned to offer treatment services to interested clients. Prevention Point Philadelphia recently expanded to offer buprenorphine maintenance treatment through its Stabilization, Treatment, and Engagement Program (STEP). OBJECTIVE: To describe the STEP model of care and report treatment outcomes. METHODS: Retrospective chart review of patients enrolled in STEP (October 2011 to August 2014). The main outcome measure was time retained in treatment, defined as time from treatment initiation to treatment failure. Secondary outcome measures were buprenorphine and opiate use, from urine toxicology screens. Retention in treatment was analyzed using Kaplan Meier survival estimates; patients who remained in treatment at the end of the study period were censored on that day. The percentage of patients who were positive for buprenorphine and opiates in each month of treatment was calculated. RESULTS: Of the 124 patients enrolled in STEP, the median age was 41 (range: 21 63) and 80% reported injection heroin use. Comorbidities were common: 33% had human immunodeficiency virus (HIV) infection, most reported anxiety (78%) or depression (71%), and 20% were homeless. The most common program outcomes were unplanned self-discharge (n = 29; 23%), incarceration (n = 20; 16%), and administrative discharge (n = 19; 15%). The percentages of patients retained in treatment at 3, 6, 9, and 12 months were 77%, 65%, 59%, and 56%, respectively. Among those retained, the percentages with a positive buprenorphine screen at 3, 6, 9, and 12 months were 88%, 100%, 96%, and 95%, respectively. The percentages with a positive opiates screen were 19%, 13%, 17%, and 16%, respectively. CONCLUSIONS: With a program that blended organizational and community resources, retention in buprenorphine maintenance treatment was comparable to retention rates reported from other settings. Further research should directly compare treatment outcomes in syringe exchange program-based settings versus primary care and specialty settings. PMID- 29474120 TI - Continuous performance test in children with intellectual disability and attention deficit hyperactivity disorder. AB - Data regarding clinical and neuropsychological features of attention deficit in children with lower cognitive ability is still scarce. The objective was to analyze the response patterns on the Continuous Performance Test II in children with Intellectual Disability and Attention Defficit Hyperactivity Disorder (ADHD). This is a cross-sectional study, in which patients were divided into 2 groups: one group with ADHD and Full IQ > 80 and another group with ADHD + Full IQ score < 80. They were afterwards administered the CPT II (Continuous Performance Test). A total of 215 children were included in the study, 57% of them with ADHD IQ > 80 and 43% with ADHD + Lower Intellectual Performance (LIP). Patients with ADHD and Lower Intellectual Performance presented more omissions error, slower reaction time and greater variability in the performance as the tests progresses, as well as worse stimulus detection and discrimination capacity. The results observed supply new information for the proper understanding of the functioning of attention processes in a poorly studied population. PMID- 29474121 TI - Communicating ALS to the public: The message effectiveness of social-media-based health campaign. AB - Celebrity endorsement has been proved to be a very powerful tool in health campaigns. This study examined how celebrity-issue matchup presented in utilitarian and hedonic appeals influences attitude toward the video, perceived issue severity, and behavioral intentions in the context of ALS communication. The findings showed that celebrity-issue matchup condition outperformed nonmatchup condition in generating positive attitude and behavioral intentions. The results also indicated that utilitarian appeal with matchup condition triggered significantly greater behavioral intention than that with nonmatchup condition. However, no difference was found in hedonic appeal between matchup and nonmatchup conditions. Theoretical and practical implications are also discussed. PMID- 29474122 TI - Non-animal methods to predict skin sensitization (II): an assessment of defined approaches *. AB - Skin sensitization is a toxicity endpoint of widespread concern, for which the mechanistic understanding and concurrent necessity for non-animal testing approaches have evolved to a critical juncture, with many available options for predicting sensitization without using animals. Cosmetics Europe and the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods collaborated to analyze the performance of multiple non animal data integration approaches for the skin sensitization safety assessment of cosmetics ingredients. The Cosmetics Europe Skin Tolerance Task Force (STTF) collected and generated data on 128 substances in multiple in vitro and in chemico skin sensitization assays selected based on a systematic assessment by the STTF. These assays, together with certain in silico predictions, are key components of various non-animal testing strategies that have been submitted to the Organization for Economic Cooperation and Development as case studies for skin sensitization. Curated murine local lymph node assay (LLNA) and human skin sensitization data were used to evaluate the performance of six defined approaches, comprising eight non-animal testing strategies, for both hazard and potency characterization. Defined approaches examined included consensus methods, artificial neural networks, support vector machine models, Bayesian networks, and decision trees, most of which were reproduced using open source software tools. Multiple non-animal testing strategies incorporating in vitro, in chemico, and in silico inputs demonstrated equivalent or superior performance to the LLNA when compared to both animal and human data for skin sensitization. PMID- 29474123 TI - Neuroprotective Effects of the Methanol Extract of Kimchi, a Korean Fermented Vegetable Food, Mediated Via Suppression of Endoplasmic Reticulum Stress and Caspase Cascade Pathways in High-Cholesterol Diet-Fed Mice. AB - Endoplasmic reticulum (ER) stress-related unfolded peptide accumulation is closely associated with the development of neurodegenerative diseases known as protein misfolding disorders. The antioxidative properties of kimchi, a traditional Korean fermented vegetable dish, have been well established. In this study, the neuroprotective effects of the kimchi methanol extract (KME) were examined in high-cholesterol diet (HCD)-fed mice. The animals were fed a HCD, with oral administration of either KME (KME group, 200 mg.kg bw-1.day-1, n = 10) or distilled water (Control group, n = 10) for 8 weeks. Compared with the levels in the control group, the reactive oxygen species, peroxynitrite, and lipid peroxidation levels in the brain were significantly decreased in the KME group (P < .05), whereas the glutathione level was increased (P < .05). In addition, the ER stress biomarkers, phospho-eukaryotic initiation factor 2 subunit alpha, glucose-regulated protein 78, X-box binding protein 1, inositol-requiring enzyme 1, and C/EBP homologous protein and the nuclear factor-kappaB-mediated inflammation were significantly reduced in the KME group (P < .05). In contrast, the expression levels of antioxidative enzymes regulated by nuclear factor erythroid 2-related factor-2 were elevated (P < .05). The amyloid-beta expression levels of the KME group were lower than that of the control group (P < .05). Moreover, the expression levels of Bcl-2-associated X, and caspases-3 and -9 were downregulated, with a concomitant upregulation of B cell lymphoma 2 (P < .05). Accordingly, KME provide neuronal cell protection via suppressing ER stress and caspase cascade signaling. PMID- 29474124 TI - Internet Use by Gynecologic Oncology Patients and Its Relationship with Anxiety. AB - This study describes the use of the Internet for health information research by patients attending a gynecologic oncology practice and examines the association between its use and anxiety. A self-administered survey assessed patients' demographic information and Internet use. The Hospital Anxiety and Depression Scale (HADS) and the State-Trait Anxiety Inventory (STAI) were administered concurrently. Of 212 patients who consented to the study, 98 (46%) had an appointment because of a cancer diagnosis. Of 199 respondents, 91 (46%) reported searching the Internet for information about their condition. Internet searching was unassociated with race/ethnicity and positively associated with education level, annual household income, and married/partnered civil status. Only 16% of the patients reported that a health-care provider recommended use of the Internet for research. Comparing patients who used the Internet for research with those who did not, the STAI state and trait anxiety scores were similar. The HADS anxiety subscale score was higher for those who used the Internet versus those who did not, which suggests heightened anxiety. Internet use for research is common in gynecologic oncology patients, and its use is associated with increased anxiety. Physicians can use this medium to educate patients about their disease, build trust, and alleviate fear. PMID- 29474125 TI - Online Health-Information Seeking Among Older Populations: Family Influences and the Role of the Medical Professional. AB - There are myriad technological devices, computer programs, and online information sources available for people to manage their health and the health of others. However, people must be technologically and health literate and capable of accessing, analyzing, and sharing the information they encounter. The authors interviewed middle-aged and older adults about their online health information seeking behavior and discovered that technology and health literacy are influenced by a collective ability to manage the health and technological needs of a family. We used information management theory to frame participants' experiences of their self-efficacy using technology to manage the health of loved ones. Findings suggest that health can be co-managed if at least one person in a family unit is technologically "savvy" and able to effectively share health information. However, individuals' confidence in their own literacy often depends on others, usually family members who tend to "do" instead of "teach." PMID- 29474126 TI - Association of Low Vitamin D Levels with Noninfectious Uveitis and Scleritis. AB - PURPOSE: To determine whether an association between Vitamin D and noninfectious ocular inflammation exists. METHODS: Retrospective case-control study with 765 patients (333 uveitis cases, 103 scleritis cases, 329 controls). Logistic regression models examined the relationship between hypovitaminosis D and ocular inflammation. RESULTS: The odds of having uveitis were 1.92 times higher for patients with hypovitaminosis D compared to patients with normal Vitamin D levels in the multivariate analysis [odds ratio (OR) = 1.92, 95% Confidence Interval (CI) = 1.36-2.72, p = 2.32 * 10-4]. A secondary analysis demonstrated that the odds of developing uveitis or scleritis were 5% lower and 4% lower, respectively, for every unit increase in Vitamin D level (uveitis: OR = 0.95, 95% CI = 0.94 0.97, p = 9.87 * 10-6; scleritis: OR = 0.96, 95% CI = 0.93-0.99, p = 0.009). CONCLUSION: Hypovitaminosis D was associated with increased risk of ocular inflammation in this retrospective study. PMID- 29474127 TI - Relationships between early alcohol experiences, drinker self-schema, and drinking and smoking in college students. AB - BACKGROUND: Drinking and smoking commonly co-occur in undergraduate students. Although an identity as a drinker is a known predictor of alcohol use and alcohol problems, and early evidence suggests that it also predicts smoking, the role of these behaviors in the development of an identity as a drinker is unknown. In this study, the authors conceptualized a drinker identity as an enduring memory structure referred to as a self-schema and conducted a preliminary investigation of the relationships between early drinking experiences, drinker self-schema, and alcohol and tobacco use in undergraduate students. METHODS: Three-hundred thirty undergraduates who reported current alcohol and tobacco use were recruited for an online survey study. Frequency of alcohol and tobacco use in the past 30 days, drinker self-schema, and early experiences with alcohol were measured. RESULTS: Structural equation modeling showed that parental alcohol problems were associated with early onset of drinking. Early onset of drinking and high school friends' drinking were associated with more alcohol use and alcohol-related problems in high school. Alcohol problems during high school were associated with high drinker self-schema scores, which were associated with high frequency of alcohol and tobacco use during college. The indirect effects through the drinker self-schema were significant. CONCLUSIONS: Although cross-sectional, this preliminary examination supports theoretical predictions that early alcohol experiences may contribute to development of the drinker self-schema, which, as expected, was positively associated with alcohol and tobacco use in college. Longitudinal studies that track the unfolding of drinking behavior and the contextual factors that are associated with it in the development of the drinker self-schema are essential to confirming the theoretical model. If supported, implications for intervention at different developmental stages to prevent early onset of drinking, limit adolescent alcohol use, and modify the development of a drinker self-schema may mitigate undergraduate drinking and smoking. PMID- 29474128 TI - Non-animal methods to predict skin sensitization (I): the Cosmetics Europe database. AB - Cosmetics Europe, the European Trade Association for the cosmetics and personal care industry, is conducting a multi-phase program to develop regulatory accepted, animal-free testing strategies enabling the cosmetics industry to conduct safety assessments. Based on a systematic evaluation of test methods for skin sensitization, five non-animal test methods (DPRA (Direct Peptide Reactivity Assay), KeratinoSensTM, h-CLAT (human cell line activation test), U-SENSTM, SENS IS) were selected for inclusion in a comprehensive database of 128 substances. Existing data were compiled and completed with newly generated data, the latter amounting to one-third of all data. The database was complemented with human and local lymph node assay (LLNA) reference data, physicochemical properties and use categories, and thoroughly curated. Focused on the availability of human data, the substance selection resulted nevertheless resulted in a high diversity of chemistries in terms of physico-chemical property ranges and use categories. Predictivities of skin sensitization potential and potency, where applicable, were calculated for the LLNA as compared to human data and for the individual test methods compared to both human and LLNA reference data. In addition, various aspects of applicability of the test methods were analyzed. Due to its high level of curation, comprehensiveness, and completeness, we propose our database as a point of reference for the evaluation and development of testing strategies, as done for example in the associated work of Kleinstreuer et al. We encourage the community to use it to meet the challenge of conducting skin sensitization safety assessment without generating new animal data. PMID- 29474129 TI - Reliability, validity and minimal detectable change of the Mini-BESTest in Greek participants with chronic stroke. AB - OBJECTIVES: This study aimed to investigate the psychometric characteristics of reliability, validity and ability to detect change of a newly developed balance assessment tool, the Mini-BESTest, in Greek patients with stroke. DESIGN: A prospective, observational design study with test-retest measures was conducted. METHODS: A convenience sample of 21 Greek patients with chronic stroke (14 male, 7 female; age of 63 +/- 16 years) was recruited. Two independent examiners administered the scale, for the inter-rater reliability, twice within 10 days for the test-retest reliability. Bland Altman Analysis for repeated measures assessed the absolute reliability and the Standard Error of Measurement (SEM) and the Minimum Detectable Change at 95% confidence interval (MDC95%) were established. The Greek Mini-BESTest (Mini-BESTestGR) was correlated with the Greek Berg Balance Scale (BBSGR) for assessing the concurrent validity and with the Timed Up and Go (TUG), the Functional Reach Test (FRT) and the Greek Falls Efficacy Scale International (FES-IGR) for the convergent validity. RESULTS: The Mini-BESTestGR demonstrated excellent inter-rater reliability (ICC (95%CI) = 0.997 (0.995-0.999, SEM = 0.46) with the scores of two raters within the limits of agreement (meandif = -0.143 +/- 0.727, p > 0.05) and test-retest reliability (ICC (95%CI) = 0.966 (0.926-0.988), SEM = 1.53). Additionally, the Mini-BESTestGR yielded very strong to moderate correlations with BBSGR (r = 0.924, p < 0.001), TUG (r = -0.823, p < 0.001), FES-IGR (r = -0.734, p < 0.001) and FRT (r = 0.689, p < 0.001). MDC95 was 4.25 points. CONCLUSION: The exceptionally high reliability and the equally good validity of the Mini-BESTestGR, strongly support its utility in Greek people with chronic stroke. Its ability to identify clinically meaningful changes and falls risk need further investigation. PMID- 29474130 TI - "It's natural and healthy, but I don't want to see it": Using Entertainment Education to Improve Attitudes Toward Breastfeeding in Public. AB - While it has been well established that breastfeeding provides the best nourishment for children, few women achieve the recommended breastfeeding duration. Negative media messages have been identified as one explanation for the lack of individual and public support for breastfeeding. This study explored the influence of media on the knowledge and attitudes of a nearly childless population to ascertain if and how entertainment media can positively impact perceptions of breastfeeding. Using cultivation and parasocial interaction, this research measured entertainment television's effect on breastfeeding attitudes using randomized-group experiments involving 375 students. Overall, participants generally held positive attitudes but were uncomfortable seeing breastfeeding. Moreover, results indicate that viewing a prime-time television clip that depicted public breastfeeding not only significantly lessened the extent to which participants believed that breastfeeding was a private activity but also improved attitudes and support for breastfeeding in public. This study concludes that more pro-breastfeeding media messages in entertainment media could help create a climate conducive to breastfeeding success. PMID- 29474131 TI - Evaluating the Effect of an Educational Intervention for Nursing Managers on the Rate of Incidents Reported at University Hospitals of Iran. AB - In this semiexperimental study conducted at the university hospitals in an urban area of Iran, the number of reported incidents-as per the information from offices-was evaluated and recorded for the improvement of the quality of hospitals. Subsequently, an educational intervention was conducted for nursing managers. Three months later, the number of reported incidents was again evaluated and recorded. According to the results, the number of reported incidents increased in the hospitals after the educational intervention. The results of this study could be helpful for hospital personnel, especially nurses, to improve the culture of incident self-reporting. PMID- 29474132 TI - Who's the Target: Mother or Baby? AB - Maternal immunization for prevention of morbidity and mortality of pregnant women and their neonates due to infectious diseases is ongoing worldwide. The complexity of vaccine research and development in this population is challenging. Not only do vaccines for pregnant women require evidence of immunogenicity, potency, stability, and limited reactogenicity, they must also provide efficacy in decreasing morbidity for the pregnant woman, her fetus, and the neonate, demonstrate safety or lack of evidence of harm, and offer benefit or potential benefit of vaccination during pregnancy. Since the 19th century, evidence of protective effects of vaccination during pregnancy has been documented. Pandemic influenza and pertussis outbreaks in recent years have affected a paradigm shift in vaccine research and development as well as current policy regarding immunization in pregnancy. Studies of the immune system in pregnant women and neonates have shown that immune changes associated with pregnancy in women do not interfere with maternal vaccine responses, multiple factors are important in transplacental transfer of antibodies, and maternal antibodies are beneficial to neonates. In recent years, guidelines have been developed by expert panels to help design studies for maternal vaccinations and for harmonization of data collection, analysis, and adverse event reporting. Further research into maternal and neonatal immunology, transplacental antibody transfer, and epidemiology of diseases is needed, especially as new vaccines to respiratory syncytial virus, cytomegalovirus, and Group B streptococcus are developed. Maternal vaccinations have the potential to change the epidemiology of infectious diseases in reproductive health and pediatrics and may lead to new clinical applications to improve global maternal and neonatal health. PMID- 29474133 TI - Spreading Ebola Panic: Newspaper and Social Media Coverage of the 2014 Ebola Health Crisis. AB - During times of hot crises, traditional news organizations have historically contributed to public fear and panic by emphasizing risks and uncertainties. The degree to which digital and social media platforms contribute to this panic is essential to consider in the new media landscape. This research examines news coverage of the 2014 Ebola crisis, exploring differences in presentation between newspaper coverage and news shared on the social news platform Reddit. Results suggest that news shared on Reddit amplified panic and uncertainty surrounding Ebola, while traditional newspaper coverage was significantly less likely to produce panic-inducing coverage. PMID- 29474134 TI - Propagation of Economic Inequality Through Reciprocity and Reputation. AB - Reciprocity and reputation are powerful tools for encouraging cooperation on a broad scale. Here, we highlight a potential side effect of these social phenomena: exacerbating economic inequality. In two novel economic games, we manipulated the amount of money with which participants were endowed and then gave them the opportunity to share resources with others. We found that people reciprocated more toward higher-wealth givers, compared with lower-wealth givers, even when those givers were equally generous. Wealthier givers also achieved better reputations than less wealthy ones and therefore received more investments in a social marketplace. These discrepancies were well described by a formal model of reinforcement learning: Individuals who weighted monetary outcomes, rather than generosity, when learning about interlocutors also most strongly helped wealthier individuals. This work demonstrates that reciprocity and reputation-although globally increasing prosociality-can widen wealth gaps and provides a precise account of how inequality grows through social processes. PMID- 29474135 TI - Clinical Features and Prognosis of Uveitis in a Turkish Patient Population with Ankylosing Spondylitis: Incidence and Management of Ocular Complications. AB - PURPOSE: To investigate clinical features, visual prognosis, and ocular complications in patients with ankylosing spondylitis (AS)-associated anterior uveitis (AU). METHODS: Data of 211 eyes of 145 patients with AU associated with AS were reviewed retrospectively. RESULTS: Mean follow-up time was 6.31 +/- 6.33 years. Men were younger than women at AS diagnosis (p = 0.035). The mean number of uveitis flares was highest during the first quarter of the year and lowest during the third quarter (p = 0.017). Immunosuppressive agent use was higher in women than men (p = 0.052). Ocular complications developed in 120 eyes (56.9%), and the complication rate was 0.146/eye year. Males developed cystoid macular edema more frequently than females (p = 0.05). Glaucoma was observed more often in early-onset disease (age at AS onset <45 years) than late-onset disease (p = 0.028). CONCLUSIONS: Visual prognosis of AU in patients with AS was good, although more than half of the eyes developed ocular complications (56.9%). PMID- 29474136 TI - Psychiatric Hospitalization after Emergency Treatment for Deliberate Self-Harm is Associated with Repeated Deliberate Self-Harm. AB - OBJECTIVES: To evaluate whether treatment at a psychiatric hospital reduces the risk of repeating parasuicide. METHODS: Participants comprised 4,483 parasuicide patients admitted to an emergency department between July 2003 and March 2012. We analyzed the effectiveness of psychiatric hospitalization in preventing repeated parasuicide. We adjusted for background factors using multivariate logistic regression. RESULTS: Effects of psychiatric hospitalization upon the likelihood of repeated parasuicide within one year varied by age (especially those aged <35 years), indicating that hospitalization was a significant risk factor. CONCLUSION: We must be mindful of the risk of repeated parasuicide following discharge in young patients and to provide them with ongoing outpatient care and multimodal support. PMID- 29474137 TI - PCR Multiplex for CMV Detection in Patients with Anterior Uveitis. AB - PURPOSE: Describing the utility of Polymerase Chain Reaction for Cytomegalovirus (CMV-PCR) in the diagnosis of suspected viral anterior uveitis (AU). PATIENTS AND METHODS: We analyzed aqueous humor (AH) CMV-PCR positivity and treatment modifications in 47 eyes of 46 patients with viral uveitis and its correlation with high intraocular pressure (HIOP), uveitis clinical characteristics and time intervals from samples to uveitis diagnosis and to relapse. RESULTS: CMV-PCR positive results occurred in 13 eyes (27.7%) of 12 patients. They were more frequent in HIOP eyes (34.2%, p = 0.047) and with Posner-Schlossman Syndrome (56.2%, p = 0.002). CMV-PCR positivity (p = 0.001) and HIOP (p = 0.038) increased the probability of treatment change. Although CMV-PCR positive results decreased over time (p = 0.002), they were not related to activity or proximity to inflammatory uveitis episode. CONCLUSION: HIOP AU eyes should be considered for CMV-PCR AH analysis due to possible treatment modifications. PMID- 29474138 TI - Exploratory study of metacognitive beliefs about coping processes in prolonged grief symptomatology. AB - Despite research examining the role of metacognitive beliefs about coping processes in maintaining psychological disorders, to date, no studies have explored their role in the maintenance of prolonged grief. Twelve semistructured interviews were conducted with bereavement specialists and bereaved people with elevated grief to identify metacognitive beliefs about coping processes relevant to prolonged grief. Analysis revealed several metacognitive beliefs potentially driving maladaptive coping processes used by people with prolonged grief symptomatology. Findings may underpin the development of interventions that aim to modify unhelpful metacognitive beliefs that perpetuate maladaptive coping processes. PMID- 29474139 TI - Levels of regulatory B cells do not predict serological responses to hepatitis B vaccine. AB - This study investigated the immunomodulatory influence of IL10 producing B regulatory cells, Bregs (CD19+CD24hiCD38hi) to standard Twinrix(r) vaccination. We also investigated HBsAg specific T-cell mediated IFN-gamma responses to Twinrix(r) which in theory could provide effective immunity despite low anti-HBs titer. A total of 309 hepatitis B negative health care students and workers completed a standard Twinrix(r) vaccination schedule (0, 1 and 6 months). Depending on the vaccination response the participants were divided in to non-, low- and high responders according to anti-HBs titer (<10, <100 and >1000 mIU/mL respectively) two months after completed vaccination schedule. Blood samples from baseline and after vaccination from all non- and low-responders (23 participants) and the same number of high-responders were used for flow cytometric analyses of IL10 producing Bregs and T-cell mediated IFN-gamma responses. A decrease in levels of IL10 producing Bregs was observed after vaccination in high responders compared to non- and low-responders. Compiling non-and low-responders against high-responders showed a lower T-cell mediated IFN-gamma response at baseline in non-and low-responders when stimulated with Engerix(r) vaccine. In contrary no positive correlation between IL10 producing Bregs or IFN-gamma positive T-cells and anti-HBs titer was observed. Hence this study cannot prove that levels of IL10 producing Bregs or IFN-gamma positive T cell affect HBV vaccine response. PMID- 29474140 TI - Prediction of performance by heart rate-derived parameters in recreational runners. AB - We investigated whether heart rate (HR)-derived parameters are accurate performance predictors in endurance recreational runners. One hundred thirty recreational athletes completed an incremental running test (4'running + 1'rest). After each stage, we recorded HR, % of maximum HR (%HRmax), and blood lactate. We also assessed HR after each recovery period, and calculated lactate and HR recovery thresholds and HR deflection point. We tested these parameters for associations with running performance, as measured by peak treadmill speed (PTS) and personal best International Association of Athletics Federations (IAAF) score. The %HRmax at 14.5 km.h-1 correlated with PTS (r = -0.92), and IAAF score (rho = -0.80). The magnitudes of the correlations of lactate-related parameters with PTS (|r| = 0.84 to 0.86) or IAAF score (|rho| = 0.70 to 0.77) in absolute values were slightly lower. The correlations detected between other HR-derived parameters and running performance were weaker (|r or rho| = 0.24 to 0.70). Regression models identified %HRmax at 14.5 km.h-1 as the strongest predictor of both PTS (beta = -0.72) and IAAF score (beta = -0.72). Consequently, tests based on %HRmax may provide a non-invasive and inexpensive alternate method for predicting the performance of these athletes. PMID- 29474141 TI - Robot-Assisted Retroperitoneal Lymphadenectomy in Testicular Cancer Treatment: A Systematic Review. AB - INTRODUCTION: Retroperitoneal lymph node dissection (RPLND) in testicular cancer is a documented treatment along with active surveillance and chemotherapy. This study aims to summarize the current evidence on the use of Robot-assisted RPLND (RARPLND) in comparison with the laparoscopic and open approach. MATERIALS AND METHODS: A search was conducted in the existing literature focusing on reports with outcomes of RARPLND for stage I-IIB testicular tumor. RESULTS: Eleven studies complied with the inclusion criteria, including 116 patients. The average follow-up of 21.2 months showed no retroperitoneal recurrence. The median lymph node yield was 22.3 and the overall positive rate was 26%. Complications were encountered in 8% of the patients. The robotic approach showed similar results to the laparoscopic approach and outperformed the open procedure in perioperative parameters. CONCLUSIONS: Relapse-free survival, nodal yield, and complication rates during RARPLND for clinical stage I-IIB are acceptable. Further studies are required to establish these findings and determine benefit from the use of robotic approach. PMID- 29474142 TI - Occurrence, Genotyping, and Antibiotic Susceptibility of Cronobacter spp. in Drinking Water and Food Samples from Northeast China. AB - Cronobacter species (formerly Enterobacter sakazakii) are emerging opportunistic bacterial pathogens that can infect both infants and adults. This study was conducted to isolate and genotype diverse Cronobacter species from drinking water, chilled fresh pork, powdered infant formula, instant noodles, cookies, fruits, vegetables, and dishes in Northeast China and to evaluate the antibiotic resistance and susceptibility of the isolates. Thirty-four Cronobacter strains were isolated and identified: 21 C. sakazakii isolates (61.8%), 10 C. malonaticus isolates (29.4%), 2 C. dublinensis isolates (5.9%), and 1 C. turicensis isolate (2.9%). These isolates were further divided into 15 sequence types (STs) by multilocus sequence typing. C. sakazakii ST4 (10 isolates, 29.4%), ST1 (3 isolates, 8.8%), and ST8 (3 isolates, 8.8%) and C. malonaticus ST7 (four isolates, 11.8%) were dominant. Antibiotic susceptibility testing indicated that all 34 Cronobacter isolates were susceptible to ampicillin-sulbactam, cefotaxime, ciprofloxacin, gentamicin, meropenem, tetracycline, piperacillin-tazobactam, and trimethoprim-sulfamethoxazole, 88.2% were susceptible to chloramphenicol, and 67.6% were resistant to cephalothin. The results of this study enhance knowledge about genotyping and antibiotic resistance of these Cronobacter species and could be used to prevent potential hazards caused by these strains in drinking water and various food products. PMID- 29474143 TI - Penicillium expansum Inhibition on Bread by Lemongrass Essential Oil in Vapor Phase. AB - The antimicrobial activity of lemongrass ( Cymbopogon citratus) essential oil (EO) in the vapor phase on the growth of Penicillium expansum inoculated on bread was evaluated, followed by a sensory evaluation of the bread's attributes after EO exposure. The lemongrass EO was extracted from dry leaves of lemongrass by microwave-assisted steam distillation. The chemical composition of the lemongrass EO was determined using a gas chromatograph coupled to a mass spectrometer. The refractive index and specific gravity of the EO were also determined. Bread was prepared and baked to reach two water activity levels, 0.86 or 0.94, and then 10 MUL of P. expansum spore (106 spores per mL) suspension was inoculated on the bread surface. Concentrations of lemongrass EO were tested from 125 to 4,000 MUL/Lair, whereas mold radial growth was measured for 21 days. For sensory evaluation, breads were treated with lemongrass EO vapor at 0, 500, or 1,000 MUL/Lair for 48 h and tested by 25 untrained panelists. The EO yield was 1.8%, with similar physical properties to those reported previously. Thirteen compounds were the main components in the EO, with citral being the major compound. P. expansum was inhibited for 21 days at 20 degrees C with 750 MUL of EO/Lair, and its inhibition increased with increasing concentrations of EO. Sensory acceptance of bread exposed to vapor concentrations of 500 or 1,000 MUL of EO/Lair or without EO was favorable; similar and no significant differences ( P > 0.05) were observed among them. PMID- 29474144 TI - Investigation of Nonionophoric Coccidiostat Residues in Feed as a Consequence of Carryover. AB - Residues of nonionophoric coccidiostats at carryover concentrations in feedstuffs collected from feed mills or animal farms in central Italy were detected as part of the official controls carried out from 2011 through 2016. The 118 samples were collected on the production line or during feed distribution and storage to determine the sampling sites at major risk of cross-contamination. For determination of nonionophoric coccidiostats, a fast, easy, and cheap method was developed and validated. Feed samples were extracted with acetonitrile-methanol and directly injected for liquid chromatography with tandem mass spectrometry. A total of 24 samples (20.3%) were positive, but only 5 (4.2%) of these samples exceeded the maximum limit set by European legislation. Most of the positive samples were collected from a batch of feed produced immediately following processing of another batch to which the coccidiostat robenidine had been added. PMID- 29474145 TI - Prevalence and Antimicrobial Resistance of Yersinia enterocolitica in Retail Seafood. AB - Yersinia enterocolitica is a zoonotic enteropathogenic bacterium that can cause acute gastroenteritis and mesenteric lymphadenitis. Although Y. enterocolitica is common in animals, food, and the environment, the reservoirs and transmission routes of this pathogen are still not fully understood. The aim of our study was to determine the prevalence of Y. enterocolitica in seafood in Germany, because only limited data are available on that topic. Seafood samples were purchased from retail shops in Berlin, Germany and examined for the presence of Y. enterocolitica by cold enrichment followed by cultivation on selective agar. Presumptive Y. enterocolitica isolates were analyzed by biotyping, serotyping, and antimicrobial susceptibility testing. The total prevalence of Y. enterocolitica in seafood samples was 2.7% (6 of 220 samples). Mussel (2 of 90), shrimp (1 of 89), and cephalopod (3 of 41) samples were positive for Y. enterocolitica. Three isolates were identified as serotype O:8, one was identified as serotype O:5,27, and two samples did not belong to any investigated serotypes. The presence of the virulence-associated genes ail, inv, and ystB was studied by multiplex PCR. Four of the six isolates contained inv and ystB, one produced no positive results for the analyzed genes, and one contained only ystB. All Y. enterocolitica isolates were susceptible to cefotaxime, cefuroxime, chloramphenicol, ciprofloxacin, gentamicin, kanamycin, nalidixic acid, streptomycin, tetracycline, and trimethoprim. Resistance was observed to cephalothin (83.3% of isolates), amoxicillin (83.3%), and ampicillin (50.0%). This study provides the first comprehensive analysis of Y. enterocolitica in retail seafood in Germany. The prevalence found in these seafood samples was comparatively low, and all isolates belonged to biotype 1A. However, seafood contaminated with Y. enterocolitica may pose a risk to consumer health because the pathogenic potential of biotype 1A strains is still being debated. PMID- 29474146 TI - Influence of Cooling Rate on Growth of Bacillus cereus from Spore Inocula in Cooked Rice, Beans, Pasta, and Combination Products Containing Meat or Poultry. AB - The objective of this study was to assess the ability of Bacillus cereus spores to germinate and grow in order to determine a safe cooling rate for cooked rice, beans, and pasta, rice-chicken (4:1), rice-chicken-vegetables (3:1:1), rice-beef (4:1), and rice-beef-vegetables (3:1:1). Samples were inoculated with a cocktail of four strains of heat-shocked (80 degrees C for 10 min) B. cereus spores (NCTC 11143, 935A/74, Brad 1, and Mac 1) to obtain a final spore concentration of approximately 2 log CFU/g. Thereafter, samples were exponentially cooled through the temperature range of 54.5 to 7.2 degrees C in 6, 9, 12, 15, 18, and 21 h. At the end of the cooling period, samples were removed and plated on mannitol egg yolk polymyxin agar. The plates were incubated at 30 degrees C for 24 h. The net B. cereus growth from spores in beans was <1 log after 9 h of cooling, but the pathogen grew faster in rice and pasta. In combination products, the net growth was as follows: 3.05, 3.89, and 4.91 log CFU/g in rice-chicken; 3.49, 4.28, and 4.96 log CFU/g in rice-beef; 3.50, 4.20, and 5.32 CFU/g in rice-chicken-mixed vegetables; and 3.68, 4.44, and 5.25 CFU/g in rice-beef-mixed vegetables after 15, 18, and 21 h of cooling, respectively. This study suggests safe cooling rates for cooling cooked rice, beans, pasta, rice-chicken, rice-chicken-vegetables, rice-beef, and rice-beef-vegetables to guard against the hazards associated with B. cereus. PMID- 29474147 TI - Precooking as a Control for Histamine Formation during the Processing of Tuna: An Industrial Process Validation. AB - An experiment to validate the precooking of tuna as a control for histamine formation was carried out at a commercial tuna factory in Fiji. Albacore tuna ( Thunnus alalunga) were brought on board long-line catcher vessels alive, immediately chilled but never frozen, and delivered to an on-shore facility within 3 to 13 days. These fish were then allowed to spoil at 25 to 30 degrees C for 21 to 25 h to induce high levels of histamine (>50 ppm), as a simulation of "worst-case" postharvest conditions, and subsequently frozen. These spoiled fish later were thawed normally and then precooked at a commercial tuna processing facility to a target maximum core temperature of 60 degrees C. These tuna were then held at ambient temperatures of 19 to 37 degrees C for up to 30 h, and samples were collected every 6 h for histamine analysis. After precooking, no further histamine formation was observed for 12 to 18 h, indicating that a conservative minimum core temperature of 60 degrees C pauses subsequent histamine formation for 12 to 18 h. Using the maximum core temperature of 60 degrees C provided a challenge study to validate a recommended minimum core temperature of 60 degrees C, and 12 to 18 h was sufficient to convert precooked tuna into frozen loins or canned tuna. This industrial-scale process validation study provides support at a high confidence level for the preventive histamine control associated with precooking. This study was conducted with tuna deliberately allowed to spoil to induce high concentrations of histamine and histamine-forming capacity and to fail standard organoleptic evaluations, and the critical limits for precooking were validated. Thus, these limits can be used in a hazard analysis critical control point plan in which precooking is identified as a critical control point. PMID- 29474148 TI - Quantitative Risk Assessment of Hemolytic Uremic Syndrome Associated with Consumption of Bulk Milk Sold Directly from Producer to Consumer in South Africa. AB - This study was conducted to estimate the hemolytic uremic syndrome (HUS) risk associated with consumption of producer-distributor bulk milk (PDBM) contaminated with Shiga toxin-producing Escherichia coli (STEC) in South Africa. Data were obtained from recently completed studies in South Africa taking into account prior collected prevalence data of STEC in raw and pasteurized PDBM and survey information from producer-distributor outlets and households. Inputs for the models were complemented with data from published and unpublished literature. A probabilistic exposure model was developed with Monte Carlo simulation in Excel add-in software using @Risk software. Hazard characterization was based on an exponential dose-response model to calculate the probability of illness from STEC infection in individuals 5 years and younger and individuals older than 5 years. The estimated mean STEC level was 0.12 CFU/mL (95% confidence interval [CI]: 0 to 1.2; sigma = 0.34) for raw PDBM and 0.08 CFU/mL (95% CI: 0 to 1; sigma = 0.27) for pasteurized PDBM. A higher risk of HUS cases per year was recorded in raw than in pasteurized PDBM and also in individuals younger than 5 years of age. For every 100,000 servings consumed, the expected median numbers of HUS cases per year from raw PDBM were 52 for 5 years and younger and 3.2 for older than 5 years. The median numbers of cases per year for pasteurized PDBM were 47 for 5 years and younger and 2.9 for older than 5 years. Sensitivity analysis revealed that serving volume and time taken to sell PDBM at producer-distributor outlets were the factors with the greatest impact on probability of illness. The models developed in this study are an example of risk assessments for milk produced and marketed from similar scenarios across the globe. PMID- 29474149 TI - Fruit Flies as Potential Vectors of Foodborne Illness. AB - Fruit flies are a familiar sight in many food service facilities. Although they have been long considered as "nuisance pests," some of their typical daily activities suggest they may pose a potential public health threat. The aim of this study was to provide evidence of the ability of small flies to transfer bacteria from a contaminated source, food, or waste to surfaces or ready-to-eat food. Laboratory experiments were conducted by using purpose-built fly enclosures to assess the bacterial transfer capability of fruit flies. Drosophila repleta were capable of transferring Escherichia coli O157:H7, Salmonella Saint Paul, and Listeria innocua from an inoculated food source to the surface of laboratory enclosures. In addition, using an inoculated doughnut and noncontaminated lettuce and doughnut surfaces, fly-mediated cross-contamination of ready-to-eat food was demonstrated. Fruit flies were shown to be capable of accumulating approximately 2.9 * 103 log CFU of E. coli per fly within 2 h of exposure to a contaminated food source. These levels of bacteria did not decrease over an observation period of 48 h. Scanning electron micrographs were taken of bacteria associated with fly food and contact body parts and hairs during a selection of these experiments. These data, coupled with the feeding and breeding behavior of fruit flies in unsanitary areas of the kitchen and their propensity to land and rest on food preparation surfaces and equipment, indicate a possible role for fruit flies in the spread of foodborne pathogens. PMID- 29474150 TI - Inhibition of Clostridium perfringens Growth during Extended Cooling of Cooked Uncured Roast Turkey and Roast Beef Using a Concentrated Buffered Vinegar Product and a Buffered Vinegar Product. AB - This research was conducted to evaluate the effectiveness of a concentrated buffered vinegar product (CBV) and a simple buffered vinegar product (BV) for controlling Clostridium perfringens outgrowth during extended cooling times of ready-to-eat roast turkey and roast beef. Whole turkey breasts and beef inside rounds were injected with a typical brine and then ground and mixed with CBV (0.0, 2.01, 2.70, and 3.30% [w/w]) or BV (0.0, 1.75, 2.25, and 3.75% [w/w]) and a three-strain C. perfringens spore cocktail to a detectable level of ca. 2 to 3 log CFU/g. The meat was divided into 10-g portions, vacuum packaged, and stored frozen until tested. The turkey and beef were cooked in a programmable water bath to 71.6 degrees C (160.8 degrees F) in 5 h and to 57.2 degrees C (135 degrees F) in 6 h, respectively. The cooked turkey and beef were then cooled exponentially from 48.9 to 12.8 degrees C (120 and 55 degrees F) in 6, 9, 12, 15, and 18 h for the five cooling treatments. The cooling continued until the temperature reached 4.4 degrees C (40 degrees F). C. perfringens counts were determined at 54.4 degrees C (130 degrees F) and 4.4 degrees C. CBV at 2.01% effectively limited C. perfringens growth in turkey to <=1 log CFU/g with up to a 9-h cooling treatment, and 2.70 and 3.30% solutions were effective with up to the 18-h cooling treatment. BV had an inhibitory effect on C. perfringens outgrowth in beef but did not limit growth to <=1 log CFU/g at any concentration tested for any of the cooling treatments. PMID- 29474151 TI - Assessment of Microbiological Safety and Quality of Marinades Used To Treat Beef and That Were Collected over a 12-Month Period from Specialty Retailers Near Raleigh, North Carolina. AB - In total, 115 marinade samples (58 fresh marinades and 57 spent marinades) were collected over 12 months from specialty retailers (four individual stores) near Raleigh, NC. These marinades were screened for total mesophilic aerobic plate count (M-APC), total psychrotrophic aerobic plate count (P-APC), and Enterobacteriaceae. These marinades were also screened for the seven regulated serogroups of Shiga toxin-producing Escherichia coli. Stores A and B used immersion to marinade raw beef cuts, whereas stores C-1 and C-2 used vacuum tumbling. In general, marinade temperatures at the stores ranged from 1.8 to 6.6 degrees C, and beef cuts were marinated from a few minutes to up to 3 days. Regardless of the process used to marinade meat, levels of M-APC and P-APC in fresh marinades ranged from 3.4 to 4.7 and 1.4 to 1.8 log CFU/mL, respectively, whereas Enterobacteriaceae were not detected in any fresh marinades, even after enrichment. However, levels of M-APC, P-APC, and Enterobacteriaceae in spent marinades collected from stores C-1 and C-2 (ca. 3.6 to 7.1 log CFU/mL) were significantly higher ( P < 0.05) compared with levels of these same types of bacteria enumerated from spent marinades collected at stores A and B (ca. <=0.7 to 4.9 log CFU/mL). None of the 115 marinade samples tested positive for Shiga toxin-producing E. coli by using a BAX system real-time PCR assay. No significant ( P > 0.05) association was observed between microbial levels (i.e., M-APC, P APC, and Enterobacteriaceae) and the temperature or duration of the marination process. Levels of M-APC, P-APC, and Enterobacteriaceae in spent marinades were significantly affected by the marination method ( P < 0.05), with levels, in general, being higher in marinades used for tumbling. Thus, retailers must continue to keep marinade solutions and meat at a safe temperature (i.e., <=4 degrees C) and to properly and frequently sanitize the equipment and environment in both the processing area and deli case. PMID- 29474152 TI - A Novel Method for Predicting Anisakid Nematode Infection of Atlantic Cod Using Rough Set Theory. AB - Atlantic cod ( Gadus morhua L.) is one of the most important fish species in the fisheries industries of many countries; however, these fish are often infected with parasites. The detection of pathogenic larval nematodes is usually performed in fish processing facilities by visual examination using candling or by digesting muscles in artificial digestive juices, but these methods are both time and labor intensive. This article presents an innovative approach to the analysis of cod parasites from both the Atlantic and Baltic Sea areas through the application of rough set theory, one of the methods of artificial intelligence, for the prediction of food safety in a food production chain. The parasitological examinations were performed focusing on nematode larvae pathogenic to humans, e.g., Anisakis simplex, Contracaecum osculatum, and Pseudoterranova decipiens. The analysis allowed identification of protocols with which it is possible to make preliminary estimates of the quantity and quality of parasites found in cod catches before detailed analyses are performed. The results indicate that the method used can be an effective analytical tool for these types of data. To achieve this goal, a database is needed that contains the patterns intensity of parasite infections and the conditions of commercial fish species in different localities in their distributions. PMID- 29474153 TI - Consumers' Use of Personal Electronic Devices in the Kitchen. AB - Smartphones, tablets, and other personal electronic devices have become ubiquitous in Americans' daily lives. These devices are used by people throughout the day, including while preparing food. For example, a device may be used to look at recipes and therefore be touched multiple times during food preparation. Previous research has indicated that cell phones can harbor bacteria, including opportunistic human pathogens such as Staphylococcus and Klebsiella spp. This investigation was conducted with data from the 2016 Food Safety Survey (FSS) and from subsequent focus groups to determine the frequency with which consumers use personal electronic devices in the kitchen while preparing food, the types of devices used, and hand washing behaviors after handling these devices. The 2016 FSS is the seventh wave of a repeated cross-sectional survey conducted by the U.S. Food and Drug Administration in collaboration with the U.S. Department of Agriculture. The goal of the FSS is to evaluate U.S. adult consumer attitudes, behaviors, and knowledge about food safety. The FSS included 4,169 adults that were contacted using a dual-frame (land line and cell phone interviews) random digit-dial sampling process. The personal electronics module was the first of three food safety topics discussed by each of eight consumer focus groups, which were convened in four U.S. cities in fall 2016. Results from the 2016 FSS revealed that of those individuals who use personal electronic devices while cooking, only about one third reported washing hands after touching the device and before continuing cooking. This proportion is significantly lower than that for self-reported hand washing behaviors after touching risky food products such as raw eggs, meat, chicken, or fish. Results from the focus groups highlight the varied usage of these devices during food preparation and the related strategies consumers are using to incorporate personal electric devices into their cooking routines. PMID- 29474154 TI - The choice of facilitators in medical tourism. AB - The study identified which of the four facilitators (themselves, agents, insurers, or doctors) consumers are most likely to use when they travel for various medical procedures. A survey conducted between 2011 and 2014 yielded 964 responses. The multinomial logistic regression results showed that being 51-64 years old was positively related to going on their own or using agents to arrange for knee replacements. Having a high school education or less was positively linked to using both agents and insurers to facilitate knee replacements, whereas having a bachelor's degree was negatively associated with going on their own for stem cell therapy. PMID- 29474155 TI - A Multiplexed Mass Spectrometry-Based Assay for Robust Quantification of Phosphosignaling in Response to DNA Damage. AB - A lack of analytically robust and multiplexed assays has hampered studies of the large, branched phosphosignaling network responsive to DNA damage. To address this need, we developed and fully analytically characterized a 62-plex assay quantifying protein expression and post-translational modification (phosphorylation and ubiquitination) after induction of DNA damage. The linear range was over 3 orders of magnitude, the median inter-assay variability was 10% CV and the vast majority (~85%) of assays were stable after extended storage. The multiplexed assay was applied in proof-of-principle studies to quantify signaling after exposure to genotoxic stress (ionizing radiation and 4-nitroquinoline 1 oxide) in immortalized cell lines and primary human cells. The effects of genomic variants and pharmacologic kinase inhibition (ATM/ATR) were profiled using the assay. This study demonstrates the utility of a quantitative multiplexed assay for studying cellular signaling dynamics, and the potential application to studies on inter-individual variation in the radiation response. PMID- 29474156 TI - Ataxia-Telangiectasia Mutated (ATM) Kinase Regulates eNOS Expression and Modulates Radiosensitivity in Endothelial Cells Exposed to Ionizing Radiation. AB - Endothelial nitric oxide synthase (eNOS), a constitutive enzyme expressed in vascular endothelial cells, is the main source of nitric oxide (NO), which plays key roles in diverse biological functions, including regulation of vascular tone. Exposure to radiation has been known to generate nitric oxide from eNOS; however, the precise mechanism of its generation and function is not known. The goal of this study was to determine the involvement of radiation-induced DNA damage response (DDR) on eNOS transcription and its effect on cell survival after irradiation. Irradiated bovine aortic endothelial cells showed increased eNOS transcription and NO generation through upregulation of ataxia-telangiectasia mutated (ATM) kinase. Radiation exposure induced NO inhibited cell death, as well as induced cellular senescence postirradiation. This study established that radiation-induced DDR uses ATM kinase to upregulate eNOS transcription and NO generation, leading to cellular senescence, which may play a critical role in radiation-mediated cardiovascular injury. PMID- 29474157 TI - Raman Spectroscopic Signatures Reveal Distinct Biochemical and Temporal Changes in Irradiated Human Breast Adenocarcinoma Xenografts. AB - Radiation therapy plays a crucial role in the management of breast cancer. However, current standards of care have yet to accommodate patient-specific radiation sensitivity. Raman spectroscopy is promising for applications in radiobiological studies and as a technique for personalized radiation oncology, since it can detect spectral changes in irradiated tissues. In this study, we used established Raman spectroscopic approaches to investigate the biochemical nature and temporal evolution of spectral changes in human breast adenocarcinoma xenografts after in vivo irradiation. Spectral alterations related to cell cycle variations with radiation dose were identified for tumors treated using a range of single-fraction ionizing radiation doses. Additional dose-dependent spectral changes linked to specific proteins, nucleic acids and lipids were also identified in irradiated tumors with a clear temporal evolution of the expression of these signatures. This study reveals distinct shifts in Raman spectra after in vivo irradiation of human breast adenocarcinoma xenografts, emphasizing the significance of Raman spectroscopy for assessing tumor response during radiation therapy. PMID- 29474158 TI - Soluble Expression in Escherichia coli of a Single-Domain Antibody-Tumor Necrosis Factor alpha Fusion Protein Specific for Epidermal Growth Factor Receptor. AB - Tumor-targeted antibody-cytokine fusion proteins, called immunocytokines, are expected to be a useful platform for the development of effective antitumor therapeutic agents; however, their design and cost-efficient production remain as challenges. In this study, we constructed an antibody-cytokine fusion protein (Ia1-TNFalpha) comprising the single-domain antibody Ia1, which targets epidermal growth factor receptor (EGFR) overexpressed in epithelial tumors and a tumor necrosis factor alpha (TNFalpha) domain, which has antitumor activity. Ia1 TNFalpha was produced in a soluble form by using an Escherichia coli expression system, and after affinity purification of the culture supernatant, an yield of ~2 mg/L of cell culture was obtained. Gel filtration analysis showed that Ia1 TNFalpha existed predominantly as a trimer, which is consistent with the multimerization state of TNFalpha. Ia1-TNFalpha exhibited approximately 7-fold lower TNFalpha biological activity than that of TNFalpha itself. Flow cytometric analysis revealed that Ia1-TNFalpha specifically bound to EGFR-expressing tumor cells and that its binding activity was higher than that of monovalent Ia1, suggesting that the fusion protein bound to the tumor cells multivalently. Altogether, these results show that fusion of TNFalpha with a single-domain antibody could be a cost-efficient means of producing antitumor therapeutic agents. PMID- 29474159 TI - Detecting Receptor Tyrosine Kinase ROR1 Using a Developed Anti-ROR1 Polyclonal Antibody. AB - Receptor tyrosine kinase ROR1 has been introduced as an interesting prognostic cancer marker in histopathology. The aim of this study was to produce a polyclonal antibody (PAb) against recombinant human ROR1 protein to be used as a tool for investigation of ROR1 expression in human cancer tissue blocks. The extracellular part of human ROR1 recombinant protein was expressed using pET 28b(+) plasmid in Escherichia coli Bl21(DE3) host. The recombinant ROR1, as a candidate immunogen, was purified and injected to a New Zealand rabbit. Followed by raising the titration of antibody, polyclonal anti-ROR1 antibody was purified through affinity chromatography column. After determining the purity of PAb anti ROR1, its specific reactivity was assessed through various assessments. Flow cytometry analysis showed that PAb anti-ROR1 specifically recognizes ROR1 molecule in a number of positive and negative cell lines. Results obtained from detection of ROR1 in paraffin-embedded breast adenocarcinoma tissue blocks (n = 11) also demonstrated that PAb anti-ROR1 can effectively be used in immunohistochemistry. In conclusion, the developed anti-ROR1 PAb can be used as a tool for determining the prognostic value of ROR1 in histopathology of cancer tissues. PMID- 29474160 TI - Generating a Battery of Monoclonal Antibodies Against Firefly Luciferase for Dot Blot Analysis, Western Blot Analysis, and Immunostaining of Cells in Culture and Paraffin Sections. AB - Firefly luciferase (FLuc) is commonly used as a reporter gene PpyLuc1 in bioanalytical assays. We have produced five mouse-derived monoclonal antibodies (mAbs) that recognize FLuc. The mAbs, DSHB-LUC-2, DSHB-LUC-3, DSHB-LUC-9, DSHB LUC-16, and DSHB-LUC-24, were generated by immunizing mice with purified 6xHIS tagged FLuc (6xHis-FLuc) in suspension with an adjuvant. All five were validated by dot blots. Four of the mAbs provided strong signals in western blot analysis, and one a weak signal. All five were validated for immunostaining in fixed cell culture. Only one stained cells embedded in paraffin. The five mAbs are available at cost through the Developmental Studies Hybridoma Bank (DSHB), a nonprofit National Resource created by the National Institutes of Health. PMID- 29474161 TI - Anti-Semaphorin3Fc Monoclonal Antibody. PMID- 29474162 TI - Synergistic Cytotoxic Effect on Gastric Cancer Cells of an Immunotoxin Cocktail in Which Antibodies Recognize Different Epitopes on CDH17. AB - Cadherin-17 (CDH17) is highly expressed in gastric cancer and is thus considered to be a good target for antibody therapy. CDH17 is classified as a nonclassical cadherin, in that it is composed of seven extracellular cadherin domains. We generated anti-CDH17 monoclonal antibodies (mAbs) which recognize the extracellular domain of CDH17. Competitive assay using AGS, a gastric cancer cell line, cells revealed that five selected anti-CDH17 mAbs recognize different epitopes on CDH17. As AGS cells were shown to exhibit broad expression pattern of CDH17 by flow cytometry, we separated three clones with a low (10,000/cell), medium (50,000/cell), and high (200,000/cell) expression level, designating them as AGSlow, AGSmed, and AGShigh, respectively. The mAbs, coupled with saporin, exhibited effective cytotoxicity to AGShigh, but poor cytotoxicity to AGSlow. By contrast, the immunotoxin cocktail using the three clones D2101, D2005, and D2008, which recognize different epitopes, exhibited efficient cytotoxicity, even to the AGSlow group. The effect of the immunotoxin cocktail is synergistic, as the combination index was demonstrated to be below 1.0, as calculated by the method of Chou and Talalay using CalcuSyn software. These results suggest that the immunotoxin cocktail targeted to multiple epitopes has synergistic effects on low expression level cells, which expand the applicable range of immunotoxin therapy for cancer. PMID- 29474163 TI - Play Ball! PMID- 29474165 TI - Celebrating the Advancement of Science in Sports Medicine: A 10-Year Collaboration Between Sports Health and the AMSSM. PMID- 29474166 TI - Preface. PMID- 29474167 TI - Editorial: Current Strategies for Drug Discovery Targeting Neurological Autoimmune Diseases. PMID- 29474168 TI - Editorial: Unmet Needs in Modern Psychiatry. PMID- 29474169 TI - Conference Report: "Serving Society through Science Policy". PMID- 29474170 TI - Conference Report: 9th Clinical Trials on Alzheimer's Disease (CTAD). PMID- 29474172 TI - Haploinsufficiency of Trp53 dramatically extends the lifespan of Sirt6-deficient mice. AB - Mammalian sirtuin 6 (Sirt6) is a conserved NAD+-dependent deacylase and mono-ADP ribosylase that is known to be involved in DNA damage repair, metabolic homeostasis, inflammation, tumorigenesis, and aging. Loss of Sirt6 in mice results in accelerated aging and premature death within a month. Here, we show that haploinsufficiency (i.e., heterozygous deletion) of Trp53 dramatically extends the lifespan of both female and male Sirt6-deficient mice. Haploinsufficiency of Trp53 in Sirt6-deficient mice rescues several age-related phenotypes of Sirt6-deficient mice, including reduced body size and weight, lordokyphosis, colitis, premature senescence, apoptosis, and bone marrow stem cell decline. Mechanistically, SIRT6 deacetylates p53 at lysine 381 to negatively regulate the stability and activity of p53. These findings establish that elevated p53 activity contributes significantly to accelerated aging in Sirt6 deficient mice. Our study demonstrates that p53 is a substrate of SIRT6, and highlights the importance of SIRT6-p53 axis in the regulation of aging. PMID- 29474173 TI - Possibility of Database Research as a Means of Pharmacovigilance in Japan Based on a Comparison with Sertraline Postmarketing Surveillance. AB - BACKGROUND: Many pharmacoepidemiologic studies using large-scale databases have recently been utilized to evaluate the safety and effectiveness of drugs in Western countries. In Japan, however, conventional methodology has been applied to postmarketing surveillance (PMS) to collect safety and effectiveness information on new drugs to meet regulatory requirements. Conventional PMS entails enormous costs and resources despite being an uncontrolled observational study method. This study is aimed at examining the possibility of database research as a more efficient pharmacovigilance approach by comparing a health care claims database and PMS with regard to the characteristics and safety profiles of sertraline-prescribed patients. METHODS: The characteristics of sertraline-prescribed patients recorded in a large-scale Japanese health insurance claims database developed by MinaCare Co. Ltd. were scanned and compared with the PMS results. We also explored the possibility of detecting signals indicative of adverse reactions based on the claims database by using sequence symmetry analysis. Diabetes mellitus, hyperlipidemia, and hyperthyroidism served as exploratory events, and their detection criteria for the claims database were reported by the Pharmaceuticals and Medical Devices Agency in Japan. RESULTS: Most of the characteristics of sertraline-prescribed patients in the claims database did not differ markedly from those in the PMS. There was no tendency for higher risks of the exploratory events after exposure to sertraline, and this was consistent with sertraline's known safety profile. CONCLUSIONS: Our results support the concept of using database research as a cost effective pharmacovigilance tool that is free of selection bias . Further investigation using database research is required to confirm our preliminary observations. PMID- 29474174 TI - The Economic Costs of Cardiovascular Disease, Diabetes Mellitus, and Associated Complications in South Asia: A Systematic Review. AB - BACKGROUND: More than 80% of global deaths caused by cardiovascular disease (CVD) and diabetes mellitus (DM) occur in developing countries. The burden of noncommunicable disease in South Asia is increasing rapidly. OBJECTIVES: To estimate the costs of CVD and the costs of DM to individuals and society in Afghanistan, Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan, and Sri Lanka. METHODS: We systematically searched six health and economic databases for studies identifying costs related to CVD or DM and their respective complications. Costs were extracted from included studies and converted to US $ for the price year 2015 to enable meaningful comparisons. RESULTS: Of the 71 articles suitable for full-text review, 29 studies met the inclusion criteria. Most were cost-of illness studies (n = 27) and were from the patient perspective (n = 23). Most collected data since 2000 (n = 23) and included data from India (n = 24). No studies included longitudinal costs at the patient level. Medical costs for routine management of CVD and DM were broadly similar. These costs escalate significantly once complications occur, which require treatment, particularly for stroke, major coronary events, and amputations. Costs are mainly borne by the individual and family. Some included studies modeled rapidly rising future costs. Most studies included had methodological weaknesses. CONCLUSIONS: Marked increases in costs have been identified when complications of these chronic diseases occur, underlining the importance of secondary prevention approaches in disease management in South Asia. Higher quality studies, especially those that include longitudinal costs, are required to establish more robust cost estimates. PMID- 29474175 TI - Health Utility of Pregnant Women Living with HIV/AIDS: Prevention of Mother-to Child Transmission of HIV (PMTCT) Programs in Yunnan Province: A Cross-Sectional Study. AB - BACKGROUND: Health utility (HU) is essential to understanding the effects of HIV infection as a chronic disease. No HU data on pregnant women living with human immunodeficiency virus (HIV) in Yunnan Province are available. This study aims to construct a database on HU and explore factors associated with HU by pregnant women living with HIV/acquired immunodeficiency syndrome (AIDS) who were enrolled in the Prevention of mother-to-child transmission of HIV (PMTCT) programs in Yunnan Province. METHODS: A cross-sectional study was conducted in Yunnan Province on pregnant women living with HIV who were selected by convenience sampling. Sociodemographic, HIV-related, social support, and HU data were collected through face-to-face interviews. The European quality of life five dimensional three-level (EQ-5D-3L) questionnaire and the social support rate scale (SSRS) were applied. RESULTS: One hundred and one pregnant women (mean age of 30.4 +/- 5.1 years) participated in the survey. The mean EQ-5D index score and the EQ visual analogue scale (EQ-VAS) score of participants were 0.77 (95% confidence interval [CI] 0.74-0.79) and 75.77 (95% CI 75.00-80.00), respectively. The effect of social support on HU was maintained significant difference even after adjusting for such factors as education level, household income per year, and HIV disclosure, demonstrating a significant difference within EQ-5D index scores and EQ-VAS scores. CONCLUSIONS: Pregnant women living with HIV/AIDS who were enrolled in PMTCT programs reported the same level of HU as other patients living with HIV/AIDS. Integrating measurements of HU by using the EQ-5D-3L questionnaire could be helpful for economic evaluation of the PMTCT program. This study also suggests a potential benefit of appropriate social support. PMID- 29474176 TI - Cost-Effectiveness of Warfarin Medication Therapy Adherence Clinic versus Usual Medical Clinic at Kuala Lumpur Hospital. AB - BACKGROUND: Systematic anticoagulation management clinic is recommended to manage patients on chronic warfarin therapy. In Malaysia, the service was introduced as warfarin medication therapy adherence clinic (WMTAC), which is managed by pharmacists with a physician advisory. OBJECTIVES: To assess the cost effectiveness of WMTAC in comparison with usual medical clinic (UMC), which is managed by medical officers in Kuala Lumpur Hospital, a tertiary referral hospital in Malaysia. METHODS: Data from a 6-month retrospective cohort study comparing the two clinics and the mean percentages of time in the therapeutic range for the patients were used to estimate the cost-effectiveness. The mean clinic costs were estimated using the time-motion study. A Markov model with a 6 monthly cycle was used to simulate lifetime cost-effectiveness from the perspective of the health care service provider. The base-case analysis assumed a cohort of patients with atrial fibrillation, 57 years of age with comorbid illnesses. The transition probabilities of these clinic outcomes were obtained from a literature search. Future costs and effectiveness were discounted by 3% to convert to present values. All costs were in Malaysian ringgit standardized for the year 2007. RESULTS: The mean 6-month treatment cost was lower for the WMTAC, which was significantly lower (P < 0.001). The UMC was found to be dominated by the WMTAC for both intermediate and lifetime analyses. The sensitivity analysis showed that clinic consultation costs had a major impact on the cost effectiveness analysis. CONCLUSIONS: WMTAC is a more cost-effective option than UMC in Kuala Lumpur Hospital. PMID- 29474177 TI - The Cost and Quality of Life of Malaysian Type 2 Diabetes Mellitus Patients with Chronic Kidney Disease and Anemia. AB - BACKGROUND: Anemia is common among patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) and an independent risk factor for renal disease progression. Health economic evidence is important in Malaysia and yet cost and quality-of-life (QOL) data are scarce. OBJECTIVES: To investigate prevalence, factors associated with anemia, and cost and QOL among T2DM patients with CKD. Here, we present the estimated 1-year cost and QOL related to anemia in this group. METHODS: A cross-sectional, observational study was performed at 20 government clinics. Treatment cost was calculated on the basis of resource utilization ascertained through data extracted from medical records and patient recall. QOL was elicited using the short form 36 health survey version 2 questionnaire. Propensity score matching was performed and costs and QOL were analyzed by anemia status and CKD stage. RESULTS: Data for 816 patients were obtained. The propensity score matching enabled a comparison of 257 patients with and without anemia. Annual treatment costs were significantly higher for patients with anemia (Ringgit Malaysia [RM] 4219 [US $983] vs. RM2705 [US $630]; P = 0.01). QOL scores were lower for patients with anemia but not statistically significant (physical component summary score: 44.8 vs. 46.2; P = 0.052; mental component summary score: 51.3 vs. 51.7; P = 0.562). Costs were higher and QOL lower among CKD stage 5 patients. CONCLUSIONS: This study was the first to examine anemia in this group of patients. Costs were significantly higher among anemic patients compared with nonanemic patients; patients with higher CKD stage 5 fared less well than did those in lower stages. This information suggests the need to increase detection, prevention, and early treatment of anemia when managing T2DM patients, particularly those with CKD. PMID- 29474178 TI - A Comparison of EQ-5D-3L Index Scores Using Malaysian, Singaporean, Thai, and UK Value Sets in Indonesian Cervical Cancer Patients. AB - OBJECTIVES: To gain insight into the most suitable foreign value set among Malaysian, Singaporean, Thai, and UK value sets for calculating the EuroQol five dimensional questionnaire index score (utility) among patients with cervical cancer in Indonesia. METHODS: Data from 87 patients with cervical cancer recruited from a referral hospital in Yogyakarta province, Indonesia, from an earlier study of health-related quality of life were used in this study. The differences among the utility scores derived from the four value sets were determined using the Friedman test. Performance of the psychometric properties of the four value sets versus visual analogue scale (VAS) was assessed. Intraclass correlation coefficients and Bland-Altman plots were used to test the agreement among the utility scores. Spearman rho correlation coefficients were used to assess convergent validity between utility scores and patients' sociodemographic and clinical characteristics. With respect to known-group validity, the Kruskal Wallis test was used to examine the differences in utility according to the stages of cancer. RESULTS: There was significant difference among utility scores derived from the four value sets, among which the Malaysian value set yielded higher utility than the other three value sets. Utility obtained from the Malaysian value set had more agreements with VAS than the other value sets versus VAS (intraclass correlation coefficients and Bland-Altman plot tests results). As for the validity, the four value sets showed equivalent psychometric properties as those that resulted from convergent and known-group validity tests. CONCLUSIONS: In the absence of an Indonesian value set, the Malaysian value set was more preferable to be used compared with the other value sets. Further studies on the development of an Indonesian value set need to be conducted. PMID- 29474180 TI - How Much Does Management of an Asthma-Related Event Cost in a Malaysian Suburban Hospital? AB - BACKGROUND: Patients with asthma need long-term management to maintain optimal control. In addition to routine maintenance, urgent visits and hospitalizations may be required, as these patients are prone to acute exacerbations. The aim of this study was to estimate the costs of maintenance and acute exacerbation managements in patients with asthma in a suburban public hospital in Malaysia. METHODS: An activity-based microcosting approach was applied to estimate the unit cost of events from the hospital's perspective. First, activities and resources that were involved in each cost center were identified and valued against a suitable form of unit. Thereafter, the mean cost of each resource per event was calculated by dividing the product of the quantity of the resource used and the unit cost of the resource by the number of events. The mean cost per event was the sum of the cost of resources for all cost centers involved. The costs were expressed in 2014 US dollars ($) and Malaysian Ringgit (RM). RESULTS: Data were collected from 15 maintenance, 20 acute exacerbation, and 50 hospitalization events. The mean (+/-SD) cost of maintenance management was $48.04 (+/-10.10); RM154.68 (+/-32.52). The cost of acute exacerbation management in the Emergency Department was $13.50 (+/-2.21), RM43.46 (+/-7.10); and in the medical ward, the cost was $552.13 (+/-303.41), RM1777.86 (+/-976.98), per hospitalization event. CONCLUSION: The microcosting of management of asthma-related events provides more accurate estimates that could be used in local economic studies. However, its possible limited generalizability to other types of health care settings in Malaysia needs to be kept in mind. PMID- 29474179 TI - Resource Use and Cost of Treating Human Papillomavirus-Related Lesions in Japanese Women. AB - BACKGROUND: Human papillomavirus (HPV) infection is established as a necessary causal factor in several pathologies including cervical cancer (CC), which recorded over 11,000 new cases in 2011 in Japan. Nevertheless, cost burden data of human papillomavirus-related diseases in Japan are lacking. OBJECTIVES: To evaluate resource use and costs in women with HPV-related lesions. METHODS: A retrospective study using insurance claims databases was performed to assess the annual medical cost for suspected cervical intra-epithelial neoplasia (CIN)/CC, genital warts (GWs), CIN (all grades), and CC. Information on the treatment of GWs was obtained from the Claims Database developed by Japan Medical Data Center Co., Ltd. Information on CIN and CC was obtained from the Evidence-Based Medicine provider database developed by Medical Data Vision Co., Ltd. Databases cover about 1% of the Japanese population. Total annual cost in Japanese yen (Y) per patient in 2011 was calculated on the basis of resource used and unit costs from Japan medical insurance tariffs. RESULTS: Average annual costs were as follows: GWs, Y34,424; suspected CIN/CC, Y6,240; CIN 1, Y17,484; CIN 2, Y46,583; CIN 3, Y166,227; and CC, Y474,756. CONCLUSIONS: To our knowledge, this is the first observational study to estimate the annual medical costs of HPV-related diseases in Japan using real-world data collected in routine clinical practice. It could provide help in estimating the economic burden of HPV-related lesions in Japanese women. PMID- 29474181 TI - Health-Related Quality of Life of Patients with HPV-Related Cancers in Indonesia. AB - BACKGROUND: Human papillomavirus (HPV)-related cancers are a serious concern in developing countries. Valid estimates of a country-specific health-related quality of life (HRQOL) for patients with HPV-related cancers provide a substantial tool in determining the burden of the disease. OBJECTIVES: To investigate the HRQOL of patients with HPV-related cancers in Indonesia. METHODS: The HRQOL of patients with HPV-related cancers (cervical, uterine, nasopharyngeal, head and neck, and anogenital cancer) was assessed using the EuroQol five-dimensional questionnaire (EQ-5D). Validity and reliability were assessed by means of construct validity and test-retest reliability methods, respectively. Subsequently, the EQ-5D utility index was calculated using the Thailand value set. RESULTS: The EQ-5D came out as a valid and reliable questionnaire for measuring the HRQOL of patients with HPV-related cancers in Indonesia. From a total of 520 patients diagnosed with HPV-related cancers, 404 patients were excluded because of not fulfilling the inclusion criteria, and so 116 patients finally participated in the study. The mean age of the patients was 47.5 +/- 12.03 years. Most of the patients were women (56.0%) and married (97.4%), and less than half of them had finished high school (32.7%). Moreover, the proportions of nasopharyngeal, cervical, head and neck, anogenital, and uterine cancers in the study population were 29.3%, 24.6%, 22.4%, 14.2%, and 9.5%, respectively. The average HRQOL of the patients with HPV-related cancers was 0.69 +/- 0.10, with the highest and lowest estimates applying to uterine cancer (0.84 +/- 0.29) and head and neck cancer (0.58 +/- 0.33), respectively. CONCLUSIONS: The HRQOL of patients with HPV-related cancers was found to be reduced to a certain extent in our study for Indonesia. PMID- 29474182 TI - Evaluation of Quality of Pharmacoeconomic Studies in Asia-Pacific Region and Identification of Influencing Variables. AB - OBJECTIVES: To assess the quality of pharmacoeconomic studies and identify different variables influencing the quality of these studies conducted in the Asia-Pacific (APAC) region. METHODS: A systematic literature search was performed with PubMed and Cochrane using different combinations of terms for cost effectiveness, cost-utility, and cost-minimization analyses. The Quality of Health Economic Studies (QHES) instrument was used for quality assessment of included studies. Logistic regression was performed to determine the association of factors with high-quality studies (QHES score >=75). RESULTS: Of 262 retrieved studies, 128 met the inclusion criteria. The mean QHES score was 67.4 +/- 1.35. The distribution of studies in each quality quartile was as follows: high (n = 59 [46.09%]), fair (n = 50 [39.06%]), and poor (n = 19 [14.83%]). Most of the high quality studies (n = 80 [62.5%]) were conducted in Japan and Australia. Only 11 high-quality studies (18.64%) were published in specialty journals and 4 (6.78%) in Asian journals. Primary authors who had advanced training in health economics were associated with a higher number of high-quality studies (n = 51 [86.44%]). Training of primary authors was significantly associated with high-quality studies (odds ratio 7.1; 95% confidence interval 2.9-19.23). Impact factor of journal, per-capita expenditure on health care, and out-of-pocket expense on health did not have a significant association with high-quality scores. CONCLUSIONS: High-quality pharmacoeconomic research is confined to a few countries of the APAC; it can be improved by advance training of authors in public health or health economics. Also, a greater interest of various stakeholders in funding the research and the introduction of specialty journals in the APAC are warranted. PMID- 29474183 TI - Health-Related Quality of Life and Functional Ability of Patients with Rheumatoid Arthritis: A Study from a Tertiary Care Hospital in Thailand. AB - OBJECTIVES: To assess the health-related quality of life and functional ability of patients with rheumatoid arthritis (RA) using the Thai EuroQol five dimensional questionnaire (EQ-5D) and the Thai Health Assessment Questionnaire (HAQ), and to analyze correlations between the scores from both questionnaires. METHODS: This cross-sectional study was conducted among 221 patients with RA aged 18 years or older at a tertiary care hospital in Thailand. Data collection methods included individual patient interviews and data gathering from medical records. The correlations between the EQ-5D and HAQ scores were analyzed using Spearman's rank correlation coefficients. RESULTS: Most patients were female (78.3%), aged 41 to 60 years (57.0%), having had RA for 12 to 60 months (43.0%), and being in an active disease state (60.6%). From the EQ-5D, most patients reported no problems in each dimension, except for mobility and pain/discomfort. For the HAQ, most patients reported no difficulty for almost all activities, except for arising. The medians (interquartile ranges) for the EQ-5D utility, EuroQol visual analogue scale (EQ VAS), and HAQ scores were 0.65 (0.55-0.73), 70 (50-80), and 0.25 (0.00-0.81), respectively. The Spearman's rank correlation coefficients were 0.42 for the EQ-5D utility and EQ VAS scores (P = 0.01), -0.65 for the EQ-5D utility and HAQ scores (P < 0.001), and -0.39 for the EQ VAS and HAQ scores (P < 0.001). CONCLUSIONS: The health-related quality of life and functional ability of most patients in our study were partially affected by the disease. The EQ-5D and HAQ scores significantly correlated at a moderate to strong level. PMID- 29474184 TI - A Review of Studies of Quality of Life for Chinese-Speaking Patients with Ischemic Heart Disease. AB - OBJECTIVES: To review published studies of the use of health-related quality-of life (HRQOL) instruments in patients with ischemic heart disease (IHD) in Chinese speaking countries/regions, namely, mainland China, Hong Kong, Taiwan, and Singapore. METHODS: Overlapping searching strategy was used for searching three electronic databases-Cochrane Library, MEDLINE, and Embase-from January 1, 1990, to September 30, 2015. After culling, the identified publications were analyzed according to the publication date, the location where the study was conducted, the disease being studied, and the nature of the study (i.e., whether it was a validation study or an application study). RESULTS: There were 109 publications identified for review, of which 15 studies (13.8%) were for validation of HRQOL instruments. Among these studies, most were conducted in China. There were 35 instruments applied and validated in the studies. The most commonly used instruments were the Short Form 36-Item Health Survey and the Seattle Angina Questionnaire. Overall, the number of studies using HRQOL instruments has been increasing in recent years. But there were only two disease-specific instruments validated in Chinese patients with IHD-one was a chronic disease-specific instrument (QLICD-GM) and the other an IHD-specific instrument (QLICD-CHD) validated only in limited sample sizes without data on patients with the three IHD subgroup diseases (angina, myocardial infarction, and heart failure). Three disease-specific instruments were validated in patients with IHD in Hong Kong. No instrument was validated in patients with IHD in Taiwan and Singapore. This showed a lack of adequately validated core IHD instruments in Chinese-speaking countries/regions. CONCLUSIONS: Considering the substantial negative impact of IHD from economical, clinical, and humanistic perspectives, psychometric evaluation of core IHD-specific instruments is still needed in patients with IHD and IHD subgroup diseases in Chinese-speaking countries/regions. PMID- 29474185 TI - Spin-flop and magnetodielectric reversal in Yb substituted GdMnO3. AB - The evolution of various spin structures in Yb doped GdMnO3 distorted orthorhombic perovskite system was investigated from their magnetic, dielectric and magnetodielectric characteristics. The Gd1-x Yb x MnO3 (0 ? x ? 0.15) revealed an enhanced magnetodielectric coupling when their magnetic structure is guided from ab to the bc-cycloidal spin structure upon Yb doping. The compounds exhibit magnetic field and temperature controlled spin-flop from c to a-axis. Additionally, magnetodielectric reversal is observed for the x = 0.1 sample which depends on both magnetic field and temperature. The resultant correlation between magnetic and electric orderings is discussed in the frame of symmetric and antisymmetric exchange interaction models. These findings provide further insight in understanding the magnetoelectric materials and importantly show a way to tune the magnetic and magnetodielectric properties towards better application potential. PMID- 29474186 TI - Local Bi-O bonds correlated with infrared emission properties in triply doped Gd2.95Yb0.02Bi0.02Er0.01Ga5O12 via temperature-dependent Raman spectra and x-ray absorption fine structure analysis. AB - A correlation function between the Raman intensities and the nearest-neighbor mean-square relative displacement (MSRD) [Formula: see text] of local Bi-O bonds is successfully established based on x-ray absorption fine structure (XAFS) and temperature-dependent Raman spectra in the temperature range 77-300 K in amorphous and crystalline Gd2.95Yb0.02Bi0.02Er0.01Ga5O12. The structural symmetries of Gd2.95Yb0.02Bi0.02Er0.01Ga5O12 are described by using [Formula: see text] of local Bi-O bonds. More importantly, Gd2.95Yb0.02Bi0.02Er0.01Ga5O12 is found to show excellent infrared (IR) emission properties due to changes in Bi-O bonds, and the IR emission intensities are found to depend on [Formula: see text], by using temperature-dependent photoluminescence spectroscopy. The maximum emission intensity at 1533 nm is obtained when [Formula: see text] [Formula: see text] at the lowest symmetry. This work shows that temperature-dependent Raman intensities can be used effectively to analyze the local covalent bonds around absorbing atoms as well as to study the emission properties of this visible-light activated IR luminophor. PMID- 29474187 TI - The elusive role of NbLi bound polaron energy in hopping charge transport in Fe: LiNbO3. AB - Charge transport due to small polarons hopping among defective (bound polarons) and regular (free polarons) sites is shown to depend in a non-trivial way on the value of the stabilization energy provided by the lattice distortion surrounding the charge carriers. This energy, normally not directly accessible for bound polarons using spectroscopic techniques, is determined here by a combination of experimental and numerical methods for the important case of small electron polarons bound to [Formula: see text] defects in the prototype ferroelectric oxide lithium niobate. Our findings provide an estimation of the [Formula: see text] polaron stabilization energy [Formula: see text] and demonstrate that in lithium niobate both free and bound polarons contribute to charge transport at room temperature, explaining the fast decay of the light-induced bound polaron population observed by transient absorption spectroscopy. PMID- 29474188 TI - Study of irradiation effect of Xe+22 and Kr+14 ions on structural properties of Zn nanotubes. AB - The paper presents the results of synthesis and directed modification of structural properties of Zn nanotubes by irradiating with heavy ions. The nanotubes were obtained by electrochemical deposition in pores of template polymer matrices. It was established using SEM, XRD and EDS methods where irradiation with Xe+22 and Kr+14 ions makes it possible to modify the crystal structure of nanotubes. As a result of irradiation with Xe+22 ions, partial destruction of nanotubes is observed, which indicates an increase in the number of defects in the structure and a decrease in strength properties. Change in the crystal structure parameters is observed when irradiation with Kr+14 ions with fluence below 5 * 1011 ion cm-2. That indicates the possibility of using Kr+14 ions for directional modification of nanostructures, while irradiation with Xe+22 ions leads to amorphization and destruction of nanotubes. PMID- 29474189 TI - Characteristic of EBT-XD and EBT3 radiochromic film dosimetry for photon and proton beams. AB - Recently, a new type of radiochromic film, the EBT-XD film, has been introduced for high dose radiotherapy. The EBT-XD film contains the same structure as the EBT3 film but has a slightly different composition and a thinner active layer. This study benchmarks the EBT-XD against EBT3 film for 6 MV and 10 MV photon beams, as well as for 97.4 MeV and 148.2 MeV proton beams and 15-100 kV x-rays. Dosimetric and film reading characteristics, such as post irradiation darkening, film orientation effect, lateral response artifact (LRA), film sensitivity, energy and beam quality dependency were investigated. Furthermore, quenching effects in the Bragg peak were investigated for a single proton beam energy for both film types, in addition measurements were performed in a spread-out Bragg peak. EBT-XD films showed the same characteristic on film darkening as EBT3. The effects between portrait and landscape orientation were reduced by 3.1% (in pixel value) for EBT-XD compared to EBT3 at a dose of 2000 cGy. The LRA is reduced for EBT-XD films for all investigated dose ranges. The sensitivity of EBT-XD films is superior to EBT3 for doses higher than 500 cGy. In addition, EBT-XD showed a similar dosimetric response for photon and proton irradiation with low energy and beam quality dependency. A quenching effect of 10% was found for both film types. The slight decrease in the thickness of the active layer and different composition configuration of EBT-XD resulted in a reduced film orientation effect and LRA, as well as a sensitivity increase in high-dose regions for both photon and proton beams. Overall, the EBT-XD film improved regarding film reading characteristics and showed advantages in the high-dose region for photon and proton beams. PMID- 29474190 TI - Tunable dynamic moduli of magnetic elastomers: from characterization by x-ray micro-computed tomography to mesoscopic modeling. AB - Ferrogels and magnetorheological elastomers are composite materials obtained by embedding magnetic particles of mesoscopic size in a crosslinked polymeric matrix. They combine the reversible elastic deformability of polymeric materials with the high responsivity of ferrofluids to external magnetic fields. These materials stand out, for example, for significant magnetostriction as well as a pronounced increase of the elastic moduli in the presence of external magnetic fields. By means of x-ray micro-computed tomography, the position and size of each magnetic particle can be measured with a high degree of accuracy. We here use data extracted from real magnetoelastic samples as input for coarse-grained dipole-spring modeling and calculations to investigate internal restructuring, stiffening, and changes in the normal modes spectrum. More precisely, we assign to each particle a dipole moment proportional to its volume and set a randomized network of springs between them that mimics the behavior of the polymeric elastic matrix. Extending our previously developed methods, we compute the resulting structural changes in the systems as well as the frequency-dependent elastic moduli when magnetic interactions are turned on. Particularly, with increasing magnetization, we observe the formation of chain-like aggregates. Interestingly, the static elastic moduli can first show a slight decrease with growing amplitude of the magnetic interactions, before a pronounced increase appears upon the chain formation. The change of the dynamic moduli with increasing magnetization depends on the frequency and can even feature nonmonotonic behavior. Overall, we demonstrate how theory and experiments can complement each other to learn more about the dynamic behavior of this interesting class of materials. PMID- 29474191 TI - A Unique Case of Dermatofibrosarcoma Protuberans With Melanocytic Differentiation. PMID- 29474192 TI - Characterization of Chemical Constituents of Human Sweat: A Study Based on Indian Population. AB - There is a strong evidence in the literature that human odor is unique to an individual; therefore, the focus of this study was to strengthen this evidence through the testing of sweat samples on unrelated individuals with the same ethnicity. Sweat samples were collected from 42 unrelated Indian males and females residing in the same city to determine the chemical constituents in human sweat. The volatile compounds of sweat were subsequently analyzed and identified using gas chromatography-mass spectrometry, and a National Institute of Standards and Technology library was used for individual profiling. A total of 78 compounds were identified in human sweat tested with 22 compounds found to be unique to the individual (frequency of occurrence one). A scent profile, or "chexmotype," unique to the sweat of each individual was obtained. This is the first extensive study on an Indian population with 36 new compounds detected in human sweat. PMID- 29474193 TI - Acute Onset of Abdominal Muscle Dyskinesia ('Belly Dancer Syndrome') From Quetiapine Exposure: A Case Report. AB - Belly dancer syndrome, also called belly dance syndrome or belly dancer dyskinesia, is a kind of abdominal dyskinesia with painful sensation. Its etiology is still unclear and there are few studies reporting its association with antipsychotics. Quetiapine is an atypical antipsychotic that causes lower risk of extrapyramidal symptoms than typical antipsychotics. Here, we presented the first case of belly dancer syndrome in a 71-year-old woman with major depressive disorder after short-term use of quetiapine. PMID- 29474194 TI - Dextromethorphan/Quinidine in Migraine Prophylaxis: An Open-label Observational Clinical Study. AB - OBJECTIVE: This study aimed to assess potential efficacy and safety of dextromethorphan/quinidine (DMQ) in prophylactic treatment of migraine in patients with multiple sclerosis (MS) with superimposed pseudobulbar affect (PBA). METHODS: Multiple sclerosis patients with superimposed PBA and comorbid migraine were enrolled into this open-label observational study at the University of Southern California Comprehensive MS Center. The baseline characteristics included, among other data, frequency and severity of acute migraine attacks and use of migraine relievers. The DMQ was used exclusively per its primary indication - PBA symptoms control - 20/10 mg orally, twice a day for the mean of 4.5 months (the shortest exposure registered was 3 months and the longest, 6 months). To determine whether treatment caused an effect on migraine frequency and severity, the baseline and posttreatment values were compared using nonparametric sign test. RESULTS: Thirty-three MS subjects with PBA, who also suffered from migraines, were identified. Twenty-nine subjects had improvement in headache frequency, 4 had no change, and none had worsening (P < 0.001 as compared with the baseline). Twenty-eight subjects had improvement in headache severity, 5 had no change, and none had worsening (P < 0.001). CONCLUSIONS: Our pilot study results provide evidence that DMQ shows promise as a candidate for larger clinical studies evaluating its efficacy for the prevention of migraine headaches. PMID- 29474195 TI - Management of Antiretrovirals in Critically Ill Patients: Great Progress But Potential Pitfalls. PMID- 29474196 TI - Adenocarcinoma Prostate With Neuroendocrine Differentiation: Potential Utility of 18F-FDG PET/CT and 68Ga-DOTANOC PET/CT Over 68Ga-PSMA PET/CT. AB - Ga-PSMA PET/CT is the upcoming imaging modality for staging, restaging and response assessment of prostate cancer. However, due to neuroendocrine differentiation in some of patients with prostate cancer, they express somatostatin receptors instead of prostate specific membrane antigen. This can be exploited and other modalities like Ga-DOTANOC PET/CT and F-FDG PET/CT should be used in such cases for guiding management. We hereby discuss a similar case of 67 year-old man of adenocarcinoma prostate with neuroendocrine differentiation, which shows the potential pitfall of Ga-PSMA PET/CT imaging and benefit of Ga DOTANOC PET/CT and F-FDG PET/CT in such cases. PMID- 29474197 TI - Measuring Surgical Skills in Simulation-based Training. PMID- 29474198 TI - High Prevalence of Antithyroid Antibodies in a New Zealand Cohort of Patients With Systemic Sclerosis. AB - BACKGROUND: Autoimmune thyroid disease affects 1% of the general population, and autoimmune thyroid antibodies are noted in up to 15%. OBJECTIVE: We hypothesized systemic sclerosis (SSc) is associated with higher prevalence of antithyroglobulin (anti-Tg) and anti-thyroid peroxidase (anti-TPO) antibodies) to justify monitoring of thyroid function for earlier detection and treatment. METHODS: Waikato Hospital SSc clinic patients were prospectively tested for thyroid function tests and antithyroid antibodies (ATAs). RESULTS: Of the 75 patients with SSc and 10 patients with SSc overlap syndrome (SOS) followed up in the SSc clinic, anti-Tg and anti-TPO were prospectively tested in 61 (70.6%) of the 85 patients. The cohort comprised 38 patients with limited cutaneous SSc (lcSSc), 15 with diffuse cutaneous SSc, and 8 with SOS.Anti-Tg and anti-TPO antibodies were found in 34.2% in lcSSc patients and 33.3% in diffuse cutaneous SSc patients, whereas in SOS they were found in 25% (Tg) and in 12.5% (TPO) of patients.At baseline, 10 patients (11.7%) had thyroid dysfunction: 8 (9.4%) with subclinical hypothyroidism and 1 each (1.2%) with subclinical hyperthyroidism and with clinical hyperthyroidism.After 18 months, 1 woman with lcSSc, positive for both ATAs, developed clinical hypothyroidism. CONCLUSIONS: There is a higher prevalence of ATAs in SSc and SOS compared with the general population. Screening these patients for ATAs is a reasonable measure. PMID- 29474199 TI - Optic Nerve Head and Macular Optical Coherence Tomography Measurements in Papilledema Compared With Pseudopapilledema. AB - BACKGROUND: To compare macular and optic nerve head optical coherence tomography (OCT) measurements in mild to moderate papilledema and pseudopapilledema. METHODS: One hundred nineteen eyes of 61 patients with mild to moderate papilledema, 84 eyes of 48 patients with pseudopapilledema, and 60 eyes of 60 healthy normal individuals were enrolled in this cross-sectional study. Using Spectralis SD-OCT, macular scans with macular ganglion cell-inner plexiform layer (GCIPL) and macular retinal nerve fiber layer (RNFL) segmentation were performed and divided into 2 regions (inner and outer, with a diameter of 3 and 6 mm, respectively); in addition, Bruch membrane opening (BMO) area and peripapillary RNFL thickness were obtained. RESULTS: BMO area was similar in papilledema (1.83 +/- 0.34 mm), pseudopapilledema (1.85 +/- 0.37 mm), and controls (1.85 +/- 0.32 mm). Average inner region macular GCIPL thickness in the papilledema, pseudopapilledema, and control groups was 87.2 +/- 14.4 MUm, 90.8 +/- 6.1 MUm, and 91.2 +/- 9.8 MUm, respectively (P > 0.05). Outer temporal region macular GCIPL was significantly thinner in the papilledema group compared with control group (P = 0.01). By contrast, outer inferior and outer nasal macular RNFL sectors were significantly thicker in the papilledema group compared with control groups (P = 0.01 and P < 0.01, respectively). Those measures were not different between pseudopapilledema and control eyes. CONCLUSIONS: In papilledema eyes, outer temporal region macular GCIPL thickness decreased and outer inferior and outer nasal macular RNFL sectors thickness increased compared with the control group. These changes were not observed in the pseudopapilledema group. PMID- 29474200 TI - Cerebellar Ataxia With Neuropathy and Vestibular Areflexia Syndrome Presenting With Neurotrophic Keratopathy. PMID- 29474201 TI - Mechanical Ventilation Induces Desensitization of Lung Axl Tyrosine Kinase Receptors. AB - BACKGROUND: Lower tidal volumes are increasingly used in acute respiratory distress syndrome, but mortality has changed little in the last 20 yr. Therefore, in addition to ventilator settings, it is important to target molecular mediators of injury. Sepsis and other inflammatory states increase circulating concentrations of Gas6, a ligand for the antiinflammatory receptor Axl, and of a soluble decoy form of Axl. We investigated the effects of lung stretch on Axl signaling. METHODS: We used a mouse model of early injury from high tidal volume and assessed the effects of inhibiting Axl on in vivo lung injury (using an antagonist R428, n = 4/group). We further determined the effects of stretch on Axl activation using in vitro lung endothelial cells. RESULTS: High tidal volume caused mild injury (compliance decreased 6%) as intended, and shedding of the Axl receptor (soluble Axl in bronchoalveolar fluid increased 77%). The Axl antagonist R428 blocked the principal downstream Axl target (suppressor of cytokine signaling 3 [SOCS3]) but did not worsen lung physiology or inflammation. Cyclic stretch in vitro caused Axl to become insensitive to activation by its agonist, Gas6. Finally, in vitro Axl responses were rescued by blocking stretch-activated calcium channels (using guanidinium chloride [GdCl3]), and the calcium ionophore ionomycin replicated the effect of stretch. CONCLUSIONS: These data suggest that lung endothelial cell overdistention activates ion channels, and the resultant influx of Ca inactivates Axl. Downstream inactivation of Axl by stretch was not anticipated; preventing this would be required to exploit Axl receptors in reducing lung injury. PMID- 29474202 TI - A decade-long clinical experience on the prophylactic use of activated prothrombin complex concentrate in acquired haemophilia A: a case series from a tertiary care centre. AB - : In acquired haemophilia A (AHA), risk for recurrent bleeding exists until the inhibitor is detectable. Thus, patients with persisting inhibitor may benefit from prophylaxis with activated prothrombin complex concentrate (aPCC). Potential thromboembolic complications and cost are also factors to consider. Today, no high level evidence or clear recommendations are available on aPCC prophylaxis in AHA. Recently, a small prospective study demonstrated a favourable outcome with short-term, daily administered aPCC infusion. Here we report a retrospective case series of 19 patients with AHA to demonstrate our practice on aPCC prophylaxis. In our practice, clinical bleeding tendency guided our decision on the initiation of aPCC prophylaxis. In patients with serious bleeding tendency, aPCC infusion was prolonged beyond bleeding resolution in a twice-weekly or thrice-weekly regimen. Serious bleeding phenotype included a single episode of life-threatening bleeding or recurrent, severe haemorrhages. Patients who did not present such events were treated on-demand. The preventive dose of aPCC was equal with the lowest effective therapeutic dose. Prophylaxis was continued until the inhibitor disappeared. Eleven patients received aPCC prophylaxis. In nine cases, prophylaxis lasted beyond two months. No severe bleeding developed spontaneously and no thromboembolic complication occurred in the median 16 weeks (interquartile range 9-34) duration of prophylaxis. Eight patients of the nonprophylaxis group did not present any severe haemorrhage. According to our experience, we consider prophylaxis with aPCC effective and well tolerated for patients with AHA and serious bleeding tendency, until the acquired inhibitor persists. PMID- 29474203 TI - Association of renin-angiotensin system genes polymorphisms and risk of premature ST elevation myocardial infarction in young Mexican population. AB - : The renin-angiotensin system plays an important role in the regulation of blood pressure and the development of coronary artery disease. The aim was to examine the association of the insertion deletion in the angiotensin-converting enzyme gene, M235T and T174M polymorphisms in the angiotensinogen gene with ST elevation acute myocardial infarction (STEAMI) in young Mexican population. We analyzed 242 unrelated patients with STEAMI 45 or less years of age, admitted to a cardiovascular intense care unit, and 242 individuals without STEAMI matched by age and sex, recruited from January 2006 and June 2013. The polymorphisms insertion deletion, M235T and T174M were determined in all participants by a polymerase chain-reaction-restriction fragment length polymorphism assay. There was a significant difference in the insertion deletion genotype distribution between two groups (P = 0.03) and a higher percentage of the T allele M235T polymorphism in the group of STEAMI patients (P = 0.02). The T174M polymorphism was not associated (P = 0.08). The insertion deletion and M235T polymorphisms, smoking, hypertension, familial history of cardiovascular disease and dyslipidemia were independent risk factors for STEAMI. Our results identified that the D allele from the insertion deletion and M235T but not T174M polymorphisms represent an independent risk factor for STEAMI in young Mexican population. PMID- 29474204 TI - Mean platelet volume and risk of thrombotic and bleeding complications in patients with Philadelphia chromosome negative myeloproliferative neoplasms. AB - : Philadelphia chromosome negative myeloproliferative neoplasms (MPNs) are associated with increased thrombosis and bleeding risk. Mean platelet volume (MPV) is associated with thrombosis in nonmalignant settings. This study evaluates the association between MPV and thrombosis and bleeding in MPN. Patients with MPN without prior thrombosis, nonhematologic malignancy or anticoagulant use were included in this retrospective analysis. The primary endpoint was arterial or venous thrombosis. The secondary endpoints were any bleeding and major bleeding. MPV was measured at diagnosis and during the index episode. A total of 135 MPN patients met the inclusion criteria. Over a median follow-up of 6.6 years, 23 patients (15.6%) experienced thrombosis. There was no difference in MPV at diagnosis (8.47 vs. 8.73 fl, P = 0.4) or during the index event between patients with or without thrombosis. Twelve patients (8.9%) had a bleeding event, whereas seven (5.2%) had major bleeding. MPV was significantly higher among patients with major bleeding, both at diagnosis (10.04 vs. 8.61, P = 0.005) and during the bleeding episode. There was no association after regression analysis of variables associated with MPV at diagnosis. MPV is not associated with thrombotic events in MPN. The study generates the hypothesis that MPV may be an indirect marker of bleeding in MPN. PMID- 29474205 TI - Perioperative management of a patient with Glanzmann thrombasthenia undergoing a coronary artery bypass graft surgery: a case report. AB - : We report herein the successful perioperative management of a 57-year-old man with a type I Glanzmann thrombasthenia undergoing coronary artery bypass graft surgery and right carotid endarterectomy. The patient suffered from several lesions in the three major coronary arteries and in the right carotid necessitating surgery. Prophylactic human leukocyte antigen (HLA)-matched platelets transfusions were continuous administrated before, and through the immediate perioperative period. Posttransfusion platelet recovery was monitored using flow cytometry to determine the percentage of circulating platelet expressing CD61 (beta3). No bleeding complications occurred during and following the procedure. The patient did not develop HLA antibodies or alphaIIbbeta3 antibodies. Thrombophilia screening revealed a heterozygous G20210A prothrombin gene mutation. The patient also suffered from an atrial fibrillation, necessitating anticoagulation therapy. During the hospital stay, a treatment with vitamin K antagonists for stroke prevention was initiated. The patient was discharged 8 days following surgery, and no further complications occurred during the 6 months follow-up. PMID- 29474206 TI - Dyadic differences in friendships of adolescents with chronic pain compared with pain-free peers. AB - A multisite cross-sectional study was conducted to examine dyadic friendship features between adolescents with chronic pain (ACP) and their friends compared with non-pain adolescent friendship dyads and the association of these friendship features with loneliness and depressive symptoms. Participants completed a battery of standardized measures to capture friendship features (friendship quality, closeness, and perceived social support from friends) and indices of social-emotional well-being. Sixty-one same sex friendship dyads (122 adolescents) participated; 30 friendship dyads included an adolescent with chronic pain and 52 dyads were female. Adolescents with chronic pain scored significantly higher on measures of loneliness and depressive symptoms compared with all other participants. Hierarchical Multiple Regression analysis revealed that friendship features predicted loneliness and depressive symptoms. Chronic pain predicted loneliness and depressive symptoms above and beyond friendship features. Actor Partner Interdependence Modeling found perceived social support from friends had differing associations on loneliness and depressive symptoms for dyads with a chronic pain member compared with pain-free control dyads. Friendship features were associated with loneliness and depressive symptoms for adolescents, but friendship features alone did not explain loneliness and depressive symptoms for ACP. Further research is needed to understand whether pain-related social support improves loneliness and depressive symptoms for ACP. Furthermore, a more nuanced understanding of loneliness in this population is warranted. Strategies to help ACP garner needed social support from friends are needed to decrease rates of loneliness to improve long-term outcomes. PMID- 29474207 TI - Health-related Fitness in Preschool Children with and without Motor Delays. AB - PURPOSE: School-age children with developmental coordination disorder (DCD) have poor health-related fitness (HRF), but little is known about when these deficits emerge. The purpose of this study was to determine if 4- and 5-yr-old children who meet the criteria for DCD exhibit poorer HRF compared with typically developing (TD) children, and if this relationship is mediated by vigorous physical activity (VPA) engagement. METHODS: Five hundred and ninety-two children participated (age, 5.0 +/- 0.6 yr) from the Coordination and Activity Tracking in CHildren study. Motor skills were assessed using the Movement Assessment Battery for Children-2, with groups defined as having DCD (<=5th percentile), at risk for DCD (6th-16th percentile), and TD (>16th percentile). Measures of body composition included body mass index, waist circumference, and body fat percentage. Musculoskeletal fitness assessments included standing long jump distance, as well as peak and mean power assessed using a 30-s Wingate protocol on a pediatric cycle ergometer. Time to exhaustion on a progressive, treadmill test was used to determine aerobic fitness. Flexibility and VPA were assessed using a sit-and-reach test and 7-d accelerometry, respectively. RESULTS: Children in the DCD group had the poorest musculoskeletal and aerobic fitness, whereas TD children had the highest. No differences in body composition among groups were found. Daily VPA was similar among groups and did not explain HRF differences. CONCLUSIONS: Preschool children with DCD have decreased anaerobic and aerobic fitness compared with TD children; however, VPA and body composition seem to be less affected by DCD in the early years. Early motor interventions may be able to improve fitness and reduce the risk of hypoactivity and obesity as children with DCD get older. PMID- 29474208 TI - Compliance of Adolescent Girls to Repeated Deployments of Wrist-Worn Accelerometers. AB - PURPOSE: This study aimed to determine the cross-sectional and cumulative compliance of adolescent girls to accelerometer wear at three deployment points and to identify variables associated with compliance. METHODS: Girls from 20 secondary schools were recruited: 10 schools were participating in the "Girls Active" intervention and 10 were control schools. Physical activity was measured using the GENEActiv accelerometer worn on the nondominant wrist 24 h.d for up to 7 d at baseline, 7 months, and 14 months. Demographic and anthropometric characteristics were recorded. RESULTS: Seven valid days (>=16 h) of accelerometer wear was obtained from 83%, 77%, and 68% of girls at baseline (n = 1734), 7 months (n = 1381), and 14 months (n = 1326), respectively. Sixty-eight percent provided 7 valid days for both baseline and 7 months, 59% for baseline and 14 months, and 52% for all three deployment points. Estimates of physical activity level from 3 d of measurement could be considered equivalent to a 7-d measure (i.e., they fell within a +/-5% equivalence zone). Cross sectionally, 3 valid days was obtained from at least 91% of girls; cumulatively, this was obtained from >=88% of girls across any two deployment points and 84% of girls across all three deployment points. When controlling for clustering at school level and other potential predictors, physical activity level, being South Asian, being in the intervention group, and prior compliance were positively associated with monitor wear. CONCLUSIONS: Compliance reduced across deployment points, with the reduction increasing as the deployment points got further apart. High prior compliance and high physical activity level were associated with the most additional wear time. PMID- 29474209 TI - Pulmonary phenotypes associated with genetic variation in telomere-related genes. AB - PURPOSE OF REVIEW: Genomic mutations in telomere-related genes have been recognized as a cause of familial forms of idiopathic pulmonary fibrosis (IPF). However, it has become increasingly clear that telomere syndromes and telomere shortening are associated with various types of pulmonary disease. Additionally, it was found that also single nucleotide polymorphisms (SNPs) in telomere-related genes are risk factors for the development of pulmonary disease. This review focuses on recent updates on pulmonary phenotypes associated with genetic variation in telomere-related genes. RECENT FINDINGS: Genomic mutations in seven telomere-related genes cause pulmonary disease. Pulmonary phenotypes associated with these mutations range from many forms of pulmonary fibrosis to emphysema and pulmonary vascular disease. Telomere-related mutations account for up to 10% of sporadic IPF, 25% of familial IPF, 10% of connective-tissue disease-associated interstitial lung disease, and 1% of COPD. Mixed disease forms have also been found. Furthermore, SNPs in TERT, TERC, OBFC1, and RTEL1, as well as short telomere length, have been associated with several pulmonary diseases. Treatment of pulmonary disease caused by telomere-related gene variation is currently based on disease diagnosis and not on the underlying cause. SUMMARY: Pulmonary phenotypes found in carriers of telomere-related gene mutations and SNPs are primarily pulmonary fibrosis, sometimes emphysema and rarely pulmonary vascular disease. Genotype-phenotype relations are weak, suggesting that environmental factors and genetic background of patients determine disease phenotypes to a large degree. A disease model is presented wherever genomic variation in telomere related genes cause specific pulmonary disease phenotypes whenever triggered by environmental exposure, comorbidity, or unknown factors. PMID- 29474211 TI - CDC's 6|18 Initiative: A Cross-Sector Approach to Translating Evidence Into Practice. AB - CONTEXT: As the US health care system continues to undergo dynamic change, the increased alignment between health care quality and payment has provided new opportunities for public health and health care sectors to work together. PROGRAM: The Centers for Disease Control and Prevention's 6|18 Initiative accelerates cross-sector collaboration between public health and health care purchasers, payers, and providers and highlights 6 high-burden conditions and 18 associated interventions with evidence of cost reduction/neutrality and improved health outcomes. This evidence can inform payment, utilization, and quality of prevention and control interventions. IMPLEMENTATION: The Centers for Disease Control and Prevention focused initially on public payer health insurance interventions for asthma control, unintended pregnancy prevention, and tobacco cessation. Nine state Medicaid and public health agency teams-in Colorado, Georgia, Louisiana, Massachusetts, Michigan, Minnesota, New York, Rhode Island, and South Carolina-participated in the initiative because they had previously prioritized the health condition(s) and specific intervention(s) and had secured state-level leadership support for state agency collaboration. The Centers for Disease Control and Prevention, the Centers for Medicare & Medicaid Services, the Center for Health Care Strategies, the Robert Wood Johnson Foundation, and other partners supported state implementation and dissemination of early lessons learned. EVALUATION: The Centers for Disease Control and Prevention conducted exploratory interviews to guide improvement of the 6|18 Initiative and to understand facilitators, barriers, and complementary roles played by each sector. Monthly technical assistance calls conducted with state teams documented collaborative activities between state Medicaid agencies and health departments and state processes to increase coverage and utilization. DISCUSSION: The 6|18 Initiative is strengthening partnerships between state health departments and Medicaid agencies and contributing to state progress in helping improve Medicaid coverage and utilization of effective prevention and control interventions. This initiative highlights early successes for others interested in strengthening collaboration between state agencies and between public and private sectors to improve payment, utilization, and quality of evidence-based interventions. PMID- 29474210 TI - The Potential for Proactive Housing Inspections to Inform Public Health Interventions. AB - Municipal housing inspection data can inform planning, targeting, and evaluating interventions aimed at reducing housing hazards (lead paint, mold, pests, etc) that may affect residents' health. However, the potential of these data to inform public health initiatives is underexplored. We determined whether home health hazards identified by city inspectors during proactive inspections of single family private rental housing are predicted by housing age, assessed value, or location in one of 26 geographic "inspector areas" in Rochester, New York. A comparison of linear mixed models, using housing inspector area as a random effect and assessment and construction year as fixed effects, shows that while a large proportion of variation (64%) in violations is due to housing stock, inspectors provide significant additional information about the presence of potential health hazards, particularly in the highest-risk housing stock. This suggests that inspector-generated housing hazard data may be valuable in designing public health interventions. PMID- 29474212 TI - A different perspective: anesthesia for extreme premature infants: is there an age limitation or how low should we go? AB - PURPOSE OF REVIEW: To put in perspective, the various challenges that faces pediatric anesthesiologists because of the recently lowered limits with regards to the viability of a fetus. Both medical and ethical considerations will be highlighted. RECENT FINDINGS: Issues related to: who should anesthetize these tiny babies; can we provide adequate and legal monitoring during the anesthetic; does these immature babies need hypnosis and amnesia and the moral/ethical implications associated with being involved with care of doubtful long-term outcome are reviewed. SUMMARY: There does currently not exist sufficient research data to provide any evidence-based guidelines for the anesthetic handling of extreme premature infants. Current practice relies on extrapolations from other patient groups and from attempting to preserve normal physiology. Thus, focused research initiatives within this specific field of anesthesia should be a priority. Furthermore, in-depth multiprofessional ethical discussions regarding long-term outcome of aggressive care of extremely premature babies are urgently needed, including the new concepts of disability-free survival and number-need-to suffer. PMID- 29474213 TI - The opioid epidemic and the current prevalence of substance use disorder in anesthesiologists. AB - PURPOSE OF REVIEW: There has been a substantial increase in prescription and illicit opioid abuse in the general population observed over the last two decades. Initially fueled by an influx of prescription opioid medications, the opioid epidemic now includes increasingly potent heroin and illicit fentanyl. Younger anesthesiologists, those currently in training or recent graduates, have come of age in a society where opioid abuse is much more prevalent. RECENT FINDINGS: The current prevalence of substance use disorder (SUD) in the physician population is slightly higher than in the general population and appears to be increasing. Although most anesthesiologists with SUD will abuse alcohol as their drug of choice, the incidence of opioid and nonopioid anesthetic agent abuse, especially propofol, is increasing. The incidence of SUD among the anesthesia resident population decreased somewhat during the 1990s but has been steadily increasing since the year 2000. SUMMARY: The increasing incidence of substance use disorder in anesthesia residents may reflect the significantly increased number of persons addicted to opioids and other drugs of abuse in the general population. Despite educational and surveillance programs put in place to prevent diversion, susceptible individuals with access are still abusing anesthetic agents. PMID- 29474214 TI - Chronic pain after hysterectomy. AB - PURPOSE OF REVIEW: Hysterectomy is a common surgical procedure with a low risk of major complications. However, some women experience long-lasting complications, including chronic postsurgical pain, which can have a negative impact on their quality of life. This review aims to present the recent literature on chronic pain following hysterectomy for benign indications. RECENT FINDINGS: Chronic pain following hysterectomy is reported in 10-50% of women. Risk factors include preoperative pelvic pain, pain elsewhere, acute postoperative pain, surgical procedure, and psychological factors such as anxiety and depression. The pain may be neuropathic in 5-50% of cases. SUMMARY: Chronic pain may occur after hysterectomy. Preoperative screening tools, including psychological screening for depression and anxiety, may identify women at risk of developing chronic postsurgical pain, and future studies should examine perioperative interventions aimed at preventing the development of chronic pain after hysterectomy. PMID- 29474215 TI - Occupational stress, burnout and personality in anesthesiologists. AB - PURPOSE OF REVIEW: There is a growing awareness of the problem of occupational stress and burnout among anesthesiologists. Occupational stress was found to be related to burnout, a process that is supposed to be moderated by personality. This article will discuss the topic of stress and burnout in relationship to anesthesiologists' personality based on recent literature. RECENT FINDINGS: Studies among anesthesiologists are in concordance with the broader body of literature on this topic. Personality consistently influences stress appraisal and coping and consequently the development of burnout. Neuroticism, negative affectivity and cooperativeness all contribute to burnout. SUMMARY: Strategies to alleviate stress and hence the development of burnout should not only be directed at adapting occupational or organizational factors but also at equipping anesthesiologists with psychological tools to deal with occupational stress. Furthermore, personality traits that predispose for development of burnout could be taken into consideration in resident selection procedures. PMID- 29474216 TI - Anesthesia and analgesia for gynecological surgery. AB - PURPOSE OF REVIEW: High-quality analgesia has been linked to improved patient satisfaction as well as improved short-term and long-term postoperative outcomes. Acute surgical pain is a modifiable risk factor for development of chronic postoperative pain, which is reported by up to 26% of gynecologic surgical patients. In other surgical populations, multimodal analgesia has shown improved pain control and decreased reliance on opioids. This review examines recent evidence for various analgesic modalities applied specifically to the gynecologic surgical population. RECENT FINDINGS: Nonopioid agents like acetaminophen, nonsteroidal anti-inflammatories, and gamma-aminobutyric acid analogs resulted in reduction in postoperative pain and opioid consumption. Application of regional anesthetic techniques had a favorable effect that persisted beyond the immediate recovery period. Preemptive analgesia remains unproven. The best evidence for effective combinations comes from ERAS studies that incorporated multimodal analgesia into a systemic approach geared towards early discharge. SUMMARY: Multimodal analgesia had demonstrated advantages for all types of gynecological surgeries in terms of improving postoperative pain control and minimizing opioid related adverse effects. Multimodal analgesia includes acetaminophen, NSAIDS, and gamma-aminobutyric acid analogs combined with intraoperative nonopioid analgesics such as ketamine, regional anesthesia or intrathecal morphine. Further research should focus on determining most effective combinations and doses of multimodal analgesia. PMID- 29474217 TI - Technology as friend or foe? Do electronic health records increase burnout? AB - PURPOSE OF REVIEW: To summarize recent relevant studies regarding the use of electronic health records and physician burnout. RECENT FINDINGS: Recently acquired knowledge regarding the relationship between electronic health record use, professional satisfaction, burnout, and desire to leave clinical practice are discussed. SUMMARY: Adoption of electronic health records has increased across the United States and worldwide. Although electronic health records have many benefits, there is growing concern about the adverse consequences of their use on physician satisfaction and burnout. Poor usability, incongruent workflows, and the addition of clerical tasks to physician documentation requirements have been previously highlighted as ongoing concerns with electronic health record adoption. In multiple recent studies, electronic health records have been shown to decrease professional satisfaction, increase burnout, and the likelihood that a physician will reduce or leave clinical practice. One interventional study demonstrated a positive effect of a dedicated electronic health record entry clerk on physicians working in an outpatient practice. PMID- 29474218 TI - An Evaluation of Output Signal to Noise Ratio as a Predictor of Cochlear Implant Speech Intelligibility. AB - OBJECTIVES: Cochlear implant (CI) sound processing strategies are usually evaluated in clinical studies involving experienced implant recipients. Metrics which estimate the capacity to perceive speech for a given set of audio and processing conditions provide an alternative means to assess the effectiveness of processing strategies. The aim of this research was to assess the ability of the output signal to noise ratio (OSNR) to accurately predict speech perception. It was hypothesized that compared with the other metrics evaluated in this study (1) OSNR would have equivalent or better accuracy and (2) OSNR would be the most accurate in the presence of variable levels of speech presentation. DESIGN: For the first time, the accuracy of OSNR as a metric which predicts speech intelligibility was compared, in a retrospective study, with that of the input signal to noise ratio (ISNR) and the short-term objective intelligibility (STOI) metric. Because STOI measured audio quality at the input to a CI sound processor, a vocoder was applied to the sound processor output and STOI was also calculated for the reconstructed audio signal (vocoder short-term objective intelligibility [VSTOI] metric). The figures of merit calculated for each metric were Pearson correlation of the metric and a psychometric function fitted to sentence scores at each predictor value (Pearson sigmoidal correlation [PSIG]), epsilon insensitive root mean square error (RMSE*) of the psychometric function and the sentence scores, and the statistical deviance of the fitted curve to the sentence scores (D). Sentence scores were taken from three existing data sets of Australian Sentence Tests in Noise results. The AuSTIN tests were conducted with experienced users of the Nucleus CI system. The score for each sentence was the proportion of morphemes the participant correctly repeated. In data set 1, all sentences were presented at 65 dB sound pressure level (SPL) in the presence of four-talker Babble noise. Each block of sentences used an adaptive procedure, with the speech presented at a fixed level and the ISNR varied. In data set 2, sentences were presented at 65 dB SPL in the presence of stationary speech weighted noise, street-side city noise, and cocktail party noise. An adaptive ISNR procedure was used. In data set 3, sentences were presented at levels ranging from 55 to 89 dB SPL with two automatic gain control configurations and two fixed ISNRs. RESULTS: For data set 1, the ISNR and OSNR were equally most accurate. STOI was significantly different for deviance (p = 0.045) and RMSE* (p < 0.001). VSTOI was significantly different for RMSE* (p < 0.001). For data set 2, ISNR and OSNR had an equivalent accuracy which was significantly better than that of STOI for PSIG (p = 0.029) and VSTOI for deviance (p = 0.001), RMSE*, and PSIG (both p < 0.001). For data set 3, OSNR was the most accurate metric and was significantly more accurate than VSTOI for deviance, RMSE*, and PSIG (all p < 0.001). ISNR and STOI were unable to predict the sentence scores for this data set. CONCLUSIONS: The study results supported the hypotheses. OSNR was found to have an accuracy equivalent to or better than ISNR, STOI, and VSTOI for tests conducted at a fixed presentation level and variable ISNR. OSNR was a more accurate metric than VSTOI for tests with fixed ISNRs and variable presentation levels. Overall, OSNR was the most accurate metric across the three data sets. OSNR holds promise as a prediction metric which could potentially improve the effectiveness of sound processor research and CI fitting. PMID- 29474220 TI - MULTICOLOR IMAGING IN A CASE OF ACUTE RETINAL PIGMENT EPITHELIITIS. AB - PURPOSE: To describe multicolor imaging findings in a case of acute retinal pigment epitheliitis. SETTING: Vitreoretinal department of a tertiary care center in Eastern India. METHODS: A 28-year-old lady presented with acute vision loss in the right eye since 3 days. Left eye examination was unremarkable. Best-corrected visual acuity in the right eye was 20/40. Anterior segment examination revealed clear lens with no evidence of inflammation. There were no vitreous cells. Fundus examination of the right eye revealed a round orange lesion surrounded by a hypopigmented halo in the fovea with multiple tiny hypopigmented lesions temporal to the fovea. Fundus autofluorescence imaging of the right eye showed hyperautofluorescent lesions temporal to the fovea corresponding to the hypopigmented lesions seen temporal to the fovea. Spectral domain optical coherence tomography of the right eye revealed subfoveal hyperreflective lesion in the outer retina with disruption of the ellipsoid zone and interdigitation zone with a linear extension upward. Multicolor composite image of the right eye revealed the foveal lesion as circular red patch with an inferior orange extension. The infrared reflectance image revealed hyperreflective area corresponding to the foveal lesion. The blue and green reflectance images were unremarkable. The patient reported an upper respiratory tract infection 7 days before the visual loss. A diagnosis of acute retinal pigment epitheliitis was made based on history, clinical and imaging findings. CONCLUSION: This is the first description of multicolor imaging signature of acute retinal pigment epitheliitis lesion in published literature. It seems to be a promising noninvasive imaging modality with a potential to replace color fundus photography. PMID- 29474219 TI - Word Learning in Children With Cochlear Implants: Examining Performance Relative to Hearing Peers and Relations With Age at Implantation. AB - OBJECTIVES: This study had two key objectives. First, to examine whether children who receive cochlear implants (CIs) before the age of 3 years and who are experienced implant users (mean length of CI use = 6 years; range = 4 to 9 years) show deficits on a word learning task relative to their hearing peers. Second, to examine whether variation in age at implantation within the first 3 years of life relates to later word learning abilities. DESIGN: Twenty-one 6- to 10-year-old children with CIs, 21 chronological age-matched (AM) hearing children, and 21 vocabulary-matched hearing children completed an auditory word learning task in which they were required to learn the names of eight rare animals. Comprehension and production probes tested their learning of these unfamiliar words. RESULTS: The children with CIs performed similarly to AM peers on the comprehension phase of the word learning task. Their production performance was significantly poorer than the AM group but was in line with that of their younger vocabulary-matched hearing peers. Differences between the CI and AM groups were accounted for by differences between the groups in terms of their existing vocabulary knowledge. Within the CI group, there was no evidence of an association between age at implantation and performance on the word learning task, but existing vocabulary size showed strong positive correlations with word learning performance, after adjustment for chronological age. CONCLUSIONS: When implanted by the age of 3 years, and with over 4 years CI experience, 6- to 10-year-old children are able to perform similarly to their AM hearing peers in terms of their comprehension of newly learned words. Producing accurate phonological forms of newly learned words may be a more challenging task for children with CIs, but their production performance is consistent with their vocabulary size. This cross-sectional study provides support for a relationship between existing vocabulary size and novel word learning skills in children with CIs; future longitudinal studies should test the hypothesis that this relationship is developmentally reciprocal. PMID- 29474221 TI - PROFOUND VISUAL RECOVERY AT 16 MONTHS AFTER RESOLUTION OF SEROUS RETINAL DETACHMENTS SECONDARY TO THROMBOTIC THROMBOCYTOPENIC PURPURA: CASE REPORT AND LITERATURE REVIEW. AB - PURPOSE: To report a unique case of dramatic improvement in objective visual function during the recovery phase, after resolution of thrombotic thrombocytopenic purpura-related serous retinal detachments and to review prognostic trends in reported cases involving the macula. METHODS: Observational case report and literature review. RESULTS: A 36-year-old white woman with thrombotic thrombocytopenic purpura developed vision loss from serous retinal detachments in both eyes. Over a 16-month period, after both retinae remained attached, best-corrected visual acuity improved from 20/400 to 20/50 in both eyes with dramatic improvement on optical coherence tomography and autofluorescence imaging. CONCLUSION: Although thrombotic thrombocytopenic purpura is a life threatening illness, visual prognosis in patients with macula off serous retinal detachments appears excellent. Most cases reviewed in literature improved to baseline visual acuity, but recovery periods ranged from days to many months. Hyperautofluorescent granularity on autofluorescence photography may be an indicator of chronic retinal detachment and a more delayed visual recovery. PMID- 29474222 TI - HEMORRHAGIC OCCLUSIVE RETINAL VASCULITIS AFTER INTRACAMERAL VANCOMYCIN USE IN CATARACT SURGERY AFTER INTRAVENOUS EXPOSURE. AB - PURPOSE: To report a case of hemorrhagic occlusive retinal vasculitis after cataract surgery. METHODS: A 74-year-old woman presented with blurry vision and distorted vision, which started 2 days after an uncomplicated cataract surgery in the left eye. Intracameral vancomycin was injected during the case. The patient reported being treated with systemic vancomycin in the past. RESULTS: The visual acuity was 20/80 in the left eye. She had trace cells in the anterior chamber with no hypopyon and intraocular lens implant within the capsular bag in the left eye. Dilated fundus examination revealed no vitritis, There were large patches of peripheral retinal hemorrhages and retinal ischemia. The patient was diagnosed with hemorrhagic occlusive retinal vasculitis likely secondary to hypersensitivity reaction to intracameral vancomycin. The patient was started on oral prednisone, and the topical difluprednate course was escalated. Within 3 weeks, vision improved to 20/30 in the left eye. She underwent pan retinal photocoagulation targeting the ischemic areas in the periphery. CONCLUSION: The patient had previous exposure to systemic vancomycin, which may have sensitized her immune system. Later on, the hypersensitivity reaction took place after exposure to intracameral vancomycin during cataract surgery. Our hemorrhagic occlusive retinal vasculitis case had a favorable visual outcome, and recognition of this entity will ensure that vancomycin will not be used for infection prophylaxis in the fellow eye at the time of cataract surgery. PMID- 29474223 TI - INVERTED INTERNAL LIMITING MEMBRANE-FLAP TECHNIQUE FOR OPTIC DISK PIT MACULOPATHY: MORPHOLOGIC AND FUNCTIONAL ANALYSIS. AB - PURPOSE: To analyze morphologic and functional changes after inverted internal limiting membrane-flap technique for optic disk pit maculopathy using optical coherence tomography, multifocal electroretinography, and microperimetry. METHODS: One case report. RESULTS: A 30-year-old woman presented us with decreased visual acuity (20/63) in the left eye because of retinoschisis and serous macular detachment associated with optic disk pit. Optical coherence tomography did not localize the source of intraretinal and subretinal fluid. A partial flattening of serous detachment after vitrectomy with internal limiting membrane peeling, inverted internal limiting membrane-flap technique, and gas tamponade was reported. Visual acuity and multifocal electroretinography improved while retinal sensitivity decreased at microperimetry during 3 months of follow up. CONCLUSION: Optical coherence tomography is helpful to assess the effectiveness of surgical maneuvers to treat optic disk pit maculopathy. Multifocal electroretinography and microperimetry might offer additional tools for follow-up analysis of retinal function after surgery. PMID- 29474224 TI - The Nursing Knowledge Pyramid: A Theory of the Structure of Nursing Knowledge. AB - A theory of the structure of nursing knowledge is proposed. Using retroductive reasoning to build upon an existing theory, the goal of the Nursing Knowledge Pyramid is to integrate disparate forms of nursing knowledge into a comprehensive, coherent, and useful structure to enhance the learning, development, automation, and accessibility of nursing knowledge. Education uses are discussed. PMID- 29474225 TI - A Model to Predict Birth Stress in Adolescents Within 72 Hours of Childbirth. AB - An organizing framework for understanding adolescent birth stress in immediate postpartum does not exist. Researchers evaluated adolescent birth stress within 72 hours postpartum via a modification of Slade's conceptual model of risk factors for posttraumatic stress (PTS). Birth stress was defined by negative birth appraisal and subjective distress. Precipitating factors pain management, partner presence, and delivery type, plus maintaining factor infant complications, predicted negative birth appraisal. Predisposing factors depression and prior trauma predicted subjective distress. Findings support utility of Slade's modified model of PTS risk factors for identification of adolescent early birth stress and generate nursing practice and research implications. PMID- 29474226 TI - The Usability and Acceptability of a Patient-Centered Mobile Health Tracking App Among a Sample of Adult Radiation Oncology Patients. AB - The usability and acceptability of patient-centered mobile health tracking apps among most clinical populations are unknown. This mixed-methods feasibility study evaluated the usability and acceptability of the Health Storylines app among 32 adult radiation oncology patients in a 2-week trial. Data were collected via pre- and post-app use surveys and digital analytics. Participants accessed the app platform a total of 711 times. The overall usability of the Heath Storylines app was rated favorably, and 81% of participants reported the app easy to use. This study provides beginning evidence of the usability and acceptability of this type of mobile health tracking app in adult oncology patients. PMID- 29474227 TI - Caring in the Margins: A Scholarship of Accompaniment for Advanced Transcultural Nursing Practice. AB - Nurses must learn essential skills based in transcultural nursing to address issues of equity and social justice. The development of a model for nursing practice for an urban nurse-led drop-in center for individuals experiencing marginalization provides an opportunity for student nurses to learn transcultural nursing skills that shifts care from acknowledging the need of others to accompanying others on their health journey. The practice model provides the opportunity for undergraduate and graduate nursing students at Augsburg University to de-emphasize tasks and build relationships. Students learn to listen to others' stories and acknowledge their struggles in the margins. Four stages of nursing practice skills, acknowledging others' needs, attending to their struggles, affirming strengths, and ultimately accompanying others, are taught and experienced. At the core of the nursing practice model is the concept of "hospitality." The nursing practice model serves as guide for student nurses to learn to suspend disbeliefs, withhold judgment, and ultimately reduce stereotypes and stigma to offer a safe space for individuals living in the margins seeking care. The future of nursing requires essential knowledge, skills, and attitudes that shift care from need-based care to accompaniment to address health inequities and provide culturally appropriate care. PMID- 29474229 TI - But You're Not a Real Doctor, I Mean Dealing With Life-Threatening Illnesses? PMID- 29474228 TI - Professional Governance Scale: Instrument Development and Content Validity Testing. AB - Instrument development and content validity testing resulted in a new instrument to measure the relatively new concept of professional governance. Professional governance is defined as the accountability, professional obligation, collateral relationships and decision making of a professional, foundational to autonomous practice and achievement of exemplary empirical outcomes. Fourteen experts with subject matter expertise either in measurement development or in creating professional practice environments assessed the validity of the proposed items and the instrument. The resulting Professional Governance Scale consisted of 75 items that adequately covered all attributes and their characteristics and had a Relevancy Mean Individual Content Validity Index of 95. PMID- 29474230 TI - Male Depression Subtypes and Suicidality: Latent Profile Analysis of Internalizing and Externalizing Symptoms in a Representative Canadian Sample. AB - Assessment of men's externalizing symptoms has been theorized to assist in the identification of those at risk of suicide. A nationally representative sample of Canadian men (N = 1000; mean, 49.63 years) provided data on internalizing and externalizing symptoms, and history of recent suicide planning and attempt (previous 4 weeks). Latent profile analysis indicted three classification subtypes. Robust effects were observed regarding history of recent suicide planning and attempt. Men with a marked externalizing profile (12.7% of sample), which included substance use, anger, and risk taking, were significantly more likely to have had a recent suicide plan (risk ratio, 14.47; p < 0.001) or to have attempted suicide within the previous 4 weeks (risk ratio, 21.32; p < 0.001) relative to asymptomatic men (67.7% of sample). Because recent suicide attempt was a rare event in the present sample (n = 13), findings need to be replicated in higher-risk populations. Results support primary care screening for both men's internalizing and externalizing depression symptoms. PMID- 29474231 TI - Clinical and Serological Predictors of Suicide in Schizophrenia and Major Mood Disorders. AB - Persons with serious mental illness are at high risk for suicide, but this outcome is difficult to predict. Serological markers may help to identify suicide risk. We prospectively assessed 733 persons with a schizophrenia spectrum disorder, 483 with bipolar disorder, and 76 with major depressive disorder for an average of 8.15 years. The initial evaluation consisted of clinical and demographic data as well as a blood samples from which immunoglobulin G antibodies to herpes viruses and Toxoplasma gondii were measured. Suicide was determined using data from the National Death Index. Cox proportional hazard regression models examined the role of baseline variables on suicide outcomes. Suicide was associated with male sex, divorced/separated status, Caucasian race, and elevated levels of antibodies to Cytomegalovirus (CMV). Increasing levels of CMV antibodies were associated with increasing hazard ratios for suicide. The identification of serological variables associated with suicide might provide more personalized methods for suicide prevention. PMID- 29474232 TI - Protein Content of Cervicovaginal Fluid Is Altered During Bacterial Vaginosis. AB - OBJECTIVES: The aim of the study was to compare, using a proteomic approach, cervicovaginal fluid (CVF) proteins of women with bacterial vaginosis (BV) with those presenting normal microbiota. MATERIALS AND METHODS: A total of 309 reproductive-aged women were cross-sectionally enrolled. Participants were tested for vaginal candidosis, Trichomonas vaginalis, Chlamydia trachomatis, and Neisseria gonorrhoeae and excluded if positive. Vaginal microbiota was classified microscopically according to Nugent criteria in normal, intermediate, and BV. Randomly selected CVF samples of 29 women with BV and an equal number with normal microbiota were subjected to proteomic analysis. Thus, a total of 58 CVF samples were evaluated using shotgun liquid chromatography-tandem mass spectrometry in a Q-Tof PREMIER API mass spectrometer (MicroMass/Waters) for peptide detection and relative quantification. RESULTS: Of the 309 women enrolled, 63 (20.4%) were excluded after testing positive for at least one of the tested co-infections or because of low-quality samples. Microscopic classification of vaginal microbiota on the remaining 246 samples revealed that 132 women (53.6%) had normal microbiota, 33 (13.4%) had intermediate microbiota, and 81 (33.0%) had BV. Proteomic analysis of CVF of 58 randomly selected women with normal microbiota (n = 29) or BV (n = 29) successfully identified 74 proteins. In addition, the comparison of abundance of those proteins between the groups showed that the following five (6.7%) were enriched in BV: neutrophil elastase, kaliocin-1, neutrophil defensin-1, Ig lambda-2 chain C regions, and protein S100-A7. All of which have a recognized role in host's immunity. CONCLUSIONS: Exclusive finding of BV affects immunity-related CVF components of reproductive-aged women. PMID- 29474233 TI - Expert Review of Cervical Cytology: Does it Affect Patient Care? AB - OBJECTIVES: The aim of the study was to evaluate whether expert review of outside cervical cytology affects patient care. MATERIALS AND METHODS: A retrospective study was conducted of 424 new patient referrals for cervical dysplasia between 2004 and 2016 at Roswell Park Cancer Institute. Records were analyzed for outside cervical cytology reports and compared with expert cervical cytology review. Differences between expert review and outside reports were documented. Charts with a difference were then assessed for additional evaluation and procedures performed. We specifically analyzed the data for cytology being upgraded or downgraded after expert review. RESULTS: Two hundred forty-six patient charts were eligible for this study. We identified 165 patients with congruent pathology reports. Of the 81 different reports, 41 led to significant pathologic differences. Twenty-four reports with different pathology were low-grade squamous intraepithelial lesions (LSIL) upgraded to high-grade squamous intraepithelial lesions (HSIL). Six were HSIL downgraded to LSIL, 4 LSIL downgraded to negative, 3 AGC upgraded to HSIL, 2 AGC upgraded to cancer, 1 each for HSIL downgraded to negative, and AGC downgraded to negative. Of the 24 patients whose cytology changed from low grade to high grade, 17 underwent an excisional procedure and 1 had a laser ablative procedure. Cervical intraepithelial neoplasia 2 or 3 was found in 11 specimens. Cervical intraepithelial neoplasia 1 was found in 4 of excisional specimens and no dysplasia found in 2. CONCLUSIONS: Expert review of cervical cytology significantly impacts patient management at a tertiary referral center, resulting in both upgrading and downgrading of community cytology reports. PMID- 29474234 TI - Simple Hysterectomy for Residual Cervical Intraepithelial Neoplasm. AB - OBJECTIVE: Many patients undergo hysterectomy for the treatment of cervical dysplasia. Factors that correlate with residual high-grade squamous intraepithelial lesions (HGSIL) at hysterectomy are not clear. We set out to determine preoperative features that may predict residual disease for patients treated for cervical dysplasia. MATERIALS AND METHODS: A retrospective database was reviewed for women who underwent simple hysterectomy for HGSIL between 1990 and 2013. Clinical data included age, history of dysplasia, initial treatment, follow-up colposcopy, indications for surgery, time elapsed between initial treatments, and pathology findings after hysterectomy. Significant residual disease was defined as HGSIL or cervical carcinoma. Statistical analyses were performed with the SPSS, independent Student t test, and Pearson chi test. Significance was set at p < .05. RESULTS: Eighty-three women met the study criteria. The indication for hysterectomy was residual histological finding at conization pathology in 30 women and patients' request in 53 women. Residual disease was found in 42 hysterectomy specimens: in 16 of 30 with residual histological finding and in 26 of the 53 patients' request. Reason for the hysterectomy was not statistically significant for residual disease (p = .708). Median age of patients with residual disease was 46.5 years versus 44.1 years for those without residua (p = .02). Postmenopausal patients had a higher rate of residual disease, 12 (32.4%) of the 28 premenopausal patients and 25 (67.6%) of the 54 postmenopausal patients (p = .04). Conization margin status was not associated with residual disease (p = .878). CONCLUSIONS: Older women and those in menopause are at significantly higher risk of residual disease at hysterectomy. PMID- 29474236 TI - Primary Langerhans Cell Histiocytosis of the Vulva in a Postmenopausal Woman: Response to Treatment With Oral Methotrexate. PMID- 29474235 TI - Effect of High-Risk Human Papillomavirus but Normal Cytology at Test of Cure on Achieving Colposcopy Standards. AB - OBJECTIVE: In United Kingdom., test of cure after treatment of any grade of cervical intraepithelial neoplasia (CIN) incorporates high-risk human papillomavirus (Hr-HPV) test and cytology at 6-month follow-up. The aims of the study were to determine the rate of recurrent CIN in women who are Hr-HPV positive and cytology negative and to explore possible associated risk factors. METHODS: A retrospective observational cohort study was performed in women treated for any grade CIN between 2010 and 2015 from a regional population, who were Hr-HPV positive and cytology negative at first follow-up. RESULTS: A total of 2729 women were identified as treated for any grade CIN, and 213 (7.8%) were re-referred to colposcopy having Hr-HPV-positive test and negative cytology at test of cure. Their mean age was 31.56 years (range = 19-62 years). The mean time of follow-up per woman was 30.50 months (range = 2-63 months). At colposcopy, 171 (80.3%) had colposcopy examination only and 42 women (19.7%) had a biopsy. Twenty four cases (11.3%) of CIN were identified of which 4 (1.9%) were CIN 2/3. Eleven women (5.2%) in total had a repeat treatment. Five women (2.3%) had biopsy-proven CIN 2/3 within 12-months after treatment. No cases of CIN 3+ after negative colposcopy were identified during the follow-up period. CONCLUSIONS: The incorporation of Hr-HPV testing yielded a very small number of women with residual CIN within 12 months of treatment. Our results suggest that women who are Hr-HPV positive and cytology negative after treatment of CIN with normal and adequate colposcopy could be discharged to routine recall if confirmed by larger national data. PMID- 29474237 TI - Trends in Cervical Cancer Screening in California's Family Planning Program. AB - OBJECTIVE: Guidelines recommend 3-year cervical cancer screening intervals to avoid unnecessary invasive procedures; however, regular testing remains critical. We evaluated trends in cervical cancer screening among low-income women receiving family planning-related services and their association with patient and provider characteristics. MATERIALS AND METHODS: Using claims and enrollment data from California's publicly funded family planning program, we identified 540,026 women with a clinician visit at 216 sites between 2011 and 2015. We calculated guideline adherent cervical cancer testing rates for 6-month periods among women aged 21 to 24, 25 to 29, and 30 to 64 years. We also calculated guideline adherent chlamydia testing for women aged 21 to 24 years. RESULTS: Having a 3 year cervical cancer screening test declined for all age groups. The odds of cervical cancer screening declined for women aged 21 to 24 years by an estimated 11% every 6 months (odds ratio [OR] = 0.90, 95% confidence interval [CI] = 0.89 0.90), a significantly greater decline than for the other age groups. Among women aged 21 to 29 years, the decrease was significantly larger for Latina (ratio of ORs = 0.95, 95% CI = 0.95-0.96) and Spanish-speaking (ratio of ORs = 0.95, 95% CI = 0.95-0.96) women compared with non-Latina and non-Spanish-speaking women. A smaller decline was seen for chlamydia screening. CONCLUSIONS: Changes in screening interval guidelines are associated with overall decreased screening. This trend was strongest among women aged 21 to 24 years, even as they continued to be screened appropriately for chlamydia, suggesting many missed opportunities. Efforts to reduce unnecessary cervical cancer screening should be monitored to maintain appropriate screening rates to avoid advanced-stage diagnoses and higher health care costs. PMID- 29474238 TI - Management of Early Cervical Stromal Invasion FIGO Stage 1A1 When Margins Are Involved With Cervical Intraepithelial Neoplasia. AB - OBJECTIVE: Women with International Federation of Gynecology and Obstetrics stage 1A1 cervical carcinoma were evaluated to determine whether repeat excision for large loop excision transformation zone margins positive with cervical intraepithelial neoplasia (CIN) had been undertaken according to the National Health Service Cervical Screening Programme guidelines and if deviations from guidelines adversely affected patient outcome. MATERIALS AND METHODS: We retrospectively studied patients with 1A1 cervical carcinoma treated in our service between May 2010 and July 2015 to determine whether NHSCSP guidelines (May 2010) were followed. This states that if the invasive disease is excised but CIN extends to the excision margin, then a repeat large loop excision transformation zone should be undertaken to exclude further invasive disease and to confirm excision of CIN. RESULTS: Seventeen patients were identified. In one, neither the invasive lesion nor CIN was fully excised. In 5, the lesion and CIN were fully excised. In eleven, the invasive lesion was excised, but CIN was present at a margin. Of these 11 patients, none opted for a repeat excision. All 11 patients had negative cytology at first follow-up (negative up to 4 years [median = 2 years]). CONCLUSIONS: Our outcomes suggest that it may not be necessary to perform a repeat excision for CIN present at the excision margin in women with 1A1 cervical carcinoma when CIN is present either at the endocervical, deep stromal, or ectocervical margin, as long as the invasive focus is fully excised, and patients have been fully counseled and have regular cytology follow up. This may be an alternative for patients wanting to minimize the risks to fertility posed by repeat excision. PMID- 29474239 TI - "The Future of Vulvar Disease: New and Ongoing Challenges": Presidential Lecture XXIV World Congress 2017, Mendoza, Argentina. AB - The 21st century brought along a number of discoveries and medical advances. With the advances, we can mention the following: target therapies for cancer, genomics and molecular biology, pharmacogenomics, minimally invasive and robotic surgery, immunosuppressive therapies in transplant patients, human papillomavirus in the era of vaccination, and aesthetic vulvovaginal procedures. All of them have greatly influenced medicine. As a scientific society, we have several challenges. In the past, you had to go to a library to get information. Now, we have readily available, accessible information. Thus, here comes the debate; we are facing a change in our educational paradigm, which needs to be approached from an integral and holistic perspective. New historical and cultural circumstances call for a deep reflection on the current social validity of scientific societies. They should be open to new ideas and allow dissent, work in teams, and speak a common language. They must be organized and, in constant communication with its members, support and organize research developing well-designed clinical trials and observational studies. We should work for our patients, recognizing the importance of the whole woman. We all have a great scientific and humanitarian challenge; to succeed, we must not lose sight of who we are working for. We work for them, our patients, and not for us. Our mission is to take care of our them! PMID- 29474240 TI - High Rates of High-Grade Cervical Dysplasia in High-Risk Young Women With Low Grade Cervical Cytology. AB - OBJECTIVE: The aim of the study was to determine rates of cervical intraepithelial neoplasia (CIN) 2 or greater in high-risk, racially diverse, young women with low-grade cytology. MATERIALS AND METHODS: After institutional review board approval, a cross-sectional study of 21- to 24-year-old women with low-grade cytology (atypical squamous cells of undetermined significance, high risk human papillomavirus+, low-grade squamous intraepithelial lesion, or human papillomavirus+ only) managed with colposcopy at our university-based clinic between May 2011 and April 2013 were identified. Demographics and pathologic data were collected including age, race, parity, smoking status, screening history, and histology. Student t test and chi tests were used to compare women with and without CIN 2 or 3. Univariate analysis was performed with demographic data. RESULTS: One thousand fifty-eight women with a mean (SD) age of 22.5 (1.1) were included. Most patients (59.5%) were parous, 36.1% were smokers, and most (52.9%) were black. These patients were considered high risk because of their lower socioeconomic status, minority status, lack of insurance, or having Medicaid and therefore had limited access to preventative health care. Based on colposcopy, the prevalence of CIN 2+ was 19.1%: 13.9% (95% CI = 11.9-16.1) CIN 2 and 5.1% (95% CI = 3.9-6.6) CIN 3. There was an overall prevalence of 4.7% (95% CI = 3.7% 6.3%) of CIN 3 from excisional pathology from the 157 of 185 patients who returned for a recommended excisional procedure. Smoking (odds ratio = 1.64, 95% CI = 1.2-2.25) and a history of high-grade cytology (odds ratio = 2.06, 95% CI = 1.02-4.01) were associated with CIN 2/3. CONCLUSIONS: High prevalence of CIN 2/3 in young women with low-grade cervical cytology in this population suggests that it may be prudent to consider alternative surveillance such as colposcopy in similar high-risk populations. PMID- 29474241 TI - Reduced Antifungal Susceptibility of Vulvovaginal Candida Species at Normal Vaginal pH Levels: Clinical Implications. AB - OBJECTIVE: The aims of the study were to assess for differences in antifungal in vitro potency at pH 7 and pH 4 and to discuss any potential clinical implications of that difference. MATERIALS AND METHODS: A retrospective analysis of 217 first positive yeast cultures from 217 patients. Yeast isolates underwent antifungal susceptibility testing, with minimum inhibitory concentrations (MICs) (microgram per milliliter) measured at pH 7 and pH 4 for fluconazole, itraconazole, miconazole, clotrimazole, terconazole, and nystatin. Only the first isolates collected from each patient were included in the analysis. RESULTS: Yeast first isolates included 173 Candida albicans, 15 Candida glabrata, and 29 isolates from 8 other species. Geometric mean (GM) MIC values for all antifungals were significantly higher when tested at pH 4 (p < .001 for all comparisons). For C. albicans, the largest GM MIC differences were observed for terconazole (0.17 pH 7 vs 6.17 pH 4) and clotrimazole (0.04 vs 0.24). For terconazole, 97.7% of the isolates had a MIC of 1 or less at pH 7 but 83.2% had a MIC of 4 or higher at pH 4. For C. glabrata, terconazole (GM MIC = 0.26 pH 7 vs >64 pH 4), clotrimazole (0.13 vs 6.96), miconazole (0.06 vs 0.76), and fluconazole (3.17 vs 26.6) were most affected. All C. glabrata isolates had a MIC of 1 or less for terconazole at pH 7 and one had a MIC of 8 at pH 4, whereas all the rest were highly resistant (MIC > 64). CONCLUSIONS: Antifungals have reduced in vitro potency when tested at lower pH. Candida glabrata is more affected than C. albicans. The impact may be greatest for the antifungal terconazole and against C. glabrata isolates. PMID- 29474242 TI - Cervical Adenocarcinoma: A Comparison of the Reproducibility of the World Health Organization 2003 and 2014 Classifications. AB - OBJECTIVE: The aim of the study was to compare the reproducibility of malignant glandular tumors of the uterine cervix classified per World Health Organization (WHO) 2003 and 2014. MATERIALS AND METHODS: Two pathologists reviewed 228 cases composed of adenocarcinoma in situ and 22 adenocarcinoma histotypes and selected 405 representative hematoxylin and eosin slides, which were digitally scanned. Six other pathologists (3 gynecological and 3 anatomical) independently reviewed and classified the images per both WHO classifications. One year later, they classified a random sample of 25 cases. Inter- (inter-OR) and intra-observer (intra-OR) reproducibility of the 6 pathologists and separately for gynecological compared with anatomical pathologists was tested using kappa statistics. RESULTS: Both classifications were collapsed into 6 categories as benign, adenocarcinoma in situ, and mucinous, endometrioid, rare, and adenosquamous-miscellaneous carcinomas. WHO 2014 had an additional category: endocervical adenocarcinoma, usual type. Inter-observer kappa values were more reliable than the intra-OR results based on 95% CIs. The average inter-OR kappa values with both classifications were moderate between the 6 pathologists and between the 3 anatomical pathologists. In contrast, they were substantial between the 3 gynecological pathologists. With both classifications, the average intra-OR kappa values of the 6 pathologists and both pathologist groups trended toward substantial. CONCLUSIONS: Reproducibility among 6 pathologists is unaffected by changes in the WHO 2014 classification and averages moderate between different and trends toward substantial between the same pathologist. Reproducibility between different pathologists can improve to substantial when they have expertise in gynecological pathology. PMID- 29474243 TI - Anticipating the Impact of Human Papillomavirus Vaccination on US Cervical Cancer Prevention Strategies. AB - Cervical cancer prevention guidelines are benchmarked to risk of cervical precancer. In younger age cohorts, vaccination against high-risk types of human papillomavirus (HPV) has reduced HPV 16/18 prevalence and cervical intraepithelial neoplasia. Lower prevalence of precancer will impair the sensitivity of cytology and colposcopy, but negative predictive value will rise. Training and skills maintenance will become more difficult as abnormalities become less common. Primary screening with HPV assays will become more attractive but will require HPV genotyping as most positive HPV tests will reflect non-16/18 infections with lower oncogenicity. Screening will begin later and will occur at longer intervals. Colposcopy and treatment thresholds will become more stringent. Historical data sets will become inappropriate for guidelines development. As women immunized using nonavalent vaccine reach screening age, these trends will become still more pronounced. PMID- 29474244 TI - From the Editor. PMID- 29474246 TI - Commentary on "Moving Toward Paying for Outcomes in Medicaid". PMID- 29474245 TI - Moving Toward Paying for Outcomes in Medicaid. AB - Medicaid can improve beneficiary health and help sustain its own future by embracing payment for outcomes. Good precedents exist from states such as Florida, Maryland, Minnesota, New York, Ohio, Pennsylvania, and Texas. Medicaid outcome measures include preventable admissions, readmissions, emergency department visits, and inpatient complications; early elective deliveries; infant and child mortality; patient-reported outcomes, satisfaction, and confidence; and reduction in low-value care. Criteria to prioritize initiatives include potential savings, availability of established models, impact on health status, and Medicaid's ability to effect change. We offer 5 principles for success, emphasizing clinically credible initiatives that generate actionable information for clinicians. PMID- 29474248 TI - Medicaid's Enduring Role in the American Health Care System. PMID- 29474247 TI - Commentary on "Moving Toward Paying for Outcomes in Medicaid". PMID- 29474249 TI - Paying for Outcomes in Medicaid: The Time Is Now. AB - Medicaid can improve quality and reduce costs by adopting a transparent quality measurement system based on outcomes that will improve quality and reduce costs. PMID- 29474250 TI - A Comment on Moving Towards Paying for Outcomes in Medicaid. PMID- 29474251 TI - Same-Day Cancellation in Ambulatory Surgery: A Retrospective Review at a Large Academic Tertiary Referral Center. AB - Although ambulatory surgery offers patients convenience and reduced costs, same day cancellation of ambulatory surgery negatively affects patient experiences and operational efficiency. We conducted a retrospective analysis to determine the frequency and reasons for same-day cancellations in an outpatient surgery center at a large academic tertiary referral center. Of 41 389 ambulatory surgical procedures performed, same-day cancellations occurred at a rate of 0.5% and were usually unforeseeable in nature. Focusing on foreseeable cancellations offers opportunities for enhanced patient satisfaction, improved quality of care, and systems-based practice improvements to mitigate cancellations related to areas such as scheduling or patient noncompliance. PMID- 29474253 TI - Differences in Certification and the Effect on Team Climate Among Community Health Workers in Texas. AB - The purpose of this study was to compare team climate among Texas community health workers (CHWs)/promotoras who were certified by the 2 different methods: (a) completing a state-approved training program, and (b) providing evidence of work experience (grandfathering). Analysis of survey results found no significant differences in Team Climate Inventory scores between CHWs who were certified either through state-approved training or through work experience. This research provides some preliminary evidence in support of experience-based certification, but there continues to be a need for more research evaluating CHW certification requirements and the impact of state certification of CHWs on population health outcomes. PMID- 29474252 TI - Coordination Across Ambulatory Care: A Comparison of Referrals and Health Information Exchange Across Convenient and Traditional Settings. AB - Urgent care centers have been identified as one means of shifting care from high cost emergency departments while increasing after-hours access to care. However, the episodic nature of urgent care also has the potential to fragment care. In this study, we examine the adoption of 2 coordination activities-referrals and the electronic exchange of health information-at urgent care centers and other ambulatory providers across the United States. We find that setting is significantly associated with both health information exchange and referrals. Several organization-level variables and environment-level variables are also related to the propensity to coordinate care. PMID- 29474254 TI - Establishing Teams: How Does It Change Practice Configuration, Size, and Composition? AB - Little is known about how practices reorganize when transitioning from traditional practice organization to team-based care. We compared practice-level (1) configuration as well as practice- and team-level (2) size and (3) composition, before and after establishing teams. We employed a pre-/poststudy using personnel lists of 1571 to 1711 staff (eg, job licenses, titles, and team assignment) and practice manager surveys. All personnel (physician and nonphysician) worked within 18 Massachusetts academic primary care practices participating in a 2-year learning collaborative aimed at establishing team-based care. We found that establishing team-based care can involve changing practice configurations and composition without substantially changing practice size. PMID- 29474255 TI - Erratum - Author, Dr. C.-H. Chen's, Affiliations Updated. PMID- 29474256 TI - Correlates of Linkage to HIV Preexposure Prophylaxis Among HIV-Testing Clients. AB - BACKGROUND: Publicly funded HIV-testing sites can identify HIV preexposure prophylaxis (PrEP) candidates and provide PrEP linkage. SETTING: Harris Health System's HIV clinic, HIV-testing program, and HIV-prevention program (HPP) in Houston, TX, a high HIV-incidence city. METHODS: A prospective assessment of individuals aged 18 years and older recruited from walk-in HIV testing from December 2013 to April 2015 included risk assessment, HIV testing, and self administered survey, with follow-up surveys at 6 and 12 months and medical record review. RESULTS: The mean age of our sample (n = 300) was 38.3 +/- 11.7 years. Men constituted 63.1% of the sample and 53.7% were black non-Hispanic, 26.3% Hispanic, and 14.7% white non-Hispanic. Most were uninsured (63.5%). Only 27% always used condoms, although 67% perceived personal HIV risk. Of 300 participants, 64 (21.3%) linked to PrEP care and 49 (16.3%) took PrEP. In multivariable analysis, compared with heterosexual men, women [adjusted OR (aOR) 4.1, 95% CI: 1.5 to 11.1] and MSM (aOR 10.2, 95% CI: 3.4 to 31.0) were more likely to attend HPP and to take PrEP (aOR 3.0, 95% CI: 1.6 to 15.1 and 3.0, 95% CI: 1.1 to 8.3, respectively). Serodiscordance and PrEP interest correlated with program attendance (aOR 14.0, 95% CI: 6.1 to 32.3 and aOR 6.7, 95% CI: 1.8 to 25.4) and taking PrEP (aOR 13.1, 95% CI: 5.2 to 32.8 and 14.4, 95% CI: 1.8 to 166.9), respectively. CONCLUSIONS: Preexposure prophylaxis interest, being female or MSM, and serodiscordance correlated with PrEP linkage. Safety-net health systems can facilitate PrEP access in marginalized populations, but the PrEP initiation rates remain low. PMID- 29474257 TI - Accuracy of Xpert Mtb/Rif Ultra for the Diagnosis of Pulmonary Tuberculosis in Children. AB - We determined the accuracy of the new Xpert MTB/RIF Ultra assay for diagnosis of pulmonary tuberculosis in children, using banked-induced sputum. Sensitivity and specificity were 75.3% and 96.9%, respectively, compared with a culture result from the same specimen. Of those children with microbiologically confirmed tuberculosis (positive Xpert, Ultra or culture), Xpert detected 63.2%, Ultra 73.7% and culture 82.9%. PMID- 29474258 TI - Etiology of Acute Otitis Media and Characterization of Pneumococcal Isolates After Introduction of 13-Valent Pneumococcal Conjugate Vaccine in Japanese Children. AB - BACKGROUND: Acute otitis media is a leading cause of childhood morbidity and antibiotic prescriptions. We examined etiologic changes in acute otitis media after introduction of 13-valent pneumococcal conjugate vaccine as routine immunization for Japanese children in 2014. Serotypes, resistance genotypes, antibiotic susceptibilities and multilocus sequence typing of pneumococcal isolates were also characterized. METHODS: Otolaryngologists prospectively collected middle ear fluid from 582 children by tympanocentesis or sampling through a spontaneously ruptured tympanic membrane between June 2016 and January 2017. Causative pathogens were identified by bacterial culture and real-time polymerase chain reaction for bacteria. Serotypes, resistance genotypes, sequence types and susceptibilities to 14 antimicrobial agents were determined for pneumococcal isolates. RESULTS: At least 1 bacterial pathogen was identified in 473 of the samples (81.3%). Nontypeable Haemophilus influenzae (54.8%) was detected most frequently, followed by Streptococcus pneumoniae (25.4%), Streptococcus pyogenes (2.9%) and others. Pneumococci of current vaccine serotypes have decreased dramatically from 82.1% in 2006 to 18.5% (P < 0.001). Commonest serotypes were 15A (14.8%), 3 (13.9%) and 35B (11.1%). Serotype 3 was significantly less frequent among children receiving 13-valent pneumococcal conjugate vaccine compared with 7-valent pneumococcal conjugate vaccine (P = 0.002). Genotypic penicillin-resistant S. pneumoniae accounted for 28.7%, slightly less than in 2006 (34.2%; P = 0.393); the penicillin-resistant serotypes 15A and 35B had increased. Serotypes 15A, 3 and 35B most often belonged to sequence types 63, 180 and 558. CONCLUSIONS: Our findings are expected to assist in development of future vaccines, and they underscore the need for appropriate clinical choice of oral agents based on testing of causative pathogens. PMID- 29474259 TI - Switching Between Antibiotics Among Danish Children 0-4 Years of Age: A Nationwide Drug Utilization Study. AB - BACKGROUND: In Denmark, the use of amoxicillin is widespread among children, despite phenoxymethylpenicillin being recommended as first-line therapy. The reason for this apparent discrepancy is not fully understood. We aimed at evaluating prescribing patterns of antibiotics among Danish children 0-4 years of age, with emphasis on incidence of treatment episodes, choice of initial antibiotic treatment and switching patterns between different types of antibiotics. METHODS: We identified all children <=4 years of age who filled a prescription of antibiotics from 2000 to 2015 according to the nationwide Danish National Prescription Registry. We estimated the incidence rate of episodes treated with antibiotics and the choice of initial antibiotic treatment over time. Further, we assessed the cumulative risk of switching within 0-3 days after initiating therapy. RESULTS: We identified 3,481,684 antibiotic treatment episodes issued to 0- to 4-year-olds from 2000 to 2015. The incidence rate was stable until 2011 both among children 0-1 years of age (approximately 880/1000) and among children 2-4 years of age (approximately 610/1000), after which it dropped. Phenoxymethylpenicillin and, increasingly, amoxicillin were most frequently used as initial treatments (39% vs. 44%). Few switched from amoxicillin (1%) or phenoxymethylpenicillin (4.7%) within the first 3 days. Of those who switched from phenoxymethylpenicillin, 64% received amoxicillin as second-line treatment. CONCLUSIONS: The incidence of episodes treated with antibiotics among Danish children 0-4 years of age has decreased considerably since 2011. In contrast to guideline recommendations, amoxicillin is the most frequently used initial treatment. Early switching between antibiotics is uncommon. Initiatives should address the extensive use of amoxicillin. PMID- 29474260 TI - High Prevalence of Extensively Drug-resistant Acinetobacter baumannii at a Children Hospital in Bolivia. AB - Acinetobacter baumannii causes serious hospital-acquired infections and has been positioned as a priority organism by the World Health Organization. This study includes 36 A. baumannii isolates from a children hospital recovered between March 2014 and May 2015 in Cochabamba. The majority of the isolates were recovered from blood cultures (n = 10, 31.3%) and respiratory samples (n = 11, 34.4%); 53% of the patients were younger than 1 month old. Most of these isolates (n = 30, 80.6%) were extremely drug resistant and 8.3% were multidrug resistant. The circulation of 2 predominant clones including 25 isolates was determined by pulsed-field gel electrophoresis; 9 of the isolates were considered sporadic strains. The isolates grouped in the predominant clones and 5 of the unrelated sporadic strains were single-locus variant or double locus variant of clonal complex (CC110), belonging to international clone 7; the rest of the isolates were single-locus variant or double locus variant of another clonal complex. All the carbapenem-resistant isolates (88.9%) carried the blaOXA-23-like in a similar structure to Tn2008 located on the chromosome, and the aac(3)-IIa gene was present in all the aminoglycoside-resistant isolates (86.1%). Strong biofilm producers were found among these isolates, being the strongest ones those recovered from the hospital environment, catheter, blood and cerebrospinal fluid (CSF) all of them belonged to the unrelated sporadic strains. The present study demonstrated the predominance and spread of closely related extremely drug resistant A. baumannii isolates, what confers increasing risk to children and is of major concern because of the kind of infections and the lack of therapeutic alternatives to treat them. PMID- 29474261 TI - Pharmacokinetics, Short-term Safety and Efficacy of the Approved Once-daily Darunavir/Ritonavir Dosing Regimen in HIV-infected Children. AB - In this multicenter pharmacokinetic study in HIV-infected children (6-12 years of age), we validated the approved once-daily darunavir/ritonavir dosing recommendations. The geometric mean darunavir area under the plasma concentration time curve was 63.1 h.mg/L, substantially lower than the mean value observed in adults. However, all trough levels were adequate, and short-term virologic outcome was good. These data support the use of the darunavir/ritonavir once daily dosing recommendations. PMID- 29474262 TI - Longitudinal Changes in Body Composition by Dual-energy Radiograph Absorptiometry Among Perinatally HIV-infected and HIV-uninfected Youth: Increased Risk of Adiposity Among HIV-infected Female Youth. AB - BACKGROUND: Combination antiretroviral therapy has allowed youth with perinatal HIV infection (PHIV+) to live into adulthood, but many youth may experience metabolic and body composition changes that predispose to greater cardiovascular disease (CVD) risk. This longitudinal study evaluated changes in body composition measured by dual-energy radiograph absorptiometry (DXA) in a cohort of PHIV+ youth compared with HIV- controls over a 7-year period. METHODS: PHIV+ youth and HIV- controls were prospectively enrolled in a single-site study to assess nutrition and CVD risk. Anthropometrics and DXA scans were longitudinally obtained to assess percent body fat and regional fat distribution. Using general linear models, we analyzed differences in body composition and anthropometric measures by sex between PHIV+ youth and controls over time. RESULTS: Two hundred thirty-five participants (156 PHIV+ and 79 HIV- controls) with at least 1 DXA performed since study enrollment were included for analysis. During the study period, 471 DXAs were obtained in the PHIV+ group and 95 in HIV- controls. PHIV+ females demonstrated greater increase in weight and body mass index over time compared with HIV- females, and significant increases in total percent body fat [estimate = 1.212 (95% confidence interval: 0.837-1.587) percent per year; P < 0.001) and percent trunk fat [1.3818 (95% confidence interval: 0.922-1.84); P < 0.001] compared with HIV- females and PHIV+ males. CONCLUSIONS: PHIV+ females demonstrate an unfavorable change in fat redistribution and percent body fat over time that exceeds the pattern seen in PHIV+ males or HIV- females. Providers should have heightened awareness of body composition changes of PHIV+ females that may eventually lead to increased CVD risk. PMID- 29474263 TI - Delayed Generalized Necrotic Purpuric Rash in a C6-deficient 12-year-old Girl Treated for Group W Meningococcal Disease. AB - We report an unusual case of generalized necrotic purpuric rash that started 48 hours after the initiation of effective third-generation cephalosporin therapy to treat Neisseria meningitidis W infection in a 12-year-old girl. The course was favorable with no shock, and she recovered completely without sequelae. This infection revealed C6 deficiency in our patient. PMID- 29474264 TI - Migrant and ethnic minority status as risk indicators for schizophrenia: new findings. AB - PURPOSE OF REVIEW: Arguably, the strongest evidence of an environmental contribution to the cause of psychosis is the increased risk for certain groups of migrants and ethnic minorities. This article summarizes findings published since 2016. RECENT FINDINGS: Two studies suggested that migration or minority status are proxies for exposure to an inferior social status. A study from Bologna, Italy, showed that the psychosis risk for internal migrants from Southern Italy was as much increased as that for international migrants. A report from New Zealand reported a higher risk for Maoris than for the remainder of the population.Furthermore, a Danish investigation showed that own-group ethnic density of the neighbourhood at age 15 strongly modified the psychosis risk at adult age. This rules out differential mobility during the prodromal phase as an explanation for the ethnic density effect. Preliminary evidence suggests that the psychotogenic effect of migration may be mediated by elevated dopamine in the striatum. SUMMARY: An increasing body of evidence suggests that the higher psychosis risk for certain migrant or ethnic minority groups is due to an inferior social status. Neuroimaging of the dopamine system appears to be a promising avenue for research into pathogenesis. PMID- 29474265 TI - Global mental health and schizophrenia. AB - PURPOSE OF REVIEW: The aim was to synthesize recent evidence on schizophrenia illness experience and outcomes and models of care in low and middle-income countries (LMICs). RECENT FINDINGS: There is a plurality of explanatory models for psychosis and increasing evidence that context influences experiences of stigma. People with schizophrenia in LMICs are vulnerable to food insecurity, violence and physical health problems, in addition to unmet needs for mental healthcare. Family support may help to improve outcomes if present, but caregivers may be overwhelmed by the challenges faced. Despite efforts to increase availability, evidence-based care remains inaccessible to many people with schizophrenia. Non-randomized evaluations in South Africa and Mexico indicate that psychosocial support groups for people with schizophrenia and caregivers may be acceptable and useful. Randomized controlled trials in Pakistan and China show that culturally adapted cognitive-behavioural therapy can reduce symptom severity. There is emerging evidence that alternative medicine, such as Tai Chi, may be beneficial, but to date most studies are of low quality. The challenges of biomedical-traditional provider collaborations have been highlighted. Evaluations of integrated mental healthcare in primary care are underway and promise to provide vital information about how to scale-up quality care. SUMMARY: Acceptable and effective responses to schizophrenia in LMICs should be cognisant of both cultural context and universal concerns. Efforts to enhance the quality of family support should be central to models of care. PMID- 29474266 TI - Recovery from schizophrenia: is it possible? AB - PURPOSE OF REVIEW: Schizophrenia has a heterogeneous range of end states, from severe cases requiring repeated hospitalization to cases in which a single illness episode is followed by complete remission. The purpose of the present review is to examine recent literature on recovery in schizophrenia, focusing on the predictive factors and on the possibility to achieve it. RECENT FINDINGS: Roughly half of schizophrenia patients recovered or significantly improved over the long term, suggesting that functional remission is possible. Several factors predict the course of schizophrenia, including demographic, clinical, and treatment characteristics, as well as socioeconomic variables. Antipsychotics are a fundamental element of schizophrenia treatment, although the available antipsychotics have significant limitations. In this context, psychosocial interventions are supported by substantial evidence of efficacy in many outcome measures and rehabilitation interventions should be considered as an evidence based practice and need to become a part of the standard treatment of schizophrenia. SUMMARY: As recovery is a multidimensional concept, some authors suggested that at least two areas should be taken into account: clinical remission and social functioning. Functional outcome should be a priority target for therapeutic interventions in schizophrenia and in this perspective measuring treatment response, remission and functional recovery is essential. Only an integrated and multifaceted approach involving pharmacotherapy, psychosocial interventions, and attention to environmental circumstances can improve outcome in schizophrenia. PMID- 29474267 TI - Perspectives on Integrated HIV and Hepatitis C Virus Testing Among Persons Entering a Northern California Jail: A Pilot Study. AB - BACKGROUND: Providing HIV and hepatitis C virus (HCV) testing on an "opt-out" basis is often considered the "gold standard" because it contributes to higher testing rates when compared with "opt-in" strategies. Although rates are crucial, an individual's testing preferences are also important, especially in correctional settings where legal and social factors influence a person's capacity to freely decide whether or not to test. Our study explored factors influencing HIV and HCV testing decisions and individuals' preferences and concerns regarding opt-in vs. opt-out testing at the time of jail entry. METHODS: We conducted semistructured interviews to explore individuals' previous testing experiences, reasons to test, understanding of their health care rights, HIV and HCV knowledge, and preferences for an opt-out vs. an opt-in testing script. RESULTS: We interviewed 30 individuals detained in the Santa Clara County Jail at intake. Participants reported that their testing decisions were influenced by their level of HIV and HCV knowledge, self-perceived risk of infection and stigma associated with infection and testing, the degree to which they felt coerced, and understanding of testing rights in a correctional setting. Most preferred the opt in script because they valued the choice of whether or not to be tested. Participants who did prefer the opt-out script did so because they felt that the script was less likely to make people feel "singled out" for testing. CONCLUSIONS: Our findings demonstrate that people care about how testing is offered and suggest a need for further research to see how much this influences their decision about whether to test. PMID- 29474269 TI - Finding Hidden HIV Clusters to Support Geographic-Oriented HIV Interventions in Kenya. AB - BACKGROUND: In a spatially well known and dispersed HIV epidemic, identifying geographic clusters with significantly higher HIV prevalence is important for focusing interventions for people living with HIV (PLHIV). METHODS: We used Kulldorff spatial-scan Poisson model to identify clusters with high numbers of HIV-infected persons 15-64 years old. We classified PLHIV as belonging to either higher prevalence or lower prevalence (HP/LP) clusters, then assessed distributions of sociodemographic and biobehavioral HIV risk factors and associations with clustering. RESULTS: About half of survey locations, 112/238 (47%) had high rates of HIV (HP clusters), with 1.1-4.6 times greater PLHIV adults observed than expected. Richer persons compared with respondents in lowest wealth index had higher odds of belonging to a HP cluster, adjusted odds ratio (aOR) 1.61 [95% confidence interval (CI): 1.13 to 2.3], aOR 1.66 (95% CI: 1.09 to 2.53), aOR 3.2 (95% CI: 1.82 to 5.65), and aOR 2.28 (95% CI: 1.09 to 4.78) in second, middle, fourth, and highest quintiles, respectively. Respondents who perceived themselves to have greater HIV risk or were already HIV-infected had higher odds of belonging to a HP cluster, aOR 1.96 (95% CI: 1.13 to 3.4) and aOR 5.51 (95% CI: 2.42 to 12.55), respectively; compared with perceived low risk. Men who had ever been clients of female sex worker had higher odds of belonging to a HP cluster than those who had never been, aOR 1.47 (95% CI: 1.04 to 2.08); and uncircumcised men vs circumcised, aOR 3.2 (95% CI: 1.74 to 5.8). CONCLUSIONS: HIV infection in Kenya exhibits localized geographic clustering associated with sociodemographic and behavioral factors, suggesting disproportionate exposure to higher HIV risk. Identification of these clusters reveals the right places for targeting priority-tailored HIV interventions. PMID- 29474270 TI - Patients' choices, quality of life and treatment selection in head and neck cancer. PMID- 29474268 TI - Twenty-Five Years of Lamivudine: Current and Future Use for the Treatment of HIV 1 Infection. AB - Innovation in medicine is a dynamic, complex, and continuous process that cannot be isolated to a single moment in time. Anniversaries offer opportunities to commemorate crucial discoveries of modern medicine, such as penicillin (1928), polio vaccination (inactivated, 1955; oral, 1961), the surface antigen of the hepatitis B virus (1967), monoclonal antibodies (1975), and the first HIV antiretroviral drugs (zidovudine, 1987). The advent of antiretroviral drugs has had a profound effect on the progress of the epidemiology of HIV infection, transforming a terminal, irreversible disease that caused a global health crisis into a treatable but chronic disease. This result has been driven by the success of antiretroviral drug combinations that include nucleoside reverse transcriptase inhibitors such as lamivudine. Lamivudine, an L-enantiomeric analog of cytosine, potently affects HIV replication by inhibiting viral reverse transcriptase enzymes at concentrations without toxicity against human polymerases. Although lamivudine was approved more than 2 decades ago, it remains a key component of first-line therapy for HIV because of its virological efficacy and ability to be partnered with other antiretroviral agents in traditional and novel combination therapies. The prominence of lamivudine in HIV therapy is highlighted by its incorporation in recent innovative treatment strategies, such as single-tablet regimens that address challenges associated with regimen complexity and treatment adherence and 2-drug regimens being developed to mitigate cumulative drug exposure and toxicities. This review summarizes how the pharmacologic and virologic properties of lamivudine have solidified its role in contemporary HIV therapy and continue to support its use in emerging therapies. PMID- 29474271 TI - De-escalation treatment of human papillomavirus-positive oropharyngeal squamous cell carcinoma: an evidence-based review for the locally advanced disease. AB - PURPOSE OF REVIEW: Oropharyngeal cancer (OPC) incidence is increasing worldwide, especially in developed countries where it seems to be etiologically related to the elevating rates of high-risk human papillomavirus (HPV) infection. Considered a distinct disease because of its weak correlation with the traditional risk factors (tobacco use and alcohol), it has different patterns of survival outcomes, locoregional and distant failure, generally with better prognosis independently of the treatment. The standard therapeutic approach for locally advanced (LA) OPCs includes radiation therapy with concurrent chemotherapy, resulting in severe toxicities with negative impacts in quality of life (QoL). Considering this, efforts emerged to de-intensify treatment modalities in selected patients and achieve less morbidity while maintaining the favorable outcome. RECENT FINDINGS: Several de-escalated treatment strategies for HPV related OPCs have been proposed to date with some of them being assessed in ongoing clinical trials. The main approaches encompass: minimally invasive surgery and reduced adjuvant treatment; antiepidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) as alternative to chemotherapy concurrent with radiation therapy; adjusted radiation therapy dose intensity in responders to induction chemotherapy; reduced-dose radiation therapy. SUMMARY: There is still a lack of evidence to support de-intensification treatment for HPV-positive LA-OPC in clinical practice, and it remains investigational. Ongoing trials based on risk stratification might identify subgroups with greatest benefits of de escalation strategies, reducing treatment morbidity without constituting the favorable prognosis. PMID- 29474272 TI - An update in the initial management of paediatric status epilepticus. AB - PURPOSE OF REVIEW: Over the last 2 years, algorithms for the optimal management of status epilepticus have changed, as the medical community has recognized the need to terminate seizures in status in a timely manner. Recent research has evaluated the different choices of benzodiazepine and has given consideration to second-line treatment options. RECENT FINDINGS: There has been a move to examine alternatives to phenytoin (such as levetiracetam and lacosamide) as second-line agents. Valproate should be used cautiously in view of the potential side effects. Three ongoing trials [Established Staus Epilepticus Treatment Trial (ESETT), Convulsive Status Epilepticus Paediatric Trial (ConSEPT), and emergency treatment with levetiracetam or phenytoin in status epilepticus in children (EcLiPSE)] are comparing the efficacy of levetiracetam and phenytoin. SUMMARY: Benzodiazepines remain the first-line agent of choice, although there is ongoing discussion about the mode of administration and the best drug to choose. The results of ESETT, ConSEPT, and EcLiPSE will affect our future management of status, as we give consideration to levetiracetam as an alternative to phenytoin. Other medications such as lacosamide may emerge in future algorithms too. PMID- 29474273 TI - Damage control resuscitation in pediatric trauma. AB - PURPOSE OF REVIEW: Damage control resuscitation is an overall management strategy used in trauma patients to rapidly restore physiologic stability, while mitigating hypothermia, coagulopathy and acidosis. We review the evidence and current practice of damage control resuscitation in pediatric trauma patients with a specific focus on fluid management. RECENT FINDINGS: There have been a number of studies over the last several years examining crystalloid fluid resuscitation, balanced blood product transfusion practice and hemostatic agents in pediatric trauma. Excessive fluid resuscitation has been linked to increased number of ICU days, ventilator days and mortality. Balanced massive transfusion (1 : 1 : 1 product ratio) has not yet been demonstrated to have the same mortality benefits in pediatric trauma patients as in adults. Similarly, tranexamic acid (TXA) has strong evidence to support its use in adult trauma and some evidence in pediatric trauma. SUMMARY: Attention to establishing rapid vascular access and correcting hypothermia and acidosis is essential. A judicious approach to crystalloid resuscitation in the bleeding pediatric trauma patient with early use of blood products in keeping with an organized approach to massive hemorrhage is recommended. The ideal crystalloid volumes and/or blood product ratios in pediatric trauma patients have yet to be determined. PMID- 29474274 TI - An Environmental influences on Child Health Outcomes viewpoint of data analysis centers for collaborative study designs. AB - PURPOSE OF REVIEW: A highly complex collaborative study design that pools and extends existing studies, such as the Environmental influences on Child Health Outcomes (ECHO) Program, requires a Data Analysis Center (DAC) with resources and expertise to create a secure environment for housing and analyzing the shared data, harmonize and structure the shared data for different purposes, and apply appropriate and innovative designs and analytic methods. The DAC, in partnership with cohort investigators, must ensure that results from ECHO-wide cohort analyses are appropriately interpreted and reproducible. RECENT FINDINGS: Understanding the cohorts contributing to ECHO is critical for developing a collaborative environment and the methods to best analyze the data without bias. We further describe the development of the ECHO-wide cohort Metadata Catalog, the architecture of the ECHO-wide cohort data platform, and analytical approaches to facilitate early productivity. SUMMARY: The ECHO DAC has established a secure environment for the transfer and storage of ECHO cohort data and information, and initiated processes to promote productive collaborations. Understanding the ECHO DAC responsibilities and assets will help to overcome communication and trust challenges encountered in the initiation of this complex ECHO-wide cohort collaborative research study. PMID- 29474276 TI - 38th American Urogynecologic Society Annual Scientific Meeting President's Address: Building Our Future on a Strong Foundation. PMID- 29474275 TI - Development and Validation of a Simultaneous Quantification Method of Ruxolitinib, Vismodegib, Olaparib, and Pazopanib in Human Plasma Using Liquid Chromatography Coupled With Tandem Mass Spectrometry. AB - BACKGROUND: A simple, rapid, and sensitive liquid chromatography coupled with tandem mass spectrometry method has been developed and validated for the quantification of ruxolitinib, olaparib, vismodegib, and pazopanib in human plasma. METHODS: After a simple protein precipitation of plasma samples, the chromatographic separation was performed using an ultraperformance liquid chromatography system coupled with mass tandem spectrometry in a positive ionization mode. The mobile phase consisted of a gradient elution of 10-mmol/L formate ammonium buffer containing 0.1% (vol/vol) formic acid (phase A) and acetonitrile with 0.1% (vol/vol) formic acid (phase B) at a flow rate at 300 uL/min. RESULTS: Analysis time was 5.0 minutes per run, and all analytes and internal standards eluted within 1.5-1.73 minutes. The calibration curves were linear over the range from 10 to 2500 ng/mL for ruxolitinib and from 100 to 100,000 ng/mL for olaparib, vismodegib, and pazopanib with coefficients of correlation above 0.99 for all analytes. The intraday and interday coefficients of variation were below 14.26% and 14.81%, respectively, for lower concentration and below 9.94% and 6.37%, respectively, for higher concentration. CONCLUSIONS: Using liquid chromatography coupled with tandem mass spectrometry, we have developed and validated a simple and rapid assay for the simultaneous quantification of olaparib, vismodegib, pazopanib, and ruxolitinib in human plasma. This method is now part of our therapeutic drug monitoring service provision and is currently used clinically to manage patients prescribed these drugs. PMID- 29474277 TI - J. Marion Sims and the Vesicovaginal Fistula: Historical Understanding, Medical Ethics, and Modern Political Sensibilities. AB - OBJECTIVES: To review the historical background surrounding the early work of Dr. J. Marion Sims, who developed the first consistently successful surgical technique for the repair of obstetric vesicovaginal fistulas by operating on a group of young, enslaved, African American women who had this condition between 1846 and 1849. METHODS: Review of primary source documents on Sims and his operations, early 19th century clinical literature on the treatment of vesicovaginal fistula, the introduction of ether and chloroform anesthesia into surgical practice, and the literature on the early 19th century medical ethics pertaining to surgical innovation. The goals are to understand Sims's operations within the clinical context of the 1840s and to avoid the problems of "presentism," in which beliefs, attitudes, and practices of the 21st century are anachronistically projected backward into the early 19th century. The object is to judge Sims within the context of his time, not to hold him accountable to standards of practice which were not developed until a century after his death. RESULTS: A narrative of what Sims did is presented within the context of the therapeutic options available to those with fistula in the early 19th century. CONCLUSIONS: Review of the available material demonstrates that Sims' first fistula operations were legal, that they were carried out with express therapeutic intent for the purpose of repairing these women's injuries, that they conformed to the ethical requirements of his time, and that they were performed with the patients' knowledge, cooperation, assent, and assistance. PMID- 29474278 TI - Operating Room Efficiency: Examining the Impact of Personnel Handoffs. AB - OBJECTIVES: This study aimed to determine if personnel handoffs or number of learners in the operating room (OR) are associated with longer OR times in women having pelvic organ prolapse surgery. METHODS: A retrospective review of women undergoing prolapse surgery in 2016 was conducted. Demographics; procedure; OR, anesthetic, and surgical time; number of handoffs between anesthesia members, circulators, and surgical technologies; and number of learners were abstracted. RESULTS: One hundred forty-eight women underwent pelvic organ prolapse surgery. Mean age was 54 +/- 14 years, and most women were healthy and white. Procedures performed were as follows: 31% laparoscopic sacrocolpoexies (LASCs), 28% robotic sacrocolpopexies (RASCs), 19% colpocleises, and 22% native tissue reconstructions. For minimally invasive sacrocolpopexies (LASC + RASC), mean OR time was 270 +/- 65 minutes. Median anesthesia, surgical technology, and circulator handoffs for sacrocolpopexies were 2 (interquartile range, 0-4), 1 (0 3), and 2 (2-6). Median number of learners in the OR for sacrocolpopexies was 4 (interquartile range, 1-7). Patient comorbidities and American Society of Anesthesiologists class were not associated with longer OR times (P = 0.9 and P = 0.4). Longer OR times were positively correlated with increasing numbers of anesthesia, surgical technology, and circulator handoffs, but not with the number of learners (Spearman rho = 0.34, P = 0.001; rho = 0.34, P < 0.001; rho = 0.59, P < 0.001, and rho = 0.16, P = 0.43). For LASC, every technology handoff was associated with 23 additional minutes of OR time (P = 0.004). For RASC, every technology handoff was associated with 31 additional minutes of OR time (P = 0.007), and each circulator handoff was associated with 15 additional minutes (P = 0.05). CONCLUSION: Handoffs between OR personnel are associated with longer OR times, independent of patient factors. PMID- 29474279 TI - The Impact of the Affordable Care Act on Urogynecologic Surgery Cancelation Rates. AB - OBJECTIVES: We examined the impact of the implementation of the Affordable Care Act (ACA) on female pelvic medicine and reconstructive surgery (FPMRS) surgical cancelation rates. METHODS: A retrospective cohort study was performed on patients scheduling FPMRS procedures 1 year before and after ACA implementation at a regional academic medical center. We compared cancelation rates as well as sociodemographic, surgical, and medical history data. Analysis included chi test, t test, and univariable and multivariable logistic regression. RESULTS: We included 746 subjects, 373 each before and after ACA implementation (January 2014). Subjects were 59.2 +/- 14.0 years old, predominantly white (94.9%), employed (45.8%), and married (66.6%), with a body mass index of 28.8 +/- 6.2. Subjects lived a median of 24 miles from the hospital. None of these were significant predictors of cancelations. Surgery cancelation rate was 17.1% and occurred 9 days before surgery.On univariable analysis, cancelation rates did not differ relative to the ACA (15.5% before vs 18.6% after; mean difference, 3.16%; 95% confidence interval [CI], -2.29% to 8.69%; P = 0.254). Only 3 variables impacted cancelation rate on univariable analysis: women whose surgery was scheduled for later in the week, liver/renal disease, and minor vs major surgery.On multivariable regression including variables with P < 0.20 as candidate variables, the same 3 variables remained significant. Cancelations increased with procedures scheduled later in the week (odds ratio [OR], 1.169 per day; 95% CI, 1.004-1.361) and liver or renal disease (OR, 2.342; 95% CI, 1.015 5.405). Major procedures had fewer cancelations (OR, 0.625; 95% CI, 0.414-0.943). The ACA implementation of still did not impact cancelations (OR, 1.230; 95% CI, 0.831-1.821). CONCLUSIONS: The implementation of the ACA did not impact FPMRS cancelation rates. Significant predictors of surgical cancelation included later day of the week, comorbid renal or liver disease, and performance of a minor procedure. PMID- 29474280 TI - The Effect of Oral Phenazopyridine on Perioperative Voiding After Midurethral Slings (EPIPhANy Study). AB - OBJECTIVE: To determine the effect of preoperative oral phenazopyridine on postoperative voiding dysfunction in women undergoing a retropubic midurethral sling. METHODS: A single-institution randomized clinical trial was performed from September 2015 to March 2017, comparing 200 mg of oral phenazopyridine versus no phenazopyridine in patients undergoing a retropubic midurethral sling under general anesthesia with no concomitant procedures. A power calculation indicated that we required at least 40 subjects per arm. Preoperative demographics, intraoperative medications, blood loss, and complications were recorded. A standardized voiding trial was performed before discharge. Voiding dysfunction was determined by the proportion of subjects who failed a postoperative voiding trial. Pain scores were obtained before and 2 to 3 hours after the surgical procedure. Patient characteristics and surgical data were compared using chi, Fisher exact test, or Wilcoxon rank sum test. RESULTS: Ninety-two subjects were enrolled in the study. Three patients cancelled their surgery and 1 had an intraoperative urethral injury, leaving 88 patients for the final analysis (44 per arm). Patient demographics showed no differences between groups. Phenazopyridine did not reduce the proportion of patients who failed the voiding trial (27%) compared with subjects who did not receive the medication (21%) (P = 0.453). Postoperative visual analog pain scores were higher in those not receiving phenazopyridine (1.76 vs 1.21, P = 0.046), but after adjusting for the difference in preoperative and postoperative pain scores, the groups showed no difference (P = 0.087). CONCLUSIONS: Our prospective trial shows that phenazopyridine has no effect on short-term postoperative voiding dysfunction. This condition appears to be multifactorial, and further research is needed. PMID- 29474281 TI - The Utility of Preoperative Laboratory Testing Before Urogynecologic Surgery. AB - OBJECTIVES: National guidelines for preoperative laboratory testing are based on limited, low-quality evidence. The role of age as a risk factor for testing is unclear. We sought to compare the prevalence of abnormal preoperative laboratory results in older vs younger urogynecologic surgical patients. METHODS: In this retrospective cohort study of women undergoing urogynecologic surgery, we compared older (age, >=65 years) with younger (age, 50-64 years) women. Our primary outcome was the prevalence of an abnormal preoperative laboratory result. RESULTS: We included 317 women, with 167 (52.7%) in the older cohort (ages, 65-91 years; mean, 73.3 +/- 5.6 years) and 150 (47.3%) in the younger cohort (ages, 50 64 years; mean, 57.3 +/- 4.1 years). Overall, 18.3% of participants had at least one abnormal preoperative laboratory, with older women more likely to have an abnormal result (28.7% vs 10.7%, P < 0.001). Compared with the younger cohort, older women had higher rates of abnormal hemoglobin (13.8% vs 6.0%, P = 0.02) and creatinine values (10.8% vs 2.7%, P = 0.005), with no significant differences for platelets (3.0% vs 1.3%, P = 0.53), sodium (3.0% vs 0.7%, P = 0.22), or potassium (6.0% vs 3.3%, P = 0.27). After adjusting for potential confounders, older age remained associated with an abnormal preoperative result (odds ratio, 3.6; 95% confidence interval, 1.9-7.1). CONCLUSIONS: In our sample, women 65 years or older had a greater than 25% chance of having an abnormal preoperative laboratory result and were at higher risk compared with younger women. Age 65 years or greater should be considered as a criterion for preoperative laboratory testing in urogynecologic patients. PMID- 29474282 TI - Online Physician Reviews in Female Pelvic Medicine and Reconstructive Surgery: What Do Patients Really Want? AB - OBJECTIVES: This study aimed to qualitatively analyze online reviews of Female Pelvic Medicine and Reconstructive Surgery (FPMRS) specialists to better understand patients' experiences and improve patient satisfaction. METHODS: Fifty urologists and urogynecologists were randomly sampled from the Society of Urodynamics, Female Pelvic Medicine, and Urogenital Reconstruction membership website. We evaluated patient ratings and reviews of physicians from 4 websites: Yelp, Healthgrades, Vitals, and UCompareHealthCare. Qualitative data analysis was performed using grounded theory methodology, as described by Charmaz (Constructing Grounded Theory, 2014). RESULTS: Across the four websites, the mean number of stars per physician ranged from 3.6 to 4.1 and the mean number of reviews per physician ranged from 1.3 to 7.6. Qualitative analysis revealed several preliminary themes: patient-physician experience, medical and surgical treatment, office staff, and analysis of worth. Physicians who developed strong connections with patients through empathetic communication were likely to receive a positive review, regardless of wait times. Bedside manner was found to be multidimensional and included physician competence and understanding patients' concerns. Failure to meet several expectations led to dissatisfaction of care and negative patient reviews. CONCLUSIONS: Patients' perspectives of quality of care in FPMRS are weighted heavily toward establishing personal connections with physicians. Accurate diagnosis and effective management of urological conditions, especially after negative experiences with previous providers, were associated with satisfaction of care. It seems that the concept of good bedside manner is multifactorial and requires the provider to demonstrate not one but several different sets of communication skills. PMID- 29474283 TI - FACE: Female Pelvic Medicine and Reconstructive Surgery Awareness Campaign: Increasing Exposure. AB - OBJECTIVE: The aims of this study are to identify screening, treatment, and referral practices of primary care physicians (PCPs) for patients with pelvic floor disorders (PFDs) and evaluate awareness of the Female Pelvic Medicine and Reconstructive Surgery (FPMRS) subspecialty. METHODS: We conducted a cross sectional survey of PCPs using a random sample of 1005 American College of Physicians members, stratified by demographic region. Electronic survey content included awareness of FPMRS certification, comfort diagnosing and treating PFDs, and PFD referral patterns for PCPs. RESULTS: The 399 survey respondents were predominately male and of diverse ages, geographic distribution, and experience level.Forty-eight percent were aware of the FPMRS subspecialty, 31% of FPMRS board certification, and 25% of American Urogynecologic Society. Less than one third screened for PFDs, only two thirds were comfortable diagnosing urinary complaints, and even fewer felt comfortable diagnosing pelvic organ prolapse and fecal incontinence (FI).Eighty-five percent recommended pelvic floor exercises for stress urinary incontinence and referred to urology (29%) or FPMRS (25%) as second-line therapy, whereas 55% recommended medication/fiber for FI and referred to gastroenterology/colorectal surgery (31%) and FPMRS (2%) as second-line therapy.Primary care physicians referred to colorectal surgery for FI (60%), to Ob/Gyn for obstetric anal sphincter injury (38%) and pelvic organ prolapse (57%), and to urology for microscopic hematuria (80%), overactive bladder (60%), recurrent urinary tract infection (75%), stress urinary incontinence (48%), and voiding dysfunction (84%). CONCLUSIONS: Most PCPs do not routinely screen for PFDs, and fewer feel comfortable treating. The majority is unaware of FPMRS and American Urogynecologic Society and more commonly refers PFD patients to other specialists. PMID- 29474284 TI - Pelvic Organ Prolapse and Urinary Incontinence in Women After Bariatric Surgery: 5-Year Follow-up. AB - OBJECTIVE: The objective of this study was to determine if weight loss surgery is associated with decreased prevalence of urinary incontinence (UI) and pelvic organ prolapse (POP) symptoms. METHODS: A survey was conducted among previously morbidly obese women who underwent bariatric surgery at Brigham and Women's Hospital, Boston from 2007 to 2015. In addition to the Pelvic Floor Distress Inventory 20, we collected demographic and clinical data including symptoms of and treatment for UI and POP before surgery. Participants were divided into 4 quartiles based on self-reported postsurgical weight loss: less than 26.1 kg, 26.1 to 36.2 kg, 36.3 to 46.2 kg, and greater than 46.2 kg. Cox proportional hazard ratios were used to estimate risk of UI and POP by quartile. Kruskal Wallis test was used to compare bother scores between the groups. RESULTS: A total of 447 women responded to the survey. Mean follow-up from surgery was 5 years. Women with Roux-en-Y gastric bypass had significantly greater weight loss than gastric banding or sleeve gastrectomy. The adjusted hazard ratios of current UI, stress UI, urgency UI, and prolapse decreased with increasing weight loss quartile (P trend <0.005). Based on the Pelvic Floor Distress Inventory 20, prevalence of POP symptoms was 26% with a mean bother score of 50. Although symptom bother by quartile of weight loss was not statistically significant, the trend (from the first to fourth quartile) for the mean values of Urogenital Distress Inventory 6 (from 13 to 9) and Pelvic Organ Prolapse Distress Inventory 6 (from 26 to 20) showed an improvement in bother symptoms. CONCLUSIONS: There exists an inverse relationship between amount of weight loss and subsequent POP and UI symptoms 5 years after bariatric surgery. PMID- 29474285 TI - Incidence of Obstetric Anal Sphincter Injuries After Training to Protect the Perineum. AB - OBJECTIVES: Obstetric anal sphincter injuries (OASISs) are a devastating postpartum complication; reducing rates is paramount to improving quality of care. In Norway, implementation of a perineal protection program decreased the incidence of OASIS by 48%. We sought to assess impact on OASIS rates following a similar program. METHODS: This institutional review board-approved, retrospective cohort study was performed in an academic hospital system. The periods of analysis were November 2014 through October 2015 for the preintervention arm and November 2015 through October 2016 for the postintervention arm. From November 2 to 6, 2015, 2 Norwegian experts conducted a didactic and hands-on, on-site workshop focusing on perineal protection. The experts were then present on labor and delivery wards to reinforce perineal protection in live deliveries. Teachings were emphasized at departmental meetings for the remainder of the year. Data were extracted from electronic medical records and manually audited. RESULTS: The rate of vaginal delivery was similar among both periods (6504 and 6650; P = 0.059). Obstetric anal sphincter injury rates decreased from 211 (3.2%) preintervention to 189 (2.8%) after the workshop. Although this represented 32 fewer injuries, it was not statistically significant (P = 0.179). Obstetric anal sphincter injuries following forceps-assisted deliveries did decline significantly from 103 (28%) to 81 (21%) (P = 0.014). In addition, incidence of fourth-degree lacerations during resident deliveries decreased significantly from 10 (0.6%) to 3 (0.2%) (P = 0.047). CONCLUSIONS: An educational workshop focusing on perineal support was not associated with a significant reduction in overall OASIS rates. Nevertheless, decreased forceps-related OASIS and fourth-degree lacerations rates support positive influence of the intervention. PMID- 29474286 TI - Cranberry Supplementation Does Not Reduce Urinary Tract Infections in Patients With Indwelling Catheters After Pelvic Reconstructive Surgery. AB - OBJECTIVES: Urinary tract infections (UTIs) are common after pelvic reconstructive surgery, likely due to high rates of urinary retention. We sought to determine if prescription of cranberry capsules reduced UTIs in postoperative patients requiring catheter use. METHODS: This was an institutional review board approved retrospective cohort study. Two 6-month periods were compared: April to September 2015, before cranberry capsules were incorporated, and April to September 2016, after cranberry capsules were implemented. Our study population included patients discharged with a catheter after pelvic reconstructive surgery. All charts were reviewed for demographics, perioperative data, and urine cultures up to 6 weeks postoperatively. A UTI was defined as treatment with antibiotics or positive cultures. Statistical analysis was performed; logistic regression evaluated for relationships between UTI and other factors. Our a priori sample size calculation determined 88 subjects per group would be necessary. RESULTS: Over the 2 periods, 167 patients met inclusion criteria: 71 before and 96 after cranberry implementation. The 2 cohorts were similar in all data. Regarding incidence of UTI, rates were overall high and not significantly different between groups (76% before cranberry vs 69% with cranberry; P = 0.299). The median duration of catheter use was 8 days in both cohorts. The UTI was most likely to occur in the second week after surgery. Logistic regression revealed no associations between age, surgery type, duration of catheter use, and UTI. CONCLUSIONS: In this retrospective study, prescription of cranberry capsules did not significantly reduce UTI rates among patients with urinary catheters after pelvic reconstructive surgery. PMID- 29474287 TI - A Systematic Review of Frailty Assessments in Women With Pelvic Floor Disorders: Are We Following the American College of Surgeons National Surgical Quality Improvement Program/American Geriatric Society Guidelines? AB - INTRODUCTION: Associations between frailty and women with pelvic floor disorders (PFDs) are not well understood. This study seeks to describe studies among women with PFD and the associated frailty assessments as recommended in the American College of Surgeons National Surgical Quality Improvement Program/American Geriatric Society (ACS NSQIP/AGS) guidelines. METHODS: This systematic review was registered with PROSPERO using the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. The GRADE (Grading of Recommendations, Assessment, Development and Evaluations) criteria are applied to assess study quality. Data synthesis is descriptive. Outcomes of interest include the ratio of studies adhering to the ACS NSQIP/AGS guidelines and evidence for frailty assessments versus usual care for women with PFDs. RESULTS: Twenty studies regarding frailty and PFDs were included for systematic review. Studies were categorized as relating to (1) epidemiology, (2) frailty and incontinence, (3) postoperative morbidity, and (4) surgical choice. Most studies (5/20) did not define frailty or failed to follow the ACS NSQIP/AGS guidelines. All studies were of very low to low quality. Collectively, each category generated very low GRADE quality evidence of frailty and the relationship to PFDs. CONCLUSIONS: Most studies regarding frailty among women with PFDs did not define frailty as recommended in the ACS NSQIP/AGS guidelines. The evidence regarding PFDs and frailty is of very low quality. This is the first systematic review regarding frailty assessments specifically among women with PFDs. Paucity of data regarding frailty in women with PFDs, particularly with regard to surgical choice and surgical counseling, highlights the need for further study in this area. PMID- 29474288 TI - Pelvic Floor Muscle Training Versus Watchful Waiting and Pelvic Floor Disorders in Postpartum Women: A Systematic Review and Meta-analysis. AB - OBJECTIVES: Pelvic floor muscle training (PFMT) is often recommended to treat postpartum urinary incontinence (UI). However, the role of postpartum PFMT in pelvic organ prolapse (POP), sexual function, and anal incontinence (AI) remains unclear. We therefore aim to assess the efficacy of postpartum PFMT on these pelvic floor disorders. METHODS: This study is a meta-analysis consisting of randomized controlled trials (RCTs). We searched databases including CENTRAL, MEDLINE, EMBASE, CINAHL, and PEDro. We also sought after grey literature including conference proceedings. We included RCTs comparing PFMT versus watchful waiting in women with stage II or less POP within 1 year postpartum. Two authors independently performed study screening, risk of bias assessments, and data extraction. RESULTS: Fifteen RCTs (3845 patients) were included. Women undergoing PFMT less likely report bothersome POP symptoms (risk ratio [RR], 0.48 [0.30 0.76]; very low-quality evidence). There is no significant difference in the number of women with stage II or greater POP (RR, 0.74 [0.45-1.24]; moderate quality evidence). Fewer women receiving PFMT report the presence of sexual dysfunction (RR, 0.48 [0.30-0.77]; low-quality evidence). There is no significant difference in AI symptoms (RR, 1.11 [0.82-1.51]), but PFMT may be more beneficial for women with anal sphincter injuries (standardized mean differencein AI scores, -0.57 [-1.12 to -0.02]; low-quality evidence). Women receiving PFMT less likely report UI (RR, 0.44 [0.25-0.75]; moderate-quality evidence) with a more pronounced effect on stress UI (SUI). CONCLUSIONS: At present, it remains uncertain whether postpartum PFMT improves POP symptoms because of very low quality evidence, and more high-quality RCTs are needed in this area. The POP staging will likely not change with postpartum PFMT. The PFMT may result in improved postpartum sexual function compared to watchful waiting, and may provide benefit for AI in women with anal sphincter injuries. Postpartum PFMT likely reduces the risk of UI, particularly stress urinary incontinence symptoms. There is currently little evidence about postpartum PFMT and long-term pelvic floor function. PMID- 29474289 TI - Sequence of Pelvic Examination Affects Patient-Reported Pain. AB - OBJECTIVE: The purpose of this trial is to compare patient-reported pain based on the sequence of the pelvic examination and to assess the relationship between pain during the examination and quality of life, self-esteem, and sexual function. METHODS: A randomized controlled trial of women presenting for annual gynecologic examinations. Women were assigned to either group A: a Q-tip touch test, speculum examination, then bimanual examination or group B: Q-tip touch test, bimanual examination, then speculum examination. The primary outcome was visual analog scales to assess pain at baseline and after each portion of the examination. Secondary outcomes were responses to questionnaires for self-esteem, quality of life, and sexual function. RESULTS: Of 200 women who enrolled, 192 (96%) completed all visual analog scale data points. Each portion of the examination caused minimal pain over baseline in each group. Pain during the speculum examination was higher than pain during the bimanual examination in both groups (P = 0.007 and P < 0.001). Group B, however, had significantly higher pain scores after the speculum examination than group A (P = 0.044). The groups did not differ on bimanual pain scores (P = 0.76). Pain scores were not statistically different when analyzed by age, parity, sexual activity, sexual orientation, education, or previous hysterectomy. Within both groups, patients who documented having any pain after the speculum examination or the bimanual examination were also more likely to have lower quality of life scores (P < 0.001 and P < 0.001). CONCLUSIONS: Pain associated with the speculum examination was lower in those undergoing speculum before bimanual examination. Speculum pain was greater than bimanual pain in both groups. Most patients reported minimal or no pain during the different portions of the examination. PMID- 29474290 TI - Does Patient Education Augment Pelvic Floor Physical Therapy Preparedness and Attendance? A Randomized Controlled Trial. AB - OBJECTIVES: The objective of this study was to evaluate patient attendance and preparedness for pelvic floor physical therapy (PFPT) after comparing standard counseling versus standard counseling plus an educational video. METHODS: A randomized controlled trial of 200 patients in a Female Pelvic Medicine and Reconstructive Surgery practice was performed in a tertiary care referral center. Participants were randomized to 1 of 2 educational modalities after being prescribed PFPT. Women either received standard handout counseling or enhanced video counseling. A sample size of 96 per group (N = 192) was needed to detect a 20% difference in PFPT attendance corresponding to a priori estimates of 50% compliance for the standard counseling group (handout) versus 70% compliance for the enhanced counseling group (handout plus video). Compliance data were assessed at least 3 months after the initial referral to determine attendance at PFPT. RESULTS: Sixty-five percent of patients attended at least 1 PFPT visit, whereas 46.5% completed therapy. There was no difference between the standard and enhanced counseling groups in PFPT attendance (P = 0.056) or in completion of half the recommended visits (P = 0.17). Similarly, level of preparedness after viewing the assigned counseling modality did not differ between standard and enhanced counseling groups. For each additional completed visit, the odds of successfully completing PFPT increased by approximately 38% (odds ratio, 1.38; 95% confidence interval, 1.19-1.59). CONCLUSIONS: The addition of enhanced patient counseling did not improve patient preparedness or odds of attending PFPT. Adherence behaviors surrounding PFPT attendance are multifactorial and require further qualitative research to elucidate barriers to PFPT attendance. PMID- 29474291 TI - Randomized Cross-over Comparison of IconTM Reusable Underwear to Disposable Pads for the Management of Mild to Moderate Urinary Incontinence. AB - OBJECTIVE: The objective of this study was to compare disposable pads to IconTM reusable underwear for the management of urinary incontinence on dimensions of quality of life and product performance. METHODS: This randomized cross-over trial included women with mild to moderate urinary incontinence as defined by baseline responses to the International Consultation on Incontinence Questionnaire-Short Form. Excluded were patients who had fecal incontinence or an active urinary tract infection. Participants were randomized to 2 days of IconTM underwear or disposable pads use and then completed another 2 days using the alternate product. Outcome measures were responses to Incontinence Quality of Life Instrument (I-QOL) and Product Performance Questionnaire for each product. RESULTS: Of the 70 women who were randomized, 52 completed the study. There was no significant difference between IconTM underwear and disposable pads with regards to I-QOL total scores (66.2 +/- 23.4 vs 65.5 +/- 24.5, P = 0.71) or I-QOL subscores: avoidance and limiting behaviors (62.1 +/- 24.4 vs 62.4 +/- 25.0, P = 0.88), psychosocial impacts (74.4 +/- 25.0 vs 73.4 +/- 25.6, P = 0.51), and social embarrassment (57.8 +/- 27.8 vs 56.1 +/- 29.5, P = 0.43). IconTM underwear scored significantly better than disposable pads on the Product Performance Questionnaire, with regards to overall impression (P = 0.0002), fit (P < 0.0001), discreteness (P < 0.0001), comfort when dry (P < 0.0001), comfort when wet (P = 0.0008), ability to keep skin dry (P = 0.0034), and kindness to skin (P < 0.0001). There was no difference between products in ability to hold urine without leaking (P = 0.40) or prevent odor when worn (P = 0.41). CONCLUSIONS: There was no difference in quality of life measures between IconTM underwear and disposable pad users; however, IconTM underwear was preferred on product performance. PMID- 29474292 TI - Changes in the Vaginal Microenvironment as Related to Frequency of Pessary Removal. AB - OBJECTIVE: The aim of the study was to describe the effect of frequency of pessary removal on the vaginal microenvironment. METHODS: We performed a secondary analysis of a multicenter randomized trial of hydroxyquinoline gel in women presenting for pessary fitting. Patients had vaginal secretions analyzed at baseline, 2 weeks, and 3 months. Patients were stratified by frequency of pessary removal at least once daily, at least once weekly, and less often than once weekly. These groups were compared for prevalence of Lactobacillus predominance (primary outcome), anaerobic predominance, Mobiluncus prominence, vaginal symptoms, and bacterial vaginosis by Nugent criteria, and correction for confounding variables was performed. RESULTS: One hundred thirty-seven women were included in this analysis: 34 (25%) removed the pessary daily, 54 (39%) at least weekly, and 49 (36%) less often than once weekly. Women who removed the pessary less often than weekly were older (P < 0.01), using more hormone therapy (P = 0.03), and more likely to have bacterial vaginosis at baseline (P < 0.01). At 2 weeks, the predominance of Lactobacillus in the group removing pessary daily was higher (41% daily vs 24% weekly vs 9% longer, P = 0.03) and this persisted after confounder correction (P < 0.01). Women who removed their pessary less than weekly were more likely to have anaerobic predominance at 3 months (P = 0.04). CONCLUSIONS: Women who remove their pessaries less often than once weekly have an increased prevalence of anaerobes at 3 months, but no difference in vaginal symptoms or pessary satisfaction. PMID- 29474293 TI - Predicting Pain Levels Following Vaginal Reconstructive Surgery: Who Is at Highest Risk? AB - OBJECTIVES: An ability to anticipate individuals at increased risk of postoperative pain would improve coordination of care and patient satisfaction. We sought to describe predictive factors of postoperative pain following vaginal reconstructive surgery. METHODS: This institutional review board-approved, retrospective study used previously collected data from research performed at 1 center from 2009 to 2015. Eligible trials enrolled subjects undergoing vaginal reconstructive surgery for pelvic organ prolapse. All studies used a validated visual analog scale (VAS) for pain on postoperative day 1. Other information collected included pain medication use, medical and surgical history, and demographics. Linear regression analyses, multiple regression analyses, Mann Whitney U, and Kruskal-Wallis tests were used to analyze the relationship between VAS scores and other variables. RESULTS: Six studies were analyzed with a total of 364 patients. The median age was 60 years (interquartile range, 16 years), and the median pain score on postoperative day 1 was 35 mm on a 100-mm VAS. Patients younger than 60 years (P < 0.001), those who used tobacco (P = 0.014), those who used pain medication prior to surgery (P = 0.007), and those who did not have a concomitant midurethral sling (P = 0.018) had significantly higher pain scores postoperatively. A trend was also noted with operating times greater than 210 minutes (P = 0.057) and preexisting history of depression (P = 0.065). Multiple regression was performed, and age, depression, tobacco use, and concomitant sling were found to be independent factors predictive of postoperative pain scores. CONCLUSIONS: Age, depression, tobacco use, and concomitant midurethral sling are significant independent factors predictive of postoperative pain following vaginal reconstructive surgery. PMID- 29474294 TI - Surgical Anatomy of Vaginal Hysterectomy-Impact of a Resident-Constructed Simulation Model. AB - OBJECTIVES: Obstetrics and gynecology residents are less prepared to perform vaginal hysterectomy (VH), despite its advantages over other hysterectomy routes. The American Congress of Obstetricians and Gynecologists and Council on Resident Education in Obstetrics and Gynecology have prioritized simulation training in VH. Our objective was to improve residents' understanding of surgical anatomy of VH using a resident-constructed, low-cost, low-fidelity model. METHODS: A single simulation session was held in November 2016. Residents constructed a pelvic model, guided by 2 surgeons. A pretest and a posttest were administered. Experienced-based responses were tabulated for frequencies and contents. Improvement on knowledge-based questions was assessed using McNemar's test. RESULTS: Of 20 residents, 16 completed the pretest and 14 (70%) completed pretests and posttests. One hundred percent of postgraduate year (PGY)-4 had performed greater than 10 VH (11-21) and 75% of PGY-3 had performed 5 to 12 VH. Although 75% of PGY-3 and 100% of PGY-4 felt comfortable performing VH, baseline knowledge of essential surgical anatomy of VH was low (65.8%). The PGY-3 and -4 group (n=8) experienced a mean improvement of 24.4% (mean pretest score 65.8% vs mean posttest score 90%; 95% confidence interval, +14.1% to +33.3%, P=0.0005). The PGY-1 and -2 groups (n=6) experienced a mean improvement of 43.3% (mean pretest score, 41.7% vs mean posttest score, 85%; 95% confidence interval, +26.7% to +59.2%, P=0.001). After the session, all residents reported improved understanding surgical anatomy of VH and "more hands-on sessions" was the most frequently requested teaching aid. CONCLUSIONS: Residents desire additional model based simulation training in VH, and such structured, model-based simulations can identify and address gaps in resident knowledge of surgical anatomy of this important operation. PMID- 29474295 TI - Refractive Outcomes After Phototherapeutic Refractive Keratectomy for Granular Corneal Dystrophy. AB - PURPOSE: This retrospective study aimed to evaluate the effectiveness of a novel procedure named phototherapeutic refractive keratectomy (PTRK), which is a sequential procedure composed of phototherapeutic keratectomy ablation for removal of opacities, followed by smoothing ablation for reducing the corneal surface irregularities and photorefractive keratectomy ablation for correcting refractive errors in eyes with primary granular corneal dystrophy. METHODS: Twenty-three eyes of 17 patients with granular corneal dystrophy were treated with PTRK. Preoperative and postoperative visual acuity, corneal topography, and changes in spherical equivalent and cylindrical refraction were examined and analyzed. RESULTS: The mean spherical equivalent power changed from -0.11 +/- 1.36 diopters (D) to 0.19 +/- 0.91 D postoperatively (P = 0.121). The change in the mean spherical equivalent was +0.30 +/- 0.99 D. The mean preoperative uncorrected distance visual acuity (logMAR) of 0.40 +/- 0.26 significantly improved to 0.075 +/- 0.145 at 3 months after PTRK (P < 0.001). The mean preoperative corrected distance visual acuity (logMAR) of 0.18 +/- 0.17 significantly improved to -0.02 +/- 0.11 at 3 months after PTRK (P < 0.01). The surface regularity index was significantly decreased from 0.93 +/- 0.46 preoperatively to 0.60 +/- 0.30 postoperatively (P < 0.001). CONCLUSIONS: Our results showed that PTRK could improve corneal surface irregularities and remove opacities. Furthermore, both corrected visual acuity and uncorrected visual acuity improved by the addition of refractive correction. PTRK is a promising surgical procedure for improving postoperative quality of life with a high degree of patient satisfaction. PMID- 29474296 TI - Assessment of Glaucomatous Damage After Boston Keratoprosthesis Implantation Based on Digital Planimetric Quantification of Visual Fields and Optic Nerve Head Imaging. AB - PURPOSE: To investigate glaucomatous damage in Boston keratoprosthesis type I (KPro) patients through structural analysis of the optic nerve head and digital planimetric quantification of Goldmann visual fields, a novel method of monitoring perimetric changes in KPro patients. METHODS: Records of patients undergoing KPro implantation from 2007 to 2015 at a single institution were reviewed. Parameters related to glaucoma status and KPro outcomes were analyzed. RESULTS: Twenty-two eyes from 21 patients met inclusion criteria, with mean follow-up of 49.4 months (range 15-90). Mean results for the following parameters before KPro implantation and at last follow-up were (pre-KPro; at last follow up): best-corrected visual acuity (2.07; 0.70 logMAR), number of glaucoma medications (1.14; 1.05), intraocular pressure (IOP) (18.4; 18.4 mm Hg), vertical cup-to-disc ratio (C/D) (0.48; 0.50), and horizontal C/D (0.52; 0.52). IOP lowering procedures were performed pre-KPro (5/22), concurrently with KPro (10/22), post-KPro (6/22), or never (6/22). An increase in C/D >=0.1 and loss of V4e isopter area >30% occurred in 22.7% and 12.5%, respectively. Development of post-KPro glaucoma, progression of preexisting or post-KPro glaucoma, and no glaucoma development as evidenced by an objective assessment of structural and functional parameters were seen in 2/22 (9.1%), 7/22 (31.8%), and 6/22 (27.3%) eyes, respectively. CONCLUSIONS: Clinicians should strive to vigilantly monitor for glaucoma despite the inherent difficulties in tonometry, optic nerve visualization and imaging, and visual field testing in KPro patients. Meticulous glaucoma surveillance with structural and functional testing combined with earlier IOP-lowering surgical intervention may result in decreased rates of glaucomatous vision loss in KPro patients. PMID- 29474297 TI - Recognition of Fungal Keratitis in Boston Type I Keratoprosthesis: Importance of Awareness and Novel Identification of Exophiala phaeomuriformis. AB - PURPOSE: To present a case of Exophiala phaeomuriformis fungal keratitis to demonstrate the heightened concern for fungal infection in patients with a keratoprosthesis and to highlight the rare involvement of Exophiala phaeomuriformis. METHODS: Case report. RESULTS: Exophiala phaeomuriformis was identified in a susceptible patient 7 years after Boston type I keratoprosthesis (KPro) implantation. CONCLUSIONS: Although fungal infiltration after KPro placement does not represent a novel clinical infection, identification of the rare Exophiala species in a patient with a KPro has not been reported and provides an opportunity for reflection on fungal identification, prophylaxis, and prevention in this vulnerable patient population. PMID- 29474298 TI - Descemet Membrane Endothelial Keratoplasty for Failed Deep Anterior Lamellar Keratoplasty: A Case Series. AB - PURPOSE: To suggest a new surgical approach for posterior opacities or persistent Descemet membrane (DM) detachment in failed deep anterior lamellar keratoplasty (DALK) and to report the outcome of Descemet membrane endothelial keratoplasty (DMEK) in a series of patients with DALK failure. METHODS: In this retrospective case series of patients who underwent DMEK for failed DALK at Toronto Western Hospital, 4 patients with failed DALK who underwent DMEK surgery were included. In all 4 cases, big bubble formation during initial DALK surgery had failed and the surgical technique was converted to manual dissection using the Melles technique. In 2 cases, the descemetorhexis in DMEK surgery was performed manually, and in 2 cases, the descemetorhexis was performed with the assistance of the femtosecond laser. RESULTS: Four eyes of 4 patients aged 70 +/- 4 years were included. Average follow-up time was 9 +/- 5 months. Indications for DALK surgery were corneal dystrophy in 2 patients and corneal scars in the other 2. DALK failure was due to persistent DM detachment that created a double chamber in 2 patients and due to posterior lamellar haze in the other 2. After DMEK surgery, 2 patients had graft detachment and required rebubbling. In 1 patient, the DMEK scroll was attached after 1 rebubble attempt, and in the other patient, a second rebubble attempt was needed. The final visual acuities were 20/40, 20/50, 20/70, and 20/200 (because of dense cataract). All procedures were uneventful. CONCLUSIONS: DMEK surgery may be effective in managing DALK failure. PMID- 29474299 TI - Descemet Membrane Endothelial Keratoplasty (DMEK) Under Previous DMEK for Secondary Endothelial Graft Failure. AB - PURPOSE: To describe an alternative treatment option for secondary Descemet membrane endothelial keratoplasty (DMEK) graft failure, using a second DMEK graft without primary graft removal ("DMEK under DMEK"). METHODS: A 72-year-old patient with pseudophakic bullous keratopathy in the left eye underwent an 8.25-mm second DMEK under an 8.5-mm failed DMEK because of previous graft rejection and subsequent secondary failure. RESULTS: Corrected distance visual acuity improved from 0.2 (decimal scale) before surgery to 0.56 (best visual potential due to concomitant preexisting macular damage) from the first month after surgery and up to sixth-month follow-up. Complete corneal transparency was achieved from the first postoperative day and remained until the end of the follow-up. Pachymetry returned to normal values within the first month. No intraoperative or postoperative complications were observed. CONCLUSIONS: A second DMEK graft without peeling or removing the first DMEK graft is an alternative treatment option for DMEK graft secondary failure. This approach is able to achieve full anatomical and functional restoration of the prefailure status. This technique allows a second graft surgery to be easier, faster, and with less intraoperative risks (as a result of a potential difficult host descemetorhexis). Future studies with larger samples and a longer follow-up are necessary to confirm the short and long-term outcomes of this new DMEK under DMEK approach. PMID- 29474300 TI - Corneal Neurotization With a Great Auricular Nerve Graft: Effective Reinnervation Demonstrated by In Vivo Confocal Microscopy. AB - PURPOSE: We describe the first case of minimally invasive corneal neurotization with the great auricular nerve (GAN) to treat unilateral neurotrophic keratopathy. We assessed corneal sensation and reinnervation by esthesiometry and confocal microscopy over 12 months of follow-up, and we provide a detailed description of the surgical technique. METHODS: Corneal neurotization was successfully achieved with the ipsilateral GAN in a 58-year-old woman. Cochet Bonnet esthesiometry and in vivo confocal microscopy were performed before and after corneal neurotization, to monitor the recovery of corneal sensation and corneal reinnervation by subbasal nerve fibers. RESULTS: Neurotrophic keratopathy was a complication of the surgical treatment of meningioma. Before surgery, the patient had no corneal sensation or corneal innervation. Six months after surgery, confocal microscopy confirmed regrowth of a large number of nerve fibers in the subepithelial space of the cornea. Nine months after surgery, a central esthesiometry score of 10-mm was attained. CONCLUSIONS: Corneal neurotization leads to reinnervation of the cornea and recovery of ocular sensation in adults. The GAN is suitable for use in corneal neurotization because of its anatomical proximity and the low level of associated morbidity. Confocal microscopy demonstrated the occurrence of corneal reinnervation, which preceded the recovery of corneal sensation. PMID- 29474301 TI - Letter to the Editor in Response to Kim et al, "Effect of Histocompatibility Y Antigen Matching on Graft Survival in Primary Penetrating Keratoplasty." PMID- 29474302 TI - ASSOCIATION BETWEEN EARLY ANATOMIC RESPONSE TO ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY AND LONG-TERM OUTCOME IN DIABETIC MACULAR EDEMA: AN INDEPENDENT ANALYSIS OF PROTOCOL I STUDY DATA. AB - PURPOSE: This post hoc analysis explores the relationship between early retinal anatomical response and long-term anatomical and visual outcomes with ranibizumab in center-involved diabetic macular edema. METHODS: Eyes randomized to the ranibizumab plus prompt laser and ranibizumab plus deferred laser treatment arms in the Protocol I study were categorized according to their proportional reduction (<20 vs. >=20%) in central retinal thickness (CRT) after 12 weeks. Adjusted and unadjusted analyses assessed the association between early (Week 12) anatomical response and long-term (Weeks 52 and 156) anatomical and best corrected visual acuity outcomes. RESULTS: Of 335 study eyes, 118 showed limited (<20%) and 217 showed strong (>=20%) CRT reduction at Week 12. In unadjusted and adjusted analyses, limited early CRT response was negatively and significantly associated with strong CRT response at Weeks 52 and 156. Sensitivity analyses indicated that this association was robust and unrelated to any "floor effect." In unadjusted analyses, a strong early CRT response was associated with greater long-term improvement in best-corrected visual acuity; after controlling for confounders, the association lost statistical significance. CONCLUSION: Early CRT response to ranibizumab is a significant prognostic indicator of medium- to long term anatomical outcome in center-involved diabetic macular edema.This is an open access article distributed under the terms of the Creative Commons Attribution Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 29474303 TI - ASSOCIATION OF OBSTRUCTIVE SLEEP APNEA WITH CENTRAL SEROUS CHORIORETINOPATHY AND CHOROIDAL THICKNESS: A Systematic Review and Meta-Analysis. AB - PURPOSE: Obstructive sleep apnea (OSA) has been associated with an array of ocular disorders. This systematic review aims to investigate the association of OSA with central serous chorioretinopathy (CSCR) and subfoveal choroidal thickness changes on enhanced depth imaging optical coherence tomography. METHODS: Systematic review and meta-analysis of all articles published up to November 2017 examining rate of OSA in patients with CSCR versus controls or examining subfoveal choroidal thickness measurements on enhanced depth imaging optical coherence tomography in patients with OSA versus controls. Pooled odds ratios and weighted mean difference with 95% confidence intervals (CIs) were calculated. RESULTS: For the CSCR/OSA analysis, 7,238 patients (1,479 with CSCR and 5,759 controls) from 6 studies were eligible. For the choroidal thickness/OSA analysis, 778 eyes of 778 patients (514 with OSA and 264 controls) from 9 studies were eligible. Patients with CSCR had a 1.56 increased odds of having OSA than controls (odds ratio, 1.56; 95% CI, 1.16-2.10). There was no statistically significant difference in choroidal thickness between mild OSA subjects and controls (weighted mean difference = -3.17; 95% CI, -19.10 to 12.76). Patients with moderate OSA (weighted mean difference = -24.14; 95% CI, -42.16 to -6.12) and severe OSA (weighted mean difference = -51.19; 95% CI, -99.30 to -3.08) had thinner choroidal thickness measurements than controls. CONCLUSION: In summary, our results suggest that patients with CSCR are more likely to have OSA, and that moderate/severe OSA is associated with smaller subfoveal choroidal measurements on enhanced depth imaging optical coherence tomography. PMID- 29474304 TI - MACULAR MICROVASCULAR NETWORKS IN HEALTHY PEDIATRIC SUBJECTS. AB - PURPOSE: To report optical coherence tomography angiography (OCTA) values in healthy pediatric eyes and to identify factors that may modify these values. METHODS: In this prospective observational cross-sectional study, macular OCTA images were acquired from healthy pediatric patients. Main outcome measures were 1) foveal avascular zone (FAZ) area at the level of the superficial retinal capillary plexus (SCP); 2) SCP and deep retinal capillary plexus (DCP) perfusion density (based on the area of vessels); 3) SCP and DCP vessel density (based on a map with vessels of 1-pixel width); and 4) CC perfusion density. Multiple regression analysis was performed to assess the effect of age, sex, ethnicity, refraction, and foveal macular thickness (FMT) on OCTA parameters. RESULTS: Seventy-seven eyes from 52 subjects (23 male and 29 female) were included in analysis. Mean age was 11.1 +/- 3.3 years (range = 5.0-17.0 years). Twenty-nine (55.8%) subjects were white, 14 (27.0%) Hispanic, 8 (15.4%) Asian, and 1 (1.8%) African-American. Mean refraction was -0.1 +/- 2.4 diopters (D) (range = -5.75 to +9.0 D). Mean FMT was 248.6 +/- 18.6 MUm. Larger FAZ area was significantly associated with older age (P = 0.014). Furthermore, larger FAZ area was associated with reduced FMT (P < 0.0001). Male sex was associated only with increased SCP perfusion density (P = 0.042). Increased CC perfusion density was associated with younger age (P = 0.022). CONCLUSION: We report data for pediatric OCTA parameters in healthy subjects. Several variables influence the density of macular microvascular networks, and these factors should be considered in the OCTA study of pediatric eye disorders. PMID- 29474305 TI - USE OF THE ISCHEMIC INDEX ON WIDEFIELD FLUORESCEIN ANGIOGRAPHY TO CHARACTERIZE A CENTRAL RETINAL VEIN OCCLUSION AS ISCHEMIC OR NONISCHEMIC. AB - PURPOSE: To understand the relationship between baseline ischemic index (IsI) values on ultra-widefield fluorescein angiography and classification as ischemic central retinal vein occlusion (CRVO). METHODS: Single-center retrospective cohort study of CRVO patients imaged using ultra-widefield fluorescein angiography from which IsI values were calculated. An ischemic CRVO was defined as those eyes with an afferent pupillary defect and counting fingers acuity or worse or neovascularization during the first year of follow-up. Logistic regression was performed to characterize the relation between the IsI and clinical outcomes. RESULTS: Sixty eyes of 60 treatment-naive CRVO patients with baseline ultra-widefield fluorescein angiography and >=1 year of follow-up were identified. Those with an IsI >=35% were significantly more likely to have an ischemic CRVO during the first year of follow-up than those with an IsI <35% (83.3 vs. 13.9%, odds ratio 111, P < 0.0001). Baseline and final logarithm of the minimum angle of resolution acuity were worse in eyes with an IsI >=35% (1.18 vs. 0.46, P < 0.001 and 1.26 vs. 0.45, P < 0.001, respectively) despite similar baseline and final central subfield thickness (P = 0.1-0.23). CONCLUSION: A baseline IsI of >=35% on ultra-widefield fluorescein angiography in eyes with treatment-naive CRVO was sensitive (90%) and specific (92.5%) for classification as an ischemic CRVO during the first year of follow-up. PMID- 29474306 TI - THREE-YEAR OUTCOMES IN A RANDOMIZED SINGLE-BLIND CONTROLLED TRIAL OF INTRAVITREAL RANIBIZUMAB AND ORAL SUPPLEMENTATION WITH DOCOSAHEXAENOIC ACID AND ANTIOXIDANTS FOR DIABETIC MACULAR EDEMA. AB - PURPOSE: To report 3-year results of a randomized single-blind controlled trial of intravitreal ranibizumab combined with oral docosahexaenoic acid (DHA) supplementation versus ranibizumab alone in patients with diabetic macular edema. METHODS: There were 26 patients (31 eyes) in the DHA group and 29 (38 eyes) in the control group. Ranibizumab (0.5 mg) was administered monthly for the first 4 months followed by a pro re nata (PRN) regimen. In the experimental group, patients received oral DHA supplementation (1,050 mg/day) (Brudyretina 1.5 g). RESULTS: At 36 months, mean decrease of central subfield macular thickness was higher in the DHA-supplementation group than in controls (275 +/- 50 MUm vs. 310 +/- 97 MUm) with significant differences at Months 25, 30, 33, and 34. Between group differences in best-corrected visual acuity were not found, but the percentages of ETRDS gains >5 and >10 letters were higher in the DHA supplementation group. Differences serum HbA1c, plasma total antioxidant capacity values, erythrocyte DHA content, and serum IL-6 levels were all significant in favor of the DHA-supplementation group. CONCLUSION: The addition of a high-rich DHA dietary supplement to intravitreal ranibizumab was effective to achieve better sustained improvement of central subfield macular thickness outcomes after 3 years of follow-up as compared with intravitreal ranibizumab alone.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. PMID- 29474307 TI - IDENTIFICATION OF POSTERIOR SEGMENT PATHOLOGY WITH EN FACE RETINAL IMAGING USING MULTICOLOR CONFOCAL SCANNING LASER OPHTHALMOSCOPY. AB - PURPOSE: To assess posterior segment findings on multicolor confocal scanning laser ophthalmoscopy by correlation with spectral domain optical coherence tomography (SD-OCT) and to quantify agreement between these imaging modalities. METHODS: Retrospective review of 159 eyes of 96 consecutive patients who underwent concurrent imaging with multicolor confocal scanning laser ophthalmoscopy and SD-OCT. Positive percent agreement and negative percent agreement were calculated for each finding identified on infrared, green, blue, and multicolor reflectance images using SD-OCT as a comparator. RESULTS: Infrared reflectance best detected outer retinal and choroidal findings such as choroidal lesions, retinal pigment epithelium atrophy, peripapillary atrophy, and drusen (positive percent agreement 100, 92, 92, and 67%, respectively). Inner retinal changes including epiretinal membrane, lamellar macular hole, and inner retinal alterations were best detected on blue reflectance (positive percent agreement 94, 50, and 100%, respectively). Composite multicolor reflectance most effectively detected conditions with retinal elevation, including pigment epithelial detachment, intraretinal fluid, and subretinal fluid (positive percent agreement 65, 49, and 54%, respectively). Multicolor confocal scanning laser ophthalmoscopy detected intraretinal and subretinal hemorrhages, which were not detected on SD-OCT (negative percent agreement 87 and 97%, respectively). CONCLUSION: Multicolor confocal scanning laser ophthalmoscopy is capable of identifying posterior segment pathology at various anatomical depths and may be a useful adjunct to SD-OCT for detecting or monitoring certain retinal conditions. PMID- 29474308 TI - RISK FACTORS, TREATMENT STRATEGIES, AND OUTCOMES OF ENDOPHTHALMITIS ASSOCIATED WITH SEVERE FUNGAL KERATITIS. AB - PURPOSE: To investigate risk factors, treatment strategies, and outcomes of endophthalmitis associated with severe fungal keratitis. METHODS: Data from 392 patients diagnosed with fungal keratitis were retrospectively examined. Patients had severe disease that was refractory to topical or systemic antifungal therapy, and the infection involved the endothelium or perforated the cornea. The incidence and risk factors for endophthalmitis, and treatment outcomes were evaluated. RESULTS: Thirty-seven of 392 patients (9.4%) had endophthalmitis. Multivariate logistic regression revealed the following risk factors for endophthalmitis: topical steroid use (odds ratio [OR] = 6.35, 95% confidence interval [CI]: 2.01-20.08), previous corneal laceration suturing (OR = 5.05, 95% CI: 1.11-22.93), large corneal ulcer size (>=10-mm diameter; OR = 4.43, 95% CI: 1.71-11.50), hypopyon (OR = 11.05, 95% CI: 2.12-57.55), and aphakia (OR = 15.45, 95% CI: 1.59-149.82). Thirty of the 37 eyes (81.1%) with endophthalmitis were saved by penetrating keratoplasty, vitrectomy, or intravitreal antifungal injection; 7 eyes (18.9%) were eviscerated. CONCLUSION: Most patients with endophthalmitis secondary to corneal fungal infection were successfully managed by penetrating keratoplasty, vitrectomy, or intravitreal antifungal therapy. Multiple risk factors for endophthalmitis were identified. Timely diagnosis and risk factor assessment were essential for ensuring early surgical intervention for fungal keratitis-related endophthalmitis. PMID- 29474309 TI - DIFFERENTIAL DIAGNOSIS FOR VITREORETINAL LYMPHOMA WITH VITREORETINAL FINDINGS, IMMUNOGLOBULIN CLONALITY TESTS, AND INTERLEUKIN LEVELS. AB - PURPOSE: To analyze vitreoretinal findings, immunoglobulin clonality tests, and interleukin (IL) levels for diagnosing vitreoretinal lymphoma (VRL). METHODS: Forty-three patients who underwent diagnostic vitrectomy for suspected VRL were retrospectively reviewed. Of those patients finally diagnosed with VRL and nonlymphoma, ophthalmic evaluation and cytology results, IL-6 and IL-10 levels, and immunoglobulin heavy chain and immunoglobulin kappa light chain clonality assays were compared. RESULTS: Sub-retinal pigment epithelium infiltration and veil-pattern vitreous opacity were specific vitreoretinal findings in patients with VRL. The area under the receiver operating characteristic curve of the IL-10 to-IL-6 ratio and of IL-10 levels was 0.972 and 0.931, respectively. A combined immunoglobulin heavy chain and immunoglobulin kappa light chain assay showed increased sensitivity, whereas the determined specificity of immunoglobulin kappa light chain, at 94.12%, was much higher than the 78.95% of immunoglobulin heavy chain. Patients with VRL with atypically elevated IL-6 levels showed extensive and severe sub-retinal pigment epithelium infiltration. CONCLUSION: Newly screened immunoglobulin kappa light chain clonality assays may be useful to distinguish VRL from uveitis with high specificity. When sub-retinal pigment epithelium or retinal infiltration is severe and extensive, the IL-10-to-IL-6 ratio may not be typical and should be carefully interpreted. PMID- 29474310 TI - Relationship Between Accountable Care Organization Status and 30-Day Hospital wide Readmissions. Are All Accountable Care Organizations Created Equal? AB - OBJECTIVE: We compare hospital readmission rates by accountable care organization (ACO) status with national readmission averages, to determine whether ACO affiliation influences 30-day hospital-wide readmission rates. METHODS: Data from the 2015 American Hospital Association Survey of Care Systems and Payment database were merged with Centers for Medicare and Medicaid's 2015 Hospital Compare Deaths and Readmissions data set. A multinomial logistic regression model is used to examine readmission rates, categorized as better, no different, or worse, in comparison to national averages, by ACO status. RESULTS: Compared with Non-ACO hospitals and holding the covariates constant, the relative risk of having better than national average readmissions was 1.85 in Medicare ACO hospitals (p = .36). Compared with facilities in the Northeast region, the relative risk of having better than national average readmissions was 2.21 for facilities in the West (p = .10). Facilities in the Midwest and Southern regions had a lower risk of having better than national average rates (Relative Risk: 0.90 and 0.23, respectively; p = .83 and .06, respectively). As hospital beds increase, facilities have significantly lower risks of having worse than national average readmissions. CONCLUSIONS: Overall, the ACO status did not significantly improve readmissions. However, Medicare ACOs performed better than non-Medicare ACOs and those hospitals without any reported ACO arrangements. PMID- 29474311 TI - Identifying Poor-Performing Hospitals in the Medicare Hospital-Acquired Condition Reduction Program: An Assessment of Reliability. AB - Centers for Medicare and Medicaid Services (CMS) estimated that Medicare's Hospital-Acquired Condition Reduction Program (HAC-RP) would reduce hospital payments by $364 million in fiscal year 2016. Although observers have questioned the validity of certain HAC-RP measures, less attention has been paid to the determination of low-performing hospitals (bottom quartile) and the reliability of penalty assignment. This study used publicly available data from CMS's Hospital Compare to simulate the consistency of hospitals' scores and the assignment of penalties under repeated measurement with no change in each hospital's underlying quality. The simulation showed that 64.0% of all hospitals and 40.6% of hospitals subject to payment penalty are statistically significantly different from the penalty threshold at the 95% confidence level. The proportion of hospitals statistically different from the threshold showed significant variation by ownership status, teaching status, bed size, and other factors. The simulation further showed that due only to chance, 18.0% of penalized hospitals would escape penalty on repeated measurement. Policymakers should consider alterations to the HAC-RP to improve its reliability. PMID- 29474312 TI - Benchmarking Implications: Analysis of Medicare Accountable Care Organizations Spending Level and Quality of Care. AB - Early evidence has shown that Accountable Care Organizations (ACOs) have achieved some success in improving the quality of care and reducing Medicare costs. However, it has been argued that the ACO rewarding model may disproportionately affect relatively low-spending (LS; considered as efficient) organizations that have fewer options to cut unnecessary services compared with high-spending (HS; inefficient) organizations. We conducted a cross-sectional retrospective study to compare ACO financial and quality of care performance between HS-ACO and LS-ACO. After adjusting for ACO organizational factors and beneficiary characteristics, we found that HS-ACOs generated greater savings per beneficiary than LS-ACOs ($501 vs. -$108, p < .001); however, HS-ACOs had a lower quality of care performance (48.79 vs. 53.29, p = .002). Specifically, LS-ACOs had better quality performance than HS-ACOs in patient experience/satisfaction (p = .02), preventive care services (p = .004), and hospitalization management (p = .001), whereas HS ACOs better performed in routine checkup/follow-up (p < .001) and risk population management (p = .048). Our findings indicated that Medicare ACO rewarding model seems to be advantageous for HS-ACOs regardless of the overall quality of care performance. PMID- 29474313 TI - Perception of Patient Safety Culture in Pediatric Long-Term Care Settings. AB - INTRODUCTION: Patient safety culture (PSC) is an emerging construct in adult long term care settings. No measures are validated to quantify PSC in pediatric long term care (pLTC) settings despite the importance of safety for this vulnerable population. The study purposes are to (1) describe PSC in pLTC, (2) assess the relationship of PSC to facility recommendation and overall safety rating, and (3) test the stability and reliability of the PSC survey over time. METHODS: A modified Nursing Home PSC (NHSPSC) survey was administered to employees at three pLTC facilities over 3 years; data were summarized and compared over time. RESULTS: In all, 208 surveys were completed. Staff perceptions on "feedback and communication about incidents" and "overall perceptions of resident safety" were most positive and associated with responses of recommending the facility and high overall ratings for child safety (p < .05). CONCLUSIONS: The modified NHSPSC survey was reliable by Cronbach alpha and findings were consistent over time in these pLTC settings. This tool may be a useful adjunct to safety initiatives in pLTC. Knowledge derived from this survey can provide actionable information for consumers, pLTC employees, managers, and administrators. PMID- 29474314 TI - Severity of Illness Measures for Pediatric Inpatients. AB - INTRODUCTION: Severity of illness (SOI) measures are commonly used in adults for comparison of treatment and outcomes in similar populations. Less is known about the psychometric properties of measures available to providers and healthcare systems caring for pediatric patients. The purpose of this study was to (1) identify SOI measures used for pediatric patients admitted to acute care hospitals and (2) compare the ability of two SOI measures to predict mortality and length of stay (LOS). METHODS: Twelve instruments were identified through literature search and one, the pediatric chronic complex condition (CCC), was retained. The CCC and the Charlson/Deyo comorbidity score were applied to an 8 year retrospective, multi-institutional data set using logistic and zero truncated negative binomial regression models. RESULTS: Records from 199,001 children were examined. The CCC performed better for predicting mortality (odds ratio = 3.36; 95% confidence interval [CI]: 3.20-3.53) and LOS (incidence rate ratio = 2.24; 95% CI: 2.22-2.26). CONCLUSIONS: The CCC may be preferable for predicting outcomes among pediatric inpatients. Pediatric SOI measures are not extensively developed and tested nor widely and freely available. The use of the CCC can predict mortality and LOS to guide care, resource allocation, and research for the pediatric population. PMID- 29474315 TI - Antibodies and the brain: anti-N-methyl-D-aspartate receptor antibody and the clinical effects in patients with systemic lupus erythematosus. AB - PURPOSE OF REVIEW: Neuropsychiatric manifestations are one of the fatal complications in patients with systemic lupus erythematosus (SLE). However, the diagnosis and monitoring of that aspect of SLE is still challenging, as there are no reliable biomarkers linked to central nervous system (CNS) damage. This review emphasizes potential candidate autoantibodies that appear to be associated with development of behavioral and psychiatric manifestations in SLE patients. RECENT FINDINGS: Developments in the pathogenesis in SLE, not surprising for this immune disorder, point to specific, autoantibody toxicity. Namely, the discovery of an antibody which reacts with DNA and with the extracellular domain of N-methyl-D aspartate (NMDA) receptor subunit GluN2A and 2B (anti-NMDA), an important receptor on neurons that is ubiquitous in the CNS, may lead to new insights into the behavioral and psychiatric manifestations in SLE. These anti-NMDA antibodies induce neuronal apoptosis and degeneration of surviving neurons in murine models. This functional antibody is also detected in SLE patients who have behavioral and psychiatric manifestations. The presence of anti-NMDA in cerebrospinal fluid but not in serum is associated significantly with overwhelming CNS abnormalities, suggesting importance of direct access of autoantibodies to brain dysfunction. SUMMARY: As anti-NMDA autoantibodies are present in patients who develop psychiatric manifestations in SLE, it is possible that novel therapeutic approaches will depend on altering the activity of these autoantibodies. PMID- 29474316 TI - Autoantibodies against N-methyl-d-aspartate receptor 1 in health and disease. AB - PURPOSE OF REVIEW: Humoral autoimmunity has gained highest interest in neurology and psychiatry. Despite numerous recent articles on this hot topic, however, the biological significance of natural autoantibodies (AB) and the normal autoimmune repertoire of mammals remained quite obscure. AB may contribute to disorder relevant phenotypes and are even believed to induce diseases themselves, but the circumstances under which AB become pathogenic are not fully understood. This review will focus on the highly frequent AB against the N-methyl-d-aspartate receptor 1 (NMDAR1-AB) as an illustrating example and provide a critical overview of current work (please note that the new nomenclature, GluN1, is disregarded here for consistency with the AB literature). In particular, it will demonstrate how little is known at this point and how many conclusions are drawn based on small numbers of individuals, fragmentary experimental approaches or missing controls. RECENT FINDINGS: NMDAR1-AB were investigated by clinicians world-wide with numerous small studies and case reports appearing yearly. Many publications were on 'anti-NMDAR encephalitis' cases or tried to separate those from other NMDAR1-AB associated conditions. Original exclusivity claims (e.g. electroencephalogram, EEG or functional magnetic resonance imaging, fMRI findings) turned out not to be exclusive for 'anti-NMDAR encephalitis'. Systematic analyses of representative NMDAR1-AB positive sera of all immunoglobulin (Ig) classes showed comparable distribution of different epitopes, often polyspecific/polyclonal, across health and disease. Sophisticated imaging tools provided findings on synapse trafficking changes induced by NMDAR1-AB from psychotic subjects but still lack epitope data to support any claimed disorder link. Persistently high titers of NMDAR1-AB (IgG) in immunized mice with open blood-brain barrier (BBB)-induced psychosis-like symptoms but failed to induce inflammation in the brain. Knowledge on peripheral NMDAR, for example in the immune system, and on potential inducers of NMDAR1-AB is only slowly increasing. SUMMARY: The present knowledge on the (patho) physiological role of NMDAR1-AB is very limited and still characterized by adamant rumors. Much more experimental work and more solid and informative clinical reports, including large numbers of subjects and adequate control groups, follow-up investigations and interdisciplinary approaches will be necessary to obtain a better understanding of the significance of humoral autoimmunity in general (in focus here: NMDAR1-AB) and its disease-relevance in particular. PMID- 29474317 TI - Primary Cervical Malignant Melanoma: 2 Cases and a Literature Review. AB - Primary cervical malignant melanoma (MM) is an extremely rare tumor, and we are only aware of 44 reported cases. Further information is needed with regard to this disease's clinicopathologic features. Two patients (55 and 81 yr old) with postmenopausal vaginal bleeding were diagnosed with primary cervical MM on the basis of hematoxylin-eosin staining and immunohistochemistry findings. Our literature review revealed that the average age in cases of primary cervical MM was 59 yr (range, 34-81 yr); 93% of patients presented with vaginal bleeding, and 82% of patients were diagnosed at an early clinical stage (International Federation of Gynecology and Obstetrics stages I-II). Primary cervical MM is an extremely rare cervical tumor and is associated with a poor prognosis. Histologic morphology and immunohistochemistry are very important considerations for diagnosing this disease, which must be differentiated from cervical undifferentiated carcinoma, leiomyosarcoma, and malignant peripheral schwannoma. PMID- 29474318 TI - Fibroblastic Malignant Peripheral Nerve Sheath Tumour of the Uterine Cervix: Report of a Case and Literature Review With Emphasis on Possible Differential Diagnosis. AB - Cervical sarcomas are rare neoplasms, accounting for <1% of all cervical malignancies and characterized by an aggressive course despite radical excision. We report the clinical and microscopic features of a spindle cell sarcoma arising as a polypoid endocervical mass in a 45-yr-old woman. The neoplasm was characterized by a monotonous, mildly atypical proliferation of spindle cells, displaying a fibrosarcoma-like parallel pattern of highly dense fascicles, growing under the cervical epithelium. Mitotic activity was conspicuous, with up to 40 mitoses per 10 HPF. On immunohistochemistry, tumor cells were patchy S-100 protein positive. Additional immunohistochemical markers performed to rule out smooth muscle, melanocytic, epithelial, and sarcomatous differentiation were negative. A possible monophasic synovial sarcoma was also excluded by negative fluorescence in situ hybridization t(X;18) analysis. Interestingly, the neoplasm showed a focal CD34 positivity, as reported in normal fibrocytic cells of the endocervical stroma. Giving the morphologic and immunohistochemical features, the neoplasm was eventually defined as malignant peripheral nerve sheath tumor. Histologic examination following radical surgery revealed the neoplasm was confined to the uterine cervix (FIGO stage IB1) and at 12 mo of follow-up, the patient is still free of disease. Malignant peripheral nerve sheath tumors are highly aggressive sarcomas that can rarely involve the uterine cervix. They have to be differentiated from melanoma, leiomyosarcoma, endometrial stromal sarcoma, synovial sarcoma, and other spindle cell neoplasms. PMID- 29474319 TI - The Association of ICU Acuity With Outcomes of Patients at Low Risk of Dying. AB - OBJECTIVE: Many ICU patients do not require critical care interventions. Whether aggressive care environments increase risks to low-acuity patients is unknown. We evaluated whether ICU acuity was associated with outcomes of low mortality-risk patients. We hypothesized that admission to high-acuity ICUs would be associated with worse outcomes. This hypothesis was based on two possibilities: 1) high acuity ICUs may have a culture of aggressive therapy that could lead to potentially avoidable complications and 2) high-acuity ICUs may focus attention toward the many sicker patients and away from the fewer low-risk patients. DESIGN: Retrospective cohort study. SETTING: Three hundred twenty-two ICUs in 199 hospitals in the Philips eICU database between 2010 and 2015. PATIENTS: Adult ICU patients at low risk of dying, defined as an Acute Physiology and Chronic Health Evaluation-IVa-predicted mortality of 3% or less. EXPOSURE: ICU acuity, defined as the mean Acute Physiology and Chronic Health Evaluation IVa score of all admitted patients in a calendar year, stratified into quartiles. MEASUREMENTS AND MAIN RESULTS: We used generalized estimating equations to test whether ICU acuity is independently associated with a primary outcome of ICU length of stay and secondary outcomes of hospital length of stay, hospital mortality, and discharge destination. The study included 381,997 low-risk patients. Mean ICU and hospital length of stay were 1.8 +/- 2.1 and 5.2 +/- 5.0 days, respectively. Mean Acute Physiology and Chronic Health Evaluation IVa-predicted hospital mortality was 1.6% +/- 0.8%; actual hospital mortality was 0.7%. In adjusted analyses, admission to low-acuity ICUs was associated with worse outcomes compared with higher-acuity ICUs. Specifically, compared with the highest-acuity quartile, ICU length of stay in low-acuity ICUs was increased by 0.24 days; in medium-acuity ICUs by 0.16 days; and in high-acuity ICUs by 0.09 days (all p < 0.001). Similar patterns existed for hospital length of stay. Patients in lower-acuity ICUs had significantly higher hospital mortality (odds ratio, 1.28 [95% CI, 1.10-1.49] for low-; 1.24 [95% CI, 1.07-1.42] for medium-, and 1.14 [95% CI, 0.99-1.31] for high acuity ICUs) and lower likelihood of discharge home (odds ratio, 0.86 [95% CI, 0.82-0.90] for low-, 0.88 [95% CI, 0.85-0.92] for medium-, and 0.95 [95% CI, 0.92 0.99] for high-acuity ICUs). CONCLUSIONS: Admission to high-acuity ICUs is associated with better outcomes among low mortality-risk patients. Future research should aim to understand factors that confer benefit to patients with different risk profiles. PMID- 29474320 TI - Temporal Trends in Incidence, Sepsis-Related Mortality, and Hospital-Based Acute Care After Sepsis. AB - OBJECTIVES: A growing number of patients survive sepsis hospitalizations each year and are at high risk for readmission. However, little is known about temporal trends in hospital-based acute care (emergency department treat-and release visits and hospital readmission) after sepsis. Our primary objective was to measure temporal trends in sepsis survivorship and hospital-based acute care use in sepsis survivors. In addition, because readmissions after pneumonia are subject to penalty under the national readmission reduction program, we examined whether readmission rates declined after sepsis hospitalizations related to pneumonia. DESIGN AND SETTING: Retrospective, observational cohort study conducted within an academic healthcare system from 2010 to 2015. PATIENTS: We used three validated, claims-based approaches to identify 17,256 sepsis or severe sepsis hospitalizations to examine trends in hospital-based acute care after sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: From 2010 to 2015, sepsis as a proportion of medical and surgical admissions increased from 3.9% to 9.4%, whereas in-hospital mortality rate for sepsis hospitalizations declined from 24.1% to 14.8%. As a result, the proportion of medical and surgical discharges at-risk for hospital readmission after sepsis increased from 2.7% to 7.8%. Over 6 years, 30-day hospital readmission rates declined modestly, from 26.4% in 2010 to 23.1% in 2015, driven largely by a decline in readmission rates among survivors of nonsevere sepsis, and nonpneumonia sepsis specifically, as the readmission rate of severe sepsis survivors was stable. The modest decline in 30 day readmission rates was offset by an increase in emergency department treat-and release visits, from 2.8% in 2010 to a peak of 5.4% in 2014. CONCLUSIONS: Owing to increasing incidence and declining mortality, the number of sepsis survivors at risk for hospital readmission rose significantly between 2010 and 2015. The 30 day hospital readmission rates for sepsis declined modestly but were offset by a rise in emergency department treat-and-release visits. PMID- 29474321 TI - Evaluation of ICU Risk Models Adapted for Use as Continuous Markers of Severity of Illness Throughout the ICU Stay. AB - OBJECTIVES: Evaluate the accuracy of different ICU risk models repurposed as continuous markers of severity of illness. DESIGN: Nonintervention cohort study. SETTING: eICU Research Institute ICUs using tele-ICU software calculating continuous ICU Discharge Readiness Scores between January 2013 and March 2016. PATIENTS: Five hundred sixty-one thousand four hundred seventy-eight adult ICU patients with an ICU length of stay between 4 hours and 30 days. INTERVENTIONS: Not available. MEASUREMENTS AND MAIN RESULTS: Hourly Acute Physiology and Chronic Health Evaluation IV, Sequential Organ Failure Assessment, and Discharge Readiness Scores were calculated beginning hour 4 of the ICU stay. Primary outcome was the area under the receiver operating characteristic curve for the mean score with ICU mortality. Secondary outcomes included area under the receiver operating characteristic curves for ICU mortality with admission, median, maximum and last scores, and for death within 24 hours. The trajectories of each score were visualized by plotting the hourly averages against time in the ICU, stratified by mortality and length of stay. The area under the receiver operating characteristic curves for mean Acute Physiology and Chronic Health Evaluation, Sequential Organ Failure Assessment, and Discharge Readiness Scores were 0.90 (0.89-0.90), 0.86 (0.86-0.86), and 0.94 (0.94-0.94), respectively. The area under the receiver operating characteristic curves for hourly Acute Physiology and Chronic Health Evaluation, Sequential Organ Failure Assessment, and Discharge Readiness Scores predicting 24-hour mortality were 0.81 (0.81 0.81), 0.76 (0.76-0.76), and 0.86 (0.86-0.86). Discharge Readiness Scores had a higher area under the receiver operating characteristic curve than both Acute Physiology and Chronic Health Evaluation and Sequential Organ Failure Assessment for each metric. Acute Physiology and Chronic Health Evaluation and Sequential Organ Failure Assessment scores increased throughout the first 24 hours in both survivors and nonsurvivors; Discharge Readiness Scores continuously decreased in survivors and temporarily decreased before increasing by hour 36 in nonsurvivors with longer length of stays. CONCLUSIONS: Acute Physiology and Chronic Health Evaluation, Sequential Organ Failure Assessment, and Discharge Readiness Scores all have relatively high discrimination for ICU mortality when used continuously; Discharge Readiness Scores tended to have slightly higher area under the receiver operating characteristic curves for each endpoint. These findings validate the use of these models on a population level for continuous risk adjustment in the ICU, although Acute Physiology and Chronic Health Evaluation and Sequential Organ Failure Assessment appear slower to respond to improvements in patient status than Discharge Readiness Scores, and Discharge Readiness Scores may reflect physiologic improvement from interventions, potentially underestimating risk. PMID- 29474322 TI - Validation of a Novel Molecular Host Response Assay to Diagnose Infection in Hospitalized Patients Admitted to the ICU With Acute Respiratory Failure. AB - OBJECTIVES: Discrimination between infectious and noninfectious causes of acute respiratory failure is difficult in patients admitted to the ICU after a period of hospitalization. Using a novel biomarker test (SeptiCyte LAB), we aimed to distinguish between infection and inflammation in this population. DESIGN: Nested cohort study. SETTING: Two tertiary mixed ICUs in the Netherlands. PATIENTS: Hospitalized patients with acute respiratory failure requiring mechanical ventilation upon ICU admission from 2011 to 2013. Patients having an established infection diagnosis or an evidently noninfectious reason for intubation were excluded. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Blood samples were collected upon ICU admission. Test results were categorized into four probability bands (higher bands indicating higher infection probability) and compared with the infection plausibility as rated by post hoc assessment using strict definitions. Of 467 included patients, 373 (80%) were treated for a suspected infection at admission. Infection plausibility was classified as ruled out, undetermined, or confirmed in 135 (29%), 135 (29%), and 197 (42%) patients, respectively. Test results correlated with infection plausibility (Spearman's rho 0.332; p < 0.001). After exclusion of undetermined cases, positive predictive values were 29%, 54%, and 76% for probability bands 2, 3, and 4, respectively, whereas the negative predictive value for band 1 was 76%. Diagnostic discrimination of SeptiCyte LAB and C-reactive protein was similar (p = 0.919). CONCLUSIONS: Among hospitalized patients admitted to the ICU with clinical uncertainty regarding the etiology of acute respiratory failure, the diagnostic value of SeptiCyte LAB was limited. PMID- 29474323 TI - Rare Events in the ICU: An Emerging Challenge in Classification and Prediction. PMID- 29474324 TI - Rethinking Mentoring. PMID- 29474325 TI - Bending the Pandemic Curve: Improving Decision-Making With Clinical Research. PMID- 29474326 TI - Transport Time and Preoperating Room Hemostatic Interventions Are Important: Improving Outcomes After Severe Truncal Injury. AB - OBJECTIVES: Experience in the ongoing wars in Iraq and Afghanistan confirm that faster transport combined with effective prehospital interventions improves the outcomes of patients suffering hemorrhagic shock. Outcomes of patients with hemorrhagic shock and extremity bleeding have improved with widespread use of tourniquets and early balanced transfusion therapy. Conversely, civilian patients suffering truncal bleeding and shock have the same mortality (46%) over the last 20 years. To understand how to decrease this substantial mortality, one must first critically evaluate all phases of care from point of injury to definitive hemorrhage control in the operating room. DATA SOURCES: Limited literature review. DATA SYNTHESIS: The peak time to death after severe truncal injury is within 30 minutes of injury. However, when adding prehospital transport time, time spent in the emergency department, followed by the time in the operating room, it currently takes 2.1 hours to achieve definitive truncal hemorrhage control. This disparity in uncontrolled truncal bleeding and time to hemorrhage control needs to be reconciled. Prehospital and emergency department whole blood transfusion and temporary truncal hemorrhage control are now possible. CONCLUSIONS: The importance of rapid transport, early truncal hemorrhage control and whole blood transfusion is now widely recognized. Prehospital temporary truncal hemorrhage control and whole blood transfusion should offer the best possibility of improving patient outcomes after severe truncal injury. PMID- 29474327 TI - Sepsis: A Threat That Needs a Global Solution. PMID- 29474328 TI - Using Default Options and Other Nudges to Improve Critical Care. PMID- 29474329 TI - How Critical Illness Affects the Brain...and Vice Versa. PMID- 29474330 TI - With Severity Scores Updated on the Hour, Data Science Inches Closer to the Bedside. PMID- 29474332 TI - One Score to Rule Them All? ICU Scoring at the Dawn of the Digital Age. PMID- 29474331 TI - Candidemia in the ICU: Does Initial Antifungal Matter? PMID- 29474333 TI - Severity of Illness VIS-a-Vis Neuropsychologic Outcomes in Critically Ill Neonates. PMID- 29474334 TI - Bedside Detection of Overassistance During Pressure Support Ventilation. PMID- 29474335 TI - The Golden Hours of ICU Sedation: The Clock Is Ticking... PMID- 29474336 TI - Endothelial Cell-Specific Molecule-1 in Critically Ill Patients With Hematologic Malignancy. AB - OBJECTIVES: To assess whether serum concentration of endothelial cell-specific molecule-1 (Endocan) at ICU admission is associated with the use of ICU resources and outcomes in critically ill hematology patients. DESIGN: Prospective multicenter cohort study. SETTING: Seventeen ICUs in France and Belgium. PATIENTS: Seven hundred forty-four consecutive critically ill hematology patients; 72 critically ill septic patients without hematologic malignancy; 276 healthy subjects. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Median total endocan concentrations were 4.46 (2.7-7.8) ng/mL. Endocan concentrations were higher in patients who had received chemotherapy before ICU admission (4.7 [2.8 8.1] ng/mL vs. 3.7 [2.5-6.3] ng/mL [p = 0.002]). In patients with acute respiratory failure, endocan levels were increased in patients with drug-induced pulmonary toxicity compared with other etiologies (p = 0.038). Total endocan levels higher than 4.46 ng/mL were associated with a higher cumulative probability of renal replacement therapy requirement (p = 0.006), a higher requirement of mechanical ventilation (p = 0.01) and a higher requirement of vasopressors throughout ICU stay (p < 0.0001). By multivariate analysis, total endocan levels at admission were independently associated with ICU mortality (odds ratios, 1.39; 95% CI, 1.06-1.83; p = 0.018). The predictive value of endocan peptide fragments of 14 kDa in terms of mortality and life-sustaining therapies requirement was inferior to that of total endocan. Endocan levels were higher in critically ill hematology patients compared with healthy subjects (p < 0.0001) but lower than endocan values in critically ill septic patients without hematologic malignancy (p = 0.005) CONCLUSIONS:: Serum concentrations of endocan at admission are associated with the use of ICU resources and mortality in critically ill hematology patients. Studies to risk-stratify patients in the emergency department or in the hematology wards based on endocan concentrations to identify those likely to benefit from early ICU management are warranted. PMID- 29474337 TI - Sepsis-3 Is a Positive Evolution in Discrimination Between Septic and Nonseptic Patients As Well As Sepsis Entities, Not a Step Backward. PMID- 29474338 TI - The authors reply. PMID- 29474339 TI - Discussion on "Effects of High-Flow Nasal Cannula on the Work of Breathing in Patients Recovering From Acute Respiratory Failure". PMID- 29474340 TI - The authors reply. PMID- 29474341 TI - Shenfu Injection After In-Hospital Cardiac Arrest: A Question Regarding Funding. PMID- 29474342 TI - The Role of Aerolized Colistin in the Treatment of Hospital-Acquired Pneumonia: Experience of Multicenter From Turkey: Erratum. PMID- 29474343 TI - Outcomes of Patient- and Family-Centered Care Interventions in the ICU: A Systematic Review and Meta-Analysis: Erratum. PMID- 29474344 TI - Concept-Based Curricula: A National Study of Critical Concepts. AB - As nursing education struggles to address a rapidly changing health care system, overcrowded curricula, and an increased focus on clinical reasoning skills, many programs have adopted or transitioned to concept-based curricula (CBCs), which are structured around key concepts and exemplars. Despite CBC's promised benefits, the process of developing a CBC framework may pose a challenge to programs. To address this barrier, a national study was conducted to develop a representative list of concepts and exemplars. This initiative expands on prior work by suggesting a leveled approach to positioning exemplars within a curricular sequence. PMID- 29474345 TI - Opioid-related genetic polymorphisms do not influence postoperative opioid requirement: A prospective observational study. AB - BACKGROUND: Among the various factors that may influence the pharmacological response to opioids, genetic polymorphisms [single nucleotide polymorphisms (SNP)] have generated some interest. OBJECTIVES: To examine the influence on morphine dose requirements and adverse events in the postoperative period of four SNP [opioid receptor mu1 (OPRM1), ATP-binding cassette subfamily B, member 1 (ABCB1) ex-21 and ex-26, catechol-o-methyltransferase (COMT)] in candidate genes involved in morphine pharmacodynamics and pharmacokinetics. DESIGN: A single centre prospective study. SETTING: University Hospital, Paris, France, from 2 January 2007 to 15 November 2011. PATIENTS: A total of 438 white adults scheduled for major orthopaedic surgery (spine, hip and knee) under general anaesthesia. The main exclusion criteria were receiving opioids for chronic pain, nonopioid drugs within 2 days prior to surgery, pregnancy, renal insufficiency, sleep apnoea obstruction syndrome, morbid obesity, severe hepatic impairment, cognitive dysfunction. INTERVENTIONS: Assays of plasma concentrations of morphine and metabolites (morphine 3-glucuronide and morphine 6-glucuronide) were performed and common polymorphisms in four candidate genes [OPRM1 A118G rs1799971; P glycoprotein (ABCB1) T3435C (rs1045642) and G2677T/A (rs2032582); COMT Val 158 Met (rs4680)] were analysed.Morphine was titrated by staff in the postanaesthesia care unit (PACU) and in the ward patient-controlled intravenous analgesia was used for 24 h. MAIN OUTCOME MEASURES: The dose of morphine required to achieve pain relief and the influence of SNP in genes involved in morphine pharmacodynamics and kinetics on morphine dose requirements. Secondary endpoints were the concentrations of morphine, morphine 6-glucuronide and morphine 3 gluguronide, the proportion of patients requiring a rescue analgesic and the proportion of morphine-related adverse events. RESULTS: A total of 404 patients completed the study to final analysis. The mean +/- SD morphine dose to achieve pain relief was 15.8 +/- 8.8 mg in the PACU and 22.7 +/- 18.6 mg during patient controlled intravenous administration. Morphine-related adverse events were observed in 37%. There was no relationship between any genetic polymorphisms and morphine dose, morphine 3-gluguronide and morphine 6-glucuronide concentration, morphine-related adverse events or pain level. In the PACU only, P-glycoprotein polymorphisms (ex-21; ex-26) were significantly associated with morphine concentration but the prediction of the model was poor (R = 0.04) CONCLUSION: No major relationship has been demonstrated between SNP of OPRM1, ABCB1, COMT and morphine requirement, pain level or adverse effects in the postoperative period. TRIAL REGISTRATION: NCT00822549 (www.clinicaltrials.gov). PMID- 29474346 TI - Level of agreement between laboratory and point-of-care prothrombin time in patients after stopping or continuation of acenocoumarol anticoagulation: A comparison of diagnostic accuracy. AB - BACKGROUND: Procedures requiring optimisation of the coagulation status of patients using vitamin K antagonists are frequently postponed due to the late availability of laboratory international normalised ratio (INR) test results. A point-of-care (POC) alternative may facilitate early decision-making in peri operative patients. OBJECTIVES: To assess the level of agreement between the POC INR and the laboratory INR in patients who continue or stop vitamin K antagonists to determine whether the POC test may be a good alternative to the laboratory INR. DESIGN: Study of diagnostic accuracy. SETTING: Single-centre study at Zaans Medical Centre, The Netherlands. PATIENTS: Included patients were scheduled for cardioversion (these continued taking vitamin K antagonists), or a surgical procedure (these stopped taking vitamin K antagonists). MAIN OUTCOME MEASURES: The level of agreement and clinical acceptability of the laboratory and POC-INR results, evaluated by Bland-Altman analysis and error grid analysis. RESULTS: The surgical and cardioversion groups consisted of 47 and 46 patients, respectively. The bias in the INR in the surgical group was -0.12 +/- 0.09 with limits of agreement of -0.29 to 0.05, whereas the cardioversion group showed a bias in the INR of -0.22 +/- 0.36 with limits of agreement from -0.93 to 0.48. The percentage errors between methods in the surgical and cardioversion groups were 16 and 21%, respectively. Error grid analysis showed that the diagnostic accuracy of the POC prothrombin time is clinically acceptable as the difference did not lead to a different clinical decision in the surgical group with INR values less than 1.8. CONCLUSION: The current study shows a good level of agreement and clinical accuracy between the laboratory and POC-INR in patients who stopped anticoagulation intake for surgery. However, in patients who continued their anticoagulation therapy, the agreement between the two methods was less accurate. PMID- 29474347 TI - Improving detection of patient deterioration in the general hospital ward environment. AB - : Patient monitoring on low acuity general hospital wards is currently based largely on intermittent observations and measurements of simple variables, such as blood pressure and temperature, by nursing staff. Often several hours can pass between such measurements and patient deterioration can go unnoticed. Moreover, the integration and interpretation of the information gleaned through these measurements remains highly dependent on clinical judgement. More intensive monitoring, which is commonly used in peri-operative and intensive care settings, is more likely to lead to the early identification of patients who are developing complications than is intermittent monitoring. Early identification can trigger appropriate management, thereby reducing the need for higher acuity care, reducing hospital lengths of stay and admission costs and even, at times, improving survival. However, this degree of monitoring has thus far been considered largely inappropriate for general hospital ward settings due to device costs and the need for staff expertise in data interpretation. In this review, we discuss some developing options to improve patient monitoring and thus detection of deterioration in low acuity general hospital wards. PMID- 29474348 TI - Downregulated Nuclear Factor E2-Related Factor 2 (Nrf2) Aggravates Cognitive Impairments via Neuroinflammation and Synaptic Plasticity in the Senescence Accelerated Mouse Prone 8 (SAMP8) Mouse: A Model of Accelerated Senescence. AB - BACKGROUND We observed the effects of nuclear factor E2-related factor 2 (Nrf2) downregulation via intrahippocampal injection of a lentiviral vector on cognition in senescence-accelerated mouse prone 8 (SAMP8) to investigate the role of the (Nrf2)/antioxidant response element (ARE) pathway in age-related changes. MATERIAL AND METHODS Control lentivirus and Nrf2-shRNA-lentivirus were separately injected into the hippocampus of 4-month-old SAMR1 and SAMP8 mice and then successfully downregulated Nrf2 expression in this brain region. Five months later, cognitive function tests, including the novel object test, the Morris water maze test, and the passive avoidance task were conducted. Glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba1) immunohistochemistry was performed to observe an inflammatory response. Presynaptic synapsin (SYN) were observed by immunofluorescence. We then determined the Nrf2-regulated, heme oxygenase-1 (HO-1), P65, postsynaptic density protein (PSD), and SYN protein levels. The ultrastructure of neurons and synapses in the hippocampal CA1 region was observed by transmission electron microscopy. RESULTS Aging led to a decline in cognitive function compared with SAMR1 mice and the Nrf2-shRNA-lentivirus further exacerbated the cognitive impairment in SAMP8 mice. Nrf2, HO-1, PSD, and SYN levels were significantly reduced (all P<0.05) but high levels of inflammation were detected in SAMP8 mice with low expression of Nrf2. Furthermore, neurons were vacuolated, the number of organelles decreased, and the number of synapses decreased. CONCLUSIONS Downregulation of Nrf2 suppressed the Nrf2/ARE pathway, activated oxidative stress and neuroinflammation, and accelerated cognitive impairment in SAMP8 mice. Downregulation of Nrf2 accelerates the aging process through neuroinflammation and synaptic plasticity. PMID- 29474349 TI - Do cannabinoids constitute a therapeutic alternative for insomnia? AB - INTRODUCTION: It has been suggested that cannabinoids would constitute a therapeutic alternative for patients with insomnia. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified eight systematic reviews including three studies overall, of which two were randomized trials. We concluded it is not clear whether cannabinoids have an effect on insomnia severity or on sleep quality; that they might have no effect on sleep conciliation, sleep awakening or behavior during wakefulness, and are probably associated with frequent adverse effects. PMID- 29474350 TI - Is parenteral hydration beneficial in terminally ill cancer patients? AB - INTRODUCTION: It is common for terminally ill patients to have a reduced fluid intake, which often results in a need for more medical support. However, it is not clear if this measure has a real clinical impact. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data from primary studies and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified four systematic reviews including 51 studies overall, from which three were randomized trials. We concluded the administration of parenteral hydration might make little or no difference in terms of survival and quality of life in terminally ill cancer patients, and that it is not clear whether it has any other benefit because the certainty of the evidence is very low. PMID- 29474351 TI - Are cannabinoids effective for fibromyalgia? AB - INTRODUCTION: Cannabinoids have been proposed as a therapeutic alternative for fibromyalgia. However, their clinical effectiveness is a matter of debate. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified fifteen systematic reviews including two randomized trials overall. We concluded it is not clear whether cannabinoids have any benefit in fibromyalgia because the certainty of the evidence is very low. On the other hand, they are associated to frequent adverse effects. PMID- 29474352 TI - A biophysical model of dynamic balancing of excitation and inhibition in fast oscillatory large-scale networks. AB - Over long timescales, neuronal dynamics can be robust to quite large perturbations, such as changes in white matter connectivity and grey matter structure through processes including learning, aging, development and certain disease processes. One possible explanation is that robust dynamics are facilitated by homeostatic mechanisms that can dynamically rebalance brain networks. In this study, we simulate a cortical brain network using the Wilson Cowan neural mass model with conduction delays and noise, and use inhibitory synaptic plasticity (ISP) to dynamically achieve a spatially local balance between excitation and inhibition. Using MEG data from 55 subjects we find that ISP enables us to simultaneously achieve high correlation with multiple measures of functional connectivity, including amplitude envelope correlation and phase locking. Further, we find that ISP successfully achieves local E/I balance, and can consistently predict the functional connectivity computed from real MEG data, for a much wider range of model parameters than is possible with a model without ISP. PMID- 29474353 TI - Deep sequencing of HBV pre-S region reveals high heterogeneity of HBV genotypes and associations of word pattern frequencies with HCC. AB - Hepatitis B virus (HBV) infection is a common problem in the world, especially in China. More than 60-80% of hepatocellular carcinoma (HCC) cases can be attributed to HBV infection in high HBV prevalent regions. Although traditional Sanger sequencing has been extensively used to investigate HBV sequences, NGS is becoming more commonly used. Further, it is unknown whether word pattern frequencies of HBV reads by Next Generation Sequencing (NGS) can be used to investigate HBV genotypes and predict HCC status. In this study, we used NGS to sequence the pre-S region of the HBV sequence of 94 HCC patients and 45 chronic HBV (CHB) infected individuals. Word pattern frequencies among the sequence data of all individuals were calculated and compared using the Manhattan distance. The individuals were grouped using principal coordinate analysis (PCoA) and hierarchical clustering. Word pattern frequencies were also used to build prediction models for HCC status using both K-nearest neighbors (KNN) and support vector machine (SVM). We showed the extremely high power of analyzing HBV sequences using word patterns. Our key findings include that the first principal coordinate of the PCoA analysis was highly associated with the fraction of genotype B (or C) sequences and the second principal coordinate was significantly associated with the probability of having HCC. Hierarchical clustering first groups the individuals according to their major genotypes followed by their HCC status. Using cross-validation, high area under the receiver operational characteristic curve (AUC) of around 0.88 for KNN and 0.92 for SVM were obtained. In the independent data set of 46 HCC patients and 31 CHB individuals, a good AUC score of 0.77 was obtained using SVM. It was further shown that 3000 reads for each individual can yield stable prediction results for SVM. Thus, another key finding is that word patterns can be used to predict HCC status with high accuracy. Therefore, our study shows clearly that word pattern frequencies of HBV sequences contain much information about the composition of different HBV genotypes and the HCC status of an individual. PMID- 29474355 TI - Assessing shortfalls and complementary conservation areas for national plant biodiversity in South Korea. AB - Protected areas (PAs) are often considered the most important biodiversity conservation areas in national plans, but PAs often do not represent national scale biodiversity. We evaluate the current conservation status of plant biodiversity within current existing PAs, and identify potential additional PAs for South Korea. We modeled species ranges for 2,297 plant species using Multivariate Adaptive Regression Splines and compared the level of mean range representation in South Korea's existing PAs, which comprise 5.7% of the country's mainland area, with an equal-area alternative PA strategy selected with the reserve algorithm Marxan. We also used Marxan to model two additional conservation scenarios that add lands to approach the Aichi Biodiversity Target objectives (17% of the country). Existing PAs in South Korea contain an average of 6.3% of each plant species' range, compared to 5.9% in the modeled equal-area alternative. However, existing PAs primarily represent a high percentage of the ranges for high-elevation and small range size species. The additional PAs scenario that adds lands to the existing PAs covers 14,587.55 km2, and would improve overall plant range representation to a mean of 16.8% of every species' range. The other additional PAs scenario, which selects new PAs from all lands and covers 13,197.35 km2, would improve overall plant range representation to a mean of 13.5%. Even though the additional PAs that includes existing PAs represents higher percentages of species' ranges, it is missing many biodiversity hotspots in non-mountainous areas and the additional PAs without locking in the existing PAs represent almost all species' ranges evenly, including low-elevation ones with larger ranges. Some priority conservation areas we identified are expansions of, or near, existing PAs, especially in northeastern and southern South Korea. However, lowland coastal areas and areas surrounding the capital city, Seoul, are also critical for biodiversity conservation in South Korea. PMID- 29474354 TI - Bombyx mori histone methyltransferase BmAsh2 is essential for silkworm piRNA mediated sex determination. AB - Sex determination is a hierarchically-regulated process with high diversity in different organisms including insects. The W chromosome-derived Fem piRNA has been identified as the primary sex determination factor in the lepidopteran insect, Bombyx mori, revealing a distinctive piRNA-mediated sex determination pathway. However, the comprehensive mechanism of silkworm sex determination is still poorly understood. We show here that the silkworm PIWI protein BmSiwi, but not BmAgo3, is essential for silkworm sex determination. CRISPR/Cas9-mediated depletion of BmSiwi results in developmental arrest in oogenesis and partial female sexual reversal, while BmAgo3 depletion only affects oogenesis. We identify three histone methyltransferases (HMTs) that are significantly down regulated in BmSiwi mutant moths. Disruption one of these, BmAsh2, causes dysregulation of piRNAs and transposable elements (TEs), supporting a role for it in the piRNA signaling pathway. More importantly, we find that BmAsh2 mutagenesis results in oogenesis arrest and partial female-to-male sexual reversal as well as dysregulation of the sex determination genes, Bmdsx and BmMasc. Mutagenesis of other two HMTs, BmSETD2 and BmEggless, does not affect piRNA-mediated sex determination. Histological analysis and immunoprecipitation results support a functional interaction between the BmAsh2 and BmSiwi proteins. Our data provide the first evidence that the HMT, BmAsh2, plays key roles in silkworm piRNA mediated sex determination. PMID- 29474356 TI - Management of severe strongyloidiasis attended at reference centers in Spain. AB - INTRODUCTION: Strongyloides stercoralis is a globally distributed nematode that causes diverse clinical symptoms in humans. Spain, once considered an endemic country, has experienced a recent increase in imported cases. The introduction of serology helps diagnosis and is currently replacing microbiological techniques in some settings, but its sensitivity is variable and can be low in immunocompromised patients. Diagnosis can only be confirmed by identification of larvae. Often, this "gold standard" can only be achieved in severe cases, such as disseminated S.stercoralis infection, or S.stercoralis hyperinfection syndrome, where parasite load is high. In addition, these clinical presentations are not well-defined. Our aim is to describe severe cases of S.stercoralis, their epidemiological profile, and their clinical details. METHODS: An observational retrospective study of disseminated S.stercoralis infection, or hyperinfection syndrome. Inclusion criteria: aged over 18, with a diagnosis of disseminated S.stercoralis infection, or hyperinfection syndrome, confirmed by visualization of larvae. Patients were identified through revision of clinical records for the period 2000-2015, in collaboration with eight reference centers throughout Spain. RESULTS: From the period 2000-2015, eighteen cases were identified, 66.7% of which were male, with a median age of 40 (range 21-70). Most of them were foreigners (94.4%), mainly from Latin America (82.3%) or Western Africa (17.6%). Only one autochthonous case was identified, from 2006. Immunosuppressive conditions were present in fourteen (77%) patients, mainly due steroids use and to retroviral coinfections (four HIV, two HTLV). Transplant preceded the clinical presentation in four of them. Other comorbidities were coinfection with HBV, Trypanosoma cruzi, Mycobacterium leprae or Aspergillus spp. All presented with digestive disorders, with 55.6% also presenting malaise. 44.4% of cases had fever, 27.8% skin complaints, and 16.7% respiratory or neurological disorders. One patient presented anemia, and one other nephrotic syndrome. Diagnosis was confirmed by identification of larvae in fresh stool samples (n = 16; 88.9%), concentration techniques (n = 6; 33.3%), larval culture (n = 5; 29.4%), or digestive biopsies (n = 8; 44%). S.stercoralis forms were identified during necropsy in one case. In addition, ten (55%) had a positive serology. All the cases were treated with ivermectin, six (33%) also received albendazole and one case received thiabendazole followed by ivermectin. All needed inpatient management, involving a mean hospitalization stay of 25 days (range 1-164). Two cases received intensive care and eventually died. CONCLUSIONS: Only eighteen cases of disseminated S.stercoralis infection/hyperinfection syndrome were identified from the 15-year period, most of which were considered to have been imported cases. Among those, immunosuppression was frequent, and mortality due to S.stercoralis was lower than previously described. PMID- 29474357 TI - Effects of flow rate on the migration of different plasticizers from PVC infusion medical devices. AB - Infusion medical devices (MDs) used in hospitals are often made of plasticized polyvinylchloride (PVC). These plasticizers may leach out into infused solutions during clinical practice, especially during risk-situations, e.g multiple infusions in Intensive Care Units and thus may enter into contact with the patients. The migrability of the plasticizers is dependent of several clinical parameters such as temperature, contact time, nature of the simulant, etc... However, no data is available about the influence of the flow rate at which drug solutions are administrated. In this study, we evaluated the impact of different flow rates on the release of the different plasticizers during an infusion procedure in order to assess if they could expose the patients to more toxic amounts of plasticizers. Migration assays with different PVC infusion sets and extension lines were performed with different flow rates that are used in clinical practice during 1h, 2h, 4h, 8h and 24h, using a lipophilic drug simulant. From a clinical point of view, the results showed that, regardless of the plasticizer, the faster the flow rate, the higher the infused volume and the higher the quantities of plasticizers released, both from infusion sets and extension lines, leading to higher patient exposure. However, physically, there was no significant difference of the migration kinetics linked to the flow rate for a same medical device, reflecting complex interactions between the PVC matrix and the simulant. The migration was especially dependent on the nature and the composition of the medical device. PMID- 29474358 TI - Technical feasibility study for production of tailored multielectrode arrays and patterning of arranged neuronal networks. AB - In this manuscript, we first reveal a simple ultra violet laser lithographic method to design and produce plain tailored multielectrode arrays. Secondly, we use the same lithographic setup for surface patterning to enable controlled attachment of primary neuronal cells and help neurite guidance. For multielectrode array production, we used flat borosilicate glass directly structured with the laser lithography system. The multi layered electrode system consists of a layer of titanium coated with a layer of di-titanium nitride. Finally, these electrodes are covered with silicon nitride for insulation. The quality of the custom made multielectrode arrays was investigated by light microscopy, electron microscopy and X-ray diffraction. The performance was verified by the detection of action potentials of primary neurons. The electrical noise of the custom-made MEA was equal to commercially available multielectrode arrays. Additionally, we demonstrated that structured coating with poly lysine, obtained with the aid of the same lithographic system, could be used to attach and guide neurons to designed structures. The process of neuron attachment and neurite guidance was investigated by light microscopy and charged particle microscopy. Importantly, the utilization of the same lithographic system for MEA fabrication and poly lysine structuring will make it easy to align the architecture of the neuronal network to the arrangement of the MEA electrode.. In future studies, this will lead to multielectrode arrays, which are able to specifically attach neuronal cell bodies to their chemically defined electrodes and guide their neurites, gaining a controlled connectivity in the neuronal network. This type of multielectrode array would be able to precisely assign a signal to a certain neuron resulting in an efficient way for analyzing the maturation of the neuronal connectivity in small neuronal networks. PMID- 29474359 TI - Support surfaces for pressure ulcer prevention: A network meta-analysis. AB - BACKGROUND: Pressure ulcers are a prevalent and global issue and support surfaces are widely used for preventing ulceration. However, the diversity of available support surfaces and the lack of direct comparisons in RCTs make decision-making difficult. OBJECTIVES: To determine, using network meta-analysis, the relative effects of different support surfaces in reducing pressure ulcer incidence and comfort and to rank these support surfaces in order of their effectiveness. METHODS: We conducted a systematic review, using a literature search up to November 2016, to identify randomised trials comparing support surfaces for pressure ulcer prevention. Two reviewers independently performed study selection, risk of bias assessment and data extraction. We grouped the support surfaces according to their characteristics and formed evidence networks using these groups. We used network meta-analysis to estimate the relative effects and effectiveness ranking of the groups for the outcomes of pressure ulcer incidence and participant comfort. GRADE was used to assess the certainty of evidence. MAIN RESULTS: We included 65 studies in the review. The network for assessing pressure ulcer incidence comprised evidence of low or very low certainty for most network contrasts. There was moderate-certainty evidence that powered active air surfaces and powered hybrid air surfaces probably reduce pressure ulcer incidence compared with standard hospital surfaces (risk ratios (RR) 0.42, 95% confidence intervals (CI) 0.29 to 0.63; 0.22, 0.07 to 0.66, respectively). The network for comfort suggested that powered active air-surfaces are probably slightly less comfortable than standard hospital mattresses (RR 0.80, 95% CI 0.69 to 0.94; moderate certainty evidence). CONCLUSIONS: This is the first network meta-analysis of the effects of support surfaces for pressure ulcer prevention. Powered active air surfaces probably reduce pressure ulcer incidence, but are probably less comfortable than standard hospital surfaces. Most prevention evidence was of low or very low certainty, and more research is required to reduce these uncertainties. PMID- 29474360 TI - Animal versus plant protein and adult bone health: A systematic review and meta analysis from the National Osteoporosis Foundation. AB - BACKGROUND: Protein may have both beneficial and detrimental effects on bone health depending on a variety of factors, including protein source. OBJECTIVE: The aim was to conduct a systematic review and meta-analysis evaluating the effects of animal versus plant protein intake on bone mineral density (BMD), bone mineral content (BMC) and select bone biomarkers in healthy adults. METHODS: Searches across five databases were conducted through 10/31/16 for randomized controlled trials (RCTs) and prospective cohort studies in healthy adults that examined the effects of animal versus plant protein intake on 1) total body (TB), total hip (TH), lumbar spine (LS) or femoral neck (FN) BMD or TB BMC for at least one year, or 2) select bone formation and resorption biomarkers for at least six months. Strength of evidence (SOE) was assessed and random effect meta-analyses were performed. RESULTS: Seven RCTs examining animal vs. isoflavone-rich soy (Soy+) protein intake in 633 healthy peri-menopausal (n = 1) and post-menopausal (n = 6) women were included. Overall risk of bias was medium. Limited SOE suggests no significant difference between Soy+ vs. animal protein on LS, TH, FN and TB BMD, TB BMC, and bone turnover markers BSAP and NTX. Meta-analysis results showed on average, the differences between Soy+ and animal protein groups were close to zero and not significant for BMD outcomes (LS: n = 4, pooled net % change: 0.24%, 95% CI: -0.80%, 1.28%; TB: n = 3, -0.24%, 95% CI: -0.81%, 0.33%; FN: n = 3, 0.13%, 95% CI: -0.94%, 1.21%). All meta-analyses had no statistical heterogeneity. CONCLUSIONS: These results do not support soy protein consumption as more advantageous than animal protein, or vice versa. Future studies are needed examining the effects of different protein sources in different populations on BMD, BMC, and fracture. PMID- 29474361 TI - Fermented whey-based product improves the quality of life of males with moderate lower urinary tract symptoms: A randomized double-blind study. AB - PURPOSE: The purpose of this research was to evaluate the effect of a specific fermented whey product on lower urinary tract symptoms, main prostate related indices and oxidative stress/inflammatory markers in urine and seminal plasma in men with moderate dysuric symptoms. An additional purpose was to clarify associations between different parameters with special emphasis on pain. METHODS: This was a prospective randomized double-blind 4-weeks study on men with moderate lower urinary tract symptoms who underwent the evaluation for quality of life at the baseline and at the end of the study. The symptoms were characterized by International Prostate Symptom Score (I-PSS) and National Institutes of Health Chronic Prostatitis Symptom Index (NIH-PSI), the maximum urinary flow and the main prostate-related indices. In order to obtain more comprehensive information about the effects of fermented whey product on systemic oxidative stress marker 8 EPI and seminal plasma inflammatory markers (interleukin-6 and interleukin-8) were also measured. RESULTS: After 4 weeks consumption of fermented whey product there was a statistically significant decrease of prostate-specific antigen level in serum and systemic stress marker 8-EPI in urine compared to control group. Maximum urinary flow and NIH-PSI all studied scores and sub-scores had also significant improvement. In addition, seminal plasma interleukin-8 level substantially decreased. CONCLUSIONS: The consumption of special fermented whey product improved urinary function, reduced lower urinary tract symptoms, systemic oxidative stress marker and seminal plasma inflammatory status. Thus it contributed to an improvement of the quality of life in men with moderate lower urinary tract symptoms. PMID- 29474362 TI - Analysis of socioeconomic differences in the quality of antenatal services in low and middle-income countries (LMICs). AB - The desired results of increasing access and availability of antenatal care (ANC) services may not be realized if the quality of care offered is not adequate. We analyzed the content/quality of antenatal care to determine whether there are socioeconomic (education and wealth) inequalities in the services provided in 59 low and middle income countries in six WHO regions-Africa, East Asia and Pacific, Europe and Central Asia, Latin America and Caribbean, Middle East and South Asia. We aggregated the most recent (2005-2015) Demographic and Health Survey for each country. The quality of content was measured on eight recommended ANC services (1) monitoring of blood pressure; (2) tetanus injection; (3) urine analysis for protein; (4) blood test; (5) information about danger signs (6); weight (7); height measurements and (8) provision of iron-folate supplement. Descriptive and Poisson regression techniques were applied to analyse the data. We found considerable wealth and educational differences prior to controlling for known covariates. Between wealth and education, however, the disparities in the latter are larger than the former. Whereas the socioeconomic differences remained at post adjusting for residence, place and number of antenatal care, parity and region, the magnitude of change was minimal. Higher number of ANC content was provided in "other" forms of private facilities; the Latin America and Caribbean region recorded the highest number of content compared to the other regions. The hypothesized socioeconomic status on content/number of ANC services was generally supported, although the associations are substantially constrained to other variables. Efforts are made to increase the number and timing of ANC services; due recognition is needed for the content offered. PMID- 29474363 TI - Continuous positive airway pressure improves gait control in severe obstructive sleep apnoea: A prospective study. AB - STUDY AIM: Severe obstructive sleep apnoea (OSA) can lead to neurocognitive alterations, including gait impairments. The beneficial effects of continuous positive airway pressure (CPAP) on improving excessive daytime sleepiness and daily functioning have been documented. However, a demonstration of CPAP treatment efficacy on gait control is still lacking. This study aims to test the hypothesis that CPAP improves gait control in severe OSA patients. MATERIAL AND METHODS: In this prospective controlled study, twelve severe OSA patients (age = 57.2+/-8.9 years, body mass index = 27.4+/-3.1 kg.m-2, apnoea-hypopnoea index = 46.3+/-11.7 events.h-1) and 10 healthy matched subjects were included. Overground gait parameters were recorded at spontaneous speed and stride time variability, a clinical marker of gait control, was calculated. To assess the role of executive functions in gait and postural control, a dual-task paradigm was applied using a Stroop test as secondary cognitive task. All assessments were performed before and after 8 weeks of CPAP treatment. RESULTS: Before CPAP treatment, OSA patients had significantly larger stride time variability (3.1+/-1.1% vs 2.1+/-0.5%) and lower cognitive performances under dual task compared to controls. After CPAP treatment, stride time variability was significantly improved and no longer different compared to controls. Cognitive performance under dual task also improved after CPAP treatment. CONCLUSION: Eight weeks of CPAP treatment improves gait control of severe OSA patients, suggesting morphological and functional cerebral improvements. Our data provide a rationale for further mechanistic studies and the use of gait as a biomarker of OSA brain consequences. PMID- 29474364 TI - beta-glucuronidase use as a single internal control gene may confound analysis in FMR1 mRNA toxicity studies. AB - Relationships between Fragile X Mental Retardation 1 (FMR1) mRNA levels in blood and intragenic FMR1 CGG triplet expansions support the pathogenic role of RNA gain of function toxicity in premutation (PM: 55-199 CGGs) related disorders. Real-time PCR (RT-PCR) studies reporting these findings normalised FMR1 mRNA level to a single internal control gene called beta-glucuronidase (GUS). This study evaluated FMR1 mRNA-CGG correlations in 33 PM and 33 age- and IQ-matched control females using three normalisation strategies in peripheral blood mononuclear cells (PBMCs): (i) GUS as a single internal control; (ii) the mean of GUS, Eukaryotic Translation Initiation Factor 4A2 (EIF4A2) and succinate dehydrogenase complex flavoprotein subunit A (SDHA); and (iii) the mean of EIF4A2 and SDHA (with no contribution from GUS). GUS mRNA levels normalised to the mean of EIF4A2 and SDHA mRNA levels and EIF4A2/SDHA ratio were also evaluated. FMR1mRNA level normalised to the mean of EIF4A2 and SDHA mRNA levels, with no contribution from GUS, showed the most significant correlation with CGG size and the greatest difference between PM and control groups (p = 10-11). Only 15% of FMR1 mRNA PM results exceeded the maximum control value when normalised to GUS, compared with over 42% when normalised to the mean of EIF4A2 and SDHA mRNA levels. Neither GUS mRNA level normalised to the mean RNA levels of EIF4A2 and SDHA, nor to the EIF4A2/SDHA ratio were correlated with CGG size. However, greater variability in GUS mRNA levels were observed for both PM and control females across the full range of CGG repeat as compared to the EIF4A2/SDHA ratio. In conclusion, normalisation with multiple control genes, excluding GUS, can improve assessment of the biological significance of FMR1 mRNA-CGG size relationships. PMID- 29474365 TI - Ultra-fast vitrification of patient-derived circulating tumor cell lines. AB - Emerging technologies have enabled the isolation and characterization of rare circulating tumor cells (CTCs) from the blood of metastatic cancer patients. CTCs represent a non-invasive opportunity to gain information regarding the primary tumor and recent reports suggest CTCs have value as an indicator of disease status. CTCs are fragile and difficult to expand in vitro, so typically molecular characterization must be performed immediately following isolation. To ease experimental timelines and enable biobanking, cryopreservation methods are needed. However, extensive cellular heterogeneity and the rarity of CTCs complicates the optimization of cryopreservation methods based upon cell type, necessitating a standardized protocol. Here, we optimized a previously reported vitrification protocol to preserve patient-derived CTC cell lines using highly conductive silica microcapillaries to achieve ultra-fast cooling rates with low cryoprotectant concentrations. Using this vitrification protocol, five CTC cell lines were cooled to cryogenic temperatures. Thawed CTCs exhibited high cell viability and expanded under in vitro cell culture conditions. EpCAM biomarker expression was maintained for each CTC cell line. One CTC cell line was selected for molecular characterization, revealing that RNA integrity was maintained after storage. A qPCR panel showed no significant difference in thawed CTCs compared to fresh controls. The data presented here suggests vitrification may enable the standardization of cryopreservation methods for CTCs. PMID- 29474367 TI - An investigation of the effect of race-based social categorization on adults' recognition of emotion. AB - Emotion recognition is important for social interaction and communication, yet previous research has identified a cross-cultural emotion recognition deficit: Recognition is less accurate for emotions expressed by individuals from a cultural group different than one's own. The current study examined whether social categorization based on race, in the absence of cultural differences, influences emotion recognition in a diverse context. South Asian and White Canadians in the Greater Toronto Area completed an emotion recognition task that required them to identify the seven basic emotional expressions when posed by members of the same two groups, allowing us to tease apart the contributions of culture and social group membership. Contrary to our hypothesis, there was no mutual in-group advantage in emotion recognition: Participants were not more accurate at recognizing emotions posed by their respective racial in-groups. Both groups were more accurate at recognizing expressions when posed by South Asian faces, and White participants were more accurate overall compared to South Asian participants. These results suggest that in a diverse environment, categorization based on race alone does not lead to the creation of social out-groups in a way that negatively impacts emotion recognition. PMID- 29474366 TI - CR6 interacting factor 1 deficiency promotes endothelial inflammation by SIRT1 downregulation. AB - AIMS: CR6 interacting factor 1 (CRIF1) deficiency impairs mitochondrial oxidative phosphorylation complexes, contributing to increased mitochondrial and cellular reactive oxygen species (ROS) production. CRIF1 downregulation has also been revealed to decrease sirtuin 1 (SIRT1) expression and impair vascular function. Inhibition of SIRT1 disturbs oxidative energy metabolism and stimulates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB)-induced inflammation. Therefore, we hypothesized that both CRIF1 deficiency-induced mitochondrial ROS production and SIRT1 reduction play stimulatory roles in vascular inflammation. METHODS AND RESULTS: Plasma levels and mRNA expression of proinflammatory cytokines (tumor necrosis factor (TNF)-alpha, interleukin (IL) 1beta, and IL-6) were markedly elevated in endothelium-specific CRIF1-knockout mice and CRIF1-silenced endothelial cells, respectively. Moreover, CRIF1 deficiency-induced vascular adhesion molecule-1 (VCAM-1) expression was consistently attenuated by the antioxidant N-acetyl-cysteine and NF-kappaB inhibitor (BAY11). We next showed that siRNA-mediated CRIF1 downregulation markedly activated NF-kappaB. SIRT1 overexpression not only rescued CRIF1 deficiency-induced NF-kappaB activation but also decreased inflammatory cytokines (TNF-alpha, IL-1beta, and IL-6) and VCAM-1 expression levels in endothelial cells. CONCLUSIONS: These results strongly suggest that CRIF1 deficiency promotes endothelial cell inflammation by increasing VCAM-1 expression, elevating inflammatory cytokines levels, and activating the transcription factor NF-kappaB, all of which were inhibited by SIRT1 overexpression. PMID- 29474368 TI - Circulating extracellular DNA is an independent predictor of mortality in elderly patients with venous thromboembolism. AB - BACKGROUND: Venous thromboembolism (VTE) is a major cause of morbidity and mortality in elderly patients. Extracellular DNA is a pro-inflammatory and pro thrombotic mediator in vitro and in animal models. Levels of circulating extracellular DNA (ceDNA) are increased in VTE patients, but the association of ceDNA with VTE extent and clinical outcome is poorly understood. OBJECTIVES: We analyzed the association of ceDNA with the extent of VTE, categorized as distal and proximal deep vein thrombosis and pulmonary embolism, and with the clinical outcomes VTE recurrence and mortality. METHODS: We quantified ceDNA by a fluorescent probe, as well as circulating nucleosomes and neutrophil extracellular traps (NETs) by ELISA in plasma from 611 patients aged >= 65 years with acute VTE of a prospective cohort study (SWITCO65+). RESULTS: Levels of ceDNA and nucleosomes, but not NETs, correlated with VTE extent. Infectious comorbidities independently increased ceDNA levels in VTE. CeDNA strongly correlated with C-reactive protein and leukocytosis, suggesting an association of ceDNA with inflammation in VTE patients. CeDNA furthermore predicted PE-related and all-cause mortality, but not VTE recurrence, during a 3-year follow-up. CONCLUSIONS: Our study suggests that ceDNA levels in VTE patients reflect the degree of inflammation and may serve as a biomarker to stratify VTE patients at risk for mortality. PMID- 29474370 TI - The relationship of blue crab (Callinectes sapidus) size class and molt stage to disease acquisition and intensity of Hematodinium perezi infections. AB - In the blue crab, Callinectes sapidus, early studies suggested a relationship between smaller crabs, which molt more frequently, and higher rates of infection by the dinoflagellate parasite, Hematodinium perezi. In order to better explore the influence of size and molting on infections, blue crabs were collected from the Maryland coastal bays and screened for the presence of H. perezi in hemolymph samples using a quantitative PCR assay. Molt stage was determined by a radioimmunoassay which measured ecdysteroid concentrations in blue crab hemolymph. Differences were seen in infection prevalence between size classes, with the medium size class (crabs 61 to 90 mm carapace width) and juvenile crabs (<= 30 mm carapace width) having the highest infection prevalence at 47.2% and 46.7%, respectively. All size classes were susceptible to infection, although fall months favored disease acquisition by juveniles, whereas mid-sized animals (31-90 mm carapace width) acquired infection predominantly in summer. Disease intensity was also most pronounced in the summer, with blue crabs > 61 mm being primary sources of proliferation. Molt status appeared to be influenced by infection, with infected crabs having significantly lower concentrations of ecdysteroids than uninfected crabs in the spring and the fall. We hypothesize that infection by H. perezi may increase molt intervals, with a delay in the spring molt cycle as an evolutionary adaptation functioning to coincide with increased host metabolism, providing optimal conditions for H. perezi propagation. Regardless of season, postmolt crabs harbored significantly higher proportions of moderate and heavy infections, suggesting that the process of ecdysis, and the postmolt recovery period, has a positive effect on parasite proliferation. PMID- 29474369 TI - A comparison of balance control during stance and gait in patients with inflammatory and non-inflammatory polyneuropathy. AB - INTRODUCTION: We compared changes in balance control due to chronic inflammatory demyelinating polyneuropathy (CIDP) and non-inflammatory (non-inf) polyneuropathy (PNP) to each other and with respect to healthy controls (HCs). Differences in patients' subjective impressions of balance capabilities were also compared. METHODS: Balance control of 11 CIDP patients (mean age 61.1+/-(sd) 11, 8 male) and 10 non-inf PNP patients (mean age 68.5+/-11.7, all male) was examined and compared to that of 18 age- and gender-matched healthy controls. Balance control during stance and gait tasks was measured as trunk sway angles and angular velocities with body-worn gyroscopes. Patients' subjective impressions of balance were obtained using the Dizziness Handicap Inventory (DHI). The Neuropathy Impairment Score in the Lower Limbs (NIS-LL) was used to measure clinical disease status. RESULTS: Non-inf PNP patients had slightly lower NIS-LL (13.5+/-7.2 vs. 17.9+/-15.1) and DHI scores (22.6+/-17.1 vs 27.6+/-16.3). Gait tasks showed a significant decrease in gait speed with respect to HCs for both patient groups but reduced trunk sway for non-inf PNP patients. Trunk sway during tandem walking and walking on the heels was greater for both groups than that of HCs. Sway during 2-legged stance tasks with eyes closed on a firm or foam surface was also greater than for HCs. DISCUSSION: Compared to HCs both groups of patients have significantly greater sway for most stance and gait tasks accompanied by reduced gait speed. As for HCs, non-inf PNP patients reduced trunk sway with slower gait speed. In CIDP patients this compensatory strategy was absent, possibly due to a greater deficit of efferent and motor nerve fibers. An interpretation of these findings is that CIDP patients have reduced ability to decrease trunk sway with slower gait speed and is possibly associated with an increased risk of falls. PMID- 29474371 TI - Correction: Antibiotic resistance rates and physician antibiotic prescription patterns of uncomplicated urinary tract infections in southern Chinese primary care. AB - [This corrects the article DOI: 10.1371/journal.pone.0177266.]. PMID- 29474372 TI - Zinc pyrithione activates K+ channels and hyperpolarizes the membrane of rat pulmonary artery smooth muscle cells. AB - The membrane potential helps determine pulmonary artery smooth muscle cell (PASMC) contraction. The Kv7 channel activators, retigabine and flupirtine, are thought to dilate pulmonary arteries by hyperpolarising PASMC. Zinc pyrithione activates Kv7 channels by a mechanism distinct from retigabine and with different Kv7 subunit selectivity. This study aimed to determine if zinc pyrithione selectively activates Kv7 channels in rat PASMC to evoke pulmonary artery dilation. Zinc pyrithione relaxed pulmonary arteries with half-maximal effect at 4.3MUM. At 10MUM it activated pronounced voltage-dependent K+ current and hyperpolarized PASMCs by around 10mV. Tetraethylammonium ions (TEA, 10mM) and paxilline (1MUM) abolished both the current and hyperpolarisation. XE991 (10MUM) blocked the hyperpolarization and reduced the current by 30%. Iberiotoxin (50nM) had no effect on the hyperpolarisation, but reduced the current by 40%. The XE991 sensitive current activated with an exponential time course (time constant 17ms), whereas the iberiotoxin-sensitive current followed a bi-exponential time course (time constants 6 and 57ms), suggesting that the drugs blocked different components of the zinc pyrithione-induced current. Zinc pyrithione therefore appears to activate at least two types of K+ channel in PASMC; an XE991, TEA and paxilline-sensitive Kv7 channel and a TEA, paxilline and iberiotoxin-sensitive BKCa channel. Both could contribute to the relaxing effect of zinc pyrithione on pulmonary artery. PMID- 29474373 TI - Hospitalization mortality and associated risk factors in patients with polymyositis and dermatomyositis: A retrospective case-control study. AB - BACKGROUND: Polymyositis and dermatomyositis (PM/DM) are systemic autoimmune diseases with multiple organ involvements that manifest as muscular and cutaneous disorders, interstitial lung disease (ILD) and malignancies. However, information concerning the outcomes and associated factors for PM/DM patients who are hospitalized is limited. METHODS: We retrospectively reviewed the medical charts of PM/DM patients admitted to a Chinese tertiary referral hospital (Peking Union Medical College Hospital, PUMCH) from 2008 to 2014. The deceased group included 63 patients who had "deceased discharge" status or were confirmed to have died within two weeks of hospital discharge. The demographic data, clinical manifestations, and direct causes of death were analyzed retrospectively. Medical records for 126 age- and sex-matched PM/DM patients were selected as controls from 982 inpatients successively admitted to the same center during the same period. In addition to the comparison of clinical manifestations between the two groups, binary logistic regression was conducted to explore the risk factors related to PM/DM mortality. RESULTS: Over the past 6 years at PUMCH, the in hospital mortality rate of PM/DM patients was 4.58%. The male gender and the elder patients had a high risk of death (P = 0.031 and P = 0.001 respectively). The three most frequent causes of death for PM/DM patients were pulmonary infection (35%), ILD exacerbation (21%) or both conditions (25%). Pulmonary infection (P<0.001, OR = 5.63, 95% CI, 2.37-13.36), pneumomediastinum (P = 0.041, OR = 11.02, 95%CI, 1.10-110.54), Gottron's papules (P = 0.010, OR = 3.24, 95%CI, 1.32-7.97), and elevated erythrocyte sedimentation rate (ESR) (P = 0.005, OR = 9.9, 95%CI 2.0-49.0) were independent risk factors for in-hospital mortality of PM/DM patients. CONCLUSION: PM/DM patients continue to display high in-hospital mortality. Pulmonary infection is the strongest predictor of poor prognosis in PM/DM patients, followed by pneumomediastinum, Gottron's papules, and elevated ESR. PMID- 29474374 TI - Neither Lys- and DAP-type peptidoglycans stimulate mouse or human innate immune cells via Toll-like receptor 2. AB - Peptidoglycan (PGN), a major component of bacterial cell walls, is a pathogen associated molecular pattern (PAMP) that causes innate immune cells to produce inflammatory cytokines that escalate the host response during infection. In order to better understand the role of PGN in infection, we wanted to gain insight into the cellular receptor for PGN. Although the receptor was initially identified as Toll-like receptor 2 (TLR2), this receptor has remained controversial and other PGN receptors have been reported. We produced PGN from live cultures of Bacillus anthracis and Staphylococcus aureus and tested samples of PGN isolated during the purification process to determine at what point TLR2 activity was removed, if at all. Our results indicate that although live B. anthracis and S. aureus express abundant TLR2 ligands, highly-purified PGN from either bacterial source is not recognized by TLR2. PMID- 29474375 TI - Dominance of P-glycoprotein 12 in phenotypic resistance conversion against ivermectin in Caenorhabditis elegans. AB - While diseases caused by nematodes remains a considerable drawback for the livestock, agriculture and public health, anthelmintics drug resistance has been observed over the past years and is a major concern for parasite control. Ivermectin, initially considered as a highly potent drug, currently presents a reduced anti-helminthic efficacy, which is influenced by expression of several ATP-binding cassette transporters (ABC), among them the P-glycoproteins (Pgps). Here we present some evidences of Pgps dominance during Ivermectin resistance/susceptibility using Pgps double silencing in C. elegans and the phylogenetic relationship of Pgps among nematodes, which strengthen the use of this model for study of drug resistance in nematodes. Firstly, we evaluated the quantitative gene expression of 12 out the 15 known Pgps from resistant and WT strains of C. elegans, we demonstrated the upregulation of Pgps 12 and 13 and downregulation of all remaining Pgps in ivermectin resistant strain. By using an RNAi loss-of-function approach we observed that Pgp 12 gene silencing reverts the resistance phenotype to ivermectin, while Pgp 4 gene silencing does not alter the resistance phenotype but induces a resistance in wild type strain. Interestingly, the dual silencing of Pgp 12 and Pgp 4 expression demonstrates the dominance of phenotype promoted by Pgp 12 silencing. Finally, in silico analysis reveals a close relationship between Pgps from C. elegans and several nematodes parasites. Taken together, our results indicate that Pgp 12 is crucial for the resistance to ivermectin and thus a good candidate for further studies aiming to develop specific inhibitors to this transporter, allowing the continuous use of ivermectin to control the burden on animal and human health inflicted by nematode parasites globally. PMID- 29474376 TI - Using single-index ODEs to study dynamic gene regulatory network. AB - With the development of biotechnology, high-throughput studies on protein protein, protein-gene, and gene-gene interactions become possible and attract remarkable attention. To explore the interactions in dynamic gene regulatory networks, we propose a single-index ordinary differential equation (ODE) model and develop a variable selection procedure. We employ the smoothly clipped absolute deviation penalty (SCAD) penalized function for variable selection. We analyze a yeast cell cycle gene expression data set to illustrate the usefulness of the single-index ODE model. In real data analysis, we group genes into functional modules using the smoothing spline clustering approach. We estimate state functions and their first derivatives for functional modules using penalized spline-based nonparametric mixed-effects models and the spline method. We substitute the estimates into the single-index ODE models, and then use the penalized profile least-squares procedure to identify network structures among the models. The results indicate that our model fits the data better than linear ODE models and our variable selection procedure identifies the interactions that may be missed by linear ODE models but confirmed in biological studies. In addition, Monte Carlo simulation studies are used to evaluate and compare the methods. PMID- 29474377 TI - Welfare states, the Great Recession and health: Trends in educational inequalities in self-reported health in 26 European countries. AB - BACKGROUND: Although socioeconomic inequalities in health have long been observed in Europe, few studies have analysed their recent patterning. In this paper, we examined how educational inequalities in self-reported health have evolved in different European countries and welfare state regimes over the last decade, which was troubled by the Great Recession. METHODS: We used cross-sectional data from the EU-SILC survey for adults from 26 European countries, from 2005 to 2014 (n = 3,030,595). We first calculated education-related absolute (SII) and relative (RII) inequalities in poor self-reported health by country-year, adjusting for age, sex, and EU-SILC survey weights. We then regressed the year- and country-specific RII and SII on a yearly time trend, globally and by welfare regime, adjusting for country fixed effects. We further adjusted the analysis for the economic cycle using GDP growth, unemployment, and income inequality. RESULTS: Overall, absolute inequalities persisted and relative inequalities slightly widened (betaRII = 0.0313, p<0.05). There were substantial differences by welfare regime: Anglo-Saxon countries experienced the largest increase in absolute inequalities (betaSII = 0.0032, p<0.05), followed by Bismarkian countries (betaSII = 0.0024, p<0.001), while they reduced in Post-Communist countries (betaSII = -0.0022, p<0.001). Post-Communist countries also experienced a widening in relative inequalities (betaRII = 0.1112, p<0.001), which were found to be stable elsewhere. Adjustment for income inequality only explained such trend in Anglo-Saxon countries. CONCLUSIONS: Educational inequalities in health have overall persisted across European countries over the last decade. However, there is considerable variation across welfare regimes, possibly related to underpinning social safety nets and to austerity measures implemented during this 10-year period. PMID- 29474378 TI - Gaze distribution analysis and saliency prediction across age groups. AB - Knowledge of the human visual system helps to develop better computational models of visual attention. State-of-the-art models have been developed to mimic the visual attention system of young adults that, however, largely ignore the variations that occur with age. In this paper, we investigated how visual scene processing changes with age and we propose an age-adapted framework that helps to develop a computational model that can predict saliency across different age groups. Our analysis uncovers how the explorativeness of an observer varies with age, how well saliency maps of an age group agree with fixation points of observers from the same or different age groups, and how age influences the center bias tendency. We analyzed the eye movement behavior of 82 observers belonging to four age groups while they explored visual scenes. Explorative- ness was quantified in terms of the entropy of a saliency map, and area under the curve (AUC) metrics was used to quantify the agreement analysis and the center bias tendency. Analysis results were used to develop age adapted saliency models. Our results suggest that the proposed age-adapted saliency model outperforms existing saliency models in predicting the regions of interest across age groups. PMID- 29474379 TI - Small RNA populations revealed by blocking rRNA fragments in Drosophila melanogaster reproductive tissues. AB - RNA interference (RNAi) is a complex and highly conserved regulatory mechanism mediated via small RNAs (sRNAs). Recent technical advances in high throughput sequencing have enabled an increasingly detailed analysis of sRNA abundances and profiles in specific body parts and tissues. This enables investigations of the localized roles of microRNAs (miRNAs) and small interfering RNAs (siRNAs). However, variation in the proportions of non-coding RNAs in the samples being compared can hinder these analyses. Specific tissues may vary significantly in the proportions of fragments of longer non-coding RNAs (such as ribosomal RNA or transfer RNA) present, potentially reflecting tissue-specific differences in biological functions. For example, in Drosophila, some tissues contain a highly abundant 30nt rRNA fragment (the 2S rRNA) as well as abundant 5' and 3' terminal rRNA fragments. These can pose difficulties for the construction of sRNA libraries as they can swamp the sequencing space and obscure sRNA abundances. Here we addressed this problem and present a modified "rRNA blocking" protocol for the construction of high-definition (HD) adapter sRNA libraries, in D. melanogaster reproductive tissues. The results showed that 2S rRNAs targeted by blocking oligos were reduced from >80% to < 0.01% total reads. In addition, the use of multiple rRNA blocking oligos to bind the most abundant rRNA fragments allowed us to reveal the underlying sRNA populations at increased resolution. Side-by-side comparisons of sequencing libraries of blocked and non-blocked samples revealed that rRNA blocking did not change the miRNA populations present, but instead enhanced their abundances. We suggest that this rRNA blocking procedure offers the potential to improve the in-depth analysis of differentially expressed sRNAs within and across different tissues. PMID- 29474380 TI - Predisposing and precipitating factors for delirium in community-dwelling older adults admitted to hospital with this condition: A prospective case series. AB - BACKGROUND: Factors associated with delirium among community-dwelling older adults have been poorly studied. Our aim was to describe the prevalence of predisposing and precipitating factors for delirium among patients admitted for delirium and to assess whether these factors were appropriately recognized at the first patient assessment at hospital. METHODS: Consecutive community-dwelling individuals admitted to three geriatric acute care units with a confirmed initial diagnosis of delirium were prospectively included. An independent investigator recorded, using a predefined form, any acute medical condition considered by the attending geriatrician to be a precipitating factor, at the first patient assessment and at the end of his stay in acute care. RESULTS: A total of 208 patients were included, 80.0% had a pre-existing cognitive or neurological disorder, or both. The most frequent precipitating factor found were infections (49.0% of all patients, mainly lung and urinary tract infections), followed by drugs (30.8%), dehydration (26.4%) and electrolytic disturbances (18.7%, mostly hyponatremia). 91% of patients had a cerebral imagery, but acute neurological conditions were found in only 18.3%. Fewer precipitating factors were found at first than at final assessment (1.4 (95%CI 1.3-1.6) versus 1.9 (95%CI 1.8-2.0) respectively, p<0.001). This difference was significant for all main categories of precipitating factors. CONCLUSIONS: Infections, followed by drugs and hydro electrolytic disorders seem to be the most frequent precipitating factors for delirium in community-dwelling elderly individuals. Early diagnostic and management of precipitating factors in these patients should be improved, as a significant number of them are missed at the initial assessment. PMID- 29474381 TI - Comprehensive analysis of clinical Burkholderia pseudomallei isolates demonstrates conservation of unique lipid A structure and TLR4-dependent innate immune activation. AB - Burkholderia pseudomallei is an environmental bacterium that causes melioidosis, a major community-acquired infection in tropical regions. Melioidosis presents with a range of clinical symptoms, is often characterized by a robust inflammatory response, may relapse after treatment, and results in high mortality rates. Lipopolysaccharide (LPS) of B. pseudomallei is a potent immunostimulatory molecule comprised of lipid A, core, and O-polysaccharide (OPS) components. Four B. pseudomallei LPS types have been described based on SDS-PAGE patterns that represent the difference of OPS-type A, type B, type B2 and rough LPS. The majority of B. pseudomallei isolates are type A. We used matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) followed by electrospray ionization quadrupole time-of-flight mass spectrometry (ESI-QqTOF MS) and gas chromatography to characterize the lipid A of B. pseudomallei within LPS type A isolates. We determined that B. pseudomallei lipid A is represented by penta- and tetra-acylated species modified with 4-amino-4-deoxy-arabinose (Ara4N). The MALDI-TOF profiles from 171 clinical B. pseudomallei isolates, including 68 paired primary and relapse isolates and 35 within-host isolates were similar. We did not observe lipid A structural changes when the bacteria were cultured in different growth conditions. Dose-dependent NF-kappaB activation in HEK cells expressing TLR4 was observed using multiple heat-killed B. pseudomallei isolates and corresponding purified LPS. We demonstrated that TLR4-dependent NF kappaB activation induced by heat-killed bacteria or LPS prepared from OPS deficient mutant was significantly greater than those induced by wild type B. pseudomallei. These findings suggest that the structure of B. pseudomallei lipid A is highly conserved in a wide variety of clinical and environmental circumstances but that the presence of OPS may modulate LPS-driven innate immune responses in melioidosis. PMID- 29474383 TI - A cross-country analysis of climate shocks and smallholder food insecurity. AB - Future climate changes will affect smallholder farmers in the developing world, posing threats to household food security. Nevertheless, there remains limited comparable evidence across multiple countries and regions regarding the global extent of climate shocks affecting smallholder food security. We examine data from 5,299 household surveys across 15 countries in Latin America, Africa and South Asia to assess the extent of climate shocks and their association with food insecurity, as well as what strategies may help buffer against climate shocks. We find that 71% of households reported experiencing a climate shock in the previous five years. Fifty-four percent reported experiencing food insecurity during one or more months annually. A multilevel statistical model estimated factors correlated with food insecurity as well as factors correlated with food insecurity among households that had experienced a climate shock. Households that reported experiencing a climate shock were 1.73 times more likely to be food insecure. As well, larger and poorer households were associated with higher odds of food insecurity while using pesticides, keeping large livestock, and being more educated are associated with lower odds of food insecurity. Among households that had experienced a climate shock, additional factors are correlated with lower odds of food insecurity when compared to otherwise similar households: use of fertilizers, pesticides, veterinary medicines, large livestock, and household assets. Together, these results demonstrate the extent of existing climate shocks affecting smallholder farmers and how interventions may potentially support adaptation and reduce food insecurity. PMID- 29474382 TI - The Turkish Neonatal Jaundice Online Registry: A national root cause analysis. AB - BACKGROUND: Neonatal jaundice (NNJ) is common, but few root cause analyses based on national quality registries have been performed. An online registry was established to estimate the incidence of NNJ in Turkey and to facilitate a root cause analysis of NNJ and its complications. METHODS: A multicenter prospective study was conducted on otherwise healthy newborns born at >=35 weeks of gestation and hospitalized for only NNJ in 50 collaborator neonatal intensive care units across Turkey over a 1-year period. Patients were analyzed for their demographic and clinical characteristics, treatment options, and complications. RESULTS: Of the 5,620 patients enrolled, 361 (6.4%) had a bilirubin level >=25 mg/dL on admission and 13 (0.23%) developed acute bilirubin encephalopathy. The leading cause of hospital admission was hemolytic jaundice, followed by dehydration related to a lack of proper feeding. Although all infants received phototherapy, 302 infants (5.4%) received intravenous immunoglobulin in addition to phototherapy and 132 (2.3%) required exchange transfusion. The infants who received exchange transfusion were more likely to experience hemolytic causes (60.6% vs. 28.1%) and a longer duration of phototherapy (58.5 +/- 31.7 vs. 29.4 +/- 18.8 h) compared to infants who were not transfused (p < 0.001). The incidence of short-term complications among discharged patients during follow-up was 8.5%; rehospitalization was the most frequent (58%), followed by jaundice for more than 2 weeks (39%), neurological abnormality (0.35%), and hearing loss (0.2%). CONCLUSIONS: Severe NNJ and bilirubin encephalopathy are still problems in Turkey. Means of identifying at-risk newborns before discharge during routine postnatal care, such as bilirubin monitoring, blood group analysis, and lactation consultations, would reduce the frequency of short- and long-term complications of severe NNJ. PMID- 29474384 TI - Development of improved therapeutic mesothelin-based vaccines for pancreatic cancer. AB - Pancreatic cancer is the 5th leading cause of cancer deaths, and there are no effective treatments. We developed a poxvirus platform vaccine with improved immunogenicity and inserted the mesothelin gene to create an anti-mesothelin cancer vaccine. Mesothelin expression is mostly restricted to tumors in adult mammals and thus may be a good target for cancer treatment. We show here that the modified vaccinia virus Ankara (MVA) virus expressing mesothelin and the enhanced MVA virus missing the immunosuppressive A35 gene and expressing mesothelin were both safe in mice and were able to induce IFN-gamma secreting T cells in response to mesothelin expressing tumor cells. In addition, the MVA virus has oncolytic properties in vitro as it can replicate in and kill Panc02 pancreatic adenocarcinoma cell line tumor cells, even though it is unable to replicate in most mammalian cells. Deletion of the A35 gene in MVA improved T cell responses as expected. However, we were unable to demonstrate inhibition of Panc02 tumor growth in immunocompetent mice with pre-vaccination of mice, boosts, or even intratumoral injections of the recombinant viruses. Vaccine efficacy may be limited by shedding of mesothelin from tumor cells thus creating a protective screen from the immune system. PMID- 29474385 TI - Influence of diabetes mellitus duration on the efficacy of ischemic preconditioning in a Zucker diabetic fatty rat model. AB - Augmented mortality and morbidity following an acute myocardial infarction in patients with diabetes mellitus Type 2 (T2DM) may be caused by increased sensitivity to ischemia reperfusion (IR) injury or altered activation of endogenous cardioprotective pathways modified by T2DM per se or ischemic preconditioning (IPC). We aimed to investigate, whether the duration of T2DM influences sensitivity against IR injury and the efficacy of IPC, and how myocardial glucose oxidation rate was involved. Male Zucker diabetic fatty rats (homozygote (fa/fa)) at ages 6-(prediabetic), 12- (onset diabetes) and 24-weeks of age (late diabetes) and their age-matched non-diabetic controls (heterozygote (fa/+) were subjected to IR injury in the Langendorff model and randomised to IPC stimulus or control. T2DM rats were endogenously protected at onset of diabetes, as infarct size was lower in 12-weeks T2DM animals than in 6- (35+/-2% vs 53+/ 4%; P = 0.006) and 24-weeks animals (35+/-2% vs 72+/-4%; P<0.0001). IPC reduced infarct size in all groups irrespective of the presence of T2DM and its duration (32+/-3%; 20+/-2%; 36+/-4% respectively; (ANOVA P<0.0001). Compared to prediabetic rats, myocardial glucose oxidation rates were reduced during stabilisation and early reperfusion at onset of T2DM, but these animals retained the ability to increase oxidation rate in late reperfusion. Late diabetic rats had low glucose oxidation rates throughout stabilisation and reperfusion. Despite inherent differences in sensitivity to IR injury, the cardioprotective effect of IPC was preserved in our animal model of pre-, early and late stage T2DM and associated with adaptations to myocardial glucose oxidation capacity. PMID- 29474387 TI - Mobile phones as monitors of personal exposure to air pollution: Is this the future? AB - Mobile phones have a large spectrum of applications, aiding in risk prevention and improving health and wellbeing of their owners. So far, however, they have not been used for direct assessment of personal exposure to air pollution. In this study, we comprehensively evaluated the first, and the only available, mobile phone-BROAD Life-equipped with air pollution sensors (PM2.5 and VOC), to answer the question whether this technology is a viable option in the quest of reducing the burden of disease to air pollution. We tested its performance, applicability and suitability for the purpose by subjecting it to varied concentrations of different types of aerosol particles (cigarette smoke, petrol exhaust and concrete dust) and formaldehyde under controlled laboratory conditions, as well as to ambient particles during field measurements. Six reference instruments were used in the study: AEROTRAK Optical Particle Counter (OPC model number 9306), DustTrak, Aerodynamic Particle Counter (APS), Scanning Mobility Particle Sizer (SMPS), Tapered Element Oscillating Microbalance (TEOM) and Formaldehyde Analyser. Overall, we found that the phone's response was linear at higher particle number concentrations in the chamber, above 5 and 10 MUg m-3, for combustion and concrete dust particles, respectively, and for higher formaldehyde concentrations, making it potentially suitable for applications in polluted environments. At lower ambient concentrations of particles around 10 ug m-3 and 20 MUg m-3 for PM2.5 and PM10, respectively, the phone's response was below its noise level, suggesting that it is not suitable for ambient monitoring under relatively clean urban conditions. This mobile phone has a number of limitations that may hinder its use in personal exposure and for continuous monitoring. Despite these limitations, it may be used for comparative assessments, for example when comparing outcomes of intervention measures or local impacts of air pollution sources. It should be kept in mind, however, that a mobile phone measuring air quality alone cannot as such 'reduce the burden of disease to air pollution, as knowing ambient concentrations is only one of the building block in this quest. As long as individuals cannot avoid exposure e.g. in urban areas, knowing concentrations is not sufficient to reduce potential adverse effects. Yet, there are many situations and microenvironments, which individuals could avoid knowing the concentrations and also being aware of the risk caused by exposure to them. This includes for example to proximity to vehicle emissions, either for social purposes (e.g. street cafes) or exercising (e.g. walking or jogging along busy roads)or indoor environments affected by combustion emissions (smoking, candle burning, open fire). PMID- 29474386 TI - Peak oxygen uptake in Paralympic sitting sports: A systematic literature review, meta- and pooled-data analysis. AB - BACKGROUND: Peak oxygen uptake (VO2peak) in Paralympic sitting sports athletes represents their maximal ability to deliver energy aerobically in an upper-body mode, with values being influenced by sex, disability-related physiological limitations, sport-specific demands, training status and how they are tested. OBJECTIVES: To identify VO2peak values in Paralympic sitting sports, examine between-sports differences and within-sports variations in VO2peak and determine the influence of sex, age, body-mass, disability and test-mode on VO2peak. DESIGN: Systematic literature review and meta-analysis. DATA SOURCES: PubMed, CINAHL, SPORTDiscusTM and EMBASE were systematically searched in October 2016 using relevant medical subject headings, keywords and a Boolean. ELIGIBILITY CRITERIA: Studies that assessed VO2peak values in sitting sports athletes with a disability in a laboratory setting were included. DATA SYNTHESIS: Data was extracted and pooled in the different sports disciplines, weighted by the Dersimonian and Laird random effects approach. Quality of the included studies was assessed with a modified version of the Downs and Black checklist by two independent reviewers. Meta-regression and pooled-data multiple regression analyses were performed to assess the influence of sex, age, body-mass, disability, test mode and study quality on VO2peak. RESULTS: Of 6542 retrieved articles, 57 studies reporting VO2peak values in 14 different sitting sports were included in this review. VO2peak values from 771 athletes were used in the data analysis, of which 30% participated in wheelchair basketball, 27% in wheelchair racing, 15% in wheelchair rugby and the remaining 28% in the 11 other disciplines. Fifty-six percent of the athletes had a spinal cord injury and 87% were men. Sports-discipline-averaged VO2peak values ranged from 2.9 L?min-1 and 45.6 mL?kg-1?min-1 in Nordic sit skiing to 1.4 L?min-1 and 17.3 mL?kg-1?min-1 in shooting and 1.3 L?min-1 and 18.9 mL?kg-1?min-1 in wheelchair rugby. Large within sports variation was found in sports with few included studies and corresponding low sample sizes. The meta-regression and pooled-data multiple regression analyses showed that being a man, having an amputation, not being tetraplegic, testing in a wheelchair ergometer and treadmill mode, were found to be favorable for high absolute and body-mass normalized VO2peak values. Furthermore, high body mass was favourable for high absolute VO2peak values and low body mass for high body-mass normalized VO2peak values. CONCLUSION: The highest VO2peak values were found in Nordic sit skiing, an endurance sport with continuously high physical efforts, and the lowest values in shooting, a sport with low levels of displacement, and in wheelchair rugby where mainly athletes with tetraplegia compete. However, VO2peak values need to be interpreted carefully in sports disciplines with few included studies and large within-sports variation. Future studies should include detailed information on training status, sex, age, test mode, as well as the type and extent of disability in order to more precisely evaluate the effect of these factors on VO2peak. PMID- 29474388 TI - Function of the natalisin receptor in mating of the oriental fruit fly, Bactrocera dorsalis (Hendel) and testing of peptidomimetics. AB - Natalisins (NTLs) are conservative neuropeptides, which are only found in arthropods and are documented to regulate reproductive behaviors in insects. In our previous study, we have confirmed that NTLs regulate the reproductive process in an important agricultural pest, Bactrocera dorsalis (Hendel). Hence, in this study, to further confirm the in vivo function of NTL receptor (NTLR) and assess the potential of NTLR as an insecticide target, RNA interference targeting NTLR mRNA was performed. We found that mating frequencies of both males and females were reduced by RNAi-mediated knockdown of the NTLR transcript, while there was no effect on mating duration. Moreover, we functionally expressed the B. dorsalis NTLR in Chinese Hamster Ovary (CHO) cells and was co-transfected with an aequorin reporter to measure ligand activities. A total of 13 biostable multi-Aib analogs were tested for agonistic and antagonistic activities. While most of these NTL analogs did not show strong activity, one analog (NLFQV[Aib]DPFF[Aib]TRamide) had moderate antagonistic activity. Taken together, we provided evidence for the important roles of NTLR in regulating mating frequencies of both male and female in this fly and also provided in vitro data on mimetic analogs that serve as leading structures for the development of agonists and antagonists to disrupt the NTL signaling pathway. PMID- 29474389 TI - Elevated temperature drives kelp microbiome dysbiosis, while elevated carbon dioxide induces water microbiome disruption. AB - Global climate change includes rising temperatures and increased pCO2 concentrations in the ocean, with potential deleterious impacts on marine organisms. In this case study we conducted a four-week climate change incubation experiment, and tested the independent and combined effects of increased temperature and partial pressure of carbon dioxide (pCO2), on the microbiomes of a foundation species, the giant kelp Macrocystis pyrifera, and the surrounding water column. The water and kelp microbiome responded differently to each of the climate stressors. In the water microbiome, each condition caused an increase in a distinct microbial order, whereas the kelp microbiome exhibited a reduction in the dominant kelp-associated order, Alteromondales. The water column microbiomes were most disrupted by elevated pCO2, with a 7.3 fold increase in Rhizobiales. The kelp microbiome was most influenced by elevated temperature and elevated temperature in combination with elevated pCO2. Kelp growth was negatively associated with elevated temperature, and the kelp microbiome showed a 5.3 fold increase Flavobacteriales and a 2.2 fold increase alginate degrading enzymes and sulfated polysaccharides. In contrast, kelp growth was positively associated with the combination of high temperature and high pCO2 'future conditions', with a 12.5 fold increase in Planctomycetales and 4.8 fold increase in Rhodobacteriales. Therefore, the water and kelp microbiomes acted as distinct communities, where the kelp was stabilizing the microbiome under changing pCO2 conditions, but lost control at high temperature. Under future conditions, a new equilibrium between the kelp and the microbiome was potentially reached, where the kelp grew rapidly and the commensal microbes responded to an increase in mucus production. PMID- 29474390 TI - Transcriptomes of Trypanosoma brucei rhodesiense from sleeping sickness patients, rodents and culture: Effects of strain, growth conditions and RNA preparation methods. AB - All of our current knowledge of African trypanosome metabolism is based on results from trypanosomes grown in culture or in rodents. Drugs against sleeping sickness must however treat trypanosomes in humans. We here compare the transcriptomes of Trypanosoma brucei rhodesiense from the blood and cerebrospinal fluid of human patients with those of trypanosomes from culture and rodents. The data were aligned and analysed using new user-friendly applications designed for Kinetoplastid RNA-Seq data. The transcriptomes of trypanosomes from human blood and cerebrospinal fluid did not predict major metabolic differences that might affect drug susceptibility. Usefully, there were relatively few differences between the transcriptomes of trypanosomes from patients and those of similar trypanosomes grown in rats. Transcriptomes of monomorphic laboratory-adapted parasites grown in in vitro culture closely resembled those of the human parasites, but some differences were seen. In poly(A)-selected mRNA transcriptomes, mRNAs encoding some protein kinases and RNA-binding proteins were under-represented relative to mRNA that had not been poly(A) selected; further investigation revealed that the selection tends to result in loss of longer mRNAs. PMID- 29474391 TI - Support service utilization and out-of-pocket payments for health services in a population-based sample of adults with neurological conditions. AB - BACKGROUND: Social support can help to deal with the consequences of neurological conditions and promote functional independence and quality of life. Our aim was to evaluate the impact of neurological conditions on the use of support and health-care services in a population-based sample of community-dwelling adults with neurological conditions. METHODS: Data were from the Survey of Living with Neurological Conditions in Canada, which was derived from a representative sample of household residents. Formal and informal support received and out-of-pocket payments were assessed by personal interviews. Logistic regression was used to explore the association between support service utilization and six common neurological conditions (Stroke, Parkinson's disease, Alzheimer's disease/dementias, traumatic brain injury, spinal cord injury and multiple sclerosis) with stroke as the reference category. RESULTS: The sample contained 2,410 respondents and equate to an estimated 459,770 when sample weights were used. A larger proportion of people within each of the neurological conditions received informal support than formal support (at least twice as much). Samples with the non-stroke conditions were more likely to receive formal assistance for personal (odds ratios 2.7 to 5.6; P < 0.05) and medical (odds ratios 2.4 to 4.4; P < 0.05) care compared to the stroke group. Also, the non-stroke conditions were more likely to receive informal assistance (odds ratios 2.7 to 17.9; P < 0.05) and less likely to make out-of-pocket payments for rehabilitation therapy (odds ratios 0.2 to 0.3; P < 0.05) than the stroke group. The Alzheimer's disease/dementia group had the highest proportion who received formal and informal support services. CONCLUSIONS: Our findings suggest that Canadians with neurological conditions receive more informal assistance than formal assistance. Furthermore, it appears that stroke survivors receive less support services, while those with Alzheimer's disease/dementia receive the most compared to other adult neurological conditions. Such data can help inform the development of support services in the community. PMID- 29474392 TI - Characterising non-urgent users of the emergency department (ED): A retrospective analysis of routine ED data. AB - BACKGROUND: The pressures of patient demand on emergency departments (EDs) continue to be reported worldwide, with an associated negative impact on ED crowding and waiting times. It has also been reported that a proportion of attendances to EDs in different international systems could be managed in settings such as primary care. This study used routine ED data to define, measure and profile non-urgent ED attendances that were suitable for management in alternative, non-emergency settings. METHODS: We undertook a retrospective analysis of three years of Hospital Episode and Statistics Accident Emergency (HES A&E) data for one large region in England, United Kingdom (April 1st 2011 to March 31st 2014). Data was collected on all adult (>16 years) ED attendances from each of the 19 EDs in the region. A validated process based definition of non urgent attendance was refined for this study and applied to the data. Using summary statistics non-urgent attenders were examined by variables hypothesised to influence them as follows: age at arrival, time of day and day of week and mode of arrival. Odds ratios were calculated to compare non-urgent attenders between groups. RESULTS: There were 3,667,601 first time attendances to EDs, of which 554,564 were defined as non-urgent (15.1%). Non-urgent attendances were significantly more likely to present out of hours than in hours (OR = 1.19, 95% CI: 1.18 to 1.20, P<0.001). The odds of a non-urgent attendance were significantly higher for younger patients (aged 16-44) compared to those aged 45 64 (odds ratio: 1.42, 95% CI: 1.41 to 1.43, P<0.001) and the over 65's (odds ratio: 3.81, 95% CI: 3.78 to 3.85, P<0.001). Younger patients were significantly more likely to attend non-urgently out of hours compared to the 45-64's (OR = 1.24, 95% CI: 1.22 to 1.25, P<0.001) and the 65+'s (OR = 1.38, 95% CI: 1.35 to 1.40, P<0.001). 110,605/554,564 (19.9%) of the non-urgent attendances arrived by ambulance, increasing significantly out of hours versus in hours (OR = 2.12, 95% CI: 2.09 to 2.15, P<0.001). CONCLUSIONS: Younger adults are significantly more likely as older counterparts to use the ED to obtain healthcare that could be provided in a less urgent setting and also more likely to do this out of hours. Alternative services are required to manage non-urgent demand, currently being borne by the ED and the ambulance service, particularly in out of hours. PMID- 29474393 TI - Poverty concentration in an affluent city: Geographic variation and correlates of neighborhood poverty rates in Hong Kong. AB - Previous investigations of geographic concentration of urban poverty indicate the contribution of a variety of factors, such as economic restructuring and class based segregation, racial segregation, demographic structure, and public policy. However, the models used by most past research do not consider the possibility that poverty concentration may take different forms in different locations across a city, and most studies have been conducted in Western settings. We investigated the spatial patterning of neighborhood poverty and its correlates in Hong Kong, which is amongst cities with the highest GDP in the region, using the city-wide ordinary least square (OLS) regression model and the local-specific geographically weighted regression (GWR) model. We found substantial geographic variations in small-area poverty rates and identified several poverty clusters in the territory. Factors found to contribute to urban poverty in Western cities, such as socioeconomic factors, ethnicity, and public housing, were also mostly associated with local poverty rates in Hong Kong. Our results also suggest some heterogeneity in the associations of poverty with specific correlates (e.g. access to hospitals) that would be masked in the city-wide OLS model. Policy aimed to alleviate poverty should consider both city-wide and local-specific factors. PMID- 29474394 TI - Assessment of water, sanitation and hygiene interventions in response to an outbreak of typhoid fever in Neno District, Malawi. AB - On May 2, 2009 an outbreak of typhoid fever began in rural villages along the Malawi-Mozambique border resulting in 748 illnesses and 44 deaths by September 2010. Despite numerous interventions, including distribution of WaterGuard (WG) for in-home water treatment and education on its use, cases of typhoid fever continued. To inform response activities during the ongoing Typhoid outbreak information on knowledge, attitudes, and practices surrounding typhoid fever, safe water, and hygiene were necessary to plan future outbreak interventions. In September 2010, a survey was administered to female heads in randomly selected households in 17 villages in Neno District, Malawi. Stored household drinking water was tested for free chlorine residual (FCR) levels using the N,N diethyl-p phenylene diamine colorimetric method (HACH Company, Loveland, CO, USA). Attendance at community-wide educational meetings was reported by 56% of household respondents. Respondents reported that typhoid fever is caused by poor hygiene (77%), drinking unsafe water (49%), and consuming unsafe food (25%), and that treating drinking water can prevent it (68%). WaterGuard, a chlorination solution for drinking water treatment, was observed in 112 (56%) households, among which 34% reported treating drinking water. FCR levels were adequate (FCR >= 0.2 mg/L) in 29 (76%) of the 38 households who reported treatment of stored water and had stored water available for testing and an observed bottle of WaterGuard in the home. Soap was observed in 154 (77%) households, among which 51% reported using soap for hand washing. Educational interventions did not reach almost one-half of target households and knowledge remains low. Despite distribution and promotion of WaterGuard and soap during the outbreak response, usage was low. Future interventions should focus on improving water, sanitation and hygiene knowledge, practices, and infrastructure. Typhoid vaccination should be considered. PMID- 29474396 TI - Rapid growth rate results in remarkably hardened breast in broilers during the middle stage of rearing: A biochemical and histopathological study. AB - The high incidence of meat of impaired quality poses a serious problem in the poultry industry. In recent years, the incidence of the pectoralis major muscle that appeared pale colored, remarkably hardened, and exudative, called "wooden breast" or "woody breast" has increased in slaughter houses. In the present study, 19-day-old Ross 308 broiler chickens affected (n = 10) and unaffected (n = 10) with remarkably hardened breast were selected from a commercial broiler farm, and reared to 55 days of age under a controlled environment. Among the affected birds, 5 of 10 birds appeared exhausted with markedly suppressed weight gain and 4 of 10 birds died during the rearing period. In contrast, all unaffected birds survived and most gained weight. Four of 10 unaffected birds lost the ability of back-to-back wing contact by the late stage of rearing. The biochemical analysis of blood plasma samples of 20-day-old birds revealed that creatine kinase and L aspartate aminotransferase values in most affected birds were higher than those in unaffected birds; however, these values in unaffected birds increased rapidly with lost wing contactability and increasing age. Postmortem examinations revealed that the mean diameter of myofibers in affected birds was smaller than that in unaffected birds. Moreover, symptoms of degenerative and regenerative muscles were observed in most birds in both groups. Among them, a decrease in, or defect of, the characteristic polygonal shape of myofibers was the most common change within the pectoralis major muscles in both groups. The present study demonstrated that broilers affected with remarkably hardened breast during the middle stage of rearing would have suppressed physical status and weight gain, or would die. It was suggested that rapid growth in broilers might be a cause of remarkably hardened breast. PMID- 29474395 TI - Genome-wide association across Saccharomyces cerevisiae strains reveals substantial variation in underlying gene requirements for toxin tolerance. AB - Cellulosic plant biomass is a promising sustainable resource for generating alternative biofuels and biochemicals with microbial factories. But a remaining bottleneck is engineering microbes that are tolerant of toxins generated during biomass processing, because mechanisms of toxin defense are only beginning to emerge. Here, we exploited natural diversity in 165 Saccharomyces cerevisiae strains isolated from diverse geographical and ecological niches, to identify mechanisms of hydrolysate-toxin tolerance. We performed genome-wide association (GWA) analysis to identify genetic variants underlying toxin tolerance, and gene knockouts and allele-swap experiments to validate the involvement of implicated genes. In the process of this work, we uncovered a surprising difference in genetic architecture depending on strain background: in all but one case, knockout of implicated genes had a significant effect on toxin tolerance in one strain, but no significant effect in another strain. In fact, whether or not the gene was involved in tolerance in each strain background had a bigger contribution to strain-specific variation than allelic differences. Our results suggest a major difference in the underlying network of causal genes in different strains, suggesting that mechanisms of hydrolysate tolerance are very dependent on the genetic background. These results could have significant implications for interpreting GWA results and raise important considerations for engineering strategies for industrial strain improvement. PMID- 29474397 TI - Beyond signal functions in global obstetric care: Using a clinical cascade to measure emergency obstetric readiness. AB - BACKGROUND: Globally, the rate of reduction in delivery-associated maternal and perinatal mortality has been slow compared to improvements in post-delivery mortality in children under five. Improving clinical readiness for basic obstetric emergencies is crucial for reducing facility-based maternal deaths. Emergency readiness is commonly assessed using tracers derived from the maternal signal functions model. OBJECTIVE-METHOD: We compare emergency readiness using the signal functions model and a novel clinical cascade. The cascades model readiness as the proportion of facilities with resources to identify the emergency (stage 1), treat it (stage 2) and monitor-modify therapy (stage 3). Data were collected from 44 Kenyan clinics as part of an implementation trial. FINDINGS: Although most facilities (77.0%) stock maternal signal function tracer drugs, far fewer have resources to practically identify and treat emergencies. In hypertensive emergencies for example, 38.6% of facilities have resources to identify the emergency (Stage 1 readiness, including sphygmomanometer, stethoscope, urine collection device, protein test). 6.8% have the resources to treat the emergency (Stage 2, consumables (IV Kit, fluids), durable goods (IV pole) and drugs (magnesium sulfate and hydralazine). No facilities could monitor or modify therapy (Stage 3). Across five maternal emergencies, the signal functions overestimate readiness by 54.5%. A consistent, step-wise pattern of readiness loss across signal functions and care stage emerged and was profoundly consistent at 33.0%. SIGNIFICANCE: Comparing estimates from the maternal signal functions and cascades illustrates four themes. First, signal functions overestimate practical readiness by 55%. Second, the cascade's intuitive indicators can support cross-sector health system or program planners to more precisely measure and improve emergency care. Third, adding few variables to existing readiness inventories permits step-wise modeling of readiness loss and can inform more precise interventions. Fourth, the novel aggregate readiness loss indicator provides an innovative and intuitive approach for modeling health system emergency readiness. Additional testing in diverse contexts is warranted. PMID- 29474398 TI - Mental toughness latent profiles in endurance athletes. AB - Mental toughness in endurance athletes, while an important factor for success, has been scarcely studied. An online survey was used to examine eight mental toughness factors in endurance athletes. The study aim was to determine mental toughness profiles via latent profile analysis in endurance athletes and whether associations exist between the latent profiles and demographics and sports characteristics. Endurance athletes >18 years of age were recruited via social media outlets (n = 1245, 53% female). Mental toughness was measured using the Sports Mental Toughness Questionnaire (SMTQ), Psychological Performance Inventory Alternative (PPI-A), and self-esteem was measured using the Rosenberg Self-Esteem Scale (RSE). A three-class solution emerged, designated as high mental toughness (High MT), moderate mental toughness (Moderate MT) and low mental toughness (Low MT). ANOVA tests showed significant differences between all three classes on all 8 factors derived from the SMTQ, PPI-A and the RSE. There was an increased odds of being in the High MT class compared to the Low MT class for males (OR = 1.99; 95% CI, 1.39, 2.83; P<0.001), athletes who were over 55 compared to those who were 18-34 (OR = 2.52; 95% CI, 1.37, 4.62; P<0.01), high sports satisfaction (OR = 8.17; 95% CI, 5.63, 11.87; P<0.001), and high division placement (OR = 2.18; 95% CI, 1.46,3.26; P<0.001). The data showed that mental toughness latent profiles exist in endurance athletes. High MT is associated with demographics and sports characteristics. Mental toughness screening in athletes may help direct practitioners with mental skills training. PMID- 29474399 TI - Exploring the relative contributions of reward-history and functionality information to children's acquisition of the Aesop's fable task. AB - Investigation of tool-using behaviours has long been a means by which to explore causal reasoning in children and nonhuman animals. Much of the recent research has focused on the "Aesop's Fable" paradigm, in which objects must be dropped into water to bring a floating reward within reach. An underlying problem with these, as with many causal reasoning studies, is that functionality information and reward history are confounded: a tool that is functionally useful is also rewarded, while a tool that is not functionally useful is not rewarded. It is therefore not possible to distinguish between behaviours motivated by functional understanding of the properties of the objects involved, and those influenced by reward-history. Here, we devised an adapted version of the Aesop's Fable paradigm which decouples functionality information and reward history by making use of situations in which the use of a particular tool should have enabled a subject to obtain (or not obtain) a reward, but the outcome was affected by the context. Children aged 4-11 were given experience of a range of tools that varied independently in whether they were functional or non-functional and rewarded or non-rewarded. They were then given the opportunity to choose which tools they would like to use in a test trial, thereby providing an assessment of whether they relied on information about functionality or the reward history associated with the object or a combination of the two. Children never significantly used reward history to drive their choices of tools, while the influence of functionality information increased with age, becoming dominant by age 7. However, not all children behaved in a consistent manner, and even by 10 years of age, only around a third exclusively used functionality as a basis for their decision-making. These findings suggest that from around the age of 7-years, children begin to emphasize functionality information when learning in novel situations, even if competing reward information is available, but that even in the oldest age-group, most children did not exclusively use functionality information. PMID- 29474400 TI - Acute liver failure in children-Is living donor liver transplantation justified? AB - OBJECTIVES: Living donor liver transplantation (LDLT) in patients with acute liver failure (ALF) has become an acceptable alternative to transplantation from deceased donors (DDLT). The aim of this study was to analyze outcomes of LDLT in pediatric patients with ALF based on our center's experience. MATERIAL AND METHODS: We enrolled 63 children (at our institution) with ALF who underwent liver transplantation between 1997 and 2016. Among them 24 (38%) underwent a LDLT and 39 (62%) received a DDLT. Retrospectively analyzed patient clinical data included: time lapse between qualification for transplantation and transplant surgery, graft characteristics, postoperative complications, long-term results post-transplantation, and living donor morbidity. Overall, we have made a comparison of clinical results between LDLT and DDLT groups. RESULTS: Follow-up periods ranged from 12 to 182 months (median 109 months) for LDLT patients and 12 to 183 months (median 72 months) for DDLT patients. The median waiting time for a transplant was shorter in LDLT group than in DDLT group. There was not a single case of primary non-function (PNF) in the LDLT group and 20 out of 24 patients (83.3%) had good early graft function; 3 patients (12.5%) in the LDLT group died within 2 months of transplantation but there was no late mortality. In comparison, 4 out of 39 patients (10.2%) had PNF in DDLT group while 20 patients (51.2%) had good early graft function; 8 patients (20.5%) died early within 2 months and 2 patients (5.1%) died late after transplantation. The LDLT group had a shorter cold ischemia time (CIT) of 4 hours in comparison to 9.2 hours in the DDLT group (p<0.0001). CONCLUSIONS: LDLT is a lifesaving procedure for pediatric patients with ALF. Our experience showed that it may be performed with very good results, and with very low morbidity and no mortality among living donors when performed by experienced teams following strict procedures. PMID- 29474401 TI - Factors determining dengue outbreak in Malaysia. AB - A large scale study was conducted to elucidate the true relationship among entomological, epidemiological and environmental factors that contributed to dengue outbreak in Malaysia. Two large areas (Selayang and Bandar Baru Bangi) were selected in this study based on five consecutive years of high dengue cases. Entomological data were collected using ovitraps where the number of larvae was used to reflect Aedes mosquito population size; followed by RT-PCR screening to detect and serotype dengue virus in mosquitoes. Notified cases, date of disease onset, and number and type of the interventions were used as epidemiological endpoint, while rainfall, temperature, relative humidity and air pollution index (API) were indicators for environmental data. The field study was conducted during 81 weeks of data collection. Correlation and Autoregressive Distributed Lag Model were used to determine the relationship. The study showed that, notified cases were indirectly related with the environmental data, but shifted one week, i.e. last 3 weeks positive PCR; last 4 weeks rainfall; last 3 weeks maximum relative humidity; last 3 weeks minimum and maximum temperature; and last 4 weeks air pollution index (API), respectively. Notified cases were also related with next week intervention, while conventional intervention only happened 4 weeks after larvae were found, indicating ample time for dengue transmission. Based on a significant relationship among the three factors (epidemiological, entomological and environmental), estimated Autoregressive Distributed Lag (ADL) model for both locations produced high accuracy 84.9% for Selayang and 84.1% for Bandar Baru Bangi in predicting the actual notified cases. Hence, such model can be used in forestalling dengue outbreak and acts as an early warning system. The existence of relationships among the entomological, epidemiological and environmental factors can be used to build an early warning system for the prediction of dengue outbreak so that preventive interventions can be taken early to avert the outbreaks. PMID- 29474402 TI - On the importance of local dynamics in statokinesigram: A multivariate approach for postural control evaluation in elderly. AB - The fact that almost one third of population >65 years-old has at least one fall per year, makes the risk-of-fall assessment through easy-to-use measurements an important issue in current clinical practice. A common way to evaluate posture is through the recording of the center-of-pressure (CoP) displacement (statokinesigram) with force platforms. Most of the previous studies, assuming homogeneous statokinesigrams in quiet standing, used global parameters in order to characterize the statokinesigrams. However the latter analysis provides little information about local characteristics of statokinesigrams. In this study, we propose a multidimensional scoring approach which locally characterizes statokinesigrams on small time-periods, or blocks, while highlighting those which are more indicative to the general individual's class (faller/non-faller). Moreover, this information can be used to provide a global score in order to evaluate the postural control and classify fallers/non-fallers. We evaluate our approach using the statokinesigram of 126 community-dwelling elderly (78.5 +/- 7.7 years). Participants were recorded with eyes open and eyes closed (25 seconds each acquisition) and information about previous falls was collected. The performance of our findings are assessed using the receiver operating characteristics (ROC) analysis and the area under the curve (AUC). The results show that global scores provided by splitting statokinesigrams in smaller blocks and analyzing them locally, classify fallers/non-fallers more effectively (AUC = 0.77 +/- 0.09 instead of AUC = 0.63 +/- 0.12 for global analysis when splitting is not used). These promising results indicate that such methodology might provide supplementary information about the risk of fall of an individual and be of major usefulness in assessment of balance-related diseases such as Parkinson's disease. PMID- 29474403 TI - Cross-sectional associations between psychological traits, and HPV vaccine uptake and intentions in young adults from the United States. AB - Human papillomavirus (HPV) is the most prevalent sexually transmitted infection worldwide and can lead to the development of genital warts, and cancers throughout the body. Despite the availability of HPV vaccines for over a decade, uptake in the United States among adolescents and young adults remains well below national targets. While most efforts to improve HPV vaccine uptake have rightly focused on adolescents, there is still a tremendous opportunity to improve vaccination among young adults who have not been vaccinated against HPV. To that end, we report an exploratory examination of associations between HPV vaccination status and intentions with psychological traits that may impact HPV vaccine uptake with a national, demographically diverse sample of young adults (N = 1358) who completed an online survey. These psychological traits conceptually mapped onto motivations to: 1) understand health-related information, 2) deliberate, 3) manage uncertainty, and 4) manage threats. We found notable gender differences for the association of these motivations and vaccination status. For women, higher interest in and ability to understand health-related information seemed to distinguish those who reported receiving the HPV vaccine from those who did not. For men, less need to deliberate and greater needs to manage threat and uncertainty seemed to be the distinguishing motives for those who reported receiving the HPV vaccine compared to those who did not. Results for vaccination intentions were less consistent, but there was some evidence to indicate that, regardless of gender, greater health-related information interest and understanding and need to manage uncertainty and threats were associated with increased intention to receive the HPV vaccine, while greater need to deliberate was associated with decreased vaccination intentions. These results suggest that there are psychological differences that are associated with HPV vaccination decisions and that these motivations should be considered in efforts to improve HPV vaccine uptake. PMID- 29474404 TI - Role of acid-sensing ion channels in hypoxia- and hypercapnia-induced ventilatory responses. AB - Previous reports indicate roles for acid-sensing ion channels (ASICs) in both peripheral and central chemoreception, but the contributions of ASICs to ventilatory drive in conscious, unrestrained animals remain largely unknown. We tested the hypotheses that ASICs contribute to hypoxic- and hypercapnic ventilatory responses. Blood samples taken from conscious, unrestrained mice chronically instrumented with femoral artery catheters were used to assess arterial O2, CO2, and pH levels during exposure to inspired gas mixtures designed to cause isocapnic hypoxemia or hypercapnia. Whole-body plethysmography was used to monitor ventilatory parameters in conscious, unrestrained ASIC1, ASIC2, or ASIC3 knockout (-/-) and wild-type (WT) mice at baseline, during isocapnic hypoxemia and during hypercapnia. Hypercapnia increased respiratory frequency, tidal volume, and minute ventilation in all groups of mice, but there were no differences between ASIC1-/-, ASIC2-/-, or ASIC3-/- and WT. Isocapnic hypoxemia also increased respiratory frequency, tidal volume, and minute ventilation in all groups of mice. Minute ventilation in ASIC2-/- mice during isocapnic hypoxemia was significantly lower compared to WT, but there were no differences in the responses to isocapnic hypoxemia between ASIC1-/- or ASIC3-/- compared to WT. Surprisingly, these findings show that loss of individual ASIC subunits does not substantially alter hypercapnic or hypoxic ventilatory responses. PMID- 29474405 TI - Phenyl sulfate, indoxyl sulfate and p-cresyl sulfate decrease glutathione level to render cells vulnerable to oxidative stress in renal tubular cells. AB - In chronic kidney disease patients, oxidative stress is generally associated with disease progression and pathogenesis of its comorbidities. Phenyl sulfate is a protein-bound uremic solute, which accumulates in chronic kidney disease patients, but little is known about its nature. Although many reports revealed that protein-bound uremic solutes induce reactive oxygen species production, the effects of these solutes on anti-oxidant level have not been well studied. Therefore, we examined the effects of protein-bound uremic solutes on glutathione levels. As a result, indoxyl sulfate, phenyl sulfate, and p-cresyl sulfate decreased glutathione levels in porcine renal tubular cells. Next we examined whether phenyl sulfate-treated cells becomes vulnerable to oxidative stress. In phenyl sulfate-treated cells, hydrogen peroxide induced higher rates of cell death than in control cells. Buthionine sulfoximine, which is known to decrease glutathione level, well mimicked the effect of phenyl sulfate. Finally, we evaluated a mixture of indoxyl sulfate, phenyl sulfate, and p-cresyl sulfate at concentrations comparable to the serum concentrations of hemodialysis patients, and we confirmed its decreasing effect on glutathione level. In conclusion, indoxyl sulfate, phenyl sulfate, and p-cresyl sulfate decrease glutathione levels, rendering the cells vulnerable to oxidative stress. PMID- 29474406 TI - The role of the folate pathway in pancreatic cancer risk. AB - BACKGROUND: Pancreatic cancer is the third leading cause of cancer related deaths in the United States. Several dietary factors have been identified that modify pancreatic cancer risk, including low folate levels. In addition to nutrition and lifestyle determinants, folate status may be influenced by genetic factors such as single nucleotide polymorphisms (SNPs). In the present study, we investigated the association between folate levels, genetic polymorphisms in genes of the folate pathway, and pancreatic cancer. METHODS: Serum and red blood cell (RBC) folate levels were measured in pancreatic cancer and control subjects. Genotypes were determined utilizing Taqman probes and SNP frequencies between cases and controls were assessed using Fisher's exact test. Logistic regression was used to estimate the odds ratio (OR) and corresponding 95% confidence intervals (CIs) to measure the association between genotypes and pancreatic cancer risk. The association between folate levels and SNP expression was calculated using one-way ANOVA. RESULTS: Mean RBC folate levels were significantly lower in pancreatic cancer cases compared to unrelated controls (508.4 +/- 215.9 ng/mL vs 588.3 +/- 229.2 ng/mL, respectively) whereas serum folate levels were similar. Irrespective of cancer status, several SNPs were found to be associated with altered serum folate concentrations, including the D919G SNP in methionine synthase (MTR), the L474F SNP in serine hydroxymethyl transferase 1 (SHMT1) and the V175M SNP in phosphatidyl ethanolamine methyltransferase (PEMT). Further, the V allele of the A222V SNP and the E allele of the E429A SNP in methylene tetrahydrofolate reductase (MTHFR) were associated with low RBC folate levels. Pancreatic cancer risk was found to be significantly lower for the LL allele of the L78R SNP in choline dehydrogenase (CHDH; OR = 0.29; 95% CI 0.12-0.76); however, it was not associated with altered serum or RBC folate levels. PMID- 29474409 TI - A generative model for scientific concept hierarchies. AB - In many scientific disciplines, each new 'product' of research (method, finding, artifact, etc.) is often built upon previous findings-leading to extension and branching of scientific concepts over time. We aim to understand the evolution of scientific concepts by placing them in phylogenetic hierarchies where scientific keyphrases from a large, longitudinal academic corpora are used as a proxy of scientific concepts. These hierarchies exhibit various important properties, including power-law degree distribution, power-law component size distribution, existence of a giant component and less probability of extending an older concept. We present a generative model based on preferential attachment to simulate the graphical and temporal properties of these hierarchies which helps us understand the underlying process behind scientific concept evolution and may be useful in simulating and predicting scientific evolution. PMID- 29474407 TI - Predicting excess cost for older inpatients with clinical complexity: A retrospective cohort study examining cognition, comorbidities and complications. AB - BACKGROUND: Hospital-acquired complications increase length of stay and contribute to poorer patient outcomes. Older adults are known to be at risk for four key hospital-acquired complications (pressure injuries, pneumonia, urinary tract infections and delirium). These complications have been identified as sensitive to nursing characteristics such as staffing levels and level of education. The cost of these complications compared to the cost of admission severity, dementia, other comorbidities or age has not been established. METHOD: To investigate costs associated with nurse-sensitive hospital-acquired complications in an older patient population 157,178 overnight public hospital episodes for all patients over age 50 from one Australian state, 2006/07 were examined. A retrospective cohort study design with linear regression analysis provided modelling of length-of-stay costs. Explanatory variables included patient age, sex, comorbidities, admission severity, dementia status, surgical status and four complications. Extra costs were based on above-average length-of stay for each patient's Diagnosis Related Group from hospital discharge data. RESULTS: For adults over 50 who have length of stay longer than average for their diagnostic condition, comorbid dementia predicts an extra cost of A$874, (US$1,247); any one of four key complications predicts A$812 (US$1,159); each increase in admission severity score predicts A$295 ($US421); each additional comorbidity predicts A$259 (US$370), and for each year of age above 50 predicts A$20 (US$29) (all estimates significant at p<0.0001). DISCUSSION: Hospital acquired complications and dementia cost more than other kinds of inpatient complexity, but admission severity is a better predictor of excess cost. Because complications are potentially preventable and dementia care in hospitals can be improved, risk-reduction strategies for common complications, particularly for patients with dementia could be cost effective. CONCLUSIONS: Complications and dementia were found to cost more than other kinds of inpatient complexity. PMID- 29474408 TI - Molecular adaptations to phosphorus deprivation and comparison with nitrogen deprivation responses in the diatom Phaeodactylum tricornutum. AB - Phosphorus, an essential element for all living organisms, is a limiting nutrient in many regions of the ocean due to its fast recycling. Changes in phosphate (Pi) availability in aquatic systems affect diatom growth and productivity. We investigated the early adaptive mechanisms in the marine diatom Phaeodactylum tricornutum to P deprivation using a combination of transcriptomics, metabolomics, physiological and biochemical experiments. Our analysis revealed strong induction of gene expression for proteins involved in phosphate acquisition and scavenging, and down-regulation of processes such as photosynthesis, nitrogen assimilation and nucleic acid and ribosome biosynthesis. P deprivation resulted in alterations of carbon allocation through the induction of the pentose phosphate pathway and cytosolic gluconeogenesis, along with repression of the Calvin cycle. Reorganization of cellular lipids was indicated by coordinated induced expression of phospholipases, sulfolipid biosynthesis enzymes and a putative betaine lipid biosynthesis enzyme. A comparative analysis of nitrogen- and phosphorus-deprived P. tricornutum revealed both common and distinct regulation patterns in response to phosphate and nitrate stress. Regulation of central carbon metabolism and amino acid metabolism was similar, whereas unique responses were found in nitrogen assimilation and phosphorus scavenging in nitrogen-deprived and phosphorus-deprived cells, respectively. PMID- 29474410 TI - Factor structure and measurement invariance across various demographic groups and over time for the PHQ-9 in primary care patients in Spain. AB - The Patient Health Questionnaire (PHQ-9) is a widely-used screening tool for depression in primary care settings. The purpose of the present study is to identify the factor structure of the PHQ-9 and to examine the measurement invariance of this instrument across different sociodemographic groups and over time in a sample of primary care patients in Spain. Data came from 836 primary care patients enrolled in a randomized controlled trial (PsicAP study) and a subsample of 218 patients who participated in a follow-up assessment at 3 months. Confirmatory factor analysis (CFA) was used to test one- and two-factor structures identified in previous studies. Analyses of multiple-group invariance were conducted to determine the extent to which the factor structure is comparable across various demographic groups (i.e., gender, age, marital status, level of education, and employment situation) and over time. Both one-factor and two-factor re-specified models met all the pre-established fit criteria. However, because the factors identified in the two-factor model were highly correlated (r = .86), the one-factor model was preferred for its parsimony. Multi-group CFA indicated measurement invariance across different demographic groups and across time. The present findings suggest that physicians in Spain can use the PHQ-9 to obtain a global score for depression severity in different demographic groups and to reliably monitor changes over time in the primary care setting. PMID- 29474411 TI - Predicting financial trouble using call data-On social capital, phone logs, and financial trouble. AB - An ability to understand and predict financial wellbeing for individuals is of interest to economists, policy designers, financial institutions, and the individuals themselves. According to the Nilson reports, there were more than 3 billion credit cards in use in 2013, accounting for purchases exceeding US$ 2.2 trillion, and according to the Federal Reserve report, 39% of American households were carrying credit card debt from month to month. Prior literature has connected individual financial wellbeing with social capital. However, as yet, there is limited empirical evidence connecting social interaction behavior with financial outcomes. This work reports results from one of the largest known studies connecting financial outcomes and phone-based social behavior (180,000 individuals; 2 years' time frame; 82.2 million monthly bills, and 350 million call logs). Our methodology tackles highly imbalanced dataset, which is a pertinent problem with modelling credit risk behavior, and offers a novel hybrid method that yields improvements over, both, a traditional transaction data only approach, and an approach that uses only call data. The results pave way for better financial modelling of billions of unbanked and underbanked customers using non-traditional metrics like phone-based credit scoring. PMID- 29474412 TI - Application of a combined approach including contamination indexes, geographic information system and multivariate statistical models in levels, distribution and sources study of metals in soils in Northern China. AB - The purpose of this study is to recognize the contamination characteristics of trace metals in soils and apportion their potential sources in Northern China to provide a scientific basis for basic of soil environment management and pollution control. The data set of metals for 12 elements in surface soil samples was collected. The enrichment factor and geoaccumulation index were used to identify the general geochemical characteristics of trace metals in soils. The UNMIX and positive matrix factorizations (PMF) models were comparatively applied to apportion their potential sources. Furthermore, geostatistical tools were used to study the spatial distribution of pollution characteristics and to identify the affected regions of sources that were derived from apportionment models. The soils were contaminated by Cd, Hg, Pb and Zn to varying degree. Industrial activities, agricultural activities and natural sources were identified as the potential sources determining the contents of trace metals in soils with contributions of 24.8%-24.9%, 33.3%-37.2% and 38.0%-41.8%, respectively. The slightly different results obtained from UNMIX and PMF might be caused by the estimations of uncertainty and different algorithms within the models. PMID- 29474413 TI - Effects of earthquake on perinatal outcomes: A Chilean register-based study. AB - BACKGROUND: Natural disasters increase the level population stress, including pregnant women, who can experience prenatal maternal stress, affecting the fetus and triggering perinatal complications, such as low birth weight, smaller head circumference, etc. However, little is known about effects of earthquake on perinatal outcomes. OBJECTIVE: To evaluate the effect of earthquake occurred on February 27, 2010 and perinatal outcomes of Chilean pregnant women, and to examine these effects by timing of exposure during pregnancy and newborn gender. METHODS: A register-based study was performed using data collected from women who had a vaginal delivery in a large private health center in Santiago, Chile, during 2009 and 2010. The study population was categorized according to exposure to earthquake and timing during gestation. Primary perinatal outcomes were gestational age at birth, birth weight, length and head circumference. Analyses adjusted for gender, gestational age at exposure, parity, maternal age and income. RESULTS: A total of 1,966 eligible vaginal deliveries occurred during 2009 and 2,110 in 2010. Birth weight was not affected by the trimester of exposure; however, length, head circumference and gestational age at birth were significantly different according to trimester of exposure and gender of newborn. In multivariable analysis, newborns were shorter by 2 mm, 5 mm and 4.5 mm, if they were exposed during their first, second and third trimester, respectively. Furthermore, newborns had a smaller head circumference by 1.2 mm and 1.5 mm if they were exposed during first and second trimester of gestation. CONCLUSION: In this cohort, exposure to the February 2010 earthquake resulted in earlier delivery and reduced length and head circumference in the offspring. This association varied according to trimester of exposure and fetal gender. Health workers should include exposed to high levels of stress associated with natural disasters when assessing pregnancy risk factors. PMID- 29474414 TI - Reproductive ecology and stand structure of Joshua tree forests across climate gradients of the Mojave Desert. AB - Climate change is restructuring plant populations and can result in range shifts depending on responses at various life stages of plants. In 2013, a widespread and episodic flowering event provided an opportunity to characterize how Joshua tree's reproductive success and population structure vary in response to the climate variability across its range. We examined the reproductive success and stand structure of 10 Joshua tree populations distributed across the Mojave Desert. Joshua tree density varied by more than an order of magnitude across sites. At 8 of the 10 sites, nearly 80% of the Joshua trees were in bloom, and at the other two 40% were in bloom. The range of seed production and fruit set across the study populations varied by more than an order of magnitude. Fruit production occurred at all of our study sites suggesting that yucca moth pollinators were present at our sites. Increasing temperature had strong positive correlations with the number of trees in bloom (R2 = 0.42), inflorescences per tree (R2 = 0.37), and fruit mass (R2 = 0.77) and seed size (R2 = 0.89. In contrast, temperature was negatively correlated with Joshua tree stand density (R2 = -0.80). Positive correlations between temperature and greater flower and seed production suggest that warming may positively affect Joshua Tree reproduction while negative relationships between temperature and stand density are suggestive of potential constraints of warmer temperatures on establishment success. PMID- 29474415 TI - Flow patterns through vascular graft models with and without cuffs. AB - The shape of a bypass graft plays an important role on its efficacy. Here, we investigated flow through two vascular graft designs-with and without cuff at the anastomosis. We conducted Digital Particle Image Velocimetry (DPIV) measurements to obtain the flow field information through these vascular grafts. Two pulsatile flow waveforms corresponding to cardiac cycles during the rest and the excitation states, with 10% and without retrograde flow out the proximal end of the native artery were examined. In the absence of retrograde flow, the straight end-to-side graft showed recirculation and stagnation regions that lasted throughout the full cardiac cycle with the stagnation region more pronounced in the excitation state. The contoured end-to-side graft had stagnation region that lasted only for a portion of the cardiac cycle and was less pronounced. With 10% retrograde flow, extended stagnation regions under both rest and excitation states for both bypass grafts were eliminated. Our results show that bypass graft designers need to consider both the type of flow waveform and presence of retrograde flow when sculpting an optimal bypass graft geometry. PMID- 29474417 TI - Evaluation of the impact of reducing national emissions of SO2 and metals in Poland on background pollution using a bioindication method. AB - Changes in environmental pollution by S, Cd, Cu, Pb and Zn in 2006-2014 were evaluated using a bioindication method. This method was based on measurements of pollutants in Scots pine (Pinus sylvestris L.) needles. The measurements were performed in the Chojnowskie Forests, a region recognized as a background area for central Poland. The changes in the contents of sulfur (S) and metals in needles were not comparable with the changes in the global emissions of the pollutants in Poland. On average, the pollution level in the study area decreased by 9.9% for S, 61.4% for Pb, 22.5% for Cd, 11.7% for Zn and 10.4% for Cu. During the same period, global emissions in Poland decreased by 38.1% for S, 8.0% for Pb, 63.2% for Cd, 11.7% for Zn and 14.0% for Cu. Therefore, the differences in the changes in emissions and the needle contents of each element should be examined separately which was not a goal of this study. However, the discrepancy between these results did not prevent the use of bioindication methods. Evaluation of pollutant contents in plants reflected their incorporation in biological processes rather than air or soil pollution levels. PMID- 29474416 TI - Primate social attention: Species differences and effects of individual experience in humans, great apes, and macaques. AB - When viewing social scenes, humans and nonhuman primates focus on particular features, such as the models' eyes, mouth, and action targets. Previous studies reported that such viewing patterns vary significantly across individuals in humans, and also across closely-related primate species. However, the nature of these individual and species differences remains unclear, particularly among nonhuman primates. In large samples of human and nonhuman primates, we examined species differences and the effects of experience on patterns of gaze toward social movies. Experiment 1 examined the species differences across rhesus macaques, nonhuman apes (bonobos, chimpanzees, and orangutans), and humans while they viewed movies of various animals' species-typical behaviors. We found that each species had distinct viewing patterns of the models' faces, eyes, mouths, and action targets. Experiment 2 tested the effect of individuals' experience on chimpanzee and human viewing patterns. We presented movies depicting natural behaviors of chimpanzees to three groups of chimpanzees (individuals from a zoo, a sanctuary, and a research institute) differing in their early social and physical experiences. We also presented the same movies to human adults and children differing in their expertise with chimpanzees (experts vs. novices) or movie-viewing generally (adults vs. preschoolers). Individuals varied within each species in their patterns of gaze toward models' faces, eyes, mouths, and action targets depending on their unique individual experiences. We thus found that the viewing patterns for social stimuli are both individual- and species-specific in these closely-related primates. Such individual/species-specificities are likely related to both individual experience and species-typical temperament, suggesting that primate individuals acquire their unique attentional biases through both ontogeny and evolution. Such unique attentional biases may help them learn efficiently about their particular social environments. PMID- 29474418 TI - Pattern of risks of rheumatoid arthritis among patients using statins: A cohort study with the clinical practice research datalink. AB - We examined the association between statin use and the risk of rheumatoid arthritis (RA), with special focus on describing the patterns of risks of RA during statin exposure in a large population-based cohort in the United Kingdom. In the Clinical Practice Research Datalink, patients aged >=40 years with at least one prescription of statins (1995-2009) were selected, and matched by age (+/-5 years), sex, practice and date of first prescription of statins to non users. The follow-up period of statin use was divided into periods of current, recent and past exposure, with patients moving between these three exposure categories over time. Time-dependent Cox models were used to derive hazard ratios (HRs) of RA, adjusted for disease history and previous drug use. The study population included 1,023,240 patients, of whom 511,620 were statin users. No associations were found between RA and current (HRadj,1.06;99%CI:0.88-1.27) or past statin users (HRadj,1.18;99%CI:0.88-1.57). However, in patients who currently used statins, hazard rates were increased shortly after the first prescription of statins and then gradually decreased to baseline level. The risk of developing RA was increased in recent statin users, as compared to non-users (HRadj,1.39;99%CI:1.01-1.90). The risk of RA is substantially increased in the first year after the start of statins and then diminishes to baseline level. These findings may suggest that statins might accelerate disease onset in patients susceptible to develop RA, but in other patients, statins are probably safe and well tolerated, even after prolonged use. Alternatively, we cannot rule out that confounding by cardiovascular risk factors and ascertainment bias may have influenced the findings. PMID- 29474419 TI - Transcriptome analysis in different developmental stages of Batocera horsfieldi (Coleoptera: Cerambycidae) and comparison of candidate olfactory genes. AB - The white-striped longhorn beetle Batocera horsfieldi (Coleoptera: Cerambycidae) is a polyphagous wood-boring pest that causes substantial damage to the lumber industry. Moreover olfactory proteins are crucial components to function in related processes, but the B. horsfieldi genome is not readily available for olfactory proteins analysis. In the present study, developmental transcriptomes of larvae from the first instar to the prepupal stage, pupae, and adults (females and males) from emergence to mating were built by RNA sequencing to establish a genetic background that may help understand olfactory genes. Approximately 199 million clean reads were obtained and assembled into 171,664 transcripts, which were classified into 23,380, 26,511, 22,393, 30,270, and 87, 732 unigenes for larvae, pupae, females, males, and combined datasets, respectively. The unigenes were annotated against NCBI's non-redundant nucleotide and protein sequences, Swiss-Prot, Gene Ontology (GO), Pfam, Clusters of Eukaryotic Orthologous Groups (KOG), and KEGG Orthology (KO) databases. A total of 43,197 unigenes were annotated into 55 sub-categories under the three main GO categories; 25,237 unigenes were classified into 26 functional KOG categories, and 25,814 unigenes were classified into five functional KEGG Pathway categories. RSEM software identified 2,983, 3,097, 870, 2,437, 5,161, and 2,882 genes that were differentially expressed between larvae and males, larvae and pupae, larvae and females, males and females, males and pupae, and females and pupae, respectively. Among them, genes encoding seven candidate odorant binding proteins (OBPs) and three chemosensory proteins (CSPs) were identified. RT-PCR and RT-qPCR analyses showed that BhorOBP3, BhorCSP2, and BhorOBPC1/C3/C4 were highly expressed in the antenna of males, indicating these genes may may play key roles in foraging and host-orientation in B. horsfieldi. Our results provide valuable molecular information about the olfactory system in B. horsfieldi and will help guide future functional studies on olfactory genes. PMID- 29474420 TI - A new high-performance liquid chromatography-tandem mass spectrometry method for the determination of paclitaxel and 6alpha-hydroxy-paclitaxel in human plasma: Development, validation and application in a clinical pharmacokinetic study. AB - Paclitaxel belongs to the taxanes family and it is used, alone or in multidrug regimens, for the therapy of several solid tumours, such as breast-, lung-, head and neck-, and ovarian cancer. Standard dosing of chemotherapy does not take into account the many inter-patient differences that make drug exposure highly variable, thus leading to the insurgence of severe toxicity. This is particularly true for paclitaxel considering that a relationship between haematological toxicity and plasma exposure was found. Therefore, in order to treat patients with the correct dose of paclitaxel, improving the overall benefit-risk ratio, Therapeutic Drug Monitoring is necessary. In order to quantify paclitaxel and its main metabolite, 6alpha-hydroxy-paclitaxel, in patients' plasma, we developed a new, sensitive and specific HPLC-MS/MS method applicable to all paclitaxel dosages used in clinical routine. The developed method used a small volume of plasma sample and is based on quick protein precipitation. The chromatographic separation of the analytes was achieved with a SunFireTM C18 column (3.5 MUM, 92 A, 2,1 x 150 mm); the mobile phases were 0.1% formic acid/bidistilled water and 0.1% formic acid/acetonitrile. The electrospray ionization source worked in positive ion mode and the mass spectrometer operated in selected reaction monitoring mode. Our bioanalytical method was successfully validated according to the FDA-EMA guidelines on bioanalytical method validation. The calibration curves resulted linear (R2 >=0.9948) over the concentration ranges (1-10000 ng/mL for paclitaxel and 1-1000 ng/mL for 6alpha-hydroxy-paclitaxel) and were characterized by a good accuracy and precision. The intra- and inter-day precision and accuracy were determined on three quality control concentrations for paclitaxel and 6alpha hydroxy-paclitaxel and resulted respectively <9.9% and within 91.1-114.8%. In addition, to further verify the assay reproducibility, we tested this method by re-analysing the incurred samples. This bioanalytical method was employed with success to a genotype-guided phase Ib study of weekly paclitaxel in ovarian cancer patients treated with a wide range of drug's dosages. PMID- 29474421 TI - Development of reaching during mid-childhood from a Developmental Systems perspective. AB - Inspired by the Developmental Systems perspective, we studied the development of reaching during mid-childhood (5-10 years of age) not just at the performance level (i.e., endpoint movements), as commonly done in earlier studies, but also at the joint angle level. Because the endpoint position (i.e., the tip of the index finger) at the reaching target can be achieved with multiple joint angle combinations, we partitioned variability in joint angles over trials into variability that does not (goal-equivalent variability, GEV) and that does (non goal-equivalent variability, NGEV) influence the endpoint position, using the Uncontrolled Manifold method. Quantifying this structure in joint angle variability allowed us to examine whether and how spatial variability of the endpoint at the reaching target is related to variability in joint angles and how this changes over development. 6-, 8- and 10-year-old children and young adults performed reaching movements to a target with the index finger. Polynomial trend analysis revealed a linear and a quadratic decreasing trend for the variable error. Linear decreasing and cubic trends were found for joint angle standard deviations at movement end. GEV and NGEV decreased gradually with age, but interestingly, the decrease of GEV was steeper than the decrease of NGEV, showing that the different parts of the joint angle variability changed differently over age. We interpreted these changes in the structure of variability as indicating changes over age in exploration for synergies (a family of task solutions), a concept that links the performance level with the joint angle level. Our results suggest changes in the search for synergies during mid-childhood development. PMID- 29474422 TI - PuLSE: Quality control and quantification of peptide sequences explored by phage display libraries. AB - The design of highly diverse phage display libraries is based on assumption that DNA bases are incorporated at similar rates within the randomized sequence. As library complexity increases and expected copy numbers of unique sequences decrease, the exploration of library space becomes sparser and the presence of truly random sequences becomes critical. We present the program PuLSE (Phage Library Sequence Evaluation) as a tool for assessing randomness and therefore diversity of phage display libraries. PuLSE runs on a collection of sequence reads in the fastq file format and generates tables profiling the library in terms of unique DNA sequence counts and positions, translated peptide sequences, and normalized 'expected' occurrences from base to residue codon frequencies. The output allows at-a-glance quantitative quality control of a phage library in terms of sequence coverage both at the DNA base and translated protein residue level, which has been missing from toolsets and literature. The open source program PuLSE is available in two formats, a C++ source code package for compilation and integration into existing bioinformatics pipelines and precompiled binaries for ease of use. PMID- 29474423 TI - Seasonal variability in the persistence of dissolved environmental DNA (eDNA) in a marine system: The role of microbial nutrient limitation. AB - Environmental DNA (eDNA) can be defined as the DNA pool recovered from an environmental sample that includes both extracellular and intracellular DNA. There has been a significant increase in the number of recent studies that have demonstrated the possibility to detect macroorganisms using eDNA. Despite the enormous potential of eDNA to serve as a biomonitoring and conservation tool in aquatic systems, there remain some important limitations concerning its application. One significant factor is the variable persistence of eDNA over natural environmental gradients, which imposes a critical constraint on the temporal and spatial scales of species detection. In the present study, a radiotracer bioassay approach was used to quantify the kinetic parameters of dissolved eDNA (d-eDNA), a component of extracellular DNA, over an annual cycle in the coastal Northwest Mediterranean. Significant seasonal variability in the biological uptake and turnover of d-eDNA was observed, the latter ranging from several hours to over one month. Maximum uptake rates of d-eDNA occurred in summer during a period of intense phosphate limitation (turnover <5 hrs). Corresponding increases in bacterial production and uptake of adenosine triphosphate (ATP) demonstrated the microbial utilization of d-eDNA as an organic phosphorus substrate. Higher temperatures during summer may amplify this effect through a general enhancement of microbial metabolism. A partial least squares regression (PLSR) model was able to reproduce the seasonal cycle in d-eDNA persistence and explained 60% of the variance in the observations. Rapid phosphate turnover and low concentrations of bioavailable phosphate, both indicative of phosphate limitation, were the most important parameters in the model. Abiotic factors such as pH, salinity and oxygen exerted minimal influence. The present study demonstrates significant seasonal variability in the persistence of d-eDNA in a natural marine environment that can be linked to the metabolic response of microbial communities to nutrient limitation. Future studies should consider the effect of natural environmental gradients on the seasonal persistence of eDNA, which will be of particular relevance for time series biomonitoring programs. PMID- 29474424 TI - The longitudinal association between changes in lung function and changes in abdominal visceral obesity in Korean non-smokers. AB - Obesity, particularly abdominal obesity, might be related to decreased lung function. We aimed to investigate whether obesity indices are associated with forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) in asymptomatic non-smokers through a longitudinal cohort study. The clinical records of 1,145 subjects (428 males, mean age 52.3 years) who underwent a comprehensive health evaluation, including spirometry and abdominal fat computed tomography, at least twice between 2007 and 2014 were retrospectively reviewed and analysed. The mean follow-up period was 1,105 days (over 3.0 years). The baseline total adipose tissue (TAT) and visceral adipose tissue (VAT) were inversely associated with both FEV1 and FVC (P < 0.05). The longitudinal study found that increasing TAT and VAT were significantly related to decreasing FEV1 and FVC, whereas decreasing TAT and VAT were related to increasing FEV1 and FVC in both males and females (P < 0.05). The strength and consistency of these associations were clearer in males than in females. However, no significant relationship was found between changes in subcutaneous adipose tissue and changes in lung function. In Korean non-smokers, longitudinal changes in abdominal visceral fat were found to be inversely related to changes in lung function over a mean period of three years. These results suggest that decreasing abdominal visceral obesity could increase lung function despite ageing. PMID- 29474425 TI - The existence of parenting styles in the owner-dog relationship. AB - Parents interact with children following specific styles, known to influence child development. These styles represent variations in the dimensions of demandingness and responsiveness, resulting in authoritarian, authoritative, permissive or uninvolved parenting. Given the similarities in the parent to child and owner to dog relationships, we determined the extent to which parenting styles exist in the owner to dog relationship using the existing Parenting Styles and Dimensions Questionnaire for the parent-child relationship and an adapted version for dog owners. Items on the parenting of children/dogs were rated for applicability on a five-point Likert scale by 518 Dutch dog owning parents. Principal Component Analyses grouped parenting propensities into styles, with some marked differences between the findings for children and dogs. Dog-directed items grouped into an authoritarian-correction orientated style, incorporating variation in demandingness and focussing on correcting a dog for behaviour verbally/physically, and in two styles based on authoritative items. An authoritative-intrinsic value orientated style reflected variation in mainly responsiveness and oriented on the assumed needs and emotions of the animal. A second authoritative-item based style, captured variations in demandingness and responsiveness. We labelled this style authoritative-training orientated, as it orientated on manners in teaching a dog how to behave in social situations. Thus, we defined dog-directed parenting styles and constructed a Dog-Directed Parenting Styles and Dimensions Questionnaire along the lines of the existing theoretical framework on parenting styles. We did not find a dog-directed parenting style of being permissive or uninvolved, which we attribute to a study population of devoted dog owners and our findings should be interpreted with this specific study population in mind. We found evidence of dog-directed parenting styles and provide a fundament for determining their possible impact on the different aspects of a dog's life. PMID- 29474426 TI - Generation of efficient mutants of endoglycosidase from Streptococcus pyogenes and their application in a novel one-pot transglycosylation reaction for antibody modification. AB - The fine structures of Fc N-glycan modulate the biological functions and physicochemical properties of antibodies. By remodeling N-glycan to obtain a homogeneous glycoform or chemically modified glycan, antibody characteristics can be controlled or modified. Such remodeling can be achieved by transglycosylation reactions using a mutant of endoglycosidase from Streptococcus pyogenes (Endo-S) and glycan oxazoline. In this study, we generated improved mutants of Endo-S by introducing additional mutations to the D233Q mutant. Notably, Endo-S D233Q/Q303L, D233Q/E350Q, and several other mutations resulted in transglycosylation efficiencies exceeding 90%, with a single-digit donor-to substrate ratio of five, and D233Q/Y402F/D405A and several other mutations resulted in slightly reduced transglycosylation efficiencies accompanied by no detectable hydrolysis activity for 48 h. We further demonstrated that the combined use of mutants of Endo-S with Endo-M or Endo-CC, endoglycosidases from Mucor hiemalis and Coprinopsis cinerea, enables one-pot transglycosylation from sialoglycopeptide to antibodies. This novel reaction enables glycosylation remodeling of antibodies, without the chemical synthesis of oxazoline in advance or in situ. PMID- 29474427 TI - Cerebrospinal fluid sCD27 levels indicate active T cell-mediated inflammation in premanifest Huntington's disease. AB - INTRODUCTION: Huntington's disease (HD) is a neurodegenerative disorder, but evidence also suggests neuroinflammation in the pathogenesis. The immune mechanisms involved and the timing of their activation need further clarification. METHODS: A clinically well-characterized HD cohort and gene negative controls were enrolled. YKL-40 reflecting innate immunity and sCD27, a marker of adaptive immunity, were measured across disease stages. Comparisons were made with markers of neurodegeneration: neurofilament light (NFL), total-tau (T-tau), and phospho-tau (P-tau). RESULTS: 52 cross-sectional cerebrospinal fluid samples and 23 follow-up samples were analyzed. sCD27 was elevated in manifest HD and premanifest gene expansion carriers, whereas controls mostly had undetectable levels. YKL-40 showed a trend toward increase in manifest HD. sCD27 correlated with YKL-40 which in turn was closely associated to all included markers of neurodegeneration. YKL-40, NFL, and both forms of tau could all independently predict HD symptoms, but only NFL levels differed between groups after age adjustment. CONCLUSION: Increased sCD27 in premanifest HD is a sign of T cell mediated neuroinflammation. This finding is novel since other reports almost exclusively have found early involvement of innate immunity. Validation of sCD27 in a larger HD cohort is needed. The role of adaptive immunity in HD needs further clarification, as it may hasten disease progression. PMID- 29474428 TI - Fat max as an index of aerobic exercise performance in mice during uphill running. AB - Endurance exercise performance has been used as a representative index in experimental animal models in the field of health sciences, exercise physiology, comparative physiology, food function or nutritional physiology. The objective of the present study was to evaluate the effectiveness of Fatmax (the exercise intensity that elicits maximal fat oxidation) as an additional index of endurance exercise performance that can be measured during running at submaximal exercise intensity in mice. We measured both Fatmax and Vo2 peak of trained ICR mice that voluntary exercised for 8 weeks and compared them with a sedentary group of mice at multiple inclinations of 20, 30, 40, and 50 degrees on a treadmill. The Vo2 at Fatmax of the training group was significantly higher than that of the sedentary group at inclinations of 30 and 40 degrees (P < 0.001). The running speed at Fatmax of the training group was significantly higher than that of the sedentary group at inclinations of 20, 30, and 40 degrees (P < 0.05). Blood lactate levels sharply increased in the sedentary group (7.33 +/- 2.58 mM) compared to the training group (3.13 +/- 1.00 mM, P < 0.01) when running speeds exceeded the Fatmax of sedentary mice. Vo2 at Fatmax significantly correlated to Vo2 peak, running time to fatigue, and lactic acid level during running (P < 0.05) although the reproducibility of Vo2 peak was higher than that of Vo2 at Fatmax. In conclusion, Fatmax can be used as a functional assessment of the endurance exercise performance of mice during submaximal exercise intensity. PMID- 29474429 TI - Early Eocene deep-sea benthic foraminiferal faunas: Recovery from the Paleocene Eocene Thermal Maximum extinction in a greenhouse world. AB - The early Eocene greenhouse world was marked by multiple transient hyperthermal events. The most extreme was the Paleocene-Eocene Thermal Maximum (PETM, ~56 Ma), linked to the extinction of the globally recognised deep-sea benthic foraminiferal Velasco fauna, which led to the development of early Eocene assemblages. This turnover has been studied at high resolution, but faunal development into the later early Eocene is poorly documented. There is no widely accepted early Eocene equivalent of the Late Cretaceous-Paleocene Velasco fauna, mainly due to the use of different taxonomic concepts. We compiled Ypresian benthic foraminiferal data from 17 middle bathyal-lower abyssal ocean drilling sites in the Pacific, Atlantic and Indian Oceans, in order to characterise early Eocene deep-sea faunas by comparing assemblages across space, paleodepth and time. Nuttallides truempyi, Oridorsalis umbonatus, Bulimina trinitatensis, the Bulimina simplex group, the Anomalinoides spissiformis group, pleurostomellids, uniserial lagenids, stilostomellids and lenticulinids were ubiquitous during the early Eocene (lower-middle Ypresian). Aragonia aragonensis, the Globocassidulina subglobosa group, the Cibicidoides eocaenus group and polymorphinids became ubiquitous during the middle Ypresian. The most abundant early Ypresian taxa were tolerant to stressed or disturbed environments, either by opportunistic behavior (Quadrimorphina profunda, Tappanina selmensis, Siphogenerinoides brevispinosa) and/or the ability to calcify in carbonate-corrosive waters (N. truempyi). Nuttallides truempyi, T. selmensis and other buliminids (Bolivinoides cf. decoratus group, Bulimina virginiana) were markedly abundant during the middle Ypresian. Contrary to the long-lived, highly diverse and equitable Velasco fauna, common and abundant taxa reflect highly perturbed assemblages through the earliest Ypresian, with lower diversity and equitability following the PETM extinction. In contrast, the middle Ypresian assemblages may indicate a recovering fauna, though to some extent persistently disturbed by the lower amplitude Eocene hyperthermals (e.g., Eocene Thermal Maximum 2 and 3). We propose the name 'Walvis Ridge fauna' for future reference to these Ypresian deep-sea benthic foraminiferal assemblages. PMID- 29474430 TI - Evidence for chemical interference effect of an allelopathic plant on neighboring plant species: A field study. AB - Many studies have reported the phytotoxicity of allelopathic compounds under controlled conditions. However, more field studies are required to provide realistic evidences for the significance of allelopathic interference in natural communities. We conducted a 2-years field experiment in a semiarid plant community (NE Spain). Specifically, we planted juvenile individuals and sowed seeds of Salsola vermiculata L., Lygeum spartum L. and Artemisia herba-alba Asso. (three co-dominant species in the community) beneath adult individuals of the allelopathic shrub A. herba-alba, and assessed the growth, vitality, seed germination and seedling survival of those target species with and without the presence of chemical interference by the incorporation of activated carbon (AC) to the soil. In addition, juveniles and seeds of the same three target species were planted and sown beneath the canopy of adults of S. vermiculata (a shrub similar to A. herba-alba, but non-allelopathic) and in open bare soil to evaluate whether the allelopathic activity of A. herba-alba modulates the net outcome of its interactions with neighboring plants under contrasting abiotic stress conditions. We found that vitality of A. herba-alba juveniles was enhanced beneath A. herba-alba individuals when AC was present. Furthermore, we found that the interaction outcome in A. herba-alba microsite was neutral, whereas a positive outcome was found for S. vermiculata microsite, suggesting that allelopathy may limit the potential facilitative effects of the enhanced microclimatic conditions in A. herba-alba microsite. Yet, L. spartum juveniles were facilitated in A. herba-alba microsite. The interaction outcome in A. herba alba microsite was positive under conditions of very high abiotic stress, indicating that facilitative interactions predominated over the interference of allelopathic plants under those conditions. These results highlight that laboratory studies can overestimate the significance of allelopathy in nature, and consequently, results obtained under controlled conditions should be interpreted carefully. PMID- 29474431 TI - Gait symmetry and hip strength in women with developmental dysplasia following hip arthroplasty compared to healthy subjects: A cross-sectional study. AB - INTRODUCTION: Untreated unilateral developmental dysplasia of the hip (DDH) results in asymmetry of gait and hip strength and may lead to early osteoarthritis, which is commonly treated with a total hip arthroplasty (THA). There is limited knowledge about the obtained symmetry of gait and hip strength after the THA. The objectives of this cross-sectional study were to: a) identify asymmetries between the operated and non-operated side in kinematics, kinetics and hip strength, b) analyze if increased walking speed changed the level of asymmetry in patients c) compare these results with those of healthy subjects. METHODS: Women (18-70 year) with unilateral DDH who had undergone unilateral THA were eligible for inclusion. Vicon gait analysis system was used to collect frontal and sagittal plane kinematic and kinetic parameters of the hip joint, pelvis and trunk during walking at comfortable walking speed and increased walking speed. Furthermore, hip abductor and extensor muscle strength was measured. RESULTS: Six patients and eight healthy subjects were included. In the patients, modest asymmetries in lower limb kinematics and kinetics were present during gait, but trunk lateral flexion asymmetry was evident. Patients' trunk lateral flexion also differed compared to healthy subjects. Walking speed did not significantly influence the level of asymmetry. The hip abduction strength asymmetry of 23% was not statistically significant, but the muscle strength of both sides were significantly weaker than those of healthy subjects. CONCLUSIONS: In patients with a DDH treated with an IBG THA modest asymmetries in gait kinematics and kinetics were present, with the exception of a substantial asymmetry of the trunk lateral flexion. Increased walking speed did not result in increased asymmetries in gait kinematics and kinetics. Hip muscle strength was symmetrical in patients, but significantly weaker than in healthy subjects. Trunk kinematics should be included as an outcome measure to assess the biomechanical benefits of the THA surgery after DDH. PMID- 29474432 TI - Interfacial water molecules at biological membranes: Structural features and role for lateral proton diffusion. AB - Proton transport at water/membrane interfaces plays a fundamental role for a myriad of bioenergetic processes. Here we have performed ab initio molecular dynamics simulations of proton transfer along two phosphatidylcholine bilayers. As found in previous theoretical studies, the excess proton is preferably located at the water/membrane interface. Further, our simulations indicate that it interacts not only with phosphate head groups, but also with water molecules at the interfaces. Interfacial water molecules turn out to be oriented relative to the lipid bilayers, consistently with experimental evidence. Hence, the specific water-proton interaction may help explain the proton mobility experimentally observed at the membrane interface. PMID- 29474433 TI - Force sharing and other collaborative strategies in a dyadic force perception task. AB - When several persons perform a physical task jointly, such as transporting an object together, the interaction force that each person experiences is the sum of the forces applied by all other persons on the same object. Therefore, there is a fundamental ambiguity about the origin of the force that each person experiences. This study investigated the ability of a dyad (two persons) to identify the direction of a small force produced by a haptic device and applied to a jointly held object. In this particular task, the dyad might split the force produced by the haptic device (the external force) in an infinite number of ways, depending on how the two partners interacted physically. A major objective of this study was to understand how the two partners coordinated their action to perceive the direction of the third force that was applied to the jointly held object. This study included a condition where each participant responded independently and another one where the two participants had to agree upon a single negotiated response. The results showed a broad range of behaviors. In general, the external force was not split in a way that would maximize the joint performance. In fact, the external force was often split very unequally, leaving one person without information about the external force. However, the performance was better than expected in this case, which led to the discovery of an unanticipated strategy whereby the person who took all the force transmitted this information to the partner by moving the jointly held object. When the dyad could negotiate the response, we found that the participant with less force information tended to switch his or her response more often. PMID- 29474434 TI - MicroRNA-19a and microRNA-19b promote the malignancy of clear cell renal cell carcinoma through targeting the tumor suppressor RhoB. AB - Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma, which shows high aggressiveness and lacks biomarkers. RhoB acts as a tumor suppressor that inhibits the progression of ccRCC. In the present study, we examined the effects of oncogenic microRNAs, miR-19a and miR-19b, on RhoB expression in ccRCC cells. The results showed that both miR-19a and miR-19b could directly target the 3'untranslated region (3'UTR) of RhoB, resulting in the reduced expression of RhoB. With RT-PCR analysis, we detected the increased expression of miR-19a and miR-19b in ccRCC tissues compared to adjacent non-tumor renal tissues. These data also demonstrated an exclusive negative correlation between miR-19a/19b and RhoB expression in ccRCC specimens and cell lines. In addition, the knockdown of RhoB or overexpression of miR-19a and miR-19b in ccRCC cells could promote cell proliferation, migration and invasion. These data demonstrate the direct roles of miR-19a and miR-19b on the repression of RhoB and its consequences on tumorigenesis, cancer cell proliferation and invasiveness. These results suggest the potential clinical impact of miR-19a and miR-19b as molecular targets for ccRCC. PMID- 29474435 TI - SUMO polymeric chains are involved in nuclear foci formation and chromatin organization in Trypanosoma brucei procyclic forms. AB - SUMOylation is a post-translational modification conserved in eukaryotic organisms that involves the covalent attachment of the small ubiquitin-like protein SUMO to internal lysine residues in target proteins. This tag usually alters the interaction surface of the modified protein and can be translated into changes in its biological activity, stability or subcellular localization, among other possible outputs. SUMO can be attached as a single moiety or as SUMO polymers in case there are internal acceptor sites in SUMO itself. These chains have been shown to be important for proteasomal degradation as well as for the formation of subnuclear structures such as the synaptonemal complex in Saccharomyces cerevisiae or promyelocytic leukemia nuclear bodies in mammals. In this work, we have examined SUMO chain formation in the protozoan parasite Trypanosoma brucei. Using a recently developed bacterial strain engineered to produce SUMOylated proteins we confirmed the ability of TbSUMO to form polymers and determined the type of linkage using site-directed mutational analysis. By generating transgenic procyclic parasites unable to form chains we demonstrated that although not essential for normal growth, SUMO polymerization determines the localization of the modified proteins in the nucleus. In addition, FISH analysis of telomeres showed a differential positioning depending on the polySUMOylation abilities of the cells. Thus, our observations suggest that TbSUMO chains might play a role in establishing interaction platforms contributing to chromatin organization. PMID- 29474436 TI - Rapid assessment of viable but non-culturable Bacillus coagulans MTCC 5856 in commercial formulations using Flow cytometry. AB - Accurate enumeration of bacterial count in probiotic formulation is imperative to ensure that the product adheres to regulatory standards and citation in consumer product label. Standard methods like plate count, can enumerate only replicating bacterial population under selected culture conditions. Viable but non culturable bacteria (VBNC) retain characteristics of living cells and can regain cultivability by a process known as resuscitation. This is a protective mechanism adapted by bacteria to evade stressful environmental conditions. B. coagulans MTCC 5856(LactoSpore(r)) is a probiotic endospore which can survive for decades in hostile environments without dividing. In the present study, we explored the use of flow cytometry to enumerate the viable count of B. coagulans MTCC 5856 under acidic and alkaline conditions, high temperature and in commercial formulations like compressed tablets and capsules. Flow cytometry (FCM) was comparable to plate count method when the spores were counted at physiological conditions. We show that VBNC state is induced in B. coagulans MTCC 5856by high temperature and acidic pH. The cells get resuscitated under physiological conditions and FCM was sensitive to detect the VBNC spores. Flow cytometry showed excellent ability to assess the viable spore count in commercial probiotic formulations of B. coagulans MTCC 5856. The results establish Flow cytometry as a reliable method to count viable bacteria in commercial probiotic preparations. Sporulation as well as existence as VBNC could contribute to the extreme stability of B. coagulans MTCC 5856. PMID- 29474437 TI - Validation of a SNP-based non-invasive prenatal test to detect the fetal 22q11.2 deletion in maternal plasma samples. AB - INTRODUCTION: Non-invasive prenatal testing (NIPT) for aneuploidy using cell-free DNA in maternal plasma has been widely adopted. Recently, NIPT coverage has expanded to detect subchromosomal abnormalities including the 22q11.2 deletion. Validation of a SNP-based NIPT for detection of 22q11.2 deletions demonstrating a high sensitivity (97.8%) and specificity (99.75%) has been reported. We sought to further demonstrate the performance of a revised version of the test in a larger set of pregnancy plasma samples. METHODS: Blood samples from pregnant women (10 with 22q11.2-deletion-affected fetuses and 390 negative controls) were successfully analyzed using a revised SNP-based NIPT for the 22q11.2 deletion. The sensitivity and specificity of the assay were measured. RESULTS: Sensitivity of the assay was 90% (9/10), and specificity of the assay was 99.74% (389/390), with a corresponding false positive-rate of 0.26%. DISCUSSION: The data presented in this study add to the growing body of evidence demonstrating the ability of the SNP-based NIPT to detect 22q11.2 deletions with high sensitivity and specificity. PMID- 29474438 TI - Researchers' participation in and motivations for engaging with research information management systems. AB - RESEARCHERS' PARTICIPATION IN ONLINE RIMSS: This article examined how researchers participated in research information management systems (RIMSs), their motivations for participation, and their priorities for those motivations. Profile maintenance, question-answering, and endorsement activities were used to define three cumulatively increasing levels of participation: Readers, Record Managers, and Community Members. Junior researchers were more engaged in RIMSs than were senior researchers. Postdocs had significantly higher odds of endorsing other researchers for skills and being categorized as Community Members than did full and associate professors. Assistant professors were significantly more likely to be Record Managers than were members of any other seniority categories. Finally, researchers from the life sciences showed a significantly higher propensity for being Community Members than Readers and Record Managers when compared with researchers from engineering and the physical sciences, respectively. RESEARCHERS' MOTIVATIONS TO PARTICIPATE IN RIMSS: When performing activities, researchers were motivated by the desire to share scholarship, feel competent, experience a sense of enjoyment, improve their status, and build ties with other members of the community. Moreover, when researchers performed activities that directly benefited other members of a RIMS, they assigned higher priorities to intrinsic motivations, such as perceived self-efficacy, enjoyment, and building community ties. Researchers at different stages of their academic careers and disciplines ranked some of the motivations for engaging with RIMSs differently. The general model of research participation in RIMSs; the relationships among RIMS activities; the motivation scales for activities; and the activity, seniority, and discipline-specific priorities for the motivations developed by this study provide the foundation for a framework for researcher participation in RIMSs. This framework can be used by RIMSs and institutional repositories to develop tools and design mechanisms to increase researchers' engagement in RIMSs. PMID- 29474439 TI - The zoonotic potential of Clostridium difficile from small companion animals and their owners. AB - BACKGROUND: Clostridium difficile infections (CDI) in humans range from asymptomatic carriage to life-threatening intestinal disease. Findings on C. difficile in various animal species and an overlap in ribotypes (RTs) suggest potential zoonotic transmission. However, the impact of animals for human CDI remains unclear. METHODS: In a large-scale survey we collected 1,447 fecal samples to determine the occurrence of C. difficile in small companion animals (dogs and cats) and their owners and to assess potential epidemiological links within the community. The Germany-wide survey was conducted from July 2012-August 2013. PCR ribotyping, Multilocus VNTR Analysis (MLVA) and PCR detection of toxin genes were used to characterize isolated C. difficile strains. A database was defined and logistic regression used to identify putative factors associated with fecal shedding of C. difficile. RESULTS: In total, 1,418 samples met the inclusion criteria. The isolation rates for small companion animals and their owners within the community were similarly low with 3.0% (25/840) and 2.9% (17/578), respectively. PCR ribotyping revealed eight and twelve different RTs in animals and humans, respectively, whereas three RTs were isolated in both, humans and animals. RT 014/0, a well-known human hospital-associated lineage, was predominantly detected in animal samples. Moreover, the potentially highly pathogenic RTs 027 and 078 were isolated from dogs. Even though, C. difficile did not occur simultaneously in animals and humans sharing the same household. The results of the epidemiological analysis of factors associated with fecal shedding of C. difficile support the hypothesis of a zoonotic potential. CONCLUSIONS: Molecular characterization and epidemiological analysis revealed that the zoonotic risk for C. difficile associated with dogs and cats within the community is low but cannot be excluded. PMID- 29474440 TI - Long-term effects of conservative treatment of Milwaukee brace on body image and mental health of patients with idiopathic scoliosis. AB - We aimed to provide a complex assessment of adult females with adolescent idiopathic scoliosis (AIS) after a minimum of 23 years after completed Milwaukee brace treatment. In the present study, a comparison between healthy female and AIS patients' perception of trunk disfigurement, self-image, mental health, pain level and everyday activity was made. Thirty AIS patients with a mean of 27.77 yrs (SD 3.30) after the treatment were included in the study. The control group consisted of 42 females, matching the age profile of the patient group. Study participants from both groups were examined using the same protocol, except for the radiological evaluation. Patients and healthy controls completed the Polish versions of the Scoliosis Research Society (SRS-22) and Spinal Appearance Questionnaire (SAQ). Patients additionally filled the Bad Sobberheim Stress Questionnaire-Deformity (BSSQ-Deformity) and Bad Sobberheim Stress Questionnaire Brace (BSSQ-Brace). The study group's SAQ results differ significantly in regard to the total score and all individual domains, indicating better functioning among healthy controls. Except for the General domain (p = 0.002), among the remaining subscales the study group's results differed significantly at p<0.001. Considering SRS-22 results, it was revealed that the patient group scored higher, signaling better functioning with reference to pain level (p = 0.016), function/activity (p<0.001) and the total score (p<0.001). The findings add to the complexity of long-term effect evaluations of AIS, particularly amongst females treated with a Milwaukee brace. Long-term results were not conclusive in terms of nonverbal assessment of body image and emotional tension regarding the experiences of brace-wearing. Future patients can be reassured that scoliosis treated conservatively does not negatively affect everyday activity, pain level, childbearing and mental health. Subjects who declared to have psychological problems due to scoliosis had a bigger curve size after treatment and in this study than the other AIS patients. PMID- 29474441 TI - Expressive writing intervention and self-reported physical health out-comes - Results from a nationwide randomized controlled trial with breast cancer patients. AB - The objective was to examine the effect of Expressive Writing Intervention (EWI) on self-reported physical symptoms and healthcare utilization in a nationwide randomized controlled trial with Danish women treated for primary breast cancer, and to explore participant characteristics related to emotion regulation as possible moderators of the effect. Women who had recently completed treatment for primary breast cancer (n = 507) were randomly assigned to three 20 min. home based writing exercises, one week apart, focusing on emotional disclosure (EWI) of a distressing experience (their cancer or a non-cancer topic) or a non disclosing topic (control). Outcomes were self-reported physical symptoms and healthcare utilization (visits and telephone contacts with GP) 3 and 9 months post-intervention. Potential moderators were repressive coping, alexithymia, rumination, social constraints, and writing topic. Results revealed no group by time interaction effects for any outcomes. Moderation analyses showed that 1) low alexithymic women in the EWI group showed larger decreases in GP telephone calls over time than both high alexithymic women and controls and 2) women in the EWI group writing about their own cancer, but not women writing about other topics, showed a larger decrease than controls. The results from this large randomized trial are concordant with previous findings showing that EWI is unlikely to be a generally applicable intervention to improve health-related outcomes in cancer patients and cancer survivors. However, written disclosure might have a beneficial impact for individuals who write about their own cancer, as well as for those low in alexithymia. PMID- 29474442 TI - Dysregulation of the IFN-gamma-STAT1 signaling pathway in a cell line model of large granular lymphocyte leukemia. AB - T cell large granular lymphocyte leukemia (T-LGLL) is a rare incurable disease that is characterized by defective apoptosis of cytotoxic CD8+ T cells. Chronic activation of the Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway is a hallmark of T-LGLL. One manifestation is the constitutive phosphorylation of tyrosine 701 of STAT1 (p-STAT1). T-LGLL patients also exhibit elevated serum levels of the STAT1 activator, interferon-gamma (IFN-gamma), thus contributing to an inflammatory environment. In normal cells, IFN-gamma production is tightly controlled through induction of IFN-gamma negative regulators. However, in T-LGLL, IFN-gamma signaling lacks this negative feedback mechanism as evidenced by excessive IFN-gamma production and decreased levels of suppressors of cytokine signaling 1 (SOCS1), a negative regulator of IFN-gamma. Here we characterize the IFN-gamma-STAT1 pathway in TL-1 cells, a cell line model of T-LGLL. TL-1 cells exhibited lower IFN-gamma receptor protein and mRNA expression compared to an IFN-gamma responsive cell line. Furthermore, IFN-gamma treatment did not induce JAK2 or STAT1 activation or transcription of IFN-gamma inducible gene targets. However, IFN-beta induced p-STAT1 and subsequent STAT1 gene transcription, demonstrating a specific IFN-gamma signaling defect in TL-1 cells. We utilized siRNA targeting of STAT1, STAT3, and STAT5b to probe their role in IL-2-mediated IFN-gamma regulation. These studies identified STAT5b as a positive regulator of IFN-gamma production. We also characterized the relationship between STAT1, STAT3, and STAT5b proteins. Surprisingly, p-STAT1 was positively correlated with STAT3 levels while STAT5b suppressed the activation of both STAT1 and STAT3. Taken together, these results suggest that the dysregulation of the IFN-gamma-STAT1 signaling pathway in TL-1 cells likely results from low levels of the IFN-gamma receptor. The resulting inability to induce negative feedback regulators explains the observed elevated IL-2 driven IFN-gamma production. Future work will elucidate the best way to target this pathway, with the ultimate goal to find a better therapeutic for T-LGLL. PMID- 29474443 TI - Amyloid formation reduces protein kinase B phosphorylation in primary islet beta cells which is improved by blocking IL-1beta signaling. AB - Amyloid formation in the pancreatic islets due to aggregation of human islet amyloid polypeptide (hIAPP) contributes to reduced beta-cell mass and function in type 2 diabetes (T2D) and islet transplantation. Protein kinase B (PKB) signaling plays a key role in the regulation of beta-cell survival, function and proliferation. In this study, we used human and hIAPP-expressing transgenic mouse islets in culture as two ex vivo models of human islet amyloid formation to: 1. Investigate the effects of amyloid formation on PKB phosphorylation in primary islet beta-cells; 2. Test if inhibition of amyloid formation and/or interleukin 1beta (IL-1beta) signaling in islets can restore the changes in beta-cell phospho PKB levels mediated by amyloid formation. Human and hIAPP-expressing mouse islets were cultured in elevated glucose with an amyloid inhibitor (Congo red) or embedded within collagen matrix to prevent amyloid formation. To block the IL 1beta signaling, human islets were treated with an IL-1 receptor antagonist (anakinra) or a glucagon-like peptide-1 agonist (exenatide). beta-cell phospho PKB levels, proliferation, apoptosis, islet IL-1beta levels and amyloid formation were assessed. Amyloid formation in both cultured human and hIAPP-expressing mouse islets reduced beta-cell phospho-PKB levels and increased islet IL-1beta levels, both of which were restored by prevention of amyloid formation either by the amyloid inhibitor or embedding islets in collagen matrix, resulting in improved beta-cell survival. Furthermore, inhibition of IL-1beta signaling by treatment with anakinra or exenatide increased beta-cell phospho-PKB levels, enhanced proliferation and reduced apoptosis in amyloid forming human islets during 7-day culture. These data suggest that amyloid formation leads to reduced PKB phosphorylation in beta-cells which is associated with elevated islet IL 1beta levels. Inhibitors of amyloid or amyloid-induced IL-1beta production may provide a new approach to restore phospho-PKB levels thereby enhance beta-cell survival and proliferation in conditions associated with islet amyloid formation such as T2D and clinical islet transplantation. PMID- 29474445 TI - Sexing of chicken eggs by fluorescence and Raman spectroscopy through the shell membrane. AB - In order to provide an alternative to day-old chick culling in the layer hatcheries, a noninvasive method for egg sexing is required at an early stage of incubation before onset of embryo sensitivity. Fluorescence and Raman spectroscopy of blood offers the potential for precise and contactless in ovo sex determination of the domestic chicken (Gallus gallus f. dom.) eggs already during the fourth incubation day. However, such kind of optical spectroscopy requires a window in the egg shell, is thus invasive to the embryo and leads to decreased hatching rates. Here, we show that near infrared Raman and fluorescence spectroscopy can be performed on perfused extraembryonic vessels while leaving the inner egg shell membrane intact. Sparing the shell membrane makes the measurement minimally invasive, so that the sexing procedure does not affect hatching rates. We analyze the effect of the membrane above the vessels on fluorescence signal intensity and on Raman spectrum of blood, and propose a correction method to compensate for it. After compensation, we attain a correct sexing rate above 90% by applying supervised classification of spectra. Therefore, this approach offers the best premises towards practical deployment in the hatcheries. PMID- 29474444 TI - Epitopes for neutralizing antibodies induced by HIV-1 envelope glycoprotein BG505 SOSIP trimers in rabbits and macaques. AB - The native-like, soluble SOSIP.664 trimer based on the BG505 clade A env gene of HIV-1 is immunogenic in various animal species, of which the most studied are rabbits and rhesus macaques. The trimer induces autologous neutralizing antibodies (NAbs) consistently but at a wide range of titers and with incompletely determined specificities. A precise delineation of immunogenic neutralization epitopes on native-like trimers could help strategies to extend the NAb response to heterologous HIV-1 strains. One autologous NAb epitope on the BG505 Env trimer is known to involve residues lining a hole in the glycan shield that is blocked by adding a glycan at either residue 241 or 289. This glycan-hole epitope accounts for the NAb response of most trimer-immunized rabbits but not for that of a substantial subset. Here, we have used a large panel of mutant BG505 Env-pseudotyped viruses to define additional sites. A frequently immunogenic epitope in rabbits is blocked by adding a glycan at residue 465 near the junction of the gp120 V5 loop and beta24 strand and is influenced by amino acid changes in the structurally nearby C3 region. We name this new site the "C3/465 epitope". Of note is that the C3 region was under selection pressure in the infected infant from whom the BG505 virus was isolated. A third NAb epitope is located in the V1 region of gp120, although it is rarely immunogenic. In macaques, NAb responses induced by BG505 SOSIP trimers are more often directed at the C3/465 epitope than the 241/289-glycan hole. PMID- 29474446 TI - PhysiCell: An open source physics-based cell simulator for 3-D multicellular systems. AB - Many multicellular systems problems can only be understood by studying how cells move, grow, divide, interact, and die. Tissue-scale dynamics emerge from systems of many interacting cells as they respond to and influence their microenvironment. The ideal "virtual laboratory" for such multicellular systems simulates both the biochemical microenvironment (the "stage") and many mechanically and biochemically interacting cells (the "players" upon the stage). PhysiCell-physics-based multicellular simulator-is an open source agent-based simulator that provides both the stage and the players for studying many interacting cells in dynamic tissue microenvironments. It builds upon a multi substrate biotransport solver to link cell phenotype to multiple diffusing substrates and signaling factors. It includes biologically-driven sub-models for cell cycling, apoptosis, necrosis, solid and fluid volume changes, mechanics, and motility "out of the box." The C++ code has minimal dependencies, making it simple to maintain and deploy across platforms. PhysiCell has been parallelized with OpenMP, and its performance scales linearly with the number of cells. Simulations up to 105-106 cells are feasible on quad-core desktop workstations; larger simulations are attainable on single HPC compute nodes. We demonstrate PhysiCell by simulating the impact of necrotic core biomechanics, 3-D geometry, and stochasticity on the dynamics of hanging drop tumor spheroids and ductal carcinoma in situ (DCIS) of the breast. We demonstrate stochastic motility, chemical and contact-based interaction of multiple cell types, and the extensibility of PhysiCell with examples in synthetic multicellular systems (a "cellular cargo delivery" system, with application to anti-cancer treatments), cancer heterogeneity, and cancer immunology. PhysiCell is a powerful multicellular systems simulator that will be continually improved with new capabilities and performance improvements. It also represents a significant independent code base for replicating results from other simulation platforms. The PhysiCell source code, examples, documentation, and support are available under the BSD license at http://PhysiCell.MathCancer.org and http://PhysiCell.sf.net. PMID- 29474448 TI - Early cessation of ceramic production for ancestral Polynesian society in Tonga. AB - Ancestral Polynesian society is the formative base for development of the Polynesian cultural template and proto-Polynesian linguistic stage. Emerging in western Polynesia ca 2700 cal BP, it is correlated in the archaeological record of Tonga with the Polynesian Plainware ceramic phase presently thought to be of approximately 800 years duration or longer. Here we re-establish the upper boundary for this phase to no more than 2350 cal BP employing a suite of 44 new and existing radiocarbon dates from 13 Polynesian Plainware site occupations across the extent of Tonga. The implications of this boundary, the abruptness of ceramic loss, and the shortening of duration to 350 years have substantive implications for archaeological interpretations in the ancestral Polynesian homeland. PMID- 29474447 TI - Contribution of S4 segments and S4-S5 linkers to the low-voltage activation properties of T-type CaV3.3 channels. AB - Voltage-gated calcium channels contain four highly conserved transmembrane helices known as S4 segments that exhibit a positively charged residue every third position, and play the role of voltage sensing. Nonetheless, the activation range between high-voltage (HVA) and low-voltage (LVA) activated calcium channels is around 30-40 mV apart, despite the high level of amino acid similarity within their S4 segments. To investigate the contribution of S4 voltage sensors for the low-voltage activation characteristics of CaV3.3 channels we constructed chimeras by swapping S4 segments between this LVA channel and the HVA CaV1.2 channel. The substitution of S4 segment of Domain II in CaV3.3 by that of CaV1.2 (chimera IIS4C) induced a ~35 mV shift in the voltage-dependence of activation towards positive potentials, showing an I-V curve that almost overlaps with that of CaV1.2 channel. This HVA behavior induced by IIS4C chimera was accompanied by a 2 fold decrease in the voltage-dependence of channel gating. The IVS4 segment had also a strong effect in the voltage sensing of activation, while substitution of segments IS4 and IIIS4 moved the activation curve of CaV3.3 to more negative potentials. Swapping of IIS4 voltage sensor influenced additional properties of this channel such as steady-state inactivation, current decay, and deactivation. Notably, Domain I voltage sensor played a major role in preventing CaV3.3 channels to inactivate from closed states at extreme hyperpolarized potentials. Finally, site-directed mutagenesis in the CaV3.3 channel revealed a partial contribution of the S4-S5 linker of Domain II to LVA behavior, with synergic effects observed in double and triple mutations. These findings indicate that IIS4 and, to a lesser degree IVS4, voltage sensors are crucial in determining the LVA properties of CaV3.3 channels, although the accomplishment of this function involves the participation of other structural elements like S4-S5 linkers. PMID- 29474449 TI - Structural equation modeling as a tool to investigate correlates of extra-pair paternity in birds. AB - Identifying relationships between variables in ecological systems is challenging due to the large number of interacting factors. One system studied in detail is avian reproduction, where molecular analyses have revealed dramatic variation in rates of extra-pair paternity-the frequency with which broods contain individuals sired by different males. Despite the attention the topic has received, identification of ecological predictors of the observed variation remains elusive. In this study we evaluate how structural equation modeling-which allows for simultaneous estimation of covariation between all variables in a model-can help identify significant relationships between ecological variables and extra pair paternity. We estimated the correlation of eight different variables using data from 36 species of passerines by including them in six different models of varying complexity. We recover strong support for species with lower rates of male care having higher rates of extra-pair paternity. Our results also suggest that testes size, range size, and longevity all potentially have a relationship with rates of extra-pair paternity; however, interpretation of this result is more challenging. More generally, these results demonstrate the utility of applying structural equation modeling to understanding correlations among interacting variables in complex biological systems. PMID- 29474451 TI - Racial residential segregation, socioeconomic disparities, and the White-Black survival gap. AB - OBJECTIVE: To evaluate the association between racial residential segregation, a prominent manifestation of systemic racism, and the White-Black survival gap in a contemporary cohort of adults, and to assess the extent to which socioeconomic inequality explains this association. DESIGN: This was a cross sectional study of White and Black men and women aged 35-75 living in 102 large US Core Based Statistical Areas. The main outcome was the White-Black survival gap. We used 2009-2013 CDC mortality data for Black and White men and women to calculate age-, sex- and race adjusted White and Black mortality rates. We measured segregation using the Dissimilarity index, obtained from the Manhattan Institute. We used the 2009-2013 American Community Survey to define indicators of socioeconomic inequality. We estimated the CBSA-level White-Black gap in probability of survival using sequential linear regression models accounting for the CBSA dissimilarity index and race-specific socioeconomic indicators. RESULTS: Black men and women had a 14% and 9% lower probability of survival from age 35 to 75 than their white counterparts. Residential segregation was strongly associated with the survival gap, and this relationship was partly, but not fully, explained by socioeconomic inequality. At the lowest observed level of segregation, and with the Black socioeconomic status (SES) assumed to be at the White SES level scenario, the survival gap is essentially eliminated. CONCLUSION: White-Black differences in survival remain wide notwithstanding public health efforts to improve life expectancy and initiatives to reduce health disparities. Eliminating racial residential segregation and bringing Black socioeconomic status (SES) to White SES levels would eliminate the White-Black survival gap. PMID- 29474450 TI - Treatment with native heterodimeric IL-15 increases cytotoxic lymphocytes and reduces SHIV RNA in lymph nodes. AB - : B cell follicles in secondary lymphoid tissues represent an immune privileged sanctuary for AIDS viruses, in part because cytotoxic CD8+ T cells are mostly excluded from entering the follicles that harbor infected T follicular helper (TFH) cells. We studied the effects of native heterodimeric IL-15 (hetIL-15) treatment on uninfected rhesus macaques and on macaques that had spontaneously controlled SHIV infection to low levels of chronic viremia. hetIL-15 increased effector CD8+ T lymphocytes with high granzyme B content in blood, mucosal sites and lymph nodes, including virus-specific MHC-peptide tetramer+ CD8+ cells in LN. Following hetIL-15 treatment, multiplexed quantitative image analysis (histo cytometry) of LN revealed increased numbers of granzyme B+ T cells in B cell follicles and SHIV RNA was decreased in plasma and in LN. Based on these properties, hetIL-15 shows promise as a potential component in combination immunotherapy regimens to target AIDS virus sanctuaries and reduce long-term viral reservoirs in HIV-1 infected individuals. TRIAL REGISTRATION: ClinicalTrials.gov NCT02452268. PMID- 29474452 TI - A 10-year case study on the changing determinants of university student satisfaction in the UK. AB - Higher Education (HE), once the prerogative of a tiny elite, is now accessible to larger numbers of people around the world than ever before yet despite the fact that an understanding of student satisfaction has never been more important for today's universities, the concept remains poorly understood. Here we use published data from the UK's National Student Survey (NSS), representing data from 2.3 million full-time students collected from 2007 to 2016, as a case study of the benefits and limitations of measuring student satisfaction that might have applicability for other countries, particularly those that, like the UK, have experienced significant growth in student numbers. The analyses showed that the factor structure of the NSS remained generally stable and that the ability of the NSS to discriminate between different subjects at different universities actually improved over the ten-year sample period. The best predictors of overall satisfaction were 'Teaching Quality' and 'Organisation & Management', with 'Assessment & Feedback' having relatively weak predictive ability, despite the sector's tangible efforts to improve on this metric. The tripling of student fees in 2012 for English students (but not the rest of the UK) was used as a 'natural experiment' to investigate the sensitivity of student satisfaction ratings to the real economic costs of HE. The tuition fee increase had no identifiable negative effect, with student satisfaction steadily improving throughout the decade. Although the NSS was never designed to measure perceived value-for-money, its insensitivity to major changes in the economic costs of HE to the individual suggest that the conventional concept of student satisfaction is incomplete. As such we propose that the concept of student satisfaction: (i) needs to be widened to take into account the broader economic benefits to the individual student by including measures of perceived value-for-money and (ii) should measure students' level of satisfaction in the years post-graduation, by which time they may have a greater appreciation of the value of their degree in the workplace. PMID- 29474453 TI - Detection of mitochondrial DNA with 4977 bp deletion in leukocytes of patients with ischemic stroke. AB - BACKGROUND: Coronary artery disease is associated with a common mitochondrial DNA alteration, a 4977 bp deletion (mtDNA4977). The role of mtDNA4977 in ischemic stroke is unknown. METHODS: Real-time quantitative PCR was performed to quantify total mtDNA and mtDNA4977 in leukocytes in 283 ischemic stroke cases and 135 controls. Ratios of mtDNA4977 to total-mtDNA and total-mtDNA to nuclear-DNA were calculated. Nested PCR and Sanger sequencing were used to confirm undetectable levels of mtDNA4977. RESULTS: For 191 patients and 74 control subjects in the male group and 92 patients and 61 control subjects in the female group, there were no significant between-group differences in age, cholesterol level, body mass index, stroke severity, or 4977 deletion. After adjusting for confounding factors, there was no correlation between mtDNA4977 amount and infarction risk, recurrent stroke, or stroke severity. However, mtDNA4977 was undetected in 6.94% subjects, and these individuals had a higher prevalence of stroke than those with detectable mtDNA4977 (OR: 0.181, 95% CI 0.041-0.798, p = 0.024). Additionally, mtDNA4977 status had no effect on stroke prognosis, including stroke severity and recurrent stroke. CONCLUSION: In conclusion, there was no apparent association between mtDNA4977 deletion and cerebral infarction. Undetectable mtDNA4977 may be a marker or risk factor for ischemic stroke. PMID- 29474455 TI - Correction: A Kolmogorov-Smirnov test for the molecular clock based on Bayesian ensembles of phylogenies. AB - [This corrects the article DOI: 10.1371/journal.pone.0190826.]. PMID- 29474454 TI - The impact of poverty reduction and development interventions on non-communicable diseases and their behavioural risk factors in low and lower-middle income countries: A systematic review. AB - INTRODUCTION: Non-communicable diseases (NCDs) disproportionately affect low- and lower-middle income countries (LLMICs) where 80% of global NCD related deaths occur. LLMICs are the primary focus of interventions to address development and poverty indicators. We aimed to synthesise the evidence of these interventions' impact on the four primary NCDs (cardiovascular disease, diabetes, chronic respiratory disease and cancer) and their common behavioural risk factors (unhealthy diets, physical inactivity, tobacco and alcohol use). METHODS: We systematically searched four online databases (Medline, Embase, Web of Science and Global Health) for primary research conducted in LLMICS, published between January 1st 1990 and February 15th 2016. Studies involved development or poverty interventions which reported on outcomes relating to NCDs. We extracted summary level data on study design, population, health outcomes and potential confounders. RESULTS: From 6383 search results, 29 studies from 24 LLMICs published between 1999 and 2015 met our inclusion criteria. The quality of included studies was limited and heterogeneity of outcome measures required narrative synthesis. One study measured impact on NCD prevalence, one physical activity and 27 dietary components. The majority of papers (23), involved agricultural interventions. Primary outcome measures tended to focus on undernutrition. Intensive agricultural interventions were associated with improved calorie, vitamin, fruit and vegetable intake. However, positive impacts were reliant on participant's land ownership, infection status and limited in generalisability. Just three studies measured adult obesity; two indicated increased income and consequential food affordability had the potential to increase obesity. Overall, there was poor alignment between included studies outcome measures and the key policy options and objectives of the Global Action Plan on NCDs. CONCLUSIONS: Though many interventions addressing poverty and development have great potential to impact on NCD prevalence and risk, most fail to measure or report these outcomes. Current evidence is limited to behavioural risk factors, namely diet and suggests a positive impact of agricultural-based food security programmes on dietary indicators. However, studies investigating the impact of improved income on obesity tend to show an increased risk. Embedding NCD impact evaluation into development programmes is crucial in the context of the Sustainable Development Goals and the rapid epidemiological transitions facing LLMICs. PMID- 29474456 TI - Correction: Stage-specific IFN-induced and IFN gene expression reveal convergence of type I and type II IFN and highlight their role in both acute and chronic stage of pathogenic SIV infection. AB - [This corrects the article DOI: 10.1371/journal.pone.0190334.]. PMID- 29474457 TI - Effect of contrast material injection duration on arterial enhancement at CT in patients with various cardiac indices: Analysis using computer simulation. AB - Arterial peak enhancement on contrast-enhanced CT (CECT) images is thought to be higher in patients with low cardiac function. Using computer simulations, we tested the hypothesis that the relationship between the cardiac index and the aortic peak CT number (PCTN) is affected by the contrast material (CM) injection duration. We created computer simulation software for the contrast enhancement of various organs and vessels based on the Bae pharmacokinetics model and implemented models for CM transmission within organs and CM diffusion in blood plasma based on the osmotic pressure. Aortic contrast enhancement at coronary- and abdominal CT angiographs (CTA) was simulated for a representative 60-year-old Japanese male 166 cm in height and 65.0 kg in weight. The injection protocol for coronary CTA was: CM dose 45.5 ml, iodine dose, 245 mg/kg body weight (BW); injection duration 8-20 sec in 2-sec increments. For abdominal CTA it was CM dose 74.3 ml; iodine dose 400 mg/kg BW; injection duration 10-40 sec in 5-sec increments. In both protocols the iodine concentration was 350 mgI/ml, osmotic pressure was 590 mOsm/kgH2O, and the cardiac index ranged from 0.1-6.0 l/min/m2. Under all protocols, the aortic PCTN increased as the injection duration decreased and as the cardiac index rose to the cardiac index value. It then decreased as it exceeded the cardiac index value. At coronary CTA, at an injection duration of 8 or 10 sec, the PCTN exceeded 350 Hounsfield units (HU) at a cardiac index from 0.9-5.6 l/min/m2. At an HU value greater than 350, the range of the cardiac index narrowed when the injection duration was 12 sec or longer. On abdominal CTA scans performed with an injection duration of 10-, 15-, or 20 sec, the PCTN exceeded 350 HU at a cardiac index ranging from 0.4-5.3 l/min/m2. When the injection duration ranged from 25-40 sec, there was narrowing of the range of the cardiac index at which the PCTN exceeded 350 HU. For coronary and abdominal CTA, contrast enhancement protocols with shorter injection durations yield a diagnostically adequate aortic PCTN at a wide range of cardiac indices. PMID- 29474459 TI - Correction: Identification of a serum-induced transcriptional signature associated with metastatic cervical cancer. AB - [This corrects the article DOI: 10.1371/journal.pone.0181242.]. PMID- 29474458 TI - Positive cytoplasmic UCHL5 tumor expression in gastric cancer is linked to improved prognosis. AB - Gastric cancer is the second most common cause of cancer-related mortality worldwide. Accurate prediction of disease progression is difficult, and new biomarkers for clinical use are essential. Recently, we reported that the proteasome-associated deubiquitinating enzyme UCHL5/Uch37 is a new prognostic marker in both rectal cancer and pancreatic ductal adenocarcinoma. Here, we have assessed by immunohistochemistry UCHL5 tumor expression in gastric cancer. The study cohort comprised 650 patients, who underwent surgery in Helsinki University Hospital, Finland, between 1983 and 2009. We investigated the association of cytoplasmic UCHL5 tumor expression to assess clinicopathological parameters and patient survival. Positive cytoplasmic UCHL5 tumor immunoexpression is linked to increased survival of patients with small (<5 cm) tumors (p = 0.001), disease stages I-II (p = 0.025), and age 66 years or older (p = 0.037). UCHL5 is thus a potential marker in gastric cancer with new prognostic relevance. PMID- 29474460 TI - Where is the left ventricle during cardiopulmonary resuscitation based on chest computed tomography in the expiration with arms down position? AB - OBJECTIVE: Patients usually receive cardiopulmonary resuscitation during ventilatory expiration and with their arms down, which does not reflect the normal imaging position. This study used scout images from low-dose chest computed tomography to compare the locations of the left ventricle (LV) in the expiration with arms down position (EAD) and in the full inspirational with arms raised position (IAR). METHODS: This cross-sectional study used a convenience sample and evaluated scout images that were obtained during screening with the participants in the EAD and IAR positions. The effective compression point was defined as being on the sternum above the longest anteroposterior diameter (APD) of the LV (using axial computed tomography images). The sternum was divided into three parts and the heart's position was evaluated on the EAD and the IAR images, and the distance from the xiphoid process to the LV's sternum landmark (XLVD) was measured. We also examined the compressible organs during CPR based on the EAD and IAR images. RESULTS: We enrolled 127 participants. The LVs were located in the middle of the sternum at EAD for 117 participants (92%) and in the lower half of the sternum at IAR for 107 participants (84%). The mean XLVD was significantly different between the EAD and IAR positions (mean: 85 +/- 21 mm vs. 33 +/- 17 mm, respectively). The liver's left lobe was located in the lower half of the sternum at EAD for 118 participants (93%). CONCLUSIONS: These findings indicate that the location of the LV during cardiopulmonary resuscitation might be in the middle of the sternum if the patient is treated in the EAD position. PMID- 29474462 TI - Advanced glycation end (AGE) product modification of laminin downregulates Kir4.1 in retinal Muller cells. AB - Diabetic retinopathy (DR) is a major cause of adult blindness. Retinal Muller cells maintain water homeostasis and potassium concentration via inwardly rectifying Kir4.1 channels. Accumulation of advanced glycation end products (AGEs) is a major pathologic event in DR. While diabetes leads to a decrease in the Kir4.1 channels, it remains unknown whether AGEs-linked to the basement membrane (BM) affect normal Kir4.1 channels. For this study, we hypothesized that AGE-modification of laminin is detrimental to Kir4.1 channels, therefore, disrupting Muller cell function. The AGE-modified laminin-coated substrates were prepared by incubating Petri-dishes with laminin and methylglyoxal for seven days. The rat Muller cells (rMC-1) were propagated on AGE-modified laminin, and Kir4.1 expression and function were evaluated. Quantification of AGEs using ELISA revealed a dose-dependent increase in methylglyoxal-hydro-imidazolone adducts. The rMC-1 propagated on AGE-modified laminin demonstrated a decrease in Kir4.1 levels in immunofluorescence and western blot studies and a decrease in the Kir4.1 channel function. Kir4.1 decrease on AGE-modified laminin resulted in a disorganization of an actin cytoskeleton and disruption of alpha-dystroglycan syntrophin-dystrophin complexes. Our studies suggest that AGE-modification of laminin is detrimental to Kir4.1 channels. By studying the role of AGEs in Kir4.1 channels we have identified a novel mechanism of Muller cell dysfunction and its subsequent involvement in DR. PMID- 29474461 TI - Distinct susceptibility of HIV vaccine vector-induced CD4 T cells to HIV infection. AB - The concerns raised from adenovirus 5 (Ad5)-based HIV vaccine clinical trials, where excess HIV infections were observed in some vaccine recipients, have highlighted the importance of understanding host responses to vaccine vectors and the HIV susceptibility of vector-specific CD4 T cells in HIV vaccination. Our recent study reported that human Ad5-specific CD4 T cells induced by Ad5 vaccination (RV156A trial) are susceptible to HIV. Here we further investigated the HIV susceptibility of vector-specific CD4 T cells induced by ALVAC, a canarypox viral vector tested in the Thai trial RV144, as compared to Ad5 vector specific CD4 T cells in the HVTN204 trial. We showed that while Ad5 vector specific CD4 T cells were readily susceptible to HIV, ALVAC-specific CD4 T cells in RV144 PBMC were substantially less susceptible to both R5 and X4 HIV in vitro. The lower HIV susceptibility of ALVAC-specific CD4 T cells was associated with the reduced surface expression of HIV entry co-receptors CCR5 and CXCR4 on these cells. Phenotypic analyses identified that ALVAC-specific CD4 T cells displayed a strong Th1 phenotype, producing higher levels of IFN-gamma and CCL4 (MIP-1beta) but little IL-17. Of interest, ALVAC and Ad5 vectors induced distinct profiles of vector-specific CD8 vs. CD4 T-cell proliferative responses in PBMC, with ALVAC preferentially inducing CD8 T-cell proliferation, while Ad5 vector induced CD4 T cell proliferation. Depletion of ALVAC-, but not Ad5-, induced CD8 T cells in PBMC led to a modest increase in HIV infection of vector-specific CD4 T cells, suggesting a role of ALVAC-specific CD8 T cells in protecting ALVAC-specific CD4 T cells from HIV. Taken together, our data provide strong evidence for distinct HIV susceptibility of CD4 T cells induced by different vaccine vectors and highlight the importance of better evaluating anti-vector responses in HIV vaccination. PMID- 29474463 TI - The development and validation of different decision-making tools to predict urine culture growth out of urine flow cytometry parameter. AB - OBJECTIVE: Patients presenting with suspected urinary tract infection are common in every day emergency practice. Urine flow cytometry has replaced microscopic urine evaluation in many emergency departments, but interpretation of the results remains challenging. The aim of this study was to develop and validate tools that predict urine culture growth out of urine flow cytometry parameter. METHODS: This retrospective study included all adult patients that presented in a large emergency department between January and July 2017 with a suspected urinary tract infection and had a urine flow cytometry as well as a urine culture obtained. The objective was to identify urine flow cytometry parameters that reliably predict urine culture growth and mixed flora growth. The data set was split into a training (70%) and a validation set (30%) and different decision-making approaches were developed and validated. RESULTS: Relevant urine culture growth (respectively mixed flora growth) was found in 40.2% (7.2% respectively) of the 613 patients included. The number of leukocytes and bacteria in flow cytometry were highly associated with urine culture growth, but mixed flora growth could not be sufficiently predicted from the urine flow cytometry parameters. A decision tree, predictive value figures, a nomogram, and a cut-off table to predict urine culture growth from bacteria and leukocyte count were developed, validated and compared. CONCLUSIONS: Urine flow cytometry parameters are insufficient to predict mixed flora growth. However, the prediction of urine culture growth based on bacteria and leukocyte count is highly accurate and the developed tools should be used as part of the decision-making process of ordering a urine culture or starting an antibiotic therapy if a urogenital infection is suspected. PMID- 29474464 TI - Clinical and genetic characterisation of dystrophin-deficient muscular dystrophy in a family of Miniature Poodle dogs. AB - Four full-sibling intact male Miniature Poodles were evaluated at 4-19 months of age. One was clinically normal and three were affected. All affected dogs were reluctant to exercise and had generalised muscle atrophy, a stiff gait and a markedly elevated serum creatine kinase activity. Two affected dogs also showed poor development, learning difficulties and episodes of abnormal behaviour. In these two dogs, investigations into forebrain structural and metabolic diseases were unremarkable; electromyography demonstrated fibrillation potentials and complex repetitive discharges in the infraspinatus, supraspinatus and epaxial muscles. Histopathological, immunohistochemical and immunoblotting analyses of muscle biopsies were consistent with dystrophin-deficient muscular dystrophy. DNA samples were obtained from all four full-sibling male Poodles, a healthy female littermate and the dam, which was clinically normal. Whole genome sequencing of one affected dog revealed a >5 Mb deletion on the X chromosome, encompassing the entire DMD gene. The exact deletion breakpoints could not be experimentally ascertained, but we confirmed that this region was deleted in all affected males, but not in the unaffected dogs. Quantitative polymerase chain reaction confirmed all three affected males were hemizygous for the mutant X chromosome, while the wildtype chromosome was observed in the unaffected male littermate. The female littermate and the dam were both heterozygous for the mutant chromosome. Forty four Miniature Poodles from the general population were screened for the mutation and were homozygous for the wildtype chromosome. The finding represents a naturally-occurring mutation causing dystrophin-deficient muscular dystrophy in the dog. PMID- 29474465 TI - Strength improvements through occlusal splints? The effects of different lower jaw positions on maximal isometric force production and performance in different jumping types. AB - OBJECTIVE: The influence of the jaw position on postural control, body posture, walking and running pattern has been reported in the literature. All these movements have in common that a relatively small, but well controlled muscle activation is required. The induced effects on motor output through changed jaw positions have been small. Therefore, it has been questioned if it could still be observed in maximal muscle activation. METHOD: Twenty-three healthy, mid age recreational runners (mean age = 34.0 +/- 10.3 years) participated in this study. Three different jump tests (squat jump, counter movement jump, and drop jumps from four different heights) and three maximal strength tests (trunk flexion and extension, leg press of the right and left leg) were conducted. Four different dental occlusion conditions and an additional familiarization condition were tested. Subjects performed the tests on different days for which the four occlusion conditions were randomly changed. RESULTS: No familiarization effect was found. Occlusion conditions with a relaxation position and with a myocentric condylar position showed significantly higher values for several tests compared to the neutral condition and the maximal occlusion position. Significance was found in the squat jump, countermovement jump, the drop jump from 32cm and 40cm, trunk extension, leg press force and rate of force development. The effect due to the splint conditions is an improvement between 3% and 12% (min and max). No influence of the jaw position on symmetry or balance between extension and flexion muscle was found. CONCLUSION: An influence of occlusion splints on rate of force development (RFD) and maximal strength tests could be confirmed. A small, but consistent increase in the performance parameters could be measured. The influence of the occlusion condition is most likely small compared to other influences as for example training status, age, gender and circadian rhythm. PMID- 29474467 TI - Pre-ingestive selection capacity and endoscopic analysis in the sympatric bivalves Mulinia edulis and Mytilus chilensis exposed to diets containing toxic and non-toxic dinoflagellates. AB - This study investigates the effects of toxic and non-toxic dinoflatellates on two sympatric bivalves, the clam Mulinia edulis and the mussel Mytilus chilensis. Groups of bivalves were fed one of three diets: (i) the toxic paralytic shellfish producing (PSP) Alexandrium catenella + Isochrysis galbana; (ii) the non-toxic Alexandrium affine + Isochrysis galbana and (iii) the control diet of Isochrysis galbana. Several physiological traits were measured, such as, clearance rate, pre ingestive selection efficiency and particle transport velocity in the gill. The clearance rates of both M. chilensis and M. edulis showed a significant reduction when fed a mixed toxic diet of 50% Alexandrium catenella: 50% Isochrysis galbana. Similarly, when both species of bivalves were fed with the non-toxic diet (50% A. affine: 50% I. galbana), clearance rate was significantly lower compared with a diet of 100% I. galbana. Under all the experimental diets, M. chilensis showed higher clearance rate values, slightly more than double that of M. edulis. M. edulis and M. chilensis have the ability to select particles at the pre-ingestive level, thus eliminating a larger proportion of the toxic dinoflagellate A. catenella as well as the non-toxic A. affine in the form of pseudofaeces. Higher values of selection efficiency were registered in M. edulis than in M. chilensis when exposed to the toxic diet. Similar results were observed when these two species were exposed to the diet containing the non-toxic dinoflagellate, explained by the fact that the infaunal Mulinia edulis is adapted to dealing with larger particle sizes and higher particle densities (Navarro et al., 1993). The lower transport particle velocity observed in the present work for both species, is related to the reduced clearance rate, the higher particle concentration, and the presence of larger, toxic dinoflagellates. In addition, the species differ in their feeding responses to diets, with and without A. catenella or A. affine, largely reflecting their adaptations to different environmental conditions. The results suggest that the presence of a dinoflagellate bloom, whether toxic or non toxic spp in Yaldad Bay, is likely to have a greater impact on the Mytilus chilensis than the infaunal Mulinia edulis, based on the combined effects on clearance rate, selection efficiency and particle transport velocity. PMID- 29474466 TI - Preclinical pharmacology of AZD9977: A novel mineralocorticoid receptor modulator separating organ protection from effects on electrolyte excretion. AB - Excess mineralocorticoid receptor (MR) activation promotes target organ dysfunction, vascular injury and fibrosis. MR antagonists like eplerenone are used for treating heart failure, but their use is limited due to the compound class-inherent hyperkalemia risk. Here we present evidence that AZD9977, a first in-class MR modulator shows cardio-renal protection despite a mechanism-based reduced liability to cause hyperkalemia. AZD9977 in vitro potency and binding mode to MR were characterized using reporter gene, binding, cofactor recruitment assays and X-ray crystallopgraphy. Organ protection was studied in uni nephrectomised db/db mice and uni-nephrectomised rats administered aldosterone and high salt. Acute effects of single compound doses on urinary electrolyte excretion were tested in rats on a low salt diet. AZD9977 and eplerenone showed similar human MR in vitro potencies. Unlike eplerenone, AZD9977 is a partial MR antagonist due to its unique interaction pattern with MR, which results in a distinct recruitment of co-factor peptides when compared to eplerenone. AZD9977 dose dependently reduced albuminuria and improved kidney histopathology similar to eplerenone in db/db uni-nephrectomised mice and uni-nephrectomised rats. In acute testing, AZD9977 did not affect urinary Na+/K+ ratio, while eplerenone increased the Na+/K+ ratio dose dependently. AZD9977 is a selective MR modulator, retaining organ protection without acute effect on urinary electrolyte excretion. This predicts a reduced hyperkalemia risk and AZD9977 therefore has the potential to deliver a safe, efficacious treatment to patients prone to hyperkalemia. PMID- 29474468 TI - Correction: Pharmacoepidemiological assessment of adherence and influencing co factors among primary open-angle glaucoma patients-An observational cohort study. AB - [This corrects the article DOI: 10.1371/journal.pone.0191185.]. PMID- 29474469 TI - Compositional shifts in root-associated bacterial and archaeal microbiota track the plant life cycle in field-grown rice. AB - Bacterial communities associated with roots impact the health and nutrition of the host plant. The dynamics of these microbial assemblies over the plant life cycle are, however, not well understood. Here, we use dense temporal sampling of 1,510 samples from root spatial compartments to characterize the bacterial and archaeal components of the root-associated microbiota of field grown rice (Oryza sativa) over the course of 3 consecutive growing seasons, as well as 2 sites in diverse geographic regions. The root microbiota was found to be highly dynamic during the vegetative phase of plant growth and then stabilized compositionally for the remainder of the life cycle. Bacterial and archaeal taxa conserved between field sites were defined as predictive features of rice plant age by modeling using a random forest approach. The age-prediction models revealed that drought-stressed plants have developmentally immature microbiota compared to unstressed plants. Further, by using genotypes with varying developmental rates, we show that shifts in the microbiome are correlated with rates of developmental transitions rather than age alone, such that different microbiota compositions reflect juvenile and adult life stages. These results suggest a model for successional dynamics of the root-associated microbiota over the plant life cycle. PMID- 29474471 TI - Real-time energy-saving metro train rescheduling with primary delay identification. AB - This paper aims to reschedule online metro trains in delay scenarios. A graph representation and a mixed integer programming model are proposed to formulate the optimization problem. The solution approach is a two-stage optimization method. In the first stage, based on a proposed train state graph and system analysis, the primary and flow-on delays are specifically analyzed and identified with a critical path algorithm. For the second stage a hybrid genetic algorithm is designed to optimize the schedule, with the delay identification results as input. Then, based on the infrastructure data of Beijing Subway Line 4 of China, case studies are presented to demonstrate the effectiveness and efficiency of the solution approach. The results show that the algorithm can quickly and accurately identify primary delays among different types of delays. The economic cost of energy consumption and total delay is considerably reduced (by more than 10% in each case). The computation time of the Hybrid-GA is low enough for rescheduling online. Sensitivity analyses further demonstrate that the proposed approach can be used as a decision-making support tool for operators. PMID- 29474470 TI - Antibiotic use, knowledge and health literacy among the general population in Berlin, Germany and its surrounding rural areas. AB - OBJECTIVES: Knowledge concerning antibiotic use in the general population is insufficient. The way health literacy is related to antibiotic use aside from knowledge needs further investigation. Our aim was to compare the levels of knowledge of antibiotics and health literacy in individuals who had taken antibiotics in recent years compared with those who not had taken antibiotics. METHODS: A population-based cross-sectional survey of 2,000 individuals aged 35 and older from Berlin, Germany and its surrounding rural and suburban areas (response rate 59%) with strata urban/rural, sex, age, and education. Computer assisted personal interviews were conducted by external, trained interviewers during home visits. Knowledge, health literacy, and antibiotic use were assessed using standardized questionnaires. RESULTS: In all, 33.3% (666/2,000) of the participants indicated having had an antimicrobial therapy during the previous 12 months. Adjusting for sex, age, educational level and health literacy, individuals with four correct answers regarding antibiotics were 1.70 times and those with three correct answers 1.94 more likely to have had a history of recent antibiotic use than those who did not have any correct answers. Individuals with sufficient health literacy were 0.57 times less likely to have had a recent history of antibiotic use than individuals with insufficient health literacy. CONCLUSION: Patients who have used antibiotics might have more knowledge as a result of their recent involvement with the topic of antibiotic use; health literacy may be a preventive mechanism to use antibiotics more critically. Besides improving the health knowledge of the general population and of vulnerable groups such as patients with low levels of health literacy, intervention strategies should focus on providers as well. PMID- 29474472 TI - Within the fortress: A specialized parasite is not discriminated against in a social insect society. AB - Social insect colonies function cohesively due, in part, to altruistic behaviors performed towards related individuals. These colonies can be affected by parasites in two distinct ways, either at the level of the individual or the entire colony. As such, colonies of social insects can experience conflict with infected individuals reducing the cohesiveness that typifies them. Parasites of social insects therefore offer us a framework to study conflicts within social insect colonies in addition to the traditionally viewed conflicts afforded by groups of low genetic relatedness due to multiple mating for example. In our study, we use the behavior manipulating fungal pathogen, Ophiocordyceps kimflemingiae (= unilateralis) and its host, Camponotus castaneus, to ask if colony members are able to detect infected individuals. Such detection would be optimal for the colony since infected workers die near foraging trails where the fungus develops its external structures and releases spores that infect other colony members. To determine if C. castaneus workers can detect these future threats, we used continuous-time point observations coupled with longer continuous observations to discern any discrimination towards infected individuals. After observing 1,240 hours of video footage we found that infected individuals are not removed from the colony and continuously received food during the course of fungal infection. We also calculated the distances between workers and the nest entrance in a total of 35,691 data points to find infected workers spent more time near the entrance of the nest. Taken together, these results suggest healthy individuals do not detect the parasite inside their nestmates. The colony's inability to detect infected individuals allows O. kimflemingiae to develop within the colony, while receiving food and protection from natural enemies, which could damage or kill its ant host before the parasite has completed its development. PMID- 29474473 TI - Correction: Quantification of Dialytic Removal and Extracellular Calcium Mass Balance during a Weekly Cycle of Hemodialysis. AB - [This corrects the article DOI: 10.1371/journal.pone.0153285.]. PMID- 29474474 TI - Lipidomic analysis of immune activation in equine leptospirosis and Leptospira vaccinated horses. AB - Currently available diagnostic assays for leptospirosis cannot differentiate vaccine from infection serum antibody. Several leptospiral proteins that are upregulated during infection have been described, but their utility as a diagnostic marker is still unclear. In this study, we undertook a lipidomics approach to determine if there are any differences in the serum lipid profiles of horses naturally infected with pathogenic Leptospira spp. and horses vaccinated against a commercially available bacterin. Utilizing a high-resolution mass spectrometry serum lipidomics analytical platform, we demonstrate that cyclic phosphatidic acids, diacylglycerols, and hydroperoxide oxidation products of choline plasmalogens are elevated in the serum of naturally infected as well as vaccinated horses. Other lipids of interest were triacylglycerols that were only elevated in the serum of infected horses and sphingomyelins that were increased only in the serum of vaccinated horses. This is the first report looking at the equine serum lipidome during leptospiral infection and vaccination. PMID- 29474475 TI - Single Nucleotide Polymorphism (SNP) markers associated with high folate content in wild potato species. AB - Micronutrient deficiency, also known as the hidden hunger, affects over two billion people worldwide. Potato is the third most consumed food crops in the world, and is therefore a fundamental element of food security for millions of people. Increasing the amount of micronutrients in food crop could help alleviate worldwide micronutrient malnutrition. In the present study, we report on the identification of single nucleotide polymorphism (SNP) markers associated with folate, an essential micronutrient in the human diet. A high folate diploid clone Fol 1.6 from the wild potato relative Solanum boliviense (PI 597736) was crossed with a low/medium folate diploid S. tuberosum clone USW4self#3. The resulting F1 progeny was intermated to generate an F2 population, and tubers from 94 F2 individuals were harvested for folate analysis and SNP genotyping using a SolCap 12K Potato SNP array. Folate content in the progeny ranged from 304 to 2,952 ng g 1 dry weight. 6,759 high quality SNPs containing 4,174 (62%) polymorphic and 2,585 (38%) monomorphic SNPs were used to investigate marker-trait association. Association analysis was performed using two different approaches: survey SNP trait association (SSTA) and SNP-trait association (STA). A total of 497 significant SNPs were identified, 489 by SSTA analysis and 43 by STA analysis. Markers identified by SSTA were located on all twelve chromosomes while those identified by STA were confined to chromosomes 2, 4, and 6. Eighteen of the significant SNPs were located within or in close proximity to folate metabolism related genes. Forty two SNPs were identical between SSTA and STA analyses. These SNPs have potential to be used in marker-assisted selection for breeding high folate potato varieties. PMID- 29474477 TI - Correction: Replication and Characterization of Association between ABO SNPs and Red Blood Cell Traits by Meta-Analysis in Europeans. AB - [This corrects the article DOI: 10.1371/journal.pone.0156914.]. PMID- 29474476 TI - RAGE-dependent potentiation of TRPV1 currents in sensory neurons exposed to high glucose. AB - Diabetes mellitus is associated with sensory abnormalities, including exacerbated responses to painful (hyperalgesia) or non-painful (allodynia) stimuli. These abnormalities are symptoms of diabetic peripheral neuropathy (DPN), which is the most common complication that affects approximately 50% of diabetic patients. Yet, the underlying mechanisms linking hyperglycemia and symptoms of DPN remain poorly understood. The transient receptor potential vanilloid 1 (TRPV1) channel plays a central role in such sensory abnormalities and shows elevated expression levels in animal models of diabetes. Here, we investigated the function of TRPV1 channels in sensory neurons cultured from the dorsal root ganglion (DRG) of neonatal mice, under control (5mM) and high glucose (25mM) conditions. After maintaining DRG neurons in high glucose for 1 week, we observed a significant increase in capsaicin (CAP)-evoked currents and CAP-evoked depolarizations, independent of TRPV1 channel expression. These functional changes were largely dependent on the expression of the receptor for Advanced Glycation End-products (RAGE), calcium influx, cytoplasmic ROS accumulation, PKC, and Src kinase activity. Like cultured neurons from neonates, mature neurons from adult mice also displayed a similar potentiation of CAP-evoked currents in the high glucose condition. Taken together, our data demonstrate that under the diabetic condition, DRG neurons are directly affected by elevated levels of glucose, independent of vascular or glial signals, and dependent on RAGE expression. These early cellular and molecular changes to sensory neurons in vitro are potential mechanisms that might contribute to sensory abnormalities that can occur in the very early stages of diabetes. PMID- 29474478 TI - Correction: A High Malaria Prevalence Identified by PCR among Patients with Acute Undifferentiated Fever in India. AB - [This corrects the article DOI: 10.1371/journal.pone.0158816.]. PMID- 29474479 TI - Exclusive breastfeeding promotion and neuropsychological outcomes in 5-8 year old children from Uganda and Burkina Faso: Results from the PROMISE EBF cluster randomized trial. AB - BACKGROUND: The beneficial effects from exclusive breastfeeding (EBF) have been widely acknowledged. We assessed the effect of exclusive breastfeeding promotion by peer counsellors in Uganda and Burkina Faso, on cognitive abilities, social emotional development, school performance and linear growth among 5-8 years old children. METHODS: Children in the PROMISE EBF trial (2006-2008) were re-enrolled in the follow-up PROMISE Saving Brains (SB) study (2013-2015). Caretaker interviews captured sociodemographic characteristics and social emotional development using the parent version of the Strengths and Difficulties Questionnaire (SDQ). Overall cognition and working memory were assessed using the Kaufman Assessment Battery for Children, second edition (KABC2), cognitive flexibility was measured with the Child Category Test (CCT), and attention with the Test of Variables of Attention (T.O.V.A), while school performance was measured by a standardized test on arithmetic and reading. Country-pooled, age adjusted z-scores from each of the above outcomes were entered into a linear regression model controlling for confounders. RESULTS: The number of children re enrolled in the intervention and control arms were: 274/396 (69.2%) and 256/369 (69.4%) in Uganda and 265/392 (67.6%) and 288/402 (71.6%) in Burkina Faso. Assessment of cognitive ability showed small and no significant differences, of which general cognition (z-scores, 95% CI) showed the largest mean difference: 0.17 (-0.40; 0.05). Social emotional symptoms were similar across arms. There were no differences in school performance or linear growth for age detected. CONCLUSION: Peer promotion for exclusive breastfeeding in Burkina Faso and Uganda was not associated with differences at 5-8 years of age in a range of measures of child development: cognitive abilities, emotion-behaviour-social symptoms or linear growth. This study from sub Saharan Africa did not reconfirm findings elsewhere that have shown an association between exclusive breastfeeding and cognitive performance. This might be due to a number of methodological limitations inherent in the current study. For example since the majority of the children were breastfed, the benefits of the intervention could have been diluted. Other factors such as the mental and HIV status of the mothers (which were not assessed in the current study) could have affected our results. Hence regarding the effect of exclusive breastfeeding on measures of child neurocognitive development in sub Saharan Africa, the jury is still out. TRIAL REGISTRATION: ClinicalTrials.gov NCT01882335. PMID- 29474481 TI - A dual boundary classifier for predicting acute hypotensive episodes in critical care. AB - An Acute Hypotensive Episode (AHE) is the sudden onset of a sustained period of low blood pressure and is one among the most critical conditions in Intensive Care Units (ICU). Without timely medical care, it can lead to an irreversible organ damage and death. By identifying patients at risk for AHE early, adequate medical intervention can save lives and improve patient outcomes. In this paper, we design a novel dual-boundary classification based approach for identifying patients at risk for AHE. Our algorithm uses only simple summary statistics of past Blood Pressure measurements and can be used in an online environment facilitating real-time updates and prediction. We perform extensive experiments with more than 4,500 patient records and demonstrate that our method outperforms the previous best approaches of AHE prediction. Our method can identify AHE patients two hours in advance of the onset, giving sufficient time for appropriate clinical intervention with nearly 80% sensitivity and at 95% specificity, thus having very few false positives. PMID- 29474480 TI - Role of Su(Hw) zinc finger 10 and interaction with CP190 and Mod(mdg4) proteins in recruiting the Su(Hw) complex to chromatin sites in Drosophila. AB - Su(Hw) belongs to the class of proteins that organize chromosome architecture and boundaries/insulators between regulatory domains. This protein contains a cluster of 12 zinc finger domains most of which are responsible for binding to three different modules in the consensus site. Su(Hw) forms a complex with CP190 and Mod(mdg4)-67.2 proteins that binds to well-known Drosophila insulators. To understand how Su(Hw) performs its activities and binds to specific sites in chromatin, we have examined the previously described su(Hw)f mutation that disrupts the 10th zinc finger (ZF10) responsible for Su(Hw) binding to the upstream module. The results have shown that Su(Hw)f loses the ability to interact with CP190 in the absence of DNA. In contrast, complete deletion of ZF10 does not prevent the interaction between Su(Hw)Delta10 and CP190. Having studied insulator complex formation in different mutant backgrounds, we conclude that both association with CP190 and Mod(mdg4)-67.2 partners and proper organization of DNA binding site are essential for the efficient recruitment of the Su(Hw) complex to chromatin insulators. PMID- 29474482 TI - Prevalence of several somatic diseases depends on the presence and severity of obstructive sleep apnea. AB - STUDY OBJECTIVES: The objective was to investigate the prevalence of heart attack, angina pectoris, stroke, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, asthma and obesity in relation to the presence and severity of obstructive sleep apnea. METHODS: The sample consisted of 1887 patients, with mean age of 48.6 years (range 16-83 years), referred to a university hospital on suspicion of obstructive sleep apnea. The patients filled out a questionnaire asking whether they were previously diagnosed with the comorbidities in interest. Obstructive sleep apnea was diagnosed and categorized based on a standard respiratory polygraphic sleep study using a type 3 portable monitor. The patients' weight, height and blood pressure were measured during the consultations. RESULTS: In total, 37.9% were categorized as not having obstructive sleep apnea (Apnea-hypopnea index <5), 29.6% mild obstructive sleep apnea (Apnea-hypopnea index 5-14.9), 17.3% moderate obstructive sleep apnea (Apnea-hypopnea index 15-29.9), and 15.2% severe obstructive sleep apnea (Apnea hypopnea index >=30). The prevalence of heart attack, angina pectoris, hypertension, measured systolic blood pressure >=140 mmHg, measured diastolic blood pressure >=90 mmHg, diabetes mellitus and obesity (body mass index>=30) were higher with greater obstructive sleep apnea severity. Logistic and linear regression analyses showed that these comorbidities were positively associated with obstructive sleep apnea severity. This was not the case for stroke, chronic obstructive pulmonary disease and asthma. After adjustment for sex, age, alcohol and smoking in the logistic regression analyses, hypertension, measured systolic blood pressure >=140 mmHg, measured diastolic blood pressure >=90 mmHg and obesity remained positively associated with obstructive sleep apnea severity. CONCLUSIONS: A higher prevalence of heart attack, angina pectoris, hypertension, diabetes mellitus, and obesity was seen with greater obstructive sleep apnea severity. Obesity and hypertension, conditions easy to clinically assess, appear as the most central comorbidities with greater obstructive sleep apnea severity. PMID- 29474483 TI - Correction: Gadolinium-enhanced cardiac MR exams of human subjects are associated with significant increases in the DNA repair marker 53BP1, but not the damage marker gammaH2AX. AB - [This corrects the article DOI: 10.1371/journal.pone.0190890.]. PMID- 29474484 TI - Transgenerational effects of prenatal restricted diet on gene expression and histone modifications in the rat. AB - Dietary triggers acting on a developing fetus can affect the functioning of the body in later life; this can be observed on various levels, including epigenetic modifications and gene expression. Early-life programmed changes may be transmitted to successive generations. In this study, the impact of prenatal restricted diet was studied in four generations of rats. We hypothesized that this diet can induce changes in the expression of major genes involved in two epigenetic mechanisms: DNA methylation and histone modifications. The transcript level of six genes involved in these processes (Dnmt1, Dnmt3a, Dnmt3b, Mecp2, Hdac1, and Sin3a) was therefore determined in three tissues (liver, adipose, and muscle). This diet was found to have no effect on the F0 pregnant females. In the F1 progeny (fetuses at day 19 of pregnancy and 4-week-old rats) significant differences in the expression of the genes were observed mostly in the liver; in subsequent generations, we therefore studied only this tissue. Among the genes encoding DNA methyltransferases, significant changes were observed for Dnmt1 in the F1 animals from the restricted group, but these were no longer evident in F2 and F3. The Dnmt3a and Dnmt3b genes showed no differences in mRNA level in F1 fetuses. Concerning the transcript level of the Mecp2 gene only in F1 generation significant changes were found. For the histone modification genes, an increase in the expression of Hdac1 in fetus liver was found in F1 and F2, while its level decreased in F3. The abundance of the Sin3a transcript varied in all generations. It was also found that the mRNA levels of the studied genes correlated highly positive with each other, but only in fetuses from the F1 restricted group. The DNA methylation cell potential, defined as the ratio of SAM (S adenosylmethionine) to SAH (S-adenosylhomocysteine), was measured in the liver, with no alterations being found in the restricted groups. Evaluation of global histone H3 acetylation showed that it underwent a significant increase in the fetal livers of F1, while during aging (four-week old animals) this difference was no longer maintained. A tendency of increased H3 acetylation in fetuses was also detected in F2 generation. In F1 fetuses from restricted group the increased H3 acetylation positively correlated with transcriptional status of the studied genes. Our results indicate that the prenatal restriction diet can affect the activity of genes involved in epigenetic mechanisms in the liver across generations. Moreover, this feeding type influenced the global histone H3 acetylation in fetal liver. PMID- 29474485 TI - Correction: Vaccination and nutritional status of children in Karawari, East Sepik Province, Papua New Guinea. AB - [This corrects the article DOI: 10.1371/journal.pone.0187796.]. PMID- 29474486 TI - Assessing changes in HIV-related legal and policy environments: Lessons learned from a multi-country evaluation. AB - INTRODUCTION: There is growing recognition in the health community that the legal environment-including laws, policies, and related procedures-impacts vulnerability to HIV and access to HIV-related services both positively and negatively. Assessing changes in the legal environment and how these affect HIV related outcomes, however, is challenging, and understanding of appropriate methodologies nascent. METHODS: We conducted an evaluation of a UNDP project designed to strengthen legal environments to support the human rights of key populations, in particular LGBT populations, women and girls, affected by HIV in sub-Saharan Africa. We analyzed data on activities designed to improve legal environments through a systematic document review and 53 qualitative interviews. RESULTS: The project made substantial strides towards legal change in many places, and examples provide broader lessons for work in this area. Two core pillars appear fundamental: a government-led participatory assessment of the legal environment, and building the capacity of those impacted by and engaged in this work. Systematic attention to human rights is vital: it can help open new spaces for dialogue among diverse stakeholders, foster new collaborations, and ensure local ownership, nuanced understanding of the political landscape, attention to marginalized populations, and accountability for (in)action. Entry points for effecting legal change go beyond "HIV laws" to also include other laws, national policies and strategies. CONCLUSION: Conducting legal environment assessments, multi-stakeholder dialogues, action planning and related activities, alongside capacity building, can contribute to changes in knowledge and attitudes directly relevant to reforming laws that are found to be harmful. Shorter-term goals along the causal pathway to legal change (e.g. changes in policy) can constitute interim markers of success, and recognition of these can maintain momentum. Increasing understanding of progress towards changes in the legal environment that can positively affect HIV-related outcomes is important in working to improve the health and lives of people living with HIV. PMID- 29474487 TI - Empirical relationships between tree fall and landscape-level amounts of logging and fire. AB - Large old trees are critically important keystone structures in forest ecosystems globally. Populations of these trees are also in rapid decline in many forest ecosystems, making it important to quantify the factors that influence their dynamics at different spatial scales. Large old trees often occur in forest landscapes also subject to fire and logging. However, the effects on the risk of collapse of large old trees of the amount of logging and fire in the surrounding landscape are not well understood. Using an 18-year study in the Mountain Ash (Eucalyptus regnans) forests of the Central Highlands of Victoria, we quantify relationships between the probability of collapse of large old hollow-bearing trees at a site and the amount of logging and the amount of fire in the surrounding landscape. We found the probability of collapse increased with an increasing amount of logged forest in the surrounding landscape. It also increased with a greater amount of burned area in the surrounding landscape, particularly for trees in highly advanced stages of decay. The most likely explanation for elevated tree fall with an increasing amount of logged or burned areas in the surrounding landscape is change in wind movement patterns associated with cutblocks or burned areas. Previous studies show that large old hollow bearing trees are already at high risk of collapse in our study area. New analyses presented here indicate that additional logging operations in the surrounding landscape will further elevate that risk. Current logging prescriptions require the protection of large old hollow-bearing trees on cutblocks. We suggest that efforts to reduce the probability of collapse of large old hollow-bearing trees on unlogged sites will demand careful landscape planning to limit the amount of timber harvesting in the surrounding landscape. PMID- 29474489 TI - Insect tissue-specific vitellogenin facilitates transmission of plant virus. AB - Insect vitellogenin (Vg) has been considered to be synthesized in the fat body. Here, we found that abundant Vg protein is synthesized in Laodelphax striatellus hemocytes as well. We also determined that only the hemocyte-produced Vg binds to Rice stripe virus (RSV) in vivo. Examination of the subunit composition of L. striatellus Vg (LsVg) revealed that LsVg was processed differently after its expression in different tissues. The LsVg subunit able to bind to RSV exist stably only in hemocytes, while fat body-produced LsVg lacks the RSV-interacting subunit. Nymph and male L. striatellus individuals also synthesize Vg but only in hemocytes, and the proteins co-localize with RSV. We observed that knockdown of LsVg transcripts by RNA interference decreased the RSV titer in the hemolymph, and thus interfered with systemic virus infection. Our results reveal the sex independent expression and tissue-specific processing of LsVg and also unprecedentedly connect the function of this protein in mediating virus transmission to its particular molecular forms existing in tissues previously known as non-Vg producing. PMID- 29474491 TI - Correction: Pre-service teachers' perceived value of general pedagogical knowledge for practice: Relations with epistemic beliefs and source beliefs. AB - [This corrects the article DOI: 10.1371/journal.pone.0184971.]. PMID- 29474488 TI - Sex- and brain region-specific patterns of gene expression associated with socially-mediated puberty in a eusocial mammal. AB - The social environment can alter pubertal timing through neuroendocrine mechanisms that are not fully understood; it is thought that stress hormones (e.g., glucocorticoids or corticotropin-releasing hormone) influence the hypothalamic-pituitary-gonadal axis to inhibit puberty. Here, we use the eusocial naked mole-rat, a unique species in which social interactions in a colony (i.e. dominance of a breeding female) suppress puberty in subordinate animals. Removing subordinate naked mole-rats from this social context initiates puberty, allowing for experimental control of pubertal timing. The present study quantified gene expression for reproduction- and stress-relevant genes acting upstream of gonadotropin-releasing hormone in brain regions with reproductive and social functions in pre-pubertal, post-pubertal, and opposite sex-paired animals (which are in various stages of pubertal transition). Results indicate sex differences in patterns of neural gene expression. Known functions of genes in brain suggest stress as a key contributing factor in regulating male pubertal delay. Network analysis implicates neurokinin B (Tac3) in the arcuate nucleus of the hypothalamus as a key node in this pathway. Results also suggest an unappreciated role for the nucleus accumbens in regulating puberty. PMID- 29474490 TI - Reproducibility of estimated optimal peak output using a force-velocity test on a cycle ergometer. AB - The current study aimed to examine the reproducibility of estimated peak power and estimated pedal velocity in a multi-trial 10-s all-out cycling test among adult athletes (n = 22; aged 23.50+/-4.73 years). Stature, sitting height and body mass were measured. Leg length was estimated as stature minus sitting height. Body volume was obtained from air displacement plethysmography and was subsequently used to calculate body density. Fat mass and fat-free mass were derived. The short-term power outputs were assessed from the force-velocity test (FVT), using a friction-braked ergometer on two separated occasions. Differences between repeated measurements were examined with paired t-test and effect sizes calculated. No significant differences were found between session 1 (898 W, 142 rpm) and session 2 (906 W, 142 rpm). Test-retest procedure showed acceptable reliability for estimated peak power output [technical error of measurement (TEM) = 31.9 W; % coefficient of variation (CV) = 3.5; intra-class correlation coefficient (ICC) = 0.986] and pedal velocity (TEM = 5.4 rpm, %CV = 3.8, ICC = 0.924). The current study demonstrated a reasonable reproducibility of estimated peak power and pedal velocity outputs in non-elite male athletes and supports that a familiarization session including a complete FVT protocol is not required. PMID- 29474492 TI - Docosahexaenoic acid antagonizes the boosting effect of palmitic acid on LPS inflammatory signaling by inhibiting gene transcription and ceramide synthesis. AB - It is well known that saturated fatty acids (SFAs) and unsaturated fatty acid, in particular omega-3 polyunsaturated fatty acids (n-3 PUFAs), have different effects on inflammatory signaling: SFAs are pro-inflammatory but n-3 PUFAs have strong anti-inflammatory properties. We have reported that palmitic acid (PA), a saturated fatty acid, robustly amplifies lipopolysaccharide (LPS) signaling to upregulate proinflammatory gene expression in macrophages. We also reported that the increased production of ceramide (CER) via sphingomyelin (SM) hydrolysis and CER de novo synthesis plays a key role in the synergistic effect of LPS and PA on proinflammatory gene expression. However, it remains unclear if n-3 PUFAs are capable of antagonizing the synergistic effect of LPS and PA on gene expression and CER production. In this study, we employed the above macrophage culture system and lipidomical analysis to assess the effect of n-3 PUFAs on proinflammatory gene expression and CER production stimulated by LPS and PA. Results showed that DHA strongly inhibited the synergistic effect of LPS and PA on proinflammatory gene expression by targeting nuclear factor kappa B (NFkappaB) dependent gene transcription. Results also showed that DHA inhibited the cooperative effect of LPS and PA on CER production by targeting CER de novo synthesis, but not SM hydrolysis. Furthermore, results showed that myriocin, a specific inhibitor of serine palmitoyltransferase, strongly inhibited both LPS-PA stimulated CER synthesis and proinflammatory gene expression, indicating that CER synthesis is associated with proinflammatory gene expression and that inhibition of CER synthesis contributes to DHA-inhibited proinflammatory gene expression. Taken together, this study demonstrates that DHA antagonizes the boosting effect of PA on LPS signaling on proinflammatory gene expression by targeting both NFkappaB-dependent transcription and CER de novo synthesis in macrophages. PMID- 29474494 TI - Accounting for polarization in the calibration of a donut beam axial optical tweezers. AB - Advances in light shaping techniques are leading to new tools for optical trapping and micromanipulation. For example, optical tweezers made from Laguerre Gaussian or donut beams display an increased axial trap strength and can impart angular momentum to rotate a specimen. However, the application of donut beam optical tweezers to precision, biophysical measurements remains limited due to a lack of methods for calibrating such devices sufficiently. For instance, one notable complication, not present when trapping with a Gaussian beam, is that the polarization of the trap light can significantly affect the tweezers' strength as well as the location of the trap. In this article, we show how to precisely calibrate the axial trap strength as a function of height above the coverslip surface while accounting for focal shifts in the trap position arising from radiation pressure, mismatches in the index of refraction, and polarization induced intensity variations. This provides a foundation for implementing a donut beam optical tweezers capable of applying precise axial forces. PMID- 29474493 TI - Construction and characterization of bacterial artificial chromosomes harboring the full-length genome of a highly attenuated vaccinia virus LC16m8. AB - LC16m8 (m8), a highly attenuated vaccinia virus (VAC) strain, was developed as a smallpox vaccine, and its safety and immunogenicity have been confirmed. Here, we aimed to develop a system that recovers infectious m8 from a bacterial artificial chromosome (BAC) that retains the full-length viral genomic DNA (m8-BAC system). The infectious virus was successfully recovered from a VAC-BAC plasmid, named pLC16m8-BAC. Furthermore, the bacterial replicon-free virus was generated by intramolecular homologous recombination and was successfully recovered from a modified VAC-BAC plasmid, named pLC16m8.8S-BAC. Also, the growth of the recovered virus was indistinguishable from that of authentic m8. The full genome sequence of the plasmid, which harbors identical inverted terminal repeats (ITR) to that of authentic m8, was determined by long-read next-generation sequencing (NGS). The ITR contains x 18 to 32 of the 70 and x 30 to 45 of 54 base pair tandem repeats, and the number of tandem repeats was different between the ITR left and right. Since the virus recovered from pLC16m8.8S-BAC was expected to retain the identical viral genome to that of m8, including the ITR, a reference-based alignment following a short-read NGS was performed to validate the sequence of the recovered virus. Based on the pattern of coverage depth in the ITR, no remarkable differences were observed between the virus and m8, and the other region was confirmed to be identical as well. In summary, this new system can recover the virus, which is geno- and phenotypically indistinguishable from authentic m8. PMID- 29474496 TI - Correction: Identification of potential antimicrobials against Salmonella typhimurium and Listeria monocytogenes using Quantitative Structure-Activity Relation modeling. AB - [This corrects the article DOI: 10.1371/journal.pone.0189580.]. PMID- 29474495 TI - In silico and in vitro studies of the reduction of unsaturated alpha,beta bonds of trans-2-hexenedioic acid and 6-amino-trans-2-hexenoic acid - Important steps towards biobased production of adipic acid. AB - The biobased production of adipic acid, a precursor in the production of nylon, is of great interest in order to replace the current petrochemical production route. Glucose-rich lignocellulosic raw materials have high potential to replace the petrochemical raw material. A number of metabolic pathways have been proposed for the microbial conversion of glucose to adipic acid, but achieved yields and titers remain to be improved before industrial applications are feasible. One proposed pathway starts with lysine, an essential metabolite industrially produced from glucose by microorganisms. However, the drawback of this pathway is that several reactions are involved where there is no known efficient enzyme. By changing the order of the enzymatic reactions, we were able to identify an alternative pathway with one unknown enzyme less compared to the original pathway. One of the reactions lacking known enzymes is the reduction of the unsaturated alpha,beta bond of 6-amino-trans-2-hexenoic acid and trans-2 hexenedioic acid. To identify the necessary enzymes, we selected N-ethylmaleimide reductase from Escherichia coli and Old Yellow Enzyme 1 from Saccharomyces pastorianus. Despite successful in silico docking studies, where both target substrates could fit in the enzyme pockets, and hydrogen bonds with catalytic residues of both enzymes were predicted, no in vitro activity was observed. We hypothesize that the lack of activity is due to a difference in electron withdrawing potential between the naturally reduced aldehyde and the carboxylate groups of our target substrates. Suggestions for protein engineering to induce the reactions are discussed, as well as the advantages and disadvantages of the two metabolic pathways from lysine. We have highlighted bottlenecks associated with the lysine pathways, and proposed ways of addressing them. PMID- 29474497 TI - MicroRNA profiling in plasma samples using qPCR arrays: Recommendations for correct analysis and interpretation. AB - MicroRNA (miRNA) regulate gene expression through posttranscriptional mRNA degradation or suppression of translation. Many (pre)analytical issues remain to be resolved for miRNA screening with TaqMan Low Density Arrays (TLDA) in plasma samples, such as optimal RNA isolation, preamplification and data normalization. We optimized the TLDA protocol using three RNA isolation protocols and preamplification dilutions. By using 100MUL elution volume during RNA isolation and adding a preamplification step without dilution, 49% of wells were amplified. Informative target miRNA were defined as having quantification cycle values <=35 in at least 20% of samples and low technical variability (CV across 2 duplicates of 1 sample <4%). A total of 218 miRNA was considered informative (= 59% of all target miRNA). Different normalization strategies were compared: exogenous Ath miR-159a, endogenous RNA U6, and three mathematical normalization techniques: geNorm (Qbase, QB) and NormFinder (NF) normalization algorithms, and global mean calculation. To select the best normalization method, technical variability, biological variability, stability, and the extent to which the normalization method reduces data dispersion were calculated. The geNorm normalization algorithm reduced data dispersion to the greatest extent, while endogenous RNA U6 performed worst. In conclusion, for miRNA profiling in plasma samples using TLDA cards we recommend: 1. Implementing a preamplification step in the TLDA protocol without diluting the final preamplification product 2. A stepwise approach to exclude non-informative miRNA based on quality control parameters 3. Against using snoRNA U6 as normalization method for relative quantification 4. Using the geNorm algorithm as normalization method for relative quantification. PMID- 29474498 TI - Joint association between body fat and its distribution with all-cause mortality: A data linkage cohort study based on NHANES (1988-2011). AB - OBJECTIVE: Although obesity is recognized as an important risk of mortality, how the amount and distribution of body fat affect mortality risk is unclear. Furthermore, whether fat distribution confers any additional risk of mortality in addition to fat amount is not understood. METHODS: This data linkage cohort study included 16415 participants (8554 females) aged 18 to 89 years from National Health and Nutrition Examination Survey III (1988-1994) and its linked mortality data (31 December 2011). Cox proportional hazard models and parametric survival models were used to estimate the association between body fat percentage (BF%), based on bioelectrical impedance analysis, and waist-hip ratio (WHR) with mortality. RESULTS: A total of 4999 deaths occurred during 19-year follow-up. A U shaped association between BF% and mortality was found in both sexes, with the adjusted hazard ratios for other groups between 1.02 (95% confidence interval: 0.89, 1.18) and 2.10 (1.47, 3.01) when BF% groups of 25-30% in males and 30-35% in females were used as references. A non-linear relationship between WHR and mortality was detected in males, with the adjusted hazard ratios among other groups ranging from 1.05 (0.94, 1.18) to 1.52 (1.15, 2.00) compared with the WHR category of 0.95-1.0. However in females, the death risk constantly increased across the WHR spectrum. Joint impact of BF% and WHR suggested males with BF% of 25-30% and WHR of 0.95-1.0 and females with BF% of 30-35% and WHR <0.9 were associated with the lowest mortality risk and longest survival age compared with their counterparts in other categories. CONCLUSIONS: This study supported the use of body fat distribution in addition to fat amount in assessing the risk of all cause mortality. PMID- 29474499 TI - Risk factors control for primary prevention of cardiovascular disease in men: Evidence from the Aragon Workers Health Study (AWHS). AB - Benefits of cardiovascular disease (CVD) risk factors control are well known, but goals achievement remains low. The objective of this study is to evaluate the prevalence of CVD risk factors among men ina worker's cohort with no previous CVD, to study control variations across time and the factors associated with poor control. To this end, we conducted a cohort reexamination (2010-2014) within the context of the Aragon Workers Health Study (AWHS). Data from working characteristics, analytical values and pharmacological prescription were included in the analysis. Prevalences of risk factor diagnosis and control were calculated, as well as factors associated with poor control. The prevalence of CVD risk factors was high. In 2014dyslipidaemia was the most prevalent (85.2%) followed by Hypertension (HT) (42.0%). People under treatment increased for the period analysed (p<0.001). The proportion of people treated varied from 72.2% in Diabetes Mellitus to 31.1% in dyslipidaemia in 2014. 46.2% of the workers with HT were controlled, decreasing to 21.9% in Diabetes and 11.0% in dyslipidaemia (2014). Working in a turn different to central shift was associated with poor control, especially for those working at night with HT (Odds Ratio in 2010: 3.6; Confidence Interval 95% 1.8-7.4) and dyslipidaemia (Odds Ratio 2010: 4.7; Confidence Interval 95% 1.3-16.4). We conclude that, although CVD control has increased significantly for the period studied, there are still many people that do not receive any treatment, and control goals are normally not achieved. PMID- 29474500 TI - Systems-level computational modeling demonstrates fuel selection switching in high capacity running and low capacity running rats. AB - High capacity and low capacity running rats, HCR and LCR respectively, have been bred to represent two extremes of running endurance and have recently demonstrated disparities in fuel usage during transient aerobic exercise. HCR rats can maintain fatty acid (FA) utilization throughout the course of transient aerobic exercise whereas LCR rats rely predominantly on glucose utilization. We hypothesized that the difference between HCR and LCR fuel utilization could be explained by a difference in mitochondrial density. To test this hypothesis and to investigate mechanisms of fuel selection, we used a constraint-based kinetic analysis of whole-body metabolism to analyze transient exercise data from these rats. Our model analysis used a thermodynamically constrained kinetic framework that accounts for glycolysis, the TCA cycle, and mitochondrial FA transport and oxidation. The model can effectively match the observed relative rates of oxidation of glucose versus FA, as a function of ATP demand. In searching for the minimal differences required to explain metabolic function in HCR versus LCR rats, it was determined that the whole-body metabolic phenotype of LCR, compared to the HCR, could be explained by a ~50% reduction in total mitochondrial activity with an additional 5-fold reduction in mitochondrial FA transport activity. Finally, we postulate that over sustained periods of exercise that LCR can partly overcome the initial deficit in FA catabolic activity by upregulating FA transport and/or oxidation processes. PMID- 29474501 TI - Risk assessment and HbA1c measurement in Norwegian community pharmacies to identify people with undiagnosed type 2 diabetes - A feasibility study. AB - OBJECTIVES: Determine the feasibility of using a diabetes risk assessment tool followed by HbA1c-measurement in a community-pharmacy setting in Norway. METHODS: In this longitudinal study two pharmacists in each of three community pharmacies were trained to perform risk assessments, HbA1c-measurements and counselling. Pharmacy customers who were > 18 years old and could understand and speak Norwegian or English were recruited in the pharmacies during a two-months-period. Information about the service was presented in local newspapers, social media, leaflets and posters at the pharmacy. Customers wishing to participate contacted the pharmacy staff. Participants completed a validated diabetes risk test and a background questionnaire including a validated instrument for self-rated health. A HbA1c measurement was performed for individuals with a moderate to high risk of developing diabetes. If HbA1c >= 6.5% they were recommended to visit their general practitioner for follow-up. The pharmacies performed internal and external quality control of the HbA1c instrument. RESULTS: Of the 211 included participants 97 (46%) were > 50 years old. HbA1c was measured for the 47 participants (22%) with high risk. Thirty-two (15%) had HbA1c values < 5.7%, twelve (5.4%) had values between 5.7%-6.4%, and three (1.4%) had an HbA1c >= 6.5%. Two participants with HbA1 >= 6.5% were diagnosed with diabetes by their general practitioner. The third was lost to follow-up. Results from internal and external quality control for HbA1c were within set limits. CONCLUSION: The pharmacists were able to perform the risk assessment and measurement of HbA1c, and pharmacy customers were willing to participate. The HbA1c measurements fulfilled the requirements for analytical quality. Thus, it is feasible to implement this service in community pharmacies in Norway. In a large-scale study the inclusion criteria should be increased to 45 years in accordance with the population the risk test has been validated for. PMID- 29474502 TI - Validation of the portable Air-Smart Spirometer. AB - BACKGROUND: The Air-Smart Spirometer is the first portable device accepted by the European Community (EC) that performs spirometric measurements by a turbine mechanism and displays the results on a smartphone or a tablet. METHODS: In this multicenter, descriptive and cross-sectional prospective study carried out in 2 hospital centers, we compare FEV1, FVC, FEV1/FVC ratio measured with the Air Smart-Spirometer device and a conventional spirometer, and analyze the ability of this new portable device to detect obstructions. Patients were included for 2 consecutive months. We calculate sensitivity, specificity, positive and negative predictive value (PPV and NPV) and likelihood ratio (LR +, LR-) as well as the Kappa Index to evaluate the concordance between the two devices for the detection of obstruction. The agreement and relation between the values of FEV1 and FVC in absolute value and the FEV1/FVC ratio measured by both devices were analyzed by calculating the intraclass correlation coefficient (ICC) and the Pearson correlation coefficient (r) respectively. RESULTS: 200 patients (100 from each center) were included with a mean age of 57 (+/- 14) years, 110 were men (55%). Obstruction was detected by conventional spirometry in 73 patients (40.1%). Using a FEV1/FVC ratio smaller than 0.7 to detect obstruction with the Air Smart Spirometer, the kappa index was 0.88, sensitivity (90.4%), specificity (97.2%), PPV (95.7%), NPV (93.7%), positive likelihood ratio (32.29), and negative likelihood ratio (0.10). The ICC and r between FEV1, FVC, and FEV1 / FVC ratio measured by the Air Smart Spirometer and the conventional spirometer were all higher than 0.94. CONCLUSION: The Air-Smart Spirometer is a simple and very precise instrument for detecting obstructive airway diseases. It is easy to use, which could make it especially useful non-specialized care and in other areas. PMID- 29474503 TI - Tree cover and species composition effects on academic performance of primary school students. AB - Human exposure to green space and vegetation is widely recognized to result in physical and mental health benefits; however, to date, the specific effects of tree cover, diversity, and species composition on student academic performance have not been investigated. We compiled standardized performance scores in Grades 3 and 6 for the collective student body in 387 schools across the Toronto District School Board (TDSB), and examined variation in relation to tree cover, tree diversity, and tree species composition based on comprehensive inventories of trees on school properties combined with aerial-photo-based assessments of tree cover. Analyses accounted for variation due to socioeconomic factors using the learning opportunity index (LOI), a regional composite index of external challenges to learning that incorporates income and other factors, such as students with English as a second language. As expected, LOI had the greatest influence on student academic performance; however, the proportion of tree cover, as distinct from other types of "green space" such as grass, was found to be a significant positive predictor of student performance, accounting for 13% of the variance explained in a statistical model predicting mean student performance assessments. The effects of tree cover and species composition were most pronounced in schools that showed the highest level of external challenges, suggesting the importance of urban forestry investments in these schools. PMID- 29474505 TI - Correction: Divalent cations are dispensable for binding to DNA of a novel positively charged olivomycin A derivative. AB - [This corrects the article DOI: 10.1371/journal.pone.0191923.]. PMID- 29474506 TI - Derivation of Outcome-Based Pediatric Critical Values. AB - Objectives: There is currently a lack of an outcomes-based definition of critical values for the pediatric population. This has contributed to a highly heterogeneous critical value reporting practice between laboratories. Methods: Anonymized results were extracted from a laboratory information system for 10 biochemistry tests. The probability of high-dependency/intensive care unit admission (as a proxy for adverse outcomes) for each individual laboratory concentration was calculated and adjusted to fit using a polynomial function to model the probability trend. The laboratory value that intersected the 90% probability trend line was considered the critical value threshold. Results: The critical value thresholds for the serum analytes were sodium (mmol/L: <131, >148), potassium (mmol/L: <2.4, >6.4), bicarbonate (mmol/L: <13, >37), chloride (mmol/L: <91, >115), urea (mmol/L: >12), creatinine (MUmol/L: >129), glucose (mmol/L: >17.2), total calcium (mmol/L: <1.9), magnesium (mmol/L: <0.6, >1.2), and phosphate (mmol/L: <0.4, >2.6). Conclusions: This study described an approach to derive contemporary pediatric critical value thresholds. PMID- 29474504 TI - The first in vivo multiparametric comparison of different radiation exposure biomarkers in human blood. AB - The increasing risk of acute large-scale radiological/nuclear exposures of population underlines the necessity of developing new, rapid and high throughput biodosimetric tools for estimation of received dose and initial triage. We aimed to compare the induction and persistence of different radiation exposure biomarkers in human peripheral blood in vivo. Blood samples of patients with indicated radiotherapy (RT) undergoing partial body irradiation (PBI) were obtained soon before the first treatment and then after 24 h, 48 h, and 5 weeks; i.e. after 1, 2, and 25 fractionated RT procedures. We collected circulating peripheral blood from ten patients with tumor of endometrium (1.8 Gy per fraction) and eight patients with tumor of head and neck (2.0-2.121 Gy per fraction). Incidence of dicentrics and micronuclei was monitored as well as determination of apoptosis and the transcription level of selected radiation responsive genes. Since mitochondrial DNA (mtDNA) has been reported to be a potential indicator of radiation damage in vitro, we also assessed mtDNA content and deletions by novel multiplex quantitative PCR. Cytogenetic data confirmed linear dose-dependent increase in dicentrics (p < 0.01) and micronuclei (p < 0.001) in peripheral blood mononuclear cells after PBI. Significant up regulations of five previously identified transcriptional biomarkers of radiation exposure (PHPT1, CCNG1, CDKN1A, GADD45, and SESN1) were also found (p < 0.01). No statistical change in mtDNA deletion levels was detected; however, our data indicate that the total mtDNA content decreased with increasing number of RT fractions. Interestingly, the number of micronuclei appears to correlate with late radiation toxicity (r2 = 0.9025) in endometrial patients suggesting the possibility of predicting the severity of RT-related toxicity by monitoring this parameter. Overall, these data represent, to our best knowledge, the first study providing a multiparametric comparison of radiation biomarkers in human blood in vivo, which have potential for improving biological dosimetry. PMID- 29474508 TI - Association between pain and the frailty phenotype in older men: longitudinal results from the Concord Health and Ageing in Men Project (CHAMP). AB - Objectives: to determine whether pain increases the risk of developing the frailty phenotype and whether frailty increases the risk of developing chronic or intrusive pain, using longitudinal data. Design/Setting: longitudinal data from the Concord Health and Ageing in Men Project (CHAMP), a prospective population based cohort study. Participants: a total of 1,705 men aged 70 years or older, living in an urban area of New South Wales, Australia. Measurements: data on the presence of chronic pain (daily pain for at least 3 months), intrusive pain (pain causing moderate to severe interference with activities) and the criteria for the Cardiovascular Health Study (CHS) frailty phenotype were collected in three waves, from January 2005 to October 2013. Data on age, living arrangements, education, smoking status, alcohol consumption, body mass index, comorbidities, cognitive function, depressive symptoms and history of vertebral or hip fracture were also collected and included as covariates in the analyses. Results: a total of 1,705 participants were included at baseline, of whom 1,332 provided data at the 2-year follow-up and 940 at the 5-year follow-up. Non-frail (robust and pre frail) men who reported chronic pain were 1.60 (95% confidence interval (CI): 1.02-2.51, P = 0.039) times more likely to develop frailty at follow-up, compared to those with no pain. Intrusive pain did not significantly increase the risk of future frailty. Likewise, the frailty status was not associated with future chronic or intrusive pain in the adjusted analysis. Conclusions: the presence of chronic pain increases the risk of developing the frailty phenotype in community dwelling older men. PMID- 29474509 TI - Blepharoplasty: Anatomy, Planning, Techniques, and Safety. AB - Blepharoplasty is one of the most commonly performed cosmetic surgical procedures. To date it remains the most powerful method of periorbital rejuvenation when compared to other non-surgical modalities, especially in the aging face. Despite that, the procedure has its shortcomings that include a steep learning curve, prolonged recovery and potential for appearance and life-changing complications. Attaining successful outcomes rely on solid understanding of facial topography, patient and technique selection, and, when appropriate, following a conservative approach. Modern blepharoplasty relies on tissue conservation and volume enhancement rather than aggressive removal. This concept was conceived after the realization that older techniques resulted in a hollowed appearance, which accentuated the aging process. It was further reinforced by advances in knowledge of periorbital anatomy and aging changes. This CME article will detail periorbital surgical anatomy, preoperative planning, and varied blepharoplasty approaches and techniques, with an emphasis on safety and tailoring the procedure to the patient's anatomy. PMID- 29474507 TI - PNPLA3 Association with Alcoholic Liver Disease in a Cohort of Heavy Drinkers. AB - Aims: Prior studies have established variation at the PNPLA3 gene to be associated with a risk of developing alcoholic liver disease (ALD). We attempt to replicate this finding and other potential genetic variations previously associated with ALD utilizing a case-control design in a cohort of subjects with alcohol use disorders. Short summary: This case-control study performed in a US clinical sample of heavy drinkers, replicates the previously reported association between ALD and rs738409 polymorphism in the PNPLA3 gene in heavy drinkers. This association persisted after accounting for the subject's diabetes status. Methods: Patients of European ancestry with a history of ALD were identified (n = 169). Controls consisted of patients without ALD who were from the same cohorts and were >= 30 years of age, had lifetime total years drinking >=20 and lifetime maximum drinks per day >=12 (n = 259). Patients were genotyped for 40 candidate single nucleotide polymorphisms (SNPs) selected for the purpose of testing their association with ALD. The association of each SNP with ALD was tested using a logistic regression model, assuming log-additive allele effects. Bonferroni correction was applied and multivariable logistic regression models were used to account for relevant covariates. Results: Age, sex, and body mass index (BMI) distributions were similar between cases and controls. Diabetes was more prevalent in the ALD cases. Three SNPs were associated with ALD at the nominal significance level (rs738409 in PNPLA3, P = 0.00029; rs3741559 in AQP2, P = 0.0185; rs4290029 in NVL, P = 0.0192); only PNPLA3 rs738409 SNP was significant at the Bonferroni-corrected P-value threshold of 0.00125. Association results remained significant after adjustment for diabetes status. Conclusion: Our case control study confirmed that PNPLA3 rs738409 SNP is associated with ALD. This is an important replication in a US clinical sample with control subjects who had long histories of alcohol consumption. PMID- 29474510 TI - Nudging and social marketing techniques encourage employees to make healthier food choices: a randomized controlled trial in 30 worksite cafeterias in The Netherlands. AB - Background: Currently, many studies focus on how the environment can be changed to encourage healthier eating behavior, referred to as choice architecture or "nudging." However, to date, these strategies are not often investigated in real life settings, such as worksite cafeterias, or are only done so on a short-term basis. Objective: The objective of this study is to examine the effects of a healthy worksite cafeteria ["worksite cafeteria 2.0" (WC 2.0)] intervention on Dutch employees' purchase behavior over a 12-wk period. Design: We conducted a randomized controlled trial in 30 worksite cafeterias. Worksite cafeterias were randomized to either the intervention or control group. The intervention aimed to encourage employees to make healthier food choices during their daily worksite cafeteria visits. The intervention consisted of 14 simultaneously executed strategies based on nudging and social marketing theories, involving product, price, placement, and promotion. Results: Adjusted multilevel models showed significant positive effects of the intervention on purchases for 3 of the 7 studied product groups: healthier sandwiches, healthier cheese as a sandwich filling, and the inclusion of fruit. The increased sales of these healthier meal options were constant throughout the 12-wk intervention period. Conclusions: This study shows that the way worksite cafeterias offer products affects purchase behavior. Situated nudging and social marketing-based strategies are effective in promoting healthier choices and aim to remain effective over time. Some product groups only indicated an upward trend in purchases. Such an intervention could ultimately help prevent and reduce obesity in the Dutch working population. This trial was registered at the Dutch Trial Register (http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=5372) as NTR5372. PMID- 29474511 TI - Organizational Strategies Partially Account for Race-related Differences in List Recall Performance. AB - Objective: Organizational strategies have been shown to improve one's ability to recall items from a list. Specifically, use of semantic clustering, the tendency to group items by category when recalling them, predicts better free recall of word lists after short and long delays. The present study utilized a healthy adult sample to examine use of efficient memory strategies as a predictor of differences in neurocognitive findings between African American and white participants. Method: Participants provided demographic information and completed the California Verbal Learning Test-Second Edition (CVLT-II) and Wechsler Abbreviated Scale of Intelligence-Second Edition (WASI-2). Results: Groups were matched across socioeconomic status and years of education. White participants used more semantic clustering and performed better on recall measures after short and long delays than their African American peers, and semantic clustering predicted recall in both groups. Regression analyses suggested that use of semantic clustering is a significant partial mediator of the relationship between race and free recall abilities. Intelligence scores from the WASI-2 were correlated with CVLT-II measures in white participants but not African American participants. Conclusions: Despite quantitatively similar backgrounds, white and African American participants differed in recall performance. However, this study showed that African American participants' poorer recall may be partially attributed to less frequent use of semantic clustering as a strategy. These discrepancies may be rooted in inequalities in educational experiences and suggest that providing organizational strategies during early learning may be an area of intervention to mitigate racial differences seen in neuropsychological testing. PMID- 29474514 TI - Large bowel obstruction: a case of uncommon aetiology of a frequent condition. PMID- 29474513 TI - Energide-cell body as smallest unit of eukaryotic life. AB - Background: The evolutionary origin of the eukaryotic nucleus is obscure and controversial. Currently preferred are autogenic concepts; ideas of a symbiotic origin are mostly discarded and forgotten. Here we briefly discuss these issues and propose a new version of the symbiotic and archaeal origin of the eukaryotic nucleus. Scope and Conclusions: The nucleus of eukaryotic cells forms via its perinuclear microtubules, the primary eukaryotic unit known also as the Energide cell body. As for all other endosymbiotic organelles, new Energides are generated only from other Energides. While the Energide cannot be generated de novo, it can use its secretory apparatus to generate de novo the cell periphery apparatus. We suggest that Virchow's tenet Omnis cellula e cellula should be updated as Omnis Energide e Energide to reflect the status of the Energide as the primary unit of the eukaryotic cell, and life. In addition, the plasma membrane provides feedback to the Energide and renders it protection via the plasma membrane-derived endosomal network. New discoveries suggest archaeal origins of both the Energide and its host cell. PMID- 29474515 TI - Validated Stability Indicating High Performance Liquid Chromatographic Determination of Lesinurad. AB - Lesinurad is a novel selective uric acid reabsorption inhibitor which has been newly approved for the treatment of the chronic gout. The behavior of lesinurad under various stress conditions (hydrolysis, oxidation, thermal and photolysis) has been investigated as per ICH guidelines. The drug has been found to be labile to acidic hydrolysis, basic hydrolysis and oxidation but stable in neutral, thermal and photolytic conditions. A high performance liquid chromatographic method has been developed for selective determination of the studied drug in the presence of its related degradation products. Good chromatographic resolution has been achieved using a reversed phase BDS Hypersil C18 stationary phase with an isocratic elution of a mobile phase consists of acetonitrile:water (65:35, v/v) at a flow rate of 1 mL/min and UV detection at 290 nm. Two degradation products have been identified by IR and mass spectral scans. The method was validated according to ICH guidelines. The linearity range has been found to be acceptable over the concentration range of 1-20 MUg/mL. The developed method has been successfully applied for the estimation of lesinurad in its pharmaceutical dosage form and could be used for the routine analysis of the studied drug in the quality control laboratories. PMID- 29474517 TI - Cost function network-based design of protein-protein interactions: predicting changes in binding affinity. AB - Motivation: Accurate and economic methods to predict change in protein binding free energy upon mutation are imperative to accelerate the design of proteins for a wide range of applications. Free energy is defined by enthalpic and entropic contributions. Following the recent progresses of Artificial Intelligence-based algorithms for guaranteed NP-hard energy optimization and partition function computation, it becomes possible to quickly compute minimum energy conformations and to reliably estimate the entropic contribution of side-chains in the change of free energy of large protein interfaces. Results: Using guaranteed Cost Function Network algorithms, Rosetta energy functions and Dunbrack's rotamer library, we developed and assessed EasyE and JayZ, two methods for binding affinity estimation that ignore or include conformational entropic contributions on a large benchmark of binding affinity experimental measures. If both approaches outperform most established tools, we observe that side-chain conformational entropy brings little or no improvement on most systems but becomes crucial in some rare cases. Availability and implementation: as open source Python/C++ code at sourcesup.renater.fr/projects/easy-jayz. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29474518 TI - Sestd1 Encodes a Developmentally Dynamic Synapse Protein That Complexes With BCR Rac1-GAP to Regulate Forebrain Dendrite, Spine and Synapse Formation. PMID- 29474516 TI - Nasal Structural and Aerodynamic Features That May Benefit Normal Olfactory Sensitivity. AB - Nasal airflow that effectively transports ambient odors to the olfactory receptors is important for human olfaction. Yet, the impact of nasal anatomical variations on airflow pattern and olfactory function is not fully understood. In this study, 22 healthy volunteers were recruited and underwent computed tomographic scans for computational simulations of nasal airflow patterns. Unilateral odor detection thresholds (ODT) to l-carvone, phenylethyl alcohol (PEA) and d-limonene were also obtained for all participants. Significant normative variations in both nasal anatomy and aerodynamics were found. The most prominent was the formation of an anterior dorsal airflow vortex in some but not all subjects, with the vortex size being significantly correlated with ODT of l carvone (r = 0.31, P < 0.05). The formation of the vortex is likely the result of anterior nasal morphology, with the vortex size varying significantly with the nasal index (ratio of the width and height of external nose, r = -0.59, P < 0.001) and nasal vestibule "notch" index (r = 0.76, P < 0.001). The "notch" is a narrowing of the upper nasal vestibule cartilage region. The degree of the notch also significantly correlates with ODT for PEA (r = 0.32, P < 0.05) and l-carvone (r = 0.33, P < 0.05). ODT of d-limonene, a low mucosal soluble odor, does not correlate with any of the anatomical or aerodynamic variables. The current study revealed that nasal anatomy and aerodynamics might have a significant impact on normal olfactory sensitivity, with greater airflow vortex and a narrower vestibule region likely intensifying the airflow vortex toward the olfactory region and resulting in greater olfactory sensitivity to high mucosal soluble odors. PMID- 29474519 TI - ViCTree: an automated framework for taxonomic classification from protein sequences. AB - Motivation: The increasing rate of submission of genetic sequences into public databases is providing a growing resource for classifying the organisms that these sequences represent. To aid viral classification, we have developed ViCTree, which automatically integrates the relevant sets of sequences in NCBI GenBank and transforms them into an interactive maximum likelihood phylogenetic tree that can be updated automatically. ViCTree incorporates ViCTreeView, which is a JavaScript-based visualization tool that enables the tree to be explored interactively in the context of pairwise distance data. Results: To demonstrate utility, ViCTree was applied to subfamily Densovirinae of family Parvoviridae. This led to the identification of six new species of insect virus. Availability and implementation: ViCTree is open-source and can be run on any Linux- or Unix based computer or cluster. A tutorial, the documentation and the source code are available under a GPL3 license, and can be accessed at http://bioinformatics.cvr.ac.uk/victree_web/. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29474520 TI - Stability Indicating RP-HPLC Method for Estimation of Potential Impurities in Ledipasvir and Characterization of a New Degradation Impurity. AB - A new sensitive and stability indicating reverse phase high-performance liquid chromatography method has been developed for the quantitative determination of potential impurities of Ledipasvir, active pharmaceutical ingredient. Efficient chromatographic separation was achieved on waters * select column contains C18 stationary phase in gradient mode, quantitation at wavelength of 325 nm and mobile phase A is 50 mM ammonium formate pH 3.5 and mobile phase B is acetonitrile with flow rate 1.2 mL. The method was validated according to International Council for Hormonisation guideline, linearity studies has shown correlation coefficient value greater than 0.999 for Ledipasvir and all known impurities. Limit of detection and Limit of quantification were determined to be 0.01% and 0.03%, respectively, for all the impurities. The consistent recoveries were obtained for all impurities (95-105%). Various stress conditions were applied to study the degradation behavior of the drug substance. LC-MS was used to analyse the degraded samples and possible structural identifications were assigned based upon known reactivity of the drug. The method was found to be specific, selective and robust to the degradation products. Major degradation of the drug substance was found to occur under photolytic stress conditions resulting a novel impurity (impurity F). The formed degradant was identified and characterized by FT-IR, 1HNMR and LC-MS/MS. The stress samples quantified against qualified working standard and the mass balance found above 98%. PMID- 29474522 TI - Effectiveness, Longevity, and Complications of Facelift by Barbed Suture Insertion. AB - Background: Minimally invasive facelift techniques involving barbed suture insertion have become popular among patients who wish to correct facial tissue ptosis. Objectives: The authors sought to determine the effectiveness, longevity, complications, and postoperative sequelae associated with facelift by means of barbed polydioxanone (PDO) threads. Methods: A total of 160 consecutive patients who underwent facelift with barbed threads were evaluated retrospectively. For malar augmentation and correction of nasolabial grooves, 2 or 3 PDO threads (23 gauge) were placed per side; for treatment of mandibular lines, 2 to 4 PDO threads (21 gauge) were inserted per side. Results: Immediately after suture placement and for 1 month postoperatively, patients experienced improvement in facial tissue ptosis. This aesthetic result declined noticeably by 6 months and was absent by 1 year. The overall complication rate in the early postoperative period was 34% (55 of 160 patients). Eighteen patients (11.2%) had superficial displacement of the barbed sutures, 15 (9.4%) experienced transient erythema, 10 (6.2%) had infection, 10 (6.2%) experienced skin dimpling, and 2 (1.2%) had temporary facial stiffness. Conclusions: Placement of barbed threads yields instantaneous improvement in facial ptosis that is no longer apparent by 1 year. Given this transient benefit and the complication rate of 34%, we recommend limiting this procedure to patients with contraindications for more invasive facial surgery. PMID- 29474521 TI - Ethnic differences in TGFbeta-signaling pathway may contribute to prostate cancer health disparity. AB - Epidemiological studies show that the incidence and mortality rates of prostate cancer (PCa) are significantly higher in African-American (AA) men when compared with Caucasian (CA) men in the United States. Transforming growth factor beta (TGFbeta) signaling pathway is linked to health disparities in AAs. Recent studies suggest a role of TGFbeta3 in cancer metastases and its effect on the migratory and invasive behavior; however, its role in PCa in AA men has not been studied. We determined the circulating levels of TGFbeta3 in AA and CA men diagnosed with PCa using ELISA. We analyzed serum samples from both AA and CA men diagnosed with and without PCa. We show that AA PCa patients had higher levels of TGFbeta3 protein compared with AA controls and CA patients. In fact, TGFbeta3 protein levels in serum were higher in AA men without PCa compared with the CA population, which may correlate with more aggressive disease seen in AA men. Studies on AA-derived PCa cell lines revealed that TGFbeta3 protein levels were also higher in these cells compared with CA-derived PCa cell lines. Our studies also reveal that TGFbeta does not inhibit cell proliferation in AA-derived PCa cell lines, but it does induce migration and invasion through activation of PI3K pathway. We suggest that increased TGFbeta3 levels are responsible for development of aggressive PCa in AA patients as a consequence of development of resistance to inhibitory effects of TGFbeta on cell proliferation and induction of invasive metastatic behavior. PMID- 29474523 TI - Progressive approach for SNP calling and haplotype assembly using single molecular sequencing data. AB - Motivation: Haplotype information is essential to the complete description and interpretation of genomes, genetic diversity and genetic ancestry. The new technologies can provide Single Molecular Sequencing (SMS) data that cover about 90% of positions over chromosomes. However, the SMS data has a higher error rate comparing to 1% error rate for short reads. Thus, it becomes very difficult for SNP calling and haplotype assembly using SMS reads. Most existing technologies do not work properly for the SMS data. Results: In this paper, we develop a progressive approach for SNP calling and haplotype assembly that works very well for the SMS data. Our method can handle more than 200 million non-N bases on Chromosome 1 with millions of reads, more than 100 blocks, each of which contains more than 2 million bases and more than 3K SNP sites on average. Experiment results show that the false discovery rate and false negative rate for our method are 15.7 and 11.0% on NA12878, and 16.5 and 11.0% on NA24385. Moreover, the overall switch errors for our method are 7.26 and 5.21 with average 3378 and 5736 SNP sites per block on NA12878 and NA24385, respectively. Here, we demonstrate that SMS reads alone can generate a high quality solution for both SNP calling and haplotype assembly. Availability and implementation: Source codes and results are available at https://github.com/guofeieileen/SMRT/wiki/Software. PMID- 29474524 TI - Hematomas in Aesthetic Surgery. AB - Hematomas represent one of the most common postoperative complications in patients undergoing aesthetic surgery. Depending on the type of procedure performed, hematoma incidence and presentation can vary greatly. Understanding the risk factors for hematoma formation and the preoperative considerations to mitigate the risk is critical to provide optimal care to the aesthetic patient. Various perioperative prevention measures may also be employed to minimize hematoma incidence. The surgeon's ability to adequately diagnose and treat hematomas after aesthetic surgery is not only crucial to patient care but also minimizes the risk of further complications or long-term sequelae. Understanding hematoma development and management enhances patient safety and will lead to overall increased patient satisfaction after aesthetic surgery. PMID- 29474525 TI - Insta-grated Plastic Surgery Residencies: The Rise of Social Media Use by Trainees and Responsible Guidelines for Use. AB - Background: Ethical guidelines for appropriate use of social media are beginning to be delineated. As social media becomes ingrained in plastic surgery culture, education of residents on appropriate use of social media is increasingly important. Recently, plastic surgery residency programs have begun to utilize social media. Objectives: This study characterized the trends and content of plastic surgery residency-associated Instagram accounts. Methods: Active individual residency program Instagram accounts were identified for integrated plastic surgery programs. Metrics for each account were retrieved on September 16, 2017, including date of first post, number of posts, and followers. Individual posts were analyzed for content of post. Results: Fourteen of 67 (21%) integrated plastic surgery programs were found to have active Instagram accounts. There has been an exponential growth of programs adopting Instagram since August 2015. A total of 806 posts were created. Thirty-two (3.97%) posts had intraoperative photos and only one (0.12%) showed a patient image. There were 4466 followers of plastic surgery residency programs. A linear correlation was found between number of posts and number of followers, while there was no correlation of number of followers and time since account start. Conclusions: Instagram use by plastic surgery integrated programs continues to grow exponentially, and programs are appropriately using the platform. Active use of the resident social media results in increased influence. Resident use of social media has many benefits. We propose social media guidelines for plastic surgery trainees and advocate for continued appropriate use and autoregulation by plastic surgery trainees. PMID- 29474526 TI - IWTomics: testing high-resolution sequence-based 'Omics' data at multiple locations and scales. AB - Summary: With increased generation of high-resolution sequence-based 'Omics' data, detecting statistically significant effects at different genomic locations and scales has become key to addressing several scientific questions. IWTomics is an R/Bioconductor package (integrated in Galaxy) that, exploiting sophisticated Functional Data Analysis techniques (i.e. statistical techniques that deal with the analysis of curves), allows users to pre-process, visualize and test these data at multiple locations and scales. The package provides a friendly, flexible and complete workflow that can be employed in many genomic and epigenomic applications. Availability and implementation: IWTomics is freely available at the Bioconductor website (http://bioconductor.org/packages/IWTomics) and on the main Galaxy instance (https://usegalaxy.org/). Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29474528 TI - Corrigendum. PMID- 29474527 TI - Aesthetic Improvement of Undeveloped Calves After Treatment of Congenital Clubfoot Deformity. AB - Background: Even when clubfoot deformity is treated in a timely manner, the consequences observed in adulthood include hypoplasia of the calf muscles, gait impairment, decreases in foot size, and it can also affect the tibial length. These consequences may have negative impacts on the patient's subjective appraisal of long-term outcomes, and can influence the patient's self-esteem in both male and female patients. Objectives: We present our experience in the treatment of undeveloped calves after surgical treatment of congenital clubfoot. Methods: In total, 72 patients underwent corrective surgery in order to improve undeveloped calves resulting from a congenital clubfoot deformity. We used calf silicone implants in combination with fat grafting in multistaged procedures, in order to decrease complication rates and improve aesthetic outcome. Results: Amongst our patients there were 54 (75%) females and 18 (25%) males. All of the patients, except one, had unilateral calf hypoplasia. The procedures were divided into several groups: (1) medial calf augmentation with silicone implants; (2) medial calf augmentation with silicone implants and fat grafting; and (3) medial and lateral calf augmentation with silicone implants and fat grafting. We had one case of a hyperpigmented scar and one case of partial scar dehiscence. There were no cases of compartment syndrome. The average follow-up period was 9.8 months. Conclusions: Calf enhancement surgery in patients with congenital clubfoot deformity is very gratifying. When combining calf implants with fat grafting in multistaged procedures, we can achieve excellent results with low complication rates. Level of Evidence 4: PMID- 29474529 TI - EPIC-CoGe: managing and analyzing genomic data. AB - Summary: The EPIC-CoGe browser is a web-based genome visualization utility that integrates the GMOD JBrowse genome browser with the extensive CoGe genome database (currently containing over 30 000 genomes). In addition, the EPIC-CoGe browser boasts many additional features over basic JBrowse, including enhanced search capability and on-the-fly analyses for comparisons and analyses between all types of functional and diversity genomics data. There is no installation required and data (genome, annotation, functional genomic and diversity data) can be loaded by following a simple point and click wizard, or using a REST API, making the browser widely accessible and easy to use by researchers of all computational skill levels. In addition, EPIC-CoGe and data tracks are easily embedded in other websites and JBrowse instances. Availability and implementation: EPIC-CoGe Browser is freely available for use online through CoGe (https://genomevolution.org). Source code (MIT open source) is available: https://github.com/LyonsLab/coge. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29474530 TI - MUGAN: Multi-GPU accelerated AmpliconNoise server for rapid microbial diversity assessment. AB - Motivation: Metagenomic sequencing has become a crucial tool for obtaining a gene catalogue of operational taxonomic units (OTUs) in a microbial community. A typical metagenomic sequencing produces a large amount of data (often in the order of terabytes or more), and computational tools are indispensable for efficient processing. In particular, error correction in metagenomics is crucial for accurate and robust genetic cataloging of microbial communities. However, many existing error-correction tools take a prohibitively long time and often bottleneck the whole analysis pipeline. Results: To overcome this computational hurdle, we analyzed and exploited the data-level parallelism that exists in the error-correction procedure and proposed a tool named MUGAN that exploits both multi-core central processing units (CPUs) and multiple graphics processing units (GPUs) for co-processing. According to the experimental results, our approach reduced not only the time demand for denoising amplicons from approximately 59 hours to only 46 minutes, but also the overestimation of the number of OTUs, estimating 6.7 times less species-level OTUs than the baseline. In addition, our approach provides web-based intuitive visualization of results. Given its efficiency and convenience, we anticipate that our approach would greatly facilitate denoising efforts in metagenomics studies. Availability: http://data.snu.ac.kr/pub/mugan. Contact: sryoon@snu.ac.kr. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29474532 TI - Infliximab as Rescue Treatment in Sweet's Syndrome Related to Corticodependent Ulcerative Colitis. PMID- 29474531 TI - Subtherapeutic Infliximab Trough Levels and Complete Mucosal Healing Are Associated With Sustained Clinical Remission After Infliximab Cessation in Paediatric-onset Crohn's Disease Patients Treated With Combined Immunosuppressive Therapy. AB - Background and Aims: We aimed to investigate the outcome in paediatric-onset Crohn's disease patients who had discontinued infliximab after maintaining clinical remission with combined immunosuppression, and to determine factors associated with clinical relapse. Methods: We conducted a retrospective observational study of 63 paediatric-onset Crohn's disease patients who had stopped scheduled infliximab during sustained corticosteroid-free clinical remission for at least 1 year with infliximab and azathioprine, and were followed up for at least 1 year thereafter. Cumulative relapse rates and the median time to relapse were estimated statistically. Factors at cessation were also evaluated for their association with clinical relapse. Results: After a median follow-up period of 4.3 years [range, 1-7.5 years], 60.3% [38/63] of patients had experienced clinical relapse. According to Kaplan-Meier survival analysis, the estimated cumulative relapse rates at 1, 4, and 6 years were 19.0%, 62.2%, and 75.2%, respectively, and the median relapse time was 3.3 years from infliximab cessation. According to multivariate Cox proportional hazard regression analysis, infliximab trough levels of >=2.5 MUg/mL and incomplete mucosal healing were associated with clinical relapse (hazard ratio [HR] = 7.199, 95% confidence interval [CI] = 1.641-31.571, p = 0.009 and HR = 3.628, 95% CI = 1.608-8.185, p = 0.002, respectively). Although re-treatment with infliximab was effective in 90.9% [30/33] of patients, 7.9% [3/38] eventually underwent surgery within 1 year of relapse. Conclusions: Considering the high cumulative relapse rates in the long term and cases of severe relapse requiring surgery, discontinuing infliximab in paediatric-onset Crohn's disease patients is currently inadvisable. However, there may be a subgroup of patients who are good candidates for infliximab withdrawal. PMID- 29474533 TI - Multimodality imaging in differential diagnosis in patient with fever and complete heart block. PMID- 29474534 TI - CDKL5 protein substitution therapy rescues neurological phenotypes of a mouse model of CDKL5 disorder. AB - Cyclin-dependent kinase like-5 (CDKL5) disorder is a rare neurodevelopmental disease caused by mutations in the CDKL5 gene. The consequent misexpression of the CDKL5 protein in the nervous system leads to a severe phenotype characterized by intellectual disability, motor impairment, visual deficits and early-onset epilepsy. No therapy is available for CDKL5 disorder. It has been reported that a protein transduction domain (TAT) is able to deliver macromolecules into cells and even into the brain when fused to a given protein. We demonstrate that TAT CDKL5 fusion protein is efficiently internalized by target cells and retains CDKL5 activity. Intracerebroventricular infusion of TAT-CDKL5 restored hippocampal development, hippocampus-dependent memory and breathing pattern in Cdkl5-null mice. Notably, systemically administered TAT-CDKL5 protein passed the blood-brain-barrier, reached the CNS, and rescued various neuroanatomical and behavioral defects, including breathing pattern and visual responses. Our results suggest that CDKL5 protein therapy may be an effective clinical tool for the treatment of CDKL5 disorder. PMID- 29474536 TI - Corrigendum: Training Programs on Endoscopic Scoring Systems for Inflammatory Bowel Disease Lead to a Significant Increase in Interobserver Agreement Among Community Gastroenterologists. PMID- 29474535 TI - Reducing 30-day readmission rates in a high-risk population using a lay-health worker model in Appalachia Kentucky. AB - This exploratory study aimed to address the effectiveness of a lay-health worker (LHW) model in addressing social needs and readmissions of high-risk patients admitted in a rural community hospital. A quasi-experimental study design assessed implementation of a LHW model for assisting high-risk patients with their post-discharge social needs. Outcome measures included 30-day hospital readmissions rates during a 4-month baseline period compared with a 6-month post implementation period. The LHW intervention involved assessment and development of a personalized social needs plan for enrolled patients (e.g. transportation and community resource identification), with post-discharge follow-up calls. There was a 47.7% relative reduction of 30-day hospital readmissions rates between baseline and intervention phases of the study. Simple regression analyses demonstrated a 56% decrease in odds (90% confidence interval 0.20-0.98) in being readmitted within 30-days among those in the intervention phase compared with those in the baseline phase. Once adjusting for education, transportation cost and anxiety symptoms, there was a 77% decrease in odds among those exposed to the LHW program. LHWs offer an effective hospital-based model to improve transitions in care from the hospital setting, especially those at high-risk with persistent social needs. PMID- 29474537 TI - Diagnostic accuracy of postmortem computed tomography, magnetic resonance imaging, and computed tomography-guided biopsies for the detection of ischaemic heart disease in a hospital setting. AB - Aims: The autopsy rate worldwide is alarmingly low (0-15%). Mortality statistics are important, and it is, therefore, essential to perform autopsies in a sufficient proportion of deaths. The imaging autopsy, non-invasive, or minimally invasive autopsy (MIA) can be used as an alternative to the conventional autopsy in an attempt to improve postmortem diagnostics by increasing the number of postmortem procedures. The aim of this study was to determine the diagnostic accuracy of postmortem magnetic resonance imaging (MRI), computed tomography (CT), and CT-guided biopsy for the detection of acute and chronic myocardial ischaemia. Methods and results: We included 100 consecutive adult patients who died in hospital, and for whom next-of-kin gave permission to perform both conventional autopsy and MIA. The MIA consists of unenhanced total-body MRI and CT followed by CT-guided biopsies. Conventional autopsy was used as reference standard. We calculated sensitivity and specificity and receiver operating characteristics curves for CT and MRI as the stand-alone test or combined with biopsy for detection of acute and chronic myocardial infarction (MI). Sensitivity and specificity of MRI with biopsies for acute MI was 0.97 and 0.95, respectively and 0.90 and 0.75, respectively for chronic MI. MRI without biopsies showed a high specificity (acute: 0.92; chronic: 1.00), but low sensitivity (acute: 0.50; chronic: 0.35). CT (total Agatston calcium score) had a good diagnostic value for chronic MI [area under curve (AUC) 0.74, 95% confidence interval (CI) 0.64-0.84], but not for acute MI (AUC 0.60, 95% CI 0.48-0.72). Conclusion: We found that the combination of MRI with biopsies had high sensitivity and specificity for the detection of acute and chronic myocardial ischaemia. PMID- 29474538 TI - How the most common mitochondrial DNA mutation (m.3243A>G) vanishes from leukocytes: a mathematical model. AB - Mitochondrial diseases may be caused by alterations of the mitochondrial genome. The pathogenic variant m.3243A>G is one of the most frequent causes of mitochondrial disease and the most common mitochondrial DNA mutation. Patients with a variant in mitochondrial DNA can have a mixture of mutated and wild-type genomes (heteroplasmy). In the case of the pathogenic variant m.3243A>G, the degree of heteroplasmy (H) correlates to some extent with the severity of the disease. Several longitudinal studies, where H is measured at two different time points, have shown an annual decline in leukocyte H values. Thus far, only an exponential decay of H with time has been noted but a mechanistic model is lacking. Here, I describe a deterministic mathematical model that accounts for the decline of H in leukocytes based on selective mechanisms acting at the stem cell level. The 'inverted-sigmoid' model provides estimates of at-birth H levels closer to those observed in post-mitotic tissues, such as skeletal muscle, than the estimates provided by an exponential decay. The new model never leads to predictions of H > 100% and provides a stronger correlation between at-birth H values in leukocytes and the scores of the Newcastle Mitochondrial Disease Scale for Adults, which can be of practical utility. This model could be extended to other mitochondrial DNA disease-causing variants. PMID- 29474539 TI - miR-1224-5p Enhances Hepatic Lipogenesis by Targeting Adenosine Monophosphate Activated Protein Kinase alpha1 in Male Mice. AB - MicroRNAs are potential therapeutic targets for metabolic diseases. Here, miR 1224-5p was highly expressed in the livers of mice fed a high-fat diet (HFD) and in obese (ob/ob) mice. To examine the potential role of miR-1224-5p, we constructed liver-specific adenoviral vectors expressing either an miR-1224-5p inhibitor sequence or miR-1224-5p mimic sequences. After tail-vein vector injection, HFD-fed mice were examined for expression of lipogenic genes. We found that miR-1224-5p inhibitors significantly attenuated hepatic lipogenesis and steatosis in HFD-fed mice, whereas miR-1224-5p mimicked promoted lipid accumulation in the liver of chow-fed C57BL/6 mice. Additional in vitro studies demonstrated that downregulation of miR-1224-5p in HepG2 and primary hepatocytes led to a reduction of cellular triglycerides after treatment with an oleic acid and palmitic acid mixture. Importantly, this study also identified adenosine monophosphate-activated protein kinase (AMPK)-alpha1 as a direct target of miR 1224-5p. miR-1224-5p binding to the 3' untranslated region of AMPKalpha1 suppressed expression of the AMPKalpha1 protein and its downstream molecules. Metformin, an activator of AMPK, also inhibited hepatic expression of miR-1224 5p. Together, these findings indicate that miR-1224-5p promotes hepatic lipogenesis by suppressing AMPKalpha1 expression and suggest that miR-1224-5p inhibitors warrant further investigation as potential therapeutic tools in the treatment of nonalcoholic fatty liver disease. PMID- 29474540 TI - SPEG-deficient skeletal muscles exhibit abnormal triad and defective calcium handling. AB - Centronuclear myopathies (CNM) are a subtype of congenital myopathies (CM) characterized by skeletal muscle weakness and an increase in the number of central myonuclei. We have previously identified three CNM probands, two with associated dilated cardiomyopathy, carrying striated preferentially expressed gene (SPEG) mutations. Currently, the role of SPEG in skeletal muscle function is unclear as constitutive SPEG-deficient mice developed severe dilated cardiomyopathy and died in utero. We have generated a conditional Speg-KO mouse model and excised Speg by crosses with striated muscle-specific cre-expressing mice (MCK-Cre). The resulting litters had a delay in Speg excision consistent with cre expression starting in early postnatal life and, therefore, an extended lifespan up to a few months. KO mice were significantly smaller and weaker than their littermate-matched controls. Histopathological skeletal muscle analysis revealed smaller myofibers, marked fiber-size variability, and poor integrity and low number of triads. Further, SPEG-deficient muscle fibers were weaker by physiological and in vitro studies and exhibited abnormal Ca2+ handling and excitation-contraction (E-C) coupling. Overall, SPEG deficiency in skeletal muscle is associated with fewer and abnormal triads, and defective calcium handling and excitation-contraction coupling, suggesting that therapies targeting calcium signaling may be beneficial in such patients. PMID- 29474541 TI - Enamel microcracks in the form of tooth damage during orthodontic debonding: a systematic review and meta-analysis of in vitro studies. AB - Objectives: To evaluate and compare the enamel microcracks (EMCs) characteristics (qualitative and quantitative) in the form of tooth damage before and after debonding from human teeth of in vitro studies. Eligibility criteria: Laboratorial studies evaluating EMCs characteristics before and after debonding metal and ceramic brackets from human teeth with intact buccal enamel. Information sources: An electronic search of four databases (all databases of the Cochrane Library, CA Web of Science, MEDLINE via PubMed, and Google Scholar) and additional manual searches were carried out, without language restrictions. Studies published between 2000 and 2017 years were selected. Reference lists of the included articles were screened, and authors were contacted when necessary. Risk of bias: The following six parameters were analyzed: blinding of examiner and outcome assessment, incomplete outcome data before bonding and after debonding, selective outcome reporting, and incomplete reporting of EMCs assessment. Included studies: Out of 430 potentially eligible studies, 259 were screened by title and abstract, 180 were selected for full-text analysis, 14 were included in the systematic review. Seven studies were selected for the meta analysis. Synthesis of results: The results for EMCs characteristics were expressed as mean differences (MDs) with their 95 per cent confidence intervals (CIs), and calculated from random-effects meta-analyses. Debonding was associated with the increase in number (three studies, MD = 3.50, 95% CI, 2.13 to 4.87, P < 0.00001), length (seven studies, MD = 3.09 mm, 95% CI, 0.75-5.43, P < 0.00001), and width (three studies, MD = 0.39 um, 95% CI, -0.01 to 0.79, P = 0.06) of EMCs. Considerable statistical heterogeneity was found for two forest plots evaluating the changes of number and length characteristics during debonding. Conclusions: There is weak evidence indicating length and width of EMCs increase following bracket removal and the scientific evidence concerning quantitative evaluation of the number parameter before and after debonding is insufficient. However, there is a strong evidence that after debonding the number of EMCs is likely to increase. Registration: No registration was performed. PMID- 29474543 TI - Three-dimensional evaluation on digital casts of maxillary palatal size and morphology in patients with functional posterior crossbite. AB - Background and objectives: Some authors have recently postulated the possibility of a unilateral contraction of the palate in patients with crossbite. This study aimed to investigate palatal dimension size and morphology in subjects with functional posterior crossbite and to localize location of the contraction through a 3D analysis procedure. Materials and methods: A study sample (SS) of 35 subjects (mean age 9.2 +/- 0.8 years), diagnosed with functional crossbite, and a control sample (CS) of 35 subjects (mean age 9.4 +/- 0.9 years) without crossbite were selected for this study. The digital models of each patient were analysed to assess palatal dimension size and symmetry by measuring linear distances between primary canines (D1) and fist molars (D2) to the median palatine plane and by performing and analysing the 3D deviation between the two specular models of the palatal vault for each patient. Results: Our findings demonstrate a significantly narrower dimension of D2 for the crossbite side than at the non-crossbite side. The 3D deviation analysis demonstrates a lower matching percentage of the palatal vault models in the SS (83.36%) compared with the CS (92.82%) and a location of that the palatal contraction is at the alveolar bone level. Conclusions: It can be assumed that there is a bilateral symmetrical contraction of the palatal vault and an asymmetric contraction of the alveolar process, but further studies are needed to corroborate this hypothesis. PMID- 29474544 TI - Invited commentary on diagnostic accuracy of postmortem computed tomography, magnetic resonance imaging, and computed tomography-guided biopsies for the detection of ischaemic heart disease in a hospital setting. PMID- 29474542 TI - Lack of correlation of desiccation and radiation tolerance in microorganisms from diverse extreme environments tested under anoxic conditions. AB - Four facultative anaerobic and two obligate anaerobic bacteria were isolated from extreme environments (deep subsurface halite mine, sulfidic anoxic spring, mineral-rich river) in the frame MASE (Mars Analogues for Space Exploration) project. The isolates were investigated under anoxic conditions for their survivability after desiccation up to 6 months and their tolerance to ionizing radiation up to 3000 Gy. The results indicated that tolerances to both stresses are strain-specific features. Yersinia intermedia MASE-LG-1 showed a high desiccation tolerance but its radiation tolerance was very low. The most radiation-tolerant strains were Buttiauxella sp. MASE-IM-9 and Halanaerobium sp. MASE-BB-1. In both cases, cultivable cells were detectable after an exposure to 3 kGy of ionizing radiation, but cells only survived desiccation for 90 and 30 days, respectively. Although a correlation between desiccation and ionizing radiation resistance has been hypothesized for some aerobic microorganisms, our data showed that there was no correlation between tolerance to desiccation and ionizing radiation, suggesting that the physiological basis of both forms of tolerances is not necessarily linked. In addition, these results indicated that facultative and obligate anaerobic organisms living in extreme environments possess varied species-specific tolerances to extremes. PMID- 29474545 TI - Simultaneous Determination of Gatifloxacin and Prednisolone in their Bulk Powder, Synthetic Mixture and Their Combined Ophthalmic Preparation Using Micellar Liquid Chromatography. AB - A simple rapid and accurate micellar high performance liquid chromatographic method was improved and validated for the analysis of mixture containing gatifloxacin sesquihydrate (GTF) and prednisolone acetate (PRED) in their synthetic mixture and their combined preparation. The separation was achieved using a C18 column, micellar mobile phase consisted of 0.2 M sodium dodecyl sulfate, 12.5% n-propanol and 0.3% triethylamine in 0.02 M orthophosphoric acid at pH 7.0 at a flow rate of 1 ml/min with UV detection at 270 nm. The proposed method was found to be rectilinear over the concentration ranges of 5.0-45 MUg ml 1 and 10-50 MUg ml-1 with recovery percentage of 99.95 +/- 0.82 and 100.07 +/- 0.84 for GTF and PRED, respectively. The separation of both drugs was accomplished in a very short chromatographic run (<5 min), the method is reproducible (R.S.D. < 1.0%) and show satisfactory resolution between GTF and PRED (Rs) = 1.67. The developed method was validated according to International Conference on Harmonization (ICH) guidelines. The limit of detection of the proposed method was 0.33 and 0.21 MUg ml-1, and the limit of quantitation was 0.99 and 0.64 MUg ml-1 for GTF and PRED, respectively. PMID- 29474546 TI - A Randomized Controlled Trial of a Text Messaging Intervention to Promote Virologic Suppression and Retention in Care in an Urban Safety-Net Human Immunodeficiency Virus Clinic: The Connect4Care Trial. AB - Background: Text messaging is a promising strategy to support human immunodeficiency virus (HIV) care engagement, but little is known about its efficacy in urban safety-net HIV clinics. Methods: We conducted a randomized controlled trial of a supportive and motivational text messaging intervention, Connect4Care (C4C), among viremic patients who had a history of poor retention or were new to the clinic. Participants were randomized (stratified by new or established HIV diagnosis status) to receive either of the following for 12 months: (1) thrice-weekly intervention messages, plus texted primary care appointment reminders and a monthly text message requesting confirmation of study participation or (2) texted reminders and monthly messages alone. Viral load was assessed at 6 and 12 months. The primary outcome was virologic suppression (<200 copies/mL) at 12 months, estimated via repeated-measures log-binomial regression, adjusted for new-diagnosis status. The secondary outcome was retention in clinic care. Results: Between August 2013 and November 2015, a total of 230 participants were randomized. Virologic suppression at 12 months was similar in intervention and control participants (48.8% vs 45.8%, respectively), yielding a rate ratio of 1.07 (95% confidence interval, .82-1.39). Suppression was higher in those with newly diagnosed infection (78.3% vs 45.3%). There were no intervention effects on the secondary outcome. Exploratory analyses suggested that patients with more responses to study text messages had better outcomes, regardless of arm. Conclusions: The C4C text messaging intervention did not significantly increase virologic suppression or retention in care. Response to text messages may be a useful way for providers to gauge risk for poor HIV outcomes. Clinical Trials Registration: NCT01917994. PMID- 29474547 TI - Suicidal Ideation and Suicide Attempts among Women Seeking Treatment for Substance Use and Trauma Symptoms. AB - Substance use disorders and posttraumatic stress disorder have been associated with suicide. Through secondary analysis of the screening data from the Women and Trauma Study conducted by the National Institute on Drug Abuse Clinical Trials Network, the present study examined rates and correlates of suicidal ideation and suicide attempts among women who sought treatment for substance use and trauma at seven outpatient substance use programs. The sample included women between the ages of 18 and 65 years (M = 39.2; SD = 9.3) and was 44 percent white, 33 percent African American, 8 percent Latina, and 15 percent other races or ethnicities. Logistic regression was used to examine factors associated with a lifetime history of recurrent suicidal ideation and a serious suicide attempt. Findings highlight the need for social workers to address elevated risk levels for suicidal thoughts and behaviors when working with women with histories of substance use and trauma. PMID- 29474548 TI - Insecticidal Activity of Lamiaceae Plant Essential Oils and Their Constituents Against Blattella germanica L. Adult. AB - The insecticidal activities of 13 Lamiaceae plant oils and their components against adult German cockroaches, Blattella germanica L. (Blattodea: Blattellidae), were evaluated using fumigant and contact bioassay. Among the tested oils, basil, pennyroyal, and spearmint showed the strongest insecticidal activities against adult B. germanica. Insecticidal activity of pennyroyal was 100% against male B. germanica at 1.25 mg concentration in fumigant bioassay. Basil and spearmint revealed 100% and 100% insecticidal activity against male B. germanica at 5 mg concentration, but their activities reduced to 80% and 25% at 2.5 mg concentration, respectively. In contact, toxicity bioassay, basil, pennyroyal, and spearmint oils exhibited 100%, 100%, and 98% mortality against female B. germanica at 1 mg/?, respectively. Among the constituents identified in basil, pennyroyal, and spearmint oils, insecticidal activity of pulegone was the strongest against male and female B. germanica. PMID- 29474549 TI - PI3K-mTOR pathway identified as a potential therapeutic target in biliary tract cancer using a newly established patient-derived cell panel assay. AB - Biliary tract carcinoma (BTC) is an extremely malignant tumor, but available treatment options are limited. Despite of needs for novel therapies, few BTC related resources are currently available for evaluation of candidate drugs. To address this issue, we have recently established 13 cell lines from surgical specimens from Japanese BTC patients. In the present study, we evaluated four new molecular targeting agents using our BTC cell-based assay panel with 17 BTC cell lines. PI3K/mTOR dual inhibitor LY3023414 showed activity at submicromolar concentration ranges against 13 of the 17 cell lines tested, including the ones with gemcitabine insensitivity. In conclusion, we demonstrated that in vitro study with the BTC cell line panel would be an efficient approach to screen for novel therapeutic strategies. Although this is preliminary result and further investigations are required for confirmation, PI3K/mTOR inhibitor might be a potential target for BTC drug development. PMID- 29474550 TI - Developmental plasticity and its relevance to assisted human reproduction. AB - The advent of assisted reproduction has allowed the conception of millions of individuals who otherwise would not have existed. Although most ART children are born healthy, there is increasing awareness of the plasticity of the human embryo causing concerns about potential long-term consequences of ART for the growth, development and health of this growing population of individuals. Evidence from studies in animals and humans suggest that physiology and metabolism may be permanently affected by ART. It suggests that ART children may be at increased risk of later cardiometabolic diseases. Part of this increased susceptibility to cardiometabolic diseases seems to be due to parental predisposition, while part of the increased susceptibility seems to be due to the ART procedure itself. Due to the fast development of new techniques in ART, it is unclear whether newer techniques are associated with similar risks. There is evidence to suggest that the newer techniques are safer, but the rapid developments in reproductive medicine and ever increasing indications for ART make it difficult to draw conclusions. Until more is known about the effectiveness and safety of ART for the broader indications in which ART is currently used, caution in using ART is mandatory.Further progress could be made if long-term follow-up studies were included in the development of new ART techniques. Harmonization of measurements in human and animal studies of ART would allow faster scientific progress and less scientific waste. Also, including more details of the ART procedures in ART registries and allowing follow up of ART children through linking registries with already collected data from perinatal registries, child health clinics and schools would help to provide a better understanding of the growth, development and health of the growing population of ART children. Ultimately, these studies will provide the much needed information on how to provide ART children with the best possible start in life. PMID- 29474551 TI - Reply: Improved understanding of very small embryonic-like stem cells in adult mammalian ovary. PMID- 29474552 TI - Study of a New Biological Control Method Combining an Enteropathogen and a Chemical Insecticide Against Solenopsis invicta (Hymenoptera: Formicidae). AB - Solenopsis invicta (Buren; Hymenoptera: Formicidae) is a species that has invaded China in recent years. Currently, S. invicta is mainly controlled by chemical treatment, though long-term use of chemical pesticides can cause serious environmental pollution. In this study, a microbial insecticide formulated for the control of S. invicta was screened for laboratory toxicity and field efficacy. The co-toxicity coefficients (CTCs) of the combination of Beauveria bassiana and thiacloprid at various mass ratios were 356.53, 251.20, 182.50, 215.03, and 143.19. When B. bassiana powder and thiacloprid were mixed at a mass ratio of 8:2, the CTC was 356.53, demonstrating a very significant synergistic effect. According to a field efficacy test, at 3 d after treatment, the efficacy of mound injection was significantly better than that of mound drenching. In this study, the insecticidal activity of pathogenic microorganisms against S. invicta was markedly enhanced by using a self-designed apparatus for mound injection of the tested preparation of a complex containing a pathogenic microbe. The results show that S. invicta can be sustainably controlled while ensuring the safety of the environment. The findings are a good reference for the promotion and application of safe control of S. invicta in the future. PMID- 29474553 TI - A multicenter Phase II study of sorafenib in Japanese patients with advanced hepatocellular carcinoma and Child Pugh A and B class. AB - Objective: To evaluate prospectively the efficacy and safety of sorafenib, which has been the first-line treatment for advanced hepatocellular carcinoma (HCC), in Japanese HCC patients (pts) with not only Child-Pugh (C-P) A class but also C-P B class. Methods: Sorafenib was administered orally at the dose of 400 mg twice daily for pts with HCC and liver function of C-P score of 5-8. Administration was continued until the detection of disease progression or appearance of unacceptable toxicity. The primary endpoint was time to progression (TTP), and toxicity and the secondary endpoints included objective response, overall survival (OS). Results: Forty C-P A pts and 12 C-P B pts were enrolled. The median TTP in the C-P A pts and C-P B pts was 3.3 months and 3.2 months, respectively. Among the pts with C-P A, complete response, partial response, and stable disease were achieved for 2.5%, 7.5% and 47.5%. Among the pts with C-P B, there were no treatment responses, 66.7% of pts had stable disease. The median OS in the C-P A pts and C-P B pts was 13.4 months and 7.4 months, respectively. With regard to toxicities, fewer C-P A pts experienced Grade 3/4 toxicities than C-P B pts (77.5% vs. 91.6%). There were no treatment-related deaths in either group of patients. Conclusions: This study shows sorafenib has similar effectiveness in the recent post-approval studies and is well-tolerated in Japanese pts with HCC and Child Pugh A class. Sorafenib should be used with great care for Child Pugh class B pts. PMID- 29474554 TI - Rim domain loops of staphylococcal beta-pore forming bi-component toxin S components recognize target human erythrocytes in a coordinated manner. AB - Staphylococcus aureus bi-component pore-forming toxins consist of S- and F components, and form hetero-octameric beta-barrel pores on target blood cell membranes. Among them, gamma-haemolysin (Hlg2 and F-component of Luk (LukF)) and LukED (LukE and LukD) possess haemolytic activity, whereas the Panton-Valentine leukocidin (LukS-PV and LukF-PV) does not lyse human erythrocytes. Here, we focussed on four loop structures in the rim domain of S-component, namely loops 1, -2, -3 and -4, and found that replacement of Loop-4 in both Hlg2 and LukE with that of LukS-PV abolished their haemolytic activity. Furthermore, LukS-PV gained haemolytic activity by Loop-4 exchange with Hlg2 or LukE, suggesting that Loop-4 of these S-components determined erythrocyte specificity. LOOP-1 and -2 enhanced the erythrocytes-binding ability of both components. Although Hlg2 and LukE recognize Duffy antigen receptor for chemokines on human erythrocytes, the ability of Loop-4 was not complementary between Hlg2 and LukE. Exchange of Hlg2 with LukE Loop-4 showed weaker activity than intact Hlg2, and LukE mutant with Hlg2 Loop-4 lost its haemolytic activity in combination of LukD. Interestingly, the haemolytic activities of these Loop-4 exchange mutants were affected by F component, namely LukF enhanced haemolytic activities of these Hlg2 and LukE Loop 4 mutants, and also haemolytic activity of LukS-PV mutant with LukE Loop-4. PMID- 29474555 TI - Health-related quality of life of patients after surgery for acute Type A aortic dissection. AB - OBJECTIVES: Acute Type A aortic dissection (ATAAD) and the ensuing surgical therapy may be experienced as a traumatic event by patients. This study aimed at analysing the prevalence of post-traumatic stress disorder (PTSD) and the physical and mental well-being of survivors of surgically treated ATAAD. METHODS: A total of 393 survivors were contacted and asked to fill in various health questionnaires. RESULTS: Two hundred and ten (53%) patients returned the questionnaires. The mean follow-up was 51 +/- 27.8 months. The results showed that 67.6% had high blood pressure, 12.9% had pre-existing diseases of the aorta and 31.5% or 27% of these groups were at risk for PTSD according to the health questionnaires. Duration of intensive care unit or hospital stay had no effect on the risk for PTSD. According to the questionnaire, Short Form 12, physical and mental well-being was significantly reduced in the patients compared to a large German norm sample, even after adjustment for differences in age between the 2 cohorts. Physical activity prior to the event was associated with improved physical and mental well-being but did not reduce the risk for PTSD. CONCLUSIONS: Emergency surgery for ATAAD is associated with high risk for PTSD, which seems to negatively affect physical and mental well-being. More efforts should be directed at prevention and early diagnosis and therapy of PTSD. This study has evaluated 8 year trends in the presentation, diagnosis and outcomes such as physical and mental measures and prevalence rates of PTSD in patients who have undergone an emergency operation for ATAAD. PMID- 29474556 TI - Improved understanding of very small embryonic-like stem cells in adult mammalian ovary. PMID- 29474557 TI - PennDiff: detecting differential alternative splicing and transcription by RNA sequencing. AB - Motivation: Alternative splicing and alternative transcription are a major mechanism for generating transcriptome diversity. Differential alternative splicing and transcription (DAST), which describe different usage of transcript isoforms across different conditions, can complement differential expression in characterizing gene regulation. However, the analysis of DAST is challenging because only a small fraction of RNA-seq reads is informative for isoforms. Several methods have been developed to detect exon-based and gene-based DAST, but they suffer from power loss for genes with many isoforms. Results: We present PennDiff, a novel statistical method that makes use of information on gene structures and pre-estimated isoform relative abundances, to detect DAST from RNA seq data. PennDiff has several advantages. First, grouping exons avoids multiple testing for 'exons' originated from the same isoform(s). Second, it utilizes all available reads in exon-inclusion level estimation, which is different from methods that only use junction reads. Third, collapsing isoforms sharing the same alternative exons reduces the impact of isoform expression estimation uncertainty. PennDiff is able to detect DAST at both exon and gene levels, thus offering more flexibility than existing methods. Simulations and analysis of a real RNA-seq dataset indicate that PennDiff has well-controlled type I error rate, and is more powerful than existing methods including DEXSeq, rMATS, Cuffdiff, IUTA and SplicingCompass. As the popularity of RNA-seq continues to grow, we expect PennDiff to be useful for diverse transcriptomics studies. Availability and implementation: PennDiff source code and user guide is freely available for download at https://github.com/tigerhu15/PennDiff. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29474559 TI - Genomic Alterations and Complex Subclonal Architecture in Sporadic GH-Secreting Pituitary Adenomas. AB - Purpose: The molecular pathogenesis of growth hormone-secreting pituitary adenomas is not fully understood. Cytogenetic alterations might serve as alternative driver events in GNAS mutation-negative somatotroph tumors. Experimental Design: We performed cytogenetic profiling of pituitary adenomas obtained from 39 patients with acromegaly and four patients with sporadic gigantism by using array comparative genomic hybridization analysis. We explored intratumor DNA copy-number heterogeneity in two tumor samples by using DNA fluorescence in situ hybridization (FISH). Results: Based on copy-number profiles, we found two groups of adenomas: a low-copy-number alteration (CNA) group (<12% of genomic disruption, 63% of tumors) and a high-CNA group (24% to 45% of genomic disruption, 37% of tumors). Arm-level CNAs were the most common abnormalities. GNAS mutation-positive adenomas belonged exclusively to the low CNA group, whereas a subgroup of GNAS mutation-negative adenomas had a high degree of genomic disruption. We detected chromothripsis-related CNA profiles in two adenoma samples from an AIP mutation-positive patient with acromegaly and a patient with sporadic gigantism. RNA sequencing of these two samples identified 17 fusion transcripts, most of which resulted from chromothripsis-related chromosomal rearrangements. DNA FISH analysis of these samples demonstrated a subclonal architecture with up to six distinct cell populations in each tumor. Conclusion: Somatotroph pituitary adenomas display substantial intertumor and intratumor DNA copy-number heterogeneity, as revealed by variable CNA profiles and complex subclonal architecture. The extensive cytogenetic burden in a subgroup of GNAS mutation-negative somatotroph adenomas points to an alternative tumorigenic pathway linked to genomic instability. PMID- 29474558 TI - Phase 3 study of ceritinib vs chemotherapy in ALK-rearranged NSCLC patients previously treated with chemotherapy and crizotinib (ASCEND-5): Japanese subset. AB - Background: In the global, Phase 3, ASCEND-5 study, ceritinib improved progression-free survival (PFS) vs chemotherapy in patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) who had previously progressed on crizotinib and platinum-based chemotherapy. Here, we report efficacy and safety in a subset of Japanese patients from the ASCEND-5 study. Methods: Patients with advanced ALK-rearranged NSCLC received oral ceritinib 750 mg/day or chemotherapy (intravenous pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 [investigator's choice], every 21 days). Results: Among the 231 patients, 29 were Japanese, of which, 11 were treated with ceritinib and 18 were treated with chemotherapy (5 with pemetrexed and 13 with docetaxel). All the patients received prior crizotinib and one or two lines of prior chemotherapy for advanced disease. Median follow-up time was 16.6 months for ceritinib arm and 16.4 months for chemotherapy arm in the overall population. The median PFS by blinded independent review committee was 9.8 months (95% CI, 4.3-14.0) in ceritinib arm vs 1.6 months (95% CI, 1.4-3.0) in chemotherapy arm. Grade 3 or 4 adverse events, suspected to be study drug related, were reported in 36.4% of ceritinib arm and 72.2% of chemotherapy arm, respectively. No Grade 3 or 4 events of diarrhea, nausea and vomiting were reported in both the treatment arms. Adverse events leading to study drug discontinuation were reported in one patient in each arm: Grade 3 central-nervous system metastases in ceritinib-treated patient and Grade 3 febrile neutropenia in chemotherapy-treated patient. Conclusions: Consistent with overall population, ceritinib demonstrated better efficacy compared with the standard second-line chemotherapy in Japanese patients with crizotinib-resistant ALK+ NSCLC. ClinicalTrials.gov identifier: NCT01828112. PMID- 29474560 TI - A Genetic Survey of Pyrethroid Insecticide Resistance in Aphids in New Brunswick, Canada, with Particular Emphasis on Aphids as Vectors of Potato virus Y. AB - Aphids are viral vectors in potatoes, most importantly of Potato virus Y (PVY), and insecticides are frequently used to reduce viral spread during the crop season. Aphids collected from the potato belt of New Brunswick, Canada, in 2015 and 2016 were surveyed for known and novel mutations in the Na-channel (para) gene, coding for the target of synthetic pyrethroid insecticides. Specific genetic mutations known to confer resistance (kdr and skdr) were found in great abundance in Myzus persicae (Sulzer) (Hemiptera: Aphididae), which rose from 76% in 2015 to 96% in 2016. Aphids other than M. persicae showed lower frequency of resistance. In 2015, 3% of individuals contained the resistance mutation skdr, rising to 13% in 2016 (of 45 species). Several novel resistance mutations or mutations not before reported in aphids were identified in this gene target. One of these mutations, I936V, is known to confer pyrethroid resistance in another unrelated insect, and three others occur immediately adjacent and prompt similar chemical shifts in the primary protein structure, to previously characterized mutations associated with pyrethroid resistance. Most novel mutations were found in species other than M. persicae or others currently tracked individually by the provincial aphid monitoring program, which were determined by cytochrome C oxidase I (cox1) sequencing. Through our cox1 DNA barcoding survey, at least 45 species of aphids were discovered in NB potato fields in 2015 and 2016, many of which are known carriers of PVY. PMID- 29474561 TI - PCR-Based Gut Content Analysis to Detect Predation of Eriococcus ironsidei (Hemiptera: Eriococcidae) by Coccinellidae Species in Macadamia Nut Orchards in Hawaii. AB - Macadamia felted coccid, Eriococcus ironsidei (Williams) (Hemiptera: Eriococcidae) was first found infesting macadamia trees in the island of Hawaii in 2005. Macadamia felted coccid infests all above-ground parts of trees to feed and reproduce. Their feeding activity distorts and stunts new growth which causes yellow spotting on older leaves, and when population densities become high, branch dieback occurs. Different predatory beetles have been observed in macadamia nut trees infested by E. ironsidei, the most abundant were Halmus chalybeus, Curinus coeruleus, Scymnodes lividigaster, Rhyzobius forestieri, and Sticholotis ruficeps. To verify predation of E. ironsidei by these beetles, a molecular assay was developed utilizing species-specific primers to determine presence in gut content of predators. Using these primers for PCR analysis, wild predator beetles were screened for the presence of E. ironsidei DNA. Analysis of beetles collected from macadamia orchards revealed predation by H. chalybeus, C. coeruleus, S. lividigaster, R. forestieri, and S. ruficeps on E. ironsidei. This study demonstrates that these beetles may play an important role in controlling the population of E. ironsidei, and these predators may be useful as biocontrol agents for E. ironsidei. PMID- 29474562 TI - Evaluation of Low-Temperature Phosphine Fumigation for Control of Oriental Fruit Fly in Loquat Fruit. AB - Oriental fruit fly, Bactrocera dorsalis (Hendel; Diptera: Tephritidae), is recognized as a quarantine pest and a threat to Chinese loquat (Eriobotrya japonica Lindl.) fruit exports. Since loquat fruit is very sensitive to methyl bromide (MB) fumigation and cold treatment, in this study, low-temperature phosphine (PH3) fumigation was investigated to develop an alternative phytosanitary treatment method. Tolerance tests showed that the third instar was the most tolerant of all life stages of B dorsalis to PH3 gas at 8 degrees C. Toxicity assay with 500-3000 ppm PH3 and subsequent probit analysis showed that 2000 ppm PH3 was optimal for fumigation and 152.75 h of treatment duration were required to achieve 99.9968% mortality. In the verification test, 144 and 168 h of treatment duration with 2000 ppm PH3 completely killed 35,277 and 35,134 B. dorsalis third instars, respectively. However, 13 live larvae were found after 120 h of treatment. Furthermore, these treatments reduced fruit respiration rates while causing no adverse effects on other fruit quality parameters, including firmness, soluble solid content, and titratable acidity over 192 h storage at 8 degrees C. The results strongly suggest that low-temperature PH3 fumigation could be used for the postharvest control of B. dorsalis in loquat fruit. PMID- 29474563 TI - Effects of heat stress during porcine reproductive and respiratory syndrome virus infection on metabolic responses in growing pigs. AB - Heat stress (HS) and immune challenges negatively impact nutrient allocation and metabolism in swine, especially due to elevated heat load. In order to assess the effects of HS during Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) infection on metabolism, 9-wk old crossbred barrows were individually housed, fed ad libitum, divided into four treatments: thermo-neutral (TN), thermo-neutral PRRSV infected (TP), HS, and HS PRRSV infected (HP), and subjected to two experimental phases. Phase 1 occurred in TN conditions (22 degrees C) where half the animals were infected with PRRS virus (n = 12), while the other half (n = 11) remained uninfected. Phase 2 began, after 10 d with half of the uninfected (n = 6) and infected groups (n = 6) transported to heated rooms (35 degrees C) for 3 d of continuous heat, while the rest remained in TN conditions. Blood samples were collected prior to each phase and at trial completion before sacrifice. PPRS viral load indicated only infected animals were infected. Individual rectal temperature (Tr), respiration rates (RR), and feed intakes (FI) were determined daily. Pigs exposed to either challenge had an increased Tr, (P < 0.0001) whereas RR increased (P < 0.0001) with HS, compared to TN. ADG and BW decreased with challenges compared to TN, with the greatest loss to HP pigs. Markers of muscle degradation such as creatine kinase, creatinine, and urea nitrogen were elevated during challenges. Blood glucose levels tended to decrease in HS pigs. HS tended to decrease white blood cell (WBC) and lymphocytes and increase monocytes and eosinophils during HS. However, neutrophils were significantly increased (P < 0.01) during HP. Metabolic flexibility tended to decrease in PRRS infected pigs as well as HS pigs. Fatty acid oxidation measured by CO2 production decreased in HP pigs. Taken together, these data demonstrate the additive effects of the HP challenge compared to either PRRSV or HS alone. PMID- 29474564 TI - Long-term outcomes of total correction for isolated total anomalous pulmonary venous connection: lessons from 50-years' experience. AB - OBJECTIVES: Isolated total anomalous pulmonary venous connection (TAPVC) is a relatively rare congenital cardiac defect, while pulmonary venous obstruction (PVO) is associated with poor prognosis. We reviewed the long-term outcome of total correction for isolated TAPVC at our institute and analysed the risk factors for mortality and morbidity. METHODS: A total of 290 isolated TAPVC patients evaluated between 1965 and 2016 were divided into 2 groups: Group Early (n = 151) underwent surgery before 1989; Group Late (n = 139) underwent surgery after 1990. The mean age at operation was 10.4 +/- 30.2 months (range 0 day to 23 years), and the mean body weight was 5.5 +/- 6.0 kg (range 1.6-48 kg). Group Late included more patients with the infracardiac type of TAPVC and preferably used the posterior approach. RESULTS: There were 53 hospital deaths and 16 late deaths. Postoperative PVO was recognized in 28 patients. The mean follow-up time was 18.2 +/- 9.7 years (range 2 months to 42.4 years). The actuarial survival rate was improved to 87.8% at 20 years in Group Late. Multivariable analysis revealed that death rate was significantly increased in patients of Group Early, with a body weight <2 kg and with postoperative PVO (P < 0.0001, P = 0.0041, P = 0.0003, respectively). Reoperations were performed 27 times in 22 patients (PVO repair, 11; staged repair, 4 and others, 12). PVO repair was performed at a mean of 2.5 +/- 1.6 months later. The actuarial freedom from reoperation rates were 88.8% and 83.2% at 20 and 30 years, respectively. Multivariable analysis revealed that the risk of reoperation was associated with mixed-type TAPVC and postoperative PVO (P = 0.0064 and P < 0.0001, respectively). CONCLUSIONS: Long term surgical outcomes of isolated TAPVC have improved over the past 25 years. Postoperative PVO, the mixed-type TAPVC and a body weight <2 kg might be the important factors contributing to mortality and morbidity. PMID- 29474565 TI - Primary prevention of cardiovascular disease: global cardiovascular risk assessment and management in clinical practice. AB - Aims: For the primary prevention of cardiovascular disease, the Framingham Risk Score (FRS) is the most well-known risk prediction method. However, there are limited data regarding physicians' method of risk assessment and guideline adherence in clinical practice. Methods and results: In the PARADIGM (Primary cARe AuDIt of Global risk Management) study (March 2009-10), 105 primary care physicians across Canada prospectively collected data for 3015 patients (mean age 56 years, 59% men) without known cardiovascular disease, diabetes, or lipid lowering medications at baseline. For each patient, the treating physician determined their cardiovascular risk, and reported the risk stratification method and subsequent treatment decisions. Kappa statistics assessed the agreement between the study-calculated FRS and the treating physician's reported risk assessment. The FRS was the most commonly reported risk assessment method, but was used in only 34.0% of patients. Regardless of the method used (even if the FRS was reportedly used), there was only fair agreement between the risk stratification as reported by the physician and the study-calculated FRS. Moreover, physicians recommended statin initiation in 92% of all patients that they identified as high risk; however, according to the study-calculated FRS, only 56% of the truly high-risk patients were recommended statin therapy. Conclusion: For the primary prevention of cardiovascular disease, these findings indicate a need to improve risk assessment and stratification, as misclassification directly contributes to suboptimal risk factor management in real-world clinical practice. Future studies should establish the optimal risk stratification method with quality improvement strategies for its subsequent implementation. Clinical Trial Registration: http://clinicaltrials.gov/ct2/show/NCT00950703; NCT00950703. PMID- 29474566 TI - Atypical chest pain in diabetic patients with suspected stable angina: impact on diagnosis and coronary outcomes. AB - Aims: Silent myocardial ischaemia occurs commonly in diabetes. Whether altered perception of ischaemia also predisposes to atypical presentations with under diagnosis of coronary disease is not known. To determine whether (i) patients with diabetes diagnosed with angina are more likely to report atypical symptoms compared with patients without diabetes, and (ii) atypical symptoms in patients with diabetes cause angina to go unrecognized, increasing the risk of coronary events. Methods and results: Prospective, multicentre cohort study of 8662 ambulatory patients with suspected angina, of whom 906 had diabetes. We recorded detailed chest pain descriptors and fatal and non-fatal coronary events over a median of 3.08 years of follow-up. Proportionately more patients with than without diabetes received a diagnosis of angina (42.7 vs. 25.1%). Among patients with diabetes diagnosed with angina, a greater proportion had atypical chest pain compared with patients without diabetes (21.0 vs. 11.3%), but the hazard of fatal and non-fatal coronary events was similar. However, among patients diagnosed with non-cardiac chest pain, those with diabetes-most of whom had atypical symptoms remained at greater risk of coronary events [2.29 (95% CI 1.54, 3.41)] and all cause mortality [1.67 (95% confidence interval, CI 1.04, 2.69)] compared with non diabetic patients. Conclusion: Patients with diabetes and atypical symptoms are nearly twice as likely to be diagnosed with angina compared with non-diabetic patients. Those diagnosed with non-cardiac pain are at increased risk of coronary events. Our study emphasizes the need for more intensive investigation of diabetic patients with chest pain, particularly those presenting with atypical symptoms. PMID- 29474567 TI - European Heart Journal - Quality of Care and Clinical Outcomes: a new journal for the 21st century. PMID- 29474568 TI - Big biomedical data and cardiovascular disease research: opportunities and challenges. AB - Electronic health records (EHRs), data generated and collected during normal clinical care, are increasingly being linked and used for translational cardiovascular disease research. Electronic health record data can be structured (e.g. coded diagnoses) or unstructured (e.g. clinical notes) and increasingly encapsulate medical imaging, genomic and patient-generated information. Large scale EHR linkages enable researchers to conduct high-resolution observational and interventional clinical research at an unprecedented scale. A significant amount of preparatory work and research, however, is required to identify, obtain, and transform raw EHR data into research-ready variables that can be statistically analysed. This study critically reviews the opportunities and challenges that EHR data present in the field of cardiovascular disease clinical research and provides a series of recommendations for advancing and facilitating EHR research. PMID- 29474569 TI - Risk prediction (or crystal ball gazing) for coronary disease. PMID- 29474570 TI - Replacing the hypertension control paradigm with a strategy of cardiovascular risk reduction. AB - In this paper we propose replacing the current hypertension control paradigm with a strategy based upon cardiovascular risk management. PMID- 29474571 TI - Filling a gap in the ESC Journal Family: a warm welcome to the EHJ - Quality of Care and Clinical Outcomes. PMID- 29474572 TI - Prediction of residual angina after percutaneous coronary intervention. AB - Aims: Angina relief is a major goal of percutaneous coronary intervention (PCI); however, about one in five patients continue to have angina after PCI. Understanding patient factors associated with residual angina would enable providers to more accurately calibrate patients' expectations of angina relief after PCI, may support different follow-up strategies or approaches to coronary revascularization, and could potentially serve as a marker of PCI quality. Methods and results: Among 2573 patients who had PCI at 10 US hospitals for stable angina, unstable angina, or non-ST-elevation myocardial infarction (NSTEMI), 24% reported angina 6 months after PCI, as assessed with the Seattle Angina Questionnaire angina frequency score (categorized as none vs. any angina; score = 100 vs. <100). Post-PCI angina was more common in those patients treated for unstable angina (30 vs. 20% stable angina and 21% NSTEMI, P < 0.001). Using a hierarchical logistic regression model, eight variables were independently associated with angina after PCI, including younger age, poor economic status, depression, and greater number of antianginal medications at the time of PCI (c index = 0.75). The amount of angina at the time of PCI was more predictive of post-PCI angina in patients with stable or unstable angina when compared with NSTEMI (pinteraction = 0.01). The model demonstrated excellent calibration, both in the original sample (slope 1.04, intercept -0.01, r = 0.98) and in bootstrap validation. Conclusion: Based on a large, multicentre cohort of PCI patients, we created a model of residual angina 6 months after PCI that can provide patients realistic expectations of angina relief, guide follow-up strategies, support the use of residual angina as a means of comparing PCI quality, and enable comparative effectiveness research. PMID- 29474573 TI - i-Clamp phenoxazine for the fine tuning of DNA i-motif stability. AB - Non-canonical DNA structures are widely used for regulation of gene expression, in DNA nanotechnology and for the development of new DNA-based sensors. I-motifs (iMs) are two intercalated parallel duplexes that are held together by hemiprotonated C-C base pairs. Previously, iMs were used as an accurate sensor for intracellular pH measurements. However, iM stability is moderate, which in turn limits its in vivo applications. Here, we report the rational design of a new substituted phenoxazine 2'-deoxynucleotide (i-clamp) for iM stabilization. This residue contains a C8-aminopropyl tether that interacts with the phosphate group within the neighboring chain without compromising base pairing. We studied the influence of i-clamp on pH-dependent stability for intra- and intermolecular iM structures and found the optimal positions for modification. Two i-clamps on opposite strands provide thermal stabilization up to 10-11 degrees C at a pH of 5.8. Thus, we developed a new modification that shows significant iM-stabilizing effect both at strongly and mildly acidic pH and increases iM transition pH values. i-Clamp can be used for tuning iM-based pH probes or assembling extra stable iM structures for various applications. PMID- 29474574 TI - Evidence-based medicine and big genomic data. AB - Genomic and other related big data (Big Genomic Data, BGD for short) are ushering a new era of precision medicine. This overview discusses whether principles of evidence-based medicine hold true for BGD and how they should be operationalized in the current era. Major evidence-based medicine principles include the systematic identification, description and analysis of the validity and utility of BGD, the combination of individual clinical expertise with individual patient needs and preferences, and the focus on obtaining experimental evidence, whenever possible. BGD emphasize information of single patients with an overemphasis on N of-1 trials to personalize treatment. However, large-scale comparative population data remain indispensable for meaningful translation of BGD personalized information. The impact of BGD on population health depends on its ability to affect large segments of the population. While several frameworks have been proposed to facilitate and standardize decision making for use of genomic tests, there are new caveats that arise from BGD that extend beyond the limitations that were applicable for more simple genetic tests. Non-evidence-based use of BGD may be harmful and result in major waste of healthcare resources. Randomized controlled trials will continue to be the strongest arbitrator for the clinical utility of genomic technologies, including BGD. Research on BGD needs to focus not only on finding robust predictive associations (clinical validity) but also more importantly on evaluating the balance of health benefits and potential harms (clinical utility), as well as implementation challenges. Appropriate features of such useful research on BGD are discussed. PMID- 29474576 TI - Lung cancer incidence rates in the world from the Cancer Incidence in Five Continents XI. PMID- 29474575 TI - TDP-43 controls lysosomal pathways thereby determining its own clearance and cytotoxicity. AB - TDP-43 is a nuclear RNA-binding protein whose cytoplasmic accumulation is the pathological hallmark of amyotrophic lateral sclerosis (ALS). For a better understanding of this devastating disorder at the molecular level, it is important to identify cellular pathways involved in the clearance of detrimental TDP-43. Using a yeast model system, we systematically analyzed to which extent TDP-43-triggered cytotoxicity is modulated by conserved lysosomal clearance pathways. We observed that the lysosomal fusion machinery and the endolysosomal pathway, which are crucial for proper lysosomal function, were pivotal for survival of cells exposed to TDP-43. Interestingly, TDP-43 itself interfered with these critical TDP-43 clearance pathways. In contrast, autophagy played a complex role in this process. It contributed to the degradation of TDP-43 in the absence of endolysosomal pathway activity, but its induction also enhanced cell death. Thus, TDP-43 interfered with lysosomal function and its own degradation via lysosomal pathways, and triggered lethal autophagy. We propose that these effects critically contribute to cellular dysfunction in TDP-43 proteinopathies. PMID- 29474577 TI - Primary lymphoma of bone. PMID- 29474578 TI - Determining the Number of Instars in Simulium quinquestriatum (Diptera: Simuliidae) Using k-Means Clustering via the Canberra Distance. AB - Simulium quinquestriatum Shiraki (Diptera: Simuliidae), a human-biting fly that is distributed widely across Asia, is a vector for multiple pathogens. However, the larval development of this species is poorly understood. In this study, we determined the number of instars in this pest using three batches of field collected larvae from Guiyang, Guizhou, China. The postgenal length, head capsule width, mandibular phragma length, and body length of 773 individuals were measured, and k-means clustering was used for instar grouping. Four distance measures-Manhattan, Euclidean, Chebyshev, and Canberra-were determined. The reported instar numbers, ranging from 4 to 11, were set as initial cluster centers for k-means clustering. The Canberra distance yielded reliable instar grouping, which was consistent with the first instar, as characterized by egg bursters and prepupae with dark histoblasts. Females and males of the last cluster of larvae were identified using Feulgen-stained gonads. Morphometric differences between the two sexes were not significant. Validation was performed using the Brooks-Dyar and Crosby rules, revealing that the larval stage of S. quinquestriatum is composed of eight instars. PMID- 29474579 TI - Direct observation of nucleic acid binding dynamics by the telomerase essential N terminal domain. AB - Telomerase is a specialized enzyme that maintains telomere length by adding DNA repeats to chromosome ends. The catalytic protein subunit of telomerase utilizes the integral telomerase RNA to direct telomere DNA synthesis. The telomerase essential N-terminal (TEN) domain is required for enzyme function; however, the precise mechanism of the TEN domain during catalysis is not known. We report a single-molecule study of dynamic TEN-induced conformational changes in its nucleic acid substrates. The TEN domain from the yeast Candida parapsilosis (Cp) exhibits a strong binding preference for double-stranded nucleic acids, with particularly high affinity for an RNA-DNA hybrid mimicking the template-product complex. Surprisingly, the telomere DNA repeat sequence from C. parapsilosis forms a DNA hairpin that also binds CpTEN with high affinity. Mutations to several residues in a putative nucleic acid-binding patch of CpTEN significantly reduced its affinity to the RNA-DNA hybrid and telomere DNA hairpin. Substitution of comparable residues in the related Candida albicans TEN domain caused telomere maintenance defects in vivo and decreased primer extension activity in vitro. Collectively, our results support a working model in which dynamic interactions with telomere DNA and the template-product hybrid underlie the functional requirement for the TEN domain during the telomerase catalytic cycle. PMID- 29474580 TI - Recently Evolved Tumor Suppressor Transcript TP73-AS1 Functions as Sponge of Human-Specific miR-941. AB - MicroRNA (miRNA) sponges are vital components of posttranscriptional gene regulation. Yet, only a limited number of miRNA sponges have been identified. Here, we show that the recently evolved noncoding tumor suppressor transcript, antisense RNA to TP73 gene (TP73-AS1), functions as a natural sponge of human specific miRNA miR-941. We find unusually nine high-affinity miR-941 binding sites clustering within 1 kb region on TP73-AS1, which forms miR-941 sponge region. This sponge region displays increased sequence constraint only in humans, and its formation can be traced to the tandem expansion of a 71-nt-long sequence containing a single miR-941 binding site in old world monkeys. We further confirm TP73-AS1 functions as an efficient miR-941 sponge based on massive transcriptome data analyses, wound-healing assay, and Argonaute protein immunoprecipitation experiments conducted in cell lines. The expression of miR-941 and its sponge correlate inversely across multiple healthy and cancerous tissues, with miR-941 being highly expressed in tumors and preferentially repressing tumor suppressors. Thus, the TP73-AS1 and miR-941 duo represents an unusual case of the extremely rapid evolution of noncoding regulators controlling cell migration, proliferation, and tumorigenesis. PMID- 29474582 TI - Genome-wide relationship between R-loop formation and antisense transcription in Escherichia coli. AB - Transcription termination by Rho is essential for viability in various bacteria, including some major pathogens. Since Rho acts by targeting nascent RNAs that are not simultaneously translated, it also regulates antisense transcription. Here we show that RNase H-deficient mutants of Escherichia coli exhibit heightened sensitivity to the Rho inhibitor bicyclomycin, and that Rho deficiency provokes increased formation of RNA-DNA hybrids (R-loops) which is ameliorated by expression of the phage T4-derived R-loop helicase UvsW. We also provide evidence that in Rho-deficient cells, R-loop formation blocks subsequent rounds of antisense transcription at more than 500 chromosomal loci. Hence these antisense transcripts, which can extend beyond 10 kb in their length, are only detected when Rho function is absent or compromised and the UvsW helicase is concurrently expressed. Thus the potential for antisense transcription in bacteria is much greater than hitherto recognized; and the cells are able to retain viability even when nearly one-quarter of their total non-rRNA abundance is accounted for by antisense transcripts, provided that R-loop formation from them is curtailed. PMID- 29474583 TI - Ochratoxin A, citrinin and deoxynivalenol decrease claudin-2 expression in mouse rectum CMT93-II cells. AB - Intestinal epithelial cells are the first targets of ingested mycotoxins, such as ochratoxin A, citrinin and deoxynivalenol. It has been reported that paracellular permeability regulated by tight junctions is modulated by several mycotoxins by reducing the expression of specific claudins and integral membrane proteins in cell-cell contacts, accompanied by increase in phosphorylation of mitogen activated protein kinases, including extracellular signal-related kinase (ERK) 1/2, p38 and c-Jun NH2-terminal protein kinase. Claudin-2 is expressed in the deep crypt cells, but not in the villus/surface cells in vivo. While Caco-2, T84 and IPEC-J2 cells, which are widely used intestinal epithelial cell lines to assess the influence of mycotoxins, do not express claudin-2, CMT93-II cells express claudin-2. We previously reported that inhibition of the ERK pathway reduced claudin-2 levels in cell-cell contacts in CMT93-II cells. In this study, we examined whether ochratoxin A, citrinin and deoxynivalenol affect claudin-2 expression and ERK1/2 phosphorylation in CMT93-II cells. We found that all mycotoxins reduced claudin-2 expression in cell-cell contacts, with reduction (by citrinin and deoxynivalenol) or no change (by ochratoxin A) in phosphorylated ERK1/2. All mycotoxins increased transepithelial electrical resistance, but did not affect flux of fluorescein. While ochratoxin A and citrinin are known to be nephrotoxic, only deoxynivalenol reduced claudin-2 expression in MDCK II cells derived from the renal tubule. These results suggest that claudin-2 expression is regulated not only by the ERK pathway, but also by other pathways in an organ specific manner. PMID- 29474581 TI - Thermopriming triggers splicing memory in Arabidopsis. AB - Abiotic and biotic stresses limit crop productivity. Exposure to a non-lethal stress, referred to as priming, can allow plants to survive subsequent and otherwise lethal conditions; the priming effect persists even after a prolonged stress-free period. However, the molecular mechanisms underlying priming are not fully understood. Here, we investigated the molecular basis of heat-shock memory and the role of priming in Arabidopsis thaliana. Comprehensive analysis of transcriptome-wide changes in gene expression and alternative splicing in primed and non-primed plants revealed that alternative splicing functions as a novel component of heat-shock memory. We show that priming of plants with a non-lethal heat stress results in de-repression of splicing after a second exposure to heat stress. By contrast, non-primed plants showed significant repression of splicing. These observations link 'splicing memory' to the ability of plants to survive subsequent and otherwise lethal heat stress. This newly discovered priming induced splicing memory may represent a general feature of heat-stress responses in plants and other organisms as many of the key components are conserved among eukaryotes. Furthermore, this finding could facilitate the development of novel approaches to improve plant survival under extreme heat stress. PMID- 29474584 TI - Clinical outcomes in patients with stable coronary artery disease with vs. without a history of myocardial revascularization. AB - Aims: The aim was to describe outcomes among patients with stable coronary artery disease (CAD) with or without a history of myocardial revascularization in a large contemporary cohort. Methods and results: Patients with stable CAD were selected from the Reduction of Atherothrombosis for Continued Health (REACH) registry. The cohort was divided into patients with ( n = 25 583) and without ( n = 13 133) a history of myocardial revascularization. Crude outcomes were described according to the use and type of revascularization: percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG). The primary outcome was cardiovascular (CV) death. At baseline, the non-revascularized group was older and had more CV risk factors. At 36-month median follow-up, previous revascularization was associated with a lower risk of CV death [crude incidence rate (CIR): 6.82 vs. 9.08%, hazard ratio (HR) 0.73 [95% confidence interval (CI) 0.66-0.80]; P < 0.01]. This association was seen for patients with a history of PCI (CIR 5.78 vs. 8.88%, HR 0.64 [0.58-0.71]; P <= 0.01), but not with CABG (HR 1.26 [1.14-1.49]; P < 0.01), and was consistent regardless of prior MI and the timing of prior revascularization. Conclusion: Among patients with stable CAD, a history of myocardial revascularization was associated with lower CV mortality, particularly when PCI was the mode of revascularization. Coronary artery disease patients managed non-invasively represent a high-risk group. PMID- 29474585 TI - The European Society of Cardiology Atlas of Cardiology: rationale, objectives, and methods. AB - The need to develop better policies for increasing the efficiency and effectiveness of cardiac care and for reducing the burden of cardiovascular disease, necessitates the availability of data on the economic, political, and organizational aspects of cardiac care. The European Society of Cardiology has this started collecting such data together with the National Cardiac Societies from across Europe. In particular, descriptive and quantitative data concerning the economy, demographics, socioeconomics, health status, health system, and health policies are gathered for every single member country of the European Society of Cardiology, alongside data concerning the number of cardiac care physicians, hospitals, beds, laboratories, interventions, and reimbursement figures. These data will be helpful in an effort to understand in more depth the dynamics of healthcare systems from a cardiology perspective and to identify trends, disparities, gaps, and best practice models, all of which will be useful for making recommendations to improve decision and policy making concerning the cardiac care field at national and cross national level. PMID- 29474586 TI - Cost-effectiveness of antiplatelet drugs after percutaneous coronary intervention. AB - Aims: Clopidogrel has, for long time, been accepted as the standard treatment for patients who have undergone a percutaneous coronary intervention (PCI). The introduction of prasugrel-and more recently, ticagrelor-has introduced a decision making problem for clinicians and governments worldwide: to use the cheaper clopidogrel or the more effective, and also more expensive prasugrel or ticagrelor. We aim to give helpful contributions to this debate by analysing the cost-effectiveness of clopidogrel, prasugrel, and ticagrelor compared with each other. Methods and results: We modified a previously developed Markov model of cardiac disease progression. In the model, we followed up cohorts of patients who have recently had a PCI until 100 years or death. Possible events are revascularization, bleeding, acute myocardial infarction, and death. Our analysis shows that ticagrelor is cost-effective in 77% of simulations at an incremental cost-effectiveness ratio of ?7700 compared with clopidogrel. Ticagrelor was also cost-effective against prasugrel at a cost-effectiveness ratio of ?7800. Given a Norwegian cost-effectiveness threshold of ?70 000, both comparisons appear to be clearly cost-effective in favour of ticagrelor. Conclusion: Ticagrelor is cost effective compared with both clopidogrel and prasugrel for patients who have undergone a PCI. PMID- 29474587 TI - Impact of additive mitral valve surgery to coronary artery bypass grafting on mortality in patients with coronary artery disease and ischaemic mitral regurgitation: a systematic review and meta-analysis of randomized trials and observational studies. AB - Aims: Treatment of ischaemic mitral regurgitation (IMR) remains controversial. While IMR is associated with worse outcomes, randomized controlled trials (RCTs) and observational studies provided conflicting evidence regarding the benefit of mitral valve replacement (MVR) or repair (MVr) in addition to coronary artery bypass grafting (CABG). We conducted a meta-analysis incorporating data from published RCTs and observational studies comparing CABG vs. CABG + MVR/MVr. Methods and results: We searched PubMed, MEDLINE, Embase, Ovid, and Cochrane for RCTs and observational studies comparing CABG (Group 1) vs. CABG + MVR/MVr (Group 2). Outcome was 30-day and 1-year mortality after surgical intervention. Mantel Haenszel odds ratio (OR) was calculated using random-effects meta-analysis for the outcome. Heterogeneity was assessed by I2 statistics. Four RCTs and 11 observational studies met the inclusion criteria (5781 patients, 507 in RCTs, 5274 in observational studies). Group 1 vs. 2 weighted mean left ventricular ejection fraction in RCTs and combined RCTs/observational studies was 41.5 +/- 12.3 vs. 40.3 +/- 10.4% ( P -value = 0.24) and 45.5 +/- 7.2 vs. 38 +/- 10% ( P value < 0.001), respectively. In RCTs, there was no difference in 30-day [OR: 0.95, 95% confidence interval (95% CI): 0.30-3.08, P = 0.94] or 1-year (OR: 0.90, 95% CI: 0.43-1.87, P = 0.78) mortality, respectively. For combined RCTs/observational studies, there was no difference in mortality at 30 days (OR: 0.67, 95% CI: 0.43-1.04, P = 0.08) or at 1 year (OR: 0.90, 95% CI: 0.7-1.15, P = 0.39). Conclusion: In a meta-analysis of RCTs and observational studies of IMR patients, the addition of MVR/MVr to CABG did not improve survival. PMID- 29474588 TI - Reperfusion therapy for ST-elevation acute myocardial infarction in Eastern Europe: the ISACS-TC registry. AB - Aims: Widespread availability of tertiary hospitals with catheterization facilities, although vigorously promoted, has yet to become a reality in many countries with economy in transition. We sought to evaluate the clinical profile and mortality of patients who were hospitalized with a diagnosis of ST-segment elevation myocardial infarction (STEMI) and either received reperfusion therapy or remained without reperfusion in Eastern Europe. Methods and results: Data were obtained from the International Survey of Acute Coronary Syndromes in Transitional Countries (ISACS-TC; NCT01218776) on STEMI patients admitted to 57 hospitals in Eastern European countries from January 2010 to February 2015. The primary endpoint was 30-day mortality. Of 7982 patients, 65 (0.8%) had a documented contraindication to reperfusion, 5973 (75.5%) received fibrinolysis ( n = 1032) or underwent primary percutaneous coronary intervention (p-PCI; n = 4941), and 1944 patients (24.6%) did not receive any reperfusion therapy. The overall unadjusted 30-day mortality rate was 7.9%. Thirty-day mortality rates were higher in non-reperfusion patients (16.0 vs. 5.0% in the p-PCI group and 7.4% in fibrinolysis group). The strongest factors associated with not attempting reperfusion therapy among these patients were female sex (OR 1.29 CI 1.07-1.56), age (OR 1.02; CI 1.01-1.03), prior MI (OR 1.79; CI 1.38-2.32), prior cerebrovascular events (OR 1.87; CI 1.30-2.68), chronic kidney disease (OR 1.76; CI 1.22-2.53), Killip class >1 (OR 1.31; CI 1.06-1.62), and time to admission >12 h (OR 15.9; CI 13.1-19.3). Conclusions: A substantial number of patients are still not offered any reperfusion therapy in many Eastern European countries with economy in transition, and this was associated with increased 30-day mortality. Time from symptoms onset to admission >12 h was the highest ranking among factors related to lack of reperfusion therapy. Quality improvement efforts should focus on minimizing delay to hospital admission among STEMI patients. PMID- 29474589 TI - Prognostic impact of percutaneous coronary intervention in stable coronary disease. PMID- 29474590 TI - Impact of operator volume for percutaneous coronary intervention on clinical outcomes: what do the numbers say? AB - The impact of operator and centre volume on clinical outcomes and quality of care has been of considerable debate in recent years in a number of surgical- and procedural-based specialities. A relationship between higher volumes at both the institutional and operator levels and better clinical outcomes would at first appear intuitive, based on the premise that performing a procedure very infrequently would be likely to lead to unfamiliarity, complications, and poorer outcomes. In the current review, we study the relationship between operator volume and outcomes in the setting of percutaneous coronary intervention (PCI), and examine the evidence for current clinical competency guidelines that advocate that a minimum number of PCI procedures be undertaken annually. Whilst both high institutional and operator volumes have been shown to be associated with better outcomes by reducing death and in-hospital mortality, these data are often derived from the pre-stent era, or when high-volume operators undertook far smaller numbers of procedures than is currently recommended to maintain clinical competency. The emphasis of specific volume requirements for optimal outcomes needs to be interpreted with caution, as volume is not a surrogate for quality and merely one of the variables associated with outcome. Healthcare providers should focus on other measures of quality such as robust clinical care pathways, evidence-based treatments, periodic case review, using validated risk assessment scores, and ascertainment of outcome to improve care and reduce adverse events. PMID- 29474591 TI - Inequalities in reperfusion therapy for STEMI. PMID- 29474592 TI - Sixty-day readmission rate after percutaneous coronary intervention: predictors and impact on long-term outcomes. AB - Aims: Thirty-day readmission rate after percutaneous coronary intervention (PCI) is used as an index of quality of care, but the complete recovery from any myocardial damage needs 8 weeks. We evaluated the readmission rate 60 days after PCI, defined its predictors, and investigated its relationship with long-term prognosis. Methods and results: All consecutive patients undergoing PCI in a large volume hospital were enrolled, and their outcomes were explored using an institutional database. The primary outcome was unplanned 60-day readmission. A composite of major adverse cardiovascular events (MACEs) including all-cause death, myocardial infarction, and repeated revascularization were the secondary endpoints. Among the 1193 enrolled patients, 71 (6.0%) underwent unplanned 60-day readmission for unstable angina (35.3%), chest pain (21.1%), heart failure (14.1%), and acute myocardial infarction (11.3%); 40.8% patients underwent repeated PCI. Readmitted patients carried more frequently left main disease (16.9 vs. 8.3%, P = 0.001), proximal left descending artery disease (31.0 vs. 27.4%, P = 0.03), and bifurcation disease (26.8 vs. 20.5%, P = 0.03). The only predictor of readmission was left main disease. After a mean follow-up of 743 +/- 334 days, patients with 60-day readmission experienced higher rates of all-cause death (8.5 vs. 3.8%, P = 0.05). General baseline conditions and multivessel disease, but not 60-day readmissions, were predictors of MACE and death at follow-up. Conclusion: Unplanned 60-day readmissions after PCI are mainly related to the extent of coronary artery disease, being associated with left main, proximal left descending artery, and bifurcation disease. Readmissions are associated with higher long-term all-cause mortality. PMID- 29474593 TI - The importance of structures and processes in determining outcomes for abdominal aortic aneurysm repair: an international perspective. AB - Annual procedural mortality reports have become mandatory for vascular surgery in England, reflecting a more widespread appetite for transparency and accountability across the National Health Service (NHS) [BMJ 2013;346:f854]. The outcomes of abdominal aortic aneurysm (AAA) repair, in particular, have attracted considerable commentary: from 1999 to 2006, postoperative mortality was higher in England than in many other countries (7.9 vs. 1.9-4.5%) [European Society for Vascular Surgery. 2nd Vascunet Report. 2008]. This stimulated considerable service reconfiguration (centralization), quality improvement initiatives, the uptake of endovascular technology, and the examination of institution-level mortality data [http://www.vascularsociety.org.uk/library/quality improvement.html], which resulted in a fall in elective AAA mortality to 1.8% by 2012 [http://www.hqip.org.uk/assets/NCAPOP-Library/NCAPOP-2013-2014/Outcomes after-Elective-Repair-of-Infra-renal-Abdominal-Aortic-Aneurysm.pdf (February 2015)]. Despite improvements at a national level, the outcomes of AAA repair vary considerably between different hospitals in the NHS [Circ Cardiovasc Qual Outcomes 2014;7:131-141], analogous to interprovider variation that has been reported across a range of emergency medical and surgical conditions [BMC Health Serv Res 2014;14:270]. This suggests that underlying institution structures and processes contribute independently to patients' outcomes. There is also considerable evidence that the outcomes of AAA repair vary in different healthcare systems, both in the elective European Society for Vascular Surgery, 2008 and emergency settings. A consideration of the role of structures and processes in influencing outcomes for AAA repair can be conducted across different institutions or even different healthcare systems. This can help identify which factors are consistently associated with the best outcomes, informing efforts to better organize and deliver services for patients requiring vascular surgery. PMID- 29474594 TI - Use of relative survival to evaluate non-ST-elevation myocardial infarction quality of care and clinical outcomes. AB - Survival after non-ST-elevation myocardial infarction (NSTEMI) is high and non cardiovascular death has become more frequent. Observational studies typically quantify quality of care and clinical outcomes using all-cause mortality, which nowadays may not reflect the impact of index NSTEMI. We review and investigate relative survival for quantifying longer term outcomes after NSTEMI. National cohort study of hospitalized NSTEMI (Myocardial Ischaemia National Audit Project; patients: n = 346 546, hospitals: n = 243, countries: England and Wales). Mortality rates derived from two relative survival techniques were compared with all-cause mortality, and the impact of relative survival adjusted patient characteristics compared with those from Cox proportional estimates. Cox proportional hazards models provide lower survival estimates because they include deaths from all causes, overestimate the impact of increasing age on survival, and underestimate temporal improvements in care. The Royston-Parmar model allows more accurate estimation of relative survival because it is flexible to the high early hazard of death after hospitalized NSTEMI. All-cause mortality gives an overall assessment of survival for a cohort of patients. Relative survival provides a more accurate and informed estimation of the impact of an index cardiovascular event and, if necessary, patient characteristics on survival. PMID- 29474595 TI - Timely publication and sharing of trial data: opportunities and challenges for comparative effectiveness research in cardiovascular disease. AB - There is growing enthusiasm for the timely publication and sharing of clinical trial data. The rationale for open access includes greater transparency, reproducibility, and efficiency of the research enterprise. In cardiovascular diseases, routinely sharing clinical trial data would create opportunities for undertaking comparative effectiveness research, providing much needed evidence on how different interventions compare to each other on key outcomes. Access to individual patient-level data would strengthen the validity of such research. Novel methodological approaches like network meta-analyses using individual patient-level data could reliably compare interventions that have not been compared with each other in head-to-head trials. However, there are significant practical, methodological, financial, and legal challenges to this utopian open access that need to be continually addressed. Sharing clinical trial data openly will only occur when the previously tolerated process of clinical research involving direct ownership and secrecy is abandoned for a new culture in which medical science is open to all of its stakeholders. With this new culture, data will be accessible, reanalysis will be considered commonplace, and comparative effectiveness research through novel synthesis approaches, such as network meta analyses, can thrive-as long as measures are taken to adequately ensure the goal remains to promote public health. PMID- 29474596 TI - A user-centred home monitoring and self-management system for patients with heart failure: a multicentre cohort study. AB - Aims: Previous generations of home monitoring systems have had limited usability. We aimed to develop and evaluate a user-centred and adaptive system for health monitoring and self-management support in patients with heart failure. Methods and results: Patients with heart failure were recruited from three UK centres and provided with Internet-enabled tablet computers that were wirelessly linked with sensor devices for blood pressure, heart rate, and weight monitoring. Patient observations, interviews, and concurrent analyses of the automatically collected data from their monitoring devices were used to increase the usability of the system. Of the 52 participants (median age 77 years, median follow-up 6 months [interquartile range, IQR, 3.6-9.2]), 24 (46%) had no, or very limited prior, experience with digital technologies. It took participants about 1.5 min to complete the daily monitoring tasks, and the rate of failed attempts in completing tasks was <5%. After 45 weeks of observation, participants still used the system on 4.5 days per week (confidence interval 3.2-5.7 days). Of the 46 patients who could complete the final survey, 93% considered the monitoring system as easy to use and 38% asked to keep the system for self-management support after the study was completed. Conclusion: We developed a user-centred home monitoring system that enabled a wide range of heart failure patients, with differing degrees of IT literacy, to monitor their health status regularly. Despite no active medical intervention, patients felt that they benefited from the reassurance and sense of connectivity that the monitoring system provided. PMID- 29474597 TI - Incidence and outcome of first myocardial infarction according to gender and age in Denmark over a 35-year period (1978-2012). AB - Aims: To examine temporal changes in incidence and 1-year mortality of first myocardial infarction (MI) in different age groups for both genders in Denmark over a 35-year period (1978-2012). Methods and results: Patients aged 30 years or older admitted with first MI in Denmark from 1978 to 2012 were included (n = 316 790). Overall, first MI incidence per 100 000 person-years (/105 p.y.) decreased significantly from 500 to 297/105 p.y. for males and from 229 to 156/105 p.y. for females. The decline was greatest among men aged 70-79 from 1460 to 643/105 p.y. (-56%). The majority of age groups also experienced declining incidence. However, men aged 30-39 and >=90 years as well as females aged 30-49 and >=90 years had increasing incidence during the study period. Moreover, the incidence decreased from 1978 to 1996 among males aged 40-49 and females aged 50-59 years, but increased in the remainder of the study period. One-year case-fatality declined significantly from 50 to 9% of MI male patients, and from 53 to 15% of MI female patients when comparing 1978 to 2012. Statistical analysis with Poisson models demonstrated that the mortality rate increased with age and decreased with time and indicated no significant difference between genders. Conclusions: During the period from 1978 to 2012, there was a significant decline in MI incidence among most age groups for both genders; however, an incidence increase was observed in men under 50 and women under 60 years, and >=90 years for both genders. One-year case-fatality decreased constantly during the study period. PMID- 29474598 TI - Remote monitoring in heart failure. PMID- 29474599 TI - Open access data sharing from clinical trials: is it really feasible? PMID- 29474600 TI - Readmission after percutaneous coronary intervention: an important clinical outcome?-60-day readmission rate after percutaneous coronary intervention: predictors and impact on long-term outcomes. PMID- 29474601 TI - RADpainter and fineRADstructure: Population Inference from RADseq Data. AB - Powerful approaches to inferring recent or current population structure based on nearest neighbor haplotype "coancestry" have so far been inaccessible to users without high quality genome-wide haplotype data. With a boom in nonmodel organism genomics, there is a pressing need to bring these methods to communities without access to such data. Here, we present RADpainter, a new program designed to infer the coancestry matrix from restriction-site-associated DNA sequencing (RADseq) data. We combine this program together with a previously published MCMC clustering algorithm into fineRADstructure-a complete, easy to use, and fast population inference package for RADseq data (https://github.com/millanek/fineRADstructure; last accessed February 24, 2018). Finally, with two example data sets, we illustrate its use, benefits, and robustness to missing RAD alleles in double digest RAD sequencing. PMID- 29474603 TI - Francois M Abboud MD. PMID- 29474602 TI - Prospective cohort studies of beta-trace protein and mortality in haemodialysis patients and patients undergoing coronary angiography. AB - Background: Beta-trace protein (BTP) is a low-molecular-weight glycoprotein, which may serve as an endogenous biomarker of kidney function and cardiovascular risk. Methods: We examined cardiovascular and all-cause mortality according to BTP concentrations in 2962 individuals referred for coronary angiography from the Ludwigshafen Risk and Cardiovascular Health study and in 907 patients with Type 2 diabetes mellitus undergoing haemodialysis from the German Diabetes and Dialysis (4D) study. Results: Haemodialysis patients had considerably higher median (interquartile range) BTP concentrations [6.00 (4.49-7.96) mg/L] and experienced a 4-fold increased mortality rate compared with coronary angiography patients [BTP concentration: 0.55 (0.44-0.67) mg/L]. After adjustment for age, sex, cardiovascular risk factors and creatinine, 4D patients in the highest quartile (>7.96 mg/L) had a 1.6-fold increased rate of all-cause mortality [hazard ratio (HR) 1.62, 95% confidence interval (CI) 1.19-2.20] compared with the lowest quartile (<4.49 mg/L) (P = 0.002) In patients undergoing coronary angiography, the adjusted HRs (95% CI) for all-cause and cardiovascular mortality were 1.23 (1.0-1.51) and 1.27 (0.99-1.63) in the highest (>0.67 mg/L) compared with the lowest (<0.44 mg/L) quartile (P = 0.043 and 0.062). In both cohorts, the BTP/creatinine ratio was a stronger predictor of all-cause and cardiovascular mortality compared with BTP. Conclusion: BTP was associated with all-cause mortality independently of renal function in haemodialysis patients. The BTP/creatinine ratio was more predictive for all-cause and cardiovascular mortality in haemodialysis patients and individuals referred for angiography compared with BTP as single marker. PMID- 29474604 TI - Cardiology Update London 2017, I. PMID- 29474605 TI - Cardiology Update London 2017, II. PMID- 29474606 TI - The Virtual University. PMID- 29474607 TI - ?6.5 million award to study impact of ECMO on myocardial infarction patients. PMID- 29474608 TI - Cutting edge research on transcatheter aortic valve implantation: moving indications, complications, and current outcomes. PMID- 29474609 TI - Prognostic value of high sensitivity troponin T after ST-segment elevation myocardial infarction in the era of cardiac magnetic resonance imaging. AB - Aims: To determine if high sensitivity troponin T (hs-TnT) measurements performed during the 'plateau phase' of troponin release (>=48 h) following ST-segment elevation myocardial infarction (STEMI) can predict major adverse cardiovascular endpoints (MACE), and to evaluate its prognostic value compared with cardiac magnetic resonance imaging (CMRI) parameters. Methods and results: We prospectively recruited 201 first presentation STEMI patients. Serial hs-TnT levels were measured at admission, peak (highest), 24, 48 and 72 h. CMRI and transthoracic echocardiography were performed (4 days median) post-STEMI, evaluating infarct scar characteristics and left ventricular ejection fraction (LVEF). Associations were determined between hs-TnT levels and CMRI parameters early after STEMI with MACE (comprising mortality, re-infarction, new or worsening of heart failure, cerebrovascular accident, and sustained ventricular arrhythmias) at medium-term follow-up. After 602 days (median), 33 (17%) patients had MACE. Upper tertile hs-TnT levels at 48 and 72 h were associated with MACE (Kaplan-Meier P = 0.002 and P = 0.012, respectively). Multivariate Cox analyses, incorporating diabetes, CMRI scar size, LVEF and hs-TnT levels (applied at a single hs-TnT time point) showed that 48 and 72 h hs-TnT levels were independent predictors for MACE (HR = 1.20, P = 0.002, and HR = 1.21, P = 0.035 respectively). Conclusion: Measurement of hs-TnT in the plateau phase after STEMI is an inexpensive method of prognostic risk assessment. PMID- 29474610 TI - Functional performance and quality of life in high-risk comorbid patients undergoing transcatheter aortic valve implantation for symptomatic aortic valve stenosis. AB - Aims: We assessed the impact of transcatheter aortic valve implantation (TAVI) on functional performance and quality of life (QoL) in a high-risk patient population with multiple comorbidities. Methods and results: Between January 2009 and December 2014, 145 high-risk patients (EuroSCORE II 7.3% [4.9; 14.9]) with severe symptomatic aortic valve stenosis (AS) underwent TAVI in a single centre. We prospectively evaluated New York Heart Association (NYHA) functional class, 6 minute walking distance (6MWD), and QoL using the validated Dutch version of the EuroQol-5D (EQ-5D) descriptive assessment and a visual analogue scale (EQ-VAS) at baseline, 30 days, as well as 6, 12, and 24 months after TAVI. All patients were eligible for analysis. New York Heart Association functional class improved significantly at 30-day, 6-, 12-, and 24-month follow-up (P < 0.001 for all). The absolute 6MWD improved significantly at 30 days (+19.3 +/- 8.2 m; P= 0.0499) and at 6 months (+23.3 +/- 8.1 m; P = 0.0194). A favourable trend was maintained at 12 months (+17.1 +/- 8.8 m; P = 0.1879), whereas at 24 months 6MWD was similar to baseline values. No significant change in the descriptive assessment of QoL (EQ5D) was observed, whereas the EQ-VAS showed a significant improvement in QoL up to 24 months (P < 0.0180 for all time-points). Conclusion: In high-risk comorbid patients with symptomatic AS, TAVI results in a significant but temporary improvement of functional performance when assessed with objective measures of 6MWD but not of EQ-5D. Moreover, TAVI has a significant and sustained impact on subjective well-being and exercise capacity assessed with the EQ-VAS and NYHA score. PMID- 29474612 TI - Quality of life after transcatheter aortic valve implantation: the need for more a complete appraisal. PMID- 29474611 TI - Cost-effectiveness of functional cardiac imaging in the diagnostic work-up of coronary heart disease. AB - Aims: The aim of this study was to assess the cost-effectiveness of eight common diagnostic work-up strategies for coronary heart disease (CHD) in patients with stable angina symptoms in Switzerland. Methods and results: A decision analytical model was used to perform a cost-effectiveness comparison of eight common multitest strategies to diagnose CHD using combinations of four diagnostic techniques: exercise treadmill test (ETT), single-photon emission computed tomography (SPECT), cardiac magnetic resonance imaging (CMR), and coronary angiography (CA). We used a Markov state transition model to extrapolate the results over a life-time horizon, from a third-party payer perspective. We used a CHD prevalence rate of 39% in patients and a base-case scenario with 60-year-old male patients with intermediate symptom severity Canadian Cardiovascular Society grading of angina pectoris 2 and at least one cardiovascular (CV) risk factor but without a history of myocardial infarction and without need for revascularization. Among the eight work-up strategies, one strategy was dominant, i.e. least costly and most effective: ETT followed by CMR if the ETT result was inconclusive and then CA if the CMR result was positive or inconclusive. The CMR features a favourable balance between false-negative diagnoses, associated with an elevated risk of CV events, and false-positive diagnoses, leading to unnecessary CA and related mortality. Key parameters guiding the diagnostic strategy are the prevalence of CHD in patients with angina symptoms and the diagnostic costs of CA and CMR. Conclusion: Cardiac magnetic resonance imaging appears to be a cost-effective work-up strategy compared with other regimens using SPECT or direct CA. Cardiac magnetic resonance imaging should be more widely recommended as a diagnostic procedure for patients with suspected angina symptoms. PMID- 29474613 TI - Measuring health-related quality of life in cardiac patients. PMID- 29474614 TI - Stable coronary disease: Cinderella must go to the ball. PMID- 29474615 TI - Factors related to outcome in heart failure with a preserved (or normal) left ventricular ejection fraction. AB - Heart failure with a preserved ejection faction (HFpEF) is a growing and expensive cause of heart failure (HF) affecting particularly the elderly. It differs in substantial ways in addition to the normal left ventricular ejection fraction, from the more easily recognized form of heart failure with a reduced ejection fraction (HFrEF or 'systolic heart failure') and unlike HFrEF there have been little advances in treatment. In part, this relates to the complexity of the pathophysiology and identifying the correct targets. In HFpEF, there appears to be widespread stiffening of the vasculature and the myocardium affecting ventricular function (both systolic and diastolic), impeding ventricular suction, and thus early diastolic filling leading to breathlessness on exertion and later atrial failure and fibrillation. Left ventricular ejection fraction tends to gradually decline and some evolve into HFrEF. Most patients also have a mixture of several co-morbidities including hypertension, diabetes, obesity, poor renal function, lack of fitness, and often poor social conditions. Therefore, many factors may influence outcome in an individual patient. In this review, the epidemiology, possible causation, pathophysiology, the influence of co morbidities and some of the many potential predictors of outcome will be considered. PMID- 29474616 TI - Big data: a new look at old problems. PMID- 29474618 TI - Assessing risk following ST-segment elevation myocardial infarction: cardiac troponin or cardiac magnetic resonance imaging? PMID- 29474617 TI - Using big data from health records from four countries to evaluate chronic disease outcomes: a study in 114 364 survivors of myocardial infarction. AB - Aims: To assess the international validity of using hospital record data to compare long-term outcomes in heart attack survivors. Methods and results: We used samples of national, ongoing, unselected record sources to assess three outcomes: cause death; a composite of myocardial infarction (MI), stroke, and all cause death; and hospitalized bleeding. Patients aged 65 years and older entered the study 1 year following the most recent discharge for acute MI in 2002-11 [n = 54 841 (Sweden), 53 909 (USA), 4653 (England), and 961 (France)]. Across each of the four countries, we found consistent associations with 12 baseline prognostic factors and each of the three outcomes. In each country, we observed high 3-year crude cumulative risks of all-cause death (from 19.6% [England] to 30.2% [USA]); the composite of MI, stroke, or death [from 26.0% (France) to 36.2% (USA)]; and hospitalized bleeding [from 3.1% (France) to 5.3% (USA)]. After adjustments for baseline risk factors, risks were similar across all countries [relative risks (RRs) compared with Sweden not statistically significant], but higher in the USA for all-cause death [RR USA vs. Sweden, 1.14 (95% confidence interval 1.04-1.26)] and hospitalized bleeding [RR USA vs. Sweden, 1.54 (1.21-1.96)]. Conclusion: The validity of using hospital record data is supported by the consistency of estimates across four countries of a high adjusted risk of death, further MI, and stroke in the chronic phase after MI. The possibility that adjusted risks of mortality and bleeding are higher in the USA warrants further study. PMID- 29474619 TI - Coordinated regional care of myocardial infarction in a rural area in Brazil: Minas Telecardio Project 2. AB - Aims: In Brazil, there are considerable disparities in access to healthcare. The aim of this study was to assess how implementation of a coordinated regional management protocol for patients with ST-elevation myocardial infarction (STEMI) affected quality of care and outcomes in a rural and deprived Brazilian region with considerable social inequalities. Methods and results: The quality of care and outcomes of STEMI was evaluated in two cohorts before (n = 214) and after (n = 143) implementation of the coordinated regional management protocol. Central to this protocol was a tablet-based digital electrocardiogram (ECG) recording in the emergency ambulance that was transmitted for analysis by trained professionals. If the pre-hospital ECG was diagnostic, it triggered a management cascade involving a direct transfer to the regional intervention centre with reperfusion by primary percutaneous coronary intervention (PPCI) or pre-hospital fibrinolysis for anticipated journey times of less than or greater than 2 h, respectively. Following implementation of the protocol, the adjusted medical delay (system delay - transport time) decreased by 40% (95% confidence intervals: -66%, -13%). The proportion of patients who received reperfusion therapy increased from 70.6 to 80.8% (P = 0.045), with increases in treatment with aspirin [94.2-100% (P = 0.003)] and P2Y12 inhibitors [87.5-100% (P < 0.001)]. The odds of in-hospital death showed a non-significant decrease [odds ratio 0.73 (95% confidence intervals: 0.34-1.60)]. Conclusion: The implementation of a coordinated regional management protocol for patients with STEMI led to marked improvements in the quality of care in a remote Brazilian region with limited resources. PMID- 29474620 TI - A conserved leucine zipper-like motif accounts for strong tetramerization capabilities of SEPALLATA-like MADS-domain transcription factors. AB - The development of angiosperm flowers is regulated by homeotic MIKC-type MADS domain transcription factors that activate or repress target genes via the formation of DNA-bound, organ-specific tetrameric complexes. The protein-protein interaction (PPI) capabilities differ considerably between different MIKC-type proteins. In Arabidopsis thaliana the floral homeotic protein SEPALLATA3 (SEP3) acts as a hub that incorporates numerous other MADS-domain proteins into tetrameric complexes that would otherwise not form. However, the molecular mechanisms that underlie these promiscuous interactions remain largely unknown. In this study, we created a collection of amino acid substitution mutants of SEP3 to quantify the contribution of individual residues on protein tetramerization during DNA-binding, employing methods of molecular biophysics. We show that leucine residues at certain key positions form a leucine-zipper structure that is essential for tetramerization of SEP3, whereas the introduction of physicochemically very similar residues at respective sites impedes the formation of DNA-bound tetramers. Comprehensive molecular evolutionary analyses of MADS domain proteins from a diverse set of flowering plants revealed exceedingly high conservation of the identified leucine residues within SEP3-subfamily proteins throughout angiosperm evolution. In contrast, MADS-domain proteins that are unable to tetramerize among themselves exhibit preferences for other amino acids at homologous sites. Our findings indicate that the subfamily-specific conservation of amino acid residues at just a few key positions accounts for subfamily-specific interaction capabilities of MADS-domain transcription factors and this has shaped the present-day structure of the PPI network controlling flower development. PMID- 29474621 TI - The incidence and relevance of site-reported vs. patient-reported angina: insights from the ABSORB II randomized trial comparing Absorb everolimus-eluting bioresorbable scaffold with XIENCE everolimus-eluting metallic stent. AB - Aims: In the ABSORB II trial, comparing AbsorbTM bioresorbable vascular scaffold with metallic XIENCETM everolimus-eluting stent (EES), a difference was found in site-reported new or worsening angina using adverse event (AE) reporting. However, the clinical relevance of this site-reported angina is unclear. The aim of the present study was therefore to investigate the clinical relevance of site reported angina by evaluating its relation with cardiac endpoints, cardiovascular resource utilization (including diagnostics and treatment), positive exercise stress tolerance tests (ETTs), and Seattle Angina Questionnaire (SAQ). Methods and results: Site-reported new or worsening angina was captured on cardiac AE forms. There was a wide variation in the total number of days with site-reported angina (overall interquartile range 35-279 days). Patients with site-reported angina showed higher rates of cardiovascular events [including the patient oriented composite endpoint of all deaths, all myocardial infarctions (MI), or all revascularizations (21.1 vs. 4.2%, P < 0.0001), all MIs (2.3 vs. 0%, P = 0.03), and all revascularizations (21.1 vs. 0.7%, P < 0.0001)], cardiovascular resource utilization (including stress tests, anti-anginal medication, diagnostic angiographies, and hospitalization), and positive ETTs (51.9 vs. 14.9%, P < 0.001), compared with those without site-reported angina. Furthermore, an event based analysis of the SAQ showed that patients with ongoing angina within the recall period of 4 weeks prior to the SAQ assessment have clinically and statistically significant decrements of >14 points in SAQ scores compared with those with no reported angina. Conclusions: We showed that the site-reported angina through AE reporting may be clinically relevant because of their relation with cardiovascular events (mostly repeat revascularizations), cardiovascular resource utilization, ETT, and SAQ. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT01425281; Unique identifier: NCT01425281. PMID- 29474622 TI - How should CT coronary angiography be integrated into the management of patients with chest pain and how does this affect outcomes? AB - When examining the role of a diagnostic test in clinical practice, consideration must be placed not only on the accuracy of the result, but also its impact on patient care and outcomes. Proving a direct effect on outcomes may be difficult because the impact of the diagnostic test largely depends on the clinician's interpretation and consequent actions as well as the patient's response to changes in their diagnosis, investigations, and treatment. Recent major clinical trials of symptomatic patients with suspected coronary heart disease (CHD) have shown that computed tomography coronary angiography (CTCA) can markedly clarify the diagnosis and lead to major changes in patient investigation and management including the use of invasive angiography, preventative therapies, and coronary revascularization. Thus, when added to our existing clinical tools, such as exercise electrocardiography, CTCA represents a powerful method of identifying and excluding CHD. Furthermore, it can identify patients with prognostically relevant non-obstructive CHD and, with recent technological advances, will be able to assess the functional impact of anatomically detected coronary artery stenoses. Overall, the routine integration of CTCA into the investigation of patients with chest pain improves clinical diagnostic certainty that has led to better targeting of investigations and evidence-based treatments that have ultimately translated into improved clinical outcomes. PMID- 29474623 TI - Underrepresentation of sex in reporting traditional and emerging biomarkers for primary prevention of cardiovascular disease: a systematic review. AB - Background: Primary prevention of cardiovascular disease (CVD) relies on the identification of individuals at increased risk of developing cardiovascular events. Circulating biomarkers mirroring the (subclinical) disease process are valuable tools for CVD risk prediction. Evidence is accumulating that the clinical presentation and mechanisms for CVD differ between men and women. A systematic review of sex-specific data was performed on biomarker levels and their association with CVD in primary prevention in order to investigate the availability of sex-specific data and to explore for any differences in the associations between men and women. Methods and results: PubMed MEDLINE and Embase were searched on 2 February 2014 and updated on 15 January 2015. Biomarkers included represented pathophysiological pathways of lipids, inflammation, kidney function, and of the heart. Data on patient characteristics, sex-specific biomarker levels, biomarker association with future CVD events and clinical value were extracted. Only 54 studies of 360 publications provided sex specific information. Most of the remaining 306 publications not providing sex specific results only corrected for sex in multivariable models. The additional clinical utility of biomarkers was reported in seven publications, one of which was stratified by sex. Conclusion: Sex-specific data on biomarkers for CVD in the general population exist, but it is underreported. There is inconsistency in sex specific differences in levels of traditional biomarkers and in their relation to CVD. To improve personalized cardiovascular diagnoses and care for men and women, reporting sex-specific data on clinical utility of biomarkers is crucial and should be encouraged in publications of sufficiently powered studies. PMID- 29474624 TI - Renal function is associated with long-term outcomes independent of degree of atherosclerosis: 6-year data from the Swedish Coronary Angiography and Angioplasty Registry. AB - Aims: To study the association between renal function and outcomes in a nationwide cohort of unselected consecutive patients with stable coronary artery disease (SCAD) symptoms and with a defined coronary anatomy by a coronary angiogram (CA). Methods and results: We included 45 348 consecutive patients with available plasma creatinine undergoing CA for suspected SCAD from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). We adjusted for clinical background, severity of CAD and subsequent revascularization in a Cox regression analysis. Patients were followed for a median (interquartile range) time of 2.6 (1.2-4.1) years. The 3-year cumulative probability of death, myocardial infarction (MI), heart failure, and stroke increased from 2.7, 4.6, 4.4, and 2.0% in patients with estimated glomerular function (eGFR) >90 to 39.8, 32.8, 30.2, and 6.2% in patients with eGFR <15. Compared with patients with eGFR > 90 mL/min/m2, patients with impaired renal function (eGFR 30-59, 15-29, and <15 mL/min/m2) had significantly higher risk of death (HR (95%CI): 1.3 (1.1-1.5), 2.2 (1.6-2.9), 7.7 (6.1-9.8)), MI (1.3 (1.1-1.5), 1.8 (1.4-2.5), 4.0 (3.1-5.1)), and heart failure (1.7 (1.5-1.9), 2.5 (1.9-3.1), 2.4 (1.8-3.2)), but not of stroke (1.1 (0.9-1.3), 1.1 (0.6-1.7), 1.4 (0.7-2.5)) after multivariable adjustment. For patients with eGFR 60-89, there was no significant difference in the risk of death, MI or stroke but increased risk of heart failure 1.2 (1.1-1.3). Conclusion: Impaired renal function is strongly associated with worse outcome in patients with SCAD and known coronary anatomy. The associations were independent of traditional cardio vascular disease risk factors, comorbidities, coronary artery obstruction severity, and subsequent revascularization. PMID- 29474625 TI - Post-percutaneous coronary intervention angina in stable coronary artery disease. PMID- 29474626 TI - Natural history of patients with insignificant coronary artery disease. AB - Aims: Approximately 30% of patients undergoing coronary angiography for chest pain have insignificant coronary artery disease (ICAD). The subsequent health status of these patients is largely unknown. The current study was a cross sectional, longitudinal comparison of health status outcomes 12 months following angiography, in a cohort of patients with stable chest pain and ICAD to: (i) patients with significant coronary artery disease (CAD) and (ii) a healthy control cohort. Methods and results: Patients undergoing elective angiography for chest pain were recruited and classified as CAD (coronary stenosis >=50%) or ICAD. Clinical and health-related quality-of-life (HRQoL) data were collected at baseline, 1, 6, and 12 months following angiography. The 12-month health status was cross-sectionally compared with a healthy control group recruited from the same geographic zone. Among 758 patients undergoing coronary angiography, 253 (33%) had ICAD. Insignificant coronary artery disease patients were younger, more often female, and had less cardiac risk factors than CAD patients. At 12 months, 48% of ICAD and 59% of CAD patients were chest pain-free, and both groups had similar Short-Form 36 Physical Component Summary (PCS) scores (41 +/- 11 vs. 41 +/- 11 for ICAD and CAD patients, respectively, P > 0.05). However, at 12 months, both the ICAD and CAD patients had significantly lower PCS scores compared with healthy controls (41 +/- 11 vs. 49 +/- 11, P < 0.05 for both CAD and ICAD). Conclusion: Although ICAD patients are frequently considered 'normal' from a cardiac perspective, they often have residual chest pain and impaired HRQoL at 12 months. Novel strategies are needed to manage ICAD patients to improve health outcomes. Clinical Trial Registration: This study was registered with the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au, trial identifier ACTRN12610000801011). PMID- 29474627 TI - Chronic obstructive pulmonary disease and acute myocardial infarction: effects on presentation, management, and outcomes. AB - Cardiovascular disease is a common cause of death in patients with chronic obstructive pulmonary disease (COPD) and is a key target for improving outcomes. However, there are concerns that patients with COPD may not have enjoyed the same mortality reductions from acute myocardial infarction (AMI) in recent decades as the general population. This has raised questions about differences in presentation, management and outcomes in COPD patients compared to non-COPD patients. The evidence points to an increased risk of death after AMI in patients with COPD, but it is unclear to what extent this is attributable to COPD itself or to modifiable factors including under-treatment with guideline-recommended interventions and drugs. We review the evidence for differences between COPD and non-COPD patients in terms of the presentation of AMI, its treatment, and outcomes both in hospital and in the longer term. PMID- 29474629 TI - Exploring the Nexus Between Chronic Kidney Disease and Cardiovascular Disease. PMID- 29474628 TI - Cardiovascular risk assessment: more sex please. PMID- 29474630 TI - Persisting chest pain in nonobstructive coronary artery disease. PMID- 29474631 TI - Explaining inequalities in receipt of care in the older patient with acute coronary syndrome. PMID- 29474632 TI - SKP2 attenuates NF-kappaB signaling by mediating IKKbeta degradation through autophagy. AB - NF-kappaB signaling controls a large set of physiological processes ranging from inflammatory responses to cell death. Its activation is tightly regulated through controlling the activity and stability of multiple signaling components. Here, we identify that NF-kappaB activation is suppressed by an F-box protein, S-phase kinase associated protein 2 (SKP2). SKP2 deficiency enhanced NF-kappaB activation as well as the production of inflammatory cytokines. In addition, SKP2 potently blocked the NF-kappaB activation at the IkappaB kinase (IKK) level. Mechanistic study further revealed that SKP2 functions as an adaptor to promote an interaction between active IKKbeta and the autophagic cargo receptor p62 to mediate IKKbeta degradation via selective autophagy. These findings identify a previously unrecognized role of SKP2 in NF-kappaB activation by which SKP2 acts as a secondary receptor to assist IKKbeta delivery to autophagosomes for degradation in a p62-dependent manner. PMID- 29474634 TI - The dynamics of strigolactone perception in Striga hermonthica: a working hypothesis. AB - Plant-derived strigolactones have diverse functions at ecological scale, including effects upon the growth of plants themselves. The parasitic plants from the family Orobanchaceae interfere with the ecological and hormonal functions of strigolactones to generate unique germination abilities based on the sensing of host-derived strigolactones. Although the recent discovery of strigolactone receptors has enabled us to begin elucidating the mechanism of strigolactone perception, how perception relates to plant parasitism is still a mystery. In this review, we explore emerging questions by introducing recent advances in strigolactone research in parasitic plants. We also attempt to construct a conceptual framework for the unique in planta dynamics of strigolactone perception uncovered through the use of fluorescent probes for strigolactone receptors. Understanding the mechanisms of strigolactone-related processes is essential for controlling the parasitic plant Striga hermonthica, which has caused devastating damage to crop production in Africa. PMID- 29474633 TI - Di-copper metallodrugs promote NCI-60 chemotherapy via singlet oxygen and superoxide production with tandem TA/TA and AT/AT oligonucleotide discrimination. AB - In order to expand the current repertoire of cancer treatments and to help circumvent limitations associated with resistance, the identification of new metallodrugs with high potency and novel mechanisms of action is of significant importance. Here we present a class of di-copper(II) complex based on the synthetic chemical nuclease [Cu(Phen)2]+ (where Phen = 1,10-phenanthroline) that is selective against solid epithelial cancer cells from the National Cancer Institute's 60 human cell line panel (NCI-60). Two metallodrug leads are studied and in each case two [Cu(Phen)2]+ units are bridged by a dicarboxylate linker but the length and rigidity of the linkers differ distinctly. Both agents catalyze intracellular superoxide (O2*-) and singlet oxygen (1O2) formation with radical species mediating oxidative damage within nuclear DNA in the form of double strand breaks and to the mitochondria in terms of membrane depolarization. The complexes are effective DNA binders and can discriminate AT/AT from TA/TA steps of duplex DNA through induction of distinctive Z-like DNA or by intercalative interactions. PMID- 29474636 TI - Mosquitocidal Activity of a Naturally Occurring Isochroman and Synthetic Analogs from the Plant Pathogenic Fungus, Diaporthe eres Against Aedes aegypti (Diptera: Culicidae). AB - The culture filtrate of a plant pathogenic fungus that infects English ivy (Hedera helix L., Araliaceae) was investigated for mosquitocidal constituents by bioassay-guided isolation. The fungus responsible for pathogenic effects on the plant H. helix has been identified as Diaporthe eres Nitschke by molecular techniques. The mosquito adulticidal constituent in the culture filtrate was identified as 3,4-dihydro-8-hydroxy-3,5-dimethylisocoumarin (1) by spectroscopic techniques. Laboratory bioassays showed that (1) had larvicidal activity against permethrin-susceptible and -resistant Aedes aegypti strains. This compound was not active as an adulticide when tested by topical bioassay. Several analogs of (1) were synthesized and had better mosquitocidal activities than the naturally occurring (1) constituent. PMID- 29474635 TI - Genetic mutations associated with lung cancer metastasis to the brain. AB - Approximately 90% of all cancer deaths arise from the metastatic spread of primary tumours. Of all the processes involved in carcinogenesis, local invasion and the formation of metastases are clinically the most relevant, but they are the least well understood at the molecular level. As a barrier to metastasis, cells normally undergo an apoptotic process known as 'anoikis', in circulation. The recent technological advances in the isolation and characterisation of rare circulating tumour cells (CTCs) will allow a better understanding of anoikis resistance. Detailed molecular and functional analyses of anoikis-resistant cells may provide insight into the biology of cancer metastasis and help identify novel targets for prevention of cancer dissemination. To uncover the molecular changes that govern the transition from a primary lung tumour to a secondary metastasis and specifically the mechanisms by which CTCs survive in circulation, we carried out whole genome sequencing (WGS) of normal lung, primary tumours and the corresponding brain metastases from five patients with progressive metastatic non small-cell lung carcinoma. We also isolated CTCs from patients with metastatic cancer and subjected them to whole genome amplification and Sanger sequencing of genes of interest. While the primary tumours showed mutations in genes associated with cell adhesion and motility, brain metastases acquired mutations in adaptive, cytoprotective genes involved in response to cellular stress such as Keap-1, Nrf2 and P300, which are key players of the Keap1-Nrf2-ARE survival pathway. Nrf2 is a transcriptional factor that upon stress translocates into the nucleus, binds to the anti-oxidant response elements (ARE) and drives the expression of anti oxidant genes. The identified mutations affect regulatory domains in all three proteins, suggesting a functional role in providing a survival advantage to CTCs in the peripheral blood allowing their dissemination to distant organs. PMID- 29474637 TI - Uncommon Human Telomerase Reverse Transcriptase Promoter Mutations Are Associated With Poor Survival in Ovarian Clear Cell Carcinoma. AB - Objectives: The present study assessed whether human telomerase reverse transcriptase (TERT) promoter mutations mediate the increased mortality risk observed in patients with ovarian clear cell carcinoma (CCC) and characterized the pathologic features of TERT promoter mutation-associated ovarian CCC. Methods: The TERT promoter region in genomic DNA extracted from paraffin-embedded ovarian CCC specimens (n = 93) was bidirectionally sequenced. Results: A total of 24 TERT promoter mutations were identified among the analyzed CCC cases, of which 11 were known "hotspot" mutations whose frequency was increased in CCC cases with compared to without coexistent adenofibroma (P < .05). In contrast, the 14 (including three novel) identified uncommon site mutations were shown to be associated with a poor progression-free survival rate (P < .01). Conclusions: The identified uncommon TERT promoter mutations exacerbate the poor prognosis characteristic of ovarian CCC cases, and the hotspot mutations appear to be a molecular feature of the adenofibroma-associated form of the disease. PMID- 29474639 TI - 'Valuable but incomplete!' A qualitative study about migrants' perspective on health examinations in Stockholm. AB - Background: A voluntary health examination is offered to asylum seekers in Sweden with the purpose of detecting infectious diseases and identifying other health needs. This study aimed to explore the organization, content and perceived value of the health examination from the perspective of asylum seekers. Methods: Semi structured interviews were conducted with 18 migrants recruited from different settings in Stockholm. Data were transcribed verbatim and analysed using thematic analysis in relation to the availability, accessibility, acceptability and quality framework. Results: Participants reported positive aspects of the health examination while raising important concerns, categorized into the following themes: availability-despite being available, the service was considered to be delayed with perceived implication for infection control; accessibility-migrants experienced no physical or economic barrier to access the health examination, especially when it was performed through a mobile clinic, however, they had limited access to information; acceptability and quality-migrants trusted the health staff, however, the examination lacked important aspects related to mental health and dental care needs, among other health needs. Conclusion: Health examinations are valued by participants but failed to identify and address many perceived health needs. Mobile clinics seem a practical strategy to improve accessibility. PMID- 29474638 TI - STAR Chimeric Post for rapid detection of circular RNA and fusion transcripts. AB - Motivation: The biological relevance of chimeric RNA alignments is now well established. Chimera arising as chromosomal fusions are often drivers of cancer and recently discovered circular RNA (circRNA) are only now being characterized. While software already exists for fusion discovery and quantitation, high false positive rates and high run-times hamper scalable fusion discovery on large datasets. Furthermore, software available for circRNA detection and quantification is limited. Results: Here, we present STAR Chimeric Post (STARChip), a novel software package that processes chimeric alignments from the STAR aligner and produces annotated circRNA and high precision fusions in a rapid, efficient and scalable manner that is appropriate for high dimensional medical omics datasets. Availability and implementation: STARChip is available at https://github.com/LosicLab/STARChip. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29474640 TI - Understanding brain penetrance of anticancer drugs. AB - This paper explicates the impact of tumor capillary permeability for glioma World Health Organization (WHO) grades II to IV on brain-penetrant drug entry and distribution within the tumor and the brain adjacent to tumor (leading edge). In addition, we consider the distribution of non-brain penetrant drugs and how, in some cases, large-molecular-weight drugs might achieve good distribution into tumor and brain adjacent to tumor. PMID- 29474641 TI - IMPROVEMENTS IN THE THERMAL NEUTRON CALIBRATION UNIT, TNF2, AT LNMRI/IRD. AB - The standard thermal neutron flux unit, TNF2, in the Brazilian National Ionizing Radiation Metrology Laboratory was rebuilt. Fluence is still achieved by moderating of four 241Am-Be sources with 0.6 TBq each. The facility was again simulated and redesigned with graphite core and paraffin added graphite blocks surrounding it. Simulations using the MCNPX code on different geometric arrangements of moderator materials and neutron sources were performed. The resulting neutron fluence quality in terms of intensity, spectrum and cadmium ratio was evaluated. After this step, the system was assembled based on the results obtained from the simulations and measurements were performed with equipment existing in LNMRI/IRD and by simulated equipment. This work focuses on the characterization of a central chamber point and external points around the TNF2 in terms of neutron spectrum, fluence and ambient dose equivalent, H*(10). This system was validated with spectra measurements, fluence and H*(10) to ensure traceability. PMID- 29474643 TI - CROSS SECTIONS MEASURED BY QUASI-MONOENERGETIC NEUTRONS. AB - 197Au, 209Bi, 59Co, natFe and 169Tm samples were irradiated several times with quasi-monoenergetic neutrons from the p+7Li reaction in the energy range of 18-34 MeV. The activities of the samples were measured with the HPGe detector and the reaction rates were calculated. The cross sections were extracted using the SAND II code with the reference cross sections from the IRDFF database. PMID- 29474642 TI - Glutamate-cysteine ligase catalytic subunit is associated with cisplatin resistance in lung adenocarcinoma. AB - Background: Cisplatin is a key drug for treating lung adenocarcinoma, and its sensitivity to cisplatin is directly related to prognosis. We aimed to reveal the roles of genes related to glutathione synthesis (glutamate-cysteine ligase catalytic subunit, GCLC) and cystine uptake (cystine/glutamate transporter, xCT and CD44v8-10) in cisplatin resistance and prognosis in lung adenocarcinoma. Methods: We established cell lines stably expressing GCLC, xCT, standard isoform of CD44, and CD44v8-10, and investigated their sensitivities to cisplatin. We also measured mRNA expression levels of these genes in the tumor tissues from 92 lung adenocarcinoma patients. Patients were divided into high-expression (upper quartile, N = 23) and low-expression groups (remaining patients, N = 69). Recurrence-free survival, overall survival (N = 92), and post-recurrence survival (N = 22) were selected as endpoints. Results: Compared with the control green fluorescent protein-expressing cell line (inhibitory concentration 50:6.9 MUM), all the stable cell lines were more resistant to cisplatin (12.9 MUM, P = 0.025; 13.9 MUM, P = 0.028; 26.7 MUM, P = 0.001; 17.7 MUM, P = 0.008, respectively). In contrast, there was no significant difference in recurrence-free or overall survival between the high- and low-expression groups for any of the genes. However, high expression of GCLC was a risk factor for poorer post-recurrence survival (hazard ratio, 6.26; 95% confidence interval, 1.37-28.7; P = 0.018). Conclusion: High expression levels of genes related to glutathione synthesis and cystine uptake promote cisplatin resistance in lung adenocarcinoma cell lines. High expression of GCLC in tumor tissue may be a potential predictor of treatment failure. PMID- 29474645 TI - Mucosa-associated lymphoid-tissue (MALT) lymphoma of the rectum. PMID- 29474644 TI - DICER1 Mutations Are Frequent in Adolescent-Onset Papillary Thyroid Carcinoma. AB - Context: Papillary thyroid carcinoma (PTC) is a common malignancy in adolescence and is molecularly and clinically distinct from adult PTC. Mutations in the DICER1 gene are associated with thyroid abnormalities, including multinodular goiter and differentiated thyroid carcinoma. Objective: In this study, we sought to characterize the prevalence of DICER1 variants in pediatric PTC, specifically in tumors without conventional PTC oncogenic alterations. Patients: Patients (N = 40) who underwent partial or total thyroidectomy and who were <18 years of age at the time of surgery were selected. Design: The 40 consecutive thyroidectomy specimens (30 malignant, 10 benign) underwent genotyping for 17 PTC-associated variants, as well as full sequencing of the exons and exon-intron boundaries of DICER1. Results: Conventional alterations were found in 12 of 30 (40%) PTCs (five BRAFV600E, three RET/PTC1, four RET/PTC3). Pathogenic DICER1 variants were identified in 3 of 30 (10%) PTCs and in 2 of 10 (20%) benign nodules, all of which lacked conventional alterations and did not recur during follow-up. DICER1 alterations thus constituted 3 of 18 (16.7%) PTCs without conventional alterations. The three DICER1-mutated carcinomas each had two somatic DICER1 alterations, whereas two follicular-nodular lesions arose in those with germline DICER1 mutations and harbored characteristic second somatic RNase IIIb "hotspot" mutations. Conclusions: DICER1 is a driver of pediatric thyroid nodules, and DICER1-mutated PTC may represent a distinct class of low-risk malignancies. Given the prevalence of variants in children, we advocate for inclusion of DICER1 sequencing and gene dosage determination in molecular analysis of pediatric thyroid specimens. PMID- 29474646 TI - Serum levels of testosterone and SHBG in association with body mass index improve the predictive capability of consolidate tumor biomarkers in pre- and postmenopausal breast cancer patients. AB - Objective: To investigate the contribution of serum levels of testosterone (TS) and sex hormone binding globulin (SHBG) in association with body mass index (BMI) as a surrogate marker of obesity, to the predictive capability of tumor size (T), lymph node (N) and estrogen receptor (ER) status and proliferative activity (TLI). Methods: We investigated 120 women with primary breast cancer and median follow-up of 138 months. Serum levels of TS and SHBG and patient's BMI were evaluated before surgery. The contribution of TS, SHBG, their ratio (TS/SHBG) and BMI to the predictive capability of tumor-specific biomarkers was investigated by Harrell's c statistic. Results: TS alone did not affect prognosis, whereas SHBG was protective in postmenopausal patients, in which BMI was associated with a progressive increase in the relapse-specific hazard ratio (HR). When in combination, TS, SHBG and BMI, affected prognosis in different ways depending on menopausal status. The best predictive capability (c = 0.78) was observed in postmenopausal patients when at the basic model (N + TLI) were added TS, BMI, TS * BMI interaction, with or without SHBG. In premenopause subgroup, the best predictive capability (c = 0.67) was provided by the basic model (N + TLI) plus TS and SHBG or their ratio, BMI and TS * BMI or TS/SHBG * BMI interaction. Conclusions: Patient-associated features such as BMI and serum levels of TS and SHBG can improve the predictive capability of consolidate tumor-specific biomarkers in both pre- and postmenopause, thus providing a relevant contribution to the decision-making process. PMID- 29474647 TI - Females have the survival advantage in glioblastoma. PMID- 29474648 TI - An Integrated Quantitative Index for Measuring Chronic Multisite Pain: The Multiple Areas of Pain (MAP) Study. AB - Objective: Despite the high prevalence of chronic multisite pain, there is little consensus on methods to characterize it. Commonly used assessments report only one dimension of pain, that is, intensity, thus ignoring the spatial aspect of pain. We developed a novel pain quantification index, the Integrated Pain Quantification Index (IPQI), on a scale of 0 to 1 that integrates multiple distinct pain measures into a single value, thus representing multidimensional pain information with a single value. Design: Single-visit, noninterventional, epidemiological study. Setting: Fourteen outpatient multidisciplinary pain management programs. Patients: Patients with chronic pain of the trunk and/or limbs for at least six months with average overall pain intensity of at least 5 on the numeric rating scale. Methods: Development of IPQI was performed in a large population (N = 810) of chronic pain patients from the Multiple Areas of Pain (MAP) study. Results: Prevalence of two or more noncontiguous painful areas was at 88.3% (95% confidence interval [CI] = 0.86-0.90), with a mean of 6.3 areas (SD = 5.57 areas). Prevalence of more than 10% body area in pain was at 52.8% (95% CI = 0.49-0.56), with a mean at 16.1% (17.16%). On average, IPQI values were near the middle of the scale, with mean and median IPQI at 0.52 (SD = 0.13) and 0.55, respectively. The IPQI was generalizable and clinically relevant across all domains recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials. Conclusions: IPQI provided a single pain score for representing complex, multidimensional pain information on one scale and has implications for comparing pain populations across longitudinal clinical trials. PMID- 29474649 TI - Characterization of Resistance to Cephus cinctus (Hymenoptera: Cephidae) in Barley Germplasm. AB - Most barley cultivars have some degree of resistance to the wheat stem sawfly (WSS), Cephus cinctus Norton (Hymenoptera: Cephidae). Damage caused by WSS is currently observed in fields of barley grown in the Northern Great Plains, but the impact of WSS damage among cultivars due to genetic differences within the barley germplasm is not known. Specifically, little is known about the mechanisms underlying WSS resistance in barley. We characterized WSS resistance in a subset of the spring barley CAP (Coordinated Agricultural Project) germplasm panel containing 193 current and historically important breeding lines from six North American breeding programs. Panel lines were grown in WSS infested fields for two consecutive years. Lines were characterized for stem solidness, stem cutting, WSS infestation (antixenosis), larval mortality (antibiosis), and parasitism (indirect plant defense). Variation in resistance to WSS in barley was compared to observations made for solid-stemmed resistant and hollow-stemmed susceptible wheat lines. Results indicate that both antibiosis and antixenosis are involved in the resistance of barley to the WSS, but antibiosis seems to be more prevalent. Almost all of the barley lines had greater larval mortality than the hollow-stemmed wheat lines, and only a few barley lines had mortality as low as that observed in the solid-stemmed wheat line. Since barley lines lack solid stems, it is apparent that barley has a different form of antibiosis. Our results provide information for use of barley in rotation to control the WSS and may provide a basis for identification of new approaches for improving WSS resistance in wheat. PMID- 29474650 TI - Internal Skin Burn Due to Novel Radiofrequency Ablation Technology. PMID- 29474651 TI - Prey Foraging Under Sublethal Lambda-Cyhalothrin Exposure on Pyrethroid Susceptible and -Resistant Lady Beetles (Eriopis connexa (Coleoptera: Coccinelidae)). AB - Sublethal insecticide exposure may affect foraging of insects, including natural enemies, although the subject is usually neglected. The lady beetle Eriopis connexa (Germar, 1824) (Coleoptera: Coccinelidae) is an important predator of aphids with existing pyrethroid-resistant populations that are undergoing scrutiny for potential use in pest management systems characterized by frequent insecticide use. However, the potential effect of sublethal pyrethroid exposure on this predator's foraging activity has not yet been assessed and may compromise its use in biological control. Therefore, our objective was to assess the effect of sublethal lambda-cyhalothrin exposure on three components of the prey foraging activity (i.e., walking, and prey searching and handling), in both pyrethroid susceptible and -resistant adults of E. connexa. Both lady beetle populations exhibited similar walking patterns without insecticide exposure in noncontaminated arenas, but in partially contaminated arenas walking differed between strains, such that the resistant insects exhibited greater walking activity. Behavioral avoidance expressed as repellence to lambda-cyhalothrin was not observed for either the susceptible or resistant populations of E. connexa, but the insecticide caused avoidance by means of inducing irritability in 40% of the individuals, irrespective of the strain. Insects remained in the insecticide contaminated portion of the arena for extended periods resulting in greater exposure. Although lambda-cyhalothrin exposure did not affect prey searching by susceptible lady beetles, prey searching was extended for exposed resistant predators. In contrast, prey handling was not affected by population or by lambda cyhalothrin exposure. Thus, sublethal exposure to the insecticide in conjunction with the insect resistance profile can affect prey foraging with pyrethroid exposed resistant predators exhibiting longer prey searching time associated with higher walking activity reducing its predatory performance. PMID- 29474652 TI - Monitoring quality of care in acute myocardial infarction patients using retrospective registry data. AB - Background: Hospital-based registries provide a key contribution in assessing the quality of care in acute myocardial infarction (MI) patients, although some concern on selection bias of included cases has recently arisen. We investigated the feasibility of a retrospective, population-based registry of MIs in monitoring the quality of care. Methods: We identified all the hospitalizations with a diagnosis of acute MI among 35-79 years old residents in the Varese province, Northern Italy, in 2007-2008. Information needed to define performance according to the American Heart Association set was extracted from hospital case histories. To characterize our approach, we focus on data completeness for critical event times and eligibility criteria, and on the analysis of ST-elevated MI (STEMI) patients according to received reperfusion treatment. Results: Exact time of hospital admission and of percutaneous coronary angioplasty (PCI) procedure was available in 96% and 77% of MIs, with no difference between non transferred (n = 1399) and inter-hospital transferred (n = 300) patients. Data completeness for eligibility to action/treatment criteria was >90% for each performance measure except statin prescription at discharge (76%). About 45% of STEMI experienced a delay in PCI-capable hospital arrival, and only one every three ST-elevated MI patients received primary PCI; these were more likely to be younger male cases with less comorbidities than un-treated patients. Conclusions: Complementary to clinical registries, the retrospective population-based is a feasible approach which allows monitoring the entire pattern of care of all hospitalized MI patients independent of their clinical characteristics. PMID- 29474653 TI - Isolated splenic metastasis from pulmonary adenoid cystic carcinoma. PMID- 29474654 TI - PRELIMINARY INVESTIGATION OF RADIATION DOSE TO PATIENTS FROM CARDIOVASCULAR INTERVENTIONAL PROCEDURES IN TANZANIA. AB - Although contemporary cardiac X-ray exams are typically set so benefits outweighs the risk, the growing use and increasing complexity of the cardiovascular interventional radiological (CVIR) procedures does increase the risk of radiation related tissue effects and stochastic effects to the individual patients and the population. In view of these radiological concerns there is a need to investigate factors that influence the doses received by the patients and enable optimisation needed. The air kerma area product (KAP), cumulative air kerma (CAK) and fluoroscopy time (FT) to patients from two major CVIR procedures: coronary angiography (CA) and percutaneous coronary interventions (PCI), were obtained from two major hospitals in Tanzania. The CAK and KAP were determined using ionisation chambers equipped in each angiographic unit. The median values of the KAP, CAK and FT for the CA procedures were 37.8 Gy cm2, 425.5 mGy and 7.6 min, respectively, while for the PCI were 86.5 Gy cm2, 1180.3 mGy and 19.0 min, respectively. The overall differences among individual KAP, CAK and FT values across the two hospitals investigated differed by factors of up to 33.5, 58.7 and 26.3 for the CA, while for the PCI procedures differed by factors of up to 10.9, 25.3 and 13.8, respectively. The mean values of KAP and FT for both CA and PCI were mostly higher than those reported values for Ireland, Belgium, Greece, France, China and Australia. The third quartiles of the KAP, CAK and FT for both CA and PCI were relatively above the preliminary diagnostic reference levels proposed by the IAEA, DIMOND III and SENTINEL. The observed substantial variations of mean values of technical parameters and patient doses (KAP, CAK and FT values) observed for the CA and PCI procedures inter and intra-hospitals were mainly explained by the complexity of the CVIR procedures, the nature of pathology, patient-specific characteristics, the variation in levels of skills and experiences among IC personnel, and the different procedural protocols employed among interventional cardiologists and hospitals. The observed great variations of procedural protocols and patient doses within and across the hospitals and relative higher dose than reported values from the literature call for the need to optimise radiation dose to patient from IC procedures. PMID- 29474656 TI - Thinker's Sign & Chronic Obstructive Pulmonary Disease (COPD). PMID- 29474655 TI - Systemic interferon type I and type II signatures in primary Sjogren's syndrome reveal differences in biological disease activity. AB - Objective: To assess the relationships between systemic IFN type I (IFN-I) and II (IFN-II) activity and disease manifestations in primary SS (pSS). Methods: RT-PCR of multiple IFN-induced genes followed by principal component analysis of whole blood RNA of 50 pSS patients was used to identify indicator genes of systemic IFN I and IFN-II activities. Systemic IFN activation levels were analysed in two independent European cohorts (n = 86 and 55, respectively) and their relationships with clinical features were analysed. Results: Three groups could be stratified according to systemic IFN activity: IFN inactive (19-47%), IFN-I (53-81%) and IFN-I + II (35-55%). No patient had isolated IFN-II activation. IgG levels were highest in patients with IFN-I + II, followed by IFN-I and IFN inactive patients. The prevalence of anti-SSA and anti-SSB was higher among those with IFN activation. There was no difference in total-EULAR SS Disease Activity Index (ESSDAI) or ClinESSDAI between the three subject groups. For individual ESSDAI domains, only the biological domain scores differed between the three groups (higher among the IFN active groups). For patient reported outcomes, there were no differences in EULAR Sjogren's syndrome patient reported index (ESSPRI), fatigue or dryness between groups, but pain scores were lower in the IFN active groups. Systemic IFN-I but not IFN-I + II activity appeared to be relatively stable over time. Conclusions: Systemic IFN activation is associated with higher activity only in the ESSDAI biological domain but not in other domains or the total score. Our data raise the possibility that the ESSDAI biological domain score may be a more sensitive endpoint for trials targeting either IFN pathway. PMID- 29474657 TI - A comprehensive framework identifying readmission risk factors using the CHAID algorithm: a prospective cohort study. AB - Objective: To identify frequency of readmission after discharge from internal medicine wards, readmission risk factors, and reasons and costs of readmission. Design: Prospective cohort study. Setting: A tertiary-care hospital in Turkey. Participants: 2622 adult patients discharged from internal-medicine wards of the hospital between 1 February 2015 and 31 January 2016. Main outcome measures: Thirty day all-cause readmission rates, reasons and costs of readmission. To identify readmission risk factors Chi-square Automatic Interaction Detector (CHAID) analysis was conducted. Results: The same hospital readmission rate was 17.9%, while the same hospital or different-hospital readmission rate was 21.3%. Receiver operating characteristic (ROC) curve analysis showed that the predictive performance of the CHAID algorithm was high. According to the CHAID algorithm, the most significant readmission risk factor was the main diagnosis of neoplasm at the index admission. In other diagnosis groups, higher Charlson comorbidity score, higher level of education, having a regular physician, and three dimensions of Readiness for Hospital Discharge Scale were significant risk factors for readmission. The most frequent reason for readmission was neoplasm, and the total cost of readmissions was ~$900 000. Conclusions: The CHAID algorithm for readmissions had a high predictive strength and provided details that aid physicians in decision-making. Measures must be taken from initial diagnosis to post-discharge follow-up, to minimize readmissions, especially in patients with neoplasm. PMID- 29474658 TI - TiO2 NPs Alleviates High-Temperature Induced Oxidative Stress in Silkworms. AB - Silkworm, Bombyx mori (L.; Lepidoptera: Bombycidae), is an economically important insect, which is sensitive to the environment and susceptible to oxidative damages at high temperature. Low concentrations of TiO2 NPs (titanium dioxide nanoparticles) can scavenge reactive oxygen species (ROS) produced by oxidative damages in vivo. To explore whether TiO2 NPs could alleviate oxidative damages of high temperature, the effects of TiO2 NPs treatment on silkworm growth, the levels of ROS and H2O2, as well as the transcription level of antioxidant-related genes were studied at 30 degrees C. These results showed that TiO2 NPs treatment increased silkworm body weight by 6.0% and reduced the occurrence of irregular cocoon at 30 degrees C. TiO2 NPs treatment at 30 degrees C decreased ROS levels in fat body and increased expression of Hsp70, SOD by 5.70-fold at 48 h, TPx by 1.61-fold, CAT by 1.81-fold. These results indicated that TiO2 NPs treatment at 30 degrees C could promote the expression of antioxidant genes and reduce oxidative stress and provide a new method to alleviate high-temperature induced oxidative stress to silkworm. PMID- 29474659 TI - Communication failure: analysis of prescribers' use of an internal free-text field on electronic prescriptions. AB - Importance: Electronic prescribing promises to improve the safety and clarity of prescriptions. However, it also can introduce miscommunication between prescribers and pharmacists. There are situations where information that is meant to be sent to pharmacists is not sent to them, which has the potential for dangerous errors. Objective: To examine how frequently prescribers or administrative personnel put information intended for pharmacists in a field not sent to pharmacists, classify the type of information included, and assess the potential harm associated with these missed messages. Design, Setting, Participants: Medication record data from our legacy electronic health record were requested for ambulatory care patients seen at an academic medical center from January 1, 2000, to May 31, 2015 (20 123 881 records). From this database, 6 060 272 medication orders met our inclusion criteria. We analyzed a random sample of 10 000 medication orders with internal comments. Main Outcomes and Measures: Reviewers classified internal comments for intent. Comments intended for pharmacists were also sorted into descriptive categories and analyzed for the potential for patient harm. Results: We found that 11.7% of the prescriptions in our sample contained comments that were intended to be sent to pharmacists. Many comments contained information about the dose, route, or duration of the prescription (38.0%). Approximately a third of the comments intended for pharmacists contained information that had the potential for significant or severe harm if not communicated. Conclusion: We found undelivered comments that were clearly intended for pharmacists and contained important information for either pharmacists or patients. This poses a legitimate safety concern, as a portion of comments contained information that could have prevented severe or significant harm. PMID- 29474660 TI - Performance of the Accelerate PhenoTM system for identification and antimicrobial susceptibility testing of a panel of multidrug-resistant Gram-negative bacilli directly from positive blood cultures. AB - Objectives: To evaluate the performance of the Accelerate PhenoTM system for the identification and antimicrobial susceptibility testing (AST) of a panel of Gram negative bacilli (GNB) with different resistance profiles (e.g. penicillinases, ESBLs, cephalosporinase overproduction, carbapenemases, impermeability) directly from positive blood cultures in <7 h. Methods: A panel of 105 clinical strains previously characterized for the presence of beta-lactamase-encoding genes was tested. Approximately 100 cfu of each isolate was inoculated into sterile blood culture bottles and incubated in a BD BACTECTM FX automated system (Becton Dickinson, USA). Positive blood cultures were subjected to parallel testing using the Accelerate PhenoTM system and conventional culture methods [identification of isolated colonies by MALDI-TOF and VITEK(r) 2 system (bioMerieux, France), and AST by disc diffusion and Etest following EUCAST recommendations]. Results: The overall identification agreement between the Accelerate PhenoTM system and conventional culture methods was 100% (105/105). The overall categorical agreement between the system and culture-based AST was 94.9% (1169/1232), with rates for minor errors of 4.1% (51/1232), major errors 0.3% (4/1232) and very major errors 0.7% (8/1232). The Accelerate PhenoTM system produced AST results indicative of third-generation cephalosporinases (26/26) and carbapenem-resistant strains (52/55). Conclusions: The Accelerate PhenoTM system is an accurate, sensitive and easy-to-use test for the rapid identification and AST of MDR GNB in bloodstream infections. Given the burden of multidrug resistance, its implementation in the microbiology laboratory could be a useful tool for prompt management of sepsis. PMID- 29474661 TI - Models of Schizotypy: The Importance of Conceptual Clarity. AB - The observation of psychosis-like traits that resemble symptoms of schizophrenia and bipolar disorder, both among healthy relatives of psychotic patients and among the general population, can be traced to the early 20th century.1,2 These traits have since been described within various models of illness and health (ie, normal/abnormal personality, abnormal psychotic continua), each giving rise to concepts such as "schizotypy," "psychoticism," and "psychosis-proneness" that are not necessarily interchangeable, although their subtle distinctions are often overlooked. Historically, there have been 3 major models of schizophrenia /psychosis-proneness, one of which is referred to as "taxonic" or "quasi dimensional,"3,4 and 2 models that can be regarded as "fully dimensional,"5,6 as distinguished by the relationship that is proposed to exist between psychosis proneness and the risk of clinical schizophrenia or other psychotic disorder. In this review, we outline the key assumptions of each model and its implications for research of psychosis in relation to mental illness and health and for the alternative models. We integrate historical concept development with current findings from various fields of research (eg, personality, neurobiology, and behavioral genetics) and highlight the remaining questions each model poses in relation to understanding the development of psychotic illness and the distribution of psychotic-like traits in the general population. PMID- 29474662 TI - Radiographic Analysis of the Vidian Canal and Its Utility in Petrous Internal Carotid Artery Localization. AB - BACKGROUND: Endoscopic endonasal surgery of the skull base requires expert knowledge of the anatomy and a systematic approach. The vidian canal is regarded as a reliable landmark to localize the petrous internal carotid artery (pICA) near the second genu, which can be used for orientation in deep skull base approaches. There is controversy about the relationship between the vidian canal and the pICA. OBJECTIVE: To further establish the vertical relationship between the vidian canal and the pICA to aid in surgical approaches to the skull base. METHODS: We utilized a collection of institutional review board-approved computed tomographic (CT) angiograms (CTAs). Fifty CTAs were studied bilaterally for 100 total sides. The vidian canal was visualized radiographically to determine whether it terminates below, at, or above the level of the pICA. RESULTS: Sixty six of 100 vidian canals terminated inferior to the pICA (66%), which was the most common relationship observed. The average distance inferior to the pICA was 1.01 mm on the right, 1.18 mm on the left, and 1.09 mm of the total 66 sides. Less commonly, the vidian canal terminated at the level of the pICA canal in 34 sides (34%). The vidian canal was not observed to terminate superior to the pICA in any of the 50 CTAs studied. CONCLUSION: The vidian canal terminates inferior to the pICA most commonly, but often terminates at the level of the pICA. Careful drilling clockwise inferior to superior around the vidian canal should allow for safe pICA localization in most cases. PMID- 29474664 TI - The wider implications of suspected cobalamin deficiency myelopathy. PMID- 29474663 TI - Muscle ischaemia associated with NXP2 autoantibodies: a severe subtype of juvenile dermatomyositis. AB - Objectives: Myositis-specific autoantibodies (MSAs) are increasingly used to delineate distinct subgroups of JDM. The aim of our study was to explore without a priori hypotheses whether MSAs are associated with distinct clinical pathological changes and severity in a monocentric JDM cohort. Methods: Clinical, biological and histological findings from 23 JDM patients were assessed. Twenty six histopathological parameters were subjected to multivariate analysis. Results: Autoantibodies included anti-NXP2 (9/23), anti-TIF1gamma (4/23), anti MDA5 (2/23), no MSAs (8/23). Multivariate analysis yielded two histopathological clusters. Cluster 1 (n = 11) showed a more severe and ischaemic pattern than cluster 2 (n = 12) assessed by: total score severity ? 20 (100.0% vs 25.0%); visual analogic score ?6 (100.0% vs 25.0%); the vascular domain score >1 (100.0% vs 41.7%); microinfarcts (100% vs 58.3%); ischaemic myofibrillary loss (focal punched-out vacuoles) (90.9 vs 25%); and obvious capillary loss (81.8% vs 16.7). Compared with cluster 2, patients in cluster 1 had strikingly more often anti NXP2 antibodies (7/11 vs 2/12), more pronounced muscle weakness, more gastrointestinal involvement and required more aggressive treatment. Furthermore, patients with anti-NXP2 antibodies, mostly assigned in the first cluster, also displayed more severe muscular disease, requiring more aggressive treatment and having a lower remission rate during the follow-up period. Conclusion: Marked muscle ischaemic involvement and the presence of anti-NXP2 autoantibodies are associated with more severe forms of JDM. PMID- 29474665 TI - Catastrophizing Interferes with Cognitive Modulation of Pain in Women with Fibromyalgia. AB - Background: Pain modulation is a critical function of the nociceptive system that includes the ability to engage descending pain control systems to maintain a functional balance between facilitation and inhibition of incoming sensory stimuli. Dysfunctional pain modulation is associated with increased risk for chronic pain and is characteristic of fibromyalgia (FM). Catastrophizing is also common in FM. However, its influence on pain modulation is poorly understood. Objective: To determine the role of catastrophizing on central nervous system processing during pain modulation in FM via examining brain responses and pain sensitivity during an attention-distraction paradigm. Methods: Twenty FM patients and 18 healthy controls (CO) underwent functional magnetic resonance imaging while receiving pain stimuli, administered alone and during distracting cognitive tasks. Pain ratings were assessed after each stimulus. Catastrophizing was assessed with the Pain Catastrophizing Scale (PCS). Results: The ability to modulate pain during distraction varied among FM patients and was associated with catastrophizing. This was demonstrated by significant positive relationships between PCS scores and pain ratings (P < 0.05) and brain responses in the dorsolateral prefrontal cortex (P < 0.01). Relationships between catastrophizing and pain modulation did not differ between FM and CO (P > 0.05). Conclusions: FM patients with higher levels of catastrophizing were less able to distract themselves from pain, indicative of catastrophizing-related impairments in pain modulation. These results suggest that the tendency to catastrophize interacts with attention-resource allocation and may represent a mechanism of chronic pain exacerbation and/or maintenance. Reducing catastrophizing may improve FM symptoms via improving central nervous system regulation of pain. PMID- 29474666 TI - Adherence to recommendations for the use of anti-tumour necrosis factor and its impact over 5 years of follow-up in axial spondyloarthritis. AB - Objectives: To describe adherence to recommendations for TNFalpha blocker (TNFb) initiation and continuation in early axial Spondyloarthropathy (axSpA); and to evaluate the impact of adherence to these recommendations over 5 years of follow up in the DEvenir des Spondyloarthrites Indifferenciees Recentes (DESIR) cohort. Methods: The first 5 years of follow-up of the DESIR early axSpA cohort were analysed. We evaluated adherence to Assessment of SpondyloArthritis International Society (ASAS) 2003/2006, 2016 and European Medicines Agency recommendations in axSpA patients for: TNFb initiation (patients were adherent if they either commenced TNFb therapy when they met the conditions for initiation or if they did not commence TNFb therapy when conditions were not met) and; TNFb continuation (either when they continued TNFb therapy when conditions to continue were met or when they discontinued when conditions were not met). The impact of adherence to these recommendations on functional disability, quality of life and sick-leave days over 5 years was explored. Results: A total of 708 patients were analysed: 440 (62.15%), 389 (54.94%) and 335 (47.32%) were considered adherent to ASAS 2003/2006, 2016 and European Medicines Agency recommendations for TNFb initiation, respectively. Adherence to 2003/2006 and 2016 recommendations for TNFb continuation was observed in 47.37 and 49.39% of patients, respectively. According to over 5 years of follow-up, better outcomes (lower BASFI, higher SF 36 and fewer days of sick leave) were found in patients adhering to recommendations for TNFb commencement and continuation. Conclusion: Less than 50% of patients were treated in agreement with recommendations for TNFb initiation and continuation. Nevertheless, adherence to such recommendations leads to better functional outcomes and fewer days of sick leave, according to long-term follow up. PMID- 29474668 TI - Real-time left ventricular pressure-volume loops during percutaneous central arteriovenous anastomosis. PMID- 29474667 TI - The transcription factor CsbHLH18 of sweet orange functions in modulation of cold tolerance and homeostasis of reactive oxygen species by regulating the antioxidant gene. AB - The basic helix-loop-helix (bHLH) transcription factors (TFs) comprise one of the largest gene families in plants, and participate in various physiological processes, but the physiological role and regulatory function of the majority of bHLHs remain poorly understood. Here, a total of 56 putative CsbHLH genes were identified in sweet orange (Citrus sinensis) based on a genome-wide analysis. The CsbHLH genes, except four members, were distributed throughout nine chromosomes and divided into 19 subgroups. Most of the CsbHLH genes were responsive to cold stress, with the greatest up-regulation being observed in CsbHLH18. CsbHLH18 is localized in the nuclei and has transcriptional activation activity. Overexpression of CsbHLH18 conferred enhanced cold tolerance in transgenic tobacco. The transgenic plants accumulated significantly less reactive oxygen species (ROS), concurrent with increased activities and transcript levels of antioxidant enzymes. In contrast, knockdown of bHLH18 by RNAi in trifoliate orange promoted cold susceptibility, accompanied by down-regulation of antioxidant genes and accumulation of more ROS. Protein-DNA interaction assays demonstrate that CsbHLH18 directly and specifically binds to and activates the promoter of CsPOD. Taken together, these findings indicate that CsbHLH18 plays a positive role in cold tolerance through, at least partly, modulation of ROS homeostasis by directly regulating the antioxidant gene. PMID- 29474670 TI - Evaluation of residual aberration in fifth-order geometrical aberration correctors. AB - Higher order geometrical aberration correctors for transmission electron microscopes are essential for atomic-resolution imaging, especially at low accelerating voltages. We quantitatively calculated the residual aberrations of fifth-order aberration correctors to determine the dominant aberrations. The calculations showed that the sixth-order three-lobe aberration was dominant when fifth-order aberrations were corrected by using the double-hexapole or delta types of aberration correctors. It was also deduced that the sixth-order three lobe aberration was generally smaller in the delta corrector than in the double hexapole corrector. The sixth-order three-lobe aberration was counterbalanced with a finite amount of the fourth-order three-lobe aberration and 3-fold astigmatism. In the experiments, we used a low-voltage microscope equipped with delta correctors for probe- and image-forming systems. Residual aberrations in each system were evaluated using Ronchigrams and diffractogram tableaux, respectively. The counterbalanced aberration correction was applied to obtain high-resolution transmission electron microscopy images of graphene and WS2 samples at 60 and 15 kV, respectively. PMID- 29474669 TI - Treatment and outcome of congenital nephrotic syndrome. AB - Background: Recommendations for management of Finnish-type congenital nephrotic syndrome (CNS) followed by many teams include daily albumin infusions, early bilateral nephrectomy, dialysis and transplantation. We aimed to assess the treatment and outcome of patients with CNS in France. Methods: We conducted a nationwide retrospective study on 55 consecutive children born between 2000 and 2014 treated for non-infectious CNS. Results: The estimated cumulative incidence of CNS was 0.5/100 000 live births. The underlying defect was biallelic mutations in NPHS1 (36/55, 65%), NPHS2 (5/55, 7%), PLCE1 (1/55, 2%), heterozygous mutation in WT1 (4/55, 7%) and not identified in nine children (16%). Fifty-three patients (96%) received daily albumin infusions from diagnosis (median age 14 days), which were spaced and withdrawn in 10 patients. Twenty children (35%) were managed as outpatients. Thirty-nine patients reached end-stage kidney disease (ESKD) at a median age of 11 months. The overall renal survival was 64% and 45% at 1 and 2 years of age, respectively. Thirteen children died during the study period including four at diagnosis, two of nosocomial catheter-related septic shock, six on dialysis and one after transplantation. The remaining 13 patients were alive with normal renal function at last follow-up [median 32 months (range 9-52)]. Renal and patient survivals were longer in patients with NPHS1 mutations than in other patients. The invasive infection rate was 2.41/patient/year. Conclusions: Our study shows: (i) a survival free from ESKD in two-thirds of patients at 1 year and in one-half at 2 years and (ii) a significant reduction or even a discontinuation of albumin infusions allowing ambulatory care in a subset of patients. These results highlight the need for new therapeutic guidelines for CNS patients. PMID- 29474671 TI - Using Genotype Abundance to Improve Phylogenetic Inference. AB - Modern biological techniques enable very dense genetic sampling of unfolding evolutionary histories, and thus frequently sample some genotypes multiple times. This motivates strategies to incorporate genotype abundance information in phylogenetic inference. In this article, we synthesize a stochastic process model with standard sequence-based phylogenetic optimality, and show that tree estimation is substantially improved by doing so. Our method is validated with extensive simulations and an experimental single-cell lineage tracing study of germinal center B cell receptor affinity maturation. PMID- 29474672 TI - Leptomeninges-Derived Induced Pluripotent Stem Cells and Directly Converted Neurons From Autopsy Cases With Varying Neuropathologic Backgrounds. AB - Patient-specific stem cell technology from skin and other biopsy sources has transformed in vitro models of neurodegenerative disease, permitting interrogation of the effects of complex human genetics on neurotoxicity. However, the neuropathologic changes that underlie cognitive and behavioral phenotypes can only be determined at autopsy. To better correlate the biology of derived neurons with age-related and neurodegenerative changes, we generated leptomeningeal cell lines from well-characterized research subjects that have undergone comprehensive postmortem neuropathologic examinations. In a series of proof of principle experiments, we reprogrammed autopsy leptomeningeal cell lines to human-induced pluripotent stem cells (hiPSCs) and differentiated these into neurons. We show that leptomeningeal-derived hiPSC lines can be generated from fresh and frozen leptomeninges, are pluripotent, and retain the karyotype of the starting cell population. Additionally, neurons differentiated from these hiPSCs are functional and produce measurable Alzheimer disease-relevant analytes (Abeta and Tau). Finally, we used direct conversion protocols to transdifferentiate leptomeningeal cells to neurons. These resources allow the generation of in vitro models to test mechanistic hypotheses as well as diagnostic and therapeutic strategies in association with neuropathology, clinical and cognitive data, and biomarker studies, aiding in the study of late-onset Alzheimer disease and other age related neurodegenerative diseases. PMID- 29474674 TI - Seasonal variations in sleep of free-ranging Arabian oryx (Oryx leucoryx) under natural hyperarid conditions. AB - Study Objectives: The Arabian oryx lives under hyperarid conditions in the Arabian Desert and exhibits temporal niche switching of activity patterns at a seasonal level. The objective of the current study was to provide a polysomnographic-based study of sleep in free-roaming Arabian oryx in their natural habitat to determine whether extreme seasonal climate variations resulted in changes in sleep patterns and physiology associated with the seasonal switching of temporal niches. Methods: Electroencephalography, nuchal electromyography, actigraphy, and subcutaneous temperature were recorded in free roaming Arabian oryx in the Mahazat as-Sayd Protected Area, Kingdom of Saudi Arabia during winter and summer. Results : Total daily sleep time in winter was 6.69 and 3.77 hr in summer. In winter, oryx exhibited nocturnal sleep typical of artiodactyls of around 60 kg body mass. In summer, oryx slept mostly during the day and subcutaneous temperature was seen to rise during sleep, but not as rapidly as the rises observed in ambient air temperature. Rapid eye movement sleep formed a very small percentage of total sleep time, especially so in the summer. Conclusions: The unusual sleep patterns and physiology during summer appear to be related to high ambient air temperatures that affect both intrinsic and extrinsic factors necessary for survival. The Arabian oryx appears to use sleep physiology as an adaptive thermoregulatory mechanism in the hot summer months. PMID- 29474673 TI - Genetic instability associated with loop or stem-loop structures within transcription units can be independent of nucleotide excision repair. AB - Simple sequence repeats (SSRs) are found throughout the genome, and under some conditions can change in length over time. Germline and somatic expansions of trinucleotide repeats are associated with a series of severely disabling illnesses, including Huntington's disease. The underlying mechanisms that effect SSR expansions and contractions have been experimentally elusive, but models suggesting a role for DNA repair have been proposed, in particular the involvement of transcription-coupled nucleotide excision repair (TCNER) that removes transcription-blocking DNA damage from the transcribed strand of actively expressed genes. If the formation of secondary DNA structures that are associated with SSRs were to block RNA polymerase progression, TCNER could be activated, resulting in the removal of the aberrant structure and a concomitant change in the region's length. To test this, TCNER activity in primary human fibroblasts was assessed on defined DNA substrates containing extrahelical DNA loops that lack discernible internal base pairs or DNA stem-loops that contain base pairs within the stem. The results show that both structures impede transcription elongation, but there is no corresponding evidence that nucleotide excision repair (NER) or TCNER operates to remove them. PMID- 29474675 TI - Machine perfusion and long-term kidney transplant recipient outcomes across allograft risk strata. AB - Background: The use of machine perfusion (MP) in kidney transplantation lowers delayed graft function (DGF) and improves 1-year graft survival in some, but not all, grafts. These associations have not been explored in grafts stratified by the Kidney Donor Profile index (KDPI). Methods: We analyzed 78 207 deceased-donor recipients using the Scientific Registry of Transplant Recipients data from 2006 to 2013. The cohort was stratified using the standard criteria donor/expanded criteria donor (ECD)/donation after cardiac death (DCD)/donation after brain death (DBD) classification and the KDPI scores. In each subgroup, MP use was compared with cold storage. Results: The overall DGF rate was 25.4% and MP use was associated with significantly lower DGF in all but the ECD-DCD donor subgroup. Using the donor source classification, the use of MP did not decrease death-censored graft failure (DCGF), except in the ECD-DCD subgroup from 0 to 1 year {adjusted hazard ratio [aHR] 0.56 [95% confidence interval (CI) 0.32-0.98]}. In the ECD-DBD subgroup, higher DCGF from 1 to 5 years was noted [aHR 1.15 (95% CI 1.01-1.31)]. Also, MP did not lower all-cause graft failure except in the ECD DCD subgroup from 0 to 1 year [aHR = 0.59 (95% CI 0.38-0.91)]. Using the KDPI classification, MP did not lower DCGF or all-cause graft failure, but in the <=70 subgroup, higher DCGF [aHR 1.16 (95% CI 1.05-1.27)] and higher all-cause graft failure [aHR 1.10 (95% CI 1.02-1.18)] was noted. Lastly, MP was not associated with mortality in any subgroup. Conclusions: Overall, MP did not lower DCGF. Neither classification better risk-stratified kidneys that have superior graft survival with MP. We question their widespread use in all allografts as an ideal approach to organ preservation. PMID- 29474676 TI - Featured Article: Caregiver Perceptions of Stress and Sibling Conflict During Pediatric Cancer Treatment. AB - Objective: The current study examined the effect of stress on sibling conflict during the first year of pediatric cancer treatment. Method: Families (N = 103) included a child with cancer (aged 2-17 years, Mage = 6.46, SD = 3.52) and at least one sibling aged <5 years of the child with cancer (Mage = 8.34, SD = 5.61). Primary caregivers completed monthly questionnaires throughout the first year of treatment assessing five sources of stress (i.e., general life, cancer related, financial, perceived treatment intensity, and life threat) and level of sibling conflict. Using multilevel modeling, we explored the effects of these stressors on conflict both at the within- and between-family levels to examine if changes in stress resulted in concurrent changes in conflict within an individual family, and whether greater average stress affected the trajectory of conflict between families, respectively. Results: At the between-family level, higher average levels of cancer-related stress, general life stress, and financial stress were associated with higher sibling conflict at the end of the first year of treatment. Perceived treatment intensity and life threat were not associated with conflict. No stressors were associated with conflict at the within-family level. Conclusions: During pediatric cancer treatment, some stressors may spill over into family relationships and contribute to increases in sibling conflict. PMID- 29474677 TI - Autophagy-related approaches for improving nutrient use efficiency and crop yield protection. AB - Autophagy is a eukaryotic catabolic pathway essential for growth and development. In plants, it is activated in response to environmental cues or developmental stimuli. However, in contrast to other eukaryotic systems, we know relatively little regarding the molecular players involved in autophagy and the regulation of this complex pathway. In the framework of the COST (European Cooperation in Science and Technology) action TRANSAUTOPHAGY (2016-2020), we decided to review our current knowledge of autophagy responses in higher plants, with emphasis on knowledge gaps. We also assess here the potential of translating the acquired knowledge to improve crop plant growth and development in a context of growing social and environmental challenges for agriculture in the near future. PMID- 29474678 TI - Society of Behavioral Medicine (SBM) position statement: restore CDC funding for firearms and gun violence prevention research. AB - The Society for Behavioral Medicine (SBM) urges restoration of Centers for Disease Control and Prevention (CDC) funding for firearms and gun violence prevention research. Gun violence in the United States is an important and costly public health issue in need of research attention. Unfortunately, there have been no concerted CDC-funded research efforts in this area since 1996, due to the passage of the Dickey Amendment. To remedy the information-gathering restrictions caused by the Dickey Amendment bans, it is recommended that Congress remove 'policy riders' on federal appropriations bills that limit firearms research at the CDC; expand NVDRS firearms-related data collection efforts to include all fifty states; fund CDC research on the risk and protective factors of gun use and gun violence prevention; fund research on evidence-based primary, secondary, and tertiary prevention and treatment initiatives for communities that are seriously impacted by the effects of gun violence; and support the development of evidence based policy and prevention recommendations for gun use and ownership. PMID- 29474679 TI - Testing the plant pneumatic method to estimate xylem embolism resistance in stems of temperate trees. AB - Methods to estimate xylem embolism resistance generally rely on hydraulic measurements, which can be far from straightforward. Recently, a pneumatic method based on air flow measurements of terminal branch ends was proposed to construct vulnerability curves by linking the amount of air extracted from a branch with the degree of embolism. We applied this novel technique for 10 temperate tree species, including six diffuse, two ring-porous and two gymnosperm species, and compared the pneumatic curves with hydraulic ones obtained from either the flow centrifuge or the hydraulic-bench dehydration method. We found that the pneumatic method provides a good estimate of the degree of xylem embolism for all angiosperm species. The xylem pressure at 50% and 88% loss of hydraulic conductivity (i.e., Psi50 and Psi88) based on the methods applied showed a strongly significant correlation for all eight angiosperms. However, the pneumatic method showed significantly reduced Psi50 values for the two conifers. Our findings suggest that the pneumatic method could provide a fast and accurate approach for angiosperms due to its convenience and feasibility, at least within the range of embolism resistances covered by our samples. PMID- 29474681 TI - Comparative transcriptome analysis reveals an early gene expression profile that contributes to cold resistance in Hevea brasiliensis (the Para rubber tree). AB - The rubber tree (Hevea brasiliensis Muell. Arg) is a tropical, perennial, woody plant that is susceptible to cold stress. In China, cold stress has been found to severely damage rubber plants in plantations in past decades. Although several Hevea clones that are resistant to cold have been developed, their cold hardiness mechanism has yet to be elucidated. For the study reported herein, we subjected the cold-resistant clone CATAS93-114 and the cold-sensitive clone Reken501 to chilling stress, and characterized their transcriptomes at 0, 2, 8 and 24 h after the start of chilling. We found that 7870 genes were differentially expressed in the transcriptomes of the two clones. In CATAS93-114, a greater number of genes were found to be up- or downregulated between 2 h and 8 h than in Reken501, which indicated a more rapid and intensive response by CATAS93-114 than by Reken501. The differentially expressed genes were grouped into seven major clusters, according to their Gene Ontology terms. The expression profiles for genes involved in abscisic acid metabolism and signaling, in an abscisic acid independent pathway, and in early signal perception were found to have distinct expression patterns for the transcriptomes of the two clones. The differential expression of 22 genes that appeared to have central roles in response to chilling was confirmed by quantitative real-time PCR. PMID- 29474680 TI - Shared Genetic Risk of Schizophrenia and Gray Matter Reduction in 6p22.1. AB - Genetic factors are known to influence both risk for schizophrenia (SZ) and variation in brain structure. A pressing question is whether the genetic underpinnings of brain phenotype and the disorder overlap. Using multivariate analytic methods and focusing on 1,402 common single-nucleotide polymorphisms (SNPs) mapped from the Psychiatric Genomics Consortium (PGC) 108 regions, in 777 discovery samples, we identified 39 SNPs to be significantly associated with SZ discriminating gray matter volume (GMV) reduction in inferior parietal and superior temporal regions. The findings were replicated in 609 independent samples. These 39 SNPs in chr6:28308034-28684183 (6p22.1), the most significant SZ-risk region reported by PGC, showed regulatory effects on both DNA methylation and gene expression of postmortem brain tissue and saliva. Furthermore, the regulated methylation site and gene showed significantly different levels of methylation and expression in the prefrontal cortex between cases and controls. In addition, for one regulated methylation site we observed a significant in vivo methylation-GMV association in saliva, suggesting a potential SNP-methylation-GMV pathway. Notably, the risk alleles inferred for GMV reduction from in vivo imaging are all consistent with the risk alleles for SZ inferred from postmortem data. Collectively, we provide evidence for shared genetic risk of SZ and regional GMV reduction in 6p22.1 and demonstrate potential molecular mechanisms that may drive the observed in vivo associations. This study motivates dissecting SZ-risk variants to better understand their associations with focal brain phenotypes and the complex pathophysiology of the illness. PMID- 29474682 TI - A multisite, longitudinal study of risk factors for incarceration and impact on mental health and substance use among young transgender women in the USA. AB - Background: Transgender women are disproportionately incarcerated in the US relative to the general population. A dearth of research has explored the factors that predict incarceration among transgender women or the longitudinal impact of incarceration on the health of this population. Methods: Between 2012 and 2015, 221 transgender women ages 16-29 from Boston, MA and Chicago, IL were prospectively assessed at baseline, 4, 8 and 12 months. Mixed effects models were used to identify risk factors for incarceration and examine whether incarceration predicts somatic, anxiety and depressive symptoms, illicit drug use, and binge drinking over time, controlling for baseline psychiatric and substance use disorders. Results: Overall, 38% experienced incarceration, before (33%) and during (18%) the study period. Significant independent predictors of recent incarceration included sex work, recent homelessness, school dropout and number of times incarcerated prior to enrollment while recent incarceration significantly predicted somatic symptoms and illicit drug use over time. Conclusions: Incarceration burden is high in young transgender women. Both structural and individual risk factors predict incarceration and poor health, suggesting the need for multilevel interventions to prevent incarceration and support young transgender women during incarceration and upon release. PMID- 29474683 TI - The response of mesophyll conductance to short-term variation in CO2 in the C4 plants Setaria viridis and Zea mays. AB - Mesophyll conductance (gm) limits rates of C3 photosynthesis but little is known about its role in C4 photosynthesis. If gm were to limit C4 photosynthesis, it would likely be at low CO2 concentrations (pCO2). However, data on C4-gm across ranges of pCO2 are scarce. We describe the response of C4-gm to short-term variation in pCO2, at three temperatures in Setaria viridis, and at 25 degrees C in Zea mays. Additionally, we quantified the effect of finite gm calculations of leakiness (phi) and the potential limitations to photosynthesis imposed by stomata, mesophyll, and carbonic anhydrase (CA) across pCO2. In both species, gm increased with decreasing pCO2. Including a finite gm resulted in either no change or increased phi compared with values calculated with infinite gm depending on whether the observed 13C discrimination was high (Setaria) or low (Zea). Post-transitional regulation of the maximal PEP carboxylation rate and PEP regeneration limitation could influence estimates of gm and phi. At pCO2 below ambient, the photosynthetic rate was limited by CO2 availability. In this case, the limitation imposed by the mesophyll was similar or slightly lower than stomata limitation. At very low pCO2, CA further constrained photosynthesis. High gm could increase CO2 assimilation at low pCO2 and improve photosynthetic efficiency under situations when CO2 is limited, such as drought. PMID- 29474684 TI - Leaf turgor loss point is correlated with drought tolerance and leaf carbon economics traits. AB - Leaf turgor loss point (pitlp) indicates the capacity of a plant to maintain cell turgor pressure during dehydration, which has been proven to be strongly predictive of the plant response to drought. In this study, we compiled a data set of pitlp for 1752 woody plant individuals belonging to 389 species from nine major woody biomes in China, along with reduced sample size of hydraulic and leaf carbon economics data. We aimed to investigate the variation of pitlp across biomes varying in water availability. We also tested two hypotheses: (i) pitlp predicts leaf hydraulic safety margins and (ii) it is correlated with leaf carbon economics traits. Our results showed that there was a positive relationship between pitlp and aridity index: biomes from humid regions had less negative values than those from arid regions. This supports the idea that pitlp may reflect drought tolerance at the scale of woody biomes. As expected, pitlp was significantly positively correlated with leaf hydraulic safety margins that varied significantly across biomes, indicating that this trait may be useful in modelling changes of forest components in response to increasing drought. Moreover, pitlp was correlated with a suite of coordinated hydraulic and economics traits; therefore, it can be used to predict the position of a given species along the 'fast-slow' whole-plant economics spectrum. This study expands our understanding of the biological significance of pitlp not only in drought tolerance, but also in the plant economics spectrum. PMID- 29474686 TI - Empowerment in Action: #SWLeadAdvocateChampion. PMID- 29474685 TI - Process evaluation of the HealtheStepsTM lifestyle prescription program. AB - Physical inactivity, sedentary behavior, and poor diet are contributing to the rise in chronic disease rates throughout the world. HealtheStepsTM is a lifestyle prescription program focused on reducing risk factors for chronic disease through in-person coaching sessions, goal setting and tracking, and technology supports. A process evaluation was conducted alongside a pragmatic randomized controlled trial to: (a) explore the acceptability of HealtheStepsTM program from coach and participant perspectives; and (b) identify where the program can be improved. Participants at risk or diagnosed with a chronic disease were recruited from five primary care/health services organizations into HealtheStepsTM. Participants met with a trained coach bi-monthly for 6 months and set goals for physical activity (step counts), exercise (moderate to vigorous activity), and healthy eating. Coaches were interviewed at month 6 and participants at month 12 (6 months postprogram). All coach interviews (n = 12) were analyzed along with a purposeful sample of participant interviews (n = 13). Coaches found that HealtheStepsTM was easy to deliver and recommendations for exercise and healthy eating were helpful. Including discussions on participant readiness to change, along with group sessions, and more in-depth healthy eating resources were suggested by coaches to improve the program. Participants described the multiple avenues of accountability provided in the program as helpful. However, more feedback and interaction during and postprogram from coaches were suggested by participants. HealtheStepsTM is an acceptable program from the perspectives of both coaches and participants with suggested improvements not requiring significant changes to the core program design. PMID- 29474687 TI - Enhanced Automatic Action Imitation and Intact Imitation-Inhibition in Schizophrenia. AB - Imitation plays a key role in social learning and in facilitating social interactions and likely constitutes a basic building block of social cognition that supports higher-level social abilities. Recent findings suggest that patients with schizophrenia have imitation impairments that could contribute to the social impairments associated with the disorder. However, extant studies have specifically assessed voluntary imitation or automatic imitation of emotional stimuli without controlling for potential confounders. The imitation impairments seen might therefore be secondary to other cognitive, motoric, or emotional deficits associated with the disorder. To overcome this issue, we used an automatic imitation paradigm with nonemotional stimuli to assess automatic imitation and the top-down modulation of imitation where participants were required to lift one of 2 fingers according to a number shown on the screen while observing the same or the other finger movement. In addition, we used a control task with a visual cue in place of a moving finger, to isolate the effect of observing finger movement from other visual cueing effects. Data from 33 patients (31 medicated) and 40 matched healthy controls were analyzed. Patients displayed enhanced imitation and intact top-down modulation of imitation. The enhanced imitation seen in patients may have been medication induced as larger effects were seen in patients receiving higher antipsychotic doses. In sum, we did not find an imitation impairment in schizophrenia. The results suggest that previous findings of impaired imitation in schizophrenia might have been due to other cognitive, motoric, and/or emotional deficits. PMID- 29474688 TI - Preoperative Use of Neuromodulators to Optimize Surgical Outcomes in Upper Blepharoplasty and Brow Lift. AB - Background: Upper eyelid dermatochalasis often triggers frontalis hyperactivity in an effort to elevate the upper lids away from the visual axis. Similarly, prior neuromodulator treatment of the brow depressors may cause false elevation of the brows, diminishing the extent of preoperative brow ptosis or dermatochalasis. Studies have quantified postoperative brow ptosis and recurrent dermatochalasis following upper blepharoplasty, but a methodology to predict the postoperative brow position remains to be elucidated. Objectives: The authors present our comprehensive perioperative protocol utilizing neuromodulators to optimize results of upper blepharoplasty and brow lift. Methods: In patients presenting with upper lid dermatochalasis and frontalis hyperactivity, who request upper blepharoplasty, the authors apply a neuromodulator treatment protocol. Patients with prior neuromodulator treatment of brow depressors wait four months after the last treatment to allow for product attrition. Two weeks prior to surgery, the authors treat the frontalis with 15 to 20 units of Botox Cosmetic. Results: From 2002 to 2016, the authors treated 521 patients (458 women, 63 men) with frontalis hyperactivity who presented for periorbital rejuvenation. This method has led to neither excessive resection of upper eyelid skin tissue nor lagophthalmos. Preoperatively, the authors have unveiled upper eyelid ptosis in 39 patients (31 women, 8 men) and brow ptosis in 131 patients (97 women, 34 men). Conclusions: Brow position and frontalis hyperactivity should be taken into consideration during preoperative evaluation for upper blepharoplasty and brow lift. Routine preoperative treatment of the hyperactive frontalis with neuromodulator, along with attrition of prior neuromodulator in the brow depressors, reveals the true anatomic brow position to optimize surgical planning. Level of Evidence 4: PMID- 29474689 TI - Pseudohypoparathyroidism type 1a. PMID- 29474690 TI - Seven-Year Evaluation of Insecticide Tools for Emerald Ash Borer in Fraxinus pennsylvanica (Lamiales: Oleaceae) Trees. AB - Emerald ash borer (EAB), Agrilus planipennis (Fairmaire; Coleoptera: Buprestidae), is decimating ash trees (Fraxinus spp.) in North America. Combatting EAB includes the use of insecticides; however, reported insecticide efficacy varies among published studies. This study assessed the effects of season of application, insecticide active ingredient, and insecticide application rate on green ash (Fraxinus pennsylvanica Marsh.) (Lamiales: Oleaceae) canopy decline caused by EAB over a 5- to 7-yr interval. Data suggested that spring treatments were generally more effective in reducing canopy decline than fall treatments, but this difference was not statistically significant. Lowest rates of decline (<5% over 5 yr) were observed in trees treated with imidacloprid injected annually in the soil during spring (at the higher of two tested application rates; 1.12 g/cm diameter at 1.3 m height) and emamectin benzoate injected biennially into the stem. All tested insecticides (dinotefuran, emamectin benzoate, and imidacloprid) under all tested conditions significantly reduced the rate of increase of dieback. PMID- 29474691 TI - Celiac artery compression syndrome (CACS) as a cause of abdominal bruit. PMID- 29474692 TI - Commonalities and Differences in Controlling Multipartite Intracellular Infections of Legume Roots by Symbiotic Microbes. AB - Legumes have the almost unique ability to establish symbiotic associations with rhizobia and arbuscular mycorrhizal fungi. Forward and reverse genetics have identified a large number of genes that are required for either or both interactions. However, and in sharp contrast to natural soils, these interactions have been almost exclusively investigated under laboratory conditions by using separate inoculation systems, whereas both symbionts are simultaneously present in the field. Considering our recent understanding of the individual symbioses, the community is now promisingly positioned to co-inoculate plants with two or more microbes in order to understand mechanistically how legumes efficiently balance, regulate and potentially separate these symbioses and other endophytic microbes within the same root. Here, we discuss a number of key control layers that should be considered when assessing tri- or multipartite beneficial interactions and that may contribute to colonization patterns in legume roots. PMID- 29474693 TI - The Use of RNA Sequencing and Correlation Network Analysis to Study Potential Regulators of Crabapple Leaf Color Transformation. AB - Anthocyanins are plant pigments that contribute to the color of leaves, flowers and fruits, and that are beneficial to human health in the form of dietary antioxidants. The study of a transformable crabapple cultivar, 'India magic', which has red buds and green mature leaves, using mRNA profiling of four leaf developmental stages, allowed us to characterize molecular mechanisms regulating red color formation in early leaf development and the subsequent rapid down regulation of anthocyanin biosynthesis. This analysis of differential gene expression during leaf development revealed that ethylene signaling-responsive genes are up-regulated during leaf pigmentation. Genes in the ethylene response factor (ERF), SPL, NAC, WRKY and MADS-box transcription factor (TF) families were identified in two weighted gene co-expression network analysis (WGCNA) modules as having a close relationship to anthocyanin accumulation. Analyses of network hub genes indicated that SPL TFs are located in central positions within anthocyanin related modules. Furthermore, cis-motif and yeast one-hybrid assays suggested that several anthocyanin biosynthetic or regulatory genes are potential targets of SPL8 and SPL13B. Transient silencing of these two genes confirmed that they play a role in co-ordinating anthocyanin biosynthesis and crabapple leaf development. We present a high-resolution method for identifying regulatory modules associated with leaf pigmentation, which provides a platform for functional genomic studies of anthocyanin biosynthesis. PMID- 29474694 TI - A MONTE CARLO TOOL FOR MULTI-TARGET NANODOSIMETRY. AB - A Monte Carlo simulation tool has been developed, based on the physical models of the Geant4-DNA extension of Geant4, to study the ionisation pattern of charged particles in a multi-target environment. The tool allows to code easily the geometry to build a simulation with multiple targets, since several parameters can be changed interactively and independently via macro commands. In this work a set of nanometric target spheres is embedded in a cylindrical water phantom 20 nm in height and 40 nm in diameter. The targets are randomly distributed in such a way that they do not overlap and are contained within a smaller cylindrical volume 20 nm in diameter and height. The water phantom is irradiated by ions which are shot parallel to the central axis and randomly distributed over the cross section of the inner cylinder. Two different types of simulations are performed. In one, the penumbra of secondary electrons is fully simulated, in the other the transport of secondary electrons is carried out only if they are produced inside one of the targets, and the electron track is terminated when it leaves the sphere of production. First results are presented and discussed. PMID- 29474695 TI - Age Differences in Beliefs about Emotion Regulation Strategies. AB - Objectives: Age shifts in emotion regulation may be rooted in beliefs about different strategies. We test whether there are age differences in the beliefs people hold about specific emotion regulation strategies (derived from the process model of emotion regulation: Gross, 1998) and whether profiles of emotion beliefs vary by age. Method: An adult lifespan sample (N = 557) sorted 13 emotion regulation strategies either by (a) how effective the strategies would be or (b) how likely they would be to use them, in 15 negative emotion-eliciting situations. Results: Younger adults ranked attentional and cognitive distraction more effective than older adults, and preferred avoidance, distraction, and rumination more (and attentional deployment less) than middle-aged and older adults. Latent profile analysis on preferences identified three distinct strategy profiles: Classically adaptive regulators preferred a variety of strategies; situation modifiers showed strong preferences for changing situations; a small percentage of people preferred avoidance and rumination. Middle-aged and older adults were more likely than younger adults to be classically adaptive regulators (as opposed to situation modifiers or avoiders/ruminators). Discussion: These findings provide insight into the reasons people of different ages may select and implement different emotion regulation strategies, which may influence their emotional well-being. PMID- 29474696 TI - Situation-Based Contingencies Underlying Wisdom-Content Manifestations: Examining Intellectual Humility in Daily Life. AB - Objectives: Existing assessments of intellectual humility (IH)-a key component of wisdom-do not examine its manifestation in daily life while sufficiently focusing on the core idea of the construct: owning up to one's intellectual shortcomings. The present research sought to examine situational contingencies underlying daily manifestations of IH-relevant characteristics. Research Design and Methods: We developed a trait version of the State-Trait IH Scale in two studies and subsequently examined daily manifestations of IH-relevant characteristics utilizing a contextualized state version of the State-Trait IH Scale in a 21-day experience sampling study. Here, we tested how specific situational contingencies (associated with the context and the personality of the individual with whom participants engaged) influenced the manifestation of IH-relevant qualities. Results: We found strong evidence for the validity of both versions of the scale. Specifically, the state measure exhibited high within-person variability, and aggregated state assessments were strongly correlated with the trait measure. Additionally, morality positively predicted manifestation of IH, whereas disagreeableness negatively predicted manifestation of IH. Discussion and Implications: These results offer new directions for research on the expression of wisdom-related characteristics in daily life. PMID- 29474697 TI - Large-Vessel Vasculitis Visualisation with [18F]-fluorodeoxyglucose Uptake. PMID- 29474698 TI - Antibodies in the Diagnosis, Prognosis, and Prediction of Psychotic Disorders. AB - Blood-based biomarker discovery for psychotic disorders has yet to impact upon routine clinical practice. In physical disorders antibodies have established roles as diagnostic, prognostic and predictive (theranostic) biomarkers, particularly in disorders thought to have a substantial autoimmune or infective aetiology. Two approaches to antibody biomarker identification are distinguished: a "top-down" approach, in which antibodies to specific antigens are sought based on the known function of the antigen and its putative role in the disorder, and emerging "bottom-up" or "omics" approaches that are agnostic as to the significance of any one antigen, using high-throughput arrays to identify distinctive components of the antibody repertoire. Here we review the evidence for antibodies (to self-antigens as well as infectious organism and dietary antigens) as biomarkers of diagnosis, prognosis, and treatment response in psychotic disorders. Neuronal autoantibodies have current, and increasing, clinical utility in the diagnosis of organic or atypical psychosis syndromes. Antibodies to selected infectious agents show some promise in predicting cognitive impairment and possibly other symptom domains (eg, suicidality) within psychotic disorders. Finally, infectious antibodies and neuronal and other autoantibodies have recently emerged as potential biomarkers of response to anti infective therapies, immunotherapies, or other novel therapeutic strategies in psychotic disorders, and have a clear role in stratifying patients for future clinical trials. As in nonpsychiatric disorders, combining biomarkers and large scale use of "bottom-up" approaches to biomarker identification are likely to maximize the eventual clinical utility of antibody biomarkers in psychotic disorders. PMID- 29474700 TI - Content analysis of Twitter chatter about indoor tanning. AB - Twitter may be useful for learning about indoor tanning behavior and attitudes. The objective of this study was to analyze the content of tweets about indoor tanning to determine the extent to which tweets are posted by people who tan, and to characterize the topics of tweets. We extracted 4,691 unique tweets from Twitter using the terms "tanning bed" or "tanning salon" over 7 days in March 2016. We content analyzed a random selection of 1,000 tweets, double-coding 20% of tweets (kappa = 0.74, 81% agreement). Most tweets (71%) were by tanners (n = 699 individuals) and included tweets expressing positive sentiment about tanning (57%), and reports of a negative tanning experience (17%), burning (15%), or sleeping in a tanning bed (9%). Four percent of tweets were by tanning salon employees. Tweets posted by people unlikely to be tanners (15%) included tweets mocking tanners (71%) and health warnings (29%). The term "tanning bed" had higher precision for identifying individuals who engage in indoor tanning than "tanning salon"; 77% versus 45% of tweets captured by these search terms were by individuals who engaged in indoor tanning, respectively. Extrapolating to the full data set of 4,691 tweets, findings suggest that an average of 468 individuals who engage in indoor tanning can be identified by their tweets per day. The majority of tweets were from tanners and included reports of especially risky habits (e.g., burning, falling asleep). Twitter provides opportunity to identify indoor tanners and examine conversations about indoor tanning. PMID- 29474699 TI - Rationale and design of the EACVI AFib Echo Europe Registry for assessing relationships of echocardiographic parameters with clinical thrombo-embolic and bleeding risk profile in non-valvular atrial fibrillation. AB - The European Society of Cardiology (ESC) guidelines for management of atrial fibrillation (AF) recommend the use of CHA2DS2VASc risk score for assessment of thromboembolic (TE) risk, whereas the stratification of bleeding risk should be obtained by HAS-Bleed to balance the most appropriate anticoagulation (OAC) therapy. However, men with CHA2DS2VASc score = 1 and women with CHA2DS2VASc = 2, who are at intermediate TE risk, represent a grey zone where guidelines do not provide a definite OAC indication. Accordingly, implementation of risk stratification with echocardiography could be extremely useful. Both prospective and cross-sectional studies on transthoracic echocardiography (TTE) prediction of TE events and studies utilizing transoesophageal echocardiographic parameters as surrogate markers of TE events makes sustainable the hypothesis that echocardiography could improve TE prediction in non-valvular AF. Moreover, considering the close association of AF and stroke, all echo-Doppler parameters that have shown to predict AF onset and recurrence could be useful also to predict TE events in this clinical setting. Accordingly, EACVI AFib Echo Europe Registry has been designed as an observational, cross-sectional study, with the aim of evaluating: (i) left atrial (LA) size and function together with left ventricular geometry, systolic and diastolic functions in paroxysmal, persistent, and permanent AF; (ii) relationships of structural/functional parameters with clinical TE and bleeding risk profile. By the AFib Echo Europe Registry, we expect to collect data on echocardiographic phenotype of patients with AF. The large data set accumulated will be useful to test the level of agreement of different echocardiographic measurements with the available risk scores. PMID- 29474701 TI - The direction of carbon and nitrogen fluxes between ramets in Agrostis stolonifera changes during ontogeny under simulated competition for light. AB - Resource sharing is universal among connected ramets of clonal plants and is driven both by the developmental status of the ramets and the resource gradients. Above-ground competition forms spatial light gradients, but the role of resource sharing in such competition is unclear. We examined translocation of resources between mother and daughter ramets of Agrostis stolonifera under light heterogeneity throughout ramet ontogeny. We labelled ramets with 13C and 15N to estimate the bidirectional translocation of resources at three developmental stages of the daughters. In addition, we compared the final biomass of integrated and severed ramets in order to estimate the effect of integration on growth. Young developing daughters were supported by carbon, whereas nitrogen was only translocated towards daughters at the beginning of rooting, regardless of the light conditions. Shading of mothers was a major determinant of resource translocation between developed ramets, with carbon being preferentially moved to daughters from shaded mothers while nitrogen translocation was limited from daughters to shaded mothers. Surprisingly, the absolute amounts of translocated resources did not decline during development. Growth of daughters was enhanced by integration regardless of the shading. Overall, A. stolonifera maximizes the resource translocation pattern in order to enable it to spread from unfavourable habitats, rather than compensating for light heterogeneity among ramets. PMID- 29474702 TI - A weight loss intervention using a commercial mobile application in Latino Americans-Adelgaza Trial. AB - More than half of Latino adults living in the USA are expected to develop type 2 diabetes in their lifetime. Despite the growing interest in smartphone use for weight loss and diabetes prevention, relatively few clinical trials have evaluated the efficacy of mobile app-based interventions in Latino populations. The aim of this study was to evaluate the potential efficacy of an in-person weight loss intervention in conjunction with a commercially available Fitbit app in a Latino sample at risk for type 2 diabetes and explore significant predictors associated with weight loss. After the run-in period, 54 self-identified Latinos with body mass index (BMI) > 24.9 kg/m2 were enrolled in an 8-week uncontrolled pilot study, and received a Fitbit Zip, its app, and two in-person weight loss sessions adapted from the Diabetes Prevention Program. Mean age was 45.3 (SD +/- 10.8) years, 61.1% were born in the USA, and mean BMI was 31.4 (SD +/- 4.1) kg/m2. Participants lost an average of 3.3 (SD +/- 3.4) % of their body weight (p < .0005). We also observed statistically significant reductions in hip and waist circumferences, and systolic and diastolic blood pressure (p < .001). After controlling for demographic factors, use of the mobile app weight diary at least twice a week (p = .01) and change in the International Physical Activity Questionnaire score (p = .03) were associated with change in percent body weight. The intervention showed the potential efficacy of this intervention, which should be formally evaluated in a randomized controlled trial. PMID- 29474703 TI - Estimation of phloem carbon translocation belowground at stand level in a hinoki cypress stand. AB - At stand level, carbon translocation in tree stems has to match canopy photosynthesis and carbohydrate requirements to sustain growth and the physiological activities of belowground sinks. This study applied the Hagen Poiseuille equation to the pressure-flow hypothesis to estimate phloem carbon translocation and evaluate what percentage of canopy photosynthate can be transported belowground in a hinoki cypress (Chamaecyparis obtusa Sieb. et Zucc.) stand. An anatomical study revealed that, in contrast to sieve cell density, conductive phloem thickness and sieve cell hydraulic diameter at 1.3 m in height increased with increasing tree diameter, as did the concentration of soluble sugars in the phloem sap. At tree level, hydraulic conductivity increased by two orders of magnitude from the smallest to the largest trees in the stand, resulting in a stand-level hydraulic conductance of 1.7 * 10-15 m Pa-1 s-1. The osmotic potential of the sap extracted from the inner bark was -0.75 MPa. Assuming that phloem water potential equalled foliage water potential at predawn, the turgor pressure in the phloem at 1.3 m in height was estimated at 0.22 MPa, 0.59 MPa lower than values estimated in the foliage. With this maximal turgor pressure gradient, which would be lower during day-time when foliage water potential drops, the estimated stand-level rate of carbon translocation was 2.0 gC m-2 day-1 (30% of daily gross canopy photosynthesis), at a time of the year when aboveground growth and related respiration is thought to consume a large fraction of photosynthate, at the expense of belowground activity. Despite relying on some assumptions and approximations, this approach, when coupled with measurements of canopy photosynthesis, may further be used to provide qualitative insight into the seasonal dynamics of belowground carbon allocation. PMID- 29474704 TI - Renewed interest in whole-plant physiology sheds light on the complexity of plant stress response architecture. PMID- 29474706 TI - Environmental History and New Directions in Modern British Historiography. PMID- 29474705 TI - PCB126 Inhibits the Activation of AMPK-CREB Signal Transduction Required for Energy Sensing in Liver. AB - 3,3',4,4',5-pentachlorobiphenyl (PCB126), a dioxin-like PCB, elicits toxicity through a wide array of noncarcinogenic effects, including metabolic syndrome, wasting, and nonalcoholic fatty-liver disease. Previously, we reported decreases in the transcription of several enzymes involved in gluconeogenesis, before the early onset of lipid accumulation. Hence, this study was aimed at understanding the impact of resultant decreases gluconeogenic enzymes on growth, weight, and metabolism in the liver, upon extended exposure. Male Sprague Dawley rats (75-100 g), fed a defined AIN-93G diet, were injected (ip) with single dose of soy oil (5 ml/kg body weight; n = 14) or PCB126 (5 umol/kg; n = 15), 28 days, prior euthanasia. A subset of rats from each group were fasted for 12 h (vehicle [n = 6] and PCB126 [n = 4]). Rats only showed significant weight loss between days 14 and 28 (p < .05) and some mortality (p = .0413). As in our previous studies, the expression levels of enzymes involved in gluconeogenesis (Pepck-c, G6Pase, Sds, Pc, and Ldh-A) and glycogenolysis (Pygl) were strongly downregulated. The decreased expression of these enzymes in PCB126-treated rats after a 12 h fast decreased hepatic glucose production from glycogen and gluconeogenic substrates, exacerbating the hypoglycemia. Additionally, PCB126 caused hepatic steatosis and decreased the expression of the transcription factor Pparalpha and its targets, necessary for fatty-acid oxidation. The observed metabolic disruption across multiple branches of fasting metabolism resulted from inhibition in the activation of enzyme AMPK and transcription factor CREB signaling, necessary for "sensing" energy-deprivation and the induction of enzymes that respond to the PCB126 triggered fuel crisis in liver. PMID- 29474707 TI - Immune Relevant Models for Ocular Inflammatory Diseases. AB - Ocular inflammatory diseases, such as dry eye and uveitis, are common, painful, difficult to treat, and may result in vision loss or blindness. Ocular side effects from the use of antiinflammatory drugs (such as corticosteroids or nonsteroidal antiinflammatories) to treat ocular inflammation have prompted development of more specific and safer medications to treat inflammatory and immune-mediated diseases of the eye. To assess the efficacy and safety of these new therapeutics, appropriate immune-relevant animal models of ocular inflammation are needed. Both induced and naturally-occurring models have been described, but the most valuable for translating treatments to the human eye are the animal models of spontaneous, immunologic ocular disease, such as those with dry eye or uveitis. The purpose of this review is to describe common immune relevant models of dry eye and uveitis with an overview of the immuno pathogenesis of each disease and reported evaluation of models from small to large animals. We will also review a selected group of naturally-occurring large animal models, equine uveitis and canine dry eye, that have promise to translate into a better understanding and treatment of clinical immune-relevant ocular disease in man. PMID- 29474708 TI - Atrial myxoma with hemiplegia. PMID- 29474709 TI - Affinity maturation of an TpoR targeting antibody in full-length IgG form for enhanced agonist activity. AB - It has been observed that converting scFv formatted antibodies to full-length IgG often associates with loss of affinity. We aim to address this issue in this paper by establishing an integrated affinity maturation method applying yeast display technology platform. To demonstrate that, we employed a human thrombopoietin receptor targeting antibody named 3D9 which was identified previously from a combinational antibody library in scFv-Fc fusion protein form. We have observed that significant potency loss happened when 3D9 was transformed to full-length IgG form. In this study, we tested whether the potency of the full length IgG can be improved by affinity maturation of 3D9 using a modified Fab yeast display platform. An efficient CDR3 targeted mutagenesis strategy was designed for Fab library with pre-designed CDR diversity. Next generation sequencing was also used for evaluation of the enrichment process and investigation of sequence-function relationship of the antibody. A variant with improved affinity and higher potency was identified. The study demonstrates that the strategy we used here are efficient for optimizing affinity and activity of full-length IgGs. PMID- 29474710 TI - Carbohydrate dynamics of three dominant species in a Chinese savanna under precipitation exclusion. AB - The potential impact of drought on the carbon balance in plants has gained great attention. Non-structural carbohydrate (NSC) dynamics have been suggested as an important trait reflecting carbon balance under drought conditions. However, NSC dynamics under drought and the response mechanisms of NSC to drought remain unclear, especially in water-limited savanna ecosystems. A precipitation exclusion experiment was performed to simulate different drought intensities in a savanna ecosystem in Yuanjiang valley in southwestern China. Growth, total NSC concentration and diurnal change of NSC were determined for the leaves and non photosynthetic organs of three dominant species (Lannea coromandelica, Polyalthia cerasoides and Heteropogon contortus) throughout the growing season. Drought significantly reduced the growth of all the three species. Total NSC concentration averaged ~8.1%, varying with species, organ and sampling period, and did not significantly decrease under drought stress. By contrast, the diurnal change of NSC in these three species increased under drought stress. These results indicate that these three dominant species did not undergo carbon limitation. Thus, relative change in NSC is a more sensitive and effective indicator than carbon reserves in evaluation of plant carbon balance. These findings provide new insights for the understanding of carbon balance and the mechanisms of carbon starvation. PMID- 29474711 TI - Glycaemic control and cardiovascular risk factor management in patients with diabetes with and without coronary artery disease: insights from the diabetes mellitus status in Canada survey. AB - Aims: Current diabetes guidelines recommend an individualized approach to glycaemic control. There are limited data on the contemporary and comprehensive management of patients with diabetes in relation to coronary artery disease (CAD). Methods and results: The Diabetes Mellitus Status in Canada (DM-SCAN) survey included 5123 patients with type 2 diabetes seen in primary care in November 2012. Primary care physicians (PCPs) collected clinical data and specified the A1C target for each patient on standardized forms. We compared management strategies and achievement of treatment targets in patients with and without CAD. Among the 4994 patients with data on CAD history, 22.5% had CAD. Primary care physicians were more likely to select a higher A1C target for patients with CAD (<=7.5 or <=8.0%) versus without (<=7.0%). There was no difference in median A1C or in the proportion of patients with A1C <=7.0% between the two groups. Compared with the group without known CAD, patients with CAD had a higher reported prevalence of hypoglycaemia in the preceding 6 months; more frequently received aspirin, statins, ACE inhibitors, or angiotensin receptor blockers, and were more likely to achieve blood pressure and low-density lipoprotein-cholesterol targets. Only 15.4 and 12.0% of patients with and without CAD (P = 0.002), respectively, achieved all three guideline-recommended targets. Conclusion: Compared with patients with diabetes without CAD, those with CAD more frequently had a less stringent A1C target selected by their PCPs but achieved similar glycaemic control. Overall, risk factor management remained suboptimal in both groups. There remains an important opportunity to improve the care and outcome of patients with diabetes. PMID- 29474712 TI - Impact of achieved systolic blood pressure on renal function in hypertensive patients. AB - Aims: There is strong evidence for the association of high blood pressure (BP) with depressed renal function. Although high BP at baseline is associated with greater progression of chronic kidney disease (CKD), randomized trials in CKD patients have found no significant relationship between more intensive BP control and glomerular filtration rate (GFR) decline. However, the relationship of GFR and change in GFR over time to lower achieved systolic BP (SBP) in hypertensive patients undergoing treatment is unclear. Methods and results: Baseline estimated GFR (eGFR) and change in eGFR during follow-up were examined in relation to average on-treatment SBP in 8778 hypertensive patients with ECG left ventricular hypertrophy (LVH) randomly assigned to losartan- or atenolol-based treatment. GFR was estimated using the Modification of Diet in Renal Disease study equation. Patients with average on-treatment SBP <=130 mmHg (lowest quintile at last measurement) and average SBP between 131 and 141 mmHg were compared with patients with average SBP >=142 mmHg (median SBP at last measurement). Patients with an average on-treatment SBP <=130 mmHg had significantly lower baseline eGFR than those with average SBP between 131 and 141 or average SBP >=142 mmHg (65.5 +/- 14.3 vs. 69.3 +/- 14.3 vs. 69.0 +/- 14.5 mL/min/1.73 m2, P < 0.001 using analysis of covariance adjusting for age, sex, race, randomized treatment, prior antihypertensive treatment, history of diabetes, myocardial infarction, ischaemic heart disease or heart failure, smoking status, baseline serum glucose, total and HDL cholesterol, albuminuria, and baseline LVH by Cornell product and Sokolow Lyon voltage). However, the decrease in eGFR between baseline and Year 4 was significantly lower among patients with average SBP <=130 mmHg (-6.3 +/- 10.3 vs. -7.9 +/- 11.1 vs. -9.2 +/- 10.6 mL/min/1.73 m2, P = 0.001 when adjusting for the same variables and for change in Cornell product and Sokolow-Lyon voltage between baseline and Year 4). These differences in eGFR change persisted even after adjusting for baseline eGFR, and there were no significant interactions with randomized treatment, sex, race, or baseline presence of proteinuria. Conclusion: Lower average on-treatment SBP (<=130 mmHg) was associated with a lower baseline eGFR but with a slower reduction in eGFR during 4-year follow-up in hypertensive patients with ECG LVH, independent of other possible risk factors for decreased GFR. Further study is necessary to determine whether randomized treatment to lower SBP goals is more protective of renal function than treatment to standard SBP goals. Clinical trial registration: http://clinicaltrials.gov/ct/show/NCT00338260?order=1; unique identifier: NCT00338260. PMID- 29474713 TI - The role of mHealth for improving medication adherence in patients with cardiovascular disease: a systematic review. AB - Cardiovascular disease is a leading cause of morbidity and mortality worldwide, and a key barrier to improved outcomes is medication non-adherence. The aim of this study is to review the role of mobile health (mHealth) tools for improving medication adherence in patients with cardiovascular disease. We performed a systematic search for randomized controlled trials that primarily investigated mHealth tools for improving adherence to cardiovascular disease medications in patients with hypertension, coronary artery disease, heart failure, peripheral arterial disease, and stroke. We extracted and reviewed data on the types of mHealth tools used, preferences of patients and healthcare providers, the effect of the mHealth interventions on medication adherence, and the limitations of trials. We identified 10 completed trials matching our selection criteria, mostly with <100 participants, and ranging in duration from 1 to 18 months. mHealth tools included text messages, Bluetooth-enabled electronic pill boxes, online messaging platforms, and interactive voice calls. Patients and healthcare providers generally preferred mHealth to other interventions. All 10 studies reported that mHealth interventions improved medication adherence, though the magnitude of benefit was not consistently large and in one study was not greater than a telehealth comparator. Limitations of trials included small sample sizes, short duration of follow-up, self-reported outcomes, and insufficient assessment of unintended harms and financial implications. Current evidence suggests that mHealth tools can improve medication adherence in patients with cardiovascular diseases. However, high-quality clinical trials of sufficient size and duration are needed to move the field forward and justify use in routine care. PMID- 29474714 TI - Rhythmic and haemodynamic determinants of long-term survival after radiofrequency ablation of atrial fibrillation in mitral valve surgery. AB - Aims: The aim of the present study was to evaluate the effects of sinus rhythm recovery on long-term survival after radiofrequency (RF) ablation in patients with permanent atrial fibrillation (AF) undergoing surgery for mitral valve disease. Methods and results: This study included 173 consecutive patients (101 men and 72 women, age 67 +/- 9 years) with AF and mitral valve disease who underwent RF ablation procedure associated with mitral valve surgery. Four patients died during hospitalization. At the 6-year follow-up, sinus rhythm was present in 68% of the surviving patients. Thirty-nine patients remained in persistent AF after hospital discharge. In patients with stable sinus rhythm, mortality (10 vs. 30%) and recurrent hospitalization were significantly lower than in patients with persistent AF, but functional capacity improved. The incidence of stroke was also lower in patients with stable sinus rhythm. A pre operative higher right and left atrial area, pulmonary hypertension, and rheumatic disease were associated with the persistence of AF despite RF ablation. At multivariate analysis, only age and concomitant tricuspid valve repair were independently associated with mortality, whereas the right atria area and tricuspid valve repair were associated with persistent AF. Conclusion: Although the re-establishment of sinus rhythm by unipolar RF ablation is associated with a higher survival rate after mitral valve surgery, our data suggest that a more severe haemodynamic impairment, in particular in patients with rheumatic valve disease, may be responsible both for higher long-term mortality and lower rate of sinus rate maintenance. PMID- 29474716 TI - Corrigendum to: The European Society of Cardiology Atlas of Cardiology: rational, objectives, and methods. PMID- 29474715 TI - Characteristics and outcomes of atrial fibrillation patients with or without specific symptoms: results from the PREFER in AF registry. AB - Aims: Atrial fibrillation (AF) is a common condition that is a major cause of stroke. A significant proportion of patients with AF are not classically symptomatic at diagnosis or soon after diagnosis. There is little information comparing their characteristics, treatment, and outcomes of patients with symptoms, which predominate in clinical trials to those without. Methods and results: We analysed data from the Prevention of Thromboembolic Events-European Registry in Atrial Fibrillation. This was a prospective, real-world registry with a 12-month follow-up that included AF patients aged 18 years and over. Patients were divided into those with and without AF symptoms using the European Heart Rhythm Association (EHRA) score (Category I vs. Categories II-IV). Of the 6196 patients (mean age 72 years) with EHRA scores available, 501 (8.1%) were asymptomatic. A lower proportion of asymptomatic patients was female (22.8 vs. 41.2%), with less noted to have heart failure and coronary artery disease (P < 0.01 for all). There were no differences in terms of the prevalence of diabetes, obesity, or prior stroke. Asymptomatic patients had a lower CHA2DS2-VASc score (2.9 +/- 1.7 vs. 3.4 +/- 1.8; P < 0.01) and HAS-BLED score (1.8 +/- 1.1 vs. 2.1 +/- 1.2; P < 0.01). During the 1-year follow-up, adverse events occurred at similar frequencies in asymptomatic and symptomatic patients (1.6 vs. 0.8% for ischaemic stroke; P = 0.061; 1.4 vs. 1.3% for transient ischaemic attack; P = 0.840). Patients with higher CHA2DS2-VASc and HAS-BLED scores experienced more events, independent of symptoms. Antithrombotic therapy was comparable for both groups at baseline and at follow-up. Conclusions: The similar clinical characteristics and frequency of adverse events between asymptomatic and symptomatic AF patients revives the question of whether screening programmes to detect people with asymptomatic AF are worthwhile, particularly in those aged 65 and over potentially likely to have clinical and economic benefits from anticoagulants. This evidence may be informative if clinicians may not be comfortable participating in future clinical trials, leaving asymptomatic patients with AF and high stroke risk without anticoagulation. PMID- 29474717 TI - Improving cardiovascular risk in type 2 diabetes: time to get personal. PMID- 29474718 TI - Improving medical adherence in cardiovascular disease management with mHealth technologies. PMID- 29474719 TI - SPRINTing towards trials of blood pressure reduction to reduce CKD progression? PMID- 29474720 TI - Attempting to cure atrial fibrillation during mitral valve surgery: can we measure a benefit? PMID- 29474721 TI - Cost and efficacy of myocardial revascularization in the drug-eluting stent era: how much for how much? PMID- 29474722 TI - A systematic review of cost-effectiveness of percutaneous coronary intervention vs. surgery for the treatment of multivessel coronary artery disease in the drug eluting stent era. AB - Aims: The suitability of percutaneous coronary intervention (PCI), compared with coronary artery bypass grafting (CABG), for patients with complex multivessel coronary artery disease (MVCAD) remains a contentious topic. While the body of evidence regarding the clinical effectiveness of these revascularization strategies is growing, there is limited evidence concerning their long-term cost effectiveness. We aim to critically appraise the body of literature investigating the cost-effectiveness of CABG compared with PCI using stents, and to assess the quality of the economic evidence available. Methods and results: A systematic review was performed across six electronic databases; Medline, Embase, the NHS Economic Evaluation Database, the Database of Abstracts of Reviews of Effects, the health technology assessment database, and the Cochrane Library. All studies comparing economic attractiveness of CABG vs. PCI using bare-metal stents (BMS) or drug-eluting stents (DES) in balanced groups of patients were considered. Sixteen studies were included. These comprised studies of conventional CABG vs. BMS (n = 8), or DES (n = 4); off-pump CABG vs. BMS (n = 2), or DES (n = 1); and minimally invasive direct CABG vs. BMS (n = 2). The majority adopted a healthcare payer perspective (n = 14). The incremental cost-effectiveness ratios (ICERs) reported across studies varied widely according to perspective and time horizon. Favourable lifetime ICERs were reported for CABG in three trials. For patients with left main coronary artery disease, however, DES was reported as the dominant (more effective and cost-saving) strategy in one study. Conclusion: Overall, CABG rather than PCI was the favoured cost-effective treatment for complex MVCAD in the long term. While the evidence base for the cost-effectiveness of DES compared with CABG is growing, there is a need for more evaluations adopting a societal perspective, and time horizons of a lifetime or 10 or more years. PMID- 29474723 TI - Long-term resource use patterns and healthcare costs after myocardial infarction in a clinical practice setting: results from a contemporary nationwide registry study. AB - Aims: Long-term contemporary nationwide data on resource use and healthcare costs after myocardial infarction (MI) in a clinical practice setting are not widely studied, and the aim of this study was to investigate resource use patterns and healthcare costs in patients with MI in a nationwide clinical practice setting. Methods and results: This retrospective cohort study included all patients identified in the compulsory Swedish nationwide patient register with a diagnosis of MI between 1 July 2006 and 30 June 2011. Cardiovascular hospitalization and outpatient visits data from the patient register were combined with data from the cause of death register and the drug utilization register. For a subset of patients, data were also available from a primary care register. Healthcare resource use patterns and annual costs [reported in 2014 euros (?) converted from Swedish kronor (SEK) using the exchange rate ?1 = SEK 9.33)] were estimated for the year prior to the occurrence of MI as well as for a maximum follow-up period of 6 years post-MI. The study included 97 252 patients with a diagnosis of MI with a total number of 285 351 observation years. The majority of healthcare consumption occurred within the first year of MI where patients were on average hospitalized 1.55 times, made 1.08 outpatient care visits, and 3.80 primary care visits. In the long term, for the majority of resource use categories, average consumption was higher in the years after MI compared with the year prior to MI. Healthcare costs at 6 years of follow-up were approximately ?20 000 of which ?12 460 occurred in the first year, and the major part was attributed to hospitalizations. Conclusion: For patients with 6 years of follow-up after MI, healthcare costs were approximately ?20 000. The major part of costs occurred in the first year after MI and was driven by hospitalizations. ClinicalTrials.gov identifier: NCT01984307. PMID- 29474724 TI - Comparative cost-effectiveness of non-invasive imaging tests in patients presenting with chronic stable chest pain with suspected coronary artery disease: a systematic review. AB - Coronary artery disease (CAD) remains one of the leading causes of morbidity and mortality globally. The most cost-effective imaging strategy to diagnose CAD in patients with stable chest pain is however uncertain. To review the evidence on comparative cost-effectiveness of different imaging strategies for patients presenting with stable chest pain symptoms suggestive for CAD. Systematic review. Studies performing a formal economic evaluation or decision analysis in the English language published between January 1995 and December 2015 were identified using PubMed, Medline (OvidSP), Embase, Web of Science, Cochrane economic evaluations library, and EconLit. Reviews and meta-analyses were excluded. Two independent reviewers assessed titles and abstracts. Of the 4498 titles identified, 70 met our selection criteria. One reviewer used a modified version of the CHEERS checklist to assess study quality. One reviewer extracted data on study details, which were checked by a second reviewer. There is a major heterogeneity between the available cost-effectiveness studies included in this study. The included studies compared very different testing strategies in very different ways and provided mostly short-term results. Strategies of no-testing and xECG were underrepresented. Nonetheless, the findings from this systematic review suggest that for patients with a low to intermediate prior probability of having obstructive CAD, computed tomography coronary angiography (CTCA) may be cost-effective as an initial diagnostic imaging test in comparison with CAG or other non-invasive diagnostic tests. If functional testing is required, stress echocardiography (SE) or single-photon emission computed tomography (SPECT) are suggested to be cost-effective initial strategies in patients with intermediate prior probability of CAD. Yet, other functional testing strategies such as xECG and positron-emission tomography (PET) scanning have not been studied as intensely. Immediate CAG is suggested to be a cost-effective strategy for patients at a high prior probability of having obstructive CAD whom may benefit from revascularization. The study emphasizes the inextricable link between clinical effectiveness and economic efficiency. Evidence suggests that the optimal diagnostic imaging strategy for individuals suspected of having CAD is CTCA for low and intermediate disease probability, followed by SE or SPECT as necessary, and invasive CAG for high disease probability. Further studies are needed to evaluate the cost-effectiveness of alternative non-invasive tests, including a no-testing strategy. PMID- 29474725 TI - Thermal stability of laser-induced modified volumes in Si as studied by in situ and ex situ heating experiments. AB - Radiation of a permeable laser beam into Si induces considerable modification of structures. Thermal stability of the laser-induced modified volumes (LIMV's) was studied comprehensively by means of in situ and ex situ heating experiments using transmission electron microscopy. The behavior in the tail region of a LIMV can be understood by dislocation theory, while that of a void formed at the very focus of a laser beam cannot be understood easily. PMID- 29474726 TI - Recruiting low-income postpartum women into two weight loss interventions: in person versus Facebook delivery. AB - Several studies, such as the Diabetes Prevention Program (DPP), have provided foundational evidence for the efficacy of lifestyle interventions on weight loss and cardiometabolic prevention. However, translating these interventions to real world settings and engaging at-risk populations has proven difficult. Social media-delivered interventions have high potential for reaching high-risk populations, but there remains a need to understand the extent to which these groups are interested in social media as a delivery mode. One potential way to this is by examining recruitment rates as a proxy for interest in the intervention delivery format. The aim of this study was to describe the recruitment rates of overweight and obese low-income postpartum women into two asynchronous behavioral weight loss interventions: one delivered in-person and the other delivered via Facebook. Both interventions used the same recruitment methods: participants were overweight low-income postpartum women who were clients of Women, Infants, and Children (WIC) clinics in Worcester, MA, screened for the study by nutritionists during routine WIC visits. Similarly, eligibility criteria were the same for both interventions except for a requirement for the Facebook-delivered intervention to currently use Facebook at least once per week. Among women pre-eligible for the in-person intervention, 42.6% gave permission to be contacted to determine full eligibility and 24.1% of eligible women enrolled. Among women pre-eligible for the Facebook intervention, 31.8% gave permission to be contacted and 28.5% of eligible women enrolled. Recruitment rates for a Facebook-based weight loss intervention were similar to recruitment rates for an in-person intervention, suggesting similar interest in the two program delivery modes among low-income postpartum women. PMID- 29474727 TI - Reply to Drs Cohen and Kendall. PMID- 29474729 TI - The science of peer support as applied to behavioral medicine and the care of individuals surviving with cancer: a commentary on "Peer mentors delivering a physical activity intervention for cancer survivors: effects among mentors by Pinto et al." AB - There is a critical gap between the resources available to promote health and wellness after cancer and services that address these public health goals. Researchers, policy makers, healthcare providers, and community stakeholders increasingly recognize the benefits of filling this gap with trained peer mentors who can provide health-promotion services to fellow cancer survivors. This commentary addresses a mixed-method study by Pinto and colleagues that investigated the responses and experiences of trained peer mentors who delivered their telephone-based physical activity intervention for breast cancer survivors. Their findings suggested that peer mentors did not experience harms from their role while revealing that peer mentors reported benefits related to helping themselves and helping others. Drawing on our expertise in peer support provision and peer mentoring, we address the significant opportunity offered by training peer mentors to deliver behavioral interventions, draw connections to relevant literatures and theoretical perspectives on potential benefits for peer mentors, and highlight the need for rigorous, theory-based research to determine the circumstances under which peer mentoring benefits mentors and the mechanisms underlying these benefits. PMID- 29474728 TI - Longitudinal changes in blood metabolites, amino acid profile, and oxidative stress markers in American Foxhounds fed a nutrient-fortified diet. AB - The objective of the present study was to evaluate the changes in blood metabolites, AA profile, and oxidative stress markers in American Foxhound dogs fed a nutrient-fortified endurance diet while undergoing unstructured endurance exercise over several months. Thirty-six adult American Foxhound dogs (mean age: 4.5, range 2 to 10 yr and mean BW: 34.7, range: 23.1 to 46.9 kg) were selected to participate in the study. Prior to the study, all dogs consumed a commercial diet for 16 wk. After collecting baseline blood samples, dogs were assigned to a standard commercial performance diet (control) or a nutrient-fortified dog food (test). Dogs were balanced by gender, age, body weight, and athletic performance between diets. During the study, dogs underwent 78 bouts of exercise, with approximately 22 km/bout. Blood samples were collected after 40, 75, 138, and 201 d on study (October 2012 to March 2013). All blood metabolites were similar at baseline and serum chemistry profile remained within normal ranges throughout the study. Over time, plasma taurine and vitamin E concentrations decreased (P < 0.05) in dogs fed the control diet but were maintained or increased (P < 0.05) in dogs fed the treatment diet. Also, plasma creatinine and triglycerides were lower (P < 0.05) and blood phosphorus and alkaline phosphatase were higher (P < 0.05) in dogs fed the treatment diet. Vitamin E and taurine status of dogs appear to be affected by extended endurance exercise. These data suggest dogs undergoing endurance exercise may benefit from supplementation of vitamin E and taurine to minimize oxidation and maintain taurine status. PMID- 29474730 TI - Integrating modelling and phenotyping approaches to identify and screen complex traits: transpiration efficiency in cereals. AB - Following advances in genetics, genomics, and phenotyping, trait selection in breeding is limited by our ability to understand interactions within the plant and with the environment, and to identify traits of most relevance to the target population of environments. We propose an integrated approach that combines insights from crop modelling, physiology, genetics, and breeding to characterize traits valuable for yield gain in the target population of environments, develop relevant high-throughput phenotyping platforms, and identify genetic controls and their value in production environments. This paper uses transpiration efficiency (biomass produced per unit of water used) as an example of a complex trait of interest to illustrate how the approach can guide modelling, phenotyping, and selection in a breeding programme. We believe that this approach, by integrating insights from diverse disciplines, can increase the resource use efficiency of breeding programmes for improving yield gains in target populations of environments. PMID- 29474731 TI - A novel mutation of dipeptidyl aminopeptidase-like protein-6 in a family with suspicious idiopathic ventricular fibrillation. AB - Background: Sudden cardiac death (SCD) occurs in a broad spectrum of cardiac pathologies and is an important cause of mortality in the general population. Idiopathic ventricular fibrillation (IVF) is a rare but important factor resulting in SCD. It is diagnosed in a resuscitated cardiac arrest victim underlying unknown cause, with documented ventricular fibrillation. Previous studies have demonstrated that mutations in dipeptidyl aminopeptidase-like protein-6 (DPP6) and cardiac sodium channel Nav1.5 (SCN5A) are the most important genetic factors involve in IVF. Aim: By using whole sequencing to identify the genetic lesion of a family with suspicious idiopathic ventricular fibrillation. Design: Prospective genetic study. Methods: In this study, we employed whole exome sequencing in combination with arrhythmia-related gene filtering to identify the genetic lesion for a family suffering from suspicious IVF, syncope and SCD. We then generated the plasmids of DPP6-pcDNA3.1+ (WT and c.1578G>C/p.Q526H). Kv4.3-pcDNA3.1+ was co-transfected together with/without DPP6 pcDNA3.1+ (WT and/or c.1578G>C/p.Q526H) into HEK293 cells to perform the patch clamp experiments. Results: A novel missense mutation (c.1578G>C/p.Q526H) of DPP6 was identified and co-segregated with affected patients in this family. Patch clamp experiments suggested that this novel mutation might result in a gain of function and disturb the efflux of potassium ion. Conclusion: Our study not only reported the second missense mutation of DPP6 in heart disease and expanded the spectrum of DPP6 mutations, but also contribute to the genetic diagnosis and counseling of families with suspicious IVF, syncope and SCD. PMID- 29474732 TI - Resource investments in reproductive growth proportionately limit investments in whole-tree vegetative growth in young olive trees with varying crop loads. AB - It has long been debated whether tree growth is source limited, or whether photosynthesis is adjusted to the actual sink demand, directly regulated by internal and environmental factors. Many studies support both possibilities, but no studies have provided quantitative data at the whole-tree level, across different cultivars and fruit load treatments. This study investigated the effect of different levels of reproductive growth on whole-tree biomass growth across two olive cultivars with different growth rates (i.e., Arbequina, slow-growing and Frantoio, fast-growing), over 2 years. Young trees of both cultivars were completely deflowered either in 2014, 2015, both years or never, providing a range of levels of cumulated reproductive growth over the 2 years. Total vegetative dry matter growth over the 2 years was assessed by destructive sampling (whole tree). Vegetative growth increased significantly less in fruiting trees, however, the total of vegetative and reproductive growth did not differ significantly for any treatment or cultivar. Vegetative growth over the 2 years was closely (R2 = 0.89) and inversely related to reproductive growth across all treatments and cultivars. When using data from 2015 only, the regression improved further (i.e., R2 = 0.99). When biomass was converted into grams of glucose equivalents, based on the chemical composition of the different parts, the results indicated that for every gram of glucose equivalent invested in reproductive growth, vegetative growth was reduced by 0.73-0.78 g of glucose equivalent. This indicates that competition for resources played a major role in determining tree growth, but also that photosynthesis was probably also enhanced at increasing fruit load (or downregulated at decreasing fruit load). The leaf area per unit of trunk cross sectional area increased with deflowering (i.e., decreased with reproductive growth), suggesting that water relations might have limited photosynthesis in deflowered plants, which had much greater canopies. Net assimilation rate (NAR) increased with reproductive growth and decreased with plant size. Net assimilation rate was also negatively correlated with the leaf area per unit of trunk cross sectional area, suggesting that water relations might have contributed to decreasing NAR at increasing plant size. PMID- 29474733 TI - Bacmeta: simulator for genomic evolution in bacterial metapopulations. AB - Summary: The advent of genomic data from densely sampled bacterial populations has created a need for flexible simulators by which models and hypotheses can be efficiently investigated in the light of empirical observations. Bacmeta provides fast stochastic simulation of neutral evolution within a large collection of interconnected bacterial populations with completely adjustable connectivity network. Stochastic events of mutations, recombinations, insertions/deletions, migrations and micro-epidemics can be simulated in discrete non-overlapping generations with a Wright-Fisher model that operates on explicit sequence data of any desired genome length. Each model component, including locus, bacterial strain, population and ultimately the whole metapopulation, is efficiently simulated using C++ objects and detailed metadata from each level can be acquired. The software can be executed in a cluster environment using simple textual input files, enabling, e.g. large-scale simulations and likelihood-free inference. Availability and implementation: Bacmeta is implemented with C++ for Linux, Mac and Windows. It is available at https://bitbucket.org/aleksisipola/bacmeta under the BSD 3-clause license. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29474734 TI - Electroantennogram Responses to Plant Volatiles Associated with Fenvalerate Resistance in the Diamondback Moth, Plutella xylostella (Lepidoptera: Plutellidae). AB - The diamondback moth (DBM), Plutella xylostella (L.) (Lepidoptera: Plutellidae), is the main destructive insect pest of brassica vegetables around the world, and has developed resistance to numerous insecticides. Although host plant volatiles are important in pest control, the mechanism of low-level insecticide resistance in P. xylostella due to plant volatiles has not been examined. Here, electroantennograms (EAGs) were used to compare the responses of adult male and female DBMs of a susceptible strain (S-strain) and a derived resistant strain, Fen-R-strain (6.52-fold more resistant than the S-strain), to different concentrations of nine plant volatiles. We found significantly different relative EAG responses between S-strain and Fen-R-strain males to different concentrations of methyl jasmonate, methyl salicylate, and octanal. The relative EAG responses of S-strain and Fen-R-strain females to different concentrations of beta-myrcene, methyl jasmonate, methyl salicylate, and allyl isothiocyanate were significantly different. Fen-R-strain females showed lower EAG responses to most of the tested plant volatiles (at concentrations of 1:10) than males, except for allyl isothiocyanate. A larger difference in relative EAG response to alpha-farnesene and beta-myrcene was found between S-strain and Fen-R-strain females than between males of the two strains. A larger difference in relative EAG response to octanal, nonanal, and octan-1-ol was found between S-strain and Fen-R-strain males than between females of the two strains. These results illustrate the relationship between the function of plant volatiles and resistance in an insect pest species, and provide a scientific basis for resistance evolutionary theory in pest management research. PMID- 29474735 TI - MADS-box genes and crop domestication: the jack of all traits. AB - MADS-box genes are key regulators of virtually every aspect of plant reproductive development. They play especially prominent roles in flowering time control, inflorescence architecture, floral organ identity determination, and seed development. The developmental and evolutionary importance of MADS-box genes is widely acknowledged. However, their role during flowering plant domestication is less well recognized. Here, we provide an overview illustrating that MADS-box genes have been important targets of selection during crop domestication and improvement. Numerous examples from a diversity of crop plants show that various developmental processes have been shaped by allelic variations in MADS-box genes. We propose that new genomic and genome editing resources provide an excellent starting point for further harnessing the potential of MADS-box genes to improve a variety of reproductive traits in crops. We also suggest that the biophysics of MADS-domain protein-protein and protein-DNA interactions, which is becoming increasingly well characterized, makes them especially suited to exploit coding sequence variations for targeted breeding approaches. PMID- 29474736 TI - Gastrointestinal Behcet's disease: periodic fever, multiple ulcers, and trisomy 8 in elderly man. PMID- 29474738 TI - Modeling the impact of players' workload on the injury-burden of English Premier League football clubs. AB - The loss of players through injury is known to affect team performance in many sports; it is important, therefore, for professional teams to be able to quantify the likely injury-burden that will be encountered throughout a season. A kinetic model, based on the rates at which match and training injuries are sustained and resolved, a team's squad size and the 2017/2018 season fixture schedule for teams competing in the English Premier League, is used to produce daily forecasts of injury-burden experienced by a typical team. The incidences and median severities of match (incidence: 26.9 injuries/1000 player-match hours, 95% CI: 21.5-33.7; severity: 17.5 days, 95% CI: 13.0-28.0) and training (incidence: 4.3 injuries/1000 player-training hours, 95% CI: 3.4-5.5; severity: 14.0 days, 95% CI: 11.0-22.0) injuries were determined using data collected from four English Premier League football clubs during the 2016/2017 season. Time-to-recovery curves for the match and training injuries sustained in the Premier League closely matched the time-to-recovery curves predicted by the kinetic model used in this study. The kinetic model predicted higher match and lower training injury burdens and a higher overall injury burden for successful teams competing in both national and European club competitions compared to teams competing only in national competitions. The model also showed that, in terms of injury-burden, there were no benefits in adopting a 4-week mid-season break during the season: reducing the number of clubs competing in the Premier League would, however, reduce the overall injury burden during a season. PMID- 29474737 TI - Association between reported aetiology of central nervous system infections and the speciality of study investigators-a bias compartmental syndrome? AB - Background: Conventional descriptions of central nervous system (CNS) infections are variably categorized into clinical syndromes for patient investigation, management and research. Aetiologies of the most commonly recognized syndromes, encephalitis and meningitis, tend to be attributed predominantly to viruses and bacteria, respectively. Methods: A systematic review was performed of aetiological studies of CNS syndromes and data extracted on reported author specialities. Results: The analysis identified an association between the author's speciality and the CNS syndrome studied, with a tendency for virologists to study encephalitis and microbiologists to study meningitis. Conclusions: We suggest there is bias in study design. Stronger multidisciplinary collaboration in CNS infection research is needed. PMID- 29474739 TI - Mst1/2 Kinases Modulate Glucose Uptake for Osteoblast Differentiation and Bone Formation. AB - Bone formation and bone homeostasis are energy-expensive processes. How they are being regulated by energy needs is not completely understood. This is of high clinical importance because diabetic-induced bone loss is common whereas the underlying mechanisms are unclear. Here, we show that Mst1/2 are important regulators for glucose uptake during osteoblast differentiation. Genetically removal of both Mst1/2 kinases simultaneously in mice in early and mature osteoblasts inhibits bone formation and bone remodeling, respectively. We found that the activity of Mst1/2 kinases is sensitive to glucose levels, and in turn, regulates glucose uptake by stabilizing key glucose transporter Glut1. In the absence of Mst1/2 kinases, Glut1 expression is loss and results in AMP-dependent protein kinase (AMPK) activation and subsequent proteasomal degradation of Runx2. The streptozotocin (STZ)-induced diabetic mouse model also recapitulates similar changes in the bone tissues. In addition, Glut1 expression regulated by Mst1/2 kinases is independent of Yap/Taz expression. Our results unravel new mechanistic insights into the orchestration of glucose level and bone homeostasis. (c) 2018 American Society for Bone and Mineral Research. PMID- 29474741 TI - A Selection of Abstracts Presented at the 44th Annual Conference of the Anatomical Society of Southern Africa (ASSA), May 8-11, 2016, Bloem Spa Hotel and Conference Centre, Bloemfontein, Free State, South Africa. AB - In memory of Professor Willie Vorster who was a long-standing member of ASSA and served on the Council for many years. He was a devoted teacher of Anatomy and Embryology at various tertiary institutions in South Africa, and the founding member of the School of Medicine at the University of Namibia where he served as the first Professor in Anatomy. PMID- 29474740 TI - Differences in nonclinical pharmacokinetics between species and prediction of human pharmacokinetics of TAK-272 (SCO-272), a novel orally active renin inhibitor. AB - In the search for orally available drugs, the prediction of human pharmacokinetics (PK) is essential for successfully selecting compounds that will be clinically useful. This report describes the selection of TAK-272 (SCO-272), a novel orally active renin inhibitor, as a clinical candidate via the detailed investigation of nonclinical PK data and human PK prediction. The bioavailability (BA) of TAK-272 after oral administration to rats and monkeys was low, especially in fasted monkeys, and the systemic exposure of TAK-272 was highly variable in monkeys. The results of mass balance studies in animals suggested that the absorbed TAK-272 was largely eliminated by metabolism. In vitro studies revealed that TAK-272 was mainly metabolized by CYP3A4/5 in humans, and it was a P glycoprotein substrate. PK analysis suggested that the factors responsible for the low BA were different in rats and monkeys. First-pass hepatic extraction was high in rats, while the fraction absorbed from the gastrointestinal tract (Fa * Fg ) was low in monkeys. It was predicted that humans would have a higher BA and a longer half-life in the plasma compared with the animals by a simple calculation using intrinsic hepatic clearance in monkeys, which correlates well with human values for CYP3A4 substrates, and Fa * Fg in rats, which correlates relatively well with human values. TAK-272 was finally selected as a clinical candidate based on the result of human PK prediction. The actual human PK after oral administration of TAK-272 was comparable to the predicted profile and was preferable for clinical usage. PMID- 29474742 TI - Deep feature classification of angiomyolipoma without visible fat and renal cell carcinoma in abdominal contrast-enhanced CT images with texture image patches and hand-crafted feature concatenation. AB - PURPOSE: To develop an automatic deep feature classification (DFC) method for distinguishing benign angiomyolipoma without visible fat (AMLwvf) from malignant clear cell renal cell carcinoma (ccRCC) from abdominal contrast-enhanced computer tomography (CE CT) images. METHODS: A dataset including 80 abdominal CT images of 39 AMLwvf and 41 ccRCC patients was used. We proposed a DFC method for differentiating the small renal masses (SRM) into AMLwvf and ccRCC using the combination of hand-crafted and deep features, and machine learning classifiers. First, 71-dimensional hand-crafted features (HCF) of texture and shape were extracted from the SRM contours. Second, 1000-4000-dimensional deep features (DF) were extracted from the ImageNet pretrained deep learning model with the SRM image patches. In DF extraction, we proposed the texture image patches (TIP) to emphasize the texture information inside the mass in DFs and reduce the mass size variability. Finally, the two features were concatenated and the random forest (RF) classifier was trained on these concatenated features to classify the types of SRMs. The proposed method was tested on our dataset using leave-one-out cross validation and evaluated using accuracy, sensitivity, specificity, positive predictive values (PPV), negative predictive values (NPV), and area under receiver operating characteristics curve (AUC). In experiments, the combinations of four deep learning models, AlexNet, VGGNet, GoogleNet, and ResNet, and four input image patches, including original, masked, mass-size, and texture image patches, were compared and analyzed. RESULTS: In qualitative evaluation, we observed the change in feature distributions between the proposed and comparative methods using tSNE method. In quantitative evaluation, we evaluated and compared the classification results, and observed that (a) the proposed HCF + DF outperformed HCF-only and DF-only, (b) AlexNet showed generally the best performances among the CNN models, and (c) the proposed TIPs not only achieved the competitive performances among the input patches, but also steady performance regardless of CNN models. As a result, the proposed method achieved the accuracy of 76.6 +/- 1.4% for the proposed HCF + DF with AlexNet and TIPs, which improved the accuracy by 6.6%p and 8.3%p compared to HCF-only and DF-only, respectively. CONCLUSIONS: The proposed shape features and TIPs improved the HCFs and DFs, respectively, and the feature concatenation further enhanced the quality of features for differentiating AMLwvf from ccRCC in abdominal CE CT images. PMID- 29474743 TI - CsSPL functions as an adaptor between HD-ZIP III and CsWUS transcription factors regulating anther and ovule development in Cucumis sativus (cucumber). AB - Anther and ovule genesis preconditions crop fertilization and fruit production; however, coordinative regulation of anther and ovule development and underlying molecular pathways remain largely elusive. Here, we found that SPOROCYTELESS (SPL)/NOZZLE (NZZ) expression was nearly abolished in a Cucumis sativus (cucumber) mutant with severely defective anther and ovule development. CsSPL was expressed specifically in the developing anthers and ovules. Knock-down of CsSPL reduced male and female fertility with malformed pollen and suppressed ovule development. Importantly, CsSPL directly interacted with CsWUS (WUSCHEL) in the nucellus and YABBY family genes in integuments, and positively regulated CsWUS expression, meanwhile the HD-ZIP III gene CsPHB (PHABULOSA), expressed specifically in the nucellus, promoted CsSPL expression by binding to the CsSPL promoter. Thus, CsSPL acts as an adaptor to link CsPHB and CsWUS functioning, underpinning a previously unidentified regulatory pathway orchestrating sex organ development in planta. In addition, auxin accumulation was reduced in the reproductive organs of CsSPL knock-down plants. Biochemical analyses further showed that CsSPL stimulated the expression of AUXIN RESPONSE FACTOR 3 (CsARF3), and was positively regulated by CsARF13 during reproductive organ development, indicating sequential interactions of CsSPL with auxin signaling components in orchestrating anther and ovule development. PMID- 29474745 TI - NK cell enteropathy: a case report with 10 years of indolent clinical behaviour. AB - AIMS: Natural killer (NK) cell enteropathy is a recently described clinically indolent condition characterised by atypical NK cell infiltrates in the gastrointestinal mucosa that mimics malignant lymphoma. We report a case that highlights the indolent clinical behaviour by documenting absence of clinical progression over 10 years. METHODS AND RESULTS: We report the case of a 69-year old female who had clinically long-standing abdominal pain and recurrent mucosal ulcerations associated with atypical NK cell infiltrates. The clinical, morphologic and immunophenotypical findings in this case were diagnostic of NK cell enteropathy. Review of the patient's prior biopsies demonstrated that this persisted without clinical progression for 10 years, confirming the clinical indolent course. CONCLUSION: Recognition of NK cell enteropathy is important to avoid over-diagnosing this benign condition as an aggressive lymphoma. PMID- 29474744 TI - Contrast - in cardiac magnetic resonance imaging. AB - The utility and role of cardiac magnetic resonance (CMR) as a non-invasive diagnostic imaging modality has been well recognized in the field of cardiovascular disease. Use of late gadolinium enhancement (LGE) has further enhanced CMR's ability to determine structural, functional, and prognostic information in various cardiovascular diseases. The delivery and distribution of gadolinium as an extracellular agent allows the detection of edema, fibrosis, and infiltration in the myocardium. The pattern of LGE in cardiomyopathies enables us to distinguish among various disease processes non-invasively. Additionally, in patients with hypertrophic cardiomyopathy and sudden cardiac death, it helps in decision making in regards to use of implantable cardioverter defibrillator. In the evaluation of cardiac masses, LGE-CMR can often times differentiate between neoplastic and non-neoplastic conditions. In this review, we will discuss the various aspects of gadolinium-based contrast agents, and its application in CMR. PMID- 29474746 TI - The ageing pancreas: a systematic review of the evidence and analysis of the consequences. AB - Senior people constitute the fastest growing segment of the population. The elderly are at risk for malnutrition, thought to be caused by reduced food intake or involution of the physiological capacity of the GI tract. Age-related changes are well known in other secretory organs such as liver, kidney and intestine. The pancreas, representing a metabolically active organ with uptake and breakdown of essential nutritional components, changes its morphology and function with age. During childhood, the volume of the pancreas increases, reaching a plateau between 20 and 60 years, and declines thereafter. This decline involves the pancreatic parenchyma and is associated with decreased perfusion, fibrosis and atrophy. As a consequence of these changes, pancreatic exocrine function is impaired in healthy older individuals without any gastrointestinal disease. Five per cent of people older than 70 years and ten per cent older than 80 years have pancreatic exocrine insufficiency (PEI) with a faecal elastase-1 below 200 MUg g 1 stool, and 5% have severe PEI with faecal elastase-1 below 100 MUg g-1 stool. This may lead to maldigestion and malnutrition. Patients may have few symptoms, for example steatorrhoea, diarrhoea, abdominal pain and weight loss. Malnutrition consists of deficits of fat-soluble vitamins and is affecting both patients with PEI and the elderly. Secondary consequences may include decreased bone mineral density and results from impaired absorption of fat-soluble vitamin D due to impaired pancreatic exocrine function. The unanswered question is whether this age-related decrease in pancreatic function warrants therapy. Therapeutic intervention, which may consist of supplementation of pancreatic enzymes and/or vitamins in aged individuals with proven exocrine pancreas insufficiency, could contribute to healthy ageing. PMID- 29474747 TI - MicroRNA-134 inhibits osteosarcoma angiogenesis and proliferation by targeting the VEGFA/VEGFR1 pathway. AB - Vascular endothelial growth factor (VEGF) A and vascular endothelial growth factor receptor 1 (VEGFR1) signaling is crucial for angiogenesis and progression of osteosarcoma (OS). However, the regulation of the VEGF/VEGFR1 expression is still unclear in OS. Here, we show lower levels of miRNA-134 (miR-134) in OS tissues and cells. Induction of miR-134 overexpression significantly reduced the proliferation of Saos-2 cells and their secretion of pro-angiogenic factors, but increased the frequency of apoptotic Saos-2 cells. Treatment with conditioned medium from the cells transfected with miR-134 reduced the tube formation in human umbilical vein endothelial cells, which was abrogated by a combination of VEGF and conditioned medium. Furthermore, miR-134 significantly inhibited the growth of implanted OS tumors in vivo and attenuated the VEGFA and VEGFR1 expression and angiogenesis in the tumors. In addition, higher levels of VEGFA and VEGFR1 were detected and miR-134 inhibited the expression of VEGFA and VEGFR1 in Saos-2 cells and OS tumors. Bioinformatic analysis indicated that the 3'-UTR of VEGFA and VEGFR1 contained the motif for miR-134 binding. Co-transfection with the luciferase reporter containing the wild-type, but not the mutant, of the 3' UTR of VEGFA or VEGFR1 together with miR-134 decreased the luciferase activity in Saos-2 cells. Finally, miR-134 dramatically inhibited AKT activation and proliferating cell nuclear antigen expression in Saos-2 cells. Collectively, these findings indicate that miR-134 is a potential tumor suppressor by targeting VEGFA/VEGFR1 signaling to attenuate the progression and angiogenesis in OS. Therefore, miR-134 may be a novel biomarker for the prognosis of OS and a target for the design of new therapies for OS. PMID- 29474748 TI - Changes in prostate orientation due to removal of a Foley catheter. AB - PURPOSE: Investigate the impact on prostate orientation caused by use and removal of a Foley catheter, and the dosimetric impact on men prospectively treated with prostate stereotactic body radiotherapy (SBRT). METHODS: Twenty-two men underwent a CT simulation with a Foley in place (FCT), followed immediately by a second treatment planning simulation without the Foley (TPCT). The change in prostate orientation was determined by rigid registration of three implanted transponders between FCT and TPCT and compared to measured orientation changes during treatment. The impact on treatment planning and delivery was investigated by analyzing the measured rotations during treatment relative to both CT scans, and introducing rotations of +/-15 degrees in the treatment plan to determine the maximum impact of allowed rotations. RESULTS: Removing the Foley caused a statistically significant prostate rotation (P < 0.0028) compared to normal biological motion in 60% of patients. The largest change in rotation due to removing a Foley occurs about the left-right axis (tilt) which has a standard deviation two to five times larger than changes in rotation about the Sup-Inf (roll) and Ant-Post (yaw) axes. The change in tilt due to removing a Foley for prone and supine patients was -1.1 degrees +/- 6.0 degrees and 0.3 degrees +/- 7.4 degrees , showing no strong directional bias. The average tilt during treatment was -1.6 degrees +/- 7.1 degrees compared to the TPCT and would have been -2.0 degrees +/- 7.1 degrees had the FCT been used as the reference. The TPCT was a better or equivalent representation of prostate tilt in 82% of patients, vs 50% had the FCT been used for treatment planning. However, 92.7% of fractions would still have been within the +/-15 degrees rotation limit if only the FCT were used for treatment planning. When rotated +/-15 degrees , urethra V105% = 38.85Gy < 20% was exceeded in 27% of the instances, and prostate (CTV) coverage was maintained above D95% > 37 Gy in all but one instance. CONCLUSIONS: Removing a Foley catheter can cause large prostate rotations. There does not appear to be a clear dosimetric benefit to obtaining the CT scan with a Foley catheter to define the urethra given the changes in urethral position from removing the Foley catheter. If urethral sparing is desired without the use of a Foley, utilization of an MRI to define the urethra may be necessary, or a pseudo urethral planning organ at risk volume (PRV) may be used to limit dosimetric hot spots. PMID- 29474749 TI - MEK-ERK signaling diametrically controls the stimulation of IL-23p19 and EBI3 expression in epithelial cells by IL-36gamma. AB - Interleukin (IL)-36 cytokines are important regulators of mucosal homeostasis and inflammation. We previously established that oral epithelial cells strongly upregulate IL-36gamma expression in response to the bacterial pathogen Porphyromonas gingivalis. Here, we have established that IL-36gamma stimulates the expression of the IL-12 cytokine family members, IL-23p19 and Epstein-Barr Virus-Induced Gene 3 (EBI3), by oral epithelial cells; their expression was also selectively stimulated by IL-36alpha. Notably, IL-23p19 and EBI3 expression was not stimulated by P. gingivalis, thus suggesting that their expression by the oral epithelium in response to P. gingivalis is likely to be mediated in an autocrine manner by IL-36gamma. The IL-36gamma-inducible expression of IL-23p19 and EBI3 was found to be diametrically regulated by the mitogen-activated protein kinase/extracellular signal regulated kinase (MEK)-extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, whereby the activation of MEK-ERK signaling likely functions as a negative feedback mechanism to limit EBI3 expression. Furthermore, epidermal growth factor receptor (EGFR) signaling, which is important for mucosal homeostasis, was demonstrated to modulate, in a MEK-ERK-dependent manner, the stimulation of IL-23p19 and EBI3 expression by IL-36gamma. IL-23p19 and EBI3 have recently been shown to heterodimerize to form the novel cytokine IL-39 and promote neutrophil expansion. EBI3 has been shown to also have IL-12 cytokine family independent functions (e.g. mediating IL-6 trans-signaling). Thus, this study not only advances our understanding of how IL-36 cytokines may control mucosal inflammation, but also establishes EGFR signaling as a potentially important modulator of IL-36 cytokine function. PMID- 29474751 TI - In Memoriam: Herbert J. Eichel (1924-2017) a Passion for Discovery. PMID- 29474750 TI - Suppressed heat shock protein response in the kidney of exercise-trained diabetic rats. AB - Impaired expression of heat shock proteins (HSPs) and increased oxidative stress may contribute to the pathophysiology of diabetes by disrupted tissue protection. Acute exercise induces oxidative stress, whereas exercise training up-regulates endogenous antioxidant defenses and HSP expression. Although diabetic nephropathy is a major contributor to diabetic morbidity, information regarding the effect of HSPs on kidney protection is limited. This study evaluated the effects of eight week exercise training on kidney HSP expression and markers of oxidative stress at rest and after acute exercise in rats with or without streptozotocin-induced diabetes. Induction of diabetes increased DNA-binding activity of heat shock factor-1, but decreased the expression of HSP72, HSP60, and HSP90. The inflammatory markers IL-6 and TNF-alpha were increased in the kidney tissue of diabetic animals. Both exercise training and acute exercise increased HSP72 and HSP90 protein levels only in non-diabetic rats. On the other hand, exercise training appeared to reverse the diabetes-induced histological changes together with decreased expression of TGF-beta as a key inducer of glomerulosclerosis, and decreased levels of IL-6 and TNF-alpha. Notably, HSP72 and TGF-beta were negatively correlated. In conclusion, impaired HSP defense seems to contribute to kidney injury vulnerability in diabetes and exercise training does not up regulate kidney HSP expression despite the improvements in histopathological and inflammatory markers. PMID- 29474752 TI - Control of "blue carbon" storage by mangrove ageing: Evidence from a 66-year chronosequence in French Guiana. AB - The role of mangroves in the blue carbon stock is critical and requires special focus. Mangroves are carbon-rich forests that are not in steady-state equilibrium at the decadal time scale. Over the last decades, the structure and zonation of mangroves have been largely disturbed by coastal changes and land use conversions. The amount of time since the last disturbance is a key parameter determining forest structure, but it has so far been overlooked in mangrove carbon stock projections. In particular, the carbon sequestration rates among mangrove successional ages after (re)establishment are poorly quantified and not used in large-scale estimations of the blue carbon stock. Here, it is hypothesized that ecosystem age structure significantly modulates mangrove carbon stocks. We analysed a 66-year chronosequence of the aboveground and belowground biomass and soil carbon stock of mangroves in French Guiana, and we found that in the year after forest establishment on newly formed mud banks, the aboveground, belowground and soil carbon stocks averaged 23.56 +/- 7.71, 13.04 +/- 3.37 and 84.26 +/- 64.14 (to a depth of 1 m) Mg C/ha, respectively. The mean annual increment (MAI) in the aboveground and belowground reservoirs was 23.56 * Age 0.52 and 13.20 * Age-0.64 Mg C ha-1 year-1 , respectively, and the MAI in the soil carbon reservoir was 3.00 +/- 1.80 Mg C ha-1 year-1 . Our results show that the plant carbon sink capacity declines with ecosystem age, while the soil carbon sequestration rate remains constant over many years. We suggest that global projections of the above- and belowground reservoirs of the carbon stock need to account for mangrove age structures, which result from historical changes in coastal morphology. Our work anticipates joint international efforts to globally quantify the multidecadal mangrove carbon balance based on the combined use of age-based parametric equations and time series of mangrove age maps at regional scales. PMID- 29474753 TI - A Delamination Strategy for Thinly Layered Defect-Free High-Mobility Black Phosphorus Flakes. AB - Extraordinary electronic and photonic features render black phosphorus (BP) an important material for the development of novel electronics and optoelectronics. Despite recent progress in the preparation of thinly layered BP flakes, scalable synthesis of large-size, pristine BP flakes remains a major challenge. An electrochemical delamination strategy is demonstrated that involves intercalation of diverse cations in non-aqueous electrolytes, thereby peeling off bulk BP crystals into defect-free flakes comprising only a few layers. The interplay between tetra-n-butylammonium cations and bisulfate anions promotes a high exfoliation yield up to 78 % and large BP flakes up to 20.6 MUm. Bottom-gate and bottom-contact field-effect transistors, comprising single BP flakes only a few layers thick, exhibit a high hole mobility of 252+/-18 cm2 V-1 s-1 and a remarkable on/off ratio of (1.2+/-0.15)*105 at 143 K under vacuum. This efficient and scalable delamination method holds great promise for development of BP-based composites and optoelectronic devices. PMID- 29474755 TI - Manganese-Catalyzed Carbonylative Annulations for Redox-Neutral Late-Stage Diversification. AB - An inexpensive, nontoxic manganese catalyst enabled unprecedented redox-neutral carbonylative annulations under ambient pressure. The manganese catalyst outperformed all other typically used base and precious-metal catalysts. The outstanding versatility of the manganese catalysis manifold was reflected by ample substrate scope, setting the stage for effective late-stage manipulations under racemization-free conditions of a wealth of marketed drugs and natural products, including alkaloids, amino acids, steroids, and carbohydrates. PMID- 29474754 TI - The mechanism of photosystem-II inactivation during sulphur deprivation-induced H2 production in Chlamydomonas reinhardtii. AB - Sulphur limitation may restrain cell growth and viability. In the green alga Chlamydomonas reinhardtii, sulphur limitation may induce H2 production lasting for several days, which can be exploited as a renewable energy source. Sulphur limitation causes a large number of physiological changes, including the inactivation of photosystem II (PSII), leading to the establishment of hypoxia, essential for the increase in hydrogenase expression and activity. The inactivation of PSII has long been assumed to be caused by the sulphur-limited turnover of its reaction center protein PsbA. Here we reinvestigated this issue in detail and show that: (i) upon transferring Chlamydomonas cells to sulphur free media, the cellular sulphur content decreases only by about 25%; (ii) as demonstrated by lincomycin treatments, PsbA has a significant turnover, and other photosynthetic subunits, namely RbcL and CP43, are degraded more rapidly than PsbA. On the other hand, sulphur limitation imposes oxidative stress early on, most probably involving the formation of singlet oxygen in PSII, which leads to an increase in the expression of GDP-L-galactose phosphorylase, playing an essential role in ascorbate biosynthesis. When accumulated to the millimolar concentration range, ascorbate may inactivate the oxygen-evolving complex and provide electrons to PSII, albeit at a low rate. In the absence of a functional donor side and sufficient electron transport, PSII reaction centers are inactivated and degraded. We therefore demonstrate that the inactivation of PSII is a complex and multistep process, which may serve to mitigate the damaging effects of sulphur limitation. PMID- 29474756 TI - ADVANCES IN PHARMACOTHERAPY OF TUBERCULOSIS. AB - Tuberculosis remains a growing threat of infectious diseases of twenty-first century. An attempt to find new antituberculosis agents was made especially to treat multidrug-resistant and extensively drug-resistant tuberculosis. One of the most promising drugs is bedaquiline - a new drug approved by Food and Drug Administration (FDA) and by the European Union countries. This compound is intended to treat multidrug-resistant pulmonary tuberculosis in adult patients in combination regimens in case of impossibility of using other drugs. This paper is also focused on some interesting molecules in treating multidrug-resistant tuberculosis which are currently tested in clinical studies: delamanid (dihydro nitroimidazooxazole derivative, phase III), AZD5847 (oxazolidinone derivative, phase II), pretomanid (nitroimidazole derivative, phase III), sutezolid (oxazolidinone derivative, phase II) and SQ109 (ethambutol analogue, phase II) and some prospective molecules at the level of preclinical studies e.g., CPZEN 45, SQ609 and SQ641. PMID- 29474757 TI - SAFETY AND EFFICACY OF INTRAVENOUS ADMINISTRATION OF IRON PREPARATIONS. AB - Iron deficiency is the main cause of anemia worldwide. Iron supplementation leads to a rise of transferrin saturation and ferritin concentration, resulting in an increased hemoglobin level and decrease of anemia symptoms. Oral iron administration is a treatment of choice in iron deficiency anemia. In patients with impaired iron absorption from the gastrointestinal tract, as well as in large deficits, or poor tolerance of oral formulations, it becomes necessary to apply iron intravenously. In this paper we present, on the basis of current publications, the characteristics of intravenous iron preparations nowadays available on the market, in various clinical situations, with particular focus on their benefits and risk related to the administration of high single iron doses. PMID- 29474759 TI - REPRESENTATIVES OF MOTHERWORT GENUS (LEONURUS SPP.): ASPECTS OF PHARMACOGNOSTIC FEATURES AND RELEVANCE OF NEW SPECIES APPLICATION. AB - The review deals with analysis and classification of literature data on phamacognostic study (botanical characteristics, geographical distribution, chemical composition and use in medicine) of species of Motherwort genus (Leonums L.). The review unveils opportunities for comprehensive study and development of approaches to the standardization of raw materials of Turkistan motherwort (L. turkestanicus V.I. Krecz. & Kuprian). That will allow to expand the range of sources of herbal remedies raw materials in the framework of realization of the state program for import substitution. PMID- 29474758 TI - INHIBITORY MECHANISM AGAINST OXIDATIVE STRESS AND BIOLOGICAL ACTIVITIES OF CANOLOL. AB - Canolol is a decarboxylated derivative of sinapic acid. Due to lipophilic nature, canolol is an excellent orally bioavailable phenol. It mainly occurs in roasted rapeseeds. It is documented in the literature as a potent antioxidant and safe for human health. The mode of antioxidant activity of canolol involves the suppression of various free radicals such as 02, ONOO and 'OOH. As evident from the literature, few studies have been carried out to explore the free radical scavenging activity of canolol. Thus, the objective of this review article is to summarize the available literature about free radical scavenging potential of this promising phenol to pave the path for further investigations about biological activities of canolol. PMID- 29474760 TI - PRELIMINARY HIGH PERFORMANCE CAPILLARY ELECTROPHORESIS (HPCE) STUDIES OF ENZYMATIC DEGRADATION OF HYALURONIC ACID BY HYALURONIDASE IN THE PRESENCE OF POLYVALENT METAL IONS. AB - The aim of this study was, at first, to examine the influence of metal ions on digestion process of hyaluronic acid by hyaluronidase (HAse) using high performance capillary electrophoresis (HPCE) method. The influence of copper(H), zinc(Il), manganese(II) ions on enzymatic degradation of HA by hyaluronidase enzyme (HA-se) were investigated. Secondly, the kinetic parameters, V(max), K(m), k(cat), and k (cat),/K(m) were determined to estimate the impact of these metal ions (Me) on digestion process of hyaluronic acid (HA). The two different HA-Me mole ratios were analyzed. The examined data were always compared to the digestion process of pure HA solution by hyaluronidase, to exhibit the differences in the digestion process of pure hyaluronan as well as the hyaluronan in the presence of metal ions. It was observed that all of the investigated metal ions have influenced the hyaluronic acid degradation process. The most important conclusion was a decrease of the kinetic parameters both K,, and V,. In the result, it can be assumed that in all of the studied samples with metal ions addition, the uncompetitive mechanism of enzyme inhibition occurred. The results of this study may give new insight into foregoing knowledge about hyaluronic acid behavior. Due to the fact that our study was carried out only for three different metal ions in two concentrations, it is necessary to continue further research comprising wider range of metal ions and their concentrations. PMID- 29474761 TI - PROTEOMIC ANALYSIS OF APIS MELLIFERA VENOM DETERMINED BY LIQUID CHROMATOGRAPHY (LC) COUPLED WITH NANO-LC-MALDI-TOF/TOF MS. AB - The integration of multidimensional liquid chromatography and mass spectrometry analytical plat- form was proposed for proteomic exploration of honeybee venom. The combination of HPLC with nanoLC-MALDI-TOF/TOF MS system was our method of choice for compressing the dynamic range of honeybee venom protein concentration. Honeybee venom samples were separated into 6 fractions using HPLC and further analyzed by nanoLC-MALDI-TOF/TOF. Applied approach allowed to identify in total 394 peptides giving the identification of 50 components including putative toxins and trace elements. Moreover, all 12 known honeybee venom allergens were acknowledged. Additionally, four novel hypothetical proteins have been observed which were not observed in other studies. The newly recognized proteins should be further investigated, in order to characterize their functions in the venom of Apis mellifera. PMID- 29474762 TI - QUANTITATIVE DETERMINATION OF RESIDUAL MONOMETHYLAMINE CONTENT IN NEBIVOLOL HYDROCHLORIDE BY HPIC WITH SUPPRESSED CONDUCTIVITY DETECTION. AB - The aim of this paper was to develop a simple analytical method which could be used to determine a synthesis-derived amount of monomethylamine (MMA) residue present in nebivolol hydrochloride. High-performance ion chromatography (HPIC) method with suppressed conductivity detection was used for this purpose. The HPIC analysis was performed with IonPac CS 14 column (250 x 4 mm) containing a macroporous weak cation-exchange stationary phase eluted with 10 mM methanesulfonic acid (MSA). Validation of the method confirmed its selectivity by achieving a satisfactory separation of alkyl- and alkanolamines and metal cations. The method also showed a sufficient precision (RSD < 5.0%) and accuracy (recovery 90-103%). The calibration plot was linear in the range 0.03-2.4 MUg/mL of MMA (r2 = 0.9997). The calculated limit of quan- tification LOQ was 0.03 MUg/mL. Amount of the MMA contained in nebivolol hydrochloride was determined by direct reading from the calibration curve and by the multiple standard additions method. Both methods showed satisfactory precision (RSD < 10.0%) and they can be used to determine the monomethylamine content in the studied active substance. PMID- 29474763 TI - STABILITY-INDICATING HPLC METHOD FOR DETERMINATION OF VANCOMYCIN HYDROCHLORIDE IN THE PHARMACEUTICAL DOSAGE FORMS. AB - A simple, rapid and selective RP-HPLC method was developed for the determination of vancomycin hydrochloride. The separation was achieved using a Capital C8 Optimal column (250 x 4.6 mm i.d., 5 MUm particle size) with a mobile phase composed of buffer citrate (pH 4), acetonitrile and methanol in the ratio of 85 : 10: 5 (by volume), respectively. The mobile phase was pumped using an isocratic HPLC system at a flow rate of I mL/min and quantification of analyte was based on measuring its peak areas at 280 nm. Cephalexin monohydrate was used as internal standard (IS). The retention times for vancomycin hydrochloride and cephalexin were about 4.30 and 7.50, respectively. The reliability of the proposed HPLC procedure was validated with respect to linearity, ranges, precision, accuracy, specificity and detection limit. Calibration curve was linear in the ranges of 1 100 MUg/mL with correlation coefficient of 0.9999. The proposed method proved to be selective and stability-indicating by the resolution of the analytes from the forced degradation (hydrolysis, oxidation, thermolysis and photolysis) products. The validated HPLC method was successfully applied to the analysis of vancomycin hydrochloride in pharmaceutical dosage forms. The degradation products resulted from the storage of the drug under stress degradation conditions described by the International Conference on Harmonisation (ICH). PMID- 29474764 TI - STABILITY INDICATIVE HPLC DETERMINATION OF RELATED SUBSTANCES AND IDENTIFICATION OF POTENTIAL DEGRADANTS USING LC-MS IN TRIPLE COMBINATION ANTIRETROVIRAL TABLETS. AB - A rapid stability indicating liquid chromatography method was developed and validated for the simultaneous quantitation of related substances of antiretrovirals in combined oral dosage formulation. Separation was achieved using a Waters, Xterra RP-18 column (250 x 4.6 mm) with a mobile phase containing a gradient mixture of sodium acetate trihydrate solution and acetonitrile with a flow rate of 1 mL/min, detec- tion at 254 nm. A simple preparative and LC-MS method were applied for the isolation and identification of degradation products. The active drugs were subjected to stress studies and significant degradation was observed. The spectral purity of the active drugs was determined to establish the stability indicating power of the developed method. The developed chromatographic method was validated as per ICH guidelines and is capable to identify and quantify all the 17 impurities at a level of 0.01 and 0.03%, respectively, with respect to test concentration. The wide range of linearity and good resolution imply that the method is suitable for routine quantification of related substances as well as for the assay of the actives. PMID- 29474765 TI - DETERMINATION OF SOTALOL, OXPRENOLOL AND LABETALOL IN BINARY MIXTURES AND IN SPIKED HUMAN SERUM BY DERIVATIVE SPECTROPHOTOMETRIC METHOD. AB - The usefulness of derivative spectrophotometry for the determination of labetalol, sotalol and oxprenolol in binary mixtures and in human spiked serum was checked. To this aim a spectrophotometric analysis of samples in the UV range was carried out and the obtained results revealed that derivative spectropho- tometry allows for the fast, accurate and precise determination of the tested substances in spite of their clear interference in the zero-order spectra. For quantitative determinations "zero-crossing" technique was used to establish wavelengths for zeros of specified component. In a mixture of labetalol and oxprenolol the following wavelengths were established: D1 lambda = 245.32 nm and 266.03 nm, D2 lambda = 243.30 nm and 301.09 nm. respectively. D3 derivative did not show zeros suitable for quantitative analysis. For the analysis of labetalol and sotalol mixture, D3 derivative spectrophotometry was used at the following wavelengths: = 246.03 nm and lambda = 249.91 rum, respectively. In this case, the curves of Dl and D2 derivatives showed no zeros that can be used in quantitative analysis. To determine the concentration of the components in a mixture containing oxprenolol and sotalol the following wavelengths were selected: for oxprenolol DI lambda = 245.32 nm, D2 lambda = 240.18 run, D3 lambda = 232.05 nm and for sotalol Dl lambda = 230.56 nm, D2 Xlambda= 232.65 nm and D3 X = 238.84 tm, respectively. The developed spectrophotometric method was characterized by high sensitivity and accuracy, LOD determined for sotalol was in the range of 0.21-1.88 MUg/mL, for labetalol 1.00-3.43 MUg/mL and for oxprenolol 0.16-2.06 MUg/mL; LOQ determined for sotalol was in the range of 0.65-5.70 MUg/mL, for labetalol 3.11-10.39 MUg/mL and for oxprenolol 0.47-6.23 MUg/mL, depending on the composition of the tested mixture and the order of the deriv- ative. The recovery of the individual components was within the range of 100 +/- 5%. The linearity range was wide and estimated for sotalol in the range of 11.00-38.50 MUg/mL, for labetalol 12.80-44.80 MUg/mL and for oxprenolol 12.60-44.10 MUg/mL with correlation coefficients in the range of 0.9977-0.9999. PMID- 29474766 TI - REPEATED EXPOSURE OF SODIUM TELLURITE ON THE RAT LIVER AND ON THE POTENTIAL MECHANISMS OF THE METALLOID-INDUCED HEPATOTOXICITY. AB - Tellurium (Te) is a semiconductor and is frequently doped with copper, tin, gold or silver. It is also used to color glass and ceramics and is one of the primary ingredients in blasting caps. Te is little known about its biological activity but it is well known for toxic to human and animals. It has inhibited the lipids profiles and oxidative stress in the brain of the mice. Sodium tellurite 4.15, 8.3 and 16.6 mg/kg (1/20, 1/10 and 1/5 of LD50, respectively) was given to male Wistar rats orally in saline for a period of 15 days. On day 16, the blood was collected and the livers were dissected out for biochemical assays. The hepatotoxicity biomarkers [biliru- bin, aspartate aminotransferase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP)] were ele- vated significantly and dose dependently in the serum of Te treated groups as compared to control group. The content of thiobarbituric acid reactive substances in Te treated groups was increased significantly and dose- dependently as compared to control group. Conversely, the content of glutathione and activities of antioxidant enzymes (glutathione peroxidase, glutathione reductase, glutathione-S transferase, superoxide dismutase and catalase) were decreased significantly in Te treated groups as compared to control group. No data of effect of inorganic Te compounds on the liver toxicity of rats are available. The aim of the present study was to evalu- ate the hepatotoxicity of inorganic Te compounds. In conclusion, Te accelerated hepatotoxicity and oxidative stress in liver tissue of rats. PMID- 29474767 TI - STUDIES OF NEW PURINE DERIVATIVES WITH ACETIC ACID MOIETY IN HUMAN KERATINOCYTES. AB - Recently we described a group of purine derivatives based on theophylline structure with acetic acid moiety. Studies in a group of these compounds demonstrated their analgesic and anti-inflammatory properties. Taking into account wide spectrum of theophylline derivatives activity and searching for their new properties. the aim of the study was to evaluate safety of newly synthesized derivatives in human keratinocytes model. The effect of new purine derivatives with acetic acid moiety: 2-(8-methoxy-1,3-dimethyl-2,6-dioxo-purin-7 yl) acetic acid and 2-(1,3-dimethyl-2,6,8-trioxo-9H-purin-7-yl) acetic acid on proliferation rate and the ability of keratinocytes to migration was carried out. The results clearly demonstrate that purine derivatives with acetic acid moiety did not affect basic keratinocytes functions. Our compounds do not inhibit cells proliferation rate as well as their ability to migration. It can be therefore concluded that new purine derivatives with acetic acid moiety are safe versus normal cells. This observation opens up additional prospects in searching for their new applications. PMID- 29474768 TI - CHARACTERIZATION OF BINDING SITES OF CLOPIDOGREL AND INTERFERENCE OF LINOLEIC ACID AT THE BINDING SITE ON BOVINE SERUM ALBUMIN. AB - Binding of clopidogrel to serum albumin has been characterized in the presence and absence of linoleic acid by equilibrium dialysis method where ranitidine and diazepam were used as specific probes. Our findings suggested two binding sites for clopidogrel: a high affinity site (k1 = 11.5 x 105 M-1) with low capaci- ty (n1 = 1.2) and low affinity site (k2 = 2.1 x 105 M-1) with high capacity (n. = 9.3). Interaction of linoleic acid with clopidogrel in the presence of ranitidine shows an increment of clopidogrel from 71 to 85.5% at concen- tration of (1 x 105 M) to (6 x 105 M). However, interaction of linoleic acid with clopidogrel in the presence of diazepam exhibits significant rise in free fraction of clopidogrel from 93 to 116% at concentration of (0 x 10' M) to (4 x 105 M). At higher concentrations, linoleic acid displaced clopidogrel from its binding sites on serum albumin. This may cause escalation of free drug in the blood, which alters pharmacokinetic properties of clopi- dogrel taken with high fat diet. PMID- 29474769 TI - SYNTHESIS AND AMINOPEPTIDASE N INHIBITING ACTIVITY OF 3-(NITROPHENOXYMETHYL) [1,3,2]DIOXABOROLAN-2-OLS AND THEIR OPEN ANALOGUES. AB - Aminopeptidase N (APN) represents a class of zinc metallopeptidases with broad substrate specifity. This enzyme is involved in control of angioneogenesis in cancer and microvascular conditions. It also serves as a superficial cellular receptor that enables attachment of some viruses including coronaviruses to the host cell. APN takes part also in metabolism of some important neuropeptides. That is why APN can be a promising therapeutic target and compounds which influence its activity interesting potential drugs. Here, synthesis of compounds which in most contain 3-phenoxypropan-1,2 diol moiety and evaluation of their inhibition activity against APN is described. 4-[1-, 2- and 3 (Nitrophenoxymethyl)]-[1,3,2]dioxaborolan-2-ols are novel compounds which have never been previously reported in the literature. 3-(Aminophenoxy)propyl-1,2 diols revealed greater activity than both 3-(nitrophenoxy)propyl-1,2-diols and 3 (nitrophenoxymethyl)-[1,3,2]dioxaborolan-2-ols. A QSAR study revealed a linear correlation between lipophilicity and inhibition activity. PMID- 29474770 TI - SYNTHESIS AND CYTOTOXIC EVALUATION OF SOME 2-{4-[(2-OXO-1,2-DIHYDRO-3H-INDOL-3 YLIDENE)METHYL] PHENOXY}-N-PHENYLACETAMIDE. AB - A series of 2-oxindole derivatives were synthesized and evaluated for cytotoxic activity against different human and murine cancer cell lines and cancer chemopreventive activity. Among the tested compounds VS-06, 08, 12 and 17 displayed cytotoxic activity in the range of 5.0 to 8.5 pM against human T lymphocyte cells (CEM). Results showed that molecules with electron withdrawing substituent at 4 position of N-phenylacetamide group exhibited an increase in activity against the human tumor cell line CEM. The cancer chemo- preventive effect of VS-01 (IC50 = 451 nM) displayed equipotent activity in comparison to standard oleanolic acid (IC50 = 449 nM). PMID- 29474771 TI - SYNTHESIS OF NOVEL 1,4,5,6,7,8-HEXAHYDROQUINOLINES OF POTENTIAL ANTIMICROBIAL ACTIVITY. AB - A number of 2,3-disubstituted-1-cyclohexyl 4-(3,4-dimethoxyphenyl-1,4,5,6,7,8) hexahydroquinolines and 5-(3,4-dimethoxyphenyl-10-cyclohexyl-3,4,5,6,7,8,9,10 octahydro)-3H-pyrimido[4,5-b]quinolines were synthesized and evaluated for antimicrobial activities. Preliminary results indicated that most compounds tested in this study demonstrated considerable activity against Gram positive, Gram negative bacteria and fungi. PMID- 29474772 TI - ANALYSIS OF PHENOLIC ACIDS AND ANTIBACTERIAL ACTIVITY OF EXTRACTS OBTAINED FROM THE FLOWERING HERBS OF CARD UUS ACANTHOIDES L. AB - In this work the phenolic acids in crude methanol extracts from the flowering herbs of Carluus acanthoides L. were identified. The samples containing free phenolic acids and those released after acid and alka- line hydrolyses were investigated by 2D TLC on cellulose. After purification by SPE, samples were also analyzed by RP-HPLC. Chlorogenic, protocatechuic, p- coumaric, caffeic, syringic, p-hydroxybenzoic, ferulic, vanillic, gentisic and gallic acids were detected in fractions of the methanolic extract obtained from the flow- ering herb of C. acanthoides. This is the first study concerning the qualitative analysis of phenolic compounds and antibacterial activity of fractions and aqueous, ethyl acetate, dichloromethane, acetone and methanol (50, 80 and 100% v/v) extracts of flowering herbs of C. acanthoides L. The antimicrobial activity of tested extracts was determined in vito against reference microorganisms of Gram-positive bacteria, Gram-negative bacteria and fungi belonging to yeasts. The results of this study support the medical usage of C. acanthoides L. due to its antimicrobial properties. PMID- 29474773 TI - ANTIOXIDANT ACTIVITY OF PISTACIA KHINJUK SUPPORTED BY PHYTOCHEMICAL INVESTIGATION. AB - Pistacia khinjuk is one of the fifteen known species of Pistacia belonging to Anacardiaceae family. Keeping in view the possible therapeutic utility of this genus and the lack of literature on this plant, this study involves phytochemical investigation of P. khinjuk and its antioxidant activity. The phytochemical investigation was conducted on crude methanolic extract and its fractions namely, n-hexane, chloroform, n-butanol, ethyl acetate and aqueous. Total phenolic contents and flavonoids were also determined by phosphomolybdenum and ferric thiocyanate method in crude extract and its fractions. The results of phytochemical investigation indicated the presence of alkaloids, tannins, flavonoids, saponins, triterpenoids, cardiac glycosides, carbohydrates, proteins and sterols in the crude extract of P. khinjuk. Crude extract and its fractions exhibited remarkable antioxidant activity. This study showed that the crude extract and its fractions have potent antioxidant activity, among all ethyl acetate showed 1.109 +/- 0.029 the highest activity. This research concluded that crude extract of P. khinjuk and its fractions contained phenolic and flavonoid compounds that show significant antioxidant activity. PMID- 29474774 TI - ANTIFUNGAL ACTIVITY OF THE ROOT EXTRACTS OF PULSATILLA PATENS AGAINST CANDIDA GLABRATA. AB - Plants from the genus of Pulsatilla produce a variety of secondary metabolites with biological activity. These species play a special role in herbal medicine and are used in traditional folk medicine to treat many diseases and ailments. Due to their numerous medicinal properties, they are now also widely used as homeopathic preparations. In the present study, the antifungal activity of crude extracts of the root of Pulsatilla patens (L.) Mill. against the yeast Candida glabrata with an IC50 of 9.37 MUg/mL is reported. PMID- 29474775 TI - EFFECT OF HYDROPHILIC AND HYDROPHOBIC POLYMER ON IN VITRO DISSOLUTION AND PERMEATION OF BISOPROLOL FUMARATE THROUGH TRANSDERMAL PATCH. AB - A matrix transdermal patch of bisoprolol fumarate was formulated with different concentrations of Eudragit RS 100 and Methocel E5 with PEG 400 as plasticizer by solvent evaporation technique. Tween 80 was added to the optimized patch to evaluate the effect of permeation enhancer at different concentration through the excised rabbit's skin. The patches were analyzed for weight variation, drug content, swelling index, erosion studies, moisture content, moisture uptake, water vapor transmission rate (WVTR) and water vapor permeability (WVP). In vitro dissolution test was carried out in USP dissolution apparatus V to select the optimized formulation. In vitr skin permeation studies were done in Franz diffusion cell using rabbit skin as a model membrane. The cumulative drug release and flux were determined to compare the result of test patches with a control patch. The greatest enhancement ratio (ER) was obtained in F03-PE with 30% Tween 80. F03-PE seemed to follow zero order kinetics with super case II mechanism of drug release. Statistical ANOVA suggested that there was a significant difference in formulations, steady flux and cumulative permeation rate at different Tween 80 concentrations. PMID- 29474776 TI - INFLUENCE OF LIPOPHILIC AND HYDROPHILIC CO-MONOMERS ON THE HYDRODYNAMIC DIAMETER OF THERMOSENSITIVE NIPA DERIVATIVES FOR THERMALLY CONTROLLED DRUG DELIVERY. AB - For modem drug delivery, new drug carriers sensitive to various factors and with size in the range of micro- and nanometers are required. The aim of this work was to evaluate the influence of hydrophilic and hydrophobic co-monomers on the hydrodynamic diameter of three co-polymers of N-isopropylacrylamide (NIPA) nanogels synthesized at 70*C in the presence of potassium persulfate (KPS) as the initiator and N.N'-methylene bis-acrylamide (MBA) as the cross-linker. The first batch of nanoparticles was synthesized without co-monomer, whereas poly(ethylene glycol) methyl ether acrylate (PEG-MEA), and N-teii-butylacrylamide (NTB), were implemented as co-monomers for the second and third batch. Hydrodynamic diameter of nanoparticles was in the range 550-800 rn. The compositions of the synthesized co-polymer nanoparticles were con- firmed via IR and NMR analyses. The SFPP conditions resulted in hydrodynamic diameters ranging from approximately 550 to 800 nm at temperatures lower than the volume phase transition temperature (VPTT) and diameters ranging from 250 to 600 nm at temperatures above the VPTT, where the VPTT was between 26 and 41'C. The polydispersity index (PDI) showed a maximum or a minimum value at the VPTT, which was an important indicator of the volume phase transition. According to the PDI observation during thermal cycling, the addition of NTB into the polymeric chain resulted in maximal values of the PDI at the VPIT, similar to the case of nanoparticles without any additional co monomers. In contrast, in the case of PEG-MEA, the PDI presented a minimal value. Dynamic light scattering (DLS) volume measurements, performed simultaneously with spectral methods, may lead to a fast evaluation of nanoparticles prepared by SFPP. PMID- 29474777 TI - IVABRADINE LOADED SOLID LIPID MICROPARTICLES: FORMULATION, CHARACTERIZATION AND OPTIMIZATION BY CENTRAL COMPOSITE ROTATABLE DESIGN. AB - The current research focused on improvement of oral bioavailability and decrease in dosing frequency of ivabradine (Iva) in order to enhance patient compliance by formulating novel sustained release Iva loaded solid lipid microparticles (SLMs) with the help of melt emulsification technique. SLMs formulations were designed with the help of three level central composite rotatable design (CCRD) to study the impact of independent variables like lipid concentration, surfactant concentration and stirring speed on responses - percentage yield (Y,) and entrapment efficiency (Y2). Compatibility between the drug and bees wax (BW) was checked by conducting Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and X-ray powder diffractometry (XRD). SLMs were further evaluated for rheological behavior, zeta potential, particle size and for morphology by scanning'electron microscope (SEM). The release of drug from SLMs was conducted by USP type-Il apparatus at pH 1.2, pH 6.8 and data were analyzed by different kinetic models like zero order, first order, Higuchi model, Korsmeyer-Peppas and Hixon-Crowell models. The rheo- logical studies approved the good flow behavior of SLMs and spherical smooth surface of SLMs was observed from SEM. DSC, FTIR and XRD studies concluded the lack of any possible interaction between formulation components. The size-of SLMs ranged from 300 to 500 pm and zeta potential study showed the presence of higher negative charge ( 30 to -52 mV). Response Y, varied from 53 to 90% and response Y2 ranged from 29 to 78% indicating the effect of formulation variables. The obtained outcomes were analyzed by second order polynomial equation and suggested quadratic model was also validated. SLMs released Iva from 54 to 90% at pH 6.8 and was significantly (p 0.05) affected by BW concentration. The release mechanism followed the zero order and Korsmeyer-Peppas (n 0.85) kinetic models suggesting slow erosion along with diffusion mechanism for Iva release. PMID- 29474778 TI - THE INFLUENCE OF THE SELECTED CATALYSTS AND MICROWAVE RADIATION ON THE COURSE OF OBTAINING POLY-e-CAPROLACTONE AS A BIODEGRADABLE CARRIER OF MEDICINAL SUBSTANCES. AB - The ring opening polymerization of epsilon-caprolactone catalyzed by organic acids had been studied. The aim of this study was to develop and optimize a process for obtaining poly-epsilon-caprolactone of high purity intend- ed for use as a drug carrier, with consideration of the impct of the monomer-catalyst ratio on the product parameters, the temperature impact and the impact of the type of catalyst on the product properties. The studies also aim to determine the possible positive effect of microwave radiation on the course of the reaction. The structures of the synthesized compounds were proven by 'H NMR spectroscopy. The average molecular weight of the obtained polymer particles was estimated based on the relations of the 'H NMR signal integrations. In the reaction catalyzed by citric acid the product was characterized by a substantially higher molecular weight compared to the analogous reaction using another type of catalysts. Higher average molecular weights were obtained by conducting the reactions under microwave radiation. PMID- 29474779 TI - HIGH-SHEAR GRANULATION PROCESS: INFLUENCE OF PROCESSING PARAMETERS ON CRITICAL QUALITY ATTRIBUTES OF ACETAMINOPHEN GRANULES AND TABLETS USING DESIGN OF EXPERIMENT APPROACH. AB - Application of quality by design (QbD) in high shear granulation process is critical and need to recognize the correlation between the granulation process parameters and the properties of intermediate (granules) and corresponding final product (tablets). The present work examined the influence of water amount (X,) and wet massing time (X2) as independent process variables on the critical quality attributes of granules and corresponding tablets using design of experiment (DoE) technique. A two factor, three level (32) full factorial design was performed; each of these variables was investigated at three levels to characterize their strength and interaction. The dried granules have been analyzed for their size distribution, density and flow pattern. Additionally, the produced tablets have been investigated for weight uniformity, crushing strength, friability and percent capping, disintegration time and drug dissolution. Statistically significant impact (p < 0.05) of water amount was identified for granule growth, percent fines and distribution width and flow behavior. Granule density and compressibility were found to be significantly influenced (p < 0.05) by the two operating conditions. Also, water amount has significant effect (p < 0.05) on tablet weight unifornity, friability and percent capping. Moreover, tablet disintegration time and drug dissolution appears to be significantly influenced (p < 0.05) by the two process variables. On the other hand, the relationship of process parameters with critical quality attributes of granule and final product tablet was identified and correlated. Ultimately, a judicious selection of process parameters in high shear granulation process will allow providing product of desirable quality. PMID- 29474780 TI - A QUALITY BY DESIGN APPROACH: FABRICATION, CHARACTERIZATION AND EVALUATION OF OPTIMIZED TRANSDERMAL THERAPEUTIC SYSTEM FOR ANTIRHEUMATIC LORNOXICAM. AB - Microemulsion was prepared using several concentrations of selected oil (pine oil), surfactant (cre- mophor RH40), co-surfactant (isopropanol) and water to improve bioavailability by increasing solubility and permeability of lomoxicam, which was then incorporated to carbomer 940 gel base to fabricate microemulsion based gel (MEBG) to sustained permeability for transdermal delivery. Initially, the formulations were investi- gated for physicochemical characteristics, i.e., pH, conductivity, viscosity, refractive index, zeta size, poly-dis- persity index and Atomic Force Microscopy. Also, the significance of the components on in vitro permeability was observed to find out optimum microemulsion (ME,) using Box Behnken-Design (BBD). MEBG was com- pared for in vitro permeation, stability, skin irritation and anti-inflammatory studies using control gel and in vivo bioavailability study with oral tablet. Microemulsions exhibited the physiological pH (5.35-5.99), oil in water nature (139-185 tsiemens/cm), isotropic (1.3390-1.4166), narrow size (62 nm), homogeneity, Newtonian flow (52 160 centipoise) and spherical shape. Predicted values (Q2, flux, lag time) of optimized microemulsions derived from BBD were in reasonable agreement with experimental values. The formulations were stable and non-irritating to the skin. Significant difference was investigated when comparing percent inhibition of edema of MEBG (80%) and control gel (40%) with respect to standard. The MEBG behavior differed significantly from oral tablet formulation in vivo bioavailability. Such BBD based estimation will reduce time and cost in drug designing, delivery and targeting. PMID- 29474781 TI - INFLUENCE OF MICROCRYSTALLINE CELLULOSE MODIFICATION ON THE PHYSICAL PARAMETERS' STABILITY OF DIRECTLY COMPRESSED PLACEBO TABLETS. AB - Directly compressed tablets manufactured with high concentrations of microcrystalline cellulose tend to soften when exposed to high humidity. Modification/co-processing of microcrystalline cellulose with hydrophobic agents using two methods was proposed to prevent hardness decrease of placebo tablets upon moisture absorption. Hardness of placebo tablets before and after exposure to humidity of 75% RH was compared. Hardness of all tested placebo tablets decreased after exposure to humidity of 75% RH, however the extent of decrease was different. Relative hardness decrease was the lowest for modification with use of hydrogenated castor oil. Co-processing of microcrystalline cellulose by 20% addition of hydrogenated castor oil allows to reduce a hardness decrease upon moisture uptake. PMID- 29474782 TI - GREEN TEA BEVERAGE AND EPIGALLOCATECIHIN GALLATE ATTENUATE NICOTINE CARDIOCYTOTOXICITY IN RAT. AB - Nicotine, the principal alkaloid in tobacco, induces a cellular damage on heart and cardiomyocyte culture. We investigate the protective role of green tea extract (GTE) against nicotine. Male albino rats were treated by injecting nicotine (1 mg/kg b.w. for 2 months) subcutaneously and thereby supplementing GTE 2% orally to them. The levels of plasma lipids, cardiac MDA (malondialdehyde) and catalase activity Mitogen-activated proteins kinases MAPKs were measured. The expression levels of (ERK 1/2, extracellular signal - regulated kinase 1/2 and P38 MAP kinase), endoplasmic reticulum stress (ERS)-related protein (GRP78 glucose regulated protein-78, HSP70 heat shock protein-70, CHOP C/EBP homologous protein), AIF (apoptosis-inducing factor) and VDAC (voltage-dependant anion channel) were evaluated by Western blot. In the in vitro study, the cardiomyocytes were exposed to nicotine (10 MUM) and major GTE polyphenol epigallocatechin gallate EGCG (50 MUM). Data showed that nicotine induced a significant increase on MDA levels, LDH (lactate dehy- drogenase) and aminotransferase activity compared with control. The heart sections of nicotine exposed-rats showed severe degenerative changes. Nicotine increased the expression of P38, but not ERK 1/2, ER stress-related proteins and AIF with no changes of VDAC. Concomitant GTE treatment significantly normalized and/or improved,the levels of MDA, enzymatic activity and histological injuries. The proteins expression was attenuated by GTE co-administration without any changes for VDAC. ERK 1/2 expression enhanced in GTE- treated groups. Exposure of cardiac cells to nicotine induced the expression of ERS markers and p38; the ERK 1/2 was highly expressed only in the presence of EGCG. It was suggested that green tea beverage can protect against nicotine toxicity by attenuating oxidative stress, endoplasmic reticulum stress and apoptosis. Otherwise, our results have showed that ERK1/2 and p38 are survival signaling pathways activated by GTE and EGCG. PMID- 29474783 TI - ANTIBACTERIAL AND CENTRAL NERVOUS SYSTEM ACTIVITY OF (4,5-DIARYL-4H-1,2,4-TRIAZOL 3-YL)METHACRYLIC ACID DERIVATIVES. AB - The series of 1,2,4-triazole derivatives containing methacrylic acid moiety were synthesized in reaction of N3-substituted amidrazones with itaconic anhydride. Preliminary calculated bioavailability parameters of obtained compounds suggested good penetration via cell membranes and their good absorption after oral intake. Antimicrobial evaluation in vitio showed diverse activity of obtained triazoles mainly on Gram-positive bacterial strains. One derivative was also examined to determine the effect on the central nervous system of mice. PMID- 29474784 TI - RISK FACTORS OF rt-PA THERAPY IN PATIENTS WITH ISCHEMIC STROKE. AB - The stroke mortality rate in Poland is one of the highest in Europe with particularly large percentage of deaths in early phase of stroke. The aim of the study was to analyze the causes and risk factors for treatment failure and early death in patient with ischemic stoke treated with thrombolysis in the Department of Neurology, Military Institute of Medicine. The study included 295 patients treated with thrombolysis over the period 2005-2015. The study protocol defined for each patient include demographic data, time of recombinant tissue plasminogen activator (rt-PA) administration from the onset of symptoms, the presence of stroke risk factors. The incidence of in-hospital deaths was 8.1% within the first week and 15.6% in the first month. In the final model, relevant death predictors were: baseline National Institutes of Health Stroke Score (NIHSS), hemorrhagic transformation type 2, hyperglycemia at admission and increased blood pressure above 180/110 mmHg during or in the first day after thrombolysis. The most common cause of death was a massive stroke with increased intracranial pressure, (36.4%), intracerebral hemorrhage (15.3%), concomitant edema and hemorrhage (27%), pneumonia (15.3%), cardiac disorders (13.4%). The important risk factors of death directly associated with thrombolytic therapy were hemorrhagic transformation and hemisphere stroke with malignant edema increasing the risk of bleeding. PMID- 29474785 TI - PRECLINICAL PHARMACOKINETIC ANALYSIS OF (E)-METHYL-4-ARYL-4-OXABUT-2-ENOATE, A NOVEL SER/THR PROTEIN KINASE B INIBITOR, IN RATS. AB - (E)-Methyl-4-aryl-4-oxabut-2-enoate, designated YH-8, is a novel Serflhr protein kinase B (PknB) inhibitor, which is designed for the treatment of tuberculosis. The aim of this study was to investigate the pharmacokinetics, bioavailability, tissue distribution and excretion characteristics of YH-8 in rats and study its plasma protein binding in vitro. The pharmacokinetic properties were examined after intravenously injected YH-8 at 10 and 20 mg/kg and oral administrated YH-8 at 50, 100 and 200 mg/kg to rats. The concentrations of YH-8 in plasma were determined with LC-MS/MS, with a liquid-liquid extraction. The tissue distribution and urinary, fecal and -biliary excretion patterns of YH-8 were investigated following a single oral dosing of 100 mg/kg. The plasma protein binding rates of YH-8 were determined using ultra-filtration method. After intra- venous and oral administration, YH-8 showed dose-independent pharmacokinetic characteristics, with T(1/2) of approximately 5.5 h and 7.1 h, respectively. The oral absolute bioavailability of YH-8 was relatively low (about 12%). YH-8 was widely distributed in various tissues and showed substantial deposition in intestine, stomach, liver, lung and kidney. The drug was mainly eliminated via fecal excretion and its binding rate with plasma protein was concentration dependent. In conclusion, this study as first provided the full pharmacokinetic characteristics of YH-8, which would be helpful for its further development and clinical application. PMID- 29474786 TI - Single Additive Enables 3D Printing of Highly Loaded Iron Oxide Suspensions. AB - A single additive, a grafted copolymer, is designed to ensure the stability of suspensions of highly loaded iron oxide nanoparticles (IOPs) and to facilitate three-dimensional (3D) printing of these suspensions in the filament form. This poly (ethylene glycol)-grafted copolymer of N [3(dimethylamino)propyl]methacrylamide and acrylic acid harnesses both electrostatic and steric repulsion to realize an optimum formulation for 3D printing. When used at 1.15 wt % (by the weight of IOPs), the suspension attains ~81 wt % solid loading-96% of the theoretical limit as calculated by the Krieger Dougherty equation. Rectangular, thick-walled toroidal, and thin-walled toroidal magnetic cores and a porous lattice structure are fabricated to demonstrate the utilization of this suspension as an ink for 3D printing. The electrical and magnetic properties of the magnetic cores are characterized through impedance spectroscopy (IS) and vibrating sample magnetometry (VSM), respectively. The IS indicates the possibility of utilizing wire-wound 3D printed cores as the inductive coils. The VSM verifies that the magnetic properties of IOPs before and after the ink formulation are kept almost unchanged because of the low dosage of the additive. This particle-targeted approach for the formulation of 3D printing inks allows embodiment of a fully aqueous system with utmost target material content. PMID- 29474788 TI - Unveiling the Aggregation Behavior of Doxorubicin Hydrochloride in Aqueous Solution of 1-Octyl-3-methylimidazolium Chloride and the Effect of Bile Salt on These Aggregates: A Microscopic Study. AB - In this article, we have unveiled the aggregation behavior of a potent chemotherapeutic drug, doxorubicin hydrochloride (Dox) in a well-known imidazolium based surface active ionic liquid (SAIL), 1-octyl-3-methylimidazolium chloride (C8mimCl). The aggregates formed by Dox in C8mimCl have been characterized using dynamic light scattering (DLS), fluorescence lifetime imaging microscopy (FLIM), high-resolution transmission electron microscopy (HR-TEM), analytical transmission electron microscopy (analytical TEM), field emission scanning electron microscopy (FESEM), atomic force microscopy (AFM), and Fourier transform infrared spectroscopy (FTIR) measurements. It is found that Dox forms large spherical aggregates in the presence of C8mimCl SAIL. We have also explored the driving force behind this aggregation behavior of Dox in C8mimCl. Furthermore, it is observed that in the presence of a common bile salt, sodium cholate (NaCh), Dox/C8mimCl spherical aggregates disrupt to form rodlike fibrillar aggregates. Therefore, formation of spherical aggregates and also its disruption into rodlike fibrillar aggregates have been performed, and this is expected to open a new scope for the design of a new generation smart drug delivery system where the drug itself aggregates to form the delivery system. PMID- 29474789 TI - Tissue and Organ 3D Bioprinting. AB - Three-dimensional (3D) bioprinting enables the creation of tissue constructs with heterogeneous compositions and complex architectures. It was initially used for preparing scaffolds for bone tissue engineering. It has recently been adopted to create living tissues, such as cartilage, skin, and heart valve. To facilitate vascularization, hollow channels have been created in the hydrogels by 3D bioprinting. This review discusses the state of the art of the technology, along with a broad range of biomaterials used for 3D bioprinting. It provides an update on recent developments in bioprinting and its applications. 3D bioprinting has profound impacts on biomedical research and industry. It offers a new way to industrialize tissue biofabrication. It has great potential for regenerating tissues and organs to overcome the shortage of organ transplantation. PMID- 29474787 TI - 1H NMR-Based Identification of Intestinally Absorbed Metabolites by Ussing Chamber Analysis of the Rat Cecum. AB - The large intestine (cecum and colon) is a complex biochemical factory of vital importance to human health. It plays a major role in digestion and absorption by salvaging nutrients from polysaccharides via fermentation initiated by the bacteria that comprise the gut microbiome. We hypothesize that the intestinal epithelium absorbs a limited number of luminal metabolites with bioactive potential while actively excluding those with toxic effects. To explore this concept, we combined 1H NMR detection with Ussing chamber measurements of absorptive transport by rat cecum. Numerous metabolites transported across the epithelium can be measured simultaneously by 1H NMR, a universal detector of organic compounds, alleviating the need for fluorescent or radiolabeled compounds. Our results demonstrate the utility of this approach to delineate the repertoire of fecal solutes that are selectively absorbed by the cecum and to determine their transport rates. PMID- 29474790 TI - Thymosin-induced immunoregulation: clinical potentials for allergy and asthma endotypes. PMID- 29474791 TI - Just another ordinary bad birth? A narrative analysis of first time mothers' traumatic birth experiences. AB - A difficult birth experience can have long lasting psychological effects on both mother and baby and this study details four in-depth accounts of first time mothers who described their birth experience as traumatizing. Narrative analysis was used to record discrepancies between the ideal and the real and produced narrative accounts that highlighted how these mothers felt invisible and dismissed in a medical culture of engineering obstetrics. Participants also detailed how their birth experience could be improved and this is set in context alongside current recommendations in maternal health care and the complexities of delivering such care in UK health settings. PMID- 29474792 TI - Academic-Based and Aerobic-Only Movement Breaks: Are There Differential Effects on Physical Activity and Achievement? AB - PURPOSE: This study investigated the academic achievement and physical activity differences between types of activity breaks implemented in elementary school classrooms. This study evaluated whether there was a difference between the impact of purely aerobic-based movement breaks and the impact of academic-based breaks on children's academic achievement outcomes. METHOD: Participants included 460 children in 3rd grade through 5th grade at 4 elementary schools. There were 176 children in the schools that engaged in academic-based breaks and 284 in the schools that engaged in aerobic-only breaks. Schools were randomly assigned at the school level to implement either aerobic movement breaks with academic content infused within the breaks ("academic-based breaks") or aerobic-only movement breaks without the addition of academic material ("aerobic-only breaks") for approximately 10 min of activity per day. Math and reading achievement as well as children's step counts were measured before and after the intervention. A mixed-effects (multilevel-growth) model, in which the repeated measures of individuals nested within a classroom are analyzed, was used to answer all posited research questions. RESULTS: Small to moderate effect sizes (ES) indicating gains in reading achievement (ES = .13) and steps (ES = .33) were found for classrooms that used aerobic-only movement breaks compared with those that used academic-based breaks. CONCLUSIONS: The type of movement breaks that are implemented in classrooms may have differential outcomes for children's achievement and activity levels. Results from the present study indicate that children who were given aerobic-only movement breaks had slightly larger gains in reading achievement and physical activity levels than children who were given academic-based breaks. PMID- 29474793 TI - "You take the private part of her body, ... you are taking a part of her life": Voices of circumcised African migrant women on female genital circumcision (FGC) in Australia. AB - Western countries working toward eradication of female genital mutilation require better inclusion of women originally from countries where the practice is prevalent. However, few authors have examined the knowledge, attitudes, and experiences of circumcised African migrant women in western countries. Our findings from 40 responses from self-reported survey and five in-depth interviews show that the participating African migrant women know the reasons behind female genital circumcision (FGC), are living with the negative consequences of FGC, and have a zero tolerance attitude toward the practice. Circumcised women are in the best position to define their health needs and champion global efforts to eradicate FGC. PMID- 29474794 TI - Recent challenges with stem cell banking. PMID- 29474796 TI - The Long-Term Effects of Cleaning on the Lungs. PMID- 29474797 TI - Maternal health in India: A survey of birth attendant competency through completeness of prescribed care during perinatal visits, in 12 randomly chosen districts of Uttar Pradesh, India. AB - We assessed the completeness of care provided during perinatal visits at public institutions in Uttar Pradesh (UP), India. Self-reported data from 53 interviews with birth attendants throughout 12 districts in UP showed that 52% of the items from a procedural checklist were covered during visits. Routine visits were found to be incomplete, provider training related to pharmaceuticals and counseling were suggested to be low, and the monitoring of vitals to be infrequent and inconsistent. We suggest further grassroots research be conducted in developing nations so that strategic and precise reform can be made to lower global maternal mortality. PMID- 29474798 TI - Loss-of-Function Mutations in the Dpp and Opp Permeases Render Erwinia amylovora Resistant to Kasugamycin and Blasticidin S. AB - Extensive use of the antibiotic streptomycin to control fire blight disease of apples and pears, caused by the enterobacterial plant pathogen Erwinia amylovora, leads to the development of streptomycin-resistant strains in the United States and elsewhere. Kasugamycin (Ksg) has been permitted to be used as an alternative or replacement to control this serious bacterial disease. In this study, we investigated the role of two major peptide ATP-binding cassette transporter systems in E. amylovora, the dipeptide permease (Dpp) and oligopeptide permease (Opp), in conferring sensitivity to Ksg and blasticidin S (BcS). Minimum inhibitory concentration and spot dilution assays showed that the dpp deletion mutants exhibited slightly enhanced resistance to Ksg in rich medium, whereas the opp mutant exhibited slightly enhanced resistance to Ksg in minimal medium and BcS in rich medium. Deletion of both dpp and opp conferred a higher level of resistance to Ksg in both rich and minimal media, whereas deletion of opp alone was sufficient to confer high level of resistance to BcS in minimal medium. In addition, bioinformatic analysis combined with reverse transcription-quantitative polymerase chain reaction showed that the Rcs phosphorelay system negatively regulates opp expression and the rcsB mutant was more sensitive to both Ksg and BcS in minimal medium as compared with the wild type. An electrophoresis motility shift assay further confirmed the direct binding of the RcsA/RcsB proteins to the promoter region of the opp operon. However, neither the Dpp nor the Opp permeases contributed to disease progress on immature pears, hypersensitive response on tobacco leaves, or exopolysaccharide amylovoran production. These results suggested that Ksg and BcS employ the Dpp and Opp permeases to enter E. amylovora cells and the Dpp and Opp permeases act synergistically for illicit transport of antibiotics. PMID- 29474799 TI - Coercion in the Evolution of Plant-Microbe Communication: A Perspective. AB - Plants and microbes are dependent on chemical signals as a means of interkingdom communication. There are two predicted paths for the evolution of these signals. Ritualization is the oft-assumed pathway for the evolution of plant-microbe communication systems. In this process, chemical signals, which benefit both receiver and sender, evolve from chemical cues, which benefit only the receiver. However, plant-microbe signaling may evolve from coercive interactions as well, a process known as sensory manipulation. Here, we aim to highlight the prevalence of coercive interactions and discuss sensory manipulation in the context of plant microbe interactions. We present two examples of stabilized coercion: microbial coercion of plants via the release of phytohormones and plant coercion of microbes via manipulation of quorum-sensing compounds. Furthermore, we provide an evolutionary framework for the emergence of signaling from coercive plant-microbe interactions through the process of sensory manipulation. We hope that researchers will recognize the relevance of coercive interactions in plant microbe systems and consider sensory manipulation as a plausible evolutionary trajectory for the emergence of plant-microbe signaling. PMID- 29474800 TI - Validity of the 4-compartment model using dual energy X-ray absorptiometry derived body volume in overweight individuals. AB - The purpose of the present study was to assess the validity of dual-energy X-ray absorptiometry (DXA) to estimate body volume (BV) for use in a 4-compartment (4C) body composition model in an overweight/obese population. Body composition of 61 overweight/obese adults (age: 37.3 +/- 10.0 years; height: 170.2 +/- 9.5 cm; body mass: 97.1 +/- 17.4 kg) was measured by 2 methods: a criterion 4C model and a DXA derived BV 4C model. For both models, bioelectrical impedance spectroscopy was used to estimate total body water; total body bone mineral content was measured by a full-body DXA scan. For the criterion 4C model, BV was derived from air displacement plethysmography; for the DXA-4C model, BV was derived from previously published coefficients. Total error (TE) and standard error of the estimate (SEE) values for BV (TE = 1.11 L; SEE = 0.01 L) and body fat percentage (%fat) (TE = 2.92%; SEE = 0.32%) represented good to very good agreement between models. The DXA-derived measures of body composition (BV: 96.6 +/- 18.1 L; %fat: 39.5% +/- 8.1%; fat mass: 38.5 +/- 11.9 kg), were significantly greater (p < 0.001) than 4C criterion measures (BV: 95.7 +/- 17.6 L; %fat: 37.0% +/- 7.6%; FM: 36.0 +/- 10.8 kg) with the exception of lean mass, which was significantly lower (p < 0.001; DXA-4C: 58.2 +/- 11.2 kg; criterion 4C: 60.7 +/- 12.0 kg). Although small statistically significant mean differences were observed, TE and SEE results support the use of the DXA-4C method, which requires less time and equipment, for valid estimates of body composition in overweight/obese individuals. PMID- 29474801 TI - Enabling Young Service Users to Provide Feedback on their Experience: An Evaluation of the Pilot Implementation of Children and Young People Accessible Friends and Family Test in General and Dental Practices in NHS England South (South Central). AB - Involvement of service users in the delivery and development of services by providing unique feedback on their own experiences is a well-established feature of continuing improvement and quality enhancement. The Friends and Family Test (FFT) is a tool that supports the fundamental principle that people who use NHS services should have the opportunity to provide feedback on their experience, however children and young people are a group of key stakeholders whose voice has not been routinely sought. This article summarises the evaluation of a pilot project which aimed to implement and test the utility of a children and young people friendly version of the FFT in general and dental practices with a view to making it more widely available in the future. One exemplar Case Study is provided and findings lead to recommendations on how to ensure the FFT is continually made accessible to children and young people. PMID- 29474803 TI - Exercise and taurine in inflammation, cognition, and peripheral markers of blood brain barrier integrity in older women. AB - Immunosenescence contribute to increase the blood-brain barrier (BBB) permeability, leading cognitive impairment and neurodegeneration. Thus, we investigated the anti-inflammatory effect of exercise and taurine supplementation on peripheral markers of BBB, inflammation, and cognition of elderly women. Forty eight elderly women (age, 83.58 +/- 6.9 years) participated in the study, and were allocated into combined exercise training (CET: n = 13), taurine supplementation (TAU: n = 12), exercise training associated with taurine (CET+TAU: n = 11), or control (CG: n = 12) groups. Exercise was applied twice a week (multi-modal exercise). Taurine ingestion was 1.5 g., once a day. Participants were evaluated before and after 14-weeks of intervention. Plasma levels of interleukin (IL)-1beta, IL-1ra, IL-6, IL-10, IL-17, tumor necrosis factor alpha (TNF-alpha), and serum concentration of S100beta and neuron specific enolase (NSE) were determined. The mini mental state examination (MMSE) was also applied. Concentrations of S100beta were maintained in all intervention groups, while a subtle increase in the CG was found. NSE levels increased only in TAU group (p < 0.05). CET reduced TNF-alpha, IL-6, and IL-1beta/IL-1ra, IL-6/IL10, and TNF-alpha/IL-10 ratios (p < 0.05). TAU decreased the IL-1beta/IL-1ra ratio (p < 0.05). MMSE score increased only in the CET+TAU group (p < 0.05). Multiple regression analysis showed that there was a trend for changes in IL-1beta and the Charlson Comorbidity Index to be independently associated with changes in S100beta. Exercise and taurine decreased inflammation, and maintained the BBB integrity in elderly women. Exercise emerged as an important tool to improve brain health even when started at advanced ages. PMID- 29474802 TI - Exploring Perceptions about Insulin Dependent Diabetes Mellitus in Adolescent Patients and Peers. AB - Friends can provide encouragement and support during stressful times. Friends are even more important for children coping with chronic illness such as adolescents managing insulin dependent diabetes mellitus (IDDM). Nurses need to recognize that the knowledge and care of both the children coping with diabetes and friends can be critical. This study explored perceptions of adolescents managing diabetes and their peers. The non-affected peers and adolescents with IDDM ranged in age between 15-18 were studied using an exploratory qualitative method. A sample of 6 subjects, 2 with diabetes and 4 peers, were interviewed. Subjects with IDDM reported manageable stress but frustration with friends' lack of knowledge. The peers reported different views of managing diabetes than those with IDDM. Adolescents with IDDM also reported positive family support. The study revealed that peers need additional education on the illness. In summary, adolescents coping with diabetes had overall positive perceptions and accurate knowledge, but limited support from peers. PMID- 29474804 TI - Use of fibers in childhood constipation treatment: systematic review with meta analysis. AB - OBJECTIVE: To gather current evidence on the use of fiber for constipation treatment in pediatric patients. SOURCE OF DATA: Systematic review with meta analysis of studies identified through Pubmed, Embase, LILACS and Cochrane databases published up to 2016. INCLUSION CRITERIA: Randomized controlled trials; patients aged between 1 and 18 years and diagnosed with functional constipation receiving or not drug treatment for constipation; articles published in Portuguese, English, Spanish, French, and German in journals accessible to the researchers. SYNTHESIS OF DATA: A total of 2963 articles were retrieved during the search and, after adequate evaluation, nine articles were considered relevant to the study objective. A total of 680 children were included, of whom 45% were boys. No statistical significance was observed for bowel movement frequency, stool consistency, therapeutic success, fecal incontinence, and abdominal pain with fiber intake in patients with childhood constipation. These results should be interpreted with care due to the high clinical heterogeneity between the studies and the methodological limitation of the articles selected for analysis. CONCLUSIONS: There is a scarcity of qualified studies to evaluate fiber supplementation in the treatment of childhood constipation, generating a low degree of confidence in estimating the real effect of this intervention on this population. Today, according to the current literature, adequate fiber intake should only be recommended for functional constipation, and fiber supplementation should not be prescribed in the diet of constipated children and adolescents. PMID- 29474805 TI - Initial Pediatric Renal Tumor Imaging: Moving from Good to Better to Best. PMID- 29474806 TI - Factors That Influence Parents' Adherence to Safe Sleep Guidelines. AB - OBJECTIVE: To explore factors that influence parental behaviors related to newborn sleep positions and environments in the home after hospital discharge. DESIGN: A descriptive qualitative study conducted by telephone. SETTING: A 290 bed academic teaching hospital in an urban setting with a Level 3 perinatal center and approximately 4,500 births per year. PARTICIPANTS: Participants (N = 60) were recruited from the patient population of the mother-baby unit. All participants were scheduled to be discharged simultaneously with their newborns. METHODS: Qualitative interviews with grand tour-style questions were conducted by telephone. An inductive analysis process was used to identify themes and meaning. RESULTS: Participants described three consistent factors that influenced how the newborn slept at home. The most frequently mentioned influence was Other People followed by Nobody/No One and Images from sources such as books, pictures, television, and the Internet. CONCLUSION: New parents need education about the rationale for the safe sleep guidelines from the American Academy of Pediatrics (AAP) as well as knowledge of the potential harm of behaviors such as bed sharing and prone or side-lying positions for sleeping. The images to which parents are exposed send mixed messages. Health care professionals should portray safe sleep for infants in media, marketing materials, and other graphic representations. Nurses should help parents understand the AAP's recommendations for safe sleep position and environment for infants so that they can become advocates for their newborns' well-being. PMID- 29474807 TI - POINT: Should an Attempt Be Made to Withdraw Inhaled Corticosteroids in All Patients With Stable GOLD 3 (30% <= FEV1 < 50% Predicted) COPD? Yes. PMID- 29474808 TI - Rebuttal From Dr Chalmers. PMID- 29474809 TI - The structure of arm and hand movements in a spontaneous and food rewarded on line string-pulling task by the mouse. AB - Arm and hand use by the mouse have been studied in a variety of tasks in order to understand the structure of skilled movements and motor learning, the anatomy and function of neural pathways, and to develop animal models of neurological conditions. The present study describes string-pulling by the mouse, a behavior in which a mouse uses hand-over-hand movements to pull down a string that hangs from the top of a test cage. Mice both spontaneously string-pull and also string pull to obtain cashew nuts tied to the end of the string as food reward. To string-pull, mice sat upright and tracked the string with their nose and then made hand-over-hand movements to reel in the string. A string-pull movement consists of four arm movements (Advance to make purchase, Pull, Push to draw the string down and Lift to return the hand for the next Advance) and four hand movements (Collect to aim the hand, Overgrasp to position the hand, and Grasp to make purchase, and Release). The kinematic profiles of the string-pull movement are distinctive with each hand making similar movements at a rate of 4 cycles per second and with the Lift and Advance movements occurring at a higher speed than Pull and Push movements. The results are discussed in relation to the antecedent repertoire of mouse behavior that lends itself to string-pulling, with respect to the utility of using string-pulling to investigate motor systems and adapting string-pulling to model neurological conditions in mice. PMID- 29474811 TI - Evaluation of behavioral parameters, hematological markers, liver and kidney functions in rodents exposed to Deepwater Horizon crude oil and Corexit. AB - The 2010 Deepwater Horizon (DWH) oil spill is the largest marine oil spill in US history. In the aftermath of the spill, the response efforts used a chemical dispersant, Corexit, to disperse the oil spill. The health impacts of crude oil and Corexit mixture to humans, mammals, fishes, and birds are mostly unknown. The purpose of this study is to investigate the in vivo effects of DWH oil, Corexit, and oil-Corexit mixture on the general behavior, hematological markers, and liver and kidney functions of rodents. C57 Bl6 mice were treated with DWH oil (80 mg/kg) and/or Corexit (95 mg/kg), and several hematological markers, lipid profile, liver and kidney functions were monitored. The results show that both DWH oil and Corexit altered the white blood cells and platelet counts. Moreover, they also impacted the lipid profile and induced toxic effects on the liver and kidney functions. The impacts were more pronounced when the mice were treated with a mixture of DWH-oil and Corexit. This study provides preliminary data to elucidate the potential toxicological effects of DWH oil, Corexit, and their mixtures on mammalian health. Residues from the DWH spill continue to remain trapped along various Gulf Coast beaches and therefore further studies are needed to fully understand their long-term impacts on coastal ecosystems. PMID- 29474810 TI - Acute and repeated exposure to social stress reduces gut microbiota diversity in Syrian hamsters. PMID- 29474812 TI - Inactivation of filter bound aerosolized MS2 bacteriophages using a non conductive ultrasound transducer. AB - The inactivation of viruses that retain their infectivity when transmitted through the air is challenging. To address this issue, this study used a non contact ultrasound transducer (NCUT) to generate shock waves in the air at specific distances, input voltages, and exposure durations, targeting bacteriophage virus aerosols captured on to H14 HEPA filters. Initially, a frequency of 27.56 kHz (50V) at 25-mm distance was used, which yielded an inactivation efficiency of up to 32.69 +/- 12.10%. Other frequencies at shorter distances were investigated, where 29.10 kHz had the highest inactivation efficiency (up to 81.95 +/- 9.79% at 8.5-mm distance and 100 V). Longer exposure times also influenced virus inactivation, but the results were inconclusive because the NCUT overheated with time. Overall, NCUT appears to be a promising method for inactivating virus aerosols that may be safer than other forms of inactivation, which can cause genetic mutations or produce dangerous by-products. PMID- 29474813 TI - A multiplexed RT-LAMP assay for detection of group M HIV-1 in plasma or whole blood. AB - Isothermal nucleic acid amplification techniques, such as reverse-transcription loop-mediated isothermal amplification (RT-LAMP), exhibit characteristics that are suitable for the development of a rapid, low-cost NAT that can be used at the POC. For demonstration of utility for global use, studies are needed to validate the performance of RT-LAMP for the detection of divergent subtypes. In this study, we designed and evaluated multiplexed HIV-1 integrase RT-LAMP primers to detect subtypes within group M, along with an RNase P positive internal processing and amplification control. Using a panel of 26 viral isolates representing the major circulating subtypes, we demonstrated detection of all isolates of subtypes A1, C, D, F1, F2, G, CRF01_AE, CRF02_AG, and two unique recombinant forms (URFs). A whole blood panel created with one representative isolate of each subtype was successfully amplified with the group M HIV-1 integrase and RNase P internal control primers. The group M HIV-1 RT-LAMP assay was further evaluated on 61 plasma specimens obtained from persons from Cameroon and Uganda. The sequence-conserved group M HIV-1 RT-LAMP primers, coupled to a low-cost amplification device, may improve diagnosis of acute infection at the POC and provide timely confirmation of HIV status. PMID- 29474814 TI - Method for simple and rapid concentration of Zika virus particles from infected cell-culture supernatants. AB - Experimental studies on Zika virus (ZIKV) may require improvement of infectious titers in viral stocks obtained by cell culture amplification. The use of centrifugal filter devices to increase infectious titers of ZIKV from cell culture supernatants is highlighted here. A mean gain of 2.33 +/- 0.12 log10 DICT50/mL was easily and rapidly obtained with this process. This efficient method of ultrafiltration may be applied to other viruses and be useful in various experimental studies requiring high viral titers. PMID- 29474815 TI - Complete mitochondrial genome of the tea looper caterpillar, Ectropis obliqua (Lepidoptera: Geometridae) with a phylogenetic analysis of Geometridae. AB - The complete mitochondrial genome (mitogenome) of the Ectropis obliqua (Lepidoptera: Geometridae) was sequenced and compared with other species of Geometridae. The mitochondrial genome of E. obliqua is 15,475bp long and contains 37 genes including 13 protein coding genes (PCGs), 22 transfer RNA genes, 2 ribosomal RNA genes and an A+T-rich region. Gene cluster trnI-trnQ-trnM rearranged to trnM-trnI-trnQ comparing with the ancestral mitogenome of insects. All tRNA genes have typical cloverleaf secondary structure except for trnS (AGN). All the sequenced mitogenomes from Geometridae have negative AT-skews and positive GC-skews except for Biston suppressaria. The synonymous and nonsynonymous substitutions ratios (Ka/Ks) indicated variable selective pressures among 13 PCGs. The phylogenetic relationship among 11 species of Geometridae was recovered based on 13 protein coding genes and 2 rRNA genes using Bayesian inference. E. obliqua is grouped with other Ennominae species and recovered to be sister-relationship with Abraxas suspecta. PMID- 29474816 TI - Coffee for Cardioprotection and Longevity. AB - Coffee, a complex brew containing hundreds of biologically active compounds, exerts potent effects on long-term human health. Recently, a plethora of studies have been published focusing on health outcomes associated with coffee intake. An inverse association between coffee consumption and all-cause mortality has been seen consistently in large prospective studies. Habitual coffee consumption is also associated with lower risks for cardiovascular (CV) death and a variety of adverse CV outcomes, including coronary heart disease (CHD), congestive heart failure (HF), and stroke; coffee's effects on arrhythmias and hypertension are neutral. Coffee consumption is associated with improvements in some CV risk factors, including type 2 diabetes (T2D), depression, and obesity. Chronic coffee consumption also appears to protect against some neurodegenerative diseases, and is associated with improved asthma control, and lower risks for liver disease and cancer. Habitual intake of 3 to 4 cups of coffee appears to be safe and is associated with the most robust beneficial effects. However, most of the studies regarding coffee's health effects are based on observational data, with very few randomized controlled trials. Furthermore, the possible benefits of coffee drinking must be weighed against potential risks, which are generally due to its high caffeine content, including anxiety, insomnia, headaches, tremulousness, and palpitations. Coffee may also increase risk of fracture in women, and when consumed in pregnancy coffee increases risk for low birth weight and preterm labor. PMID- 29474818 TI - Assessment of intradimensional/extradimensional attentional set-shifting in rats. AB - The rat intradimensional/extradimensional (ID/ED) task, first described by Birrell and Brown 18 years ago, has become the predominant means by which attentional set-shifting is investigated in rodents: the use of rats in the task has been described in over 135 publications by researchers from nearly 90 universities and pharmaceutical companies. There is variation in the protocols used by different groups, including differences in apparatus, stimuli (both stimulus dimensions and exemplars within), and also the methodology. Nevertheless, most of these variations seem to be of little consequence: there is remarkable similarity in the profile of published data, with consistency of learning rates and in the size and reliability of the set-shifting and reversal 'costs'. However, we suspect that there may be inconsistent data that is unpublished or perhaps 'failed experiments' that may have been caused by unintended deviations from effective protocols. The purpose of this review is to describe our approach and the rationale behind certain aspects of the protocol, including common pitfalls that are encountered when establishing an effective local protocol. PMID- 29474817 TI - Activation of the unfolded protein response downregulates cardiac ion channels in human induced pluripotent stem cell-derived cardiomyocytes. AB - RATIONALE: Heart failure is characterized by electrical remodeling that contributes to arrhythmic risk. The unfolded protein response (UPR) is active in heart failure and can decrease protein levels by increasing mRNA decay, accelerating protein degradation, and inhibiting protein translation. OBJECTIVE: Therefore, we investigated whether the UPR downregulated cardiac ion channels that may contribute to arrhythmogenic electrical remodeling. METHODS: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were used to study cardiac ion channels. Action potentials (APs) and ion channel currents were measured by patch clamp recording. The mRNA and protein levels of channels and the UPR effectors were determined by quantitative RT-PCR and Western blotting. Tunicamycin (TM, 50 ng/mL and 5 MUg/mL), GSK2606414 (GSK, 300 nmol/L), and 4MU8C (5 MUmol/L) were utilized to activate the UPR, inhibit protein kinase-like ER kinase (PERK) and inositol-requiring protein-1 (IRE1), respectively. RESULTS: TM induced activation of the UPR caused significant prolongation of the AP duration (APD) and a reduction of the maximum upstroke velocity (dV/dtmax) of the AP phase 0 in both acute (20-24 h) and chronic treatment (6 days). These changes were explained by reductions in the sodium, L-type calcium, the transient outward and rapidly/slowly activating delayed rectifier potassium currents. Nav1.5, Cav1.2, Kv4.3, and KvLQT1 channels showed concomitant reductions in mRNA and protein levels under activated UPR. Inhibition of PERK or IRE1 shortened the APD and reinstated dV/dtmax. The PERK branch regulated Nav1.5, Kv4.3, hERG, and KvLQT1. The IRE1 branch regulated Nav1.5, hERG, KvLQT1, and Cav1.2. CONCLUSIONS: Activated UPR downregulates all major cardiac ion currents and results in electrical remodeling in hiPSC-CMs. Both PERK and IRE1 branches downregulate Nav1.5, hERG, and KvLQT1. The PERK branch specifically downregulates Kv4.3, while the IRE1 branch downregulates Cav1.2. Therefore, the UPR contributed to electrical remodeling, and targeting the UPR might be anti-arrhythmic. PMID- 29474819 TI - Direct evidence for high affinity blockade of NaV1.6 channel subtype by huwentoxin-IV spider peptide, using multiscale functional approaches. AB - The Chinese bird spider huwentoxin-IV (HwTx-IV) is well-known to be a highly potent blocker of NaV1.7 subtype of voltage-gated sodium (NaV) channels, a genetically validated analgesic target, and thus promising as a potential lead molecule for the development of novel pain therapeutics. In the present study, the interaction between HwTx-IV and NaV1.6 channel subtype was investigated using multiscale (from in vivo to individual cell) functional approaches. HwTx-IV was approximatively 2 times more efficient than tetrodotoxin (TTX) to inhibit the compound muscle action potential recorded from the mouse skeletal neuromuscular system in vivo, and 30 times more effective to inhibit nerve-evoked than directly elicited muscle contractile force of isolated mouse hemidiaphragms. These results strongly suggest that the inhibition of nerve-evoked skeletal muscle functioning, produced by HwTx-IV, resulted from a toxin-induced preferential blockade of NaV1.6, compared to NaV1.4, channel subtype. This was confirmed by whole-cell automated patch-clamp experiments performed on human embryonic kidney (HEK)-293 cells overexpressing hNaV1.1-1.8 channel subtypes. HwTx-IV was also approximatively 850 times more efficient to inhibit TTX-sensitive than TTX resistant sodium currents recorded from mouse dorsal root ganglia neurons. Finally, based on our data, we predict that blockade of the NaV1.6 channel subtype was involved in the in vivo toxicity of HwTx-IV, although this toxicity was more than 2 times lower than that of TTX. In conclusion, our results provide detailed information regarding the effects of HwTx-IV and allow a better understanding of the side-effect mechanisms involved in vivo and of channel subtype interactions resulting from the toxin activity. PMID- 29474820 TI - Effects of two doses of anti-T lymphocyte globulin-Fresenius given after full match sibling stem cell transplantation in acute myeloblastic leukemia patients who underwent myeloablative fludarabine/busulfan conditioning. AB - OBJECTIVE/BACKGROUND: Anti-T lymphocyte globulin Fresenius (rATG-F; ATG Fresenius) and antithymocyte globulin (thymoglobulin), which are included in transplant protocols, are used to reduce the risk of chronic graft-versus-host disease (cGVHD) or suppress allograft rejection. Available clinical studies have been conducted in heterogenous patient populations and with different administration protocols including stem cell sources. Additionally, the pharmacokinetics of ATG is variable, and the clinically effective dose of rATG-F, in particular, is not exactly known. The aim of the study was to investigate the clinical outcomes of acute myeloid leukemia (AML) patients who underwent hemopoietic peripheral stem cell transplantation from full-matched sibling donors and given two different doses of r-ATG-F. METHODS: This was a single-center, retrospective chart review conducted between July 2005 and July 2016. Sixty-nine consecutive AML patients who underwent transplant with fludarabine- and busulfan based conditioning were included in the study. Patients in Group 1 received 15 mg/kg body weight rATG-F to 2013 (n = 46), and Group 2 received 30 mg/kg of rATG F dose begining in 2013 to reduce to cGVHD (n = 23). Cyclosporine and methotrexate were used to treat acute GVHD (aGVHD) prophylaxis. Outcome parameters were compared between the groups. RESULTS: Although the recommended dose r-ATG-F had led to a decrease in the cumulative incidence of cGVHD (27 [58.7%] vs. 8 [34.8%]; p = .03), it also increased the infection rate at 1 year (3 [6.5%] vs. 4 [17.4%]; p = .02). The two groups were similar in terms of engraftment time, aGVHD, relapse, nonrelapse mortality, and rATG-F-related toxicity. A Cox regression model revealed that aGVHD III-IV was associated with increased nonrelapse mortality at 1 year (hazard ratio = 18.2; 95% confidence interval, 1.667-199.255; p = <.02). No patients developed rATG-F-related severe adverse events (Common Terminology Criteria grade 4 or 5). CONCLUSION: Dose difference of rATG-F did not influence survival parameters; however, increasing the dose to 30 mg/kg seems to be effective for reducing cGVHD with an increase in infection rate requiring close monitoring of infections in AML patients who received myeloablative fludarabine/busulfan conditioning. PMID- 29474821 TI - Immunopanning purification and culture of retinal ganglion cells from mouse. PMID- 29474822 TI - Male urinary biomarkers of antimicrobial exposure and bi-directional associations with semen quality parameters. AB - Antimicrobials including parabens, triclosan, and triclocarban have endocrine disrupting properties. Among 501 male partners of couples planning to become pregnant, preconception urinary biomarkers of parabens, triclosan and triclocarban exposure were quantified in spot urine samples. Men also provided two fresh semen samples collected approximately one month to undergo 24-h semen quality analysis. Linear mixed-effects models, adjusted for creatinine, race, age and body mass index, were utilized to assess the relationship between log transformed chemical concentrations rescaled by their standard deviations and semen parameters. Methyl, ethyl and butyl parabens, were associated with diminished sperm count and several sperm motility parameters. Hydroxylated paraben metabolites and triclosan were significantly positively associated with select semen quality parameters. Overall, our findings suggest that specific urinary parabens found in consumer goods (methyl, ethyl and butyl parabens) may adversely impact sperm quality parameters among reproductive-age male partners of couples trying for pregnancy. PMID- 29474823 TI - Investigation of structure and function of mitochondrial alcohol dehydrogenase isozyme III from Komagataella phaffii GS115. AB - BACKGROUND: Alcohol dehydrogenases (ADHs) catalyze the reversible oxidation of alcohol using NAD+ or NADP+ as cofactor. Three ADH homologues have been identified in Komagataella phaffii GS115 (also named Pichia pastoris GS115), ADH1, ADH2 and ADH3, among which adh3 is the only gene responsible for consumption of ethanol in Komagataella phaffii GS115. However, the relationship between structure and function of mitochondrial alcohol dehydrogenase isozyme III from Komagataella phaffii GS115 (KpADH3) is still not clear yet. METHODS: KpADH3 was purified, identified and characterized by multiple biophysical techniques (Nano LC-MS/MS, Enzymatic activity assay, X-ray crystallography). RESULTS: The crystal structure of KpADH3, which was the first ADH structure from Komagataella phaffii GS115, was solved at 1.745 A resolution. Structural analysis indicated that KpADH3 was the sole dimeric ADH structure with face-to-face orientation quaternary structure from yeast. The major structural different conformations located on residues 100-114 (the structural zinc binding loop) and residues 337 344 (the loop between alpha12 and beta15 which covered the catalytic domain). In addition, three channels were observed in KpADH3 crystal structure, channel 2 and channel 3 may be essential for substrate specific recognition, ingress and egress, channel 1 may be the pass-through for cofactor. CONCLUSIONS: KpADH3 plays an important role in the metabolism of alcohols in Komagataella phaffii GS115, and its crystal structure is the only dimeric medium-chain ADH from yeast described so far. GENERAL SIGNIFICANCE: Knowledge of the relationship between structure and function of KpADH3 is crucial for understanding the role of KpADH3 in Komagataella phaffii GS115 mitochondrial metabolism. PMID- 29474824 TI - Genomic evidence for the population genetic differentiation of Misgurnus anguillicaudatus in the Yangtze River basin of China. AB - Misgurnus anguillicaudatus, an important aquatic species, is mainly distributed in the Yangtze River basin. To reveal the population genetic structure of M. anguillicaudatus distributed in the Yangtze River basin, genotyping by sequencing (GBS) technique was employed to detect the genome wide genetic variations of M. anguillicaudatus. A total of 30.03 Gb raw data were yielded from 70 samples collected from 15 geographic sites located in the Yangtze River basin. Subsequently, 2092 high quality SNPs were genotyped across these samples and used for a series of genetic analysis. The results of genetic analysis showed that high levels of genetic diversity were observed and the populations from upper reaches (UR) were significantly differentiated from the middle and lower reaches (MLR) of Yangtze River basin. Meanwhile, no significant isolation by distance was detected among the populations. Ecological factors (e.g. complicated topography and climatic environment) and anthropogenic factors (e.g. aquaculture and agriculture cultivation) might account for the genetic disconnectivity between UR and MLR populations. This study provided valuable genetic data for the future breeding program and also for the conversation and scientific utilization of those abundant genetic resources stored in the Yangtze River basin. PMID- 29474825 TI - Characterization of the genome of a Nocardia strain isolated from soils in the Qinghai-Tibetan Plateau that specifically degrades crude oil and of this biodegradation. AB - A strain of Nocardia isolated from crude oil-contaminated soils in the Qinghai Tibetan Plateau degrades nearly all components of crude oil. This strain was identified as Nocardia soli Y48, and its growth conditions were determined. Complete genome sequencing showed that N. soli Y48 has a 7.3 Mb genome and many genes responsible for hydrocarbon degradation, biosurfactant synthesis, emulsification and other hydrocarbon degradation-related metabolisms. Analysis of the clusters of orthologous groups (COGs) and genomic islands (GIs) revealed that Y48 has undergone significant gene transfer events to adapt to changing environmental conditions (crude oil contamination). The structural features of the genome might provide a competitive edge for the survival of N. soli Y48 in oil-polluted environments and reflect the adaptation of coexisting bacteria to distinct nutritional niches. PMID- 29474826 TI - Endovascular Aortic Repair Complications and the Power of Endovascular Solutions. AB - We report the case of a 75-year-old man submitted to traditional endovascular aortic repair (EVAR) for infrarenal abdominal aortic aneurysm. He presented a late type II endoleak 6 months after operation, initially without sac enlargement. One year later, a computed tomography scan control demonstrated a sac expansion >10 mm, also responsible for a secondary proximal type I endoleak. The patient was submitted to transarterial embolization of lumbar arteries through left internal iliac artery, followed by type I endoleak correction with a proximal cuff deployment. Intraoperative angiography revealed no signs of endoleak. Six months later, a sudden enlargement of the sac was detected, with evidence of type III endoleak, probably consequence of the lumbar arteries embolization, promptly corrected through an aortoaortic endograft. In conclusion, even if a conservative approach for type II endoleak without sac enlargement is proposed, sometimes a sudden sac enlargement could be responsible for catastrophic events in the absence of strict follow-up. The sac embolization during EVAR could reduce the incidence of type II endoleak during follow-up, with reoperation and hospital cost reduction. PMID- 29474827 TI - Review on pathogenicity mechanism of enterotoxigenic Escherichia coli and vaccines against it. AB - Enterotoxigenic Escherichia coli (ETEC) is the most common cause of diarrhea in children. Colonization factors (CFs) and LT enterotoxin are the major ETEC candidate vaccines. To cause disease, ETEC must adhere to the epithelium of the small intestine by means of CFs. Watery diarrhea is produced due to the effects of the enterotoxins. Vaccine development against ETEC has been identified as an important primary prevention strategy in developing countries and for travelers to these regions. Mucosal immunization can cause secretory IgA antibody (sIgA) responses that prevents the attachment of bacteria to the intestine and are of particular importance for provide protection against ETEC infection. The design of multivalent ETEC vaccine containing various colonization factors and ETEC toxin may provide protection against a wide range of bacterial strains. In this review, the importance and pathogenesis of ETEC, and the latest ETEC vaccine research results are discussed. PMID- 29474828 TI - Isolation and molecular characterization of Corynebacterium pseudotuberculosis from sheep and goats in Mexico. AB - The pathogenic bacteria of Corynebacterium pseudotuberculosis caused a chronic contagious infectious disease of the caseous lymphadenitis or pseudotuberculosis. Globally, isolates obtained from different injuries that affect sheep and goats, have been identified by fully or partially gene sequencing. However, in Mexico there is no complete study to identify by molecular and phylogenetic techniques the circulating isolates as well as its virulence factors. Therefore, in the present study we reported the identification of 57 isolates of C. pseudotuberculosis by bacteriological tests and the amplification of 16S rRNA, rpoB and pld genes, as well as, genes involved in virulence and pathogenicity: Fag A, Fag B, Fag C, Fag D and hsp60. Phylogenetic analysis was performed based on the partial sequence of the rpoB gene. Genes involved in virulence and pathogenicity were identified in the 98.2% of the isolates. Regarding the phylogenetic analysis, were identified the species and subspecies to which they belong of all the tested isolates. The phenotypic and genotypic characterization will allow to establish preventive and prophylactic measures aimed to the creation of effective immunogens against Corynebacterium pseudotuberculosis. PMID- 29474829 TI - Corrigendum to "Adolescent Binge Ethanol Exposure Alters Specific Forebrain Cholinergic Cell Populations and Leads to Selective Functional Deficits in the Prefrontal Cortex" [Neuroscience 361 (2017) 129-143]. PMID- 29474830 TI - Erythema Nodosum Leprosum: Update and challenges on the treatment of a neglected condition. AB - Erythema Nodosum Leprosum (ENL) occurs due to the immunological complication of multibacillary leprosy and is characterized by painful nodules and systemic compromising. It is usually recurrent and/or chronic and has both physical and economic impact on the patient, being a very important cause of disability. In addition, ENL is a major health problem in countries where leprosy is endemic. Therefore, adequate control of this condition is important. The management of ENL aims to control acute inflammation and neuritis and prevent the onset of new episodes. However, all currently available treatment modalities have one or two drawbacks and are not effective for all patients. Corticosteroid is the anti inflammatory of choice in ENL but may cause dependence, especially for chronic patients. Thalidomide has a rapid action but its use is limited due the teratogenicity and neurotoxicity. Clofazimine and pentoxifylline have slow action and have important adverse effects. Finally, there is no pattern or guidelines for treating these patients, becoming more difficult to evaluate and to control this condition. This review aims to show the main drugs used in the treatment of ENL and the challenges in the management of the reaction. PMID- 29474831 TI - Comparative genomic analysis of Rickettsia rickettsii for identification of drug and vaccine targets: tolC as a proposed candidate for case study. AB - BACKGROUND: Antibiotic resistance is increasing rapidly in pathogenic organisms, creating more complications for treatment of diseases. Rocky Mountain spotted fever (RMSF) is a neglected tropical disease in humans caused by Rickettsia rickettsii for which no effective therapeutic is available. Subtractive genomics methods facilitate the characterization of non-homologous essential proteins that could be targeted for the discovery of potential therapeutic compounds against R. rickettsii to combat RMSF. Present study followed an in-silico based methodology, involving scanning and filtering the complete proteome of Rickettsia rickettsii by using several prioritization parameters in the search of potential candidates for drug development. Further the putative targets were subjected to series of molecular dockings with ligands obtained from PDB ligand database to identify suitable potential inhibitors. The comparative genomic analysis revealed 606 non homologous proteins and 233 essential non-homologous proteins of R. rickettsii. The metabolic pathway analysis predicted 120 proteins as putative drug targets, out of which 56 proteins were found to be associated with metabolic pathways unique to the bacteria and further subcellular localization analysis revealed that 9 proteins as potential drug targets which are secretion proteins, involved in peptidoglycan biosynthesis, folate biosynthesis and bacterial secretion system. As secretion proteins are more feasible as vaccine candidates, we have selected a most potential target i.e. tolC, an outer membrane efflux protein that belongs to type I secretion system and has major role in pathogen survival as well as MDR persistence. So for case study, we have modelled the three dimensional structure of tolC (tunnel protein). The model was further subjected to virtual screening and in-silico docking. The study identified three potential inhibitors having PDB Id 19V, 6Q8 and 39H. Further we have suggested that the above study would be most important while considering the selection of candidate targets and drug or vaccine designing against R. rickettsii. PMID- 29474833 TI - One-step integrated clarification and purification of a monoclonal antibody using Protein A Mag Sepharose beads and a cGMP-compliant high-gradient magnetic separator. AB - Monoclonal antibodies are a dominant component of today's biopharmaceutical market and are typically purified by classical platform processes. However, high costs and rising demands are drivers for the development of new, efficient and flexible integrated purification processes. Currently, high-gradient magnetic separation as a direct capturing tool for protein purification suffers from the lack of suitable GMP-compliant separation equipment for industrial scale. As a solution for this bottleneck, we present a purification process for a monoclonal antibody directly from CHO cell culture by use of protein A-functionalized magnetic particles together with the first pilot-scale GMP-compliant 'rotor stator' high-gradient magnetic separator. Five consecutive purification cycles were performed, achieving consistent yields of over 85% and purities of over 95%. Stable cell viabilities during the magnetic separation process enable integration of the device as an in situ product removal tool. A comparison with state-of-the art protein A column-based purification processes reveals a 3-times higher process productivity per mL of applied resin and demonstrates the great potential of magnetic separation in downstream processing. PMID- 29474832 TI - Detection of West Nile Virus - Lineage 2 in Culex pipiens mosquitoes, associated with disease outbreak in Greece, 2017. AB - During July-October 2017 a WNV outbreak took place in the Peloponnese, Southern Greece with five confirmed deaths. During routine monitoring survey in the Peloponnese, supported by the local Prefecture, we have confirmed the presence of all three Culex pipiens biotypes in the region, with a high percentage of Culex pipiens/molestus hybrids (37.0%) which are considered a highly competent vector of WNV. Kdr mutations related to pyrethroid resistance were found at relatively low levels (14.3% homozygosity) while no mosquitoes harboring the recently identified chitin synthase diflubenzuron-resistance mutations were detected in the region. As an immediate action, following the disease outbreak (within days), we collected a large number of mosquitoes using CO2 CDC traps from the villages in the Argolis area of the Peloponnese, where high incidence of WNV human infections were reported. WNV lineage 2 was detected in 3 out of 47 Cx. pipiens mosquito pools (detection rate = 6.38%). The virus was not detected in any other mosquito species, such as Aedes albopictus, sampled from the region at the time of the disease outbreak. Our results show that detection of WNV lineage 2 in Cx. pipiens pools is spatially and chronologically associated with human clinical cases, thus implicating Cx. pipiens mosquitoes as the most likely WNV vector. The absence of diflubenzuron resistance mutations and the low frequency of pyrethroid (kdr) resistance mutations indicates the suitability of these insecticides for Cx. pipiens control, in the format of larvicides and/or residual spraying applications respectively, which was indeed the main (evidence based) response, following the disease outbreak. PMID- 29474834 TI - Non-immunoglobulin scaffold proteins: Precision tools for studying protein protein interactions in cancer. AB - Cancer is frequently characterised by dysregulation of the cellular signalling processes that govern proliferation, survival and attachment. Understanding such dysregulation continues to present a challenge given the importance of protein protein interactions in intracellular processes. Exploring this protein-protein interactome requires novel tools capable of discriminating between highly homologous proteins, individual domains and post-translational modifications. This review examines the potential of scaffold-based binding proteins to fulfil these requirements. It also explores protein-protein interactions in the context of intracellular signalling pathways and cancer, and demonstrates the uses of scaffold proteins as functional moderators, biosensors and imaging reagents. This review also highlights the timeliness and potential to develop international consortia to develop and validate highly specific "proteome" scaffold-based binding protein reagents with the ultimate aim of developing screening tools for studying the interactome. PMID- 29474835 TI - Development of a new screening method to determine the main 52 mitochondrial haplogroups through a single minisequencing reaction. AB - This work presents the design, development and optimization of a screening method based on single-base extension sequencing to simultaneously analyze a panel of 52 mitochondrial SNPs. This enables to recognize the main mitochondrial haplogroups and to discriminate even between lineages from the same phylogenetic branch that diverged in different continents. The unavailability of individuals harboring infrequent variants was a limitation to optimize the panel. To overcome this, we have modified DNA by site-directed mutagenesis to create the unavailable allelic variants. This allowed us to verify the reliability of this panel and its usefulness to be applied in biomedicine, forensic and population genetic studies. PMID- 29474836 TI - Quantitative neuroimaging biomarkers in a series of 20 adult patients with POLG mutations. AB - Mutations in the gene encoding polymerase gamma (POLG) are a common cause of mitochondrial diseases in adults. We retrospectively analyzed volumetric and diffusion tensor imaging data from 20 adult POLG-mutated patients compared to healthy controls. We used an original clinical binary load score and electroneuromyography to evaluate disease severity. Patients showed atrophy in the basal ganglia, amygdala, and brainstem (p < 0.05) compared to controls, as well as decreased fractional anisotropy (FA) in the cingulate gyrus, the internal capsule and the corona radiata (p < 0.05). Clinical scores correlated with decreased FA and increased radial diffusivity in several brain regions (p < 0.05). PMID- 29474838 TI - Time allocation and dietary habits in the United States: Time for re-evaluation? AB - In this non-exhaustive narrative review, time allocation and its relation to dietary habits are discussed. Drawing from reports relying on time use surveys, the amount of time dedicated to cooking and dining is found to be associated with health outcomes such as BMI and cardiovascular risk. Important modifiers include gender, race, ethnicity and household income. Perception of time intensity is also discussed. Individuals who perceive time pressure or strain may be less likely to engage in healthy food related activities and be at greater risk for poor health outcomes. Finally, the direct observation of allocation during meal occasions is discussed. The author calls for a socio-ecological approach to the study of time allocation and dietary habits in the United States and further consideration of direct observation of time use. PMID- 29474837 TI - Mitochondrial accumulation of doxorubicin in cardiac and diaphragm muscle following exercise preconditioning. AB - Doxorubicin (DOX) is a highly effective anthracycline antibiotic. Unfortunately, the clinical use of DOX is limited by the risk of deleterious effects to cardiac and respiratory (i.e. diaphragm) muscle, resulting from mitochondrial reactive oxygen species (ROS) production. In this regard, exercise is demonstrated to protect against DOX-induced myotoxicity and prevent mitochondrial dysfunction. However, the protective mechanisms are currently unclear. We hypothesized that exercise may induce protection by increasing the expression of mitochondria specific ATP-binding cassette (ABC) transporters and reducing mitochondrial DOX accumulation. Our results confirm this finding and demonstrate that two weeks of exercise preconditioning is sufficient to prevent cardiorespiratory dysfunction. PMID- 29474839 TI - Impact of male presence on female sociality and stress endocrinology in wild house mice (Mus musculus domesticus). AB - In group living animals, reproductive competition plays an important role in shaping social relationships and associations among female group members. In this study, we investigated the impact of male presence on the development of female female competition and female sociality in groups of female wild house mice, using physiological and behavioral parameters. We predicted that, by eliciting intra-sexual competition, males influence social relationships among female group members and thus affect female associations to potential cooperation partners. To test this hypothesis we compared stress hormone production, the frequency of agonistic interactions, social hierarchies and social partner preferences in groups of unrelated, unfamiliar females in the absence and presence of males. Our results revealed no indication that the introduction of males into all-female groups of wild house mice elicited increased competition among female group members, neither on the physiological nor on the behavioral level. We found no effect of male presence on female glucocorticoid secretion, aggression, dominance hierarchies or on the females' sociability. Females thus seem not to intensely compete over access to males. This female ability to behaviorally and physiologically deal with even previously unfamiliar same-sex group members may be an important feature of female house mouse societies. In fact, it could be a necessary prerequisite to establish cooperative relationships between females in the context of reproduction, such as communal nursing of young. PMID- 29474840 TI - Production of muconic acid in plants. AB - Muconic acid (MA) is a dicarboxylic acid used for the production of industrially relevant chemicals such as adipic acid, terephthalic acid, and caprolactam. Because the synthesis of these polymer precursors generates toxic intermediates by utilizing petroleum-derived chemicals and corrosive catalysts, the development of alternative strategies for the bio-based production of MA has garnered significant interest. Plants produce organic carbon skeletons by harvesting carbon dioxide and energy from the sun, and therefore represent advantageous hosts for engineered metabolic pathways towards the manufacturing of chemicals. In this work, we engineered Arabidopsis to demonstrate that plants can serve as green factories for the bio-manufacturing of MA. In particular, dual expression of plastid-targeted bacterial salicylate hydroxylase (NahG) and catechol 1,2 dioxygenase (CatA) resulted in the conversion of the endogenous salicylic acid (SA) pool into MA via catechol. Sequential increase of SA derived from the shikimate pathway was achieved by expressing plastid-targeted versions of bacterial salicylate synthase (Irp9) and feedback-resistant 3-deoxy-D-arabino heptulosonate synthase (AroG). Introducing this SA over-producing strategy into engineered plants that co-express NahG and CatA resulted in a 50-fold increase in MA titers. Considering that MA was easily recovered from senesced plant biomass after harvest, we envision the phytoproduction of MA as a beneficial option to add value to bioenergy crops. PMID- 29474841 TI - Extraction of high-quality RNA from Bacillus subtilis with a lysozyme pre treatment followed by the Trizol method. AB - A suitable technique (lysozyme combined with Trizol reagent) was developed to improve the RNA yield, purity and integrity from Bacillus subtilis, under different bacterial growth stages. The obtained RNA was intact, having the required characteristics for downstream applications. PMID- 29474842 TI - The invariant natural killer T cell-mediated chemokine X-C motif chemokine ligand 1-X-C motif chemokine receptor 1 axis promotes allergic airway hyperresponsiveness by recruiting CD103+ dendritic cells. AB - BACKGROUND: The chemokine X-C motif chemokine ligand 1 (XCL1)-X-C motif chemokine receptor 1 (XCR1) axis has been reported to play a role in immune homeostasis and inflammation. However, it is not known whether this axis has a critical function in patients with allergic asthma. OBJECTIVE: In the present study we explored whether the invariant natural killer T (iNKT) cell-mediated XCL1-XCR1 axis regulated allergic asthma. METHODS: Ovalbumin (OVA)- or house dust mite-induced asthma was developed in XCL1 or XCR1 knockout (KO) mice. RESULTS: XCL1 or XCR1 KO mice showed attenuation in airway hyperresponsiveness (AHR), numbers of CD103+ dendritic cells (DCs), and TH2 responses in the lungs compared with wild-type (WT) mice during OVA- or house dust mite-induced asthma. These effects were reversed by intratracheal administration of recombinant XCL1 or adoptive transfer of CD103+ DCs but not CD11b+ DCs into XCL1 KO mice. Moreover, iNKT cells highly expressed XCL1 both in vitro and in vivo. On intranasal alpha-galactosyl ceramide challenge, CD103+ DC numbers in the lungs were increased in WT but not XCL1 KO mice. Furthermore, adoptive transfer of WT iNKT cells increased AHR, CD103+ DC recruitment, and TH2 responses in the lungs of CD1d KO mice during OVA-induced asthma, whereas adoptive transfer of XCL1-deficient iNKT cells did not. In human patients, percentages and XCL1 production capacity of iNKT cells from PBMCs were greater in patients with asthma than in healthy control subjects. CONCLUSION: These data demonstrate that the iNKT cell-mediated XCL1-XCR1 axis promotes AHR by recruiting CD103+ DCs into the lung in patients with allergic asthma. PMID- 29474843 TI - Comparison of staples vs subcuticular suture in class III obese women undergoing cesarean: a randomized controlled trial. AB - BACKGROUND: Obesity is a risk factor for infectious morbidity and wound complications after cesarean delivery. There are currently insufficient data to determine optimal skin closure technique for cesarean delivery, specifically for those women with class III obesity, defined as a body mass index >=40 kg/m2. OBJECTIVE: We sought to compare stainless steel staples vs subcuticular suture for skin closure for cesarean delivery in class III obese women with body mass index >=40 kg/m2. STUDY DESIGN: We conducted a randomized controlled trial at 2 teaching hospitals from 2015 through 2016 in which women with body mass index >=40 kg/m2 undergoing cesarean delivery were randomly assigned to stainless steel staples or subcuticular suture skin closure. The primary outcome was composite wound complication defined as superficial or deep separation and infection occurring up to 6 weeks following delivery. Secondary outcomes included operative time, and patient pain and satisfaction scores. RESULTS: A total of 242 women were enrolled. In all, 119 in the staples group and 119 in the subcuticular suture group were analyzed. Maternal demographics and characteristics were similar in both groups. The composite wound complication frequency was 19.3% in the staples group and 17.6% in the subcuticular suture group (P = .74) with an overall wound complication incidence of 18.5% in the entire study cohort. There were also no differences in the frequencies of infection, or in superficial or deep wound separation between the 2 study groups. In a univariate analysis of predictors of wound complications, only current tobacco use was a significant predictor of wound complications (relative risk, 4.97; 95% confidence interval, 1.37-18.03; P = .02). Fewer women with staple closure would choose the same method with a future delivery (P = .01), however, self-reported pain and concern about wound healing were equal between the 2 groups. CONCLUSION: In class III obese women undergoing cesarean delivery, there was no difference in composite wound outcome up to 6 weeks postpartum between those who had staples and those who had subcuticular suture skin closure. PMID- 29474845 TI - Expectations of future provision of pharmacist-prescribed hormonal contraception in California. PMID- 29474844 TI - Early and late preeclampsia are characterized by high cardiac output, but in the presence of fetal growth restriction, cardiac output is low: insights from a prospective study. AB - BACKGROUND: Preeclampsia and fetal growth restriction are considered to be placentally mediated disorders. The clinical manifestations are widely held to relate to gestation age at onset with early- and late-onset preeclampsia considered to be phenotypically distinct. Recent studies have reported conflicting findings in relation to cardiovascular function, and in particular cardiac output, in preeclampsia and fetal growth restriction. OBJECTIVE: We conducted this study to examine the possible relation between cardiac output and peripheral vascular resistance in preeclampsia and fetal growth restriction. STUDY DESIGN: We investigated maternal cardiovascular function in relation to clinical subtype in 45 pathological pregnancies (14 preeclampsia only, 16 fetal growth restriction only, 15 preeclampsia and fetal growth restriction) and compared these with 107 healthy person observations. Cardiac output was the primary outcome measure and was assessed using an inert gas-rebreathing method (Innocor), from which peripheral vascular resistance was derived; arterial function was assessed by Vicorder, a cuff-based oscillometric device. Cardiovascular parameters were normalized for gestational age in relation to healthy pregnancies using Z scores, thus allowing for comparison across the gestational range of 24-40 weeks. RESULTS: Compared with healthy control pregnancies, women with preeclampsia had higher cardiac output Z scores (1.87 +/- 1.35; P = .0001) and lower peripheral vascular resistance Z scores (-0.76 +/- 0.89; P = .025); those with fetal growth restriction had higher peripheral vascular resistance Z scores (0.57 +/- 1.18; P = .04) and those with both preeclampsia and fetal growth restriction had lower cardiac output Z scores ( 0.80 +/- 1.3 P = .007) and higher peripheral vascular resistance Z scores (2.16 +/- 1.96; P = .0001). These changes were not related to gestational age of onset. All those affected by preeclampsia and/or fetal growth restriction had abnormally raised augmentation index and pulse wave velocity. Furthermore, in preeclampsia, low cardiac output was associated with low birthweight and high cardiac output with high birthweight (r = 0.42, P = .03). CONCLUSION: Preeclampsia is associated with high cardiac output, but if preeclampsia presents with fetal growth restriction, the opposite is true; both conditions are nevertheless defined by hypertension. Fetal growth restriction without preeclampsia is associated with high peripheral vascular resistance. Although early and late gestation preeclampsias are considered to be different diseases, we show that the hemodynamic characteristics of preeclampsia were unrelated to gestational age at onset but were strongly associated with the presence or absence of fetal growth restriction. Fetal growth restriction more commonly coexists with preeclampsia at early gestation, thus explaining the conflicting results of previous studies. Furthermore, antihypertensive agents act by reducing cardiac output or peripheral vascular resistance and are administered without reference to cardiovascular function in preeclampsia. The underlying pathology (preeclampsia, fetal growth restriction, preeclampsia and fetal growth restriction) defines cardiovascular phenotype, providing a rational basis for choice of therapy in which high or low cardiac output or peripheral vascular resistance is the predominant feature. PMID- 29474846 TI - Diagnostic Accuracy of Multiparametric Magnetic Resonance Imaging and Fusion Guided Targeted Biopsy Evaluated by Transperineal Template Saturation Prostate Biopsy for the Detection and Characterization of Prostate Cancer. AB - PURPOSE: We evaluated the diagnostic accuracy of multiparametric magnetic resonance imaging and multiparametric magnetic resonance imaging/transrectal ultrasound fusion guided targeted biopsy against that of transperineal template saturation prostate biopsy to detect prostate cancer. MATERIALS AND METHODS: We retrospectively analyzed the records of 415 men who consecutively presented for prostate biopsy between November 2014 and September 2016 at our tertiary care center. Multiparametric magnetic resonance imaging was performed using a 3 Tesla device without an endorectal coil, followed by transperineal template saturation prostate biopsy with the BiopSee(r) fusion system. Additional fusion guided targeted biopsy was done in men with a suspicious lesion on multiparametric magnetic resonance imaging, defined as Likert score 3 to 5. Any Gleason pattern 4 or greater was defined as clinically significant prostate cancer. The detection rates of multiparametric magnetic resonance imaging and fusion guided targeted biopsy were compared with the detection rate of transperineal template saturation prostate biopsy using the McNemar test. RESULTS: We obtained a median of 40 (range 30 to 55) and 3 (range 2 to 4) transperineal template saturation prostate biopsy and fusion guided targeted biopsy cores, respectively. Of the 124 patients (29.9%) without a suspicious lesion on multiparametric magnetic resonance imaging 32 (25.8%) were found to have clinically significant prostate cancer on transperineal template saturation prostate biopsy. Of the 291 patients (70.1%) with a Likert score of 3 to 5 clinically significant prostate cancer was detected in 129 (44.3%) by multiparametric magnetic resonance imaging fusion guided targeted biopsy, in 176 (60.5%) by transperineal template saturation prostate biopsy and in 187 (64.3%) by the combined approach. Overall 58 cases (19.9%) of clinically significant prostate cancer would have been missed if fusion guided targeted biopsy had been performed exclusively. The sensitivity of multiparametric magnetic resonance imaging and fusion guided targeted biopsy for clinically significant prostate cancer was 84.6% and 56.7% with a negative likelihood ratio of 0.35 and 0.46, respectively. CONCLUSIONS: Multiparametric magnetic resonance imaging alone should not be performed as a triage test due to a substantial number of false-negative cases with clinically significant prostate cancer. Systematic biopsy outperformed fusion guided targeted biopsy. Therefore, it will remain crucial in the diagnostic pathway of prostate cancer. PMID- 29474847 TI - Serum miRNA Predicts Viable Disease after Chemotherapy in Patients with Testicular Nonseminoma Germ Cell Tumor. AB - PURPOSE: Retroperitoneal lymph node dissection is recommended for residual masses greater than 1 cm after chemotherapy of nonseminomatous germ cell tumors. Currently there is no reliable predictor of post-chemotherapy retroperitoneal lymph node dissection histology. Up to 50% of patients harbor necrosis/fibrosis only so that a potentially morbid surgery has limited therapeutic value. In this study we evaluated the ability of defined serum miRNAs to predict residual viable nonseminomatous germ cell tumors after chemotherapy. MATERIALS AND METHODS: Levels of serum miRNA, including miR-371a-3p, miR-373-3p and miR-367-3p, were measured using the ampTSmiR (amplification targeted serum miRNA) test in 82 patients, including 39 in cohort 1 and 43 in cohort 2, who were treated with orchiectomy, chemotherapy and post-chemotherapy retroperitoneal lymph node dissection. miRNA levels were compared to clinical characteristics and serum tumor markers, and correlated with the presence of viable germ cell tumor vs fibrosis/necrosis and teratoma. ROC analysis was done to determine miRNA discriminative capacity. RESULTS: miRNA levels were significantly associated with disease extent at chemotherapy and they decreased significantly after chemotherapy. Conventional serum tumor marker levels were uninformative after chemotherapy. However, after chemotherapy miRNA levels remained elevated in patients harboring viable germ cell tumor in post-chemotherapy retroperitoneal lymph node dissection specimens. miR-371a-3p demonstrated the highest discriminative capacity for viable germ cell tumors (AUC 0.874, 95% CI 0.774 0.974, p <0.0001). Using an adapted hypothetical cutoff of 3 cm or less for surgical intervention miR-371a-3p correctly stratified all patients with viable residual retroperitoneal germ cell tumors with 100% sensitivity (p = 0.02). CONCLUSIONS: Our study demonstrates for the first time the potential value of miR 371a-3p to predict viable germ cell tumors in residual masses after chemotherapy. Prospective studies are required to confirm clinical usefulness. PMID- 29474848 TI - Urology Consultation and Emergency Department Revisits for Children with Urinary Stone Disease. AB - PURPOSE: We determined the association between urology consultation and emergency department revisits for children with urinary stones. MATERIALS AND METHODS: This retrospective cohort study included patients 18 years old or younger who presented to an emergency department in South Carolina with a urinary stone from 1997 to 2015. The primary exposure was urology consultation during the index emergency department visit. The primary outcome was a stone related emergency department revisit occurring within 180 days of discharge from an index emergency department visit. Secondary outcomes included computerized tomography use, inpatient admission and emergent surgery. RESULTS: Of 5,642 index emergency department visits for acute urinary stones 11% resulted in at least 1 stone related emergency department revisit within 180 days. Of revisits 59% occurred within 30 days of discharge and 39% were due to pain. The odds of emergency department revisit were highest within the first 48 hours of discharge home (OR 22.6, 95% CI 18.0 to 28.5) and rapidly decreased thereafter. Urology consultation was associated with a 37% lower adjusted odds of emergency department revisit (OR 0.63, 95% CI 0.44 to 0.90) and 68% lower odds of computerized tomography use across all emergency department visits (OR 0.32, 95% CI 0.15 to 0.69). Among patients who revisited the emergency department the frequency of pain complaints was 27% in those with a urological consultation at the index visit and 39% in those without. CONCLUSIONS: Urology consultation was associated with decreased emergency department revisits and computerized tomography use in pediatric patients with urinary stones. Future studies should identify patients who benefit most from urology consultation and ascertain processes of care that decrease emergency department revisits among high risk patients. PMID- 29474849 TI - Looking younger, dying later: General practitioners' intuitive clinical impression predicts mortality. PMID- 29474850 TI - Lack of interest in physical activity - individual and environmental attributes in adults across Europe: The SPOTLIGHT project. AB - A considerable proportion of European adults report little or no interest in physical activity. Identifying individual-level and environmental-level characteristics of these individuals can help designing effective interventions and policies to promote physical activity. This cross-sectional study additionally explored associations between level of interest and physical activity, after controlling for other individual and environmental variables. Measures of objective and perceived features of the physical environment of residence, self-reported physical activity and other lifestyle behaviors, barriers towards physical activity, general health, and demographics were obtained from 5205 European adults participating in the 2014 online SPOTLIGHT survey. t-Tests, chi-square tests, and generalized estimating equations with negative binomial log-link function were conducted. Adults not interested in physical activity reported a higher BMI and a lower self-rated health, were less educated, and to a smaller extent female and less frequently employed. They were more prone to have less healthy eating habits, and to perceive more barriers towards physical activity. Only minor differences were observed in environmental attributes: the non-interested were slightly more likely to live in neighborhoods objectively characterized as less aesthetic and containing more destinations, and perceived as less functional, safe, and aesthetic. Even after controlling for other individual and environmental factors, interest in physical activity remained a significant correlate of physical activity, supporting the importance of this association. This study is among the first to describe characteristics of individuals with reduced interest in physical activity, suggesting that (lack of) interest is a robust correlate of physical activity in several personal and environmental conditions. PMID- 29474851 TI - Active learning improves on-task behaviors in 4th grade children. AB - While increased opportunities for physical activity (PA) are a critical, public health need for children, school-based interventions often place teachers in the position to choose between PA and time spent on academic lessons. Active learning is designed to overcome this by combining PA with academic material. Moreover, teachers are likely to be more responsive to change in academic-related outcomes than in PA. This study utilizes a large, cluster randomized control trial in which student attention, or time on task (TOT) and accelerometer-based PA is assessed in conjunction with active learning. Participants were 2716 children (46% male, 46% white) from 28 elementary schools in Central Texas that were assigned to either: 1) active learning (math n = 10; spelling n = 9); or 2) traditional, sedentary academic lessons (n = 9). PA was measured with accelerometers. TOT was measured through a momentary time sampling protocol. A series of three-level (student, classroom, school) regression models estimated the effect of the intervention. The intervention lead to significantly increased TOT. Moreover, the dose of PA (steps) during the intervention was positively associated with the increase in TOT. In contrast, a greater dose of PA was associated with reduced TOT for students in control schools. Race, gender, and SES did not moderate these effects. Planned PA - as a part of an active, academic lesson - positively impacted TOT. In contrast, a traditional, sedentary lesson was associated with lower TOT. This differential impact offers intriguing possibilities to better understand the relationship between PA and academic performance. PMID- 29474852 TI - Forming groups of aggressive sows based on a predictive test of aggression does not affect overall sow aggression or welfare. AB - This experiment examined the effects of group composition on sow aggressive behaviour and welfare. Over 6 time replicates, 360 sows (parity 1-6) were mixed into groups (10 sows per pen, 1.8 m2/sow) composed of animals that were predicted to be aggressive (n = 18 pens) or groups composed of animals that were randomly selected (n = 18 pens). Predicted aggressive sows were selected based on a model pig test that has been shown to be related to the aggressive behaviour of parity 2 sows when subsequently mixed in groups. Measurements were taken on aggression delivered post-mixing, and aggression delivered around feeding, fresh skin injuries and plasma cortisol concentrations at days 2 and 24 post-mixing. Live weight gain, litter size (born alive, total born, stillborn piglets), and farrowing rate were also recorded. Manipulating the group composition based on predicted sow aggressiveness had no effect (P > 0.05) on sow aggression delivered at mixing or around feeding, fresh injuries, cortisol, weight gain from day 2 to day 24, farrowing rate, or litter size. The lack of treatment effects in the present experiment could be attributed to (1) a failure of the model-pig test to predict aggression in older sows in groups, or (2) the dependence of the expression of the aggressive phenotype on factors such as social experience and characteristics (e.g., physical size and aggressive phenotype) of pen mates. This research draws attention to the intrinsic difficulties associated with predicting behaviour across contexts, particularly when the behaviour is highly dependent on interactions with conspecifics, and highlights the social complexities involved in the presentation of a behavioural phenotype. PMID- 29474853 TI - Non-invasive imaging modalities to study neurodegenerative diseases of aging brain. AB - The aim of this article is to highlight current approaches for imaging elderly brain, indispensable for cognitive neuroscience research with emphasis on the basic physical principles of various non-invasive neuroimaging techniques. The first part of this article presents a quick overview of the primary non-invasive neuroimaging modalities used by cognitive neuroscientists such as transcranial magnetic stimulation (TMS), transcranial electrical stimulation (tES), electroencephalography (EEG), magnetoencephalography (MEG), single photon emission computed tomography (SPECT), positron emission tomography (PET), magnetic resonance spectroscopic imaging (MRSI), Profusion imaging, functional magnetic resonance imaging (fMRI), near infrared spectroscopy (NIRS) and diffusion tensor imaging (DTI) along with tractography and connectomics. The second part provides a comprehensive overview of different multimodality imaging techniques for various cognitive neuroscience studies of aging brain. PMID- 29474855 TI - Multidimensionality of plant defenses and herbivore niches: Implications for eco evolutionary dynamics. AB - Plant defenses are very diverse and often involve contrasted costs and benefits. Quantitative defenses, whose protective effect is dependent on the dose, are effective against a wide range of herbivores, but often divert energy from growth and reproduction. Qualitative defenses often have little allocation costs. However, while deterrent to some herbivores, they often incur costs through other interactions within the community (e.g., decrease in pollination or attraction of other enemies). In the present work, we model the evolutionary dynamics of these two types of defenses, as well and the evolutionary dynamics of the herbivore niche. We assess the effects of such evolutionary dynamics for the maintenance of diversity within the plant-herbivore system, and for the functioning of such systems under various levels of resource availability. We show that the two types of defenses have different implications. Evolution of quantitative defenses often helps to maintain or even increase diversity, while evolution of qualitative defenses most often has a detrimental effect on species coexistence. From a functional point of view, increased resource availability selects for higher levels of quantitative defenses, which reduces top-down controls exerted by herbivores. Resource availability does not affect qualitative defenses, nor the evolution of the herbivore niche. The growing evidence that plant defenses are diverse in types, benefits and costs has large implications not only for the evolution of these traits, but also for their impacts on community diversity and ecosystem functioning. PMID- 29474854 TI - Evidence for a neural signature of musical preference during silence. AB - One of the most basic and person-specific affective responses to music is liking. The present investigation sought to determine whether liking was preserved during spontaneous auditory imagery. To this purpose, we inserted two-second silent intervals into liked and disliked songs, a method known to automatically recreate a mental image of these songs. Neural correlates of musical preference were measured by high-density electroencephalography in twenty subjects who had to listen to a set of five pre-selected unknown songs the same number of times for two weeks. Time frequency analysis of the two most liked and the two most disliked songs confirmed the presence of neural responses related to liking. At the beginning of silent intervals (400-900 ms and 1000-1300 ms), significant differences in theta activity were originating from the inferior frontal and superior temporal gyrus. These two brain structures are known to work together to process various aspects of music and are also activated when measuring liking while listening to music. At the end of silent intervals (1400-1900 ms), significant alpha activity differences originating from the insula were observed, whose exact role remains to be explored. Although exposure was controlled for liked and disliked songs, liked songs were rated as more familiar, underlying the strong relationship that exists between liking, exposure, and familiarity. PMID- 29474856 TI - Interactions between immunotoxicants and parasite stress: Implications for host health. AB - Many organisms face a wide variety of biotic and abiotic stressors which reduce individual survival, interacting to further reduce fitness. Here we studied the effects of two such interacting stressors: immunotoxicant exposure and parasite infection. We model the dynamics of a within-host infection and the associated immune response of an individual. We consider both the indirect sub-lethal effects on immunosuppression and the direct effects on health and mortality of individuals exposed to toxicants. We demonstrate that sub-lethal exposure to toxicants can promote infection through the suppression of the immune system. This happens through the depletion of the immune response which causes rapid proliferation in parasite load. We predict that the within-host parasite density is maximised by an intermediate toxicant exposure, rather than continuing to increase with toxicant exposure. In addition, high toxicant exposure can alter cellular regulation and cause the breakdown of normal healthy tissue, from which we infer higher mortality risk of the host. We classify this breakdown into three phases of increasing toxicant stress, and demonstrate the range of conditions under which toxicant exposure causes failure at the within-host level. These phases are determined by the relationship between the immunity status, overall cellular health and the level of toxicant exposure. We discuss the implications of our model in the context of individual bee health. Our model provides an assessment of how pesticide stress and infection interact to cause the breakdown of the within-host dynamics of individual bees. PMID- 29474857 TI - The importance of ion fluxes for cancer proliferation and metastasis: A thermodynamic analysis. AB - Following a thermodynamic approach, we develop a new theoretical analysis of ion transfer across cell membranes. Supported also by experimental data from the literature, we highlight that ion channels determine the typical features of cancer cells, i.e. independence from growth-regulatory signals, avoidance of apoptosis, indefinite proliferative potential, and the capability of inducing angiogenesis. Specifically, we analyse how ion transport, with particular regards to Ca2+ fluxes, modulates cancer cell proliferation, and regulates cell cycle checkpoints. Finally, our analysis also suggests that in malignant tumours aerobic glycolysis is the more efficient metabolic process when taking the required solvent capacity into account. PMID- 29474858 TI - Molecular targets and anti-cancer potential of escin. AB - Escin is a mixture of triterpenoid saponins extracted from the horse chestnut tree, Aesculus hippocastanum. Its potent anti-inflammatory and anti-odematous properties makes it a choice of therapy against chronic venous insufficiency and odema. More recently, escin is being actively investigated for its potential activity against diverse cancers. It exhibits anti-cancer effects in many cancer cell models including lung adenocarcinoma, hepatocellular carcinoma and leukemia. Escin also attenuates tumor growth and metastases in various in vivo models. Importantly, escin augments the effects of existing chemotherapeutic drugs, thereby supporting the role of escin as an adjunct or alternative anti-cancer therapy. The beneficial effects of escin can be attributed to its inhibition of proliferation and induction of cell cycle arrest. By regulating transcription factors/growth factors mediated oncogenic pathways, escin also potentially mitigates chronic inflammatory processes that are linked to cancer survival and resistance. This review provides a comprehensive overview of the current knowledge of escin and its potential as an anti-cancer therapy through its anti proliferative, pro-apoptotic, and anti-inflammatory effects. PMID- 29474859 TI - Phytochemicals as potent modulators of autophagy for cancer therapy. AB - The dysregulation of autophagy is involved in the pathogenesis of a broad range of diseases, and accordingly universal research efforts have focused on exploring novel compounds with autophagy-modulating properties. While a number of synthetic autophagy modulators have been identified as promising cancer therapy candidates, autophagy-modulating phytochemicals have also attracted attention as potential treatments with minimal side effects. In this review, we firstly highlight the importance of autophagy and its relevance in the pathogenesis and treatment of cancer. Subsequently, we present the data on common phytochemicals and their mechanism of action as autophagy modulators. Finally, we discuss the challenges associated with harnessing the autophagic potential of phytochemicals for cancer therapy. PMID- 29474860 TI - Pharmacological targeting of the mammalian clock reveals a novel analgesic for osteoarthritis-induced pain. AB - Environmental disruption of the circadian rhythm is linked with increased pain due to osteoarthritis (OA). We aimed to characterize the role of the clock gene in OA-induced pain more systemically using both genetic and pharmacological approaches. Genetically modified mice, (bmal1f/fNav1.8CreERT mice), generated by deleting the critical clock gene, bmal1, from Nav1.8 sensory neurons, were resistant to the development of mechanical hyperalgesia associated with OA induced by partial medial meniscectomy (PMM) of the knee. In wild-type mice, induction of OA by PMM surgery led to a substantial increase in BMAL1 expression in DRG neurons. Interestingly, pharmacological activation of the REV-ERB (a negative regulator of bmal1 transcription) with SR9009 resulted in reduction of BMAL1 expression, and a significant decrease in mechanical hyperalgesia associated with OA. Cartilage degeneration was also significantly reduced in mice treated with the REV-ERB agonist SR9009. Based on these data, we also assessed the effect of pharmacological activation of REV-ERB using a model of environmental circadian disruption with its associated mechanical hyperalgesia, and noted that SR9009 was an effective analgesic in this model as well. Our data clearly demonstrate that genetic disruption of the molecular clock, via deletion of bmal1 in the sensory neurons of the DRG, decreases pain in a model of OA. Furthermore, pharmacological activation of REV-ERB leading to suppression of BMAL1 expression may be an effective method for treating OA-related pain, as well as to reduce joint damage associated with this disease. PMID- 29474862 TI - Patterns and effects of GC3 heterogeneity and parsimony informative sites on the phylogenetic tree of genes. AB - The explosive growth in genomic data has provided novel insights into the conflicting signals hidden in phylogenetic trees. Although some studies have explored the effects of the GC content and parsimony informative sites (PIS) on the phylogenetic tree, the effect of the heterogeneity of the GC content at the first/second/third codon position on parsimony informative sites (GC1/2/3PIS) among different species and the effect of PIS on phylogenetic tree construction remain largely unexplored. Here, we used two different mammal genomic datasets to explore the patterns of GC1/2/3PIS heterogeneity and the effect of PIS on the phylogenetic tree of genes: (i) all GC1/2/3PIS have obvious heterogeneity between different mammals, and the levels of heterogeneity are GC3PIS > GC2PIS > GC1PIS; (ii) the number of PIS is positively correlated with the metrics of "good" gene tree topologies, and excluding the third codon position (C3) decreases the quality of gene trees by removing too many PIS. These results provide novel insights into the heterogeneity pattern of GC1/2/3PIS in mammals and the relationship between GC3/PIS and gene trees. Additionally, it is necessary to carefully consider whether to exclude C3 to improve the quality of gene trees, especially in the super-tree method. PMID- 29474861 TI - Overexpression of serum MicroRNA-140-3p in premenopausal women with newly diagnosed breast cancer. AB - AIMS: The purpose of the present study was to evaluate microRNA-140-3p expression level in breast cancer patients in comparison to healthy controls. PATIENTS & METHODS: Serum microRNA-140-3p level was quantified by realtime quantitative reverse transcription PCR in 40 women with breast cancer and 40 healthy subjects. RESULTS: Serum microRNA-140-3p level in patients compared to healthy subjects was significantly up-regulated (P = 0.01). MicroRNA-140-3p had a good diagnostic accuracy for discrimination of the two groups (AUC = 0.667; sensitivity = 70%; specificity = 50%). Serum microRNA-140-3p level was overexpressed in premenopausal patients who were <=48 years old. ROC curve showed a similar pattern again (AUC = 0.690; sensitivity = 73%; specificity = 50%). CONCLUSIONS: microRNA-140-3p has the potential for detection of breast cancer, especially in premenopausal and in <=48 years old women. PMID- 29474863 TI - Attenuated strength gains during prolonged resistance exercise training in older adults with high inflammatory status. AB - OBJECTIVES: Chronic systemic low grade inflammation is associated with the age related loss of muscle mass. Resistance exercise has been suggested to reduce or lower chronic systemic low grade inflammation. However, systemic chronic low grade inflammation may adversely affect the adaptive response to exercise training. We investigated the effect of resistance exercise training on systemic chronic low-grade inflammation in older adults. In addition, we studied the association between systemic chronic low-grade inflammation and the adaptive response to exercise training. DESIGN/SETTING/PARTICIPANTS: Frail and pre-frail older adults (61 subjects) performed 24 weeks of progressive resistance exercise training. Frailty was assessed using the Fried frailty criteria. MEASUREMENTS: Lean body mass (DXA), strength (1RM), circulating levels of IL-1beta, IL-6, IL-8 and TNF-alpha were measured prior to exercise training, after 12 weeks of training, and after 24 weeks of training. RESULTS: Prolonged progressive resistance exercise training did not affect circulating levels of IL-6, IL-8 and TNF-alpha. However, exercise training led to a small but significant increase of 0.052 pg/mL in IL-1beta. Higher circulating levels of TNF-alpha, IL-8 and IL-6 during the training period were negatively associated with strength gains for the leg press. A doubling of plasma TNF-alpha, IL-8 or IL-6 resulted in reduced strength gains for leg press with coefficients of -3.52, -3.42 and -1.54 respectively. High levels of circulating TNF-alpha were also associated with decreased strength gains for the leg extension (coefficient -1.50). Inflammatory cytokines did not appear to have an effect on gains in lean mass. CONCLUSION: Our findings suggest that increased levels of plasma cytokines (TNF-alpha, IL-6 and IL-8) are associated with lower strength gains during resistance exercise training. PMID- 29474864 TI - A crucial role of ROCK for alleviation of senescence-associated phenotype. AB - In our previous study, we uncovered a novel mechanism in which amelioration of Hutchinson-Gilford progeria syndrome (HGPS) phenotype is mediated by mitochondrial functional recovery upon rho-associated protein kinase (ROCK) inhibition. However, it remains elusive whether this mechanism is also applied to the amelioration of normal aging cells. In this study, we used Y-27632 and fasudil as effective ROCK inhibitors, and examined their role in senescence. We found that ROCK inhibition induced the functional recovery of the mitochondria as well as the metabolic reprogramming, which are two salient features that are altered in normal aging cells. Moreover, microarray analysis revealed that the up regulated pathway upon ROCK inhibition is enriched for chromatin remodeling genes, which may play an important role in the alleviation of senescence associated cell cycle arrest. Indeed, ROCK inhibition induced cellular proliferation, concomitant with the amelioration of senescent phenotype. Furthermore, the restorative effect by ROCK inhibition was observed in vivo as evidenced by the facilitated cutaneous wound healing. Taken together, our data indicate that ROCK inhibition might be utilized to ameliorate normal aging process and to treat age-related disease. PMID- 29474866 TI - Targeted proteomic analysis of cognitive dysfunction in remitted major depressive disorder: Opportunities of multi-omics approaches towards predictive, preventive, and personalized psychiatry. AB - : In order to accelerate the understanding of pathophysiological mechanisms and clinical biomarker discovery and in psychiatry, approaches that integrate multiple -omics platforms are needed. We introduce a workflow that investigates a narrowly defined psychiatric phenotype, makes use of the potent and cost effective discovery technology of gene expression microarrays, applies Weighted Gene Co-Expression Network Analysis (WGCNA) to better capture complex and polygenic traits, and finally explores gene expression findings on the proteomic level using targeted mass-spectrometry (MS) technologies. To illustrate the effectiveness of the workflow, we present a proteomic analysis of peripheral blood plasma from patient's remitted major depressive disorder (MDD) who experience ongoing cognitive deficits. We show that co-expression patterns previous detected on the transcript level could be replicated for plasma proteins, as could the module eigengene correlation with cognitive performance. Further, we demonstrate that functional analysis of multi-omics data has the potential to point to cellular mechanisms and candidate biomarkers for cognitive dysfunction in MDD, implicating cell cycle regulation by cyclin D3 (CCND3), regulation of protein processing in the endoplasmatic reticulum by Thioredoxin domain-containing protein 5 (TXND5), and modulation of inflammatory cytokines by Tripartite Motif Containing 26 (TRI26). SIGNIFICANCE: This paper discusses how data from multiple -omics platforms can be integrated to accelerate biomarker discovery in psychiatry. Using the phenotype of cognitive impairment in remitted major depressive disorder (MDD) as an example, we show that the application of a systems biology approach - weighted gene co-expression network analysis (WGCNA) - in the discovery phase, and targeted proteomic follow-up of results, provides a structured avenue towards uncovering novel candidate markers and pathways for personalized clinical psychiatry. PMID- 29474865 TI - Trajectories of plasma IGF-1, IGFBP-3, and their ratio in the Mayo Clinic Study of Aging. AB - Insulin-like growth factor 1 (IGF-1) has been associated with osteoporosis, cardiovascular disease, cancer, neurodegenerative diseases, and mortality in middle and older aged adults. Cross-sectionally, IGF-1 decreases with age and levels of IGF-1 are markedly different between individuals. However, little is known about intra-individual trajectories of IGF-1. We examined baseline and serial measures of plasma total IGF-1, IGF binding protein (IGFBP)-3, and their ratio, which is a proxy for bioavailable IGF-1, among 1618 adults, aged 50-95, enrolled in the Mayo Clinic Study of Aging. At baseline, IGF-1 and IGFBP-3 were strongly correlated (r = 0.62, p < 0.001). Total IGF-1 and IGFBP-3 decreased across age, while the ratio of IGF-1/IGFBP-3 increased across age. This pattern was consistent across ages at baseline and intra-individually over an average 2.3 years follow-up (range = 10 months-5.6 years). In age-adjusted linear regression models, baseline levels of total IGF-1, IGFBP-3, and IGF-1/IGFBP-3 varied by participant characteristics (sex, BMI, gait speed), medical comorbidities (Charlson comorbidity index score, hypertension, diabetes, and cardiovascular disease), and hormone replacement therapy use in women. High interclass correlation coefficients (ICCs) suggest little intra-individual variability in levels of total IGF-1 (ICC = 0.84), IGFBP-3 (ICC = 0.88), and IGF-1/IGFBP-3 (ICC = 0.81) over time. In mixed effects models that specified age as a time scale, men showed greater decreases in total IGF-1 and IGFBP-3 with age, while more comorbidities and decreasing gait speed were associated with increasing IGFBP-3. In sex-stratified models, trajectories of total IGF-1, IGFBP-3, and IGF-1/IGFBP 3, as a function of participant demographics, health characteristics, and medical conditions, differed between men and women. These results suggest that change in levels of plasma total IGF-1, IGFBP-3, and IGF-1/IGFBP-3 are associated with demographics, health characteristics, and medical conditions, and that the trajectories of change differ by sex. Future research should consider how IGF-1 and IGFBP-3 might be useful in research or clinic, paying particular attention to how sex may impact levels as a function of demographics, health characteristics, and medical conditions. PMID- 29474867 TI - "Innovative processes for bio-pharmaceuticals and poorly water-soluble API". PMID- 29474868 TI - Active site CP-loop dynamics modulate substrate binding, catalysis, oligomerization, stability, over-oxidation and recycling of 2-Cys Peroxiredoxins. AB - Peroxiredoxins (Prxs) catalyse the rapid reduction of hydrogen peroxide, organic hydroperoxide and peroxynitrite, using a fully conserved peroxidatic cysteine (CP) located in a conserved sequence Pxxx(T/S)xxCP motif known as CP-loop. In addition, Prxs are involved in cellular signaling pathways and regulate several redox-dependent process related disease. The effective catalysis of Prxs is associated with alterations in the CP-loop between reduced, Fully Folded (FF), and oxidized, Locally Unfolded (LU) conformations, which are linked to dramatic changes in the oligomeric structure. Despite many studies, little is known about the precise structural and dynamic roles of the CP-loop on Prxs functions. Herein, the comprehensive biochemical and biophysical studies on Escherichia coli alkyl hydroperoxide reductase subunit C (EcAhpC) and the CP-loop mutants, EcAhpC F45A and EcAhpC-F45P reveal that the reduced form of the CP-loop adopts conformational dynamics, which is essential for effective peroxide reduction. Furthermore, the point mutants alter the structure and dynamics of the reduced form of the CP-loop and, thereby, affect substrate binding, catalysis, oligomerization, stability and overoxidiation. In the oxidized form, due to restricted CP-loop dynamics, the EcAhpC-F45P mutant favours a decamer formation, which enhances the effective recycling by physiological reductases compared to wild-type EcAhpC. In addition, the study reveals that residue F45 increases the specificity of Prxs-reductase interactions. Based on these studies, we propose an evolution of the CP-loop with confined sequence conservation within Prxs subfamilies that might optimize the functional adaptation of Prxs into various physiological roles. PMID- 29474869 TI - In the Era of BCR-ABL1 Inhibitors, Are We Closing the Survival Gap Between Allogeneic Hematopoietic Cell Transplantation and Chemotherapy for Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in First Complete Remission? PMID- 29474871 TI - Effects of antidyskinetic nicotine treatment on dopamine release in dorsal and ventral striatum. AB - The treatment of Parkinson's disease is often complicated by levodopa-induced dyskinesia (LID), and antidyskinetic treatment options are currently sparse. Nicotinic acetylcholine receptors have been suggested as potential targets for treatment of LID, as nicotinic agonists have been reported to alleviate LID in animal models. We aimed at the first independent replication of an antidyskinetic effect by nicotine using a mouse model of LID, and at investigation of its mechanisms by studying the release of [3H]dopamine from synaptosomes prepared from the dorsal and ventral striatum. Chronic nicotine treatment in drinking water inhibited the development of LID in mice lesioned unilaterally with 6 hydroxydopamine and treated chronically with levodopa and benserazide. The antidyskinetic nicotine treatment had no effect on [3H]dopamine release mediated by alpha4beta2* nicotinic receptors, but decreased alpha6beta2*-mediated [3H]dopamine release in the lesioned dorsal striatum and the ventral striatum. In addition, nicotine treatment restored [3H]dopamine release in the lesioned ventral striatum to intact levels. The results support a role for nicotinic receptors as drug targets for treatment of LID, and suggest that striatal presynaptic alpha6beta2* receptors are important mediators of nicotine's antidyskinetic effect. PMID- 29474870 TI - Improving Revised International Prognostic Scoring System Pre-Allogeneic Stem Cell Transplantation Does Not Translate Into Better Post-Transplantation Outcomes for Patients with Myelodysplastic Syndromes: A Single-Center Experience. AB - The natural history of patients with myelodysplastic syndromes (MDS) is variable. The Revised International Prognostic Score (IPSS-R) is commonly used in practice to predict outcomes in patients with MDS at both diagnosis and before hematopoietic stem cell transplantation (HSCT). However, the effect of change in the IPSS-R before allogeneic HSCT with chemotherapy or hypomethylating agents on post-transplantation outcomes is currently unknown. We assessed whether improvement in IPSS-R prognostic score pre-HSCT would result in improvement in clinical outcomes post-HSCT. Secondary goals included studying the effect of prognostic factors on post-transplantation survival. All patients with MDS who underwent allogeneic HSCT at the Leukemia/BMT Program of British Columbia between February 1997 and April 2013 were included. Pertinent information was reviewed from the program database. IPSS-R was calculated based on data from the time of MDS diagnosis and before HSCT. Outcomes of patients who had improved IPSS-R pre HSCT were compared with those with stable or worse IPSS-R. Overall survival (OS) and event-free survival (EFS) were estimated using the Kaplan-Meier method, with P values determined using the log-rank test. Hazard ratios were calculated using multivariable Cox proportional hazards regression models to study the effects of the prognostic variables on OS and EFS. A total of 138 consecutive patients were included. IPSS-R improved in 62 of these patients (45%), worsened in 23 (17%), remained stable in 41 (30%), and was unknown in 12 (9%). OS was not statistically different across the improved, worsened, and stable groups (30% versus 22% versus 40%, respectively; P = .63). The cumulative incidences of relapse and nonrelapse mortality at 5 years were 28.4% (95% confidence interval [CI], 21.1 to 36.1) and 31.6% (95% CI, 23.8 to 39.7), respectively. The rate of relapse was 23% in patients with <5% blasts at the time of HSCT, 69% in those with 5% to 20% blasts, and 66% in those with >20% blasts (P = .0004). In the entire cohort OS was 34% and EFS was 33%. There was no significant difference in outcomes between patients who received myeloablative conditioning and those who received nonmyeloablative conditioning before HSCT (OS, 34% and 39%, respectively; P = .63 and EFS, 34% and 32%, respectively; P = .86). OS was not statistically different among patients with improved, worsened, or stable IPSS-R. On multivariate analysis, only 3 factors were associated with OS: cytogenetic risk group at diagnosis, blast count at transplantation, and the presence or absence of chronic graft-versus-host disease. Improving IPSS-R before HSCT does not translate into better survival outcomes. Blast count pretransplantation was highly predictive of post transplantation outcomes. PMID- 29474872 TI - Non-myelinated C-fibers, but not myelinated A-fibers, elongate into the epidermis in dry skin with itch. AB - Chronic skin diseases with itch and dry skin show increased peripheral nerve fiber elongation into the epidermis. However, the characteristics of the elongated nerve fibers remain unclear. Therefore, we investigated the characteristics of the elongated nerve fibers using a dry skin mouse model with itch. In this mouse model, prepared via repetitive treatments with an acetone/ether mixture and water, the stratum corneum water content was decreased, whereas spontaneous scratching and epidermal hyperplasia were increased. In addition, the number of substance P (SP)- and calcitonin gene-related peptide (CGRP)-immunoreactive nerve fibers (C-fibers) was increased in the epidermis of treated mice compared to that in non-treated control mice. However, neurofilament 200-immunoreactive nerve fibers (A-fibers) were not detected in the epidermis of treated mice. These results suggest that the elongated epidermal peripheral nerve fibers comprise SP/CGRP-containing C-fibers but not A-fibers. Thus, these fibers may be involved in the induction of dry skin pruritus. PMID- 29474873 TI - Expression of nucleotide excision repair in Alzheimer's disease is higher in brain tissue than in blood. AB - Age-related changes are increased in patients with Alzheimer's disease (AD), including oxidative stress and DNA damage. We propose that genotoxic stress and DNA repair responses influence neurodegeneration in the pathogenesis of AD. Here, we focus on nucleotide excision repair (NER). Real-time qPCR and mass spectrometry were employed to determine the expression levels of selected NER components. The mRNA levels of the genes encoding the NER proteins RAD23B, RPA1, ERCC1, PCNA and LIG3 as well as the NER-interacting base excision repair protein MPG in blood and brain tissue from four brain regions in patients with AD or mild cognitive impairment and healthy controls (HC), were assessed. NER mRNA levels were significantly higher in brain tissue than in blood. Further, LIG3 mRNA levels in the frontal cortex was higher in AD versus HC, while mRNA levels of MPG and LIG3 in entorhinal cortex and RPA1 in the cerebellum were lower in AD versus HC. In blood, RPA1 and ERCC1 mRNA levels were lower in AD patients than in HC. Alterations in gene expression of NER components between brain regions were associated with AD, connecting DNA repair to AD pathogenesis and suggesting a distinct role for NER in the brain. PMID- 29474874 TI - Audiovisual plasticity following early abnormal visual experience: Reduced McGurk effect in people with one eye. AB - Previously, we have shown that people who have had one eye surgically removed early in life during visual development have enhanced sound localization [1] and lack visual dominance, commonly observed in binocular and monocular (eye-patched) viewing controls [2]. Despite these changes, people with one eye integrate auditory and visual components of multisensory events optimally [3]. The current study investigates how people with one eye perceive the McGurk effect, an audiovisual illusion where a new syllable is perceived when visual lip movements do not match the corresponding sound [4]. We compared individuals with one eye to binocular and monocular viewing controls and found that they have a significantly smaller McGurk effect compared to binocular controls. Additionally, monocular controls tended to perceive the McGurk effect less often than binocular controls suggesting a small transient modulation of the McGurk effect. These results suggest altered weighting of the auditory and visual modalities with both short and long-term monocular viewing. These results indicate the presence of permanent adaptive perceptual accommodations in people who have lost one eye early in life that may serve to mitigate the loss of binocularity during early brain development. PMID- 29474875 TI - Rig-I is involved in inflammation through the IPS-1/TRAF6 pathway in astrocytes under chemical hypoxia. AB - The retinoic acid-inducible gene I (RIG-I) is a crucial cytoplasmic pathogen recognition receptor involved in neuroinflammation in degenerative diseases. In the present study, in vitro human astrocytes were subjected to a chemical hypoxia model using cobalt chloride pretreatment. Chemical hypoxia induces the up regulation of RIG-I in astrocytes and results in the expression of inflammatory cytokines IL-1beta, IL-6, and TNF-alpha in an NF-kappaB dependent manner. Elevated RIG-I modulates the interaction of interferon-beta promoter stimulator-1 (IPS-1) and TNF receptor-associated factor 6 (TRAF6) following chemical hypoxia. Inhibition of IPS-1 or TRAF6 suppresses RIG-I-induced NF-kappaB activation and inflammatory cytokines in response to chemical hypoxia. These data suggest that chemical hypoxia leads to RIG-I activation and the expression of inflammatory cytokines through the NF-kappaB pathway. Blocking IPS-1/TRAF6 pathway relieves RIG-I-induced neuroinflammation in astrocytes subjected to hypoxia. PMID- 29474876 TI - Visual mismatch negativity (vMMN) is elicited with para-foveal hemifield oddball stimulation: An event-related brain potential (ERP) study. AB - The visual mismatch negativity (vMMN) is a component of the human event-related brain potential (ERP) that indicates the automatic processing and detection of changes in the visual sensory input. The study tested whether the vMMN was observable when the visual input is restricted to one visual hemifield and, with this, only para-foveal input to one of the two primary sensory cortices in the visual system is available for stimulus processing. The vMMN was elicited by the stimulation restricted to a small portion of the visual field. This demonstrates that in general vMMN elicitation is not confined to stimulations covering a broad range of the visual field or to the propagation of sensory information to both sensory visual cortices. In addition, the vMMN amplitudes showed a high variability between the different conditions, including non-significant vMMN amplitudes. This suggests that pronounced vMMNs observed in experimental settings relies on salient visual stimuli covering different channels of sensory information in vision. PMID- 29474877 TI - The GRP78/BiP inhibitor HA15 synergizes with mitotane action against adrenocortical carcinoma cells through convergent activation of ER stress pathways. AB - Many types of cancer cells present constitutively activated ER stress pathways because of their significant burden of misfolded proteins coded by mutated and rearranged genes. Further increase of ER stress by pharmacological intervention may shift the balance towards cell death and can be exploited therapeutically. Recent studies have shown that an important component in the mechanism of action of mitotane, the only approved drug for the medical treatment of adrenocortical carcinoma (ACC), is represented by activation of ER stress through inhibition of the SOAT1 enzyme and accumulation of toxic lipids. Here we show that HA15, a novel inhibitor of the essential ER chaperone GRP78/BiP, inhibits ACC H295R cell proliferation and steroidogenesis and is able to synergize with mitotane action. These results suggest that convergent activation of ER stress pathways by drugs acting via different mechanisms represents a valuable therapeutic option for ACC. PMID- 29474878 TI - Long-term effects of brief hypoxia due to cardiac arrest: Hippocampal reductions and memory deficits. AB - OBJECTIVE: To examine the effects of brief hypoxia (<7 min) due to cardiac arrest on the integrity of the brain and performance on memory and executive functions tasks. METHODS: Patients after out-of-hospital cardiac arrest (CA) (n = 9), who were deemed neurologically intact on discharge, were compared to matched patients with myocardial infarction (MI) (n = 9). A battery of clinical and experimental memory and executive functions neuropsychological tests were administered and MRI scans for all patients were collected. Measures of subcortical and cortical volumes and cortical thickness were obtained using FreeSurfer. Manual segmentations of the hippocampus were also performed. APACHE-II scores were calculated based on metrics collected at admission to ICCU for all patients. RESULTS: Significant differences between the two groups were observed on several verbal memory tests. Both hippocampi were significantly reduced (p < 0.05) in the CA patients, relative to MI patients. Hippocampal subfields segmentation showed significantly reduced presubiculum volumes bilaterally. CA patients had on average 10% reduction in volumes bilaterally across hippocampal subfields. No cortical thickness differences survived correction. Significant correlations were observed in the CA group only between the hippocampal volumes and performance on verbal memory tasks, including recollection. Hippocampal volumes and several memory measures (but not other cognitive domains) were strongly correlated with APACHE-II scores on admission in the CA group, but not in the MI group CONCLUSIONS: Chronic patients with cardiac arrest who were discharged from hospital in "good neurological condition" showed an average of 10% reduction in hippocampal volume bilaterally and significant verbal memory deficits relative to matched controls with myocardial infarction, suggesting even brief hypoxic periods suffice to lead to specific hippocampal damage. PMID- 29474879 TI - Quantitative analysis of relative volume of low apparent diffusion coefficient value can predict neurologic outcome after cardiac arrest. AB - INTRODUCTION: Predicting neurologic outcomes after cardiac arrest (CA) is challenging. This study tested the hypothesis that a quantitative analysis of diffusion weighted imaging (DWI) using the FMRIB Software Library (FSL) can predict neurologic outcomes after CA and can clarify the optimal apparent diffusion coefficient (ADC) thresholds for predicting poor neurologic outcomes. METHODS: Out-of-hospital CA patients treated with targeted temperature management (TTM) who underwent DWI were included in this study. Voxel-based analysis was performed to calculate the mean ADC value. ADC thresholds (750, 700, 650, 600, 550, 500, 450 and 400) and brain volumes below each threshold were also analyzed for their correlation with outcomes. The patients were divided into early (within 48 h after return of spontaneous circulation (ROSC)) and late group (between 48 h and 7 days after ROSC) according to the DWI scan time. The primary outcome was a poor neurologic outcome at 6 months after CA, defined as a cerebral performance category (CPC) of 3-5. RESULTS: One hundred ten DWIs were analyzed. The mean ADC values were 789.0 (761.5-826.5) * 10-6 mm2/s for the good neurologic outcome group and 715.2 (663.1-778.4) * 10-6 mm2/s for the poor neurologic outcome group (p < 0.001). All the ADC thresholds could differentiate patients with good versus poor outcomes. The ADC threshold of 400 * 10-6 mm2/s had the highest odds ratio (4.648 in the early group and 11.283 in the late group) after adjusting for initial rhythm and anoxic time. To achieve 100% specificity using an ADC threshold of 400 * 10-6 mm2/s, the sensitivity was 64% (cutoff value; >2.5% ADC threshold of 400 * 10-6 mm2/s) in the early group and 79.2% (cutoff value; >1.66% ADC threshold of 400 * 10-6 mm2/s) in the late group. CONCLUSIONS: Voxel-based analysis using FSL software can predict neurologic outcomes after CA. The ADC threshold of 400 * 10-6 mm2/s had the highest OR for predicting a poor neurologic outcome. PMID- 29474880 TI - Automated video surveillance and machine learning: Leveraging existing infrastructure for cardiac arrest detection and emergency response activation. PMID- 29474881 TI - Ruptured extracranial carotid artery: Endovascular treatment with covered stent graft. AB - BACKGROUND AND PURPOSE: Rupture of the extracranial carotid artery is a rare, but potentially disastrous event. We aimed to review the clinical presentations and radiologic findings of this entity and to evaluate the efficacy of endovascular treatment with covered stent graft. MATERIALS AND METHODS: Since January 2009, eight patients with extracranial carotid artery rupture received endovascular treatment with covered stent graft. We retrospectively reviewed their medical records and radiologic findings. RESULTS: The ruptured sites were in the common carotid artery (n=5), cervical ICA (n=2) and petrous ICA (n=1), respectively. The causes of injury included spontaneous (n=2), carotid blowout syndrome (CBS) (n=2), iatrogenic (n=2) and traumatic (n=2). Technical success and immediate hemostasis were achieved in all cases. Procedure-related complications occurred in 3 patients (37.5%). In a patient, the ipsilateral angular branch of the MCA was occluded during the procedure and it was completely reopened via mechanical thrombectomy without any neurologic deficit. Minor cerebral infarction was developed in 2 patients (25%). During a mean follow-up of 334 days (range 3-2053 days), two patients died: one from recurrent CBS and the other from aspiration pneumonia. CONCLUSIONS: The covered stent grafting is an effective method for the treatment of extracranial carotid artery rupture. PMID- 29474882 TI - The angiographic and clinical outcomes of intracranial aneurysms following irradiation in patients with nasopharyngeal carcinoma: A 13-year experience and literature review. AB - BACKGROUND AND PURPOSE: Intracranial aneurysms are a known but rare complication of radiotherapy (RT). We reviewed the angiographic and clinical outcomes of intracranial aneurysms following RT in patients with nasopharyngeal carcinoma (NPC), a malignancy endemic in Hong Kong. MATERIALS AND METHODS: The clinical, angiographic and laboratory data was collected for nine NPC patients harboring fifteen intracranial aneurysms following RT, diagnosed between 1st January 2000 and 31st December 2012. RESULTS: The median age at aneurysm diagnosis was 56 years with a male predilection (67%). The median latent period to diagnosis was nine years (0.3-30). Eight patients (89%) presented with aneurysmal subarachnoid hemorrhage. Nine aneurysms were located at the anterior circulation, and 14 were saccular in morphology. Of the treated aneurysms, eight underwent endovascular intervention and two were surgically clipped. Within a year, 50% of the treated aneurysms had recurred. Poor neurological outcome was noted. At two-year follow up, the median score for modified Rankin score and Glasgow Outcome score was 5 and 2 respectively. The two-year mortality rate of patients with treated ruptured intracranial aneurysms was 50%. CONCLUSION: Compared to previous studies, our irradiated NPC patients had higher mortality and morbidity rates after aneurysm rupture and a higher angiographic recurrence rate following treatment. Greater vigilance is required in the detection of post-treatment recurrence of these aneurysms due to the higher risk of rupture. The authors recommend dedicated screening of intracranial aneurysms by active surveillance in routine CT protocols or the addition of three-dimensional time-of-flight magnetic resonance angiography in MR protocols. PMID- 29474883 TI - Newly observed anterior thalamocortical fiber of the thalamus using 7.0T super resolution magnetic resonance tractography and its implications for the classical Papez circuit. AB - Here, we have employed recently developed super-resolution tractography using 7.0T-MRI to analyze the fine structures involved in thalamocortical connections, something that has proved difficult using conventional techniques. We detail a newly observed thalamocortical pathway connecting the anterior nucleus of the thalamus and the cingulate cortex not via the internal capsule but via the septal area. The observed pathway is believed to be a classical pathway of the Papez circuit but had not been previously identified. PMID- 29474884 TI - Cardiopulmonary exercise testing in hepato-biliary & pancreas cancer surgery - A systematic review: Are we any further than walking up a flight of stairs? AB - INTRODUCTION: Cardiopulmonary exercise testing (CPET) is a reliable, reproducible and non-invasive measure of functional capacity. CPET has been increasingly used to assess pre-operative risk and stratify patients at risk of mortality and morbidity following surgery. CPET parameters that predict outcomes within liver and pancreas cancer surgery still remain to be defined. METHODS: A systematic review to assess CPET use in predicting post-operative outcomes in liver and pancreas cancer surgery was carried out using the following databases AMED, CINAHL, Cochrane Library, EMBASE, Google Scholar and PubMED. RESULTS: Data were extracted from four liver and four pancreas cancer studies. All were single institution, cohort series reporting outcomes with CPET used pre-operatively to assess patient morbidity, length of hospital stay and or mortality. In liver cancer surgery, all four papers reported outcome data on morbidity and patients who were more likely to suffer with complications tended to have an anaerobic threshold (AT) of less than 9.9-11.5 mL min-1.Kg-1. Whilst in pancreas cancer surgery, rates of pancreas fistulae tended to be higher in those patients who had an AT of less than 10 or 10.1 mL min-1.Kg-1. DISCUSSION: The CPET variable most reported and relevant to morbidity in both liver and pancreas cancer surgery appeared to be AT. A pre-operative AT of approximately 10.5 mL min-1.Kg-1 seems to be associated with a worse post-operative convalescence. PMID- 29474885 TI - Purse-string closure versus conventional primary closure of wound following stoma reversal: Meta-analysis of randomized controlled trials. AB - PURPOSE: Surgical site infection (SSI) is one of the most frequent complications after stoma closure and the optimal skin closure technique is still not clear. The goal of this review was to compare outcomes with purse-string closure technique (PSC) versus conventional closure technique (CCT) for skin closure after stoma reversal. METHODS: We performed a systematic review and meta-analysis of available randomized controlled trials (RCTs) to compare SSI rate within 30 days, operative time, hospital stay, incisional hernia and intestinal obstruction rates between PSC and CCT. RESULTS: The pooled analysis of 5 studies showed a statically significant lower rate of SSI in favor of PSC compared to CCT (OR 0.24; 95% CI -0.32, - 0.15; p < 0.00001). No statistically significant differences were observed in the operative time (OR -0.05; 95% CI -3.95, 3.84; p = 0.98) and in the length of hospital stay (OR -0.20; 95% CI -0.76, 0.36; p = 0.48), between the two techniques. Additionally, two out of the five studies provided data on incisional hernia and intestinal obstruction and the pooled analysis revealed no statistically significant differences between PSC and CCT techniques: incisional hernia (OR 0.81, 95% CI 0.27-2.47; p = 0.71) and intestinal obstruction (OR 1.07, 95% CI 0.41-2.84; p = 0.88). CONCLUSIONS: The analysis of 5 RCTs showed that SSI rate is statistically significant lower when PSC is performed, compared to CCT. Whereas, no significant differences were found between the two techniques with regards to operative time, length of hospital stay, incisional hernia and intestinal obstruction rates. PMID- 29474886 TI - Patient reported outcomes in prospective cohort study of Electrochemotherapy. AB - Metastatic spread of malignant tumours to skin is a well described phenomenon with incidence of approximately 0.7-9% of all metastases depending on histological type of primary cancer. Electrochemotherapy (ECT) is an efficient local tumour ablation modality that has proven clinical efficacy in the treatment of various types of tumours metastasis to skin. Aims of this study are to evaluate the activity, toxicity, and feasibility of treating patients with electrochemotherapy (ECT); their clinical outcomes and patient report outcome measures. This was a cohort study of 48 patients. In this study a good or excellent response to treatment was observed in 74% of patients on the basis of the clinical photographs. Five patients had partial responses (14%) and three patients had no response (8.5%). One patient died during the study period (2.8%). 87% of patients said they would have ECT again if clinically indicated. Spearman's' rank correlation of clinical efficacy for anatomical location was found to be positive with poorer outcomes in head and neck compared to trunk and limbs. Complications were found in 16patients, of which all were either grade 1 or 2 Clavien classification. The complications were predominantly in patients treated with ECT for tumours the head and neck area. Initial assessment of applicable patient report outcome measures for our patient cohort demonstrate that there are no validated tools exist for ECT. Further work is required here. PMID- 29474887 TI - Genome Writing: Current Progress and Related Applications. AB - The ultimate goal of synthetic biology is to build customized cells or organisms to meet specific industrial or medical needs. The most important part of the customized cell is a synthetic genome. Advanced genomic writing technologies are required to build such an artificial genome. Recently, the partially-completed synthetic yeast genome project represents a milestone in this field. In this mini review, we briefly introduce the techniques for de novo genome synthesis and genome editing. Furthermore, we summarize recent research progresses and highlight several applications in the synthetic genome field. Finally, we discuss current challenges and future prospects. PMID- 29474888 TI - Preprocessing of 2-Dimensional Gel Electrophoresis Images Applied to Proteomic Analysis: A Review. AB - Various methods and specialized software programs are available for processing two-dimensional gel electrophoresis (2-DGE) images. However, due to the anomalies present in these images, a reliable, automated, and highly reproducible system for 2-DGE image analysis has still not been achieved. The most common anomalies found in 2-DGE images include vertical and horizontal streaking, fuzzy spots, and background noise, which greatly complicate computational analysis. In this paper, we review the preprocessing techniques applied to 2-DGE images for noise reduction, intensity normalization, and background correction. We also present a quantitative comparison of non-linear filtering techniques applied to synthetic gel images, through analyzing the performance of the filters under specific conditions. Synthetic proteins were modeled into a two-dimensional Gaussian distribution with adjustable parameters for changing the size, intensity, and degradation. Three types of noise were added to the images: Gaussian, Rayleigh, and exponential, with signal-to-noise ratios (SNRs) ranging 8-20 decibels (dB). We compared the performance of wavelet, contourlet, total variation (TV), and wavelet-total variation (WTTV) techniques using parameters SNR and spot efficiency. In terms of spot efficiency, contourlet and TV were more sensitive to noise than wavelet and WTTV. Wavelet worked the best for images with SNR ranging 10-20 dB, whereas WTTV performed better with high noise levels. Wavelet also presented the best performance with any level of Gaussian noise and low levels (20-14 dB) of Rayleigh and exponential noise in terms of SNR. Finally, the performance of the non-linear filtering techniques was evaluated using a real 2 DGE image with previously identified proteins marked. Wavelet achieved the best detection rate for the real image. PMID- 29474890 TI - Structural model of the SARS coronavirus E channel in LMPG micelles. AB - Coronaviruses (CoV) cause common colds in humans, but are also responsible for the recent Severe Acute, and Middle East, respiratory syndromes (SARS and MERS, respectively). A promising approach for prevention are live attenuated vaccines (LAVs), some of which target the envelope (E) protein, which is a small membrane protein that forms ion channels. Unfortunately, detailed structural information is still limited for SARS-CoV E, and non-existent for other CoV E proteins. Herein, we report a structural model of a SARS-CoV E construct in LMPG micelles with, for the first time, unequivocal intermolecular NOEs. The model corresponding to the detergent-embedded region is consistent with previously obtained orientational restraints obtained in lipid bilayers and in vivo escape mutants. The C-terminal domain is mostly alpha-helical, and extramembrane intermolecular NOEs suggest interactions that may affect the TM channel conformation. PMID- 29474891 TI - Regulation of Kv7.2/Kv7.3 channels by cholesterol: Relevance of an optimum plasma membrane cholesterol content. AB - Kv7.2/Kv7.3 channels are the molecular correlate of the M-current, which stabilizes the membrane potential and controls neuronal excitability. Previous studies have shown the relevance of plasma membrane lipids on both M-currents and Kv7.2/Kv7.3 channels. Here, we report the sensitive modulation of Kv7.2/Kv7.3 channels by membrane cholesterol level. Kv7.2/Kv7.3 channels transiently expressed in HEK-293 cells were significantly inhibited by decreasing the cholesterol level in the plasma membrane by three different pharmacological strategies: methyl-beta-cyclodextrin (MbetaCD), Filipin III, and cholesterol oxidase treatment. Surprisingly, Kv7.2/Kv7.3 channels were also inhibited by membrane cholesterol loading with the MbetaCD/cholesterol complex. Depletion or enrichment of plasma membrane cholesterol differentially affected the biophysical parameters of the macroscopic Kv7.2/Kv7.3 currents. These results indicate a complex mechanism of Kv7.2/Kv7.3 channels modulation by membrane cholesterol. We propose that inhibition of Kv7.2/Kv7.3 channels by membrane cholesterol depletion involves a loss of a direct cholesterol-channel interaction. However, the inhibition of Kv7.2/Kv7.3 channels by membrane cholesterol enrichment could include an additional direct cholesterol-channel interaction, or changes in the physical properties of the plasma membrane. In summary, our results indicate that an optimum cholesterol level in the plasma membrane is required for the proper functioning of Kv7.2/Kv7.3 channels. PMID- 29474892 TI - EEG frequency tagging reveals higher order intermodulation components as neural markers of learned holistic shape representations. AB - Shape perception is intrinsically holistic: combinations of features give rise to configurations with emergent properties that are different from the sum of the parts. The current study investigated neural markers of holistic shape representations learned by means of categorization training. We used the EEG frequency tagging technique, where two parts of a shape stimulus were 'tagged' by modifying their contrast at different temporal frequencies. Signals from both parts are integrated and, as a result, emergent frequency components (so-called, intermodulation responses, IMs), caused by nonlinear interaction of two frequency signals, are observed in the EEG spectrum. First, participants were trained in 4 sessions to discriminate highly similar, unfamiliar shapes into two categories, defined based on the combination of features. After training, EEG was recorded while frequency-tagged shapes from either the trained or the untrained shape family were presented. For all IMs combined, no learning effects were detected, but post hoc analyses of higher-order IMs revealed stronger occipital and occipito-temporal IMs for both trained and untrained exemplars of the trained shape family as compared to the untrained shape family. In line with recent findings, we suggest that the higher-order IMs may reflect high-level visual computations, like holistic shape categorization, resulting from a cascade of non linear operations. Higher order frequency responses are relatively low in power, hence results should be interpreted cautiously and future research is needed to confirm these effects. In general, these findings are, to our knowledge, the first to show IMs as a neural correlate of perceptual learning. PMID- 29474893 TI - Better airway resistance reduction profile in intubated COPD patients by personalized bronchodilator dosing: A pilot randomized control trial. AB - INTRODUCTION: The optimal dose of inhaled metered-dose bronchodilators for intubated patients with chronic obstructive pulmonary disease (COPD) is unknown. In this study, we proposed a bronchodilator dosing schedule based on an individual's airway resistance (Raw) and tested its efficacy in reducing Raw. METHODS: A total of 51 newly admitted patients with invasively ventilated COPD were randomly assigned to receive personalized or fixed bronchodilator dosing. Personal target Raw was defined by measuring each individual's Raw after maximal pharmacologic bronchodilatation. Thereafter, Raw was measured every 8 h until the 28th day. Patients in the fixed-dosing group received only predetermined doses. Additional doses of bronchodilators were given to patients in the personalized dosing group when the measured Raw exceeded their target Raw. RESULTS: The median daily doses of salmeterol/fluticasone were 9.2 (personalized-dosing) vs 7.6 (fixed-dosing) puffs (P < 0.001). The relative deviation of Raw from the personal target was expressed as (measured Raw - target Raw)/target Raw. The experimental group showed a smaller relative Raw deviation than the control group (0.09 +/- 0.10 vs 0.44 +/- 0.11, P = 0.02). There were no differences between the two groups in terms of ventilator-free days from day 1 to day 28, number of episodes of nosocomial pneumonia, total number of puffs of rescue bronchodilator, number of drug-related adverse effects or mortality rate at day 180. CONCLUSION: Personalized dosing of inhaled bronchodilator administered to invasively ventilated COPD patients can produce a better reduction in Raw. Further studies with larger sample size are required to verify the conclusion of this pilot study. PMID- 29474889 TI - Human Gut Microbiota and Gastrointestinal Cancer. AB - Human gut microbiota play an essential role in both healthy and diseased states of humans. In the past decade, the interactions between microorganisms and tumors have attracted much attention in the efforts to understand various features of the complex microbial communities, as well as the possible mechanisms through which the microbiota are involved in cancer prevention, carcinogenesis, and anti cancer therapy. A large number of studies have indicated that microbial dysbiosis contributes to cancer susceptibility via multiple pathways. Further studies have suggested that the microbiota and their associated metabolites are not only closely related to carcinogenesis by inducing inflammation and immune dysregulation, which lead to genetic instability, but also interfere with the pharmacodynamics of anticancer agents. In this article, we mainly reviewed the influence of gut microbiota on cancers in the gastrointestinal (GI) tract (including esophageal, gastric, colorectal, liver, and pancreatic cancers) and the regulation of microbiota by diet, prebiotics, probiotics, synbiotics, antibiotics, or the Traditional Chinese Medicine. We also proposed some new strategies in the prevention and treatment of GI cancers that could be explored in the future. We hope that this review could provide a comprehensive overview of the studies on the interactions between the gut microbiota and GI cancers, which are likely to yield translational opportunities to reduce cancer morbidity and mortality by improving prevention, diagnosis, and treatment. PMID- 29474895 TI - Just do the right thing. PMID- 29474894 TI - The two processes underlying the testing effect- Evidence from Event-Related Potentials (ERPs). AB - Theoretical explanations of the testing effect (why people learn better from a test than a re-study) have largely focused on either the benefit of attempting to retrieve the answer or on the benefit of re-encoding the queried information after a successful retrieval. While a less parsimonious account, prior neuroimaging evidence has led us to postulate that both of these processes contribute to the benefit of testing over re-study. To provide further empirical support for our position, we recorded ERPs while subjects attempted to recall the second word of a pair when cued with the first. These ERPs were analyzed based on the current response accuracy and as a function of accuracy on the subsequent test, yielding three groups: the first and second tests were correct, the first was correct and the second was not, both were incorrect. Mean amplitude waveforms during the first test showed different patterns depending on the outcome patterns: Between 400 and 700 ms the amplitudes were most positive when both tests were correct and least positive when both were incorrect; mean amplitudes between 700 and 1000 ms only differed as a function of subsequent memory. They were more positive when the second test was correct. Importantly, the later component only predicted subsequent memory when the answers were not overlearned, i.e. only correctly recalled once previously. We interpret the 400-700 ms time window as a component reflecting a retrieval attempt process, which differs as a function of both current and subsequent accuracy, and the later time window as a component reflecting a re-encoding process, which only involves learning from tests, both of which are involved in the testing effect. PMID- 29474896 TI - Flexible and precise dosing of enalapril maleate for all paediatric age groups utilizing orodispersible minitablets. AB - Enalapril is an off-patent angiotensin-converting enzyme inhibitor for which no paediatric age-appropriate formulation is commercially available in Europe, and enalapril maleate (EM) orodispersible minitablets (ODMTs) have previously been formulated within the LENA (labelling enalapril from neonates to adolescents) project. In this study, a dilution method has been developed by dispersing the lowest dose strength ODMTs to enable flexible and precise EM dosing during the dose titration phase of the therapy. Furthermore, the physicochemical stability of the ODMTs has been investigated in child-friendly beverages and the administration of ODMTs via nasogastric tubes (NGT) of different sizes and materials has been evaluated. The results for the ODMT dilution procedure reveal that dispersion within an oral syringe is preferred over dispersion in a separate container, leading to flexible and precise dosing down to 0.025 mg EM. Although ODMTs were stable in the beverages over the investigated time period, dispersion in tap water only is recommended due to prolonged disintegration times within the other beverages. Dispersed ODMTs can be administered through NGTs of CH5. Almost no adsoprtion of EM on silicone, polyurethane or polyvinyl chloride could be observed. The ODMT concept together with the investigated dispersion method enables the safe administration of EM for all paediatric subpopulations from new borns to adolescents. PMID- 29474897 TI - Aqueous injection of quercetin: An approach for confirmation of its direct in vivo cardiovascular effects. AB - Potential positive effects of flavonol quercetin on humans were suggested by many studies. However, it is not clear if these effects are mediated by quercetin or its metabolites. The in vivo confirmation of quercetin effects is largely hindered by its low water solubility and thus impossibility to test directly its impact. Therefore, a solid dispersion of quercetin with polyvinylpyrrolidone (PVP) was developed to prepare an injectable formulation of water-soluble quercetin. The optimized formulation provided a 20,000-fold increase in quercetin solubility. This formulation was tested on conventional and spontaneously hypertensive rats; it lowered their blood pressure in both short- and long-term basis. Pharmacokinetic data are also provided. This study reports for the first time an injectable water-soluble formulation of quercetin suitable for confirmation of its vascular effect in vivo. PMID- 29474898 TI - DoE based Olanzapine loaded poly-caprolactone nanoparticles decreases extrapyramidal effects in rodent model. AB - The purpose of present investigation was to nano-encapsulate atypical antipsychotic such as Olanzapine in polymeric nanoparticles in order to explore the possibility of minimizing drug associated extrapyramidal adverse effects. The polymeric nanoparticulate systems were prepared using FDA approved polymer, polycaprolactone, by simple technique of nanoprecipitation using factorial design by DoE approach. The significant factors selected for the optimization during formulation development process were polymer content and surfactant concentration at three different levels (32 factorial design). The effect of selected significant factors were studied in depth on significant responses such as particle size and encapsulation efficiency. The optimized formulation was further surface modified with surfactant (polysorbate 80) so as to enhance the brain targeting efficiency of developed nanoparticles via endocytosis pathway. Furthermore, catalepsy was induced in rodent model and the designed formulations were investigated in comparison with pure drug solution for efficiency in decreasing extrapyramidal adverse effects. The results of in vitro characterization studies demonstrated a narrow size distributed nanoparticles (73.28 +/- 2.14 nm) with high stability indicating zetapotential (-32.46 +/- 1.15 mV) and high encapsulation efficiency (78.77 +/- 2.83%). In vitro release studies resulted in an extended release of atypical antipsychotic for 60 h from drug loaded optimized nanoparticulate formulations. The catalepsy studies in rodent model demonstrated a significant decrease in extra pyramidal adverse effects as compared to the pure atypical antipsychotic. Thus, the designed antipsychotic loaded polymeric nanoparticulate system may be highly promising for the tremendous improvement of antipsychotic therapy with reduced adverse effects. PMID- 29474899 TI - High altitude organic gold: The production network for Ophiocordyceps sinensis from far-western Nepal. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ophiocordyceps sinensis (Berk.) G.H.Sung, J.M.Sung, Hywel-Jones & Spatafora, a high altitude Himalayan fungus-caterpillar product found in alpine meadows in China, Bhutan, Nepal, and India, has been used in the Traditional Chinese Medicine system for over 2000 years. Heightened demand in China over the past 15 years, coupled with limited production, has led to a price hike and increased economic importance of harvests to rural households throughout the species' range. There is, however, limited knowledge on the actors and profit distribution in the O. sinensis production network, especially from the distribution areas on the southern flanks of the Himalayas. Filling in this knowledge gap is essential to the identification and design of public interventions. AIM OF THE STUDY: To describe and quantify the O. sinensis production network originating from Darchula District in far-western Nepal. MATERIALS AND METHODS: Data was collected, for fiscal year 2014-15, in spring and summer 2016 using standardized collector (n=56) and trader (n=45) questionnaires in Darchula District, and central wholesaler (n=9) questionnaires in cities of Nepal. All questionnaires contained quantitative and qualitative components focusing on key elements of the production network, i.e. value creation, enhancement, and capture; and network and territorial embeddedness. RESULTS: Trade is sustained and significant even at the margins of the distributional range, with 384.1 kg of O. sinensis harvested in and traded from Darchula District in 2014-15, having a collector value of approximately USD 4.7 million and constituting the dominant household-level source of income for collectors. The functioning production network is characterised by conflicts in relation to value creation, a high share of value capture by collectors, limited value enhancement, and a high degree of network and territorial embeddedness. CONCLUSIONS: O. sinensis income is of major economic importance for rural households at the margin of its distribution range in Nepal. Production networks operated by informal actors establishing trust-based relationships allow responses to cross-border market signals, enabling the flow of rural and remote environmental resources to urban centres of demand. There is scope for public interventions, e.g. to determine the drivers of demand. PMID- 29474900 TI - Hepatoprotective effect of Forsythiae Fructus water extract against carbon tetrachloride-induced liver fibrosis in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The fruit of Forsythia suspensa (Thunb.) Vahl, named Forsythiae Fructus (Lian-Qiao), is a well-known traditional Chinese medicine (TCM) used for clearing away heat and toxic material, eliminating the mass and relieving swelling. AIM OF THE STUDY: This study aims to observe the attenuation of the water extract of Forsythiae Fructus (FSE) on carbon tetrachloride (CCl4)-induced hepatic fibrosis in male C57BL/6 mice. MATERIALS AND METHODS: Hepatic fibrosis was induced in male C57BL/6 mice by intraperitoneal injection with 2 ml/kg CCl4 (mixed 1: 3 in olive oil) twice a week for 4 weeks. At the same time, the mice were orally given with FSE (1, 2 g/kg) every day for 4 weeks. Serum biochemical parameters, gene and protein expression related to liver fibrosis were analyzed. The contents of forsythiaside A and forsythin in FSE were measured by high-performance liquid chromatography (HPLC). RESULTS: Results of serum alanine/aspartate aminotransferase (ALT/AST) activity and liver histological evaluation both showed the protection of FSE against CCl4-induced liver injury. Further, the anti-fibrotic effects of FSE was evidenced by the results of Masson's trichrome and Sirius red staining, liver hydroxyproline content, and serum amounts of hyaluronic acid, laminin, collagen IV and type III procollagen (PCIII). FSE also reduced the expression of alpha-smooth muscle actin (alpha-SMA) in livers from CCl4-injured mice. Additionally, FSE decreased the increased hepatic expression of fibroblast-specific protein 1 (FSP1) and vimentin induced by CCl4 in mice. CONCLUSIONS: FSE attenuates CCl4-induced liver fibrosis in mice by inhibiting hepatic stellate cells (HSCs) activation, reducing hepatic extracellular matrix (ECM) disposition and reversing epithelial-mesenchymal transition (EMT). PMID- 29474901 TI - Arachidonic acid metabonomics study for understanding therapeutic mechanism of Huo Luo Xiao Ling Dan on rat model of rheumatoid arthritis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Huo Luo Xiao Ling Dan (HLXLD), a traditional Chinese medicine (TCM), is commonly used for the treatment of rheumatoid arthritis (RA). AIM OF THE STUDY: To explore the potential therapeutic mechanism of HLXLD on anti-inflammatory activity. MATERIALS AND METHODS: A metabolomic approach based on UFLC-MS/MS to profile arachidonic acid (AA) metabolic changes was used. The cyclooxygenase (COX) and lipoxygenase (LOX) catalyzed metabolites in plasma were quantified on 7, 14, 21, and 28 days after the rats injected with Complete Freund's adjuvant and orally administrated with HLXLD, methotrexate and dexamethasone in parallel as the positive control drugs. RESULTS: Nineteen metabolites involved in COX and LOX pathways in RA model group were significant increased compared with normal group (P < 0.05), including 12 hydroxyeicosatetraenoic acid (12-HETE), 15-HETE, 8-HETE, leukotriene B4(LTB4), prostaglandin E2 (PGE2), PGI2, PGD2, PGF2alpha, thromboxane B2 (TXB2), etc. From day 7 to day 28, the trajectory direction of HLXLD group and positive control groups gradually moved towards the initial space, and the concentrations of AA and its metabolites after HLXLD treatment were significantly reduced in dual pathways compared to control groups. CONCLUSION: HLXLD induced a substantial change in the AA metabolic profiles through refrain the expression of COX and LOX. The present investigation also highlights that distinct ingredients of this formula tend to inhibit different target to achieve a therapeutic effect. PMID- 29474902 TI - Chloroform fraction of Foeniculum vulgare induced ROS mediated, mitochondria caspase-dependent apoptotic pathway in MCF-7, human breast cancer cell line. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Foeniculum vulgare Mill. (Fennel) is one of the most common herbs used in alternative medicines for its varied range of bioactivity. In Ecuador (South America), use of fennel in traditional cancer treatment is on record. AIM OF THE STUDY: The objective of the present study was to demonstrate the anti-proliferative and apoptotic effect of chloroform fraction of fennel (CFF) in MCF-7 cells. MATERIALS AND METHODS: Anti-proliferative assay (MTT assay) and colony formation assay were performed to study the growth inhibitory effect of CFF. Various morphological changes of apoptosis were observed using Giemsa, Hoechst and Acridine orange/ ethidium bromide stains in MCF-7 cells. The extent of apoptosis and cell cycle arrest was measured by flow cytometer. Levels of ROS and mitochondrial membrane potential was measured by DCFH-DA and JC-1 respectively. Caspases activity was measured by luminescence and DNA fragmentation by comet assay. RESULTS: CFF appeared as a good inhibitor of growth against MCF-7 and MDA-MB-237 in time- and concentration-dependent manners. All the morphological changes of apoptosis were evident in treatment groups. Annexin V/PI-assay of apoptosis gave around 49% of apoptotic cells upon treatment of 0.5 mg/ml of CFF and PI-stained cells showed the G1 phase cell cycle arrest. Elevated levels of ROS, disrupted mitochondrial membrane, increased levels of caspase-9 & caspase-3 and DNA fragmentation were noted in treated MCF-7 cells. CONCLUSION: Our findings revealed the proliferation inhibition, cell cycle arrest and apoptosis induction effect of CFF, which may help in exploring the novel anti cancer drug for therapeutic implications. PMID- 29474904 TI - Intermediate filament protein expression pattern and inflammatory response changes in kidneys of rats receiving doxorubicin chemotherapy and quercetin. AB - The aim of this study was to explore the potential effects of quercetin (QUR) on doxorubicin (DOX)-induced nephrotoxicity. Fifty male rats were assigned to five groups (10 rats each): a control group, a DOX-treated group (total dose, 15 mg/kg bw, intraperitoneally), a QUR-treated group (50 mg/kg bw/day, orally), a prophylaxis co-treated group, and a therapeutic co-treated group. Biochemical parameters and renal function were measured. Moreover, kidney tissues were homogenized for inflammatory marker evaluation and real-time qPCR analysis to determine the changes in intermediate filament protein mRNA levels (desmin, vimentin, connexin 43 and nestin). QUR exhibited a significant nephroprotective effect, particularly when it was administered prior to and simultaneously with DOX treatment (prophylaxis co-treated group). This role was biochemically demonstrated by the significant modulation of DOX-induced body weight loss, hypoproteinemia, and elevated serum creatinine and urea. Moreover, QUR attenuated the inflammatory response as shown by decreased renal nitric oxide, tumor necrosis factor-alpha production and myeloperoxidase activity elicited by DOX injection. These biochemical improvements were accompanied by a significant histopathological restoration of rat kidney tissue and successful down-regulation of the intermediate filament protein mRNA levels, indicating amelioration of DOX induced podocyte injury. Taken together, these results conclusively demonstrated that QUR administration has a prophylactic effect on DOX-induced injury in the rat kidney. PMID- 29474903 TI - Hexamoll(r) DINCH: Lack of in vivo evidence for obesogenic properties. AB - Hexamoll(r) DINCH is an important alternative to phthalate plasticizers. Although regulatory reviews have not identified any potential hazards even in sensitive populations, an in vitro study by Campioli et al. (2015) suggested Hexamoll(r) DINCH might alter fat storage in adipocytes resulting in obesity. To evaluate this hypothesis, data from studies with Hexamoll(r) DINCH were reviewed for evidence of deposition in fat, changes in body weight, or changes in serum chemistry reflecting altered metabolic status. Body weights of F1 and F2 pups in a two-generation study did not differ from controls even at 1000 mg Hexamoll(r) DINCH/kg body weight. Mean relative liver weights from the 1000 and 300 mg/kg bw groups were increased, but without histopathologic changes. Triglyceride and cholesterol levels in serum were not affected. In addition, subchronic and chronic studies in rats did not give evidence of an obesogenic effect. Radioactivity from 20 or 1000 mg/kg bw 14C-labelled Hexamoll(r) DINCH dosed orally remained 2-3 times longer in adipose tissue than in well-perfused tissues; however, levels were 20-500% below other tissues at 1 and 8 h post dosing. Radioactivity concentrations in organs and tissues excluding the GI tract declined rapidly and continuously, and decreased in parallel to the concentration in plasma during the following 20 h. Both, initial and terminal half-lives of radioactivity concentration do not indicate a potential for accumulation. Furthermore, a metabolomic comparison of Hexamoll(r) DINCH with DEHP and other phthalates shows complete separation of the metabolomic profile of these two chemical classes, meaning that their effects on the body and the body's reaction to the substance are different. Hence, comprehensive in vivo data do not show any evidence of Hexamoll(r) DINCH altering fat metabolism or having obesogenic properties. PMID- 29474905 TI - A Non-catalytic Function of SETD1A Regulates Cyclin K and the DNA Damage Response. AB - MLL/SET methyltransferases catalyze methylation of histone 3 lysine 4 and play critical roles in development and cancer. We assessed MLL/SET proteins and found that SETD1A is required for survival of acute myeloid leukemia (AML) cells. Mutagenesis studies and CRISPR-Cas9 domain screening show the enzymatic SET domain is not necessary for AML cell survival but that a newly identified region termed the "FLOS" (functional location on SETD1A) domain is indispensable. FLOS disruption suppresses DNA damage response genes and induces p53-dependent apoptosis. The FLOS domain acts as a cyclin-K-binding site that is required for chromosomal recruitment of cyclin K and for DNA-repair-associated gene expression in S phase. These data identify a connection between the chromatin regulator SETD1A and the DNA damage response that is independent of histone methylation and suggests that targeting SETD1A and cyclin K complexes may represent a therapeutic opportunity for AML and, potentially, for other cancers. PMID- 29474906 TI - A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases. AB - While the preponderance of morbidity and mortality in medulloblastoma patients are due to metastatic disease, most research focuses on the primary tumor due to a dearth of metastatic tissue samples and model systems. Medulloblastoma metastases are found almost exclusively on the leptomeningeal surface of the brain and spinal cord; dissemination is therefore thought to occur through shedding of primary tumor cells into the cerebrospinal fluid followed by distal re-implantation on the leptomeninges. We present evidence for medulloblastoma circulating tumor cells (CTCs) in therapy-naive patients and demonstrate in vivo, through flank xenografting and parabiosis, that medulloblastoma CTCs can spread through the blood to the leptomeningeal space to form leptomeningeal metastases. Medulloblastoma leptomeningeal metastases express high levels of the chemokine CCL2, and expression of CCL2 in medulloblastoma in vivo is sufficient to drive leptomeningeal dissemination. Hematogenous dissemination of medulloblastoma offers a new opportunity to diagnose and treat lethal disseminated medulloblastoma. PMID- 29474907 TI - Cell-Intrinsic Control of Interneuron Migration Drives Cortical Morphogenesis. AB - Interneurons navigate along multiple tangential paths to settle into appropriate cortical layers. They undergo a saltatory migration paced by intermittent nuclear jumps whose regulation relies on interplay between extracellular cues and genetic encoded information. It remains unclear how cycles of pause and movement are coordinated at the molecular level. Post-translational modification of proteins contributes to cell migration regulation. The present study uncovers that carboxypeptidase 1, which promotes post-translational protein deglutamylation, controls the pausing of migrating cortical interneurons. Moreover, we demonstrate that pausing during migration attenuates movement simultaneity at the population level, thereby controlling the flow of interneurons invading the cortex. Interfering with the regulation of pausing not only affects the size of the cortical interneuron cohort but also impairs the generation of age-matched projection neurons of the upper layers. PMID- 29474910 TI - Super-Resolution Imaging of the Extracellular Space in Living Brain Tissue. AB - The extracellular space (ECS) of the brain has an extremely complex spatial organization, which has defied conventional light microscopy. Consequently, despite a marked interest in the physiological roles of brain ECS, its structure and dynamics remain largely inaccessible for experimenters. We combined 3D-STED microscopy and fluorescent labeling of the extracellular fluid to develop super resolution shadow imaging (SUSHI) of brain ECS in living organotypic brain slices. SUSHI enables quantitative analysis of ECS structure and reveals dynamics on multiple scales in response to a variety of physiological stimuli. Because SUSHI produces sharp negative images of all cellular structures, it also enables unbiased imaging of unlabeled brain cells with respect to their anatomical context. Moreover, the extracellular labeling strategy greatly alleviates problems of photobleaching and phototoxicity associated with traditional imaging approaches. As a straightforward variant of STED microscopy, SUSHI provides unprecedented access to the structure and dynamics of live brain ECS and neuropil. PMID- 29474909 TI - Mapping the Mouse Cell Atlas by Microwell-Seq. AB - Single-cell RNA sequencing (scRNA-seq) technologies are poised to reshape the current cell-type classification system. However, a transcriptome-based single cell atlas has not been achieved for complex mammalian systems. Here, we developed Microwell-seq, a high-throughput and low-cost scRNA-seq platform using simple, inexpensive devices. Using Microwell-seq, we analyzed more than 400,000 single cells covering all of the major mouse organs and constructed a basic scheme for a mouse cell atlas (MCA). We reveal a single-cell hierarchy for many tissues that have not been well characterized previously. We built a web-based "single-cell MCA analysis" pipeline that accurately defines cell types based on single-cell digital expression. Our study demonstrates the wide applicability of the Microwell-seq technology and MCA resource. PMID- 29474908 TI - Modulation of Phase Shift between Wnt and Notch Signaling Oscillations Controls Mesoderm Segmentation. AB - How signaling dynamics encode information is a central question in biology. During vertebrate development, dynamic Notch signaling oscillations control segmentation of the presomitic mesoderm (PSM). In mouse embryos, this molecular clock comprises signaling oscillations of several pathways, i.e., Notch, Wnt, and FGF signaling. Here, we directly address the role of the relative timing between Wnt and Notch signaling oscillations during PSM patterning. To this end, we developed a new experimental strategy using microfluidics-based entrainment that enables specific control of the rhythm of segmentation clock oscillations. Using this approach, we find that Wnt and Notch signaling are coupled at the level of their oscillation dynamics. Furthermore, we provide functional evidence that the oscillation phase shift between Wnt and Notch signaling is critical for PSM segmentation. Our work hence reveals that dynamic signaling, i.e., the relative timing between oscillatory signals, encodes essential information during multicellular development. PMID- 29474911 TI - Identifying Medical Diagnoses and Treatable Diseases by Image-Based Deep Learning. AB - The implementation of clinical-decision support algorithms for medical imaging faces challenges with reliability and interpretability. Here, we establish a diagnostic tool based on a deep-learning framework for the screening of patients with common treatable blinding retinal diseases. Our framework utilizes transfer learning, which trains a neural network with a fraction of the data of conventional approaches. Applying this approach to a dataset of optical coherence tomography images, we demonstrate performance comparable to that of human experts in classifying age-related macular degeneration and diabetic macular edema. We also provide a more transparent and interpretable diagnosis by highlighting the regions recognized by the neural network. We further demonstrate the general applicability of our AI system for diagnosis of pediatric pneumonia using chest X ray images. This tool may ultimately aid in expediting the diagnosis and referral of these treatable conditions, thereby facilitating earlier treatment, resulting in improved clinical outcomes. VIDEO ABSTRACT. PMID- 29474913 TI - (p)ppGpp Controls Bacterial Persistence by Stochastic Induction of Toxin Antitoxin Activity. PMID- 29474912 TI - Direct Identification of Hundreds of Expression-Modulating Variants using a Multiplexed Reporter Assay. PMID- 29474914 TI - Antibiotic Resistance. AB - Bacterial mechanisms of drug resistance operate at sequential lines of defense tackling drug at entry, accumulation, target binding, or downstream toxicity. These mechanisms are encoded by genomic changes ranging in scale from point mutations, through assembly of preexisting genetic elements, to horizontal import of genes from the environment. A many-to-many relationship prevails between resistance mechanisms and the spectrum of genetic changes encoding them. PMID- 29474915 TI - Solving Mendelian Mysteries: The Non-coding Genome May Hold the Key. AB - Despite revolutionary advances in sequencing approaches, many mendelian disorders have remained unexplained. In this issue of Cell, Aneichyk et al. combine genomic and cell-type-specific transcriptomic data to causally link a non-coding mutation in the ubiquitous TAF1 gene to X-linked dystonia-parkinsonism. PMID- 29474916 TI - The Unexpected Effects of the Combination of Antibiotics and Immunity. AB - beta-lactam antibiotics and immune enzymes, including lysozyme, kill bacteria by rupturing the cell wall. Curiously, their combination can select for viable, wall less bacteria. Kawai and colleagues describe the molecular details regarding the emergence of these forms, illustrating a novel and potentially clinically relevant mechanism by which bacteria escape killing by antibiotics. PMID- 29474917 TI - Learning from Everyday Images Enables Expert-like Diagnosis of Retinal Diseases. AB - Kermany et al. report an application of a neural network trained on millions of everyday images to a database of thousands of retinal tomography images that they gathered and expert labeled, resulting in a rapid and accurate diagnosis of retinal diseases. PMID- 29474919 TI - Pervasive, Coordinated Protein-Level Changes Driven by Transcript Isoform Switching during Meiosis. AB - To better understand the gene regulatory mechanisms that program developmental processes, we carried out simultaneous genome-wide measurements of mRNA, translation, and protein through meiotic differentiation in budding yeast. Surprisingly, we observed that the levels of several hundred mRNAs are anti correlated with their corresponding protein products. We show that rather than arising from canonical forms of gene regulatory control, the regulation of at least 380 such cases, or over 8% of all measured genes, involves temporally regulated switching between production of a canonical, translatable transcript and a 5' extended isoform that is not efficiently translated into protein. By this pervasive mechanism for the modulation of protein levels through a natural developmental program, a single transcription factor can coordinately activate and repress protein synthesis for distinct sets of genes. The distinction is not based on whether or not an mRNA is induced but rather on the type of transcript produced. PMID- 29474918 TI - Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly. AB - X-linked Dystonia-Parkinsonism (XDP) is a Mendelian neurodegenerative disease that is endemic to the Philippines and is associated with a founder haplotype. We integrated multiple genome and transcriptome assembly technologies to narrow the causal mutation to the TAF1 locus, which included a SINE-VNTR-Alu (SVA) retrotransposition into intron 32 of the gene. Transcriptome analyses identified decreased expression of the canonical cTAF1 transcript among XDP probands, and de novo assembly across multiple pluripotent stem-cell-derived neuronal lineages discovered aberrant TAF1 transcription that involved alternative splicing and intron retention (IR) in proximity to the SVA that was anti-correlated with overall TAF1 expression. CRISPR/Cas9 excision of the SVA rescued this XDP specific transcriptional signature and normalized TAF1 expression in probands. These data suggest an SVA-mediated aberrant transcriptional mechanism associated with XDP and may provide a roadmap for layered technologies and integrated assembly-based analyses for other unsolved Mendelian disorders. PMID- 29474923 TI - A visible fluorescent nanovaccine based on functional genipin crosslinked ovalbumin protein nanoparticles. AB - Accurate and efficient antigen delivery is crucial for inducing a strong and long term immune response. A visible protein nanovaccine made from antigen could provide a novel and promising technology for secure and efficient delivery of the antigen with imaging visualization. In this study, a functional nanovaccine based on genipin crosslinked ovalbumin (OVA) fluorescent nanoparticles with chitosan (CS-OVA-NPs) was developed. The nanovaccine can carry abundant antigens by self crosslinking without additional carriers. The fluorescence imaging technique was applied to monitor and reveal the process of antigen delivery in vivo based on the fluorescence of genipin with a non-invasive and real-time manner. This functional OVA nanovaccine can enhance the uptake of OVA in Dendritic Cells (DCs) and further promote DCs to maturate in vitro. In vivo study further indicated CS OVA-NPs could trigger antigen-specific immune responses, which demonstrated that this fluorescent nanovaccine provided a novel design approach for accurate and efficient vaccine delivery. PMID- 29474924 TI - Neuroprotective effect of gold nanoparticles composites in Parkinson's disease model. AB - Parkinson's disease (PD) is second most common neurodegenerative disorder worldwide. Although drugs and surgery can relieve the symptoms of PD, these therapies are incapable of fundamentally treating the disease. For PD patients, over-expression of alpha-synuclein (SNCA) leads to the death of dopaminergic neurons. This process can be prevented by suppressing SNCA over-expression through RNA interference. Here, we successfully synthesized gold nanoparticles (GNP) composites (CTS@GNP-pDNA-NGF) via the combination of electrostatic adsorption and photochemical immobilization, which could load plasmid DNA (pDNA) and target specific cell types. GNP was transfected into cells via endocytosis to inhibiting the apoptosis of PC12 cells and dopaminergic neurons. Simultaneously, GNP composites are also used in PD models in vivo, and it can successfully cross the blood-brain barrier by contents of GNP in the mice brain. In general, all the works demonstrated that GNP composites have good therapeutic effects for PD models in vitro and in vivo. PMID- 29474920 TI - A Mild PUM1 Mutation Is Associated with Adult-Onset Ataxia, whereas Haploinsufficiency Causes Developmental Delay and Seizures. AB - Certain mutations can cause proteins to accumulate in neurons, leading to neurodegeneration. We recently showed, however, that upregulation of a wild-type protein, Ataxin1, caused by haploinsufficiency of its repressor, the RNA-binding protein Pumilio1 (PUM1), also causes neurodegeneration in mice. We therefore searched for human patients with PUM1 mutations. We identified eleven individuals with either PUM1 deletions or de novo missense variants who suffer a developmental syndrome (Pumilio1-associated developmental disability, ataxia, and seizure; PADDAS). We also identified a milder missense mutation in a family with adult-onset ataxia with incomplete penetrance (Pumilio1-related cerebellar ataxia, PRCA). Studies in patient-derived cells revealed that the missense mutations reduced PUM1 protein levels by ~25% in the adult-onset cases and by ~50% in the infantile-onset cases; levels of known PUM1 targets increased accordingly. Changes in protein levels thus track with phenotypic severity, and identifying posttranscriptional modulators of protein expression should identify new candidate disease genes. PMID- 29474925 TI - MicroRNA-221 may be involved in lipid metabolism in mammary epithelial cells. AB - Milk lipids, important for infant growth and development, are produced and secreted by mammary gland under the regulation of steroid hormones, growth factors, and microRNAs (miRNAs). miR-221 has been identified in milk and adipocytes and it plays important roles in regulating normal mammary epithelial hierarchy and breast cancer stem cells; however, its roles in lipid metabolism in mammary epithelial cells (MECs), the cells of lipid synthesis and secretion, are as yet unknown. Through overexpression or inhibition of miR-221 expression, we found that it regulated lipid metabolism in MECs and was expressed differentially at various stages during murine mammary gland development. Inhibition of miR-221 expression increased lipid content in MECs through elevation of the lipid synthesis enzyme FASN, while overexpression of miR-221 reduced MEC lipid content. Moreover, the steroid hormones estradiol and progesterone decreased miR-221 expression with a subsequent increase in lipid formation in MECs. The expression of miR-221 was lower during lactation, which suggests that it may be involved in milk production. Therefore, miR-221 might be a useful target for influencing milk lipid production. PMID- 29474926 TI - The fibrogenic actions of the coagulant and plasminogen activation systems in pulmonary fibrosis. AB - Fibrosis causes irreversible damage to lung structure and function in restrictive lung diseases such as idiopathic pulmonary fibrosis (IPF). Extravascular coagulation involving fibrin formation in the intra-alveolar compartment is postulated to have a pivotal role in the development of pulmonary fibrosis, serving as a provisional matrix for migrating fibroblasts. Furthermore, proteases of the coagulation and plasminogen activation (plasminergic) systems that form and breakdown fibrin respectively directly contribute to pulmonary fibrosis. The coagulants, thrombin and factor Xa (FXa) evoke fibrogenic effects via cleavage of the N-terminus of protease-activated receptors (PARs). Whilst the formation and activity of plasmin, the principle plasminergic mediator is suppressed in the airspaces of patients with IPF, localized increases are likely to occur in the lung interstitium. Plasmin-evoked proteolytic activation of factor XII (FXII), matrix metalloproteases (MMPs) and latent, matrix-bound growth factors such as epidermal growth factor (EGF) indirectly implicate plasmin in pulmonary fibrosis. Another plasminergic protease, urokinase plasminogen activator (uPA) is associated with regions of fibrosis in the remodelled lung of IPF patients and elicits fibrogenic activity via binding its receptor (uPAR). Plasminogen activator inhibitor-1 (PAI-1) formed in the injured alveolar epithelium also contributes to pulmonary fibrosis in a manner that involves vitronectin binding. This review describes the mechanisms by which components of the two systems primarily involved in fibrin homeostasis contribute to interstitial fibrosis, with a particular focus on IPF. Selectively targeting the receptor-mediated mechanisms of coagulant and plasminergic proteases may limit pulmonary fibrosis, without the bleeding complications associated with conventional anti-coagulant and thrombolytic therapies. PMID- 29474922 TI - Electron Cryo-microscopy Structure of Ebola Virus Nucleoprotein Reveals a Mechanism for Nucleocapsid-like Assembly. AB - Ebola virus nucleoprotein (eNP) assembles into higher-ordered structures that form the viral nucleocapsid (NC) and serve as the scaffold for viral RNA synthesis. However, molecular insights into the NC assembly process are lacking. Using a hybrid approach, we characterized the NC-like assembly of eNP, identified novel regulatory elements, and described how these elements impact function. We generated a three-dimensional structure of the eNP NC-like assembly at 5.8 A using electron cryo-microscopy and identified a new regulatory role for eNP helices alpha22-alpha23. Biochemical, biophysical, and mutational analyses revealed that inter-eNP contacts within alpha22-alpha23 are critical for viral NC assembly and regulate viral RNA synthesis. These observations suggest that the N terminus and alpha22-alpha23 of eNP function as context-dependent regulatory modules (CDRMs). Our current study provides a framework for a structural mechanism for NC-like assembly and a new therapeutic target. PMID- 29474921 TI - Inborn Errors of RNA Lariat Metabolism in Humans with Brainstem Viral Infection. AB - Viruses that are typically benign sometimes invade the brainstem in otherwise healthy children. We report bi-allelic DBR1 mutations in unrelated patients from different ethnicities, each of whom had brainstem infection due to herpes simplex virus 1 (HSV1), influenza virus, or norovirus. DBR1 encodes the only known RNA lariat debranching enzyme. We show that DBR1 expression is ubiquitous, but strongest in the spinal cord and brainstem. We also show that all DBR1 mutant alleles are severely hypomorphic, in terms of expression and function. The fibroblasts of DBR1-mutated patients contain higher RNA lariat levels than control cells, this difference becoming even more marked during HSV1 infection. Finally, we show that the patients' fibroblasts are highly susceptible to HSV1. RNA lariat accumulation and viral susceptibility are rescued by wild-type DBR1. Autosomal recessive, partial DBR1 deficiency underlies viral infection of the brainstem in humans through the disruption of tissue-specific and cell-intrinsic immunity to viruses. PMID- 29474927 TI - Post-meiotic DNA double-strand breaks are conserved in fission yeast. AB - In mammals, spermiogenesis is characterized by transient formation of DNA double strand breaks (DSBs) in the whole population of haploid spermatids. DSB repair in such haploid context may represent a mutational transition. Using a combination of pulsed-field gel electrophoresis and specific labelling of DSBs at 3'OH DNA ends, we showed that post-meiotic, enzyme-induced DSBs are also observed in the synchronizable pat1-114 mutant of Shizosaccharomyces pombe as well as in a wild type strain, while DNA repair is observed at later stages. This transient DNA fragmentation arises in the whole cell population and is seemingly independent of the caspase apoptotic pathway. Because histones are still present in spores, the transient DSBs do not require a major change in chromatin structure. These observations confirm the highly-conserved nature of the process in eukaryotes and provide a powerful model to study the underlying mechanism and its impact on the genetic landscape and adaptation. PMID- 29474928 TI - LncRNA HOTTIP promotes papillary thyroid carcinoma cell proliferation, invasion and migration by regulating miR-637. AB - BACKGROUND: Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy. Besides, increasing evidence has demonstrated that long non-coding RNA (lncRNA) HOTTIP played a crucial role in cancer pathogenesis. MiR-637 mediated Akt1 was involved in cell growth, invasion and migration in various malignancies. This study was aimed to investigate the potential biological effect and regulatory mechanism of HOTTIP on cell proliferation, invasion and migration in PTC. METHODS: Expression of HOTTIP, miR-637 and Akt1 were determined by quantitative RT-PCR (qRT-PCR) and western blotting in PTC tissues, normal tissues, PTC cells (TPC-1 and HTH83) or non-tumor thyroid cells (Nthy-ori 3-1). Cell proliferation, invasion and migration following HOTTIP knockdown were investigated in PTC cells. The target of HOTTIP was validated by RNA immunoprecipitation (RIP) and pull-down assay. Moreover, a xenograft model was performed. RESULTS: HOTTIP was upregulated in human PTC tissues and PTC cell lines. In addition, HOTTIP knockdown inhibited the proliferation, invasion and migration in vitro together with in vivo tumorigenesis of PTC cells. Additionally, HOTTIP knockdown downregulated Akt1 expression and suppressed cell proliferation, invasion and migration in PTC cells by regulating miR-637. In contrast, miR-637 inhibitor reversed above-mentioned tendencies caused by HOTTIP knockdown. CONCLUSION: HOTTIP is a potential oncogene in PTC and may serve as a therapeutic target for malignancies. PMID- 29474929 TI - Multi-posttranscriptional regulations lessen the repressive effect of SRPK1 on brown adipogenesis. AB - Alternative splicing has been widely demonstrated to function as pivotal regulation in specifying cellular fates and biological functions. The relative expression or cellular localization of a splicing factor constitutes an important mechanism in spatiotemporal programming of cell- and stage-specific splicing profiles. In this study, results of deep RNA-sequencing (RNA-Seq) analyses first revealed the reprogrammed splicing profile and reduced expression of serine/arginine-rich splicing factor protein kinase 1 (SRPK1) throughout the development of brown adipose tissue (BAT). A gradual increase in the exon 10 skipped SRPK1 transcript, a potential target of a nonsense-mediated decay (NMD) mechanism, was noted during brown adipogenesis. Elevated RBM4a constituted the regulatory mechanism that led to skipping of SRPK1 exon 10. Moreover, brown adipogenesis-induced upregulation of microRNA (miR)-485 interfered with SRPK1 expression by targeting its 3'-untranslated region (UTR). Depletion of endogenous SRPK1 enhanced the development of C3H10T1/2 cells toward brown adipocytes. Taking our results together, multiple post-transcriptional regulations reduced SRPK1 expression, which subsequently affected brown adipogenesis. PMID- 29474930 TI - Prep1 deficiency improves metabolic response in white adipose tissue. AB - Prep1 is a gene encoding for a homeodomain transcription factor which induces hepatic and muscular insulin resistance. In this study, we show that Prep1 hypomorphic heterozygous (Prep1i/+) mice, expressing low levels of protein, featured a 23% and a 25% reduction of total body lipid content and epididymal fat, respectively. The percentage of the small adipocytes (25-75 MUm) was 30% higher in Prep1i/+ animals than in the WT, with a reciprocal difference in the large adipose cells (100-150 and >150 MUm). Insulin-stimulated insulin receptor tyrosine and Akt serine phosphorylation markedly increased in Prep1i/+ mice, paralleled by 3-fold higher glucose uptake and a significant increase of proadipogenic genes such as C/EBPalpha, GLUT4, and FABP4. Moreover, T cells infiltration and TNF-alpha, IFNgamma and leptin expression were reduced in adipose tissue from Prep1i/+ mice, while adiponectin levels were 2-fold higher. Furthermore, Prep1i/+ mature adipocytes released lower amounts of pro inflammatory cytokines and higher amount of adiponectin compared to WT cells. Incubation of murine liver cell line (NMuLi) with conditioned media (CM) from mature adipocytes of Prep1i/+ mice improved glucose metabolism, while those from WT mice had no effect. Consistent with these data, Prep1 overexpression in 3T3-L1 adipocytes impaired adipogenesis and insulin signaling, and increased proinflammatory cytokine secretion. All these findings suggest that Prep1 silencing reduces inflammatory response and increases insulin sensitivity in adipose tissue. In addition, CM from mature adipocytes of Prep1i/+ mice improve metabolism in hepatic cells. PMID- 29474931 TI - Alpha-syntrophin null mice are protected from non-alcoholic steatohepatitis in the methionine-choline-deficient diet model but not the atherogenic diet model. AB - Adipose tissue dysfunction contributes to the pathogenesis of non-alcoholic steatohepatitis (NASH). The adapter protein alpha-syntrophin (SNTA) is expressed in adipocytes. Knock-down of SNTA increases preadipocyte proliferation and formation of small lipid droplets, which are both characteristics of healthy adipose tissue. To elucidate a potential protective role of SNTA in NASH, SNTA null mice were fed a methionine-choline-deficient (MCD) diet or an atherogenic diet which are widely used as preclinical NASH models. MCD diet mediated loss of fat mass was largely improved in SNTA-/- mice compared to the respective wild type animals. Hepatic lipids were mostly unchanged while the oxidative stress marker malondialdehyde was only induced in the wild type mice. The expression of inflammatory markers and macrophage immigration into the liver were reduced in SNTA-/- animals. This protective function of SNTA loss was absent in atherogenic diet induced NASH. Here, hepatic expression of inflammatory and fibrotic genes was similar in both genotypes though mutant mice gained less body fat during feeding. Hepatic cholesterol and ceramide were strongly induced in both strains upon feeding the atherogenic diet, while hepatic sphingomyelin, phosphatidylserine and phosphatidylethanolamine levels were suppressed. SNTA deficient mice are protected from fat loss and NASH in the experimental MCD model. NASH induced by an atherogenic diet is not influenced by loss of SNTA. The present study suggests the use of different experimental NASH models to study the pathophysiological role of proteins like SNTA in NASH. PMID- 29474933 TI - An optimised multi-arm multi-stage clinical trial design for unknown variance. AB - Multi-arm multi-stage trial designs can bring notable gains in efficiency to the drug development process. However, for normally distributed endpoints, the determination of a design typically depends on the assumption that the patient variance in response is known. In practice, this will not usually be the case. To allow for unknown variance, previous research explored the performance of t-test statistics, coupled with a quantile substitution procedure for modifying the stopping boundaries, at controlling the familywise error-rate to the nominal level. Here, we discuss an alternative method based on Monte Carlo simulation that allows the group size and stopping boundaries of a multi-arm multi-stage t test to be optimised, according to some nominated optimality criteria. We consider several examples, provide R code for general implementation, and show that our designs confer a familywise error-rate and power close to the desired level. Consequently, this methodology will provide utility in future multi-arm multi-stage trials. PMID- 29474934 TI - Design and statistical considerations for studies evaluating the efficacy of a single dose of the human papillomavirus (HPV) vaccine. AB - Cervical cancer is a leading cause of cancer mortality in women worldwide. Human papillomavirus (HPV) types 16 and 18 cause about 70% of all cervical cancers. Clinical trials have demonstrated that three doses of either commercially available HPV vaccine, Cervarix (r) or Gardasil (r), prevent most new HPV 16/18 infections and associated precancerous lesions. Based on evidence of immunological non-inferiority, 2-dose regimens have been licensed for adolescents in the United States, European Union, and elsewhere. However, if a single dose were effective, vaccine costs would be reduced substantially and the logistics of vaccination would be greatly simplified, enabling vaccination programs in developing countries. The National Cancer Institute (NCI) and the Agencia Costarricense de Investigaciones Biomedicas (ACIB) are conducting, with support from the Bill & Melinda Gates Foundation and the International Agency for Research on Cancer (IARC), a large 24,000 girl study to evaluate the efficacy of a 1-dose regimen. The first component of the study is a four-year non-inferiority trial comparing 1- to 2-dose regimens of the two licensed vaccines. The second component is an observational study that estimates the vaccine efficacy (VE) of each regimen by comparing the HPV infection rates in the trial arms to those in a contemporaneous survey group of unvaccinated girls. In this paper, we describe the design and statistical analysis for this study. We explain the advantage of defining non-inferiority on the absolute risk scale when the expected event rate is near 0 and, given this definition, suggest an approach to account for missing clinic visits. We then describe the problem of estimating VE in the absence of a randomized placebo arm and offer our solution. PMID- 29474932 TI - Profiling G protein-coupled receptors of Fasciola hepatica identifies orphan rhodopsins unique to phylum Platyhelminthes. AB - G protein-coupled receptors (GPCRs) are established drug targets. Despite their considerable appeal as targets for next-generation anthelmintics, poor understanding of their diversity and function in parasitic helminths has thwarted progress towards GPCR-targeted anti-parasite drugs. This study facilitates GPCR research in the liver fluke, Fasciola hepatica, by generating the first profile of GPCRs from the F. hepatica genome. Our dataset describes 147 high confidence GPCRs, representing the largest cohort of GPCRs, and the largest set of in silico ligand-receptor predictions, yet reported in any parasitic helminth. All GPCRs fall within the established GRAFS nomenclature; comprising three glutamate, 135 rhodopsin, two adhesion, five frizzled, one smoothened, and one secretin GPCR. Stringent annotation pipelines identified 18 highly diverged rhodopsins in F. hepatica that maintained core rhodopsin signatures, but lacked significant similarity with non-flatworm sequences, providing a new sub-group of potential flukicide targets. These facilitated identification of a larger cohort of 76 related sequences from available flatworm genomes, representing new members of existing groups (PROF1/Srfb, Rho-L, Rho-R, Srfa, Srfc) of flatworm-specific rhodopsins. These receptors imply flatworm specific GPCR functions, and/or co evolution with unique flatworm ligands, and could facilitate the development of exquisitely selective anthelmintics. Ligand binding domain sequence conservation relative to deorphanised rhodopsins enabled high confidence ligand-receptor matching of seventeen receptors activated by acetylcholine, neuropeptide F/Y, octopamine or serotonin. RNA-Seq analyses showed expression of 101 GPCRs across various developmental stages, with the majority expressed most highly in the pathogenic intra-mammalian juvenile parasites. These data identify a broad complement of GPCRs in F. hepatica, including rhodopsins likely to have key functions in neuromuscular control and sensory perception, as well as frizzled and adhesion/secretin families implicated, in other species, in growth, development and reproduction. This catalogue of liver fluke GPCRs provides a platform for new avenues into our understanding of flatworm biology and anthelmintic discovery. PMID- 29474935 TI - The use of methacholine provocation when assessing therapeutic equivalence between two inhalers in asthmatic patients. AB - A planned change from Bricanyl(r) (terbutaline) Turbuhaler(r) M2 to M3 device required a pharmacodynamic study to evaluate therapeutic equivalence of the two devices. Because of the flat dose-response curve for this type of agent over this dose range when assessing bronchodilation, a bronchoprotection study was considered more feasible. In this double-blind, double-dummy, multicentre, single dose, two-factor, crossover study, patients with stable mild-to-moderate asthma were randomised to 0.5 or 1.5 mg terbutaline via Turbuhaler(r) M2 or Turbuhaler(r) M3 followed by a methacholine challenge test. Primary outcome variable: concentration of methacholine causing a 20% fall in FEV1 (PC20). Pairwise contrasts were constructed with 95% CIs to determine assay sensitivity for M2 and M3 devices and therapeutic equivalence at each dose level (95% CI for M3:M2 devices within pre-specified limit [0.67-1.50]) and the relative dose potency (RDP) between M3 and M2 determined with 90% CI. Sixty patients were randomised and all completed the study. Between-device ratios of PC20 (M3:M2) were 0.92 (95% CI: 0.75-1.13) for 0.5 mg and 0.88 (95% CI 0.72-1.08) for 1.5 mg and estimated RDP was 1.20 (0.96-1.53). In conclusion, a methacholine provocation study (PC20 primary variable) is a useful alternative to the standard bronchodilation study when assessing therapeutic equivalence of a bronchodilator. PMID- 29474936 TI - Adiposity associated changes in serum glucose and adiponectin levels modulate ovarian steroidogenesis during delayed embryonic development in the fruit bat, Cynopterus sphinx. AB - The aim of the present study was to evaluate the mechanism by which embryonic development in Cynopterus sphinx is impaired during the period of increased accumulation of white adipose tissue during winter scarcity of food. The change in the mass of white adipose tissue during adipogenesis showed significant positive correlation with the circulating glucose level. But increase in circulating glucose level during the adipogenesis showed negative correlation with circulating progesterone and adiponectin levels. The in vivo study showed increased glucose uptake by the adipose tissue during adipogenesis due to increased expression of insulin receptor (IR) and glucose transporter (GLUT) 4 proteins. This study showed decline in the adiponectin level during fat accumulation. In the in vitro study, ovary treated with high doses of glucose showed impaired progesterone synthesis. This is due to decreased glucose uptake mediated decrease in the expression of luteinizing hormone-receptor, steroidogenic acute regulatory protein, IR, GLUT4 and AdipoR1 proteins. But the ovary treated with adiponectin either alone or with higher concentration of glucose showed improvement in progesterone synthesis due to increased expression of IR, GLUT4 and AdipoR1 mediated increased glucose uptake. In conclusion, increased circulating glucose level prior to winter dormancy preferably transported to white adipose tissue for fat accumulation diverting glucose away from the ovary. Consequently the decreased availability of adiponectin and glucose to the ovary and utero-embryonic unit may be responsible for impaired progesterone synthesis and delayed embryonic development. The delayed embryonic development in Cynopterus sphinx may have evolved, in part, as a mechanism to prevent pregnancy loss during the period of decreased energy availability. PMID- 29474937 TI - Completing the Bucket List: Leveraging Telemedicine in Oncologic Palliative Care to Support Legacy-Making and Dignity. PMID- 29474938 TI - Differential Family Experience of Palliative Sedation Therapy in Specialized Palliative or Critical Care Units. AB - CONTEXT: No study has examined the varying family experience of palliative sedation therapy (PST) for terminally ill patients in different settings. OBJECTIVES: To examine and compare family concerns about PST use and its effect on the grief suffered by terminally ill patients' families in palliative care units (PCUs) or intensive care units (ICUs). METHODS: A total of 154 family members of such patients were recruited in Taiwan, of whom 143 completed the study, with 81 from the PCU and 62 from the ICU. Data were collected on their concerns regarding PST during recruitment. Grief levels were assessed at three days and one month after the patient's death with the Texas Revised Inventory of Grief. RESULTS: Families' major concern about sedated patients in the PCU was that "there might be other ways to relieve symptoms" (90.2%), whereas families of ICU sedated patients gave the highest ratings to "feeling they still had something more to do" (93.55%), and "the patient's sleeping condition was not dignified" (93.55%). Family members recruited from the ICU tended to experience more grief than those from the PCU (P = 0.005 at Day 3 and < 0.001 at Month 1). PST use predicted higher levels of grief in family members recruited from the PCU (P < 0.001 at Day 3 and Month 1). CONCLUSION: Family experiences with the use of PST in terminally ill patients varied in different settings. Supportive care should address family concerns about PST use, and regular attention should be paid to the grief of individuals at higher risk. PMID- 29474939 TI - Adapting an Early Palliative Care Intervention to Family Caregivers of Persons With Advanced Cancer in the Rural Deep South: A Qualitative Formative Evaluation. AB - CONTEXT: There is a scarcity of early palliative care interventions to support family caregivers of persons with advanced cancer living in the rural Southern U.S. OBJECTIVE: The objective of this study was to adapt the content, format, and delivery of a six session, palliative care, telehealth intervention with monthly follow-up for rural family caregivers to enhance their own self-care and caregiving skills. METHODS: Qualitative formative evaluation consisting of one-on one, semistructured interviews with rural-dwelling persons with metastatic cancer (n = 18), their primary family caregiver (n = 20), and lay patient navigators (n = 26) were conducted to elicit feedback on a family caregiver intervention outline based on published evidence-based interventions. Transcribed interviews were analyzed using a thematic analysis approach. Coinvestigators reviewed and refined preliminary themes. RESULTS: Participants recommended that intervention topical content be flexible and has an adaptable format based on continuous needs assessment. Sessions should be 20 minutes long at minimum, and additional sessions should be offered if requested. Faith and spirituality is essential to address but should not be an overarching intervention theme. Content needs to be communicated in simple language. Intervention delivery via telephone is acceptable, but face-to-face contact is desired to establish relationships. Other Internet-based technologies (e.g., video-conferencing) could be helpful, but many rural dwellers may not be technology savvy or have Internet access. Most lay navigators believed they could lead the intervention with additional training, protocols for professional referral, and supervision by specialty-trained palliative care clinicians. CONCLUSIONS: A potentially scalable palliative care intervention is being adapted for family caregivers of rural-dwelling persons with advanced cancer and will undergo piloting in a small-scale randomized controlled trial. PMID- 29474940 TI - Information Framing Reduces Initial Negative Attitudes in Cancer Patients' Decisions About Hospice Care. AB - BACKGROUND: Negative attitudes toward hospice care might prevent patients with cancer from discussing and choosing hospice as they approach end of life. When making a decision, people often naturally focus on either expected benefits or the avoidance of harm. Behavioral research has demonstrated that framing information in an incongruent manner with patients' underlying motivational focus reduces their negative attitudes toward a disliked option. OBJECTIVE: Our study tests this communication technique with cancer patients, aiming to reduce negative attitudes toward a potentially beneficial but often-disliked option, that is, hospice care. METHODS: Patients (n = 42) with active cancer of different types and/or stages completed a paper survey. Participants read a vignette about a patient with advanced cancer and a limited prognosis. In the vignette, the physician's advice to enroll in a hospice program was randomized, creating a congruent message or an incongruent message with patients' underlying motivational focus (e.g., a congruent message for someone most interested in benefits focuses on the benefits of hospice, whereas an incongruent message for this patient focuses on avoiding harm). Patients' attitudes toward hospice were measured before and after receiving the physician's advice. RESULTS: Regression analyses indicated that information framing significantly influenced patients with strong initial negative attitudes. Patients were more likely to reduce intensity of their initial negative attitude about hospice when receiving an incongruent message (b = -0.23; P < 0.01) than a congruent one (b = -0.13; P = 0.08). CONCLUSION: This finding suggests a new theory-driven approach to conversations with cancer patients who may harbor negative reactions toward hospice care. PMID- 29474941 TI - Blocking Wnt5a signaling decreases CD36 expression and foam cell formation in atherosclerosis. AB - BACKGROUND AND AIMS: Wnt5a is a highly studied member of the Wnt family and recently has been implicated in the pathogenesis of atherosclerosis, but its precise role is unknown. Foam cell development is a critical process to atherosclerotic plaque formation. In the present study, we investigated the role of noncanonical Wnt5a signaling in the development of foam cells. METHODS: Human carotid atherosclerotic tissue and THP-1-derived macrophages were used to investigate the contribution of Wnt5a signaling in the formation of foam cells. Immunohistochemistry was used to evaluate protein expression of scavenger receptors and noncanonical Wnt5a receptors [frizzled 5 (Fz5) and receptor tyrosine kinase-like orphan receptor 2 (Ror2)] in human atherosclerotic macrophages/foam cells. Changes in protein expression in response to Wnt5a stimulation/inhibition were determined by Western blot, and lipid accumulation was evaluated by fluorescent lipid droplet staining. RESULTS: Wnt5a (P<.05), Fz5 (P<.01), and Ror2 (P<.01) were significantly expressed in advanced atherosclerotic lesions compared to less advanced lesions (N=10). Wnt5a, Fz5, and Ror2 were expressed in macrophages/foam cells within the plaque. In vitro studies revealed that Wnt5a significantly increased the expression of the lipid uptake receptor CD36 (P<.05) but not the lipid efflux receptor ATP-binding cassette transporter (P>.05). rWnt5a also significantly increased lipid accumulation in THP-1 macrophages (P<.05). Furthermore, inhibition of Wnt5a signaling with Box5 prevented lipid accumulation (P<.01) and prevented CD36 up-regulation (P<.01). CONCLUSIONS: These results suggest a direct role for Wnt5a signaling in the pathogenesis of atherosclerosis, specifically the accumulation of lipid in macrophages and the formation of foam cells. PMID- 29474942 TI - CXCL5 Facilitates Melanoma Cell-Neutrophil Interaction and Lymph Node Metastasis. AB - Chemokines influence tumor metastasis by targeting tumor, stromal, and hematopoietic cells. Characterizing the chemokine mRNA expression profile of human primary melanoma samples, we found CXCL5 significantly up-regulated in stage T4 primary melanomas when compared to thin melanomas (T1 stage). To characterize the role of CXCL5 in melanoma progression, we established a metastasizing murine xenograft model using CXCL5-overexpressing human melanoma cells. CXCL5 had no effect on melanoma proliferation in vitro and on primary tumor growth in vivo, but CXCL5-overexpressing tumors recruited high amounts of neutrophils and exhibited significantly increased lymphangiogenesis in our severe combined immune-deficient mouse model. Recruited neutrophils were found in close proximity to or within lymphatic vessels, often in direct contact with melanoma cells. Clinically, CXCL5-overexpressing melanomas had significantly increased lymph node metastases. We were able to translate these findings to human patient samples and found a positive correlation between CXCL5 expression, numbers of neutrophils in stage T4 primary melanoma, and the occurrence of subsequent locoregional metastasis. PMID- 29474943 TI - Attenuated Activation of Homeostatic Glucocorticoid in Keratinocytes Induces Alloknesis via Aberrant Artemin Production. AB - Intense chronic itch significantly reduces quality of life for atopic dermatitis patients, impairing daily activity. Although abnormal itch sensation can be induced by innocuous stimuli, known as alloknesis, the mechanisms driving this process remain obscure. Psychological and environmental stimuli are known to aggravate atopic dermatitis symptoms. Recently, the enzyme 11beta-hydroxysteroid dehydrogenase-1 (HSD11beta1), which is expressed in keratinocytes, has been implicated in maintaining homeostasis against environmental stimuli by activating endogenous glucocorticoids. To investigate the role of HSD11beta1 in keratinocytes, we generated keratinocyte-specific Hsd11b1-knockout (Hsd11b1KC-/-) mice and analyzed skin phenotype. Hsd11b1KC-/- mice exhibited abnormal cutaneous innervation and skin sensitivity, including light mechanical stimulus-evoked itch (i.e., alloknesis). Attenuated endogenous glucocorticoid activation induced by aberrant artemin production in keratinocytes was involved in alloknesis in Hsd11b1KC-/- mice. Finally, we observed a significant negative correlation between expression of HSD11beta1 and artemin in human skin with and without AD. These results suggest that endogenous glucocorticoids that maintain skin homeostasis in the epidermis affect both skin innervation and cutaneous sensation. Modulation of HSD11beta1 activation could be a therapeutic target for sensitive or itchy skin. PMID- 29474944 TI - Langerhans Cells Transfer Targeted Antigen to Dermal Dendritic Cells and Acquire Major Histocompatibility Complex II In Vivo. PMID- 29474945 TI - Neutralization of IL-17C Reduces Skin Inflammation in Mouse Models of Psoriasis and Atopic Dermatitis. AB - IL-17C is a functionally distinct member of the IL-17 family that was believed to play a role in the pathogenesis of psoriasis. Here we confirmed that IL-17C is involved in psoriasis and explored potential roles for IL-17C in atopic dermatitis (AD). An anti-IL-17C antibody, MOR106, was generated that potently and selectively binds to human and mouse IL-17C, thereby inhibiting the binding of IL 17C to its IL-17RE receptor. The antibody inhibited cutaneous inflammation in an IL-23-induced psoriatic-like skin inflammation model. In lesional skin of patients with AD, IL-17C expression levels were increased and localized to keratinocytes and infiltrating immune cells. To determine the contribution of IL 17C to AD pathogenesis, MOR106 was tested in two distinct in vivo models. In the calcipotriol-induced AD model, ear skin inflammation, TSLP, and IL-33 protein production in ears was suppressed by MOR106. Consistently, in the flaky tail strain mouse model, spontaneous development of AD-like skin inflammation was reduced by MOR106. Moreover, serum IgE levels, number of mast cells in skin and T helper type 2-related cytokines IL-4 and CCL17 in serum were all reduced. Overall, our results indicate that IL-17C is a central mediator of skin inflammation beyond psoriasis and is relevant in particular in AD. PMID- 29474946 TI - Functional results and patient satisfaction after long fusion for spinal deformity in Parkinson's disease. AB - BACKGROUND: Patients with Parkinson's disease often present abnormal posture or severe sagittal malalignment, causing significant disability. Surgical fusion is these cases shows high rates of complications, but may nevertheless provide functional benefit; however, this remains to be assessed. HYPOTHESIS: Long fusion for patients with Parkinson's disease and postural disorder could alleviate disability despite the high risk of complications. METHODS: We retrospectively reviewed 18 Parkinson patients treated by long fusion for spinal deformity. Functional results on the Oswestry Disability Index (ODI) and patient satisfaction were assessed at a minimum 2 years' follow-up. Predictive factors for good outcome were analyzed. RESULTS: Median follow-up was 44.4 months (IQR, 36-62.4 months). ODI showed significant improvement, from 64 (IQR, 59-77) preoperatively to 49 (IQR, 40-57) at last follow-up (p=0.0014). Fifteen patients (83%) were very satisfied (n=5) or satisfied (n=10) with the procedure. On multivariate analysis, only age was significantly associated with improvement in ODI at last follow-up (estimate: -9.8; p=0.5). DISCUSSION: Although long spinal fusion involves a high risk of complications in Parkinson's patients, the improvement in autonomy and patient satisfaction should be borne in mind before rejecting surgery, especially with motivated patients. LEVEL OF EVIDENCE: IV. PMID- 29474947 TI - What information? For which patients? A new paradigm in orthopedic surgery. PMID- 29474948 TI - Assessment of a press-fit proximal femoral modular reconstruction implant (PFMR(r)) at 14.5 years. A 48-case series with a disturbing rate of implant fracture. AB - INTRODUCTION: The PFMR(r) proximal femoral modular reconstruction implant (Protek, Sulzer Orthopedics, Switzerland) is a straight modular stem in sanded titanium with press-fit anchorage, intended to achieve spontaneous bone reconstruction following Wagner's principle. The aim of the present study was to analyze long-term clinical and radiological outcome. MATERIAL AND METHOD: A single-center retrospective study included 48 PFMR stems implanted in 47 patients between 1998 and 2002. Results in this series were previously reported at 7 years' follow-up. Clinical assessment used PMA and Harris scores. Radiologic assessment focused on stem stability and osseointegration, and bone stock following Le Beguec. RESULTS: Twenty-three patients were seen at a mean 14.5 years' follow-up (13 deceased, 11 lost to follow-up), including 1 with bilateral implants, i.e., 24 stems. PMA and Harris scores, stem stability and osseointegration and bone stock were stable with respect to the 7-year findings. Radiology found 7 stem fractures in the Morse taper, i.e., in 29% of implants. Two of these cases required femoral implant replacement; 5 were asymptomatic. DISCUSSION AND CONCLUSION: Long-term outcome for PFMR stems was clinically and radiologically satisfactory for the 16 patients free of mechanical complications. The Morse taper fracture rate was high, and higher than reported elsewhere. The usual risk factors for implant fracture were not found in the present series. The modular design of the press-fit revision implant is its weak point; monoblock implants should be used in patients with good life-expectancy. LEVEL OF EVIDENCE: IV (retrospective study). PMID- 29474949 TI - Anterior and lateral overcoverage after triple pelvic osteotomy in childhood for developmental dislocation of the hip with acetabular dysplasia: Frequency, features, and medium-term clinical impact. AB - BACKGROUND: Triple pelvic osteotomy (TPO) is a treatment option in children and adolescents with residual acetabular dysplasia after developmental dislocation of the hip (DDH). However, TPO to redirect the acetabulum is often blamed for anterior and lateral overcoverage of the femoral head. The main objectives of this study were to assess the potential clinical impact, frequency, and radiological features of acetabular overcorrection. Evidence of post-operative remodelling and associations linking younger age at surgery and/or dysplasia severity to the existence and magnitude of overcorrection were sought. HYPOTHESIS: Acetabular overcorrection has little or no clinical impact. PATIENTS AND METHODS: TPO was performed on 41 hips in 31 patients at a mean age of 6.3 years (range, 3.0-15.2 years). Mean follow-up was 13.8 years (range, 5.4-28.7 years) and mean age at last re-evaluation was 22.1 years (range, 13-39 years). Clinical outcomes were assessed based on the Harris Hip Score (HHS) and Postel Merle d'Aubigne (PMA) score. Radiographs were used to look for a cross-over sign (CO+) and to measure the vertical-centre edge (VCE) and vertical-centre anterior (VCA) angles and the acetabular index (AI). Overcorrection was defined as AI<=0 degrees and/or VCE>=35 degrees and/or VCA>=40 degrees and/or CO+. RESULTS: The HHS and PMA score values were good or excellent for 39 (94%) hips. One or more parameters indicated overcorrection of 33 (80.5%) hips. No significant differences were found between the overcorrected hips and the hips with normal parameters. DISCUSSION: TPO effectively corrects residual acetabular dysplasia. Overcorrection is common in all three planes but has little clinical impact in young adults. The high frequency of overcorrection mandates a careful pre- and intra-operative evaluation of acetabular version. LEVEL OF EVIDENCE: IV, retrospective study. PMID- 29474950 TI - Remineralisation of enamel white spot lesions pre-treated with chitosan in the presence of salivary pellicle. AB - OBJECTIVE: To investigate the remineralisation of chitosan pre-treated enamel white spot lesions (WSLs) by bioglass in the presence of the pellicle layer. METHODS: 50 artificial enamel white spot lesions were created by acidic gel. Two lesions were used to investigate the formation of the pellicle layer by treating with human whole saliva for 3 min. 48 lesions were assigned to 6 experimental groups (n = 8): (1) bioactive glass slurry, (2) bioactive glass containing polyacrylic acid (BG + PAA) slurry, (3) chitosan pre-treated WSLs with BG slurry (CS-BG), (4) chitosan pre-treated WSLs with BG + PAA slurry (CS-BG + PAA), (5) "standard" remineralisation solution (RS) and (6) de-ionised water (negative control, NC). Remineralisation was carried out using a pH-cycling model for 7 days. Before each treatment using remineralising agents, 3-min pellicle was formed on lesions' surfaces. Mineral content changes, surface and subsurface microhardness and ultrastructure were evaluated by Raman intensity mapping, Knoop microhardness and scanning electron microscopy, respectively. Data were statistically analysed using one-way ANOVA with Tukey's test (p < 0.05 is considered as significant). RESULTS: Despite the heterogeneously formed pellicle layer, all groups showed an increase in surface mineral content after pH-cycling. Chitosan pre-treatment enhanced the subsurface remineralisation of WSLs using bioglass as both pre-treated groups showed greater surface and subsurface microhardness compared to NC. CS-BG exhibited denser subsurface structure than BG, while in CS-BG + PAA the crystals were bigger in size but resemble more enamel-like compared to BG + PAA as shown in SEM observations. Remineralisation of RS was limited to the surface as no significant subsurface changes of mechanical properties and structure were found. CONCLUSIONS: Chitosan pre treatment can enhance WSL remineralisation with bioglass biomaterials when a short-term salivary pellicle is present. A further investigation using a long term pH-cycling model with mature pellicle is suggested with regards to clinical application. CLINICAL SIGNIFICANCE: Chitosan pre-treatment has the potential in clinical application to remineralise subsurface lesions to achieve lesion consolidation. PMID- 29474951 TI - Teaching of posterior composites in dental schools in Japan - 30 years and beyond. AB - OBJECTIVES: The teaching of posterior composites has been a major part of the curriculum in Japanese dental education for several decades. The aim of this paper was to investigate the current trends in the teaching of posterior composites to undergraduate dental students in Japan by comparing the results of surveys conducted for over 30 years. METHODS: In late 2016-early 2017, a questionnaire seeking information on the teaching of posterior composites was distributed via e-mail to the persons responsible for teaching operative dentistry in 29 dental schools having undergraduate dental degree programs in Japan. The results obtained were compared to those from surveys conducted in 1986, 1997, and 2007. RESULTS: All 29 schools that were sent the questionnaire completed the responses (response rate = 100%). All 29 schools reported teaching the placement of composite in occlusal and two-surface occluso-proximal cavities in both premolars and molars. Four schools reported not teaching the placement of three-surface occluso-proximal composites in premolars and five schools reported not teaching it for molars. Twenty-seven (93%) schools taught composite first as a part of the preclinical curriculum, whereas 15 (65%) schools did so in the survey of 2007. Variations were noted between schools in the teaching of, cavity design. In contrast, greater consistency was observed in the teaching of techniques for protecting exposed dentin and light-curing technologies. CONCLUSIONS: It is hoped that measures intended to increase the clinical experience of restoring teeth with direct composite-resin for dental students in Japan will be effective, providing opportunity to bring dental education in Japan more into line with international norms. PMID- 29474952 TI - Modulation of defensive airway reflexes during continuous positive airway pressure in the rabbit. AB - Lung hyperinflation may alter the pattern of ventilatory reflexes in chronic respiratory disorders. The aim of the study was to test the effect of continuous positive airway pressure (CPAP) on ventilatory responses to mechanical stimulation of the trachea. PMID- 29474954 TI - Orexin 1 and orexin 2 receptor antagonism in the basolateral amygdala modulate long-term potentiation of the population spike in the perforant path-dentate gyrus-evoked field potential in rats. AB - Involvement of amygdalo-hippocampal substructures in patients with narcolepsy due to deficiencies in the orexinergic system, and the presence of hippocampus dependent memory impairments in this disorder, have led us to investigate the effects of orexin 1 and 2 receptor antagonism in the basolateral amygdala (BLA) on long-term potentiation (LTP) of dentate gyrus (DG) granular cells. We used a 200-Hz high-frequency stimulation protocol in anesthetized rats. We studied the long-term synaptic plasticity of perforant path-dentate gyrus granule cells following the inactivation of orexin receptors before and after tetanic stimulation. LTP of the DG population spike was attenuated in the presence of orexin 1 and 2 receptor antagonism (treatment with SB-334867-A and TCS-OX2-29, respectively) in the BLA when compared to that observed following treatment with dimethyl sulfoxide (DMSO). However, the population excitatory post-synaptic potentials were not affected. Moreover, when orexin 1 and 2 receptors in the BLA were blocked after LTP induction, there were no differences between the DMSO and treatment groups. Our findings suggest that the orexinergic system of the BLA plays a modulatory role in the regulation of hippocampal plasticity in rats. PMID- 29474953 TI - GABA-ergic neurotransmission in the nucleus of the solitary tract modulates cough in the cat. AB - GABA, muscimol, and baclofen were microinjected into the rostral (rNTS) and caudal solitary tract nucleus (cNTS) in 24 anesthetized cats. Electromyograms (EMGs) of diaphragm (DIA) and abdominal muscles (ABD), blood pressure and esophageal pressure (EP) were recorded and analysed. Bilateral microinjections of 1 mM GABA (total 66 +/- 4 nl), 1 mM baclofen (64 +/- 4 nl) and unilateral microinjections of 0.5 mM muscimol (33 +/- 1 nl) in the rNTS significantly reduced cough number (CN), amplitudes of ABD EMGs, expiratory EP, and prolonged the duration of the cough inspiratory phase. GABA microinjections decreased the amplitudes of cough-related DIA EMGs and inspiratory EP; muscimol microinjections decreased the cough DIA EMG on the contralateral side. Only microinjections of GABA into the cNTS suppressed CN. In some cases, microinjections prolonged the inspiratory phase, lowered respiratory rate, changed the depth of breathing, and increased blood pressure and heart rate. Our results confirm that GABA-ergic inhibitory mechanisms in the rNTS can regulate coughing in the anesthetized cat. PMID- 29474955 TI - Prior knowledge modulates the neural substrates of encoding and retrieving naturalistic events at short and long delays. AB - Congruence with prior knowledge and incongruence/novelty have long been identified as two prominent factors that, despite their opposing characteristics, can both enhance episodic memory. Using narrative film clip stimuli, this study investigated these effects in naturalistic event memories - examining behaviour and neural activation to help explain this paradox. Furthermore, we examined encoding, immediate retrieval, and one-week delayed retrieval to determine how these effects evolve over time. Behaviourally, both congruence with prior knowledge and incongruence/novelty enhanced memory for events, though incongruent events were recalled with more errors over time. During encoding, greater congruence with prior knowledge was correlated with medial prefrontal cortex (mPFC) and parietal activation, suggesting that these areas may play a key role in linking current episodic processing with prior knowledge. Encoding of increasingly incongruent events, on the other hand, was correlated with increasing activation in, and functional connectivity between, the medial temporal lobe (MTL) and posterior sensory cortices. During immediate and delayed retrieval the mPFC and MTL each demonstrated functional connectivity that varied based on the congruence of events with prior knowledge; with connectivity between the MTL and occipital regions found for incongruent events, while congruent events were associated with functional connectivity between the mPFC and the inferior parietal lobules and middle frontal gyri. These results demonstrate patterns of neural activity and connectivity that shift based on the nature of the event being experienced or remembered, and that evolve over time. Furthermore, they suggest potential mechanisms by which both congruence with prior knowledge and incongruence/novelty may enhance memory, through mPFC and MTL functional connectivity, respectively. PMID- 29474956 TI - The clock gene period differentially regulates sleep and memory in Drosophila. AB - Circadian regulation is a conserved phenomenon across the animal kingdom, and its disruption can have severe behavioral and physiological consequences. Core circadian clock proteins are likewise well conserved from Drosophila to humans. While the molecular clock interactions that regulate circadian rhythms have been extensively described, additional roles for clock genes during complex behaviors are less understood. Here, we show that mutations in the clock gene period result in differential time-of-day effects on acquisition and long-term memory of aversive olfactory conditioning. Sleep is also altered in period mutants: while its overall levels don't correlate with memory, sleep plasticity in different genotypes correlates with immediate performance after training. We further describe distinct anatomical bases for Period function by manipulating Period activity in restricted brain cells and testing the effects on specific aspects of memory and sleep. In the null mutant background, different features of sleep and memory are affected when we reintroduce a form of the period gene in glia, lateral neurons, and the fan-shaped body. Our results indicate that the role of the clock gene period may be separable in specific aspects of sleep or memory; further studies into the molecular mechanisms of these processes suggest independent neural circuits and molecular cascades that mediate connections between the distinct phenomena. PMID- 29474957 TI - Limits on lability: Boundaries of reconsolidation and the relationship to metaplasticity. AB - Reconsolidation, a process by which long-term memories are rendered malleable following retrieval, has been shown to occur across many different species and types of memory. However, there are conditions under which memories do not reconsolidate, and the reasons for this are poorly understood. One emerging theory is that these boundary conditions are mediated by a form of metaplasticity: cellular changes through which experience can affect future synaptic plasticity. We review evidence that N-methyl-D-aspartate receptors (NMDARs) might contribute to this phenomenon, and hypothesize that resistance to memory destabilization may be mediated by the ratio of GluN2A/GluN2B subunits that make up these receptors. Qualities such as memory strength and the age of the memory may increase the GluN2A/GluN2B ratio, reducing the ability of reactivation cues to induce destabilization, thereby preventing reconsolidation. Other examples of experience-dependent learning and evolutionary perspectives of reconsolidation are also discussed. PMID- 29474958 TI - Cognitive, emotional and social phenotyping of mice in an observer-independent setting. AB - Based on the intellicage paradigm, we have developed a novel cognitive, emotional and social phenotyping battery that permits comprehensive standardized behavioral characterization of mice in an experimenter-independent social setting. Evaluation of this battery in a large number of male and female C57BL/6 wildtype mice, tested in >20 independent cohorts, revealed high reproducibility of the behavioral readouts and may serve as future reference tool. We noticed robust sex specific differences in general activity, cognitive and emotional behavior, but not regarding preference for social pheromones. Specifically, female mice revealed higher activity, decreased sucrose preference, impaired reversal and place-time-reward learning. Furthermore, female mice reacted more sensitively than males to reward-withdrawal showing a negative emotional contrast/Crespi effect. In a series of validation experiments, we tested mice with different pathologies, including neuroligin-3 deficient mice (male Nlgn3y/- and female Nlgn3+/-) for autistic behavior, oligodendrocyte-specific erythropoietin receptor knockout (oEpoR-/-) mice for cognitive impairment, as well as mouse models of renal failure (unilateral ureteral obstruction and 5/6 nephrectomy) and of type 2 diabetes (ApoE-/-) - for delineating potentially confounding effects of motivational factors (thirst, glucose-craving) on learning and memory assessments. As prominent features, we saw in Nlgn3 mutants reduced preference for social pheromones, whereas oEpoR-/- mice showed learning deficits in place or reversal learning tasks. Renal failure led to increased water intake, and diabetic metabolism to enhanced glucose preference, limiting interpretation of hereon based learning and memory performance in these mice. The phenotyping battery presented here may be well-suited as high-throughput multifaceted diagnostic instrument for translational neuropsychiatry and behavioral genetics. PMID- 29474959 TI - Alpha-gamma phase amplitude coupling subserves information transfer during perceptual sequence learning. AB - Cross-frequency coupling is suggested to serve transfer of information between wide-spread neuronal assemblies and has been shown to underlie many cognitive functions including learning and memory. In previous work, we found that alpha (8 13 Hz) - gamma (30-48 Hz) phase amplitude coupling (alphagammaPAC) is decreased during sequence learning in bilateral frontal cortex and right parietal cortex. We interpreted this to reflect decreased demands for visuo-motor mapping once the sequence has been encoded. In the present study, we put this hypothesis to the test by adding a "simple" condition to the standard serial reaction time task (SRTT) with minimal needs for visuo-motor mapping. The standard SRTT in our paradigm entailed a perceptual sequence allowing for implicit learning of a sequence of colors with randomly assigned motor responses. Sequence learning in this case was thus not associated with reduced demands for visuo-motor mapping. Analysis of oscillatory power revealed a learning-related alpha decrease pointing to a stronger recruitment of occipito-parietal areas when encoding the perceptual sequence. Replicating our previous findings but in contrast to our hypothesis, alphagammaPAC was decreased in sequence compared to random trials over right frontal and parietal cortex. It also tended to be smaller compared to trials requiring a simple motor sequence. We additionally analyzed alphagammaPAC in resting-state data of a separate cohort. PAC in electrodes over right parietal cortex was significantly stronger compared to sequence trials and tended to be higher compared to simple and random trials of the SRTT data. We suggest that alphagammaPAC in right parietal cortex reflects a "default-mode" brain state, which gets perturbed to allow for encoding of visual regularities into memory. PMID- 29474960 TI - Anti-tumor efficacy of hyaluronan-based nanoparticles for the co-delivery of drugs in lung cancer. AB - Combinations of therapeutic agents could synergistically enhance the response of lung cancer cells. Co-delivery systems capable of transporting chemotherapeutics with different physicochemical properties and with the simultaneous release of drugs remain elusive. Here, we assess the ability of nanoparticles of 30-nm diameter obtained from the self-assembly of hyaluronan-based copolymer targeting CD44 receptors to encapsulate both gefitinib and vorinostat for effective combinational lung cancer treatment. Drug loading was performed by nanoprecipitation. Drug release experiments showed a slow release of both drugs after 5 days. Using two- and three-dimensional lung adenocarcinoma cell cultures, we observed that the nanoparticles were mostly found at the periphery of the CD44 expressing spheroids. These drug-loaded nanoparticles were as cytotoxic as free drugs in the two- and three-dimensional systems and toxicity was due to apoptosis induction. In mouse models, intravenous injection of hyaluronan-based nanoparticles showed a selective delivery to subcutaneous CD44-overexpressing tumors, despite a significant liver capture. In addition, the systemic toxicity of the free drugs was reduced by their co-delivery using the nanoparticles. Finally, intrapulmonary administration of drug-loaded nanoparticles, to avoid a possible hepatic toxicity due to their accumulation in the liver, showed a stronger inhibition of orthotopic lung tumor growth compared to free drugs. In conclusion, hyaluronan-based nanoparticles provide active targeting partially mediated by CD44, less-toxic drug release and improved antitumor efficiency. PMID- 29474961 TI - The presence of glutamate residues on the PAS sequence of the stimuli-sensitive nano-ferritin improves in vivo biodistribution and mitoxantrone encapsulation homogeneity. AB - A genetically engineered human ferritin heavy chain (HFt)-based construct has been recently shown by our group to efficiently entrap and deliver doxorubicin to cancer cells. This construct, named HFt-MP-PAS, contained a tumor-selective sequence (MP) responsive to proteolytic cleavage by tumor proteases (MMPs), located between each HFt subunit and an outer shielding polypeptide sequence rich in proline (P), serine (S) and alanine (A) residues (PAS). HFt-MP-PAS displayed excellent therapeutic efficacy in xenogenic pancreatic and head and neck cancer models in vivo, leading to a significant increase in overall animal survivals. Here we report a new construct obtained by the genetic insertion of two glutamate residues in the PAS sequence of HFt-MP-PAS. Such new construct, named HFt-MP PASE, is characterized by improved performances as drug biodistribution in a xenogenic pancreatic cancer model in vivo. Moreover, HFt-MP-PASE efficiently encapsulates the anti-cancer drug mitoxantrone (MIT), and the resulting MIT loaded nanoparticles proved to be more soluble and monodispersed than the HFt-MP PAS counterparts. Importantly, in vitro MIT-loaded HFt-MP-PASE kills several cancer cell lines of different origin (colon, breast, sarcoma and pancreas) at least as efficiently as the free drug. Finally, our MIT loaded protein nanocages allowed in vivo an impressive incrementing of the drug accumulation in the tumor with respect to the free drug. PMID- 29474963 TI - Mass fabrication of uniform sized 3D tumor spheroid using high-throughput microfluidic system. AB - In vivo tumors develop in a three-dimensional manner and have unique and complex characteristics. Physico-biochemical barriers on tumors cause drug resistance and limit drug delivery efficiency. Currently, 2D cancer cell monolayer platforms are frequently used to test the efficiency of new drug materials. However, the monolayer platform generally overestimates drug efficiency because of the absence of physico-biochemical barriers. Many literatures indicated that a 3D tumor spheroid model has very similar characteristics to in vivo tumor models, and studies demonstrated the accurate prediction of drug efficiency using this model. The use of a 3D tumor spheroid model in drug development process remains challenging because of the low generation yield and difficulties in size control. In this study, we developed a droplet-based microfluidic system that can generate cancer cells encapsulated by micro-droplets with very high generation yield (16 20 Hz, 1000 droplets/min). The system can control the number of encapsulated cancer cells in the droplet or diameter of the 3D spheroid model precisely between 50 and 150 MUm. Moreover, the formed 3D tumor spheroid model can be cultured for >2 weeks by an additional step of droplet disruption and recollection, and can grow up to 245 MUm in diameter. PMID- 29474962 TI - In vitro and in vivo delivery of siRNA via VIPER polymer system to lung cells. AB - The block copolymer VIPER (virus-inspired polymer for endosomal release) has been reported to be a promising novel delivery system of DNA plasmids both in vitro and in vivo. VIPER is comprised of a polycation segment for condensation of nucleic acids as well as a pH-sensitive segment that exposes the membrane lytic peptide melittin in acidic environments to facilitate endosomal escape. The objective of this study was to investigate VIPER/siRNA polyplex characteristics, and compare their in vitro and in vivo performance with commercially available transfection reagents and a control version of VIPER lacking melittin. VIPER/siRNA polyplexes were formulated and characterized at various charge ratios and shown to be efficiently internalized in cultured cells. Target mRNA knockdown was confirmed by both flow cytometry and qRT-PCR and the kinetics of knockdown was monitored by live cell spinning disk microscopy, revealing knockdown starting by 4 h post-delivery. Intratracheal instillation of VIPER particles formulated with sequence specific siRNA to the lung of mice resulted in a significantly more efficient knockdown of GAPDH compared to treatment with VIPER particles formulated with scrambled sequence siRNA. We also demonstrated using pH-sensitive labels that VIPER particles experience less acidic environments compared to control polyplexes. In summary, VIPER/siRNA polyplexes efficiently deliver siRNA in vivo resulting in robust gene silencing (>75% knockdown) within the lung. PMID- 29474965 TI - GERD. PMID- 29474964 TI - Hypoxia-specific therapeutic agents delivery nanotheranostics: A sequential strategy for ultrasound mediated on-demand tritherapies and imaging of cancer. AB - The hypoxic microenvironment induced by sonodynamic therapy (SDT) via sonochemical oxygen consumption usually triggered tumor resistance to SDT, impeding therapeutic efficacy. In this sense, it was highly desired to tackle the hypoxia-related negative issues. Here we provide the therapeutic agents delivery system, TPZ/HMTNPs-SNO, which was constructed by loading tirapazamine (TPZ) into hollow mesoporous titanium dioxide nanoparticles (HMTNPs) with modification of S nitrosothiol (R-SNO). Upon encountering ultrasound waves, the HMTNPs as sonosensitizers would generate reactive oxygen species (ROS) for SDT. In a sequential manner, the followed SDT-induced hypoxia further activated the "hypoxic cytotoxin", TPZ, for hypoxia-specific killing effect. Meanwhile, the generated ROS could sensitize -SNO groups for on-demand nitric oxide (NO) release in an "anticancer therapeutic window", resulting in the NO sensitized SDT effect. This study confirmed that the TPZ/HMTNPs-SNO with multi-mechanisms exploited the merits of synergistic combination of the three therapeutic modes, consequently potentiating the anticancer efficacy of SDT. Moreover, the echogenic property of NO made the nanoplatform as an ultrasound contrast agent to enhance ultrasound imaging. In this sense, we developed a sequential strategy for ultrasound mediated all-in-one nanotheranostic platform of TPZ/HMTNPs-SNO, which highlighted new possibilities of advancing cancer theranostics in biomedical fields. PMID- 29474967 TI - A Patient With Rectal Schwannoma. PMID- 29474966 TI - Annual Burden and Costs of Hospitalization for High-Need, High-Cost Patients With Chronic Gastrointestinal and Liver Diseases. AB - BACKGROUND & AIMS: We estimated the annual burden and costs of hospitalization in patients with chronic gastrointestinal and liver diseases, and identified characteristics of high-need, high-cost patients, in a nationally representative sample. METHODS: Using Nationwide Readmissions Database 2013, we identified patients with at least 1 hospitalization between January and June 2013, and a diagnosis of inflammatory bowel diseases (IBDs), chronic liver diseases (CLDs), functional gastrointestinal disorders (FGIDs), gastrointestinal hemorrhage, or pancreatic diseases, with 6 months or more of follow up. We calculated days spent in hospital/month and estimated costs of the entire cohort, and identified characteristics of high-need, high-cost patients (top decile of days spent in hospital/month). RESULTS: Patients with IBD (n = 47,402), CLDs (n = 376,810), FGIDs (n = 351,583), gastrointestinal hemorrhage (n = 190,881), or pancreatic diseases (n = 98,432), hospitalized at least once, spent a median of 6 to 7 days (interquartile range, 3-14 d) in the hospital each year (total for all diseases). Compared to patients in the lowest decile (median, 0.13-0.14 d/mo spent in the hospital), patients in the highest decile spent a median 3.7-4.1 days/month in hospital (total for all diseases), with hospitalization costs ranging from $7502/month to $8925/month and 1 hospitalization every 2 months. Gastrointestinal diseases, infections, and cardiopulmonary causes were leading reasons for hospitalization of these patients. Based on multivariate logistic regression, high-need, high-cost patients were more likely to have Medicare/Medicaid insurance, lower income status, index hospitalization in a large rural hospital, high comorbidity burden, obesity, and infection-related hospitalization. CONCLUSIONS: In a nationwide database analysis of patients with IBD, CLD, FGID, gastrointestinal hemorrhage, or pancreatic diseases hospitalized at least once, we found that a small fraction of high-need, high-cost patients contribute disproportionately to hospitalization costs. Population health management directed toward these patients would facilitate high-value care. PMID- 29474968 TI - A String-Like Structure in the Center of Colonic Polypoid Lesion. PMID- 29474969 TI - Small-Bowel Solitary Peutz-Jeghers-Type Hamartomatous Polyp Treated With Endoscopic Polypectomy. PMID- 29474970 TI - Increased Incidence of Pseudoaneurysm Bleeding With Lumen-Apposing Metal Stents Compared to Double-Pigtail Plastic Stents in Patients With Peripancreatic Fluid Collections. AB - BACKGROUND & AIMS: There have been few studies that compared the effects of lumen apposing metal stents (LAMS) and double-pigtail plastic stents (DPS) in patients with peripancreatic fluid collections from pancreatitis. We aimed to compare technical and clinical success and adverse events in patients who received LAMS vs DPS for pancreatic pseudocysts and walled-off necrosis. METHODS: We performed a retrospective study of endoscopic ultrasound-mediated drainage in 149 patients (65% male; mean age, 47 y) with pancreatic pseudocysts or walled-off necrosis (97 received LAMS and 152 received DPS), from January 2011 through September 2016 at a single center. We collected data on patient characteristics, outcomes, hospitalizations, and imaging findings. Technical success was defined as LAMS insertion or a minimum of 2 DPS. Clinical success was defined as resolution of pancreatic pseudocysts or walled-off necrosis based on imaging results. The primary outcome was resolution of peripancreatic fluid collection with reduced abdominal pain or obstructive signs or symptoms. Secondary outcomes included the identification and management of adverse events, number of additional procedures required to resolve fluid collection, and the recurrence of fluid collection. RESULTS: Patients who received LAMS had larger peripancreatic fluid collections than patients who received DPS prior to intervention (P = .001), and underwent an average 1.7 interventions vs 1.9 interventions for patients who received DPS (P = .93). Technical success was achieved for 90 patients with LAMS (92.8%) vs 137 patients with DPS (90.1%) (odds ratio [OR] for success with DPS, 0.82; 95% CI, 0.33-2.0; P = .67). Despite larger fluid collections in the LAMS group, there was no significant difference in proportions of patients with clinical success following placement of LAMS (82 of 84 patients, 97.6%) vs DPS (118 of 122 patients, 96.7%) (OR for clinical success with DPS, 0.73; 95% CI, 0.13-4.0; P = .71). Adverse events developed in 24 patients who received LAMS (24.7%) vs 27 patients who received DPS (17.8%) (OR for an adverse event in a patient receiving a DPS, 0.82; 95% CI, 0.33-2.0; P = .67). However, patients with LAMS had a higher risk of pseudoaneurysm bleeding than patients with DPS (OR, 10.0; 95% CI, 1.19 84.6; P = .009). CONCLUSIONS: In a retrospective study of patients undergoing drainage of pancreatic pseudocysts or walled-off necrosis, we found LAMS and DPS to have comparable rates of technical and clinical success and adverse events. Drainage of walled-off necrosis or pancreatic pseudocysts using DPS was associated with fewer bleeding events overall, including pseudoaneurysm bleeding, but bleeding risk with LAMS should be weighed against the trend of higher actionable perforation and infection rates with DPS. PMID- 29474973 TI - Nonalcoholic Fatty Liver Disease and Mortality. PMID- 29474971 TI - Prediagnosis Use of Statins Associates With Increased Survival Times of Patients With Pancreatic Cancer. AB - BACKGROUND & AIMS: Statin medications, most commonly prescribed to reduce lipid levels and prevent cardiovascular disease, may be associated with longer survival times of patients with cancer. However, the association of statins with outcomes of patients with pancreatic adenocarcinoma is not clear. METHODS: We analyzed the association of statin use before a diagnosis of pancreatic cancer with survival times of 648 participants in the Nurses' Health Study and Health Professionals Follow-up Study who were diagnosed with pancreatic adenocarcinoma from 2000 through 2013. We estimated hazard ratios (HRs) for overall mortality using Cox proportional hazards models with adjustment for potential confounders. We assessed the temporal association between prediagnosis statin use and cancer survival by 2-year lag periods to account for a possible latency period between statin use and cancer survival. RESULTS: Regular statin use before diagnosis of pancreatic cancer was associated with modestly prolonged survival compared with nonregular use (adjusted HR, 0.82; 95% CI, 0.69-0.97; P = .02). A 1-month longer median survival was observed in regular statin users compared with nonregular users. Regular statin use within the 2 years prior to cancer diagnosis was most strongly associated with longer survival. We observed no statistically significant effect modification by smoking status, body mass index, diabetes, or cancer stage (all Pinteraction > .53). Regular statin use before diagnosis was similarly associated with survival in the Nurses' Health Study (HR, 0.79; 95% CI, 0.64-0.97) and Health Professionals Follow-up Study (HR, 0.86; 95% CI, 0.63 1.15). CONCLUSIONS: Regular statin use before diagnosis of pancreatic cancer was associated with modest increases in survival times in 2 large prospective cohort studies. PMID- 29474972 TI - Risk Factors for Fecal Urgency Among Individuals With and Without Diarrhea, Based on Data From the National Health and Nutrition Examination Survey. AB - BACKGROUND & AIMS: Fecal urgency is a common symptom among patients with gastrointestinal disorders, but can also occur in healthy individuals with normal bowel habits. There have been few studies of fecal urgency in the general population. We performed a cross-sectional analysis of data from the National Health and Nutrition Examination Survey (NHANES) to analyze the prevalence of and risk factors for this symptom. METHODS: We analyzed data from 4676 persons who completed the Bowel Health Questionnaire from the NHANES, from 2009 through 2010. The NHANES sampled a nationally representative group of adults in the United States and provides information on demographics, medical comorbidities, and dietary habits of survey participants. The Bowel Health Questionnaire provided additional information about bowel symptoms such as urgency, incontinence, constipation, and diarrhea. We identified individuals with fecal urgency and calculated differences in fecal urgency among subgroups using chi-squared analysis. We used logistic regression to identify factors associated with urgency. RESULTS: In our study population, the prevalence of fecal urgency was 3.3%; 29.5% of individuals with fecal urgency had diarrhea. The prevalence of fecal urgency was significantly higher in individuals who had diarrhea (14.8%) than in individuals without diarrhea (3.1%). Older age, female sex, poverty, urinary urge incontinence, diarrhea, and increased stool frequency were all associated with fecal urgency on multivariable analysis. Decreased fiber intake and increased carbohydrate intake were associated with urgency among individuals with diarrhea. CONCLUSIONS: In an analysis of data from 4676 individuals who completed a Bowel Health Questionnaire from the NHANES, we found a significantly higher proportion of individuals with diarrhea to have fecal urgency. However, most individuals with fecal urgency do not have diarrhea. Factors associated with fecal urgency vary among individuals with and without diarrhea. PMID- 29474974 TI - WITHDRAWN: Structural and biophysical insight into dual site binding of the protoberberine alkaloid palmatine to parallel G-quadruplex DNA using NMR, fluorescence and circular dichroism spectroscopy. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.biochi.2018.02.002. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal. PMID- 29474975 TI - Profile of CYP19A1 mRNA expression and aromatase activity during syncytialization of primary human villous trophoblast cells at term. AB - Estrogen production by the human villous trophoblast is dependent on the biosynthetic enzyme aromatase (CYP19; CYP19A1) and is crucial for successful placental development and pregnancy outcome. Using villous cytotrophoblast cells (vCTs) freshly isolated from normal term placenta, we characterized the promoter specific expression of CYP19A1 mRNA (derived from promoters I.1, I.4, I.8 or total transcript) and aromatase activity during villous trophoblast syncytialization. CYP19A1 mRNA levels and aromatase activity in vCTs reached a maximum after about 48 h of culture. The cAMP inducer forskolin (10 MUM) and protein kinase C stimulant phorbol myristate acetate (1 MUM) increased CYP19A1 mRNA levels by 1.8- and 1.6-fold, respectively, as well as inducing aromatase catalytic activity. Dexamethasone (100 nM) and vascular endothelial growth factor (5 ng/mL) decreased CYP19A1 mRNA levels, while having no effect on aromatase activity. Our results emphasize the importance of not solely studying CYP19A1 regulation and function at the mRNA level but also considering posttranslational mechanisms that alter the final catalytic activity of aromatase. PMID- 29474976 TI - Hidden diversity of forest birds in Madagascar revealed using integrative taxonomy. AB - Madagascar is renowned as a global biodiversity hotspot with high levels of microendemism. However, there are few molecular phylogenetic studies of Malagasy birds, particularly for forest-dwelling species, signifying a substantial gap in current measures of species diversity in the absence of genetic data. We evaluated species limits and explored patterns of diversification within the genus Newtonia (Family Vangidae), a group of forest-dwelling songbirds endemic to Madagascar. Our modern systematics approach combined genomic, morphometric, and ecological niche data to analyze the evolutionary history of the group. Our integrative analysis uncovered hidden species-level diversity within N. amphichroa, with two deeply divergent and morphologically distinct lineages isolated in different regions of humid forest. We describe the southern lineage as a new species. Conversely, N. brunneicauda, which we initially hypothesized may harbor cryptic diversity owing to its large distribution spanning a range of habitats, was found to have no distinct lineages and shared haplotypes across much of its distribution. The contrasting diversification patterns between Newtonia lineages may be the result of their elevational tolerances. Newtonia brunneicauda has a broad habitat tolerance and elevational range that appears to have facilitated population expansion and gene flow across the island, limiting opportunities for diversification. On the other hand, N. amphichroa is found predominantly in mid-elevation and montane humid forests, a restriction that appears to have promoted speciation associated with climatic fluctuations during the Pleistocene. Our findings indicate that species diversity of Malagasy forest dwelling birds may be greater than currently recognized, suggesting an urgent need for further studies to quantify biodiversity in Madagascar's rapidly disappearing native forests. PMID- 29474977 TI - Activated production of silent metabolites from marine-derived fungus Penicillium citrinum. AB - As an attempt to utilize of rare earth elements as a novel method to activate the silent genes in fungus, the marine-derived fungus Penicillium citrinum was cultured under ordinary laboratory fermentation conditions in the presence of scandium chloride (ScCl3, 50 MUM), and chemical investigation led to the isolation and characterization of three new peptide derivatives (1-3), along with four known pyrrolidine alkaloids (4-7). Those structures were elucidated by spectroscopic data interpretation, as well as chemical reactions. Comparative metabolic profiling of the culture extracts (with/without scandium chloride) indicated that compounds 1-3 scarcely detected in the absence of ScCl3. In addition, the antibacterial and cytotoxic activities of all isolated products were evaluated. PMID- 29474978 TI - Chiral resolution and anticancer effect of xanthones from Garcinia paucinervis. AB - Bioassay-guided fractionation of the dichloromethane-soluble portion of the stems of Garcinia paucinervis led to the isolation of eight new xanthones, including three pairs of enantiomers, (+) and (-) paucinervins L-N (1a-3a, and 1b-3b), one optically pure compound, (-) paucinervin O (4), and one new analogue, paucinervin P (5), as well as thirteen known xanthones (6-18). Their structures were established by detailed analysis of extensive spectroscopic data. The absolute configurations of 1-4 were confirmed by ECD calculations. All the isolates 1-18 displayed antiproliferative effect against HL-60 with IC50 values ranging from 0.87 to 29.14 MUM, of which compound 5 was the most active. Compounds 6, and 14 exhibited potential inhibitory activity against PC-3 cells, while compounds 5-7, 14, and 16-17 displayed cytotoxic potency against Caco-2 cells. A preliminary structure-activity relationship was also discussed. PMID- 29474980 TI - A case of dextrocardia following maternal exposure to generic Fingolimod during the first trimester of pregnancy. AB - Fingolimod, taken orally once per day, is approved for the treatment of relapsing remitting multiple sclerosis (MS). It should be stopped at least two months before conception as it is not considered safe during pregnancy or when breast feeding. In vitro and animal studies have found a possibly increased risk of congenital abnormalities following exposure to Fingolimod. Here, we report a 34 year-old female, with a 10-year history of MS who had unexpected pregnancy with exposure to generic Fingolimod during the first 7 weeks. The infant was born with dextrocardia, but without any further structural cardiac or other abnormalities. PMID- 29474979 TI - The influence of natural deep eutectic solvents on bioactive natural products: studying interactions between a hydrogel model and Schisandra chinensis metabolites. AB - Natural Deep Eutectic Solvent (NADES) species can exhibit unexpected solubilizing power for lipophilic molecules despite their simple composition: hydrophilic organic molecules and water. In the present study, the unique properties of NADES species were applied in combination with a model polymer system: a hydrophilic chitosan/alginate hydrogel. Briefly, NADES species (e.g., mannose-dimethylurea water, 2:5:5, mole/mole) formed matrices to 1) dissolve lipophilic molecules (e.g., curcumin), 2) load lipophilic molecule(s) into the hydrogel, and 3) spontaneously vacate from the system. NADES species ubiquitously occur in natural sources, and a crude extract is a mixture of the NADES species and bioactive metabolites. Based on these ideas, we hypothesized that the crude extract may also allow the loading of natural bioactive molecules from a natural NADES species into (bio)hydrogel systems. To evaluate this hypothesis in vitro, Schisandra chinensis fruit extract was chosen as a representative mixture of lipophilic botanical molecules and hydrophilic NADES species. The results showed that the NADES matrix of S. chinensis was capable of loading at least three bioactive lignans (i.e., gomisin A, gomisin J, and angeloylgomisin H) into the polymer system. The lipophilic metabolites can subsequently be released from the hydrogel. The outcomes suggest that a unique drug delivery mechanism may exist in nature, thereby potentially improving the bioavailability of lipophilic metabolites through physicochemical interactions with the NADES. PMID- 29474982 TI - Deciphering Elevated Microsatellite Alterations at Selected Tetra/Pentanucleotide Repeats, Microsatellite Instability, and Loss of Heterozygosity in Colorectal Cancers. AB - Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) are common in colorectal cancers (CRCs). The association between EMAST and classic mono/dinucleotide microsatellite instability (MSI) is unknown. We assessed the stability of 13 tetranucleotide and three pentanucleotide repeat markers in tumor and normal tissue from 22 MSI-high and 107 microsatellite-stable CRC samples. When present, instability was observed at tetra/pentanucleotide repeats and was defined as elevated microsatellite alterations at selected tetra/pentanucleotide repeats-high (EMASTP-H; >=30% instability), -low (EMASTP-L; <30% instability), or -stable (EMASTP-S). EMASTP instability, including high and low, was observed in 50 of 123 CRCs (41%), including all MSI-high tumors and 28 of 101 microsatellite-stable tumors (28%). MSI-high CRCs were more likely to be EMASTP-H compared with microsatellite-stable tumors with EMASTP instability. Tetranucleotide markers VWA and D13S317 were the two most frequently altered loci. Loss of heterozygosity was more common in EMASTP-L/S than in EMASTP-H CRCs. Frequencies of loss of heterozygosity at three loci were different between EMASTP L and EMASTP-S tumors. In addition, right-sided tumor site, large tumor size, high tumor grade, and the presence of Crohn-like reaction were significantly associated with EMASTP-H CRCs. However, there were no differences in clinicopathologic features between EMASTP-L and EMASTP-S tumors. In summary, more CRCs exhibited genomic instability as EMASTP than as MSI. EMASTP instability may prove to be an important prognostic/therapeutic indicator in CRCs. PMID- 29474983 TI - An In-Depth Evaluation of the Validity and Logistics Surrounding the Testing of AR-V7 mRNA Expression in Circulating Tumor Cells. AB - Recent reports have emphasized the clinical relevance of detecting AR-V7 in circulating tumor cells (CTCs). Our aim was to set up a validated multicenter pipeline to measure AR-V7 by quantitative RT-PCR (RT-qPCR) in RNA isolated from CellSearch-enriched CTCs to provide an AR-V7-positive or AR-V7-negative score in a clinically acceptable time range. CellSearch-enirched CTCs from patients with metastatic castration-resistant prostate cancer were characterized by RT-qPCR. After optimization, it was prospectively tested whether it was possible to report the AR-V7 status within 11 days (PRELUDE study). In the range of the RNA equivalent of 0.2 to 12 VCaP cells, the CV for AR-V7 was 9% (n = 37). The limit of detection was 0.3, and the limit of quantitation was 3 cells in the final RT qPCR. No differences were observed between AR-V7 data generated by five technicians or in two different laboratories. For the 45 patients in PRELUDE, 13 patients were ineligible, 22 patients were AR-V7 negative, and 10 were AR-V7 positive. The median time to inform the physician of the test result was 7 days (range, 2 to 11 days). This assay can establish the AR-V7 status in CTCs from patients with metastatic castration-resistant prostate cancer. Furthermore, it was possible to provide an AR-V7 outcome within 11 days, indicating that it may be used to choose between an anti-androgen receptor or taxane-based cabazitaxel treatment. PMID- 29474984 TI - Chimerism Analysis in the Pediatric Setting: Direct PCR from Bone Marrow, Whole Blood, and Cell Fractions. AB - Certain blood components and anticoagulants interfere with the PCR process and subsequent analysis. Here we demonstrate that reliable test results can be obtained for chimerism analysis despite omitting a DNA-extraction step and performing PCR and fragment analysis directly on bone marrow, whole blood, and individual cell fractions. For chimerism analysis, direct-tissue PCR is possible with the use of a robust, commercially available PCR mix containing a DNA polymerase capable of DNA amplification directly from the sample without the need for pretreatment. A total of 178 chimerism samples were processed directly, and results were compared to those obtained from the corresponding DNA sample. No differences were observed between the two sets of results. For the cell fraction purity assessment, commercially available PCR kits were used directly on T and B cells without the use of any additional lysing agent. A total of 53 purity samples and their corresponding DNA samples were analyzed and showed a correlation similar to that obtained for the chimerism samples. The results show that chimerism testing and associated cell fraction-purity assessment can be performed reliably without the need for prior DNA extraction and that this method can easily be integrated into existing routine laboratory procedures. PMID- 29474981 TI - Physiological functions of FBW7 in cancer and metabolism. AB - FBW7 is one of the most well characterized F-box proteins that serve as substrate recognition subunits of SCF (Skp1-Cullin 1-F-box proteins) E3 ubiquitin ligase complexes. SCFFBW7 plays key roles in regulating cell cycle progression, differentiation, and stem cell maintenance largely through targeting a broad range of oncogenic substrates for proteasome-dependent degradation. The identification of an increasing number of FBW7 substrates for ubiquitination, and intensive in vitro and in vivo studies have revealed a network of signaling components controlled by FBW7 that contributes to metabolic regulation as well as its tumor suppressor role. Here we mainly focus on recent findings that highlight a critical role for FBW7 in cancer and metabolism. PMID- 29474985 TI - Optimal Reference Gene Selection for Expression Studies in Human Reticulocytes. AB - Reference genes are indispensable for normalizing mRNA levels across samples in real-time quantitative PCR. Their expression levels vary under different experimental conditions and because of several inherent characteristics. Appropriate reference gene selection is thus critical for gene-expression studies. This study aimed at selecting optimal reference genes for gene expression analysis of reticulocytes and at validating them in hereditary spherocytosis (HS) and beta-thalassemia intermedia (betaTI) patients. Seven reference genes (PGK1, MPP1, HPRT1, ACTB, GAPDH, RN18S1, and SDHA) were selected because of published reports. Real-time quantitative PCR was performed on reticulocytes in 20 healthy volunteers, 15 HS patients, and 10 betaTI patients. Threshold cycle values were compared with fold-change method and RefFinder software. The stable reference genes recommended by RefFinder were validated with SLC4A1 and flow cytometric eosin-5'-maleimide binding assay values in HS patients and HBG2 and high performance liquid chromatography-derived percentage of hemoglobin F in betaTI. Comprehensive ranking predicted MPP1 and GAPDH as optimal reference genes for reticulocytes that were not affected in HS and betaTI. This was further confirmed on validation with eosin-5'-maleimide results and percentage of hemoglobin F in HS and betaTI patients, respectively. Hence, MPP1 and GAPDH are good reference genes for reticulocyte expression studies compared with ACTB and RN18S1, the two most commonly used reference genes. PMID- 29474986 TI - Recommendations for Clinical CYP2C19 Genotyping Allele Selection: A Report of the Association for Molecular Pathology. AB - This document was developed by the Pharmacogenomics (PGx) Working Group of the Association for Molecular Pathology Clinical Practice Committee, whose aim is to recommend variants for inclusion in clinical pharmacogenomic testing panels. The goals of the Association for Molecular Pathology PGx Working Group are to define the key attributes of PGx alleles recommended for clinical testing and to define a minimum set of variants that should be included in clinical PGx genotyping assays. These recommendations include a minimum panel of variant alleles (tier 1) and an extended panel of variant alleles (tier 2) that will aid clinical laboratories when designing PGx assays. The Working Group considered variant allele frequencies in different populations and ethnicities, the availability of reference materials, and other technical considerations for PGx testing when developing these recommendations. These CYP2C19 genotyping recommendations are the first of a series of recommendations for PGx testing. These recommendations are not to be interpreted as restrictive, but they are meant to provide a helpful guide. PMID- 29474987 TI - Organic and inorganic nano-Fe3O4: Alga Ulva flexuosa-based synthesis, antimicrobial effects and acute toxicity to briny water rotifer Brachionus rotundiformis. AB - Following the recent progress in magnetic nanotechnology, concern over the optimal benefits and potential risks of iron oxide nanoparticles (Fe NPs), has increased. Hence, to minimize the negative impacts of inorganic Fe NPs, we report the phyco-synthesis and characterization of superparamagnetic Fe3O4 NPs via reduction of ferric/ferrous chloride solution (2:1 M ratio; 88 degrees C) with green macroalga, Ulva flexuosa (wulfen) J.Agardh aqueous extract. The biogenic process is clean, eco-friendly, rapid, and facile to handle. These green fabricated magnetite NPs are characterized by Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), transmission electron microscopy (TEM), field emission scanning electron microscopy (FESEM), thermogravimetric analysis (TGA), particle size analysers (PSA), zeta potential (ZP) measurement, and vibrating sample magnetometry (VSM) techniques. The results confirmed that the cubo-spherical, polydisperse of biosynthesized Fe3O4 NPs with an average diameter of 12.3 nm was formed. The antagonistic effects of algal extract, chemo route and U. flexuosa-derived Fe3O4 MgNPs on selective human pathogenic microbes (i.e. n = 11) resulted in strong antibacterial and moderate antifungal activity. The comparative toxic and reproductive effects of the chemo- and bio-routes of Fe3O4-MgNPs against rotifer B. rotundiformis exhibited low acute toxicity with a lower inducing effect of biogenic nano-magnetite on reduction rotifer reproductive rate than its chemogenic counterpart. In view of the nanoecotoxicity, though the current study covered a wide range of exposure concentrations (10-500 mg/L) of organic and inorganic nano sizes of Fe3O4 in brackish water rotifer, a biotoxicity assay at higher dosage or a comprehensive risk assessment in different aqua-organisms is recommended. PMID- 29474988 TI - Changes of total and freely dissolved polycyclic aromatic hydrocarbons and toxicity of biochars treated with various aging processes. AB - The aim of this study was to determine the effect of biochar aging on the content of polycyclic aromatic hydrocarbons (PAHs) (the total content - Ctot, and the freely dissolved - Cfree) in biochar and its ecotoxicity. Two biochars (BCS and BCM) with varying properties were aged for 420 days at different temperatures ( 20 degrees C, 4 degrees C, 20 degrees C, 70 degrees C), at a variable temperature (-20/20 degrees C), in the presence of nutrients, and in the presence of inoculum and nutrients. After the aging process, Ctot and Cfree PAHs were determined in samples obtained and an ecotoxicological analysis was performed, which involved tests with bacteria (Vibrio fischeri), invertebrates (Folsomia candida) and plants (Lepidium sativum). Aging significantly affected all the parameters tested. The range of changes in the studied parameters depended on the type of biochar and ageing conditions. In the case of most of the aging methods, PAH content (Ctot, Cfree) and toxicity were found to decrease. Aging in the presence of microorganisms and nutrients and in the presence of nutrients alone caused the greatest reduction in Ctot PAH content (a reduction from 30 to 100% relative to non-aged biochar), Cfree PAH content (a reduction from 12 to 100%), root growth inhibition (a reduction from 73 to 90%), and luminescence inhibition (a reduction from 24 to 100%). In the case of Cfree PAHs and toxicity to F. candida, some aging methods caused their increase. The study also found a significant relationship between the changes in Ctot PAH content during aging and inhibition of root growth (BCS, BCM) and inhibition of V. fischerii luminescence (BCM). In no case was a significant correlation (P >= 0.05) between Cfree PAHs and the investigated toxicity parameters found. PMID- 29474990 TI - Estimation of stature from hand and foot dimensions in a Korean population. AB - The estimation of stature using foot and hand dimensions is essential in the process of personal identification. The shapes of feet and hands vary depending on races and gender, and it is of great importance to design an adequate equation in consideration of variances to estimate stature. This study is based on a total of 5,195 South Korean males and females, aged from 20 to 59 years. Body dimensions of stature, hand length, hand breadth, foot length, and foot breadth were measured according to standard anthropometric procedures. The independent t test was performed in order to verify significant gender-induced differences and the results showed that there was significant difference between males and females for all the foot-hand dimensions (p<0.01). All dimensions showed a positive and statistically significant relation with stature in both genders (p<0.01). For both genders, the foot length showed highest correlation, whereas the hand breadth showed least correlation. The stepwise regression analysis was conducted, and the results showed that males had the highest prediction accuracy in the regression equation consisting of foot length and hand length (R2=0.532), whereas females had the highest accuracy in the regression model consisting of foot length and hand breadth (R2=0.437) The findings of this study indicated that hand and foot dimensions can be used to predict the stature of South Korean in the forensic science field. PMID- 29474989 TI - Proportion of adult community-acquired pneumonia cases attributable to Streptococcus pneumoniae among Hajj pilgrims in 2016. AB - BACKGROUND: The Hajj mass gathering is a risk for pneumococcal disease. This study was performed to evaluate the proportion of adult community-acquired pneumonia (CAP) cases attributable to Streptococcus pneumoniae among Hajj pilgrims in 2016. To add sensitivity to etiological attribution, a urine antigen test was used in addition to culture-based methods. METHODS: Adult subjects hospitalized with X-ray-confirmed CAP were enrolled prospectively from all general hospitals designated to treat Hajj pilgrims in the holy cities of Mecca and Medina. Patients were treated according to local standard of care and administered the BinaxNow S. pneumoniae urine antigen test. RESULTS: From August 23 to September 23, 2016, a total of 266 patients with CAP were enrolled in the study, 70.6% of whom were admitted to hospitals in Mecca; 53% of the cases were admitted after the peak of Hajj. Patients originated from 43 countries. Their mean age was 65.3 years and the male to female ratio was 2:1. Just over 36% of the cases had diabetes, 10% declared that they were smokers, and 45.4% of cases were treated in the intensive care unit (ICU). The overall case-fatality rate was 10.1%, but was higher among those treated in the ICU and in those with invasive disease. The proportion of CAP cases positive for S. pneumoniae, based on culture or urine antigen test, was 18.0% (95% confidence interval 13.9-23.1%). CONCLUSIONS: CAP during Hajj has an important clinical impact. A proportion of CAP cases among Hajj pilgrims were attributable to S. pneumoniae, a pathogen for which vaccines are available. Additional studies to determine the serotypes causing pneumococcal disease could further inform vaccine policy for Hajj pilgrims. PMID- 29474991 TI - Endocrine therapy and palbociclib within a compassionate use program in heavily pretreated hormone receptor-positive, HER2-negative metastatic breast cancer. AB - This is a single center retrospective analysis of patients with hormone receptor positive, HER2-negative metastatic breast cancer progressing after >= 4 treatment lines treated with palbociclib in combination with endocrine therapy within a compassionate use program. Thirty-four patients were included between 10/2015 and 02/2017, the majority (82.4%) being previously treated with mTOR inhibitors. Disease control rate was 52.9% and 24.4% at week 12 and 24. Overall progression free survival was 3.1 months with no difference between mTOR inhibitor-pretreated (3.5 months) and -naive patients (2.7 months; hazard ratio, 0.83). Toxicity profile in this population was comparable to that seen in previous trials. PMID- 29474992 TI - Anatomical total shoulder arthroplasty used for glenohumeral osteoarthritis has higher survival rates than hemiarthroplasty: a Nordic registry-based study. AB - OBJECTIVE: To report the10-year survival rates of different shoulder arthroplasty types used for glenohumeral osteoarthritis. DESIGN: Data from 2004 to 2013 was prospectively collected by the national shoulder arthroplasty registers in Denmark, Norway and Sweden and merged into a harmonized dataset under the umbrella of the Nordic Arthroplasty Register Association. The common dataset included data that all three registers could deliver and where consensus regarding definitions could be made. Revision was defined as removal or exchange of any component or the addition of a glenoid component. RESULTS: The cumulative survival rates at 10 years after resurfacing hemiarthroplasty (RHA) (n = 1,923), stemmed hemiarthroplasty (SHA) (n = 1,587) and anatomical total shoulder arthroplasty (TSA) (n = 2,340) were 0.85, 0.93 and 0.96 respectively (P < 0.001, Log rank test). RHA (HR: 2.5; CI 1.9-3.4, P < 0.001) and SHA (HR: 1.4; CI 1.0 2.0, P < 0.04) had an increased risk of revision compared to TSA. Gender, age and period of surgery were included in the Cox regression model. For patients below 55 years, the 10-year cumulative survival rates were 0.75 (RHA, n = 354), 0.81 (SHA, n = 146), and 0.87 (TSA, n = 201). CONCLUSIONS: Anatomical TSA had the highest implant-survival rate. Young patients had, independently of the arthroplasty type, lower implant-survival rates. The treatment of young patients with end-stage osteoarthritis remains a challenge. PMID- 29474993 TI - Biomechanical changes and recovery of gait function after total hip arthroplasty for osteoarthritis: a systematic review and meta-analysis. AB - OBJECTIVE: To determine the change in walking gait biomechanics after total hip arthroplasty (THA) for osteoarthritis (OA) compared to the pre-operative gait status, and to compare the recovery of gait following THA with healthy individuals. METHODS: Systematic review with meta-analysis of studies investigating changes in gait biomechanics after THA compared to (1) preoperative levels and (2) healthy individuals. Data were pooled at commonly reported time points and standardised mean differences (SMDs) were calculated in meta-analyses for spatiotemporal, kinematic and kinetic parameters. RESULTS: Seventy-four studies with a total of 2,477 patients were included. At 6 weeks postoperative, increases were evident for walking speed (SMD: 0.32, 95% confidence intervals (CI) 0.14, 0.50), stride length (SMD: 0.40, 95% CI 0.19, 0.61), step length (SMD: 0.41, 95% CI 0.23, 0.59), and transverse plane hip range of motion (ROM) (SMD: 0.36, 95% CI 0.05, 0.67) compared to pre-operative gait. Sagittal, coronal and transverse hip ROM was significantly increased at 3 months (SMDs: 0.50 to 1.07). At 12 months postoperative, patients demonstrated deficits compared with healthy individuals for walking speed (SMD: -0.59, 95% CI -1.08 to -0.11), stride length (SMD: -1.27, 95% CI -1.63, -0.91), single limb support time (SMD: -0.82, 95% CI 1.23, -0.41) and sagittal plane hip ROM (SMD: -1.16, 95% CI -1.83, -0.49). Risk of bias scores ranged from seven to 24 out of 26. CONCLUSIONS: Following THA for OA, early improvements were demonstrated for spatiotemporal and kinematic gait patterns compared to the pre-operative levels. Deficits were still observed in THA patients compared to healthy individuals at 12 months. PMID- 29474994 TI - The association between ambulatory activity, body composition and hip or knee joint replacement due to osteoarthritis: a prospective cohort study. AB - OBJECTIVE: To examine the association between ambulatory activity (AA), body composition measures and hip or knee joint replacement (JR) due to osteoarthritis. DESIGN: At baseline, 1082 community-dwelling older-adults aged 50 80 years were studied. AA was measured objectively using pedometer and body composition by dual-energy X-ray absorptiometry. The incidence of primary (first time) JR was determined by data linkage to the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR). Log binomial regression with generalized estimating equations were used to estimate the risk of JR associated with baseline AA and body composition measures, adjusting for age, sex, X-ray disease severity, and pain. RESULTS: Over 13 years of follow-up, 74 (6.8%) participants had a knee replacement (KR) and 50 (4.7%) a hip replacement (HR). AA was associated with a higher risk of KR (RR 1.09/1000 steps/day, 95% CI 1.01, 1.16) and a lower risk of HR (RR 0.90/1000 steps/day, 95% CI 0.81, 0.99). Body mass index (BMI) (RR 1.07/kg/m2, 95% CI 1.03, 1.12), total fat mass (RR 1.03/kg, 95% CI 1.01, 1.06), trunk fat mass (RR 1.05/kg, 95% CI 1.00, 1.09), and waist circumference (RR 1.02/cm, 95% CI 1.00, 1.04) were associated with a higher risk of KR. Body composition measures were not associated with HR. CONCLUSIONS: An objective measure of AA was associated with a small increased risk of KR and a small reduced risk of HR. Worse body composition profiles were associated with KR, but not HR. Altogether this may suggest different causal pathways for each site with regard to habitual activity and obesity. PMID- 29474996 TI - Considerations for Exercise Prescription in Patients With Bone Metastases: A Comprehensive Narrative Review. AB - : Metastatic disease is a frequent complication of advanced cancer, with bone representing one of the most common sites of metastatic occurrence. Patients with bone metastases receive long-term systemic treatments that have a significant attritional impact on muscle strength, fatigue, and physical functioning. Physical rehabilitation involving exercise and physical activity prescription has a considerable role in counteracting these changes; however, exercise is often perceived as a contraindication in the presence of bone metastases due to concerns about aggravating skeletal related events. This article examines the physical sequelae of bone metastases and outlines the factors for consideration with exercise prescription in metastatic bone disease, including bone health, pain levels, and oncologic treatment. This article includes a comprehensive review of the evidence from trials of exercise prescription in this population, including the efficacy and safety outcomes of exercise interventions. Exercise interventions for patients with bone metastases are associated with positive physical and self-reported outcomes. Studies reviewed reporting adverse events did not find a high fracture incidence with exercise in comparison with control participants, or an association between exercise and fracture risk. The need to individualize exercise prescription and adapt exercises to patient ability were reinforced in all papers reviewed. Exercise prescription to patients with bone metastases does involve complex decision making; however, a number of tools are available that may inform both the assessment of patients and the prescription of exercise. LEVEL OF EVIDENCE: NA. PMID- 29474995 TI - Evaluation of Performance-Based Outcome Measures for the Upper Limb: A Comprehensive Narrative Review. AB - : Objective performance-based outcome measures (OMs) have the potential to provide unbiased and reproducible assessments of limb function. However, very few of these performance-based OMs have been validated for upper limb (UL) prosthesis users. OMs validated in other clinical populations (eg, neurologic or musculoskeletal conditions) could be used to fill gaps in existing performance based OMs for UL amputees. Additionally, a joint review might reveal consistent gaps across multiple clinical populations. Therefore, the objective of this review was to systematically characterize prominent measures used in both sets of clinical populations with regard to (1) location of task performance around the body, (2) possible grips employed, (3) bilateral versus unilateral task participation, and (4) details of scoring mechanisms. A systematic literature search was conducted in EMBASE, Medline, and Cumulative Index to Nursing and Allied Health electronic databases for variations of the following terms: stroke, musculoskeletal dysfunction, amputation, prosthesis, upper limb, outcome, assessments. Articles were included if they described performance-based OMs developed for disabilities of the UL. Results show most tasks were performed with 1 hand in the space directly in front of the participant. The tip, tripod, and cylindrical grips were most commonly used for the specific tasks. Few measures assessed sensation and movement quality. Overall, several limitations in OMs were identified. The solution to these limitations may be to modify and validate existing measures originally developed for other clinical populations as first steps to more aptly measure prosthesis use while more complete assessments for UL prosthesis users are being developed. LEVEL OF EVIDENCE: Level III. PMID- 29474997 TI - Footwear-Generated Dynamic Biomechanical Manipulation and Perturbation Training for Chronic Nonspecific Low Back Pain. AB - BACKGROUND: Home-based therapy optimizing biomechanics and neuromuscular control is increasingly recognized as a treatment option for chronic nonspecific low back pain (CNSLBP). However, its impact on pain, function, and gait is limited among patients in a metropolitan area. OBJECTIVE: To evaluate the change of pain, function, and gait parameters with home-based therapy with the use of footwear generated biomechanical manipulation and perturbation training in a population with CNSLBP in a metropolitan area. DESIGN: Prospective observational study. SETTING: Outpatient rehabilitation clinic at an academic teaching hospital. PARTICIPANTS: One hundred sixteen patients with CNSLBP for more than 6 months. INTERVENTION: Six months of home-based therapy with a biomechanical device using 4 modular elements attached to a foot-worn platform. MAIN OUTCOME MEASURES: Instrumental gait analysis (gait velocity, step length, single limb support phase % of gait cycle), Numeric Rating Scale for pain, and Oswestry Disability Questionnaire Index for pain and function. RESULTS: Only 43 patients (37.1%) completed the study. Among 43 patients, mean gait velocity increased from 86.6 +/ 20.7 to 99.7 +/- 22.1 cm/s (P < .0001) in 6 months. Mean left step length increased from 51.1 +/- 8.4 to 54.8 +/- 9.8 cm (P < .0001). Mean right step length increased from 51.0 +/- 7.9 to 55.4 +/- 9.0 cm (P < .0001). Mean single limb support increased from 36.4 +/- 2.8 to 37.2 +/- 2.5%, (P = .208) in the right side and from 36.6 +/- 3.0 to 37.8 +/- 4.4%, (P = .019) in the left side. Median Oswestry Disability Questionnaire Index score improved from 28 (18-44; interquartile range) to 17 (10-35) (P = .045). Mean Numeric Rating Scale for back pain improved from 7.7 +/- 1.8 to 3.3 +/- 3.1 (P < .0001). CONCLUSION: At 6 months, patients with CNSLBP undergoing home-based therapy with footwear generated biomechanical manipulation and perturbation training demonstrated significant improvement of objective gait parameters, pain, and function. LEVEL OF EVIDENCE: IV. PMID- 29474998 TI - Anthropometric Prediction of Visceral Adipose Tissue in Persons With Motor Complete Spinal Cord Injury. AB - BACKGROUND: Spinal cord injury (SCI) results in increased accumulation of visceral adipose tissue (VAT). Anthropometrics may provide an alternative to estimate VAT cross-section area (CSA) compared to magnetic resonance imaging (MRI). OBJECTIVE: To validate the use of anthropometrics, including abdominal circumference and skinfold thickness (SFT) measurements against MRI to predict subcutaneous adipose tissue (SAT) and VAT cross-sectional areas in persons with SCI. DESIGN: Cross-sectional. SETTING: Clinical research center PARTICIPANT: Twenty-two men with motor complete SCI METHODS: Anthropometric measurements and MRI were taken during a single visit. Abdominal circumference and SFT were used to derive prediction equations for subcutaneous adipose tissue (SATAnthro-CSA) and VAT (VATAnthro-CSA). Three-axial MRI at the level of umbilicus was used to establish the prediction equations. VATAnthro-CSA was compared against body mass index (BMI), waist circumference, and SFT. Bland-Altman plots were used to determine limits of agreement between prediction equations and MRI. MAIN OUTCOME MEASUREMENTS: SAT and VAT cross-sectional areas. RESULTS: SATAnthro-CSA explained 76% of the variance in SAT cross-sectional area (r2 = 0.76, standard error of the estimate [SEE] = 49.5 cm2, P <.001). VATAnthro-CSA explained 72% of VAT cross sectional area (r2 = 0.72, SEE = 45.8 cm2, P <.001). Compared to VATAnthro-CSA, BMI, waist circumference, and SFT explained only 37%, 63%, and 31%, respectively, in the variance of VAT MRI. CONCLUSION: Abdominal circumference and SFT demonstrated an alternative way to predict VAT CSA. VATAnthro-CSA estimated VATMRI more accurately than BMI, waist circumference, and SFT in individuals with chronic SCI. LEVEL OF EVIDENCE: I. PMID- 29474999 TI - Serum metabolomics study in a group of Parkinson's disease patients from northern India. AB - BACKGROUND: Parkinson's disease (PD) is the result of progressive degeneration of the nigrostriatal dopaminergic pathway and depletion of neurotransmitter dopamine in the striatum. METHODS: We included 17 patients with PD along with 7 patients of progressive supranuclear palsy (PSP), 6 patients of multiple system atrophy (MSA) and 22 age and sex-matched healthy controls. We analyzed metabolite profiles in the serum of these patients and controls using 1H NMR spectroscopy. RESULTS: Isoleucine, valine, alanine, glutamine and histidine in PD, PSP and MSA were significantly (P < 0.001) higher than controls, whereas, glutamate and glucose were significantly increased in PD (P < 0.001), PSP and MSA (P < 0.05) vs. CONTROL: Citrate was increased in PD, PSP and MSA (P < 0.05) vs. CONTROL: While, acetone, lactate and formate were higher at P < 0.001, threonine is increased at P < 0.05. The 3D scattered score plot of OPLS-DA model revealed clear differentiation among the groups, R2 = 0.92 and Q2 = 0.78. CONCLUSION: Significant differences in various metabolite levels were found between control and disease groups. Common amino acids that are significantly higher in all groups include branched chain amino acids, which could increase neuronal excitability. PMID- 29475000 TI - Quantitation of 25-hydroxyvitamin D in dried blood spots by 2D LC-MS/MS without derivatization and correlation with serum in adult and pediatric studies. AB - BACKGROUND: Demand for measurement of 25-hydroxyvitamin D (25OHD) is growing and dried blood spot (DBS) sampling is attractive as samples are easier to collect, transport and store. METHODS: A 2D LC-MS/MS assay without derivatization was developed. DBS punches (3.2 mm) were ultrasonicated with d6-25OHD3 in 70% methanol followed by hexane extraction, dry-down and reconstitution. The assay was validated and applied to two studies comparing whole blood adult DBS with serum samples (n = 40) and neonatal whole blood DBS with cord serum samples (n = 80). RESULTS: The assay was validated in whole blood DBS over the range 13-106 nmol/L 25OHD3 and 11-91 nmol/L 25OHD2 with a limit of detection of 3 nmol/L. Intra- and inter-day imprecision was <13% CV and bias <12%. The assay had high recovery and minimal matrix effects. Triplicate DBS study samples had a mean CV of <=13% for 25OHD3. No 25OHD2 was detected. DBS calculated serum 25OHD3 concentrations correlated strongly with serum concentrations in the adult DBS/serum study (r = 0.94) and moderately in the neonatal DBS/cord serum study (r = 0.69). CONCLUSIONS: Direct quantitation of 25OHD in DBS by 2D LC-MS/MS without derivatization was found to be an alternative to serum quantitation applicable to clinical research studies on adult DBS samples. PMID- 29475001 TI - Regulation of Tak1 alternative splicing by splice-switching oligonucleotides. AB - Alternative splicing (AS) generates multiple isoforms from a single precursor mRNA, and these isoforms usually exhibit different tissue distributions and functions. Aberrant protein isoforms can lead to abnormalities in protein function and may even result in genetic disorders or cancer. In recent years, splice-switching oligonucleotides (SSOs) have emerged as a promising therapeutic strategy for several neurological diseases, but the efficacy of this strategy in other organs is less reported. In this study, we designed and synthesized SSOs targeting the splicing regulators of exon 12 of the Tak1 gene, inducing variant switching between Tak1-A and Tak1-B. We also designed SSOs capable of knockdown both Tak1 variants by inducing the aberrant splicing of exon 4. The Vivo morpholino SSOs showed significant splice-switching of Tak1 in mouse liver, with a persistence of at least 10 days after initial SSOs delivery. Bioinformatics analysis indicated a lipid metabolism-related function for Tak1-B but not Tak1-A. The conversion of Tak1-B to Tak1-A consistently led to significant accumulation of lipids in cultured AML12 cells, as well as the dysregulation of several lipid metabolism-related genes in mouse liver. Different functional properties of the two isoforms may explain the conflicting functions previously reported for Tak1. In conclusion, our research clarified the different functions of Tak1 isoforms, and provided an efficient strategy for the functional research of the AS isoforms. PMID- 29475002 TI - Celastrol pretreatment attenuates rat myocardial ischemia/ reperfusion injury by inhibiting high mobility group box 1 protein expression via the PI3K/Akt pathway. AB - BACKGROUND/AIMS: Celastrol pretreatment has been shown to protect against myocardial ischemia/reperfusion (I/R) injury, but the underlying mechanism is poorly understood. This study aimed to investigate the cardioprotective effects of celastrol pretreatment on I/R injury and to further explore whether its mechanism of action was associated with the inhibition of high mobility group box 1 protein (HMGB1) expression via the phosphoinositide 3-kinase (PI3K)/Akt pathway. METHODS: In a fixed-dose study, hematoxylin and eosin staining and myocardial enzyme measurements were used to determine the optimal dose of celastrol that elicited the best cardioprotective effects against I/R injury. Furthermore, rats were pretreated with 4 mg/kg celastrol, and infarct size and the levels of myocardial enzymes, apoptosis, inflammatory and oxidative indices, and HMGB1 and p-Akt expression were measured. RESULTS: Our results indicated that celastrol dose-dependently attenuated histopathological changes and the elevation in myocardial enzymes induced by I/R. Moreover, the celastrol pretreatment (4 mg/kg) not only significantly decreased infarct size as well as myocardial enzyme levels but also inhibited myocardial apoptosis, inflammatory response and oxidative stress. Additionally, celastrol downregulated HMGB1 expression and upregulated p-Akt expression in the myocardium. LY294002, a specific pI3k inhibitor, partially reversed the decreased HMGB1 expression, increased p-Akt expression induced by celastrol, and abolished the anti-apoptotic, anti inflammatory and anti-oxidative effects of celastrol. CONCLUSION: These findings suggest that short-term pretreatment with celastrol protects against myocardial I/R injury by suppressing myocardial apoptosis, inflammatory response and oxidative stress via pI3k/Akt pathway activation and HMGB1 inhibition. PMID- 29475003 TI - Neuropathic Pain models caused by damage to central or peripheral nervous system. AB - Neuropathic Pain (NP) is a painful condition which is a direct consequence of a lesion or disease affecting the somatosensory system with symptoms like allodynia, hyperalgesia. It has complex pathogenesis as it involves several molecular signaling pathways, thus numerous reliable animal models are crucial to understand the underlying mechanism of NP and formulate effective management therapy. Some models like spinal cord injury, chronic constriction injury, spinal nerve ligation, chemotherapy induced peripheral neuropathy, diabetes-induced NP and many more are discussed. This review contains an overview of the procedures followed to induce neuropathy and specific characteristics of that particular model. Some new techniques like spared nerve ligation, have omitted the limitation of methods not presently used where complete nerve damage occurs. Since animal models provide a window to experienced symptoms and physiology and impact the translation of bench discoveries to the bedside, the reporting, interpretation and comparison of these models is necessary because slight variation in procedure of model generation can drastically alter the results. The development of novel, but rational analgesic drugs to alleviate this intractable pain demands elucidation of molecular mechanisms of NP for which different types of animal models have been established. PMID- 29475004 TI - Novel compounds targeting InhA for TB therapy. AB - Tuberculosis (TB) is described as lethal disease in the world. Resistant to TB drugs is the main reason to have unfavourable outcomes in the treatment of TB. Therefore, new agents to replace existing drugs are urgently needed. Previous reports suggested that InhA inhibitors, an enoyl-ACP-reductase, might provide auspicious candidates which can be developed into novel antitubercular agents. In this review, we explain the role of InhA in the resistance of isoniazid. Furthermore, five classes of InhA inhibitors, which display novel binding modes and deliver evidence of their prosperous target engagement, have been debated. PMID- 29475005 TI - The effect of bromocriptine treatment on sexual functioning and depressive symptoms in women with mild hyperprolactinemia. AB - BACKGROUND: Elevated prolactin levels are associated with sexual dysfunction in women. No previous study has investigated the effect of dopamine agonists on sexual functioning in women. METHODS: The study enrolled 30 young women with mild hyperprolactinemia (serum prolactin levels in the range between 25 and 50ng/mL), 15 of whom were later treated with bromocriptine (5-10mg daily), as well as 14 age- and weight-matched healthy women. All women completed a questionnaire evaluating female sexual function (Female Sexual Function Index - FSFI) and a questionnaire evaluating the presence and severity of depressive symptoms (Beck Depression Inventory Second Edition - BDI-II). RESULTS: Women with mild hyperprolactinemia had a lower total FSFI score, lower scores in all domains of sexual functioning (desire, arousal, lubrication, and dyspareunia), as well as a lower total BDI-II score than control women. Bromocriptine increased the FSFI score and tended to reduce BDI-II score. Moreover, the drug normalized desire, arousal, lubrication and dyspareunia, as well as improved orgasm and sexual satisfaction and this action correlated with changes in prolactin levels and an improvement in insulin sensitivity. No changes in sexual functioning and depressive symptoms were observed in untreated women with mild hyperprolactinemia and healthy controls. CONCLUSIONS: Bromocriptine treatment improves female sexual functioning and slightly affects depressive symptoms in women with elevated prolactin levels and this effect is related to its prolactin-lowering and metabolic effects. PMID- 29475006 TI - Glutamine up-regulates pancreatic sodium-dependent neutral aminoacid transporter 2 and mitigates islets apoptosis in diabetic rats. AB - BACKGROUND: Glutamine aminoacid regulates insulin exocytosis from pancreatic beta cells. Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue that has fascinated function in inhibiting beta-cell apoptosis and preserving pancreatic beta-cell mass. The present study investigated the benefit of adding glutamine to a regimen of liraglutide in diabetic rats focusing on their role in increasing insulin production and upregulation of the expression of sodium-dependent neutral aminoacid transporter-2 (SNAT2). METHODS: In the present study, diabetes mellitus was induced in rats using streptozotocin (STZ, 50mg/kg, ip). Male rats were allocated into 5 groups, (i) vehicle group, (ii) STZ-diabetic rats, (iii) STZ diabetic rats treated with liraglutide (150MUg/kg, sc), (iv) STZ-diabetic rats treated with glutamine (po) and (v) STZ-diabetic rats treated with a combination of liraglutide and glutamine for four weeks. After finishing the therapeutic courses, the fasting blood glucose value was determined and rats were sacrificed. Pancreases were used for quantification of mRNA expression for SNAT2. Paraffin fixed samples were used for histologic staining and immunohistochemistry for insulin and apoptosis markers (activated caspase-3, BCL2 and BAX). RESULTS: Treatment with liraglutide and/or glutamine enhanced insulin production and hence glycemic control in diabetic male rats with favorable effects on apoptosis markers. Treatment with glutamine and its combination with liraglutide significantly increased pancreatic expression of SNAT2 by approximately 30-35 folds. CONCLUSION: Addition of glutamine to liraglutide regimen enhances the glycemic control and may have utility in clinical settings. PMID- 29475008 TI - Comparison of the effects of rosuvastatin monotherapy and atorvastatin-ezetimibe combined therapy on the structure of erythrocyte membranes in patients with coronary artery disease. AB - BACKGROUND: Abnormalities in the physical properties of the red blood cells (RBCs) membranes may underlie the defects that are strongly linked to cardiovascular diseases (CVD). The aim of the study was to compare the effects of two therapies of equal hipolipemic efficacy on the erythrocyte membrane fluidity, concentration of membrane cholesterol, lipids peroxidation and RBCs distribution witdh in patients with CVD. METHODS: The study included 44 patients with angiographic evidence of CVD, who despite previous 6-month hypolipemic therapy, did not achieve the concentration of LDL-C <70mg/dl. They were randomly assigned to: rosuvastatin 20mg/day (R20) and atorvastatin 10mg/day combined with ezetimibe 10mg/day (A10+E10). The membrane fluidity, the concentration of thiobarbituric acid reactive substances -TBARS, concentration of membrane cholesterol were evaluated after 6 months therapy. RESULTS: An improvement in lipid parameters was observed in each of the groups studied. In R20 the treatment resulted in 33% reduction concentrations of TBARS in serum, as well as in a decrease in membrane cholesterol by 16%, fluorescence anisotropy of TMA-DPH by 17.7%, fluorescence anisotropy of DPH by 2.8%. In A10+E10 the reduction of TBARS by 20.5% in serum, membrane cholesterol by 15.8% as well as a 14.25% increase in RBC membrane fluidity in the superficial layer (TMA-DPH) and decrease fluidity in the deep layer (DPH) were observed. CONCLUSION: Rosuvastatin increases the fluidity of erythrocyte membrane and decreases the TBARS in serum to greater extent than does equal hipolipemic combined therapy atorvastatin with ezetimibe. PMID- 29475007 TI - P-gp is involved in the intestinal absorption and biliary excretion of afatinib in vitro and in rats. AB - BACKGROUND: Afatinib is an irreversible multi-targeted TKI, used in the treatment with EGFR mutated non-small cell lung cancer (NSCLC). The purpose of this study is to explore the molecular pharmacokinetic mechanism underlying the effect of P gp inhibitors on the intestinal absorption and biliary excretion and to understand how P-gp inhibitors affect afatinib pharmacokinetics. METHODS: Pharmacokinetics in vivo, in situ intestinal perfusion, perfused rat liver in situ, Caco-2 cells, P-gp ATPase activity, sandwich-cultured rat hepatocytes (SCRH) and transfected-cell transport were used in the evaluation. RESULTS: P-gp inhibitor verapamil (Ver) markedly increased the plasma concentrations and significantly decreased the biliary excretion of afatinib in vivo. Ver increased the intestinal absorption and decreased biliary excretion of afatinib in situ single-pass intestinal perfusion studies and in situ perfused rat liver, respectively. The accumulation of afatinib in Caco-2 cells was enhanced by Ver and Cyclosporin A (CsA). The biliary excretion index (BEI) of afatinib in SCRH was decreased by Ver and CsA, respectively. The net efflux ratio of afatinib was 2.3 across vector-/MDR1-MDCKII cell monolayers and was decreased by P-gp inhibitor. The activity of P-gp ATPase was induced by afatinib and the Km and Vmax were 1.05MUM and 59.88nmol ATP/mg hP-gp/min, respectively. CONCLUSION: At least partly P-gp is involved in increasing the intestinal absorption and decreasing the biliary excretion of afatinib in rats. PMID- 29475009 TI - Effects of lipoic acid and n-3 long-chain polyunsaturated fatty acid on the liver ovariectomized rat model of menopause. AB - BACKGROUND: Bilateral ovariectomy is an experimental model used to analyse the effects of menopause and develop strategies to mitigate the deleterious effects of this condition. Supplementation of the diet with antioxidants has been used to reduce potential oxidative stress caused by menopause. The purpose of the study was to analyse the effects of alpha-lipoic acid (LA), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), dietary supplementation on oxidative stress in the livers of ovariectomized rats. METHODS: In this study, we evaluated the effect of dietary supplementation with LA, DHA and EPA for a period of 16 weeks on oestrogen levels and oxidative stress biomarkers in the livers of ovariectomized 25 three-month-old rats. RESULTS: Serum oestrogen levels were lower after ovariectomy but were not altered by dietary treatments. LA was capable of acting in the liver, recovering the activity of the antioxidant enzymes superoxide dismutase and glutathione peroxidase, and reducing protein oxidative damage. Moreover, LA supplementation reduced nitrite and nitrate levels. DHA and EPA recovered the antioxidant activity of cytosolic and mitochondrial superoxide dismutase, decreasing protein oxidation. Protection against lipid oxidation differed between treatments. The DHA-treated group showed increased levels of the lipid peroxidation biomarker malondialdehyde compared to the ovariectomized group. However, malondialdehyde levels were not altered by EPA treatment. CONCLUSIONS: The results suggest that the antioxidant response varies among evaluated supplementations and all supplements were able to alter enzymatic and non-enzymatic antioxidants in the livers of ovariectomized rats. DHA presented the most evident antioxidant effect, decreasing protein and lipid damage. PMID- 29475011 TI - The Cranky Thermometers: Visual analogue scales measuring irritability in youth. AB - This study assessed the psychometric properties of two visual analogue scales of irritability, known as the Cranky Thermometers (CT), in both an Australian community secondary-school sample (N = 164) and a sample of adolescents with a depressive disorder (N = 127). The first scale Cranky Now measures current irritability, and the second, Cranky Two Weeks, measures peak irritability within the last two weeks. CT scores were significantly higher in adolescents with major depressive disorder than in the school sample and showed improvement following treatment for depression. Positive associations were found between CT and irritability scores as determined by Kiddie Schedule for Affective Disorders and Schizophrenia (not irritable, sub-threshold, threshold irritability) and Affective Reactivity Index scores. Results suggest that the CTs are rapidly administered, have promising psychometric properties and demonstrate utility in measuring irritability in clinical and community settings. PMID- 29475010 TI - Impact of a mental health based primary care program on emergency department visits and inpatient stays. AB - OBJECTIVE: Integrating primary care services into specialty mental health clinics has been proposed as a method for improving health care utilization for medical conditions by adults with serious mental illness. This paper examines the impact of a mental health based primary care program on emergency department (ED) visits and hospitalizations. METHOD: The program was implemented in seven New York City outpatient mental health clinics in two waves. Medicaid claims were used to identify patients treated in intervention clinics and a control group of patients treated in otherwise similar clinics in New York City. Impacts of the program were estimated using propensity score adjusted difference-in-differences models on a longitudinally followed cohort. RESULTS: Hospital stays for medical conditions increased significantly in intervention clinics relative to control clinics in both waves (ORs = 1.21 (Wave 1) and 1.33 (Wave 2)). ED visits for behavioral health conditions decreased significantly relative to controls in Wave 1 (OR = 0.89), but not in Wave 2. No other significant differences in utilization trends between the intervention and control clinics were found. CONCLUSION: Introducing primary care services into mental health clinics may increase utilization of inpatient services, perhaps due to newly identified unmet medical need in this population. PMID- 29475012 TI - Emergence, transmission and phylogeny of meticillin-resistant Staphylococcus aureus sequence type 8 (USA300) in Taiwan. AB - Twenty-seven (0.51%) USA300 isolates were identified from a pool of 5308 meticillin-resistant Staphylococcus aureus (MRSA) isolates collected in Taiwan between 1995 and October 2015, including 12 infecting isolates from 10 patients. The first two isolates were identified in 2005, and 23 isolates have been collected since 2010. Phylogenetic analysis revealed that all the local isolates were closely related to those in North America, and there was a clade consisting of 13 local isolates from 10 patients. MRSA USA300 existed in Taiwan in 2005 or earlier, with increasing identification since 2010. Local transmission of USA300 has occurred in Taiwan after importation from North America. PMID- 29475013 TI - Recommendations for the successful control of a large outbreak of vancomycin resistant Enterococcus faecium in a non-endemic hospital setting. AB - BACKGROUND: A large outbreak of three epidemic vancomycin-resistant Enterococcus faecium (VRE) clones affected the study hospital for almost two years. AIM: To describe the strategy to successfully control this outbreak and eradicate VRE from the study hospital. METHODS: Infection control interventions started after detection of VRE in three patients. Hospital-wide surveillance was started after ongoing transmission despite isolation precautions, cleaning and contact tracing. Hygiene education and discipline were enhanced. Despite these interventions, additional measures were required to control the outbreak, such as ward disinfection with hydrogen peroxide vapour and the introduction of a VRE quarantine ward. Ultimately, ciprofloxacin prophylaxis for haematological patients on chemotherapy was abandoned. FINDINGS: Over a 22-month period, 242 VRE carriers were identified. Of these, 128 (53%) patients were detected by hospital wide surveillance alone. Three epidemic clones were detected: ST494-vanA (N = 160), ST78-vanA (N = 23) and ST117-vanB (N = 32). In total, 5614 possible contacts were identified. VRE transmission occurred on 13 out of 23 wards. VRE was cultured from clinical specimens in 22 patients (seven with bacteraemia). Since January 2014, no further transmission of these VRE clones has been observed. CONCLUSION: Infection control measures according to international guidelines were insufficient to expose the outbreak to its full extent and control it. Its full extent only became apparent after sustained hospital-wide screening. Successful control of this hospital-wide VRE outbreak was feasible, but required great effort. Final containment and eradication of the epidemic clones was achieved by environmental decontamination with hydrogen peroxide vapour, strict isolation precautions, a VRE quarantine ward and antimicrobial stewardship. PMID- 29475014 TI - Accelerated low-rank representation for subspace clustering and semi-supervised classification on large-scale data. AB - The scalability of low-rank representation (LRR) to large-scale data is still a major research issue, because it is extremely time-consuming to solve singular value decomposition (SVD) in each optimization iteration especially for large matrices. Several methods were proposed to speed up LRR, but they are still computationally heavy, and the overall representation results were also found degenerated. In this paper, a novel method, called accelerated LRR (ALRR) is proposed for large-scale data. The proposed accelerated method integrates matrix factorization with nuclear-norm minimization to find a low-rank representation. In our proposed method, the large square matrix of representation coefficients is transformed into a significantly smaller square matrix, on which SVD can be efficiently implemented. The size of the transformed matrix is not related to the number of data points and the optimization of ALRR is linear with the number of data points. The proposed ALRR is convex, accurate, robust, and efficient for large-scale data. In this paper, ALRR is compared with state-of-the-art in subspace clustering and semi-supervised classification on real image datasets. The obtained results verify the effectiveness and superiority of the proposed ALRR method. PMID- 29475015 TI - Reflection and transmission characteristics of a layer obeying the two-pressure field poroelastic phenomenological model of Berryman and Wang. AB - The characteristics of the reflection and transmission by a fluid-loaded double porosity layer are studied. The medium obeys the two-pressure field poroelastic phenomenological model of Berryman and Wang. The open pore hydraulic conditions applied at the interfaces yield factorized expressions for the coefficients exhibiting on the one hand a separation allowing to distinguish between symmetrical and antisymmetrical motions and on the other hand the way each of the three dilatational waves associate with the shear wave. The numerical study done for a layer of Berea sandstone saturated by water shows clearly the role of each of the dilatational waves. There are peculiarities such as the absence of the fundamental antisymmetrical mode (zero order) and a singular behaviour of the symmetrical fundamental mode. The low frequency approximation for this latter is derived from the proposed formulas and compared with the numerical results. PMID- 29475016 TI - Dual-functionalized nanoparticles loaded microbubbles for enhancement of drug uptake. AB - The application of microbubble (MB)-assisted ultrasound (US) can combine the advantages of real-time imaging and targeted drug delivery. However, the drug loading capacity of MB is limited restricting its application in antitumor procedure. In contrast, nanoparticles (NPs) can carry drugs more efficiently, but adverse side effect induced by unspecific accumulation can not be ignored. Herein, we developed a dual-functionalized NP loaded MB to investigate its potential feasibility for tumor-targeted drug delivery. Firstly, we prepared NPs using heparin as backbone. Targeting ligand folate and cell-penetrating ligand Tat peptide were conjugated to the backbone to deliver paclitaxel (H-F-Tat-P NPs). Subsequently, the dual-functionalized NPs were incorporated with MBs via avidin-biotin linkage to fabricate H-F-Tat-P NPs loaded MBs (NPs-loaded MBs). The combined strategy can take profit of dual functionalities from NPs and sonoporation effect from MBs triggered by US. The prepared NPs have been characterized. The excellent cellular uptake of NPs were qualitative and quantitative analysis by flow cytometry and confocal microscope, the results indicated that it was attributed to not only dual functionalities but also US effect. Foremost, the NPs-loaded MBs combined with US exhibited significant cytotoxicity on both folate receptor (FR) overexpressing and deficiency cells. The combination of dual-functionalized NPs and MBs with US is expected to be a promising strategy for targeted anticancer drug delivery and ultrasound imaging simultaneously. PMID- 29475017 TI - Anxiolytic effects of ascorbic acid and ketamine in mice. AB - Some studies have demonstrated that ascorbic acid, similarly to ketamine, exhibits antidepressant-like effects mediated, at least in part, by modulation of the glutamatergic system. Despite the involvement of glutamatergic system in the pathophysiology of anxiety disorders, the ability of ascorbic acid and ketamine to elicit anxiolytic effects in animal models remains to be established. Therefore, this study investigated the effects of a single administration of ascorbic acid, ketamine or diazepam (positive control) in different animal models of anxiety. Mice were treated with ascorbic acid (1, 3 and 10 mg/kg, p.o.), ketamine (1 and 10 mg/kg, i.p.) or diazepam (2 mg/kg, p.o) and their behavioral responses were assessed in the elevated plus maze, open field test (OFT), ligh/dark preference test and marble burying test. Ascorbic acid increased total time spent in the open arms of elevated plus maze, increased total time in the center of the OFT, decreased rearing responses, increased the latency to grooming, decreased the rostral grooming, but did not affect body grooming. Furthermore, ascorbic acid increased the latency time and total time in light area in the ligh/dark preference test, but did not affect the performance of mice in the marble burying test. Ketamine demonstrated an anxiolytic-like effect in elevated plus maze, OFT, and ligh/dark preference test. Diazepam exhibited an anxiolytic-like effect in all the behavioral tests. Altogether, the results indicate the potential anxiolytic effect of ascorbic acid and ketamine, providing a possible new avenue for the management of anxiety-related disorders. PMID- 29475018 TI - Kynurenine pathway metabolism and the neurobiology of treatment-resistant depression: Comparison of multiple ketamine infusions and electroconvulsive therapy. AB - Current first-line antidepressants can take weeks or months to decrease depressive symptoms. Low dose ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, shows potential for a more rapid antidepressant effect, with efficacy also evident in previously treatment-resistant populations. However, a greater understanding of the physiological mechanisms underlying such effects is required. We assessed the potential impact of ketamine infusion on neurobiological drivers of kynurenine pathway metabolism in major depression (HPA axis hyperactivity, inflammation) in patients with treatment-resistant depression compared to gender-matched healthy controls. Furthermore, we assessed these biomarkers before and after electroconvulsive therapy (ECT), which is currently the gold standard for management of treatment-resistant depression. As previously demonstrated, treatment with ketamine and ECT was associated with improved depressive symptoms in patients. At baseline, waking cortisol output was greater in the ECT cohort, kynurenine was greater in the ketamine cohort, and kynurenic acid was lower in patients compared to healthy controls, although inflammatory markers (IL-6, IL-8, IL-10 or IFN-gamma) were similar in patients and controls. Furthermore, in patients who responded to ECT, the cortisol awakening response was decreased following treatment. Despite a trend towards reduced kynurenine concentrations in those who responded to ketamine, ketamine was not associated with significant alterations in any of the biomarkers assessed. PMID- 29475019 TI - Diastolic blood pressure is a potentially modifiable risk factor for preeclampsia in women with pre-existing diabetes. AB - AIMS: To identify early clinical, modifiable risk factors for preeclampsia present at first antenatal visit and assess the prevalence of pregnancy-related hypertensive disorders in women with pre-existing diabetes treated with tight glycemic and blood pressure (BP) control. METHODS: A population-based cohort study of 494 women with pre-existing diabetes (307 and 187 women with type 1 and type 2 diabetes, respectively), included at their first antenatal visit from 2012 to 2016. The prevalence of chronic hypertension (without diabetic nephropathy or microalbuminuria), gestational hypertension and preeclampsia was recorded. Diabetic microangiopathy included presence of nephropathy, microalbuminuria and/or retinopathy. Treatment target was BP <135/85 mmHg. RESULTS: HbA1c was 6.9 +/- 2.4% (50 +/- 12 mmol/mol) at first antenatal visit and 6.0 +/- 0.6% (43 +/- 6 mmol/mol) before delivery with no differences between women with type 1 and type 2 diabetes. At the first antenatal visit, the prevalence of microalbuminuria was 6% (6% vs. 6%), nephropathy 2% (1% vs. 2%) and chronic hypertension 6% (3% vs. 10%, p = 0.03). Gestational hypertension developed in 8% (9% vs. 6%) and preeclampsia developed in 8% (9% vs. 7%). Presence of diabetic microangiopathy (adjusted odds ratio (OR) 4.35 (confidence interval 2.12-8.93)) and diastolic BP (adjusted OR 1.72 per 10 mmHg (1.05-2.82)) at the first antenatal visit were independent risk factors for preeclampsia. CONCLUSIONS: At the first antenatal visit, diastolic BP was the only independent, potentially modifiable risk factor for preeclampsia in women with pre-existing diabetes in the context of tight glycemic and BP control. One out of four women had hypertensive disorders during pregnancy. PMID- 29475020 TI - Cancer survivors: An expanding population with an increased cardiometabolic risk. AB - In the last decades the survival rate of patients diagnosed with cancer - both in childhood and adulthood - significantly improved, leading to a growing number of cancer survivors (CS) within general population. Despite the better survival rate related to the cancer diagnosis, CS show increased mortality and morbidity if compared to non-cancer population, due to the occurrence of health conditions categorized as late effects of previous anticancer treatments. Cardiovascular (CV) diseases are one of the main responsible for this increased morbidity of CS. Besides the direct injury that both chemotherapy and radiotherapy can produce to CV system, in recent years the role of metabolic syndrome in the pathogenesis of CV diseases in CS is emerging. The relationship between anticancer treatments and the development of metabolic alterations is crucial to understand and manage the cardiometabolic risk in CS. The aim of this manuscript is to review the pathophysiological and clinical features of CV risk factors in CS, exploring in more detail certain subgroups of CS (breast cancer, transplanted patients as well as lymphoma survivors) that show peculiar clinical aspects and are burdened by a greater CV risk. PMID- 29475021 TI - Take home message: Start where life begins and follow the life-course approach. PMID- 29475022 TI - Association between depressive symptoms and dietary intake in patients with type 1 diabetes. AB - AIMS: Depressive mood negatively affects self-care practices, and thereby increases the risk of long-term complications. Not much is known about the association between depressive symptoms and dietary intake in patients with type 1 diabetes, a population with high risk of cardiovascular disease. METHODS: Subjects (n = 976, 41% men, age 48 +/- 14 years) were participants in the Finnish Diabetic Nephropathy Study. Depressive symptomatology was assessed with the Beck Depression Inventory (BDI). Dietary patterns were derived from food frequency questionnaire-entries by exploratory factor analysis. Energy and macronutrient intakes were calculated from food records. In the same record, participants also reported the results of their daily blood glucose monitoring. Associations between BDI score and self-care variables were analysed using generalized linear regression. For macronutrients, a substitution model was applied. RESULTS: Two dietary patterns ("Fish and vegetables", and "Traditional") negatively associated with the BDI score. Instead, an increase in the "Sweet" pattern score was positively associated with depressive symptomatology. Of the macronutrients, favouring protein over carbohydrates or fats associated with lower depression scores. Higher blood glucose self-monitoring frequency and higher variability of the measurements were positively associated with the BDI score. However, no association was observed between depressive symptoms and the mean of the blood glucose measurements. CONCLUSIONS: Depressive symptoms are reflected in the dietary intake and the self-monitoring of blood glucose, in type 1 diabetes. Whether depression, via compromised self-care practices, negatively affect long term outcomes in this patient group has to be the subject of future studies. PMID- 29475023 TI - The multifaceted roles of perlecan in fibrosis. AB - Perlecan, or heparan sulfate proteoglycan 2 (HSPG2), is a ubiquitous heparan sulfate proteoglycan that has major roles in tissue and organ development and wound healing by orchestrating the binding and signaling of mitogens and morphogens to cells in a temporal and dynamic fashion. In this review, its roles in fibrosis are reviewed by drawing upon evidence from tissue and organ systems that undergo fibrosis as a result of an uncontrolled response to either inflammation or traumatic cellular injury leading to an over production of a collagen-rich extracellular matrix. This review focuses on examples of fibrosis that occurs in lung, liver, kidney, skin, kidney, neural tissues and blood vessels and its link to the expression of perlecan in that particular organ system. PMID- 29475024 TI - Chromatin dynamics at the core of kidney fibrosis. AB - Progression of chronic kidney disease is a principal challenge in Nephrology, as effective therapies to halt or even reverse established lesion are not available yet. While numerous growth factors and environmental stimuli that drive progression of chronic kidney disease are present within the fibrotic microenvironment, the effector cells' genetic information needs to be accessible in order to enable the pro-fibrotic response. As more than 2 m of DNA encoding the genetic information is crammed as protein-DNA complex called chromatin within the nucleus of each cell, an accessible chromatin state is a prerequisite in the hierarchical order of events to enable production of fibrotic proteins and fibrotic cellular responses. Here, we review contribution and underlying mechanisms of chromatin organization, histone modifications and DNA methylation to progression of chronic kidney disease, provide recent evidence for cell type specific cell fate decisions and discuss possible diagnostic and therapeutic applications. PMID- 29475025 TI - Protein-anchoring therapy to target extracellular matrix proteins to their physiological destinations. AB - Endplate acetylcholinesterase (AChE) deficiency is a form of congenital myasthenic syndrome (CMS) caused by mutations in COLQ, which encodes collagen Q (ColQ). ColQ is an extracellular matrix (ECM) protein that anchors AChE to the synaptic basal lamina. Biglycan, encoded by BGN, is another ECM protein that binds to the dystrophin-associated protein complex (DAPC) on skeletal muscle, which links the actin cytoskeleton and ECM proteins to stabilize the sarcolemma during repeated muscle contractions. Upregulation of biglycan stabilizes the DPAC. Gene therapy can potentially ameliorate any disease that can be recapitulated in cultured cells. However, the difficulty of tissue-specific and developmental stage-specific regulated expression of transgenes, as well as the difficulty of introducing a transgene into all cells in a specific tissue, prevents us from successfully applying gene therapy to many human diseases. In contrast to intracellular proteins, an ECM protein is anchored to the target tissue via its specific binding affinity for protein(s) expressed on the cell surface within the target tissue. Exploiting this unique feature of ECM proteins, we developed protein-anchoring therapy in which a transgene product expressed even in remote tissues can be delivered and anchored to a target tissue using specific binding signals. We demonstrate the application of protein-anchoring therapy to two disease models. First, intravenous administration of adeno associated virus (AAV) serotype 8-COLQ to Colq-deficient mice, resulting in specific anchoring of ectopically expressed ColQ-AChE at the NMJ, markedly improved motor functions, synaptic transmission, and the ultrastructure of the neuromuscular junction (NMJ). In the second example, Mdx mice, a model for Duchenne muscular dystrophy, were intravenously injected with AAV8-BGN. The treatment ameliorated motor deficits, mitigated muscle histopathologies, decreased plasma creatine kinase activities, and upregulated expression of utrophin and DAPC component proteins. We propose that protein-anchoring therapy could be applied to hereditary/acquired defects in ECM and secreted proteins, as well as therapeutic overexpression of such factors. PMID- 29475026 TI - Results of interdisciplinary management of 693 patients with aneurysmal subarachnoid hemorrhage: Clinical outcome and relevant prognostic factors. AB - OBJECTIVES: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high rates of morbidities and fatalities. The continuous evolution of neurosurgical, endovascular and neuro-intensive cares has improved the overall mortality. In this study we sought to evaluate the clinical outcome after aSAH from a single tertiary center. PATIENTS AND METHODS: We retrospectively identified and reviewed all consecutive patients with aSAH treated at our center between 2007 and 2016. Records were made of the initial clinical and radiological findings, treatment modalities, medical complications and length of hospitalization as well as the early and most recent clinical outcome. RESULTS: 693 consecutive patients with aSAH were reviewed (34.2% males, mean age 56.1 +/- 14.1 years). The mean diameter of the ruptured aneurysms was 5.8 +/- 3.6 mm. A total of 265 (38.2%) patients had poor Hunt and Hess (HH) grade. Supportive care was provided in 73 cases. Endovascular or surgical management of the ruptured aneurysm was performed in 77% and 23% of the remaining cases, respectively. Cerebral vasospasm (CVS) was recorded in 177 (25.5%) cases, of which 42.7% had poor outcome. There were 134 (19.3%) early mortalities. Good clinical outcome (mRS <= 2) was achieved in 59.5% of the total cohort and 73.7% of the survivors). Variables with significant association with the clinical outcome included age at presentation, HH grade, early aneurysm re-rupture, parenchymal hemorrhage (PH) and MCA-aneurysms. There was a trend for worse outcome with larger ruptured aneurysms, CVS, and intraventricular hemorrhage. CONCLUSION: The management of aSAH remains challenging but good clinical outcome can be achieved in a substantial subset of patients. Age, initial clinical condition, early aneurysm re-rupture, PH and MCA aneurysm are important prognostic factors. Early detection and appropriate treatment of CVS are crucial for successful management. PMID- 29475027 TI - Spontaneous speech in patients with gliomas in eloquent areas: Evaluation until 1 year after surgery. AB - OBJECTIVE: Glioma patients often complain about problems in daily conversation with a negative impact on quality of life. Disorders in standardized language tests (e.g. naming and fluency), are frequently observed. Most studies claim recovery of language functions within 3 months. However, long-term effects of surgery on spontaneous speech remain unknown. PATIENTS AND METHODS: Eighteen glioma patients were compared to healthy controls in spontaneous speech variables: Type Token Ratio (TTR), Mean Length of Utterance words (MLUw), Incomplete Sentences, Self-corrections and Repetitions. Boston Naming Test (BNT) and Category Fluency (CF) were also assessed. We compared: pre- and 3 months postoperatively (T1-T2), 3 months and 1 year postoperatively (T2-T3), pre- and 1 year postoperatively (T1-T3). Correlations were computed between deviating variables and BNT/CF, tumor localization, and tumor grade. RESULTS: Patients had deficits in Incomplete sentences (T1, T2, T3), TTR (T2,T3), MLUw (T3) and Self corrections (T2). Between T1-T2 no decline was present. Between T2-T3 and T1-T3, there was a decrease of MLUw, Self-corrections and Repetitions and an increase of Incomplete Sentences, BNT and CF were impaired (T1, T2, T3) without differences between test-moments. Most spontaneous speech variables did not correlate with standardized tests. Tumor localization and grade had no influence on spontaneous speech. CONCLUSION: Glioma patients showed impaired spontaneous speech combined with naming and fluency deficits. Surgery appeared to have deteriorated the quality of spontaneous speech until long-term but not the performance at test level. Hence, spontaneous speech has an added value to standardized tests for diagnosis of language impairments. PMID- 29475028 TI - N-nitrosamines in drinking water and beer: Detection and risk assessment. AB - Occurrence and risk related to nitrosamines, a group of carcinogenic compounds found in some drinking waters and beer, are studied. An analytical method using a solid-phase micro-extraction (SPME) along with gas chromatography (GC) and mass spectrometry (MS) was developed to determine seven N-nitrosamines in drinking water and beer, including N-nitrosomethylamine (NMEA), N-nitrosodiethylamine (NDEA), N-nitrosodimethylamine (NDMA), N-nitrosodi-n-propylamine (NDPA), N nitrosopyrrolidine (NPyr), N-nitrosopiperidine (NPip), and N-nitrosodinbutylamine (NDBA). The analysis can be completed in 70 min, and only a 4 mL sample is required, with a detection limit of 0.1-0.8 ng/L for the seven nitrosamines in water and 6-15.7 ng/L in beer. The method was applied to analyze water samples collected from 11 reservoirs and their associated drinking water treatment plants in Taiwan and 10 beer samples from 6 brands with factories located in 6 countries. In the drinking water samples, all seven N-nitrosamines were detected, with NDMA having the highest level at 10.2 ng/L. In the beer samples, NDMA was detected at much lower concentrations (0.12-0.23 MUg/L) than the 5 MUg/L US standard, while NPip was detected at much higher concentrations (4.1-5.3 MUg/L) compared to NDMA. The risk assessment indicates that the risk associated with NDMA is the highest among the studied N-nitrosamines in Taiwan's drinking water, with an average cancer risk of 6.4 * 10-06. For other nitrosamines, the risks are all below 10-6. For the risks associated with N-nitrosamines in beer, NDMA, NDEA, NDPA, and NPip are in the range of 1.5 * 10-05 to 4.6 * 10-04, while that for other nitrosamines are much lower. As for beer, no information for NPip and no modern information for NDEA and NDPA have previously been available, more studies about nitrosamines in beer are suggested for better estimation and control of the risks associated with consumption of beer. PMID- 29475029 TI - Linking nitrous oxide emissions to population dynamics of nitrifying and denitrifying prokaryotes in four full-scale wastewater treatment plants. AB - Ammonia-oxidizing bacteria (AOB), ammonia oxidizing archaea (AOA) and N2O reducing denitrifiers were measured by quantitative real-time PCR (qPCR) in activated sludge samples from four full-scale wastewater treatment plants (WWTPs) in South Spain, and their abundances were linked to the generation of N2O in the samples using multivariate analysis (Non-metric multidimensional scaling, MDS, and BIO-ENV). The average abundances of AOA remained in similar orders of magnitude in all WWTPs (106 copies amoA/L activated sludge mixed liquor), while significant differences were detected for AOB (105-109copies amoA/L) and N2O reducers (107-1010copies nosZ/L). Average N2O emissions measured in activated sludge samples ranged from 0.10 +/- 0.05 to 6.49 +/- 8.89 mg N2O-N/h/L activated sludge, and were strongly correlated with increased abundances of AOB and lower counts of N2O-reducers. A significant contribution of AOA to N2O generation was unlikely, since their abundance correlated negatively to N2O emissions. AOB abundance was favoured by higher NO3- and NO2-concentrations in the activated sludge. PMID- 29475030 TI - Screening for protein adducts of naphthalene and chrysene in plasma of exposed Atlantic cod (Gadus morhua). AB - Polycyclic aromatic hydrocarbons (PAHs) are well known contaminants, ubiquitously present in the habitat and spawning areas for Atlantic cod (Gadus morhua). The Atlantic cod is a key species and a globally important food source, thus continuous monitoring of PAHs is considered highly valuable to ensure ecosystem sustainability and human food safety. PAH adducts to plasma proteins are applied as sensitive biomarkers of PAH exposure in humans and other species, thus the presence of PAH protein adducts in Atlantic cod plasma was investigated to identify PAH protein adduct biomarker candidates of exposure to PAHs. Blood plasma samples were collected from Atlantic cod (n = 66) one week after exposure by intramuscular injection of single PAHs (i.e. naphthalene and chrysene), and their corresponding dihydrodiol metabolites (i.e. (-)-(1R,2R)-1,2 dihydronaphthalene-1,2-diol and (-)-(1R,2R)-1,2-dihydrochrysene-1,2-diol). The samples were analyzed by shotgun tandem mass spectrometry (MS) and the resulting MS data were analyzed in ByonicTM to screen for proteins susceptible to adduct formation with naphthalene and chrysene. Furthermore, a wildcard modification search was performed to obtain additional information regarding potential modifications other than the targeted metabolites. The amino acid adductation sites and the metabolites involved in PAH adductation are reported. Forty-four proteins were found to bind PAHs. Alpha-2-macroglobulin-like proteins, apolipoproteins B-100-like proteins and an alpha-2-HS-glycoprotein were detected with the highest number of bound PAHs. This first insight into PAH protein adducts of Atlantic cod plasma generates valuable knowledge for the development of highly sensitive biomarkers of PAH exposure. PMID- 29475031 TI - Online monitoring of N-nitrosodimethylamine rejection as a performance indicator of trace organic chemical removal by reverse osmosis. AB - The security of recycled water quality in potable reuse can be enhanced by improving the credibility of reverse osmosis (RO) treatment for the removal of trace organic chemicals (TOrCs). This study evaluated the potential of online monitoring of N-nitrosodimethylamine (NDMA) before and after RO treatment as a surrogate indicator for TOrC removal by RO. This pilot-scale study monitored NDMA concentrations in RO feedwater (ultrafiltration-treated wastewater) and RO permeate every 22 min using novel online NDMA analyzers-high-performance liquid chromatography followed by photochemical reaction and chemiluminescence detection. NDMA rejection by RO varied considerably in response to changes in operating conditions (permeate flux and feedwater temperature). A high linear correlation between NDMA rejection and the rejection of six other TOrCs was observed. The linear correlation was also identified for an RO membrane damaged with chlorine. The correlation between another potential surrogate indicator (conductivity rejection) and TOrC rejection was relatively low. NDMA, which is the smallest compound among regulated TOrCs, revealed rejections lower than the other TOrCs, indicating that NDMA rejection can be a conservative surrogate indicator capable of predicting changes in TOrC removal. PMID- 29475032 TI - Optimization of coagulation pre-treatment for alleviating ultrafiltration membrane fouling: The role of floc properties on Al species. AB - This study investigated membrane fouling in a coagulation/ultrafiltration (C-UF) process by comparing the floc properties and humic acid (HA) removal efficiency of three hydrous Al(III) species (Ala, Alb, and Alc). The results indicated that the coagulation and membrane mechanisms were different for all three Al species because of the differences in floc properties. The HA removal efficiency increased with increasing Al dosage until an equilibrium was reached at the optimal dosage of 6 mg L-1. In addition, membrane fouling gradually decreased as the Al dosages increased. Regardless of coagulant type, the OH and COOH functional groups of HA reacted with the Al species. Both external and internal membrane fouling were strongly dependent on the porosity of the cake layer and on the size distribution of the floc particulates, respectively. The pore area of the cake layer formed by the Ala-coagulated effluent was large because of the strong charge neutralization. Moreover, Ala generated large and loose flocs with a porous cake layer that mitigated external fouling. However, the internal fouling with the Alc coagulant was significant because the concentration of residual aggregates in the membrane pores was high. PMID- 29475033 TI - Morphophysiological and transcriptome analysis reveals a multiline defense system enabling cyanobacterium Leptolyngbya strain JSC-1 to withstand iron induced oxidative stress. AB - Iron intoxications induce severe oxidative stress by producing reactive oxygen species (ROS) in cyanobacteria, leading to membrane lipid peroxidation, altered morphology, impaired photosynthesis and other oxidative stress injuries. Given these stresses, mitigation of ROS is a prerequisite for all aerobic organisms. Study of siderophilic cyanobacterium Leptolyngbya strain JSC-1 inhabiting iron rich hot springs may provide insight into the mechanism of iron homeostasis and alleviation of oxidative stress. In this study, we investigated the morphophysiological and molecular mechanisms enabling this cyanobacterium to cope with iron-induced oxidative stress. Strain JSC-1 biomineralized extracellular iron via an exopolymeric sheath (acting as a first line of defense) and intracellular iron via polyphosphate inclusions (second line of defense), thus minimizing the burden of free ferric ions. Physiological parameters, SOD, CAT and POD activities, bacterioferritin and total protein contents fluctuated in response to iron elevation, displaying a third line of defense to mitigate ROS. Differential gene expression analysis of JSC-1 indicated up-regulation of 94 and 125 genes and down-regulation of 89 and 183 genes at low (4 MUM) and high (400 MUM) iron concentration, respectively. The differentially expressed genes (DEGs) were enriched in 100 KEGG pathways and were found to be involved in lipopolysaccharide and fatty acid biosynthesis, starch, sucrose, chlorophyll and other metabolic pathways. Together with metabolic reprogramming (fourth line of defense), JSC-1 established a unique multiline defense system that allows JSC-1 to withstand severe oxidative stress. These findings also provide insight into potential survival strategies of ancient microorganisms inhabiting similar environment present in early earth history. PMID- 29475034 TI - Stable-State Midrange Proadrenomedullin Is Associated With Severe Exacerbations in COPD. AB - BACKGROUND: Elevated levels of midrange proadrenomedullin (MR-proADM) are associated with worse outcome in different diseases, including COPD. The association of stable-state MR-proADM with severe acute exacerbations of COPD (AECOPDs) requiring hospitalization, or with community-acquired pneumonia (CAP) in patients with COPD, has not been studied yet. The aim of this study was to evaluate the association of stable-state MR-proADM with severe AECOPD and CAP in patients with COPD. METHODS: This study pooled data of 1,285 patients from the Cohort of Mortality and Inflammation in COPD (COMIC) and PRedicting Outcome using systemic Markers In Severe Exacerbations of Chronic Obstructive Pulmonary Disease (PROMISE-COPD) cohort studies. Time until first severe AECOPD was compared between patients with high (>= 0.87 nmol/L) or low (< 0.87 nmol/L) levels of plasma MR-proADM in stable state as previously defined. For time until first CAP, only COMIC data (n = 795) were available. RESULTS: Patients with COPD with high level stable-state MR-proADM have a significantly higher risk for severe AECOPD compared with those with low-level MR-proADM with a corrected hazard ratio (HR) of 1.30 (95% CI, 1.01-1.68). Patients with high-level stable-state MR-proADM had a significantly higher risk for CAP compared with patients with COPD with low level MR-proADM in univariate analysis (HR, 1.93; 95% CI, 1.24-3.01), but after correction for age, lung function, and previous AECOPD, the association was no longer significant (corrected HR, 1.10; 95% CI, 0.68-1.80). CONCLUSIONS: Stable state high-level MR-proADM in patients with COPD is associated with severe AECOPD but not with CAP. PMID- 29475035 TI - Nickel-cysteine nanoparticles: Synthesis, characterization and application for direct electron transfer studies. AB - Nickel-cysteine nanostructures (Ni-CysNSs) are prepared by a simple wet chemistry procedure under mild conditions, in which l-cysteine acts both as precursor and structure directing agent. This method involves the reaction of nickel chloride with l-cysteine, followed by simultaneous adjusting the pH in the range of 6-8.5 by addition of an aqueous NaOH solution. The structure and morphology of the prepared products are characterized using various techniques, including X-ray powder diffraction (XRD), Fourier transform-infrared (FT-IR) spectroscopy, CHNS elemental analysis, Field emission scanning electron microscopy (FESEM) and Transmission electron microscopy (TEM). The effects of a variety of synthetic conditions on the structure and morphology of the Ni-CysNSs are studied, including the molar ratio of precursors, dispersing solvent, pH value of the reaction solution, reaction time and reaction temperature. FT-IR measurements reveal that synthesized Ni-CysNSs contain many free carboxylic groups on the surface, which could be used as binding sites to anchor biological molecules in order to develop various bioelectronic devices. In this work, the applicability of synthesized nanostructure in biosensing is studied by using Ni-CysNSs as a platform for covalently immobilization of GOx, as a model enzyme, on the surface. Cyclic voltammetric measurements reveal that the direct electron transfer from the active center of GOx to the glassy carbon electrode facilitated upon its immobilization on the Ni-CysNSs film. More importantly, GOx preserves its native structure and catalytic activity for the oxidation of glucose after immobilization on the Ni-CysNSs surface. The electrocatalytic characteristics of the GC/NiCysNS/GOx electrode toward the oxidation of glucose are investigated by cyclic voltammetry, which displayed acceptable electrical and sensing performance. Simple preparation of Ni-CysNPs and their biocompatibility make them attractive platforms for integration of various biomolecules such as proteine/enzymes with surface. PMID- 29475036 TI - ADAMTS-6 is a predictor of poor prognosis in patients with esophageal squamous cell carcinoma. AB - BACKGROUND: A disintegrin and metalloprotease with thrombospondin motif (ADAMTS) enzymes play important roles in cell functions including adhesion, invasion, migration, and proliferation. ADAMTS-6 is a member of the ADAMTS family; reports of its relationship with esophageal squamous cell carcinoma (ESCC) progression are rare. It is unclear whether ADAMTS-6 could be an independent ESCC biomarker. METHODS: ADAMTS-6 expression was detected by immunohistochemistry (IHC) in 171 paraffin-embedded ESCC specimens; relationships with patients' clinicopathological features and Twist-1 expression were analyzed by the Pearson Chi-square method, respectively. Overall survival (OS) and disease-free survival (DFS) were determined using the Kaplan-Meier method and compared using the long rank test. RESULTS: ADAMTS-6 was expressed mainly in the cytoplasm and nucleus; the expression was significantly higher in tumor tissues. Increased expression of ADAMTS-6 correlated with clinical stage (P = 0.009), pT stage (P = 0.042), lymph node metastasis (P = 0.014) and recurrence (P = 0.033). There were no significant correlations between ADAMTS-6 expression and other clinicopathological parameters including age, sex, tumor size, distant metastasis, differentiation, ...chemotherapy, radiotherapy, CD68 expression and epithelial mesenchymal transition (EMT) status. Kaplan-Meier survival curves revealed that upregulated expression of ADAMTS-6 indicated short OS (P = 0.001) and DFS (P = 0.002). Multivariate analysis confirmed that high ADAMTS-6 expression was an independent factor for ESCC prognosis. ADAMTS-6 expression was significantly correlated with Twist-1 expression in ESCC cancer cells (P = 0.007) and stromal cells (P < 0.001). Patients with ESCC revealing expression of both ADAMTS-6 and Twist-1 exhibited significantly reduced OS and DFS rates than other patients. CONCLUSIONS: High ADAMTS-6 expression is a useful marker of poor prognosis in patients with ESCC. PMID- 29475037 TI - Lanthionine ketimine-5-ethyl ester provides neuroprotection in a zebrafish model of okadaic acid-induced Alzheimer's disease. AB - Okadaic acid (OKA) is a protein phosphatase 2A inhibitor that is used to induce neurodegeneration and study disease states such as Alzheimer's disease (AD). Lanthionine ketimine-5-ethyl ester (LKE) is a bioavailable derivative of the naturally occurring brain sulfur metabolite, lanthionine ketimine (LK). In previously conducted studies, LKE exhibited neuroprotective and neurotrophic properties in murine models but its mechanism of action remains to be clarified. In this study, a recently established zebrafish OKA-induced AD model was utilized to further elucidate the neuroprotective and neurotrophic properties of LKE in the context of an AD-like condition. The fish were divided into 3 groups containing 8 fish per group. Group #1 = negative control, Group #2 = 100 nM OKA, Group #3 = 100 nM OKA +500 MUM LKE. OKA caused severe cognitive impairments in the zebrafish, but concomitant treatment with LKE protected against cognitive impairments. Further, LKE significantly and substantially reduced the number of apoptotic brain cells, increased brain-derived neurotrophic factor (BDNF), and increased phospho-activation of the pro-survival factors pAkt (Ser 473) and pCREB (Ser133). These findings clarify the neuroprotective and neurotrophic effects of LKE by highlighting particular survival pathways that are bolstered by the experimental therapeutic LKE. PMID- 29475038 TI - Astaxanthin protects against kainic acid-induced seizures and pathological consequences. AB - Excitotoxic damage caused by increased glutamate levels is involved in the pathogenesis of neurodegenerative diseases. Astaxanthin, a natural carotenoid with multiple health benefits, inhibits glutamate release from the brain tissue; however, whether it possesses the ability to affect glutamate-induced brain injury is unknown. The present study investigated the neuroprotective effects of astaxanthin on kainic acid (KA)-induced excitotoxicity in rats and the possible underlying intracellular signaling pathway. The rats were orally administrated with astaxanthin (50 or 100 mg/kg) for 7 days (once a day), and KA (15 mg/kg) was administered intraperitoneally at 1 h after the final administration. The results revealed that KA induced seizures, increased the hippocampal glutamate levels, caused considerable neuronal death and microglial activation in the hippocampal CA3 regions, and increased the production of proinflammatory cytokines. Astaxanthin pretreatment prevented these changes. Furthermore, astaxanthin pretreatment increased the expression of neuronal cell survival-related factors, including phosphorylated Akt, phosphorylated glycogen synthase kinase-3beta, and Bcl-2 in the hippocampus of KA-injected rats. These results suggested that astaxanthin can attenuate seizures, mitigate inflammation, augment survival signals, and prevent hippocampal neuronal damage in the animal model of KA induced excitotoxicity. PMID- 29475040 TI - Metabo-Devo: A metabolic perspective of development. AB - In the last years, several reports have established the notion that metabolism is not just a housekeeping process, but instead an active effector of physiological changes. The idea that the metabolic status may rule a wide range of phenomena in cell biology is starting to be broadly accepted. Thus, current developmental biology has begun to describe different ways by which the metabolic profile of the cell and developmental programs of the organism can crosstalk. In this review, we discuss mechanisms by which metabolism impacts on processes governing development. We review the growing body of evidence that supports the notion that aerobic glycolysis is required in cells undergoing fast growth and high proliferation, similarly to the Warburg effect described in tumor cells. Glycolytic metabolism explains not only the higher ATP synthesis rate required for cell growth, but also the uncoupling between mitochondrial activity and bioenergetics needed to provide anabolism with sufficient precursors. We also discuss some recent studies, which show that in addition to its role in providing energy and carbon chains, the metabolic status of the cell can also influence epigenetic regulation of developmental processes. Although metabolic aspects of development are just starting to be explored, there is no doubt that ongoing research in this field will shape the future landscape of Developmental Biology. PMID- 29475039 TI - Genes and microRNAs associated with mouse cleft palate: A systematic review and bioinformatics analysis. AB - Cleft palate (CP) is the most prevalent craniofacial deformity, with ethnic and geographic variation in prevalence in humans. Mice have been used as an animal model to study the cause(s) of CP by several approaches, including genetic and chemical-induced approaches. Mouse genetic approaches revealed that significant amounts of genes are involved in the CP pathology. The aim of this study was to identify common features of CP-associated genes and to explore the roles of microRNAs (miRNAs) as important post-transcriptional regulators that may be involved in the regulation of CP genes. To generate an accurate list of genes associated with CP, we first conducted systematic literature searches through main databases such as Medline, Embase, and PubMed, as well as other sources such as Scopus and Mouse Genome Informatics. We found that 195 mouse strains with single-gene mutations and 140 mouse strains with compound-gene mutations were reported to have CP. The CP genes were categorized by functions and pathways using the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology annotations, highlighting the contribution of cellular metabolism to CP. A total of 18 miRNAs were involved in the regulation of multiple CP genes. Human genotype-phenotype analysis revealed that variants in five human homologous CP genes (IRF6, FOXE1, VAX1, WNT9B, and GAD1) significantly contributed to the human CP phenotype. Thus, our results suggest that cellular metabolism and miRNAs play an important role in the regulation of genetic pathways and networks crucial for palatal formation. PMID- 29475041 TI - Antrodia cinnamomea mycelial fermentation broth inhibits the epithelial mesenchymal transition of human esophageal adenocarcinoma cancer cells. AB - Esophageal cancer is associated with a high mortality rate and easy metastasis. The aim of this study is to investigate the effect of the bio-product Antrodia cinnamomea mycelial fermentation broth (AC-MFB) on the epithelial mesenchymal transition (EMT) of human esophageal cancer cells and the molecular mechanisms underlying these effects. Transforming growth factor beta (TGF-beta) was used to induce EMT in human esophageal BE3 cancer cells. Changes in cell morphology and migration potential were examined. The expression of E-cadherin, N-cadherin, vimentin, and other transcriptional factors was studied by western blot assay. The results showed that AC-MFB was not only able to upregulate the expression of Ecadherin and attenuate the TGF-beta-induced overexpression of vimentin and N cadherin, but it also reversed the TGF-beta-induced changes in cell morphology from polygonal to spindle-shaped and delayed the migration potential of BE3 cells. Furthermore, AC-MFB treatment was able to inhibit the expression levels of both Twist and Twist1. Overall, AC-MFB was able to inhibit the EMT of esophageal cancer BE3 cells, which was accompanied by Twist and Twist1 downregulation. PMID- 29475042 TI - Pulmonary Heart Valves: Redefining Outcomes. PMID- 29475043 TI - Sublobar Resections-the Margins Justify the Means. PMID- 29475044 TI - Rapid-Deployment Aortic Valve Replacement: Clear Benefits Without a Clear Target Patient Population. PMID- 29475045 TI - Is This a Good Study? PMID- 29475046 TI - Antepartum and intrapartum screening for Group B Streptococcus. PMID- 29475047 TI - Are 3D ultrasound and office hysteroscopy useful for the assessment of uterine cavity after late foetal loss? AB - OBJECTIVE: To assess the efficacy of office hysteroscopy and 3D ultrasound for the diagnostic of uterine anomalies after late foetal loss. METHOD: This retrospective observational study took place in the gynaecologic unit of a teaching hospital from 2009 to 2014. Women with late foetal loss (<22 weeks of gestation) had an office hysteroscopy and 3D ultrasound within three months after delivery. The results of the ultrasound and hysteroscopy were recorded and compared. RESULTS: Eighty women were included with a mean age of 29.8 years (28.2 31.4). Forty-seven women had both hysteroscopy and 3D ultrasound, and a uterine cavity's anomaly (bicornuate uterus, T-Shape uterus and septate uterus) was found in ten women (21%) at 3D sonography and in 13 women (28%) at office hysteroscopy. Concordance between the two exams was very good with a kappa at 0.83. In three cases, a uterine cavity's anomaly was found at hysteroscopy whereas sonography was normal. Anomalies at ultrasound (uterine cavity's anomaly, myometrium anomaly or ovarian anomaly) were found in 27.6% of cases. CONCLUSIONS: Both 3D ultrasound and office hysteroscopy are useful for assessment of the uterine cavity after late foetal loss. The application of these two exams is important, as hysteroscopy is generally used for assessment of the uterine cavity and endometrium, while 3D ultrasound is generally used to identify the precise type of uterine malformation and for the examination of the myometrium and annexes. PMID- 29475048 TI - The function of serpin-2 from Eriocheir sinensis in Spiroplasma eriocheiris infection. AB - Serpin families classified serine protease inhibitors regulate various physiological processes. However, there is not study on the role of serpin in immune responses against Spiroplasma eriocheiris as a novel causative pathogen in the Chinese mitten crab, Eriocheir sinensis. In our study, quantitative real-time PCR (qRT-PCR) revealed that the mRNA transcripts of Esserpin-2 were ubiquitous in every tissue, relative higher expression in hepatopancreas, gill and hemocytes, while the intestine, muscle, heart and nerve showed relative lower expression. Followed by infection with S. eriocheiris, the transcripts of Esserpin-2 were significantly down-regulated from 1 d to 7 d. After double-stranded RNA injection, the transcripts of Esserpin-2 dramatically declined from 48 h to 96 h. The transcripts of proPO were found to be obviously increased after Esserpin-2 silenced, meanwhile, LGBP with no significant difference. The copy number of S. eriocheiris and subsequently the mortality of crabs in a silencing Esserpin-2 group were significantly less than control groups during infection. The subcellular localization experiment suggested that recombinant Esserpin-2 was mainly located in the cytoplasm. Finally, over-expression assay in Drosophila S2 cells indicated that Esserpin-2 could increase copies of S. eriocheiris and result in cell death. These findings demonstrated that Esserpin-2 involved in the innate immune mechanism of E. sinensis in response to S. eriocheiris infection. PMID- 29475049 TI - Three newly identified galectin homologues from triangle sail mussel (Hyriopsis cumingii) function as potential pattern-recognition receptors. AB - Galactoside-binding lectins, also known as galectins, play crucial roles in innate immune response in invertebrates. In this study, three cDNA sequences from Hyriopsis cumingii were identified and collectively called HcGalec genes. Each of the three deduced HcGalec proteins contained a galactose-binding lectin domain or a GLECT domain. All the three HcGalec genes are mainly present in the hepatopancreas and gills, and their expression is induced at 24 h after bacterial challenge. Three recombinant HcGalec proteins can bind and agglutinate (Ca2+ dependent) various microorganisms, including Gram-positive and Gram-negative bacteria. These proteins can attach to mannan and peptidoglycan. Meanwhile, the expression of the three HcGalec genes in the gills were significantly down regulated after dsRNA interference (HcGalec1-RNAi, HcGalec2-RNAi, and HcGalec3 RNAi) and Vibrio parahaemolyticus injection. The expression levels of some antimicrobial peptides, including lysozyme 1 and lysozyme 2, were also markedly decreased after dsRNA interference. Overall, these results suggested that these three HcGalec proteins may function as potential receptors participating in the innate immune responses of H. cumingii against bacterial infection. PMID- 29475050 TI - Cyanidin-3-O-glucoside functions like chemical chaperone and attenuates the glycation mediated amyloid formation in albumin. AB - In this study, chemical chaperone like function of cyanidin-3-O-glucoside (C3G) was investigated through fluorescence spectroscopy, UV-visible spectroscopy, circular dichroism spectroscopy, confocal microscopy, scanning electron microscopy and molecular docking studies. Early and advanced glycation inhibitory effect was evaluated by fluorescence spectroscopy and agarose gel electrophoresis. Amyloids were investigated based on their propensity to bind Congo Red (CR) and Thioflavin T (ThT) by multiple microscopic approaches. Circular dichroism studies were used to analyze the changes in the secondary structure due to glycation. C3G effectively inhibited early and advanced glycation by masking like function, carbonyl scavenging and chemical chaperone activity. C3G had molecular interaction with Glu186, Arg427, Ser428, Lys431, Arg435, and Arg458 of BSA. Based on the microscopic analysis, it is evident that C3G can inhibit protein aggregation and amyloid formation. Circular dichroism studies suggested that glycation had resulted in augmented beta-sheet propensity, whereas C3G had a protective effect on the helical conformation of BSA. We conclude that C3G has a chemical chaperone like function on the event of glycation mediated amyloid formation in BSA. PMID- 29475051 TI - Highly efficient heterostructured stannic disulfide/stannic anhydride hybrids: Synthesis, morphology, and photocatalytic reduction of chromium (VI) under visible light. AB - Highly efficient heterostructured stannic disulfide/stannic anhydride (SnS2/SnO2) hybrids with different morphologies were fabricated via a two-step hydrothermal method. The composition and morphology of the obtained products were investigated by X-ray diffraction (XRD), scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and UV-vis diffuse reflectance spectroscopy (DRS). The SEM images showed that core-shell structured SnS2/SnO2 nanotubes and hierarchical SnS2 flowers decorated with SnO2 particles were fabricated under different synthetic conditions. The DRS results of the hybrids showed that the absorption edges were gradually redshifted with increasing SnS2 content. In the photocatalytic reduction of chromium (VI) under visible light, the SnS2/SnO2 hybrid prepared with thioacetamide addition of 0.60 g exhibited the best photocatalytic activity, which was approximately 6.8 times higher than that of pure SnS2. This increase in the reduction performance might be ascribed to the strengthened absorption of visible light, the rapid interfacial charge transfer and the promoted charge separation efficiency. Photocurrent- response measurements, electrochemical impedance spectroscopy, and photoluminescence emission tests confirmed the faster charge transfer and efficient charge separation over the heterostructured SnS2/SnO2 hybrids. Lastly, a photocatalytic reduction mechanism for chromium (VI) over SnS2/SnO2 hybrids was proposed. PMID- 29475052 TI - Energy transfer and distribution in photosystem super/megacomplexes of plants. AB - Traditionally, two types of photosystem reaction centers (PSI and PSII) are thought to be spatially dispersed in the plant thylakoid membrane. In this model, PSI and PSII independently accept excitation energy from their own peripheral light-harvesting complexes, LHCI and LHCII, respectively, and form supercomplexes (PSI-LHCI and PSII-LHCII). However, recent studies using a combination of mild detergent treatment and spectroscopic analysis have revealed the existence of various megacomplexes such as a PSI-PSII megacomplex and a PSII megacomplex. Flexibility in the formation of supercomplexes and megacomplexes is important for land plants to regulate excitation energy to survive under strong and fluctuating sunlight on land. PMID- 29475053 TI - Exploring the role of cellular homologous of the 30K-superfamily of plant virus movement proteins. AB - Genes orthologous to the 30K-superfamily of movement proteins (MP) from plant viruses have been recently discovered by bioinformatics analyses as integrated elements in the genome of most vascular plants. However, their functional relevance for plants is still unclear. Here, we undertake some preliminary steps into the functional characterization of one of these putative MP genes found in Arabidopsis thaliana. We found that the AtMP gene is expressed at different stages of the plant development, with accumulation being highest in flowers but lowest in mature siliques. We also found down-regulation of the gene may result in a small delay in plant development and in an exacerbation of the negative effect of salinity in germination efficiency. We have also explored whether changes in expression of the endogenous AtMP have any effect on susceptibility to infection with several viruses, and found that the infectivity of tobacco rattle tobravirus was strongly dependent on the expression of the endogenous AtMP. Finally, we have cloned the endogenous MP from four different plant species into an expression vector that allows for specifically assessing their activity as cell-to-cell movement proteins and have shown that though some may still retain the ancestral activity, they do so in a quite inefficient manner, thus suggesting they have acquired a novel function during adaptation to the host genome. PMID- 29475054 TI - Intravenous infusion of mesenchymal stem cells reduces epileptogenesis in a rat model of status epilepticus. AB - OBJECTIVE: Status epilepticus (SE) causes neuronal cell death, aberrant mossy fiber sprouting (MFS), and cognitive deteriorations. The present study tested the hypothesis that systemically infused mesenchymal stem cells (MSCs) reduce epileptogenesis by inhibiting neuronal cell death and suppressing aberrant MFS, leading to cognitive function preservation in a rat model of epilepsy. METHODS: SE was induced using the lithium-pilocarpine injection model. The seizure frequency was scored using a video-monitoring system and the Morris water maze test was carried out to evaluate cognitive function. Comparisons were made between MSCs- and vehicle-infused rats. Immunohistochemical staining was performed to detect Green fluorescent protein (GFP)+ MSCs and to quantify the number of GAD67+ and NeuN+ neurons in the hippocampus. Manganese-enhanced magnetic resonance imaging (MEMRI) and Timm staining were also performed to assess the MFS. RESULTS: MSC infusion inhibited epileptogenesis and preserved cognitive function after SE. The infused GFP+ MSCs were accumulated in the hippocampus and were associated with the preservation of GAD67+ and NeuN+ hippocampal neurons. Furthermore, the MSC infusion suppressed the aberrant MFS in the hippocampus as evidenced by MEMRI and Timm staining. CONCLUSIONS: This study demonstrated that the intravenous infusion of MSCs mitigated epileptogenesis, thus advancing MSCs as an effective approach for epilepsy in clinical practice. PMID- 29475055 TI - Toxic stress history and hypothalamic-pituitary-adrenal axis function in a social stress task: Genetic and epigenetic factors. AB - Histories of early life stress (ELS) or social discrimination can reach levels of severity characterized as toxic to mental and physical health. Such toxic social stress during development has been linked to altered acute hypothalamic-pituitary adrenal (HPA) response to social stress in adulthood. However, there are important individual differences in the size and direction of these effects. We explored developmental, genetic, epigenetic, and contextual sources of individual differences in the relationship between ELS, discrimination, and adult responses to acute social stress in a standard laboratory test. Additional measures included perceived status, social support, background activity of HPA axis, and genetic variants in aspects of the stress response system. Participants (n = 90) answered questions about historical and ongoing stress, provided a DNA sample to examine genetic polymorphisms and epigenetic marks, and underwent the Trier Social Stress Test (TSST) during which three saliva samples were collected to assess HPA function. Individuals who reported high levels of childhood adversity had a blunted salivary cortisol response to the TSST. Childhood adversity, discrimination experiences, and FKBP5 genotype were found to predict pretest cortisol levels. Following up on recent observations that the glucocorticoid receptor directly interacts with the mitochondrial genome, particularly the NADH dehydrogenase 6 (MT-ND6) gene, individuals who reported high childhood adversity were also found to have higher percent methylation across six CpG sites upstream of MT-ND6. These findings suggest multiple contributions across psychological, genetic, epigenetic, and social domains to vulnerability and resilience in hypothalamic-pituitary-adrenal axis regulation. Further study to examine how these multiple contributors affect developmental endpoints through integrated or independent pathways will be of use. PMID- 29475056 TI - Dysfunctional personality disorder beliefs and lifetime suicide attempts among psychiatrically hospitalized military personnel. AB - BACKGROUND: Personality disorders (PDs) are associated with an increased risk for suicide. However, the association between PDs and suicide risk has not been examined among military personnel. This study evaluated whether endorsement of different PD dysfunctional beliefs was associated with lifetime suicide attempt status. METHODS AND MATERIALS: Cross-sectional data were collected during the baseline phase of a randomized controlled trial, evaluating the efficacy of an inpatient cognitive behavior therapy protocol for the prevention of suicide. Participants (N = 185) were military service members admitted for inpatient psychiatric care following a suicide-related event. MANOVA and Poisson regression evaluated the association between each type of PD dysfunctional belief and the number of suicide attempts. RESULTS: Service members' PBQ subscale scores for borderline (p = 0.049) and histrionic PD dysfunctional beliefs (p = 0.034) significantly differed across those with suicide ideation only, single attempt, and multiple attempts. Upon further analysis, histrionic PD dysfunctional beliefs scores were significantly higher among those with multiple suicide attempts than those with single attempts. One point increase of dependent (Incidence Risk Ratio = 1.04, p = 0.009), narcissistic (IRR = 1.07, p < 0.001), and paranoid PD dysfunctional beliefs (IRR = 1.04, p = 0.002) was associated with a greater number of lifetime suicide attempts. CONCLUSIONS: Assessment and targeting dependent, narcissistic, paranoid, borderline, and histrionic beliefs as part of a psychosocial intervention will be useful. PMID- 29475057 TI - Evaluation of cash transfer programs in sub-Saharan Africa: A methodological review. AB - Cash transfer programs (CTs) have been rigorously evaluated since their inception in the 1990s. However, to date, there has been no study critically examining the utility of the methodological approaches used to evaluate CTs. This article reviews the approaches used to evaluate CTs in sub-Saharan Africa (SSA) to provide recommendations for improving future CTs evaluations. We conducted searches for CTs evaluation studies in SSA in the peer-reviewed and grey literature using electronic databases, hand searching of selected journals, organisational websites, Google Scholar and Scirus Internet search engines. The review included 53 evaluation studies which were largely outcome-focused evaluations (95%; n = 50). The studies were undertaken within 24 CT programs comprising 11 unconditional CTs (UCTs), eight conditional CTs (CCTs) and five combined UCTs and CCTs. The review finds that while there is evidence of CTs impacts on a broad range of outcomes, the current evaluation approaches have primarily been experimental designs and have largely failed to provide explanations for mechanisms of change. To improve CTs policy and practice, there is the need to consider theory-based evaluation approaches such as realist evaluation that provide insights about the contexts and mechanisms through which programs generate outcomes in different circumstances. PMID- 29475058 TI - Using Intervention Mapping for child development and wellbeing programs in early childhood education and care settings. AB - Supporting children's social and emotional learning benefits all elements of children's development and has been associated with positive mental health and wellbeing, development of values and life skills. However, literature relating to the creation of interventions designed for use within the early childhood education and care settings to support children's social and emotional skills and learning is lacking. Intervention Mapping (IM) is a systematic intervention development framework, utilising principles centred on participatory co-design methods, multiple theoretical approaches and existing literature to enable effective decision-making during the development process. Early childhood pedagogical programs are also shaped by these principles; however, educators tend to draw on implicit knowledge when working with families. IM offers this sector the opportunity to formally incorporate theoretical, evidence-based research into the development of early childhood education and care social and emotional interventions. Emerging literature indicates IM is useful for designing health and wellbeing interventions for children within early childhood education and care settings. Considering the similar underlying principles of IM, existing applications within early childhood education and care and development of interventions beyond health behaviour change, it is recommended IM be utilised to design early childhood education and care interventions focusing on supporting children's social and emotional development. PMID- 29475059 TI - Ventrolateral Motor Thalamus Abnormal Connectivity in Essential Tremor Before and After Thalamotomy: A Resting-State Functional Magnetic Resonance Imaging Study. AB - OBJECTIVE: To evaluate functional connectivity (FC) of the ventrolateral thalamus, a common target for drug-resistant essential tremor (ET), resting-state data were analyzed before and 1 year after stereotactic radiosurgical thalamotomy and compared against healthy controls (HCs). METHODS: In total, 17 consecutive patients with ET and 10 HCs were enrolled. Tremor network was investigated using the ventrolateral ventral (VLV) thalamic nucleus as the region of interest, extracted with automated segmentation from pretherapeutic diffusion magnetic resonance imaging. Temporal correlations of VLV at whole brain level were evaluated by comparing drug-naive patients with ET with HCs, and longitudinally, 1 year after stereotactic radiosurgical thalamotomy. 1 year thalamotomy MR signature was always located inside VLV and did not correlate with any of FC measures (P > 0.05). This suggested presence of longitudinal changes in VLV FC independently of the MR signature volume. RESULTS: Pretherapeutic ET displayed altered VLV FC with left primary sensory-motor cortex, pedunculopontine nucleus, dorsal anterior cingulate, left visual association, and left superior parietal areas. Pretherapeutic negative FC with primary somatosensory cortex and pedunculopontine nucleus correlated with poorer baseline tremor scores (Spearman = 0.04 and 0.01). Longitudinal study displayed changes within right dorsal attention (frontal eye-fields and posterior parietal) and salience (anterior insula) networks, as well as areas involved in hand movement planning or language production. CONCLUSIONS: Our results demonstrated that patients with ET and HCs differ in their left VLV FC to primary somatosensory and supplementary motor, visual association, or brainstem areas (pedunculopontine nucleus). Longitudinal changes display reorganization of dorsal attention and salience networks after thalamotomy. Beside attentional gateway, they are also known for their major role in facilitating a rapid access to the motor system. PMID- 29475060 TI - Lanatoside C inhibits cell proliferation and induces apoptosis through attenuating Wnt/beta-catenin/c-Myc signaling pathway in human gastric cancer cell. AB - Gastric cancer is the third common cause of cancer mortality in the world with poor prognosis and high recurrence due to lack of effective medicines. Our studies revealed that lanatoside C, a FDA-approved cardiac glycoside, had an anti proliferation effect on different human cancer cell lines (MKN-45; SGC-7901; HN4; MCF-7; HepG2) and gastric cell lines MKN-45 and SGC-7901 were the most sensitive cell lines to lanatoside C. MKN-45 cells treated with lanatoside C showed cell cycle arrest at G2/M phase and inhibition of cell migration. Meanwhile, upregulation of cleaved caspase-9 and cleaved PARP and downregulation of Bcl-xl were accompanied with the loss of mitochondrial membrane potential (MMP) and induction of intracellular reactive oxygen species (ROS). Lanatoside C inhibited Wnt/beta-catenin signaling with downregulation of c-Myc, while overexpression of c-Myc reversed the anti-tumor effect of lanatoside C, confirming that c-Myc is a key drug target of lanatoside C. Furthermore, we discovered that lanatoside C prompted c-Myc degradation in proteasome-ubiquitin pathway with attenuating the binding of USP28 to c-Myc. These findings indicate that lanatoside C targeted c Myc ubiquitination to inhibit MKN-45 proliferation and support the potential value of lanatoside C as a chemotherapeutic candidate. PMID- 29475061 TI - A fungal metabolite zearalenone as a CFTR inhibitor and potential therapy of secretory diarrheas. AB - Overstimulation of CFTR-mediated Cl- secretion plays an important role in the pathogenesis of secretory diarrheas, which remain an important global health problem. This study aimed to identify inhibitors of CFTR-mediated Cl- secretion from a library of fungus-derived compounds and to evaluate their pharmacological properties and anti-diarrheal utility. We identified zearalenone, 7' dehydrozearalenone and 8'-hydroxyzearalenone isolated from the seagrass-derived fungus Fusarium sp. PSU-ES123 as inhibitors of CFTR-mediated Cl- secretion in human intestinal epithelial (T84) cells. Being the most potent fungal metabolite capable of inhibiting CFTR-mediated Cl- secretion, zearalenone reversibly inhibited CFTR Cl- channel activity in T84 cells with an IC50 of ~0.5 MUM. Functional and biochemical analyses and molecular docking studies indicate that zearalenone binds to the beta-estradiol binding sites in the ATP-binding pockets on NBD1 and NBD2 of CFTR. Mechanisms of CFTR inhibition by zearalenone do not involve activation of phosphodiesterases, protein phosphatases, multidrug resistance protein 4 and AMP-activated protein kinases. Importantly, zearalenone significantly inhibited cholera toxin (CT)-induced Cl- secretion in T84 cells and blocked CT-induced intestinal fluid secretion in mice. Collectively, our study indicates that zearalenone represents the first class of fungus-derived CFTR inhibitors. Further development of this class of compounds may provide an effective treatment of secretory diarrheas. PMID- 29475062 TI - Resveratrol suppresses doxorubicin-induced cardiotoxicity by disrupting E2F1 mediated autophagy inhibition and apoptosis promotion. AB - The clinical use of doxorubicin (DOX) is limited by cardiotoxicity, involving the dysregulation of autophagy and apoptosis in the myocardium, which were partly reversed by resveratrol (RSV) supplement. However, a definitive mechanisms accounting for DOX's cardiotoxicity and the protective role of RSV remain poorly defined. The aim of the present study was to clarify the specific role of E2F transcription factor 1 (E2F1) in regulating autophagy and apoptosis in DOX induced cardiotoxicity as well as the protective effects of RSV. Autophagy and apoptosis were successfully induced by the serum deprivation strategy in H9c2 cardiomyocytes. DOX inhibited autophagy through activating E2F1/mammalian target of rapamycin complex 1 (mTORC1) pathway and further induced apoptosis by activating E2F1/AMP-activated protein kinase alpha2 (AMPKalpha2) pathway in starved H9C2 cells. And RSV supplement showed increased autophagy and decreased apoptosis, accompanied with inhibitory effect on E2F1/mTORC1 as well as E2F1/AMPKalpha2 pathway. Moreover, the favorable effect of RSV on autophagy and apoptosis was dependent on E2F1. The same result was observed in the mouse model of DOX-induced cardiotoxicity in both non-myocardial ischemia and myocardial ischemia condition. Injection with DOX and RSV in combination, resulted in a reduced apoptotic ratio and activated autophagy process compared with the DOX treatment alone. In conclusions, RSV, which has been suggested to attenuate DOX induced cytotoxicity, significantly blocks induction of E2F1/mTORC1 and E2F1/AMPKalpha2 pathway by DOX, leading to acceleratory autophagy and inhibitory apoptosis. And E2F1 plays a key role for the protective effect of RSV. PMID- 29475063 TI - Characterization of a novel selective factor Xa inhibitor, DJT06001, which reduces thrombus formation with low risk of bleeding. AB - Factor Xa (FXa) is a serine protease that plays key roles in linking the intrinsic and extrinsic coagulation pathways to the final common pathway. DJT06001 is an oral, highly specific and direct FXa inhibitor for the prevention and treatment of thromboembolic diseases. We characterized the compound in vitro and studied its in vivo activity in rat thrombosis models, as well as bleeding risk and Pharmacokinetics and Pharmacodynamics (PK/PD) relationship. DJT06001 inhibited free FXa with an inhibitory constant (Ki) of 0.99 nM, and exhibited >10000-fold selectivity for FXa than for other related serine proteases. DJT06001 concentration-dependently inhibited FXa activity in the prothrombinase complex with an IC50 of 2.53 nM. The concentrations for DJT06001 to double the prothrombin time (PT) and activated partial thromboplastin time (APTT) were 0.74 and 0.57 MUM, respectively. Importantly, DJT06001 did not impair platelet aggregation induced by ADP, platelet activating factor (PAF) and collagen. Furthermore, DJT06001 inhibited thrombus formation in rat thrombosis models in a dose dependent manner. And in rat tail bleeding risk test, it caused less bleeding than rivaroxaban at doses that achieve the same antithrombotic effect. PK/PD studies further demonstrated that there was a good correlation between the plasma concentrations of DJT06001and its inhibition of plasma FXa activity and prolongation of PT. In conclusion, DJT06001 was shown to be a potent and specific FXa inhibitor with excellent PK/PD profiles and it could be developed as a new anticoagulant for the management of thromboembolic diseases. PMID- 29475064 TI - Ursodeoxycholyl lysophosphatidylethanolamide negatively regulates TLR-mediated lipopolysaccharide response in human THP-1-derived macrophages. AB - The bile acid-phospholipid conjugate ursodeoxycholyl oleoyl lysophophatidylethanolamide (UDCA-18:1LPE) is an anti-inflammatory and anti fibrotic agent as previously shown in cultured hepatocytes and hepatic stellate cells as well as in in vivo models of liver injury. We hypothesize that UDCA 18:1LPE may directly inhibit the activation of immune cells. We found that UDCA 18:1LPE was capable of inhibiting the migration of phorbol ester-differentiated human THP-1 cells. We examined anti-inflammatory activity of UDCA-18:1LPE during activation of THP1-derived macrophages. Treatment of these macrophages by bacterial lipopolysaccharide (LPS) for 24 h induced the release of pro inflammatory cytokines TNF-alpha, IL-6 and IL-1beta. This release was markedly inhibited by pretreatment with UDCA-18:1LPE by ~ 65-90%. Derivatives with a different fatty-acid chain in LPE moiety also exhibited anti-inflammatory property. Western blotting and indirect immunofluorescence analyses revealed that UDCA-18:1LPE attenuated the expression of phosphorylated p38, MKK4/MKK7, JNK1/2, and c-Jun as well as nuclear translocation of NF-kappaB by ~ 22-86%. After LPS stimulation, the Toll-like receptor adaptor proteins, myeloid differentiation factor 88 and TNF receptor associated factor 6, were recruited into lipid rafts and UDCA-18:1LPE inhibited this recruitment by 22% and 58%, respectively. Moreover, LPS treatment caused a decrease of the known cytoprotective lysophosphatidylcholine species containing polyunsaturated fatty acids by 43%, and UDCA-18:1LPE co-treatment reversed this decrease. In conclusion, UDCA-18:1LPE and derivatives inhibited LPS inflammatory response by interfering with Toll-like receptor signaling in lipid rafts leading to an inhibition of MAPK and NF-kappaB activation. These conjugates may represent a class of lead compounds for development of anti-inflammatory drugs. PMID- 29475065 TI - Antiviral therapy improves survival in patients with HBV infection and intrahepatic cholangiocarcinoma undergoing liver resection: Novel concerns. PMID- 29475066 TI - Zwitterionic cocrystal of diclofenac and l-proline: Structure determination, solubility, kinetics of cocrystallization, and stability study. PMID- 29475067 TI - Transcriptional profiling of male CD-1 mouse lungs and Harderian glands supports the involvement of calcium signaling in acrylamide-induced tumors. AB - Acrylamide (AA) exposure causes increased incidence of forestomach, lung, and Harderian gland tumors in male mice. One hypothesized mode of action (MOA) for AA carcinogenicity includes genotoxicity/mutagenicity as a key event, possibly resulting from AA metabolism to the direct genotoxic metabolite glycidamide. Alternatively, altered calcium signaling (CS) has been proposed as a central key event in the MOA. To examine the plausibility of these proposed MOAs, RNA sequencing was performed on tumor target tissues: Harderian glands (the most sensitive tumor target tissue in the rodent 2-year cancer bioassay) and lungs of AA-exposed male CD-1 mice. Animals were exposed to 0.0, 1.5, 3.0, 6.0, 12.0, or 24.0 mg AA/kg bw-day in drinking water for 5, 15, or 31 days. We observed a pronounced effect on genes involved in CS and cytoskeletal processes in both tissues, but no evidence supporting a genotoxic MOA. Benchmark dose modeling suggests transcriptional points of departure (PODs) of 0.54 and 2.21 mg/kg bw-day for the Harderian glands and lungs, respectively. These are concordant with PODs of 0.17 and 1.27 mg/kg bw-day derived from the cancer bioassay data for these tissues in male mice, respectively. Overall, this study supports the involvement of CS in AA-induced mouse carcinogenicity, which is consistent with a recently proposed CS-based MOA in rat thyroid, and with other published reports of aberrant CS in malignant tumors in rodents and humans. PMID- 29475068 TI - Acute, subchronic oral toxicity, toxicokinetics, and genotoxicity studies of DFC 2, an antitubercular drug candidate. AB - The infectious disease tuberculosis remains a serious global health issue and is responsible for nearly 1.8 million deaths every year. In our previous study, DFC 2 was confirmed to show anti-tubercular activity against drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis. To support the safety-in use of DFC-2 as an anti-tubercular drug, DFC-2 was tested via single- and 28-day repeated-dose oral toxicity study and mutagenicity assays. In the oral toxicity study, a single oral dose of DFC-2 at 2000 mg/kg did not produce deaths or abnormal lesions in the internal organs of rats. The results of a 28-day orally repeated dose of DFC-2 did not show treatment-related deaths or obvious toxicity symptoms in the animals treated with a dose of 300 mg/kg/day during the experimental period. Therefore, the no-observed-adverse-effect level (NOAEL) of DFC-2 was determined as 300 mg/kg/day for both male and female rats. In addition, DFC-2 showed no genetic toxicity in in vitro bacterial reverse mutation test, in vitro chromosomal aberration test, and in vivo mouse bone marrow micronucleus formation test. These results indicate that DFC-2 is a promising anti-tubercular drug candidate with a favorable safety profile. PMID- 29475069 TI - In vitro model to study cocaine and its contaminants. AB - Cocaine is one of the most popular illicit drug worldwide. Due its great addictive potential, which leads to euphoria and hyperactivity, it is considered a public health concern. At the central nervous system, the drug acts inhibiting catecholamine re-uptake. It is now known that in addition to the toxicity of the drug itself, the contaminants present in the street drug have raised concern about the harmful effects on health. Toxicological in vivo and in vitro studies have demonstrated the toxic effects of cocaine correlated with the generation of reactive oxygen species (ROS), which in turn lead to oxidative damage to the cells. Therefore the aim of this work was to propose an in vitro model that reunites the main parameters of toxicity of the cocaine already observed in the literature so far, and we tested this model using cocaine and seizure cocaine sample (SCS), kindly provided by Federal Police of Brazil. For that, we used a C6 glioblastoma cells and evaluated cell death, oxygen reactive species induction, oxidation of macromolecules as membrane lipids and DNA and loss of mitochondrial membrane potential after cocaine exposure. The results showed that cocaine can decrease cellular viability in a dose-dependent way in the C6 cell immortalized and astrocytes primary culture. Cocaine also induced cellular death by apoptosis. However, in the seizure cocaine sample (SCS), the predominant cell death was due to necrosis. Using dichlorofluorescein (DCF) assay, we confirmed ROS production after cocaine exposition. In agreement with these findings, occurred an increasing in MDA production, as well as increased superoxide dismutase (SOD) and catalase (CAT) activity. The induction of DNA damage was observed after cocaine. Our results demonstrate the occurrence of mitochondrial dysfunction by depolarization of mitochondrial membrane as a consequence of cocaine treatment. In summary, these results demonstrated that cocaine can induce reactive oxygen species formation, leading to oxidative stress. As a consequence of this unbalance, DNA damage, lipidic peroxidation and loss of mitochondrial membrane occurred, which could be an answer to cell death observed. PMID- 29475070 TI - Distinct regions of the hippocampus are associated with memory for different spatial locations. AB - In the present functional magnetic resonance imaging (fMRI) study, we aimed to evaluate whether distinct regions of the hippocampus were associated with spatial memory for items presented in different locations of the visual field. In Experiment 1, during the study phase, participants viewed abstract shapes in the left or right visual field while maintaining central fixation. At test, old shapes were presented at fixation and participants classified each shape as previously in the "left" or "right" visual field followed by an "unsure"-"sure" "very sure" confidence rating. Accurate spatial memory for shapes in the left visual field was isolated by contrasting accurate versus inaccurate spatial location responses. This contrast produced one hippocampal activation in which the interaction between item type and accuracy was significant. The analogous contrast for right visual field shapes did not produce activity in the hippocampus; however, the contrast of high confidence versus low confidence right hits produced one hippocampal activation in which the interaction between item type and confidence was significant. In Experiment 2, the same paradigm was used but shapes were presented in each quadrant of the visual field during the study phase. Accurate memory for shapes in each quadrant, exclusively masked by accurate memory for shapes in the other quadrants, produced a distinct activation in the hippocampus. A multi-voxel pattern analysis (MVPA) of hippocampal activity revealed a significant correlation between behavioral spatial location accuracy and hippocampal MVPA accuracy across participants. The findings of both experiments indicate that distinct hippocampal regions are associated with memory for different visual field locations. PMID- 29475071 TI - Pre-clinical validation of a closed surface system (Cryotop SC) for the vitrification of oocytes and embryos in the mouse model. AB - Vitrification is currently a well-established technique for the cryopreservation of oocytes and embryos. It can be achieved either by direct (open systems) or indirect (closed systems) contact with liquid nitrogen. While there is not a direct evidence of disease transmission by transferred cryopreserved embryos, it was experimentally demonstrated that cross-contamination between liquid nitrogen and embryos may occur, and thus, the use of closed devices has been recommended to avoid the risk of contamination. Unfortunately, closed systems may result in lower cooling rates compared to open systems, due to the thermal insulation of the samples, which may cause ice crystal formation resulting in impaired results. In our study, we aimed to validate a newly developed vitrification device (Cryotop SC) that has been specifically designed for being used as a closed system. The cooling and warming rates calculated for the closed system were 5.254 degrees C/min and 43.522 degrees C/min, respectively. Results obtained with the closed system were equivalent to those with the classic Cryotop (open system), with survival rates in oocytes close to 100%. Similarly, the potential of the survived oocytes to develop up to good quality blastocysts after parthenogenetic activation between both groups was statistically equivalent. Assessment of the meiotic spindle and chromosome distribution by fluorescence microscopy in vitrified oocytes showed alike morphologies between the open and closed system. No differences were found either between the both systems in terms of survival rates of one-cell stage embryos or blastocysts, as well as, in the potential of the vitrified/warmed blastocysts to develop to full-term after transferred to surrogate females. PMID- 29475072 TI - Digital Gene Expression Profiling reveals transcriptional responses to acute cold stress in Chinese soft-shelled turtle Pelodiscus sinensis juveniles. AB - Turtles are well known for their stress tolerance, including an ability to deal with temperature extremes or rapid thermal change. To know more about the comprehensive molecular basis of thermal stress responses in turtles, we assessed differentially expressed genes (DEGs) in the brain, liver and kidney of juvenile soft-shelled turtles, Pelodiscus sinensis, after acute cold stress (28 degrees C 8 degrees C acute transfer and held for 12 h) and following recovery (back to 28 degrees C and held for 24 h) by digital gene expression profiling. Selected DEGs were also validated via real-time PCR. We found the fewest DEGs in the brain, only one-tenth of the number seen in liver, indicating a tissue-specific gene expression pattern. The DEGs indicated the potential activation of several important functions in response to cold stress and recovery in P. sinensis. This included response to oxidative stress or regulation of reactive oxygen species metabolism in the brain and liver, cerebral inositol metabolism, hepatic monosaccharide metabolism, hepatic complement system, renal DNA repair mechanisms, and TNF and PI3K-Akt signaling pathways in the kidney. These functions likely responded to cold stress in different tissues of P. sinensis to help minimize or repair cell damage as well as enhance innate immunity. The outcomes of this study provide some fundamental insight into the tissue specific complex mechanisms underlining cold stress responses in the soft-shelled turtle P. sinensis. PMID- 29475073 TI - Development and preliminary validation of the Parenting around SNAcking Questionnaire (P-SNAQ). AB - Snacking makes significant contributions to children's dietary intake but is poorly understood from a parenting perspective. This research was designed to develop and evaluate the psychometrics of a theoretically grounded, empirically informed measure of snack parenting. The Parenting around SNAcking Questionnaire (P-SNAQ) was developed using a conceptual model derived from current theory and mixed-methods research to include 20 hypothesized snack parenting practices along 4 parenting dimensions (autonomy support, structure, coercive control and permissiveness). Expert panel evaluation and cognitive interviews were used to refine items and construct definitions. The initial instrument of 105 items was administered to an ethnically diverse, low-income sample of 305 parents (92% mothers) of children aged 1-6 y participating in three existing cohort studies. The sample was randomly split into two equal samples. Exploratory factor analysis was conducted with the first sample to identify snack parenting practices within each parenting dimension, followed by confirmatory factor analysis with the second sample to test the hypothesized factor structure. Internal consistency of sub-scales and associations with existing measures of food parenting practices and styles and child weight status were evaluated. The final P-SNAQ scale included 51 items reflecting 14 snack parenting practices across four parenting dimensions. The factor structure of the P-SNAQ was consistent with prior theoretical frameworks. Internal consistency coefficients were good to very good for 12 out of 14 scales and subscale scores were moderately correlated with previously validated measures. In conclusion, initial evidence suggests that P SNAQ is a psychometrically sound measure for evaluating a wide range of snack parenting practices in young children. PMID- 29475074 TI - Stapled truncated orexin peptides as orexin receptor agonists. AB - The peptides orexin-A and -B, the endogenous agonists of the orexin receptors, have similar 19-amino-acid C-termini which retain full maximum response as truncated peptides with only marginally reduced potency, while further N-terminal truncations successively reduce the activity. The peptides have been suggested to bind in an alpha-helical conformation, and truncation beyond a certain critical length is likely to disrupt the overall helical structure. In this study, we set out to stabilize the alpha-helical conformation of orexin-A15-33 via peptide stapling at four different sites. At a suggested hinge region, we varied the length of the cross-linker as well as replaced the staple with two alpha aminoisobutyric acid residues. Modifications close to the peptide C-terminus, which is crucial for activity, were not allowed. However, central and N-terminal modifications yielded bioactive peptides, albeit with decreased potencies. This provides evidence that the orexin receptors can accommodate and be activated by alpha-helical peptides. The decrease in potency is likely linked to a stabilization of suboptimal peptide conformation or blocking of peptide backbone receptor interactions at the hinge region by the helical stabilization or the modified amino acids. PMID- 29475075 TI - Nesfatin-1 and visfatin expression is associated with reduced atherosclerotic disease risk in patients with rheumatoid arthritis. AB - Nesfatin is an anti-inflammatory molecule that reduces atherosclerotic cardiovascular risk. By contrast, visfatin has pro-inflammatory properties and is pro-atherogenic. We examined the potential impact of nesfatin and visfatin on atherosclerotic disease in 232 (113 black and 119 white) consecutive rheumatoid arthritis (RA) patients from 2 centers. Independent relationships of nesfatin and visfatin concentrations with metabolic risk factors, endothelial activation, carotid atherosclerosis and altered plaque stability were determined in multivariable regression models. Rheumatoid factor (RF) positivity was associated with both nesfatin (beta = 0.650, p < 0.0001) and visfatin levels (beta = 0.157, p = 0.03). Visfatin concentrations were related to increased diastolic blood pressure (beta = 4.536, p = 0.01) and diabetes prevalence (beta = 0.092, p = 0.04). Nesfatin levels were associated with reduced carotid intima-media thickness (beta = -0.017, p = 0.008). Nesfatin (beta = 0.116, p = 0.001) and visfatin concentrations (beta = 0.234, p = 0.001) were related to those of matrix metalloproteinase-2 (MMP-2), a plaque stability mediator. Nesfatin and visfatin concentrations were directly correlated (Spearman's rho = 0.516). The nesfatin MMP-2 and visfatin-MMP-2 relations were both stronger in RF negative compared to RF positive patients (interaction p = 0.01 and p = 0.04, respectively). Nesfatin is associated with reduced atherosclerosis and increased plaque stability mediator levels in RA. Visfatin is related to adverse cardio-metabolic risk in RA. Increased MMP-2 expression in relation to visfatin may represent a compensatory mechanism aimed at reducing cardiovascular risk in RA. PMID- 29475077 TI - Inequality between biases in face memory: Event-related potentials reveal dissociable neural correlates of own-race and own-gender biases. AB - Humans are more accurate at remembering faces from their own relative to a different ethnic group (own-race bias). Moreover, better memory for faces from an observer's own relative to the other-gender (own-gender bias) has also been reported, particularly for female participants. Theoretical explanations for these effects either emphasize differential perceptual expertise or socio cognitive factors. Importantly, both types of explanations typically assume a single common mechanism for the various biases. The present study examined event related potentials (ERP) in a combined own-race/own-gender bias experiment. Whereas both male and female participants demonstrated clear own-race biases in memory performance, enhanced memory for own-gender faces was only observed in female participants. Moreover, the own-race bias was accompanied by larger N170 responses for other-race faces, presumably reflecting more effortful perceptual processing of this face category. Neural correlates of the own-gender bias manifested at later processing stages, reflecting the processing of individual faces (N250) and recollection-based memory retrieval (late ERP old/new effect). We conclude that different face memory biases occur at temporally distinct stages of face processing and are therefore based on different mechanisms. This suggestion is at variance with the assumption of a single common mechanism to underlie the various biases in face memory. PMID- 29475076 TI - From percept to concept in the ventral temporal lobes: Graded hemispheric specialisation based on stimulus and task. AB - The left and right ventral anterior temporal lobes (vATL) have been implicated as key regions for the representation of conceptual knowledge. However, the nature and degree of hemispheric specialisation in their function is unclear. To address this issue, we investigated hemispheric specialisation in the ventral temporal lobes using a distortion-corrected spin-echo fMRI protocol that enhanced signal in vATL. We employed an orthogonal manipulation of stimulus (written words vs pictured objects) and task (naming vs recognition). Words elicited left lateralised vATL activation while objects elicited bilateral activation with no hemispheric bias. In contrast, posterior ventral temporal cortex exhibited a rightward bias for objects as well as a leftward bias for words. Naming tasks produced left-lateralised activation in vATL while activity for recognition was equal in left and right vATLs. These findings are incompatible with proposals that left and right ATLs are strongly modular in function, since these predict rightward as well as leftward biases. Instead, they support an alternative model in which (a) left and right ATL together form a bilateral, integrated system for the representation of concepts and (b) within this system, graded hemispheric specialisation emerges as a consequence of differential connectivity with other neural systems. On this view, greater left vATL activation for written word processing develops as a consequence of the inputs this region receives from left lateralised visual word processing system in posterior temporal cortex. Greater left vATL activation during naming tasks is most likely due to connectivity with left-lateralised speech output systems in prefrontal and motor cortices. PMID- 29475078 TI - Damage of the temporal lobe and APOE status determine neural compensation in mild cognitive impairment. AB - In mild cognitive impairment (MCI), the APOE4 genotype is associated with accelerated memory decline, likely due to the impact of neuropathology on main cerebral networks required for successful memory retrieval and/or to decreased capacity for recruiting secondary networks that might compensate for that brain damage. Here, we tested this hypothesis in twenty-six healthy older adults and thirty-four MCI patients, of which sixteen were APOE4 carriers. Compared to controls, MCI showed hippocampal volume reduction, cortical thinning in frontal, temporal and parietal regions, and dysfunctional EEG oscillations across fronto temporal networks. But importantly, APOE4 status was the critical factor in determining the impact of temporal lobe degeneration on memory in MCI individuals. Specifically, path analyses revealed that hippocampal damage in MCI was responsible for memory deterioration in APOE4 carriers, a relationship mediated by the serial intervention of three related factors in noncarriers. Temporal cortical thickness (first mediator) accounted for activation of functional networks through synchronized theta activity across temporal regions (second mediator), which, in turn, coordinated memory reactivation through desynchronized alpha/beta activity across sensorimotor areas (third mediator). Results revealed that, contrary to APOE4-carrier patients, noncarriers are successful in recruiting secondary cortical networks to improve memory performance as long as the integrity and functionality of the temporal lobe is preserved, a fact primarily dependent on hippocampal degeneration. PMID- 29475079 TI - Blind readers break mirror invariance as sighted do. AB - Mirror invariance refers to a predisposition of humans, including infants and animals, which urge them to consider mirrored images as corresponding to the same object. Yet in order to learn to read a written system that incorporates mirrored letters (e.g., vs. in the Latin alphabet), humans learn to break this perceptual bias. Here we examined the role visual experience and input modality play in the emergence of this bias. To this end, we tested congenital blind (CB) participants in two same-different tactile comparison tasks including pairs of mirrored and non-mirrored Braille letters as well as embossed unfamiliar geometric shapes and Latin letters, and compared their results to those of age matched sighted participants involved in similar but visually-presented tasks. Sighted participants showed a classical pattern of results for their material of expertise, Latin letters. CB's results signed for their expertise with the Braille script compared to the other two materials that they processed according to an internal frame of reference. They also evidenced that they automatically break mirror invariance for different materials explored through the tactile modality, including Braille letters. Altogether, these results demonstrate that learning to read Braille through the tactile modality allows breaking mirror invariance in a comparable way to what is observed in sighted individuals for the mirrored letters of the Latin alphabet. PMID- 29475080 TI - Partial maxillectomy for ameloblastoma of the maxilla with infratemporal fossa involvement: A combined endoscopic endonasal and transoral approach. AB - Ameloblastoma represents the most common epithelial odontogenic tumor. Because of the proximity of the maxillary tumors to the orbit and skull base, it should be managed as radically as possible. Maxillectomy, mainly via the transfacial or transoral approach, represents the most common type of surgical procedure. Drawback of these approaches is limited control of the superiomedial extent of the tumour in the paranasal area. We report the use of a combined endoscopic endonasal and transoral approach to manage maxillary plexiform ameloblastoma in a 48-year-old male patient. A combined endoscopic endonasal and transoral approach enabled the radical removal of tumour with a 1.5cm margin of radiographically intact bone with good control from both intrasinusal and intraoral aspects. Adequate visualization of the extent of the lesion (e.g. orbit, infratemporal fossa, anterior cranial base) had been achieved. Non-complicated healing was achieved. This technique of partial maxillectomy led to very good aesthetic and functional results. No recurrence had been noted during review appointments. The combination of endoscopic endonasal and transoral approach for a partial maxillectomy allows sufficient reduction of the defect, thus eliminating the necessity for reconstruction and reducing the morbidity associated with it. PMID- 29475081 TI - Evaluation of neurosensory disturbances of the inferior alveolar nerve after intraoral verticosagittal ramus osteotomy. AB - PURPOSE: To assess the incidence of neurosensory disturbances (NSD) of the inferior alveolar nerve (IAN) after Intraoral verticosagittal ramus osteotomy (IVSRO). MATERIALS AND METHODS: The sensibility of the chin and lower lip of ten consecutive patients undergoing IVSRO was assessed. Evaluations were performed at 7 days preoperatively, 7 days, one month and six months postoperatively. The chin was divided into four quadrants, which were tested separately. The tests used were: two-point discrimination (2-P), brush stroke direction discrimination (BSD) and thermal stimuli (TH). Postoperatively, patients also answered a questionnaire. RESULTS: The values for 2-P showed statistically significant difference when compared to preoperative measurements (P>0.05) in all quadrants, with exception to quadrant D. There was no statistically significant difference among preoperative values and 7 days, 1 month and 6 months postoperative values. For BSD and TH tests, no differences were found among time points. None of the 10 patients reported complete numbness after 1 week. After 6 months, complete recovery of the chin sensibility was reported in all 10 cases. CONCLUSION: This study showed, objectively and subjectively, a low incidence of NSD after IVSRO. Further studies with larger samples are necessary to confirm these results. PMID- 29475082 TI - A rare case of oral metastasis of colon adenocarcinoma. AB - INTRODUCTION: Metastatic carcinoma of the colon is frequently encountered. In the literature, metastasis of malignant tumors in the buccal cavity are rare. They represent less than 1% of oral malignant lesions. OBSERVATION: We present a case of oral metastasis of colon adenocarcinoma in the mandible of a 62-year-old patient. The physical examination revealed a swelling in the mandibular symphysis associated with dental displacement. The panoramic X-ray showed significant bone lysis of the symphysis. The neoplastic tissue showed marked positivity for Cytokeratin 20 and CDX2, confirming the diagnosis of metastasis of the oral cavity from colorectal adenocarcinoma. DISCUSSION: Metastatic adenocarcinoma from the colon to the oral cavity are rare but should be included in the differential diagnosis of tumors in the oral cavity. PMID- 29475083 TI - Seasonal dynamics in the community structure and trophic structure of testate amoebae inhabiting the Sanjiang peatlands, Northeast China. AB - Peatlands cover 3% of the earth's land surface but contain 30% of the world's soil carbon pool. Microbial communities constitute a crucial detrital food web for nutrient and carbon cycling in peatlands. Heterotrophic protozoans are considered top predators in the microbial food web; however, they are not yet well understood. In this study, we investigated seasonal dynamics in the community and the trophic structure of testate amoebae in four peatlands. Testate amoebae density and biomass in August were significantly higher than those in May and October. The highest density, 6.7 * 104 individual g-1 dry moss, was recorded in August 2014. The highest biomass, 7.7 * 102 MUg C g-1 dry moss, was recorded in August 2013. Redundancy analyses showed that water-table depth was the most important factor, explaining over one third of the variance in fauna communities in all sampled seasons. High trophic position taxa dominated testate amoebae communities. The Shannon diversity index and community size structure index declined from August to October in 2013 and from May to October in 2014. These seasonal patterns of testate amoebae indicated the seasonal variations of the peatlands' microbial food web and are possibly related to the seasonal carbon dynamics in Northeast Chinese peatlands. PMID- 29475084 TI - Full-length myocilin protein is purified from mammalian cells as a dimer. AB - Myocilin (MYOC) is a secreted protein found in human aqueous humor (AH) and mutations in the MYOC gene are the most common mutation observed in glaucoma patients. Human AH analyzed under non-reducing conditions suggests that MYOC is not normally found in a monomeric form, but rather is predominantly dimeric. Although MYOC was first reported almost 20 years ago, a technical challenge still faced by researchers is an inability to isolate full-length MYOC protein for experimental purposes. Herein we describe two methods by which to isolate sufficient quantities of human full-length MYOC protein from mammalian cells. One method involved identification of a cell line (HeLa S3) that would secrete full length protein (15 mg/L) while the second method involved a purification approach from 293 cells requiring identification and modification of an internal MYOC cleavage site (Glu214/Leu215). MYOC protein yield from 293 cells was improved by mutation of two MYOC N-terminal cysteines (C47 and C61) to serines. Analytical size exclusion chromatography of our full-length MYOC protein purified from 293 cells indicated that it is predominantly dimeric and we propose a structure for the MYOC dimer. We hope that by providing methods to obtain MYOC protein, researchers will be able to utilize the protein to obtain new insights into MYOC biology. The ultimate goal of MYOC research is to better understand this target so we can help the patient that carries a MYOC mutation retain vision and maintain quality of life. PMID- 29475085 TI - Simulation of alpha and beta gross activity measurement of soil samples with proportional counters. AB - In this paper, we have simulated the performance of a proportional counter for alpha and beta measurement of soil samples. The simulations were performed for alpha particles from 210Po and beta particles from 90Sr. The results of the simulations indicate that the maximum count-to-background ratio can be achieved by using sample thicknesses greater than 4 um and 100 um, respectively, for alpha and beta measurements. The maximum efficiencies for alpha and beta counting were calculated to be, respectively, 25% and 42.50%. The maximum alpha-to-beta cross talk was also calculated to be 5.51%. The results of the simulations are also compared with the reported experimental values and a good agreement with the experimental results is found. PMID- 29475086 TI - Fluorescently-tagged polyamines for the staining of siliceous materials. AB - Siliceous frustules of diatom algae contain unique long-chain polyamines, including those having more than six nitrogen atoms. These polyamines participate in the formation of the siliceous frustules of the diatoms but their precise physiological role is not clear. The main hypotheses include formation of a polyamine and polyphosphate supramolecular matrix. We have synthesized novel fluorescent dyes from a synthetic oligomeric mixture of polyamines and the fluorophore 7-nitro-2,1,3-benzoxadiazole. The long polyamine chain ensures the high affinity of these dyes to silica, which allows their application in the staining of siliceous materials, such as valves of diatom algae and fossilized samples from sediments. The fluorescently stained diatom valves were found to be promising liquid flow tracers in hydrodynamic tests. Furthermore, complexation of the polyamine component of the dyes with carbonic polymeric acids results in changes to the visible spectrum of the fluorophore, which allows study of the stability of the complex vs the length of the polyamine chain. Using poly (vinyl phosphonic acid) as a model for phosphate functionality in silaffins (a potential matrix in the formation of biogenic silica) little complexation with the polyamine fluorophores was observed, bringing into question the role of a polyamine - polymeric phosphate matrix in biosilicification. PMID- 29475087 TI - The SEC14 phospholipid transfer protein regulates pathogen-associated molecular pattern-triggered immunity in Nicotiana benthamiana. AB - We previously revealed that the SEC14 phospholipid transfer protein from Nicotiana benthamiana (NbSEC14) has a role in plant immune responses against phytopathogenic bacteria in a hypersensitive response-independent manner. To characterize the role of NbSEC14 on plant immunity, we analyzed the relationship between NbSEC14 and pathogen-associated molecular pattern-triggered immunity (PTI). NbSEC14-silenced plants exhibited down-regulated expression of PTI marker genes (NbAcre31 and NbPti5) after being inoculated with Pseudomonas syringae pv. tabaci. Additionally, we observed accelerated bacterial growth and inhibited expression of PTI marker genes in NbSEC14-silenced plants infected with the hrp deficient P. syringae pv. tabaci mutant. We used Pseudomonas fluorescens and flg22 as PTI inducers to further examine the association between NbSEC14 and the induction of PTI. The expression of PTI marker genes was compromised in NbSEC14 silenced plants infiltrated with P. fluorescens and flg22. Meanwhile, a cell death-based PTI assay indicated NbSEC14 was required for PTI. Furthermore, callose deposition and disease resistance induced by flg22 were compromised in NbSEC14-silenced plants. These results suggest that NbSEC14 may help regulate the induction of PTI. PMID- 29475088 TI - The Arabidopsis GORK K+-channel is phosphorylated by calcium-dependent protein kinase 21 (CPK21), which in turn is activated by 14-3-3 proteins. AB - Potassium (K+) is a vital ion for many processes in the plant and fine-tuned ion channels control the K+-fluxes across the plasma membrane. GORK is an outward rectifying K+-channel with important functions in stomatal closure and in root K+ homeostasis. In this study, post-translational modification of the Arabidopsis GORK ion channel and its regulation by 14-3-3 proteins was investigated. To investigate the possible interaction between GORK and 14-3-3s an in vivo pull down from an Arabidopsis protein extract with recombinant GORK C-terminus (GORK C) indeed identified endogenous 14-3-3s (LAMBDA, CHI, NU) as binding partners in a phosphorylation dependent manner. However, a direct interaction between 14-3 3's and GORK-C could not be demonstrated. Since the pull-down of 14-3-3s was phosphorylation dependent, we determined GORK-C as substrate for CPK21 phosphorylation and identified three CPK21 phospho-sites in the GORK protein (T344, S518 and S649). Moreover, interaction of 14-3-3 to CPK21 strongly stimulates its kinase activity; an effect that can result in increased GORK phosphorylation and change in activity. Using the non-invasive vibrating probe technique, we measured the predominantly GORK mediated salt induced K+-efflux from wild-type, gork, cpk21, aha2 and 14-3-3 mutant roots. The mutants cpk21 and aha2 did not show statistical significant differences compared to WT. However, two (out of six) 14-3-3 isoforms, CHI and PHI, have a clear function in the salt induced K+-efflux. In conclusion, our results show that GORK can be phosphorylated by CPK21 and suggest that 14-3-3 proteins control GORK activity through binding with and activation of CPK21. PMID- 29475089 TI - The effect of 1-methylcyclopropene (1-MCP) on expression of ethylene receptor genes in durian pulp during ripening. AB - Rapid fruit ripening is a significant problem that limits the shelf life of durian, with ethylene having a major impact on the regulation of this event. Durian treated with ethephon ripened 3 d after treatment with increased pulp total soluble solids, ethylene production of the whole fruit and decreased pulp firmness compared to the control fruit. 1-MCP treatment delayed ripening by up to 9 d with inhibited accumulation of total soluble solids, color change, softening and ethylene production. Genes related to ethylene perception (DzETR1 and DzETR2) and the signaling pathway (DzCTR1, DzEIL1 and DzEIL2) in the pulp were investigated during this process, using qPCR to quantify changes in gene transcription. All candidate genes were significantly up-regulated in ripening durian pulp. Ethephon treatment increased the expression of DzETR1 and DzETR2 genes, while expression of DzCTR1, DzEIL1 and DzEIL2 were slightly affected. 1 MCP treatment significantly inhibited the expression of the DzETR2 and DzEIL1 genes. The promoters of DzETR2 genes were isolated and their activation by fruit transcription factors studied using transient expression in tobacco leaves. It was found that members of the kiwifruit and apple EIL1, EIL2 and EIL3 genes strongly activated the DzETR2 promoter. These results suggest that ethylene induced ripening of durian is via the regulation of DzETR2 by EIL transcription factors. PMID- 29475090 TI - Elevated intragraft expression of innate immunity and cell death-related markers is a risk factor for adverse graft outcome. AB - BACKGROUND: Molecules of the innate immune response are increasingly recognized as important mediators in allograft injury during and after kidney transplantation. We therefore aimed to establish the relationship between the expression of these genes at implantation, during an acute rejection (AR) and on graft outcome. METHODS: A total of 19 genes, including Toll like receptors (TLRs), complement components and regulators, and apoptosis-related genes were analyzed at the mRNA level by qPCR in 123 biopsies with acute rejection and paired pre-transplantation tissue (n = 75). RESULTS: Before transplantation, relative mRNA expression of BAX:BCL2 ratio (apoptosis marker) and several complement genes was significantly higher in tissue samples from deceased donors compared to living donors. During AR, TLRs and complement genes showed an increased expression compared to pre-transplant conditions, whereas complement regulators were decreased. A relatively high TLR4 expression level and BAX:BCL2 ratio during AR in the deceased donor group was associated with adverse graft outcome, independently of clinical risk factors. CONCLUSIONS: Complement- and apoptosis-related gene expression is elevated in deceased donor transplants before transplantation. High BAX:BCL2 ratio and TLR4 expression during AR may reflect enhanced intragraft cell death and immunogenic danger signals, and pose a risk factor for adverse graft outcome. PMID- 29475091 TI - Effect of induction therapy on peripheral blood lymphocytes after lung transplantation: A multicenter international study. PMID- 29475092 TI - The impact of donor characteristics on the invariant natural killer T cells of granulocyte-colony-stimulating factor-mobilized marrow grafts and peripheral blood grafts. AB - INTRODUCTION: Invariant natural killer T cells (iNKTs) are a rare but vital subset of immunomodulatory T cells and play an important role in allogeneic hematopoietic stem cell trans-plantation (HSCT). The association of donor characteristics with the number and frequency of the iNKTs subsets in allografts remains poorly understood. In this paper, we prospectively investigate the association of donor characteristics with iNKTs dose and frequency in granulocyte colony-stimulating factor (G-CSF) mobilized marrow and peripheral blood harvests. MATERIALS AND METHODS: 100 bone marrow (BM) units and 100 peripheral blood (PB) units from 100 healthy donors were examined. Parameters including donor age, sex, weight, height, BMI and blood count [including white blood cells (WBCs), lymphocytes and monocytes] at three time points [donor's steady state before G CSF administration, the day of G-BM harvesting and the day of G-PB apheresis] were analyzed to explore the impact of donor characteristics on iNKTs composition in BM and PB grafts. RESULTS: Multivariate analysis showed monocyte counts before G-BM harvest could predict higher frequency of iNKTs in WBC (OR = 2.593, 95%CI: 1.128-5.961, p = 0.025), higher total CD4+ iNKTs dose (OR = 2.250, 95%CI: 1.011 5.008, p = 0.047) and higher total iNKTs dose (OR = 2.662, 95%CI: 1.187-5.970, p = 0.017) in mixture allografts. DISCUSSION: The results suggested that monocyte counts pre G-BM harvest could predict the yield of total CD4+ iNKTs and total iNKTs in mixture allografts. The male and older donors were associated with a higher dose of total CD4- iNKTs in mixture allografts. PMID- 29475093 TI - Nurse practitioner independence, health care utilization, and health outcomes. AB - Many states allow nurse practitioners (NPs) to practice and prescribe drugs without physician oversight, increasing the number of autonomous primary care providers. We estimate the causal impact of NP independence on population health care utilization rates and health outcomes, exploiting variation in the timing of state law passage. We find that NP independence increases the frequency of routine checkups, improves care quality, and decreases emergency room use by patients with ambulatory care sensitive conditions. These effects come from decreases in administrative costs for physicians and NPs and patients' indirect costs of accessing medical care. PMID- 29475095 TI - Immunomodulatory effects of thionin Thi2.1 from Arabidopsis thaliana on bovine mammary epithelial cells. AB - Antimicrobial peptides (AMPs) are key elements of plant defense mechanisms, resembling conserved protection strategies also present in mammals. Among the AMPs, plant thionins are particularly interesting due that display antibacterial and antifungal activities. In Arabidopsis thaliana have been described four thionins: Thi2.1, Thi2.2, Thi2.3 and Thi2.4. Work from our group shows that Thi2.1 expressed by bovine endothelial cells has direct antibacterial activity against Staphylococcus aureus mastitis isolates, bacteria able to persist inside bovine mammary epithelial cells (bMECs). Thus, the objective of this work was to analyze the immunomodulatory effects of the AMP thionin Thi2.1 from A. thaliana on bMECs during S. aureus infection. According to the results, S. aureus internalization into bMECs was reduced in cells pre-treated with Thi2.1 at 5 and 10 MUg/mL during 24 h, effect related to the participation of TLR2. In addition, bMECs pre-treated with Thi2.1 (24 h) significantly increased TNF-alpha (~2-fold) and IL-6 (~7-fold), whereas decreased IL-10 gene expression (~0.5-fold). Interestingly, Thi2.1 inhibits the up-regulation induced by S. aureus of TNF alpha and IL-10 gene expression, as well as NO production. In addition, Thi2.1 (10 MUg/mL) up-regulates the expression of the chemokine IL-8 (~3-fold) in infected bMECs. Some of these effects are related to TLR2 activation. In this sense, Thi2.1 also reduces S. aureus-induced TLR2 gene expression and membrane abundance. In conclusion, Thi2.1 from A. thaliana modulates bMEC innate immune response by inducing the production of pro- and anti-inflammatory molecules while inhibits S. aureus internalization. Some of these effects are mediated by TLR2. PMID- 29475094 TI - Effects of Levetiracetam and Sulthiame on EEG in benign epilepsy with centrotemporal spikes: A randomized controlled trial. AB - PURPOSE: BECTS (benign childhood epilepsy with centrotemporal spikes) is associated with characteristic EEG findings. This study examines the influence of anti-convulsive treatment on the EEG. METHODS: In a randomized controlled trial including 43 children with BECTS, EEGs were performed prior to treatment with either Sulthiame or Levetiracetam as well as three times under treatment. Using the spike-wave-index, the degree of EEG pathology was quantified. The EEG before and after initiation of treatment was analyzed. Both treatment arms were compared and the EEG of the children that were to develop recurrent seizures was compared with those that were successfully treated. RESULTS: Regardless of the treatment agent, the spike-wave-index was reduced significantly under treatment. There were no differences between the two treatment groups. In an additional analysis, the EEG characteristics of the children with recurrent seizures differed statistically significant from those that did not have any further seizures. CONCLUSION: Both Sulthiame and Levetiracetam influence the EEG of children with BECTS. Persistent EEG pathologies are associated with treatment failures. PMID- 29475097 TI - Kaempferol-3-o-beta-d-glucuronate exhibit potential anti-inflammatory effect in LPS stimulated RAW 264.7 cells and mice model. AB - Kaempferol-3-O-beta-d-glucuronide (K3G) having various pharmacological effects was explored for its anti-inflammatory effect in LPS induced RAW 264.7 cells and mice model. K3G significantly inhibited various pro-inflammatory mediators like IL-1beta, NO, PGE2, and LTB4. It upregulated the secretion of anti-inflammatory cytokine IL-10. K3G is found to reduce inflammation when studied for parameters like phagocytic index, carrageenan induced paw edema in mice and organ weight. It reduced inflammation in a dose dependent manner both in-vitro and in-vivo. Further molecular insights into the study reveal that K3G blocks the phosphorylation of NF-kB which is key regulator of inflammation, thereby exhibiting anti-inflammatory potential. Hence, this study permits further investigation to develop K3G as anti-inflammatory drug. PMID- 29475096 TI - Phenotypic and functional profile of Th17 and Treg cells in allergic fungal sinusitis. AB - Interleukin-17 producing T helper (Th17) and regulatory T cells (Treg) cells have been identified to play a critical role in atopic inflammation. However, conflicting reports on the role of Th17/Treg cells in allergic fungal rhinosinusitis (AFRS) patients of different ethnicities has mystified its pathogenesis. To better understand the pathophysiological mechanisms involved in AFRS, we conducted a prospective, analytical, case-control study involving 40 confirmed immunocompetent AFRS patients and 20 healthy controls. The distribution of Th17 and Treg cells in PBMC, intracellular mRNA expression of retinoid orphan nuclear receptor (RORgammat) in Th17 and forkhead transcription factor (FoxP3) in Treg cells, and serum cytokine levels were investigated. Aspergillus flavus was identified from majority (85%) of patient tissue biopsies. Total serum IgE level along with cytokines IL-17, IL-21, IL-1beta and TGF-beta were comparatively elevated in AFRS. Nevertheless, IL-2 and IL-10 were reduced. Higher percentages of CD3+CD4+ T cells in AFRS with increased expression of CD161 and/or IL-23R markers were observed. Though, lower percentages of CD4+CD25+ Treg cells with elevated expression of GITR were patent. Transcription factor RORgammat mRNA was upregulated, whereas FoxP3 mRNA was downregulated in AFRS patients. This inclination of Th17/Treg balance towards Th17, and the proposed role of Tregs on Th1 and Th2 cells in AFRS, directed us to conclude that Aspergillus infestation may lead to development of atopy and immunological dysbalance inciting a Th17 driven response, thereby, promoting aggravation of nasal polyposis. The observation may provide new insight into the molecular mechanisms leading to revision of the classical paradigm. PMID- 29475098 TI - XQ-1H protects against ischemic stroke by regulating microglia polarization through PPARgamma pathway in mice. AB - Cerebral ischemic and reperfusion injury often accompany with inflammation, and lead to severe neuronal damage, which further result in neurological disorders and memory disorders. In this study, we researched XQ-1H, a novel derivative of ginkgolide B, protecting against ischemic stroke in mice through regulation of microglia polarization. Middle cerebral artery occlusion (MCAO)/reperfusion in mice is applied to mimic ischemic stroke in vivo. Immediately after MCAO, mice are intragastric administrated with different dose (31 or 62 mg/kg) of XQ-1H for one or continuative three days. The in vivo experiments indicated that post treatment with XQ-1H decreased cerebral infarction size, lessened brain edema, improved behavior and memory recover, inhibited pro-inflammatory and promoted anti-inflammatory cytokines expression and releasing in MCAO mice. Oxygen-glucose deprivation/reoxygenation (OGD/R) injury in BV-2 (microglia) cells is served in vitro. The in vitro findings revealed that incubation with XQ-1H protected against BV2 from OGD/R injury, regulated BV2 polarized from pro-inflammatory into anti-inflammatory phenotype, and promoted PPARgamma mobilizing from nuclear to cytoplasm. In conclusion, the present study demonstrates that XQ-1H alleviated ischemic stroke by regulating balance of pro-/anti-inflammatory microglia polarization through PPARgamma pathway both in vivo and in vitro, offering an alternative medication for stroke associated with inflammation. PMID- 29475099 TI - Andrographolide derivative CX-10 ameliorates dextran sulphate sodium-induced ulcerative colitis in mice: Involvement of NF-kappaB and MAPK signalling pathways. AB - Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD), which is characterized by chronic intestinal inflammation and leads to an increased risk of colon cancer. There are many studies using phyto-ingredients as a novel approach for the treatment of UC. The plant Andrographis paniculata (Acanthaceae) is a safe and edible vegetable that has been extensively adopted in traditional Chinese medicine for conditions involving inflammation, and the most active phytochemical agent is andrographolide. The andrographolide derivative 3,14,19 triacetyl andrographolide, which is known as CX-10 (a hemi chemical synthesized from andrographolide), has been found to possess strong anti-inflammatory properties. In the present study, we investigated the therapeutic potential of CX 10 as a complementary and alternative medicine against dextran sulphate sodium (DSS)-induced ulcerative colitis in mice. Our results revealed that CX-10 treatment reduced body weight loss, reduced colon length shortening, decreased colon weight, decreased the spleen index, decreased the disease activity index (DAI), and alleviated histological damage in the colon. The expression of TNF alpha and IL-6 and the activity of myeloperoxidase (MPO) in colonic tissues were significantly reduced in CX-10 supplemented mice. It is noteworthy that the efficacy of 200 mg/kg of CX-10 was equivalent to that of the mesalazine positive control (200 mg/kg). Furthermore, western blot analysis revealed that CX-10 treatment reduced the expression of nuclear factor-kappaB (NF-kappaB) p65 and p IkappaBalpha, increased the expression of IkappaBalpha and down-regulated the phosphorylation of p38 mitogen-activated protein kinase (MAPK), ERK and JNK. In conclusion, CX-10 treatment attenuated DSS-induced UC in mice through inhibiting the activation of NF-kappaB and MAPK pathways and reducing TNF-alpha and IL-6 levels, suggesting that CX-10 is a potential therapeutic drug for UC. PMID- 29475101 TI - Analyzing MU-Calpain induced proteolysis in a myofibril model system with vibrational and fluorescence spectroscopy. AB - Degree of post-mortem proteolysis influences overall meat quality (e.g. tenderness and water holding capacity). Degradation of isolated pork myofibril proteins by MU-Calpain for 0, 15 or 45 min was analyzed using four spectroscopic techniques; Raman, Fourier transform infrared (FT-IR), near infrared (NIR) and fluorescence spectroscopy. Sodium dodecyl sulfate polyacrylamide gel electrophoresis was used to determine degree of proteolysis. The main changes detected by FT-IR and Raman spectroscopy were degradation of protein backbones manifested in the spectra as an increase in terminal carboxylic acid vibrations, a decrease in CN vibration, as well as an increase in skeletal vibrations. A reduction in beta-sheet secondary structures was also detected, while alpha-helix secondary structure seemed to stay relatively unchanged. NIR and fluorescence were not suited to analyze degree of proteolysis in this model system. PMID- 29475102 TI - Predictors of benzodiazepine use in a transdiagnostic sample of panic disorder, social anxiety disorder, and obsessive-compulsive disorder patients. AB - We investigated the rates of current and past benzodiazepine (BZD) use in a sample of 102 subjects attending specialized anxiety disorder clinics, including panic disorder (PD; N = 36), social anxiety disorder (SAD; N = 28) and obsessive compulsive disorder (OCD; N = 38) patients. Almost 56% of the entire sample was using BZDs at the moment of the assessment, and 74.5% described having used them at some point during their lifetimes. The duration of psychiatric treatment and a lifetime history of PD, but not any other "transdiagnostic" measure of severity (such as the Panic and Agoraphobia Scale, the Social Phobia Inventory, the Dimensional Obsessive-Compulsive Scale, the Anxiety Sensitivity Index-36, and the Beck Inventories) were independent risk factors for current prescription of BZDs. Patients who continued to use BZDs differed from patients who stopped them by being older (both currently and when firstly seen in the clinic), by having a later age at onset of their most significant anxiety disorder, by being more agoraphobic/avoidant, and by believing to be less capable of stopping their BZDs for the fear of not being able to sleep. PMID- 29475100 TI - New thiazolidinedione LPSF/GQ-2 inhibits NFkappaB and MAPK activation in LPS induced acute lung inflammation. AB - Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are responsible for high mortality rates in critical patients. Despite >50 years of intensive research, there is no pharmacologically effective treatment to treat ALI. PPARs agonists, chemically named thiazolidinediones (TZDs) have emerged as potential drugs for the treatment of ALI and ARDS due to their anti-inflammatory efficacy. The present study aims to evaluate the potential anti-inflammatory effects of new TZDs derivatives, LPSF/GQ-2 and LPSF/RA-4, on ALI induced by LPS. BALB/c mice were divided into five groups: 1) Control; 2) LPS intranasal 25 MUg; 3) LPSF/GQ-2 30 mg/kg + LPS; 4) LPSF/RA-4 20 mg/kg + LPS; and 5) DEXA 1 mg/Kg + LPS. BALF analyses revealed that LPSF/GQ-2 and LPSF/RA-4 reduced NO levels in BALF and inflammatory cell infiltration induced by LPS. MPO levels were also reduced by the LPSF/GQ-2 and LPSF/RA-4 pre-treatments. In contrast, histopathological analyses showed better tissue protection with LPSF/GQ-2 than DEXA and LPSF/RA-4 groups. Similarly, LPSF/GQ-2 reduced inflammatory markers (IL 1, iNOS, TNFalpha, IL-1beta, IL-6) better than LPSF/RA-4. The LPSF/GQ-2 anti inflammatory action could be attributed to the inhibition of NFkappaB, ERK, p38, and PARP pathways. In contrast, LPSF/RA-4 had no effect on the expression of p38, JNK, NFkappaB. The present study indicates that LPSF/GQ-2 presents a potential therapeutic role as an anti-inflammatory drug for ALI. PMID- 29475103 TI - Increased delayed reward during intertemporal decision-making in schizophrenic patients and their unaffected siblings. AB - Intertemporal choices are decisions with consequences in multiple time periods and constitute a significant part of social cognition. The shared neuropathological characteristics of patients with schizophrenia and their siblings might express intermediate phenotypes in behavior that could be used to further characterize the illness. Schizophrenic patients, unaffected siblings, and healthy controls underwent a computerized version of the "Intertemporal Choice Task". All participants could choose between sooner-smaller (SS) and later larger (LL) options in now-trials and in not-now-trials. Subjects also underwent a battery of cognitive neuropsychological assessment. Our results indicated that schizophrenic patients and unaffected siblings both had a tendency to choose LL options in now-trials or not-now-trials compared to healthy controls. Schizophrenic patients had significantly lower scores in several cognitive tasks, including MoCA, attention, executive functions, and information processing when compared with the other two groups. Moreover, within the schizophrenic patient group, significant correlations were found between intertemporal decision-making performance and executive function. The present study showed that both schizophrenic patients and unaffected siblings preferred to choose larger-delayed rewards during intertemporal decision-making, which may result from frontal striatal and frontal-parietal network dysfunction. Their intertemporal decision making performance was associated with executive function performance. PMID- 29475104 TI - Distress and sleep quality in young amphetamine-type stimulant users with an affective or psychotic illness. AB - Misuse of amphetamine-type stimulant (ATS) drugs may disrupt key neurodevelopmental processes in young people and confer protracted neurocognitive and psychopathological harm. ATS users with a co-occurring psychiatric illness are typically excluded from research, reducing generalisability of findings. Accordingly, we conducted a cross-sectional examination of key clinical, sleep, socio-occupational and neurocognitive measures in current, past and never users of ATS drugs who were accessing a youth mental health service (headspace) for affective- or psychotic-spectrum illnesses. Contrary to hypotheses, groups did not differ in psychotic symptomology, socio-occupational functioning or neurocognitive performance. Current ATS users were however significantly more distressed and reported poorer subjective sleep quality and greater subjective sleep disturbances than never users, with a trend toward greater depressive symptomology in current users. Regression analyses revealed that depressive symptoms, daily ATS use and socio-occupational functioning predicted distress, and depressive symptoms and distress predicted subjective sleep quality. Our findings suggest that distress and poor sleep quality reflect a particular pathophysiology among ATS-using patients, which may negatively impact treatment engagement. Delineating the factors that disrupt social and neurobiological development in young people (such as substance use) warrants further investigation, including longitudinal study. PMID- 29475105 TI - The prevalence of posttraumatic stress in adolescents eight years after the Wenchuan earthquake. AB - In 2008, an 8.0 Richter scale earthquake devastated Wenchuan in China, which resulted in heavy casualties, and had wide-reaching psychological effects on survivors. To examine its impact on the survivors, this study aims to investigate the prevalence of posttraumatic stress disorder (PTSD) and posttraumatic growth (PTG) in adolescents eight years after the earthquake. The cross-section survey was conducted in two different earthquake-affected areas, and data were collected from 4118 respondents. Instruments included the questionnaire on demographic information, the questionnaire on seismic exposure, PTSD Checklist-Civilian Version (PCL-C) questionnaire, Posttraumatic Growth Inventory (PTGI), Perceived Social Support Scale (PSSS) and Simple Coping Style Questionnaire (SCSQ). During the survey, there were 1998 valid questionnaires from the generally affected area and 2120 questionnaires from the severely affected area. The rate of PTSD is 1.9% in the generally affected area and 2.7% in the severely affected disaster area; there is no significant difference between the two differently affected areas. Occurrences of PTSD and PTG are significantly positively correlated in the generally affected area, nevertheless, there is a significant negative correlation between PTSD and PTG in most systems of the severely affected area. The results of this study help to expand our knowledge regarding posttraumatic stress in adolescents 8 years after the Wenchuan earthquake, and it provides suggestions for specific long-term health interventions in such populations. To prevent earthquake-related psychological issues among adolescent survivors, social support, psychological aid, and improvement of the living environment are necessary to buffer negative posttraumatic stress. PMID- 29475106 TI - Combining biotechnology with circular bioeconomy: From poultry, swine, cattle, brewery, dairy and urban wastewaters to biohydrogen. AB - The ability of microalgae to grow in nutrient-rich environments and to accumulate nutrients from wastewaters (WW) makes them attractive for the sustainable and low cost treatment of WW. The valuable biomass produced can be further used for the generation of bioenergy, animal feed, fertilizers, and biopolymers, among others. In this study, Scenedesmus obliquus was able to remove nutrients from different wastewaters (poultry, swine and cattle breeding, brewery and dairy industries, and urban) with removal ranges of 95-100% for nitrogen, 63-99% for phosphorus and 48-70% for chemical oxygen demand. The biomass productivity using wastewaters was higher (except for poultry) than in synthetic medium (Bristol), the highest value being obtained in brewery wastewater (1025 mg/(L.day) of freeze-dried biomass). The produced biomass contained 31-53% of proteins, 12-36% of sugars and 8-23% of lipids, regardless of the type of wastewater. The potential of the produced Scenedesmus obliquus biomass for the generation of BioH2 through batch dark fermentation processes with Enterobacter aerogenes was evaluated. The obtained yields ranged, in mL H2/g Volatile Solids (VS), from 50.1 for biomass from anaerobically digested cattle WW to 390 for swine WW, whereas the yield with biomass cultivated in Bristol medium was 57.6 mL H2/gVS. PMID- 29475107 TI - Effect of socio-economic status, family smoking and mental health through social network on the substance use potential in adolescents: a mediation analysis. AB - OBJECTIVES: Understanding pathways that influence substance use potential (SUP) can help with effective substance use prevention interventions among adolescents. The aim of the present study is to contribute to a better understanding of the SUP of adolescents by examining the mediating role of social network quality in the SUP of Iranian adolescents. STUDY DESIGN: A cross-sectional study. METHODS: Structural equation modeling was conducted to assess the hypothesized model that social network quality would mediate the association of family socio-economic status, a mental health disorder, and family smoking with addiction potential. RESULTS: The model shows a good fit to the data. Social network quality mediated the effect of family smoking on the SUP for boys. A mental health disorder had a positive significant direct effect on addiction potential for both girls and boys. CONCLUSIONS: Social network quality mediates the effect of family smoking on boys' addiction potential in the context of Iran. Educational programs based on local societal ways and cultural norms are recommended to change tobacco smoking behavior among family members. In addition, to prevent subsequent substance use among adolescents, more effort is needed to improve their mental health. PMID- 29475108 TI - Intriguing changes in molecular size and composition of dissolved organic matter induced by microbial degradation and self-assembly. AB - Dissolved organic matter (DOM) is ubiquitous and plays an important role in regulating water quality, ecological function, and the fate and transport of trace elements and pollutants in aquatic environments. Both the colloidal precursors (i.e. <1 kDa) and bulk DOM collected from a freshwater estuary were incubated in the dark for 21 days to examine dynamic changes in molecular size and composition induced by microbial degradation and self-assembly. Results showed that the concentrations of total organic carbon, carbohydrates, and protein-like substances decreased by 11-30% during incubation, while those of humic- and fulvic-like substances remained relatively constant, indicating humic substances are more resistant to microbial utilization compared to carbohydrates and protein-like DOM. Despite the different extents in decline, these DOM components had a similar transformation pathway from the <1 kDa to colloids (1 kDa-0.45 MUm) and further to microparticles (>0.45 MUm). Overall, carbohydrates and protein-like substances, especially the high molecular weight components, were preferentially decomposed by microorganisms whereas humic- and fulvic-like DOM components significantly coagulated through abiotic self-assembly. The contrasting degradation/transformation pathways between the humic-like and protein-like substances along the size continuum, as also characterized by flow field-flow fractionation analysis, demonstrated that the dynamic transformation and degradation of DOM is regulated by both molecular size and organic composition. This finding provides new insights into the biogeochemical cycling pathways of heterogeneous DOM and its environmental fate and ecological role in aquatic systems. PMID- 29475109 TI - Solar treatment (H2O2, TiO2-P25 and GO-TiO2 photocatalysis, photo-Fenton) of organic micropollutants, human pathogen indicators, antibiotic resistant bacteria and related genes in urban wastewater. AB - Solar-driven advanced oxidation processes were studied in a pilot-scale photoreactor, as tertiary treatments of effluents from an urban wastewater treatment plant. Solar-H2O2, heterogeneous photocatalysis (with and/or without the addition of H2O2 and employing three different photocatalysts) and the photo Fenton process were investigated. Chemical (sulfamethoxazole, carbamazepine, and diclofenac) and biological contaminants (faecal contamination indicators, their antibiotic resistant counterparts, 16S rRNA and antibiotic resistance genes), as well as the whole bacterial community, were characterized. Heterogeneous photocatalysis using TiO2-P25 and assisted with H2O2 (P25/H2O2) was the most efficient process on the degradation of the chemical organic micropollutants, attaining levels below the limits of quantification in less than 4 h of treatment (corresponding to QUV < 40 kJ L-1). This performance was followed by the same process without H2O2, using TiO2-P25 or a composite material based on graphene oxide and TiO2. Regarding the biological indicators, total faecal coliforms and enterococci and their antibiotic resistant (tetracycline and ciprofloxacin) counterparts were reduced to values close, or beneath, the detection limit (1 CFU 100 mL-1) for all treatments employing H2O2, even upon storage of the treated wastewater for 3-days. Moreover, P25/H2O2 and solar-H2O2 were the most efficient processes in the reduction of the abundance (gene copy number per volume of wastewater) of the analysed genes. However, this reduction was transient for 16S rRNA, intI1 and sul1 genes, since after 3-days storage of the treated wastewater their abundance increased to values close to pre-treatment levels. Similar behaviour was observed for the genes qnrS (using TiO2-P25), blaCTX-M and blaTEM (using TiO2-P25 and TiO2-P25/H2O2). Interestingly, higher proportions of sequence reads affiliated to the phylum Proteobacteria (Beta- and Gammaproteobacteria) were found after 3-days storage of treated wastewater than before its treatment. Members of the genera Pseudomonas, Rheinheimera and Methylotenera were among those with overgrowth. PMID- 29475110 TI - Pathological fracture risk assessment in patients with femoral metastases using CT-based finite element methods. A retrospective clinical study. AB - Physician recommendation for prophylactic surgical fixation of a femur with metastatic bone disease (MBD) is usually based on Mirels' criteria and clinical experience, both of which suffer from poor specificity. This may result in a significant number of these health compromised patients undergoing unnecessary surgery. CT-based finite element analyses (CTFEA) have been shown to accurately predict strength in femurs with metastatic tumors in an ex-vivo study. In order to assess the utility of CTFEA as a clinical tool to determine the need for fixation of patients with MBD of the femur, an ad hoc CTFEA was performed on a retrospective cohort of fifty patients. Patients with CT scans appropriate for CTFEA analysis were analyzed. Group 1 was composed of 5 MBD patients who presented with a pathologic femoral fracture and had a scan of their femurs just prior to fracture. Group 2 was composed of 45 MBD patients who were scheduled for a prophylactic surgery because of an impending femoral fracture. CTFEA models were constructed for both femurs for all patients, loaded with a hip contact force representing stance position loading accounting for the patient's weight and femur anatomy. CTFEA analysis of Group 1 patients revealed that they all had higher tumor associated strains compared to typical non-diseased femur bone strains at the same region (>45%). Based on analysis of the 5 patients in Group 1, the ratio between the absolute maximum principal strain in the vicinity of the tumor and the typical median strain in the region of the tumor of healthy bones (typical strain fold ratio) was found to be the 1.48. This was considered to be the predictive threshold for a pathological femoral fracture. Based on this typical strain fold ratio, twenty patients (44.4%) in Group 2 were at low risk of fracture and twenty-five patients (55.5%) high risk of fracture. Eleven patients in Group 2 choose not to have surgery and none fractured in the 5month follow-up period. CTFEA predicted that seven of these patients were below the pathological fracture threshold and four above, for a specificity of 63% Based on CTFEA, 39% of the patients with femoral MBD who were referred and underwent prophylactic stabilization may not have needed surgery. These results indicate that a prospective randomized clinical trial evaluating CTFEA as a criterion for determining the need for surgical stabilization in patients with MBD of the femur may be warranted. PMID- 29475111 TI - PTH (1-34) and growth hormone in prevention of disuse osteopenia and sarcopenia in rats. AB - Osteopenia and sarcopenia develops rapidly during disuse. The study investigated whether intermittent parathyroid hormone (1-34) (PTH) and growth hormone (GH) administered alone or in combination could prevent or mitigate disuse osteopenia and sarcopenia in rats. Disuse was achieved by injecting 4IU botulinum toxin A (BTX) into the right hindlimb musculature of 12-14-week-old female Wistar rats. Seventy-two rats were divided into six groups: 1. Baseline; 2. Ctrl; 3. BTX; 4. BTX+GH; 5. BTX+PTH; 6. BTX+PTH+GH. PTH (1-34) (60MUg/kg/day) and GH (5mg/kg/day). The animals were sacrificed after 6weeks of treatment. Sarcopenia was established by histomorphometry, while the skeletal properties were determined using DXA, MUCT, mechanical testing, and dynamic bone histomorphometry. Disuse resulted in lower muscle mass (-63%, p<0.05), trabecular BV/TV (-28%, p<0.05), Tb.Th (-11%, p<0.05), lower diaphyseal cortical thickness (-10%, p<0.001), and lower bone strength at the distal femoral metaphysis (-27%, p<0.001) compared to Ctrl animals. PTH fully counteracted the immobilization-induced lower BV/TV, Tb.Th, and distal femoral metaphyseal strength. GH increased muscle mass (+17%, p<0.05) compared to BTX, but did not prevent the immobilization-induced loss of bone strength, BV/TV, and cortical trabecular thickness. Combination of PTH and GH increased distal femoral metaphyseal bone strength (+45%, p<0.001), BV/TV (+50%, p<0.05), Tb.Th (+40%, p<0.05), and whole femoral aBMD (+15%, p<0.001) compared to BTX and muscle mass (+21%, p<0.05) compared to BTX+PTH. In conclusion, PTH and GH in combination is more efficient at preventing the disuse-related deterioration of bone strength, density, and micro-architecture than either PTH or GH given as monotherapy. Furthermore, GH, either alone or in combination with PTH, attenuated disuse-induced loss of muscle mass. The combination of PTH and GH resulted in a more effective treatment than PTH and GH as monotherapy. PMID- 29475112 TI - What's the point? The contribution of a sustainability view in contaminated site remediation. AB - Decision support tools (DST) are often used in remediation projects to aid in the complex decision on how best to remediate a contaminated site. In recent years, the sustainable remediation concept has brought increased attention to the often overlooked contradictory effects of site remediation, with a number of sustainability assessment tools now available. The aim of the present study is twofold: (1) to demonstrate how and when different assessment views affect the decision support outcome on remediation alternatives in a DST, and (2) to demonstrate the contribution of a full sustainability assessment. The SCORE tool was used in the analysis; it is based on a holistic multi-criteria decision analysis (MCDA) approach, assessing sustainability in three dimensions: environmental, social, and economic. Four assessment scenarios, compared to a full sustainability assessment, were considered to reflect different possible assessment views; considering public and private problem owner perspectives, as well as green and traditional assessment scopes. Four real case study sites in Sweden were analyzed. The results show that the decision support outcome from a full sustainability assessment most often differs to that of other assessment views, and results in remediation alternatives which balance trade-offs in most of the scenarios. In relation to the public perspective and traditional scope, which is seen to lead to the most extensive and expensive remediation alternatives, the trade-off is related to less contaminant removal in favour of reduced negative secondary effects such as emissions and waste disposal. Compared to the private perspective, associated with the lowest cost alternatives, the trade-off is higher costs, but more positive environmental and social effects. Generally, both the green and traditional assessment scopes miss out on relevant social and local environmental secondary effects which may ultimately be very important for the actual decision in a remediation project. PMID- 29475113 TI - Assessment of heavy metal pollution and human health risks in urban soils around an electronics manufacturing facility. AB - Heavy metal pollution has pervaded many parts of the world, especially in developing countries. The purpose of this study was to determine the concentrations and health risks of heavy metals in urban soils around an electronics manufacturing site in the Hubei Province of China. Soils samples were collected from commercial, roadside, farmland, and residential areas around the electronics manufacturing facility. A total of 136 topsoil samples were collected, and these samples were analyzed for Cr, Cu, Zn, As, Cd, Ni, and Pb. The geoaccumulation index (Igeo), pollution index (PI), and potential ecological risk index (PER) were calculated to assess the soil pollution levels. The hazard index (HI) was used to assess the human health risks posed by the presence of heavy metals. The total concentrations of the seven congeners (?metals) ranged from 3738.86 to 5173.25mgkg-1, and the concentrations were highest in the commercial area followed (in decreasing order) by the roadside, farmland, and residential areas. The HI for children and adults descended in the order of Cr>As>Pb>Cd>Cu>Ni>Zn. The carcinogenic risks of two metals, namely, Cr and As, for children and adults were higher than 10-4, and children faced greater health risks. PMID- 29475114 TI - Experimental and simulation study of the restoration of a thallium (I) contaminated aquifer by Permeable Adsorptive Barriers (PABs). AB - Permeable Adsorptive Barriers (PABs), filled with a commercial activated carbon, are tested as a technique for the remediation of a thallium (I)-contaminated aquifer located in the south of Italy. Thallium adsorption capacity of the activated carbon is experimentally determined through dedicated laboratory tests, allowing to obtain the main modelling parameters to describe the adsorption phenomena within the barrier. A 2D numerical model, solved by using a finite element approach via COMSOL Multi-physics(r), is used to simulate the contaminant transport within the aquifer and for the PAB design. Investigations are carried out on an innovative barrier configuration, called Discontinuous Permeable Adsorptive Barrier (PAB-D). In addition, an optimization procedure is followed to determine the optimum PAB-D parameters, and to evaluate the total costs of the intervention. A PAB-D made by an array of wells having a diameter of 1.5m and spaced at a distance of 4m from each other, is shown to be the most cost effective of those tested, and ensures the aquifer restoration within 80years. The simulation outcomes demonstrate that the designed PAB-D is an effective tool for the remediation of the aquifer under analysis, since the contaminant concentration downstream of the barrier is below the thallium regulatory limit for groundwater, also accounting for possible desorption phenomena. Finally, the best PAB-D configuration is compared with a continuous barrier (PAB-C), resulting in a 32% saving of adsorbing material volume, and 36% of the overall costs for the PAB-D. PMID- 29475115 TI - Chemical composition and sources of PM1 and PM2.5 in Beijing in autumn. AB - Beijing, the capital of China, suffers from severe atmospheric aerosol pollution; nevertheless, a comprehensive study of the constituents and sources of PM1 is still lacking, and the differences between PM1 and PM2.5 are still unclear. In this study, an intensive observation was conducted to reveal the pollution characteristics of PM1 and PM2.5 in Beijing in autumn. Positive matrix factorization (PMF), backward trajectories and a potential source contribution function (PSCF) model were used to identify the source categories and source areas of PM1 and PM2.5. The results showed that the average concentrations of PM1 and PM2.5 reached 78.20MUg/m3 and 95.47MUg/m3 during the study period, respectively. PM1 contributed greatly to PM2.5. The PM1/PM2.5 value increased from 73.6% to 90.1% with PM1 concentration growing from <50MUg/m3 to >150MUg/m3. Higher secondary inorganic aerosol (SIA) proportions (31.3%-70.8%) were found in PM1. The higher fraction of SIA, OC, EC and typical elements in PM1 illustrated that anthropogenic components accumulated more in smaller size particles. Three typical weather patterns causing the heavy pollution in autumn were found as follows: (1) Siberian high and uniform high pressure field, (2) cold front and low-voltage system, and (3) uniform low pressure field. A PMF analysis indicated that secondary aerosols and coal combustion, vehicle, industry, biomass burning, and dust were the important sources of PM, accounting for 53.8%, 8.0%, 13.0%, 13.2% and 12.0% of PM1, respectively, and for 47.5%, 9.9%, 12.4%, 8.4% and 21.8% of PM2.5, respectively. The HYSPLIT and chemical components analysis indicated the potential contribution from biomass burning and fertilization ammonia emissions to PM1 in autumn. The source areas were similar for PM1 and PM1-2.5 under general polluted conditions, but during the heavily polluted periods, the source areas were distributed in farther regions from Beijing for PM1 than for PM1-2.5. PMID- 29475116 TI - Sources and fate of polycyclic aromatic compounds (PAHs, oxygenated PAHs and azaarenes) in forest soil profiles opposite of an aluminium plant. AB - Little is known about oxygenated polycyclic aromatic hydrocarbons (OPAHs) and azaarenes (AZAs) in forest soils. We sampled all horizons of forest soils from five locations at increasing distances from an Al plant in Slovakia, and determined their polycyclic aromatic compound (PACs) concentrations. The ?29PAHs concentrations were highest in the Oa and lowest in the Oi horizon, while the ?14OPAHs and ?4AZAs concentrations did not show a consistent vertical distribution among the organic horizons. The concentration ratios of PAHs and OPAHs between deeper O horizons and their overlying horizon (enrichment factors) were positively correlated with the octanol-water partition coefficients (KOW) at several locations. This is attributed to the slower degradation of the more hydrophobic PACs during organic matter decomposition. PACs concentrations decreased from the organic layer to the mineral horizons. The concentrations of ?29PAHs (2400-17,000 ng g-1), ?14OPAHs (430-2900 ng g-1) and ?4AZAs (27-280 ng g 1) in the mineral A horizon generally decreased with increasing distance from the Al plant. In the A horizons, the concentrations of ?29PAHs were correlated with those of ?14OPAHs (r = 0.95, p = 0.02) and ?4AZAs (r = 0.93, p = 0.02) suggesting that bioturbation was the main transport process of PACs from the organic layer into the mineral soil. At each location, the concentrations of PACs generally decreased with increasing depth of the mineral soil. Enrichment factors of PAHs in the mineral horizons were not correlated with KOW, pointing at colloid assisted transport and bioturbation. The enrichment factors of OPAHs (in mineral horizons) at a site were negatively correlated with their KOW values indicating that these compounds were leached in dissolved form. Compared to a study 13 years before, the concentrations of PAHs had decreased in the O horizons but increased in the A and B horizons because of soil-internal redistribution after emissions had been reduced. PMID- 29475117 TI - Effects of soil depth and plant-soil interaction on microbial community in temperate grasslands of northern China. AB - Although the patterns and drivers of soil microbial community composition are well studied, little is known about the effects of plant-soil interactions and soil depth on soil microbial distribution at a regional scale. We examined 195 soil samples from 13 sites along a climatic transect in the temperate grasslands of northern China to measure the composition of and factors influencing soil microbial communities within a 1-m soil profile. Soil microbial community composition was measured using phospholipid fatty acids (PLFA) analysis. Fungi predominated in topsoil (0-10 cm) and bacteria and actinomycetes in deep soils (40-100 cm), independent of steppe types. This variation was explained by contemporary environmental factors (including above- and below-ground plant biomass, soil physicochemical and climatic factors) >58% in the 0-40 cm of soil depth, but <45% in deep soils. Interestingly, when we considered the interactive effects between plant traits (above ground biomass and root biomass) and soil factors (pH, clay content, and soil total carbon, nitrogen, phosphorous), we observed a significant interaction effect occurring at depths of 10-20 cm soil layer, due to different internal and external factors of the plant-soil system along the soil profile. These results improve understanding of the drivers of soil microbial community composition at regional scales. PMID- 29475118 TI - Kockdown of OIP5-AS1 expression inhibits proliferation, metastasis and EMT progress in hepatoblastoma cells through up-regulating miR-186a-5p and down regulating ZEB1. AB - Long non-coding RNA OIP5-AS1 has been studied in human diseases, including several kinds of cancers. It was not studied or reported in hepatoblastoma, so we chose it to do our research in hepatoblastoma. We thought OIP5-AS1 was oncogenic in hepatoblastoma for the high expression of it in hepatoblastoma tissues and cells. OIP5-AS1 knockdown was carried out in cancer cells. Unsurprisingly, this action was verified to be able to inhibit cell proliferation, metastasis and EMT progress in hepatoblastoma. We then measured the low expression level of miR-186a 5p and the high expression level of ZEB1 in hepatoblastoma tissues and cells. The relevance among them was analyzed by using correlation analysis. In order to prove the ceRNA pattern in this study, nuclear separation experiment, RIP assay and dual luciferase assays were all put into use. We discovered OIP5-AS1 is located in nucleus of cancerous cells. It could target to miR-186a-5p and up regulate the target gene of miR-186a-5p (ZEB1). Finally, rescue assay was utilized and proved the effect of OIP5-AS1-miR-186a-5p-ZEB1 axis on hepatoblastoma cell activities. Based on all above findings, we came into a conclusion that OIP5-AS1 is a ceRNA in Hepatoblastoma cells through modulating miR-186a-5p/ZEB1. PMID- 29475119 TI - The correlation of morphological and thrombotic villous arterial lesions with fetal Doppler echocardiographic measurements in the placentas of low-risk term pregnancies. AB - OBJECTIVE: Few studies have correlated the placental vasculature with fetal cardiac function other than umbilical artery Doppler assessment in low-risk pregnancies. We assessed the contribution of the placental vasculature to fetal echocardiographic parameters using histopathological and morphometric analyses of placental resistance arteries. STUDY DESIGN: Thirty-four low-risk singleton term pregnancies were assessed, including 24 thrombosis-negative cases (no/minimal gross and histological placental abnormalities) and 10 thrombosis-positive cases (histologically identified chorionic plate/stem vessel thrombosis). Fetal ventricular Doppler inflow velocities (E and A waves) and myocardial systolic (S'), early (E'), and late diastolic (A') tissue Doppler velocities were measured within three days before birth. The myocardial performance index (MPI') was calculated. Morphometric variables of placental stem villi arterioles (external diameter 10-150 MUm) were examined, including the mean arteriolar density, total cross-sectional lumen area, and wall area/total vessel area (WA/TVA) ratio. RESULTS: The thrombosis-positive group had a higher umbilical artery pulsatility index and a lower tricuspid E'/A' ratio compared to the thrombosis-negative group. The WA/TVA ratio of stem villi arterioles was negatively correlated with tricuspid E, A, and S' velocities as well as the E/E' ratio (n = 34). The tricuspid MPI' was positively correlated with the total cross-sectional lumen area of stem villi arterioles (n = 34). CONCLUSION: We conclude that changes in several fetal echocardiographic parameters are associated with placental vascular histopathological and morphological characteristics in a low-risk population. Further studies are needed to assess whether fetal echocardiographic assessment is a promising prenatal predictor of placental vascular histopathological and morphological characteristics in the general population. PMID- 29475120 TI - Infant fatality case with excessive chylous ascites. AB - An 11-month-old boy with marked abdominal distension was found dead in the prone position at home. Since there were many bruises in the non-protruding regions of the head, face, and abdomen, a medicolegal autopsy was performed the following day. The boy was smaller than average (height: 68.5 cm; weight: 7.8 kg); his extremities were thin; and his abdomen was remarkably bulging. Chylous ascites (1600 mL) was observed in the peritoneal cavity and chylous pleural effusion (left: 5 mL; right: 10 mL) in the thoracic cavity. A fibrous induration, approximately 2.0 * 1.5 cm in size, was observed in the root of the small bowel mesentery. Congenital chylothorax and chylous ascites were suspected. However, the remarkably withered thymus and an old injury in the superior labial frenulum suggested that the chylous ascites may have been further deteriorated by injuries sustained during physical abuse. Examination suggested that the death was sudden. Thus, we inferred that the cause of death was circulatory and respiratory failure due to excessive chylous ascites. Among the reported cases of chylous ascites in pediatric patients, some patients experiencing abuse were identified on the basis of their chief complaints of vomiting or abdominal distension. Medical and child welfare staff should be made aware of this information. PMID- 29475121 TI - Cardiopulmonary effects of overnight indoor air filtration in healthy non-smoking adults: A double-blind randomized crossover study. AB - BACKGROUND: More than 90% of the world's population lives in areas where outdoor air pollution levels exceed health-based limits. In these areas, individuals may use indoor air filtration, often on a sporadic basis, in their residences to reduce exposure to respirable particles (PM2.5). Whether this intervention can lead to improvements in health outcomes has not been evaluated. METHODS: Seventy non-smoking healthy adults, aged 19 to 26 years, received both true and sham indoor air filtration in a double-blinded randomized crossover study. Each filtration session was approximately 13 h long. True and sham filtration sessions were separated by a two-week washout interval. The study was carried out in a suburb of Shanghai. RESULTS: During the study period, outdoor PM2.5 concentrations ranged from 18.6 to 106.9 MUg/m3, which overlapped with levels measured in Western Europe and North America. Compared to sham filtration, true filtration on average decreased indoor PM2.5 concentration by 72.4% to 10.0 MUg/m3 and particle number concentration by 59.2% to 2316/cm3. For lung function measured immediately after the end of filtration, true filtration significantly lowered airway impedance at 5 Hz (Z5) by 7.1% [95% CI: 2.4%, 11.9%], airway resistance at 5 Hz (R5) by 7.4% [95% CI: 2.4%, 12.5%], and small airway resistance (R5-R20) by 20.3% [95% CI: 0.1%, 40.5%], reflecting improved airway mechanics especially for the small airways. However, no significant improvements for spirometry indicators (FEV1, FVC) were observed. True filtration also significantly lowered von Willebrand factor (VWF) by 26.9% [95% CI: 7.3%, 46.4%] 24 h after the end of filtration, indicating reduced risk for thrombosis. Stratified analysis in male and female participants showed that true filtration significantly decreased pulse pressure by 3.3% [95% CI: 0.8%, 7.4%] in females, and significantly reduced VWF by 42.4% [95% CI: 17.4%, 67.4%] and interleukin-6 by 22.6% [95% CI: 0.4%, 44.9%] in males. Effect modification analyses indicated that filtration effects in male and female participants were not significantly different. CONCLUSION: A single overnight residential air filtration, capable of reducing indoor particle concentrations substantially, can lead to improved airway mechanics and reduced thrombosis risk. PMID- 29475122 TI - Blue light irradiation triggers the antimicrobial potential of ZnO nanoparticles on drug-resistant Acinetobacter baumannii. AB - Photodynamic inactivation (PDI) is a non-invasive and safe therapeutic method for microbial infections. Bacterial antibiotic resistance is caused by antibiotics abuse. Drug-resistant Acinetobacter spp. is a serious problem in hospitals around the world. These pathogens from nosocomial infections have high mortality rates in frailer people, and Acinetobacter spp. is commonly found in immunocompromised patients. Visible light is safer than ultraviolet light (UV) for PDI of nosocomial pathogens with mammalian cells. Zinc oxide nanoparticles (ZnO-NPs) were used in this study as an antimicrobial agent and a photosensitizer. ZnO is recognized as safe and has extensive usage in food additives, medical and cosmetic products. In this study, we used 0.125 mg/ml ZnO-NPs combined with 10.8 J/cm2 blue light (BL) on Acinetobacter baumannii (A. baumannii) that could significantly reduce microbial survival. However, individual exposure to ZnO-NPs does not affect the viability of A. baumannii. BL irradiation could trigger the antimicrobial ability of ZnO nanoparticles on A. baumannii. The mechanism of photocatalytic ZnO-NPs treatment for sterilization occurs through bacterial membrane disruptions. Otherwise, the photocatalytic ZnO-NPs treatment showed high microbial eradication in nosocomial pathogens, including colistin-resistant and imipenem-resistant A. baumannii and Klebsiella pneumoniae. Based on our results, the photocatalytic ZnO-NPs treatment could support hygiene control and clinical therapies without antibiotics to nosocomial bacterial infections. PMID- 29475123 TI - Induced accumulation of Au, Ag and Cu in Brassica napus grown in a mine tailings with the inoculation of Aspergillus niger and the application of two chemical compounds. AB - This study evaluated the ability of Brassica napus for extracting gold (Au), silver (Ag) and copper (Cu) from a mine tailings, with the inoculation of two Aspergillus niger strains, and the application of ammonium thiocyanate (NH4SCN) or ammonium thiosulfate [(NH4)2S2O3]. After seven weeks of growth inoculated or non-inoculated plants were applied with 1 or 2 g kg-1 of either NH4SCN or (NH4)2S2O3, respectively. Eight days after the application of the chemical compounds, plants were harvested for determining the total dry biomass, and the content of Au, Ag, and Cu in plant organs. Application of (NH4)2S2O3 or NH4SCN resulted in enhanced Au-accumulation in stems (447% and 507%, respectively), while either (NH4)2S2O3+Aspergillus, or NH4SCN increased the Au-accumulation in roots (198.5% and 404%, respectively) when compared to the control. Treatments with (NH4)2S2O3 or (NH4)2S2O3+Aspergillus significantly increased (P <= 0.001) the accumulation of Ag in leaves (677% and 1376%, respectively), while NH4SCN + Aspergillus, and (NH4)2S2O3 enhanced the accumulation in stems (7153% and 6717.5%). The Ag-accumulation in roots was stimulated by NH4SCN+ Aspergillus, and (NH4)2S2O3+ Aspergillus (132.5% and 178%, respectively), when compared to the control. The combination of NH4SCN+Aspergillus significantly enhanced the Cu accumulation in leaves (228%); whereas NH4SCN+ Aspergillus, or (NH4)2S2O3+ Aspergillus resulted in greater accumulation of Cu in stems (1233.5% and 1580%, respectively) than the control. Results suggest that either NH4SCN or (NH4)2S2O3 (with or without Aspergillus) improved the accumulation of Au and Ag by B. napus. Accumulation of Au and Ag in plant organs overpassed the hyperaccumulation criterion (> 1 mg kg-1 of plant biomass); whereas Cu-accumulation in stems and roots also overpassed such criterion (> 1000 mg kg-1) by applying either NH4SCN or (NH4)2S2O3 + A. niger. PMID- 29475124 TI - The defensive role of silicon in wheat against stress conditions induced by drought, salinity or cadmium. AB - In the crust of earth, silicon (Si) is one of the two major elements. For plant growth and development, importance of Si remains controversial due to the widely differences in ability of plants to take up this element. In this paper, pot experiments were done to study Si roles in improving salt, drought or cadmium (Cd) stress tolerance in wheat. Up to full emergence, all pots were watered at 100% field capacity (FC) every other day with nutrient solution without any treatments. Fifteen days after sowing, pots were divided into four plots, each with 40 pots for no stress (control) and three stress treatments; drought (50% FC), salinity (200 mM NaCl) and cadmium (2 mM Cd). For all plots, Si was applied at four levels (0, 2, 4 and 6 mM). Under no stress condition, Si applications increased Si content and improved growth as a result of reduced electrolyte leakage (EL), malondialdehyde (MDA) and Na+ contents. Under stress conditions, Si supplementation conferred higher growth, gas exchange, tissue water and membranes stabilities, and K+ content, and had limited MDA and Na+ contents and EL compared to those obtained without Si. Compared to those without Si, enzyme (e.g., superoxide dismutase, catalase and peroxidase) activity was improved by Si applications, which were linked with elevated antioxidants and osmoprotectants (e.g., free proline, soluble sugars, ascorbic acid and glutathione) contents, might providing antioxidant defense against abiotic stress in wheat. The level of 4 mM Si was most effective for mitigating the salt and drought stress conditions, while 6 mM Si level was most influentially for alleviating the Cd stress condition. These results suggest that Si is beneficial in remarkably affecting physiological phenomena and improving wheat growth under abiotic stress. PMID- 29475125 TI - Reactive oxygen species initiate a protective response in plant roots to stress induced by environmental bisphenol A. AB - Bisphenol A (BPA), a contaminant of emerging concern, can affect plant growth and development at high concentrations. Reactive oxygen species (ROS) production is a general primary response in plants to stress. Here, the aim is to investigate whether ROS in plants play protective roles for stress induced by BPA exposure at environmental concentrations. In this study, soybean roots (seedling, flowering and podding stages) were exposed to 1.5 and 3.0 mg L-1 BPA, and ROS response was measured. The relationship between ROS levels and residual BPA content in soybean roots was evaluated. The results showed that exposure (9 h) to 1.5 mg L-1 BPA elicited changes in ROS production. ROS then gradually accumulated in soybean roots (seedling stage). Exposure to 3.0 mg L-1 BPA elicited a stronger and earlier ROS responses at the flowering and podding stage, but did not lead to membrane lipid peroxidation. Residual BPA content in soybean roots reached peak concentrations after 9 h of exposure, and then gradually decreased at the flowering and podding stage. These results indicate that ROS in soybean roots might be involved in the oxidative metabolism of BPA, which could prevent BPA from damaging exposed plants. In conclusion, the observed ROS metabolic effects may be self-protection responses of plants to stress induced by BPA exposure. PMID- 29475126 TI - SNP rs403212791 in exon 2 of the MTNR1A gene is associated with reproductive seasonality in the Rasa aragonesa sheep breed. AB - The aim of this study was to characterize and identify causative SNPs in the MTNR1A gene responsible for the reproductive seasonality traits in the Rasa aragonesa sheep breed. A total of 290 ewes (155, 84 and 51 mature, young and ewe lambs, respectively) from one flock were controlled from January to August. The following three reproductive seasonality traits were considered: the total days of anoestrus (TDA) and the progesterone cycling months (P4CM); both ovarian function seasonality traits based on blood progesterone levels; and the oestrus cycling months (OCM) based on oestrous detection, which indicate behavioural signs of oestrous. We have sequenced the total coding region plus 733 and 251 bp from the promoter and 3'-UTR regions, respectively, from the gene in 268 ewes. We found 9 and 4 SNPs associated with seasonality traits in the promoter (for TDA and P4CM) and exon 2 (for the three traits), respectively. The SNPs located in the gene promoter modify the putative binding sites for various trans-acting factors. In exon 2, two synonymous SNPs affect RFLP sites, rs406779174/RsaI (for the three traits) and rs430181568/MnlI (for OCM), and they have been related with seasonal reproductive activity in previous association studies with other breeds. SNP rs400830807, which is located in the 3'-UTR, was associated with the three traits, but this did not modify the putative target sites for ovine miRNAs according to in silico predictions. Finally, the SNP rs403212791 (NW_014639035.1: g.15099004G > A), which is also associated with the three seasonality phenotypes, was the most significant SNP detected in this study and was a non-synonymous polymorphism, leading a change from an Arginine to a Cysteine (R336C). Haplotype analyses confirmed the association results and showed that the effects found for the seasonality traits were caused by the SNPs located in exon 2. We have demonstrated that the T allele in the SNP rs403212791 in the MNTR1A gene is associated with a lower TDA and higher P4CM and OCM values in the Rasa Aragonesa breed. PMID- 29475127 TI - Brief hypoxic cycles improve uterine contractile function after prolonged hypoxia in term-pregnant but not in nonpregnant rats in vitro. AB - During labour, the uterus itself is vulnerable to hypoxia/ischemia that can occur with each strong contraction and this may ultimately cause dysfunctional labour in some women. Periods of Intermittent re-oxygenations are beneficial to tissues subjected to hypoxia to wash out metabolic by-products that have been accumulated during hypoxic stresses which may affect the tissue viability. We proposed that short intermittent hypoxic episodes may protect the uterus from subsequent sustained long hypoxia. To investigate this, two sets of experiments were performed on term-pregnant and nonpregnant rat uterine tissues. In one set of experiment the uterus was subjected to sustained long hypoxia for 40 min and then allowed to recover in 100% O2. In the other set of experiment the uterus was subjected to 3 cycles of 2 min hypoxia each separated by 20 min reoxygenation and followed by a sustained long hypoxia for 40 min and then allowed to recover. We found that challenging the uterine tissues with intermittent short hypoxic episodes improved the uterine contractility significantly after the sustained long hypoxia in term-pregnant but not in non-pregnant tissues. These results suggest that a mechanism of uterine tolerance (preconditioning) is confined to uterine tissues very close to labour and it is a protective phenomenon to improve the uterine activity despite the long-lasting paradoxical metabolic challenges that occur during the repeated strong labour contractions. PMID- 29475128 TI - Effect of sodium alginate on mouse ovary vitrification. AB - The survival rate of vitrified-thawed ovarian tissues after autotransplantation still needs to be improved. Therefore finding an ideal cryoprectant to reduce the damage to ovaries that caused by vitrification will pave the way for application of ovary cryopreservation on clinics. Experiments were conducted to investigate the effect of sodium alginate in cryoprotectant solution on mouse ovaries during the vitrification process. The ovaries obtained from 6-weeks old CD1 were assigned into six groups from A to F. Group A without treatment was used as the normal control. Group B cryopreserved with the basic cryoprotectant solution containing 15% each Me2SO and EG was used as the experimental control. Groups C, D, E, and F cryopreserved with the basic cryoprotectant solution supplemented with 0.05%, 0.10%, 0.15%, and 0.20% of sodium alginate, respectively, were assigned for the experimental groups. The in vitro analyses showed that the developmental capability of the oocytes isolated from vitrified-thawed ovaries significantly increased with increasing concentration of sodium alginate in the cryoprotectant solution (groups: A = 70 +/- 2; B = 43 +/- 2; C = 48 +/- 3; D = 53 +/- 3; E = 60 +/- 3; B < C < D < A, P < 0.05), and reached its highest level in group E with 0.15% of sodium alginate (P < 0.05). The lowest developmental capability of all groups was group F (41 +/- 1%)(P < 0.05) with 0.20% of sodium alginate. The similar results were obtained by the autotransplantation in vivo. These finding demonstrated that sodium alginate can significantly reduce the damage to ovaries by vitrification. PMID- 29475129 TI - Effects of short-term feeding of different sources of fatty acids in pre-mating diets on reproductive performance and blood metabolites of fat-tailed Iranian Afshari ewes. AB - The effects of dietary omega-3 and omega-6 fatty acids (FAs) in pre-mating diets on reproductive performances and metabolic status of ewes have not been well investigated. Therefore, this study investigated the effect of supplementing different source of FAs on different aspects of reproductive performance of fat tailed Iranian Afshari ewes. Thirty-two cycling, multiparous Afshari ewes were divided into four groups and fed one of the isocaloric and isonitrogenous diets supplemented with Sunflower oil (SFO), Fish oil (FO), calcium salt of palm oil (CaPO) and/or an equal mixture of SFO + FO (SFOFO). One day after the start of the flushing, the estrous cycles of all ewes were synchronized using 12-day CIDRs. After detecting signs of estrous, all ewes were mated with rams for 2 days. The examination of ovarian follicles was done by a transrectal ultrasonography. After counting all visible follicles, they were classified into 3 classes based on their diameters: small (<=3 mm), medium (3-4 mm) and large (>=4 mm). The results showed that fat sources had no impact on dry matter intake (DMI) and body condition score (BCS) of animals (P > 0.05). Plasma glucose, total cholesterol, and albumin concentrations also were not significantly affected by supplemental fat sources (P > 0.05). Plasma insulin levels were higher at the end of the flushing (on the day of CIDR removal) and the day of mating for ewes on CaPO diet (P < 0.05). Plasma estradiol-17beta concentration was greater on the day of mating for ewes fed FO (P < 0.05). Progesterone levels in pregnant ewes fed FO were higher 30 d after mating (11.02 ng/mL; P < 0.05). Dietary treatments had no significant effect on number of small, medium and total follicles as well as the average size of small and medium follicles at the end of the flushing and the day of mating. The number of medium follicles on the day of oestrus (mating) were significantly higher for the ewes fed FO or SFO diets (P < 0.05). Likewise, the mean number and size of large follicles at the end of flushing and the day of oestrus were higher in ewes on FO diet (P < 0.05). Lambing rate and twinning rate increased (P < 0.05) in ewes fed FO or SFO, respectively. In conclusion, supplementation of n-3 PUFA rich FA especially FO in pre-mating diets showed beneficial effects on some indices of reproductive performance of Afshari ewes including lambing and twining rate due to higher number of medium sized follicles and size of the ovulatory (large) follicles at the day of oestrus and increased plasma progesterone levels in pregnant ewes. PMID- 29475130 TI - The influence of winter and summer seasons on physical fitness in aged population. AB - Epidemiological studies have described the association between physical fitness and health. Few have reported the impact of seasonal variation on fitness determinants, in elderly. We investigated the effects of summer and winter environmental conditions on physical fitness, in both exercise and non-exercise elders. 371 non-institutionalized older adults (74.1% female; 78.4 +/- 5.3 years) randomly recruited from a total sample of 1338 subjects from north of Portugal, were prospectively followed during 1 year and 3 assessments were performed - April (baseline), October (summer season) and April (winter season). Four groups were defined, according to reported habits of exercising: Exercise (EG); Winter Exercise (WG); and Summer Exercise (SG); non-Exercise (nEG). Muscle strength was assessed with handgrip and isometric knee extension test, and aerobic capacity with the 6 min walking test. Repeated measures ANOVA with two between-subjects factors were run for independent variables, considering a three Time points. Significance set at p < .05. Findings show that: (1) men were fitter than women; (2) EG showed better results than nEG (p = .000), but not different than WG or SG, (3) nEG physical fitness was not significantly different from WG and SG; (4) SG and WG showed similar results; (5) there was significant group-by-time interaction for all variables in study. Among elderly, the regular physical exercise determined better cardiorespiratory fitness and levels of strength compared to individuals that were not exercising, however, no season impact was observed. Independently of exercising mode, regular, seasonal or not exercising, the pattern of changes in physical fitness throughout the year was similar. PMID- 29475131 TI - Factors affecting premature plantarflexor muscle activity during hemiparetic gait. AB - In hemiparetic stroke survivors, premature plantarflexor muscle activity (PPF) often appears as a gait abnormality from terminal swing to the loading response on the paretic side. This study aimed to discern factors giving rise to PPF. Lower extremity function, spasticity magnitude, and gait electromyograms were assessed in 31 hemiparetic stroke survivors. Mean amplitudes during gait phases were determined for the paretic soleus, tibialis anterior, rectus femoris, and biceps femoris. The subjects were classified into PPF and non-PPF groups based on their relative soleus amplitude at different phases of gait, and group differences in each measurement were calculated and subjected to logistic regression. The PPF group showed less activity of the tibialis anterior during the swing phase but greater activity of the rectus femoris during the swing phase and of the biceps femoris, both prematurely and during the loading response. Logistic regression revealed premature activity of the biceps femoris to be a significant variable related to presence of PPF (odds ratio = 1.054). PPF in hemiparetic gait may work with the biceps femoris to supplement compromised lower extremity extension strength. PPF might be reduced by attaining enhanced strength of the hip and knee extensors at the time of initial contact during gait. PMID- 29475132 TI - Differential effects of short chain fatty acids on endothelial Nlrp3 inflammasome activation and neointima formation: Antioxidant action of butyrate. AB - Short chain fatty acids (SCFAs), a family of gut microbial metabolites, have been reported to promote preservation of endothelial function and thereby exert anti atherosclerotic action. However, the precise mechanism mediating this protective action of SCFAs remains unknown. The present study investigated the effects of SCFAs (acetate, propionate and butyrate) on the activation of Nod-like receptor pyrin domain 3 (Nlrp3) inflammasome in endothelial cells (ECs) and associated carotid neointima formation. Using a partial ligated carotid artery (PLCA) mouse model fed with the Western diet (WD), we found that butyrate significantly decreased Nlrp3 inflammasome formation and activation in the carotid arterial wall of wild type mice (Asc+/+), which was comparable to the effect of gene deletion of the adaptor protein apoptosis-associated speck-like protein gene (Asc /-). Nevertheless, both acetate and propionate markedly enhanced the formation and activation of the Nlrp3 inflammasome as well as carotid neointima formation in the carotid arteries with PLCA in Asc+/+, but not Asc-/- mice. In cultured ECs (EOMA cells), butyrate was found to significantly decrease the formation and activation of Nlrp3 inflammasomes induced by 7-ketocholesterol (7-Ket) or cholesterol crystals (CHC), while acetate did not inhibit Nlrp3 inflammasome activation induced by either 7-Ket or CHC, but itself even activated Nlrp3 inflammsomes. Mechanistically, the inhibitory action of butyrate on the Nlrp3 inflammasome was attributed to a blockade of lipid raft redox signaling platforms to produce O2*- upon 7-Ket or CHC stimulations. These results indicate that SCFAs have differential effects on endothelial Nlrp3 inflammasome activation and associated carotid neointima formation. PMID- 29475135 TI - The multiplicative effect of combining alcohol with energy drinks on adolescent gambling. AB - PURPOSE: There has been increased concern about the negative effects of adolescents consuming a combination of alcohol mixed with energy drinks (AmED). To date, few studies have focused on AmED use and gambling. The present study analyzed the multiplicative effect of AmED consumption, compared to alcohol alone, on the likelihood of at-risk or problem gambling during adolescence. METHODS: Data from the ESPAD(r)Italia 2015 study, a cross-sectional survey conducted in a nationally representative sample of students (ages 15 to 19years) were used to examine the association between self-reported AmED use (>=6 times,>=10 times, and >=20 times during the last month) and self-reported gambling severity. Multivariate models were used to calculate adjusted prevalence ratios to evaluate the association between alcohol use, AmED use, and gambling among a representative sample of adolescents who reported gambling in the last year and completed a gambling severity scale (n=4495). RESULTS: Among the 19% students classed as at-risk and problem gamblers, 43.9% were classed as AmED consumers, while 23.6% were classed as alcohol consumers (i.e. did not mix alcohol with energy drinks). In multivariate analyses that controlled for covariates, AmED consumers were three times more likely to be at-risk and problem gamblers (OR=3.05) compared to non-consuming adolescents, while the effect became less pronounced with considering those who consumed alcohol without the addition of energy drinks (OR=1.37). CONCLUSIONS: The present study clearly established that consuming AmED might pose a significantly greater risk of experiencing gambling-related problems among adolescents. PMID- 29475133 TI - Reactive oxygen species promote tubular injury in diabetic nephropathy: The role of the mitochondrial ros-txnip-nlrp3 biological axis. AB - NLRP3/IL-1beta activation via thioredoxin (TRX)/thioredoxin-interacting protein (TXNIP) following mitochondria ROS (mtROS) overproduction plays a key role in inflammation. However, the involvement of this process in tubular damage in the kidneys of patients with diabetic nephropathy (DN) is unclear. Here, we demonstrated that mtROS overproduction is accompanied by decreases in TRX expression and TXNIP up-regulation. In addition, we discovered that mtROS overproduction is also associated with increases in NLRP3/IL-1beta and TGF-beta expression in the kidneys of patients with DN and db/db mice. We reversed these changes in db/db mice by administering a peritoneal injection of MitoQ, an antioxidant targeting mtROS. Similar results were observed in human tubular HK-2 cells subjected to high-glucose (HG) conditions and treated with MitoQ. Treating HK-2 cells with MitoQ suppressed the dissociation of TRX from TXNIP and subsequently blocked the interaction between TXNIP and NLRP3, leading to the inhibition of NLRP3 inflammasome activation and IL-1beta maturation. The effects of MitoQ were enhanced by pretreatment with TXNIP siRNA and abolished by pretreatment with monosodium urate (MSU) and TRX siRNA in vitro. These results suggest that mitochondrial ROS-TXNIP/NLRP3/IL-1beta axis activation is responsible for tubular oxidative injury, which can be ameliorated by MitoQ via the inhibition of mtROS overproduction. PMID- 29475136 TI - Unloosing the Gordian knot of peroxisome formation. AB - Peroxisome biogenesis is governed by molecular machineries, which are either unique to peroxisomes or are partially shared with mitochondria. As peroxisomes have important protective functions in the cell, modulation of their number is important for human health and disease. Significant progress has been made towards our understanding of the mechanisms of peroxisome formation, revealing a remarkable plasticity of the peroxisome biogenesis pathway. Here we discuss most recent findings with particular focus on peroxisome formation in mammalian cells. PMID- 29475137 TI - Polarized trafficking: the palmitoylation cycle distributes cytoplasmic proteins to distinct neuronal compartments. AB - In neurons, polarized cargo distribution occurs mainly between the soma and axonal and dendritic compartments, and requires coordinated regulation of cytoskeletal remodeling and membrane trafficking. The Golgi complex plays a critical role during neuronal polarization and secretory trafficking has been shown to differentially transport proteins to both axons and dendrites. Besides the Golgi protein sorting, recent data revealed that palmitoylation cycles are an efficient mechanism to localize cytoplasmic, non-transmembrane proteins to particular neuronal compartments, such as the newly formed axon. Palmitoylation allows substrate proteins to bind to and ride with Golgi-derived secretory vesicles to all neuronal compartments. By allowing cytoplasmic proteins to 'hitchhike' on transport carriers in a non-polarized fashion, compartmentalized depalmitoylation may act as a selective retention mechanism. PMID- 29475134 TI - Inhibition of phosphodiesterase 4 by FCPR16 protects SH-SY5Y cells against MPP+ induced decline of mitochondrial membrane potential and oxidative stress. AB - Phosphodiesterase 4 (PDE4) is a promising target for the treatment of Parkinson's disease (PD). However, the underlying mechanism has not yet been well elucidated. Additionally, most of current PDE4 inhibitors produce severe nausea and vomiting response in patients, which limit their clinical application. FCPR16 is a novel PDE4 inhibitor with little emetic potential. In the present study, the neuroprotective effect and underlying mechanism of FCPR16 against cellular apoptosis induced by 1-methyl-4-phenylpyridinium (MPP+) were examined in SH-SY5Y cells. FCPR16 (12.5-50 MUM) dose-dependently reduced MPP+-induced loss of cell viability, accompanied by reductions in nuclear condensation and lactate dehydrogenase release. The level of cleaved caspase 3 and the ratio of Bax/Bcl-2 were also decreased after treatment with FCPR16 in MPP+-treated cells. Furthermore, FCPR16 (25 MUM) significantly suppressed the accumulation of reactive oxygen species (ROS), prevented the decline of mitochondrial membrane potential (Deltapsim) and attenuated the expression of malonaldehyde level. Further studies disclosed that FCPR16 enhanced the levels of cAMP and the exchange protein directly activated by cAMP (Epac) in SH-SY5Y cells. Western blotting analysis revealed that FCPR16 increased the phosphorylation of cAMP response element-binding protein (CREB) and protein kinase B (Akt) down-regulated by MPP+ in SH-SY5Y cells. Moreover, the inhibitory effects of FCPR16 on the production of ROS and Deltapsim loss could be blocked by PKA inhibitor H-89 and Akt inhibitor KRX-0401. Collectively, these results suggest that FCPR16 attenuates MPP+-induced dopaminergic degeneration via lowering ROS and preventing the loss of Deltapsim in SH-SY5Y cells. Mechanistically, cAMP/PKA/CREB and Epac/Akt signaling pathways are involved in these processes. Our findings indicate that FCPR16 is a promising pre-clinical candidate for the treatment of PD and possibly other oxidative stress-related neuronal diseases. PMID- 29475138 TI - Novel polymorph of ambrisentan: Characterization and stability. AB - The present work highlights a novel polymorph (form II) of ambrisentan (AMT), a selective endothelin type A (ETA) receptor antagonist used in the treatment of pulmonary arterial hypertension (PAH). Form II was isolated by solution crystallization and characterised by differential scanning calorimetry, powder X ray diffraction, solution calorimetry and aqueous solubility. The single crystal X-ray diffraction shows that it crystallizes in monoclinic system with space group P21/c different from the form I (commercial form). Form II was found to be enantiotropically related to form I. Apparent solubility of form II was performed in 0.1 N HCl (pH 1.2) was found to be higher (1.5 fold) than of form I. Solution mediated and stress-induced phase transformation studies revealed conversion of form II to form I. Accelerated stability studies (40 degrees C & 75% RH) also reveal that form II converted to form I after one month. However, this does not belittle the improved solubility of a new solid form. PMID- 29475139 TI - Superior Therapeutic Efficacy of Nanoparticle Albumin Bound Paclitaxel Over Cremophor-Bound Paclitaxel in Experimental Esophageal Adenocarcinoma. AB - Esophageal adenocarcinoma (EAC) is the fastest growing cancer in the western world and the overall 5 year survival rate of EAC is below 20%. Most patients with EAC present with locally advanced or widespread metastatic disease, where current treatment is largely ineffective. Therefore, new therapeutic approaches are urgently needed. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a novel albumin-stabilized, cremophor-free and water soluble nanoparticle formulation of paclitaxel, and the potential role of nab-paclitaxel has not been tested yet in experimental EAC. Here we tested the antiproliferative and antitumor efficacy with survival advantage of nab-paclitaxel as monotherapy and in combinations in in-vitro, and in murine subcutaneous xenograft and peritoneal metastatic survival models of human EAC. Nab-paclitaxel significantly inhibited in-vitro cell proliferation with higher in-vivo antitumour efficacy and survival benefit compared to paclitaxel or carboplatin treatments both in mono- and combination therapies. Nab-paclitaxel treatment increased expression of mitotic spindle associated phospho-stathmin, decreased expression of proliferative markers and enhanced apoptosis. This study demonstrates that nab-paclitaxel had stronger antiproliferative and antitumor activity in experimental EAC than the current standard chemotherapeutic agents which supports the rationale for its clinical use in EAC. PMID- 29475140 TI - The Prognostic Relevance of Sentinel Lymph Node Metastases Assessed by PHGR1 mRNA Quantification in Stage I to III Colon Cancer. AB - BACKGROUND: Regional lymph node (LN) metastasis is a strong and well-established prognostic factor in colon cancer, and recent data suggest a prognostic value of detecting micrometastases and isolated tumor cells in regional LNs. The aim of the study was to investigate the clinical relevance of detecting sentinel lymph node (SLN) metastases in colon cancer patients by measuring the novel metastasis marker PHGR1 mRNA. METHODS: Using quantitative reverse-transcription polymerase chain reaction, we measured PHGR1 mRNA levels in SLNs and primary tumors from 206 patients surgically treated for stage I to III colon cancer and 52 normal LNs from patients undergoing surgery for benign colon diseases. The prognostic impact of these findings was evaluated by Kaplan-Meier analysis and Cox proportional hazards regression. RESULTS: Compared to normal LNs, elevated PHGR1 mRNA levels were detected in SLNs from 56 (89%) of the 63 patients with pN+ disease. Furthermore, 68 (48%) of the 143 node-negative (pN0) patients had elevated PHGR1 mRNA levels in SLNs, suggesting occult metastases. With a median follow-up of 7.2 years, a significantly shorter recurrence-free (P=.005) and disease-specific (P=.02) survival was observed in patients with elevated PHGR1 mRNA levels in SLNs. Multivariable modeling showed that the SLN PHGR1 mRNA level was an independent prognostic factor. However, when the survival analyses were restricted to pN0 patients, no significant prognostic information was found. CONCLUSION: Measuring PHGR1 mRNA in SLNs provided independent prognostic information on operable colon cancer patients but not in the pN0 subgroup. PMID- 29475141 TI - Quercetin enhances chemotherapeutic effect of doxorubicin against human breast cancer cells while reducing toxic side effects of it. AB - Doxorubicin (Dox) is an efficient drug for breast cancer chemotherapy, however, its toxic side effects on non-tumor tissues, especially on myocardial cells, sometimes limit its clinical application. Therefore, it is necessary to develop a new drug, which can be combined with Dox to potentiate the anti-tumor effect of Dox at a lower concentration and attenuate the toxic side effects of it. Quercetin (Que) has anti-tumor activity in addition to its protective effects on various cells. By preparing human non-tumoral MCF-10A mammary cells, human breast cancer MCF-7 and MDA-MB-231 cells and human myocardial AC16 cells, here, we wanted to evaluate whether Que might represent such an agent and investigate its possible mechanisms of potentiating the anti-tumor effect of Dox at a lower concentration. The results showed that Que could increase intracellular accumulation of Dox in breast cancer cells through down-regulating the expression of efflux ABC transporters including P-gp, BCRP and MRP1, which can effectively eliminate cancerous cells including breast cancer stem cells (BCSCs), thereby potentiating the anti-tumor effect of Dox. Furthermore, Que attenuated the cytotoxicity of Dox to non-tumoral MCF-10A mammary cells and myocardial AC16 cells. Therefore, Que could be used as a novel agent combined with Dox in breast cancer therapy, which could potentiate the anti-tumor effect of Dox at a lower concentration and attenuate the toxic side effects of it. PMID- 29475142 TI - Neural electrical activity and neural network growth. AB - The development of central and peripheral neural system depends in part on the emergence of the correct functional connectivity in its input and output pathways. Now it is generally accepted that molecular factors guide neurons to establish a primary scaffold that undergoes activity-dependent refinement for building a fully functional circuit. However, a number of experimental results obtained recently shows that the neuronal electrical activity plays an important role in the establishing of initial interneuronal connections. Nevertheless, these processes are rather difficult to study experimentally, due to the absence of theoretical description and quantitative parameters for estimation of the neuronal activity influence on growth in neural networks. In this work we propose a general framework for a theoretical description of the activity-dependent neural network growth. The theoretical description incorporates a closed-loop growth model in which the neural activity can affect neurite outgrowth, which in turn can affect neural activity. We carried out the detailed quantitative analysis of spatiotemporal activity patterns and studied the relationship between individual cells and the network as a whole to explore the relationship between developing connectivity and activity patterns. The model, developed in this work will allow us to develop new experimental techniques for studying and quantifying the influence of the neuronal activity on growth processes in neural networks and may lead to a novel techniques for constructing large-scale neural networks by self-organization. PMID- 29475143 TI - Unified synchronization criteria in an array of coupled neural networks with hybrid impulses. AB - This paper investigates the problem of globally exponential synchronization of coupled neural networks with hybrid impulses. Two new concepts on average impulsive interval and average impulsive gain are proposed to deal with the difficulties coming from hybrid impulses. By employing the Lyapunov method combined with some mathematical analysis, some efficient unified criteria are obtained to guarantee the globally exponential synchronization of impulsive networks. Our method and criteria are proved to be effective for impulsively coupled neural networks simultaneously with synchronizing impulses and desynchronizing impulses, and we do not need to discuss these two kinds of impulses separately. Moreover, by using our average impulsive interval method, we can obtain an interesting and valuable result for the case of average impulsive interval Ta=infinity. For some sparse impulsive sequences with Ta=infinity, the impulses can happen for infinite number of times, but they do not have essential influence on the synchronization property of networks. Finally, numerical examples including scale-free networks are exploited to illustrate our theoretical results. PMID- 29475144 TI - Highly efficient nitrogen removal of a coldness-resistant and low nutrient needed bacterium, Janthinobacterium sp. M-11. AB - A novel heterotrophic nitrification-aerobic denitrification bacterium, identified as Janthinobacterium sp. M-11, was isolated from the Songhua River. When the initial ammonium concentration was 5 mg.L-1, 98% of ammonium was removed under cold condition (2 degrees C) with the C/N ratio of 5 at initial pH 7 and aerobic condition, which demonstrated the significant ammonium removal capacity of M-11 with low nutrient consumption at cold temperature. Denitrification processes under aerobic and anaerobic conditions were also investigated. 89% of nitrite and 89% of nitrate were removed under aerobic condition. Under anaerobic condition, 93% of nitrite and 98% of nitrate were removed. Interestingly, a high amount of nitrite accumulation was observed in the mid-stage of anaerobic denitrification for nitrate. This special phenomenon was probably because of the existence of narG gene amplified in the strain M-11, which would encode membrane-bound nitrate reductase and accelerate the nitrate conversion rate of M-11 under anaerobic condition. PMID- 29475145 TI - Spatial variation of electrode position in bioelectrochemical treatment system: Design consideration for azo dye remediation. AB - In the present study, three bio-electrochemical treatment systems (BET) were designed with variations in cathode electrode placement [air exposed (BET1), partially submerged (BET2) and fully submerged (BET3)] to evaluate azo-dye based wastewater treatment at three dye loading concentrations (50, 250 and 500 mg L 1). Highest dye decolorization (94.5 +/- 0.4%) and COD removal (62.2 +/- 0.8%) efficiencies were observed in BET3 (fully submerged electrodes) followed by BET1 and BET2, while bioelectrogenic activity was highest in BET1 followed by BET2 and BET3. It was observed that competition among electron acceptors (electrode, dye molecules and intermediates) critically regulated the fate of bio-electrogenesis to be higher in BET1 and dye removal higher in BET3. Maximum half-cell potentials in BET3 depict higher electron acceptance by electrodes utilized for dye degradation. Study infers that spatial positioning of electrodes in BET3 is more suitable towards dye remediation, which can be considered for scaling up/designing a treatment plant for large-scale industrial applications. PMID- 29475146 TI - The fate of trace organic contaminants during anaerobic digestion of primary sludge: A pilot scale study. AB - A pilot-scale study was conducted to investigate the fate of trace organic contaminants (TrOCs) during anaerobic digestion of primary sludge. Of the 44 TrOCs monitored, 24 were detected in all primary sludge samples. Phase distribution of TrOCs was correlated well with their hydrophobicity (>67% mass in the solid phase when LogD > 1.5). The pilot-scale anaerobic digester achieved a steady performance with a specific methane yield of 0.39-0.92 L/gVSremoved and methane composition of 63-65% despite considerable variation in the primary sludge. The fate of TrOCs in the aqueous and solid phases was governed by their physicochemical properties. Biotransformation was significant (>83%) for five TrOCs with logD < 1.5 and electron donating functional groups in molecular structure. The remaining TrOCs with logD < 1.5 were persistent and thus accumulated in the aqueous phase. Most TrOCs with logD > 1.5 were poorly removed under anaerobic conditions. Sorption onto the solid phase appears to impede the biodegradation of these TrOCs. PMID- 29475147 TI - Halophilic starch degrading bacteria isolated from Sambhar Lake, India, as potential anode catalyst in microbial fuel cell: A promising process for saline water treatment. AB - In this study, Microbial Fuel Cell (MFC) capable of treating saline starch water was developed. Sodium chloride (NaCl) concentrations ranging from 500 mM to 3000 mM were tested at the anode. Nitrate was used as an electron acceptor at the biocathode. The halophilic bacteria were isolated from Sambhar Lake, India. Results indicated successful removal of starch (1.83 kg/m3-d) and nitrate (0.13 kg/m3-d NO3--N) with concomitant power output of 207.05 mW/m2 at 1000 mM NaCl concentration. An increase in power density from 71.06 mW/m2 to 207.05 mW/m2 (2.92 folds) was observed when NaCl concentration was increased from 500 mM to 1000 mM. A decline in power density was observed when the salt concentrations >1000 mM were used. Concentration of 3000 mM supported power output as well as the highest starch degradation (3.2 kg/m3-d) and amylase activity of 2.26 IU/ml. The halophilic exoelectrogens were isolated and identified. The present study demonstrates the utility of MFC for degrading starch in saline water. PMID- 29475148 TI - An integrated process for xylooligosaccharide and bioethanol production from corncob. AB - An integrated process for xylooligosaccharides (XOs) and bioethanol production from corncob was investigated. XOs were produced by a consecutive process of KOH treatment and hydrolysis by an in-house thermostable endo-xylanase from Streptomyces thermovulgaris. XO yields of 0.15 g/gKOH-treated corncob (22.13 g/L) and 0.52 g/graw corncob of cellulose-rich corncob (CRC) were obtained. After 96 h of enzymatic hydrolysis, CRC hydrolysate contained 62.16, 51.21, 10.03 and 0.92 g/L of total sugar, glucose, xylose and arabinose, respectively. Bioethanol production by separate hydrolysis and fermentation (SHF) using CRC hydrolysate, and by simultaneous saccharification and fermentation (SSF) using CRC was studied at 40 degrees C for thermotolerant Candida glabrata. SHF showed an ethanol yield of 0.28 g/gCRC (21.92 g/L) and ethanol productivity of 0.304 g/L/h with 93% theoretical yield. Surprisingly, by SSF, those parameters were 0.27 g/gCRC (31.32 g/L), 0.33 g/L/h and 89%, respectively. This integrated process might be a new cost-effective approach for corncob valorization. PMID- 29475149 TI - Study on titanium-magnesium composites with bicontinuous structure fabricated by powder metallurgy and ultrasonic infiltration. AB - Titanium-magnesium (Ti-Mg) composites with bicontinuous structure have been successfully fabricated by powder metallurgy and ultrasonic infiltration for biomaterial potential. In the composites, Ti phase is distributed continuously by sintering necks, while Mg phase is also continuous, distributing at the interconnected pores surrounding the Ti phase. The results showed that the fabricated Ti-Mg composites exhibited low modulus and high strength, which are very suitable for load bearing biomedical materials. The composites with 100 um and 230 um particle sizes exhibited Young's modulus of 37.6 GPa and 23.4 GPa, 500.7 MPa and 340 MPa of compressive strength and 631.5 MPa and 375.2 MPa of bending strength, respectively. Moreover, both of the modulus and strength of the composites increase with decreasing of Ti particle sizes. In vitro study has been done for the preliminary evaluation of the Ti-Mg composites. PMID- 29475150 TI - Thyrotoxicosis induced cardiomyopathy requiring support with extracorporeal membrane oxygenation. AB - PURPOSE: Thyrotoxicosis-induced cardiomyopathy (TCM) is a rare, potentially life threatening complication requiring extracorporeal membrane oxygenation (ECMO) for temporary mechanical support while a euthyroid state is being achieved. MATERIALS AND METHODS: The current review searched Ovid Medline and PubMed for all relevant studies reported in English from January 1, 1970 to December 31, 2017. We included studies where patients were diagnosed with thyrotoxicosis, eventually deteriorating into TCM, requiring veno-arterial ECMO. We were predominantly interested in the clinical pathway that led to the initiation and duration of ECMO, including the trend of ejection fraction (EF) pre- and post-ECMO. RESULTS: The initial search strategy produced 71 articles of which only 5 studies were eligible for inclusion. These 5 articles included 13 case reports. The majority of the patients (77%) survived with complete recovery of their left ventricular function following initiation of VA-ECMO. Key issues in the current management of TCM are delayed recognition of the underlying thyroid hormone imbalance and when to initiate mechanical support. CONCLUSION: The definitive therapy of TCM is returning the patient to a euthyroid state. For those patients who develop circulatory collapse, however, temporary mechanical support should be strongly considered to allow time for a euthyroid state to be achieved. PMID- 29475151 TI - CT-angiography of the aorta in patients with Marfan disease - High-pitch MDCT at different levels of tube voltage combined with Sinogram Affirmed Iterative Reconstruction. AB - OBJECTIVES: Aim of the study was the comparison of high-pitch dual-source CTA of the aorta acquired with different tube currents and methods of image reconstruction in patients with Marfan Disease (MFS). BACKGROUND: Patients with MFS receive repeatedly CT examinations of the entire aorta what leads to high cumulative lifetime radiation doses. Routine clinical use of low-kV-protocols in combination with iterative reconstruction for imaging of the aorta is still limited although this approach may be of great benefit for patients in need of serial follow-up scans. METHODS: 106 patients with MFS received CTA of the entire aorta in a 2nd generation dual-source Flash-CT at 120, 100 or 80 kV. 120 kV images were reconstructed with FBP, low-kV images with an IR algorithm (SAFIRE) at different noise reduction levels. CTDIvol, DLP and effective dose were analyzed. Quantitative image analysis included comparison of SNR, CNR and Noise levels. For qualitative analysis, two blinded readers assessed noise, contour delineation, contrast, overall image quality and diagnostic confidence. RESULTS: Effective dose was 9.4 (+/-1.5) mSv for 120 kV, 4.2 (+/-1.1) mSv for 100 kV and 1.9 (+/-0.42) mSv for 80 kV. 100 kV images showed the highest SNR and CNR values, followed by 80 kV and 120 kV. Qualitative image analysis showed the lowest scores for all evaluated aspects at 80 kV. Overall image quality and diagnostic confidence was excellent at all kV strengths. CONCLUSIONS: In MFS patients low-kV CT protocols with IR allow for CTA of the entire aorta in excellent image quality and diagnostic confidence with a dose reduction of up to 80% compared to 120 kV. For baseline CT, we recommend 100 kV, for follow-up CT scans 80 kV as tube voltage. PMID- 29475152 TI - Relationship between rearfoot, tibia and femur kinematics in runners with and without patellofemoral pain. AB - BACKGROUND: Patellofemoral pain (PFP) is the most common running overuse injury. Excessive rearfoot eversion is commonly considered as a PFP risk factor and the relationship between ankle-foot complex movement and lower limb may be involved with this dysfunction. The purpose of this study was to evaluate the correlation between rearfoot eversion with tibia and femur kinematics in frontal and transverse planes during running in individuals with and without PFP. The secondary purpose was to compare the lower limb kinematics between runners with and without PFP. METHODS: Fifty-four recreational runners were divided into 2 groups: healthy runners (CG, n = 27) and runners with patellofemoral pain (PFPG, n = 27). Kinematics during running were assessed using three-dimensional motion analysis system. Pearson's correlation coefficients (r) were calculated to establish the correlation of rearfoot eversion with tibial and femur movements. FINDINGS: Greater peak rearfoot eversion was correlated with greater peak femur adduction in PFP runners. Greater peak rearfoot eversion was correlated with greater peak tibial internal rotation and tibial adduction in the PFPG and CG. Additionally, greater peak rearfoot eversion was correlated with greater tibial internal rotation range of motion in the PFPG and CG. No significant differences were found between the PFPG and CG for all kinematics variables. INTERPRETATION: Correlation between greater rearfoot eversion and greater peak hip adduction in the PFPG might be related to PFP persistence in runners with excessive rearfoot eversion, and indicates that treatment strategies aimed at controlling the movement of the rearfoot could help modify the symptoms. PMID- 29475153 TI - Effects of high heeled shoes on gait. A review. AB - BACKGROUND: Walking in high heels (HH) may alter gait in various ways, which may be of importance to designers and physicians. RESEARCH QUESTION: How does walking in high heels alter gait and how can this be explained from a biomechanical and control point of view. METHODS: Relevant literature has been collected in which high heeled walking was studied, after which the results were bundled and interpreted in a framework of biomechanics and control. RESULTS: Major changes were found in the rollover function of the feet, the ankle and knee joints and the lower back, while step length and balance were compromised. An increase in heel height forces the foot in an increased plantar flexion, which in its turn increases knee flexion and lordosis of the lower back. All changes can be related with each other in a plausible pattern of movement and control. PMID- 29475154 TI - Nursing students' and preceptors' experience of assessment during clinical practice: A multilevel repeated-interview study of student-preceptor dyads. AB - Nursing students' learning process during clinical practice is dependent on the quality of their assessment, and the feedback that is given, however an issue that is very little examined. The aim of this study was to investigate student preceptor dyads and their experiences of mid-course discussions and final assessment. Data were collected through repeated semi-structured individual interviews with 13 dyads close in time to the assessment discussions, and were analyzed by searching for similarities and differences in their experiences. Both students and preceptors shared the view that the preparations before the discussions caused uncertainty, but they described different reasons. Both students and preceptors meant that the assessment tool was used in a structured way. The feedback mediated to students emphasized what was important to concentrate on in the next part or next period, but less about the individual students' progress. The student-preceptor dyads did not share the view of what content had been in focus in the discussions and there were variations in the details. Conclusions can be drawn that one of the crucial elements of an assessment discussion, to give students constructive feedback in relation to learning outcomes, was not fulfilled. PMID- 29475155 TI - Development of anti-fungal pesticides from protein kinase inhibitor-based anticancer agents. AB - Repurposing the novel p21-activated protein kinase inhibitor compound 15 identified its antifungal activity against five selected species of phytopathogenic fungi. Lead optimization based on its structure gave rise to a focused library of 20 derivatives, among which compound 3c demonstrated increased activity over compound 15 and even comparable to that of some commercialized fungicides in the market including carbendazim, tebuconazole, and pyraclostrobin. This study showed that p21-activated protein kinase inhibitor compound 15 was able to serve as a molecular platform to develop effective fungicides against fungal phytopathogens and indicate that screening existing protein kinase inhibitors might be an effective way to identify lead compounds for antifungal pesticides development. PMID- 29475156 TI - Potent hydrazone derivatives targeting esophageal cancer cells. AB - Hydrazone and their derivatives are a series of highly active molecules, which are widely used as lead compounds for the research and development of new anti cancer drugs. In this study, 20 compounds were synthesized, based on this scaffold and their in vitro cytotoxicity against 6 cancer cell lines, including EC9706, SMMC-7721, MCF7, PC3, MGC-803 and EC109 was tested. Among them, compound 6p, showed strong anti-proliferative activities on esophageal carcinoma cells: EC9706 and EC109 with IC50 values of 1.09 +/- 0.03 and 2.79 +/- 0.45 MUM, respectively. 6p also significantly induces both EC9706 and EC109 cell cycle arrest at G0/G1 phase and cell apoptosis, as well as intracellular ROS accumulation, which could be markedly reversed caspase or ROS inhibitor: NAC. Meanwhile, treatment of compound 6p results in significant declined mitochondria membrane potential, increases in the expression of P53 and bax, as well as decrease in Bcl-2. 6p also activates caspase-8/9/3, PARP and Bid, indicating that 6p induces cancer cell apoptosis via the death receptor-mediated extrinsic pathway and the mitochondria-mediated intrinsic pathway. Further studies also proved that 6p does not show obvious side effects at cellular and in vivo levels. Our findings suggested that hydrazone derivative: compound 6p may serve as a lead compound for further optimization against esophageal cancer cells. PMID- 29475157 TI - The role of the N-terminal domain of human apurinic/apyrimidinic endonuclease 1, APE1, in DNA glycosylase stimulation. AB - : The base excision repair (BER) pathway consists of sequential action of DNA glycosylase and apurinic/apyrimidinic (AP) endonuclease necessary to remove a damaged base and generate a single-strand break in duplex DNA. Human multifunctional AP endonuclease 1 (APE1, a.k.a. APEX1, HAP-1, or Ref-1) plays essential roles in BER by acting downstream of DNA glycosylases to incise a DNA duplex at AP sites and remove 3'-blocking sugar moieties at DNA strand breaks. Human 8-oxoguanine-DNA glycosylase (OGG1), methyl-CpG-binding domain 4 (MBD4, a.k.a. MED1), and alkyl-N-purine-DNA glycosylase (ANPG, a.k.a. Aag or MPG) excise a variety of damaged bases from DNA. Here we demonstrated that the redox deficient truncated APE1 protein lacking the first N-terminal 61 amino acid residues (APE1-NDelta61) cannot stimulate DNA glycosylase activities of OGG1, MBD4, and ANPG on duplex DNA substrates. Electron microscopy imaging of APE1-DNA complexes revealed oligomerization of APE1 along the DNA duplex and APE1-mediated DNA bridging followed by DNA aggregation. APE1 polymerizes on both undamaged and damaged DNA in cooperative mode. Association of APE1 with undamaged DNA may enable scanning for damage; however, this event reduces effective concentration of the enzyme and subsequently decreases APE1-catalyzed cleavage rates on long DNA substrates. We propose that APE1 oligomers on DNA induce helix distortions thereby enhancing molecular recognition of DNA lesions by DNA glycosylases via a conformational proofreading/selection mechanism. Thus, APE1-mediated structural deformations of the DNA helix stabilize the enzyme-substrate complex and promote dissociation of human DNA glycosylases from the AP site with a subsequent increase in their turnover rate. SIGNIFICANCE STATEMENT: The major human apurinic/apyrimidinic (AP) endonuclease, APE1, stimulates DNA glycosylases by increasing their turnover rate on duplex DNA substrates. At present, the mechanism of the stimulation remains unclear. We report that the redox domain of APE1 is necessary for the active mode of stimulation of DNA glycosylases. Electron microscopy revealed that full-length APE1 oligomerizes on DNA possibly via cooperative binding to DNA. Consequently, APE1 shows DNA length dependence with preferential repair of short DNA duplexes. We propose that APE1-catalyzed oligomerization along DNA induces helix distortions, which in turn enable conformational selection and stimulation of DNA glycosylases. This new biochemical property of APE1 sheds light on the mechanism of redox function and its role in DNA repair. PMID- 29475158 TI - Modeling the effects of different fuel treatment mosaics on wildfire spread and behavior in a Mediterranean agro-pastoral area. AB - Wildfire spread and behavior can be limited by fuel treatments, even if their effects can vary according to a number of factors including type, intensity, extension, and spatial arrangement. In this work, we simulated the response of key wildfire exposure metrics to variations in the percentage of treated area, treatment unit size, and spatial arrangement of fuel treatments under different wind intensities. The study was carried out in a fire-prone 625 km2 agro-pastoral area mostly covered by herbaceous fuels, and located in Northern Sardinia, Italy. We constrained the selection of fuel treatment units to areas covered by specific herbaceous land use classes and low terrain slope (<10%). We treated 2%, 5% and 8% of the landscape area, and identified priority sites to locate the fuel treatment units for all treatment alternatives. The fuel treatment alternatives were designed create diverse mosaics of disconnected treatment units with different sizes (0.5-10 ha, LOW strategy; 10-25 ha, MED strategy; 25-50 ha, LAR strategy); in addition, treatment units in a 100-m buffer around the road network (ROAD strategy) were tested. We assessed pre- and post-treatment wildfire behavior by the Minimum Travel Time (MTT) fire spread algorithm. The simulations replicated a set of southwestern wind speed scenarios (16, 24 and 32 km h-1) and the driest fuel moisture conditions observed in the study area. Our results showed that fuel treatments implemented near the existing road network were significantly more efficient than the other alternatives, and this difference was amplified at the highest wind speed. Moreover, the largest treatment unit sizes were the most effective in containing wildfire growth. As expected, increasing the percentage of the landscape treated and reducing wind speed lowered fire exposure profiles for all fuel treatment alternatives, and this was observed at both the landscape scale and for highly valued resources. The methodology presented in this study can support the design and optimization of fuel management programs and policies in agro-pastoral areas of the Mediterranean Basin and herbaceous type landscapes elsewhere, where recurrent grassland fires pose a threat to rural communities, farms and infrastructures. PMID- 29475159 TI - Trace metal mobilization by organic soil amendments: insights gained from analyses of solid and solution phase complexation of cadmium, nickel and zinc. AB - The accumulation of Cd in soils worldwide has increased the demand for methods to reduce the metal's plant bioavailability. Organic matter rich soil amendments have been shown to be effective in achieving this. However, it is not known how long these amendments can retain the Cd, and whether dissolved organic matter (DOM) released from them can enhance the metal's mobility in the environment. In this study we sought to test the Cd binding capacity of various organic soil amendments, and evaluate differences in characteristics of the DOM released to see if they can explain the lability of the Cd-DOM complexes. We collected ten organic soil amendments from around New Zealand: five different composts, biosolids from two sources, two types of peat and spent coffee grounds. We characterised the amendments' elemental composition and their ability to bind the Cd. We then selected two composts and two peats for further tests, where we measured the sorption of Ni or Zn by the amendments. We analysed the quality of the extracted DOM from the four amendments using 3D Excitation Emission Matrix analysis, and tested the lability of the metal-DOM complexes using an adapted diffusive gradients in thin-films (DGT) method. We found that composts bound the most Cd and that the emergent Cd-DOM complexes were less labile than those from the peats. Ni-DOM complexes were the least labile. The aromaticity of the extracted DOM appears to be an important factor in determining the lability of Ni complexes, but less so for Zn and Cd. PMID- 29475160 TI - Immunotoxicity of ochratoxin A and aflatoxin B1 in combination is associated with the nuclear factor kappa B signaling pathway in 3D4/21 cells. AB - The co-contamination of cereals, grains, crops, and animal feeds by mycotoxins is a universal problem. Humans and animals are exposed to several mycotoxins simultaneously as evidenced by extensive studies on this topic. Yet, most studies have addressed the effects of mycotoxins individually. Aflatoxin B1 and ochratoxin A can induce immunotoxicity. However, it remains unclear whether a combination of these mycotoxins aggravates immunotoxicity and the potential mechanism underlying this effect. In this study, we used the cell line 3D4/21, swine alveolus macrophages and innate immune cell. The results showed that the percentage of cell inhibition, annexin V/PI-positive rates, and the expression of pro-inflammatory cytokines (tumor necrosis factor alpha and interleukin-6) significantly increased and the release of lactate dehydrogenase and phagocytotic index were significantly decreased at different concentrations of aflatoxin B1 and ochratoxin A combination when compared with control. The combination of aflatoxin B1 and ochratoxin A significantly decreased the production of GSH and increased reactive oxygen species level. However, N-acetylcysteine suppressed the oxidative stress and alleviated the immunotoxicity induced by the combination. The combination of aflatoxin B1 and ochratoxin A markedly enhanced the degradation of IkappaBa, the phosphorylation of nuclear factor kappa B (p65), and the translocation of activated nuclear factor kappa B (NF-kappaB) into the nuclei as demonstrated by western blotting and confocal laser scanning microscopy. These effects could be reversed by BAY 11-7082, a specific inhibitor of NF-kappaB. Taken together, a combination of aflatoxin B1 and ochratoxin A could aggravate immunotoxicity by activating the NF-kappaB signaling pathway. PMID- 29475161 TI - House hold unit for the treatment of fluoride, iron, arsenic and microorganism contaminated drinking water. AB - A first of its kind hybrid electrocoagulation-filtration prototype unit was fabricated for the removal of fluoride, iron, arsenic and microorganisms contaminated drinking water. The unit comprised of 3 chambers, chamber A consisting of an inlet for the water to be treated and an outlet for the treated water along with one block of aluminum electrodes. Chamber B consisted of ceramic membrane filtration assembly at the bottom over a metallic support which filters the flocs so produced in chamber A and chamber C consisting of space to collect the treated water. Operating parameters were maintained as current density of 625 A m-2 and an electrode distance of 0.005 m. Contaminated drinking water containing mixture of fluoride (10 mg L-1), iron (25 mg L-1), arsenic (200 MUg L 1) and microorganisms (35 CFU ml-1) was used for the experiment. A removal of 98.74%, 95.65%, 93.2% and 100% were obtained for iron, arsenic, fluoride and microorganisms, respectively. The apparatus and method made it possible to efficiently treat contaminated drinking water to produce drinkable water as per WHO specification. By-products obtained from the electrocoagulation bath were analyzed using SEM, EDX and XRD and explained. PMID- 29475163 TI - Meditation induced psychosis: Case report. PMID- 29475162 TI - The evaluation of arsenic contamination potential, speciation and hydrogeochemical behaviour in aquifers of Punjab, Pakistan. AB - In this study, we tested 123 groundwater wells from five different areas of Punjab, Pakistan for arsenic (As) contamination level and species, as well as delineated hydrogeochemical behaviour of As in aquifers. Results revealed that 75% and 41% of the groundwater wells exceeded the safe As limit of World Health Organisation (WHO, 10 MUg L-1) and Pakistan-EPA (50 MUg L-1), respectively. Arsenite (As(III)) and arsenate (As(V)) spanned 0-80% and 20-100% of total As (1.2-206 MUg L-1), respectively. The mean As content (5.2 MUg L-1) of shallow wells at 9-40 m depth did not exceed the WHO safe limit, representing a safe aquifer zone for pumping of groundwater compared to deeper wells at 41-90 m (51 MUg L-1) and >90 m (23 MUg L-1) depths. Piper-plot elucidated that the aqueous chemistry was dominated with Na-SO4, Na-Ca-SO4, Na-Mg-SO4 type saline water. Principal component analysis grouped As concentration with well depth, pH, salinity, Fe and CO3, exhibiting that these hydrogeochemical factors could have potential role in controlling As release/sequestration into the aquifers of study area. Geochemical modeling showed positive saturation indices only for iron (Fe) oxide-phases, indicating Fe oxides as the major carriers of As. Overall, this study provides insights to tackle emerging As threat to the communities in Punjab, Pakistan, as well as help develop suitable management/mitigation strategies - based on the baseline knowledge of As levels/species and factors governing As contamination in the study area. PMID- 29475164 TI - Thiazolidinediones as antidiabetic agents: A critical review. AB - Thiazolidinediones (TZDs) or Glitazones are an important class of insulin sensitizers used in the treatment of Type 2 diabetes mellitus (T2DM). TZDs were reported for their antidiabetic effect through antihyperglycemic, hypoglycemic and hypolipidemic agents. In time, these drugs were known to act by increasing the transactivation activity of Peroxisome Proliferators Activated Receptors (PPARs). The clinically used TZDs that suffered from several serious side effects and hence withdrawn/updated later, were full agonists of PPAR-gamma and potent insulin sensitizers. These drugs were developed at a time when limited data were available on the structure and mechanism of PPARs. In recent years, however, PPAR alpha/gamma, PPAR-alpha/delta and PPAR-delta/gamma dual agonists, PPAR pan agonists, selective PPAR-gamma modulators and partial agonists have been investigated. In addition to these, several non PPAR protein alternatives of TZDs such as FFAR1 agonism, GPR40 agonism and ALR2, PTP1B and alpha-glucosidase inhibition have been investigated to address the problems associated with the TZDs. Using these rationalized approaches, several investigations have been carried out in recent years to develop newer TZDs devoid of side effects. This report critically reviews TZDs, their history, chemistry, mechanism mediated through PPAR, recent advances and future prospects. PMID- 29475165 TI - Non-acidic 1,3,4-trisubstituted-pyrazole derivatives as lonazolac analogs with promising COX-2 selectivity, anti-inflammatory activity and gastric safety profile. AB - Twelve new compounds of 1,3,4-trisubstituted-pyrazole derivatives possessing two cyclooxygenase-2 (COX-2) pharmacophoric moieties (SO2Me or/and SO2NH2) 11a-c, 12a c, 13a-c and 14a-c were designed and synthesized to be evaluated for their COX inhibition, anti-inflammatory activity, ulcerogenic liability. All compounds were more selective for COX-2 isozyme and showed good in vivo anti-inflammatory activity. The bisaminosulphonyl derivatives (14a-c) were the most COX-2 selective compounds (S.I. = 9.87, 9.50 and 9.22 respectively) and showed good anti inflammatory potency (ED50 = 15.06, 42.51 and 50.43 MUmol/kg respectively) in comparison with celecoxib (COX-2 S.I. = 8.61, ED50 = 82.2 MUmol/kg). Also, compounds 14a-c were less ulcerogenic (ulcer indexes = 2.72-3.72) than ibuprofen (ulcer index = 20.25) and comparable to celecoxib (ulcer index = 2.93). In addition, to explain the preferential (COX-2) inhibitory and selectivity, the designed compounds were subjected to molecular docking studies. It was found that compound 14c with the highest COX-2 activity and selectivity exhibited a binding pattern and interactions similar to that of celecoxib with formation of more hydrogen-bond features. PMID- 29475166 TI - Orthogonal synthesis of a novel hybrid layered material containing three different zincous components and its photocatalytic property investigation. AB - A novel hybrid layered material-Schiff Base-Zinc Complexes intercalated ZnCr-LDHs supported ZnO-was synthesized by one-step coprecipitation method and characterized by XRD, UV-vis DRS, SEM, TEM, BET, ICP-AES and XPS analysis. The influences of the three Zn components (intercalated between the layers, supported on the surface, distributed in the host layers of the layered material) on the crystallinity and the photocatalytic activity of ZnO/ZnCr-SalenZn-LDHs for Rhodamine B (RhB) degradation were studied in detail by orthogonal design. The results showed that the percentage of the three components has a great effect on the structure and photocatalytic performance of ZnO/ZnCr-SalenZn-LDHs. The SalenZn intercalated between the layers and the Zn distributed in the layers of the layered material were the main influencing factors, and the ZnO supported on the surface of the layered material was the secondary influencing factor. The optimum initial molar ratios were SalenZn:Cr = 0.5, Zn:Cr = 3, and ZnO:Cr = 0.75, respectively, and the photocatalytic degradation efficiency of RhB reached 96.9%. In addition, a possible mechanism of photocatalysis was discussed from the perspectives of photogenerated reactive species and photoinduced carries transfer. While, the regeneration of the best photocatalytic material was also investigated in detail. PMID- 29475167 TI - Sulfate reduction processes in salt marshes affected by phosphogypsum: Geochemical influences on contaminant mobility. AB - Sulfate reduction and its associated contaminant immobilization in marsh soils supporting a phosphogypsum stack was examined by pore-water and solid analysis, selective extractions, microscopy and sulfur K-edge X-ray absorption near-edge structure (XANES) spectroscopy. The negative impact of this stack on estuarine environments is a concerning problem. In the weathering profile, total concentrations of most pollutants increase with depth; instead, dissolved contents in pore-waters increase to middle of the saturated zone but then decrease drastically down to reach the marsh due to sulfide precipitation. Excess of acid-volatile sulfide plus pyritic sulfur over metals bound to the oxidizable fraction indicates that sulfide precipitation is the main mechanism responsible for metal removal in the marsh. Thus, abundant pyrite occurred as framboidal grains, in addition to other minor sulfides of As, Zn and Cu as isolated particles. Moreover, high contents of elemental sulfur were found, which suggest partial sulfide oxidation, but marsh may have capacity to buffer potential release of contaminants. The importance of sulfur species was quantitatively confirmed by XANES, which also supports the accuracy of selective extraction schemes. Accordingly, managing pore-water quality through organic carbon-rich amendments over phosphogypsum stacks could lead to a decrease in contaminant loading of leakages resulting from weathering. PMID- 29475168 TI - Spontaneous mesenteric hematoma of the sigmoid colon associated with rivaroxaban: A case report. AB - INTRODUCTION: Mesenteric hematoma is a rare condition caused by bleeding localized in the mesenteric vascular tree. This is a first report of spontaneous mesenteric hematoma caused by rivaroxaban. PRESENTATION OF CASE: The patient was a 71-year-old man who had taken rivaroxaban for paroxysmal atrial fibrillation. He had experienced abdominal pain and diarrhea for the prior 3 days. He had little melena and was referred to our institute. He presented with hypotension on arrival. Computed tomography (CT) revealed a 10 cm mass in the mesentery of the sigmoid colon with extravasation. Active bleeding from the sigmoid colic arteries was embolized with angiography on the day of admission. On the second day, we operated on the patient. We detected 200 mL of bloody ascites accumulated in the abdomen. The serosa of the sigmoid colon was ruptured along the tenia due to the compression of the hematoma in the mesentery. The sigmoid colon was resected and a descending colostomy was reconstructed. Operative and pathological findings did not reveal the cause of bleeding. We finally diagnosed the patient with spontaneous mesenteric hematoma associated with rivaroxaban. DISCUSSION: Previous reports of mesenteric hematoma with anticoagulant were associated with warfarin. Since rivaroxaban is not affect to the value of prothrombin time (PT) and activated partial thromboplastin time (APTT) and mesenteric hematoma presents non specific symptoms, it is difficult to diagnose mesenteric hematoma in the patients taking rivaroxaban. CONCLUSION: It is important to keep in mind that mesenteric hematoma is one of the critical complications in patients taking rivaroxaban. PMID- 29475169 TI - Raoultella Planticola associated necrotizing appendicitis: A novel case report. AB - INTRODUCTION: Raoultella Planticola is a gram negative, aerobic, rod bacteria found in water and soil and is rarely reported to cause infections in humans. This case study is the first of its kind in reporting R. planticola appendicitis. PRESENTATION OF CASE: We report a case of a woman presenting with a two-day history of increased weakness, fatigue and anorexia, localized pain to the right lower quadrant, and elevated white blood cell count. CT results demonstrated acute uncomplicated appendicitis which was managed via laparoscopic appendectomy. The patient became febrile on the day of the procedure and was found to have R. planticola bacteremia which was treated with amoxicillin-clavulanate. She was discharged on postoperative day two and reported an unremarkable recovery at her five-week follow-up appointment. DISCUSSION: R. planticola is a common organism that is rarely, though increasingly, associated with human infection. Interestingly, prior to hospitalization, this patient did not have any risk factors commonly associated with R. planticola infection, such as seafood consumption. However, she may have had gastrointestinal tract colonization with R. planticola prior to onset of appendicitis and appendectomy. Bacteremia likely resulted from micro-perforation of the appendix. CONCLUSION: Although infection with R. planticola is typically benign when treated appropriately, this pathogen has homology with Klebsiella species, and has the potential to acquire antimicrobial resistance. The case presented here suggests that R. planticola should be considered as a potential source of bacteremia in inflammatory/infectious gastrointestinal tract diseases even in the absence of typical risk factors. PMID- 29475170 TI - A case report of anterior cruciate ligament and posterolateral corner reconstruction using tendon graft preserved in situ. AB - INTRODUCTION: Combined anterior cruciate ligament (ACL) and posterolateral corner (PLC) reconstruction are a rare clinical entity in orthopedic literature, whose management requires different types of tendon grafts. Missed PLC injury leads to the failure of ACL repair due to the joint instability. PRESENTATION OF CASE: We are presenting a case of posttraumatic right ACL, PLC and lateral meniscus injury. The patient was taken to theatre for arthroscopic meniscectomy, ACL and PLC reconstruction. We had to harvest bilateral Gracilis and semitendinosus tendon grafts. Intraoperatively, we used a pump and after meniscectomy and ACL reconstruction the knee was quite swollen; we opted to offer a two-staged procedure for PLC reconstruction. Hence we had to preserve the graft in situ for the next procedure. Posterolateral corner reconstruction was done in a week's time and preserved ligament was found to be intact. DISCUSSION: The fact that we did not have a tissue bank or facilities for cryopreservation of the harvested tendons at -80 degrees C or with liquid nitrogen at -179 degrees C yet we had to keep the harvested tendons safe. CONCLUSION: In case of absence of graft and bone bank, tendon graft was in situ and found intact and ready to be used after seven days. PMID- 29475171 TI - Intrahepatic splenosis mimicking hepatic neoplasia. AB - INTRODUCTION: Splenosis is defined as the heterotopic autoimplantation of splenic tissue following trauma to or surgery on the spleen. CLINICAL CASE: We present a case of an asymptomatic 73-year-old male in whom hypervascular lesions were detected during routine exams. The patient reported a history of carotid artery surgery and cholecystectomy; he had a laparotomy incision from childhood but was unaware of the reason for it. The patient exhibited slightly elevated carcinoembryonic antigen (CEA) levels. Histopathology revealed intrahepatic heterotopic splenic parenchyma, with no evidence of neoplasia in either of the two lesions, the diameters of which were 1.5 cm and 3.6 cm. Patient received outpatient follow-up care for 24 months and experienced no complications. DISCUSSION: Our clinical, laboratory, and imaging exams failed to reveal the etiology of the lesion. Because the masses were hypervascular lesions, a percutaneous liver biopsy was not feasible. CONCLUSION: Through this report, we emphasize the importance of considering intrahepatic splenosis as a remote possibility in patients with hepatic nodules who have a history of splenectomy. PMID- 29475172 TI - Brain network alteration in patients with temporal lobe epilepsy with cognitive impairment. AB - The aims of this study were to investigate the brain network alternation in patients with temporal lobe epilepsy (TLE) with and without cognitive impairment (CI) using functional magnetic resonance imaging (fMRI) and to further explore the potential mechanisms of epilepsy-induced CI. Forty patients with TLE and nineteen healthy controls (HCs) were recruited for this study. All participants received the Montreal Cognitive Assessment (MoCA) test, and the patients were divided into CI (n=21) and cognitive nonimpairment (CNI) groups (n=19) according to MoCA performance. Functional connectivity (FC) differences of resting state networks (RSNs) were compared among the CI, CNI, and HC groups. Correlation between FC and MoCA scores was also observed. When compared with the HC group, significantly decreased FC between medial visual network (mVN) and left frontoparietal network (lFPN) as well as between visuospatial network (VSN) and the anterior default mode network (aDMN) were revealed in both CI and CNI groups. In addition, significantly decreased FC between lFPN and executive control network (ECN) and increased FC between ECN and sensorimotor-related network (SMN) were found in CNI and CI groups, respectively. When compared with the CNI group, the CI group exhibited significant increased FC between ECN and lFPN as well as between ECN and SMN. Moreover, in the CI group, FC between ECN and lFPN showed negative correlation with attention scores. Our findings suggested that cognitive networks are different from epileptic networks, and the increased FC between RSNs closely related to cognitive function changes may help us to further understand the mechanism of CI in TLE. PMID- 29475173 TI - Presence of artisanal gold mining predicts mercury bioaccumulation in five genera of bats (Chiroptera). AB - Mercury, a toxic trace metal, has been used extensively as an inexpensive and readily available method of extracting gold from fine-grained sediment. Worldwide, artisanal mining is responsible for one third of all mercury released into the environment. By testing bat hair from museum specimens and field collected samples from areas both impacted and unimpacted by artisanal gold mining in Peru, we show monomethylmercury (MMHg) has increased in the last 100 years. MMHg concentrations were also greatest in the highest bat trophic level (insectivores), and in areas experiencing extractive artisanal mining. Reproductive female bats had higher MMHg concentrations, and both juvenile and adult bats from mercury contaminated sites had more MMHg than those from uncontaminated sites. Bats have important ecological functions, providing vital ecosystem services such as pollination, seed dispersal, and insect control. Natural populations can act as environmental sentinels and offer the chance to expand our understanding of, and responses to, environmental and human health concerns. PMID- 29475174 TI - Early maltreatment is associated with greater risk of conduct problems and lack of guilt in adolescence. AB - Previous research indicates a link between childhood maltreatment and elevated conduct problems. Yet the literature is less clear on associations between maltreatment and callousness (e.g., lack of empathy or guilt). This is a critical gap given that callousness is a robust predictor of serious aggressive and violent behavior. We examine the association between substantiated maltreatment events in childhood and adolescence (up to age 13) and conduct problems and lack of guilt at age 14. We analyze self- and parent-report data along with official maltreatment records on 557 youth (50% female; 69% non-white) from a larger dataset (Longitudinal Studies on Childhood Abuse and Neglect; N = 1354). Results of multinomial logistic regression models indicate that youth with histories of substantiated maltreatment events are more likely to have elevated conduct problems and decreased guilt at age 14, particularly if they experienced maltreatment before the age of four years old. Youth who exhibit conduct problems and also appear to lack guilt are more likely to have a personal history of substantiated maltreatment. We discuss our results in terms of their implications for theory and practice. PMID- 29475175 TI - Guiding exploration in conformational feature space with Lipschitz underestimation for ab-initio protein structure prediction. AB - Computing conformations which are essential to associate structural and functional information with gene sequences, is challenging due to the high dimensionality and rugged energy surface of the protein conformational space. Consequently, the dimension of the protein conformational space should be reduced to a proper level, and an effective exploring algorithm should be proposed. In this paper, a plug-in method for guiding exploration in conformational feature space with Lipschitz underestimation (LUE) for ab-initio protein structure prediction is proposed. The conformational space is converted into ultrafast shape recognition (USR) feature space firstly. Based on the USR feature space, the conformational space can be further converted into Underestimation space according to Lipschitz estimation theory for guiding exploration. As a consequence of the use of underestimation model, the tight lower bound estimate information can be used for exploration guidance, the invalid sampling areas can be eliminated in advance, and the number of energy function evaluations can be reduced. The proposed method provides a novel technique to solve the exploring problem of protein conformational space. LUE is applied to differential evolution (DE) algorithm, and metropolis Monte Carlo(MMC) algorithm which is available in the Rosetta; When LUE is applied to DE and MMC, it will be screened by the underestimation method prior to energy calculation and selection. Further, LUE is compared with DE and MMC by testing on 15 small-to-medium structurally diverse proteins. Test results show that near-native protein structures with higher accuracy can be obtained more rapidly and efficiently with the use of LUE. PMID- 29475176 TI - Rational design of methicillin resistance staphylococcus aureus inhibitors through 3D-QSAR, molecular docking and molecular dynamics simulations. AB - Staphylococcus aureus is a gram positive bacterium. It is the leading cause of skin and respiratory infections, osteomyelitis, Ritter's disease, endocarditis, and bacteraemia in the developed world. We employed combined studies of 3D QSAR, molecular docking which are validated by molecular dynamics simulations and in silico ADME prediction have been performed on Isothiazoloquinolones inhibitors against methicillin resistance Staphylococcus aureus. Three-dimensional quantitative structure-activity relationship (3D-QSAR) study was applied using comparative molecular field analysis (CoMFA) with Q2 of 0.578, R2 of 0.988, and comparative molecular similarity indices analysis (CoMSIA) with Q2 of 0.554, R2 of 0.975. The predictive ability of these model was determined using a test set of molecules that gave acceptable predictive correlation (r2 Pred) values 0.55 and 0.57 of CoMFA and CoMSIA respectively. Docking, simulations were employed to position the inhibitors into protein active site to find out the most probable binding mode and most reliable conformations. Developed models and Docking methods provide guidance to design molecules with enhanced activity. PMID- 29475177 TI - Impact of pre-procedural dual antiplatelet therapy on periprocedural myocardial infarction in patients undergoing percutaneous coronary interventions with adjunctive tirofiban. AB - BACKGROUND: Recent trials have failed to demonstrate any clinical benefit from pre-treatment with dual antiplatelet therapy (DAPT) in patients undergoing percutaneous coronary interventions, (PCI), even in the setting of acute coronary syndrome. However, suboptimal platelet inhibition during (PCI) has been shown to enhance the risk of acute ischemic complications, such as stent thrombosis and periprocedural myocardial infarction (PMI), thus raising the attention on the potential advantages of adjunctive glycoprotein IIbIIIa inhibitors to obviate to the delayed onset of action of oral antiplatelet drugs. The aim of the present study was then to evaluate the impact of platelet reactivity and pre-procedural DAPT on PMI in patients undergoing PCI with adjunctive tirofiban. METHODS: In a consecutive cohort of patients undergoing PCI with tirofiban (intracoronary/intravenous +/- prolonged infusion), periprocedural myonecrosis was defined as troponin I increase by 3 times the ULN or by 50% of an elevated baseline value, whereas PMI as CKMB increase by 3 times the ULN or 50% of baseline. Platelet function was assessed by impedance aggregometry. RESULTS: A total of 168 patients were included, 77 (45.8%) of whom were on DAPT at the time of PCI. Patients on DAPT had more often a history of previous PCI (p = 0.03), higher ACS at admission (p < 0.001) and creatinine levels (p = 0.03). Coronary calcifications and type C lesions were more frequent in patients without DAPT (p = 0.02 and p = 0.03, respectively), as much as TIMI flow < 3 (p = 0.03), while procedural characteristics were comparable. Baseline platelet reactivity was significantly reduced in DAPT treated patients (p < 0.001 for ASPI, COL and ADP tests). However the rate of periprocedural myonecrosis did not differ according to pre-procedural DAPT (68.4%vs 67%, p = 0.87; adjusted OR[95%CI] = 1.34[0.71 2.53], p = 0.36) and neither the occurrence of PMI (13.3% vs 12.6%, p = 0.99; adjusted OR[95%CI] = 1.24[0.51-3.1], p = 0.64). Furthermore, baseline platelet reactivity was similar in patients with and without PMI/myonecrosis with no relationship between platelet function and Troponin I peak. CONCLUSION: In patients undergoing PCI with adjunctive GP IIb-IIIa inhibitors, preprocedural DAPT and baseline platelet reactivity are not associated to the risk of periprocedural myocardial infarction or myonecrosis. These data further support the role of periprocedural Gp IIb-IIIa inhibitors in order to overcome any suboptimal inhibition of platelet aggregation at the time of the procedure due to drug-resistance or delayed (downstream) administration of ADP antagonists, especially in complex high-risk procedures. PMID- 29475179 TI - Comprehensive characteristics of the anticoagulant activity of dabigatran in relation to its plasma concentration. AB - BACKGROUND: Issues with laboratory measurement of dabigatran include: 1. Do coagulation assays reflect dabigatran plasma concentrations? 2. Do samples from patients treated with dabigatran have the same coagulability as dabigatran-spiked samples from healthy volunteers? 3. What is the long-term stability of dabigatran after storage at -80 degrees C? This study aims to evaluate these questions. MATERIALS AND METHODS: Ecarin chromogenic assay (ECA), a laboratory-developed diluted thrombin time (LD-dTT), prothrombin time (PT) and activated partial thromboplastin time (APTT) and ROTEM(r) were used to measure dabigatran anticoagulant activity and liquid chromatography-tandem mass spectrometry (LC MS/MS) to measure dabigatran plasma concentrations. ROTEM(r) (EXTEM, INTEM, FIBTEM) was performed in whole blood and the other assays in platelet poor plasma (PPP), both in samples spiked with dabigatran (0, 25, 50, 100, 250, 500 and 1000 ng/mL) from healthy donors and in ex vivo samples from patients treated with dabigatran etexilate. Citrated PPP samples were frozen and stored at -80 degrees C, 1, 3, 6 and 12 months until analysis. RESULTS: EXTEM and FIBTEM clotting time (CT), ECA and LD-dTT correlate well with dabigatran plasma concentrations. With the exception of few ROTEM(r) parameters, there were no differences between spiked and patient samples. Samples were stable for at least 12 months at -80 degrees C. CONCLUSIONS: EXTEM and FIBTEM CT, ECA and LD-dTT are suitable for measuring the effect of dabigatran in treated patients. In general, results from spiked plasma samples are similar to those of patient samples. Storage of dabigatran plasma samples for up to 12 months does not influence measured levels. PMID- 29475178 TI - Progranulin facilitates the increase of platelet count in immune thrombocytopenia. AB - INTRODUCTION: Progranulin (PGRN) is emerging as a critical immune mediator involved in a variety of autoimmune disorders. However, its role in immune thrombocytopenia (ITP) remains unclear. MATERIALS AND METHODS: In this study, the enzyme-linked immunosorbent assay was used for determining the plasma levels of PGRN in ITP patients vs. healthy controls. In addition, the role of PGRN in ITP was investigated in two kinds of ITP murine models. Further, we explored whether PGRN functioned by affecting the number of T regulatory cells (Tregs) using flow cytometry. RESULTS: We first observed that plasma levels of PGRN were significantly elevated in ITP patients (n = 52) compared to healthy controls (n = 40), and the levels of PGRN declined in patients after receiving treatment. Additionally, we found a negative correlation between plasma PGRN levels and platelet count of ITP patients, suggesting that PGRN is involved in the pathogenesis of ITP. PGRN deficiency further decreased platelet count in a passive-transfer ITP murine model. By contrast, administration of recombinant PGRN increased platelet count in SCID mice with chronic ITP. Meanwhile, PGRN deficiency impaired proliferation of Tregs in the passive transfer ITP murine model. These data suggest that PGRN may exert a protective role in ITP by promoting Treg proliferation. CONCLUSION: Our study revealed a new regulator involved in the pathogenesis of ITP and provided a potential strategy for management of ITP. PMID- 29475180 TI - Altered neural processing of reward and punishment in adolescents with Major Depressive Disorder. AB - BACKGROUND: Altered reward and punishment function has been suggested as an important vulnerability factor for the development of Major Depressive Disorder (MDD). Prior ERP studies found evidence for neurophysiological dysfunctions in reinforcement processes in adults with MDD. To date, only few ERP studies have examined the neural underpinnings of reinforcement processing in adolescents diagnosed with MDD. The present event-related potential (ERP) study aimed to investigate neurophysiological mechanisms of anticipation and consumption of reward and punishment in adolescents with MDD in one comprehensive paradigm. METHOD: During ERP recording, 25 adolescents with MDD and 29 healthy controls (12 17 years) completed a Monetary Incentive Delay Task comprising both a monetary reward and a monetary punishment condition. During anticipation, the cue-P3 signaling attentional allocation was recorded. During consumption, the feedback P3 and Reward Positivity (RewP) were recorded to capture attentional allocation and outcome evaluation, respectively. RESULTS: Compared to controls, adolescents with MDD showed prolonged cue-P3 latencies to reward cues. Furthermore, unlike controls, adolescents with MDD displayed shorter feedback-P3 latencies in the reward versus punishment condition. RewPs did not differ between groups. LIMITATIONS: It remains unanswered whether the observed alterations in adolescent MDD represent a state or trait. CONCLUSIONS: Delayed neural processing of reward cues corresponds to the clinical presentation of adolescent MDD with reduced motivational tendencies to obtain rewards. Relatively shorter feedback-P3 latencies in the reward versus punishment condition could indicate a high salience of performance-contingent reward. Frequent exposure of negatively biased adolescents with MDD to performance-contingent rewards might constitute a promising intervention approach. PMID- 29475181 TI - Impact of the alkyl chain length on binding of imidazolium-based ionic liquids to bovine serum albumin. AB - The effects of six imidazolium-based ionic liquids (ILs) with different alkyl chain length ([CnMim]Cl, n=2, 4, 6, 8, 10, 12) on the structure and functions of bovine serum albumin (BSA) were studied by multi-spectral methods and molecular docking. ILs with the longer alkyl chain length have the stronger binding interaction with BSA and the greater conformational damage to protein. The effects of ILs on the functional properties of BSA were further studied by the determination of non-enzyme esterase activity, beta-fibrosis and other properties of BSA. The thermal stability of BSA was reduced, the rate of the formation of beta sheet structures of BSA was lowered, and the esterase-like activity of BSA were decreased with the increase of ILs concentration. Simultaneous molecular modeling technique revealed the favorable binding sites of ILs on protein. The hydrophobic force and polar interactions were the mainly binding forces of them. The calculated results are in a good agreement with the spectroscopic experiments. These studies on the impact of the alkyl chain length on binding of imidazolium-based ionic liquids to BSA are of great significance for understanding and developing the application of ionic liquid in life and physiological system. PMID- 29475182 TI - A comprehensive study on the photocatalytic activity of coupled copper oxide cadmium sulfide nanoparticles. AB - Coupled CdS-CuO nanoparticles (NPs) subjected in the photocatalytic degradation of Methylene blue (MB) aqueous solution. The calcination temperature and the crystallite phase of CuO had a significant role on the photocatalytic activity of the coupled system and CuO200/2h-CdS catalyst (containing CuO calcined at 200 degrees C for 2h) showed the best photocatalytic activity. The coupled system showed increased activity with respect to the monocomponent semiconductors. The prepared catalysts characterized by x-ray diffraction (XRD), scanning electron microscope equipped with energy dispersive X-ray (EDX) analyzer, x-ray mapping, Fourier transform infrared (FTIR) spectroscopy, diffuse reflectance spectroscopy (DRS) and electrochemical impedance spectroscopy (EIS) techniques. The best degradation extent of MB was obtained at: CMB: 1mgL-1, pH5, 80min irradiation time and 0.8gL-1 of the CuO200/2h-CdS catalyst. The chemical oxygen demand (COD) confirmed about 83% of MB molecules can be mineralized at the optimum conditions. PMID- 29475183 TI - The role of dimethyl sulfoxide (DMSO) in ex-vivo examination of human skin burn injury treatment. AB - Dimethyl sulfoxide (DMSO) is one of the most versatile solvents in biological science, therefore it is frequently used as a solvent in biological studies and as a vehicle for drug therapy. DMSO readily penetrates, diffuses through biological membranes and ipso facto increases fluidity of liposomal membranes modelling stratum corneum. Thermal injury is associated with the appearance of lipid peroxidation products in the burned skin. The influence of DMSO on protein structure and stability is concentration and temperature dependant. The aim of this study was to assess the impact of DMSO on human burn wounds and examine the interactions between DMSO and skin surface. The real problem in burn treatment is hypoalbuminemia. At the level of the laboratory studies there was an attempt at answering the question of whether the DMSO will modify the standard serum solution. In the case of the incubation of skin fragments in 1%-100% DMSO, the following findings were reported: modification of the serum, appearance of low molecular weight oligomer bands, disappearance of albumin bands or reconstruction of native serum bands during incubation in antioxidant solutions. The result of the modification is also the exposure of FTIR 1603 and 1046cm-1 bands observed in frozen serum solutions. In the case of modification of the burned skin by DMSO solutions or antioxidants - frequency shifts, an increase in the intensity of amide I band as well as the appearance of the 1601cm-1 band can be specific biomarkers of the tissue regeneration process. In this study the areas 1780 1580cm-1 and 1418-1250cm-1 on the Raman spectra are particularly rich in spectral information. PMID- 29475184 TI - Improving the first hyperpolarizability of anthracene through interaction with HX molecules (XF, Cl, Br): A theoretical study. AB - The variations in nonlinear optical activity (NLO) of anthracene (C14H10) was investigated via intermolecular interactions between C14H10 and HX molecules (XF, Cl and Br) using B3LYP-D3 method at 6-311++G(d,p) basis set. The stabilization of those complexes was investigated via vibrational analysis, quantum theory of atoms in molecules, molecular electrostatic potential, natural bond orbitals and symmetry-adapted perturbation theory (SAPT) analysis. Furthermore, the optical spectra and the first hyperpolarizabilities of C14H10?HX complexes were computed. The adsorption of hydrogen halide through C14H10?HX complex formation, didn't change much the linear optical activities of C14H10 molecule, but the magnitude of the first hyperpolarizability of the C14H10?HX complexes to be as much as that of urea. PMID- 29475185 TI - A highly specific and ultrasensitive near-infrared fluorescent probe for imaging basal hypochlorite in the mitochondria of living cells. AB - The development of highly specific and ultrasensitive fluorescent probes for tracking basal mitochondrial hypochlorite is very important to unravel its diverse cellular functions in the mitochondria of living cells. In this paper, we have developed a water-soluble, mitochondria-targeted near-infrared fluorescent probe NB-OCl for selectively measuring OCl- in the presence of higher concentration (500 MUM) other biologically important substances. Surprisingly, the obtained results demonstrated that probe NB-OCl could sensitively determine OCl- in the range of 0-200 pM with the detection limit of 10.8 pM. To the best of our knowledge, NB-OCl is the first fluorescent probe for the specific determination of OCl- at the picomolar level. Moreover, probe NB-OCl exhibits a fast response for OCl- (< 5 s), which would be in favor of tracking the highly reactive and short-lived OCl- in the living systems. The preeminent recognition properties of probe NB-OCl enable its applications in the monitoring of basal OCl and the fluctuations of endogenous/exogenous OCl- levels in the mitochondria of living cells. PMID- 29475186 TI - An optofluidic metasurface for lateral flow-through detection of breast cancer biomarker. AB - The rapid growth of point-of-care tests demands for biosensors with high sensitivity and small size. This paper demonstrates an optofluidic metasurface that combines silicon-on-insulator (SOI) nanophotonics and nanofluidics to realize a high-performance, lateral flow-through biosensor. The metasurface is made of a periodic array of silicon nanoposts on an SOI substrate, and functionalized with specific receptor molecules. Bonding of a polydimethylsiloxane slab directly onto the surface results in an ultracompact biosensor, where analyte solutions are restricted to flow only in the space between the nanoposts. No flow exists above the nanoposts. This sensor design overcomes the issue with diffusion-limited detection of many other biosensors. The lateral flow-through feature, in conjunction with high-Q resonance modes associated with optical bound states of the metasurface, offers an improved sensitivity to subtle molecule-bonding induced changes in refractive index. The device exhibits a resonance mode around 1550 nm wavelength and provides an index sensitivity of 720 nm/RIU. Biosensing is conducted to detect the epidermal growth factor receptor 2 (ErbB2), a protein biomarker for early-stage breast cancer screening, by monitoring resonance wavelength shifts in response to specific analyte-ligand binding events at the metasurface. The limit of detection of the device is 0.7 ng mL-1 for ErbB2. PMID- 29475187 TI - Small-scale production of 67Cu for a preclinical study via the 64Ni(alpha, p)67Cu channel. AB - INTRODUCTION: Copper-67 is an attractive beta emitter for targeted radionuclide therapy. However, the availability of 67Cu limits its potential use in a wide range of applications. In this study, we propose an easy small-scale production of 67Cu using 64Ni target for a preclinical study. METHODS: 67Cu was produced from an electrodeposited 64Ni target via the 64Ni(alpha, p)67Cu-reaction with a 36 MeV alpha beam at 15 eMUA (electrical microampere) conducted for 7 h. The chemical separation process of 67Cu from the 64Ni target was performed following by our routine procedure of 64Cu production using cation exchange resin, AG50W X8, with minor modification. The target and its holder were redesigned in the preparation. RESULTS: The 67Cu product was obtained with a yield of 55 +/- 10 MBq at the end of bombardment (EOB), and the yield was 527 +/- 96 kBq/MUAh at the EOB. The copper impurity in the product was low (0.71 +/- 0.21 MUg) and the product was suitable for a preclinical study. CONCLUSIONS: We produced 67Cu with sufficient activity and quality for a preclinical study using a 64Ni-target. This production method also showed advantages as a routine method, i.e., shorten the processing time, reducing the radiation exposure and ready target recycling, when compared with that of a conventional Zn-target used for 67Cu production. PMID- 29475188 TI - Effects of molecular weight of hyaluronic acid on its viscosity and enzymatic activities of lysozyme and peroxidase. AB - OBJECTIVES: To investigate the effects of the molecular weight of hyaluronic acid on its viscosity and enzymatic activities of lysozyme and peroxidase in solution and on the hydroxyapatite surface. DESIGN: Hyaluronic acids of four different molecular weights (10 kDa, 100 kDa, 1 MDa, and 2 MDa), hen egg-white lysozyme, bovine lactoperoxidase, and human whole saliva were used. Viscosity values of hyaluronic acids were measured using a cone-and-plate viscometer at six different concentrations (0.1-5.0 mg/mL). Enzymatic activities of lysozyme and peroxidase were examined by hydrolysis of fluorescein-labeled Micrococcus lysodeikticus and oxidation of fluorogenic 2',7'-dichlorofluorescein to fluorescing 2',7' dichlorofluorescein, respectively. RESULTS: In solution assays, only 2 MDa hyaluronic acid significantly inhibited lysozyme activities in saliva. In surface assays, hyaluronic acids inhibited lysozyme and peroxidase activities; the inhibitory activities were more apparent with high-molecular-weight ones in saliva than in purified enzymes. The 100 kDa-hyaluronic acid at 5.0 mg/mL, 1 MDa one at 0.5 mg/mL, and 2 MDa-one at 0.2 mg/mL showed viscosity values similar to those of human whole saliva at a shear rate range required for normal oral functions. The differences among the influences of the three conditions on the enzymatic activities were not statistically significant. CONCLUSIONS: High molecular-weight hyaluronic acids at low concentration and low-molecular-weight ones at high concentration showed viscosity values similar to those of human whole saliva. Inhibitory effects of hyaluronic acids on lysozyme and peroxidase activities were more significant with high-molecular-weight ones on the surface and in saliva compared with in solution and on purified enzymes. PMID- 29475189 TI - Efficacy of different strategies to treat root dentin eroded by liquid or gaseous hydrochloric acid associated with brushing abrasion. AB - OBJECTIVE: This study aims to evaluate how casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) associated with Nd:YAG or Diode laser affects dentin exposed to hydrochloric acid (HCl) with or without tooth brushing. DESIGN: One hundred and sixty human root dentin blocks were selected after they were initially eroded with liquid HCl (pH 1.2) 3x for one day. The blocks were divided into the following groups: G1- liquid HCl (HCl-l), G2- HCl-l + brushing, G3- gaseous HCl (HCl-g), and G4- HCl-g + brushing. Each group was randomly assigned to the following treatments (n = 10): A) Control (no treatment), B) CPP-ACP, C) CPP-ACP associated with Nd:YAG laser (lambda = 1064 nm) (40 mJ, 10 Hz, 0.4 W, 15 s), and D) CPP-ACP associated with Diode laser (lambda = 980 nm) (0.5 W, 200 MUs, 15 s). The treatment with CPP-ACP (G2, G3 and G4) was applied on the dentine surface for 5 min. Erosion (6x/day/20 s) and erosion (6x/day/20 s) with abrasion (2x/10 s) were performed for five days. Dentin volume loss was determined by 3D confocal laser microscopy. Data were analyzed with two-way ANOVA and Tukey's tests. RESULTS: G1 - CPP-ACP (10.77 +/- 1.66) and CPP-ACP associated with Diode laser (9.98 +/- 0.89) showed lower volume loss in relation Control group (12.86 +/- 0.63) (p < 0.05). G2 - CPP-ACP associated with Diode laser (12.41 +/- 1.08) elicited lower volume loss as compared to the Control (14.42 +/- 1.24) (p < 0.05). As for G3 and G4, all treatments showed similar volume loss. CONCLUSION: CPP-ACP and CPP-ACP associated with Diode laser could control dental tissue loss in dentin eroded by liquid HCl. Moreover, CPP-ACP associated with Diode laser could effectively decrease dental tissue loss in dentin exposed to liquid HCl and brushing. PMID- 29475190 TI - Factors Dancers Associate with their Body Dissatisfaction. AB - Body dissatisfaction constitutes an important factor in the development of eating pathologies, particularly among dancers. The aim of this research was to test the factors that dancers identified as relevant to their body dissatisfaction using an exploratory mixed method design. Participants were 369 dancers from two Spanish dance conservatories. Questionnaires assessed body dissatisfaction, abnormal eating attitudes and behaviors, and risk factors to eating disorders in the dance domain. Nine factors were found; the "teacher", the "uniform", and the "mirrors" were the most common. Individuals with a greater likelihood of developing an eating disorder identified teachers influence as a key factor in their body dissatisfaction. Specifically, ballet dancers were more likely to indicate that teachers were a negative influence compared to students in other dance genres (contemporary, flamenco, and Spanish dance). Programs to reduce negative body image and improve positive body image in dance conservatories are needed, specifically focusing on teachers. PMID- 29475191 TI - Factor structure and psychometric properties of a Romanian translation of the drive for Muscularity Scale (DMS) in university men. AB - We examined the psychometric properties of a Romanian translation of the 15-item Drive for Muscularity Scale (DMS). Male university students from Romania (N = 343) completed the DMS, as well as measures of self-esteem, body appreciation, and muscle discrepancy. Exploratory factor analysis indicated that DMS scores reduced to two factors that related to muscularity-oriented attitudes and behaviours, with both first-order factors loading onto a higher-order factor. However, confirmatory factor analysis indicated that a model with two first-order factors and a higher-order factor had poor fit. A two-factor model without a higher-order construct achieved acceptable but mediocre fit. Scores on the two factor DMS model had adequate internal consistency and demonstrated acceptable convergent validity (significant correlations with self-esteem, body appreciation, and muscle discrepancy). These results provide support for a two factor model of DMS scores in a Romanian-speaking sample and extends the availability of the DMS to a rarely-examined linguistic group. PMID- 29475192 TI - Infants' understanding of the definite/indefinite article in a third-party communicative situation. AB - The present study examines how infants use their emergent perspective-taking and language comprehension abilities to make sense of interactions between two human agents. In the study, one agent (Agent1) could see only one of two identical balls on an apparatus because of a screen obstructing her view while the infant and another agent (Agent2) could see both balls. 19-month-old English-learning monolingual infants seemed to expect Agent2 to grasp the ball visible to Agent1 when she said to Agent2 "Give me the ball" but not when she said "Give me a ball." 14-month-olds appeared to accept that Agent2 could grasp either ball when Agent1 said "Give me the ball." Therefore, by 19 months of age, English-learning infants seem to attend to the specific linguistic units used, e.g., the definite article, to identify the referent of others' speech. Possible reasons in connection with language acquisition processes and/or environmental factors for the two age groups' respective failures with the definite and the indefinite articles are discussed. PMID- 29475193 TI - Site-specific immobilization of endoglycosidases for streamlined chemoenzymatic glycan remodeling of antibodies. AB - Chemoenzymatic glycan remodeling of antibodies using an endoglycosidase and its mutant is emerging as an attractive approach for producing homogeneous antibody glycoforms. We report in this paper a site-specific covalent immobilization of the endoglycosidases (Endo-S2 and its glycosynthase mutant D184M) using a recombinant microbial transglutaminase (MTG) and evaluation of the immobilized enzymes in deglycosylation and glycosylation of a therapeutic antibody. The site specific covalent immobilization was achieved by introduction of a Q-tag at the C terminus of the recombinant enzymes followed by conjugation of the enzymes to a primary amine-containing solid support through MTG-catalyzed transglutamination. Using rituximab as a model system, we found that the Endo-S2 wild-type and D184M glycosynthase mutant immobilized by this approach were efficient in the two step antibody glycan remodeling to generate homogeneous antibody glycoforms. Notably using the covalently immobilized enzymes can efficiently avoid the need of intermediate purification and eliminate the residual contamination of wild type enzyme for product hydrolysis, thus streamlining the chemoenzymatic Fc glycan remodeling of antibodies. PMID- 29475194 TI - Scope and limitations of carbohydrate hydrolysis for de novo glycan sequencing using a hydrogen peroxide/metallopeptide-based glycosidase mimetic. AB - Acidic hydrolysis is commonly used as a first step to break down oligo- and polysaccharides into monosaccharide units for structural analysis. While easy to set up and amenable to mass spectrometry detection, acid hydrolysis is not without its drawbacks. For example, ring-destruction side reactions and degradation products, along with difficulties in optimizing conditions from analyte to analyte, greatly limits its broad utility. Herein we report studies on a hydrogen peroxide/CuGGH metallopeptide-based glycosidase mimetic design for a more efficient and controllable carbohydrate hydrolysis. A library of methyl glycosides consisting of ten common monosaccharide substrates, along with oligosaccharide substrates, was screened with the artificial glycosidase for hydrolytic activity in a high-throughput format with a robotic liquid handling system. The artificial glycosidase was found to be active towards most screened linkages, including alpha- and beta-anomers, thus serving as a potential alternative method for traditional acidic hydrolysis approaches of oligosaccharides. PMID- 29475195 TI - Instant messaging and nursing students' clinical learning experience. AB - BACKGROUND: Although learning in clinical settings is a key element of nursing education, for many learners these are challenging developmental contexts often marked by isolation and a lack of belongingness. Despite the massive appropriation of mobile instant messaging (MIM) platforms and the connective properties attendant to them, very little is known about their role in and impact on nursing students' clinical learning experiences. APPROACH AND METHODS: To address this gap, the study, which was part of a multinational research project on the use of mobile social media in health professions education in developing countries, examined the use of the instant messaging platform WhatsApp by nursing students during placements and potential associations with socio-professional indicators. The survey involved a total number of 196 nursing students from 5 schools in Oyo State, Nigeria. RESULTS: The findings suggest that students used WhatsApp relatively frequently and they perceived that this platform strongly enhanced their communication with other students and nurses. WhatsApp use during placements was positively associated with students' maintained social capital with peer students, the development of a professional identity, placement satisfaction and with reduced feelings of isolation from professional communities. The determinants that influenced WhatsApp use during placements were perceived usefulness and perceived ease of use. No associations were found between WhatsApp use during placement and age, attitude, subjective norms and placement duration. CONCLUSION: This study is one of the first of its kind that points to the relevance of mobile instant messaging as part of nursing students' (inter)personal learning environments in clinical settings and, particularly, in the development setting under investigation. Further research is needed to corroborate these findings, to enhance the understanding of the impact mechanisms, and to evaluate a more systematic use of MIM in clinical learning contexts. PMID- 29475196 TI - Self-tracking, governmentality, and Nursing and Midwifery Council's (2016) revalidation policy. AB - In April 2016 the Nursing and Midwifery Council (NMC) introduced a new revalidation continuous professional development (CPD) policy. This policy states that revalidation is the responsibility of nurses, and although employers are urged to support the revalidation process, the NMC clearly states that employers have no legal requirement to provide either time or funds for the CPD activities of nurses and midwives (NMC, 2014, 2016; Royal College of Nursing, 2016). The aim of this professional development policy is to ensure that nurses and midwives maintain their professional competency and to promote public safety and confidence in nurses and midwives. A closer look at the process of revalidation suggests that several measures have been introduced to ensure that nurses and midwives conform to the CPD policy, and this paper examines the influence of governmentality and neoliberalism on the NMC's self-tracking revalidation policy. It will be recommended that the responsibility for the revalidation process should be shared by nurses, midwives, and their employers, and that time and money should be allocated for the professional development of nurses and midwives. PMID- 29475197 TI - High-risk soft tissue sarcomas treated with perioperative chemotherapy: Improving prognostic classification in a randomised clinical trial. AB - BACKGROUND: Patients with extremity and trunk wall soft tissue sarcoma (STS) with high malignancy grade and size >5 cm are at high-risk of death. This risk varies depending also on other patient and tumour features, including histologic subtype. This study investigated whether a prognostic nomogram can improve risk assessment of these patients. METHODS: Data from high-risk STS patients enrolled in a randomised controlled trial investigating different perioperative chemotherapy regimens were analysed. Ten-year probability of overall survival (OS) and incidence of distant metastasis (DM) were computed using the prognostic nomogram Sarculator (pr-OS and inc-DM, respectively). Tumour response according to RECIST and Choi criteria was also investigated. FINDINGS: Variation in pr-OS and inc-DM were observed and patients stratified in three prognostic groups. The 10-year OS in the low, intermediate, and high pr-OS categories were 0.42 (95%CI 0.32-0.52), 0.63 (95%CI 0.53-0.72), and 0.78 (95%CI 0.68-0.85), respectively. Patients in the intermediate (HR 0.51, P = 0.002) and high (HR 0.28, P < 0.001) pr-OS categories were at statistically significant lower risk of death compared with those in the low pr-OS category. Higher rate of Choi partial tumour responses were detected in intermediate pr-OS category. Tumour response according to Choi but not to RECIST criteria stratified patient survival of pr-OS categories, particularly for patients with intermediate to low pr-OS. Analyses conducted for 10-year inc-DM were consistent with results for pr-OS for prognostic value of Sarculator predictions and Choi tumour response. INTERPRETATION: Sarculator identifies variations in outcomes of high-risk STS treated with perioperative chemotherapy and improve prognostic classification, which is also associated with different patterns of tumour response, an outcome that further stratifies survival particularly for patients predicted at higher risk. Future trials investigating neoadjuvant chemotherapy should consider prognostic tool for selecting patients to be enrolled. TRIAL REGISTRATION NUMBER: European Union Drug Regulating Authorities Clinical Trials No. 2004-003979-36. PMID- 29475198 TI - Willingness to use drug checking within future supervised injection services among people who inject drugs in a mid-sized Canadian city. AB - BACKGROUND: Esclating epidemics of fatal overdose are affecting communities across Canada. In many instances, the unanticipated presence of powerful opioids, such as fentanyl, in street drugs is a contributing factor. Drug checking offered within supervised injection services (SIS) is being considered as a potential measure for reducing overdose and related harms. We therefore sought to characterize the willingness of people who inject drugs (PWID) to use drug checking within SIS. METHODS: Data were derived from a cross-sectional survey examining the feasibility of SIS in London, Canada, a mid-sized city. Multivariable logistic regression was used to examine factors associated with willingness to frequently (always or usually) use drug checking at SIS. RESULTS: Between March and April 2016, 180 PWID were included in the present study, including 68 (38%) women. In total, 78 (43%) reported that they would frequently check their drugs at SIS if this service were available. In multivariable analyses, female gender (Adjusted Odds Ratio [AOR] = 2.31; 95% confidence interval [CI]: (1.20-4.46), homelessness (AOR = 2.36; 95% CI: 1.14-4.86), and drug dealing (AOR = 2.16; 95% CI: 1.07-4.33) were positively associated with willingness to frequently check drugs at SIS. CONCLUSION: These findings highlight the potential of drug checking as a complement to other services offered within SIS, particularly given that subpopulations of PWID at heightened risk of overdose were more likely to report willingness to frequently use this service. However, further research is needed to determine the possible health impacts of offering drug checking at SIS. PMID- 29475199 TI - The Role of a Single Dose of Vancomycin in Reducing Clinical Sepsis in Premature Infants Prior to Removal of Peripherally Inserted Central Catheter: A Retrospective Study. AB - OBJECTIVE: Peripherally inserted central catheter (PICC) line removal is associated with bloodstream infections and clinical sepsis. We aim to investigate the role of a single prophylactic dose of vancomycin in decreasing the incidence of central line associated bloodstream infection associated with PICC removal. METHODS: A retrospective chart review of patients in the neonatal intensive care unit was conducted. Patients were divided into two study groups based on whether a single dose of vancomycin was administered (exposed) or not (nonexposed). The primary outcome measured was clinical sepsis with or without positive blood culture. RESULTS: The incidence of clinical sepsis in the exposed group was 7.3% compared with 6.3% in the nonexposed group (p-value: 0.7860). The incidence of culture-positive sepsis in the exposed group was 2.2% compared with 1.6% in the nonexposed group (p-value: 0.7673). The overall incidence of clinical and culture positive sepsis in the subgroup with infants weighing <1,500 g and <32 weeks' gestational age was similar to the main study group. CONCLUSION: Our data do not support routine vancomycin prophylaxis prior to PICC line removal in premature infants to prevent sepsis associated with PICC removal. However, a large randomized controlled trial is further needed to delineate these results. PMID- 29475200 TI - Cardiovascular Associations with Abnormal Brain Magnetic Resonance Imaging in Neonates with Hypoxic Ischemic Encephalopathy Undergoing Therapeutic Hypothermia and Rewarming. AB - OBJECTIVE: This article compares hemodynamic characteristics of neonates with hypoxic ischemic encephalopathy (HIE) receiving therapeutic hypothermia (TH) with normal versus abnormal brain magnetic resonance imaging (MRI). METHODS: Serial echocardiography (echo) was performed within 24 hours, after 48 to 72 hours of cooling, within 24 hours of normothermia, and after starting feeds. Pulmonary hemodynamics, cardiac output, and ventricular function were evaluated. All neonates underwent brain MRI (day 4-5), per clinical standard of care. Clinical cardiovascular and echocardiography characteristics were compared between patients with normal versus abnormal MRI. Cardiovascular changes during TH and after rewarming were identified. RESULTS: Twenty neonates at median gestation and birth weight of 40 weeks (interquartile range [IQR]: 39, 41) and 3,410 g (IQR: 2,885, 4,093), respectively, were enrolled. Increased median left ventricular output (LVO) (106-159 mL/kg/min, p < 0.001) and reduced isovolumic relaxation time (IVRT) (48-42 ms, p < 0.001) were seen after rewarming. Echocardiography evidence of pulmonary hypertension (PH) was identified in five neonates. Eight neonates (40%) had brain injury identified on MRI (watershed [n = 4], basal ganglia [n = 4]); this subgroup were more likely to have echo evidence of PH at 24 hours. CONCLUSION: Longitudinal changes in cardiac output were noted in neonates with HIE during TH and rewarming. Echocardiography evidence of PH, however, was associated with abnormal MRI brain. The prognostic relevance of these physiologic changes requires more comprehensive delineation. PMID- 29475201 TI - Association of Antibiotic Utilization and Neurodevelopmental Outcomes among Extremely Low Gestational Age Neonates without Proven Sepsis or Necrotizing Enterocolitis. AB - OBJECTIVE: The objective is to evaluate the association between antibiotic utilization and neurodevelopmental outcomes at 18 to 21 months' corrected age among extremely low gestational age neonates without culture-proven sepsis or necrotizing enterocolitis (NEC). STUDY DESIGN: We conducted a retrospective cohort study of infants born between April 2009 and September 2011 at <29 weeks' gestation and admitted to the neonatal intensive care units contributing data to the Canadian Neonatal Network. Multivariable analysis was performed to examine the primary composite outcome of death or significant neurodevelopmental impairment (sNDI) in infants with various antibiotic utilization rates (AURs). RESULT: There were 1,373 infants who fulfilled our inclusion criteria. Compared with infants in the lowest AUR quartile (Q1), those in the highest quartile (Q4) had higher odds of death or sNDI (adjusted odds ratio [AOR] = 7.44; 95% confidence interval [CI]: 4.55, 12.2) and death (AOR = 39.3; 95% CI: 16.1, 95.9). CONCLUSION: Our results indicate an association between high AUR and a composite outcome of death or adverse neurodevelopmental outcomes at 18 to 21 months' corrected age. PMID- 29475202 TI - Postpartum Genital Melanoma - A Case Report. AB - Melanomas of the female genital tract may occur in the vulva, the vagina, the ovary or the cervix. Pregnancy has been considered an aggravating factor in the evolution and prognosis of melanoma. A 35-year-old female presented with vaginal bleeding 2 months after a term cesarean delivery. An endovaginal ultrasound revealed a lesion in the uterine cervix. The pathological report revealed a small round-cell neoplasm, and the immunohistochemistry confirmed the diagnosis of malignant melanoma. A positron emission tomography revealed an expansive hypermetabolic lesion centered on the cervix, and hypermetabolic lesions in the liver and right kidney. Non-surgical treatment was provided, with biochemotherapy followed by ipilimumab and nivolumab. The patient died one year later. Postpartum vaginal bleeding, even if late-onset, should be investigated, as it may be a pregnancy-associated malignant melanoma, which has a poor prognosis. PMID- 29475203 TI - Venous Thromboembolism and Route of Delivery - Review of the Literature. AB - Venous thromboembolism events are important causes of maternal death during pregnancy and the postpartum period worldwide. A review of the literature with the objective of evaluating venous thromboembolism events in the puerperium according to the route of delivery was performed through a bibliographic survey in the Medline, LILACS and Scielo databases. We observed that patients submitted to cesarean sections present a significantly higher risk of developing venous thromboembolism when compared with those who undergo spontaneous vaginal delivery. The pathophysiological bases for this difference were explored and described in this review, as well as the indications of prophylaxis and treatment. Doctors and health professionals must be continuously vigilant regarding this condition, since it is associated with high morbidity and mortality. PMID- 29475204 TI - Time-frequency Features for Impedance Cardiography Signals During Anesthesia Using Different Distribution Kernels. AB - OBJECTIVE: This works investigates the time-frequency content of impedance cardiography signals during a propofol-remifentanil anesthesia. MATERIALS AND METHODS: In the last years, impedance cardiography (ICG) is a technique which has gained much attention. However, ICG signals need further investigation. Time Frequency Distributions (TFDs) with 5 different kernels are used in order to analyze impedance cardiography signals (ICG) before the start of the anesthesia and after the loss of consciousness. In total, ICG signals from one hundred and thirty-one consecutive patients undergoing major surgery under general anesthesia were analyzed. Several features were extracted from the calculated TFDs in order to characterize the time-frequency content of the ICG signals. Differences between those features before and after the loss of consciousness were studied. RESULTS: The Extended Modified Beta Distribution (EMBD) was the kernel for which most features shows statistically significant changes between before and after the loss of consciousness. Among all analyzed features, those based on entropy showed a sensibility, specificity and area under the curve of the receiver operating characteristic above 60%. CONCLUSION: The anesthetic state of the patient is reflected on linear and non-linear features extracted from the TFDs of the ICG signals. Especially, the EMBD is a suitable kernel for the analysis of ICG signals and offers a great range of features which change according to the patient's anesthesia state in a statistically significant way. PMID- 29475205 TI - The Pituitary-Thyroid Axis and Prolactin Secretion in Hemodialysis Patients in Two Endemic Regions of Eastern Germany. AB - INTRODUCTION: Endocrine disorders of the pituitary axes are frequent in patients with hemodialysis (CKD5D). The aim of this multicenter study (Leipzig (L), Quedlinburg and Blankenburg in the Harz region (Hz)) in CKD5D patients was to evaluate influences of CKD5D related factors, morphological and biochemical parameters, and serum iodine and prolactin concentrations on the pituitary thyroid axis. PATIENTS AND METHODS: 170 patients (L n=58; Hz n=112) were included in this prospective, non-interventional, cross-sectional study. Mann-Whitney-U test and bivariate correlation analyses with Spearman-Rho test (r correlation coefficient) were used in statistical analysis. RESULTS: TSH was higher in patients with prolactin concentrations>370 mIU/l (p=0.013), in patients with high flux membranes (p=0.0013) and in patients with longer dialysis vintage (p=0.04). Median iodine serum concentrations were slightly elevated in the Leipzig cohort (p=0.001) and correlated with fT4 (p<0.001, r=0.43) and albumin (p=0.001, r=0.245) but not with morphological signs. Albumin was correlated with fT3 (p<0.001, r=0.339) and fT4 (p<0.001, r=0.421). Prolactin was correlated with residual excretion rate (p=0.001, r=- 0.303) and thyroid volume (p=0.027, r=0.217). CONCLUSIONS: In the assessment of the thyroid status in CKD5D patients, the synopsis of the clinical and nutritional status, comorbidities, ultrasound of the thyroid gland and laboratory results is necessary for further intervention with hormone replacement. Standardized reference values of the pituitary-thyroid axis should be critically evaluated and are still lacking in CKD5D. PMID- 29475206 TI - Association between Forefoot Bone Length and Performance in Male Endurance Runners. AB - Recently, we reported that the forefoot bones were longer in sprinters than in non-sprinters, and that longer forefoot bones correlated with higher sprint performance in sprinters. To further understand the superiority of long forefoot bones in athletic performance, we examined whether forefoot bone length was associated with running performance in endurance runners. The length of the forefoot bones of the big and second toes were measured using magnetic resonance imaging in 45 male well-trained endurance runners and 45 male untrained subjects. After normalization with the foot length, it was found that the forefoot bones of the big and second toes were significantly longer in endurance runners than in untrained subjects (P<0.05 for both). Furthermore, longer forefoot bones of the big toe, but not of the second toe, correlated significantly with better personal best 5000-m race time in endurance runners (r=-0.322, P=0.031). The present findings demonstrated that forefoot bones were longer in endurance runners than in untrained subjects. These findings were similar to our findings for sprinters. In addition, we found that longer forefoot bones may be advantageous for achieving higher running performance in endurance runners. PMID- 29475207 TI - The Impact of Soccer Match Play on the Muscle Damage Response in Youth Female Athletes. AB - Post-match assessment of creatine kinase (CK) activity and delayed-onset muscle soreness (DOMS) are common markers of exercise-induced muscle damage and recovery status in soccer players. These responses have not been examined in youth female players. This study examined the effect of competitive match play on CK activity and DOMS in elite youth players. Thirty-four elite female players, divided into three chronological age groups (U13, n=11; U15, n=10; U17 n=12). Players completed baseline testing for CK and DOMS that was repeated immediately (for DOMS), 80, 128 and 168 h post-competitive match play for CK. Significant time effects were reported for CK (P=0.006) and DOMS (P<0.01). Significant differences between baseline and 168 h post-match were reported for CK (P<0.01), with significant group differences between the U13 and U17 groups for CK (P<0.01). All parameters returned to baseline in U17s at 168 h, but increased CK was evident for U13s and U15s at 168 h. In conclusion, seven days may be insufficient for biochemical recovery in youth female athletes. Therefore, monitoring strategies to assess muscle damage between training and match play should be considered to track recovery and potentially reduce muscular injury risk. PMID- 29475208 TI - Resistance Training Threshold for Elevating Bone Mineral Density in Growing Female Rats. AB - The purpose of this study was to determine the minimum amount of resistance exercise that would stimulate bone formation yielding an elevation in bone mineral density (BMD) during the growth period in female rats. Female rats were randomly divided into: Control (Con, n=8), 3 ladder climb resistance-trained group (3LC, n=8), 4 ladder climb resistance-trained group (4LC, n=8), 5 ladder climb resistance-trained group (5LC, n=8), and 6 ladder climb resistance-trained group (6LC, n=8). All exercised groups were conditioned to climb a vertical ladder with weights appended to their tail 3 days/wk for a total of 6 wks. After 6 wks, left tibia BMD (g/cm2) was significantly greater for 4LC (0.197+/-0.003), 5LC (0.200+/-0.004) and 6LC (0.202+/-0.003) when compared to Con (0.185+/-0.006). Left femur BMD (g/cm2) was significantly greater for 4LC (0.260+/-0.005), 5LC (0.269+/-0.004) and 6LC (0.272+/-0.006) when compared to Con (0.244+/-0.006). There were no significant differences in tibia and femur BMD between 4LC, 5LC, and 6LC groups. The results suggest that during growth, a high volume of resistance exercise was required to elicit an elevation in BMD in females. PMID- 29475209 TI - Perceptually Regulated Exercise Test Allows Determination of VO2max and Ventilatory Threshold But Not Respiratory Compensation Point In Trained Runners. AB - This study aimed to investigate the differences in maximal oxygen uptake (VO2max) and submaximal thresholds between a standard graded exercise test (GXT) and a perceptually regulated graded exercise test (PRGXT) in trained runners. Eleven well-trained middle- to long-distance runners performed both tests in a randomized order. PRGXT used incremental "clamps" of rating of perceived exertion (RPE) over 10*1-min stages on an automated treadmill equipped with a sonar sensor allowing them to change their running speed instantly and in a natural way. GXT used fixed 1 km.h-1 increment every minute. Ventilatory threshold (VT) and respiratory compensation point (RCP) were determined using ventilatory equivalents. No differences were found in VO2max (68.0 (5.3) vs. 69.5 (5.9) ml.min-1.kg-1, p=0.243), minute ventilation (VE) (159.4 (35.0) vs. 162.4 (33.7) l.min-1, p=0.175), heart rate (HR) (188.4 (6.9) vs. 190.7 (5.2) bpm, p=0.254) and speed (21.0 (1.7) vs. 21.1 (2.3) km.h-1, p=0.761) between GXT and PRGXT. At VT, there were no significant differences between GXT and PRGXT for any outcome variables. For 8 of 11 subjects, it was not possible to determine RCP from ventilatory equivalent in PRGXT. GXT appears more relevant for a comprehensive gas analysis in trained runners. PMID- 29475210 TI - [Comparison of International Guidelines For the Application of Cardiotocography]. AB - OBJECTIVE: This study examines the recommendations of international guidelines on the use of antepartum and intrapartum cardiotocography. MATERIAL AND METHODS: The guidelines of Germany, Canada, UK, USA, Sri Lanka, Australia as well as FIGO have been compared. The recommendations on the use of cardiotocography were separately evaluated for antepartum and intrapartum use. RESULTS: Antepartum: In risk-free pregnancies the use of cardiotocography is not recommended in all countries. On the other hand the use of cardiotocography is indicated in the presence of a defined maternal and fetal risk factors. While the NICE guidelines recommend cardiotocography in the case of maternal hypertension, as well as preeclampsia, the German guidelines as well as SOGC list considerably more risk factors. Intrapartually, the recommendations vary greatly from country to country. While German guidelines suggest the use of cardiotocography from late 1st stage of labor, the other countries strongly recommend the auscultation of the fetal heart rate of non-risk pregnancies. This is due to the current study situation, which does not show any advantage of cardiotocography as opposed to intermittent auscultation. Furthermore studies have indicated that the use of cardiotocography caused an increase in iatrogenic induced cesarean sections. In high risk pregnancies the use of cardiotocography is strongly recommended in the compared countries, however there are major differences in the definition of high risk pregnancy and therefore the indication for cardiotocographic monitoring. CONCLUSION: Intermittent auscultation is a more cost-effective alternative compared to cardiotocography. However, in the case of legal litigation intermittent auscultation is harder to reconstruct the well-being of the newborn during birth. On the other hand cardiotocography might result in a higher cesarean section rate, but can be more helpful to prove fetal well-being during birth for a legal litigation process. Despite the lack of evidence only German guidelines recommend cardiotocographic monitoring from the late 1st stage of labor for risk-free pregnancies. PMID- 29475211 TI - Preoperative Care of the TKA Patient. AB - Total knee arthroplasty continues to increase in popularity and remains the most common joint replacement surgery. The success of total knee replacement surgery is attributed to improved outcomes, a better patient experience, and lower cost. Rapid recovery total knee replacement protocols have led to these advances by decreasing length of hospital stay, minimizing readmissions, and reducing the cost of surgery. Rapid recovery total knee replacement pathway efforts should focus on preoperative education, optimization of modifiable risk factors, and identification of patients that may not be suitable for this pathway. PMID- 29475212 TI - The Effects of Vitamin D Supplementation on Biomarkers of Inflammation and Oxidative Stress Among Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - The current systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to summarize the effect of vitamin D supplementation on biomarkers of inflammation and oxidative stress among women with polycystic ovary syndrome (PCOS). Cochrane library, Embase, PubMed, and Web of Science database were searched to identify related randomized-controlled articles (RCTs) published up to November 2017. Two researchers assessed study eligibility, extracted data, and evaluated risk of bias of included RCTs, independently. To check heterogeneity Q-test and I2 statistics were used. Data were pooled by using the random-effect model and standardized mean difference (SMD) was considered as summary effect size. Seven RCTs were included into our meta-analysis. The findings showed that vitamin D supplementation in women with PCOS significantly decreased high-sensitivity C-reactive protein (hs-CRP) (SMD -1.03; 95% CI, -1.58, -0.49; p <0.001) and malondialdehyde (MDA) (SMD -1.64, 95% CI -2.26 to -1.02, p <0.001), and significantly increased total antioxidant capacity (TAC) levels (SMD 0.86, 95% CI 0.08 to 1.64, p=0.03). Vitamin D supplementation had no significant effect on nitric oxide (NO) (SMD 0.11, 95% CI -0.44 to 0.66, p=0.69) and total glutathione (GSH) levels (SMD 0.54, 95% CI -0.20 to 1.28, p=0.15). Overall, the current meta-analysis demonstrated that vitamin D supplementation to women with PCOS resulted in an improvement in hs-CRP, MDA and TAC, but did not affect NO and GSH levels. PMID- 29475213 TI - Modified Multivisceral Transplantation with Native Spleen Removal in Rats. AB - BACKGROUND: Modified multivisceral transplantation (MMVTx) refers to the use of a graft that includes all abdominal organs except the liver. The use of this type of transplant in children and adults expanded over the last years with good results. However, long-term survival in experimental models has not been reported. Our aim is to describe in detail some technical modifications of MMVTx to obtain long-term survival. MATERIALS AND METHODS: Syngeneic (Lewis-Lewis) heterotopic MMVTx was performed in 16 male rats (180-250 g). All procedures were performed under isoflurane anesthesia. The graft consisted of stomach, duodenopancreatic axis, spleen, and small bowel. The vascular pedicle consisted of a conduit of aorta, including the celiac trunk and the superior mesenteric artery (SMA), and the portal vein (PV). The engraftment was performed by end-to side anastomosis to the infra-renal cava vein and aorta. After reperfusion, the graft was accommodated in the right side of the abdomen, and a terminal ileostomy performed. The native spleen was removed. RESULTS: Donor and recipient time was 39 +/- 4.4 minutes and 69 +/- 7 minutes, respectively; venous and arterial anastomosis time was 14 +/- 1 minutes and 12.3 +/- 1 minutes, respectively. Total ischemia time was 77.2 +/- 7.9 minutes. Survival was 75% (12/16), six were sacrificed after 2 hours, and six were kept alive for long-term evaluation (more than 1 week). CONCLUSION: Long-term survival is reported after heterotopic MMVTx in rats. The heterotopic MMVTx with native spleen removal would potentially improve the existent models for transplant research. The usefulness of this model warrants further confirmation in allogeneic experiments. PMID- 29475214 TI - Micro-environment and intracellular metabolism modulation of adipose tissue macrophage polarization in relation to chronic inflammatory diseases. AB - The accumulation and pro-inflammatory polarization of immune cells, mainly macrophages, in adipose tissue (AT) are considered crucial factors for obesity induced chronic inflammatory diseases. In this review, we highlighted the role of adipose tissue macrophage (ATM) polarization on AT function in the obese state and the effect of the micro-environment and intracellular metabolism on the dynamic switch of ATMs into their pro-inflammatory or anti-inflammatory phenotypes, which may have distinct influences on obesity-related chronic inflammatory diseases. Obesity-associated metabolic dysfunctions, including those of glucose, fatty acid, cholesterol, and other nutrient substrates such as vitamin D and iron in AT, promote the pro-inflammatory polarization of ATMs and AT inflammation via regulating the interaction between ATMs and adipocytes and intracellular metabolic pathways, including glycolysis, fatty acid oxidation, and reverse cholesterol transportation. Focusing on the regulation of ATM metabolism will provide a novel target for the treatment of obesity-related chronic inflammatory diseases, including insulin resistance, cardiovascular diseases, and cancers. PMID- 29475215 TI - Korean Guidelines for the Pharmacological Treatment of Social Anxiety Disorder: Initial Treatment Strategies. AB - OBJECTIVE: The aim of the present study was to provide clinical consensus and evidence regarding initial treatment strategies for the pharmacological treatment of social anxiety disorder (SAD) in Korea. METHODS: We prepared a questionnaire to derive a consensus from clinicians regarding their preference for the pharmacological treatment of SAD in Korea. Data regarding medication regimens and psychotropic drugs used during initial treatment, the doses used, and the pharmacological treatment duration were obtained. Responses were obtained from 66 SAD experts, and their opinions were classified into three categories (first line, second-line, third-line) using a chi-square analysis. RESULTS: Clinicians agreed upon first-line regimens for SAD involving monotherapy with selective serotonin reuptake inhibitors (SSRIs) or the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine, or combined therapy using antidepressants with betablockers or benzodiazepines on a standing or as-needed basis. First-line psychotropic drug choices for initial treatment included the following: escitalopram, paroxetine, sertraline, venlafaxine, and propranolol. The medication dosage used by domestic clinicians was found to be comparable with foreign guidelines. Domestic clinicians tended to make treatment decisions in a shorter amount of time and preferred a similar duration of maintenance treatment for SAD when compared with foreign clinicians. CONCLUSION: This study may provide significant information for developing SAD pharmacotherapy guidelines in Korea, especially in the early stage of treatment. PMID- 29475216 TI - Relationship of Probable Attention Deficit Hyperactivity Disorder with Severity of Psychopathology and Impulsivity in a Sample of Male Patients with Opioid Use Disorder. AB - OBJECTIVE: The aim of the present study was to evaluate relationship of probable attention deficit hyperactivity disorder (ADHD) with severity of psychopathology and the effect of impulsivity on this relationship in a sample of male patients with opioid use disorder (OUD). METHODS: Participants included 234 patients (115 inpatients and 119 outpatients) with OUD. Participants were evaluated with the Adult ADHD Self-Report Scale (ASRS-v1.1), the Symptom Checklist-90-R (SCL-90-R) and the Short Form of Barratt Impulsiveness Scale (BIS-11-SF). RESULTS: Psychopathology and impulsivity scores were higher among those with the probable ADHD. ADHD scores were midly to moderately correlated with impulsivity and psychopathology scores. In logistic regression analyses, while severity of general psychopathology and impulsivity predicted probable ADHD in the first Model, in the second Model, among dimensions of psychopathology obsessive compulsive (OC) dimension, whereas among dimensions of impulsivity non-planning and motor impulsivity predicted probable ADHD. CONCLUSION: These findings suggest that probable ADHD is related with the severity of psychopathology, particularly OC dimension, while the severity of impulsivity may have an partial mediator (particularly non-planning and motor impulsivity) effect on this relationship among patients with OUD. PMID- 29475217 TI - Long-Term Culture of Organotypic Hippocampal Slice from Old 3xTg-AD Mouse: An ex vivo Model of Alzheimer's Disease. AB - OBJECTIVE: Conventional methods for organotypic hippocampal tissue slice culture (OHSC) have shown several disadvantages or limitations regarding age of animals used, duration of culture and difficulty using neurodegenerative models. Therefore, we tried to establish OHSC from old 3xTg-Alzheimer's disease (AD) mice for longer period (over 4 weeks) and to validate utility of this system as a valid platform for translational neuroscience of AD. METHODS: OHSC was performed with old 3xTg-AD mice (12-14 months), old wild type mice (12-14 months) and young 3xTg-AD mice (2-4 months) using serum-free medium for 4 weeks. Hippocampal structure was evaluated by 4', 6-diamidino-2-phenylindole (DAPI) intensity and neuronal metabolism was measured by Alamarblue assay. Pathologic characteristics of AD were also investigated; beta-amyloid levels by ELISA, amyloid plaque deposition by Thioflavin-S staining, and glial activation by immunohistochemistry. RESULTS: Following 4-week culture in serum-free media, hippocampal cells and layers were well preserved in cultured slices from old AD mice as was in those from young AD and old wild type mice. On the contrary, excessive regression of total visible cells was observed in conventional serum containing medium regardless of genotype of mice. In parallel with this well preserved structure, major pathologic characteristics of AD were also well manifested in hippocampal slices from old AD mice. CONCLUSION: Our findings suggest that long-term OHSC from old 3xTg-AD mouse can serve as a promising ex vivo system for studies on pathophysiology of AD, especially with the minimum number of sacrifice of experimental animals. PMID- 29475218 TI - Gender Differences of Occupational Stress Associated with Suicidal Ideation among South Korean Employees: The Kangbuk Samsung Health Study. AB - OBJECTIVE: In this study, the relationship between occupational stress and suicidal ideation was investigated, focusing on gender differences among Korean employees. METHODS: Cross-sectional data for 53,969 workers were collected at Kangbuk Samsung Hospital health screening centers. Risk of suicidal ideation was assessed using a self-reported questionnaire examining suicidal ideation during the past year. Occupational stress was measured using 24 items of the Korean Occupational Stress Scale-Short Form (KOSS-SF). Logistic regression analysis was employed to estimate the odds ratios and 95% confidence intervals of the relationships between suicidal ideation and components of occupational stress. RESULTS: In multivariable-adjusted models, all job stress contributed to increased risk of suicidal ideation in males. Most subscales, except insufficient job control and organizational system, were risk factors of suicidal ideation in females. Further adjustments for depression markedly attenuated this relationship. However, the effects of insufficient job control and lack of reward on suicidal ideation remained significant in males, and interpersonal conflict remained significant in females. CONCLUSION: The results suggest that occupational stress plays a significant role in increasing risk of suicidal ideation through elevation of depressive symptoms. Gender differences in components of occupational stress associated with suicidal ideation were also observed. PMID- 29475219 TI - A Neuroleptic Malignant Syndrome Without Rigidity. AB - Neuroleptic malignant syndrome (NMS) is an uncommon but potentially lethal idiosyncratic reaction which may emerge in the aftermath of the treatments with neuroleptics demonstrating itself with the symptoms of altered consciousness, high fever, impaired autonomic functions, and muscle rigidity. Although various risk factors have been identified for NMS, its etiology is not completely known. The mortality and morbidity related with NMS could be reduced by early diagnosis, interruption of the neuroleptics used within a short period and aggressive treatment. Our case is different from general NMS cases due to lack of rigidity. A NMS case which developed within a short time in the aftermath of multiple antipsychotic use and wherein no rigidity was observed shall be discussed in this case report. PMID- 29475220 TI - The Correlations among Depressive Symptoms, Cognitive Performance and Serum BDNF Levels in the Patients with Chronic Kidney Disease. AB - OBJECTIVE: In the current study, we investigated whether there are relations among depressive symptoms, cognitive performance and serum BDNF levels in the patients with chronic kidney disease (CKD). METHODS: Sixty patients with CKD and 65 healthy controls participated. Depressive symptoms were evaluated with Beck depression inventory (BDI) and Hamilton Depression Rating Scale (HDRS). Mini Mental State Examination included in the Korean version of the Consortium to Establish a Registry for Alzheimer's disease (MMSE-KC) assessment packet was used for the evaluation of overall cognitive function. To assess memory function, the Korean version of the Hopkins Verbal Learning Test (K-HVLT) was used. BDNF levels were measured using an enzyme-linked immunosorbent assay (ELISA) kit. RESULTS: The CKD patients showed more depressive symptoms when compared with controls. The depressive symptoms and cognitive function were not associated with serum BDNF levels in the CKD patients. CONCLUSION: In the current study, CKD patients had more depressive symptoms when compared controls. However, the serum BDNF levels of CKD patients were not associated with depressive symptoms and cognitive functions. These findings suggested that the serum BDNF levels may not be reflect the cognitive function and depressive mood state in the CKD patients. PMID- 29475221 TI - Effects of 5HT1A Activation on Gating Profile Following 5HT Depletion in Rats Lacking Social Attachment Since Weanling. AB - OBJECTIVE: Central 5-HT1A receptor is involved in the modulation of sensorimotor gating function. However, its precise role is not clearly defined in developmentally social deprived (isolation rearing, IR) rats featured with impaired sensorimotor gating ability. We therefore aimed to examine the effects of 5HT1A activation on acoustic startle response (ASR) and prepulse inhibition (PPI) in IR rats in a condition of compromised presynaptic 5-HT functions. METHODS: Social control (SOC) and IR rats received an intracerebraoventricular (ICV) injection of 5-HT depletor, 5,7-DHT. Seven days later rats entered a protocol of 8-OH-DPAT, a 5-HT1A agonist, in which locomotor activity, ASR and PPI and their tissue levels of 5-HT were measured. RESULTS: Our results found that both IR and 5,7-DHT decreased the tissue concentration of 5-HT. IR-induced hyperactivity and gating impairment were unaffected by 5-HT depletion. 8-OH-DPAT strengthened the ASR in IR but not SOC rats and the drug-reduced PPI could be adjusted by 5,7-DHT pretreatment. 8-OH-DPAT at 100 MUg/kg enhanced PPI in 5-HT depleted SOC rats. However for IR rats, 8-OH-DPAT strengthened PPI in sham rats but downgraded it in depletion condition. CONCLUSION: The integrity of central 5 HT system is important to 5-HT1A-modulated sensorimotor gating in isolation reared rats. PMID- 29475222 TI - Evaluating the Levels of Nesfatin-1 and Ghrelin Hormones in Patients with Moderate and Severe Major Depressive Disorders. AB - OBJECTIVE: The goal of this study was to evaluate the importance of nesfatin-1, acylated and des-acylated ghrelin, which are known as energy regulatory hormones, in patients with moderate and severe major depression disorders (MDD). METHODS: Thirty patients with a moderate degree of MDD and, 30 with a severe degree of MDD were used as participants in this study. Thirty subjects without depression were enrolled as a control group. The Hamilton Depression Rating Scale was used to classify the patients with MDD. Blood samples were taken after overnight fasting. The plasma nesfatin-1, acylated ghrelin and des-acylated ghrelin levels were measured using a commercially available enzyme-linked immunosorbent assay kit. RESULTS: The nesfatin-1, the acylated ghrelin and the des-acylated ghrelin levels were found to be significantly higher in severe MDD (3.92+/-0.4 ng/mL; 88.56+/ 4.1 pg/mL; 962.76+/-67 pg/mL) as compared to moderate MDD (2.91+/-0.5 ng/mL; 77.63+/-4.19 pg/mL; 631.16+/-35 pg/mL), or the control (1.01+/-0.3 ng/mL; 58.60+/ 9.00 pg/mL; 543.13+/-62 pg/mL), respectively. CONCLUSION: Although nesfatin-1 and ghrelin are known as adversely affecting the hormones involving the regulation of appetite and food intake, they all increase in depressive patients and are even associated with the severity of the disease. In clinical medicine, the evaluation of the role of nesfatin-1 and ghrelin in endocrine and neu-roendocrine regulation of major metabolic functions is an important key mechanism in solving numerous diseases associated with endocrine and neuroendocrine disturbance. Increased levels of nesfatin-1 and ghrelin may also be important criteria in describing the prognoses of the patients and the effectiveness of the treatments. PMID- 29475223 TI - Longitudinal Impact of Depression on Quality of Life in Stroke Patients. AB - OBJECTIVE: Stroke is associated with significant long-term morbidity and poor quality of life (QOL). Depression is one of the most common complications after stroke and has been associated with QOL cross-sectionally. We investigated the longitudinal impact of depression in the acute phase of stroke on QOL 1 year after stroke. METHODS: In total, 423 patients were evaluated 2 weeks after stroke, and 288 (68%) were followed 1 year later. QOL was assessed using the World Health Organization Quality of Life-Abbreviated form (WHOQOL-BREF) at baseline and follow-up. Depression was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders-IV criteria; demographic and clinical characteristics data, including stroke severity, were obtained at baseline. The longitudinal associations of post-stroke depression (PSD) at baseline with QOL across two evaluation points were assessed using a repeated-measures analysis of variance. RESULTS: The WHOQOL-BREF scores were significantly and persistently lower 1 year after stroke in patients with PSD at baseline compared with those without PSD at baseline independent of demographic and clinical characteristics, including stroke severity. CONCLUSION: PSD in the acute phase of stroke is an independent predictor of QOL in both the acute and chronic phases of stroke. Our findings underscore the importance of evaluating depression in the acute phase of stroke. PMID- 29475224 TI - Prevalence Risk of Metabolic Syndrome Associated with Alcohol Use Behavior in Korean Women. AB - OBJECTIVE: Considerable research has been conducted on the relationship between alcohol consumption and metabolic syndrome. Although various standards for the amount and frequency of alcohol consumption have been suggested, a tool to measure individual alcohol use behavior against a consistent standard is required. Moreover, the association of alcohol use behavior with health should be examined on the basis of such a standard. In this study, we examined the relationships between alcohol use behavior according to the Alcohol Use Disorders Identification Test (AUDIT) and metabolic syndrome and its components in Korean women. METHODS: This study utilized data from the fifth Korean National Health and Nutrition Examination Survey, which was administered from 2010 through 2012. We investigated the relationships between alcohol use behavior and metabolic syndrome and its components in a sample of 2,906 women by using analysis of covariance and logistic regression analysis. RESULTS: After adjusting for confounding variables, alcohol use behavior was significantly associated with metabolic syndrome [odds ratio (OR) 2.877; 95% confidence interval (CI) 1.523 5.435 in the problem use group]. AUDIT score also was significantly related to abdominal obesity (OR 2.263; 95% CI 1.704-4.459 in the problem use group), hypertension (OR 3.377; 95% CI 1.871-6.095 in the problem use group), hypertriglyceridemia (OR 3.204; 95% CI 1.800-5.702 in the problem use group), and impaired fasting glucose (OR 3.034; 95% CI 1.721-5.348 in the problem use group). CONCLUSION: In this study, positive associations were observed between AUDIT score and risk of metabolic syndrome and its components. PMID- 29475225 TI - Characteristics of Residual Symptoms in Korean Patients with Major Depressive Disorder: A Validation Study for the Korean Version of Depression Residual Symptom Scale. AB - OBJECTIVE: Residual symptoms of depression are related to more severe and chronic course of functional impairment with higher risk of relapse. The objective of this study was to validate, and determine psychometric properties of the Korean version of Depression Residual Symptom Scale (KDRSS). METHODS: A total of 203 outpatients with recent episode of major depression based on DSM-IV criteria were enrolled in this study. They had been treated with antidepressants and assessed by KDRSS, Hamilton Depression Rating Scale-24 (HDRS-24), and Montgomery-Asberg Depression Rating Scale (MARDS). The validity and reliability of KDRSS were assessed, including internal consistency reliability, concurrent validity, temporal stability, factorial validity, and discriminative validity. RESULTS: Internal consistency (Cronbach's alpha=0.961), concurrent validity (MADRS: r=0.731, p<0.01, HDRS-24: r=0.663, p<0.01), and temporal stability (r=0.726, p<0.01) of KDRSS were all excellent. KDRSS showed good discriminative validity based on MARDS. KDRSS consisted of one-factor structure accounting for 63.8% of total variance. All subjects except two in full remission group had one or more residual symptoms. In 7 subscales of KDRSS consisting of similar items respectively, 'lack of energy' was the most commonly reported, followed by 'increased emotionalism' in this group. CONCLUSION: KDRSS is a useful and sensitive instrument for measuring residual depressive symptoms. Since some depressive symptoms including 'lack of energy' and 'increased emotionalism' in patients with full remission might be persistent during psychiatric intervention, these symptoms need to be focused on in clinical practice. PMID- 29475226 TI - Comparative Analysis of the WISC between Two ADHD Subgroups. AB - OBJECTIVE: The prevalence of attention deficit/hyperactivity disorder (ADHD) in school-age children is 7.2%, and ADHD is divided into clinical subtypes. METHODS: The current study explored whether specific cognitive profiles as assessed using the Wechsler Intelligence Scale for Children (WISC)-IV could be obtained for each clinical ADHD subtype (ADHD-Inattentive type and ADHD-Combined type) and investigated the correlation between WISC scores and parental age at their children's birth or birthweight. The enrolled sample comprised 12 ADHD-I and 15 ADHD-C subjects. RESULTS: An impaired Processing Speed Index was found in ADHD-I. The age of the father at the child's birth and birthweight positively correlated with the full scale intelligence quotient (FSIQ) score in the WISC assessment. CONCLUSION: Inattentiveness within the behaviors of the children with ADHD-I is partly due to the impaired processing speed, therefore effective support for ADHD will be conducted if educator decreases their speaking speed. Since biological basis of ADHD is still largely unknown, future studies using both psychological and biological methods will reveal the etiology of ADHD. These scientific assessments will provide information for more effective approaches in the care of children with ADHD. PMID- 29475227 TI - Incidence and Comorbidity of Reactive Attachment Disorder: Based on National Health Insurance Claims Data, 2010-2012 in Korea. AB - OBJECTIVE: We aimed to investigate the current diagnostic incidence, and medical and psychiatric comorbidities of reactive attachment disorder (RAD) using the National Health Insurance Review and Assessment (HIRA) claims data. METHODS: To examine the diagnostic incidence, we selected patients who were under 10-year-old and who had at least one medical claim containing a 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) code for RAD (F94.1 and F94.2) and who had not been diagnosed in the previous 360 days, from 2010 to 2012. In this study, we used the term 'reactive attachment disorder' representing for both RAD per se and Disinhibited social engagement disorder. Comorbid disorders were categorized according to ICD-10. RESULTS: Among 14,029,571, the total population under 10-year-old during 2010 2012, incident cases of RAD were 736. The mean diagnostic incidence of RAD was 5.25 per 100,000 annually. Language disorders (F80-84) were the most common psychiatric comorbidities in both boys and girls in age groups 0-3 years and 4-6 years, and attention deficit hyperactivity disorder was the most common in both sex aged 7-9 years. In non-psychiatric comorbidities, diseases of the respiratory system (J00-99) were the commonest in both sex in all age groups, and diseases of the digestive system (K00-99) were the next. CONCLUSION: RAD was very rare in practice and would be disguised as other psychiatric disorders. Children with RAD might have more medical comorbidities than typically developed children. PMID- 29475228 TI - Validation of the Center for Epidemiological Studies Depression Scale among Korean Adolescents. AB - OBJECTIVE: The Center for Epidemiological Studies Depression Scale (CES-D) is designed to measure the current level of depressive symptomatology in the general population. However, no review has examined whether the scale is reliable and valid among children and adolescents in Korea. The purpose of this study was to test whether the Korean form of the CES-D is valid in adolescents. METHODS: Data were obtained from 1,884 adolescents attending grades 1-3 in Korean middle schools. Reliability was evaluated by internal consistency (Cronbach's alpha). Concurrent validity was evaluated by a correlation analysis between the CES-D and other scales. Construct validity was evaluated by exploratory factor and confirmatory factor analyses. RESULTS: The internal consistency coefficient for the entire group was 0.88. The CES-D was positively correlated with scales that measure negative psychological constructs, such as the State Anxiety Inventory for Children, the Korean Social Anxiety Scale for Children and Adolescents, and the Reynold Suicidal Ideation Questionnaire, but it was negatively correlated with scales that measure positive psychological constructs, such as the Korean version of the Rosenberg Self-Esteem Scale and the Connor-Davidson Resilience Scale-2. The CES-D was examined by three-dimensional exploratory factor analysis, and the three-factor structure of the scale explained 53.165% of the total variance. The variance explained by factor I was 24.836%, that explained by factor II was 15.988%, and that explained by factor III was 12.341%. The construct validity of the CES-D was tested by confirmatory factor analysis, and we applied the entire group's data using a three-factor hierarchical model. The fit index showed a level similar to those of other countries' adolescent samples. CONCLUSION: The CES-D has high internal consistency and addresses psychological constructs similar to those addressed by other scales. The CES-D showed a three factor structure in an exploratory factor analysis. The present findings suggest that the CES-D is a useful and reliable tool for measuring depression in Korean adolescents. PMID- 29475229 TI - Empathy Study in Rodent Model of Autism Spectrum Disorders. AB - There is a highly cognitive and social context to empathy behavior in human. In various social contexts, rodents also display remarkable affective sensitivity and exhibit primitive forms of empathy similar to human. Therefore, we aimed to elaborate the concept of empathy about various components of empathetic behavior in rodents with the similar contexts of a human. In this review, we highlighted the behavioral paradigm that already examined different aspects of rodent empathetic behavior in response to conspecific distress. Additionally, we summarized homologous brain parts of human and rodents to express the empathetic behavior. Integrating the findings with corresponding experiments in the human will provide a novel insight into therapeutic intervention or expanded experimental approaches for neuropsychiatric disorders like autism spectrum disorders associated with empathetic behavior. PMID- 29475230 TI - Association of G-Protein beta3 Subunit C825T Polymorphism with Seasonal Variations in Mood and Behavior. AB - OBJECTIVE: Seasonal affective disorder and seasonal changes in mood and behavior are associated with several genes that regulate circadian rhythms. In this study, we investigated the relationship between the C825T polymorphism of the G-protein beta3 subunit and seasonal variations in mood and behavior in a young healthy Korean population. METHODS: A total of 507 young Korean participants were recruited through a newspaper advertisement, and their seasonality was evaluated by the Korean version of the Seasonal Pattern Assessment Questionnaire to assess the global seasonality score (GSS). We analyzed the CC, CT, and TT genotypes and their association with the GSS score and subscales. RESULTS: T allele carriers of the GNB3 C825T polymorphism were more likely to score higher on body weight and GSS. In the female group, the T allele carriers obtained significantly high total GSS and its subscale scores for mood, body weight, energy level, and appetite; however, differences in genotypes and allele carriers were also observed in the male participants. CONCLUSION: These results suggested that GNB3 C825T polymorphism plays a role in seasonal variations in mood, body weight, energy level, and appetite in a Korean population, particularly in females. PMID- 29475231 TI - Validation of the Korean version of the 16-Item Prodromal Questionnaire in a Non Help-Seeking College Population. AB - OBJECTIVE: To examine the reliability and validity of the Korean version of the 16-item Prodromal Questionnaire (KPQ-16) in non-help-seeking university students. METHODS: Among 2,246 university students participated in the initial screening, 257 subjects with KPQ-16 scores >=4 were interviewed. The criteria for ultra-high risk (UHR) of psychosis of the Comprehensive Assessment of At-Risk Mental States (CAARMS) were the gold standard for diagnosis. An exploratory modified version of the questionnaire (mKPQ-16), to which three items from the Eppendorf Schizophrenia Inventory were added, was also used to compensate for items on thought and cognitive problems. RESULTS: Seventeen subjects met the CAARMS criteria for UHR of psychosis. The area under the receiver operating characteristic curve (AUROC) was highest for the mKPQ-16 total score (AUROC=0.831, p<0.001). The use of cutoff total scores of 7 for the mKPQ-16 and 6 for the KPQ-16 resulted in the best balance of sensitivity (76.5% and 64.7%, respectively) and specificity (75.4% and 71.2%, respectively). CONCLUSION: The Korean versions of the PQ-16 are good instruments for screening for psychosis risk in university students. This validation of a questionnaire version with a small number of items may make it feasible to screen large numbers of young adults in the community. PMID- 29475232 TI - The Goldwater Rule from the Perspective of Phenomenological Psychopathology. PMID- 29475234 TI - Is It Unethical for Psychiatrists to Give an Opinion on a Public Figure's Mental State? PMID- 29475233 TI - Associations Among Plasma Stress Markers and Symptoms of Anxiety and Depression in Patients with Breast Cancer Following Surgery. AB - OBJECTIVE: The objective of present study is to analyze the prevalence of depression and anxiety following breast cancer surgery and to assess the factors that affect postoperative psychological symptoms. METHODS: The Hamilton Rating Scale for Depression (HAM-D), Hamilton Anxiety Rating Scale (HAM-A), Body Image Scale (BIS), and Rosenberg Self Esteem Scale (RSES) were used to assess the psychological states of patients who had been diagnosed with and had undergone surgery for breast cancer. Blood concentrations of the stress markers adrenocorticotropic hormone, cortisol, arginine-vasopressin, and angiotensin converting enzyme were measured. Pearson's correlation analysis and multilinear regression analysis were used to analyse the data. RESULTS: At least mild depressive symptoms were noted in 50.5% of patients, while 42.4% of patients exhibited at least mild anxiety symptoms. HAM-D score was positively correlated with HAM-A (r=0.83, p<0.001) and BIS (r=0.29, p<0.001) scores and negatively correlated with RSES score (r=-0.41, p<0.001). HAM-A score was positively correlated with BIS score (r=0.32, p<0.001) and negatively correlated with RSES score (r=-0.27, p<0.001). There were no statistically significant associations between stress markers and depression/anxiety. CONCLUSION: Patients with breast cancer frequently exhibit postoperative depression and anxiety, which are related to low levels of self-esteem and distorted body image. PMID- 29475235 TI - Screening for Normal Cognition, Mild Cognitive Impairment, and Dementia with the Korean Dementia Screening Questionnaire. AB - OBJECTIVE: The Korean Dementia Screening Questionnaire (KDSQ) is an informant based instrument used to screen for cognitive dysfunction. However, its ability to only dichotomously discriminate between dementia and normal cognition has been previously investigated. This study investigated the ability of the KDSQ to classify not only dichotomous but also multiple stages of cognitive dysfunction. METHODS: We examined 582 participants. Receiver operating characteristic (ROC) curves were used to determine dichotomous classification parameters. Multi category ROC surfaces were evaluated to classify the three stages of cognitive dysfunction. RESULTS: Dichotomous classification using the ROC curve analyses showed that the area under the curve was 0.92 for dementia for subjects without dementia and 0.96 for dementia in controls. Simultaneous multi-category classification analyses showed that the volume under the ROC surface (VUS) was 0.57 and that the derived optimal cut-off points were 2 and 8 for controls, MCI, and dementia. The estimated Youden index for the KDSQ was 0.48, and the derived optimal cut-off points were 5 and 10. The overall classification accuracy of the VUS and Youden index was 61.2% and 58.6%, respectively. CONCLUSION: The KDSQ is useful for classifying dichotomous and multi-category stages of cognitive dysfunction. PMID- 29475236 TI - A Retrospective and Prospective Follow-up Study of Psychological Distress in the Danwon High School Survivors of the Sewol Ferry Disaster. AB - OBJECTIVE: We monitored a group of students from Danwon High School who survived the Sewol ferry disaster for 27 months to examine the course of their psychological symptoms. METHODS: We performed a chart review at the Danwon High School Mental Health Center at the following time points (T): 9 months (T1), 12 months (T2), and 15 months (T3) after the disaster. Additionally, we performed a follow-up review at 27 months (T4). Subjects completed the 'State' section of the State-Trait Anxiety Inventory for Children, the Center for Epidemiological Studies-Depression assessment, the Child Report of Post-traumatic Symptoms, and the Inventory of Complicated Grief. Data from the 32 subjects who completed all four assessments were used in the statistical analyses. RESULTS: Scores of psychological variables tended to increase until T2 and then slowly decreased until T4. The severity of anxiety and complicated grief symptoms changed significantly over time, but the severity of depression and posttraumatic stress symptoms did not. CONCLUSION: We found that the symptoms of anxiety and complicated grief reported by Sewol ferry survivors from Danwon High School were exacerbated at the first anniversary of the disaster, but these symptoms subsided after the students graduated from high school. PMID- 29475237 TI - School Counselors' Recognition of the Ultra-High Risk for Psychosis. AB - The ability to identify students at ultra-high risk (UHR) for psychosis in school settings is crucial for enabling appropriate referral to a clinician and positive therapeutic results. The aim of this study was to examine school counselors' recognition of the diagnosis and appropriate treatment recommendations for students at UHR for psychosis. In total, 132 school counselors completed surveys, including questions relating to a vignette about a student at UHR for psychosis. In total, 12.4% of the sample provided the correct diagnosis, much lower than that for other schizophrenia spectrum disorders and non-psychotic disorders, including depressive disorder. Although most school counselors preferred psychiatrists as the first-line treatment for students at UHR for psychosis, counseling centers were also mentioned as potential treatment options. In terms of medication, antipsychotics were preferred over other medication classes. It is necessary to design appropriate educational and training programs for school counselors to promote identification and effective referral of those at UHR for psychosis. PMID- 29475238 TI - Temperament in Adulthood Attention Deficit-Hyperactivity Disorder without Bipolar Disorder. AB - OBJECTIVE: We examined whether some temperamental traits would be associated with persistence of attention deficit-hyperacitivty disorder (ADHD) in adulthood independent from bipolar disorder (BD). METHODS: Eighty-one ADHD patients without a comorbid diagnosis of BD were divided into two groups, those with childhood ADHD (n=46), and those with Adulthood ADHD (n=35). The severity of childhood and adulthood ADHD were assessed by using the Wender Utah Rating Scale (WURS-25) and Turgay's Adult ADD/ADHD Diagnosis and Evaluation Scale (DES). Subjects' temperamental characteristics were examined using the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-auto questionnaire (TEMPS-A). RESULTS: The mean scores of WURS-25 were higher in adult ADHD group than in childhood ADHD group (p<0.001). Adult ADHD group had significantly higher scores on cyclothymic (p=0.002), irritable (p<0.0001), and anxious (p=0.042) subscales of TEMPS-A. The scores of WURS-25 in adulthood ADHD group were positively correlated with cyclothymia scores (r=0.366, p=0.033). Total scores of Turgay's Adult ADD/ADHD DES were positively correlated with cyclothymic (r=0.354, p=0.040), hyperthymic (r=0.380, p=0.026), and irritable (r=0.380, p=0.026) subscale scores. Cychlothymic and irritable temperaments were significantly associated with the severity of adulthood symptoms of ADHD. CONCLUSION: We might suggest that cyclothymic and irritable temperaments would predict the diagnosis of adulthood ADHD independent from BD. PMID- 29475239 TI - An Investigation of SDF1/CXCR4 Gene Polymorphisms in Autism Spectrum Disorder: A Family-Based Study. AB - OBJECTIVE: Autism spectrum disorders (ASD) have a complex pathophysiology including genetic, inflammatory and neurodevelopmental components. We aim to investigate the relationship between ASD and gene polymorphisms of stromal cell derived factor-1 (SDF-1) and its receptor CXC chemokine receptor-4 (CXCR4), which may affect inflammatory and neurodevelopmental processes. METHODS: 101 children diagnosed with ASD aged 2-18 and their biological parents were included in the study. All participants were assessed using an information form and the Children were assessed using Childhood Autism Rating Scale (CARS). SDF-1 G801->A and CXCR4 C13->T polymorphisms were detected by genetic techniques. The results were evaluated using the transmission disequilibrium test (TDT) and haplotype relative risk (HRR). RESULTS: Following TDT evaluation for CXCR4, the assumption of equality was not rejected (chi2=1.385, p=0.239). HRR for the C allele was 1.037 [HRR (95%CI)=0.937 (0.450-2.387), chi2=0.007, p=0.933] and HRR for the T allele was 0.965 [HRR (95%CI)=0.965 (0.419- 2.221), chi2=1.219, p=0.270], but the findings were statistically insignificant. Based on TDT evaluation for SDF1, the assumption of equality cannot be rejected (chi2=0, p=0.999). HRR for the A allele was 0.701 [HRR (95%CI)=0.701 (0.372-1.319), chi2=1.219, p=0.270] and HRR for the G allele was 1.427 [HRR (95%CI)=1.427 (0.758-2.686), chi2=1.219, p=0.270], but the findings were statistically insignificant. CONCLUSION: The genetic screening of blood samples from mother, father and child trios could not show a significant association between SDF1/CXCR4 genes and ASD on the basis of TDT and HRR tests. More extensive genetic studies are now needed to investigate the relationship between SDF1/CXCR4 gene polymorphisms and ASD. PMID- 29475240 TI - Factors Associated with Complicated Grief in Students Who Survived the Sewol Ferry Disaster in South Korea. AB - OBJECTIVE: The Sewol ferry disaster caused shock and grief in South Korea. The aim of this study was to identify the factors associated with symptoms of complicated grief (CG) among the surviving students 20 months after that disaster. METHODS: This study was conducted using a cross-sectional design and a sample of 57 students who survived the Sewol ferry disaster. Data were collected using the following instruments: Inventory of Complicated Grief (ICG), the Lifetime Incidence of Traumatic Events-Child, the Child Report of Post-Traumatic Symptoms (CROPS), KIDSCREEN-27, Family Adaptability and Cohesion Evaluation Scales-III, the Peri-traumatic Dissociation-Post-traumatic Negative Beliefs-Post traumatic Social Support scale, and the Strengths and Difficulties Questionnaire. A generalized linear model using a log link and Poisson distribution was performed to identify factors associated with symptoms of CG. RESULTS: The mean score on the ICG was 15.57 (standard deviation: 12.72). Being born in 1999, a higher score on the CROPS and a lower score in autonomy and relationship with parents on the KIDSCREEN-27 were related to higher levels of CG. CONCLUSION: Twenty months after the Sewol ferry disaster, 24.5% of surviving students were suffering from CG. This study uncovered a vulnerable population of bereaved children at high risk for CG. PMID- 29475241 TI - Serum N-Desmethylcitalopram Concentrations are Associated with the Clinical Response to Citalopram of Patients with Major Depression. AB - OBJECTIVE: Citalopram (CITA) is a widely used and well-tolerated selective serotonin reuptake inhibitor. The aim of the study was to evaluate the possible influences of serum concentrations of CITA and its major metabolite n desmethylcitalopram (NDCITA) on the efficacy and tolerability of CITA in patients with major depressive disorder. METHODS: The study included 46 outpatients with major depressive disorder who received CITA. The efficacy and tolerability were assessed for 6 weeks. Serum CITA and NDCITA levels were measured at the 4th week. RESULTS: The HDRS17 total scores of the patients with high NDCITA and CITA & NDCITA concentrations showed a more significant reduction compared to the patients with expected and low serum NDCITA and CITA & NDCITA concentrations. However, we did not observe a correlation between the serum concentrations and the side effects of CITA, NDCITA, and CITA & NDCITA. CONCLUSION: Our results suggested the potential contribution of NDCITA to the antidepressant effect of CITA. Further studies involving larger clinical samples are required to confirm the impact of serum NDCITA concentrations on the efficacy of CITA. PMID- 29475242 TI - A 12-Week Multi-Domain Lifestyle Modification to Reduce Depressive Symptoms in Older Adults: A Preliminary Report. AB - OBJECTIVE: The objective of this study was to compare the effectiveness of usual care management (UCM) and a newly-developed lifestyle modification with contingency management (LMCM) for geriatric depressive symptoms in the community. METHODS: A randomized controlled trial was conducted in 93 older adults with major depressive disorder at community mental health centers. A 12 week multi domain LMCM was developed by providing positive reinforcement using 'gold medal stickers' as a symbolic incentive to motivate their participation and adherence. Participants were allocated to LMCM (n=47) and UCM (n=46) groups. They were then subjected to the 12 week treatment. Effects of the two intervention methods on Geriatric Depression Scale were determined using mixed model analysis. RESULTS: Participants in the LMCM group had greater decline in GDS score per month than participants in the UCM group after adjusting for age, sex, years of education, living alone, and MMSE scores at baseline examination [coefficient for GDS score (95% CI): -1.08 (-1.51, -0.65), p<0.001, reference: UCM group]. CONCLUSION: LMCM is safe and easy to use with a low cost. LMCM is suitable as psychosocial intervention for older adults with depressive symptoms in the community. PMID- 29475244 TI - Frequency uncertainty improvement in a STFT-BOTDR using highly nonlinear optical fibers. AB - The sensitivity of a sensor to strain or the temperature variations due to distributed Brillouin scattering are partially related to the type of fibers used and the Brillouin scattering induced effective index. In this paper, a highly nonlinear fiber that can generate a higher Brillouin scattering signal is compared to a standard single mode fiber in a short-time-Fourier-transform Brillouin optical time domain reflectometer (STFT-BOTDR). The results show that much higher signal to noise ratios of the Brillouin scattering spectrum and smaller frequency uncertainties in the sensing measurement can be achieved in the highly nonlinear fiber for comparable launched powers. With a measurement speed of 4 Hz, the frequency uncertainty can be 0.43 MHz, corresponding to 10 MUepsilon in strain or 0.43 degrees C in temperature uncertainty for the highly nonlinear fiber. In contrast, for the standard single mode fiber case, the value would increase to about 1.02 MHz (25 MUepsilon or 1.02 degrees C), demonstrating the advantage of the highly nonlinear fiber for distributed strain/temperature sensing. PMID- 29475245 TI - Anti-stiction coating for mechanically tunable photonic crystal devices. AB - A method to avoid the stiction failure in nano-electro-opto-mechanical systems has been demonstrated by coating the system with an anti-stiction layer of Al2O3 grown by atomic layer deposition techniques. The device based on a double membrane photonic crystal cavity can be reversibly operated from the pull-in back to its release status. This enables to electrically switch the wavelength of a mode over ~50 nm with a potential modulation frequency above 2 MHz. These results pave the way to reliable nano-mechanical sensors and optical switches. PMID- 29475246 TI - Motionless microscopy with tunable thermal lens. AB - The ability to modify the lens focal length has an advantage of giving sharp images without moving the lens. This work presents for the first time the use of the thermal lens as a tunable imaging element of the microscope. It shows also that the thermal lens can modify the image of a selected area of the sample, leaving the rest part of the image unaffected. Thus, appropriate tuning of thermal lens can lead to a simultaneously sharp image of two objects lying in different object planes separated by a distance exceeding the depth of field of the imaging optics. PMID- 29475243 TI - The Impact of General Medical Conditions in Obsessive-Compulsive Disorder. AB - OBJECTIVE: The co-occurrence of general medical conditions (GMCs) and major psychiatric disorders is well documented. The aim of this study was to assess the prevalence of GMCs in patients with a primary diagnosis of obsessive-compulsive disorder (OCD) and, secondly, to investigate which clinical variables are associated with the presence of a GMC. METHODS: Subjects with a primary diagnosis of OCD were included. Socio-demographic and clinical characteristics were collected. GMCs were classified using the ICD-10 and grouped according to the Cumulative Illness Rating Scale (CIRS) in: cardiac, vascular, hematopoietic, respiratory, ear/nose/throat, upper and lower gastrointestinal, hepatic, renal, genitourinary, musculoskeletal, neurologic, endocrine/metabolic. The association between the presence of GMCs and demographic/clinical variables of OCD was investigated. RESULTS: A total of 162 patients with OCD were included. 78 (48.1%) patients had at least one comorbid GMC. Most frequent GMCs were endocrine/metabolic diseases (25.9%), followed by upper/lower gastrointestinal (20.5%) and cardio-vascular diseases (13.6%). The presence of a GMC was significantly associated with female gender, older age, duration of untreated illness (DUI), and absence of physical activity. CONCLUSION: Patients with OCD have high rates of comorbid GMCs. A longer DUI is associated with having at least one GMCs; this might be due to the long-lasting adoption of unhealthy lifestyles, not counterbalanced by appropriate treatment and psychoeducation. PMID- 29475247 TI - Light-controllable fiber interferometer utilizing photoexcitation dynamics in colloidal quantum dot. AB - The development of highly efficient light-controlled functional fiber elements has become indispensable to optical fiber communication systems. Traditional nonlinearity-based optical fiber devices suffer from the demerits of complex/expensive components, high peak power requirements, and poor efficiency. In this study, we utilize colloidal quantum dots (CQDs) to develop a light controlled optical fiber interferometer (FI) for the all-optical control of the transmission spectrum. A specially designed exposed-core microstructure fiber (ECMF) is utilized to form the functional structure. Two types of PbS CQDs with absorption wavelengths around 1180 nm and 1580 nm, respectively, are deposited on the ECMF to enable the functional FI. The wavelength and power of control light are key factors for tailoring the FI transmission spectrum. A satisfactory recovery property and linear relationship between the spectrum shift and the power of control light at certain wavelength are achieved. The highest wavelength shift sensitivity of our light-controlled FI is 4.6 pm/mW, corresponding to an effective refractive index (RI) change of 5 * 10-6 /mW. We established a theoretical model to reveal that the RI of the CQD layer is governed by photoexcitation dynamics in CQD with the light absorption at certain wavelength. The concentration of charge carriers in the CQD layer can be relatively high under light illumination owing to their small size-related quantum confinement, which implies that low light power (mW-level in this work) can change the refractive index of the CQDs. Meanwhile, the absorption wavelength of quantum dots can be easily tuned via CQD size control to match specific operating wavelength windows. We further apply the CQD-based FI as a light-controllable fiber filter (LCFF) in a 50-km standard single-mode fiber-based communication system with 12.5-Gbps on-off keying direct modulation. Chirp management and dispersion compensation are successfully achieved by using the developed LCFF to obtain error-free transmission. CQDs possess excellent solution processability, and they can be deposited uniformly and conformally on various substrates such as fibers, silicon chips, and other complex structure surfaces, offering a powerful new degree of freedom to develop light control devices for optical communication. PMID- 29475248 TI - Coherent two-dimensional fluorescence micro-spectroscopy. AB - We have developed coherent two-dimensional (2D) fluorescence micro-spectroscopy which probes the nonlinear optical response at surfaces via fluorescence detection with sub-micron spatial resolution. This enables the investigation of microscopic variations in heterogeneous systems. An LCD-based pulse shaper in 4f geometry is used to create collinear trains of 12-fs visible/NIR laser pulses in the focus of an NA = 1.4 immersion-oil microscope objective. We demonstrate the capabilities of the new method by presenting 2D spectra, analyzed via phase cycling, as a function of position of selected sub-micron regions from a laterally nanostructured polycrystalline thin film of fluorinated zinc phthalocyanine (F16ZnPc). PMID- 29475249 TI - Projecting non-diffracting waves with intermediate-plane holography. AB - We introduce intermediate-plane holography, which substantially improves the ability of holographic trapping systems to project propagation-invariant modes of light using phase-only diffractive optical elements. Translating the mode-forming hologram to an intermediate plane in the optical train can reduce the need to encode amplitude variations in the field, and therefore complements well established techniques for encoding complex-valued transfer functions into phase only holograms. Compared to standard holographic trapping implementations, intermediate-plane holograms greatly improve diffraction efficiency and mode purity of propagation-invariant modes, and so increase their useful non diffracting range. We demonstrate this technique through experimental realizations of accelerating modes and long-range tractor beams. PMID- 29475250 TI - Efficient resonantly-clad-pumped laser based on a Er:YAG-core planar waveguide. AB - We demonstrated continuous wave operation of an in-band pumped Er:YAG planar waveguide laser with the output of 75 W at 1645 nm and a slope efficiency of 64% with respect to the absorbed pump power at 1532 nm. PMID- 29475251 TI - Characterizations of the nonlinear optical properties for (010) and (2-01) beta phase gallium oxide. AB - We report, for the first time, the characterizations on optical nonlinearities of beta-phase gallium oxide (beta-Ga2O3), where both (010) beta-Ga2O3 and (2-01) beta-Ga2O3 were examined for two-photon absorption coefficient, Kerr nonlinear refractive index, and their polarization dependence. The wavelength dependence of two-photo absorption coefficient and Kerr nonlinear refractive index were also estimated by a widely used analytical model. beta-Ga2O3 exhibits a two photon absorption (TPA) coefficient of 1.2 cm/GW for (010) beta-Ga2O3 and 0.6 cm/GW for (2-01) beta-Ga2O3. The Kerr nonlinear refractive index is -2.1 * 10-15 cm2/W for (010) beta-Ga2O3 and -2.9 * 10-15 cm2/W for (2-01) beta-Ga2O3. In addition, beta Ga2O3 shows stronger in-plane nonlinear optical anisotropy on (2-01) plane than on (010) plane. Compared with GaN, TPA coefficient of beta-Ga2O3 is 20 times smaller, and the Kerr nonlinear refractive index of beta-Ga2O3 is also found to be 4-5 times smaller. These results indicate that beta-Ga2O3 have the potential for ultra-low loss waveguides and ultra-stable resonators and integrated photonics, especially in UV and visible wavelength spectral range. PMID- 29475252 TI - Demonstration of a superconducting nanowire single photon detector with an ultrahigh polarization extinction ratio over 400. AB - Polarization sensitive photo-detectors are the key to the implementation of the polarimetric imaging systems, which are proved to have superior performance than their traditional counterparts based on intensity discriminations. In this article, we report the demonstration of a superconducting nanowire single photon detector (SNSPD) of which the response is ultra-sensitive to the polarization state of the incident photons. Measurements carried out on a fabricated SNSPD show that a device efficiency of ~48% can be achieved at 1550 nm for the case of parallel polarization, which is ~420 times larger than that for the case of perpendicular polarization. While the reported polarization ultra-sensitive technique is demonstrated on a single-pixel SNSPD, it is also fully compatible with the multi-pixel SNSPD array platforms that emerged recently. PMID- 29475253 TI - Enhanced normal-incidence Goos-Hanchen effects induced by magnetic surface plasmons in magneto-optical metamaterials. AB - Goos-Hanchen (GH) effects at normal incidence are investigated for metamaterials consisting of an array of ferrite rods. A new effective-medium approach is presented and applied to retrieve the effective parameters of the magneto-optical (MO) metamaterials based on a transformation method. Giant normal-incidence Goos Hanchen (NIGH) shifts on total reflection and enhanced magnetic switching effects are predicted near magnetic surface plasmon (MSP) resonances for structures with small effective permittivity. Numerical simulations are performed and the results are in good agreement with those from the transformation effective-medium approach. PMID- 29475254 TI - Engineering equations for characterizing non-linear laser intensity propagation in air with loss. AB - The propagation of high peak-power laser beams in real atmospheres will be affected at long range by both linear and nonlinear effects contained therein. Arguably, J. H. Marburger is associated with the mathematical characterization of this phenomenon. This paper provides a validated set of engineering equations for characterizing the self-focusing distance from a laser beam propagating through non-turbulent air with, and without, loss as well as three source configurations: (1) no lens, (2) converging lens and (3) diverging lens. The validation was done against wave-optics simulation results. Some validated equations follow Marburger completely, but others do not, requiring modification of the original theory. Our results can provide a guide for numerical simulations and field experiments. PMID- 29475255 TI - Highly sensitive surface plasmon resonance biosensor based on a low-index polymer optical fiber. AB - A highly sensitive refractive index sensor based on surface plasmon resonance in a side-polished low-index polymer optical fiber is proposed for biosensing. Benefitting from the low refractive index of the fiber core, the sensitivity of the device can reach ~44567 nm/RIU theoretically for aqueous solutions, at the expense of a lowered upper detection limit that is down to ~1.340. The sensor is fabricated by coating 55-nm-thick Au-film on the polished surface of a graded index perfluorinated polymer optical fiber. Results show that the sensor exhibits a sensitivity of ~22779 nm/RIU at 1.335 with a figure of merit of 61.2. When employed for glucose sensing, the sensor presents an averaged sensitivity of 24.50 nm/wt%, or 0.46 nm/mM. This device is expected to have potential applications in cost-effective bio- and chemical-sensing. PMID- 29475256 TI - Finite-difference beam-propagation method for anisotropic waveguides with torsional birefringence. AB - A new three-dimensional finite-difference (FD)-based beam propagation method (BPM) is proposed for simulating optical propagation in weakly guiding waveguides with torsional birefringence, which cannot be simulated by existing FD-BPM algorithms. We also demonstrate that this new BPM algorithm is capable of obtaining eigenmode solutions in a helically-symmetric z-dependent waveguide structure with torsional birefringence. PMID- 29475257 TI - De-multiplexing vortex modes in optical communications using transport-based pattern recognition. AB - Free space optical communications utilizing orbital angular momentum beams have recently emerged as a new technique for communications with potential for increased channel capacity. Turbulence due to changes in the index of refraction emanating from temperature, humidity, and air flow patterns, however, add nonlinear effects to the received patterns, thus making the demultiplexing task more difficult. Deep learning techniques have been previously been applied to solve the demultiplexing problem as an image classification task. Here we make use of a newly developed theory suggesting a link between image turbulence and photon transport through the continuity equation to describe a method that utilizes a "shallow" learning method instead. The decoding technique is tested and compared against previous approaches using deep convolutional neural networks. Results show that the new method can obtain similar classification accuracies (bit error ratio) at a small fraction (1/90) of the computational cost, thus enabling higher bit rates. PMID- 29475258 TI - Fully-automated optimization of grating couplers. AB - We present a gradient-based algorithm to design general 1D grating couplers without any human input from start to finish, including a choice of initial condition. We show that we can reliably design efficient couplers to have multiple functionalities in different geometries, including conventional couplers for single-polarization and single-wavelength operation, polarization-insensitive couplers, and wavelength-demultiplexing couplers. In particular, we design a fiber-to-chip blazed grating with under 0.2 dB insertion loss that requires a single etch to fabricate and no back-reflector. PMID- 29475259 TI - Dual-polarized light-field imaging micro-system via a liquid-crystal microlens array for direct three-dimensional observation. AB - Light-field imaging is a crucial and straightforward way of measuring and analyzing surrounding light worlds. In this paper, a dual-polarized light-field imaging micro-system based on a twisted nematic liquid-crystal microlens array (TN-LCMLA) for direct three-dimensional (3D) observation is fabricated and demonstrated. The prototyped camera has been constructed by integrating a TN LCMLA with a common CMOS sensor array. By switching the working state of the TN LCMLA, two orthogonally polarized light-field images can be remapped through the functioned imaging sensors. The imaging micro-system in conjunction with the electric-optical microstructure can be used to perform polarization and light field imaging, simultaneously. Compared with conventional plenoptic cameras using liquid-crystal microlens array, the polarization-independent light-field images with a high image quality can be obtained in the arbitrary polarization state selected. We experimentally demonstrate characters including a relatively wide operation range in the manipulation of incident beams and the multiple imaging modes, such as conventional two-dimensional imaging, light-field imaging, and polarization imaging. Considering the obvious features of the TN-LCMLA, such as very low power consumption, providing multiple imaging modes mentioned, simple and low-cost manufacturing, the imaging micro-system integrated with this kind of liquid-crystal microstructure driven electrically presents the potential capability of directly observing a 3D object in typical scattering media. PMID- 29475260 TI - Noise in phase-(in)sensitive dual-core fiber parametric amplification. AB - Flat and wide-bandwidth gain spectrum, along with phase-sensitive gain with no need to generate amplifier input idlers, can be achieved with a coupled dual-core fiber optical parametric amplifier. In this paper, we analyze the noise properties of such an amplifier. We achieve a 3 dB noise figure in the phase insensitive case and a minimum of -6 dB noise figure in the phase-sensitive configuration. An alternative phase-sensitive configuration is also studied, that avoids the use of idlers at the input of the amplifier, leading to a 3 dB flat spectrum combined noise figure for the output signals. Pump transfer noise in phase-insensitive and phase-sensitive configurations is also studied along with the noise figure variation against the length of the amplifier. PMID- 29475261 TI - Bifocal computational near eye light field displays and Structure parameters determination scheme for bifocal computational display. AB - We propose a bifocal computational near eye light field display (bifocal computational display) and structure parameters determination scheme (SPDS) for bifocal computational display that achieves greater depth of field (DOF), high resolution, accommodation and compact form factor. Using a liquid varifocal lens, two single-focal computational light fields are superimposed to reconstruct a virtual object's light field by time multiplex and avoid the limitation on high refresh rate. By minimizing the deviation between reconstructed light field and original light field, we propose a determination framework to determine the structure parameters of bifocal computational light field display. When applied to different objective to SPDS, it can achieve high average resolution or uniform resolution display over scene depth range. To analyze the advantages and limitation of our proposed method, we have conducted simulations and constructed a simple prototype which comprises a liquid varifocal lens, dual-layer LCDs and a uniform backlight. The results of simulation and experiments with our method show that the proposed system can achieve expected performance well. Owing to the excellent performance of our system, we motivate bifocal computational display and SPDS to contribute to a daily-use and commercial virtual reality display. PMID- 29475262 TI - Transparent effect on the gray scale perception of a transparent OLED display. AB - Gray scale perception of transparent OLED displays was explored. The difference in luminance between transparent and non-transparent stimuli in the overall gray range was compared. The transparent effect appeared in gray scale perception. The range of the transparent effect was determined experimentally. To explore the practical application of this effect, we proposed a new tone-curve based on the transparent effect. In the preference experiment, participants indicated a higher preference score for the new tone-curve. This implied that the transparent effect is valid and applicable to real situations. PMID- 29475263 TI - Passively Q-switched Nd3+ solid-state lasers with antimonene as saturable absorber. AB - Based on the saturable absorption feature of a two-dimensional (2D) nano material, antimonene, the passively Q-switched operation for solid-state laser was realized for the first time. For the 946 and 1064 nm laser emissions of the Nd:YAG crystal, the Q-switched pulse widths were 209 and 129 ns, and the peak powers were 1.48, 1.77 W, respectively. For the 1342 nm laser emission of the Nd:YVO4 crystal, the Q-switched pulse width was 48 ns, giving a peak power of 28.17 W. Our research shows that antimonene can be used as a stable, broadband optical modulating device for a solid-state laser, which will be particularly effective for long wavelength operation. PMID- 29475264 TI - Intensity guided cost metric for fast stereo matching under radiometric variations. AB - Reliable and efficient stereo matching is a challenging task due to the presence of multiple radiometric variations. In stereo matching, correspondence between left and right images can become hard owing to low correlation between radiometric changes in left and right images. Previously presented cost metrics are not robust enough against intensive radiometric variations and/or are computationally expensive. In this work, we propose a new similarity metric coined as Intensity Guided Cost Metric (IGCM). IGCM turns out to significantly contribute to the depth accuracy by rejecting outliers and reducing the edge fattening effect in object boundaries. IGCM is further combined explicitly with a color formation model to handle various radiometric changes that occur between stereo images. Experimental results on Middlebury dataset show 13.8%, 22.8%, 20.9%, 19.5 % and 9.1% decrease in average error rate compared to Adaptive Normalized Cross-Correlation (ANCC), Dense Adaptive Self-Correlation (DASC), Adaptive Descriptor(AD), Fast Cost Volume Filtering (FCVF) and Iterative Guided Filter (IGF)-based methods, respectively. Moreover, using integral images IGCM can achieve a speedup of 20x, 6x, 41x, 25x and 45x compared to the aforementioned methods. PMID- 29475265 TI - Vertical variations in optical properties of the waters in the Yellow Sea and Bohai Sea at seasonal scales and their influencing mechanisms. AB - This research used the profile data measured extensively in the Yellow Sea and Bohai Sea (YSBS) to explain the temporal and spatial distribution characteristics of optical properties and systematically analyzed the influencing mechanisms of the seasonal variations of optical properties in the YSBS in conjunction with synchronously measured hydrological and biogeochemical data in vertical profiles. The main conclusions obtained are as follows: the vertical variations in the optical properties in the YSBS are mainly influenced by the stratification effect, vertical mixing function, and phytoplankton growth process; and the variations of optical properties are dominated by the change of particle characteristics. The backscattering ratio can be used to discriminate particle types as a proxy of particulate bulk refractive index. In the YSBS, for waters with a backscattering ratio of less than 0.012, the variations of optical properties are dominated by the phytoplankton particles. For waters with a backscattering ratio greater than 0.012, the variations of optical properties are dominated by inorganic sediment particles. In addition, for the YSBS, the variations in optical properties of upper surface layer waters can be elucidated well by the vertical variations. PMID- 29475266 TI - Analyses of multi-color plant-growth light sources in achieving maximum photosynthesis efficiencies with enhanced color qualities. AB - An optimal design of light-emitting diode (LED) lighting that benefits both the photosynthesis performance for plants and the visional health for human eyes has drawn considerable attention. In the present study, we have developed a multi color driving algorithm that serves as a liaison between desired spectral power distributions and pulse-width-modulation duty cycles. With the aid of this algorithm, our multi-color plant-growth light sources can optimize correlated color temperature (CCT) and color rendering index (CRI) such that photosynthetic luminous efficacy of radiation (PLER) is maximized regardless of the number of LEDs and the type of photosynthetic action spectrum (PAS). In order to illustrate the accuracies of the proposed algorithm and the practicalities of our plant growth light sources, we choose six color LEDs and German PAS for experiments. Finally, our study can help provide a useful guide to improve light qualities in plant factories, in which long-term co-inhabitance of plants and human beings is required. PMID- 29475267 TI - Estimation of land surface temperature from three thermal infrared channels of MODIS data for dust aerosol skies. AB - Studies indicated that a root mean square error (RMSE) of 3.7 K was found if dust aerosol was not considered in the traditional land surface temperature (LST) retrieval algorithm. To reduce the influence of dust aerosol on LST estimation, a three-channel algorithm is proposed using MODIS channels 29, 31, and 32 with model coefficients irrelevant to the aerosol optical depth (AOD). Compared with actual and estimated LSTs, the RMSEs are 1.8 K and 1.6 K for dry and wet atmospheres, respectively, when the AOD is 1.0. Sensitivity analyses considering instrument noise, land surface emissivity uncertainties, and the algorithm error itself show that the LST errors are 2.5 K and 1.7 K for dry and wet atmospheres, respectively, when the AOD is 1.0. Finally, some in situ measured LSTs at the Jichanghuangmo, Huazhaizi, and Yingke sites in northwest China are taken as referenced LST values and compared with the MODIS LST products MOD11_L2/MYD11_L2 and those estimated with the proposed method. The results show that the proposed method can improve the LST retrieval accuracy from 1.4 K to 2.2 K in dust aerosol atmospheres. PMID- 29475268 TI - Dissipative-soliton generation with nonlinear-polarization-evolution in a polarization maintaining fiber. AB - A long-term stable picosecond dissipative soliton (DS) is achieved for the first time using nonlinear polarization evolution. The environmental stabilization is performed by a Faraday mirror, which can cancel environmentally induced changes in the birefringence of the fiber. The laser cavity with all-polarization maintaining fiber components generates DS pulses with 2.9 nJ single pulse energy and 5.9 ps pulse width. The output power test over 2 hours shows the excellent mode-locking stability of this design. PMID- 29475269 TI - Fabrication of polymer microlens array with controllable focal length by modifying surface wettability. AB - A straightforward technique for fabricating low-cost microlens arrays with controllable focal length is developed. By harnessing and manipulating the interfacial energy between the liquid-state acrylate resin and the solidified polydimethylsiloxane (PDMS), the surface of the acrylate resin in the PDMS microhole presents a spherical shape and the curvature can be flexibly controlled. With the change of the processing time for the surface modification of the PDMS microholes, the focal length of the concave microlenses varies from 296.3 MUm to -67.4 MUm. The numerical aperture of 0.45 is realized. The focal length and the aperture of the microlenses are also affected by the diameter of the microholes. The fabricated concave microlens array can be employed as a master to further duplicate convex microlens array. A good image quality can be achieved by using the convex microlens arrays. PMID- 29475270 TI - Ghost imaging via sparse structured illumination source. AB - We generate a type of pseudo-thermal light field via sparse structured illumination source. Genetic algorithm is utilized to optimize the source's spatial configuration and the property of pseudo-thermal light field is improved. Both simulated and experimental results demonstrate that the periodic distribution of normalized second-order intensity correlation function is effectively suppressed by optimizing the spatial configuration of sparse structured illumination source and the quality of ghost imaging can be obviously increased. This optimized sparse structured illumination source may be applied to the applications like remote sensing with moving targets. PMID- 29475271 TI - Division of amplitude RGB full-Stokes camera using micro-polarizer arrays: erratum. AB - We correct two figures showing the micro-polarizer arrangement on the RGB full Stokes camera. PMID- 29475272 TI - Quasi-phase-matched second harmonic generation of long-range surface plasmon polaritons. AB - In this paper, we experimentally demonstrate the second harmonic generation of long-range surface plasmon polaritons via quasi-phase matching in lithium niobate. After depositing a 9/13 nm thick Au film on periodically poled lithium niobate, TiO2 of about 2.3 MUm in thickness is evaporated on the sample as a refractive-index-matching material. This dielectric (periodically poled lithium niobate)-metal(Au)-dielectric(TiO2) sandwich structure can support the transmission of long-range surface plasmon polaritons through it. By designing a moderate ferroelectric domain period of periodically poled lithium niobate, the phase mismatch between the fundamental wave and second harmonic wave of the long range surface plasmon polaritons can be compensated and a second harmonic wave can be generated effectively. This can be used to provide integrated plasmonic devices with attractive applications in quantum and classic information processing. PMID- 29475274 TI - Biased three-intensity decoy-state scheme on the measurement-device-independent quantum key distribution using heralded single-photon sources. AB - At present, most of the measurement-device-independent quantum key distributions (MDI-QKD) are based on weak coherent sources and limited in the transmission distance under realistic experimental conditions, e.g., considering the finite size-key effects. Hence in this paper, we propose a new biased decoy-state scheme using heralded single-photon sources for the three-intensity MDI-QKD, where we prepare the decoy pulses only in X basis and adopt both the collective constraints and joint parameter estimation techniques. Compared with former schemes with WCS or HSPS, after implementing full parameter optimizations, our scheme gives distinct reduced quantum bit error rate in the X basis and thus show excellent performance, especially when the data size is relatively small. PMID- 29475273 TI - Tuning the strain-induced resonance shift in silicon racetrack resonators by their orientation. AB - In this work, we analyze the role of strain on a set of silicon racetrack resonators presenting different orientations with respect to the applied strain. The strain induces a variation of the resonance wavelength, caused by the photoelastic variation of the material refractive index as well as by the mechanical deformation of the device. In particular, the mechanical deformation alters both the resonator perimeter and the waveguide cross-section. Finite element simulations taking into account all these effects are presented, providing good agreement with experimental results. By studying the role of the resonator orientation we identify interesting features, such as the tuning of the resonance shift from negative to positive values and the possibility of realizing strain insensitive devices. PMID- 29475275 TI - Performance verification of adaptive optics for satellite-to-ground coherent optical communications at large zenith angle. AB - Although there is an urgent demand, it is still a tremendous challenge to use the coherent optical communication technology to the satellite-to-ground data transmission system especially at large zenith angle due to the influence of atmospheric turbulence. Adaptive optics (AO) is a considerable scheme to solve the problem. In this paper, we integrate the adaptive optics (AO) to the coherent laser communications and the performances of mixing efficiency as well as bit error-rate (BER) at different zenith angles are studied. The analytical results show that the increasing of zenith angle can severely decrease the performances of the coherent detection, and increase the BER to higher than 10-3, which is unacceptable. The simulative results of coherent detection with AO compensation indicate that the larger mixing efficiency and lower BER can be performed by the coherent receiver with a high-mode AO compensation. The experiment of correcting the atmospheric turbulence wavefront distortion using a 249-element AO system at large zenith angles is carried out. The result demonstrates that the AO system has a significant improvement on satellite-to-ground coherent optical communication system at large zenith angle. It also indicates that the 249 element AO system can only meet the needs of coherent communication systems at zenith angle smaller than 65 for the 1.8m telescope under weak and moderate turbulence. PMID- 29475276 TI - Orbital-angular-momentum mode-group multiplexed transmission over a graded-index ring-core fiber based on receive diversity and maximal ratio combining. AB - An orbital-angular-momentum (OAM) mode-group multiplexing (MGM) scheme using high order mode groups (MGs) in a graded-index ring-core fiber (GIRCF) is proposed, in which a receive-diversity architecture is designed for each MG to suppress the mode partition noise resulting from random intra-group mode crosstalk. The signal to-noise ratio (SNR) of the received signals is further improved by a simple maximal ratio combining (MRC) technique on the receiver side to efficiently take advantage of the diversity gain of the receiver. Intensity-modulated direct detection (IM-DD) systems transmitting three OAM mode groups with total 100-Gb/s discrete multi-tone (DMT) signals over a 1-km GIRCF and two OAM mode groups with total 40-Gb/s DMT signals over an 18.4-km GIRCF are experimentally demonstrated, respectively, to confirm the feasibility of our proposed OAM-MGM scheme. PMID- 29475277 TI - Instability of projection light source and real-time phase error correction method for phase-shifting profilometry. AB - The time-dependent phase error induced by the instability of projection light source (IPLS) is systematically studied for phase-shifting profilometry (PSP). The IPLS of the projection device is investigated by a specially designed experimental setup. Based on the results of the investigation, a new mathematical model to analyze the time-dependent phase error induced by IPLS is established and verified. Two real-time phase error correction methods using a new designed three-dimensional shape measurement system are proposed for the effect of IPLS. Experimental results demonstrate the two methods can effectively eliminate the induced time-dependent phase error with a good robustness and high accuracy. The two real-time correction methods for PSP will be promising for high-accuracy measurements. PMID- 29475279 TI - Tunable dual-band thermal emitter consisting of single-sized phase-changing GST nanodisks. AB - Thermal emission control has been attracting increased attention in both fundamental science and many applications including infrared sensing, radiative cooling and thermophotovoltaics. In this paper, a tunable dual-band thermal emitter including phase-changing material Ge2Sb2Te5 (GST) is experimentally demonstrated. Two emission peak wavelengths are at 7.36 MUm and 5.40 MUm at amorphous phase, and can be continuously tuned to 10.01 MUm and 7.56 MUm while GST is tuned to crystalline phase. Compared with other dual-band metamaterial emitters, this tunable dual-band thermal emitter is only composed of an array of single-sized GST nanodisks (on a gold film), which can greatly simplify the design and manufacturing process, and pave the way towards dynamical thermal emission control. PMID- 29475278 TI - Large-field-of-view optical resolution photoacoustic microscopy. AB - The use of existing optical resolution photoacoustic microscopy (ORPAM) has been limited to small organs or part of large organs due to the millimeter-scale field of view (FOV) in both lateral and axial directions. Here, we report a large-field of-view ORPAM (L-ORPAM) using a combination of a new scanning mechanism and an ultrafast pulsed laser. Phantom and in vivo experiments show that L-ORPAM has a spatial FOV of 40 mm in lateral and 12 mm in axial, which expends the effective imaging domain to one order that of existing ORPAMs. To show the advantages of L ORPAM, we apply it to imaging vasculatures of both brain and ears simultaneously in mice, and to visualizing intestinal vasculatures in rats. The result suggests that L-ORPAM has sufficient contrast, resolution and spatial FOV to carry out studies of large rodents. PMID- 29475280 TI - Continuously adjustable period optical grating based on flexoelectric effect of a bent-core nematic liquid crystal in planar cells. AB - The structures of flexodomains, which are similar to optical gratings and can be controlled by the amplitude of applied voltage and temperature, were verified through polarizing microscopy and light diffraction techniques. The properties of the optical grating induced by a bent-core nematic liquid crystal in planar cells with varied cell gaps and pretilt angles were studied. The period of optical grating decreases with the increase in the amplitude of the applied voltage and pretilt angle. In addition, the period increases with the increase in cell gap and temperature. The period of optical grating has a linear relationship with temperature. The continuously adjustable period has the potential to become an important and extended application of optical grating. PMID- 29475281 TI - Achieving a tunable metasurface based on a structurally reconfigurable array using SMA. AB - We introduce a structurally reconfigurable metasurface which is made of shape memory alloys (SMA). It could change the morphology of the unit cells repeatedly as we expect in response to a thermal stimulus and realize a tuning range from 13.3GHz to 17.2GHz for both polarizations simultaneously. Equivalent circuit models describe the operational principle and design methodology, the physical mechanism is interpreted with the variation of surface current distribution on the structure. The experimental results coincide with the numerical simulations, making the all-metal metasurface an attractive choice for manipulating the electromagnetic wave in a wide range of spectrums with the merits of higher controllability for dynamic behavior and greater freedom for design and manufacturing. PMID- 29475282 TI - Multi-wavelength optical data processing and recording based on azo-dyes doped organic-inorganic hybrid film. AB - While single wavelength all-optical information encoding through optically induced orientation of azobenzene dyes is being extensively pursued, we propose multi-wavelength optical data processing and recording based on disperse red 1 (DR1) and 4-(4-hydroxybutyloxy) azobenzene doped organic-inorganic hybrid films to increase the density of recording data. By investigating the change of absorbance spectrum of the doped film under different irradiations, results indicate a laser pulses around 470 nm would be suitable as the probe beam. In the measurement of optical data processing and recording, two cw lasers pulse at 532 nm and 355 nm induce trans-cis isomerization of the azo-dyes in the film, while the output of the probe beam record the processed data as {(-1), (0), (1)} according to different inputs of the pump beams. Since the light induced isomerization has a sensitive response in the as-prepared solid organic-inorganic matrix system, the films is promising as recording and monitoring element in all optical devices over a wide range of repetition rates. PMID- 29475284 TI - Integrated polar microstructure and template-matching method for optical position measurement. AB - This paper presents an integrated polar microstructure and template-matching method for optical position measurement that is developed based on the technology of ultra-precision machining (UPM) and computer vision. For computer vision, this paper makes use of the template-matching method as the basic working principle to match the position on the surface. For UPM, an optical microstructure that is named a 'polar microstructure' is purposely designed and fabricated by ultra precision diamond machining technology to provide the high resolution of the position measurement. To demonstrate the performance of the proposed method for optical position measurement, a high-precision multi-sensor coordinate measuring machine was used to test the position accuracy and the length uncertainty for the two axes of this positioning method. The experimental results show that the average length uncertainty and the corresponding standard deviation errors are 109.6 nm and 76.4 nm on the X-axis, and 91.8 nm and 69.7 nm on the Y-axis, respectively. PMID- 29475283 TI - Theoretical investigation on asymmetrical spinning and orbiting motions of particles in a tightly focused power-exponent azimuthal-variant vector field. AB - We generate a new kind of azimuthal-variant vector field with a distribution of states of polarization (SoPs) described by the square of the azimuthal angle. Owing to asymmetrical SoPs distribution of this localized linearly polarized vector field, the tightly focused field exhibits a double half-moon shaped pattern with the localized elliptical polarization in the cross section of field at the focal plane. Moreover, we study the three-dimensional distributions of spin and orbital linear and angular momenta in the focal region. We numerically investigate the gradient force, radiation force, spin torque, and orbital torque on a dielectric Rayleigh particle produced by the tightly focused vector field. It is found that asymmetrical spinning and orbiting motions of trapped Rayleigh particles can be realized by the use of a tight vector field with power-exponent azimuthal-variant SoPs. PMID- 29475285 TI - Spectrally shaping high-temperature radiators for thermophotovoltaics using Mo HfO2 trilayer-on-substrate structures. AB - Easy-to-fabricate, high-temperature, thermally-stable radiators are critical elements for developing efficient and sustainable thermophotovoltaic energy conversion devices. In this frame, a trilayer-on-substrate structure is selected. It is composed of a refractory metal -molybdenum - constituting the substrate and an intermediate thin film sandwiched between two hafnia transparent layers. An in depth analysis shows that two spectrally distinct interference regimes take place in the hafnia layer-molybdenum thin film substructure, and that backward and forward thermally-emitted waves by the thin film are selected in two distinct interferential resonating cavities. The interference regimes within and between these cavities are key to the spectral shaping of thermal emission. The radiative performances of the structures are evaluated by introducing a figure of merit. Using the example of a GaSb cell, it is shown that the structure can be optimized for providing the broadband large emission with a steep cutoff required for mitigating photoconversion losses. PMID- 29475286 TI - Reconfigurable and tunable compact comb filter and (de)interleaver on silicon platform. AB - We propose and demonstrate a reconfigurable and tunable chip-scale comb filter and (de)interleaver on a silicon platform. The silicon-based photonic integrated device is formed by Sagnac loop mirrors (SLMs) with directional couplers replaced by multi-mode interference (MMI) assisted tunable Mach-Zehnder interferometer (MZI) couplers. The device can be regarded as a large SLM incorporating two small SLMs which form a Fabry-Perot (FP) cavity. By appropriately adjusting the micro heaters in tunable MZI couplers and cavity, switchable operation between comb filter and (de)interleaver and extinction ratio and wavelength tunable operations of comb filter and (de)interleaver are achievable by thermo-optic tuning. Reconfigurable comb filter and (de)interleaver is demonstrated in the experiment. The central wavelength shifts of comb filter and (de)interleaver are demonstrated with wavelength tuning efficiencies of ~0.0224 nm/mW and ~0.0193 nm/mW, respectively. The 3-dB bandwidth of the comb filter is ~0.032 nm. The 3-dB and 20 dB bandwidths of the (de)interleaver passband are ~0.225 nm and ~0.326 nm. The obtained results indicate that the designed and fabricated device provides switchable comb filtering and interleaving functions together with extinction ratio and wavelength tunabilities. Reconfigurable and tunable silicon-based comb filter and (de)interleaver may find potential applications in robust wavelength division multiplexing (WDM) optical communication systems. PMID- 29475287 TI - 102-nm, 44.5-MHz inertial-free swept source by mode-locked fiber laser and time stretch technique for optical coherence tomography. AB - A swept source with both high repetition-rate and broad bandwidth is indispensable to enable optical coherence tomography (OCT) with high imaging rate and high axial resolution. However, available swept sources are commonly either limited in speed (sub-MHz) by inertial or kinetic component, or limited in bandwidth (<100 nm) by the gain medium. Here we report an ultrafast broadband (over 100 nm centered at 1.55-um) all-fiber inertial-free swept source built upon a high-power dispersion-managed fiber laser in conjunction with an optical time stretch module which bypasses complex optical amplification scheme, which result in a portable and compact implementation of time-stretch OCT (TS-OCT) at A-scan rate of 44.5-MHz, axial resolution of 14 um in air (or 10 um in tissue), and flat sensitivity roll-off within 4.3 mm imaging range. Together with the demonstration of two- and three-dimensional OCT imaging of a mud-fish eye anterior segment, we also perform comprehensive studies on the imaging depth, receiver bandwidth, and group velocity dispersion condition. This all-fiber inertia-free swept source could provide a promising source solution for SS-OCT system to realize high performance volumetric OCT imaging in real time. PMID- 29475288 TI - Engineering optical emission in sub-diffraction hyperbolic metamaterial resonators. AB - Sub-diffraction hyperbolic metamaterial resonators are promising structures for engineering light-matter interactions in semiconductor-based emitters and materials. The optical properties of these resonators are determined by a number of device characteristics including the metamaterial permittivity and resonator geometry. In this letter, we develop an optical model based on the modified long wavelength approximation to calculate the radiative and non-radiative photon loss of the resonators. We fabricate and characterize 11 different resonator arrays to demonstrate the effectiveness of model. Using the model, we demonstrate how the radiative properties of the resonators can be engineered via the design of the semiconductor metamaterial and the aspect ratio of the resonator. Over the explored design space, we demonstrate an eightfold increase in the radiative rate compared to the non-radiative rate. Our work reduces the complexity of designing sub-diffraction hyperbolic metamaterial resonators, allowing broader incorporation of these optical structures into novel devices and materials. PMID- 29475289 TI - Dual-channel simultaneous spatial and temporal polarization phase-shifting interferometry. AB - Without the limitations of fringe number and fringe shape, a dual-channel simultaneous spatial and temporal polarization (DC-SSTP) phase-shifting interferometry system is proposed to achieve rapid and accurate phase retrieval through only one-time phase-shifting procedure with unknown phase shifts. First, an arbitrary phase shifts is simultaneously introduced into two channels of DC SSTP system by a spatial light modulator (SLM). Second, by performing the subtraction operation between each pair of phase-shifting interferograms captured in the same channel, the background deduction of interferogram can be achieved easily, so the accurate phase can be retrieved rapidly. Especially, it is found even if the fringe number in interferogram is less than one, the proposed DC-SSTP method still reveals high accuracy of phase retrieval. Both the simulation and experimental results demonstrate the outstanding performance of proposed DC-SSTP method in phase measurement. PMID- 29475290 TI - Radially polarized passively mode-locked thin-disk laser oscillator emitting sub picosecond pulses with an average output power exceeding the 100 W level. AB - We report on a high-power passively mode-locked radially polarized Yb:YAG thin disk oscillator providing 125 W of average output power. To the best of our knowledge, this is the highest average power ever reported from a mode-locked radially polarized oscillator without subsequent amplification stages. Mode locking was achieved by implementing a SESAM as the cavity end mirror and the radial polarization of the LG*01 mode was obtained by means of a circular Grating Waveguide Output Coupler. The repetition rate was 78 MHz. A pulse duration of 0.97 ps and a spectral bandwidth of 1.4 nm (FWHM) were measured at the maximum output power. This corresponds to a pulse energy of 1.6 uJ and a pulse peak power of 1.45 MW. A high degree of radial polarization of 97.3 +/- 1% and an M2-value of 2.16 which is close to the theoretical value for the LG*01 doughnut mode were measured. PMID- 29475291 TI - Fabrication of tunable chirped mPOF Bragg gratings using a uniform phase mask. AB - We demonstrate chirped Bragg gratings fabrication in doped microstructured tapered polymer fibers by using a uniform phase mask. The use of high photosensitive benzyl dimethyl ketal (BDK) doped core fiber allows to obtain chirped Bragg gratings by means of a single krypton fluoride laser pulse. The stability of the gratings has been confirmed and the strain and temperature sensitivity measurements demonstrate their tunable properties. Finally, different tapered profiles have been implemented in order to show the potentiality of this fabrication technique in polymer optical fibers. PMID- 29475292 TI - Ultra-low loss ridge waveguides on lithium niobate via argon ion milling and gas clustered ion beam smoothening. AB - Lithium niobate's use in integrated optics is somewhat hampered by the lack of a capability to create low loss waveguides with strong lateral index confinement. Thin film single crystal lithium niobate is a promising platform for future applications in integrated optics due to the availability of a strong electro optic effect in this material coupled with the possibility of strong vertical index confinement. However, sidewalls of etched waveguides are typically rough in most etching procedures, exacerbating propagation losses. In this paper, we propose a fabrication method that creates significantly smoother ridge waveguides. This involves argon ion milling and subsequent gas clustered ion beam smoothening. We have fabricated and characterized ultra-low loss waveguides with this technique, with propagation losses as low as 0.3 dB/cm at 1.55 um. PMID- 29475293 TI - Rapid and efficient formation of propagation invariant shaped laser beams. AB - A rapid and efficient all-optical method for forming propagation invariant shaped beams by exploiting the optical feedback of a laser cavity is presented. The method is based on the modified degenerate cavity laser (MDCL), which is a highly incoherent cavity laser. The MDCL has a very large number of degrees of freedom (320,000 modes in our system) that can be coupled and controlled, and allows direct access to both the real space and Fourier space of the laser beam. By inserting amplitude masks into the cavity, constraints can be imposed on the laser in order to obtain minimal loss solutions that would optimally lead to a superposition of Bessel-Gauss beams forming a desired shaped beam. The resulting beam maintains its transverse intensity distribution for relatively long propagation distances. PMID- 29475294 TI - Highly efficient nanosecond 560 nm source by SHG of a combined Yb-Raman fiber amplifier. AB - We demonstrate a nanosecond 560 nm pulse source based on frequency-doubling the output of a combined Yb-Raman fiber amplifier, achieving a pulse energy of 2.0 uJ with a conversion efficiency of 32% from the 976 nm pump light. By introducing a continuous-wave 1120 nm signal before the cladding pumped amplifier of a pulsed Yb:fiber master oscillator power amplifier system operating at 1064 nm, efficient conversion to 1120 nm occurs within the fiber amplifier due to stimulated Raman scattering. The output of the combined Yb-Raman amplifier is frequency-doubled to 560 nm using a periodically poled lithium tantalate crystal with a conversion efficiency of 47%, resulting in an average power of 3.0 W at a repetition rate of 1.5 MHz. The 560 nm pulse duration of 1.7 ns and the near diffraction-limited beam quality (M2<=1.18) make this source ideally suited to biomedical imaging applications such as optical-resolution photoacoustic microscopy and stimulated emission depletion microscopy. PMID- 29475295 TI - Broadband and efficient adiabatic three-wave-mixing in a temperature-controlled bulk crystal. AB - Nonlinear interactions are commonly used to access to wavelengths not covered by standard laser systems. In particular, optical parametric amplification (OPA) is a powerful technique to produce broadly tunable light. However, common implementations of OPA suffer from a well-known trade-off, either achieving high efficiency for narrow spectra or inefficient conversion over a broad bandwidth. This shortcoming can be addressed using adiabatic processes. Here, we demonstrate a novel technique towards this direction, based on a temperature-controlled phase mismatch between the interacting waves. Using this approach, we demonstrate, by tailoring the temperature profile, an increase in conversion efficiency by 21%, reaching a maximum of 57%, while simultaneously expanding the bandwidth to over 300 nm. Our technique can readily enhance the performances of current OPA systems. PMID- 29475296 TI - Laser absorption spectroscopy data processing method based on co-frequency and dual-wavelength and its application. AB - In the detection process of atmospheric laser absorption spectroscopy in open space, the transmitted beam is inevitably affected by atmospheric turbulence, resulting in superimposed fluctuation noise in the received optical signal. First, the correction method of atmospheric turbulence is theoretically analyzed. In order to reduce the error influence factors and the error transfer coefficient, a new method of spectral data processing based on co-frequency and dual-wave has been proposed. By modifying scintillation noise and background noise, the influence of atmospheric turbulence noise in open space is reduced. An atmospheric detection system in open space based on co-frequency and dual-wave has been established. The experimental results show that the maximum fluctuation of the spectral signal processed by the method of spectrum data processing based on the co-frequency and dual-wave is reduced from 12.854% to 4.635%, and the single-intensity absorbance is fitted by Voigt with its correlation coefficient of 0.9525. The mean of the standard deviation of the algorithm is 0.1370, while the mean value of the standard deviation of the existing algorithm in a short time is 0.6928. And, through the comparative experiment, the standard deviation of the existing data processing techniques of two-wavelength differential absorption is 0.2974, while the standard deviation of the method of spectrum data processing based on the co-frequency and dual-wave is 0.1038. It can be concluded that the co-frequency and dual-wave method can effectively reduce the influence of atmospheric turbulence noise and laser flashing to improve the stability of concentration measurement, which has practical engineering value. PMID- 29475297 TI - Experimental demonstration of wave-particle duality relation based on coherence measure. AB - Wave-particle duality is a typical example of Bohr's complementarity principle that plays a significant role in quantum mechanics. Previous studies used the visibility of an interference pattern to quantify the wave property and used path information to quantify the particle property. However, coherence is the core and basis of the interference phenomenon. If we could use coherence to characterize the wave property, the understanding of wave-particle duality would be strengthened. A recent theoretical work [ Phys. Rev. Lett.116, 160406 (2016)] found two relations between quantum coherence and path information. Here, we demonstrate the new measure of wave-particle duality based on two kinds of coherence measures quantitatively for the first time. The wave property, quantified by the coherence in the l1-norm measure and the relative entropy measure, can be obtained via tomography of the target state, which is encoded in the path degree of freedom of the photons. The particle property, quantified by the path information, can be obtained via the discrimination of detector states, which is encoded in the polarization degree of freedom of the photons. Our work may deepen people's understanding of coherence and provide a new perspective regarding wave-particle duality. PMID- 29475298 TI - Spatial coherence measurement and partially coherent diffractive imaging using self-referencing holography. AB - The complete characterization of spatial coherence is extremely difficult because the mutual coherence function (MCF) is a complex-valued function of four independent Cartesian coordinates. This difficulty limits the ability to control and to optimize the spatial coherence in a broad range of key applications. Here we propose an efficient and robust scheme for measuring the complete MCF of an arbitrary partially coherent beam using self-referencing holography, which does not require any prior knowledge or making any assumptions about the MCF. We further apply our method to lensless diffractive imaging, and experimentally demonstrate the reconstruction of a phase object under spatially partially coherent illumination. This application is particularly useful for imaging at short wavelengths, where the illumination sources lack spatial coherence and no high-quality imaging optics are available. PMID- 29475299 TI - Continuously tunable distributed feedback polymer laser. AB - A fanshaped structure is proposed to achieve a continuously tunable polymer laser. The structure with gradual periods is fabricated by electron beam lithography, which acts as a distributed feedback cavity for the polymer laser. A light-emitting polymer is spin-coated on the cavity to form an active layer. The pump beam is focused by a cylindrical lens to a narrow stripe on the sample surface. When the position of the pump stripe on the fanshaped cavity is changed from long period (370 nm) to short period (340 nm) and vice versa, the output wavelength of the laser is continuously tuned from 584 nm to 552 nm. Tuning behavior can be interpreted by the Bragg condition. These results can be used to explore compact laser sources. PMID- 29475300 TI - One-step implementation of a hybrid Fredkin gate with quantum memories and single superconducting qubit in circuit QED and its applications. AB - In a recent remarkable experiment [Sci. Adv. 2, e1501531 (2016)], a 3-qubit quantum Fredkin (i.e., controlled-SWAP) gate was demonstrated by using linear optics. Here we propose a simple experimental scheme by utilizing the dispersive interaction in superconducting quantum circuit to implement a hybrid Fredkin gate with a superconducting flux qubit as the control qubit and two separated quantum memories as the target qudits. The quantum memories considered here are prepared by the superconducting coplanar waveguide resonators or nitrogen-vacancy center ensembles. In particular, it is shown that this Fredkin gate can be realized using a single-step operation and more importantly, each target qudit can be in an arbitrary state with arbitrary degrees of freedom. Furthermore, we show that this experimental scheme has many potential applications in quantum computation and quantum information processing such as generating arbitrary entangled states (discrete-variable states or continuous-variable states) of the two memories, measuring the fidelity and the entanglement between the two memories. With state of-the-art circuit QED technology, the numerical simulation is performed to demonstrate that two-memory NOON states, entangled coherent states, and entangled cat states can be efficiently synthesized. PMID- 29475301 TI - Low-loss graded-index polymer crossed optical waveguide with high thermal resistance. AB - In this paper, crossed polymer waveguides with graded-index (GI) square cores are fabricated using the soft-lithography method. We experimentally demonstrate that the fabricated GI-core crossed waveguides exhibit a much lower insertion loss than conventional step index (SI)-core counterparts, which is almost independent of the cross angle. We also show in this paper that the crossed waveguides fabricated applying organic-inorganic hybrid resins show remarkably high thermal resistance compared to the waveguides fabricated utilizing an acrylate resin and a dopant system we previously reported. PMID- 29475302 TI - Probabilistically shaped PDM 4096-QAM transmission over up to 200 km of fiber using standard intradyne detection. AB - We demonstrate transmission of a probabilistically shaped polarization-division multiplexed 3-GBd 4096-QAM signal over up to 200 km of backward Raman amplified Corning(r) Vascade(r) EX2000 fiber. The 3-GBd signal with a root-raised-cosine roll-off of 0.01 has the potential to generate a spectral efficiency of 19.77 bit/s/Hz over 50 km of fiber. PMID- 29475303 TI - Characterizing isolated attosecond pulses with angular streaking. AB - We present a reconstruction algorithm for isolated attosecond pulses, which exploits the phase dependent energy modulation of a photoelectron ionized in the presence of a strong laser field. The energy modulation due to a circularly polarized laser field is manifest strongly in the angle-resolved photoelectron momentum distribution, allowing for complete reconstruction of the temporal and spectral profile of an attosecond burst. We show that this type of reconstruction algorithm is robust against counting noise and suitable for single-shot experiments. This algorithm holds potential for a variety of applications for attosecond pulse sources. PMID- 29475304 TI - Attosecond delay in the molecular photoionization of asymmetric molecules. AB - We report theoretical calculations of the delay in photoemission from CO with particular emphasis on the role of the ultrafast electronic bound dynamics. We study the delays in photoionization in the HOMO and HOMO-1 orbitals of the CO molecule by looking into the stereo Wigner time delay technique. That compares the delay in photoemission from electrons emitted to the left and right to extract structural and dynamical information of the ionization process. For this we apply two techniques: The attosecond streak camera and the time of flight technique. Although they should provide the same results we have found large discrepancies of up to 36 in the case of HOMO, while for the HOMO-1 we obtain the same results with the two techniques. We have found that the large time delays observed in the HOMO orbital with the streaking technique are a consequence of the resonant transition triggered by the streaking field. This resonant transition produces a bound electron wavepacket that modifies the measurements of delay in photoionization. As a result of this observation, our technique allows us to reconstruct the bound wavepacket dynamics induced by the streaking field. By measuring the expected value of the electron momentum along the polarization direction after the streaking field has finished, we can recover the relative phase between the complex amplitudes of the HOMO and LUMO orbitals. These theoretical calculations pave the way for the measurement of ultrafast bound bound electron transitionsand its crucial role for the delay in photoemission observation. PMID- 29475305 TI - Highly sensitive torsion sensor with femtosecond laser-induced low birefringence single-mode fiber based Sagnac interferometer. AB - A highly sensitive optical fiber torsion sensor with femtosecond laser-induced low birefringence SMF-based Sagnac interferometer (SI) is proposed and experimentally demonstrated in this paper. A straight-line waveguide positioned horizontally with respect to the fiber core is inscribed by the femtosecond laser in the cladding of the SMF, which leads to the asymmetry stress distribution in the SMF, and then gives rise to the low birefringence in the SMF. Compared with most of the previous reported SI based torsion sensors, there is no splicing joint in the femtosecond laser-induced low birefringence SMF-based SI, which lowers the transmission loss and makes the SI based torsion sensor more robust simultaneously. The experiment result shows that the proposed torsion sensor exhibits a torsion sensitivity of up to 3.2562 nm/degree, with the high torsion resolution of 0.003 degree. In contrast, the temperature cross-sensitivity and strain cross-sensitivity of the proposed torsion sensor are low, to -0.000055 degree/ degrees C and 0.000013 degree/MUepsilon, respectively, thus overcoming the cross-sensitivity problem resulting from temperature and strain. Moreover, theoretical analysis are carried out to compare with the experimental results to demonstrate the feasibility and good consistency. PMID- 29475306 TI - Isolated elliptically polarized attosecond soft X-ray with high-brilliance using polarization gating of harmonics from relativistic plasmas at oblique incidence. AB - The production of intense isolated attosecond pulse is a major goal in ultrafast research. Recent advances in high harmonic generation from relativistic plasma mirrors under oblique incidence interactions gave rise to photon-rich attosecond pulses with circular or elliptical polarization. However, to achieve an isolated elliptical attosecond pulse via polarization gating using currently available long driving pulses remains a challenge, because polarization gating of high harmonics from relativistic plasmas is assumed only possible at normal or near normal incidence. Here we numerically demonstrate a scheme around this problem. We show that via control of plasma dynamics by managing laser polarization, it is possible to gate an intense single attosecond pulse with high ellipticity extending to the soft X-ray regime at oblique incidence. This approach thus paves the way towards a powerful tool enabling high-time-resolution probe of dynamics of chiral systems and magnetic materials with current laser technology. PMID- 29475307 TI - Stabilization of self-mode-locked quantum dash lasers by symmetric dual-loop optical feedback. AB - We report experimental studies of the influence of symmetric dual-loop optical feedback on the RF linewidth and timing jitter of self-mode-locked two-section quantum dash lasers emitting at 1550 nm. Various feedback schemes were investigated and optimum levels determined for narrowest RF linewidth and low timing jitter, for single-loop and symmetric dual-loop feedback. Two symmetric dual-loop configurations, with balanced and unbalanced feedback ratios, were studied. We demonstrate that unbalanced symmetric dual loop feedback, with the inner cavity resonant and fine delay tuning of the outer loop, gives the narrowest RF linewidth and reduced timing jitter over a wide range of delay, unlike single and balanced symmetric dual-loop configurations. This configuration with feedback lengths of 80 and 140 m narrows the RF linewidth by ~ 4-67x and ~ 10-100x, respectively, across the widest delay range, compared to free-running. For symmetric dual-loop feedback, the influence of different power split ratios through the feedback loops was determined. Our results show that symmetric dual loop feedback is markedly more effective than single-loop feedback in reducing RF linewidth and timing jitter, and is much less sensitive to delay phase, making this technique ideal for applications where robustness and alignment tolerance are essential. PMID- 29475308 TI - Design of an ultra-compact graphene-based integrated microphotonic tunable delay line. AB - The design of a continuously tunable optical delay line based on a compact graphene-based silicon Bragg grating is reported. High performance, in terms of electro-optical switching time (tswitch < 8 ns), delay range (Deltatau = 200 ps), and figure of merit FOM = Deltatau/A = 1.54x105 ps/mm2, has been achieved with an ultra-compact device footprint (A ~1.3 x 10-3 mm2), so improving the state-of-the art of integrated optical delay lines. A continuous and complete tunability of the delay time can be achieved with a very low delay loss ( = 0.03 dB/ps) and a weak power consumption ( = 0.05 mW/ps). A flat bandwidth B = 1.19 GHz has been calculated by exploiting the slow-light effect in the device. This performance makes the proposed optical delay line suitable for several applications in Microwave Photonics (MWP), such as beamsteering/beamforming, for which large delay range, flat and wide bandwidth and small volume are required. PMID- 29475309 TI - Characterization of the stochastic time evolution of short-term average intercore crosstalk in multicore fibers with multiple interfering cores. AB - A theoretical model for the stochastic time evolution of the intercore crosstalk (ICXT) in homogeneous weakly-coupled multicore fibers (MCF) with multiple interfering cores is proposed and validated experimentally. The model relies on the introduction of non-stationary time varying random phase shifts at every center point between the phase matching points of the MCF where the difference of the effective refractive indexes of the core of the originating signal and the core suffering from ICXT is zero. Closed form-expressions for the autocovariance of the short-term average ICXT (STAXT) with stationary and non-stationary phase shift models in MCFs with multiple excited cores are derived and validated by comparison with experimental results. These expressions enable estimating the decorrelation time of the STAXT generated by multiple interfering cores from the decorrelation times of the STAXT generated by each pair of cores. The proposed model and the ICXT measurements taken continuously over more than 150 hours show that the decorrelation time of the STAXT generated by multiple interfering cores exceeds the one obtained for the pair of cores with shorter decorrelation time. The proposed model is increasingly important to simulate and design MCF-based systems where the ICXT dynamics must be properly accounted for to develop efficient ICXT-tolerant techniques. PMID- 29475310 TI - Photonic molecules for improving the optical response of macroporous silicon photonic crystals for gas sensing purposes. AB - In this paper, we report the benefits of working with photonic molecules in macroporous silicon photonic crystals. In particular, we theoretically and experimentally demonstrate that the optical properties of a resonant peak produced by a single photonic atom of 2.6 um wide can be sequentially improved if a second and a third cavity of the same length are introduced in the structure. As a consequence of that, the base of the peak is reduced from 500 nm to 100 nm, while its amplitude remains constant, increasing its Q-factor from its initial value of 25 up to 175. In addition, the bandgap is enlarged almost twice and the noise within it is mostly eliminated. In this study we also provide a way of reducing the amplitude of one or two peaks, depending whether we are in the two- or three-cavity case, by modifying the length of the involved photonic molecules so that the remainder can be used to measure gas by spectroscopic methods. PMID- 29475311 TI - Maximizing the field of view and accuracy in 3D Single Molecule Localization Microscopy. AB - Super-resolution techniques that localize single molecules in three dimensions through point spread function (PSF) engineering are very sensitive to aberrations and optical alignment. Here we show how double-helix point spread function is affected by such mis-alignment and aberration. Specifically, we demonstrate through simulation and experiment how misplacement of phase masks in infinity corrected systems is a common source of significant loss of accuracy. We also describe an optimal alignment and calibration procedure to correct for these errors. In combination, these optimizations allow for a maximal field of view with high accuracy and precision. Though discussed with reference to double-helix point spread function (DHPSF), the optimization techniques are equally applicable to other engineered PSFs. PMID- 29475312 TI - Effect of grinding parameters on surface roughness and subsurface damage and their evaluation in fused silica. AB - Based on micro-indentation mechanics and kinematics of grinding processes, theoretical formulas are deduced to calculate surface roughness (SR) and subsurface damage (SSD) depth. The SRs and SSD depths of a series of fused silica samples, which are prepared under different grinding parameters, are measured. By experimental and theoretical analysis, the relationship between SR and SSD depth is discussed. The effect of grinding parameters on SR and SSD depth is investigated quantitatively. The results show that SR and SSD depth decrease with the increase of wheel speed or the decrease of feed speed as well as cutting depth. The interaction effect between wheel speed and feed speed should be emphasized greatly. Furthermore, a relationship model between SSD depth and grinding parameters is established, which could be employed to evaluate SSD depth efficiently. PMID- 29475313 TI - Mode-filtering technique based on all-fiber-based external cavity for fiber-based optical frequency comb. AB - We developed a mode-filtering technique based on the all-fiber-based external cavity for a fiber-based optical frequency comb for high repetition rate (frep) frequency comb, and the carrier envelope offset frequency (fceo) can be detected and stabilized and is robust to environmental fluctuations. To achieve multiplication of the frep with a high multiplication factor using the fiber ring cavity, a long fiber was developed to mitigate the physical limitation inhibiting the shortening of the cavity length. In this study, the length of the fiber cavity was set to 6.7 m (free spectral range = 44.7 MHz) as the fiber-based comb length was 6.1 m. We were able to demonstrate a multiplication factor of 11, i.e., frep increased from 48.7 MHz to 536.0 MHz with a side mode suppression ratio of about 25 dB using the double-pass configuration. PMID- 29475314 TI - Proposed liquid-cooled nanowire lasers. AB - While the nanowire (NW) lasers have attracted much attentions as nanoscale coherent sources in recent years, the heat accumulation and temperature-rise induced breakdown remain challenges to improving the lasers for practical applications. Here we propose a microscale liquid-cooled approach to address the issue. Calculated results show that, compared with conventional air-cooled lasing systems, liquid-cooled NW lasers can allow much higher thermal power. By keeping the NW temperature below 373 K, the allowed thermal power in water is about 21 times that in air (850 uW in water versus 40 uW in air). Transient temperature evolution reveals a much faster heat dissipation of the NW in water (30 ns) than in air (7 us), indicating a much higher allowable repetition rate in water than in air (e.g., 10 MHz versus 100 kHz). Our results suggest a possible route to compact NW lasers with higher power, new materials and new operation modes. PMID- 29475315 TI - Fast recognition of single quantum dots from high multi-exciton emission and clustering effects. AB - Recognition of single quantum dots (QDs) from high multi-exciton emission and clustering effects is challenging using the conventional second-order correlation function method. Here we demonstrate a method for fast recognizing single QDs based on the probabilities of detecting single- and two-photon events. The time tagged, time-resolved and time-correlated single-photon counting technique is applied to effectively remove multi-exciton emission and low-counting background. By this way, single QDs can be fastly recognized by the spatial coincidence counting model. In addition, the fast recognition of single QDs by using the collected photons during the confocal scanning imaging process has been achieved synchronously. PMID- 29475316 TI - Tuning the dispersion of effective surface plasmon polaritons with multilayer systems. AB - Recently, effective surface plasmon polaritons (ESPPs) induced by structural dispersion in bounded waveguides were theoretically demonstrated and experimentally verified. Despite the theoretical and experimental efforts, whether ESPPs can mimic real SPPs in every aspect still remains an open question. In this work, we go one step further to study the hybridization of ESPPs in multilayer systems. We consider transverse electric (TE) modes in a conventional rectangular waveguide and a parallel-plate waveguide (PPW) and derive analytically the dispersion relations and asymptotic frequencies of the corresponding ESPPs modes in sandwiched structures consisting of alternating dielectrics of different permittivities. Our results show that the ESPPs can be categorized into odd and even parities (owing to the 'plasmon' hybridization) in a similar way as natural SPPs supported by the insulator/metal/insulator (IMI) and metal/insulator/metal (MIM) heterostructures in the optical regime. The similarities and differences between ESSPs and their optical counterparts are also discussed in details, which may provide valuable guidance for future application of ESPPs at the microwave and terahertz frequencies. PMID- 29475317 TI - Multifocal diffractive lens generating several fixed foci at different design wavelengths. AB - We propose a method for designing multifocal diffractive lenses generating prescribed sets of foci with fixed positions at several different wavelengths. The method is based on minimizing the difference between the complex amplitudes of the beams generated by the lens microrelief at the design wavelengths, and the functions of the complex transmission of multifocal lenses calculated for these wavelengths. As an example, a zone plate generating three fixed foci at three different wavelengths was designed, fabricated, and experimentally investigated. The proof-of-concept experimental results confirm the formation of foci with fixed positions at the design wavelengths. The obtained results may find applications in the design and fabrication of novel multifocal contact and intraocular lenses with reduced chromatic effects. PMID- 29475318 TI - Secure communications using nonlinear silicon photonic keys. AB - We present a secure communication system constructed using pairs of nonlinear photonic physical unclonable functions (PUFs) that harness physical chaos in integrated silicon micro-cavities. Compared to a large, electronically stored one time pad, our method provisions large amounts of information within the intrinsically complex nanostructure of the micro-cavities. By probing a micro cavity with a rapid sequence of spectrally-encoded ultrafast optical pulses and measuring the lightwave responses, we experimentally demonstrate the ability to extract 2.4 Gb of key material from a single micro-cavity device. Subsequently, in a secure communication experiment with pairs of devices, we achieve bit error rates below 10-5 at code rates of up to 0.1. The PUFs' responses are never transmitted over the channel or stored in digital memory, thus enhancing the security of the system. Additionally, the micro-cavity PUFs are extremely small, inexpensive, robust, and fully compatible with telecommunications infrastructure, components, and electronic fabrication. This approach can serve one-time pad or public key exchange applications where high security is required. PMID- 29475319 TI - Wideband multi-stage CROW filters with relaxed fabrication tolerances. AB - We present wideband and large free spectral range optical filters with steep passband edges for the selection of adjacent WDM communication channels that can be reliably fabricated with mainstream silicon photonics technology. The devices are based on three cascaded stages of coupled resonator optical waveguides loaded on a common bus waveguide. These stages differ in the number of resonators but are implemented with exactly identical unit cells, comprised of a matched racetrack resonator layout and a uniform spacing between cells. The different number of resonators in each stage allows a high rejection in the through port response enabled by the interleaved distribution of zeros. Furthermore, the exact replication of a unique cell avoids the passband ripple and high lobes in the stopband that typically arise in apodized coupled resonator optical waveguide based filters due to fabrication and coupling induced variations in the effective path length of each resonator. Silicon photonics filters designed for the selection of 9 adjacent optical carriers generated by a 100 GHz free spectral range comb laser have been successfully fabricated with 248 nm DUV lithography, achieving an out-of-band rejection above 11 dB and an insertion loss of less than 0.5 dB for the worst channels. PMID- 29475320 TI - Enhancing the magneto-optical Kerr effect through the use of a plasmonic antenna. AB - We employ an extended finite-element model as a design tool capable of incorporating the interaction between plasmonic antennas and magneto-optical effects, specifically the magneto-optical Kerr effect (MOKE). We first test our model in the absence of an antenna and show that for a semi-infinite thin-film, good agreement is obtained between our finite-element model and analytical calculations. The addition of a plasmonic antenna is shown to yield a wavelength dependent enhancement of the MOKE. The antenna geometry and its separation from the magnetic material are found to impact the strength of the observed MOKE signal, as well as the antenna's resonance wavelength. Through optimization of these parameters we achieved a MOKE enhancement of more than 100 when compared to a magnetic film alone. These initial results show that our modeling methodology offers a tool to guide the future fabrication of hybrid plasmonic magneto-optical devices and plasmonic antennas for magneto-optical sensing. PMID- 29475321 TI - Nonlinear dynamics of solitary and optically injected two-element laser arrays with four different waveguide structures: a numerical study. AB - We study the nonlinear dynamics of solitary and optically injected two-element laser arrays with a range of waveguide structures. The analysis is performed with a detailed direct numerical simulation, where high-resolution dynamic maps are generated to identify regions of dynamic instability in the parameter space of interest. Our combined one- and two-parameter bifurcation analysis uncovers globally diverse dynamical regimes (steady-state, oscillation, and chaos) in the solitary laser arrays, which are greatly influenced by static design waveguiding structures, the amplitude-phase coupling factor of the electric field, i.e. the linewidth-enhancement factor, as well as the control parameter, e.g. the pump rate. When external optical injection is introduced to one element of the arrays, we show that the whole system can be either injection-locked simultaneously or display rich, different dynamics outside the locking region. The effect of optical injection is to significantly modify the nature and the regions of nonlinear dynamics from those found in the solitary case. We also show similarities and differences (asymmetry) between the oscillation amplitude of the two elements of the array in specific well-defined regions, which hold for all the waveguiding structures considered. Our findings pave the way to a better understanding of dynamic instability in large arrays of lasers. PMID- 29475322 TI - 1.65 mm diameter forward-viewing confocal endomicroscopic catheter using a flip chip bonded electrothermal MEMS fiber scanner. AB - We report a 1.65 mm diameter forward-viewing confocal endomicroscopic catheter using a flip-chip bonded electrothermal MEMS fiber scanner. Lissajous scanning was implemented by the electrothermal MEMS fiber scanner. The Lissajous scanned MEMS fiber scanner was precisely fabricated to facilitate flip-chip connection, and bonded with a printed circuit board. The scanner was successfully combined with a fiber-based confocal imaging system. A two-dimensional reflectance image of the metal pattern 'OPTICS' was successfully obtained with the scanner. The flip-chip bonded scanner minimizes electrical packaging dimensions. The inner diameter of the flip-chip bonded MEMS fiber scanner is 1.3 mm. The flip-chip bonded MEMS fiber scanner is fully packaged with a 1.65 mm diameter housing tube, 1 mm diameter GRIN lens, and a single mode optical fiber. The packaged confocal endomicroscopic catheter can provide a new breakthrough for diverse in-vivo endomicroscopic applications. PMID- 29475323 TI - Average intensity and beam quality of optical coherence lattices in oceanic turbulence with anisotropy. AB - Based on the extended Huygens-Fresnel principle, we have derived the analytical expression of the average intensity of optical coherence lattices (OCLs) in oceanic turbulence with anisotropy, and then the beam quality parameters including the Strehl ratio (SR) and the power-in-the-bucket (PIB) are obtained. One can find that the OCLs will eventually evolve into Gaussian shape with the periodicity reciprocity gradually breaking down when propagating through the anisotropic ocean water, and that the trend of evolving into Gaussian can be accelerated for increasing the ratio of temperature and salinity contributions to the refractive index spectrum omega, the lattice constant a and the rate of dissipation of mean square temperature chiT or decreasing the anisotropic factor xi and the rate of dissipation of turbulent kinetic energy per unit mass of fluid epsilon. Further, the SR and PIB in the target plane under the effects of oceanic parameters are discussed in detail, and the SR and PIB can be increased for the larger xi and epsilon or the smaller chiT and omega, namely, the beam quality becomes better. Our results can find potential application in the future optical communication system in an oceanic environment. PMID- 29475324 TI - Distributed measurement of polarization mode coupling in fiber ring based on P OTDR complete polarization state detection. AB - Using a quaternion method, the polarization mode-coupling coefficient can be derived from three components of the Stokes vectors at three adjacent points along a fiber. A complete polarization optical time-domain reflectometry scheme for polarization mode coupling distributed measurement in polarization maintaining fiber ring is proposed based on the above theoretical derivations. By comparing the measurement results of two opposite incident directions and two orthogonal polarization axes of polarization-maintaining fiber rings with different lengths, the feasibility and repeatability of the measurement scheme are verified experimentally with a positioning spatial resolution of 1 meter. PMID- 29475325 TI - Spontaneous feedback for the simultaneous narrowing and elevation of fluorescence spectral lines. AB - Narrow linewidth and high intensity of the fluorescence spectra are two important elements to improve the accuracy and efficiency of related practical measurements, but so far they have not been achievable simultaneously. We propose a new approach to sharpen the linewidth and to heighten the intensity simultaneously. Rather than double coherent mechanisms, it uses the spontaneous emission of inverted atoms in a cavity below the threshold as a resource for feedback control. The spontaneous feedback is simpler in principle and easier to realize technologically, and represents a kind of new way of controlling spontaneous emission. PMID- 29475326 TI - Precision PGC demodulation for homodyne interferometer modulated with a combined sinusoidal and triangular signal. AB - A precision PGC demodulation for homodyne interferometer modulated with a combined sinusoidal and triangular signal is proposed. Using a triangular signal as additional modulation, a continuous phase-shifted interference signal for ellipse fitting is generated whether the measured object is in static or moving state. The real-time ellipse fitting and correction of the AC amplitudes and DC offsets of the quadrature components in PGC demodulation can be realized. The merit of this modulation is that it can eliminate thoroughly the periodic nonlinearity resulting from the influences of light intensity disturbance, the drift of modulation depth, the carrier phase delay, and non-ideal performance of the low pass filters in the conversional PGC demodulation. The principle and realization of the signal processing with the combined modulation signal are described in detail. The experiments of accuracy and rate evaluations of ellipse fitting, nanometer, and millimeter displacement measurements were performed to verify the feasibility of the proposed demodulation. The experimental results show that the elliptical parameters of the quadrature components can be achieved precisely in real time and nanometer accuracy was realized in displacement measurements. PMID- 29475327 TI - Inverse design of near unity efficiency perfectly vertical grating couplers. AB - Efficient coupling between integrated optical waveguides and optical fibers is essential to the success of silicon photonics. While many solutions exist, perfectly vertical grating couplers that scatter light out of a waveguide in the direction normal to the waveguide's top surface are an ideal candidate due to their potential to reduce packaging complexity. Designing such couplers with high efficiencies, however, has proven difficult. In this paper, we use inverse electromagnetic design techniques to optimize a high efficiency two-layer perfectly vertical silicon grating coupler. Our base design achieves a chip-to fiber coupling efficiency of 99.2% (-0.035 dB) at 1550 nm. Using this base design as a starting point, we run subsequent constrained optimizations to realize vertical couplers with coupling efficiencies over 96% and back reflections of less than -40 dB which can be fabricated using 65 nm-resolution lithography. These results demonstrate a new path forward for designing fabrication-tolerant ultra high efficiency grating couplers. PMID- 29475328 TI - Inverse spin Hall effect induced by linearly polarized light in the topological insulator Bi2Se3. AB - The inverse spin Hall effect (ISHE) induced by the normal incidence of linearly polarized infrared radiation has been observed in the topological insulator Bi2Se3. A model has been proposed to explain the phenomenon, and the spin transverse force has been determined by the model fitting. The anomalous linear photogalvanic effect (ALPGE) is also observed, and the photoinduced momentum anisotropy is extracted. Furthermore, the ISHE and ALPGE are investigated at different temperatures between 77 and 300 K, and the temperature dependence of the spin transverse force and photoinduced momentum anisotropy are obtained. This study suggests a new way to investigate the inverse spin Hall effect via linearly polarized light even at room temperature. PMID- 29475329 TI - InGaAsP Mach-Zehnder interferometer optical modulator monolithically integrated with InGaAs driver MOSFET on a III-V CMOS photonics platform. AB - We demonstrated the monolithic integration of a carrier-injection InGaAsP Mach Zehnder interferometer (MZI) optical modulator and InGaAs metal-oxide semiconductor field-effect transistor (MOSFET) on a III-V-on-insulator (III-V-OI) wafer. A low-resistivity lateral PIN junction was formed along an InGaAsP rib waveguide by Zn diffusion and Ni-InGaAsP alloy, enabling direct driving of the InGaAsP optical modulator by the InGaAs MOSFET. A pi phase shift of the InGaAsP optical modulator was obtained through the injection of a drain current from the InGaAs MOSFET with a gate voltage of approximately 1 V. This proof-of-concept demonstration of the monolithic integration of the InGaAsP optical modulator and InGaAs driver MOSFET will enable us to develop high-performance and low-power electronic-photonic integrated circuits on a III-V CMOS photonics platform. PMID- 29475330 TI - Demonstration of a carrier frequency offset estimator for 16-/32-QAM coherent receivers: a hardware perspective. AB - We propose and implement a hardware-efficient frequency offset estimator (FOE) optimized for 16- and 32-QAM coherent optical receivers with low hardware cost and high estimation accuracy. The proposed FOE combines a wide-range coarse estimator and a narrow-range highly accurate estimator in a feedforward architecture. We numerically and experimentally investigate the performance of the proposed estimator by using a field-programmable-logic-array (FPGA) based real-time coherent receiver. Compared with other state-of-the-art estimators in literature, the proposed method reduces over 40% of hardware utilizations while maintaining the same level of estimation accuracy in terms of mean-squared-error (MSE) and optical signal-to-noise ratio (OSNR) sensitivity. These results enable the development of next generation DSP circuit capable of supporting high capacity coherent optical communication link with advanced modulation formats. PMID- 29475331 TI - High-resolution additive light field near-eye display by switchable Pancharatnam Berry phase lenses. AB - Conventional head-mounted displays present different images to each eye, and thereby create three-dimensional (3D) sensation for viewers. This method can only control the stimulus to vergence but not accommodation, which is located at the apparent location of the physical displays. The disrupted coupling between vergence and accommodation could cause considerable visual discomfort. To address this problem, in this paper a novel multi-focal plane 3D display system is proposed. A stack of switchable liquid crystal Pancharatnam-Berry phase lenses is implemented to create real depths for each eye, which is able to provide approximate focus cue and relieve the discomfort from vergence-accommodation conflict. The proposed multi-focal plane generation method has great potential for both virtual reality and augmented reality applications, where correct focus cue is highly desirable. PMID- 29475332 TI - High-order-helix point spread functions for monocular three-dimensional imaging with superior aberration robustness. AB - An approach for designing purely refractive optical elements that generate engineered, multi-order-helix point spread functions (PSFs) with large peak separation for passive, optical depth measurement is presented. The influence of aberrations on the PSF's rotation angle, which limits the depth retrieval accuracy, is studied numerically and analytically. It appears that only Zernike modes with an azimuthal index that is an integer multiple of the number of PSF peaks introduce PSF rotation, and hence depth estimation errors. This implies that high-order-helix designs have superior robustness with respect to aberrations. This is experimentally demonstrated by imaging an extended scene in the presence of severe system aberrations using novel, cost-efficient phase elements based on UV-replication on the wafer-scale. PMID- 29475333 TI - Temperature dependence of the spectral characteristics of distributed-feedback resonators. AB - We characterize the spectral response of a distributed-feedback resonator when subject to a thermal chirp. An Al2O3 rib waveguide with a corrugated surface Bragg grating inscribed into its SiO2 top cladding is experimentally investigated. We induce a near-to-linear temperature gradient along the resonator, leading to a similar variation of the grating period, and characterize its spectral response in terms of wavelength and linewidth of the resonance peak. Simulations are carried out, showing good agreement with the experimental results and indicating that the wavelength of the resonance peak is a result only of the total accumulated phase shift. For any chirp profile we are able to calculate the reflectivities at the resonance wavelength, and this information largely explains how the linewidth of the resonance changes. This result shows that the increase in linewidth is governed by the increase of the resonator outcoupling losses. PMID- 29475334 TI - Analysis of microcantilevers excited by pulsed-laser-induced photoacoustic waves. AB - This study presents a simulation-based analysis on the excitation of microcantilever in air using pulsed-laser-induced photoacoustic waves. A model was designed and coded to investigate the effects of consecutive photoacoustic waves, arising from a spherical light absorber illuminated by short laser pulses. The consecutiveness of the waves were adjusted with respect to the pulse repetition frequency of the laser to examine their cumulative effects on the oscillation of microcantilever. Using this approach, oscillation characteristics of two rectangular cantilevers with different resonant frequencies (16.9 kHz and 505.7 kHz) were investigated in the presence of the random oscillations. The results show that the effective responses of the microcantilevers to the consecutive photoacoustic waves provide steady-state oscillations, when the pulse repetition frequency matches to the fundamental resonant frequency or its lower harmonics. Another major finding is that being driven by the same photoacoustic pressure value, the high frequency cantilever tend to oscillate at higher amplitudes. Some of the issues emerging from these findings may find application area in atomic force microscopy actuation and photoacoustic signal detection. PMID- 29475335 TI - Fully controllable adiabatic geometric phase in nonlinear optics. AB - We propose and analyze a new way for obtaining an adiabatic geometric phase for light, via the sum-frequency-generation nonlinear process. The state of light is represented by the complex amplitudes at two different optical frequencies, coupled by the second order nonlinearity of the medium. The dynamics of this system is then shown to be equivalent to that of a spin-1/2 particle in a magnetic field, which in turn can be rotated adiabatically on the Bloch sphere. When the input wave itself is an eigenstate of the magnetic field equivalent, the geometric phase is manifested as a pure phase factor. Two adiabatic rotation schemes, based on specific modulations of the quasi-phase-matching poling parameters, are discussed. In the first, the geometric phase is shown to be sensitive to the pump intensity variations, as a result of the Bloch sphere deformation. The second can be utilized for the realization of nonlinear-optics based geometric phase plates. Moreover, non-closed adiabatic trajectories are investigated, which are expected to provide a robust and broadband geometric wavefront shaping in the sum frequency. PMID- 29475336 TI - Experimental realization of structured super-oscillatory pulses. AB - We demonstrate experimentally a generic method for the synthesis of optical femtosecond pulses based on Gaussian, Airy and Hermite-Gauss functions, which are transformed to exhibit fringes with tunable width. The width of the fringes is set in some cases to be much narrower than the inverse of the spectral bandwidth. Such pulses might be useful for ultrafast spectroscopy, coherent control and nonlinear optics. PMID- 29475337 TI - Transmission analysis for OFDM signals over hybrid RF-optical high-throughput satellite. AB - In this paper, a theoretical investigation of the performance of a communication scenario where a geostationary-orbit satellite provides radio-frequency broadband access to the users through orthogonal-frequency-division multiplexing technology and has an optical feeder link is presented. The interface between the radio frequency and the optical parts is achieved by using radio-on-fiber technology for optical-electro and electro-optical conversion onboard and no further signal processing is required. The proposed scheme has significant potential, but presents limitations related to the noise. The noise in both forward and reverse links is described, and the system performance for an example scenario with 1280 MHz bandwidth for QPSK, 16QAM, and 64QAM subcarrier modulation is estimated. The obtained results show that under certain conditions regarding link budget and components choice, the proposed solution is feasible. PMID- 29475338 TI - Simultaneous Raman based power combining and wavelength conversion of high-power fiber lasers. AB - We present a technique for simultaneous power-combining and wavelength-conversion of multiple fiber lasers into a single, longer wavelength in a different band through Raman-based, nonlinear power combining. We illustrate this by power combining of two independent Ytterbium lasers into a single wavelength around 1.5micron with high output powers of upto 99W. A high conversion efficiency of ~64% of the quantum limited efficiency and a high level of wavelength conversion with >85% of the output power in the final wavelength is demonstrated. The proposed method enables power-scaling in various wavelength bands where conventional fiber lasers are unavailable or limited in power. PMID- 29475339 TI - Tm:KY1-x-yGdxLuy(WO4)2 planar waveguide laser passively Q-switched by single walled carbon nanotubes. AB - A Tm3+ monoclinic double tungstate planar waveguide laser is passively Q-switched (PQS) by a saturable absorber (SA) based on single-walled carbon nanotubes (SWCNTs) randomly oriented in a polymer film. The laser is based on a 18 um-thick 5 at.% Tm:KY1-x-yGdxLuy(WO4)2 active layer grown on an undoped (010)-oriented KY(WO4)2 substrate by liquid phase epitaxy with determined propagation losses 0.7 +/- 0.2 dB/cm. The PQS laser generated a maximum average output power of 45.6 mW at 1.8354 um with a slope efficiency of 22.5%. Stable 83-ns-long laser pulses with an energy of 33 nJ were achieved at a repetition rate of 1.39 MHz. The use of SWCNTs as SA is promising for generation of sub-100 ns pulses in such waveguide lasers at ~2 um. PMID- 29475340 TI - Label-free photoacoustic imaging guided sclerotherapy for vascular malformations: a feasibility study. AB - We used high-resolution photoacoustic imaging (PAI) to guide sclerotherapy of vascular malformations in an in vivo animal model. A focus-adjustable PAI system was developed. It can adapt to the imaging needs of different depths by adjusting the focus. Blood samples drawn before and after sclerosis were examined with PAI, which could distinguish whether or not the blood had been exposed to a sclerosing agent. Superficial and deep vessels in the animal model were examined in vivo to prove the feasibility of guiding sclerotherapy. We found that PAI can distinguish sclerotic vessels from normal vessels within a certain depth range. Our findings suggest the potential of PAI to find accurate injection points and to localize thrombi, making it possible to reduce the dosage of sclerosing agents. PMID- 29475341 TI - Enhanced device performances of a new inverted top-emitting OLEDs with relatively thick Ag electrode. AB - To improve the device performances of top-emitting organic light emitting diodes (TEOLEDs), we developed a new inverted TEOLEDs structure with silver (Ag) metal as a semi-transparent top electrode. Especially, we found that the use of relatively thick Ag electrode without using any carrier injection layer is beneficial to realize highly efficient device performances. Also, we could insert very thick overlying hole transport layer (HTL) on the emitting layer (EML) which could be very helpful to suppress the surface plasmon polariton (SPP) coupling if it is applied to the common bottom-emission OLEDs (BEOLEDs). As a result, we could realize noteworthy high current efficiency of approximately ~188.1 cd/A in our new inverted TEOLEDs with 25 nm thick Ag electrode. PMID- 29475342 TI - At-wavelength optics characterisation via X-ray speckle- and grating-based unified modulated pattern analysis. AB - The current advances in new generation X-ray sources are calling for the development and improvement of high-performance optics. Techniques for high sensitivity phase sensing and wavefront characterisation, preferably performed at wavelength, are increasingly required for quality control, optimisation and development of such devices. We here show that the recently proposed unified modulated pattern analysis (UMPA) can be used for these purposes. We characterised two polymer X-ray refractive lenses and quantified the effect of beam damage and shape errors on their refractive properties. Measurements were performed with two different setups for UMPA and validated with conventional X ray grating interferometry. Due to its adaptability to different setups, the ease of implementation and cost-effectiveness, we expect UMPA to find applications for high-throughput quantitative optics characterisation and wavefront sensing. PMID- 29475343 TI - Projector-defocusing rectification for Fourier single-pixel imaging. AB - Fourier single-pixel imaging (FSI) is an efficient single-pixel imaging method of obtaining high-quality (resolution/signal-to-noise ratio) 2D images, which projects sinusoid patterns on the object and reconstructs the image through reflected light. The typical system of FSI consists of a single-pixel detector and a digital projector. However, the defocusing of the projector lens blurs the projected patterns, which results in reduced imaging quality. In this work, we propose the projector-defocusing rectification for FSI, which optimizes projector defocusing for the first time. The proposed method rectifies Fourier coefficients using the amplitude ratio between original and defocused patterns, which we can acquire through a controlled experiment on a whiteboard. The enhancement of imaging quality in imperfect circumstances is demonstrated by simulations and experiments. PMID- 29475344 TI - White appearance of a tablet display under different ambient lighting conditions. AB - In comparison to the great efforts made on the enhancement of image quality for tablet displays, little attention has been paid on the concept of white point. Given the increasing popularity of the light sources with chromaticities off the Planckian locus and color-tunable LED lighting, it is important to investigate human's white perception of tablet display under different ambient lighting conditions. This study investigated the white appearance of a tablet display under 17 ambient lighting conditions, including a dark condition, seven conditions with chromaticities on the Planckian locus, and nine conditions with chromaticities off the Planckian locus, (i.e., Duv = + 0.02, -0.02, and -0.04). It was found that both the white appearance boundary defined by the fitted one standard-deviation error ellipse and the whitest stimulus rated by the observers or identified by the bivariate Gaussian distribution were different under the various ambient lighting conditions. The optimization based on the whitest stimulus under each ambient lighting condition suggested a lower degree of chromatic adaptation under the conditions with a lower Correlated Color Temperature (CCT). For the conditions with a same CCT, a Duv of -0.02 was found to provide a higher degree of chromatic adaptation than Duv values of + 0.02 and 0.04. PMID- 29475345 TI - All-optical retro-modulation for free-space optical communication. AB - This work presents device and system architectures for free-space optical and optical wireless communication at high data rates over multidirectional links. This is particularly important for all-optical networks, with high data rates, low latencies, and network protocol transparency, and for asymmetrical networks, with multidirectional links from one transceiver to multiple distributed transceivers. These two goals can be met by implementing a passive uplink via all optical retro-modulation (AORM), which harnesses the optical power from an active downlink to form a passive uplink through retroreflection. The retroreflected optical power is modulated all-optically to ideally achieve terabit-per-second data rates. The proposed AORM architecture, for passive uplinks, uses high refractive-index S-LAH79 hemispheres to realize effective retroreflection and an interior semiconductor thin film of CuO nanocrystals to realize ultrafast all optical modulation on a timescale of approximately 770 fs. The AORM architecture is fabricated and tested, and ultimately shown to be capable of enabling multidirectional free-space optical communication with terabit-per-second aggregate data rates. PMID- 29475346 TI - Room-temperature electrically pumped InGaN-based microdisk laser grown on Si. AB - Silicon photonics has been longing for an efficient on-chip light source that is electrically driven at room temperature. Microdisk laser featured with low-loss whispering gallery modes can emit directional lasing beam through a closely coupled on-chip waveguide efficiently, and hence is particularly suitable for photonics integration. The realization of electrically pumped III-nitride microdisk laser grown on Si has been impeded by the conventional undercut structure, poor material quality, and a limited quality of GaN microdisk formed by dry etching. Here we report a successful fabrication of room-temperature electrically pumped InGaN-based microdisk lasers grown on Si. A dramatic narrowing of the electroluminescence spectral line-width and a clear discontinuity in the slope of light output power plotted as a function of the injection current provide an unambiguous evidence of lasing. This is the first observation of electrically pumped lasing in InGaN-based microdisk lasers grown on Si at room temperature. PMID- 29475347 TI - Water metamaterial for ultra-broadband and wide-angle absorption. AB - A subwavelength water metamaterial is proposed and analyzed for ultra-broadband perfect absorption at microwave frequencies. We experimentally demonstrate that this metamaterial shows over 90% absorption within almost the entire frequency band of 12-29.6 GHz. It is also shown that the proposed metamaterial exhibits a good thermal stability with its absorption performance almost unchanged for the temperature range from 0 to 100 degrees C. The study of the angular tolerance of the metamaterial absorber shows its ability of working at wide angles of incidence. Given that the proposed water metamaterial absorber is low-cost and easy for manufacture, we envision it may find numerous applications in electromagnetics such as broadband scattering reduction and electromagnetic energy harvesting. PMID- 29475348 TI - Scattering center models of backscattering waves by dielectric spheroid objects. AB - Scattering center models provide a simple and effective way of describing the complex electromagnetic scattering phenomena of targets and have been successfully applied in radar applications. However, the existing models are limited to conducting objects. Numerical results show that scattering centers of dielectric objects are far more complex than conducting objects and most of them are distributed beyond the object. For the lossless and low-loss media, the major scattering contributions to total fields are surface waves and multiple internal reflections rather than the direct reflection. Concise scattering center models for backscattering from dielectric spheroid objects are proposed in this work, which can characterize the backscattered waves by scattering centers with sparse and physical parameters. Good agreement has been demonstrated between the high resolution range profiles simulated by this model with those obtained by Mie series and the full wave numerical method. PMID- 29475349 TI - Zemax simulations describing collective effects in transition and diffraction radiation. AB - Transition and diffraction radiation from charged particles is commonly used for diagnostics purposes in accelerator facilities as well as THz sources for spectroscopy applications. Therefore, an accurate analysis of the emission process and the transport optics is crucial to properly characterize the source and precisely retrieve beam parameters. In this regard, we have developed a new algorithm, based on Zemax, to simulate both transition and diffraction radiation as generated by relativistic electron bunches, therefore considering collective effects. In particular, unlike other previous works, we take into account electron beam physical size and transverse momentum, reproducing some effects visible on the produced radiation, not observable in a single electron analysis. The simulation results have been compared with two experiments showing an excellent agreement. PMID- 29475350 TI - Nonlinear frequency up-conversion via double topological edge modes. AB - We study the nonlinear frequency up-conversion in a plasmonic thin film sandwiched between one-dimensional photonic crystals (PCs) of different Zak phases by rigorous numerical time-domain nonlinear hydrodynamic calculations. We show that the proposed hetero-structure can support robust fundamental and high order topological edge modes that simultaneously enhance the third-harmonic generation. Numerical simulations also show that femtosecond pulses can excite double topological edge modes through optical tunneling in band gaps, leading to a large nonlinear response. The obtained third harmonic generation (THG) conversion efficiency of the hetero-structure is three orders of magnitude larger than that of a single plasmonic film. The results presented here may open new avenues for designing high-efficiency nonlinear photonic devices. PMID- 29475351 TI - Low-loss 'crystalline-core/crystalline-clad' (C4) fibers for highly power scalable high efficiency fiber lasers. AB - We report the latest progress in fabrication and laser performance of the fully crystalline double-clad 'Yb:YAG-core/undoped-YAG-clad' fibers grown by the hybrid crystal growth method. The single-crystalline ytterbium (Yb) doped yttrium aluminum garnet (YAG) fiber cores were grown by the laser heated pedestal growth (LHPG) method, and the single-crystalline undoped YAG claddings were grown by the liquid phase epitaxy (LPE) technique, in which the single-crystalline Yb:YAG cores were used as the growth seeds. The key parameters of the hybrid-grown 'crystalline core/crystalline clad' (C4) fibers, including material composition, crystal structure, and fiber propagation loss, were characterized. The results confirmed that the grown C4 fibers, indeed, have both the single-crystalline fiber core and single-crystalline fiber clad. By utilizing a double-clad low-loss C4 fiber as a diode-cladding-pumped laser gain medium, we realized a fiber laser with the optical-to-optical conversion efficiency of 68.7% versus the incident pump power. PMID- 29475352 TI - Ultra-narrow photonic nanojets through a glass cuboid embedded in a dielectric cylinder. AB - A glass cuboid, embedded inside a dielectric cylinder is studied when illuminated with a monochromatic plane wave. A photonic nanojet (PNJ) with a full-width at half-maximum (FWHM) waist of around 0.25lambda0 is obtained outside the external surface of the cuboid. The influence of the parameters of a square section cuboid is studied. Three particular phenomena can be obtained and are discussed: an ultra-narrow PNJ on the external surface of the cuboid, a long photonic jet and the excitation of whispering gallery modes (WGMs). A parametric study, over the width and the height of a rectangular section cuboid, shows that these parameters can be used to control the photonic jet properties. We also study several other geometries of the insert, which shows that the key parameter is the refractive index of the inserted material. Finally, we show that by changing the incident angle we can obtain a curved photonic jet. PMID- 29475353 TI - Bragg resonance in microfiber realized by two-photon polymerization. AB - A new method for microfiber Bragg gratings (MU-FBGs) fabrication by means of two photon polymerization in photosensitive resin is reported. Such polymerized MU FBGs were cured along with the surface of microfibers without any damage or distortion to the substrate. The laser intensity was optimized to improve the spectral properties of the polymerized gratings. The refractive index measurement was performed and the maximum sensitivity obtained is ~207 nm/RIU at the refractive index value of 1.440 with the fiber diameter being 1.7 MUm. This work opens a new idea for optical structure integration and further optical functionality integration. PMID- 29475354 TI - Optimization of lithography source illumination arrays using diffraction subspaces. AB - An efficient and robust lithography illumination optimization (ILO) approach is developed based on subspace compressive sensing (CS) and an lp-norm reconstruction algorithm. Instead of optimizing the source pattern over all its degrees of freedom, the proposed method only optimizes the source pixels in a subspace. The subspace includes the source pixels inducing interference between different diffraction orders of the mask pattern. The ILO is then formulated as an lp-norm (0 < p < 1) inverse reconstruction problem under the sparse representation of the source pattern. The subspace CS method benefits from having a significantly smaller number of optimization variables, thus effectively improving the computation speed. In addition, an lp-norm reconstruction algorithm is used, which is more robust than l1-norm reconstruction algorithms. Based on the simulations at 45nm and 14nm technology nodes, the proposed methods prove to improve the computational efficiency, robustness and imaging performance of current ILO methods based on adaptive CS. PMID- 29475355 TI - Axial localization using time reversal multiple signal classification in optical scanning holography. AB - This paper presents a method to identify the axial location of targets in an optical scanning holography (OSH) system. By combining time reversal (TR) technique with the multiple signal classification (MUSIC) method in OSH, axial location can be detected with high resolution. Both simulation and experimental work have been carried out to verify the feasibility of the proposed work. PMID- 29475356 TI - Four dimensional phase unwrapping of dynamic objects in digital holography. AB - We present a new four-dimensional phase unwrapping approach for time-lapse quantitative phase microscopy, which allows reconstruction of optically thick objects that are optically thin in a certain temporal point and angular view. We thus use all four dimensions of the dynamic quantitative phase profile acquired, including the angular dimension and the temporal dimension, in addition to the x y dimensions. We first demonstrate the capabilities of this algorithm on simulative data, enabling the quantification of the reconstruction quality relative to both the ground truth and existing unwrapping approaches. Then, we demonstrate the applicability of the proposed four-dimensional phase unwrapping algorithm by experimentally capturing a dual-angular dynamic off-axis hologram with simultaneous recording of two angular views, using multiplexing of two off axis holograms into a single multiplexed hologram. PMID- 29475357 TI - Virtual phase conjugation based optical tomography for single-shot three dimensional imaging. AB - We propose a virtual phase conjugation (VPC) based optical tomography (VPC-OT) for realizing single-shot optical tomographic imaging systems. Using a computer based numerical beam propagation, the VPC combines pre-modulation and post demodulation of the probe beam's wavefront, which provides an optical sectioning capability for resolving the depth coordinates. In VPC-OT, the physical optical microscope system and VPC are coupled using digital holography. Therefore, in contrast to conventional optical tomographic imaging (OTI) systems, this method does not require additional elements such as low-coherence light sources or confocal pinholes. It is challenging to obtain single-shot three-dimensional (3D) tomographic images using a conventional OTI system; however, this can be achieved using VPC-OT, which employs both digital holography and computer based numerical beam propagation. In addition, taking into account that VPC-OT is based on a complex amplitude detection using digital holography, this method allows us to simultaneously obtain quantitative phase contrast images. Using an objective lens with a numerical aperture (NA) of 0.8, we demonstrate a single-shot 3D imaging of frog blood cells with a depth resolution of 0.94 MUm. PMID- 29475358 TI - Separating azimuthal orientation dependence in polarization measurements of anisotropic media. AB - Polarization imaging and Mueller polarimetry provide powerful tools for probing the microstructure of complex anisotropic media, which is a core task in material science, biomedical diagnosis and many research fields. However, Mueller matrix elements and many polarization parameters are sensitive to the spatial orientation of the sample and experimental configurations, hindering the effectiveness for distinguishing different sources of anisotropies. In this paper, we propose a set of rotation invariant parameters and corresponding orientation parameters, which are explicit functions of the Mueller matrix elements. They are valid under the condition that the illumination and detection directions are collinear with the rotation axis of the sample. More detailed examinations show that these parameters have potential applications for fast analyzing different anisotropy contributions in the media, such as birefringence, dichroism, and their coexistence. The conclusions are validated with Monte Carlo simulations and the experimental results of transparent tape samples. PMID- 29475359 TI - Incubation during laser ablation with bursts of femtosecond pulses with picosecond delays. AB - We report on an experimental investigation of the incubation effect during irradiation of stainless steel with bursts of ultrashort laser pulses. A series of birefringent crystals was used to split the pristine 650-fs pulses into bursts of up to 32 sub-pulses with time separations of 1.5 ps and 3 ps, respectively. The number of selected bursts was varied between 50 and 1600. The threshold fluence was measured in case of Burst Mode (BM) processing depending on the burst features, i.e. the number of sub-pulses and their separation time, and on the number of bursts. We found as many values of threshold fluence as the combinations of the number of bursts and of sub-pulses constituting the bursts set to give the same total number of impinging sub-pulses. However, existing incubation models developed for Normal Pulse Mode (NPM) return, for a given number of impinging pulses, a constant value of threshold fluence. Therefore, a dependence of the incubation coefficient with the burst features was hypothesized and experimentally investigated. Numerical solutions of the Two Temperature Model (TTM) in case of irradiation with single bursts of up to 4 sub-pulses have been performed to interpret the experimental results. PMID- 29475360 TI - Silver-based surface plasmon waveguide for terahertz quantum cascade lasers. AB - Terahertz-frequency quantum cascade lasers (THz QCLs) based on ridge waveguides incorporating silver waveguide layers have been investigated theoretically and experimentally, and compared with traditional gold-based devices. The threshold gain associated with silver-, gold- and copper-based devices, and the effects of titanium adhesion layers and top contact layers, in both surface-plasmon and double-metal waveguide geometries, have been analysed. Our simulations show that silver-based waveguides yield lower losses for THz QCLs across all practical operating temperatures and frequencies. Experimentally, QCLs with silver-based surface-plasmon waveguides were found to exhibit higher operating temperatures and higher output powers compared to those with identical but gold-based waveguides. Specifically, for a three-well resonant phonon active region with a scaled oscillator strength of 0.43 and doping density of 6.83 * 1015 cm-3, an increase of 5 K in the maximum operating temperature and 40% increase in the output power were demonstrated. These effects were found to be dependent on the active region design, and greater improvements were observed for QCLs with a larger radiative diagonality. Our results indicate that silver-based waveguide structures could potentially enable THz QCLs to operate at high temperatures. PMID- 29475361 TI - Phase modulated high density collinear holographic data storage system with phase retrieval reference beam locking and orthogonal reference encoding. AB - A novel phase modulation method for holographic data storage with phase-retrieval reference beam locking is proposed and incorporated into an amplitude-encoding collinear holographic storage system. Unlike the conventional phase retrieval method, the proposed method locks the data page and the corresponding phase retrieval interference beam together at the same location with a sequential recording process, which eliminates piezoelectric elements, phase shift arrays and extra interference beams, making the system more compact and phase retrieval easier. To evaluate our proposed phase modulation method, we recorded and then recovered data pages with multilevel phase modulation using two spatial light modulators experimentally. For 4-level, 8-level, and 16-level phase modulation, we achieved the bit error rate (BER) of 0.3%, 1.5% and 6.6% respectively. To further improve data storage density, an orthogonal reference encoding multiplexing method at the same position of medium is also proposed and validated experimentally. We increased the code rate of pure 3/16 amplitude encoding method from 0.5 up to 1.0 and 1.5 using 4-level and 8-level phase modulation respectively. PMID- 29475362 TI - Unidirectional reflectionless phenomena in a non-Hermitian quantum system of quantum dots coupled to a plasmonic waveguide. AB - Unidirectional reflectionless phenomena are investigated theoretically in a non Hermitian quantum system composed of several quantum dots and a plasmonic waveguide. By adjusting the phase shifts between quantum dots, single- and dual band unidirectional reflectionlessnesses are realized at exceptional points based on two and three quantum dots coupled to a plasmonic waveguide, respectively. In addition, single- and dual-band unidirectional perfect absorptions with high quality factors are obtained at the vicinity of exceptional points. PMID- 29475363 TI - Upconversion detector for range-resolved DIAL measurement of atmospheric CH4. AB - We demonstrate a robust, compact, portable and efficient upconversion detector (UCD) for a differential absorption lidar (DIAL) system designed for range resolved methane (CH4) atmospheric sensing. The UCD is built on an intracavity pump system that mixes a 1064 nm pump laser with the lidar backscatter signal at 1646 nm in a 25-mm long periodically poled lithium niobate crystal. The upconverted signal at 646 nm is detected by a photomultiplier tube (PMT). The UCD with a noise equivalent power around 127 fW/Hz1/2 outperforms a conventional InGaAs based avalanche photodetector when both are used for DIAL measurements. Using the UCD, CH4 DIAL measurements have been performed yielding differential absorption optical depths with relative errors of less than 11% at ranges between 3 km and 9 km. PMID- 29475364 TI - Compression of picosecond pulses from a thin-disk laser to 30fs at 4W average power. AB - We investigate two approaches for the spectral broadening and compression of 1-ps long pulses of a thin-disk laser amplifier running at 50 kHz repetition rate at 1030 nm wavelength. We find that with a single, 2.66-m long stretched flexible hollow fiber filled with xenon gas, Fourier transform limited output pulse duration of 66 fs can be directly reached. For larger pulse shortening, we applied a hybrid cascaded approach involving a BBO-based pre-compressor and a long hollow fiber. We could achieve 33-times temporal shortening of 1-ps pulses down to a duration of 30 fs at an overall efficiency of ~29% with an output power level of 3.7 W. These results demonstrate the potential of stretched flexible fibers with their free length scalability for shortening laser pulses of moderate peak power. PMID- 29475365 TI - A New Case of Chanarin-Dorfman Syndrome with a Novel Deletion in ABHD5 Gene AB - Chanarin-Dorfman syndrome (CDS) is a rare autosomal recessive metabolic disorder caused by mutations in gene encoding the domain-5 of alpha/beta-hydrolase enzyme (ABHD5). It is known as a natural lipid storage disorder arising from impaired lipid metabolism often characterized by hepatomegaly, myopathy, ataxia, non bullous ichthyosiform erythroderma, hearing loss, and mental retardation. In the present study, we report two affected 28-month-old monozygotic twin boys as new cases of CDS. Genetic analysis was performed in patients, and the results showed a homozygote deletion in exon 4 of ABHD5. According to the the American College of Medical Genetics and Genomics, this variant is categorized as a pathogenic variant. PMID- 29475366 TI - Assessing the Diagnostic Value of Plasma-Free DNA in Prostate Cancer Screening AB - Background: Prostate cancer is the second form of cancer among men worldwide. For early cancer detection, we should identify tumors in initial stages before the physical signs become visible. The present study aims to evaluate the diagnostic value of cell-free DNA (cfDNA), its comparison with prostate-specific antigen (PSA) level in prostate cancer screening and also in patients with localized prostate cancer, metastatic form, and benign prostatic hyperplasia (BPH). Methods: The participants of this study were selected from 126 patients with genitourinary symptoms suspected prostate cancer, rising PSA, and/or abnormal rectal examination results and 10 healthy subjects as controls. Peripheral blood plasma before any treatment measures was considered. cfDNA was extracted using a commercial kit, and PSA levels were measured by ELISA. The ANOVA test was used to compare the average serum level of PSA and plasma concentration of cfDNA between the groups. The correlation between variables was measured by the Pearson test. Results: The subgroups consisted of 50 patients with localized prostate cancer, 26 patients with metastatic prostate cancer, 50 patients with BPH, and 10 healthy subjects; the average concentrations of cfDNA in these subgroups were 15.04, 19.62, 9.51, and 8.7 ng/MUl, respectively. According to p < 0.0001 obtained from multivariate test, there was a significant difference between all the groups. Conclusion: Our findings indicated significant differences between cfDNA levels of patients with localized and metastatic prostate cancer, and differences of these two groups from BPH and healthy cases show the importance of this biomarker in non-invasive diagnostic procedures. PMID- 29475367 TI - miR-148b-3p affects the pathogenesis of adjuvant-induced arthritis rats through the direct target DNMT1. AB - Our previous study showed that up-regulated DNA methyltransferase-1 (DNMT1) played an important role in the hypermethylation modification of SFRP4 in adjuvant-induced arthritis (AIA) rats. This work focused on the role of disordered miR-148b-3p in RA pathology and its corresponding regulatory targets. The expression of miR-148b-3p and DNMT1, and the effect of miR-148b-3p on the DNMT1 expression were determined by real-time qPCR, western blotting and double luciferase reporter genes. The role of miR-148b-3p on the SFRP4 expression, the canonical Wnt signaling and the pathology of AIA rats was investigated using real time qPCR, western blotting and methylation-specific PCR (MSP). The results showed that the expression of miR-148b-3p was significantly decreased, the expression of DNMT1 was significantly increased and the DNMT1 was the direct target of miR-148b-3p in AIA rats compared with normal group. Transfection of miR 148b-3p mimics up-regulated the SFRP4 expression, inhibited the canonical Wnt signaling and the pathogenesis of AIA rats by targeting the DNMT1. The role of miR-148b-3p knockdown was opposite to that of miR-148b-3p overexpression. These results suggest that miR-148b-3p may influence the pathogenesis of RA with the DNMT1 as a direct target and miR-148b-3p may be a potential diagnostic and therapeutic target for RA patients. PMID- 29475368 TI - Immunological compatibility status of placenta-derived stem cells is mediated by scaffold 3D structure. AB - Placenta-derived amniotic epithelial cells (AECs), a great cell source for tissue engineering and stem cell therapy, are immunologically inert in their native state; however, immunological changes in these cells after culture and differentiation have challenged their applications. The aim of this study was to investigate the effect of 2D and 3D scaffolds on human lymphocyte antigens (HLA) expression by AECs. The effect of different preparation parameters including pre freezing time and temperature was evaluated on 3D chitosan-gelatine scaffolds properties. Evaluation of MHC class I, HLA-DR and HLA-G expression in AECs after 7 d culture on 2D bed and 3D scaffold of chitosan-gelatine showed that culture of AECs on the 2D substrate up-regulated MHC class I and HLA-DR protein markers on AECs surface and down-regulated HLA-G protein. In contrast, 3D scaffold did not increase protein expression of MHC class I and HLA-DR. Moreover, HLA-G protein expression remained unchanged in 3D culture. These results confirm that 3D scaffold can remain AECs in their native immunological state and modification of physical properties of the scaffold is a key regulator of immunological markers at the gene and protein expression levels; a strategy which circumvents rejection challenge of amniotic stem cells to be translated into the clinic. PMID- 29475369 TI - Falling through the gaps: exploring the role of integrated commissioning in improving transition from children's to adults' services for young people with long-term health conditions in England. AB - Objectives To explore the role of integrated commissioning in improving the transition of young people with long-term conditions from child to adult services. We aimed to identify organizational and policy gaps around transition services and provide recommendations for integrated commissioning practice. Methods Semi-structured in-depth interviews were conducted with two groups of participants: (1) twenty-four stakeholders involved in the commissioning and provision of transition services for young people with long-term conditions in two regions in England; (2) five professionals with national roles in relation to planning for transition. Transcripts were interrogated using thematic analysis. Results There is little evidence of integrated commissioning for transitional care for young people with long-term conditions. Commissioners perceive there to be a lack of national and local policy to guide integrated commissioning for transitional care; and limited resources for transition. Furthermore, commissioning organizations responsible for transition have different cultures, funding arrangements and related practices which make inter- and intra-agency co ordination and cross-boundary continuity of care difficult to achieve. Conclusions Integrated commissioning may be an effective way to achieve successful transitional care for young people with long-term health conditions. However, this innovative relational approach to commissioning requires a national steer together with recognition of common values and joint ownership between relevant stakeholders. PMID- 29475370 TI - Content validation of the Patient-Reported Hamilton Inventory for Complex Regional Pain Syndrome: Validite de contenu du Hamilton Inventory for Complex Regional Pain Syndrome, une mesure des resultats declares par le patient. AB - BACKGROUND: Complex regional pain syndrome (CRPS) is a perplexing neurological condition, and persons with CRPS experience substantial loss of daily roles and activities. A condition-specific measure is being developed to evaluate CRPS. PURPOSE: We describe the use of cognitive interviews to examine content validity of this patient-reported outcome measure for CRPS. METHOD: Interviews with 44 persons with CRPS were analyzed to identify problems with wording and support content validation. Item-total correlations were calculated for proposed subscales, and scores were plotted to consider floor/ceiling effects. FINDINGS: Interviews identified questions where respondents considered factors unrelated to the construct of interest or were underaddressed by the questionnaire, including depression and skin temperature. The symptoms, daily function, and coping/social impact scales demonstrated satisfactory correlations (Cronbach's alpha 0.76 0.86). Despite a sampling bias of severity, no frank floor/ceiling effects were noted. IMPLICATIONS: This study builds a foundation for continuing development and evaluation of the measurement properties of the Patient-Reported Hamilton Inventory for CRPS. It makes explicit the iterative decisions involved in rigorous instrument development. PMID- 29475371 TI - Surgical treatments for essential tremor. AB - INTRODUCTION: Essential tremor is the most common form of pathologic tremor. Surgical therapies disrupt tremorogenic oscillation in the cerebellothalamocortical pathway and are capable of abolishing severe tremor that is refractory to available pharmacotherapies. Surgical methods are raspidly improving and are the subject of this review. Areas covered: A PubMed search on 18 January 2018 using the query essential tremor AND surgery produced 839 abstracts. 379 papers were selected for review of the methods, efficacy, safety and expense of stereotactic deep brain stimulation (DBS), stereotactic radiosurgery (SRS), focused ultrasound (FUS) ablation, and radiofrequency ablation of the cerebellothalamocortical pathway. Expert commentary: DBS and SRS, FUS and radiofrequency ablations are capable of reducing upper extremity tremor by more than 80% and are far more effective than any available drug. The main research questions at this time are: 1) the relative safety, efficacy, and expense of DBS, SRS, and FUS performed unilaterally and bilaterally; 2) the relative safety and efficacy of thalamic versus subthalamic targeting; 3) the relative safety and efficacy of atlas-based versus direct imaging tractography based anatomical targeting; and 4) the need for intraoperative microelectrode recordings and macroelectrode stimulation in awake patients to identify the optimum anatomical target. Randomized controlled trials are needed. PMID- 29475372 TI - Accommodations and support services preferred by college students with autism spectrum disorder. AB - This 2-year study investigated the accommodations and support services preferred by college students with autism spectrum disorder using sequential mixed methods non-experimental survey and semi-structured follow-up interviews. Students with autism spectrum disorder reported using both academic and non-academic supports with frequency (e.g. extended time on exams, transition program), using academic supports in line with other disability populations, and using non-academic supports connecting them one-to-one with a faculty member or coach as preferred (e.g. academic coach, counselor, faculty mentor). Findings suggest a need for university disability service centers, counseling services, and faculty to work together to develop systematic support systems for college students with autism spectrum disorder. PMID- 29475374 TI - Radial spoke proteins regulate otolith formation during early zebrafish development. AB - Radial spokes are structurally conserved, macromolecular complexes that are essential for the motility of 9 + 2 motile cilia. In Chlamydomonas species, mutations in radial spoke proteins result in ciliary motility defects. However, little is known about the function of radial spoke proteins during embryonic development. Here, we investigated the role of a novel radial spoke protein, leucine-rich repeat containing protein 23 (Lrrc23), during zebrafish embryonic development. Mutations in lrrc23 resulted in a selective otolith formation defect during early ear development. Similar otolith defects were also present in the radial spoke head 3 homolog ( rsph3) and radial spoke head 4 homolog A ( rsph4a) radial spoke mutants. Notably, the radial spoke protein mutations specifically affected ciliary motility in the otic vesicle (OV), whereas motile cilia in other organs functioned normally. Via high-speed video microscopy, we found that motile cilia formation was stochastic and transient in the OV. Importantly, all the motile cilia in the OV beat circularly, in contrast to the planar beating pattern of typical 9 + 2 motile cilia. We identified the key time frame for motile cilia formation during OV development. Finally, we showed that the functions of radial spoke proteins were conserved between zebrafish and Tetrahymena. Together, our results suggest that radial spoke proteins are essential for ciliary motility in the OV and that radial spoke-regulated OV motile cilia represent a unique type of cilia during early zebrafish embryonic development.-Han, X., Xie, H., Wang, Y., Zhao, C. Radial spoke proteins regulate otolith formation during early zebrafish development. PMID- 29475373 TI - Inflammatory bone loss associated with MFG-E8 deficiency is rescued by teriparatide. AB - A prolonged increase in proinflammatory cytokines is associated with osteoporotic and autoimmune bone loss and, conversely, anti-inflammatory pathways are associated with protection against bone loss. Milk fat globule-epidermal growth factor (MFG-E)-8 is a glycoprotein that is proresolving, regulates apoptotic cell clearance, and has been linked to autoimmune disease and skeletal homeostasis. The role of MFG-E8 in the young vs. adult skeleton was determined in mice deficient in MFG-E8 (KO). In vivo, trabecular bone was similar in MFG-E8KO and wild-type (WT) mice at 6 and 16 wk, whereas 22 wk adult MFG-E8KO mice displayed significantly reduced trabecular BV/TV. The number of osteoclasts per bone surface was increased in 22-wk MFG-E8 KO vs. WT mice, and recombinant murine MFG E8 decreased the number and size of osteoclasts in vitro. Adult MFG-E8KO spleen weight:body weight was increased compared with WT, and flow cytometric analysis showed significantly increased myeloid-derived suppressor cells (CD11bhiGR-1+) and neutrophils (CD11bhiLy6G+) in MFG-E8KO bone marrow, suggesting an inflammatory phenotype. PTH-treated MFG-E8KO mice showed a greater anabolic response (+124% BV/TV) than observed in PTH-treated WT mice (+64% BV/TV). These data give insight into the role of MFG-E8 in the adult skeleton and suggest that anabolic PTH may be a valuable therapeutic approach for autoimmune-associated skeletal disease.-Michalski, M. N., Seydel, A. L., Siismets, E. M., Zweifler, L. E., Koh, A. J., Sinder, B. P., Aguirre, J. I., Atabai, K., Roca, H., McCauley, L. K. Inflammatory bone loss associated with MFG-E8 deficiency is rescued by teriparatide. PMID- 29475375 TI - Barriers and facilitators to clinical trial participation among parents of children with pediatric neuromuscular disorders. AB - BACKGROUND/AIMS: Pediatric rare disease presents a challenging situation of high unmet need and a limited pool of potential clinical trial participants. Understanding perspectives of parents of children who have not participated in trials may facilitate approaches to optimize participation rates. The objective of this study was to explore factors associated with parental interest in enrolling children with pediatric neuromuscular disorders in clinical trials. METHODS: Parents of individuals with Duchenne or Becker muscular dystrophy and spinal muscular atrophy were recruited through advocacy organizations, a registry, and clinics. These parents ( N = 203) completed a questionnaire including assessments of barriers and facilitators to clinical trial participation, parents' interest in trial participation, and their perceptions of others' views about participation in a clinical trial. RESULTS: Trial interest in participating parents was high (64% combined group). The most highly endorsed barrier to participation was the possibility of receiving placebo, followed by not having enough information on risks and trial procedures. Compared to parents of children with Duchenne or Becker muscular dystrophy, parents of children with spinal muscular atrophy endorsed significantly more information and knowledge barriers. The greatest facilitators of participation were (1) confidence in improving disease understanding and (2) guarantee to receive the treatment after a successful trial. A logistic regression model, chi2 (4, n = 188) = 80.64, p < .001, indicated that higher perceived barriers and more frequent trial communication by the provider were associated with lower interest, while positive trial perceptions by the child's providers and concordance in trial perceptions among those close to the decision-maker were associated with higher interest. CONCLUSION: We found high parental interest in pediatric neuromuscular trials that was tempered by concerns about the potential for randomization to a placebo arm. Participants perceived that their trial participation would be facilitated by additional education and guidance from their clinicians. Yet, intentions were negatively associated with frequency of provider communication, perhaps reflecting waning parental interest with a greater understanding of limitations in trial access, increased sophistication in their understanding of trial design, and appreciation of potential burden. To support parents' informed decisions, it is important to educate them to evaluate the quality of research, as well as providing lay information explaining the use of placebo, trial processes, and potential barriers to long-term drug access. Our findings should inform the development of targeted educational content, clinician training, and decision support tools. PMID- 29475376 TI - Forty years of medical education through the eyes of Medical Teacher: From chrysalis to butterfly. AB - To mark the 40th Anniversary of Medical Teacher, issues this year will document changes in medical education that have taken place over the past 40 years in undergraduate, postgraduate and continuing education with regard to curriculum themes and approaches, teaching and learning methods, assessment techniques and management issues. Trends such as adaptive learning will be highlighted and one issue will look at the medical school of the future. An analysis of papers published in the journal has identified four general trends in medical education increased collaboration, greater international interest, student engagement with the education process and a move to a more evidence-informed approach to medical education. These changes over the years have been dramatic. PMID- 29475377 TI - Current research into novel therapeutic vaccines against cervical cancer. AB - INTRODUCTION: Cervical cancer and cervical intraepithelial neoplasia (CIN) are well-known outcomes of a human papillomavirus (HPV) infection. Viral oncogenes expressions like E6, E7, and, recently recognized E5, lead to HPV-related malignant progression. Although HPV prevention by powerful vaccines against most frequent and oncogenic genotypes is feasible, current treatment against cervical neoplasia is distant from an ideal one. In addition, late diagnosis is commonly associated with a poor prognosis. On top of that, radiotherapy, chemotherapy, or surgery are less effective in high-grade lesions. Areas covered: Due to their peculiarities, HPV oncogenes represent an excellent target for cancer immunotherapy. Safety, efficacy, and potential immunogenicity are features achieved by DNA vaccines targeting HPV. The literature search has indicated that genetic immunotherapy is becoming a pharmacological tool and therapeutic option against cervical disease, as more and more DNA vaccines are reaching clinical trial phases. Expert commentary: Among some of the promising results, a phase II randomized trial showed a clinical activity of a nucleic acid-based vaccine in HPV16 or HPV18 positive CIN patients. The concept of a synergic combination of anti-HPV DNA vaccines with radiotherapy, chemotherapy, sophisticated delivery methods, immunomodulators or immune adjuvants opens a new and interesting perspective in cervical malignancy treatment. PMID- 29475378 TI - On self-identity: the process of inclusion of individuals with intellectual disabilities in the military. AB - PURPOSE: Identity development among individuals with disabilities may depend on their being included in central institutions in society. The centrality of the military in Israeli society makes it a highly important setting for inclusion and identity development. We examined the self-identity of young adults with intellectual disabilities who serve in the "Equal in Uniform" project. MATERIAL AND METHODS: Forty-nine interviews were conducted with 31 individuals with intellectual disabilities. RESULTS: Findings showed that military service helped develop the identity of soldiers, which enhanced their self-efficacy. Participants described their participation in the military as an opportunity to take an active part in socially valued roles. CONCLUSIONS: Findings are discussed with reference to the effect of the project on the self-identity of individuals with intellectual disabilities. The meaning of successfully serving in socially valued roles for self-efficacy is discussed. Implications for rehabilitation Completing socially valued roles leads to greater self-efficacy, enhanced self esteem and greater psychological well-being among individuals with intellectual disabilities. Inclusion of individuals with intellectual disabilities within a central community setting (specifically the military) allows them to deal with issues of identity development, as it does for other young people without intellectual disabilities. Receiving ongoing positive input from others for one's abilities and success is a conducive factor in positive identity formation. PMID- 29475379 TI - Transmastoid implantability of an active transcutaneous bone conduction implant in adults with regard to the underlying pathology: a radiological simulation study. AB - OBJECTIVES: To compare the feasibility of transmastoid implantation of an active transcutaneous bone conduction device (BCD) in the most important pathologies of the temporal bone and the impact of implant lifts in adulthood. METHODS: First, clinical predominant pathologies for implantation of this BCD were evaluated by a literature review. Then, high-resolution CT of 240 temporal bones with neuro otologic diseases (NOD), chronic otitis media (COM), or cholesteatoma, respectively, were investigated regarding their implantability, using a radiological simulation program. RESULTS: Chronic inflammatory diseases (CID) of the temporal bone with or without cholesteatoma account for most adults scheduled for an active BCD. Complete implantation was possible in almost all cases with NOD as well as COM, requiring an implant lift in 50% of COM and 20% of NOD (p = .025) cases. In contrast, in subjects with cholesteatoma, implantation required an additional tool in 92% of cases, leading to 59% implantability rate in these temporal bones. CONCLUSION: Adult subjects with CID of the temporal bone show more limiting anatomical conditions for transmastoid placement of an active transcutaneous BCD than those with single-sided deafness. Implant lifts increase the implantability significantly in subjects with COM and particularly in those with cholesteatoma. PMID- 29475380 TI - Using entrustable professional activities (EPAs) to assess teaching competence and transfer of training: A personal view. AB - Faculty development (FD) activities aim to improve teaching competencies. Success of these activities is conditioned with the ability of participants to transfer the learned competencies into their teaching practices. Unfortunately, evaluation of the effectiveness of FD rely mostly upon self-reported or verbal feedback, without valid evaluation of their progress in teaching performance. This shortcoming may be attributed to the unavailability of a systematic assessment system to evaluate participants' performance in the workplace. In this article, we advocate how the concept and principles of entrustable professional activities (EPAs) can be used in assessment of teaching competencies and ensuring the transfer of training to the workplace. PMID- 29475382 TI - British Fertility Society. PMID- 29475381 TI - Motivational impairment predicts functional remission in first-episode psychosis: 3-Year follow-up of the randomized controlled trial on extended early intervention. AB - OBJECTIVE: Functional remission represents an intermediate functional milestone toward recovery. Differential relationships of negative symptom sub-domains with functional remission in first-episode psychosis are understudied. We aimed to examine rate and predictors of functional remission in people with first-episode psychosis in the context of a 3-year follow-up of a randomized controlled trial comparing 1-year extension of early intervention (i.e. 3-year early intervention) with step-down psychiatric care (i.e. 2-year early intervention). METHOD: A total of 160 participants were recruited upon completion of a 2-year specialized early intervention program for first-episode psychosis in Hong Kong and underwent a 1 year randomized controlled trial comparing 1-year extended early intervention with step-down care. Participants were followed up and reassessed 3 years after inclusion to the trial (i.e. 3-year follow-up). Functional remission was operationalized as simultaneous fulfillment of attaining adequate functioning (measured by Social and Occupational Functioning Scale and Role Functioning Scale) at 3-year follow-up and sustained employment in the last 6 months of 3 year study period. Negative symptom measure was delineated into amotivation (i.e. motivational impairment) and diminished expression (i.e. reduced affect and speech output). Data analysis was based on 143 participants who completed follow up functional assessments. RESULTS: A total of 31 (21.7%) participants achieved functional remission status at 3-year follow-up. Multivariate regression analysis showed that lower levels of amotivation ( p = 0.010) and better functioning at study intake ( p = 0.004) independently predicted functional remission (Final model: Nagelkerke R2 = 0.40, chi2 = 42.9, p < 0.001). Extended early intervention, duration of untreated psychosis and diminished expression did not predict functional remission. CONCLUSION: Only approximately one-fifths of early psychosis patients were found to achieve functional remission. Functional impairment remains an unmet treatment need in the early stage of psychotic illness. Our results further suggest that amotivation may represent a critical therapeutic target for functional remission attainment in early psychosis. PMID- 29475383 TI - In vitro antibacterial and time-kill assay of ethanolic extract of Davilla nitida bark on multidrug resistant bacteria isolated from diabetic foot lesions. AB - This study reported the antimicrobial activity of the bark extract of Davilla nitida on multidrug resistant bacteria isolated from Diabetic Foot Infections. Antibacterial activity of the bark extract was evaluated by agar Disk-Diffusion (DD), Broth Dilution (BD), Checkerboard and Time-kill methods. The extract showed a significant antibacterial activity against all groups of bacteria tested. BD was more sensitive for determining the antibacterial activity of the bark extract than the DD method. The bark extract inhibited the growth of bacteria with high levels of antibiotic-resistance, such as Pseudomonas spp. (100.0%), Enterobacer spp. (88.89%), Staphylococcus aureus (54.55%), Streptococcus pneumoniae (75.0%), Staphylococcus saprophyticus (92.86%). The combination of extract with antibiotics resulted in an additive effect against most of the strains tested. Time-kill kinetics profiles of bark extract showed bactericidal and time dependent properties. Our results suggest that the bark extract of Davilla nitida is a source of bioactive compounds, which may be useful against antibiotic resistant bacteria. PMID- 29475384 TI - Occupational health care return-to-work practices for workers with job burnout. AB - BACKGROUND: Occupational health care supports return to work in cases of burnout; however, there is little research on return-to-work practices. AIM: To describe occupational health care return-to-work practices for workers with burnout and to identify potential for the development of the practices. METHODS: Open-ended interviews and essays were used to collect data from 25 occupational health care professionals. A qualitative content analysis method was used. RESULTS: Occupational health care was involved in the return-to-work support in the off work, work re-entry and maintenance phases during the return-to-work process. However, occupational health care had no influence in the advancement phase. The key return-to-work actions were: (i) defining burnout, (ii) supporting disengagement from work, (iii) supporting recovery, (iv) determining the return to-work goal, (v) supporting re-engagement with work, (vi) monitoring the job person match, (vii) re-evaluating the return-to-work goal, (viii) supporting the maintenance of the achieved return-to-work goal, and, where appropriate, (ix) supporting an alternative return-to-work goal. There were varied return-to-work practices among the occupational health care centers evaluated. CONCLUSIONS: The occupational health care return-to-work practices for workers with burnout are described with recommendations to further develop common practice guidelines. PMID- 29475385 TI - Utility of the Croatian translation of the community integration questionnaire revised in a sample of adults with moderate to severe traumatic brain injury. AB - PURPOSE: To examine the utility of the Community Integration Questionnaire Revised, translated into Croatian, in a sample of adults with moderate to severe traumatic brain injury. METHOD: The Community Integration Questionnaire-Revised was administered to a sample of 88 adults with traumatic brain injury and to a control sample matched by gender, age and education. Participants with traumatic brain injury were divided into four subgroups according to injury severity. RESULTS: The internal consistency of the Community Integration Questionnaire Revised was satisfactory. The differences between the group with traumatic brain injury and the control group were statistically significant for the overall Community Integration Questionnaire-Revised score, as well as for all the subscales apart from the Home Integration subscale. The community Integration Questionnaire-Revised score varied significantly for subgroups with different severity of traumatic brain injury. CONCLUSIONS: The results show that the Croatian translation of the Community Integration Questionnaire-Revised is useful in assessing participation in adults with traumatic brain injury and confirm previous findings that severity of injury predicts community integration. Results of the new Electronic Social Networking scale indicate that persons who are more active on electronic social networks report better results for other domains of community integration, especially social activities. Implications for rehabilitation The Croatian translation of the Community Integration Questionnaire-Revised is a valid tool for long-term assessment of participation in various domains in persons with moderate to severe traumatic brain injury Persons with traumatic brain injury who are more active in the use of electronic social networking are also more integrated into social and productivity domains. Targeted training in the use of new technologies could enhance participation after traumatic brain injury. PMID- 29475386 TI - Ion-sensitive in situ hydrogels of natamycin bilosomes for enhanced and prolonged ocular pharmacotherapy: in vitro permeability, cytotoxicity and in vivo evaluation. AB - Delivery of therapeutic molecules into the deeper ocular compartments is mainly hampered by short precorneal residence and limited transmembrane permeability of topically administered drugs. Hence, the current study was undertaken to fabricate the ion-sensitive in situ gels of natamycin (NT) bilosomes (NB) for efficient ocular delivery. The effect of cholesterol and sodium taurocholate proportion on the properties of the bilosomes were studied and the formulation with better physicochemical properties was optimized and utilized to derive the in situ gelling system (IG). The impact of type/composition of gelling agent on the formation and characteristics of the hydrogel was investigated. The hydrogel formed from IG with 0.3% w/v gellan gum showed optimal viscoelastic and adhesive characteristics. The ocular safety and cytocompatibility of NB and its IG was confirmed by corneal histology and in vitro cytotoxicity evaluation. A 6- to 9 fold enhancement in the transcorneal flux of NB demonstrated efficient ocular penetration of bilosomes. Moreover, the superior mean dose normalized NT levels in the ocular tissues of rabbits treated with optimized NB and IG illustrated the effectiveness of bilosomes loaded ion-sensitive in situ hydrogels as a potential platform for the improved and prolonged ocular pharmacotherapy. PMID- 29475387 TI - Choline-phosphate cytidylyltransferase-alpha as a possible predictor of survival and response to cisplatin neoadjuvant chemotherapy in urothelial cancer of the bladder. AB - OBJECTIVES: The aim of this study was to test choline-phosphate cytidylyltransferase-alpha (CCT-alpha) protein as a biomarker for neoadjuvant cisplatin chemotherapy response in a bladder tumor setting. MATERIALS AND METHODS: A total of 238 patients with T2-T4 bladder cancer enrolled into two prior randomized trials comparing neoadjuvant cisplatin-based chemotherapy (NAC) plus cystectomy with cystectomy only (no-NAC) were used as discovery and validation cohorts. Protein expression was determined with immunohistochemistry and assessed with Histo (H)-scoring. RESULTS: In the discovery cohort, comprising 61 patients, the survival ratio after NAC treatment for CCT-alpha-negative patients was significantly increased (p = 0.001) while there was no survival advantage in the CCT-alpha-positive patient group. Similarly, in the validation cohort with 177 patients, NAC treatment improved survival only in the CCT-alpha negative group (p = 0.006). Although there was a tendency for a good NAC response with negative CCT-alpha status, the interaction variable between biomarker and treatment was not significant (p = 0.24). In the cystectomy-only group, patients with positive CCT-alpha expression had a better survival than CCT-alpha-negative patients. This prognostic effect of CCT-alpha expression remained significant after adjusting for well-known prognostic factors in a multivariate analysis. In a pooled database of both patient data sets, multivariate analyses showed CCT alpha status as an independent factor for overall survival (p = 0.018; hazard ratio = 1.80, 95% confidence interval 1.11-2.93). CONCLUSION: CCT-alpha status was not predictive of outcome of NAC response; however, in the control group with cystectomy only it was found to have prognostic value. PMID- 29475388 TI - Women with inflammatory bowel diseases have a suboptimal cervical cancer screening rate and are not aware of the recommended human papilloma virus vaccine. AB - The aim of the study was to assess the self-reported cervical cancer screening rate among patients with inflammatory bowel diseases (IBD) and patient attitude towards human papilloma virus (HPV) vaccination. A self-designed survey was conducted in hospitalized IBD patients. The survey comprised demographic data, questions regarding cervical smear test frequency and vaccinations recommended for an IBD patient. Randomly, patients completed the survey with a physician present to determine question comprehension. In order to provide test-retest reliability a group of 10 patients completed it twice. Survey data from 150 IBD patients (mean age: 36 years, SD +/- 13; mean IBD duration: 10 years, SD +/- 6.5) were analyzed. Fifteen percent of the patients reported irregular cervical testing and 15% do not remember when having had a previous cervical testing performed. Only 69% of the patients undergo testing regularly; 30% annually, 32% every 2-3 years; 7% every 5 years. The mean age of patients tested regularly was 22 years, vs. 32 years tested irregularly (p < .001). Only 10% of women claimed that HPV vaccine is recommended for an IBD patient. There is a low adherence to the recommendations regarding cervical cancer screening and prophylaxis. Better multi-disciplinary cooperation between patients and physicians is required to improve patient education and outcomes. PMID- 29475389 TI - Remediation in Canadian medical residency programs: Established and emerging best practices. AB - BACKGROUND: Policies to guide remediation in postgraduate medical education exist in all Canadian medical schools. This study examines concordance between these policies and processes, and published "best practices" in remediation. METHOD: We conducted a literature review to identify best practices in the area of remediation. We then reviewed remediation policies from all 13 English medical schools in Canada other than our own and conducted interviews with key informants from each institution. Each policy and interview transcript pair was then reviewed for evidence of pre-defined "best practices." Team members also noted additional potential policy or process enablers of successful remediation. RESULTS: Most policies and processes aligned with some but not all published best practices. For instance, all participating schools tailored remediation strategies to individual resident needs, and a majority encouraged faculty student relationships during remediation. Conversely, few required the teaching of goal-setting, strategic planning, self-monitoring, and self-awareness. In addition, we identified avoidance of automatic training extension and the use of an educational review board to support the remediation process as enablers for success. DISCUSSION: Remediation policies and practices in Canada align well with published best practices in this area. Based on key informant opinions, flexibility to avoid training extension and use of an educational review board may also support optimal remediation outcomes. PMID- 29475390 TI - Nucleoside diphosphate kinase 2 confers acquired 5-fluorouracil resistance in colorectal cancer cells. AB - Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide. 5-fluorouracil (5-FU)-based chemotherapeutic regimens are routinely used for the treatment of patients with CRC. However, recurrence and chemotherapeutic drug resistance limit the survival rates of patients with CRC. DNA methylation participates in diverse cellular processes by regulating the transcription of a large number of genes expression, cell division, apoptosis, cell adhesion and differentiation, and metabolism, thus it might mediate chemoresistance. Using an Illumina Infinium HD Assay, DNA methylation levels in a human 5-FU-resistant HCT-8 CRC cell line (HCT-8/FU) and its progenitor cell line HCT-8 were analysed. A total of 16,580 differentially methylated genes were identified, of which 8885 were hypermethylated and 7695 were hypomethylated in resistant cells. Among these genes, NME2 (nucleoside diphosphate kinase 2) exhibited a significant difference in methylation between cell lines and has known roles in gastric cancer and breast cancer; accordingly, we hypothesized that it plays a role in acquired resistance in CRC. Knockdown of NME2 restored 5 FU sensitivity in 5-FU-resistant CRC cells, reduced cell survival and increased cell apoptosis; and overexpression of NME2 in HCT-8 cells results in the acquisition of resistance to 5-FU, this alteration enhanced HCT-8 cells growth abilities and reduced apoptosis. These findings suggest that NME2 mediates chemoresistance to 5-FU in CRC and that specific NME2 inhibition could optimize 5 FU-based chemotherapy of CRC. PMID- 29475392 TI - Should we teach medical students to handle zebras? PMID- 29475391 TI - A decade of reform in medical education: Experiences and challenges at Tehran University of Medical Sciences. AB - PURPOSE: In this paper, we present the major curricular reform in MD program of Tehran University of Medical Sciences, the oldest and the largest medical university in Iran, initiated about a decade ago. MATERIALS AND METHODS: Following a comprehensive program evaluation, many of the basic challenges of the traditional curriculum were revealed, namely, lack of pre-defined competencies for graduates, over-reliance on teacher-centered teaching methods, over-emphasis on knowledge base in student assessments, and focusing solely on biomedical aspects of patient care. In 2010, a vision statement for reform was created and approved by the University Council. The new curriculum was launched in 2011. RESULTS: The changes included: revising the content of the courses, assimilating horizontal and vertical integration, emphasizing clinical skills, encouraging active involvement in patient management, providing more opportunity for supervised practice, integrating behavioral and psychosocial topics into the curriculum, incorporating interactive teaching methods, assessing students' higher levels of cognition, and strengthening workplace assessments. To evaluate the changes, data were continuously collected and analyzed from the beginning. CONCLUSIONS: Changing the curriculum of an MD program is a laborious task which should be planned and undertaken carefully and cautiously. It is an endless, yet invaluable and satisfying endeavor toward better future. PMID- 29475393 TI - Preparation of PEGylated cationic nanoliposome-siRNA complexes for cancer therapy. AB - Cationic liposomes have been investigated as non-viral vectors for gene delivery for more than a decade to overcome challenges associated with viral gene delivery. However, due to instability of liposomes, siRNA delivery is still a serious problem. In this study, we developed stealth PEGylated liposome formulations and focused on the effects of PEGylated liposomes on parameters related to size, zeta potential, polydispersity index, siRNA-loading efficiency and long-term stability of the siRNA-liposome complex. We were able to generate siRNA lipoplexes that could be very efficiently loaded, did not aggregate, could be stored at 4 degrees C for at least 6 months with only marginal release (1-5%) of siRNA and enhanced intracellular delivery of siRNA. Moreover, we could demonstrate that PEGylation positively contributed to all these parameters compared to liposomes, which were not PEGylated. The prepared lipoplex was successfully silenced J1P1 expression in MG-63 osteosarcoma cell line. In conclusion, our novel PEGylated liposomes have high potential for systemic delivery of siRNA and can improve in vivo stability of free siRNA and also siRNA lipoplexes. PMID- 29475395 TI - Application of resonance metallic stents for malignant ureteral obstruction. AB - PURPOSE: To determine the effectiveness of the Resonance metallic stent in treating malignant ureteral obstruction (MUO) and clarify the risk factors that lead to stent failure. MATERIAL AND METHODS: We retrospectively identified and analyzed the records of patients who had MUO and underwent placement of Resonance metallic stents from November 2014 to June 2017 in our hospital. Stent failure was defined as unexpected interventions including stent exchange, need of percutaneous nephrostomies (PCN) or ureterocutaneostomy. RESULTS: A total of 22 stents were placed in 14 patients with MUO. The median follow-up was 145 days (4.8 months) and the maximum duration of stenting was 21.3 months. The technique success rate was 100%. Two patients experienced early postoperative increasing creatinine with oliguria but only one of them failed to achieve primary patency. The overall success rate was 90% (9/10). CONCLUSION: Resonance metallic stent is a safe and effective treatment for MUO and can maintain durable patency over 12 months. Preoperative urinary tract infection (UTI) and tumor invasion into the bladder are considered as risk factors of stent blockage and failure. Early postoperative elevated creatinine oliguria, suggestive with intrarenal and prerenal disease, should not be deemed to be stent failure. PMID- 29475394 TI - Emerging drugs for the treatment of axial spondyloarthritis. AB - INTRODUCTION: The treatment of axial spondyloarthritis(axSpA) has been for nearly 15 years constricted to non-steroidal antirheumatic drugs and TNFalpha inhibitors. With the approval of secukinumab, a drug targeting the interleukin(IL)-17 axis became available. Nonetheless, an unmet need for further emerging therapeutic options remains. Areas covered: This review summarizes the recent and ongoing clinical trials with novel drugs in axSpA. Besides secukinumab, further therapeutics directed against the IL-17A (e.g. ixekizumab) as well as the dual IL-17A and F inhibitor bimekizumab and the IL-17RA antibody brodalumab are in development. Furthermore, several drugs targeting the IL-12/-23 axis are being evaluated. Pan-JAK and JAK-1 inhibitors might offer another effective mode of action. Expert opinion: The number of treatment options in axSpA is likely to be further extended in the coming years. Data of ongoing studies are needed to prove the efficacy of drugs directed against the IL-12/-23 axis as well as of JAK inhibition, whilst targeting the IL-17 axis was shown to be as effective as TNF inhibition by indirect comparison. There is an emerging need for trials aiming at identification of optimal treatment strategies in the scope of the treat-to-target concept in axSpA. PMID- 29475396 TI - Insulin signaling in female Drosophila links diet and sexual attractiveness. AB - Appropriate sexual selection or individual sexual attractiveness is closely associated with the reproductive success of a species. Here, we report that young male flies exhibit innate courtship preference for female flies that are raised on higher-yeast diets and that have greater body weight and fecundity, but reduced locomotor activity and shortened lifespan. Male flies discriminate among females that have been fed diets that contain 3 different yeast concentrations-1, 5, and 20% yeast- via gustatory, but not visual or olfactory, perception. Female flies that are raised on higher-yeast diets exhibit elevated expression levels of Drosophila insulin-like peptides (di lps), and we demonstrate that hypomorphic mutations of di lp2, 3, 5 or foxo, as well as oenocyte-specific gene disruption of the insulin receptor, all abolish this male courtship preference for high yeast-fed females. Moreover, our data demonstrate that disrupted di lp signaling can alter the expression profile of some cuticular hydrocarbons (CHCs) in female flies, and that genetic inhibition of an enzyme involved in the biosynthesis of CHCs in oenocytes, elongase F, also eliminates the male courtship preference. Together, our findings provide mechanistic insights that link female reproductive potential to sexual attractiveness, thereby encouraging adaptive mating and optimal reproductive success.-Lin, W.-S., Yeh, S.-R., Fan, S.-Z., Chen, L.-Y., Yen, J.-H., Fu, T.-F., Wu, M.-S., Wang, P.-Y. Insulin signaling in female Drosophila links diet and sexual attractiveness. PMID- 29475398 TI - Regulation of KLF12 by microRNA-20b and microRNA-106a in cystogenesis. AB - Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited disorders. ADPKD is caused by mutations in the gene encoding either polycystic kidney disease 1 ( PKD1) or polycystic kidney disease 2 ( PKD2). Patients with ADPKD show progressive growth of cystic fluid-filled renal cysts. Here, we used Pkd2f/f control mice and Pkd2f/f:HoxB7-Cre experimental mice, which are bred to have a conditional deletion of Pkd2 in the collecting ducts, and analyzed the expression pattern of microRNAs (miRNAs) of kidney tissues from Pkd2f/f and Pkd2f/f:HoxB7-Cre mice. Decreased expression of miR-20b-5p and miR 106a-5p in Pkd2f/f:HoxB7-Cre mice compared to that in Pkd2f/f mice was observed. These miRNAs target Klf12 (Kruppel-like factor 12), which has low expression in kidney tissues of Pkd2f/f mice; however, its expression is enhanced in Pkd2f/f:HoxB7-Cre mice over time. Moreover, miR-20b-5p and miR-106a-5p directly target Klf12 mRNA by binding to the 3'-UTR of Klf12. In addition, human and mouse cell lines exhibit similar patterns. These findings were also consistent with the data from Pkd2 knockout mouse embryonic fibroblasts. Furthermore, direct and indirect knockdown of Klf12 slows cyst growth and cell proliferation in mouse inner medullary collecting duct cells. Taken together, we suggest that the induction of miR-20b-5p or miR-106a-5p or the down-regulation of KLF12 could be used as potential novel therapies for inhibiting cyst growth in patients with ADPKD.-Shin, Y., Kim, D. Y., Ko, J. Y., Woo, Y. M., Park, J. H. Regulation of KLF12 by microRNA-20b and microRNA-106a in cystogenesis. PMID- 29475399 TI - NOACs only for those who cannot tolerate a VKA: where is the evidence? AB - The 2016 European Society of Cardiology Guidelines recommend non-vitamin K antagonist oral anticoagulants (NOACs) in preference to vitamin K antagonists (VKA) for stroke prevention in atrial fibrillation. A recent report from the Belgian Healthcare Knowledge Centre (KCE) raised concerns about the results of the phase 3 randomised trials that led to the approval of the NOACs for this indication and concluded that NOACs should only be used for patients who fail or cannot undergo treatment with a vitamin K antagonist because they cannot achieve stable INR values. Evidence from community-based studies suggests that NOACs are often not optimally used; however, our critical review of the randomised trial data provides no support for the concerns raised by the Belgian KCE about the trials. Furthermore, the results of observational studies involving more than 700,000 participants replicate those of the randomised trials, indicating that the benefits of NOACs seen in the trials can be readily translated to patient care. Due to their superior convenience and safety, NOACs also have the potential to reduce undertreatment of atrial fibrillation patients. PMID- 29475397 TI - Fatty acid synthase is required for profibrotic TGF-beta signaling. AB - Evidence is provided that the fibroproliferative actions of TGF-beta are dependent on a metabolic adaptation that sustains pathologic growth. Specifically, profibrotic TGF-beta signaling is shown to require fatty acid synthase (FASN), an essential anabolic enzyme responsible for the de novo synthesis of fatty acids. With the use of pharmacologic and genetic approaches, we show that TGF-beta-stimulated FASN expression is independent of Smad2/3 and is mediated via mammalian target of rapamycin complex 1. In the absence of FASN activity or protein, TGF-beta-driven fibrogenic processes are reduced with no apparent toxicity. Furthermore, as increased FASN expression was also observed to correlate with the degree of lung fibrosis in bleomycin-treated mice, inhibition of FASN was examined in a murine-treatment model of pulmonary fibrosis. Remarkably, inhibition of FASN not only decreased expression of profibrotic targets, but lung function was also stabilized/improved, as assessed by peripheral blood oxygenation.-Jung, M.-Y., Kang, J.-H., Hernandez, D. M., Yin, X., Andrianifahanana, M., Wang, Y., Gonzalez-Guerrico, A., Limper, A. H., Lupu, R., Leof, E. B. Fatty acid synthase is required for profibrotic TGF-beta signaling. PMID- 29475400 TI - Molecular diversity of tuliposide B-converting enzyme in tulip (Tulipa gesneriana): identification of the third isozyme with a distinct expression profile. AB - 6-Tuliposide B (PosB), a major secondary metabolite that accumulates in tulip (Tulipa gesneriana), is converted to the antibacterial lactone, tulipalin B (PaB), by PosB-converting enzyme (TCEB). TgTCEB1 and TgTCEB-R, which encode TCEB, are specifically expressed in tulip pollen and roots, respectively, but are hardly expressed in other tissues (e.g. leaves) despite the presence of substantial PosB-converting activity, suggesting the existence of another TCEB isozyme. Here, we describe the identification of TgTCEB-L ("L" for leaf), a paralog of TgTCEB1 and TgTCEB-R, from leaves via native enzyme purification. The enzymatic characters of TgTCEB-L, including catalytic activity and subcellular localization, were substantially the same as those of TgTCEB1 and TgTCEB-R. However, TgTCEB-L did not exhibit tissue-specific expression. Identification of TgTCEB-L explains the PosB-converting activity detected in tissues where TgTCEB1 and TgTCEB-R transcripts could not be detected, indicating that tulip subtilizes the three TgTCEB isozymes depending on the tissue. PMID- 29475401 TI - Corrigendum. AB - Castanon, J.; Roman, J. P.; Jessop, T. C.; et al. Design and Development of a Technology Platform for DNA-Encoded Library Production and Affinity Selection. SLAS Discovery. [Online early access]. (Original DOI: 10.1177/2472555217752091) In this article, the author order was incorrectly listed in the initial OnlineFirst version. The online and print versions have been updated to reflect the correct order: Jesus Castanon, Jose Pablo Roman, Theodore C. Jessop, Jesus de Blas, and Ruben Haro. PMID- 29475402 TI - Progressive subcutaneous emphysema of unknown origin: a surgical dilemma. AB - OBJECTIVE: Subcutaneous emphysema can be an alarming sign of a necrotizing soft tissue infection. However, non-infectious etiologies exist that can be treated conservatively. This case report describes a subcutaneous emphysema of unknown origin and highlights the importance of distinguishing these clinical entities. METHODS: We present a 17-year old female with pain and subcutaneous emphysema of the left arm. There were no systemic symptoms. Inflammatory parameters were slightly elevated. Computed tomography (CT) scan of the chest excluded intrathoracic abnormalities. Despite antibiotic treatment, the pain increased and the emphysema extended. Necrotizing fasciitis was feared. A surgical exploration was performed and hyperbaric oxygen therapy was started. RESULTS: Intraoperatively, puncture marks were identified on the left arm. Air noticeably escaped, but normal, unaffected tissues were identified and microbiological cultures remained negative. We observed a good clinical evolution. CONCLUSION: The lack of apparent causes, the unexplained puncture marks and psychiatric comorbidity suggests the possibility of subcutaneous emphysema due to factitious manipulations. Patients with subcutaneous emphysema who remain clinically stable, have minimal pain and no significant inflammatory changes could be treated conservatively. Close clinical monitoring is essential to avoid delayed intervention in case of a necrotizing soft tissue infection. PMID- 29475403 TI - Xylanase and feruloyl esterase from actinomycetes cultures could enhance sugarcane bagasse hydrolysis in the production of fermentable sugars. AB - The addition of enzymes that are capable of degrading hemicellulose has a potential to reduce the need for commercial enzymes during biomass hydrolysis in the production of fermentable sugars. In this study, a high xylanase producing actinomycete strain (Kitasatospora sp. ID06-480) and the first ethyl ferulate producing actinomycete strain (Nonomuraea sp. ID06-094) were selected from 797 rare actinomycetes, respectively, which were isolated in Indonesia. The addition (30%, v/v) of a crude enzyme supernatant from the selected strains in sugarcane bagasse hydrolysis with low-level loading (1 FPU/g-biomass) of Cellic(r) CTec2 enhanced both the released amount of glucose and reducing sugars. When the reaction with Ctec2 was combined with crude enzymes containing either xylanase or feruloyl esterase, high conversion yield of glucose from cellulose at 60.5% could be achieved after 72 h-saccharification. PMID- 29475404 TI - Dose-related mucositis with hydroxyurea for cytoreduction in acute myeloid leukemia. AB - Hyperleukocytosis occurs in 15-20% of all newly diagnosed acute myeloid leukemia patients and requires emergent treatment with leukapheresis or hydroxyurea when accompanied by signs or symptoms of leukostasis. Currently, there is no standardized hydroxyurea dosing strategy, although usual dosing ranges from 50 to 150 mg/kg/day, and prescribing patterns vary significantly among oncologists and institutions. In addition to other hematologic and dermatologic toxicities, the use of hydroxyurea may be associated with significant mucositis and mucositis related pain. The purpose of this study was to compare mucositis-related pain between two different hydroxyurea dosing strategies in patients who received hydroxyurea for cytoreduction during induction. A retrospective chart review of adult patients with acute myeloid leukemia treated with chemotherapy at UNC Medical Center from April 2014 to April 2016 who received at least one dose of hydroxyurea for cytoreduction was conducted. This study compared the safety and toxicity profiles of hydroxyurea in patients who received high-dose hydroxyurea (>=75 mg/kg/day) versus low-dose hydroxyurea (<75 mg/kg/day). Safety and toxicity were evaluated based on indicators of mucositis and cumulative intravenous narcotic requirements following induction chemotherapy. Data collection included baseline demographics, mucositis risk factors, baseline laboratory values, hydroxyurea dosing, mucositis indicators, and pain indicators. A total of 55 patients were included in the study, 21 patients (38.2%) received the high-dose hydroxyurea dosing strategy. The high-dose hydroxyurea dosing strategy had a significantly higher white blood cell count at diagnosis, increased duration of hydroxyurea, and received a higher cumulative dose of hydroxyurea. Additionally, the high-dose hydroxyurea dosing strategy patients were associated with significantly more grade 3 or 4 mucositis requiring a formulation change (0% versus 28.6%, p = 0.002) and significantly higher cumulative intravenous narcotic requirements during induction (p = 0.019). No significant differences in baseline demographics or mucositis risk factors between dosing strategies were identified. The high-dose hydroxyurea dosing strategy patients had a significant increase in cumulative intravenous narcotic requirements and formulation changes, both common interventions made for the treatment of mucositis. Additional studies are needed to further elucidate the safety and toxicity profiles of hydroxyurea dosing strategies and to explore the correlation between total cumulative hydroxyurea dose and total cumulative narcotic requirements. PMID- 29475405 TI - Interstitial pneumonitis and myelosuppression associated to mitomycin C urinary tract instillations: A case report. AB - Mitomycin C as a treatment for superficial bladder carcinomas and upper urinary tract tumours has been linked to local adverse events. Systemic toxicity has been documented for just a very few cases. This report presents a case of interstitial pneumonitis accompanied by myelosuppression in a 74-year-old patient after receiving the fifth administration of mitomycin C through a ureteral catheter as a treatment for left kidney pyelocaliceal urothelial carcinoma. Therefore, suspecting mitomycin C toxicity, urinary tract instillations were discontinued, and intravenous filgrastim and methylprednisolone were initiated. Currently, after five months since the last mitomycin C urinary tract instillation, the patient is still receiving filgrastim and corticosteroids. A moderate effort dyspnoea persists despite interstitial pulmonary infiltrates have presented a very important reduction. Pancytopenia has also persisted. Blood count and lung function monitoring would be appropriate in patients undergoing mitomycin C instillations, especially in those with established prior lung disease. PMID- 29475406 TI - Subacute prosthesis migration and rotation following percutaneous transcatheter aortic valve implantation. PMID- 29475407 TI - Probing the interaction of human serum albumin with iprodione, a fungicide: spectroscopic and molecular docking insight. PMID- 29475408 TI - Identification of selective MMP-9 inhibitors through multiple e-pharmacophore, ligand-based pharmacophore, molecular docking, and density functional theory approaches. AB - Matrix metalloproteinase-9 (MMP-9) is a significant target for the development of drugs for the treatment of arthritis, CNS disorders, and cancer metastasis. The structure-based and ligand-based methods were used for the virtual screening (VS) of database compounds to obtain potent and selective MMP-9 inhibitors. Experimentally known MMP-9 inhibitors were used to grow up ligand-based three pharmacophore models utilizing Schrodinger suite. The X-ray crystallographic structures of MMP-9 with different inhibitors were used to develop five energy optimized structure-based (e-pharmacophore) models. All developed pharmacophores were validated and applied to screen the Zinc database. Pharmacophore matched compounds were subjected to molecular docking to retrieve hits with novel scaffolds. The molecules with diverse structures, high docking scores and low binding energies for various crystal structures of MMP-9, were selected as final hits. The Induced fit docking (IFD) analysis provided significant information about the driving of inhibitor to approve a suitable bioactive conformational position in the active site of protein. Since charge transfer reaction occurs during receptor-ligand interaction, therefore, electronic features of hits (ligands) are interesting parameters to explain the binding interactions. Density functional theory (DFT) at B3LYP/6-31G* level was utilized to explore electronic features of hits. The docking study of hits using AutoDock was helpful to establish the binding interactions. The study illustrates that the combined pharmacophore approach is advantageous to identify diverse hits which have better binding affinity to the active site of the enzyme for all possible bioactive conformations. The approach used in the study is worthy to design drugs for other targets. PMID- 29475409 TI - Acute supplementation of valine reduces fatigue during swimming exercise in rats. AB - We investigated the respective effects of the acute supplementation of valine, leucine, and isoleucine on metabolism-related markers by administering a swimming exercise test to rats. As a behavioral analysis, we evaluated the effect of valine and that of leucine on spontaneous activity after exercise. Acute supplementation of valine before exercise significantly suppressed the depression of the liver glycogen and the blood glucose after exercise, whereas leucine decreased the blood glucose and isoleucine had no effect. Valine or leucine supplementation significantly decreased the plasma corticosterone level after exercise, while isoleucine had no effect. In the behavioral analysis, valine significantly increased the spontaneous activity after exercise, whereas leucine had no effect. These results indicate that in rats, the acute supplementation of valine, not leucine or isoleucine, is effective for maintaining liver glycogen and blood glucose and increasing spontaneous activity after exercise, which could contribute to the reduction of fatigue during exercise. PMID- 29475410 TI - A systems dynamics approach for supporting regional decisions on the energetic use of regional biomass residues. AB - This article presents the definition, building, calibration and application of a system dynamics simulation model to quantify the present and future comparative advantages and disadvantages of using forest and agricultural residual biomass for energetic purpose through different processes and technologies, on a regional basis. A dynamic structure of the agricultural and forestry biomass process activities (i.e. production, transport, conversion and consumption) based on regional time-series data was built, implemented into and calibrated within a dynamic simulation tool (Vensim software) within a Hungarian county. Besides the agriculture and forestry sectors, the model includes data about demography, economy, environment and land use, among others. For carrying out the assessment, realistic scenarios of future biomass processes and of biomass use were formulated, characterised by quantitative sustainable development indicators and simulated within the dynamic model. The results prove that the introduced model supports decision making of biomass utilisation in a regional scale, through comparing and analysing quantitative changes of economic, social and environment indicators, which characterise a sustainable regional development. The model therefore allows analyses and evaluation of not only partial prosperous or adverse characteristics of biomass processes and use, but also to relate regional components and their development over time. The developed dynamic tool is therefore a powerful method to model complex systems, such as a regional energy system, considering the framework of the regional preferences stated by the regional stakeholders. It can thus provide useful decision support, especially when used as a priority-based screening of potential regional development programmes in the energy field. PMID- 29475411 TI - Waste management in the Irkutsk region, Siberia, Russia: An environmental assessment of alternative development scenarios. AB - The current waste management system, handling around 500,000 t of household, commercial, and institutional waste annually in the Irkutsk region, Siberia, is based on landfilling in an old landfill with no controls of leachate and gas. Life-cycle assessment modelling of the current system shows that it is a major load on the environment, while the simulation of seven alternative systems results in large savings in many impact categories. With respect to climate change, it is estimated that a saving of about 1200 kg CO2 equivalents is possible per year, per inhabitant, which is a significant reduction in greenhouse gas emissions. The best alternatives involve efficient energy recovery from waste and recycling by source separation for commercial and institutional waste, the major waste type in the Irkutsk region. Recycling of household waste seems less attractive, and it is therefore recommended only to consider this option after experience has been gained with the commercial and institutional waste. Sensitivity analysis shows that recovery of energy - in particular electricity, heat, and steam - from waste is crucial to the environmental performance of the waste management system. This relates to the efficiencies of energy recovery as well as what the recovered energy substitutes, that is, the 'dirtier' the off-set energy, the higher the environmental savings for the waste management system. Since recovered energy may be utilised by only a few energy grids or industrial users, it is recommended to perform additional local assessments of the integration of the waste energy into existing systems and facilities. PMID- 29475412 TI - Urological approach for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in a clinical care center. AB - BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is associated with significant manipulation of the urinary tract (UT). We aim to describe the urological events and their management in patients who underwent CRS-HIPEC. METHODS: Clinical records of patients who underwent treatment between 2007 and 2015 were reviewed. Urological events and their multidisciplinary management were analyzed. Descriptive statistics were calculated. RESULTS: A total of 103 patients were included. Mean age was 51 years (SD +/- 11.8). Mean peritoneal cancer index (PCI) was 20.4 (SD +/- 10.1). Primary tumors included appendicular (64%), gynecological (16%), colorectal (10%), and peritoneal mesotheliomas (9%). Ninety-three percent of patients had bilateral ureteral catheters inserted prior to surgery, without complications. Intraoperative UT injuries occurred in 7% of patients. In 5% of patients, tumor invasion of the bladder was evident at surgery and partial resection and primary repair of the bladder wall was performed. Urological complications included urinary tract infection (UTI) (21%) acute post-renal failure (4%), urinary fistulae (4%), and acute urinary retention (AUR) (1%). CONCLUSIONS: In our study, intraoperative UT events and postoperative complications, although not neglectable, were infrequent. Due to the high complexity of these cases, a multidisciplinary approach is mandatory. However, randomized clinical trials are necessary to clarify current data on the need and efficacy of prophylactic ureteral catheterization in patients undergoing CRS-HIPEC. PMID- 29475413 TI - Biomechanical comparison of transdiscal fixation and posterior fixation with and without transforaminal lumbar interbody fusion in the treatment of L5-S1 lumbosacral joint. AB - Transdiscal screw fixation is generally performed in the treatment of high-grade L5-S1 spondylolisthesis. The main thought of the study is that the biomechanical performances of the transdiscal pedicle screw fixation can be identical to standard posterior pedicle screw fixations with or without transforaminal lumbar interbody fusion cage insertion. Lumbosacral portions and pelvises of 45 healthy lambs' vertebrae were dissected. Animal cadavers were randomly and equally divided into three groups for instrumentation. Three fixation systems, L5-S1 posterior pedicle screw fixation, L5-S1 posterior pedicle screw fixation with transforaminal lumbar interbody fusion cage insertion, and L5-S1 transdiscal pedicle screw fixation, were generated. Axial compression, flexion, and torsion tests were conducted on test samples of each system. In axial compression, L5-S1 transdiscal fixation was less stiff than L5-S1 posterior pedicle screw fixation with transforaminal lumbar interbody fusion cage insertion. There were no significant differences between groups in flexion. Furthermore, L5-S1 posterior fixation was stiffest under torsional loads. When axial compression and flexion loads are taken into consideration, transdiscal fixation can be alternatively used instead of posterior pedicle screw fixation in the treatment of L5-S1 spondylolisthesis because it satisfies enough stability. However, in torsion, posterior fixation is shown as a better option due to its higher stiffness. PMID- 29475414 TI - Stiffness of meniscus tissue depends on tibio-femoral load and structural integrity of the meniscus root. AB - Development of meniscus replacements requires in-depth knowledge of the material properties and biomechanical behavior of the native meniscus. The compressive properties are of particular interest in this context, which are often assessed with indentation tests. However, those tests are usually done on isolated tissue specimens ex situ, which could have a significant impact on the results. It was, therefore, the goal of the study to assess the stiffness of the meniscus tissue in situ in porcine specimens and to compare it to that of artificial substitutes. Porcine knees (n = 8) were prepared such that the medial meniscus periphery was exposed and the knees could be mounted in a materials testing machine. The tissue stiffness was than measured on the meniscus periphery using a Shore-A durometer in (1) the unloaded knee, (2) with 500-N tibio-femoral compressive load, and (3) with 500-N tibio-femoral load and the posterior meniscus root detached. The stiffness of the meniscus tissue was significantly increased when tibio-femoral load was applied, while this effect was lost when the meniscus root was cut (average measurements on a 0-100 Shore-A durometer scale: group A, 33.8; group B, 58.4; and group C, 36.2). Polyurethane and collagen meniscus implants showed an inferior stiffness compared to the native meniscus. These findings might be relevant for the material choice in artificial meniscus replacements and the fixation of allografts. Biomechanical testing of isolated tissue specimens could underestimate the effective meniscus tissue stiffness compared to a physiological joint environment. PMID- 29475415 TI - The predictive role of modified TIMI risk index in patients with ST-segment elevation myocardial infarction. AB - BACKGROUND: The prognostic value of thrombolysis in myocardial infarction (TIMI) risk index (TRI) has been reported in patients with coronary artery disease. In this study, we evaluated the additional prognostic value of blood urea nitrogen (BUN) level to the TRI in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: We evaluated the in-hospital and long-term (3-year) prognostic value of modified TRI (mTRI) in patients with STEMI. The mTRI is calculated using the following equation; mTRI = (TRI * BUN)/10. Patients were stratified into 5 groups according to 20-point increments of mTRI. RESULTS: The patients with higher mTRI had significantly higher in-hospital and long-term mortality. The risk for in-hospital and long-term mortality was highest for those within the Q5 (36.8 and 42.3%, respectively) and it was significantly higher than all the other groups (p < .001 for both). CONCLUSIONS: In this study, the prognostic value of TRI has been augmented by multiplication of TRI with BUN/10. Therefore, we present a pilot study of association of mTRI with overall STEMI patients. PMID- 29475416 TI - Red light accelerates the formation of a human dermal equivalent. AB - Development of biomaterials' substitutes and/or equivalents to mimic normal tissue is a current challenge in tissue engineering. Thus, three-dimensional cell culture using type I collagen as a polymeric matrix cell support designed to promote cell proliferation and differentiation was employed to create a dermal equivalent in vitro, as well to evaluate the photobiomodulation using red light. Polymeric matrix cell support was prepared from porcine serous collagen (1.1%) hydrolyzed for 96 h. The biomaterial exhibited porosity of 95%, a median pore of 44 um and channels with an average distance between the walls of 78 +/- 14 um. The absorption of culture medium was 95%, and the sponge showed no cytotoxicity to Vero cells, a non-tumor cell line. Additionally, it was observed that irradiation with light at 630 nm (fluency 30 J cm-2) leads to the cellular photobiomodulation in both monolayer and human dermal equivalent (three dimensional cell culture system). It was also verified that the cells cultured in the presence of the polymeric matrix cell support, allows differentiation and extracellular matrix secretion. Therefore, the results showed that the collagen sponge used as polymeric matrix cell support and the photobiomodulation at 630 nm are efficient for the production of a reconstructed human dermal equivalent in vitro. PMID- 29475417 TI - Understanding Revenge Pornography: A National Survey of Police Officers and Staff in England and Wales. AB - Online abuse, facilitated via social media and mobile technologies, has recently attracted considerable academic attention. The nonconsensual sharing of intimate images-revenge pornography-can have a devastating effect on victims, is a global problem, and constitutes interpersonal violence. The national helpline in the United Kingdom has now received over 7,000 calls. In the United Kingdom, new legislation making revenge pornography a crime was introduced in 2014, yet the police do not always respond appropriately to victims. This article presents the findings of a national online survey of police understanding of revenge pornography, undertaken in the United Kingdom in March 2017. The study set out to investigate police knowledge of revenge pornography legislation, their confidence in responding to cases of revenge pornography, and what level of training they had received. A total of 783 members of the police force responded to the survey and, to the authors' knowledge, this the first study to seek to quantify the understanding of revenge pornography by police officers and staff in England and Wales. The findings suggest that the police in the United Kingdom have a limited understanding of revenge pornography legislation and lack confidence both in investigating cases and in effectively responding to victims. The implications of the study demonstrate that there is an urgent need for training across police forces to ensure that cases of revenge pornography are appropriately responded to, victims are safeguarded, and offenders brought to justice. PMID- 29475418 TI - Insecure Attachment, Maladaptive Personality Traits, and the Perpetration of In Person and Cyber Psychological Abuse. AB - Although past findings show that insecure attachment and maladaptive personality traits confer risk for perpetrating intimate partner violence (IPV), little is known about how these factors may underpin psychological abuse (PA) committed in person and via technology. This study examined whether borderline personality disorder (BPD) traits and psychopathic traits account for indirect effects of insecure attachment on the perpetration of face-to-face and cyber PA. Participants included a community-based sample ( N = 200; Mage = 22.28 years) in Australia who completed a battery of online questionnaires. Results from bivariate correlations showed that elevated levels of attachment anxiety and avoidance, and higher scores on BPD traits and psychopathic traits, were significantly associated with the perpetration of both face-to-face and cyber PA. Findings from mediation analysis indicated that attachment anxiety was indirectly linked with the perpetration of both forms of PA via elevated scores on BPD traits and psychopathic traits. High levels of psychopathic traits accounted for the indirect effects of attachment avoidance on both forms of PA. Results support the theory that insecure attachment and maladaptive personality functioning might be involved in the development and/or maintenance of the perpetration of PA. These findings have implications for preventive and treatment programs for the perpetration of IPV in terms of shedding new light on potential risk factors for engagement in face-to-face and technology-based PA. PMID- 29475419 TI - Child Victimization and Polyvictimization Among Young Adults in Northern Chile. AB - This study examined the prevalence of victimization and polyvictimization and gender differences in young adults from Arica in northern Chile. In all, 718 college students participated (46.9% men, 53.1% women), aged between 17 and 28 years old ( M = 21.6; SD = 4.11). The Spanish version of Juvenile Victimization Questionnaire ( JVQ) was used to access five categories of child victimization (conventional crime, child maltreatment, peer and siblings victimization, sexual victimization, and indirect victimization). In total, 98.7% of young adults reported at least one type of victimization throughout their life. In general, males are more exposed to victimization for conventional crimes and indirect victimization and women to sexual victimization and bullying. A total of 89.1% of the sample was considered polyvictims (i.e., experienced five or more forms of victimization). This research provides information about the epidemiology of victimization and polyvictimization in young adults in the international context, and is the first study from this point of view in a South American country. The results show that young adults in northern Chile experience a high level of victimization, even mostly higher than others studies realized in the international context. Gender is a variable that has a significant influence and must be taken into account in the analyses of this complex subject of study. PMID- 29475420 TI - Effect of Victimization and Perceived Support on Maintenance of Dating Relationships Among College Students in Guadalajara, Mexico. AB - This study analyzes the influence of the victimization suffered (sexual, physical, coercion, humiliation, and emotional punishment) and the support network available (as Independent Variables (IIVV)) on the trajectory of young couples (feeling trapped in a relationship, Dependent Variable (DV)). A total of 990 Mexican university students (M = 19.5, SD = 1.82 years) of both sexes (66% women) participated in the study. Family and friends were perceived as providing the greatest support (in over 85% of respondents), while the resources provided by the university (teachers, central resources) were regarded as unhelpful by 40%. A linear regression analysis showed that the feeling of being trapped in the relationship was influenced by all the IIVV (* p < .05), although perceived support proved to be a poor predictor ( beta = -.053). A path analysis reflected a negative effect of coercion (regression weight = -.533) and physical violence ( .926) on perceived support, with all forms of victimization being precursors for feeling trapped in a relationship. These results show the negative effect of victimization on expectations of support in young people, which may make it difficult to begin the process of seeking help. They also highlight the need to increase the visibility of resources available in educational settings to provide an early response to intimate partner violence. PMID- 29475421 TI - Mediating the Maltreatment-Delinquency Relationship: The Role of Triad Gang Membership. AB - The primary aim of this article is to examine the role of triad affiliation in mediating the relationship between child maltreatment (neglect, punishment, emotional abuse, and sexual abuse) and delinquency among active young gang members in Hong Kong. A sample of 177 gang members aged 12 to 24 was recruited to complete a questionnaire with the assistance of a youth outreach social work team. Neglect was identified as the most common form of maltreatment, followed by emotional abuse, punishment, and sexual abuse. Mediation analyses confirmed that triad affiliation acts as a mediating variable in the child maltreatment delinquency relationship, except in cases of sexual abuse. Only the relationship between punishment and delinquency was found to be fully mediated by triad affiliation; partial mediation effects were found for neglect and emotional abuse. Recommendations for child protection and youth workers are provided. PMID- 29475422 TI - A Latent Class Analysis of Early Adolescent Peer and Dating Violence: Associations With Symptoms of Depression and Anxiety. AB - Violence within peer and dating contexts is prevalent among early adolescents. Youth may be victims and/or aggressors and be involved in violence across multiple contexts, resulting in negative outcomes. This study identified patterns of perpetration and victimization for peer and dating violence, using a latent class analysis (LCA), and examined how different patterns of engaging in or experiencing violence among early adolescents were associated with symptoms of depression and anxiety. Participants included a sample of 508 racially and ethnically diverse youth (51% male) who had dated in the past 3 months. Youth were in the seventh grade within 37 schools and were primarily from economically disadvantaged communities across four sites in the United States. LCA identified three classes: (a) a low involvement in violence class, (b) a peer aggression and peer victimization class, and (c) a peer and dating violence class. Youth involved with multiple forms of violence displayed significantly higher levels of depressive and anxious symptoms than those with low involvement in violence. Study findings revealed the importance of understanding how peer and dating violence co-occur, and how different patterns of aggression and victimization were related to internalizing symptoms. Prevention efforts should address the intersection of victimization and perpetration in peer and dating contexts in potentially reducing internalizing symptoms among early adolescents. PMID- 29475423 TI - Poor Parenting, Attachment Style, and Dating Violence Perpetration Among College Students. AB - Although dating violence is prevalent among college students, little is known about how both attachment style and participation in risky behaviors contribute to this pattern of violence. To address this literature gap, we examine the role of poor parenting, child abuse, attachment style, and risky sexual and drug use behaviors on dating violence perpetration among 1,432 college students (51% female). Path analysis results revealed that females were more likely to report greater attachment anxiety but lower attachment avoidance compared with males. Correlates of attachment anxiety included child physical abuse, witnessing parental violence, and poorer maternal relationship quality whereas attachment avoidant behavior was linked to more physical abuse and poorer maternal relationship quality. Females were more likely to perpetrate dating violence as were those with greater attachment anxiety and lower attachment avoidance. Other correlates of dating violence perpetration included sexual and drug risk behaviors. Finally, distal factors (i.e., more child physical abuse and poorer maternal relationship quality) also were associated with dating violence perpetration. Study implications are also discussed. PMID- 29475424 TI - Validation of the English Language Version of the Violent Ideations Scale. AB - This study used a within-participant design to evaluate the concurrent validity and test-retest reliability of the Violent Ideations Scale in a general population, English-speaking opportunistic sample. Data from 116 adult participants ( M age = 33.7, SD = 11.9, male = 30 [25.9%]) were used to compare scores on the Violent Ideations Scale and Aggression Questionnaire and responses to the Schedule of Imagined Violence. A subgroup of 27 participants ( M age = 37.2, SD = 13.6, male = 8 [29.6%]) completed the Violent Ideations Scale on a second occasion, 2 weeks later. The Violent Ideations Scale was found to correlate significantly with the Aggression Questionnaire subscale and total scores, with the strongest correlations being with physical aggression and total scores. Participants were more likely to be categorized as having experienced a violent ideation based on responses to the Violent Ideation Scale, compared with the Schedule of Imagined Violence, most likely due to the Schedule of Imagined Violence underestimating the prevalence of violent ideation. A significant, strong correlation was found between total Violent Ideations Scale scores at Time 1 and Time 2. Overall, the Violent Ideations Scale was found to have concurrent validity when compared with the Aggression Questionnaire and good test-retest reliability, suggesting that it would be suitable for use with a nonclinical, English-speaking sample. PMID- 29475425 TI - Gender and Educational Differences in Perception of Domestic Violence Against Women Among Libyan Migrants in Manchester. AB - Domestic violence against women (DVAW) is a worldwide phenomenon and refers to any act committed against women that results in physical and psychological harm, and coercion, loss of liberty, and deprivation. There is a dearth of research and information about the extent and prevalence of domestic violence among Libyan communities. The aim of the study was to explore community knowledge of, and attitudes toward, DVAW and to improve our understanding of the factors that influence knowledge, attitudes, and responses, particularly educational and gender differences. Using snowball sampling, we analyzed 20 semistructured interviews with Libyans living in Manchester, United Kingdom. We found gender and education-influenced participants' perception of DVAW. Men in general did not recognize DVAW as a serious social problem; noticeably, they saw it as a personal and family issue. Knowing attitudes toward DVAW is necessary for government and communities' prevention policies as attitudes influence perpetration of DVAW. PMID- 29475426 TI - Understanding Empathy, Self-Esteem, and Adult Attachment in Sexual Offenders and Partner-Violent Men. AB - The assessment and treatment of emotional variables is a priority in the rehabilitation of offenders. Although theoretical proposals suggest a clear relationship between violence and self-esteem, attachment, and empathy, the research carried out to date has reached contradictory results due mainly to differences in the measurements used, the reliability of self-reports, or even to problems with the definition of the constructs. The present study analyzed these three variables in a prison sample of sexual offenders ( n = 48) and partner violent men ( n = 68), using the Interpersonal Reactivity Index, the Rape Empathy Measure, the Rosenberg Self-Esteem Scale, and the Adult Attachment Questionnaire. Results confirmed the low utility of nonspecific empathy, the predominance of high self-esteem, and the difficulty of identifying an insecure attachment. The implications of the use of these variables in the treatment of offenders, and the need to improve the assessment tools, are discussed. PMID- 29475428 TI - Editorial: New Experimental and Computational Tools for Drug Discovery: From Chemistry to Biology. Part-III. PMID- 29475429 TI - Editorial: Biological Profiles of Coumarin Scaffold - Part 1. PMID- 29475431 TI - The effect of CBT and its modifications for relapse prevention in major depressive disorder: a systematic review and meta-analysis. AB - BACKGROUND: The risk of relapse in major depressive disorder (MDD) is associated with high worldwide disease burden. Cognitive behavioral therapy (CBT) and its modifications might be effective in relapse prevention. The aim of this review was to evaluate the efficacy of these treatments for reducing relapse of MDD. METHODS: The retrieval was performed in the databases of MEDLINE via Pubmed, EMBASE and PsycINFO via OVID, The Cochrane Library and four Chinese databases. Clinical trials registry platforms and references of relevant articles were retrieved as well. Hazard ratio (HR) and corresponding 95% confidence interval (CI) were used to pool evidences. RESULTS: A total of 16 eligible trials involving 1945 participants were included. In the first 12 months, CBT was more efficacious than control in reducing the risk of developing a new episode of depression for MDD patients in remission (HR:0.50, 95%CI:0.35-0.72, I2 = 11%). Mindfulness-based cognitive therapy (MBCT) was more efficacious than control only among patients with 3 or more previous depressive episodes (HR:0.46, 95%CI:0.31 0.70, I2 = 38%). Besides, compared with maintenance antidepressant medication (m ADM), MBCT was a more effective intervention (HR:0.76, 95%CI:0.58-0.98, I2 = 0%). These positive effects might be only maintained at two and nearly 6 years follow up for CBT. CONCLUSION: The use of CBT for MDD patients in remission might reduce risk of relapse. Besides, the effect of MBCT was moderated by number of prior episodes and MBCT might only be effective for MDD patients with 3 or more previous episodes. Further exploration for the influence of previous psychological intervention is required. PMID- 29475430 TI - Systematic review of pediatric health outcomes associated with childhood adversity. AB - BACKGROUND: Early detection of and intervention in childhood adversity has powerful potential to improve the health and well-being of children. A systematic review was conducted to better understand the pediatric health outcomes associated with childhood adversity. METHODS: PubMed, PsycArticles, and CINAHL were searched for relevant articles. Longitudinal studies examining various adverse childhood experiences and biological health outcomes occurring prior to age 20 were selected. Mental and behavioral health outcomes were excluded, as were physical health outcomes that were a direct result of adversity (i.e. abusive head trauma). Data were extracted and risk of bias was assessed by 2 independent reviewers. RESULTS: After identifying 15940 records, 35 studies were included in this review. Selected studies indicated that exposure to childhood adversity was associated with delays in cognitive development, asthma, infection, somatic complaints, and sleep disruption. Studies on household dysfunction reported an effect on weight during early childhood, and studies on maltreatment reported an effect on weight during adolescence. Maternal mental health issues were associated with elevated cortisol levels, and maltreatment was associated with blunted cortisol levels in childhood. Furthermore, exposure to childhood adversity was associated with alterations of immune and inflammatory response and stress-related accelerated telomere erosion. CONCLUSION: Childhood adversity affects brain development and multiple body systems, and the physiologic manifestations can be detectable in childhood. A history of childhood adversity should be considered in the differential diagnosis of developmental delay, asthma, recurrent infections requiring hospitalization, somatic complaints, and sleep disruption. The variability in children's response to adversity suggests complex underlying mechanisms and poses a challenge in the development of uniform diagnostic guidelines. More large longitudinal studies are needed to better understand how adversity, its timing and severity, and the presence of individual genetic, epigenetic, and protective factors affects children's health and development. PMID- 29475432 TI - Comparison of neonatal red cell transfusion reporting in neonatal intensive care units with blood product issue data: a validation study. AB - BACKGROUND: Infants in Neonatal Intensive Care Units represent a heavily transfused population, and are the focus of much research interest. Such research commonly relies on custom research databases or routinely collected data. Knowledge of the accuracy of transfusion recording in these databases is important. This study aims to assess the reporting of red blood cell transfusion neonatal intensive care unit data compared with routinely collected hospital blood bank ("Blood Watch") data. METHODS: Blood Watch data was linked with the NICUS Data Collection, and with routinely collected birth and hospital data for births between 2007 and 2010. The sensitivity, specificity, and positive and negative predictive values for transfusion were calculated, compared to the Blood Watch data. The agreement between the NICUS and Blood Watch datasets on quantity transfused was also assessed. RESULTS: Data was available on 3934 infants, of which 16.2% were transfused. Transfusion was reported in the NICUS Data Collection with high specificity (98.3%, 95% confidence interval (97.8%,98.7%)), but with some under-enumeration (sensitivity 89.2% (95% CI 86.5%,91.5%)). There was excellent agreement between the NICUS and Blood Watch datasets on quantity transfused (Kappa 0.90, 95% CI (0.88,0.92)). Transfusion reporting in the hospital data for these infants was also reliably reported (Sensitivity 83.7% (95% CI 80.6%,86.5%), specificity 99.1% (95% CI 98.7%,99.4%)). CONCLUSIONS: Transfusion is reliably reported in the neonatal intensive care unit data, with some under-reporting, and quantity transfused is well recorded. The NICUS Data Collection provides useful information on blood transfusions, including quantity of blood transfused in a high risk population. PMID- 29475433 TI - The minimally effective dose of sucrose for procedural pain relief in neonates: a randomized controlled trial. AB - BACKGROUND: Orally administered sucrose is effective and safe in reducing pain intensity during single, tissue-damaging procedures in neonates, and is commonly recommended in neonatal pain guidelines. However, there is wide variability in sucrose doses examined in research, and more than a 20-fold variation across neonatal care settings. The aim of this study was to determine the minimally effective dose of 24% sucrose for reducing pain in hospitalized neonates undergoing a single skin-breaking heel lance procedure. METHODS: A total of 245 neonates from 4 Canadian tertiary neonatal intensive care units (NICUs), born between 24 and 42 weeks gestational age (GA), were prospectively randomized to receive one of three doses of 24% sucrose, plus non-nutritive sucking/pacifier, 2 min before a routine heel lance: 0.1 ml (Group 1; n = 81), 0.5 ml (Group 2; n = 81), or 1.0 ml (Group 3; n = 83). The primary outcome was pain intensity measured at 30 and 60 s following the heel lance, using the Premature Infant Pain Profile Revised (PIPP-R). The secondary outcome was the incidence of adverse events. Analysis of covariance models, adjusting for GA and study site examined between group differences in pain intensity across intervention groups. RESULTS: There was no difference in mean pain intensity PIPP-R scores between treatment groups at 30 s (P = .97) and 60 s (P = .93); however, pain was not fully eliminated during the heel lance procedure. There were 5 reported adverse events among 5/245 (2.0%) neonates, with no significant differences in the proportion of events by sucrose dose (P = .62). All events resolved spontaneously without medical intervention. CONCLUSIONS: The minimally effective dose of 24% sucrose required to treat pain associated with a single heel lance in neonates was 0.1 ml. Further evaluation regarding the sustained effectiveness of this dose in reducing pain intensity in neonates for repeated painful procedures is warranted. TRIAL REGISTRATION: ClinicalTrials.gov : NCT02134873. Date: May 5, 2014 (retrospectively registered). PMID- 29475434 TI - Insulin/IGF-driven cancer cell-stroma crosstalk as a novel therapeutic target in pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) is unrivalled the deadliest gastrointestinal cancer in the western world. There is substantial evidence implying that insulin and insulin-like growth factor (IGF) signaling axis prompt PDAC into an advanced stage by enhancing tumor growth, metastasis and by driving therapy resistance. Numerous efforts have been made to block Insulin/IGF signaling pathway in cancer therapy. However, therapies that target the IGF1 receptor (IGF-1R) and IGF subtypes (IGF-1 and IGF-2) have been repeatedly unsuccessful. This failure may not only be due to the complexity and homology that is shared by Insulin and IGF receptors, but also due to the complex stroma cancer interactions in the pancreas. Shedding light on the interactions between the endocrine/exocrine pancreas and the stroma in PDAC is likely to steer us toward the development of novel treatments. In this review, we highlight the stroma-derived IGF signaling and IGF-binding proteins as potential novel therapeutic targets in PDAC. PMID- 29475436 TI - Correction to: the role of the complement system in traumatic brain injury: a review. AB - After publication of the article [1], it was brought to our attention that Tables 1 and 2 were missing from the final manuscript, These tables can be seen below and have now been added to the revised version of the article. PMID- 29475435 TI - Immune-enhancing activity of C. militaris fermented with Pediococcus pentosaceus (GRC-ON89A) in CY-induced immunosuppressed model. AB - BACKGROUND: Cordyceps militaris (C. militaris) is reported to exert various immune-activities. To enhance its activity, we fermented C.militaris with Pediococcus pentosaceus ON89A (GRC-ON89A). In this study, we investigated the immune-enhancing activity GRC-ON89A, using immunosuppressed model. METHODS: Immunosuppression was induced by intraperitoneal injection of cyclophosphamide (CY). Each group was orally administered distilled water, GRC-ON89A or GRC, respectively. The phagocytic activities against IgG -opsonized FITC particles were measured using phagocytosis assay kit. The contents beta-glucan, cordycepin and SCFA were measured using beta-glucan kit, liquid chromatography-mass spectrometry analysis and Gas chromatography-mass spectrometry analysis, respectively. RESULTS: Among GRC fermented with different probiotic strains (Pediococcus pentossaceus ON89A, Lactobacillus pentosus SC64, Weissella cibaria Sal.Cla22), GRC-ON89A induced the highest elevation of nitric oxide production and enhanced phagocytic activity of RAW 264.7 cells. In primary cultured murine macrophages from normal and CY-treated mice, GRC-ON89A increased phagocytic activity, compared to that in control cells. GRC-ON89A also significantly induced the mRNA expression of TNF-alpha and IL-10 and the levels of phosphorylated Lyn, Syk and MAPK. The contents of beta-glucan, cordycepin and SCFA in GRC significantly increased after ON89A fermentation, compared to those in unfermented GRC. CONCLUSION: These results indicate that GRC-ON89A exerted the enhanced immunostimulatory activity and contained more nutritional components, compared to unfermented GRC. Our results suggested that GRC-ON89A may be applied as an agent for immune boosting therapy in immune suppressed patients. PMID- 29475437 TI - Ethical implications of digital communication for the patient-clinician relationship: analysis of interviews with clinicians and young adults with long term conditions (the LYNC study). AB - BACKGROUND: Digital communication between a patient and their clinician offers the potential for improved patient care, particularly for young people with long term conditions who are at risk of service disengagement. However, its use raises a number of ethical questions which have not been explored in empirical studies. The objective of this study was to examine, from the patient and clinician perspective, the ethical implications of the use of digital clinical communication in the context of young people living with long-term conditions. METHODS: A total of 129 semi-structured interviews, 59 with young people and 70 with healthcare professionals, from 20 United Kingdom (UK)-based specialist clinics were conducted as part of the LYNC study. Transcripts from five sites (cancer, liver, renal, cystic fibrosis and mental health) were read by a core team to identify explicit and implicit ethical issues and develop descriptive ethical codes. Our subsequent thematic analysis was developed iteratively with reference to professional and ethical norms. RESULTS: Clinician participants saw digital clinical communication as potentially increasing patient empowerment and autonomy; improving trust between patient and healthcare professional; and reducing harm because of rapid access to clinical advice. However, they also described ethical challenges, including: difficulty with defining and maintaining boundaries of confidentiality; uncertainty regarding the level of consent required; and blurring of the limits of a clinician's duty of care when unlimited access is possible. Paradoxically, the use of digital clinical communication can create dependence rather than promote autonomy in some patients. Patient participants varied in their understanding of, and concern about, confidentiality in the context of digital communication. An overarching theme emerging from the data was a shifting of the boundaries of the patient-clinician relationship and the professional duty of care in the context of use of clinical digital communication. CONCLUSIONS: The ethical implications of clinical digital communication are complex and go beyond concerns about confidentiality and consent. Any development of this form of communication should consider its impact on the patient-clinician-relationship, and include appropriate safeguards to ensure that professional ethical obligations are adhered to. PMID- 29475438 TI - Selective killing of spinal cord neural stem cells impairs locomotor recovery in a mouse model of spinal cord injury. AB - BACKGROUND: Spinal cord injury (SCI) is a devastating condition mainly deriving from a traumatic damage of the spinal cord (SC). Immune cells and endogenous SC neural stem cells (SC-NSCs) play a critical role in wound healing processes, although both are ineffective to completely restore tissue functioning. The role of SC-NSCs in SCI and, in particular, whether such cells can interplay with the immune response are poorly investigated issues, although mechanisms governing such interactions might open new avenues to develop novel therapeutic approaches. METHODS: We used two transgenic mouse lines to trace as well as to kill SC-NSCs in mice receiving SCI. We used Nestin CreERT2 mice to trace SC-NSCs descendants in the spinal cord of mice subjected to SCI. While mice carrying the suicide gene thymidine kinase (TK) along with the GFP reporter, under the control of the Nestin promoter regions (NestinTK mice) were used to label and selectively kill SC-NSCs. RESULTS: We found that SC-NSCs are capable to self-activate after SCI. In addition, a significant worsening of clinical and pathological features of SCI was observed in the NestinTK mice, upon selective ablation of SC-NSCs before the injury induction. Finally, mice lacking in SC-NSCs and receiving SCI displayed reduced levels of different neurotrophic factors in the SC and significantly higher number of M1-like myeloid cells. CONCLUSION: Our data show that SC-NSCs undergo cell proliferation in response to traumatic spinal cord injury. Mice lacking SC-NSCs display overt microglia activation and exaggerate expression of pro-inflammatory cytokines. The absence of SC-NSCs impaired functional recovery as well as neuronal and oligodendrocyte cell survival. Collectively our data indicate that SC-NSCs can interact with microglia/macrophages modulating their activation/responses and that such interaction is importantly involved in mechanisms leading tissue recovery. PMID- 29475439 TI - Malaria training for community health workers in the setting of elimination: a qualitative study from China. AB - BACKGROUND: Continuous training of health workers is a key intervention to maintain their good performance and keep their vigilance during malaria elimination programmes. However, countries progressing toward malaria elimination have a largely decreased malaria disease burden, less frequent exposure of health workers to malaria patients, and new challenges in the epidemiology of the remaining malaria cases. Moreover, competing health priorities and usually a decline in resources and in political commitment also pose challenges to the elimination programme. As a consequence, the acceptability, sustainability, and impact of malaria training and education programmes face challenges. However, little is known of the perceptions and expectations of malaria training and education programmes of health workers being engaged in countries with malaria elimination programmes. METHODS: This qualitative study provides information on perceptions and expectations of health workers of malaria training programmes from China, which aims to malaria elimination by the year 2020. This study was embedded into a larger study on the challenges and lessons learned during the malaria surveillance strategy in China, involving 42 interviews with malaria experts, health staff, laboratory practitioners, and village doctors at the provincial, city, county, township, and village levels from Gansu province (northwestern China) and Jiangsu province (southeastern China). RESULTS: In the context of an increasing number of imported malaria cases in China, the majority of respondents emphasized the necessity and importance of such programmes and complained about a decreasing frequency of training courses. Moreover, they called for innovative strategies to improve the implementation and sustainability of the malaria training programmes until the elimination goal has been achieved. Perceptions and expectations of health workers from different health centres were quite different. Health workers from higher-level facilities were more concerned about technical training aspects, while health workers from periphery of the health system expected to receive more training on field work coordination and on specific public health actions with regard to case detection and focus investigation. CONCLUSIONS: There is need to guarantee an ongoing good training of health workers in China on malaria aspects until the year 2020 and probably beyond. PMID- 29475441 TI - SOX2OT variant 7 contributes to the synergistic interaction between EGCG and Doxorubicin to kill osteosarcoma via autophagy and stemness inhibition. AB - BACKGROUND: Doxorubicin is the preferred chemotherapeuticdrug for osteosarcoma treatment of which clinical efficacy is limited because of its chemo-resistance and cardiac toxicity. It is necessary to develop the combination regimen with complementary molecular mechanisms to reduce the side effects and enhance sensitivity of Doxorubicin. EGCG is a polyphenol in green tea with antitumor bioactivity,which has been found that its combination with certain chemotherapeutic drugs could improve the antitumor efficiency. METHODS: In this study, MTT assay was used to detect the cell growth inhibition The CD133+/CD44+ cells were isolated from U2OS and SaoS2 cell lines using magnetic-activated cell sorting and identified by flow cytometry analysis. qRT-PCR was used for determining the relative mRNA levels of key genes. Immunofluorescence was performed to evaluate the autophagy flux alterations. Self-renewal ability was accessed by sphere-forming assay. Tumorigenicity in nude mice was preformed to evaluate tumorigenicity in vivo. RESULTS: We found that EGCG targeting LncRNA SOX2OT variant 7 produced synergistic effects with Doxorubicin on osteosarcoma cell growth inhibition. On the one hand, EGCG could reduce the Doxorubicin induced pro-survival autophagy through decreasing SOX2OT variant 7 to improve the growth inhibition of Doxorubicin. On the other hand, EGCG could partially inactivate Notch3/DLL3 signaling cascade targeting SOX2OT variant 7 to reduce the stemness then abated drug-resistance of osteosarcoma cells. CONCLUSIONS: This study will help to reveal the molecular mechanisms of synergistic effects of EGCG and Doxorubicin on OS chemotherapy and improve the clinical efficacy of chemotherapy as well as provide a basis for developing antitumor drugs targeting osteosarcoma stem cells. PMID- 29475440 TI - Hospital-based interventions: a systematic review of staff-reported barriers and facilitators to implementation processes. AB - BACKGROUND: Translation of evidence-based interventions into hospital systems can provide immediate and substantial benefits to patient care and outcomes, but successful implementation is often not achieved. Existing literature describes a range of barriers and facilitators to the implementation process. This systematic review identifies and explores relationships between these barriers and facilitators to highlight key domains that need to be addressed by researchers and clinicians seeking to implement hospital-based, patient-focused interventions. METHODS: We searched MEDLINE, PsychInfo, Embase, Web of Science, and CINAHL using search terms focused specifically on barriers and facilitators to the implementation of patient-focused interventions in hospital settings. To be eligible, papers needed to have collected formal data (qualitative or quantitative) that specifically assessed the implementation process, as experienced by the staff involved. RESULTS: Of 4239 papers initially retrieved, 43 papers met inclusion criteria. Staff-identified barriers and facilitators to implementation were grouped into three main domains: system, staff, and intervention. Bi-directional associations were evident between these domains, with the strongest links evident between staff and intervention. CONCLUSIONS: Researchers and health professionals engaged in designing patient-focused interventions need to consider barriers and facilitators across all three identified domains to increase the likelihood of implementation success. The interrelationships between domains are also crucial, as resources in one area can be leveraged to address barriers in others. These findings emphasize the importance of careful intervention design and pre-implementation planning in response to the specific system and staff context in order to increase likelihood of effective and sustainable implementation. TRIAL REGISTRATION: This review was registered on the PROSPERO database: CRD42017057554 in February 2017. PMID- 29475442 TI - Correction to: A vicious circle between insulin resistance and inflammation in nonalcoholic fatty liver disease. AB - Following publication of the original article [1], the corresponding author reported that he had mistyped the first author's unit. The affiliation of Zhonge Chen, "Medical Center of the Graduate School, Nanchang University, China", should be changed to "Department of Gastroenterology, Second Affiliated Hospital, Nanchang University Nanchang, China". All the other authors have agreed to this change. The corrected version should be as follows. PMID- 29475443 TI - Correction to: Open-label pilot for treatment targeting gut dysbiosis in myalgic encephalomyelitis/chronic fatigue syndrome: neuropsychological symptoms and sex comparisons. AB - The original version of this article [1], published on 6 February 2018, contains a mistake in the 'Conclusions' section. The corrected version of the affected sentence is given below and the corrected part is marked in bold. PMID- 29475444 TI - Trial Forge Guidance 1: what is a Study Within A Trial (SWAT)? AB - Randomised trials are a central component of all evidence-informed health care systems and the evidence coming from them helps to support health care users, health professionals and others to make more informed decisions about treatment. The evidence available to trialists to support decisions on design, conduct and reporting of randomised trials is, however, sparse. Trial Forge is an initiative that aims to increase the evidence base for trial decision-making and in doing so, to improve trial efficiency.One way to fill gaps in evidence is to run Studies Within A Trial, or SWATs. This guidance document provides a brief definition of SWATs, an explanation of why they are important and some practical 'top tips' that come from existing experience of doing SWATs. We hope the guidance will be useful to trialists, methodologists, funders, approvals agencies and others in making clear what a SWAT is, as well as what is involved in doing one. PMID- 29475445 TI - Prognosis of patients excluded by the definition of septic shock based on their lactate levels after initial fluid resuscitation: a prospective multi-center observational study. AB - BACKGROUND: Septic shock can be defined both by the presence of hyperlactatemia and need of vasopressors. Lactate levels should be measured after volume resuscitation (as per the Sepsis-3 definition). However, currently, no studies have evaluated patients who have been excluded by the new criteria for septic shock. The aim of this study was to determine the clinical characteristics and prognosis of these patients, based on their lactate levels after initial fluid resuscitation. METHODS: This observational study was performed using a prospective, multi-center registry of septic shock, with the participation of 10 hospitals in the Korean Shock Society, between October 2015 and February 2017. We compared the 28-day mortality between patients who were excluded from the new definition (defined as lactate level <2 mmol/L after volume resuscitation) and those who were not (>=2 mmol/L after volume resuscitation), from among a cohort of patients with refractory hypotension, and requiring the use of vasopressors. Other outcome variables such as in-hospital mortality, intensive care unit (ICU) stay (days), Sequential Organ Failure Assessment (SOFA) scores and Acute Physiology and Chronic Health Evaluation (APACHE) II scores were also analyzed. RESULTS: Of 567 patients with refractory hypotension, requiring the use of vasopressors, 435 had elevated lactate levels, while 83 did not have elevated lactate levels (either initially or after volume resuscitation), and 49 (8.2%) had elevated lactate levels initially, which normalized after fluid resuscitation. Thus, these 49 patients were excluded by the new definition of septic shock. These patients, in whom perfusion was restored, demonstrated significantly lower age, platelet count, and initial and subsequent lactate levels (all p < 0.01). Similarly, significantly lower 28-day mortality was observed in these patients than in those who had not been excluded (8.2% vs 25.5%, p = 0.02). In-hospital mortality and the maximum SOFA score were also significantly lower in the excluded patients group (p = 0.03, both). CONCLUSIONS: It seems reasonable for septic shock to be defined by the lactate levels after volume resuscitation. However, owing to the small number of patients in whom lactate levels were improved, further study is warranted. PMID- 29475447 TI - Correction to: dengue virus causes changes of MicroRNA-genes regulatory network revealing potential targets for antiviral drugs. AB - After publication of the article [1], it has been brought to our attention that an author's name was spelt incorrectly in the original published article. Yonghua Wang was previously spelt "Yonghua Wan". This has now been corrected in the revised version of the article. PMID- 29475446 TI - The effects of fatty fish intake on adolescents' nutritional status and associations with attention performance: results from the FINS-TEENS randomized controlled trial. AB - BACKGROUND: Adolescence involves changes in dietary habits that may induce imbalances in the intake of different nutrients. Fish is an important dietary source of omega-3 (n-3) long-chain polyunsaturated fatty acids (LCPUFAs), vitamin D, several minerals and high-quality protein. By using secondary outcomes and exploratory analyses, the aims of this paper were to evaluate if nutritional biomarkers (red blood cell fatty acids, serum (s)-25(OH)D, s-ferritin and urinary iodine concentration (UIC)) were altered during a dietary intervention, and if they mediated previously reported changes in attention performance. In addition, to examine the status of the biomarkers and explore associations between dietary pattern, biomarkers and attention performance cross-sectionally at baseline. METHODS: The Fish Intervention Studies-TEENS (FINS-TEENS) was a three-armed intervention trial, including adolescents from eight secondary schools (n = 415; age: 14-15y) in Bergen, Norway. Participants were individually randomized to receive either fish meals, meat meals or n-3 LCPUFA supplements, three times a week for a total of 12 weeks. Blood and urine samples were collected pre and post intervention and attention performance was assessed with the d2 test of attention. Analyses of covariance (ANCOVA) assessed differences between groups in changes of biomarkers and linear mixed models were applied in analyses of attention performance and biomarkers. The trial is registered in ClinicalTrials.gov (NCT02350322). RESULTS: At baseline, the mean omega-3 index was 5.8 +/- 1.3% and deficient status were identified for s-25(OH)D (54%), s ferritin (10%) and UIC (40%). The intervention resulted in an increase in DHA and the omega-3 index which was larger in the supplement group compared to the fish and meat group (P < 0.01), and in the fish group compared to the meat group (P < 0.01). No differences between the groups were observed for changes in 25(OH)D, s ferritin or UIC. None of the biomarkers mediated performance in the d2 test. The intake of fatty fish and a healthy dietary pattern was associated with scores in processing speed at baseline. CONCLUSIONS: These results show that Norwegian adolescents have insufficient status of important nutrients, which may be improved with fatty fish consumption or n-3 LCPUFA supplements. However, nutritional status was not associated with scores in the d2 test of attention. PMID- 29475448 TI - Protective and restorative effects of the traditional Chinese medicine Jitai tablet against methamphetamine-induced dopaminergic neurotoxicity. AB - BACKGROUND: Methamphetamine (METH) is a psychostimulant with high abuse liability that affects the monoamine neurotransmitter systems, particularly the dopamine system. Currently there are no effective medications for the treatment of METH abuse to restore METH-induced dopaminergic dysfunction. The Jitai tablet (JTT), a commercial traditional Chinese medicinal preparation, has been shown to modulate the dopaminergic function both in heroin addicts and in morphine-dependent rats. The purpose of this study was to investigate, in a rodent model, whether JTT can protect against METH-induced neurotoxicity, and/or restore METH-damaged dopaminergic function. METHODS: Immunohistochemical staining and/or autoradiography staining were used to detect tyrosine hydroxylase (TH) expression in the substantia nigra, and to examine the levels of dopamine transporter (DAT), dopamine D2 receptor (D2R) and TH levels in the striatum. Using a stereotyped behavior rating scale, we evaluated the inhibitory effect of JTT on METH-induced behavioral sensitization. RESULTS: Repeated METH administration induced obvious stereotyped behavior and neurotoxicity on the dopaminergic system. Pre-treatment with JTT significantly attenuated METH-induced stereotyped responses, and interdicted METH-induced changes in the levels of DAT, D2R and TH expression. Treatment with JTT after METH administration restored DAT, D2R and TH expression to normal levels. CONCLUSIONS: Our results indicated that JTT protects against METH-induced neurotoxicity and restores the dopaminergic function, and thus might be a potential treatment for the dopaminergic deficits associated with METH abuse. PMID- 29475449 TI - Cardio-metabolic and socio-environmental correlates of waist-to-height ratio in German primary schoolchildren: a cross-sectional exploration. AB - BACKGROUND: Controversial messages of childhood obesity emerge: Levelling off in terms of body mass index (BMI) is foiled by increases in abdominal obesity. Waist to-height ratio (WHtR) may be used as a screening tool for abdominal obesity in children. The aim of this study was to investigate clinical and socio environmental correlates of abdominal obesity in primary schoolchildren. METHODS: Cross-sectional data from 753 children participating in baseline assessments of the outcome evaluation of a school-based prevention program were analysed. Abdominal obesity was defined as WHtR >=0.5. According to German age and sex specific BMI-percentiles, overweight (>90th percentile) and obesity (>97th percentile) were determined. Anthropometric and sonographic measurements, blood pressure and blood samples were taken by clinical staff in a standardized manner. Socio-environmental and lifestyle data were assessed via parental questionnaires. Differences between abdominally obese children and others, and correlations of WHtR with clinical data were tested. Socio-environmental correlates of abdominal obesity were explored in a logistic regression analysis. RESULTS: At the time of the examination children were 7.57 +/- 0.42 years old. Abdominal obesity was observed in 132 (17.5%) children. According to BMI-percentiles, 22.9% of these children were obese, 38.2% overweight, and 38.2% normal weight. Affected children more often used screen media and less often participated in club sports. Abdominal obesity was associated with higher blood pressure, lower HDL- and higher LDL-cholesterol. WHtR significantly correlated with intra-abdominal fat thickness (IAF). The logistic regression model revealed migration background (odds ratio (OR) 2.12, 95% confidence interval (CI) [1.41, 3.19]), smoking during pregnancy (OR 2.30, 95% CI [1.37, 3.86]), parental obesity (OR 1.95, 95% CI [1.22, 3.10]) and higher educational level (OR 0.64, 95% CI [0.42, 0.98]) to be significantly associated with abdominal obesity in children. CONCLUSION: WHtR correlates strongly with IAF. Abdominal obesity in primary schoolchildren is associated with cardio-metabolic risk factors and also occurs in otherwise normal weight children. Against the background of rising numbers of abdominal obesity in children, targeted preventive measures are long overdue. The focus of such measures should be used on children with migration background and involve parents, especially those who are obese and those with lower educational levels. PMID- 29475450 TI - NEOnatal Central-venous Line Observational study on Thrombosis (NEOCLOT): evaluation of a national guideline on management of neonatal catheter-related thrombosis. AB - BACKGROUND: In critically ill (preterm) neonates, central venous catheters (CVCs) are increasingly used for administration of medication or parenteral nutrition. A serious complication, however, is the development of catheter-related thrombosis (CVC-thrombosis), which may resolve by itself or cause severe complications. Due to lack of evidence, management of neonatal CVC-thrombosis varies among neonatal intensive care units (NICUs). In the Netherlands an expert-based national management guideline has been developed which is implemented in all 10 NICUs in 2014. METHODS: The NEOCLOT study is a multicentre prospective observational cohort study, including 150 preterm and term infants (0-6 months) admitted to one of the 10 NICUs, developing CVC-thrombosis. Patient characteristics, thrombosis characteristics, risk factors, treatment strategies and outcome measures will be collected in a web-based database. Management of CVC-thrombosis will be performed as recommended in the protocol. Violations of the protocol will be noted. Primary outcome measures are a composite efficacy outcome consisting of death due to CVC thrombosis and recurrent thrombosis, and a safety outcome consisting of the incidence of major bleedings during therapy. Secondary outcomes include individual components of primary efficacy outcome, clinically relevant non-major and minor bleedings and the frequency of risk factors, protocol variations, residual thrombosis and post thrombotic syndrome. DISCUSSION: The NEOCLOT study will evaluate the efficacy and safety of the new, national, neonatal CVC thrombosis guideline. Furthermore, risk factors as well as long-term consequences of CVC-thrombosis will be analysed. TRIAL REGISTRATION: Trial registration: Nederlands Trial Register NTR4336 . Registered 24 December 2013. PMID- 29475451 TI - Measuring behavior across scales. AB - The need for high-throughput, precise, and meaningful methods for measuring behavior has been amplified by our recent successes in measuring and manipulating neural circuitry. The largest challenges associated with moving in this direction, however, are not technical but are instead conceptual: what numbers should one put on the movements an animal is performing (or not performing)? In this review, I will describe how theoretical and data analytical ideas are interfacing with recently-developed computational and experimental methodologies to answer these questions across a variety of contexts, length scales, and time scales. I will attempt to highlight commonalities between approaches and areas where further advances are necessary to place behavior on the same quantitative footing as other scientific fields. PMID- 29475452 TI - Impact of the Macmillan specialist Care at Home service: a mixed methods evaluation across six sites. AB - BACKGROUND: The Midhurst Macmillan Specialist Palliative Care at Home Service was founded in 2006 to improve community-based palliative care provision. Principal components include; early referral; home-based clinical interventions; close partnership working; and flexible teamwork. Following a successful introduction, the model was implemented in six further sites across England. This article reports a mixed methods evaluation of the implementation across these 'Innovation Centres'. The evaluation aimed to assess the process and impact on staff, patients and carers of providing Macmillan Specialist Care at Home services across the six sites. METHODS: The study was set within a Realist Evaluation framework and used a longitudinal, mixed methods research design. Data collection over 15 months (2014-2016) included: Quantitative outcome measures - Palliative Performance Scale [PPS] and Palliative Prognostic Index [PPI] (n = 2711); Integrated Palliative Outcome Scales [IPOS] (n = 1157); Carers Support Needs Assessment Tool [CSNAT] (n = 241); Views of Informal Carers -Evaluation of Services [VOICES-SF] (n = 102); a custom-designed Service Data Tool [SDT] that gathered prospective data from each site (n = 88). Qualitative data methods included: focus groups with project team and staff (n = 32 groups with n = 190 participants), and, volunteers (n = 6 groups with n = 32 participants). Quantitative data were analysed using SPPS Vs. 21 and qualitative data was examined via thematic analysis. RESULTS: Comparison of findings across the six sites revealed the impact of their unique configurations on outcomes, compounded by variations in stage and mode of implementation. PPS, PPI and IPOS data revealed disparity in early referral criteria, complicated by contrasting interpretations of palliative care. The qualitative analysis, CSNAT and VOICES-SF data confirmed the value of the Macmillan model of care but uptake of specialist home-based clinical interventions was limited. The Macmillan brand engendered patient and carer confidence, bringing added value to existing services. Significant findings included better co-ordination of palliative care through project management and a single referral point and multi-disciplinary teamwork including leadership from consultants in palliative medicine, the role of health care assistants in rapid referral, and volunteer support. CONCLUSIONS: Macmillan Specialist Care at Home increases patient choice about place of death and enhances the quality of end of life experience. Clarification of key components is advocated to aid consistency of implementation across different sites and support future evaluative work. PMID- 29475453 TI - Whole transcriptome analysis reveals differential gene expression profile reflecting macrophage polarization in response to influenza A H5N1 virus infection. AB - BACKGROUND: Avian influenza A H5N1 virus can cause lethal disease in humans. The virus can trigger severe pneumonia and lead to acute respiratory distress syndrome. Data from clinical, in vitro and in vivo suggest that virus-induced cytokine dysregulation could be a contributory factor to the pathogenesis of human H5N1 disease. However, the precise mechanism of H5N1 infection eliciting the unique host response are still not well understood. METHODS: To obtain a better understanding of the molecular events at the earliest time points, we used RNA-Seq to quantify and compare the host mRNA and miRNA transcriptomes induced by the highly pathogenic influenza A H5N1 (A/Vietnam/3212/04) or low virulent H1N1 (A/Hong Kong/54/98) viruses in human monocyte-derived macrophages at 1-, 3-, and 6-h post infection. RESULTS: Our data reveals that two macrophage populations corresponding to M1 (classically activated) and M2 (alternatively activated) macrophage subtypes respond distinctly to H5N1 virus infection when compared to H1N1 virus or mock infection, a distinction that could not be made from previous microarray studies. When this confounding variable is considered in our statistical model, a clear set of dysregulated genes and pathways emerges specifically in H5N1 virus-infected macrophages at 6-h post infection, whilst was not found with H1N1 virus infection. Furthermore, altered expression of genes in these pathways, which have been previously implicated in viral host response, occurs specifically in the M1 subtype. We observe a significant up-regulation of genes in the RIG-I-like receptor signaling pathway. In particular, interferons, and interferon-stimulated genes are broadly affected. The negative regulators of interferon signaling, the suppressors of cytokine signaling, SOCS-1 and SOCS-3, were found to be markedly up-regulated in the initial round of H5N1 virus replication. Elevated levels of these suppressors could lead to the eventual suppression of cellular antiviral genes, contributing to pathophysiology of H5N1 virus infection. CONCLUSIONS: Our study provides important mechanistic insights into the understanding of H5N1 viral pathogenesis and the multi-faceted host immune responses. The dysregulated genes could be potential candidates as therapeutic targets for treating H5N1 disease. PMID- 29475454 TI - Can P-glycoprotein and beta-tubulin polymorphisms be used as genetic markers of resistance in Dirofilaria immitis from Rio de Janeiro, Brazil? AB - OBJECTIVE: Dirofilaria immitis, the causative agent of canine heartworm infection, is worldwide the most important filarid to affect domestic dogs. Prevention of this infection is done by macrocyclic lactones, but some reports on the lack of efficacy have been published. Although the actual cause of resistance is unknown, single nucleotide polymorphisms (SNPs) on a P-glycoprotein ABC transporter and beta-tubulin genes have been pointed out as candidates for genetic markers of resistance. We conducted a survey to verify the presence of these suggested genetic markers in microfilariae from 30 naturally infected dogs under macrocyclic lactones treatment living in an endemic area in the state of Rio de Janeiro. RESULTS: The analysis of these specific SNPs demonstrated no sign of polymorphism on the P-glycoprotein loci, while 72 and 48% of the samples were polymorphic to the first and second SNPs on beta-tubulin loci, respectively. This work demonstrates that the P-glycoprotein position 11 and 618 were not polymorphic and, therefore, not suitable as a genetic marker of resistance in Rio de Janeiro whereas both beta-tubulin loci were polimorphic. This work points out the difficulty of finding a universal genetic marker for resistance. PMID- 29475455 TI - Rapid bupropion-induced hepatotoxicity: a case report and review of the literature. AB - BACKGROUND: Bupropion is an antidepressant that is also used as a non-nicotine method to aid in smoking cessation. Bupropion-induced hepatotoxicity is quoted to affect between 0.1% and 1% of treated patients with either a hepatocellular and/or cholestatic pattern of damage. The mechanism of damage is considered to be predominantly immune-mediated with the presence of a hypersensitivity syndrome (fever, rash, eosinophilia, autoantibodies) and a short latency period (1-6 weeks). We believe our reporting of this case to the already existing small list of only seven cases in the world literature will help practicing physicians to deal with the diagnostic and management dilemmas that bupropion-induced hepatotoxicity brings. CASE PRESENTATION: A 50-year-old Caucasian woman presented to our hospital with significant derangement of liver transaminases after 6 days of bupropion treatment for smoking cessation. The patient's other medications were considered unlikely to be the cause of the hepatotoxicity and were therefore continued. The patient's liver function tests normalized on withdrawal of bupropion, confirming that bupropion was the probable cause of the patient's hepatotoxicity. CONCLUSIONS: We conclude that hepatotoxicity is a rare adverse effect of bupropion use, but physicians should be aware of the possibility of this potentially serious clinical picture of drug-induced hepatotoxicity with varied clinical presentation and prognosis. PMID- 29475456 TI - Detection of inspiratory recruitment of atelectasis by automated lung sound analysis as compared to four-dimensional computed tomography in a porcine lung injury model. AB - BACKGROUND: Cyclic recruitment and de-recruitment of atelectasis (c-R/D) is a contributor to ventilator-induced lung injury (VILI). Bedside detection of this dynamic process could improve ventilator management. This study investigated the potential of automated lung sound analysis to detect c-R/D as compared to four dimensional computed tomography (4DCT). METHODS: In ten piglets (25 +/- 2 kg), acoustic measurements from 34 thoracic piezoelectric sensors (Meditron ASA, Norway) were performed, time synchronized to 4DCT scans, at positive end expiratory pressures of 0, 5, 10, and 15 cmH2O during mechanical ventilation, before and after induction of c-R/D by surfactant washout. 4DCT was post processed for within-breath variation in atelectatic volume (Delta atelectasis) as a measure of c-R/D. Sound waveforms were evaluated for: 1) dynamic crackle energy (dCE): filtered crackle sounds (600-700 Hz); 2) fast Fourier transform area (FFT area): spectral content above 500 Hz in frequency and above -70 dB in amplitude in proportion to the total amount of sound above -70 dB amplitude; and 3) dynamic spectral coherence (dSC): variation in acoustical homogeneity over time. Parameters were analyzed for global, nondependent, central, and dependent lung areas. RESULTS: In healthy lungs, negligible values of Delta atelectasis, dCE, and FFT area occurred. In lavage lung injury, the novel dCE parameter showed the best correlation to Delta atelectasis in dependent lung areas (R2 = 0.88) where c-R/D took place. dCE was superior to FFT area analysis for each lung region examined. The analysis of dSC could predict the lung regions where c-R/D originated. CONCLUSIONS: c-R/D is associated with the occurrence of fine crackle sounds as demonstrated by dCE analysis. Standardized computer-assisted analysis of dCE and dSC seems to be a promising method for depicting c-R/D. PMID- 29475457 TI - Latent class analysis to evaluate performance of point-of-care CCA for low intensity Schistosoma mansoni infections in Burundi. AB - BACKGROUND: Kato-Katz examination of stool smears is the field-standard method for detecting Schistosoma mansoni infection. However, Kato-Katz misses many active infections, especially of light intensity. Point-of-care circulating cathodic antigen (CCA) is an alternative field diagnostic that is more sensitive than Kato-Katz when intensity is low, but interpretation of CCA-trace results is unclear. To evaluate trace results, we tested urine and stool specimens from 398 pupils from eight schools in Burundi using four approaches: two in Burundi and two in a laboratory in Leiden, the Netherlands. In Burundi, we used Kato-Katz and point-of-care CCA (CCAB). In Leiden, we repeated the CCA (CCAL) and also used Up Converting Phosphor Circulating Anodic Antigen (CAA). METHODS: We applied Bayesian latent class analyses (LCA), first considering CCA traces as negative and then as positive. We used the LCA output to estimate validity of the prevalence estimates of each test in comparison to the population-level infection prevalence and estimated the proportion of trace results that were likely true positives. RESULTS: Kato-Katz yielded the lowest prevalence (6.8%), and CCAB with trace considered positive yielded the highest (53.5%). There were many more trace results recorded by CCA in Burundi (32.4%) than in Leiden (2.3%). Estimated prevalence with CAA was 46.5%. LCA indicated that Kato-Katz had the lowest sensitivity: 15.9% [Bayesian Credible Interval (BCI): 9.2-23.5%] with CCA-trace considered negative and 15.0% with trace as positive (BCI: 9.6-21.4%), implying that Kato-Katz missed approximately 85% of infections. CCAB underestimated disease prevalence when trace was considered negative and overestimated disease prevalence when trace was considered positive, by approximately 12 percentage points each way, and CAA overestimated prevalence in both models. Our results suggest that approximately 52.2% (BCI: 37.8-5.8%) of the CCAB trace readings were true infections. CONCLUSIONS: Whether measured in the laboratory or the field, CCA outperformed Kato-Katz at the low infection intensities in Burundi. CCA with trace as negative likely missed many infections, whereas CCA with trace as positive overestimated prevalence. In the absence of a field-friendly gold standard diagnostic, the use of a variety of diagnostics with differing properties will become increasingly important as programs move towards elimination of schistosomiasis. It is clear that CCA is a valuable tool for the detection and mapping of S. mansoni infection in the field and CAA may be a valuable field tool in the future. PMID- 29475458 TI - Clinical significance of polyglutamylation in primary central nervous system lymphoma. AB - The therapeutic response to high-dose methotrexate (HD-MTX) therapy for primary central nervous system lymphoma (PCNSL) varies. Polyglutamylation is a reversible protein modification with a high occurrence rate in tumor cells. MTX incorporated into cells is polyglutamylated and strongly binds to dihydrofolate reductase without competitive inhibition by leucovorin (LV). Tumor cells with high polyglutamylation levels are selectively killed, whereas normal cells with lower polyglutamylation are rescued by LV. We hypothesized that the extent of polyglutamylation in tumor cells determines treatment resistance. Here, we investigated the therapeutic response of PCNSL to HD-MTX therapy with LV rescue based on polyglutamylation status. Among 113 consecutive PCNSL patients who underwent HD-MTX therapy in our department between 2001 and 2014, polyglutamylation was evaluated by immunostaining in 82 cases, with relationships between polyglutamylation and therapeutic response retrospectively examined. Human malignant lymphoma lines were used for in vitro experiments, and folpolyglutamate synthetase (FPGS), which induces polyglutamylation, was knocked down with short-hairpin RNA, and a stable cell line with a low rate of polyglutamylation was established. Cell viability after MTX treatment with LV rescue was evaluated using sodium butyrate (NaBu), a histone-deacetylase inhibitor that induces polyglutamylation by elevating FPGS expression. The complete response rate was significantly higher in the group with polyglutamylation than in the non-polyglutamylation group [58.1% (25/43) and 33.3% (13/39), respectively] (p < 0.05), and progression-free survival was also significantly increased in the group with polyglutamylation (p < 0.01). In vitro, the relief effect of LV after MTX administration was significantly enhanced after FPGS knockdown in al cell lines, whereas enhancement of FPGS expression by NaBu treatment significantly reduced this relief effect. These findings suggested that polyglutamylation could be a predictor of therapeutic response to HD-MTX therapy with LV rescue in PCNSL. Combination therapy with HD-MTX and polyglutamylation inducing agents might represent a promising strategy for PCNSL treatment. PMID- 29475459 TI - Immune profiling of human prostate epithelial cells determined by expression of p38/TRAF-6/ERK MAP kinases pathways. AB - The aim of the present work was to study the immune profiling of prostate epithelial cells by the expression of ASK-1/p38 and Raf-1/ERK MAP Kinases signaling pathways mediated by TRAF-6. Immunohistochemical and Western blot analyses for TRAF-6, ASK-1, MEK-6, p38, Raf-1, MEK-1, ERK-1, ERK-2 and PSA were carried out in 5 samples of normal prostate gland, 24 samples of BPH and 19 samples of PC. Immunoreaction to TRAF-6 was found in the cytoplasm of epithelial cells of BPH and tumor cells of PC samples. For patients with the profile (TRAF 6+), optical densities revealed a weak immunoexpression of ASK-1 in PC compared to BPH patients. Whereas, immunoexpression to Raf-1 was higher in PC than in BPH. According to the expression of ASK-1 and Raf-1, two main profiles were identified: (TRAF-6+, ASK-1+, Raf-1+) and (TRAF-6+, ASK-1+, RAF-1-) in both BPH and PC. In addition, ASK-1/p38 axis expression was increased in BPH. Raf-1/ERK signaling pathway was increased in PC samples. On the other hand, representing of individual signaling protein expression enclosing each of p38 and ERK MAP Kinases according to TRAF-6+ showed a qualitative behavior of ASK61/p38 and Raf-1/ERK signaling pathways and a dynamic expression of PSA associated with immune and inflammatory process. These findings suggest that prostate epithelial cell could able an immune and inflammatory setting. PMID- 29475460 TI - Brain-derived neurotrophic factor preserves intestinal mucosal barrier function and alters gut microbiota in mice. AB - The intestinal mucosal barrier (IMB) enables the intestine to provide adequate containment of luminal microorganisms and molecules while preserving the ability to absorb nutrients. In this study, we explored the effect of brain-derived neurotrophic factor (BDNF) on IMB function and gut microbiota in mice. BDNF gene knock-out mice (the BDNF+/- group) and wild-type mice (the BDNF+/+ group) were selected. The gut microbiota of these mice was analyzed by denaturing gradient gel electrophoresis (DGGE) assay. The ultrastructure of the ileum and the colonic epithelium obtained from decapitated mice were observed by transmission electron microscopy. The protein expression of epithelial tight junction proteins, zonula occludens-1 (ZO-1) and occludin was detected by immunohistochemistry staining. The protein expression of claudin-1 and claudin-2 was determined by Western blotting. The DGGE band patterns of gut microbiota in the BDNF+/- group were significantly different from that in the BDNF+/+ group, which indicated that the BDNF expression alters the gut microbiota in mice. Compared with the BDNF+/+ group, the BDNF+/- group presented no significant difference in the ultrastructure of ileal epithelium; however, a significant difference was observed in the colonic epithelial barrier, manifested by decreased microvilli, widening intercellular space and bacterial invasion. Compared with the BDNF+/+ group, the expression of ZO-1 and occludin in the BDNF+/- group was significantly decreased. The expression of claudin-1 in the BDNF+/- group was significantly reduced, while the expression of claudin-2 was elevated. These findings indicate that BDNF preserves IMB function and modulates gut microbiota in mice. PMID- 29475463 TI - The effectiveness of interprofessional education in healthcare: A systematic review and meta-analysis. AB - Interprofessional education (IPE) emphasizes collaborative practice that aims at promoting the working relationships between two or more healthcare professions. However, there is paucity of literature about the effectiveness of IPE program in the healthcare. This systematic review and meta-analysis aims to objectively determine the effectiveness of IPE in that field in terms of the improvement of students' knowledge, skills and attitudes. The databases of OVID, ISI Knowledge of Science, and Medline (PubMed) were searched for the full-text English language articles published during 2000-2016 using the MeSH terms "interprofessional education" AND "healthcare professionals" AND "multi-professional" AND "impact" AND "effectiveness" OR "collaborative practice" OR "medical students" in Endnote X7. A systematic search finally selected 12 articles for detailed review and meta analysis. The effect summary value of 1.37 with confidence interval of 0.92-1.82 identifies statistically significant effectiveness of intervention by IPE program in healthcare. The Z test value of 5.99, significant at 5% level of significance, also shows a significant impact of IPE intervention as calculated by the random effects model. This meta-analysis shows a positive impact and effectiveness of educational intervention by IPE program in various disciplines of healthcare. However, analysis of further clinical trials may be helpful in identifying the effect of IPE program on the students' clinical competence. PMID- 29475462 TI - Artemisia capillaris inhibited enterovirus 71-induced cell injury by preventing viral internalization. AB - Artemisia capillaris (A. capillaris) is a common herbal drug used for thousands years in ancient China. A. capillaris has been empirically used to manage hand foot-mouth disease (HFMD), which is commonly caused by enterovirus 71 (EV71). EV71 can cause meningoencephalitis with mortality and neurologic sequelae without effective management. It is presently unknown whether A. capillaris is effective against EV71 infection. To test the hypothesis that it could protect cells from EV71-induced injury, a hot water extract of A. capillaris was tested in human foreskin fibroblast cells (CCFS-1/KMC) and human rhabdomyosarcoma cells (RD cells) by plaque reduction assay and flow cytometry. Inhibition of viral replication was examined by reverse quantitative RT-PCR (qRT-PCR). Its effect on translations of viral proteins (VP0, VP1, VP2, protease 2B and 3AB), and apoptotic proteins were examined by western blot. A. capillaris was dose dependently effective against EV71 infection in both CCFS-1/KMC cells and RD cells by inhibiting viral internalization. However, A. capillaris was minimally effective on viral attachment, VP2 translation, and inhibition of virus-induced apoptosis. Further isolation of effective molecules is needed. In conclusion, A. capillaris has anti-EV71 activity mainly by inhibiting viral internalization. A. capillaris would be better to manage EV71 infection in combination with other agents. PMID- 29475461 TI - Eugenosedin-A improves glucose metabolism and inhibits MAPKs expression in streptozotocin/nicotinamide-induced diabetic rats. AB - This study examined the effects of eugenosedin-A (Eu-A) in a streptozotocin (STZ)/nicotinamide-induced rat model of type II diabetes mellitus (T2DM). Six week-old Sprague-Dawley rats were randomly divided into three groups: (1) RD group, normal rats fed a regular diet (RD), (2) DM group, T2DM rats fed a high fat diet, and (3) Eu-A group, T2DM rats fed a high fat diet plus oral Eu-A (5 mg/kg/day). After 30 days, the DM group had higher body weight, higher blood glucose and lower insulin levels than the RD group. The DM group also had increased protein expression of glycogen synthase kinase (GSK) in liver and skeletal muscle and decreased protein expression of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), IRS-2, AMP-activated protein kinase (AMPK), glucose transporter-4 (GLUT-4), glucokinase (GCK), and peroxisome proliferator activated receptor gamma (PPAR-gamma). STZ/nicotinamide-induced T2DM increased the expression of mitogen-activated protein kinases (MAPKs: p38, ERK, JNK) and inflammatory p65 protein. In the Eu-A treated T2DM rats, however, blood glucose was attenuated and the insulin concentration stimulated. Changes in IR, IRS-1 and IRS-2 proteins as well as AMPK, GLUT-4, GCK, GSK, PPAR-gamma, MAPKs, and inflammatory p65 proteins were ameliorated. These results suggested that Eu-A alleviates STZ/nicotinamide-induced hyperglycemia by improving insulin levels and glucose metabolism, and inhibiting the MAPKs- and p65-mediated inflammatory pathway. PMID- 29475464 TI - Optical coherence tomography findings in Parkinson's disease. AB - The aim of this study is to compare optical coherence tomography (OCT) findings of retinal thickness (RT) and retinal nerve fiber layer thickness (RNFLT) of idiopathic Parkinson's disease (IPD) patients to those of healthy subjects, and to investigate whether there is any relationship between the severity of the disease and the RNFLT values. This prospective study was included 25 IPD patients and 29 healthy controls. In the IPD group, the Hoehn and Yahr (H&Y), Unified Parkinson's Disease Rating Scale (UPDRS), and Mini-Mental State Exam (MMSE) were performed. Intraocular pressure (IOP), visual acuity (VA), spherical equivalent, axial length (AL), and central corneal thickness (CCT) were measured using OCT in both groups. The RT was measured in the central retinal (RTc), nasal (RTn), and temporal (RTt) segments. Nasal (RNFLTn), nasal superior (RNFLTns), nasal inferior (RNFLTni), temporal (RNFLTt), temporal superior (RNFLTts), and temporal inferior (RNFLTti) measurements were made and mean RTFLT was calculated (RNFLTg) for each individual. In the patient group, IOP and VA values were statistically significantly lower The RTn and RNFLTg were significantly thinner in the patient group. There was no statistically significant relationship between the severity of IPD and these findings. In our study, RNFLTg and RTn were found to be thinner in the IPD group, which may have caused lower VA scores. The effects of retinal dopamine depletion on RT and RNFLT, and lower IOP values in the non-glaucomatous IPD patients should be further investigated. PMID- 29475465 TI - A nomogram predicting re-operation due to secondary hemorrhage after monopolar transurethral resection of prostate. AB - We aim to develop a nomogram to predict re-operation due to secondary hemorrhage after Monopolar transurethral resection of the prostate (M-TURP). We identified patients undergoing M-TURP at Peking University First Hospital from 2000 to 2013. Univariate and multivariate logistic regression models were developed to predict the occurrence re-operation due to secondary hemorrhage. The discriminatory ability of the nomogram was tested using the area under the receiver operating characteristic curve (ROC), and internal validation was performed via bootstrap resampling. Of the 1901 patients who underwent M-TURP during the study period, 9.1% (173 patients) experienced hemorrhage after M-TURP, and they had a 22.0% re operation rate (38 patients). Benign prostatic hyperplasia (BPH)-related complications (odds ratio, 0.386; 95% CI, 0.177-0.841), percent of resected prostate (OR, 0.156; 95% CI, 0.023-1.060) and suprapubic cystostomy (OR, 0.298; 95% CI, 0.101-0.881) were independently associated with re-operation. The nomogram accurately predicted re-operation (area under the ROC curve 0.718). The negative predictive value was 88.0%, while the positive predictive value was 47.9%. Re-operation due to secondary hemorrhage after M-TURP was associated with no BPH-related complications, lower percent of resected prostate and no suprapubic cystostomy and was accurately predicted with using the nomogram. PMID- 29475466 TI - QuantiFERON(r)-TB Gold test conversion in a psoriatic patient with pleural tuberculosis one year after adalimumab treatment. PMID- 29475467 TI - Beau's lines in nails: An indicator of recent Docetaxel and 5-FU use. PMID- 29475468 TI - Corrigendum to "Computed tomography findings predicting the success of silodosin for medical expulsive therapy of ureteral stones" [Kaohsiung J Med Sci 33 (6) (2017) 290-294]. PMID- 29475470 TI - Review: Microfluidics technologies for blood-based cancer liquid biopsies. AB - Blood-based liquid biopsies provide a minimally invasive alternative to identify cellular and molecular signatures that can be used as biomarkers to detect early stage cancer, predict disease progression, longitudinally monitor response to chemotherapeutic drugs, and provide personalized treatment options. Specific targets in blood that can be used for detailed molecular analysis to develop highly specific and sensitive biomarkers include circulating tumor cells (CTCs), exosomes shed from tumor cells, cell-free circulating tumor DNA (cfDNA), and circulating RNA. Given the low abundance of CTCs and other tumor-derived products in blood, clinical evaluation of liquid biopsies is extremely challenging. Microfluidics technologies for cellular and molecular separations have great potential to either outperform conventional methods or enable completely new approaches for efficient separation of targets from complex samples like blood. In this article, we provide a comprehensive overview of blood-based targets that can be used for analysis of cancer, review microfluidic technologies that are currently used for isolation of CTCs, tumor derived exosomes, cfDNA, and circulating RNA, and provide a detailed discussion regarding potential opportunities for microfluidics-based approaches in cancer diagnostics. PMID- 29475469 TI - Strong cation exchange-reversed phase liquid chromatography-capillary zone electrophoresis-tandem mass spectrometry platform with high peak capacity for deep bottom-up proteomics. AB - Two-dimensional (2D) liquid chromatography (LC)-tandem mass spectrometry (MS/MS) are typically employed for deep bottom-up proteomics, and the state-of-the-art 2D LC-MS/MS has approached over 8000 protein identifications (IDs) from mammalian cell lines or tissues in 1-3 days of mass spectrometer time. Capillary zone electrophoresis (CZE)-MS/MS has been suggested as an alternative to LC-MS/MS for bottom-up proteomics. CZE-MS/MS and LC-MS/MS are complementary in protein/peptide ID from complex proteome digests because CZE and LC are orthogonal for peptide separation. In addition, the migration time of peptides from CZE-MS can be predicted accurately, which is invaluable for evaluating the confidence of peptide ID from the database search and even guiding the database search. However, the number of protein IDs from complex proteomes using CZE-MS/MS is still much lower than the state of the art using 2D-LC-MS/MS. In this work, for the first time, we established a strong cation exchange (SCX)-reversed phase LC (RPLC)-CZE-MS/MS platform for deep bottom-up proteomics. The platform identified around 8200 protein groups and 65,000 unique peptides from a mouse brain proteome digest in 70 h. The data represents the largest bottom-up proteomics dataset using CZE-MS/MS and provides a valuable resource for further improving the tool for prediction of peptide migration time in CZE. The peak capacity of the orthogonal SCX-RPLC-CZE platform was estimated to be around 7000. SCX-RPLC-CZE MS/MS produced comparable numbers of protein and peptide IDs with 2D-LC-MS/MS (8200 vs. 8900 protein groups, 65,000 vs. 70,000 unique peptides) from the mouse brain proteome digest using comparable instrument time. This is the first time that CZE-MS/MS showed its capability to approach comparable performance to the state-of-the-art 2D-LC-MS/MS for deep proteomic sequencing. SCX-RPLC-CZE-MS/MS and 2D-LC-MS/MS showed good complementarity in protein and peptide IDs and combining those two methods improved the number of protein group and unique peptide IDs by nearly 10% and over 40%, respectively, compared with 2D-LC-MS/MS alone. PMID- 29475471 TI - Allosterically regulated DNA-based switches: From design to bioanalytical applications. AB - DNA-based switches are structure-switching biomolecules widely employed in different bioanalytical applications. Of particular interest are DNA-based switches whose activity is regulated through the use of allostery. Allostery is a naturally occurring mechanism in which ligand binding induces the modulation and fine control of a connected biomolecule function as a consequence of changes in concentration of the effector. Through this general mechanism, many different allosteric DNA-based switches able to respond in a highly controlled way at the presence of a specific molecular effector have been engineered. Here, we discuss how to design allosterically regulated DNA-based switches and their applications in the field of molecular sensing, diagnostic and drug release. PMID- 29475472 TI - Determination of halides using Ag nanoparticles-modified disposable electrodes. A first approach to a wearable sensor for quantification of chloride ions. AB - This work reports a simple voltammetric method for the determination of chloride, bromide, and iodide ions using screen-printed carbon electrodes modified with silver nanoparticles electrochemically deposited on the working electrode surface. UV/Vis absorption spectroelectrochemistry was used to study the electrodeposition of silver nanoparticles on the working carbon electrode on PET or Gore-Tex(r) supports, and their subsequent oxidation in the presence of halide ions. The main figures of merit of the developed sensors, such as reproducibility and detection limit, have been calculated. Reproducibility values of 2.22%, 2.83% and 3.23% were obtained for chloride, bromide and iodide determinations, respectively. Additionally, the lowest detected amount of chloride, bromide and iodide ions were 3.0.10-6 M, 5.0.10-6 M and 5.0.10-6 M, respectively. Taking into account the relevance of the determination of chloride ion concentration in sweat, the voltammetric method for the determination of halides has been successfully transferred to a Gore-Tex(r) support to build a first approach to a wearable sensor that facilitates the quantification of this ion in sweat samples. The Gore-Tex(r) sensor provides a good reproducibility (RSD = 1.61%). PMID- 29475473 TI - Inkjet printing-based photo-induced electron transfer reaction on parchment paper using riboflavin as a photosensitizer. AB - In this study, we report the photo-induced electron transfer (PET) on parchment paper using riboflavin as a photo inducer and ultraviolet lamp (362 nm) as the light source. To this end, a conventional inkjet printer equipped with 4 cartridges was used. Parchment paper was found to be a favorable substrate due to its insignificant self-absorption while assisting efficient sample interaction. Upon UV-irradiation, riboflavin generated superoxide anion radical (O2-.) and it was available to interact with superoxide dismutase present on the same spot. A decrease in NBT formazan in the reaction spot indicates increased O2-. scavenging activity of molecule. It was estimated that the well-plate based-colorimetric method used 12.5 MUM (1.25 * 10-9 mole) of riboflavin and 0.25 mM (2.50 * 10-8 mole) of NBT to react with different superoxide dismutase or drug concentrations, while the printing technique consumed 3.19 * 10-13 mole of NBT and 2.98 * 10-13 mole of riboflavin to react with gradient superoxide dismutase or drug concentration. In contrast to the conventional well plate method, inkjet printing based molecular assay provides automatic delivery in the nanoliter range with precise time, which ensures four-to five-order lower reagent consumption. The inkjet printing-based quantitative measurement specifies the amount of a particular drug/enzyme printed on a surface. Therefore, applicability of inkjet printing technique conjoined radical scavenging assay will be more competent to determine the radical scavenging potential of natural plant products. In addition, this inkjet printing approach offers easy, fast, cost-effective, and less time-consuming method to determine PET reaction on paper. PMID- 29475474 TI - Conjugated polymer nanoparticles-based fluorescent biosensor for ultrasensitive detection of hydroquinone. AB - This work describes a simple and sensitive fluorescent method for detection of hydroquinone utilizing conjugated polymer nanoparticles (CPNs). The CPNs serve both as a catalyst to accelerate the conversion of hydroquinone to benzoquinone and a fluorescent probe. In the presence of hydroquinone, the fluorescence of CPNs can be effectively quenched by benzoquinone. The detection limit of hydroquinone was down to 5 nM and excellent selectivity toward possible interferences was obtained. This method was successfully applied for hydroquinone detection in lake water and satisfactory results were achieved. PMID- 29475475 TI - DNA-hosted copper nanoclusters/graphene oxide based fluorescent biosensor for protein kinase activity detection. AB - A novel fluorescent biosensor for protein kinase activity (PKA) detection was designed by applying double-strands DNA-hosted copper nanoclusters (dsDNA-CuNCs) and graphene oxide (GO). One DNA strand of the dsDNA consisted of two domains, one domain can hybridize with another complementary DNA strand to stabilize the fluorescent CuNCs and another domain was adenosine 5'-triphosphate (ATP) aptamer. ATP aptamer of the dsDNA-CuNCs would be spontaneously absorbed onto the GO surface through pi-pi stacking interactions. Thus GO can efficiently quench the fluorescence (FL) of dsDNA-CuNCs through fluorescence resonance energy transfer (FRET). In the present of ATP, ATP specifically combined with ATP aptamer to form ATP-ATP aptamer binding complexes, which had much less affinity to GO, resulting in the fluorescence recovery of the system. Nevertheless, in the presence of PKA, ATP could be translated into ADP and ADP could not combine with ATP aptamer resulting in the fluorescence quenching of dsDNA-CuNCs again. According to the change of the fluorescence signal, PKA activity could be successfully monitored in the range of 0.1-5.0 U mL-1 with a detection limit (LOD) of 0.039 U mL-1. Besides, the inhibitory effect of H-89 on PKA activity was studied. The sensor was performed for PKA activity detection in cell lysates with satisfactory results. PMID- 29475476 TI - Multifunctional fluorescent sensing of chemical and physical stimuli using smart riboflavin-5'-phosphate/Eu3+ coordination polymers. AB - A novel type of stimuli-responsive fluorescent polymers has been developed via the self-assembly of riboflavin-5'-phosphate (RiP) as ligand and europium (III) (Eu3+) as central metal ion coordinated with the ligand. The as-prepared RiP/Eu3+ coordination polymers (RiP/Eu3+ CPs) are smart and multifunctional for respectively responding to chemical and physical stimuli, in which RiP acts as the stimuli-responsive fluorescent signal indicator. For sensing chemical stimuli, 2,6-pyridinedicarboxylic acid (DPA, an anthrax biomarker) having higher bonding force towards Eu3+ can grab it from smart RiP/Eu3+ CPs through competition reaction, resulting in the release of RiP for highly sensitive and selective DPA monitoring in a mix-and-read fluorescent enhancement format, and the detection limit is as low as 41.5 nM. Density functional theory (DFT) calculations has been also performed to verify the DPA sensing principle. For sensing physical stimuli, the smart RiP/Eu3+ CPs can be acting as a novel sensory probe for the determination of temperature from 10 degrees C to 40 degrees C based on the thermal-induced disruption of the binding between Eu3+ and RiP and the disassembly of the smart RiP/Eu3+ CPs accompanying with the recovery of the fluorescence of RiP. This work establishes an effective platform for multifunctional sensing of chemical and physical stimuli utilizing both smart lanthanide nanoscale coordination polymers (LNCPs) and novel sensing strategies. PMID- 29475477 TI - The point-of-care colorimetric detection of the biomarker of phenylamine in the human urine based on Tb3+ functionalized metal-organic framework. AB - Phenylamine has been recognized as one of the most important industrially relevant ingredient and a crucial intermediate in chemical products. Yet, its internal exposure detection in human remains largely elusive due to the lack of potent monitoring method. Hereby this issue is addressed with a probe based on lanthanide functionalized organic-inorganic hybrid material Al(OH)(bpydc) (1) through post-synthetically modified metal-organic framework. The as-synthesized Tb3+@1 exhibits the strong luminescence of Tb3+ originated from efficient energy transfer from the ligand, which can sense the biological metabolite p-aminophenol (PAP) of the phenylamine in the human urine. Linear correlation between the integrated fluorescence intensity and the concentration of PAP was investigated, enabling quantitative analysis of PAP in physiologically ranges (0.005-5 mg mL-1) with low detection limit (5 MUg mL-1). This probe demonstrates excellent sensitivity, high selectivity, good reusability and quick response to PAP. Furthermore, a simple and rapid smartphone-based medical portable test paper was developed, whose quantitative color change can be easily distinguished visually. Hence, the PAP sensing platform can serve as a potential diagnostic tool for home monitoring of PAP. PMID- 29475479 TI - Test for arsenic speciation in waters based on a paper-based analytical device with scanometric detection. AB - A rapid, simple and affordable method for arsenic speciation analysis is described in this work. The proposed methodology involves in situ arsine generation, transfer of the volatile to the headspace and its reaction with silver nitrate at the detection zone of a paper-based analytical device (PAD). Thus, silver nitrate acts as a recognition element for arsine in the paper-based sensor. The chemical reaction between the recognition element and the analyte derivative results in the formation of a colored product which can be detected by scanning the detection zone and data treatment with an image processing and analysis program. Detection and injection zones were defined in the paper substrate by formation of hydrophobic barriers, thus enabling the formation of the volatile derivative without affecting the chemical stability of the recognition element present in the PAD. Experimental parameters influencing the analytical performance of the methodology, namely color mode detection, composition of the paper-based sensor and hydride generation and mass transfer conditions, were evaluated. Under optimal conditions, the proposed method showed limits of detection and quantification of 1.1 and 3.6 ng mL-1, respectively. Remarkably, the limit of detection of the method reported herein was much lower than the maximum contaminant levels set by both the World Health Organization and the US Environmental Protection Agency for arsenic in drinking water, unlike several commercially available arsenic test kits. The repeatability, expressed as relative standard deviation, was found to be 7.1% (n = 8). The method was validated against the European Reference Material ERM(r)-CA615 groundwater and successfully applied to the determination of As(III), As(V) and total inorganic As in different water samples. Furthermore, the method can be used for the screening analysis of total arsenic in waters when a cut-off level of 7 ng mL-1 is used. PMID- 29475478 TI - Development of a broad-specificity antibody-based immunoassay for triazines in ginger and the quantitative structure-activity relationship study of cross reactive molecules by molecular modeling. AB - In the present study, molecular modeling and principle component analysis (PCA) were used to select appropriate haptens for group detection of triazine herbicides. Four new structures together with three reported triazine derivatives were chosen for the screening of immunizing and coating haptens. A total of 31 triazines coupled with a 3D-QSAR methodology were employed to investigate the relationship between antigen-antibody recognition and molecular structures, the results of which revealed that the antibodies may recognize triazines from the side of molecules with the distinguishing atom and a steric volume matching with the spatial structure of antibodies. Finally, a broad-specificity heterologous immunoassay was developed for determining 10 triazine herbicides in ginger, where the detection limits were 2.5-15.1 MUg kg-1 and recoveries were 67.9-102.6%. This study may broaden insight into triazine-antibody interactions and benefit designing novel performance-enhanced antibodies. The developed immunoassay can be further used for triazine detection in other complicated matrices. PMID- 29475480 TI - Comparison of analytical methods using enzymatic activity, immunoaffinity and selenium-specific mass spectrometric detection for the quantitation of glutathione peroxidase 1. AB - Glutathione peroxidase 1 (Gpx1), one of the most responsive selenoproteins to the variation of selenium concentration, is often used to evaluate "selenium status" at a cellular or organismal level. The four major types of analytical methodologies to quantify Gpx1 were revisited. They include (i) an enzymatic assay, (ii, iii) polyacrylamide gel electrophoresis (PAGE) with (ii) western blot detection of protein or (iii) inductively coupled plasma mass spectrometry (ICP MS) detection of selenium, and (iv) size-exclusion chromatography with ICP MS detection. Each of the four methods was optimized for the quantification of Gpx1 with maximum sensitivity. The methods based on the enzymatic and immunodetection offer a much higher sensitivity but their accuracy is compromised by the limited selectivity and limited dynamic range. The advantages, drawbacks and sources of error of each technique are critically discussed and the need for the cross validation of the results using the different techniques to assure the quality assurance of quantitative analysis is emphasized. PMID- 29475481 TI - Error Covariance Penalized Regression: A novel multivariate model combining penalized regression with multivariate error structure. AB - A new multivariate regression model, named Error Covariance Penalized Regression (ECPR) is presented. Following a penalized regression strategy, the proposed model incorporates information about the measurement error structure of the system, using the error covariance matrix (ECM) as a penalization term. Results are reported from both simulations and experimental data based on replicate mid and near infrared (MIR and NIR) spectral measurements. The results for ECPR are better under non-iid conditions when compared with traditional first-order multivariate methods such as ridge regression (RR), principal component regression (PCR) and partial least-squares regression (PLS). PMID- 29475482 TI - Ultrasensitive determination of receptor tyrosine kinase with a label-free electrochemical immunosensor using graphene quantum dots-modified screen-printed electrodes. AB - A new label-free electrochemical immunosensor is constructed for the selective and sensitive determination of the clinically relevant biomarker receptor tyrosine kinase (AXL) in human serum. The disposable immunosensing platform is prepared by immobilization of the specific anti-AXL antibody onto amine functionalized graphene quantum dots (fGQDs)-modified screen-printed carbon electrodes (SPCEs). The affinity reactions were monitored by measuring the decrease in the differential pulse voltammetric (DPV) response of the redox probe Fe(CN)63-/4-. All the experimental variables involved in the preparation of the modified electrodes and in the immunosensor performance were optimized. The as prepared immunosensor exhibits an improved analytical performance with respect to other electrochemical immunosensors reported so far, with a wider range of linearity and a lower detection limit, 0.5 pg mL-1, which is more than one hundred thousand times lower than the established cut-off value for heart failure (HF) diagnosis in serum (71 ng mL-1). The developed immunosensor was successfully applied to the determination of the endogenous content of AXL in serum of HF patients without any matrix effect observed after just a sample dilution. PMID- 29475483 TI - Graphene oxide activation with a constant magnetic field. AB - The effect of constant magnetic field strength on activation of sensors modified with graphene oxide monolayers was investigated. The use of constant magnetic field resulted in improved electroanalytical properties of the sensors. It was proven that level of GO activation is clearly related to constant magnetic field strength. Moreover, it was demonstrated that observed phenomenon is stable in time. PMID- 29475484 TI - Simultaneous determination of bifenox, dichlobenil and diclofop methyl by hollow carbon nanospheres enhanced magnetic carboxylic multi-walled carbon nanotubes. AB - A novel analytical method based on magnetic solid-phase extraction (MSPE) coupled with high performance liquid chromatography-diode array detection (HPLC-DAD) was established for three herbicides simultaneous determination. The key of the method was the explored extractant, which was a composite of hollow carbon nanospheres (HCSs) enhanced magnetic carboxylic MWCNTs (HCSs@Fe3O4-MWCNTs-COOH). MWCNTs-COOH was inserted in the pores of HCSs by oscillation and sonication with the capillary forces, making the carboxylic groups and structure intervals of the composite increase as compared to MWCNTs-COOH, therefore the extractant exhibited enhanced hydrophilicity, dispersibility, adsorptivity and selectivity. The extractant was sensitive to analytes with the structure of multi-aromatic ring, more hydrogen bond acceptor and large molecular polar surface area, which can be attributed to hydrogen bonding and pi-pi electron-donor-acceptor (EDA) interactions. The morphology, structure and magnetic property of the extractant were characterized. Then the explored extractant based MSPE-HPLC-DAD method was applied for bifenox (BFO), dichlobenil (DCB) and diclofop methyl (DCM) determination from wheat flour samples. Prior to real sample analysis, critical extraction parameters such as solution pH, extraction time, salt addition and temperature were investigated and optimized, and the analytical method was evaluated. It was indicated that the method had satisfactory linearities with the linear coefficients above 0.99, good precision with the RSD less than 3.5%, desirable recoveries ranged from 88.8% to 96.6%, and low limits of detection (LOD) that were 0.39, 0.24, and 0.68 ng/g for DCB, BFO and DCM, respectively. The established MSPE-HPLC-DAD method has great potentials for trace polar herbicides selective determination from complex matrix samples. PMID- 29475485 TI - Efficient extraction of perfluorocarboxylic acids in complex samples with a monolithic adsorbent combining fluorophilic and anion-exchange interactions. AB - Efficient extraction of perfluorocarboxylic acids (PFCAs) is a key step for the accurate and sensitive determination of PFCAs due to their low concentration and the complexity of sample matrices. Herein, according to the chemical characteristics of PFCAs, a new adsorbent based on poly (2,2,3,3,4,4,5,5,6,6,7,7 dodecafluoroheptyl acrylate/(vinylbenzyl)trimethylammonium chloride-co divinylbenzene/ethylenedimethacrylate) monolith was fabricated and utilized as the extraction medium of multiple monolithic fiber solid-phase microextraction (MMF-SPME). Results well indicted that the prepared monolithic adsorbent (MA) could efficient extract PFCAs through fluorophilic and anion-exchange interactions. Under the optimal conditions, the MA/MMF-SPME was combined with HPLC-MS/MS for the sensitive monitoring of ultra-trace PFCAs in water and milks samples. The limits of detection (S/N = 3) of the target PFCAs in water and milk samples were 0.40-4.40 ng/L and 0.9-12.1 ng/L, respectively. Furthermore, the proposed method also exhibited some merits including wide linear dynamic ranges, satisfactory sensitivity, good method precision and low consumption of sample and organic solvent. Isotope internal standard calibration curve method was used to quantify the concentration of PFCAs in real samples, and trace levels of PFCAs in tap water and milk samples had been successfully detected. PMID- 29475486 TI - Time-resolved method to distinguish protein/peptide oxidation during electrospray ionization mass spectrometry. AB - Electrospray ionization mass spectrometry (ESI-MS) is one of the most prevalent techniques used to monitor protein/peptide oxidation induced by reactive oxygen species (ROSs). However, both corona discharge (CD) and electrochemistry (EC) can also lead to protein/peptide oxidation during ESI. Because the two types of oxidation occur almost simultaneously, determining the extent to which the two pathways contribute to protein/peptide oxidation is difficult. Herein, a time resolved method was introduced to identify and differentiate CD- and EC-induced oxidation. Using this approach, we separated the instantaneous CD-induced oxidation from the hysteretic EC-induced oxidation, and the effects of the spray voltage and flow rate of the ESI source on both oxidation types were investigated with a homemade ESI source. For angiotensin II analogue (b-DRVYVHPF-y), the dehydrogenation and oxygenation species were the detected EC-induced oxidation products, while the oxygenation species were the major CD-induced oxidation products. This time-resolved approach was also applicable to a commercial HESI source, in which both CD and EC were responsible for hemoglobin and cytochrome c oxidation with upstream grounding while CD dominated the oxidation without upstream grounding. PMID- 29475488 TI - Fluorescent conjugated microporous polymer based on perylene tetraanhydride bisimide for sensing o-nitrophenol. AB - A novel conjugated microporous polymer based on perylene tetraanhydride bisimide (DP2A2) has been synthesized through Sonogashira-Hagihara cross-coupling polymerization of tetrabromo-substituted perylene tetraanhydride bisimide derivative (DPBr2ABr2) with 1,4-diethynylbenzene, whose Brunauer-Emmett-Teller (BET) specific surface area is about 378 m2 g-1. The fluorescence quenching behaviors of the DP2A2 were investigated. It is found that the DP2A2 shows high sensitivity and selectivity to tracing o-nitrophenol (o-NP) in THF with KsV constant of 2.00 * 104 L mol-1. The detection limit (LOD) is 1.50 * 10-9 mol L-1. The possible sensing mechanism for the luminescent quenching of DP2A2 towards o NP exciting at 365 nm was considered the donor-acceptor electron transfer mechanism, which is a combined result from both dynamic (collisional) and static quenching. Moreover, the static quenching process is dominant for DP2A2. PMID- 29475487 TI - Highly sensitive and selective determination of redox states of coenzymes Q9 and Q10 in mice tissues: Application of orbitrap mass spectrometry. AB - Coenzyme Q (CoQ) is a redox active molecule that plays a fundamental role in mitochondrial energy generation and functions as a potent endogenous antioxidant. Redox ratio of CoQ has been suggested as a good marker of mitochondrial dysfunction and oxidative stress. Nevertheless, simultaneous measurement of redox states of CoQ is challenging owing to its hydrophobicity and instability of the reduced form. In order to improve the analytical methodology, paying special attention to this instability, we developed a highly sensitive and selective high resolution/accurate-mass (HR/AM) UHPLC-MS/MS method for the rapid determination of redox states of CoQ9 and CoQ10 by ultra-performance liquid chromatography hybrid quadrupole-Orbitrap mass spectrometry. CoQs were extracted using hexane with the addition of butylated hydroxytoluene to limit oxidation during sample preparation. Chromatographic separation of the analytes was achieved on a Kinetex C18 column with the isocratic elution of 5 mM ammonium formate in 2 propanol/methanol (60:40) within 4 min. A full MS/all ion fragmentation (AIF) acquisition mode with mass accuracy < 5 ppm was used for detection and determination of redox states of CoQ9 and CoQ10 in healthy mice tissues using reduced and oxidized CoQ4 as internal standards. The validated method showed good linearity (r2 >= 0.9991), intraday, inter-day precision (CVs <= 11.9%) and accuracy (RE <=+/-15.2%). In contrast to existing methods, the current method offers enhanced sensitivity (up to 52 fold) with LOD and LOQ ranged from 0.01 to 0.49 ng mL-1 and 0.04-1.48 ng mL-1, respectively. Moreover, we evaluated various diluents to investigate bench top stability (at 4 degrees C) of targeted analytes in tissue samples during LC-MS assay up to 24 h. Ethanol was determined to be an optimum diluent without any significant oxidation of reduced CoQ up to 24 h. The developed method offers a rapid, highly sensitive and selective strategy for the measurement of redox states of CoQs in clinical studies. PMID- 29475490 TI - Editorial overview: Folding and binding: In silico, in vitro and in cellula. PMID- 29475489 TI - Twin target self-amplification-based DNA machine for highly sensitive detection of cancer-related gene. AB - The sensitive detection of cancer-related genes is of great significance for early diagnosis and treatment of human cancers, and previous isothermal amplification sensing systems were often based on the reuse of target DNA, the amplification of enzymatic products and the accumulation of reporting probes. However, no reporting probes are able to be transformed into target species and in turn initiate the signal of other probes. Herein we reported a simple, isothermal and highly sensitive homogeneous assay system for tumor suppressor p53 gene detection based on a new autonomous DNA machine, where the signaling probe, molecular beacon (MB), was able to execute the function similar to target DNA besides providing the common signal. In the presence of target p53 gene, the operation of DNA machine can be initiated, and cyclical nucleic acid strand displacement polymerization (CNDP) and nicking/polymerization cyclical amplification (NPCA) occur, during which the MB was opened by target species and cleaved by restriction endonuclease. In turn, the cleaved fragments could activate the next signaling process as target DNA did. According to the functional similarity, the cleaved fragment was called twin target, and the corresponding fashion to amplify the signal was named twin target self amplification. Utilizing this newly-proposed DNA machine, the target DNA could be detected down to 0.1 pM with a wide dynamic range (6 orders of magnitude) and single-base mismatched targets were discriminated, indicating a very high assay sensitivity and good specificity. In addition, the DNA machine was not only used to screen the p53 gene in complex biological matrix but also was capable of practically detecting genomic DNA p53 extracted from A549 cell line. This indicates that the proposed DNA machine holds the potential application in biomedical research and early clinical diagnosis. PMID- 29475491 TI - Editorial overview: A perspective on protein evolution. PMID- 29475492 TI - Testosterone therapy: has overuse undermined use? PMID- 29475493 TI - Treatment of cystic fibrosis-related diabetes - Authors' reply. PMID- 29475494 TI - Treatment of cystic fibrosis-related diabetes. PMID- 29475495 TI - Genetic risk scores in adult-onset type 1 diabetes. PMID- 29475496 TI - Genetic risk scores in adult-onset type 1 diabetes - Authors' reply. PMID- 29475497 TI - Weight stigma and discrimination: a call to the media. PMID- 29475499 TI - Correction to Lancet Diabetes Endocrinol 2016; 4: 233-43. PMID- 29475500 TI - Generation of murine monoclonal antibodies with specificity against conventional camelid IgG1 and heavy-chain only IgG2/3. AB - Camelids possess antibodies with a conventional four-chain structure consisting of two heavy and two light chains (of subclass IgG1) but further they also generate heavy-chain only antibodies (of subclass IgG2 and 3) which are fully functional in antigen binding. In this study subclass-specific murine monoclonal antibodies specific to conventional camelid IgG1 and heavy-chain only IgG2/3 were generated and validated for the use as potent secondary detection reagents. The monoclonal antibodies are able to differentiate between all camelid IgGs, conventional four-chain camelid antibodies (of subclass IgG1) and exclusively heavy chain-only antibodies (of subclasses IgG2 and IgG3). Further these antibodies were used to detect specific immune responses after vaccination of Camelids against bovine corona- and rotavirus strains and different E.coli and Clostridia - antigens and to identify Erysipelothrix rhusiopathiae infected animals within a herd. The described antibodies are suitable as new secondary agents for the detection of different camelid subclasses and the validation of camelid immune reactions. PMID- 29475501 TI - Expression of cytokines following vaccination of goats with a recombinant capripoxvirus vaccine expressing Rift Valley fever virus proteins. AB - The mosquito-borne Rift Valley fever virus (RVFV) causes severe diseases in domesticated animals including cattle, sheep, camels and goats. Capripoxviruses (CPV) are suitable vectors for multivalent vaccine development. A recombinant rKS1-based CPV expressing the gene encoding the viral glycoprotein Gn of RVFV has been shown to induce protection in mice and sheep. The aim of this study was to evaluate the immunogenicity induced by this candidate vaccine in goats, and the level of cytokines produced by RVFV-specific Th1 and Th2 lymphocytes. The results of this study suggest that Th2 mediates immunity mainly through the significant production of IL4, which, coupled with a decrease in IFN-gamma, may be involved in the replication of the capripoxvirus expressing the GN of RVFV. CD4+ cells may play the role of helper cells in B cell responses and neutralizing antibody production in the anti-CPV humoral response, leading to strong immunity against RVFV. PMID- 29475502 TI - Short communication: Evaluation of an automated method for assessing white blood cell concentrations in Holstein dairy cows. AB - Assessing white blood cell (WBC) differentials is one way to assess cow health and well-being. The objective of this study was to determine the agreement between WBC populations identified by manual evaluation via microscopy and an automated approach. Data were collected from mid-to-late lactation dairy cows sampled at 6-h intervals starting at 2100 over a 48 period (n = 192). The agreement between the two methods was calculated using a regression model in SAS (v9.4, SAS Institute Inc., Cary, NC) to construct limits of agreement. Data were analyzed by comparing the mean response of the methods for each sample against the difference between the methods The maximum allowable difference (MAD) was set at +/-10% for each response variable. Agreement between methods was evident for neutrophils and lymphocytes, but not for monocytes and eosinophils. Agreement for these factors was established from an insignificant P-value, a low R2 value, and concentration of the data within the MAD. This data indicates that the automated method is appropriate for analysis of neutrophil and lymphocyte concentrations. However, accuracy needs to be improved for analysis of monocytes and eosinophils if differentiation of all WBC populations is necessary. PMID- 29475503 TI - Absence of relationship between type-I interferon suppression and neuropathogenicity of EHV-1. AB - Equine herpesvirus-1 (EHV-1) infection is an important and highly prevalent disease in equine populations worldwide. Previously we have demonstrated that a neuropathogenic strain of EHV-1, T953, suppresses the host cell's antiviral type I interferon (IFN) response in vitro. Whether or not this is unique to EHV-1 strains possessing the neuropathogenic genotype has been undetermined. Here, we examined whether there is any direct relationship between neuropathogenic genotype and the induced IFN-beta response in equine endothelial cells (EECs) infected with 10 different strains of EHV-1. The extent of virus cell-to-cell spread following infection in EECs was also compared between the neuropathogenic and the non-neuropathogenic genotype of EHV-1. We then compared IFN-beta and the total type-I IFN protein suppression between T953, an EHV-1 strain that is neuropathogenic and T445, an EHV-4 strain mainly associated only with respiratory disease. Data from our study revealed no relationship between the neuropathogenic genotype of EHV-1 and the induced IFN-beta mRNA by the host cell. Results also indicate no statistically significant difference in plaque sizes of both genotypes of EHV-1 produced in EECs. However, while the T953 strain of EHV-1 was able to suppress IFN-beta mRNA and type-I IFN biological activity at 12 h post infection (hpi), EHV-4 weakly induces both IFN-beta mRNA and type-I IFN biological activity. This finding correlated with a statistically significant difference in the mean plaque sizes produced by the two EHV subtypes in EECs. Our data help illuminate how EHV-1, irrespective of its genotype, evades the host cell's innate immune response thereby enabling viral spread to susceptible cells. PMID- 29475504 TI - Goose toll-like receptor 3 (TLR3) mediated IFN-gamma and IL-6 in anti-H5N1 avian influenza virus response. AB - Induction of the innate immune pathways is critical for early anti-viral defense. How geese recognize viral molecules and activate these pathways is not well understood. In mammals, Toll-like receptor 3 (TLR3) recognizes double-stranded RNA. Activation of TLR3 induces the activation of NF-kB and the production of type-I interferon. In this study, the goose TLR3 gene was cloned using rapid amplification of cDNA ends. Goose TLR3 encoded an 896-amino-acid protein, containing a signal secretion peptide, 14 extracellular leucine-rich repeat domains, a transmembrane domain, a Toll/interleukin-1 receptor signaling domain, and shared 46.7-84.4% homology with other species. Tissue expression of goose TLR3 varied markedly and was highest in the pancreas and lowest in the skin. Human embryonic kidney 293 cells transfected with goose TLR3 and NF-kappaB luciferase-containing plasmids responded significantly to poly i:c. The expression of TLR3, IL-6 and IFN-gamma mRNA, but not IL-1 mRNA, was significantly upregulated after poly i:c or high pathogenic avian influenza virus (H5N1) stimulation in goose peripheral blood mononuclear cells cultured in vitro. Furthermore, geese infected with H5N1 showed significant upregulation of TLR3, especially in the lung and brain. We conclude that goose TLR3 is a functional TLR3 homologue of the protein in other species and plays an important role in virus recognition. PMID- 29475505 TI - Bovine monocyte derived dendritic cell based assay for measuring vaccine immunogenicity in vitro. AB - During both human and animal vaccine development phases, animal testing is necessary to demonstrate vaccine efficacy. Since the number of antigen candidates for testing is usually large when developing a potential vaccine, it is too costly, time consuming and would involve higher risks to carry out selection using in vivo models. The currently available in vitro assays that measure immunogenicity do not adequately reproduce the in vivo state and this is especially true for vaccine research in livestock species. With this in mind, we have developed a bovine monocyte derived dendritic cell (MODC)s based assay to prime CD4 and CD8 lymphocytes in order to investigate vaccine immunogenicity in vitro. MODCs were generated, pulsed with diphtheria toxoid (DT) and co-cultured with lymphocytes for priming. Immunogenicity was measured through antigen recall when antigen pulsed MODC were re-introduced to the co-culture and proliferation of CD4 and CD8 positive lymphocytes were quantified using expressed Ki-67. Having developed the protocol for the assay, we then employed two licenced vaccines against blue tongue virus and rabies virus to validate the assay. Our results show the ability of the assay to satisfactorily measure immunogenicity in cattle. The assay could be used to identify antigens that induce CD4 and CD8 T cell responses prior to embarking on in vivo experiments and can also be used for the quality control of established vaccines in vaccine production facilities as a supplement for in vivo experiments. PMID- 29475506 TI - Immunohistochemical characterization of gastrointestinal macrophages/phagocytes in dogs with inflammatory bowel disease (IBD) and non-IBD dogs. AB - Intestinal Mphi play a pivotal role in the maintenance of gut homeostasis, but can also contribute to inflammation such as inflammatory bowel disease (IBD). In contrast to human tissues, little is known about phenotypes of Mphi in the canine gastrointestinal tract. Therefore, an immunohistochemical study was performed using Abs against Mphi-associated molecules (Cluster of differentiation (CD)64, CD163, CD204, ionized calcium-binding adaptor molecule 1, L1 Ag, and MHC II) on stomach, duodenum, jejunum, ileum and colon from non-IBD dogs. In addition, marker-expression in the stomach, duodenum and colon of the non-IBD dogs was compared to that in dogs with IBD. Results revealed predominance of resident Mphi displaying an anti-inflammatory phenotype represented by expression of CD163 as well as CD204 in the gut of non-IBD dogs with high Mphi numbers especially present in the small intestinal villus area. Compared to non-IBD tissue counterparts, stomach, duodenum, and colon from dogs with IBD showed reduced Mphi numbers with the exception of slightly increased numbers of CD64+ Mphi. Correlation analyses between marker-expression of Mphi and the Canine Inflammatory Bowel Disease Activity Index as well as histological scores failed to reveal relevant relationships. The present study provides evidence of the canine steady state gastrointestinal tract being dominated by Mphi with anti inflammatory properties maintaining gut homeostasis. A significant reduction in these resident Mphi may reflect disturbances in homeostatic capacity that could contribute to the development of canine IBD. In contrast to human IBD and murine disease models, infiltration of pro-inflammatory Mphi does not significantly contribute to the inflammatory process of canine IBD, which may illustrate possible species-specific differences in IBD pathogenesis. PMID- 29475507 TI - Monocyte derived macrophages as an appropriate model for porcine cytomegalovirus immunobiology studies. AB - Porcine cytomegalovirus (PCMV) causes lifelong latent infections in swine. The pathogen is occasionally associated with inclusion body rhinitis and pneumonia in piglets, reproductive disorders in pregnant sows and respiratory disease complex in older pigs. Immunosuppressive potential of PCMV infection is discussed. Macrophages were recognised as one of target cell types where propagation of virus occurs. The aim of present study was to set up model PCMV infection of monocyte derived macrophages (MDMs) in vitro for PCMV immunobiology research. Obtained results showed that PCMV is able to infect and propagate in MDMs. Possible immunosuppressive effect of PCMV on infected macrophages was evaluated by measurement of immune relevant gene expression in MDMs. Infection decreased expression of IL-8 and TNF-alpha (pro-inflammatory cytokines) and increased expression of IL-10 (anti-inflammatory cytokine) on mRNA transcription level. Obtained data support hypothesis that higher sensitivity of animals to coinfection with other swine pathogens and its more severe clinical manifestations could potentially be the consequence of PCMV infection. PMID- 29475508 TI - In vivo effects of aspirin and cyclosporine on regulatory T cells and T-cell cytokine production in healthy dogs. AB - Cyclosporine and aspirin are routinely used in combination to treat immune mediated hemolytic anemia (IMHA) in dogs. Cyclosporine is a potent immunosuppressive agent that targets T cell production of the cytokines IL-2 and IFN-gamma. Low-dose aspirin is often used to inhibit platelet function in dogs with IMHA, since these animals are prone to life-threatening thromboembolic disease. In rodents and humans, aspirin and cyclosporine have both been shown to variably affect T cell cytokine production, and also numbers of circulating regulatory T cells (Tregs). In dogs, it has not yet been determined if concurrent aspirin alters the effects of cyclosporine on T-cell cytokine expression, or if either drug influences Treg numbers. In a crossover study, seven healthy young adult dogs were given either oral high-dose cyclosporine (10 mg/kg Q12 h), oral low-dose aspirin (1 mg/kg Q24 h), oral high-dose aspirin (10 mg/kg Q12 h), or combined low-dose aspirin with cyclosporine, each for 8 days, with a washout of at least 2 weeks after each treatment. Activated T cell cytokine expression (IL-2 & IFN-gamma) and percent CD4 + CD25 + FOXP3+ Tregs were evaluated using flow cytometry, both prior to and on the last day of treatment. The difference between pre- and post-treatment values for each group, as well as the difference between treatment groups, was evaluated. Cyclosporine significantly decreased IL-2 and IFN-gamma expression when used alone or in combination with low-dose aspirin. High-dose aspirin, but not low-dose aspirin, also significantly decreased IL-2 expression, although the decrease was not as marked as that seen with cyclosporine alone or in combination with aspirin. Neither low-dose nor high-dose aspirin significantly affected IFN-gamma expression. No drug or drug combination affected Treg numbers. Low-dose aspirin given with cyclosporine creates the same degree of T-cell cytokine suppression as does cyclosporine alone, suggesting that the two drugs can be used concurrently without significantly altering the immunosuppressive mechanism of action of cyclosporine. PMID- 29475509 TI - Oral immunization with cell-free self-assembly virus-like particles against orange-spotted grouper nervous necrosis virus in grouper larvae, Epinephelus coioides. AB - Nervous necrosis virus (NNV) infection causes viral nervous necrosis, inflicting serious economic losses in marine fish cultivation. Vaccination is the most effective choice for controlling and preventing viral infection. Virus-like particles (VLPs) are considered a novel vaccine platform because they are not infectious and they induce neutralizing antibodies efficiently. In the present study, we investigated the effect of the recombinant orange-spotted grouper NNV (OSGNNV) capsid proteins produced in Escherichia coli and cell-free self assembled into VLPs on protective immune responses in orange-spotted grouper following immersion, intramuscular injection and oral immunization. We found the OSGNNV VLPs elicited neutralizing antibody with high efficacy, and provided the fish with full protection against OSGNNV challenge. In addition, the cell-free self-assembled OSGNNV VLPs did not contain residual host cell components and was safer compared with the intracellular assembled VLPs. Thus, oral vaccination is a more convenient and preferred route for fish vaccination. Our results show that the fish fed four times with a diet supplemented with 50-200 MUg/g OSGNNV VLPs at 7-day intervals have sufficient protection. These findings demonstrate that cell free self-assembled OSGNNV VLPs have potential as oral vaccines in grouper. PMID- 29475510 TI - Th-17 cell mediated immune responses to Mycoplasma bovis proteins formulated with Montanide ISA61 VG and curdlan are not sufficient for protection against an experimental challenge with Mycoplasma bovis. AB - The current avenues for prevention and/or control of Mycoplasma bovis infection in cattle involve antibiotic treatment of affected animals, herd management practices including separation and or culling infected animals, and the use of commercial vaccines, which offer limited protection. Some bacterin vaccines may cause negative reactions; therefore a different approach is needed, such as the use of recombinant vaccines based on protective antigens formulated with effective adjuvants. The role of Th-17 immune responses in protection against bacterial infections has been investigated for several pathogens. In this study, our goal was to identify M. bovis antigens that may elicit Th-17 protective responses. We tested a vaccine containing M. bovis proteins formulated with Montanide ISA61TM VG and curdlan. After vaccination, the animals were challenged using a BHV-1/M. bovis co-infection model. We detected IL-17 and other cytokines in supernatants of PBMCs incubated with the recall antigens. In addition, we detected antibody and PBMC proliferative responses to the antigens. Despite observing slight decreases in the proportion of the lung lesions and in weight loss in the vaccinated group, we concluded that Th-17 responses to the antigens used here were not protective. PMID- 29475511 TI - The canine MHC class Ia allele DLA-88*508:01 presents diverse self- and canine distemper virus-origin peptides of varying length that have a conserved binding motif. AB - Ideally, CD8+ T-cell responses against virally infected or malignant cells are defined at the level of the specific peptide and restricting MHC class I element, a determination not yet made in the dog. To advance the discovery of canine CTL epitopes, we sought to determine whether a putative classical MHC class Ia gene, Dog Leukocyte Antigen (DLA)-88, presents peptides from a viral pathogen, canine distemper virus (CDV). To investigate this possibility, DLA-88*508:01, an allele prevalent in Golden Retrievers, was expressed as a FLAG-tagged construct in canine histiocytic cells to allow affinity purification of peptide-DLA-88 complexes and subsequent elution of bound peptides. Pattern analysis of self peptide sequences, which were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS), permitted binding preferences to be inferred. DLA 88*508:01 binds peptides that are 9-to-12 amino acids in length, with a modest preference for 9- and 11-mers. Hydrophobic residues are favored at positions 2 and 3, as are K, R or F residues at the C-terminus. Testing motif-matched and unmatched synthetic peptides via peptide-MHC surface stabilization assay using a DLA-88*508:01-transfected, TAP-deficient RMA-S line supported these conclusions. With CDV infection, 22 viral peptides ranging from 9-to-12 residues in length were identified in DLA-88*508:01 eluates by LC-MS/MS. Combined motif analysis and surface stabilization assay data suggested that 11 of these 22 peptides, derived from CDV hemagglutinin, large polymerase, matrix, nucleocapsid, and V proteins, were processed and presented, and thus, potential targets of anti-viral CTL in DLA-88*508:01-bearing dogs. The presentation of diverse self and viral peptides indicates that DLA-88 is a classical MHC class Ia gene. PMID- 29475512 TI - Activation of liver X receptors inhibit LPS-induced inflammatory response in primary bovine mammary epithelial cells. AB - Liver X Receptors (LXRs) belong to the nuclear receptor superfamily, have been reported that activation of LXRs with synthetic ligands has anti-inflammatory effects in various inflammatory diseases. This study aims at investigating the effects of T0901317 (T0), a synthetic LXRs ligand, on lipopolysaccharide (LPS) stimulated primary bovine mammary epithelial cells (bMECs). BMECs were stimulated by LPS in the presence or absence of T0. The results showed that treatment with T0 significantly inhibited LPS-induced tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6) expression. LPS-induced NF kappaB activation was also suppressed by T0. Furthermore, T0 was found to inhibit the translocation of TLR4 to lipid rafts. T0 could activate ATP-binding cassette transporter A1 (ABCA1) dependent pathway which induced cholesterol efflux from cells and disrupted the formation of lipid rafts. Thus, based on those findings we proposed that LXRs agonist might become a novel therapeutic target for inflammation. PMID- 29475513 TI - Single blinded, randomized, placebo-controlled study on the effects of ciclosporin on cutaneous barrier function and immunological response in atopic beagles. AB - Ciclosporin (CsA) is a common treatment for canine atopic dermatitis (cAD). cAD is a very common skin disease with a multifactorial pathogenesis due to complex interactions between the host and the environment. The purpose of this study was to describe the physical and immunological effects of CsA in cAD using a canine model of AD. Fourteen beagles were enrolled; seven received CsA orally every 24 h for 28 days, and seven received placebo. All dogs were exposed to relevant allergens, house dust mite solution, one day prior to treatment and once weekly thereafter for 28 consecutive days. Canine atopic dermatitis extent and severity index-03 (CADESI-03) and skin biopsies were performed on day 0, 14, and 28. Quantitative RT-PCR was used to determine levels of cutaneous cytokines and barrier function markers. Indirect immunofluorescence was used to determine protein expression and distribution of nuclear messengers, barrier function and inflammatory [thymic stromal lymphopoietin (TSLP)] markers. The data were tested for normality and then the upaired two samples Student's t-test and the repeated measurements ANOVA, followed by the Dunnett's Multiple Comparison Test as post hoc analysis, were performed. A P value of <0.05 was considered statistically significant. A significant decrease in CADESI-03 occurred for the treatment group compared to placebo (p = 0.023) on day 28. On day 14, a significant increase in TSLP protein expression [p = 0.019 (placebo); p = 0.02 (CsA)] and a significant decrease in Transforming Growth Factor (TGF)-beta mRNA [p = 0.01 (placebo); p = 0.015 (CsA)] were noted in both groups compared to baseline. On day 28, a significant increase in canine beta defensin (cBD)103 [p = 0.012 (placebo)] and cBD3-like mRNAs [p = 0.044 (placebo)], and filaggrin [p = 0.035 (CsA)] and TSLP protein expressions [p = 0.0092 (CsA)] were seen compared to baseline. In contrast, a significant decrease in mRNA of Tumor Necrosis factor (TNF)-alpha [p = 0.013 (CsA)], Interleukin (IL)-10 [p = 0.038 (CsA)], TGF-beta [p = 0.017 (CsA)], and caspase 14 [p = 0.014 (CsA)] was seen on day 28 compared to baseline. Comparison of the groups revealed no significant effect on skin immunologic milieu or barrier markers despite evident improvement of physical signs in the treatment group. Although this study confirmed the usefulness of CsA for the treatment of cAD, a clear involvement of CsA on some of the currently known immunological alterations present in cAD was not determined. However, it is important to note that there was no measurable exacerbation of skin barrier dysfunction secondary to CsA administration in this model. PMID- 29475514 TI - Developing a technique to enhance durability of fibrous ion-exchange resin substrate for space greenhouses. AB - One way to cut consumables for space plant growth facilities (PGF) with artificial soil in the form of fibrous ion-exchange resin substrate (FIERS) is on board regeneration of the used medium. After crop harvest the procedure includes removal of the roots from the fibrous media with preservation of the exchanger properties and capillary structure. One type of FIERS, namely BIONA-V3?, has been used in Russian prototypes of space conveyors. We describe a two-stage treatment of BIONA-V3? including primary microwave heating of the used FIERS until (90 +/- 5) degrees C in alkali-peroxide solution during 3.5 hrs. The second stage of the treatment is decomposition of root vestiges inside pores of BIONA-V3? by using thermophilic and mesophilic anaerobic bacteria Clostridium thermocellum, Clostridium cellulolyticum and Cellulosilyticum lentocellum during 7-10 days at 55 degrees C. The two-stage procedure allows extraction of 90% dead roots from the FIERS' pores and the preservation of root zone hydro-physical properties. A posterior enrichment of the FIERS by minerals makes BIONA- V3? reusable. PMID- 29475515 TI - Synthetic torpor: A method for safely and practically transporting experimental animals aboard spaceflight missions to deep space. AB - Animal research aboard the Space Shuttle and International Space Station has provided vital information on the physiological, cellular, and molecular effects of spaceflight. The relevance of this information to human spaceflight is enhanced when it is coupled with information gleaned from human-based research. As NASA and other space agencies initiate plans for human exploration missions beyond low Earth orbit (LEO), incorporating animal research into these missions is vitally important to understanding the biological impacts of deep space. However, new technologies will be required to integrate experimental animals into spacecraft design and transport them beyond LEO in a safe and practical way. In this communication, we propose the use of metabolic control technologies to reversibly depress the metabolic rates of experimental animals while in transit aboard the spacecraft. Compared to holding experimental animals in active metabolic states, the advantages of artificially inducing regulated, depressed metabolic states (called synthetic torpor) include significantly reduced mass, volume, and power requirements within the spacecraft owing to reduced life support requirements, and mitigated radiation- and microgravity-induced negative health effects on the animals owing to intrinsic physiological properties of torpor. In addition to directly benefitting animal research, synthetic torpor inducing systems will also serve as test beds for systems that may eventually hold human crewmembers in similar metabolic states on long-duration missions. The technologies for inducing synthetic torpor, which we discuss, are at relatively early stages of development, but there is ample evidence to show that this is a viable idea and one with very real benefits to spaceflight programs. The increasingly ambitious goals of world's many spaceflight programs will be most quickly and safely achieved with the help of animal research systems transported beyond LEO; synthetic torpor may enable this to be done as practically and inexpensively as possible. PMID- 29475516 TI - Exposure to microgravity for 30 days onboard Bion M1 caused muscle atrophy and impaired regeneration in murine femoral Quadriceps. AB - Mechanical unloading in microgravity during spaceflight is known to cause muscular atrophy, changes in muscle fiber composition, gene expression, and reduction in regenerative muscle growth. Although some limited data exists for long-term effects of microgravity in human muscle, these processes have mostly been studied in rodents for short periods of time. Here we report on how long term (30-day long) mechanical unloading in microgravity affects murine muscles of the femoral Quadriceps group. To conduct these studies we used muscle tissue from 6 microgravity mice, in comparison to habitat (7), and vivarium (14) ground control mice from the NASA Biospecimen Sharing Program conducted in collaboration with the Institute for Biomedical Problems of the Russian Academy of Sciences, during the Russian Bion M1 biosatellite mission in 2013. Muscle histomorphology from microgravity specimens showed signs of extensive atrophy and regenerative hypoplasia relative to ground controls. Specifically, we observed a two-fold decrease in the number of myonuclei, compared to vivarium and ground controls, and central location of myonuclei, low density of myofibers in the tissue, and of myofibrils within a fiber, as well as fragmentation and swelling of myofibers. Despite obvious atrophy, muscle regeneration nevertheless appeared to have continued after 30 days in microgravity as evidenced by thin and short newly formed myofibers. Many of them, however, showed evidence of apoptotic cells and myofibril degradation, suggesting that long-term unloading in microgravity may affect late stages of myofiber differentiation. Ground asynchronous and vivarium control animals demonstrated normal, well-developed tissue structure with sufficient blood and nerve supply and evidence of regenerative formation of new myofibers free of apoptotic nuclei. Regenerative activity of satellite cells in muscles was observed both in microgravity and ground control groups, using Pax7 and Myogenin immunolocalization, as well as Myogenin expression analysis. In addition, we have detected positive nuclear immunolocalization of c-Jun and c-Myc proteins indicating their sensitivity to changes in gravitational loading in a given model. In summary, long-term spaceflight in microgravity caused significant atrophy and degeneration of the femoral Quadriceps muscle group, and it may interfere with muscle regenerative processes by inducing apoptosis in newly formed myofibrils during their differentiation phase. PMID- 29475517 TI - Microgels for long-term storage of vitamins for extended spaceflight. AB - Biocompatible materials that can encapsulate large amounts of nutrients while protecting them from degrading environmental influences are highly desired for extended manned spaceflight. In this study, alkaline-degradable microgels based on poly(N-vinylcaprolactam) (PVCL) were prepared and analysed with their regard to stabilise retinol which acts as a model vitamin (vitamin A1). It was investigated whether the secondary crosslinking of the particles with a polyphenol can prevent the isomerisation of biologically active all-trans retinol to biologically inactive cis-trans retinol. Both loading with retinol and secondary crosslinking of the particles was performed at room temperature to prevent an early degradation of the vitamin. This study showed that PVCL microgels drastically improve the water solubility of hydrophobic retinol. Additionally, it is demonstrated that the highly crosslinked microgel particles in aqueous solution can be utilised to greatly retard the light- and temperature induced isomerisation process of retinol by a factor of almost 100 compared to pure retinol stored in ethanol. The use of microgels offers various advantages over other drug delivery systems as they exhibit enhanced biocompatibility and superior aqueous solubility. PMID- 29475518 TI - An innovative in vitro device providing continuous low doses of gamma-rays mimicking exposure to the space environment: A dosimetric study. AB - Astronauts are exposed to microgravity and chronic irradiation but experimental conditions combining these two factors are difficult to reproduce on earth. We have created an experimental device able to combine chronic irradiation and altered gravity that may be used for cell cultures or plant models in a ground based facility. Irradiation was provided by thorium nitrate powder, conditioned so as to constitute a sealed source that could be placed in an incubator. Cell plates or plant seedlings could be placed in direct contact with the source or at various distances above it. Moreover, a random positioning machine (RPM) could be positioned on the source to simulate microgravity. The activity of the source was established using the Bateman formula. The spectrum of the source, calculated according to the natural decrease of radioactivity and the gamma spectrometry, showed very good adequacy. The experimental fluence was close to the theoretical fluence evaluation, attesting its uniform distribution. A Monte Carlo model of the irradiation device was processed by GATE code. Dosimetry was performed with radiophotoluminescent dosimeters exposed for one month at different locations (x and y axes) in various cell culture conditions. Using the RPM placed on the source, we reached a mean absorbed dose of gamma rays of (0.33 +/- 0.17) mSv per day. In conclusion, we have elaborated an innovative device allowing chronic radiation exposure to be combined with altered gravity. Given the limited access to the International Space Station, this device could be useful to researchers interested in the field of space biology. PMID- 29475519 TI - Estimating CO2 gas exchange in mixed age vegetable plant communities grown on soil-like substrates for life support systems. AB - If soil-like substrate (SLS) is to be used in human life support systems with a high degree of mass closure, the rate of its gas exchange as a compartment for mineralization of plant biomass should be understood. The purpose of this study was to compare variations in CO2 gas exchange of vegetable plant communities grown on the soil-like substrate using a number of plant age groups, which determined the so-called conveyor interval. Two experimental plant communities were grown as plant conveyors with different conveyor intervals. The first plant community consisted of conveyors with intervals of 7 days for carrot and beet and 14 days for chufa sedge. The conveyor intervals in the second plant community were 14 days for carrot and beet and 28 days for chufa sedge. This study showed that increasing the number of age groups in the conveyor and, thus, increasing the frequency of adding plant waste to the SLS, decreased the range of variations in CO2 concentration in the "plant-soil-like substrate" system. However, the resultant CO2 gas exchange was shifted towards CO2 release to the atmosphere of the plant community with short conveyor intervals. The duration of the conveyor interval did not significantly affect productivity and mineral composition of plants grown on the SLS. PMID- 29475520 TI - Forces associated with launch into space do not impact bone fracture healing. AB - Segmental bone defects (SBDs) secondary to trauma invariably result in a prolonged recovery with an extended period of limited weight bearing on the affected limb. Soldiers sustaining blast injuries and civilians sustaining high energy trauma typify such a clinical scenario. These patients frequently sustain composite injuries with SBDs in concert with extensive soft tissue damage. For soft tissue injury resolution and skeletal reconstruction a patient may experience limited weight bearing for upwards of 6 months. Many small animal investigations have evaluated interventions for SBDs. While providing foundational information regarding the treatment of bone defects, these models do not simulate limited weight bearing conditions after injury. For example, mice ambulate immediately following anesthetic recovery, and in most cases are normally ambulating within 1-3 days post-surgery. Thus, investigations that combine disuse with bone healing may better test novel bone healing strategies. To remove weight bearing, we have designed a SBD rodent healing study in microgravity (uG) on the International Space Station (ISS) for the Rodent Research-4 (RR-4) Mission, which launched February 19, 2017 on SpaceX CRS-10 (Commercial Resupply Services). In preparation for this mission, we conducted an end-to-end mission simulation consisting of surgical infliction of SBD followed by launch simulation and hindlimb unloading (HLU) studies. In brief, a 2 mm defect was created in the femur of 10 week-old C57BL6/J male mice (n = 9 10/group). Three days after surgery, 6 groups of mice were treated as follows: 1) Vivarium Control (maintained continuously in standard cages); 2) Launch Negative Control (placed in the same spaceflight-like hardware as the Launch Positive Control group but were not subjected to launch simulation conditions); 3) Launch Positive Control (placed in spaceflight-like hardware and also subjected to vibration followed by centrifugation); 4) Launch Positive Experimental (identical to Launch Positive Control group, but placed in qualified spaceflight hardware); 5) Hindlimb Unloaded (HLU, were subjected to HLU immediately after launch simulation tests to simulate unloading in spaceflight); and 6) HLU Control (single housed in identical HLU cages but not suspended). Mice were euthanized 28 days after launch simulation and bone healing was examined via micro-Computed Tomography (uCT). These studies demonstrated that the mice post-surgery can tolerate launch conditions. Additionally, forces and vibrations associated with launch did not impact bone healing (p = .3). However, HLU resulted in a 52.5% reduction in total callus volume compared to HLU Controls (p = .0003). Taken together, these findings suggest that mice having a femoral SBD surgery tolerated the vibration and hypergravity associated with launch, and that launch simulation itself did not impact bone healing, but that the prolonged lack of weight bearing associated with HLU did impair bone healing. Based on these findings, we proceeded with testing the efficacy of FDA approved and novel SBD therapies using the unique spaceflight environment as a novel unloading model on SpaceX CRS-10. PMID- 29475522 TI - Dynamical modeling approach to risk assessment for radiogenic leukemia among astronauts engaged in interplanetary space missions. AB - A recently developed biologically motivated dynamical model of the assessment of the excess relative risk (ERR) for radiogenic leukemia among acutely/continuously irradiated humans (Smirnova, 2015, 2017) is applied to estimate the ERR for radiogenic leukemia among astronauts engaged in long-term interplanetary space missions. Numerous scenarios of space radiation exposure during space missions are used in the modeling studies. The dependence of the ERR for leukemia among astronauts on several mission parameters including the dose equivalent rates of galactic cosmic rays (GCR) and large solar particle events (SPEs), the number of large SPEs, the time interval between SPEs, mission duration, the degree of astronaut's additional shielding during SPEs, the degree of their additional 12 hour's daily shielding, as well as the total mission dose equivalent, is examined. The results of the estimation of ERR for radiogenic leukemia among astronauts, which are obtained in the framework of the developed dynamical model for various scenarios of space radiation exposure, are compared with the corresponding results, computed by the commonly used linear model. It is revealed that the developed dynamical model along with the linear model can be applied to estimate ERR for radiogenic leukemia among astronauts engaged in long-term interplanetary space missions in the range of applicability of the latter. In turn, the developed dynamical model is capable of predicting the ERR for leukemia among astronauts for the irradiation regimes beyond the applicability range of the linear model in emergency cases. As a supplement to the estimations of cancer incidence and death (REIC and REID) (Cucinotta et al., 2013, 2017), the developed dynamical model for the assessment of the ERR for leukemia can be employed on the pre-mission design phase for, e.g., the optimization of the regimes of astronaut's additional shielding in the course of interplanetary space missions. The developed model can also be used on the phase of the real-time responses during the space mission to make the decisions on the operational application of appropriate countermeasures to minimize the risks of occurrences of leukemia, especially, for emergency cases. PMID- 29475521 TI - Effects of spaceflight on the immunoglobulin repertoire of unimmunized C57BL/6 mice. AB - Spaceflight has been shown to suppress the adaptive immune response, altering the distribution and function of lymphocyte populations. B lymphocytes express highly specific and highly diversified receptors, known as immunoglobulins (Ig), that directly bind and neutralize pathogens. Ig diversity is achieved through the enzymatic splicing of gene segments within the genomic DNA of each B cell in a host. The collection of Ig specificities within a host, or Ig repertoire, has been increasingly characterized in both basic research and clinical settings using high-throughput sequencing technology (HTS). We utilized HTS to test the hypothesis that spaceflight affects the B-cell repertoire. To test this hypothesis, we characterized the impact of spaceflight on the unimmunized Ig repertoire of C57BL/6 mice that were flown aboard the International Space Station (ISS) during the Rodent Research One validation flight in comparison to ground controls. Individual gene segment usage was similar between ground control and flight animals, however, gene segment combinations and the junctions in which gene segments combine was varied among animals within and between treatment groups. We also found that spontaneous somatic mutations in the IgH and Igkappa gene loci were not increased. These data suggest that space flight did not affect the B cell repertoire of mice flown and housed on the ISS over a short period of time. PMID- 29475523 TI - Spacecraft cabin environment effects on the growth and behavior of Chlorella vulgaris for life support applications. AB - An Environmental Control and Life Support System (ECLSS) is necessary for humans to survive in the hostile environment of space. As future missions move beyond Earth orbit for extended durations, reclaiming human metabolic waste streams for recycled use becomes increasingly important. Historically, these functions have been accomplished using a variety of physical and chemical processes with limited recycling capabilities. In contrast, biological systems can also be incorporated into a spacecraft to essentially mimic the balance of photosynthesis and respiration that occurs in Earth's ecosystem, along with increasing the reuse of biomass throughout the food chain. In particular, algal photobioreactors that use Chlorella vulgaris have been identified as potential multifunctional components for use as part of such a bioregenerative life support system (BLSS). However, a connection between the biological research examining C. vulgaris behavior and the engineered spacecraft cabin environmental conditions has not yet been thoroughly established. This review article characterizes the ranges of prior and expected cabin parameters (e.g. temperature, lighting, carbon dioxide, pH, oxygen, pressure, growth media, contamination, gravity, and radiation) and reviews algal metabolic response (e.g. growth rate, composition, carbon dioxide fixation rates, and oxygen evolution rates) to changes in those parameters that have been reported in prior space research and from related Earth-based experimental observations. Based on our findings, it appears that C. vulgaris offers many promising advantages for use in a BLSS. Typical atmospheric conditions found in spacecraft such as elevated carbon dioxide levels are, in fact, beneficial for algal cultivation. Other spacecraft cabin parameters, however, introduce unique environmental factors, such as reduced total pressure with elevated oxygen concentration, increased radiation, and altered gravity, whose effects on the biological responses of C. vulgaris are not yet well understood. A summary of optimum growth parameter ranges for C. vulgaris is presented in this article as a guideline for designing and integrating an algal photobioreactor into a spacecraft life support system. Additional research challenges for evaluating as of yet uncharacterized parameters are also identified in this article that have the potential for improving spaceflight applications as well as terrestrial aquatic algal cultivation systems. PMID- 29475525 TI - High LET radiation shows no major cellular and functional effects on primary cardiomyocytes in vitro. AB - It is well known that ionizing radiation causes adverse effects on various mammalian tissues. However, there is little information on the biological effects of heavy ion radiation on the heart. In order to fill this gap, we systematically examined DNA-damage induction and repair, as well as proliferation and apoptosis in avian cardiomyocyte cultures irradiated with heavy ions such as titanium and iron, relevant for manned space-flight, and carbon ions, as used for radiotherapy. Further, and to our knowledge for the first time, we analyzed the effect of heavy ion radiation on the electrophysiology of primary cardiomyocytes derived from chicken embryos using the non-invasive microelectrode array (MEA) technology. As electrophysiological endpoints beat rate and field action potential duration were analyzed. The cultures clearly exhibited the capacity to repair induced DNA damage almost completely within 24 h, even at doses of 7 Gy, and almost completely recovered from radiation-induced changes in proliferative behavior. Interestingly, no significant effects on apoptosis could be detected. Especially the functionality of primary cardiac cells exhibited a surprisingly high robustness against heavy ion radiation, even at doses of up to 7 Gy. In contrast to our previous study with X-rays the beat rate remained more or less unaffected after heavy ion radiation, independently of beam quality. The only change we could observe was an increase of the field action potential duration of up to 30% after titanium irradiation, diminishing within the following three days. This potentially pathological observation may be an indication that heavy ion irradiation at high doses could bear a long-term risk for cardiovascular disease induction. PMID- 29475526 TI - From the desk of the Editor in Chief. PMID- 29475524 TI - Age as a factor in the responsiveness of the organism to the disruption of cognitive performance by exposure to HZE particles differing in linear energy transfer. AB - Exposure to particles of high energy and charge (HZE particles) can produce decrements in cognitive performance. A series of experiments exposing rats to different HZE particles was run to evaluate whether the performance decrement was dependent on the age of the subject at the time of irradiation. Fischer 344 rats that were 2-, 11- and 15/16-months of age were exposed to 16O, 48Ti, or 4He particles at the NASA Space Radiation Laboratory at Brookhaven National Laboratory. As previously observed following exposure to 56Fe particles, exposure to the higher LET 48Ti particles produced a disruption of cognitive performance at a lower dose in the older subjects compared to the dose needed to disrupt performance in the younger subjects. There were no age related changes in the dose needed to produce a disruption of cognitive performance following exposure to lower LET 16O or 4He particles. The threshold for the rats exposed to either 16O or 4He particles was similar at all ages. Because the 11- and 15-month old rats are more representative of the age of astronauts (45-55 years old) the present results indicate that particle LET may be a critical factor in estimating the risk of developing a cognitive deficit following exposure to space radiation on exploratory class missions. PMID- 29475528 TI - Finding Kawasaki Disease. PMID- 29475527 TI - 2018 Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology Focused Update of the Guidelines for the Use of Antiplatelet Therapy. AB - Antiplatelet therapy (APT) has become an important tool in the treatment and prevention of atherosclerotic events, particularly those associated with coronary artery disease. A large evidence base has evolved regarding the relationship between APT prescription in various clinical contexts and risk/benefit relationships. The Guidelines Committee of the Canadian Cardiovascular Society and Canadian Association of Interventional Cardiology publishes regular updates of its recommendations, taking into consideration the most recent clinical evidence. The present update to the 2011 and 2013 Canadian Cardiovascular Society APT guidelines incorporates new evidence on how to optimize APT use, particularly in situations in which few to no data were previously available. The recommendations update focuses on the following primary topics: (1) the duration of dual APT (DAPT) in patients who undergo percutaneous coronary intervention (PCI) for acute coronary syndrome and non-acute coronary syndrome indications; (2) management of DAPT in patients who undergo noncardiac surgery; (3) management of DAPT in patients who undergo elective and semiurgent coronary artery bypass graft surgery; (4) when and how to switch between different oral antiplatelet therapies; and (5) management of antiplatelet and anticoagulant therapy in patients who undergo PCI. For PCI patients, we specifically analyze the particular considerations in patients with atrial fibrillation, mechanical or bioprosthetic valves (including transcatheter aortic valve replacement), venous thromboembolic disease, and established left ventricular thrombus or possible left ventricular thrombus with reduced ejection fraction after ST-segment elevation myocardial infarction. In addition to specific recommendations, we provide values and preferences and practical tips to aid the practicing clinician in the day to day use of these important agents. PMID- 29475529 TI - High Stakes: CTO-PCI in the Post-CABG Patient. PMID- 29475530 TI - Management of Non-ST-Elevation Myocardial Infarction in Elderly Patients: Time to Consider Frailty and Quality of Life. PMID- 29475532 TI - The Transcatheter Aortic Valve Implantation (TAVI) Quality Report: A Call to Arms for Improving Quality in Canada. AB - Transcatheter aortic valve implantation (TAVI) is a disruptive technology that has dramatically changed the way clinicians care for patients with aortic stenosis. In 15 short years, this technology has progressed from first-in-human to the standard of care for high-risk and inoperable patients with aortic stenosis. In 2016 the Canadian Cardiovascular Society published the first ever report of quality of care for TAVI in Canada. This report provided multiple insights into evaluating such care delivered to Canadians and the challenges that lie ahead. In this article, we summarize these challenges and encourage cardiologists to join the call to arms for improving quality of TAVI care in Canada. PMID- 29475531 TI - Associations Between Complex PCI and Prasugrel or Clopidogrel Use in Patients With Acute Coronary Syndrome Who Undergo PCI: From the PROMETHEUS Study. AB - BACKGROUND: Potent P2Y12 inhibitors might offer enhanced benefit against thrombotic events in complex percutaneous coronary intervention (PCI). We examined prasugrel use and outcomes according to PCI complexity, as well as analyzing treatment effects according to thienopyridine type. METHODS: PROMETHEUS was a multicentre observational study that compared clopidogrel vs prasugrel in acute coronary syndrome patients who underwent PCI (n = 19,914). Complex PCI was defined as PCI of the left main, bifurcation lesion, moderate-severely calcified lesion, or total stent length >= 30 mm. Major adverse cardiac events (MACE) were a composite of death, myocardial infarction, stroke, or unplanned revascularization. Outcomes were adjusted using multivariable Cox regression for effect of PCI complexity and propensity-stratified analysis for effect of thienopyridine type. RESULTS: The study cohort included 48.9% (n = 9735) complex and 51.1% (n = 10,179) noncomplex patients. Second generation drug-eluting stents were used in 70.1% complex and 66.2% noncomplex PCI patients (P < 0.0001). Complex PCI was associated with greater adjusted risk of 1-year MACE (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.20-1.39; P < 0.001). Prasugrel was prescribed in 20.7% of complex and 20.1% of noncomplex PCI patients (P = 0.30). Compared with clopidogrel, prasugrel significantly decreased adjusted risk for 1-year MACE in complex PCI (HR, 0.79; 95% CI, 0.68-0.92) but not noncomplex PCI (HR, 0.91; 95% CI, 0.77-1.08), albeit there was no evidence of interaction (P interaction = 0.281). CONCLUSIONS: Despite the use of contemporary techniques, acute coronary syndrome patients who undergo complex PCI had significantly higher rates of 1-year MACE. Adjusted magnitude of treatment effects with prasugrel vs clopidogrel were consistent in complex and noncomplex PCI without evidence of interaction. PMID- 29475533 TI - The State of Cardiovascular Magnetic Resonance Imaging in Canada: Results from the CanSCMR Pan-Canadian Survey. AB - Over the past 25 years, cardiovascular magnetic resonance imaging (CMR) has developed into an increasingly valuable imaging modality. CMR is now a routine clinical tool for the evaluation of cardiovascular structure and function. However, current patterns in the utilization of CMR in Canada are unknown as are data on important issues such as wait times and appropriate use of this technology. To address these issues, we sought to perform a staged pan-Canadian Survey to initiate dialogue regarding the utilization and appropriate use of CMR in Canada. Two surveys were sent out to participants involved with the performance of CMR at tertiary care referral centres across Canada, one in 2015 and the other in 2017. Questions for both surveys were vetted by the executive committee of the Canadian Society for Cardiovascular Magnetic Resonance and were distributed to sites identified through Canadian Society for Cardiovascular Magnetic Resonance memberships. Descriptive statistics were used to summarize data. Twenty-one sites participated in the 2015 survey and 17 in the 2017 survey. Our results highlighted that most participants believe that CMR is an important component in the clinical decision-making process. They also exposed important issues such as excessive and seemingly worsening wait times for CMR and suggested potential drivers of this phenomenon. Finally, our results confirm ongoing challenges in the imaging community in meeting quality assurance guidelines aimed at documenting appropriate use criteria. Researchers and policy makers should focus on mechanisms aimed to reduce wait times as well as increase use of appropriate use criteria. PMID- 29475534 TI - Increased Susceptibility for Atrial and Ventricular Cardiac Arrhythmias in Mice Treated With a Single High Dose of Ibrutinib. AB - Atrial fibrillation is a side effect of ibrutinib, an irreversible inhibitor of Bruton tyrosine kinase used for treatment of B-cell lymphoproliferative disorders. We determined if single (2 or 10 mg/kg), or chronic (14 days) oral ibrutinib followed by 24-hour washout conferred susceptibility to electrically induced arrhythmias in 1-month-old male C57BL/6 mice. A single higher dose of ibrutinib increased arrhythmia inducibility. There was no inducibility difference after chronic dosing with washout. This suggests that high serum drug levels might be responsible for the proarrhythmic effect of ibrutinib and that an altered dosing strategy might mitigate the side effects. PMID- 29475535 TI - Zero-Contrast Percutaneous Coronary Intervention Guided by Dextran-Based Optical Coherence Tomography. AB - Individuals with advanced chronic kidney disease (CKD) and coronary artery disease are often denied percutaneous coronary intervention (PCI) because of an aversion to the risk of contrast-induced nephropathy. We present the case of a 76 year-old man with stage 4 CKD requiring coronary revascularization. Zero-contrast PCI was successfully performed using dextran-based optical coherence tomography (OCT) guidance. Our report suggests the feasibility of dextran-based, OCT-guided, zero-contrast PCI in patients with advanced CKD. Further studies should evaluate the safety and efficacy of this novel approach. PMID- 29475536 TI - Multiple Thromboembolic Events from a Left Atrial Appendage Occlusion Device. AB - Left atrial appendage occlusion devices are an alternative to oral anticoagulation in patients with nonvalvular atrial fibrillation who are at risk of ischemic stroke. Thromboprophylaxis after implantation is recommended, but the optimal regimen is unknown. We report a clinicopathologic case in which thrombus adherent to an incompletely endothelialized WATCHMAN device (Boston Scientific, Marlborough, MA) resulted in multiple thromboembolic events, contributing to a fatal outcome. This case illustrates uncertainties regarding the device's endothelialization process. PMID- 29475537 TI - Transcatheter Aortic Valve Replacement for Severe Aortic Regurgitation With Acute Refractory Cardiogenic Shock. AB - From January 2013 to January 2017, 686 consecutive patients were referred to our centre for transcatheter aortic valve replacement, including 5 subjects with severe aortic regurgitation and acute refractory cardiogenic shock. These patients were contraindicated for surgical treatment by the heart team because of high surgical risk (median logistic EuroSCORE: 74.6/Society of Thoracic Surgeons score: 37.9). The success rate of valve implantation was 100% through transfemoral access with self-expandable devices. The observed 30-day mortality rate was 20%. Hence, the transcatheter aortic valve replacement procedure might represent a successful and life-saving intervention for treatment of patients with severe aortic regurgitation who present with acute refractory cardiogenic shock. PMID- 29475538 TI - Perioperative Cardiac Risk Assessment for the Frail Older Adult. PMID- 29475540 TI - Going Beyond Left Anterior Descending Artery Occlusion: Recognizing the Variable Clinical Associations of the de Winter Pattern on Electrocardiography. PMID- 29475539 TI - Frailty, the Elderly, and the Guidelines on Perioperative Cardiac Risk Assessment and Management in Noncardiac Surgery. PMID- 29475542 TI - Intersection of salt- and immune-mediated mechanisms of hypertension in the gut microbiome. PMID- 29475543 TI - Claudins: a tale of interactions in the thick ascending limb. AB - The claudins are the main proteins composing the tight junctions. The differential expression of claudin isoforms contributes to the specificity of paracellular transport pathways along the kidney tubule. Recent studies focusing on claudin-10 and claudin-16 support the longitudinal specialization of paracellular transport of cations within the thick ascending limb and demonstrate that complex tubular adaptations operate to buffer the consequences of chronic segmental lesions in the kidney. PMID- 29475544 TI - Mesoamerican nephropathy: pathology in search of etiology. AB - Mesoamerican nephropathy is a progressive, often fatal form of tubulointerstitial nephritis affecting young agricultural laborers in Central America. Initially described as a chronic disease, a study by Fischer and coworkers in this issue of Kidney International suggests that Mesoamerican nephropathy goes through an active, inflammatory phase. Although the pathologic findings are nonspecific and the etiology of Mesoamerican nephropathy remains unclear, inflammatory infiltrates in areas of evolving and established interstitial fibrosis appear to cause progressive kidney injury. PMID- 29475545 TI - Total kidney volume: the most valuable predictor of autosomal dominant polycystic kidney disease progression. AB - Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney cysts resulting in damage to kidney structure and function. Yu et al. showed that height-adjusted total kidney volume (htTKV) was a significant independent predictor of ADPKD progression after a follow-up of 14.5 years. The genotype was not an independent prognostic factor after adjusting for htTKV. This commentary discusses several considerations in model comparison, biomarker validation, and future challenges in ADPKD research. PMID- 29475546 TI - IgA nephropathy: toward more specific diagnosis (and rescue of snails). AB - The diagnosis of IgA nephropathy relies on the histologic demonstration of glomerular mesangial IgA deposits. However, only a very small fraction of IgA, namely, galactose-deficient IgA1, seems to induce the disease. So far, this type of IgA could only be detected using mass spectrometry or lectins, which are relatively difficult to standardize. A novel monoclonal antibody, KM55, specifically recognizing galactose-deficient IgA1, may now change this. PMID- 29475547 TI - A rare presentation of a posttransplant lymphoproliferative disorder. PMID- 29475548 TI - Native kidney pyelonephritis as the cause of recurrent urinary tract infections in a kidney transplant recipient. PMID- 29475549 TI - The Case | Life-threatening lactic acidosis in a patient with jaundice and liver masses. PMID- 29475550 TI - The negative effect of perioperative red blood cell transfusion on morbidity and mortality after major abdominal operations. AB - BACKGROUND: This study aims to test associations between perioperative blood transfusion and postoperative morbidity and mortality after major abdominal operations. METHODS: The 2014 ACS NSQIP dataset was queried for all patients who underwent one of the ten major abdominal operations. Separate multivariable regression models, were developed to evaluate the independent effects of perioperative blood transfusion on morbidity and mortality. RESULTS: Of 48,854 patients in the study cohort, 4887 (10%) received a blood transfusion. Rates of transfusion ranged from 4% for laparoscopic gastrointestinal resection to 58% for open AAA. After adjusting for significant effects of NSQIP-estimated probabilities, transfusion was independently associated with morbidity and mortality after open AAA repair (OR = 1.99/14.4 respectively, p <= 0.010), esophagectomy (OR = 2.80/3.0, p < 0.001), pancreatectomy (OR = 1.88/3.01, p < 0.001), hepatectomy (OR = 2.82/5.78, p < 0.001), colectomy (OR = 2.15/3.17, p < 0.001), small bowel resection (OR = 2.81/3.83, p <= 0.004), and laparoscopic gastrointestinal operations (OR = 2.73/4.05, p < 0.001). CONCLUSIONS: Perioperative blood transfusion is independently associated with an increased risk of morbidity and mortality after most major abdominal operations. PMID- 29475552 TI - Insufficient evidence about the association between caries and type 1 diabetes and metabolic status in children and adolescents. PMID- 29475551 TI - Long-term shunt patency and overall survival of transjugular intrahepatic portosystemic shunt placement using covered stents with bare stents versus covered stents alone. AB - AIM: To investigate the long-term shunt patency and overall survival of transjugular intrahepatic portosystemic shunt (TIPS) placement using covered stents with or without bare stents over a follow-up period up to 7 years. MATERIALS AND METHODS: A total of 154 patients undergoing TIPS placement were enrolled and analysed retrospectively. They were divided into two groups: those undergoing TIPS placement using covered with bare stents (group A, n=42) and those without bare stents (group B, n=112). RESULTS: The cumulative 5-year primary patency rate was significantly lower in group A than in group B (group A: 0% versus group B: 66.7%; p<0.001). The cumulative 5-year overall survival rates were comparable between the two groups (group A: 76% versus group B: 58.7%; p=0.214). The baseline portal vein thrombosis (hazard ratio [HR]:4.610; 95% confidence interval [CI]:2.691-7.897; p=0.000), portal pressure decrement (HR: 0.911; 95% CI: 0.845-0.982; p=0.015), and group (HR: 0.419; 95% CI: 0.239-0.736; p=0.002) were independent predictors for shunt dysfunction, while hepatocellular carcinoma (HR: 6.615; 95% CI: 2.863-15.283; p=0.000) and ascites (HR: 2.166; 95% CI: 1.298-3.615; p=0.003) were independent predictors for mortality. CONCLUSIONS: Although TIPS placement using covered with bare stents led to lowered long-term shunt patency than using covered stents alone, the overall survival rates were similar. PMID- 29475553 TI - Oral appliances may have trivial benefits in surrogate cardiovascular outcomes in patients with obstructive sleep apnea. PMID- 29475555 TI - Low-quality evidence suggesting benefits of vibration on distalization of canines during orthodontic treatment. PMID- 29475556 TI - Preemptive submucosal diclofenac may reduce postoperative pain up to 6 hours after surgical mandibular third-molar extraction but may increase adverse effects. PMID- 29475554 TI - Influence of 2 caries-detecting devices on clinical decision making and lesion depth for suspicious occlusal lesions: A randomized trial from The National Dental Practice-Based Research Network. AB - BACKGROUND: A suspicious occlusal carious lesion (SOCL) can be defined as a lesion with no cavitation and no radiographic radiolucency but for which caries is suspected. The authors evaluated whether using a device changed the percentage of SOCLs that were opened surgically and, among those SOCLs that were opened, the proportion that had penetrated into dentin. METHODS: Eighty-two dentists participated. In phase 1 of the study, dentists identified approximately 20 SOCLs, obtained patient consent, and recorded information about the lesion, treatment or treatments, and depth, if opened. Dentists were then randomly assigned into 1 of 3 groups: no device, DIAGNOdent (KaVo), and Spectra (Air Techniques). In phase 2, dentists enrolled approximately 20 additional patients and recorded the same phase 1 information while using the assigned device to help make their treatment decisions. A mixed-model logistic regression was used to determine any differences after randomization in the proportion of lesions opened and, if opened, the proportion of lesions that penetrated into dentin. RESULTS: A total of 1,500 SOCLs were enrolled in each phase. No statistically significant difference was found in the change in proportion of lesions receiving invasive treatment from phase 1 to phase 2 across the 3 groups (P = .33) or in the change in proportion of percentage of opened lesions that extended into dentin (P = .31). CONCLUSION: Caries-detecting devices in the study did not change substantially dentists' decisions to intervene or the accuracy of the intervention decision in predicting lesion penetration into dentin. PRACTICAL IMPLICATIONS: The caries-detecting devices tested may not improve dentists' clinical decision making for SOCLs. PMID- 29475558 TI - Fetal monocytes and the origins of tissue-resident macrophages. AB - Tissue-resident macrophages have pivotal functions for tissue defense and homeostasis. Two main discoveries have changed our current understanding of macrophage development: Their embryonic origin and their ability to self-renew throughout the lifespan. It is now well accepted that most tissue-resident macrophages are long-lived cells derived from a transient hematopoietic wave of erythro-myeloid progenitors (EMPs) emerging in the yolk sac. At least two distinct pathways derived from EMPs have been implicated in macrophage development. The first one, c-Myb-independent is giving rise to yolk sac macrophages also called primitive macrophages, and bypassing the classical monocytic intermediates. The second requires c-Myb expression and start once EMPs seed the fetal liver where they generate fetal monocytes. Sequentially, primitive macrophages seed every tissue and will ultimately give rise to microglia in the brain, rapidly isolated by the blood brain barrier, while EMP-derived fetal monocytes infiltrate every other tissues and gradually generate the major pool of adult tissue-resident macrophages by diluting the initial primitive macrophage contribution. A third wave of hematopoietic stem cells (HSC)-derived monocytes is also emerging from the fetal liver to contribute to the long-lived macrophage pool established at birth while the adult hematopoiesis is only starting in the bone marrow. We propose here to review recent insights about the different embryonic hematopoietic programs responsible for the generation of long-lived tissue-resident macrophages and their maintenance after birth. PMID- 29475557 TI - Drug therapy problems identification by clinical pharmacists in a private hospital in Kuwait. AB - OBJECTIVES: To report the types and frequency of drug therapy problems (DTPs) identified and the physician acceptance of the clinical pharmacist interventions in a private hospital in Kuwait. METHODS: A retrospective cross-sectional study was conducted on 3500 patients admitted to the hospital between December 2010 and April 2013. A structured approach was used to identify DTPs and recommend interventions. Data were analyzed using MAXQDA version 11. KEY FINDINGS: A total of 670 DTPs were identified and recommendations were proposed to treating physicians for each DTP. Overdosage was the most frequently identified drug therapy problem (30.8%), followed by low dosage (17.6%), unnecessary drug therapy (17.3%), need for additional drug therapy (11.6%), and need for different drug product (11.6%). The drug classes most frequently involved were anti-infectives (36.9%), analgesics (25.2%), and gastrointestinal agents (15.5%). More than two third of the interventions (67.5%) were accepted and implemented by physicians. The most frequently accepted interventions were related to nonadherence, adverse drug reaction, monitoring parameters, inappropriate dosage, and need for additional drug therapy. CONCLUSION: The current findings expand the existing body of data by reporting on pharmacist recommendations of identified DTPs and importantly, their high rate of acceptance and implementation by the treating physician. These results could serve as a springboard to support further development and implementation of clinical pharmacy services in other healthcare settings in Kuwait. PMID- 29475559 TI - Sleeve gastrectomy: Globalization and its controversies. PMID- 29475560 TI - The Utility of Ultrasound in the Diagnosis of Muscle Hernias in the Dermatology Clinic. PMID- 29475561 TI - Updated guidelines for the diagnosis and management of high blood pressure: implications for clinical practice in nephrology. PMID- 29475562 TI - Interleukin-6/Stat3 signaling has an essential role in the host antimicrobial response to urinary tract infection. AB - The signaling networks regulating antimicrobial activity during urinary tract infection (UTI) are incompletely understood. Interleukin-6 (IL-6) levels increase with UTI severity, but the specific contributions of IL-6 to host immunity against bacterial uropathogens are unknown. To clarify this we tested whether IL 6 activates the Stat3 transcription factor, to drive a program of antimicrobial peptide gene expression in infected urothelium during UTI. Transurethral inoculation of uropathogenic Escherichia coli led to IL-6 secretion, urothelial Stat3 phosphorylation, and activation of antimicrobial peptide transcription, in a Toll-like receptor 4-dependent manner in a murine model of cystitis. Recombinant IL-6 elicited Stat3 phosphorylation in primary urothelial cells in vitro, and systemic IL-6 administration promoted urothelial Stat3 phosphorylation and antimicrobial peptide expression in vivo. IL-6 deficiency led to decreased urothelial Stat3 phosphorylation and antimicrobial peptide mRNA expression following UTI, a finding mirrored by conditional Stat3 deletion. Deficiency in IL 6 or Stat3 was associated with increased formation of intracellular bacterial communities, and exogenous IL-6 reversed this phenotype in IL-6 knockout mice. Moreover, chronic IL-6 depletion led to increased renal bacterial burden and severe pyelonephritis in C3H/HeOuJ mice. Thus, IL-6/Stat3 signaling drives a transcriptional program of antimicrobial gene expression in infected urothelium, with key roles in limiting epithelial invasion and ascending infection. PMID- 29475563 TI - Global trends on reef fishes' ecology of fear: Flight initiation distance for conservation. AB - Escape behaviors have a great potential as an indicator of the efficacy of management. For instance, the degree of fear perceived by fishes targeted by fisheries is frequently higher in unprotected marine areas than in areas where some protection is provided. We systematically reviewed the literature on how fear, which we define as variation in escape behavior, was quantified in reef fishes. In the past 25 years, a total of 33 studies were identified, many of which were published within the last five years and nearly 40% of those (n = 13) focused on Indo-Pacific reefs, showing that there are still many geographical gaps. While eleven escape metrics were identified to evaluate fish escape, flight initiation distance (FID) was the most commonly employed (n = 23). FID was used to study different questions of applied and theoretical ecology, which involved 14 reef fish families. We also used a formal meta-analysis to investigate the effects of fishing by comparing FID inside and outside marine protected areas. Fishes outside MPAs had increased FID compared to those inside MPAs. The Labridae family had a significantly higher effect sizes than Acanthuridae and Epinephelidae, suggesting that fishes in this family may be indicators of effective MPAs using FID. We conclude that protocols aimed to quantify fear in fishes, which provide accurate assessments of fishing effects on fish escape behavior, will help gauge the compliance of marine protected areas. PMID- 29475565 TI - The influence of motor ability rehabilitation on temporal-spatial parameters of gait in Huntington's disease patients on the basis of a three-dimensional motion analysis system: An experimental trial. AB - OBJECTIVE: There is no existing standard, evidence-based, scientific model for motor ability improvement in Huntington's Disease (HD) patients aimed at maintaining independent gait for as long as possible, or performing activities of daily living, the effectiveness of which would be supported by the results of studies using objective research tools. Under these circumstances, the aim of this study was to analyze the influence of motor ability rehabilitation on the spatial-temporal parameters of gait in HD patients. DESIGN: It was an experimental trial. The studied group consisted of 30 patients (17 women and 13 men) with HD. In hospital conditions, the patients participated in the 3-week motor ability l rehabilitation programme tailored to individual needs. The study group was tested using the Vicon 250 three-dimensional gait analysis system before and after the physical exercise programme. RESULTS: Walking speed after therapy increased for the left lower limb from 1.06 (SD 0.24) [m/s] to 1.21 (SD 0.23) [m/s], and for the right lower limb from 1.07 (SD 0.25) [m/s] to 1.20 (SD 0.25) [m/s]. The cycle length increased after the applied therapy for the left lower limb from 1.17 (SD 0.20) [m] to 1.23 (SD 0.19) [m]. CONCLUSION: The three week motor ability rehabilitation programme positively influences spatial temporal gait parameters in HD patients. PMID- 29475566 TI - Nicorandil and cutaneous ulcerations, their misdiagnosis and consequences: Illustration by five cases reports and a review of the French pharmacovigilance database. AB - While physicians increasingly recognize nicorandil-related mucocutaneous ulcerations, there are still misdiagnoses, particularly in the case of unusual location and late onset ulceration after nicorandil introduction. The goal of our study was to remind clinicians about the link between nicorandil use and the development of cutaneous ulcerations and to highlight the risk of misdiagnosis. We describe five reports diagnosed by the same dermatologist, complemented by an analysis of the French pharmacovigilance database (FPVD) from 1 January 1994 to 5 January 2017. During this period, 28 reports of strict cutaneous ulcerations due to nicorandil, in addition to our five reports, were registered in the FPVD. For those 28 reports, the time to onset between nicorandil introduction and cutaneous ulcerations was quite long and exceeded one year in 16 reports (information specified in 25 reports). The delay between ulcerations observation and nicorandil discontinuation was variable, with immediate diagnosis in seven reports, but ranged from fifteen days to twelve years in 21 reports. The main locations were lower limbs, thorax and face. Ulcerations could be localized on surgery or trauma scars. Regression after nicorandil discontinuation was observed in all but two reports and ranged from three days to three months. Characteristics were comparable in our five patient's series. All patients exposed to nicorandil and healthcare practitioners prescribing nicorandil should be aware of the risk of cutaneous ulcerations to enable early diagnosis and drug withdrawal. The risk of misdiagnosis of this serious adverse drug reaction, along with the risk of sequelae, the costs of unnecessary additional investigations and the recent update on nicorandil as second-line treatment for stable angina, with existing alternative drugs, question about the benefit/risk balance of nicorandil. PMID- 29475564 TI - Long Road to Ruin: Noradrenergic Dysfunction in Neurodegenerative Disease. AB - It has been known for decades that degeneration of the locus coeruleus (LC), the major noradrenergic nucleus in the brain, occurs in both Alzheimer's disease (AD) and Parkinson's disease (PD), but it was given scant attention. It is now recognized that hyperphosphorylated tau in the LC is the first detectable AD-like neuropathology in the human brain, alpha-synuclein inclusions in the LC represent an early step in PD, and experimental LC lesions exacerbate neuropathology and cognitive/behavioral deficits in animal models. The purpose of this review is to consider the causes and consequences of LC pathology, dysfunction, and degeneration, as well as their implications for early detection and treatment. PMID- 29475567 TI - A Lymph Node Metastatic Lung Adenocarcinoma in a Previous Mediastinal Lymphoma. PMID- 29475568 TI - Emergence of plasmid-mediated colistin resistance (mcr-1) among Enterobacteriaceae strains: Laboratory detection of resistance and measures to control its dissemination. AB - The increasing use of colistin has contributed to the emergence of resistant bacteria and to an increase in the frequency of infections caused by naturally resistant Enterobacteriaceae strains such as Proteus, Providencia, Morganella, and Serratia. In August 2016, the French High Council for Public Health (French acronym HCSP) received a request from the Ministry of Health on the advice of the French National Public Health agency (Sante publique France) with regard to measures that should be taken to tackle the emergence of plasmid-mediated colistin resistance among Enterobacteriaceae strains. French healthcare facilities were asked to take the necessary measures as soon as possible, such as updating the definition of emerging highly resistant bacteria and defining the identification methods so as to take account of the evolving epidemiology of this type of resistance. This article describes the epidemiological context of the discovery of this emergence in France and worldwide, the resistance mechanisms, the microbiological methods of routine laboratory detection and the level of hygiene measures to implement in French facilities. PMID- 29475569 TI - Residents' Perceptions of Usage of the Current Alumni and Attending Network for a Formal Mentorship Program in an Academic Affiliated Community Hospital Radiology Residency. AB - Mentor-mentee relationships within radiology residencies can add significant value to a resident's overall experience. Studies demonstrate that mentorship programs can increase satisfaction for residents and faculty alike by reducing stress, easing career related decisions, increasing involvement with research, improving teaching and communication skills, and finally increasing leadership roles. In a survey of radiology program directors, 85% of program directors find such a program beneficial but only 57% have a formal program in place. Totally, 42% of program directors believe a structured mentorship program is necessary. Studies have also shown that female residents prefer female mentors. Alumni serve as an ideal group for resident mentorship as they do not face the pressures of internal faculty. No study to date in diagnostic radiology literature uses an alumni network in establishing a formal mentorship program. The objective of this study is to implement a formal mentorship program within an academic affiliated radiology residency by using program alumni and internal attending physicians for potentially increasing faculty engagement, improving resident morale, research opportunities, and networking for fellowship and job opportunities. PMID- 29475570 TI - Determinants of gestation length in Thoroughbred mares on German stud farms. AB - The aim of the present study was to analyze the effects of stallion and mare, their ages, and maternal lineage on the gestation length (GL) in Thoroughbreds. In addition, additive genetic effects of the dam, stallion and fetus were analyzed. Data were taken from 1993 through 2009, and included 16,226 pregnancies from 5959 Th oroughbred mares mated with 290 different stallions. All analyses were performed using linear mixed models. The GL ranged from 306 to 390 days, with a mean length of 347.0 +/- 14.4 days. Mating of mares with stallions aged 17 years and older resulted in a significantly longer GL compared to younger stallions. Furthermore, the GL significantly increased with the increasing age of the mares, and the GL was longer with male foals. The month and year of breeding, as well as the mare's breeding history (parity and reproductive status) also affected GL. The mare and stallion themselves explained 18% and 4% of the variance in GL. Coefficients of inbreeding of mares and foals had no significant effect on GL. The heritability for the GL was 0.17 for the dam and 0.006 for the fetus, whereas an additive genetic paternal effect was not estimable. The relative proportions among the additive genetic and permanent environmental contributions of the dam were 76.5% and 23.5%. A maternal lineage effect was not obvious. PMID- 29475571 TI - Effects of L-glutamine on boar sperm quality during liquid storage at 17 degrees C. AB - The quality of boar spermatozoa is affected by oxidative stress during preservation in vitro. It has been demonstrated that L-Glutamine (Gln) can effectively protect cells from oxidative stress-induced injury. There are, however, no reports to date evaluating the effects of Gln on boar semen liquid preservation at 17 degrees C. The aims of the present study were to elucidate whether the addition of Gln to the extender BTS could improve the quality of boar spermatozoa when stored at 17 degrees C and to determine the mechanism underlying Gln protection of spermatozoa against preservation-induced damage. Boar semen samples were collected and diluted with Beltsville Thawing Solution (BTS) containing different concentrations (0, 10, 20, 40 or 80 mM) of Gln. The results indicated the addition of 20 mM Gln to the BTS improved (P < 0.05) the motility, acrosome integrity and membrane integrity of boar sperm during liquid preservation. Interestingly, treatment of spermatozoa with Gln addition to the extender resulted in ROS quenching, while enhancing gamma-glutamyl cysteine synthetase (gamma-GCS) activity, and glutathione (GSH) content of spermatozoa. These results suggest that BTS supplemented with Gln can provide greater protective capacity to boar sperm against oxidative stress by enhancing GSH synthesis during liquid preservation. PMID- 29475572 TI - Abditibacterium utsteinense sp. nov., the first cultivated member of candidate phylum FBP, isolated from ice-free Antarctic soil samples. AB - Most bacterial lineages are known only by molecular sequence data from environmental surveys and represent the uncultivated majority. One of these lineages, candidate phylum FBP, is widespread in extreme environments on Earth, ranging from polar and desert ecosystems to wastewater and contaminated mine sites. Here we report on the characterization of strain LMG 29911T, the first cultivated representative of the FBP lineage. The strain was isolated from a terrestrial surface sample from Utsteinen, Sor Rondane Mountains, East Antarctica and is a Gram-negative, aerobic, oligotrophic chemoheterotrophic bacterium. It displays growth in a very narrow pH range, use of only a limited number of carbon sources, but also a metabolism optimized for survival in low-nutrient habitats. Remarkably, phenotypic and genome analysis indicated an extreme resistance against antibiotics and toxic compounds. We propose the names Abditibacterium utsteinense for this bacterium and Abditibacteriota for the former candidate phylum FBP. Furthermore, inter- and intra-phylum relationships indicate Armatimonadetes, a neighboring lineage to the Abditibacteriota, to be a superphylum. PMID- 29475573 TI - Avoiding Postoperative Wound Complications in Total Joint Arthroplasty. AB - Avoidance of early wound complications is critical to the success of total joint arthroplasty. The magnitude of postoperative complications can be as simple as quickly resolving wound drainage, to persistent wound drainage and full-thickness soft tissue necrosis. Persistent postoperative drainage and wound complications can lead to a devastating deep periprosthetic infection. Attention to several steps in the clinical and perioperative pathway should be addressed to avoid this complication including addressing modifiable patient risk factors, implementing meticulous surgical technique, and following an algorithmic approach in response to persistent wound drainage. PMID- 29475574 TI - Editorial overview: Innate immunity: The finely tuned STING of innate immunity. PMID- 29475575 TI - Head and Neck Contouring Peer Review. PMID- 29475576 TI - Pharmacological interventions for treating sialorrhea associated with neurological disorders: A mixed treatment network meta-analysis of randomized controlled trials. AB - Sialorrhea is a common distress associated with certain neurological disorders. The aim of this study is to compare the pharmacological agents used for treating sialorrhea by network meta-analysis. Electronic databases were searched for randomized clinical trials comparing active drugs with either placebo or other active drugs. Total drooling scores was the primary outcome measure. Inverse variance heterogeneity model was used for both direct and mixed treatment comparison analysis. Twenty one studies were included in the systematic review and 15 in the meta-analysis. Compared to placebo, benztropine, botulinum toxins A and B are associated with a significant reduction in the frequency and severity of drooling both in the overall neurological disorders as well as for children with cerebral palsy. Only botulinum toxin A and B were associated with significant therapeutic effects in Parkinson's disease. Benztropine and botulinum toxins A and B were observed to be effective in reducing sialorrhea associated with neurological disorders. PMID- 29475578 TI - Brain Feeding Circuits after Roux-en-Y Gastric Bypass. AB - Metabolic surgical procedures, such as Roux-en-Y gastric bypass (RYGB), uniquely reprogram feeding behavior and body weight in obese subjects. Clinical neuroimaging and animal studies are only now beginning to shed light on some of the underlying central mechanisms. We present here the roles of key brain neurotransmitter/neuromodulator systems in food choice, value, and intake at various stages after RYGB. In doing so, we elaborate on how known signals emanating from the reorganized gut, including peptide hormones and microbiota products, impinge on newly mapped homeostatic and hedonic brain feeding circuits. Continued progress in the rapidly evolving field of metabolic surgery will inform the design of more effective weight-loss compounds. PMID- 29475577 TI - Lumbar disc herniation surgery with microdiscectomy plus interspinous stabilization: Good clinical results, but failure to lower the incidence of re operation. AB - BACKGROUND: Discectomy is sometimes associated with recurrence of disc herniation and pain after surgery. The evidence to use an interspinous dynamic stabilization system (IDSS) in association with disc excision to prevent pain and re-operation, remains controversial. METHODS: Patients (age 18-50 years) presenting with lumbago/sciatica (ICD-10-CM M54.3, M54.4) due to voluminous lumbar disc herniation were eligible for participation. Patients underwent microdiscectomy plus IDSS. The primary outcome measure was the clinical efficacy using Owestry disability index(ODI) and visual analogue pain scale (VAS). We also evaluated several other outcome parameters including: length of stay and costs during hospital admission, 90-day complication rate, and 1-year re-operation rate. This prospective observational study was carried out from January 2015 to August 2016. RESULTS: A total of 30 patients whose mean age was 38.6(+/-9.2) years were included. ODI score dropped from 62.93(+/-16.45) to 13.50(+/-16.67), representing 78.54% (95% C.I 68.07-88.66%) improvement of the baseline score after one year (p < 0.001). Patients had 90 day re-admission and 1 year re-operation rates of 4/30(13.3%) and 3/30(10%) respectively. Length of stay was 2.1 +/- 1.2 days. In Hospital cost was 1069.8 +/- 288.4 ? (not including 1500? of the implant). Implant related complications were common 12/30(40%), although they did not have any clinical consequences. CONCLUSION: Our short-term experience indicates that microdiscectomy plus interspinous device is safe and it shows good clinical results, although the clinical improvement seems to be due to microdiscectomy, without the implant adding any extra benefit. The addition of IDSS did not protect against re-operation, and it increased the surgical expenses. PMID- 29475579 TI - Taking Aim at Glycolysis with CDK8 Inhibitors. AB - Dependence on glycolysis under aerobic conditions, a frequent metabolic derangement in cancer cells, suggests a therapeutic opportunity. Now, through chemical genetics, CDK8, a kinase associated with the Mediator transcriptional coactivator complex, has emerged as an upstream inducer of glycolysis and a possible target for anticancer drug discovery. PMID- 29475581 TI - Investigation of multi-target-directed ligands (MTDLs) with butyrylcholinesterase (BuChE) and indoleamine 2,3-dioxygenase 1 (IDO1) inhibition: The design, synthesis of miconazole analogues targeting Alzheimer's disease. AB - In our endeavor towards the development of potent multi-target ligands for the treatment of Alzheimer's disease, miconazole was identified to show BuChE-IDO1 dual-target inhibitory effects. Morris water maze test indicated that miconazole obviously ameliorated the cognitive function impaired by scopolamine. Furthermore, it showed good safety in primary hepatotoxicity evaluation. Based on these results, we designed, synthesized, and evaluated a series of miconazole derivatives as BuChE-IDO1 dual-target inhibitors. Out of the 12 compounds, 5i and 5j exhibited the best potency in enzymatic evaluation, thus were selected for subsequent behavioral study, in which the two compounds exerted much improved effect than tacrine. Meanwhile, 5i and 5j displayed no apparent hepatotoxicity. The results suggest that miconazole analogue offers an attractive starting point for further development of new BuChE-IDO1 dual-target inhibitors against Alzheimer's disease. PMID- 29475580 TI - Evidence of cardiac involvement in the fetal inflammatory response syndrome: disruption of gene networks programming cardiac development in nonhuman primates. AB - BACKGROUND: Most early preterm births are associated with intraamniotic infection and inflammation, which can lead to systemic inflammation in the fetus. The fetal inflammatory response syndrome describes elevations in the fetal interleukin-6 level, which is a marker for inflammation and fetal organ injury. An understanding of the effects of inflammation on fetal cardiac development may lead to insight into the fetal origins of adult cardiovascular disease. OBJECTIVE: The purpose of this study was to determine whether the fetal inflammatory response syndrome is associated with disruptions in gene networks that program fetal cardiac development. STUDY DESIGN: We obtained fetal cardiac tissue after necropsy from a well-described pregnant nonhuman primate model (pigtail macaque, Macaca nemestrina) of intrauterine infection (n=5) and controls (n=5). Cases with the fetal inflammatory response syndrome (fetal plasma interleukin-6 >11 pg/mL) were induced by either choriodecidual inoculation of a hypervirulent group B streptococcus strain (n=4) or intraamniotic inoculation of Escherichia coli (n=1). RNA and protein were extracted from fetal hearts and profiled by microarray and Luminex (Millipore, Billerica, MA) for cytokine analysis, respectively. Results were validated by quantitative reverse transcriptase polymerase chain reaction. Statistical and bioinformatics analyses included single gene analysis, gene set analysis, Ingenuity Pathway Analysis (Qiagen, Valencia, CA), and Wilcoxon rank sum. RESULTS: Severe fetal inflammation developed in the context of intraamniotic infection and a disseminated bacterial infection in the fetus. Interleukin-6 and -8 in fetal cardiac tissues were elevated significantly in fetal inflammatory response syndrome cases vs controls (P<.05). A total of 609 probe sets were expressed differentially (>1.5-fold change, P<.05) in the fetal heart (analysis of variance). Altered expression of select genes was validated by quantitative reverse transcriptase polymerase chain reaction that included several with known functions in cardiac injury, morphogenesis, angiogenesis, and tissue remodeling (eg, angiotensin I converting enzyme 2, STEAP family member 4, natriuretic peptide A, and secreted frizzled related protein 4; all P<.05). Multiple gene sets and pathways that are involved in cardiac morphogenesis and vasculogenesis were downregulated significantly by gene set and Ingenuity Pathway Analysis (hallmark transforming growth factor beta signaling, cellular morphogenesis during differentiation, morphology of cardiovascular system; all P<.05). CONCLUSION: Disruption of gene networks for cardiac morphogenesis and vasculogenesis occurred in the preterm fetal heart of nonhuman primates with preterm labor, intraamniotic infection, and severe fetal inflammation. Inflammatory injury to the fetal heart in utero may contribute to the development of heart disease later in life. Development of preterm labor therapeutics must also target fetal inflammation to lessen organ injury and potential long-term effects on cardiac function. PMID- 29475582 TI - Novel 4-aminoquinazoline derivatives induce growth inhibition, cell cycle arrest and apoptosis via PI3Kalpha inhibition. AB - Phosphatidylinositol 3-kinase (PI3K) signaling pathway has diverse functions, including the regulation of cellular survival, proliferation, cell cycle, migration, angiogenesis and apoptosis. Among class I PI3Ks (PI3Kalpha, beta, gamma, delta), the PIK3CA gene encoding PI3K p110alpha is frequently mutated and overexpressed in a large portion of human cancers. Therefore, the inhibition of PI3Kalpha has been considered as a promising target for the development of a therapeutic treatment of cancer. In this study, we designed and synthesized a series of 4-aminoquinazoline derivatives and evaluated their antiproliferative activities against six cancer cell lines, including HCT-116, SK-HEP-1, MDA-MB 231, SNU638, A549 and MCF-7. Compound 6b with the most potent antiproliferative activity and without obvious cytotoxicity to human normal cells was selected for further biological evaluation. PI3K kinase assay showed that 6b has selectivity for PI3Kalpha distinguished from other isoforms. The western blot assay and PI3K kinase assay indicated that 6b effectively inhibited cell proliferation via suppression of PI3Kalpha kinase activity with an IC50 of 13.6 nM and subsequently blocked PI3K/Akt pathway activation in HCT116 cells. In addition, 6b caused G1 cell cycle arrest owing to the inhibition of PI3K signaling and induced apoptosis via mitochondrial dependent apoptotic pathway. Our findings suggested that 6b has a therapeutic value as an anticancer agent via PI3Kalpha inhibition. PMID- 29475583 TI - Endovascular Management of Microcerebral Aneurysms with Diameter Smaller than 3 mm: Is It Feasible and Safe? AB - BACKGROUND: The neurosurgical management of microcerebral aneurysms with diameter smaller than 3 mm remains a great challenge as many complications can occur. AIM: Our target was to assess the efficacy and usefulness of endovascular treatment of these lesions. METHODS: We did a prospective and retrospective gathering of the results of endovascular treatments for a group of 16 patients with 16 microcerebral aneurysms. Four patients were treated by direct coil embolization, and 12 patients were managed by remodeling techniques. RESULTS: Coil embolization was technically accessible in all cases. Initial complete occlusion is achieved in 12 patients. We did not face major technical complications such as aneurysmal rupture or coil migration during the endovascular management in 15 patients. Only in 1 case the second and last coil (2/1 mm) migrated distally and could not be retrieved. In this case clinical evidence of neurologic deterioration and weakness in left lower limb due to right anterior cerebral artery territory stroke was evidenced in the follow-up computed tomography scan. Follow-up clinical and radiological studies were available for 9 of 12 surviving patients and showed complete occlusion in 7 cases, and in 1 case aneurysm tiny recanalization was demonstrated after 1 year, which was retreated with complete occlusion, and in another case tiny aneurysm recanalization at the neck appeared after 2 years, which was left under observation. CONCLUSIONS: Endovascular treatment is a beneficial and effective therapeutic alternative to microsurgery for microaneurysms. The long-term assessment of endovascular management for these lesions was not included in that study. PMID- 29475584 TI - Comments on "RNF213 p.R4810k Variant and Intracranial Arterial Stenosis or Occlusion in Relatives of Patients with Moyamoya Disease". PMID- 29475585 TI - Regioselective and efficient enzymatic synthesis of antimicrobial andrographolide derivatives. AB - Labdane diterpene andrographolide (1) is a major constituent of Andrographis paniculata and known to exhibit wide spectrum of biological activities. In this study, regioselective monoesters of (1) have been synthesized by using Amano lipase AK (Pseudomonas fluorescens) as a biocatalyst. Amano lipase AK was able to execute highly efficient esterification of hydroxyl group attached to C-14 carbon of (1) in presence of acyl donors. Among the various synthesized derivatives including two novel compounds such as andrographolide-14-propionate (3) and andrographolide-14-caproate (5) displayed antimicrobial activity against Staphylococcus aureus with low minimal inhibitory concentration (MIC) 4 ug/mL and 16 ug/mL respectively. Furthermore, they have shown low hemolysis activity at their respective MIC and increase in the permeability of the bacterial cell membrane as delineated by FITC uptake and SEM imaging studies. PMID- 29475586 TI - Design and characterization of bivalent compounds as potential neuroprotectants for Alzheimer's disease: Impact of the spacer on biological activity. AB - In our continuing efforts to develop bivalent compounds as potential neuroprotectants for Alzheimer's disease, a series of bivalent compounds that contain cholesterylamine and an extended spacer were synthesized and biologically characterized. Our results demonstrated that incorporation of a piperazine ring into the spacer composition significantly improved the protective potency in MC65 cell models. Our results also suggested that the optimal spacer length for such bivalent compounds ranges from 17 to 21 atoms, and further spacer extension beyond 21 atoms results no further optimization. Notably, incorporation of a piperazine ring into the spacer diminished the biometal chelating capacity for these bivalent compounds, thus suggesting structural flexibility of these compounds in interactions with metals. Collectively, the results provided valuable guidance to develop new bivalent compounds as neuroprotectants for Alzheimer's disease. PMID- 29475588 TI - Interferon alpha subtypes in HIV infection. AB - Type I interferons (IFN), which are immediately induced after most virus infections, are central for direct antiviral immunity and link innate and adaptive immune responses. However, several viruses have evolved strategies to evade the IFN response by preventing IFN induction or blocking IFN signaling pathways. Thus, therapeutic application of exogenous type I IFN or agonists inducing type I IFN responses are a considerable option for future immunotherapies against chronic viral infections. An important part of the type I IFN family are 12 IFNalpha subtypes, which all bind the same receptor, but significantly differ in their biological activities. Up to date only one IFNalpha subtype (IFNalpha2) is being used in clinical treatment against chronic virus infections, however its therapeutic success rate is rather limited, especially during Human Immunodeficiency Virus (HIV) infection. Recent studies addressed the important question if other IFNalpha subtypes would be more potent against retroviral infections in in vitro and in vivo experiments. Indeed, very potent IFNalpha subtypes were defined and their antiviral and immunomodulatory properties were characterized. In this review we summarize the recent findings on the role of individual IFNalpha subtypes during HIV and Simian Immunodeficiency Virus infection. This includes their induction during HIV/SIV infection, their antiretroviral activity and the regulation of immune response against HIV by different IFNalpha subtypes. The findings might facilitate novel strategies for HIV cure or functional cure studies. PMID- 29475587 TI - Two new coumarins and a new xanthone from the leaves of Rhizophora mucronata. AB - Two new coumarins (1, 2) and a new xanthone (3), together with 14 known compounds eight coumarins (4, 5, 9, 10, 12-15), three xanthones (11, 16, 17), a benzoic acid (6) and two flavonones (7, 8)-were isolated from the leaves of Rhizophora mucronata. The structures of the compounds were elucidated by spectroscopic (IR, MS, and NMR) analyses. The isolated compounds were tested for cytotoxicity against human cancer cell lines HL-60 and HeLa. Among these compounds, only compound 16 inhibited the growth of both HeLa (IC50 = 4.8 MUM) and HL-60 (IC50 = 1.0 MUM) cells. Compounds 4, 7, 10, and 12 exhibited moderate activity against HeLa cells (IC50 = 3.8-8.3 MUM). Compounds 5, 9, 11, and 17 showed moderate activity against HL-60 cells (IC50 = 2.2-6.3 MUM). Higher selectivity against HL 60 cell lines was observed for compounds 5, 9, 11, and 16 with SI values (NIH 3T3/HL-60) of 8.6, 19.2, 9.4, and 10.2, respectively. PMID- 29475590 TI - Validation of Iodine-131-meta-iodobenzylguanidine cardiac scintigraphy in Parkinsonism: A preliminary study. AB - INTRODUCTION: 123I-MIBG is the most commonly used radiopharmaceutical to depict cardiac sympathetic innervation. The purpose of this study was to validate the feasibility of 131I-MIBG as an alternative myocardial sympathetic imaging probe in differential diagnosis of Parkinsonism. METHODS: We recruited 17 patients with PD, 21 patients with other parkinsonism (17 with MSA and 4 with PSP), and 6 normal controls. All participants underwent 131I-MIBG scintigraphy for both early and delayed imaging. The image quality was independently assessed by two experienced nuclear medicine specialists and graded into three categories: 1, good image quality; 2, suboptimal but sufficient for diagnosis; and 3, poor or nondiagnostic. Cardiac MIBG uptake was quantitatively measured using H/M ratio and washout rate. RESULTS: The image quality was good (Grade 1) in 74 and 73 of a total of 88 images by the two reviewers, respectively. No image was poor or nondiagnostic (Grade 3). Patients with PD had a significantly lower H/M ratio for both the early and the delayed images than did those with MSA or PSP and the controls (P < 0.001). For differentiating PD from other parkinsonism, the sensitivity and specificity were 95% and 94% for the early images and 100% and 94% for the delayed images, respectively. Patients with MSA or PSP has a significantly lower WR compared with those with PD. (WR = 0.15 +/- 0.23 and 0.48 +/- 0.17, respectively; P < 0.001). CONCLUSION: 131I-MIBG scintigraphy is a feasible method to depict cardiac sympathetic activity. The diagnostic performance is comparable to that of 123I-MIBG. PMID- 29475589 TI - Design and experimental force analysis of a novel elliptical vibration assisted orthopedic oscillating saw. AB - Orthopedic oscillating saws (OOSs) are widely used for plane processing in orthopedic surgery such as knee and hip replacement. However, sawing has been associated with bone breakthrough and necrosis problems. In this paper, a novel elliptical vibration assisted OOS was designed to achieve a low cutting force under the condition of deepening cut depth and reducing cutting speed, based on the analysis of brittle fractures of the bone and elliptical vibration assisted cutting kinematics. The elliptical vibration was generated using two parallel stacked piezoelectric actuators assembled with the fixture. In order to reduce the large cutting forces due to the large cutting depth, a series of experiments was also conducted to investigate the influence of processing parameters on cutting forces. It was demonstrated that cutting forces are significantly reduced by increasing the vibration frequency and vibration amplitude, and decreasing the sawing speed in the current design. The new design could minimize the cutting forces during sawing and allow surgeons to have better control over the sawing process. PMID- 29475591 TI - Cerebrospinal fluid biomarkers of central dopamine deficiency predict Parkinson's disease. AB - BACKGROUND: Consistent with nigrostriatal dopamine depletion, low cerebrospinal fluid (CSF) concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC), the main neuronal metabolite of dopamine, characterize Parkinson's disease (PD) even in recently diagnosed patients. Whether low CSF levels of DOPAC or DOPA, the precursor of dopamine, identify pre-clinical PD in at-risk healthy individuals has been unknown. METHODS: Participants in the intramural NINDS PDRisk study entered information about family history of PD, olfactory dysfunction, dream enactment behavior, and orthostatic hypotension at a protocol-specific website. After at least 3 risk factors were confirmed by on-site screening, 26 subjects had CSF sampled for levels of catechols and were followed for at least 3 years. RESULTS: Of 26 PDRisk subjects, 4 were diagnosed with PD (Pre-Clinical PD group); 22 risk-matched (mean 3.2 risk factors) subjects remained disease-free after a median of 3.7 years (No-PD group). The Pre-Clinical PD group had lower initial DOPA and DOPAC levels than did the No-PD group (p = 0.0302, p = 0.0190). All 3 subjects with both low DOPA (<2.63 pmol/mL) and low DOPAC (<1.22 pmol/mL) levels, based on optimum cut-off points using the minimum distance method, developed PD, whereas none of 14 subjects with both normal DOPA and DOPAC levels did so (75% sensitivity at 100% specificity, p = 0.0015 by 2-tailed Fisher's exact test). CONCLUSIONS: In people with multiple PD risk factors, those with low CSF DOPA and low CSF DOPAC levels develop clinical disease during follow-up. We suggest that neurochemical biomarkers of central dopamine deficiency identify the disease in a pre-clinical phase. PMID- 29475592 TI - Threading the Eye of the Needle: A Challenging Case of Iatrogenic Spiral Coronary Artery Dissection. AB - Catheter induced coronary dissection is an uncommon but potentially catastrophic complication of coronary angiography. We report a case of a 48-year-old female with normal coronary arteries on angiography complicated by extensive catheter induced spiral dissection. Wiring into the true lumen was a formidable challenge as a consequence of the large false lumen obliterating the true lumen. We present management strategies and in particular, highlight the important role of intravascular ultrasound (IVUS) imaging. PMID- 29475593 TI - Coronary Artery Occlusion Caused by Cardiac Metastasis. PMID- 29475594 TI - Common errors in image interpretation in oncology. AB - Errors in image interpretation are inevitable and generally multifactorial. They can be due to the radiologist's failure to interpret the findings correctly (including cognitive causes, perceptual errors, or ambiguity in reporting) or to problems related with the system (technical problems in image acquisition, incorrect clinical information, excessive workload, or inadequate working conditions). It is the radiologist's responsibility to know why errors occur and how to detect them to prevent them from occurring again. This article focuses on the problem of errors in diagnosing oncologic patients, both at the time of diagnosis and during follow-up as well as in the study of the response to treatment with new molecular therapies. To reduce possible errors, radiologists should ensure a systematic reading and an assessment of the oncologic response over time in the clinical context of the patient; they also need to have and apply knowledge of the new specific criteria for the response of each tumor type in the management of the patient. PMID- 29475595 TI - [Onco-Hematology Division (ONCOH) ANSM: A willingness to be in tune with the needs of patients and to facilitate clinical research in a secure environment]. PMID- 29475596 TI - [Radiation therapy in inflammatory breast cancer]. AB - BACKGROUND: Inflammatory breast cancer accounts for 1-5% of all breast cancers. It is associated with a poor prognosis, because of an increased risk to develop metastases in comparison with all breast malignancies. The treatment is multimodal. We have evaluated the role of radiotherapy: indications, techniques and impact for local control and overall survival. METHOD: The series of the literature with more than 40 patients irradiated for inflammatory breast cancer published since 1995 were analyzed. RESULTS: Chemotherapy was always delivered first. Adjuvant radiotherapy was associated with local control and overall survival at 10 years of 63-92% and 51-64 respectively. Without surgery, local control was 65% and overal survival 38% at 10years. Results of concomitant radiochemotherapy were reported: the studies were heterogenous. Modalities of radiotherapy were detailed with respect to dose and fractionation, target-volumes and technical considerations (including bolus). CONCLUSION: The multimodal strategy comprises systematically radiotherapy with an evaluation of tumor response to maximise resecability. PMID- 29475597 TI - [Autoimmune hypophysitis associated with new anti-cancer immunotherapies]. AB - Recently developed immunotherapeutic agents, like anti-cytotoxic T lymphocyte antigen 4 antibody (CTLA4), anti-programmed cell death 1 (PD1) or anti-programmed cell death-ligand 1 (PDL1), have demonstrated substantial potential for the treatment of a variety of malignancies. Autoimmune side effects from these agents are diverse and can include multiple endocrinopathies like immunotherapy induced hypophysitis (IH). These toxicities appear to be more frequent in patients receiving anti-CTLA4 antibody compared to PD1/PDL1 agents. The diagnosis of IH is generally based on the presence of new hypopituitarism without an alternative etiology and radiographic pituitary enlargement or not while on treatment with Immunotherapy. Patients with IH frequently present non-specifics symptoms like headache, fatigue or weakness. ACTH and TSH deficiencies are more frequent. TSH and gonadotrophin deficiencies may be reversible but ACTH deficiency appears permanent. Glucocorticoid and thyroid hormone replacement should be instituted early after the diagnosis of IH, androgen replacement can be deferred initially and discussed by the patient. High-dose glucocorticoid does not improve the outcome of IH and should be reserved for patients with persistent severe headache, severe hyponatremia or visual defects. Patient education, early identification by measuring TSH, free thyroxine, morning ACTH and cortisol levels before each treatment cycle and proper treatment are the core of IH management. PMID- 29475598 TI - Editorial. PMID- 29475600 TI - Metalloprotease ADAM17 regulates porcine epidemic diarrhea virus infection by modifying aminopeptidase N. AB - Porcine epidemic diarrhea virus (PEDV) is a causative agent of porcine epidemic diarrhea (PED). PED, characterized by acute diarrhea, vomiting, dehydration, has caused serious economic losses in pig industry worldwide. Here, we demonstrate that activation of a disintergrin and metalloprotease 17 (ADAM17) induced the decrease of PEDV infection in HEK293 and IPEC-J2 cells and the downregulation of cell surface aminopeptidase N (APN) expression, an important entry factor for PEDV infection. Furthermore, overexpression of ADAM17 suppressed PEDV infection in HEK293 and IPEC-J2 cells, whereas ablation of ADAM17 expression using ADAM17 specific siRNA resulted in a corresponding increase of PEDV infection and an upregulation of cell surface APN expression. Taken together, these data demonstrate that modulation of APN expression by metalloprotease ADAM17 regulates PEDV infection. Hence, the reduction in APN expression represents another component of the anti-PEDV infection response initiated by ADAM17. PMID- 29475601 TI - Accelerated long-term forgetting in focal epilepsies with special consideration given to patients with diagnosed and suspected limbic encephalitis. AB - RATIONALE: Accelerated long-term forgetting (ALF) is a phenomenon found in late onset epilepsy and in transient epileptic amnesia (TEA). Here we evaluated ALF in patients with focal epilepsies and limbic encephalitis (LE) in particular. METHODS: ALF was assessed in 36 patients with focal epilepsy and 154 healthy subjects using an extended version of the Verbal Learning and Memory Test (VLMT), with free recall after 30 min and again after one week. From these patients, 89% had temporal lobe epilepsy; 42% left-lateralized; 39% right; 19% bilateral; 17% were diagnosed with hippocampal sclerosis; 64% displayed features indicating LE; 52% with amygdala pathology, and 61% were antibody positive. ALF was defined as either having unimpaired free recall after 30 min and impaired recall after a week (A) or as a loss in recall exceeding the absolute (B) and percentage loss (C) in the interval of the 30 min and one week recall seen in controls by more than one standard deviation. RESULTS: Repeated measures analysis revealed an association between LE and ALF. Depending on its definition (A, B, or C), ALF was evident in 31%, 42%, or 67% of the patients. Poor verbal memory and ALF (C) were prominent in left-lateralized epilepsies. ALF (A) appeared more frequently in auto-antibody negative patients with LE, ALF (B) less frequently with hippocampal sclerosis. Seizures during the interval did not explain ALF. CONCLUSION: Depending on its definition, ALF is seen in patients with normal or impaired memory at 1/2 h. ALF seems related to LE but might as well be the first sign of memory impairment in patients with milder epilepsies and not yet definite structural temporal lobe pathology. Longitudinal assessment would be essential for discerning when ALF becomes evident, whether conditions exist in which ALF precedes short-term forgetting, and whether ALF responds to treatment. PMID- 29475602 TI - The 3rd International Lafora Epilepsy Workshop: Evidence for a cure. PMID- 29475599 TI - New insights about the regulation of Nidovirus subgenomic mRNA synthesis. AB - The members of the Order Nidovirales share a similar genome organization with two overlapping nonstructural polyproteins encoded in the 5' two-thirds and the structural proteins encoded in the 3' third. They also express their 3' region proteins from a nested set of 3' co-terminal subgenomic messenger RNAs (sg mRNAs). Some but not all of the Nidovirus sg mRNAs also have a common 5' leader sequence that is acquired by a discontinuous RNA synthesis mechanism regulated by multiple 3' body transcription regulating sequences (TRSs) and the 5' leader TRS. Initial studies detected a single major body TRS for each 3' sg mRNA with a few alternative functional TRSs reported. The recent application of advanced techniques, such as next generation sequencing and ribosomal profiling, in studies of arteriviruses and coronaviruses has revealed an expanded sg mRNA transcriptome and coding capacity. PMID- 29475603 TI - Review and appraisal of guidelines for the management of asthma during pregnancy. AB - BACKGROUND: Asthma affects 12.7% of pregnancies in Australia. Poorly controlled asthma is associated with increased maternal and infant morbidity and mortality. Optimal antenatal management of asthma during pregnancy has the potential to reduce complications relating to asthma. Evidence-based clinical practice guidelines help to translate health research findings into practice and when implemented can improve health outcomes. National and International guidelines currently provide recommendations for optimal asthma care in pregnancy. AIM: To appraise the existing asthma in pregnancy guidelines with respect to their evidence for recommendations, consistency of recommendations and appropriateness for clinical practice. METHOD: The Appraisal of Guidelines for Research and Evaluation (AGREE II) tool was used to appraise four English language asthma in pregnancy guidelines, published or updated between 2007 and 2016. The recommendations, range and level of evidence was analysed. RESULTS: Two of the four guidelines scored highly in most domains of the appraisal. Many of the recommendations made in the appraised guidelines were consistent. Due to the lack of randomised controlled trials involving pregnant women with asthma, most recommendations were evidenced by consensus and expert opinion rather than high quality meta-analysis, systematic reviews of randomised controlled trials. CONCLUSION: The recommended antenatal asthma management was generally consistent among the guidelines but lacked clarity in some areas which then leave them open to interpretation. More randomised controlled trials involving pregnant women with asthma are required to fortify the recommendations made and asthma management guidelines should be included in Australian Antenatal Care Guidelines as they currently are not. PMID- 29475604 TI - Deep brain stimulation as a therapeutic option for obesity: A critical review. AB - Despite a better understanding of obesity pathophysiology, treating this disease remains a challenge. New therapeutic options are needed. Targeting the brain is a promising way, considering both the brain abnormalities in obesity and the effects of bariatric surgery on the gut-brain axis. Deep brain stimulation could be an alternative treatment for obesity since this safe and reversible neurosurgical procedure modulates neural circuits for therapeutic purposes. We aimed to provide a critical review of published clinical and preclinical studies in this field. Owing to the physiology of eating and brain alterations in people with obesity, two brain areas, namely the hypothalamus and the nucleus accumbens are putative targets. Preclinical studies with animal models of obesity showed that deep brain stimulation of hypothalamus or nucleus accumbens induces weight loss. The mechanisms of action remain to be fully elucidated. Preclinical data suggest that stimulation of nucleus accumbens reduces food intake, while stimulation of hypothalamus could increase resting energy expenditure. Clinical experience with deep brain stimulation for obesity remains limited to six patients with mixed results, but some clinical trials are ongoing. Thus, drawing clear conclusions about the effectiveness of this treatment is not yet possible, even if the results of preclinical studies are encouraging. Future clinical studies should examine its efficacy and safety, while preclinical studies could help understand its mechanisms of action. We hope that our review will provide ways to design further studies. PMID- 29475605 TI - Optical partial discharge diagnostic in SF6 gas insulated system via multi spectral detection. AB - Light emitted from partial discharges (PDs) in SF6 gas is investigated in the view point of insulation status diagnostics. Light intensity and integral spectrum of PD are proved to have significant correlations with PD activities and the involved dielectric interfaces. Based on synchronous light pulse detections in ultraviolet (UV), visible (VIS) and near-infrared (NIR) regions, the multispectral stochastic PD diagnosis is realized with more information beyond the conventional PD detections. The optical PD detection is also compared with ultra-high frequency (UHF) PD detection and acoustic emission (AE) PD detection in term of linearity, sensitivity and statistical property. Beyond that, a clustering analysis is performed on the multispectral photon counts of different conditions by quantifying them in a ternary diagram where some distinguishable regions emerge for PD recognition. PMID- 29475606 TI - Robust iterative learning contouring controller with disturbance observer for machine tool feed drives. AB - In feed drive systems, particularly machine tools, a contour error is more significant than the individual axial tracking errors from the view point of enhancing precision in manufacturing and production systems. The contour error must be within the permissible tolerance of given products. In machining complex or sharp-corner products, large contour errors occur mainly owing to discontinuous trajectories and the existence of nonlinear uncertainties. Therefore, it is indispensable to design robust controllers that can enhance the tracking ability of feed drive systems. In this study, an iterative learning contouring controller consisting of a classical Proportional-Derivative (PD) controller and disturbance observer is proposed. The proposed controller was evaluated experimentally by using a typical sharp-corner trajectory, and its performance was compared with that of conventional controllers. The results revealed that the maximum contour error can be reduced by about 37% on average. PMID- 29475607 TI - Identification of look-up tables using gradient algorithm. AB - In view of the relatively low computational load, look-up tables (or maps) are usually used to approximate nonlinear function or characterize operating-point dependent system variables in typical embedded applications. Aiming at the problem of off-line identifying the look-up tables, a method based on the gradient algorithm is presented to estimate the look-up table parameters in this paper. The nonlinear function is approximated in terms of the piecewise linear interpolation model with the look-up table parameters, which can be rewritten as a dot product between the regression vector and unknown parameter vector using membership function. With the approximation error of the nonlinear function, a method for updating look-up tables using the gradient algorithm is given, and the relationship between the parameter estimation error and model approximation error is explicitly derived. To guarantee the convergence of the look-up table parameters estimation, a condition for the persistent excitation of the look-up table input is derived, which also provides a theoretical basis for the data characteristics of the look-up table input required to identify look-up table parameters offline using dynamic data. The validity of the proposed method is verified respectively by updating a one-dimensional (1D) look-up table, and the identification of the two-dimensional (2D) look-up table for the throttle discharge coefficient of a spark ignition gasoline engine form engine simulation tool enDYNA. PMID- 29475608 TI - Solitary fibrous tumours and haemangiopericytoma of the meninges. A retrospective study for outcome and prognostic factor assessment. AB - BACKGROUND: To report on the outcome of patients diagnosed with central nervous system haemangiopericytoma (HPC) or solitary fibrous tumours (SFT) and identify factors that may influence recurrence and survival. MATERIAL AND METHODS: Between January 1977 and December 2016, a retrospective search identified 22 HPCs/SFTs. The patients underwent a total of 40 surgical resections and 63.6% received radiotherapy. Median follow-up was 7.8 years. RESULTS: Six patients (27.3%) were re-operated for tumour recurrence. At the end of the study, 15 patients (68.2%) had no residual tumour on the last imaging. Surgical recurrence-free survival at 5 years was 77.4%, [95% CI: 60.1-99.8]. None of the investigated variables was associated with recurrence. At the end of the study, 5 patients were deceased (22.7%) and only 10 patients (45.5%) had no residual tumour on the last imaging and were alive. Overall survival at 5 years was 95%, [95% CI: 85.9-100]. None of the investigated variables was associated with overall survival. Patients who received radiotherapy demonstrated neither a reduced risk of surgical recurrence (P=0.378) nor a longer overall survival (P=0.405). CONCLUSION: SFTs/HPCs are associated with a significant risk of recurrence that may reduce the survival. Even if we could not demonstrate their benefit in this limited series, we believe that tailored maximal tumour resection on initial surgery is beneficial and that adjuvant RT is useful for tumours displaying grade II or III, even in case of complete removal. PMID- 29475610 TI - Passion, integrity, resilience: core values to carry us forward. PMID- 29475609 TI - Moya-Moya syndrome after cranial radiation for optic glioma with NF1. Case report and literature review of syndromic cases. AB - INTRODUCTION: Moya-Moya angiopathy is a neurovascular disease that predisposes to ischemic or hemorrhagic strokes. It is generated by a steno-occlusion of the terminal portion of the internal carotid arteries, which induces the development of abnormal neovessels in the deep regions of the brain. Some pathologies such as sickle cell disease, Down syndrome or Graves' disease may be associated with Moya Moya angiopathy. These syndromic forms harbor several differences compared with idiopathic Moya-Moya disease. CASE REPORT: We report the case of a young patient who presented with a syndromic form of Moya-Moya angiopathy after cranial radiation therapy for an optic glioma associated with type 1 neurofibromatosis treated by combined revascularization. We discuss the particularities of syndromic forms, in their presentation and management based on a review of the literature. CONCLUSION: Many diseases can be associated with Moya-Moya syndrome. Symptomatic patients should undergo surgery, but the risk of postoperative complications appears to be greater than that encountered in patients with non syndromic Moya-Moya angiopathy. PMID- 29475611 TI - Hepatitis B virus X protein represses LKB1 expression to promote tumor progression and poor postoperative outcome in hepatocellular carcinoma. AB - BACKGROUND: Hepatitis B virus X (HBx) protein plays critical roles in hepatitis B virus (HBV)-associated hepatocellular tumorigenesis through different molecular mechanisms, including inactivation of p53, a key transcription factor of liver kinase B1 (LKB1). We hypothesized that p53 inactivation by HBx protein could decrease LKB1 expression, thereby promoting tumor progression and poor outcomes in patients with HBV-associated hepatocellular carcinoma. METHODS: Manipulation strategies for HBx protein and/or p53 were used to verify that loss of LKB1 could promote colony formation and invasiveness in HepG2 and Hep3B cells. The expressions of HBx protein and LKB1 in 93 hepatocellular carcinomas (HCC) were also evaluated by immunohistochemistry. Kaplan-Meier and Cox regression models were used to assess the prognostic value of both HBx protein and LKB1 proteins in patients with hepatocellular carcinoma. RESULTS: Mechanistically, LKB1 expression was decreased at the transcriptional level after inactivation of p53 by HBx protein. Decreases in LKB1 expression were also associated with HBx protein mediated colony formation and invasive capabilities. HBx protein, LKB1, and a combination of both proteins had prognostic significance for overall survival and relapse-free survival in our study population. CONCLUSION: The results from cell line experiments and evaluation of patient prognosis according to expression of HBx protein and LKB1 in their HCC strongly support the hypothesis that decreases in LKB1 expression by HBx protein-mediated p53 inactivation may play an important role in HBV-associated hepatocellular tumorigenesis. PMID- 29475613 TI - A late life-threatening complication of laparoscopic adjustable gastric banding. PMID- 29475612 TI - Long-term follow-up and risk factors for strictures after hepaticojejunostomy for bile duct injury: An analysis of surgical and percutaneous treatment in a tertiary center. AB - BACKGROUND: Hepaticojejunostomy is commonly indicated for major bile duct injury after cholecystectomy. The debate about the timing of hepaticojejunostomy for bile duct injury persists since data on postoperative outcomes, including postoperative strictures, are lacking. The aim of this study was to analyze short and long-term outcomes of hepaticojejunostomy for bile duct injury, including risk factors for strictures. METHOD: Analysis of outcome of hepaticojejunostomy in bile duct injury patients referred to a multidisciplinary team. RESULTS: Between the years1991 and 2016, 281 patients underwent hepaticojejunostomy for bile duct injury. Clavien-Dindo grade III complications occurred in 31 patients (11%) and 90-day mortality occurred in 2 patients (0.7%). After a median follow up of 10.5 years (interquartile range 6.7-14.8 years), clinically relevant strictures were found in 37 patients (13.2%). Strictures were treated with percutaneous dilatation in 33 patients (89.2%), and 4 patients (1.4%) were reoperated. The stricture rate in patients undergoing hepaticojejunostomy <14 days, between 14-90 days, and >90 days after bile duct injury was 15.8%, 18.7%, and 9.9%, respectively. The stricture rate for early versus intermediate and late repair did not differ (P = 0.766 and 0.431, respectively). The stricture rate for repair after 14-90 days, however, was higher compared with repair >90 days after bile duct injury (P = 0.045). In multivariable analysis male gender was the only independent variable associated with stricture formation (OR 6.7, 95% CI 1.8 25.4, P = 0.005). CONCLUSION: Hepaticojejunostomy is a relatively safe treatment of bile duct injury. Timing of surgery and intermediate repair affect long-term stricture rate; most anastomotic strictures can be treated successfully with percutaneous dilation. PMID- 29475615 TI - Current status of circularity for aluminum from household waste in Austria. AB - Aluminum (Al) represents the metal with the highest consumption growth in the last few decades. Beside its increasing usage in the transport (lightweight construction of vehicles) and building sector, Al is used ever more frequently for household goods like packaging material, which represents a readily available source for secondary aluminum due to its short lifetime. The present paper investigates the extent to which this potential source for recycling of Al is already utilized in Austria and highlights areas for future improvements. Thereto a detailed material flow analysis for Al used in packaging & household non packaging in 2013 was conducted. In practice, all Al flows starting from market entrance through waste collection and processing until its final recycling or disposal have been investigated. The results indicate that about 25,100 t/a (2.96 kg/cap/a) of Al packaging & household non-packaging arose as waste. At present about 9800 t/a, or 39%, are recycled as secondary Al, of which 26% is regained from separate collection and sorting, 8% from bottom ash and 5% from mechanical treatment. The type of Al packaging & household non-packaging affects the recycling rate: 82% of the total recycled quantities come from rigid packaging & household non-packaging, while only 3% of the total recycled Al derives from flexible materials. A significant amount of Al was lost during thermal waste treatment due to oxidation (10%) and insufficient recovery of Al from both waste incineration bottom ash and municipal solid waste treated in mechanical biological treatment plants (49%). Overall it can be concluded that once Al ends up in commingled waste the recovery of Al becomes less likely and its material quality is reduced. Although Austria can refer to a highly developed recycling system, the Austrian packaging industry, collection and recovery systems and waste management need to increase their efforts to comply with future recycling targets. PMID- 29475614 TI - Ventral approach for resecting hepatocellular carcinoma in the caval portion of the caudate lobe. AB - BACKGROUND: Resection of hepatocellular carcinoma located in the caudate lobe is challenging because this anatomical location is difficult to approach, especially the caval portion. METHODS: We performed resection of the caval portion of the caudate lobe using a ventral approach combined with the resection of segment IV, VII, or VIII for hepatocellular carcinoma in 41 patients (extended segmentectomy group). As a control group, 138 patients with hepatocellular carcinoma who underwent segmentectomy for IV, VII, or VIII (segmentectomy group) were studied. We compared surgical outcomes, including postoperative morbidity and survival, between the 2 groups. RESULTS: When compared with the segmentectomy group, platelet count was lower (12.8 * 104/uL [range, 2.4-33.8] vs 14.8 * 104/uL [3.2 41.4], P = .085), operation time was significantly longer (442 minutes [range, 184-710] vs 333 minutes [131-810], P < .001), blood loss was significantly greater (579 mL [range, 25-2688] vs 301 mL [10-3887], P = .001), and the percentage of patients with cirrhosis was greater (19 [46.3%] vs 41 [29.7%], P = .059) in the extended segmentectomy group. However, the morbidity rate (48.7% and 33.3%, P = .096) and median overall survival period (5.2 years; [95% confidence interval, 4.6-6.6] vs 6.2 years, [5.4-9.7], P = .203) were not significantly different between the 2 groups. CONCLUSION: The ventral approach for the resection of hepatocellular carcinoma in the caval portion of the caudate lobe is a viable alternative to other approaches, especially in patients with insufficient liver function. PMID- 29475617 TI - ? PMID- 29475616 TI - Impact of community engagement on public acceptance towards waste-to-energy incineration projects: Empirical evidence from China. AB - As one of the most popular methods for the treatment of municipal solid waste (MSW), waste-to-energy (WTE) incineration offers effective solutions to deal with the MSW surge and globe energy issues. Nevertheless, the construction of WTE facilities faces considerable and strong opposition from local communities due to the perceived potential risks. The present study aims to understand whether, and how, community engagement improves local residents' public acceptance towards waste-to-energy (WTE) incineration facilities using a questionnaire survey conducted with nearby residents of two selected WTE incineration plants located in Zhejiang province, China. The results of data analysis using Structural Equation Modeling (SEM) reveal that firstly, a lower level of public acceptance exists among local residents of over the age of 35, of lower education levels, living within 3 km from the WTE Plant and from WTE incineration Plants which are under construction. Secondly, the public trust of local government and other authorities was positively associated with the public acceptance of the WTE incineration project, both directly and indirectly based on perceived risk. Thirdly, community engagement can effectively enhance public trust in local government and other authorities related to the WTE incineration project. The findings contribute to the literature on MSW treatment policy-making and potentially hazardous facility siting, by exploring the determinants of public acceptance towards WTE incineration projects. PMID- 29475618 TI - ? PMID- 29475619 TI - ? PMID- 29475620 TI - ? PMID- 29475621 TI - The Synergy of Scaffold-Based and Scaffold-Free Tissue Engineering Strategies. AB - Tissue engineering (TE) is a highly interdisciplinary research field driven by the goal to restore, replace, or regenerate defective tissues. Throughout more than two decades of intense research, different technological approaches, which can be principally categorized into scaffold-based and scaffold-free strategies, have been developed. In this opinion article, we discuss the emergence of a third strategy in TE. This synergetic strategy integrates the advantages of both of these traditional approaches, while being clearly distinct from them. Its characteristic attributes, numerous practical benefits, and recent literature reports supporting our opinion, are discussed in detail. PMID- 29475622 TI - Dealing with Confounders in Omics Analysis. AB - The Anna Karenina effect is a manifestation of the theory-practice gap that exists when theoretical statistics are applied on real-world data. In the course of analyzing biological data for differential features such as genes or proteins, it derives from the situation where the null hypothesis is rejected for extraneous reasons (or confounders), rather than because the alternative hypothesis is relevant to the disease phenotype. The mechanics of applying statistical tests therefore must address and resolve confounders. It is inadequate to simply rely on manipulating the P-value. We discuss three mechanistic elements (hypothesis statement construction, null distribution appropriateness, and test-statistic construction) and suggest how they can be designed to foil the Anna Karenina effect to select phenotypically relevant biological features. PMID- 29475623 TI - SCCT President's page: Exceeding expectations and delivering excellence - From London to Dallas in 2018. PMID- 29475624 TI - Neuromyelitis optica spectrum disorder associated with dengue virus infection. AB - Dengue virus infection is a disease with high incidence in some tropical and subtropical countries. A variety of neurological complications of dengue fever (DF) has been described including two cases with the phenotype of neuromyelitis optica spectrum disorder (NMOSD). However, aquaporin-4 serostatus was unknown or negative in these patients. We report two patients with NMOSD occurring in association with DF. The first patient presented with brainstem symptoms and the second one with isolated unilateral optic neuritis. Both patients tested positive for serum AQP4-antibody. This report shows that DF may trigger seropositive NMOSD. PMID- 29475625 TI - The New Kid on the Block: A Specialized Secretion System during Bacterial Sporulation. AB - The transport of proteins across the bacterial cell envelope is mediated by protein complexes called specialized secretion systems. These nanomachines exist in both Gram-positive and Gram-negative bacteria and have been categorized into different types based on their structural components and function. Interestingly, multiple studies suggest the existence of a protein complex in endospore-forming bacteria that appears to be a new type of specialized secretion system. This protein complex is called the SpoIIIA-SpoIIQ complex and is an exception to the categorical norm since it appears to be a hybrid composed of different parts from well-defined specialized secretion systems. Here we summarize and discuss the current understanding of this complex and its potential role as a specialized secretion system. PMID- 29475626 TI - Deferoxamine preconditioning activated hypoxia-inducible factor-1alpha and MyD88 dependent Toll-like receptor 4 signaling in intestinal stem cells. AB - BACKGROUND/PURPOSE: Toll-like receptors (TLRs) are important regulators of innate immunity, and TLR4 pathway can regulate the survival, migration, and differentiation of stem cells, including intestinal stem cells (ISCs). Deferoxamine (DFO), a hypoxia-mimic compound, can activate the proliferation of ISCs. In this study, we investigated the response of TLR4 signaling to DFO induced hypoxia in cultured ISCs in vitro. METHODS: After DFO treatment, the crypt organoid number was counted, and the expression levels of Lgr5, Hsp70, HMGB1, HIF-1alpha, TLR4, MyD88, TRIF, and TRAM in ISCs were examined using QPCR and Western blotting. The chemical inhibitors of different signaling molecules were then used to determine their role in DFO-induced change in ISCs. RESULTS: The expression levels of Lgr5, HIF-1alpha, TLR4, MyD88, and TRIF in ISCs increased after DFO treatment, with peak expression of these molecules 6h after DFO treatment. In addition, DFO-induced gene expression of Lgr5 and HIF-1alpha was partially reversed by pretreatment with the inhibitor of TLR4 or MyD88, but not TRIF inhibitor. Inhibition of HIF-1alpha also resulted in partial downregulation of DFO-induced elevation of Lgr5 and TLR4. CONCLUSIONS: These results demonstrated that DFO treatment activated HIF-1alpha and the TLR4-MyD88 signaling pathway, which might mediate the activation of ISCs. PMID- 29475627 TI - Cybersecurity for Cardiac Implantable Electronic Devices: What Should You Know? AB - Medical devices have been targets of hacking for over a decade, and this cybersecurity issue has affected many types of medical devices. Lately, the potential for hacking of cardiac devices (pacemakers and defibrillators) claimed the attention of the media, patients, and health care providers. This is a burgeoning problem that our newly electronically connected world faces. In this paper from the Electrophysiology Section Council, we briefly discuss various aspects of this relatively new threat in light of recent incidents involving the potential for hacking of cardiac devices. We explore the possible risks for the patients and the effect of device reconfiguration in an attempt to thwart cybersecurity threats. We provide an outline of what can be done to improve cybersecurity from the standpoint of the manufacturer, government, professional societies, physician, and patient. PMID- 29475628 TI - Study on the polymorphism of G-quadruplexes by reversed-phase HPLC and LC-MS. AB - Polymorphism is inherent for G-quadruplexes (G4s), and the different structural forms are important for the participation in different biological functions of telomeres. A lot of progress has been made in the exploration of G4 polymorphism. However, quick separation and reliable assessment methods for different conformations of G4 are still very few. In this work, the polymorphism of three sequences d[(G3T)3G3], d[(G3C)3G3] and d[(G3T)4] annealed in six different solutions were investigated by means of reversed-phase high performance liquid chromatography (RP-HPLC), liquid chromatography-mass spectrometry (LC-MS), fluorescence spectroscopy, circular dichroism spectroscopy, together with native polyacrylamide gel electrophoresis. Different G4 conformations of these three sequences can be separated clearly by RP-HPLC, and further characterized by on line LC-MS analysis. It is revealed that high-order structures other than intramolecular quadruplexes were favored for d[(G3T)3G3] and d[(G3C)3G3] under the annealing conditions. However, flanking loop impeded d[(G3T)4] to form higher order structures than dimer. In addition, the nature and concentration of cation, as well as the annealing solution component, all have decent influence on the stability and relative ratios of various G4 building blocks. Based on the above findings, RP-HPLC and LC-MS combined with spectroscopic techniques can be used as a facile and powerful tool for quick separation and identification of G4s in solutions, and for effective assessment of DNA sequences and annealing environments on G4 polymorphism. The established protocol provides a novel strategy for evaluating G4 polymorphism, which will facilitate studies on quadruplex structures and their biophysical properties. PMID- 29475629 TI - [Regional protocol for adjusting the therapeutic intensity. Southern Metropolitan Area of Barcelona]. AB - The identification of patients with advanced and complex chronic diseases, and the fragmentation of care towards the end of life, requires the drawing up a long term therapeutic plan. This should take into account the values and preferences of the patients, as well as the vital and functional prognosis. Having an adjustment tool for determining the diagnostic and therapeutic effort is helpful in the continuity of care, as well as in decision-making in the transitions and dynamic changes of patients as they approach the end of life process. PMID- 29475630 TI - Access to Care and Health Outcomes Among Women Veterans Using Veterans Administration Health Care: Association With Food Insufficiency. AB - BACKGROUND: Food insecurity has been associated with worse health outcomes in the civilian population. Male veterans of the Gulf Wars have been shown to have a higher prevalence of food insecurity than similarly situated civilians. Women veterans have more risk factors for food insecurity, relative to male veterans, yet little is known about the prevalence of food insecurity in this cohort. METHODS: We used the Women Veterans' Health Utilization and Experience Survey for this analysis. Our study population consisted of women veterans who had at least three primary care or women's health visits to 1 of 12 Veteran's Health Administration health care facilities from December 2013 to November 2014. Multiple logistic regression was used to examine the relationship between food insufficiency (an inadequate amount of food intake owing to a lack of money or resources), delayed/missed care, anxiety, depression, and self-reported fair to poor health, controlling for race/ethnicity, marital status, and employment status. RESULTS: The prevalence of food insufficiency among women veterans was 27.6%. Being food insufficient was associated with 16.4, 15.4, 14.9, and 12.1 percentage point increases in the probability of delayed/missed care, screening positive for anxiety, screening positive for depression, and reporting fair to poor health, respectively (p < .05). CONCLUSIONS: The prevalence of food insufficiency in this cohort was associated with delayed access to health care and worse health outcomes. Interventions addressing Veterans Administration access and health outcomes will need to examine the potential role of food insufficiency. PMID- 29475631 TI - Using echo state networks for classification: A case study in Parkinson's disease diagnosis. AB - Despite having notable advantages over established machine learning methods for time series analysis, reservoir computing methods, such as echo state networks (ESNs), have yet to be widely used for practical data mining applications. In this paper, we address this deficit with a case study that demonstrates how ESNs can be trained to predict disease labels when stimulated with movement data. Since there has been relatively little prior research into using ESNs for classification, we also consider a number of different approaches for realising input-output mappings. Our results show that ESNs can carry out effective classification and are competitive with existing approaches that have significantly longer training times, in addition to performing similarly with models employing conventional feature extraction strategies that require expert domain knowledge. This suggests that ESNs may prove beneficial in situations where predictive models must be trained rapidly and without the benefit of domain knowledge, for example on high-dimensional data produced by wearable medical technologies. This application area is emphasized with a case study of Parkinson's disease patients who have been recorded by wearable sensors while performing basic movement tasks. PMID- 29475632 TI - Representing and querying now-relative relational medical data. AB - Temporal information plays a crucial role in medicine. Patients' clinical records are intrinsically temporal. Thus, in Medical Informatics there is an increasing need to store, support and query temporal data (particularly in relational databases), in order, for instance, to supplement decision-support systems. In this paper, we show that current approaches to relational data have remarkable limitations in the treatment of "now-relative" data (i.e., data holding true at the current time). This can severely compromise their applicability in general, and specifically in the medical context, where "now-relative" data are essential to assess the current status of the patients. We propose a theoretically grounded and application-independent relational approach to cope with now-relative data (which can be paired, e.g., with different decision support systems) overcoming such limitations. We propose a new temporal relational representation, which is the first relational model coping with the temporal indeterminacy intrinsic in now-relative data. We also propose new temporal algebraic operators to query them, supporting the distinction between possible and necessary time, and Allen's temporal relations between data. We exemplify the impact of our approach, and study the theoretical and computational properties of the new representation and algebra. PMID- 29475633 TI - Clinical pharmacy services in the emergency department. AB - The emergency department (ED) is a fast-paced, high-risk, and often overburdened work environment. Formal policy statements from several notable organizations, including the American College of Emergency Physicians (ACEP) and the American Society of Health-System Pharmacists (ASHP), have recognized the importance of clinical pharmacists in the emergency medicine (EM) setting. EM clinical pharmacists work alongside emergency physicians and nurses at the bedside to optimize pharmacotherapy, improve patient safety, increase efficiency and cost effectiveness of care, facilitate antibiotic stewardship, educate patients and clinicians, and contribute to scholarly efforts. This paper examines the history of EM clinical pharmacists and associated training programs, the diverse responsibilities and roles of EM clinical pharmacists, their impact on clinical and financial outcomes, and proposes a conceptual model for EM clinical pharmacist integration into ED patient care. Finally, barriers to implementing EM clinical pharmacy programs and limitations are considered. PMID- 29475634 TI - Intubrite laryngoscope as an alternative to the standard Macintosh laryngoscope? PMID- 29475635 TI - Reaffirming the Sensory Recruitment Account of Working Memory. PMID- 29475636 TI - The Partisan Brain: An Identity-Based Model of Political Belief. AB - Democracies assume accurate knowledge by the populace, but the human attraction to fake and untrustworthy news poses a serious problem for healthy democratic functioning. We articulate why and how identification with political parties - known as partisanship - can bias information processing in the human brain. There is extensive evidence that people engage in motivated political reasoning, but recent research suggests that partisanship can alter memory, implicit evaluation, and even perceptual judgments. We propose an identity-based model of belief for understanding the influence of partisanship on these cognitive processes. This framework helps to explain why people place party loyalty over policy, and even over truth. Finally, we discuss strategies for de-biasing information processing to help to create a shared reality across partisan divides. PMID- 29475639 TI - Neonatal SIRPIDs, a Confusing EEG Finding. PMID- 29475637 TI - The Myth of Optimality in Clinical Neuroscience. AB - Clear evidence supports a dimensional view of psychiatric illness. Within this framework the expression of disorder-relevant phenotypes is often interpreted as a breakdown or departure from normal brain function. Conversely, health is reified, conceptualized as possessing a single ideal state. We challenge this concept here, arguing that there is no universally optimal profile of brain functioning. The evolutionary forces that shape our species select for a staggering diversity of human behaviors. To support our position we highlight pervasive population-level variability within large-scale functional networks and discrete circuits. We propose that, instead of examining behaviors in isolation, psychiatric illnesses can be best understood through the study of domains of functioning and associated multivariate patterns of variation across distributed brain systems. PMID- 29475638 TI - Hierarchical Active Inference: A Theory of Motivated Control. AB - Motivated control refers to the coordination of behaviour to achieve affectively valenced outcomes or goals. The study of motivated control traditionally assumes a distinction between control and motivational processes, which map to distinct (dorsolateral versus ventromedial) brain systems. However, the respective roles and interactions between these processes remain controversial. We offer a novel perspective that casts control and motivational processes as complementary aspects - goal propagation and prioritization, respectively - of active inference and hierarchical goal processing under deep generative models. We propose that the control hierarchy propagates prior preferences or goals, but their precision is informed by the motivational context, inferred at different levels of the motivational hierarchy. The ensuing integration of control and motivational processes underwrites action and policy selection and, ultimately, motivated behaviour, by enabling deep inference to prioritize goals in a context-sensitive way. PMID- 29475640 TI - Geochemical behavior, environmental availability, and reconstruction of historical trends of Cu, Pb, and Zn in sediment cores of the Cananeia-Iguape coastal system, Southeastern Brazil. AB - The Cananeia-Iguape system is located in a coastal region of southeastern Brazil, recognized by UNESCO as an Atlantic Forest Biosphere Reserve. This system has suffered substantial environmental impacts due to the opening of an artificial channel and by past intensive mining activities. In this paper was performed the sequential chemical extraction of Cu, Pb, and Zn, on previously described sediment cores, and the statistical treatment of the data, allowing to estimate the remobilization geochemical behavior, the available content and the trend of accumulation between 1926 and 2008. The maximum available level (sum of all mobile fraction) were, in mgkg-1, 18.74 for Cu, 177.55 for Pb and 123.03 for Zn. Considering its environmental availability, Pb remains a concern in the system. It was possible to recognize the anthropic contribution of Pb, being the mining activities considered the only potential source of this metal in the region. PMID- 29475641 TI - The chronicles of the contaminated Mediterranean seas: a story told by the cetaceans' skin genes. AB - Wild animals in their natural environment could provide a big source of information, but sampling can be very challenging, above all for protected species, like marine mammals. Nevertheless, significant data can be obtained sampling stranded animals right after their death, taking into account proper sampling time and methodology. RNA samples from the skin of 12 individuals including the species Stenella coeruleoalba, Tursiops truncatus, and Grampus griseus were used to test 4 potential gene markers of anthropogenic contaminants exposure. The individuals were sampled in 3 geographic areas: the Adriatic, Ionian and Tyrrhenian seas. Three out of the 4 genes tested showed higher expression in the samples collected from the Adriatic Sea. Minute skin samples tell the story of the specific geographic location where the marine mammal spent its life, thanks to the different impact on gene expression exerted by different contamination levels. PMID- 29475642 TI - Highly efficient oil-in-water emulsion and oil layer/water mixture separation based on durably superhydrophobic sponge prepared via a facile route. AB - The fabrication of the materials with special wettability being capable of removing oil layer on water surface and oil droplets in oil-in-water emulsion is an important issue for water pollution. So far, it still remains challenging to explore a simple, facile, environmentally friendly approach for achieving this goal. Herein, inspired by the adhesion of marine mussels, the polydopamine (PDA) coating with hierarchical structure was directly fabricated onto the surface of melamine (MF) sponge by facile self-polymerization in dopamine solution. Then, a superhydrophobic and superoleophilic sponge was successfully obtained after the modification by dodecanethiol (DDT) at ambient temperature. The as-prepared sponge can selectively separate a series of oil droplets in oil-in-water emulsion with high efficiency (transparency: 76.6-93.8%) and absorb various oils or organic solvents up to 45.2-98.6 times of its own weight. Moreover, in conjunction with a vacuum system, great amounts of oils up to 20 times its own weight can be effectively separated from water surface within 1s by the sponge. Due to low cost, simple process, and easy accessibility, the as-prepared sponge has potential applications in oil-in-water emulsion separation and oil spill cleanup. PMID- 29475643 TI - Seasonal assessment of trace element contamination in intertidal sediments of the meso-macrotidal Hooghly (Ganges) River Estuary with a note on mercury speciation. AB - The spatial and seasonal distribution of trace elements (TEs) (n=16) in surficial sediment were examined along the Hooghly River Estuary (~175km), India. A synchronous elevation of majority of TEs concentration (mgkg-1) was encountered during monsoon with the following descending order: Al (67070); Fe (31300); Cd (5.73); Cr (71.17); Cu (29.09); Mn (658.74); Ni (35.89). An overall low and homogeneous concentration of total Hg (THg=17.85+/-4.98ngg-1) was recorded in which methyl mercury (MeHg) shared minor fraction (8-31%) of the THg. Sediment pollution indices, viz. geo-accumulation index (Igeo) and enrichment factor (EF) for Cd (Igeo=1.92-3.67; EF=13.83-31.17) and Ba (Igeo=0.79-5.03; EF=5.79-108.94) suggested high contamination from anthropogenic sources. From factor analysis it was inferred that TEs primarily originated from lithogenic sources. This study would provide the latest benchmark of TE pollution along with the first record of MeHg in this fluvial system which recommends reliable monitoring to safeguard geochemical health of this stressed environment. PMID- 29475644 TI - Mercury in blue shark (Prionace glauca) and shortfin mako (Isurus oxyrinchus) from north-eastern Atlantic: Implication for fishery management. AB - Pelagic sharks (blue shark Prionace glauca and shortfin mako Isurus oxyrinchus) caught by long-line Spanish and Portuguese fleets in the NE Atlantic, were sampled at Vigo fish market (Spain) for total mercury (Hg) analysis. Hg concentration in white muscle increased with size and weight in both species, but at a higher rate in shortfin mako than in the blue shark. No difference was found with sex, year and season. Spatial variation was observed in the blue shark with higher Hg values in the North of the Azorean archipelago, but not in the shortfin mako. These high-level predators are particularly susceptible to bioaccumulate contaminants (Hg) in their tissues (muscle). However, a significant positive relationship between Hg concentration and trophic level (delta15N) of individuals was observed only in the shortfin mako. Most sharks landed were juveniles which presented Hg concentration lower than the maximum limit allowed by the European Union (1mgkg-1 wet weight) for marketing. However, concentrations above this threshold were most recorded in blue sharks larger than 250cm total length (TL) and in shortfin makos larger than 190cm TL, raising the question of the commercialization of large-sized individuals. PMID- 29475645 TI - Environmental DNA metabarcoding of benthic bacterial communities indicates the benthic footprint of salmon aquaculture. AB - We evaluated benthic bacterial communities as bioindicators in environmental impact assessments of salmon aquaculture, a rapidly growing sector of seafood industry. Sediment samples (n=72) were collected from below salmon cages towards distant reference sites. Bacterial community profiles inferred from DNA metabarcodes were compared to reference data from standard macrofauna biomonitoring surveys of the same samples. Deltaproteobacteria were predominant in immediate vicinity of the salmon cages. Along the transect, significant shifts in bacterial community structures were observed with Gammaproteobacteria dominating the less-impacted sites. Alpha- and beta-diversity measures of bacterial communities correlated significantly with macrofauna diversity metrics and with five ecological status indices. Benthic bacterial communities mirror the reaction of macrofauna bioindicators to environmental disturbances caused by salmon farming. The implementation of bacterial eDNA metabarcoding in future Strategic Framework Directives is an alternative cost-effective high-throughput biomonitoring solution, providing a basis for management strategies in a matter of days rather than months. PMID- 29475646 TI - Growth kinetics and biodeterioration of polypropylene microplastics by Bacillus sp. and Rhodococcus sp. isolated from mangrove sediment. AB - Interest in the biodegradation of microplastics is due to their ubiquitous distribution, availability, high persistence in the environment and deleterious impact on marine biota. The present study evaluates the growth response and mechanism of polypropylene (PP) degradation by Bacillus sp. strain 27 and Rhodococcus sp. strain 36 isolated from mangrove sediments upon exposure to PP microplastics. Both bacteria strains were able to utilise PP microplastic for growth as confirmed by the reduction of the polymer mass. The weight loss was 6.4% by Rhodococcus sp. strain 36 and 4.0% by Bacillus sp. strain 27 after 40days of incubation. PP biodegradation was further confirmed using Fourier-transform infrared spectroscopy and scanning electron microscopy analyses, which revealed structural and morphological changes in the PP microplastics with microbial treatment. These analyses showed that the isolates can colonise, modify and utilise PP microplastics as carbon source. PMID- 29475647 TI - Acute toxicity test of copper pyrithione on Javanese medaka and the behavioural stress symptoms. AB - This study was conducted to investigate the median lethal concentration (LC50) of copper pyrithione (CuPT) at 96-hr exposure on adult Javanese medaka (Oryzias javanicus) in revealing toxicological effects of CuPT contamination in the tropical area. Wild stock fishes were acclimatized for 14-days prior analysis. Triplicate of test tanks for seven test concentrations were placed with ten fishes each, this includes two control tanks. The behaviour of the tested fishes was manually observed through a camera. The LC50 of CuPT at 96-h was found to be 16.58mg/L. Tested fishes swam slowly in vertical movement and swam fast towards food during feeding time as the sign of stress behaviour. Meanwhile, fishes in the two control groups swam actively in a horizontal manner and no excitement during feeding time. No mortality in control groups. Results indicate CuPT to be toxic to Javanese medaka at low concentration and caused behavioural stress. PMID- 29475648 TI - Ingestion and fragmentation of plastic carrier bags by the amphipod Orchestia gammarellus: Effects of plastic type and fouling load. AB - Inappropriate disposal of plastic debris has led to the contamination of marine habitats worldwide. This debris can be ingested by organisms; however, the extent to which chewing and gut transit modifies plastic debris is unclear. Detritivores, such as amphipods, ingest and shred natural organic matter and are fundamental to its breakdown. Here we examine ingestion and shredding of plastic carrier bags by Orchestia gammarellus. A laboratory experiment showed these amphipods shredded plastic carrier bags, generating numerous microplastic fragments (average diameter 488.59MUm). The presence of a biofilm significantly increased the amount of shredding, but plastic type (conventional, degradable and biodegradable) had no effect. Subsequent field observations confirmed similar shredding occurred on the strandline. Rates of shredding will vary according to amphipod density; however, our data indicates that shredding by organisms could substantially accelerate the formation microplastics in the environment. PMID- 29475649 TI - Refining the tethering of American oysters (Crassostrea virginica) to measure the effects of two environmental stressors. AB - Tethering assays, or the physical restraint of test organisms, has been used in the past to measure selected organisms' response to stressors while removing the observer from the experimental setting. Although informative for monitoring and hypothesis testing, these assays often used microfilaments that have been found to be too invasive or prone to biases given their effects on test organisms' behavior. Here, we describe a new variation of tethering using American oysters (Crassostrea virginica) and illustrate its use in the study of their mortality rates as a result of two stressors: siltation and predation by a non-indigenous species. Our protocol identified a resistant (non-toxic) glue that could be used to attach oysters to stone slabs, thus partially mimicking the natural cementation of the shell to natural substrates. This variation of tethering was harmless and maintained oysters' body position and natural ability to filter feed. Using tethered oysters in separate two-week field cage experiments, we also show how siltation and predation by a non-indigenous species (the European green crab, Carcinus maenas), caused a gradual, easily measurable increase in oyster mortality rates. We argue that this variation of tethering is a cost-effective and advantageous way to monitor or test the effects of these and other stressors on oysters and similar species. PMID- 29475650 TI - Chasing phthalates in tissues of marine turtles from the Mediterranean sea. AB - Tissues from thirteen specimens of marine turtles, one Dermochelys coriacea and twelve Caretta caretta, found dead along the Sicilian coasts in 2016 were analyzed for the presence of phthalates. Four phthalates (DEP, DBP, BBP, and DEHP) were found at different significant concentrations in liver and gonads, while only DBP was found in muscle tissues and at a fourfold lower concentration than other phthalates in Dermochelys coriacea. No traces of DEP were detected in C. caretta tissues where DOTP was also revealed. The presence of phthalates in fat tissue in specimens of C. caretta showed a major prevalence of the most lipophilic phthalates DEHP and DOTP. The total concentration of all analyzed phthalates, showed high values in all tissues. Results suggested that for monitoring purposes from live specimens sample collection should be addressed to fat tissue with accurate manipulations. PMID- 29475651 TI - Effects of glyphosate herbicide on the gastrointestinal microflora of Hawaiian green turtles (Chelonia mydas) Linnaeus. AB - In Hawaii, glyphosate-based herbicides frequently sprayed near shorelines may be affecting non-target marine species. Glyphosate inhibits aromatic amino acid biosynthesis (shikimate pathway), and is toxic to beneficial gut bacteria in cattle and chickens. Effects of glyphosate on gut bacteria in marine herbivorous turtles were assessed in vitro. When cultures of mixed bacterial communities from gastrointestinal tracts of freshly euthanized green turtles (Chelonia mydas), were exposed for 24h to six glyphosate concentrations (plus deionized water control), bacterial density was significantly lower at glyphosate concentrations>=2.2*10-4gL-1 (absorbance measured at 600nm wavelength). Using a modified Kirby-Bauer disk diffusion assay, the growth of four bacterial isolates (Pantoea, Proteus, Shigella, and Staphylococcus) was significantly inhibited by glyphosate concentrations>=1.76*10-3gL-1. Reduced growth or lower survival of gut bacteria in green turtles exposed to glyphosate could have adverse effects on turtle digestion and overall health. PMID- 29475652 TI - The sensitivity of the surface oil signature to subsurface dispersant injection and weather conditions. AB - Subsea blowouts have the potential to spread oil across large geographical areas, and subsea dispersant injection (SSDI) is a response option targeted at reducing the impact of a blowout, especially reducing persistent surface oil slicks. Modified Weber scaling was used to predict oil droplet sizes with the OSCAR oil spill model, and to evaluate the surface oil volume and area when using SSDI under different conditions. Generally, SSDI reduces the amount of oil on the surface, and creates wider and thinner surface oil slicks. It was found that the reduction of surface oil area and volume with SSDI was enhanced for higher wind speeds. Overall, given the effect of SSDI on oil volume and weathering, it may be suggested that tar ball formation, requiring thick and weathered oil, could possibly be reduced when SSDI is used. PMID- 29475653 TI - Distribution and speciation of phosphorus in foreshore sediments of the Thames estuary, UK. AB - Estuarine sediments can be a source of Phosphorus (P) to coastal waters, contributing to nutrient budgets and geochemical cycles. In this work, the concentration and speciation of P in 47 cores were examined from the inter-tidal mud flats of the tidal river Thames (~120km). Results of P concentration and speciation were combined with published data relating to known sediment dynamics and water chemistry (salinity) within the estuary to produce a conceptual model of sediment-P behaviour. Results demonstrated significant P desorption occurring after sediment passed through the Estuarine Turbidity Maximum and when the salinity of the river water exceeded ~6ppt. It was found that organic P was desorbed to a greater extent than inorganic P in the lower estuary. Models were used to identify those geochemical parameters that contributed to the Total P (R2=0.80), oxalate extractable P (R2=0.80) and inorganic P (R2=0.76) concentrations within the Thames estuary. PMID- 29475654 TI - Metals in size-fractionated core sediments of Jiaozhou Bay, China: Records of recent anthropogenic activities and risk assessments. AB - Total contents and chemical speciation of Co, Ni, Cu, Ga, Mo, Cd, In, Sn, Sb, V, W, Tl, Bi and U in size-fractionated (<32, 32-63 and >63MUm) core sediments from Jiaozhou Bay were investigated to reveal their responses to anthropogenic activities. Metal contents showed a decreasing trend with increasing grain sizes. However, the loadings of metal fraction on <32, 32-63 and >63MUm grain sizes were 16%, 47% and 37%, respectively. Anthropogenic fluxes and enrichment factors of metals in >63MUm fraction were closely linked to anthropogenic activities, with an obvious increase in upper 27cm (1998-2015) and a slight decrease in 2009year. Metals (especially for Cd, Co, Cu and Ni) in >63MUm fraction were more easily released, with the highest percentage of acid soluble form and lowest residual form. Thus, the size fraction of >63MUm cannot be ignored. PMID- 29475655 TI - First observations of perfluorooctane sulfonate occurrence and depuration from Sydney Rock Oysters, Saccostrea glomerata, in Port Stephens NSW Australia. AB - Following the discovery of potential chronic perfluoroalkyl substances (PFAS) contamination of Tilligerry Creek, Port Stephens (New South Wales Australia), sampling was undertaken to confirm the presence, extent and levels of contamination in commercial oyster crops of Sydney Rock Oyster (Saccostrea glomerata) and Pacific Oyster (Crassostrea gigas) grown within the estuary. Among a range of PFAS tested, only perfluorooctane sulfonate (PFOS) was detected. Concentrations of PFOS in oyster tissues for S. glomerata ranged from 1.6MUgkg-1 ww (wet weight) to below the limit of reporting of 0.3MUgkg-1 ww, with concentrations generally decreasing toward the lower reaches of the estuary. The sample of C. gigas tested had a PFOS concentration of 0.71MUgkg-1 ww that was consistent with concentrations observed in nearby S. glomerata. For harvest size (50-60g) S. glomerata, both holding contaminated oysters in a depuration system, and relocation to a non-contaminated area, saw significant reductions in the tissue PFOS concentrations. For oysters held in a depuration system, PFOS depurated at a rate of 0.008h-1 (0.004-0.019h-1; 90% CI), which corresponded with a depuration half-life of 87h (35-155h; 90%). A more conservative model (fitted to data that assumed concentrations1, respectively. Absorbed dose rate in air (D) showed significant values in sediments, which were generally over the maximum recommended value of 55nGyh-1. Phytostabilization of radionuclides and heavy metals may serve as an appropriate strategy for mangrove polluted areas. D values in sediments were considered sufficiently high to recommend long-term monitoring. Radionuclide activities may increase in the food chain via uptake and accumulation of edible plants, ultimately resulting in harm to human health. PMID- 29475669 TI - Long-term shifts in the north western Mediterranean coastal seascape: The habitat forming seaweed Codium vermilara. AB - Long-term ecological studies are crucial to understand how and why natural ecosystems change over time and space. Through a revision of historical data and a comparison with current in situ field data, we contribute to the understanding of how the Mediterranean coastal seascape has changed in the last decades. Here we describe the large decrease of the main habitat-forming species Codium vermilara along the Catalan coast (NW Mediterranean). We have analyzed data on presence/absence, abundance and biomass. Since the 70s-80s, when the species reached its highest abundances, the species has totally disappeared from 45% of the revisited sites, and showed a decrease in 95% of its abundance and 97% of its biomass. Codium vermilara has also shown a reduction in its depth range, from 30 to the first 20m depth. This study highlights the importance of having historical data to detect and describe changes in ecological systems. PMID- 29475670 TI - Volcanic ash in the water column: Physiological impact on the suspension-feeding bivalve Mytilus chilensis. AB - Ashes settling into the sea from volcanic explosions expose suspension-feeding species to reduced seston quality. Adults and juveniles of the mussel Mytilus chilensis were exposed for 15days to the phytoplankton Isochrysis galbana together with various concentrations of ashes. We then quantified impact on survival and physiology. Although no individuals died during the experiment, by the end of the study clearance rates and oxygen consumption rates had decreased substantially, and tissue weight of mussels exposed to the highest ash concentrations declined substantially. Gills showed no physical damage, but did show abundant mucus secretion in response to ash particles. Moreover, as the relative proportions of microalgae to ash in the diet decreased, individuals showed increasing preferential ingestion of microalgal particles. Increased ash content in the diet altered physiological rates and activated distinct particle selection with a high production of pseudofeces and high energy costs, with potential long-term consequences. PMID- 29475671 TI - Polycyclic aromatic hydrocarbons (PAH) in superficial water from a tropical estuarine system: Distribution, seasonal variations, sources and ecological risk assessment. AB - This study aimed to evaluate the PAH distribution, sources, seasonal variations and ecological risk assessment in superficial water from the Japaratuba River, Brazil. PAH concentrations ranged from 4 to 119ngL-1. It was observed that the PAH total concentrations and profiles showed significant differences when comparing the dry season (summer) with the rainy season (winter). Furthermore, most of the PAH originated from pyrogenic sources in the winter, whereas a mixture of sources was observed in the summer. PAH concentration levels found in this study were considered lower than those obtained in other estuarine systems. Ecological risk assessment was determined for individual PAH, based on the risk quotient (RQ) to evaluate the risk of aquatic biota's exposure to PAH. Results suggested that the Japaratuba River has achieved a moderate degree of ecological risk for high molecular weight, showing the importance of identifying these carcinogenic and mutagenic compounds in aquatic systems. PMID- 29475672 TI - Pollution levels of DDTs and their spatiotemporal trend from sediment records in the Southern Yellow Sea, China. AB - In order to study the pollution levels and spatiotemporal trend of Dichlorodiphenyltrichloroethanes (DDTs) in the Southern Yellow Sea (SYS), thirty two surface sediment samples and a sediment core have been analyzed, and our results have been compared with previous reports. DDTs contents in our samples ranged from below detection limit to 5.1ng/gdry weight (d.w.), which presented lower ecological risks in the SYS. Surface sediment results show a seaward increasing trend with high values in the northern region of the central basin of the SYS. Our reconstructed core record and historical data from previous reports reveal an increasing trend from 1905 to 1955 but a decline trend since 1985 for DDTs, which is consistent of the production, usage and banning of DDTs in China. The source identification, based on (DDE+DDD)/DDTs, suggested that aged DDTs were the major contributor, though there were some inputs of fresh DDTs from the usage of 1,1-bis(p-Chlorophenyl)-2,2,2-trichloroethanol (dicofol). PMID- 29475673 TI - Synthetic microfibers in the marine environment: A review on their occurrence in seawater and sediments. AB - The objective of this review is to summarize information on microfibers in seawater and sediments from available scientific information. Microfibers were found in all reviewed documents. An heterogeneous approach is observed, with regard to sampling methodologies and units. Microfibers in sediments range from 1.4 to 40 items per 50mL or 13.15 to 39.48 items per 250g dry weight. In the case of water, microfibers values ranges from 0 to 450items.m-3 or from 503 to 459,681items.km-2. Blue is the most common color in seawater and sediments, followed by transparent and black in the case of seawater, and black and colorful in sediments. Related with polymer type, polypropylene is the most common in water and sediments, followed by polyethylene in water and polyester in water and sediments. Some polymers were described only in water samples: high-density polyethylene, low-density polyethylene and cellophane, whilst only rayon was reported in sediments. PMID- 29475674 TI - Environmental radiation and potential ecological risk levels in the intertidal zone of southern region of Tamil Nadu coast (HBRAs), India. AB - Natural radioactivity content and heavy metal concentration in the intertidal zone sand samples from the southern region of Tamil Nadu coast, India, have been analyzed using gamma ray spectrometer and ICP-OES, respectively. From gamma spectral analysis, the average radioactivity contents of 238U, 232Th, and 40K in the intertidal zone sand samples are 12.13+/-4.21, 59.03+/-4.26, and 197.03+/ 26.24Bq/kg, respectively. The average radioactivity content of 232Th alone is higher than the world average value. From the heavy metal analysis, the average Cd, Cr, Cu, Ni, Pb, and Zn concentrations are 3.1, 80.24, 82.84, 23.66, 91.67, and 137.07ppm, respectively. The average Cr and Ni concentrations are lower, whereas other four metal (Cd, Cu, Pb, and Zn) concentrations are higher than world surface rock average values. From pollution assessment parameter values, the pollution level is "uncontaminated to moderately contaminated" in the study area. PMID- 29475675 TI - Erosion as a possible mechanism for the decrease of size of plastic pieces floating in oceans. AB - A sea water wave tank fitted in an artificial UV light weathering chamber was built to study the behaviour of polypropylene (PP) injected pieces in close ocean like conditions. In air, the same pieces sees a degradation in the bulk with a decrease of mechanical properties, a little change of crystal properties and nearly no change of surface chemistry. Weathering in the sea water wave tank shows only a surface changes, with no effect on crystals or mechanical properties with loss of small pieces of matter in the sub-micron range and a change of surface chemistry. This suggests an erosion dispersion mechanism. Such mechanism could explain why no particle smaller than about one millimeter is found when collecting plastic debris at sea: there are much smaller, eroded from plastic surfaces by a mechano-chemical process similar to the erosion mechanism found in the dispersion of agglomerate under flow. PMID- 29475676 TI - Comparison of radiocesium and stable isotope ratios of carbon and nitrogen among three stocks of Pacific cod (Gadus macrocephalus) around Hokkaido, Japan. AB - Hokkaido, the northernmost of the main islands of Japan, is surrounded by the North Pacific Ocean, the Japan Sea and the Okhotsk Sea, and three independent stocks of Pacific cod are thought to inhabit those three areas. The Fukushima Dai ichi Nuclear Power Plant (FDNPP), which is located in the north of Honshu, the main island of Japan, was disputed in 2011. Most of the radiocesium from the FDNPP was released into the western North Pacific Ocean, and the biota in those areas were considerably contaminated soon after the FDNPP accident. We analyzed radiocesium in Pacific cod caught around Hokkaido between 2011 and 2015. The radiocesium was predominantly detected in the cod caught in the North Pacific Ocean, and not in those caught the Japan Sea and the Okhotsk Sea. These results suggest that the cod caught in the Pacific Ocean around Hokkaido moved through the contaminated area off the FDNPP. PMID- 29475677 TI - Trophic and growth baseline of dominant subtidal gastropods in contrasting subtropical marine environments. AB - Using 13C/12C, 15N/14N and 18O/16O isotopes, the trophic relationship and growth estimation were analyzed in gastropods Nassarius siquijorensis, Murex trapa and Turritella bacillum and their potential food sources and predators in summer and winter from estuarine and oceanic environments in subtropical Hong Kong. Results of delta13C and delta15N values and isotopic mixing model revealed N. siquijorensis and M. trapa were one trophic level higher than T. bacillum, in which its main food source was particulate organic matter (POM) whereas N. siquijorensis largely consumed POM and polychaetes and M. trapa also preyed on other gastropods. Crabs were the major predator of gastropods. Organisms collected from oceanic waters were more 13C enriched than from estuarine waters, reflecting different carbon food sources from marine or terrestrial origin. The delta18O profile from shell carbonate suggested these gastropods were one to two years old. T. bacillum exhibited faster summer growth than the other two species. PMID- 29475678 TI - Hydrochemistry and nutrient distribution in southern deep-water basin of the Caspian Sea. AB - In this work, the results of hydrochemical studies aboard the R/V Iran Behshahr in southern Caspian Sea in late-winter 2014 were presented. Salinity, temperature, dissolved oxygen, pH, total dissolved inorganic carbon, total alkalinity, nitrate, phosphate and silicate concentrations in water column of Neka-Amir Kabir oil platform section in the southern Caspian Sea were measured to study the status of hydrochemistry of this area. Results showed that the hypoxia continues to intensify in the deep-water basin of the South Caspian Sea. Near zero concentration of dissolved oxygen and accumulation of phosphate, silicate and total dissolved inorganic carbon in near-bottom layers in the study area showed that vertical winter mixing of water column did not reach the near-bottom layers at the time of this survey. Nitrate showed its maximum concentration at the intermediate maximum depth of 300m. PMID- 29475679 TI - Perennial occurrence of heterotrophic, indicator and pathogenic bacteria in the coastal Bay of Bengal (off Visakhapatnam) - Impact of physical and atmospheric processes. AB - In order to examine the health of the coastal waters off Visakhapatnam in terms of prevalence and abundance of heterotrophic (H), indicator and pathogenic (P) bacterial counts (BC) and influence of physical processes on them, time-series observations were conducted during January (winter), March (spring), July (summer) and October (post-monsoon). We noticed the impact of physical forces on substantial variations in abundance and distribution of the HBC, total coliforms, Enterococcus faecalis and Pseudomonas aeruginosa in the study region. Based on our results Escherichia coli and other PBC were not much influenced by the physical conditions. It has been noticed that the perennial existence of the high abundance of IBC and PBC above the standard limits during the entire study period leading to an alarming situation in the coastal waters off Visakhapatnam. PMID- 29475680 TI - Development of a novel methodology for in vivo quantification of N/O/S-containing polycyclic aromatic hydrocarbons located on the epidermis of mangrove roots using graphene quantum dots as a fluorescence quencher. AB - A novel approach for in vivo determination of typical N/O/S-containing PAHs located on the epidermis of mangrove roots was developed using graphene quantum dots (GQDs) as a fluorescence quencher. The decreasing fluorescence intensity from GQDs was attributed to the amount of N/O/S-containing PAHs introduced onto the epidermis of mangrove roots. The linear ranges of the proposed method were 10.3-980ngg-1, 9.5-1350ngg-1 and 7.8-1200ngg-1 for DBF, DBT and CAR located on the epidermis of K. obovata roots, respectively. This method was also shown to be valid for quantifying the N/O/S-containing PAHs on the root epidermis in the presence of heavy metal (10mmolL-1) and dissolved organic matter (1mgL-1 C). Moreover, the death rates of epidermal cells were almost unchanged (p>0.05) after acquiring the fluorescence spectra, which is superior to the previously reported LITRF method with which the cell death rates increased to 42.6%. PMID- 29475681 TI - Different effects of reclamation methods on macrobenthos community structure in the Yangtze Estuary, China. AB - The effects of enclosed, semi-closed, and opened reclamation methods on the macrobenthos community structure were investigated. Compared with their paired controls, water salinity decreased sharply in the enclosed reclamation region with no apparent change in the opened reclamation region. Declining species and biodiversity was observed in the reclamation regions, but the extent of this declining trend was weaker in the semi-closed and opened reclamations than in the enclosed reclamation region. The ABC curve indicated that the enclosed reclamation was disturbed, whereas the semi-closed and opened reclamations were undisturbed. Taken together, these results suggest that reclamation may have a negative effect on the community and health status of macrobenthos in the intertidal wetlands of the Yangtze Estuary. Semi-closed and opened reclamation methods may mitigate the problem of a salinity decrease caused by enclosed reclamation, while also having a relatively weaker negative effect on community structure and wetland habitat. PMID- 29475682 TI - High genetic variability of Alexandrium catenella directly detected in environmental samples from the Southern Austral Ecosystem of Chile. AB - Chilean waters are often affected by Alexandrium catenella, one of the leading organisms behind Harmful Algae Blooms (HABs). Genetic variability for this species are commonly carried out from cultured samples, approach that may not accurately quantify genetic variability of this organism in the water column. In this study, genetic variability of A. catenella was determined by sequencing the rDNA region, in water samples from the Canal Puyuhuapi (South Austral Ecosystem of Chile). A. catenella was detected in 8,8% of samples analysed. All sequences obtained were A. catenella (Tamara complex group I), with three highly frequent haplotypes (34%), and twenty new haplotypes. These haplotypes increase the genetic variability from 2.8% to 3.14% in this area. Through this new method, genetic determination of A. catenella can accurately be monitored and ecological studies of this species can be implemented. PMID- 29475683 TI - Seawater quality assessment and identification of pollution sources along the central coastal area of Gabes Gulf (SE Tunisia): Evidence of industrial impact and implications for marine environment protection. AB - Temperature, pH and trace elements (F, P, Cr, Cu, Zn, Cd, and Pb) contents were determined in 16 stations as well as in 2 industrial and 2 domestic discharge sources, in the central coastal area of the Gulf of Gabes. Compared to the northern and southern areas of the study area, the highest contents of contaminants were reached in the central area which hosts the coastal industrial complex. The seawater in this central area was also found to be acid and of higher temperature. Based on the Water Pollution Index results, an increasing degradation gradient of the seawater quality was revealed from northern and/or southern stations to central ones, categorized as 'strongly to seriously affected'. Phosphogypsum wastes dumped by the Tunisian Chemical Group (GCT) seem to have continuously degraded the seawater quality in the study area. A rapid intervention is needed to stop the effects on the marine environment. PMID- 29475684 TI - Impacts of Fukushima Daiichi Nuclear Power Plant accident on the Western North Pacific and the China Seas: Evaluation based on field observation of 137Cs. AB - After the Fukushima nuclear accident (FNA), 137Cs activities of seawater in the Western North Pacific (WNP) and China Seas were determined in order to examine whether 137Cs derived from FNA across the Kuroshio was still existed and if there were any indications of FNA's impact. High 137Cs activities at 200-500m were observed in the south of Kuroshio during 2015, indicating 137Cs from FNA could cross the Kuroshio. Surface 137Cs activities were on average 1.43+/-0.42Bqm-3 for WNP, 1.11+/-0.14Bqm-3 for South China Sea (SCS) and 1.10+/-0.29Bqm-3 for East China Sea (ECS) during 2011-2015. The activities and inventories of 137Cs were almost identical before and after the FNA, indicating the impacts of FNA on the WNP and China Seas were minor. The effective environmental half-lives of 137Cs in surface seawater were firstly estimated to be 14.4+/-1.7yrs for ECS and 16.9+/ 2.1yrs for SCS. PMID- 29475686 TI - Present status of 137Cs in seawaters of the Lombok Strait and the Flores Sea at the Indonesia Through Flow (ITF) following the Fukushima accident. AB - Due to thermocline and surface water from the western equatorial Pacific Ocean, which are transported to the Indian Ocean, Indonesian marine waters play an important role in the global ocean circulation. The objective of this study was to assess the spatial distribution of 137Cs in the Lombok Strait as part of a national monitoring program concerning the possible impacts of radionuclides released as a result of the Fukushima accident. Sampling was conducted in the Flores sea and Lombok Strait on 15 to 24 November 2013. Measurements for the Lombok strait showed that 137Cs concentrations at surface layer, thermocline layer and 1000m depth were 0.27Bqm-3; 0.42Bqm-3 and 1 indicates sediment contamination from anthropogenic activities. Cr, Ni and Pb were found to have moderate accumulation in geoaccumulation index with Fe showing high accumulation. Normalized data of trace metals shows 87.5% from Indian site and 80% of Bangladesh site as outlier, indicating anthropogenic influence. Out of total sampling site 50% of Indian and 40% of Bangladesh site show trace metal values enriched more than predicted value of trace metals indicating Indian part have more polluted sites than Bangladesh side of Sundarban, which is also confirmed by enrichment factor, I-geo and normalization values in both the sides. PMID- 29475696 TI - Critical evaluation of different methods to calculate the Geoaccumulation Index for environmental studies: A new approach for Baixada Santista - Southeastern Brazil. AB - Although the Igeo is widely used in heavy metal contamination studies, its application differs in each study in terms of the mathematical equation used, the chosen background, and whether the fine fraction or whole sediment matrix is used. This study aims to assess these different methods, propose a new equation to calculate this index and use the index to evaluate the environmental quality of Baixada Santista. The levels of heavy metals were quantified in fifty sediment samples using both in the whole sediment sample and only in the fine fraction. The index was calculated in both fractions and in the normalized levels. Using the fine fraction of the sample was more suitable to the classification. The ratio of the levels in the whole sediment to the fine content did not present a significant statistical difference compared to the levels obtained from the fine fraction. Based on this study, a new equation is proposed for use in future environmental studies. PMID- 29475697 TI - The dynamics of a dominant dinoflagellate, Noctiluca scintillans, in the subtropical coastal waters of the Matsu archipelago. AB - Bioluminescent seas caused by blooms of the dinoflagellate Noctiluca scintillans are a famous scenic attraction in the Matsu archipelago near the Chinese coast in the northern part of the Taiwan Strait. The relationship between the abundance of N. scintillans and various environmental factors was examined in the subtropical coastal waters of these islands from April to December, 2016. N. scintillans disappeared after June 20th, when the sea water temperature exceeded 27 degrees C. A strong inverse correlation between N. scintillans and diatoms in PCA analysis indicated that diatoms suffer high grazing pressure from N. scintillans. N. scintillans appeared most abundantly during the flood season, when diatoms are most abundant. Strong inverse correlations between N. scintillans and the wind speed and wind direction in PCA further point to the effect of wind on the accumulation of cells. PMID- 29475698 TI - Impact of nutrient enrichment on productivity of coastal water along the SE Mediterranean shore of Israel - A bioassay approach. AB - The coastal waters of the southeastern Mediterranean-Sea (SEMS) are routinely enriched with naturally-occurring and anthropogenic land-based nutrient loads. These external inputs may affect autotrophic and heterotrophic microbial biomass and activity. Here, we conducted 13 microcosm bioassays with different additions of inorganic NO3-(N), PO4-(P) and Si(OH)4-(Si) in different seasons along the Mediterranean coast of Israel. Our results indicate that cyanobacteria are mainly N-limited, whereas N or Si (or both) limit pico-eukaryotes. Furthermore, the degree to which N affects phytoplankton depends on the ambient seawater's inorganic N and N:P characteristics. Heterotrophic bacteria displayed no response in all treatments, except when all nutrients were added simultaneously, suggesting a possible co-limitation by nutrients. These results contrast the N+P co-limitation of phytoplankton and the P-limitation of bacteria in the open waters of the SEMS. These observations enable the application for a better science-based environmental monitoring and policy implementation along the SEMS coast of Israel. PMID- 29475699 TI - Metals and their ecological impact on beach sediments near the marine protected sites of Sodwana Bay and St. Lucia, South Africa. AB - A baseline study on metal concentrations in sediments was initiated from the Sodwana Bay and St. Lucia, adjacent to marine protected areas (MPAs) of South Africa. They were analysed to identify the acid leachable metal (ALM) (Fe, Mg, Mn, Cr, Cu, Mo, Ni, Co, Pb, Cd, Zn and Hg) concentration pattern. Metal distribution in 65 sediment samples exhibits higher abundances of Cr, Mo, Cd and Hg compared to the Upper Continental Crust. We relate the enrichment of these metals to beach placer deposits and activities related to former gold mining. Geochemical indices affirmed that Cr and Hg caused contamination, and Hg posed ~90% harmful effect on the biological community. These beach sediments, however, host lower metal concentrations compared to many worldwide beaches and other beaches in South Africa. This study suggests that it is largely unaffected by human activities, however, the overabundance of Hg demands regular monitoring. PMID- 29475700 TI - Barriers and benefits to desired behaviors for single use plastic items in northeast Ohio's Lake Erie basin. AB - Given the growing saliency of plastic marine debris, and the impact of plastics on beaches and aquatic environments in the Laurentian Great Lakes, applied research is needed to support municipal and nongovernmental campaigns to prevent debris from reaching the water's edge. This study addresses this need by examining the barriers and benefits to positive behavior for two plastic debris items in northeast Ohio's Lake Erie basin: plastic bags and plastic water bottles. An online survey is employed to gather data on the use and disposal of these plastic items and to solicit recommendations on how to positively change behavior to reduce improper disposal. Results support a ban on plastic bags and plastic water bottles, with more enthusiasm for a bag ban. Financial incentives are also seen as an effective way to influence behavior change, as are location specific solutions focused on education and outreach. PMID- 29475701 TI - Effective and easy to use extraction method shows low numbers of microplastics in offshore planktivorous fish from the northern Baltic Sea. AB - Although the presence of microplastics in marine biota has been widely recorded, extraction methods, method validation and approaches to monitoring are not standardized. In this study a method for microplastic extraction from fish guts based on a chemical alkaline digestion is presented. The average particle retrieval rate from spiked fish guts, used for method validation, was 84%. The weight and shape of the test particles (PET, PC, HD-PE) were also analysed with no noticeable changes in any particle shapes and only minor weight change in PET (2.63%). Microplastics were found in 1.8% of herrings (n=164) and in 0.9% of sprat (n=154). None of the three-spined sticklebacks (n=355) contained microplastic particles. PMID- 29475702 TI - Impact of intense rains and flooding on mercury riverine input to the coastal zone. AB - The aim of the present research was to determine the impact of intense rains and flooding on mercury riverine input to the coastal zone. This study focused on four small rivers (Reda, Zagorska Struga, Plutnica, Gizdepka), typical of the Southern Baltic region, with no significant mercury sources. Samples were collected for 16months during average flow conditions and during selected meteorological events: floods, downpours, thaws and droughts. Results showed decreased retention of mercury during intense rainfalls, thus demonstrating mercury elution from the catchment. Floods and melting snow also have a tremendous impact on the outflow of mercury from the catchment. Development of urban infrastructure and farmlands increases the outflow of mercury from the catchment too, making such areas a significant source of mercury in the river. On the other hand, areas with natural character, predominated by forests, stimulate retention of mercury that reaches them through dry and wet atmospheric deposition. PMID- 29475703 TI - Differential impact of marine debris ingestion during ontogenetic dietary shift of green turtles in Uruguayan waters. AB - Anthropogenic debris ingestion has been reported for green turtles in all their life stages worldwide. The aim of the present study is to evaluate the marine debris ingestion by green turtles stranded in Uruguayan coast between 2005 and 2013. Debris items were categorized and quantified by frequency of occurrence, relative weight, volume and number of items. A total of 96 dead stranded turtles were analyzed and 70% presented debris in their guts. The majority of debris found were plastic, being hard plastics the most abundant in weight. We found no differences in debris ingestion in stranded turtles a long the Uruguayan coast. However we detected a negative correlation between the presence of debris and turtle's size. Smaller turtles are new recruits to neritic grounds indicating that the early juvenile stage of this species is the most vulnerable to this threat in the Southwestern Atlantic. PMID- 29475704 TI - Marine litter on the seafloor of the southern Baltic. AB - Marine litter occurrence and composition were investigated during routine bottom trawl fish surveys type BITS performed in the Polish Maritime Areas (the southern Baltic Sea). Sampling covered a distance of 325km and an area of 16km2 at a depth range of 19-110m. Litter densities varying between 0 items/ha (34% of tows) and 2.23items/ha with a mean of 0.20items/ha (SD=0.30) are at the bottom range of densities reported from other shelf habitats worldwide at similar water depths. The majority of the items (40%) were found at a depth range of 51-60m. Overall, plastic was the most common litter type (67% of all items) found in all tows with litter. The results of this study indicate that despite the Baltic being a semi enclosed basin, with a densely populated coastline and extensive shipping, marine litter pollution of the southern Baltic seafloor is low compared to other coastal areas. PMID- 29475705 TI - Spectroscopic analyses and genotoxicity of dioxins in the aquatic environment of Alexandria. AB - Dioxins have global concerns because of the bioaccumulation tendency and persistency in the environment. Water, seabream Pagrus auratus and seabass Dicentrarchus labrax samples were collected from Abu Qir, Alexandria to evaluate the concentration of dioxin. Fourier Transform Infrared Spectrometer (FTIR) and molecular modeling was applied for elucidating the molecular structure of fish samples. Furthermore, HPLC with UV detection was used to determine the concentration of dioxins (2,8-dichloro dibenzo-p-dioxin). RT-PCR assay was conducted to verify the expression of some immune genes in the fish species as a result of water pollution. The average detected concentrations varied from 0.2 to 1.3MUg/l. Gene expression revealed that MHC class 1 and C3 were highly upregulated in liver and muscle of seabass and seabream while T2BP was highly regulated in seabass liver and seabream muscle and seabass muscle for transferrin, FTIR and molecular modeling indicate that dioxin finds its way to fish protein. PMID- 29475706 TI - Evaluation of the ability of calcite, bentonite and barite to enhance oil dispersion under arctic conditions. AB - A test program was conducted at laboratory and pilot scale to assess the ability of clays used in drilling mud (calcite, bentonite and barite) to create oil mineral aggregates and disperse crude oil under arctic conditions. Laboratory tests were performed in order to determine the most efficient conditions (type of clay, MOR (Mineral/Oil Ratio), mixing energy) for OMA (Oil Mineral Aggregate) formation. The dispersion rates of four crude oils were assessed at two salinities. Dispersion was characterized in terms of oil concentration in the water column and median OMA size. Calcite appeared to be the best candidate at a MOR of 2:5. High mixing energy was required to initiate OMA formation and low energy was then necessary to prevent the OMAs from resurfacing. Oil dispersion using Corexit 9500 was compared with oil dispersion using mineral fines. PMID- 29475707 TI - Ecological shifts due to anthropogenic activities in the coastal seas of the Seto Inland Sea, Japan, since the 20th century. AB - Multiproxy analyses were conducted using sediment cores in a low-polluted coastal site (Hiuchi-nada) in the Seto Inland Sea (SIS), Japan. Heavy metal and organic pollution peaked in the 1960s and the bottom environments have ameliorated since the 1980s due to several environmental regulations. First ecological shifts in meiobenthic ostracodes and diatoms occurred in the 1960s due to the initiation of eutrophication. Then, a second ecological shift occurred in the 1980s due to the amelioration of the water and the bottom quality. A compilation of similar analytical results in the coastal seas of the SIS reveals three types of ecological and environmental history since the 20th century. The environmental improvement since the 1980s affects the ecosystems, in particular, in a low polluted bay. However, ecological compositions are different from those prior to the 1960s, suggesting that the ecosystem was not recovered but changed into the next stage in the SIS. PMID- 29475708 TI - Elevated concentrations of naturally occurring radionuclides in heavy mineral rich beach sands of Langkawi Island, Malaysia. AB - Study is made of the radioactivity in the beach sands of Langkawi island, a well known tourist destination. Investigation is made of the relative presence of the naturally occurring radionuclide 40K and the natural-series indicator radionuclides 226Ra and 232Th, the gamma radiation exposure also being estimated. Sample quantities of black and white sand were collected for gamma ray spectrometry, yielding activity concentration in black sands of 226Ra, 232Th and 40K from 451+/-9 to 2411+/-65Bqkg-1 (mean of 1478Bqkg-1); 232+/-4 to 1272+/ 35Bqkg-1 (mean of 718Bqkg-1) and 61+/-6 to 136+/-7Bqkg-1 (mean of 103Bqkg-1) respectively. Conversely, in white sands the respective values for 226Ra and 232Th were appreciably lower, at 8.3+/-0.5 to 13.7+/-1.4Bqkg-1 (mean of 9.8Bqkg 1) and 4.5+/-0.7 to 9.4+/-1.0Bqkg-1 (mean of 5.9Bqkg-1); 40K activities differed insubstantially from that in black sands, at 85+/-4 to 133+/-7Bqkg-1 with a mean of 102Bqkg-1. The mean activity concentrations of 226Ra and 232Th in black sands are comparable with that of high background areas elsewhere in the world. The heavy minerals content gives rise to elevated 226Ra and 232Th activity concentrations in all of black sand samples. Evaluation of the various radiological risk parameters points to values which in some cases could be in excess of recommendations providing for safe living and working. Statistical analysis examines correlations between the origins of the radionuclides, also identifying and classifying the radiological parameters. Present results may help to form an interest in rare-earth resources for the electronics industry, power generation and the viability of nuclear fuels cycle resources. PMID- 29475709 TI - Release of PAHs and heavy metals in coastal environments linked to leisure boats. AB - Leisure boats are responsible for elevated levels of heavy metals and PAHs in sediments in- and near marinas and natural harbours. As these compounds are released directly into the water column they also pose a threat to organisms in the pelagic environment. Passive samplers were deployed during peak and post tourist season in the water column of natural harbours, leisure boat waterways and small marinas to measure the dissolved fraction of PAHs and metal ions. Differences between seasons indicative of leisure boat activities were found as PAH composition differed between peak and post season for natural harbours and waterways, where heavier PAHs increased during peak season. During peak season, metal samplers were covered by biofouling, which likely affected the uptake. Post season metal concentrations differ between locations, with concentrations exceeding quality standards at near mainland locations where boats are maintained, compared to the sites in the archipelago. PMID- 29475710 TI - Nutrient bioextraction and microalgae growth inhibition using submerged macrophyte Myriophyllum spicatum in a low salinity area of East China Sea. AB - Myriophyllum spicatum was cultivated in a low salinity area of Hangzhou Bay (salinity 5.8-6.5), from August to October in 2016, to evaluate the abilities of its nutrient bioextraction and microalgae growth inhibition. During the 72-day cultivation period, M. spicatum had a specific growth rate (SGR) of 6.23%day-1 and increased 20-fold in biomass (wet weight). Tissue C, N and P assimilation quantities of M. spicatum were found to be 3279.39kg, 360.61kg and 26.97kg, respectively. The concentration of NH4-N, NO3-N, NO2-N and PO4-P after M. spicatum cultivation was decreased by 47.92%, 58.28%, 36.40% and 55.57%, respectively. The phytoplankton density was decreased from 1064.60*104cellsL-1 to 12.85*104cellsL-1. These results indicated that cultivation of M. spicatum can help in nutrient bioextraction and microalgae growth inhibition in low salinity marine water bodies. PMID- 29475711 TI - Atmospheric deposition of trace elements to Daya Bay, South China Sea: Fluxes and sources. AB - This study was conducted from October 2015 to March 2017, with the aim of providing the first data on the fluxes and sources of wet and dry deposition of trace elements (TEs) in Daya Bay, South China Sea. Wet deposition flux of TEs was always preponderant and orders of magnitude higher than that of dry deposition owing to the high rainfall frequency in Daya Bay. The total deposition fluxes of TEs in the target area were higher than in most places worldwide, but at a moderate level within China. Wet deposition was highest in summer and lowest in winter, whereas dry deposition showed an opposite seasonal trend. The main sources of TEs in wet deposition were seasalt/dust, fossil fuel combustion, and crustal sources, and in dry deposition, they were dust/metallurgic, fossil fuel, petrochemical industry and crustal sources. PMID- 29475712 TI - Threat of plastic ageing in marine environment. Adsorption/desorption of micropollutants. AB - Ageing of various plastics in marine environment was monitored after immersion of two synthetic (polyvinylchloride, PVC, and polyethylene terephthalate, PET) and one biodegradable (poly(butylene adipate co-terephtalate), PBAT) plastics for 502days in the bay of Lorient (Brittany, France). Data analysis indicates that aged PVC rapidly releases estrogenic compounds in seawater with a later adsorption of heavy metals; PET undergoes a low weakening of the surface whereas no estrogenic activity is detected; PBAT ages faster in marine environment than PVC. Aged PBAT exhibits heterogeneous surface with some cavities likely containing clay minerals from the chlorite group. Besides, this degraded material occasionally shows a high estrogenic activity. Overall, this study reports, for the first time, that some aged plastics, without being cytotoxic, can release estrogenic compounds in marine environment. PMID- 29475713 TI - Effects of seawater mixing on the mobility of trace elements in acid phosphogypsum leachates. AB - This research reports the effects of pH increase on contaminant mobility in phosphogypsum leachates by seawater mixing, as occurs with dumpings on marine environments. Acid leachates from a phosphogypsum stack located in the Estuary of Huelva (Spain) were mixed with seawater to achieve gradually pH7. Concentrations of Al, Fe, Cr, Pb and U in mixed solutions significantly decreased with increasing pH by sorption and/or precipitation processes. Nevertheless, this study provides insight into the high contribution of the phosphogypsum stack to the release of other toxic elements (Co, Ni, Cu, Zn, As, Cd and Sb) to the coastal areas, as 80-100% of their initial concentrations behaved conservatively in mixing solutions with no participation in sorption processes. Stable isotopes ruled out connexion between different phosphogypsum-related wastewaters and unveiled possible weathering inputs of estuarine waters to the stack. The urgency of adopting effective restoration measures in the study area is also stressed. PMID- 29475714 TI - Validation of ATR FT-IR to identify polymers of plastic marine debris, including those ingested by marine organisms. AB - Polymer identification of plastic marine debris can help identify its sources, degradation, and fate. We optimized and validated a fast, simple, and accessible technique, attenuated total reflectance Fourier transform infrared spectroscopy (ATR FT-IR), to identify polymers contained in plastic ingested by sea turtles. Spectra of consumer good items with known resin identification codes #1-6 and several #7 plastics were compared to standard and raw manufactured polymers. High temperature size exclusion chromatography measurements confirmed ATR FT-IR could differentiate these polymers. High-density (HDPE) and low-density polyethylene (LDPE) discrimination is challenging but a clear step-by-step guide is provided that identified 78% of ingested PE samples. The optimal cleaning methods consisted of wiping ingested pieces with water or cutting. Of 828 ingested plastics pieces from 50 Pacific sea turtles, 96% were identified by ATR FT-IR as HDPE, LDPE, unknown PE, polypropylene (PP), PE and PP mixtures, polystyrene, polyvinyl chloride, and nylon. PMID- 29475715 TI - A novel biomarker for marine environmental pollution of CAT from Mytilus coruscus. AB - Bivalves use anti-oxidative enzyme systems to defend themselves against excessive reactive oxygen species, which are often catalyzed by environmental pollution. As a key member of anti-oxidative enzyme family, catalase plays a crucial role in scavenging the high level of reactive oxygen species to protect organisms against various oxidative stresses. In this study, a catalase homologue was identified from Mytilus coruscus (named McCAT, KX957929). The open reading frame of McCAT was 1844bp with a 5' untranslated region of 341bp and a 3' untranslated region of 927bp. The deduced amino acid sequence was 512 residues in length with theoretical pI/MW 8.02/57.91kDa. BLASTn and phylogenetic analyses strongly suggested that it was a member of catalase, also known as CAT family for its conserved catalytic site motif and proximal heme-ligand signature motif. Real time fluorescence quantitative PCR showed that constitutive expression of McCAT was occurred, with increasing order in mantle, adductor, gill, hemocyte, gonad and hepatopancreas. It was observed that bacterial infection and heavy metals stimulation up-regulated McCAT mRNA expression in hepatopancreas with time dependent manners. The maximum expression appeared at 8h after pathogenic bacteria injecting, with 15-fold in Vibrio parahemolyticus and 60-fold in Aeromonas hydrophila than that of 0h. The highest point of McCAT mRNA appeared at different times for exposure to heavy metals with copper at day 5 (0.1mg/L 30 fold, 0.5mg/L 15-fold, 1.5mg/L 6-fold) and plumbum at day 3 (3.0mg/L 20-fold). The enzymatic activity analysis found that McCAT activity in the gill of M. coruscus was affected by heavy metals concentration. The results suggested that McCAT plays a significant role in antioxidation and the expression of McCAT can be used as a biomarker for detection of marine environmental pollution. PMID- 29475716 TI - Functional diversity of benthic ciliate communities in response to environmental gradients in a wetland of Yangtze Estuary, China. AB - Researches on the functional diversity of benthic ecosystems have mainly focused on macrofauna, and studies on functional structure of ciliate communities have been based only on trophic- or size-groups. Current research was carried out on the changing patterns of classical and functional diversity of benthic ciliates in response to environmental gradients at three sites in a wetland in Yangtze Estuary. The results showed that changes of environmental factors (e.g. salinity, sediment grain size and hydrodynamic conditions) in the Yangtze Estuary induce variability in species composition and functional trait distribution. Furthermore, increased species richness and diversity did not lead to significant changes in functional diversity due to functional redundancy. However, salt water intrusion of Yangtze Estuary during the dry season could cause reduced functional diversity of ciliate communities. Current study provides the first insight into the functional diversity of ciliate communities in response to environmental gradients. PMID- 29475717 TI - Concentrations of selected radionuclides and their spatial distribution in marine sediments from the northwestern Gulf, Kuwait. AB - This study focuses on creating a baseline for 40K, 210Pb, 137Cs, 90Sr, 226Ra, 228Ra, 238U, 235U, 234U, 239+240Pu and 238Pu in marine sediments in the northwestern Gulf. The respective measured concentration ranges were 386-489, 32.3-48.8, 1.5-2.9, 4.53-5.42, 18.3-23.1, 18.8-23.0, 22.3-30.5, 0.99-1.33, 25.6 34.8, 0.30-0.93, and 0.0008-0.00018Bqkg-1. The levels of these radionuclides are generally comparable to values reported for other marine waters in the northern hemisphere. The 137Cs activity in the Gulf sediments offshore Kuwait is an order of magnitude lower compared to sediments from northeastern Iran. Other than that finding, no hot spots were observed in sediments adjacent to power and desalination plants, oil and gas industrial activities or wastewater treatment facilities. These data will serve as a baseline to gauge possible future inputs of radionuclides in the northern Gulf. The calculated average ratio of 235U/238U activity in the area is in agreement with the reported figure of the natural uranium ratio, suggesting the absence of depleted uranium (DU) at all the stations. The low concentration of 239+240Pu suggests that there is no significant source of plutonium except that from atmospheric fallout from weapon testing and possible dry deposition via long-range dust transport. PMID- 29475718 TI - Addressing the impact of mercury estuarine contamination in the European eel (Anguilla anguilla L., 1758) - An early diagnosis in glass eel stage based on erythrocytic nuclear morphology. AB - The decline of the European eel (Anguilla anguilla L., 1758) population throughout Europe has been partially attributed to pollution. As glass eel estuarine migration may represent a considerable threat, the impact of mercury (Hg) contamination at this stage was evaluated through an in situ experiment (7days). Total Hg (tHg) bioaccumulation was evaluated concomitantly with erythrocytic nuclear morphology alterations: erythrocytic nuclear abnormalities assay (ENA), frequency of immature erythrocytes (IE) and the erythrocytic maturity index (EMI). The ENA results suggested a genotoxic pressure at the most contaminated sites, in line with the tHg increase. The EMI data, together with IE frequency, showed that fish exposed to high levels of Hg exhibited alterations of haematological dynamics, translated into an erythropoiesis increment. Despite the presence of these compensatory mechanisms, the present findings suggest a harmful impact of Hg on genome integrity at this early development stage, potentially affecting eels' condition and ultimately the population sustainability. PMID- 29475719 TI - Ingestion of microplastic debris by green sea turtles (Chelonia mydas) in the Great Barrier Reef: Validation of a sequential extraction protocol. AB - Ocean contamination by plastics is a global issue. Although ingestion of plastic debris by sea turtles has been widely documented, contamination by microplastics (<5mm) is poorly known and likely to be under-reported. We developed a microplastic extraction protocol for examining green turtle (Chelonia mydas) chyme, which is multifarious in nature, by modifying and combining pre established methods used to separate microplastics from organic matter and sediments. This protocol consists of visual inspection, nitric acid digestion, emulsification of residual fat, density separation, and chemical identification by Fourier transform infrared spectroscopy. This protocol enables the extraction of polyethylene, high-density polyethylene, (aminoethyl) polystyrene, polypropylene, and polyvinyl chloride microplastics >100MUm. Two macroplastics and seven microplastics (two plastic paint chips and five synthetic fabric particles) were isolated from subsamples of two green turtles. Our results highlight the need for more research towards understanding the impact of microplastics on these threatened marine reptiles. PMID- 29475720 TI - Three-dimensional hydrodynamic modelling study of reverse estuarine circulation: Kuwait Bay. AB - Hydrodynamics and associated environmental processes have always been of major concern to coastal-dependent countries, such as Kuwait. This is due to the environmental impact that accompanies the economic and commercial activities along the coastal areas. In the current study, a three-dimensional numerical model is utilized to unveil the main dynamic and physical properties of Kuwait Bay during the critical season. The model performance over the summer months (June, July and August 2012) is assessed against comprehensive field measurements of water levels, velocity, temperature and salinity data before using the model to describe the circulation as driven by tides, gravitational convection and winds. The results showed that the baroclinic conditions in the Bay are mainly determined by the horizontal salinity gradient and to much less extent temperature gradient. The gradients stretched over the southern coast of the Bay where dense water is found at the inner and enclosed areas, while relatively lighter waters are found near the mouth of the Bay. This gradient imposed a reversed estuarine circulation at the main axis of the Bay, particularly during neap tides when landward flow near the surface and seaward flow near the bed are most evident. The results also revealed that the shallow areas, including Sulaibikhat and Jahra Bays, are well mixed and generally flow in the counter clockwise direction. Clockwise circulations dominated the northern portion of the Bay, forming a sort of large eddy, while turbulent fields associated with tidal currents were localized near the headlands. PMID- 29475721 TI - A cross-taxa study using environmental DNA/RNA metabarcoding to measure biological impacts of offshore oil and gas drilling and production operations. AB - Standardized ecosystem-based monitoring surveys are critical for providing information on marine ecosystem health. Environmental DNA/RNA (eDNA/eRNA) metabarcoding may facilitate such surveys by quickly and effectively characterizing multi-trophic levels. In this study, we assessed the suitability of eDNA/eRNA metabarcoding to evaluate changes in benthic assemblages of bacteria, Foraminifera and other eukaryotes along transects at three offshore oil and gas (O&G) drilling and production sites, and compared these to morphologically characterized macro-faunal assemblages. Bacterial communities were the most responsive to O&G activities, followed by Foraminifera, and macro fauna (the latter assessed by morphology). The molecular approach enabled detection of hydrocarbon degrading taxa such as the bacteria Alcanivorax and Microbulbifer at petroleum impacted stations. Most identified indicator taxa, notably among macro-fauna, were highly specific to site conditions. Based on our results we suggest that eDNA/eRNA metabarcoding can be used as a stand-alone method for biodiversity assessment or as a complement to morphology-based monitoring approaches. PMID- 29475722 TI - Predicting early relapse in follicular lymphoma: have we turned a corner? PMID- 29475723 TI - Umbralisib, a novel PI3Kdelta and casein kinase-1epsilon inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study. AB - BACKGROUND: Umbralisib (TGR-1202) is a novel next-generation inhibitor of phosphatidylinositol 3-kinase (PI3K) isoform p110delta (PI3Kdelta), which is structurally distinct from other PI3Kdelta inhibitors and shows improved isoform selectivity. Umbralisib also uniquely inhibits casein kinase-1epsilon, a major regulator of protein translation. The aim of this first-in-human phase 1 study was to establish the safety and preliminary activity profile of umbralisib in patients with haematological malignancies. METHODS: We did an open-label, phase 1, dose-escalation study at seven clinics in the USA. We recruited patients aged at least 18 years with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, B-cell and T-cell non-Hodgkin lymphoma, or Hodgkin's lymphoma, who had received one or more previous lines of therapy, with measurable and assessable disease, and adequate organ system function. Patients self administered an umbralisib oral tablet once per day in 28-day cycles, with dose escalation done in a traditional 3 + 3 design to establish safety and determine the maximum tolerated dose. In initial cohorts, patients took umbralisib in a fasting state at a starting dose of 50 mg, increasing to 100, 200, 400, 800, 1200, and 1800 mg until the maximum tolerated dose was reached, or the maximal dose cohort was accrued without a dose-limiting toxicity. Subsequent cohorts self administered a micronised formulation of umbralisib tablet in a fed state at an initial dose of 200 mg, increased in increments to 400, 800, 1200, and 1800 mg until the maximum tolerated dose or the maximal dose level was accrued. In August, 2014, all patients still on study were transitioned to 800 mg of the micronised formulation and dosing of the initial formulation was discontinued. The primary endpoints of the study were investigator-assessed safety in all treated patients (the safety population), the maximum tolerated dose, and the pharmacokinetics of umbralisib. Secondary endpoints included preliminary assessments of anti-cancer activity (objective responses and duration of response). Follow-up stopped for a patient once they discontinued therapy. This study has been completed and is registered with ClinicalTrials.gov, number NCT01767766. FINDINGS: Between Jan 17, 2013, and Jan 14, 2016, we enrolled and treated 90 patients with umbralisib. The median duration of treatment and follow up was 4.7 cycles (IQR 2.0-14.0) or 133 days (IQR 55-335). The most common treatment-emergent adverse events irrespective of causality were diarrhoea (in 39 [43%] of 90 patients), nausea (38 [42%]), and fatigue (28 [31%]). The most common grade 3 or 4 adverse events were neutropenia (in 12 [13%] patients), anaemia (eight [9%]) and thrombocytopenia (six [7%]). Serious adverse events considered at least possibly related to umbralisib occurred in seven patients: pneumonia in three (3%) patients, lung infection in one (1%), febrile neutropenia in one (1%), and colitis in two (2%), one of whom also had febrile neutropenia. The maximum tolerated dose was 1200 mg of the micronised formulation, with 800 mg of this formulation selected as the recommended phase 2 dose. Both cases of colitis occurred at above the recommended phase 2 dose. 33 (37%) of the 90 patients enrolled had an objective response to treatment with umbralisib. INTERPRETATION: Umbralisib was well tolerated and showed preliminary signs of activity in patients with relapsed or refractory haematological malignancies. The safety profile of umbralisib in this phase 1 study was distinct from that of other PI3Kdelta inhibitors, with fewer occurrences of autoimmune-like toxicities such as colitis. These findings warrant further evaluation of this agent in this setting. FUNDING: TG Therapeutics. PMID- 29475725 TI - Can umbralisib bring PI3Kdelta out of the shadows? PMID- 29475726 TI - Respecting the 'stages' of depression: Considering depression severity and readiness to seek help. AB - OBJECTIVE: Despite knowing the value of message customization, empirical results have failed to provide clear indicators of what make a depression help-seeking message effective. The present research examines stages of depression in response to a prominent communication strategy, gain versus loss framing, to inform possibilities for effective message customization. METHODS: Two experimental studies were conducted with a student (N = 126) and U.S. adult (N = 738) sample that tested the effects of gain versus loss framing at different stages of depression. RESULTS: A persuasive gain-frame advantage was found for those with mild and severe depression, whereas a boomerang effect was found for both gain and loss framing among those with moderately severe depression. With regards to intention to seek help, neither gain nor loss framing was found to influence intentions. Stages of depression was a strong predictor, with strongest intentions to seek help observed among those with either minor or severe symptoms of depression. CONCLUSION: Effective health messaging must be matched with unique characteristics and needs of individuals at each 'stage' of depression in order to produce favorable outcomes. PRACTICE IMPLICATIONS: 'Stages' of depression should be known and carefully assessed before the creation and launch of communication interventions. PMID- 29475724 TI - A gene-expression profiling score for prediction of outcome in patients with follicular lymphoma: a retrospective training and validation analysis in three international cohorts. AB - BACKGROUND: Patients with follicular lymphoma have heterogeneous outcomes. Predictor models to distinguish, at diagnosis, between patients at high and low risk of progression are needed. The objective of this study was to use gene expression profiling data to build and validate a predictive model of outcome for patients treated in the rituximab era. METHODS: A training set of fresh-frozen tumour biopsies was prospectively obtained from 160 untreated patients with high tumour-burden follicular lymphoma enrolled in the phase 3 randomised PRIMA trial, in which rituximab maintenance was evaluated after rituximab plus chemotherapy induction (median follow-up 6.6 years [IQR 6.0-7.0]). RNA of sufficient quality was obtained for 149 of 160 cases, and Affymetrix U133 Plus 2.0 microarrays were used for gene-expression profiling. We did a multivariate Cox regression analysis to identify genes with expression levels associated with progression-free survival independently of maintenance treatment in a subgroup of 134 randomised patients. Expression levels from 95 curated genes were then determined by digital expression profiling (NanoString technology) in 53 formalin-fixed paraffin embedded samples of the training set to compare the technical reproducibility of expression levels for each gene between technologies. Genes with high correlation (>0.75) were included in an L2-penalised Cox model adjusted on rituximab maintenance to build a predictive score for progression-free survival. The model was validated using NanoString technology to digitally quantify gene expression in 488 formalin-fixed, paraffin-embedded samples from three independent international patient cohorts from the PRIMA trial (n=178; distinct from the training cohort), the University of Iowa/Mayo Clinic Lymphoma SPORE project (n=201), and the Barcelona Hospital Clinic (n=109). All tissue samples consisted of pretreatment diagnostic biopsies and were confirmed as follicular lymphoma grade 1-3a. The patients were all treated with regimens containing rituximab and chemotherapy, possibly followed by either rituximab maintenance or ibritumomab tiuxetan consolidation. We determined an optimum threshold on the score to predict patients at low risk and high risk of progression. The model, including the multigene score and the threshold, was initially evaluated in the three validation cohorts separately. The sensitivity and specificity of the score for the prediction of the risk of lymphoma progression at 2 years were assessed on the combined validation cohorts. FINDINGS: In the training cohort, the expression levels of 395 genes were associated with a risk of progression. 23 genes reflecting both B-cell biology and tumour microenvironment with correlation coefficients greater than 0.75 between the two technologies and sample types were retained to build a predictive model that identified a population at an increased risk of progression (p<0.0001). In a multivariate Cox model for progression-free survival adjusted on rituximab maintenance treatment and Follicular Lymphoma International Prognostic Index 1 (FLIPI-1) score, this predictor independently predicted progression (adjusted hazard ratio [aHR] of the high-risk group compared with the low-risk group 3.68, 95% CI 2.19-6.17 [p<0.0001]). The 5-year progression-free survival was 26% (95% CI 16-43) in the high-risk group and 73% (64-83) in the low-risk group. The predictor performances were confirmed in each of the individual validation cohorts (aHR comparing high-risk to low-risk groups 2.57 [95% CI 1.65-4.01] in cohort 1; 2.12 [1.32-3.39] in cohort 2; and 2.11 [1.01 4.41] in cohort 3). In the combined validation cohort, the median progression free survival was 3.1 years (95% CI 2.4-4.8) in the high-risk group and 10.8 years (10.1-not reached) in the low-risk group (p<0.0001). The risk of lymphoma progression at 2 years was 38% (95% CI 29-46) in the high-risk group and 19% (15 24) in the low-risk group. In a multivariate analysis, the score predicted progression-free survival independently of anti-CD20 maintenance treatment and of the FLIPI score (aHR for the combined cohort 2.30, 95% CI 1.72-3.07). INTERPRETATION: We developed and validated a robust 23-gene expression-based predictor of progression-free survival that is applicable to routinely available formalin-fixed, paraffin-embedded tumour biopsies from patients with follicular lymphoma at time of diagnosis. Applying this score could allow individualised therapy for patients according to their risk category. FUNDING: Roche, SIRIC Lyric, LYSARC, National Institutes of Health, the Henry J Predolin Foundation, and the Spanish Plan Nacional de Investigacion. PMID- 29475727 TI - Limited mobility of dioxins near San Jacinto super fund site (waste pit) in the Houston Ship Channel, Texas due to strong sediment sorption. AB - Sediments from a waste pit in Houston Ship Channel (HSC) were characterized using a number of molecular markers of natural organic matter fractions (e.g., pyrogenic carbon residues, PAHs, lignins), in addition to dioxins, in order to test the hypothesis that the dispersal and mobility of dioxins from the waste pit in the San Jacinto River is minimal. Station SG-6, sampled at the site of the submerged waste pit, had the highest dioxin/furan concentrations reported for the Houston Ship Channel/Galveston Bay (HSC/GB) system (10,000-46,000 pg/g), which translated into some of the highest reported World Health Organization Toxic Equivalents (TEQs: 2000-11,000 pg/g) in HSC sediments. Using a multi-tracer approach, this study confirmed our hypothesis that sludges from chlorinated pulps are a very likely source of dioxins/furans to this pit. However, this material also contained large quantities of additional hydrophobic organic contaminants (PAHs) and pyrogenic markers (soot-BC, levoglucosan), pointing to the co occurrence of petroleum hydrocarbons and combustion byproducts. Comparison of dioxin/furan signatures in the waste pit with those from sediments of the HSC and a control site suggests that the remobilization of contaminated particles did not occur beyond the close vicinity of the pit itself. The dioxins/furans in sediments outside the waste pit within the HSC are rather from other diffuse inputs, entering the sedimentary environment through the air and water, and which are comprised of a mixture of industrial and municipal sources. Fingerprinting of waste pit dioxins indicates that their composition is typical of pulp and paper sources. Measured pore water concentrations were 1 order of magnitude lower than estimated values, calculated from a multiphase sorption model, indicating low mobility of dioxins within the waste pit. This is likely accomplished by co occurring and strong sorbing pyrogenic and petrogenic residues in the waste pit, which tend to keep dioxins strongly sorbed to particles. PMID- 29475728 TI - An alternative static progressive orthosis for forearm pronation and supination. PMID- 29475729 TI - Evaluating Community Pharmacy Responses About Levonorgestrel Emergency Contraception by Mystery Caller Characteristics. AB - PURPOSE: Since restrictions on nonprescription sales were removed in 2013, levonorgestrel emergency contraception (EC) should be available without a prescription at pharmacies for consumers of all genders and ages. Using mystery callers, we assessed variations in availability of and access to EC. METHODS: In 2015-2016, three sets of mystery callers (two female physicians, two adolescent females, and two adolescent males) each called all licensed retail pharmacies in five U.S. cities using standardized call scripts. Scripts assessed same-day availability and subsequent access to EC for 17-year-olds. Data on various characteristics of calls were collected and compared by caller type. RESULTS: Among the 993 pharmacies called, same-day availability for EC was approximately 80%, with no differences by caller types (p = .34). However, 10.7% of calls made by the adolescent male caller and 8.3% made by the adolescent female caller resulted in incorrectly being told they could not obtain EC based on age, compared to only 1.6% of calls made by the physician (p < .01). Pharmacy staff stated correctly that EC was available over-the-counter more often to adolescent male callers (62.0%) than adolescent females (51.6%) or female physicians (57%) (p < .01). Physicians were more likely to be placed on hold, talk to a pharmacist, or be transferred to a pharmacist (p < .01) than adolescents. CONCLUSIONS: Persistent barriers to accessing EC exist for adolescents despite regulatory changes to make EC available over-the-counter, especially for females. Additional work to remove these barriers is needed to assure timely access for those who require effective pregnancy prevention. PMID- 29475730 TI - Evaluation of the use of various rat strains for immunogenic potency tests of Sabin-derived inactivated polio vaccines. AB - Slc:Wistar rats have been the only strain used in Japan for purpose of evaluating a national reference vaccine for the Sabin-derived inactivated polio vaccine (sIPV) and the immunogenicity of sIPV-containing products. However, following the discovery that the Slc:Wistar strain was genetically related to the Fischer 344 strain, other "real" Wistar strains, such as Crlj:WI, that are available worldwide were tested in terms of their usefulness in evaluating the immunogenicity of the past and current lots of a national reference vaccine. The response of the Crlj:WI rats against the serotype 1 of sIPV was comparable to that of the Slc:Wistar rats, while the Crlj:WI rats exhibited a higher level of response against the serotypes 2 and 3. The immunogenic potency units of a national reference vaccine determined using the Slc:Wistar rats were reproduced on tests using the Crlj:WI rats. These results indicate that a titer of the neutralizing antibody obtained in response to a given dose of sIPV cannot be directly compared between these two rat strains, but that, more importantly, the potency units are almost equivalent for the two rat strains. PMID- 29475731 TI - [Adjuvant contact radiotherapy for conjunctival malignancies: Preliminary results of a series of 14 patients treated with the Papillon 50 machine]. AB - PURPOSE: To evaluate the results of an adjuvant contact irradiation using 50kV photons after resection of conjunctival malignancies. MATERIALS AND METHOD: From 2012 to 2014, 14 patients (male: nine; female: five) have been treated by contact irradiation after resection of a malignant tumor of the conjunctiva (melanoma: five patients; malignant fibrous histiocytoma: one patient; carcinoma: eight patients) The treatment was performed using the Papillon 50 machine (Ariane). Three to four sessions were delivered, each giving a dose of 10Gy. The median follow-up in survivors was 33 months. RESULTS: The tolerance was good. A cataract was seen in one patient, and a moderate eye dryness in one. There was no corneal ulcer. One patient died of intercurrent disease. One patient with carcinoma recurred locally. CONCLUSION: Adjuvant contact radiotherapy provides a good local control after resection of conjunctival malignancies (melanoma, malignant histiocytofibroma, carcinoma). Thanks to its precision, this technique is well tolerated with a low rate of complications. Furthermore, it is delivered on an ambulatory basis. PMID- 29475732 TI - The Time Is Ripe for Somatic Genome Editing: NIH Program to Strengthen Translation. PMID- 29475733 TI - Decoy-Based, Targeted Inhibition of STAT3: A New Step forward for B Cell Lymphoma Immunotherapy. PMID- 29475734 TI - miR-145 Antagonizes SNAI1-Mediated Stemness and Radiation Resistance in Colorectal Cancer. AB - Epithelial-to-mesenchymal transition (EMT) has been closely linked with therapy resistance and cancer stem cells (CSCs). However, EMT pathways have proven challenging to therapeutically target. MicroRNA 145 (miR-145) targets multiple stem cell transcription factors and its expression is inversely correlated with EMT. Therefore, we hypothesized that miR-145 represents a therapeutic target to reverse snail family transcriptional repressor 1 (SNAI1)-mediated stemness and radiation resistance (RT). Stable expression of SNAI1 in DLD1 and HCT116 cells (DLD1-SNAI1; HCT116-SNAI1) increased expression of Nanog and decreased miR-145 expression compared to control cells. Using a miR-145 luciferase reporter assay, we determined that ectopic SNAI1 expression significantly repressed the miR-145 promoter. DLD1-SNAI1 and HCT116-SNAI1 cells demonstrated decreased RT sensitivity and, conversely, miR-145 replacement significantly enhanced RT sensitivity. Of the five parental colon cancer cell lines, SW620 cells demonstrated relatively high endogenous SNAI1 and low miR-145 levels. In the SW620 cells, miR-145 replacement decreased CSC-related transcription factor expression, spheroid formation, and radiation resistance. In rectal cancer patient-derived xenografts, CSC identified by EpCAM+/aldehyde dehydrogenase (ALDH)+ demonstrated high expression of SNAI1, c-Myc, and Nanog compared with non-CSCs (EpCAM+/ALDH-). Conversely, patient-derived CSCs demonstrated low miR-145 expression levels relative to non-CSCs. These results suggest that the SNAI1:miR-145 pathway represents a novel therapeutic target in colorectal cancer to overcome RT resistance. PMID- 29475735 TI - Interactive effect of temperature, acidification and ammonium enrichment on the seagrass Cymodocea nodosa. AB - Global (e.g. climate change) and local factors (e.g. nutrient enrichment) act together in nature strongly hammering coastal ecosystems, where seagrasses play a critical ecological role. This experiment explores the combined effects of warming, acidification and ammonium enrichment on the seagrass Cymodocea nodosa under a full factorial mesocosm design. Warming increased plant production but at the expense of reducing carbon reserves. Meanwhile, acidification had not effects on plant production but increased slightly carbon reserves, while a slight stimulation of net production and a slight decrease on carbon reserves under ammonium supply were recorded. When all the factors were combined together improved the production and carbon reserves of Cymodocea nodosa, indicating that acidification improved ammonium assimilation and buffered the enhanced respiration promoted by temperature. Therefore, it could indicate that this temperate species may benefit under the simulated future scenarios, but indirect effects (e.g. herbivory, mechanical stress, etc.) may counteract this balance. PMID- 29475736 TI - Re: Duration of Urethral Catheterization After Urethroplasty: How Long Is Enough? PMID- 29475738 TI - The Risks of Theft and Copyright Breach from Camera Use During Scientific Presentations: It's Time for a Debate. AB - Photographs are frequently taken during urological presentations and distributed on social media; they may represent a breach of copyright and, in instances of clinical photographs, a breach of data protection and human rights laws. Presenters and delegates attending conferences should be advised of the conference's copyright policies. Acceptable use of camera phones during scientific presentations should be debated by the scientific community. PMID- 29475737 TI - Burden of Metastatic Castrate Naive Prostate Cancer Patients, to Identify Men More Likely to Benefit from Early Docetaxel: Further Analyses of CHAARTED and GETUG-AFU15 Studies. AB - BACKGROUND: Docetaxel (D) at the time of starting androgen deprivation therapy (ADT) for metastatic castrate naive prostate cancer shows a clear survival benefit for patients with high-volume (HV) disease. It is unclear whether patients with low-volume (LV) disease benefit from early D. OBJECTIVE: To define the overall survival (OS) of aggregate data of patient subgroups from the CHAARTED and GETUG-AFU15 studies, defined by metastatic burden (HV and LV) and time of metastasis occurrence (at diagnosis or after prior local treatment [PRLT]). DESIGN, SETTING, AND PARTICIPANTS: Data were accessed from two independent phase III trials of ADT alone or ADT+D-GETUG-AFU15 (N=385) and CHAARTED (N=790), with median follow-ups for survivors of 83.2 and 48.2 mo, respectively. The definition of HV and LV disease was harmonized. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary end point was OS. RESULTS AND LIMITATIONS: Meta-analysis results of the aggregate data showed significant heterogeneity in ADT+D versus ADT effect sizes between HV and LV subgroups (p=0.017), and failed to detect heterogeneity in ADT+D versus ADT effect sizes between upfront and PRLT subgroups (p=0.4). Adding D in patients with HV disease has a consistent effect in improving median OS (HV-ADT: 34.4 and 35.1 mo, HV ADT+D: 51.2 and 39.8 mo in CHAARTED and GETUG-AFU15, respectively; pooled average hazard ratio or HR (95% confidence interval [CI]) 0.68 ([95% CI 0.56; 0.82], p<0.001). Patients with LV disease showed much longer OS, without evidence that D improved OS (LV-ADT: not reached [NR] and 83.4; LV-ADT+D: 63.5 and NR in CHAARTED and GETUG-AFU15, respectively; pooled HR (95% CI) 1.03 (95% CI 0.77; 1.38). Aggregate data showed no evidence of heterogeneity of early D in LV and HV subgroups irrespective of whether patients had PRLT or not. Post hoc subgroup analysis was based on aggregated data from two independent phase III randomized trials. CONCLUSIONS: There was no apparent survival benefit in the CHAARTED and GETUG-AFU15 studies with D for LV. Across both studies, early D showed consistent effect and improved OS in HV patients. PATIENT SUMMARY: Patients with a higher burden of metastatic prostate cancer starting androgen deprivation therapy (ADT) have a poorer prognosis and are more likely to benefit from early docetaxel. Low volume patients have longer overall survival with ADT alone, and the toxicity of docetaxel may outweigh its benefits. PMID- 29475739 TI - Hospital centralization and performance in Denmark-Ten years on. AB - Denmark implemented a major reform of the administrative and political structure in 2007 when the previous 13 counties were merged into five new regions and the number of municipalities was reduced from 271 to 98. A main objective was to create administrative units that were large enough to support a hospital structure with few acute hospitals in each region and to centralize specialized care in fewer hospitals. This paper analyses the reorganization of the somatic hospital sector in Denmark since 2007, discusses the mechanisms behind the changes and analyses hospital performance after the reform. The reform focused on improving acute services and quality of care. The number of acute hospitals was reduced from about 40-21 hospitals with new joint acute facilities, which include emergency care wards. The restructuring and geographical placement of acute hospitals took place in a democratic process subject to central guidelines and requirements. Since the reform, hospital productivity has increased by more than 2 per cent per year and costs have been stable. Overall, indicators point to a successful reform. However, it has also been criticized that some people in remote areas feel "left behind" in the economic development and that hospital staff are under increased workload pressure. Concurrent with the centralization of hospitals municipalities strengthened their health service with an emphasis on prevention and health promotion. PMID- 29475740 TI - Implementing the medicines reconciliation tool in practice: challenges and opportunities for pharmacists in Kuwait. AB - BACKGROUND: Using the medicines reconciliation tool which involves preparing an updated list of patient's medications at each transition of care can significantly enhance patient safety. The pharmacist has been leading this process in western healthcare systems. Little is known about pharmacists' role in medicines reconciliation in Middle Eastern Countries. OBJECTIVES: To explore the implementation of medicines reconciliation in Kuwait hospitals, pharmacists' role in this process and perceptions of the challenges in implementing it in practice. METHODS: This was an exploratory descriptive study of medicines reconciliation practices at eleven secondary/tertiary hospitals in Kuwait. A mixed-methods research design was used whereby 110 hospital pharmacists participated in 11 focus groups and 88 of them completed self-administered surveys. RESULTS: Participants reported that medicines reconciliation is poorly applied in hospitals and that they had limited role in the process. The current medicines reconciliation policy does not assign any responsibilities for pharmacists in this process. The most significant barriers to applying medicines reconciliation by pharmacists were inadequate staff numbers, lack of time, difficult access to patient information, lack of policy to support pharmacist role and patients' poor knowledge about their medications. CONCLUSIONS: Hospital pharmacists in Kuwait advocate implementing medicines reconciliation but report significant strategic/operational barriers to its application. Efforts are needed in policy reform and team training to enable pharmacists provide effective patient care services including medicines reconciliation. PMID- 29475741 TI - Evolved Dependence in Response to Cancer. AB - Evolved dependence is a process through which one species becomes 'dependent' on another following a long evolutionary history of interaction. This happens when adaptations selected in the first species for interacting lead to fitness costs when the second species is not encountered. Evolved dependence is frequent in host-parasite interactions, where hosts may achieve a higher fitness in the presence of the parasite than in its absence. Since oncogenic manifestations are (i) ubiquitous across multicellular life, (ii) involved in parasitic-like interactions with their hosts, and (iii) have effectively driven the selection of numerous adaptations, it is possible that multicellular organisms display evolved dependence in response to oncogenic processes. We provide a comprehensive overview of the topic, including the implications for cancer prevention and treatment. PMID- 29475742 TI - Redescription of the adult stages of Ixodes (Afrixodes) rasus Neumann 1899, with notes on its phylogenetic position within the genus Ixodes. AB - The tick subgenus Afrixodes Morel 1966 (Ixodidae) is distributed in sub-Saharan Africa. It consists of about 60 species which are described based on a few specimens and/or only some developmental stages, mostly adults. Because of this, the diagnosis of the African species of Ixodes is in many aspects complicated. Ixodes rasus Neumann 1899 is a common species, widely distributed in tropical and subtropical moist broadleaved forests in central Africa, whose morphology remains poorly described. We redescribe the adults of the species and provide molecular data for 16S rDNA based on three questing females and one male collected in the Central African Republic. Both sexes have an anal groove rounded and closed. The female has syncoxae on coxae I to III, a dental formula of 2/2, and long, curved auriculae. The male has moderate syncoxae on coxae I-III, coxae I-II carry one single internal spur each: coxae III and IV unarmed. The cornua are absent in the male, and the auriculae are small lobes. The male pregenital plate is longer than broad, with an anterior margin widely rounded; the median plate is large and clearly divergent posteriorly, with adanal plates fused posteriorly to the anus, and a dental formula of 4/4 (one row of 5/5). The molecular features of 16S rDNA place I. rasus near I. aulacodi (the only other Afrixodes species for which 16S rDNA is available) and near I. turdus and I. frontalis; two species of ticks of the Palearctic region, which commonly infest birds. The paucity of data regarding the subgenus Afrixodes makes it necessary to provide reliable and comparable re descriptions of several species, as well as description of the immature stages for many of the currently known taxa. PMID- 29475743 TI - Environmental factors influencing the distribution of "Theileria annae" in red foxes, Vulpes vulpes in Romania. AB - Red foxes, Vulpes vulpes are among the most widely spread carnivores in the world, invading also urban areas and are often parasitized by various ticks and directly exposed to several vector-borne pathogens, including the commonly present "Theileria annae". Considering the paucity of data on the possible vectors of this pathogen and the presence of the infection in various locations across the globe, the aim of our study was to understand the potential role of various environmental factors on the distribution of "T. annae" in red foxes from a well-defined region within the Carpathians, Romania. Between July 2016 and April 2017, a total of 347 blood samples originating from red foxes from 13 counties were tested using a PCR specifically designed for "T. annae". In order to assess the potential distribution of "T. annae" based on niche modelling, we used presence-only data and 15 ecological variables. The probability of presence models was built using MaxEnt software. Of all sampled foxes, 20.1% (66 unique locations in 8 counties) were positive for "T. annae" DNA. There was no significant difference between the prevalence in males and females, nor between juveniles and adults. The sequences were all identical to each other and showed 100% identity to other sequences deposited in GenBank. The highest contribution to the spatial model was represented by the agricultural land coverage. This is the first study to demonstrate the presence of "T. annae" in foxes in Romania and the first spatial analysis for "T. annae" highlighting the importance of the environmental factors on its distribution. PMID- 29475744 TI - Rethinking burns for low & middle-income countries: Differing patterns of burn epidemiology, care seeking behavior, and outcomes across four countries. AB - PURPOSE: Low-and middle-income (LMIC) countries account for 90% of all reported burns, nevertheless there is a paucity of providers to treat burns. Current studies on burns in LMICs have not evaluated the gap between care seeking and receiving. This study explores this gap across socioeconomically similar populations in a multi-country population based assessment to inform burn care strategies. METHODS: The Surgeons OverSeas Assessment of Surgical Need (SOSAS) instrument is a cross sectional national, cluster random sampling survey administered in Nepal, Rwanda, Sierra Leone, and Uganda from 2011 to 2014. The survey identifies burn etiology, demographics, timing, disability, and barriers to receiving care. RESULTS: Among 13,763 individuals surveyed, 896 burns were identified. Rwanda had the highest proportion of individuals seeking and receiving care (91.6% vs 88.5%) while Sierra Leone reported the fewest (79.3% vs 70.3%). Rwanda reported the largest disability while Nepal reported the highest proportion with no disability (47.5% vs 76.2%). Lack of money, healthcare providers, and rural living reduce the odds of receiving care by 68% and 85% respectively. CONCLUSIONS: Despite similar country socioeconomic characteristics there was significant variability in burn demographics, timing, and disability. Nevertheless, being geographically and economically disadvantaged predict lack of access to burn care. PMID- 29475745 TI - Validation of the burn intervention score in a National Burn Centre. AB - The Linkoping burn score has been used for two decades to calculate the cost to the hospital of each burned patient. Our aim was to validate the Burn Score in a dedicated Burn Centre by analysing the associations with burn-specific factors: percentage of total body surface area burned (TBSA%), cause of injury, patients referred from other (non-specialist) centres, and survival, to find out which of these factors resulted in higher scores. Our second aim was to analyse the variation in scores of each category of care (surveillance, respiration, circulation, wound care, mobilisation, laboratory tests, infusions, and operation). We made a retrospective analysis of all burned patients admitted during the period 2000-15. Multivariable regression models were used to analyse predictive factors for an increased daily burn score, the cumulative burn score (the sum of the daily burn scores for each patient) and the total burn score (total sum of burn scores for the whole group throughout the study period) in addition to sub-analysis of the different categories of care that make up the burn score. We retrieved 22301 daily recordings for inpatients. Mobilisation and care of the wound accounted for more than half of the total burn score during the study. Increased TBSA% and age over 45 years were associated with increased cumulative (model R2 0.43, p<0.001) and daily (model R2 0.61, p<0.001) burn scores. Patients who died had higher daily burn scores, while the cumulative burn score decreased with shorter duration of hospital stay (p<0.001). To our knowledge this is the first long term analysis and validation of a system for scoring burn interventions in patients with burns that explores its association with the factors important for outcome. Calculations of costs are based on the score, and it provides an indicator of the nurses' workload. It also gives important information about the different dimensions of the care provided from thorough investigation of the scores for each category. PMID- 29475746 TI - From skin allograft coverage to allograft-micrograft sandwich method: A retrospective review of severe burn patients who received conjunctive application of cultured epithelial autografts. AB - A 12-year retrospective review of severe burn patients who received cultured epithelial autografts (CEA) at the Singapore General Hospital Burns Centre from January 2005 to December 2016 was carried out. During this period, two different surgical modalities were employed to manage these burn injuries. In the earlier period, following early excision of the burn wounds, exposed surfaces were covered with a combination of split thickness skin autografts (STSG) and allografts. Surfaces covered with skin allografts were subsequently debrided of the allo-epidermis in about 3 weeks later, exposing the allodermis with granulating tissues for grafting of CEA; a technique known as the Cuono's method. In the later period, allograft-autologous micrograft sandwich technique was used to graft on the early excised burns with subsequent CEA grafting. The former and latter groups represented by STSG/C (n=10) and M/CEA (n=14) respectively, were compared in terms of clinical profiles, outcomes, allograft/CEA usage and total graft cost. No significant differences were found based on mean age and presence of inhalation burns between the two treatment methods However, percentage total body surface area (TBSA) and Revised Baux Score were significantly higher (p<0.05) in the M/CEA group compared to the STSG/C group. Differences in clinical outcomes of mortality and length of hospital stay between the 2 groups were statistically insignificant. The average area amount of skin allografts used per patient in the M/CEA group was significantly lower compared to the STSG/C method group which contributed to lower total average cost of grafts used per % TBSA in the M/CEA method group. This might be attributed to the presence of micrografts which seemed to improve stabilization of the wound bed resulting in less operating procedures and improving CEA take. To conclude, the M/CEA method introduced was able to treat more severe burn patients at lower graft costs without compromising critical clinical outcomes significantly. PMID- 29475748 TI - Laparoscopic Heller myotomy. PMID- 29475747 TI - Dasatinib-induced immune mediated-thrombotic thrombocytopenic purpura. AB - Most commonly seen side effects with Tyrosine kinase inhibitors (TKI's) are hematologic toxicities. Besides, with dasatinib autoimmune side effects can be seen. Thrombotic thrombocytopenic purpura (TTP) is a life- threatening disease that can be related to various causes mainly autoimmune disorders or antineoplastic drugs. Few cases of TKI associated secondary thrombotic microangiopathies (TMA) have been reported in literature. Most of cases were diagnosed as hemolytic uremic syndrome (HUS) rather than TTP. Herein, we describe a 37-year-old CML patient who was diagnosed as immune-mediated TTP related to dasatinib. PMID- 29475749 TI - Delayed Recurrent and Bilateral Breast Cancer in Patients With Partial Poland's Anomaly: Report of 2 Rare Cases and Review of the Literature. PMID- 29475750 TI - The influence of lower leg configurations on muscle force variability. AB - The maintenance of steady contractions is required in many daily tasks. However, there is little understanding of how various lower limb configurations influence the ability to maintain force. The purpose of the current investigation was to examine the influence of joint angle on various lower-limb constant force contractions. Nineteen adults performed knee extension, knee flexion, and ankle plantarflexion isometric force contractions to 11 target forces, ranging from 2 to 95% maximal voluntary contraction (MVC) at 2 angles. Force variability was quantified with mean force, standard deviation, and the coefficient of variation of force output. Non-linearities in force output were quantified with approximate entropy. Curve fitting analyses were performed on each set of data from each individual across contractions to further examine whether joint angle interacts with global functions of lower-limb force variability. Joint angle had significant effects on the model parameters used to describe the force variability function for each muscle contraction (p < 0.05). Regularities in force output were more explained by force level in smaller angle conditions relative to the larger angle conditions (p < 0.05). The findings support the notion that limb configuration influences the magnitude and regularities in force production. Biomechanical factors, such as joint angle, along with neurophysiological factors should be considered together in the discussion of the dynamics of constant force production. PMID- 29475751 TI - Validity of time series kinematical data as measured by a markerless motion capture system on a flatland for gait assessment. AB - As a cost-effective, clinician-friendly gait assessment tool, the Kinect v2 sensor may be effective for assessing lower extremity joint kinematics. This study aims to examine the validity of time series kinematical data as measured by the Kinect v2 on a flatland for gait assessment. In this study, 51 healthy subjects walked on a flatland while kinematic data were extracted concurrently using the Kinect and Vicon systems. The kinematic outcomes comprised the hip and knee joint angles. Parallel translation of Kinect data obtained throughout the gait cycle was performed to minimize the differences between the Kinect and Vicon data. The ensemble curves of the hip and knee joint angles were compared to investigate whether the Kinect sensor can consistently and accurately assess lower extremity joint motion throughout the gait cycle. Relative consistency was assessed using Pearson correlation coefficients. Joint angles measured by the Kinect v2 followed the trend of the trajectories made by the Vicon data in both the hip and knee joints in the sagittal plane. The trajectories of the hip and knee joint angles in the frontal plane differed between the Kinect and Vicon data. We observed moderate to high correlation coefficients of 20%-60% of the gait cycle, and the largest difference between Kinect and Vicon data was 4.2 degrees . Kinect v2 time series kinematical data obtained on the flatland are validated if the appropriate correction procedures are performed. Future studies are warranted to examine the reproducibility and systematic bias of the Kinect v2. PMID- 29475752 TI - Translucency of IPS e.max and cubic zirconia monolithic crowns. AB - STATEMENT OF PROBLEM: Although several monolithic zirconia ceramics have recently been introduced, the need for improved optical properties remains. The newest cubic-zirconia has been claimed to have optimal translucency characteristics for esthetic restorations. PURPOSE: This in vitro study evaluated the optical properties of novel cubic ultratranslucent (UT) and supertranslucent (ST) zirconia by comparing them with lithium disilicate (L-DIS) glass-ceramic for the manufacture of monolithic computer-aided design and computer-aided manufacturing (CAD-CAM) molar crowns. MATERIAL AND METHODS: The UT and ST multilayered zirconia and the low-translucency grade L-DIS were milled. Eighty monolithic crowns were made from 2 CAD files, corresponding to thicknesses of 1.0 and 1.5 mm, and subdivided (n=20) into 4 groups: UT1.0, UT1.5, ST1.0, and L-DIS1.5. All groups were shaded using A2 color standard. Translucency of the crowns was measured by total transmission, using a photoradiometer in a dark chamber; furthermore, the contrast ratio was analyzed using a dental spectrophotometer applied to the buccal surface of the crowns. Data were analyzed using the Kruskal-Wallis and post hoc multiple Mann-Whitney U tests with Bonferroni correction (alpha=.05 divided by the number of tests performed in each set). RESULTS: When the ceramic types were analyzed, using total transmission and contrast methods, they showed significantly different translucency levels: UT1.0>ST1.0>UT1.5>L-DIS1.5 (total transmission P<.001). Contrast ratio evaluation yielded similar results (P<=.006); however, the differences between ST1.0 and UT1.5 were not significant. CONCLUSIONS: Both the ST1.0 and UT1.0 crowns, even at the maximum thickness tested (UT1.5), showed significantly higher translucency than L-DIS. Zirconia translucency was improved by eliminating the tetragonal phase, which is responsible for the toughening effect; thus, further studies are advocated to investigate the mechanical resistance of cubic zirconia. PMID- 29475753 TI - Three-dimensional comparative study on the accuracy and reproducibility of dental casts fabricated by 3D printers. AB - STATEMENT OF PROBLEM: Studies investigating the precision of 3-dimensional (3D) printed casts for fixed prosthodontics are scarce. PURPOSE: The purpose of this in vitro study was to compare the accuracy and reproducibility of dental casts made by the conventional method and by 3D printing. MATERIAL AND METHODS: A master model was designed and fabricated with polyetherketoneketone. Ten specimens were fabricated with Type IV dental stone with polyvinyl siloxane. A light scanner was used to scan the master model, and the data were converted to standard tessellation language (STL) files. Three different types of 3D printers (Objet EDEN260V, ProMaker D35, and LC-3Dprint) were used to make 10 specimens each. All specimens were scanned by the light scanner, and the scanned files were superimposed on the files of the master model with specialized software to analyze the volumetric changes. The Kruskal-Wallis test, Mann-Whitney U tests, and Bonferroni method were performed with statistical analysis software (alpha=.05). RESULTS: The volumetric changes in casts made by the conventional method and by the 3D printers were significantly different. The conventional casts showed smaller volumetric change than the 3D-printed casts. Significant differences (P<.05) were found among the different types of 3D printers. The ultraviolet-polymerizing polymer with digital light processing exhibited the smallest volumetric change. In 3D color maps, the deformations were in similar patterns with all the 3D printers. CONCLUSIONS: The conventional method of die fabrication was more reliable than that of 3D printers. PMID- 29475754 TI - Antibacterial activity against Streptococcus mutans and diametrical tensile strength of an interim cement modified with zinc oxide nanoparticles and terpenes: An in vitro study. AB - STATEMENT OF PROBLEM: Interim restorations are occasionally left in the mouth for extended periods and are susceptible to bacterial infiltration. Thus, dental interim cements with antibacterial properties are required. PURPOSE: The purpose of this in vitro study was to determine in vitro antibacterial activity against Streptococcus mutans and to compare the diametrical tensile strength (DTSs) of dental interim cement modified with zinc oxide nanoparticles (ZnO-NPs) with that of cement modified with terpenes. MATERIAL AND METHODS: Antibacterial properties of ZnO-NPs, terpenes, and dental interim cement modified with ZnO-NPs and cement modified with terpenes against S mutans were tested according to minimum inhibitory concentration (MIC) and direct contact inhibition (DCI). Tensile strength levels were evaluated using DTS. Results were analyzed using the Kolmogorov-Smirnov, ANOVA, and Tamhane tests (alpha=.05). RESULTS: The MICs of ZnO-NPs and terpenes against S mutans were 61.94 MUg/g and 0.25% v/v, respectively. The DCI assay under the cylinders of cement (area of contact with the agar surface) revealed significant bacterial growth inhibition on Temp-Bond NE specimens with ZnO-NPs at MIC of 495.2 MUg/g (8* MIC) and with terpenes at MIC 0.999% v/v (4* MIC) (P<.05). The Temp-Bond NE cement cylinder (control group) showed the lowest DTS (1.05 +/-0.27 MPa) of all other test groups. In the Zn-NPs group, the greatest increase occurred in the NP8 (8* MIC; 495.2 MUg/g) group with a value of 1.50 +/-0.23 MPa, a significant increase in DTS compared with the control and terpene groups (P<.05). In the terpene group, the highest increase corresponded to group T2 (2* MIC; 0.4995% v/v) with a value of 1.29 +/-0.18 MPa. CONCLUSIONS: The addition of terpenes and ZnO-NPs to interim cement showed antibacterial activity when in contact with S. mutans ATCC 25175. Both terpenes and ZnO-NPs antimicrobial agents increased diametral tensile strength. PMID- 29475755 TI - Marginal discrepancy of CAD-CAM complete-arch fixed implant-supported frameworks. AB - STATEMENT OF PROBLEM: Computer-aided design and computer-aided manufacturing (CAD CAM) high-density polymers (HDPs) have recently been marketed for the fabrication of long-term interim implant-supported fixed prostheses. However, information regarding the precision of fit of CAD-CAM HDP implant-supported complete-arch screw-retained prostheses is scarce. PURPOSE: The purpose of this in vitro study was to evaluate the marginal discrepancy of CAD-CAM HDP complete-arch implant supported screw-retained fixed prosthesis frameworks and compare them with conventional titanium (Ti) and zirconia (Zir) frameworks. MATERIAL AND METHODS: A screw-retained complete-arch acrylic resin prototype with multiunit abutments was fabricated on a typodont model with 2 straight implants in the anterior region and 2 implants with a 30-degree distal tilt in the posterior region. A 3 dimensional (3D) laboratory laser scanner was used to digitize the typodont model with scan bodies and the resin prototype to generate a virtual 3D CAD framework. A CAM milling unit was used to fabricate 5 frameworks from HDP, Ti, and Zir blocks. The 1-screw test was performed by tightening the prosthetic screw in the maxillary left first molar abutment (terminal location) when the frameworks were on the typodont model, and the marginal discrepancy of frameworks was evaluated using an industrial computed tomographic scanner and a 3D volumetric software. The 3D marginal discrepancy at the abutment-framework interface of the maxillary left canine (L1), right canine (L2), and right first molar (L3) sites was measured. The mean values for 3D marginal discrepancy were calculated for each location in a group with 95% confidence limits. The results were analyzed by repeated-measures 2-way ANOVA using the restricted maximum likelihood estimation and the Satterthwaite degrees of freedom methods, which do not require normality and homoscedasticity in the data. The between-subjects factor was material, the within-subjects factor was location, and the interaction was included in the model. Tukey tests were applied to resolve any statistically significant source of variation (overall alpha=.05). RESULTS: The 3D marginal discrepancy measurement was possible only for L2 and L3 because the L1 values were too small to detect. The mean discrepancy values at L2 were 60 MUm for HDP, 74 MUm for Ti, and 84 MUm for Zir. At the L3 location, the mean discrepancy values were 55 MUm for HDP, 102 MUm for Ti, and 94 MUm for Zir. The ANOVA did not find a statistically significant overall effect for implant location (P=.072) or a statistically significant interaction of location and material (P=.078), but it did find a statistically significant overall effect of material (P=.019). Statistical differences were found overall between HDP and the other 2 materials (P<=.037). CONCLUSIONS: When the tested materials were used with the CAD-CAM system, the 3D marginal discrepancy of CAD-CAM HDP frameworks was smaller than that of titanium or zirconia frameworks. PMID- 29475756 TI - Evaluation of the success rate of cone beam computed tomography in determining the location and direction of screw access holes in cement-retained implant supported prostheses: An in vitro study. AB - STATEMENT OF PROBLEM: Cement-retained implant-supported restorations have advantages over screw-retained restorations but are difficult to retrieve. Identifying the approximate location of the screw access hole (SAH) may reduce damage to the prosthesis. PURPOSE: The purpose of this in vitro study was to evaluate the ability of cone beam computed tomography (CBCT) imaging to determine the location and direction of SAHs in cement-retained implant prostheses. MATERIAL AND METHODS: Five clear acrylic resin casts were made based on a mandibular model. Several implant osteotomies (n=30) were created on the models with surgical burs, and crowns were made using the standard laboratory method with a transfer coping and the closed tray impression technique. CBCT images from the acrylic resin casts were evaluated by a maxillofacial radiologist who was blind to the locations and angles of the osteotomies. The locations of the access holes were determined on multiplanar reconstruction images and transferred to the clinical crown surface as defined points. Based on cross-sectional images, the predicted angle of the access hole was provided to a prosthodontist who was requested to pierce the crown at the proposed location in the specified direction. If the location and/or direction of the access hole were found, the process was considered successful, as the crown could then be removed from the implant abutment through the SAH. The success rate in the detection of the location and direction of the SAH was calculated, and chi-square and Fisher exact tests were applied for data analysis (alpha=.05). RESULTS: According to the results of this study, the success rate of CBCT to define the location of SAHs was 83.3% and 80% to determine the direction. No significant differences were found among the different dental groups in determination of the location (P=.79) or the direction (P=.53) of the SAHs. Most of the failures in determining the location and direction of the access hole in the buccolingual and mesiodistal directions were in the buccal and mesial locations of the SAH. The success rate of using CBCT to determine the location of SAHs in straight abutments was 100%. A significant difference was found between angled and straight abutments (P=.042). CONCLUSIONS: Using CBCT could help determine the direction and location of SAHs in clinical situations. PMID- 29475757 TI - The history of The Glossary of Prosthodontic Terms. PMID- 29475758 TI - A technique for obtaining flawless cast-to-implant custom abutments. PMID- 29475759 TI - Effect of thickness of monolithic zirconia ceramic on final color. AB - STATEMENT OF PROBLEM: Achieving excellent esthetics with monolithic zirconia restorations is challenging, and the impact of monolithic zirconia thickness on the final color is unclear. PURPOSE: The purpose of this in vitro study was to assess the effect of thickness of monolithic zirconia ceramic on its final color and to define the minimum thickness needed to gain an acceptable final color. MATERIAL AND METHODS: Sixty monolithic zirconia disk specimens with a 10-mm diameter and 3 different thicknesses (0.7, 0.9, and 1.1 mm) were fabricated from 2 zirconia brands. The specimens were divided into 6 groups of 10 based on the thickness and brand. All the specimens were colored with an A2 shade liquid. The specimens were placed on an A4 shade substrate, and their CIELab values were measured with a spectrophotometer. DeltaE values were calculated to determine color differences between the specimens and the A2 VITA classical shade tab. The DeltaE values were compared with an acceptability threshold (DeltaE=3.3). Two-way ANOVA, the Bonferroni test, and 1-sample t test were used to analyze data (alpha=.05). RESULTS: Mean DeltaE values ranged between 2.4 and 4.1. The zirconia thickness affected the DeltaE (P<.001); however, the zirconia brand did not affect the DeltaE (P=.059). The mean DeltaE values for the zirconia thickness of 0.7 mm for both brands were more than the threshold (P<.05). CONCLUSIONS: The thickness of monolithic zirconia ceramic affected its final color. The minimum thickness of a monolithic zirconia ceramic should be 0.9 mm to gain the acceptable final color. PMID- 29475760 TI - Scanning of root canal impression for the fabrication of a resin CAD-CAM customized post-and-core. AB - Customization of post-and-cores using computer-aided design and computer-aided manufacturing (CAD-CAM) requires the scanning of a pattern and the subsequent digital design. This technique describes a method of fabricating a CAD-CAM customized post-and-core designed from a scanned polyvinyl siloxane impression and milled from a nanoparticle/nanocluster-filled resin block. The polyvinyl siloxane impression allowed a faster and more efficient customization of the CAD CAM post-and-core than a conventional acrylic resin pattern. The properties of the nanoparticle/nanocluster filled resin block make the material suitable for chairside CAD-CAM post-and-core fabrication. PMID- 29475761 TI - The evolution of immunization waiver education in Michigan: A qualitative study of vaccine educators. AB - BACKGROUND: In 2015, Michigan implemented an education requirement for parents who requested nonmedical exemptions from school or daycare immunization mandates. Michigan required parents to receive education from public health staff, unlike other states, whose vaccine education requirements could be completed online or at physicians' offices. METHODS AND FINDINGS: Results of focus group interviews with 39 of Michigan's vaccine waiver educators, conducted during 2016 and 2017, were analyzed to identify themes describing educators' experiences of waiver education. The core theme that emerged from the data was that educators changed their perception of the purpose of waiver education, from convincing vaccine refusing parents to vaccinate their children to promoting more diffuse and forward-looking goals. CONCLUSIONS: Michigan, and other communities that require vaccine waiver education, ought to investigate whether and how waiver education contributes to public health goals other than short-term vaccination compliance. Research shows that education requirements can decrease nonmedical exemption rates by discouraging some parents from applying for exemptions, but further studies are needed to identify ways in which waiver education can promote other public health goals, while minimizing costs and burdens on staff. PMID- 29475762 TI - Safety and immunogenicity of investigational recombinant botulinum vaccine, rBV A/B, in volunteers with pre-existing botulinum toxoid immunity. AB - OBJECTIVES: We undertook an open-label, uncontrolled study of investigational recombinant botulinum vaccine for botulinum neurotoxin (BoNT) serotypes A and B (rBV A/B) to assess its safety and immunogenicity in healthy volunteers who had been previously immunized with investigational pentavalent botulinum toxoid. Study participants who wished to do so could donate their hyperimmune plasma for production of Human Botulism Immune Globulin Intravenous (BIG-IV, BabyBIG(r)). STUDY DESIGN: A single 0.5 ml (mL), 40-microgram intramuscular injection of rBV A/B was administered to study participants. Post-vaccination sera collected at approximately 2-week intervals were evaluated for anti-BoNT/A and anti-BoNT/B neutralizing antibody concentrations (NAC). Local and systemic treatment-emergent adverse events (TEAEs) were identified by clinical and laboratory monitoring for 12 weeks post-vaccination with a final telephone follow-up for additional safety assessment at 6 months. The primary endpoint for immunogenicity was a >=4-fold rise in NAC in >=50% of participants by Week 4 post-vaccination. RESULTS: All 45 enrolled participants completed the study. Forty-two of 45 participants (93.3%) experienced at least one TEAE. Overall, 138 of 218 (63.3%) reported TEAEs were treatment-related, the majority of which were mild injection-site reactions. No serious or unexpected adverse events occurred. The study achieved its primary immunogenicity endpoint with 37/45 (82.2%) participants and 39/45 (86.7%) participants having a >=4-fold rise in NAC to anti-BoNT/A and to anti-BoNT/B, respectively, by Week 4 post-vaccination. CONCLUSION: A single 0.5 mL dose of rBV A/B was safe, well-tolerated and immunogenic in participants previously immunized with pentavalent botulinum toxoid. The tolerability and immunogenicity characteristics of rBV A/B vaccination of individuals with existing BoNT immunity support its potential future use to provide occupational protection to botulism laboratory workers. Almost all study participants donated hyperimmune plasma for production of BIG-IV. ClinicalTrials.gov registration number: NCT01701999. PMID- 29475763 TI - Evaluation of the immunogenic capability of the BCG strains BCGDeltaBCG1419c and BCGDeltaBCG1416c in a three-dimensional human lung tissue model. AB - Tuberculosis (TB) still remains as an unmet global threat. The current vaccine is not fully effective and novel alternatives are needed. Here, two vaccine candidate strains derived from BCG carrying deletions in the BCG1416c or BCG1419c genes were analysed for their capacity to modulate the cytokine/chemokine profile and granuloma formation in a human lung tissue model (LTM). We show that the clustering of monocytes, reminiscent of early granuloma formation, in LTMs infected with BCG strains was similar for all of them. However, BCGDeltaBCG1419c, like M. tuberculosis, was capable of inducing the production of IL-6 in contrast to the other BCG strains. This work suggests that LTM could be a useful ex vivo assay to evaluate the potential immunogenicity of novel TB vaccine candidates. PMID- 29475764 TI - Treatment of pediatric esthesioneuroblastoma with smell preservation. AB - Olfactory neuroblastoma is a rare malignant tumor of neuroectodermal origin and represents the most common cancer of the nasal cavity in pediatric age. The gold standard of treatment consists of en bloc resection, numerous studies have shown as the endoscopic approaches permit good control of the disease improving the quality of life after the treatment. Herein we describe the case of a 13-year-old patient referred to our outpatient clinic with a polypoid multi-lobed lesion occupying the left nasal cavity and imaging that confirmed a left-sided nasal mass without cribriform plate involvement (Kadish B). We performed an unilateral endoscopic resection with transnasal craniectomy and anterior skull base reconstruction with a flap from the contralateral nasal septum based on the septal branches of the anterior and posterior ethmoidal arteries (Septal Flip Flap, SFF), that provided a faster healing process with reduction of nasal crusting, improvement in the quality of life of patient in the postoperative period and the preservation of the contralateral olfactory bulb that has allowed to save the smell. This treatment strategy of pediatric esthesioneuroblastoma was analyzed in the context of the current literature. PMID- 29475765 TI - Environmental factors associated with allergic rhinitis symptoms in Japanese university students: A cross-sectional study. AB - OBJECTIVE: Numerous studies have reported that various environmental factors during early life are key determinants for developing allergic disease. Herein, we aimed to investigate the impact of environmental factors on allergic rhinitis. METHODS: This cross-sectional study was conducted in a single university in Japan (from April to June, in 2015 and 2016). Students voluntarily answered online questionnaires regarding their allergic rhinitis symptoms and their exposure to various environmental factors during preschool-age. RESULTS: Overall, 3075 students participated the questionnaire. After excluding those with incomplete datasets, 3016 students were eligible. Of these, 49% had allergic rhinitis symptoms. Female sex was associated with a lower risk of allergic rhinitis symptoms (odds ratio [OR], 0.82; 95% confidence interval [CI], 0.68-0.99). Comorbidity of asthma or atopic dermatitis and a family history of allergy (asthma, atopic dermatitis, or allergic rhinitis) were associated with higher risks of allergic rhinitis symptoms. Regarding the number of household members, compared with subjects with <3 people, those with 5 (OR, 0.74; 95% CI, 0.57-0.97) and >=6 people (OR, 0.66; 95% CI, 0.49-0.88) in their household showed lower incidences of allergic rhinitis symptoms. No other environmental factors, including birth order, number of siblings, living environment, passive smoking, furry pet ownership, housing, bedding, breastfeeding, dairy product intake, preschool setting, and starting age of preschool, was associated with the incidence of allergic rhinitis symptoms. CONCLUSION: Sex, current asthma and atopic dermatitis symptoms, family history of allergies, and the number of people in the household at preschool-age were associated with the incidence of allergic rhinitis symptoms. PMID- 29475766 TI - An atypical cause of chest pain. PMID- 29475767 TI - Foods Served in Child Care Facilities Participating in the Child and Adult Care Food Program: Menu Match and Agreement with the New Meal Patterns and Best Practices. AB - OBJECTIVE: To assess the agreement of posted menus with foods served to 3- to 5 year-old children attending federal Child and Adult Care Food Program (CACFP) enrolled facilities, and the degree to which the facilities met the new meal patterns and best practices. DESIGN: On-site observations and menu coding. PARTICIPANTS/SETTING: Nine early care and education centers. MAIN OUTCOME MEASURES: Agreement of posted menus with foods served, and comparison of foods served and consumed with the new CACFP meal guidelines and best practices. ANALYSIS: Data were compiled for each meal (breakfast, lunch, and snacks). Frequencies and percentages of agreement with the posted menu (coded matches, substitutions, additions, and omissions) were calculated for each food component in the CACFP menu guidelines. Menu total match was created by summing the menu match plus acceptable substitutions. Menus were compared with the new CACFP meal guidelines and best practices. RESULTS: The match between the posted menus and foods actually served to children at breakfast, lunch, and snack was high when the acceptable menu substitutions were considered (approximately 94% to 100% total match). Comparing the menus with the new meal guidelines and best practices, the 1 guideline that was fully implemented was serving only unflavored, low-fat, or 1% milk; fruit and vegetable guidelines were partially met; fruit juice was not served often, nor were legumes; the guideline for 1 whole grain-rich serving/d was not met; and regular beef and full-fat cheese products were commonly served. CONCLUSIONS AND IMPLICATIONS: Early care and education centers enrolled in CACFP provided meals that met the current CACFP guidelines. Some menu improvements are needed for the centers to meet the new guidelines and best practices. PMID- 29475768 TI - Scope and Consistency of Outcomes Reported in Randomized Trials Conducted in Adults Receiving Hemodialysis: A Systematic Review. AB - BACKGROUND: Clinical trials are most informative for evidence-based decision making when they consistently measure and report outcomes of relevance to stakeholders. We aimed to assess the scope and consistency of outcomes reported in trials for hemodialysis. STUDY DESIGN: Systematic review. SETTING & POPULATION: Adults requiring maintenance hemodialysis enrolled in clinical trials. SELECTION CRITERIA: All Cochrane systematic reviews of interventions published by August 29, 2016, and the trials published and registered in ClinicalTrials.gov since January 2011. INTERVENTIONS: Any hemodialysis-related interventions. OUTCOMES: Frequency and characteristics of the reported outcome domains and measures. RESULTS: From the 362 trials, we extracted and classified 10,713 outcome measures (a median of 21 [IQR, 10-39] per trial) into 81 different outcome domains, of which 42 (52%) were surrogate; 25 (31%), clinical; and 14 (17%), patient reported. The number of outcome measures reported significantly changed over time. The 5 most commonly reported domains were all surrogates: phosphate (125 [35%] trials), dialysis adequacy (120 [33%]), anemia (115 [32%]), inflammatory markers (114 [31%]), and calcium (109 [30%]). Mortality, cardiovascular diseases, and quality of life were reported very infrequently (73 [20%], 44 [12%], and 32 [9%], respectively). LIMITATIONS: For feasibility, we included a sampling frame that included only trials identified in Cochrane systematic reviews or ClinicalTrials.gov. CONCLUSIONS: Outcomes reported in clinical trials involving adults receiving hemodialysis are focused on surrogate outcomes, rather than clinical and patient-centered outcomes. There is also extreme multiplicity and heterogeneity at every level: domain, measure, metric, and time point. Estimates of the comparative effectiveness of available interventions are unreliable and improvements over time have been inconsistent. PMID- 29475770 TI - Declining prevalence and increasing awareness of HCV infection in Italy: A population-based survey in five metropolitan areas. AB - BACKGROUND: Data on the prevalence of hepatitis C virus (HCV) infection in Italy are outdated and usually derived from studying residents in small towns. METHODS: To assess prevalence of and risk factors for HCV infection among Italian residents in 5 metropolitan areas, subjects >=20 years of age were randomly selected from the list of the general practitioners' registers in 2015. Anti-HCV was tested by a salivary test; HCV-RNA, HCV genotypes, and ALT were determined in positive individuals. Logistic regression analysis evaluated independent risk factors for HCV. RESULTS: Of the 4907 enrolled subjects, 112 (2.3%) tested anti HCV positive. The prevalence of HCV increased with age, from 0.2% in subjects born after the year 1984, to 4.2% in those born before the year 1935 (P < 0.01). The birth-cohort prevalence peaked (7.0%) in elderly. Serum HCV-RNA was detected in 1.7% of the whole population. Nearly 80% of anti-HCV subjects were aware of their status. Age > 70 years, low education level, past use of glass syringes, blood transfusion, intravenous drug use, and cohabitation with an anti-HCV positive subject predicted the HCV positivity. INTERPRETATION: In metropolitan areas in Italy, HCV is prevalent in elderly, reflecting a cohort effect determined by modalities of viral transmission no longer operative. The impact of the infection will further diminish in the years to come due to the natural depletion of the reservoir of the virus. This age pattern and the high proportion of subjects aware of their status do not warrant a policy of screening. PMID- 29475771 TI - Lyme borreliosis and depressive symptoms in patients aged 65 years and older referred to a tertiary Lyme centre. PMID- 29475773 TI - Most adolescents' melanomas are conventional malignant adult-type melanomas. PMID- 29475772 TI - Investigating multi-radiomic models for enhancing prediction power of cervical cancer treatment outcomes. AB - Quantitative image features, also known as radiomic features, have shown potential for predicting treatment outcomes in several body sites. We quantitatively analyzed 18Fluorine-fluorodeoxyglucose (18F-FDG) Positron Emission Tomography (PET) uptake heterogeneity in the Metabolic Tumor Volume (MTV) of eighty cervical cancer patients to investigate the predictive performance of radiomic features for two treatment outcomes: the development of distant metastases (DM) and loco-regional recurrent disease (LRR). We aimed to fit the highest predictive features in multiple logistic regression models (MLRs). To generate such models, we applied backward feature selection method as part of Leave-One-Out Cross Validation (LOOCV) within a training set consisting of 70% of the original patient cohort. The trained MLRs were tested on an independent set consisted of 30% of the original cohort. We evaluated the performance of the final models using the Area under the Receiver Operator Characteristic Curve (AUC). Accordingly, six models demonstrated superior predictive performance for both outcomes (four for DM and two for LRR) when compared to both univariate radiomic feature models and Standard Uptake Value (SUV) measurements. This demonstrated approach suggests that the ability of the pre-radiochemotherapy PET radiomics to stratify patient risk for DM and LRR could potentially guide management decisions such as adjuvant systemic therapy or radiation dose escalation. PMID- 29475774 TI - Diamine oxidase (DAO) supplement reduces headache in episodic migraine patients with DAO deficiency: A randomized double-blind trial. AB - BACKGROUND & AIMS: Histamine intolerance is a disorder in the homeostasis of histamine due to a reduced intestinal degradation of this amine, mainly caused by a deficiency in the enzyme diamine oxidase (DAO). Among histamine related symptoms, headache is one of the most recorded. Current clinical strategies for the treatment of the symptomatology related to this disorder are based on the exclusion of foods with histamine or other bioactive amines and/or exogenous DAO supplementation. The aim of this study was to assess the efficacy of a food supplement consisting of DAO enzyme as a preventive treatment of migraine in patients with DAO deficiency through a randomized double-blind trial. METHODS: 100 patients with confirmed episodic migraine according to current International Headache Society (IHS) criteria and DAO deficiency (levels below 80 HDU/ml) were randomized in two groups. One group received DAO enzyme supplementation and the other received placebo for one month. Clinical outcomes assessed were duration and number of attacks, perception of pain intensity and adverse effects during treatment. The use of triptans was also recorded. RESULTS: Great variability was found in the duration of migraine attacks reported by placebo and DAO groups. A significant reduction (p = 0.0217) in hours of pain was achieved in patients treated with DAO supplement, with mean durations of 6.14 (+/-3.06) and 4.76 (+/ 2.68) hours before and after treatment, respectively. A smaller reduction without statistical signification was also observed for this outcome in the placebo group, from 7.53 (+/-4.24) to 6.68 (+/-4.42) hours. Only in DAO group, a decrease in the percentage of patients taking triptans was observed. The number of attacks and the scores of pain intensity showed a similar reduction in both groups. No adverse effects were registered in patients treated with DAO enzyme. CONCLUSIONS: Migrainous patients supplemented with DAO enzyme during one month significantly reduced the duration of their migraine attacks by 1.4 h. No statistically significant reduction was found in placebo group before and after treatment. The reduction of pain hours observed in placebo group (0.9 h) could explain the lack of significant differences between both study groups. One month of DAO supplementation has demonstrated a positive trend in the improvement of migraine but more studies with a longer treatment period are needed to better assess the efficacy of DAO supplementation. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN10091019; www.isrctn.org. PMID- 29475775 TI - Monitoring well utility in a heterogeneous DNAPL source zone area: Insights from proximal multilevel sampler wells and sampling capture-zone modelling. AB - Groundwater-quality assessment at contaminated sites often involves the use of short-screen (1.5 to 3 m) monitoring wells. However, even over these intervals considerable variation may occur in contaminant concentrations in groundwater adjacent to the well screen. This is especially true in heterogeneous dense non aqueous phase liquid (DNAPL) source zones, where cm-scale contamination variability may call into question the effectiveness of monitoring wells to deliver representative data. The utility of monitoring wells in such settings is evaluated by reference to high-resolution multilevel sampler (MLS) wells located proximally to short-screen wells, together with sampling capture-zone modelling to explore controls upon well sample provenance and sensitivity to monitoring protocols. Field data are analysed from the highly instrumented SABRE research site that contained an old trichloroethene source zone within a shallow alluvial aquifer at a UK industrial facility. With increased purging, monitoring-well samples tend to a flow-weighted average concentration but may exhibit sensitivity to the implemented protocol and degree of purging. Formation heterogeneity adjacent to the well-screen particularly, alongside pump-intake position and water level, influence this sensitivity. Purging of low volumes is vulnerable to poor reproducibility arising from concentration variability predicted over the initial 1 to 2 screen volumes purged. Marked heterogeneity may also result in limited long-term sample concentration stabilization. Development of bespoke monitoring protocols, that consider screen volumes purged, alongside water quality indicator parameter stabilization, is recommended to validate and reduce uncertainty when interpreting monitoring-well data within source zone areas. Generalised recommendations on monitoring well based protocols are also developed. A key monitoring well utility is their proportionately greater sample draw from permeable horizons constituting a significant contaminant flux pathway and hence representative fraction of source mass flux. Acquisition of complementary, high-resolution, site monitoring data, however, vitally underpins optimal interpretation of monitoring-well datasets and appropriate advancement of a site conceptual model and remedial implementation. PMID- 29475776 TI - Hepatic metastasis from basal cell carcinoma: A rare location with an unreported presentation. PMID- 29475777 TI - Diagnostic value of unenhanced postmortem computed tomography in the detection of traumatic abdominal injuries. AB - OBJECTIVE: To determine the diagnostic capabilities of unenhanced postmortem computed tomography (UPMCT) in detecting traumatic abdominal injuries. MATERIAL AND METHODS: Cases of traumatic death with both UPMCT and classical autopsy were collected retrospectively from our institution "virtopsy" database in a period of 5 years. Cadavers with gunshot injuries were excluded. Sensitivity, specificity, accuracy, negative (NPV) and positive (PPV) predictive values of PMCT globally and for hemoperitoneum, liver, spleen, pancreas and kidney injuries individually were estimated using the autopsy report as gold standard. RESULTS: Seventy-one cadavers were included. UPMCT had a sensitivity of 80% and a specificity 94%, with an accuracy of 83%, a PPV of 98% and a NPV of 59% for the diagnosis of traumatic abdominal injuries. The highest sensitivity was obtained for the detection of hepatic injuries (71%) and the lowest for pancreatic injuries (12%). UPMCT had a specificity of 100% for the detection of hemoperitoneum. A NPV of 98% was found for the detection of perihepatic hematomas. CONCLUSION: The low sensitivity and low NPV do not support the use of UPMCT as an alternative to conventional autopsy to diagnose and/or rule out traumatic abdominal injuries. Nevertheless, UPMCT remains a helpful tool as it helps detect hemoperitoneum and virtually exclude presence of perihepatic hematomas. PMID- 29475778 TI - Fused micro-computed tomography (MUCT) and histological images of bone specimens. AB - OBJECTIVES: To describe a stepwise process to obtain fused images from micro computed tomography (MUCT) and histological images of bone specimens. MATERIAL AND METHODS: Four surgically resected human femoral heads from four patients who had total hip replacement were imaged at a spatial resolution of 12-microns by using MUCT. Histological sections of four focal bone lesions including bone cyst in osteoarthritis (n=2) and subchondral bone plate fracture in osteonecrosis (n=2) were prepared and digitized. MUCT images were reformatted and adjusted to match the histological images using a landmark-based visual co-registration. Fused MUCT and histological images were displayed in a cine-loop video mode with a gradual transition from one image to the other. RESULTS: MUCT images of the four focal bone lesions could be successfully fused with the corresponding histological images with a near perfect match of the bone trabeculae. CONCLUSION: We present a stepwise process to obtain fused images from histological and reformatted MUCT images of human femoral heads. PMID- 29475779 TI - Anti-cancer vaccine therapy for hematologic malignancies: An evolving era. AB - The potential promise of therapeutic vaccination as effective therapy for hematologic malignancies is supported by the observation that allogeneic hematopoietic cell transplantation is curative for a subset of patients due to the graft-versus-tumor effect mediated by alloreactive lymphocytes. Tumor vaccines are being explored as a therapeutic strategy to re-educate host immunity to recognize and target malignant cells through the activation and expansion of effector cell populations. Via several mechanisms, tumor cells induce T cell dysfunction and senescence, amplifying and maintaining tumor cell immunosuppressive effects, resulting in failure of clinical trials of tumor vaccines and adoptive T cell therapies. The fundamental premise of successful vaccine design involves the introduction of tumor-associated antigens in the context of effective antigen presentation so that tolerance can be reversed and a productive response can be generated. With the increasing understanding of the role of both the tumor and tumor microenvironment in fostering immune tolerance, vaccine therapy is being explored in the context of immunomodulatory therapies. The most effective strategy may be to use combination therapies such as anti cancer vaccines with checkpoint blockade to target critical aspects of this environment in an effort to prevent the re-establishment of tumor tolerance while limiting toxicity associated with autoimmunity. PMID- 29475780 TI - Treatment Strategy for STEMI With Bifurcation Culprit Lesion Undergoing Primary PCI: The COBIS II Registry. AB - INTRODUCTION AND OBJECTIVES: There are limited data on the preferred treatment strategy in ST-segment elevation myocardial infarction (STEMI) patients with bifurcation lesions. This study aimed to compare clinical outcomes between 1 stent and 2-stent strategies in STEMI patients with bifurcation lesions undergoing primary percutaneous coronary intervention (PCI). METHODS: The COronary BIfurcation Stenting II is a retrospective multicenter registry of 2897 consecutive patients with bifurcation lesions undergoing PCI with drug-eluting stents from January 2003 through December 2009. Among the registered population, 367 (12.7%) patients had STEMI; of these, a 1-stent strategy was used in 304 patients and a 2-stent strategy in 63 patients; 77.1% of the patients received primary PCI with a first-generation drug-eluting stent. The inverse-probability of-treatment-weighting method was used to adjust for confounding factors. The primary outcome was major adverse cardiovascular events (MACE), a composite of cardiac death, myocardial infarction, target lesion revascularization, and stent thrombosis. RESULTS: The median length of follow-up was 38 months. Postprocedural side branch diameter stenosis differed significantly between the 2 groups (1 stent vs 2-stent, 42.7% vs 9.7%; P < .001). After the performance of inverse probability-of-treatment-weighting methods, the rate of MACE was significantly higher in the 2-stent group than in the 1-stent group (HR, 1.85; 95%CI, 1.19 2.87; P = .006), mainly driven by target lesion revascularization and stent thrombosis. CONCLUSIONS: In STEMI patients with bifurcation culprit lesions undergoing primary PCI, the 2-stent strategy had significantly higher rates of MACE than the 1-stent strategy, despite successful treatment of the side branch. However, this result should be interpreted with caution because this study does not reflect current practice. PMID- 29475781 TI - Comparative functional analysis between pyrolytic carbon prostheses and ligamentous suspension/reconstruction in the treatment of rhizarthrosis. AB - OBJECTIVE: To evaluate midterm functional outcome after pyrolytic carbon prosthesis (PyroDisk) implantation in the treatment of rhizarthrosis of the thumb, comparing outcomes with those of ligamentous resection/suspension/reconstruction. MATERIAL AND METHODS: A cross-sectional study retrospectively comparing 2patient groups aged between 40 and 65 years with rhizarthrosis of the thumb. Thirty-two patients operated between 2009 and 2013 were distributed between group i (interposition arthroplasy with PyroDisk implant) and group ii (ligamentous resection/suspension/reconstruction arthroplasty). Data on pain, functionality (Quick-Dash questionnaire) and articular movement were collected in 2015. In addition, a radiological study was undertaken using radiographs and CT. RESULTS: Thirty-two patients, 16 in each group with mean follow-up of 35 months (23-47). Pain at the end of follow-up was greater in the group with the pyrolytic carbon prosthesis (p=0.000). According to the QuickDash questionnaire, the patients in group i achieved a mean functionality of 31.14 (0-70) points compared to 15.81 (8-24) points for group ii (p=0.027). No differences were found in degree of mobility at the end of follow up (p=0.46). The prosthesis had to be removed in 6 cases. DISCUSSION: The pyrolytic carbon prosthesis has been presented as an alternative treatment for rhizarthrosis of the thumb. The papers pubslished to date highlight the discrepancies in midterm functional outcomes. CONCLUSIONS: Pyrolitic carbon prostheses have shown inferior functional outcomes, compared with resection/suspension/reconstruction arthroplasties. PMID- 29475782 TI - Mid-term survivorship and clinical outcomes of the Avon patellofemoral joint replacement. AB - BACKGROUND: We present the largest series of Avon patellofemoral joint (PFJ) replacements outside of the design centre. There is discussion over its efficacy and usefulness. We report an independent opinion of its indications, survivorship and outcomes. METHODS: We prospectively collected demographic data and patient reported outcome measures (PROM's) on our cohort of Avon Patellofemoral replacements since its adoption in our unit in 2003 until 2014. We performed a retrospective review of radiographs. RESULTS: We performed 103 PFJ replacements in 85 patients, 36 were male (mean age 61 - range 34 to 78) and 67 female (mean age 60 - range 38 to 82), mean follow up time was 5.6years (range 2.9 to 14.2years) with 93 implants still in situ. Their mean post-operative Oxford Knee Score was 36 (range seven to 48). There were nine conversions to TKR for disease progression and one revision of a femoral component for trochlear malpositioning. Mean time to revision was 2.9years (1.0 to 6.0years). Radiographic evidence of progression on Kellgren and Lawrence score in the un-replaced compartments was demonstrated in 23% of cases with imaging available. The Avon PFJ replacement delivers reproducible and effective pain relief and function to patients with isolated patellofemoral osteoarthritis. We believe PFJ replacement has an important role to play, and we will continue to perform this procedure for a carefully selected group of patients. Conversion to TKR does not and should not be regarded as failure of the index operation. PMID- 29475783 TI - Comment on: "Influence of an omega3-fatty acid-enriched enteral diet with and without added glutamine on the metabolic response to injury in a rat model of prolonged acute catabolism". PMID- 29475784 TI - Age Differences by Sex in Antiretroviral-Naive Participants: Pooled Analysis from Randomized Clinical Trials. AB - Age and sex effects on antiretroviral therapy (ART) response are not well elucidated. Our pooled analysis of 40 randomized clinical trials measured the association of age and sex on CD4+ T cell count changes and virologic suppression using multivariable regression modeling. The average increase in CD4+ T cell count from baseline to week 48 was 17.3 cells/mm3 lower and clinically insignificant (95% confidence interval -30.8 to -3.8) among women ages >= 50 years (n = 573), compared to women <= 35 years (n = 3,939). Results were similar for men. Virologic suppression odds were 60% and 21% times greater among participants >=50 years compared to <=35 years, in women and men, respectively. In both sexes, larger increases in CD4+ T cell count changes were observed in younger, compared to older, participants; however, virologic suppression was higher in older, compared to younger, participants suggesting a non-sex-specific age effect response to ART. PMID- 29475785 TI - Inferring the global phylodynamics of influenza A/H3N2 viruses in Taiwan. AB - BACKGROUND/PURPOSE: Influenza A/H3N2 viruses are characterized by highly mutated RNA genomes. In this study, we focused on tracing the phylodynamics of Taiwanese strains over the past four decades. METHODS: All Taiwanese H3N2 HA1 sequences and references were downloaded from public database. A Bayesian skyline plot (BSP) and phylogenetic tree were used to analyze the evolutionary history, and Bayesian phylogeographic analysis was applied to predict the spatiotemporal migrations of influenza outbreaks. RESULTS: Genetic diversity was found to have peaked near the summer of 2009 in BSP, in addition to the two earlier reported ones in summer of 2005 and 2007. We predicted their spatiotemporal migrations and found the summer epidemic of 2005 from Korea, and 2007 and 2009 from the Western United States. BSP also predicted an elevated genetic diversity in 2015-2017. Quasispecies were found over approximately 20% of the strains included in this time span. In addition, a first-time seen N31S mutation was noted in Taiwan in 2016-2017. CONCLUSION: We comprehensively investigated the evolutionary history of Taiwanese strains in 1979-2017. An epidemic caution could thus be raised if genetic diversity was found to have peaked. An example showed a newly-discovered cluster in 2016-2017 strains featuring a mutation N31S together with HA-160 quasispecies. Phylogeographic analysis, moreover, provided useful insights in tracing the possible source and migrations of these epidemics around the world. We demonstrated that Asian destinations including Taiwan were the immediate followers, while U.S. continent was predicted the origin of two summer epidemics in 2007 and 2009. PMID- 29475786 TI - Injury to the axillary and suprascapular nerves in rotator cuff arthropathy and after reverse shoulder arthroplasty: a prospective electromyographic analysis. AB - BACKGROUND: Neurologic pre- and postoperative injuries to the axillary and/or suprascapular nerve (SSN) have a higher incidence than expected and may lead to significantly decreased functional outcomes and increased risk of reverse shoulder arthroplasty (RSA) failure. METHODS: Patients who underwent a RSA for rotator cuff tear arthropathy (RCTA) were included from December 2014 to December 2015. This study focused on the clinical (Constant score), radiographic, and pre- and postoperative electromyographic evaluations at 3 and 6 months. RESULTS: Twenty patients met the inclusion criteria. One was lost to follow-up. Preoperatively, 15 patients showed changes on electromyography (9 SSN and 15 axillary nerve lesions); all of them were chronic and disuse injuries. The mean preoperative relative Constant score (rCS) of all included patients was 39 +/- 9 (range, 19-64). At 3 months postsurgery, the prevalence of acute injuries for both nerves was 31.5%. At 6 months postsurgery, 2 axillary nerve injuries and 6 SSN injuries remain unchanged, and the rest improved or normalized. The mean postsurgery rCS of the entire cohort at 6-month follow-up was 78 +/- 6.5. Mean postoperative rCS for acute postoperative nerve injury was 71 +/- 3 for the axillary nerve and 64 +/- 5 for SSN. CONCLUSIONS: Axillary and SSN injuries in RCTA have a much higher incidence than expected. Most of these axillary lesions are transient, with an almost complete recovery seen on electromyography at 6 months and with scarce functional impact. However, SSN lesions appear to behave differently, with poor functional results and having a lower potential for a complete recovery. PMID- 29475787 TI - Added value of CA19-9 response in predicting resectability of locally advanced pancreatic cancer following induction chemotherapy. AB - BACKGROUND: Determining the resectability of locally advanced pancreatic cancer (LAPC) after induction chemotherapy is complex since CT-imaging cannot accurately portray tumor response. We hypothesized that CA19-9 response adds to RECIST staging in predicting resectability of LAPC. METHODS: Post-hoc analysis within a prospective study on LAPC (>90 degrees arterial or >270 degrees venous involvement). CA19-9 response was determined after induction chemotherapy. Surgical exploration was performed in RECIST-stable or -regressive disease. The relation between CA19-9 response, resectability and survival was assessed. RESULTS: Restaging in 54 patients with LAPC after induction chemotherapy (mostly FOLFIRINOX) identified 6 RECIST-regressive, 32 RECIST-stable, and 16 patients with RECIST-progressive disease. The resection rate was 20.3% (11/54 patients). Sensitivity and specificity of RECIST-regression for resection were 40% and 87% whereas the positive predictive value (PPV) and negative predictive value (NPV) were 67% and 68%. Using a 30% decrease of CA19-9 as cut-off, 9/10 patients were correctly classified as resectable (90% sensitivity, PPV 43%) and 3/15 as unresectable (20% specificity, NPV 75%). In the total cohort, a CA19-9 decrease >=30% was associated with improved survival (22.4 vs. 12.7 months, p = 0.02). CONCLUSION: Adding CA19-9 response after induction chemotherapy seems useful in determining which patients with RECIST non-progressive LAPC should undergo exploratory surgery. PMID- 29475788 TI - Three phase-ictal scalp EEG patterns in patients with seizures arising from the cortex facing the interhemispheric fissure. AB - OBJECTIVE: Ictal scalp EEG patterns have been reported to vary across onset regions. We assessed the sequential EEG changes during seizure events on scalp EEG, and tested our hypothesis that patients with focal seizures arising from the cortex facing the interhemispheric fissure (IHF cortex) would be specifically characterized by 3 phase-EEG patterns (3Ph-EEG). METHODS: Patient inclusion criteria were: 1) focal epilepsy and 2) ictal onset records on scalp and intracranial video-EEG. Patients were classified into one of the three groups: the IHF group, mesial temporal (MT) group, or lateral convexity (LC) group, based on the localization of the ictal onset zone (IOZ) on intracranial video-EEG. We defined 3Ph-EEG on ictal scalp EEG as follows: phase 1, brief spike/fast wave burst; phase 2, diffuse attenuation; and phase 3, focal rhythmic activity with evolution. We determined if the occurrence ratios of 3Ph-EEG and each of the three phases differed between the groups (IHF and others). RESULTS: We studied 36 patients aged 8-59 years (mean, 30 years). Ten patients were classified as IHF, 16 as MT, and 10 as LC group from 303 ictal events on intracranial EEG. 193 seizures on scalp EEG consisted of 79 seizures in IHF; 58 in MT; 56 in LC group. Sixty-nine seizures (92%) in nine patients (90%) in IHF group showed 3Ph-EEG, whereas none of the seizures in MT and LC groups showed the 3Ph-EEG. Multivariate logistic regression analysis suggested that the presence of 3Ph-EEG (p < 0.01) and phase 2 (p = 0.03) components were predictive of IHF scalp EEG onset. SIGNIFICANCE: The 3Ph-EEG may be observed preferentially in patients with focal seizures from IHF cortex. Observation of the ictal phases on scalp EEG may warrant consideration of intracranial EEG sampling for the presurgical evaluation. PMID- 29475789 TI - A new approach to CAR T-cell gene engineering and cultivation using piggyBac transposon in the presence of IL-4, IL-7 and IL-21. AB - BACKGROUND AIMS: Clinical-grade chimeric antigenic receptor (CAR)19 T cells are routinely manufactured by lentiviral/retroviral (LV/RV) transduction of an anti CD3/CD28 activated T cells, which are then propagated in a culture medium supplemented with interleukin (IL)-2. The use of LV/RVs for T-cell modification represents a manufacturing challenge due to the complexity of the transduction approach and the necessity of thorough quality control. METHODS: We present here a significantly improved protocol for CAR19 T-cell manufacture that is based on the electroporation of peripheral blood mononuclear cells with plasmid DNA encoding the piggyBac transposon/transposase vectors and their cultivation in the presence of cytokines IL-4, IL-7 and IL-21. RESULTS: We found that activation of the CAR receptor by either its cognate ligand (i.e., CD19 expressed on the surface of B cells) or anti-CAR antibody, followed by cultivation in the presence of cytokines IL-4 and IL-7, enables strong and highly selective expansion of functional CAR19 T cells, resulting in >90% CAR+ T cells. Addition of cytokine IL 21 to the mixture of IL-4 and IL-7 supported development of immature CAR19 T cells with central memory and stem cell memory phenotypes and expressing very low amounts of inhibitory receptors PD-1, LAG-3 and TIM-3. CONCLUSIONS: Our protocol provides a simple and cost-effective method for engineering high-quality T cells for adoptive therapies. PMID- 29475790 TI - Oral Health Knowledge and Practices of Pediatric and Family Nurse Practitioners. AB - INTRODUCTION: The purpose of the study was to assess the relationship between oral health educational activities of NPs and their current oral health knowledge and practices. METHOD: An online survey was distributed to practicing NPs and members of the NAPNAP organization. RESULTS: The study results from n = 147 NPs indicated an association between oral health CE attendance and knowledge on the age to initiate fluoride toothpaste, age for an initial dental visit, as well as NPs comfort in educating about oral hygiene, diets to reduce caries, bacterial transmission and caries development, in addition to the NPs comfort in performing a risk assessment, oral exam, and identifying decay and other oral pathology compared to NPs that had not attended a CE course. DISCUSSION: The study findings demonstrate the importance of CE courses for NPs on the latest oral health guidelines and practices beyond their traditional academic education, in order to improve oral health outcomes among children. PMID- 29475792 TI - Influence of dressing application time after breast augmentation on cutaneous colonization: A randomized clinical trial. AB - Concepts regarding the best way to treat a surgical wound vary, in literature, ranging from no dressing use to dressing maintenance for 24 to 48 hours or until suture removal. This study aimed to evaluate the influence of the length of dressing maintenance after breast augmentation with implants on cutaneous colonization and surgical site infection. This is a two-arm, parallel group, randomized clinical trial. Eighty patients who were candidates for augmentation mammoplasty with silicone implants were randomly allocated to two groups, in which the dressing was removed on postoperative day 1 (group A, n = 40) or postoperative day 6 (group B, n = 40). Cutaneous colonization was examined by culturing samples collected before and after dressing removal. The criteria defined by the Centers for Disease Control and Prevention were used to assess surgical site infection. No significant difference regarding cutaneous colonization was observed between groups before dressing application. On postoperative day 6, significantly more bacterial growth was observed in group A (p = 0.01). No surgical site infection occurred. We concluded that maintaining the dressing for 6 days led to a lower cutaneous colonization but did not influence surgical site infection rates. PMID- 29475791 TI - Breast reconstruction and risk of arm lymphedema development: A meta-analysis. AB - BACKGROUND: Lymphedema remains a significant complication following breast cancer surgery when there is axillary lymph node intervention. Previous systematic reviews have identified risk factors for breast cancer-related lymphedema, including increased BMI, number of lymph nodes dissected and radiotherapy. However, they have not examined the effect of breast reconstruction on lymphedema occurrence. In this systematic review and meta-analysis, we sought to evaluate the association between breast reconstruction (BR) and lymphedema. METHODS: We searched PubMed (1966-2016), Embase (1966-2016), Scopus (2004-2016) and Google Scholar (2004-2016) for studies involving breast reconstruction and upper extremity lymphedema or breast cancer-related lymphedema. Our primary outcome was lymphedema occurrence. We performed a meta-analysis using random effects due to heterogeneity of the studies. RESULTS: Our search strategy identified 934 articles. After screening, 19 studies were included in our meta-analysis evaluating outcomes based on number of patients (7501) or number of breasts surgically treated (2063). Breast reconstruction was significantly associated with lower odds of lymphedema (p < 0.001) compared to mastectomy only or breast conserving surgery. Lymphedema rates were not statistically significantly different between patients undergoing implant-based or autologous BR. CONCLUSIONS: Breast reconstruction is associated with lower rates of lymphedema compared to mastectomy only or breast conserving surgery patients. Although the study does not prove causation, we hypothesize that this association is likely due to multiple factors, including a self-selecting population and mechanisms through which BR may contribute to primary or secondary prevention of lymphedema. Further prospective studies are needed to clarify this beneficial relationship between breast reconstruction and reduced lymphedema risk. PMID- 29475793 TI - Nicotine and caffeine modulate haloperidol-induced changes in postsynaptic density transcripts expression: Translational insights in psychosis therapy and treatment resistance. AB - Caffeine and nicotine are widely used by schizophrenia patients and may worsen psychosis and affect antipsychotic therapies. However, they have also been accounted as augmentation strategies in treatment-resistant schizophrenia. Despite both substances are known to modulate dopamine and glutamate transmission, little is known about the molecular changes induced by these compounds in association to antipsychotics, mostly at the level of the postsynaptic density (PSD), a site of dopamine-glutamate interplay. Here we investigated whether caffeine and nicotine, alone or combined with haloperidol, elicited significant changes in the levels of both transcripts and proteins of the PSD members Homer1 and Arc, which have been implicated in synaptic plasticity, schizophrenia pathophysiology, and antipsychotics molecular action. Homer1a mRNA expression was significantly reduced by caffeine and nicotine, alone or combined with haloperidol, compared to haloperidol. Haloperidol induced significantly higher Arc mRNA levels than both caffeine and caffeine plus haloperidol in the striatum. Arc mRNA expression was significantly higher by nicotine plus haloperidol vs. haloperidol in the cortex, while in striatum gene expression by nicotine was significantly lower than that by both haloperidol and nicotine plus haloperidol. Both Homer1a and Arc protein levels were significantly increased by caffeine, nicotine, and nicotine plus haloperidol. Homer1b mRNA expression was significantly increased by nicotine and nicotine plus haloperidol, while protein levels were unaffected. Locomotor activity was not significantly affected by caffeine, while it was reduced by nicotine. These data indicate that both caffeine and nicotine trigger relevant molecular changes in PSD sites when given in association with haloperidol. PMID- 29475794 TI - Mining the electronic medical record in patients with atrial fibrillation. PMID- 29475795 TI - Race and stroke in an atrial fibrillation inception cohort: Findings from the Penn Atrial Fibrillation Free study. AB - BACKGROUND: Stroke may be the initial manifestation of atrial fibrillation (AF). Limited studies, however, have evaluated racial differences in stroke before the diagnosis of AF. OBJECTIVE: We assessed racial differences in strokes that occurred before and after AF diagnosis in the Penn Atrial Fibrillation Free study. METHODS: The Penn Atrial Fibrillation Free study consists of 56,835 patients from the University of Pennsylvania Health System who were free of AF at the index visit. We developed an inception cohort of 3507 patients with incident AF and without any remote history of stroke. RESULTS: Among the AF inception cohort, there were 538 patients with ischemic strokes and 54 with hemorrhagic strokes. Nearly half (n = 254; 47%) of the ischemic strokes occurred within a 6 month period before the diagnosis of AF. Of these, the majority of strokes occurred either on the day of (n = 158) or within a 7-day period before (n = 30) the diagnosis of incident AF. The remaining 284 (53%) ischemic strokes occurred a median of 3.6 years (interquartile range 1.9-5.4 years) after AF diagnosis. Compared with whites, blacks had an independently higher risk of having an ischemic stroke either before (adjusted odds ratio 1.37; 95% confidence interval 1.03-1.81) or after (adjusted hazard ratio 1.67; 95% confidence interval 1.30 2.14) AF diagnosis. CONCLUSION: In the population with incident AF, nearly half of the ischemic strokes occurred before the diagnosis of AF. Compared with whites, blacks had a higher risk of developing an ischemic stroke that persisted whether the stroke occurred in the period either before or after AF diagnosis. PMID- 29475796 TI - Advanced immunostaining approaches to study early male germ cell development. AB - Mammalian male germ cell development takes place in the testis under the influence of a variety of somatic cells and an incompletely defined paracrine and endocrine influences. Since it is not recapitulated well in vitro, researchers studying spermatogenesis often manipulate the germline by creating transgenic or knockout mice or by administering pharmaceutical agonists/antagonists or inhibitors. The effects of these types of manipulations on germline development can often be determined following microscopic imaging, both of stained and immunostained testis sections. Here, we describe approaches for microscopic analysis of the developing male germline, provide detailed protocols for a variety of immunostaining approaches, and discuss transgenic fluorescent reporter lines for studying the early stages of spermatogenesis. PMID- 29475797 TI - The elusive keys to nucleic acid stability: Comment on "DNA melting and energetics of the double helix" by Alexander Vologodskii and Maxim D. Frank Kamenetskii. PMID- 29475798 TI - [Pubertal growth of 1,453 healthy children according to age at pubertal growth spurt onset. The Barcelona longitudinal growth study]. AB - INTRODUCTION: Pubertal growth pattern differs according to age at pubertal growth spurt onset which occurs over a five years period (girls: 8-13 years, boys: 10-15 years). The need for more than one pubertal reference pattern has been proposed. We aimed to obtain five 1-year-age-interval pubertal patterns. SUBJECTS AND METHODS: Longitudinal (6 years of age-adult height) growth study of 1,453 healthy children to evaluate height-for-age, growth velocity-for-age and weight-for-age values. According to age at pubertal growth spurt onset girls were considered: very-early matures (8-9 years, n=119), early matures (9-10 years, n=157), intermediate matures (10-11 years, n=238), late matures (11-12 years, n=127) and very-late matures (12-13 years, n=102), and boys: very-early matures (10-11 years, n=110), early matures (11-12 years, n=139), intermediate matures (12-13 years, n=225), late matures (13-14 years, n=133) and very-late matures (14-15 years, n=103). Age at menarche and growth up to adult height were recorded. RESULTS: In both sexes, statistically-significant (P<.0001) and clinically pertinent differences in pubertal growth pattern (mean height-for-age, mean growth velocity-for-age and mean pubertal height gain, values) were found among the five pubertal maturity groups and between each group and the whole population, despite similar adult height values. The same occurred for age at menarche and growth from menarche to adult height (P<.05). CONCLUSIONS: In both sexes, pubertal growth spurt onset is a critical milestone determining pubertal growth and sexual development. The contribution of our data to better clinical evaluation of growth according to the pubertal maturity tempo of each child will obviate the mistakes made when only one pubertal growth reference is used. PMID- 29475799 TI - Reprint of "Investigating ensemble perception of emotions in autistic and typical children and adolescents". AB - Ensemble perception, the ability to assess automatically the summary of large amounts of information presented in visual scenes, is available early in typical development. This ability might be compromised in autistic children, who are thought to present limitations in maintaining summary statistics representations for the recent history of sensory input. Here we examined ensemble perception of facial emotional expressions in 35 autistic children, 30 age- and ability-matched typical children and 25 typical adults. Participants received three tasks: a) an 'ensemble' emotion discrimination task; b) a baseline (single-face) emotion discrimination task; and c) a facial expression identification task. Children performed worse than adults on all three tasks. Unexpectedly, autistic and typical children were, on average, indistinguishable in their precision and accuracy on all three tasks. Computational modelling suggested that, on average, autistic and typical children used ensemble-encoding strategies to a similar extent; but ensemble perception was related to non-verbal reasoning abilities in autistic but not in typical children. Eye-movement data also showed no group differences in the way children attended to the stimuli. Our combined findings suggest that the abilities of autistic and typical children for ensemble perception of emotions are comparable on average. PMID- 29475801 TI - Role of tissue-specific promoter DNA methylation in regulating the human EKLF gene. AB - Erythroid Kruppel-like factor (EKLF/KLF1) is an erythroid-specific transcription factor whose activity is essential for erythropoiesis. The underlying mechanisms for EKLF specifically restricted to erythroid cells are of great interest but remain incompletely understood. To explore the epigenetic regulation of EKLF expression by promoter DNA methylation, we investigated the methylation status of the EKLF promoter and EKLF gene expression from a panel of human tissues. We observed that erythroid-specific hypomethylation of the EKLF promoter in adult erythroid cells was positively associated with EKLF expression. Demethylation of the EKLF promoter by 5-aza-2'-deoxycytidine led to elevated EKLF expression in non-erythroid cells. We further uncovered that EKLF promoter DNA methylation reduced the binding affinity for the transcription factors GATA1 and c-myb (MYB), which in turn silenced EKLF expression. These results suggest that hypomethylation of the EKLF promoter has functional significance in the establishment and maintenance of erythroid-specific gene expression. PMID- 29475800 TI - Macrovascular disease and risk factors in youth with type 1 diabetes: time to be more attentive to treatment? AB - Cardiovascular disease remains the leading cause of mortality in patients with type 1 diabetes. Although cardiovascular disease complications are rare until adulthood, pathology and early markers can manifest in adolescence. Whereas advances have been made in the management of microvascular complications of type 1 diabetes, similar progress in reducing macrovascular complications has not been made. The reasons for the absence of progress remain incompletely understood, but most likely relate to the long time needed for cardiovascular disease to manifest clinically and hence for risk factor management to show a clinical benefit, thus allowing inertia to prevail for diagnosis and particularly for targeting risk factors. In this Review, we summarise paediatric data on traditional and novel risk factors of cardiovascular disease, provide an overview of data from previous and current clinical trials, discuss future directions in cardiovascular disease research for paediatric patients with type 1 diabetes, and advocate for the early identification and treatment of cardiovascular disease risk factors as recommended in multiple guidelines. PMID- 29475802 TI - The effects of two different water exercise trainings on pain, functional status and balance in patients with knee osteoarthritis. AB - METHODS: Eighty-nine female patients who had been diagnosed with knee osteoarthritis were divided into three groups as two experimental and a control group. All groups have received the standard therapy (hotpack, ultrasound, TENS). Both experimental groups underwent water exercise program. While Group 1 performed lower extremity exercise training, Group 2 performed upper extremity exercises as well as trunk exercises in addition to the lower extremity exercises used in the Group 1. The third group was control group who did not receive water exercise treatment. The pain severity was measured with the Visual Analog Scale (VAS). Functional status was assessed by using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Balance was evaluated by using the single leg stance test. RESULTS: The change in VAS scores from pre-to post treatment was highest in Group 1 (p < 0.001). On the other hand, the change in WOMAC pain, stiffness and physical function values from pre-to post-treatment was highest in Group 2 (p < 0.001). DISCUSSION: Water exercise training was found to be beneficial in the treatment of knee osteoarthritis in both groups. Moreover, adding upper extremity and trunk exercises to the lower extremity exercises was found to be more effective for improving the function. PMID- 29475803 TI - Are toxicities of current nucleosides still a concern? PMID- 29475805 TI - PPIs for prevention and treatment of peptic ulcer. PMID- 29475804 TI - Tenofovir alafenamide plus emtricitabine versus abacavir plus lamivudine for treatment of virologically suppressed HIV-1-infected adults: a randomised, double blind, active-controlled, non-inferiority phase 3 trial. AB - BACKGROUND: Abacavir and tenofovir alafenamide offer reduced bone toxicity compared with tenofovir disoproxil fumarate. We aimed to compare safety and efficacy of tenofovir alafenamide plus emtricitabine with that of abacavir plus lamivudine. METHODS: In this randomised, double-blind, active-controlled, non inferiority phase 3 trial, HIV-1-positive adults (>=18 years) were screened at 79 sites in 11 countries in North America and Europe. Eligible participants were virologically suppressed (HIV-1 RNA <50 copies per mL) and on a stable three-drug regimen containing abacavir plus lamivudine. Participants were randomly assigned (1:1) by a computer-generated allocation sequence (block size 4) to switch to fixed-dose tablets of tenofovir alafenamide (10 mg or 25 mg) plus emtricitabine (200 mg) or remain on abacavir (600 mg) plus lamivudine (300 mg), with matching placebo, while continuing to take the third drug. Randomisation was stratified by the third drug (boosted protease inhibitor vs other drug) at screening. Investigators, participants, and study staff giving treatment, assessing outcomes, and collecting data were masked to treatment group. The primary endpoint was the proportion of participants with virological suppression (HIV-1 RNA <50 copies per mL) at week 48 (assessed by snapshot algorithm), with a 10% non-inferiority margin. We analysed the primary endpoint in participants enrolled before May 23, 2016 (when target sample size was reached), and we analysed safety in all enrolled participants who received at least one dose of study drug (including patients enrolled after these dates). This study was registered with ClinicalTrials.gov, number NCT02469246. FINDINGS: Study enrolment began on June 29, 2015, and the cutoff enrolment date for the week 48 primary endpoint analysis was May 23, 2016. 501 participants were randomly assigned and treated. At week 48, virological suppression was maintained in 227 (90%) of 253 participants receiving tenofovir alafenamide plus emtricitabine compared with 230 (93%) of 248 receiving abacavir plus lamivudine (difference -3.0%, 95% CI -8.2 to 2.0), showing non-inferiority. Few participants discontinued treatment because of adverse events: 12 (4%) of 280 participants in the tenofovir alafenimide plus emtricitabine group and nine (3%) of 276 in the abacavir plus lamivudine group. Three participants had serious, treatment-related adverse events: one each with renal colic and neutropenia in the tenofovir alafenamide plus emtricitabine group, and one myocardial infarction in the abacavir plus lamivudine group. There were no treatment-related deaths. INTERPRETATION: Tenofovir alafenamide, in combination with emtricitabine and various third drugs, maintained high efficacy with a renal and bone safety profile similar to that of abacavir. In virologically suppressed patients, a regimen containing tenofovir alafenamide could be an alternative to those containing abacavir, without concern for new onset of renal or bone toxicities or hyperlipidaemia. FUNDING: Gilead Sciences Inc. PMID- 29475807 TI - The occurrence of respiratory events in young subjects with a frequent rhythmic masticatory muscle activity: a pilot study. AB - PURPOSE: Concomitant occurrence of respiratory events can be often overlooked in the clinical practice of SB. This study assessed physiological characteristics of rhythmic masticatory muscle activity (RMMA) and concomitant respiratory events in young sleep bruxism (SB) subjects asymptomatic to obstructive sleep apnea (OSA). METHODS: Twenty-two subjects (age: 24.1+/-1.9years; F 8: M 14; BMI: 20.2+/ 1.9kg/m2) were polysomnographically diagnosed as moderate-severe SB. Sleep architecture, oromotor (RMMA and non-specific masseter activity [NSMA]) and apnea/hypopnea events were scored. RESULTS: All subjects showed normal sleep architecture whereas 6 exhibited respiratory events at a mild level of OSA. In all subjects, RMMA predominantly occurred in Stage N1+N2 while NSMA occurred in Stage N1+N2 (approximately 60 %) and in Stage R (up to 30 %). Up to 50% of respiratory events were scored in Stage R. RMMA occurred more frequently in close association (e.g., within 10s) with respiratory events in 6 subjects with OSA than those without. The percentage of RMMA occurring closely to respiratory events was positively correlated with apnea-hypopnea index (AHI) in Stage N1+N2 only while that of NSMA was positively correlated with AHI in Stage N1+N2 and Stage R. A sub-analysis in 6 subjects with OSA, RMMA after respiratory events was followed to arousals while those before respiratory events were mostly associated with central apnea. CONCLUSIONS: A subpopulation of young SB subjects can show concomitant respiratory events. Further large sample studies are needed to demonstrate that the occurrence of subclinical respiratory events represents a clinical subtype of SB. PMID- 29475806 TI - Effects of gastroprotectant drugs for the prevention and treatment of peptic ulcer disease and its complications: a meta-analysis of randomised trials. AB - BACKGROUND: Gastroprotectant drugs are used for the prevention and treatment of peptic ulcer disease and might reduce its associated complications, but reliable estimates of the effects of gastroprotectants in different clinical settings are scarce. We aimed to examine the effects of proton-pump inhibitors (PPIs), prostaglandin analogues, and histamine-2 receptor antagonists (H2RAs) in different clinical circumstances by doing meta-analyses of tabular data from all relevant unconfounded randomised trials of gastroprotectant drugs. METHODS: We searched MEDLINE and Embase from Jan 1, 1950, to Dec 31, 2015, to identify unconfounded, randomised trials of a gastroprotectant drug (defined as a PPI, prostaglandin analogue, or H2RA) versus control, or versus another gastroprotectant. Two independent researchers reviewed the search results and extracted the prespecified outcomes and key characteristics for each trial. We did meta-analyses of the effects of gastroprotectant drugs on ulcer development, bleeding, and mortality overall, according to the class of gastroprotectant, and according to the individual drug within a gastroprotectant class. FINDINGS: We identified comparisons of gastroprotectant versus control in 849 trials (142 485 participants): 580 prevention trials (110 626 participants), 233 healing trials (24 033 participants), and 36 trials for the treatment of acute upper gastrointestinal bleeding (7826 participants). Comparisons of one gastroprotectant drug versus another were available in 345 trials (64 905 participants), comprising 160 prevention trials (32 959 participants), 167 healing trials (28 306 participants), and 18 trials for treatment of acute upper gastrointestinal bleeding (3640 participants). The median number of patients in each trial was 78 (IQR 44.0-210.5) and the median duration was 1.4 months (0.9 2.8). In prevention trials, gastroprotectant drugs reduced development of endoscopic ulcers (odds ratio [OR] 0.27, 95% CI 0.25-0.29; p<0.0001), symptomatic ulcers (0.25, 0.22-0.29; p<0.0001), and upper gastrointestinal bleeding (0.40, 0.32-0.50; p<0.0001), but did not significantly reduce mortality (0.85, 0.69 1.04; p=0.11). Larger proportional reductions in upper gastrointestinal bleeding were observed for PPIs than for other gastroprotectant drugs (PPIs 0.21, 99% CI 0.12-0.36; prostaglandin analogues 0.63, 0.35-1.12; H2RAs 0.49, 0.30-0.80; phet=0.0005). Gastroprotectant drugs were effective in preventing bleeding irrespective of the use of non-steroidal anti-inflammatory drugs (phet=0.56). In healing trials, gastroprotectants increased endoscopic ulcer healing (3.49, 95% CI 3.28-3.72; p<0.0001), with PPIs more effective (5.22, 99% CI 4.00-6.80) than prostaglandin analogues (2.27, 1.91-2.70) and H2RAs (3.80, 3.44-4.20; phet<0.0001). In trials among patients with acute bleeding, gastroprotectants reduced further bleeding (OR 0.68, 95% CI 0.60-0.78; p<0.0001), blood transfusion (0.75, 0.65-0.88; p=0.0003), further endoscopic intervention (0.56, 0.45-0.70; p<0.0001), and surgery (0.72, 0.61-0.84; p<0.0001), but did not significantly reduce mortality (OR 0.90, 0.72-1.11; p=0.31). PPIs had larger protective effects than did H2RAs for further bleeding (phet=0.0107) and blood transfusion (phet=0.0130). INTERPRETATION: Gastroprotectants, in particular PPIs, reduce the risk of peptic ulcer disease and its complications and promote healing of peptic ulcers in a wide range of clinical circumstances. However, this meta-analysis might have overestimated the benefits owing to small study bias. FUNDING: UK Medical Research Council and the British Heart Foundation. PMID- 29475808 TI - Effects of tooth loss on brain structure: a voxel-based morphometry study. AB - PURPOSE: One of the most prominent issues in a super-aging society is the rapid increase in dementia patients. Cross-sectional studies in dentistry have indicated that patients with dementia have worse oral health compared to healthy people. The purpose of this study was to clarify the influence of tooth loss on brain structure by comparing the volumes of gray matter (GM) and white matter (WM) between edentulous and dentulous subjects. METHODS: Subjects were recruited from the Denture Clinic at Iwate Medical University Hospital Dental Center. Experiments were performed on edentulous (5 males, 8 females, 81.8+/-1.24years) and dentulous subjects (4 males, 7 females, 77.1+/-4.25years). Patients with dementia were excluded from this study. Brain volumes of GM and WM in edentulous and dentulous subjects were compared using intracranial volume, age, gender and history of hypertension as covariates. Analyzed brain areas were identified by transforming the Montreal Neurological Institute coordinate into the anatomical coordinate in edentulous subjects. RESULTS: The analysis of WM structural images found no morphological differences between dentulous and edentulous subjects. However, significant atrophy of GM was observed in the hippocampus, caudate nucleus and temporal pole of the right hemisphere in edentulous subjects. CONCLUSIONS: The results of this study suggest that tooth loss was a causal factor for volume reduction in brain areas related to memory, learning and cognition. PMID- 29475809 TI - Glass fiber-reinforced thermoplastics for use in metal-free removable partial dentures: combined effects of fiber loading and pigmentation on color differences and flexural properties. AB - PURPOSE: The purpose of this study was to investigate the combined effects of fiber loading and pigmentation on the color differences and flexural properties of glass fiber-reinforced thermoplastics (GFRTPs), for use in non-metal clasp dentures (NMCDs). METHODS: The GFRTPs consisted mainly of E-glass fibers, a polypropylene matrix, and a coloring pigment: the GFRTPs with various fiber loadings (0, 10, and 20mass%) and pigmentations (0, 1, 2, and 4mass%) were fabricated by using an injection molding. The color differences of GFRTPs were measured based on the Commission Internationale de l'Eclairage (CIE) Lab color system, by comparing with a commercially available NMCD. The flexural properties of GFRTPs were evaluated by using a three-point bending test, according to International Standards Organization (ISO) specification number 20795-1. RESULTS: The visible colors of GFRTPs with pigment contents of 2mass% were acceptable for gingival color, and the glass fibers harmonized well with the resins. The DeltaE* values of the GFRTPs with pigment contents of 2mass% obtained by using the CIE Lab system were lowest at all fiber loadings. For GFRTPs with fiber contents of 10 and 20mass% at 2mass% pigment content, these GFRTPs surpassed the ISO 20795-1 specification regarding flexural strength (> 60MPa) and modulus (> 1.5GPa). CONCLUSIONS: A combination of the results of color difference evaluation and mechanical examination indicates that the GFRTPs with fiber contents of 10 or 20mass%, and with pigment contents of 2mass% have acceptable esthetic appearance and sufficient rigidity for NMCDs. PMID- 29475811 TI - Alcohol and dementia: a complex relationship with potential for dementia prevention. PMID- 29475810 TI - Contribution of alcohol use disorders to the burden of dementia in France 2008 13: a nationwide retrospective cohort study. AB - BACKGROUND: Dementia is a prevalent condition, affecting 5-7% of people aged 60 years and older, and a leading cause of disability in people aged 60 years and older globally. We aimed to examine the association between alcohol use disorders and dementia risk, with an emphasis on early-onset dementia (<65 years). METHODS: We analysed a nationwide retrospective cohort of all adult (>=20 years) patients admitted to hospital in metropolitan France between 2008 and 2013. The primary exposure was alcohol use disorders and the main outcome was dementia, both defined by International Classification of Diseases, tenth revision discharge diagnosis codes. Characteristics of early-onset dementia were studied among prevalent cases in 2008-13. Associations of alcohol use disorders and other risk factors with dementia onset were analysed in multivariate Cox models among patients admitted to hospital in 2011-13 with no record of dementia in 2008-10. FINDINGS: Of 31 624 156 adults discharged from French hospitals between 2008 and 2013, 1 109 343 were diagnosed with dementia and were included in the analyses. Of the 57 353 (5.2%) cases of early-onset dementia, most were either alcohol related by definition (22 338 [38.9%]) or had an additional diagnosis of alcohol use disorders (10 115 [17.6%]). Alcohol use disorders were the strongest modifiable risk factor for dementia onset, with an adjusted hazard ratio of 3.34 (95% CI 3.28-3.41) for women and 3.36 (3.31-3.41) for men. Alcohol use disorders remained associated with dementia onset for both sexes (adjusted hazard ratios >1.7) in sensitivity analyses on dementia case definition (including Alzheimer's disease) or older study populations. Also, alcohol use disorders were significantly associated with all other risk factors for dementia onset (all p<0.0001). INTERPRETATION: Alcohol use disorders were a major risk factor for onset of all types of dementia, and especially early-onset dementia. Thus, screening for heavy drinking should be part of regular medical care, with intervention or treatment being offered when necessary. Additionally, other alcohol policies should be considered to reduce heavy drinking in the general population. FUNDING: None. PMID- 29475812 TI - Acorrelation study between histological results and thyroid ultrasound findings. The TI-RADS classification. AB - INTRODUCTION: There are several classifications based on thyroid ultrasound for selecting suspected malignant thyroid nodules. The Thyroid Imaging Reporting and Data System (TI-RADS) classification proposed by Horvath in 2009 includes 6 categories. OBJETIVES: To assess the sensitivity of the TI-RADS classification for diagnosing thyroid nodules. METHODS: A retrospective study of all patients who underwent thyroidectomy at our hospital (n=263) from September 2013 to December 2015. After thyroidectomy, histological results were correlated to the ultrasound findings reported. RESULTS: Of the 263 study patients, 75 (28.5%) were diagnosed with thyroid cancer and 188 (71.5%) with benign disease. Correlation of histological results with preoperative ultrasound reports showed an initial sensitivity of 65%. After excluding 15 patients diagnosed with occult microcarcinoma, sensitivity increased to 81.6%. The ultrasound images from 11 false negatives cases were then reassessed by a radiologist who knew histological diagnosis and reclassified 10 of them as TI-RADS>=4. This procedure could have increased sensitivity up to 98.3%. CONCLUSIONS: Although the sensitivity initially found in our study using the TI-RADS scale was relatively low, the value markedly improved when patients with occult microcarcinoma were excluded. Thus, use of the TI-RADS scale would allow for an adequate selection of patients amenable to fine needle aspiration of the nodule. PMID- 29475813 TI - Algorithmic approaches to the diagnosis of gallbladder intraluminal lesions on ultrasonography. AB - Ultrasound is a frequently used diagnostic tool for gallbladder diseases. Polypoid lesions are commonly depicted at routine abdominal ultrasonography (US). The characteristics of these lesions vary. Since most early malignant tumors in the gallbladder are asymptomatic, differentiation between malignancy and benignity is crucial. Knowledge of gallbladder polypoid lesions is important so that they can be appropriately included in the differential diagnosis in patients presenting with intra-gallbladder nodules on US. This article summarizes the algorithmic approach to the diagnosis of these lesions and our recent experience with contrast-enhanced US. The clinical and imaging features of gallbladder polypoid lesions are reviewed. PMID- 29475814 TI - Complete genome sequence of a multi-recombinant echovirus 6 strain isolated from CSF in Ahvaz, Southwestern Iran. AB - BACKGROUND: Echovirus 6 (E6), is one of the main enteroviral serotypes, was initially isolated from patients with aseptic meningitis (AM) and is a major cause of hospitalization among children and adults worldwide. METHODS: A cerebrospinal fluid (CSF) sample was collected from patient with clinically suspected aseptic meningitis (AM) in August 2011. Following detection of a virus and subsequent virus serotyping, the whole genome sequence was determined. The sequence of the VP1 region of the isolated strain E6 RA/E6/Ahvaz/Iran/2011 showed 79% (>75%) nucleotide and 94% (>85%) amino acid homology with prototype strain D'Amori. The isolated strain was identified as an E6 serotype. A specimen was cultured in a human rhabdomyosarcoma (RD) cell line. Following propagation, the virus was further analyzed using the plaque assay technique, reverse transcription PCR (RT-PCR), rapid amplification of CDNA ends (RACE), TA cloning, sequencing, phylogenetic analysis, Simplot and boot scanning analyses (ver. 3.5) were applied to find evidence of recombination in the isolated strain. RESULTS: The isolated Echo6 strain RA/E6/Ahvaz/Iran/2011 has been recorded in GenBank with a partial and complete genome accession numbers (KX619440) (KX198605), respectively. The complete genomic sequence was 7435 nt, with a 742 bp 5' UTR, 117 bp 3' UTR, and an open reading frame (ORF) encoding a polypeptide of 2191 amino acids. The nucleotide analysis of the VP1 and structural genomic regions of the isolated strain showed high similarity with strain E6-10887-99 isolated from patient with facial nerve paresis in Russia in 1999. The recombinations evidence were observed in the isolated strain E6 RA/E6/Ahvaz/Iran/2011 and found to have a high levels of inter-serotypic exchanges in 2C and 3A-3C genomic regions with Echovirus13 and Echovirus14, respectively. CONCLUSION: Full genome sequence analysis of enteroviral is required to understand the epidemiological pattern and to evaluate the new enterovirus circulating in community. PMID- 29475816 TI - Ground-Glass Component in Lung Adenocarcinoma and Better Survival. PMID- 29475815 TI - The Academy for the Advancement of Postmaterialist Sciences: Integrating Consciousness into Mainstream Science. PMID- 29475817 TI - Mini-Review: What Is New in Urolift? AB - CONTEXT: Lower urinary tract symptoms (LUTS) are one of the most common benign conditions affecting aging men. Among surgical procedures, minimally invasive treatment options have emerged with the main objective to be at least equally effective as current standard techniques, but with a more favourable safety profile. OBJECTIVE: To present the technical principle for prostatic urethral lift (PUL) and review clinical outcomes. EVIDENCE ACQUISITION: Medline, PubMed, the Cochrane database, and Embase were screened for randomised controlled trials, clinical trials, and reviews on PUL. EVIDENCE SYNTHESIS: Data from the L.I.F.T study proved that PUL can provide rapid and durable relief of LUTS without compromising sexual function. The BPH6 trial compared PUL with transurethral resection of the prostate (TURP), and its outcomes indicated that improvement of LUTS was more pronounced after TURP, whereas PUL was superior in terms of quality of recovery, ejaculatory function, and quality of sleep. CONCLUSIONS: PUL is an attractive option for selected patients who seek rapid and durable relief of LUTS with complete preservation of sexual function and fast recovery after intervention. PATIENT SUMMARY: Prostatic urethral lift is an efficient and safe minimally invasive procedure that offers rapid and durable relief of lower urinary tract symptoms without compromising sexual function. PMID- 29475818 TI - Outcome measures for children with movement disorders. AB - The huge contribution of advances in the pediatric neurosciences, improvements in clinical practice, and new therapeutic options, has led to the development of new models of treatment and rehabilitation for dystonia in the last decade. It is now generally agreed that a multidimensional therapeutic approach is needed for children with motor disorders, whose motor function-conceived as a complex perceptive, motor and cognitive process - is impaired at a crucial time in their development, with a fall out on how their various adaptive functions evolve. Neurophysiological studies, modern neuroimaging techniques, and advances in cognitive psychology have all contributed to improving our understanding of the potential effects of treatments in early age - not only on the symptoms, but also on plasticity processes and neuronal reorganization. The International Classification of Functioning, Disability and Health (ICF) promoted by the WHO, and the diffusion of family-centered models of healthcare have underscored the importance of the ecological perspective with a view to providing effective therapies and a satisfactory quality of life for dystonic children and their families. The advances made in this area have made it necessary to study and develope more appropriate treatment outcome measures. In the light of these aspects, there is still not enough literature on the generally-accepted, exhaustive dystonia assessment tools. Given these limits, it might be useful to discuss the strengths and weaknesses of the main tools currently used in this setting. PMID- 29475819 TI - Helsmoortel-Van der Aa Syndrome as emerging clinical diagnosis in intellectually disabled children with autistic traits and ocular involvement. AB - A recent syndromic condition with craniofacial dysmorphisms, comprising congenital ocular defect and neurodevelopmental delay named Helsmoortel-Van der Aa Syndrome (HVDAS) (OMIM#615873), has been described and molecularly defined, identifying pathogenic mutations in the ADNP gene (OMIM#611386) as biological cause. We report on two children, displaying intellectual disability (ID) and peculiar congenital eyes anomalies, both carrying a de novo nonsense mutation in the ADNP gene. The review of present and literature reports, suggests that the diagnosis of HVDAS should be suspected in patients with ID accompanied by behavioral features in the Autism Spectrum Disorder and distinctive craniofacial phenotype. Among dysmorphisms due to malformation of the periorbital region, ptosis appears to be particularly recurrent in HVDAS. Furthermore, the present patients could support the inclusion of the HVDAS associated with specific mutations clustering within a small ADNP genomic region among clinical conditions reminiscent of the blepharophimosis/mental retardation syndromes (BMRS). PMID- 29475820 TI - How do parents perceive adverse drug events of their children's anticonvulsant medication? AB - BACKGROUND: The main source of knowledge on adverse drug events (ADE) are physicians' reports in controlled clinical trials. In contrast, little is known about the parents' perception of ADE of anticonvulsants their children receive. METHODS: After approval by the local ethics committee, we performed a survey in a neuropediatric outpatient clinic of a university hospital. Based on a structured questionnaire, we interviewed parents of children with current anticonvulsant treatment regarding (i) their fears about potential ADE, (ii) experienced ADE according to parents, and (iii) implications of ADE on the child's life. RESULTS: Parents of 150 patients took part in the interview. (i) 95 (63.3%) parents expressed fears concerning ADE, mostly liver injury/liver failure (33 [22%]). (ii) 129 (86%) parents reported experienced ADE, mostly sedation (65 [43.3%]) and abnormal behavior (54 [36%]). (iii) Parents reported substantial implications of ADE on the child's daily life for 84 (56%) children, and 63 (42%) parents expressed a negative impact on the child's development. CONCLUSION: We recognized a great discrepancy between those ADE that were feared and those that were experienced. Parents feared life-threatening ADE and experienced less severe ADE that nevertheless have a negative impact on the child's daily life. PMID- 29475821 TI - Systematic Literature Review of Treatment Options and Clinical Outcomes for Patients With Higher-Risk Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia. AB - High-dose chemotherapy with allogeneic hematopoietic stem cell transplantation (allo-HSCT) can produce long-term remission in patients with higher-risk myelodysplastic syndromes (HR-MDS) and chronic myelomonocytic leukemia (CMML). However, this treatment regimen is not appropriate for elderly and/or comorbid patients; in these cases, azacitidine is a standard treatment. This systematic review was conducted to evaluate real-world evidence of treatment options for patients with HR-MDS/CMML. Medline and Embase (January 2006 to May 2016) were searched, in addition to conference proceedings and treatment guideline reviews. Studies on clinical effectiveness/efficacy outcomes with a sample size >=50 patients were included. From 1061 unique citations identified, 87 full-text articles were reviewed, of which 24 articles reported at least 1 outcome of interest. Studies showed that HR-MDS/CMML patients treated with a conventional chemotherapy regimen (CCR) have poorer overall survival (OS). Key findings from individual HR-MDS studies showed improved survival with azacitidine over CCRs and higher overall response rates with clofarabine relative to low-dose cytosine arabinoside (but no significant difference in 2-year OS favoring clofarabine). OS was highest for patients treated with allo-HSCT. Findings indicate limited real world data on treatment strategies available for HR-MDS/CMML patients. Most studies address the effect of chemotherapy or allo-HSCT on clinical outcomes, so are not applicable to elderly/comorbid patients who are too frail for those treatments. In particular, our analysis revealed limited evidence on viable options after failure of treatment with azacitidine, identifying a significant unmet need in this patient population. PMID- 29475822 TI - Gastric Perforation as a complication of intragastric balloon. AB - Obesity is considered the most common nutritional disorder in Western countries and is related to multiple morbidity and mortality. There are different options for obesity treatment, including diet, behavioral therapy, medications, and surgery. If patients do not meet the criteria for bariatric surgery, intragastric balloons may be used to achieve weight reduction. Currently, the intragastric balloon is one of the most common bariatric procedures in obese patients in Europe. Gastric perforation associated with intragastric balloon is a rare but dangerous complication. We report a case of a 42-year-old female patient who presented to the emergency department with acute abdomen. Chest x-ray in an erect posture indicated free gas under the diaphragm. She had undergone placement of an intragastric adjustable balloon device 13 months earlier and was overdue for removal of the balloon. In the emergency theater, a large perforated ulcer was found in the posterior wall of the stomach, which was repaired laparoscopically. Her postoperative course was uneventful. We also review the literature on intragastric balloon-induced gastric perforation. Our case is a very rare report of late gastric perforation after adjustable intragastric balloon placement. We recommend regular follow-up and removal in proper time after insertion of the gastric balloon. PMID- 29475823 TI - Acceptability, Use, and Safety of a Mobile Phone App (BlueIce) for Young People Who Self-Harm: Qualitative Study of Service Users' Experience. AB - BACKGROUND: Self-harm is common among adolescents and is associated with a number of negative psychosocial outcomes including a higher risk of suicide. Recent reviews highlight the lack of research into specific interventions for children and young people who self-harm. Developing innovative interventions that are coproduced with individuals with lived experience and that reduce self-harm are key challenges for self-harm prevention. OBJECTIVE: The aim of this study was to explore the acceptability, use, and safety of BlueIce, a mobile phone app for young people who self-harm and who are attending child and adolescent mental health services (CAMHS). METHODS: This study is part of a mixed methods phase 1 trial of BlueIce. Young people aged 12-17 years attending specialist CAMHS were recruited. Clinicians were invited to refer young people who were self-harming or who had a history of self-harm. On consent being obtained and baseline measures taken, participants used BlueIce as an adjunct to usual care for an initial familiarization period of 2 weeks. If after this time they wanted to continue, they used BlueIce for a further 10 weeks. Semistructured interviews were conducted at postfamiliarization (2 weeks after using BlueIce) and postuse (12 weeks after using BlueIce) to assess the acceptability, use, and safety of BlueIce. We undertook a qualitative analysis using a deductive approach, and then an inductive approach, to investigate common themes. RESULTS: Postfamiliarization interviews were conducted with 40 participants. Of these, 37 participants elected to use BlueIce, with postuse interviews being conducted with 33 participants. Following 6 key themes emerged from the data: (1) appraisal of BlueIce, (2) usability of BlueIce, (3) safety, (4) benefits of BlueIce, (5) agency and control, and (6) BlueIce less helpful. The participants reported that BlueIce was accessible, easy to use, and convenient. Many highlighted the mood diary and mood lifter sections as particularly helpful in offering a way to track their moods and offering new strategies to manage their thoughts to self-harm. No adverse effects were reported. For those who did not find BlueIce helpful, issues around motivation to stop self-harming impeded their ability to use the app. CONCLUSIONS: BlueIce was judged to be a helpful and safe way of supporting adolescents to manage thoughts of self-harming. Adolescents reported numerous benefits of using BlueIce, and all would recommend the app to other young people who were struggling with self-harm. These preliminary findings are encouraging and provide initial support for the acceptability of BlueIce as a self-help intervention used in conjunction with the traditional face-to-face therapy. PMID- 29475824 TI - Characterizing and Managing Missing Structured Data in Electronic Health Records: Data Analysis. AB - BACKGROUND: Missing data is a challenge for all studies; however, this is especially true for electronic health record (EHR)-based analyses. Failure to appropriately consider missing data can lead to biased results. While there has been extensive theoretical work on imputation, and many sophisticated methods are now available, it remains quite challenging for researchers to implement these methods appropriately. Here, we provide detailed procedures for when and how to conduct imputation of EHR laboratory results. OBJECTIVE: The objective of this study was to demonstrate how the mechanism of missingness can be assessed, evaluate the performance of a variety of imputation methods, and describe some of the most frequent problems that can be encountered. METHODS: We analyzed clinical laboratory measures from 602,366 patients in the EHR of Geisinger Health System in Pennsylvania, USA. Using these data, we constructed a representative set of complete cases and assessed the performance of 12 different imputation methods for missing data that was simulated based on 4 mechanisms of missingness (missing completely at random, missing not at random, missing at random, and real data modelling). RESULTS: Our results showed that several methods, including variations of Multivariate Imputation by Chained Equations (MICE) and softImpute, consistently imputed missing values with low error; however, only a subset of the MICE methods was suitable for multiple imputation. CONCLUSIONS: The analyses we describe provide an outline of considerations for dealing with missing EHR data, steps that researchers can perform to characterize missingness within their own data, and an evaluation of methods that can be applied to impute clinical data. While the performance of methods may vary between datasets, the process we describe can be generalized to the majority of structured data types that exist in EHRs, and all of our methods and code are publicly available. PMID- 29475825 TI - Near-Real-Time Surveillance of Illnesses Related to Shellfish Consumption in British Columbia: Analysis of Poison Center Data. AB - BACKGROUND: Data from poison centers have the potential to be valuable for public health surveillance of long-term trends, short-term aberrations from those trends, and poisonings occurring in near-real-time. This information can enable long-term prevention via programs and policies and short-term control via immediate public health response. Over the past decade, there has been an increasing use of poison control data for surveillance in the United States, Europe, and New Zealand, but this resource still remains widely underused. OBJECTIVE: The British Columbia (BC) Drug and Poison Information Centre (DPIC) is one of five such services in Canada, and it is the only one nested within a public health agency. This study aimed to demonstrate how DPIC data are used for routine public health surveillance in near-real-time using the case study of its alerting system for illness related to consumption of shellfish (ASIRCS). METHODS: Every hour, a connection is opened between the WBM software Visual Dotlab Enterprise, which holds the DPIC database, and the R statistical computing environment. This platform is used to extract, clean, and merge all necessary raw data tables into a single data file. ASIRCS automatically and retrospectively scans a 24-hour window within the data file for new cases related to illnesses from shellfish consumption. Detected cases are queried using a list of attributes: the caller location, exposure type, reasons for the exposure, and a list of keywords searched in the clinical notes. The alert generates a report that is tailored to the needs of food safety specialists, who then assess and respond to detected cases. RESULTS: The ASIRCS system alerted on 79 cases between January 2015 and December 2016, and retrospective analysis found 11 cases that were missed. All cases were reviewed by food safety specialists, and 58% (46/79) were referred to designated regional health authority contacts for follow-up. Of the 42% (33/79) cases that were not referred to health authorities, some were missing follow-up information, some were triggered by allergies to shellfish, and some were triggered by shellfish-related keywords appearing in the case notes for nonshellfish-related cases. Improvements were made between 2015 and 2016 to reduce the number of cases with missing follow-up information. CONCLUSIONS: The surveillance capacity is evident within poison control data as shown from the novel use of DPIC data for identifying illnesses related to shellfish consumption in BC. The further development of surveillance programs could improve and enhance response to public health emergencies related to acute illnesses, chronic diseases, and environmental exposures. PMID- 29475826 TI - Pharmacy Customers' Experiences With Electronic Prescriptions: Cross-Sectional Survey on Nationwide Implementation in Finland. AB - BACKGROUND: One of the forerunners in electronic health, Finland has introduced electronic prescriptions (ePrescriptions) nationwide by law. This has led to significant changes for pharmacy customers. Despite the worldwide ambition to develop ePrescription services, there are few reports of nationally adopted systems and particularly on the experiences of pharmacy customers. OBJECTIVE: The aim of this study was to investigate Finnish pharmacy customers' (1) experiences with purchasing medicines with ePrescriptions; (2) experiences with renewing ePrescriptions and acting on behalf of someone else at the pharmacy; (3) ways in which customers keep up to date with their ePrescriptions; and (4) overall satisfaction with ePrescriptions. METHODS: Questionnaires were distributed to 2913 pharmacy customers aged >=18 years purchasing prescription medicines for themselves with an ePrescription in 18 community pharmacies across Finland in autumn 2015. Customers' experiences were explored with 10 structured questions. The data were stored in SPSS for Windows and subjected to descriptive analysis, chi-square, Fisher exact, Kolmogorov-Smirnov, the Mann-Whitney U, and Kruskal Wallis tests. RESULTS: Completed questionnaires were returned by 1288 customers, a response rate of 44.19% (1288/2913). The majority of the respondents did not encounter any problems during pharmacy visits (1161/1278, 90.85%) and were informed about the current status of their ePrescriptions after their medication was dispensed (1013/1276, 79.44%). Over half of the respondents had usually received a patient instruction sheet from their physician (752/1255, 59.92%), and nearly all of them regarded its content as clear (711/724, 98.2%). Half of the respondents had renewed their ePrescriptions through the pharmacy (645/1281, 50.35%), and one-third of them had acted on behalf of someone else with ePrescriptions (432/1280, 33.75%). Problems were rarely encountered in the renewal process (49/628, 7.8%) or when acting on behalf of another person (25/418, 6.0%) at the pharmacy. The most common way of keeping up to date with ePrescriptions was to ask at the pharmacy (631/1278, 49.37%). The vast majority of the respondents were satisfied with ePrescriptions as a whole (1221/1274, 95.84%). CONCLUSIONS: Finnish pharmacy customers are satisfied with the recently implemented nationwide ePrescription system. They seldom have any difficulties purchasing medicines, renewing their ePrescriptions, or acting on behalf of someone else at the pharmacy. Customers usually keep up to date with their ePrescriptions by asking at the pharmacy. However, some customers are unaware of the practices or have difficulty keeping up to date with the status of their ePrescriptions. The provision of relevant information and assistance by health care professionals is therefore required to promote customers' adoption of the ePrescription system. PMID- 29475827 TI - Physiotherapy Questionnaires App to Deliver Main Musculoskeletal Assessment Questionnaires: Development and Validation Study. AB - BACKGROUND: Patient-reported outcomes (PROs) translate subjective outcomes into objective data that can be quantified and analyzed. Nevertheless, the use of PROs in their traditional paper format is not practical for clinical practice due to limitations associated with the analysis and management of the data. To address the need for a viable way to group and utilize the main functioning assessment tools in the field of musculoskeletal disorders, the Physiotherapy Questionnaires app was developed. OBJECTIVE: This study aims to explain the development of the app, to validate it using two questionnaires, and to analyze whether participants prefer to use the app or the paper version of the questionnaires. METHODS: In the first stage, the app for an Android operational system was developed. In the second stage, the aim was to select questionnaires that were most often used in musculoskeletal clinical practice and research. The Foot and Ankle Outcome Score (FAOS) and American Orthopaedic Foot and Ankle Society (AOFAS) questionnaire were selected to validate the app. In total, 50 participants completed the paper and app versions of the AOFAS and 50 completed the FAOS. The study's outcomes were the correlation of the data between the paper and app versions as well as the preference of the participants between the two versions. RESULTS: The app was approved by experts after the adaptations of the layout for mobile phones and a total of 18 questionnaires were included in the app. Moreover, the app allows the generation of PDF and Excel files with the patients' data. In regards to validity, the mean of the total scores of the FAOS were 91.54% (SD 8.86%) for the paper version and 91.74% (SD 9.20%) for the app. There was no statistically significant differences in the means of the total scores or the subscales (P=.11 .94). The mean total scores for the AOFAS were 93.94 (SD 8.47) for the paper version and 93.96 (SD 8.48) for the app. No statistically significant differences were found for the total scores for the AOFAS or the subscales (P>.99). The app showed excellent agreement with the paper version of the FAOS, with an ICC value of 0.98 for the total score (95% CI 0.98-0.99), which was also found for the AOFAS with the ICC for the total score of 0.99 (95% CI 0.98-0.99). For compliance, 72% (36/50) of the participants in the FAOS group and 94% (47/50) in the AOFAS group preferred the app version. CONCLUSIONS: The Physiotherapy Questionnaires app showed validity and high levels of compliance for the FAOS and AOFAS, which indicates it is not inferior to the paper version of these two questionnaires and confirms its viability and feasibility for use in clinical practice. PMID- 29475828 TI - Integration of eHealth Tools in the Process of Workplace Health Promotion: Proposal for Design and Implementation. AB - BACKGROUND: Electronic health (eHealth) and mobile health (mHealth) tools can support and improve the whole process of workplace health promotion (WHP) projects. However, several challenges and opportunities have to be considered while integrating these tools in WHP projects. Currently, a large number of eHealth tools are developed for changing health behavior, but these tools can support the whole WHP process, including group administration, information flow, assessment, intervention development process, or evaluation. OBJECTIVE: To support a successful implementation of eHealth tools in the whole WHP processes, we introduce a concept of WHP (life cycle model of WHP) with 7 steps and present critical and success factors for the implementation of eHealth tools in each step. METHODS: We developed a life cycle model of WHP based on the World Health Organization (WHO) model of healthy workplace continual improvement process. We suggest adaptations to the WHO model to demonstrate the large number of possibilities to implement eHealth tools in WHP as well as possible critical points in the implementation process. RESULTS: eHealth tools can enhance the efficiency of WHP in each of the 7 steps of the presented life cycle model of WHP. Specifically, eHealth tools can support by offering easier administration, providing an information and communication platform, supporting assessments, presenting and discussing assessment results in a dashboard, and offering interventions to change individual health behavior. Important success factors include the possibility to give automatic feedback about health parameters, create incentive systems, or bring together a large number of health experts in one place. Critical factors such as data security, anonymity, or lack of management involvement have to be addressed carefully to prevent nonparticipation and dropouts. CONCLUSIONS: Using eHealth tools can support WHP, but clear regulations for the usage and implementation of these tools at the workplace are needed to secure quality and reach sustainable results. PMID- 29475829 TI - The Patient Perspective on the Impact of Tenosynovial Giant Cell Tumors on Daily Living: Crowdsourcing Study on Physical Function and Quality of Life. AB - BACKGROUND: Tenosynovial giant cell tumor (TGCT) is a rare, benign lesion affecting the synovial lining of joints, bursae, and tendon sheaths. It is generally characterized as a locally aggressive and often recurring tumor. A distinction is made between localized- and diffuse-type. The impact of TGCT on daily living is currently ill-described. OBJECTIVE: The aim of this crowdsourcing study was to evaluate the impact of TGCT on physical function, daily activities, societal participation (work, sports, and hobbies), and overall quality of life from a patient perspective. The secondary aim was to define risk factors for deteriorated outcome in TGCT. METHODS: Members of the largest known TGCT Facebook community, PVNS is Pants!!, were invited to an e-survey, partially consisting of validated questionnaires, for 6 months. To confirm disease presence and TGCT type, patients were requested to share histological or radiological proof of TGCT. Unpaired t tests and chi-square tests were used to compare groups with and without proof and to define risk factors for deteriorated outcome. RESULTS: Three hundred thirty-seven questionnaires, originating from 30 countries, were completed. Median age at diagnosis was 33 (interquartile range [IQR]=25-42) years, majority was female (79.8% [269/337]), diffuse TGCT (70.3% [237/337]), and affected lower extremities (knee 70.9% [239/337] and hip 9.5% [32/337]). In 299 lower-extremity TGCT patients (32.4% [97/299]) with disease confirmation, recurrence rate was 36% and 69.5% in localized and diffuse type, respectively. For both types, pain and swelling decreased after treatment; in contrast, stiffness and range of motion worsened. Patients were limited in their employment (localized 13% [8/61]; diffuse 11.0% [21/191]) and sport-activities (localized 58% [40/69]; diffuse 63.9% [147/230]). Compared with general US population, all patients showed lower Patient-Reported Outcomes Measurements Information System Physical Function (PROMIS-PF), Short Form-12 (SF-12), and EuroQoL 5 Dimensions 5 Levels (EQ5D-5L) scores, considered clinically relevant, according to estimated minimal important difference (MID). Diffuse versus localized type scored almost 0.5 standard deviation lower for PROMIS-PF (P<.001) and demonstrated a utility score of 5% lower for EQ-5D-5L (P=.03). In localized TGCT, recurrent disease and >=2 surgeries negatively influenced scores of Visual Analog Scale (VAS) pain/stiffness, SF-12, and EQ-5D-5L (P<.05). In diffuse type, recurrence resulted in lower score for VAS, PROMIS-PF, SF-12, and EQ-5D-5L (P<.05). In both types, patients with treatment <=1year had significantly lower SF-12. CONCLUSIONS: TGCT has a major impact on daily living in a relatively young and working population. Patients with diffuse type, recurrent disease, and >=2 surgeries represent lowest functional and quality of life outcomes. Physicians should be aware that TGCT patients frequently continue to experience declined health-related quality of life and physical function and often remain limited in daily life, even after treatment(s). PMID- 29475830 TI - Eighteen doctors were struck off for sexual assault or rape in past four years. PMID- 29475832 TI - Hepatic F-Box Protein FBXW7 Maintains Glucose Homeostasis Through Degradation of Fetuin-A. AB - Type 2 diabetes mellitus (T2DM) has become one of the most serious and long-term threats to human health. However, the molecular mechanism that links obesity to insulin resistance remains largely unknown. Here, we show that F-box and WD repeat domain-containing 7 (FBXW7), an E3 ubiquitin protein ligase, is markedly downregulated in the liver of two obese mouse models and obese human subjects. We further identify a functional low-frequency human FBXW7 coding variant (p.Ala204Thr) in the Chinese population, which is associated with elevated blood glucose and T2DM risk. Notably, mice with liver-specific knockout of FBXW7 develop hyperglycemia, glucose intolerance, and insulin resistance even on a normal chow diet. Conversely, overexpression of FBXW7 in the liver not only prevents the development of high-fat diet-induced insulin resistance but also attenuates the disease signature of obese mice. Mechanistically, FBXW7 directly binds to hepatokine fetuin-A to induce its ubiquitination and subsequent proteasomal degradation, comprising an important mechanism maintaining glucose homeostasis. Thus, we provide evidence showing a beneficial role of FBXW7 in glucose homeostasis. PMID- 29475831 TI - Sleeve Gastrectomy Improves Glycemia Independent of Weight Loss by Restoring Hepatic Insulin Sensitivity. AB - Bariatric surgery dramatically improves glycemic control, yet the underlying molecular mechanisms remain controversial because of confounding weight loss. We performed sleeve gastrectomy (SG) on obese and diabetic leptin receptor-deficient mice (db/db). One week postsurgery, mice weighed 5% less and displayed improved glycemia compared with sham-operated controls, and islets from SG mice displayed reduced expression of diabetes markers. One month postsurgery SG mice weighed more than preoperatively but remained near-euglycemic and displayed reduced hepatic lipid droplets. Pair feeding of SG and sham db/db mice showed that surgery rather than weight loss was responsible for reduced glycemia after SG. Although insulin secretion profiles from islets of sham and SG mice were indistinguishable, clamp studies revealed that SG causes a dramatic improvement in muscle and hepatic insulin sensitivity accompanied by hepatic regulation of hepatocyte nuclear factor-alpha and peroxisome proliferator-activated receptor alpha targets. We conclude that long-term weight loss after SG requires leptin signaling. Nevertheless, SG elicits a remarkable improvement in glycemia through insulin sensitization independent of reduced feeding and weight loss. PMID- 29475833 TI - Physiologically Based Pharmacokinetic Modeling of Bosentan Identifies the Saturable Hepatic Uptake As a Major Contributor to Its Nonlinear Pharmacokinetics. AB - Bosentan is a substrate of hepatic uptake transporter organic anion-transporting polypeptides (OATPs), and undergoes extensive hepatic metabolism by cytochrome P450 (P450), namely, CYP3A4 and CYP2C9. Several clinical investigations have reported a nonlinear relationship between bosentan doses and its systemic exposure, which likely involves the saturation of OATP-mediated uptake, P450 mediated metabolism, or both in the liver. Yet, the underlying causes for the nonlinear bosentan pharmacokinetics are not fully delineated. To address this, we performed physiologically based pharmacokinetic (PBPK) modeling analyses for bosentan after its intravenous administration at different doses. As a bottom-up approach, PBPK modeling analyses were performed using in vitro kinetic parameters, other relevant parameters, and scaling factors. As top-down approaches, three different types of PBPK models that incorporate the saturation of hepatic uptake, metabolism, or both were compared. The prediction from the bottom-up approach (models 1 and 2) yielded blood bosentan concentration-time profiles and their systemic clearance values that were not in good agreement with the clinically observed data. From top-down approaches (models 3, 4, 5-1, and 5 2), the prediction accuracy was best only with the incorporation of the saturable hepatic uptake for bosentan. Taken together, the PBPK models for bosentan were successfully established, and the comparison of different PBPK models identified the saturation of the hepatic uptake process as a major contributing factor for the nonlinear pharmacokinetics of bosentan. PMID- 29475834 TI - Biosynthesis and Identification of Metabolites of Maraviroc and Their Use in Experiments to Delineate the Relative Contributions of Cytochrome P4503A4 versus 3A5. AB - Maraviroc (MVC) is a CCR5 coreceptor antagonist indicated in combination with other antiretroviral agents for the treatment of CCR5-tropic human immunodefinciency virus-1 infection. In this study, the metabolism of MVC was investigated in human liver microsomes to delineate the relative roles of CYP3A4 and CYP3A5. MVC is metabolized to five hydroxylated metabolites, all of which were biosynthesized and identified using mass and NMR spectroscopy. The sites of metabolism were the 2- and 3-positions of the 4,4-difluorocyclohexyl moiety and the methyl of the triazole moiety. Absolute configurations were ultimately ascertained by comparison to authentic standards. The biosynthesized metabolites were used for quantitative in vitro experiments in liver microsomes using cyp3cide, a selective inactivator of CYP3A4. (1S,2S)-2-OH-MVC was the main metabolite representing approximately half of the total metabolism, and CYP3A5 contributed approximately 40% to that pathway in microsomes from CYP3A5*1/*1 donors. The other four metabolites were almost exclusively metabolized by CYP3A4. (1S,2S)-2-hydroxylation also correlated to T-5 N-oxidation, a CYP3A5-specific activity. These data are consistent with clinical pharmacokinetic data wherein CYP3A5 extensive metabolizer subjects showed a modestly lower exposure to MVC. PMID- 29475835 TI - Debunking early single sport specialisation and reshaping the youth sport experience: an NBA perspective. PMID- 29475836 TI - Why are acute admissions to hospital of children under 5 years of age increasing in the UK? PMID- 29475837 TI - Socially awkward: how can we better promote walking as a social behaviour? PMID- 29475838 TI - What statistical data of observational performance can tell us and what they cannot: the case of Dutee Chand v. AFI & IAAF. PMID- 29475839 TI - Lowest perceived exertion in the late morning due to effects of the endogenous circadian system. PMID- 29475840 TI - Ten treatments to avoid in patients with lower limb tendon pain. PMID- 29475842 TI - Erratum. Validation of the Diabetes Prevention Trial-Type 1 Risk Score in the TrialNet Natural History Study. Diabetes Care 2011;34:1785-1787. PMID- 29475841 TI - Changes in Health Insurance Coverage Under the Affordable Care Act: A National Sample of U.S. Adults With Diabetes, 2009 and 2016. AB - OBJECTIVE: To assess national changes in health insurance coverage and related costs before and after implementation of the Affordable Care Act (ACA) among U.S. adults with diabetes. RESEARCH DESIGN AND METHODS: Data were cross-sectional from the 2009 and 2016 National Health Interview Surveys (NHIS). Participants were adults age >=18 years with a previous diagnosis of diabetes who self-reported on their health insurance coverage, demographic information, diabetes-related factors, and amount spent on medical expenses and insurance premiums (N = 6,220). RESULTS: Among adults with diabetes age 18-64 years, health insurance coverage increased from 84.7% in 2009 to 90.1% in 2016 (P < 0.001). Coverage remained near universal for those age >=65 years (99.5%). For adults age 18-64 years, coverage increased for almost all subgroups and significantly for men; non-Hispanic whites, non-Hispanic blacks, and Hispanics; those who were married; those with less than or more than a high school education, family income <$35,000, or diabetes duration <5 or >15 years; and those taking oral agents (P < 0.05 for all). Among adults age 18-64 years, Medicaid coverage significantly increased between 2009 and 2016 (19.4% vs. 24.3%, P = 0.006), and for those with private insurance, 7.8% acquired their plan through HealthCare.gov. For adults age >=65 years, private insurance decreased and Medicare Part D increased (P < 0.007 for both). Among those age 18-64 years with an income <$35,000, the proportion of income spent on family medical costs decreased (6.3% vs. 4.8% for 2009 vs. 2016, respectively; P = 0.004). CONCLUSIONS: Health insurance coverage among adults with diabetes age 18-64 years increased significantly after implementation of the ACA, and medical costs to families decreased among those with lower incomes. PMID- 29475843 TI - Global Economic Burden of Diabetes in Adults: Projections From 2015 to 2030. AB - OBJECTIVE: Despite the importance of diabetes for global health, the future economic consequences of the disease remain opaque. We forecast the full global costs of diabetes in adults through the year 2030 and predict the economic consequences of diabetes if global targets under the Sustainable Development Goals (SDG) and World Health Organization Global Action Plan for the Prevention and Control of Noncommunicable Diseases 2013-2020 are met. RESEARCH DESIGN AND METHODS: We modeled the absolute and gross domestic product (GDP)-relative economic burden of diabetes in individuals aged 20-79 years using epidemiological and demographic data, as well as recent GDP forecasts for 180 countries. We assumed three scenarios: prevalence and mortality 1) increased only with urbanization and population aging (baseline scenario), 2) increased in line with previous trends (past trends scenario), and 3) achieved global targets (target scenario). RESULTS: The absolute global economic burden will increase from U.S. $1.3 trillion (95% CI 1.3-1.4) in 2015 to $2.2 trillion (2.2-2.3) in the baseline, $2.5 trillion (2.4-2.6) in the past trends, and $2.1 trillion (2.1-2.2) in the target scenarios by 2030. This translates to an increase in costs as a share of global GDP from 1.8% (1.7-1.9) in 2015 to a maximum of 2.2% (2.1-2.2). CONCLUSIONS: The global costs of diabetes and its consequences are large and will substantially increase by 2030. Even if countries meet international targets, the global economic burden will not decrease. Policy makers need to take urgent action to prepare health and social security systems to mitigate the effects of diabetes. PMID- 29475844 TI - Erratum. Impact of Lifestyle and Metformin Interventions on the Risk of Progression to Diabetes and Regression to Normal Glucose Regulation in Overweight or Obese People With Impaired Glucose Regulation. Diabetes Care 2017;40:1668 1677. PMID- 29475845 TI - Training in genitourinary medicine is still good, despite the Health and Social Care Act. PMID- 29475847 TI - Risks of reformulation: French patients complain after Merck modifies levothyroxine pills. PMID- 29475846 TI - No evidence that employing management consultants improves efficiency in NHS. PMID- 29475848 TI - Psychiatrist who failed in care of teenager with epilepsy who died in bath is suspended for 12 months. PMID- 29475850 TI - Association of hand and arm disinfection with asthma control in US nurses. AB - OBJECTIVES: To investigate the association between occupational exposure to disinfectants/antiseptics used for hand hygiene and asthma control in nurses. METHODS: In 2014, we invited female nurses with asthma drawn from the Nurses' Health Study II to complete two supplemental questionnaires on their occupation and asthma (cross-sectional study, response rate: 80%). Among 4055 nurses (mean age: 59 years) with physician-diagnosed asthma and asthma medication use in the past year, we examined asthma control, as defined by the Asthma Control Test (ACT). Nurses were asked about the daily frequency of hand hygiene tasks: 'wash/scrub hands with disinfectants/hand sanitizers' (hand hygiene) and 'wash/scrub arms with disinfecting products' (surrogate of surgical hand/arm antisepsis). Analyses were adjusted for age, race, ethnicity, smoking status and body mass index. RESULTS: Nurses with partly controlled asthma (ACT: 20-24, 50%) and poorly controlled asthma (ACT <=19, 18%) were compared with nurses with controlled asthma (ACT=25, 32%). In separate models, both hand and arm hygiene were associated with poorly controlled asthma. After mutual adjustment, only arm hygiene was associated with poorly controlled asthma: OR (95% CI) for <1 time/day, 1.38 (1.06 to 1.80); >=1 time/day, 1.96 (1.52 to 2.51), versus never. We observed a consistent dose-response relationship between frequency of arm hygiene tasks (never to >10 times/day) and poor asthma control. Associations persisted after further adjustment for surfaces/instruments disinfection tasks. CONCLUSIONS: Frequency of hand/arm hygiene tasks in nurses was associated with poor asthma control. The results suggest an adverse effect of products used for surgical hand/arm antisepsis. This potential new occupational risk factor for asthma warrants further study. PMID- 29475849 TI - Dysregulated invertebrate tropomyosin-dectin-1 interaction confers susceptibility to allergic diseases. AB - The key factors underlying the development of allergic diseases-the propensity for a minority of individuals to develop dysfunctional responses to harmless environmental molecules-remain undefined. We report a pathway of immune counter regulation that suppresses the development of aeroallergy and shrimp-induced anaphylaxis. In mice, signaling through epithelially expressed dectin-1 suppresses the development of type 2 immune responses through inhibition of interleukin-33 (IL-33) secretion and the subsequent recruitment of IL-13 producing innate lymphoid cells. Although this homeostatic pathway is functional in respiratory epithelial cells from healthy humans, it is dramatically impaired in epithelial cells from asthmatic and chronic rhinosinusitis patients, resulting in elevated IL-33 production. Moreover, we identify an association between a single-nucleotide polymorphism (SNP) in the dectin-1 gene loci and reduced pulmonary function in two cohorts of asthmatics. This intronic SNP is a predicted eQTL (expression quantitative trait locus) that is associated with reduced dectin 1 expression in human tissue. We identify invertebrate tropomyosin, a ubiquitous arthropod-derived molecule, as an immunobiologically relevant dectin-1 ligand that normally serves to restrain IL-33 release and dampen type 2 immunity in healthy individuals. However, invertebrate tropomyosin presented in the context of impaired dectin-1 function, as observed in allergic individuals, leads to unrestrained IL-33 secretion and skewing of immune responses toward type 2 immunity. Collectively, we uncover a previously unrecognized mechanism of protection against allergy to a conserved recognition element omnipresent in our environment. PMID- 29475852 TI - Alcohol dysregulates miR-148a in hepatocytes through FoxO1, facilitating pyroptosis via TXNIP overexpression. AB - OBJECTIVE: Alcoholic liver disease (ALD) is a leading cause of death among chronic liver diseases. However, its pathogenesis has not been completely established. MicroRNAs (miRNAs) are key contributors to liver diseases progression. This study investigated hepatocyte-abundant miRNAs dysregulated by ALD, its impact on hepatocyte injury and the underlying basis. DESIGN: Alcoholic hepatitis (AH) human and animal liver samples and hepatocytes were used to assess miR-148a levels. Pre-miR-148a was delivered specifically to hepatocytes in vivo using lentivirus. Immunoblottings, luciferase reporter assays, chromatin immunoprecipitation and immunofluorescence assays were carried out in cell models. RESULTS: The miRNA profile and PCR analyses enabled us to find substantial decrease of miR-148a in the liver of patients with AH. In mice subjected to Lieber-DeCarli alcohol diet or binge alcohol drinking, miR-148a levels were also markedly reduced. In cultured hepatocytes and mouse livers, alcohol exposure inhibited forkhead box protein O1 (FoxO1) expression, which correlated with miR-148a levels and significantly decreased in human AH specimens. FoxO1 was identified as a transcription factor for MIR148A transactivation. MiR-148a directly inhibited thioredoxin-interacting protein (TXNIP) expression. Consequently, treatment of hepatocytes with ethanol resulted in TXNIP overexpression, activating NLRP3 inflammasome and caspase-1-mediated pyroptosis. These events were reversed by miR-148a mimic or TXNIP small interfering RNA transfection. Hepatocyte-specific delivery of miR-148a to mice abrogated alcohol-induced TXNIP overexpression and inflammasome activation, attenuating liver injury. CONCLUSION: Alcohol decreases miR-148a expression in hepatocytes through FoxO1, facilitating TXNIP overexpression and NLRP3 inflammasome activation, which induces hepatocyte pyroptosis. Our findings provide information on novel targets for reducing incidence and progression of ALD. PMID- 29475853 TI - Acupuncture 'dose' (number of treatments) and insurance benefits in the USA. AB - BACKGROUND: An adequate treatment dose, including a sufficient number of acupuncture treatments, is important for the clinical effectiveness of acupuncture treatment for common conditions. OBJECTIVE: To examine the characteristics of US adults who used a full course of acupuncture (>=6 treatments), a short course (1-5 treatments) or no acupuncture, including use of insurance benefits for acupuncture among users. METHODS: We used population-based survey data from the 2012 National Health Interview Survey (NHIS), the most current nationally representative data including use of acupuncture. We described subgroups of acupuncture users and used logistic regression to estimate the odds of past year acupuncture use versus non-use and completion of a full treatment course versus a short course. Covariates included demographic factors and health status. Analyses used strata, weights and clustering to account for the complex sample design. RESULTS: Among acupuncture users, 38% completed a full course. Acupuncture use was low (1.5%), but odds were higher among women and those with greater education and less poverty. Those who used acupuncture insurance benefits and who had greater education were more likely to receive a full treatment course. Insurance benefits attenuated disparities in use by sex and race/ethnicity. CONCLUSION: Nationally, most people who use acupuncture do not receive a full treatment course. Considering evidence of effectiveness, low risk and relatively low cost of delivery, acupuncture could play a larger role in non pharmaceutical treatment of common conditions such as pain. Policymakers should consider that, without insurance benefits for acupuncture, people are less likely to complete a full treatment course, which may contribute to disparities in use and health outcomes. PMID- 29475854 TI - Sialendoscopy enhances salivary gland function in Sjogren's syndrome: a 6-month follow-up, randomised and controlled, single blind study. AB - OBJECTIVES: To assess the effect of sialendoscopy of the major salivary glands on salivary flow and xerostomia in patients with Sjogren's syndrome (SS). METHODS: Forty-nine patients with SS were randomly assigned to a control group (n=15) and two intervention groups: irrigation of the major glands with saline (n=16) or with saline followed by triamcinolone acetonide (TA) in saline (n=18). Unstimulated whole saliva flow (UWS), chewing-stimulated whole saliva flow (SWS), citric acid-stimulated parotid flow (SPF), Clinical Oral Dryness Score (CODS), Xerostomia Inventory (XI) score and the European League Against Rheumatism (EULAR) SS Patient-Reported Index (ESSPRI) were obtained 1 week (T0) before, and 1 (T1), 8 (T8), 16 (T16) and 24 (T24) weeks after sialendoscopy. RESULTS: Median baseline UWS, SWS and SPF scores were 0.14, 0.46 and 0.22 mL/min, respectively. After intervention, significant increases in UWS and SWS were observed in the saline group (at T8 (P=0.013) and T24 (P=0.004)) and the saline/TA group (at T24 (P=0.03) and T=16 (P=0.035)). SPF was increased significantly in the saline/TA group at T24 (P=0.03). XI scores declined after sialendoscopy in both intervention groups. Compared with the control group, CODS, XI and ESSPRI improved in the intervention groups. UWS, SWS and SPF were higher in the intervention groups compared with the control group, but these differences were not significant except for SPF in the saline/TA group at T24 (P=0.005). CONCLUSIONS: Irrigation of the major salivary glands in patients with SS enhances salivary flow and reduces xerostomia up to 6 months after sialendoscopy. PMID- 29475851 TI - Regulation of Glutamate Signaling in the Sensorimotor Circuit by CASY 1A/Calsyntenin in Caenorhabditis elegans. AB - Locomotion is one of the most prominent behaviors in the nematode Caenorhabditis elegans Neuronal circuits that ultimately produce coordinated dorso-ventral sinusoidal bends mediate this behavior. Synchronized locomotion requires an intricate balance between excitation and inhibition at the neuromuscular junctions (NMJ), the complex cellular and molecular mechanisms of which are not fully understood. Here, we describe the role of a cell adhesion molecule CASY-1, which functions to maintain this balance at the NMJ. In this study, we dissect out mechanisms by which the longer CASY-1A isoform could be affecting the excitatory cholinergic signaling at the NMJ by modulating the activity of sensory neurons. Mutants in casy-1 appear to have hyperactive sensory neurons, resulting in accelerated locomotion and motor circuit activity. These sensory neurons mediate increased motor activity via enhanced glutamate release. Using genetic, pharmacological, and optogenetic manipulations, we establish that CASY-1A is required to monitor the activity of these neurons. Our study illustrates a novel neuromodulatory role of CASY-1-mediated signaling in regulating the excitation inhibition balance of the motor circuit. PMID- 29475855 TI - Have the 10-year outcomes of patients with early inflammatory arthritis improved in the new millennium compared with the decade before? Results from the Norfolk Arthritis Register. AB - OBJECTIVE: To compare the 10-year outcome (disease activity, disability, mortality) of two cohorts of patients with inflammatory polyarthritis (IP) recruited 10 years apart. METHODS: Patients with IP were recruited to the Norfolk Arthritis Register from 1990 to 1994 (cohort 1 (C1)) and from 2000 to 2004 (cohort 2 (C2)). Demographic and clinical data were collected at baseline and at years 1, 2, 3, 5, 7 and 10. Longitudinal disease activity (swollen/tender 51 joint counts (SJC51/TJC51)) and disability (Health Assessment Questionnaire (HAQ)) were compared between the cohorts using population-average negative binomial regression and generalised estimating equation analysis, respectively. Risk of 10-year mortality was compared between cohorts using Cox models. Risk of cardiovascular disease (CVD) mortality was compared between cohorts using competing risks analysis. Mortality rate ratios (MRR), adjusted for changes in mortality risk of the general population, were calculated using Poisson regression. RESULTS: In total 1653 patients were recruited (C1=1022, C2=631). Patients in C2 had 17% lower SJC51 than C1 over 10 years (95% CI -23% to -10%), whereas TJC51 and HAQ were comparable. C2 patients had reduced risk of all-cause and CVD mortality compared with C1 (all-cause: HR 0.72, 95% CI 0.56 to 0.95; CVD: subhazard ratio 0.58, 95% CI 0.37 to 0.93). After accounting for changes in mortality risk in the general population, the difference in mortality was non significant (all-cause: MRR 0.78, 95% CI 0.56 to 1.10; CVD: MRR 0.77, 95% CI 0.48 to 1.24). CONCLUSION: Disease activity significantly improved in the new millennium, whereas disability and mortality were unchanged. PMID- 29475856 TI - Biomechanical properties of bone are impaired in patients with ACPA-positive rheumatoid arthritis and associated with the occurrence of fractures. AB - OBJECTIVES: Bone loss is a well-established consequence of rheumatoid arthritis (RA). To date, bone disease in RA is exclusively characterised by bone density measurements, while the functional properties of bone in RA are undefined. This study aimed to define the impact of RA on the functional properties of bone, such as failure load and stiffness. METHODS: Micro-finite element analysis (uFEA) was carried out to measure failure load and stiffness of bone based on high resolution peripheral quantitative CT data from the distal radius of anti citrullinated protein antibody (ACPA)-positive RA (RA+), ACPA-negative RA (RA-) and healthy controls (HC). In addition, total, trabecular and cortical bone densities as well as microstructural parameters of bone were recorded. Correlations and multivariate models were used to determine the role of demographic, disease-specific and structural data of bone strength as well as its relation to prevalent fractures. RESULTS: 276 individuals were analysed. Failure load and stiffness (both P<0.001) of bone were decreased in RA+, but not RA-, compared with HC. Lower bone strength affected both female and male patients with RA+, was related to longer disease duration and significantly (stiffness P=0.020; failure load P=0.012) associated with the occurrence of osteoporotic fractures. Impaired bone strength was correlated with altered bone density and microstructural parameters, which were all decreased in RA+. Multivariate models showed that ACPA status (P=0.007) and sex (P<0.001) were independently associated with reduced biomechanical properties of bone in RA. CONCLUSION: In summary, uFEA showed that bone strength is significantly decreased in RA+ and associated with fractures. PMID- 29475857 TI - Comorbid TNF-mediated heart valve disease and chronic polyarthritis share common mesenchymal cell-mediated aetiopathogenesis. AB - OBJECTIVES: Patients with rheumatoid arthritis and spondyloarthritisshow higher mortality rates, mainly caused by cardiac comorbidities. The TghuTNF (Tg197) arthritis model develops tumour necrosis factor (TNF)-driven and mesenchymalsynovial fibroblast (SF)-dependent polyarthritis. Here, we investigate whether this model develops, similarly to human patients, comorbid heart pathology and explore cellular and molecular mechanisms linking arthritis to cardiac comorbidities. METHODS: Histopathological analysis and echocardiographic evaluation of cardiac function were performed in the Tg197 model. Valve interstitial cells (VICs) were targeted by mice carrying the ColVI-Cretransgene. Tg197 ColVI-Cre Tnfr1fl/fl and Tg197 ColVI-Cre Tnfr1cneo/cneo mutant mice were used to explore the role of mesenchymal TNF signalling in the development of heart valve disease. Pathogenic VICs and SFs were further analysed by comparative RNA-sequencing analysis. RESULTS: Tg197 mice develop left-sided heart valve disease, characterised by valvular fibrosis with minimal signs of inflammation. Thickened valve areas consist almost entirely of hyperproliferative ColVI expressing mesenchymal VICs. Development of pathology results in valve stenosis and left ventricular dysfunction, accompanied by arrhythmic episodes and, occasionally, valvular regurgitation. TNF dependency of the pathology was indicated by disease modulation following pharmacological inhibition or mesenchymal-specific genetic ablation or activation of TNF/TNFR1 signalling. Tg197-derived VICs exhibited an activated phenotype ex vivo, reminiscent of the activated pathogenic phenotype of Tg197-derived SFs. Significant functional similarities between SFs and VICs were revealed by RNA-seq analysis, demonstrating common cellular mechanisms underlying TNF-mediated arthritides and cardiac comorbidities. CONCLUSIONS: Comorbidheart valve disease and chronic polyarthritis are efficiently modelled in the Tg197 arthritis model and share common TNF/TNFR1-mediated, mesenchymal cell-specific aetiopathogenic mechanisms. PMID- 29475859 TI - Government takes steps to reduce annual burden of medication errors in England. PMID- 29475858 TI - The STAT4 SLE risk allele rs7574865[T] is associated with increased IL-12-induced IFN-gamma production in T cells from patients with SLE. AB - OBJECTIVES: Genetic variants in the transcription factor STAT4 are associated with increased susceptibility to systemic lupus erythematosus (SLE) and a more severe disease phenotype. This study aimed to clarify how the SLE-associated intronic STAT4 risk allele rs7574865[T] affects the function of immune cells in SLE. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from 52 genotyped patients with SLE. Phosphorylation of STAT4 (pSTAT4) and STAT1 (pSTAT1) in response to interferon (IFN)-alpha, IFN-gamma or interleukin (IL)-12, total levels of STAT4, STAT1 and T-bet, and frequency of IFN-gamma+ cells on IL-12 stimulation were determined by flow cytometry in subsets of immune cells before and after preactivation of cells with phytohaemagglutinin (PHA) and IL-2. Cellular responses and phenotypes were correlated to STAT4 risk allele carriership. Janus kinase inhibitors (JAKi) selective for TYK2 (TYK2i) or JAK2 (JAK2i) were evaluated for inhibition of IL-12 or IFN-gamma-induced activation of SLE PBMCs. RESULTS: In resting PBMCs, the STAT4 risk allele was neither associated with total levels of STAT4 or STAT1, nor cytokine-induced pSTAT4 or pSTAT1. Following PHA/IL-2 activation, CD8+ T cells from STAT4 risk allele carriers displayed increased levels of STAT4 resulting in increased pSTAT4 in response to IL-12 and IFN-alpha, and an augmented IL-12-induced IFN-gamma production in CD8+ and CD4+ T cells. The TYK2i and the JAK2i efficiently blocked IL-12 and IFN-gamma-induced activation of PBMCs from STAT4 risk patients, respectively. CONCLUSIONS: T cells from patients with SLE carrying the STAT4 risk allele rs7574865[T] display an augmented response to IL-12 and IFN-alpha. This subset of patients may benefit from JAKi treatment. PMID- 29475860 TI - Microbiota-Mediated Modulation of Organophosphate Insecticide Toxicity by Species Dependent Interactions with Lactobacilli in a Drosophila melanogaster Insect Model. AB - Despite the benefits to the global food supply and agricultural economies, pesticides are believed to pose a threat to the health of both humans and wildlife. Chlorpyrifos (CP), a commonly used organophosphate insecticide, has poor target specificity and causes acute neurotoxicity in a wide range of species via the suppression of acetylcholinesterase. This effect is exacerbated 10- to 100-fold by chlorpyrifos oxon (CPO), a principal metabolite of CP. Since many animal-associated symbiont microorganisms are known to hydrolyze CP into CPO, we used a Drosophila melanogaster insect model to investigate the hypothesis that indigenous and probiotic bacteria could affect CP metabolism and toxicity. Antibiotic-treated and germfree D. melanogaster insects lived significantly longer than their conventionally reared counterparts when exposed to 10 MUM CP. Drosophila melanogaster gut-derived Lactobacillus plantarum, but not Acetobacterindonesiensis, was shown to metabolize CP. Liquid chromatography tandem-mass spectrometry confirmed that the L. plantarum isolate preferentially metabolized CP into CPO when grown in CP-spiked culture medium. Further experiments showed that monoassociating germfree D. melanogaster with the L. plantarum isolate could reestablish a conventional-like sensitivity to CP. Interestingly, supplementation with the human probiotic Lactobacillus rhamnosus GG (a strain that binds but does not metabolize CP) significantly increased the survival of the CP-exposed germfree D. melanogaster This suggests strain-specific differences in CP metabolism may exist among lactobacilli and emphasizes the need for further investigation. In summary, these results suggest that (i) CPO formation by the gut microbiota can have biologically relevant consequences for the host, and (ii) probiotic lactobacilli may be beneficial in reducing in vivo CP toxicity.IMPORTANCE An understudied area of research is how the microbiota (microorganisms living in/on an animal) affects the metabolism and toxic outcomes of environmental pollutants such as pesticides. This study focused specifically on how the microbial biotransformation of chlorpyrifos (CP; a common organophosphate insecticide) affected host exposure and toxicity parameters in a Drosophila melanogaster insect model. Our results demonstrate that the biotransformation of CP by the gut microbiota had biologically relevant and toxic consequences on host health and that certain probiotic lactobacilli may be beneficial in reducing CP toxicity. Since inadvertent pesticide exposure is suspected to negatively impact the health of off-target species, these findings may provide useful information for wildlife conservation and environmental sustainability planning. Furthermore, the results highlight the need to consider microbiota composition differences between beneficial and pest insects in future insecticide designs. More broadly, this study supports the use of beneficial microorganisms to modulate the microbiota-mediated biotransformation of xenobiotics. PMID- 29475861 TI - Inactivation Efficacy of Nonthermal Plasma-Activated Solutions against Newcastle Disease Virus. AB - In recent years, plasma-activated solutions (PASs) have made good progress in the disinfection of medical devices, tooth whitening, and fruit preservation. In this study, we investigated the inactivation efficacy of Newcastle disease virus by PASs. Water, 0.9% NaCl, and 0.3% H2O2 were excited by plasma to obtain the corresponding solutions PAS(H2O), PAS(NaCl), and PAS(H2O2). The complete inactivation of virus after PAS treatment for 30 min was confirmed by the embryo lethality assay (ELA) and hemagglutination (HA) test. Scanning electron microscopy (SEM) results showed that the morphology of the viral particle changed under PAS treatments. The total protein concentration of virus decreased as measured by a Bradford protein assay due to PAS treatment. The nucleic acid integrity assay demonstrated that viral RNA degraded into smaller fragments. Moreover, the physicochemical properties of PASs, including the oxidation reduction potential (ORP), electrical conductivity, and H2O2 concentration, and electron spin resonance spectra analysis indicated that reactive oxygen and nitrogen species play a major role in the virus inactivation. Therefore, the application of PASs, as an environmentally friendly method, would be a promising alternative strategy in poultry industries.IMPORTANCE Newcastle disease (ND), as an infectious viral disease of avian species, caused significant economic losses to domestic animal and poultry industries. The traditional chemical sanitizers, such as chlorine-based products, are associated with risks of by-product formation with carcinogenic effects and environmental pollution. On the basis of this, plasma-activated water as a green disinfection product is a promising alternative for applications in stock farming and sterilization in hospitals and public places. In this study, we explored the inactivation efficacy of different plasma-activated solutions (PASs) against ND virus (NDV) and the possible underlying mechanisms. Our results demonstrated that reactive oxygen and nitrogen species detected in PASs, including short-lived OH and NO and long-lived H2O2, changed the morphology, destroyed the RNA structure, and degraded the protein of the virus, consequently resulting in virus inactivation. These lay a foundation for the application of PASs to resolve the issues of public health and environmental sanitation. PMID- 29475862 TI - Assessing Performance of Spore Samplers in Monitoring Aeromycobiota and Fungal Plant Pathogen Diversity in Canada. AB - Spore samplers are widely used in pathogen surveillance but not so much for monitoring the composition of aeromycobiota. In Canada, a nationwide spore sampling network (AeroNet) was established as a pilot project to assess fungal community composition in air and rain samples collected using three different spore samplers in the summers of 2010 and 2011. Metabarcodes of the internal transcribed spacer (ITS) were exhaustively characterized for three of the network sites, in British Columbia (BC), Quebec (QC), and Prince Edward Island (PEI), to compare performance of the samplers. Sampler type accounted for ca. 20% of the total explainable variance in aeromycobiota compositional heterogeneity, with air samplers recovering more Ascomycota and rain samplers recovering more Basidiomycota. Spore samplers showed different abilities to collect 27 fungal genera that are plant pathogens. For instance, Cladosporium spp., Drechslera spp., and Entyloma spp. were collected mainly by air samplers, while Fusarium spp., Microdochium spp., and Ustilago spp. were recovered more frequently with rain samplers. The diversity and abundance of some fungi were significantly affected by sampling location and time (e.g., Alternaria and Bipolaris) and weather conditions (e.g., Mycocentrospora and Leptosphaeria), and depended on using ITS1 or ITS2 as the barcoding region (e.g., Epicoccum and Botrytis). The observation that Canada's aeromycobiota diversity correlates with cooler, wetter conditions and northward wind requires support from more long-term data sets. Our vision of the AeroNet network, combined with high-throughput sequencing (HTS) and well-designed sampling strategies, may contribute significantly to a national biovigilance network for protecting plants of agricultural and economic importance in Canada.IMPORTANCE The current study compared the performance of spore samplers for collecting broad-spectrum air- and rain-borne fungal pathogens using a metabarcoding approach. The results provided a thorough characterization of the aeromycobiota in the coastal regions of Canada in relation to the influence of climatic factors. This study lays the methodological basis to eventually develop knowledge-based guidance on pest surveillance by assisting in the selection of appropriate spore samplers. PMID- 29475863 TI - Environmental Controls of Oyster-Pathogenic Vibrio spp. in Oregon Estuaries and a Shellfish Hatchery. AB - Vibrio spp. have been a persistent concern for coastal bivalve hatcheries, which are vulnerable to environmental pathogens in the seawater used for rearing larvae, yet the biogeochemical drivers of oyster-pathogenic Vibrio spp. in their planktonic state are poorly understood. Here, we present data tracking oyster pathogenic Vibrio bacteria in Netarts Bay and Yaquina Bay in Oregon, USA, as well as in adjacent coastal waters and a local shellfish hatchery, through the 2015 upwelling season. Vibrio populations were quantified using a culture-independent approach of high-throughput Vibrio-specific 16S rRNA gene sequencing paired with droplet digital PCR, and abundances were analyzed in the context of local biogeochemistry. The most abundant putative pathogen in our samples was Vibrio coralliilyticus Environmental concentrations of total Vibrio spp. and V. coralliilyticus were highest in Netarts Bay sediment samples and higher in seawater from Netarts Bay than from nearshore coastal waters or Yaquina Bay. In Netarts Bay, the highest V. coralliilyticus concentrations were observed during low tide, and abundances increased throughout the summer. We hypothesize that the warm shallow waters in estuarine mudflats facilitate the local growth of the V. coralliilyticus pathogen. Samples from larval oyster tanks in Whiskey Creek Shellfish Hatchery, which uses seawater pumped directly from Netarts Bay, contained significantly lower total Vibrio species concentrations, but roughly similar V. coralliilyticus concentrations, than did the bay water, resulting in a 30-fold increase in the relative abundance of the V. coralliilyticus pathogen in hatchery tanks. This suggests that the V. coralliilyticus pathogen is able to grow or persist under hatchery conditions.IMPORTANCE It has been argued that oyster-pathogenic Vibrio spp. have contributed to recent mortality events in U.S. shellfish hatcheries (R. A. Elston, H. Hasegawa, K. L. Humphrey, I. K. Polyak, and C. Hase, Dis Aquat Organ 82:119-134, 2008, https://doi.org/10.3354/dao01982); however, these events are often sporadic and unpredictable. The success of hatcheries is critically linked to the chemical and biological composition of inflowing seawater resources; thus, it is pertinent to understand the biogeochemical drivers of oyster-pathogenic Vibrio spp. in their planktonic state. Here, we show that Netarts Bay, the location of a local hatchery, is enriched in oyster-pathogenic V. coralliilyticus compared to coastal seawater, and we hypothesize that conditions in tidal flats promote the local growth of this pathogen. Furthermore, V. coralliilyticus appears to persist in seawater pumped into the local hatchery. These results improve our understanding of the ecology and environmental controls of the V. coralliilyticus pathogen and could be used to improve future aquaculture efforts, as multiple stressors impact hatchery success. PMID- 29475864 TI - Impact of Wastewater Treatment on the Prevalence of Integrons and the Genetic Diversity of Integron Gene Cassettes. AB - The integron platform allows the acquisition, expression, and dissemination of antibiotic resistance genes within gene cassettes. Wastewater treatment plants (WWTPs) contain abundant resistance genes; however, knowledge about the impacts of wastewater treatment on integrons and their gene cassettes is limited. In this study, by using clone library analysis and high-throughput sequencing, we investigated the abundance of class 1, 2, and 3 integrons and their corresponding gene cassettes in three urban WWTPs. Our results showed that class 1 integrons were most abundant in WWTPs and that wastewater treatment significantly reduced the abundance of all integrons. The WWTP influents harbored the highest diversity of class 1 integron gene cassettes, whereas class 3 integron gene cassettes exhibited highest diversity in activated sludge. Most of the gene cassette arrays detected in class 1 integrons were novel. Aminoglycoside, beta-lactam, and trimethoprim resistance genes were highly prevalent in class 1 integron gene cassettes, while class 3 integrons mainly carried beta-lactam resistance gene cassettes. A core class 1 integron resistance gene cassette pool persisted during wastewater treatment, implying that these resistance genes could have high potential to spread into environments through WWTPs. These data provide new insights into the impact of wastewater treatment on integron pools and highlight the need for surveillance of resistance genes within both class 1 and 3 integrons.IMPORTANCE Wastewater treatment plants represent a significant sink and transport medium for antibiotic resistance bacteria and genes spreading into environments. Integrons are important genetic elements involved in the evolution of antibiotic resistance. To better understand the impact of wastewater treatment on integrons and their gene cassette contexts, we conducted clone library construction and high-throughput sequencing to analyze gene cassette contexts for class 1 and class 3 integrons during the wastewater treatment process. This study comprehensively profiled the distribution of integrons and their gene cassettes (especially class 3 integrons) in influents, activated sludge, and effluents of conventional municipal wastewater treatment plants. We further demonstrated that while wastewater treatment significantly reduced the abundance of integrons and the diversity of associated gene cassettes, a large fraction of integrons persisted in wastewater effluents and were consequentially discharged into downstream natural environments. PMID- 29475865 TI - Bacterial Community Dynamics across the Gastrointestinal Tracts of Dairy Calves during Preweaning Development. AB - Microbial communities play critical roles in the gastrointestinal tracts (GIT) of preruminant calves by influencing performance and health. However, little is known about the establishment of microbial communities in the calf GIT or their dynamics during development. In this study, next-generation sequencing was used to assess changes in the bacterial communities of the rumen, jejunum, cecum, and colon in 26 crossbred calves at four developmental stages (7, 28, 49, and 63 days old). Alpha diversity differed among GIT regions with the lowest diversity and evenness in the jejunum, whereas no changes in alpha diversity were observed across developmental stage. Beta diversity analysis showed both region and age effects, with low numbers of operational taxonomic units (OTUs) shared between regions within a given age group or between ages in a given region. Taxonomic analysis revealed that several taxa coexisted in the rumen, jejunum, cecum, and colon but that their abundances differed considerably by GIT region and age. As calves aged, we observed lower abundances of taxa such as Bacteroides, Parabacteroides, and Paraprevotella with higher abundances of Bulleidia and Succiniclasticum in the rumen. The jejunum also displayed taxonomic changes with increases in Clostridiaceae and Turicibacter taxa in older calves. In the lower gut, taxa such as Lactobacillus, Blautia, and Faecalibacterium decreased and S24 7, Paraprevotella, and Prevotella increased as calves aged. These data support a model whereby early and successive colonization by bacteria occurs across the GIT of calves and provides insights into the temporal dynamics of the GIT microbiota of dairy calves during preweaning development.IMPORTANCE The gastrointestinal tracts (GIT) of ruminants, such as dairy cows, house complex microbial communities that contribute to their overall health and support their ability to produce milk. For example, the rumen microbiota converts feed into usable nutrients, while the jejunal microbiota provides access to protein. Thus, establishing a properly functioning GIT microbiota in dairy calves is critical to their productivity as adult cows. However, little is known about the establishment, maintenance, and dynamics of the calf GIT microbiota in early life. In this study, we evaluated the bacterial communities in the rumen, jejunum, cecum, and colon in dairy calves across preweaning development and show that they are highly variable early on in life before transitioning to a stable community. Understanding the dairy calf GIT microbiota has implications for ensuring proper health during early life and will aid in efforts to develop strategies for improving downstream production. PMID- 29475866 TI - Microbial Community Dynamics during Rearing of Black Soldier Fly Larvae (Hermetia illucens) and Impact on Exploitation Potential. AB - The need to increase sustainability in agriculture, to ensure food security for the future generations, is leading to the emergence of industrial rearing facilities for insects. One promising species being industrially reared as an alternative protein source for animal feed and as a raw material for the chemical industry is the black soldier fly (Hermetia illucens). However, scientific knowledge toward the optimization of the productivity for this insect is scarce. One knowledge gap concerns the impact of the microbial community associated with H. illucens on the performance and health of this insect. In this review, the first steps in the characterization of the microbiota in H. illucens and the analysis of substrate-dependent dynamics in its composition are summarized and discussed. Furthermore, this review zooms in on the interactions between microorganisms and the insect during H. illucens development. Finally, attention is paid to how the microbiome research can lead to alternative valorization strategies for H. illucens, such as (i) the manipulation of the microbiota to optimize insect biomass production and (ii) the exploitation of the H. illucens microbiota interplay for the discovery of new enzymes and novel antimicrobial strategies based on H. illucens immunity using either the whole organism or its molecules. The next decade promises to be extremely interesting for this research field and will see an emergence of the microbiological optimization of H. illucens as a sustainable insect for industrial rearing and the exploitation of its microbiome for novel biotechnological applications. PMID- 29475867 TI - Deletion of sll1541 in Synechocystis sp. Strain PCC 6803 Allows Formation of a Far-Red-Shifted holo-Proteorhodopsin In Vivo. AB - In many pro- and eukaryotes, a retinal-based proton pump equips the cell to drive ATP synthesis with (sun)light. Such pumps, therefore, have been proposed as a plug-in for cyanobacteria to artificially increase the efficiency of oxygenic photosynthesis. However, little information on the metabolism of retinal, their chromophore, is available for these organisms. We have studied the in vivo roles of five genes (sll1541, slr1648, slr0091, slr1192, and slr0574) potentially involved in retinal metabolism in Synechocystis sp. strain PCC 6803. With a gene deletion approach, we have shown that Synechocystis apo-carotenoid-15,15 oxygenase (SynACO), encoded by gene sll1541, is an indispensable enzyme for retinal synthesis in Synechocystis, presumably via asymmetric cleavage of beta apo-carotenal. The second carotenoid oxygenase (SynDiox2), encoded by gene slr1648, competes with SynACO for substrate(s) but only measurably contributes to retinal biosynthesis in stationary phase via an as-yet-unknown mechanism. In vivo degradation of retinal may proceed through spontaneous chemical oxidation and via enzyme-catalyzed processes. Deletion of gene slr0574 (encoding CYP120A1), but not of slr0091 or of slr1192, causes an increase (relative to the level in wild-type Synechocystis) in the retinal content in both the linear and stationary growth phases. These results suggest that CYP120A1 does contribute to retinal degradation. Preliminary data obtained using 13C-labeled retinal suggest that conversion to retinol and retinoic acid and subsequent further oxidation also play a role. Deletion of sll1541 leads to deficiency in retinal synthesis and allows the in vivo reconstitution of far-red-absorbing holo-proteorhodopsin with exogenous retinal analogues, as demonstrated here for all-trans 3,4 dehydroretinal and 3-methylamino-16-nor-1,2,3,4-didehydroretinal.IMPORTANCE Retinal is formed by many cyanobacteria and has a critical role in most forms of life for processes such as photoreception, growth, and stress survival. However, the metabolic pathways in cyanobacteria for synthesis and degradation of retinal are poorly understood. In this paper we identify genes involved in its synthesis, characterize their role, and provide an initial characterization of the pathway of its degradation. This led to the identification of sll1541 (encoding SynACO) as the essential gene for retinal synthesis. Multiple pathways for retinal degradation presumably exist. These results have allowed us to construct a strain that expresses a light-dependent proton pump with an action spectrum extending beyond 700 nm. The availability of this strain will be important for further work aimed at increasing the overall efficiency of oxygenic photosynthesis. PMID- 29475868 TI - Establishing Statistical Equivalence of Data from Different Sampling Approaches for Assessment of Bacterial Phenotypic Antimicrobial Resistance. AB - To assess phenotypic bacterial antimicrobial resistance (AMR) in different strata (e.g., host populations, environmental areas, manure, or sewage effluents) for epidemiological purposes, isolates of target bacteria can be obtained from a stratum using various sample types. Also, different sample processing methods can be applied. The MIC of each target antimicrobial drug for each isolate is measured. Statistical equivalence testing of the MIC data for the isolates allows evaluation of whether different sample types or sample processing methods yield equivalent estimates of the bacterial antimicrobial susceptibility in the stratum. We demonstrate this approach on the antimicrobial susceptibility estimates for (i) nontyphoidal Salmonella spp. from ground or trimmed meat versus cecal content samples of cattle in processing plants in 2013-2014 and (ii) nontyphoidal Salmonella spp. from urine, fecal, and blood human samples in 2015 (U.S. National Antimicrobial Resistance Monitoring System data). We found that the sample types for cattle yielded nonequivalent susceptibility estimates for several antimicrobial drug classes and thus may gauge distinct subpopulations of salmonellae. The quinolone and fluoroquinolone susceptibility estimates for nontyphoidal salmonellae from human blood are nonequivalent to those from urine or feces, conjecturally due to the fluoroquinolone (ciprofloxacin) use to treat infections caused by nontyphoidal salmonellae. We also demonstrate statistical equivalence testing for comparing sample processing methods for fecal samples (culturing one versus multiple aliquots per sample) to assess AMR in fecal Escherichia coli These methods yield equivalent results, except for tetracyclines. Importantly, statistical equivalence testing provides the MIC difference at which the data from two sample types or sample processing methods differ statistically. Data users (e.g., microbiologists and epidemiologists) may then interpret practical relevance of the difference.IMPORTANCE Bacterial antimicrobial resistance (AMR) needs to be assessed in different populations or strata for the purposes of surveillance and determination of the efficacy of interventions to halt AMR dissemination. To assess phenotypic antimicrobial susceptibility, isolates of target bacteria can be obtained from a stratum using different sample types or employing different sample processing methods in the laboratory. The MIC of each target antimicrobial drug for each of the isolates is measured, yielding the MIC distribution across the isolates from each sample type or sample processing method. We describe statistical equivalence testing for the MIC data for evaluating whether two sample types or sample processing methods yield equivalent estimates of the bacterial phenotypic antimicrobial susceptibility in the stratum. This includes estimating the MIC difference at which the data from the two approaches differ statistically. Data users (e.g., microbiologists, epidemiologists, and public health professionals) can then interpret whether that present difference is practically relevant. PMID- 29475869 TI - Genus-Wide Assessment of Lignocellulose Utilization in the Extremely Thermophilic Genus Caldicellulosiruptor by Genomic, Pangenomic, and Metagenomic Analyses. AB - Metagenomic data from Obsidian Pool (Yellowstone National Park, USA) and 13 genome sequences were used to reassess genus-wide biodiversity for the extremely thermophilic Caldicellulosiruptor The updated core genome contains 1,401 ortholog groups (average genome size for 13 species = 2,516 genes). The pangenome, which remains open with a revised total of 3,493 ortholog groups, encodes a variety of multidomain glycoside hydrolases (GHs). These include three cellulases with GH48 domains that are colocated in the glucan degradation locus (GDL) and are specific determinants for microcrystalline cellulose utilization. Three recently sequenced species, Caldicellulosiruptor sp. strain Rt8.B8 (renamed here Caldicellulosiruptor morganii), Thermoanaerobacter cellulolyticus strain NA10 (renamed here Caldicellulosiruptor naganoensis), and Caldicellulosiruptor sp. strain Wai35.B1 (renamed here Caldicellulosiruptor danielii), degraded Avicel and lignocellulose (switchgrass). C. morganii was more efficient than Caldicellulosiruptor bescii in this regard and differed from the other 12 species examined, both based on genome content and organization and in the specific domain features of conserved GHs. Metagenomic analysis of lignocellulose-enriched samples from Obsidian Pool revealed limited new information on genus biodiversity. Enrichments yielded genomic signatures closely related to that of Caldicellulosiruptor obsidiansis, but there was also evidence for other thermophilic fermentative anaerobes (Caldanaerobacter, Fervidobacterium, Caloramator, and Clostridium). One enrichment, containing 89.8% Caldicellulosiruptor and 9.7% Caloramator, had a capacity for switchgrass solubilization comparable to that of C. bescii These results refine the known biodiversity of Caldicellulosiruptor and indicate that microcrystalline cellulose degradation at temperatures above 70 degrees C, based on current information, is limited to certain members of this genus that produce GH48 domain-containing enzymes.IMPORTANCE The genus Caldicellulosiruptor contains the most thermophilic bacteria capable of lignocellulose deconstruction, which are promising candidates for consolidated bioprocessing for the production of biofuels and bio-based chemicals. The focus here is on the extant capability of this genus for plant biomass degradation and the extent to which this can be inferred from the core and pangenomes, based on analysis of 13 species and metagenomic sequence information from environmental samples. Key to microcrystalline hydrolysis is the content of the glucan degradation locus (GDL), a set of genes encoding glycoside hydrolases (GHs), several of which have GH48 and family 3 carbohydrate binding module domains, that function as primary cellulases. Resolving the relationship between the GDL and lignocellulose degradation will inform efforts to identify more prolific members of the genus and to develop metabolic engineering strategies to improve this characteristic. PMID- 29475870 TI - Shigella sonnei Does Not Use Amoebae as Protective Hosts. AB - Shigella flexneri and Shigella sonnei bacteria cause the majority of all shigellosis cases worldwide. However, their distributions differ, with S. sonnei predominating in middle- and high-income countries and S. flexneri predominating in low-income countries. One proposed explanation for the continued range expansion of S. sonnei is that it can survive in amoebae, which could provide a protective environment for the bacteria. In this study, we demonstrate that while both S. sonnei and S. flexneri can survive coculture with the free-living amoebae Acanthamoebae castellanii, bacterial growth is predominantly extracellular. All isolates of Shigella were degraded following phagocytosis by A. castellanii, unlike those of Legionella pneumophila, which can replicate intracellularly. Our data suggest that S. sonnei is not able to use amoebae as a protective host to enhance environmental survival. Therefore, alternative explanations for S. sonnei emergence need to be considered.IMPORTANCE The distribution of Shigella species closely mirrors a country's socioeconomic conditions. With the transition of many populous nations from low- to middle-income countries, S. sonnei infections have emerged as a major public health issue. Understanding why S. sonnei infections are resistant to improvements in living conditions is key to developing methods to reduce exposure to this pathogen. We show that free-living amoebae are not likely to be environmental hosts of S. sonnei, as all Shigella strains tested were phagocytosed and degraded by amoebae. Therefore, alternative scenarios are required to explain the emergence and persistence of S. sonnei infections. PMID- 29475872 TI - Endorsing performance measures is a matter of trust. PMID- 29475871 TI - On the Enigma of Glutathione-Dependent Styrene Degradation in Gordonia rubripertincta CWB2. AB - Among bacteria, only a single styrene-specific degradation pathway has been reported so far. It comprises the activity of styrene monooxygenase, styrene oxide isomerase, and phenylacetaldehyde dehydrogenase, yielding phenylacetic acid as the central metabolite. The alternative route comprises ring-hydroxylating enzymes and yields vinyl catechol as central metabolite, which undergoes meta cleavage. This was reported to be unspecific and also allows the degradation of benzene derivatives. However, some bacteria had been described to degrade styrene but do not employ one of those routes or only parts of them. Here, we describe a novel "hybrid" degradation pathway for styrene located on a plasmid of foreign origin. As putatively also unspecific, it allows metabolizing chemically analogous compounds (e.g., halogenated and/or alkylated styrene derivatives). Gordonia rubripertincta CWB2 was isolated with styrene as the sole source of carbon and energy. It employs an assembled route of the styrene side-chain degradation and isoprene degradation pathways that also funnels into phenylacetic acid as the central metabolite. Metabolites, enzyme activity, genome, transcriptome, and proteome data reinforce this observation and allow us to understand this biotechnologically relevant pathway, which can be used for the production of ibuprofen.IMPORTANCE The degradation of xenobiotics by bacteria is not only important for bioremediation but also because the involved enzymes are potential catalysts in biotechnological applications. This study reveals a novel degradation pathway for the hazardous organic compound styrene in Gordonia rubripertincta CWB2. This study provides an impressive illustration of horizontal gene transfer, which enables novel metabolic capabilities. This study presents glutathione-dependent styrene metabolization in an (actino-)bacterium. Further, the genomic background of the ability of strain CWB2 to produce ibuprofen is demonstrated. PMID- 29475873 TI - Twenty-Four-Hour Central Pulse Pressure for Cardiovascular Events Prediction in a Low-Cardiovascular-Risk Population: Results From the Bordeaux Cohort. AB - BACKGROUND: Central blood pressure (BP) is a promising marker to identify subjects with higher cardiovascular risk than expected by traditional risk factors. Significant results have been obtained in populations with high cardiovascular risk, but little is known about low-cardiovascular-risk patients, although the differences between central and peripheral BP (amplification) are usually greater in this population. The study aim was to evaluate central BP over 24 hours for cardiovascular event prediction in hypertensive subjects with low cardiovascular risk. METHODS AND RESULTS: Peripheral and central BPs were recorded during clinical visits and over 24 hours in hypertensive patients with low cardiovascular risk (Systematic Coronary Risk Evaluation <=5%). Our primary end point is the occurrence of a cardiovascular event during follow-up. To assess the potential interest in central pulse pressure over 24 hours, we performed Cox proportional hazard models analysis and comparison of area under the curves using the contrast test for peripheral and central BP. A cohort of 703 hypertensive subjects from Bordeaux were included. After the first 24 hours of BP measurement, the subjects were then followed up for an average of 112.5+/-70 months. We recorded 65 cardiovascular events during follow-up. Amplification was found to be significantly associated with cardiovascular events when added to peripheral 24 hour pulse pressure (P=0.0259). The area under the curve of 24-hour central pulse pressure is significantly more important than area under the curve of office BP (P=0.0296), and there is a trend of superiority with the area under the curve of peripheral 24-hour pulse pressure. CONCLUSIONS: Central pulse pressure over 24 hours improves the prediction of cardiovascular events for hypertensive patients with low cardiovascular risk compared to peripheral pulse pressure. PMID- 29475874 TI - Diastolic Blood Pressure and Adverse Outcomes in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) Trial. AB - BACKGROUND: Although diastolic blood pressure (DBP) is independently associated with an increased risk of adverse cardiovascular outcomes in the general population, it is unclear if a similar relationship exists in patients with heart failure with preserved ejection fraction. METHODS AND RESULTS: This analysis included 1703 (mean age, 72+/-10 years; 50% men; 78% white) patients with heart failure with preserved ejection fraction enrolled in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) Trial from the Americas who were treated for hypertension. Multivariable Cox regression was used to examine the risk of hospitalization for heart failure, death, and cardiovascular death associated with DBP. The relationship between hospitalization for heart failure and DBP was linear, with an increased risk observed with decreasing DBP values (>=90 mm Hg: referent; 80-89 mm Hg: hazard ratio [HR], 1.44; 95% confidence interval [CI], 0.85-2.44; 70-79 mm Hg: HR, 1.18; 95% CI, 0.69-2.01; 60-69 mm Hg: HR, 1.54; 95% CI, 0.90-2.63; <60 mm Hg: HR, 2.12; 95% CI, 1.20-3.74; P=0.0055 for trend). The associations of DBP with death (>=90 mm Hg: HR, 1.86; 95% CI, 1.12-3.06; 80-89 mm Hg: HR, 1.23; 95% CI, 0.89-1.70; 70 79 mm Hg: referent; 60-69 mm Hg: HR, 1.20; 95% CI, 0.90-1.59; <60 mm Hg: HR, 1.68; 95% CI, 1.21-2.33) and cardiovascular death (>=90 mm Hg: HR, 2.02; 95% CI, 1.10-3.71; 80-89 mm Hg: HR, 1.17; 95% CI, 0.77-1.79; 70-79 mm Hg: referent; 60-69 mm Hg: HR, 1.16; 95% CI, 0.80-1.70; <60 mm Hg: HR, 1.85; 95% CI, 1.21-2.82) were nonlinear, with a greater risk of each outcome observed with DBP values >=90 and <60 mm Hg. CONCLUSIONS: DBP values >=90 and <60 mm Hg are associated with a significant risk of adverse outcomes in patients with heart failure with preserved ejection fraction who are treated for hypertension. Further research is needed to determine optimal DBP targets to reduce the risk of adverse events in patients with heart failure with preserved ejection fraction. PMID- 29475875 TI - Prospective Randomized Evaluation of Implantable Cardioverter-Defibrillator Programming in Patients With a Left Ventricular Assist Device. AB - BACKGROUND: Ventricular arrhythmias are common in patients with left ventricular assist devices (LVADs) but are often hemodynamically tolerated. Optimal implantable cardioverter defibrillator (ICD) tachy-programming strategies in patients with LVAD have not been determined. We sought to determine if an ultra conservative ICD programming strategy in patients with LVAD affects ICD shocks. METHODS AND RESULTS: Adult patients with an existing ICD undergoing continuous flow LVAD implantation were randomized to standard ICD programming by their treating physician or an ultra-conservative ICD programming strategy utilizing maximal allowable intervals to detection in the ventricular fibrillation and ventricular tachycardia zones with use of ATP. Patients with cardiac resynchronization therapy (CRT) devices were also randomized to CRT ON or OFF. Patients were followed a minimum of 6 months. The primary outcome was time to first ICD shock. Among the 83 patients studied, we found no statistically significant difference in time to first ICD shock or total ICD shocks between groups. In the ultra-conservative group 16% of patients experienced at least one shock compared with 21% in the control group (P=0.66). There was no difference in mortality, arrhythmic hospitalization, or hospitalization for heart failure. In the 41 patients with CRT ICDs fewer shocks were observed with CRT-ON but this was not statistically significant: 10% of patients with CRT-ON (n=21) versus 38% with CRT-OFF (n=20) received shocks (P=0.08). CONCLUSIONS: An ultra-conservative programming strategy did not reduce ICD shocks. Programming restrictions on ventricular tachycardia and ventricular fibrillation zone therapy should be reconsidered for the LVAD population. The role of CRT in patients with LVAD warrants further investigation. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01977703. PMID- 29475876 TI - Predictive Value of Collagen Biomarkers for Heart Failure With and Without Preserved Ejection Fraction: MESA (Multi-Ethnic Study of Atherosclerosis). AB - BACKGROUND: Collagen biomarkers may correlate with incident heart failure (HF) and its subtypes. We hypothesized that circulating procollagen type III N terminal propeptide (PIIINP) and collagen type I carboxy-terminal telopeptide (ICTP) predict incident HF. METHODS AND RESULTS: We used a stratified sampling design in a multiethnic sample of 3187 subjects, initially aged 45 to 84 years and free of cardiovascular disease. We assayed baseline serum PIIINP and ICTP concentrations using radioimmunoassay. Incident HF was adjudicated, distinguishing reduced ejection fraction (HFrEF; EF <45%) from preserved EF (HFpEF; EF >=45%). The incidence density for HFpEF and HFrEF was computed using Poisson regression per SD for each of PIIINP and ICTP, adjusting in model 1 for age, race, sex, and renal function or in model 2 for these variables plus blood pressure and medication. Mean (SD) ICTP was 3.38+/-1.77 MUg/L, and mean (SD) PIIINP was 5.48+/-2.04 MUg/L. Among the HF cases, 96 were HFrEF and 107 were HFpEF. Neither ICTP nor PIIINP significantly predicted incident HFrEF. The incidence density for HFpEF per 100 people observed for 13 years was 1.65 for low PIIINP (lower 6 octiles) versus 3.00 for higher PIIINP (P=0.002) in model 1 and correspondingly 1.45 versus 2.59 (P=0.003) in model 2. For low ICTP (lower 7 octiles) versus higher ICTP (octile 8), incidence densities were 1.79 versus 3.64 (P=0.002) in model 1 and 1.58 versus 3.12 (P=0.002) in model 2. CONCLUSIONS: High levels of circulating ICTP and PIIINP as collagen biomarkers appear to be associated with incident HFpEF, but not HFrEF. PMID- 29475877 TI - MANAGEMENT OF ENDOCRINE DISEASE: Adrenocortical carcinoma: differentiating the good from the poor prognosis tumors. AB - Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis, the five-years overall survival being below 40%. However, there is great variability of outcomes and we have now a better view of the heterogeneity of tumor aggressiveness. The extent of the disease at the time of diagnosis, best assayed by the European Network for the Study of Adrenal Tumors (ENSAT) Staging Score, is a major determinant of survival. The tumor grade, including the mitotic count and the Ki67 proliferation index, also appears as a strong prognostic factor. The assessment of tumor grade, even by expert pathologists, still suffers from inter observer reproducibility. The emergence of genomics in the last decade has revolutionized the knowledge of molecular biology and genetics of cancers. In ACC, genomic approaches - including pan-genomic studies of gene expression (transcriptome), recurrent mutations (exome or whole-genome sequencing), chromosome alterations, DNA methylation (methylome), miRNA expression (miRnome) - converge in a new classification of ACC, characterized by distinct molecular profiles and very different outcomes. Targeted measurements of a few discriminant molecular alterations have been developed in the perspective of clinical routine, and thus, may help defining therapeutic strategy. By individualizing patients' prognosis and tumor biology, these recent progresses appear as an important step forward towards precision medicine. PMID- 29475878 TI - Rethinking pain education. AB - EBN engages readers through a range of Online social media activities to debate issues important to nurses and nursing. EBN Opinion papers highlight and expand on these debates. PMID- 29475879 TI - Corticosteroids for the prevention of bronchopulmonary dysplasia in preterm infants: a network meta-analysis. AB - OBJECTIVE: To determine the comparative efficacy and safety of corticosteroids in the prevention of bronchopulmonary dysplasia (BPD) in preterm infants. STUDY DESIGN: We systematically searched PubMed, EMBASE and the Cochrane Library. Two reviewers independently selected randomised controlled trials (RCTs) of postnatal corticosteroids in preterm infants. A Bayesian network meta-analysis and subgroup analyses were performed. RESULTS: We included 47 RCTs with 6747 participants. The use of dexamethasone at either high dose or low dose decreased the risk of BPD (OR 0.29, 95% credible interval (CrI) 0.14 to 0.52; OR 0.58, 95% CrI 0.39 to 0.76, respectively). High-dose dexamethasone was more effective than hydrocortisone, beclomethasone and low-dose dexamethasone. Early and long-term dexamethasone at either high dose or low dose decreased the risk of BPD (OR 0.11, 95% CrI 0.02 to 0.4; OR 0.37, 95% CrI 0.16 to 0.67, respectively). There were no statistically significant differences in the risk of cerebral palsy (CP) between different corticosteroids. However, high-dose and long-term dexamethasone ranked lower than placebo and other regimens in terms of CP. Subgroup analyses indicated budesonide was associated with a decreased risk of BPD in extremely preterm and extremely low birthweight infants (OR 0.60, 95% CrI 0.36 to 0.93). CONCLUSIONS: Dexamethasone can reduce the risk of BPD in preterm infants. Of the different dexamethasone regimens, aggressive initiation seems beneficial, while a combination of high-dose and long-term use should be avoided because of the possible adverse neurodevelopmental outcome. Dexamethasone and inhaled corticosteroids need to be further evaluated in large-scale RCTs with long-term follow-ups. PMID- 29475880 TI - Identification of Tumoricidal TCRs from Tumor-Infiltrating Lymphocytes by Single Cell Analysis. AB - T-cell receptor (TCR) gene therapy is a promising next-generation antitumor treatment. We previously developed a single-T-cell analysis protocol that allows the rapid capture of paired TCRalpha and beta cDNAs. Here, we applied the protocol to analyze the TCR repertoire of tumor-infiltrating lymphocytes (TIL) of various cancer patients. We found clonally expanded populations of T cells that expressed the same clonotypic TCR in 50% to 70% of CD137+CD8+ TILs, indicating that they responded to certain antigens in the tumor environment. To assess the tumor reactivity of the TCRs derived from those clonally expanded TILs in detail, we then analyzed the CD137+CD8+ TILs from the tumor of B16F10 melanoma cells in six C57BL/6 mice and analyzed their TCR repertoire. We also found clonally expanded T cells in 60% to 90% of CD137+CD8+ TILs. When the tumor reactivity of dominant clonotypic TCRs in each mouse was analyzed, 9 of 13 TCRs induced the secretion of IFNgamma in response to, and showed killing of, B16F10 cells in vitro, and 2 of them showed strong antitumor activity in vivo Concerning their antigen specificity, 7 of them reacted to p15E peptide of endogenous murine leukemia virus-derived envelope glycoprotein 70, and the rest reacted to tumor associated antigens expressed on EL4 lymphoma as well as B16 melanoma cells. These results show that our strategy enables us to simply and rapidly obtain the tumor-specific TCR repertoire with high fidelity in an antigen- and MHC haplotype independent manner from primary TILs. Cancer Immunol Res; 6(4); 378-88. (c)2018 AACR. PMID- 29475882 TI - Start-ups Bring AI to Pathology. AB - New startups are developing pattern-recognition algorithms that could one day help pathologists more accurately spot tumors on digitized tissue images, thereby aiding in diagnosis, treatment, drug discovery, and more. PMID- 29475883 TI - TGFbeta Promotes Immune Evasion to Limit the Efficacy of Anti-PD-1/PD-L1. AB - The TGFbeta-activated stroma induces T-cell exclusion to suppress antitumor immunity. PMID- 29475884 TI - Axitinib plus Pembrolizumab Is Effective in Renal Cell Carcinoma. AB - Axitinib plus pembrolizumab has a 73% response rate in previously untreated advanced renal cell carcinoma. PMID- 29475881 TI - PINK1 autophosphorylation is required for ubiquitin recognition. AB - Mutations in PINK1 cause autosomal recessive Parkinson's disease (PD), a neurodegenerative movement disorder. PINK1 is a kinase that acts as a sensor of mitochondrial damage and initiates Parkin-mediated clearance of the damaged organelle. PINK1 phosphorylates Ser65 in both ubiquitin and the ubiquitin-like (Ubl) domain of Parkin, which stimulates its E3 ligase activity. Autophosphorylation of PINK1 is required for Parkin activation, but how this modulates the ubiquitin kinase activity is unclear. Here, we show that autophosphorylation of Tribolium castaneum PINK1 is required for substrate recognition. Using enzyme kinetics and NMR spectroscopy, we reveal that PINK1 binds the Parkin Ubl with a 10-fold higher affinity than ubiquitin via a conserved interface that is also implicated in RING1 and SH3 binding. The interaction requires phosphorylation at Ser205, an invariant PINK1 residue (Ser228 in human). Using mass spectrometry, we demonstrate that PINK1 rapidly autophosphorylates in trans at Ser205. Small-angle X-ray scattering and hydrogen deuterium exchange experiments provide insights into the structure of the PINK1 catalytic domain. Our findings suggest that multiple PINK1 molecules autophosphorylate first prior to binding and phosphorylating ubiquitin and Parkin. PMID- 29475885 TI - MEK Binding to KSR Promotes Allosteric Activation of BRAF. AB - KSR-MEK complexes allosterically activate BRAF, which then phosphorylates a second MEK molecule. PMID- 29475886 TI - The Oncolytic Adenovirus DNX-2401 Has Antitumor Activity in Glioblastoma. AB - In a phase I trial, DNX-2401 is safe and achieves durable responses in patients with recurrent glioma. PMID- 29475887 TI - Erratum for Micek et al., "Risk Factors and Outcomes for Ineffective Empiric Treatment of Sepsis Caused by Gram-Negative Pathogens: Stratification by Onset of Infection". PMID- 29475889 TI - Correction for Mercer et al., "NP108, an Antimicrobial Polymer with Activity against Methicillin- and Mupirocin-Resistant Staphylococcus aureus". PMID- 29475888 TI - Erratum for Arias et al., "A Prospective Cohort Multicenter Study of Molecular Epidemiology and Phylogenomics of Staphylococcus aureus Bacteremia in Nine Latin American Countries". PMID- 29475890 TI - Mutation in luxR Family Transcriptional Regulator Rv0890c Is Not a Marker of Linezolid Resistance. PMID- 29475891 TI - Application of the DRIP Score at a Veterans Affairs Hospital. PMID- 29475892 TI - Reply to Zimenkov, "Mutation in luxR Family Transcriptional Regulator Rv0890c Is Not a Marker of Linezolid Resistance". PMID- 29475893 TI - Reply to Babbel et al., "Application of the DRIP Score at a Veterans Affairs Hospital". PMID- 29475894 TI - Transcriptional profiling reveals distinct classes of parathyroid tumors in PHPT. AB - The clinical presentation of primary hyperparathyroidism (PHPT) varies widely, although the underlying mechanistic reasons for this disparity remain unknown. We recently reported that parathyroid tumors can be functionally segregated into two distinct groups on the basis of their relative responsiveness to ambient calcium, and that patients in these groups differ significantly in their likelihood of manifesting bone disability. To examine the molecular basis for this phenotypic variation in PHPT, we compared the global gene expression profiles of calcium sensitive and calcium-resistant parathyroid tumors. RNAseq and proteomic analysis identified a candidate set of differentially expressed genes highly correlated with calcium-sensing capacity. Subsequent quantitative assessment of the expression levels of these genes in an independent cohort of parathyroid tumors confirmed that calcium-sensitive tumors cluster in a discrete transcriptional profile group. These data indicate that PHPT is not an etiologically monolithic disorder and suggest that divergent molecular mechanisms could drive the observed phenotypic differences in PHPT disease course, provenance, and outcome. PMID- 29475895 TI - Comprehensive analysis of haemostatic profile depending on clinicopathological determinants in breast cancer patients. AB - Thrombosis is one of the leading causes of mortality in cancer patients. The aim of the study was to evaluate the concentrations and activities of selected haemostatic parameters in the plasma of patients diagnosed with breast cancer (BrCa) and to make an attempt at finding associations with their levels and selected clinicopathological factors; clinical classification, histological grading, and molecular subtype of BrCa. The study involved 145 Caucasian ethnicity women. Eighty-five women aged 45-66 with primary BrCa without distant metastases (M0). Inclusion criteria were as follows: histopathological examination confirming the diagnosis of primary BrCa, without previous radiotherapy and chemotherapy. The control group consisted of 60, post-menopausal women, aged 45-68. Haemostatic profile expressed by concentrations and activities of tissue factor (TF) and its inhibitor (TFPI) as well as concentrations of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) were measured applying immunoassay techniques. A significantly higher concentration of PAI-1 was noted in patients with BrCa localized in the left breast. We observed significantly lower activity of TFPI and significantly higher concentration of PAI-1 in the group of patients with invasive ductal carcinoma as compared with invasive lobular carcinoma. A significantly higher concentration of t-PA in patients with pT2 BrCa in relation to pT1 cases was noted. Based on comprehensive analysis of haemostatic profile depending on clinicopathological features, we suggest that haemostatic parameters play crucial roles in invasion and metastases of malignant tumours. PMID- 29475896 TI - Music therapy in UK palliative and end-of-life care: a service evaluation. AB - : Music therapy aligns to the holistic approach to palliative and end-of-life care (PEOLC), with an emergent evidence base reporting positive effect on a range of health-related outcomes for both patient and family carer alongside high client demand. However, the current service provision and the role of music therapists in supporting individuals receiving PEOLC in the UK is currently unknown. OBJECTIVES: This service evaluation aims to identify the provision, role and perceived impact of UK music therapists in supporting patients receiving PEOLC, their families and health and social care professionals. METHODS: A survey was distributed to the British Association for Music Therapy (BAMT) member mailing list in July 2017. BAMT is the professional body for Health and Care Professions Council registered music therapists in the UK. RESULTS: Fifty respondents identified themselves as music therapists currently working with clients receiving PEOLC. The respondents largely reported (84.7%) less than 10 years of experience working in PEOLC settings, with only a minority receiving statutory funding for their role. Music therapists most commonly reported supporting adults with neurological conditions, cancers and dementia. CONCLUSIONS: Although promising that evidence suggests provision of music therapy in UK PEOLC settings in the past 10 years to have increased, lack of sustainable funding suggests the role to not be consistently accessible in PEOLC. PMID- 29475898 TI - Discovery, Biosynthesis and Stress-Related Accumulation of Dolabradiene-Derived Defenses in Maize. AB - Terpenoids are a major component of maize (Zea mays) chemical defenses that mediate responses to herbivores, pathogens, and other environmental challenges. Here, we describe the biosynthesis and elicited production of a class of maize diterpenoids, named dolabralexins. Dolabralexin biosynthesis involves the sequential activity of two diterpene synthases, ENT-COPALYL DIPHOSPHATE SYNTHASE (ZmAN2) and KAURENE SYNTHASE-LIKE4 (ZmKSL4). Together, ZmAN2 and ZmKSL4 form the diterpene hydrocarbon dolabradiene. In addition, we biochemically characterized a cytochrome P450 monooxygenase, ZmCYP71Z16, which catalyzes the oxygenation of dolabradiene to yield the epoxides 15,16-epoxydolabrene (epoxydolabrene) and 3beta-hydroxy-15,16-epoxydolabrene (epoxydolabranol). The absence of dolabradiene and epoxydolabranol in Zman2 mutants under elicited conditions confirmed the in vivo biosynthetic requirement of ZmAN2. Combined mass spectrometry and NMR experiments demonstrated that much of the epoxydolabranol is further converted into 3beta,15,16-trihydroxydolabrene (trihydroxydolabrene). Metabolite profiling of field-grown maize root tissues indicated that dolabralexin biosynthesis is widespread across common maize cultivars, with trihydroxydolabrene as the predominant diterpenoid. Oxidative stress induced dolabralexin accumulation and transcript expression of ZmAN2 and ZmKSL4 in root tissues, and metabolite and transcript accumulation were up-regulated in response to elicitation with the fungal pathogens Fusarium verticillioides and Fusarium graminearum Consistently, epoxydolabranol significantly inhibited the growth of both pathogens in vitro at 10 ug mL-1, while trihydroxydolabrene-mediated inhibition was specific to Fverticillioides These findings suggest that dolabralexins have defense-related roles in maize stress interactions and expand the known chemical space of diterpenoid defenses as genetic targets for understanding and ultimately improving maize resilience. PMID- 29475897 TI - Time-Course Transcriptomics Analysis Reveals Key Responses of Submerged Deepwater Rice to Flooding. AB - Water submergence is an environmental factor that limits plant growth and survival. Deepwater rice (Oryza sativa) adapts to submergence by rapidly elongating its internodes and thereby maintaining its leaves above the water surface. We performed a comparative RNA sequencing transcriptome analysis of the shoot base region, including basal nodes, internodes, and shoot apices of seedlings at two developmental stages from two varieties with contrasting deepwater growth responses. A transcriptomic comparison between deepwater rice cv C9285 and nondeepwater rice cv Taichung 65 revealed both similar and differential expression patterns between the two genotypes during submergence. The expression of genes related to gibberellin biosynthesis, trehalose biosynthesis, anaerobic fermentation, cell wall modification, and transcription factors that include ethylene-responsive factors was significantly different between the varieties. Interestingly, in both varieties, the jasmonic acid content at the shoot base decreased during submergence, while exogenous jasmonic acid inhibited submergence induced internode elongation in cv C9285, suggesting that jasmonic acid plays a role in the submergence response of rice. Furthermore, a targeted de novo transcript assembly revealed transcripts that were specific to cv C9285, including submergence-induced biotic stress-related genes. Our multifaceted transcriptome approach using the rice shoot base region illustrates a differential response to submergence between deepwater and nondeepwater rice. Jasmonic acid metabolism appears to participate in the submergence-mediated internode elongation response of deepwater rice. PMID- 29475900 TI - Fifteen-minute consultation: The child with an incidental finding of low IgA. AB - Low or absent immunoglobulin A (IgA) levels are frequently found in children in whom immunodeficiency is not suspected. IgA deficiency is the most common primary immunodeficiency disorder in the UK affecting approximately 1 in 600 people. Isolated IgA deficiency is often identified coincidentally when investigating a child for conditions such as coeliac disease. The aim of this article is to provide a structured approach to the history, investigation and management of an isolated IgA deficiency. PMID- 29475899 TI - The Phosphate Fast-Responsive Genes PECP1 and PPsPase1 Affect Phosphocholine and Phosphoethanolamine Content. AB - Phosphate starvation-mediated induction of the HAD-type phosphatases PPsPase1 (AT1G73010) and PECP1 (AT1G17710) has been reported in Arabidopsis (Arabidopsis thaliana). However, little is known about their in vivo function or impact on plant responses to nutrient deficiency. The preferences of PPsPase1 and PECP1 for different substrates have been studied in vitro but require confirmation in planta. Here, we examined the in vivo function of both enzymes using a reverse genetics approach. We demonstrated that PPsPase1 and PECP1 affect plant phosphocholine and phosphoethanolamine content, but not the pyrophosphate-related phenotypes. These observations suggest that the enzymes play a similar role in planta related to the recycling of polar heads from membrane lipids that is triggered during phosphate starvation. Altering the expression of the genes encoding these enzymes had no effect on lipid composition, possibly due to compensation by other lipid recycling pathways triggered during phosphate starvation. Furthermore, our results indicated that PPsPase1 and PECP1 do not influence phosphate homeostasis, since the inactivation of these genes had no effect on phosphate content or on the induction of molecular markers related to phosphate starvation. A combination of transcriptomics and imaging analyses revealed that PPsPase1 and PECP1 display a highly dynamic expression pattern that closely mirrors the phosphate status. This temporal dynamism, combined with the wide range of induction levels, broad expression, and lack of a direct effect on Pi content and regulation, makes PPsPase1 and PECP1 useful molecular markers of the phosphate starvation response. PMID- 29475901 TI - Erratum for Chodur et al., "The Proline Variant of the W[F/L/M][T/S]R Cyclic Di GMP Binding Motif Suppresses Dependence on Signal Association for Regulator Function". PMID- 29475903 TI - Non Lipomatous Benign Lesions Mimicking Soft-tissue Sarcomas: A Pictorial Essay. AB - The incidental finding of soft tissue masses is a challenge for the radiologist. Benign and malignant lesions can be differentiated relying on patient history, symptoms and mostly with the help of imaging. Ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI) become fundamental in order to distinguish these lesions but the radiologist needs to know the main characteristics of benign soft tissue masses and sarcomas. Herein, we present a pictorial review of lesions mimicking soft tissue sarcomas features. PMID- 29475902 TI - In Vivo Analysis of Prostaglandins-induced Ocular Surface and Periocular Adnexa Modifications in Patients with Glaucoma. AB - BACKGROUND/AIM: Prostaglandin analogues (PGAs) are a first-line medical treatment for glaucoma because of their powerful intraocular pressure (IOP) lowering effect, few systemic side-effects (SEs), and the once daily administration. Despite the high systemic safety profile, the chronic use of PGAs may induce periocular and ocular surface (OS)-related side effects, which affect a significant proportion of glaucomatous patients. In this review, we summarize the current knowledge about SEs of PGAs on periocular structures and OS, and their implications in clinical practice. MATERIALS AND METHODS: A comprehensive literature search on the PubMed platform was performed. Two hundred fifty articles fulfilling key words were identified, of which 180 were excluded since they did not concern the effects of PGAs on the periocular tissues and OS, or because of their limited relevance. The following key words were used and combined, to narrow-down the literature: "prostaglandin" and "ocular surface," which identified 184 unique publications, of which 68 were selected; "prostaglandin" and "periocular" which identified 46 unique publications, of which 11 were selected. An additional search was conducted using "prostaglandin" and "Meibomian glands (MGs)", which identified twenty unique publications, of which 8 were selected. Thus, a total of 70 articles were chosen based on their relevance and were included in this review. RESULTS: Prostaglandin-associated peri-orbitopathy, skin pigmentation and hypertrichosis, eyelash growth, and MGs dysfunction are the most frequent modifications of periocular tissues. They are induced by the tissue accumulation of PGAs, and FP receptor stimulation. Without preservatives, PGAs act as stimulators of conjunctival goblet cells, which are the main source of ocular surface mucoproteins, and seem to increase conjunctival epithelium microcysts proposed as in vivo hallmark of the trans-scleral aqueous humour outflow. Additional PGA-induced modifications can be recognized in the cornea, corneo-scleral limbus, conjunctival stroma and, conjunctiva-associated lymphoid tissue, mainly appearing as inflammatory changes. OS epithelia desquamation, chemosis, apoptosis, dendritic cell activation, conjunctival or episcleral vasodilation, and sub-basal nerve plexus disruption were also described in patients receiving preserved PGAs. CONCLUSION: PGAs induce several modifications of the OS structures and adnexa; nonetheless, none of them significantly reduces the local safety profile of this class of drugs. Moreover, the OS changes do not affect the IOP lowering efficacy of PGAs. On these bases, local SEs of PGAs should not discourage clinicians in using this class of medications because of their efficacy, the systemic safety profile, and the better adherence. PMID- 29475904 TI - Protection of Differentiating Neuronal Cells from Amyloid beta Peptide-induced Injury by Alkaline Extract of Leaves of Sasa senanensis Rehder. AB - BACKGROUND/AIM: We have previously reported the protection of doxorubicin-induced keratinocyte toxicity by alkaline extract of the leaves of Sasa senanensis Rehder (SE). In order to extend the generality of the cell protective effect of SE, we investigated whether it also protects rat PC12 and human SH-SY5Y neuron model cells from amyloid beta-peptide (Abeta)-induced injury. MATERIALS AND METHODS: Viability of cells was determined by the MTT method. Cytotoxicity was evaluated by the concentration that reduces the cell viability by 50% (CC50). Protection from Abeta-induced cytotoxicity was evaluated by the concentration that reversed the Abeta-induced reduction of viability by 50% (EC50). The selectivity index (SI) of neuroprotective activity was defined as the ratio of EC50 to CC50 Abeta1 42 aggregation was assayed using Abeta1-42 ammonium hydroxide. RESULTS: SE showed hormetic growth stimulation at lower concentrations in both neuron precursors and differentiated cells. SE reproducibly inhibited Abeta-induced cytotoxicity against both undifferentiated and differentiated neuron cells. Both the extent of differentiation induction and viability depended on the cell density, suggesting the release of growth and differentiation stimulation substances into culture supernatant. Higher concentrations of SE partially reduced the Abeta1-42 aggregation. CONCLUSION: Hormetic growth stimulation and inhibition of aggregation may be involved in the neuroprotective activity of SE. PMID- 29475905 TI - Plasma Electrolytic Oxidation of Titanium Implant Surfaces: Microgroove Structures Improve Cellular Adhesion and Viability. AB - BACKGROUND/AIM: Plasma electrolytic oxidation (PEO) is an established electrochemical treatment technique that can be used for surface modifications of metal implants. In this study we to treated titanium implants with PEO, to examine the resulting microstructure and to characterize adhesion and viability of cells on the treated surfaces. Our aim was to identify an optimal surface modification for titanium implants in order to improve soft-tissue integration. MATERIALS AND METHODS: Three surface-variants were generated on titanium alloy Ti6Al4V by PEO-treatment. The elemental composition and the microstructures of the surfaces were characterized using energy dispersive X-ray spectroscopy, scanning electron microscopy and profilometry. In vitro cytocompatibility of the surfaces was assessed by seeding L929 fibroblasts onto them and measuring the adhesion, viability and cytotoxicity of cells by means of live/dead staining, XTT assay and LDH assay. RESULTS: Electron microscopy and profilometry revealed that the PEO-surface variants differed largely in microstructure/topography, porosity and roughness from the untreated control material as well as from one another. Roughness was generally increased after PEO-treatment. In vitro, PEO-treatment led to improved cellular adhesion and viability of cells accompanied by decreased cytotoxicity. CONCLUSION: PEO-treatment provides a promising strategy to improve the integration of titanium implants with surrounding tissues. PMID- 29475906 TI - The Impact of Exercise Training on Breast Cancer. AB - BACKGROUND/AIM: Physical exercise is increasingly considered by many authors to be a factor reducing the risk of cancer development and premature cancer-related death. Data indicate higher cure rates and longer times of survival in cancer patients who regularly exercise. MATERIALS AND METHODS: A total of 50 female Sprague-Dawley rats were used in the experiment. Animals at 1 month of age were intraperitoneally injected with N-methyl-N-nitrosourea. Three months following drug administration, rats underwent supervised physical training. The animals were divided into four groups: control untrained group and 3 groups trained with different intensities - i.e. low, moderate and high. Routine histopathological examination of tumors was performed and mitotic activity was assessed by immunohistochemical expression of the Ki-67 antigen. RESULTS: Ki-67 antigen expression was observed in all analyzed tumors. The increase in Ki-67 antigen expression correlated positively with the increase in training intensity. CONCLUSION: It can be assumed that low-intensity physical training is safe for patients with breast cancer. However, moderate- and high-intensity training may induce tumor cell proliferation worsening patients' prognosis. PMID- 29475907 TI - Anti-inflammatory Activity of beta-Carotene, Lycopene and Tri-n-butylborane, a Scavenger of Reactive Oxygen Species. AB - BACKGROUND/AIM: The polyene carotenoids beta-carotene and lycopene are antioxidants that not only quench singlet oxygen but also inhibit lipid peroxidation. Tri-n-butyl borane (TBB) is used as an initiator for dental resin materials and is extremely reactive with oxygen and reactive oxygen species (ROS). This reactionability of TBB may be analogous to that of carotenoids with ROS. To clarify the biological activity of such ROS scavengers, we investigated the anti-inflammatory activity of beta-carotene, lycopene and TBB in terms of the expression of RNA for lipopolysaccharide (LPS)-induced cyclooxygenase-2 (Cox2), nitric oxide synthase 2 (Nos2) and tumor necrosis factor-alpha (Tnfa), and mRNA expression and up-regulation of heme oxygenase 1 (Hmox1) mRNA in RAW264.7 cells. MATERIALS AND METHODS: mRNA expression was investigated using real-time reverse transcriptase-polymerase chain reaction (PCR). The antioxidant activity of carotenoids was evaluated using the induction period method in the azobisisobutyronitrile or benzoyl peroxide-methyl methacrylate system. RESULTS: Hmox1 mRNA, but not Cox2 and Nos2 mRNA, was up-regulated by 100 MUM beta-carotene and lycopene, and by 0.125% TBB. LPS-stimulated Cox2, Nos2 and Tnfa gene expression was inhibited by 50 MUM beta-carotene and lycopene, and by 0.5-1% TBB. Both beta-carotene and lycopene had weak antioxidant activity, but beta-carotene showed pro-oxidant activity at higher concentrations. CONCLUSION: The anti inflammatory activity of beta-carotene, lycopene and TBB may be related to their ROS-scavenging activity. Additionally, the activity of carotenoids and TBB may be attributed to the electrophilicity of ROS-induced carotenoid intermediates and boranes, respectively. Their anti-inflammatory activity may be attributable to enhancement of the potency of the electrophile/antioxidant response element transcription system in view of their up-regulation of Hmox1 mRNA expression. PMID- 29475908 TI - Effects of Diets with Different Proportions of Protein/Carbohydrate on Retinal Manifestations in db Mice. AB - BACKGROUND/AIM: Diabetic nephropathy is aggravated by a higher intake of total protein. The effects of diets with different proportions of protein and carbohydrate on diabetic retinopathy in db mice, a type-2 diabetes animal model, were examined, as well as diabetic nephropathy. MATERIALS AND METHODS: Control and db mice at 5 weeks of age were fed the diets (% energy of protein/carbohydrate/fat; L-diet: 12/71/17; H-diet: 24/59/17) under ad libitum conditions and pair-feeding conditions for 6 weeks, respectively. RESULTS: Mice fed the H-diet showed significantly greater retinal thickness by optical coherence tomography, and lower mRNA levels of angiotensinogen. Comparing combinations of diets and genotypes, db-H mice showed significantly higher mRNA levels of angiotensin-converting enzyme, advanced glycosylation end product specific receptor, and cluster of differentiation molecule 11b (a microglial marker) than db-L mice. CONCLUSION: Dietary protein and carbohydrate proportions influenced retinal manifestations, including retinal thickness and gene expression in control and diabetic mice. PMID- 29475909 TI - Inhibition of Systemic Hyaluronan Synthesis Exacerbates Murine Hepatic Carcinogenesis. AB - BACKGROUND/AIM: Hyaluronan (HA) is used as a biomarker of liver fibrosis, which is a key risk factor for the development of hepatocellular carcinoma (HCC). We examined the effects of prolonged pharmacological inhibition of HA synthesis on liver carcinogenesis. MATERIALS AND METHODS: Liver tumors were induced in mice by administering 0.03% thioacetamide (TAA) in drinking water over a 12-month period. Animals simultaneously received either a diet containing of an inhibitor of HA synthesis [4-methylumbelliferone (4-MU)], or a control diet. RESULTS: Addition of 4-MU resulted in a significantly higher number of tumors compared to TAA treatment alone. Moreover, addition of 4-MU resulted in a dose-dependent increase in maximum tumor size. CONCLUSION: While local HA suppression has been shown to have an inhibitory effect on HCC in vitro and in tumor cell implantation experiments, the present results indicate that systemic inhibition of HA synthesis by 4-MU supplementation facilitates hepatic carcinogenesis in vivo. PMID- 29475910 TI - Amentoflavone Induces Apoptosis and Inhibits NF-KB-modulated Anti-apoptotic Signaling in Glioblastoma Cells. AB - The goal of the present study was to investigate anticancer effect of amentoflavone on glioblastoma cells in vitro. Our results demonstrated that amentoflavone not only significantly reduced cell viability, nuclear factor-Kappa B (NF-KB) activation, and protein expression of cellular Fas-associated protein with death domain-like interleukin 1 beta-converting enzyme inhibitory protein (C FLIP) and myeloid cell leukemia 1 (MCL1), but significantly triggered cell accumulation at the sub-G1 phase, loss of mitochondrial membrane potential, and expression of active caspase-3 and -8. In order to verify the effect of NF-KB inhibitor on expression of anti-apoptotic proteins, we performed western blotting. We found that the of NF-KB inhibitor or amentoflavone markedly diminished protein levels of MCL1 and C-FLIP. Taken all together, our findings show that amentoflavone induces intrinsic and extrinsic apoptosis and inhibits NF KB-modulated anti-apoptotic signaling in U-87 MG cells in vitro. PMID- 29475911 TI - Tumor Necrosis Factor-Alpha (TNF-alpha-308 G>A) Polymorphism in High-grade Gliomas. AB - BACKGROUND/AIM: High-grade gliomas (HGG) consist of anaplastic oligoastrocytomas, anaplastic oligodendrogliomas, anaplastic astrocytomas and glioblastoma multiforme. The present study aimed to evaluate TNF-alpha -308 G>A polymorphism in a Turkish population. PATIENTS AND METHODS: This was a prospective case control study that included 45 patients with HGG and 49 healthy individuals. All patients were operated for intracranial tumors and the pathology results consist of high grade (Grade3 and 4) glial tumors. RESULTS: No significant differences were found between the HGG and control groups in terms of the median age (p=0.898). There were no significant differences with regard to gender (p=0.577). The TNF genotype frequency comparison between patients and controls was not statistically significant (p=0.598). CONCLUSION: TNF genotype frequency comparison between the patients and controls was not statistically significant in the Turkish population tested. However, further studies are needed to evaluate the genotype and phenotype correlations in large cohorts of various ethnicities. PMID- 29475912 TI - Novel Feed Including Olive Oil Mill Wastewater Bioactive Compounds Enhanced the Redox Status of Lambs. AB - BACKGROUND/AIM: The aim of the present study was to investigate the antioxidant effects of a feed supplemented with polyphenolic additives from olive mill wastewater (OMW) on lambs. MATERIALS AND METHODS: Lambs received breast milk until the postnatal period, and then they were divided into two groups and received control and OMW feed for 55 days. Redox biomarkers were measured in blood and tissues at days 15, 42 and 70 after feeding. RESULTS: Feed supplemented with OMW reduced thiobarbituric acid reactive species and protein carbonyls and increased total antioxidant capacity, glutathione and catalase activity in both blood and tissues. CONCLUSION: The administration of OMW-containing feed reinforced the antioxidant defense of lambs, which may improve their wellbeing and productivity. Additionally, this exploitation of OMW may solve problems of environmental pollution in areas with olive oil industries. PMID- 29475914 TI - Expression of miR-208b and miR-499 in Greek Patients with Acute Myocardial Infarction. AB - BACKGROUND/AIM: Certain microRNAs (miRs) present in human plasma are candidate biomarkers for cardiovascular diseases, including acute myocardial infarction (AMI). We examined the expression of two cardiac-specific miRs (miR-208b and miR 499) in a Greek pathological population. MATERIALS AND METHODS: Plasma samples from AMI patients and healthy subjects (controls) were analyzed using TaqMan(r) MicroRNA assays. RESULTS: The concentration of both miRs was significantly elevated in AMI patients compared to healthy controls. Moreover, receiver operating characteristic (ROC) curve analysis showed that miR-208b and miR-499 displayed similar properties with the established AMI biomarker cardiac troponin T (cTnT). CONCLUSION: We showed, for the first time, that these miRs could be used as AMI biomarkers in our population as well. Our data are in agreement with those of studies based on different population groups and further strengthen the observation that plasma levels of circulating miR-208b and miR-499 could serve as potential AMI biomarkers. PMID- 29475913 TI - Expression and Clinical Significance of Claudin-7, PDL-1, PTEN, c-Kit, c-Met, c Myc, ALK, CK5/6, CK17, p53, EGFR, Ki67, p63 in Triple-negative Breast Cancer-A Single Centre Prospective Observational Study. AB - BACKGROUND/AIM: To explore the relationship between p53, p63, c-kit, Ki67, cMet, claudin7, CK5/6, CK17, AR, PTEN, EGFR, ALK, PDL-1 and c-MYC expression with the clinicopathological features of triple- negative breast cancer. MATERIALS AND METHODS: Immunohistochemistry was performed in 84 triple-negative breast cancer samples. RESULTS: A statistically significant relationship between tumour grade and claudin-7 (p=0.004) and between protein p53 and positive lymph nodes (p=0.015) was found. High expression of claudin-7 (OR=65.8, 95%CI=4.35-995.19, p value=0.003) and low expression of c-kit (OR=0.14, 95%CI=0.025-0.793, p value=0.026) and protein p63 (OR=0.18 95%CI=0.035-0.978, p-value=0.047) was associated with higher tumour grade. Higher AR expression (OR=13.44, 95%CI=1.28 141.56, p-value=0.031) and lower expression of CK5/6 cytokeratins was found in patients with positive lymphovascular invasion (LVI) (OR=0.072, 95%CI=0.007 0.732, p-value=0.026). Only the cell proliferation index (Ki67) has been proven to be statistically significant for disease-free survival (p-value=0.0378), and overall survival (p-value=0.0186). CONCLUSION: High expression of claudin-7 and low expression of c-kit and protein p63 are associated with higher tumour grade. AR and CK5/6 expression seem to be important in LVI. PMID- 29475915 TI - Reduced Peripheral Blood Mononuclear Cell ROCK1 and ROCK2 Levels in Obstructive Sleep Apnea Syndrome. AB - BACKGROUND/AIM: Obstructive sleep apnea syndrome (OSAS) is associated with intermittent episodes of hypoxia, endothelial dysfunction and associated cardiovascular problems. Our aim was to investigate whether OSAS-related hypoxia alters the expression of rho-associated protein kinase (ROCK), a marker of chronic hypoxia and endothelial dysfunction. MATERIALS AND METHODS: ROCK1 and ROCK2 levels were measured by immunoblotting in peripheral blood mononuclear cells (PBMC) of 47 OSAS patients and 17 healthy controls. RESULTS: OSAS patients showed significantly lower PBMC ROCK1 and ROCK2 levels than healthy controls in the morning, but not in the evening. ROCK1/2 levels were correlated with blood triglyceride, visceral adiposity index, minimum oxygen saturation, C-reactive protein concentration, lymphocyte levels and sleep efficiency. CONCLUSION: Intermittent hypoxia induced by OSAS does not permanently alter ROCK protein expression levels. OSAS appears to be associated with endothelial dysfunction through inflammation and lipid metabolism pathways. PMID- 29475916 TI - Does Marital Status Influence Levels of Anxiety and Depression Before Palliative Radiotherapy? AB - BACKGROUND/AIM: To evaluate whether or not single patients report increased levels of anxiety and depression, compared to married or partnered patients scheduled to receive palliative radiotherapy. In principle, different levels of social support might cause such disparities. PATIENTS AND METHODS: Retrospective comparison of two groups of patients (28% single, overall 100 patients), who scored their symptoms before palliative radiotherapy with the Edmonton symptom assessment system (ESAS). RESULTS: The two groups differed significantly with regard to irradiated target sites (more brain irradiation in the married/partnered group), receipt of systemic therapy, which was more common in the married/partnered group, and mean age (single patients were older). Mean anxiety and depression scores were not significantly different between the two groups. Survival was similar, too (median 6 months, p=0.77). CONCLUSION: Similar ESAS scores of anxiety and depression were observed in the two groups (single vs. married/partnered patients). PMID- 29475917 TI - How Should Palliative Thoracic Radiotherapy Be Fractionated for Octogenarians with Lung Cancer? AB - BACKGROUND/AIM: Geriatric oncology practice should be based on dedicated studies and real-world experience. Therefore, we evaluated survival outcomes after palliative thoracic radiotherapy in octogenarian patients with lung cancer and analyzed prognostic factors. PATIENTS AND METHODS: We carried out a retrospective analysis of 51 patients with a median age of 83 years. Three different fractionation regimens were compared: two fractions of 8.5 Gy, 10 fractions of 3 Gy, and higher doses than 30 Gy (maximum biologically equivalent dose in 2-Gy fractions (EQD2) was always lower than 50 Gy). No concomitant chemotherapy was prescribed. Patients with incomplete radiotherapy (16%) were included, in line with the intention-to-treat principle, i.e. based on prescribed rather than accumulated dose. RESULTS: Median survival was 3.4 months. We observed a relatively high proportion of patients who received radiotherapy in the last 30 days of life (24%). Nevertheless, approximately 10% of patients were alive 3-5 years after treatment. Prognosis was similar for those with stage III and IV disease. Multivariate analysis identified four significant prognostic factors for shorter survival: reduced performance status, serum C-reactive protein (CRP) >=30 mg/l, leukocytosis, and prescribed radiation dose <=30 Gy (EQD2=33 Gy). The three different radiotherapy regimens resulted in median survival of 2.4, 2.6 and 11.8 months, respectively. CONCLUSION: Survival outcomes were highly variable. Given that survival after 10 fractions of 3 Gy was indistinguishable from that after two fractions of 8.5 Gy, we suggest that the latter regimen should be considered for patients with poor prognosis. Patients with favorable prognostic factors should be treated with higher radiation doses, e.g. 15 fractions of 3 Gy. PMID- 29475918 TI - Pulmonary Tumor Embolism Due to Squamous Cell Carcinoma of the Uterine Cervix: A Case Report. AB - BACKGROUND/AIM: We report on a case of pulmonary tumor embolism caused by squamous cell carcinoma of the uterine cervix. PATIENTS AND METHODS: A 60-year old female diagnosed with stage IVB (cT4N1M1) squamous cell carcinoma of the uterine cervix was admitted to our institution with a chief complaint of progressive dyspnea that developed within a few days after admission. RESULTS: A chest CT scan showed dilated pulmonary arteries, right ventricular enlargement and mosaic ground-glass opacities in both lungs. An echocardiogram revealed elevated right ventricular pressure and a floppy mass in the right ventricle. Pulmonary tumor embolism was highly suspected. However, she died from respiratory failure on the fourth day after admission. Autopsy revealed diffuse tumor emboli in bilateral pulmonary arteries and arterioles. CONCLUSION: Pulmonary tumor embolism should be considered when patients with malignant disease develop unexplained dyspnea, hypoxemia, and pulmonary hypertension. PMID- 29475919 TI - Thyrotoxicosis and Adrenocortical Hormone Deficiency During Immune-checkpoint Inhibitor Treatment for Malignant Melanoma. AB - BACKGROUND: Immune-checkpoint inhibitors (ICIs) are novel promising agents for the treatment of malignant tumors. However, critical endocrine immune-related adverse events (irAEs) by ICIs often occur. CASE REPORT: A 63-year-old woman with advanced malignant melanoma had received anti-PD-1 antibody (nivolumab, 2 mg/kg every 3 weeks) for 8 cycles (from day 0 to day 147). On day 168, nivolumab was switched to anti-CTLA-4 antibody (ipilimumab, 3mg/kg every 3 weeks). Twenty-eight days later, she was diagnosed with thyrotoxicosis due to painless thyroiditis (day 196). Thirty-five days later (day 231), thyrotoxicosis turned to hypothyroidism. In addition, twenty-five days later (day 256), she was diagnosed with adrenocortical insufficiency due to adrenocortical hormone (ACTH) deficiency. Hormone replacements with levothyroxine and hydrocortisone were administered. She showed eosinophilia, ESR/CRP/LDH elevation, liver dysfunction and hyponatremia before diagnosis of ACTH insufficiency. Eosinophilia, thrombocytopenia, ESR/CRP/LDH elevation, and liver dysfunction might be important for early detection of thyrotoxicosis in our case. CONCLUSION: The present report provides the first detailed presentation of combined thyrotoxicosis and isolated ACTH deficiency induced by ICIs. Since rapidly progressive fatal endocrine system failure may be provoked during ICI therapy, precise diagnosis and prompt treatment as well as close follow-up is critical. We propose routine monitoring of endocrine functions and related symptoms (worsened fatigue, hypoglycemia, hypotension or hyponatremia), as well as other laboratory tests during ICI therapy. PMID- 29475920 TI - The Difference in Prognostic Outcomes Between De Novo Stage IV and Recurrent Metastatic Patients with Hormone Receptor-positive, HER2-negative Breast Cancer. AB - BACKGROUND/AIM: Patients with de novo stage IV and recurrent metastatic breast cancer are often treated with the same strategies, although the difference in prognostic outcomes remains unclear. The objective of this retrospective chart review study was to compare the prognostic outcomes between two types of patients with hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer. PATIENTS AND METHODS: We estimated overall survival of the two groups and evaluated the progressive course of the disease using disease-free interval (DFI) and interval from the end of adjuvant treatment to the first recurrence (AFI). RESULTS: We studied 172 patients with HR+/HER2- breast cancer, of which 65 were de novo and 107 were recurrent. Median OS between de novo and recurrent BC was 4.85 and 3.45 years, respectively (p=0.046). Recurrent patients with a DFI<2 years were found to have a significantly poorer prognosis than recurrent patients with a DFI>=2 years (p=0.016) and de novo patients (p=0.002). Similarly, recurrent patients with an AFI<1 year had a significantly poorer prognosis compared to de novo patients (p=0.026). CONCLUSION: De novo patients had better prognoses than recurrent patients with DFI<2 years or AFI<1 year, likely due to their therapy-naive status or lower resistance to systemic treatment. PMID- 29475921 TI - Clinical Impact of a Surgical Energy Device in Advanced Ovarian Cancer Surgery Including Bowel Resection. AB - AIM: To evaluate the clinical impact of the use of the Caiman(r) articulating energy device in advanced ovarian cancer (AOC) including rectosigmoid resection [e.g. modified posterior exenteration (MPE)]. PATIENTS AND METHODS: This was a prospective single-institution observational study with women undergoing MPE where all soft-tissue dissections and vessel ligations were performed using the Caiman(r) device. Intraoperative and postoperative surgical data were collected. Bladder function after nerve-sparing surgery was analyzed before and 6 months after surgery. RESULTS: Forty patients were registered in the study. The median time for specimen removal using Caiman(r) was 86 min (range=70-120 min). Major vessel ligation was successful in all patients with a median of a single (range=1 4) Caiman(r) application to seal major vessels. No intraoperative or postoperative complications or bladder dysfunctions associated with the use of Caiman(r) were noted. CONCLUSION: Caiman(r) can be safely used in AOC surgery and may save time through faster dissection. However, comparative studies with other energy devices are needed to confirm this finding. PMID- 29475922 TI - DCLK1 Expression in Colorectal Polyps Increases with the Severity of Dysplasia. AB - BACKGROUND: The expression of doublecortin-like kinase 1 (DCLK1) has been investigated in cancer; however not in precancerous adenomatous polyps. MATERIALS AND METHODS: Immunohistological expression of DCLK1 was evaluated in various grades of adenomas, cancerous polyps, and hyperplastic polyps in resected human tissue specimens. RESULTS: Ninety-two specimens were positive for DCLK1 and 134 were negative. Cancerous polyps showed a high DCLK1 positivity rate compared to adenomas (68.4% vs. 36.8%; p<0.01). The rate of DCLK1 positivity was not significantly different among the three grades of adenomas (mild, moderate, and severe). DCLK1 was highly positive in advanced adenomas than low risk adenomas (49.6% vs. 29.3%; p<0.01). CONCLUSION: The expression of DCLK1 was found in low grade adenomas and increased with worsening severity of dysplasia. DCLK1 expression was highly observed in advanced adenomas, which had a clinically higher malignant potential. PMID- 29475923 TI - Determinants of Survival After Emergency Intrapericardial Cisplatin Treatment in Cancer Patients with Recurrent Hemodynamic Instability After Pericardiocentesis. AB - BACKGROUND: Pericardial effusion is associated with high mortality in oncology. The etiology of infectious pericarditis and iatrogenic effects of previous radio /chemotherapy may be always suspected, especially when a subsequent episode is observed. PATIENTS AND METHODS: The study included 17 hemodynamically-unstable patients with cancer due to recurrent pericardial bloody effusion after previous pericardiocentesis and analyzed survival determinants after intrapericardial chemotherapy with cisplatin. RESULTS: The mortality rate was not significantly associated with the level of N-terminal pro-B type natriuretic peptide, low hemoglobin (<12 g/dl), elevated white blood cell account (>104/MUl), large volume (>1500 ml) and long duration (>8 days) of pericardial drainage, cardiac arrhythmias, positive culture test results nor fever occurring during cisplatin administration. Subsequent systemic anticancer therapy was the strongest factor determining a longer survival (hazard ratio(HR)=0.31, 95% confidence interval(CI)=0.11-0.9; p=0.03). CONCLUSION: Efficacy of rescue intrapericardial chemotherapy with cisplatin is independent of parameters of hemodynamic instability and levels of inflammatory markers in recurrent pericardial effusion. PMID- 29475924 TI - Validation of a Survival Score for Patients Receiving Radiosurgery or Fractionated Stereotactic Radiotherapy for 1 to 3 Brain Metastases. AB - BACKGROUND/AIM: We developed a scoring system to predict 1-year survival after radiosurgery for 1-3 brain metastases. This study aimed to validate this system. PATIENTS AND METHODS: Seventy-six new patients were included in this validation study. Like in the original scoring-system, three factors (age, performance status, extra-cranial metastases) were used. For each factor, 1-year survival rates in % were divided by 10, and the three scoring-points were added for each patient. RESULTS: Patient's scores were 10, 11, 13, 14, 16 or 17 points with 1 year survival rates ranging between 31% and 80%. Two groups, 10-14 and 16-17 points were formed. In the 14-16 points group, 1-year survival was 47% (versus 33% in the preceding study, p=0.060). In the 16-17 points group, 1-year survival rates were 75% versus 77% (p=0.79). CONCLUSION: In the more favorable group, the scoring-system was very reproducible. In the less favorable group, the difference was larger, but also not signficant. PMID- 29475925 TI - Normal Size Ovary Carcinoma Syndrome with Inguinal Ovarian Cancer Lymph Node Metastases - A Case Report and Literature Review. AB - Inguinal lymph node mass as the first sign in patients with ovarian cancer represents a rare situation, with only few cases being reported so far. We present the case of a 46-year-old patient who presented for the apparition of bilateral inguinal tumoral masses in the absence of any other pathological signs. The biopsy revealed the presence of an adenocarcinoma with probable genital origin; however, neither the gynaecological examination nor the computed tomography demonstrated the presence of any suspect lesion. The patient was submitted to a positron emission computed tomography which revealed a high capitation in both adnexal areas as well as at the level of the inguinal lymph nodes. The patient was submitted to surgery, the frozen section of the adnexas confirming the ovarian origin of the tumor. Complete cytoreduction to no residual disease was successfully performed. At one-year follow-up the patient is free of any recurrent disease. PMID- 29475926 TI - Cullin-1 and -2 Protein Expression in Colorectal Cancer: Correlation with Clinicopathological Variables. AB - BACKGROUND/AIM: The cullin (CUL) family of proteins is involved in the ubiquitin/mediated degradation of proteins, regulating cell proliferation, cell cycle control, migration, invasion and metastasis in the process of tumor progression. The aim of the present study was to examine if there is any correlation between the immunohistochemical (IHC) expression of Cullin-1 and -2 proteins in colorectal cancer tissue specimens with several clinicopathological variables. MATERIALS AND METHODS: Between January 2012 and December 2014, 96 consecutive adenocarcinoma patients were submitted to oncological colectomy, as the first therapeutic option, with a curative intent. CUL-1 and -2 protein expression was examined with IHC on paraffin-embedded tissue sections. CUL-1 and 2 protein positivity, was correlated with patients' age, gender, stage, histological grade, proliferative capacity (Ki-67 labeling index) and mutant p53 protein expression. The positivity for CUL-1, CUL-2, mutant p53 protein and Ki-67 index, was determined by the percentage of their IHC expression in the total number of cancer cells. RESULTS: Choosing as a cut-off point for CUL-1 positivity the 10%, a statistically significant relationship of the expression of the mutant p53 protein (p=0.04) and the co-expression of CUL-2 (p=0.003) were noticed. By setting the cut-off limit for CUL-2 expression to 10%, no statistically significant differences were observed between its expression and the examined clinicopathological variables. However, by increasing the cut-off limit for CUL-2 expression to 30%, a statistically significant correlation of its expression to the mutated p53 protein was noticed (p=0.047). Co-expression of CUL-1 and -2 in more than 10%, significantly correlated to the coexistence of adenomatous polyps along the large bowel (p=0.0329). Multivariate analysis of CUL-1 and -2 co expression in more than 10% disclosed their expression as an independent factor for adenomatous polyps development in the large bowel (p=0.035, RR=2.1). CONCLUSION: CUL-1 overexpression may happen early in the process of carcinogenesis mainly affecting the vulnerable p53(+) large bowel cells, arresting them in the G1 phase of cell-cycle, while it may also induce the expression of CUL-2. Co-expression of CUL-1 and CUL-2, in the arrested (in G1 phase) large bowel cells, promotes carcinogenesis up to adenomatous polyp formation. Since no relationship between cullins expression and development of cancer on adenoma was found, the results of the present study may be useful explaining the initiation but not the progression of carcinogenesis in colorectal cancer. Further molecular and clinical studies are needed in order to delineate the clinical importance of these proteins in the management of colorectal cancer patients. PMID- 29475927 TI - Increase in Serum Amylase and Resistive Index After Kidney Transplant Are Biomarkers of Delayed Graft Function. AB - BACKGROUND: Both amylase and resistive index (RI) are routinely measured after kidney transplant and proposed as markers of delayed graft function (DGF). MATERIAL AND METHODS: This retrospective cross-sectional study analyzed amylase and RI in 269 renal transplant recipients before and after transplantation, and at discharge. An increase above 20% of total amylase with/without RI>0.7 were evaluated as prognostic markers of DGF, hospitalization length and risk of rejection. RESULTS: Serum amylase increase >20% was found in 103/269 (38.3%) patients who showed DGF (45.6% vs. 25.3%, p=0.001) and had lower estimated glomerular filtration rate compared to those with an amylase increase <20% (42.0+/-21.7 vs. 49.8+/-23.2 ml/min, p=0.007). The double condition consisting of concomitant amylase increase >20% and RI>0.7 was associated with higher DGF occurrence (65% vs. 24%, p<0.001), longer hospital stay, lower eGFR at discharge, and higher risk of rejection. CONCLUSION: Patients with concomitant amylase increase >20% and RI>0.7 might require closer monitoring to diagnose DGF early and modify the therapeutic approach accordingly. PMID- 29475928 TI - Tear Film Osmolarity in Subjects with Acute Allergic Rhinoconjunctivitis. AB - BACKGROUND/AIM: Acute allergic rhinoconjuctivitis is the most common form of ocular allergies. The pathogenetic mechanisms are based on an immunoglobulin E (IgE)-mediated hypersensitivity reaction. On the other hand, tear osmolarity has been suggested to be an index of ocular surface damage and inflammation. These data were the motive to investigate the levels of tear osmolarity in subjects with acute allergic rhinoconjuctivitis, before and after administration of artificial tears. PATIENTS AND METHODS: Forty-five subjects with acute allergic rhinoconjuctivitis were randomly divided into three groups, based on the type of artificial tears that they received: Group A (Thera tears), Group B (Wet therapy) and Group C (Tears Naturale free). The eye drops were administered six times a day for 60 days and all subjects underwent grading of subjective symptoms and clinical examination at baseline and at the end of the treatment. RESULTS: The diagnosis of severe eye disease, which was based on ocular surface disease index (OSDI; Allergan, Inc, Irvine, CA, USA) and tear osmolarity values, concerned all patients at baseline. Although the administration of artificial tears significantly ameliorated the symptoms and the ocular variables in all groups, the results were better in the first group. Tear osmolarity was strongly and negatively correlated with tear film breakup time (BUT) and Schirmer I test at 2 months. Contrariwise, symptoms were eliminated, when tear osmolarity was decreased. CONCLUSION: Acute allergic rhinoconjuctivitis is characterized by tear hyperosmolarity, which can be rehabilitated with the administration of hypotonic artificial tears. PMID- 29475929 TI - Effect of Androgen-deprivation Therapy on Bone Mineral Density in Japanese Patients with Prostate Cancer. AB - BACKGROUND/AIM: To evaluate bone mineral density (BMD) in Japanese patients with prostate cancer (PCa) after administering androgen deprivation therapy (ADT) for 2 years. PATIENTS AND METHODS: A total of 84 Japanese patients with PCa were enrolled in this study during the period 2008-2011. BMD was measured by dual energy X-ray absorptiometry, every 6 months. The fracture risk assessment tool (FRAX) score was calculated before starting ADT. We evaluated the change in BMD over a 2-year period and the relationship between this change, the FRAX score, and the estimated glomerular filtration rate (eGFR). RESULTS: Compared to baseline, BMD decreased by 2.50% at 6 months after ADT, by 4.28% after 12 months, by 5.34% after 18 months, and by 6.16% after 2 years (all p<0.05). Multivariate analysis revealed that the eGFR, according to a threshold rate of 73.5 ml/min, was a significant factor in BMD. CONCLUSION: Lumbar BMD in Japanese patients with PCa decreased by 4.28% at 1 year after ADT and by 6.16% after 2 years. We found a correlation between the decrease in BMD and the eGFR before initiating ADT, suggesting a small BMD reduction in patients with PCa who have good renal function. PMID- 29475930 TI - Primary Gastric EBV-positive Diffuse Large B Cell Lymphoma (DLBCL) of the Elderly with Plasmablastic Differentiation. AB - Epstein-Barr virus (EBV)-positive diffuse large B cell lymphoma (DLBCL) of the elderly is a rare subtype of B-cell neoplasms. Primary gastric EBV-positive DLBCL of the elderly with partial plasmablastic phenotype is extremely rare. Differentiation of EBV-positive DLBCL of the elderly with partial plasmablastic phenotype from true plasmablastic lymphoma (PBL) is difficult and very important from the therapeutic and prognostic point of view. Here we report a case of a 59 year-old man with upper gastrointestinal bleeding. The esophagogastroduodenoscopy revealed a 2-cm malignant-appearing non-bleeding gastric ulcer in the gastric cardia. Biopsy showed ulcerated tissue with atypical lymphoid cell infiltrate, morphologically consistent with immunoblasts. The atypical large cells were positive for CD20, PAX5, MUM-1, and a subset of large cells was positive for CD30, BCL6 and CD138. Ki-67 proliferation index exceeded 90% of the tumor cells. In situ hybridization (ISH) for EBV-encoded RNAs (EBERs) was extensively positive. Kappa/Lambda ISH showed lambda restriction. The final diagnosis was primary gastric EBV-positive DLBCL of the elderly with plasmablastic phenotype. The patient finished 5 cycles of R-DA-EPOCH with significant clinical improvement. To the best of our knowledge, this is an extremely rare case of primary gastric EBV-positive DLBCL of the elderly with plasmablastic phenotype. PMID- 29475931 TI - The Influence of Cardiac Pacemaker Programming Modes on Exercise Capacity. AB - BACKGROUND/AIM: The cardiac pacing mode influences the atrioventricular synchronicity and the response of the heart rate to physical exercise. The aim of this study was to compare the influence of the most common pacemaker programming modes on exercise capacity. PATIENTS AND METHODS: Fifty-two pacemaker-wearing patients were clinically evaluated and submitted to an exercise stress test. RESULTS: Symptoms of heart failure were more frequently met in the single-chamber pacemaker group compared to the dual-chamber group. The parameters recorded during the exercise stress test were significantly better with the rate responsive function (RRF) activated. The effort time was higher by an average of 2.1 minutes and the exercise capacity was higher by 0.92 metabolic equivalents. CONCLUSION: Dual-chamber pacing is superior to single-chamber (ventricular) pacing and the activation of the RRF in single-chamber pacemakers has similar impact on exercise capacity as the preservation of atrioventricular synchronicity by dual-chamber pacemakers. PMID- 29475932 TI - Differences in Urinary Amino Acid Patterns in Individuals with Different Types of Urological Tumor Urinary Amino Acid Patterns as Markers of Urological Tumors. AB - BACKGROUND: Insufficient specificity and invasiveness of currently used diagnostic methods raises the need for new markers of urological tumors. The aim of this study was to find a link between the urinary excretion of amino acids and the presence of urological tumors. MATERIALS AND METHODS: Using ion-exchange chromatography, we tested urine samples of patients with prostate cancer (n=30), urinary bladder cancer (n=28), renal cell carcinoma (n=16) and healthy volunteers (control group; n=21). RESULTS: In each category, we found a group of amino acids which differed in concentration compared to the control group. These differences were most significant in sarcosine in patients with prostate cancer; leucine, phenylalanine and arginine in those with bladder cancer; and sarcosine, glutamic acid, glycine, tyrosine and arginine in the those with renal cell carcinoma. CONCLUSION: Results of our research imply a possible connection between the occurrence of specific types of amino acids in the urine and the presence of urological tumors. PMID- 29475933 TI - Association of Diaphragmatic Surgery as Part of Cytoreductive Effort in Advanced Stage Ovarian Cancer. AB - BACKGROUND/AIM: Diaphragmatic surgery in advanced-stage ovarian cancer has been considered since long time to increase the rates of postoperative complications. However, improvement of surgical techniques and perioperative management of these patients has lead in the last decade to a safe association of such procedures as part of debulking process. The aim of the current paper was to report our experience regarding the role of diaphragmatic resections as part of debulking surgery for advanced stage ovarian cancer. MATERIALS AND METHODS: Between 2014 and 2016 diaphragmatic surgery was performed in 22 cases with advanced stage ovarian cancer. RESULTS: Diaphragmatic surgery consisted of diaphragmatic peritoneal resection in 10 cases, full thickness diaphragmatic resections in four cases and coagulation of peritoneal nodules in eight cases. In all but two cases debulking surgery to no residual disease was achieved. Other upper abdominal resections consisted of splenectomy - in four cases, liver resections - in three cases, glissonian capsule resections - in eight cases, distal pancreatectomy - in one case and partial gastrectomies in two cases. The postoperative outcomes were similar irrespective of type of diaphragmatic surgical procedure. CONCLUSION: Diaphragmatic surgery is a crucial procedure which can be safely associated as part of debulking surgery for advanced stage ovarian cancer. PMID- 29475934 TI - In Vivo Scanning Laser Confocal Microscopy of Conjunctival Goblet Cells in Medically-controlled Glaucoma. AB - AIM: The aim of this study was to evaluate the goblet cell density (GCD) of conjunctiva in medically-controlled glaucoma using laser scanning confocal microscopy (LSCM). MATERIALS AND METHODS: Fifty-five glaucomatous patients were enrolled and divided into two groups: Group 1 (27 eyes), controlled with one medication; and group 2 (28 eyes), controlled with two medications. Seventeen patients with dry eye disease (DED) and 17 healthy individuals served as controls. Patients completed the Ocular Surface Disease Index (OSDI) questionnaire and underwent determination of tear film break-up time (BUT), corneal staining, and Schirmer test I. For the GCD assessment, 12 high-quality images were acquired from the upper conjunctival epithelium (superior nasal, superior central, and superior temporal sectors). RESULTS: Overall, GCD was significantly reduced in both glaucoma groups and those with DED compared to healthy controls (p<0.001), with values markedly lower in group 2 compared to group 1 (p<0.05). GCD was not significantly different between those with DED and group 2. A significant negative correlation was found of GCD with OSDI and with BUT (p<0.001; R=-0.795 and R=-0.756, respectively). CONCLUSION: Glaucoma therapy leads to a marked reduction of GCs, especially in the associative regimens. Given the negative correlation with tear film function tests, GCD reduction may play a pivotal role in the pathophysiology of the glaucoma-related disease of the ocular surface. PMID- 29475936 TI - The Trojan Horse Approach to Protein Jockeying. PMID- 29475935 TI - Prognostic Impact of Inflammation-related Biomarkers on Overall Survival of Patients with Inoperable Malignant Pleural Mesothelioma. AB - AIM: The aim of the present study was to assess the prognostic utility of the pretreatment blood neutrophil-to-lymphocyte ratio (NLR) and the C-reactive protein-to-albumin ratio (CAR) in patients with inoperable malignant pleural mesothelioma (MPM). MATERIALS AND METHODS: The medical records of consecutive patients with histologically confirmed MPM from our hospital between January 2007 and August 2017 were retrospectively reviewed. The primary outcome was overall survival (OS). Univariate and multivariate analyses for the prognostic factors were performed using a Cox proportional hazards model. RESULTS: A total of 143 patients with inoperable MPM were included. On multivariate analysis, pretreatment CAR was an independent factor associated with worse OS (hazard ratio(HR)=1.72; 95% confidence interval(CI)=1.11-2.67; p=0.016). However, NLR was not associated with OS in any of the analyses. CONCLUSION: CAR appears to be a prognostic factor in patients with inoperable MPM. PMID- 29475937 TI - Expression of the Nitrate Transporter Gene OsNRT1.1A/OsNPF6.3 Confers High Yield and Early Maturation in Rice. AB - Nitrogen (N) is a major driving force for crop yield improvement, but application of high levels of N delays flowering, prolonging maturation and thus increasing the risk of yield losses. Therefore, traits that enable utilization of high levels of N without delaying maturation will be highly desirable for crop breeding. Here, we show that OsNRT1.1A (OsNPF6.3), a member of the rice (Oryza sativa) nitrate transporter 1/peptide transporter family, is involved in regulating N utilization and flowering, providing a target to produce high yield and early maturation simultaneously. OsNRT.1A has functionally diverged from previously reported NRT1.1 genes in plants and functions in upregulating the expression of N utilization-related genes not only for nitrate but also for ammonium, as well as flowering-related genes. Relative to the wild type, osnrt1.1a mutants exhibited reduced N utilization and late flowering. By contrast, overexpression of OsNRT1.1A in rice greatly improved N utilization and grain yield, and maturation time was also significantly shortened. These effects were further confirmed in different rice backgrounds and also in Arabidopsis thaliana Our study paves a path for the use of a single gene to dramatically increase yield and shorten maturation time for crops, outcomes that promise to substantially increase world food security. PMID- 29475938 TI - HSI2/VAL1 Silences AGL15 to Regulate the Developmental Transition from Seed Maturation to Vegetative Growth in Arabidopsis. AB - Gene expression during seed development in Arabidopsis thaliana is controlled by transcription factors including LEAFY COTYLEDON1 (LEC1) and LEC2, ABA INSENSITIVE3 (ABI3), FUSCA3 (FUS3), known as LAFL proteins, and AGAMOUS-LIKE15 (AGL15). The transition from seed maturation to germination and seedling growth requires the transcriptional silencing of these seed maturation-specific factors leading to downregulation of structural genes including those that encode seed storage proteins, oleosins, and dehydrins. During seed germination and vegetative growth, B3-domain protein HSI2/VAL1 is required for the transcriptional silencing of LAFL genes. Here, we report chromatin immunoprecipitation analysis indicating that HSI2/VAL1 binds to the upstream sequences of the AGL15 gene but not at LEC1, ABI3, FUS3, or LEC2 loci. Functional analysis indicates that the HSI2/VAL1 B3 domain interacts with two RY elements upstream of the AGL15 coding region and at least one of them is required for HSI2/VAL1-dependent AGL15 repression. Expression analysis of the major seed maturation regulatory genes LEC1, ABI3, FUS3, and LEC2 in different genetic backgrounds demonstrates that HSI2/VAL1 is epistatic to AGL15 and represses the seed maturation regulatory program through downregulation of AGL15 by deposition of H3K27me3 at this locus. This hypothesis is further supported by results that show that HSI2/VAL1 physically interacts with the Polycomb Repressive Complex 2 component protein MSI1, which is also enriched at the AGL15 locus. PMID- 29475939 TI - The ST6Gal-I sialyltransferase protects tumor cells against hypoxia by enhancing HIF-1alpha signaling. AB - Aberrant cell surface glycosylation is prevalent in tumor cells, and there is ample evidence that glycans have functional roles in carcinogenesis. Nonetheless, many molecular details remain unclear. Tumor cells frequently exhibit increased alpha2-6 sialylation on N-glycans, a modification that is added by the ST6Gal-I sialyltransferase, and emerging evidence suggests that ST6Gal-I-mediated sialylation promotes the survival of tumor cells exposed to various cell stressors. Here we report that ST6Gal-I protects cancer cells from hypoxic stress. It is well known that hypoxia-inducible factor 1alpha (HIF-1alpha) is stabilized in hypoxic cells, and, in turn, HIF-1alpha directs the transcription of genes important for cell survival. To investigate a putative role for ST6Gal-I in the hypoxic response, we examined HIF-1alpha accumulation in ovarian and pancreatic cancer cells in ST6Gal-I overexpression or knockdown experiments. We found that ST6Gal-I activity augmented HIF-1alpha accumulation in cells grown in a hypoxic environment or treated with two chemical hypoxia mimetics, deferoxamine and dimethyloxalylglycine. Correspondingly, hypoxic cells with high ST6Gal-I expression had increased mRNA levels of HIF-1alpha transcriptional targets, including the glucose transporter genes GLUT1 and GLUT3 and the glycolytic enzyme gene PDHK1 Interestingly, high ST6Gal-I-expressing cells also had an increased pool of HIF-1alpha mRNA, suggesting that ST6Gal-I may influence HIF-1alpha expression. Finally, cells grown in hypoxia for several weeks displayed enriched ST6Gal-I expression, consistent with a pro-survival function. Taken together, these findings unravel a glycosylation-dependent mechanism that facilitates tumor cell adaptation to a hypoxic milieu. PMID- 29475940 TI - Identification of multiple isomeric core chitobiose-modified high-mannose and paucimannose N-glycans in the planarian Schmidtea mediterranea. AB - Cell surface-associated glycans mediate many cellular processes, including adhesion, migration, signaling, and extracellular matrix organization. The galactosylation of core fucose (GalFuc epitope) in paucimannose and complex-type N-glycans is characteristic of protostome organisms, including flatworms (planarians). Although uninvestigated, the structures of these glycans may play a role in planarian regeneration. Whole-organism MALDI-MS analysis of N-linked oligosaccharides from the planarian Schmidtea mediterranea revealed the presence of multiple isomeric high-mannose and paucimannose structures with unusual mono-, di-, and polygalactosylated (n = 3-5) core fucose structures; the latter structures have not been reported in other systems. Di- and trigalactosylated core fucoses were the most dominant glycomers. N-Glycans showed extensive, yet selective, methylation patterns, ranging from non-methylated to polymethylated glycoforms. Although the majority of glycoforms were polymethylated, a small fraction also consisted of non-methylated glycans. Remarkably, monogalactosylated core fucose remained unmethylated, whereas its polygalactosylated forms were methylated, indicating structurally selective methylation. Using database searches, we identified two potential homologs of the Galbeta1-4Fuc-synthesizing enzyme from nematodes (GALT-1) that were expressed in the prepharyngeal, pharyngeal, and mesenchymal regions in S. mediterranea. The presence of two GALT 1 homologs suggests different requirements for mono- and polygalactosylation of core fucose for the formation of multiple isomers. Furthermore, we observed variations in core fucose glycosylation patterns in different planarian strains, suggesting evolutionary adaptation in fucose glycosylation. The various core chitobiose modifications and methylations create >60 different glycoforms in S. mediterranea. These results contribute greatly to our understanding of N-glycan biosynthesis and suggest the presence of a GlcNAc-independent biosynthetic pathway in S. mediterranea. PMID- 29475941 TI - Genetic disruption of multiple alpha1,2-mannosidases generates mammalian cells producing recombinant proteins with high-mannose-type N-glycans. AB - Recombinant therapeutic proteins are becoming very important pharmaceutical agents for treating intractable diseases. Most biopharmaceutical proteins are produced in mammalian cells because this ensures correct folding and glycosylation for protein stability and function. However, protein production in mammalian cells has several drawbacks, including heterogeneity of glycans attached to the produced protein. In this study, we established cell lines with high-mannose-type N-linked, low-complexity glycans. We first knocked out two genes encoding Golgi mannosidases (MAN1A1 and MAN1A2) in HEK293 cells. Single knockout (KO) cells did not exhibit changes in N-glycan structures, whereas double KO cells displayed increased high-mannose-type and decreased complex-type glycans. In our effort to eliminate the remaining complex-type glycans, we found that knocking out a gene encoding the endoplasmic reticulum mannosidase I (MAN1B1) in the double KO cells reduced most of the complex-type glycans. In triple KO (MAN1A1, MAN1A2, and MAN1B1) cells, Man9GlcNAc2 and Man8GlcNAc2 were the major N-glycan structures. Therefore, we expressed two lysosomal enzymes, alpha-galactosidase-A and lysosomal acid lipase, in the triple KO cells and found that the glycans on these enzymes were sensitive to endoglycosidase H treatment. The N-glycan structures on recombinant proteins expressed in triple KO cells were simplified and changed from complex types to high-mannose types at the protein level. Our results indicate that the triple KO HEK293 cells are suitable for producing recombinant proteins, including lysosomal enzymes with high-mannose type N-glycans. PMID- 29475942 TI - Induction of autophagy by PI3K/MTOR and PI3K/MTOR/BRD4 inhibitors suppresses HIV 1 replication. AB - In this study, we investigated the effects of the dual phosphatidylinositol 3 kinase/mechanistic target of rapamycin (PI3K/MTOR) inhibitor dactolisib (NVP BEZ235), the PI3K/MTOR/bromodomain-containing protein 4 (BRD4) inhibitor SF2523, and the bromodomain and extra terminal domain inhibitor JQ1 on the productive infection of primary macrophages with human immunodeficiency type-1 (HIV). These inhibitors did not alter the initial susceptibility of macrophages to HIV infection. However, dactolisib, JQ1, and SF2523 all decreased HIV replication in macrophages in a dose-dependent manner via degradation of intracellular HIV through autophagy. Macrophages treated with dactolisib, JQ1, or SF2523 displayed an increase in LC3B lipidation combined with SQSTM1 degradation without inducing increased cell death. LC3B-II levels were further increased in the presence of pepstatin A suggesting that these inhibitors induce autophagic flux. RNA interference for ATG5 and ATG7 and pharmacological inhibitors of autophagosome lysosome fusion and of lysosomal hydrolases all blocked the inhibition of HIV. Thus, we demonstrate that the mechanism of PI3K/MTOR and PI3K/MTOR/BRD4 inhibitor suppression of HIV requires the formation of autophagosomes, as well as their subsequent maturation into autolysosomes. These data provide further evidence in support of a role for autophagy in the control of HIV infection and open new avenues for the use of this class of drugs in HIV therapy. PMID- 29475944 TI - Hepatic loss of Lissencephaly 1 (Lis1) induces fatty liver and accelerates liver tumorigenesis in mice. AB - The liver is a major organ in lipid metabolism, and its malfunction leads to various diseases. Nonalcoholic fatty liver disease, the most common chronic liver disorder in developed countries, is characterized by the abnormal retention of excess lipid within hepatocytes and predisposes individuals to liver cancer. We previously reported that the levels of Lissencephaly 1 (LIS1, also known as PAFAH1B1) are down-regulated in human hepatocellular carcinoma. Following up on this observation, we found that genetic deletion of Lis1 in the mouse liver increases lipid accumulation and inflammation in this organ. Further analysis revealed that loss of Lis1 triggers endoplasmic reticulum (ER) stress and reduces triglyceride secretion. Attenuation of ER stress by addition of tauroursodeoxycholic acid (TUDCA) diminished lipid accumulation in the Lis1 deficient hepatocytes. Moreover, the Golgi stacks were disorganized in Lis1 deficient liver cells. Of note, the Lis1 liver-knockout mice exhibited increased hepatocyte ploidy and accelerated development of liver cancer after exposure to the liver carcinogen diethylnitrosamine (DEN). Taken together, these findings suggest that reduced Lis1 levels can spur the development of liver diseases from steatosis to liver cancer and provide a useful model for delineating the molecular pathways that lead to these diseases. PMID- 29475943 TI - Guanosine tetra- and pentaphosphate increase antibiotic tolerance by reducing reactive oxygen species production in Vibrio cholerae. AB - The pathogen Vibrio cholerae is the causative agent of cholera. Emergence of antibiotic-resistant V. cholerae strains is increasing, but the underlying mechanisms remain unclear. Herein, we report that the stringent response regulator and stress alarmone guanosine tetra- and pentaphosphate ((p)ppGpp) significantly contributes to antibiotic tolerance in V. cholerae We found that N16961, a pandemic V. cholerae strain, and its isogenic (p)ppGpp-overexpressing mutant DeltarelADeltaspoT are both more antibiotic-resistant than (p)ppGpp0 (DeltarelADeltarelVDeltaspoT) and DeltadksA mutants, which cannot produce or utilize (p)ppGpp, respectively. We also found that additional disruption of the aconitase B-encoding and tricarboxylic acid (TCA) cycle gene acnB in the (p)ppGpp0 mutant increases its antibiotic tolerance. Moreover, expression of TCA cycle genes, including acnB, was increased in (p)ppGpp0, but not in the antibiotic-resistant DeltarelADeltaspoT mutant, suggesting that (p)ppGpp suppresses TCA cycle activity, thereby entailing antibiotic resistance. Importantly, when grown anaerobically or incubated with an iron chelator, the (p)ppGpp0 mutant became antibiotic-tolerant, suggesting that reactive oxygen species (ROS) are involved in antibiotic-mediated bacterial killing. Consistent with that hypothesis, tetracycline treatment markedly increased ROS production in the antibiotic-susceptible mutants. Interestingly, expression of the Fe(III) ABC transporter substrate-binding protein FbpA was increased 10-fold in (p)ppGpp0, and fbpA gene deletion restored viability of tetracycline-exposed (p)ppGpp0 cells. Of note, FbpA expression was repressed in the (p)ppGpp-accumulating mutant, resulting in a reduction of intracellular free iron, required for the ROS generating Fenton reaction. Our results indicate that (p)ppGpp-mediated suppression of central metabolism and iron uptake reduces antibiotic-induced oxidative stress in V. cholerae. PMID- 29475945 TI - Solution structure of the cytochrome P450 reductase-cytochrome c complex determined by neutron scattering. AB - Electron transfer in all living organisms critically relies on formation of complexes between the proteins involved. The function of these complexes requires specificity of the interaction to allow for selective electron transfer but also a fast turnover of the complex, and they are therefore often transient in nature, making them challenging to study. Here, using small-angle neutron scattering with contrast matching with deuterated protein, we report the solution structure of the electron transfer complex between cytochrome P450 reductase (CPR) and its electron transfer partner cytochrome c This is the first reported solution structure of a complex between CPR and an electron transfer partner. The structure shows that the interprotein interface includes residues from both the FMN- and FAD-binding domains of CPR. In addition, the FMN is close to the heme of cytochrome c but distant from the FAD, indicating that domain movement is required between the electron transfer steps in the catalytic cycle of CPR. In summary, our results reveal key details of the CPR catalytic mechanism, including interactions of two domains of the reductase with cytochrome c and motions of these domains relative to one another. These findings shed light on interprotein electron transfer in this system and illustrate a powerful approach for studying solution structures of protein-protein complexes. PMID- 29475946 TI - The anaplerotic node is essential for the intracellular survival of Mycobacterium tuberculosis. AB - Enzymes at the phosphoenolpyruvate (PEP)-pyruvate-oxaloacetate or anaplerotic (ANA) node control the metabolic flux to glycolysis, gluconeogenesis, and anaplerosis. Here we used genetic, biochemical, and 13C isotopomer analysis to characterize the role of the enzymes at the ANA node in intracellular survival of the world's most successful bacterial pathogen, Mycobacterium tuberculosis (Mtb). We show that each of the four ANA enzymes, pyruvate carboxylase (PCA), PEP carboxykinase (PCK), malic enzyme (MEZ), and pyruvate phosphate dikinase (PPDK), performs a unique and essential metabolic function during the intracellular survival of Mtb. We show that in addition to PCK, intracellular Mtb requires PPDK as an alternative gateway into gluconeogenesis. Propionate and cholesterol detoxification was also identified as an essential function of PPDK revealing an unexpected role for the ANA node in the metabolism of these physiologically important intracellular substrates and highlighting this enzyme as a tuberculosis (TB)-specific drug target. We show that anaplerotic fixation of CO2 through the ANA node is essential for intracellular survival of Mtb and that Mtb possesses three enzymes (PCA, PCK, and MEZ) capable of fulfilling this function. In addition to providing a back-up role in anaplerosis we show that MEZ also has a role in lipid biosynthesis. MEZ knockout strains have an altered cell wall and were deficient in the initial entry into macrophages. This work reveals that the ANA node is a focal point for controlling the intracellular replication of Mtb, which goes beyond canonical gluconeogenesis and represents a promising target for designing novel anti-TB drugs. PMID- 29475947 TI - Functional organization of cytoplasmic portals controlling access to the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel pore. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) is a Cl- channel that apparently has evolved from an ancestral active transporter. Key to the CFTR's switch from pump to channel function may have been the appearance of one or more "lateral portals." Such portals connect the cytoplasm to the transmembrane channel pore, allowing a continuous pathway for the electrodiffusional movement of Cl- ions. However, these portals remain the least well-characterized part of the Cl- transport pathway; even the number of functional portals is uncertain, and if multiple portals do exist, their relative functional contributions are unknown. Here, we used patch-clamp recording to identify the contributions of positively charged amino acid side chains located in CFTR's cytoplasmic transmembrane extensions to portal function. Mutagenesis mediated neutralization of several charged side chains reduced single-channel Cl- conductance. However, these same mutations differentially affected channel blockade by cytoplasmic suramin and Pt(NO2)42- anions. We considered and tested several models by which the contribution of these positively charged side chains to one or more independent or non-independent portals to the pore could affect Cl conductance and interactions with blockers. Overall, our results suggest the existence of a single portal that is lined by several positively charged side chains that interact electrostatically with both Cl- and blocking anions. We further propose that mutations at other sites indirectly alter the function of this single portal. Comparison of our functional results with recent structural information on CFTR completes our picture of the overall molecular architecture of the Cl- permeation pathway. PMID- 29475948 TI - Antagonism between the dynein and Ndc80 complexes at kinetochores controls the stability of kinetochore-microtubule attachments during mitosis. AB - Chromosome alignment and segregation during mitosis require kinetochore microtubule (kMT) attachments that are mediated by the molecular motor dynein and the kMT-binding complex Ndc80. The Rod-ZW10-Zwilch (RZZ) complex is central to this coordination as it has an important role in dynein recruitment and has recently been reported to have a key function in the regulation of stable kMT attachments in Caenorhabditis elegans besides its role in activating the spindle assembly checkpoint (SAC). However, the mechanism by which these protein complexes control kMT attachments to drive chromosome motility during early mitosis is still unclear. Here, using in vitro total internal reflection fluorescence microscopy, we observed that higher concentrations of Ndc80 inhibited dynein binding to MTs, providing evidence that Ndc80 and dynein antagonize each other's function. High-resolution microscopy and siRNA-mediated functional disruption revealed that severe defects in chromosome alignment induced by depletion of dynein or the dynein adapter Spindly are rescued by codepletion of the RZZ component Rod in human cells. Interestingly, rescue of the chromosome alignment defects was independent of Rod function in SAC activation and was accompanied by a remarkable restoration of stable kMT attachments. Furthermore, the chromosome alignment rescue depended on the plus-end-directed motility of centromere protein E (CENP-E) because cells codepleted of CENP-E, Rod, and dynein could not establish stable kMT attachments or align their chromosomes properly. Our findings support the idea that dynein may control the function of the Ndc80 complex in stabilizing kMT attachments directly by interfering with Ndc80-MT binding or indirectly by controlling the Rod-mediated inhibition of Ndc80. PMID- 29475949 TI - Cbp3 and Cbp6 are dispensable for synthesis regulation of cytochrome b in yeast mitochondria. AB - Cytochrome b (Cytb) is the only mitochondrial encoded subunit from the bc1 complex. Cbp3 and Cbp6 are chaperones necessary for translation of the COB mRNA and Cytb hemylation. Here we demonstrate that their role in translation is dispensable in some laboratory strains, whereas their role in Cytb hemylation seems to be universally conserved. BY4742 yeast requires Cbp3 and Cbp6 for efficient COB mRNA translation, whereas the D273-10b strain synthesizes Cytb at wildtype levels in the absence of Cbp3 and Cbp6. Steady-state levels of Cytb are close to wildtype in mutant D273-10b cells, and Cytb forms non-functional, supercomplex-like species with cytochrome c oxidase, in which at least core 1, cytochrome c1, and Rieske iron-sulfur subunits are present. We demonstrated that Cbp3 interacts with the mitochondrial ribosome and with the COB mRNA in both BY4742 and D273-10b strains. The polymorphism(s) causing the differential function of Cbp3, Cbp6, and the assembly feedback regulation of Cytb synthesis is of nuclear origin rather than mitochondrial, and Smt1, a COB mRNA-binding protein, does not seem to be involved in the observed differential phenotype. Our results indicate that the essential role of Cbp3 and Cbp6 is to assist Cytb hemylation and demonstrate that in the absence of heme b, Cytb can form non functional supercomplexes with cytochrome c oxidase. Our observations support that an additional protein or proteins are involved in Cytb synthesis in some yeast strains. PMID- 29475950 TI - A chemical genetic approach to engineer phototropin kinases for substrate labeling. AB - Protein kinases (PKs) control many aspects of plant physiology by regulating signaling networks through protein phosphorylation. Phototropins (phots) are plasma membrane-associated serine/threonine PKs that control a range of physiological processes that collectively serve to optimize photosynthetic efficiency in plants. These include phototropism, leaf positioning and flattening, chloroplast movement, and stomatal opening. Despite their identification over two decades ago, only a handful of substrates have been identified for these PKs. Progress in this area has been hampered by the lack of a convenient means to confirm the identity of potential substrate candidates. Here we demonstrate that the kinase domain of Arabidopsis phot1 and phot2 can be successfully engineered to accommodate non-natural ATP analogues by substituting the bulky gatekeeper residue threonine for glycine. This approach circumvents the need for radioactivity to track phot kinase activity and follow light-induced receptor autophosphorylation in vitro by incorporating thiophosphate from N6 benzyl-ATPgammaS. Consequently, thiophosphorylation of phot substrate candidates can be readily monitored when added or co-expressed with phots in vitro Furthermore, gatekeeper-modified phot1 retained its functionality and its ability to accommodate N6-benzyl-ATPgammaS as a phosphodonor when expressed in Arabidopsis We therefore anticipate that this chemical genetic approach will provide new opportunities for labeling and identifying substrates for phots and other related AGC kinases under in vitro and near-native in vivo conditions. PMID- 29475952 TI - CCG is told it can't pull L600 000 from children's respite centre. PMID- 29475954 TI - 'Stop me before I kill again': why Philip Morris International needs governments' help to quit smoking, and why governments need more pressure to do so. PMID- 29475953 TI - Prevalence of medical workplace violence and the shortage of secondary and tertiary interventions among healthcare workers in China. AB - Medical workplace violence (MWV) is a key occupational hazard facing medical professionals worldwide. MWV involves incident where medical staff are abused, threatened and assaulted. MWV affects the health and well-being of medical staff exposed, causes significant erosion of patient-physician trust and leads to poorer health outcomes for patients. In China, the prevalence of MWV appears to be rising. Laws were enacted to keep medical staff safe, but clear surveillance and enforcement is needed to improve the condition. In the current essay, we conducted a systematic literature review to identify secondary and tertiary prevention programmes designed to ameliorate psychological suffering following MWV. This review identified only 10 published studies. A critical gap in the intervention literature exists with regard to addressing the public health burden of MWV. PMID- 29475951 TI - Soluble syntaxin 3 functions as a transcriptional regulator. AB - Syntaxins are a conserved family of SNARE proteins and contain C-terminal transmembrane anchors required for their membrane fusion activity. Here we show that Stx3 (syntaxin 3) unexpectedly also functions as a nuclear regulator of gene expression. We found that alternative splicing creates a soluble isoform that we termed Stx3S, lacking the transmembrane anchor. Soluble Stx3S binds to the nuclear import factor RanBP5 (RAN-binding protein 5), targets to the nucleus, and interacts physically and functionally with several transcription factors, including ETV4 (ETS variant 4) and ATF2 (activating transcription factor 2). Stx3S is differentially expressed in normal human tissues, during epithelial cell polarization, and in breast cancer versus normal breast tissue. Inhibition of endogenous Stx3S expression alters the expression of cancer-associated genes and promotes cell proliferation. Similar nuclear-targeted, soluble forms of other syntaxins were identified, suggesting that nuclear signaling is a conserved, novel function common among these membrane-trafficking proteins. PMID- 29475955 TI - The Tobacco Control Vaccine: a population-based framework for preventing tobacco related disease and death. PMID- 29475956 TI - What factors influenced the choice of medical specialty for doctors surveyed in the final year at medical school and again having entered their specialty training destination? PMID- 29475957 TI - An isomerase completes the circuit for a redox switch. AB - The activity of human transglutaminase 2 (TG2), which forms protein cross-links between glutamine and lysine residues, is controlled by an allosteric disulfide bond. However, the mechanism by which this bond is formed, like many systems regulated by oxidative cysteine modifications, was not clear. A new study from Khosla and colleagues shows that TG2 is oxidatively inactivated by the protein disulfide isomerase ERp57, providing the first example of a defined and reversible protein-controlled redox switch and pointing to new strategies to inhibit undesirable TG2 activity in pathological states. PMID- 29475958 TI - Palmitoylation of MPP1 (membrane-palmitoylated protein 1)/p55 is crucial for lateral membrane organization in erythroid cells. PMID- 29475959 TI - High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with diffuse large B-cell lymphoma morphology. AB - High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL DH/TH) is a newly defined entity in the latest World Health Organization Classification. Accurate diagnosis would appear to mandate fluorescence in situ hybridization (FISH) for all tumors with diffuse large B-cell lymphoma (DLBCL) morphology. We present the results of FISH, cell-of-origin, and immunohistochemistry (IHC) testing from 1228 DLBCL biopsies from 3 clinical trials and a population-based registry. HGBL-DH/TH made up 7.9% of the DLBCL, confined primarily to the germinal center B-cell-like (GCB; 13.3%) compared with activated B-cell-like (ABC; 1.7%) subtype (P < .001). HGBL-DH/TH with BCL2 rearrangement is a GCB phenomenon with no cases observed in 415 ABC DLBCL. A screening strategy restricting FISH testing to tumors of GCB subtype (by Lymph2Cx or Hans IHC) plus dual protein expression of MYC and BCL2 by IHC could limit testing to 11% to 14% of tumors, with a positive predictive value of 30% to 37%; however, this strategy would miss approximately one-quarter of tumors with HBGL DH/TH with BCL2 rearrangement and one-third of all HGBL-DH/TH. These results provide accurate estimation of the proportion of HGBL-DH/TH among tumors with DLBCL morphology and allow determination of the impact of various methods available to screen DLBCL tumors for FISH testing. PMID- 29475960 TI - The phosphotyrosine phosphatase SHP2 promotes anergy in chronic lymphocytic leukemia. PMID- 29475961 TI - Alterations in the Rho pathway contribute to Epstein-Barr virus-induced lymphomagenesis in immunosuppressed environments. AB - Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphomas (EBV+-DLBLs) tend to occur in immunocompromised patients, such as the elderly or those undergoing solid organ transplantation. The pathogenesis and genomic characteristics of EBV+-DLBLs are largely unknown because of the limited availability of human samples and lack of experimental animal models. We observed the development of 25 human EBV+-DLBLs during the engraftment of gastric adenocarcinomas into immunodeficient mice. An integrated genomic analysis of the human-derived EBV+-DLBLs revealed enrichment of mutations in Rho pathway genes, including RHPN2, and Rho pathway transcriptomic activation. Targeting the Rho pathway using a Rho-associated protein kinase (ROCK) inhibitor, fasudil, markedly decreased tumor growth in EBV+-DLBL patient-derived xenograft (PDX) models. Thus, alterations in the Rho pathway appear to contribute to EBV-induced lymphomagenesis in immunosuppressed environments. PMID- 29475963 TI - Comparison of Urine 4-(Methylnitrosamino)-1-(3)Pyridyl-1-Butanol and Cotinine for Assessment of Active and Passive Smoke Exposure in Urban Adolescents. AB - Background: Many adolescents are exposed to tobacco smoke, from either active smoking (CS) or secondhand smoke (SHS) exposure. Tobacco-specific biomarkers of exposure include cotinine (detects use in past 2-4 days) and 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL; detects use for a month or longer). NNAL is expected to detect more intermittent tobacco exposure. We compared NNAL and cotinine as biomarkers of exposure to tobacco in urban adolescents and determined the optimal NNAL cutoff point to distinguish CS from SHS exposure.Methods: Surplus urine samples, collected from 466 adolescents attending pediatric well or urgent care visits at Zuckerberg San Francisco General Hospital in 2013 to 2014, were assayed for cotinine and NNAL.Results: Ninety-four percent of adolescents had measurable levels of NNAL compared with 87% for cotinine. The optimal NNAL cutoff point to distinguish CS from SHS was 9.6 pg/mL by latent class or 14.4 pg/mL by receiver-operating characteristic analysis. Cotinine and NNAL were strongly correlated, but the correlation slopes differed for active versus SHS-exposed adolescents. Among nonsmokers, NNAL levels were significantly higher in African American (median, 3.3 pg/mL) compared with other groups (0.9-1.9 pg/mL), suggesting greater exposure to SHS.Conclusions: Urine NNAL screening finds a large majority (94%) of urban adolescents are exposed to tobacco. African Americans are exposed to higher levels of SHS than other ethnic/racial groups.Impact: SHS is associated with significant medical morbidity in adolescents. Routine biochemical screening with NNAL or cotinine detects high prevalence of SHS exposure and should be considered as a tool to reduce SHS exposure in high-risk populations. Cancer Epidemiol Biomarkers Prev; 27(3); 254-61. (c)2018 AACR. PMID- 29475962 TI - Mechanisms of platelet clearance and translation to improve platelet storage. AB - Hundreds of billions of platelets are cleared daily from circulation via efficient and highly regulated mechanisms. These mechanisms may be stimulated by exogenous reagents or environmental changes to accelerate platelet clearance, leading to thrombocytopenia. The interplay between antiapoptotic Bcl-xL and proapoptotic molecules Bax and Bak sets an internal clock for the platelet lifespan, and BH3-only proteins, mitochondrial permeabilization, and phosphatidylserine (PS) exposure may also contribute to apoptosis-induced platelet clearance. Binding of plasma von Willebrand factor or antibodies to the ligand-binding domain of glycoprotein Ibalpha (GPIbalpha) on platelets can activate GPIb-IX in a shear-dependent manner by inducing unfolding of the mechanosensory domain therein, and trigger downstream signaling in the platelet including desialylation and PS exposure. Deglycosylated platelets are recognized by the Ashwell-Morell receptor and potentially other scavenger receptors, and are rapidly cleared by hepatocytes and/or macrophages. Inhibitors of platelet clearance pathways, including inhibitors of GPIbalpha shedding, neuraminidases, and platelet signaling, are efficacious at preserving the viability of platelets during storage and improving their recovery and survival in vivo. Overall, common mechanisms of platelet clearance have begun to emerge, suggesting potential strategies to extend the shelf-life of platelets stored at room temperature or to enable refrigerated storage. PMID- 29475965 TI - Migration History, Language Acculturation, and Mammographic Breast Density. AB - Background: Breast cancer incidence is lower in many U.S. ethnic minority and foreign-born population groups. Investigating whether migration and acculturation patterns in risk are reflected in disease biomarkers may help to elucidate the underlying mechanisms.Methods: We compared the distribution of breast cancer risk factors across U.S.-born white, African American and Hispanic women, and foreign born Hispanic women (n = 477, ages 40-64 years, 287 born in Caribbean countries). We used linear regression models to examine the associations of migration history and linguistic acculturation with mammographic breast density (MBD), measured using computer-assisted methods as percent and area of dense breast tissue.Results: The distribution of most breast cancer risk factors varied by ethnicity, nativity, and age at migration. In age- and body mass index-adjusted models, U.S.-born women did not differ in average MBD according to ethnicity, but foreign-born Hispanic women had lower MBD [e.g., -4.50%; 95% confidence interval (CI), -7.12 to -1.89 lower percent density in foreign- vs. U.S.-born Hispanic women]. Lower linguistic acculturation and lower percent of life spent in the United States were also associated with lower MBD [e.g., monolingual Spanish and bilingual vs. monolingual English speakers, respectively, had 5.09% (95% CI, 8.33 to -1.85) and 3.34% (95% CI, -6.57 to -0.12) lower percent density]. Adjusting for risk factors (e.g., childhood body size, parity) attenuated some of these associations.Conclusions: Hispanic women predominantly born in Caribbean countries have lower MBD than U.S.-born women of diverse ethnic backgrounds, including U.S.-born Hispanic women of Caribbean heritage.Impact: MBD may provide insight into mechanisms driving geographic and migration variations in breast cancer risk. Cancer Epidemiol Biomarkers Prev; 27(5); 566-74. (c)2018 AACR. PMID- 29475964 TI - Physical Activity and Pancreatic Cancer Risk among Urban Chinese: Results from Two Prospective Cohort Studies. AB - Background: Associations between physical activity and pancreatic cancer risk are unclear.Methods: In two prospective cohort studies, the Shanghai Women's Health Study and Shanghai Men's Health Study, physical activity and other information were collected at the baseline interview of 72,451 women and 60,037 men. Participants were followed up through annual linkage with a cancer registry in combination with in-person interviews taking place every 2 to 4 years.Results: We identified 225 female and 159 male cases during a median follow up of 16.1 and 10.3 years, respectively. Adult exercise participation was significantly associated with a decreased pancreatic cancer risk in men [hazard ratio (HR), 95% confidence interval (CI): 0.71 (0.50-1.00)]. Meeting the recommended minimum exercise threshold to achieve health benefits of 150 min/week of moderate intensity or 75 min/week of vigorous-intensity exercise was associated with further decreased pancreatic cancer risk [HR (95% CI): 0.59 (0.40-0.87)]. We also observed an inverse association between adolescent physical activity and pancreatic cancer risk in men [HR (95% CI): 0.54 (0.33-0.90)]. Exercise throughout one's lifetime was associated with a 68% decrease in pancreatic cancer risk [HR (95% CI): 0.32 (0.16-0.66)]. No significant association was found in women. Adult non-exercise daily activity and occupational activity were not associated with pancreatic cancer risk in either men or women.Conclusions: Adult exercise and adolescent physical activity were significantly associated with a decreased pancreatic cancer risk in men but not in women.Impact: These findings underscore the importance of investigating the possible modification by sex on the exercise and pancreatic cancer risk association. Cancer Epidemiol Biomarkers Prev; 27(4); 479-87. (c)2018 AACR. PMID- 29475966 TI - Social Relationships, Inflammation, and Cancer Survival. AB - Background: Social stressors, such as social relationship deficits, have been increasingly linked to chronic disease outcomes, including cancer. However, critical gaps exist in our understanding of the nature and strength of such links, as well as the underlying biological mechanisms relating social relationships to cancer progression and survival.Methods: Utilizing novel questionnaire and biomarker data from the UNC Health Registry/Cancer Survivorship Cohort, this study examines the associations between diverse measures of social support and mortality risk among individuals with cancer (N = 1,004). We further assess the role of multiple serum markers of inflammation, including high sensitivity C-reactive protein (CRP), IL6, TNFalpha, and VEGF, as potential mediators in the social relationship-cancer link.Results: The findings revealed that one's appraisal of their social support was associated with cancer mortality, such that individuals reporting higher levels of social support satisfaction had lower mortality risk than individuals reporting lower levels of satisfaction. The amount of support received, on the other hand, was not predictive of cancer survival. We further found evidence that inflammatory processes may undergird the link between social support satisfaction and mortality among individuals with cancer, with individuals reporting higher levels of social support satisfaction having lower levels of CRP, IL6, and TNFalpha.Conclusions: These results provide new knowledge of the biosocial processes producing population disparities in cancer outcomes.Impact: Our study offers new insights for intervention efforts aimed at promoting social connectedness as a means for improving cancer survival. Cancer Epidemiol Biomarkers Prev; 27(5); 541-9. (c)2018 AACR. PMID- 29475967 TI - An Examination of HPV16 Natural Immunity in Men Who Have Sex with Men (MSM) in the HPV in Men (HIM) Study. AB - Background: Evidence suggests that natural antibodies developed after HPV16 infection may protect some women but not men against subsequent HPV16 reacquisition. Less is known whether antibodies developed following HPV16 infection are protective among men who have sex with men (MSM).Methods: Four hundred seventy-five MSM from the Human Papillomavirus Infection in Men (HIM) study were tested for serum antibodies to HPV16 L1 using enzyme-linked immunosorbent assays, and for anal and genital HPV16 DNA using PCR consensus primer system (PGMY 09/11). Adjusted Cox regression was used to evaluate whether baseline HPV16 seropositivity impacts subsequent genital or anal HPV16 DNA.Results: The risk of subsequent genital HPV16 [aHR = 1.05, 95% confidence interval (CI) = 0.66-1.68] and anal HPV16 infections among MSM (aHR = 2.34, 95% CI = 0.92-5.98) was similar or nonsignificantly higher in HPV16-seropositive than HPV16-seronegative MSM. The risk of genital HPV16 was also similar between HPV16 seronegative and HPV16-seropositive MSM in the highest tertile of HPV16 antibody levels and when restricting to those with new sex partners during follow-up (P > 0.20). Among the 118 MSM who were HPV16 seropositive, 90% remained HPV16 seropositive up to 4 years later. When tested together, MSM with the highest antibody titers (top tertile) had similar levels to females (mean = 130.3 vs. 134.5 EU/mL, P = 0.84).Conclusions: Despite years of HPV16 seropositivity persistence and antibody titers comparable with females, this study suggested no evidence of HPV16 natural antibodies protecting against subsequent genital or anal HPV16 infection in MSM.Impact: This could help partially explain the high incidence of genital and anal HPV16 infection and related anal cancer seen in middle-aged and older MSM. Cancer Epidemiol Biomarkers Prev; 27(4); 496-502. (c)2018 AACR. PMID- 29475968 TI - miRNA-Processing Gene Methylation and Cancer Risk. AB - Background: Dysregulation of miRNA and methylation levels are epigenetic hallmarks of cancer, potentially linked via miRNA-processing genes. Studies have found genetic alterations to miRNA-processing genes in cancer cells and human population studies. Our objective was to prospectively examine changes in DNA methylation of miRNA-processing genes and their associations with cancer risk.Methods: We examined cohort data from the Department of Veterans' Affairs Normative Aging Study. Participants were assessed every 3 to 5 years starting in 1999 through 2013 including questionnaires, medical record review, and blood collection. Blood from 686 consenting participants was analyzed using the Illumina 450K BeadChip array to measure methylation at CpG sites throughout the genome. We selected 19 genes based on a literature review, with 519 corresponding CpG sites. We then used Cox proportional hazards models to examine associations with cancer incidence, and generalized estimating equations to examine associations with cancer prevalence. Associations at false discovery rate < 0.05 were considered statistically significant.Results: Methylation of three CpGs (DROSHA: cg23230564, TNRC6B: cg06751583, and TNRC6B: cg21034183) was prospectively associated with time to cancer development (positively for cg06751583, inversely for cg23230564 and cg21034183), whereas methylation of one CpG site (DROSHA: cg16131300) was positively associated with cancer prevalence.Conclusions: DNA methylation of DROSHA, a key miRNA-processing gene, and TNRC6B may play a role in early carcinogenesis.Impact: Changes in miRNA processing may exert multiple effects on cancer development, including protecting against it via altered global miRNAs, and may be a useful early detection biomarker of cancer. Cancer Epidemiol Biomarkers Prev; 27(5); 550-7. (c)2018 AACR. PMID- 29475969 TI - Temporal Variability of Oral Microbiota over 10 Months and the Implications for Future Epidemiologic Studies. AB - Background: Few studies have prospectively evaluated the association between oral microbiota and health outcomes. Precise estimates of the intrasubject microbial metric stability will allow better study planning. Therefore, we conducted a study to evaluate the temporal variability of oral microbiota.Methods: Forty individuals provided six oral samples using the OMNIgene ORAL kit and Scope mouthwash oral rinses approximately every two months over 10 months. DNA was extracted using the QIAsymphony and the V4 region of the 16S rRNA gene was amplified and sequenced using the MiSeq. To estimate temporal variation, we calculated intraclass correlation coefficients (ICCs) for a variety of metrics and examined stability after clustering samples into distinct community types using Dirichlet multinomial models (DMMs).Results: The ICCs for the alpha diversity measures were high, including for number of observed bacterial species [0.74; 95% confidence interval (CI): 0.65-0.82 and 0.79; 95% CI: 0.75-0.94] from OMNIgene ORAL and Scope mouthwash, respectively. The ICCs for the relative abundance of the top four phyla and beta diversity matrices were lower. Three clusters provided the best model fit for the DMM from the OMNIgene ORAL samples, and the probability of remaining in a specific cluster was high (59.5% 80.7%).Conclusions: The oral microbiota appears to be stable over time for multiple metrics, but some measures, particularly relative abundance, were less stable.Impact: We used this information to calculate stability-adjusted power calculations that will inform future field study protocols and experimental analytic designs. Cancer Epidemiol Biomarkers Prev; 27(5); 594-600. (c)2018 AACR. PMID- 29475970 TI - Neonatal Hormone Concentrations and Risk of Testicular Germ Cell Tumors (TGCT). AB - Background: Testicular germ cell tumor (TGCT) incidence has increased over the last 40 years in the United States. In contrast to TGCT among infants, it is hypothesized that TGCT in adolescents and young men is the result of sex steroid hormone imbalance during early fetal development. However, little is known about the neonatal period when abrupt hormonal changes occur, and direct supporting evidence is scarce due to the difficulties in obtaining prediagnostic specimens.Methods: We conducted a population-based case-control study examining hormone levels at birth among 91 infants (0-4 years) and 276 adolescents (15-19 years) diagnosed with TGCT, and 344 matched controls. Estrogen and androgen levels were quantified using liquid chromatography-tandem mass spectrometry (LC MS/MS) from archived newborn dried blood spots. Logistic regression models were used to estimate the association between each hormone level and TGCT risk.Results: Higher levels of androstenedione were associated with increased TGCT risk among adolescents [odds ratio (OR): 2.33, 95% confidence interval (CI): 1.37-3.97 for highest vs. lowest quartile; P trend = 0.003] but not among infants (OR: 0.70, 95% CI: 0.28-1.77). A similar pattern was observed for testosterone (OR: 1.73, 95% CI: 1.00-3.00,) although the trend was not significant (P trend = 0.12). Associations were stronger among non-Hispanic white subjects, relative to Hispanics. There was no difference by tumor histologic subtype. Estriol (the only detectable estrogen) was not associated with TGCT risk in either age group.Conclusions: Higher levels of neonatal androgens were associated with increased risk of TGCT among adolescents, suggesting that early life hormone levels are related to the later development of TGCT.Impact: This is the first study with direct measures of sex steroid hormones to examine the relationship between estrogens and androgens at birth and risk of adolescent TGCT. Cancer Epidemiol Biomarkers Prev; 27(4); 488-95. (c)2018 AACR. PMID- 29475971 TI - Exogenous Hormone Use and Endometrial Cancer in U.S. Black Women. AB - Background: Although endometrial cancer risk differs among white and black women, few data on its associations with exogenous hormone use in the latter group are available. Studies have reported lower endometrial cancer risk among users of oral contraceptives (OCs), but higher risk among users of estrogen-only female menopausal hormones (FMHs). Evidence for the risk among estrogen plus progestin FMHs users is equivocal.Methods: We followed 47,555 Black Women's Health Study participants with an intact uterus from 1995 through 2013. Data on exogenous hormone use, covariates, and endometrial cancer were obtained biennially. Self reported incident cases of endometrial cancer were confirmed by medical records or cancer registries whenever possible. We estimated incidence rate ratios (IRRs) and 95% confidence intervals (CIs) using Cox proportional hazards regression.Results: We observed 300 endometrial cancer cases during 689,546 person-years of follow-up. Compared with never use, >=10 years' duration of OC use was associated with lower risk (multivariable IRR = 0.45, 95% CI, 0.27-0.74), but risk was higher among current users of estrogen-only (IRR = 3.78, 95% CI, 1.69-8.43) and estrogen plus progestin FMH (IRR = 1.55, 95% CI, 0.78-3.11). Risk was not increased among former users of estrogen-only (IRR = 0.87, 95% CI, 0.44 1.72) or estrogen plus progestin FMH (IRR = 0.63, 95% CI, 0.36-1.09).Conclusions: Current use of estrogen-only and estrogen plus progestin FMH was associated with increased risk of endometrial cancer. Risk appeared lower among former users of estrogen plus progestin FMH. Long-term OC use was associated with reduced risk.Impact: Our results are generally consistent with those among white women. Cancer Epidemiol Biomarkers Prev; 27(5); 558-65. (c)2018 AACR. PMID- 29475972 TI - Connexin 30 controls astroglial polarization during postnatal brain development. AB - Astrocytes undergo intense morphological maturation during development, changing from individual sparsely branched cells to polarized and tremendously ramified cells. Connexin 30, an astroglial gap-junction channel-forming protein expressed postnatally, regulates in situ the extension and ramification of astroglial processes. However, the involvement of connexin 30 in astroglial polarization, which is known to control cell morphology, remains unexplored. We found that connexin 30, independently of gap-junction-mediated intercellular biochemical coupling, alters the orientation of astrocyte protrusion, centrosome and Golgi apparatus during polarized migration in an in vitro wound-healing assay. Connexin 30 sets the orientation of astroglial motile protrusions via modulation of the laminin/beta1 integrin/Cdc42 polarity pathway. Connexin 30 indeed reduces laminin levels, inhibits the redistribution of the beta1-integrin extracellular matrix receptors, and inhibits the recruitment and activation of the small Rho GTPase Cdc42 at the leading edge of migrating astrocytes. In vivo, connexin 30, the expression of which is developmentally regulated, also contributes to the establishment of hippocampal astrocyte polarity during postnatal maturation. This study thus reveals that connexin 30 controls astroglial polarity during development. PMID- 29475973 TI - Microbiota promote secretory cell determination in the intestinal epithelium by modulating host Notch signaling. AB - Resident microbes promote many aspects of host development, although the mechanisms by which microbiota influence host tissues remain unclear. We showed previously that the microbiota is required for allocation of appropriate numbers of secretory cells in the zebrafish intestinal epithelium. Because Notch signaling is crucial for secretory fate determination, we conducted epistasis experiments to establish whether the microbiota modulates host Notch signaling. We also investigated whether innate immune signaling transduces microbiota cues via the Myd88 adaptor protein. We provide the first evidence that microbiota induced, Myd88-dependent signaling inhibits host Notch signaling in the intestinal epithelium, thereby promoting secretory cell fate determination. These results connect microbiota activity via innate immune signaling to the Notch pathway, which also plays crucial roles in intestinal homeostasis throughout life and when impaired can result in chronic inflammation and cancer. PMID- 29475974 TI - Forced lipophagy reveals that lipid droplets are required for early embryonic development in mouse. AB - Although autophagy is classically viewed as a non-selective degradation system, recent studies have revealed that various forms of selective autophagy also play crucial physiological roles. However, the induction of selective autophagy is not well understood. In this study, we established a forced selective autophagy system using a fusion of an autophagy adaptor and a substrate-binding protein. In both mammalian cells and fertilized mouse embryos, efficient forced lipophagy was induced by expression of a fusion of p62 (Sqstm1) and a lipid droplet (LD) binding domain. In mouse embryos, induction of forced lipophagy caused a reduction in LD size and number, and decreased the triglyceride level throughout embryonic development, resulting in developmental retardation. Furthermore, lipophagy-induced embryos could eliminate excess LDs and were tolerant of lipotoxicity. Thus, by inducing forced lipophagy, expression of the p62 fusion protein generated LD-depleted cells, revealing an unexpected role of LD during preimplantation development. PMID- 29475977 TI - Risk factors for falls among older community dwellers in Shenzhen, China. AB - OBJECTIVE: To determine the rate of falls reported by older community dwellers in Shenzhen, China and to identify fall-related risk factors. METHOD: Participants were community dwellers residing in Shenzhen, China, who were aged 60 years and over and were recruited using multistage random sampling. All participants were surveyed about demographic and health-related information, mood, vision and hearing impairment, self-rated health and retrospective falls, and a test of balance was administered. Univariate and multivariate negative binomial regression was used to identify factors associated with a greater number of falls. RESULT: Study participants were 1290 people aged 60-98 years (mean 68.2 years, SD +/-6.5). One hundred and seventy-seven falls were reported. One hundred and eleven (8.6%) participants reported one fall in the past year, 17 (1.3%) participants reported two falls and 10 (0.8%) participants reported three or more falls. Univariate analysis showed that age, living alone, presence of a medical condition, medication usage, visual impairment, poor subjective body sense perception, low mood, poor self-rated health and poor balance were associated with a greater number of falls in the past year. Multivariate analysis identified presence of a medical condition (incidence rate ratio (IRR)=1.40, 95% CI 1.19 to 1.67), living alone (IRR=2.46, 95% CI 1.12 to 5.41), visual impairment (IRR=1.46, 95% CI 1.03 to 2.08), walking aid use (IRR=2.29, 95% CI 1.12 to 4.69) and impaired balance (IRR=1.05, 95% CI 1.00 to 1.10) to be significantly associated with a greater number of falls in the past year. CONCLUSION: More falls occurred in older Chinese people with presence of a medical condition, living alone, visual impairment, used a walking aid and impaired balance. PMID- 29475976 TI - SIRF: Quantitative in situ analysis of protein interactions at DNA replication forks. AB - DNA replication reactions are central to diverse cellular processes including development, cancer etiology, drug treatment, and resistance. Many proteins and pathways exist to ensure DNA replication fidelity and protection of stalled or damaged replication forks. Consistently, mutations in proteins involved in DNA replication are implicated in diverse diseases that include defects during embryonic development and immunity, accelerated aging, increased inflammation, blood disease, and cancer. Thus, tools for efficient quantitative analysis of protein interactions at active and stalled replication forks are key for advanced and accurate biological understanding. Here we describe a sensitive single-cell level assay system for the quantitative analysis of protein interactions with nascent DNA. Specifically, we achieve robust in situ analysis of protein interactions at DNA replication forks (SIRF) using proximity ligation coupled with 5'-ethylene-2'-deoxyuridine click chemistry suitable for multiparameter analysis in heterogeneous cell populations. We provide validation data for sensitivity, accuracy, proximity, and quantitation. Using SIRF, we obtained new insight on the regulation of pathway choice by 53BP1 at transiently stalled replication forks. PMID- 29475978 TI - A draft map of the human ovarian proteome for tissue engineering and clinical applications. AB - Fertility preservation research in women today is increasingly taking advantage of bioengineering techniques to develop new biomimetic materials and solutions to safeguard ovarian cell function and microenvironment in vitro and in vivo. However, available data on the human ovary are limited and fundamental differences between animal models and humans are hampering researchers in their quest for more extensive knowledge of human ovarian physiology and key reproductive proteins that need to be preserved. We therefore turned to multi dimensional label-free mass spectrometry to analyze human ovarian cortex, as it is a high-throughput and conclusive technique providing information on the proteomic composition of complex tissues like the ovary. In-depth proteomic profiling through two-dimensional liquid chromatography-mass spectrometry, western blot, histological and immunohistochemical analyses, and data mining helped us to confidently identify 1,508 proteins. Moreover, our method allowed us to chart the most complete representation so far of the ovarian matrisome, defined as the ensemble of extracellular matrix proteins and associated factors, including more than 80 proteins. In conclusion, this study will provide a better understanding of ovarian proteomics, with a detailed characterization of the ovarian follicle microenvironment, in order to enable bioengineers to create biomimetic scaffolds for transplantation and three-dimensional in vitro culture. By publishing our proteomic data, we also hope to contribute to accelerating biomedical research into ovarian health and disease in general. PMID- 29475979 TI - Ethical decision-making climate in the ICU: theoretical framework and validation of a self-assessment tool. AB - BACKGROUND: Literature depicts differences in ethical decision-making (EDM) between countries and intensive care units (ICU). OBJECTIVES: To better conceptualise EDM climate in the ICU and to validate a tool to assess EDM climates. METHODS: Using a modified Delphi method, we built a theoretical framework and a self-assessment instrument consisting of 35 statements. This Ethical Decision-Making Climate Questionnaire (EDMCQ) was developed to capture three EDM domains in healthcare: interdisciplinary collaboration and communication; leadership by physicians; and ethical environment. This instrument was subsequently validated among clinicians working in 68 adult ICUs in 13 European countries and the USA. Exploratory and confirmatory factor analysis was used to determine the structure of the EDM climate as perceived by clinicians. Measurement invariance was tested to make sure that variables used in the analysis were comparable constructs across different groups. RESULTS: Of 3610 nurses and 1137 physicians providing ICU bedside care, 2275 (63.1%) and 717 (62.9%) participated respectively. Statistical analyses revealed that a shortened 32-item version of the EDMCQ scale provides a factorial valid measurement of seven facets of the extent to which clinicians perceive an EDM climate: self reflective and empowering leadership by physicians; practice and culture of open interdisciplinary reflection; culture of not avoiding end-of-life decisions; culture of mutual respect within the interdisciplinary team; active involvement of nurses in end-of-life care and decision-making; active decision-making by physicians; and practice and culture of ethical awareness. Measurement invariance of the EDMCQ across occupational groups was shown, reflecting that nurses and physicians interpret the EDMCQ items in a similar manner. CONCLUSIONS: The 32 item version of the EDMCQ might enrich the EDM climate measurement, clinicians' behaviour and the performance of healthcare organisations. This instrument offers opportunities to develop tailored ICU team interventions. PMID- 29475980 TI - Patient participation in inpatient ward rounds on acute inpatient medical wards: a descriptive study. AB - BACKGROUND: Meaningful partnering with patients is advocated to enhance care delivery. Little is known about how this is operationalised at the point of care during hospital ward rounds, where decision-making concerning patient care frequently occurs. OBJECTIVE: Describe participation of patients, with differing preferences for participation, during ward rounds in acute medical inpatient services. METHODS: Naturalistic, multimethod design. Data were collected using surveys and observations of ward rounds at two hospitals in Melbourne, Australia. Using convenience sampling, a stratified sample of acute general medical patients were recruited. Prior to observation and interview, patient responses to the Control Preference Scale were used to stratify them into three groups representing diverse participation preferences: active control where the patient makes decisions; shared control where the patient prefers to make decisions jointly with clinicians; and passive control where the patient prefers clinicians make decisions. RESULTS: Of the 52 patients observed over 133 ward rounds, 30.8% (n=16) reported an active control preference for participation in decision-making during ward rounds, 25% (n=13) expressed shared control preference and 44.2% (n=23) expressed low control preference. Patients' participation was observed in 75% (n=85) of ward rounds, but few rounds (18%, n=20) involved patient contribution to decisions about their care. Clinicians prompted patient participation in 54% of rounds; and in 15% patients initiated their own participation. Thematic analysis of qualitative observation and patient interview data revealed two themes, supporting patient capability and clinician-led opportunity, that contributed to patient participation or non-participation in ward rounds. CONCLUSIONS: Participation in ward rounds was similar for patients irrespective of control preference. This study demonstrates the need to better understand clinician roles in supporting strategies that promote patient participation in day-to-day hospital care. PMID- 29475981 TI - Enhancing Renal Lymphatic Expansion Prevents Hypertension in Mice. AB - RATIONALE: Hypertension is associated with renal infiltration of activated immune cells; however, the role of renal lymphatics and immune cell exfiltration is unknown. OBJECTIVE: We tested the hypotheses that increased renal lymphatic density is associated with 2 different forms of hypertension in mice and that further augmenting renal lymphatic vessel expansion prevents hypertension by reducing renal immune cell accumulation. METHODS AND RESULTS: Mice with salt sensitive hypertension or nitric oxide synthase inhibition-induced hypertension exhibited significant increases in renal lymphatic vessel density and immune cell infiltration associated with inflammation. Genetic induction of enhanced lymphangiogenesis only in the kidney, however, reduced renal immune cell accumulation and prevented hypertension. CONCLUSIONS: These data demonstrate that renal lymphatics play a key role in immune cell trafficking in the kidney and blood pressure regulation in hypertension. PMID- 29475982 TI - LncRNA ZFAS1 as a SERCA2a Inhibitor to Cause Intracellular Ca2+ Overload and Contractile Dysfunction in a Mouse Model of Myocardial Infarction. AB - RATIONALE: Ca2+ homeostasis-a critical determinant of cardiac contractile function-is critically regulated by SERCA2a (sarcoplasmic reticulum Ca2+-ATPase 2a). Our previous study has identified ZFAS1 as a new lncRNA biomarker of acute myocardial infarction (MI). OBJECTIVE: To evaluate the effects of ZFAS1 on SERCA2a and the associated Ca2+ homeostasis and cardiac contractile function in the setting of MI. METHODS AND RESULTS: ZFAS1 expression was robustly increased in cytoplasm and sarcoplasmic reticulum in a mouse model of MI and a cellular model of hypoxia. Knockdown of endogenous ZFAS1 by virus-mediated silencing shRNA partially abrogated the ischemia-induced contractile dysfunction. Overexpression of ZFAS1 in otherwise normal mice created similar impairment of cardiac function as that observed in MI mice. Moreover, at the cellular level, ZFAS1 overexpression weakened the contractility of cardiac muscles. At the subcellular level, ZFAS1 deleteriously altered the Ca2+ transient leading to intracellular Ca2+ overload in cardiomyocytes. At the molecular level, ZFAS1 was found to directly bind SERCA2a protein and to limit its activity, as well as to repress its expression. The effects of ZFAS1 were readily reversible on knockdown of this lncRNA. Notably, a sequence domain of ZFAS1 gene that is conserved across species mimicked the effects of the full-length ZFAS1. Mutation of this domain or application of an antisense fragment to this conserved region efficiently canceled out the deleterious actions of ZFAS1. ZFAS1 had no significant effects on other Ca2+-handling regulatory proteins. CONCLUSIONS: ZFAS1 is an endogenous SERCA2a inhibitor, acting by binding to SERCA2a protein to limit its intracellular level and inhibit its activity, and a contributor to the impairment of cardiac contractile function in MI. Therefore, anti-ZFAS1 might be considered as a new therapeutic strategy for preserving SERCA2a activity and cardiac function under pathological conditions of the heart. PMID- 29475983 TI - S1P-S1PR2 Axis Mediates Homing of Muse Cells Into Damaged Heart for Long-Lasting Tissue Repair and Functional Recovery After Acute Myocardial Infarction. AB - RATIONALE: Multilineage-differentiating stress enduring (Muse) cells, pluripotent marker stage-specific embryonic antigen-3+ cells, are nontumorigenic endogenous pluripotent-like stem cells obtainable from various tissues including the bone marrow. Their therapeutic efficiency has not been validated in acute myocardial infarction. OBJECTIVE: The main objective of this study is to clarify the efficiency of intravenously infused rabbit autograft, allograft, and xenograft (human) bone marrow-Muse cells in a rabbit acute myocardial infarction model and their mechanisms of tissue repair. METHODS AND RESULTS: In vivo dynamics of Nano lantern-labeled Muse cells showed preferential homing of the cells to the postinfarct heart at 3 days and 2 weeks, with ~14.5% of injected GFP (green fluorescent protein)-Muse cells estimated to be engrafted into the heart at 3 days. The migration and homing of the Muse cells was confirmed pharmacologically (S1PR2 [sphingosine monophosphate receptor 2]-specific antagonist JTE-013 coinjection) and genetically (S1PR2-siRNA [small interfering ribonucleic acid] introduced Muse cells) to be mediated through the S1P (sphingosine monophosphate) S1PR2 axis. They spontaneously differentiated into cells positive for cardiac markers, such as cardiac troponin-I, sarcomeric alpha-actinin, and connexin-43, and vascular markers. GCaMP3 (GFP-based Ca calmodulin probe)-labeled Muse cells that engrafted into the ischemic region exhibited increased GCaMP3 fluorescence during systole and decreased fluorescence during diastole. Infarct size was reduced by ~52%, and the ejection fraction was increased by ~38% compared with vehicle injection at 2 months, ~2.5 and ~2.1 times higher, respectively, than that induced by mesenchymal stem cells. These effects were partially attenuated by the administration of GATA4-gene-silenced Muse cells. Muse cell allografts and xenografts efficiently engrafted and recovered functions, and allografts remained in the tissue and sustained functional recovery for up to 6 months without immunosuppression. CONCLUSIONS: Muse cells may provide reparative effects and robust functional recovery and may, thus, provide a novel strategy for the treatment of acute myocardial infarction. PMID- 29475984 TI - Correction: Green Tea Polyphenol EGCG Upregulates Tollip Expression by Suppressing Elf-1 Expression. PMID- 29475985 TI - Correction: B Cells Drive Autoimmunity in Mice with CD28-Deficient Regulatory T Cells. PMID- 29475986 TI - Cutting Edge: A New Player in the Alternative Complement Pathway, MASP-1 Is Essential for LPS-Induced, but Not for Zymosan-Induced, Alternative Pathway Activation. AB - The complement system is a sophisticated network of proteases. In this article, we describe an unexpected link between two linear activation routes of the complement system: the lectin pathway (LP) and the alternative pathway (AP). Mannose-lectin binding-associated serine protease (MASP)-1 is known to be the initiator protease of the LP. Using a specific and potent inhibitor of MASP-1, SGMI-1, as well as other MASP-1 inhibitors with different mechanisms of action, we demonstrated that, in addition to its functions in the LP, MASP-1 is essential for bacterial LPS-induced AP activation, whereas it has little effect on zymosan induced AP activation. We have shown that MASP-1 inhibition prevents AP activation, as well as attenuates the already initiated AP activity on the LPS surface. This newly recognized function of MASP-1 can be important for the defense against certain bacterial infections. Our results also emphasize that the mechanism of AP activation depends on the activator surface. PMID- 29475987 TI - A Novel Biological Role for Peptidyl-Arginine Deiminases: Citrullination of Cathelicidin LL-37 Controls the Immunostimulatory Potential of Cell-Free DNA. AB - LL-37, the only human cathelicidin that is released during inflammation, is a potent regulator of immune responses by facilitating delivery of oligonucleotides to intracellular TLR-9, thereby enhancing the response of human plasmacytoid dendritic cells (pDCs) to extracellular DNA. Although important for pathogen recognition, this mechanism may facilitate development of autoimmune diseases. In this article, we show that citrullination of LL-37 by peptidyl-arginine deiminases (PADs) hindered peptide-dependent DNA uptake and sensing by pDCs. In contrast, carbamylation of the peptide (homocitrullination of Lys residues) had no effect. The efficiency of LL-37 binding to oligonucleotides and activation of pDCs was found to be inversely proportional to the number of citrullinated residues in the peptide. Similarly, preincubation of carbamylated LL-37 with PAD2 abrogated the peptide's ability to bind DNA. Conversely, LL-37 with Arg residues substituted by homoarginine, which cannot be deiminated, elicited full activity of native LL-37 regardless of PAD2 treatment. Taken together, the data showed that citrullination abolished LL-37 ability to bind DNA and altered the immunomodulatory function of the peptide. Both activities were dependent on the proper distribution of guanidinium side chains in the native peptide sequence. Moreover, our data suggest that cathelicidin/LL-37 is citrullinated by PADs during NET formation, thus affecting the inflammatory potential of NETs. Together this may represent a novel mechanism for preventing the breakdown of immunotolerance, which is dependent on the response of APCs to self-molecules (including cell-free DNA); overactivation may facilitate development of autoimmunity. PMID- 29475989 TI - Correction: Predominant Expression of CCL2 at the Tumor Site of Prostate Cancer Patients Directs a Selective Loss of Immunological Tolerance to CCL2 That Could Be Amplified in a Beneficial Manner. PMID- 29475990 TI - Approach to the Young Patient with New-Onset Hypertension. PMID- 29475988 TI - HLA Class II-Triggered Signaling Cascades Cause Endothelial Cell Proliferation and Migration: Relevance to Antibody-Mediated Transplant Rejection. AB - Transplant recipients developing donor-specific HLA class II (HLA-II) Abs are at higher risk for Ab-mediated rejection (AMR) and transplant vasculopathy. To understand how HLA-II Abs cause AMR and transplant vasculopathy, we determined the signaling events triggered in vascular endothelial cells (EC) following Ab ligation of HLA-II molecules. HLA-II expression in EC was induced by adenoviral vector expression of CIITA or by pretreatment with TNF-alpha/IFN-gamma. Ab ligation of class II stimulated EC proliferation and migration. Class II Ab also induced activation of key signaling nodes Src, focal adhesion kinase, PI3K, and ERK that regulated downstream targets of the mammalian target of rapamycin (mTOR) pathway Akt, p70 ribosomal S6 kinase, and S6 ribosomal protein. Pharmacological inhibitors and small interfering RNA showed the protein kinases Src, focal adhesion kinase, PI3K/Akt, and MEK/ERK regulate class II Ab-stimulated cell proliferation and migration. Treatment with rapalogs for 2 h did not affect HLA II Ab-induced phosphorylation of ERK; instead, mTOR complex (mTORC)1 targets were dependent on activation of ERK. Importantly, suppression of mTORC2 for 24 h with rapamycin or everolimus or treatment with mTOR active-site inhibitors enhanced HLA-II Ab-stimulated phosphorylation of ERK. Furthermore, knockdown of Rictor with small interfering RNA caused overactivation of ERK while abolishing phosphorylation of Akt Ser473 induced by class II Ab. These data are different from HLA class I Ab-induced activation of ERK, which is mTORC2-dependent. Our results identify a complex signaling network triggered by HLA-II Ab in EC and indicate that combined ERK and mTORC2 inhibitors may be required to achieve optimal efficacy in controlling HLA-II Ab-mediated AMR. PMID- 29475991 TI - Glucocorticoids in the Treatment of Glomerular Diseases: Pitfalls and Pearls. AB - Glucocorticoids exert anti-inflammatory and immunosuppressive activities by genomic and nongenomic effects. The classic genomic effects are mediated by cytosolic glucocorticoid receptors that can upregulate the expression of anti inflammatory proteins in the nucleus (transactivation) or repress the translocation of proinflammatory transcription factors from the cytosol into the nucleus (transrepression). The nongenomic effects are probably mediated by membrane glucocorticoid receptors. Glucocorticoid receptors are expressed also in podocytes and experimental data suggest that glucocorticoids may protect from podocyte injury. Glucocorticoids have a low therapeutic index and may exert a number of time-dependent and dose-dependent side effects. Measures to prevent or attenuate side effects include single-morning administration of short-acting glucocorticoids, dietetic counseling, increasing physical activity, frequent monitoring, and adapting the doses to the clinical conditions of the patient. Synthetic glucocorticoids, either given alone or in combination with other immunosuppressive drugs, are still the cornerstone therapy in multiple glomerular disorders. However, glucocorticoids are of little benefit in C3 glomerulopathy and may be potentially deleterious in patients with maladaptive focal glomerulosclerosis. Their efficacy depends not only on the type and severity of glomerular disease, but also on the timeliness of administration, the dosage, and the duration of treatment. Whereas an excessive use of glucocorticoids can be responsible for severe toxicity, too low a dosage and too short duration of glucocorticoid treatment can result in false steroid resistance. PMID- 29475993 TI - Endoplasmic Reticulum Network Formation with Xenopus Egg Extracts. AB - The endoplasmic reticulum (ER) consists of morphologically distinct domains, including a polygonal network of tubules that is connected by three-way junctions. This network is found in all eukaryotic cells. Extracts from Xenopus laevis eggs contain stockpiles of components that allow the assembly of an ER network in vitro. Here we provide protocols for assembly of ER networks in extracts that are arrested at different stages of the cell cycle. Unfertilized Xenopus laevis eggs contain a cytostatic factor (CSF) that keeps them in the metaphase stage of the cell cycle. Disruption of the eggs by low-speed centrifugation releases calcium and the eggs cycle into interphase. This state can then be maintained by the addition of cycloheximide, which prevents the synthesis of cyclin B. CSF extracts can be also prepared in the presence of a calcium chelator, thus keeping the extract in metaphase. In this protocol, we outline procedures for the assembly of an ER network using either interphase- or metaphase-arrested Xenopus egg extracts. The network assembled is strikingly similar to the network observed in tissue culture cells. The extract allows easy biochemical manipulation, permitting the effects of purified proteins or small molecules, or the depletion of cytosolic components to be tested. PMID- 29475994 TI - Chromosome Cohesion and Condensation in Xenopus Egg Extracts. AB - Chromosome structure in both interphase and M-phase cells is strongly influenced by the action of the cohesin and condensin protein complexes. The cohesin complex tethers the identical copies of each chromosome, called sister chromatids, together following DNA replication and promotes normal interphase chromosome structure and gene expression. In contrast, condensin is active largely in M phase and promotes the compaction of individual chromosomes. The Xenopus egg extract system is uniquely suited to analyze the functions of both complexes. Egg extracts, in which the cell cycle state can be manipulated, contain stockpiles of nuclear proteins (including condensin and cohesin) sufficient for the assembly of thousands of nuclei per microliter. Extract prepared from unfertilized eggs is arrested by the presence of cytostatic factor (CSF) in a state with high levels of M-phase kinase activity, but can be stimulated to enter interphase, in which DNA replication occurs spontaneously. For cohesion assays, demembranated sperm nuclei are incubated in interphase extract, where they undergo rapid and synchronous DNA replication and cohesion establishment through the recruitment of proteins and other factors (e.g., nucleotides) from the extract. Sister chromatid cohesion is assessed by then driving the extract into M phase by the addition of fresh CSF-arrested extract. In contrast, because chromosome condensation occurs spontaneously in M-phase extracts, sperm nuclei are added directly to CSF extracts to assay condensation. PMID- 29475995 TI - Centromere and Kinetochore Assembly in Xenopus laevis Egg Extract. AB - During cell division, chromosomes must be equally segregated to daughter cells. Centromeres, the primary interaction site between chromosomes and microtubules, mediate faithful chromosome segregation during mitosis. Functional studies of centromere proteins in cells have proven difficult, as mutation or deletion of most centromeric proteins often results in cell lethality. In this protocol, sperm chromatin or reconstituted chromatin arrays, together with Xenopus laevis egg extracts, are used to overcome these limitations and study centromere and kinetochore assembly in vitro. X. laevis egg extract is a powerful tool, as it can be readily cycled in vitro by addition of calcium and easily modified biochemically. Coupled with the addition of customizable reconstituted chromatin arrays or sperm chromatin, X. laevis egg extract provides distinct advantages over cell-based approaches in which similar experiments would not be feasible. Following incubation in egg extract, reconstituted centromeric chromatin arrays and sperm chromatin specifically assemble core centromere and kinetochore components that can be analyzed via immunofluorescence. PMID- 29475992 TI - Central Blood Pressure and Cardiovascular Outcomes in Chronic Kidney Disease. AB - BACKGROUND AND OBJECTIVES: Central BP measurements provide noninvasive measurement of aortic BP; our objectives were to examine the association of central and brachial BP measurements with risk of cardiovascular outcomes and mortality in patients with CKD and to determine the role of central BP measurement in conjunction with brachial BP in estimating cardiovascular risk. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a prospective, longitudinal study (the Chronic Renal Insufficiency Cohort), central BP was measured in participants with CKD using the SphygmoCorPVx System. Cox proportional hazards models were used for analyses. RESULTS: Mean age of the participants (n=2875) was 60 years old. After a median follow-up of 5.5 years, participants in the highest quartile of brachial systolic BP (>=138 mm Hg) were at higher risk for the composite cardiovascular outcome (hazard ratio, 1.59; 95% confidence interval, 1.17 to 2.17; c statistic, 0.76) but not all-cause mortality (hazard ratio, 1.28; 95% confidence interval, 0.90 to 1.80) compared with those in the lowest quartile. Participants in the highest quartile of central systolic BP were also at higher risk for the composite cardiovascular outcome (hazard ratio, 1.69; 95% confidence interval, 1.24 to 2.31; c statistic, 0.76) compared with participants in the lowest quartile. CONCLUSIONS: We show that elevated brachial and central BP measurements are both associated with higher risk of cardiovascular disease outcomes in patients with CKD. Measurement of central BP does not improve the ability to predict cardiovascular disease outcomes or mortality in patients with CKD compared with brachial BP measurement. PMID- 29475996 TI - Chemical Screening Using Cell-Free Xenopus Egg Extract. AB - Most drug screening methods use purified proteins, cultured cells, and/or small model organisms such as Xenopus, zebrafish, flies, or nematodes. These systems have proven successes in drug discovery, but they also have weaknesses. Although purified cellular components allow for identification of compounds with activity against specific targets, such systems lack the complex biological interactions present in cellular and organismal screens. In vivo systems overcome these weaknesses, but the lack of cellular permeability, efflux by cellular pumps, and/or toxicity can be major limitations. Xenopus laevis egg extract, a concentrated and biologically active cytosol, can potentially overcome these weaknesses. Drug interactions occur in a near-physiological milieu, thereby functioning in a "truer" endogenous manner than purified components. Also, Xenopus egg extract is a cell-free system that lacks intact plasma membranes that could restrict drug access to potential targets. Finally, Xenopus egg extract is readily manipulated at the protein level: Proteins are easily depleted or added to the system, an important feature for analyzing drug effects in disease states. Thus, Xenopus egg extract offers an attractive media for screening drugs that merges strengths of both in vitro and in vivo systems. PMID- 29475997 TI - Robustly Cycling Xenopus laevis Cell-Free Extracts in Teflon Chambers. AB - A central advantage of studying Xenopus laevis is the manipulability of its cell free extracts, which perform the cell cycle in vitro. However, these extracts are known to be experimentally temperamental and will often complete at most one or two cycles. Over the course of developing systems for imaging cell cycle events in extracts in real time, we unexpectedly found that when standard Xenopus extracts are placed in Teflon tubes, they cycle extremely robustly; in one series of experiments, over 90% (n = 13) of extracts cycled an average of seven and as many as 14 times. Extracts incubated in other materials, such as glass and polydimethylsiloxane, do not cycle as robustly. Here we present protocols for preparing Xenopus extracts and imaging them in Teflon tubes. This method extends the usefulness of this powerful model organism. PMID- 29475998 TI - Chromatin Characterization in Xenopus laevis Cell-Free Egg Extracts and Embryos. AB - Xenopus laevis development is marked by accelerated cell division solely supported by the proteins maternally deposited in the egg. Oocytes mature to eggs with concomitant transcriptional silencing. The unique maternal chromatin state contributing to this silencing and subsequent zygotic activation is likely established by histone posttranslational modifications and histone variants. Therefore, tools for understanding the nature and function of maternal and embryonic histones are essential to deciphering mechanisms of regulation of development, chromatin assembly, and transcription. Here we describe protocols for isolating pronuclear sperm chromatin from Xenopus egg extracts and hydroxyapatite-based histone purification from this chromatin. The histones purified through this method can be directly assembled into chromatin through in vitro assembly reactions, providing a unique opportunity to biochemically dissect the effect of histone variants, histone modifications, and other factors in chromatin replication and assembly. We also describe how to isolate chromatin from staged embryos and analyze the proteins to reveal dynamic developmental histone modifications. Finally, we present protocols to measure chromatin assembly in extracts, including supercoiling and micrococcal nuclease assays. Using these approaches, analysis of maternal and zygotic histone posttranslational modifications concomitant with cell-cycle and developmental transitions can be tested. PMID- 29475999 TI - The BEIR VII Estimates of Low-Dose Radiation Health Risks Are Based on Faulty Assumptions and Data Analyses: A Call for Reassessment. AB - The 2006 National Academy of Sciences Biologic Effects of Ionizing Radiation (BEIR) VII report is a well-recognized and frequently cited source on the legitimacy of the linear no-threshold (LNT) model-a model entailing a linear and causal relationship between ionizing radiation and human cancer risk. Linearity means that all radiation causes cancer and explicitly excludes a threshold below which radiogenic cancer risk disappears. However, the BEIR VII committee has erred in the interpretation of its selected literature; specifically, the in vitro data quoted fail to support LNT. Moreover, in vitro data cannot be considered as definitive proof of cancer development in intact organisms. This review is presented to stimulate a critical reevaluation by a BEIR VIII committee to reassess the validity, and use, of LNT and its derived policies. PMID- 29476000 TI - Comparison of 68Ga-PSMA-11 and 18F-Fluciclovine PET/CT in a Case Series of 10 Patients with Prostate Cancer Recurrence: Interesting, but Far from Definitive. PMID- 29476001 TI - Simplified Quantification and Acquisition Protocol for 123I-MIBG Dynamic SPECT. AB - Previous studies have demonstrated the feasibility of absolute quantification of dynamic 123I-metaiodobenzylguanidine (123I-MIBG) SPECT imaging in humans. This work reports a simplified quantification method for dynamic 123I-MIBG SPECT using practical protocols with shortened acquisition time and voxel-by-voxel parametric imaging. Methods: Twelve healthy human volunteers underwent five 15-min dynamic SPECT scans at 0, 15, 90, 120, and 180 min after 123I-MIBG injection. List-mode SPECT data were binned into 29 frames and reconstructed with corrections for attenuation, scatter, and decay. Population-based blood-to-plasma correction and metabolite correction were applied to the image-derived input function. Likelihood estimation in graphical analysis (LEGA) was used as a simplified model to obtain volume of distribution (V T) values, which were compared with those obtained with the reversible 2-tissue (2T) compartment model. Three simplified protocols were evaluated with 2T and LEGA using a 30-min scan started simultaneously with tracer injection plus a 15-min scan at 90, 120, or 180 min after injection. Voxel-by-voxel LEGA fitting was applied to the aligned dynamic images using both the full protocol (five 15-min scans) and the simplified protocols. Results: Correlation analysis (y = 0.955x + 0.547, R 2 = 0.997) and Bland-Altman plot (mean difference, -0.8 mL/cm3; 95% limits of agreement, [-2.5, 1.0] mL/cm3; normal V T range, 29.0 +/- 12.4 mL/cm3) showed that LEGA can be used as a simplified model of 2T for 123I-MIBG. High-quality V T parametric images could be obtained with LEGA. Region-of-interest (ROI) modeling and parametric imaging results were in excellent agreement as determined by correlation analysis (y = 0.999x - 1.026, R 2 = 0.982) and Bland-Altman plot (mean difference, -1.0 mL/cm3; 95% limits of agreement, [-4.2, 2.1] mL/cm3). V T correlated reasonably well between all simplified protocols and the full protocol with LEGA but not with 2T. The V T results were more reliable when there was a longer interval between the 2 acquisitions in the simplified protocols. Conclusion: For ROI-based kinetic modeling and parametric imaging, reliable quantification of dynamic 123I MIBG SPECT can be achieved with LEGA using a simplified protocol of a 30-min scan starting with tracer injection plus a 15-min scan no earlier than 180 min after injection. PMID- 29476002 TI - Thymidine Metabolism as a Confounding Factor for 3'-Deoxy-3'-18F-Fluorothymidine Uptake After Therapy in a Colorectal Cancer Model. AB - Noninvasive monitoring of tumor therapy response helps in developing personalized treatment strategies. Here, we performed sequential PET and diffusion-weighted MRI to evaluate changes induced by a FOLFOX-like combination chemotherapy in colorectal cancer xenografts, to identify the cellular and molecular determinants of these imaging biomarkers. Methods: Tumor-bearing CD1 nude mice, engrafted with FOLFOX-sensitive Colo205 colorectal cancer xenografts, were treated with FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) weekly. On days 1, 2, 6, 9, and 13 of therapy, tumors were assessed by in vivo imaging and ex vivo analyses. In addition, HCT116 xenografts, which did not respond to the FOLFOX treatment, were imaged on day 1 of therapy. Results: In Colo205 xenografts, FOLFOX induced a profound increase in uptake of the proliferation PET tracer 3'-deoxy-3'-18F fluorothymidine (18F-FLT) accompanied by increases in markers for proliferation (Ki-67, thymidine kinase 1) and for activated DNA damage response (gammaH2AX), whereas the effect on cell death was minimal. Because tracer uptake was unaltered in the HCT116 model, these changes appear to be specific for tumor response. Conclusion: We demonstrated that 18F-FLT PET can noninvasively monitor cancer treatment-induced molecular alterations, including thymidine metabolism and DNA damage response. The cellular or imaging changes may not, however, be directly related to therapy response as assessed by volumetric measurements. PMID- 29476003 TI - Impact of the Arterial Input Function Recording Method on Kinetic Parameters in Small-Animal PET. AB - The goal of this study was to validate the use of an MR-compatible blood sampler (BS) with a detector system based on a lutetium oxyorthosilicate scintillator and avalanche photodiodes for small-animal PET. Methods: Five rats underwent a 60-min 18F-FDG study. For each animal, the arterial input function (AIF) was derived from the BS recording, from manual sampling (MS), and from the PET image. These AIFs were applied for kinetic modeling of the striatum using the irreversible 2 tissue-compartment model. The MS-based technique with a dispersion correction served as a reference approach, and the kinetic parameters that were estimated with the BS- and the image-derived AIFs were compared with the reference values. Additionally, the effect of applying a population-based activity ratio for plasma to whole blood (p/wb) and the dispersion correction was assessed. Results: The K1, k2, and k3 values estimated with the reference approach were 0.174 +/- 0.037 mL/min/cm3, 0.342 +/- 0.080 1/min, and 0.048 +/- 0.009 1/min, respectively. The corresponding parameters obtained with the BS- and image-derived AIFs deviated from these values by 0.6%-18.8% and 16.7%-47.9%, respectively. To compensate for the error in the BS-based technique, data from one MS collected at the end of the experiment were combined with the data from the first 10 min of the BS recording. This approach reduced the deviation in the kinetic parameters to 1.8%-6.3%. Using p/wb led to a 1.7%-8.3% difference from the reference parameters. The sensitivity of the BS was 23%, the energy resolution for the 511-keV photopeak was 19%, and the timing resolution was 11.2 ns. Conclusion: Online recording of the blood activity level with the BS allows precise measurement of AIF, without loss of blood volume. Combining the BS data with one MS is the most accurate approach for the data analysis. The high sensitivity of the device may allow application of lower radioactivity doses. PMID- 29476005 TI - Physicians' framing and recommendations. Are they nudging? And do they violate the requirements of informed consent? PMID- 29476004 TI - The Metabolic Pattern of Idiopathic REM Sleep Behavior Disorder Reflects Early Stage Parkinson Disease. AB - Idiopathic REM sleep behavior disorder (iRBD) is considered a prodromal stage of Parkinson disease (PD) and other Lewy body disorders. Spatial covariance analysis of 18F-FDG PET data has disclosed a specific brain pattern of altered glucose metabolism in PD. In this study, we identify the metabolic pattern underlying iRBD and compare it with the known PD pattern. To understand the relevance of the iRBD pattern to disease progression, we studied the expression of the iRBD pattern in de novo PD patients. Methods: The iRBD-related pattern was identified in 18F-FDG PET scans of 21 patients with polysomnographically confirmed iRBD and 19 controls using spatial covariance analysis. Expression of the iRBD-related pattern was subsequently computed in 18F-FDG PET scans of 44 controls and 38 de novo, treatment-naive PD patients. Of these 38 PD patients, 24 had probable REM sleep behavior disorder (RBD) according to the Mayo Sleep Questionnaire. Neuropsychologic evaluation showed mild cognitive impairment in 20 PD patients (PD-MCI), of whom 16 also had concomitant RBD and roughly half (11/20) had bilateral motor symptoms. Results: The iRBD-related pattern was characterized by relative hypermetabolism in the cerebellum, brain stem, thalamus, sensorimotor cortex, and hippocampus, and by relative hypometabolism in the middle cingulate, temporal, occipital, and parietal cortices. This topography partially overlapped with the PD-related pattern (PDRP). The iRBD-related pattern was significantly expressed in PD patients compared with controls (P < 0.0001). iRBD-related pattern expression was not significantly different between PD patients with and without probable RBD, or between PD patients with unilateral or bilateral parkinsonism. iRBD-related pattern (iRBDRP) expression was higher in PD-MCI patients than in PD patients with preserved cognition (P = 0.001). Subject scores on the iRBD-related pattern were highly correlated to subject scores on the PDRP (r = 0.94, P < 0.0001). Conclusion: Our results show that the iRBDRP is an early manifestation of the PDRP. Expression of both PDRP and iRBDRP was higher in patients with a more severe form of PD (PD-MCI), which indicates that expression of the 2 patterns increases with disease severity. PMID- 29476006 TI - Estrogen-dependent control and cell-to-cell variability of transcriptional bursting. AB - Cellular decision-making and environmental adaptation are dependent upon a heterogeneous response of gene expression to external cues. Heterogeneity arises in transcription from random switching between transcriptionally active and inactive states, resulting in bursts of RNA synthesis. Furthermore, the cellular state influences the competency of transcription, thereby globally affecting gene expression in a cell-specific manner. We determined how external stimuli interplay with cellular state to modulate the kinetics of bursting. To this end, single-cell dynamics of nascent transcripts were monitored at the endogenous estrogen-responsive GREB1 locus. Stochastic modeling of gene expression implicated a two-state promoter model in which the estrogen stimulus modulates the frequency of transcriptional bursting. The cellular state affects transcriptional dynamics by altering initiation and elongation kinetics and acts globally, as GREB1 alleles in the same cell correlate in their transcriptional output. Our results suggest that cellular state strongly affects the first step of the central dogma of gene expression, to promote heterogeneity in the transcriptional output of isogenic cells. PMID- 29476007 TI - Characterization of Coding/Noncoding Variants for SHROOM3 in Patients with CKD. AB - Background Interpreting genetic variants is one of the greatest challenges impeding analysis of rapidly increasing volumes of genomic data from patients. For example, SHROOM3 is an associated risk gene for CKD, yet causative mechanism(s) of SHROOM3 allele(s) are unknown.Methods We used our analytic pipeline that integrates genetic, computational, biochemical, CRISPR/Cas9 editing, molecular, and physiologic data to characterize coding and noncoding variants to study the human SHROOM3 risk locus for CKD.Results We identified a novel SHROOM3 transcriptional start site, which results in a shorter isoform lacking the PDZ domain and is regulated by a common noncoding sequence variant associated with CKD (rs17319721, allele frequency: 0.35). This variant disrupted allele binding to the transcription factor TCF7L2 in podocyte cell nuclear extracts and altered transcription levels of SHROOM3 in cultured cells, potentially through the loss of repressive looping between rs17319721 and the novel start site. Although common variant mechanisms are of high utility, sequencing is beginning to identify rare variants involved in disease; therefore, we used our biophysical tools to analyze an average of 112,849 individual human genome sequences for rare SHROOM3 missense variants, revealing 35 high-effect variants. The high-effect alleles include a coding variant (P1244L) previously associated with CKD (P=0.01, odds ratio=7.95; 95% CI, 1.53 to 41.46) that we find to be present in East Asian individuals at an allele frequency of 0.0027. We determined that P1244L attenuates the interaction of SHROOM3 with 14-3-3, suggesting alterations to the Hippo pathway, a known mediator of CKD.Conclusions These data demonstrate multiple new SHROOM3-dependent genetic/molecular mechanisms that likely affect CKD. PMID- 29476009 TI - Neutrophils in hot pursuit of MRSA in the lymph nodes. PMID- 29476008 TI - Coamplification of miR-4728 protects HER2-amplified breast cancers from targeted therapy. AB - HER2 (ERBB2) amplification is a driving oncogenic event in breast cancer. Clinical trials have consistently shown the benefit of HER2 inhibitors (HER2i) in treating patients with both local and advanced HER2+ breast cancer. Despite this benefit, their efficacy as single agents is limited, unlike the robust responses to other receptor tyrosine kinase inhibitors like EGFR inhibitors in EGFR-mutant lung cancer. Interestingly, the lack of HER2i efficacy occurs despite sufficient intracellular signaling shutdown following HER2i treatment. Exploring possible intrinsic causes for this lack of response, we uncovered remarkably depressed levels of NOXA, an endogenous inhibitor of the antiapoptotic MCL-1, in HER2 amplified breast cancer. Upon investigation of the mechanism leading to low NOXA, we identified a micro-RNA encoded in an intron of HER2, termed miR-4728, that targets the mRNA of the Estrogen Receptor alpha (ESR1). Reduced ESR1 expression in turn prevents ERalpha-mediated transcription of NOXA, mitigating apoptosis following treatment with the HER2i lapatinib. Importantly, resistance can be overcome with pharmacological inhibition of MCL-1. More generally, while many cancers like EGFR-mutant lung cancer are driven by activated kinases that when drugged lead to robust monotherapeutic responses, we demonstrate that the efficacy of targeted therapies directed against oncogenes active through focal amplification may be mitigated by coamplified genes. PMID- 29476010 TI - Highly multiplexed and quantitative cell-surface protein profiling using genetically barcoded antibodies. AB - Human cells express thousands of different surface proteins that can be used for cell classification, or to distinguish healthy and disease conditions. A method capable of profiling a substantial fraction of the surface proteome simultaneously and inexpensively would enable more accurate and complete classification of cell states. We present a highly multiplexed and quantitative surface proteomic method using genetically barcoded antibodies called phage antibody next-generation sequencing (PhaNGS). Using 144 preselected antibodies displayed on filamentous phage (Fab-phage) against 44 receptor targets, we assess changes in B cell surface proteins after the development of drug resistance in a patient with acute lymphoblastic leukemia (ALL) and in adaptation to oncogene expression in a Myc-inducible Burkitt lymphoma model. We further show PhaNGS can be applied at the single-cell level. Our results reveal that a common set of proteins including FLT3, NCR3LG1, and ROR1 dominate the response to similar oncogenic perturbations in B cells. Linking high-affinity, selective, genetically encoded binders to NGS enables direct and highly multiplexed protein detection, comparable to RNA-sequencing for mRNA. PhaNGS has the potential to profile a substantial fraction of the surface proteome simultaneously and inexpensively to enable more accurate and complete classification of cell states. PMID- 29476011 TI - Porin self-association enables cell-to-cell contact in Providencia stuartii floating communities. AB - The gram-negative pathogen Providencia stuartii forms floating communities within which adjacent cells are in apparent contact, before depositing as canonical surface-attached biofilms. Because porins are the most abundant proteins in the outer membrane of gram-negative bacteria, we hypothesized that they could be involved in cell-to-cell contact and undertook a structure-function relationship study on the two porins of P. stuartii, Omp-Pst1 and Omp-Pst2. Our crystal structures reveal that these porins can self-associate through their extracellular loops, forming dimers of trimers (DOTs) that could enable cell-to cell contact within floating communities. Support for this hypothesis was obtained by studying the porin-dependent aggregation of liposomes and model cells. The observation that facing channels are open in the two porin structures suggests that DOTs could not only promote cell-to-cell contact but also contribute to intercellular communication. PMID- 29476012 TI - Treg cells limit IFN-gamma production to control macrophage accrual and phenotype during skeletal muscle regeneration. AB - Skeletal muscle regeneration is a highly orchestrated process that depends on multiple immune-system cell types, notably macrophages (MFs) and Foxp3+CD4+ regulatory T (Treg) cells. This study addressed how Treg cells rein in MFs during regeneration of murine muscle after acute injury with cardiotoxin. We first delineated and characterized two subsets of MFs according to their expression of major histocompatibility complex class II (MHCII) molecules, i.e., their ability to present antigens. Then, we assessed the impact of Treg cells on these MF subsets by punctually depleting Foxp3+ cells during the regenerative process. Treg cells controlled both the accumulation and phenotype of the two types of MFs. Their absence after injury promoted IFN-gamma production, primarily by NK and effector T cells, which ultimately resulted in MF dysregulation and increased inflammation and fibrosis, pointing to compromised muscle repair. Thus, we uncovered an IFN-gamma-centered regulatory layer by which Treg cells keep MFs in check and dampen inflammation during regeneration of skeletal muscle. PMID- 29476014 TI - Positive Allosteric Modulation as a Potential Therapeutic Strategy in Anti-NMDA Receptor Encephalitis. AB - N-methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate receptors important for synaptic plasticity, memory, and neuropsychiatric health. NMDAR hypofunction contributes to multiple disorders, including anti-NMDAR encephalitis (NMDARE), an autoimmune disease of the CNS associated with GluN1 antibody mediated NMDAR internalization. Here we characterize the functional/pharmacological consequences of exposure to CSF from female human NMDARE patients on NMDAR function, and we characterize the effects of intervention with recently described positive allosteric modulators (PAMs) of NMDARs. Incubation (48 h) of rat hippocampal neurons of both sexes in confirmed NMDARE patient CSF, but not control CSF, attenuated NMDA-induced current. Residual NMDAR function was characterized by lack of change in channel open probability, indiscriminate loss of synaptic and extrasynaptic NMDARs, and indiscriminate loss of GluN2B-containing and GluN2B-lacking NMDARs. NMDARs tagged with N-terminal pHluorin fluorescence demonstrated loss of surface receptors. Thus, function of residual NMDARs following CSF exposure was indistinguishable from baseline, and deficits appear wholly accounted for by receptor loss. Coapplication of CSF and PAMs of NMDARs (SGE-301 or SGE-550, oxysterol-mimetic) for 24 h restored NMDAR function following 24 h incubation in patient CSF. Curiously, restoration of NMDAR function was observed despite washout of PAMs before electrophysiological recordings. Subsequent experiments suggested that residual allosteric potentiation of NMDAR function explained the persistent rescue. Further studies of the pathogenesis of NMDARE and intervention with PAMs may inform new treatments for NMDARE and other disorders associated with NMDAR hypofunction.SIGNIFICANCE STATEMENT Anti-N-methyl-d-aspartate receptor encephalitis (NMDARE) is increasingly recognized as an important cause of sudden onset psychosis and other neuropsychiatric symptoms. Current treatment leaves unmet medical need. Here we demonstrate cellular evidence that newly identified positive allosteric modulators of NMDAR function may be a viable therapeutic strategy. PMID- 29476015 TI - A Novel Retrieval-Dependent Memory Process Revealed by the Arrest of ERK1/2 Activation in the Basolateral Amygdala. AB - Fully consolidated fear memories can be maintained or inhibited by retrieval dependent mechanisms depending on the degree of re-exposure to fear cues. Short exposures promote memory maintenance through reconsolidation, and long exposures promote inhibition through extinction. Little is known about the neural mechanisms by which increasing cue exposure overrides reconsolidation and instead triggers extinction. Using auditory fear conditioning in male rats, we analyzed the role of a molecular mechanism common to reconsolidation and extinction of fear, ERK1/2 activation within the basolateral amygdala (BLA), after intermediate conditioned stimulus (CS) exposure events. We show that an intermediate re exposure (four CS presentations) failed to activate ERK1/2 in the BLA, suggesting the absence of reconsolidation or extinction mechanisms. Supporting this hypothesis, pharmacologically inhibiting the BLA ERK1/2-dependent signaling pathway in conjunction with four CS presentations had no effect on fear expression, and the NMDA receptor partial agonist d-cycloserine, which enhanced extinction and ERK1/2 activation in partial extinction protocols (seven CSs), had no behavioral or molecular effect when given in association with four CS presentations. These molecular and behavioral data reveal a novel retrieval dependent memory phase occurring along the transition between conditioned fear maintenance and inhibition. CS-dependent molecular events in the BLA may arrest reconsolidation intracellular signaling mechanism in an extinction-independent manner. These findings are critical for understanding the molecular underpinnings of fear memory persistence after retrieval both in health and disease.SIGNIFICANCE STATEMENT Consolidated fear memories can be altered by retrieval-dependent mechanisms. Whereas a brief conditioned stimulus (CS) exposure promotes fear memory maintenance through reconsolidation, a prolonged exposure engages extinction and fear inhibition. The nature of this transition and whether an intermediate degree of CS exposure engages reconsolidation or extinction is unknown. We show that an intermediate cue exposure session (four CSs) produces the arrest of ERK1/2 activation in the basolateral amygdala, a common mechanism for reconsolidation and extinction. Amnestic or hypermnestic treatments given in association with four CSs had no behavioral or molecular effects, respectively. This evidence reveals a novel retrieval-dependent memory phase. Intermediate degrees of CS exposure fail to trigger reconsolidation or extinction, leaving the original memory in an insensitive state. PMID- 29476016 TI - Doctor, Teacher, and Stethoscope: Neural Representation of Different Types of Semantic Relations. AB - Concepts can be related in many ways. They can belong to the same taxonomic category (e.g., "doctor" and "teacher," both in the category of people) or be associated with the same event context (e.g., "doctor" and "stethoscope," both associated with medical scenarios). How are these two major types of semantic relations coded in the brain? We constructed stimuli from three taxonomic categories (people, manmade objects, and locations) and three thematic categories (school, medicine, and sports) and investigated the neural representations of these two dimensions using representational similarity analyses in human participants (10 men and nine women). In specific regions of interest, the left anterior temporal lobe (ATL) and the left temporoparietal junction (TPJ), we found that, whereas both areas had significant effects of taxonomic information, the taxonomic relations had stronger effects in the ATL than in the TPJ ("doctor" and "teacher" closer in ATL neural activity), with the reverse being true for thematic relations ("doctor" and "stethoscope" closer in TPJ neural activity). A whole-brain searchlight analysis revealed that widely distributed regions, mainly in the left hemisphere, represented the taxonomic dimension. Interestingly, the significant effects of the thematic relations were only observed after the taxonomic differences were controlled for in the left TPJ, the right superior lateral occipital cortex, and other frontal, temporal, and parietal regions. In summary, taxonomic grouping is a primary organizational dimension across distributed brain regions, with thematic grouping further embedded within such taxonomic structures.SIGNIFICANCE STATEMENT How are concepts organized in the brain? It is well established that concepts belonging to the same taxonomic categories (e.g., "doctor" and "teacher") share neural representations in specific brain regions. How concepts are associated in other manners (e.g., "doctor" and "stethoscope," which are thematically related) remains poorly understood. We used representational similarity analyses to unravel the neural representations of these different types of semantic relations by testing the same set of words that could be differently grouped by taxonomic categories or by thematic categories. We found that widely distributed brain areas primarily represented taxonomic categories, with the thematic categories further embedded within the taxonomic structure. PMID- 29476013 TI - Karyopherin alpha-3 is a key protein in the pathogenesis of spinocerebellar ataxia type 3 controlling the nuclear localization of ataxin-3. AB - Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder caused by a CAG expansion in the ATXN3 gene leading to a polyglutamine expansion in the ataxin-3 protein. The nuclear presence and aggregation of expanded ataxin-3 are critical steps in disease pathogenesis. To identify novel therapeutic targets, we investigated the nucleocytoplasmic transport system by screening a collection of importins and exportins that potentially modulate this nuclear localization. Using cell, Drosophila, and mouse models, we focused on three transport proteins, namely, CRM1, IPO13, KPNA3, and their respective Drosophila orthologs Emb, Cdm, and Kap-alpha3. While overexpression of CRM1/Emb demonstrated positive effects in Drosophila, KPNA3/Kap-alpha3 emerged as the most promising target, as knockdown via multiple RNAi lines demonstrated its ability to shuttle both truncated and full-length expanded ataxin-3, rescue neurodegeneration, restore photoreceptor formation, and reduce aggregation. Furthermore, KPNA3 knockout in SCA3 mice resulted in an amelioration of molecular and behavioral disturbances such as total activity, anxiety, and gait. Since KPNA3 is known to function as an import protein and recognize nuclear localization signals (NLSs), this work unites ataxin-3 structure to the nuclear pore machinery and provides a link between karyopherins, NLS signals, and polyglutamine disease, as well as demonstrates that KPNA3 is a key player in the pathogenesis of SCA3. PMID- 29476017 TI - Administration of Hypoxia-Activated Prodrug Evofosfamide after Conventional Adjuvant Therapy Enhances Therapeutic Outcome and Targets Cancer-Initiating Cells in Preclinical Models of Colorectal Cancer. AB - Purpose: Cancer-initiating cells (C-IC) have been described in multiple cancer types, including colorectal cancer. C-ICs are defined by their capacity to self renew, thereby driving tumor growth. C-ICs were initially thought to be static entities; however, recent studies have determined these cells to be dynamic and influenced by microenvironmental cues such as hypoxia. If hypoxia drives the formation of C-ICs, then therapeutic targeting of hypoxia could represent a novel means to target C-ICs.Experimental Design: Patient-derived colorectal cancer xenografts were treated with evofosfamide, a hypoxia-activated prodrug (HAP), in combination with 5-fluorouracil (5-FU) or chemoradiotherapy (5-FU and radiation; CRT). Treatment groups included both concurrent and sequential dosing regimens. Effects on the colorectal cancer-initiating cell (CC-IC) fraction were assessed by serial passage in vivo limiting dilution assays. FAZA-PET imaging was utilized as a noninvasive method to assess intratumoral hypoxia.Results: Hypoxia was sufficient to drive the formation of CC-ICs and colorectal cancer cells surviving conventional therapy were more hypoxic and C-IC-like. Using a novel approach to combination therapy, we show that sequential treatment with 5-FU or CRT followed by evofosfamide not only inhibits tumor growth of xenografts compared with 5-FU or CRT alone, but also significantly decreases the CC-IC fraction. Furthermore, noninvasive FAZA-PET hypoxia imaging was predictive of a tumor's response to evofosfamide.Conclusions: Our data demonstrate a novel means to target the CC-IC fraction by adding a HAP sequentially after conventional adjuvant therapy, as well as the use of FAZA-PET as a biomarker for hypoxia to identify tumors that will benefit most from this approach. Clin Cancer Res; 24(9); 2116-27. (c)2018 AACR. PMID- 29476018 TI - FDA Approval: Gemtuzumab Ozogamicin for the Treatment of Adults with Newly Diagnosed CD33-Positive Acute Myeloid Leukemia. AB - On September 1, 2017, the FDA granted approval for gemtuzumab ozogamicin (Mylotarg; Pfizer Inc.) in combination with daunorubicin and cytarabine and as a monotherapy for the treatment of adult patients with newly diagnosed CD33 positive acute myeloid leukemia (AML). Gemtuzumab ozogamicin is a CD33-targeted antibody-drug conjugate joined to calicheamicin. Approval of gemtuzumab ozogamicin combination treatment was based on a randomized trial of 271 patients with newly diagnosed AML treated with daunorubicin and cytarabine with or without 3 mg/m2 fractionated gemtuzumab ozogamicin, which resulted in an event-free survival (EFS) of 13.6 months for gemtuzumab ozogamicin + daunorubicin and cytarabine and 8.8 months for daunorubicin and cytarabine alone [HR = 0.68 (95% confidence interval (CI), 0.51-0.91)]. Hemorrhage, prolonged thrombocytopenia, and veno-occlusive disease were serious toxicities that were more common in patients treated with gemtuzumab ozogamicin + daunorubicin and cytarabine. Approval of gemtuzumab ozogamicin monotherapy was based on a randomized trial of 237 patients with newly diagnosed AML treated without curative intent. Median overall survival (OS) was 4.9 months with gemtuzumab ozogamicin versus 3.6 months on best supportive care [HR = 0.69 (95% CI, 0.53-0.90)]. Adverse events were similar on both arms. Postapproval, several studies are required including evaluation of fractionated gemtuzumab ozogamicin pharmacokinetics, safety of combination gemtuzumab ozogamicin in the pediatric population, immunogenicity, and the effects of gemtuzumab ozogamicin on platelet function. Clin Cancer Res; 24(14); 3242-6. (c)2018 AACR. PMID- 29476020 TI - Vitamin D-Binding Protein Enhances Epithelial Ovarian Cancer Progression by Regulating the Insulin-like Growth Factor-1/Akt Pathway and Vitamin D Receptor Transcription. AB - Purpose: Malignant ascites of epithelial ovarian cancer (EOC) helps identify prognostic biomarkers or mechanisms of tumor progression. Vitamin D-binding protein (DBP) was revealed to be upregulated in EOC ascites in our previous proteomic study. Here, we examined the role of DBP in EOC.Experimental Design: We analyzed ascites, serum, and tissue samples of patients with newly diagnosed EOC to determine the prognostic effects of DBP. We verified DBP function using orthotopic animal models and DBP regulation in ovarian cancer cell lines.Results: Elevated ascitic DBP was significantly associated with poor response to chemotherapy, short progression-free interval, increased cancer progression, and death. Ascitic DBP overexpression was an independent unfavorable biomarker for progression-free survival; DBP overexpression in cancerous tissue was significantly related to chemoresistance. In vivo and in vitro investigations demonstrated an important role for DBP in ovarian cancer progression. Orthotopic model mice inoculated with DBP knockdown ovarian cancer cells displayed a significant reduction in tumor formation, malignant cell number, ascitic DBP levels, invasiveness, and metastasis, and increased survival compared with controls. In presence of vitamin D receptor (VDR), DBP promoted cell aggression (invasion and doubling time) via activation of the insulin-like growth factor 1/insulin-like growth factor-binding protein-2/Akt axis, and induced suppression of vitamin D-responsive genes. A NF-kappaB p65-binding site in the VDR promoter was identified as a major determinant of DBP-dependent VDR promoter activation.Conclusions: This study highlights the importance of DBP in ovarian tumor progression and the potential application of DBP as a therapeutic target for EOC. Clin Cancer Res; 24(13); 3217-28. (c)2018 AACR. PMID- 29476019 TI - Focal Irradiation and Systemic TGFbeta Blockade in Metastatic Breast Cancer. AB - Purpose: This study examined the feasibility, efficacy (abscopal effect), and immune effects of TGFbeta blockade during radiotherapy in metastatic breast cancer patients.Experimental Design: Prospective randomized trial comparing two doses of TGFbeta blocking antibody fresolimumab. Metastatic breast cancer patients with at least three distinct metastatic sites whose tumor had progressed after at least one line of therapy were randomized to receive 1 or 10 mg/kg of fresolimumab, every 3 weeks for five cycles, with focal radiotherapy to a metastatic site at week 1 (three doses of 7.5 Gy), that could be repeated to a second lesion at week 7. Research bloods were drawn at baseline, week 2, 5, and 15 to isolate PBMCs, plasma, and serum.Results: Twenty-three patients were randomized, median age 57 (range 35-77). Seven grade 3/4 adverse events occurred in 5 of 11 patients in the 1 mg/kg arm and in 2 of 12 patients in the 10 mg/kg arm, respectively. Response was limited to three stable disease. At a median follow up of 12 months, 20 of 23 patients are deceased. Patients receiving the 10 mg/kg had a significantly higher median overall survival than those receiving 1 mg/kg fresolimumab dose [hazard ratio: 2.73 with 95% confidence interval (CI), 1.02-7.30; P = 0.039]. The higher dose correlated with improved peripheral blood mononuclear cell counts and a striking boost in the CD8 central memory pool.Conclusions: TGFbeta blockade during radiotherapy was feasible and well tolerated. Patients receiving the higher fresolimumab dose had a favorable systemic immune response and experienced longer median overall survival than the lower dose group. Clin Cancer Res; 24(11); 2493-504. (c)2018 AACR. PMID- 29476021 TI - Updated Results of Rituximab Pre- and Post-BEAM with or without 90Yttrium Ibritumomab Tiuxetan during Autologous Transplant for Diffuse Large B-cell Lymphoma. AB - Purpose: We evaluated the effect on long-term survival of adding rituximab (R) to BEAM (carmustine, etoposide, cytarabine, and melphalan) conditioning with or without yttrium-90 ibritumomab tiuxetan (90YIT) in patients with relapsed diffuse large B-cell lymphoma (DLBCL) undergoing autologous stem cell transplant (ASCT).Experimental design: Patients were enrolled on three consecutive phase II clinical trials. Patients received two doses of rituximab (375 and 1,000 mg/m2) during mobilization of stem cells, followed by 1,000 mg/m2 on days +1 and +8 after ASCT with R-BEAM or 90YIT-R-BEAM (90YIT dose of 0.4 mCi/kg) conditioning.Results: One hundred thirteen patients were enrolled, with 73 receiving R-BEAM and 40 receiving 90YIT-R-BEAM. All patients had a prior exposure to rituximab. The median follow-up intervals for survivors were 11.8, 8.1, and 4.2 years in the three trials, respectively. The 5-year disease-free survival (DFS) rates were 62% for R-BEAM and 65% for 90YIT-R-BEAM (P = 0.82). The 5-year overall survival rates were 73% and 77%, respectively (P = 0.65). In patients with de novo DLBCL, survival outcomes of the germinal center/activated b-cell histologic subtypes were similar with 5-year OS rates (P = 0.52) and DFS rates (P = 0.64), irrespective of their time of relapse (<1 vs. >1 year) after initial induction chemotherapy (P = 0.97).Conclusions: Administering ASCT with rituximab during stem cell collection and immediately after transplantation induces long term disease remission and abolishes the negative prognostic impact of cell-of origin in patients with relapsed DLBCL. The addition of 90YIT does not confer a further survival benefit. Clin Cancer Res; 24(10); 2304-11. (c)2018 AACR. PMID- 29476022 TI - Introducing a New Series: Immunotherapy Facts and Hopes. PMID- 29476023 TI - Genomic-Enabled Prediction Kernel Models with Random Intercepts for Multi environment Trials. AB - In this study, we compared the prediction accuracy of the main genotypic effect model (MM) without G*E interactions, the multi-environment single variance G*E deviation model (MDs), and the multi-environment environment-specific variance G*E deviation model (MDe) where the random genetic effects of the lines are modeled with the markers (or pedigree). With the objective of further modeling the genetic residual of the lines, we incorporated the random intercepts of the lines ([Formula: see text]) and generated another three models. Each of these 6 models were fitted with a linear kernel method (Genomic Best Linear Unbiased Predictor, GB) and a Gaussian Kernel (GK) method. We compared these 12 model method combinations with another two multi-environment G*E interactions models with unstructured variance-covariances (MUC) using GB and GK kernels (4 model method). Thus, we compared the genomic-enabled prediction accuracy of a total of 16 model-method combinations on two maize data sets with positive phenotypic correlations among environments, and on two wheat data sets with complex G*E that includes some negative and close to zero phenotypic correlations among environments. The two models (MDs and MDE with the random intercept of the lines and the GK method) were computationally efficient and gave high prediction accuracy in the two maize data sets. Regarding the more complex G*E wheat data sets, the prediction accuracy of the model-method combination with G*E, MDs and MDe, including the random intercepts of the lines with GK method had important savings in computing time as compared with the G*E interaction multi-environment models with unstructured variance-covariances but with lower genomic prediction accuracy. PMID- 29476025 TI - Protocol for the health economic evaluation of increasing the weekend specialist to patient ratio in hospitals in England. AB - INTRODUCTION: This protocol concerns the evaluation of increased specialist staffing at weekends in hospitals in England. Seven-day health services are a key policy for the UK government and other health systems trying to improve use of infrastructure and resources. A particular motivation for the 7-day policy has been the observed increase in the risk of death associated with weekend admission, which has been attributed to fewer hospital specialists being available at weekends. However, the causes of the weekend effect have not been adequately characterised; many of the excess deaths associated with the 'weekend effect' may not be preventable, and the presumed benefits of improved specialist cover might be offset by the cost of implementation. METHODS/DESIGN: The Bayesian founded method we propose will consist of four major steps. First, the development of a qualitative causal model. Specialist presence can affect multiple, interacting causal processes. One or more models will be developed from the results of an expert elicitation workshop and probabilities elicited for each model and relevant model parameters. Second, systematic review of the literature. The model from the first step will provide search limits for a review to identify relevant studies. Third, a statistical model for the effects of specialist presence on care quality and patient outcomes. Fourth, valuation of outcomes. The expected net benefits of different levels of specialist intensity will then be evaluated with respect to the posterior distributions of the parameters. ETHICS AND DISSEMINATION: The study was approved by the Review Subcommittee of the South West Wales REC on 11 November 2013. Informed consent was not required for accessing anonymised patient case records from which patient identifiers had been removed. The findings of this study will be published in peer-reviewed journals; the outputs from this research will also form part of the project report to the HS&DR Programme Board. PMID- 29476024 TI - Targeted Long-Read Sequencing of a Locus Under Long-Term Balancing Selection in Capsella. AB - Rapid advances in short-read DNA sequencing technologies have revolutionized population genomic studies, but there are genomic regions where this technology reaches its limits. Limitations mostly arise due to the difficulties in assembly or alignment to genomic regions of high sequence divergence and high repeat content, which are typical characteristics for loci under strong long-term balancing selection. Studying genetic diversity at such loci therefore remains challenging. Here, we investigate the feasibility and error rates associated with targeted long-read sequencing of a locus under balancing selection. For this purpose, we generated bacterial artificial chromosomes (BACs) containing the Brassicaceae S-locus, a region under strong negative frequency-dependent selection which has previously proven difficult to assemble in its entirety using short reads. We sequence S-locus BACs with single-molecule long-read sequencing technology and conduct de novo assembly of these S-locus haplotypes. By comparing repeated assemblies resulting from independent long-read sequencing runs on the same BAC clone we do not detect any structural errors, suggesting that reliable assemblies are generated, but we estimate an indel error rate of 5.7*10-5 A similar error rate was estimated based on comparison of Illumina short-read sequences and BAC assemblies. Our results show that, until de novo assembly of multiple individuals using long-read sequencing becomes feasible, targeted long read sequencing of loci under balancing selection is a viable option with low error rates for single nucleotide polymorphisms or structural variation. We further find that short-read sequencing is a valuable complement, allowing correction of the relatively high rate of indel errors that result from this approach. PMID- 29476026 TI - Racial/ethnic heterogeneity in associations of blood pressure and incident cardiovascular disease by functional status in a prospective cohort: the Multi Ethnic Study of Atherosclerosis. AB - OBJECTIVES: Research has demonstrated that the association between high blood pressure and outcomes is attenuated among older adults with functional limitations, compared with healthier elders. However, it is not known whether these patterns vary by racial/ethnic group. We evaluated race/ethnicity-specific patterns of effect modification in the association between blood pressure and incident cardiovascular disease (CVD) by functional status. SETTING: We used data from the Multi-Ethnic Study of Atherosclerosis (2002-2004, with an average of 8.8 years of follow-up for incident CVD). We assessed effect modification of systolic blood pressure and cardiovascular outcomes by self-reported physical limitations and by age. PARTICIPANTS: The study included 6117 participants (aged 46 to 87; 40% white, 27% black, 22% Hispanic and 12% Chinese) who did not have CVD at the second study examination (when self-reported physical limitations were assessed). OUTCOME MEASURES: Incident CVD was defined as an incident myocardial infarction, coronary revascularisation, resuscitated cardiac arrest, angina, stroke (fatal or non-fatal) or death from CVD. RESULTS: We observed weaker associations between systolic blood pressure (SBP) and CVD among white adults with physical limitations (incident rate ratio (IRR) per 10 mm Hg higher SBP: 1.09 (95% CI 0.99 to 1.20)) than those without physical limitations (IRR 1.29 (1.19, 1.40); P value for interaction <0.01). We found a similar pattern among black adults. Poor precision among the estimates for Hispanic or Chinese participants limited the findings in these groups. The attenuated associations were consistent across both multiplicative and additive scales, though physical limitations showed clearer patterns than age on an additive scale. CONCLUSION: Attenuated associations between high blood pressure and incident CVD were observed for blacks and whites with poor function, though small sample sizes remain a limitation for identifying differences among Hispanic or Chinese participants. Identifying the characteristics that distinguish those in whom higher SBP is associated with less risk of morbidity or mortality may inform our understanding of the consequences of hypertension among older adults. PMID- 29476027 TI - Sex differences in presenting symptoms of acute coronary syndrome: the EPIHeart cohort study. AB - OBJECTIVES: Prompt diagnosis of acute coronary syndrome (ACS) remains a challenge, with presenting symptoms affecting the diagnosis algorithm and, consequently, management and outcomes. This study aimed to identify sex differences in presenting symptoms of ACS. DESIGN: Data were collected within a prospective cohort study (EPIHeart). SETTING: Patients with confirmed diagnosis of type 1 (primary spontaneous) ACS who were consecutively admitted to the Cardiology Department of two tertiary hospitals in Portugal between August 2013 and December 2014. PARTICIPANTS: Presenting symptoms of 873 patients (227 women) were obtained through a face-to-face interview. OUTCOME MEASURES: Typical pain was defined according to the definition of cardiology societies. Clusters of symptoms other than pain were identified by latent class analysis. Logistic regression was used to quantify differences in presentation of ACS symptoms by sex. RESULTS: Chest pain was reported by 82% of patients, with no differences in frequency or location between sexes. Women were more likely to feel pain with an intensity higher than 8/10 and this association was stronger for patients aged under 65 years (interaction P=0.028). Referred pain was also more likely in women, particularly pain referred to typical and atypical locations simultaneously. The multiple symptoms cluster, which was characterised by a high probability of presenting with all symptoms, was almost fourfold more prevalent in women (3.92, 95% CI 2.21 to 6.98). Presentation with this cluster was associated with a higher 30-day mortality rate adjusted for the GRACE V.2.0 risk score (4.9% vs 0.9% for the two other clusters, P<0.001). CONCLUSIONS: While there are no significant differences in the frequency or location of pain between sexes, women are more likely to feel pain of higher intensity and to present with referred pain and symptoms other than pain. Knowledge of these ACS presentation profiles is important for health policy decisions and clinical practice. PMID- 29476028 TI - Long-term incidence trends of HPV-related cancers, and cases preventable by HPV vaccination: a registry-based study in Norway. AB - OBJECTIVES: Examine long-term incidence trends of human papillomavirus (HPV) related cancer in Norway, and estimate the number of cancer cases preventable by vaccines against HPV 16/18 or HPV 16/18/31/33/45/52/58. DESIGN: Observational registry-based study. We extracted incident cases of HPV-related cancer during 1953-2015 from the Cancer Registry of Norway. Tumour HPV prevalence estimates from large international meta-analyses or from Norway were used to estimate the protective potential of HPV vaccines. PARTICIPANTS AND SETTING: The Norwegian population. PRIMARY OUTCOME MEASURES: Incidence trend analyses during 1953-2015 for squamous cell carcinoma (SCC) of the cervix, vulva, vagina, oropharynx, anus and penis, and adenocarcinoma of the cervix. Additionally, the number of cancer cases preventable by HPV vaccination. RESULTS: Among women, incidences of SCC of the anus, oropharynx, vulva and cervical adenocarcinoma increased, while vaginal SCC showed no trend. For these cancers combined, the average annual percentage change (AAPC) during 1953-2015 was 1.2 (95% CI 0.7 to 1.6). The incidence of cervical SCC generally decreased during 1976-2004 and remained stable thereafter. Among men, incidences of SCC of the anus, oropharynx and penis increased. The AAPC during 1953-2015 combined for all male HPV-related cancer was 1.9 (95% CI 1.3 to 2.5). A vaccine against HPV 16/18 might yearly prevent 402 (95% CI 382 to 420) cancers. A vaccine against HPV 16/18/31/33/45/52/58 might yearly prevent 478 (95% CI 464 to 490) cancers, of which 206 (95% CI 202 to 209) occur in non cervical organs, and 113 (95% CI 110 to 115) occur among men. CONCLUSIONS: The incidences of HPV-related cancers that are not effectively prevented by screening have generally increased during 1953-2015. HPV vaccination can prevent a substantial number of cancers in Norway, in cervical and non-cervical organs, among women and men. PMID- 29476029 TI - OpenPrescribing: normalised data and software tool to research trends in English NHS primary care prescribing 1998-2016. AB - OBJECTIVES: We aimed to compile and normalise England's national prescribing data for 1998-2016 to facilitate research on long-term time trends and create an open data exploration tool for wider use. DESIGN: We compiled data from each individual year's national statistical publications and normalised them by mapping each drug to its current classification within the national formulary where possible. We created a freely accessible, interactive web tool to allow anyone to interact with the processed data. SETTING AND PARTICIPANTS: We downloaded all available annual prescription cost analysis datasets, which include cost and quantity for all prescription items dispensed in the community in England. Medical devices and appliances were excluded. PRIMARY AND SECONDARY OUTCOME MEASURES: We measured the extent of normalisation of data and aimed to produce a functioning accessible analysis tool. RESULTS: All data were imported successfully. 87.5% of drugs were matched exactly on name to the current formulary and a further 6.5% to similar drug names. All drugs in core clinical chapters were reconciled to their current location in the data schema, with only 1.26% of drugs not assigned a current chemical code. We created an openly accessible interactive tool to facilitate wider use of these data. CONCLUSIONS: Publicly available data can be made accessible through interactive online tools to help researchers and policy-makers explore time trends in prescribing. PMID- 29476030 TI - Does macrolide use confer risk of out-of-hospital cardiac arrest compared with penicillin V? A Danish national case-crossover and case-time-control study. AB - INTRODUCTION AND OBJECTIVES: Macrolides have been associated with proarrhythmic properties, but the evidence is conflicting. We evaluated the risk of out-of hospital cardiac arrest (OHCA) associated with specific macrolides in a retrospective study. Associations between specific macrolides and OHCA were examined by conditional logistic regression analyses in case-crossover and case time-control models, using penicillin-V treatment as the comparative reference. From nationwide registries, we identified all OHCAs in Denmark from 2001 to 2010 and use of antibiotics. ETHICS: The present study was approved by the Danish Data Protection Agency (Danish Data Protection Agency (ref.no. 2007-58-0015, local ref.no. GEH-2014-017, (I-Suite.nr. 02 735)). PARTICIPANTS: We identified 29 111 patients with an OHCA. Of these, 514 were in macrolide treatment <=7 days before OHCA and 1237 in penicillin-V treatment. RESULTS: In the case-crossover analyses, overall macrolide use was not associated with OHCA with penicillin V as negative comparative reference (OR=0.90; 95% CI 0.73 to 1.10). Compared with penicillin-V treatment, specific macrolides were not associated with increased risk of OHCA: roxithromycin (OR=0.97; 95% CI 0.74 to 1.26), erythromycin (OR=0.68; 95% CI 0.44 to 1.06), clarithromycin (OR=0.95; 95% CI 0.61 to 1.48) and azithromycin (OR=0.85; 95% CI 0.57 to 1.27).Similar results were obtained using case-time control models: overall macrolide use (OR=0.81; 95% CI 0.62 to 1.06) and specific macrolides (roxithromycin (OR=0.70; 95% CI 0.49 to 1.00), erythromycin (OR=0.67; 95% CI 0.38 to 1.18), clarithromycin (OR=0.75; 95% CI 0.41 to 1.39) or azithromycin (OR=1.17; 95% CI 0.70 to 1.95)). CONCLUSION: The risk of OHCA during treatment with macrolides was similar to that of penicillin V, suggesting no additional risk of OHCA associated with macrolides. PMID- 29476031 TI - Characteristics, consequences and prevention of falls in institutionalised older adults in the province of Malaga (Spain): a prospective, cohort, multicentre study. AB - OBJECTIVES: Falls are an important adverse event among institutionalised persons. It is in this clinical setting where falls occur more frequently than in any other, despite the measures commonly taken to prevent them. This study aimed to determine the characteristics of a typical institutionalised elderly patient who suffers a fall and to describe the physical harms resulting from this event. We then examined the association between falls and the preventive measures used. METHODS: This was a prospective cohort study in 37 nursing homes in Spain. The participants were all the nursing home residents institutionalised in these centres from May 2014 to July 2016. Participants were followed up for 9 months. During this period, two observations were made to evaluate the preventive measures taken and to record the occurrence of falls. RESULTS: 896 residents were recruited, of whom 647 completed the study. During this period, 411 falls took place, affecting 213 residents. The injuries caused by the falls were mostly minor or moderate. They took place more frequently among women and provoked 22 fractures (5.35%). The most commonly used fall prevention measure was bed rails (53.53% of cases), followed by physical restraint (16.79%). The latter measure was associated with a higher incidence of injuries not requiring stitches (OR=2.06, 95% CI 1.01 to 4.22, P=0.054) and of injuries that did require stitches (OR=3.51, 95% CI 1.36 to 9.01, P=0.014) as a consequence of falls. Bed rails protected against night-time falls. CONCLUSIONS: Falls are a very common adverse event in nursing homes. The prevention of falls is most commonly addressed by methods to restrain movement. The use of physical restraints is associated with a greater occurrence of injuries caused by a fall. PMID- 29476032 TI - Evaluation of metrics for benchmarking antimicrobial use in the UK dairy industry. AB - The issue of antimicrobial resistance is of global concern across human and animal health. In 2016, the UK government committed to new targets for reducing antimicrobial use (AMU) in livestock. Although a number of metrics for quantifying AMU are defined in the literature, all give slightly different interpretations. This paper evaluates a selection of metrics for AMU in the dairy industry: total mg, total mg/kg, daily dose and daily course metrics. Although the focus is on their application to the dairy industry, the metrics and issues discussed are relevant across livestock sectors. In order to be used widely, a metric should be understandable and relevant to the veterinarians and farmers who are prescribing and using antimicrobials. This means that clear methods, assumptions (and possible biases), standardised values and exceptions should be published for all metrics. Particularly relevant are assumptions around the number and weight of cattle at risk of treatment and definitions of dose rates and course lengths; incorrect assumptions can mean metrics over-represent or under-represent AMU. The authors recommend that the UK dairy industry work towards the UK-specific metrics using the UK-specific medicine dose and course regimens as well as cattle weights in order to monitor trends nationally. PMID- 29476034 TI - No handshake agreement on postural tremor subtypes in Parkinson disease? PMID- 29476033 TI - Midlife insulin resistance, APOE genotype, and late-life brain amyloid accumulation. AB - OBJECTIVE: To examine whether midlife insulin resistance is an independent risk factor for brain amyloid accumulation in vivo after 15 years, and whether this risk is modulated by APOE epsilon4 genotype. METHODS: This observational study examined 60 elderly volunteers without dementia (mean age at baseline 55.4 and at follow-up 70.9 years, 55.5% women) from the Finnish population-based, nationwide Health2000 study with [11C]Pittsburgh compound B-PET imaging in 2014-2016. The participants were recruited according to their homeostatic model assessment of insulin resistance (HOMA-IR) values in the year 2000, and their APOE epsilon4 genotype. The exposure group (IR+, n = 30) consisted of individuals with HOMA-IR >2.17 at baseline (highest tertile of the Health2000 study population), and the control group (IR-, n = 30) consisted of individuals with HOMA-IR <1.25 at baseline (lowest tertile). The groups were enriched for APOE epsilon4 carriers, resulting in 50% (n = 15) APOE epsilon4 carriers in both groups. Analyses were performed with multivariate logistic and linear regression. RESULTS: An amyloid positive PET scan was found in 33.3% of the IR- group and 60.0% of the IR+ group (odds ratio 3.0, 95% confidence interval 1.1-8.9, p = 0.04). The increased risk was seen in carriers and noncarriers of APOE epsilon4 genotype. Higher midlife, but not late-life continuous HOMA-IR was associated with a greater brain amyloid burden at follow-up after multivariate adjustments for other cognitive and metabolic risk factors (beta = 0.11, 95% confidence interval 0.002-0.22, p = 0.04). CONCLUSIONS: These results indicate that midlife insulin resistance is an independent risk factor for brain amyloid accumulation in elderly individuals without dementia. PMID- 29476035 TI - Stem cell injection-induced glioneuronal lesion of the cauda equina. PMID- 29476036 TI - Comment: Has the relationship between ADHD medications and seizures been settled? PMID- 29476037 TI - Attention-deficit/hyperactivity disorder medication and seizures. AB - OBJECTIVE: Individuals with attention-deficit/hyperactivity disorder (ADHD) are at increased risk of seizures, but there is uncertainty about whether ADHD medication treatment increases risk among patients with and without preexisting seizures. METHODS: We followed a sample of 801,838 patients with ADHD who had prescribed drug claims from the Truven Health MarketScan Commercial Claims and Encounters databases to examine whether ADHD medication increases the likelihood of seizures among ADHD patients with and without a history of seizures. First, we assessed overall risk of seizures among patients with ADHD. Second, within individual concurrent analyses assessed odds of seizure events during months when a patient with ADHD received ADHD medication compared with when the same individual did not, while adjusting for antiepileptic medications. Third, within individual long-term analyses examined odds of seizure events in relation to the duration of months over the previous 2 years patients received medication. RESULTS: Patients with ADHD were at higher odds for any seizure compared with non ADHD controls (odds ratio [OR] = 2.33, 95% confidence interval [CI] = 2.24-2.42 males; OR = 2.31, 95% CI = 2.22-2.42 females). In adjusted within-individual comparisons, ADHD medication was associated with lower odds of seizures among patients with (OR = 0.71, 95% CI = 0.60-0.85) and without (OR = 0.71, 95% CI = 0.62-0.82) prior seizures. Long-term within-individual comparisons suggested no evidence of an association between medication use and seizures among individuals with (OR = 0.87, 95% CI = 0.59-1.30) and without (OR = 1.01, 95% CI = 0.80-1.28) a seizure history. CONCLUSIONS: Results reaffirm that patients with ADHD are at higher risk of seizures. However, ADHD medication was associated with lower risk of seizures within individuals while they were dispensed medication, which is not consistent with the hypothesis that ADHD medication increases risk of seizures. PMID- 29476038 TI - The nature of postural tremor in Parkinson disease. AB - OBJECTIVE: To disentangle the different forms of postural tremors in Parkinson disease (PD). METHODS: In this combined observational and intervention study, we measured resting and postural tremor characteristics in 73 patients with tremulous PD by using EMG of forearm muscles. Patients were measured both "off" medication (overnight withdrawal) and after dispersible levodopa-benserazide 200/50 mg. We performed an automated 2-step cluster analysis on 3 postural tremor characteristics: the frequency difference with resting tremor, the degree of tremor suppression after posturing, and the dopamine response. RESULTS: The cluster analysis revealed 2 distinct postural tremor phenotypes: 81% had re emergent tremor (amplitude suppression, frequency difference with resting tremor 0.4 Hz, clear dopamine response) and 19% had pure postural tremor (no amplitude suppression, frequency difference with resting tremor 3.5 Hz, no dopamine response). This finding was manually validated (accuracy of 93%). Pure postural tremor was not associated with clinical signs of essential tremor or dystonia, and it was not influenced by weighing. CONCLUSION: There are 2 distinct postural tremor phenotypes in PD, which have a different pathophysiology and require different treatment. Re-emergent tremor is a continuation of resting tremor during stable posturing, and it has a dopaminergic basis. Pure postural tremor is a less common type of tremor that is inherent to PD, but has a largely nondopaminergic basis. PMID- 29476039 TI - Estrogen-induced inhibition of spermatogenesis in zebrafish is largely reversed by androgen. AB - The hormonal regulation of spermatogenesis involves both gonadotropins and steroid hormones. Long-term in vivo exposure of adult zebrafish to estrogen impaired spermatogenesis associated with an androgen insufficiency, possibly induced by inhibiting gonadotropin release. Using this experimental model, we investigated if androgen treatment could enhance spermatogenesis, while maintaining the inhibition of gonadotropin release through continued estrogen exposure. Moreover, we also exposed animals to androgen alone, in order to examine androgen effects in the absence of estrogen-induced gonadotropin inhibition. Estrogen exposure depleted type B spermatogonia, meiotic and postmeiotic germ cells from the adult testis, but promoted the proliferation of type A undifferentiated spermatogonia, which accumulated in the testis. This change in germ cell composition was accompanied by reduced mRNA levels of those growth factors (e.g. insl3 and igf3) expressed by testicular somatic cells and known to stimulate spermatogonial differentiation in zebrafish. Additional androgen (11-ketoandrostenedione, which is converted to 11-ketotestosterone) treatment in vivo reversed most of the effects of estrogen exposure on spermatogenesis while insl3 and igf3 transcript levels remained suppressed. When androgen treatment was given alone, it promoted the production of haploid cells at the expense of spermatogonia, and increased transcript levels of some growth factor and hormone receptor genes, but not those of insl3 or igf3 We conclude that estrogen exposure efficiently inhibits spermatogenesis because it induces androgen insufficiency and suppresses gonadotropin-regulated growth factors known to stimulate germ cell differentiation. Moreover, our results suggest that androgens and the growth factors Insl3 and Igf3 stimulate spermatogenesis via independent pathways. PMID- 29476040 TI - Hemodynamic Effects of Glutathione-Liganded Binuclear Dinitrosyl Iron Complex: Evidence for Nitroxyl Generation and Modulation by Plasma Albumin. AB - Glutathione-liganded binuclear dinitrosyl iron complex (glut-BDNIC) has been proposed to be a donor of nitric oxide (NO). This study was undertaken to investigate the mechanisms of vasoactivity, systemic hemodynamic effects, and pharmacokinetics of glut-BDNIC. To test the hypothesis that glut-BDNICs vasodilate by releasing NO in its reduced [nitroxyl (HNO)] state, a bioassay method of isolated, preconstricted ovine mesenteric arterial rings was used in the presence of selective scavengers of HNO or NO free radical (NO*); the vasodilatory effects of glut-BDNIC were found to have characteristics similar to those of an HNO donor and markedly different than an NO* donor. In addition, products of the reaction of glut-BDNIC with CPTIO [2-(4-carboxyphenyl)-4,4,5 tetramethyl imidazoline-1-oxyl-3-oxide] were found to have electron paramagnetic characteristics similar to those of an HNO donor compared with an NO* donor. In contrast to S-nitroso-glutathione, which was vasodilative both in vitro and in vivo, the potency of glut-BDNIC-mediated vasodilation was markedly diminished in both rats and sheep. Wire myography showed that plasma albumin contributed to this loss of hypotensive effects, an effect abolished by modification of the cysteine-thiol residue of albumin. High doses of glut-BDNIC caused long-lasting hypotension in rats that can be at least partially attributed to its long circulating half-life of ~44 minutes. This study suggests that glut-BDNIC is an HNO donor, and that its vasoactive effects are modulated by binding to the cysteine residue of plasma proteins, such as albumin. PMID- 29476041 TI - CYP26C1 Is a Hydroxylase of Multiple Active Retinoids and Interacts with Cellular Retinoic Acid Binding Proteins. AB - The clearance of retinoic acid (RA) and its metabolites is believed to be regulated by the CYP26 enzymes, but the specific roles of CYP26A1, CYP26B1, and CYP26C1 in clearing active vitamin A metabolites have not been defined. The goal of this study was to establish the substrate specificity of CYP26C1, and determine whether CYP26C1 interacts with cellular retinoic acid binding proteins (CRABPs). CYP26C1 was found to effectively metabolize all-trans retinoic acid (atRA), 9-cis-retinoic acid (9-cis-RA), 13-cis-retinoic acid, and 4-oxo-atRA with the highest intrinsic clearance toward 9-cis-RA. In comparison with CYP26A1 and CYP26B1, CYP26C1 resulted in a different metabolite profile for retinoids, suggesting differences in the active-site structure of CYP26C1 compared with other CYP26s. Homology modeling of CYP26C1 suggested that this is attributable to the distinct binding orientation of retinoids within the CYP26C1 active site. In comparison with other CYP26 family members, CYP26C1 was up to 10-fold more efficient in clearing 4-oxo-atRA (intrinsic clearance 153 MUl/min/pmol) than CYP26A1 and CYP26B1, suggesting that CYP26C1 may be important in clearing this active retinoid. In support of this, CRABPs delivered 4-oxo-atRA and atRA for metabolism by CYP26C1. Despite the tight binding of 4-oxo-atRA and atRA with CRABPs, the apparent Michaelis-Menten constant in biological matrix (Km) value of these substrates with CYP26C1 was not increased when the substrates were bound with CRABPs, in contrast to what is predicted by free drug hypothesis. Together these findings suggest that CYP26C1 is a 4-oxo-atRA hydroxylase and may be important in regulating the concentrations of this active retinoid in human tissues. PMID- 29476043 TI - Targeting Epigenetics to Prevent Obesity Promoted Cancers. AB - Epigenetic changes in DNA and associated chromatin proteins are increasingly being considered as important mediators of the linkage between obesity and cancer. Although multiple agents, targeted at epigenetic changes, are being tested for therapy of established cancers, this issue of Cancer Prevention Research carries two articles demonstrating that the bromodomain inhibitor I-BET 762 can attenuate adipose tissue-promoted cancers. Although I-BET-762 significantly delayed, rather than completely prevented, the onset of adiposity promoted transformation and malignancy, these experiments provide important proof of principle for the strategies of targeting epigenetic changes to disrupt the obesity-cancer linkage. Because bromodomain proteins represent only one of multiple epigenetic mediators, it is probable that targeting other epigenetic processes, alone or in combination, may serve to even more effectively disrupt the obesity promotion of cancer. Given the magnitude of the current obesity pandemic and its impact on cancer, preventive measures to disrupt this linkage are critically important. Cancer Prev Res; 11(3); 125-8. (c)2018 AACRSee related article by Chakraborty et al., p. 129. PMID- 29476042 TI - Gedunin- and Khivorin-Derivatives Are Small-Molecule Partial Agonists for Adhesion G Protein-Coupled Receptors GPR56/ADGRG1 and GPR114/ADGRG5. AB - Adhesion G protein-coupled receptors (aGPCRs) have emerged as potential therapeutic targets in multiple cancers and in neurologic diseases. However, there are few modulatory compounds that act on these receptors. The majority of aGPCRs are orphans and a general activation mechanism has only recently been defined: aGPCRs are activated by a tethered agonist. aGPCRs constitutively cleave themselves during biosynthesis to generated two-part receptors comprising an extracellular domain (ECD) and a 7-transmembrane spanning domain (7TM). ECD dissociation reveals the tethered agonist initiating G protein signaling. Synthetic peptides that mimic the tethered agonist region can activate aGPCRs. We hypothesized that small molecules could act in the same way as peptide agonists. High throughput screening of the 2000-compound Spectrum Collection library using the serum response element luciferase gene reporter assay revealed two related classes of small molecules that could activate the aGPCR GPR56/ADGRG1. The most potent compound identified was 3-alpha-acetoxydihydrodeoxygedunin, or 3-alpha DOG. 3-alpha-DOG activated engineered, low-activity GPR56 7TM in independent biochemical and cell-based assays with an EC50 of ~5 MUM. The compound also activated a subset of aGPCRs but not two class A GPCRs tested. The mode of 3 alpha-DOG-mediated receptor activation is that of partial agonist. 3-alpha-DOG activated GPR56 less efficaciously than peptide agonist and could antagonize both the peptide agonist and the endogenous tethered agonist, which are pharmacological hallmarks of partial agonists. Taken together, we have uncovered a novel group of aGPCR partial agonists that will serve as invaluable resources for understanding this unique class receptors. PMID- 29476044 TI - Antiretroviral Drug Metabolism in Humanized PXR-CAR-CYP3A-NOG Mice. AB - Antiretroviral drug (ARV) metabolism is linked largely to hepatic cytochrome P450 activity. One ARV drug class known to be metabolized by intestinal and hepatic CYP3A are the protease inhibitors (PIs). Plasma drug concentrations are boosted by CYP3A inhibitors such as cobisistat and ritonavir (RTV). Studies of such drug drug interactions are limited since the enzyme pathways are human specific. While immune-deficient mice reconstituted with human cells are an excellent model to study ARVs during human immunodeficiency virus type 1 (HIV-1) infection, they cannot reflect human drug metabolism. Thus, we created a mouse strain with the human pregnane X receptor, constitutive androstane receptor, and CYP3A4/7 genes on a NOD.Cg-Prkdcscid Il2rgtm1Sug /JicTac background (hCYP3A-NOG) and used them to evaluate the impact of human CYP3A metabolism on ARV pharmacokinetics. In proof-of-concept studies we used nanoformulated atazanavir (nanoATV) with or without RTV. NOG and hCYP3A-NOG mice were treated weekly with 50 mg/kg nanoATV alone or boosted with nanoformulated ritonavir (nanoATV/r). Plasma was collected weekly and liver was collected at 28 days post-treatment. Plasma and liver atazanavir (ATV) concentrations in nanoATV/r-treated hCYP3A-NOG mice were 2- to 4 fold higher than in replicate NOG mice. RTV enhanced plasma and liver ATV concentrations 3-fold in hCYP3A-NOG mice and 1.7-fold in NOG mice. The results indicate that human CYP3A-mediated drug metabolism is reduced compared with mouse and that RTV differentially affects human gene activity. These differences can affect responses to PIs in humanized mouse models of HIV-1 infection. Importantly, hCYP3A-NOG mice reconstituted with human immune cells can be used for bench-to-bedside translation. PMID- 29476046 TI - Prognostic Significance of Zinc Finger E-Box-Binding Homeobox Family in Glioblastoma. AB - BACKGROUND Epithelial-mesenchymal transition (EMT) is an essential progress for tumor cell invasion to both epithelial and non-epithelial cancers, and zinc finger E-box-binding homeobox 1/2 (ZEB1/2) is a well-known promoter of EMT. In glioma cell lines, both ZEB1 and ZEB2 have been demonstrated to facilitate cancer cell proliferation and invasion with experiments in vitro. However, the clinical significance of ZEB1 and ZEB2 in glioblastoma (GBM) is still controversial. MATERIAL AND METHODS We detected the expression of ZEB1 and ZEB2 in 91 cases of GBM with immunohistochemistry and investigated the correlation between clinicopathological factors and ZEB family expression with Fisher test. By univariate analysis with Kaplan-Meier test, we explored the prognostic significance of ZEB1/2 expression and the clinicopathological factors in GBM. By multivariate analysis with the Cox regression model, we identified the independent prognostic factors in GBM. RESULTS The percentages of ZEB1 high expression and ZEB2 high expression were 31.9% (29/91) and 41.9% (36/91), respectively. High expression of ZEB2 was significantly associated with lower survival rate of GBM patients (P=0.001). ZEB2, lower KPS score (P=0.004), gross total resection (P<0.001) and higher Ki67 percentage (P=0.001) were notably correlated to worse prognosis of GBM. With multivariate analysis, high expression of ZEB2 was demonstrated to be an independent prognostic factor indicating unfavorable prognosis of GBM (P=0.001, HR=3.86, and 95%CI=1.61-9.23). CONCLUSIONS High expression of ZEB2 is an independent prognostic factor predicting unfavorable prognosis of GBM, indicating that ZEB2 or its downstream proteins may be potential drug targets of GBM therapy. PMID- 29476045 TI - Heart rate variability as predictive factor for sudden cardiac death. AB - Sudden cardiac death (SCD) represents about 25% of deaths in clinical cardiology. The identification of risk factors for SCD is the philosopher's stone of cardiology and the identification of non-invasive markers of risk of SCD remains one of the most important goals for the scientific community.The aim of this review is to analyze the state of the art around the heart rate variability (HRV) as a predictor factor for SCD.HRV is probably the most analyzed index in cardiovascular risk stratification technical literature, therefore an important number of models and methods have been developed.Nowadays, low HRV has been shown to be independently predictive of increased mortality in post- myocardial infarction patients, heart failure patients, in contrast with the data of the general population.Contrariwise, the relationship between HRV and SCD has received scarce attention in low-risk cohorts. Furthermore, in general population the attributable risk is modest and the cost/benefit ratio is not always convenient.The HRV evaluation could become an important tool for health status in risks population, even though the use of HRV alone for risk stratification of SCD is limited and further studies are needed. PMID- 29476047 TI - Correlating chemical diversity with taxonomic distance for discovery of natural products in myxobacteria. AB - Some bacterial clades are important sources of novel bioactive natural products. Estimating the magnitude of chemical diversity available from such a resource is complicated by issues including cultivability, isolation bias and limited analytical data sets. Here we perform a systematic metabolite survey of ~2300 bacterial strains of the order Myxococcales, a well-established source of natural products, using mass spectrometry. Our analysis encompasses both known and previously unidentified metabolites detected under laboratory cultivation conditions, thereby enabling large-scale comparison of production profiles in relation to myxobacterial taxonomy. We find a correlation between taxonomic distance and the production of distinct secondary metabolite families, further supporting the idea that the chances of discovering novel metabolites are greater by examining strains from new genera rather than additional representatives within the same genus. In addition, we report the discovery and structure elucidation of rowithocin, a myxobacterial secondary metabolite featuring an uncommon phosphorylated polyketide scaffold. PMID- 29476048 TI - Molecular demultiplexer as a terminator automaton. AB - Molecular logic gates are expected to play an important role on the way to information processing therapeutic agents, especially considering the wide variety of physical and chemical responses that they can elicit in response to the inputs applied. Here, we show that a 1:2 demultiplexer based on a Zn2+ terpyridine-Bodipy conjugate with a quenched fluorescent emission, is efficient in photosensitized singlet oxygen generation as inferred from trap compound experiments and cell culture data. However, once the singlet oxygen generated by photosensitization triggers apoptotic response, the Zn2+ complex then interacts with the exposed phosphatidylserine lipids in the external leaflet of the membrane bilayer, autonomously switching off singlet oxygen generation, and simultaneously switching on a bright emission response. This is the confirmatory signal of the cancer cell death by the action of molecular automaton and the confinement of unintended damage by excessive singlet oxygen production. PMID- 29476049 TI - Vps3 and Vps8 control integrin trafficking from early to recycling endosomes and regulate integrin-dependent functions. AB - Recycling endosomes maintain plasma membrane homeostasis and are important for cell polarity, migration, and cytokinesis. Yet, the molecular machineries that drive endocytic recycling remain largely unclear. The CORVET complex is a multi subunit tether required for fusion between early endosomes. Here we show that the CORVET-specific subunits Vps3 and Vps8 also regulate vesicular transport from early to recycling endosomes. Vps3 and Vps8 localise to Rab4-positive recycling vesicles and co-localise with the CHEVI complex on Rab11-positive recycling endosomes. Depletion of Vps3 or Vps8 does not affect transferrin recycling, but delays the delivery of internalised integrins to recycling endosomes and their subsequent return to the plasma membrane. Consequently, Vps3/8 depletion results in defects in integrin-dependent cell adhesion and spreading, focal adhesion formation, and cell migration. These data reveal a role for Vps3 and Vps8 in a specialised recycling pathway important for integrin trafficking. PMID- 29476050 TI - Bounding cross-shelf transport time and degradation in Siberian-Arctic land-ocean carbon transfer. AB - The burial of terrestrial organic carbon (terrOC) in marine sediments contributes to the regulation of atmospheric CO2 on geological timescales and may mitigate positive feedback to present-day climate warming. However, the fate of terrOC in marine settings is debated, with uncertainties regarding its degradation during transport. Here, we employ compound-specific radiocarbon analyses of terrestrial biomarkers to determine cross-shelf transport times. For the World's largest marginal sea, the East Siberian Arctic shelf, transport requires 3600 +/- 300 years for the 600 km from the Lena River to the Laptev Sea shelf edge. TerrOC was reduced by ~85% during transit resulting in a degradation rate constant of 2.4 +/ 0.6 kyr-1. Hence, terrOC degradation during cross-shelf transport constitutes a carbon source to the atmosphere over millennial time. For the contemporary carbon cycle on the other hand, slow terrOC degradation brings considerable attenuation of the decadal-centennial permafrost carbon-climate feedback caused by global warming. PMID- 29476051 TI - CASC2/miR-24/miR-221 modulates the TRAIL resistance of hepatocellular carcinoma cell through caspase-8/caspase-3. AB - Hepatocellular carcinoma is one of the most common solid tumors in the digestive system. The prognosis of patients with hepatocellular carcinoma is still poor due to the acquisition of multi-drug resistance. TNF Related Apoptosis Inducing Ligand (TRAIL), an attractive anticancer agent, exerts its effect of selectively inducing apoptosis in tumor cells through death receptors and the formation of the downstream death-inducing signaling complex, which activates apical caspases 3/8 and leads to apoptosis. However, hepatocellular carcinoma cells are resistant to TRAIL. Non-coding RNAs, including long non-coding RNAs (lncRNAs) and miRNAs have been regarded as major regulators of normal development and diseases, including cancers. Moreover, lncRNAs and miRNAs have been reported to be associated with multi-drug resistance. In the present study, we investigated the mechanism by which TRAIL resistance of hepatocellular carcinoma is affected from the view of non-coding RNA regulation. We selected and validated candidate miRNAs, miR-24 and miR-221, that regulated caspase 3/8 expression through direct targeting, and thereby affecting TRAIL-induced tumor cell apoptosis TRAIL resistance of hepatocellular carcinoma. In addition, we revealed that CASC2, a well-established tumor suppressive long non-coding RNA, could serve as a "Sponge" of miR-24 and miR-221, thus modulating TRAIL-induced tumor cell apoptosis TRAIL resistance of hepatocellular carcinoma. Taken together, we demonstrated a CASC2/miR-24/miR-221 axis, which can affect the TRAIL resistance of hepatocellular carcinoma through regulating caspase 3/8; through acting as a "Sponge" of miR-24 and miR-221, CASC2 may contribute to improving hepatocellular carcinoma TRAIL resistance, and finally promoting the treatment efficiency of TRAIL-based therapies. PMID- 29476052 TI - Plasma exosomes induced by remote ischaemic preconditioning attenuate myocardial ischaemia/reperfusion injury by transferring miR-24. AB - Remote ischaemic preconditioning (RIPC) is well known to protect the myocardium against ischaemia/reperfusion injury (IRI). Exosomes are small extracellular vesicles that have become the key mediators of intercellular communication. Various studies have confirmed that circulating exosomes mediate RIPC. However, the underlying mechanisms for RIPC-induced exosome-mediated cardioprotection remain elusive. In our study, we found that the expression level of miR-24 was higher in exosomes derived from the plasma of rats subjected to RIPC than in exosomes derived from the plasma of control rats in vivo. The rat plasma exosomes could be taken up by H9c2 cells. In addition, miR-24 was present in RIPC-induced exosomes and played a role in reducing oxidative stress-mediated injury and decreasing apoptosis by downregulating Bim expression in H2O2-treated H9c2 cells in vitro. In vivo, miR-24 in RIPC-induced exosomes reduced cardiomyocyte apoptosis, attenuated the infarct size and improved heart function. Furthermore, the apoptosis-reducing effect of miR-24 was counteracted by miR-24 antagomirs or inhibitors both in vitro and in vivo. Therefore, we provided evidence that RIPC induced exosomes could reduce apoptosis by transferring miR-24 in a paracrine manner and that miR-24 in the exosomes plays a central role in mediating the protective effects of RIPC. PMID- 29476053 TI - TCF7L2 positively regulates aerobic glycolysis via the EGLN2/HIF-1alpha axis and indicates prognosis in pancreatic cancer. AB - Patients with pancreatic ductal adenocarcinoma have much worse prognoses, and much effort has been directed toward understanding the molecular biological aspects of this disease. Accumulated evidence suggests that constitutive activation of the Wnt/beta-catenin signalling contributes to the oncogenesis and progression of pancreatic cancer. Transcription factor 7-like2/transcription factor 4 (TCF7L2/TCF4), a beta-catenin transcriptional partner, plays a vital role in the Wnt/beta-catenin signalling pathway. In the present study, we investigated the clinicopathological significance of TCF7L2 in pancreatic cancer. Our results demonstrated that patients with higher TCF7L2 expression had worse prognosis. Our in vitro studies demonstrated that TCF7L2 positively regulated aerobic glycolysis by suppressing Egl-9 family hypoxia inducible factor 2 (EGLN2), leading to upregulation of hypoxia inducible factor 1 alpha subunit (HIF 1alpha). The impact of TCF7L2 on aerobic glycolysis was further confirmed in vivo by assessing 18FDG uptake in pancreatic cancer patients and in a subcutaneous xenograft mouse model. In summary, we identified novel predictive markers for prognosis and suggest a previously unrecognized role for TCF7L2 in control of aerobic glycolysis in pancreatic cancer. PMID- 29476054 TI - Membrane cholesterol mediates the cellular effects of monolayer graphene substrates. AB - Graphene possesses extraordinary properties that promise great potential in biomedicine. However, fully leveraging these properties requires close contact with the cell surface, raising the concern of unexpected biological consequences. Computational models have demonstrated that graphene preferentially interacts with cholesterol, a multifunctional lipid unique to eukaryotic membranes. Here we demonstrate an interaction between graphene and cholesterol. We find that graphene increases cell membrane cholesterol and potentiates neurotransmission, which is mediated by increases in the number, release probability, and recycling rate of synaptic vesicles. In fibroblasts grown on graphene, we also find an increase in cholesterol, which promotes the activation of P2Y receptors, a family of receptor regulated by cholesterol. In both cases, direct manipulation of cholesterol levels elucidates that a graphene-induced cholesterol increase underlies the observed potentiation of each cell signaling pathway. These findings identify cholesterol as a mediator of graphene's cellular effects, providing insight into the biological impact of graphene. PMID- 29476055 TI - Sub-cellular In-situ Characterization of Ferritin(iron) in a Rodent Model of Spinal Cord Injury. AB - Iron (Fe) is an essential metal involved in a wide spectrum of physiological functions. Sub-cellular characterization of the size, composition, and distribution of ferritin(iron) can provide valuable information on iron storage and transport in health and disease. In this study we employ magnetic force microscopy (MFM), transmission electron microscopy (TEM), and electron energy loss spectroscopy (EELS) to characterize differences in ferritin(iron) distribution and composition across injured and non-injured tissues by employing a rodent model of spinal cord injury (SCI). Our biophysical and ultrastructural analyses provide novel insights into iron distribution which are not obtained by routine biochemical stains. In particular, ferritin(iron) rich lysosomes revealed increased heterogeneity in MFM signal from tissues of SCI animals. Ultrastructural analysis using TEM elucidated that both cytosolic and lysosomal ferritin(iron) density was increased in the injured (spinal cord) and non-injured (spleen) tissues of SCI as compared to naive animals. In-situ EELs analysis revealed that ferritin(iron) was primarily in Fe3+ oxidation state in both naive and SCI animal tissues. The insights provided by this study and the approaches utilized here can be applied broadly to other systemic problems involving iron regulation or to understand the fate of exogenously delivered iron-oxide nanoparticles. PMID- 29476056 TI - Evolution of Barrett's esophagus through space and time at single-crypt and whole biopsy levels. AB - The low risk of progression of Barrett's esophagus (BE) to esophageal adenocarcinoma can lead to over-diagnosis and over-treatment of BE patients. This may be addressed through a better understanding of the dynamics surrounding BE malignant progression. Although genetic diversity has been characterized as a marker of malignant development, it is still unclear how BE arises and develops. Here we uncover the evolutionary dynamics of BE at crypt and biopsy levels in eight individuals, including four patients that experienced malignant progression. We assay eight individual crypts and the remaining epithelium by SNP array for each of 6-11 biopsies over 2 time points per patient (358 samples in total). Our results indicate that most Barrett's segments are clonal, with similar number and inferred rates of alterations observed for crypts and biopsies. Divergence correlates with geographical location, being higher near the gastro-esophageal junction. Relaxed clock analyses show that genomic instability precedes and is enhanced by genome doubling. These results shed light on the clinically relevant evolutionary dynamics of BE. PMID- 29476057 TI - Cobalt-catalyzed electrooxidative C-H/N-H [4+2] annulation with ethylene or ethyne. AB - Ethylene and ethyne are among the simplest two-carbon building blocks. However, quite limited methods can be applied to incorporate ethylene or ethyne into fine chemicals. Here we demonstrate a cobalt-catalyzed dehydrogenative C-H/N-H [4+2] annulation of aryl/vinyl amides with ethylene or ethyne by using an electrochemical reaction protocol. Significantly, this work shows an example of electrochemical recycling of cobalt catalyst in oxidative C-H functionalization reactions, avoiding the use of external chemical oxidants and co-oxidants. The electrochemical method provides a reliable and safe way for incorporating gas phase ethylene or ethyne into fine chemicals. High reaction efficiency and good functional group tolerance are observed under divided electrolytic conditions. PMID- 29476058 TI - Changes in Ugandan Climate Rainfall at the Village and Forest Level. AB - In 2013, the US National Oceanographic and Atmospheric Administration (NOAA) refined the historical rainfall estimates over the African Continent and produced the African Rainfall Climate version 2.0 (ARC2) estimator. ARC2 offers a nearly complete record of daily rainfall estimates since 1983 at 0.1 degrees * 0.1 degrees resolution. Despite short-term anomalies, we identify an overall decrease in average rainfall of about 12% during the past 34 years in Uganda. Spatiotemporally, these decreases are greatest in agricultural regions of central and western Uganda, but similar rainfall decreases are also reflected in the gorilla habitat within the Bwindi Forest in Southwest Uganda. The findings carry significant implications for agriculture production, food security, wildlife habitat, and economic impact at the community and societal level. PMID- 29476059 TI - Identification and characterization of the BRI2 interactome in the brain. AB - BRI family proteins are ubiquitous type II transmembrane proteins but BRI2 is highly expressed in some neuronal tissues. Possible BRI2 functions include neuronal maturation and differentiation. Protein complexes appear to be important in mediating its functions. Previously described BRI2 interactors include the Alzheimer's amyloid precursor protein and protein phosphatase 1, but clearly the identification of novel interactors provides an important tool to understand the role and function of BRI2. To this end three rat brain regions (cerebellum, hippocampus, and cerebral cortex) were processed by BRI2 immunoprecipitation; co precipitating proteins were identified by Nano-HPLC-MS/MS. The pool of the brain regions resulted in 511 BRI2 interacting proteins (BRI2 brain interactome) of which 120 were brain specific and 49 involved in neuronal differentiation. Brain region-specific analyses were also carried out for cerebellum, hippocampus, and cerebral cortex. Several novel BRI2 interactors were identified among them DLG4/PSD-95, which is singularly important as it places BRI2 in the postsynaptic compartment. This interaction was validated as well as the interaction with GAP 43 and synaptophysin. In essence, the resulting BRI2 brain interactome, associates this protein with neurite outgrowth and neuronal differentiation, as well as synaptic signalling and plasticity. It follows that further studies should address BRI2 particularly given its relevance to neuropathological conditions. PMID- 29476060 TI - Quantitative 3-D morphometric analysis of individual dendritic spines. AB - The observation and analysis of dendritic spines morphological changes poses a major challenge in neuroscience studies. The alterations of their density and/or morphology are indicators of the cellular processes involved in neural plasticity underlying learning and memory, and are symptomatic in neuropsychiatric disorders. Despite ongoing intense investigations in imaging approaches, the relationship between changes in spine morphology and synaptic function is still unknown. The existing quantitative analyses are difficult to perform and require extensive user intervention. Here, we propose a new method for (1) the three dimensional (3-D) segmentation of dendritic spines using a multi-scale opening approach and (2) define 3-D morphological attributes of individual spines for the effective assessment of their structural plasticity. The method was validated using confocal light microscopy images of dendritic spines from dissociated hippocampal cultures and brain slices (1) to evaluate accuracy relative to manually labeled ground-truth annotations and relative to the state-of-the-art Imaris tool, (2) to analyze reproducibility of user-independence of the segmentation method, and (3) to quantitatively analyze morphological changes in individual spines before and after chemically induced long-term potentiation. The method was monitored and used to precisely describe the morphology of individual spines in real-time using consecutive images of the same dendritic fragment. PMID- 29476061 TI - Direct observation of single-molecule hydrogen-bond dynamics with single-bond resolution. AB - The hydrogen bond represents a fundamental interaction widely existing in nature, which plays a key role in chemical, physical and biochemical processes. However, hydrogen bond dynamics at the molecular level are extremely difficult to directly investigate. Here, in this work we address direct electrical measurements of hydrogen bond dynamics at the single-molecule and single-event level on the basis of the platform of molecular nanocircuits, where a quadrupolar hydrogen bonding system is covalently incorporated into graphene point contacts to build stable supramolecule-assembled single-molecule junctions. The dynamics of individual hydrogen bonds in different solvents at different temperatures are studied in combination with density functional theory. Both experimental and theoretical results consistently show a multimodal distribution, stemming from the stochastic rearrangement of the hydrogen bond structure mainly through intermolecular proton transfer and lactam-lactim tautomerism. This work demonstrates an approach of probing hydrogen bond dynamics with single-bond resolution, making an important contribution to broad fields beyond supramolecular chemistry. PMID- 29476062 TI - Histone deacetylase inhibitors protect against cisplatin-induced acute kidney injury by activating autophagy in proximal tubular cells. AB - Histone deacetylase inhibitors (HDACi) have therapeutic effects in models of various renal diseases including acute kidney injury (AKI); however, the underlying mechanism remains unclear. Here we demonstrate that two widely tested HDACi (suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA)) protect the kidneys in cisplatin-induced AKI by enhancing autophagy. In cultured renal proximal tubular cells, SAHA and TSA enhanced autophagy during cisplatin treatment. We further verified the protective effect of TSA against cisplatin induced apoptosis in these cells. Notably, inhibition of autophagy by chloroquine or by autophagy gene 7 (Atg7) ablation diminished the protective effect of TSA. In mice, TSA increased autophagy in renal proximal tubules and protected against cisplatin-induced AKI. The in vivo effect of TSA was also abolished by chloroquine and by Atg7 knockout specifically from renal proximal tubules. Mechanistically, TSA stimulated AMPK and inactivated mTOR during cisplatin treatment of proximal tubule cells and kidneys in mice. Together, these results suggest that HDACi may protect kidneys by activating autophagy in proximal tubular cells. PMID- 29476063 TI - Single amino acid in V2 encoded by TYLCV is responsible for its self-interaction, aggregates and pathogenicity. AB - The V2 protein encoded by Begomovirus is essential for virus infection and is involved in multiple functions, such as virus movement and suppression of the host defence response. In this study, we reported that V2 encoded by the Tomato yellow leaf curl virus (TYLCV), which is one of the most devastating tomato infecting begomoviruses, could interact with itself and a S71A mutation of V2 (V2S71A) abolished its self-interaction. Fluorescence results showed that V2 localized primarily in the cytoplasm and around the nucleus. Site-directed mutagenesis V2S71A had the similar subcellular localization, but V2S71A formed fewer large aggregates in the cytoplasm compared to wild-type V2, whereas the level of aggregates came to a similar after treatment with MG132, which indicates that the S71A mutation might affect 26S proteasome-mediated degradation of V2 aggregates. Meanwhile, heterologous expression of V2S71A from a Potato virus X vector induced mild symptoms compared to wild-type V2, delay of virus infection associated with mild symptoms was observed in plants inoculated with TYLCV-S71A, which indicates that the amino acid on position 71 is also involved in the pathogenicity of V2. To the best of our knowledge, this report is the first to state that the S71A mutation of V2 encoded by TYLCV affects the self-interaction, aggregate formation and pathogenicity of V2. PMID- 29476064 TI - An all-trans-retinal-binding opsin peropsin as a potential dark-active and light inactivated G protein-coupled receptor. AB - Peropsin or retinal pigment epithelium-derived rhodopsin homolog, found in many animals, belongs to the opsin family. Most opsins bind to 11-cis-retinal as a chromophore and act as light-activated G protein-coupled receptors. Some peropsins, however, bind all-trans-retinal and isomerise it into 11-cis form by light, and peropsin has been suggested to supply other visual opsins with 11-cis retinal. Additionally, peropsin has some amino acid sequence motifs that are highly conserved among G protein-coupled opsins. Here, using chimeric mutant peropsins, we found that peropsin potentially generates an "active form" that drives G-protein signalling in the dark by binding to all-trans-retinal and that the active form photo-converts to an inactive form containing 11-cis-retinal. Comparative spectroscopic analysis demonstrated that spider peropsin exhibited catalytic efficiency for retinal photoisomerisation that was much lower than a retinal photoisomerase, squid retinochrome. The chimeric peropsins, constructed by replacing the third intracellular loop region with that of Gs- or Gi-coupled opsin, were active and drove Gs- or Gi-mediated signalling in the dark, respectively, and were inactivated upon illumination in mammalian cultured cells. These results suggest that peropsin acts as a dark-active, light-inactivated G protein-coupled receptor and is useful as a novel optogenetic tool. PMID- 29476065 TI - Role of the Metal-Oxide Work Function on Photocurrent Generation in Hybrid Solar Cells. AB - ZnO is a widely used metal-oxide semiconductor for photovoltaic application. In solar cell heterostructures they not only serve as a charge selective contact, but also act as electron acceptor. Although ZnO offers a suitable interface for exciton dissociation, charge separation efficiencies have stayed rather poor and conceptual differences to organic acceptors are rarely investigated. In this work, we employ Sn doping to ZnO nanowires in order to understand the role of defect and surface states in the charge separation process. Upon doping we are able to modify the metal-oxide work function and we show its direct correlation with the charge separation efficiency. For this purpose, we use the polymer poly(3-hexylthiophene) as donor and the squaraine dye SQ2 as interlayer. Interestingly, neither mobilities nor defects are prime performance limiting factor, but rather the density of available states around the conduction band is of crucial importance for hybrid interfaces. This work highlights crucial aspects to improve the charge generation process of metal-oxide based solar cells and reveals new strategies to improve the power conversion efficiency of hybrid solar cells. PMID- 29476066 TI - Vertical Transmission of the Zika Virus Causes Neurological Disorders in Mouse Offspring. AB - The association between Zika virus (ZIKV) infection and congenital malformations such as microcephaly in infants is a public health emergency. Although various in vivo and in vitro models are used for ZIKV research, few animal models are available for resolving the effects of maternal ZIKV infection on neonatal development. Here, we established an immunocompetent mouse model via intrauterine inoculation. Our results confirmed that ZIKV, but not dengue virus, infection caused spontaneous abortions, brain malformations, ocular abnormalities, spinal cord defects and paralysis in mouse offspring. Aside from microcephaly and hippocampal dysplasia, eye abnormalities, including microphthalmia, thinner optic nerves, damaged retinae, and deficient visual projection, were also observed following ZIKV infection. Moreover, ZIKV-infected offspring showed a loss of alpha motor neurons in the spinal cord and cerebellar malformation, which may cause paralysis. ZIKV also impaired adult neurogenesis in neonatal mice. Due to its intact immunity, our rodent model can be used to systematically evaluate the impact of ZIKV on embryonic and neonatal development and to explore potential therapies. PMID- 29476067 TI - BI-2536 and BI-6727, dual Polo-like kinase/bromodomain inhibitors, effectively reactivate latent HIV-1. AB - HIV-1 latent reservoirs harbouring silenced but replication-competent proviruses are a major obstacle against viral eradication in infected patients. The "shock and kill" strategy aims to reactivate latent provirus with latency reversing agents (LRAs) in the presence of antiretroviral drugs, necessitating the development of effective and efficient LRAs. We screened a chemical library for potential LRAs and identified two dual Polo-like kinase (PLK)/bromodomain inhibitors, BI-2536 and BI-6727 (volasertib), which are currently undergoing clinical trials against various cancers. BI-2536 and BI-6727 significantly reactivated silenced HIV-1 provirus at both the mRNA and protein level in two latently infected model cell lines (ACH2 and U1). BI-2536 dramatically reactivated transcription of latent HIV-1 provirus in peripheral blood mononuclear cells derived from infected patients. Long terminal repeat activation by the inhibitors was associated with bromodomain rather than PLK inhibition. We also found that BI-2536 synergistically activates the latent provirus in combination with SAHA, a histone deacetylase inhibitor, or the non-tumour promoting phorbol ester prostratin. Our findings strongly suggest that BI-2536 and BI-6727 are potent LRAs for the "shock and kill" HIV-1 eradication strategy. PMID- 29476068 TI - Diversity and evolution of four-domain voltage-gated cation channels of eukaryotes and their ancestral functional determinants. AB - Four-domain voltage-gated cation channels (FVCCs) represent a large family of pseudo-tetrameric ion channels which includes voltage-gated calcium (Cav) and sodium (Nav) channels, as well as their homologues. These transmembrane proteins are involved in a wide range of physiological processes, such as membrane excitability, rhythmical activity, intracellular signalling, etc. Information about actual diversity and phylogenetic relationships of FVCCs across the eukaryotic tree of life is scarce. We for the first time performed a taxonomically broad phylogenetic analysis of 277 FVCC sequences from a variety of eukaryotes and showed that many groups of eukaryotic organisms have their own clades of FVCCs. Moreover, the number of FVCC lineages in several groups of unicellular eukaryotes is comparable to that in animals. Based on the primary structure of FVCC sequences, we characterised their functional determinants (selectivity filter, voltage sensor, Nav-like inactivation gates, Cavbeta interaction motif, and calmodulin-binding region) and mapped them on the obtained phylogeny. This allowed uncovering of lineage-specific structural gains and losses in the course of FVCC evolution and identification of ancient structural features of these channels. Our results indicate that the ancestral FVCC was voltage-sensitive, possessed a Cav-like selectivity filter, Nav-like inactivation gates, calmodulin-binding motifs and did not bear the structure for Cavbeta binding. PMID- 29476069 TI - Kupffer cell-derived TNF-alpha promotes hepatocytes to produce CXCL1 and mobilize neutrophils in response to necrotic cells. AB - The damage-associated molecular pattern molecules (DAMPs) released by necrotic cells can trigger inflammatory response, which will facilitate the clearance of these dead cells. Neutrophil mobilization is a very important step for the dead cell clearance, however the detailed mechanisms for DAMPs induce neutrophil mobilization remains largely elusive. In this study, by using a necrotic cell induced neutrophil mobilization mice model, we found that both neutrophil number and percentage rapidly (as early as 30 min) increased with necrotic cells but not live cell treatment. CXCL1 was rapidly increased in the serum and was responsible for the neutrophil mobilization when treated with necrotic cells. We further demonstrated that the hepatocytes in the liver were the main source of CXCL1 production in response to necrotic cells challenge. However, the hepatocytes did not express CXCL1 when incubating with necrotic cells alone. When Kupffer cells were ablated, the increased CXCL1 levels as well as neutrophil mobilization were abolished with necrotic cells challenge. Moreover, we clarified Kupffer cells derived TNF-alpha activates the NF-kappaB pathway in hepatocytes and promote hepatocytes to express CXCL1. In summary, we showed that the liver is the main source for necrotic cell-induced CXCL1 production and neutrophil mobilization. Kupffer cells in the liver sense DAMPs and release TNF-alpha to activate the NF kappaB pathway in hepatocytes. The interaction between Kupffer cells and hepatocytes is critical for CXCL1 production. PMID- 29476070 TI - A genetic variant in SLC30A2 causes breast dysfunction during lactation by inducing ER stress, oxidative stress and epithelial barrier defects. AB - SLC30A2 encodes a zinc (Zn) transporter (ZnT2) that imports Zn into vesicles in highly-specialized secretory cells. Numerous mutations and non-synonymous variants in ZnT2 have been reported in humans and in breastfeeding women; ZnT2 variants are associated with abnormally low milk Zn levels and can lead to severe infantile Zn deficiency. However, ZnT2-null mice have profound defects in mammary epithelial cell (MEC) polarity and vesicle secretion, indicating that normal ZnT2 function is critical for MEC function. Here we report that women who harbor a common ZnT2 variant (T288S) present with elevated levels of several oxidative and endoplasmic reticulum (ER) stress markers in their breast milk. Functional studies in vitro suggest that substitution of threonine for serine at amino acid 288 leads to hyperphosphorylation retaining ZnT2 in the ER and lysosomes, increasing ER and lysosomal Zn accumulation, ER stress, the generation of reactive oxygen species, and STAT3 activation. These changes were associated with decreased abundance of zona occludens-1 and increased tight junction permeability. This study confirms that ZnT2 is important for normal breast function in women during lactation, and suggests that women who harbor defective variants in ZnT2 may be at-risk for poor lactation performance. PMID- 29476071 TI - Bioinspired leaves-on-branchlet hybrid carbon nanostructure for supercapacitors. AB - Designing electrodes in a highly ordered structure simultaneously with appropriate orientation, outstanding mechanical robustness, and high electrical conductivity to achieve excellent electrochemical performance remains a daunting challenge. Inspired by the phenomenon in nature that leaves significantly increase exposed tree surface area to absorb carbon dioxide (like ions) from the environments (like electrolyte) for photosynthesis, we report a design of micro conduits in a bioinspired leaves-on-branchlet structure consisting of carbon nanotube arrays serving as branchlets and graphene petals as leaves for such electrodes. The hierarchical all-carbon micro-conduit electrodes with hollow channels exhibit high areal capacitance of 2.35 F cm-2 (~500 F g-1 based on active material mass), high rate capability and outstanding cyclic stability (capacitance retention of ~95% over 10,000 cycles). Furthermore, Nernst-Planck Poisson calculations elucidate the underlying mechanism of charge transfer and storage governed by sharp graphene petal edges, and thus provides insights into their outstanding electrochemical performance. PMID- 29476072 TI - Circular RNA GRB10 as a competitive endogenous RNA regulating nucleus pulposus cells death in degenerative intervertebral disk. AB - Intervertebral disc degeneration (IDD) is an important factor leading to low back pain, but the underlying mechanisms remain poorly understood. Compared with normal nucleus pulposus (NP) tissues, the expression of circ-GRB10 was downregulated in IDD. Furthermore, overexpression of circ-GRB10 inhibited NP cell apoptosis. circ-GRB10 could sequester miR-328-5p, which could potentially lead to the upregulation of target genes related to cell proliferation via the ErbB pathway. In conclusion, the present study revealed that circ-GRB10/miR-328 5p/ERBB2 signaling pathway is involved in IDD development, suggesting that circ GRB10 might be a novel therapeutic target for IDD. PMID- 29476073 TI - Increasing temperature of cooling granular gases. AB - The kinetic energy of a force-free granular gas decays monotonously due to inelastic collisions of the particles. For a homogeneous granular gas of identical particles, the corresponding decay of granular temperature is quantified by Haff's law. Here, we report that for a granular gas of aggregating particles, the granular temperature does not necessarily decay but may even increase. Surprisingly, the increase of temperature is accompanied by the continuous loss of total gas energy. This stunning effect arises from a subtle interplay between decaying kinetic energy and gradual reduction of the number of degrees of freedom associated with the particles' dynamics. We derive a set of kinetic equations of Smoluchowski type for the concentrations of aggregates of different sizes and their energies. We find scaling solutions to these equations and a condition for the aggregation mechanism predicting growth of temperature. Numerical direct simulation Monte Carlo results confirm the theoretical predictions. PMID- 29476075 TI - The cytoprotective role of DJ-1 and p45 NFE2 against human primary alveolar type II cell injury and emphysema. AB - Emphysema is characterized by irreversibly enlarged airspaces and destruction of alveolar walls. One of the factors contributing to this disease pathogenesis is an elevation in extracellular matrix (ECM) degradation in the lung. Alveolar type II (ATII) cells produce and secrete pulmonary surfactants and proliferate to restore the epithelium after damage. We isolated ATII cells from control non smokers, smokers and patients with emphysema to determine the role of NFE2 (nuclear factor, erythroid-derived 2). NFE2 is a heterodimer composed of two subunits, a 45 kDa (p45 NFE2) and 18 kDa (p18 NFE2) polypeptides. Low expression of p45 NFE2 in patients with emphysema correlated with a high ECM degradation. Moreover, we found that NFE2 knockdown increased cell death induced by cigarette smoke extract. We also studied the cross talk between p45 NFE2 and DJ-1. DJ-1 protein is a redox-sensitive chaperone that protects cells from oxidative stress. We detected that cigarette smoke significantly increased p45 NFE2 levels in DJ-1 KO mice compared to wild-type mice. Our results indicate that p45 NFE2 expression is induced by exposure to cigarette smoke, has a cytoprotective activity against cell injury, and its downregulation in human primary ATII cells may contribute to emphysema pathogenesis. PMID- 29476074 TI - Somatic mutagenesis in satellite cells associates with human skeletal muscle aging. AB - Human aging is associated with a decline in skeletal muscle (SkM) function and a reduction in the number and activity of satellite cells (SCs), the resident stem cells. To study the connection between SC aging and muscle impairment, we analyze the whole genome of single SC clones of the leg muscle vastus lateralis from healthy individuals of different ages (21-78 years). We find an accumulation rate of 13 somatic mutations per genome per year, consistent with proliferation of SCs in the healthy adult muscle. SkM-expressed genes are protected from mutations, but aging results in an increase in mutations in exons and promoters, targeting genes involved in SC activity and muscle function. In agreement with SC mutations affecting the whole tissue, we detect a missense mutation in a SC propagating to the muscle. Our results suggest somatic mutagenesis in SCs as a driving force in the age-related decline of SkM function. PMID- 29476076 TI - fam20C participates in the shell formation in the pearl oyster, Pinctada fucata. AB - Kinase-family with sequence similarity 20, member C (Fam20C) is a protein kinase, which can phosphorylate biomineralization related proteins in vertebrate animals. However, the function of Fam20C in invertebrate animals especially the role in biomineralization is still unknown. Herein, we cloned the cDNA of fam20C from the pearl oyster, Pinctada fucata. It is showed that the expression of fam20C in the mantle edge was much higher than other tissues. In situ hybridization showed that fam20C was expressed mostly in the outer epithelial cells of the middle fold, indicating it may play important roles in the shell formation. Besides, fam20C expression increased greatly in the D-shape stage of pearl oyster development, when the shell was first formed. During the shell repair process, the expression level of fam20C increased 1.5 times at 6 h after shell notching. Knockdown of fam20C in vivo by RNA interference resulted in abnormally stacking of calcium carbonate crystals at the edges of nacre tablets, showing direct evidence that fam20C participates in the shell formation. This study provides an insight into the role of kinase protein in the shell formation in mollusk and broaden our understanding of biomineralization mechanism. PMID- 29476077 TI - A combinatorial framework to quantify peak/pit asymmetries in complex dynamics. AB - We explore a combinatorial framework which efficiently quantifies the asymmetries between minima and maxima in local fluctuations of time series. We first showcase its performance by applying it to a battery of synthetic cases. We find rigorous results on some canonical dynamical models (stochastic processes with and without correlations, chaotic processes) complemented by extensive numerical simulations for a range of processes which indicate that the methodology correctly distinguishes different complex dynamics and outperforms state of the art metrics in several cases. Subsequently, we apply this methodology to real-world problems emerging across several disciplines including cases in neurobiology, finance and climate science. We conclude that differences between the statistics of local maxima and local minima in time series are highly informative of the complex underlying dynamics and a graph-theoretic extraction procedure allows to use these features for statistical learning purposes. PMID- 29476078 TI - Single-cell RNA-seq of rheumatoid arthritis synovial tissue using low-cost microfluidic instrumentation. AB - Droplet-based single-cell RNA-seq has emerged as a powerful technique for massively parallel cellular profiling. While this approach offers the exciting promise to deconvolute cellular heterogeneity in diseased tissues, the lack of cost-effective and user-friendly instrumentation has hindered widespread adoption of droplet microfluidic techniques. To address this, we developed a 3D-printed, low-cost droplet microfluidic control instrument and deploy it in a clinical environment to perform single-cell transcriptome profiling of disaggregated synovial tissue from five rheumatoid arthritis patients. We sequence 20,387 single cells revealing 13 transcriptomically distinct clusters. These encompass an unsupervised draft atlas of the autoimmune infiltrate that contribute to disease biology. Additionally, we identify previously uncharacterized fibroblast subpopulations and discern their spatial location within the synovium. We envision that this instrument will have broad utility in both research and clinical settings, enabling low-cost and routine application of microfluidic techniques. PMID- 29476079 TI - Co-occurring expression and methylation QTLs allow detection of common causal variants and shared biological mechanisms. AB - Inherited genetic variation affects local gene expression and DNA methylation in humans. Most expression quantitative trait loci (cis-eQTLs) occur at the same genomic location as a methylation QTL (cis-meQTL), suggesting a common causal variant and shared mechanism. Using DNA and RNA from peripheral blood of Bangladeshi individuals, here we use co-localization methods to identify eQTL meQTL pairs likely to share a causal variant. We use partial correlation and mediation analyses to identify >400 of these pairs showing evidence of a causal relationship between expression and methylation (i.e., shared mechanism) with many additional pairs we are underpowered to detect. These co-localized pairs are enriched for SNPs showing opposite associations with expression and methylation, although many SNPs affect multiple CpGs in opposite directions. This work demonstrates the pervasiveness of co-regulated expression and methylation in the human genome. Applying this approach to other types of molecular QTLs can enhance our understanding of regulatory mechanisms. PMID- 29476080 TI - Profiling Atlantic salmon B cell populations: CpG-mediated TLR-ligation enhances IgM secretion and modulates immune gene expression. AB - While TLR-activated pathways are key regulators of B cell responses in mammals, their impact on teleost B cells are scarcely addressed. Here, the potential of Atlantic salmon B cells to respond to TLR ligands was shown by demonstrating a constitutive expression of nucleic-acid sensing TLRs in magnetic sorted IgM+ cells. Of the two receptors recognizing CpG in teleosts, tlr9 was the dominating receptor with over ten-fold higher expression than tlr21. Upon CpG-stimulation, IgM secretion increased for head kidney (HK) and splenic IgM+ cells, while blood B cells were marginally affected. The results suggest that CpG directly affects salmon B cells to differentiate into antibody secreting cells (ASCs). IgM secretion was also detected in the non-treated controls, again with the highest levels in the HK derived population, signifying that persisting ASCs are present in this tissue. In all tissues, the IgM+ cells expressed high MHCII levels, suggesting antigen-presenting functions. Upon CpG-treatment the co-stimulatory molecules cd83 and cd40 were upregulated, while cd86 was down-regulated under the same conditions. Finally, ifna1 was upregulated upon CpG-stimulation in all tissues, while a restricted upregulation was evident for ifnb, proposing that salmon IgM+ B cells exhibit a type I IFN-response. PMID- 29476081 TI - Amyloid-beta with isomerized Asp7 cytotoxicity is coupled to protein phosphorylation. AB - Neuronal dysfunction and loss associated with the accumulation of amyloid-beta (Abeta) in the form of extracellular amyloid plaques and hyperphosphorylated tau in the form of intraneuronal neurofibrillary tangles represent key features of Alzheimer's disease (AD). Amyloid plaques found in the brains of AD patients are predominantly composed of Abeta42 and its multiple chemically or structurally modified isoforms. Recently, we demonstrated that Abeta42 with isomerised Asp7 (isoAbeta42) which is one of the most abundant Abeta isoform in plaques, exhibited high neurotoxicity in human neuronal cells. Here, we show that, in SH SY5Y neuroblastoma cells, the administration of synthetic isoAbeta42 rather than intact Abeta42 resulted in a significantly higher level of protein phosphorylation, especially the phosphorylation of tau, tubulins, and matrin 3. IsoAbeta42 induced a drastic reduction of tau protein levels. Our data demonstrate, for the first time, that isoAbeta42, being to date the only known synthetic Abeta species to cause AD-like amyloidogenesis in an animal AD model, induced cell death by disabling structural proteins in a manner characteristic of that observed in the neurons of AD patients. The data emphasize an important role of isoAbeta42 in AD progression and provide possible neurotoxicity paths for this particular isoform. PMID- 29476082 TI - The big freeze may be over: a contracting universe for cryopreservation? AB - According to current cosmological theory, the universe will continue to expand indefinitely. If so, it should cool eventually reaching temperatures too cold to sustain life. This theory is commonly referred to as heat-death or the big freeze. Putting aside this potentially unpleasant scenario, unlikely in the lifetime of current readers (about 10 * E + 2500 years from now), freezing, in contrast, has played an important role in hematopoietic cell autotransplants for disease such as plasma cell myeloma and lymphomas. Let us consider how. PMID- 29476084 TI - Do not leave FIT positives alone! PMID- 29476083 TI - Lung Metabolism and Inflammation during Mechanical Ventilation; An Imaging Approach. AB - Acute respiratory distress syndrome (ARDS) is a major cause of mortality in critically ill patients. Patients are currently managed by protective ventilation and alveolar recruitment using positive-end expiratory pressure (PEEP). However, the PEEP's effect on both pulmonary metabolism and regional inflammation is poorly understood. Here, we demonstrate the effect of PEEP on pulmonary anaerobic metabolism in mechanically ventilated injured rats, using hyperpolarized carbon 13 imaging. Pulmonary lactate-to-pyruvate ratio was measured in 21 rats; 14 rats received intratracheal instillation of hydrochloric-acid, while 7 rats received sham saline. 1 hour after acid/saline instillation, PEEP was lowered to 0 cmH2O in 7 injured rats (ZEEP group) and in all sham rats; PEEP was continued in the remaining 7 injured rats (PEEP group). Pulmonary compliance, oxygen saturation, histological injury scores, ICAM-1 expression and myeloperoxidase expression were measured. Lactate-to-pyruvate ratio progressively increased in the dependent lung during mechanical ventilation at ZEEP (p < 0.001), but remained unchanged in PEEP and sham rats. Lactate-to-pyruvate ratio was correlated with hyaline membrane deposition (r = 0.612), edema severity (r = 0.663), ICAM-1 (r = 0.782) and myeloperoxidase expressions (r = 0.817). Anaerobic pulmonary metabolism increases during lung injury progression and is contained by PEEP. Pulmonary lactate-to pyruvate ratio may indicate in-vivo neutrophil activity due to atelectasis. PMID- 29476085 TI - Defining the relationship between depression and disease activity in IBD using clinical disease activity indices: merit or misnomer? PMID- 29476086 TI - Quantitative Imaging of Regional Aerosol Deposition, Lung Ventilation and Morphology by Synchrotron Radiation CT. AB - To understand the determinants of inhaled aerosol particle distribution and targeting in the lung, knowledge of regional deposition, lung morphology and regional ventilation, is crucial. No single imaging modality allows the acquisition of all such data together. Here we assessed the feasibility of dual energy synchrotron radiation imaging to this end in anesthetized rabbits; both in normal lung (n = 6) and following methacholine (MCH)-induced bronchoconstriction (n = 6), a model of asthma. We used K-edge subtraction CT (KES) imaging to quantitatively map the regional deposition of iodine-containing aerosol particles. Morphological and regional ventilation images were obtained, followed by quantitative regional iodine deposition maps, after 5 and 10 minutes of aerosol administration. Iodine deposition was markedly inhomogeneous both in normal lung and after induced bronchoconstrition. Deposition was significantly reduced in the MCH group at both time points, with a strong dependency on inspiratory flow in both conditions (R2 = 0.71; p < 0.0001). We demonstrate for the first time, the feasibility of KES CT for quantitative imaging of lung deposition of aerosol particles, regional ventilation and morphology. Since these are among the main factors determining lung aerosol deposition, we expect this imaging approach to bring new contributions to the understanding of lung aerosol delivery, targeting, and ultimately biological efficacy. PMID- 29476087 TI - Diversification of insects since the Devonian: a new approach based on morphological disparity of mouthparts. AB - The majority of the analyses of the evolutionary history of the megadiverse class Insecta are based on the documented taxonomic palaeobiodiversity. A different approach, poorly investigated, is to focus on morphological disparity, linked to changes in the organisms' functioning. Here we establish a hierarchy of the great geological epochs based on a new method using Wagner parsimony and a 'presence/absence of a morphological type of mouthpart of Hexapoda' dataset. We showed the absence of major rupture in the evolution of the mouthparts, but six epochs during which numerous innovations and few extinctions happened, i.e., Late Carboniferous, Middle and Late Triassic, 'Callovian-Oxfordian', 'Early' Cretaceous, and 'Albian-Cenomanian'. The three crises Permian-Triassic, Triassic Jurassic, and Cretaceous-Cenozoic had no strong, visible impact on mouthparts types. We particularly emphasize the origination of mouthparts linked to nectarivory during the Cretaceous Terrestrial Revolution. We also underline the origination of mouthparts linked to phytophagy during the Middle and the Late Triassic, correlated to the diversification of the gymnosperms, especially in relation to the complex 'flowers' producing nectar of the Bennettitales and Gnetales. PMID- 29476088 TI - Probing of sub-picometer vertical differential resolutions using cavity plasmons. AB - Plasmon rulers can be used for resolving ultrasmall environmental, dimensional, and material changes owing to their high sensitivity associated with a light scattering spectral shift in response to changes in the separation between plasmonic nanostructures. Here, we show, in several experimental setups, how cavity plasmons in a metal nanowire-on-mirror setup can be used to probe vertical dimensional changes with sub-picometer differential resolutions using two carefully chosen material systems. Specifically, we monitor the dielectric layer thickness changes in response to growth using atomic-layer deposition and to thermal expansion, demonstrating a sensitivity of 14-nm spectral shift per Angstrom thickness change and 0.58 pm of vertical differential resolution, respectively. The findings confirm theoretical predictions and highlight the potential use of cavity plasmons in some ultrasensitive sensing applications. PMID- 29476089 TI - Horizontal transfer of code fragments between protocells can explain the origins of the genetic code without vertical descent. AB - Theories of the origin of the genetic code typically appeal to natural selection and/or mutation of hereditable traits to explain its regularities and error robustness, yet the present translation system presupposes high-fidelity replication. Woese's solution to this bootstrapping problem was to assume that code optimization had played a key role in reducing the effect of errors caused by the early translation system. He further conjectured that initially evolution was dominated by horizontal exchange of cellular components among loosely organized protocells ("progenotes"), rather than by vertical transmission of genes. Here we simulated such communal evolution based on horizontal transfer of code fragments, possibly involving pairs of tRNAs and their cognate aminoacyl tRNA synthetases or a precursor tRNA ribozyme capable of catalysing its own aminoacylation, by using an iterated learning model. This is the first model to confirm Woese's conjecture that regularity, optimality, and (near) universality could have emerged via horizontal interactions alone. PMID- 29476090 TI - "Betting on nature" or "betting on others": anti-coordination induces uniquely high levels of entropy. AB - Uncertainty in the form of risk or ambiguity can arise from the interaction with nature and other players, while strategic uncertainty arises only in interactions with others. Here, we systematically compare binary decisions between a safe option and a potentially higher paying but uncertain option in four experimental conditions with the same potential monetary outcomes: coordination vs. anti coordination games, as well as risky and ambiguous lotteries. In each condition, we progressively increase the value of the safe option and measure subjects' certainty equivalents (i.e., the specific safe payoff-threshold that makes a subject indifferent between the two options). We find that anti-coordination games and ambiguous lotteries elicit equally high aversion to uncertainty, relative to the other domains. In spite of this similarity, we find that subjects alternate between the safe and uncertain options much more frequently, thus displaying higher entropy, under anti-coordination relative to any of the other environments. These differences are predicted by theories of recursive reasoning in strategic games (e.g., thinking what others think we think etc.). Indeed, this can occur when interacting with intentional counterparts, but not with nature. PMID- 29476091 TI - Reduced graphene oxide (rGO) based wideband optical sensor and the role of Temperature, Defect States and Quantum Efficiency. AB - We report a facile and cost-effective approach to develop self-standing reduced Graphene Oxide (rGO) film based optical sensor and its low-temperature performance analysis where midgap defect states play a key role in tuning the crucial sensor parameters. Graphite oxide (GO) is produced by modified Hummers' method and reduced thermally at 250 degrees C for 1 h in Argon atmosphere to obtain rGO. Self-standing rGO film is prepared via vacuum filtration. The developed film is characterized by HRTEM, FESEM, Raman, and XRD techniques. The developed sensor exhibits highest sensitivity towards 635 nm illumination wavelength, irrespective of the operating temperature. For a given excitation wavelength, photoresponse study at low temperature (123K-303K) reveals inverse relationship between sensitivity and operating temperature. Highest sensitivity of 49.2% is obtained at 123 K for 635 nm laser at power density of 1.4 mW/mm2. Unlike sensitivity, response- and recovery-time demonstrate directly proportional dependence with operating temperature. Power dependent studies establish linear relation between power-density and sensitivity, and a safe limit beyond which sample heating prolongs the recovery time. Wavelength-dependent studies shows that proposed sensor can efficiently operate from visible to near NIR region. To the best of our knowledge such rGO based optical sensor performance at low temperature had not been reported earlier. PMID- 29476092 TI - Linear peptidomimetics as potent antagonists of Staphylococcus aureus agr quorum sensing. AB - Staphylococcus aureus is an important pathogen causing infections in humans and animals. Increasing problems with antimicrobial resistance has prompted the development of alternative treatment strategies, including antivirulence approaches targeting virulence regulation such as the agr quorum sensing system. agr is naturally induced by cyclic auto-inducing peptides (AIPs) binding to the AgrC receptor and cyclic peptide inhibitors have been identified competing with AIP binding to AgrC. Here, we disclose that small, linear peptidomimetics can act as specific and potent inhibitors of the S. aureus agr system via intercepting AIP-AgrC signal interaction at low micromolar concentrations. The corresponding linear peptide did not have this ability. This is the first report of a linear peptide-like molecule that interferes with agr activation by competitive binding to AgrC. Prospectively, these peptidomimetics may be valuable starting scaffolds for the development of new inhibitors of staphylococcal quorum sensing and virulence gene expression. PMID- 29476093 TI - Zebrafish and medaka offer insights into the neurobehavioral correlates of vertebrate magnetoreception. AB - An impediment to a mechanistic understanding of how some species sense the geomagnetic field ("magnetoreception") is the lack of vertebrate genetic models that exhibit well-characterized magnetoreceptive behavior and are amenable to whole-brain analysis. We investigated the genetic model organisms zebrafish and medaka, whose young stages are transparent and optically accessible. In an unfamiliar environment, adult fish orient according to the directional change of a magnetic field even in darkness. To enable experiments also in juveniles, we applied slowly oscillating magnetic fields, aimed at generating conflicting sensory inputs during exploratory behavior. Medaka (but not zebrafish) increase their locomotor activity in this assay. Complementary brain activity mapping reveals neuronal activation in the lateral hindbrain during magnetic stimulation. These comparative data support magnetoreception in teleosts, provide evidence for a light-independent mechanism, and demonstrate the usefulness of zebrafish and medaka as genetic vertebrate models for studying the biophysical and neuronal mechanisms underlying magnetoreception. PMID- 29476095 TI - Experimental evidence of quantum radiation reaction in aligned crystals. AB - Quantum radiation reaction is the influence of multiple photon emissions from a charged particle on the particle's dynamics, characterized by a significant energy-momentum loss per emission. Here we report experimental radiation emission spectra from ultrarelativistic positrons in silicon in a regime where quantum radiation reaction effects dominate the positron's dynamics. Our analysis shows that while the widely used quantum approach is overall the best model, it does not completely describe all the data in this regime. Thus, these experimental findings may prompt seeking more generally valid methods to describe quantum radiation reaction. This experiment is a fundamental test of quantum electrodynamics in a regime where the dynamics of charged particles is strongly influenced not only by the external electromagnetic fields but also by the radiation field generated by the charges themselves and where each photon emission may significantly reduce the energy of the charge. PMID- 29476094 TI - A family of unconventional deubiquitinases with modular chain specificity determinants. AB - Deubiquitinating enzymes (DUBs) regulate ubiquitin signaling by trimming ubiquitin chains or removing ubiquitin from modified substrates. Similar activities exist for ubiquitin-related modifiers, although the enzymes involved are usually not related. Here, we report human ZUFSP (also known as ZUP1 and C6orf113) and fission yeast Mug105 as founding members of a DUB family different from the six known DUB classes. The crystal structure of human ZUFSP in covalent complex with propargylated ubiquitin shows that the DUB family shares a fold with UFM1- and Atg8-specific proteases, but uses a different active site more similar to canonical DUB enzymes. ZUFSP family members differ widely in linkage specificity through differential use of modular ubiquitin-binding domains (UBDs). While the minimalistic Mug105 prefers K48 chains, ZUFSP uses multiple UBDs for its K63-specific endo-DUB activity. K63 specificity, localization, and protein interaction network suggest a role for ZUFSP in DNA damage response. PMID- 29476096 TI - Low-level Gestational Lead Exposure Alters Dendritic Spine Plasticity in the Hippocampus and Reduces Learning and Memory in Rats. AB - Lead (Pb) is known to impair children's cognitive function. It has been previously shown that developmental Pb exposure alters dendritic spine formation in hippocampal pyramidal neurons. However, the underlying mechanism has not yet been defined. In this study, a low-level gestational Pb exposure (GLE) rat model was employed to investigate the impact of Pb on the spine density of the hippocampal pyramidal neurons and its regulatory mechanism. Pb exposure resulted in impaired performance of the rats in the Morris water maze tasks, and in decreased EPSC amplitudes in hippocampal CA3-CA1 regions. With a 3D reconstruction by the Imaris software, the results from Golgi staining showed that the spine density in the CA1 region was reduced in the Pb-exposed rats in a dose-dependent manner. Decreased spine density was also observed in cultured hippocampal neurons following the Pb treatment. Furthermore, the expression level of NLGN1, a postsynaptic protein that mediates synaptogenesis, was significantly decreased following the Pb exposure both in vivo and in vitro. Up-regulation of NLGN1 in cultured primary neurons partially attenuated the impact of Pb on the spine density. Taken together, our resultssuggest that Pb exposure alters spine plasticity in the developing hippocampus by down-regulating NLGN1 protein levels. PMID- 29476098 TI - Quantum and electrochemical interplays in hydrogenated graphene. AB - The design of electrochemically gated graphene field-effect transistors for detecting charged species in real time, greatly depends on our ability to understand and maintain a low level of electrochemical current. Here, we exploit the interplay between the electrical in-plane transport and the electrochemical activity of graphene. We found that the addition of one H-sp3 defect per hundred thousand carbon atoms reduces the electron transfer rate of the graphene basal plane by more than five times while preserving its excellent carrier mobility. Remarkably, the quantum capacitance provides insight into the changes of the electronic structure of graphene upon hydrogenation, which predicts well the suppression of the electrochemical activity based on the non-adiabatic theory of electron transfer. Thus, our work unravels the interplay between the quantum transport and electrochemical kinetics of graphene and suggests hydrogenated graphene as a potent material for sensing applications with performances going beyond previously reported graphene transistor-based sensors. PMID- 29476097 TI - Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis. AB - Fibroblasts regulate tissue homeostasis, coordinate inflammatory responses, and mediate tissue damage. In rheumatoid arthritis (RA), synovial fibroblasts maintain chronic inflammation which leads to joint destruction. Little is known about fibroblast heterogeneity or if aberrations in fibroblast subsets relate to pathology. Here, we show functional and transcriptional differences between fibroblast subsets from human synovial tissues using bulk transcriptomics of targeted subpopulations and single-cell transcriptomics. We identify seven fibroblast subsets with distinct surface protein phenotypes, and collapse them into three subsets by integrating transcriptomic data. One fibroblast subset, characterized by the expression of proteins podoplanin, THY1 membrane glycoprotein and cadherin-11, but lacking CD34, is threefold expanded in patients with RA relative to patients with osteoarthritis. These fibroblasts localize to the perivascular zone in inflamed synovium, secrete proinflammatory cytokines, are proliferative, and have an in vitro phenotype characteristic of invasive cells. Our strategy may be used as a template to identify pathogenic stromal cellular subsets in other complex diseases. PMID- 29476099 TI - Sequential Membrane Rupture and Vesiculation during Plasmodium berghei Gametocyte Egress from the Red Blood Cell. AB - Malaria parasites alternate between intracellular and extracellular stages and successful egress from the host cell is crucial for continuation of the life cycle. We investigated egress of Plasmodium berghei gametocytes, an essential process taking place within a few minutes after uptake of a blood meal by the mosquito. Egress entails the rupture of two membranes surrounding the parasite: the parasitophorous vacuole membrane (PVM), and the red blood cell membrane (RBCM). High-speed video microscopy of 56 events revealed that egress in both genders comprises four well-defined phases, although each event is slightly different. The first phase is swelling of the host cell, followed by rupture and immediate vesiculation of the PVM. These vesicles are extruded through a single stabilized pore of the RBCM, and the latter is subsequently vesiculated releasing the free gametes. The time from PVM vesiculation to completion of egress varies between events. These observations were supported by immunofluorescence microscopy using antibodies against proteins of the RBCM and PVM. The combined results reveal dynamic re-organization of the membranes and the cortical cytoskeleton of the erythrocyte during egress. PMID- 29476100 TI - Skin gland concentrations adapted to different evolutionary pressures in the head and posterior regions of the caecilian Siphonops annulatus. AB - Amphibian skin is rich in mucous glands and poison glands, secreting substances important for gas exchange and playing a fundamental role in chemical defense against predators and microorganisms. In the caecilian Siphonops annulatus (Mikan, 1920) we observed a concentration of enlarged mucous glands in the head region. In the posterior region of the body a similar concentration is made up of enlarged poison glands. These accumulations of glands structurally resemble the macroglands previously reported in anurans and salamanders. The skin glands in these regions are each surrounded by collagen walls forming a honeycomb-like structure. The collagen network in the head region firmly attaches to tiny pits in the bones of the skull. The two extremities of the body produce different secretions, containing exclusive molecules. Considering the fossorial lifestyle of caecilians, it seems evident that the secretions of the head and caudal region serve different functions. The anterior macrogland of mucous glands, rich in mucous/lipid secretion, in conjunction with the funnel-shaped head, may act to lubricate the body and penetrate the soil, thus facilitating locomotion underground. The blunt posterior end bearing an internalized macrogland of poison glands in the dermis may act in chemical defense and/or by blocking invasion of tunnels. PMID- 29476102 TI - Do genetics help epidemiologists? Arterial hypertension and cardiovascular events in the light of genetic demiology. PMID- 29476101 TI - Membrane sculpting by curved DNA origami scaffolds. AB - Membrane sculpting and transformation is essential for many cellular functions, thus being largely regulated by self-assembling and self-organizing protein coats. Their functionality is often encoded by particular spatial structures. Prominent examples are BAR domain proteins, the 'banana-like' shapes of which are thought to aid scaffolding and membrane tubulation. To elucidate whether 3D structure can be uncoupled from other functional features of complex scaffolding proteins, we hereby develop curved DNA origami in various shapes and stacking features, following the presumable design features of BAR proteins, and characterize their ability for membrane binding and transformation. We show that dependent on curvature, membrane affinity and surface density, DNA origami coats can indeed reproduce the activity of membrane-sculpting proteins such as BAR, suggesting exciting perspectives for using them in bottom-up approaches towards minimal biomimetic cellular machineries. PMID- 29476103 TI - An integrated microfluidic device for the sorting of yeast cells using image processing. AB - The process of detection and separation of yeast cells based on their morphological characteristics is critical to the understanding of cell division cycles, which is of vital importance to the understanding of some diseases such as cancer. The traditional process of manual detection is usually tedious and inconsistent. This paper presents a microfluidic device integrated with microvalves for fluid control for the sorting of yeast cells using image processing algorithms and confirmation based on their fluorescent tag. The proposed device is completely automated, low cost and easy to implement in an academic research setting. Design details of the integrated microfluidic system are highlighted in this paper, along with experimental validation. Real time cell sorting was demonstrated with a cell detection rate of 12 cells per minute. PMID- 29476104 TI - Exploring the Link between Serum Phosphate Levels and Low Muscle Strength, Dynapenia, and Sarcopenia. AB - Emerging evidences addressed an association between phosphate and muscle function. Because little attention was focused on this issue, the objective of our study was to explore the relationship of phosphate with muscle strength, dynapenia, and sarcopenia. From the National Health and Nutrition Examination Survey, a total of 7421 participants aged 20 years or older were included in our study with comprehensive examinations included anthropometric parameters, strength of the quadriceps muscle, and appendicular lean masses. Within the normal range of serum phosphate, we used quartile-based analyses to determine the potential relationships of serum phosphate with dynapenia, and sarcopenia through multivariate regression models. After adjusting for the pertinent variables, an inverse association between the serum phosphate quartiles and muscle strength was observed and the linear association was stronger than other anthropometric parameters. Notably, the significant association between phosphate and muscle strength was existed in >65 years old age group, not in 20-65 years old. The higher quartiles of phosphate had higher likelihood for predicting the presence of dynapenia rather than sarcopenia in entire population. Our study highlighted that higher quartiles of phosphate had significant association with lower muscle strength and higher risks for predicting the presence of dynapenia. PMID- 29476105 TI - mTOR-dependent alterations of Kv1.1 subunit expression in the neuronal subset specific Pten knockout mouse model of cortical dysplasia with epilepsy. AB - Cortical dysplasia (CD) is a common cause for intractable epilepsy. Hyperactivation of the mechanistic target of rapamycin (mTOR) pathway has been implicated in CD; however, the mechanisms by which mTOR hyperactivation contribute to the epilepsy phenotype remain elusive. Here, we investigated whether constitutive mTOR hyperactivation in the hippocampus is associated with altered voltage-gated ion channel expression in the neuronal subset-specific Pten knockout (NS-Pten KO) mouse model of CD with epilepsy. We found that the protein levels of Kv1.1, but not Kv1.2, Kv1.4, or Kvbeta2, potassium channel subunits were increased, along with altered Kv1.1 distribution, within the hippocampus of NS-Pten KO mice. The aberrant Kv1.1 protein levels were present in young adult (>=postnatal week 6) but not juvenile (<=postnatal week 4) NS-Pten KO mice. No changes in hippocampal Kv1.1 mRNA levels were found between NS-Pten KO and WT mice. Interestingly, mTOR inhibition with rapamycin treatment at early and late stages of the pathology normalized Kv1.1 protein levels in NS-Pten KO mice to WT levels. Together, these studies demonstrate altered Kv1.1 protein expression in association with mTOR hyperactivation in NS-Pten KO mice and suggest a role for mTOR signaling in the modulation of voltage-gated ion channel expression in this model. PMID- 29476106 TI - Longitudinal change in the serology of antibodies to Chlamydia trachomatis pgp3 in children residing in a trachoma area. AB - A serologic test for antibodies to chlamydial antigen pgp3 may be a useful tool for trachoma surveillance. However, little is known about the stability of antibody status over time, or factors associated with seroreversion/conversion. A cohort of 2,111 children ages 1-9 years in Tanzania were followed for one year in the absence of mass azithromycin. At baseline and follow-up, they were evaluated for trachoma, chlamydial infection, and antibodies to chlamydial antigen pgp3. At baseline, 31% of children were seropositive for pgp3 antibodies and 6.4% seroreverted to negative over one year. Of those seronegative, 9.8% seroconverted over the year. The seroreverters had lower baseline mean fluorescence intensity (MFI-BG) values compared to the seropositives who remained positive (Odds Ratio = 0.04 for every unit increase in log10MFI-BG, 95% CI = 0.02-0.09), and were more likely to live in communities with trachoma <5% (p < 0.008). While seroconversion was expected, seroreversion was unexpected. The low seroprevalence rate reported from low endemic areas may be due to seroreversion as well as lack of exposure. PMID- 29476107 TI - Scalable Culturing of Primary Human Glioblastoma Tumor-Initiating Cells with a Cell-Friendly Culture System. AB - Glioblastoma is the most aggressive and deadly brain cancer. There is growing interest to develop drugs that specifically target to glioblastoma tumor initiating cells (TICs). However, the cost-effective production of large numbers of high quality glioblastoma TICs for drug discovery with current cell culturing technologies remains very challenging. Here, we report a new method that cultures glioblastoma TICs in microscale alginate hydrogel tubes (or AlgTubes). The AlgTubes allowed long-term culturing (~50 days, 10 passages) of glioblastoma TICs with high growth rate (~700-fold expansion/14 days), high cell viability and high volumetric yield (~3.0 * 108 cells/mL) without losing the stem cell properties, all offered large advancements over current culturing methods. This method can be applied for the scalable production of glioblastoma TICs at affordable cost for drug discovery. PMID- 29476108 TI - Non-empirical identification of trigger sites in heterogeneous processes using persistent homology. AB - Macroscopic phenomena, such as fracture, corrosion, and degradation of materials, are associated with various reactions which progress heterogeneously. Thus, material properties are generally determined not by their averaged characteristics but by specific features in heterogeneity (or 'trigger sites') of phases, chemical states, etc., where the key reactions that dictate macroscopic properties initiate and propagate. Therefore, the identification of trigger sites is crucial for controlling macroscopic properties. However, this is a challenging task. Previous studies have attempted to identify trigger sites based on the knowledge of materials science derived from experimental data ('empirical approach'). However, this approach becomes impractical when little is known about the reaction or when large multi-dimensional datasets, such as those with multiscale heterogeneities in time and/or space, are considered. Here, we introduce a new persistent homology approach for identifying trigger sites and apply it to the heterogeneous reduction of iron ore sinters. Four types of trigger sites, 'hourglass'-shaped calcium ferrites and 'island'- shaped iron oxides, were determined to initiate crack formation using only mapping data depicting the heterogeneities of phases and cracks without prior mechanistic information. The identification of these trigger sites can provide a design rule for reducing mechanical degradation during reduction. PMID- 29476109 TI - STAT3 regulates cytotoxicity of human CD57+ CD4+ T cells in blood and lymphoid follicles. AB - A subset of human follicular helper T cells (TFH) cells expresses CD57 for which no distinct function has been identified. We show that CD57+ TFH cells are universally PD-1hi, but compared to their CD57- PD-1hi counterparts, express little IL-21 or IL-10 among others. Instead, CD57 expression on TFH cells marks cytotoxicity transcriptional signatures that translate into only a weak cytotoxic phenotype. Similarly, circulating PD-1+ CD57+ CD4+ T cells make less cytokine than their CD57- PD-1+ counterparts, but have a prominent cytotoxic phenotype. By analysis of responses to STAT3-dependent cytokines and cells from patients with gain- or loss-of-function STAT3 mutations, we show that CD4+ T cell cytotoxicity is STAT3-dependent. TFH formation also requires STAT3, but paradoxically, once formed, PD-1hi cells become unresponsive to STAT3. These findings suggest that changes in blood and germinal center cytotoxicity might be affected by changes in STAT3 signaling, or modulation of PD-1 by therapy. PMID- 29476110 TI - A mouse model of miR-96, miR-182 and miR-183 misexpression implicates miRNAs in cochlear cell fate and homeostasis. AB - Germline mutations in Mir96, one of three co-expressed polycistronic miRNA genes (Mir96, Mir182, Mir183), cause hereditary hearing loss in humans and mice. Transgenic FVB/NCrl- Tg(GFAP-Mir183,Mir96,Mir182)MDW1 mice (Tg1MDW), which overexpress this neurosensory-specific miRNA cluster in the inner ear, were developed as a model system to identify, in the aggregate, target genes and biologic processes regulated by the miR-183 cluster. Histological assessments demonstrate Tg1MDW/1MDW homozygotes have a modest increase in cochlear inner hair cells (IHCs). Affymetrix mRNA microarray data analysis revealed that downregulated genes in P5 Tg1MDW/1MDW cochlea are statistically enriched for evolutionarily conserved predicted miR-96, miR-182 or miR-183 target sites. ABR and DPOAE tests from 18 days to 3 months of age revealed that Tg1MDW/1MDW homozygotes develop progressive neurosensory hearing loss that correlates with histologic assessments showing massive losses of both IHCs and outer hair cells (OHCs). This mammalian miRNA misexpression model demonstrates a potency and specificity of cochlear homeostasis for one of the dozens of endogenously co expressed, evolutionally conserved, small non-protein coding miRNA families. It should be a valuable tool to predict and elucidate miRNA-regulated genes and integrated functional gene expression networks that significantly influence neurosensory cell differentiation, maturation and homeostasis. PMID- 29476111 TI - Protective effects of Chinese Fenggang zinc selenium tea on metabolic syndrome in high-sucrose-high-fat diet-induced obese rats. AB - The protective effect of zinc selenium tea against metabolic syndrome (MetS) was tested by using a high-sucrose-high-fat diet (HSHFD)-induced MetS model. Fifty Sprague-Dawley rats were randomly divided into five groups: normal diet (C group), HSHFD (CH-group), HSHFD + green tea (0.24 g/kg/day) (TH-group), HSHFD + low-dose zinc selenium organic tea (0.24 g/kg/day) (ZTHL-group), and HSHFD + high dose zinc selenium organic tea (1.20 g/kg/day) (ZTHH-group). After 8 weeks, compared to both the C-group and CH-group, the hepatosomatic index (HI) was significantly reduced in the ZTHL-group (p < 0.05). Fasting blood glucose (FBG) levels were highest in the TH-group, followed by the CH-group, then the ZTHL group, then the ZTHH-group, and finally the C-group. Compared with the CH-group, the serum total cholesterol (TC) and low density lipid-cholesterol (LDL-C) concentrations were significantly lower in the ZTHH-group (p < 0.05). Significant decreases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bile acids (TBA), alkaline phosphatase (ALP), and direct bilirubin (DBIL) levels were observed in ZTHL-group versus the CH-group (p < 0.05). Serum alpha-L-fucosidase (AFU) levels in the ZTHH-group were lower than in the CH-group (P < 0.01). Histopathological examination of the liver and fat biopsies illustrates that the liver cells showed a decrease in the extent of necrosis and dropsy in the ZTHL-group and ZTHH-group versus the CH-group. Zinc selenium tea showed a protection effect against hepatic damage. PMID- 29476113 TI - Validity of Weyl fermion picture for transition metals monopnictides TaAs, TaP, NbAs, and NbP from ab initio studies. AB - We investigate electronic and optical properties of the topological Weyl semimetals TaAs, TaP, NbAs and NbP crystallizing in bct geometry by means of the ab initio density functional theory with spin-orbit interaction within the independent-particle approximation. The small energetical overlap of Ta5d or Nb4d derived conduction and valence bands leads to electron and/or hole pockets near the Fermi energy at the 24 Weyl nodes. The nodes give rise to two-(three )dimensional Dirac cones for the W1 (W2) Weyl type. The band dispersion and occupation near the Weyl nodes determine the infrared optical properties. They are dominated by interband transitions, which lead to a deviation from the expected constant values of the imaginary part of the dielectric function. The resulting polarization anisotropy is also visible in the real part of the optical conductivity, whose lineshape deviates from the expected linearity. The details of the Weyl nodes are discussed in relation to recent ARPES results for TaAs and NbP, and compared with measured optical spectra for TaAs. The spectral features of the anisotropic and tilted Weyl fermions are restricted to low excitation energies above absorption onsets due to the band occupation. PMID- 29476112 TI - Investigation of the prevalence of Cognitive Impairment and its risk factors within the elderly population in Shanghai, China. AB - To investigate the prevalence of cognitive impairment and its risk factors among Chinese elders aged over 80 years, a community-based, cross-sectional study was conducted from May to June 2016 in Shanghai, China. Cognitive function was measured by using Mini-Mental Status Examination. Multiple logistic regression assessed associations between risk factors and cognitive impairment. Of 480 participants, 30% were diagnosed with cognitive impairment. Women [adjusted odds ratio (AOR): 1.71, 95% confidence interval (CI): 1.03-2.83], solitary life (AOR: 3.15, 1.89-5.26), monthly income less than 2000 Chinese yuan (AOR: 3.47, 1.18 10.23) were significantly associated with increased risk of cognitive impairment, compared with men, non-solitary life, and monthly income greater than 4000 Chinese yuan, respectively. Overweight (AOR: 0.59, 0.36-0.97), being physically active at least 60 minutes per day (AOR: 0.59, 0.35-0.95), antihypertensive drugs users (AOR: 0.45, 0.28-0.72), and lipid lowering drugs users (AOR: 0.21, 0.06 0.76) significantly lowered the risk of cognitive impairment, compared with normal weight, inadequate outdoor activity, and non-medication users, respectively. Accordingly, this study found that women, solitary life, lower income was associated with increased risk of cognitive impairment, while overweight, being physically active, and antihypertensive and lipid lowering drugs usage might lower the risk. PMID- 29476114 TI - Alleviation of drought stress in pulse crops with ACC deaminase producing rhizobacteria isolated from acidic soil of Northeast India. AB - The agricultural crops are often affected by the scarcity of fresh water. Seasonal drought is a major constraint on Northeast Indian agriculture. Almost 80% of the agricultural land in this region is acidic and facing severe drought during the winter period. Apart from classical breeding and transgenic approaches, the application of plant-growth-promoting bacteria (PGPB) is an alternative strategy for improving plant fitness under stressful conditions. The 1-aminocyclopropane-1-carboxylate (ACC) deaminase-producing PGPB offer drought stress tolerance by regulating plant ethylene levels. The aim of the present study was to evaluate the consortium effect of three ACC-deaminase producing rhizobacteria - Ochrobactrum pseudogrignonenseRJ12, Pseudomonas sp.RJ15 and Bacillus subtilisRJ46 on drought stress alleviation in Vigna mungo L. and Pisum sativum L. Consortium treatment significantly increase seed germination percentage, root length, shoot length, and dry weight of treated plants. An elevated production of reactive oxygen species scavenging enzymes and cellular osmolytes; higher leaf chlorophyll content; increase in relative water content and root recovery intension were observed after consortium treatment in comparison with the uninoculated plants under drought conditions. The consortium treatment decreased the ACC accumulation and down-regulated ACC-oxidase gene expression. This consortium could be an effective bio-formulator for crop health improvement in drought-affected acidic agricultural fields. PMID- 29476115 TI - Body temperature measurement in mice during acute illness: implantable temperature transponder versus surface infrared thermometry. AB - Body temperature is a valuable parameter in determining the wellbeing of laboratory animals. However, using body temperature to refine humane endpoints during acute illness generally lacks comprehensiveness and exposes to inter observer bias. Here we compared two methods to assess body temperature in mice, namely implanted radio frequency identification (RFID) temperature transponders (method 1) to non-contact infrared thermometry (method 2) in 435 mice for up to 7 days during normothermia and lipopolysaccharide (LPS) endotoxin-induced hypothermia. There was excellent agreement between core and surface temperature as determined by method 1 and 2, respectively, whereas the intra- and inter subject variation was higher for method 2. Nevertheless, using machine learning algorithms to determine temperature-based endpoints both methods had excellent accuracy in predicting death as an outcome event. Therefore, less expensive and cumbersome non-contact infrared thermometry can serve as a reliable alternative for implantable transponder-based systems for hypothermic responses, although requiring standardization between experimenters. PMID- 29476116 TI - HMG-CoA reductase from Camphor Tulsi (Ocimum kilimandscharicum) regulated MVA dependent biosynthesis of diverse terpenoids in homologous and heterologous plant systems. AB - Ocimum kilimandscharicum is unique in possessing terpenoids whereas other Ocimum species are renowned for phenylpropanoids as major constituents of essential oil. The key enzyme of MVA/terpenoid metabolic pathway viz 3-hydroxy-3-methylglutaryl Co-A reductase (OkHMGR) of 1.7-Kb ORF encoding ~60-kDa protein was cloned from O. kilimandscharicum and its kinetic characteristics revealed the availability of HMG-CoA as a control point of MVA-pathway. Transcript profiling of the OkHMGR elucidated tissue-specific functions of the gene in flower and leaf tissues in accumulation of terpenoidal essential oil. OkHMGR was differentially regulated in response to exposure to methyl-jasmonate, salicylic-acid, and stress conditions such-as salt and temperature stress, demonstrating its key role in managing signaling and stress-responses. To elucidate its functional role, OkHMGR was transiently over-expressed in homologous and heterologous plants such as O. sanctum, O. basilicum, O. gratissimum, Withania somnifera and Artemisia annua. The over-expression and inhibition dual strategy revealed that the additional OkHMGR in-planta could afford endogenous flow of isoprenoid units towards synthesis of terpenoids. The present study provides in-depth insight of OkHMGR in regulation of biosynthesis of non-plastidal isoprenoids. This is first report on any gene of MVA/isoprenoid pathway from under-explored Camphor Tulsi belonging to genus Ocimum. Studies also suggested that OkHMGR could be a potential tool for attempting metabolic engineering for enhancing medicinally important terpenoidal metabolites in plants. PMID- 29476117 TI - Strong mechanical squeezing in an electromechanical system. AB - The mechanical squeezing can be used to explore quantum behavior in macroscopic system and realize precision measurement. Here we present a potentially practical method for generating strong squeezing of the mechanical oscillator in an electromechanical system. Through the Coulomb interaction between a charged mechanical oscillator and two fixed charged bodies, we engineer a quadratic electromechanical Hamiltonian for the vibration mode of mechanical oscillator. We show that the strong position squeezing would be obtained on the currently available experimental technologies. PMID- 29476118 TI - Disentangling thermal stress responses in a reef-calcifier and its photosymbionts by shotgun proteomics. AB - The proliferation of key marine ecological engineers and carbonate producers often relies on their association with photosymbiotic algae. Evaluating stress responses of these organisms is important to predict their fate under future climate projections. Physiological approaches are limited in their ability to resolve the involved molecular mechanisms and attribute stress effects to the host or symbiont, while probing and partitioning of proteins cannot be applied in organisms where the host and symbiont are small and cannot be physically separated. Here we apply a label-free quantitative proteomics approach to detect changes of proteome composition in the diatom-bearing benthic foraminifera Amphistegina gibbosa experimentally exposed to three thermal-stress scenarios. We developed a workflow for protein extraction from less than ten specimens and simultaneously analysed host and symbiont proteomes. Despite little genomic data for the host, 1,618 proteins could be partially assembled and assigned. The proteomes revealed identical pattern of stress response among stress scenarios as that indicated by physiological measurements, but allowed identification of compartment-specific stress reactions. In the symbiont, stress-response and proteolysis-related proteins were up regulated while photosynthesis-related proteins declined. In contrast, host homeostasis was maintained through chaperone up-regulation associated with elevated proteosynthesis and proteolysis, and the host metabolism shifted to heterotrophy. PMID- 29476119 TI - Trans-generational inheritance of herbivory-induced phenotypic changes in Brassica rapa. AB - Biotic stress can induce plastic changes in fitness-relevant plant traits. Recently, it has been shown that such changes can be transmitted to subsequent generations. However, the occurrence and extent of transmission across different types of traits is still unexplored. Here, we assessed the emergence and transmission of herbivory-induced changes in Brassica rapa and their impact on interactions with insects. We analysed changes in morphology and reproductive traits as well as in flower and leaf volatile emission during two generations with leaf herbivory by Mamestra brassicae and Pieris brassicae and two subsequent generations without herbivory. Herbivory induced changes in all trait types, increasing attractiveness of the plants to the parasitoid wasp Cotesia glomerata and decreasing visitation by the pollinator Bombus terrestris, a potential trade off. While changes in floral and leaf volatiles disappeared in the first generation after herbivory, some changes in morphology and reproductive traits were still measurable two generations after herbivory. However, neither parasitoids nor pollinators further discriminated between groups with different past treatments. Our results suggest that transmission of herbivore-induced changes occurs preferentially in resource-limited traits connected to plant growth and reproduction. The lack of alterations in plant-insect interactions was likely due to the transient nature of volatile changes. PMID- 29476121 TI - Shuang-Huang-Lian injection induces an immediate hypersensitivity reaction via C5a but not IgE. AB - Among traditional Chinese medicine injections, intravenous Shuang-Huang-Lian (IV SHL) has the highest incidence of injection-induced immediate hypersensitivity reactions (IHRs). The precise mechanisms of IV-SHL-induced IHRs remain ambiguous. In this study, we investigated the mechanisms of SHL injection (SHLI)-induced IHRs. Our data showed that serum total IgE and mouse mast cell protease 1 (MMCP1) levels were higher in the SHLI antiserum; however, these effects of SHLI disappeared in the antibiotic-treated mice. SHLI caused intraplantar vasopermeability and shock during the first local or systemic injection. SHLI induced nonallergic IHRs were attributed to its intermediate fraction F2 (the extract of Lonicerae Japonicae Flos and Fructus forsythiae), and could be blocked by antagonists for histamine or C5a, rather than PAF or C3a. Eight constituents of F2 were able to directly activate C5 to promote local vasopermeability at the mg/mL level. In conclusion, SHLI-induced IHRs are not mediated by IgE. SHLI or its F2 can directly activate blood C5. Subsequently, C5a is likely to provoke histamine release from its effector cells (e.g., mast cells and basophils), indicating that histamine is a principal effector of IHRs induced by SHLI. PMID- 29476122 TI - Author Correction: Cryo-electron tomography reveals that dynactin recruits a team of dyneins for processive motility. AB - In the version of this article initially published online, an incorrect accession code, EMD-5NW4, was introduced on page 1 of the article PDF, in section 'BICD2N mediates the association of two dynein dimers with a single dynactin'. This has been corrected to PDB 5NW4. The error has been corrected in the PDF and HTML versions of this article. PMID- 29476120 TI - The transcriptomic signature of different sexes in two protogynous hermaphrodites: Insights into the molecular network underlying sex phenotype in fish. AB - Sex differentiation is a puzzling problem in fish due to the variety of reproductive systems and the flexibility of their sex determination mechanisms. The Sparidae, a teleost family, reflects this remarkable diversity of sexual mechanisms found in fish. Our aim was to capture the transcriptomic signature of different sexes in two protogynous hermaphrodite sparids, the common pandora Pagellus erythrinus and the red porgy Pagrus pagrus in order to shed light on the molecular network contributing to either the female or the male phenotype in these organisms. Through RNA sequencing, we investigated sex-specific differences in gene expression in both species' brains and gonads. The analysis revealed common male and female specific genes/pathways between these protogynous fish. Whereas limited sex differences found in the brain indicate a sexually plastic tissue, in contrast, the great amount of sex-biased genes observed in gonads reflects the functional divergence of the transformed tissue to either its male or female character. Alpha common "crew" of well-known molecular players is acting to preserve either sex identity of the gonad in these fish. Lastly, this study lays the ground for a deeper understanding of the complex process of sex differentiation in two species with an evolutionary significant reproductive system. PMID- 29476123 TI - Wrinkled Nitrogen-doped Carbon Belts. AB - Graphene, carbon nanotubes, and fullerenes are nanomaterials with outstanding properties such as electrical, thermal, mechanical strength, flexibility, and high surface area. These nanomaterials are used as building blocks for the construction of novel and astonishing 3D-dimensional networks. In the present work, nitrogen-doped carbon belt (N-CB) structures containing wrinkled carbon fibres as building blocks were synthesized under unstable conditions in a chemical vapour deposition experiment. N-CB structures with 0.2-3.0 microns of wide and 350 nm thick were assembled from complex individual wrinkled carbon fibres grown on Co/Cu films. These complex structures have a tubular appearance, showing holed and wrinkled graphite layers. Sulphur and copper atoms drastically affect the catalytic role of cobalt, changing the conventional growth of carbon nanotubes. Chemical functional groups, N-doping, and carbons hybridizations involved in the winkled carbon fibres are investigated. These findings provides a novel material that can be used as an excellent oxygen-reduction reaction catalyst or nano-electronics component. PMID- 29476124 TI - Interpregnancy interval, maternal age, and offspring's BMI and blood pressure at 7 years of age. AB - Interpregnancy interval and maternal age are associated with birth outcomes. However, it is unknown regarding their long-term effects on child health. We aim to assess the associations between interpregnancy interval and offspring's body mass index (BMI) and blood pressure (BP) at age of 7 years and to examine the role of maternal age in the associations. A secondary analysis was performed among 2604 mother-infant pairs in the prospective National Collaborative Perinatal Project, in which the children were followed up until 7 yrs of age. Interpregnancy interval was positively associated with offspring's diastolic BP at 7 yrs (beta = 0.053, 95% CI: 0.004-0.102) after adjusting for maternal and perinatal characteristics, feeding pattern, rapid weight gain in the first year of life, and current BMI z score and height z score. The inclusion of maternal age in the model did not change the effect size. Maternal age was independently associated with offspring's BMI z score at 7 yrs (beta = 0.014, 95% CI: 0.001 0.027). An interaction between interpregnancy interval and maternal age was present in the association with diastolic BP (P = 0.019), and the increasing maternal age aggravated the effects of long interpregnancy interval. Our finding suggests long interpregnancy interval is a risk factor for higher diastolic BP of the offspring. Increasing maternal age could amplify the impact. Our study challenges the current WHO recommendation for ideal interpregnancy interval, and we would suggest lowering the recommendation to <24 months and even shorter for women of advanced age. PMID- 29476126 TI - Following the pathway to Alzheimer's disease. PMID- 29476125 TI - Nanodelivery of a functional membrane receptor to manipulate cellular phenotype. AB - Modification of membrane receptor makeup is one of the most efficient ways to control input-output signals but is usually achieved by expressing DNA or RNA encoded proteins or by using other genome-editing methods, which can be technically challenging and produce unwanted side effects. Here we develop and validate a nanodelivery approach to transfer in vitro synthesized, functional membrane receptors into the plasma membrane of living cells. Using beta2 adrenergic receptor (beta2AR), a prototypical G-protein coupled receptor, as an example, we demonstrated efficient incorporation of a full-length beta2AR into a variety of mammalian cells, which imparts pharmacologic control over cellular signaling and affects cellular phenotype in an ex-vivo wound-healing model. Our approach for nanodelivery of functional membrane receptors expands the current toolkit for DNA and RNA-free manipulation of cellular function. We expect this approach to be readily applicable to the synthesis and nanodelivery of other types of GPCRs and membrane receptors, opening new doors for therapeutic development at the intersection between synthetic biology and nanomedicine. PMID- 29476127 TI - Huntington modeling improves with age. PMID- 29476129 TI - Stress and sociability. PMID- 29476128 TI - An innate circuit for object craving. PMID- 29476130 TI - Allopurinol partially prevents disuse muscle atrophy in mice and humans. AB - Disuse muscle wasting will likely affect everyone in his or her lifetime in response to pathologies such as joint immobilization, inactivity or bed rest. There are no good therapies to treat it. We previously found that allopurinol, a drug widely used to treat gout, protects muscle damage after exhaustive exercise and results in functional gains in old individuals. Thus, we decided to test its effect in the prevention of soleus muscle atrophy after two weeks of hindlimb unloading in mice, and lower leg immobilization following ankle sprain in humans (EudraCT: 2011-003541-17). Our results show that allopurinol partially protects against muscle atrophy in both mice and humans. The protective effect of allopurinol is similar to that of resistance exercise which is the best-known way to prevent muscle mass loss in disuse human models. We report that allopurinol protects against the loss of muscle mass by inhibiting the expression of ubiquitin ligases. Our results suggest that the ubiquitin-proteasome pathway is an appropriate therapeutic target to inhibit muscle wasting and emphasizes the role of allopurinol as a non-hormonal intervention to treat disuse muscle atrophy. PMID- 29476132 TI - Evolution of relative survival for acute promyelocytic leukemia patients alive at landmark time-points: a population-based study. PMID- 29476131 TI - The Mechanisms of Carnosol in Chemoprevention of Ultraviolet B-Light-Induced Non Melanoma Skin Cancer Formation. AB - Carnosol is a natural compound extracted from rosemary and sage, which has been demonstrated to have anti-inflammatory, anti-oxidant, and anti-cancer properties. In this report, we evaluated the therapeutic potential and elucidated the potential mechanism of action of carnosol in chemoprevention of ultraviolet B light (UVB) induced non-melanoma skin cancer formation. Our data indicated that carnosol could partially reduce UVB-induced reactive oxygen species (ROS) elevation and thus reduce DNA damage. It could also reduce UVB-induced formation of cyclobutane pyrimidine dimers (CDP) in keratinocytes possibly through its ability in absorbing UVB radiation. In addition, carnosol could inhibit the UVB induced activation of NF-kappaB and also reduce UVB-induced transformation of keratinocytes. Taken together, the results indicate the role of carnosol as a potential chemopreventive agent upon UVB radiation. PMID- 29476133 TI - Precipitation of binary quasicrystals along dislocations. AB - Dislocations in crystals naturally break the symmetry of the bulk, introducing local atomic configurations with symmetries such as fivefold rings. But dislocations do not usually nucleate aperiodic structure along their length. Here we demonstrate the formation of extended binary quasicrystalline precipitates with Penrose-like random-tiling structures, beginning with chemical ordering within the pentagonal structure at cores of prismatic dislocations in Mg-Zn alloys. Atomic resolution observations indicate that icosahedral chains centered along [0001] pillars of Zn interstitial atoms are formed templated by the fivefold rings at dislocation cores. They subsequently form columns of rhombic and elongated hexagonal tiles parallel to the dislocation lines. Quasicrystalline precipitates are formed by random tiling of these rhombic and hexagonal tiles. Such precipitation may impact dislocation glide and alloy strength. PMID- 29476134 TI - ATLANTIS - Attractor Landscape Analysis Toolbox for Cell Fate Discovery and Reprogramming. AB - Boolean modelling of biological networks is a well-established technique for abstracting dynamical biomolecular regulation in cells. Specifically, decoding linkages between salient regulatory network states and corresponding cell fate outcomes can help uncover pathological foundations of diseases such as cancer. Attractor landscape analysis is one such methodology which converts complex network behavior into a landscape of network states wherein each state is represented by propensity of its occurrence. Towards undertaking attractor landscape analysis of Boolean networks, we propose an Attractor Landscape Analysis Toolbox (ATLANTIS) for cell fate discovery, from biomolecular networks, and reprogramming upon network perturbation. ATLANTIS can be employed to perform both deterministic and probabilistic analyses. It has been validated by successfully reconstructing attractor landscapes from several published case studies followed by reprogramming of cell fates upon therapeutic treatment of network. Additionally, the biomolecular network of HCT-116 colorectal cancer cell line has been screened for therapeutic evaluation of drug-targets. Our results show agreement between therapeutic efficacies reported by ATLANTIS and the published literature. These case studies sufficiently highlight the in silico cell fate prediction and therapeutic screening potential of the toolbox. Lastly, ATLANTIS can also help guide single or combinatorial therapy responses towards reprogramming biomolecular networks to recover cell fates. PMID- 29476135 TI - Development differentially sculpts receptive fields across early and high-level human visual cortex. AB - Receptive fields (RFs) processing information in restricted parts of the visual field are a key property of visual system neurons. However, how RFs develop in humans is unknown. Using fMRI and population receptive field (pRF) modeling in children and adults, we determine where and how pRFs develop across the ventral visual stream. Here we report that pRF properties in visual field maps, from the first visual area, V1, through the first ventro-occipital area, VO1, are adult like by age 5. However, pRF properties in face-selective and character-selective regions develop into adulthood, increasing the foveal coverage bias for faces in the right hemisphere and words in the left hemisphere. Eye-tracking indicates that pRF changes are related to changing fixation patterns on words and faces across development. These findings suggest a link between face and word viewing behavior and the differential development of pRFs across visual cortex, potentially due to competition on foveal coverage. PMID- 29476136 TI - A recurrent kinase domain mutation in PRKCA defines chordoid glioma of the third ventricle. AB - Chordoid glioma is a rare brain tumor thought to arise from specialized glial cells of the lamina terminalis along the anterior wall of the third ventricle. Despite being histologically low-grade, chordoid gliomas are often associated with poor outcome, as their stereotypic location in the third ventricle makes resection challenging and efficacious adjuvant therapies have not been developed. Here we performed genomic profiling on 13 chordoid gliomas and identified a recurrent D463H missense mutation in PRKCA in all tumors, which localizes in the kinase domain of the encoded protein kinase C alpha (PKCalpha). Expression of mutant PRKCA in immortalized human astrocytes led to increased phospho-ERK and anchorage-independent growth that could be blocked by MEK inhibition. These studies define PRKCA as a recurrently mutated oncogene in human cancer and identify a potential therapeutic vulnerability in this uncommon brain tumor. PMID- 29476138 TI - Distribution of metals and metalloids in dried seaweeds and health risk to population in southeastern China. AB - Concern about metals and metalloids, especially heavy metals in seaweeds has risen due to potential health risk. This study investigated the distribution of 10 metals and metalloids in 295 dried seaweeds (brown and red) and estimated the possible health risk via hazard index (HI). Elements in seaweeds can be sequenced in descending order by mean values: Al > Mn > As > Cu > Cr > Ni > Cd > Se > Pb > Hg. The levels of Cd, Cu, Mn and Ni in red seaweeds were significantly higher than those in brown seaweeds (P < 0.01). Correlation analysis showed contents of Ni-Cr (r = 0.59, P < 0.01) in seaweeds had moderate positive correlations. Seaweeds from different geographical origins had diverse element distribution. Risk assessment showed that HI at mean level was less than the threshold of 1. It indicates that for the general people there is low health risk to these elements by the intake of seaweeds. Furthermore, in terms of the confirmative toxicity of some metals, such as Cd, Pb and Hg, surveillance of metals in seaweeds should be performed continuously. PMID- 29476137 TI - Phospholipase D functional ablation has a protective effect in an Alzheimer's disease Caenorhabditis elegans model. AB - Phospholipase D (PLD) is a key player in the modulation of multiple aspects of cell physiology and has been proposed as a therapeutic target for Alzheimer's disease (AD). Here, we characterize a PLD mutant, pld-1, using the Caenorhabditis elegans animal model. We show that pld-1 animals present decreased phosphatidic acid levels, that PLD is the only source of total PLD activity and that pld-1 animals are more sensitive to the acute effects of ethanol. We further show that PLD is not essential for survival or for the normal performance in a battery of behavioral tests. Interestingly, pld-1 animals present both increased size and lipid stores levels. While ablation of PLD has no important effect in worm behavior, its ablation in an AD-like model that overexpresses amyloid-beta (Abeta), markedly improves various phenotypes such as motor tasks, prevents susceptibility to a proconvulsivant drug, has a protective effect upon serotonin treatment and reverts the biometric changes in the Abeta animals, leading to the normalization of the worm body size. Overall, this work proposes the C. elegans model as a relevant tool to study the functions of PLD and further supports the notion that PLD has a significant role in neurodegeneration. PMID- 29476139 TI - Depth matters: effects of precipitation regime on soil microbial activity upon rewetting of a plant-soil system. AB - Changes in frequency and amplitude of rain events, that is, precipitation patterns, result in different water conditions with soil depth, and likely affect plant growth and shape plant and soil microbial activity. Here, we used 18O stable isotope probing (SIP) to investigate bacterial and fungal communities that actively grew or not upon rewetting, at three different depths in soil mesocosms previously subjected to frequent or infrequent watering for 12 weeks (equal total water input). Phylogenetic marker genes for bacteria and fungi were sequenced after rewetting, and plant-soil microbial coupling documented by plant 13C-CO2 labeling. Soil depth, rather than precipitation pattern, was most influential in shaping microbial response to rewetting, and had differential effects on active and inactive bacterial and fungal communities. After rewetting, active bacterial communities were less rich, more even and phylogenetically related than the inactive, and reactivated throughout the soil profile. Active fungal communities after rewetting were less abundant and rich than the inactive. The coupling between plants and soil microbes decreased under infrequent watering in the top soil layer. We suggest that differences in fungal and bacterial abundance and relative activity could result in large effects on subsequent soil biogeochemical cycling. PMID- 29476140 TI - Proteorhodopsin variability and distribution in the North Pacific Subtropical Gyre. AB - Proteorhodopsin is a light-activated retinal-containing proton pump found in many marine bacteria. These photoproteins are globally distributed in the ocean's photic zone and are capable of generating a proton motive force across the cell membrane. We investigated the phylogenetic diversity, distribution, and abundance of proteorhodopsin encoding genes in free-living bacterioplankton in the North Pacific Subtropical Gyre, leveraging a gene catalog derived from metagenomic samples from the ocean's surface to 1000 m depth. Proteorhodopsin genes were identified at all depths sampled, but were most abundant at depths shallower than 200 m. The majority of proteorhodopsin gene sequences (60.9%) belonged to members of the SAR11 lineage, with remaining sequences distributed among other diverse taxa. We observed variations in the conserved residues involved in ion pumping and spectral tuning, and biochemically confirmed four different proton pumping proteorhodopsin motifs, including one unique to deep-water SAR11. We also identified a new group of putative proteorhodopsins having unknown function. Our results reveal a broad organismal and unexpected depth distribution for different proteorhodopsin types, as well as substantial within-taxon variability. These data provide a framework for exploring the ecological relevance of proteorhodopsins and their spatiotemporal variation and function in heterotrophic bacteria in the open ocean. PMID- 29476141 TI - Genome-resolved metagenomics identifies genetic mobility, metabolic interactions, and unexpected diversity in perchlorate-reducing communities. AB - Dissimilatory perchlorate reduction is an anaerobic respiratory pathway that in communities might be influenced by metabolic interactions. Because the genes for perchlorate reduction are horizontally transferred, previous studies have been unable to identify uncultivated perchlorate-reducing populations. Here we recovered metagenome-assembled genomes from perchlorate-reducing sediment enrichments and employed a manual scaffolding approach to reconstruct gene clusters for perchlorate reduction found within mobile genetic elements. De novo assembly and binning of four enriched communities yielded 48 total draft genomes. In addition to canonical perchlorate reduction gene clusters and taxa, a new type of gene cluster with an alternative perchlorate reductase was identified. Phylogenetic analysis indicated past exchange between these gene clusters, and the presence of plasmids with either gene cluster shows that the potential for gene transfer via plasmid persisted throughout enrichment. However, a majority of genomes in each community lacked perchlorate reduction genes. Putative chlorate reducing or sulfur-reducing populations were dominant in most communities, supporting the hypothesis that metabolic interactions might result from perchlorate reduction intermediates and byproducts. Other populations included a novel phylum-level lineage (Ca. Muirbacteria) and epibiotic prokaryotes with no known role in perchlorate reduction. These results reveal unexpected genetic diversity, suggest that perchlorate-reducing communities involve substantial metabolic interactions, and encourage expanded strategies to further understand the evolution and ecology of this metabolism. PMID- 29476142 TI - Mycoplasma-related endobacteria within Mortierellomycotina fungi: diversity, distribution and functional insights into their lifestyle. AB - Bacterial interactions with animals and plants have been examined for over a century; by contrast, the study of bacterial-fungal interactions has received less attention. Bacteria interact with fungi in diverse ways, and endobacteria that reside inside fungal cells represent the most intimate interaction. The most significant bacterial endosymbionts that have been studied are associated with Mucoromycota and include two main groups: Burkholderia-related and Mycoplasma related endobacteria (MRE). Examples of Burkholderia-related endobacteria have been reported in the three Mucoromycota subphyla. By contrast, MRE have only been identified in Glomeromycotina and Mucoromycotina. This study aims to understand whether MRE dwell in Mortierellomycotina and, if so, to determine their impact on the fungal host. We carried out a large-scale screening of 394 Mortierellomycotina strains and employed a combination of microscopy, molecular phylogeny, next-generation sequencing and qPCR. We detected MRE in 12 strains. These endosymbionts represent novel bacterial phylotypes and show evidence of recombination. Their presence in Mortierellomycotina demonstrates that MRE occur within fungi across Mucoromycota and they may have lived in their common ancestor. We cured the fungus of its endosymbionts with antibiotics and observed improved biomass production in isogenic lines lacking MRE, demonstrating that these endobacteria impose some fitness costs to their fungal host. Here we provided the first functional insights into the lifestyle of MRE. Our findings indicate that MRE may be antagonistic to their fungal hosts, and adapted to a non lethal parasitic lifestyle in the mycelium of Mucoromycota. However, context dependent adaptive benefits to their host at minimal cost cannot not be excluded. Finally, we conclude that Mortierellomycotina represent attractive model organisms for exploring interactions between MRE and fungi. PMID- 29476144 TI - Hypoglycemic and hypolipidemic effect of S-allyl-cysteine sulfoxide (alliin) in DIO mice. AB - Alliin (S-allyl cysteine sulfoxide) is a bioactive sulfoxide compound derived from garlic. To evaluate the preventive effect of alliin against metabolic risk factors in diet induced obese (DIO) mice, we treated the C57BL/6J DIO mice with drinking water with or without alliin (0.1 mg/ml) for 8 weeks. Results showed that alliin had no significant effect on the body weight, adiposity or energy balance. However, alliin treatment enhanced glucose homeostasis, increased insulin sensitivity and improved the lipid profile in the DIO mice. This was, at least partly, attributable to alliin induced modulation of the intestinal microbiota composition, typically decreased Lachnospiraceae and increased Ruminococcaceae. From above, we conclude that alliin has nutraceutical or even medicinal potential in prevention of diabetes and lipid metabolic disorders. PMID- 29476143 TI - Peatland Acidobacteria with a dissimilatory sulfur metabolism. AB - Sulfur-cycling microorganisms impact organic matter decomposition in wetlands and consequently greenhouse gas emissions from these globally relevant environments. However, their identities and physiological properties are largely unknown. By applying a functional metagenomics approach to an acidic peatland, we recovered draft genomes of seven novel Acidobacteria species with the potential for dissimilatory sulfite (dsrAB, dsrC, dsrD, dsrN, dsrT, dsrMKJOP) or sulfate respiration (sat, aprBA, qmoABC plus dsr genes). Surprisingly, the genomes also encoded DsrL, which so far was only found in sulfur-oxidizing microorganisms. Metatranscriptome analysis demonstrated expression of acidobacterial sulfur metabolism genes in native peat soil and their upregulation in diverse anoxic microcosms. This indicated an active sulfate respiration pathway, which, however, might also operate in reverse for dissimilatory sulfur oxidation or disproportionation as proposed for the sulfur-oxidizing Desulfurivibrio alkaliphilus. Acidobacteria that only harbored genes for sulfite reduction additionally encoded enzymes that liberate sulfite from organosulfonates, which suggested organic sulfur compounds as complementary energy sources. Further metabolic potentials included polysaccharide hydrolysis and sugar utilization, aerobic respiration, several fermentative capabilities, and hydrogen oxidation. Our findings extend both, the known physiological and genetic properties of Acidobacteria and the known taxonomic diversity of microorganisms with a DsrAB based sulfur metabolism, and highlight new fundamental niches for facultative anaerobic Acidobacteria in wetlands based on exploitation of inorganic and organic sulfur molecules for energy conservation. PMID- 29476145 TI - Coordinate and redox interactions of epinephrine with ferric and ferrous iron at physiological pH. AB - Coordinate and redox interactions of epinephrine (Epi) with iron at physiological pH are essential for understanding two very different phenomena - the detrimental effects of chronic stress on the cardiovascular system and the cross-linking of catecholamine-rich biopolymers and frameworks. Here we show that Epi and Fe3+ form stable high-spin complexes in the 1:1 or 3:1 stoichiometry, depending on the Epi/Fe3+ concentration ratio (low or high). Oxygen atoms on the catechol ring represent the sites of coordinate bond formation within physiologically relevant bidentate 1:1 complex. Redox properties of Epi are slightly impacted by Fe3+. On the other hand, Epi and Fe2+ form a complex that acts as a strong reducing agent, which leads to the production of hydrogen peroxide via O2 reduction, and to a facilitated formation of the Epi-Fe3+ complexes. Epi is not oxidized in this process, i.e. Fe2+ is not an electron shuttle, but the electron donor. Epi catalyzed oxidation of Fe2+ represents a plausible chemical basis of stress related damage to heart cells. In addition, our results support the previous findings on the interactions of catecholamine moieties in polymers with iron and provide a novel strategy for improving the efficiency of cross-linking. PMID- 29476146 TI - Solution processable and optically switchable 1D photonic structures. AB - We report the first demonstration of a solution processable, optically switchable 1D photonic crystal which incorporates phototunable doped metal oxide nanocrystals. The resulting device structure shows a dual optical response with the photonic bandgap covering the visible spectral range and the plasmon resonance of the doped metal oxide the near infrared. By means of a facile photodoping process, we tuned the plasmonic response and switched effectively the optical properties of the photonic crystal, translating the effect from the near infrared to the visible. The ultrafast bandgap pumping induces a signal change in the region of the photonic stopband, with recovery times of several picoseconds, providing a step toward the ultrafast optical switching. Optical modeling uncovers the importance of a complete modeling of the variations of the dielectric function of the photodoped material, including the high frequency region of the Drude response which is responsible for the strong switching in the visible after photodoping. Our device configuration offers unprecedented tunability due to flexibility in device design, covering a wavelength range from the visible to the near infrared. Our findings indicate a new protocol to modify the optical response of photonic devices by optical triggers only. PMID- 29476148 TI - Optical control of cytoplasmic flows. PMID- 29476147 TI - MEMS-tunable dielectric metasurface lens. AB - Varifocal lenses, conventionally implemented by changing the axial distance between multiple optical elements, have a wide range of applications in imaging and optical beam scanning. The use of conventional bulky refractive elements makes these varifocal lenses large, slow, and limits their tunability. Metasurfaces, a new category of lithographically defined diffractive devices, enable thin and lightweight optical elements with precisely engineered phase profiles. Here we demonstrate tunable metasurface doublets, based on microelectromechanical systems (MEMS), with more than 60 diopters (about 4%) change in the optical power upon a 1-MUm movement of one metasurface, and a scanning frequency that can potentially reach a few kHz. They can also be integrated with a third metasurface to make compact microscopes (~1 mm thick) with a large corrected field of view (~500 MUm or 40 degrees) and fast axial scanning for 3D imaging. This paves the way towards MEMS-integrated metasurfaces as a platform for tunable and reconfigurable optics. PMID- 29476149 TI - Exosomes deliver ROS for regeneration. PMID- 29476150 TI - An additional class of m6A readers. PMID- 29476153 TI - The autophagic network and cancer. AB - Mammalian cells harness autophagy to eliminate physiological byproducts of metabolism and cope with microenvironmental perturbations. Moreover, autophagy connects cellular adaptation with extracellular circuitries that impinge on immunity and metabolism. As it links transformed and non-transformed components of the tumour microenvironment, such an autophagic network is important for cancer initiation, progression and response to therapy. Here, we discuss the mechanisms whereby the autophagic network interfaces with multiple aspects of malignant disease. PMID- 29476151 TI - Cargo recognition and degradation by selective autophagy. AB - Macroautophagy, initially described as a non-selective nutrient recycling process, is essential for the removal of multiple cellular components. In the past three decades, selective autophagy has been characterized as a highly regulated and specific degradation pathway for removal of unwanted cytosolic components and damaged and/or superfluous organelles. Here, we discuss different types of selective autophagy, emphasizing the role of ligand receptors and scaffold proteins in providing cargo specificity, and highlight unanswered questions in the field. PMID- 29476155 TI - Liver autophagy's sweet side. PMID- 29476154 TI - Size matters in nanoscale communication. PMID- 29476152 TI - Recognition of RNA N6-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. AB - N6-methyladenosine (m6A) is the most prevalent modification in eukaryotic messenger RNAs (mRNAs) and is interpreted by its readers, such as YTH domain containing proteins, to regulate mRNA fate. Here, we report the insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs; including IGF2BP1/2/3) as a distinct family of m6A readers that target thousands of mRNA transcripts through recognizing the consensus GG(m6A)C sequence. In contrast to the mRNA-decay promoting function of YTH domain-containing family protein 2, IGF2BPs promote the stability and storage of their target mRNAs (for example, MYC) in an m6A dependent manner under normal and stress conditions and therefore affect gene expression output. Moreover, the K homology domains of IGF2BPs are required for their recognition of m6A and are critical for their oncogenic functions. Thus, our work reveals a different facet of the m6A-reading process that promotes mRNA stability and translation, and highlights the functional importance of IGF2BPs as m6A readers in post-transcriptional gene regulation and cancer biology. PMID- 29476156 TI - Splitting up for mitophagy. PMID- 29476157 TI - A STING in ER-phagy. PMID- 29476159 TI - Highlighting advances in autophagy. PMID- 29476158 TI - Acetylation rules VPS34. PMID- 29476160 TI - Controlling and modelling the wetting properties of III-V semiconductor surfaces using re-entrant nanostructures. AB - Inorganic semiconductors such as III-V materials are very important in our everyday life as they are used for manufacturing optoelectronic and microelectronic components with important applications span from energy harvesting to telecommunications. In some applications, these components are required to operate in harsh environments. In these cases, having waterproofing capability is essential. Here we demonstrate design and control of the wettability of indium phosphide based multilayer material (InP/InGaAs/InP) using re-entrant structures fabricated by a fast electron beam lithography technique. This patterning technique enabled us to fabricate highly uniform nanostructure arrays with at least one order of magnitude shorter patterning times compared to conventional electron beam lithography methods. We reduced the surface contact fraction significantly such that the water droplets may be completely removed from our nanostructured surface. We predicted the wettability of our patterned surface by modelling the adhesion energies between the water droplet and both the patterned surface and the dispensing needle. This is very useful for the development of coating-free waterproof optoelectronic and microelectronic components where the coating may hinder the performance of such devices and cause problems with semiconductor fabrication compatibility. PMID- 29476161 TI - Directed evolution of SIRT6 for improved deacylation and glucose homeostasis maintenance. AB - Mammalian SIRT6 is a well-studied histone deacetylase that was recently shown to exhibit high protein deacylation activity enabling the removal of long chain fatty acyl groups from proteins. SIRT6 was shown to play key roles in cellular homeostasis by regulating a variety of cellular processes including DNA repair and glucose metabolism. However, the link between SIRT6 enzymatic activities and its cellular functions is not clear. Here, we utilized a directed enzyme evolution approach to generate SIRT6 mutants with improved deacylation activity. We found that while two mutants show increased deacylation activity at high substrate concentration and improved glucose metabolism they exhibit no improvement and even abolished deacetylation activity on H3K9Ac and H3K56Ac in cells. Our results demonstrate the separation of function between SIRT6 catalytic activities and suggest that SIRT6 deacylation activity in cells is important for glucose metabolism and can be mediated by still unknown acylated cellular proteins. PMID- 29476162 TI - Comparative transcriptomics of multidrug-resistant Acinetobacter baumannii in response to antibiotic treatments. AB - Multidrug-resistant Acinetobacter baumannii, a major hospital-acquired pathogen, is a serious health threat and poses a great challenge to healthcare providers. Although there have been many genomic studies on the evolution and antibiotic resistance of this species, there have been very limited transcriptome studies on its responses to antibiotics. We conducted a comparative transcriptomic study on 12 strains with different growth rates and antibiotic resistance profiles, including 3 fast-growing pan-drug-resistant strains, under separate treatment with 3 antibiotics, namely amikacin, imipenem, and meropenem. We performed deep sequencing using a strand-specific RNA-sequencing protocol, and used de novo transcriptome assembly to analyze gene expression in the form of polycistronic transcripts. Our results indicated that genes associated with transposable elements generally showed higher levels of expression under antibiotic-treated conditions, and many of these transposon-associated genes have previously been linked to drug resistance. Using co-expressed transposon genes as markers, we further identified and experimentally validated two novel genes of which overexpression conferred significant increases in amikacin resistance. To the best of our knowledge, this study represents the first comparative transcriptomic analysis of multidrug-resistant A. baumannii under different antibiotic treatments, and revealed a new relationship between transposons and antibiotic resistance. PMID- 29476163 TI - Genetic predictors of systemic sclerosis-associated interstitial lung disease: a review of recent literature. AB - The interplay between genetic and environmental factors is likely involved in the pathogenesis of systemic sclerosis (SSc). Interstitial lung disease associated in the context of SSc (SSc-ILD) is associated with significant morbidity, and is the leading cause of death in SSc. The spectrum of SSc-ILD severity is wide, ranging from patients with only limited and inherently stable pulmonary involvement, to those with extensive and progressive pulmonary fibrosis. In order to provide accurate prognostic information for patients, and to initiate appropriate monitoring and treatment regimens, the ability to identify patients at risk of developing severe ILD early in the disease course is crucial. Identification of genetic variants involved in disease pathogenesis can not only potentially provide diagnostic/prognostic markers, but can also highlight dysregulated molecular pathways for therapeutic targeting. A number of genetic associations have been established for susceptibility to SSc, but far fewer studies have investigated genetic susceptibility to SSc-ILD specifically. In this review we present a summary of the studies assessing genetic associations with SSc-ILD. PMID- 29476164 TI - A genome-wide characterization of copy number variations in native populations of Peninsular Malaysia. AB - Copy number variations (CNVs) are genomic structural variations that result from the deletion or duplication of large genomic segments. The characterization of CNVs is largely underrepresented, particularly those of indigenous populations, such as the Orang Asli in Peninsular Malaysia. In the present study, we first characterized the genome-wide CNVs of four major native populations from Peninsular Malaysia, including the Malays and three Orang Asli populations; namely, Proto-Malay, Senoi, and Negrito (collectively called PM). We subsequently assessed the distribution of CNVs across the four populations. The resulting global CNV map revealed 3102 CNVs, with an average of more than 100 CNVs per individual. We identified genes harboring CNVs that are highly differentiated between PM and global populations, indicating that these genes are predominantly enriched in immune responses and defense functions, including APOBEC3A_B, beta defensin genes, and CCL3L1, followed by other biological functions, such as drug and toxin metabolism and responses to radiation, suggesting some attributions between CNV variations and adaptations of the PM groups to the local environmental conditions of tropical rainforests. PMID- 29476165 TI - Genetics of dementia in a Finnish cohort. AB - Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the two most common neurodegenerative dementias. Variants in APP, PSEN1 and PSEN2 are typically linked to early-onset AD, and several genetic risk loci are associated with late-onset AD. Inherited FTD can be caused by hexanucleotide expansions in C9orf72, or variants in GRN, MAPT or CHMP2B. Several other genes have also been linked to FTD or FTD with motor neuron disease. Here we describe a cohort of 60 Finnish families with possible inherited dementia. Our aim was to clarify the genetic background of dementia in this cohort by analysing both known dementia associated genes (APOE, APP, C9ORF72, GRN, PSEN1 and PSEN2) and searching for rare or novel segregating variants with exome sequencing. C9orf72 repeat expansions were detected in 12 (20%) of the 60 families, including, in addition to FTD, a family with neuropathologically verified AD. Twelve families (10 with AD and 2 with FTD) with representative samples from affected and unaffected subjects and without C9orf72 expansions were selected for whole-exome sequencing. Exome sequencing did not reveal any variants that could be regarded unequivocally causative, but revealed potentially damaging variants in UNC13C and MARCH4. PMID- 29476166 TI - Intentions to share exome sequencing results with family members: exploring spousal beliefs and attitudes. AB - Given familial implications of genetic information, it is important to understand intentions to share carrier results with family members. To our knowledge, no studies among individuals undergoing exome sequencing have used dyadic data analysis to examine the effect of spousal perceptions and beliefs. Survey responses from 136 individuals (68 couples) undergoing exome sequencing in a research study were analyzed using dyadic analysis (the actor-partner interdependence model). Intention to share carrier results with family members was correlated between spouses (ICC = 0.43; 95% CI: 0.21-0.61; p = 0.004), as was worry about risk of a genetic condition in the family (ICC = 0.45; 95% CI: 0.24 0.62; p < 0.001). Perceived value of result and worry about risk of a genetic condition in the family were associated with one's own intentions to share carrier results. However, spousal status on these variables did not explain additional variance in an individual's intentions. Although we found no partner effects on intentions, spouses have comparable intentions to share carrier results, suggesting it may be important to account for non-independence in other research studies. PMID- 29476167 TI - A novel variant associated with HDL-C levels by modifying DAGLB expression levels: An annotation-based genome-wide association study. AB - Although numbers of genome-wide association studies (GWAS) have been performed for serum lipid levels, limited heritability has been explained. Studies showed that combining data from GWAS and expression quantitative trait loci (eQTLs) signals can both enhance the discovery of trait-associated SNPs and gain a better understanding of the mechanism. We performed an annotation-based, multistage genome-wide screening for serum-lipid-level-associated loci in totally 6863 Han Chinese. A serum high-density lipoprotein cholesterol (HDL-C) associated variant rs1880118 (hg19 chr7:g. 6435220G>C) was replicated (Pcombined = 1.4E-10). rs1880118 was associated with DAGLB (diacylglycerol lipase, beta) expression levels in subcutaneous adipose tissue (P = 5.9E-42) and explained 47.7% of the expression variance. After the replication, an active segment covering variants tagged by rs1880118 near 5' of DAGLB was annotated using histone modification and transcription factor binding signals. The luciferase report assay revealed that the segment containing the minor alleles showed increased transcriptional activity compared with segment contains the major alleles, which was consistent with the eQTL analyses. The expression-trait association tests indicated the association between the DAGLB and serum HDL-C levels using gene-based approaches called "TWAS" (P = 3.0E-8), "SMR" (P = 1.1E-4), and "Sherlock" (P = 1.6E-6). To summarize, we identified a novel HDL-C-associated variant which explained nearly half of the expression variance of DAGLB. Integrated analyses established a genotype-gene-phenotype three-way association and expanded our knowledge of DAGLB in lipid metabolism. PMID- 29476168 TI - Semi-quantitative Analysis of EBUS Elastography as a Feasible Approach in Diagnosing Mediastinal and Hilar Lymph Nodes of Lung Cancer Patients. AB - This study aimed to semi-quantitatively evaluate the elastographic imaging color distribution of mediastinal and hilar lymph nodes (LNs), and explored its utility in helping define malignant and benign LNs for lung cancer patients. We prospectively collected patients who underwent preoperative mediastinal staging of suspected lung cancer by EBUS-TBNA. We analyzed the elastography color distribution of each LN and calculated the blue color proportion (BCP). The LN elastographic patterns were compared with the final EBUS-TBNA pathological results. A receiver operating characteristic (ROC) curve was constructed to evaluate the diagnostic value of BCP. We sampled and analyzed 79 LNs from 60 patients. The average BCP in malignant LNs was remarkably higher than that in benign LNs (57.1% versus 30.8%, P < 0.001). The area under the ROC curve (AUC) for the BCP was 0.86 (95% CI: 0.78-0.94). The best cutoff BCP for differentiating between benign and malignant LNs was determined as 36.7%. All the 16 LNs (20.3%) with a BCP lower than 27.9% were diagnosed as benign tissues. Our study suggests that elastography is a feasible technique that may safely help to predict LN metastasis during EBUS-TBNA. We found a clear BCP cutoff value to help define positive and negative LNs. PMID- 29476169 TI - Snap-through transition of buckled graphene membranes for memcapacitor applications. AB - Using computational and theoretical approaches, we investigate the snap-through transition of buckled graphene membranes. Our main interest is related to the possibility of using the buckled membrane as a plate of capacitor with memory (memcapacitor). For this purpose, we performed molecular-dynamics (MD) simulations and elasticity theory calculations of the up-to-down and down-to-up snap-through transitions for membranes of several sizes. We have obtained expressions for the threshold switching forces for both up-to-down and down-to-up transitions. Moreover, the up-to-down threshold switching force was calculated using the density functional theory (DFT). Our DFT results are in general agreement with MD and analytical theory findings. Our systematic approach can be used for the description of other structures, including nanomechanical and biological ones, experiencing the snap-through transition. PMID- 29476171 TI - Summaries of Cochrane Systematic Reviews: making high-quality evidence accessible. PMID- 29476170 TI - Multiscale dynamical network mechanisms underlying aging of an online organism from birth to death. AB - We present the continuous-time evolution of an online organism network from birth to death which crosses all organizational and temporal scales, from individual components through to the mesoscopic and entire system scale. These continuous time data reveal a lifespan driven by punctuated, real-time co-evolution of the structural and functional networks. Aging sees these structural and functional networks gradually diverge in terms of their small-worldness and eventually their connectivity. Dying emerges as an extended process associated with the formation of large but disjoint functional sub-networks together with an increasingly detached core. Our mathematical model quantifies the very different impacts that interventions will have on the overall lifetime, period of initial growth, peak of potency, and duration of old age, depending on when and how they are administered. In addition to their direct relevance to online extremism, our findings may offer insight into aging in other network systems of comparable complexity for which extensive in vivo data is not yet available. PMID- 29476173 TI - THz characterization and demonstration of visible-transparent/terahertz functional electromagnetic structures in ultra-conductive La-doped BaSnO3 Films. AB - We report on terahertz characterization of La-doped BaSnO3 (BSO) thin-films. BSO is a transparent complex oxide material, which has attracted substantial interest due to its large electrical conductivity and wide bandgap. The complex refractive index of these films is extracted in the 0.3 to 1.5 THz frequency range, which shows a metal-like response across this broad frequency window. The large optical conductivity found in these films at terahertz wavelengths makes this material an interesting platform for developing electromagnetic structures having a strong response at terahertz wavelengths, i.e. terahertz-functional, while being transparent at visible and near-IR wavelengths. As an example of such application, we demonstrate a visible-transparent terahertz polarizer. PMID- 29476172 TI - Foxm1 controls a pro-stemness microRNA network in neural stem cells. AB - Cerebellar neural stem cells (NSCs) require Hedgehog-Gli (Hh-Gli) signalling for their maintenance and Nanog expression for their self-renewal. To identify novel molecular features of this regulatory pathway, we used next-generation sequencing technology to profile mRNA and microRNA expression in cerebellar NSCs, before and after induced differentiation (Diff-NSCs). Genes with higher transcript levels in NSCs (vs. Diff-NSCs) included Foxm1, which proved to be directly regulated by Gli and Nanog. Foxm1 in turn regulated several microRNAs that were overexpressed in NSCs: miR-130b, miR-301a, and members of the miR-15~16 and miR-17~92 clusters and whose knockdown significantly impaired the neurosphere formation ability. Our results reveal a novel Hh-Gli-Nanog-driven Foxm1-microRNA network that controls the self-renewal capacity of NSCs. PMID- 29476175 TI - Interaction of Glide Dislocations with Extended Precipitates in Mg-Nd alloys. AB - The unit processes of precipitate-dislocation interaction in dilute Mg-Nd alloys are elucidated through in situ indentation experiments in TEM. Results suggest that pinned dislocations can glide along the broad facets of extended beta1 precipitates, a common strengthening phase in Mg- rare earth (RE) alloys. A dislocation-theory based analysis suggests that the shape, spacing and orientation (with respect to the glide plane) of beta1 precipitates may favor glide of pinned dislocations along interfaces as opposed to the classical mechanism of bowing and looping around the precipitate. PMID- 29476174 TI - Retrosynthesis of multi-component metal-organic frameworks. AB - Crystal engineering of metal-organic frameworks (MOFs) has allowed the construction of complex structures at atomic precision, but has yet to reach the same level of sophistication as organic synthesis. The synthesis of complex MOFs with multiple organic and/or inorganic components is ultimately limited by the lack of control over framework assembly in one-pot reactions. Herein, we demonstrate that multi-component MOFs with unprecedented complexity can be constructed in a predictable and stepwise manner under simple kinetic guidance, which conceptually mimics the retrosynthetic approach utilized to construct complicated organic molecules. Four multi-component MOFs were synthesized by the subsequent incorporation of organic linkers and inorganic clusters into the cavity of a mesoporous MOF, each composed of up to three different metals and two different linkers. Furthermore, we demonstrated the utility of such a retrosynthetic design through the construction of a cooperative bimetallic catalytic system with two collaborative metal sites for three-component Strecker reactions. PMID- 29476176 TI - Indian Summer Monsoon Simulations: Usefulness of Increasing Horizontal Resolution, Manual Tuning, and Semi-Automatic Tuning in Reducing Present-Day Model Biases. AB - Coupled Global Climate Models (CGCMs) of the Coupled Model Intercomparison Project Phase 5 (CMIP5) are unable to resolve the spatial and temporal characteristics of the South Asian Monsoon satisfactorily. A CGCM with the capability to reliably project the global as well as the regional climatic features would be a valuable tool for scientists and policymakers. Analysis of 28 CMIP5 models highlights varying degree of biases in precipitation and 2 m surface air temperature (T2m) over south Asia, and the Community Earth System Model (CESM) developed at the National Center for Atmospheric Research is found to be one of the best performing models. However, like all other CMIP5 models, CESM also has some inherent model biases. Using CESM, it is found that the precipitation and T2M biases reduce with increase in the model horizontal resolution from 2 degrees to 0.5 degrees . Further, a few deep convective parameters in the Zhang-McFarlane convection scheme are tuned for 2 degrees and 1 degrees model resolutions using both manual and semi-automatic model tuning methods. Comparing results from the two tuning methods we find that the performance of the manually tuned model is better than that of the semi-automated one. PMID- 29476177 TI - Tumor architecture. PMID- 29476178 TI - B-1a cell metabolism. PMID- 29476180 TI - Alu element risk. PMID- 29476179 TI - Inflammatory brain ripples. PMID- 29476181 TI - HLA influence on HIV control. PMID- 29476182 TI - Mitochondrial DNA webs. PMID- 29476183 TI - Toll-like receptor 9 antagonizes antibody affinity maturation. AB - Key events in T cell-dependent antibody responses, including affinity maturation, are dependent on the B cell's presentation of antigen to helper T cells at critical checkpoints in germinal-center formation in secondary lymphoid organs. Here we found that signaling via Toll-like receptor 9 (TLR9) blocked the ability of antigen-specific B cells to capture, process and present antigen and to activate antigen-specific helper T cells in vitro. In a mouse model in vivo and in a human clinical trial, the TLR9 agonist CpG enhanced the magnitude of the antibody response to a protein vaccine but failed to promote affinity maturation. Thus, TLR9 signaling might enhance antibody titers at the expense of the ability of B cells to engage in germinal-center events that are highly dependent on B cells' capture and presentation of antigen. PMID- 29476185 TI - The origins of diversity in human immunity. PMID- 29476186 TI - Hoxb5, a Trojan horse to generate T cells. PMID- 29476184 TI - Natural variation in the parameters of innate immune cells is preferentially driven by genetic factors. AB - The quantification and characterization of circulating immune cells provide key indicators of human health and disease. To identify the relative effects of environmental and genetic factors on variation in the parameters of innate and adaptive immune cells in homeostatic conditions, we combined standardized flow cytometry of blood leukocytes and genome-wide DNA genotyping of 1,000 healthy, unrelated people of Western European ancestry. We found that smoking, together with age, sex and latent infection with cytomegalovirus, were the main non genetic factors that affected variation in parameters of human immune cells. Genome-wide association studies of 166 immunophenotypes identified 15 loci that showed enrichment for disease-associated variants. Finally, we demonstrated that the parameters of innate cells were more strongly controlled by genetic variation than were those of adaptive cells, which were driven by mainly environmental exposure. Our data establish a resource that will generate new hypotheses in immunology and highlight the role of innate immunity in susceptibility to common autoimmune diseases. PMID- 29476187 TI - Cancer cells deliver a suppressive cargo. PMID- 29476188 TI - Capturing resting T cells: the perils of PLL. PMID- 29476189 TI - The synergic effects of CTLA-4/Foxp3-related genotypes and chromosomal aberrations on the risk of recurrent spontaneous abortion among a Chinese Han population. AB - The current study was aimed to investigate the association of CLTA-4/Foxp3 polymorphisms and chromosomal abnormalities with recurrent spontaneous abortion (RSA) risk in a Chinese Han population. Altogether, 1284 RSA women and 1046 women with normal pregnancy were incorporated in this study. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was implemented to genotype the single-nucleotide polymorphisms (SNPs) located within CTLA4 and Foxp3. Moreover, the cytogenetic diagnosis was performed in line with the standards of G banding karyotype. As a consequence, rs231775 and rs3087243 of CTLA4, as well as rs2232365 and rs2232368 of Foxp3, all appeared to modify the risk of RSA. Besides, significant differences were found between the ratio of structural abnormality and that of numerical abnormality (P < 0.038), and chromosome abnormality was associated with higher miscarriage frequency (>3) than normal karyotypes. Of note, the synergic effects of the genotypes and chromosomal abnormality all tallied with the sub-multiplication model (ORchromosome * ORSNP > ORchromosome+SNP), while rs2232365 GG and chromosomal aberration impacted the RSA risk in a super-multiplicative way that ORchromosome * ORSNP < ORchromosome+SNP. In conclusion, susceptibility to RSA was subject to the synthetic regulation of chromosomal aberrations and genetic mutations within CLTA-4 and Foxp3, suggesting that the conduction of karyotype analysis and genetic detection for RSA patients could effectively guide effective RSA counseling and sound child rearing. PMID- 29476191 TI - Characteristics of macrolide responders in persistent post-surgical rhinosinusitis. AB - INTRODUCTION: The anti-inflammatory effects of long term low dose macrolide therapy have shown benefit in the management of diffuse panbronchiolitis. Dramatic responses to macrolide in the upper airway are seen but our understanding of the patient phenotype predisposing to macrolide response in chronic rhinosinusitis (CRS) is poor. METHODS: A case control study was performed in a tertiary level rhinology practice of consecutive chronic rhinosinusitis patients placed on a 3-month low dose macrolide therapy after failing at least 3 months of corticosteroid irrigation therapy post-endoscopic sinus surgery. Patients were defined as a macrolide responder when having near normal endoscopy after a 3-month period of clarithromycin treatment. Patient characteristics of smoking, asthma, atopy status, revision surgery, symptom severity (SNOT-22) along with biomarkers from serum and tissue histopathology results were compared between groups. RESULTS: Of twenty-eight consecutive macrolide treated patients, 19 responders were compared to 9 non-responders. The groups were similar in age, female gender, non-smoking, asthma, and atopy. Macrolide response was associated with a lack of tissue eosinophilia (more than 10/HPF) and lower serum eosinophilia. Neutrophil expression was similar in tissue and serum. Squamous metaplasia was overexpressed in non-responders. CONCLUSION: Low tissue and serum eosinophilia, and absence of tissue squamous metaplasia may predict a CRS phenotype suitable to a trial of long-term macrolide therapy when surgery and topical therapy has failed. PMID- 29476190 TI - Pattern of TSC1 and TSC2 germline mutations in Russian patients with tuberous sclerosis. AB - Tuberous sclerosis (TS) is a rare autosomal-dominant genetic disease. TS is manifested by the development of multiple hamartomas, which affect brain, kidneys, retina, skin and other organs. This study aimed to reveal specific features of molecular epidemiology of TS in Russia. Blood DNA samples from 61 patients with definite (n = 53) or probable (n = 8) clinical diagnosis of TS were tested for mutations in TSC1 and TSC2 genes using Sanger sequencing and MLPA analysis. Five TSC1/2 mutation-negative patients were further analyzed by exome sequencing. TSC1/2 mutations were detected in 53/61 patients (87%): 39 (74%) carried mutations in the TSC2 and 14 (26%) in the TSC1. Large rearrangements (exon deletions/duplications) affected exclusively TSC2, accounting for 15% of lesions of this gene. 6/8 (75%) patients with incomplete clinical manifestation of TS carried TSC1/2 gene lesion. Overall, 96% of detected germline TSC1/2 mutations occurred de novo. Patients with no mutation identified (NMI) differed from TSC1/2 mutation carriers, being lacking cortical tubers and subependymal nodules but having higher frequencies of renal angiomyolipomas, rhabdomyomas, and lymphangioleiomyomatosis. Exome sequencing failed to identify overt disease causing mutation candidates among NMI patients. Russian patients with TS have increased frequency of TSC2 large gene rearrangements and TSC1/2 mutations occurring de novo as compared to other studies. Patients with suspected TS diagnosis but NMI status may represent a distinct disease entity. PMID- 29476192 TI - EPOS2012 has better specificity compared to IDSA2012 for diagnosing acute bacterial rhinosinusitis. AB - BACKGROUND: Acute bacterial rhinosinusitis (ABRS) is a subtype of acute rhinosinusitis (ARS). To prevent excessive antibiotic prescribing, clinical criteria for diagnosing ABRS are presented in two major international guidelines from European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS2012) and the Infectious Diseases Society of America (IDSA2012). This study aims to assess accuracy of these criteria. METHODOLOGY: Patients with ARS were recruited. Clinical features were collected including discolored nasal discharge, facial pain, fever, double sickening, symptoms persisting longer than 10 days, and elevated serum C reactive protein (CRP) and erythrocyte sedimentation rate (ERS). Using middle meatal bacterial culture as a reference, accuracy of EPOS2012 and IDSA2012 criteria were analyzed. RESULTS: Eighty-eight patients (age 43.2+/-14.5 years, 67% female) with ARS were recruited. Using the two criteria for diagnosing ABRS, EPOS2012 and IDSA2012 have sensitivity of 50% (95%CI: 38%-62%) versus 69% (95%CI: 57%-79%), specificity of 63% (95%CI: 43%-79%) versus 46% (95%CI: 28% 65%), and accuracy of 53% versus 63%, respectively. CONCLUSION: Both EPOS2012 and IDSA2012 had modest accuracy. EPOS2012 had less sensitivity but a better specificity compared to IDSA2012. This suggests that IDSA2012 diagnostic criteria may contribute to inappropriate use of antibiotics due to poorer specificity. PMID- 29476193 TI - [Psychosocial effects in patients with penile cancer : A systematic review]. AB - BACKGROUND: Psychological stress of patients with penile cancer arises from the cancer diagnosis itself and the treatment consequences. In addition, there is cancer-specific distress. There is the chance of cure in localized stages and in those with limited regional lymph node metastases but this requires surgery and often adjuvant chemotherapy. This systematic review gives a summary of the existing literature to date. MATERIALS AND METHODS: A critical database search using Medline was made in Ovid from 1946 to 2017, in the Cochrane Central Register of Controlled Trials (CENTRAL) and in the Web of Science from 1900 to 2017. This was complemented by a search of the World Health Organization's International Clinical Trials Registry Platform Search Portal and ClinicalTrials.gov. The reference lists of the included studies were manually searched for additional references. RESULTS: Selected studies (n = 10) addressed the psychosocial effects of penile cancer treatment on quality of life and sexual function. Due to the heterogeneity of the study designs only a narrative description of the results was possible. Defects or mutilation due to penile cancer cause psychological distress in a significant number of patients. Organ sparing interventions have a positive impact on quality of life and sexual function. CONCLUSION: The external genitals are a focus of sexual identity. Mutilating treatment causes significant distress but organ-sparing treatment and reconstruction positively influence quality of life. PMID- 29476194 TI - [Inflammatory gastrointestinal diseases in children : Radiological diagnosis]. AB - BACKGROUND/CLINICAL ISSUE: Inflammatory bowel diseases are frequently seen in the clinical routine of a pediatric radiologist. The timely diagnosis of inflammatory bowel diseases in children is particularly important in acute cases. STANDARD RADIOLOGICAL METHODS/METHODOLOGICAL INNOVATIONS: This nonsystematic article intends to give an overview of the radiologic imaging methods for the diagnosis and work-up of pediatric patients with inflammatory bowel diseases. PERFORMANCE: Ultrasound imaging is an important basis tool in pediatric clinical practice. However, sensitivity and specificity depends on the experience of the operator. Cross-sectional imaging modalities in pediatric patients with inflammatory bowel disease are performed only in exceptional cases when clinically justified. Dedicated computed tomography (CT) protocols for children are indispensable to lower radiation dose. ACHIEVEMENTS: Knowledge about particularities in inflammatory bowel diseases in pediatric patients and a rational approach to the use of radiological investigations in order to prevent the harmful effects of ionizing radiation are indispensable in dedicated pediatric imaging departments. PRACTICAL RECOMMENDATIONS: From a radiation-hygiene point of view, the clinical application of ultrasound imaging should be favored in the work-up of pediatric patients with inflammatory bowel diseases. Knowledge about advanced imaging procedures is essential particularly in imaging departments specialized in pediatric radiology. PMID- 29476195 TI - [Inflammatory diseases of the upper gastrointestinal tract : Role of radiology in diagnostics]. AB - BACKGROUND: The radiological evaluation of the upper gastrointestinal tract (GI tract) is a diagnostic challenge. Although endoscopy has pushed radiographic methods into the background, these methods continue to play a key role in the diagnosis of dysphagia. In addition, cross-sectional imaging (computed tomography, magnetic resonance imaging) is increasingly used in complex clinical cases to evaluate surrounding tissue changes. METHODS: By combining conventional double-contrast techniques with a video recording, the entire upper GI tract can be assessed both anatomically and functionally in one examination procedure. CONCLUSION: In addition to the clarification of swallowing disorders, videofluoroscopy can be used to assess postoperative control after antireflux and bariatric surgery. To obtain optimal results in video swallowing studies, the procedure should be adapted to the individual symptoms of the patient. PMID- 29476196 TI - Persistence time of SIS infections in heterogeneous populations and networks. AB - For a susceptible-infectious-susceptible infection model in a heterogeneous population, we present simple formulae giving the leading-order asymptotic (large population) behaviour of the mean persistence time, from an endemic state to extinction of infection. Our model may be interpreted as describing an infection spreading through either (1) a population with heterogeneity in individuals' susceptibility and/or infectiousness; or (2) a heterogeneous directed network. Using our asymptotic formulae, we show that such heterogeneity can only reduce (to leading order) the mean persistence time compared to a corresponding homogeneous population, and that the greater the degree of heterogeneity, the more quickly infection will die out. PMID- 29476197 TI - Dynamics of virus and immune response in multi-epitope network. AB - The host immune response can often efficiently suppress a virus infection, which may lead to selection for immune-resistant viral variants within the host. For example, during HIV infection, an array of CTL immune response populations recognize specific epitopes (viral proteins) presented on the surface of infected cells to effectively mediate their killing. However HIV can rapidly evolve resistance to CTL attack at different epitopes, inducing a dynamic network of interacting viral and immune response variants. We consider models for the network of virus and immune response populations, consisting of Lotka-Volterra like systems of ordinary differential equations. Stability of feasible equilibria and corresponding uniform persistence of distinct variants are characterized via a Lyapunov function. We specialize the model to a "binary sequence" setting, where for n epitopes there can be [Formula: see text] distinct viral variants mapped on a hypercube graph. The dynamics in several cases are analyzed and sharp polychotomies are derived characterizing persistent variants. In particular, we prove that if the viral fitness costs for gaining resistance to each epitope are equal, then the system of [Formula: see text] virus strains converges to a "perfectly nested network" with less than or equal to [Formula: see text] persistent virus strains. Overall, our results suggest that immunodominance, i.e. relative strength of immune response to an epitope, is the most important factor determining the persistent network structure. PMID- 29476199 TI - Correction to: Guidelines for the diagnosis and management of critical illness related corticosteroid insufficiency (CIRCI) in critically ill patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. AB - To update the 2008 consensus statements for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in adult and pediatric patients. PMID- 29476198 TI - Posterior tibial slope impacts intraoperatively measured mid-flexion anteroposterior kinematics during cruciate-retaining total knee arthroplasty. AB - PURPOSE: Posterior tibial slope (PTS) for cruciate-retaining (CR) total knee arthroplasty (TKA) is usually pre-determined by the surgeon. Limited information is available comparing different choices of PTS on the kinematics of the CR TKA, independent of the balancing of the extension gap. This study hypothesized that with the same balanced extension gap, the choice of PTS significantly impacts the intraoperatively measured kinematics of CR TKA. METHODS: Navigated CR TKAs were performed on seven fresh-frozen cadavers with healthy knees and intact posterior cruciate ligament (PCL). A custom designed tibial baseplate was implanted to allow in situ modification of the PTS, which altered the flexion gap but maintained the extension gap. Knee kinematics were measured by performing passive range of motion (ROM) tests from full extension to 120 degrees of flexion on the intact knee and CR TKAs with four different PTSs (1 degrees , 4 degrees , 7 degrees , and 10 degrees ). The measured kinematics were compared across test conditions to assess the impact of PTS. RESULTS: With a consistent extension gap, the change of PTS had significant impact on the anteroposterior (AP) kinematics of the CR TKA knees in mid-flexion range (45 degrees -90 degrees ), but not so much for the high-flexion range (90 degrees -120 degrees ). No considerable impacts were found on internal/external (I/E) rotation and hip-knee-ankle (HKA) angle. However, the findings on the individual basis suggested the impact of PTS on I/E rotation and HKA angle may be patient-specific. CONCLUSIONS: The data suggested that the choice of PTS had the greatest impact on the mid-flexion AP translation among the intraoperatively measured kinematics. This impact may be considered while making surgical decisions in the context of AP kinematics. When using a tibial component designed with "center" pivoting PTS, a surgeon may be able to fine tune the PTS to achieve proper mid-flexion AP stability. PMID- 29476200 TI - Hyperviscosity syndrome. PMID- 29476202 TI - Multiple vertebral fractures associated with glucocorticoid-induced osteoporosis treated with teriparatide followed by kyphosis correction fusion: a case report. AB - : Surgical treatment of multiple vertebral fractures in patients with glucocorticoid-induced osteoporosis is difficult because of a high rate of secondary fracture postoperatively. A case is described in which initial treatment with teriparatide to improve osteoporosis followed by treatment of kyphosis with correction fusion achieved a favorable outcome. INTRODUCTION: Secondary fracture frequently occurs after treatment of vertebral fracture with vertebroplasty and balloon kyphoplasty in patients with glucocorticoid-induced osteoporosis, but effective treatment of multiple vertebral fractures has rarely been reported. Thus, a treatment of kyphosis following multiple vertebral fractures associated with glucocorticoid-induced osteoporosis is required. METHODS: The patient was a 24-year-old woman diagnosed with glucocorticoid induced osteoporosis who was under treatment with oral alendronate, vitamin D, and elcatonin injection. Secondary multiple vertebral fractures occurred despite these treatments and low back pain gradually aggravated. RESULTS: Vertebroplasty or balloon kyphoplasty was not performed in the early phase. Instead, treatment with teriparatide was used for initial improvement of osteoporosis. Kyphosis in the center of the residual thoracolumbar junction was then treated with posterior correction fusion. At 2 years after surgery, the corrected position has been maintained and no new fracture has occurred. CONCLUSION: There is no established method for treatment of multiple vertebral fractures caused by glucocorticoid induced osteoporosis. Initial treatment with teriparatide to improve osteoporosis followed by treatment of kyphosis with correction fusion may result in a more favorable outcome. PMID- 29476204 TI - Cor triatriatum sinister. PMID- 29476203 TI - First experience with zero-fluoroscopic ablation for supraventricular tachycardias using a novel impedance and magnetic-field-based mapping system. AB - AIMS: Zero- and near-zero-fluoroscopic ablation techniques reduce the harmful effects of ionizing radiation during invasive electrophysiology procedures. We aimed to test the feasibility and safety of a zero-fluoroscopic strategy using a novel integrated magnetic and impedance-based electroanatomical mapping system for radiofrequency ablation (RFA) of supraventricular tachycardias (SVTs). METHODS: We retrospectively studied 92 consecutive patients undergoing electrophysiology studies with/without RFA for supraventricular tachycardia (SVT) performed by a single operator at a single center. The first 42 (Group 1) underwent a conventional fluoroscopic-guided approach and the second 50 (Group 2) underwent a zero-fluoroscopic approach using the Ensite PrecisionTM 3-D magnetic and impedance-based mapping system (Abbott Inc). RESULTS: Group 1 comprised 14 AV nodal re-entrant tachycardia (AVNRT), 12 typical atrial flutter, 4 accessory pathway (AP), 2 atrial tachycardia (AT), and 9 diagnostic EP studies (EPS). Group 2 comprised 16 AVNRT, 17 atrial flutter, 6 AP, 3 AT, 2 AV-nodal ablations, and 7 EPS. A complete zero-fluoroscopic approach was achieved in 94% of Group 2 patients. All procedures were acutely successful, and no complications occurred. There was a significant reduction in fluoroscopy dose, dose area product, and time (p < 0.0001, for all), with no difference in procedure times. Ablation time for typical atrial flutter was shorter in Group 2 (p = 0.006). CONCLUSIONS: A zero-fluoroscopic strategy for diagnosis and treatment of SVTs using this novel 3D-electroanatomical mapping system is feasible in majority of patients, is safe, reduces ionizing radiation exposure, and does not compromise procedural times, success rates, or complication rates. PMID- 29476205 TI - Prevention of ovariectomy-induced osteoporosis in rats : Comparative study of zoledronic acid, parathyroid hormone (1-34) and strontium ranelate. AB - Recently, the use of the pharmacological agents strontium ranelate (SR), parathyroid hormone (1-34, PTH) and zoledronic acid (ZA) has come to prominence for the treatment of osteoporosis due to their ability to prevent bone loss in osteoporotic patients. Although much emphasis has been placed on using pharmacological agents for the prevention of disease, much less attention has been placed on which one is more effective. There is still no direct comparative study on these three drugs. The aim of the present study was to investigate the effect of SR, PTH, ZA on preventing ovariectomy-induced osteoporosis in rats. After bilateral ovariectomy the rats randomly received vehicle, SR (500 mg/kg body weight/day, orally), PTH (20 MUg/kg/day, subcutaneously) or a single injection of ZA (0.1 mg/kg, i.v.) until death at 12 weeks. The distal femurs were harvested for evaluation of bone metabolism. The rats treated with ZA demonstrated the highest levels of new bone formation as assessed by microcomputed tomography (CT), biomechanical strength, histological analysis and bone metabolism. Furthermore, PTH and SR showed a stronger effect on improving trabecular bone mass at 12 weeks. The results from the present study demonstrate that systemic administration of PTH, SR and ZA could prevent bone loss, while a single dose of ZA has a better effect on preventing ovariectomy-induced osteoporosis than either PTH or SR. PMID- 29476201 TI - Pharmacological targets of breast cancer stem cells: a review. AB - Breast cancers contain small population of tumor-initiating cells called breast cancer stem cells (BCSCs), which are spared even after chemotherapy. Recently, BCSCs are implicated to be a cause of metastasis, tumor relapse, and therapy resistance in breast cancer. BCSCs have unique molecular mechanisms, which can be targeted to eliminate them. These include surface biomarkers, proteins involved in self-renewal pathways, drug efflux transporters, apoptotic/antiapoptotic proteins, autophagy, metabolism, and microenvironment regulation. The complex molecular mechanisms behind the survival of BCSCs and pharmacological targets for elimination of BCSCs are described in this review. PMID- 29476207 TI - Evaluation of the chitin-binding dye Congo red as a selection agent for the isolation, classification, and enumeration of ascomycete yeasts. AB - Thirty-nine strains of ascomycete yeasts representing 35 species and 33 genera were tested for their ability to grow on solid agar medium containing increasing concentrations of the chitin-binding dye Congo red. Six strains were classified as hypersensitive (weak or no growth at 10 mg/l Congo red), five were moderately sensitive (weak or no growth at 50 mg/l), three were moderately tolerant (weak or no growth at 100 mg/l), while the remaining 25 strains were classified as resistant (robust growth at >= 100 mg/l) with 20 of these strains classified as hyper-resistant (robust growth at 200 mg/l). Congo red growth phenotypes were consistent within some families but not others. The frequency of Congo red resistance among ascomycete yeasts was deemed too high for the practical use of Congo red as a selection agent for targeted isolation, but can be useful for identification and enumeration of yeasts. PMID- 29476206 TI - Mechanism of arsenic resistance in endophytic bacteria isolated from endemic plant of mine tailings and their arsenophore production. AB - Arsenic contamination is an important environmental problem around the world since its high toxicity, and bacteria resist to this element serve as valuable resource for its bioremediation. Aiming at searching the arsenic-resistant bacteria and determining their resistant mechanism, a total of 27 strains isolated from roots of Prosopis laevigata and Spharealcea angustifolia grown in a heavy metal-contaminated region in Mexico were investigated. The minimum inhibitory concentration (MIC) and transformation abilities of arsenate (As5+) and arsenite (As3+), arsenophore synthesis, arsenate uptake, and cytoplasmatic arsenate reductase (arsC), and arsenite transporter (arsB) genes were studied for these strains. Based on these results and the 16S rDNA sequence analysis, these isolates were identified as arsenic-resistant endophytic bacteria (AREB) belonging to the genera Arthrobacter, Bacillus, Brevibacterium, Kocuria, Microbacterium, Micrococcus, Pseudomonas, and Staphylococcus. They could tolerate high concentrations of arsenic with MIC from 20 to > 100 mM for As5+ and 10-20 mM for As3+. Eleven isolates presented dual abilities of As5+ reduction and As3+ oxidation. As the most effective strains, Micrococcus luteus NE2E1 reduced 94% of the As5+ and Pseudomonas zhaodongensis NM2E7 oxidized 46% of As3+ under aerobic condition. About 70 and 44% of the test strains produced arsenophores to chelate As5+ and As3+, respectively. The AREB may absorb arsenate via the same receptor of phosphate uptake or via other way in some case. The cytoplasmic arsenate reductase and alternative arsenate reduction pathways exist in these AREB. Therefore, these AREB could be candidates for the bioremediation process. PMID- 29476208 TI - MR findings of the orbit in patients with Vogt-Koyanagi-Harada disease. AB - PURPOSE: We aimed to evaluate the MR findings of the orbit in patients with Vogt Koyanagi-Harada disease (VKHD). METHODS: We included 14 patients with clinically diagnosed VKHD, who underwent orbital MR imaging before treatment between May 2011 and August 2017. The mean duration from initial symptom onset to MR imaging was 16 days (range, 2-36 days). Fat-suppressed gadolinium-enhanced T1-weighted images were obtained in six patients. We retrospectively assessed the choroids and Tenon's capsules for the presence of thickening on unenhanced images and abnormal enhancement on contrast-enhanced images. RESULTS: Bilateral choroidal thickening was observed in 14 patients (100%) on T1-weighted images and in 12 patients (85.7%) on T2-weighted images. Choroidal thickening showed posterior pole predominance in 11 patients (78.6%) and diffusely distributed in the remaining three patients (21.4%). Bilateral Tenon's capsule thickening was observed in five patients (35.7%) on T1-weighted images and in 14 patients (100%) on T2-weighted images. On contrast-enhanced images, the choroids and Tenon's capsules were abnormally enhanced in six patients (100%). CONCLUSION: MR imaging sensitively detected abnormalities of the choroids and Tenon's capsules in patients with VKHD. Bilaterality and predominant posterior pole distribution were characteristic of choroidal VKHD. PMID- 29476209 TI - Brain computed tomography using iterative reconstruction to diagnose acute middle cerebral artery stroke: usefulness in combination of narrow window setting and thin slice reconstruction. AB - PURPOSE: The purpose of this study is to determine whether iterative model reconstruction (IMR) optimized for brain CT could improve the detection of acute stroke in the setting of thin image slices and narrow window settings. METHODS: We retrospectively reviewed 27 patients who presented acute middle cerebral artery (MCA) stroke. Images were reconstructed using filtered back projection (FBP; 1- and 5-mm slice thickness) and IMR (1 mm thickness), and contrast-to noise ratios (CNRs) of infarcted and non-infarcted areas were compared. To analyze the performance of acute MCA stroke detection, we used receiver operating characteristic (ROC) curve techniques and compared 5-mm FBP with standard and narrow window settings, and 1-mm FBP and IMR with narrow window settings. RESULTS: The CNR in 1-mm IMR (1.1 +/- 1.0) was significantly higher than in 5- (0.8 +/- 0.7) and 1-mm FBP (0.4 +/- 0.4) (p < 0.001). Furthermore, the average area under the ROC curve was significantly higher with 1-mm IMR with narrow window settings (0.90, 95% CI: 0.86, 0.94) than it was with 5-mm FBP (0.78, 95% CI: 0.72, 0.83). CONCLUSION: The combination of thin image slices and narrow window settings under IMR reconstruction provide better diagnostic performance for acute MCA stroke than conventional reconstruction methods. PMID- 29476210 TI - A child with Apert syndrome and Sturge-Weber syndrome: could fibronectin or the RAS/MAPK signaling pathway be the connection? AB - BACKGROUND: Apert syndrome is one of the most common craniosynostosis syndrome caused by mutation in genes encoding fibroblast growth factor receptor 2 (FGFR2). Craniosynostosis, midfacial hypoplasia, and syndactyly/symphalangism are features of this syndrome. Sturge-Weber syndrome (SWS) on the other hand is a congenital neurocutaneous disorder characterized by facial port-wine stains (PWSs) and leptomeningeal vascular capillary malformations. In 2013, the causative mutation underlying SWS (p.R183Q somatic activating mutation in the guanine nucleotide binding protein alpha-q (GNAQ) gene) was identified. This mutation increases downstream signaling along the RAS/MAPK pathway, resulting in increased cell proliferation. The interaction between FGFR and the RAS/MAPK signaling pathway was proposed in recent years. Elevated synthesis of fibronectin in the calvaria of patients with Apert syndrome and increased fibronectin gene expression in port wine-derived fibroblasts of patients with Sturge-Weber disease have also been reported. CASE PRESENTATION: We report a unique case of Apert and Sturge-Weber syndromes occurring in the same patient. The child was noted to demonstrate features suggestive of Apert syndrome at birth, including brachycephaly, midface hypoplasia, and syndactyly. In addition, a left-sided facial port wine stain in the forehead was noted. Magnetic resonance imaging (MRI) of the brain was performed and confirmed the diagnosis of Sturge-Weber syndrome by demonstrating the presence of left sided leptomeningeal vascular capillary malformation and left-sided cerebral hemiatrophy. CONCLUSION: To the best of our knowledge, there has been no prior described case of Apert and Sturge-Weber syndromes occurring in the same patient. This case report identifies an area of potential research on fibronectin and derangement of the RAS/MAPK signaling pathway in relation to Apert syndrome and Sturge-Weber syndrome. In view of the rare concurrence of Apert and Sturge-Weber syndromes, the underlying pathogenesis is thought to be multifactorial, one of which may be related to either increased fibronectin gene expression or derangement of the RAS/MAPK signaling pathway. PMID- 29476211 TI - The status of triangular fibrocartilage complex after the union of distal radius fractures with internal plate fixation. AB - PURPOSE: Distal radius fractures are associated with a high incidence of triangular fibrocartilage complex (TFCC) tears. This study aims to evaluate the status of TFCC after the healing of distal radius fractures, and its clinical significance. METHODS: Wrist arthroscopies were performed on 43 distal radius fractures, with an average age of 54 years old. RESULTS: Twenty-six complete tears and 15 partial healed tears were noted. Five out of eight patients with intact TFCC tears had neither signs nor symptoms, while eight patients with TFCC tears had no complaint. While no association was found between ulnar wrist pain and TFCC tears, there was association between DRUJ instability and TFCC tears and fovea tears. The function outcome did not differ with respect to the integrity of TFCC. CONCLUSIONS: A large majority of TFCC tears remained unhealed after the union of distal radius fractures. However, not all patients with tear were symptomatic. PMID- 29476212 TI - Correction to: Biomechanical comparisons of current suspensory fixation devices for anterior cruciate ligament reconstruction. AB - The original publication of this paper contains mistakes. The first author name "Jin Cheng" is changed to "Cheng Jin ". PMID- 29476213 TI - Radiologists in Iraq and Afghanistan: a meager, but heartfelt thank-you. PMID- 29476214 TI - Comparison of ultrasound versus computed tomography for the detection of kidney stones in the pediatric population: a clinical effectiveness study. AB - BACKGROUND: The incidence of pediatric nephrolithiasis in the United States is increasing. There is a paucity of literature comparing the diagnostic performance of computed ultrasound (US) to tomography (CT) in the pediatric population. OBJECTIVE: To determine the diagnostic performance of renal US for nephrolithiasis in children using a clinical effectiveness approach. MATERIALS AND METHODS: Institutional review board approval with a waiver of informed consent was obtained for this retrospective, HIPAA-complaint investigation. Billing records and imaging reports were used to identify children (<=18 years old) evaluated for nephrolithiasis by both US and unenhanced CT within 24 h between March 2012 and March 2017. Imaging reports were reviewed for presence, number, size and location of kidney stones. Diagnostic performance of US (reference standard=CT) was calculated per renal unit (left/right kidney) and per renal sector (four sectors per kidney). For sector analysis, US was considered truly positive if a stone was identified at CT in the same or an adjacent sector. RESULTS: There were 68 renal stones identified by CT in 30/69 patients (43%). Mean patient age was 14.7+/-3.6 years, and 35 were boys. For detecting nephrolithiasis in any kidney, US was 66.7% (48.8-80.8%) sensitive and 97.4% (86.8-99.9%) specific (positive predictive value=95.2% [77.3-99.8%], negative predictive value=79.2% [65.7-88.3%], positive likelihood ratio=26.0). Per renal sector, US was 59.7% (46.7-71.4%) sensitive and 97.4% (95.5-98.5%) specific (positive predictive value=72.3% [58.2-83.1%], negative predictive value=95.4% [93.2-96.9%], positive likelihood ratio=22.5). Of the 30 stones not detected by US, only 3 were >3 mm at CT. CONCLUSION: In clinical practice, US has high specificity for detecting nephrolithiasis in children but only moderate sensitivity and false negatives are common. PMID- 29476215 TI - Natural evolution of popliteomeniscal fascicle tears over 2 years and its association with lateral articular knee cartilage degeneration in patients with traumatic anterior cruciate ligament tear. AB - OBJECTIVES: To assess (i) normal imaging anatomy of the popliteomeniscal fascicles, (ii) prevalence and natural evolution of popliteomeniscal fascicle tears (PMFT) in subjects with traumatic anterior cruciate ligament (ACL) tears over 2 years and (iii) compare knee cartilage degeneration in subjects with and without PMFT longitudinally. METHODS: 57 subjects with ACL tears were screened for PMFT. Morphological (high-resolution 3D fast spin-echo) and compositional (T1rho and T2 mapping) MR imaging was performed prior to and 2 years after ACL reconstruction. Differences of morphological and compositional parameters were compared between subjects with and without PMFT using logistic regression, adjusting for age, sex and BMI. RESULTS: In 24% (n = 14) of the subjects with ACL tear a PMFT was detected on baseline MRI. One subject with PMFT developed a meniscal tear over 2 years. Cartilage ?T1rho of the lateral femur increased significantly more in subjects with isolated PMFT compared to controls (mean difference, 2.0 +/- 2.9 vs. -1.3 +/- 1.6, p = 0.027). CONCLUSION: PMFT detected by MRI are a common finding in subjects with ACL tears. Subjects with these defects showed higher compositional cartilage deterioration compared to controls, over 2 years in the lateral femoral compartment, indicating accelerated cartilage degeneration. KEY POINTS: * Popliteomeniscal fascicle lesions are a common finding in subjects with ACL tears. * Progression to a meniscal tear over 2 years is not frequent. * Anteroinferior popliteomeniscal fascicle is injured most frequently. * Patients with popliteomeniscal fascicle lesions showed accelerated cartilage degeneration. PMID- 29476216 TI - Late gadolinium enhancement of colorectal liver metastases post-chemotherapy is associated with tumour fibrosis and overall survival post-hepatectomy. AB - PURPOSE: To determine whether late gadolinium MRI enhancement of colorectal liver metastases (CRCLM) post-chemotherapy is associated with tumour fibrosis and survival post-hepatectomy. MATERIALS AND METHODS: The institutional review board approved this retrospective cohort study and waived the requirement for informed consent. A cohort of 121 surgical patients who received preoperative MRI after chemotherapy between 2006-2012 was included in this study. Target tumour enhancement (TTE), defined as the mean contrast-to-noise ratio of up to two target lesions on late-phase gadobutrol-enhanced MRI, was determined by two independent raters. The average TTE was correlated with tumour fibrosis on post hepatectomy specimens using Spearman correlation and with survival post hepatectomy using Kaplan-Meier and Cox regression. Inter-rater reliability was determined using relative intra-class correlation coefficients. RESULTS: In the surgical cohort (mean age: 63.0 years; male: 58%), TTE was associated with tumour fibrosis (r = 0.43, p < 0.001). Strong TTE was associated with improved survival compared to weak TTE (3-year survival: 88.4% vs. 58.8%, p = 0.003) with a hazard ratio of 0.32 (95% CI: 0.14-0.75, p = 0.008), after taking into account known prognostic variables. Inter-rater reliability was very good with a relative intraclass correlation of 0.84 (95% CI: 0.77-0.89). CONCLUSION: Late gadolinium MRI enhancement of CRCLM post-chemotherapy is associated with tumour fibrosis and survival. KEY POINTS: * MRI enhancement of colorectal liver metastases is associated with survival post-hepatectomy * MRI enhancement of chemotherapy treated colorectal liver metastases correlates with tumour fibrosis * Measuring late MRI enhancement using target tumour enhancement is reliable. PMID- 29476217 TI - Monitoring cerebral blood flow change through use of arterial spin labelling in acute ischaemic stroke patients after intra-arterial thrombectomy. AB - OBJECTIVES: To evaluate the ability of arterial spin labelling perfusion-weighted imaging (ASL-PWI) to identify reperfusion status and to predict the early neurological outcome of acute ischaemic stroke patients after intra-arterial (IA) thrombectomy. METHODS: A total of 51 acute ischaemic stroke patients who underwent IA thrombectomy were retrospectively reviewed. Asymmetrical index before and after IA thrombectomy (AICBFpre and AICBFpost) and volume ratio of the reperfused territory to the baseline perfusion abnormality (reperfusion volume ratio) were calculated on ASL-PWI. A paired t-test was used to compare AICBFpre and AICBFpost. Pearson correlation and multiple linear regression were performed to evaluate correlations between the imaging parameters and NIHSS scores. RESULTS: Mean AICBFpost was significantly higher than mean AICBFpre (0.923+/ 0.352 vs. 0.312+/-0.191, p<0.001). AICBFpre had a significant correlation with NIHSSpre (pr=-0.430, p=.004). ?AICBF had significant correlations with NIHSS24 h, NIHSS5-7 days and ?NIHSS5-7 days (r=-0.356, p=0.028; r=-0.597, p<0.001; r=-0.346, p=0.033, respectively). ?AICBF, reperfusion volume ratio and baseline infarct volume were significant independent predictors for NIHSS5-7 days. CONCLUSIONS: ASL-PWI has the potential to serve as a non-invasive imaging tool to monitor the reperfusion status and predict the early neurological outcome of acute ischaemic stroke patients after IA thrombectomy. KEY POINTS: * CBF change on ASL-PWI after IA thrombectomy correlated with NIHSS scores. * ASL-PWI can non-invasively monitor reperfusion in AIS patients after IA thrombectomy. * ASL-PWI may predict early outcome of AIS patients after IA thrombectomy. PMID- 29476218 TI - How reliable are ADC measurements? A phantom and clinical study of cervical lymph nodes. AB - OBJECTIVE: To assess the reliability of ADC measurements in vitro and in cervical lymph nodes of healthy volunteers. METHODS: We used a GE 1.5 T MRI scanner and a first ice-water phantom according to recommendations released by the Quantitative Imaging Biomarker Alliance (QIBA) for assessing ADC against reference values. We analysed the target size effect by using a second phantom made of six inserted spheres with diameters ranging from 10 to 37 mm. Thirteen healthy volunteers were also scanned to assess the inter- and intra-observer reproducibility of volumetric ADC measurements of cervical lymph nodes. RESULTS: On the ice-water phantom, the error in ADC measurements was less than 4.3 %. The spatial bias due to the non-linearity of gradient fields was found to be 24 % at 8 cm from the isocentre. ADC measure reliability decreased when addressing small targets due to partial volume effects (up to 12.8 %). The mean ADC value of cervical lymph nodes was 0.87.10-3 +/- 0.12.10-3 mm2/s with a good intra-observer reliability. Inter observer reproducibility featured a bias of -5.5 % due to segmentation issues. CONCLUSION: ADC is a potentially important imaging biomarker in oncology; however, variability issues preclude its broader adoption. Reliable use of ADC requires technical advances and systematic quality control. KEY POINTS: * ADC is a promising quantitative imaging biomarker. * ADC has a fair inter-reader variability and good intra-reader variability. * Partial volume effect, post processing software and non-linearity of scanners are limiting factors. * No threshold values for detecting cervical lymph node malignancy can be drawn. PMID- 29476219 TI - Prediction of rupture risk in anterior communicating artery aneurysms with a feed forward artificial neural network. AB - OBJECTIVES: Anterior communicating artery (ACOM) aneurysms are the most common intracranial aneurysms, and predicting their rupture risk is challenging. We aimed to predict this risk using a two-layer feed-forward artificial neural network (ANN). MATERIALS AND METHOD: 594 ACOM aneurysms, 54 unruptured and 540 ruptured, were reviewed. A two-layer feed-forward ANN was designed for ACOM aneurysm rupture-risk analysis. To improve ANN efficiency, an adaptive synthetic (ADASYN) sampling approach was applied to generate more synthetic data for unruptured aneurysms. Seventeen parameters (13 morphological parameters of ACOM aneurysm measured from these patients' CT angiography (CTA) images, two demographic factors, and hypertension and smoking histories) were adopted as ANN input. RESULTS: Age, vessel size, aneurysm height, perpendicular height, aneurysm neck size, aspect ratio, size ratio, aneurysm angle, vessel angle, aneurysm projection, A1 segment configuration, aneurysm lobulations and hypertension were significantly different between the ruptured and unruptured groups. Areas under the ROC curve for training, validating, testing and overall data sets were 0.953, 0.937, 0.928 and 0.950, respectively. Overall prediction accuracy for raw 594 samples was 94.8 %. CONCLUSION: This ANN presents good performance and offers a valuable tool for prediction of rupture risk in ACOM aneurysms, which may facilitate management of unruptured ACOM aneurysms. KEY POINTS: * A feed-forward ANN was designed for the prediction of rupture risk in ACOM aneurysms. * Two demographic parameters, 13 morphological aneurysm parameters, and hypertension/smoking history were acquired. * An ADASYN sampling approach was used to improve ANN quality. * Overall prediction accuracy of 94.8 % for the raw samples was achieved. PMID- 29476220 TI - From radiation osteitis to osteoradionecrosis: incidence and MR morphology of radiation-induced sacral pathologies following pelvic radiotherapy. AB - OBJECTIVE: To investigate the incidence rate, time-to-onset and recovery, MRI morphology and occurrence of insufficiency fractures in radiation-induced changes in the sacrum following pelvic radiotherapy. MATERIAL AND METHODS: 410 patients with pelvic malignancies treated with radiotherapy were reviewed. Follow-up was 1 124 months (mean 22 months). Serial MRI (average four studies/patient) were analysed using a new semi-quantitative score (Radiation-Induced Sacral Changes=RISC). A size category (I/II/III), a type category for MR signal morphologies (a/b/c) and sacral insufficiency fractures (+/-) were applied. RESULTS: Seventy-two patients (17.6 %) were found to have new pathological signal changes. Radiation osteitis was documented in 83.3 % (60/72, RISC stage a + b), and definite osteonecrosis (stage c) in 12 patients (16.7 %, 12/72). Thirty-one patients (43.1 %) had sacral insufficiency fractures. Initial bone marrow signal changes were found 1-35 months (median 4 months) after radiotherapy. The maximum manifestation of radiation-induced signal changes occurred after 1-35 months (mean 11 months). Fifty-six cases (77.8 %) showed a significant signal recovery within 16.5 months. CONCLUSION: Radiation-induced bone marrow changes appear with a high incidence at the sacrum with an early onset and frequent recovery. The majority presented a pattern of radiation osteitis, whereas osteoradionecrosis was proportionately rare. KEY POINTS: * Radiation-induced sacral bone marrow changes appear frequently (17.6 %) following pelvic radiotherapy. * Insufficiency fractures are common late effects (43 %). * Radiation osteitis develops early (4 mo), with recovery between 16.5 and 39.5 months. * Definite radiological osteoradionecrosis is proportionately rare (3 %). * A 3-stage classification system simplifies and standardizes the morphological disease staging. PMID- 29476222 TI - Ibrutinib brain distribution: a preclinical study. AB - PURPOSE: Central nervous system (CNS) dissemination occurs in 4.1% of mantle cell lymphoma (MCL) patients and clinically significant CNS involvement in chronic lymphocytic leukemia (CLL) patients reaches 4%. Ibrutinib, an orally administered Bruton's tyrosine kinase (BTK) inhibitor, has shown substantial activity in CLL or MCL patients with CNS localization, and in primary central nervous system lymphoma (PCNSL). The drug efficacy to treat primary or secondary CNS impairments relies on its brain distribution through the blood-brain barrier (BBB), the aim of the present work was to study the brain distribution of ibrutinib using an in vivo mice model. METHODS: Brain and plasma pharmacokinetics of ibrutinib were assessed in a healthy Swiss mice model. Brain accumulation of ibrutinib was evaluated through an escalation single-dose study and a multiple-dose study in whole brain and in its specific anatomic structures. Ibrutinib plasma and brain quantification was performed using a validated liquid-chromatography mass tandem spectrometry method. RESULTS: Maximal concentration of ibrutinib in plasma and brain were close thus showing that ibrutinib rapidly crosses the BBB in 0.29 h (0.2-0.32 h) [median (min-max)]. Ibrutinib brain exposure was also correlated to the dose, and correlated to plasma exposure. AUC0-t brain to AUC0-t plasma ratio average for ibrutinib was found to reach 0.7 and ibrutinib accumulates in the ventricle area. CONCLUSION: The high level of ibrutinib brain distribution supports the clinical efficacy of this drug in CNS localization of MCL, CLL or PCNSL. PMID- 29476221 TI - MRI-based decision tree model for diagnosis of biliary atresia. AB - OBJECTIVES: To evaluate MRI findings and to generate a decision tree model for diagnosis of biliary atresia (BA) in infants with jaundice. METHODS: We retrospectively reviewed features of MRI and ultrasonography (US) performed in infants with jaundice between January 2009 and June 2016 under approval of the institutional review board, including the maximum diameter of periportal signal change on MRI (MR triangular cord thickness, MR-TCT) or US (US-TCT), visibility of common bile duct (CBD) and abnormality of gallbladder (GB). Hepatic subcapsular flow was reviewed on Doppler US. We performed conditional inference tree analysis using MRI findings to generate a decision tree model. RESULTS: A total of 208 infants were included, 112 in the BA group and 96 in the non-BA group. Mean age at the time of MRI was 58.7 +/- 36.6 days. Visibility of CBD, abnormality of GB and MR-TCT were good discriminators for the diagnosis of BA and the MRI-based decision tree using these findings with MR-TCT cut-off 5.1 mm showed 97.3 % sensitivity, 94.8 % specificity and 96.2 % accuracy. CONCLUSIONS: MRI-based decision tree model reliably differentiates BA in infants with jaundice. MRI can be an objective imaging modality for the diagnosis of BA. KEY POINTS: * MRI-based decision tree model reliably differentiates biliary atresia in neonatal cholestasis. * Common bile duct, gallbladder and periportal signal changes are the discriminators. * MRI has comparable performance to ultrasonography for diagnosis of biliary atresia. PMID- 29476223 TI - Phosphorylation of AKT and ERK1/2 and mutations of PIK3CA and PTEN are predictive of breast cancer cell sensitivity to everolimus in vitro. AB - BACKGROUND: Everolimus is the hydroxyethyl derivative of sirolimus and a strong inhibitor of mammalian target of rapamycin (mTOR). This drug has immunosuppressive and anticancer activities and the present in vitro study was aimed at identifying the cellular and molecular profiles of breast cancer cells predictive of sensitivity to everolimus. MATERIALS AND METHODS: MCF-7, T-47D, ZR 75-1, CAMA-1, HCC-1500 and MCF-10A cells were used and viability was assessed using WST-1 dye. Sensitivity to everolimus was correlated with phosphorylation of AKT (Ser473/Thr308), mTOR (Ser2448), and ERK1/2 (Thr202/Tyr204) and mutational profile of KRAS, NRAS, BRAF, PIK3CA, PTEN, TSC1, TSC2 and FRAP genes. Protein phosphorylation was evaluated by AlphaScreen SureFire, while the mutational status was examined by digital droplet PCR and Sanger sequencing. RESULTS: Everolimus showed a transient growth inhibition in non-tumorigenic cells, while in tumorigenic lines the drug suppressed the proliferation in a concentration dependent manner but with different potency (IC50) and efficacy (Emax), being ZR 75-1 the most sensitive and T47D the least sensitive. MCF-7, T47D and HCC1500 had activating mutations in PIK3CA gene, while loss-of-activity PTEN mutations were detected in sensitive cell lines, including ZR-75-1, which showed no changes or minimal increase in the amount of p-AKT(Ser473/Thr308) and p ERK1/2(Thr202/Tyr204) induced by everolimus compared to the resistant cell line T47D in which phosphorylation of AKT and ERK was increased. CONCLUSIONS: Cellular levels of p-AKT(Ser473/Thr308) and p-ERK1/2(Thr202/Tyr204), activating mutations of PIK3CA and inactivating mutations of PTEN may predict response to everolimus in breast cancer cells; these findings have potential applications for treatment personalization of everolimus in breast cancer patients. PMID- 29476224 TI - Is a single-level measurement of paraspinal muscle fat infiltration and cross sectional area representative of the entire lumbar spine? AB - PURPOSE: Lumbar paraspinal muscle morphology has recently been evaluated in several studies with conflicting results. Several studies have performed single slice evaluations of paraspinal muscle morphology, whereas other studies have done a multi-level assessment; this methodological difference might explain the observed different results. Our study evaluated if a single-slice axial measurement is representative of the entire lumbar musculature. METHODS: We included 80 adult patients who were consecutively evaluated with magnetic resonance imaging (MRI) for spinal symptoms. Using T2-weighted axial images, we measured the fat signal fractions (FSF) and cross-sectional area (CSA) of the erector spinae and multifidus at the five levels of the lumbar spine (from L1-L2 to L5-S1). We used the ANOVA test for repeated measurements (with Bonferroni correction) to compare the FSF and CSA among the levels. RESULTS: Erector spinae showed an increasing FSF from L1-L2 to L5-S1; all erector spinae FSF comparisons among the different levels were significantly different. Multifidus FSF also increased caudally below L2-L3, although significant differences were observed only with two or more levels of distance. The CSA of the erector spinae showed a caudal decrease (L4-L5 and L5-S1 being significantly smaller than all the levels above). The CSA of the multifidus showed that all levels exhibited a significantly different area compared to their adjacent level (except L5-S1 compared to L4-L5). CONCLUSIONS: No single-level FSF or CSA is representative of the whole lumbar spine. A standardized multi-level evaluation of the paraspinal musculature should be used in future research. PMID- 29476225 TI - High-resolution genetic mapping of a novel brown planthopper resistance locus, Bph34 in Oryza sativa L. X Oryza nivara (Sharma & Shastry) derived interspecific F2 population. AB - KEY MESSAGE: A BPH-resistant locus designated as Bph34 identified in Oryza nivara acc. IRGC104646 on long arm of chromosome 4 using high-resolution mapping with 50 K SNP chip. BPH resistance contributed by locus showed dominant inheritance in F2 and F3. The Bph34 locus is 91 kb in size and contains 11 candidate genes. In addition to SNP markers, SSR markers, RM16994 and RM17007 co-segregated with the BPH resistance. These two SSR markers can facilitate marker-assisted transfer of the Bph34 locus into elite rice cultivars in all labs. Brown planthopper (BPH, Nilaparvata lugen Stal) is one of the most destructive insects of rice (Oryza sativa L.) causing significant yield losses annually. Exploiting host plant resistance to BPH and incorporating resistant genes in susceptible commercial cultivars is economical and environmentally friendly approach to manage this pest. Here, we report high-resolution mapping of a novel genetic locus for resistance to BPH, designated as Bph34 on long arm of rice chromosome 4. The locus was mapped using an interspecific F2 population derived from a cross between susceptible indica cultivar PR122 and BPH-resistant wild species, O. nivara acc. IRGC104646. Inheritance studies performed using F2 and F2:3 populations revealed the presence of single dominant gene. Construction of high density linkage map using 50 K SNP chip (OsSNPnks) followed by QTL mapping identified single major locus at 28.8 LOD score between SNP markers, AX-95952039 and AX-95921548. The major locus contributing resistance to BPH designated as Bph34 and explained 68.3% of total phenotypic variance. The Bph34 locus is 91 Kb in size on Nipponbare reference genome-IRGSP-1.0 and contains 11 candidate genes. In addition to associated SNP markers, two SSR markers, RM16994 and RM17007, also co-segregated with the Bph34 which can be used efficiently for markers assisted transfer into elite rice cultivars across the labs. PMID- 29476226 TI - Remapping of the stripe rust resistance gene Yr10 in common wheat. AB - KEY MESSAGE: Yr10 is an important gene to control wheat stripe rust, and the search for Yr10 needs to be continued. Wheat stripe rust or yellow rust is a devastating fungal disease caused by Puccinia striiformis f. sp. tritici (Pst). Host disease resistance offers a primary source for controlling wheat stripe rust. The stripe rust resistance gene Yr10 confers the race-specific resistance to most tested Pst races in China including CYR29. Early studies proposed that Yr10 was a nucleotide-binding site, leucine-rich repeat gene archived as GenBank accession AF149112 (hereafter designated the Yr10 candidate gene or Yr10 CG ). In this study, we revealed that 15 Chinese wheat cultivars positive for Yr10 CG are susceptible to CYR29. We then expressed the Yr10 CG cDNA in the common wheat 'Bobwhite'. The Yr10 CG -cDNA positive transgenic plants were also susceptible to CYR29. Thus, it is highly unlikely that Yr10 CG corresponds to the Yr10 resistance gene. Using the Yr10 donor 'Moro' and the Pst-susceptible wheat 'Huixianhong', we generated two F3 populations that displayed a single Mendelian segregation on the Yr10 gene, and used them to remap the Yr10 gene. Six markers were placed in the Yr10 region, with the Yr10 CG gene now mapping about 1.2-cM proximal to the Yr10 locus and the Xsdauw79 marker is completely linked to the Yr10 locus. Apparently, the Yr10 gene has not yet been identified. Fine mapping and positional cloning of Yr10 is important for gene pyramiding for stripe rust resistance in wheat. PMID- 29476227 TI - 18F-FDG-PET/CT based total metabolic tumor volume change during neoadjuvant chemotherapy predicts outcome in advanced epithelial ovarian cancer. AB - OBJECTIVE: To evaluate the predictive potential of total metabolic tumor volume (MTV) reduction during neoadjuvant chemotherapy (NACT) with 18F-FDG-PET/CT in an advanced FIGO stage III/IV epithelial ovarian cancer (EOC) patient cohort. METHODS: Twenty-nine primarily inoperable EOC patients underwent 18F-FDG-PET/CT before and after NACT. The pre- and post-NACT total MTV, in addition to the percentage MTV reduction during NACT, were compared with primary therapy outcome and progression-free survival (PFS). ROC-analysis determined an optimal threshold for MTV reduction identifying patients with progressive or stable disease (PD/SD) at the end of primary therapy. A multivariate analysis with residual tumor (0/>0), FIGO stage (III/IV) and MTV reduction compared to PFS was performed. The association between MTV reduction and overall survival (OS) was evaluated. RESULTS: The median pre- and post-NACT total MTV were 352 cm3 (range 150 to 1322 cm3) and 51 cm3 (range 0 to 417 cm3), respectively. The median MTV reduction during NACT was 89% (range 24% to 100%). Post-NACT MTV and MTV reduction associated with primary therapy outcome (MTV post-NACT p = 0.007, MTV reduction p = 0.001) and PFS (MTV post-NACT p = 0.005, MTV reduction p = 0.005). MTV reduction <85% identified the PD/SD patients (sensitivity 70%, specificity 78%, AUC 0.79). In a multivariate analysis, MTV reduction (p = 0.002) and FIGO stage (p = 0.003) were statistically significant variables associated with PFS. MTV reduction during NACT corresponded to OS (p = 0.05). CONCLUSION: 18F-FDG-PET/CT is helpful in NACT response evaluation. Patients with total MTV reduction <85% during NACT might be candidates for second-line chemotherapy and clinical trials, instead of interval debulking surgery. PMID- 29476228 TI - Optimal time-point for 68Ga-PSMA-11 PET/CT imaging in assessment of prostate cancer: feasibility of sterile cold-kit tracer preparation? AB - PURPOSE: In this prospective study, we evaluated the optimal time-point for 68Ga PSMA-11 PET/CT acquisition in the assessment of prostate cancer. We also examined, for the first time the feasibility of tracer production using a PSMA-11 sterile cold-kit in the clinical workflow of PET/CT centres. METHODS: Fifty prostate cancer patients (25 staging, 25 biochemical recurrence) were enrolled in this study. All patients received an intravenous dose of 2.0 MBq/kg body weight 68Ga-PSMA-11 prepared using a sterile cold kit (ANMI SA, Liege, Belgium), followed by an early (20 min after injection) semi-whole-body PET/CT scan and a standard-delay (100 min after injection) abdominopelvic PET/CT scan. The detection rates with 68Ga-PSMA-11 were compared between the two acquisitions. The pattern of physiological background activity and tumour to background ratio were also analysed. RESULTS: The total preparation time was reduced to 5 min using the PSMA-11 sterile cold kit, which improved the final radionuclide activity by about 30% per single 68Ge/68Ga generator elution. Overall, 158 pathological lesions were analysed in 45 patients (90%) suggestive of malignancy on both (early and standard-delay) 68Ga-PSMA PET/CT images. There was a significant (p < 0.001) increase in SUVmax on delayed images in suspicious prostates (11.6 +/- 8.2 to 14.8 +/- 1.0) and lymph nodes (LNs; 9.7 +/- 5.9 to 12.3 +/- 8.8), while bone lesions showed no significant increase (8.5 +/- 5.6 to 9.2 +/- 7.0, p = 0.188). However, the SUVmax of suspicious lesions on early images was adequate to support the criteria for correct interpretation (mean SUVmax 9.83 +/- 6.7).In 26 of 157 lesions, but a decrease in SUV was seen, mostly in subcentimetre lesions in patients with multiple metastases. However, it did not affect the staging of the disease or patient management. The tumour to background ratio of primary prostate lesions and LNs showed a significant (p < 0.001) increase from the early to the standard-delay acquisition, but no significant increase was seen in bony lesions (p = 0.11). CONCLUSION: The PSMA-11 sterile cold kit seems to be feasible for use in routine clinical practice, and it has a shorter radionuclide preparation time and is less operator-dependent than the synthesizer-based production method. In addition, early 68Ga-PSMA-11 PET/CT imaging seems to provide a detection rate comparable with that of standard-delay imaging. Furthermore, the shorter preparation time using the 68Ga-PSMA-11 sterile cold kit and promising value of early PET/CT scanning could allow tailoring of imaging protocols which may reduce the costs and improve the time efficiency in PET/CT centres. PMID- 29476229 TI - Multiparametric PET/MR imaging biomarkers are associated with overall survival in patients with pancreatic cancer. AB - PURPOSE: To correlate the overall survival (OS) with the imaging biomarkers of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), diffusion weighted imaging (DWI), magnetic resonance spectroscopy, and glucose metabolic activity derived from integrated fluorine 18 fluorodeoxyglucose positron emission tomography (18F-FDG PET)/MRI in patients with pancreatic cancer. METHODS: This prospective study was approved by the institutional review board and informed consent was obtained from all participants. Sixty-three consecutive patients (mean age, 62.7 +/- 12 y; men/women, 40/23) with pancreatic cancer underwent PET/MRI before treatment. The imaging biomarkers were comprised of DCE-MRI parameters (peak, IAUC 60 , K trans , k ep , v e ), the minimum apparent diffusion coefficient (ADCmin), choline level, standardized uptake values, metabolic tumor volume, and total lesion glycolysis (TLG) of the tumors. The relationships between these imaging biomarkers with OS were evaluated with the Kaplan-Meier and Cox proportional hazard models. RESULTS: Seventeen (27%) patients received curative surgery, with the median follow-up duration being 638 days. Univariate analysis showed that patients at a low TNM stage (?3, P = 0.041), high peak (P = 0.006), high ADCmin (P = 0.002) and low TLG (P = 0.01) had better OS. Moreover, high TLG/peak ratio was associated with poor OS (P = 0.016). Multivariate analysis indicated that ADCmin (P = 0.011) and TLG/peak ratio (P = 0.006) were independent predictors of OS after adjustment for age, gender, tumor size, and TNM stage. The TLG/peak ratio was an independent predictor of OS in a subgroup of patients who did not receive curative surgery (P = 0.013). CONCLUSION: The flow-metabolism mismatch reflected by the TLG/peak ratio may better predict OS than other imaging biomarkers from PET/MRI in pancreatic cancer patients. PMID- 29476230 TI - Peptidomic strategy for purification and identification of potential ACE inhibitory and antioxidant peptides in Tetradesmus obliquus microalgae. AB - Microalgae are unicellular marine organisms that have promoted complex biochemical pathways to survive in greatly competitive marine environments. They could contain significant amounts of high-quality proteins which, because of their structural diversity, contain a range of yet undiscovered novel bioactive peptides. In this work, a peptidomic platform was developed for the separation and identification of bioactive peptides in protein hydrolysates. In this work, a peptidomic platform was developed for the extraction, separation, and identification of bioactive peptides in protein hydrolysates. Indeed, extraction of proteins from recalcitrant tissues is still a challenge due to their strong cell walls and high levels of non-protein interfering compounds. Therefore, seven different protein extraction protocols, based on mechanical and chemical methods, were tested in order to produce high-quality protein extracts. Proteins obtained by means of the best protocol, consisting of milling the recalcitrant tissue with glass beads, were subjected to enzymatic digestion with Alcalase(r) and subsequently the hydrolysate was purified by two-dimensional semi-preparative reversed phase liquid chromatography. Fractions were assayed for antioxidant and antihypertensive activities and only the most active ones were finally analyzed by RP nanoHPLC-MS/MS. Around 500 peptide sequences were identified in these fractions. The identified peptides were subjected to an in silico analysis by PeptideRanker algorithm in order to assign a score of bioactivity probability. Twenty-five sequenced peptides were found with potential antioxidant and angiotensin-converting-enzyme-inhibitory activities. Four of these peptides, WPRGYFL, GPDRPKFLGPF, WYGPDRPKFL, SDWDRF, were selected for synthesis and in vitro tested for specific bioactivity, exhibiting good values of antioxidant and ACE-inhibitory activity. Graphical abstract Workflow showing the entire peptidomic approach developed for identification of bioactive peptides in microalgae. PMID- 29476232 TI - Cellular dielectrophoresis coupled with single-cell analysis. AB - In this review, recent advances that leverage dielectrophoretic approaches to accomplish single-cell analysis (both "on-chip" and "off-chip") are discussed with special emphasis on eukaryotic cells. Dielectrophoresis as an electric-field induced force utilized for cell manipulation can confer selectivity without labeling. Recent technical improvements have increased the volumetric throughput of the separation of cells from complex mixtures, introduced new strategies for massively parallel single-cell confinement for subsequent on-chip analysis, made possible selective transport of individual cells off-chip, and integrated preconcentration and prefocusing steps to enhance dielectrophoretic performance. Collectively, these studies potentiate all-in-one platforms capable of taking as their input complex mixtures of cells and accomplishing single-cell analysis. Assays requiring small reaction volumes (e.g., enzymatic assays, fluorescent in situ hybridization, and immunostaining) have been demonstrated. Still greater opportunities to unravel cell-to-cell variations and for point-of-care applications can be realized by making possible on-chip gene amplification, live cell assays, and either dielectrophoretic manipulation in native media or on-chip exchange of media. We therefore conclude with a discussion of emerging capabilities in these areas. PMID- 29476233 TI - Speciation analysis of arsenic in seafood and seaweed: Part II-single laboratory validation of method. AB - Single laboratory validation of a method for arsenic speciation analysis in seafood and seaweed is presented. The method is based on stepwise extraction of water-soluble and non-polar arsenic with hot water and a mixture of dichloromethane and methanol, respectively. While the water-soluble arsenicals were speciated by anion and cation exchange liquid chromatography inductively coupled plasma mass spectrometry (LC-ICP-MS), the non-polar arsenicals were collectively determined by ICP-MS after digestion in acid. The performance characteristics and broad application of the method were evaluated by analyzing eight commercial samples (cod, haddock, mackerel, crab, shrimp, geoduck clam, oyster, and kombu) and four reference materials (fish protein (DORM-4), lobster hepatopancreas (TORT-3), mussel tissue (SRM 2976), and hijiki seaweed (CRM 7405 a)) representing finfish, crustaceans, molluscs, and seaweed. Matrices spiked at three levels in duplicates were also analyzed. The stepwise extraction provided 76-106% extraction of the total arsenic from the test materials. The method demonstrated satisfactory repeatability for analysis of replicate extracts prepared over several days. The accuracy of the method was evaluated by analyzing reference materials certified for both total arsenic and a few arsenicals; the experimental results were 90-105% of the certified values. Comparison between the total water-soluble arsenic and the sum of the concentrations of the chromatographed species gave 80-92% mass balance. While spike recoveries of most arsenicals were in the acceptance range set by CODEX, a few species spiked into cod, haddock, and shrimp were poorly recovered due to transformation to other forms. After thorough investigations, strategies were devised to improve the recoveries of these species by averting their transformations. Limits of quantification (LOQ) for the extraction and quantification of 16 arsenicals using the current method were in the range 6-16 ng g-1 arsenic. PMID- 29476231 TI - Comparison of metabolic pathways of different alpha-N-heterocyclic thiosemicarbazones. AB - Clinical failure of novel drugs is often related to their rapid metabolism and excretion. This highlights the importance of elucidation of their pharmacokinetic profile already at the preclinical stage of drug development. Triapine, the most prominent representative of alpha-N-heterocyclic thiosemicarbazones, was investigated in more than 30 clinical phase I/II trials, but the results against solid tumors were disappointing. Recent investigations from our group suggested that this is, at least partially, based on the fast metabolism and excretion. In order to establish more detailed structure/activity/metabolism relationships, herein a panel of 10 different Triapine derivatives was investigated for their metabolic pathways. From the biological point of view, the panel consists of terminally dimethylated thiosemicarbazones with nanomolar IC50 values, derivatives with micromolar cytotoxicities comparable to Triapine and a completely inactive representative. To study the oxidative metabolism, a purely instrumental approach based on electrochemistry/mass spectrometry was applied and the results were compared to the data obtained from microsomal incubations. Overall, the investigated thiosemicarbazones underwent the phase I metabolic reactions dehydrogenation, hydroxylation, oxidative desulfuration (to semicarbazone and amidrazone) and demethylation. Notably, dehydrogenation resulted in a ring-closure reaction with formation of thiadiazoles. Although strong differences between the metabolic pathways of the different thiosemicarbazones were observed, they could not be directly correlated to their cytotoxicities. Finally, the metabolic pathways for the most cytotoxic compound were elucidated also in tissues collected from drug-treated mice, confirming the data obtained by electrochemical oxidation and microsomes. In addition, the in vivo experiments revealed a very fast metabolism and excretion of the compound. Graphical abstract Structure/activity/metabolisation relationships for 10 anticancer thiosemicarbazones were established using electrochemical oxidation coupled to mass spectrometry (EC-MS) and human liver microsomes analyzed by LC MS. PMID- 29476234 TI - Screening for anti-proliferative and anti-inflammatory components from Rhamnus davurica Pall. using bio-affinity ultrafiltration with multiple drug targets. AB - Rhamnus davurica Pall. (R. davurica) has been used as a traditional medicine for many years in China and abroad and shown a wide spectrum of biological activities. Previously, we reported the phytochemical fingerprinting profile of R. davurica, its distinct anti-proliferative activities against HT-29 and SGC 7901 cell lines, and the topoisomerase I (Top I) ligands based on bio-affinity ultrafiltration and HPLC-MS (UF-HPLC-MS). Nevertheless, among the 32 peaks detected in the fingerprinting profile, the common bioactive constituents responsible for the anti-inflammatory and anti-proliferative activities in the extracts remain elusive. To further explore the specific responsible components for their diversified activities and their potential action targets/mechanisms, the method based on bio-affinity UF-HPLC-MS using therapeutic targets like Top I and cyclooxygenase 2 (COX-2) was established to rapidly screen and identify the ligands binding to these known target enzymes. As a result, 12 components were revealed as potential Top I ligands along with 11 components as potential COX-2 ligands, where several components were revealed to possess both activities. Further validations of these bioactive components have also been conducted and confirmed their highlighted activities. This integrated method of UF-HPLC-MS exhibits high efficiency in rapidly screening for multi-target bioactive components responsible for multiple pharmacological effects from the complex natural products and could be very useful to explain the complex action mechanisms of herb medicines in a complex multi-component and multi-target mode at the molecular level. Graphical abstract Schematic diagram of UF-HPLC-MS assay to screen for Top I and COX-2 ligands. The principle of the assay usually involves the following steps: incubation, ultrafiltration, and identification. PMID- 29476235 TI - MCEE: a data preprocessing approach for metabolic confounding effect elimination. AB - It is well recognized that physiological and environmental factors such as race, age, gender, and diurnal cycles often have a definite influence on metabolic results that statistically manifests as confounding variables. Currently, removal or controlling of confounding effects relies heavily on experimental design. There are no available data processing techniques focusing on the compensation of their effects. We therefore proposed a new method, Metabolic confounding effect elimination (MCEE), to remove the influence of specified confounding factors and make the data more accurate. The method consists of three steps: metabolites grouping, confounder-related metabolites selection, and metabolites modification. Its effectiveness and advantages were evaluated comprehensively by several simulated models and real datasets, and were compared with two typical methods, the principal component analysis (PCA)- and the direct orthogonal signal correction (DOSC)-based methods. MCEE is simple, effective, and safe, and is independent of sample number, association degree, and missing value. Hence, it may serve as a good complement to existing metabolomics data preprocessing methods and aid in better understanding the metabolic and biological status of interest. Graphical Abstract Algorithm flow and demo performance of MCEE. PMID- 29476236 TI - Leveraging human genetic and adverse outcome pathway (AOP) data to inform susceptibility in human health risk assessment. AB - Estimation of susceptibility differences in human health risk assessment (HHRA) has been challenged by a lack of available susceptibility and variability data after exposure to a specific environmental chemical or pharmaceutical. With the increasingly large number of available data sources that contain polymorphism and other genetic data, human genetic variability that informs susceptibility can be better incorporated into HHRA. A recent policy, the 2016 The Frank R. Lautenberg Chemical Safety for the twenty-first Century Act, requires the US Environmental Protection Agency to evaluate new and existing toxic chemicals with explicit consideration of susceptible populations of all types (life stage, exposure, genetic, etc.). We propose using the adverse outcome pathway (AOP) construct to organize, identify, and characterize human genetic susceptibility in HHRA. We explore how publicly available human genetic datasets can be used to gain mechanistic understanding of molecular events and characterize human susceptibility for an adverse outcome. We present a computational method that implements publicly available human genetic data to prioritize AOPs with potential for human genetic variability. We describe the application of this approach across multiple described AOPs for health outcomes of interest, and by focusing on a single molecular initiating event. This contributes to a long-term goal to improve estimates of human susceptibility for use in HHRA for single and multiple chemicals. PMID- 29476238 TI - Chronic consumption of a low calorie, high polyphenol cranberry beverage attenuates inflammation and improves glucoregulation and HDL cholesterol in healthy overweight humans: a randomized controlled trial. AB - PURPOSE: We studied the health benefits of low calorie cranberry beverage consumption on glucoregulation, oxidative damage, inflammation, and lipid metabolism in overweight but otherwise healthy humans. METHODS: 78 overweight or obese men and women (30-70 years; BMI 27-35 kg/m2) with abdominal adiposity (waist: hip > 0.8 for women and > 0.9 for men; waist: height >= 0.5) consumed 450 mL placebo or low calorie, high polyphenol cranberry extract beverage (CEB) daily for 8 week in a randomized, double-blind, placebo-controlled, parallel design trial. Blood and urine samples were collected after overnight fast at baseline and after 8 weeks of daily beverage consumption. Blood and urine samples were also collected during 3 oral glucose tolerance test (OGTT) challenges: (1) pre intervention without the test beverages, (2) following a single dose of placebo or CEB at baseline (week 0), and (3) following a single dose of placebo or CEB at 8 week. RESULTS: Compared to placebo, a single CEB dose at baseline lowered endothelin-1 and elevated nitric oxide and the reduced:oxidized glutathione ratio (P < 0.05). Interferon-gamma was elevated (P < 0.05) after a single CEB dose at baseline; however, after 8 week of CEB intervention, fasting C-reactive protein was lower (P < 0.05). CEB consumption for 8 week also reduced serum insulin and increased HDL cholesterol compared to placebo (P < 0.05). CONCLUSIONS: An acute dose of low calorie, high polyphenol cranberry beverage improved antioxidant status, while 8 week daily consumption reduced cardiovascular disease risk factors by improving glucoregulation, downregulating inflammatory biomarkers, and increasing HDL cholesterol. PMID- 29476237 TI - Improved Y-STR typing for disaster victim identification, missing persons investigations, and historical human skeletal remains. AB - Bones are a valuable source of DNA in forensic, anthropological, and archaeological investigations. There are a number of scenarios in which the only samples available for testing are highly degraded and/or skeletonized. Often it is necessary to perform more than one type of marker analysis on such samples in order to compile sufficient data for identification. Lineage markers, such as Y STRs and mitochondrial DNA (mtDNA), represent important systems to complement autosomal DNA markers and anthropological metadata in making associations between unidentified remains and living relatives or for characterization of the remains for historical and archaeological studies. In this comparative study, Y-STR typing with both YfilerTM and YfilerTM Plus (Thermo Fisher Scientific, Waltham, MA, USA) was performed on a variety of human skeletal remains, including samples from the American Civil War (1861-1865), the late nineteenth century gold rush era in Deadwood, SD, USA (1874-1877), the Seven Years' War (1756-1763), a seventeenth-century archaeological site in Raspenava, Bohemia (Czech Republic), and World War II (1939-1945). The skeletal remains used for this study were recovered from a wide range of environmental conditions and were extracted using several common methods. Regardless of the DNA extraction method used and the age/condition of the remains, 22 out of 24 bone samples yielded a greater number of alleles using the YfilerTM Plus kit compared to the YfilerTM kit using the same quantity of input DNA. There was no discernable correlation with the degradation index values for these samples. Overall, the efficacy of the YfilerTM Plus assay was demonstrated on degraded DNA from skeletal remains. YfilerTM Plus increases the discriminatory power over the previous generation multiplex due to the larger set of Y-STR markers available for analysis and buffer modifications with the newer version kit. Increased haplotype resolution is provided to infer or refute putative genetic relationships. PMID- 29476239 TI - Postnatal refinement of interareal feedforward projections in ferret visual cortex. AB - We studied the postnatal refinement of feedforward (FF) projections from ferret V1 to multiple cortical targets during the period around eye opening. Our goal was to establish (a) whether the developmental refinement of FF projections parallels that of feedback (FB) cortical circuits, and (b) whether FF pathways from V1 to different target areas refine with a similar rate. We injected the tracer CTb into V1 of juvenile ferrets, and visualized the pattern of labeled axon terminals in extrastriate cortex. Bouton density of FF projections to target areas 18, 19, and 21 declined steadily from 4 to 8 weeks postnatal. However, in area Ssy this decline was delayed somewhat, not occurring until after 6 weeks. During this postnatal period, mean interbouton intervals along individual FF axons to all visual areas increased, and we observed a concomitant moderate decrease in axon density in areas 18, 21, and Ssy. These data suggest that FF circuits linking V1 to its main extrastriate targets remodel largely synchronously in the weeks following eye opening, that FF and FB cortical circuits share a broadly similar developmental timecourse, and that postnatal visual experience is critical for the refinement of both FF and FB cortical circuits. PMID- 29476240 TI - Vesicular glutamate transporter 1 (VGLUT1)- and VGLUT2-immunopositive axon terminals on the rat jaw-closing and jaw-opening motoneurons. AB - To provide information on the glutamatergic synapses on the trigeminal motoneurons, which may be important for understanding the mechanism of control of jaw movements, we investigated the distribution of vesicular glutamate transporter (VGLUT)1-immunopositive (+) and VGLUT2 + axon terminals (boutons) on the rat jaw-closing (JC) and jaw-opening (JO) motoneurons, and their morphological determinants of synaptic strength by retrograde tracing, electron microscopic immunohistochemistry, and quantitative ultrastructural analysis. We found that (1) the large majority of VGLUT + boutons on JC and JO motoneurons were VGLUT2+, (2) the density of VGLUT1 + boutons terminating on JC motoneurons was significantly higher than that on JO motoneurons, (3) the density of VGLUT1 + boutons terminating on non-primary dendrites of JC motoneurons was significantly higher than that on somata or primary dendrites, whereas the density of VGLUT2 + boutons was not significantly different between JC and JO motoneurons and among various compartments of the postsynaptic neurons, and (4) the bouton volume, mitochondrial volume, and active zone area of the VGLUT1 + boutons forming synapses on JC motoneurons were significantly bigger than those of VGLUT2 + boutons. These findings suggest that JC and JO motoneurons receive glutamatergic input primarily from VGLUT2-expressing intrinsic neurons (premotoneurons), and may be controlled differently by neurons in the trigeminal mesencephalic nucleus and by glutamatergic premotoneurons. PMID- 29476241 TI - Neurocognitive and behavioural performance of healthy volunteers receiving an increasing analgesic-range infusion of ketamine. AB - BACKGROUND: The acute and delayed effect of analgesic-range doses of ketamine on neurocognitive and behavioural outcomes is understudied. Using a non-controlled open-labelled design, three (1-h duration) increasing intravenous (IV) ketamine infusions comprising (i) 30 mg bolus of ketamine + 8 mg/h IV infusion, (ii) 12 mg/h IV infusion and (iii) 20 mg/h infusion were administered to 20 participants (15 male, 5 female, mean age = 30.8 years). Whole-blood ketamine and norketamine concentrations were determined at each treatment step and post-infusion. METHODS: The Cambridge Neuropsychological Test Automated Battery (CANTAB) was used to assess reaction/movement time (RTI, Simple and 5-Choice), visuospatial working memory (SWM), spatial planning (SOC) and subjective effects (visual analogue scale; VAS) during treatment and at post-treatment. RESULTS: Significant main effects were reported for time (dose) on CANTAB RTI 5-Choice reaction (F(4,18) = 3.41, p = 0.029) and movement time (F(4,18) = 4.42, p = 0.011), SWM (F(4,18) = 4.19, p = 0.014) and SOC (F(4,18) = 4.13, p = 0.015), but not RTI Simple reaction or movement time. Post hoc analyses revealed dose-dependent effects for both RTI 5-Choice reaction and movement time (all p < 0.05). Post-treatment performance on all neurocognitive and behavioural tasks returned to baseline levels. Regression analyses revealed a weak positive linear association between SWM 'strategy' score (R2 = 0.103, p < 0.001), all performance-based CANTAB VAS items (R2 range 0.005 0.137, all p < 0.05) and ketamine blood concentrations. DISCUSSION: The open label, non-controlled trial design somewhat precludes the ability to adequately account for random treatment effects. Notwithstanding, these results suggest that analgesic doses of ketamine produce acute, selective, dose-dependent deficits in higher-order neurocognitive and behavioural domains. PMID- 29476242 TI - Serum glutathione S-transferase Pi as predictor of the outcome and acute kidney injury in premature newborns. AB - BACKGROUND: The incidence of acute kidney injury (AKI) among the neonates treated at the Neonatal Intensive Care Unit is high with high mortality rates. Glutathione S-transferase (GST) class Pi plays an important role in the protection of cells from cytotoxic and oncogenic agents. The aim of the study was to examine whether the levels of serum glutathione S-transferase Pi (GST Pi) determined after birth have any predictive value for the outcome and development of AKI in premature neonates. METHODS: The prospective study included 36 premature neonates. The data about morbidity was gathered for all the neonates included in the study. The blood samples were taken in the first 6 h of life and GST Pi levels were measured. RESULTS: The mean values and standard deviations of GST Pi among the neonates who died and who survived were 1.904 +/- 0.4535 vs 1.434 +/- 0.444 ng/ml (p = 0.0128). Logistic regression revealed a statistically significant, positive correlation between GST Pi levels and death (p = 0.0180, OR7.5954; CI 1.4148-40.7748).The mean value of GST Pi levels in the neonates with AKI was higher than in neonates without AKI (p = 0.011). CONCLUSIONS: The conclusion of our study is that high levels of serum GST Pi in the first 6 h after birth are associated with an increased mortality and development of AKI in prematurely born neonates. PMID- 29476244 TI - Association of body mass index and waist circumference with osteocalcin and C terminal telopeptide in Iranian elderly: results from a cross-sectional study. AB - There is no agreement on the role of obesity as a protection or unfavorable factor on bone. In the present study, the association of body mass index (BMI) and waist circumference (WC) with osteocalcin, C-terminal telopeptide of type 1 collagen (CTX-I), highly sensitive C-reactive protein (hs-CRP), parathormon (PTH) and 25-hydroxyvitamin D (25(OH)D) in elderly people was investigated. This cross sectional study was conducted on 178 elderly residents in Tehran, with a mean age of 67.04 (60-83). Serum osteocalcin, hs-CRP, 25(OH) D, PTH and urine CTX-I were measured for all participants. Waist circumference, weight and height were measured and BMI was calculated. Linear regression and Pearson correlation were performed to evaluate the relation of BMI and waist circumference with other variables. A significant inverse association was found between BMI with osteocalcin (beta = - 0.171, p = 0.027) after control for covariates. In addition, there were a significant relation of BMI and WC with hs-CRP (beta = 0.246, p = 0.002 and beta = 0.219, p = 0.006, respectively) and PTH (beta = 0.1169, p = 0.040 and beta = 0.200, p = 0.018), respectively. The present study did not show a significant relation of BMI and WC with urine CTX-I even after adjustment for potential confounders (beta = - 0.143, p = 0.065 and beta = - 0.104, p = 0.183, respectively). The present study has concluded that obesity is an undesirable factor for bone metabolism by reducing serum osteocalcin and by increasing hs-CRP and PTH which contribute to bone resorption. PMID- 29476243 TI - Increased platelet count and reticulated platelets in recently symptomatic versus asymptomatic carotid artery stenosis and in cerebral microembolic signal-negative patient subgroups: results from the HaEmostasis In carotid STenosis (HEIST) study. AB - BACKGROUND: The pathophysiological mechanisms responsible for the disparity in stroke risk between asymptomatic and symptomatic carotid stenosis patients are not fully understood. The functionally important reticulated platelet fraction and reticulocytes could play a role. OBJECTIVES: We performed a prospective, multi-centre, observational analytical study comparing full blood count parameters and platelet production/turnover/activation markers in patients with asymptomatic versus recently symptomatic moderate (>= 50-69%) or severe (>= 70 99%) carotid stenosis. PATIENTS/METHODS: Data from 34 asymptomatic patients were compared with 43 symptomatic patients in the 'early phase' (<= 4 weeks) and 37 of these patients in the 'late phase' (>= 3 months) after TIA/ischaemic stroke. Reticulated platelets were quantified by whole blood flow cytometry and reticulated platelets and red cell reticulocytes by 'automated assays' (Sysmex XE 2100TM). Bilateral simultaneous transcranial Doppler ultrasound monitoring classified patients as micro-embolic signal (MES)+ve or MES-ve. RESULTS: Mean platelet count was higher in early (216 * 109/L; P = 0.04) and late symptomatic (219 * 109/L; P = 0.044) than asymptomatic patients (194 * 109/L). Mean platelet volume was higher in early symptomatic than asymptomatic patients (10.8 vs. 10.45 fl; P = 0.045). Automated assays revealed higher % reticulated platelet fractions in early (5.78%; P < 0.001) and late symptomatic (5.11%; P = 0.01) than asymptomatic patients (3.48%). Red cell reticulocyte counts were lower in early (0.92%; P = 0.035) and late symptomatic (0.93%; P = 0.036) than asymptomatic patients (1.07%). The automated % reticulated platelet fraction was also higher in early symptomatic than asymptomatic MES-ve patients (5.7 vs. 3.55%; P = 0.001). DISCUSSION: The combination of increased platelet counts and a shift towards production of an increased population of larger, young, reticulated platelets could contribute to a higher risk of first or recurrent cerebrovascular events in recently symptomatic versus asymptomatic carotid stenosis, including those who are MES-ve. PMID- 29476245 TI - Distinct transgenic effects of poplar TDIF genes on vascular development in Arabidopsis. AB - KEY MESSAGE: Poplar CLE genes encoding TDIF motifs differentially regulate vascular cambial cell division and woody tissue organization in transgenic Arabidopsis. In Arabidopsis, CLE41 and CLE44 genes encode the tracheary element differentiation inhibitory factor (TDIF) peptide, which functions as a non-cell autonomous signal to regulate vascular development, and overexpression of AtCLE41/CLE44 generate similar phenotypic defects. In poplar, there are six CLE genes (PtTDIF1-4 and PtTDIF-like1-2) encoding two TDIF peptides (TDIF and TDIF like peptide), which exhibit nearly same activities when exogenously applied to Arabidopsis seedlings. In this work, for each TDIF peptide, we chose two poplar CLE genes (PtTDIF2 and 3 for TDIF, and PtTDIF-like1-2 for TDIF-like peptide) to compare their in vivo effects in transgenic Arabidopsis. Our results showed that transgenic Arabidopsis lines overexpressing each individual PtTDIF gene exhibited dramatically distinct phenotypes associated with vascular development, demonstrating that TDIF motif is not the only functional determinant after genetic transformation. Moreover, we revealed that overexpressed poplar TDIFs enhanced the proliferation of (pro)cambial cells only in hypocotyls, but not in inflorescence stems by differentially regulating the transcriptional levels of WOX4 and WOX14 in these two tissues. PMID- 29476246 TI - Sucrose is involved in the regulation of iron deficiency responses in rice (Oryza sativa L.). AB - KEY MESSAGE: Sucrose signaling pathways were rapidly induced in response to early iron deficiency in rice plants, and the change of sucrose contents in plants was essential for the activation of iron deficiency responses. Sucrose is the main product of photosynthesis in plants, and it functions not only as an energy metabolite but also a signal molecule. However, a few studies have examined the involvement of sucrose in mediating iron deficiency responses in rice. In this study, we found that the decrease in photosynthesis and total chlorophyll concentration (SPAD values) in leaves occurred at a very early stage under iron deficiency. In addition, the sucrose was increased in leaves but decreased in roots of rice plants under iron deficiency, and also the sucrose transporter (SUT) encoded genes' expression levels in leaves were all inhibited, including OsSUT1, OsSUT2, OsSUT3, OsSUT4, and OsSUT5. The carbohydrate distribution was changed under iron deficiency and sucrose might be involved in the iron deficiency responses of rice plants. Furthermore, exogenous application of sucrose or dark treatment experiments were used to test the hypothesis; we found that the increased endogenous sucrose would cause the repression of iron acquisition-related genes in roots, while further stimulated iron transport related genes in leaves. Compared to the exogenous application of sucrose, the dark treatment had the opposite effects. All the above results highlighted the important role of sucrose in regulating the responses of rice plants to iron deficiency. PMID- 29476247 TI - Effects of topical topiramate in wound healing in mice. AB - Recent studies have indicated that systemic topiramate can induce an improvement on the aesthetic appearance of skin scars. Here, we evaluated topical topiramate as an agent to improve wound healing in C57/BL6 mice. Mice were inflicted with a 6.0 mm punch to create two wounds in the skin of the dorsal region. Thereafter, mice were randomly assigned to either vehicle or topical topiramate (20 ul of 2% cream) once a day for 14 days, beginning on the same day as wound generation. We analyzed the wound samples over real-time PCR, Western blotting, and microscopy. There was no effect of the topiramate treatment on the time for complete reepithelization of the wound. However, on microscopic analysis, topiramate treatment resulted in increased granulation tissue, thicker epidermal repair, and improved deposition of type I collagen fibers. During wound healing, there were increased expressions of anti-inflammatory markers, such as IL-10, TGF-beta1, and reduced expression of the active form of JNK. In addition, topiramate treatment increased the expression of active forms of two intermediaries in the insulin signaling pathway, IRS-1 and Akt. Finally, at the end of the wound-healing process, topiramate treatment resulted in increased expression of SOX-2, a transcription factor that is essential to maintain cell self-renewal of undifferentiated embryonic stem cells. We conclude that topical topiramate can improve the overall quality of wound healing in the healthy skin of mice. This improvement is accompanied by reduced expression of markers involved in inflammation and increased expression of proteins of the insulin-signaling pathway. PMID- 29476248 TI - Considerable observations in cesarean section surgical technique and proposed steps. PMID- 29476249 TI - Correlation between central stromal demarcation line depth and changes in K values after corneal cross-linking (CXL). AB - PURPOSE: A stromal demarcation line (DL) after corneal cross-linking (CXL) has lately been suggested as a surrogate parameter for the success of CXL. The aim of this study was to investigate the correlation between depth of the central DL 1 month and the change in K values 12 months after CXL. METHODS: Treatment-naive subjects with keratoconus were treated using an accelerated CXL protocol [A CXL(9*10)]. Depth of the DL/relative depth of the DL (DL%) was measured using Visante OCT imaging 1 month postoperatively (OP). Kmax/K2.5 (preOP) and change in Kmax/K2.5 (preOP - 12 months postOP) were assessed using corneal tomography (Pentacam HR, Oculus GmBH). RESULTS: Forty eyes were treated following the A CXL(9*10). The mean DL depth was 200 +/- 99 MUm (range 71 to 479)/mean DL% = 42.70 +/- 20.00% (range 17-90). There was no statistically significant correlation between stromal depth of the DL and change in Kmax or K2.5, respectively (Spearman rho DL/?Kmax - 0.14 and DL/?K2.5 - 0.14). Between DL% and the changes in maximum K values or K2.5, no statistically significant correlation was found as well (Spearman rho DL%/?Kmax - 0.10 and DL%/?K2.5 - 0.19). Mean change in Kmax after 12 months was - 0.68 +/- 2.26 diopters (D) (median - 0.35 D) and - 0.82 +/- 1.6 D (median - 0.65 D) for K2.5 (p = 0.07; p = 0.02). CONCLUSIONS: No statistically significant correlation was found between the stromal central depth of the DL and any outcome parameter for CXL after 12 months. Therefore, the interpretation of the DL as a predictive parameter for the effect of the procedure may not apply. PMID- 29476250 TI - Antidepressant treatment effects on dopamine transporter availability in patients with major depression: a prospective 123I-FP-CIT SPECT imaging genetic study. AB - We investigated if sleep deprivation (SD) and electroconvulsive therapy (ECT) affect striatal dopamine transporter (DAT) availability assessed by single-photon emission computed tomography (SPECT) and 123I-FP-CIT, if dopamine transporter gene (SLC6A3; DAT) variation modifies aforementioned parameters, and if SD response or SD-induced DAT changes correlate with ECT response. Sixteen patients with major depression (MDD) referred for ECT and 12 matched controls were prospectively recruited for imaging and SLC6A3 VNTR genotyping. After withdrawal from any psychiatric medication, 123I-FP-CIT-SPECT was acquired at baseline, after SD and after ECT series. Striatal DAT availability was assessed by volume of-interest analysis of SPECT data. Eleven patients underwent combined treatment with SD and ECT (five ECT responders and six non-responders). Per-protocol analyses yielded no significant effect of SD or ECT on striatal DAT availability using repeated-measures ANOVA. However, intention-to-treat analysis indicated a significant decrease of striatal DAT availability due to SD (paired t test, p < 0.01). Stratification by SLC6A3 VNTR genotype suggested the 9R allele to drive this effect. In an exploratory analysis, SD-induced change in DAT availability of the left caudate nucleus predicted ECT response. This study revealed a treatment effect of SD on striatal DAT availability-possibly depending on SLC6A3 VNTR genotype. This and the observed association between SD-induced change of striatal DAT availability and response to ECT may help to identify treatment mechanisms and response predictors useful for precision medicine approaches in the treatment of MDD. PMID- 29476251 TI - Clinical features of autoimmune hepatitis with acute presentation: a Japanese nationwide survey. AB - BACKGROUND: Autoimmune hepatitis (AIH) is characterized by progressive inflammation and necrosis of hepatocytes and eventually leads to a variety of phenotypes, including acute liver dysfunction, chronic progressive liver disease, and fulminant hepatic failure. Although the precise mechanisms of AIH are unknown, environmental factors may trigger disease onset in genetically predisposed individuals. Patients with the recently established entity of AIH with acute presentation often display atypical clinical features that mimic those of acute hepatitis forms even though AIH is categorized as a chronic liver disease. The aim of this study was to identify the precise clinical features of AIH with acute presentation. METHODS: Eighty-six AIH patients with acute presentation were retrospectively enrolled from facilities across Japan and analyzed for clinical features, histopathological findings, and disease outcomes. RESULTS: Seventy-five patients were female and 11 were male. Patient age ranged from adolescent to over 80 years old, with a median age of 55 years. Median alanine transaminase (ALT) was 776 U/L and median immunoglobulin G (IgG) was 1671 mg/dL. There were no significant differences between genders in terms of ALT (P = 0.27) or IgG (P = 0.51). The number of patients without and with histopathological fibrosis was 29 and 57, respectively. The patients with fibrosis were significantly older than those without (P = 0.015), but no other differences in clinical or histopathological findings were observed. Moreover, antinuclear antibody (ANA)-positive (defined as * 40, N = 63) and -negative (N = 23) patients showed no significant differences in clinical or histopathological findings or disease outcomes. Twenty-five patients experienced disease relapse and two patients died during the study period. ALP >= 500 U/L [odds ratio (OR) 3.20; 95% confidence interval (CI) 1.12-9.10; P < 0.030] and GGT >= 200 U/L (OR 2.98; 95% CI 1.01-8.77; P = 0.047) were identified as independent risk factors of disease relapse. CONCLUSIONS: AIH with acute presentation is a newly recognized disease entity for which diagnostic hallmarks, such as ALT, fibrosis, and ANA, are needed. Further investigation is also required on the mechanisms of this disorder. Clinicians should be mindful of disease relapse during patient care. PMID- 29476253 TI - Behavioral activation for children and adolescents: a systematic review of progress and promise. AB - Behavioral activation (BA) effectively treats depression in adults, and shows promise in treating anxiety. Research into its application to children and adolescents is emerging. This review aimed to explore the scope of studies, current evidence of effectiveness and how the intervention has been delivered and adapted, to inform future research. A systematic review was undertaken searching PsycInfo, PubMed including Medline, EMBASE, and Scopus for terms relating to BA and children and adolescents. Two researchers scored abstracts for inclusion. Data extraction was completed by one researcher and checked by another. 19 studies were identified, across 21 published articles. 12 were case studies, with three pre-post pilot designs and four randomized-controlled trials. Case studies found early support for the feasibility and potential effectiveness of BA to address both anxiety and depression. The RCTs reported largely positive outcomes. Meta-analysis of depression scores indicated that BA may be effective; however, high heterogeneity was observed. Sample sizes to date have been small. BA has been delivered by trained therapists, doctoral trainee psychologists, social workers, or psychology graduates. Studies are uniquely in high-income settings. Adaptations include flexibility in content delivery, youth friendly materials, and parental involvement. There is some limited evidence to support BA as effective for young people. Feasibility and acceptability are supported. Fully powered trials are now required, with expansion to delivery in low- and middle income settings, and detailed consideration of implementation issues that consider culture and environment. PMID- 29476252 TI - Unexpected fungal communities in the Rehai thermal springs of Tengchong influenced by abiotic factors. AB - Fungal communities represent an indispensable part of the geothermal spring ecosystem; however, studies on fungal community within hot springs are still scant. Here, we used Illumina HiSeq 2500 sequencing to detect fungal community diversity in extremely acidic hot springs (pH < 4) and neutral and alkaline springs (pH > 6) of Tengchong-indicated by the presence of over 0.75 million valid reads. These sequences were phylogenetically assigned to 5 fungal phyla, 67 order, and 375 genera, indicating unexpected fungal diversity in the hot springs. The genera such as Penicillium, Entyloma, and Cladosporium dominated the fungal community in the acidic geothermal springs, while the groups such as Penicillium, Engyodontium, and Schizophyllum controlled the fungal assemblages in the alkaline hot springs. The alpha-diversity indices and the abundant fungal taxa were significantly correlated with physicochemical factors of the hot springs particularly pH, temperature, and concentrations of Fe2+, NH4+, NO 2-, and S2-, suggesting that the diversity and distribution of fungal assemblages can be influenced by the complex environmental factors of hot springs. PMID- 29476254 TI - Evaporation process in histological tissue sections for neutron autoradiography. AB - The analysis of the distribution and density of nuclear tracks forming an autoradiography in a nuclear track detector (NTD) allows the determination of 10B atoms concentration and location in tissue samples from Boron Neutron Capture Therapy (BNCT) protocols. This knowledge is of great importance for BNCT dosimetry and treatment planning. Tissue sections studied with this technique are obtained by cryosectioning frozen tissue specimens. After the slicing procedure, the tissue section is put on the NTD and the sample starts drying. The thickness varies from its original value allowing more particles to reach the detector and, as the mass of the sample decreases, the boron concentration in the sample increases. So in order to determine the concentration present in the hydrated tissue, the application of corrective coefficients is required. Evaporation mechanisms as well as various factors that could affect the process of mass variation are outlined in this work. Mass evolution for tissue samples coming from BDIX rats was registered with a semimicro analytical scale and measurements were analyzed with software developed to that end. Ambient conditions were simultaneously recorded, obtaining reproducible evaporation curves. Mathematical models found in the literature were applied for the first time to this type of samples and the best fit of the experimental data was determined. The correlation coefficients and the variability of the parameters were evaluated, pointing to Page's model as the one that best represented the evaporation curves. These studies will contribute to a more precise assessment of boron concentration in tissue samples by the Neutron Autoradiography technique. PMID- 29476255 TI - Special issue on plant reproduction research in Asia. PMID- 29476256 TI - Lessons from the sky: an aviation-based framework for maximizing the delivery of quality anesthetic care. AB - Though aviation is practiced in airplanes and anesthesiology in operating rooms, the two professions have substantial parallels. Both require readiness to manage a crisis situation, where lives are at stake, at a moment's notice and with incomplete information. The determinants of quality performance in both professions extend far beyond knowledge base and formal training. The science of human factors, a prominent cornerstone of the aviation industry, has not yet found the same place in medicine, but it could change the understanding and execution of medical decision-making in profound ways. This article reviews specific components of crisis management and root cause analysis in aviation that can serve as models for improving those same aspects within anesthesiology. PMID- 29476257 TI - A case of anosmia and hypogeusia as a complication of propofol. AB - Anesthetics represent an uncommon cause of taste and smell disorders. We describe a case of anosmia and hypogeusia for 6 weeks after recovery from a uterine curettage operation in a 32-year-old woman. The case is unusual because propofol was the only anesthetic used during surgery and anesthesia. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed no abnormality. This case may highly suggest that propofol could induce smell and taste disorders. PMID- 29476258 TI - Postoperative adalimumab maintenance therapy for Japanese patients with Crohn's disease: a single-center, single-arm phase II trial (CCOG-1107 study). AB - PURPOSE: To investigate the efficacy and safety of planned postoperative adalimumab (ADA) therapy for Japanese patients with Crohn's disease (CD). METHODS: The subjects of this study were 26 patients who underwent bowel resection for CD. All patients received subcutaneous injections of ADA 160/80 mg at the time of surgery and 2 weeks later, followed by 40 mg every 2 weeks thereafter. The primary endpoint of this study was the incidence of endoscopic recurrence, defined by Rutgeerts endoscopic recurrence scale >= i2, 1 year after surgery. RESULTS: After the median follow-up period of 41.3 months, the median number of treatments with ADA was 56 and the median time-to-treatment failure was 25.6 months. Endoscopic recurrence was observed in 34.6% of the patients 1 year after surgery. Univariate analyses showed that preoperative ADA therapy was significantly associated with endoscopic recurrence. Clinical recurrence developed in 16.7% of the patients within 1 year after surgery. Secondary surgery for recurrence was not required. Although adverse events (>= grade 3) were experienced by 15.4% of patients, none was withdrawn from this study. CONCLUSION: Planned postoperative ADA therapy reduced the incidence of endoscopic and clinical recurrence after bowel resection in Japanese patients with CD. TRIAL REGISTRATION: This trial is registered with the University Hospital Medical Information Network (UMIN000007514). PMID- 29476259 TI - Detection of HBV genome in the plasma and peripheral blood mononuclear cells of Iranian HBsAg negative patients with HIV infection: occult HBV infection. AB - The presence of hepatitis B virus (HBV) DNA in the absence of traceable hepatitis B surface antigen (HBsAg) in the plasma specimen of patients is defined as occult HBV infection (OBI). This study aimed to detect HBV-DNA in the plasma and peripheral blood mononuclear cells (PBMCs) of Iranian HBsAg negative patients with human immunodeficiency virus (HIV) infection. This cross-sectional study was conducted on 172 patients with HIV infection from September 2015 to August 2017. The patients were tested for serological parameters (HBsAg, HBcAb, HBeAg and HBeAb) against HBV infection. Moreover, they were tested for HBV viral load (using COBAS TaqMan 48 Kit, Roche, USA) in plasma and the presence of the HBV genome in PBMC specimens using real-time PCR. The mean age of the patients was 35.4 +/- 13.4 years. Of the 172 studied patients, 109 (63.4%) were male. In this study, 151 (87.8%) patients were negative for HBsAg, 111 (64.5%) patients were negative for all HBV infection serological markers, 9 (5.2%) patients were only positive for HBsAg and 29 (16.9%) patients were only positive for HBcAb. Moreover, five (3.3%) patients with HBsAg negative had OBI (in the plasma sample of four patients and PBMC specimens of all five patients, HBV-DNA was detected). The present study revealed that 3.3% of the patients with HIV infection had occult HBV infection. Presumably, designing prospective studies to identify this infection in patients with HIV infection is informative and valuable. PMID- 29476260 TI - Exploring the Viral Channel KcvPBCV-1 Function via Computation. AB - Viral potassium channels (Kcv) are homologous to the pore module of complex [Formula: see text]-selective ion channels of cellular organisms. Due to their relative simplicity, they have attracted interest towards understanding the principles of [Formula: see text] conduction and channel gating. In this work, we construct a homology model of the [Formula: see text] open state, which we validate by studying the binding of known blockers and by monitoring ion conduction through the channel. Molecular dynamics simulations of this model reveal that the re-orientation of selectivity filter carbonyl groups coincides with the transport of potassium ions, suggesting a possible mechanism for fast gating. In addition, we show that the voltage sensitivity of this mechanism can originate from the relocation of potassium ions inside the selectivity filter. We also explore the interaction of [Formula: see text] with the surrounding bilayer and observe the binding of lipids in the area between two adjacent subunits. The model is available to the scientific community to further explore the structure/function relationship of Kcv channels. PMID- 29476261 TI - Cholesterol Enriched Archaeosomes as a Molecular System for Studying Interactions of Cholesterol-Dependent Cytolysins with Membranes. AB - Archaeosomes are vesicles made of lipids from archaea. They possess many unique features in comparison to other lipid systems, with their high stability being the most prominent one, making them a promising system for biotechnological applications. Here, we report a preparation protocol of large unilamellar vesicles, giant unilamellar vesicles (GUVs), and nanodiscs from archaeal lipids with incorporated cholesterol. Incorporation of cholesterol led to additional increase in thermal stability of vesicles. Surface plasmon resonance, sedimentation assays, intrinsic tryptophan fluorescence measurements, calcein release experiments, and GUVs experiments showed that members of cholesterol dependent cytolysins, listeriolysin O (LLO), and perfringolysin O (PFO), bind to cholesterol-rich archaeosomes and thereby retain their pore-forming activity. Interestingly, we observed specific binding of LLO, but not PFO, to archaeosomes even in the absence of cholesterol. This suggests a new capacity of LLO to bind to carbohydrate headgroups of archaeal lipids. Furthermore, we were able to express LLO inside GUVs by cell-free expression. GUVs made from archaeal lipids were highly stable, which could be beneficial for synthetic biology applications. In summary, our results describe novel model membrane systems for studying membrane interactions of proteins and their potential use in biotechnology. PMID- 29476262 TI - Beveled Incisions: What is the Evidence? AB - BACKGROUND: Although many aesthetic surgeons believe that beveling the angle of an incision improves the aesthetic outcome with regard to scaring, the literature remains scarce largely because few studies have been conducted. OBJECTIVE: This systematic review therefore aims to identify whether using a beveled incision adds an aesthetic benefit, to determine whether there is a specific angle that yields a superior outcome, and for the first time, to present a complete discussion of this subject for practicing surgeons. METHODS: A comprehensive literature search was performed using the PubMed database to search for primary articles. The main inclusion criteria were primary journal articles investigating the use of a beveled angle via a controlled study. RESULTS: A total of fifty-four publications were reviewed, with only four publications including 124 patients suitable for use in this systematic review. All the studies concluded that the use of a beveled angle incision improved aesthetic outcomes, with the ideal angle ranging from 10 degrees to 45 degrees . CONCLUSIONS: The use of a beveled angle incision can improve scar aesthetics and encourages the regrowth of hair follicles and shafts through the scars via multiple mechanisms. Nevertheless, the paucity of literature available to the practitioner compels further research assessing this important topic. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29476263 TI - Long-term Management of Ureterocele in Duplex Collecting Systems: Reconstruction Implications. AB - PURPOSE OF REVIEW: Significant variance exists in the management of duplex collecting system ureteroceles (DSU). There is a great spectrum in classification, management, and surgical interventions. The practice of performing bladder level operations for vesicoureteral reflux (VUR) and trigonal anatomic distortion, either after ureterocele puncture or in a single setting, has come into question as to whether all DSU patients require it. In this review, we sought to discuss DSU management trends and the need for bladder reconstruction in these patients, as well as to describe our institution's practices. RECENT FINDINGS: Recent advances regarding DSU management revolve around differing surgical approaches, although adequately powered randomized control trials are lacking. These approaches include nonoperative management, various forms of endoscopic puncture, ureteroureterostomy, and most recently upper pole ureteral ligation. A common theme appears to reflect the acceptance that "less is more" when it comes to managing DSU. There is no consensus for the decision to treat or the surgical approach of DSU. Ureteral reimplantation and bladder neck reconstruction appears to be unnecessary in a significant portion of the DSU population, but ureterocele treatment needs to be individualized. There is an ongoing need for large, multi-institutional randomized control trials to evaluate this further. PMID- 29476264 TI - Hyaluronidase Enzyme-responsive Targeted Nanoparticles for Effective Delivery of 5-Fluorouracil in Colon Cancer. AB - PURPOSE: In this study, we have successfully prepared the hyaluronic acid (HA) conjugated mesoporous silica nanoparticles loaded with 5-fluorouracil (5-FU) to increase the anticancer efficacy in colon cancers. METHODS: The particles were nanosized and perfectly spherical. In vitro release kinetics clearly showed the enzyme-sensitive release of 5-FU from HA-conjugated 5-FU loaded mesoporous silica nanoparticles (HA/FMSN). RESULTS: The presence of HA on the surface of nanoparticles targeted the CD44 receptors overexpressed in the colon cancer cells In vitro cell viability and apoptosis assay clearly showed the superior anticancer effect of HA/FMSN in HT29 colon cancer cells. HA/FMSN exhibited a remarkably higher 43% of cells in early apoptosis phase and 55% of cells in late apoptosis phase indicating the superior anticancer effect of HA/FMSN. HA/FMSN exhibited a significant reduction in the tumor burden compared to that of any group. HA/FMSN was 3-fold more effective than free drug and 2-fold more effective than -FU loaded mesoporous silica nanoparticles (FMSN). CONCLUSIONS: Overall, results suggest that the novel delivery strategy could hold enormous potential in colon cancer targeting. PMID- 29476266 TI - Headache Diagnosis in Children and Adolescents. AB - PURPOSE OF REVIEW: Headache phenotypes can differ between adults and children. While most headaches are due to primary headache disorders, in a small population, they can be an indication of a potentially life-threatening neurologic condition. The challenge lies in identifying warning signs that warrant further workup. This article reviews different types of pediatric headaches and headache evaluation in children and teens, and focuses on the approach for diagnosis of secondary headaches. RECENT FINDINGS: Common thought is that increased frequency and severity of headache may reflect secondary pathology; however, headache phenotype may not be fully developed and can evolve in adolescence or adulthood. Headache location, particularly occipital headache alone, does not necessarily signify secondary intracranial pathology. Certain warning signs warrant neuroimaging, but others only warrant imaging in certain clinical contexts. Brain MRI is the neuroimaging modality of choice, though there is a high rate of incidental findings and often does not change headache management. A stepwise approach is essential to avoid missing secondary headaches. There are several differences between adults and children in clinical manifestations of headache. Evaluation and diagnosis of pediatric headache starts with a thorough headache and medical history, family and social history, and identification of risk factors. A thorough physical and neurologic exam is important, with close attention to features that could suggest secondary headache pathology. Neuroimaging and other testing should only be performed if there is concern for secondary headache. PMID- 29476267 TI - Prophylaxis of Pulmonary Embolism in Kidney Transplant Recipients. AB - PURPOSE OF REVIEW: Kidney transplant recipients have an increased risk of pulmonary embolism; however, thromboprophylaxis poses a challenge as the risk of thrombosis must be balanced against the risk of bleeding. This review summarizes the evidence on whether thromboprophylaxis is required in kidney transplantation. RECENT FINDINGS: Incidence of venous thromboembolism, comprising pulmonary embolism and deep venous thrombosis, is increased in kidney transplant recipients compared to the general population, with augmented risk of death and graft loss. Findings suggest a benefit of prophylaxis with heparin and mechanical prophylaxis for low-risk patients. For patients at high risk, with previous thrombosis, and/or abnormal thrombophilia screen, dose and prophylaxis time need to be increased. There is no established thromboprophylaxis strategy. It is crucial to evaluate patient's risk profile and opt for a multidisciplinary approach for the development of appropriate prophylaxis. There remains a paucity of high-quality evidence for effective prophylaxis strategies in this population. PMID- 29476268 TI - Landscape-based upstream-downstream prevalence of land-use/cover change drivers in southeastern rift escarpment of Ethiopia. AB - Characterized by high population density on a rugged topography, the Gedeo-Abaya landscape dominantly contains a multi-strata traditional agroforests showing the insight of Gedeo farmers on natural resource management practices. Currently, this area has been losing its resilience and is becoming unable to sustain its inhabitants. Based on both RS-derived and GIS-computed land-use/cover changes (LUCC) as well as socioeconomic validations, this article explored the LUCC and agroecological-based driver patterns in Gedeo-Abaya landscape from 1986 to 2015. A combination of geo-spatial technology and cross-sectional survey design were employed to detect the drivers behind these changes. The article discussed that LUCC and the prevalence of drivers are highly diverse and vary throughout agroecological zones. Except for the population, most downstream top drivers are perceived as insignificant in the upstream region and vice versa. In the downstream, land-use/cover (LUC) classes are more dynamic, diverse, and challenged by nearly all anticipated drivers than are upstream ones. Agroforestry LUC has been increasing (by 25% of its initial cover) and is becoming the predominant cover type, although socioeconomic analysis and related findings show its rapid LUC modification. A rapid reduction of woodland/shrubland (63%) occurred in the downstream, while wetland/marshy land increased threefold (158%), from 1986 to 2015 with annual change rates of - 3.7 and + 6%, respectively. Land degradation induced by changes in land use is a serious problem in Africa, especially in the densely populated sub-Saharan regions such as Ethiopia (FAO 2015). Throughout the landscape, LUCC is prominently affecting land-use system of the study landscape due to population pressure in the upstream region and drought/rainfall variability, agribusiness investment, and charcoaling in the downstream that necessitate urgent action. PMID- 29476270 TI - Cognitive Behavioral Therapy (CBT) for Subacute Low Back Pain: a Systematic Review. AB - PURPOSE OF REVIEW: Chronic low back pain (CLBP) is a major source of physical and psychiatric morbidity and mortality, and the current overreliance on opioid analgesics has contributed to a burgeoning epidemic in the USA. Cognitive behavioral therapy (CBT) is an empirically supported treatment for CLBP, but little information exists regarding its potential efficacy for CLBP's precursor condition, subacute low back pain (sALBP), defined here as having a 7-12-week duration. Earlier intervention with CBT at the sALBP stage could produce larger clinical benefits. This systematic review was undertaken to characterize and highlight this knowledge gap. RECENT FINDINGS: Of 240 unique articles identified by comprehensive database searches, only six prospective, sALBP-focused, randomized controlled trials (RCTs) published within the past 20 years met criteria for inclusion in this review. These studies varied widely in their sample sizes, precise definition of sALBP, nature of CBT intervention, and outcome measures. Five of the six showed significant improvements associated with CBT, but the heterogeneity of the studies prevented quantitative comparisons. CBT has not been adequately studied as a potential early intervention treatment for sALBP patients. None of the six identified papers studied US civilians or leveraged innovations such as teletherapy-able to reach patients in remote or underserved areas-underscoring critical gaps in current back pain treatment. Given the severity of the US opioid epidemic, non-pharmacologic options such as CBT should be rigorously explored in the sALBP population. PMID- 29476269 TI - Interaction of drugs amlodipine and paroxetine with the metabolizing enzyme CYP2B4: a molecular dynamics simulation study. AB - The interactions of the drugs amlodipine and paroxetine, which are prescribed respectively for treatment of hypertension and depression, with the metabolizing enzyme cytochrome CYP2B4 as the drug target, have been studied by molecular dynamics (MD) simulation. Poly ethylene glycol was used to control the drugs' interactions with each other and with the target CYP2B4. Thirteen simulation systems were carefully designed, and the results obtained from MD simulations indicated that amlodipine in the PEGylated form prescribed with paroxetine in the nonPEGylated form promotes higher cytochrome stability and causes fewer fluctuations as the drugs approach the target CYP2B4 and interact with it. The simulation results led us to hypothesize that the combination of the drugs with a specific drug ratio, as proposed in this work, manifests more effective diffusivity and less instability while metabolizing with enzyme CYP2B4. Also, the active residues in the CYP2B4 enzyme that interact with the drugs were determined by MD simulation, which were consistent with the reported experimental results. Graphical Abstract Efficient drug-enzyme interactions, as a result of PEGylation. PMID- 29476271 TI - A study on the determination of the natural park's sustainable tourism potential. AB - The surface site of Yesilyuva Nature Park encompasses natural, social, economic, and cultural characteristics and has become a marker of the region's natural and cultural heritage. To support the preservation of this site, promotional activities should be planned. In this study, because of tourism and related opinions of residents and visitors alike in terms of their natural determination, an important cultural and historical feature is aimed at evaluating the tourism potential of Yesilyuva Nature Park. This framework is designed to establish prospective tourism sustainability. As a result, Yesilyuva Nature Park's natural and cultural properties have been determined to be suitable for sustainable tourism activities using geographic information systems (GIS). This protection in the field, which balances sustainability and landscape design, will provide for the development of tourism activities. In the Strengths, Weaknesses, Opportunities and Threats (SWOT) analysis and survey, residents and visitors reported that the most important feature of the Yesilyuva Nature Park was its natural beauty. Visitors often come to observe traditional and natural life and to engage in tourism activities. All the data, which includes maps derived from GIS, represents landscape planning for sustainable tourism areas in Yesilyuva Nature Park. PMID- 29476272 TI - Risk assessment of trace metals in an extreme environment sediment: shallow, hypersaline, alkaline, and industrial Lake Acigol, Denizli, Turkey. AB - The major and trace element component of 48 recent sediment samples in three distinct intervals (0-10, 10-20, and 20-30 cm) from Lake Acigol is described to present the current contamination levels and grift structure of detrital and evaporate mineral patterns of these sediments in this extreme saline environment. The spatial and vertical concentrations of major oxides were not uniform in the each subsurface interval. However, similar spatial distribution patterns were observed for some major element couples, due mainly to the detrital and evaporate origin of these elements. A sequential extraction procedure including five distinct steps was also performed to determine the different bonds of trace elements in the < 60-MU particulate size of recent sediments. Eleven trace elements (Ni, Fe, Cd, Pb, Cu, Zn, As, Co, Cr, Al and Mn) in nine surface and subsurface sediment samples were analyzed with chemical partitioning procedures to determine the trace element percentage loads in these different sequential extraction phases. The obtained accuracy values via comparison of the bulk trace metal loads with the total loads of five extraction steps were satisfying for the Ni, Fe, Cd, Zn, and Co. While, bulk analysis results of the Cu, Ni, and V elements have good correlation with total organic matter, organic fraction of sequential extraction characterized by Cu, As, Cd, and Pb. Shallow Lake Acigol sediment is characteristic with two different redox layer a) oxic upper level sediments, where trace metals are mobilized, b) reduced subsurface level, where the trace metals are precipitated. PMID- 29476273 TI - Targeted Delivery of Doxorubicin via CD147-Mediated ROS/pH Dual-Sensitive Nanomicelles for the Efficient Therapy of Hepatocellular Carcinoma. AB - Low accumulation in tumor sites and slow intracellular drug release remain as the obstacles for nanoparticles to achieve effective delivery of chemotherapeutic drugs. In this study, multifunctional micelles were designed to deliver doxorubicin (Dox) to tumor sites to provide more efficient therapy against hepatic carcinoma. The micelles were based on pH-responsive carboxymethyl chitosan (CMCh) modified with a reactive oxygen species (ROS)-responsive segment phenylboronic acid pinacol ester (BAPE) and an active targeted ligand CD147 monoclonal antibody. The Dox-loaded micelles provided rapid and complete drug release in pH 5.3 incubation conditions with 1 mM H2O2. In addition, an in vitro cell uptake study revealed that CD147 modification significantly enhanced cellular internalization due to the high affinity to CD147 receptors, which are overexpressed on tumor cells. An in vivo study revealed that CD147-modified micellar formulations exhibited high accumulation in tumor sites and markedly enhanced antiproliferation effects with fewer side effects than other formulations. In conclusion, this CD147 receptor targeted delivery system with ROS/pH dual sensitivity provides a promising strategy for the treatment of hepatic carcinoma. PMID- 29476274 TI - Hysteropexy: an Option for the Repair of Pelvic Organ Prolapse. AB - PURPOSE OF REVIEW: Women have an estimated 12.6% lifetime risk of undergoing surgery for pelvic organ prolapse in the USA (Wu et al. in Obstet Gynecol 123(6): 1201-6, 2014). Surgical repair of uterovaginal prolapse most commonly includes hysterectomy and vaginal vault suspension; however, the value of concomitant hysterectomy is uncertain, and there appears to be growing interest in uterine conservation. Multiple procedures have evolved using a variety of approaches. The aim of this paper is to review uterine sparing (hysteropexy) prolapse repair techniques and outcomes. RECENT FINDINGS: Several randomized controlled trials (RCT) have shown comparable success rates for apical compartment support with sacrospinous hysteropexy as compared to vaginal hysterectomy with uterosacral ligament suspension, with shorter hospitalization and quicker return to work. (Detollenaere et al. in BMJ 351: h3717, 2015); (Dietz et al. in Int Urogynecol J Pelvic Floor Dysfunct 21(2): 209-16, 2010). Available data suggest vaginal mesh hysteropexy is as effective as vaginal mesh with hysterectomy, with lower rates of mesh exposure. (Maher et al., 2017) To date, no RCTs have been published comparing sacral hysteropexy to hysterectomy with sacral colpopexy. Overall, there is a higher reoperation rate for sacral hysteropexy and a higher mesh exposure rate for hysterectomy with sacral colpopexy. (Maher et al., 2017) No RCTs have been published comparing hysteropexy surgical approaches. Although hysteropexy data is expanding, there is a need for more information regarding long-term surgical durability, appropriate patient selection, and whether one approach is superior to another. PMID- 29476276 TI - Migraine and Autonomic Dysfunction: Which Is the Horse and Which Is the Jockey? AB - PURPOSE OF REVIEW: Symptoms of autonomic dysfunction are common in patients with migraine, both during and between migraine attacks. Studies evaluating objective autonomic testing in patients have found significant, though somewhat conflicting results. The purposes of this review are to summarize and interpret the key findings of these studies, including those evaluating heart rate variability, autonomic reflex testing, and functional imaging in patients with migraine. The neuroanatomy of the central autonomic network as it relates to migraine is also reviewed. RECENT FINDINGS: Several studies have evaluated autonomic balance in migraineurs, with conflicting results on the magnitude of sympathetic versus parasympathetic dysfunction. Most studies demonstrate sympathetic impairment, with a lesser degree of parasympathetic impairment. Three trends have emerged: (1) migraine with aura tends to produce more significant autonomic dysfunction than migraine without aura, (2) sympathetic impairment is more common than parasympathetic impairment, and (3) sympathetic impairment is common in the interictal period, with increased sympathetic responsiveness during the ictal period, suggesting adrenoreceptor hypersensitivity. PMID- 29476275 TI - Maturation of the Coordination Between Respiration and Deglutition with and Without Recurrent Laryngeal Nerve Lesion in an Animal Model. AB - The timing of the occurrence of a swallow in a respiratory cycle is critical for safe swallowing, and changes with infant development. Infants with damage to the recurrent laryngeal nerve, which receives sensory information from the larynx and supplies the intrinsic muscles of the larynx, experience a significant incidence of dysphagia. Using our validated infant pig model, we determined the interaction between this nerve damage and the coordination between respiration and swallowing during postnatal development. We recorded 23 infant pigs at two ages (neonatal and older, pre-weaning) feeding on milk with barium using simultaneous high-speed videofluoroscopy and measurements of thoracic movement. With a complete linear model, we tested for changes with maturation, and whether these changes are the same in control and lesioned individuals. We found (1) the timing of swallowing and respiration coordination changes with maturation; (2) no overall effect of RLN lesion on the timing of coordination, but (3) a greater magnitude of maturational change occurs with RLN injury. We also determined that animals with no surgical intervention did not differ from animals that had surgery for marker placement and a sham procedure for nerve lesion. The coordination between respiration and swallowing changes in normal, intact individuals to provide increased airway protection prior to weaning. Further, in animals with an RLN lesion, the maturation process has a larger effect. Finally, these results suggest a high level of brainstem sensorimotor interactions with respect to these two functions. PMID- 29476277 TI - A new family of azanaphthoquinones for antimicrobial evaluation. AB - This article presents a complete and detailed study of synthesis, structural characterization, and possible applications of a new family of azanaphthoquinones as antimicrobial agents. A series of (alkoxy)phenylamino-chloro-2-methylquinoline 5,8-dione derivatives (3a-j, 3a', 3e') was prepared by regioselective nucleophilic substitution of 6,7-dichloro-2-methylquinoline-5,8-dione (1) with (alkoxy)arylamines (2) in the presence of CeCl3.7H2O. In vitro antimicrobial study of the newly synthesized compounds was evaluated in a panel of three fungi and seven bacterial strains (three Gram-positive and four Gram-negative bacteria). As a result, the compounds (3a, 3b, and 3h) were identified as the hits with the strong antibacterial efficiency against the human originated pathogens S. epidermidis and E. faecalis with some minimal inhibitory concentration values. The antibacterial activity of the compound (3h) was two times more active against S. epidermidis than the reference antimicrobial compound (Cefuroxime). Two compounds (3a and 3b) exhibited excellent antibacterial activity (four times more active than Cefuroxime) against S. epidermidis. In addition to S. epidermidis, these three compounds (3a, 3b, and 3h) were more active against E. faecalis than the reference antimicrobial compound (Amikacin). The antibacterial activity of the compounds (3a and 3h) was three times more active against E. faecalis. The compound (3b) was long dozen times more active against E. faecalis. For that reason, these three compounds (3a, 3b, and 3h) were thought to be considered as the promising antibacterial agents. PMID- 29476278 TI - Human Primary Cell-Based Organotypic Microtissues for Modeling Small Intestinal Drug Absorption. AB - PURPOSE: The study evaluates the use of new in vitro primary human cell-based organotypic small intestinal (SMI) microtissues for predicting intestinal drug absorption and drug-drug interaction. METHODS: The SMI microtissues were reconstructed using human intestinal fibroblasts and enterocytes cultured on a permeable support. To evaluate the suitability of the intestinal microtissues to model drug absorption, the permeability coefficients across the microtissues were determined for a panel of 11 benchmark drugs with known human absorption and Caco 2 permeability data. Drug-drug interactions were examined using efflux transporter substrates and inhibitors. RESULTS: The 3D-intestinal microtissues recapitulate the structural features and physiological barrier properties of the human small intestine. The microtissues also expressed drug transporters and metabolizing enzymes found on the intestinal wall. Functionally, the SMI microtissues were able to discriminate between low and high permeability drugs and correlated better with human absorption data (r2 = 0.91) compared to Caco-2 cells (r2 = 0.71). Finally, the functionality of efflux transporters was confirmed using efflux substrates and inhibitors which resulted in efflux ratios of >2.0 fold and by a decrease in efflux ratios following the addition of inhibitors. CONCLUSION: The SMI microtissues appear to be a useful pre-clinical tool for predicting drug bioavailability of orally administered drugs. PMID- 29476279 TI - Management of severe persistent fetal vasculature: case series and review of the literature. AB - PURPOSE: Persistent fetal vasculature (PFV) is a unique ocular disorder usually presenting early in life. The unregressed embryonal hyaloid vasculature poses a risk of severe ocular complications leading to decreased visual acuity. Surgery is the mainstay of therapy in complicated cases. We describe the clinical presentation and surgical treatment of PFV managed at our center from 2012 to 2015. METHODS: The study is a case series comprised eight patients who were diagnosed with complicated severe PFV. All were managed with a tailored surgical approach. The clinical characteristics, medical and surgical treatment, and follow-up findings of each case are described. RESULTS: There were six males and two females. Surgical intervention involved anterior or posterior vitrectomy, lens extraction, and intraocular lens implantation. Hyaloid stalk removal with release of ciliary traction was variably utilized in selected cases. Endodiathermy controlled intraocular bleeding, and intraocular scissors proved helpful in anterior PFV for disinserting the ciliary process from an abnormally thickened posterior lens capsule. Visual outcomes differed in each case, depending on multiple clinical factors. CONCLUSION: Severe complex PFV presents a therapeutic challenge. A tailored surgical approach with meticulous postoperative management is essential for visual rehabilitation. PMID- 29476280 TI - Response: microdialysis as a useful tool to detect cerebral metabolic crises. PMID- 29476281 TI - Evaluation of cerebral aneurysm wall thickness in experimental aneurysms: comparison of 3T-MR imaging with direct microscopic measurements. PMID- 29476282 TI - Resting Heart Rate Variability and the Effects of Biofeedback Intervention in Women with Low-Risk Pregnancy and Prenatal Childbirth Fear. AB - Anxiety about labor in women at the end of pregnancy sometimes reaches levels that are clinically concerning. We investigated whether low-risk pregnant women with childbirth fear during the last trimester demonstrate specific findings with regard to resting heart rate variability (HRV) and examined whether HRV biofeedback can reduce this fear and alter resting HRV. We measured the levels of childbirth fear (Wijma delivery expectancy/experience questionnaire, W-DEQ) and resting HRV indexes in 97 low-risk pregnant women in their 32nd-34th week of gestation and advised women with W-DEQ scores of >= 66 (n = 40) to practice HRV biofeedback (StressEraser) at home. We then reassessed these measures 3-4 weeks later in the 36th-37th week of gestation regardless of whether the women practiced the method. We found that childbirth fear had no significant effect on resting HRV indexes when the W-DEQ cutoff was conventionally set at >= 66. However, women with W-DEQ scores of >= 90 (n = 5) had a significantly lower high frequency power than their counterparts (p = 0.028). The W-DEQ scores reduced significantly in women who performed HRV biofeedback (n = 18, p < 0.001), but there was no change in those who did not perform the method (n = 20). These findings suggested that very high W-DEQ scores (>= 90), but not the conventional criteria (W-DEQ score >= 66), of the fear of childbirth were associated with low parasympathetic activity among low-risk pregnant women and that HRV biofeedback intervention can effectively decrease the fear of childbirth in these women. PMID- 29476283 TI - Correction to: Validation of the Community Integration Scale for Adults with Psychiatric Disorders (CIS-APP-34). AB - The original version of the article unfortunately contained a typo in the author name. PMID- 29476284 TI - Hours of Care and Caring Tasks Performed by Australian Carers of Adults with Mental Illness: Results from an Online Survey. AB - The aim of this study was to provide a detailed profile of the hours of care Australian mental health carers provide for different types of caring tasks. The UQ Carer Survey 2016 was administered online to 105 adults caring for someone aged 16 years or older whose main condition is mental illness. Mental health carers reported providing on average 37.2 h of care per week to their main care recipient. Carers spent most of their active caring time providing emotional support, and the least of their time assisting with activities of daily living. Carers highlighted that this care time fluctuates with the undulating nature of mental illness, and many noted additional hours devoted to being 'on call' in case of emergency. Carers provide large amounts of support on a long-term and often unpredictable basis. Government services need to match the undulating nature of the illness by providing more flexible support options for mental health carers. PMID- 29476285 TI - Preferences, personality and health behaviors: results from an explorative economic experiment. AB - This research note analyzes the relationship between experimentally elicited, incentivized economic preference parameters, personality traits, and three health behaviors: smoking, drinking, and physical activity. While there is a strand of economic research that uses proxy measures of risk and time preference that are not derived from an incentivized experiment and personality traits at the same time, and a considerably smaller one that uses experimentally elicited measures of risk and time preference only, the innovation of my work is to use experimentally elicited, incentivized preference measures and personality traits at the same time to explain a range of health behaviors. Findings presented in this paper suggest that personality traits seem to be more important determinants of health behaviors than economic preference parameters, and that Big Five personality traits, especially Agreeableness, seem to be more important determinants than the Grit score developed by Duckworth et al. (J Pers Soc Psychol 92(6):1087, 2007). When also controlling for a host of personality traits, risk preference is not related to the analyzed behaviors, but time preference is negatively related to smoking. When controlling for economic preferences and Big Five personality traits, the Grit score is unrelated to the analyzed health behaviors. Big Five openness is negatively related to the probability of engaging in physical activity, while Big Five agreeableness is negatively related to the probability of both drinking and binge drinking, but also to the probability of engaging in physical activity. Big Five neuroticism is negatively related to the probability of binge drinking. PMID- 29476287 TI - Photovoltaic Performance of a Nanowire/Quantum Dot Hybrid Nanostructure Array Solar Cell. AB - An innovative solar cell based on a nanowire/quantum dot hybrid nanostructure array is designed and analyzed. By growing multilayer InAs quantum dots on the sidewalls of GaAs nanowires, not only the absorption spectrum of GaAs nanowires is extended by quantum dots but also the light absorption of quantum dots is dramatically enhanced due to the light-trapping effect of the nanowire array. By incorporating five layers of InAs quantum dots into a 500-nm high-GaAs nanowire array, the power conversion efficiency enhancement induced by the quantum dots is six times higher than the power conversion efficiency enhancement in thin-film solar cells which contain the same amount of quantum dots, indicating that the nanowire array structure can benefit the photovoltaic performance of quantum dot solar cells. PMID- 29476286 TI - Disability progression in multiple sclerosis: a Tunisian prospective cohort study. AB - Data regarding multiple sclerosis (MS) course in North Africans are scarce and mainly retrospective. To prospectively assess disability progression of multiple sclerosis in Tunisia. Analysis was performed in 600 patients from the MS database of the Mongi Ben Hmida National Institute of Neurology (Tunis, Tunisia), prospectively recorded over a 10-year period. Two MS phases were defined: phase 1, from MS clinical onset to Disability Status Scale (DSS) 3; and phase 2, from DSS 3 to DSS 6. Median durations of both phases and median ages at DSS 3 and DSS 6 were estimated using the Kaplan-Meier method. Median ages at DSS scores 3 and 6 were 48 years (95% confidence interval (CI), 45-50) and 53 years (95% CI, 52-55), respectively. Median time from onset to DSS 3 (phase 1 duration) was 9 years (95% CI, 7-11) and median time to DSS 6 was 12 years (95% CI, 10-15). Median phase 2 duration was 3 years (95% CI, 2.4-3.6). Males and progressive-onset patients had faster disability worsening during the first phase of the disease. Conversely, disability progression during the second phase was independent of gender and MS phenotype at onset. Our study showed that disability progression followed a two stage process in Tunisian MS patients with however a more aggressive course compared to that in Westerners. PMID- 29476288 TI - Chimpanzee Velu: the wild chimpanzee who passed away at the estimated age of 58. PMID- 29476289 TI - Impact on Health-Related Quality of Life in Adults with Eosinophilic Gastritis and Gastroenteritis: A Qualitative Assessment. AB - BACKGROUND: Eosinophilic gastritis (EG) and eosinophilic gastroenteritis (EGE) are chronic immune-mediated conditions of the digestive tract, which affect the stomach only, or the stomach and small intestines, respectively. Though these disorders are uncommon, they are being increasingly recognized and diagnosed. While health-related quality of life (HRQOL) has been evaluated in other eosinophilic gastrointestinal diseases, this study is the first to describe HRQOL impacts unique to EG/EGE. AIMS: This study aims to qualitatively describe experiences of adults diagnosed with EG and EGE. We aim to identify impacts on HRQOL in this population in order to inform clinical care and assessment. METHODS: Seven patients diagnosed with EG or EGE participated in semi-structured interviews assessing common domains of HRQOL. RESULTS: Four distinct themes emerged from qualitative analyses, which represent impacts to HRQOL: the psychological impact of the diagnosis, impact on social relationships, financial impact, and impact on the body. These generally improved over time and with effective treatment. CONCLUSIONS: This study demonstrated that patients with EG/EGE experience impacts to HRQOL, some of which differ from HRQOL of other eosinophilic gastrointestinal diseases. These results support the development of a disease-specific measure, or adaptation of an existing measure, to assess HRQOL in EG/EGE. PMID- 29476291 TI - The Relationship Between Perceived Unmet Mental Health Care Needs and Suicidal Ideation and Attempt. AB - This study utilizes data from the National Survey of Drug Use and Health (NSDUH) to analyze the relationship between perceived unmet mental health care needs and suicidal ideation and attempt. Estimates from multivariable logistic regression models suggest that individuals who report perceived unmet mental health care needs have higher probability of experiencing suicidal ideation and attempt. Perceived unmet mental health care need has an important association with suicidal ideation and attempt, and efforts aimed at improving access to care are needed to address this issue. PMID- 29476290 TI - Taste and smell perception and quality of life during and after systemic therapy for breast cancer. AB - PURPOSE: The purpose of the study was to assess self-reported taste and smell perception after chemotherapy in breast cancer patients compared with women without cancer, and to assess whether taste and smell perception is associated with quality of life after the end of chemotherapy. METHODS: We included 135 newly diagnosed breast cancer patients who completed chemotherapy and 114 women without cancer. Questionnaires on taste, smell, and quality of life were completed shortly after and 6 months after chemotherapy (patients) or at two moments with 6 months' time window in between (comparisons). RESULTS: Self reported taste and smell perception were significantly lower in patients shortly after chemotherapy compared to the comparison group. Most patients recovered 6 months after chemotherapy, although patients who were still receiving trastuzumab then reported a lower taste and smell perception compared to patients who were not. A lower self-reported taste and smell were statistically significantly associated with a worse quality of life, social, emotional, and role functioning shortly after chemotherapy. Six months after chemotherapy, taste and smell were statistically significantly associated with quality of life, social and role functioning, but only in patients receiving trastuzumab. CONCLUSIONS: Most taste and smell alterations recovered within 6 months after the end of chemotherapy for breast cancer, but not for patients receiving trastuzumab. These results highlight the importance of monitoring taste and smell alterations during and after treatment with chemotherapy and trastuzumab, as they may impact quality of life. PMID- 29476292 TI - Utilization of Mental Health Services by Preschool-Aged Children with Private Insurance Coverage. AB - There is increasing recognition that some preschool-aged children suffer from mental health conditions, but little is known about the treatment they receive. Using the 2014 MarketScan Commercial Claims and Encounters database (N = 1,987,759) the study finds that only a small proportion of preschool-aged children receive any behavioral interventions, including psychotherapy, in conjunction with having a filled psychiatric prescription. Nearly all of the preschool-aged children who had psychotropic prescriptions filled had no other claims for treatment, and among those children who had prescriptions for psychotropic medication filled, the vast majority did not have a mental health diagnosis on a claim. PMID- 29476293 TI - Whole-exome sequencing of a meningeal melanocytic tumour reveals activating CYSLTR2 and EIF1AX hotspot mutations and similarities to uveal melanoma. PMID- 29476294 TI - Relationship between the binding free energy and PCBs' migration, persistence, toxicity and bioaccumulation using a combination of the molecular docking method and 3D-QSAR. AB - The molecular docking method was used to calculate the binding free energies between biphenyl dioxygenase and 209 polychlorinated biphenyl (PCB) congeners. The relationships between the calculated binding free energies and migration (octanol-air partition coefficients, KOA), persistence (half-life, t1/2), toxicity (half maximal inhibitory concentration, IC50), and bioaccumulation (bioconcentration factor, BCF) values for the PCBs were used to gain insight into the degradation of PCBs in the presence of biphenyl dioxygenase. The relationships between the calculated binding free energies and the molecular weights, KOA, BCF, and t1/2 values for the PCBs were statistically significant (P < 0.01), whereas the relationship between the calculated binding free energies and the IC50 for the PCBs was not statistically significant (P > 0.05). The electrostatic field, derived from three-dimensional quantitative structure activity relationship studies, was a primary factor governing the binding free energy, which agreed with literature findings for KOA, t1/2, and BCF. Comparative molecular field analysis and comparative molecular similarity indices analysis contour maps showed that the binding free energies, KOA, t1/2, and BCF values for the PCBs decreased simultaneously when substituents with electropositive groups at the 3-position or electronegative groups at the 3'-position were introduced. This indicated the binding free energy was correlated with the persistent organic pollutant characteristics of PCBs. Furthermore, low binding free energies improved the degradation of the PCBs and simultaneously decreased the KOA, t1/2, and BCF values, thereby reducing the persistent organic pollutant characteristics of PCBs in the environment. These results are expected to be beneficial in providing a theoretical foundation for further elucidation of the degradation and molecular modification of PCBs. PMID- 29476295 TI - Predicting Survival and Response to Treatment in Gastroesophageal Neuroendocrine Tumors: An Analysis of the National Cancer Database. AB - BACKGROUND: Neuroendocrine tumors (NETs) of the esophagus and stomach are rare neoplasms with variable behavior. We aim to describe their epidemiology and response to treatment. METHODS: NETs of the stomach and the esophagus were selected from the National Cancer Database (2004-2013) and classified by location. Survival analyses were performed with respect to tumor characteristics and treatment variables. RESULTS: NETs of the stomach (n = 2700; 92.8%) and esophagus (n = 210, 7.2%) were identified. Gastric cardia NETs had demographics and behavior similar to esophageal tumors and were associated with worse overall survival than NETs of the noncardia stomach independent of grade (p < 0.001). Poorly differentiated histology [hazard ratio (HR) 4.14, 95% confidence interval (CI) 2.26-7.57; p < 0.001] and distant metastases (HR 3.28, 95% CI 1.94-5.56; p < 0.001) were the greatest independent predictors of survival. For patients with poorly differentiated NETs, surgery was the only treatment to have benefit on overall survival (HR 0.38, 95% CI 0.27-0.54; p < 0.001) regardless of extent of disease. There was no additional benefit to adjuvant chemotherapy or radiation in patients undergoing resection (p = 0.39), even for patients with lymph node metastases (surgery alone versus surgery plus adjuvant therapy, p = 0.46), distant metastases (p = 0.19), or positive margins (p = 0.33). CONCLUSIONS: Esophageal and gastric cardia NETs have worse survival than those of the noncardia stomach. Surgery offers the only survival benefit for poorly differentiated tumors, with no additional survival advantage to adjuvant chemotherapy or radiation. PMID- 29476296 TI - Elucidation of the Anatomical Mechanism of Nodal Skip Metastasis in Superficial Thoracic Esophageal Squamous Cell Carcinoma. AB - BACKGROUND: Lymph node metastasis (LNM) is a standard mechanism of cancer progression in esophageal squamous cell carcinoma (ESCC). We aimed to clarify the anatomical mechanism of skip nodal metastasis to mediastinal zones by analyzing the relationship between LNM to sentinel zones and lymphatic vessel counts in the muscle layer adjacent to the outer esophagus. METHODS: We examined the surgical records of 287 patients with ESCC who underwent potentially curative surgery (three-field lymphadenectomy) and whole esophagi, including pharynges and stomachs from 10 cadavers, to determine the number of lymphatic vessels in the intra-outer longitudinal muscle layer adjacent to the outer esophagus of the cervical (Ce), upper thoracic, middle thoracic (Mt), lower thoracic (Lt), and abdominal esophagi (Ae). RESULTS: The frequency of LNM to the middle mediastinal and supraclavicular zones, including the Mt and Ce, respectively, was lower than to the upper and lower mediastinal and abdominal zone in patients with superficial and advanced thoracic ESCC. In cadavers, the lymphatic vessel counts of the intra-outer longitudinal muscle layer in the Mt and Ce were significantly lower than those of the Lt and Ae, suggesting that lymphatic flow toward the outside of the Mt and Ce was not more abundant than to other sites. CONCLUSION: Our anatomical data suggested that the absence of intra-muscle lymphatic vessels in the middle mediastinal and supraclavicular zones causes skip LNM in patients with thoracic ESCC. Thus, standard esophagectomy with lymph node dissection, including distant zones, may be appropriate for treating patients with superficial thoracic ESCC. PMID- 29476297 TI - Keith Haring, Felix Gonzalez-Torres, Wolfgang Tillmans, and the AIDS Epidemic: The Use of Visual Art in a Health Humanities Course. AB - Contemporary art can be a powerful pedagogical tool in the health humanities. Students in an undergraduate course in the health humanities explore the subjective experience of illness and develop their empathy by studying three artists in the context of the AIDS epidemic: Keith Haring, Felix Gonzalez-Torres, and Wolfgang Tillmans. Using assignments based in narrative pedagogy, students expand their empathic response to pain and suffering. The role of visual art in health humanities pedagogy is discussed. PMID- 29476298 TI - Pregnant Women's Perspectives on Expanded Carrier Screening. AB - Expanded carrier screening (ECS) is a relatively new carrier screening option that assesses many conditions simultaneously, as opposed to traditional ethnicity based carrier screening for a limited number of conditions. This study aimed to explore pregnant women's perspectives on ECS, including reasons for electing or declining and anxiety associated with this decision-making. A total of 80 pregnant women were surveyed from Northwestern Medicine's Clinical Genetics Division after presenting for aneuploidy screening. Of the 80 participants, 40 elected and 40 declined ECS. Trends regarding reasons for electing or declining ECS include ethnicity, desire for genetic risk information, lack of family history, perceived likelihood of being a carrier, and perceived impact on reproductive decisions. Individuals who declined ECS seemed to prefer ethnicity based carrier screening and believed that ECS would increase their anxiety, whereas individuals who elected ECS seemed to prefer more screening and tended to believe that ECS would reduce their anxiety. These findings provide insight on decision-making with regard to ECS and can help guide interactions that genetic counselors and other healthcare providers have with patients, including assisting patients in the decision-making process. PMID- 29476299 TI - Spiritual Care in General Practice: Rushing in or Fearing to Tread? An Integrative Review of Qualitative Literature. AB - Guidance for medical staff reminds employees of the responsibility to deliver spiritual care in its broadest sense, respecting the dignity, humanity, individuality and diversity of the people whose cultures, faiths and beliefs coexist in society. This is no small or simple task, and although GPs (family practitioners) have been encouraged to deliver spiritual care, we suggest this is proving to be challenging and needs further careful debate. This literature review critiques and analyses existing studies and points to four categories of attitude to spiritual care, and two related but distinct concepts of spirituality in use by GPs. Our aims were to search for, summarise and critique the qualitative literature regarding general practitioners' views on spirituality and their role in relation to spiritual care. An integrative review was made by a multidisciplinary team using a critical realism framework. We searched seven databases and completed thematic and matrix analyses of the qualitative literature. A number of good-quality studies exist and show that some but not all GPs are willing to offer spiritual care. Four patterns of attitude towards delivering spiritual care emerge from the studies which indicate different levels of engagement with spiritual care: embracing, pragmatic, guarded and rejecting. Further research is needed to identify whether these four views are fixed or fluid, whether training in spiritual care modifies these and whether they relate to patterns of care in practice, or patient outcomes. The authors suggest that some of the difference in viewpoint relate to the lack of clear philosophical framework. The authors suggest critical realism as having potential to facilitate interdisciplinary research and create clearer concepts of spiritual care for GPs. PMID- 29476300 TI - Homozygous nonsense mutation Trp28X in the LHB gene causes male hypogonadism. AB - PURPOSE: The purpose of this study was to investigate a novel mutation in the luteinizing hormone beta-subunit (LHB) gene in one male patient with hypogonadism due to selective luteinizing hormone (LH) deficiency. METHODS: Sanger sequencing of one 28-year-old man born to consanguineous parents was performed. Treatment with human chorionic gonadotropin (hCG) (2000 IU, twice a week) was initiated for 3 months, followed by 5000 IU weekly to date. RESULTS: We identified a novel c.84G>A[p.W28X] nonsense LHB mutation. The W28X mutation produces a truncated LHB peptide of seven amino acids, which prevents the synthesis of intact LH. After 40 days of treatment with hCG, the patient exhibited a few spermatozoa in the semen. Treated for 6 months, the patient exhibited normal seminal parameters. CONCLUSIONS: We identified a novel mutation in the LHB gene in a male patient with hypogonadism and provided evidence that LHB nonsense mutation can cause selective LH deficiency. We reconfirmed hCG treatment may restore male fertility due to LHB mutation. PMID- 29476302 TI - Apoptotic effects of epsilon-viniferin in combination with cis-platin in C6 cells. AB - Glioblastoma (GBM) is one of the most common and lethal forms of primary brain tumors in human adults. Treatment options are limited, and in most cases ineffective. Natural products are sources of novel compounds endowed with therapeutic properties in many human diseases like cancer. epsilon-viniferin is a resveratrol dimer and well known for having antiproliferative and apoptotic effects on cancer cells. Cisplatin is a platinum containing anti-cancer drug. In this study, we aimed to investigate antiproliferative and apoptotic effects of using cis-platin and epsilon-viniferin alone or in combined treatment of C6 cells. Cell proliferation was detected by WST-1. Mitochondrial membrane potential changes in the cells (DeltaPsim) were evaluated using cationic dye JC1. Apoptotic index which is a hallmark of late apoptosis was detected by using Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) method and apoptotic alterations were observed by transmission electron microscope (TEM). Activation of caspase-8, -9, -3 in C6 cells at various incubation periods was measured by flow cytometer. Apoptotic index increased at highest level in only combined treatment cells (91.6%) after 48 h incubation. These results were supported by TEM images. Caspase-8 activation in C6 cells increased to a maximum (12.5%) after 6 h by using combined cis-platin/epsilon-viniferin treatment (13.25/95 MUM). Caspase-9 was activated at 44.5% after combined treatment for 24 h. This rate is higher than using cis-platin (14.2%) or epsilon-viniferin (43.3%) alone. The combined 13.25 MUM/cisplatin and 95 MUM epsilon-viniferin treatment caused maximum caspase-3 activation in C6 cells (15.5%) at the end of the 72 h incubation. In conclusion, it was observed that caspase-8, -9, -3 activation which was determined in vitro, trigerred apoptotic mechanism in C6 cells by using low concentrations of combined cis-platin and epsilon-viniferin. PMID- 29476301 TI - The Placental Barrier: the Gate and the Fate in Drug Distribution. AB - Optimal development of the embryo and the fetus depends on placental passage of gases, nutrients, hormones, and waste products. These molecules are transferred across the placenta via passive diffusion, carrier-mediated cellular uptake and efflux, and transcytosis pathways. The same mechanisms additionally control the rate and extent of transplacental transfer of drugs taken by the pregnant mother. Essentially all drugs cross the placenta to a certain extent, and some accumulate in the placenta itself at levels that can even exceed those in maternal plasma. Hence, even drugs that are not efficiently transferred across the placenta may indirectly affect fetal development by interfering with placental function. In this article, we describe key properties of the placental barrier and their modulation by medications. We highlight implications for pharmacotherapy and novel approaches for drug delivery in pregnant women and their fetuses. PMID- 29476303 TI - Antero-cervical thermophysiological characterization of obstructive sleep apnea patients. AB - PURPOSE: Obstructive sleep apnea syndrome (OSAS) is characterized by upper airway inflammation. The aim of this study was to characterize thermal profile of the antero-cervical region in OSAS patients through medical thermal imaging and to compare the respective subjects with non-OSAS individuals. METHODS: Image capture followed the Glamorgan Protocol. A dynamic thermographic examination of the anterior cervical region (at baseline and after a cold stimulus) was conducted in 26 patients diagnosed with overnight polysomnography (PSG). PSG results stratified the subjects into OSAS and non-OSAS groups and their thermograms were compared. RESULTS: Eleven non-OSAS and 15 OSAS subjects were evaluated. Antero cervical right side (RS) temperature was higher in OSAS group at baseline (p = 0.014). Right side index (RSI) temperature-the difference between RS and submental region, considered as control-was lower in OSAS subjects at baseline (p = 0.020) and 10 min after the cold stimuli was applied (p = 0.008), indicating higher absolute temperatures in this group. Left side index (LSI) was also lower at 10 min in OSAS group (p = 0.021). Statistical correlation was found between apnea-hypopnea index and RS at baseline (r = 0.424, p = 0.031) and at 10 min (r = 0.403, p = 0.041) and RSI at baseline (r = - 0.458, p = 0.019) and 10 min after cold provocation was applied (r = - 0.435, p = 0.025). CONCLUSIONS: OSAS patients have shown higher antero-cervical temperatures compared with non-OSAS counterparts and temperature was associated with severity of the condition. Medical thermography may be a suitable tool in the setting of OSAS suspicion. PMID- 29476305 TI - Immunotherapy-induced autoimmune diabetes and concomitant hypophysitis. PMID- 29476304 TI - Impact of pre-admission treatment with non-vitamin K oral anticoagulants on stroke severity in patients with acute ischemic stroke. AB - BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOACs) have gained increasing importance for stroke prevention in patients with non-valvular atrial fibrillation (AF). With changing prescription practice, among other factors, clinicians can expect to see rising numbers of patients with ischemic stroke and pre-existing NOAC therapy. Few data exist regarding a potential impact of NOAC on stroke severity and outcome. AIMS: To evaluate the impact of pre-admission NOAC therapy on ischemic stroke severity. METHODS: Retrospective analysis of medical data of 376 patients with newly detected AF or known AF with either no pre admission oral anticoagulation (n = 277) or existing NOAC therapy (n = 99; Apixaban, n = 33, Dabigatran, n = 16; Edoxaban, n = 1; Rivaroxaban, n = 49) consecutively admitted for acute ischemic stroke between January 2015 and December 2016. RESULTS: Patients with pre-admission NOAC had significantly more often experienced a prior stroke than patients not on NOAC therapy (45.5 vs. 18.4%, p < 0.001) and were significantly more frequently non-smokers (1.0 vs. 7.2%, p = 0.021). Significantly more patients without pre-admission NOAC received thrombolysis (33.8 vs. 8.1%, p < 0.001). Pre-admission NOAC therapy was associated with significantly lower NIHSS and mRS scores upon admission (median NIHSS score 6 vs. 10, p = 0.018, median mRS score 4 vs. 5, p = 0.035) and trend level lower NIHSS scores at discharge (median NIHSS score 3 vs. 5, p = 0.057). There were no differences regarding the frequency of symptomatic intracerebral hemorrhage between NOAC and non-NOAC patients (p > 0.05). CONCLUSIONS: We report a positive impact of pre-admission NOAC on ischemic stroke severity, which is particularly remarkable in light of the increased prevalence of prior stroke and lower rates of thrombolysis in this patient population. PMID- 29476307 TI - Paracoccidioides brasiliensis Infection Mimicking Recurrent Hodgkin Lymphoma: A Case Report and Review of the Literature. AB - Paracoccidioides infection is a rare entity in the USA. This dimorphic fungus is found in Central and South America and is thought to be acquired by inhalation through the soil. We report a case of Paracoccidioides brasiliensis infection presenting as a clavicular bone lesion, peripancreatic mass, and various skin lesions. A 35-year-old man with a history significant for Hodgkin lymphoma presented with a left clavicular mass that was suspected clinically and radiologically as recurrent Hodgkin lymphoma. He was not experiencing any associated symptoms and was undergoing chemotherapy treatment for his known Hodgkin disease. On CT imaging, the mass was seen as a lytic bone lesion with an overlying soft tissue mass. This was biopsied and histologically diagnosed as a Paracoccidioides brasiliensis infection with associated necrotizing granulomatous inflammation. Also found on the CT scan was an enlarging peripancreatic mass which on endoscopic biopsy had similar histologic findings. In conclusion, this report presents a rare case of Paracoccidioides brasiliensis infection mimicking recurrent Hodgkin lymphoma. PMID- 29476306 TI - Potential high-frequency off-target mutagenesis induced by CRISPR/Cas9 in Arabidopsis and its prevention. AB - KEY MESSAGE: We present novel observations of high-specificity SpCas9 variants, sgRNA expression strategies based on mutant sgRNA scaffold and tRNA processing system, and CRISPR/Cas9-mediated T-DNA integrations. Specificity of CRISPR/Cas9 tools has been a major concern along with the reports of their successful applications. We report unexpected observations of high frequency off-target mutagenesis induced by CRISPR/Cas9 in T1 Arabidopsis mutants although the sgRNA was predicted to have a high specificity score. We also present evidence that the off-target effects were further exacerbated in the T2 progeny. To prevent the off target effects, we tested and optimized two strategies in Arabidopsis, including introduction of a mCherry cassette for a simple and reliable isolation of Cas9 free mutants and the use of highly specific mutant SpCas9 variants. Optimization of the mCherry vectors and subsequent validation found that fusion of tRNA with the mutant rather than the original sgRNA scaffold significantly improves editing efficiency. We then examined the editing efficiency of eight high-specificity SpCas9 variants in combination with the improved tRNA-sgRNA fusion strategy. Our results suggest that highly specific SpCas9 variants require a higher level of expression than their wild-type counterpart to maintain high editing efficiency. Additionally, we demonstrate that T-DNA can be inserted into the cleavage sites of CRISPR/Cas9 targets with high frequency. Altogether, our results suggest that in plants, continuous attention should be paid to off-target effects induced by CRISPR/Cas9 in current and subsequent generations, and that the tools optimized in this report will be useful in improving genome editing efficiency and specificity in plants and other organisms. PMID- 29476308 TI - Implementing a Statewide Safe to Sleep Hospital Initiative: Lessons Learned. AB - Sleep-related infant deaths continue to be a major, largely preventable cause of infant mortality, especially in Georgia. The Georgia Department of Public Health (DPH), as part of a multi-pronged safe infant sleep campaign, implemented a hospital initiative to (1) provide accurate safe infant sleep information to hospital personnel; (2) support hospitals in implementing and modeling safe sleep practices; and (3) provide guidance on addressing caregiver safe sleep concerns. A process evaluation was conducted to determine progress toward four goals set out by DPH: (1) all birthing hospitals have a safe infant sleep policy; (2) all safe infant sleep policies reference the AAP 2011 recommendations; (3) all safe infant sleep policies specify the type and/or content of patient safe sleep education; and (4) all hospitals require regular staff training on safe sleep recommendations. Data were collected via structured interviews and document review of crib audit data and safe sleep policies. All 79 birthing hospitals in the state participated in the statewide campaign. Prior to the initiative, 44.3% of hospitals had a safe sleep policy in place; currently, 87.3% have a policy in place. The majority (91.4%) of hospitals have provided safe sleep training to their staff at this time. Important lessons include: (1) Engagement is vital to success; (2) A comprehensive implementation guide is critical; (3) Piloting the program provides opportunities for refinement; (4) Ongoing support addresses barriers; and (5) Senior leadership facilitates success. PMID- 29476309 TI - The utility of "low current" stimulation threshold of intraoperative electromyography monitoring in predicting facial nerve function outcome after vestibular schwannoma surgery: a prospective cohort study of 103 large tumors. AB - To investigate the predictive utility of stimulation threshold (ST) of intraoperative electromyography monitoring for facial nerve (FN) outcomes among vestibular schwannoma (VS) patients postoperatively. The authors enrolled 103 unilateral VS patients who underwent surgical resection into a prospective cohort observational study from January 2013 to April 2015 in our hospital. ST values were used to categorize 81 patients into the "low current" (ST <= 0.05 mA) group and 22 patients into the control (ST > 0.05 mA) group. The FN function outcomes were summarized and correlated with these two groups at 1, 3, 6, and 12 months after surgery. Binary regression analysis revealed that the percentage of "good" FN outcome, defined by House-Brackmann (HB) classification of facial function (I II), in the "low current" group was significantly higher than that of the control group (42.0 vs. 4.5% at 1 month, P = 0.015; 64.2 vs. 31.8% at 3 months, P = 0.024; 72.8 vs. 40.9% at 6 months, P = 0.021; 84.0 vs. 45.5% at 12 months, P = 0.002). Ordinal regression analysis showed that the distribution of HB scores was shifted in a favorable direction in the "low current" group at 1, 3, 6, and 12 months postoperatively. For patients with HB IV at the first month postoperative period, the recovery rate of the "low current" group was significantly higher than that of control group (P = 0.003). "Low current" can predict FN function outcomes better and has faster recovery rates than that of the control group. PMID- 29476310 TI - Anti-differentiation non-coding RNA, ANCR, is differentially expressed in different types of brain tumors. AB - Long non-coding RNAs (lncRNAs) are important modulators of various cellular and molecular events, including cancer-associated pathways. The Anti-differentiation ncRNA (ANCR) is a key regulator of keratinocyte differentiation, where its expression is necessary to maintain epidermal progenitor's cells. Herein, we investigated the expression pattern of ANCR in the course of neural differentiation. Moreover, we used published RNAseq data and clinical samples to evaluate the alteration of ANCR expression in different cell types and brain tumors. Furthermore, we manipulated ANCR expression in glioma cell lines to clarify a potential functional role for ANCR in tumorigenesis. Our qRT-PCR results revealed a significant upregulation of ANCR in more malignant and less differentiated types of brain tumors (P = 0.03). This data was in accordance with down regulation of ANCR during neural differentiation. ANCR suppression caused an elevation in apoptosis rate, as well as a G1 cell cycle arrest in glioblastoma cell line. Altogether, our data demonstrated that ANCR may play a role in glioma genesis and that it could be considered as a potential diagnostic and therapeutic target to combat brain cancers. PMID- 29476311 TI - Do Health Service Use and Return-to-Work Outcomes Differ with GPs' Injured-Worker Caseload? AB - Purpose To determine whether healthcare use and return-to-work (RTW) outcomes differ with GPs' injured-worker caseload. Methods Retrospective analyses of the Compensation Research Database, which captures approximately 85% of all injured worker claims in Victoria, Australia was conducted. Four injured-worker caseload groups were examined that represented the 25th, 50th, 75th, and 100th percentiles of claimants seen per GP over the 8-year study period (2003-2010): (i) 1-13 claimants; (ii) 14-26 claimants; (iii) 27-48 claimants; and (iv) 49+ claimants (total claims, n = 124,342; total GPs, n = 9748).The characteristics of claimants in each caseload group, as well as the influence of caseload on three outcomes relevant to RTW (weekly compensation paid, work incapacity days, medical-and-like costs), were examined. Results Distinct profiles for high versus low caseload groups emerged. High caseload GPs treated significantly more men in blue collar occupations and issued significantly more 'alternate duties' certificates. Conversely, low caseload GPs treated significantly more women in white collar occupations, predominantly for mental health injuries, and issued significantly more 'unfit-for-work' certificates. Few significant differences were found between the two intermediate GP caseload groups. High caseload was associated with significantly greater medical-and-like costs, however, no caseload group differences were detected for weekly compensation paid or duration of time-off work. Conclusions Training GPs who have a low injured-worker caseload in workers' compensation processes, utilising high caseload GPs in initiatives involving peer to-peer support, or system changes where employers are encouraged to provide preventive or rehabilitative support in the workplace may improve RTW outcomes for injured workers. PMID- 29476312 TI - Some recommendations for developing multidimensional computerized adaptive tests for patient-reported outcomes. AB - PURPOSE: Multidimensional item response theory and computerized adaptive testing (CAT) are increasingly used in mental health, quality of life (QoL), and patient reported outcome measurement. Although multidimensional assessment techniques hold promises, they are more challenging in their application than unidimensional ones. The authors comment on minimal standards when developing multidimensional CATs. METHODS: Prompted by pioneering papers published in QLR, the authors reflect on existing guidance and discussions from different psychometric communities, including guidelines developed for unidimensional CATs in the PROMIS project. RESULTS: The commentary focuses on two key topics: (1) the design, evaluation, and calibration of multidimensional item banks and (2) how to study the efficiency and precision of a multidimensional item bank. The authors suggest that the development of a carefully designed and calibrated item bank encompasses a construction phase and a psychometric phase. With respect to efficiency and precision, item banks should be large enough to provide adequate precision over the full range of the latent constructs. Therefore CAT performance should be studied as a function of the latent constructs and with reference to relevant benchmarks. Solutions are also suggested for simulation studies using real data, which often result in too optimistic evaluations of an item bank's efficiency and precision. DISCUSSION: Multidimensional CAT applications are promising but complex statistical assessment tools which necessitate detailed theoretical frameworks and methodological scrutiny when testing their appropriateness for practical applications. The authors advise researchers to evaluate item banks with a broad set of methods, describe their choices in detail, and substantiate their approach for validation. PMID- 29476314 TI - Socioeconomically Disadvantaged Adolescents with Elevated Externalizing Symptoms Show Heightened Emotion Reactivity to Daily Stress: An Experience Sampling Study. AB - Numerous theories assert that youth with externalizing symptomatology experience intensified emotion reactivity to stressful events; yet scant empirical research has assessed this notion. Using in-vivo data collected via experience sampling methodology, we assessed whether externalizing symptoms conditioned adolescents' emotion reactivity to daily stressors (i.e. change in emotion pre-post stressor) among 206 socioeconomically disadvantaged adolescents. We also assessed whether higher externalizing symptomology was associated with experiencing more stressors overall, and whether adolescents' emotional upheavals resulted in experiencing a subsequent stressor. Hierarchical linear models showed that adolescents higher in externalizing symptoms experienced stronger emotion reactivity in sadness, anger, jealously, loneliness, and (dips in) excitement. Externalizing symptomatology was not associated with more stressful events, but a stress-preventative effect was found for recent upheavals in jealousy among youth low in externalizing. Findings pinpoint intense emotion reactivity to daily stress as a risk factor for youth with externalizing symptoms living in socioeconomic disadvantage. PMID- 29476313 TI - Sensitivity to Peer Evaluation and Its Genetic and Environmental Determinants: Findings from a Population-Based Twin Study. AB - Adolescents and young adults are highly focused on peer evaluation, but little is known about sources of their differential sensitivity. We examined to what extent sensitivity to peer evaluation is influenced by interacting environmental and genetic factors. A sample of 354 healthy adolescent twin pairs (n = 708) took part in a structured, laboratory task in which they were exposed to peer evaluation. The proportion of the variance in sensitivity to peer evaluation due to genetic and environmental factors was estimated, as was the association with specific a priori environmental risk factors. Differences in sensitivity to peer evaluation between adolescents were explained mainly by non-shared environmental influences. The results on shared environmental influences were not conclusive. No impact of latent genetic factors or gene-environment interactions was found. Adolescents with lower self-rated positions on the social ladder or who reported to have been bullied more severely showed significantly stronger responses to peer evaluation. Not genes, but subjective social status and past experience of being bullied seem to impact sensitivity to peer evaluation. This suggests that altered response to peer evaluation is the outcome of cumulative sensitization to social interactions. PMID- 29476315 TI - Bias in dyslexia screening in a Dutch multicultural population. AB - We set out to address the adequacy of dyslexia screening in Dutch and non-western immigrant children, using the Dutch Dyslexia Screening Test (DST-NL) and outcomes of the Dutch dyslexia protocol, both of which are susceptible to cultural bias. Using the protocol as standard, we conducted an ROC (Receiver Operating Characteristics) analysis in Dutch and immigrant third, fifth, and seventh graders, combining a cross-sectional and longitudinal design. Sensitivity and specificity increased with grade, but were non-significant for various subtests in the lowest grade, suggesting considerable non-convergence between the two measures. Effective subtests in all grades, presumably not strongly influenced by Cultural Background or Word Lexicon, were One-Minute Reading, Non-Word Reading, and Nonsense Passage Reading. In a multilevel analysis, cultural background, dyslexia diagnosis, parental education, and grade of first assessment were predictors of subtest performance. In a second analysis, Word Lexicon was added as a proxy of knowledge of the Dutch language and culture. After controlling for Word Lexicon, cultural background became significant for most subtests, suggesting the presence of cultural bias. Subtests assessing technical literacy, such as One-Minute-Reading, Non-Word-Reading, One-Minute-Writing, or Two-Minutes Spelling, showed more convergence between the two assessments. Less-effective subtests were Naming Pictures, Backward Digit Span, and Verbal and Semantic Fluency. It is concluded that the DST-NL and the standard protocol do not show complete convergence, notably in the lower grades in the multilingual pupil group of our cohort, mainly because dyslexia and literacy difficulties are hard to disentangle. PMID- 29476316 TI - Information transmission in microbial and fungal communication: from classical to quantum. AB - Microbes have their own communication systems. Secretion and reception of chemical signaling molecules and ion-channels mediated electrical signaling mechanism are yet observed two special ways of information transmission in microbial community. In this article, we address the aspects of various crucial machineries which set the backbone of microbial cell-to-cell communication process such as quorum sensing mechanism (bacterial and fungal), quorum sensing regulated biofilm formation, gene expression, virulence, swarming, quorum quenching, role of noise in quorum sensing, mathematical models (therapy model, evolutionary model, molecular mechanism model and many more), synthetic bacterial communication, bacterial ion-channels, bacterial nanowires and electrical communication. In particular, we highlight bacterial collective behavior with classical and quantum mechanical approaches (including quantum information). Moreover, we shed a new light to introduce the concept of quantum synthetic biology and possible cellular quantum Turing test. PMID- 29476317 TI - Atypical erythroblastosis in a patient with Diamond-Blackfan anemia who developed del(20q) myelodysplasia. AB - Diamond-Blackfan anemia (DBA) is a congenital red cell aplasia arising from ribosomal protein (RP) defects. Affected patients present with neonatal anemia, occasional dysmorphism, and cancer predisposition. An anemic newborn was diagnosed with DBA due to RPL5 mutation (c.473_474del, p.K158SfsX26). Refractory anemia required regular transfusions and iron chelation therapy. Pancytopenia occurred at age 16 years. Bone-marrow studies showed myelodysplasia, erythroblastosis, and clonal evolution of del(20)(q11.2q13.3). Severe anemia required transfusions. Del(20q), including the L3MBTL1 gene, is reported to be relevant to the hematological phenotype of Shwachman-Diamond syndrome. A combined defect of RPL5 and L3MBTL1 may contribute to the aberrant erythropoiesis in the present case. PMID- 29476318 TI - Comparative Study of Withanolide Biosynthesis-Related miRNAs in Root and Leaf Tissues of Withania somnifera. AB - Withania somnifera, popularly known as Indian ginseng, is one of the most important medicinal plants. The plant is well studied in terms of its pharmaceutical activities and genes involved in biosynthetic pathways. However, not much is known about the regulatory mechanism of genes responsible for the production of secondary metabolites. The idea was to identify miRNA transcriptome responsible for the regulation of withanolide biosynthesis, specifically of root and leaf tissues individually. The transcriptome data of in vitro culture of root and leaf tissues of the plant was considered for miRNA identification. A total of 24 and 39 miRNA families were identified in root and leaf tissues, respectively. Out of these, 15 and 27 miRNA families have shown their involvement in different biological functions in root and leaf tissues, respectively. We report here, specific miRNAs and their corresponding target genes for corresponding root and leaf tissues. The target genes have also been analyzed for their role in withanolide metabolism. Endogenous root-miR5140, root-miR159, leaf-miR477, and leaf-miR530 were reported for regulation of withanolide biosynthesis. PMID- 29476319 TI - Hypericum japonicum: a Double-Headed Sword to Combat Vector Control and Cancer. AB - Mosquito control with naturally derived herbal insecticides has gained much momentum, with the increased insecticide resistance of vectors and the multiple infectious diseases spread by them. Yet, recent studies also suggest that mosquitoes could probably transmit some cancerous cells or cancer-causing viruses from one individual to another between their blood meals. The current research thus focused on the screening and characterization of novel plants with both mosquitocidal and anticancerous properties. Accordingly, different solvent extracts of Hypericum japonicum, a key plant in Chinese medicine, were screened for its larvicidal efficacy using the fourth instar larvae of Aedes aegypti (major vector of Dengue and chikungunya). Methanolic extracts of the plant showed effective larvicidal property with LC50 7.37 ppm and LC9011.59 ppm values. The anticancerous property of the plant extract was also evaluated by in vitro cytotoxicity assay against Daltons Lymphoma Ascites (DLA) cells. The results indicated that H. japonicum plant extracts at very low concentrations of LC500.95 ppm and LC901.85 ppm were potent cytotoxic agents. To the best of our knowledge, this is the first and the foremost report of Hypericum japonicum as a potent mosquitocidal and anticancerous agent. Identification and characterization of such plant-derived bioactive plants thus could serve as a double-headed sword against the spread of infectious diseases and cancer. PMID- 29476320 TI - Dependence of excitability indices on membrane channel dynamics, myelin impedance, electrode location and stimulus waveforms in myelinated and unmyelinated fibre models. AB - Neuronal excitability is determined in a complex way by several interacting factors, such as membrane dynamics, fibre geometry, electrode configuration, myelin impedance, neuronal terminations[Formula: see text] This study aims to increase understanding in excitability, by investigating the impact of these factors on different models of myelinated and unmyelinated fibres (five well known membrane models are combined with three electrostimulation models, that take into account the spatial structure of the neuron). Several excitability indices (rheobase, polarity ratio, bi/monophasic ratio, time constants[Formula: see text]) are calculated during extensive parameter sweeps, allowing us to obtain novel findings on how these factors interact, e.g. how the dependency of excitability indices on the fibre diameter and myelin impedance is influenced by the electrode location and membrane dynamics. It was found that excitability is profoundly impacted by the used membrane model and the location of the neuronal terminations. The approximation of infinite myelin impedance was investigated by two implementations of the spatially extended non-linear node model. The impact of this approximation on the time constant of strength-duration plots is significant, most importantly in the Frankenhaeuser-Huxley membrane model for large electrode-neuron separations. Finally, a multi-compartmental model for C fibres is used to determine the impact of the absence of internodes on excitability. Graphical Abstract Electrostimulation models, obtained by combining five membrane models with three representations of the neuronal cable equation, are fed with electrode and stimulus input parameters. The dependency of neuronal excitability on the interaction of these input parameters is determined by deriving excitability indices from the spatiotemporal model response. The impact of the myelin impedance and the fibre diameter on neural excitability is also considered. PMID- 29476321 TI - Interaction of interaural cues and their contribution to the lateralisation of Mongolian gerbils (Meriones unguiculatus). AB - The main sound localisation cues in the horizontal plane are interaural time and level differences (ITDs and ILDs, respectively). ITDs are thought to be the dominant cue in the low-frequency range, ILDs the dominant cue in the high frequency range. ITDs and ILDs co-occur. Their interaction and contribution to the lateralisation of pure tones by Mongolian gerbils was investigated behaviourally using cross-talk cancellation techniques for presenting ITDs and ILDs independently. First, ITDs were applied to pure tones with frequencies <= 2 kHz to the ongoing waveform, at the onsets and offsets, or in both the ongoing waveform and at the onsets and offsets. Gerbils could lateralise tones only if ongoing ITDs were present indicating that ongoing ITDs are decisive for the lateralisation of low-frequency tones. Second, an ITD was added to 2-to-6-kHz tones with varying ILD. Gerbils' lateralisation was unaffected by the ITD indicating that a large ILD provides a strong lateralisation cue at those frequencies. Finally, small ILDs were applied to 2-kHz tones with an ongoing ITD, pointing either to the same or opposing sides as the ITD. Gerbils' lateralisation was driven by the ITD but strongly affected by the ILD indicating that both interaural cues contribute to the lateralisation. PMID- 29476323 TI - Ten-year survival and patient-reported outcomes of a medial unicompartmental knee arthroplasty incorporating an all-polyethylene tibial component. AB - INTRODUCTION: Biomechanical studies have suggested that proximal tibial strain is elevated in UKAs incorporating all-polyethylene tibial components with concern that this leads to premature failure. This study reports minimum 10-year outcomes for a UKA incorporating an all-polyethylene tibial component to determine whether these concerns were realised. MATERIALS AND METHODS: 109 fixed bearing UKAs (97 patients, mean age 68 (range 48-87), 54/97 (56%) female) with all-polyethylene tibial components were followed up for >= 10 years with Oxford Knee Scores, Forgotten Joint Scores and Kaplan-Meier analysis. 106/109 implants were 7 mm, 3 were 9.5 mm. RESULTS: Ten-year survival was 85.5% (78.6-92.4 95% CI) with the end point failure for any reason. Unexplained pain was the commonest mode of failure (6/17) followed by lateral compartment osteoarthritis (5/17) and tibial subsidence/loosening (4/17). Revision rate was highest at 2-5 years due to revisions for unexplained pain. Ten-year survival was worse in patients < 65 years old (p = 0.035), in those with BMI > 30 (p = 0.017) and in those with postoperative increases in medial tibial sclerosis (p < 0.001 log-rank). Implant malalignment was not significantly associated with failure. Radioisotope bone scans in 16 patients all remained "hot" at mean 6.1 years (range 2.1-11.5). Relative risk of failure in patients < 65 years was 2.9 (1.2-7.0 95% CI) and when BMI > 30 was 2.9 (1.2-6.9 95% CI). In those with intact UKAs at 10 years, mean Oxford Knee Score was 34.8 +/- 10.7, Forgotten Joint Score was 37.9 +/- 26.7 and 96% were satisfied with their knee. CONCLUSION: The high rate of early failure between 2 and 5 years in this all-polyethylene tibial component UKA did not persist in the long term. Though medial proximal tibial metabolic changes appear to persist they are not necessarily symptomatic. BMI > 30 and age < 65 years were significant risk factors for revision. PMID- 29476322 TI - Radiotherapy in soft-tissue sarcoma of the extremities. AB - Sarcomas are an infrequent and heterogeneous group of neoplasia. Surgery with or without associated radiotherapy (RT) is the basic treatment for this type of tumour. To increase the therapeutic ratio (the index between cytotoxic effects in tumours and normal tissue complications with a certain dose of radiation), new advances are being investigated to increase local and distant control and to decrease the morbidity of the treatment. The aim of this review was to analyse the different strategies, based on technology and biology, which are being investigated to increase the therapeutic ratio of this disease. PMID- 29476324 TI - Prostatectomies for localized prostate cancer: a mixed comparison network and cumulative meta-analysis. AB - No consensus has been attained regarding the utility of open retropubic radical prostatectomy (RRP), laparoscopic radical prostatectomy (LRP) and robot-assisted laparoscopic radical prostatectomy (RALRP) for localized prostate cancer (PCa). We carried out a network meta-analysis and cumulative meta-analysis comparing RRP, LRP and RALRP on peri-operative and functional outcome measures. Electronic databases were searched for either randomized clinical trials or cohort studies comparing RALRP either with LRP or RRP in patients with localized PCa. Outcome measures were as follows: overall, pT2 and pT3-positive surgical margins (PSMs); biochemical recurrence (BCR); complication rates; estimated blood loss; blood transfusion rate; continence and potency rates; duration of catheterization and hospital stay. Publication bias, risk of bias and inconsistency were assessed. Inverse heterogeneity model was used for analysis. A total of 45 studies were included for the final analysis. We observed that RALRP and LRP did not differ significantly from RRP with regard to the following outcomes: overall PSM; pT2 and pT3 PSMs; OT; complication rate; continence and potency rates; total blood loss and hospital stay. Duration of catheterization was significantly shorter in RALRP than LRP and RRP while significant reductions in the need for blood transfusion and BCR were observed for both RALRP and LRP in comparison with RRP. To conclude, similar functional, operative and oncologic outcomes were observed for both RALRP and LRP compared to RRP. PMID- 29476325 TI - The cost-effectiveness of hypertonic saline inhalations for infant bronchiolitis: a decision analysis. AB - BACKGROUND: This study evaluated the cost-effectiveness of hypertonic saline (HS) inhalations for infant bronchiolitis, compared to normal saline inhalations or standard treatment without inhalations as controls. METHODS: The decision tree in the decision analysis was used to calculate the expected costs. Actual cost data were obtained from our retrospective case-control study on bronchiolitis treatment. The effectiveness of treatment, based on the hospitalization rate of those admitted to the emergency department and the length of stay (LOS) of those who were hospitalized, was collected from previous studies. For the effectiveness estimations, we made a meta-analysis summarizing the results of the meta-analysis of the Cochrane review in 2013 and the results of 10 studies published after it. RESULTS: The mean hospitalization rate was 24.7% in the HS inhalation group and 32.6% in the control group [risk ratio: 0.80, 95% confidence interval (CI) 0.67 0.96] and the mean LOS was 3.736 (HS group) and 4.292 (controls) days (mean difference: - 0.55 days, 95% CI - 0.96 to - 0.15), respectively. The expected costs per patient, when both inpatients and outpatients were included, were ?816 ($1111) in the HS inhalation group and ?962 ($1310) in the control group. The expected costs per hospitalization, when only inpatients were included, were ?2600 ($3540) in the HS inhalation group and ?2890 ($3935) in the control group. CONCLUSIONS: HS inhalations slightly reduced the expected hospitalization costs of infant bronchiolitis. However, the low effectiveness, rather than the cost, is the factor that will limit the use of HS inhalations in infant bronchiolitis. PMID- 29476326 TI - Multiple Avenues of Modulating the Nitric Oxide Pathway in Heart Failure Clinical Trials. AB - PURPOSE OF REVIEW: This review discusses the integral role of the nitric oxide (NO) pathway in the pathophysiology of heart failure (HF). We emphasize potential therapeutic targets in the NO pathway and review contemporary clinical trials evaluating these novel therapeutic options. RECENT FINDINGS: Nitrates, neprilysin inhibitors, and phosphodiesterase (PDE) inhibitors have all proven to be efficacious in HF patients with systolic dysfunction, with the former two classes of medications producing a net mortality benefit. However, neither PDE inhibitors nor nitrates have demonstrated significant clinical benefit in patients with HF with preserved ejection fraction (HFpEF), and neprilysin inhibitors have yet to be evaluated in this population. Soluble guanylate cyclase (sGC) stimulators have shown significant promise in all HF patients, leading to improvements in both quality of life scores and exercise capacity. Conversely, sGC activators have limited clinical utility in HF, owing largely to safety concerns of hypotension. Inorganic nitrates and nitrites, meanwhile, may be emerging as potential therapies for the HFpEF population. The advent of novel therapies targeting the NO pathway is beginning to create a paradigm shift in the treatment of the HF patient. These therapies offer a promising outlook for the future, with hopes of reducing HF-associated morbidity and mortality. PMID- 29476327 TI - Improved oil quality in transgenic soybean seeds by RNAi-mediated knockdown of GmFAD2-1B. AB - Soybean oil contains approximately 20% oleic acid and 63% polyunsaturated fatty acids, which limits its uses in food products and industrial applications because of its poor oxidative stability. Increasing the oleic acid content in soybean seeds provides improved oxidative stability and is also beneficial to human health. Endoplasmic reticulum-associated delta-12 fatty acid desaturase 2 (FAD2) is the key enzyme responsible for converting oleic acid (18:1) precursors to linoleic acid (18:2) in the lipid biosynthetic pathway. In this study, a 390-bp conserved sequence of GmFAD2-1B was used to trigger a fragment of RNAi-mediated gene knockdown, and a seed-specific promoter of the beta-conglycinin alpha subunit gene was employed to downregulate the expression of this gene in soybean seeds to increase the oleic acid content. PCR and Southern blot analysis showed that the T-DNA had inserted into the soybean genome and was stably inherited by the progeny. In addition, the expression analysis indicated that GmFAD2-1B was significantly downregulated in the seeds by RNAi-mediated post-transcription gene knockdown driven by the seed-specific promoter. The oleic acid content significantly increased from 20 to ~ 80% in the transgenic seeds, and the linoleic and linolenic acid content decreased concomitantly in the transgenic lines compared with that in the wild types. The fatty acid profiles also exhibited steady changes in three consecutive generations. However, the total protein and oil contents and agronomic traits of the transgenic lines did not show a significant difference compared with the wild types. PMID- 29476328 TI - Resonance assignments of an alpha-synuclein fibril prepared in Tris buffer at moderate ionic strength. AB - Fibrils of the protein alpha-synuclein (alpha-syn) are implicated in the pathogenesis of Parkinson's disease and related neurodegenerative disorders. We have reported a high-resolution structure (PDB 2N0A) of an alpha-syn fibril form prepared by in vitro incubation of monomeric protein in 50 mM sodium phosphate buffer pH 7.4 with 0.1 mM EDTA and 0.01% sodium azide. In parallel with this structure determination, ongoing studies of small molecule ligands binding to alpha-syn fibrils, prepared in 2-amino-2-(hydroxymethyl)-1,3-propanediol (Tris) buffer, have been in progress, and it is therefore of interest to determine the structural similarity of these forms. Here we report the 13C and 15N resonance assignments for alpha-syn fibrils prepared with Tris-HCl buffer (pH 7.7 at 37 degrees C) and 100 mM NaCl. These fibrillization conditions yield a form with fibril core chemical shifts highly similar to those we reported (BMRB 16939) in the course of determining the high-resolution 2N0A structure, with the exception of some small perturbations from T44 to V55, including two sets of peaks observed for residues T44-V48. Additional differences occur in the patterns of observed residues in the primarily unstructured N-terminus. These results demonstrate a common fold of the fibril core for alpha-syn fibrils prepared in phosphate or Tris-HCl buffer at moderate ionic strength. PMID- 29476329 TI - Detecting crucial dispersal pathways using a virtual ecology approach: A case study of the mirid bug Stenotus rubrovittatus. AB - Detecting dispersal pathways is important both for understanding species range expansion and for managing nuisance species. However, direct detection is difficult. Here, we propose detecting these crucial pathways using a virtual ecology approach, simulating species dynamics using models, and virtual observations. As a case study, we developed a dispersal model based on cellular automata for the pest insect Stenotus rubrovittatus and simulated its expansion. We tested models for species expansion based on four landscape parameters as candidate pathways; these are river density, road density, area of paddy fields, and area of abandoned farmland, and validated their accuracy. We found that both road density and abandoned area models had prediction accuracy. The simulation requires simple data only to have predictive power, allowing for fast modeling and swift establishment of management plans. PMID- 29476330 TI - Nalmefene Phase IV Study: A Seeding Flying in the Face of Evidence? PMID- 29476331 TI - How to inhibit a distractor location? Statistical learning versus active, top down suppression. AB - Recently, Wang and Theeuwes (Journal of Experimental Psychology: Human Perception and Performance, 44(1), 13-17, 2018a) demonstrated the role of lingering selection biases in an additional singleton search task in which the distractor singleton appeared much more often in one location than in all other locations. For this location, there was less capture and selection efficiency was reduced. It was argued that statistical learning induces plasticity within the spatial priority map such that particular locations that are high likely to contain a distractor are suppressed relative to all other locations. The current study replicated these findings regarding statistical learning (Experiment 1) and investigated whether similar effects can be obtained by cueing the distractor location in a top-down way on a trial-by-trial basis. The results show that top down cueing of the distractor location with long (1,500 ms; Experiment 2) and short stimulus-onset symmetries (SOAs) (600 ms; Experiment 3) does not result in suppression: The amount of capture nor the efficiency of selection was affected by the cue. If anything, we found an attentional benefit (instead of the suppression) for the short SOA. We argue that through statistical learning, weights within the attentional priority map are changed such that one location containing a salient distractor is suppressed relative to all other locations. Our cueing experiments show that this effect cannot be accomplished by active, top-down suppression. Consequences for recent theories of distractor suppression are discussed. PMID- 29476332 TI - Motion and position shifts induced by the double-drift stimulus are unaffected by attentional load. AB - The double-drift stimulus produces a strong shift in apparent motion direction that generates large errors of perceived position. In this study, we tested the effect of attentional load on the perceptual estimates of motion direction and position for double-drift stimuli. In each trial, four objects appeared, one in each quadrant of a large screen, and they moved upward or downward on an angled trajectory. The target object whose direction or position was to be judged was either cued with a small arrow prior to object motion (low attentional load condition) or cued after the objects stopped moving and disappeared (high attentional load condition). In Experiment 1, these objects appeared 10 degrees from the central fixation, and participants reported the perceived direction of the target's trajectory after the stimulus disappeared by adjusting the direction of an arrow at the center of the response screen. In Experiment 2, the four double-drift objects could appear between 6 degrees and 14 degrees from the central fixation, and participants reported the location of the target object after its disappearance by moving the position of a small circle on the response screen. The errors in direction and position judgments showed little effect of the attentional manipulation-similar errors were seen in both experiments whether or not the participant knew which double-drift object would be tested. This suggests that orienting endogenous attention (i.e., by only attending to one object in the precued trials) does not interact with the strength of the motion or position shifts for the double-drift stimulus. PMID- 29476333 TI - Ethical Considerations for the Participation of Children of Minor Parents in Clinical Trials. AB - Children of minor parents are under-represented in clinical trials. This is largely because of the ethical, legal, and regulatory complexities in the enrolment, consent, and appropriate access of children of minor parents to clinical research. Using a case-based approach, we examine appropriate access of children of minor parents in an international vaccine trial. We first consider the scientific justification for inclusion of children of minor parents in a vaccine trial. Laws and regulations governing consent generally do not address the issue of minor parents. In their absence, local community and cultural contexts may influence consent processes. Rights of the minor parent include dignity in their role as a parent and respect for their decision-making capacity in that role. Rights of the child include the right to have decisions made in their best interest and the right to the highest attainable standard of health. Children of minor parents may have vulnerabilities related to the age of their parent, such as increased rates of poverty, that have implications for consent. Neuroscience research suggests that, by age 12-14 years, minors have adult-level capacity to make research decisions in situations with low emotion and low distraction. We conclude with a set of recommendations based on these findings to facilitate appropriate access and equity related to the participation of children of minor parents in clinical research. PMID- 29476334 TI - Oral health in Alzheimer's disease: a multicenter case-control study. AB - OBJECTIVES: The aim of this case-control study was to carry out an oral health assessment on a group of Alzheimer's patients and to establish a hypothesis regarding the implication of the characteristics of the disease and the treatment of oral health. MATERIALS AND METHODS: A total of 70 Alzheimer's patients, residents at the Alzheimer Center Reina Sofia Foundation (Madrid, Spain) and at the Alzheimer State Reference Center (Salamanca, Spain), and 36 controls (companions/acquaintances), were studied by oral examination and saliva sampling. The oral health indices DMFT/DMFS, CPI, the prosthetic condition, oral hygiene, saliva volume, and pH, as well as the specific microbiological parameters governing the risk of developing caries were assessed. RESULTS: Alzheimer's patients exhibited, as compared to the control group, (1) fewer teeth (10.9 +/- 10.5 vs 23.7 +/- 6.5), (2) fewer obturations (2.2 +/- 3.4 vs 6.6 +/- 5.6), (3) fewer periodontally healthy sextants (0.1 +/- 0.4 vs 1.4 +/- 2.2), (4) worse oral hygiene (43.1 vs 72.2% brushed), (5) greater use of removable prostheses (47.8 vs 8.4%), (6) higher incidence of candida infection (11.8 vs 0.0%) and cheilitis (15.9 vs 0.0%), (7) lower salivary flow (0.6 +/- 0.6 vs 1.1 +/- 0.6), and (8) lower buffering capacity (46 vs 80%). CONCLUSIONS: After taking into account the influence of age, Alzheimer's patients had worse oral health (caries and periodontal disease), more mucosal lesions (cheilitis and candidiasis), and worse saliva quantity and quality. CLINICAL RELEVANCE: Clinicians should be aware of the implications of Alzheimer's disease in oral health, in order to stablish the effective preventive measures and the optimal treatment plan. PMID- 29476336 TI - Neuroanatomical and Neurochemical Bases of Vigilance States. AB - In the present chapter, hypotheses on the mechanisms responsible for the genesis of the three vigilance states, namely, waking, non-rapid eye movement (non-REM) also called slow-wave sleep (SWS), and REM sleep also called paradoxical sleep (PS), are presented. A huge number of studies first indicate that waking is induced by the activation of multiple waking systems, including the serotonergic, noradrenergic, cholinergic, and hypocretin systems. At the onset of sleep, the SWS-active neurons would be activated by the circadian clock localized in the suprachiasmatic nucleus and a hypnogenic factor, adenosine, which progressively accumulates in the brain during waking. A number of studies support the hypothesis that SWS results from the activation of GABAergic neurons localized in the ventrolateral preoptic nucleus (VLPO). However, new GABAergic systems recently described localized in the parafacial, accumbens, and reticular thalamic nuclei will be also presented. In addition, we will show that a large body of data strongly suggests that the switch from SWS to PS is due to the interaction of multiple populations of glutamatergic and GABAergic neurons localized in the posterior hypothalamus and the brainstem. PMID- 29476335 TI - Transmission patterns of Streptococcus mutans demonstrated by a combined rep-PCR and MLST approach. AB - OBJECTIVE: Clinical typing methods of the oral pathogen Streptococcus mutans with molecular analysis can be very specific, but expensive. Repetitive extragenic palindromic PCR (rep-PCR) is a relatively inexpensive pre-screening alternative for isolate selection for additional analyses. This study evaluated the prediction accuracy of using rep-PCR to identify S. mutans multilocus sequence typing (MLST) sequence types (ST) among children and their family members. Potential S. mutans strain sources were evaluated for evidence of transmission. MATERIAL AND METHODS: Ten dendrograms (rep-PCR), with 20 isolates each of the 10 most common S. mutans genotypes, were generated from different subjects. Using a cut-off of 98% similarity, 7-11 isolates of each genotype were selected for MLST analysis to determine ST match/no-match. RESULTS: Overall, rep-PCR was 75% effective at determining MLST ST match/no-match and 90% effective when applied to related individuals. Most genotypes were further differentiated by MLST. MLST ST diversity was greatest for one genotype (genotype 12, G12) and evidence of transmission among children and their family members was identified by rep-PCR and MLST. Younger children (6 months to 4 years old) shared ST with their mothers but 50% of older children (5-9 years old) had ST not identified in their mother. Six ST were shared between different families and probable source members were identified. CONCLUSION: This study confirms that rep-PCR offers an affordable option to predict diverse isolates for downstream applications. CLINICAL RELEVANCE: Using a combined rep-PCR and MLST approach, it is possible to track probable transmission and strain sources for S. mutans genotypes. PMID- 29476337 TI - Toxicokinetics of NPS: Update 2017. AB - This summarizing and descriptive review article is an update on previously published reviews. It covers English-written and PubMed-listed review articles and original studies published between May 2016 and November 2017 on the toxicokinetics of new psychoactive substances (NPS). Compounds covered include stimulants and entactogens, synthetic cannabinoids, tryptamines, phenethylamine and phencyclidine-like drugs, benzodiazepines, and opioids. First, an overview and discussion is provided on selected review articles followed by an overview and discussion on selected original studies. Both sections are then concluded by an opinion on these latest developments. The present review shows that the NPS market is still highly dynamic and that studies regarding their toxicokinetics are necessary to understand risks associated with their consumption. Data collection and studies are encouraged to allow for detection of NPS in biological matrices in cases of acute intoxications or chronic consumption. Although some data are available, scientific papers dealing with the mechanistic reasons behind acute and chronic toxicity are still lacking. PMID- 29476340 TI - Correction to: A new microsporidium Fibrillaspora daphniae g. n. sp. n. infecting Daphnia magna (Crustacea: Cladocera) in Siberia and its taxonomic placing within a new family Fibrillasporidae and new superfamily Tubulinosematoidea (Opisthosporidia: Microsporidia). AB - Ultrastructure of Fibrillaspora is highly similar to that of Berwaldia but the former is phylogenetically distant from the taxon annotated as Berwaldia schaefernai (Genbank accession # AY090042). It was shown recently, however, that the latter sequence was not derived from Berwaldia, and correct nucleotide sequence data were provided for Berwaldia. This allowed recondideration of Fibrillaspora as a junior synonym of Berwaldia and redefinition of Fibrillaspora daphniae as a new combination, Berwaldia daphniae comb. nov. PMID- 29476338 TI - Human cystic echinococcosis in Turkey: a preliminary study on DNA polymorphisms of hydatid cysts removed from confirmed patients. AB - Cystic echinococcosis caused by the larval stages of Echinococcus granulosus sensu lato s.l is endemic in Turkey with a high public health impact particularly in rural areas. The aim of this study was to investigate the genetic variation and population structure of E. granulosus s.s using metacestode isolates removed from surgically confirmed patients originating from several regions in Turkey and to investigate the occurrence of autochthonous transmission. Using DNA extracted from a total of 46 human-derived CE isolates, we successfully analysed an 827-bp fragment within the cox1 mitochondrial gene and confirmed the causative agent of human cystic echinococcosis in patients included in this study to be Echinococcus granulosus s.s (G1 and G3 genotypes). The haplotype parsimony network consisted of 28 haplotypes arranged within three main clusters and the neutrality indices were both negative and significant indicating negative selection or population expansion. The assessment carried out in this study using GenBank nucleotide sequence data from Turkey for sheep and cattle hosts demonstrated the importance of autochthonous transmission with sheep, cattle and humans harbouring the same haplotypes. Further studies are required to investigate the biological significance, if any, of E. granulosus s.s haplotypes and the genetic variability of CE from human patients using longer nucleotide sequences and a larger sample set. PMID- 29476339 TI - Role of glutathione, ROS, and Bcl-xL in the inhibition of apoptosis of monocyte derived dendritic cells by Leishmania mexicana promastigotes. AB - Dendritic cells (DCs) are one of the principal host cells of the obligate intracellular parasite Leishmania that can survive and reproduce within cells due to the ability to regulate different cellular events, including apoptosis. Inhibition of host cell apoptosis is a strategy employed by multiple pathogens to ensure their survival in the infected cell. We have previously reported that Leishmania mexicana promastigotes and amastigotes inhibit camptothecin-induced apoptosis of monocyte-derived dendritic cells (moDCs) through the downregulation of p38 and JNK phosphorylation. The upregulation of glutathione (GSH), the most important regulator of reactive oxygen species (ROS) concentration, has proven to protect cells from apoptosis through the inhibition of JNK1. Another mechanism employed by cells for the protection of apoptosis is the expression of anti apoptotic proteins of the Bcl-2 family. The aim of this study was to determine if GSH, ROS, and Bcl-xL participate in the inhibition of camptothecin-induced apoptosis of moDC by L. mexicana promastigotes. GSH quantification assays showed that camptothecin and BSO (an inhibitor of glutathione synthesis) strongly decreased intracellular GSH concentration in moDC, while infection with L. mexicana promastigotes had no effect in the level of GSH. On the other hand, infection with L. mexicana promastigotes of BSO- and camptothecin-treated moDC diminished the concentration of ROS and induced the expression of the anti apoptotic protein Bcl-xL. Our findings suggest that inhibition of camptothecin induced apoptosis of moDC by L. mexicana promastigotes is preferentially regulated by the expression of anti-apoptotic proteins of the Bcl-2 family rather than by the redox status of the cell. PMID- 29476341 TI - The effect of the SNP g.18475 A>G in the 3'UTR of NCF4 on mastitis susceptibility in dairy cattle. AB - Neutrophil cytosolic factor 4 (NCF4) is a member of the nicotinamide adenine dinucleotide phosphate oxidase subunit. This protein functions as an essential factor in the host defense against the progression of bacterial infection. To explore the variability of the NCF4 gene and the susceptibility of cows to mastitis, NCF4 functional single nucleotide polymorphism (SNP) of the 3' untranslated region (3'UTR) and its targeted microRNA (miRNA) were identified. One SNP g.18475 A>G in the 3'UTR of NCF4 was found within the binding seed region of bta-miR-2426. We constructed two recombinant pMIR-REPORTTM vectors with the A or G allele in the g.18475 locus and transiently co-transfected the vectors in human embryo kidney 293T (HEK 293T) cells, along with bta-miR-2426 mimics. A luciferase assay indicated that this SNP affects the binding of NCF4 and bta-miR 2426. In addition, the association analysis results showed that cows with the GG genotype in SNP g.18475 A>G had a relatively lower SCS value than cows with the AA genotype. Finally, quantitative real-time PCR (RT-qPCR) results showed that the cows with genotype GG had a relatively higher expression of NCF4 mRNA compared to the cows with genotype AA. NCF4 expression was regulated by the miRNA mRNA interaction mechanism, and an important role for NCF4 in mastitis susceptibility in dairy cow was suggested. PMID- 29476342 TI - Structural and functional aspects of the interaction partners of the small heat shock protein in Synechocystis. AB - The canonical function of small heat-shock proteins (sHSPs) is to interact with proteins destabilized under conditions of cellular stress. While the breadth of interactions made by many sHSPs is well-known, there is currently little knowledge about what structural features of the interactors form the basis for their recognition. Here, we have identified 83 in vivo interactors of the sole sHSP in the cyanobacterium Synechocystis sp. PCC 6803, HSP16.6, reflective of stable associations with soluble proteins made under heat-shock conditions. By performing bioinformatic analyses on these interactors, we identify primary and secondary structural elements that are enriched relative to expectations from the cyanobacterial genome. In addition, by examining the Synechocystis interactors and comparing them with those identified to bind sHSPs in other prokaryotes, we show that sHSPs associate with specific proteins and biological processes. Our data are therefore consistent with a picture of sHSPs being broadly specific molecular chaperones that act to protect multiple cellular pathways. PMID- 29476343 TI - Plant Growth-Promoting Genes can Switch to be Virulence Factors via Horizontal Gene Transfer. AB - There are increasing evidences that horizontal gene transfer (HGT) is a critical mechanism of bacterial evolution, while its complete impact remains unclear. A main constraint of HGT effects on microbial evolution seems to be the conservation of the function of the horizontally transferred genes. From this perspective, inflexible nomenclature and functionality criteria have been established for some mobile genetic elements such as pathogenic and symbiotic islands. Adhesion is a universal prerequisite for both beneficial and pathogenic plant-microbe interactions, and thus, adhesion systems (e.g., the Lap cluster) are candidates to have a dual function depending on the genomic background. In this study, we showed that the virulent factor Lap of the phytopathogen Erwinia carotovora SCRI1043, which is located within a genomic island, was acquired by HGT and probably derived from Pseudomonas. The transformation of the phytopathogen Erwinia pyrifoliae Ep1/96 with the beneficial factor Lap from the plant growth-promoting bacterium Pseudomonas fluorescens Pf-5 significantly increased its natural virulence, experimentally recapitulating the beneficial-to virulence functional switch of the Lap cluster via HGT. To our knowledge, this is the first report of a functional switch of an individual gene or a cluster of genes mediated by HGT. PMID- 29476344 TI - Detecting Symbioses in Complex Communities: the Fungal Symbionts of Bark and Ambrosia Beetles Within Asian Pines. AB - Separating symbioses from incidental associations is a major obstacle in symbiosis research. In this survey of fungi associated with Asian bark and ambrosia beetles, we used quantitative culture and DNA barcode identification to characterize fungal communities associated with co-infesting beetle species in pines (Pinus) of China and Vietnam. To quantitatively discern likely symbioses from coincidental associations, we used multivariate analysis and multilevel pattern analysis (a type of indicator species analysis). Nearly half of the variation in fungal community composition in beetle galleries and on beetle bodies was explained by beetle species. We inferred a spectrum of ecological strategies among beetle-associated fungi: from generalist multispecies associates to highly specialized single-host symbionts that were consistently dominant within the mycangia of their hosts. Statistically significant fungal associates of ambrosia beetles were typically only found with one beetle species. In contrast, bark beetle-associated fungi were often associated with multiple beetle species. Ambrosia beetles and their galleries were frequently colonized by low prevalence ambrosia fungi, suggesting that facultative ambrosial associations are commonplace, and ecological mechanisms such as specialization and competition may be important in these dynamic associations. The approach used here could effectively delimit symbiotic interactions in any system where symbioses are obscured by frequent incidental associations. It has multiple advantages including (1) powerful statistical tests for non-random associations among potential symbionts, (2) simultaneous evaluation of multiple co-occurring host and symbiont associations, and (3) identifying symbionts that are significantly associated with multiple host species. PMID- 29476345 TI - The diagnostic accuracy of presepsin in neonatal sepsis: a meta-analysis. AB - : There is growing evidence that presepsin is a promising biomarker in the diagnosis of sepsis in adults. The objective of our study is to investigate current evidence related to the diagnostic accuracy of presepsin in neonatal sepsis. To accomplish this, we searched the Medline (1966-2017), Scopus (2004 2017), Clinicaltrials.gov (2008-2017), EMBASE (1980-2017), Cochrane Central Register of Controlled Trials CENTRAL (1999-2017), and Google Scholar (2004-2017) databases. Eleven studies were included in the present meta-analysis, with a total number of 783 neonates. The pooled sensitivity of serum presepsin for the prediction of neonatal sepsis was 0.91 (95% CI [0.87-0.93]) and the pooled specificity was 0.91 (95% CI [0.88-0.94]). The diagnostic odds ratio was 170.28 (95% CI [51.13-567.11]) and the area under the curve (AUC) was 0.9751 (SE 0.0117). Head-to-head comparison with AUC values of C-reactive protein (0.9748 vs. 0.8580) and procalcitonin (0.9596 vs. 0.7831) revealed that presepsin was more sensitive in detecting neonatal sepsis. CONCLUSION: Current evidence support the use of presepsin in the early neonatal period in high-risk populations as its diagnostic accuracy seems to be high in detecting neonatal sepsis. What is known: * Neonatal sepsis is a leading cause of morbidity and mortality. * Current laboratory tests cannot accurately discriminate endangered neonates. What is new: * The diagnostic odds ratio of presepsin is 170.28 and the area under the curve is 0.9751. * According to our meta-analysis, presepsin is a useful protein that may help clinicians identify neonates at risk. PMID- 29476347 TI - Liver function correlates with liver-to-portal vein contrast ratio during the hepatobiliary phase with Gd-EOB-DTPA-enhanced MR at 3 Tesla. AB - PURPOSES: To determine if liver-to-portal vein contrast ratio (LPC) correlates with liver function in patients with hepatitis B virus (HBV)-related cirrhosis on gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid (Gd-EOB-DTPA) enhanced MR imaging. METHODS: A total of 92 patients with normal (n = 20) or HBV related cirrhotic livers graded by Child-Pugh class A (n = 50), B (n = 17) or C (n = 5) who underwent Gd-EOB-DTPA-enhanced 3Tesla MR imaging were retrospectively reviewed. LPC was defined as the signal intensity ratio of liver parenchyma to portal vein on hepatobiliary phase (HBP) acquired at 20 min, and it was compared between normal and cirrhotic livers. The correlation between LPC and hepatic function parameters at HBP after injection was quantitatively analyzed as well. RESULTS: LPC differed between normal and cirrhotic livers significantly (P < 0.001). LPC constantly and significantly decreased from normal to cirrhotic livers with Child-Pugh class C at HBP imaging (P < 0.001). Multiple regression analysis revealed that total bilirubin (P = 0.011), albumin (P < 0.001), and platelet count (P = 0.007) were independent predictors of LPC at HBP imaging. A receiver operating characteristic (ROC) curve analysis revealed that the optimal cutoff value for LPC to distinguish normal group from cirrhotic groups was 2.05 (AUC 0.98) with a sensitivity of 84.1% and a specificity of 100%. CONCLUSION: The level of LPC on Gd-EOB-DTPA MR imaging can efficaciously indicate the severity of liver function in patients with HBV-related cirrhosis and was correlated with liver function parameters significantly. It might be used as an alternative imaging biomarker for assessing liver function. PMID- 29476348 TI - Ertugliflozin: First Global Approval. AB - Ertugliflozin (SteglatroTM) is an orally active sodium glucose co-transporter type 2 inhibitor being developed by Merck and Pfizer as a treatment for type 2 diabetes mellitus (T2DM). Ertugliflozin as monotherapy and in combination with various other antidiabetic drugs was associated with improvements in glycaemic control and secondary outcome measures in the VERTIS phase III clinical trial program. Ertugliflozin and fixed-dose combinations of ertugliflozin and metformin (SeglurometTM) and ertugliflozin and sitagliptin (SteglujanTM) have recently been approved by the US FDA as an adjunct to diet and exercise to improve glycaemic control in adults with T2DM. These products have also received a positive opinion from the EU Committee for Medicinal Products for Human Use (CHMP). This article summarizes the milestones in the development of ertugliflozin leading to its first approval for T2DM. PMID- 29476349 TI - Therapeutic Drug Monitoring of Beta-Lactams and Other Antibiotics in the Intensive Care Unit: Which Agents, Which Patients and Which Infections? AB - Antibiotics are among the medications most frequently administered to the critically ill, a population with high levels of intra- and inter-individual pharmacokinetic variability. Our knowledge of the relationships among antibiotic dosing, exposure and clinical effect in this population has increased in recent decades. Therapeutic drug monitoring (TDM) of serum antibiotic concentrations is the most practical means of assessing adequate antibiotic exposure, though until recently, it has been underutilised for this end. Now TDM is becoming more widespread, particularly for the beta-lactam antibiotics, a class historically thought to have a wide therapeutic range. We review the basic requirements, indications, and targets for effective TDM of the glycopeptides, aminoglycosides, quinolones and beta-lactam antibiotics in the adult intensive-care setting, with a special focus on TDM of the beta-lactam antibiotics, the most widely used antibiotic class. PMID- 29476350 TI - Genetic polymorphism of rs9277535 in HLA-DP associated with rheumatoid arthritis and anti-CCP production in a Chinese population. AB - HLA-II molecules are critical in triggering human immune response, especially in activating CD4+ T cells. HLA-DP, belonging to HLA-II molecules, draws increasing attention for its role in presentation of viral antigen and autoantigen to T cells. Researches reported single nucleotide polymorphism (SNP) of HLA-DP associated with HBV infection and autoimmune diseases such as SLE. However, little is known about the relationship between HLA-DP and rheumatoid arthritis (RA). Rs9277535 is located in 3' UTR region of HLA-DPB1, a subunit of HLA-DP, and was reported to affect HLA-DP mRNA expression. In the present study, we explored the relationship between gene polymorphism of rs9277535 in HLA-DPB1 and RA susceptibility and progression. Samples from 254 patients with RA and 391 age- and sex-matched healthy controls were collected and genotyped by a polymerase chain reaction-high-resolution melting (PCR-HRM) assay. Serological tests (anti CCP, rheumatoid factor, C-reactive protein, anti-keratin antibody) were detected by laboratory assays. Strong association was observed between SNP rs9277535 in HLA-DP and RA susceptibility (allele frequency distribution: OR = 1.409, 95%CI = 1.121-1.773, P = 0.004). Further validation was provided by disease model analysis (recessive model: OR = 1.889, 95%CI = 1.194-2.990, P = 0.008; dominant model: OR = 1.464, 95%CI = 1.050-2.041, P = 0.025; additive model: OR = 2.208, 95%CI = 1.335-3.652, P = 0.003). Allele A was correlated to increased risk of RA. Serological test results demonstrated patients carrying allele A of rs9277535 had elevated serum anti-CCP antibody level. The present study provided evidence that HLA-DP gene polymorphism associated with RA susceptibility. Allele A of rs9277535 in HLA-DP correlated to increased risk of RA and elevated serum anti-CCP level. PMID- 29476351 TI - Can nailfold videocapillaroscopy images be interpreted reliably by different observers? Results of an inter-reader and intra-reader exercise among rheumatologists with different experience in this field. AB - : Nailfold videocapillaroscopy (VCP) allows non-invasive assessment of the microcirculation. Adequate training in this field is relevant for rheumatologists. There is increasing evidence of the reliability of VCP findings among different readers. OBJECTIVE: To evaluate inter- and intra-reader agreement of rheumatologists to identify normal images and systemic sclerosis (SSc) patterns on VCP ("early," "active," and "late" proposed by Cutolo et al.). Thirteen rheumatologists with different experience in nailfold VCP received training to standardize reading criteria. They rated 60 VCP images from healthy and SSc patients at baseline and 4 weeks later, using an electronic platform. The reading of an expert was considered the gold standard. Data were analyzed using Cohen's kappa for concordance and Student's t test and ANOVA to compare kappa means for inter-reader, intra-reader, and inter-pattern readings. Mean inter reader and intra-reader kappa were 0.45 and 0.49, respectively, (moderate agreement). Kappa scores were higher among experienced vs inexperienced readers (inter-reader kappa 0.58 vs 0.34, p = 0.001, intra-reader kappa 0.65 vs 0.37, p = 0.01). Agreement was substantial (kappa = 0.61) for the identification of normal vs abnormal images and higher for the identification of active (0.48, p = 0.009) and late SSc patterns (0.56, p = 0.008) than for the early SSc pattern (0.35, p = 0.003). There is moderate agreement among rheumatologists for the identification of SSc videocapillaroscopy patterns (higher among experienced rheumatologists) and substantial agreement, regardless of previous experience in VCP, in the identification of normal and abnormal images. Agreement for the identification of active and late patterns is higher than for the early pattern. PMID- 29476352 TI - Psoriatic arthritis: tissue-directed inflammation? AB - The clinical picture of psoriatic arthritis (PsA) is heterogeneous, potentially involving numerous organs and tissues, such as skin and joint. From a clinical point of view, discrete tissue PsA features develop and respond to treatments apparently independently. The pathogenic events occurring in the various tissues are only partially understood. Although the vast majority of known genetic predisposing factors are shared between patients with skin psoriasis (PSO) and those affected by PsA, some tissue-specific variants have been identified. Furthermore, current data suggest that the TNF pathway and IL-23/Th17 pathways may be differentially activated in distinct tissue sites. In this review, we briefly describe current knowledge on the pathogenesis of PsA in terms of genetic predisposition, environmental factors and immunology, advancing our hypothesis to explain why a common immunologic process can express itself with significant differences in various tissues. PMID- 29476353 TI - High prevalence of occupational exposure to solvents or silica in male systemic sclerosis patients: a Belgian cohort analysis. AB - Increasing evidence supports a relation of some occupational exposures to systemic sclerosis pathogenesis. We aimed to evaluate occupational exposure and clinical characteristics in male patients with systemic sclerosis followed in two Belgian academic hospitals. One hundred and three male patients, included in the Belgian Systemic Sclerosis Cohort, were identified. An expert in occupational medicine reviewed the occupational history and allocated the patients to one of the following groups: probable exposure to crystalline silica, probable exposure to solvents, probable exposure to other toxins, or no suspected occupational exposure. Clinical characteristics were extracted from the Belgian Systemic Sclerosis Cohort database. Sufficient data were available for 96/103 patients. Most of these male patients (70/96, 72.9%) had a history of occupational exposure, 55 patients were likely exposed to crystalline silica, 11 patients to solvents, 2 patients to both silica and solvents, and 2 patients to asbestos. Only 26 patients had no suspected occupational exposure (27.1%). We noticed a significant difference in smoking status between exposed and non-exposed patients, with the highest percentage of ever smokers in the group with solvent exposure (p = 0.011). We found no significant differences in disease phenotype between exposed and non-exposed patients. However, we noted a trend to a higher prevalence of anti-Scl70 antibodies, cardiac dysfunction, and higher disease activity score in patients with occupational exposure. We observed a strikingly high prevalence of occupational exposure to both silica and solvents in male systemic sclerosis patients. Occupational exposure to silica or solvents is highly prevalent in male systemic sclerosis patients. PMID- 29476354 TI - Disparities in Female Pelvic Floor Disorders. AB - PURPOSE OF REVIEW: Pelvic floor disorders include urinary incontinence, pelvic organ prolapse, fecal incontinence, and other sensory and emptying abnormalities of the lower urinary and gastrointestinal tracts which are widely prevalent among women and largely undertreated. Many disparities exist among women with pelvic floor disorders which may affect prevalence estimates and treatment options offered. RECENT FINDINGS: Findings suggest that there are many disparities among women with pelvic floor disorders including age, race, inadequate knowledge, access to care, and socioeconomic status. Better understanding disparities among women with pelvic floor disorders can help to guide further programs for education, outreach, and treatment of women with pelvic floor disorders. PMID- 29476355 TI - Pain States, the Opioid Epidemic, and the Role of Radiologists. AB - PURPOSE OF REVIEW: The prevalence of chronic pain and prescription opioid abuse has resulted in epidemic problems for patients and clinicians. The consequences are taking a heavy toll on patients, physicians, and society. Specific to radiology, a significant need exists for best practice assessment and treatment approaches for pain management, as patients with chronic pain often undergo radiological tests of unclear clinical relevance. RECENT FINDINGS: The USA is amid an opioid-prescribing epidemic and resultant overdose public health emergency. A variety of reasons, which are examined in this manuscript, have contributed to the dramatic increase in the use of chronic opioid therapy for chronic non-cancer pain. This increase of opioid prescriptions and related deaths is based on many factors including the perception that there was systemic undertreatment of pain, the philosophical approach of advocacy groups for pain relief, promotion by the pharmaceutical industry, Joint Commission's Fifth Vital Sign, and permissive regulations by boards of medical licensures promoting excessive use of opioids. Overall, opioid treatment has been based on subjective pain relief and radiographic findings, which may not correlate with the source of pain generation. Radiologists, along with interventionalists, frequently interact with patients on chronic opioid therapy and at times take responsibility for patients with chronic pain. Beyond reading studies, diagnostic radiologists provide care to larger percentages of patients taking narcotics than ever before. This manuscript focuses on chronic pain, escalating opioid therapy, and adverse consequences, including the epidemic of overdoses and deaths. Radiologists' expertise can potentially reduce unnecessary radiological tests and inappropriate prescribing of medications. PMID- 29476356 TI - Coffee consumption and risk of rare cancers in Scandinavian countries. AB - Studies on the association between heavy coffee consumption and risk of less frequently diagnosed cancers are scarce. We aimed to quantify the association between filtered, boiled, and total coffee consumption and the risk of bladder, esophageal, kidney, pancreatic, and stomach cancers. We used data from the Norwegian Women and Cancer Study and the Northern Sweden Health and Disease Study. Information on coffee consumption was available for 193,439 participants. We used multivariable Cox proportional hazards models to calculate hazard ratios (HR) with 95% confidence intervals (CI) for the investigated cancer sites by category of total, filtered, and boiled coffee consumption. Heavy filtered coffee consumers (>= 4 cups/day) had a multivariable adjusted HR of 0.74 of being diagnosed with pancreatic cancer (95% CI 0.57-0.95) when compared with light filtered coffee consumers (<= 1 cup/day). We did not observe significant associations between total or boiled coffee consumption and any of the investigated cancer sites, neither in the entire study sample nor in analyses stratified by sex. We found an increased risk of bladder cancer among never smokers who were heavy filtered or total coffee consumers, and an increased risk of stomach cancer in never smokers who were heavy boiled coffee consumers. Our data suggest that increased filtered coffee consumption might reduce the risk of pancreatic cancer. We did not find evidence of an association between coffee consumption and the risk of esophageal or kidney cancer. The increased risk of bladder and stomach cancer was confined to never smokers. PMID- 29476357 TI - Allostatic load and subsequent all-cause mortality: which biological markers drive the relationship? Findings from a UK birth cohort. AB - The concept of allostatic load (AL) refers to the idea of a global physiological 'wear and tear' resulting from the adaptation to the environment through the stress response systems over the life span. The link between socioeconomic position (SEP) and mortality has now been established, and there is evidence that AL may capture the link between SEP and mortality. In order to quantitatively assess the role of AL on mortality, we use data from the 1958 British birth cohort including eleven year mortality in 8,113 adults. Specifically, we interrogate the hypothesis of a cumulative biological risk (allostatic load) reflecting 4 physiological systems potentially predicting future risk of death (N = 132). AL was defined using 14 biomarkers assayed in blood from a biosample collected at 44 years of age. Cox proportional hazard regression analysis revealed that higher allostatic load at 44 years old was a significant predictor of mortality 11 years later [HR = 3.56 (2.3 to 5.53)]. We found that this relationship was not solely related to early-life SEP, adverse childhood experiences and young adulthood health status, behaviours and SEP [HR = 2.57 (1.59 to 4.15)]. Regarding the ability of each physiological system and biomarkers to predict future death, our results suggest that the cumulative measure was advantageous compared to evaluating each physiological system sub score and biomarker separately. Our findings add some evidence of a biological embodiment in response to stress which ultimately affects mortality. PMID- 29476358 TI - The Opioid Crisis: a Comprehensive Overview. AB - PURPOSE OF REVIEW: The opioid crisis most likely is the most profound public health crisis our nation has faced. In 2015 alone, 52,000 people died of drug overdoses, with over 30,000 of those people dying from opioid drugs. A recent community forum led by the Cleveland Clinic contrasted this yearly death rate with the loss of 58,000 American lives in 4 years of the Vietnam War. The present review describes the origins of this opioid epidemic and provides context for our present circumstances. RECENT FINDINGS: Alarmingly, the overwhelming majority of opioid abusers begin their addiction with prescription medications, primarily for chronic pain. Chronic postoperative pain, which occurs in 10-50% of surgical patients, is a major concern in many types of surgery. Nationwide, the medical community has made it a priority to ensure that postsurgical analgesia is sufficient to control pain without increasing non-medically appropriate opioid use. The opioid epidemic remains a significant pressing issue and will not resolve easily. Numerous factors, including the inappropriate prescription of opioids, lack of understanding of the potential adverse effects of long-term therapy, opioid misuse, abuse, and dependence, have contributed to the current crisis. PMID- 29476359 TI - Type 1 diabetes mellitus induces structural changes and molecular remodelling in the rat kidney. AB - There is much evidence that diabetes mellitus (DM)-induced hyperglycemia (HG) is responsible for kidney failure or nephropathy leading to cardiovascular complications. Cellular and molecular mechanism(s) whereby DM can damage the kidney is still not fully understood. This study investigated the effect of streptozotocin (STZ)-induced diabetes (T1DM) on the structure and associated molecular alterations of the isolated rat left kidney following 2 and 4 months of the disorder compared to the respective age-matched controls. The results revealed hypertrophy and general disorganized architecture of the kidney characterized by expansion in glomerular borders, tubular atrophy and increased vacuolization of renal tubular epithelial cells in the diabetic groups compared to controls. Electron microscopic analysis revealed ultrastructural alterations in the left kidney highlighted by an increase in glomerular basement membrane width. In addition, increased caspase-3 immunoreactivity was observed in the kidney of T1DM animals compared to age-matched controls. These structural changes were associated with elevated extracellular matrix (ECM) deposition and consequently, altered gene expression profile of ECM key components, together with elevated levels of key mediators (MMP9, integrin 5alpha, TIMP4, CTGF, vimentin) and reduced expressions of Cx43 and MMP2 of the ECM. Marked hypertrophy of the kidney was highlighted by increased atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) gene expression. These changes also correlated with increased TGFbeta1 activity, gene expression in the left kidney and elevated active TGFbeta1 in the plasma of T1DM rats compared to control. The results clearly demonstrated that TIDM could elicit severe structural changes and alteration in biochemical markers (remodelling) in the kidney leading to diabetic nephropathy (DN). PMID- 29476360 TI - Systematic Review of Radiofrequency Ablation and Pulsed Radiofrequency for Management of Cervicogenic Headaches. AB - PURPOSE OF REVIEW: Cervicogenic headache (CHA) is a secondary headache which has a source in the upper cervical spine. Many traditional analgesic choices lack good efficacy in managing the associated pain. As a result, in management of CHA, radiofrequency ablation (RFA) or pulse radiofrequency (PRF) has been tried with success. Our study investigated the use of RFA and PRF for the management of CHA. RECENT FINDINGS: In the present investigation, a review of the literature was conducted using PubMed (1966 to February 2017). The quality assessment was determined using The Cochrane Risk of Bias. After initial search and consultation with experts, 34 articles were identified for initial review and 10 articles met inclusion for review. Criteria for inclusion were primarily based on identification of articles discussing cervicogenic headaches which were previously treatment resistant and occurred without any other pathology of the craniofacial region or inciting event such as trauma. This systematic review demonstrated that RFA and PRFA provide very limited benefit in the management of CHA. At present, there is no high-quality RCT and/or strong non-RCTs to support the use of these techniques, despite numerous case reports which have demonstrated benefit. This review is one of the first to provide a comprehensive overview of the use of RFA and PRF in the management of CHA. PMID- 29476361 TI - Combining Clinical and Molecular Data to Predict the Benefits of Carmustine Wafers in Newly Diagnosed High-Grade Gliomas. AB - PURPOSE OF REVIEW: The purpose of this study was to retrospectively evaluate the use of carmustine wafers (CWs) in the management of high-grade gliomas (HGGs). The data from our monoinstitutional series was compared with studies reported in the literature. Special emphasis was placed on the evaluation of side effects and the analysis of extent of resection and molecular profile as risk factors. RECENT FINDINGS: The implantation of CWs into the resection cavity during HGG treatment to deliver localized chemotherapy, followed by the Stupp protocol, remains debated in a clinical setting, largely due to the lack of appropriate phase III studies. Given the high expense and poorly characterized side effects associated with CW treatment, identification of patients most likely to benefit from this therapy could be clinically relevant. CWs may represent an effective and safe first-line treatment for patients with HGG that exhibit complete tumor resection and harboring a methylated MGMT promoter. Our investigation showed a much larger group of patients exhibiting long-term survival (> = 36 months), strongly supporting a potential survival benefit conferred via CW treatment. The pre surgical definition of the MGMT promoter status could be of clinical use in identifying "good responders" to CW implantation. PMID- 29476362 TI - Author Correction to: Adjuvant Trastuzumab Therapy for Early HER2-Positive Breast Cancer in Iran: A Cost-Effectiveness and Scenario Analysis for an Optimal Treatment Strategy. AB - ABSTARCT: Page 95, Table 2, final row, second column: the mean Advanced treatment annual cost which. PMID- 29476364 TI - Medical school education at the turning point? PMID- 29476363 TI - Comparing the UK EQ-5D-3L and English EQ-5D-5L Value Sets. AB - BACKGROUND: Three EQ-5D value sets (EQ-5D-3L, crosswalk, and EQ-5D-5L) are now available for cost-utility analysis in the UK and/or England. The value sets' characteristics differ, and it is important to assess the implications of these differences. OBJECTIVE: The aim of this paper is to compare the three value sets. METHODS: We carried out analysis comparing the predicted values from each value set, and investigated how differences in health on the descriptive system is reflected in the utility score by assessing the value of adjacent states. We also assessed differences in values using data from patients who completed both EQ-5D 3L and EQ-5D-5L. RESULTS: The distribution of the value sets systematically differed. EQ-5D-5L values were higher than EQ-5D-3L/crosswalk values. The overall range and difference between adjacent states was smaller. In the patient data, the EQ-5D-5L produced higher values across all conditions and there was some evidence that the value sets rank different health conditions in a similar severity order. CONCLUSIONS: There are important differences between the value sets. Due to the smaller range of EQ-5D-5L values, the possible change in quality adjusted life years (QALYs) might be reduced, but they will apply to both control and intervention groups, and will depend on whether the gain is in quality of life, survival, or both. The increased sensitivity of EQ-5D-5L may also favour QALY gains even if the changes in utility are smaller. Further work should assess the impact of the different value sets on cost effectiveness by repeating the analysis on clinical trial data. PMID- 29476365 TI - Challenges in early diagnosis of Kawasaki disease in the pediatric emergency department: differentiation from adenoviral and invasive pneumococcal disease. AB - Early recognition and distinction of Kawasaki disease (KD) from other febrile infectious diseases is one of the biggest challenges in pediatric emergency departments (PED). The aim of this study was to assess the utility of clinical findings and routinely used laboratory parameters for early discrimination between KD, invasive pneumococcal disease (IPD) and adenovirosis (AdV). A retrospective, cross-sectional study of children aged 3-36 months consecutively admitted to the PED and diagnosed with either KD (n = 110), AdV (n = 440) or IPD (n = 122) was conducted. At first presentation to the PED, 56.3% of KD patients had none or only one clinical criterion, 31% of patients with AdV and 11% with IPD had > 2 criteria. The levels of platelets (Plt), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were higher and white blood cells (WBC) significantly lower in KD than in IPD and AdV group. The WBC < 20 *109/l showed a sensitivity of 80.9% and specificity of 79.7% in comparison to AdV. The ROC curve showed a significant, but low sensitivity for AST, ALT and Plt. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) did not show any significant diagnostic accuracy. Significant association between incomplete KD and rash, WBC < 20 *109 and Plt > 400 *109/L compared to AdV and conjuctivitis, rash and Plt > 400 * 109/L, was found. Due to the time delay and nonspecific early presentation, differentiating KD from IPD and AdV is challenging. Tools used for identification of patients at risk for severe bacterial infections in PED lack sensitivity for identification of KD cases. New biomarkers are warranted for distinction of KD from IPD or AdV. PMID- 29476366 TI - Establishing end-of-life boards for palliative care of patients with advanced diseases. AB - BACKGROUND: Interdisciplinary tumor board decisions improve the quality of oncological therapies, while no such boards exist for end-of-life (EOL) decisions. The aim of this study was to assess the willingness of hemato oncological and palliative care professionals to develop and participate in EOL boards. An aim of an EOL board would be to establish an interdisciplinary and comprehensive care for the remaining lifetime of patients suffering from advanced incurable diseases. STUDY DESIGN: Staff from the interdisciplinary teams of all hemato-oncological and palliative care wards in Vienna were invited to anonymously participate in an online survey. RESULTS: 309 professionals responded. 91% respondents reported a need to establish an EOL board, 63% expressed their willingness to actively participate in an EOL board, and 25% were indecisive. Regarding patient presence, 50% voted for an EOL board in the presence of the patients, and 36% voted for an EOL board in the absence of the patients. 95% had the opinion that an EOL board could improve patient care in the last phase of life. 64% stated that the development of an EOL board would be worthwhile, while 28% did not see enough resources available at their institutions. Regarding the desired type of documentation, 61% voted for a centrally available EOL decision, and 31% supported an in-house-based documentation. 94% voted for the availability of an information folder about EOL care. CONCLUSION: The willingness of professionals to establish an EOL board was very high. Further steps should be taken to implement such boards to improve EOL care. PMID- 29476367 TI - Performance of sorghum cultivars for biomass quality and biomethane yield grown in semi-arid area of Pakistan. AB - Biomass is a promising renewable energy source and its significance is escalating in the context of climate change and depletion of fossil foils. This study was conducted for two consecutive years 2016 and 2017, using five sorghum cultivars, i.e., JS-263, Jawar-2011, Hagari, JS-2002, and YS-2016, in order to determine the best cultivars in terms of dry matter yield, chemical composition, and biomethane yield grown under semi-arid conditions in Pakistan. The results revealed that sorghum cultivars responded differently in terms of growth, biomass yield, chemical composition, and methane yield. Cultivars Jawar-2011 produced maximum leaf area index, leaf area duration, crop growth rate, plant height, and leaves per plant, however, they were comparable with Sorghum-2016, whereas cultivar JS 2002 performed poorly among the tested cultivars. Similarly, cultivar Jawar-2011 produced maximum dry matter yield (16.37 t ha-1) similar to that of YS-2016, further cultivar JS-2002 performed poorly and gave lower dry matter yield (12.87 t ha-1). The maximum protein concentration (10.95), neutral detergent fibers (61.20), and lignin contents (5.55) found in Jawar-2011 were comparable with those in YS-2016, while the lowest neutral detergent fiber and lignin contents were found in JS-2002. Although JS-2002 produced the highest specific methane yield per kilogram of volatile solids, it was overcompensated by Jawar-2011 owing to higher dry matter yield per hectare. These results suggested that cultivar Jawar-2011 can be grown successfully in semi-arid conditions of Pakistan in order to get good biomass yield along with higher methane yield. PMID- 29476368 TI - Adsorption and desorption of potentially toxic metals on modified biosorbents through new green grafting process. AB - Six lignocellulosic waste-derived biosorbents [cantaloupe peel (CAN), pine cone (PC), litchi fruit peel (LP), annona squamosal (AS), bamboo shoot (BS), and sugarcane bagasse (SB)] were selected as low-cost and renewable materials to prepare chemically modified biosorbent. The modified biosorbent was prepared through a newer carboxyl groups-grafting process onto the biosorbent's surface using acrylic acid. The results showed that the cation exchange capacity (CEC) of biosorbents increased by approximately 66.3-104% after modified. The modified biosorbent exhibited significantly higher adsorption capacity of Pb2+, Cu2+, and Cd2+ ions than the pristine biosorbent. The maximum Langmuir adsorption capacity (Qomax) of both pristine and modified biosorbents toward three metal ions (Pb2+, Cu2+, and Cd2+) followed the decreasing order: CAN > PC > LP > AS > BS > SB. The preference ranking of three metal ions on the pristine and modified biosorbents (mmol/kg) was generally in the order: Pb2+ > Cu2+ > Cd2+. Among these biosorbents, cantaloupe peel exhibited an excellent adsorption affinity to metal cations compared to the five others. The Qomax values of modified and pristine cantaloupe peels were ordered as follows: 143.2 and 81.1 mg/g for Pb2+ adsorption, > 45.4 and 30.4 mg/g for Cd2+ adsorption, > 33.1 and 23.5 mg/g for Cu2+ adsorption. After five adsorption-desorption cycles, the removal efficiency of Pb2+ by modified CAN was maintained at around 70%. The ion exchange played a determining role in adsorption mechanism. It can be concluded that modified cantaloupe peel can serve as a newer and promising biosorbent with a high adsorption capacity to various potentially toxic metals. PMID- 29476369 TI - In vivo toxicity evaluation of pristine graphene in developing zebrafish (Danio rerio) embryos. AB - Graphene has been used in several fields covering from electronics to biomedicine, especially exhibiting a widespread variety of promising biological and biomedical applications. In the past decade, the biomedical applications of graphene have attracted much interest. However, the effect of pristine graphene (pG) toxicity in aquatic vertebrates has not been fully studied. Thus, in this study, the toxicity of pG was experimentally evaluated using developing zebrafish embryos as in vivo model system. To determine this, 4-hpf embryos were exposed to different concentrations of pG (1, 5, 10, 15, 20, 25, 30, 35, 40, 45, and 50 MUg/L) and different early life-stage parameters were observed at 24, 48, 72, and 96 hpf. Through embryogenesis, pG was observed to induce significant embryonic mortality, delayed hatching, heartbeat, several morphological defects, pericardial toxicity, and bradycardia. Yolk sac edema and pericardial edema were induced by pG in developing embryos. These outcomes would provide new insights into the adverse effects of pG on the developing embryonic cardiac defects in vertebrates and highlight the probable natural environment and health hazards of pG flakes. PMID- 29476371 TI - A novel approach in red mud neutralization using cow dung. AB - In this study, cow dung was identified as a neutralizing agent for red mud (RM). Present research estimated a significant reduction in pH value of red mud (10 g) from 10.28 to 8.15 and reduction in alkalinity of ~148 mg/L from ~488 mg/L by adding 80 g of cow dung in 40 days of anaerobic condition. XRD results exhibit a high intensity of quartz and found new compound, the calcium carbide. The acid neutralizing capacity (ANC) of NRM reduces to ~0.87 from ~1.506 mol H+/kg. Based on the resultant research, present study proposes cow dung as an efficient neutralizing agent for reducing the pH and alkalinity in the red mud. PMID- 29476370 TI - Arbuscular mycorrhizal fungi in two vertical-flow wetlands constructed for heavy metal-contaminated wastewater bioremediation. AB - Over the last three decades, the presence of arbuscular mycorrhizal fungi (AMF) in wetland habitats had been proven, and their roles played in wetland ecosystems and potential functions in wastewater bioremediation technical installations are interesting issues. To increase knowledge on the functions of AMF in the plant based bioremediation of wastewater, we constructed two vertical-flow wetlands planting with Phragmites australis and investigated AMF distribution in plant roots and their roles played in purification of wastewater polluted by heavy metals (HMs), utilizing the Illumina sequencing technique. A total of 17 operational taxonomic units (OTUs) from 33,031 AMF sequences were obtained, with Glomus being the most dominant. P. australis living in the two vertical-flow constructed wetlands (CWs) harbored diverse AMF comparable with the AM fungal communities in upland habitats. The AMF composition profiles of CW1 (vegetated with non-inoculated plants) and CW2 (vegetated with mycorrhizal plants inoculated with Rhizophagus intraradices) were significantly different. CW1 (15 OTUs) harbored more diverse AMF than CW2 (7 OTUs); however, CW2 harbored much more OTU13 than CW1. In addition, a zipf species abundance distribution (SAD), which might due to the heavy overdominance of OTU13, was observed across AM fugal taxa in P. australis roots of the two CWs. CW1 and CW2 showed high (> 70%) removal capacity of HMs. CW2 exhibited significant higher Cd and Zn removal efficiencies than CW1 (CK) (p = 0.005 and p = 0.008, respectively). It was considered that AMF might play a role in HM removal in CWs. PMID- 29476372 TI - Ecotoxicity tests with Allium cepa to determine the efficiency of rice husk ash in the treatment of groundwater contaminated with benzene, toluene, ethylbenzene, and xylene. AB - The validation of adsorption treatment based on toxicity assays aims to assess the actual environmental impact caused by effluents after treatment. This study describes the use of rice husk ash as adsorbent and evaluates the efficiency of adsorption treatment to remediate groundwater contaminated with benzene, toluene, ethylbenzene, and xylene (BTEX). The synthetic effluent was prepared with standard benzene, toluene, ethylbenzene, and xylene solutions. Adsorption was assessed at treatment times 0, 60, 120, and 240 min. Compounds were quantified by gas chromatography with flame ionization detector. The treatment was validated based on ecotoxicity assays using Allium cepa as indicator organism. For the treatment times stipulated, samples containing 25, 50, and 100% of BTEX were used. The dilutions were carried out with drinking water according to Fiskesjo (1985). The relative growth index (RGI), root inhibition index (Ii), and germination index (GI) confirmed the efficiency of the treatment approach tested. The best adsorption time for an initial BTEX concentration of 3.378 mg/L was 60 min. Critical level (EC50) and critical concentration that induced phytotoxic effect on A. cepa germination was observed only for the undiluted effluent. PMID- 29476373 TI - Enhancement of nitrogen and phosphorus removal in landscape water using polymeric ferric sulfate as well as the synergistic effect of four kinds of natural rocks as promoter. AB - Eutrophication in lakes and rivers caused by the nitrogen (N) and phosphorus (P) is urgent since the accumulation of N and P can possibly cause the algal blooms and devastation to the water ecological system. The removal of N and P in the landscape water would be an efficient way to reduce the enrichment of nutrition before they reach the large water system. The N and P removal efficiency of PFS as well as the synergistic effect of natural rocks (four types of purple parent rock (J3p, J2s, T1f, and J3s)) as promoter was examined under laboratory conditions. The results indicated that TN and TP removal efficiency of the composite coagulant was significantly better than that of PFS or purple parent rock alone and J3p + PFS (combination of PFS and J3p purple parent rock) showed the best TN and TP removal efficiency. TN and TP removal efficiency of 53.53 and 86.48%, respectively, were achieved with coagulant dosage of 6 g L-1 J3p and 30 mg L-1 PFS, water temperature of 30 degrees C, and wastewater initial pH of 9. In addition, Fourier transformed infrared (FTIR) spectrophotometer, X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive analysis (EDX), and the water quality index analysis revealed that the treatment of TN and TP by using J3p + PFS was taking advantage of the flocculation function of PFS and the adsorption function of PFS and J3p. In which, the flocculation mechanism was mainly charge neutralization; adsorption mechanism was mainly physical and chemical adsorption. PMID- 29476374 TI - Method for identifying outliers of soil heavy metal data. AB - Artificial errors in the experimental process may lead to some outliers, which reduce data quality and cause erroneous judgment in soil pollution assessment. Based on this, a method for detecting outliers of soil heavy metal data was proposed in this study. The As, Cd, and Pb concentrations of the soil in Beijing, China, were taken as samples to verify the validity of the method. Results showed that there were 8, 34, and 38 outliers for the As, Cd, and Pb concentrations in the Beijing soil, respectively. The result of re-analyzed revealed that 75.0, 76.5, and 92.1% of the As, Cd, and Pb outliers, respectively, were caused by artificial errors. After correcting, the interpolation accuracy for data was improved significantly. The mean relative error (MRE) of the As, Cd, and Pb outliers decreased by 48.0, 44.6, and 54.7%, while the mean square error of these outliers decreased by 34.2, 33.3, and 46.4%, respectively. The MRE values of the nearest neighboring points which were influenced by the outliers decreased by 5.2, 20.6, and 27.6%, while the mean square error of these points decreased by 5.3, 17.3, and 33.2%, respectively. To our knowledge, this is the first study on detecting outliers of soil heavy metal data. The method considers both spatial and numerical outliers, which avoids the limitation of single method, and can effectively improve the data quality of soil heavy metal concentrations with a finite sample size and analysis time. PMID- 29476375 TI - Perceived Access and Parental Monitoring as Moderators of Impulsivity and Marijuana Use Among Adolescents. AB - The social and political climate regarding marijuana use has been changing in the US over the past decade. Research suggests that many adolescents report relatively easy access to marijuana and perceptions that recreational use involves minimal harm despite a growing body of research implicating the deleterious effects of use on cognitive and psychological development. Not surprisingly, prevalence rates have been rising in recent years, making it important to identify risk and protective factors associated with adolescent marijuana use. We tested a 3-way interaction model designed to (a) examine the relationship between behavioral impulsivity and marijuana use in adolescents, and (b) evaluate the roles of perceived access and parental monitoring as moderators of this relationship. High school students (N = 498, M age = 15.7, 53% female, 77% White) completed an anonymous self-report assessment examining substance use, perceived access, and psychosocial factors related to substance use (i.e., behavioral impulsivity and parental monitoring). Results indicated that higher levels of impulsivity, greater access, and reduced parental monitoring were related to marijuana use. Significant moderating effects were found for perceived access and parental monitoring, such that use was greater for adolescents who perceived that marijuana was easier to acquire and for those with lower levels of parental monitoring. Among individuals with greater levels of impulsivity, parental monitoring reduced the impact of perceived access. Overall, results highlight risk and protective factors related to adolescent marijuana use and indicate that parental monitoring can be an effective means for reducing consumption. PMID- 29476376 TI - Regenerative treatment of osteochondral lesions of distal tibial plafond. AB - OBJECTIVES: Osteochondral lesions of the distal tibial plafond (OLTP) are rare and far less common than osteochondral lesions of the talus. Literature data do not report clinical records with significant number of cases and follow-up. The aim of our study was to evaluate clinical and MRI outcomes following arthroscopic treatment of distal tibia osteochondral lesions and to report our results with treating these rare lesions. METHODS: Between October 2010 and November 2011, a consecutive series of 27 patients, 15 males and 12 females, were treated arthroscopically with the one-step BMDCT for OLTPs. Exclusion criteria were: age < 18 or > 50 years, patients with severe osteoarthritis (stage III according to Van Dijk classification), presence of kissing lesions of the ankle and patients with rheumatoid or hemophilic arthritis. All patients were evaluated through X rays; MRI was performed preoperatively and at the final follow-up with MOCART score; clinical evaluation was assessed by AOFAS score at various follow-ups of 12, 24, 36, 60 and 72 months. RESULTS: No complications were observed post surgery or during the rehabilitation period. The AOFAS score improved from 52.4 preoperatively to 80.6 at the mean final follow-up. All the patients were satisfied with the procedure. In 14 cases the MRI showed a complete filling of the osteochondral defect, in three patients a hypertrophic tissue was observed, and in the other two patients an incomplete repair of the lesion associated with a persistent slight subchondral edema was reported. A topographic study was also performed. CONCLUSIONS: Osteochondral lesions of the distal tibia represent a challenge for the orthopedic surgeon because of their difficulty diagnostic and rarities. The high incidence of good outcome in our series indicates that the one step BMDCT could be a valid option for the treatment of this rare type of lesions. Further studies with a longer follow-up and more accurate imaging studies are necessary to confirm these results. PMID- 29476377 TI - Self-Report of Aerobic Activity among Older African Americans with Multiple Chronic Conditions. AB - Physical inactivity among older adults around the world is a growing concern. In the United States, older African Americans report high levels of physical inactivity, especially older African Americans with chronic conditions. This study examined the influence of chronic conditions on aerobic activity among a sample of community-dwelling, older African Americans with a self-reported diagnosis of type 2 diabetes and other chronic conditions, such as hypertension and arthritis. Findings indicate that regardless of age, the number of chronic conditions was a significant influence in self-report of aerobic activity. Successful self-management of type 2 diabetes and other chronic conditions may promote physical activity among sedentary older African Americans with multiple chronic conditions. Furthermore, research that considers a life course epidemiological approach are needed to enhance our understanding about the cumulative effects of MCC on physical activity among sedentary, older African Americans with MCC. PMID- 29476378 TI - Impact of inducing general anesthesia with Propiscin (etomidate) on the physiology and health of European perch (Perca fluviatilis L.). AB - The aim of the study was to describe the course and timing of the different stages of anesthesia induced with Propiscin (etomidate) on juvenile European perch (experiment I) and to describe the effect of immersing specimens of this species had on selected hematological and biochemical parameters (experiment II). The study was conducted on material with body weights (BW) of 162.98 (experiment I) and 171.60 g (experiment II). In experiment I, general anesthesia was induced with two different anesthetic concentrations (1 or 2 ml l-1; anesthesia time 10 min). In experiment II, blood was drawn for hematological and biochemical analyses from the fish that had been exposed to anesthetic immersion baths with two different concentrations of Propiscin (1 and 2 ml l-1) and for different exposure times (3 and 10 min). Blood samples were collected immediately following immersion (0 h) and 24 h later (24 h). Specimens that were immersed at the higher concentration of anesthetic achieved subsequent stages of general anesthesia two times faster (P <= 0.05). However, during recovery, some statistically significant differences were observed, but these lasted only until stage I was achieved. Among the hematological parameters (0 h), significant differences were observed in hematocrit (HCT) and mean corpuscular volume (MCV), while among the biochemical determinations (0 h), statistically significant differences were noted in the concentrations of glucose, calcium, lactate, and ammonia. After 24 h, the levels of these parameters in all fish groups returned to initial values. The hematological and biochemical tests conducted permit concluding that the anesthetic tested, at the concentrations (1 and 2 ml l-1) and the exposure times of up to 10 min at which it was tested, is safe and can be used successfully to induce general anesthesia in perch. PMID- 29476379 TI - Design and performance evaluation of collision protection-based safety operation for a haptic robot-assisted catheter operating system. AB - The robot-assisted catheter system can increase operating distance thus preventing the exposure radiation of the surgeon to X-ray for endovascular catheterization. However, few designs have considered the collision protection between the catheter tip and the vessel wall. This paper presents a novel catheter operating system based on tissue protection to prevent vessel puncture caused by collision. The integrated haptic interface not only allows the operator to feel the real force feedback, but also combines with the newly proposed collision protection mechanism (CPM) to mitigate the collision trauma. The CPM can release the catheter quickly when the measured force exceeds a certain threshold, so as to avoid the vessel puncture. A significant advantage is that the proposed mechanism can adjust the protection threshold in real time by the current according to the actual characteristics of the blood vessel. To verify the effectiveness of the tissue protection by the system, the evaluation experiments in vitro were carried out. The results show that the further collision damage can be effectively prevented by the CPM, which implies the realization of relative safe catheterization. This research provides some insights into the functional improvements of safe and reliable robot-assisted catheter systems. PMID- 29476380 TI - New-onset pericardial effusion during transvenous lead extraction: incidence, causative mechanisms, and associated factors. AB - PURPOSE: Pericardial effusion (PE) may occur during the lead extraction procedure (TLE). Little is known about the incidence, causes, and predictors of this complication. METHODS: From January 2009 to October 2016, TLE was attempted for 297 leads in 212 patients (age 69.3 +/- 12.9 years, 169 male, BMI 27.2 +/- 9.9 m2/kg, LVEF 43.4 +/- 24.6%) for lead dysfunction (62.7%), upgrade (16.0%), infection (14.2%), or other (7.0%) indications. TLE was performed under general anesthesia with continuous invasive arterial blood pressure and transesophageal echocardiography (TEE) monitoring. For lead removal, the mechanical approach was first attempted, followed by the laser-assisted technique when needed. Severity of PE was defined by the presence of hemodynamically significant PE > 10 mm at TEE. RESULTS: Clinical success was achieved for 292 leads (98.3%). New-onset PE was observed in 14 patients (6.6%) [mild entity in 7 patients (3.3%) and severe in 7 (3.3%)]. In these latter patients, intra-procedural management included surgery (n = 3), pericardiocentesis (n = 2), or a conservative approach (n = 2). Right ventricular (RV) site lesions were treated with a simple fluid infusion. Laceration of the superior vena cava and other vessels resulted in rescue surgery. Lesions of the right atrial free wall (n = 1) and coronary sinus (n = 1) were treated with pericardiocentesis. NYHA III/IV, LVEF < 35%, renal impairment, right-sided implant, and >=2 leads targeted for TLE were associated with new onset PE. More than two factors identified a higher risk group (16.2%, 95% CI 6.2 32.0%, P = 0.02). CONCLUSIONS: New-onset PE is common during TLE and is associated with specific factors. PE severity and subsequent patient management depend on the site of injury. PMID- 29476381 TI - Genome-wide single nucleotide polymorphisms (SNPs) for a model invasive ascidian Botryllus schlosseri. AB - Invasive species cause huge damages to ecology, environment and economy globally. The comprehensive understanding of invasion mechanisms, particularly genetic bases of micro-evolutionary processes responsible for invasion success, is essential for reducing potential damages caused by invasive species. The golden star tunicate, Botryllus schlosseri, has become a model species in invasion biology, mainly owing to its high invasiveness nature and small well-sequenced genome. However, the genome-wide genetic markers have not been well developed in this highly invasive species, thus limiting the comprehensive understanding of genetic mechanisms of invasion success. Using restriction site-associated DNA (RAD) tag sequencing, here we developed a high-quality resource of 14,119 out of 158,821 SNPs for B. schlosseri. These SNPs were relatively evenly distributed at each chromosome. SNP annotations showed that the majority of SNPs (63.20%) were located at intergenic regions, and 21.51% and 14.58% were located at introns and exons, respectively. In addition, the potential use of the developed SNPs for population genomics studies was primarily assessed, such as the estimate of observed heterozygosity (H O ), expected heterozygosity (H E ), nucleotide diversity (pi), Wright's inbreeding coefficient (F IS ) and effective population size (Ne). Our developed SNP resource would provide future studies the genome wide genetic markers for genetic and genomic investigations, such as genetic bases of micro-evolutionary processes responsible for invasion success. PMID- 29476382 TI - Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features in Asian Practice: Perspectives for Surgical Pathology and Cytopathology. AB - The introduction of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was initiated and promoted by pathologists. Recent Asian studies added new knowledge to the existing literature to aid a better understanding of NIFTP. Our original data and the results of a meta-analysis suggest that the initial rate of NIFTP has been overestimated, averaging 9.1% (95% confidence interval [CI] 6.0-12.7%) of all papillary thyroid cancers worldwide. The incidence of NIFTP in the Asian population (1.6%, 95% CI 0.9-2.5%; 7 studies) is significantly lower than that reported in the non-Asian series (13.3%, 95% CI 9.0-18.3%; 18 studies). Such difference could be attributed to various perceptions of histological diagnostic thresholds, different nature of papillary thyroid carcinoma, and different approaches in the management of thyroid nodules. The active surveillance for indeterminate nodules and NIFTP, largely represented in the indeterminate cytologic categories, promoted by Japanese institutions establishes a new paradigm to reduce overtreatment of these patients. The lower prevalence of NIFTP in the Asian series indicates a low impact on the risk of malignancy in cytopathology, as it was demonstrated in our original multi-institutional cohort of thyroid nodules, and may predict a low impact on the performance of commercial molecular tests. Several Korean studies addressed the issue of BRAF mutation in NIFTP, which prompted the current refinement of the diagnostic criteria for NIFTP. Our survey of Asian pathologists found that the term NIFTP has not been universally adopted in the local practice. Endocrine pathologists must promote the new entity through provision of educational activities. PMID- 29476383 TI - A phase 2 study of OSI-906 (linsitinib, an insulin-like growth factor receptor-1 inhibitor) in patients with asymptomatic or mildly symptomatic (non-opioid requiring) metastatic castrate resistant prostate cancer (CRPC). AB - Background The inhibition of insulin-like growth factor receptor-1 (IGF-1R) induces cell cycle arrest and enhancing the effect of castration by delay of progression of human prostate cancer models. Linsitinib is a small molecule and potent dual inhibitor of IGF-1R and insulin receptor tyrosine kinase activity. We report results of a single-arm, phase II study evaluating the safety and efficacy of linsitinib in men with chemotherapy-naive asymptomatic or mildly symptomatic metastatic castration resistant prostate cancer (mCRPC). Methods Patients received at 150 mg orally twice daily on a 28-day cycle. The primary endpoint was prostate specific (PSA) response at 12 weeks and correlative studies included circulating tumor cells (CTCs) and circulating endothelial cells (CECs). Results Seventeen patients, median age 68 (55-78) and pre-treatment PSA of 55.23 (2.46 277.60) were enrolled and completed 12 weeks of therapy. All but two patients discontinued therapy secondary to PSA progression, which met the predefined futility criteria and led to early termination of this study. Overall best response (RECIST v1.1) included a partial response in 1 patient and stable disease in 8 patients. Higher baseline CTCs were associated with higher pre treatment PSA levels (Spearman r = 0.49, p = 0.04) but no correlation between PSA progression and CTCs/CECs were observed. Most common adverse events included fatigue, nausea/vomiting, AST/ALT changes and prolonged QT interval. Conclusions Single-agent linsitinib was safe and well tolerated but failed to show activity in men with mCRPC. These results highlight the complexity of using IGF-1R as a therapeutic target in this patient population. ClinicalTrials.gov NCT01533246. PMID- 29476384 TI - Youths Perceived Parental Influence on Substance Use Changes and Motivation to Seek Treatment. AB - Drug and alcohol use among youth has serious consequences for the physical and mental health of youth and strains their relationships with family and friends. While the task of dealing with substance-related issues often falls on families, particularly parents, very little research has explored the importance of family as a motivator for seeking treatment. This paper reports on a qualitative study of youth seeking substance abuse treatment at a large urban psychiatric hospital. Following primarily self-determination theory, the study examines youths' descriptions of how their parents motivated them to (1) change their substance use behaviors and (2) seek treatment. The sample consisted of 31 youth ages 17 to 25 engaged in outpatient services with various substance use concerns. Youth described complex and evolving relationships with their parents along their journey to enter treatment. Implications for service delivery and important insights for engaging youth and their parents are discussed. PMID- 29476385 TI - Agency-Based Empowerment Interventions: Efforts to Enhance Decision-Making and Action in Health and Development. AB - This paper outlines the critical role of personal agency in influencing health and development outcomes and presents a framework for implementing non therapeutic cognitive-behavioral interventions that foster agency, especially for women, in resource-poor settings. The United Nations' Sustainable Development Goals (SDGs) has placed "empowerment" at the center of global targets, particularly to improve individuals' health and development. Despite extensive research on individual and community empowerment, there is limited focus on the role of psychological and behavioral approaches directly fostering individual and collective agency in health programs. Fundamental to this process is the understanding that decision-making is an interaction between mental processes and one's current context. Approaches that allow individuals to understand how their beliefs, values, emotions, and thoughts impact their behaviors and can be modulated to increase their personal agency are needed. This model is illustrated through a pilot behavioral intervention with women engaged in sex work in Pune, India, demonstrating substantive benefits. PMID- 29476386 TI - Assessing Risk Perceptions of E-Smoking Devices: a Cross-Sectional Consumer Survey. PMID- 29476387 TI - The mystery of defining aortic valve area: what have we learnt from three dimensional imaging modalities? AB - Aortic valve area is one of the main criteria used by echocardiography to determine the degree of valvular aortic stenosis, and it is calculated using the continuity equation which assumes that the flow volume of blood is equal at two points, the aortic valve area and the left ventricular outflow tract (LVOT). The main fallacy of this equation is the assumption that the LVOT area which is used to calculate the flow volume at the LVOT level is circular, where it is often an ellipse and sometimes irregular. The aim of this review is to explain the physiology of the continuity equation, the different sources of errors, the added benefits of using three-dimensional imaging modalities to measure LVOT area, the latest recommendations related to valvular aortic stenosis, and to introduce future perspectives. A literature review of studies comparing aortic valve area and LVOT area, after using three-dimensional data, has shown underestimation of both measurements when using the continuity equation. This has more impact on patients with discordant echocardiographic measurements when aortic valve area is disproportionate to haemodynamic measurements in assessing the degree of aortic stenosis. Although fusion imaging modalities of LVOT area can help in certain group of patients to address the issue of aortic valve area underestimation, further research on introducing a correction factor to the conventional continuity equation might be more rewarding, saving patients additional tests and potential radiation, with no clear evidence of cost-effectiveness. PMID- 29476388 TI - Left atrial dilatation in systolic heart failure: a marker of poor prognosis, not just a buffer between the left ventricle and pulmonary circulation. AB - BACKGROUND: The relation between systolic pulmonary pressure (sPAP) and left atrium in patients with heart failure (HF) is unclear. Diastolic dysfunction, expressed as restrictive mitral filling pattern (RMP), and functional mitral regurgitation (FMR) are associated with both LA enlargement and increased sPAP. We aimed to evaluate whether atrial dilation might modulate the consequences of RMP and FMR on the pulmonary circulation of patients with HF with reduced ejection fraction (HFrEF). METHODS: 1256 HFrEF patients were retrospectively recruited in four Italian centers. Left ventricular (LVD) and atrial (LAD) diameters were measure by m-mode, and EF were measured. RMP was defined as E-wave deceleration time lower than 140 ms. FMR was quantitatively measured. sPAP was evaluated based on maximal tricuspid regurgitant velocity and estimated right atrial pressure. RESULTS: Final study population was formed by 1005 patients because of unavailability of sPAP in 252 patients. Mean EF was 33 +/- 3, 35% had RMP, 67% had mild, and 26% moderate-to-severe FMR. 69% of patients had increased sPAP. A significant association was observed between sPAP and EF, RMP, FMR, and LAD (p < 0.0001 for all). At multivariate analysis, LAD was positively associated with sPAP (p < 0.0001) independently of EF, RMP, and FMR. Analogously, LAD (p < 0.05) was associated with more severe symptoms and worse prognosis after adjustment for LV function and FMR. CONCLUSION: LA dilation was positively associated with sPAP independently of EF, RMP, and FMR. This highlights that LA size should be considered a marker of the severity of the disease. PMID- 29476390 TI - Spontaneous Intracranial Hemorrhage in Pregnancy: A Systematic Review of the Literature. AB - Stroke in pregnant women has a mortality rate of 1.4 deaths per 100,000 deliveries. Vascular malformations are the most common cause of hemorrhagic stroke in this population; preeclampsia and other risk factors have been identified. However, nearly a quarter of strokes have an undeterminable cause. Spontaneous intracranial hemorrhage (ICH) is less frequent but results in significant morbidity. The main objective of this study is to review the literature on pregnant patients who had a spontaneous ICH. A systematic review of the literature was conducted on PubMed and the Cochrane library from January 1992 to September 2016 following the PRISMA guidelines. Studies reporting pregnant patients with spontaneous intraparenchymal hemorrhage (IPH), subarachnoid hemorrhage (SAH), and subdural hemorrhage (SDH) were selected and included if patients had non-structural ICH during pregnancy or up to 6 weeks postpartum confirmed by imaging. Twenty studies were included, and 43 patients identified. Twenty-two patients (51.3%) presented with IPH, 15 patients (34.8%) with SAH, and five patients (11.6%) with SDH. The most common neurosurgical management was clinical in 76.7% of patients, and cesarean section was the most common obstetrical management in 28% of patients. The most common maternal outcome was death (48.8%), and fetal outcomes were evenly distributed among term delivery, preterm delivery, and fetal or neonatal death. Spontaneous ICH carries a high maternal mortality with IPH being the most common type, most frequently presenting in the third trimester. Diagnosis and management do not differ for the parturient compared to the non-pregnant woman. PMID- 29476389 TI - Age and Mortality in Pediatric Severe Traumatic Brain Injury: Results from an International Study. AB - BACKGROUND: Although small series have suggested that younger age is associated with less favorable outcome after severe traumatic brain injury (TBI), confounders and biases have limited our understanding of this relationship. We hypothesized that there would be an association between age and mortality in children within an ongoing observational, cohort study. METHODS: The first 200 subjects from the Approaches and Decisions for Acute Pediatric TBI trial were eligible for this analysis (inclusion criteria: severe TBI (Glasgow Coma Scale [GCS] score <= 8], age 18 years, and intracranial pressure (ICP) monitor placed; exclusion: pregnancy). Children with suspected abusive head trauma (AHT) were excluded to avoid bias related to the association between AHT and mortality. Demographics, and prehospital and resuscitation events were collected/analyzed, and children were stratified based on age at time of injury (< 5, 5-< 11, 11-18 years) and presented as mean +/- standard error of the mean (SEM). Analyses of variance were used to test the equality of the means across the group for continuous variable, and Chi-square tests were used to compare percentages for discrete variables (post hoc comparisons were made using t test and Bonferroni corrections, as needed). Kaplan-Meier curves were generated for each age subgroup describing the time of death, and log-rank was used to compare the curves. Cox proportional hazards regression models were used to assess the effect of age on time to death while controlling for covariates. RESULTS: In the final cohort (n = 155, 45 excluded for AHT), overall age was 9.2 years +/- 0.4 and GCS was 5.3 +/- 0.1. Mortality was similar between strata (14.0, 20.0, 20.9%, respectively, p = 0.58). Motor vehicle accidents were the most common mechanism across all strata, while falls tended to be more common in the youngest stratum (p = 0.08). The youngest stratum demonstrated increased incidence of spontaneous hypothermia at presentation and decreased hemoglobin concentrations and coagulopathies, while the oldest demonstrated lower platelet counts. CONCLUSIONS: In contrast to previous reports, we failed to detect mortality differences across age strata in children with severe TBI. We have discerned novel associations between age and various markers of injury-unrelated to AHT-that may lead to testable hypotheses in the future. PMID- 29476391 TI - Non-electrographic Seizures Due to Subdural Hematoma: A Case Series and Review of the Literature. AB - Seizures due to subdural hematoma (SDH) are a common finding, typically diagnosed using electroencephalography (EEG). At times, aggressive management of seizures is necessary to improve neurologic recovery and outcomes. Here, we present three patients who had undergone emergent SDH evacuation and showed postoperative focal deficits without accompanying electrographic epileptiform activity. After infarction and recurrent hemorrhage were ruled out, seizures were suspected despite a negative EEG. Patients were treated aggressively with AEDs and eventually showed clinical improvement. Long-term monitoring with EEG revealed electrographic seizures in a delayed fashion. EEG recordings are an important tool for seizure detection, but should be used as an adjunct to, rather than a replacement for, the clinical examination in the acute setting. At times, aggressive treatment of suspected postoperative seizures is warranted despite lack of corresponding electrographic activity and can improve clinical outcomes. PMID- 29476392 TI - Collaborative and Reproducible Research: Goals, Challenges, and Strategies. AB - Combining imaging biomarkers with genomic and clinical phenotype data is the foundation of precision medicine research efforts. Yet, biomedical imaging research requires unique infrastructure compared with principally text-driven clinical electronic medical record (EMR) data. The issues are related to the binary nature of the file format and transport mechanism for medical images as well as the post-processing image segmentation and registration needed to combine anatomical and physiological imaging data sources. The SiiM Machine Learning Committee was formed to analyze the gaps and challenges surrounding research into machine learning in medical imaging and to find ways to mitigate these issues. At the 2017 annual meeting, a whiteboard session was held to rank the most pressing issues and develop strategies to meet them. The results, and further reflections, are summarized in this paper. PMID- 29476393 TI - Marrow Adiposity and Hematopoiesis in Aging and Obesity: Exercise as an Intervention. AB - PURPOSE OF REVIEW: Changes in the bone marrow microenvironment, which accompany aging and obesity, including increased marrow adiposity, can compromise hematopoiesis. Here, we review deleterious shifts in molecular, cellular, and tissue activity and consider the potential of exercise to slow degenerative changes associated with aging and obesity. RECENT FINDINGS: While bone marrow hematopoietic stem cells (HSC) are increased in frequency and myeloid-biased with age, the effect of obesity on HSC proliferation and differentiation remains controversial. HSC from both aged and obese environment have reduced hematopoietic reconstitution capacity following bone marrow transplant. Increased marrow adiposity affects HSC function, causing upregulation of myelopoiesis and downregulation of lymphopoiesis. Exercise, in contrast, can reduce marrow adiposity and restore hematopoiesis. The impact of marrow adiposity on hematopoiesis is determined mainly through correlations. Mechanistic studies are needed to determine a causative relationship between marrow adiposity and declines in hematopoiesis, which could aid in developing treatments for conditions that arise from disruptions in the marrow microenvironment. PMID- 29476394 TI - Good, Bad, or Ugly: the Biological Roles of Bone Marrow Fat. AB - PURPOSE OF REVIEW: Bone marrow fat expresses mixed characteristics, which could correspond to white, brown, and beige types of fat. Marrow fat could act as either energy storing and adipokine secreting white fat or as a source of energy for hematopoiesis and bone metabolism, thus acting as brown fat. However, there is also a negative interaction between marrow fat and other elements of the bone marrow milieu, which is known as lipotoxicity. In this review, we will describe the good and bad roles of marrow fat in the bone, while focusing on the specific components of the negative effect of marrow fat on bone metabolism. RECENT FINDINGS: Lipotoxicity in the bone is exerted by bone marrow fat through the secretion of adipokines and free fatty acids (FFA) (predominantly palmitate). High levels of FFA found in the bone marrow of aged and osteoporotic bone are associated with decreased osteoblastogenesis and bone formation, decreased hematopoiesis, and increased osteoclastogenesis. In addition, FFA such as palmitate and stearate induce apoptosis and dysfunctional autophagy in the osteoblasts, thus affecting their differentiation and function. Regulation of marrow fat could become a therapeutic target for osteoporosis. Inhibition of the synthesis of FFA by marrow fat could facilitate osteoblastogenesis and bone formation while affecting osteoclastogenesis. However, further studies testing this hypothesis are still required. PMID- 29476395 TI - Atmospheric ambient trace element concentrations of PM10 at urban and sub-urban sites: source apportionment and health risk estimation. AB - In this study, PM10 concentrations and elemental (Al, Fe, Sc, V, Cr, Mn, Co, Ni, Cu, Zn, As, Se, Mo, Ag, Cd, Sn, Sb, Ba, Pb, and Bi) contents of particles were determined in Duzce, Turkey. The particulate matter samplings were carried out in the winter and summer seasons simultaneously in both urban and sub-urban sampling sites. The average PM10 concentration measured in the winter season was 86.4 and 27.3 MUg/m3, respectively, in the urban and sub-urban sampling sites, while it was measured as 53.2 and 34.7 MUg/m3 in the summer season. According to the results, it was observed that the PM10 levels and the element concentrations reached higher levels, especially at the urban sampling site, in the winter season. The positive matrix factorization model (PMF) was applied to the data set for source apportionment. Analysis with the PMF model revealed six factors for both the urban (coal combustion, traffic, oil combustion, industry, biomass combustion, and soil) and sub-urban (industry, oil combustion, traffic, road dust, soil resuspension, domestic heating) sampling sites. Loadings of grouped elements on these factors showed that the major sources of the elements in the atmosphere of Duzce were traffic, fossil fuel combustion, and metal industry related emissions. PMID- 29476396 TI - Tilted-wire method for measuring resolution properties of CT images under extremely low-contrast and high-noise conditions. AB - Edge methods are predominantly used for modulation transfer function (MTF) measurements in computed tomography (CT) images reconstructed using iterative methods. However, edge methods employ a relatively large and distinct test object, which is intended to simulate relatively large and distinct clinical organs. If one wants to assess the image quality of a small low-contrast object that is visually indistinct against a noisy background, a small and indistinct test object is desired. Another concern is that information related to the signal amount is discarded during MTF measurements. Choosing a weak impulse as the ultimately small test object, we have developed a tilted-wire method, which is a type of point spread function (PSF) method compatible with extremely low contrast to-noise ratio (CNR) conditions. The signal amount is measured as the PSF volume. We used two commercial CT systems to evaluate the measurement accuracy of the tilted-wire method. When ensemble-averaged images are used, one can measure the MTF even when the wire is indiscernible from noise. The measurement error under such conditions is a few percent for both the MTF and signal amount. We also applied the tilted-wire method to two hybrid iterative reconstruction methods, namely AIDR-3D and ASiR. The results show that the MTF of ASiR is completely CNR dependent, but that of AIDR-3D is noise-dependent. The signal amount obtained with ASiR is unchanged from that obtained through filtered back-projection (FBP). The signal amount obtained with AIDR-3D is less than that obtained through FBP, depending on the noise level. PMID- 29476399 TI - On the Accuracy of Ancestral Sequence Reconstruction for Ultrametric Trees with Parsimony. AB - We examine a mathematical question concerning the reconstruction accuracy of the Fitch algorithm for reconstructing the ancestral sequence of the most recent common ancestor given a phylogenetic tree and sequence data for all taxa under consideration. In particular, for the symmetric four-state substitution model which is also known as Jukes-Cantor model, we answer affirmatively a conjecture of Li, Steel and Zhang which states that for any ultrametric phylogenetic tree and a symmetric model, the Fitch parsimony method using all terminal taxa is more accurate, or at least as accurate, for ancestral state reconstruction than using any particular terminal taxon or any particular pair of taxa. This conjecture had so far only been answered for two-state data by Fischer and Thatte. Here, we focus on answering the biologically more relevant case with four states, which corresponds to ancestral sequence reconstruction from DNA or RNA data. PMID- 29476398 TI - Multiple Spectroscopic, Docking and Cytotoxic Study of a Synthesized 2,2' Bipyridin Phenyl Isopentylglycin Pt(II) Nitrate Complex: Human Serum Albumin and Breast Cancer Cell Line of MDA-MB231 as Targets. AB - In the present study, the biological activities of a new synthesized Pt(II) complex, 2,2' bipyridinphenyl isopentylglycin Pt(II) nitrate was investigated via its interaction with the most important blood carrier protein of human serum albumin (HSA), using fluorescence and Far-UV circular dichroism (CD) spectroscopic techniques and also molecular docking. Moreover, cytotoxicity activity of the complex was studied against breast cancer cell line of MDA MB231 using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The Pt(II)-complex has a strong ability to quench the intrinsic fluorescence of HSA through a static quenching mechanism. According fluorescence quenching data, the binding parameters of the interaction were calculated and showed that hydrophobic interaction has an important role. The molecular docking results in coherent with fluorescence measurements illustrated that Pt(II) complex can bind to HSA at one position that located in the hydrophobic cavity of groove between drug site I and II. Also, experimental data on driving force in binding site was confirmed whereas theoretical results demonstrated Pt(II) complexinteract to HSA by hydrophobic interaction. Far-UV-CD results showed that Pt(II)-complex induced an increasing in the content of alpha-helical structure of the protein and stabilized it. Also, MTT assay represented growth inhibitory effect of the complex toward the breast cancer cell line. PMID- 29476397 TI - Detection of novel RNA viruses from free-living gorillas, Republic of the Congo: genetic diversity of picobirnaviruses. AB - Most of the emerging infectious diseases reported so far originated in wildlife. Therefore, virological surveillance of animals and particularly great apes is of great interest to establish the repertory of viruses associated with healthy hosts. This will further help to identify the emergence of new viruses and predict the possibility of interspecies transmission. In this study, we performed shotgun viral metagenomics on stool samples collected from seventeen free-living wild gorillas from the Republic of the Congo. The analysis revealed the presence of novel RNA viruses (picobirnaviruses, partitivirus, and Picornavirales (posa like and dicistrovirus-like viruses)). Among these, picobirnavirus-related sequences were abundantly covered in the stools. Based on genetic variations both in capsid and RdRp proteins of picobirnaviruses, at least 96 variants were identified and most of them were novel. Among the 96, 22 variants had a nearly complete genome or segment. A comprehensive sequence analysis identified a potential new genogroup/genetic cluster and the presence of a short linear amino acid motif (ExxRxNxxxE) in a hypothetical protein. The sequence analysis of posa like virus and dicistrovirus showed that these two viruses were novel members in the respective viral families. In conclusion, the identification of novel RNA viruses and their genetic diversity increases our knowledge about viruses that are associated with stools of wild gorillas and contributes to the initiatives in the search for potential emerging zoonotic viruses. PMID- 29476400 TI - A novel Aspergillus oryzae diglycosidase that hydrolyzes 6-O-alpha-L-rhamnosyl beta-D-glucoside from flavonoids. AB - alpha-L-Rhamnosyl-beta-D-glucosidase (rutinosidase) hydrolyzes the glycosidic linkage between the disaccharide 6-O-alpha-L-rhamnosyl-beta-D-glucoside (rutinose) and the aglycone. We identified a hypothetical protein (annotated as AO090012000917) encoded in the Aspergillus oryzae genome that exhibits sequence similarity with Aspergillus niger rutinosidase. The recombinant enzyme was expressed in Pichia pastoris GS115 and purified as a glyco-protein with apparent molecular mass of 65-75 kDa by SDS-PAGE. After N-deglycosylation, we observed a 42- and 40-kDa band, representing proteins before and after N-terminal signal peptide processing, respectively. Optimal enzymatic activity was observed at pH 4.0 and temperature of 45 degrees C. This enzyme is also significantly thermo stable, with 90% activity retained after 1 h at 45 degrees C and 70% activity retained after 4 h, even at 50 degrees C. Biochemical characterization revealed that the enzyme has higher substrate specificity for 3-O-linked flavonoid beta rutinosides like rutin and kaempferol-3-O-rutinoside, than for 7-O-linked flavonoid beta-rutinoside like hesperidin. However, no activity was found with naringin, diosmin, monoglycosylated chromogenic substrates, and polymeric laminarin substrate. Kinetic analyses showed that K m value toward rutin was higher than those toward hesperidin and kaempferol-3-O-rutinoside. Meanwhile, kcat value toward hesperidin was lower than those toward kaempferol-3-O rutinoside and rutin. Overall, the catalytic efficiency (kcat/K m ) was highest for kaempferol-3-O-rutinoside. PMID- 29476401 TI - Recent advances on biological production of difructose dianhydride III. AB - Difructose dianhydride III (DFA III) is a cyclic difructose containing two reciprocal glycosidic linkages. It is easily generated with a small amount by sucrose caramelization and thus occurs in a wide range of food-stuffs during food processing. DFA III has half sweetness but only 1/15 energy of sucrose, showing potential industrial application as low-calorie sucrose substitute. In addition, it displays many benefits including prebiotic effect, low cariogenicity property, and hypocholesterolemic effect, and improves absorption of minerals, flavonoids, and immunoglobulin G. DFA III is biologically produced from inulin by inulin fructotransferase (IFTase, EC 4.2.2.18). Plenty of DFA III-producing enzymes have been identified. The crystal structure of inulin fructotransferase has been determined, and its molecular modification has been performed to improve the catalytic activity and structural stability. Large-scale production of DFA III has been studied by various IFTases, especially using an ultrafiltration membrane bioreactor. In this article, the recent findings on physiological effects of DFA III are briefly summarized; the research progresses on identification, expression, and molecular modification of IFTase and large-scale biological production of DFA III by IFTase are reviewed in detail. PMID- 29476402 TI - Enzyme and microbial technology for synthesis of bioactive oligosaccharides: an update. AB - Oligosaccharides, in either free or bound forms, play crucial roles in a wide range of biological processes. Increasing appreciation of their roles in cellular communication, interaction, pathogenesis, and prebiotic functions has stimulated tremendous interests in their synthesis. Pure and structurally defined oligosaccharides are essential for fundamental studies. On the other hand, for those with near term medical and nutraceutical applications, their large-scale synthesis is necessary. Unfortunately, oligosaccharides are notoriously difficult in their synthesis, and their enormous diverse structures leave a vast gap between what have been synthesized in laboratory and those present in various biological systems. While enzymes and microbes are nature's catalysts for oligosaccharides, their effective use is not without challenges. Using examples of galactose-containing oligosaccharides, this review analyzes the pros and cons of these two forms of biocatalysts and provides an updated view on the status of biocatalysis in this important field. Over the past few years, a large number of novel galactosidases were discovered and/or engineered for improved synthesis via transglycosylation. The use of salvage pathway for regeneration of uridine diphosphate (UDP)-galactose has made the use of Leloir glycosyltransferases simpler and more efficient. The recent success of large-scale synthesis of 2' fucosyllactose heralded the power of whole-cell biocatalysis as a scalable technology. While it still lags behind enzyme catalysis in terms of the number of oligosaccharides synthesized, an acceleration in the use of this form of biocatalyst is expected as rapid advances in synthetic biology have made the engineering of whole cell biocatalysts less arduous and less time consuming. PMID- 29476403 TI - The impact of reducing intensive care unit length of stay on hospital costs: evidence from a tertiary care hospital in Canada. AB - PURPOSE: To use theoretical modelling exercises to determine the effect of reduced intensive care unit (ICU) length of stay (LOS) on total hospital costs at a Canadian centre. METHODS: We conducted a retrospective cost analysis from the perspective of one tertiary teaching hospital in Canada. Cost, demographic, clinical, and LOS data were retrieved through case-costing, patient registry, and hospital abstract systems of The Ottawa Hospital Data Warehouse for all new in patient ward (30,483) and ICU (2,239) encounters between April 2012 and March 2013. Aggregate mean daily variable direct (VD) costs for ICU vs ward encounters were summarized by admission day number, LOS, and cost centre. RESULTS: The mean daily VD cost per ICU patient was $2,472 (CAD), accounting for 67.0% of total daily ICU costs per patient and $717 for patients admitted to the ward. Variable direct cost is greatest on the first day of ICU admission ($3,708), and then decreases by 39.8% to plateau by the fifth day of admission. Reducing LOS among patients with ICU stays >= four days could potentially result in an annual hospital cost saving of $852,146 which represents 0.3% of total in-patient hospital costs and 1.2% of ICU costs. CONCLUSION: Reducing ICU LOS has limited cost-saving potential given that ICU costs are greatest early in the course of admission, and this study does not support the notion of reducing ICU LOS as a sole cost-saving strategy. PMID- 29476404 TI - Alcohol-related acute-on-chronic liver failure-Comparison of various prognostic scores in predicting outcome. AB - BACKGROUND AND AIMS: Various prognostic scores are available for predicting outcome in acute-on-chronic liver failure (ACLF). We compared the available prognostic models as predictors of outcome in alcohol-related ACLF patients. METHODS: All consecutive patients with alcohol-related ACLF were included. At admission, prognostic indices-acute physiology and chronic health evaluation score (APACHE II), model for end-stage liver disease (MELD), MELD-Na, Maddrey's discriminant function (DF), age-bilirubin-INR-creatinine (ABIC), and Chronic Liver Failure Consortium (CLIF-C) ACLF score (CLIF-C ACLF) score were calculated. Receiver operator characteristic (ROC) curves were plotted for all prognostic scores with in-hospital, 90-day, and 1-year mortality as outcome. RESULTS: Of the 171 patients, 170 were males, and grade 1 ACLF in 20 (11.7%), grade 2 in 52 (30.4%), and grade 3 in 99 (57.9%) patients. One hundred and nineteen (69.6%) died in-hospital. The median (IQR) Maddrey's score, MELD, MELD-Na, ABIC, APACHE II, and CLIF-C ACLF were 87.8 (66.5-123.0), 33.1 (27.6-40.0), 34.4 (29.5-40.0), 8.5 (7.3-9.6), 15 (12-21), and 51.1 (44.1-56.4), respectively. On multivariate Cox regression analysis, independent predictors of in-hospital outcome were presence of hepatic encephalopathy (early HR, 2.078; 95%CI, 1.173-3.682, p = 0.012 and advanced, HR, 2.330; 95% CI, 1.270-4.276, p = 0.006), elevated serum creatinine (HR, 1.140; 95% CI, 1.023-1.270, p = 0.018), and infection at admission (HR, 1.874; 95% CI, 1.160-23.029, p = 0.010). On comparison of ROC curves, APACHE II and CLIF-C ACLF AUROC were significantly higher than MELD, MELD Na, DF, and ABIC (p < 0.05) for predicting in-hospital, 90-day, and 1-year mortality. The AUROC was highest for APACHE II followed by CLIF-C ACLF (Hanley and McNeil, p = 0.660). CONCLUSIONS: Alcohol-related ACLF has high in-hospital mortality. Among the available prognostic scores, CLIF-C ACLF and APACHE II perform best. PMID- 29476405 TI - PRSS1 (R122H) mutation in an Indian family with low penetrance is associated with pancreatitis phenotype. AB - Mutations in PRSS1 gene namely R122H and N29I cause hereditary pancreatitis. They are autosomal dominant with a high penetrance (80%) reported in North American, North-east Asian, and North European ethnicities. However, the mutations are reportedly absent in Indian, African, and South American ethnicities. We report here for the first time a family from India that is positive for R122H mutation in the PRSS1 gene. The proband is symptomatic with chronic pancreatitis, however, the father although heterozygous for R122H is asymptomatic. PMID- 29476406 TI - Clinical outcomes, histopathological patterns, and chemical analysis of Ayurveda and herbal medicine associated with severe liver injury-A single-center experience from southern India. AB - INTRODUCTION: Ayurvedic and herbal medicines (AHM) are known to cause varying degrees of drug-induced liver injury (DILI). Clinical, biochemical, histological spectrum and outcomes of AHM linked to severe DILI are not well studied. METHODS: Out of 1440 liver disease patients, 94 were found to have a severe liver injury and associated AHM intake. Thirty-three patients were suspected to have AHM-DILI on Roussel Uclaf Causality Assessment Scoring Method. Forty-seven and 30 of retrieved AHM samples were analyzed for heavy metals and hepatotoxic volatile organic compounds (hVOCs), respectively. Eleven patients ingested AHM from unregistered traditional healers (UTH). Clinicopathological outcomes were analyzed in 27 patients (who underwent liver biopsy) and outcomes with respect to chemical analyses were studied in 33 patients. RESULTS: Males predominated (70.4%) with mean age 46.9+/-15.8 years. Mean follow up was 119.2+/-81.4 days. The median duration of drug intake was 28 days (10 - 84). Five patients died (18.5%). Hepatic encephalopathy, hypoalbuminemia, and hepatic necrosis were significantly associated with mortality (p < 0.005). Arsenic and mercury ingestion was significantly associated with death (p < 0.005). hVOCs were detected in more than 70% of samples. AHM intake from UTH was associated with higher mortality. CONCLUSION: Adequate regulation and scrutiny regarding AHM use among the general population is an unmet need. Early liver biopsy after clinical identification of at-risk patients can expedite definitive treatment with a liver transplant. PMID- 29476407 TI - Cross-sectional survey of brucellosis and associated risk factors in the livestock-wildlife interface area of Nechisar National Park, Ethiopia. AB - A cross-sectional survey was carried out to investigate the seroprevalence of ovine and bovine brucellosis in the livestock-wildlife interface area of Nechisar National Park, Ethiopia. Furthermore, producer's knowledge about brucellosis and its zoonotic potential was assessed using a structured questionnaire. A total of 268 cattle and 246 goat sera were collected from 50 herds and 46 flocks and subjected to Rose Bengal test (RBT) and enzyme-linked immunosorbent assay (ELISA) in parallel to detect anti-Brucella species antibodies. Positive reactions were further confirmed with compliment fixation test (CFT). Flock and herd level seroprevalence rate was 12.8% (95% CI 4.8-25.7) and 32.0% (95% CI 19.5-46.7) in goats and cattle, respectively. An overall animal-level seroprevalence of 4.5% (95% CI 2.25-7.86) and 9.7% (95% CI 6.44-13.89) was recorded for goats and cattle, respectively. Seroprevalence showed an increasing trend with age, where adult cattle > 2 years. Goats (> 1 year) recorded relatively higher seroprevalence, but the differences were not statistically significant. Similarly, female cattle and goats recorded a relatively higher seroprevalence, 11 and 5.6%, respectively, compared to males but the difference was not significant. However, a significant (P < 0.01) variation of seroprevalence was noted for parity (bovine), higher in animals in second parity, and abortion history, in both species, higher in animals that experienced abortion. Interviews revealed lack of awareness about brucellosis and food safety related to the zoonotic potential from consuming raw animal products (milk and meat). Ninety eight percent of respondents did not consider handling abortion material is risky, and only a very low proportion (8%, n = 50) was able to mention limited zoonotic diseases (anthrax and Taenia cysticercosis) could be transmissible to people. The study indicated that brucellosis is endemic in domestic animals in the interface area and calls for further broad epidemiological investigation of the disease in livestock, human and wildlife following 'one health' unified research approaches beside enhancing public awareness. PMID- 29476409 TI - Responsibility/Threat Overestimation Moderates the Relationship Between Contamination-Based Disgust and Obsessive-Compulsive Concerns About Sexual Orientation. AB - Disgust has been shown to perform a "disease-avoidance" function in contamination fears. However, no studies have examined the relevance of disgust to obsessive compulsive (OC) concerns about sexual orientation (e.g., fear of one's sexual orientation transforming against one's will, and compulsive avoidance of same-sex and/or gay or lesbian individuals to prevent that from happening). Therefore, we investigated whether the specific domain of contamination-based disgust (i.e., evoked by the perceived threat of transmission of essences between individuals) predicted OC concerns about sexual orientation, and whether this effect was moderated/amplified by obsessive beliefs, in evaluation of a "sexual orientation transformation-avoidance" function. We recruited 283 self-identified heterosexual college students (152 females, 131 males; mean age = 20.88 years, SD = 3.19) who completed three measures assessing disgust, obsessive beliefs, and OC concerns about sexual orientation. Results showed that contamination-based disgust (beta = .17), responsibility/threat overestimation beliefs (beta = .15), and their interaction (beta = .17) each uniquely predicted OC concerns about sexual orientation, ts = 2.22, 2.50, and 2.90, ps < .05. Post hoc probing indicated that high contamination-based disgust accompanied by strong responsibility/threat overestimation beliefs predicted more severe OC concerns about sexual orientation, beta = .48, t = 3.24, p < .001. The present study, therefore, provided preliminary evidence for a "sexual orientation transformation-avoidance" process underlying OC concerns about sexual orientation in heterosexual college students, which is facilitated by contamination-based disgust, and exacerbated by responsibility/threat overestimation beliefs. Treatment for OC concerns about sexual orientation should target such beliefs. PMID- 29476408 TI - Zika virus-induced acute myelitis and motor deficits in adult interferon alphabeta/gamma receptor knockout mice. AB - Zika virus (ZIKV) has received widespread attention because of its effect on the developing fetus. It is becoming apparent, however, that severe neurological sequelae, such as Guillian-Barre syndrome (GBS), myelitis, encephalitis, and seizures can occur after infection of adults. This study demonstrates that a contemporary strain of ZIKV can widely infect astrocytes and neurons in the brain and spinal cord of adult, interferon alpha/beta receptor knockout mice (AG129 strain) and cause progressive hindlimb paralysis, as well as severe seizure-like activity during the acute phase of disease. The severity of hindlimb motor deficits correlated with increased numbers of ZIKV-infected lumbosacral spinal motor neurons and decreased numbers of spinal motor neurons. Electrophysiological compound muscle action potential (CMAP) amplitudes in response to stimulation of the lumbosacral spinal cord were reduced when obvious motor deficits were present. ZIKV immunoreactivity was high, intense, and obvious in tissue sections of the brain and spinal cord. Infection in the brain and spinal cord was also associated with astrogliosis as well as T cell and neutrophil infiltration. CMAP and histological analysis indicated that peripheral nerve and muscle functions were intact. Consequently, motor deficits in these circumstances appear to be primarily due to myelitis and possibly encephalitis as opposed to a peripheral neuropathy or a GBS-like syndrome. Thus, acute ZIKV infection of adult AG129 mice may be a useful model for ZIKV-induced myelitis, encephalitis, and seizure activity. PMID- 29476410 TI - Bisexual Women's Experience of Microaggressions and Microaffirmations: A Community-Based, Mixed-Methods Scale Development Project. AB - In order to better serve bisexual women, clinicians and researchers need tools that accurately reflect and capture bisexual women's experiences of stigma and affirmation. These tools are essential as research indicates that bisexual women experience poorer mental health than either heterosexual or lesbian women. Our community-based study developed and psychometrically evaluated the Bisexual Microaggression and Microaffirmation Scales for Women (BMMS-W). We held focus groups and advisory committee meetings with bisexual women to identify common experiences of microaggressions and microaffirmations and drafted over 200 potential survey items. Exploratory factor analysis of data from 382 participants across Canada and the U.S. yielded five microaggression factors (dismissal; mistrust; sexualization; social exclusion; and denial of complexity) and four microaffirmation factors (acceptance; social support; recognition of bisexuality and biphobia; and emotional support). Confirmatory factor analysis of data from a separate sample of 323 participants across Canada and the U.S. tested the model. The development of the BMMS-W responds to calls to examine the distinctiveness of bisexual women's experience and gives mental health service providers and researchers a tool to better understand their experiences. PMID- 29476411 TI - Evaluation of adequacy of levo-thyroxine dosage in patients with differentiated thyroid carcinoma: correlation between morning and afternoon TSH determination. AB - PURPOSE: The aim of this study was to judge the reliability of evaluating thyroid stimulating hormone (TSH) and free thyroxine (f-T4) in the morning and afternoon in differentiated thyroid carcinoma (DTC) patients. METHODS: We evaluated 153 DTC patients, aged 61 +/- 13 years, in active follow-up in our center after primary treatments and under stabilized levo-thyroxine (L-T4) posology. In each patient, morning and afternoon examinations were performed 1-3 months apart. Blood samples were collected at 08:00-09:00 h and 15:00-16:00 h. TSH and f-T4 were evaluated in both samples. Thyroglobulin (Tg), Tg-antibodies and neck ultrasonography were also evaluated. RESULTS: According to clinical and laboratory examinations, 92% of patients were disease-free, 6% had biochemical disease, and 2% structural disease. L-T4 dosages (1.64 +/- 0.38 ug/kg b.w.) proved the same on both occasions, despite slight changes in body weight or L-T4 posology in 15% of patients. Free-T4 values were significantly higher in the afternoon (21.5 +/- 0.3 pmol/L) than in the morning (18.8 +/- 0.4 pmol/L; P < 0.0001), whereas TSH values were statistically unchanged (morning 0.85 +/- 0.25 mIU/L; afternoon 0.72 +/- 0.20 mIU/L). There was a significant correlation (P < 0.0001) between the two TSH determinations in the same patients. CONCLUSIONS: In DTC patients, follow-up examination consists of clinical and laboratory evaluations. The majority of patients have good disease control. Our study suggests that the adequacy of L-T4 therapy can be monitored equally well either in the morning or in the afternoon. Afternoon examinations can alleviate crowding in hospital ambulatories in the morning. PMID- 29476412 TI - Clinical features of infection caused by non-tuberculous mycobacteria: 7 years' experience. AB - INTRODUCTION: Non-tuberculous mycobacteria (NTM) are ubiquitous organisms associated with various infections. The aim of the study was to determine the most relevant clinical characteristics of NTM during the 7-year period. METHODOLOGY: A retrospective study of NTM infections was conducted between January 2009 and December 2016. The American Thoracic Society/Infectious Disease Society of America criteria were used to define cases of pulmonary or an extrapulmonary site. RESULTS: A total of 85 patients were included in the study. Pulmonary cases predominated 83/85 (98%), while extrapulmonary NTM were present in 2/95 (2%) patients. Overall, ten different NTM species were isolated. The most common organisms were slow-growing mycobacteria (SGM) presented in 70/85 (82.35%) patients. Isolated SGM strains were Mycobacterium avium complex (MAC) in 25/85 (29.41%) patients, M. xenopi in 20/85 (23.53%) patients, M. kansasii in 15/85 (17.65%) patients and M. peregrinum and M. gordonae in 5/85 (5.88%) patients each. Isolated rapid-growing mycobacteria (RGM) strains were M. abscessus in 8/85 (9.41%) patients, M. fortuitum in 4/85 (4.71%) patients and M. chelonae in 3/85 (3.53%) patients. Almost all patients (98%; 83/85) had comorbidities. Among 75 (88.24%) patients who completed follow-up, 59 (69.41%), 10 (11.76%) and 6 (7%), were cured, experienced relapse and died, respectively. CONCLUSION: In the present study, pulmonary NTM infections were more frequent compared to extrapulmonary disease forms. SGM were most common isolates with MAC pulmonary disease the most frequently found. Comorbidities have an important role in NTM occurrence. Further investigation should focus on an NTM drug susceptibility testing. PMID- 29476413 TI - A Real-World Anti-Diabetes Medication Cost Comparison Between Premixed Insulin Analogs and Long-Acting Insulin Analogs in Chinese Patients with Type 2 Diabetes: A Retrospective Database Analysis. AB - INTRODUCTION: To assess and compare per-day anti-diabetic medication costs for Chinese type-2 diabetes mellitus (T2DM) insulin-naive patients between those who initiated premixed insulin analogs ("premixed group") and those who initiated long-acting insulin analogs ("long-acting group"). METHODS: Data were obtained from an electronic medical record database between 2010.01.01 and 2015.06.30 covering medical encounter records from all general hospitals in a district from Shanghai, China. Insulin-naive T2DM patients who were aged >= 18 years, treated with an oral anti-diabetic drug (OAD) only during the baseline period (3 months prior to insulin initiation), and initiated premixed or long-acting insulin analogs were included. Patients were followed until index insulin discontinuation or 12 months after initiation, whichever came first. The t test and generalized linear models adjusting for propensity score (PS) (including baseline demographics, number of OAD classes, comorbidities, costs, and healthcare resource utilization) were used to examine the differences between the two insulin groups. RESULTS: A total of 570 and 185 patients were identified for the premixed and long-acting groups, with mean (SD) ages of 63.0 (12.8) and 61.1 (11.9) (P = 0.08) and male proportions of 47.4% and 51.4% (P = 0.35), respectively. During the baseline period, 19.3% of the premixed users had T2DM related hospitalizations, while the rate was 12.4% in the long-acting group (P = 0.03). The mean number of T2DM-related outpatient visits was 0.98 and 1.23 for the premixed and long-acting groups, respectively (P = 0.07). During the follow up period, the per-day insulin dose averaged 31.7 and 15.3 international units (IU) for the premixed and long-acting groups, respectively. Compared with the patients on premixed insulin, the mean per-day cost for patients on long-acting insulin was 37.3% higher [15.3 vs 11.2 Chinese yuan (RMB); mean difference (MD) (95% CI): 4.2 (3.2, 5.1)] for the overall anti-diabetes medication, 81.3% higher [3.3 vs 1.8 RMB; MD (95% CI): 1.5 (0.8, 2.2)] for OAD, and 28.6% higher [12.0 vs 9.3 RMB; MD (95% CI): 2.7 (2.1, 3.3)] for insulin. The results were consistent after adjusting for the PS. CONCLUSION: Among Chinese T2DM insulin-naive patients, those who initiated premixed insulin had a lower per-day antidiabetic medication cost than those who initiated long-acting insulin. FUNDING: Lilly Suzhou Pharmaceutical Co. Ltd, China. PMID- 29476415 TI - A Rare Cause of Upper Gastrointestinal Bleeding: Adult Pulmonary Sequestration. PMID- 29476414 TI - Insulin Matters: A Practical Approach to Basal Insulin Management in Type 2 Diabetes. AB - It is currently estimated that 11 million Canadians are living with diabetes or prediabetes. Although hyperglycemia is associated with serious complications, it is well established that improved glycemic control reduces the risk of microvascular complications and can also reduce cardiovascular (CV) complications over the long term. The UKPDS and ADVANCE landmark trials have resulted in diabetes guidelines recommending an A1C target of <= 7.0% for most patients or a target of <= 6.5% to further reduce the risk of nephropathy and retinopathy in those with type 2 diabetes (T2D), if it can be achieved safely. However, half of the people with T2D in Canada are not achieving these glycemic targets, despite advances in diabetes pharmacological management. There are many contributing factors to account for this poor outcome; however, one of the major factors is the delay in treatment advancement, particularly a resistance to insulin initiation and intensification. To simplify the process of initiating and titrating insulin in T2D patients, a group of Canadian experts reviewed the evidence and best clinical practices with the goal of providing guidance and practical recommendations to the diabetes healthcare community at large. This expert panel included general practitioners (GPs), nurses, nurse practitioners, endocrinologists, dieticians, pharmacists, and a psychologist. This article summarizes the panel recommendations. PMID- 29476416 TI - Longitudinal Impact of a Randomized Clinical Trial to Improve Family Function, Reduce Maternal Stress and Improve Child Outcomes in Families of Children with ADHD. AB - Objective Evaluate the efficacy of a 12 month nursing case-management intervention over a period of 18 months, 6 months after the end of intervention, for families of children attention deficit hyperactivity disorder (ADHD). Methods Mother and child dyads were enrolled to participate in a randomized controlled clinical trial. Children were 4-18 years old. Data were collected at baseline, 6, 12, and 18 months or 6 months after the termination of direct intervention. Longitudinal analyses, using generalized estimating equations, were conducted to assess change in study outcomes relating to family function, maternal stress, and child behavior over the 18 month period. Results Compared to control families, some family function outcomes were moderately improved in the intervention group. In particular, intervention families demonstrated substantial improvement in implementing family behavior controls (p value = 0.038) and improvement in family satisfaction (not statistically significant p = 0.062). Although there was improvement in the overall family function measure there was not a statistically significant difference between groups. Maternal stress and child behavior outcomes were not significantly different between control and intervention groups by the end of the intervention. Conclusions for Practice Addressing ADHD is complex and requires the assessment of comorbidities that might exacerbate negative behavior. Our findings support the latest American Academy of Pediatrics guidelines to use behavioral therapy as the first line of treatment in young children. Nursing case-management interventions that provide direct family education and improve family function, especially with respect to providing structure and behavior control, may complement and facilitate behavioral therapy for treatment of ADHD and improving child behavior. PMID- 29476417 TI - Redesigning the Maternal, Infant and Early Childhood Home Visiting Program Performance Measurement System. AB - Objectives Statute for the Maternal, Infant and Early Childhood Home Visiting (MIECHV) Program requires that states and territories receiving Program funding assess improvements for participating families across six areas that address maternal and child well-being. In 2015, the MIECHV Program performance measurement system was redesigned to allow for national-level analyses and cross grantee comparisons. The new measures were aligned with other federal performance measures to help ensure context for program analyses. The number of measures was also reduced to lessen reporting burden. This paper describes the redesign process and resulting national performance measures. Methods The redesign process included holding listening sessions with stakeholders and experts; reviewing the findings from other home visiting performance initiatives; consulting with experts; soliciting and responding to public comment on draft measures; seeking clearance from the Office of Management and Budget; and specifying each measure with detailed eligibility criteria, the timing and frequency of assessments, and the window for data collection. Results The redesign resulted in a set of 19 measures that all MIECHV-funded home visiting programs began collecting in 2016. This is nearly half the number of measures that MIECHV awardees had been reporting prior to the redesign. The measures are aligned with other federal measures, including those used in Healthy People 2020 and those used for other maternal and child health programs. Conclusions for Practice Data reported by MIECHV Program awardees will be used to assess their performance, identify areas for targeted technical assistance to support continuous improvement, and ensure meaningful impacts for at-risk families. PMID- 29476418 TI - Easily size-adjustable homemade snare effective for bailout of kinked guiding catheter. PMID- 29476419 TI - Text mining-based in silico drug discovery in oral mucositis caused by high-dose cancer therapy. AB - INTRODUCTION: Oral mucositis (OM) is a major dose-limiting side effect of chemotherapy and radiation used in cancer treatment. Due to the complex nature of OM, currently available drug-based treatments are of limited efficacy. OBJECTIVES: Our objectives were (i) to determine genes and molecular pathways associated with OM and wound healing using computational tools and publicly available data and (ii) to identify drugs formulated for topical use targeting the relevant OM molecular pathways. METHODS: OM and wound healing-associated genes were determined by text mining, and the intersection of the two gene sets was selected for gene ontology analysis using the GeneCodis program. Protein interaction network analysis was performed using STRING-db. Enriched gene sets belonging to the identified pathways were queried against the Drug-Gene Interaction database to find drug candidates for topical use in OM. RESULTS: Our analysis identified 447 genes common to both the "OM" and "wound healing" text mining concepts. Gene enrichment analysis yielded 20 genes representing six pathways and targetable by a total of 32 drugs which could possibly be formulated for topical application. A manual search on ClinicalTrials.gov confirmed no relevant pathway/drug candidate had been overlooked. Twenty-five of the 32 drugs can directly affect the PTGS2 (COX-2) pathway, the pathway that has been targeted in previous clinical trials with limited success. CONCLUSIONS: Drug discovery using in silico text mining and pathway analysis tools can facilitate the identification of existing drugs that have the potential of topical administration to improve OM treatment. PMID- 29476420 TI - An Evaluation of "Drug Ineffective" Postmarketing Reports in Drug Safety Surveillance. AB - INTRODUCTION: The most commonly reported adverse event, based on frequency of Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (PTs), in the US FDA Adverse Event Reporting System (FAERS) database is "drug ineffective" (DI). This study aimed to describe the DI reports and provide data to support recommendations on how to best evaluate these reports. METHODS: We characterized all FAERS reports coded with the MedDRA PT "drug ineffective" received between 1 September 2012 and 31 August 2016 using all other FAERS reports as a comparator. Additionally, we conducted a manual evaluation to identify informative data elements in the report narratives. RESULTS: During the study period, 247,513 (6.4% of all FAERS reports) DI reports were entered in FAERS. Compared with non DI reports, DI reports were more likely to be reported by consumers (69.8 vs. 48.1%) and less likely to report a serious outcome (26.2 vs. 56.3%). Most DI reports (88%) were from the USA. Manual evaluation of 552 sample US reports identified 43 reports (7.8%) deemed "useful"; a higher proportion of "useful" reports provided a batch or lot number (39.5 vs. 17.2%) and were coded with additional PTs beyond "drug ineffective" (83.7 vs. 59.2%), the most frequent of which were "product quality issue" (23.3%) and "product substitution issue" (18.6%). CONCLUSIONS: DI was the most frequently reported adverse event in the FAERS database; however, the yield from these reports in terms of usefulness from a pharmacovigilance perspective was low. Efficient strategies are needed to identify which DI reports are more likely to contain useful information. PMID- 29476422 TI - Electron requirements for carbon incorporation along a diel light cycle in three marine diatom species. AB - Diatoms account for about 40% of primary production in highly productive ecosystems. The development of a new generation of fluorometers has made it possible to improve estimation of the electron transport rate from photosystem II, which, when coupled with the carbon incorporation rate enables estimation of the electrons required for carbon fixation. The aim of this study was to investigate the daily dynamics of these electron requirements as a function of the diel light cycle in three relevant diatom species and to apprehend if the method of estimating the electron transport rate can lead to different pictures of the dynamics. The results confirmed the species-dependent capacity for photoacclimation under increasing light levels. Despite daily variations in the photosynthetic parameters, the results of this study underline the low daily variability of the electron requirements estimated using functional absorption of the photosystem II compared to an estimation based on a specific absorption cross section of chlorophyll a. The stability of the electron requirements throughout the day would suggest it is potentially possible to estimate high-frequency primary production by using autonomous variable fluorescence measurements from ships-of-opportunity or moorings, without taking potential daily variation in this parameter into consideration, but this result has to be confirmed on natural phytoplankton assemblages. The results obtained in this study confirm the low electron requirements of diatoms to perform photosynthesis, and suggest a potential additional source of energy for carbon fixation, as recently described in the literature for this class. PMID- 29476421 TI - Immunosuppression in pregnant women with renal disease: review of the latest evidence in the biologics era. AB - Care of pregnant woman, including fertility and procreation counseling, has become a significant part of the nephrological practice in the last years. In this context, the management of immunosuppression assumes a primary role both for autoimmune diseases and for post-transplant follow up. The present review analyzes the latest evidence on immunosuppressive drugs of current use in nephrology and kidney transplantation. Although the placenta inactivates prednisone and prednisolone, it is advisable to limit the dose to the minimal effective one, to prevent side effects. Azathioprine is generally the immunosuppressive of choice in many high-risk pregnancies in autoimmune diseases because of the safety profile and its steroid-sparing property. In lupus nephropathy, hydroxychloroquine is a current indication in the prevention of flares. Cyclosporine and tacrolimus can also be used as steroid-sparing agents as well as in post-transplant maintenance therapy. Experience on mammalian target of rapamycin inhibitors is limited and its use during pregnancy is still controversial even if initial positive data are emerging. Intravenous immunoglobulins are safe and represent an important option for relapses of lupus and vasculitis. Mycophenolate mofetil and cyclophosphamide are to avoid. An important part is reserved to biologic agents, which are having a huge impact on therapy protocols for several pathologies. Data on the utilization of these molecules during pregnancy, however, are still scant and therefore they do not yet allow a definitive evaluation of their safety profile. PMID- 29476424 TI - Enhanced particle self-ordering in a double-layer channel. AB - In this work, a novel double-layer microfluidic device for enhancing particle focusing was presented. The double-layer device consists of a channel with expansion-contraction array and periodical slanted grooves. The secondary flows induced by the grooves modulate the flow patterns in the expansion-contraction array (ECA) channel, further affecting the particle migration. Compared with the single ECA channel, the double-layer channel can focus the particles over a wider range of flow rate. Due to the differentiation of lateral migration, the double layer channel is able to distinguish the particles with different sizes. Furthermore, the equilibrium positions could be modulated by the orientation of grooves. This work demonstrates the possibility to enhance and adjust the inertial focusing in an ECA channel with the assistance of grooves, which may provide a simple and portable platform for downstream filtration, separation, and detection. PMID- 29476423 TI - Differential stem cell aging kinetics in Hutchinson-Gilford progeria syndrome and Werner syndrome. AB - Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A (LMNA) gene, resulting in the production of a truncated protein product-progerin. WS is caused by mutations in WRN gene, encoding a loss of-function RecQ DNA helicase. Here, by gene editing we created isogenic human embryonic stem cells (ESCs) with heterozygous (G608G/+) or homozygous (G608G/G608G) LMNA mutation and biallelic WRN knockout, for modeling HGPS and WS pathogenesis, respectively. While ESCs and endothelial cells (ECs) did not present any features of premature senescence, HGPS- and WS-mesenchymal stem cells (MSCs) showed aging-associated phenotypes with different kinetics. WS-MSCs had early-onset mild premature aging phenotypes while HGPS-MSCs exhibited late-onset acute premature aging characterisitcs. Taken together, our study compares and contrasts the distinct pathologies underpinning the two premature aging disorders, and provides reliable stem-cell based models to identify new therapeutic strategies for pathological and physiological aging. PMID- 29476425 TI - The learning environment and resident burnout: a national study. AB - INTRODUCTION: Concerns exist about the negative impact of burnout on the professional and personal lives of residents. It is suggested that the origins of burnout among residents are rooted in the learning environment. We aimed to evaluate the association between the learning environment and burnout in a national sample of Dutch residents. METHODS: We conducted a cross-sectional online survey among all Dutch residents in September 2015. We measured the learning environment using the three domain scores on content, organization, and atmosphere from the Scan of Postgraduate Educational Environment Domains (SPEED) and burnout using the Dutch version of the Maslach Burnout Inventory (UBOS-C). RESULTS: Of 1,231 responding residents (33 specialties), 185 (15.0%) met criteria for burnout. After adjusting for demographic (age, gender and marital status) and work-related factors (year of training, type of teaching hospital and type of specialty), we found a consistent inverse association between SPEED scores and the risk of burnout (aOR 0.54, 95% CI 0.46 to 0.62, p < 0.001). DISCUSSION: We found a strong and consistent inverse association between the perceived quality of the learning environment and burnout among residents. This suggests that the learning environment is of key importance in preventing resident burnout. PMID- 29476426 TI - Current practice of orthopaedic surgical skills training raises performance of supervised residents in total knee arthroplasty to levels equal to those of orthopaedic surgeons. AB - AIM: To investigate whether the current, generally accepted practice of orthopaedic surgical skills training can raise the performance of supervised residents to levels equal to those of experienced orthopaedic surgeons when it comes to clinical outcomes or implant position after total knee arthroplasty. METHODS: In a retrospective analysis of primary total knee arthroplasty outcomes (minimum follow-up of 12 months) procedures were split into two groups: supervised orthopaedic residents as first surgeon (group R), and experienced senior orthopaedic surgeons as first surgeon (group S). Outcome data that were compared 1 year postoperatively were operation times, complications, revisions, Knee Society Scores (KSS) and radiological implant positions. RESULTS: Of 642 included procedures, 220 were assigned to group R and 422 to group S. No statistically significant differences between the two groups were found in patient demographics. Operation time differed significantly (group R: 81.3 min vs. group S: 71.3 min (p = 0.000)). No statistically significant differences were found for complications (p = 0.659), revision rate (p = 0.722), femoral angle (p = 0.871), tibial angle (p = 0.804), femoral slope (p = 0.779), tibial slope (p = 0.765) and KSS (p = 0.148). DISCUSSION AND CONCLUSION: Supervised residents needed 10 minutes extra operation time, but they provided the same quality of care in primary total knee arthroplasty as experienced orthopaedic surgeons concerning complication rates, revisions, implant position on radiographs and KSS. The currently used training procedure in which the supervising surgeon and the resident decide if the resident is ready to be first surgeon is safe for patients. PMID- 29476428 TI - Summary of the proceedings of the International Forum 2017: "Position of interventional radiology within radiology". AB - : The International Forum is held once a year by the ESR and its international radiological partner societies with the aim to address and discuss selected topics of global relevance in radiology. In 2017, the issue of the position of interventional radiology (IR) within radiology was analysed. IR is expanding because of the increased patient demand for minimally invasive therapies performed under imaging guidance, and its success in improving patient outcomes, reducing in-hospital stays, reducing morbidity and mortality of treatment in many organs and organ-systems. Despite the many successes of IR, public awareness about it is quite low. IR requires specific training and, in most countries, the majority of interventional radiologists do not dedicate their time completely to IR but perform diagnostic radiology investigations as well. Turf battles in IR are common in many countries. To preserve and keep IR within radiology, it is necessary to focus more on direct and longitudinal patient care. Having beds dedicated to IR within radiology departments is very important to increase clinical involvement of interventional radiologists. IR procedures fit perfectly within "value-based healthcare", but the metrics have to be developed. MAIN MESSAGES: * IR should stay a prominent subspecialty within radiology. * Dedicated IR training pathways are mandatory. * Measures to increase recruitment of young doctors to IR and to increase public awareness of IR are needed. * Beds dedicated to IR within radiology departments are important in order to increase clinical involvement of interventional radiologists. PMID- 29476427 TI - Wearable Inertial Sensor Systems for Lower Limb Exercise Detection and Evaluation: A Systematic Review. AB - BACKGROUND: Analysis of lower limb exercises is traditionally completed with four distinct methods: (1) 3D motion capture; (2) depth-camera-based systems; (3) visual analysis from a qualified exercise professional; and (4) self-assessment. Each method is associated with a number of limitations. OBJECTIVE: The aim of this systematic review is to synthesise and evaluate studies which have investigated the capacity for inertial measurement unit (IMU) technologies to assess movement quality in lower limb exercises. DATA SOURCES: A systematic review of studies identified through the databases of PubMed, ScienceDirect and Scopus was conducted. STUDY ELIGIBILITY CRITERIA: Articles written in English and published in the last 10 years which investigated an IMU system for the analysis of repetition-based targeted lower limb exercises were included. STUDY APPRAISAL AND SYNTHESIS METHODS: The quality of included studies was measured using an adapted version of the STROBE assessment criteria for cross-sectional studies. The studies were categorised into three groupings: exercise detection, movement classification or measurement validation. Each study was then qualitatively summarised. RESULTS: From the 2452 articles that were identified with the search strategies, 47 papers are included in this review. Twenty-six of the 47 included studies were deemed as being of high quality. CONCLUSIONS: Wearable inertial sensor systems for analysing lower limb exercises is a rapidly growing field of research. Research over the past 10 years has predominantly focused on validating measurements that the systems produce and classifying users' exercise quality. There have been very few user evaluation studies and no clinical trials in this field to date. PMID- 29476429 TI - Hyperechoic breast images: all that glitters is not gold! AB - : Hyperechogenicity is a sign classically reported to be in favour of a benign lesion and can be observed in many types of benign breast lesions such as hamartoma, lipoma, angiolipoma, haemangioma, haematoma, fat necrosis, fibrosis and galactocele, among others. However, some rare malignant breast lesions can also present a hyperechoic appearance. Most of these hyperechoic malignant lesions present other characteristics that are more typically suggestive of malignancy such as posterior shadowing, a more vertical axis or irregular margins that help to guide the diagnosis. Post magnetic resonance imaging, second-look ultrasound may visualise hyperechoic malignant lesions that would not have been identified at first sight and radiologists must know how to recognise these lesions. TEACHING POINTS: * Some rare malignant breast lesions can present a hyperechoic appearance. * Malignant lesions present other characteristics that are suggestive of malignancy. * An echogenic mass with fat density on mammography does not require biopsy. PMID- 29476430 TI - Manipulation of metabolic pathways controlled by signaling molecules, inducers of antibiotic production, for genome mining in Streptomyces spp. AB - Streptomyces is well characterized by an ability to produce a wide variety of secondary metabolites including antibiotics, whose expression is strictly controlled by small diffusible signaling molecules at nano-molar concentrations. The signaling molecules identified to date are classified into three skeletons; gamma-butyrolactones, furans, and gamma-butenolides. Accumulated data suggest the structural diversity of the signaling molecules in Streptomyces species and their potential in activating cryptic secondary metabolite biosynthetic pathways. Several genome mining approaches to activate silent biosynthetic gene clusters have been reported for natural product discovery. This review updates recent examples on genetic manipulation including blockage of metabolic pathways together with inactivation of transcriptional repressor genes. PMID- 29476431 TI - Renalase contributes to protection against renal fibrosis via inhibiting oxidative stress in rats. AB - BACKGROUND: Renal interstitial fibrosis (RIF) is a common pathway for progression of chronic kidney disease (CKD) to end-stage renal disease. In our previous study, it has been provided that renalase can ameliorate renal interstitial fibrosis in unilateral ureteral obstruction (UUO) rats. The other mechanism of renalase to alleviate renal fibrosis should be explored. MATERIALS AND METHODS: In this study, we evaluated the role of oxidative stress in UUO rats and epithelial-mesenchymal transition (EMT) in human proximal renal tubular epithelial (HK-2) cells and examined the association of renalase. RESULTS: Oxidative stress could induce EMT and fibrosis in HK-2 cells. In the UUO model, oxidative stress occurred and maintained at a high level leading to RIF. Administration of renalase by adenovirus significantly attenuated oxidative stress and further in vitro study showed that renalase can exert anti-fibrosis by inhibiting oxidative stress. CONCLUSION: Our results prompt another mechanism of anti-fibrotic renal protection of renalase, which may be partly associated with inhibiting oxidative stress. These data provided another theoretical basis that supplementation with exogenous renalase may be a promising strategy for slowing or halting the progression of CKD. PMID- 29476432 TI - Cigarette smoking and risk of albuminuria in patients with type 2 diabetes: a systematic review and meta-analysis of observational studies. AB - BACKGROUND: The aim of this study was to assess the effects of smoking on albuminuria risk in adults with type 2 diabetes mellitus (T2DM). METHODS: A literature search was conducted using MEDLINE, EMBASE, and China National Knowledge Infrastructure from the established date to October 2017. Summary relative risks (SRR) and 95% confidence intervals (CI) were computed utilizing a random effect inverse variance method. RESULTS: This meta-analysis included a total of 19 relevant observational studies (four prospective cohort, seven case control, and eight cross-sectional studies), reporting 105,031 participants and 23,366 albuminuria events. Compared with never-smokers with T2DM, the SRRs of albuminuria were 1.43 (95% CIs 1.27-1.61) for ever-smokers, 2.61 (95% CIs 1.86 3.64) for current smokers, and 1.86 (95% CIs 1.37-2.52) for former smokers. Considerable heterogeneity was observed among these studies, and study design was a significant modifier for this association. There were significantly elevated risk associations for microalbuminuria (SRRs = 1.24, 95% CIs 1.05-1.46) and for macroalbuminuria (SRRs = 1.65, 95% CIs 1.03-2.66), respectively. CONCLUSIONS: Our systematic review and meta-analysis indicates that cigarette smoking might be a potential factor for the development of albuminuria in adults with T2DM. Future studies are required to investigate the association between smoking cessation and intensity and incident albuminuria in adults with T2DM. PMID- 29476433 TI - Prediction of hemodialysis vascular access failure using segmental bioimpedance analysis parameters. AB - PURPOSE: Segmental bioimpedance analysis (BIA) can identify fluid volume changes in the arms of patients on hemodialysis (HD) after vascular access surgery. We investigated whether the difference in fluid volumes between the arms of the patients using segmental BIA is associated with vascular access outcome. METHODS: Body composition measurements were taken for 127 patients on HD with segmental, multi-frequency BIA equipment (InBody 1.0, Biospace Co. Ltd, Seoul, Korea). The difference in fluid volume between the arms of the patients was calculated from the fluid volume of the arm with the vascular access minus that of the other. The primary outcome was the loss of vascular access patency within 3 months of BIA measurement. RESULTS: The median absolute and relative inter-arm fluid volume differences were 150 ml [interquartile range (IQR) 90-250 ml] and 9.6% (IQR 4.9 14.4%), respectively. Within 3 months of BIA measurement, 38 patients (30.0%) experienced vascular access failure. When the patients were divided into three groups based on the tertiles of relative inter-arm fluid volume differences (lowest tertile: < 6.8%; middle tertile: 6.8-12.7%; highest tertile: > 12.7%), greater difference in relative inter-arm fluid volume differences was associated with higher vascular access failure rates (14 vs. 28 vs. 48%, p value for trend across tertiles = 0.003). CONCLUSIONS: We conclude that segmental BIA may be used as a tool that can predict vascular access failure in patients on HD by calculating the relative difference in fluid volume between the arms of the patients with and without vascular access. PMID- 29476434 TI - Complementary medicines in pregnancy: recommendations and information sources of healthcare professionals in Australia. AB - Background The use of oral complementary and alternative medicines, including herbal supplements, has been increasing in pregnant women worldwide despite limited safety data. The decision of healthcare professionals to recommend these products to pregnant patients is controversial and not well documented. Objective To explore the recommendations and information sources that healthcare professionals use to determine the safety of oral non-prescribed supplements during pregnancy. Setting An Australian metropolitan maternity hospital. Method An electronic survey was distributed to doctors, midwives, pharmacists, dietitians, lactation consultants and physiotherapists. Main outcome measure The nature of recommendations and information sources that healthcare professionals use to determine the safety of oral non-prescribed supplements during pregnancy. Results Responses were received from 54 healthcare professionals. Forty of 54 (74.1%) were concerned about the safety of their patients' supplements, while 35 of 54 (64.8%) felt that they had access to trustworthy safety information. Supplements most commonly recommended as safe to use were ginger (40.7%), probiotics (29.6%) and raspberry leaf (22.2%). Participants specifically requested further safety information for raspberry leaf, evening primrose oil, fish oil, probiotics, ginger, vitamin C, valerian, turmeric, blue cohosh and colloidal silver. Written resources most frequently consulted included MIMS(r) (61.1%) and 'Google Searches' (29.6%), and healthcare professionals most referred to were pharmacists (74.1%), doctors (22.2%), and naturopaths or herbalists (3.7%). Conclusion The recommendations of maternity heath care professionals and quality of information sources used varied. Further education and access to unbiased safety information is required to empower healthcare professionals to provide informed recommendations to pregnant patients. PMID- 29476435 TI - Age at Sexual Initiation and Sexual and Health Risk Behaviors Among Jamaican Adolescents and Young Adults. AB - Current policies limit access to sexual and reproductive health services for adolescents younger than 16 years in Jamaica. Using data from a national survey, we explored the relationship between age at sexual initiation and subsequent sexual risk behaviors in a random sample of 837 Jamaican adolescents and young adults aged 15-24 years. In the sample overall, 21.0% had not yet had sex. Among the 661 sexually active participants, the mean age at first sex was 14.7 years. High percentages of sexually active youth reported engaging in risk behaviors such as inconsistent condom use (58.8%), multiple sex partners (44.5%), and transactional sex (43.0%). Age of sexual initiation for males was unrelated to subsequent sexual risk behaviors. However, earlier sexual debut for females was associated with their number of partners during the preceding year. Findings underscore the potential benefits of access to sexual and reproductive education and services at earlier ages than current policies allow. Interventions before and during the period of sexual debut may reduce sexual risk for Jamaican adolescents and young adults. PMID- 29476436 TI - The Impact of Quality Assurance Initiatives and Workplace Policies and Procedures on HIV/AIDS-Related Stigma Experienced by Patients and Nurses in Regions with High Prevalence of HIV/AIDS. AB - Stigma is commonly experienced by people living with HIV/AIDS and by those providing care to HIV/AIDS patients. Few intervention studies have explored the impact of workplace policies and/or quality improvement on stigma. We examine the contribution of health care workplace policies, procedures and quality assurance initiatives, and self- and peer-assessed individual nurse practices, to nurse reported HIV/AIDS-stigma practices toward patients living with HIV/AIDS and nurses in health care settings. Our sample of survey respondents (n = 1157) included managers (n = 392) and registered/enrolled nurses (n = 765) from 29 facilities in 4 countries (South Africa, Uganda, Jamaica, Kenya). This is one of the first studies in LMIC countries to use hierarchical linear modeling to examine the contributions of organizational and individual factors to HIV/AIDS stigma. Based on our results, we argue that organizational interventions explicitly targeting HIV/AIDS stigma are required to reduce the incidence, prevalence and morbidity of HIV/AIDS. PMID- 29476437 TI - Incidence and Persistence of Depression Among Women Living with and Without HIV in South Africa: A Longitudinal Study. AB - Depression and trauma are common among women living with HIV. This is the first study to track the longitudinal course of depression and examine the relationship between depression and trauma over time among women in South Africa. HIV-infected and uninfected women (N = 148) were assessed at baseline and one year later. Results of a path analysis show the multi-directional and entwined influence of early life stress, other life-threatening traumas across the lifespan, depression and PTSD over the course of HIV. We also observed higher rates of depressive symptomatology and more persistent cases among infected women compared to uninfected women, as well as a more consistent and enduring relationship between childhood trauma and depression among women living with HIV. The present study is unique in documenting the course of untreated depression and PTSD in women with and without HIV infection with a high prevalence of early childhood trauma. PMID- 29476438 TI - Re: Effects of serial macrocyclic-based contrast materials gadoterate meglumine and gadobutrol administrations on gadolinium-related dentate nuclei signal increases in unenhanced T1-weighted brain: a retrospective study in 158 multiple sclerosis (MS) patients. PMID- 29476439 TI - Sclerotherapy of peripheral low-flow vascular malformations: technical aspects and mid-term clinical outcome. AB - PURPOSE: The therapeutical management of low-flow vascular malformations (LFVMs) is challenging because of high recurrence rate; multiple strategies have been proposed. This paper aims to report a single-center experience of direct puncture sclerotherapy of peripheral LFVMs, focusing on technical aspects and clinical outcome in mid-term follow-up. MATERIALS AND METHODS: 16 patients have been treated for peripheral LFVMs (mean age 36.1 years), complaining mild pain, swelling of the region of interest, and cosmetic nuisance. Preprocedural US and MR were acquired; angiography performed only in doubt vascular supply. Standard procedure consisted of direct puncture of the nidus using 20-23 gauge needles under US guidance and injection of up to 15 ml foam of sodium tetradecyl sulphate under fluoroscopic guidance. Clinical and radiological follow-up were assessed at 1, 3, and 6 months. RESULTS: Lesions were localized: 8 in the upper and 5 the in lower limbs, 2 in the cheeks, and 1 in the vaginal labia. All procedures have been technically accomplished (100%). At 6 month follow-up, technical and clinical success were obtained in all cases, while radiological follow-up showed 81.2% (13 patients) complete vessels thrombosis after multiple sclerotherapy sessions. No major complications have been recorded; five patients (31.2%) referred minor complications. CONCLUSIONS: Sclerotherapy via direct puncture of LFVMs is a clinically effective procedure, well tolerated by patients, with reduced costs and mild minor complications rate; interventionalists should always clarify to the patients that multiple sessions would be performed and recurrences are expected at imaging follow-up despite clinical improvement. PMID- 29476440 TI - Biopsy is not necessary for the diagnosis of soft tissue hemangiomas. AB - OBJECTIVE: To describe the clinical and ultrasonography (US) findings of soft tissue hemangiomas, and to compare with the results of histologic diagnosis after US-guided biopsy. METHOD AND MATERIALS: We retrospectively studied the files of 97 patients (48 female, 49 male; mean age, 34 years; range 4-84 years) with soft tissue hemangiomas diagnosed from 2004 to 2011. Mean follow-up was 9 years (range 7-13 years). Clinical presentation included intermittent mild pain associated with a soft tissue swelling/palpable mass in all patients, chronic pain and increased local heat in 29 patients, local swelling and decreased range of motion of the adjacent joint in 45 patients, and all the above symptoms in 23 patients. B-mode and color Doppler US evaluation included the site, location, size, shape, margins, presence of calcifications, echo structure and echogenicity. All patients had US-guided biopsy for histologic analysis. RESULTS: US-guided biopsy and histology confirmed the diagnosis of soft tissue hemangioma in 92 of the 97 lesions (94.8%). Histologic examination of the remaining five lesions showed nodular fasciitis (two lesions), endometriosis (one lesion), hemangioendothelioma (two lesions); US of these lesions showed variable size, irregular margins, and deep-seated location. Histologically documented soft tissue hemangiomas were most commonly superficial (74 lesions) and arteriovenous (45 lesions). Shape was most commonly oval (fusiform), margins were most commonly not well defined (irregular, hazing but circumscribed), phleboliths were more common in deep-seated lesions, echo structure was heterogeneous, and echogenicity was most commonly hyperechogen and involuting. CONCLUSION: Clinical presentation and typical B-mode and color Doppler US findings are adequate for the diagnosis of soft tissue hemangiomas without the need for biopsy and histologic analysis. If any clinical or US doubt, an US-guided biopsy should be performed. PMID- 29476441 TI - Association Between Body Mass Index and Disease Severity in Chinese Spinocerebellar Ataxia Type 3 Patients. AB - Spinocerebellar ataxia type 3 (SCA3), the most common subtype of SCA worldwide, is caused by mutation of CAG repeats expansion in ATXN3. Body mass index (BMI) is an important modulatory factor in the progression of neurodegenerative disorders such as Huntington disease and amyotrophic lateral sclerosis. However, its relevance in SCA3 is not well understood. In this study, BMI was investigated in 134 molecularly confirmed SCA3 patients and 136 healthy controls from China. The multivariable linear regression models were performed to establish the putative risk factors for BMI, and whether BMI could affect the severity of ataxia. We found that BMI was significantly lower in the case group than that in the control group. The age at onset (positive correlation) and severity of ataxia (negative correlation) were the risk factors affecting BMI. Conversely, BMI along with the disease duration, the age at onset, and the numbers of CAG repeats could also have influence on the severity of ataxia. In conclusion, SCA3 patients had lower BMI than matched controls and BMI is a predictor of disease progression in SCA3. Nutritional intervention to promote weight gain could be a promising strategy to impede SCA3 progression. PMID- 29476442 TI - Novel Homozygous KCNJ10 Mutation in a Patient with Non-syndromic Early-Onset Cerebellar Ataxia. AB - Mutations in KCNJ10, which encodes the inwardly rectifying potassium channel Kir4.1, a primary regulator of membrane excitability and potassium homeostasis, cause a complex syndrome characterized by seizures, sensorineural deafness, ataxia, intellectual disability, and electrolyte imbalance called SeSAME/EAST syndrome. We describe a 41-year-old patient with non-syndromic, slowly progressive, early-onset ataxia. Targeted next-generation sequencing identified a novel c.180 T > G (p.Ile60Met) missense homozygous mutation. The mutated residue Ile60Met likely impairs phosphatidylinositol 4, 5-bisphosphate (PIP2) binding which is known to play an essential role in channel gating. Our study expands the clinical and mutational spectrum of KCNJ10-related disorders and suggests that screening of this gene should be implemented in patients with early-onset ataxia, with or without syndromic features. PMID- 29476444 TI - Dose Titration of Pregabalin in Patients with Painful Diabetic Peripheral Neuropathy: Simulation Based on Observational Study Patients Enriched with Data from Randomized Studies. AB - INTRODUCTION: Achieving a therapeutic response to pregabalin in patients with painful diabetic peripheral neuropathy (pDPN) requires adequate upward dose titration. Our goal was to identify relationships between titration and response to pregabalin in patients with pDPN. METHODS: Data were integrated from nine randomized, placebo-controlled clinical trials as well as one 6-week open-label observational study conducted by 5808 physicians (2642 patients with pDPN) in standard outpatient settings in Germany. These studies evaluated pregabalin for treatment of pDPN. Using these data, we examined "what if" scenarios using a microsimulation platform that integrates data from randomized and observational sources as well as autoregressive-moving-average with exogenous inputs models that predict pain outcomes, taking into account weekly changes in pain, sleep interference, dose, and other patient characteristics that were unchanging. RESULTS: Final pain levels were significantly different depending on dose changes (P < 0.0001), with greater proportions improving with upward titration regardless of baseline pain severity. Altogether, 78.5% of patients with pDPN had 0-1 dose change, and 15.2% had >= 2 dose changes. Simulation demonstrated that the 4.8% of inadequately titrated patients who did not improve/very much improve their pain levels would have benefited from >= 2 dose changes. Patient satisfaction with tolerability (range 90.3-96.2%) was similar, regardless of baseline pain severity, number of titrations, or extent of improvement, suggesting that tolerability did not influence treatment response patterns. CONCLUSION: Upward dose titration reduced pain in patients with pDPN who actually received it. Simulation also predicted pain reduction in an inadequately titrated nonresponder subgroup of patients had they actually received adequate titration. The decision not to uptitrate must have been driven by factors other than tolerability. FUNDING: Pfizer, Inc. PMID- 29476443 TI - Prospective Evaluation of Two iStent(r) Trabecular Stents, One iStent Supra(r) Suprachoroidal Stent, and Postoperative Prostaglandin in Refractory Glaucoma: 4 year Outcomes. AB - INTRODUCTION: This study evaluates long-term outcomes of two trabecular micro bypass stents, one suprachoroidal stent, and postoperative prostaglandin in eyes with refractory open angle glaucoma (OAG). METHODS: Prospective ongoing 5-year study of 80 eligible subjects (70 with 4-year follow-up) with OAG and IOP >= 18 mmHg after prior trabeculectomy and while taking 1-3 glaucoma medications. Subjects received two iStent(r) trabecular micro-bypass stents, one iStent Supra(r) suprachoroidal stent, and postoperative travoprost. Postoperative IOP was measured with medication and annually following medication washouts. Performance was measured by the proportion of eyes with >= 20% IOP reduction on one medication (the protocol-specified prostaglandin) versus preoperative medicated IOP (primary outcome); and the proportion of eyes with postoperative IOP <= 15 and <= 18 mmHg on one medication (secondary outcome). Additional clinical and safety data included medications, visual field, pachymetry, gonioscopy, adverse events, visual acuity, and slit-lamp and fundus examinations. RESULTS: Preoperatively, mean medicated IOP was 22.0 +/- 3.1 mmHg on 1.2 +/- 0.4 medications, and mean unmedicated IOP was 26.4 +/- 2.4 mmHg. Postoperatively, among eyes without later cataract surgery, mean medicated IOP at all visits through 48 months was <= 13.7 mmHg (>= 37% reduction), and annual unmedicated IOP was <= 18.4 mmHg (reductions of >= 30% vs. preoperative unmedicated IOP and >= 16% vs. preoperative medicated IOP). At all postoperative visits among eyes without additional surgery or medication, >= 91% of eyes had >= 20% IOP reduction on one medication versus preoperative medicated IOP. At month 48, 97 and 98% of eyes achieved IOP <= 15 and <= 18 mmHg, respectively, on one medication. Six eyes required additional medication, no eyes required additional glaucoma surgery, and safety measurements were favorable throughout follow-up. CONCLUSION: IOP control was achieved safely with two trabecular micro-bypass stents, one suprachoroidal stent, and postoperative prostaglandin. This microinvasive, ab interno approach introduces a possible new treatment option for refractory disease. TRIAL REGISTRATION: NCT01456390. FUNDING: Glaukos Corporation. PMID- 29476445 TI - Response to: the nearly complete TME quality conundrum. PMID- 29476446 TI - Random duodenal biopsy to exclude coeliac disease as a cause of anaemia is not cost-efective and should be replaced with universally performed pre-endoscopy serology in patients on a suspected cancer pathway. AB - BACKGROUND: Random duodenal biopsy to exclude coeliac disease during upper gastrointestinal endoscopy for the investigation of iron deficiency anaemia remains a common procedure, but is expensive and time-consuming. Serological investigation for coeliac disease is also recommended, having excellent accuracy with the added benefit of lower cost. This study sought to examine the utility of duodenal biopsy and coeliac serology in the diagnosis of coeliac disease. METHODS: A prospectively maintained database was interrogated to identify all patients having upper gastrointestinal endoscopy for the investigation of anaemia between January 01, 2016, and December 31, 2016. RESULTS: Of the 1131 patients having an endoscopy, coeliac serology was measured in only 412 (36%) and was positive in 9 cases (2%), leading to 6 histological diagnoses of coeliac disease and 3 false positives. Two-hundred and seventy-four patients with negative serology had biopsies taken which were all negative. Only 2/451 (0.4%) patients who had biopsies performed in the absence of a serology test were histologically positive for coeliac disease. The cost per diagnosis of a case of coeliac disease in those with either negative or absent coeliac serology was L18,839 (US$25,244, ?21,196). CONCLUSIONS: Random duodenal biopsy is not a cost-effective method of diagnosing coeliac disease and should be replaced with pre-endoscopy coeliac serology. PMID- 29476447 TI - Release of IL-6 After Stroke Contributes to Impaired Cerebral Autoregulation and Hippocampal Neuronal Necrosis Through NMDA Receptor Activation and Upregulation of ET-1 and JNK. AB - The sole FDA-approved drug treatment for ischemic stroke is tissue-type plasminogen activator (tPA). However, upregulation of JNK mitogen-activated protein kinase (MAPK) and endothelin 1 (ET-1) by tPA after stroke contributes to impaired cerebrovascular autoregulation. Wild-type (wt) tPA can bind to the lipoprotein-related receptor (LRP), which mediates vasodilation, or NMDA receptors (NMDA-Rs), exacerbating vasoconstriction. Elevations in IL-6, a marker of inflammation that accompanies stroke, are reported to be an adverse prognostic factor. We hypothesized that IL-6 released into CSF after stroke by wt-tPA through activation of NMDA-Rs and upregulation of ET-1 and JNK contribute to impairment of cerebrovascular autoregulation and increased histopathology. Results show that IL-6 was increased post stroke in pigs, which was increased further by wt-tPA. Co-administration of the IL-6 antagonist LMT-28 with wt-tPA prevented impairment of cerebrovascular autoregulation and necrosis of hippocampal cells. wt-tPA co-administered with the JNK inhibitor SP 600125 and the ET-1 antagonist BQ 123 blocked stroke-induced elevation of IL-6. Co administration of LMT-28 with wt-tPA blocked the augmentation of JNK and ET-1 post stroke. In conclusion, IL-6 released after stroke, which is enhanced by wt tPA through activation of NMDA-Rs and upregulation of ET-1 and JNK, impairs cerebrovascular autoregulation and increases histopathology. Strategies that promote fibrinolysis while limiting activation of NMDA-Rs and upregulation of IL 6 may improve the benefit/risk ratio compared to wt-tPA in treatment of stroke. PMID- 29476449 TI - AMPA-Type Glutamate Receptor Conductance Changes and Plasticity: Still a Lot of Noise. AB - Twenty years ago, we reported from the Collingridge Lab that a single-channel conductance increase through alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type ionotropic glutamate receptors (AMPARs) could mediate one form of plasticity associated with long-term potentiation (LTP) in the hippocampus (Benke et al., Nature 395:793-797, 1998). Revealed through peak-scaled non stationary fluctuation analysis (PS-NSFA, also known as noise analysis), this component of LTP could be exclusively mediated by direct increases in channel conductance or by increases in the number of high conductance synaptic AMPARs. Re evaluation of our original data in the light of the molecular details regarding AMPARs, conductance changes and plasticity suggests that insertion of high conductance GluA1 homomers can account for our initial findings. Any potential cost associated with manufacture or trafficking of new receptors could be mitigated if pre-existing synaptic AMPARs also undergo a modest conductance change. The literature suggests that the presence of high conductance AMPARs and/or GluA1 homomers confers an unstable synaptic state, suggesting state transitions. An experimental paradigm is proposed to differentiate these possibilities. Validation of this state diagram could provide insight into development, disease pathogenesis and treatment. PMID- 29476448 TI - Ras-Related C3 Botulinum Toxin Substrate 1 Promotes Axonal Regeneration after Stroke in Mice. AB - Neurite plasticity is a critical aspect of brain functional recovery after stroke. Emerging data suggest that Ras-related C3 botulinum toxin substrate 1 (Rac1) plays a central role in axonal regeneration in the injured brain, specifically by stimulating neuronal intrinsic growth and counteracting the growth inhibitory signaling that leads to growth cone collapse. Therefore, we investigated the functional role of Rac1 in axonal regeneration after stroke.Delayed treatment with a specific Rac1 inhibitor, NSC 23766, worsened functional recovery, which was assessed by the pellet reaching test from day 14 to day 28 after stroke. It additionally reduced axonal density in the peri infarct zone, assessed 28 days after stroke, with no effect on brain cavity size or on the number of newly formed cells. Accordingly, Rac1 overexpression using lentivirus promoted axonal regeneration and functional recovery after stroke from day 14 to day 28. Rac1 inhibition led to inactivation of pro-regenerative molecules, including mitogen-activated protein kinase kinase (p-MEK)1/2, LIM domain kinase (LIMK)1, and extracellular signal-regulated kinase (p-ERK)1/2 at 14 days after stroke. Inhibition of Rac1 reduced axonal length and number in cultured primary mouse cortical neurons using microfluidic chambers after oxygen glucose deprivation (OGD) without affecting cell viability. In contrast, inhibition of Rac1 increased levels of glial fibrillary acidic protein, an extrinsic inhibitory signal for axonal growth, after stroke in vivo and in primary astrocytes after OGD.In conclusion, Rac1 signaling enhances axonal regeneration and improve post-stroke functional recovery in experimental models of stroke. PMID- 29476450 TI - Dopamine Promotes Ascorbate Release from Retinal Neurons: Role of D1 Receptors and the Exchange Protein Directly Activated by cAMP type 2 (EPAC2). AB - Ascorbate, the reduced form of vitamin C, is highly concentrated in the central nervous system (CNS), including the retina, where it plays important physiological functions. In the CNS, the plasma membrane transporter sodium vitamin C co-transporter 2 (SVCT2) is responsible for ascorbate transport in neurons. The neurotransmitter dopamine (DA), acting through D1- and D2-like receptor subfamilies and classically coupled to adenylyl cyclase, is known to modulate synaptic transmission in the retina. Here, we reveal that DA controls the release of ascorbate from retinal neurons. Using primary retinal cultures, we show that this DA effect is dose-dependent, occurring by the reversal of the SVCT2, and could be elicited by brief and repetitive pulses of DA. The DA effect in inducing ascorbate release occurs by the activation of D1R and is independent of PKA. Moreover, the exchange protein directly activated by cAMP type 2 (EPAC2) is present in retinal neurons and its specific knockdown using shRNAs abrogates the D1R-induced ascorbate release. Confirming the physiological relevance of this pathway, activation of D1R or EPAC2 also triggered ascorbate release ex vivo in acute preparations of the intact retina. Overall, DA plays pivotal roles in regulating ascorbate homeostasis through an unanticipated signaling pathway involving D1R/adenylyl cyclase/cAMP/EPAC2, thereby suggesting that vitamin C might fine-tune dopaminergic neurotransmission in the retina. PMID- 29476454 TI - Isolated cardiac amyloidosis. Utility of bone seeking tracers scintigraphy in differentiating the subtype of amyloid: A case report. AB - BACKGROUND: Three types of amyloid are responsible for cardiac amyloidosis. Differentiation of the subtype is critical for the disease progression and the therapeutic decision. RESULTS: Myocardial scintigraphy using Tc-PYP is able to differentiate the cardiac amyloid subtype with high sensitivity and specificity. The myocardial uptake of PYP is higher in patients with TTR amyloidosis. CONCLUSION: Non-invasive tests for the detection of cardiac amyloidosis, like myocardial scintigraphy with bone seeking tracers, can play a major role in the diagnosis progression and therapeutic management of patients with cardiac amyloidosis. PMID- 29476451 TI - The Role of Renin-Angiotensin-Aldosterone System and Its New Components in Arterial Stiffness and Vascular Aging. AB - Many cardiovascular diseases present renin-angiotensin-aldosterone system (RAAS) hyperactivity as an important pathophysiological mechanism to be target in the therapeutic approaches. Moreover, arterial stiffness is currently considered as a new independent risk factor for cardiovascular disease in different clinical conditions, including hypertension and chronic kidney disease. In fact, excessive stimulation of angiotensin type 1 (AT1) receptors, as well as mineralocorticoid receptors, results in cellular growth, oxidative stress and vascular inflammation, which may lead to arterial stiffness and accelerate the process of vascular aging. In the last decades, a vasoprotective axis of the RAAS has been discovered, and now it is well established that new components with antioxidant and anti-inflammatory properties play important roles promoting vasodilation, natriuresis and reducing collagen deposition, thus attenuating arterial stiffness and improving endothelial function. In this review, we will focus on these pathophysiological mechanisms and the relevance of RAAS inhibition by different strategies to increase arterial compliance and to decelerate vascular aging. PMID- 29476452 TI - Neuroimaging Signatures of Cerebral Small Vessel Disease at Blood Pressure Cutoff Levels of 130/80 and 140/90 mmHg: A Population-Based Study in Community-Dwellers Aged >= 60 Years. AB - INTRODUCTION: Recent guidelines suggest that a blood pressure cutoff of 130/80 mmHg should be used to define arterial hypertension. This contrasts with the previously accepted cutoff of 140/90 mmHg. AIM: Using the Atahualpa Project cohort, we aimed to assess the cutoff that better correlates with signatures of cerebral small vessel disease (SVD), which are related to arterial hypertension. METHODS: Of 437 Atahualpa residents aged >= 60 years, 363 (83%) underwent brain MRI and blood pressure determinations. Using logistic regression models, we evaluated the association between SVD and the two different cutoffs, after adjusting for demographics and cardiovascular risk factors. Using receiver operator characteristics curve analysis, we calculated sensitivity, specificity, and the area under the curve for the predictive value of the two cutoffs for detecting signatures of SVD. RESULTS: A comparison between the old and new cutoffs showed no differences in the ability to predict subjects with white matter hyperintensities, deep cerebral microbleeds or basal ganglia perivascular spaces. However, the new cutoff improved the identification of individuals with lacunar infarctions, which went from no association using the old cutoff (p = 0.097) to a significant association using the new cutoff (p = 0.036). The new cutoff was more sensitive but less specific than the old cutoff for identifying signatures of cerebral SVD. Areas under the curve were non-significantly higher for the old than for the new cutoffs for all the lesions of interest. CONCLUSIONS: The new blood pressure cutoff is consistently more sensitive but less specific than the old cutoff for detecting signatures of cerebral SVD. The most striking effect of the new cutoff is the improvement in the identification of lacunar infarctions. PMID- 29476455 TI - What is the value of motion and thickening in gated myocardial perfusion SPECT? PMID- 29476456 TI - CEUS in the differential diagnosis between biliary sludge, benign lesions and malignant lesions. AB - PURPOSE: Conventional grayscale ultrasound (US) is accurate in the diagnosis of gallbladder disease (GD), but in some cases, it is not decisive. Contrast enhanced ultrasound (CEUS) improves the diagnostic accuracy of US. The primary objective of this study is to assess the reliability of CEUS in the diagnosis of sludge; the secondary objective is to assess the ability of CEUS to diagnose cancer. METHODS: We retrospectively reviewed the US of 4137 patients positive for GD. In 43/4137 (1.04%), the use of could not discriminate between sludge and neoplasms. Then, we evaluated CEUS in only 39 of these patients, and in 4/43 (9%) cases it was not performable. After CEUS, the absence of enhancement was considered diagnostic for sludge, while contrast washout within 60 s diagnosed malignant lesions. RESULTS: Among the 39 patients, 16 had biliary sludge and 23 had lesions of the gallbladder wall; 9 of these were carcinomas and 14 were benign tumors. The absence of enhancement was present in 16/16 patients with sludge and in 0/23 patients with lesions of the gallbladder (sensitivity and specificity 100%). Washout was within 60 s in 9/9 gallbladder carcinomas and 2/14 benign lesions (sensitivity 100%; specificity 85%). CONCLUSIONS: US is confirmed to be accurate in the diagnosis of GD. In doubtful cases, CEUS is very accurate in biliary sludge diagnosis. An intralesional washout at 60 s is a pattern of malignancy that can orient towards a correct diagnosis, but it is limited by the presence of false positive results, especially for smaller lesions. PMID- 29476458 TI - Author Correction to: Comparative Efficacy of Drugs for Preventing Acute Kidney Injury after Cardiac Surgery: A Network Meta-Analysis. AB - In the print publication, the affiliations were incorrectly published. The author affiliations which previously read Xi Chen1 . Tianlun Huang2 . Xuan Cao1 . Gaosi Xu2 1Grade 2013, The Second Clinical Medical College of Nanchang University, Nanchang, Jiangxi, People's Republic of China 2Department of Nephrology, The Second Affiliated Hospital of Nanchang University, No. 1, Minde Road, Donghu District, 330006 Nanchang, Jiangxi, People's Republic of China. PMID- 29476457 TI - Psychosocial Adjustment Throughout University: A Longitudinal Investigation of the Roles of Sleep Quality and Emotion Dysregulation. AB - Sleep problems and emotion dysregulation are associated with depressive symptoms and alcohol use but little research has examined the long-term associations and the direction of effects between these factors. We examined these relationships with 1132 undergraduates (70.5% female) over 5 years. Sleep problems and emotion dysregulation, sleep problems and depressive symptoms, and emotion dysregulation and depressive symptoms were all related bidirectionally. Tests of indirect effects indicated that sleep problems predicted depressive symptoms over time (and vice versa) via emotion dysregulation and emotion dysregulation predicted depressive symptoms over time (and vice versa) via sleep problems. The results highlight the need to assess direction of effects, given that many factors that are typically seen as "predictors" also can be framed as "outcomes". PMID- 29476459 TI - Warfarin Safety: A Cross-Sectional Study of the Factors Associated with the Consumption of Medicinal Plants in a Brazilian Anticoagulation Clinic. AB - OBJECTIVE: The aim of this study was to analyze factors associated with the consumption of medicinal plants by patients being treated with warfarin in a Brazilian anticoagulation clinic and to study the safety of medicinal plant use in patients on warfarin therapy. METHODS: The study was performed as an observational cross-sectional analysis. Study participants were outpatients on long-term warfarin therapy for at least 2 months for atrial fibrillation or prosthetic cardiac valves. Interviews were carried out concerning information about the habits of medicinal herb consumption, and logistic regression analysis was performed to identify factors associated with the consumption of herbs. The scientific names of the medicinal plants were identified to search for information on the effects on the hemostasis of the interactions between the medicinal herbs reported and warfarin. RESULTS: The mean age of the 273 patients included was 60.8 years; 58.7% were women. Medicinal plants were used by 67% of the participants. No association between demographic and clinical data and the use of medicinal plants was identified. Patients reported a total of 64 different plants, primarily consumed in the form of tea. The plants were mainly used to treat respiratory tract and central nervous system disorders. About 40% of the plants cited have been reported to potentially interfere with the anticoagulation therapy, principally by potentiating the effects of warfarin, which could, increase the risk of bleeding. CONCLUSION: The use of medicinal plants was highly common and widespread in patients receiving warfarin as an anticoagulation therapy. Univariate analysis of variables associated with the consumption of herbs showed no statistically significant difference in the consumption of medicinal plants for any of the sociodemographic and clinical data. The medicinal plants that were reportedly consumed by the patients could affect hemostasis. This study reinforces the need for further studies evaluating the habits of patients consuming medicinal plants and their clinical implications, and will help to design strategies to manage the risks associated with warfarin-herbal interactions. PMID- 29476460 TI - Heterogeneity of Metazoan Cells and Beyond: To Integrative Analysis of Cellular Populations at Single-Cell Level. AB - In this paper, we review some of the recent advances in cellular heterogeneity and single-cell analysis methods. In modern research of cellular heterogeneity, there are four major approaches: analysis of pooled samples, single-cell analysis, high-throughput single-cell analysis, and lately integrated analysis of cellular population at a single-cell level. Recently developed high-throughput single-cell genetic analysis methods such as RNA-Seq require purification step and destruction of an analyzed cell often are providing a snapshot of the investigated cell without spatiotemporal context. Correlative analysis of multiparameter morphological, functional, and molecular information is important for differentiation of more uniform groups in the spectrum of different cell types. Simplified distributions (histograms and 2D plots) can underrepresent biologically significant subpopulations. Future directions may include the development of nondestructive methods for dissecting molecular events in intact cells, simultaneous correlative cellular analysis of phenotypic and molecular features by hybrid technologies such as imaging flow cytometry, and further progress in supervised and non-supervised statistical analysis algorithms. PMID- 29476461 TI - Integrating Analysis of Cellular Heterogeneity in High-Content Dose-Response Studies. AB - Heterogeneity is a complex property of cellular systems and therefore presents challenges to the reliable identification and characterization. Large-scale biology projects may span many months, requiring a systematic approach to quality control to track reproducibility and correct for instrumental variation and assay drift that could mask biological heterogeneity and preclude comparisons of heterogeneity between runs or even between plates. However, presently there is no standard approach to the tracking and analysis of heterogeneity. Previously, we demonstrated the use of the Kolmogorov-Smirnov statistic as a metric for monitoring the reproducibility of heterogeneity in a screen and described the use of three heterogeneity indices as a means to characterize, filter, and browse cellular heterogeneity in big data sets (Gough et al., Methods 96:12-26, 2016). In this chapter, we present a detailed method for integrating the analysis of cellular heterogeneity in assay development, validation, screening, and post screen. Importantly, we provide a detailed method for quality control, to normalize cellular data, track heterogeneity over time, and analyze heterogeneity in big data sets, along with software tools to assist in that process. The example screen for this method is from an HCS project, but the approach applies equally to other experimental methods that measure populations of cells. PMID- 29476462 TI - Image-Based Tracking of Heterogeneous Single-Cell Phenotypes. AB - Cells display broad heterogeneity across multiple phenotypic features, including motility, morphology, and cell signaling. Live-cell imaging techniques are beginning to capture the importance and interdependence of these phenomena. However, existing image analysis pipelines often fail to capture the intricate changes that occur in small subpopulations, either due to poor segmentation protocols or cell tracking errors. Here we report a pipeline designed to image and track single-cell dynamic phenotypes in heterogeneous cell populations. We provide step-by-step instructions for three phenotypically different cell lines across two time scales as well as recommendations for adaptation to custom data sets. Our protocols include steps for quality control that can be used to filter out erroneous tracks and improve assessment of heterogeneity. We demonstrate possible phenotypic readouts including motility, nuclear receptor translocation, and mitosis. PMID- 29476463 TI - Broad Immune Monitoring and Profiling of T Cell Subsets with Mass Cytometry. AB - Mass cytometry (cytometry by time-of-flight, CyTOF) is a high-dimensional single cell analytical technology that allows for highly multiplexed measurements of protein or nucleic acid abundances by bringing together the detection capacity of atomic mass spectroscopy and the sample preparation workflow typical of regular flow cytometry. In 2014 the mass cytometer was adapted for the acquisition of samples from microscopy slides (termed imaging mass cytometry), greatly increasing the applicability of this technology with the inclusion of spatial information. By using antibodies (or other probes) labeled with purified metal isotopes, mass cytometers are currently able to detect more than 50 different parameters at a single-cell level, exceeding the dimensionality of any other flow cytometry methodology currently on the market. This capability licenses unprecedented possibilities in many areas dealing with complex cellular mixtures (immunology, cell biology, and beyond), improving biomarker discovery and moving us closer to affordable personalized medicine than before. PMID- 29476464 TI - Spectral and Imaging Flow Cytometry in Phytoplankton Research. AB - Spectral and imaging flow cytometry are emerging technologies that allow quantifying spectral, fluorescent, and/or morphological parameters of heterogeneous cellular populations. The protocol describes a detailed step-by step analysis of microalgae using these techniques and examples from our laboratory (Aphanizomenon sp., Cryptomonas pyrenoidifera, and Chlorella sp.). Moreover, the chapter will be helpful to scientists who want to perform spectral flow cytometry and apply principal component analysis. PMID- 29476465 TI - X-Ray Fluorescence-Detected Flow Cytometry. AB - X-ray fluorescence-detected flow cytometry can enable the detection and characterization of ultra-trace, trace, and bulk elemental content at the cellular level using synchrotron-induced x-ray emission from fully aquated actively respiring cells. Although very much still a technique in development, this technique has been used to characterize cell-to-cell elemental variability in bovine red blood cells, Saccharomyces cerevisiae, and NIH3T3 mouse fibroblasts. Herein we describe the experimental setup and the key methodological aspects of data collection and processing. PMID- 29476466 TI - Multiparametric Analysis of Myeloid Populations by Flow Cytometry. AB - Flow cytometry is extensively used for the immune-profiling of leukocytes in tissue during homeostasis and inflammation. The multiparametric power of using fluorescently conjugated antibodies for specific surface and activation markers provides a comprehensive profile of immune cells. This chapter describes the identification and characterization of myeloid populations using flow cytometric analysis in an acute model of resolving inflammation. This model allows the examination of heterogenic populations across different systemic and tissue locations. We describe tissue processing, antibody staining, and analysis, which include a newly described viSNE tool to generate two-dimensional clustering within myeloid populations. We also reference the use of transgenic reporter mice on specific myeloid cells that provides enhanced specificity and profiling when defining myeloid heterogeneity. PMID- 29476467 TI - Quantitation of IRF3 Nuclear Translocation in Heterogeneous Cellular Populations from Cervical Tissue Using Imaging Flow Cytometry. AB - Imaging flow cytometry (IFC) has become a powerful tool for studying the activation of transcriptional factors in heterogeneous cell populations in high content imaging mode. With considerable interest to the clinical development of IFC, the question becomes how we can accelerate its application to solid tissues. We developed the first IFC-based procedure to quantify the nuclear translocation of interferon regulatory factor (IRF) 3, an important measure of induction of type I interferon antiviral response, in primary human immune cells including in solid tissues. After tissue digestion and protocol optimization by spectral flow cytometry, cell suspension is stained for intracellular IRF3 and acquired by IFC. Image analysis is performed using an optimized nuclear mask and similarity score parameter to correlate the location of IRF3 staining and a nuclear dye. The technique measures IRF3 activation at a single cell level and can detect small changes in the percent of activated cells providing objective quantitative data for statistical analysis. PMID- 29476469 TI - Usage of Multiparameter Flow Cytometry to Study Microglia and Macrophage Heterogeneity in the Central Nervous System During Neuroinflammation and Neurodegeneration. AB - The resident macrophages of the central nervous system (CNS), also known as microglia, and blood-derived macrophages play an important role in the functional activity of the normal CNS, as well as in the development of neuroinflammation during various neurodegenerative disorders. Microglia and macrophages represent heterogeneous populations, which can modulate CNS environment and have different effects on neuronal regeneration. In this chapter, the main features of microglial and macrophage subsets and current methods for investigation of their heterogeneity will be discussed. PMID- 29476468 TI - Methods of Study of Neuron Structural Heterogeneity: Flow Cytometry vs. Laser Interferometry. AB - Neuronal cells are probably the less studied cells regarding their heterogeneity on a single cell or population levels. One of the main problems of studying of individual neurons is the presence of long processes (axons) on differentiated adult neurons that hamper their isolation without significant damage to the cells. Therefore, the most common method to study neuronal cells is immunofluorescent microscopy of sections of the brain, which remains poorly quantitative and allows analyzing a small number of fixed cells. Also, immunofluorescent microscopy has a number of staining artifacts since histology section has high level of autofluorescence and non-specific binding of fluorescent probes. Alternative methods that could overcome disadvantages of immunofluorescent histology include flow cytometry, scanning cytometry, and laser interferometry. Flow cytometry and, to some extent of degree, scanning cytometry allow performing analysis of multiple markers with a low level of non-specific background and very robust statistics. Laser interferometry allows studies intact, alive neurons without staining. Limitations and advantages of these methods are discussed in this chapter. PMID- 29476470 TI - Analysis of Microtubule Dynamics Heterogeneity in Cell Culture. AB - Microtubules (MTs) are dynamic components of the cytoskeleton playing an important role in a large number of cell functions. Individual MTs in living cells undergo stochastic switching between alternate states of growth, shortening and attenuated phase, a phenomenon known as tempered dynamic instability. Dynamic instability of MTs is usually analyzed by labeling MTs with +TIPs, namely, EB proteins. Tracking of +TIP trajectories allows analyzing MT growth in cells with a different density of MTs. Numerous labs now use +TIP to track growing MTs in a variety of cell cultures. However, heterogeneity of MT dynamics is usually underestimated, and rather small sampling for the description of dynamic instability parameters is often used. The strategy described in this chapter is the method for repetitive quantitative analysis of MT growth rate within the same cell that allows minimization of the variation in MT dynamics measurement. We show that variability in MT dynamics within a cell when using repeated measurements is significantly less than between different cells in the same chamber. This approach allows better estimation of the heterogeneity of cells' responses to different treatments. To compare the effects of different MT inhibitors, the protocol using normalized values for MT dynamics and repetitive measurements for each cell is employed. This chapter provides detailed methods for analysis of MT dynamics in tissue cultures. We describe protocols for imaging MT dynamics by fluorescent microscopy, contrast enhancement technique, and MT dynamics analysis using triple color-coded display based on sequential subtraction analysis. PMID- 29476471 TI - Heterogeneity of Focal Adhesions and Focal Contacts in Motile Fibroblasts. AB - Cell-extracellular matrix (ECM) adhesion is an important property of virtually all cells in multicellular organisms. Cell-ECM adhesion studies, therefore, are very significant both for biology and medicine. Over the last three decades, biomedical studies resulted in a tremendous advance in our understanding of the molecular basis and functions of cell-ECM adhesion. Based on morphological and molecular criteria, several different types of model cell-ECM adhesion structures including focal adhesions, focal complexes, fibrillar adhesions, podosomes, and three-dimensional matrix adhesions have been described. All the subcellular structures that mediate cell-ECM adhesion are quite heterogeneous, often varying in size, shape, distribution, dynamics, and, to a certain extent, molecular constituents. The morphological "plasticity" of cell-ECM adhesion perhaps reflects the needs of cells to sense, adapt, and respond to a variety of extracellular environments. In addition, cell type (e.g., differentiation status, oncogenic transformation, etc.) often exerts marked influence on the structure of cell-ECM adhesions. Although molecular, genetic, biochemical, and structural studies provide important maps or "snapshots" of cell-ECM adhesions, the area of research that is equally valuable is to study the heterogeneity of FA subpopulations within cells. Recently time-lapse observations on the FA dynamics become feasible, and behavior of individual FA gives additional information on cell-ECM interactions. Here we describe a robust method of labeling of FA using plasmids with fluorescent markers for paxillin and vinculin and quantifying the morphological and dynamical parameters of FA. PMID- 29476472 TI - Laser Tweezers Raman Microspectroscopy of Single Cells and Biological Particles. AB - Laser tweezers Raman spectroscopy (LTRS) is a variation of micro-Raman spectroscopy that is used to analyze single cells and biological particles suspended in an aqueous environment. The Raman spectrum of the cell/particle reflects its intrinsic biochemical composition and molecular structures. The technique utilizes a laser trap generated by a tightly focused Gaussian laser beam to physically manipulate individual cells and immobilize them in the laser focal volume. The same laser that is used for optical trapping also simultaneously excites Raman signals from the trapped cell, which are detected using a spectrometer and a confocal detection setup. LTRS offers unique capabilities not commonly found in other optical cytometry methods, such as label free chemical analysis, multi-parametric chemical detection with a single excitation laser, and a non-photobleaching signal that can be used to quantitate and monitor dynamic chemical changes. This chapter provides guidelines on the design of a single beam LTRS microscope and methods for building and aligning the system. Operating procedures for trapping particles and acquiring spectra and a summary of data analysis techniques are provided. PMID- 29476473 TI - Quantification of the Metabolic Heterogeneity in Mycobacterial Cells Through the Measurement of the NADH/NAD+ Ratio Using a Genetically Encoded Sensor. AB - NADH/NAD+ levels are an indicator of the bacterial metabolic state. NAD(H) levels are maintained through coordination of pathways involved in NAD(H) synthesis and its catabolic utilization. Conventional methods of estimating NADH/NAD+ require cell disruption and suffer from low specificity and sensitivity and are inadequate in providing spatiotemporal resolution. Recently, genetically encoded biosensors of the NADH/NAD+ ratio have been developed. One of these sensors, Peredox-mCherry, was adapted for the measurement of cellular levels of NADH/NAD+ in the slow-growing Mycobacterium tuberculosis (Mtb) and the fast-growing Mycobacterium smegmatis. Importantly, the use of the engineered reporter strains of Mtb demonstrated a significantly higher heterogeneity among the bacteria residing in macrophages compared to the bacteria grown in synthetic media. Previous estimations of NADH/NAD+ levels have missed this important aspect of the biology of Mtb, which may contribute to the variable response of intracellular Mtb to different antimycobacterial agents. In this chapter, we describe the details of a method used in the generation of reporter strains for the measurement of the NADH/NAD+ ratio in mycobacteria. Importantly, once the reporter strains are created, they can be exploited with fluorescence spectroscopy, FACS, and confocal microscopy to access the dynamic changes in the NADH/NAD+ levels in intact individual bacterial cells. Although we have only described the method for the creation of reporter strains capable of measuring NADH/NAD+ in mycobacteria in this chapter, a similar method can be used for generating reporter strains for other bacterial species, as well. We believe that such reporter stains can be used in novel screens for small molecules that could alter the metabolism of bacterial cells and thus aid in the development of new class of therapeutic agents. PMID- 29476474 TI - Characterizing Cell Heterogeneity Using PCR Fingerprinting of Surface Multigene Families in Protozoan Parasites. AB - Parasites counteract the action of the immune system and other environmental pressures by modulating and changing the composition of their cell surfaces. Surface multigene protein families are defined not only by highly variable regions in length and/or sequence exposed to the outer space but also by conserved sequences codifying for the signal peptide, hydrophobic C-terminal regions necessary for GPI modifications, as well as conserved UTR regions for mRNA regulation. The method here presented exploits these conserved signatures for characterizing variations in the mRNA expression of clonal cell populations of protozoan parasites using a combination of nested PCR amplification and capillary electrophoresis. With this workflow, in silico gels from isolated cell clones can be generated, thus providing an excellent tool for analyzing cellular heterogeneity in protozoan parasites. PMID- 29476475 TI - Assessing Carbon Source-Dependent Phenotypic Variability in Pseudomonas putida. AB - The soil bacterium Pseudomonas putida is rapidly becoming a platform of choice for applications that require a microbial host highly resistant to different types of stresses and elevated rates of reducing power regeneration. P. putida is capable of growing in a wide variety of carbon sources that range from simple sugars to complex substrates such as aromatic compounds. Interestingly, the growth of the reference strain KT2440 on glycerol as the sole carbon source is characterized by a prolonged lag phase, not observed with other carbon substrates. This macroscopic phenomenon has been shown to be connected with the stochastic expression of the glp genes, which encode the enzymes needed for glycerol processing. In this protocol, we propose a general procedure to examine bacterial growth in small-scale cultures while monitoring the metabolic activity of individual cells. Assessing the metabolic capacity of single bacteria by means of fluorescence microscopy and flow cytometry, in combination with the analysis of the temporal takeoff of growth in single-cell cultures, is a simple and easy to-implement approach. It can help to understand the link between macroscopic phenotypes (e.g., microbial growth in batch cultures) and stochastic phenomena at the genetic level. The implementation of these methodologies revealed that the adoption of a glycerol-metabolizing regime by P. putida KT2440 is not the result of a gradual change in the whole population, but it rather reflects a time dependent bimodal switch between metabolically inactive (i.e., not growing) to fully active (i.e., growing) bacteria. PMID- 29476476 TI - The Retinal Pigment Epithelial Cell Line (ARPE-19) Displays Mosaic Structural Chromosomal Aberrations. AB - The retinal pigment epithelial cell line ARPE-19 was established in 1996 and remains widely used today for biomedical and in particular ophthalmology research. We have analyzed the chromosomes of the ARPE-19 cell line and found cultured cells exist as a heterogeneous mixture having both normal karyotypes and chromosomal rearrangements. In ARPE-19 cells, we observed metaphases with a single translocation t(15;19) and metaphases with two translocations t(5;15) and t(15;19) and a derivative chromosome 9. Aneuploidies have also been detected (monosomy: -16; trisomy: +11, +18). Multiple attempts to isolate clones with a normal karyotype from those with aberrant karyotypes failed due to senescence of cells of normal karyotypes. We could, however, isolate clones with the translocation t(15;19) and clones with two translocations t(5;15) and t(15;19). In continued cell culture after second subcloning for 30 passages, all clones maintained their cytogenetic integrity.We have further investigated the chromosomal profiles of the ARPE-19 cell line from another laboratory and observed cells with a normal karyotype as well as abnormalities in chromosomes 6p and 11q. The DNA profiles of the ARPE-19 cells from both labs were identical to the ATCC profiles, excluding contamination with other cell lines. Since chromosomal translocations in ARPE-19 cells differ from lab to lab and display a mosaicism for structural chromosomal aberrations, researchers dealing with ARPE 19 cells should screen their stocks for chromosomal aberrations and proceed with caution against misinterpretations during experimental manipulations with this cell line. This chapter describes in detail our laboratory methods for single cell cloning, karyotype analysis and fluorescence in situ hybridization (FISH), which we used for the identification and characterization of chromosomal translocations in the retinal pigment epithelial cell line ARPE-19. PMID- 29476477 TI - FACS Isolation of Viable Cells in Different Cell Cycle Stages from Asynchronous Culture for RNA Sequencing. AB - Recently developed high-throughput analytical techniques (e.g., protein mass spectrometry and nucleic acid sequencing) allow unprecedentedly sensitive, in depth studies in molecular biology of cell proliferation, differentiation, aging, and death. However, the initial population of asynchronous cultured cells is highly heterogeneous by cell cycle stage, which complicates immediate analysis of some biological processes. Widely used cell synchronization protocols are time consuming and can affect the finely tuned biochemical pathways leading to biased results. Besides, certain cell lines cannot be effectively synchronized. The current methodological challenge is thus to provide an effective tool for cell cycle phase-based population enrichment compatible with other required experimental procedures. Here, we describe an optimized approach to live cell FACS based on Hoechst 33342 cell-permeable DNA-binding fluorochrome staining. The proposed protocol is fast compared to traditional synchronization methods and yields reasonably pure fractions of viable cells for further experimental studies including high-throughput RNA-seq analysis. PMID- 29476478 TI - Measuring Nanoscale Chromatin Heterogeneity with Partial Wave Spectroscopic Microscopy. AB - Despite extensive research in the area, current understanding of the structural organization of higher-order chromatin topology (between 20 and 200 nm) is limited due to a lack of proper imaging techniques at these length scales. The organization of chromatin at these scales defines the physical context (nanoenvironment) in which many important biological processes occur. Improving our understanding of the nanoenvironment is crucial because it has been shown to play a critical functional role in the regulation of chemical reactions. Recent progress in partial wave spectroscopic (PWS) microscopy enables real-time measurement of higher-order chromatin organization within label-free live cells. Specifically, PWS quantifies the nanoscale variations in mass density (heterogeneity) within the cell. These advancements have made it possible to study the functional role of chromatin topology, such as its regulation of the global transcriptional state of the cell and its role in the development of cancer. In this chapter, the importance of studying chromatin topology is explained, the theory and instrumentation of PWS are described, the measurements and analysis processes for PWS are laid out in detail, and common issues, troubleshooting steps, and validation techniques are provided. PMID- 29476480 TI - Educational strategies to train health care professionals across the education continuum on the process of frailty prevention and frailty management: a systematic review. AB - BACKGROUND: In addition to the normal process of ageing, frailty, defined as a geriatric syndrome, is becoming more prevalent. Around 10% of people over 65 years and 25-50% of those aged over 85 years are frail. Frail elderly are more vulnerable to external stressors and have an increased risk of adverse health outcomes. To tackle these challenges, European Union (EU) member states need to develop a health work force capable of the right skills mix. A goal-centred education and training of professionals is crucial for effective and efficient health care delivery for Europe's greying population. AIMS: The aim of this study was to systematically collect, review and critically appraise studies carried out to investigate the efficacy and effectiveness of comprehensive educational programmes for health professionals related to frailty prevention and/or frailty management. METHODS: A systematic review was carried out searching the databases PubMed, CINAHL, Cochrane CENTRAL, Medline, Up to date and Embase. Additionally, a manual search of the reference lists and searches via Google Scholar and greylit.org was done. RESULTS: No relevant publications addressing the evidence and sustainability of educational/training programmes for frailty prevention and/or frailty management were identified. DISCUSSION: The result of an empty review is surprising because several educational programmes in different countries are currently run. CONCLUSIONS: A significant knowledge gap exists in the scientific literature regarding education and training of health care workers regarding prevention and management of frailty. Further research is needed to identify effective educational strategies for health professionals to prevent and manage frailty. PMID- 29476479 TI - Vitamin D3 Supplementation Reduces Subsequent Brain Injury and Inflammation Associated with Ischemic Stroke. AB - Acute inflammation can exacerbate brain injury after ischemic stroke. Beyond its well-characterized role in calcium metabolism, it is becoming increasingly appreciated that the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25 VitD3), has potent immunomodulatory properties. Here, we aimed to determine whether 1,25-VitD3 supplementation could reduce subsequent brain injury and associated inflammation after ischemic stroke. Male C57Bl6 mice were randomly assigned to be administered either 1,25-VitD3 (100 ng/kg/day) or vehicle i.p. for 5 day prior to stroke. Stroke was induced via middle cerebral artery occlusion for 1 h followed by 23 h reperfusion. At 24 h post-stroke, we assessed infarct volume, functional deficit, expression of inflammatory mediators and numbers of infiltrating immune cells. Supplementation with 1,25-VitD3 reduced infarct volume by 50% compared to vehicle. Expression of pro-inflammatory mediators IL-6, IL 1beta, IL-23a, TGF-beta and NADPH oxidase-2 was reduced in brains of mice that received 1,25-VitD3 versus vehicle. Brain expression of the T regulatory cell marker, Foxp3, was higher in mice supplemented with 1,25-VitD3 versus vehicle, while expression of the transcription factor, ROR-gamma, was decreased, suggestive of a reduced Th17/gammadelta T cell response. Immunohistochemistry indicated that similar numbers of neutrophils and T cells were present in the ischemic hemispheres of 1,25-VitD3- and vehicle-supplemented mice. At this early time point, there were also no differences in the impairment of motor function. These data indicate that prior administration of exogenous vitamin D, even to vitamin D-replete mice, can attenuate infarct development and exert acute anti inflammatory actions in the ischemic and reperfused brain. PMID- 29476481 TI - Extent of, and variables associated with, blood pressure variability among older subjects. AB - BACKGROUND: Blood pressure variability (BPV) may have prognostic implications for cardiovascular risk and cognitive decline; however, BPV has yet to be studied in old and very old people. AIMS: Aim of the present study was to evaluate the extent of BPV and to identify variables associated with BPV among older subjects. METHODS: A retrospective study of patients aged >= 65 years who underwent 24-h ambulatory blood pressure monitoring (ABPM) was carried out. Three different BPV indexes were calculated for systolic and diastolic blood pressure (SBP and DBP): standard deviation (SD), coefficient of variation (CV), and average real variability (ARV). Demographic variables and use of antihypertensive medications were considered. RESULTS: The study included 738 patients. Mean age was 74.8 +/- 6.8 years. Mean SBP and DBP SD were 20.5 +/- 4.4 and 14.6 +/- 3.4 mmHg. Mean SBP and DBP CV were 16 +/- 3 and 20 +/- 5%. Mean SBP and DBP ARV were 15.7 +/- 3.9 and 11.8 +/- 3.6 mmHg. At multivariate analysis older age, female sex and uncontrolled mean blood pressure were associated with both systolic and diastolic BPV indexes. The use of calcium channel blockers and alpha-adrenergic antagonists was associated with lower systolic and diastolic BPV indexes, respectively. CONCLUSIONS: Among elderly subjects undergoing 24-h ABPM, we observed remarkably high indexes of BPV, which were associated with older age, female sex, and uncontrolled blood pressure values. PMID- 29476482 TI - Why checking model assumptions using null hypothesis significance tests does not suffice: A plea for plausibility. AB - This article explores whether the null hypothesis significance testing (NHST) framework provides a sufficient basis for the evaluation of statistical model assumptions. It is argued that while NHST-based tests can provide some degree of confirmation for the model assumption that is evaluated-formulated as the null hypothesis-these tests do not inform us of the degree of support that the data provide for the null hypothesis and to what extent the null hypothesis should be considered to be plausible after having taken the data into account. Addressing the prior plausibility of the model assumption is unavoidable if the goal is to determine how plausible it is that the model assumption holds. Without assessing the prior plausibility of the model assumptions, it remains fully uncertain whether the model of interest gives an adequate description of the data and thus whether it can be considered valid for the application at hand. Although addressing the prior plausibility is difficult, ignoring the prior plausibility is not an option if we want to claim that the inferences of our statistical model can be relied upon. PMID- 29476483 TI - Bone Imaging: Osteoclast and Osteoblast Dynamics. AB - Bone is continually remodeled by bone-resorbing osteoclasts and bone-forming osteoblasts. Although it has long been believed that bone homeostasis is tightly regulated by communication between osteoclasts and osteoblasts, the fundamental process and dynamics have remained elusive. To resolve this, we established an intravital bone imaging system using multiphoton microscopy to visualize mature osteoclasts and osteoblasts in living bone.We herein describe the methodology for visualizing the in vivo behavior of bone-resorbing osteoclasts and bone-forming osteoblasts in living bone tissues using intravital multiphoton microscopy. This approach facilitates investigation of cellular dynamics in the pathogenesis of bone-destructive disorders, such as osteoporosis and rheumatoid arthritis in vivo, and would thus be useful for evaluating the efficacy of novel anti-bone resorptive drugs. PMID- 29476484 TI - Intravital Imaging of Mouse Bone Marrow: Hemodynamics and Vascular Permeability. AB - The bone marrow is a unique microenvironment where blood cells are produced and released into the circulation. At the top of the blood cell lineage are the hematopoietic stem cells (HSC), which are thought to reside in close association with the bone marrow vascular endothelial cells (Morrison and Scadden, Nature 505:327-334, 2014). Recent efforts at characterizing the HSC niche have prompted us to make close examinations of two distinct types of blood vessel in the bone marrow, the arteriolar vessels originating from arteries and sinusoidal vessels connected to veins. We found the two vessel types to exhibit different vascular permeabilites, hemodynamics, cell trafficking behaviors, and oxygen content (Itkin et al., Nature 532:323-328, 2016; Spencer et al., Nature 508:269-273, 2014). Here, we describe a method to quantitatively measure the permeability and hemodynamics of arterioles and sinusoids in murine calvarial bone marrow using intravital microscopy. PMID- 29476486 TI - Live Imaging of Interstitial T Cell Migration Using Lymph Node Slices. AB - Live imaging using various microscopic technologies is an indispensable tool for investigating the dynamic nature of immune cells. One of the most powerful techniques is the two-photon laser-scanning microscopy (TP-LSM), which has various advantages in observing deep tissues in vivo. Interstitial T cell migration in the lymph node (LN) is a phenomenon intensively examined using TP LSM in the field of immunology. Intravital and explant methods have been standards for imaging T cell behaviors in the LN, though there are several limitations. Live imaging of LN slices, an LN explant sliced by a vibratome to expose tissue parenchyma, could provide an alternative approach with technical advantages for an in-depth analysis of interstitial T cell migration in vivo. PMID- 29476485 TI - Bone Imaging: Platelet Formation Dynamics. AB - Bone imaging using multiphoton microscopy enables dynamic observation of platelet formation in living animals. Two-photon excitation microscopy is superior to confocal microscopy as it enables deeper tissue penetration, efficient light detection, and reduced phototoxicity. Using this microscopy approach, thrombopoiesis by megakaryocytes is clearly visualized in the skull at significant depth from the surface. Here we describe our microscopy setup and dye recipe for visualization of bone marrow in the mouse skull. PMID- 29476487 TI - Two-Photon Imaging of T-Cell Motility in Lymph Nodes: In Vivo and Ex Vivo Approaches. AB - T-cell motility is essential for the T cells' ability to scan antigens within lymph nodes and initiate contact with antigen-presenting cells. While T-cell migration has been extensively studied using in vitro migration assays, accumulating evidence indicates that the T-cell migration within lymph nodes is modulated by the surrounding cells and extracellular matrix, which form the confined architecture of the lymph nodes. Therefore, to understand the mechanisms of T-cell motility in vivo, their cell migration must be analyzed under physiological conditions. To this end, two-photon microscopy is extremely useful; this technique enables the tracking of fluorescently labeled cells in vivo and ex vivo, with high spatial and temporal resolutions. Here we describe the experimental procedures for applying two-photon microscopy to the in vivo and ex vivo imaging of T-cell migration in mouse lymph nodes. These approaches provide physiological insight into the mechanisms of T-cell behavior at a single-cell level in the three-dimensional lymph node environment. PMID- 29476488 TI - Imaging the Lymph Node Stroma. AB - Lymph node (LN) stromal cells are being recognized as key organizers of the immune system. They assemble in complex 3D networks and hence, need to be studied in situ to fully understand their exact functions. Here, we describe two distinct but complementary procedures that allow analyzing LN stromal cells at high resolution by confocal imaging. PMID- 29476489 TI - Intravital Imaging of B Cell Responses in Lymph Nodes. AB - Humoral immune responses depend on B cells encountering antigen (Ag) in lymph nodes (LNs) draining infection sites, getting activated, interacting with different cells, proliferating and differentiating into antibody (Ab)-secreting cells. Each of these events occurs in distinct LN sub-compartments, requiring the migration of B cells from niche to niche in a fast and tightly coordinated fashion. While some of the rules that characterize B cell behavior in secondary lymphoid organs have been elucidated at the population level, we have only limited knowledge of the precise dynamics of B cell interactions with different kinds of LN cells at the single-cell level. Here, we describe in detail an intravital microscopy technique that allows the analysis of B cell dynamic behavior in the popliteal lymph node of anesthetized mice at high spatial and temporal resolution. A detailed understanding of the spatiotemporal dynamics of B cells within secondary lymphoid organs may lead to novel, rational vaccine strategies aimed at inducing rapid and long-lived humoral immune responses. PMID- 29476490 TI - Live Imaging of the Skin Immune Responses: Visualization of the Contact Hypersensitivity Response. AB - A variety of immune cells are involved in cutaneous immune responses. Over the last decade, intravital imaging has become an important technique used to capture the dynamic behavior of immune cells in the physiological context. In this chapter, we describe essential techniques for visualizing immune cells in the skin, focusing on the contact hypersensitivity response. Using fluorescent dyes and transgenic reporter animals, many kinds of immune cells and skin components can be visualized in three dimensions and in a noninvasive manner. PMID- 29476491 TI - Imaging of Inflammatory Responses in the Mouse Ear Skin. AB - The skin is one of the most physiologically important organs where the organism comes into contact with the external environment and is often a site where pathogen entry first occurs. Thus, a better understanding of the specialized cellular behavior of the immune system in the skin may be important for the improved treatment of diseases. Here, we describe in detail a procedure to image the dorsal mouse ear skin, using a customized ear stage and its associated coverslip holder, with an upright multiphoton microscope. As a demonstrative example, we describe the specific protocol for visualizing robust neutrophil trafficking in albino lysozyme-EGFP mice in response to zymosan particles. Instructive sections are provided for the mouse ear preparation, intradermal delivery of zymosan, design and use of the custom ear stage, as well as a solution for the uninterrupted live imaging of mice during prolonged sessions within a dark box. The mouse ear is easily accessible for imaging, and unlike most other organs, does not require any invasive surgery to be performed. PMID- 29476492 TI - In Vivo Imaging of Immune Cells in Peyer's Patches. AB - Peyer's patches (PPs) are secondary lymphoid organs that coordinate the immunoglobulin A (IgA) response against commensal and pathogenic bacteria. In contrast to the immune dynamics in peripheral lymph nodes, the dynamics of immune response in PP have not been extensively characterized in vivo by two-photon microscopy, mainly due to the PP location on the anti-mesenteric side of the small intestine and the associated peristaltic movement.Here, we describe an approach based on a custom-made spring-loaded platform to immobilize PPs and allow for two-photon microscopy imaging in vivo. We also list different strategies based on fluorescent dyes, as well as Cre/Lox and Reporter-based system, that can be used to image specific immune cell populations in distinct areas of PPs. PMID- 29476493 TI - Intravital Imaging of T Cells Within the Spinal Cord. AB - Intravital imaging is a powerful tool for analyzing cellular functions in living animals. In particular, after the two-photon microscopy technique was introduced, a number of studies have visualized important processes. Here, we describe the methods for performing intravital imaging of the central nervous system. This method can be used for imaging not only lymphocytes but also blood vessels for ischemia studies, as well as glia cell activities. PMID- 29476494 TI - Kidney Imaging: Intravital Microscopy. AB - Intravital two-photon microscopy is a powerful imaging tool for investigating various biological processes in live animals. This chapter describes an overview of intravital imaging of the rodent kidney including animal surgery, characteristics of renal tubular autofluorescence, in vivo use of fluorescent probes, and renal immune-cell tracking. PMID- 29476495 TI - Intravital Imaging of Liver Cell Dynamics. AB - The liver is a vital organ in the body. It has various essential functions, including detoxification, protein synthesis, and control of infection. Because of its medical importance, liver diseases such as hepatitis and cirrhosis can be crucial for an individual. Exploring dynamics of living cells in the liver would provide the clues for understanding the pathology. However, due to its technical difficulty, few studies have used intravital liver imaging. To resolve this, we have established a novel imaging system for visualizing liver cell dynamics in living animals.Herein we describe the methodology for visualizing the in vivo behavior of liver cells using intravital multiphoton microscopy. This approach will be useful for understanding the pathogenesis of liver disorders, as well as liver biology, in vivo. PMID- 29476496 TI - Intravital Imaging of the Heart at the Cellular Level Using Two-Photon Microscopy. AB - Recent molecular approaches have provided deeper insight on heart failure. However, real-time in vivo cellular dynamics have not been satisfactorily visualized. Here, we present a detailed protocol for in vivo cellular imaging for visualization of the rat heart using two-photon microscopy. PMID- 29476497 TI - Imaging Window Device for Subcutaneous Implantation Tumor. AB - Most of preclinical cancer studies use xenograft models established from human cell lines or patient-derived cancer cells subcutaneously implanted into the flank of immunocompromised mice. These models are often assumed to represent the original diseases and are valuable tools, at least to some extent, for understanding both the basic biology of cancer and for proof-of-concept studies of molecularly targeted therapies. However, analyzing the cellular behavior of individual components within xenografts, including tumor cells, stromal cells, immune cells, and blood vessels, is challenging. In particular, it has been difficult and urgently required to trace the whole process of heterogeneous tumor microenvironment formation mediated by various components described above. Here we demonstrate a method for monitoring this process using a window device system that we have recently developed and a subcutaneous xenograft model that accurately recapitulates the histology of human lung adenocarcinoma. Use of our imaging window device and a multiphoton laser scanning microscope provides a powerful tool for investigating tumor heterogeneity and responses to drug treatments in an in vivo live imaging system. PMID- 29476498 TI - New Tools for Imaging of Immune Systems: Visualization of Cell Cycle, Cell Death, and Cell Movement by Using the Mice Lines Expressing Fucci, SCAT3.1, and Kaede and KikGR. AB - Visualization of biological events in real time in vivo has become a crucial to understand immune responses. We have been established novel visualization tools for life of immune cells: proliferation, cell death, and migration. Fucci transgenic mice allow us to visualize cell cycle phases by reciprocal expression of mKusabira-Orange2 in G1 phase and mAzami-Green in S/G2/M phase. Caspase-3 indicator SCAT3.1 knock-in mice visualize cell death by changing color. Photoconvertible proteins, Kaede and KikGR expressing mice track cell movement between organs by labeling immune cells as red color. Here, I will introduce how to use and visualize these mice. These techniques will help to understand immune system in the living whole body. PMID- 29476499 TI - Population Pharmacokinetics of Elagolix in Healthy Women and Women with Endometriosis. AB - INTRODUCTION: Elagolix is a novel, orally active, non-peptide, competitive gonadotropin-releasing hormone (GnRH) receptor antagonist in development for the management of endometriosis with associated pain and heavy menstrual bleeding due to uterine fibroids. The pharmacokinetics of elagolix have been well characterized in phase I studies; however, elagolix population pharmacokinetics have not been previously reported. Therefore, a robust model was developed to describe elagolix population pharmacokinetics and to evaluate factors affecting elagolix pharmacokinetic parameters. METHODS: The data from nine clinical studies (a total of 1624 women) were included in the analysis: five phase I studies in healthy, premenopausal women and four phase III studies in premenopausal women with endometriosis. RESULTS: Elagolix population pharmacokinetics were best described by a two-compartment model with a lag time in absorption. Of the 15 covariates tested for effect on elagolix apparent clearance (CL/F) and/or volume of distribution only one covariate, organic anion transporting polypeptide (OATP) 1B1 genotype status, had a statistically significant, but not clinically meaningful, effect on elagolix CL/F. CONCLUSION: Elagolix pharmacokinetics were not affected by patient demographics and were similar between healthy women and women with endometriosis. Clinical Trial Registration Numbers NCT01403038, NCT01620528, NCT01760954, NCT01931670, NCT02143713. PMID- 29476500 TI - Defending and reducing belief in memories: An experimental laboratory analogue. AB - When receiving disconfirmatory social feedback about recollected events, people sometimes defend and sometimes reduce their belief that the event genuinely occurred. To improve estimates of the rates of memory defense and reduction, and of the magnitude of the change in belief in occurrence that results, in the present studies we examined the effect of disconfirmatory social challenges made to correctly recalled memories for actions performed in the lab. Adult participants performed, imagined, or heard action statements and imagined some of the initial actions multiple times. One week later, they completed a source monitoring test and rated the actions on belief in their occurrence, recollection, visual detail, vividness, and reexperiencing. Four of the correctly recalled performed actions were challenged either prior to making the ratings during the test (Study 1, N = 44) or after making initial ratings after completing the test, following which the ratings were taken again (Study 2, N = 85). Across both studies, challenges were associated with lower belief-in occurrence and recollection ratings on average than for control items, and belief in occurrence was affected to a greater extent than recollective features. Challenges that occurred during the test produced more instances of defense, whereas challenges that occurred after the test produced more instances of reduction. A closer analysis showed that some participants always defended, some always reduced, and some both defended and reduced belief. Responses to the first challenge positively predicted the responses to subsequent challenges. In addition, the procedure in Study 2 produced a variety of types of nonbelieved memories. PMID- 29476501 TI - Origins, Technological Development, and Applications of Peptidomics. AB - Peptidomics is the comprehensive characterization of peptides from biological sources mainly by HPLC and mass spectrometry. Mass spectrometry allows the detection of a multitude of single peptides in complex mixtures. The term first appeared in full papers in the year 2001, after over 100 years of peptide research with a main focus on one or a few specific peptides. Within the last 15 years, this new field has grown to over 1200 publications. Mass spectrometry techniques, in combination with other analytical methods, were developed for the fast and comprehensive analysis of peptides in proteomics and specifically adjusted to implement peptidomics technologies. Although peptidomics is closely linked to proteomics, there are fundamental differences with conventional bottom up proteomics. The development of peptidomics is described, including the most important implementations for its technological basis. Different strategies are covered which are applied to several important applications, such as neuropeptidomics and discovery of bioactive peptides or biomarkers. This overview includes links to all other chapters in the book as well as recent developments of separation, mass spectrometric, and data processing technologies. Additionally, some new applications in food and plant peptidomics as well as immunopeptidomics are introduced. PMID- 29476502 TI - Brain Tissue Sample Stabilization and Extraction Strategies for Neuropeptidomics. AB - Neuropeptides are bioactive peptides that are synthesized and secreted by neurons in signaling pathways in the brain. Peptides and proteins are extremely vulnerable to proteolytic cleavage when their biological surrounding changes. This makes neuropeptidomics challenging due to the rapid alterations that occur to the peptidome after harvesting of brain tissue samples. For a successful neuropeptidomic study the biological tissue sample analyzed should resemble the premortem state as much as possible. Heat stabilization has been proven to inhibit postmortem degradation by denaturing proteolytic enzymes, hence increasing identification rates of neuropeptides. Here, we describe a stabilization protocol of a frozen tissue specimen that increases the number of intact mature neuropeptides identified and minimizes interference of degradation products from abundant proteins. Additionally, we present an extraction protocol that aims to extract a wide range of hydrophilic and hydrophobic neuropeptides by using both an aqueous and an organic extraction medium. PMID- 29476503 TI - Isolation of Endogenous Peptides from Cultured Cell Conditioned Media for Mass Spectrometry. AB - Media conditioned by cultured cells represent an excellent source rich in endogenous peptides. Unbiased mass spectrometric analysis of the constituent peptides provides an opportunity to look into proteolytic events such as bioactive peptide processing, membrane protein ectodomain shedding, or even regulated intramembrane proteolysis. If conducted on a large scale, peptidomics has the potential to pinpoint primary cleavage sites. Here a method is described for isolating peptides from cultured cell conditioned media before mass spectrometry analysis. PMID- 29476504 TI - Mass Spectrometric Identification of Endogenous Peptides. AB - Peptidomics is an emerging field focused in the analysis of endogenous peptides. Naturally occurring peptides are often endogenously produced protein fragments. Cleavage of precursor proteins by proteases generates peptides that may gain specialized functions not ascribed to their precursors, and which could reflect the state of a cell under certain physiological conditions or pathological processes.Since peptides are found in complex matrices (e.g., serum, tear, urine, cerebrospinal fluid), they need to be isolated from the matrix and concentrated before they can be analyzed on mass spectrometry. This chapter describes methods for sample preparation prior to mass spectrometry analysis. In addition, different peptide fragmentation techniques are described which are complementary when analyzing naturally occurring peptides by liquid chromatography coupled online to tandem mass spectrometry. PMID- 29476506 TI - Substrate Capture Assay Using Inactive Oligopeptidases to Identify Novel Peptides. AB - Researchers are always searching for novel biologically active molecules including peptides. With the improvement of equipment for electrospray mass spectrometry, it is now possible to identify hundreds of novel peptides in a single run. However, after identifying the peptide sequences it is expensive to synthesize all the peptides to perform biological activity assays. Here, we describe a substrate capture assay that uses inactive oligopeptidases to identify putative biologically active peptides in complexes peptide mixtures. This methodology can use any crude extracts of biological tissues or cells, with the advantage to introduce a filter (i.e., binding to an inactive oligopeptidase) as a prior step in screening to bioactive peptides. PMID- 29476505 TI - Bioinformatics for Prohormone and Neuropeptide Discovery. AB - Neuropeptides and peptide hormones are signaling molecules produced via complex post-translational modifications of precursor proteins known as prohormones. Neuropeptides activate specific receptors and are associated with the regulation of physiological systems and behaviors. The identification of prohormones-and the neuropeptides created by these prohormones-from genomic assemblies has become essential to support the annotation and use of the rapidly growing number of sequenced genomes. Here we describe a methodology for identifying the prohormone complement from genomic assemblies that employs widely available public toolsets and databases. The uncovered prohormone sequences can then be screened for putative neuropeptides to enable accurate proteomic discovery and validation. PMID- 29476508 TI - Quantitative Peptidomics: General Considerations. AB - Peptidomics is the detection and identification of the peptides present in a sample, while quantitative peptidomics provides additional information about the amounts of these peptides. Comparison of peptide levels among two or more samples is termed relative quantitation. It is also possible to perform absolute quantitation of peptide levels in which the biological sample is compared to synthetic standards, which requires a separate standard for each peptide. In contrast, relative quantitation can compare levels of all peptides that are detectable in a sample, which can exceed 1000 peptides in a complex sample. In this chapter, various techniques used for quantitative peptidomics are described along with discussion of the advantages and disadvantages of each approach. A guide to selecting the optimal quantitative approach is provided, based on the goals of the experiment and the resources that are available. PMID- 29476507 TI - Non-targeted Identification of D-Amino Acid-Containing Peptides Through Enzymatic Screening, Chiral Amino Acid Analysis, and LC-MS. AB - D-Amino acid-containing peptides (DAACPs) in animals are a class of bioactive molecules formed via the posttranslational modification of peptides consisting of all-L-amino acid residues. Amino acid residue isomerization greatly impacts the function of the resulting DAACP. However, because isomerization does not change the peptide's mass, this modification is difficult to detect by most mass spectrometry-based peptidomic approaches. Here we describe a method for the identification of DAACPs that can be used to systematically survey peptides extracted from a tissue sample in a non-targeted manner. PMID- 29476509 TI - Quantitative Peptidomics with Isotopic and Isobaric Tags. AB - In differential peptidomics, peptide profiles are compared between biological samples and the resulting expression levels are correlated to a phenotype of interest. This, in turn, allows us insight into how peptides may affect the phenotype of interest. In quantitative differential peptidomics, both label-based and label-free techniques are often employed. Label-based techniques have several advantages over label-free methods, primarily that labels allow for various samples to be pooled prior to liquid chromatography-mass spectrometry (LC-MS) analysis, reducing between-run variation. Here, we detail a method for performing quantitative peptidomics using stable amine-binding isotopic and isobaric tags. PMID- 29476510 TI - Quantitative Peptidomics Using Reductive Methylation of Amines. AB - A number of different approaches have been used for quantitative peptidomics. In this protocol we describe the method in which peptides are reacted with formaldehyde and sodium cyanoborohydride, which converts primary and secondary amines into tertiary amines. By using different combinations of regular reagents, deuterated reagents (2H), and reagents containing deuterium and 13C, it is possible to produce five isotopically distinct forms of the methylated peptides which can be quantified by mass spectrometry. Peptides with free N-termini that are primary amines incorporate two methyl groups using this procedure, which differ by 2 Da for each of the five isotopic combinations. Peptides that contain unmodified lysine residues incorporate additional pairs of methyl groups, leading to larger mass differences between isotopic forms. The reagents are commercially available, relatively inexpensive, and chemically stable. PMID- 29476511 TI - Metabolic Labeling to Quantify Drosophila Neuropeptides and Peptide Hormones. AB - Neuropeptides and peptide hormones are involved in the regulation of most if not all body functions, ranging from physiology to neuronal processing and the control of behavior. To assess their functions, it is often vital to determine when and in which quantities they are produced, stored, and released. The latter is especially difficult to assess in small insects, such as the genetically amenable fruit fly Drosophila melanogaster, and cannot be achieved merely by quantifying mRNA transcripts. We have adapted and optimized methods to quantify neuropeptides and peptide hormones by metabolic labeling followed by LC-MS. In this chapter, we describe the labeling protocols used in our laboratory and discuss problems and pitfalls that we encountered. PMID- 29476512 TI - Data Preprocessing, Visualization, and Statistical Analyses of Nontargeted Peptidomics Data from MALDI-MS. AB - Mass spectrometric (MS) comparative analysis of peptides in biological specimens (nontargeted peptidomics) can result in large amounts of data due to chromatographic separation of a multitude of samples and subsequent MS analysis of numerous chromatographic fractions. Efficient yet effective strategies are needed to obtain relevant information. Combining visual and numerical data analysis offers a suitable approach to retrieve information and to filter data for significant differences as targets for succeeding MS/MS identifications.Visual analysis allows assessing features within a spatial context. Specific patterns are easily recognizable by the human eye. For example, derivatives representing modified forms of signals present are easily identifiable due to an apparent shift in mass and chromatographic retention times. On the other hand numerical data analysis offers the possibility to optimize spectra and to perform high-throughput calculations. A useful tool for such calculations is R, a freely available language and environment for statistical computing. R can be extended via packages to enable functionalities like mzML (open mass spectrometric data format) import and processing. R is capable of parallel processing enabling faster computation using the power of multicore systems.The combination and interplay of both approaches allows evaluating the data in a holistic way, thus helping the researcher to better understand data and experimental outcomes. PMID- 29476513 TI - Affinity Purification of Neuropeptide Precursors from Mice Lacking Carboxypeptidase E Activity. AB - Peptidomic techniques are powerful tools to identify peptides in a biological sample. This protocol describes a targeted peptidomic approach that uses affinity chromatography to purify peptides that are substrates of carboxypeptidase E (CPE), an enzyme present in the secretory pathway of neuroendocrine cells. Many CPE products function as neuropeptides and/or peptide hormones, and therefore represent an important subset of the peptidome. Because CPE removes C-terminal Lys and Arg residues from peptide-processing intermediates, organisms lacking CPE show a large decrease in the levels of the mature forms of most neuropeptides and peptide hormones, and a very large increase in the levels of the processing intermediates that contain C-terminal Lys and/or Arg (i.e., the CPE substrates). These CPE substrates can be purified on an anhydrotrypsin-agarose affinity resin, which specifically binds peptides with C-terminal basic residues. Not all peptides with basic C-terminal residues within a cell are CPE substrates, and these other peptides will also be purified on the anhydrotrypsin affinity column. However, a comparison of peptides purified from wild-type mice and from mice lacking CPE allows for the rapid identification of CPE substrates based on their large increase in the absence of CPE. PMID- 29476514 TI - Mass Spectrometry Based Immunopeptidomics for the Discovery of Cancer Neoantigens. AB - Recent data indicate that endogenous mutated cancer proteins can be processed and presented as HLA binding peptides, leading to their recognition in vivo as "non self." Targeting such neoantigens would enable immune cells to distinguish between normal and cancerous cells, avoiding the risk of autoimmunity. So far, discovery of such neoantigens relies mainly on prediction-based interrogation of the "mutanome" using genomic information as input, followed by highly laborious and time-consuming T cell screening assays. Currently, mass spectrometry is the only unbiased methodology to comprehensively interrogate the naturally presented repertoire of HLA binding peptides, including peptides derived from tumor associated antigens and post-translational modified peptides. This chapter describes a detailed protocol for in-depth and accurate mass spectrometry based immunopeptidomics, enabling the direct identification of tissue-derived neoantigens extracted from human tumors. PMID- 29476515 TI - Milk Peptidomics to Identify Functional Peptides and for Quality Control of Dairy Products. AB - Human milk and dairy products are important parts of human nutrition. In addition to supplying nutrients, milk proteins contain fragments-peptides-with important biological functions that are released during processing or digestion. Besides their potential functional relevance, peptides released during processing can be used as markers of ripening stage or product deterioration. Hence, identification and quantification of peptides in milk can be used to assay potential health benefits or product quality. This chapter describes how to extract, identify, and analyze peptides within breast milk, dairy products, and dairy digestive samples. We describe how to analyze extracted peptides with liquid chromatography-mass spectrometry, to use software to identify peptides based on database searching, and to extract peak areas for relative quantification of each peptide. We describe methods for data analysis, including predicting which enzymes are responsible for protein cleavage, identifying the site specificity of protein breakdown, mapping identified peptides to known bioactive peptides, and applying models to predict novel functional peptides. PMID- 29476516 TI - Neuropeptidomic Analysis of Zebrafish Brain. AB - A wide variety of bioactive peptides are present in all metazoan species where they govern diverse functions as small messenger molecules. In the last 15 years, mass spectrometry-based methods have identified endogenous peptides in diverse species. Mass spectrometry enables the precise peptide sequences to be determined, including the potential existence of truncated versions or the presence of post-translational modifications. Because small modifications can have a large effect on biological activity, knowledge of the actual peptide sequences paves the way for further functional studies such as analysis of neuropeptidergic signaling cascades. Zebrafish (Danio rerio) is an important animal model that is commonly used in a wide range of studies. Here we provide a detailed description of the peptide extraction procedure and peptidomics workflow for zebrafish. PMID- 29476517 TI - Identification, Quantitation, and Imaging of the Crustacean Peptidome. AB - Crustaceans serve as a useful, simplified model for studying peptides and neuromodulation, as they contain numerous neuropeptide homologs to mammals and enable electrophysiological studies at the single-cell and neural circuit levels. In particular, crustaceans contain well-defined neural networks, including the stomatogastric ganglion, esophageal ganglion, commissural ganglia, and several neuropeptide-rich organs, such as the brain, pericardial organs, and sinus glands. Due to the lack of a genomic database for crustacean peptides, an important step of crustacean peptidomics involves the discovery and identification of novel peptides and the construction of a database, more recently with the aid of mass spectrometry (MS). Herein, we present a general workflow and detailed methods for MS-based peptidomic analysis of crustacean tissue samples and circulating fluids. In conjunction with profiling, quantitation can also be performed with isotopic or isobaric labeling. Information regarding the localization patterns and changes of peptides can be studied via mass spectrometry imaging. Combining these sample preparation strategies and MS analytical techniques allows for a multifaceted approach to obtaining deep knowledge of crustacean peptidergic signaling pathways. PMID- 29476518 TI - Identification of Endogenous Neuropeptides in the Nematode C. elegans Using Mass Spectrometry. AB - The nematode Caenorhabditis elegans lends itself as an excellent model organism for peptidomics studies. Its ease of cultivation and quick generation time make it suitable for high-throughput studies. Adult hermaphrodites contain 959 somatic nuclei that are ordered in defined, differentiated tissues. The nervous system, with its 302 neurons, is probably the most known and studied endocrine tissue. Moreover, its neuropeptidergic signaling pathways display a large number of similarities with those observed in other metazoans. However, various other tissues have also been shown to express several neuropeptides. This includes the hypodermis, gonad, gut, and even muscle. Hence, whole mount peptidomics of C. elegans cultures provides an integral overview of peptidergic signaling between the different tissues of the entire organism. Here, we describe a peptidomics approach used for the identification of endogenous (neuro)peptides in C. elegans. Starting from a detailed peptide extraction procedure, we will outline the setup for an online liquid chromatography-mass spectrometry (LC-MS) analysis and describe subsequent data analysis approaches. PMID- 29476519 TI - EndoProteoFASP as a Tool to Unveil the Peptidome-Protease Profile: Application to Salivary Diagnostics. AB - In the quest to fully comprehend the proteolytic events leading to the generation of the salivary peptidome, we have developed a method for the sequential elution of salivary peptides throughout progressive endogenous proteolysis. By screening the time-dependent changes in the salivary peptidome we can predict the activity pattern of salivary proteases responsible for such peptide fingerprint and identify susceptible protein targets. Herein, we describe a step-by-step tutorial based on a filter-aided sample preparation (FASP) method, taking advantage of the endogenous salivary proteases armamentarium (endoProteoFASP), to produce new peptides from the salivary proteins, adding to those present in the sample at the time of collection. In this protocol, the different sets of peptides retrieved after sample elution are identified following a liquid chromatography-tandem mass spectrometry approach. The likelihood of a large set of endogenous proteases (collected from several public sources) to be responsible for the generation of such peptides can be predicted by the analysis of the cleavage site specificity by Proteasix ( http://proteasix.cs.man.ac.uk /) algorithm. The attained peptidome protease profile can be useful to elucidate the peptidome dynamics and the proteolytic events underpinning pathophysiological phenomena taking place locally within the oral cavity. This may help clinicians to diagnose oral pathologies and develop preventive therapeutic plans. PMID- 29476520 TI - Methodology for Urine Peptidome Analysis Based on Nano-HPLC Coupled to Fourier Transform Ion Cyclotron Resonance Mass Spectrometry. AB - Urine is a sample of choice for noninvasive biomarkers search because it is easily available in large amounts and its molecular composition provides information on processes in the organism. The high potential of urine peptidomics has been demonstrated for clinical purpose. Several mass spectrometry based approaches have been successfully applied for urine peptidome analysis and potential biomarkers search. Summarizing literature data and our own experience we developed a protocol for comprehensive urine peptidome analysis. The technology includes several stages and consists of urine sample preparation by size exclusion chromatography and identification of featured peptides by nano HPLC coupled to Fourier transform ion cyclotron resonance mass spectrometry, semiquantitative and statistical data analysis. PMID- 29476521 TI - Identification of Components in Frog Skin Secretions with Therapeutic Potential as Antidiabetic Agents. AB - Several peptides that were first identified on the basis of their antimicrobial or immunomodulatory properties have subsequently shown potential for development into agents for the treatment of patients with Type 2 diabetes. A strategy is presented for the isolation and characterization of such peptides in norepinephrine-stimulated skin secretions from a range of frog species. The methodology involves fractionation of the secretions by reversed-phase HPLC, identification of fractions containing components that stimulate the rate of release of insulin from BRIN-BD11 clonal beta-cells without simultaneously stimulating the release of lactate dehydrogenase, identification of active peptides in the mass range 1-6 kDa by MALDI-TOF mass spectrometry, purification of the peptides to near homogeneity by further HPLC, and structural characterization by automated Edman degradation. The effect of synthetic replicates of the active peptides on glucose homeostasis in vivo may be evaluated in mice fed a high fat diet to produce obesity, glucose intolerance, and insulin resistance. PMID- 29476522 TI - High-Accuracy Mass Spectrometry Based Screening Method for the Discovery of Cysteine Containing Peptides in Animal Venoms and Toxins. AB - Venom and toxin samples derived from animal origins are a rich source of bioactive peptides. A high proportion of bioactive peptides that have been identified in venom contain one or more disulfide bridges, which are thought to stabilize tertiary structure, and therefore influence the peptides' specificity and activity. In this chapter, we describe a label-free mass spectrometry-based screening workflow specifically to detect peptides that contain inter- and intramolecular disulfide bonds, followed by elucidation of their primary structure. This method is based on the determination of the normalized isotope shift (NIS) and the normalized mass defect (NMD) of peptides, two parameters which are heavily influenced by the presence of sulfur in a peptide, where cysteines are the main contributing residues. Using ant defensive secretions as an example, we describe the initial fractionation of the venom on strong cation exchange followed by nanoflow HPLC and mass spectrometry. High resolution zoom scan spectra of high-abundance peptides are acquired, allowing an accurate determination of both monoisotopic and average mass, which are essential for calculation of NMD and NIS. Candidate peptides exhibiting relative low NMD and high NIS values are selected for targeted de novo sequencing. By fine-tuning the collision energy for optimal fragmentation of each selected precursor ions, the full sequence of several novel inter- and intramolecular disulfide bond containing ant defensive peptides can be established. PMID- 29476523 TI - Analysis of the Snake Venom Peptidome. AB - Snake venom peptidomes are known to be a large source of molecules with different pharmacological properties. The complexity and variability of snake venoms, the presence of proteinases, and the lack of complete species-specific genome sequences make snake venom peptidome profiling a challenging task that requires especial technical strategies for sample processing and mass spectrometric analysis. Here we describe a method for assessing the content of snake venom peptides and highlight the importance of sampling procedures, as they substantially influence the peptidomic complexity of snake venoms. PMID- 29476524 TI - Identification of Peptides in Spider Venom Using Mass Spectrometry. AB - Spider venoms are composed of hundreds of proteins and peptides. Several of these venom toxins are cysteine-rich peptides in the mass range of 3-9 kDa. Small peptides (<3 kDa) can be fully characterized by mass spectrometry analysis, while proteins are generally identified by the bottom-up approach in which proteins are first digested with trypsin to generate shorter peptides for MS/MS characterization. In general, it is sufficient for protein identification to sequence two or more peptides, but for venom peptidomics it is desirable to completely elucidate peptide sequences and the number of disulfide bonds in the molecules. In this chapter we describe a methodology to completely sequence and determine the number of disulfide bonds of spider venom peptides in the mass range of 3-9 kDa by multiple enzyme digestion, mass spectrometry of native and digested peptides, de novo analysis, and sequence overlap alignment. PMID- 29476525 TI - Single Cell Peptidomics: Approach for Peptide Identification by N-Terminal Peptide Derivatization. AB - In recent years, single cell microanalysis techniques have moved into the center stage to study fundamental intracellular interactions and cell-cell communication events, and have led to a better understanding of physiological processes and behavioral patterns. The availability of more sensitive, robust, and precise mass spectrometers improved the detection and characterization of putative neuroactive substances from individual cells. For sequence characterization, particularly when working with samples as small as a single cell, the most crucial step to obtain usable data is sample preparation. For some studies, genetic or molecular data are not available to confirm an amino acid sequence of a putative neuropeptide, and it is necessary to sequence the peptide from the mass spectrometry analysis alone (i.e., de novo sequencing). In this chapter, a protocol is described for de novo sequencing of neuropeptides from individual single cells by N-terminal derivatization using 4-sulfophenyl isothiocyanate and subsequent mass spectrometric analysis. PMID- 29476526 TI - Peptidomic Identification of Cysteine-Rich Peptides from Plants. AB - Plant cysteine-rich peptides (CRPs) constitute a majority of plant-derived peptides with high molecular diversity. This protocol describes a rapid and efficient peptidomic approach to identify a whole spectrum of CRPs in a plant extract and decipher their molecular diversity and bioprocessing mechanism. Cyclotides from C. ternatea are used as the model CRPs to demonstrate our methodology. Cyclotides exist naturally in both cyclic and linear forms, although the linear forms (acyclotide) are generally present at much lower concentrations. Both cyclotides and acyclotides require linearization of their backbone prior to fragmentation and sequencing. A novel and practical three-step chemoenzymatic treatment was developed to linearize and distinguish both forms: (1) N-terminal acetylation that pre-labels the acyclotides; (2) conversion of Cys into pseudo Lys through aziridine-mediated S-alkylation to reduce disulfide bonds and to increase the net charge of peptides; and (3) opening of cyclic backbones by the novel asparaginyl endopeptidase butelase 2 that cleaves at the native bioprocessing site. The treated peptides are subsequently analyzed by liquid chromatography coupled to mass spectrometry using electron transfer dissociation fragmentation and sequences are identified by matching the MS/MS spectra directly with the transcriptomic database. PMID- 29476527 TI - Analysis of Endogenous Peptide Pools of Physcomitrella patens Moss. AB - Here, we report our approach to peptidomic analysis of the plant object which led to structure elucidation of the title peptides. P. patens samples were extracted under conditions preventing proteolytic digestion by endogenous proteases. The extracts were fractionated on size exclusion columns and the peptide fractions subjected to LC-MS/MS analysis. Mass spectra datasets were analyzed for the presence of peptides derived from the proteins encoded by the moss genome. Experimental details are given for each step, selected chromatograms and mass spectra are presented in figures. PMID- 29476528 TI - The Bright Future of Peptidomics. AB - In this final chapter I project my personal perspective on the future of peptidomics. A bird's eye view is shed on the discipline and a bid is made to frame it in the broader arena of the life sciences of tomorrow. Inferring from its present state-of-the-art and from the general direction of some evolutionary trends which are to be discerned, a case is made that peptidomics enjoys full ripeness as a young branch of science today, from which a bright future for the discipline can be predicted. PMID- 29476529 TI - Parent emotion regulation socializes children's adaptive physiological regulation. AB - Parenting practices play a major role in socializing children's developing regulatory abilities, but less is known about how parents' regulatory abilities relate to children's healthy functioning. This study examined whether parents' physiological and emotion regulation abilities corresponded to children's physiological and emotional responding to a structured laboratory-based disappointment task. Ninety-seven 3- to 7-year-olds (56 girls; M = 5.79 years) and one parent participated in a multi-method assessment of parents' and children's regulatory functioning. Direct (coaching children to use reappraisal) and indirect (resting physiology, dispositional use of reappraisal) aspects of parents' regulatory abilities were assessed. As expected, an adaptive pattern of parent regulatory abilities composed of higher resting respiratory sinus arrhythmia, use of reappraisal, and coaching reappraisal was associated with children's physiological reactivity after a disappointment indicative of more effective physiological calming in a recovery context (increased parasympathetic activation). In contrast, parents' regulatory abilities did not relate to changes in children's expressions of emotional distress. PMID- 29476530 TI - Effects of Low-Intensity Contractions of Different Craniofacial Muscles in Healthy Participants - An Experimental Cross-Over Study. AB - OBJECTIVE: Repetitive jaw-muscle activity characterized by clenching or grinding of the teeth and/or by bracing or thrusting of the mandible, ie, bruxism, is traditionally linked to pain and unpleasantness in the active muscles. The aim of this study was to investigate the effects of standardized craniofacial muscle contractions on self-reported symptoms. METHODS: Sixteen healthy volunteers performed six 5-minute bouts of 20% maximal voluntary contraction task of the jaw closing (Jaw), the orbicularis-oris (O-oris), and the orbicularis-oculi (O-oculi) muscles. Participants rated their perceived pain, unpleasantness, fatigue, and mental stress levels before, during, and after the contraction tasks on 0-10 Numeric Rating Scales (NRS). Each muscle contraction task (= 1 session) was separated by at least 1 week and the order of the sessions was randomized in each subject. RESULTS: All muscle contraction tasks evoked significant increases in NRS scores of pain (mean +/- SD: Jaw; 3.8 +/- 2.7, O-oris; 1.9 +/- 2.2, O-oculi; 1.4 +/- 1.3, P < .014), unpleasantness (Jaw; 4.1 +/- 2.5, O-oris; 2.1 +/- 1.9, O oculi; 2.9 +/- 1.8, P < .001), fatigue (Jaw; 5.8 +/- 2.0, O-oris; 3.2 +/- 2.3, O oculi; 3.6 +/- 1.9, P < .001), and mental stress (Jaw; 4.1 +/- 2.1, O-oris; 2.2 +/- 2.7, O-oculi; 2.9 +/- 2.2, P < .001). The Jaw contractions were associated with higher NRS scores compared with the O-oris and the O-oculi contractions (P < .005) without differences between the O-oris and the O-oculi (P > .063). All symptoms disappeared within 1 day (P > .469). CONCLUSIONS: The results showed that submaximal static contractions of different craniofacial muscle groups could evoke transient, mild to moderate levels of muscle pain and fatigue and increased stress scores. The fatigue resistance may differ between different muscle groups. Further studies are warranted to better understand the contribution of specific craniofacial muscle groups for the characteristic presentation of musculoskeletal pain conditions in the head. PMID- 29476531 TI - Common bean varieties demonstrate differential physiological and metabolic responses to the pathogenic fungus Sclerotinia sclerotiorum. AB - Plant physiology and metabolism are important components of a plant response to microbial pathogens. Physiological resistance of common bean (Phaseolus vulgaris L.) to the fungal pathogen Sclerotinia sclerotiorum has been established, but the mechanisms of resistance are largely unknown. Here, the physiological and metabolic responses of bean varieties that differ in physiological resistance to S. sclerotiorum are investigated. Upon infection, the resistant bean variety A195 had a unique physiological response that included reduced photosynthesis and maintaining a higher leaf surface pH during infection. Leaf metabolomics was performed on healthy tissue adjacent to the necrotic lesion at 16, 24, and 48 hr post inoculation, and 144 metabolites were detected that varied between A195 and Sacramento following infection. The metabolites that varied in leaves included amines/amino acids, organic acids, phytoalexins, and ureides. The metabolic pathways associated with resistance included amine metabolism, uriede-based nitrogen remobilization, antioxidant production, and bean-specific phytoalexin production. A second experiment was conducted in stems of 13 bean genotypes with varying resistance. Stem resistance was associated with phytoalexin production, but unlike leaf metabolism, lipid changes were associated with susceptibility. Taken together, the data supports a multifaceted, physiometabolic response of common bean to S. sclerotiorum that mediates resistance. PMID- 29476532 TI - Research Imaging of Brain Structure and Function After Concussion. AB - Even when concussions are associated with prolonged physical and cognitive sequelae, concussions are typically "invisible" on diagnostic brain imaging, indicating that the neuropathology associated with concussion lies under the detection threshold of routine imaging. However, data from brain structural and functional research imaging studies using diffusion tensor imaging, resting-state functional magnetic resonance imaging, and brain perfusion imaging indicate that these imaging sequences have a role in identifying concussion-related neuropathology. These advanced imaging techniques provide insights into concussion neuropathology and might be useful for differentiating concussed patients from healthy controls. In this review article, we provide an overview of research findings from brain structural and functional imaging studies of concussion, and discuss the accuracy of classification models developed via machine-learning algorithms for identifying individual patients with concussion based on imaging data. PMID- 29476533 TI - Cost-effectiveness of omalizumab for the treatment of chronic spontaneous urticaria. AB - BACKGROUND: Chronic spontaneous urticaria (CSU) is a skin disease with itchy hives and/or angio-oedema that last for at least 6 weeks without an obvious external trigger. OBJECTIVES: To determine the cost-effectiveness of omalizumab relative to standard of care (SoC; up to four times the daily dose of H1 antihistamines) in the Netherlands from a societal perspective. METHODS: The Markov model used consisted of five health states based on Urticaria Activity Score over 7 days. Model settings and characteristics of the Dutch patient population were based on an online survey among clinical experts and were validated during an expert committee meeting. Transition probabilities were derived from the GLACIAL trial. Healthcare consumption, quality of life (using EuroQol-5D) and productivity losses were derived from a burden-of-illness study (ASSURE-CSU) among 93 Dutch patients. Healthcare consumption and productivity losses were evaluated using the Dutch costing manual. The comparator treatment was SoC, consisting of (updosed) antihistamines. A 10-year time horizon was used. RESULTS: The incremental cost-effectiveness ratio (ICER) of omalizumab vs. SoC was ?17 502 per quality-adjusted life-year (QALY) gained. Productivity costs played an important role in the value of the ICER; discarding productivity costs resulted in an ICER of ?85 310 per QALY. CONCLUSIONS: Omalizumab is cost effective compared with SoC. The outcomes of this study were used to establish omalizumab as third-line therapy in the Dutch treatment guidelines for CSU. PMID- 29476534 TI - Sensitivity of different Lupinus species to calcium under a low phosphorus supply. AB - To study mechanism underpinning the calcifuge habit of some Lupinus species, especially under low-phosphorus (P) conditions, Lupinus species that were likely to respond differently to calcium (Ca) availability were assembled, and the sensitivity to Ca under a low-P supply was assessed. Seven Lupinus species (9 genotypes, L. albus L. cv Kiev, L. albus L. P26766, L. angustifolius L. cv Mandelup, L. angustifolius L. P26723, L. luteus L. cv Pootalong, L. hispanicus ssp. bicolor Boiss. and Reut. P22999, L. pilosus Murr. P27440, L. cosentinii Guss. P27225, and L. atlanticus Gladst. P27219) were grown hydroponically at 10 or 6000 MUM Ca. Leaf symptoms, gas exchange and biomass were recorded; leaf and root nutrient concentrations were analysed, and the leaf cell types in which Ca and P accumulated were determined using elemental X-ray microanalyses. Calcium toxicity was demonstrated for L. angustifolius P26723, L. hispanicus ssp. bicolor. P22999, and L. cosentinii P27225, whereas the other species were tolerant of a high Ca supply under low-P conditions. In addition, genotypic differences in Ca toxicity were found within L. angustifolius. Most Ca accumulated in the mesophyll cells in all species, whereas most P was located in epidermal cells. PMID- 29476535 TI - New-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES): State of the art and perspectives. AB - We report the proceedings of the First International new-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES) Symposium. To promote awareness of this condition and foster research efforts, we conveyed the First International new-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES) Symposium. The conference was supported by The NORSE Institute (http://www.norseinstitute.org). This article summarizes the discussions that were held during the Symposium and presents our strategy to unravel the cause of these disorders and to improve patient care. The standardized definitions for these disorders that have been developed, are required to improve communication and facilitate the development of multicenter registries and biobanks. A distinction between childhood- and adult-onset forms of the syndrome is not supported by strong scientific evidence and it is argued that both should be studied together. Although the pathophysiology remains elusive, nascent evidence suggests a role for a postinfectious cytokine-mediated mechanism, which should be further investigated. It also appears important to develop tools for their early recognition and prompt treatment. Recent evidence suggests that specific electroencephalography (EEG) features might be helpful. The optimal treatment options remain to be determined; immune therapies are usually disappointing, but the ketogenic diet has proved effective in uncontrolled trials. NORSE and FIRES represent a very delicate clinical situation with specific communication issues between physicians and with patients and families. Standardized consensus definitions and a multidisciplinary multicenter strategy will help research efforts and improve clinical care for patients with NORSE and FIRES. PMID- 29476536 TI - Undersensing of ventricular tachycardia in a pacemaker patient: What is the mechanism? PMID- 29476537 TI - Secondary transfer effect among children: The role of social dominance orientation and outgroup attitudes. AB - Research has provided evidence that the effects of intergroup contact on prejudice reduction are not limited to the outgroup one has contact with (primary outgroup). Rather, they extend to secondary outgroups uninvolved in the contact situation (secondary transfer effect; Pettigrew, 2009, Social Psychology, 40, 55). We aimed to provide the first empirical evidence for the emergence of the secondary transfer effect among children. Majority (Italian) and minority (with an immigrant background) elementary schoolchildren were administered a questionnaire including measures of contact with the primary outgroup (minority children for the majority, majority children for the minority), prejudice towards the primary outgroup and towards a dissimilar secondary outgroup (disabled children), and social dominance orientation. Results revealed that among the majority group, contact with the primary outgroup had indirect associations with reduced prejudice towards the secondary outgroup. Specifically, we found evidence for sequential mediation by social dominance orientation and prejudice towards the primary outgroup. No secondary transfer effects emerged among minority group members. We discuss theoretical and practical implications of the findings, arguing for the importance of identifying the core processes driving the secondary transfer effect. PMID- 29476539 TI - Blockage of a fluid administration set. PMID- 29476540 TI - Critical incident due to a Guedel airway. PMID- 29476541 TI - Of poisons and parasites-the defensive role of tetrodotoxin against infections in newts. AB - Classical research on animal toxicity has focused on the role of toxins in protection against predators, but recent studies suggest these same compounds can offer a powerful defense against parasites and infectious diseases. Newts in the genus Taricha are brightly coloured and contain the potent neurotoxin, tetrodotoxin (TTX), which is hypothesized to have evolved as a defense against vertebrate predators such as garter snakes. However, newt populations often vary dramatically in toxicity, which is only partially explained by predation pressure. The primary aim of this study was to evaluate the relationships between TTX concentration and infection by parasites. By systematically assessing micro- and macroparasite infections among 345 adult newts (sympatric populations of Taricha granulosa and T. torosa), we detected 18 unique taxa of helminths, fungi, viruses and protozoans. For both newt species, per-host concentrations of TTX, which varied from undetectable to >60 MUg/cm2 skin, negatively predicted overall parasite richness as well as the likelihood of infection by the chytrid fungus, Batrachochytrium dendrobatidis, and ranavirus. No such effect was found on infection load among infected hosts. Despite commonly occurring at the same wetlands, T. torosa supported higher parasite richness and average infection load than T. granulosa. Host body size and sex (females > males) tended to positively predict infection levels in both species. For hosts in which we quantified leucocyte profiles, total white blood cell count correlated positively with both parasite richness and total infection load. By coupling data on host toxicity and infection by a broad range of micro- and macroparasites, these results suggest that-alongside its effects on predators-tetrodotoxin may help protect newts against parasitic infections, highlighting the importance of integrative research on animal chemistry, immunological defenses and natural enemy ecology. PMID- 29476542 TI - Comparison of patient (POEM), observer (EASI, SASSAD, TIS) and corneometry measures of emollient effectiveness in children with eczema: findings from the COMET feasibility trial. AB - BACKGROUND: Eczema affects around 20% of children, but multiple different outcome measures have hampered research into the effectiveness of different treatments. OBJECTIVES: To compare the change in scores and correlations within and between five measures of eczema severity: Patient-Orientated Eczema Measure (POEM), Eczema Area and Severity Index (EASI), Six Area, Six Sign Atopic Dermatitis (SASSAD), Three Item Severity (TIS) and skin hydration (corneometry). METHODS: Data from a feasibility trial that randomized young children with eczema to one of four emollients were used. Participants were followed for 3 months (84 days). Descriptive statistics (by emollient over time) and Spearman's correlation coefficients comparing scores at each time point and absolute change (between adjacent time points) for each outcome measure were calculated. RESULTS: In total, 197 children, mean +/- SD age 21.7 +/- 12.8 months, were randomized. POEM and TIS appeared to capture a range of eczema severity at baseline, but only POEM had close approximation to normal distribution. Mean POEM, EASI, SASSAD and TIS scores improved month by month, with POEM showing the greatest sensitivity (effect size 0.42). Correlations within POEM, EASI, SASSAD and TIS were moderate to good, decreasing over time. Correlations between measures were strongest for EASI, SASSAD and TIS. By contrast, corneometry scores were more variable, correlated less well over time and were poorly correlated with the other measures. CONCLUSIONS: Except for corneometry, all measures appear to change in relation to emollient use over time and correlate well with themselves. POEM demonstrated the greatest range of scores at baseline and change in eczema severity over the first 28 days. PMID- 29476543 TI - Increased incidence of inguinal hernia in offspring of female survivors of childhood central nervous system tumors. AB - Female survivors of childhood central nervous system (CNS) tumors experience an increased risk of infertility and various pregnancy complications. We aimed to explore whether the incidence of inguinal hernia could be higher in offspring of female CNS tumor survivors as compared to the general population. Girls who were younger than 15 years of age and diagnosed with CNS tumors between 1958 and 2013 were identified from the Swedish Cancer Registry. By linking with the Swedish Medical Birth Registry, we identified 580 children who were born to mothers of CNS tumor survivors. After 9,662 person-years of follow-up, 23 of them were diagnosed with inguinal hernia, giving an incidence rate (IR) of 2.4 per 1,000 person-years, whereas the IR was 1.2 for the matched controls. Cox regression analysis was used to calculate the hazard ratio (HR) of inguinal hernia. After adjusting for some confounding factors, the incidence of inguinal hernia was significantly increased with an HR of 1.92 (95%CI 1.08-3.41). The association was predominant in offspring whose mothers were diagnosed with CNS tumors at the age of 10 and older, and with CNS tumors located in the brain. PMID- 29476544 TI - Linking demographic processes and foraging ecology in wandering albatross Conservation implications. AB - Population dynamics and foraging ecology are two fields of the population ecology that are generally studied separately. Yet, foraging determines allocation processes and therefore demography. Studies on wandering albatrosses Diomedea exulans over the past 50 years have contributed to better understand the links between population dynamics and foraging ecology. This article reviews how these two facets of population ecology have been combined to better understand ecological processes, but also have contributed fundamentally for the conservation of this long-lived threatened species. Wandering albatross research has combined a 50-year long-term study of marked individuals with two decades of tracking studies that have been initiated on this species, favoured by its large size and tameness. At all stages of their life history, the body mass of individuals plays a central role in allocation processes, in particular in influencing adult and juvenile survival, decisions to recruit into the population or to invest into provisioning the offspring or into maintenance. Strong age related variations in demographic parameters are observed and are linked to age related differences in foraging distribution and efficiency. Marked sex-specific differences in foraging distribution, foraging efficiency and changes in mass over lifetime are directly related to the strong sex-specific investment in breeding and survival trajectories of the two sexes, with body mass playing a pivotal role especially in males. Long-term study has allowed determining the sex specific and age-specific demographic causes of population decline, and the tracking studies have been able to derive where and how these impacts occur, in particular the role of long-line fisheries. PMID- 29476545 TI - Artificial intelligence will soon change the landscape of medical physics research and practice. PMID- 29476546 TI - A randomized split-scalp study comparing calcipotriol-assisted methyl aminolaevulinate photodynamic therapy (MAL-PDT) with conventional MAL-PDT for the treatment of actinic keratosis. AB - BACKGROUND: Topical photodynamic therapy (PDT) is an approved treatment for actinic keratosis (AK). To enhance the efficacy of PDT for AKs, physical and chemical pretreatments have been suggested. OBJECTIVES: To compare the efficacy and safety of the combination of topical calcipotriol (CAL) before methyl aminolaevulinate (MAL)-PDT for AKs of the scalp vs. conventional MAL-PDT in a randomized controlled clinical trial. METHODS: Twenty patients with multiple AKs on the scalp were randomized to receive conventional MAL-PDT with previous curettage on one side of the scalp and CAL-assisted MAL-PDT once a day for 15 days before illumination on the other side. After 3 months, patients were evaluated for clearance of AKs, side-effects and histopathology before and after the procedure. Protoporphyrin IX (PpIX) fluorescence was measured before and after illumination on both sides. RESULTS: All 20 patients completed the study. Overall AK clearance rates were 92.1% and 82.0% for CAL-PDT and conventional PDT, respectively (P < 0.001). Grade 1 AKs showed similar response rates for both sides (P = 0.055). However, grade II AKs showed more improvement on the CAL-PDT side (90%) than on the MAL-PDT side (63%) (P < 0.001). Before illumination, PpIX fluorescence intensity was higher on the CAL-assisted side (P = 0.048). The treatment was more painful on the CAL-PDT side, although well tolerated. The mean visual analogue scale score was 5.4 +/- 1.4 on the CAL-PDT side and 4.0 +/- 0.69 on the conventional MAL-PDT side (P = 0.001). Side-effects such as erythema (P = 0.019), oedema (P = 0.002) and crusts (P < 0.001) were more pronounced on the CAL assisted side. Histopathological analyses were obtained from five patients and both sides showed improved keratinocyte atypia following PDT, with slightly more improvement on the CAL-assisted side. CONCLUSIONS: CAL-assisted PDT proved to be safe and more effective than conventional MAL-PDT for the treatment of AKs on the scalp. CAL pretreatment increased PpIX accumulation within the skin and may have enhanced the efficacy in this first human trial. PMID- 29476547 TI - TEMPERAMENTAL ADAPTABILITY, PERSISTENCE, AND REGULARITY: PARENTAL RATINGS OF NORWEGIAN INFANTS AGED 6 TO 12 MONTHS, WITH SOME IMPLICATIONS FOR PREVENTIVE PRACTICE. AB - : There is a need for standardized measures of infant temperament to strengthen current practices in prevention and early intervention. The present study provides Norwegian data on the Cameron-Rice Infant Temperament Questionnaire (CRITQ; J.R. Cameron & D.C. Rice, 1986a), which comprises 46 items and is used within a U.S. health maintenance organization. The CRITQ was filled out by mothers and fathers at 6 and again at 12 months as part of a longitudinal study of mental health during the first years of life (the "Little in Norway" study, N = 1,041 families enrolled; V. Moe & L. Smith, 2010). Results showed that internal consistencies were comparable with U.S. DATA: The temperament dimensions of persistence, adaptability, and regularity had acceptable or close-to-acceptable reliabilities in the U.S. study as well as in this study, and also were unifactorial in confirmatory factor analysis. These dimensions are the focus in this article. Findings concerning parents' differential ratings of their infants on the three dimensions are reported, as is the stability of parents' ratings of temperament from 6 to 12 months. In addition, results on the relation between temperament and parenting stress are presented. The study suggests that temperamental adaptability, persistence, and regularity may be relevant when assessing infant behavior, and may be applied in systematic prevention trials for families with infants. The inclusion of concepts related to individual differences in response tendencies and regulatory efforts may broaden the understanding of parent-infant transactions, and thus enrich prevention and sensitizing interventions with the aim of assisting infants' development. PMID- 29476548 TI - Mechanisms of GTP hydrolysis and conformational transitions in the dynamin superfamily. PMID- 29476549 TI - Bureaucratic power in note-writing: authoritative expertise within the state. AB - What produces the power of senior civil servants at ministries of finance, positioned at the top of the bureaucratic hierarchy? Max Weber has claimed that a hierarchical organization, meritocratic recruitment and procedural work provide bureaucracies with legitimacy. In particular he insisted on the role of Fachwissen (disciplinary knowledge) obtained through formal education. However, he also argued for the role of Dienstwissen, forms of knowledge and skills stemming from the experience of service in itself. Weber did not elaborate on this concept in detail, and few analysts of governmental expertise have examined this notion. We draw on the practice-turn in sociology, combining the study of governmental expertise with micro-sociological studies of administrative practices. By analysing interviews with 48 senior civil servants at the British, French and Norwegian ministries of finance about their daily practices, this article demonstrates that bureaucratic note-writing and the procedural evaluation of such notes constitute a key form of expertise that yields authority. The study provides an analytical framework for understanding what administrative expertise consists of, how it is integral to procedural work, the forms bureaucratic hierarchies take in practice and how these three dimensions provide authority. PMID- 29476550 TI - Diagnosis of Fetal Structural Anomalies at 11 to 14 Weeks. AB - OBJECTIVES: To assess the performance of first-trimester ultrasound (US) in identifying major fetal structural abnormalities in an unselected population. METHODS: We conducted a retrospective analysis of all pregnancies that underwent the 11- to 14-week scan in the Fetal Medicine Department of Filantropia Hospital in Bucharest, which were prospectively examined within our screening program. The purpose of the first-trimester US was to evaluate the risk for chromosomal abnormalities and to conduct fetal anatomic examination using a detailed protocol. RESULTS: Our population consisted of 7480 pregnant patients (7576 fetuses). The follow-up was completed for 6045 patients (6114 fetuses). The prevalence of major structural anomalies was 1.89%. In the first trimester, we identified 79% of all major structural anomalies. The highest detection rates were achieved for abdominal wall defects (100%), major central nervous system anomalies (88%), cardiac defects (74%), and skeletal anomalies (71%). The nuchal translucency was increased in 35% of the cases with structural anomalies, and 95% of these were diagnosed in the first trimester. Seventy percent of the patients who presented with structural anomalies and a normal nuchal translucency were diagnosed in the first trimester. CONCLUSIONS: Our results emphasize the importance of performing a detailed US examination at 11 to 14 weeks' gestation in identification of fetal structural defects. PMID- 29476552 TI - Ultrasound Diagnosis of Osteophytic Impingement of the Popliteus Tendon After Total Knee Replacement. AB - We report our experience with 6 patients who had total knee replacements with lateral-sided knee pain, referred for ultrasound (US) assessment and US-guided injection. All cases showed an osteophyte within the popliteus sulcus of the lateral femoral condyle impinging on the adjacent tendon. Five of 6 patients reported improvement of symptoms immediately after US-guided injection of an anesthetic and a steroid. Ultrasound has a unique role in the imaging of knee replacements because of its real-time capabilities and absence of artifacts at the popliteus tendon origin. PMID- 29476551 TI - Whole-brain 3D FLAIR at 7T using direct signal control. AB - PURPOSE: Image quality obtained for brain imaging at 7T can be hampered by inhomogeneities in the static magnetic field, B0 , and the RF electromagnetic field, B1 . In imaging sequences such as fluid-attenuated inversion recovery (FLAIR), which is used to assess neurological disorders, these inhomogeneities cause spatial variations in signal that can reduce clinical efficacy. In this work, we aim to correct for signal inhomogeneities to ensure whole-brain coverage with 3D FLAIR at 7T. METHODS: The direct signal control (DSC) framework was used to optimize channel weightings applied to the 8 transmit channels used in this work on a pulse-by-pulse basis through the echo train in the FLAIR sequences. 3D FLAIR brain images were acquired on 5 different subjects and compared with imaging using a quadrature-like mode of the transmit array. Precomputed "universal" DSC solutions calculated from a separate set of 5 subjects were also explored. RESULTS: DSC consistently enabled improved imaging across all subjects, with no dropouts in signal seen over the entire brain volume, which contrasted with imaging in quadrature mode. Further, the universal DSC solutions also consistently improved imaging despite not being optimized specifically for the subject being imaged. CONCLUSION: 3D FLAIR brain imaging at 7T is substantially improved using DSC and is able to recover regions of low signal without increasing imaging time or interecho spacing. PMID- 29476553 TI - Intra- and Inter-rater Agreement of Superior Vena Cava Flow and Right Ventricular Outflow Measurements in Late Preterm and Term Neonates. AB - OBJECTIVES: To explore the intra- and inter-rater agreement of superior vena cava (SVC) flow and right ventricular (RV) outflow in healthy and unwell late preterm neonates (33-37 weeks' gestational age), term neonates (>=37 weeks' gestational age), and neonates receiving total-body cooling. METHODS: The intra- and inter rater agreement (n = 25 and 41 neonates, respectively) rates for SVC flow and RV outflow were determined by echocardiography in healthy and unwell late preterm and term neonates with the use of Bland-Altman plots, the repeatability coefficient, the repeatability index, and intraclass correlation coefficients. RESULTS: The intra-rater repeatability index values were 41% for SVC flow and 31% for RV outflow, with intraclass correlation coefficients indicating good agreement for both measures. The inter-rater repeatability index values for SVC flow and RV outflow were 63% and 51%, respectively, with intraclass correlation coefficients indicating moderate agreement for both measures. CONCLUSIONS: If SVC flow or RV outflow is used in the hemodynamic treatment of neonates, sequential measurements should ideally be performed by the same clinician to reduce potential variability. PMID- 29476555 TI - Multiparameter estimation using multi-echo spoiled gradient echo with variable flip angles and multicontrast compressed sensing. AB - PURPOSE: To develop multiparameter mapping including T1 , R2*, and proton density fat fraction with a single breath-hold to evaluate liver disease and liver function. METHODS: A 6-echo spoiled gradient-echo sequence with dual flip angles was used to acquire a 12-set MRI volume data set. To shorten the scan time, undersampling and multicontrast compressed-sensing reconstruction were used. The scan time was 18 seconds. R2* and proton density fat fraction mapping were achieved by using the iterative least-squares method. T1 mapping was estimated using driven equilibrium single-pulse observation of T1 . Quantitative values were validated by performing phantom and volunteer studies. RESULTS: Statistical analysis showed that the quantitative values measured using the proposed methods agreed with those measured using conventional methods. T1 values of water proton measured by the proposed method in phantom and volunteer studies were in good agreement with those by MRS. CONCLUSION: The results showed that accurate quantitative mapping of T1 , R2*, and proton density fat fraction with a single breath-hold was achieved using our approach. PMID- 29476554 TI - Glia in brain energy metabolism: A perspective. AB - Early views of glia as relatively inert, housekeeping cells have evolved, and glia are now recognized as dynamic cells that not only respond to neuronal activity but also sense metabolic changes and regulate neuronal metabolism. This evolution has been aided in part by technical advances permitting progressively better spatial and temporal resolution. Recent advances in cell-type specific genetic manipulation and sub-cellular metabolic probes promise to further this evolution by enabling study of metabolic interactions between intertwined fine neuronal and glial processes in vivo. Views of glia in disease processes have also evolved. Long considered purely reactive, glia and particularly microglia are now seen to play active roles in both promoting and limiting brain injury. At the same time, established concepts of glial energetics are now being linked to areas such as learning and neural network function, topics previously considered far removed from glial biology. PMID- 29476556 TI - N-myc downstream-regulated gene 2 protects blood-brain barrier integrity following cerebral ischemia. AB - Disruption of the blood-brain barrier (BBB) following cerebral ischemia is closely related to the infiltration of peripheral cells into the brain, progression of lesion formation, and clinical exacerbation. However, the mechanism that regulates BBB integrity, especially after permanent ischemia, remains unclear. Here, we present evidence that astrocytic N-myc downstream regulated gene 2 (NDRG2), a differentiation- and stress-associated molecule, may function as a modulator of BBB permeability following ischemic stroke, using a mouse model of permanent cerebral ischemia. Immunohistological analysis showed that the expression of NDRG2 increases dominantly in astrocytes following permanent middle cerebral artery occlusion (MCAO). Genetic deletion of Ndrg2 exhibited enhanced levels of infarct volume and accumulation of immune cells into the ipsilateral brain hemisphere following ischemia. Extravasation of serum proteins including fibrinogen and immunoglobulin, after MCAO, was enhanced at the ischemic core and perivascular region of the peri-infarct area in the ipsilateral cortex of Ndrg2-deficient mice. Furthermore, the expression of matrix metalloproteinases (MMPs) after MCAO markedly increased in Ndrg2-/- mice. In culture, expression and secretion of MMP-3 was increased in Ndrg2-/- astrocytes, and this increase was reversed by adenovirus-mediated re-expression of NDRG2. These findings suggest that NDRG2, expressed in astrocytes, may play a critical role in the regulation of BBB permeability and immune cell infiltration through the modulation of MMP expression following cerebral ischemia. PMID- 29476557 TI - Expression of interleukin-17 in primary Sjogren's syndrome and the correlation with disease severity: A systematic review and meta-analysis. AB - The aberrant expression of interleukin-17 (IL-17) has been reported in primary Sjogren's syndrome (pSS). Abnormalities in IL-17 can promote the production of pro-inflammatory cytokines and aggravate autoimmune disorders. The aim of this study was to investigate alterations of IL-17 in patients with pSS and explore the correlation between IL-17 and disease severity. Eight databases were searched for original studies reporting the expression of IL-17 in patients with pSS and controls. Eligible reports were included in the pooled analysis, and subgroup evaluations were performed according to different types of controls and IL-17 measurement methods. Newcastle-Ottawa Scale criteria were used to assess the risk of bias of the included studies. In total, 45 articles are included in the meta analysis. The expression of IL-17 is significantly increased in patients with pSS compared to controls. Furthermore, patients with pSS without immunosuppressive treatment show markedly higher IL-17 levels. In addition, patients with pSS with positive rheumatoid factors tend to express a higher level of IL-17 than patients with negative rheumatoid factors. Negative correlations between IL-17 levels and ocular parameters are also found in patients with pSS. The results are similar after adjustment by "trim and fill" methods. In conclusion, the expression of IL 17 is obviously increased in patients with pSS, especially among those without immunosuppressive treatment. In addition, IL-17 level correlates with the disease severity of pSS. These findings demonstrate the significance of IL-17 overexpression in patients with pSS and may provide insights for the development of therapeutic interventions targeting IL-17 for pSS. PMID- 29476558 TI - Correlation Between Liver Stiffness Measured by Shear Wave Elastography and Child Pugh Classification. AB - OBJECTIVES: To explore the association between liver stiffness and the Child-Pugh classification of liver function by shear wave elastography (SWE). METHODS: A total of 116 patients with liver cirrhosis were divided into 3 groups according to the Child-Pugh classification prospectively. Conventional ultrasound imaging and SWE were performed for all patients. The associations of liver stiffness measured by SWE with ultrasound measurements, serum biochemical indicators, and the Child-Pugh classification were analyzed. Receiver operating characteristic curves were analyzed and compared to determine the ability of liver stiffness to diagnose cirrhosis. RESULTS: Liver stiffness measured by SWE increased with an increasing Child-Pugh classification, internal diameter of the hepatic portal and splenic veins, spleen thickness, spleen length, total bilirubin level, and prothrombin time, which were positively correlated with the Child-Pugh classification (all P < .05). The albumin level and liver stiffness showed higher areas under the curve in comparison with other parameters for evaluating the Child-Pugh classification. Albumin and cholinesterase levels were negatively correlated with the Child-Pugh classification (P < .05). All of these indicators were significantly different between each pair of groups (all P < .05), except for the internal diameter of the hepatic portal vein, prothrombin time, and total bilirubin, and cholinesterase levels between groups B and C (P > 0.05) and the thickness and length of spleen and internal diameter of the splenic vein between groups A and B (P > 0.05). There were no differences among the groups for alanine aminotransferase, aspartate aminotransferase, and globulin levels. CONCLUSIONS: Liver stiffness measured by SWE was correlated with the Child-Pugh classification, and it may be able to help evaluate liver function in patients with cirrhosis. PMID- 29476559 TI - Significance and Outcomes of Fetal Growth Restriction Below the 5th Percentile Compared to the 5th to 10th Percentiles on Midgestation Growth Ultrasonography. AB - OBJECTIVE: To determine whether there are differences in neonatal and pregnancy outcomes in pregnancies complicated by severe fetal growth restriction, defined as estimated fetal weight below the 5th percentile, compared with estimated fetal weight in the 5th to 10th percentiles at midgestation. METHODS: We conducted a retrospective review of singleton nonanomalous gestations with estimated fetal weight at or below the 10th percentile (Hadlock et al. Radiology 1991; 181:129 133) at 18 to 24 weeks' gestation. The cohort was divided into fetuses with estimated fetal weight below the 5th percentile and estimated fetal weight in the 5th to 10th percentiles. Antenatal and neonatal outcomes were compared across the groups. RESULTS: Of the 254 growth-restricted fetuses, 91 had estimated fetal weight below the 5th percentile, and 163 were in the 5th to 10th percentiles. Fetuses below the 5th percentile were 2.82 times more likely to be born small for gestational age compared to fetuses at the 5th to 10th percentiles (P = .001). Fetuses with estimated fetal weight below the 5th percentile had higher rates of hypertensive disorders of pregnancy (relative risk [RR], 1.79; P = .04), abnormal umbilical artery Doppler waveforms (RR, 6.27; P = .01), labor induction (RR, 1.45; P = .002), neonatal intensive care unit admission (RR, 1.73; P = .02), and Apgar scores of less than 7 at 1 minute (RR, 2.05; P = .04). CONCLUSIONS: Severely growth-restricted fetuses with an estimated fetal weight below the 5th percentile at 18 to 24 weeks are born smaller and have worse antepartum and neonatal outcomes than those with an estimated fetal weight in the 5th to 10th percentiles. These findings suggest that severely growth-restricted fetuses at midgestation should be treated and counseled differently than those in the 5th to 10th percentiles. PMID- 29476560 TI - Common challenges managing bed and staff availability on labor and delivery units in the United States: A qualitative analysis. AB - BACKGROUND: Managers of labor and delivery units need to ensure that their limited supply of beds and nursing staff are adequately available, despite uncertainty with respect to patient needs. The ability to address this challenge has been associated with patient outcomes; however, best practices have not been defined. METHODS: We conducted a secondary analysis of 96 interviews with nurse and physician managers from 48 labor and delivery units across the United States. Included units represented a diverse range of characteristics, but skewed toward higher volume teaching hospitals. The prior study scored management practice based on their proactiveness (ability to mitigate challenges before they occur). Based on emerging themes, we identified common challenges in managing bed and staff availability and performed an analysis of positive deviants to identify an additional criterion for effective management performance. RESULTS: We identified four key challenges common to all labor and delivery units, (1) scheduling planned cases, (2) tracking patient flow, (3) monitoring bed and staff availability in the moment, and (4) adjusting bed and staff availability in the moment. We also identified "systematicness" (ability to address challenges in a consistent and reliable manner) as an emerging criterion for effective management. We observed that being proactive and systematic represented distinct characteristics, and units with both proactive and systematic practices appeared best positioned to effectively manage limited beds and staffing. DISCUSSION: Labor and delivery unit managers should distinctly assess both the proactiveness and systematicness of their existing management practices and consider how their practices could be modified to improve care. PMID- 29476562 TI - Functional lower lip reconstruction with the partial latissimus dorsi muscle free flap without nerve coaptation. AB - BACKGROUND: The repair of extensive lower lip defects is difficult due to the presence of both functional and esthetic requirements. This report describes functional lip repair using the partial latissimus dorsi free flap without nerve coaptation. METHODS: Reconstruction of the lower lip due to subtotal and total tissue defects was performed using latissimus dorsi free flap on twelve patients, between 2013 and 2017. The etiology was squamous cell carcinoma in six patients, malignant melanoma in one, firearm injury in three and microstomia in two. Following exposure of the lip defect, the partial latissumus dorsi muscle flap was harvested and transfered into the lower lip defect. The microvascular anastomoses was done and no nerve coaptation was performed. The muscle was covered with a skin graft taken from the thigh for mucosal and skin lining. Functional outcomes were assessed using physical examination, electromyography (EMG), electroneuromyography, cold/warm and pain sensation, two point discrimination (TPD), and Semmes Weinstein (SMW) tests. RESULTS: Postoperative course was uneventful for all of the flaps. Patients were followed for between fifteen months and four years (mean 28.2 months).Color match between the flap and the face and functional outcome was satisfactory. Reinnervation was detected at EMG in eleven patients undergoing surgery six months postoperatively.After 1 year, the patients demonstrated quite normal results of the test with SMW and TDP results. None of patients perceived both hot and cold sensation. CONCLUSION: The technique is an alternative option in lower lip reconstruction since it provides satisfactory functional and esthetic results despite absence of any neural coaptation. PMID- 29476561 TI - Novel chiral ionic liquids stationary phases for the enantiomer separation of chiral acid by high-performance liquid chromatography. AB - Novel chiral ionic liquid stationary phases based on chiral imidazolium were prepared. The ionic liquid chiral selector was synthesized by ring opening of cyclohexene oxide with imidazole or 5,6-dimethylbenzimidazole, and then chemically modified by different substitute groups. Chiral stationary phases were prepared by bonding to the surface of silica sphere through thioene "click" reaction. Their enantioselective separations of chiral acids were evaluated by high-performance liquid chromatography. The retention of acid sample was related to the counterion concentration and showed a typical ion exchange process. The chiral separation abilities of chiral stationary phases were greatly influenced by the substituent group on the chiral selector as well as the mobile phase, which indicated that, besides ion exchange, other interactions such as steric hindrance, pi-pi interaction, and hydrogen bonding are important for the enantioselectivity. In this report, the influence of bulk solvent components, the effects of varying concentration, and the type of the counterion as well as the proportion of acid and basic additives were investigated in detail. PMID- 29476563 TI - Point-of-Care Ultrasound in Undergraduate Urology Education: A Prospective Control-Intervention Study. AB - OBJECTIVES: The effect of point-of-care ultrasound (US) training on clinical reasoning in undergraduate medical education remains largely unknown, with concerns arising about possible confusion among learners when such clinical tools are introduced too early. We studied the effect of a urology point-of-care US module on the performance of questions designed to assess clinical reasoning in urinary tract obstruction and voiding dysfunction. METHODS: All second-year medical students at the University of Saskatchewan (Regina [n = 36] and Saskatoon [n = 61]) were enrolled in the study. Each cohort participated in the urology point-of-care US module concurrently with its Foundations in the Kidney and Urinary Tract course. The Regina cohort completed the point-of-care US module 1 week before the Saskatoon cohort, thus allowing for a control-intervention comparison of script concordance question scores to evaluate the effect that the urology point-of-care US module had on clinical reasoning skills. Secondary outcomes included program evaluation metrics, such as overall course performance, urology point-of-care US objective structured clinical examination performance, and student course evaluation data. RESULTS: The introduction of the urology point-of-care US module was not associated with a deterioration in scores on script concordance questions. There were no statistically significant differences between the Regina and Saskatoon students in their responses to the script concordance questions. There were statistically significant increases in student self-reported achievement of learning objectives, with the effect size being medium to large (Cohen d, 0.5-0.8). CONCLUSIONS: Point-of-care US training complements standard undergraduate classroom teaching of urology. Students effectively learned the skills to apply point-of-care US in their assessment of patients, and this process did not interfere with achieving the course objectives. PMID- 29476564 TI - Frontiers in baboon research: an integrative symposium. PMID- 29476565 TI - Human Periodontal Ligament-Derived Stem Cells Promote Retinal Ganglion Cell Survival and Axon Regeneration After Optic Nerve Injury. AB - Optic neuropathies are the leading cause of irreversible blindness and visual impairment in the developed countries, affecting more than 80 million people worldwide. While most optic neuropathies have no effective treatment, there is intensive research on retinal ganglion cell (RGC) protection and axon regeneration. We previously demonstrated potential of human periodontal ligament derived stem cells (PDLSCs) for retinal cell replacement. Here, we report the neuroprotective effect of human PDLSCs to ameliorate RGC degeneration and promote axonal regeneration after optic nerve crush (ONC) injury. Human PDLSCs were intravitreally injected into the vitreous chamber of adult Fischer rats after ONC in vivo as well as cocultured with retinal explants in vitro. Human PDLSCs survived in the vitreous chamber and were maintained on the RGC layer even at 3 weeks after ONC. Immunofluorescence analysis of betaIII-tubulin and Gap43 showed that the numbers of surviving RGCs and regenerating axons were significantly increased in the rats with human PDLSC transplantation. In vitro coculture experiments confirmed that PDLSCs enhanced RGC survival and neurite regeneration in retinal explants without inducing inflammatory responses. Direct cell-cell interaction and elevated brain-derived neurotrophic factor secretion, but not promoting endogenous progenitor cell regeneration, were the RGC protective mechanisms of human PDLSCs. In summary, our results revealed the neuroprotective role of human PDLSCs by strongly promoting RGC survival and axonal regeneration both in vivo and in vitro, indicating a therapeutic potential for RGC protection against optic neuropathies. Stem Cells 2018;36:844-855. PMID- 29476566 TI - Changing health behaviour with rehabilitation in thoracic cancer: A systematic review and synthesis. AB - OBJECTIVES: International guidelines recommend that rehabilitation be offered to people with thoracic cancer to improve symptoms, function, and quality of life. When rehabilitation interventions require a change in behaviour, the use of theory and behaviour change techniques (BCTs) enhance participation. Our objective was to systematically identify BCTs and examine their use in relation to the Capability, Opportunity, Motivation-Behaviour model and known enablers and barriers to engagement in this population. METHOD: Bibliographic databases and grey literature were searched for controlled trials of rehabilitation interventions for adults with lung cancer or mesothelioma, with no limits on language or date. Data on the application of behavioural change theory and BCTs were extracted, categorised using the BCT Taxonomy (v1) and described according to the "Capability, Opportunity, Motivation-Behaviour" model. RESULTS: Twenty seven studies of exercise (n = 15) and symptom self-management (n = 12) interventions were identified. Four studies reported use of behavioural change theory; one study used symptom theory. Across studies, a mean (range) of 7 (1-18) BCTs were used, representing 26 of 93 possible BCTs included in the taxonomy. Most frequent enabling BCTs were "instructions on how to perform behaviours" (74%), "behavioural practice" (74%), and "action planning" (70%). BCTs to address barriers were less frequent and included "information about health consequences" (22%) and "verbal persuasion about capability" (7%) to change perceptions about benefits, burden, and harms. CONCLUSION: The application of behavioural change tools appears sub-optimal in this group of patients. Explicit use of BCTs targeting behavioural components upon which outcomes depend may improve the uptake and effectiveness of rehabilitation interventions. PMID- 29476567 TI - Estimating impacts of the nuclear family and heritability of nutritional outcomes in a boat-dwelling community. AB - OBJECTIVES: General health status is reflected in measures of height, weight, and BMI. Assessing sources of variation in these outcomes reveals population-specific variables of importance to health and nutrition. We characterize the impacts of socioeconomic variables related to the nuclear family on health outcomes of boat dwelling Shodagor children, mothers, and fathers, and to estimate the proportion of variation in height, weight, and BMI influenced by both genetic variation and nongenetic variation among household environments. METHODS: Bayesian linear mixed models (LMMs) estimate heritability and household-effect variance components among the Shodagor. These models also assess the influences of specific socioeconomic predictor variables on different types of individuals within the household (children, mothers, and fathers). RESULTS: Overall, models explain 61.7% of variation in height, 59.4% in weight, and 65.8% in BMI for this sample of Shodagor. Mother's decision-making and household income have expected, positive associations with children's weight and BMI. Number of children has an unexpected positive relationship to children's height and a negative relationship to father's BMI. Genetic variation explains less than 26% of phenotypic variation for each of these traits on average. CONCLUSIONS: Our results show that resource flows and distributions within Shodagor households account for a significant amount of variance in nutritional outcomes. Problems commonly associated with increasing market integration may lead to negative outcomes for children, while mother's autonomy may lead to positive outcomes. Our models also indicate that environmental factors account for more variation in these outcomes than expected, relative to genetics, and we discuss the implications. PMID- 29476568 TI - Asymmetric All-Metal-Oxide Supercapacitor with Superb Cycle Performance. AB - Metal oxides have great potential for developing high-performance supercapacitors due to their high specific capacitances. However, achieving high energy densities while maintaining good rate capability and long cycle life has proved to be challenging. We propose herein a strategy for constructing all-metal-oxide asymmetric supercapacitors (ASCs), in which both the cathode and anode are based on metal oxides, and demonstrate their outstanding electrochemical performance. We anchored SnO2 nanoparticles on the surface of reduced graphene oxide (RGO) through Sn-O-C bonds (as the cathode of ACSs), and employed low-crystalline RGO/MoO3 nanosheets as the anode, based on the large work function difference between SnO2 and MoO3 . The resulting ASC can operate stably at 1.8 V in neutral aqueous electrolyte and deliver an energy density of up to 33 W h kg-1 , which remains at 13.8 W h kg-1 even at 37.5 kW kg-1 . Moreover, the ASC exhibits a good cycling stability of 92.5 % capacitance retention after 20 000 cycles. PMID- 29476569 TI - The role of pregnancy, perinatal factors and hormones in maternal cancer risk: a review of the evidence. AB - An understanding of the origin of cancer is critical for cancer prevention and treatment. Complex biological mechanisms promote carcinogenesis, and there is increasing evidence that pregnancy-related exposures influence foetal growth cell division and organ functioning and may have a long-lasting impact on health and disease susceptibility in the mothers and offspring. Nulliparity is an established risk factor for breast, ovarian, endometrial and possibly pancreatic cancer, whilst the risk of kidney cancer is elevated in parous compared with nulliparous women. For breast, endometrial and ovarian cancer, each pregnancy provides an additional risk reduction. The associations of parity with thyroid and colorectal cancers are uncertain. The timing of reproductive events is also recognized to be important. Older age at first birth is associated with an increased risk of breast cancer, and older age at last birth is associated with a reduced risk of endometrial cancer. The risks of breast and endometrial cancers increase with younger age at menarche and older age at menopause. The mechanisms, and hormone profiles, that underlie alterations in maternal cancer risk are not fully understood and may differ by malignancy. Linking health registries and pooling of data in the Nordic countries have provided opportunities to conduct epidemiologic research of pregnancy exposures and subsequent cancer. We review the maternal risk of several malignancies, including those with a well-known hormonal aetiology and those with less established relationships. The tendency for women to have fewer pregnancies and at later ages, together with the age dependent increase in the incidence of most malignancies, is expected to affect the incidence of pregnancy-associated cancer. PMID- 29476570 TI - Does the presence of sentinel lymph node macrometastases in breast cancer patients require axillary lymph node dissection?-Single-center analysis. AB - According to the current guidelines on treatment of breast cancer patients, identification of metastases in the sentinel lymph node (SLN (+)) is not an absolute indication for necessary axillary lymph node dissection (ALND). In our study, we present long-term outcomes of treatment among SLN(+) patients referred for conservative treatment, for example, no further ALND. A total of 3145 breast cancer patients subjected to sentinel lymph node biopsy (SLNB) between November 2008 and June 2015. SLN metastases were identified in 719 patients (22.9%). Locoregional recurrences and distant metastases as endpoints were distinquished. The mean follow-up time for patients after ALND was 36.2 months (6-74 months); 18.8 months (6-38 months) for patients with SLN macrometastases without ALND; and 34.0 months (6-74 months) for patients with micrometastases. Adjuvant ALND was performed in 626 of SLN(+) patients. Conservative treatment was applied in the remaining 93 cases. Among SLN(+) patients without adjuvant ALND, there was one case of recurrence (1.07%). In the group of patients without SLN, metastases recurrence was noted in 32 patients (1.32%). Among SLN(+) patients diagnosed with macrometastases, recurrence concerned 2.01% of analyzed cases (all subjected to ALND). Lack of radical surgical treatment in SLN(+) breast cancer patients did not lead to worsening long-term outcomes. In the occurrence of macrometastases to the sentinel lymph node, abandoning completion axillary lymph node dissection might be a reasonable option. However, it would require continuation of current research, preferably involving a clinical trial. PMID- 29476571 TI - Diagnostic value of the cardiac electrical biomarker, a novel ECG marker indicating myocardial injury, in patients with symptoms suggestive of non-ST elevation myocardial infarction. AB - BACKGROUND: The cardiac electrical biomarker (CEB) is a novel electrocardiographic (ECG) marker quantifying the dipolar activity of the heart with higher levels indicating myocardial injury. METHODS: We prospectively enrolled 1097 patients presenting with suspected non-ST-elevation myocardial infarction (NSTEMI) to the emergency department (ED). Digital 12-lead ECGs were recorded at presentation and the CEB values were calculated in a blinded fashion. The final diagnosis was adjudicated by two independent cardiologists. The prognostic endpoint was all-cause mortality during 2 years of follow-up. RESULTS: NSTEMI was the final diagnosis in 14% of patients. CEB levels were higher in patients with NSTEMI compared to other causes of chest pain (median 44 (IQR 21 98) vs. 30 (IQR 16-61), p < .001). A weak but significant correlation between levels of high-sensitivity cardiac troponin T (hs-cTnT) at admission to the ED and the CEB was found (r = .23, p < .001). The use of the CEB in addition to conventional ECG criteria improved the diagnostic accuracy for the diagnosis of NSTEMI as quantified by the area under the receiver operating characteristics curve from 0.66 to 0.71 (p < .001) and the sensitivity improved from 43% to 79% (p < .001). CONCLUSION: In conclusion, the CEB, an ECG marker of myocardial injury, significantly improves the accuracy and sensitivity of the ECG for the diagnosis of NSTEMI. PMID- 29476572 TI - Direct medical costs associated with the extrahepatic manifestations of hepatitis C infection in Europe. AB - Hepatitis C virus (HCV) infection is a systemic disease associated with both hepatic and extrahepatic manifestations. The burden associated with the hepatic manifestation of HCV infection has been well documented in Europe, although that of HCV extrahepatic manifestations remains unknown. In this study, we estimated the annual direct medical costs associated with HCV extrahepatic manifestations in five European countries. A previously validated economic model was used to estimate the annual direct medical cost associated with HCV extrahepatic manifestations. Global excess prevalence of extrahepatic manifestations in HCV patients relative to that in non-HCV patients was obtained from a recent meta analysis. Per-patient per-year inpatient, outpatient and medication costs to treat each extrahepatic manifestation were from the literature, national databases or expert opinion if unavailable otherwise. All costs were adjusted to 2016 euros (?). The overall direct medical costs associated with HCV extrahepatic manifestations were calculated by multiplying the total per-patient per-year costs of each by the respective excess prevalence rates and then by the size of the HCV-infected population in each country. Treatment impact with direct-acting antivirals (DAAs) was explored using HCV extrahepatic manifestations excess prevalence rates among cured patients compared to untreated HCV patients, as sourced from a meta-analysis. The total annual direct medical cost associated with HCV extrahepatic manifestations was estimated to be 2.17 billion euro (?), with a per-HCV-patient cost ranging from ?899 to ?1647 annually. DAA treatment was projected to result in cost savings of ?316 million per year. We find that the annual economic burden of extrahepatic manifestations is significant and may be partly mitigated by treatment with DAAs. PMID- 29476573 TI - Transient left septal fascicular block in the setting of acute coronary syndrome associated with giant slurring variant J-wave. AB - We report a case of acute coronary syndrome with transient prominent anterior QRS forces (PAF) caused by proximal subocclusion of the left anterior descending (LAD) coronary artery before the first septal perforator branch. The ECG change indicates left septal fascicular block (LSFB) with associated slurring-type giant J-wave. Currently, this J-wave variant is considered as a lambda-like wave or QRS ST-T "triangulation". Its presence is indicative of poor prognosis because of the risk for cardiac arrest as a consequence of ventricular tachycardia/ventricular fibrillation (VT/VF). PMID- 29476574 TI - Clinicopathologic analysis of a large series of microinvasive breast cancers. AB - Clinical management of microinvasive breast cancer (Tmic) remains controversial. Although metastases are infrequent in Tmic carcinoma patients, surgical treatment typically includes lymph node sampling. The objective of this study was to determine the rate and predictors of lymph node metastases, recurrence, and survival in a large series of Tmic breast carcinomas. Consecutive cases of Tmic were identified within our health care system from 2001 to 2015. We reviewed results of lymph node sampling and other pathologic factors including hormone receptor/HER2 status, associated in situ tumor size/grade, margin status, number of invasive foci, surgical/adjuvant therapies, and recurrence/survival outcomes. In this cohort, 294 Tmic cases were identified with mean follow-up of 4.6 years. Of 260 patients who underwent axillary staging, lymph node metastases were identified in 1.5% (all of which were ductal type). All Tmic cases with positive lymph node metastases had associated DCIS with size > 5 cm (5.3-8.5 cm) compared to a median DCIS tumor size of 2.5 cm (0.2-19.0 cm) for the entire cohort. No lymph node metastases were seen with microinvasive lobular carcinoma. During the follow-up period, there were no regional/distant recurrences or breast cancer associated deaths in a mean follow-up period of 4.6 years. Two patients developed subsequent ipsilateral breast cancer (DCIS) in a different quadrant than the original Tmic. Clinical behavior of microinvasive breast cancer in this series is similar to DCIS. Lymph node metastases are uncommon and were only seen with ductal type microinvasive carcinoma. Our data suggest limited benefit for routine node sampling and support management of Tmic similar to DCIS, particularly for patients with DCIS < 5 cm in size. PMID- 29476575 TI - Supporting junior doctors: The sad saga of Dr Bawa-Garba. PMID- 29476576 TI - Prenatal stress exposure and early childhood BMI: Exploring associations in a New Zealand context. AB - OBJECTIVES: The primary purpose of this study was to (i) examine associations between prenatal objective vulnerability and subjective stress, and (ii) investigate the relationships between prenatal vulnerability and subjective stress and early childhood BMI at 24- and 54- months of age after controlling for covariates. METHODS: The Growing Up in New Zealand (GUiNZ) longitudinal study provided information on 5839 pregnant women and their children to assess the study objectives. Vulnerability, operationalized by nine objective-risk factors, and subjective stress, operationalized by the Perceived Stress Scale, were independently investigated. Hierarchical linear regression models were conducted to analyze the associations between both prenatal measures and childhood BMI at 24- and 54- months of age. RESULTS: Correlations between subjective stress and objective vulnerability were low but significant (r = .28, P < .01). Exposure to one additional risk factor during pregnancy was significantly associated with a .11 increase in BMI z-score at 24-months (P < .01) and a .15 increase in BMI z score at 54-months (P < .01), after controlling for covariates including maternal prepregnancy BMI. Subjective prenatal stress was not significantly associated with either child BMI outcome. CONCLUSIONS: Vulnerability and subjective stress were minimally correlated in this sample. Vulnerability, but not subjective stress, was associated with childhood BMI at 24- and 54- months of age. This study informs our understanding of how risk exposures and stress responses early in life impacts offspring obesity risk, and it may help identify strategies that decrease early life predisposition to adult disease. PMID- 29476577 TI - Cutaneous tuberculosis in China - A multicentre retrospective study of cases diagnosed between 1957 and 2013. AB - BACKGROUND: China has one of the largest populations with tuberculosis worldwide. Cutaneous tuberculosis (CTB) is a rare manifestation of mycobacterial infection. Although CTB is well described, it is important to periodically revisit the prevailing clinical and epidemiological features in most populated countries such as China, India, and Indonesia, where tuberculosis is still a major health problem. OBJECTIVE: This retrospective study aimed to re-evaluate the CTB cases in China in the past 50 years to obtain a comprehensive insight into this multiplex entity. METHODS: Cases of diagnosed CTB with confirmed histology from four large medical centres in central China between 1957 and 2013 were collected and analysed, including demographic data, clinical manifestations and pathological findings. RESULTS: Of the 1194 cases enrolled, there were 666 (55.78%) and 528 cases (44.22%) of true CTB and tuberculids, respectively. Erythema induratum of Bazin (EIB) was the most common CTB (35.8%), followed by lupus vulgaris (LV, 32.7%), tuberculosis verrucosa cutis (18.9%), papulonecrotic tuberculid (8.0%), scrofuloderma (2.8%), tuberculosis cutis ulcerosa (1.3%), penile tuberculids (0.4%), and lichen scrofulosorum (0.1%). EIB was the predominant tuberculid (80.87%), while LV the predominant true CTB (58.7%). The number of diagnosed CTB showed a decreasing trend in the 1960s and 1970s, then increased again, and peaked in the 1990s. CONCLUSIONS: Cutaneous tuberculosis is still a common problem in China. Chronologic changes in CTB cases reported in China over the past 50 years may reflect the prevalence transition of overall tuberculosis. CTB has diverse clinical presentations, and each subtype is characterized by specific gender predilection, duration, age, clinic and pathological findings. PMID- 29476578 TI - "I don't want to take chances.": A qualitative exploration of surgical decision making in young breast cancer survivors. AB - OBJECTIVE: Young women with unilateral breast cancer are increasingly choosing contralateral prophylactic mastectomy (CPM), despite its limited medical benefit for most women. The purpose of this study was to better understand this choice through a qualitative exploration of surgical decision-making in young survivors, including how issues particular to younger women affected their decision and the post-surgical experience. METHODS: Women age <= 40 years with stage 0 to III breast cancer, 1 to 3 years from diagnosis who had undergone breast cancer surgery were recruited to participate. Four focus groups were conducted: 2 with women who had bilateral mastectomy and 2 with women who kept their contralateral breast. Focus groups were recorded and transcribed with identifiers removed. Emergent themes were identified by thematic content analysis using NVivo 11. RESULTS: Of the 20 participants, median age at diagnosis was 37 years. Emergent themes were categorized into the following domains: (1) emotions/feelings surrounding surgery/decision about surgery; (2) factors affecting the decision; (3) communication and interaction with the healthcare team; (4) impact on post surgical life and recovery; and (5) support needs. Young women who chose CPM often were concerned about a future breast event, despite this low risk, suggesting some gain peace of mind by choosing CPM. Young survivors also had many physical and emotional concerns after surgery for which they did not always feel prepared. CONCLUSIONS: Informational resources and decision aids may enhance patient-doctor communication and help young survivors better understand risk and manage expectations surrounding short and longer-term physical and emotional effects after surgery. PMID- 29476579 TI - Reporting the incidence of unplanned extubation in the neonatal intensive care unit. AB - AIM: The aim of this study was to highlight the incidence of unplanned extubation (UE) and identify associated factors in our neonatal population. METHODS: This study was a prospective audit. RESULTS: A specifically designed audit tool was used to capture UE events; 182 neonates required mechanical ventilation for 863 days. There were 41 episodes of UE. The UE rate was 4.75 per 100 days of ventilation. At the time of UE, median gestational age of patients was 27.3 weeks (23.4-37.6), with a corrected age median of 29.2 weeks (23.4-37.6). Re-intubation was required in two thirds of the patients for increasing apnoea and increased work of breathing. Endotracheal tubes are secured in a standardised way either using Neobar or brown tape. UE events occurred with both methods. The two most common factors associated with UE included active handling of the baby and the time of day (0700-1000 h). CONCLUSIONS: This audit has provided our neonatal intensive care unit with a benchmark for improvement. It has also created staff awareness of the risk of UE and promoted staff engagement to reduce UE. A bundle approach to reduce UE has been introduced. Future audits are planned to monitor the impact of these initiatives. PMID- 29476580 TI - The case for the omission of axillary staging in invasive breast carcinoma that exhibits a predominant tubular growth pattern on preoperative biopsy. AB - True invasive tubular breast carcinoma (TBC) is unlikely to metastasize to axillary nodes, yet it is routinely subjected to sentinel lymph node biopsy (SLNB), even if the diagnosis was suspected preoperatively. The positive predictive value (PPV) of core biopsy for TBC and the incidence and predictors of axillary metastasis in invasive breast carcinomas identified as tubular-rich on core biopsy are unknown. Prospective patient and tumor data regarding postoperatively confirmed TBCs, and tubular-rich carcinoma identified on preoperative core biopsy between January 2005 and May 2016 was analyzed retrospectively. Axillary metastasis occurred in only 4.2% (4/95) of TBCs, all of which measured >15 mm pathologically. In 11.1% (11/99) of TBCs, the initial core biopsy was either indeterminate/suspicious or ductal carcinoma in situ (DCIS); therefore, their true tubular histotype and size were ascertained following operative excision and before SLNB. Nine were <=15 mm, and all were node negative. Only 63.9% (46/72) of tubular-rich core biopsies were confirmed as TBCs; the remaining 36.1% (26/72) were well-differentiated invasive nontubular carcinomas. None of the preoperative patient or tumor features were predictive of true TBC on multivariable analysis; 10.1% (7/69) of carcinomas identified as tubular-rich on core biopsy (regardless of their true histotypes) were node positive; 23.1% (6/26) in nontubular and 2.3% (1/43) in true tubular carcinomas. Preoperative ultrasound size >15 mm was associated with axillary metastasis in 40.0% (4/10) compared to 5.7% (3/53) in those <=15 mm (OR = 11.11, 95% CI = 1.99 62.04; multivariable P = .010). Axillary metastasis in TBC is dependent on pathological size; therefore, a case is made for omitting SLNB in small true TBCs confirmed following excision. Preoperative tubular-rich core biopsy is not adequately diagnostic of TBC; however, it selects carcinomas that are well differentiated, small, and unlikely to metastasize to the axilla, thus allowing for the selective omission of SLNB. PMID- 29476581 TI - Persistently altered liver test results in hepatitis C patients after sustained virological response with direct-acting antivirals. AB - Guidelines recommend evaluating persistent alteration of liver tests in HCV infected patients after sustained virological response (SVR) and its influence on liver disease progression. We studied the prevalence, etiology, associated factors and evolutionary implications of persistent alteration of liver tests in HCV patients after direct-acting antivirals (DAA)-induced SVR. This was a prospective study of HCV-infected patients and SVR after DAA. Those with another previously diagnosed liver disease were excluded. Persistent alteration of liver tests was defined as any increase in ALT, AST or GGT at SVR12 and SVR24. Causes were determined according to standard clinical practice, including liver biopsy and follow-up transient elastography. A total of 1112 patients were included (70.8% males, median age 53 years, 38.8% cirrhosis, 34.9% interferon-experienced, 56.8% HIV-coinfected). Persistent alteration of liver tests was detected in 130/1112 patients (11.7% [95%CI: 9.7-13.6]). Its frequency differed between HCV monoinfected (45/480: 9.4% [95%CI: 6.7-12.1]) and HIV-coinfected (85/632: 13.5% [95%CI: 10.7-16.2]) (P = .046). In multivariable analysis, cirrhosis (OR 2.12; 95%CI: 1.28-3.53; P = .004) and baseline transient elastography values (OR 1.03; 95%CI: 1.01-1.04; P = .000) were associated with persistent alteration of liver tests. The main etiologies were clinical diagnosis suggestive of nonalcoholic fatty liver disease in 47 (36.2%), alcohol in 30 (23.1%) and drug consumption in 19 (14.6%). Baseline and follow-up transient elastography was performed in 594 patients and showed a significantly different decrease in patients who did or did not have a persistent alteration of liver tests (-21.1% vs -30%, respectively; P = .003), independently of sex, HIV status or baseline TE value. In conclusion, persistent alteration of liver tests is not infrequent after SVR. It is associated with cirrhosis and baseline transient elastography, and the main cause is fatty liver. According to transient elastography changes, persistent alteration of liver tests seems to affect the course of liver disease. PMID- 29476582 TI - Generating standardized image data for testing and calibrating quantification of volumes, surfaces, lengths, and object counts in fibrous and porous materials using X-ray microtomography. AB - Quantification of the structure and composition of biomaterials using micro-CT requires image segmentation due to the low contrast and overlapping radioopacity of biological materials. The amount of bias introduced by segmentation procedures is generally unknown. We aim to develop software that generates three-dimensional models of fibrous and porous structures with known volumes, surfaces, lengths, and object counts in fibrous materials and to provide a software tool that calibrates quantitative micro-CT assessments. Virtual image stacks were generated using the newly developed software TeIGen, enabling the simulation of micro-CT scans of unconnected tubes, connected tubes, and porosities. A realistic noise generator was incorporated. Forty image stacks were evaluated using micro-CT, and the error between the true known and estimated data was quantified. Starting with geometric primitives, the error of the numerical estimation of surfaces and volumes was eliminated, thereby enabling the quantification of volumes and surfaces of colliding objects. Analysis of the sensitivity of the thresholding upon parameters of generated testing image sets revealed the effects of decreasing resolution and increasing noise on the accuracy of the micro-CT quantification. The size of the error increased with decreasing resolution when the voxel size exceeded 1/10 of the typical object size, which simulated the effect of the smallest details that could still be reliably quantified. Open source software for calibrating quantitative micro-CT assessments by producing and saving virtually generated image data sets with known morphometric data was made freely available to researchers involved in morphometry of three-dimensional fibrillar and porous structures in micro-CT scans. PMID- 29476583 TI - Web-based counseling for families with parental cancer: A case report. PMID- 29476584 TI - Retrospective evaluation of extended heat-pressed ceramic veneers after a mean observational period of 7 years. AB - OBJECTIVES: Retrospective evaluation of extended anterior glass-ceramic veneers 7 years after placement in a private practice. MATERIALS AND METHODS: A total of 31 patients (20 females/11 males) underwent restoration with adhesively luted extended veneers that were fabricated using heat-pressed glass-ceramic (Cergo, Dentsply Sirona). A single dentist restored 101 teeth (maxilla, n = 65; mandible, n = 36). Adhesive cementation was performed using an etch-and-rinse adhesive (OptibondFL, Kerr Corporation), and two different dual-curing composite cements (Variolink, Ivoclar Vivadent/Calibra, Dentsply Sirona). RESULTS: After 7 years, the Kaplan-Meier survival rate (in situ criteria) was 93.6% (95% CI: 0.89; 0.98). The observed failures were caused by ceramic fractures for seven restorations and biological failure for one restoration. In total 80 of the 101 restorations were still in service and did not require any clinical intervention (7-year success rate: 84.3% [95% CI]: 0.76; 0.93). Interventions were necessary in 13 cases (8 recementations, 2 endodontic treatments, 2 composite fillings (caries), and 1 polishing of minor fractures). The clinical performance was not influenced by the veneer position (maxilla/mandible, survival P = .56/success P = .30). The veneers that covered large areas of exposed dentin (>50%) exhibited a significantly increased risk (hazard ratio 3.71, P = .0041) for requiring a clinical intervention; however, no effect on the survival rate was observed for these veneers (P = .35). CONCLUSIONS: Following 7 years of clinical service, extended anterior ceramic veneer restorations exhibited comparable survival and success rates for the upper and lower jaw. Large areas of exposed dentin (>50%) were associated with significantly lower success rates. CLINICAL SIGNIFICANCE: Dentin exposure (more than 50% of the preparation surface) during preparation significantly affects the clinical performance of extended heat-pressed glass ceramic veneers. PMID- 29476585 TI - Distinguishing papillary endothelial hyperplasia and angiosarcoma on core needle biopsy of the breast: The importance of clinical and radiologic correlation. AB - Papillary endothelial hyperplasia (PEH) is a rare non-neoplastic exuberant organizing hematoma that can closely mimic angiosarcoma due to a resemblance to malignant anastomosing blood vessels. It could be particularly difficult to distinguish PEH from angiosarcoma in breast core needle biopsies. We identified all cases of these lesions diagnosed on core needle biopsy in order to identify clinical, radiologic, and pathologic features that could prove helpful to arrive at the correct diagnosis. Four cases of PEH and 4 cases of angiosarcoma were identified. The mean age at diagnosis was 62 for PEH and 33 for primary angiosarcoma. All cases of PEH formed small masses with circumscribed or lobulated margins by imaging (mean size 0.9 cm). In 3 cases, the masses were difficult or impossible to identify after the biopsy. Angiosarcomas presented as larger masses with ill-defined margins (mean size 2.8 cm) that were unchanged in size after biopsy. PEH was surrounded by adipose tissue, whereas angiosarcoma invaded into fibrous stroma and involved lobules. The pseudopapillary structures of PEH were composed mainly of collagen, and thus, additional histologic stains for fibrin were not helpful for diagnosis. The 4 patients with PEH received no further treatment and are alive and disease-free at 2-11 years of follow-up. In contrast, the patients with angiosarcoma underwent mastectomy and chemotherapy or radiation therapy. Two of the patients with angiosarcoma died 3 years after diagnosis and the other 2 patients are alive without disease at 5 and 6 years. Therefore, distinguishing PEH and angiosarcoma is essential for appropriate management. This is the first series to compare these lesions on core needle biopsy and the first to note important clinical, imaging, and histologic differences that aid in making a diagnosis of PEH with confidence on breast core needle biopsy. PMID- 29476586 TI - Using Big Data to Accelerate Evidence-Based Practice. PMID- 29476587 TI - Color difference thresholds for computer-simulated human Gingiva. AB - OBJECTIVE: To determine 50:50% perceptibility threshold (PT) and 50:50% acceptability threshold (AT) for computer-simulated samples of human gingiva using CIEDE2000 and CIELAB color difference formulas. MATERIALS AND METHODS: Each of the 60 pairs of simulated human gingiva was displayed on a calibrated monitor, together with three pairs of upper central incisors of different lightness. The color of gingiva left and right from the midline was compared. A total of 30 observers (15 dentists, 15 laypersons) participated in the study. CIEDE2000 and CIELAB formulas were used to calculate the thresholds and a Takagi-Sugeno-Kang Fuzzy Approximation model was used as fitting procedure. Paired t-test (alpha = 0.05) was used in evaluation of statistical significance of differences. RESULTS: The PT and AT for CIEDE2000 and 95% confidence intervals were 1.1 [0.4, 1.7] and 2.8 [1.8, 4.0], respectively. Corresponding CIELAB values were 1.7 [0.2, 2.6] and 3.7 [2.1, 5.7]. Significant differences (P < .01) were recorded between PT and AT, between the corresponding threshold values in CIEDE2000 and CIELAB formulas as well as between dentists and laypersons. CONCLUSIONS: The difference between the perceptibility and acceptability threshold for gingiva was statistically significant in both CIEDE2000 and CIELAB. The same was true for differences between the corresponding thresholds using two color difference formulas, and between dentists and laypersons. Visual thresholds of human gingiva were not dependent upon lightness of adjacent teeth. Overall, CIEDE2000 color difference formula provided better fit than CIELAB formula in the evaluation of color difference thresholds of human gingiva. CLINICAL SIGNIFICANCE: The data on visual thresholds for healthy human gingiva can be used as quality control tool/guide for selection and evaluation of dental materials, interpretation of color-related findings in clinical dentistry and research, and for standardization in dentistry. It is of particular value that this study was designed based on in vivo color evaluation of healthy keratinized gingiva of subjects of different ethnicities, age groups, and gender. PMID- 29476588 TI - Institutional experience with SRS VMAT planning for multiple cranial metastases. AB - BACKGROUND AND PURPOSE: This study summarizes the cranial stereotactic radiosurgery (SRS) volumetric modulated arc therapy (VMAT) procedure at our institution. MATERIALS AND METHODS: Volumetric modulated arc therapy plans were generated for 40 patients with 188 lesions (range 2-8, median 5) in Eclipse and treated on a TrueBeam STx. Limitations of the custom beam model outside the central 2.5 mm leaves necessitated more than one isocenter pending the spatial distribution of lesions. Two to nine arcs were used per isocenter. Conformity index (CI), gradient index (GI) and target dose heterogeneity index (HI) were determined for each lesion. Dose to critical structures and treatment times are reported. RESULTS: Lesion size ranged 0.05-17.74 cm3 (median 0.77 cm3 ), and total tumor volume per case ranged 1.09-26.95 cm3 (median 7.11 cm3 ). For each lesion, HI ranged 1.2-1.5 (median 1.3), CI ranged 1.0-2.9 (median 1.2), and GI ranged 2.5-8.4 (median 4.4). By correlating GI to PTV volume a predicted GI = 4/PTV0.2 was determined and implemented in a script in Eclipse and used for plan evaluation. Brain volume receiving 7 Gy (V7 Gy ) ranged 10-136 cm3 (median 42 cm3 ). Total treatment time ranged 24-138 min (median 61 min). CONCLUSIONS: Volumetric modulated arc therapy provide plans with steep dose gradients around the targets and low dose to critical structures, and VMAT treatment is delivered in a shorter time than conventional methods using one isocenter per lesion. To further improve VMAT planning for multiple cranial metastases, better tools to shorten planning time are needed. The most significant improvement would come from better dose modeling in Eclipse, possibly by allowing for customizing the dynamic leaf gap (DLG) for a special SRS model and not limit to one DLG per energy per treatment machine and thereby remove the limitation on the Y-jaw and allow planning with a single isocenter. PMID- 29476589 TI - Emotional food cravings predicts poor short-term weight loss following laparoscopic sleeve gastrectomy. AB - OBJECTIVES: Laparoscopic sleeve gastrectomy (LSG) incidence has increased worldwide. However, a proportion of patients achieve inadequate weight loss and some experience weight regain. Little is known of the influence of eating beliefs and behaviours in response to cravings on early weight loss trajectory. This study aimed to identify the post-surgery eating cravings that predicted patients not achieving excess weight loss outcome (EWL) at 6-8 months post-LSG. DESIGN: A total of 106 (80.7% female) participants who underwent LSG from four sites completed the questionnaires at 4-6 weeks post-bariatric surgery and 6 months post-LSG. Achieving <40% EWL at 6-month follow-up was included as the outcome variable, and the nine subscales of the Food Cravings Questionnaire-Trait version (FCQ-T) were included as potential predictors of that change. METHODS: Logistic regression was used to examine the relationship between EWL and the nine subscales of the FCQ-T (intentions to eat, positive reinforcement, negative reinforcement, lack of control, preoccupation with food, feelings of hunger, negative affect, emotions experienced before or during food cravings or eating, and guilty feelings). RESULTS: Participants lost an average 64% EWL (SD = 21% EWL) 6-8 months after LSG surgery. Results indicated the overall model was significant and, of the nine variables, the emotional food craving subscale (adjusted OR = 4.19, p = .018) predicted a failure to achieve EWL. CONCLUSION: Emotional food cravings experienced 4-6 weeks following LSG may predict poor weight loss outcomes at 6 months. Statement of contribution What is already known on this subject? The prevalence of obesity has reached epidemic proportions worldwide. Bariatric surgery is currently the most viable and cost-effective treatment for obesity and shows sustainability. Laparoscopic sleeve gastrectomy (LSG) is now the most common procedure. Not all patients achieve excess weight loss outcome (EWL) following LSG. What does this study add? Emotional food cravings contribute to weight loss outcomes at 6 months' post-LSG surgery. Emotional food cravings may be a maladaptive coping mechanism that represents important area for early psychological intervention. PMID- 29476590 TI - Assessment of voice, speech and communication changes associated with cervical spinal cord injury. AB - BACKGROUND: Respiratory muscle impairment following cervical spinal cord injury (CSCI) may lead to reduced voice function, although the individual variation is large. Voice problems in this population may not always receive attention since individuals with CSCI face other, more acute and life-threatening issues that need/receive attention. Currently there is no consensus on the tasks suitable to identify the specific voice impairments and functional voice changes experienced by individuals with CSCI. AIMS: To examine which voice/speech tasks identify the specific voice and communication changes associated with CSCI, habitual and maximum speech performance of a group with CSCI was compared with that of a healthy control group (CG), and the findings were related to respiratory function and to self-reported voice problems. METHODS & PROCEDURES: Respiratory, aerodynamic, acoustic and self-reported voice data from 19 individuals (nine women and 10 men, aged 23-59 years, heights = 153-192 cm) with CSCI (levels C3 C7) were compared with data from a CG consisting of 19 carefully matched non injured people (nine women and 10 men, aged 19-59 years, heights = 152-187 cm). OUTCOMES & RESULTS: Despite considerable variability of performance, highly significant differences between the group with CSCI and the CG were found in maximum phonation time, maximum duration of breath phrases, maximum sound pressure level and maximum voice area in voice-range profiles (all p = .000). Subglottal pressure was lower and phonatory stability was reduced in some of the individuals with CSCI, but differences between the groups were not statistically significant. Six of 19 had voice handicap index (VHI) scores above 20 (the cut off for voice disorder). Individuals with a vital capacity below 50% of the expected for an equivalent reference individual performed significantly worse than participants with more normal vital capacity. Completeness and level of injury seemed to impact vocal function in some individuals. CONCLUSIONS & IMPLICATIONS: A combination of maximum performance speech tasks, respiratory tasks and self-reported information on voice problems help to identify individuals with reduced voice function following CSCI. Early identification of individuals with voice changes post-CSCI, and introducing appropriate rehabilitation strategies, may help to minimize development of maladaptive voice behaviours such as vocal strain, which can lead to further impairments and limitations to communication participation. PMID- 29476591 TI - Effect of Fluorination on Skin Sensitization Potential and Fragrant Properties of Cinnamyl Compounds. AB - A series of three alpha- and three beta-fluorinated representatives of the family of cinnamate-derived odorants (cinnamaldehyde (1), cinnamyl alcohol (2), and ethyl cinnamate (3)) as used as fragrance ingredients is described. Olfactive evaluation shows that the fluorinated compounds exhibit a similar odor profile to their parent compounds, but the olfactive detection thresholds are clearly higher. In vitro evaluation of the skin sensitizing properties with three different assays indicates that alpha-fluorination of Michael acceptor systems 1 and 3 slightly improves the skin sensitization profile. alpha-Fluorocinnamyl alcohol 2b is a weaker skin sensitizer than cinnamyl alcohol 2a by in vitro tests and the fluorinated product drops below the sensitization threshold of the KeratinoSens(r) assay. On the other hand, beta-fluorination of compounds 1 - 3 results in highly reactive products which display a worsened in vitro skin sensitization profile. PMID- 29476592 TI - Chemical Features Important for Activity in a Class of Inhibitors Targeting the Wip1 Flap Subdomain. AB - The wild-type p53 induced phosphatase 1, Wip1 (PP2Cdelta), is a protein phosphatase 2C (PP2C) family serine/threonine phosphatase that negatively regulates the function of the tumor suppressor p53 and several of its positive regulators such as ATM, Chk1, Chk2, Mdm2, and p38 MAPK. Wip1 dephosphorylates and inactivates its protein targets, which are critical for cellular stress responses. Additionally, Wip1 is frequently amplified and overexpressed in several human cancer types. Because of its negative role in regulating the function of tumor suppressor proteins, Wip1 has been identified as a potential therapeutic target in various types of cancers. Based on a recently reported Wip1 inhibitor (G-1), we performed an extensive structure-activity relationship (SAR) analysis. This led us to interesting findings in SAR trends and to the discovery of new chemical analogues with good specificity and bioavailability. PMID- 29476593 TI - Cell-Free DNA Blood Collection Tubes Are Appropriate for Clinical Proteomics: A Demonstration in Colorectal Cancer. AB - BACKGROUND: Optimized blood collection tubes (BCT) have been developed to expand the utility of plasma cell-free DNA (cfDNA) and are in clinical use. The appropriateness of plasma collected and stored in these tubes for proteomic analysis is unknown. METHODS: Paired blood samples were collected in BCT and traditional K3EDTA (EDTA) tubes from healthy controls and from colorectal cancer (CRC) patients before and after surgery, and stored for between 45 min and 48 h at room temperature. Plasma proteins were analyzed following high-abundant plasma protein depletion in quantitative discovery and targeted proteomics by liquid chromatography tandem-mass spectrometry (LC-MS/MS). RESULTS: BCT reduced cellular protein contamination in healthy controls over time, and increased the number of high confident low-abundant protein identifications in CRC blood samples compared to matched samples collected in EDTA tubes. The known CRC plasma protein biomarker, carcinoembryonic antigen (CEA), showed elevated levels across patients pre-operatively when collected and stored in BCT compared to EDTA tubes. Emerging CRC biomarkers, Dickkopf-3 (DKK3) and Gelsolin (GSN), showed elevated levels pre operatively when collected in BCT. CONCLUSIONS: Optimized BCT are appropriate for low-abundant plasma protein analysis and can be used with confidence for clinical proteomics. PMID- 29476594 TI - Compartment model analysis of intravenous contrast-enhanced dynamic computed tomography in hepatic hemodynamics: A validation study using intra-arterial contrast-enhanced computed tomography. AB - AIM: To verify the utility of the 2-in-1-out-compartment model analysis (CMA) of intravenous contrast-enhanced dynamic computed tomography (IV-CT) for evaluating hepatic arterial and portal venous flow using intra-arterial contrast-enhanced CT (IA-CT). METHODS: We retrospectively evaluated 49 consecutive patients who underwent IV-CT and were radiologically or histologically diagnosed as having hepatic malignant lesion (51 classical hepatocellular carcinomas [HCC], 4 early HCC, 3 cholangiolocellular carcinomas, 1 mixed HCC, 3 cholangiocellular carcinomas). As a gold standard for hepatic arterial and portal blood flows, we defined the normalized enhancement in CT values on CTAP (nCTAP) and CTHA (nCTHA). The hepatic arterial (k1a ) and portal venous inflow velocity (k1p ) constants in hepatic lesions and surrounding liver parenchyma were obtained from the CMA of IV CT with various outflow velocity constant (k2 ) limits using the nonlinear least square method. The correlation coefficient between the normalized enhancement in IA-CT and CMA of IV-CT was statistically evaluated according to various k2 limits. RESULTS: The highest mean correlation coefficient between k1a and nCTHA (r = 0.65, P < 0.0001) was observed when k2 ?0.035. The highest mean correlation coefficient between k1p and nCTAP (r = 0.69, P < 0.0001) was observed when k2 ?0.045. The decrease in correlation coefficient was significant when the upper k2 limit was lower than 0.03 or higher than 0.07 compared to the best mean correlation coefficient (P < 0.05). CONCLUSION: Hepatic arterial and portal venous flows can be evaluated quantitatively to some extent with appropriate outflow velocity constant limits using the CMA of IV-CT. PMID- 29476595 TI - Neuroimaging genomic studies in major depressive disorder: A systematic review. AB - Genetic-neuroimaging studies could identify new potential endophenotypes of major depressive disorder (MDD). Morphological and functional alterations may be attributable to genetic factors that regulate neurogenesis and neurodegeneration. Given that the association between gene polymorphisms and brain morphology or function has varied across studies, this systematic review aims at evaluating and summarizing all available genetic-neuroimaging studies. Twenty-eight gene variants were evaluated in 64 studies by structural or functional magnetic resonance imaging. Significant genetic-neuroimaging associations were found in monoaminergic genes, BDNF genes, glutamatergic genes, HPA axis genes, and the other common genes, which were consistent with common hypotheses of the pathogenesis of MDD. PMID- 29476596 TI - Visible-Light-Promoted Dearomative Fluoroalkylation of beta-Naphthols through Intermolecular Charge Transfer. AB - The first visible-light-promoted dearomative fluoroalkylation of beta-naphthols was realized without the assistance of any transition-metal catalysts or external photosensitizers. Inexpensive fluoroalkyl iodides were directly used as efficient fluoroalkylation reagents under very mild reaction conditions. The scope of this process was found to be general and broad, and both trifluoromethyl and perfluoroalkyl groups (-C4 F9 , -C6 F13 , and -C8 F17 ) were installed in excellent yields. Preliminary mechanistic studies suggest that visible-light promoted intermolecular charge transfer within the naphtholate-fluoroalkyl iodide electron donor-acceptor (EDA) complex induces a single electron transfer in the absence of photocatalysts. PMID- 29476597 TI - The Mental health Master Class: An innovative approach to improving student learning in mental health nursing. AB - The Master Class was developed as an additional educational innovation designed to promote learning about mental health and illness and mental health nursing as a career option to 2nd-year undergraduate nursing students. A number of students had approached the mental health nursing academics expressing two polar views on mental health. They either expressed extreme interest in mental health nursing or significant distress and concern related to studying the core 2nd-year subject. It was considered that the Master Class could potentially provide students with additional support. It was thought the Master Class may either consolidate their interest in mental health or relieve their stress. This article presents the findings of a pre- and postevaluation which was employed to explore the effectiveness of the 5-day intensive mental health Master Class programme on student's mental health learning and their understanding of the role of a mental health nurse. The findings highlighted that prior to participating in the Master Class, there was a significant sense of uncertainty associated with perceived levels of competence required within the profession of mental health nursing. This was coupled with students expressing they wanted to disengage with the profession even before they had commenced any theory or clinical experience. The post-Master Class findings illustrated a significant improvement in students desire to consider mental health nursing. PMID- 29476598 TI - Rhythm disturbances and treatment strategies in children with congenitally corrected transposition of the great arteries. AB - BACKGROUND: We aimed to evaluate rhythm abnormalities in cases of congenitally corrected transposition of the great arteries (ccTGA) and associated treatment strategies. PATIENTS AND METHODS: This retrospective cohort study included 65 pediatric patients with ccTGA who were admitted to the clinic between 2009 and 2017. The patients were divided into two groups, and surgical data, Holter electrocardiographic (ECG) recordings, ECG recordings, electrophysiological data, and device implantation data on the two groups were compared. RESULTS: Group I (n = 53, 82%) consisted of patients with significant associated lesions, and Group II (n = 12, 18%) consisted of those with minor or no associated lesions (isolated ccTGA). Rhythm abnormalities were diagnosed in 22 (34%) of the patients based on initial ECG findings and Holter ECG recordings. Eleven (17%) of these patients had atrioventricular (AV) block of different degrees, and the other 11 (17%) had supraventricular arrhythmia (SVA). The median follow-up was 49 months (range, 9 89 months), and the rhythm remained normal in 26 (42%) of the patients. Three patients died on follow-up. Of 40 patients with normal initial findings, nine required pacemaker implantation due to complete heart block, and SVA developed in seven patients on follow-up. No ventricular tachycardia was seen initially or on follow-up. Ablation was performed in four patients. During the follow-up period, pacemakers were implanted in 12 (23%) of patients in Group I and 4 (33%) of patients in Group II due to complete heart block. Cardiac resynchronization therapy (CRT) was performed in four patients due to systemic ventricular dysfunction. Notably, all four of these patients had a pacemaker implanted postoperatively. PMID- 29476599 TI - Evaluation of the effect scan pattern has on the trueness and precision of six intraoral digital impression systems. AB - OBJECTIVE: Clinicians have been slow to adopt digital impression technologies due possibly to perceived technique sensitivities involved in data acquisition. This research has two aims: determine whether scan pattern and sequence affects the accuracy of the three-dimensional (3D) model created from this digital impression and to compare the 5 imaging systems with regards to their scanning accuracy for sextant impressions. MATERIALS AND METHODS: Six digital intraoral impression systems were used to scan a typodont sextant with optical properties similar to natural teeth. The impressions were taken using five different scan patterns and the resulting digital models were overlayed on a master digital model to determine the accuracy of each scanner performing each scan pattern. Furthermore, regardless of scan pattern, each digital impression system was evaluated for accuracy to the other systems in this same manner. RESULTS: No differences of significance were noted in the accuracy of 3D models created using six distinct scan patterns with one exception involving the CEREC Omnicam. Planmeca Planscan was determined to be the truest scanner while 3Shape Trios was determined to be the most precise for sextant impression making. CONCLUSIONS: Scan pattern does not significantly affect the accuracy of the resulting digital model for sextant scanning. CLINICAL SIGNIFICANCE: Companies who make digital impression systems often recommend a scan pattern specific for their system. However, every clinical scanning scenario is different and may require a different approach. Knowing how important scan pattern is with regards to accuracy would be helpful for guiding a growing number of practitioners who are utilizing this technology. PMID- 29476600 TI - International dog travelling and risk for zoonotic Onchocerca lupi. AB - Onchocerca lupi is a recently recognized threat for the health of animals and humans in European, American, African and Middle Eastern countries. We describe a case of imported O. lupi infection in Italy and report the lifespan of this parasite in a non-endemic area, to advocate increased awareness of the veterinary community for this zoonotic parasitosis. PMID- 29476601 TI - The Impact of Pre-Analytical Conditions on Human Serum Peptidome Profiling. AB - The successful use of proteomic technology for the discovery of clinically relevant, new candidate biomarkers, especially in the low molecular weight range (peptidome), calls for a careful consideration of standardized operating procedures (SOP) for pre-analytical variables, including samples handling and storage. The current lack of standardization, widely considered a relevant source of random and systematic errors, underlies the uncertainty of analytical results and poor comparability, especially in multi-centric or inter-laboratory studies. In their recent study, Tsuchida et al. used the MALDI-TOF/MS technique to investigate the effect of long-term storage at -20 degrees C, -80 degrees C, and in liquid nitrogen on serum samples obtained for peptidomic analyses. The authors have also evaluated the effects of different sample thawing modalities. By including results from the same series as that reported on in a previous publication, they have effectively defined some important requirements for the peptidomic analysis of serum samples (e.g., maximum time intervals between venepuncture and serum separation [1 h], minimum temperature for long-term sera storage temperature [-80 degrees C], ideal conditions for sample thawing). PMID- 29476602 TI - An Extract of Russian Tarragon Prevents Obesity-Related Ectopic Lipid Accumulation. AB - SCOPE: The primary disorder underlying metabolic syndrome is insulin resistance due to excess body weight and abdominal visceral fat accumulation. In this study, it is asked if dietary intake of an ethanolic extract from Russian tarragon (Artemisia dracunculus L., termed PMI5011), shown to improve glucose utilization by enhancing insulin signaling in skeletal muscle, could prevent obesity-induced insulin resistance, skeletal muscle metabolic inflexibility, and ectopic lipid accumulation in the skeletal muscle and liver. METHODS AND RESULTS: Male wild type mice are fed a high-fat diet alone or supplemented with PMI5011 (1% w/w) over 3 months. Dietary intake of PMI5011 improved fatty acid oxidation and metabolic flexibility in the skeletal muscle, reduced insulin levels, and enhanced insulin signaling in the skeletal muscle and liver independent of robust changes in expression of factors that control fatty acid oxidation. This corresponds with significantly reduced lipid accumulation in the skeletal muscle and liver, although body weight gain is comparable to a high-fat diet alone. CONCLUSION: Previous studies showed that PMI5011 enhances insulin sensitivity in the setting of established obesity-induced insulin resistance. The current study demonstrates that dietary intake of PMI5011 prevents high-fat diet-induced insulin resistance, metabolic dysfunction, and ectopic lipid accumulation in the skeletal muscle and liver without reducing body weight. PMID- 29476603 TI - Validation of a deformable MRI to CT registration algorithm employing same day planning MRI for surrogate analysis. AB - PURPOSE: Validating deformable multimodality image registrations is challenging due to intrinsic differences in signal characteristics and their spatial intensity distributions. Evaluating multimodality registrations using these spatial intensity distributions is also complicated by the fact that these metrics are often employed in the registration optimization process. This work evaluates rigid and deformable image registrations of the prostate in between diagnostic-MRI and radiation treatment planning-CT by utilizing a planning-MRI after fiducial marker placement as a surrogate. The surrogate allows for the direct quantitative analysis that can be difficult in the multimodality domain. METHODS: For thirteen prostate patients, T2 images were acquired at two different time points, the first several weeks prior to planning (diagnostic-MRI) and the second on the same day as the planning-CT (planning-MRI). The diagnostic-MRI was deformed to the planning-CT utilizing a commercially available algorithm which synthesizes a deformable image registration (DIR) algorithm from local rigid registrations. The planning-MRI provided an independent surrogate for the planning-CT for assessing registration accuracy using image similarity metrics, including Pearson correlation and normalized mutual information (NMI). A local analysis was performed by looking only within the prostate, proximal seminal vesicles, penile bulb, and combined areas. RESULTS: The planning-MRI provided an excellent surrogate for the planning-CT with residual error in fiducial alignment between the two datasets being submillimeter, 0.78 mm. DIR was superior to the rigid registration in 11 of 13 cases demonstrating a 27.37% improvement in NMI (P < 0.009) within a regional area surrounding the prostate and associated critical organs. Pearson correlations showed similar results, demonstrating a 13.02% improvement (P < 0.013). CONCLUSION: By utilizing the planning-MRI as a surrogate for the planning-CT, an independent evaluation of registration accuracy is possible. This population provides an ideal testing ground for MRI to CT DIR by obviating the need for multimodality comparisons which are inherently more challenging. PMID- 29476605 TI - Letter to the editor concerning "First report of peste des petits ruminants virus lineage II in Hydropotes inermis, China" by Zhou et al. (Transbound Emerg Dis; 2017: https://doi.org/10.1111/tbed.12683). PMID- 29476604 TI - Cut loose and run: The complex role of ADAM proteases during neural crest cell development. AB - ADAM metalloproteases have been shown to play critical roles during development. In this review, we will describe functional evidence that implicates ADAM proteins during the genesis, migration and differentiation of neural crest cells. We will restrict our analysis to the transmembrane ADAMs as other reviews have addressed the role of extracellular metalloproteases (Christian et al. [2013] Critical Reviews in Biochemistry and Molecular Biology 48:544-560). This review will describe advances that have been obtained mainly through the use of two vertebrate model systems, the frog, and avian embryos. The role of the principal substrates of ADAMs, the cadherins, has been extensively described in other reviews, most recently in (Cousin [1997] Mechanisms of Development 148:79-88; Taneyhill and Schiffmacher [2017] Genesis, 55). The function of ADAMs in the migration of other cell types, including the immune system, wound healing and cancer has been described previously in (Dreymueller et al. [2017] Mediators of Inflammation 2017: 9621724). Our goal is to illustrate both the importance of ADAMs in controlling neural crest behavior and how neural crest cells have helped us understand the molecular interactions, substrates, and functions of ADAM proteins in vivo. PMID- 29476606 TI - Integrated Multi-Omic Analyses Support Distinguishing Secretory Carcinoma of the Breast from Basal-Like Triple-Negative Breast Cancer. AB - PURPOSE: Secretory carcinoma (SC) of the breast is defined as an indolent tumor but is still categorized into a basal-like triple-negative breast cancer (BL TNBC) subgroup that generally shows aggressive behavior according to the current classification. Despite the unique clinical behavior of SC, molecular characteristics that reflect biological behaviors of SC remain largely unknown. EXPERIMENTAL DESIGN: A combinatorial approach of whole-exome sequencing and mass spectrometry-based in-depth quantitative proteomics to determine the entire molecular landscape of SC using three SC formalin-fixed paraffin-embedded (FFPE) tissues is employed. RESULTS: Exome sequencing and proteomic analysis of SC identified 419 unique somatic mutations and 721 differentially expressed proteins as compared with triple-negative breast cancer (TNBC), respectively. Several pathways related to cancer metabolism were significantly upregulated in the SC group. Comparative analyses with multiple datasets revealed that SC shares genomic mutations and biological pathways more closely related to hormone receptor-positive breast cancer than BL-TNBC. CONCLUSION AND CLINICAL RELEVANCE: These multi-omic analyses provide evidence that SC harbors substantially different molecular genomic and proteomic landscapes compared with BL-TNBC. These results provide an entire spectrum of in-depth molecular landscapes to support the hypothesis that SC is distinct from BL-TNBC. PMID- 29476607 TI - Factors influencing decision-making processes for unwell residents in residential aged care: Hospital transfer or Residential InReach referral? AB - OBJECTIVE: To investigate decision-making around hospital transfer and/or referral of residents to a Residential InReach (RiR) service in north-eastern metropolitan Melbourne, Australia, from the perspectives of residential aged care facility (RACF) staff, general practitioners (GPs) and RiR registered nurses (RNs). METHODS: Thirty-one staff from eight RACFs, five GPs and four RiR RNs participated in individual or group interviews. RESULTS: Residential aged care facility staff and GPs valued and relied upon RiR to manage unwell residents. Thematic analysis identified RiR utilisation was driven by the following: (i) complexity of decision-making processes in RACFs; (ii) variability in facility based medical and nursing care; and (iii) impact of RiR service outcomes on patients and referrers. CONCLUSION: Availability of timely and appropriate medical and nursing care in RACFs was reported to influence transfers to the hospital and/or referrals to RiR. RiR was used to complement or substitute usual care available to residents. Further research and improvements in RACF and RiR resources are required. PMID- 29476608 TI - Clinical performance of endobronchial ultrasound-guided transbronchial needle aspiration for assessing programmed death ligand-1 expression in nonsmall cell lung cancer. AB - BACKGROUND: Pembrolizumab was recently approved as a first line agent for metastatic NSCLC in patients with high programmed death-ligand 1 (PD-L1) expression. OBJECTIVES: Since a significant portion of lung cancer is diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS TBNA); there is a need for PD-L1 testing in these specimens. However, to date few studies have evaluated performance of cytology specimens from EBUS TBNA for PD-L1 analysis. METHODS: Patients who had a diagnosis of NSCLC and in whom ancillary testing, i.e., next generation sequencing (NGS), anaplastic lymphoma kinase (ALK), and PD-L1 expression was requested between January and May 2017 were reviewed. RESULTS: Fifty of the 112 patients reviewed had the diagnosis of NSCLC for which ancillary testing was requested. Twelve patients (24%) had squamous cell carcinoma, twenty-seven had adenocarcinoma (54%), five had NSCLC favor adenocarcinoma (10%), two had NSCLC favor squamous cell cancer (4%), and four had NSCLC not otherwise specified (NOS) (8%). Size of the lymph nodes or lesion sampled ranged from 10 to 50 mm. Four (8%) patients had insufficient number of tumor cells in the cell block for any of the ancillary molecular testing. Forty one (82%) patients had an adequate sample for all three ancillary tests. Satisfactory results for PD-L1 expression for all cases was 86% with 14 (32%) patients having levels of PD-L1 expression >50%. CONCLUSION: EBUS TBNA is effective and has a high proportion of satisfactory results for testing PD-L1 expression on tumor cells in addition to NGS and ALK FISH. PMID- 29476609 TI - 27-Hydroxycholesterol Inhibits Sterol Regulatory Element-Binding Protein 1 Activation and Hepatic Lipid Accumulation in Mice. AB - OBJECTIVE: Although 27-hydroxycholesterol (27-HC) has been reported as a potent regulator of lipid homeostasis, its role in hepatic lipogenesis remains obscure. The present study was designed to investigate the impact of 27-HC on sterol regulatory element-binding protein 1 (SREBP-1) and hepatic steatosis. METHODS: In this study, the 27-HC level in mice was upregulated by overexpressing CYP27A1 or treating primary hepatocytes with 27-HC, and then the hepatic lipid accumulation was detected. RESULTS: 27-HC inhibited hepatic lipid accumulation and decreased the levels of the mature active form of SREBP-1. The expression of lipogenic genes, including acetyl coenzyme A carboxylase, fatty acid synthase, stearoyl coenzyme A desaturase-1, and glycerol-3-phosphate acyltransferase, were also suppressed after 27-HC intervention. Furthermore, 27-HC induced expression of insulin-induced gene-2 (Insig-2), an endoplasmic reticulum protein that prevents SREBP activation, both in vivo and in vitro. The inhibitory effect of 27-HC on SREBP-1 activation was absent when Insig-2 was silenced. Finally, coimmunoprecipitation showed that 27-HC promoted the binding of Insig-2 to SREBP 1. CONCLUSIONS: These studies demonstrated the suppressive effect of 27-HC on hepatic lipid accumulation and revealed a novel mechanism by which 27-HC regulates lipogenesis. PMID- 29476610 TI - Inspissated cyst fluid in endoscopic ultrasound-guided fine needle aspiration of pancreatic cysts. AB - BACKGROUND: Inspissated cyst fluid may be identified on pancreatic cyst aspiration cytology. We report on the cytomorphologic characteristics of inspissated cyst fluid on EUS-FNA of pancreatic cysts and correlate this finding with histopathology or multimodal (cytology, cyst fluid analysis, molecular pathology, imaging) classification of cyst type. METHODS: The department archives were searched for pancreatic cyst fine-needle aspiration biopsies that contained dessicated, crystalline or inspissated material on cytologic preparations. RESULTS: Twenty-eight cases of pancreatic cysts containing inspissated material were identified. The cytomorphology of the inspissated material ranged from fibrillary fan-like structure (54%), ball-like structures (57%), and granular material (43%). When present, the fibrillary inspissated material was associated with neoplastic mucinous cysts in 11/15 (73%) cases, but was also seen in 2 pseudocysts, 1 serous cystadenoma, and 1 cyst of uncertain type (suggestive of mucinous cyst on EUS). The presence of fibrillary inspissated cyst material on cytology had a positive predictive value of 79% and a specificity of 63% for a neoplastic mucinous cyst. CONCLUSION: Although not highly specific, the presence of inspissated cyst fluid with fibrillary architecture should be recognized by cytopathologists and interpreted as at least "atypical" given the potential association with neoplastic mucinous cysts of the pancreas. PMID- 29476611 TI - No Significant Effect of Maternal Perception of the Food Environment on Reproductive Success or Pup Outcomes in C57BL/6J Mice. AB - OBJECTIVE: Prior work concerning maternal perception of the food environment suggests that perceived disparities in food resources resulted in reduced pup mass and dam reproductive success. This study attempted to replicate this result with increased sample size and additional measures. METHODS: Female C57BL/6J mice (n = 160; 3 weeks old) were randomly assigned to either subject or peer and were pair housed in partitioned cages with olfactory and visual contact. After a 6 week maturation period on an energy-rich cafeteria diet, cages were randomly assigned to Control (subject and peer fed pelleted diet) or Treatment (subject fed pellets, peer fed cafeteria diet), and subjects were bred. After weaning, one pup from each sex per litter was reared to 5 months. RESULTS: Treatment did not affect the number of births, pup size at birth, or the proportion of pups surviving to weaning (P > 0.09). Treatment did not affect dam body or fat mass at parturition (P > 0.22), but these measures were higher in some Treatment dams at weaning (P < 0.05). Smaller female pups were weaned from Treatment dams pregnant on the first breeding attempt (P = 0.01), but no other pup effects were observed (P > 0.07). CONCLUSIONS: Exposure to food-environment disparity in this study did not replicate previous findings or affect pup growth after weaning. PMID- 29476612 TI - Prognostic performance of serial in-hospital measurements of copeptin and multiple novel biomarkers among patients with worsening heart failure: results from the MOLITOR study. AB - AIMS: In heart failure, various biomarkers are established for diagnosis and risk stratification; however, little is known about the relevance of serial measurements during an episode worsening heart failure (WHF). This study sought to investigate the trajectory of natriuretic peptides and multiple novel biomarkers during hospitalization for WHF and to determine the best time point to predict outcome. METHODS AND RESULTS: MOLITOR (Impact of Therapy Optimisation on the Level of Biomarkers in Patients with Acute and Decompensated Chronic Heart Failure) was an eight-centre prospective study of 164 patients hospitalized with a primary diagnosis of WHF. C-terminal fragment of pre-pro-vasopressin (copeptin), N-terminal pro-B-type natriuretic peptide (NT-proBNP), mid-regional pro-atrial natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin (MR proADM), and C-terminal pro-endothelin-1 (CT-proET1) were measured on admission, after 24, 48, and 72 h, and every 72 h thereafter, at discharge and follow-up visits. Their performance to predict all-cause mortality and rehospitalization at 90 days was compared. All biomarkers decreased during recompensation (P < 0.05) except MR-proADM. Copeptin at admission was the best predictor of 90 day mortality or rehospitalization (chi2 = 16.63, C-index = 0.724, P < 0.001), followed by NT-proBNP (chi2 = 10.53, C-index = 0.646, P = 0.001), MR-proADM (chi2 = 9.29, C-index = 0.686, P = 0.002), MR-proANP (chi2 = 8.75, C-index = 0.631, P = 0.003), and CT-proET1 (chi2 = 6.60, C-index = 0.64, P = 0.010). Re measurement of copeptin at 72 h and of NT-proBNP at 48 h increased prognostic value (chi2 = 23.48, C-index = 0.718, P = 0.00001; chi2 = 14.23, C-index = 0.650, P = 0.00081, respectively). CONCLUSIONS: This largest sample of serial measurements of multiple biomarkers in WHF found copeptin at admission with re measurement at 72 h to be the best predictor of 90 day mortality and rehospitalization. PMID- 29476613 TI - Effect of Progressive Weight Loss on Lactate Metabolism: A Randomized Controlled Trial. AB - OBJECTIVE: Lactate is an intermediate of glucose metabolism that has been implicated in the pathogenesis of insulin resistance. This study evaluated the relationship between glucose kinetics and plasma lactate concentration ([LAC]) before and after manipulating insulin sensitivity by progressive weight loss. METHODS: Forty people with obesity (BMI = 37.9 +/- 4.3 kg/m2 ) were randomized to weight maintenance (n = 14) or weight loss (n = 19). Subjects were studied before and after 6 months of weight maintenance and before and after 5%, 11%, and 16% weight loss. A hyperinsulinemic-euglycemic clamp procedure in conjunction with [6,6-2 H2 ]glucose tracer infusion was used to assess glucose kinetics. RESULTS: At baseline, fasting [LAC] correlated positively with endogenous glucose production rate (r = 0.532; P = 0.001) and negatively with insulin sensitivity, assessed as the insulin-stimulated glucose disposal (r = -0.361; P = 0.04). Progressive (5% through 16%) weight loss caused a progressive decrease in fasting [LAC], and the decrease in fasting [LAC] after 5% weight loss was correlated with the decrease in endogenous glucose production (r = 0.654; P = 0.002) and the increase in insulin sensitivity (r = -0.595; P = 0.007). CONCLUSIONS: This study demonstrates the interrelationships among weight loss, hepatic and muscle glucose kinetics, insulin sensitivity, and [LAC], and it suggests that [LAC] can serve as an additional biomarker of glucose-related insulin resistance. PMID- 29476614 TI - Sensitive detection of Bacillus thuringiensis Cry1B toxin based on camel single domain antibodies. AB - Bt Cry1B toxin, a residue in insect-resistant transgenic plants, has been identified to be harmful to human health. Therefore, it is urgent to detect the Cry1B toxin level in each kind of transgenic plant. Nbs, with prominently unique physiochemical properties, are becoming more and more promising tools in the detection of target antigens. In this study, an immune phage display library that was of high quality was successfully constructed for the screening of Cry1B specific Nbs with excellent specificity, affinity, and thermostable. Subsequently, a novel sandwich ELISA for Cry1B detection was established, which was based on the biotin-streptavidin system using these aforementioned Nbs. This established detection system presented a linear working range from 5 to 1000 ng ml-1 and a low detection limit of 3.46 ng ml-1 . The recoveries from spiked samples were in the range of 82.51%-113.56% with a relative standard deviation (RSD) lower than 5.00%. Taken together, the proposed sandwich ELISA would be a potential method for the detection of Cry1B toxin in transgenic Bt plants specifically and sensitively. PMID- 29476615 TI - Pioglitazone and bladder cancer risk: a systematic review and meta-analysis. AB - Current evidence about the association between pioglitazone and bladder cancer risk remains conflict. We aimed to assess the risk of bladder cancer associated with the use of pioglitazone and identify modifiers that affect the results. We systematically searched PubMed, Embase, and Cochrane Central Register of Controlled Trials from inception to 25 August 2016 for randomized controlled trials (RCTs) and observational studies that evaluated the association between pioglitazone and bladder cancer risk. Conventional and cumulative meta-analyses were used to calculate the odds ratio (OR) with 95% confidence interval (CI). A restricted spline regression analysis was used to examine the dose-response relationship with a generalized least-squares trend test. We included two RCTs involving 9114 patients and 20 observational studies (n = 4,846,088 individuals). An increased risk of bladder cancer in patients treated with pioglitazone versus placebo was noted from RCTs (OR, 1.84; 95%CI, 0.99 to 3.42). In observational studies, the increased risk of bladder cancer was slight but significant among ever-users of pioglitazone versus never-users (OR, 1.13; 95%CI, 1.03 to 1.25), which appeared to be both time- (P = 0.003) and dose-dependent (P = 0.05). In addition, we observed the association differed by region of studies (Europe, United States, or Asia) or source of funding (sponsored by industry or not). Current evidence suggests that pioglitazone may increase the risk of bladder cancer, possibly in a dose- and time-dependent manner. Patients with long-term and high-dose exposure to pioglitazone should be monitored regularly for signs of bladder cancer. PMID- 29476616 TI - Upregulation of extraneuronal TRPV1 expression in chronic rhinosinusitis with nasal polyps. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is a multifactorial upper airway disease with unclear etiology. Neuronal Transient Receptor Potential Vanilloid 1 (TRPV1) and Ankyrin 1 (TRPA1) channels have been implicated in the pathogenesis of CRS. We aimed to detect the expression of extraneuronal TRPV1 and TRPA1 receptors in nasal polyp (NP) tissue samples. METHODOLOGY: Samples were obtained from fourty two CRS pateints with nasal polyp and sixteen healthy controls to measure receptor gene expression by quantitative PCR, protein localization by immunohistochemistry and cytokine profile by multiplex bead immunoassay. RESULTS: Non-neuronal TRPV1, TRPA1 receptors were expressed in biopsy samples of NP. A population of mast cells and macrophages were immunopositive for TRPV1 and TRPA1. A fraction of plasma cells expressed TRPV1 but not TRPA1 and neither receptor was present on eosinophils. The local gene expression of extraneuronal TRPV1, TRPA1 receptors was also proven. TRPV1 mRNA levels were significantly increased in CRSwNP patients with asthma and allergic rhinitis compared to their NP counterparts. CONCLUSIONS: Elevated TRPV1 levels in comorbid asthma and allergy may have a function in CRSwNP. Subpopulation-specific TRPV1 presence on plasma and mast cells can indicate delicate roles in regulating activation and release of inflammatory mediators. PMID- 29476617 TI - Impact of digoxin on risk of death in heart failure patients treated with b blockers. Results from Polish part of ESC Heart Failure Long-Term Registry. AB - BACKGROUND: Digoxin is used in the treatment of atrial fibrillation (AF) and heart failure (HF). It was reported to increase the risk of death in HF. Studies on digoxin are based mainly on patients treated some years ago, before the era of common b-blocker use. AIM: This study aims to show the influence of digoxin in a modern cohort of HF patients on top of the contemporary guideline-directed treatment. METHODS: This study retrospectively analyses the Polish part of the European Society of Cardiology Heart Failure Long-Term Registry. It includes 912 patients treated for HF between February 2012 and January 2013, and followed until May 2014. At baseline, 19.1% took digoxin, 89.6% angiotensin convertase enzyme inhibitors or angiotensin receptor blockers, 91.9% b-blockers, and 69.4% mineralocorticoid receptor antagonists. RESULTS: Digoxin is associated with increased risk of death after adjustment for significant covariates in patients who have HF with reduced ejection fraction (HFrEF) but no AF history (hazard ratio [HR] 2.52, 95% confidence interval [CI] 1.23-5.19; p = 0.011), and it does not influence significantly the risk of hospitalisation (adjusted HR 1.46, 95% CI 1.05-1.72; p = 0.11). Digoxin use shows no significant association with the risk of death or hospitalisation in patients with AF and HFrEF or HF with preserved ejection fraction (HFpEF). Patients on digoxin present a significantly worse clinical status with lower left ventricular ejection fraction and higher New York Heart Association class, and fewer of them received the guideline-directed treatment. CONCLUSIONS: Digoxin is associated with increased risk of death in HFrEF patients without AF history receiving the guideline- -directed treatment. Digoxin seems to be employed in patients with worse clinical status, which may at least partially explain its association with increased risk of death. PMID- 29476618 TI - Enhancement of malate production through engineering of the periplasmic rTCA pathway in Escherichia coli. AB - The compartmentalization of enzymes into organelles is a promising strategy for limiting metabolic crosstalk and improving pathway efficiency; however, prokaryotes are unicellular organisms that lack membrane-bound organelles. To mimic this natural compartmentalization, we present here the targeting of the reductive tricarboxylic acid (rTCA) pathway to the periplasm to enhance the production of malate. A multigene combination knockout strategy was used to construct a phosphoenolpyruvate (PEP) pool. Then, the genes encoding phosphoenolpyruvate carboxykinase and malate dehydrogenase were combinatorially overexpressed to construct a cytoplasmic rTCA pathway for malate biosynthesis; however, the efficiency of malate production was low. To further enhance malate production, the rTCA pathway was targeted to the periplasm, which led to a 100% increase in malate production to 18.8 mM. Next, dual metabolic engineering regulation was adopted to balance the cytoplasmic and periplasmic pathways, leading to an increase in malate production to 58.8 mM. The final engineered strain, GL2306, produced 193 mM malate with a yield of 0.53 mol/mol in 5 L of pH stat fed-batch culture. The strategy described here paves the way for the development of metabolic engineering and synthetic biology in the microbial production of chemicals. PMID- 29476619 TI - Sequential processing with fermentative Caldicellulosiruptor kronotskyensis and chemolithoautotrophic Cupriavidus necator for converting rice straw and CO2 to polyhydroxybutyrate. AB - Unpretreated rice straw was fermented by the extremely thermophilic bacterium Caldicellulosiruptor kronotskyensis, generating solubilized carbohydrates, organic acids, lignin-derived aromatics, H2 , and CO2 , which were subsequently used to produce polyhydroxybutyrate (PHB) by the chemolithoautotrophic bacterium Cupriavidus necator. The fermented liquid significantly enhanced the growth of C. necator, leading to a five-fold cell biomass yield, and a nine-fold PHB yield compared to what was obtained from conventional mineral media. This integrated process utilized all products of lignocellulose fermentation without H (electron) loss and carbon emission, while concomitantly enhancing CO2 fixation by C. necator for PHB production. The sequential coupling of C. kronotskyensis and C. necator provides not only a new biorefinery paradigm characterized by reduced pretreatment and saccharification requirements but also an efficient way for enhancing CO2 fixation. PMID- 29476620 TI - Nectar yeasts: a natural microcosm for ecology. AB - The species of yeasts that colonize floral nectar can modify the mutualistic relationships between plants and pollinators by changing the chemical properties of nectar. Recent evidence supporting this possibility has led to increased interest among ecologists in studying these fungi as well as the bacteria that interact with them in nectar. Although not fully explored, nectar yeasts also constitute a promising natural microcosm that can be used to facilitate development of general ecological theory. We discuss the methodological and conceptual advantages of using nectar yeasts from this perspective, including simplicity of communities, tractability of dispersal, replicability of community assembly, and the ease with which the mechanisms of species interactions can be studied in complementary experiments conducted in the field and the laboratory. To illustrate the power of nectar yeasts as a study system, we discuss several topics in community ecology, including environmental filtering, priority effects, and metacommunity dynamics. An exciting new direction is to integrate metagenomics and comparative genomics into nectar yeast research to address these fundamental ecological topics. PMID- 29476621 TI - Risks and outcomes of direct current cardioversion in children and young adults with congenital heart disease. AB - OBJECTIVES: Evaluate the efficacy, outcomes, and complications associated with direct current cardioversion (DCCV) in the treatment of arrhythmias in pediatric and adult congenital heart disease (CHD) populations and identify patient and procedural characteristics associated with adverse events. BACKGROUND: Pediatric and adult patients with CHD are at risk of atrial arrhythmias. DCCV is effective but is associated with potential complications. METHODS: In this single-center retrospective series, patients who underwent DCCV between January 2010 and May 2015 were identified and categorized as pediatric (<18 years) or adult (> 18 years). Records were reviewed for demographic, arrhythmic, and CHD-specific characteristics; acute efficacy; and 3-month arrhythmia recurrence. Complications were categorized as life-threatening (LT) or non-life-threatening (NLT). Univariate followed by multiple variable and logistic regression (LR) analyses were used to identify characteristics associated with complications. RESULTS: We identified 104 patients with 152 discrete DCCV events with median age 17.4 years (0.15-62.2). DCCV efficacy was 89% with 3-month recurrence of 46%. There were 52 complications among 24 patients, median age 17.7 years (0.15-49). Risks associated with NLT complications are as follows: moderate-severe systolic dysfunction (8/152 encounters, P = < 0.01) and more than one shock per DCCV encounter (P = < 0.01). Six of eight encounters with moderate-severe systolic dysfunction were <18 years (P = 0.1). Risks for LT complications included age >18 years and associated NLT complication. Adults had more frequent arrhythmia recurrence within 3 months than children (P = < 0.01). CONCLUSIONS: DCCV is effective for arrhythmias but is associated with frequent recurrence, particularly in adult patients. Complications associated with DCCV may be greater than previously reported. Additional support and precautions should be in place for those at greatest risk. PMID- 29476622 TI - 24-hour oxygen saturation recordings in preterm infants: editing artefact. AB - AIM: To create editing guidelines for artefact removal in preterm infant pulse oximetry recordings. METHODS: 38 preterm infants ready for discharge home from the neonatal intensive care unit underwent 24-hour pulse oximetry recording using the Masimo(r) Rad-8 device. An expert panel determined editing rules based on clinical protocols. For each recording, three reports were generated, 'raw' no editing, 'auto' using the software editing feature and 'manual' reviewed and edited according to the rules. Primary outcome measures were desaturation indices including desaturation index 3% and 4%. Secondary measures included heart rate, mean oxygen saturation and time below 90%. RESULTS: While all oximetry outcomes differed significantly between editing modes, the majority were not considered likely to influence clinical management. Use of the auto editing compared to no editing did alter by >5%: Time spent <90% oxygen saturation and Desaturation index 4% >10 seconds. The use of manual editing removed extremely low pulse values that were considered unphysiological in this group of otherwise healthy infants. CONCLUSION: We recommend that oximetry recordings to determine cardiorespiratory stability in newborn infants ready for discharge from the neonatal unit have software editing features applied. This will remove artefact without consuming time in a busy unit. PMID- 29476624 TI - Telomere length was similar in school-age children with bronchopulmonary dysplasia and allergic asthma. AB - AIM: Inflammation is a major factor in the pathophysiology of bronchopulmonary dysplasia (BPD), and it contributes to accelerated telomere shortening and cellular ageing. This study aimed to determine its effect on telomere length and lung function in school-aged children born preterm with BPD. METHODS: We examined 29 children with BPD, born preterm in Stockholm county 1998-99, along with 28 children with allergic asthma born at term matched for age and gender. At 10 years of age, we measured relative telomere length (RTL) in blood by quantitative polymerase chain reaction, lung function by spirometry and inflammation by fractional exhaled nitric oxide and blood cytokines. RESULTS: RTL was not different in preterm born with BPD compared to term born children with asthma. The gender effect was strong in both groups; girls had significantly longer median RTL than boys (1.8 versus 1.5, p < 0.01). Short RTL was associated with low forced expiratory flow, also after adjusting for gender, but was not affected by severity of BPD or ongoing inflammation. CONCLUSION: Telomere length was similar in 10-year-old children born preterm with a history of BPD and term born children with allergic asthma. However, impaired lung function and male gender were associated with short telomeres. PMID- 29476623 TI - The Influence of Adding Spices to Reduced Sugar Foods on Overall Liking. AB - : Reducing sugar intake is a major public health goal but many consumers are reluctant to use low calorie sweeteners. Two studies were conducted in healthy adults aged 18 to 65 to investigate whether addition of culinary spices to foods reduced in sugar could preserve hedonic liking. Test foods, black tea, oatmeal, and apple crisp, were prepared in full sugar (FS), reduced sugar (RS), and reduced sugar with spice (RSS) versions. Sugar reductions were 100%, 35%, and 37% for tea, oatmeal, and apple crisp, respectively. In Study 1, 160 subjects rated absolute liking of FS, RS, and RSS versions of a breakfast of oatmeal and tea and an afternoon snack of apple crisp on consecutive weeks. In Study 2, 150 subjects rated relative liking of all 3 versions of one food at the same seating, with different foods tested 1 wk apart. Liking was assessed using a 9-point Likert scale. Both studies yielded similar results. For all 3 test items, liking was significantly higher for FS than for RS (P < 0.03). For tea, addition of spices did not significantly improve liking in either study. For oatmeal, addition of spices did not consistently improve liking compared to RS. For apple crisp, relative liking of RSS was not different then FS. These results indicate that it is possible to preserve the hedonic pleasure of a reduced sugar version of a dessert food, apple crisp, by addition of culinary spices. This may be a promising strategy to reduce sugar in some foods without using low calorie sweeteners. PRACTICAL APPLICATION: Reducing sugar consumption is an important public health goal. Many consumers are reluctant to use low calorie sweeteners and alternative approaches are needed. Using culinary spices to enhance the flavor of foods may allow sugar reduction while still preserving acceptable overall liking. PMID- 29476625 TI - Continuous, intrinsic magnetic depletion of erythrocytes from whole blood with a quadrupole magnet and annular flow channel; pilot scale study. AB - The ability to separate RBCs from the other components of whole blood has a number of useful clinical and research applications ranging from removing RBCs from typical clinical blood draw, bone marrow transplants to transfusions of these RBCs to patients after significant blood loss. Viewed from a mechanistic/process perspective, there are three routine methodologies to remove RBCs: 1) RBCs lysis, 2) separation of the RBCs from the nucleated cells (i.e., stem cells) based on density differences typically facilitated through centrifugation or sedimentation agents, and 3) antibody based separation in which a targeted RBC is bound with an affinity ligand that facilitates its removal. More recently, several microfluidic based techniques have also been reported. In this report, we describe the performance of continuous RBC separation achieved by the deflection of intrinsically magnetic, deoxygenated RBCs as they flow through a magnetic energy gradient created by quadrupole magnet. This quadrupole magnetic, with aperture of 9.65 mm, has a maximum field of B0 = 1.36 T at the pole tips and a constant field gradient of B0 /r0 = 286 T/m. The annular flow channel, contained within this quadrupole magnet, is 203 mm long, has an inner radius of 3.98 mm, and an inner, outer radius of 4.36 mm, which corresponds to an annulus radius of 380 micrometer. At the entrance and exit to this annular channel, a manifold was designed which allows a cell suspension and sheath fluid to be injected, and a RBC enriched exit flow (containing the magnetically deflected RBCs) and a RBC depleted exit flow to be collected. Guided by theoretical models previously published, a limited number of operating parameters; total flow rate, flow rate ratios of flows in and flow out, and ratios of RBC to polystyrene control beads was tested. The overall performance of this system is consistent with our previously presented, theoretical models and our intuition. As expected, the normalized recovery of RBCs in the RBC exit fraction ranged from approximately 95% down to 60%, as the total flow rate through the system increased from 0.1 to 0.6 ml/min. At the cell concentrations studied, this corresponds to a flow rate of 1.5 * 106 -9 * 106 cells/min. While the throughput of these pilot scale studies are slow for practical applications, the general agreement with theory, and the small cross-sectional area in which the actual separation is achieved, 77 mm2 (annulus radius times the length), and corresponding volume of approximately 2 mls, suggests the potential to scale-up a system for practical applications exists and is actively being pursued. PMID- 29476626 TI - Sonocrystallization of Interesterified Soybean Oil: Effect of Saturation Level and Supercooling. AB - : The aim of this study was to investigate the effects of supercooling and degree of saturation on lipid sonocrystallization under similar driving force of crystallization. Samples consisting of 100%, 50%, and 20% interesterified soybean oil (IESBO) diluted in high-oleic sunflower oil (HOSFO) were crystallized with and without high-intensity ultrasound (HIU). Two power levels were used by changing the amplitude of vibration of the tip (24 MUm and 108 MUm of tip amplitude). HIU operating at a frequency of 20 kHz was applied for 10 s. Sonication induced crystallization in the 100% IESBO sample and sonication power did not affect the results. A greater induction in crystallization was observed when higher power levels were used in the 50% IESBO sample, while no effect was observed in the crystallization kinetics of the 20% IESBO samples. Changes in the crystallization kinetics affected physical properties of the material, influencing elasticity. For example, sonication increased the elasticity of the 100% IESBO sample for both tip amplitudes from 435.9 +/- 173.3 Pa to 72735.0 +/- 9547.9 Pa for the nonsonicated and sonicated samples using 108 MUm of amplitude, respectively. However, sonication only increased the elasticity in the 50% sample when used at the higher power level of 108 MUm from 564.2 +/- 175.2 Pa to 21774.0 +/- 5694.9 Pa, and it did not affect the elasticity of the 20% IESBO samples. These results show that the level of saturation and the degree of supercooling affect sonication efficiency. PRACTICAL APPLICATIONS: High-intensity ultrasound (HIU) has been used as a novel method for changing the crystallization behavior of fats. HIU can be used to improve the physical properties of trans-free fats that are low in saturated fatty acids. Although recent studies have proven the effectiveness of this method to induce crystallization, the process must still be optimized to the industrial setting. All process parameters should be considered during the application of HIU, as they directly affect the final product. The aim of this paper was to investigate the effects of HIU and process conditions such as tip amplitude, degree of supercooling, and saturation level on the crystallization behavior of commercial interesterified soybean oil. PMID- 29476627 TI - Construction, expression, and characterization of a single-chain variable fragment (ScFv) antibody targeting to the encephalomyocarditis virus. AB - Encephalomyocarditis virus (EMCV) is as a potential zoonotic agent with a wide host range. Here, applying gene splicing by overlap extension PCR (SOE-PCR), we describe a simple method for producing single-chain variable fragment (scFv) antibody against EMCV that configurates in the orientation of VH-(GGGGS)4 -VL. DNA template was resverse transcribed by total RNA that derived from hyperimmunized antibody positive mice spleen after inoculation inactivated EMCV PV21 as antigen. Using the degenerate primers designed for the variable regions of IgG of murine antibody, the 417 bp of gene encoding VH-linker (VHL) and 360 bp of gene encoding linker-VL (LVL) of the anti-EMCV was individually amplified from DNA template by PCR, repectively. The 762 bp gene encoding anti-EMCV scFv was constructed by SOE-PCR when the mixed VHL and LVL genes were used as the template. The amplified gene subcloned into pGEX-6P1 to yield pGEX-6P1/EMCV-scFv. Recombinant vector transformed into the Escherichia coli BL21 (DE3) and a 53 KDa GST-scFv fusion protein was obtained by SDS-PAGE electrophoresis. Animal experiment results showed that the pretective rate of mice in group A which challenged 500 MUL 104 TCID50 EMCV per mouse for 7 d post-inoculation scFv 3 d (0.5 mg purified recombinant scFv per mouse) was 91.67% (11/12). The serum anti EMCV antibody titer in group A mice was most significantly higher than that in positive control mouse (P < 0.01), coversely the serum relative mRNA copies were significantly lower than that in positive control mouse (P < 0.05). These findings indicated that recombinant anti-EMCV scFv has remarkable anti-EMCV effect in mice. PMID- 29476628 TI - Comparing the efficiency of Fib-4, Egy-score, APRI, and GUCI in liver fibrosis staging in Egyptians with chronic hepatitis C. AB - Assessment of hepatic fibrosis in chronic hepatitis C virus patients by liver biopsy is not widely accepted despite its accuracy, being invasive, carrying complications, and adding cost. This paved the way to development and use of non invasive markers of fibrosis in diagnosis of hepatic fibrosis. We aimed at evaluating the efficiency of Fib-4, Egy-score, Aspartate-to-platelet ratio index (APRI), and Goteborg University Cirrhosis Index (GUCI) in comparison to liver biopsy, in the assessment of hepatic fibrosis in chronic hepatitis C patients. This was a cross sectional study including 200 chronic HCV patients were divided into two groups according to stage of fibrosis (Metavir score) into non significant fibrosis (=F2). Reference needle liver biopsy was compared to Fib-4, Egyscore, APRI, and GUCI. Older age (P < 0.001) and higher BMI (P = 0.005) were significantly related to significant fibrosis and positively correlated with fibrosis progression (r = 0.361, P = 0.000, and r = 0.165, P = 0.019 respectively). Fib-4 >1.27, APRI >0.48, Egy-score >0.73, and GUCI >0.57 significantly predict significant fibrosis (P < 0.01). Fib 4 carries the best performance and significant reliability with AUROC 0.783, sensitivity 74%, specificity 69%, PPV 0.55, and NPV 0.86. The addition of BMI to Fib-4 improved the significant fibrosis AUROC curve performance but did not reach statistical significant improvement. We concluded that age and BMI are good predictors of hepatic fibrosis. Fib-4 (>1.27) is the best method of prediction of significant fibrosis compared to Egy-score, APRI, and GUCI. Addition of BMI to Fib-4 did not improve diagnostic value of Fib-4. PMID- 29476629 TI - pH-dependent speciation and hydrogen (H2 ) control U(VI) respiration by Desulfovibrio vulgaris. AB - In situ bioreduction of soluble hexavalent uranium U(VI) to insoluble U(IV) (as UO2 ) has been proposed as a means of preventing U migration in the groundwater. This work focuses on the bioreduction of U(VI) and precipitation of U(IV). It uses anaerobic batch reactors with Desulfovibrio vulgaris, a well-known sulfate, iron, and U(VI) reducer, growing on lactate as the electron donor, in the absence of sulfate, and with a 30-mM bicarbonate buffering. In the absence of sulfate, D. vulgaris reduced >90% of the total soluble U(VI) (1 mM) to form U(IV) solids that were characterized by X-ray diffraction and confirmed to be nano-crystalline uraninite with crystallite size 2.8 +/- 0.2 nm. pH values between 6 and 10 had minimal impact on bacterial growth and end-product distribution, supporting that the mono-nuclear, and poly-nuclear forms of U(VI) were equally bioavailable as electron acceptors. Electron balances support that H2 transiently accumulated, but was ultimately oxidized via U(VI) respiration. Thus, D. vulgaris utilized H2 as the electron carrier to drive respiration of U(VI). Rapid lactate utilization and biomass growth occurred only when U(VI) respiration began to draw down the sink of H2 and relieve thermodynamic inhibition of fermentation. PMID- 29476631 TI - Is there a role for MR-guided focused ultrasound in Parkinson's disease? PMID- 29476630 TI - Experimental strategies to assess the biological ramifications of multiple drivers of global ocean change-A review. AB - Marine life is controlled by multiple physical and chemical drivers and by diverse ecological processes. Many of these oceanic properties are being altered by climate change and other anthropogenic pressures. Hence, identifying the influences of multifaceted ocean change, from local to global scales, is a complex task. To guide policy-making and make projections of the future of the marine biosphere, it is essential to understand biological responses at physiological, evolutionary and ecological levels. Here, we contrast and compare different approaches to multiple driver experiments that aim to elucidate biological responses to a complex matrix of ocean global change. We present the benefits and the challenges of each approach with a focus on marine research, and guidelines to navigate through these different categories to help identify strategies that might best address research questions in fundamental physiology, experimental evolutionary biology and community ecology. Our review reveals that the field of multiple driver research is being pulled in complementary directions: the need for reductionist approaches to obtain process-oriented, mechanistic understanding and a requirement to quantify responses to projected future scenarios of ocean change. We conclude the review with recommendations on how best to align different experimental approaches to contribute fundamental information needed for science-based policy formulation. PMID- 29476632 TI - Biosynthesis of a ganoderic acid in Saccharomyces cerevisiae by expressing a cytochrome P450 gene from Ganoderma lucidum. AB - Ganoderic acid (GA), a triterpenoid from the traditional Chinese medicinal higher fungus Ganoderma lucidum, possesses antitumor and other significant pharmacological activities. Owing to the notorious difficulty and immaturity in genetic manipulation of higher fungi as well as their slow growth, biosynthesis of GAs in a heterologous host is an attractive alternative for their efficient bioproduction. In this study, using Saccharomyces cerevisiae as a host, we did a systematic screening of cytochrome P450 monooxygenase (CYP450) gene candidates from G. lucidum, which may be responsible for the GA biosynthesis from lanosterol but have not been functionally characterized. As a result, overexpression of a CYP450 gene cyp5150l8 was firstly found to produce an antitumor GA, 3-hydroxy lanosta-8, 24-dien-26 oic acid (HLDOA) in S. cerevisiae, as confirmed by HPLC, LC MS and NMR. A final titer of 14.5 mg/L of HLDOA was obtained at 120 hr of the yeast fermentation. Furthermore, our in vitro enzymatic experiments indicate that CYP5150L8 catalyzes a three-step biotransformation of lanosterol at C-26 to synthesize HLDOA. To our knowledge, this is the first report on the heterologous biosynthesis of GAs. The results will be helpful to the GA biosynthetic pathway elucidation and to future optimization of heterologous cell factories for GA production. PMID- 29476633 TI - Global patterns of nonanalogous climates in the past and future derived from thermal and hydraulic factors. AB - Nonanalogous climates (NACs), climates without modern analogs on Earth, challenge our understanding of eco-evolutionary processes that shape global biodiversity, particularly because of their propensity to promote novel ecosystems. However, NAC studies are generally inadequate and partial. Specifically, systematic comparisons between the future and the past are generally lacking, and hydraulic NACs tend to be underemphasized. In the present study, by adopting a frequency distribution-based method that facilitates the procedures of contributions parsing and conducting multiple comparisons, we provide a global overview of multidimensional NACs for both the past and the future within a unified framework. We show that NACs are globally prevalent, covering roughly half of the land area across the time-periods under investigation, and have a high degree of spatial structure. Patterns of NACs differ dramatically between the past and the future. Hydraulic NACs are more complex both in spatial patterns and in major contributions of variables than are thermal NACs. However, hydraulic NACs are more predictable than originally thought. Generally, hydraulic NACs in the future (2100 AD) exhibit comparable predictability to thermal NACs in the last glacial maximum (LGM) (21k BP). Identifying these NAC patterns has potential implications on climate-adaptive managements and preparing in advance to possibly frequent novel ecosystems. However, a learning-from-the-past strategy might be of limited utility for management under present circumstances. PMID- 29476634 TI - Sugar yield and composition of tubers from Jerusalem Artichoke (Helianthus tuberosus) irrigated with saline waters. AB - Currently, major biofuel crops are also food crops that demand fertile soils and good-quality water. Jerusalem artichoke (Helianthus tuberosus, Asteraceae) produces high tonnage of tubers that are rich in sugars, mainly in the form of inulin. In this study, plants of the cultivar "White Fuseau" grown under five salinity levels were evaluated for tuber yield. Results indicated that this cultivar is moderately salt-tolerant if the goal is tuber production. Hydraulic pressings of the tubers produced juice that contained 15% (wet weight) or 55% (dry weight) free sugars, with 70% of these in the form of inulin and the rest as fructose, sucrose, and glucose. Importantly, salinity did not affect the total free sugar or inulin content of the tubers. Tubers were composed of about 12% dry washed bagasse (wet weight) or 44% (dry matter basis) and bagasse retained such high quantities of free sugars after pressing that washing was required for complete sugar recovery. Chemical composition analysis of tuber bagasse suggested that it had low lignin content (11-13 wt%), and its structural sugar composition was similar to chicory root bagasse. Because of the high hemicellulose and pectin content of the bagasse, adding xylanase and pectinase to cellulase substantially improved sugar yields from enzymatic hydrolysis compared to at the same protein loading as cellulase alone. In addition to the high total sugar yield of tuber, these first findings on the sugar and lignin content and enzymatic hydrolysis of tuber bagasse can lead to low-cost production of ethanol for transportation fuels. PMID- 29476635 TI - GII.4 norovirus recombinant causes gastroenteritis epidemic in Eastern Australia, winter 2017. AB - In Victoria, Australia, 160 gastroenteritis outbreaks were norovirus positive for the period January-September 2017. A distinctive peak in norovirus outbreaks was seen May-August, with 118 positive outbreaks occurring in the peak period. The peak was primarily due to the emergence of a GII.P4_NewOrleans_2009/GII.4_Sydney_2012 recombinant that had genetically changed sufficiently to escape herd immunity. This recombinant was also identified elsewhere in Australia, with highly similar sequences identified in Queensland during the same time period. The recombinant GII.P4_NewOrleans_2009/GII.4_Sydney_2012 has not been reported to cause norovirus epidemics outside Australia, suggesting regional factors play a role in determining norovirus genotype incidence. PMID- 29476636 TI - Trajectories of caregiver burden and related factors in family caregivers of patients with lung cancer. AB - OBJECTIVE: This study aimed to (1) identify the changes of 5 domains of family caregiver (FC) burden, overall burden, and its subtrajectories when caring for newly diagnosed advanced lung cancer patients during the first 6 months following cancer diagnosis; and (2) identify the FC-related and patient-related factors most associated with the overall FC burden and each of its subtrajectories. METHODS: A total of 150 newly diagnosed advanced lung cancer patient-FC dyads were recruited from a Taiwanese medical center. The overall FC burden was evaluated 4 times: before treatment, and 1, 3, and 6 months after treatment. The potential subtrajectory of the caregiver burden was investigated by latent class growth analysis. The FC-related and patient-related factors having the greatest effect on the overall FC burden and its subtrajectories over time were identified by generalized estimating equations. RESULTS: The highest level of burden domain was "Impact on daily schedule" over time. Generally, most of the FC reported a moderate level of overall burden over the investigation period. Three subtrajectories of the overall FC burden over time (% caregivers) were identified: high burden (34.7%), moderate burden (56.0%), and low burden (9.3%), respectively. The self-efficacy of FC was the strongest factor related to the changes of the FC's burden and burden in each subtrajectory. CONCLUSION: The results support the existing and different types of subtrajectories of the FC's burden. Health care professionals should provide care based on those differences. Further research to test interventions which integrate those important factors related to FC's burden, particularly FC's self-efficacy, is strongly suggested. PMID- 29476637 TI - The effects of parental carbamazepine and gemfibrozil exposure on sexual differentiation in zebrafish (Danio rerio). AB - The effects of parental exposure to pharmaceuticals on sexual differentiation in F1 offspring were examined in zebrafish (Danio rerio). Adult zebrafish were exposed to 0 or 10 MUg/L of carbamazepine or gemfibrozil for 6 wk and bred in pairwise crosses to generate 7 distinct lineages. Lineages were formed with both parents from the same treatment group or with only one parent exposed, to delineate between maternal and paternal effects. The F1 offspring from each lineage were reared in clean water and sampled at 45 and 60 d post fertilization (dpf). Gonadal differentiation was assessed by histology. The morphological stages of the gonads were converted to a quantitative day-equivalent based on data from offspring of untreated parents sampled from 15 to 75 dpf, which enabled a quantitative statistical analysis on the timing of sexual differentiation. Paternal, but not maternal, exposure to carbamazepine resulted in significantly faster sexual differentiation and a male-biased sex ratio; these effects were not observed when both parents were exposed. Combined paternal and maternal exposure to gemfibrozil resulted in significantly faster sexual differentiation, and paternal, but not maternal, exposure to gemfibrozil led to male-biased sex ratios. The present study demonstrates the ability of parental exposure to pharmaceuticals to disrupt sexual differentiation in the F1 offspring and also shows that effects may be uniquely influenced by which parent was exposed. Environ Toxicol Chem 2018;37:1696-1706. (c) 2018 SETAC. PMID- 29476638 TI - Carbon quality and soil microbial property control the latitudinal pattern in temperature sensitivity of soil microbial respiration across Chinese forest ecosystems. AB - Understanding the temperature sensitivity (Q10 ) of soil organic C (SOC) decomposition is critical to quantifying the climate-carbon cycle feedback and predicting the response of ecosystems to climate change. However, the driving factors of the spatial variation in Q10 at a continental scale are fully unidentified. In this study, we conducted a novel incubation experiment with periodically varying temperature based on the mean annual temperature of the soil origin sites. A total of 140 soil samples were collected from 22 sites along a 3,800 km long north-south transect of forests in China, and the Q10 of soil microbial respiration and corresponding environmental variables were measured. Results showed that changes in the Q10 values were nonlinear with latitude, particularly showing low Q10 values in subtropical forests and high Q10 values in temperate forests. The soil C:N ratio was positively related to the Q10 values, and coniferous forest soils with low SOC quality had higher Q10 values than broadleaved forest soils with high SOC quality, which supported the "C quality temperature" hypothesis. Out of the spatial variations in Q10 across all ecosystems, gram-negative bacteria exhibited the most importance in regulating the variation in Q10 and contributed 25.1%, followed by the C:N ratio (C quality), fungi, and the fungi:bacteria ratio. However, the dominant factors that regulate the regional variations in Q10 differed among the tropical, subtropical, and temperate forest ecosystems. Overall, our findings highlight the importance of C quality and microbial controls over Q10 value in China's forest ecosystems. Meanwhile, C dynamics in temperate forests under a global warming scenario can be robustly predicted through the incorporation of substrate quality and microbial property into models. PMID- 29476639 TI - Response of primary and secondary rainforest flowers and fruits to a cyclone, and implications for plant-servicing bats. AB - The response of primary (PF) and secondary (SF) rainforests to cyclones has broad implications for servicing fauna and the resilience of forest functions. We collected fine-scale data on the reproductive phenology of plant communities in Fijian PF and SF in 12 monthly surveys before and after Cyclone Tomas (2010). We generated a resource index from the reproductive loads of 2218 trees and 1150 non trees (>190 species) and trunk and stem diameter to assess patterns in resource abundance for nectarivores and frugivores (hereafter NF resources). We aimed to determine (i) whether species richness of NF resources differed between forests; (ii) the patterns of resilience of NF resources at community level in both forests after a cyclone; and (iii) the effect of response on NF resources for plant-servicing bats (Pteropodidae). In 12 months preceding the cyclone, NF resources were greater in PF trees; non-tree resources fluctuated and were greater in SF. Lower species richness of NF resources in SF indicated that fewer opportunities exist there for exploitation by a diverse fauna. More resources were available for bats in PF. In 12 months following the cyclone, PF flowers and fruits, and SF fruits specifically used by pteropodid bats decreased for trees. Non-tree resources were especially susceptible to the cyclone. No universal pattern of decline was associated with the cyclone; instead, some NF resources declined and others were resilient or responded rapidly to a post-cyclone environment. Both PF and SF demonstrated resilience at the community level via increased flower survival (PF) and rapid flower production (SF). Reduced species richness of NF resources in SF will compromise future resilience and response to disturbance, including for threatened pteropodid bat species. These findings are critical for long-term management of forests, given predicted increases in cyclone frequency and intensity associated with anthropogenic climate change. PMID- 29476640 TI - K3 B6 O9 F3 : A New Fluorooxoborate with Four Different Anionic Units. AB - K3 B6 O9 F3 , a first fluorooxoborate containing four different units, that is, [BO3 ]3- , [BO4 ]5- , [BO3 F]4- , and [BO2 F2 ]3- , has been designed and synthesized by two different routes. The unique anionic 2infinity [B6 O9 F3 ]3- layers avoid forming terminal oxygen atoms, which are beneficial to enlarge the band gap. The structure-properties relationship of the title compound is discussed. PMID- 29476641 TI - Sound the alarm: A meta-analysis on the effect of aquatic noise on fish behavior and physiology. AB - The aquatic environment is increasingly bombarded by a wide variety of noise pollutants whose range and intensity are increasing with each passing decade. Yet, little is known about how aquatic noise affects marine communities. To determine the implications that changes to the soundscape may have on fishes, a meta-analysis was conducted focusing on the ramifications of noise on fish behavior and physiology. Our meta-analysis identified 42 studies that produced 2,354 data points, which in turn indicated that anthropogenic noise negatively affects fish behavior and physiology. The most predominate responses occurred within foraging ability, predation risk, and reproductive success. Additionally, anthropogenic noise was shown to increase the hearing thresholds and cortisol levels of numerous species while tones, biological, and environmental noise were most likely to affect complex movements and swimming abilities. These findings suggest that the majority of fish species are sensitive to changes in the aquatic soundscape, and depending on the noise source, species responses may have extreme and negative fitness consequences. As such, this global synthesis should serve as a warning of the potentially dire consequences facing marine ecosystems if alterations to aquatic soundscapes continue on their current trajectory. PMID- 29476643 TI - Pre-pregnancy cardiovascular indices and birth outcomes of subsequent pregnancies: a 'sequential stress test' revealing hidden cardiovascular weakness? PMID- 29476642 TI - The unfolded protein response in neurodegenerative disorders - therapeutic modulation of the PERK pathway. AB - The unfolded protein response (UPR) is a highly conserved protein quality control mechanism, activated in response to Endoplasmic Reticulum (ER) stress. Signalling is mediated through three branches, PERK, IRE1, and ATF6, respectively, that together provide a coordinated response that contributes to overcoming disrupted proteostasis. PERK branch activation predominantly causes a rapid reduction in global rates of translation, while the IRE1 and ATF6 branch signalling induce a transcriptional response resulting in expression of chaperones and components of the protein degradation machinery. Protein misfolding neurodegenerative diseases show disruption of proteostasis as a biochemical feature. In the brains of animal models of disease and in human post mortem tissue from many of these disorders, markers of UPR induction, particularly, the PERK pathway can be observed in close association with disease progression. Recent research has revealed dysregulated UPR signalling to be a major pathogenic mechanism in neurodegeneration, and that genetic and pharmacological modulation of the PERK pathway results in potent neuroprotection. Targeting aberrant UPR signalling is the focus of new therapeutic strategies, which importantly could be beneficial across the broad spectrum of neurodegenerative diseases. PMID- 29476644 TI - Axial and cellular heterogeneity in electrolyte transport pathways along the thick ascending limb. AB - The thick ascending limb (TAL) extends from the border of the inner medulla to the renal cortex, thus ascending through regions with wide differences in tissue solute and electrolyte concentrations. Structural and functional differences between TAL cells in the medulla (mTAL) and the cortex (cTAL) would therefore be useful to adapt TAL transport function to a changing external fluid composition. While mechanisms common to all TAL cells play a central role in the reclamation of about 25% of the NaCl filtered by the kidney, morphological features, Na+ / K+ -ATPase activity, NKCC2 splicing and phosphorylation do vary between segments and cells. The TAL contributes to K+ homeostasis and TAL cells with high or low basolateral K+ conductances have been identified which may be involved in K+ reabsorption and secretion respectively. Although transport rates for HCO3- do not differ between mTAL and cTAL, divergent axial and cellular expression of H+ transport proteins in TAL have been documented. The reabsorption of the divalent cations Ca2+ and Mg2+ is highest in cTAL and paralleled by differences in divalent cation permeability and the expression of select claudins. Morphologically, two cell types with different cell surface phenotypes have been described that still need to be linked to specific functional characteristics. The unique external environment and its change along the longitudinal axis require an axial functional heterogeneity for the TAL to optimally participate in conserving electrolyte homeostasis. Despite substantial progress in understanding TAL function, there are still considerable knowledge gaps that are just beginning to become bridged. PMID- 29476645 TI - Crystal structures of sampatrilat and sampatrilat-Asp in complex with human ACE - a molecular basis for domain selectivity. AB - : Angiotensin-1-converting enzyme (ACE) is a zinc metallopeptidase that consists of two homologous catalytic domains (known as nACE and cACE) with different substrate specificities. Based on kinetic studies it was previously reported that sampatrilat, a tight-binding inhibitor of ACE, Ki = 13.8 nm and 171.9 nm for cACE and nACE respectively [Sharma et al., Journal of Chemical Information and Modeling (2016), 56, 2486-2494], was 12.4-fold more selective for cACE. In addition, samAsp, in which an aspartate group replaces the sampatrilat lysine, was found to be a nonspecific and lower micromolar affinity inhibitor. Here, we report a detailed three-dimensional structural analysis of sampatrilat and samAsp binding to ACE using high-resolution crystal structures elucidated by X-ray crystallography, which provides a molecular basis for differences in inhibitor affinity and selectivity for nACE and cACE. The structures show that the specificity of sampatrilat can be explained by increased hydrophobic interactions and a H-bond from Glu403 of cACE with the lysine side chain of sampatrilat that are not observed in nACE. In addition, the structures clearly show a significantly greater number of hydrophilic and hydrophobic interactions with sampatrilat compared to samAsp in both cACE and nACE consistent with the difference in affinities. Our findings provide new experimental insights into ligand binding at the active site pockets that are important for the design of highly specific domain selective inhibitors of ACE. DATABASE: The atomic coordinates and structure factors for N- and C-domains of ACE bound to sampatrilat and sampatrilat-Asp complexes (6F9V, 6F9R, 6F9T and 6F9U respectively) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/). PMID- 29476646 TI - Metabolite accumulation in VLCAD deficiency markedly disrupts mitochondrial bioenergetics and Ca2+ homeostasis in the heart. AB - We studied the effects of the major long-chain fatty acids accumulating in very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, namely cis-5-tetradecenoic acid (Cis-5) and myristic acid (Myr), on important mitochondrial functions in isolated mitochondria from cardiac fibers and cardiomyocytes of juvenile rats. Cis-5 and Myr at pathological concentrations markedly reduced mitochondrial membrane potential (DeltaPsim ), matrix NAD(P)H pool, Ca2+ retention capacity, ADP- (state 3) and carbonyl cyanide 3-chlorophenyl hydrazine-stimulated (uncoupled) respiration, and ATP generation. By contrast, these fatty acids increased resting (state 4) respiration (uncoupling effect) with the involvement of the adenine nucleotide translocator because carboxyatractyloside significantly attenuated the increased state 4 respiration provoked by Cis-5 and Myr. Furthermore, the classical inhibitors of mitochondrial permeability transition (MPT) pore cyclosporin A plus ADP, as well as the Ca2+ uptake blocker ruthenium red, fully prevented the Cis-5- and Myr-induced decrease in DeltaPsim in Ca2+ loaded mitochondria, suggesting, respectively, the induction of MPT pore opening and the contribution of Ca2+ toward these effects. The findings of the present study indicate that the major long-chain fatty acids that accumulate in VLCAD deficiency disrupt mitochondrial bioenergetics and Ca2+ homeostasis, acting as uncouplers and metabolic inhibitors of oxidative phosphorylation, as well as inducers of MPT pore opening, in the heart at pathological relevant concentrations. It is therefore presumed that a disturbance of bioenergetics and Ca2+ homeostasis may contribute to the cardiac manifestations observed in VLCAD deficiency. PMID- 29476647 TI - Prenatal diagnosis in rare bleeding disorders-An unresolved issue? AB - Intracranial haemorrhage (ICH) is the most dreadful complication, and the main cause of death among patients with rare bleeding disorders (RBD) and prenatal diagnosis (PND) is a preventative lifesaving program. A total of 39 PNDs were reported in the literature through a search on PubMed, EMBASE, SCOPUS and Web of Science databases, most often for congenital factor (F) XIII and FVII deficiencies and rarely in FX, FV deficiencies and afibrinogenemia. The main cause to request a PND is ICH and related morbidity and mortality. Different molecular methods including direct sequencing and linkage analysis as well as polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for a specific mutation are the most common used methods for PND, while factor assay and combination of molecular and factor assay also were used. In this research, 7 severely affected foetuses were identified during PND including 3 foetuses with FXIII deficiency, 3 with FVII deficiency and 1 with FX deficiency. Out of these 7 cases, intrauterine ICH occurred in 1 case with FXIII deficiency, 1 was electively aborted and 1 case with severe FVII deficiency received intrauterine factor transfusion. Postdelivery ICH was reported for 1 patient with severe FVII deficiency within the first month of life. All other pregnancies were uneventful. PMID- 29476648 TI - Ammonothermal Synthesis of Nitrides: Recent Developments and Future Perspectives. AB - Nitrides represent an intriguing class of functional materials with a broad range of application fields. Within the past decade, the ammonothermal method became increasingly attractive for the synthesis and crystal growth of nitride materials. The ammonothermal approach proved to be eminently suitable for the growth of bulk III-nitride semiconductors like GaN, and furthermore provided access to numerous ternary and multinary nitrides and oxonitrides with promising optical and electronic properties. In this minireview, we will shed light on the latest research findings covering the synthesis of nitrides by this method. An overview of synthesis strategies for binary, ternary, and multinary nitrides and oxonitrides, as well as their properties and potential applications will be given. The recent development of autoclave technologies for syntheses at high temperatures and pressures, in situ methods for investigations of crystallization processes, and solubility measurements by ultrasonic velocity experiments is briefly reviewed as well. In conclusion, challenges and future perspectives regarding the synthesis and crystal growth of novel nitrides, as well as the advancement of autoclave techniques are discussed. PMID- 29476649 TI - Efficacy of slow oscillatory-transcranial direct current stimulation on EEG and memory - contribution of an inter-individual factor. AB - Despite many reports on beneficial effects of anodal slow oscillatory transcranial direct current stimulation (so-tDCS) during non-rapid eye movement (NREM) sleep on memory consolidation, frequent negative outcomes have also been observed. Our working hypothesis is that so-tDCS efficacy is strongly dependent upon the susceptibility of the underlying network. One component determining susceptibility of the network is hypothesized to be reflected in learning or 'task-induced' plastic changes. Another component is hypothesized to represent inter-individual confounds. Twenty-five (15 female) healthy students participated in two learning conditions with and without so-tDCS during early nocturnal NREM sleep and in one control condition without learning tasks. So-tDCS was applied in five 5-min blocks. EEG was assessed during two time windows: an acute period with five 1-min epochs after each stimulation block and a 150-min post-stimulation time period. Inter-individual differences were assessed by a memory quotient (MQ) and subjects classified into high- vs. low-scoring groups. Although so-tDCS was efficient in enhancing fast spindle parameters in the 150-min time period in all subjects, so-tDCS failed to modulate memory consolidation. In contrast, in subjects with a high MQ, memory retention on a figural paired-associate task was significantly increased after so-tDCS. Task-induced slow spindle density was modulated in the opposite direction in subjects with high vs. low MQ being increased in the high-MQ group only. Effects of so-tDCS on EEG were limited to fast spindle modulations in both time windows. These results reveal that inter individual confound can impact so-tDCS efficacy, suggesting potential use of such factors as biomarkers. PMID- 29476650 TI - Induction and recovery of copy number variation in banana through gamma irradiation and low-coverage whole-genome sequencing. AB - Traditional breeding methods are hindered in bananas due to the fact that major cultivars are sterile, parthenocarpic, triploid and thus clonally propagated. This has resulted in a narrow genetic base and limited resilience to biotic and abiotic stresses. Mutagenesis of in vitro propagated bananas is one method to introduce novel alleles and broaden genetic diversity. We previously established a method for the induction and recovery of single nucleotide mutations generated with the chemical mutagen EMS. However, officially released mutant banana varieties have been created using gamma rays, a mutagen that can produce large genomic insertions and deletions (indels). Such dosage mutations may be important for generating observable phenotypes in polyploids. In this study, we establish a low-coverage whole-genome sequencing approach in triploid bananas to recover large genomic indels caused by treatment with gamma irradiation. We first evaluated the commercially released mutant cultivar 'Novaria' and found that it harbours multiple predicted deletions, ranging from 0.3 to 3.8 million base pairs (Mbp). In total, predicted deletions span 189 coding regions. To evaluate the feasibility of generating and maintaining new mutations, we developed a pipeline for mutagenesis and screening for copy number variation in Cavendish bananas using the cultivar 'Williams'. Putative mutations were recovered in 70% of lines treated with 20 Gy and 60% of the lines treated with 40 Gy. While deletion events predominate, insertions were identified in 20 Gy-treated material. Based on these results, we believe this approach can be scaled up to support large breeding projects. PMID- 29476651 TI - Linkage and association mapping reveals the genetic basis of brown fibre (Gossypium hirsutum). AB - Brown fibre cotton is an environmental-friendly resource that plays a key role in the textile industry. However, the fibre quality and yield of natural brown cotton are poor, and fundamental research on brown cotton is relatively scarce. To understand the genetic basis of brown fibre cotton, we constructed linkage and association populations to systematically examine brown fibre accessions. We fine mapped the brown fibre region, Lc1 , and dissected it into 2 loci, qBF-A07-1 and qBF-A07-2. The qBF-A07-1 locus mediates the initiation of brown fibre production, whereas the shade of the brown fibre is affected by the interaction between qBF A07-1 and qBF-A07-2. Gh_A07G2341 and Gh_A07G0100 were identified as candidate genes for qBF-A07-1 and qBF-A07-2, respectively. Haploid analysis of the signals significantly associated with these two loci showed that most tetraploid modern brown cotton accessions exhibit the introgression signature of Gossypium barbadense. We identified 10 quantitative trait loci (QTLs) for fibre yield and 19 QTLs for fibre quality through a genome-wide association study (GWAS) and found that qBF-A07-2 negatively affects fibre yield and quality through an epistatic interaction with qBF-A07-1. This study sheds light on the genetics of fibre colour and lint-related traits in brown fibre cotton, which will guide the elite cultivars breeding of brown fibre cotton. PMID- 29476653 TI - Effectiveness of brief alcohol interventions in primary care populations. AB - BACKGROUND: Excessive drinking is a significant cause of mortality, morbidity and social problems in many countries. Brief interventions aim to reduce alcohol consumption and related harm in hazardous and harmful drinkers who are not actively seeking help for alcohol problems. Interventions usually take the form of a conversation with a primary care provider and may include feedback on the person's alcohol use, information about potential harms and benefits of reducing intake, and advice on how to reduce consumption. Discussion informs the development of a personal plan to help reduce consumption. Brief interventions can also include behaviour change or motivationally-focused counselling.This is an update of a Cochrane Review published in 2007. OBJECTIVES: To assess the effectiveness of screening and brief alcohol intervention to reduce excessive alcohol consumption in hazardous or harmful drinkers in general practice or emergency care settings. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and 12 other bibliographic databases to September 2017. We searched Alcohol and Alcohol Problems Science Database (to December 2003, after which the database was discontinued), trials registries, and websites. We carried out handsearching and checked reference lists of included studies and relevant reviews. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of brief interventions to reduce hazardous or harmful alcohol consumption in people attending general practice, emergency care or other primary care settings for reasons other than alcohol treatment. The comparison group was no or minimal intervention, where a measure of alcohol consumption was reported. 'Brief intervention' was defined as a conversation comprising five or fewer sessions of brief advice or brief lifestyle counselling and a total duration of less than 60 minutes. Any more was considered an extended intervention. Digital interventions were not included in this review. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We carried out subgroup analyses where possible to investigate the impact of factors such as gender, age, setting (general practice versus emergency care), treatment exposure and baseline consumption. MAIN RESULTS: We included 69 studies that randomised a total of 33,642 participants. Of these, 42 studies were added for this update (24,057 participants). Most interventions were delivered in general practice (38 studies, 55%) or emergency care (27 studies, 39%) settings. Most studies (61 studies, 88%) compared brief intervention to minimal or no intervention. Extended interventions were compared with brief (4 studies, 6%), minimal or no intervention (7 studies, 10%). Few studies targeted particular age groups: adolescents or young adults (6 studies, 9%) and older adults (4 studies, 6%). Mean baseline alcohol consumption was 244 g/week (30.5 standard UK units) among the studies that reported these data. Main sources of bias were attrition and lack of provider or participant blinding. The primary meta-analysis included 34 studies (15,197 participants) and provided moderate-quality evidence that participants who received brief intervention consumed less alcohol than minimal or no intervention participants after one year (mean difference (MD) -20 g/week, 95% confidence interval (CI) -28 to -12). There was substantial heterogeneity among studies (I2 = 73%). A subgroup analysis by gender demonstrated that both men and women reduced alcohol consumption after receiving a brief intervention.We found moderate-quality evidence that brief alcohol interventions have little impact on frequency of binges per week (MD -0.08, 95% CI -0.14 to -0.02; 15 studies, 6946 participants); drinking days per week (MD -0.13, 95% CI -0.23 to 0.04; 11 studies, 5469 participants); or drinking intensity (-0.2 g/drinking day, 95% CI -3.1 to 2.7; 10 studies, 3128 participants).We found moderate-quality evidence of little difference in quantity of alcohol consumed when extended and no or minimal interventions were compared (-14 g/week, 95% CI -37 to 9; 6 studies, 1296 participants). There was little difference in binges per week ( 0.08, 95% CI -0.28 to 0.12; 2 studies, 456 participants; moderate-quality evidence) or difference in days drinking per week (-0.45, 95% CI -0.81 to -0.09; 2 studies, 319 participants; moderate-quality evidence). Extended versus no or minimal intervention provided little impact on drinking intensity (9 g/drinking day, 95% CI -26 to 9; 1 study, 158 participants; low-quality evidence).Extended intervention had no greater impact than brief intervention on alcohol consumption, although findings were imprecise (MD 2 g/week, 95% CI -42 to 45; 3 studies, 552 participants; low-quality evidence). Numbers of binges were not reported for this comparison, but one trial suggested a possible drop in days drinking per week (-0.5, 95% CI -1.2 to 0.2; 147 participants; low-quality evidence). Results from this trial also suggested very little impact on drinking intensity (-1.7 g/drinking day, 95% CI -18.9 to 15.5; 147 participants; very low quality evidence).Only five studies reported adverse effects (very low-quality evidence). No participants experienced any adverse effects in two studies; one study reported that the intervention increased binge drinking for women and two studies reported adverse events related to driving outcomes but concluded they were equivalent in both study arms.Sources of funding were reported by 67 studies (87%). With two exceptions, studies were funded by government institutes, research bodies or charitable foundations. One study was partly funded by a pharmaceutical company and a brewers association, another by a company developing diagnostic testing equipment. AUTHORS' CONCLUSIONS: We found moderate-quality evidence that brief interventions can reduce alcohol consumption in hazardous and harmful drinkers compared to minimal or no intervention. Longer counselling duration probably has little additional effect. Future studies should focus on identifying the components of interventions which are most closely associated with effectiveness. PMID- 29476654 TI - Subcutaneous ICD screening with the Boston Scientific ZOOM programmer versus a 12 lead ECG machine. AB - BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (S-ICD) requires preimplant screening to ensure appropriate sensing and reduce risk of inappropriate shocks. Screening can be performed using either an ICD programmer or a 12-lead electrocardiogram (ECG) machine. It is unclear whether differences in signal filtering and digital sampling change the screening success rate. METHODS: Subjects were recruited if they had a transvenous single-lead ICD without pacing requirements or were candidates for a new ICD. Screening was performed using both a Boston Scientific ZOOM programmer (Marlborough, MA, USA) and General Electric MAC 5000 ECG machine (Fairfield, CT, USA). A pass was defined as having at least one lead that fit within the screening template in both supine and sitting positions. RESULTS: A total of 69 subjects were included and 27 sets of ECG leads had differing screening results between the two machines (7%). Of these sets, 22 (81%) passed using the ECG machine but failed using the programmer and five (19%) passed using the ECG machine but failed using the programmer (P < 0.001). Four subjects (6%) passed screening using the ECG machine but failed using the programmer. No subject passed screening with the programmer but failed with the ECG machine. CONCLUSION: There can be occasional disagreement in S-ICD patient screening between an ICD programmer and ECG machine, all of whom passed with the ECG machine but failed using the programmer. On a per lead basis, the ECG machine passes more subjects. It is unknown what the inappropriate shock rate would be if an S-ICD was implanted. Clinical judgment should be used in borderline cases. PMID- 29476652 TI - Ageing effects on humoral immune responses in chronic periodontitis. AB - : Periodontal disease is a dominant global bacterial infection that increases with ageing. AIM: This report focuses on host adaptive immune responses in periodontitis. While experimental models and humans diagnosed with periodontitis demonstrate an antigenic specificity for particular oral bacteria, we have a limited understanding of (i) how ageing affects the adaptive immune responses to these bacteria that chronically colonize the oral cavity for decades prior to disease expression and (ii) how the magnitude and specificity of the response interface with pathogens that emerge within the bacterial ecology during exacerbations of disease. MATERIALS AND METHODS: Serum antibody levels to a group of pathogenic and commensal oral bacteria were measured in a population of individuals from 21 to 74 years of age, stratified based on clinical status of the periodontium, smoking and sex. RESULTS: Clinical parameters were not significantly different within health, gingivitis or periodontitis groups related to age. Antibody to oral pathogens and commensals was similar in different age groups in each of the clinical categories, with no age correlation noted in the periodontitis patients. CONCLUSIONS: The adaptive immune responses to oral bacteria that chronically colonize the oral cavity appear generally unaffected by age, but clearly are linked to the extent of disease. PMID- 29476655 TI - Exposure to far-infrared ray attenuates methamphetamine-induced impairment in recognition memory through inhibition of protein kinase C delta in male mice: Comparison with the antipsychotic clozapine. AB - We have previously demonstrated that repeated treatment with methamphetamine (MA) results in a recognition memory impairment via upregulation of protein kinase C (PKC) delta and downregulation of the glutathione peroxidase-1 (GPx-1)-dependent antioxidant system. We also demonstrated that far-infrared ray (FIR) attenuates acute restraint stress via induction of the GPx-1 gene. Herein, we investigated whether exposure to FIR modulates MA-induced recognition memory impairment in male mice, and whether cognitive potentials mediated by FIR require modulation of the PKCdelta gene, extracellular signal-regulated kinase (ERK) 1/2, and glutathione-dependent system. Repeated treatment with MA significantly increased PKCdelta expression and its phosphorylation out of PKC isoenzymes (i.e., PKCalpha, PKCbetaI, PKCbetaII, PKCzeta, and PKCdelta expression) in the prefrontal cortex of mice. Exposure to FIR significantly attenuated MA-induced increase in phospho-PKCdelta and decrease in phospho-ERK 1/2. In addition, FIR further facilitated the nuclear factor E2-related factor 2 (Nrf2)-dependent glutathione synthetic system. Moreover, L-buthionine-(S, R)-sulfoximine, an inhibitor of glutathione synthesis, counteracted the FIR-mediated phospho-ERK 1/2 induction and memory-enhancing activity against MA insult. More important, positive effects of FIR are comparable to those of genetic depletion of PKCdelta or the antipsychotic clozapine. Our results indicate that FIR protects against MA induced memory impairment via activations of the Nrf2-dependent glutathione synthetic system, and ERK 1/2 signaling by inhibition of the PKCdelta gene. PMID- 29476657 TI - Medawar's "actively acquired tolerance" and the Danger model: Setting the record straight. AB - I describe here what I believe is a misrepresentation of the classic observations of Billingham, Brent and Medawar on "actively acquired tolerance," by Ridge, Fuchs and Matzinger; I set the record straight by revisiting the original literature and discussing the implications of this misinterpretation. PMID- 29476656 TI - Borrelia burgdorferi genes, bb0639-0642, encode a putative putrescine/spermidine transport system, PotABCD, that is spermidine specific and essential for cell survival. AB - Polyamines are an essential class of metabolites found throughout all kingdoms in life. Borrelia burgdorferi harbors no enzymes to synthesize or degrade polyamines yet does contain a polyamine uptake system, potABCD. In this report, we describe the initial characterization of this putative transport system. After several unsuccessful attempts to inactivate potABCD, we placed the operon under the control of an inducible LacI promoter expression system. Analyses of this construct confirmed that potABCD was required for in vitro survival. Additionally, we demonstrated that the potABCD operon were upregulated in vitro by low osmolarity. Previously, we had shown that low osmolarity triggers the activation of the Rrp2/RpoN/RpoS regulatory cascade, which regulates genes essential for the transmission of spirochetes from ticks to mammalian hosts. Interestingly, induction of the pot operon was only affected in an rpoS mutant but not in a rpoN mutant, suggesting that the genes were RpoS dependent and RpoN independent. Furthermore, potABCD was upregulated during tick feeding concomitant with the initiation of spirochete replication. Finally, uptake experiments determined the specificity of B. burgdorferi's PotABCD for spermidine. PMID- 29476658 TI - Mortality and short-term morbidity in infants with exomphalos. AB - BACKGROUND: Infants with exomphalos major have a high mortality and morbidity. The aims of this study were to identify predictors of survival regardless of the size of the exomphalos, and to analyze morbidity in infants with exomphalos minor. METHODS: Patients were classified as having exomphalos major or minor based on whether the liver was in the exomphalos sac, and the size of the abdominal wall defect. The respiratory, gastrointestinal and surgical outcomes of 50 infants with exomphalos (including 27 with exomphalos major) were assessed. Receiver operating characteristic (ROC) curves were constructed to identify factors predictive of survival. RESULTS: No infant with exomphalos minor died; there were seven deaths in the exomphalos major group (P < 0.001). Infants with exomphalos minor who had chromosomal abnormalities (six had a genetic diagnosis of Beckwith-Wiedemann syndrome) developed severe respiratory distress or chronic respiratory morbidity. Nasogastric feeding at discharge was required in 37% of infants with exomphalos major and in 17% with exomphalos minor. Lower gestational age (area under the ROC curve [AUROC], 0.814) and birthweight (AUROC, 0.797), and longer duration of ventilation (AUROC, 0.853) and of supplementary oxygen (AUROC, 0.810) were predictive of mortality. CONCLUSIONS: Infants with exomphalos regardless of size can have chronic morbidity. Mortality is commonest in those with exomphalos major born at lower gestational age and birthweight. PMID- 29476659 TI - The evolutionary impact of intragenic FliA promoters in proteobacteria. AB - In Escherichia coli, one sigma factor recognizes the majority of promoters, and six 'alternative' sigma factors recognize specific subsets of promoters. The alternative sigma factor FliA (sigma28 ) recognizes promoters upstream of many flagellar genes. We previously showed that most E. coli FliA binding sites are located inside genes. However, it was unclear whether these intragenic binding sites represent active promoters. Here, we construct and assay transcriptional promoter-lacZ fusions for all 52 putative FliA promoters previously identified by ChIP-seq. These experiments, coupled with integrative analysis of published genome-scale transcriptional datasets, strongly suggest that most intragenic FliA binding sites are active promoters that transcribe highly unstable RNAs. Additionally, we show that widespread intragenic FliA-dependent transcription may be a conserved phenomenon, but that specific promoters are not themselves conserved. We conclude that intragenic FliA-dependent promoters and the resulting RNAs are unlikely to have important regulatory functions. Nonetheless, one intragenic FliA promoter is broadly conserved and constrains evolution of the overlapping protein-coding gene. Thus, our data indicate that intragenic regulatory elements can influence bacterial protein evolution and suggest that the impact of intragenic regulatory sequences on genome evolution should be considered more broadly. PMID- 29476660 TI - Leadless pacemaker implantation and concurrent atrioventricular junction ablation in patients with atrial fibrillation. AB - BACKGROUND: Atrioventricular junctional (AVJ) ablation and pacemaker implantation are indicated when pharmacotherapy fails to achieve adequate rate control in atrial fibrillation (AF). The purpose of our study is to assess the feasibility and safety of concurrent Micra leadless transcatheter pacemaker implantation and AVJ ablation. METHODS: We retrospectively assessed patients who underwent Micra implantation and concurrent AVJ ablation at three institutions between August 2014 and March 2016. All patients and devices were followed at baseline and at 1, 3, 6, and 12 months postimplantion. RESULTS: Twenty-one patients with permanent AF (median age 77 [range: 62-88], female 15 [71.4%]) underwent successful Micra implantation followed by concurrent AVJ ablation. There was no device dislodgement or malfunction during the 12-month follow-up. Complete 12-month electrical performance data were available in 14 patients (67%). Among patients with the complete data set, median pacing thresholds at implant and at 1, 3, 6, and 12 months were 0.5 V (range: 0.25-0.88), 0.44 V (range: 0.25-2.0), 0.5 V (range: 0.25-1.63), 0.5 V (range: 0.25-1.13), and 0.5 V (range: 0.25-1.13) at a pulse width of 0.24 msec, respectively. Two patients died due to noncardiac causes during follow-up. There were no patients with major device-related complications. CONCLUSIONS: Concurrent Micra implantation and AVJ ablation is feasible and appears safe. There was no device dislodgement, malfunction, or significant pacing threshold rise requiring device reimplantation during the 12 month follow-up. This combined approach can be considered for patients with AF with suboptimal rate control who have failed AF catheter ablation and/or pharmacotherapy. PMID- 29476661 TI - Epigenomic signature of adrenoleukodystrophy predicts compromised oligodendrocyte differentiation. AB - Epigenomic changes may either cause disease or modulate its expressivity, adding a layer of complexity to mendelian diseases. X-linked adrenoleukodystrophy (X ALD) is a rare neurometabolic condition exhibiting discordant phenotypes, ranging from a childhood cerebral inflammatory demyelination (cALD) to an adult-onset mild axonopathy in spinal cords (AMN). The AMN form may occur with superimposed inflammatory brain demyelination (cAMN). All patients harbor loss of function mutations in the ABCD1 peroxisomal transporter of very-long chain fatty acids. The factors that account for the lack of genotype-phenotype correlation, even within the same family, remain largely unknown. To gain insight into this matter, here we compared the genome-wide DNA methylation profiles of morphologically intact frontal white matter areas of children affected by cALD with adult cAMN patients, including male controls in the same age group. We identified a common methylomic signature between the two phenotypes, comprising (i) hypermethylation of genes harboring the H3K27me3 mark at promoter regions, (ii) hypermethylation of genes with major roles in oligodendrocyte differentiation such as MBP, CNP, MOG and PLP1 and (iii) hypomethylation of immune-associated genes such as IFITM1 and CD59. Moreover, we found increased hypermethylation in CpGs of genes involved in oligodendrocyte differentiation, and also in genes with H3K27me3 marks in their promoter regions in cALD compared with cAMN, correlating with transcriptional and translational changes. Further, using a penalized logistic regression model, we identified the combined methylation levels of SPG20, UNC45A and COL9A3 and also, the combined expression levels of ID4 and MYRF to be good markers capable of discriminating childhood from adult inflammatory phenotypes. We thus propose the hypothesis that an epigenetically controlled, altered transcriptional program may drive an impaired oligodendrocyte differentiation and aberrant immune activation in X-ALD patients. These results shed light into disease pathomechanisms and uncover putative biomarkers of interest for prognosis and phenotypic stratification. PMID- 29476662 TI - New clinicopathological associations and histoprognostic markers in ILAE types of hippocampal sclerosis. AB - Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is a heterogeneous syndrome. Surgery results in seizure freedom for most pharmacoresistant patients, but the epileptic and cognitive prognosis remains variable. The 2013 International League Against Epilepsy (ILAE) histopathological classification of hippocampal sclerosis (HS) has fostered research to understand MTLE-HS heterogeneity. We investigated the associations between histopathological features (ILAE types, hypertrophic CA4 neurons, granule cell layer alterations, CD34 immunopositive cells) and clinical features (presurgical history, postsurgical outcome) in a monocentric series of 247 MTLE-HS patients treated by surgery. NeuN, GFAP and CD34 immunostainings and a double independent pathological examination were performed. 186 samples were type 1, 47 type 2, 7 type 3 and 7 samples were gliosis only but no neuronal loss (noHS). In the type 1, hypertrophic CA4 neurons were associated with a worse postsurgical outcome and granule cell layer duplication was associated with generalized seizures and episodes of status epilepticus. In the type 2, granule cell layer duplication was associated with generalized seizures. CD34+ stellate cells were more frequent in the type 2, type 3 and in noHS. These cells had a Nestin and SOX2 positive, immature neural immunophenotype. Patients with nodules of CD34+ cells had more frequent dysmnesic auras. CD34+ stellate cells in scarce pattern were associated with higher ratio of normal MRI and of stereo-electroencephalographic studies. CD34+ cells were associated with a trend for a better postsurgical outcome. Among CD34+ cases, we proposed a new entity of BRAF V600E positive HS and we described three hippocampal multinodular and vacuolating neuronal tumors. To conclude, our data identified new clinicopathological associations with ILAE types. They showed the prognostic value of CA4 hypertrophic neurons. They highlighted CD34+ stellate cells and BRAF V600E as biomarkers to further decipher MTLE-HS heterogeneity. PMID- 29476663 TI - Mitochondrial contributions to neuronal development and function. AB - Mitochondria are critical to tissues and organs characterized by high-energy demands, such as the nervous system. They provide essential energy and metabolites, and maintain Ca2+ balance, which is imperative for proper neuronal function and development. Emerging findings further underline the role of mitochondria in neurons. Technical advances in the last decades made it possible to investigate key mechanisms in neuronal development and the contribution of mitochondria therein. In this article, we discuss the latest findings relevant to the involvement of mitochondria in neuronal development, placing emphasis on mitochondrial metabolism and dynamics. In addition, we survey the role of mitochondrial energy metabolism and Ca2+ homeostasis in proper neuronal function, and the involvement of mitochondria in axon myelination. PMID- 29476664 TI - Silymarin prevents lipid accumulation in the liver of rats with type 2 diabetes via sirtuin1 and SREBP-1c. AB - BACKGROUND: In this study, we have investigated whether silymarin intake influences lipid and glycogen content in conjunction with sirtuin1 (SIRT1) and sterol regulatory element-binding protein 1c (SREBP-1c) expressions in liver of type 2 diabetic rat. METHODS: Thirty-six male Wistar rats were randomly divided into six groups: control groups (C) and diabetic groups (D); the control groups received 60 or 120 mg/kg silymarin (C+S60 or C+S120), and the diabetic groups received 60 or 120 mg/kg silymarin (D+S60 or D+S120) daily for 8 weeks. Serum biochemical parameters, as well as glycogen, lipid and oxidative stress biomarkers, in the liver tissue were measured by spectrophotometric methods. Additionally, SIRT1 and SREBP-1c messenger RNA (mRNA) expressions were evaluated by quantitative polymerase chain reaction. RESULTS: Diabetes caused a significantly increased fasting blood sugar, homeostasis model assessment for insulin resistance, liver total cholesterol and triglyceride (TG) content, which were attenuated after the administration of silymarin. Dietary silymarin caused the improvement of lipid content in the liver of diabetic rats. Moreover, silymarin administration promoted SIRT1, suppressed SREBP-1c mRNA expression, reduced liver nitric oxide and protein carbonyl content, and increased liver glycogen, catalase and glutathione peroxidase activity. Furthermore, histopathological changes were improved in the treated groups. CONCLUSIONS: Silymarin administration considerably restored hepatic changes induced by streptozotocin and nicotinamide. The upregulation of SIRT1 mRNA expression by silymarin may be associated with decreased lipid, increased glycogen content and downregulation of the SREBP-1c gene in the liver. PMID- 29476665 TI - Employing a results-based algorithm to reduce laboratory utilization in ACTH stimulation testing. AB - BACKGROUND: The High Dose Adrenocorticotropic Hormone (ACTH) Stimulation Test is the gold standard to diagnose adrenal insufficiency. Normal adrenal function is defined as a peak cortisol response to pharmacologic stimulation with cosyntropin of >=18 MUg/dL. Our practice was to obtain cortisol levels at 0, 30 and 60 min after cosyntropin administration. Once a value of >=18 MUg/dL has been obtained, adrenal insufficiency is ruled out and there is little diagnostic utility in subsequent stimulated levels. METHODS: We aimed to decrease laboratory utilization by developing a results-based algorithm in the electronic medical record (EMR). Cortisol levels were analyzed on the 0 and 60 min samples; then an EMR discern rule automatically generated an order to analyze the 30-min sample if the 60-min cortisol level was subnormal. RESULTS: Exclusion of adrenal insufficiency was excluded using one stimulated cortisol level in 8% prior to algorithm development. After several plan-do-study-act cycles, 99% of normal tests were performed using only one stimulated cortisol level. CONCLUSIONS: This laboratory-based algorithm resulted in reduced laboratory utilization, and aligned our practice to recommendations of the Pediatric Endocrine Society. Similar algorithms could be created for other dynamic tests to reduce unnecessary laboratory utilization. PMID- 29476666 TI - Problem-based learning implementation in a health sciences blended-learning program in Argentina. PMID- 29476667 TI - Beckwith-Wiedemann Syndrome: Open bite evolution after tongue reduction. AB - BACKGROUND: Macroglossia causes functional deficits such as airway obstruction, drooling, phonation difficulties, and leads to protrusion of dentoalveolar structures resulting in an anterior open bite and a prognathic mandibular appearance. Macroglossia is present in the majority of patients with Beckwith Wiedemann syndrome (BWS) and surgical treatment may be indicated. MATERIAL AND METHODS: A retrospective review was conducted including BWS patients who underwent surgical tongue reduction between 2000 and 2015 at the Hospital Universitario La Paz, Madrid. RESULTS: Out of 16 patients with BWS, surgery was performed in 11 cases. Tongue protrusion with open bite was the main indication for surgical treatment. Reduction glossectomy was performed using the keyhole technique. We analysed the relationship between age at surgery and evolution of open bite. Complications were minimal and satisfactory outcomes were observed with a decrease in anterior open bite. CONCLUSIONS: In this study we have observed that surgical treatment in patients with BWS and open bite accompanied by macroglossia seems to provide positive results with a satisfactory outcome in dentoskeletal alterations. PMID- 29476668 TI - Clinical features and molecular genetic analysis in a Turkish family with oral white sponge nevus. AB - BACKGROUND: Oral white sponge nevus (WSN) is a rare autosomal dominant benign condition, characterized by asymptomatic spongy white plaques. Mutations in Keratin 4 (KRT4) and 13 (KRT13) have been shown to cause WSN. Familial cases are uncommon due to irregular penetrance. Thus, the aim of the study was: a) to demonstrate the clinical and histopathological features of a three-generation Turkish family with oral WSN b) to determine whether KRT4 or KRT13 gene mutation was the molecular basis of WSN. MATERIAL AND METHODS: Out of twenty members of the family ten were available for assessment. Venous blood samples from six affected and five unaffected members and 48 healthy controls were obtained for genetic mutational analysis. Polymerase chain reaction was used to amplify all exons within KRT4 and KRT13 genes. These products were sequenced and the data was examined for mutations and polymorphisms. RESULTS: Varying presentation and severity of clinical features were observed. Analysis of the KRT13 gene revealed the sequence variant Y118D as the disease-causing mutation. One patient revealed several previously unreported polymorphisms including a novel mutation in exon 1 of the KRT13 gene and a heterozygous deletion in exon 1 of KRT4. This deletion in the KRT4 gene was found to be a common polymorphism reflecting a high allele frequency of 31.25% in the Turkish population. CONCLUSIONS: Oral WSN may manifest variable clinical features. The novel mutation found in the KRT13 gene is believed to add evidence for a mutational hotspot in the mucosal keratins. Molecular genetic analysis is required to establish correct diagnosis and appropriate genetic consultation. PMID- 29476670 TI - Hematinic deficiencies in patients with recurrent aphthous stomatitis: variations by gender and age. AB - BACKGROUND: The aim of this study was to evaluate the association between hematinic deficiencies and recurrent aphthous stomatitis (RAS). MATERIAL AND METHODS: 517 RAS patients and 187 healthy controls were enrolled in the present study. Hematinic deficiencies, including serum ferritin, folic acid, and vitamin B12 deficiencies were assessed for each participant. Gender and age were taken into account and the collected data were statistically analysed. RESULTS: Compared with the healthy controls, a significantly higher overall frequency of hematinic deficiencies was found in RAS patients (p<0.001). When gender and age were taken into account, significant differences in hematinic deficiencies were observed among RAS patients. Serum ferritin deficiency was much more common in young and middle-aged female RAS patients (age<60). Serum folate deficiency and serum vitamin B12 deficiency were both much more common in the young adult group of male RAS patients (21-40 years of age). Logistic regression analysis revealed that both gender and age have significant correlation with the presence of hematinic deficiencies in the RAS patients. CONCLUSION: Significant variations in hematinic deficiencies were demonstrated in RAS patients across different genders and age groups. We suggest that further studies on the hematinic deficiencies of RAS patients should take into account the gender and age of participants. PMID- 29476669 TI - Survival rates and bone loss after immediate loading of implants in fresh extraction sockets (single gaps). A clinical prospective study with 4 year follow up. AB - BACKGROUND: The aim of this prospective study was to report the outcome of treatment with implants inserted after tooth extraction and immediately loaded. MATERIAL AND METHODS: Fifty-six patients with single tooth loss were treated with 116 IPX Galimplant(r) implants with internal connections and a sandblasted, acid etched surface. All implants were placed after tooth extraction using a flapless approach without bone regeneration, and they were then immediately loaded with cemented acrylic prostheses. After a period of three months, definitive cemented ceramic prostheses were placed. Patients were examined throughout a total of 4 years of follow-up. Marginal bone loss and survival rates were evaluated using digital periapical radiographs, taking into account clinical variables such as age, gender, smoking, history of periodontitis, etiology of extraction, placement site, diameter, and implant length. The Mann-Whitney U and Kruskal-Wallis non parametric tests were used to compare differences between subgroups created based on the different clinical variables identified. RESULTS: Clinical results indicate an implant survival and success rate of 97.4%. Three implants were lost. Of the 116 immediate acrylic single crowns initially placed, 113 were replaced with definitive ceramic crowns after 3 months. A total of 77.8% of implants were inserted in the maxilla, while 22.2% were inserted in the mandible. No further complications were reported after the follow-up period (4 years). The mean marginal bone loss was 0.67 mm +/- 0.40 mm. No differences were found among the subgroups of study patients. CONCLUSIONS: This study indicates that dental implants that are inserted after tooth extraction and immediately loaded may constitute a successful and predictable alternative implant treatment. PMID- 29476671 TI - Outcome of CO2 laser vaporization for oral potentially malignant disorders treatment. AB - BACKGROUND: Oral cancer is a public health issue worldwide. Oral potentially malignant disorders (OMPDs) are lesions of the oral mucosa that are predisposed to malignant transformation. The mainstay of OMPDs treatment around the world is now the carbon dioxide (CO2) laser but the reported recurrence and malignant transformation rates vary widely in the literature. We aimed to estimate the recurrence and the malignant transformation rates of OPMDs treated with CO2 laser at the University Hospital of Bordeaux, in France, from 2010 to 2014, and to identify associated factors with recurrence or malignant transformation. MATERIAL AND METHODS: We conducted a retrospective study in patients with a minimum follow up of 12 months. Collected variables included characteristics of the patients (gender, age, alcohol and tobacco consumption, previous diagnosis of graft-versus host disease, previous treatments for OPMD or for upper aerodigestive tract cancers and human immunodeficiency virus infection), characteristics of the lesions (form, colour, size, location, degree of dysplasia), laser treatment outcome (complications, recurrence, malignant transformation). RESULTS: Twenty five patients were included. Mean follow-up was 28.9 months. Recurrence was observed in 11 patients (44%). Annual recurrence rate was 18.3% and annual malignant transformation rate was 1.7%. Hyperplasia without dysplasia was the only factor found to be statistically associated with recurrence. CONCLUSIONS: Our results suggest that OMPDs treated by CO2 laser vaporization have high recurrence rates, particularly those presenting hyperplasia. A standardized definition of recurrence would be necessary for inter-study comparisons. Long term follow-up is recommended in order to detect and treat squamous cell carcinoma in its early stages. PMID- 29476672 TI - Block iliac bone grafting enhances osseous healing of alveolar reconstruction in older cleft patients: A radiological and histological evaluation. AB - BACKGROUND: Older alveolar cleft patients (>12 years old) often have wide bone defect as well as teeth loss, resulting in poor osseous healing with conventional alveolar bone grafting (ABG). In this study, we investigated a surgical technique of block iliac bone grafting for the alveolar cleft reconstruction and evaluated the clinical and radiological outcomes of these cleft patients. MATERIAL AND METHODS: Fifteen patients were included in this study. All cases received preoperative cone bean computed tomography (CBCT) scans for the alveolar cleft evaluation. Osseous outcomes of block iliac bone grafting were assessed at 1 week, 3- and 6-month postoperatively. Volume changes and bone resorption rates were calculated using the measurement modules of Simplant software. Bone samples from one patient undergoing dental implantation were assessed by micro-CT and histological examination. The morbidities of donor-site were analyzed by clinical examination and questionnaire survey. RESULTS: The average age of the case series was 18.53+/-2.50 years. The intraoral incision of thirteen cases healed well. However, two cases had oronasal fistula and graft exposure at 1-week postoperatively. The results of follow-up CBCT scans showed significant resistance to radiation on both sides of the bone graft, suggesting a good osseous healing and new bone formation. The mean residual bone volume was 1.68+/ 0.26 cm3, 1.29+/-0.23 cm3 and 1.15+/-0.23 cm3 at 1-week, 3- and 6-month postoperatively. Correspondingly, the mean bone resorption rates in 3- and 6 month postoperative were 21.78+/-6.88% and 30.66+/-8.97%, respectively. From micro-CT and HE examinations, the block bone samples exhibited a cancellous structure in which mature bone trabecula and functional blood vessels appeared. The average scores of donor-site morbidities were drastically decreased at 3- and 6-month postoperatively compared with those at 1-week postoperatively. CONCLUSIONS: Our results demonstrated that block iliac bone grafting could achieve satisfying osseous outcomes in older alveolar cleft patients, and this technique provided favorable bony condition for further treatments, especially dental implantation. PMID- 29476674 TI - Apoptosis and cell cycle aberrations in epithelial odontogenic lesions: An evidence by the expression of p53, Bcl-2 and Bax. AB - BACKGROUND: Ameloblastoma (AMB), odontogenic keratocyst (OKC) and adenomatoid odontogenic tumor (AOT) are epithelial odontogenic lesions with diverse biologic profiles. Defects in regulation of apoptosis and cell cycle may be involved in the development and progression of those lesions, therefore we aimed to investigate the expression of Bcl-2, Bax and p53 to better understand the possible role of these proteins in AMBs, OKCs and AOTs. MATERIAL AND METHODS: The studied sample consisted of 20 AMBs, 20 OKCs and 20 AOTs. Immunohistochemistry technique was performed for the antibodies p53, Bcl-2 and Bax. Immunoreactivity was observed in the epithelial component and positive cells were counted in five fields (100x magnification). Statistical analysis was performed with Kruskal Wallis and Spearman tests (p <0.05). RESULTS: All lesions exhibited staining for the three studied proteins. There was no statistically significant associations between the expression of proteins and the lesions, however we identified a positive correlation between the expression of p53 and Bcl-2 (r = 0.200) and a negative correlation between p53 and Bax expressions (r = -0.100). In addition, p53 and Bax were similarly expressed between AMBs and OKCs. Bcl-2 was similarly expressed in AMBs and AOTs. CONCLUSIONS: Apoptosis regulatory proteins, as well as cell cycle proteins, are differently expressed in epithelial odontogenic lesions and their expression is possibly related to the biological behavior of AMB, OKC and AOT. PMID- 29476673 TI - Oral cancer associated with chronic mechanical irritation of the oral mucosa. AB - BACKGROUND: Most of the studies dealing with Chronic Mechanical Irritation (CMI) and Oral Cancer (OC) only considered prosthetic and dental variables separately, and CMI functional factors are not registered. Thus, the aim of this study was to assess OC risk in individuals with dental, prosthetic and functional CMI. Also, we examined CMI presence in relation to tumor size. MATERIAL AND METHODS: A case control study was carried out from 2009 to 2013. Study group were squamous cell carcinoma cases; control group was patients seeking dental treatment in the same institution. RESULTS: 153 patients were studied (Study group n=53, Control group n=100). CMI reproducibility displayed a correlation coefficient of 1 (p<0.0001). Bivariate analysis showed statistically significant associations for all variables (age, gender, tobacco and alcohol consumption and CMI). Multivariate analysis exhibited statistical significance for age, alcohol, and CMI, but not for gender or tobacco. Relationship of CMI with tumor size showed no statistically significant differences. CONCLUSIONS: CMI could be regarded as a risk factor for oral cancer. In individuals with other OC risk factors, proper treatment of the mechanical injuring factors (dental, prosthetic and functional) could be an important measure to reduce the risk of oral cancer. PMID- 29476675 TI - Factors associated with the quality of life of subjects with facial disfigurement due to surgical treatment of head and neck cancer. AB - BACKGROUND: Facial disfigurement has been considered one of the most challenging consequences of the surgical treatment for head and neck cancer patients, mainly due to the importance of the facial region for the personal identity, body self image and interpersonal interactions, which might affect negatively the quality of life. The aim of this study was to assess factors associated with the quality of life of subjects with facial disfigurement due to surgical treatment. MATERIAL AND METHODS: Clinical data were retrieved from 103 patient's medical records and quality of life data were collected using the Functional Assessment of Cancer Therapy (FACT-H&N) questionnaire. Moreover, the degree of facial disfigurement was classified by means of a specific ordinal scale. RESULTS: Data from the FACT H&N questionnaire showed that the domain directly related to head and neck symptoms was considered the most impacted, while emotional domain was the least affected. Lower quality of life was associated with sequels in the neck and/or lower third of the face (beta=-0.39; p=0.001), a higher level of disfigurement (beta=-0.29; p=0.016) and female gender (beta=-0.20; p=0.038). CONCLUSIONS: Disfigurement due to surgical treatment was significantly associated with the functional dimension of the patients, especially in extensive sequels in the cervical and lower regions of the face. PMID- 29476676 TI - Clinicopathological analysis of head and neck rhabdomyosarcoma: A series of 10 cases and literature review. AB - BACKGROUND: To describe the clinicopathological characteristics of a series of head and neck rhabdomyosarcoma (RMS) and to review the literature. MATERIAL AND METHODS: Cases diagnosed as RMS affecting the head and neck region were retrospectively retrieved from the files of two Brazilian institutions from January 2006 to January 2017. Data on clinical features (sex, age and affected site), microscopic subtype, immunohistochemical results, treatment employed and follow-up status were obtained from the patient's medical charts. RESULTS: During the period considered, 10 cases of RMS were identified. Females predominated (4M:6F), the mean age at diagnosis was 16.5 years-old and the orbit was the most affected site (4 cases). Microscopically, most cases were classified as embryonal RMS (6 cases) and the Desmin/Myogenin/Myo-D1 immunohistochemical positivity was useful to confirm the diagnosis. Chemotherapy and radiotherapy were applied to 9 and 8 patients respectively, whereas 2 patients were treated by surgery. Recurrences occurred in 3 patients and distant metastasis in 2 cases. Nine patients were alive in their last follow-up, 3 of them with disease, whereas 1 patient died due to the disease. CONCLUSION: Head and neck RMS is an aggressive malignant neoplasm which demands especial concern to achieve early diagnosis and successful treatment. PMID- 29476677 TI - A controlled study comparing salivary osmolality, caries experience and caries risk in patients with cerebral palsy. AB - BACKGROUND: Cerebral palsy (CP) is a permanent neurological disorder accompanied by secondary musculoskeletal masticatory disorder, with repercussion on chewing and deglutition functions. In these conditions, the liquids ingestion is compromised resulting in salivary osmolality alteration. The objective of this study was to compare salivary osmolality, caries experience and caries risk between normoreactive individuals and patients with CP. MATERIAL AND METHODS: The participants were 4-20 years old: 52 patients with CP treated at a reference rehabilitation centre (study group, SG), and 52 normoreactive individuals (control group, CG). Saliva was collected for five minutes using cotton rolls. Following centrifugation, salivary osmolality was determined by freezing point depression osmometry. Evaluations included caries experience (DMFT index), and caries risk based on a caries-risk assessment tool (CAT). Descriptive and inferential statistics (Chi square and Student t tests) were used to compare the groups. Receiver operating characteristic (ROC) analyses were performed and the area under the ROC curve (Az) was calculated. The level of significance was set at 5%. RESULTS: The groups were homogeneous for sex (p=0.843) and age (p=0.128). In the SG, spastic type CP was the most prevalent (80.8%), and patients showed significantly higher salivary osmolality values compared with the CG (p<0.001). No significant differences in caries experience (p=0.159) or caries risk (p=0.297) were observed. ROC curve analysis determined a salivary osmolality cutoff point of >74 for the SG and >54 for the CG in the presence of dental caries. A significant correlation was verified between salivary osmolality and the DMFT index for the SG (p<=0.05). CONCLUSIONS: Although patients with CP showed higher salivary osmolality values, higher caries experience and caries risk were not observed compared with normoreactive individuals. PMID- 29476678 TI - Craniomaxillofacial morphology alterations in children, adolescents and adults with neurofibromatosis 1: A cone beam computed tomography analysis of a Brazilian sample. AB - BACKGROUND: Oral manifestations are common in neurofibromatosis 1 (NF1), and include jaws and teeth alterations. Our aim was to investigate the craniomaxillofacial morphology of Brazilian children, adolescents and adults with NF1 using cone beam computed tomography. MATERIAL AND METHODS: This study was conducted with 36 Brazilian individuals with NF1 with ages ranging from 4 to 75. The participants were submitted to anamnesis, extra and intraoral exam and cephalometric analysis using cone beam computed tomography. Height of the NF1 individuals was compared to the length of jaws and skull base. The results of the cephalometric measurements of the NF1 group were compared with a control group paired by age, gender and skin color. RESULTS: Individuals with NF1 had lower maxillary length (p<0.0001), lower mandibular length (p<0.0001), lower skull base length (p<0.0001). In children and adolescents, the mandible was more posteriorly positioned (p=0.01), when compared with the control group. There was no association between jaws and skull base length with the height of the individuals with NF1. CONCLUSIONS: Brazilian children, adolescents and adults with NF1 have short mandible, maxilla and skull base. Moreover, children and adolescents present mandibular retrusion. PMID- 29476680 TI - Oral findings in secondary syphilis. AB - BACKGROUND: Syphilis is a sexually transmitted disease caused by Treponema pallidum. However, there are of hematogenic and vertical transmission. All health care professionals must be aware of the manifestations of this condition, such as oral lesions. OBJECTIVES: This study to analyze and compare four clinical cases of syphilis that were diagnosed based on lesions in the oral cavity with published literature. MATERIAL AND METHODS: Four patients with a confirmed sorologic and clinical diagnosis of syphilis were examined, confirmated from manifestation of oral lesions together with analysis of serological laboratory tests and histopathological analyses. RESULTS: Lesions were found in classic sites such as lips, tongue and skin. However, there were also lesions on the hard palate, and labial commissure, which correspond to less than 5% of the syphilis oral manifestations. CONCLUSIONS: The practice of unprotected oral sex may result in infection and development of syphilis. The acknowledgment of the oral manifestations of syphilis in all its period of training for health professionals is of basic importance, the association of clinical features, histopathological findings and serological tests are required to complete the diagnosis and correct treatment. PMID- 29476679 TI - Tooth loss in middle-aged adults with diabetes and hypertension: Social determinants, health perceptions, oral impact on daily performance (OIDP) and treatment need. AB - BACKGROUND: This study aimed to explore the association between tooth loss and social determinants, health self-perceptions, OIDP and self-concept of dental treatment need in middle-aged adults with diabetes and hypertension. MATERIAL AND METHODS: A cross-sectional study was developed with 212 hypertensive and diabetic middle-aged adults (50-65 years). Data were collected from clinical examinations (DMFT) and a questionnaire regarding socioeconomic status, dental health assistance, self-perceptions of oral and general health, OIDP, and the self concept of dental treatment need. Tooth loss was dichotomized considering the cutoff point of 12 (Model I) or 24 missing teeth (Model II). Data were analyzed using Chi-square, Fisher's exact test and logistic regression (p<=0.05). RESULTS: Tooth loss was significantly associated with variables such as last dental visit, reason for dental visit, OIDP, perception of dental treatment need, and general self-perception (Model I). Schooling, last dental visit, oral health self perception and perception of dental treatment need were significantly associated with tooth loss in the Model II. When Model 1 and 2 were adjusted, they demonstrated that last dental visit and perception of dental treatment need were predictor variables. CONCLUSIONS: The annual dental visit and the self-concept of dental treatment need were associated with tooth loss, demonstrating that these variables reduce the tooth loss prevalence. PMID- 29476681 TI - Expression of hMLH1 and hMSH2 proteins in ameloblastomas and tooth germs. AB - BACKGROUND: Mismatch repair proteins (MMRPs) are a group of nuclear enzymes that participate in the repair of base mismatches that occur during DNA replication in all proliferating cells. The most studied MMRPs are hMSH2 and hMLH1, which are known to be highly expressed in normal tissues. A loss of MMRPs leads to the accumulation of DNA replication errors in proliferating cells. Ki-67 is a biomarker regarded to be the gold-standard tool for determining cell proliferation by immunohistochemical methods. The aim of this study was to investigate the immunohistochemical expression of hMLH1, hMSH2 and Ki-67 proteins in ameloblastomas and tooth germs, to contribute to the understanding of the development of this odontogenic neoplasm. MATERIAL AND METHODS: Immunohistochemical assays to determine the presence of proteins hMSH2, hMLH1 and Ki-67 were performed in 80 ameloblastomas (40 solid and 40 unicystic) and five tooth germs. RESULTS: Unicystic ameloblastomas showed higher MMRP expression (hMLH1: 62.5 +/- 43.4; hMSH2: 83.3 +/- 47.8) than did solid ameloblastomas (hMLH1: 59.4 +/- 13.5; hMSH2: 75.8 +/- 40.2). Additionally, the cell proliferation index assessed by Ki-67 was inversely proportional to the expression of MMRP. Comparison between tooth germs and ameloblastoma revealed significantly higher expression of hMLH1, hMSH2 and Ki-67 in tooth germs (p=0.02). CONCLUSIONS: The differences of MMRP and Ki-67 immunoexpression between ameloblastomas and tooth germ suggest that alterations in the MMRP mechanisms could participate in the biological behavior of ameloblastomas. PMID- 29476682 TI - Benign oral vascular lesions treated by sclerotherapy with ethanolamine oleate: A retrospective study of 43 patients. AB - BACKGROUND: Although sclerotherapy is a common treatment for benign oral vascular lesions, there is no well-standardized protocol for this purpose. The aim of the present study was to describe the clinical characteristics of patients treated by sclerotherapy with ethanolamine oleate (EO), in order to contribute to a better understanding of this technique. MATERIAL AND METHODS: Medical records and images of 90 patients treated by the same sclerotherapy protocol were retrieved and analysed. Thus, 43 cases with complete information were selected and described. RESULTS: The most affected age group was 41-70 years, with a female predominance and 86% of patients being Caucasian. Lips were the most affect site (70%) followed by the tongue (16%). Regarding clinical appearance, approximately 90% of lesions were classified as nodules, and 90% of patients reported no pain. Approximately 40% of lesions were 0.5-1.0 cm in size. In 58% of the patients, only one application of ethanolamine oleate was necessary. The application doses varied according to the lesion size and number of applications. Complete clinical regression occurred in 91% of cases, whereas 9% showed partial regression. CONCLUSIONS: Sclerotherapy with EO is an acceptable, effective and affordable treatment for benign oral vascular lesions. PMID- 29476683 TI - Changing pattern and etiology of maxillofacial fractures during the civil uprising in Western Libya. AB - BACKGROUND: The purpose of the present study was to evaluate changing pattern in characteristics of maxillofacial fractures and concomitant injuries in Western Libya During revolution and to assess the association between mechanism of injury and fracture patterns. MATERIAL AND METHODS: A retrospective review of medical records and radiographs of 187 patients treated for maxillofacial fractures from January 2010 to December 2012 was performed, there were 326 fractures in 187 patients. RESULTS: The male: female ratio was 6:1. Most fractures occurred in patients aged 11 to 40 years, and few injuries occurred in patients aged > 50 years. Most fractures occurred from motor vehicle accidents, and other most frequent causes included assault, gunshot, and fall injuries. Most maxillofacial fractures involved the mandible, zygomatic complex, or maxilla. Most mandibular fractures occurred at the parasymphysis, angle, or condyle. Associated injuries most frequently involved the head, chest, and extremities. Most patients were treated with open reduction (132 patients [71%]), and 26 patients (14%) were treated nonoperatively. There were 21 complications (11%). CONCLUSIONS: In summary, motor vehicle accidents were the most frequent cause of maxillofacial fracture in western Libya, possibly because of the lack of seat belt legislation. Interpersonal violence was a less frequent cause of maxillofacial fracture, possibly because of the religious restriction on alcohol consumption. PMID- 29476684 TI - How general dentists could manage a patient with oral lichen planus. AB - BACKGROUND: The literature hardly contains information on how patients suffering from oral lichen planus could be managed by dentists. MATERIAL AND METHODS: Based on the limited available literature and particularly on the long-term clinical and histopathological experience of one of the authors, suggestions on how dentists could manage patients with oral lichen planus have been put forward. RESULTS: In most cases, the dentist should be able to establish a correct diagnosis. Occasionally, the dentist may call upon a specialist, usually an oral medicine specialist or an oral and maxillofacial surgeon for confirmation of the diagnosis, possibly a biopsy procedure, and management of the patient in case of severe symptoms. Proper patient information is of utmost importance in the management. CONCLUSIONS: General dentists can be expected to manage the majority of patients with oral lichen planus. Some patients may need to be referred for diagnostic purposes to a specialist; this is also the case for the rare patient with severe symptoms, possibly requiring systemic treatment. PMID- 29476686 TI - The SCORE2 Comparison of Treat-and-Extend vs Monthly Anti-Vascular Endothelial Growth Factor Dosing: Short-term Similarities and Longer-term Questions. PMID- 29476685 TI - Ovarian Reserve Assessment in Celiac Patients of Reproductive Age. AB - BACKGROUND This study aimed to investigate ovarian reserve in patients of reproductive age with Celiac disease (CD) using anti-Mullerian hormone (AMH) levels, antral follicle counts (AFCs), and ovarian volume. MATERIAL AND METHODS We included into this study 46 CD female patients and 40 healthy female subjects of reproductive age, ages 18-45 years. Venous blood samples were taken from both groups on days 2-4 of the menstrual cycle, and follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), prolactin (PRL), and AMH levels were measured. On the same day, AFCs and ovarian volumes were determined. Data on body mass index (BMI), gravidity/parity/abortions/alive counts, disease duration, and Marsh histological classification were recorded. RESULTS There were no statistically significant differences between CD and control groups in terms of mean age, BMI, or median gravidity/parity/abortions/alive counts (p>0.05). Also, there were no statistically significant differences between the 2 groups in terms of mean FSH, LH, E2, PRL levels, right and left ovarian volumes, and median right and left ovarian AFCs (p>0.05). However, AMH level was significantly lower in the CD group (p=0.032). No statistically significant correlation was found between AMH levels and age, BMI, FSH, LH, E2, PRL levels, right and left ovarian volumes, right and left ovarian AFCs, or Marsh histological classification using the Spearman correlation test (p>0.05). However, an inverse correlation was detected showing that AMH levels decrease with increasing CD duration (r=-0.054, p=0.001). CONCLUSIONS We found that AMH level and ovarian reserve was decreased in CD patients of reproductive age compared to healthy controls, and that AMH level and ovarian reserve decreased with increasing disease duration in CD patients. PMID- 29476687 TI - Comparison of Monthly vs Treat-and-Extend Regimens for Individuals With Macular Edema Who Respond Well to Anti-Vascular Endothelial Growth Factor Medications: Secondary Outcomes From the SCORE2 Randomized Clinical Trial. AB - Importance: Comparisons of monthly vs treat-and-extend anti-vascular endothelial growth factor (anti-VEGF) regimens for macular edema from central retinal vein occlusion or hemiretinal vein occlusion is needed. Objective: To compare visual acuity letter score and central subfield thickness outcomes of participants in the Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2) trial who then received either monthly injections or treat-and-extend (TAE) regimens of aflibercept or bevacizumab after a good response at month 6. Design, Setting, and Participants: This randomized clinical trial enrolled participants from 66 private practice or academic centers in the United States. All participants had macular edema associated with central retinal vein occlusion or hemiretinal vein occlusion, had enrolled in the SCORE2 trial, and had a protocol-defined good response to monthly injections in the first 6 months of the trial. Participants initially assigned to receive monthly aflibercept were randomized to aflibercept on a monthly or TAE schedule, and participants initially assigned to receive monthly injections of bevacizumab were randomized to receive bevacizumab on a monthly or TAE schedule. The first participant was randomized in the SCORE2 trial on September 17, 2014, and the last month 12 visit occurred on October 24, 2016. Main Outcomes and Measures: Change from month 6 to month 12 in best-corrected electronic visual acuity letter score (per the Early Treatment Diabetic Retinopathy Study). Results: The 293 participants had a mean (SD) age of 68.9 (11.9) years; 127 (43.3%) were female. Of these, 79 were randomized to aflibercept on a monthly schedule, 80 to aflibercept on a TAE schedule, 67 to monthly bevacizumab, and 67 to bevacizumab on a TAE schedule. Mean treatment group difference (the change in visual acuity letter score in the monthly group minus the change in the TAE group) from month 6 to month 12 was 1.88 (97.5% CI, 1.07 to 4.83; P = .15) for aflibercept and 1.98 (97.5% CI, -1.08 to 5.03; P = .15) for bevacizumab. In the aflibercept arm, the mean number of injections between months 6 and 11 was 5.8 in the monthly injection group (95% CI, 5.6 to 5.9) and 3.8 in the TAE group (95% CI, 3.5 to 4.1; P < .001); in the bevacizumab arm, the mean number of injections was 5.8 (95% CI, 5.6 to 5.9) in the monthly group and 4.5 in the TAE group (95% CI, 4.2 to 4.8; P < .001). Conclusions and Relevance: One to 2 fewer injections of aflibercept or bevacizumab were given to the TAE groups than the monthly groups in months 6 to 12 for macular edema associated with central retinal or hemiretinal vein occlusion. Because of wide confidence intervals on the differences between the groups, caution is warranted before concluding that the regimens are associated with similar vision outcomes. Trial Registration: www.clinicaltrials.gov identifier: NCT01969708. PMID- 29476688 TI - Mental Health-related Emergency Department Visits Associated With Cannabis in Colorado. AB - BACKGROUND: Cannabis legalization in Colorado resulted in increased cannabis associated health care utilization. Our objective was to examine cooccurrence of cannabis and mental health diagnostic coding in Colorado emergency department (ED) discharges and replicate the study in a subpopulation of ED visits where cannabis involvement and psychiatric diagnosis were confirmed through medical review. METHODS: We collected statewide ED International Classification of Diseases, 9th Revision, Clinical Modification diagnoses from the Colorado Hospital Association and a subpopulation of ED visits from a large, academic hospital from 2012 to 2014. Diagnosis codes identified visits associated with mental health and cannabis. Codes for mental health conditions and cannabis were confirmed by manual records review in the academic hospital subpopulation. Prevalence ratios (PRs) of mental health ED discharges were calculated to compare cannabis-associated visits to those without cannabis. Rates of mental health and cannabis-associated ED discharges were examined over time. RESULTS: Statewide data demonstrated a fivefold higher prevalence of mental health diagnoses in cannabis-associated ED visits (PR = 5.35, 95% confidence interval [CI], 5.27 5.43) compared to visits without cannabis. The hospital subpopulation supported this finding with a fourfold higher prevalence of psychiatric complaints in cannabis attributable ED visits (PR = 4.87, 95% CI = 4.36-5.44) compared to visits not attributable to cannabis. Statewide rates of ED visits associated with both cannabis and mental health significantly increased from 2012 to 2014 from 224.5 to 268.4 per 100,000 (p < 0.0001). CONCLUSIONS: In Colorado, the prevalence of mental health conditions in ED visits with cannabis-associated diagnostic codes is higher than in those without cannabis. There is a need for further research determining if these findings are truly attributed to cannabis or merely coincident with concurrent increased use and availability. PMID- 29476689 TI - Dermaseptin-S1 decreases Candida albicans growth, biofilm formation and the expression of hyphal wall protein 1 and aspartic protease genes. AB - AIMS: This study aimed to investigate the effect of synthetic antimicrobial peptide dermaseptin-S1 (DS1) (ALWKTMLKKLGTMALHAGKAALGAADTISQGTQ) on the growth of Candida albicans, its transition from blastospore to hyphae, and its biofilm formation. We also analysed the expression of different genes (HWP1 and SAPs) involved in C. albicans virulence. METHODS AND RESULTS: Using cell count we showed that in addition to decreasing C. albicans growth, peptide DS1 inhibited its transition from blastospore to hyphal form. These effects are comparable to those obtained with amphotericin B (AmB). Electron microscopy analyses showed that C. albicans cells treated with either DS1 or AmB displayed a distorted cell wall surface, suggesting that the effect of DS1 was similar to that of AmB on C. albicans cell membrane structure. These observations were confirmed by our results with biofilms showing that both DS1 peptide and AmB significantly inhibited biofilm formation after 2 and 4 days. The effect of DS1 on C. albicans growth, transition and biofilm formation may occur through gene modulation, as the expression of HWP1, SAP1, SAP2, SAP3, SAP9 and SAP10 genes involved in C. albicans pathogenesis were all downregulated when C. albicans was treated with DS1. CONCLUSIONS: DS1 inhibits the growth and hyphal transition of C. albicans. DS1 was also able to decrease the expression of and gene expression of hyphal wall protein 1 and aspartic proteases genes by C. albicans. SIGNIFICANCE AND IMPACT OF THE STUDY: These data provide new insight into the efficacy of DS1 against C. albicans and its potential for use as an antifungal therapy. PMID- 29476690 TI - Impact of a first study of early transplantation in acute alcoholic hepatitis: Results of a nationwide survey in french liver transplantation programs. PMID- 29476691 TI - Cochlear dead regions: Using the Threshold Equalising Noise (TEN) test to improve the assessment of potential cochlear implant candidates-The Oxford experience. PMID- 29476692 TI - Predicting myofiber size with electrical impedance myography: A study in immature mice. AB - INTRODUCTION: Electrical impedance can be used to estimate cellular characteristics. We sought to determine whether it could be used to approximate myofiber size using standard prediction modeling approaches. METHODS: Forty-four C57BL/6J wild-type immature mice of varying ages underwent electrical impedance myography (EIM) with a needle electrode array placed in the gastrocnemius. Animals were then humanely killed and muscle fixed, stained, and myofiber size quantified. Two different statistical prediction models were then applied. RESULTS: Impedance parameters showed major variation with increasing myofiber size. The prediction models based on EIM data alone were able to predict fiber size, with errors in the range of +/-69.05-78.44 um2 (16.19%-18.40% with respect to the average myofiber size). DISCUSSION: By using well-established statistical models, EIM data alone can provide a satisfactory estimate of myofiber size. Additional study of this approach for approximating myofiber size without the requirement of removing tissue for histological analysis is warranted. Muscle Nerve, 2018. PMID- 29476693 TI - Cold ischemia time is an important risk factor for post-liver transplant prolonged length of stay. AB - Risk analysis of cold ischemia time (CIT) in liver transplantation has largely focused on patient and graft survival. Posttransplant length of stay is a sensitive marker of morbidity and cost. We hypothesize that CIT is a risk factor for posttransplant prolonged length of stay (PLOS) and aim to conduct an hour-by hour analysis of CIT and PLOS. We retrospectively reviewed all adult, first-time liver transplants between March 2002 and September 2016 in the United Network for Organ Sharing database. The 67,426 recipients were categorized by hourly CIT increments. Multivariate logistic regression of PLOS (defined as >30 days), CIT groups, and an extensive list of confounding variables was performed. Linear regression between length of stay and CIT as continuous variables was also performed. CIT 1-6 hours was protective against PLOS, whereas CIT >7 hours was associated with increased odds for PLOS. The lowest odds for PLOS were observed with 1-2 hours (odds ratio [OR], 0.65; 95% confidence interval [CI], 0.45-0.92) and 2-3 hours (OR, 0.65; 95% CI, 0.55-0.78) of CIT. OR for PLOS steadily increased with increasing CIT, reaching the greatest odds for PLOS with 13-14 hours (OR, 2.05; 95% CI, 1.57-2.67) and 15-16 hours (OR, 2.06; 95% CI, 1.27-3.33) of CIT. Linear regression revealed a positive correlation between length of stay and CIT with a correlation coefficient of +0.35 (P < 0.001). In conclusion, post liver transplant length of stay is sensitive to CIT, with a substantial increase in the odds of PLOS observed with nearly every additional hour of cold ischemia. We conclude that CIT should be minimized to protect against the morbidity and cost associated with posttransplant PLOS. Liver Transplantation 24 762-768 2018 AASLD. PMID- 29476694 TI - Direct-acting antivirals do not increase the risk of hepatocellular carcinoma recurrence after local-regional therapy or liver transplant waitlist dropout. AB - : Whether direct-acting antivirals (DAAs) increase the risk of hepatocellular carcinoma (HCC) recurrence after tumor-directed therapy is controversial. We sought to determine the impact of DAA therapy on HCC recurrence after local regional therapy (LRT) and waitlist dropout among liver transplant (LT) candidates with HCC. We performed a retrospective cohort study of 149 LT candidates with hepatitis C virus (HCV) and HCC at a single center from 2014 through 2016. Cumulative incidence of HCC recurrence post-LRT and waitlist dropout was estimated by the DAA group. Factors associated with each outcome were evaluated using competing risks regression. A propensity score stabilized inverse probability weighting approach was used to account for differences in baseline characteristics between groups. The no DAA group (n = 87) had more severe cirrhosis and lower rates of complete radiologic tumor response after LRT than those treated with DAA (n = 62) but had similar alpha-fetoprotein and tumor burden at listing. Cumulative incidence of HCC recurrence within 1 year of complete response after LRT was 47.0% in the DAA group and 49.8% in the no DAA group (P = 0.93). In adjusted competing risk analysis using weighted propensity score modeling, risk of HCC recurrence was similar in the DAA group compared to those without DAA (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.58 1.42; P = 0.67). Patients treated with DAAs had lower risk of waitlist dropout due to tumor progression or death compared to the no DAA group in adjusted weighted analysis (HR, 0.30; 95% CI 0.13-0.69; P = 0.005). CONCLUSION: In LT candidates with HCV and HCC with initial complete response to LRT, DAA use is not associated with increased risk of HCC recurrence but rather is associated with reduced risk of waitlist dropout due to tumor progression or death. (Hepatology 2018). PMID- 29476695 TI - Morphological and functional analyses of skeletal muscles from an immunodeficient animal model of limb-girdle muscular dystrophy type 2E. AB - INTRODUCTION: Limb-girdle muscular dystrophy type 2E (LGMD2E) is caused by mutations in the beta-sarcoglycan gene, which is expressed in skeletal, cardiac, and smooth muscles. beta-Sarcoglycan-deficient (Sgcb-null) mice develop severe muscular dystrophy and cardiomyopathy with focal areas of necrosis. METHODS: In this study we performed morphological (histological and cellular characterization) and functional (isometric tetanic force and fatigue) analyses in dystrophic mice. Comparison studies were carried out in 1-month-old (clinical onset of the disease) and 7-month-old control mice (C57Bl/6J, Rag2/gammac-null) and immunocompetent and immunodeficient dystrophic mice (Sgcb-null and Sgcb/Rag2/gammac-null, respectively). RESULTS: We found that the lack of an immunological system resulted in an increase of calcification in striated muscles without impairing extensor digitorum longus muscle performance. Sgcb/Rag2/gammac null muscles showed a significant reduction of alkaline phosphate-positive mesoangioblasts. DISCUSSION: The immunological system counteracts skeletal muscle degeneration in the murine model of LGMD2E. Muscle Nerve, 2018. PMID- 29476696 TI - Treatment of a case of severe insulin resistance as a result of a PIK3R1 mutation with a sodium-glucose cotransporter 2 inhibitor. AB - A Japanese woman aged in her late 30s with severe insulin resistance and bodily features including a triangular face, prominent forehead, small chin, large and low-set ears, and ocular depression was investigated. A similar phenotype was not observed in other family members with the exception of her son, suggesting that the condition was caused by a de novo mutation that was transmitted from mother to son. Exome analysis showed the presence in the proband and her son of a c.1945C>T mutation in PIK3R1, a common mutation associated with SHORT (short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Rieger anomaly, and teething delay) syndrome. Administration of a sodium-glucose cotransporter 2 inhibitor lowered the proband's hemoglobin A1c level and allowed a reduction in her insulin dose without treatment-related adverse events including ketoacidosis, exaggerated loss of body mass or hypoglycemia. Sodium glucose cotransporter 2 inhibitors might thus offer an additional option for the treatment of genetic syndromes of severe insulin resistance. PMID- 29476697 TI - Salbutamol-induced Decrease in Augmentation Index is Related to the Parallel Increase in Heart Rate. AB - The change in augmentation index following salbutamol inhalation has been applied to evaluate endothelial function. We examined the contribution of salbutamol induced increase in heart rate to the observed decrease in augmentation index. Haemodynamics were recorded using whole-body impedance cardiography and continuous pulse wave analysis from tonometric radial blood pressure. All subjects (n = 335, mean age 46, body mass index 26, 48% men) were without medications with cardiovascular influences. The effects of salbutamol inhalation (0.4 mg) versus the endothelium-independent agent nitroglycerin resoriblet (0.25 mg) were examined during passive head-up tilt, as the haemodynamic influences of these compounds depend on body position. Salbutamol decreased augmentation index by ~3-4% units in supine and upright positions. Although salbutamol moderately increased cardiac index (+4.5%) and decreased systemic vascular resistance ( 8.5%), the significant haemodynamic explanatory factors for decreased augmentation index in multivariate analysis were increased supine heart rate, and increased upright heart rate and decreased ejection duration (p < 0.001 for all, r2 = 0.36-0.37). Sublingual nitroglycerin decreased supine and upright augmentation index by ~15% units and ~23% units, respectively. The haemodynamic explanatory factors for these changes in multivariate analysis were increased heart rate, reduced ejection duration and reduced systemic vascular resistance (p <= 0.021 for all, r2 = 0.22-0.34). In conclusion, the lowering influence of salbutamol on augmentation index may be largely explained by increased heart rate, suggesting that this effect may not predominantly reflect endothelial function. PMID- 29476698 TI - Risk factors for cesarean delivery and adverse neonatal outcome in twin pregnancies attempting vaginal delivery. AB - INTRODUCTION: Twin vaginal delivery presents a unique clinical challenge for obstetricians. The Twin Birth Study demonstrated the safety of planned vaginal delivery regarding neonatal outcomes. However, that study lacked a description of the risk factors associated with and the outcome of unplanned cesarean section. The aim of this study is to identify potential risk factors for cesarean section and delivery related neonatal morbidity and mortality in women with twin pregnancy attempting vaginal delivery. MATERIAL AND METHODS: A retrospective cohort study including 1070 women with twin pregnancy that underwent a trial of labor between 2003 and 2015. The study population was divided according to the mode of delivery: vaginal delivery, combined vaginal-cesarean and intrapartum cesarean delivery of both twins. Several risk factors and neonatal outcomes were examined by both univariate analysis and multinomial logistic regression analysis. RESULTS: The rate of vaginal delivery of both twins was 88.3%, whereas the rates of combined vaginal cesarean and unplanned cesarean delivery were 4.6% and 7.1%, respectively. Nulliparity and nonvertex presentation of twin B were found to be independently associated with cesarean delivery for both twins. Additionally, nonvertex presentation of twin B was independently associated with combined vaginal-cesarean delivery. The proportion of neonates with Apgar score <7 at 5 min was increased for both twins in the combined vaginal-cesarean group compared with those delivered by the vaginal route alone. CONCLUSION: Nulliparity and nonvertex presentation of twin B were found to be associated with intrapartum cesarean delivery in twin pregnancies. PMID- 29476699 TI - Improving Medication Safety in Psychiatry - A Controlled Intervention Study of Nurse Involvement in Avoidance of Potentially Inappropriate Prescriptions. AB - The aim of this controlled, before-and-after study in the Department of Psychiatry in a university hospital in Denmark was to examine the potential effects and characteristics of nurses reviewing psychiatric patients' medication records to identify potentially inappropriate prescriptions (PIPs). The control group and the intervention group each consisted of two bed units chosen based on patients' diagnoses and age categories. There were 396 patients (age >=18 years) included in the study. Senior clinical pharmacology physicians performed medication reviews for all patients in the study; these medication reviews were considered gold standard. The intervention group: nurses were given a pharmacology course after which the nurses reviewed medication lists and subsequently conferred any identified PIPs with physicians. The control group: medication was reviewed as usual and nurses did not participate. Primary outcome measure was the potential difference in PIPs between the control group and the intervention group, analysed in two ways: (i) difference in mean number of PIPs and (ii) difference in number of patients exposed to >=1 PIP, using regression analysis with an approximated difference-in-difference (DID) approach. Secondary outcome measure was characteristics of PIPs where physicians responded to nurse identified PIPs. The DID between intervention group and control group for mean number of PIPs per patient was -0.23 (-1.07 to 0.60), and for number of patients receiving >=1 PIP, the odds ratio was 0.61 (0.25 to 1.46). Physicians changed most prescriptions in the category interaction between drugs. Nurses could not significantly reduce the prevalence of PIPs for psychiatric patients. PMID- 29476700 TI - Evaluation of CD307a expression patterns during normal B-cell maturation and in B cell malignancies by flow cytometry. AB - BACKGROUND: Flow cytometric immunophenotyping is deemed a fundamental tool for the diagnosis of B-cell neoplasms. Currently, the investigation of novel immunophenotypic markers has gained importance, as they can assist in the precise subclassification of B-cell malignancies by flow cytometry. Therefore, the purpose of the present study was to evaluate the expression of CD307a during normal B-cell maturation and in B-cell malignancies as well as to investigate its potential role in the differential diagnosis of these entities. METHODS: CD307a expression was assessed by flow cytometry in normal precursor and mature B cells and in 115 samples collected from patients diagnosed with precursor and mature B cell neoplasms. CD307a expression was compared between neoplastic and normal B cells. RESULTS: B-acute lymphoblastic leukemia cases exhibited minimal expression of CD307a, displaying a similar expression pattern to that of normal B-cell precursors. Mantle cell lymphoma (MCL) cases showed the lowest levels of CD307a among mature B-cell neoplasms. CD307a expression was statistically lower in MCL cases than in chronic B lymphocytic leukemia (CLL) and marginal zone lymphoma (MZL) cases. No statistical differences were observed between CD307a expression in neoplastic and normal plasma cells. CONCLUSION: These results indicate that the assessment of CD307a expression by flow cytometry could be helpful to distinguish CLL from MCL, and the latter from MZL. Although these results are not entirely conclusive, they provide a basis for further studies in a larger cohort of patients. (c) 2018 International Clinical Cytometry Society. PMID- 29476701 TI - Human HLA-B27 typing using the BDTM HLA-B27 kit on the BD FACSViaTM system: A multicenter study. AB - The BD FACSViaTM system is a novel flow cytometer with improved workflow efficiencies. To evaluate the HLA-B27 application developed on the BD FACSVia system utilizing the BDTM HLA-B27 kit, we conducted a concordance study at three centers to compare with the BD FACSCaliburTM system. Prepared donor samples (n = 594) were analyzed on both the BD FACSVia and BD FACSCalibur for the HLA-B27 assay. Adjudication of HLA-B27 discordant results was performed using the reverse sequence-specific oligonucleotide (rSSO) DNA typing method (LABType(r) SSO, One Lambda). On the BD FACSVia system 80 B27 positive, 499 B27 negative and 15 "Inconclusive" samples were observed. The corresponding BD FACSCalibur results were 73 B27 positive, 502 B27 negative and 19 "gray zone" samples. The overall concordance of HLA-B27 determination was 98% between the two systems with seven more positives identified on BD FACSVia as compared to BD FACSCalibur. The equivocal zone between positive and negative on BD FACSVia (named "Inconclusive") and on BD FACSCalibur (named "gray zone") is due to antibody cross reactivity of HLA-B27 clone GS145.2. One negative sample verified with the rSSO DNA method was reported as HLA-B27 positive by the BD FACSVia system leading to a false positive result. Our study demonstrated concordance results between the BD FACSVia system and BD FACSCalibur. Intersite reproducibility of BD HLA-B27 assay remained within the limits of acceptability. (c) 2018 The Authors. Cytometry Part B: Clinical Cytometry published by Wiley Periodicals, Inc. on behalf of International Clinical Cytometry Society. PMID- 29476702 TI - Use of a clinical decision support tool for the management of traumatic dental injuries in the primary dentition by novice and expert clinicians. AB - BACKGROUND/AIM: Studies reveal many dental students and general dentists have inadequate knowledge about treating children who sustain traumatic dental injuries. The aims of this study were to assess dental trauma knowledge among novice clinicians and expert pediatric dentists and determine the effectiveness of a clinical decision support tool (CDST) for the management of trauma scenarios. A secondary purpose was to compare the effects of a print and mobile app format of the CDST. METHODS: A print and mobile app CDST was developed based upon current AAPD and IADT clinical guidelines. Baseline knowledge for dental students (n = 84) and pediatric dentists (n = 60) was assessed using a multiple choice Pre-test. A Post-test was used to evaluate changes in the knowledge level following the random assignment of participants into 3 groups: Group A (control) had no CDST provided; Group B (print CDST) had access to the print paper pamphlet; and Group C (mobile app CDST) had access to the mobile app on a handheld device for use during the Post-test. Test scores and time required to complete each test were recorded. RESULTS: Pediatric dentists scored significantly higher and required less time on both the Pre-test (P < .001) and Post-test (P < .05) compared to dental students. Dental students and pediatric dentists who had access to the mobile app CDST scored significantly higher (P < .05) in the Post-test compared to the control and the print CDST groups. Post test time for the dental students in the mobile app group was significantly longer (P < .001) compared to the control and print format. CONCLUSION: Expert pediatric dentists demonstrated greater knowledge of dental trauma compared to novice clinicians. The mobile app clinical decision support tool was a more effective means of improving the diagnosis and management of traumatic dental injuries by both dental students and pediatric dentists than the print CDST. PMID- 29476703 TI - The use of anti-Mullerian hormone for controlled ovarian stimulation in assisted reproductive technology, fertility assessment and -counseling. AB - Ovarian reserve can be determined by serum anti-Mullerian hormone (AMH) level and/or antral follicle count before controlled ovarian stimulation. The aim of controlled ovarian stimulation is to achieve an appropriate number of mature follicles and avoid complications such as ovarian hyperstimulation syndrome. Measurement of the ovarian reserve is useful for clinicians as it predicts the ovarian response to controlled ovarian stimulation. Further, it assists in giving the patient realistic expectations regarding the treatment. By determining the ovarian reserve, the most appropriate stimulation protocol and gonadotropin dose can be chosen specifically for each woman enabling so-called "individualized treatment" in line with the personalized treatment concept. Many benefits come with using AMH as a biomarker for ovarian reserve; the hormone is considered fairly cycle independent apart from a small decrease in the late follicular phase and there is no inter-observer variance. However, the use of AMH also has limitations; since the implementation of AMH in fertility treatment several AMH assays have been developed. This has made direct comparisons of AMH serum levels complicated. Currently, no international standardized assays exist. AMH is a valid predictor of the ovarian response to controlled ovarian stimulation and to some extent the chance of pregnancy in relation to assisted reproductive technology, but AMH is less optimal in prediction of spontaneous pregnancy and live birth after assisted reproductive technology. Accordingly, AMH can be used to optimize gonadotropin stimulation in fertility treatment, but is not recommended as a screening tool in the general population. PMID- 29476705 TI - Tracking of secretory phospholipase A2 enzyme activity levels from childhood to adulthood: a 21-year cohort. AB - OBJECTIVE: Secretory phospholipase A2 (sPLA2) enzyme activity is a potential inflammatory biomarker for cardiovascular disease. We examined the tracking, or persistence, of sPLA2 enzyme activity levels from childhood to adulthood, and identify potentially modifiable factors affecting tracking. METHOD: Prospective cohort of 1735 children (45% females) who had serum sPLA2 enzyme activity levels and other cardiovascular disease risk factors measured in 1980 that were followed up in 2001. RESULTS: sPLA2 activity tracked from childhood to adulthood for males (r=0.39) and females (r=0.45). Those who decreased body mass index relative to their peers were more likely to resolve elevated childhood sPLA2 levels than have persistent elevated sPLA2 levels in childhood and adulthood. Those who consumed less fruit, and gained more body mass index relative to their peers, began smoking or were a persistent smoker between childhood and adulthood were more likely to develop incident elevated sPLA2 levels than those with persistent not elevated sPLA2 levels. CONCLUSIONS: Childhood sPLA2 enzyme activity levels associate with adult sPLA2 levels 21 years later. Healthful changes in modifiable risk factors that occur between childhood and adulthood might prevent children from developing elevated sPLA2 levels in adulthood. PMID- 29476704 TI - Fibroblast growth factor 21 is an early predictor of acute-on-chronic liver failure in critically ill patients with cirrhosis. AB - Acute-on-chronic liver failure (ACLF) develops in acute decompensation (AD) of cirrhosis and shows high mortality. In critically ill patients, early diagnosis of ACLF could be important for therapeutic decisions (eg, renal replacement, artificial liver support, liver transplantation). This study evaluated fibroblast growth factor 21 (FGF21) as a marker of mitochondrial dysfunction in the context of ACLF. The study included 154 individuals (112 critically patients and 42 healthy controls) divided into a training and a validation cohort. In the training cohort of 42 healthy controls and 34 critically ill patients (of whom 24 were patients with cirrhosis), levels of FGF21, interleukin (IL) 6, and IL8 were measured. In the validation cohort of 78 patients with cirrhosis, 17 patients were admitted with or developed ACLF during follow-up and underwent daily clinical and nutritional assessment. Levels of FGF21 were higher in critically ill patients, especially in patients with cirrhosis admitted to the intensive care unit (ICU). Moreover, FGF21 as well as IL6 and IL8 levels were higher in patients with ACLF, but they did not increase with the severity of ACLF. Interestingly, in the validation cohort, FGF21 was also elevated in the patients who developed ACLF in the next 7 days. In these patients, FGF21 levels were an independent predictor of ACLF presence and development in multivariate analysis together with Child-Pugh score. FGF21 levels had no impact on the survival of critically ill patients with cirrhosis. In conclusion, this study demonstrates that FGF21 levels are of specific diagnostic value regarding the presence and development of ACLF in patients admitted to ICU for AD of liver cirrhosis. Further studies are warranted to address pathophysiological and possible therapeutic implications. Liver Transplantation 24 595-605 2018 AASLD. PMID- 29476706 TI - Is willingness to exercise programmed in utero? Reviewing sedentary behavior and the benefits of physical activity in intrauterine growth restricted individuals. AB - OBJECTIVE: The literature suggests that a fetus will adapt to surrounding adversities by optimizing its use of energy to improve survival, ultimately leading to the programming of the individual's energy intake and expenditure. While recent reviews focused on the fetal programming of energy intake and food preferences, there is also some evidence that fetal adversity is associated with diminished physical activity levels. Therefore, we aimed to review (a) the evidence for an association between being born with intrauterine growth restriction and sedentarism over the life-course and (b) the potential benefits of physical activity over cardiometabolic risk factors for this population. SOURCES: PubMed, Scielo, Scopus and Embase. SUMMARY OF FINDINGS: Most clinical studies that used objective measures found no association between intrauterine growth restriction and physical activity levels, while most studies that used self-reported questionnaires revealed such relationships, particularly leisure time physical activity. Experimental studies support the existence of fetal programming of physical activity, and show that exposure to exercise during IUGR individuals' life improves metabolic outcomes but less effect was seen on muscle architecture or function. CONCLUSIONS: Alterations in muscle strength and metabolism, as well as altered aerobic performance, may predispose IUGR individuals to be spontaneously less physically active, suggesting that this population may be an important target for preventive interventions. Although very heterogeneous, the different studies allow us to infer that physical activity may have beneficial effects especially for individuals that are more vulnerable to metabolic modifications such as those with IUGR. PMID- 29476707 TI - Damocles' syndrome revisited: Update on the fear of cancer recurrence in the complex world of today's treatments and survivorship. AB - OBJECTIVE/BACKGROUND: Improvements in curative treatments for many types of cancer have emerged over the past several decades, resulting in a growing population of long-term cancer survivors - of both adult and childhood cancers. Despite this incredible medical achievement, long-term survivors of cancer face a unique fear: the fear of relapse. METHODS: We conducted a review of the literature for data on fear of relapse among cancer survivors. RESULTS: The fear of cancer recurrence is present in survivors of childhood and adult cancers as well as family members and often leads to psychological sequelae. CONCLUSION: Literature on the fear of cancer recurrence has begun to emerge. However, herein we provide a unique approach through the use of a metaphor: Cicero's story of Damocles' sword. We aim to outline the many fear-related and emotional challenges faced by cancer survivors with an extensive review of studies demonstrating such challenges. PMID- 29476708 TI - Non-polarized cytokine profile of a long-term non-progressor HIV infected patient. AB - The HIV-1 initial viral infection may present diverse clinical and laboratory course and lead to rapid, intermediate, or long-term progression. Among the group of non-progressors, the elite controllers are those who control the infection most effectively, in the absence of antiretroviral therapy (ART). In this paper, the TH1, TH2 and TH17 cytokines profiles are described, as well as clinical and laboratory aspects of an HIV-infected patient with undetectable viral load without antiretroviral therapy. Production of IL-6, IL-10, TNF-alpha, IFN-gamma, and IL-17 was detected; in contrast IL-4 was identified. Host-related factors could help explain such a level of infection control, namely the differentiated modulation of the cellular immune response and a non-polarized cytokine response of the TH1 and TH2 profiles. PMID- 29476709 TI - A highly sensitive electrochemical sensor for the determination of methanol based on PdNPs@SBA-15-PrEn modified electrode. AB - In this study, a novel electrochemical sensor for the determination of methanol based on palladium nanoparticles supported on Santa barbara amorphous-15- PrNHEtNH2 (PdNPs@SBA-15-PrEn) as nanocatalysis platform is presented. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD) and electrochemical methods are employed to characterize the PdNPs@SBA-15-PrEn nanocomposite. The Nafion-Pd@SBA-15-PrEn modified glassy carbon electrode (Nafion-PdNPs@SBA-15-PrEn/GCE) displayed the high electrochemical activity and excellent catalytic characteristic for electro-oxidation of methanol in an alkaline solution. The electro-oxidation performance of the proposed sensor was investigated using cyclic voltammetry (CV) and amperometry. The sensor exhibits a good sensitivity of 0.0905 Amol-1 Lcm-2, linear range of 20-1000 MUM and the corresponding detection limit of 12 MUM (3sigma). The results demonstrate that the Nafion-PdNPs@SBA-15-PrEn/GCE has potential as an efficient and integrated sensor for methanol detection. PMID- 29476710 TI - COUNTERPOINT: Is ICD-10 Diagnosis Coding Important in the Era of Big Data? No. PMID- 29476711 TI - Rebuttal From Drs Liebovitz and Fahrenbach. PMID- 29476713 TI - Best Core Stabilization for Anticipatory Postural Adjustment and Falls in Hemiparetic Stroke. AB - OBJECTIVES: To compare the effects of conventional core stabilization and dynamic neuromuscular stabilization (DNS) on anticipatory postural adjustment (APA) time, balance performance, and fear of falls in chronic hemiparetic stroke. DESIGN: Two group randomized controlled trial with pretest-posttest design. SETTING: Hospital rehabilitation center. PARTICIPANTS: Adults with chronic hemiparetic stroke (N=28). INTERVENTIONS: Participants were randomly divided into either conventional core stabilization (n=14) or DNS (n=14) groups. Both groups received a total of 20 sessions of conventional core stabilization or DNS training for 30 minutes per session 5 times a week during the 4-week period. MAIN OUTCOME MEASURES: Electromyography was used to measure the APA time for bilateral external oblique (EO), transverse abdominis (TrA)/internal oblique (IO), and erector spinae (ES) activation during rapid shoulder flexion. Trunk Impairment Scale (TIS), Berg Balance Scale (BBS), and Falls Efficacy Scale (FES) were used to measure trunk movement control, balance performance, and fear of falling. RESULTS: Baseline APA times were delayed and fear of falling was moderately high in both the conventional core stabilization and DNS groups. After the interventions, the APA times for EO, TrA/IO, and ES were shorter in the DNS group than in the conventional core stabilization group (P<.008). The BBS and TIS scores (P<.008) and the FES score (P<.003) were improved compared with baseline in both groups, but FES remained stable through the 2-year follow-up period only in the DNS group (P<.003). CONCLUSIONS: This is the first clinical evidence highlighting the importance of core stabilization exercises for improving APA control, balance, and fear of falls in individuals with hemiparetic stroke. PMID- 29476714 TI - STAT3 contributes to lysosomal-mediated cell death in a novel derivative of riccardin D-treated breast cancer cells in association with TFEB. AB - RDD648, a novel derivative of a natural molecule riccardin D, exhibited potent anticancer activity by targeting lysosomes in vitro and in vivo. Mechanistic studies revealed that RDD648 facilitated STAT3 to translocate into the nucleus, and this activity was involved in lysosome-mediated cell death as evidenced by our finding that inhibition of STAT3 alleviated lysosomal membrane permeabilization. Further investigation indicated that nuclear STAT3 directly interacted with transcription factor TFEB, leading to the partial loss of function of TFEB, which is essential for lysosome turnover. The present study first uncovers that STAT3 contributes to lysosomal-mediated cell death in RDD648 treated breast cancer cells though interacting with TFEB, and the findings may be significant in the design of treatments for breast cancers where STAT3 is constitutively expressed. PMID- 29476715 TI - Reply. PMID- 29476712 TI - Progressive glomerular and tubular damage in sickle cell trait and sickle cell anemia mouse models. AB - Homozygosity for the hemoglobin (Hb) S mutation (HbSS, sickle cell anemia) results in hemoglobin polymerization under hypoxic conditions leading to vaso occlusion and hemolysis. Sickle cell anemia affects 1:500 African Americans and is a strong risk factor for kidney disease, although the mechanisms are not well understood. Heterozygous inheritance (HbAS; sickle cell trait) affects 1:10 African Americans and is associated with an increased risk for kidney disease in some reports. Using transgenic sickle mice, we investigated the histopathologic, ultrastructural, and gene expression differences with the HbS mutation. Consistent with progressive glomerular damage, we observed progressively greater urine protein concentrations (P = 0.03), glomerular hypertrophy (P = 0.002), and glomerular cellularity (P = 0.01) in HbAA, HbAS, and HbSS mice, respectively. Ultrastructural studies demonstrated progressive podocyte foot process effacement, glomerular basement membrane thickening with reduplication, and tubular villous atrophy with the HbS mutation. Gene expression studies highlighted the differential expression of several genes involved in prostaglandin metabolism (AKR1C18), heme and iron metabolism (HbA-A2, HMOX1, SCL25A37), electrolyte balance (SLC4A1, AQP6), immunity (RSAD2, C3, UBE2O), fatty acid metabolism (FASN), hypoxia hall-mark genes (GCK, SDC3, VEGFA, ETS1, CP, BCL2), as well as genes implicated in other forms of kidney disease (PODXL, ELMO1, FRMD3, MYH9, APOA1). Pathway analysis highlighted increased gene enrichment in focal adhesion, extracellular matrix-receptor interaction, and axon guidance pathways. In summary, using transgenic sickle mice, we observed that inheritance of the HbS mutation is associated with glomerular and tubular damage and identified several candidate genes and pathways for future investigation in sickle cell trait and sickle cell anemia-related kidney disease. PMID- 29476716 TI - Compressive Giant Left Atrium. PMID- 29476717 TI - Creation, Implementation, and Assessment of a General Thoracic Surgery Simulation Course in Rwanda. AB - BACKGROUND: The primary objective was to provide proof of concept of conducting thoracic surgical simulation in a low-middle income country. Secondary objectives were to accelerate general thoracic surgery skills acquisition by general surgery residents and sustain simulation surgery teaching through a website, simulation models, and teaching of local faculty. METHODS: Five training models were created for use in a low-middle income country setting and implemented during on-site courses with Rwandan general surgery residents. A website was created as a supplement to the on-site teaching. All participants completed a course knowledge assessment before and after the simulation and feedback/confidence surveys. Descriptive and univariate analyses were performed on participants' responses. RESULTS: Twenty-three participants completed the simulation course. Eight (35%) had previous training with the course models. All training levels were represented. Participants reported higher rates of meaningful confidence, defined as moderate to complete on a Likert scale, for all simulated thoracic procedures (p < 0.05). The overall mean knowledge assessment score improved from 42.5% presimulation to 78.6% postsimulation, (p < 0.0001). When stratified by procedure, the mean scores for each simulated procedure showed statistically significant improvement, except for ruptured diaphragm repair (p = 0.45). CONCLUSIONS: General thoracic surgery simulation provides a practical, inexpensive, and expedited learning experience in settings lacking experienced faculty and fellowship training opportunities. Resident feedback showed enhanced confidence and knowledge of thoracic procedures suggesting simulation surgery could be an effective tool in expanding the resident knowledge base and preparedness for performing clinically needed thoracic procedures. Repeated skills exposure remains a challenge for achieving sustainable progress. PMID- 29476718 TI - Assessing Predictive Ability of Biomarkers for Pediatric Acute Kidney Injury: Methodological Issues. PMID- 29476719 TI - Expression of CD9 and CD81 in bovine germinal vesicle oocytes after vitrification followed by in vitro maturation. AB - The present study aimed to investigate the effect of vitrification on the expression of fertilization related genes (CD9 and CD81) and DNA methyl transferases (DNMT1 and DNMT3b) in bovine germinal vesicle (GV) oocytes and their resulting metaphase II (MII) stages after in vitro maturation culture. GV oocytes were vitrified using the open-pulled straw method; after warming, they were cultured in vitro. The vitrified-warmed GV oocytes and more developed MII oocytes were used to calculate the maturation rates (first polar body extrusion under a stereomicroscopy), and to detect mRNA expression (qRT-PCR). Fresh GV oocytes and their in vitro-derived MII oocytes served as controls. The results showed that both the maturation rate (54.23% vs. 42.93%) and the relative abundance of CD9 mRNA decreased significantly (p < 0.05) in bovine GV oocytes after vitrification, but the expression of CD81 and DNMT3b increased significantly. After in vitro maturation of vitrified GV oocytes, the resulting MII oocytes showed lower (p < 0.05) mRNA expression of genes (CD9, CD81, DNMT1 and DNMT3b) when compared to the control group (MII oocytes). Altogether, vitrification decreased the maturation rate of bovine GV oocytes and changed the expression of fertilization related genes and DNA methyl transferases during in vitro maturation. PMID- 29476720 TI - A luciferase immunoprecipitation assay for the detection of proinsulin/insulin autoantibodies. AB - AIM: Luciferase immunoprecipitation (LIPS) assays show good sensitivity and specificity in testing islet specific autoantibodies for diagnosis of type 1 diabetes (T1D). However, there are currently no LIPS assays available for detecting proinsulin/insulin autoantibody (IAA) previously. We here developed a LIPS assay to measure IAA using nano luciferase (NanoLuc)-proinsulin fusion protein. METHODS: The NanoLuc-proinsulin fusion protein expression plasmid was constructed and transfected to COS1 cells. Expression and binding specificity to IAA of the fusion protein were validated. A LIPS assay using the NL-proinsulin fusion protein was developed and compared to radioimmunoassay (RIPA) in testing sera from 50 healthy controls and 34 T1D patients. RESULTS: The fusion protein was correctly expressed in transfected COS1 cells. Both NANOLUC activity and proinsulin were detected in the medium of transfected COS1 cells. Fusion protein bound to monoclonal anti insulin antibody and sera from T1D patients or NOD mice, these bindings were inhibited by recombinant human insulin. The LIPS assay using the fusion protein showed sensitivity of 47.1% and specificity of 98.0%. Further analysis supported correlation between the IAA indexes of all the T1D samples detected by LIPS assay and radioimmunoassay (RIPA, R2 = 0.6132, p < 0.0001). CONCLUSIONS: The NanoLuc-proinsulin fusion protein based LIPS has the potential to detect IAA for diagnosis of T1D. PMID- 29476721 TI - C3-epimerization of 25-hydroxyvitamin D increases with increasing serum 25 hydroxyvitamin D levels and shows a high degree of tracking over time. AB - OBJECTIVE: Evaluate the effects of serum 25-hydroxyvitamin D (25(OH)D) levels, vitamin D binding protein (DBP) and genetic factors on C3-epimerization of 25(OH)D and follow the tracking of the epimer during one year. DESIGN: Cross sectional and longitudinal study. METHODS: Data from eight previously conducted, Tromso based studies (3 observational, 5 randomized controlled trials) were combined. 25(OH)D serum samples were re-analyzed with a LC-MS/MS method that also resolves and measures the metabolite C3-epi-25(OH)D3. Data on vitamin D binding protein (DBP) phenotype (based on single nucleotide polymorphisms (SNPs) rs4588 and rs7041) and genetic determinants for serum 25(OH)D (SNPs rs2282679, rs10741657, rs3829251 and rs6013897) were collected where available. RESULTS: 2219 subjects were included. Median (5th, 95th percentiles) baseline serum values of 25(OH)D3, C3-epi-25(OH)D3, and %-C3-epi-25(OH)D3 were 49.1 (22.1, 92.8) nmol/L, 2.3 (0.9, 6.0) nmol/L and 4.4 (2.7, 8.4) %, respectively. The highest baseline values were 230.5 nmol/L for 25(OH)D3, 79.7 nmol/L for C3-epi-25(OH)D3 and 48.2% for %-C3-epi-25(OH)D3. There was a strong correlation between serum 25(OH)D3 and C3-epi-25(OH)D3. The %-C3-epi-25(OH)D3 value increased with increasing serum 25(OH)D3, but leveled off at ~7% at a 25(OH)D3 concentration of ~120-140 nmol/L. There was a significant degree of tracking for %-C3-epi-25(OH)D3 (correlation coefficient rho between baseline and 1-year values 0.39, P < 0.001). The %-C3-epi-25(OH)D3 level was not related to serum DBP level, DBP phenotype nor to SNPs related to serum 25(OH)D3 level. The serum 25(OH)D3 level could explain less than 3% of %-C3-epi-25(OH)D3 variation. CONCLUSIONS: There are considerable individual and reproducible differences in percent C3-epimerization of uncertain clinical importance. PMID- 29476722 TI - miR-51 regulates GABAergic synapses by targeting Rab GEF GLO-4 and lysosomal trafficking-related GLO/AP-3 pathway in Caenorhabditis elegans. AB - A deficit of GABA (gamma-aminobutyric acid) transmission will lead to epilepsy and other cognitive disorders. Recent evidence has shown that neuronal miRNAs affect various synapses, including GABAergic synapses. However, the miRNAs that control GABAergic synapses remain not fully understood. Here, we identified miR 51, a member of Caenorhabditis elegans miR-99/100 family, as a key regulator of GABAergic synapses. Loss of mir-51 increased PTZ (Pentylenetetrazole) and aldicarb hypersensitivities, and decreased the number of GABAergic synapses and abundance of GABAA receptors. A Rab guaninenucleotide exchange factor (GEF) GLO 4, a well-known component in lysosomal trafficking-related GLO-4/GLO-1/AP-3 (GLO/AP-3) pathway, was discovered to be the direct target of miR-51. Rescue experiments showed that GLO-4 expressed in GABAergic motor neurons functioned as a suppressor of miR-51. Disruption of glo-1 or AP-3 gene apm-3 attenuated the defects of GABAergic synapse in mir-51 mutants, suggesting miR-51 regulated GABAergic synapses through GLO/AP-3 pathway. The present study implies the essential roles of miRNAs on the nervous pathologies characterized by mis regulated GABA signaling, such as epilepsy. PMID- 29476723 TI - Notum balances Wnt signaling during tracheal cartilage development. PMID- 29476724 TI - A Conserved Distal Lung Regenerative Pathway in Acute Lung Injury. AB - Improved tools have led to a burgeoning understanding of lung regeneration in mice, but it is not yet known how these insights may be relevant to acute lung injury in humans. We report in detail two cases of fulminant idiopathic acute lung injury requiring extracorporeal membrane oxygenation in previously healthy young adults with acute respiratory distress syndrome, one of whom required lung transplantation. Biopsy specimens showed diffuse alveolar injury with a striking paucity of alveolar epithelial regeneration, rare hyaline membranes, and diffuse contiguous airspace lining by macrophages. This novel constellation was termed diffuse alveolar injury with delayed epithelization. In addition, mirroring data from murine models of lung injury/regeneration, peribronchiolar basaloid pods (previously described as squamous metaplasia) and ciliated bronchiolarization were identified in these patients and in 39% of 57 historical cases with diffuse alveolar damage. These findings demonstrate a common and clinically relevant human disease correlate for murine models of severe acute lung injury. Evidence suggests that peribronchiolar basaloid pods and bronchiolarization are related spatially and temporally and likely represent overlapping sequential stages of the response to severe distal airway injury. PMID- 29476725 TI - The Effect of Botulinum Toxin Augmentation on Strabismus Surgery for Large-Angle Infantile Esotropia. AB - PURPOSE: To determine whether botulinum toxin augments the effect of strabismus surgery in pediatric patients with large-angle infantile esotropia. DESIGN: Retrospective, comparative, case series. METHODS: Setting: Tertiary-care pediatric hospital. STUDY POPULATION: Patients with large-angle infantile esotropia. INTERVENTION: Treatment with botulinum toxin-augmented bilateral medial rectus muscle recessions ("augmented-surgery group") or traditional bilateral medial rectus muscle recessions ("surgery-only group"). MAIN OUTCOME MEASURE: The effect of surgery on ocular alignment at 4 months, measured in prism diopters of change per mm of surgery (PD/mm). RESULTS: There were 14 patients in the augmented-surgery group and 16 patients in the surgery-only group. The mean effect on alignment was significantly greater in the augmented-surgery group compared to the surgery-only group at 4 months (5.7 +/- 1.3 vs 4.0 +/- 1.4 PD/mm, P = .002) and at 1 year (5.4 +/- 1.2 vs 3.7 +/- 1.2 PD/mm, P = .002). There was a partial loss of treatment effect between 4 months and 1 year in both groups, which was similar in magnitude (P = .57). On linear regression, there was a trend toward a positive correlation between botulinum toxin dose and treatment effect, but this was not statistically significant (P = .09). CONCLUSIONS: Botulinum toxin augments the surgical effect of medial rectus muscle recession. Botulinum toxin-augmented surgery may be an alternative to traditional options for large angle infantile esotropia. A surgical dosing table is proposed for this technique. PMID- 29476726 TI - Spatio-temporal distribution of mosquitoes and risk of malaria infection in Rwanda. AB - To date, the Republic of Rwanda has not systematically reported on distribution, diversity and malaria infectivity rate of mosquito species throughout the country. Therefore, we assessed the spatial and temporal variation of mosquitoes in the domestic environment, as well as the nocturnal biting behavior and infection patterns of the main malaria vectors in Rwanda. For this purpose, mosquitoes were collected monthly from 2010 to 2013 by human landing catches (HLC) and pyrethrum spray collections (PSC) in seven sentinel sites. Mosquitoes were identified using morphological characteristics and PCR. Plasmodium falciparum sporozoite infection rates were determined using ELISA. A total of 340,684 mosquitoes was collected by HLC and 73.8% were morphologically identified as culicines and 26.2% as anophelines. Of the latter, 94.3% were Anopheles gambiae s.l., 0.4% Anopheles funestus and 5.3% other Anopheles species. Of An. gambiae s.l., An. arabiensis and An. gambiae s.s. represented 84.4% and 15.6%, respectively. Of all An. gambiae s.l. collected indoor and outdoor, the proportion collected indoors was 51.3% in 2010 and 44.9% in 2013. A total of 17,022 mosquitoes was collected by PSC of which 20.5% were An. gambiae s.l. and 79.5% were culicines. For the seven sentinel sites, the mean indoor density for An. gambiae s.l. varied from 0.0 to 1.0 mosquitoes/house/night. P. falciparum infection rates in mosquitoes varied from 0.87 to 4.06%. The entomological inoculation rate (EIR) ranged from 1.0 to 329.8 with an annual average of 99.5 infective bites/person/year. This longitudinal study shows, for the first time, the abundance, species composition, and entomological inoculation rate of malaria mosquitoes collected throughout Rwanda. PMID- 29476727 TI - Molecular diagnosis of Trypanosoma cruzi. AB - Chagas disease, caused by the kinetoplastid protozoan Trypanosoma cruzi, affects millions of people, most of them neglected populations. The different phases of the disease, the transmission mode and the high genetic variability of the parasite determine that molecular detection methods display different degree of success. Molecular diagnostic tests may be employed during epidemiological surveys of transmission, for early diagnosis of congenital transmission and acute infections due to oral transmission, transfusion or transplantation routes, reactivation due to immunosuppression and monitoring of treatment response in chronically infected patients receiving trypanocidal chemotherapy. This manuscript summarizes the most widely used molecular tools to detect T. cruzi infection in different epidemiological and clinical scenarios. PMID- 29476728 TI - Melatonin attenuates scopolamine-induced cognitive impairment via protecting against demyelination through BDNF-TrkB signaling in the mouse dentate gyrus. AB - Animal models of scopolamine-induced amnesia are widely used to study underlying mechanisms and treatment of cognitive impairment in neurodegenerative diseases such as Alzheimer's disease (AD). Previous studies have identified that melatonin improves cognitive dysfunction in animal models. In this study, using a mouse model of scopolamine-induced amnesia, we assessed spatial and short-term memory functions for 4 weeks, investigated the expression of myelin-basic protein (MBP) in the dentate gyrus, and examined whether melatonin and scopolamine cotreatment could keep cognitive function and MBP expression. In addition, to study functions of melatonin for keeping cognitive function and MBP expression, we examined expressions of brain-derived neurotrophic factor (BDNF) and tropomycin receptor kinase B (TrkB) in the mouse dentate gyrus. Scopolamine (1 mg/kg) and melatonin (10 mg/kg) were intraperitoneally treated for 2 and 4 weeks. Two and 4 weeks after scopolamine treatment, mice showed significant cognitive impairment; however, melatonin and scopolamine cotreatment recovered cognitive impairment. Two and 4 weeks of scopolamine treatment, the density of MBP immunoreactive myelinated nerve fibers was significantly decreased in the dentate gyrus; however, scopolamine and melatonin cotreatment significantly increased the scopolamine-induced reduction of MBP expression in the dentate gyrus. Furthermore, the cotreatment of scopolamine and melatonin significantly increased the scopolamine-induced decrease of BDNF and TrKB immunoreactivity in the dentate gyrus. Taken together, our results indicate that melatonin treatment exerts anti amnesic effect and restores the scopolamine-induced reduction of MBP expression through increasing BDNF and TrkB expressions in the mouse dentate gyrus. PMID- 29476729 TI - Synthesis, spectroscopic, physicochemical and structural characterization of tetrandrine-based macrocycles functionalized with acridine and anthracene groups: DNA binding and anti-proliferative activity. AB - In this work, we report on the synthesis of two new mono-alkylated tetrandrine derivatives with acridine and anthracene units, MAcT and MAnT. The compounds were fully characterized by physicochemical techniques and single-crystal X-ray diffraction analysis. In addition, both derivatives were studied as nucleotide receptors and double-stranded DNA binders in aqueous phosphate buffer at pH = 7.2 using UV-vis and fluorescence spectroscopy. According to the molecular recognition studies, MAcT and MAnT exhibit high affinity (K ~ 105 M-1) and selectivity for ds-DNA, presumably in an intercalation mode. Finally, the anti proliferative effects of the tetrandrine derivatives on different cancer cell lines were explored, revealing promising activities. Particularly, the mono anthracene tetrandrine derivative MAnT showed an IC50 of 2.74 MUg/mL on the HeLa cervical cancer cell line, representing a value 3.3 times smaller than that obtained for unsubstituted tetrandrine. Examination of the cytotoxic effects on the HeLa cell line by inverted microscopy suggests that the cell death mechanism consists basically in apoptosis. The molecular modelling of three ds-DNA-MAcT complexes, suggested that the macrocycles may use an intercalation binding mode towards DNA. MAcT is predicted to bind into the major groove of the ds-DNA providing non-covalent interactions such as electrostatic, van der Waals and hydrophobic interactions that lead to selectivity. Overall experimental data supports the mode of action of MAnT and MAcT as cytotoxic compounds against cancer cell lines via a DNA interaction mechanism. PMID- 29476730 TI - Oroxylin A prevents alcohol-induced hepatic steatosis through inhibition of hypoxia inducible factor 1alpha. AB - Accumulating data reveal that oroxylin A has beneficial effects against chronic liver disease. The previously studies showed oroxylin A, a flavonoid extracted from Scutellariae radix, improved acute liver injury and accelerated liver regeneration in vivo. However, it's unclear that the effect of oroxylin A on alcoholic liver disease. The present study was aimed at elucidating the effect of oroxylin A on alcohol-induced hepatic steatosis and the underlying mechanisms. Human hepatocyte LO2 were cultured and stimulated with ethanol for inducing LO2 damage. We examined the effects of oroxylin A on the accumulation of lipid droplets in ethanol-treated LO2. The results showed that oroxylin A reduced the accumulation of lipid droplets associated with regulating the lipid metabolism genes. Moreover, oroxylin A significantly suppressed the nuclear translocation of HIF-1alpha in ethanol-treated LO2. Furthermore, activation of HIF-1alpha significantly attenuated the effect of oroxylin A on lipid droplets accumulation and genes related to lipid metabolism in vitro and in vivo. Altogether, we demonstrated a HIF-1alpha-associated mechanism underlying oroxylin A inhibition of lipid deposition in ethanol-stimulated LO2. Oroxylin A modulation of HIF 1alpha level may represent a therapeutic remedy for ALD. PMID- 29476732 TI - Evaluating the diagnostic value of rescaled beta-trace protein in combination with serum creatinine and serum cystatin C in older adults. AB - BACKGROUND: Beta trace protein (BTP) is a novel renal biomarker that has emerged as potential alternative or addition to serum creatinine (Scr) and serum cystatin C (ScysC). We analyzed BTP's diagnostic ability to detect impaired kidney function by rescaling it and we tested whether rescaling BTP allowed us to expand the Full-Age-Spectrum (FAS)-equation to BTP. METHODS: 566 participants aged >=70 years with measured glomerular filtration rate (mGFR), Scr, ScysC and BTP from the population-based Berlin Initiative Study (BIS) were considered. We developed a single and combined FAS-equation using rescaled BTP (BTP/0.60) and calculated its sensitivity (S) and specificity (Sp) to identify kidney disease using a fixed (60 mL/min/1.73 m2) and age-dependent threshold for mGFR. RESULTS: Rescaled BTP shared the same reference interval with rescaled Scr and ScysC and showed acceptable diagnostic performance (S = 73.1%, Sp = 86.5%), comparable to Scr (S = 71.0%, Sp = 90.5%) and ScysC (S = 80.7%, Sp = 92.9%). Rescaled BTP can be used in the FAS-equation with comparable performance as Scr and ScysC, but the Scr/ScysC/BTP-combined FAS-eq. (P10 = 57.8%, P30 = 96.6%) did not outperform the Scr/ScysC-combined FAS-eq. (P10 = 57.1%, P30 = 96.3%). CONCLUSIONS: Rescaled BTP is a valid alternative to Scr or ScysC to diagnose kidney function. The FAS concept can be applied to BTP or the combination of BTP, Scr and ScysC. PMID- 29476731 TI - Metabolic causes of nonimmune hydrops fetalis: A next-generation sequencing panel as a first-line investigation. AB - PURPOSES: Hydrops fetalis is a life-threatening fetal condition, and 85% of all cases are classified as nonimmune hydrops fetalis (NIHF). Up to 15% of NIHF cases may be due to inborn errors of metabolism (IEM), but a large proportion of cases linked to metabolic disorders remains undiagnosed. This lack of diagnosis may be related to the limitations of conventional biological procedures, which involve sequential investigations and require multiple samples and steps. In addition, this approach is time consuming. We have developed a next-generation sequencing (NGS) panel to investigate metabolic causes of NIHF, ascites, and polyhydramnios associated to another fetal abnormality. METHODS: The hydrops fetalis (HydFet) panel was designed to cover the coding regions and flanking intronic sequences of 41 genes. A retrospective study of amniotic fluid samples from 40 subjects was conducted. A prospective study was subsequently initiated, and six samples were analyzed using the NGS panel. RESULTS: Five IEM diagnoses were made using the HydFet panel (Niemann-Pick type C (NPC), Barth syndrome, HNF1Beta deficiency, GM1 gangliosidosis, and Gaucher disease). This analysis also allowed the identification of 8p sequence triplication in an additional case. CONCLUSION: NGS combined with robust bioinformatics analyses is a useful tool for identifying the causative variants of NIHF. Subsequent functional characterization of the protein encoded by the altered gene and morphological studies may confirm the diagnosis. This paradigm shift allows a significant improvement of IEM diagnosis in NIHF. PMID- 29476733 TI - Impact of C-reactive protein on long-term mortality in acute myocardial infarction patients with diabetes and those without. AB - BACKGROUND: Little is known about the relationship between C-reactive protein (CRP) and long-term mortality after acute myocardial infarction (AMI) in diabetic patients. The current study aimed to examine whether CRP levels are associated with for long-term all-cause, cardiovascular, and cardiac mortality in AMI patients with diabetes and those without separately. METHODS: The cohort study included 663 diabetic and 1853 non-diabetic patients with AMI. The median follow up time was 1045 days (2.9 years). RESULTS: According to the median concentration of serum CRP (8.95 mg/l), the patients were divided into two groups. The low CRP level group (<8.95 mg/l) served as a reference. In diabetic patients with AMI, the adjusted hazard ratios (HRs) for long-term all-cause, cardiovascular, and cardiac mortality were 1.62 (P = 0.027), 1.91 (P = 0.008), and 2.08 (P = 0.007), respectively. In non-diabetic patients with AMI, the adjusted hazard ratios (HRs) for long-term all-cause, cardiovascular, and cardiac mortality were 1.72 (P < 0.001), 1.8 (P < 0.001), and 1.78 (P = 0.001), respectively. CONCLUSIONS: Regardless of whether patients had diabetes or not, CRP value is an independent predictor of long-term, all-cause, cardiovascular, and cardiac mortality after AMI. PMID- 29476734 TI - Bioactive leptin is stronger related to parameters of fat mass and distribution than conventionally measured leptin: Findings from a longitudinal study in obese children participating in a lifestyle intervention. AB - OBJECTIVE: This study analyzed the relationships between bioactive leptin, conventionally measured leptin, and parameters of fat mass and distribution in obese children before and after weight reduction. METHODS: We determined bioactive leptin (bioLep), conventional measured leptin (conLep), weight, height, body fat based on skinfold measurements and bioimpedance analyses, waist circumference (wc), and pubertal stage in 88 obese children participating in a lifestyle intervention at baseline and one year later. RESULTS: We identified no child with homozygous or heterozygous status for bioinactive leptin mutations. The baseline associations between bioLep and BMI (r = 0.53), BMI-SDS (r = 0.48), body fat (bioimpedance: r = 0.61, skinfold thickness: r = 0.49), wc (r = 0.42), and waist to height ratio (whr) (r = 0.39) were stronger than the associations between conLep and BMI (r = 0.50), BMI-SDS (r = 0.44), body fat (bioimpedance: r = 0.57, skinfold thickness: r = 0.41), wc (r = 0.41), and whr (r = 0.37). The changes of bioLep were stronger related to changes of BMI-SDS (r = 0.54), body fat (bioimpedance r = 0.59, skinfold thickness: r = 0.37), wc (r = 0.22), and whr (r = 0.21) than the associations between changes of conLep and changes of BMI-SDS (r = 0.48), body fat (bioimpedance: r = 0.56, skinfold thickness: r = 0.43), wc (r = 0.20), and whr (r = 0.20). The same findings were observed in multiple linear regression analyses adjusted to multiple confounders. In contrast to changes of conLep (r = 0.22), the changes of bioLep during intervention were not related to weight regain after the end of intervention. BioLep concentrations did not differ between prepubertal girls and boys, but were higher in pubertal girls compared to pubertal boys (p = 0.031). CONCLUSIONS: Bioactive leptin was stronger related to fat mass and distribution compared to conventionally measured leptin. PMID- 29476735 TI - Functional and pharmacological evaluation of novel GLA variants in Fabry disease identifies six (two de novo) causative mutations and two amenable variants to the chaperone DGJ. AB - BACKGROUND: Allelic heterogeneity is an important feature of the GLA gene for which almost 900 known genetic variants have been discovered so far. Pathogenetic GLA variants cause alpha-galactosidase A (alpha-Gal A) enzyme deficiency leading to the X-linked lysosomal storage disorder Fabry disease (FD). Benign GLA intronic and exonic variants (e.g. pseudodeficient p.Asp313Tyr) have also been described. Some GLA missense variants, previously deemed to be pathogenetic (e.g. p.Glu66Gln and p.Arg118Cys), they have been reclassified as benign after re evaluation by functional and population studies. Hence, the functional role of novel GLA variants should be investigated to assess their clinical relevance. RESULTS: We identified six GLA variants in 4 males and 2 females who exhibited symptoms of FD: c.159C>G p.(Asn53Lys), c.400T>C p.(Tyr134His), c.680G>C (p.Arg227Pro), c.815A>T p.(Asn272Ile), c.907A>T p.(Ile303Phe) and c.1163_1165delTCC (p.Leu388del). We evaluated their impact on the alpha-Gal A protein by bioinformatic analysis and homology modelling, by analysis of the GLA mRNA, and by site-directed mutagenesis and in vitro expression studies. We also measured their responsiveness to the pharmacological chaperone DGJ. CONCLUSIONS: The six detected GLA variants cause deficient alpha-Gal A activity and impairment or loss of the protein wild-type structure. We found p.Asn53Lys and p.Ile303Phe variants to be susceptible to DGJ. PMID- 29476736 TI - Single and combined use of neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and carcinoembryonic antigen in diagnosing gastric cancer. AB - To investigate the value of neutrophil-lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR) and carcinoembryonic antigen (CEA), alone or in combination, in diagnosing gastric cancer (GC), we retrospectively analyzed a cohort of 201 patients with GC, 161 patients with benign gastric lesions, and 157 healthy subjects. We obtained routine blood indices and CEA levels to evaluate the diagnostic value of NLR, PLR and CEA for GC, based on receiver operating characteristic (ROC) curves. We found that serum NLR, PLR and CEA in the GC group were significantly higher than those in the benign lesion group (PNLR < 0.001,PPLR < 0.001,PCEA = 0.034) or the healthy control group (PNLR < 0.001,PPLR < 0.001,PCEA = 0.028). Moreover, there were significant differences in NLR and PLR among different serosa invasion, lymph node metastasis, tumor size and stage. CEA showed a difference in distant metastasis and tumor size. Combining PLR with CEA produced a larger AUC (AUC: 0.780, 95% CI: 0.734-0.822) than using PLR (P = 0.011) or CEA (P < 0.001) alone. Similarly, NLR + CEA produced a larger AUC (AUC: 0.756, 95% CI:0.709-0.800) than using NLR (P = 0.004) or CEA (P = 0.001) alone. Whereas NLR, PLR and CEA are known to help distinguish GC from benign gastric lesions, combining CEA with PLR or NLR offers better diagnostic value for GC than any of them used alone. PMID- 29476737 TI - Serum levels of IL-17 are elevated in patients with acute gouty arthritis. AB - Acute gouty arthritis (AGA) is one of the most common forms of auto-inflammatory arthritis. IL-17 is a key proinflammatory cytokine which has been implicated in several autoimmune diseases. However, to date little is known about the role of IL-17 in AGA. In the present study, we show that serum IL-17 levels are significantly elevated in AGA patients early in the onset of symptoms of gout, and decrease gradually as symptoms diminish. Correlation analysis indicated that IL-17 expression is not only positively correlated with disease activity, but is also correlated with serum levels of IL-1beta which plays a critical role in the differentiation of IL-17- gammadeltaT cells into IL-17+gammadeltaT cells. Flow cytometry analysis indicated that gammadelta T cells are a major source of IL-17 production during the early onset of AGA. We therefore identify IL-17 as a potential novel biomarker for AGA and suggest that targeting the gammadelta T cell/IL-17 immune axis is a potential strategy for treatment of acute flares of AGA. PMID- 29476738 TI - Identification of a non-competitive inhibitor of Plasmodium falciparum aspartate transcarbamoylase. AB - Aspartate transcarbamoylase catalyzes the second step of de-novo pyrimidine biosynthesis. As malarial parasites lack pyrimidine salvage machinery and rely on de-novo production for growth and proliferation, this pathway is a target for drug discovery. Previously, an apo crystal structure of aspartate transcarbamoylase from Plasmodium falciparum (PfATC) in its T-state has been reported. Here we present crystal structures of PfATC in the liganded R-state as well as in complex with the novel inhibitor, 2,3-napthalenediol, identified by high-throughput screening. Our data shows that 2,3-napthalediol binds in close proximity to the active site, implying an allosteric mechanism of inhibition. Furthermore, we report biophysical characterization of 2,3-napthalenediol. These data provide a promising starting point for structure based drug design targeting PfATC and malarial de-novo pyrimidine biosynthesis. PMID- 29476739 TI - IL-17A regulates the autophagic activity of osteoclast precursors through RANKL JNK1 signaling during osteoclastogenesis in vitro. AB - Interleukin-17A(IL-17A), a proinflammatory cytokine, may have effects on osteoclastic resorption in inflammation-mediated bone loss, including postmenopausal osteoporosis. IL-17A could alter autophagic activity among other tissues and cells, thereby causing corresponding lesions. The aim of this study was to clarify how IL-17A influenced osteoclastogenesis by regulating autophagy. The present study showed that IL-17A could facilitate osteoclast precursors (OCPs) autophagy and osteoclastogenesis at a low concentration. Furthermore, suppression of autophagy with chloroquine (CQ) or 3-MA could significantly attenuate the enhanced osteoclastogenesis by a low level of IL-17A. It was also found that a low level of IL-17A couldn't up-regulate OCPs autophagy after removal of RANKL(Receptor Activator for Nuclear Factor-kappaB Ligand), and JNK(c Jun N-terminal kinase) inhibitor only inhibited autophagy at a low level of IL 17A. These results suggest that a low concentration of IL-17A is likely to promote autophagic activity via activating RANKL-JNK pathway during osteoclastogenesis. PMID- 29476740 TI - A selective c-Fos/AP-1 inhibitor prevents cartilage destruction and subsequent osteophyte formation. AB - The objective of the present study is to demonstrate that a newly developed selective c-Fos/activator protein (AP)-1 inhibitor, T-5224, inhibits the expression of matrix metalloproteinases (MMPs) in human articular chondrocytes, and prevents cartilage destruction in an osteoarthritis (OA)-induced mouse model. First, we examined the effect of T-5224 on MMP and inflammatory cytokine expression by real-time polymerase chain reaction in human articular chondrocytes. We created an OA model by destabilization of the medial meniscus (DMM) in mice. T-5224 was orally administered once a day and the OA pathology was assessed by histological, immunohistochemical, and micro-computed tomography (CT) analyses. T-5224 inhibited the mRNA expression levels of MMP-1, 3, and 13, and interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha and IL-6 in IL-1 stimulated human chondrocytes. Oral administration of T-5224 to OA-induced mice prevented cartilage destruction. The histological scores for OA were significantly better in the T-5224-treated group than the vehicle-treated group. Type X collagen and MMP-13 were not increased in the T-5224-treated group by immunohistochemical staining. Micro-CT analysis showed mild but apparent osteophyte development in the femoral condyle and antero-medial aspect of the tibia in the vehicle-treated group but not in the T-5224-treated group. Taken together, specific inhibition of c-Fos/AP-1 and the resulting inhibition of the transactivation of a broad spectrum of downstream MMPs, along with inflammatory cytokines, effectively prevented cartilage destruction and osteophyte formation. PMID- 29476741 TI - Exosomes from C2C12 myoblasts enhance osteogenic differentiation of MC3T3-E1 pre osteoblasts by delivering miR-27a-3p. AB - Many regulators have been identified to participate in the cross-talk between muscle and bone, however, most previous studies focus on secreting proteins. In this study, we demonstrated that exosomes from myoblasts C2C12 can promote pre osteoblasts MC3T3-E1 differentiation to osteoblasts. We revealed that the effect of C2C12 exosomes depended on its miR-27a-3p component, they can increase miR-27a 3p level in the recipient cells, and decrease its direct target adenomatous polyposis coli (APC) expression, thus activating beta-catenin pathway. Furthermore, C2C12 exosomes failed to exert above effects when miR-27a-3p was deprived. These findings indicates exosomal microRNAs can be regarded as a novel type of "myokines" with osteogenesis promoting potential, which would broad our understanding of the muscle-bone interaction under physiological and pathological conditions. PMID- 29476743 TI - Koplik's Spots and Measles. PMID- 29476742 TI - Celastrol mediates Th17 and Treg cell generation via metabolic signaling. AB - A T helper 17 (Th17) cell/regulatory T (Treg) cell imbalance is involved in many immune disorders and diseases. Celastrol, a Chinese herbal compound that has anti inflammatory and immunosuppressive properties, has been indicated to suppress T cell proliferation and Th17 cell induction, while facilitating Forkhead box P3 (Foxp3) expression and Treg cell generation. In this study, we explored the impact and mechanism of celastrol on Th17 cell/induced Treg (iTreg) cell induction. CD4+CD25- T cells were purified, stimulated with anti-CD3 and anti CD28 antibodies, and polarized in vitro to generate Th17 or iTreg cells in the presence or absence of celastrol. Initially, we determined that Interleukin (IL) 17 expression by celastrol-treated Th17 was significantly decreased compared with untreated cells; however, the frequency of Foxp3+ cells was increased in celastrol-treated cells. We verified that celastrol inhibited phospho-STAT3 expression in cultured Th17 cells and up-regulated phospho-STAT5 expression in iTreg cells. Furthermore, T cells treated with celastrol were more likely to participate in FAO metabolism instead of glycolysis. Celastrol suppressed the expression of glucose transporter, Glut1, and the rate-limiting enzyme, HK2, in addition to mTOR, HIF-1alpha, c-Myc and Akt expression in Th17 cells. Conversely, celastrol promoted FAO of lipids by up-regulating CPT1A and AMPKalpha expression in iTreg cells. Our results suggest that celastrol suppresses Th17 cell induction, while promoting the generation of iTreg cells. We found that celastrol inhibits glycolysis in Th17 cells and promotes FAO by iTreg cells, suggesting that celastrol could mediate the metabolism of Th17 and iTreg cells. PMID- 29476744 TI - Rivaroxaban Versus Warfarin and Risk of Post-Thrombotic Syndrome Among Patients with Venous Thromboembolism. AB - BACKGROUND: The effectiveness of rivaroxaban to reduce post-thrombotic syndrome in patients with venous thromboembolism is largely unknown. We compared rates of post-thrombotic syndrome in patients given rivaroxaban versus warfarin in a cohort of patients with incident venous thromboembolism receiving routine clinical care. METHODS: We linked Danish nationwide registries to identify all patients with incident venous thromboembolism who were new users of rivaroxaban or warfarin and compared rates of post-thrombotic syndrome using an inverse probability of treatment-weighting approach to account for baseline confounding. RESULTS: We identified 19,957 oral anticoagulation-naive patients with incident venous thromboembolism treated with warfarin or rivaroxaban (mean age, 64 years; 48% were female, 45.5% had pulmonary embolism). The propensity-weighted rate of post-thrombotic syndrome at 3 years follow-up was 0.53 incidents per 100 person years with rivaroxaban versus 0.55 per 100 person-years with warfarin, yielding a hazard rate of 0.88 (95% confidence interval, 0.66-1.17). This association remained consistent across types of venous thromboembolism (deep venous thrombosis vs pulmonary embolism, and provoked vs unprovoked venous thromboembolism) and when censoring patients with recurrent venous thromboembolism. CONCLUSIONS: In this clinical practice setting, rivaroxaban was associated with lower but statistically nonsignificant rates of post-thrombotic syndrome, which did not appear to be mediated only by an effect on recurrent venous thromboembolism. PMID- 29476745 TI - Atypical Cause of Functional Decline in Parkinson's Disease. PMID- 29476746 TI - Polymyalgia Rheumatica with Normal Inflammatory Markers. PMID- 29476747 TI - House Calls. PMID- 29476748 TI - Preventing Postoperative Atrial Fibrillation After Noncardiac Surgery: A Meta analysis. AB - BACKGROUND: Although postoperative atrial fibrillation is common after noncardiac surgery, there is a paucity of data regarding prophylaxis. We sought to determine whether pharmacologic prophylaxis reduces the incidence of postoperative atrial fibrillation after noncardiac surgery. METHODS: We performed an electronic search of Ovid MEDLINE, the Cochrane central register of controlled trials database, and SCOPUS from inception to September 7, 2016 and included prospective randomized studies in which patients in sinus rhythm underwent noncardiac surgery and examined the incidence of postoperative atrial fibrillation as well as secondary safety outcomes. RESULTS: Twenty-one studies including 11,608 patients were included. Types of surgery included vascular surgery (3465 patients), thoracic surgery (2757 patients), general surgery (2292 patients), orthopedic surgery (1756 patients), and other surgery (1338 patients). Beta-blockers (relative risk [RR] 0.32; 95% confidence interval [CI], 0.11-0.87), amiodarone (RR 0.42; 95% CI, 0.26 to 0.67), and statins (RR 0.43; 95% CI, 0.27 to 0.68) reduced postoperative atrial fibrillation compared with placebo or active controls. Calcium channel blockers (RR 0.55; 95% CI, 0.30 to 1.01), digoxin (RR 1.62; 95% CI, 0.95 to 2.76), and magnesium (RR 0.73; 95% CI, 0.23 to 2.33) had no statistically significant effect on postoperative atrial fibrillation incidence. The incidence of adverse events was comparable across agents, except for increased mortality (RR 1.33; 95% CI, 1.03 to 1.37) and bradycardia (RR 2.74; 95% CI, 2.19 to 3.43) in patients receiving beta-blockers. CONCLUSIONS: Pharmacologic prophylaxis with amiodarone, beta-blockers, or statins reduces the incidence of postoperative atrial fibrillation after noncardiac surgery. Amiodarone and statins have a relatively low overall risk of short-term adverse events. PMID- 29476749 TI - Ghrelin acts centrally to induce an antinociceptive action during colonic distension through the orexinergic, dopaminergic and opioid systems in conscious rats. AB - Increasing evidence implicates brain ghrelin in a wide variety of physiological functions. Among its gastrointestinal functions, ghrelin is known to act centrally to regulate gastrointestinal motility. Visceral sensation is one of the key gastrointestinal functions controlled by the central nervous system. Little is, however, known about the role of central ghrelin in visceral sensation. The present study thus aimed to clarify whether brain ghrelin is involved in visceral sensation. Visceral sensation was evaluated by the colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Intracisternally administered ghrelin increased the threshold volume of colonic distension-induced AWR in a dose-dependent manner. By contrast, neither intraperitoneal injection of ghrelin nor intracisternal des-acyl-ghrelin altered the threshold volume. Pretreatment with subcutaneous injection of either naloxone hydrochloride or sulpiride, a dopamine D2 receptor antagonist, significantly blocked ghrelin induced visceral antinociception; furthermore, neither subcutaneous injection of naloxone methiodide, a peripheral selective opioid antagonist, SCH23390, a dopamine D1 receptor antagonist, nor DPCPX, an adenosine A1 receptor antagonist, blocked antinociception. Although intracisternal SB334867, an orexin 1 receptor antagonist, alone failed to change the threshold volume, centrally injected SB334867 potently blocked ghrelin-induced antinociceptive action during colonic distension. These results provide the first evidence that ghrelin acts centrally in the brain to enhance antinociceptive response to colonic distension through the central opioid system, dopamine D2 signaling, and the orexinergic pathway. PMID- 29476750 TI - Functional relationship between brainstem putative pain-facilitating neurons and spinal nociceptfive neurons during development of inflammation in rats. AB - The so-called on- and off-cells of the rostral ventromedial medulla (RVM) send their axons to the spinal dorsal horn. Activation of on-cells precedes and coincides with a facilitation, and activation of off-cells coincides with an inhibition, of withdrawal reflexes elicited by noxious agents. Considerable evidence supports the notion that on- and off-cells modulate nocifensive reflexes during opioid and non-opioid action and also during normal circumstances and during peripheral neuropathy and inflammation. Yet it is unclear whether on- and off-cells act upon sensory spinal circuits that might lead to ascending projections and the experience of pain. Here, in deeply anesthetized rats we recorded single unit discharges from pairs of one on-like or off-like cell in RVM and a nociceptive neuron in the spinal dorsal horn with input from a hind paw. Both ongoing activity and responses to a calibrated noxious stimulus applied to the paw were documented during basal conditions and during development of paw inflammation. Probably due to the strong barbiturate anesthesia, off-like cells were depressed and did not yield interpretable results. However, we showed for the first time that during the increase in neuronal activity that results from paw inflammation the activity of spinal nociceptive neurons reflects the activity of their partner on-like cells in a highly correlated manner. This implies a tight relationship between spinal sensory and RVM modulatory functions that may underlie inflammation-induced hyperreflexia and clinically relevant hyperalgesia. PMID- 29476751 TI - Evidence of a role for spinal HMGB1 in ischemic stress-induced mechanical allodynia in mice. AB - We have previously showed that spinal high-mobility group box-1 (HMGB1) plays an important role in the induction of central post-stroke pain (CPSP). It has been reported that HMGB1 exacerbates inflammation and pain via TLR4 or RAGE. Furthermore, the relationship between glial cells, such as microglia and astrocytes, involved in pain exacerbation and HMGB1 has also attracted attention. In this study, we investigated whether the interaction between spinal glial cells and HMGB1 signaling, including its receptors TLR4 or RAGE, is directly involved in the induction of CPSP. Spinal HMGB1 expression increased on day 3 after bilateral carotid artery occlusion (BCAO), and spinal microglia and astrocytes were clearly activated. HMGB1 colocalized with neurons, but not with microglia and astrocytes after BCAO. Intrathecal (i.t.) injection of lipopolysaccharides from Rhodobacter sphaeroides (LPS-RS, a TLR4 antagonist) and low-molecular-weight heparin (LMWH, a RAGE antagonist) significantly blocked mechanical allodynia on day 3 after BCAO. BCAO-induced activation of spinal microglia and astrocyte were suppressed by i.t. anti-HMGB1 monoclonal antibody (mAb) and LPS-RS administration. In addition, i.t. injection of NG-nitro-l-arginine methyl ester [a nonselective nitric oxide synthetase (NOS) inhibitor] significantly blocked mechanical allodynia on day 3 after BCAO and i.t. administration of anti-HMGB1 mAb, LPS-RS, and LMWH significantly inhibited the increase of NOS activity in the spinal cord on day 3 after BCAO. These results showed that the interaction between spinal glial cells and HMGB1/TLR4/NOS or HMGB1/RAGE/NOS is directly involved in the induction of CPSP. PMID- 29476752 TI - Activation of A1 and A2a adenosine receptors promotes neural progenitor cell proliferation. AB - Neural progenitor cells (NPCs) play a key role not only in the maintenance of the adult central nervous system (CNS) but also in the ability to recover from injury and disease. In this study, we established a 96-well-based screening system to screen small molecules modulating the proliferation of NPCs. A compound library composed of 1280 compounds was screened. We found that the A1 adenosine receptor agonist cyclopentyladenosine (CPA) and the A2a adenosine receptor agonist CGS 21680 increased proliferation of NPCs. The A1 adenosine receptor agonist-induced cell proliferation was attenuated by A1 adenosine receptor antagonist 8 cyclopentyl-1,3-dipropylxanthine (DPCPA). Accordingly, the A2a adenosine receptor agonist-induced cell proliferation was attenuated by A2a adenosine receptor antagonist SCH-58261. Further study indicated that CPA and CGS-21680 treatment induced phosphorylation of extracellular signal-regulated kinase (ERK) and Akt, and CPA-induced or CGS-21680-induced cell proliferation was inhibited by ERK and Akt inhibitors. These results suggested that the activation of A1 and A2a adenosine receptor stimulated the proliferation of NPCs via the ERK and Akt signaling pathways. PMID- 29476753 TI - Modality effects in implicit artificial grammar learning: An EEG study. AB - Recently, it has been proposed that sequence learning engages a combination of modality-specific operating networks and modality-independent computational principles. In the present study, we compared the behavioural and EEG outcomes of implicit artificial grammar learning in the visual vs. auditory modality. We controlled for the influence of surface characteristics of sequences (Associative Chunk Strength), thus focusing on the strictly structural aspects of sequence learning, and we adapted the paradigms to compensate for known frailties of the visual modality compared to audition (temporal presentation, fast presentation rate). The behavioural outcomes were similar across modalities. Favouring the idea of modality-specificity, ERPs in response to grammar violations differed in topography and latency (earlier and more anterior component in the visual modality), and ERPs in response to surface features emerged only in the auditory modality. In favour of modality-independence, we observed three common functional properties in the late ERPs of the two grammars: both were free of interactions between structural and surface influences, both were more extended in a grammaticality classification test than in a preference classification test, and both correlated positively and strongly with theta event-related-synchronization during baseline testing. Our findings support the idea of modality-specificity combined with modality-independence, and suggest that memory for visual vs. auditory sequences may largely contribute to cross-modal differences. PMID- 29476754 TI - Switching between ranibizumab and aflibercept for the treatment of neovascular age-related macular degeneration. AB - The introduction of antivascular endothelial growth factor agents such as ranibizumab and aflibercept has revolutionized the management of neovascular age related macular degeneration. A number of randomized clinical trials have shown that ranibizumab and aflibercept produce similar efficacy and safety outcomes. Most of the switching studies published to date show that efficacy benefits are uncontrolled, retrospective trials with limitations in terms of their selection, monitoring, numbers, and assessment criteria. Based on the published literature to date, we propose arguments for and against switching antivascular endothelial growth factor agents, provide our own perspective on this topic, and suggest a focus for future research. PMID- 29476755 TI - Human IgG subclass cross-species reactivity to mouse and cynomolgus monkey Fcgamma receptors. AB - In therapeutic antibody discovery and early development, mice and cynomolgus monkey are used as animal models to assess toxicity, efficacy and other properties of candidate molecules. As more candidate antibodies are based on human immunoglobulin (IgG) subclasses, many strategies are pursued to simulate the human system in the test animal. However, translation rate from a successful preclinical trial to an approved drug is extremely low. This may partly be due to differences in interaction of human IgG based candidate molecules to endogenous Fcgamma receptors of model animals in comparison to those of human Fcgamma receptors. In this study, we compare binding characteristics of human IgG subclasses commonly used in drug development (IgG1, IgG2, IgG4) and their respective Fc silent versions (IgG1sigma, IgG2sigma, IgG4 PAA) to human, mouse, and cynomolgus monkey Fcgamma receptors. To control interactions between Fab and Fc domains, the test IgGs all have the same variable region sequences. We found distinct variations of interaction of human IgG subclasses to model animal Fcgamma receptors in comparison to their human counterparts. Particularly, cynomolgus monkey Fcgamma receptors showed consistently tighter binding to human IgGs than human Fcgamma receptors. Moreover, the presumably Fc silent human IgG4 PAA framework bound to cynomolgus monkey FcgammaRI with nanomolar affinity while only very weak binding was observed for the human FcgammaRI. Our results highlighted the need for a thorough in vitro affinity characterization of candidate IgGs against model animal Fcgamma receptors and careful design of preclinical studies. PMID- 29476756 TI - Hyperbilirubinemia-induced pro-angiogenic activity of infantile endothelial progenitor cells. AB - OBJECTIVES: Bilirubin, a by-product of heme degradation, is suggested to have a role for vascular protection. There is increasing evidence that bilirubin may directly affect the function and secretory activity of endothelial cells. In this study, potential effect of hyperbilirubinemia on biological features of circulation endothelial progenitor cells (cEPCs) isolated from infants was investigated. METHODS: Circulation concentration, differentiation and migratory activity of cEPCs isolated from infants with (n = 111) or without (n = 73) hyperbilirubinemia were analyzed. Then, the potential beneficial effect of conditioned medium of cEPCs from infants with or without hyperbilirubinemia was examined on experimental mouse wounds. RESULTS: Our results revealed significantly higher percentages of cEPCs in infants with hyperbilirubinemia. Cell proliferation, and migratory properties of cEPCs isolated and expanded from infants with hyperbilirubinemia were significantly improved. Also, the conditioned medium of cEPCs from hyperbilirubinemic infants possessed a superior beneficial effect on wound healing, which was associated with increased protein levels of VEGF, IL-10, and Pho-ERK/ERK, and decreased TNF-alpha in the wound tissues. CONCLUSIONS: Our results showed that hyperbilirubinemia can activate migration, proliferating and angiogenic properties of cEPCs. Hyperbilirubinemia can promote the proangiogenic secretory activity of cEPCs, thereby resulting in enhancement of their regenerative wound healing properties. PMID- 29476757 TI - Fractal dimension and lacunarity analysis of retinal microvascular morphology in hypertension and diabetes. AB - Hypertension and diabetes mellitus represent modifiable risk factors for vascular disease. They cause microvascular remodeling, and ultimately result in end-organ damage. Therefore, development of methods for noninvasive quantification of the effects of hypertension and diabetes mellitus on microvasculature is of paramount importance. The two goals of the study were: 1) to characterize the geometric complexity and inhomogeneity of retinal vasculature in hypertensive retinopathy (HR) and in proliferative diabetic retinopathy (PDR) by using box counting fractal dimension and lacunarity analysis, and 2) to determine if the combination of these two parameters can be used to describe differences in the vascular tree geometry between HR and PDR. The extended set of retinal images from the publicly available STARE database was manually segmented by our expert, validated, and made available for other researchers to use. The healthy retinal vascular network has a higher complexity (fractal dimension) compared to that in HR and in PDR. However, there is no difference in microvascular complexity between HR and PDR. The inhomogeneity of the retinal microvascular tree (lacunarity) was higher in PDR compared to HR. Lacunarity and fractal dimension together quantitatively characterize microvascular geometry in the retina with higher specificity than fractal analysis alone. PMID- 29476758 TI - Red fluorescent protein (DsRFP) optimization for Entamoeba histolytica expression. AB - Entamoeba histolytica genetic organization and genome structure is complex and under intense research. The genome is fully sequenced, and several tools have been developed for the molecular study of this organism. Nevertheless, good protein tracking tags that are easy to measure and image, like the fluorescent proteins are lacking. In this report, we codon-optimized the red fluorescent protein from the coral Discosoma striata (DsRFP) for its use in E. histolytica and demonstrated functionality in vivo. We envision that this protein can be widely used for the development of transcriptional reporter systems and protein tagging applications. PMID- 29476759 TI - Synthesis and biological evaluation of estrone 3-O-ether derivatives containing the piperazine moiety. AB - A series of new estrone derivatives were designed and synthesized, and their structures were confirmed by spectroscopic methods. All new estrone derivatives were investigated for their in vitro cytotoxic efficacies against a panel of three human prostate cancer cell lines (PC-3, LNCaP, and DU145). The derivatives 6, 7, 10, 15, 16, 20, 21, 22, 24 and 26 showed important cytotoxic actions against individual carcinoma cell line collections. Moreover, antagonistic activities of compounds (7, 15, 16 and 21) towards a1-ARs (alpha1A, alpha1B, and alpha1D) were further evaluated using dual-luciferase reporter assays, and the compounds 16 and 21 exhibited better a1-ARs subtype selectivity. The structure activity relationship (SAR) suggested that the substitute's type and position on the phenyl group leads to the interesting variations within pharmacological effects of resultant molecular systems. PMID- 29476760 TI - Fecal steroid hormones reveal reproductive state in female blue whales sampled in the Gulf of California, Mexico. AB - Steroid hormone assessment using non-invasive sample collection techniques can reveal the reproductive status of aquatic mammals and the physiological mechanisms by which they respond to changes in their environment. A portion of the eastern North Pacific blue whale (Balaenoptera musculus) population that seasonally visits the Gulf of California, Mexico has been monitored using photo identified individuals for over 30 years. The whales use the area in winter-early spring for nursing their calves and feeding and it therefore is well suited for fecal sample collection. Using radioimmunoassays in 25 fecal samples collected between 2009 and 2012 to determine reproductive state and stress, we validated three steroid hormones (progesterone, corticosterone and cortisol) in adult female blue whales. Females that were categorized as pregnant had higher mean fecal progesterone metabolite concentrations (1292.6 +/- 415.6 ng.g-1) than resting and lactating females (14.0 +/- 3.7 ng.g-1; 23.0 +/- 5.4 ng.g-1, respectively). Females classified as pregnant also had higher concentrations of corticosterone metabolites (37.5 +/- 9.9 ng.g-1) than resting and lactating females (17.4 +/- 2.0 ng.g-1; 16.8 +/- 2.8 ng.g-1, respectively). In contrast, cortisol metabolite concentrations showed high variability between groups and no significant relationship to reproductive state. We successfully determined preliminary baseline parameters of key steroid hormones by reproductive state in adult female blue whales. The presence of pregnant or with luteal activity and known lactating females confirms that the Gulf of California is an important winter-spring area for the reproductive phase of these blue whales. The baseline corticosterone levels we are developing will be useful for assessing the impact of the increasing coastal development and whale-watching activities on the whales in the Gulf of California. PMID- 29476761 TI - Loop-mediated isothermal amplification assay for detection of four immunosuppressive viruses in chicken. AB - Loop-mediated isothermal amplification (LAMP) methods to detect chicken infectious anemia virus (CIAV), reticuloendotheliosis virus (REV), and Marek's disease virus (MDV), and a reverse transcription (RT)-LAMP assay to detect infectious bursal disease virus (IBDV), were developed. The CIAV-LAMP, REV-LAMP, MDV-LAMP, and IBDV-RT-LAMP methods were performed using four sets of six primers targeting the VP1 gene of CIAV, the gp90 gene of REV, the Meq gene of MDV, and the VP2 gene of IBDV. The results (a change in color) were observed visually. The methods showed high specificity and sensitivity. The detection limits were 50 genomic copies of CIAV, 16 genomic copies of REV, 20 genomic copies of MDV, and 250 genomic copies of IBDV. When used to test clinical samples, the results of the LAMP assays were in 100% agreement with a previously described PCR. Therefore, the LAMP assays are simple, rapid, highly sensitive, and specific methods for detecting four immune-suppressive viruses. PMID- 29476762 TI - Challenges in 3D culturing of neutrophils: Assessment of cell viability. AB - Standard cell culturing on plastic plates (two dimensional (2D) cultures) does not represent the actual microenvironment where cells reside in tissues. The three dimensional (3D) systems, composed of extracellular matrix and/or pure amino acids which form a scaffold for cells, are more accurate in this respect. 3D cultures were primarily developed for cancer cells but there is also a need for their application in studies on inflammatory leukocytes. Herein we describe our approach to study neutrophil-like cells in the 3D system. We describe measures taken to establish a neutrophil-like cell line (nHL-60) and selection of 3D scaffolds (PuraMatrix alone or enriched with collagen type I) for their culturing. We focus on challenges in measurement of neutrophil viability in 3D cultures and based on our data we suggest application of resazurin, rather than tetrazolium-based dyes or trypan blue exclusion, for evaluation of neutrophil viability. PMID- 29476763 TI - A Phase 1 Study to Evaluate the Effect of Crushing, Cutting Into Half, or Grinding of Glecaprevir/Pibrentasvir Tablets on Exposures in Healthy Subjects. AB - Glecaprevir (GLE) and pibrentasvir (PIB) are direct-acting antivirals coformulated as a combination tablet for once-daily treatment of chronic hepatitis C virus infection. The objective of this study was to evaluate the effect of different methods of tablet manipulations-cutting in half, grinding into powder, or crushing-on the bioavailability of GLE and PIB relative to whole film-coated bilayer tablets. This was a phase 1, single-dose, open-label, randomized, 5-period, nonfasting crossover study in 25 healthy adult male and female subjects. Intensive pharmacokinetic measurements were carried out up to 48 h after dosing on day 1 of each period. Safety and tolerability was assessed throughout the study. Compared with the reference whole tablets, cutting into half had minimal impact on GLE and PIB exposures (<=15% difference), whereas grinding or crushing the tablets resulted in lower exposures (27% to 61%) for GLE and higher exposures (21% to 83%) for PIB. These results provide guidance on appropriate administration of GLE/PIB in patients who have difficulty swallowing whole tablets. PMID- 29476764 TI - Genetic deletion of CD38 confers post-ischemic myocardial protection through preserved pyridine nucleotides. AB - Following the onset of ischemia/reperfusion (I/R), CD38 activation occurs and is associated with depletion of NAD(P)(H) in the heart as well as myocardial injury and endothelial dysfunction. Studies with pharmacological inhibitors suggest that the NADP+-hydrolyzing ability of CD38 can deplete the NAD(P)(H) pools. However, there is a need for more specific studies on the importance of CD38 and its role in the process of endothelial dysfunction and myocardial injury in the post ischemic heart. Therefore, experiments were performed in hearts of mice with global gene knockout of CD38. Isolated perfused CD38-/- and wild type (WT) mouse hearts were studied to determine the link between CD38 activation, the levels of NADP(H), endothelial dysfunction, and myocardial injury after I/R. Genetic deletion of CD38 preserves the myocardial and endothelial NADP(H) pools compared to WT. Whole heart BH4 levels in CD38-/- hearts were also preserved. Post ischemic levels of cGMP were greatly depleted in WT hearts, but preserved to near baseline levels in CD38-/- hearts. The preservation of these metabolite pools in CD38-/- hearts was accompanied by near full recovery of NOS-dependent coronary flow, while in WT hearts, severe impairment of endothelial function and NOS uncoupling occurred with decreased NO and enhanced superoxide generation. CD38-/- hearts also exhibited marked protection against I/R with preserved glutathione levels, increased recovery of left ventricular contractile function, decreased myocyte enzyme release, and decreased infarct size. Thus, CD38 activation causes post-ischemic depletion of NADP(H) within the heart, with severe depletion from the endothelium, resulting in endothelial dysfunction and myocardial injury. PMID- 29476765 TI - Neural responses to visually observed social interactions. AB - Success in the social world requires the ability to perceive not just individuals and their actions, but pairs of people and the interactions between them. Despite the complexity of social interactions, humans are adept at interpreting those interactions they observe. Although the brain basis of this remarkable ability has remained relatively unexplored, converging functional MRI evidence suggests the posterior superior temporal sulcus (pSTS) is centrally involved. Here, we sought to determine whether this region is sensitive to both the presence of interactive information, as well as to the content of qualitatively different interactions (i.e. competition vs. cooperation). Using point-light human figure stimuli, we demonstrate that the right pSTS is maximally activated when contrasting dyadic interactions vs. dyads performing independent, non-interactive actions. We then used this task to localize the same pSTS region in an independent participant group, and tested responses to non-human moving shape stimuli (i.e. two circles' movements conveying either interactive or non interactive behaviour). We observed significant support vector machine classification for both the presence and type of interaction (i.e. interaction vs. non-interaction, and competition vs. cooperation, respectively) in the pSTS, as well as neighbouring temporo-parietal junction (TPJ). These findings demonstrate the important role that these regions play in perceiving and understanding social interactions, and lay the foundations for further research to fully characterize interaction responses in these areas. PMID- 29476766 TI - Attitudes towards tobacco product regulations and their relationship with the tobacco control policies. AB - The objective of this work is to describe the acceptability of some tobacco products regulations and to explore their relation with tobacco control legislation levels in Europe. We used data on tobacco control activities in Europe in 2007, 2010 and 2013 measured by the Tobacco Control Scale (TCS) and data regarding attitudes about tobacco control regulations (i.e. adding picture health warnings on all packages of tobacco products or increasing taxes on tobacco products) from the Special Eurobarometer of 2009, 2012 and 2014 (n = 80,831). We calculated the prevalence ratio of favorable attitudes towards tobacco products restrictions in the reference year 2009 vs. the most current year (i.e. 2009 vs 2014), and the effect of previous TCS scores on the attitudes towards tobacco products regulations adjusted for sociodemographic variables. Strong support for the studied tobacco products regulations, which modestly increased over time, was observed. A positive relation was generally observed between TCS scores and support for the studied tobacco products regulations at both the ecological and individual level. A positive correlation was found between TCS scores and support for increasing taxes on tobacco products (rsp:0.29; 95%CI: 0.10, 0.48) at the ecological level, while at the individual level, the positive association was more remarkable in the case of support for adding large health warning labels to packaging. In conclusion, support for the studied tobacco products regulations were positively related with European tobacco control levels of implementation both at the ecological and individual level. PMID- 29476767 TI - Microbial insecticides in Iran: History, current status, challenges and perspective. AB - Biological control programs with arthropods have been in practice in Iran since the 1930s. However, development and registration of microbial biopesticides is much more recent. Currently, about 15 biopesticide products are registered or pending registration for commercial use on various crops. Products based on Bacillus thuringiensis subsp. kurstaki are most widely sold for lepidopteran pest control, followed by B. thuringiensis subsp. isralensis against dipteran pests in vector control programs. Additionally, mycoinsecticides based on Lecanicillium lecanii and Beauveria bassiana, against various arthropod pests, and a mycofungicide based on Trichoderma harzianum for controlling soilborne diseases are also registered. In Iran, the national Plant Protection Organization (PPO) manages regulation of microbial pesticides and the Pesticide Supervision Board within the PPO oversees registration of all pesticides. Currently, two Iranian companies produce microbial pesticides and two more companies are approved to start production in the near future. We review the history of microbial control of arthropod pests in Iran with examples of sustainable agricultural practices, the current status of the market and registration procedures for microbial pesticides, along with the challenges and opportunities for the advancement of microbial control in Iran. PMID- 29476768 TI - A viral map of gastrointestinal cancers. AB - Cancers of the gastrointestinal tract (GIT) are expected to account for approximately 20% of all cancers in 2017. Apart from their high incidence, GIT cancers show high mortality rates, placing these malignancies among the most prominent public health issues of our time. Cancers of the GIT are the result of a complex interplay between host genetic factors and environmental factors and frequently arise in the context of a continued active inflammatory response. Several tumor viruses are able to elicit such chronic inflammatory responses. In fact, several viruses have an impact on GIT tumor initiation and progression, as well as on patients' response to therapy and prognosis, through direct and indirect mechanisms. In this review, we have gathered information on different viruses' rates of infection, viral-driven specific carcinogenesis mechanisms and viral-related impact on the prognosis of cancers of the GIT (specifically in organs that have an interface with the environment - esophagus, stomach, intestines and anus). Overall, while some viral infections show a strong causal relation with specific gastrointestinal cancers, these represent a relatively small fraction of GIT malignancies. Other types of cancer, like Esophageal Squamous Cell Carcinoma, require further studies to confirm the carcinogenic role of some viral agents. PMID- 29476769 TI - Oleuropein potentiates anti-tumor activity of cisplatin against HepG2 through affecting proNGF/NGF balance. AB - AIMS: Oleuropein is considered as a new chemotherapeutic agent in human hepatocellular carcinoma (HCC) while, its exact underlying molecular mechanism still not yet explored. In addition, cisplatin is a standard anticancer drug against solid tumors with toxic side effects. Therefore, we conducted this study to assess antitumor activity of oleuropein either alone or in combination with cisplatin against HepG2, human HCC cell lines, via targeting pro-NGF/NGF signaling pathway. MAIN METHODS: HepG2 cells were treated with cisplatin (20, 50, 100 MUM) and oleuropein (100, 200, 300 and 400 MUM) as well as some of the cells were treated with 50 MUM cisplatin and different concentrations of oleuropein. Gene expressions of nerve growth factor (NGF), matrix metalloproteinase-7 (MMP-7) and caspase-3 were evaluated by real time-PCR. In addition, protein levels of NGF and pro-form of NGF (pro-NGF) were measured by ELISA while, nitric oxide (NO) content was determined colorimetrically. KEY FINDINGS: Cisplatin treatment showed a significant elevation of NO content and pro-NGF protein level with a marked reduction of NGF protein level in addition to the upregulation of caspase-3 along with downregulation of MMP-7 gene expressions in a dose-dependent manner. However, the combination of 50 MUM cisplatin and 200 MUM oleuropein showed the most potent effect on the molecular level when compared with oleuropein or cisplatin alone. SIGNIFICANCE: Our results showed for the first time that the anti-tumor activity of oleuropein against HCC could be attributed to influencing the pro-NGF/NGF balance via affecting MMP-7 activity without affecting the gene expression of NGF. Concurrent treatment with both oleuropein and cisplatin could lead to more effective chemotherapeutic combination against HCC. PMID- 29476770 TI - C-type lectin B (SpCTL-B) regulates the expression of antimicrobial peptides and promotes phagocytosis in mud crab Scylla paramamosain. AB - As pattern recognition receptors, C-type lectins (CTLs) play important roles in immune system of crustaceans through identifying and binding to the conservative pathogen-associated molecular patterns (PAMPs) on pathogen surfaces. In this study, a new CTL, SpCTL-B, was identified from the hemocytes of mud crab Scylla paramamosain. The full-length of SpCTL-B cDNA was 1278 bp with an open reading frame (ORF) of 348 bp. The predicted SpCTL-B protein contains a single carbohydrate-recognition domain (CRD). SpCTL-B transcripts were distributed in all examined tissues with the highest levels in hepatopancreas. After challenged with Vibrio parahaemolyticus, LPS, polyI:C and white spot syndrome virus (WSSV), the mRNA levels of SpCTL-B in hemocytes and hepatopancreas were up-regulated. The recombinant SpCTL-B (rSpCTL-B) purified by Ni-affinity chromatography showed stronger binding activities with Staphylococcus aureus, beta-hemolytic Streptococcus, Escherichia coli, Aeromonas hydrophila, Vibrio alginolyticus than those with V. parahaemolyticus and Saccharomyces cerevisiae. rSpCTL-B exhibited a broad spectrum of microorganism-agglutination activities against Gram-positive bacteria (S. aureus, beta-hemolytic Streptococcus) and Gram-negative bacteria (E. coli, V. parahaemolyticus, A. hydrophila, V. alginolyticus) in a Ca2+-dependent manner. The agglutination activities of rSpCTL-B could be inhibited by D-mannose and LPS, but not by d-fructose and galactose. The antimicrobial assay showed that rSpCTL-B exhibited the growth inhibition against all examined gram-positive bacteria and gram-negative bacteria. When SpCTL-B was silenced by RNAi, the bacterial clearance ability in mud crab was decreased and the transcript levels of five antimicrobial peptides (AMPs) (SpCrustin, SpHistin, SpALF4 (anti lipopolysaccharide factor), SpALF5 and SpALF6) were significantly decreased in hemocytes. In our study, knockdown of SpCTL-B could down-regulate the expression of SpSTAT at mRNA transcriptional level and protein translational level in mud crab. Meantime, the phagocytosis rate and the expression of three phagocytosis related genes were declined after RNAi of SpCTL-B in hemocytes in mud crab. Collectively, our results suggest that SpCTL-B might play its roles as a pattern recognition receptor (PRR) in immune response towards pathogens infection through influencing the expression of AMPs and the phagocytosis of hemocytes in mud crab S. paramamosain. PMID- 29476772 TI - Biogenesis and function of extracellular vesicles in cancer. AB - Extracellular vesicles (EVs) are heterogeneous multi-signal messengers that support cancer growth and dissemination by mediating the tumor-stroma crosstalk. Exosomes are a subtype of EVs that originate from the limiting membrane of late endosomes, and as such contain information linked to both the intrinsic cell "state" and the extracellular signals cells received from their environment. Resolving the signals affecting exosome biogenesis, cargo sorting and release will increase our understanding of tumorigenesis. In this review we highlight key cell biological processes that couple exosome biogenesis to cargo sorting in cancer cells. Moreover, we discuss how the bidirectional communication between tumor and non-malignant cells affect cancer growth and metastatic behavior. PMID- 29476773 TI - A potential role for Eph receptor signalling during migration of corneal endothelial cells. AB - The corneal endothelium is a monolayer of epithelial cells that lines the posterior surface of the cornea and is essential for maintenance of corneal transparency. Wound healing within the corneal endothelium typically occurs through cell spreading and migration rather than through proliferation. The mechanisms that control corneal endothelial cell migration are unclear. In this study we demonstrate that cultures of corneal endothelial cells display reduced migration in scratch wound assays, and reduced levels of E-cadherin mRNA, following suppression of ligand-activated Eph receptor signalling by treatment with lithocholic acid. Two Eph receptors, EphA1 and EphA2, were subsequently detected in corneal endothelial cells, and their potential involvement during migration was explored through gene silencing using siRNAs. EphA2 siRNA reduced levels of mRNA for both EphA2 and N-cadherin, but increased levels of mRNA for both EphA1 and E-cadherin. No effect, however, was observed for EphA2 siRNA on migration. Our results indicate a potential role for Eph receptor signalling during corneal endothelial cell migration via changes in cadherin expression. Nevertheless, defining a precise role for select Eph receptors is likely to be complicated by crosstalk between Eph-mediated signalling pathways. PMID- 29476774 TI - Specimen Provenance Testing Identifies Contamination That Affects Molecular Prognostic Assay Results in Prostate Cancer Biopsy Specimens. AB - OBJECTIVE: To determine if tissue contamination in histologic specimens can significantly affect the results of prognostic molecular markers that are routinely used as confirmatory tests to safely assign appropriate candidates to prostate cancer active surveillance protocols. MATERIALS AND METHODS: This study evaluates 2134 cases from a single, large urology practice that were successfully tested for DNA specimen provenance verification using short tandem repeat analysis for the presence of a significant level of contaminating DNA. After removal of the contamination, 5 of the samples were retested, and the results of the molecular diagnostic test were compared. RESULTS: Forty-nine of the 2134 cases (2.3%) sent for DNA provenance analysis were found to possess significant levels of contamination. Of these 49 cases, 7 were resent for a repeat molecular diagnostic test after being decontaminated. Five of these prostate cancer specimens had sufficient tissue and RNA to give a more accurate cell cycle progression (CCP) score. The average absolute change in these patients' CCP scores was 0.48, with a minimum of 0.1-unit and a maximum of 1.0-unit difference. These changes in CCP scores are significant enough to cause meaningful alterations in a patient's calculated 10-year mortality rate, as defined by their combined risk score. CONCLUSION: DNA contamination in unstained tissue sections sent for prognostic prostate cancer molecular diagnostic testing occurs in 2.3% of the cases, and can be of a magnitude that affects the results and subsequent clinical decision of appropriateness for active surveillance. PMID- 29476775 TI - Whole-Exome Sequencing of Acquired Nevi Identifies Mechanisms for Development and Maintenance of Benign Neoplasms. AB - The melanoma transformation rate of an individual nevus is very low despite the detection of oncogenic BRAF or NRAS mutations in 100% of nevi. Acquired melanocytic nevi do, however, mimic melanoma, and approximately 30% of all melanomas arise within pre-existing nevi. Using whole-exome sequencing of 30 matched nevi, adjacent normal skin, and saliva we sought to identify the underlying genetic mechanisms for nevus development. All nevi were clinically, dermoscopically, and histopathologically documented. In addition to identifying somatic mutations, we found mutational signatures relating to UVR mirroring those found in cutaneous melanoma. In nevi we frequently observed the presence of the UVR mutation signature compared with adjacent normal skin (97% vs. 10%, respectively). Copy number aberration analysis showed that for nevi with copy number loss of tumor suppressor genes, this loss was balanced by loss of potent oncogenes. Moreover, reticular and nonspecific patterned nevi showed an increased (P < 0.0001) number of copy number aberrations compared with globular nevi. The mutation signature data generated in this study confirms that UVR strongly contributes to nevogenesis. Copy number changes reflect at a genomic level the dermoscopic differences of acquired melanocytic nevi. Finally, we propose that the balanced loss of tumor suppressor genes and oncogenes is a protective mechanism of acquired melanocytic nevi. PMID- 29476776 TI - beta-Adrenergic Receptor Trafficking, Degradation, and Cell Surface Expression Are Altered in Dermal Fibroblasts from Hypertrophic Scars. AB - Burn trauma elevates catecholamines for up to 2 years and causes hypertrophic scarring. Propranolol, a nonspecific beta1-, beta2-adrenergic receptor (AR) inverse agonist, counters the hypermetabolic response to elevated catecholamines and may decrease hypertrophic scarring by an unknown mechanism. We investigated the effect of burn injury on beta1-, beta2-, and beta3-AR expression, trafficking, and degradation in human dermal fibroblasts from hypertrophic scar [HSF], non-scar fibroblasts, and normal fibroblasts. We also investigated the modulation of these events by propranolol. Catecholamine-stimulated cAMP production was lower in HSFs and non-scar fibroblasts than in normal fibroblasts. beta1- and beta2-AR cell surface expression was lowest in HSFs, but propranolol increased cell surface expression of these receptors. Basal beta2-AR ubiquitination was higher in HSFs than non-scar or normal fibroblasts, suggesting accelerated receptor degradation. beta-AR degradation was mainly driven by lysosomal-specific polyubiquitination at Lys-63 in normal fibroblasts and HSFs, which was abrogated by propranolol. Propranolol also targeted beta-AR to the proteasome in HSFs. Confocal imaging showed a lack of beta2-AR-GFP trafficking to lysosomal compartments in catecholamine-stimulated HSFs. These data suggest that burn trauma alters the expression, trafficking, and degradation of beta-ARs in dermal fibroblasts, which may then affect fibroblast responses to propranolol. PMID- 29476777 TI - Can distinctly different rapid estrogen actions share a common mechanistic step? AB - Contribution to Special Issue on Fast effects of steroids. This paper reviews early evidence for the existence of rapid, non-genomic effects of estrogens on neurons, and, further, proposes that these rapid effects are often synergistic with later, genomic effects. Finally, suggestions about potential molecular mechanisms underlying the rapid effects of estrogens are offered. A mechanistic step we propose to be common among rapid estrogenic actions includes membrane ER's binding to histamine, and NMDA receptors and subsequent dimerization, and clustering (respectively) in a manner that enhances histamine and NMDA actions. PMID- 29476779 TI - Psychedelics: Where we are now, why we got here, what we must do. AB - The purpose of this commentary is to provide an introduction to this special issue of Neuropharmacology with a historical perspective of psychedelic drug research, their use in psychiatric disorders, research-restricting regulatory controls, and their recent emergence as potential breakthrough therapies for several brain-related disorders. It begins with the discovery of lysergic acid diethylamide (LSD) and its promising development as a treatment for several types of mental illnesses during the 1940s. This was followed by its abuse and stigmatization in the 1960s that ultimately led to the placement of LSD and other psychedelic drugs into the most restrictively regulated drug schedule of the United States Controlled Substances Act (Schedule I) in 1970 and its international counterparts. These regulatory controls severely constrained development of psychedelic substances and their potential for clinical research in psychiatric disorders. Despite the limitations, there was continued research into brain mechanisms of action for psychedelic drugs with potential clinical applications which began during the 1990s and early 2000s. Finding pathways to accelerate clinical research in psychedelic drug development is supported by the growing body of research findings that are documented throughout this special issue of Neuropharmacology. Accumulated research to date suggests psychedelic drug assisted psychotherapy may emerge as a potential breakthrough treatment for several types of mental illnesses including depression, anxiety, post-traumatic stress disorder, and addiction that are refractory to current evidenced based therapies. This research equally shows promise in advancing the understanding of the brain, brain related functioning, and the consequential effects of untreated brain related diseases that have been implicated in causing and/or exacerbating numerous physical disease state conditions. The authors conclude that more must be done to effectively address mental illnesses and brain related diseases which have become so pervasive, destructive, and whose treatments are becoming increasingly resistant to current evidenced based therapies. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'. PMID- 29476778 TI - Changes in brain oxygen and glucose induced by oxycodone: Relationships with brain temperature and peripheral vascular tone. AB - Oxycodone is a semi-synthetic opioid drug that is used to alleviate acute and chronic pain. However, oxycodone is often abused and, when taken at high doses, can induce powerful CNS depression that manifests in respiratory abnormalities, hypotension, coma, and death. Here, we employed several techniques to examine the effects of intravenous oxycodone at a wide range of doses on various metabolism related parameters in awake, freely-moving rats. High-speed amperometry was used to assess how oxycodone affects oxygen and glucose levels in the nucleus accumbens (NAc). These measurements were supplemented by recordings of locomotor activity and temperature in the NAc, temporal muscle, and skin. At low doses, which are known to maintain self-administration behavior (0.15-0.3 mg/kg), oxycodone transiently decreased locomotor activity, induced modest brain and body hyperthermia, and monotonically increased NAc oxygen and glucose levels. While locomotor inhibition became stronger with higher oxycodone doses (0.6-1.2 mg/kg), NAc oxygen and glucose transiently decreased and subsequently increased. High dose oxycodone induced similar biphasic down-up changes in brain and body temperature, with the initial decreases followed by increases. While cerebral vasodilation induced by neural activation appears to be the underlying mechanism for the correlative increases in brain oxygen and glucose levels, respiratory depression and the subsequent drop in blood oxygen likely mediate the brain hypoxia induced by large-dose oxycodone injections. The initial inhibitory effects induced by large-dose oxycodone injections could be attributed to rapid and profound CNS depression-the most dangerous health complication linked to opioid overdose in humans. PMID- 29476780 TI - Acute effect of bisphenol A: Signaling pathways on calcium influx in immature rat testes. AB - We investigated the acute effect of low concentrations of BPA on calcium influx and the mechanism of action of BPA in this rapid response in the rat testis. BPA increased calcium influx at 1 pM and 1 nM at 300 s of incubation, in a similar manner to that of estradiol. At 1 pM, BPA stimulated calcium influx independently of classical estrogen receptors, consistent with a G-protein coupled receptor. This effect also involves the modulation of ionic channels, such as K+, TRPV1 and Cl- channels. Furthermore, BPA is able to modulate calcium from intracellular storages by inhibiting SERCA and activating IP3 receptor/Ca2+ channels at the endoplasmic reticulum and activate kinase proteins, such as PKA and PKC. The rapid responses of BPA on calcium influx could, in turn, trigger a cross talk by MEK and p38MAPK activation and also mediate genomic responses. PMID- 29476771 TI - Subliminal (latent) processing of pain and its evolution to conscious awareness. AB - By unconscious or covert processing of pain we refer to nascent interactions that affect the eventual deliverance of pain awareness. Thus, internal processes (viz., repeated nociceptive events, inflammatory kindling, reorganization of brain networks, genetic) or external processes (viz., environment, socioeconomic levels, modulation of epigenetic status) contribute to enhancing or inhibiting the presentation of pain awareness. Here we put forward the notion that for many patients, ongoing sub-conscious changes in brain function are significant players in the eventual manifestation of chronic pain. In this review, we provide clinical examples of nascent or what we term pre-pain processes and the neurobiological mechanisms of how these changes may contribute to pain, but also potential opportunities to define the process for early therapeutic interventions. PMID- 29476781 TI - Repeatability and correlations of dynamic contrast enhanced and T2* MRI in patients with advanced pancreatic ductal adenocarcinoma. AB - BACKGROUND: In current oncological practice of pancreatic ductal adenocarcinoma (PDAC), there is a great demand for response predictors and markers for early treatment evaluation. In this study, we investigated the repeatability and the interaction of dynamic contrast enhanced (DCE) and T2* MRI in patients with advanced PDAC to enable for such evaluation using these techniques. MATERIALS & METHODS: 15 PDAC patients underwent two DCE, T2* and anatomical 3 T MRI sessions before start of treatment. Parametric maps were calculated for the transfer constant (Ktrans), rate constant (kep), extracellular extravascular space (ve) and perfusion fraction (vp). Quantitative R2* (1/T2*) maps were obtained from the multi-echo T2* images. Differences between normal and cancerous pancreas were determined using a Wilcoxon matched pairs test. Repeatability was obtained using Bland-Altman analysis and relations between DCE and T2*/R2* were observed by Spearman correlation and voxel-wise binned plots of tumor voxels. RESULTS: PDAC Ktrans (p = 0.007), kep (p < 0.001), vp (p = 0.035) were lower and ve (p < 0.001) was higher compared to normal pancreas. The coefficient of variation between sessions was 21.8% for Ktrans, 9.9% for kep, 19.3% for ve, 18.2% for vp and 18.7% for R2*. Variation between patients ranged from 20.2% for kep to 43.6% for Ktrans. In the tumor both Ktrans (r = 0.56, p = 0.030) and ve (r = 0.54, p = 0.037) showed a positive correlation with T2*. Voxel wise analysis showed a steep increase in R2* for tumor voxels with lower Ktrans and ve. CONCLUSION: We showed good repeatability of DCE and T2* related MRI parameters in advanced PDAC patients. Furthermore, we have illustrated the relation of DCE Ktrans and ve with tissue T2* and R2* indicating substantial value of these parameters for detecting tumor hypoxia in future studies. The results from our study pave the way for further response evaluation studies and patient selection based on DCE and T2* parameters. PMID- 29476782 TI - Extermination of influenza virus H1N1 by a new visible-light-induced photocatalyst under fluorescent light. AB - A new visible-light-induced photocatalyst based on several transition metals (iron, magnesium and manganese)-loaded TiO2 was evaluated for its anti-viral activity with influenza virus H1N1. Under a fluorescent lamp of 1000 lx, lambda > 410 nm, the virus was eradicated to more than 99% within 30 min. Since this photocatalyst can be used for coating plastics, wall papers and walls, it would be desirable to use this photocatalyst to reduce viral transmission via droplets and aerosols as well as surface contact for disinfection. PMID- 29476783 TI - Lipid-based nanosuspensions for oral delivery of peptides, a critical review. AB - Peptides are therapeutic molecules that can treat selectively and efficiently a wide range of pathologies. However, their intrinsic properties cause their rapid degradation in the human gastrointestinal (GI) tract resulting in poor bioavailability after oral administration. Yet, their encapsulation in nanocarriers offers them protection from this harsh environment and increases their permeability across the epithelium border. In particular, Solid Lipid Nanoparticles (SLN) and Nanostructured Lipid Carriers (NLC) have proven to improve peptide oral bioavailability. This article details different techniques used to produce SLN and NLC with potential or effective peptide encapsulation. Basic principles of covalent and non-covalent lipidization are described and discussed as a prerequisite to improve hydrophilic peptide encapsulation in lipid based nanosuspensions. The last part of this review provides the key evaluation techniques to assay SLN and NLC for peptide oral bioavailability enhancement. Methods to assess the protective effects of the carriers are described as well as the techniques to evaluate peptide release upon lipid digestion by lipases. Furthermore, this review suggests different techniques to measure permeability improvements and describes the main in vitro cell models associated. PMID- 29476784 TI - Genome-wide identification, evolution and expression analysis of cyclic nucleotide-gated channels in tobacco (Nicotiana tabacum L.). AB - Tobacco (Nicotiana tabacum) serve as the top leading commercial, non-food, and model crop worldwide. Cyclic nucleotide-gated channels (CNGCs) are ligand-gated, calcium-permeable, divalent, cation-selective channels, involved in important biological functions. Here, we systematically characterized thirty-five CNGC genes in the genome of Nicotiana tabacum, and classified into four phylogenetic groups. Evolutionary analysis showed that NtabCNGC family of N. tabacum originated from the parental genome of N. sylvestris and N. tomentosiformis, and further expanded via tandem and segmental duplication events. Tissue-specific expression analysis showed that twenty-three NtabCNGC genes are involved in the development of various tobacco tissues. Subsequent RT-qPCR analyses indicated that these genes are sensitive towards external abiotic and biotic stresses. Notable performances were exhibited by group-I and IV CNGC genes against black shank, Cucumber mosaic virus, Potato virus Y, cold, drought, and cadmium stresses. Our analyses also suggested that NtabCNGCs can be regulated by phosphorylation and miRNAs, and multiple light, temperature, and pathogen responsive cis-acting regulatory elements present in promotors. These results will be useful for elaborating the biological roles of NtabCNGCs in tobacco growth and development. PMID- 29476786 TI - Sensitization of tumor cells to chemotherapy by natural products: A systematic review of preclinical data and molecular mechanisms. AB - PURPOSE: Tumor cells are spontaneously or adaptively resistant to chemotherapeutic drugs, eventually leading to the selection of multiresistant cells responsible for tumor growth and metastasis. Chemosensitization of tumor cells to conventional drugs using non-toxic natural products is a recent and innovative strategy aiming to increase the cytotoxic efficiency of anticancer drugs, limit their toxic side effects and delay the appearance of acquired chemoresistance. This systematic review summarizes data obtained from preclinical studies reporting the use of natural products to sensitize tumor cells to chemotherapeutic agents. It also details the cellular and molecular mechanisms involved in chemosensitization. DESIGN: Search terms were combined and used to retrieve English language reports in PubMed, Science Direct and Scopus databases, published until October 2017. All articles were carefully analyzed and data extraction was conducted through standardized forms. Methodological quality assessment of in vivo studies was also performed. RESULTS: From a total of 669 articles surveyed, 104 met the inclusion criteria established. The main studied compounds as chemosensitizers were phenolic derivatives (26.9%) and flavonoids (17.3%). Most reports were authored by researchers from China (33.7%) and USA (26.9%). A large number of articles were published from 2011 to 2015 (50.0%), suggesting that the use of natural products as chemosensitizers is a recent issue. In vivo studies were conducted mainly using xenograft models, which were considered of moderate methodological quality. CONCLUSION: Several natural products, belonging to diverse chemical families, are potent chemosentisizers in tumor cells enhancing the cytotoxicity of conventional drugs. These molecules usually have a pleiotropic effect on different molecular targets, acting on several cellular and molecular processes with low selectivity. All studied molecules were obtained from terrestrial plants and major developments should arise from future studies, considering the chemodiversity of molecules purified from other terrestrial taxa and marine organisms. PMID- 29476787 TI - Expression kinetics of ISG15, IRF3, IFNgamma, IL10, IL2 and IL4 genes vis-a-vis virus shedding, tissue tropism and antibody dynamics in PPRV vaccinated, challenged, infected sheep and goats. AB - Here, we studied the in vivo expression of Th1 (IL2 and IFN gamma) and Th2 (IL4 and IL10) - cytokines and antiviral molecules - IRF3 and ISG15 in peripheral blood mononuclear cells in relation to antigen and antibody dynamics under Peste des petits ruminants virus (PPRV) vaccination, infection and challenge in both sheep and goats. Vaccinated goats were seropositive by 9 days post vaccination (dpv) while in sheep idiosyncratic response was observed between 9 and 14 dpv for different animals. Expression of PPRV N gene was not detected in PBMCs of vaccinated and vaccinated challenged groups of both species, but was detected in unvaccinated infected PBMCs at 9 and 14 days post infection. The higher viral load at 9 dpi coincided with the peak clinical signs of the disease. The peak in viral replication at 9 dpi correlated with significant expression of antiviral molecules IRF3, ISG15 and IFN gamma in both the species. With the progression of disease, the decrease in N gene expression also correlated with the decrease in expression of IRF3, ISG15 and IFN gamma. In the unvaccinated infected animals ISG15, IRF3, IFN gamma and IL10 expression was higher than vaccinated animals. The IFN gamma expression predominated over IL4 in both vaccinated and infected animals with the infected exhibiting a stronger Th1 response. The persistent upregulation of this antiviral molecular signature - ISG15 and IRF3 even after 2 weeks post vaccination, presumably reflects the ongoing stimulation of innate immune cells. PMID- 29476788 TI - Induction profiles of mRNA of toll like receptors and cytokines in chickens pre exposed to low pathogenic avian influenza H9N2 virus followed by challenge with highly pathogenic avian influenza H5N1 virus. AB - Herein, the induction of TLRs and cytokines in chickens pre-exposed to low pathogenic avian influenza H9N2 virus followed by challenge with highly pathogenic avian influenza (HPAI) H5N1 virus was studied. Four groups (1-4) of chickens inoculated with 106 EID50 of H9N2 virus were challenged with 106 EID50 of H5N1 virus on days 1, 3, 7 and 14 post H9N2 inoculation, respectively. In groups (1-4) TLRs and cytokines induction was studied in chicken PBMCs on day 3 post H5N1 challenge. In H5N1 control group TLRs (1, 2, 5 and 7) cytokines (IFNalpha, IFNbeta, IFNgamma, IL1beta, IL2, IL4, IL8 and TGF beta3) were down regulated. In group 1 down regulation of cytokines and TLRs was similar to H5N1 control birds. Down regulation of TLRs and cytokines in H5N1 control and group 1 resulted death of all the chickens. In group 2, up-regulation of TLRs (3, 7 and 15) and induction of TNFalpha, IFNalpha, IFNbeta, IFNgamma aided virus clearance leading to survival of all the chickens. In group 3 significant up-regulation of TLRs (3, 4 and 15) and significant induction of cytokines (IFNgamma, TNFalpha, IL1beta, IL4, IL6, IL8, IL10 and TGF beta3) was detected. In group 4 significant up-regulation of TLRs (2, 3, 7 and 15) and significant induction of cytokines (IFNgamma, TNFalpha, IL1beta, IL2, IL6, IL8 and IL10) was detected. In groups 3 and 4 simultaneous and significant induction of pro-inflammatory, antiviral and anti-inflammatory cytokine resulted cytokine dysregulation leading to death of (2/6) and (3/6) chickens respectively. Hence, the study revealed TLRs and cytokines role in modulating the H5N1 infection outcome in chickens pre-exposed to H9N2 virus. PMID- 29476789 TI - Behavioral and neuroanatomical outcomes in a rat model of preterm hypoxic ischemic brain Injury: Effects of caffeine and hypothermia. AB - The current study investigated behavioral and post mortem neuroanatomical outcomes in Wistar rats with a neonatal hypoxic-ischemic (HI) brain injury induced on postnatal day 6 (P6; Rice-Vannucci HI method; Rice et al., 1981). This preparation models brain injury seen in premature infants (gestational age (GA) 32-35 weeks) based on shared neurodevelopmental markers at time of insult, coupled with similar neuropathologic sequelae (Rice et al., 1981; Workman et al., 2013). Clinically, HI insult during this window is associated with poor outcomes that include attention deficit hyperactivity disorder (ADHD), motor coordination deficits, spatial memory deficits, and language/learning disabilities. To assess therapies that might offer translational potential for improved outcomes, we used a P6 HI rat model to measure the behavioral and neuroanatomical effects of two prospective preterm neuroprotective treatments - hypothermia and caffeine. Hypothermia (aka "cooling") is an approved and moderately efficacious intervention therapy for fullterm infants with perinatal hypoxic-ischemic (HI) injury, but is not currently approved for preterm use. Caffeine is a respiratory stimulant used during removal of infants from ventilation but has shown surprising long-term benefits, leading to consideration as a therapy for HI of prematurity. Current findings support caffeine as a preterm neuroprotectant; treatment significantly improved some behavioral outcomes in a P6 HI rat model and partially rescued neuropathology. Hypothermia treatment (involving core temperature reduction by 4 degrees C for 5 h), conversely, was found to be largely ineffective and even deleterious for some measures in both HI and sham rats. These results have important implications for therapeutic intervention in at-risk preterm populations, and promote caution in the application of hypothermia protocols to at-risk premature infants without further research. PMID- 29476790 TI - Oncogene-induced regulation of microRNA expression: Implications for cancer initiation, progression and therapy. AB - A plethora of tumours have characteristic oncogenic mutations which are the main causes of malignant transformation, exerting their effects through multiple signalling pathways. Downstream of such pathways, microRNAs are small non-coding RNAs that negatively regulate gene expression, assisting or antagonizing oncogenic signalling. The differential expression of microRNAs in cancer is well documented and is considered a fundamental aspect of tumourigenesis. While data mapping the interaction between oncogenic lesions and microRNAs are accruing, we provide particular cases of such interaction. Except for notable, well-studied examples of microRNAs regulated by oncogenes, we examine the effect of this relationship in regard to tumour initiation, progression, metastasis and ultimately, its implications for the development of new therapeutics. PMID- 29476791 TI - An ADAM12 and FAK positive feedback loop amplifies the interaction signal of tumor cells with extracellular matrix to promote esophageal cancer metastasis. AB - Esophageal squamous cell carcinomas (ESCCs) have a poor prognosis mostly due to early metastasis. To explore the early event of metastasis in ESCC, we established an in vitro selection model to mimic the interaction of tumor cells with extracellular matrix, through which a sub-line of ESCC cells with high invasive ability was generated. By comparing the gene expression profile of the highly invasive sub-line to that of the parental cells, ADAM12-L was identified as a candidate gene promoting ESCC cell invasion. Immunohistochemistry revealed that the ADAM12-L was overexpressed in human ESCC tissues, especially at cancer invasive edge, and ADAM12-L overexpression tightly correlated with increased metastasis and poor outcome of ESCC patients. Indeed, ADAM12-L knockdown reduced the invasion and metastasis of ESCC cells both in vitro and in vivo. Furthermore, we demonstrated that ADAM12-L participated in focal adhesion turnover and promoted the activation of focal adhesion kinase (FAK), which in turn increased ADAM12-L transcription through FAK/JNK/c-Jun axis. Therefore, a loop initiated from the cancer cell upon the engagement with extracellular matrix through FAK and c-Jun to enhance ADAM12-L expression is established, leading to the positive feedback of further FAK activation and prompting metastasis. Our study indicates that overexpression of ADAM12-L can serve as a precision marker to determine the activation of this loop. Targeting ADAM12-L to disrupt this positive feedback loop represents a promising strategy to treat the metastasis of esophageal cancers. PMID- 29476792 TI - A review of the mycotoxin adsorbing agents, with an emphasis on their multi binding capacity, for animal feed decontamination. AB - Contamination of animal feed with mycotoxins still occurs very often, despite great efforts in preventing it. Animal feeds are contaminated, at low levels, with several mycotoxins, particularly with those produced by Aspergillus and Fusarium genera (Aflatoxin B1, Ochratoxin A, Zearalenone, Deoxynivalenol and Fumonisina B1). In animal feed, to date, only Aflatoxin B1 is limited through EU regulation. Consequently, mycotoxins cause serious disorders and diseases in farm animals. In 2009, the European Union (386/2009/EC) approved the use of mycotoxin detoxifying agents, as feed additives, to prevent mycotoxicoses in farm animals. The present review gives an overview of the problem of multi-mycotoxin contamination of feed, and aims to classify mycotoxin adsorbing agents (minerals, organic, and synthetic) for feed decontamination, focusing on adsorbents with the ability to bind to multiple mycotoxins, which should have a more effective application in farms but they are still little studied in scientific literature. PMID- 29476793 TI - The antioxidant activity of a prenyl flavonoid alters its antifungal toxicity on Candida albicans biofilms. AB - The antioxidant effect of 8PP, a prenylflavonoid from Dalea elegans on Candida albicans biofilms, was investigated. We previously reported that sensitive (SCa) and resistant C. albicans (RCa) biofilms were strongly inhibited by this compound, in a dose-depending manner (50 MUM-100 MUM), with a prooxidant effect leading to accumulation of endogenous oxidative metabolites and increased antioxidant defenses. In this work, the antifungal activity of high concentrations of 8PP (200-1000 MUM), the cellular stress imbalance and the architecture of biofilms were evaluated. Biofilms were studied by crystal violet and confocal scanning laser microscopy (CSLM) with COMSTAT analysis. Superoxide anion radical, the activity of the superoxide dismutase and the total antioxidant capacity were measured. Intracellular ROS were detected by a DCFH-DA and visualized by CSLM; reactive nitrogen intermediates by Griess. An antioxidant effect was detected at 1000 MUM and levels of oxidant metabolites remained low, with major changes in the SCa. COMSTAT analysis showed that biofilms treated with higher concentrations exhibited different diffusion distances with altered topographic surface architectures, voids, channels and pores that could change the flow inside the matrix of biofilms. We demonstrate for first time, a concentration-dependent antioxidant action of 8PP, which can alter its antifungal activity on biofilms. PMID- 29476794 TI - Effectiveness of prosthodontic interventions and survival of remaining teeth in adult patients with shortened dental arches-A systematic review. AB - OBJECTIVES: A systematic review of randomised and non-randomised controlled trials was conducted to evaluate studies of the effectiveness of different tooth replacement strategies in adult patients with shortened dental arches. The objectives of the review were to determine the survival rates of different prosthodontic interventions, the risk of tooth loss with and without prosthodontic interventions, and the impact of different tooth replacement strategies on oral-health related quality of life (OHRQoL). METHODS: The protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO CRD42017064851), and the review was conducted in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta analyses (PRISMA). RESULTS: The search strategy identified 112 potentially relevant publications; 22 from Medline (OVID), 54 from EMBASE (OVID), 35 from CENTRAL, one from the authors' knowledge of the subject area, and none from OpenSIGLE. Ten articles were included in this systematic review. Of these, four were analyses of different outcomes from a multicentre randomized controlled trial in Germany, whilst one study was the pilot phase for this trial. Two further randomized controlled trials were included from the United Kingdom and Republic of Ireland. The remaining articles were reports of prospective cohort studies from Denmark and the Netherlands. CONCLUSIONS: there is currently insufficient evidence to recommend one tooth replacement strategy over another in adult patients with reduced dentitions. CLINICAL SIGNIFICANCE: There is a need for further research as there are insufficient numbers of good quality randomised controlled trials currently available. Authors should be encouraged to adhere to CONSORT guidelines for randomized controlled trials, and report findings in such a way that facilitates future meta-analysis. PMID- 29476785 TI - Enhancing endogenous capacity to repair a stroke-damaged brain: An evolving field for stroke research. AB - Stroke represents a severe medical condition that causes stroke survivors to suffer from long-term and even lifelong disability. Over the past several decades, a vast majority of stroke research targets neuroprotection in the acute phase, while little work has been done to enhance stroke recovery at the later stage. Through reviewing current understanding of brain plasticity, stroke pathology, and emerging preclinical and clinical restorative approaches, this review aims to provide new insights to advance the research field for stroke recovery. Lifelong brain plasticity offers the long-lasting possibility to repair a stroke-damaged brain. Stroke impairs the structural and functional integrity of entire brain networks; the restorative approaches containing multi-components have great potential to maximize stroke recovery by rebuilding and normalizing the stroke-disrupted entire brain networks and brain functioning. The restorative window for stroke recovery is much longer than previously thought. The optimal time for brain repair appears to be at later stage of stroke rather than the earlier stage. It is expected that these new insights will advance our understanding of stroke recovery and assist in developing the next generation of restorative approaches for enhancing brain repair after stroke. PMID- 29476795 TI - Effects of volatile anaesthetics on heme metabolism in a murine genetic model of Acute Intermittent Porphyria. A comparative study with other porphyrinogenic drugs. AB - BACKGROUND: Acute Intermittent Porphyria (AIP) is an inherited disease produced by a deficiency of Porphobilinogen deaminase (PBG-D). The aim of this work was to evaluate the effects of Isoflurane and Sevoflurane on heme metabolism in a mouse genetic model of AIP to further support our previous proposal for avoiding their use in porphyric patients. A comparative study was performed administering the porphyrinogenic drugs allylisopropylacetamide (AIA), barbital and ethanol, and also between sex and mutation using AIP (PBG-D activity 70% reduced) and T1 (PBG D activity 50% diminished) mice. METHODS: The activities of 5-Aminolevulinic synthetase (ALA-S), PBG-D, Heme oxygenase (HO) and CYP2E1; the expression of ALA S and the levels of 5-aminolevulinic acid (ALA) were measured in different tissues of mice treated with the drugs mentioned. RESULTS: Isoflurane increased liver, kidney and brain ALA-S activity of AIP females but only affected kidney AIP males. Sevoflurane induced ALA-S activity in kidney and brain of female AIP group. PBG-D activity was further reduced by Isoflurane in liver male T1; in AIP male mice activity remained in its low basal levels. Ethanol and barbital also caused biochemical alterations. Only AIA triggered neurological signs similar to those observed during human acute attacks in male AIP being the symptoms less pronounced in females although ALA-S induction was greater. Heme degradation was affected. DISCUSSION: Biochemical alterations caused by the porphyrinogenic drugs assayed were different in male and female mice and also between T1 and AIP being more affected the females of AIP group. GENERAL SIGNIFICANCE: This is the first study using volatile anaesthetics in an AIP genetic model confirming Isoflurane and Sevoflurane porphyrinogenicity. PMID- 29476796 TI - Protocols of non-invasive brain stimulation for neuroplasticity induction. AB - Transcranial non-invasive brain stimulation (NIBS) has been widely applied in basic research and clinical intervention in the past few decades. It modulates cortical excitability through varies combinations of current form, stimulation position, strength, frequency, duration and intervals. In this review, protocols of different types of NIBS and their aftereffect are introduced. Moreover, evidences in physiology, pharmacology and behavior response are provided to support the effects of NIBS are plasticity-like effects because of their common mechanisms of synaptic plasticity. This is further confirmed by experiments on small animals at the cellular level. PMID- 29476797 TI - The pedunculopontine and laterodorsal tegmental nuclei in the kainate model of epilepsy. AB - Prior studies showed that epilepsy can be associated with reorganization of the septohippocampal cholinergic fiber system. Using the kainate model of epilepsy, we wished to further examine the structural integrity of the mesopontine tegmental nuclei (pedunculopontine, PPN, and laterodorsal, LDT), which provide the cholinergic input to the thalamus. It was found that the total numbers of the PPN and LDT cells immunoreactive to the vesicular acetylcholine transporter did not differ between control and epileptic rats. However, the cholinergic cells had enlarged perikarya in epileptic rats. We further examined the effects of epilepsy on the distribution pattern of cholinergic fiber varicosities in the parafascicular nucleus, one of the principal thalamic targets of PPN projections. The density of cholinergic varicosities, represented by two distinct populations, was increased in epileptic rats. These data provide the first morphological evidence for structural alterations in mesopontine cholinergic neurons in experimental epilepsy. They suggest dysfunctional cholinergic transmission in the brainstem-thalamic pathway, which may partly account for various epilepsy-related neurological disturbances. PMID- 29476798 TI - Prevalence of Dyspnea Among Hospitalized Patients at the Time of Admission. AB - CONTEXT: Dyspnea is an uncomfortable and distressing sensation experienced by hospitalized patients. OBJECTIVES: There is no large-scale study of the prevalence and intensity of patient-reported dyspnea at the time of admission to the hospital. METHODS: Between March 2014 and September 2016, we conducted a prospective cohort study among all consecutive hospitalized patients at a single tertiary care center in Boston, MA. During the first 12 hours of admission to medical-surgical and obstetric units, nurses at our institution routinely collect a patient's 1) current level of dyspnea on a 0-10 scale with 10 anchored at "unbearable," 2) worst dyspnea in the past 24 hours before arrival at the hospital on the same 0-10 scale, and 3) activities that were associated with dyspnea before admission. The prevalence of dyspnea was identified, and tests of difference were performed across patient characteristics. RESULTS: We analyzed 67,362 patients, 12% of whom were obstetric patients. Fifty percent of patients were admitted to a medical-surgical unit after treatment in the emergency department. Among all noncritically ill inpatients, 16% of patients experienced dyspnea in the 24 hours before the admission. Twenty-three percent of patients admitted through the emergency department reported any dyspnea in the past 24 hours. Eleven percent experienced some current dyspnea when interviewed within 12 hours of admission with 4% of patients experiencing dyspnea that was rated 4 or greater. Dyspnea of 4 or more was present in 43% of patients admitted with respiratory diagnoses and 25% of patients with cardiovascular diagnoses. After multivariable adjustment for severity of illness and patient comorbidities, patients admitted on the weekend or during the overnight nursing shift were more likely to report dyspnea on admission. CONCLUSION: Dyspnea is a common symptom among all hospitalized patients. Routine documentation of dyspnea is feasible in a large tertiary care center. PMID- 29476800 TI - Eating when depressed, anxious, bored, or happy: Are emotional eating types associated with unique psychological and physical health correlates? AB - The majority of research on emotional eating has examined general emotional eating, to the exclusion of more distinct emotions such as boredom and positive emotions. The current study aimed to examine whether specific types of emotional eating (i.e., eating in response to depression (EE-D), anxiety/anger (EE-A), boredom (EE-B), and positive emotions (EE-P)) were related to a range of psychological (i.e., global psychological well-being, eating disorder symptoms, emotion regulation) and physical health variables. A sample of adults (n = 189) with overweight/obesity were recruited via Amazon Mechanical Turk. Participants self-reported height and weight and completed a battery of questionnaires. Correlational analyses showed that more frequent EE-D, EE-A, and EE-B were related to poorer psychological well-being, greater eating disorder symptoms, and more difficulties with emotion regulation. EE-P was not significantly related to outcome variables. In regression analyses, eating in response to depression (EE D) was the type of emotional eating most closely related to psychological well being, eating disorder symptoms, and emotion regulation difficulties. Exploratory analyses revealed associations between EE-D, EE-A, and EE-B and facets of emotion regulation and specific disordered eating symptoms. Findings suggest that unique patterns exist between specific types of emotional eating and psychological outcomes. PMID- 29476799 TI - Effects of rhynchophylline on the hippocampal miRNA expression profile in ketamine-addicted rats. AB - In the past few years, ketamine, a noncompetitive NMDA antagonist, has been widely abused worldwide as a new type of synthetic drug, severely affecting the physical and mental health of ketamine abusers. Previous studies have suggested that rhynchophylline can alleviate drug abuse and reverse the conditioned place preference caused by the abuse. MicroRNAs (miRNAs) are important factors regulating gene expression and are involved in the drug addiction process. The hippocampus is a critical area in the brain involved in causing drug addiction. However, the hippocampal miRNA expression profile and the effects of rhynchophylline on miRNA expression during ketamine abuse have not been reported. Thus, this study analyzed the hippocampal miRNA expression profile during ketamine-dependence formation and the effects of rhynchophylline on the differential expression of miRNAs induced by ketamine. The results of microarray analysis suggested that the expression levels of miR-331-5p were significantly different among three groups (the control, ketamine, and ketamine + rhynchophylline groups). miR-331-5p levels were significantly decreased in the ketamine model group and were upregulated in the ketamine + rhynchophylline group. Bioinformatics analysis of miR-331-5p and the 3' UTR of nuclear receptor related 1 protein (Nurr1) identified binding sites and showed downregulation, and the overexpression of miR-331-5p in hippocampal tissues showed that miR-331-5p is a negative transcription regulatory factor of Nurr1. Interestingly, we found that the downstream protein of Nurr1, brain-derived neurotrophic factor (BDNF), showed identical expression trends in the hippocampus as Nurr1. However, the transcription of the protein upstream of Nurr1, cyclic adenosine monophosphate response element-binding protein (CREB), did not show any significant differences between the ketamine group and the ketamine + rhynchophylline group. However, after rhynchophylline intervention, p-CREB showed significant differences between the ketamine and the ketamine + rhynchophylline groups. In summary, miR-331-5p is a key regulatory factor of Nurr1, and rhynchophylline can participate in the process of resistance to ketamine addiction through the miR-331-5p/Nurr1/BDNF pathway or inhibition of CREB phosphorylation. PMID- 29476801 TI - Unravelling the association between inhibitory control and loss of control over eating among adolescents. AB - OBJECTIVE: Loss of control over eating is common among adolescents and is associated with negative developmental outcomes. Recent evidence points to impaired self-regulation, and more specifically poor inhibitory control, as a contributing factor to loss of control over eating among adults; however evidence in adolescent samples is limited. Moreover, in line with dual-process models, researchers have recently started to investigate the moderating role of automatic processes in this relationship, but again studies in adolescents are lacking. Therefore, the aim of the current study was to: (1) investigate whether there is an association between poor inhibitory control and loss of control over eating also among adolescents, and (2) explore whether this relationship is moderated by automatic processing. METHOD: A community sample of 124 adolescents (10-17 years; 65.3% girls; Mage = 14 years; SD = 1.90) was divided into a 'Loss of Control Group' (n = 30) and a 'No Loss of Control Group' (n = 94) based on a clinical interview. Inhibitory control and automatic processing (general and food specific) were measured by self-report questionnaires. RESULTS: Adolescents in the Loss of Control Group reported significantly more problems with overall self regulation compared to the No Loss of Control Group; however, there was no group difference for inhibition specifically. Contrary to dual-process predictions, there was a trend significant interaction between poor inhibitory control and weaker food specific automatic processing in explaining loss of control over eating. CONCLUSIONS: Evidence was found for problems with overall self-regulation in adolescents with loss of control over eating. Concerning the specific role of inhibitory control, future studies should replicate whether automatic processing is indeed a crucial moderator. PMID- 29476802 TI - A model of optimal protein allocation during phototrophic growth. AB - Photoautotrophic growth depends upon an optimal allocation of finite cellular resources to diverse intracellular processes. Commitment of a certain mass fraction of the proteome to a specific cellular function typically reduces the proteome available for other cellular functions. Here, we develop a semi quantitative kinetic model of cyanobacterial phototrophic growth to describe such trade-offs of cellular protein allocation. The model is based on coarse-grained descriptions of key cellular processes, in particular carbon uptake, metabolism, photosynthesis, and protein translation. The model is parameterized using literature data and experimentally obtained growth curves. Of particular interest are the resulting cyanobacterial growth laws as fundamental characteristics of cellular growth. We show that the model gives rise to similar growth laws as observed for heterotrophic organisms, with several important differences due to the distinction between light energy and carbon uptake. We discuss recent experimental data supporting the model results and show that coarse-grained growth models have implications for our understanding of the limits of phototrophic growth and bridge a gap between molecular physiology and ecology. PMID- 29476803 TI - Water-based aerobic and combined training in elderly women: Effects on functional capacity and quality of life. AB - This study aimed to investigate the effects of two water-based training programs (aerobic and combined) and a non-periodized physical activity program on functional capacity and quality of life (QoL) of elderly women. Forty-one elderly female volunteers (65 +/- 4 years) were divided into three groups: aerobic training group (WBA, n = 13), combined training (sequence: resistance/aerobic; WBC; n = 11) and a control group of non-periodized physical activity program (CG, n = 9). The participants performed the water-based trainings twice a week for 12 weeks. The resistance training sets were performed at maximal effort and the aerobic training was performed in the percentage of the heart rate corresponding to the anaerobic threshold (85-110%) determined in an aquatic progressive test. Assessments of QoL perception (WHOQOL-BREF) and functional tests 30-Second Chair Stand, 6-Minute Walk and 8-Foot Up-and-go were performed before and after training. The data were analyzed using Generalized Estimating Equations (GEE), and Bonferroni post-hoc test (alpha = 0.05). In CG, QoL perception in the physical domain decreased (12 +/- 10%) and there was no difference in the other domains. On the other hand, QoL perception was significantly increased in the water-based training groups after the training period in the physical (WBC: 13 +/ 16%), psychological (WBA: 9 +/- 16%; WBC: 10 +/- 11%), social relationships (WBA: 19 +/- 42%; WBC: 16 +/- 21%) and environmental (WBA: 10 +/- 17%; WBC: 16 +/ 28%) domains and overall QoL (WBA: 17 +/- 22%). No significant difference was observed in the physical domain for WBA and in the overall for WBC. Significant improvements were observed for all groups in the functional tests 30-Second Chair Stand (WBA: 32 +/- 11%; WBC: 24 +/- 14%; CG: 20 +/- 9), 6-Minute Walk (WBA: 10 +/ 7%; WBC: 7 +/- 6%; CG: 7 +/- 5%) and 8-Foot Up-and-go (WBA: 11 +/- 5%; WBC: 10 +/- 9%; CG: 10 +/- 6%). Based on the results observed in this study, it can be concluded that both water-based trainings (aerobic and combined) are effective in improving functional capacity and QoL perception of elderly women. Although non periodized physical activities seem to be sufficient to positively modify the functional capacity of this population, they are not efficient in improving QoL perception. PMID- 29476804 TI - Plasticity in central neural drive with short-term disuse and recovery - effects on muscle strength and influence of aging. AB - While short-term disuse negatively affects mechanical muscle function (e.g. isometric muscle strength) little is known of the relative contribution of adaptions in central neural drive and peripheral muscle contractility. The present study investigated the relative contribution of adaptations in central neural drive and peripheral muscle contractility on changes in isometric muscle strength following short-term unilateral disuse (4 days, knee brace) and subsequent active recovery (7 days, one session of resistance training) in young (n = 11, 24 yrs) and old healthy men (n = 11, 67 yrs). Maximal isometric knee extensor strength (MVC) (isokinetic dynamometer), voluntary muscle activation (superimposed twitch technique), and electrically evoked muscle twitch force (single and doublet twitch stimulation) were assessed prior to and after disuse, and after recovery. Following disuse, relative decreases in MVC did not differ statistically between old (16.4 +/- 3.7%, p < 0.05) and young (-9.7 +/- 2.9%, p < 0.05) (mean +/- SE), whereas voluntary muscle activation decreased more (p < 0.05) in old (-8.4 +/- 3.5%, p < 0.05) compared to young (-1.1 +/- 1.0%, ns) as did peak single (-25.8 +/- 6.6%, p < 0.05 vs -7.6 +/- 3.3%, p < 0.05) and doublet twitch force (-23.2 +/- 5.5%, p < 0.05 vs -2.0 +/- 2.6%, ns). All parameters were restored in young following 7 days recovery, whereas MVC and peak twitch force remained suppressed in old. Regression analysis revealed that disuse-induced changes in MVC relied more on changes in single twitch force in young (p < 0.05) and more on changes in voluntary muscle activation in old (p < 0.05), whereas recovery-induced changes in MVC mainly were explained by gains in voluntary muscle activation in both young and old. Altogether, the present data demonstrate that plasticity in voluntary muscle activation (~central neural drive) is a dominant mechanism affecting short-term disuse- and recovery-induced changes in muscle strength in older adults. PMID- 29476805 TI - An RNA-seq based transcriptomic investigation into the productivity and growth variants with Chinese hamster ovary cells. AB - Chinese hamster ovary (CHO) cells are widely used in producing monoclonal antibodies (mAbs), however, these cell lines can show variants associated with productivity and growth. Fundamental understanding of cellular mechanisms can benefit high mAbs production while maintaining robust cell growth. In this study, RNA sequencing (RNA-seq) based approach was used to study the transcriptomic space among three mAb-producing CHO cell lines. A phenotypic contrast of higher productivity but lower growth was found with one cell line versus the other two cell lines. The messenger RNAs (mRNAs) from those cells at two different time points in culture were sequenced to seek the gene functions possibly associated with the phenotypic differences. It was found that the mAb transcripts from each cell line were correlated with the mAb production level, indicating a strong determination of production by the expression level of gene of interest (GOI). Further exploration in the global transcriptome showed that the high producers had more expression with genes related with secretion and protein transportation. In the meantime, the slower growth of the high producers was linked to higher regulation to cell growth as well as lower gene expression on biosynthesis, central metabolism and nutrient transport. PMID- 29476806 TI - Chicken feather peptone: A new alternative nitrogen source for pigment production by Monascus purpureus. AB - Peptones are accepted as one of the most favourable nitrogen sources supporting pigment synthesis in Monascus purpureus. The present study was performed to test the feasibility of chicken feather peptone (CFP) as nitrogen source for pigment production from M. purpureus ATCC16365. CFP was compared with fish peptone (FP) and protease peptone (PP) in order to elucidate its effectiveness on pigment production. CFP was prepared from waste feathers using hydrolysis (KOH) and neutralization (H2SO4) methods. The protein content of CFP was determined as 67.2 g/100 g. Optimal concentrations of CFP and glucose for pigment production were determined as 3 and 20 g/L, respectively. A medium pH of 5.5 and an incubation period of 7-days were found to be more favourable for pigment production. In CFP, PP and FP media, yellow pigment absorbances were 2.819, 2.870 and 2.831, red pigment absorbances were 2.709, 2.304 and 2.748, and orange pigment absorbances were 2.643, 2.132 and 2.743, respectively. Sugar consumption and mycelia growth showed the similar trends in CFP, FP and PP media. This study indicates that the peptone from chicken feathers may be a good nutritional substrate for pigment production from M. purpureus. PMID- 29476807 TI - Advancing translational research and precision medicine with targeted proteomics. AB - Remarkable advances in quantitative mass spectrometry have shifted the focus of proteomics from the characterization of protein expression profiles to detailed investigations on the spatial and temporal organization of the proteome. Demands for precision therapy and personalized medicine are challenged by heterogeneity in the larger population, which have led to drawbacks in biomarker performance and therapeutic efficacy. The consistent adaptation of the cellular proteome in response to distinctive signals defines a phenotype. Acquisition of quantitative multi-layered omics data on multiple individuals over defined time scales has made it possible to establish means to probe the extent to which the genome, transcriptome and environment influence the variability of the proteome in given conditions, over time. Comprehensive, reproducible datasets generated with contemporary quantitative, massively parallel, targeted proteomic approaches offer as yet untapped benefits for biomarker discovery, development, and validation. The objective of this review is to recapitulate on advances in targeted proteomics approaches for quantifying the cellular proteome and to address ways to incorporate these data towards improving present day methodologies for biomarker evaluation and precision medicine. SIGNIFICANCE: Advances in quantitative mass spectrometry have shifted the focus of proteomics from the characterization of protein expression profiles to detailed investigations on the spatial and temporal organization of the proteome. This review expounds on avenues through which targeted proteomic methodologies can be constructively implemented in translational research and precision medicine to overcome existing challenges that hinder the success of protein biomarkers in clinics, and to develop precise therapeutics for future applications. PMID- 29476808 TI - Host defense cathelicidins in cattle: types, production, bioactive functions and potential therapeutic and diagnostic applications. AB - Cathelicidins are a primitive class of host defense peptides and are known for their broad-spectrum antimicrobial activity against bacteria, fungi, and enveloped viruses. These small, cationic, proteolytically-activated peptides are diverse in structure, encompassing a wide range of activities on host immune and inflammatory cell responses. The dual capacity of cathelicidins to directly control infection and regulate host defenses highlights the potential use of these peptides as alternatives to antibiotics and immunomodulators. Cathelicidins are found in many mammalian species; this review focuses on bovine cathelicidins. Eight naturally and two synthetically occurring bovine cathelicidins are described in detail, with a focus on recent advances in their expression, location and biological roles. This review also presents an overview of the bioactive functions of cathelicidins in bovine mastitis, a disease causing economic losses in cattle dairy production. Comparison of the structural, antimicrobial, cytotoxic and mechanistic properties of bovine cathelicidins advances the knowledge needed for the development of these peptides as potential identifiers of infectious diseases (e.g., bovine mastitis) and as novel therapeutic alternatives to antibiotics. PMID- 29476809 TI - Percutaneous and open iliac screw safety and accuracy using a tactile technique with adjunctive anteroposterior fluoroscopy. AB - BACKGROUND CONTEXT: All currently described percutaneous iliac screw placement methods are entirely dependent on fluoroscopy. PURPOSE: The purpose of this study was to determine the safety and the accuracy of percutaneous and open iliac screw placement using a primarily tactile technique with adjunctive anteroposterior (AP) fluoroscopy. STUDY DESIGN/CONTEXT: All patients who underwent open and percutaneous iliac screw placement over a 5-year period were identified. Charts were reviewed to assess for any instances of neurologic or vascular injury associated with iliac screw placement. Screw accuracy was judged with postoperative computed tomography (CT) scans. PATIENT SAMPLE: A total of 133 patients were identified who underwent open or percutaneous iliac screw placement. Computed tomography scans were available for 57 patients, and all of these patients were included in the study, with a total of 115 iliac screws. OUTCOME MEASURES: Radiographic measurements were performed, consisting of the distance of the iliac screw to the sciatic notch on postoperative radiographs and CT scans. Computed tomography scans were used to determine iliac screw accuracy. METHODS: Charts were reviewed to assess for any neurologic or vascular injuries related to screw placement. The distance of the iliac screw to the sciatic notch was measured and compared on AP radiography and CT scans. Computed tomography scans were assessed for any screw violation of the iliac cortex or the sciatic notch. The accuracy of open iliac screw placement was compared with minimally invasive percutaneous placement. RESULTS: There were no neurologic or vascular injuries related to screw placement in the 133 patients. Computed tomography scans were available for 115 iliac screws, with 3 cortical breaches, all by less than 2 mm. All 112 other screws were accurately intraosseous. There was a strong correlation between the iliac screw to the sciatic notch distance when measured by CT scan compared with AP radiography (r=0.9), thus validating the accuracy of AP fluoroscopy in guiding iliac screw placement with respect to the sciatic notch. Iliac screw accuracy was equal with the open and percutaneous insertion techniques. CONCLUSIONS: The described surgical technique represents a safe and reliable surgical option for iliac screw placement. Intraoperative AP fluoroscopy accurately reflects the distance of the iliac screw to the sciatic notch. Percutaneous iliac screws placed with this technique are as accurate as open iliac screws. PMID- 29476810 TI - Impact of Ultrasound-Guided Transvaginal Ovarian Needle Drilling Versus Laparoscopic Ovarian Drilling on Ovarian Reserve and Pregnancy Rate in Polycystic Ovary Syndrome: A Randomized Clinical Trial. AB - STUDY OBJECTIVE: To compare the impact of ultrasound-guided transvaginal ovarian needle drilling (TND) versus laparoscopic ovarian drilling (LOD) on ovarian reserve and pregnancy rate in patients with clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS). DESIGN: A randomized clinical trial (Canadian Task Force classification I). SETTING: A university hospital. PATIENTS: Of 644 patients who presented at an infertility clinic, 246 with CC-resistant PCOS were randomized for treatment. INTERVENTIONS: Patients were randomly allocated to ultrasound-guided TND (n = 124) and LOD (n = 122). MEASUREMENTS AND MAIN RESULTS: Ovarian reserve parameters (serum antimullerian hormone [AMH] and antral follicle count [AFC]) and pregnancy rate at 3 and 6 months were evaluated. At 3 months, patients in the LOD group experienced a significantly lower AMH (p < .001) and a higher ovulation rate (p < .05) with comparable AFC and pregnancy rate to patients in the TND group (p > .05) and a significant decrease in AMH and AFC within each individual group when compared with baseline (p < .001). At 6 months, patients in the LOD group experienced a significantly lower AMH (p < .001), lower AFC (p < .001), higher ovulation rate (p < .001) and higher pregnancy rate (p < .001) when compared with patients in the TND group. This effect started to diminish between the fourth and sixth month with an increase of AMH and AFC compared with baseline values (p < .05). CONCLUSIONS: Although TND is simple, safe, and less invasive than LOD, its effect on ovarian reserve appears to be transient and diminishes at 6 months. Multicenter studies are warranted to confirm efficacy as a second-line treatment in patients with CC-resistant PCOS. PMID- 29476811 TI - Progressive severe B cell and NK cell deficiency with T cell senescence in adult CD40L deficiency. PMID- 29476812 TI - Genomic characterization and evolution of Tacaiuma orthobunyavirus (Peribunyaviridae family) isolated in Brazil. AB - Tacaiuma virus (TCMV) is antigenically characterized as a member of the Anopheles A complex in the Orthobunyavirus genus, Peribunyaviridae family (Bunyavirales order). Clinically, the TCMV infection is characterized by acute febrile illness with myalgia and arthralgia lasting three to five days. However, the genomic and evolutionary aspect of this virus has not been elucidated. In this study, we described the complete coding sequences of three segments of two TCMV strains isolated in Brazil and three complete coding sequences of the small segment of three TCMV strains. All the strains sequenced in this study showed the typical genomic organization of orthobunyaviruses that infect vertebrates, except for the absence of the open reading frame that encodes the well-described non-structural small protein. This study presents the genomic and evolutionary characterization of TCMV strains and would be helpful for diagnostic purposes and epidemiology. PMID- 29476813 TI - ArgO145, a Stx2a prophage of a bovine O145:H- STEC strain, is closely related to phages of virulent human strains. AB - Shiga toxins (Stx) are the main virulence factor of a pathogroup of Escherichia coli strains that cause severe human diseases. These toxins are encoded in prophages (Stx prophages), and generally their expression depends on prophage induction. Several studies have reported high diversity among both Stx prophages and Stx. In particular, the toxin subtype Stx2a is associated with high virulence and HUS. Here, we report the genome of ArgO145, an inducible Stx2a prophage identified in a bovine O145:H- strain which produced high levels of Shiga toxin and Stx phage particles. The ArgO145 genome shared lambda phage organization, with recombination, regulation, replication, lysis, and head and tail structural gene regions, although some lambda genes encoding regulatory proteins could not be identified. Remarkably, some Stx2a phages of strains isolated from patients in other countries showed high similarity to ArgO145. PMID- 29476815 TI - Enhanced bioproduction of 2-phenylethanol in a biphasic system with rapeseed oil. AB - Increasing demand for natural fragrance ingredients and products has led to their global market growth. 2-Phenylethanol (2-PE) is a volatile substance widely used in food and cosmetics manufacturing. It is generally known that yeast can metabolize l-phenylalanine (l-Phe) to produce 2-PE. However, because the product exhibits an inhibitory effect on yeast cells, simple batch cultivation is uneconomic. The aim of this study was to enhance 2-PE productivity using in situ product removal. Here we present a new method of 2-PE production by yeast in a biphasic system with rapeseed oil as the second phase. The chosen solvent is safe, inexpensive and suitable for the extraction of 2-PE. In addition, rapeseed oil appeared to be a valuable source of intermediates for 2-PE synthesis as its presence in the yeast culture significantly enhanced productivity. The process is an environmentally friendly route and gives two final products that can be considered natural: rapeseed oil with a rose odor and pure 2-PE. Both may be subsequently used as food or cosmetics additives. The results obtained are competitive with previously reported values, as it was possible to enhance the overall concentration of 2-PE by 2.7-fold. The total 2-PE concentration in the biphasic system in the 4.5-L biofermentor used was increased to 9.79 g/L, while the 2-PE concentration in the organic phase attained a value of 18.50 g/L. PMID- 29476814 TI - The Right Axillary Incision: A Potential New Standard of Care for Selected Congenital Heart Surgery. AB - Although the median sternotomy has been the traditional approach for congenital heart surgery, young patients and their families often find the midline scar to be cosmetically unappealing. At our center, a right transverse axillary incision has become the standard approach for many congenital cardiac lesions because of its safety, versatility, and unsurpassed aesthetic result. We present our experience with the axillary approach for a diverse array of congenital defects. A retrospective review of patients receiving a right transverse axillary incision for congenital cardiac surgery between 2005 and 2016 was conducted. The right transverse axillary incision was performed in 358 patients for 24 unique procedures. Median age was 5 years (range 1 month-60 years) and 225 patients (63%) were female. Median weight was 17 kg (range 4-124 kg), with 19 patients (5%) weighing less than 6 kg. The most common lesions were atrial septal defects (n = 244, 68%) and ventricular septal defects (n = 72, 20%). As experience with this approach increased, other repairs included subvalvular aortic membrane resection (n = 10, 3%), tetralogy of Fallot repair (n = 7, 2%), ventricular assist device placement (n = 3, 1%), and mitral valve repair (n = 2, 1%). There were no intraoperative deaths or conversions to sternotomy. In-hospital complications included mortality (n = 1, 0.3%), reoperations for bleeding (n = 5, 1%), pneumothorax or pleural effusion (n = 6, 2%), and permanent pacemaker (n = 4, 1%). The right axillary incision allows a safe and effective repair for a broad range of congenital heart defects and is a potential new standard of care for many patients. PMID- 29476816 TI - Potential use of ricotta cheese whey for the production of lactobionic acid by Pseudomonas taetrolens strains. AB - Lactobionic acid (LBA) is a fine chemical largely applied in the food, chemical, cosmetics and pharmaceutical industries. Here, its production from ricotta cheese whey (RCW), or scotta, the main by-product obtained from ricotta cheese production process and currently employed mainly for cattle feed, was evaluated. Among seven bacterial species tested, only two Pseudomonas taetrolens strains were selected after preliminary screening in shake-flasks. When autoclaved RCW was used, a lactobionic acid titer of 34.25 +/- 2.86 g/l, with a conversion yield (defined as mol LBA/mol of consumed lactose%) of up to 85 +/- 7.0%, was obtained after 48 h of batch fermentation in 3 L stirred tank bioreactor. This study is a preliminary investigation on the potential industrial use of scotta as a substrate for bacterial growth and lactobionic acid production that details the possible biotechnological valorization pathways and feasibility of the process. PMID- 29476817 TI - Basal Tear Osmolarity as a metric to estimate body hydration and dry eye severity. AB - The osmolarities of various bodily fluids, including tears, saliva and urine, have been used as indices of plasma osmolality, a measure of body hydration, while tear osmolarity is used routinely in dry eye diagnosis, the degree of tear hyperosmolarity providing an index of disease severity. Systemic dehydration, due to inadequate water intake or excessive water loss is common in the elderly population, has a high morbidity and may cause loss of life. Its diagnosis is often overlooked and there is a need to develop a simple, bedside test to detect dehydration in this population. We hypothesize that, in the absence of tear evaporation and with continued secretion, mixing and drainage of tears, tear osmolarity falls to a basal level that is closer to that of the plasma than that of a tear sample taken in open eye conditions. We term this value the Basal Tear Osmolarity (BTO) and propose that it may be measured in tear samples immediately after a period of evaporative suppression. This value will be particular to an individual and since plasma osmolarity is controlled within narrow limits, it is predicted that it will be stable and have a small variance. It is proposed that the BTO, measured immediately after a defined period of eye closure, can provide a new metric in the diagnosis of systemic dehydration and a yardstick against which to gauge the severity of dry eye disease. PMID- 29476818 TI - Immune defense of emodin enriched diet in Clarias batrachus against Aeromonas hydrophila. AB - This study investigates the effect of emodin enriched diet on growth, hematology, and immune response in walking catfish, Clarias batrachus against Aeromonas hydrophila. The basal (control) diet supplemented with emodin at 0.0, 0.1, 0.2, or 0.4 g kg-1 was fed to the experimental groups for a period of four weeks. Feeding infected fish with 0.2 g kg-1 and 0.4 g kg-1 emodin enriched diets resulted in an overall weight gain, enhanced PER and FCR when compared to other diets. The survival rates were 98.3% and 96.7% in 0.1 g kg-1 and 0.4 g kg-1 emodin diet fed groups. Feeding with 0.2 g kg-1 diet the RBC level significantly elevated on week 1 and with 0.4 g kg-1 diet on weeks 2 and 4. The WBC, the percentage of globulin and neutrophils increased significantly with 0.2 g kg-1 diet only on week 4; however with 0.4 g kg-1 diet the increase was observed from week 1-4. The phagocytic activity increased significantly on being fed with 0.4 g kg-1 diet on week 2 while with 0.2 g kg-1 and 0.4 g kg-1 diets the increase manifested only on week 4; the respiratory burst activity also significantly increased on week 4 whereas increased the complement activity on weeks 2 and 4. The superoxide dismutase (SOD) activity was high on being fed with 0.4 g kg-1 diet on week 1; with 0.2 g kg-1 or 0.4 g kg-1 diets the increase was observed on weeks 2 and 4. The serum IgM level significantly increased when fed with 0.4 g kg 1 diet whereas the lysozyme activity was enhanced with 0.2 g kg-1 and 0.4 g kg-1 emodin diets on weeks 2 and 4. The percentage cumulative mortality was 10% with 0.1 g kg-1 or 0.2 g kg-1 diets while with 0.2 g kg-1 diet it was 15%. The results demonstrate that as a feed additive emodin acts as an immunostimulant enhancing the specific and nonspecific immune defense affording increased disease protection, enhances better growth and boosts hematology parameters in C. batrachus against A. hydrophila infection. PMID- 29476819 TI - Role of Sirtuin1-p53 regulatory axis in aging, cancer and cellular reprogramming. AB - Regulatory role of Sirtuin 1 (SIRT1), one of the most extensively studied members of its kind in histone deacetylase family in governing multiple cellular fates, is predominantly linked to p53 activity. SIRT1 deacetylates p53 in a NAD+ dependent manner to inhibit transcription activity of p53, in turn modulate pathways that are implicated in regulation of tissue homoeostasis and many disease states. In this review, we discuss the role of SIRT1-p53 pathway and its regulatory axis in the cellular events which are implicated in cellular aging, cancer and reprogramming. It is noteworthy that these cellular events share few common regulatory pathways, including SIRT1-p53-LDHA-Myc, miR-34a,-Let7 regulatory network, which forms a positive feedback loop that controls cell cycle, metabolism, proliferation, differentiation, epigenetics and many others. In the context of aging, SIRT1 expression is reduced as a protective mechanism against oncogenesis and for maintenance of tissue homeostasis. Interestingly, its activation in aged cells is evidenced in response to DNA damage to protect the cells from p53-dependent apoptosis or senescence, predispose these cells to neoplastic transformation. Importantly, the dual roles of SIRT1-p53 axis in aging and tumourigenesis, either as tumour suppressor or tumour promoter are determined by SIRT1 localisation and type of cells. Conceptualising the distinct similarity between tumorigenesis and cellular reprogramming, this review provides a perspective discussion on involvement of SIRT1 in improving efficiency in the induction and maintenance of pluripotent state. Further research in understanding the role of SIRT1-p53 pathway and their associated regulators and strategies to manipulate this regulatory axis very likely foster the development of therapeutics and strategies for treating cancer and aging-associated degenerative diseases. PMID- 29476820 TI - Testosterone complex and non-steroidal ligands of human aromatase. AB - Cytochrome P450 aromatase (AROM) catalyzes the biosynthesis of estrogen from androgen. Previously crystal structures of human AROM in complex with the substrate androstenedione, and inhibitors exemestane, as well as the newly designed steroidal compounds, have been reported. Here we report the first crystal structure of testosterone complex of human placental AROM. Testosterone binds at the androgen-specific heme distal pocket. The polar and hydrophobic interactions with the surrounding residues resemble the interactions observed for other ligands. The heme proximal region comprises the intermolecular interface in AROM, and also the putative interaction surface of its redox partner cytochrome P450 reductase. Unreported previously, the proximal region is characterized by a large surface cavity, unlike most known P450's. Using five best X-ray data sets from androstenedione and testosterone complexes of AROM, we now unequivocally show the presence of an unexplained ligand electron density inside the proximal cavity. The density is interpreted as ordered five ethylene glycol units of polyethylene glycols used as a solvent for steroids and also in crystallization. Interestingly, polyethylene glycol exhibits weak inhibition of AROM enzyme activity in a time dependent manner. Besides its critical role in the redox partner coupling and electron transfer process, the proximal cavity possibly serves as the interaction site for other molecules that may have regulatory effects on AROM activity. In addition, the new data also reveal a previously unidentified water channel linking the active site to the lipid interface. The channel could be the predicted passage for water molecules involved in catalysis. PMID- 29476821 TI - Assessing complex movement behaviors in rodent models of neurological disorders. AB - Behavioral phenotyping is a crucial step in validating animal models of human disease. Most traditional behavioral analyses rely on investigator observation of animal subjects, which can be confounded by inter-observer variability, scoring consistency, and the ability to observe extremely rapid, small, or repetitive movements. Force-Plate Actimeter (FPA)-based assessments can quantify locomotor activity and detailed motor activity with an incredibly rich data stream that can reveal details of movement unobservable by the naked eye. This report describes four specific examples of FPA analysis of behavior that have been useful in specific rat or mouse models of human neurological disease, which show how FPA analysis can be used to capture and quantify specific features of the complex behavioral phenotypes of these animal models. The first example quantifies nociceptive behavior of the rat following injection of formalin into the footpad as a common model of persistent inflammatory pain. The second uses actimetry to quantify intense, rapid circling behaviors in a transgenic mouse that overexpresses human laminin alpha5, a basement membrane protein. The third example assesses place preference behaviors in a rat model of migraine headache modeling phonophobia and photophobia. In the fourth example, FPA analysis revealed a unique movement signature emerged with age in a digenic mutant mouse model of Tourette Syndrome. Taken together, these approaches demonstrate the power and usefulness of the FPA in the examination and quantification of minute details of motor behaviors, greatly expanding the scope and detail of behavioral phenotyping of preclinical models of human disease. PMID- 29476822 TI - Hippocampal network oscillations as mediators of behavioural metaplasticity: Insights from emotional learning. AB - Behavioural metaplasticity is evident in experience-dependent changes of network activity patterns in neuronal circuits that connect the hippocampus, amygdala and medial prefrontal cortex. These limbic regions are key structures of a brain-wide neural network that translates emotionally salient events into persistent and vivid memories. Communication in this network by-and-large depends on behavioural state-dependent rhythmic network activity patterns that are typically generated and/or relayed via the hippocampus. In fact, specific hippocampal network oscillations have been implicated to the acquisition, consolidation and retrieval, as well as the reconsolidation and extinction of emotional memories. The hippocampal circuits that contribute to these network activities, at the same time, are subject to both Hebbian and non-Hebbian forms of plasticity during memory formation. Further, it has become evident that adaptive changes in the hippocampus-dependent network activity patterns provide an important means of adjusting synaptic plasticity. We here summarise our current knowledge on how these processes in the hippocampus in interaction with amygdala and medial prefrontal cortex mediate the formation and persistence of emotional memories. PMID- 29476823 TI - Lipophorin receptor regulates Nilaparvata lugens fecundity by promoting lipid accumulation and vitellogenin biosynthesis. AB - Insect lipophorin receptor (LpR) belongs to the low-density lipoprotein receptor (LDLR) superfamily and plays an essential role in fecundity by mediating the incorporation of lipophorin into developing oocytes. Here we report the identification and characterization of a full-length cDNA encoding a putative LpR from the brown planthopper, Nilaparvata lugens. The deduced amino acid sequence of NlLpR possesses the conserved structural motifs of LDLR family members, and displays a high degree of similarity with sequences from other insect LpRs. NlLpR is transcribed throughout oogenesis with its maximum level on day 7 after adult female emergence. NlLpR is highly expressed in the fat body and ovary, with relative low levels in the head, epidermis and midgut. Knockdown of NlLpR using double-stranded RNA (dsRNA) led to decreased triacylglycerol (TAG) content, retarded development of ovaries and decreased fecundity. Further functional analyses revealed that NlLpR works through nutritional signaling pathway dependent activation of S6 kinase to regulate vitellogenin (Vg) biosynthesis during vitellogenesis and oocyte development. Disrupting of ecdysone receptor (EcR) expression and 20-hydroxyecdysone (20E) topical application demonstrated that NlLpR is regulated by ecdysone at transcript level. These results suggest that LpR is essential for Vg synthesis in the fat body and lipid uptake by developing oocytes, thus playing a critical role in insect reproduction. PMID- 29476824 TI - Functional characterization of the Sporothrix schenckii Ktr4 and Ktr5, mannosyltransferases involved in the N-linked glycosylation pathway. AB - Sporothrix schenckii is one of the causative agents of the deep-seated mycosis sporotrichosis, a fungal infection with worldwide distribution. Fungus-specific molecules and biosynthetic pathways are potential targets for the development of new antifungal drugs. The MNT1/KRE2 gene family is a group of genes that encode fungus-specific Golgi-resident mannosyltransferases that participate in the synthesis of O-linked and N-linked glycans. While this family is composed of five and nine members in Candida albicans and Saccharomyces cerevisiae, respectively, the S. schenckii genome contains only three putative members. MNT1 has been previously characterized as an enzyme that participates in the synthesis of both N-linked and O-linked glycans. Here, we aimed to establish the functional role of the two remaining family members, KTR4 and KTR5, in the protein glycosylation pathways by using heterologous complementation in C. albicans mutants lacking genes of the MNT1/KRE2 family. The two S. schenckii genes restored defects in the elaboration of N-linked glycans, but no complementation of mutants that synthesize truncated O-linked glycans was observed. Therefore, our results suggest that MNT1 is the sole member with a role in O-linked glycan elaboration, whereas the three family members have redundant activity in the S. schenckii N linked glycan synthesis. PMID- 29476825 TI - Unipolar atrial electrogram morphology from an epicardial and endocardial perspective. AB - BACKGROUND: Endo-epicardial asynchrony (EEA) and the interplay between the endocardial and epicardial layers could be important in the pathophysiology of atrial arrhythmias. The morphologic differences between epicardial and endocardial atrial electrograms have not yet been described, and electrogram morphology may hold information about the presence of EEA. OBJECTIVE: The purpose of this study was to directly compare epicardial to endocardial unipolar electrogram morphology during sinus rhythm (SR) and to evaluate whether EEA contributes to electrogram fractionation by correlating fractionation to spatial activation patterns. METHODS: In 26 patients undergoing cardiac surgery, unipolar electrograms were simultaneously recorded from the epicardium and endocardium at the inferior, middle, and superior right atrial (RA) free wall during SR. Potentials were analyzed for epi-endocardial differences in local activation time, voltage, RS ratio, and fractionation. The surrounding and opposite electrograms of fractionated deflections were evaluated for corresponding local activation times in order to determine whether fractionation originated from EEA. RESULTS: The superior RA was predisposed to delayed activation, EEA, and fractionation. Both epicardial and endocardial electrograms demonstrated an S predominance. Fractionation was mostly similar between the 2 sides; however, incidentally deflections up to 4 mV on 1 side could be absent on the other side. Remote activation was responsible for most fractionated deflections (95%) in SR, of which 4% could be attributed to EEA. CONCLUSION: Local epi-endocardial differences in electrogram fractionation occur occasionally during SR but will likely increase during arrhythmias due to increasing EEA and (functional) conduction disorders. Electrogram fractionation can originate from EEA, and this study demonstrated that unipolar electrogram fractionation can potentially identify EEA. PMID- 29476826 TI - Effective phthalocyanines mediated photodynamic therapy with doxorubicin or methotrexate combination therapy at sub-micromolar concentrations in vitro. AB - To improve a cancer patient's quality of life, short treatment duration resulting in rapid tumour removal while sparing normal tissue are highly desirable. Photodynamic therapy (PDT) commonly applied in a single treatment, while often effective can be limited at low photosensitizer or light doses. Combination therapies can overcome the efficacy limitations while not increasing treatment associated morbidity. Here the efficacy of combination therapy comprised of doxorubicin (DOX) or methotrexate (MTX) with Photosens mediated PDT was investigated in three cell lines in vitro, employing multiple incubation sequences. Photosense is a mixture of aluminium phthalocyanines with different sulfonation. The results demonstrated higher synergistic effects when DOX or MTX mediated chemotherapy preceded PDT light activation by 24 h. MTX is marginally more cytotoxic than DOX, when combined with Photosens (AlPcS2-4) mediated PDT. While MTX and DOX exposure prior to AlPcS2-4 incubation may enhance mitochondrial localisation photosensitizer, the simultaneous targeting of DNA, proteins, and lipids of the combination therapies leads to the observed high cytotoxicity at sub MUM drug doses. PMID- 29476827 TI - Superficial resection combined with photodynamic therapy for successful treatment of facial lupus vulgaris with squamous cell carcinoma. AB - Skin squamous cell carcinoma is the second most common non-melanoma skin tumor worldwide. Most skin squamous cell carcinoma patients have underlying diseases. Here, we report a 56 year-old patient diagnosed with skin squamous cell carcinoma and with a 30 year course of neglected lupus vulgaris, which was very rare. In this case, we adopted a treatment strategy involving a small wound: superficial resection combined with photodynamic therapy with a satisfied result. PMID- 29476828 TI - Phosphatidylglycerophosphate phosphatase is required for root growth in Arabidopsis. AB - Phosphatidylglycerol (PG) is an indispensable lipid class in photosynthetic activity. However, the importance of PG biosynthesis in non-photosynthetic organs remains elusive. We previously identified phosphatidylglycerophosphate phosphatase 1 (PGPP1), which catalyzes the last step of PG biosynthesis in Arabidopsis thaliana. In the present report, we noted considerably shorter roots of the pgpp1-1 mutant compared to the wild type. We observed defective order of columella cells in the root apices, which was complemented by introducing the wild-type PGPP1 gene. Although PGPP1 is chloroplast-localized in leaf mesophyll cells, we observed mitochondrial localization of PGPP1 in root cells, suggesting possible dual targeting of PGPP1. Moreover, we identified previously uncharacterized 2 protein tyrosine phosphatase-like proteins as functional PGPPs. These proteins, designated PTPMT1 and PTPMT2, complemented growth and lipid phenotypes of Deltagep4, a Saccharomyces cerevisiae mutant of PGPP. The ptpmt1-1 ptpmt2-1 exhibited no visible phenotype; however, the pgpp1-1 ptpmt1-1 ptpmt2-1 significantly enhanced the root phenotype of pgpp1-1 without further affecting the photosynthesis, suggesting that these newly found PGPPs are involved in the root phenotype. Radiolabeling experiment of mutant roots showed that decreased PG biosynthesis is associated with the mutation of PGPP1. These results suggest that PG biosynthesis is required for the root growth. PMID- 29476829 TI - Management of red blood cell alloimmunization in pregnancy. AB - The main cause of fetal anemia is maternal red blood cell alloimmunization (AI). The search of maternal antibodies by indirect antiglobulin test allows screening for AI during pregnancy. In case of AI, fetal genotyping (for Rh-D, Rh-c, Rh-E and Kell), quantification (for anti-rhesus antibodies) and antibody titration, as well as ultrasound monitoring, are performed. This surveillance aims at screening for severe anemia before hydrops fetalis occurs. Management of severe anemia is based on intrauterine transfusion (IUT) or labor induction depending on gestational age. After intrauterine transfusion, follow-up will focus on detecting recurrence of anemia and detecting fetal brain injury. With IUT, survival of fetuses with alloimmunization is greater than 90% but 4.8% of children with at least one IUT have neurodevelopmental impairment. PMID- 29476830 TI - Origins of robustness in translational control via eukaryotic translation initiation factor (eIF) 2. AB - Phosphorylation of eukaryotic translation initiation factor 2 (eIF2) is one of the best studied and most widely used means for regulating protein synthesis activity in eukaryotic cells. This pathway regulates protein synthesis in response to stresses, viral infections, and nutrient depletion, among others. We present analyses of an ordinary differential equation-based model of this pathway, which aim to identify its principal robustness-conferring features. Our analyses indicate that robustness is a distributed property, rather than arising from the properties of any one individual pathway species. However, robustness conferring properties are unevenly distributed between the different species, and we identify a guanine nucleotide dissociation inhibitor (GDI) complex as a species that likely contributes strongly to the robustness of the pathway. Our analyses make further predictions on the dynamic response to different types of kinases that impinge on eIF2. PMID- 29476831 TI - Adhesion and volume constraints via nonlocal interactions determine cell organisation and migration profiles. AB - The description of the cell spatial pattern and characteristic distances is fundamental in a wide range of physio-pathological biological phenomena, from morphogenesis to cancer growth. Discrete particle models are widely used in this field, since they are focused on the cell-level of abstraction and are able to preserve the identity of single individuals reproducing their behavior. In particular, a fundamental role in determining the usefulness and the realism of a particle mathematical approach is played by the choice of the intercellular pairwise interaction kernel and by the estimate of its parameters. The aim of the paper is to demonstrate how the concept of H-stability, deriving from statistical mechanics, can have important implications in this respect. For any given interaction kernel, it in fact allows to a priori predict the regions of the free parameter space that result in stable configurations of the system characterized by a finite and strictly positive minimal interparticle distance, which is fundamental when dealing with biological phenomena. The proposed analytical arguments are indeed able to restrict the range of possible variations of selected model coefficients, whose exact estimate however requires further investigations (e.g., fitting with empirical data), as illustrated in this paper by series of representative simulations dealing with cell colony reorganization, sorting phenomena and zebrafish embryonic development. PMID- 29476832 TI - Using Chou's general PseAAC to analyze the evolutionary relationship of receptor associated proteins (RAP) with various folding patterns of protein domains. AB - The receptor-associated protein (RAP) is an inhibitor of endocytic receptors that belong to the lipoprotein receptor gene family. In this study, a computational approach was tried to find the evolutionarily related fold of the RAP proteins. Through the structural and sequence-based analysis, found various protein folds that are very close to the RAP folds. Remote homolog datasets were used potentially to develop a different support vector machine (SVM) methods to recognize the homologous RAP fold. This study helps in understanding the relationship of RAP homologs folds based on the structure, function and evolutionary history. PMID- 29476833 TI - Recognition of the long range enhancer-promoter interactions by further adding DNA structure properties and transcription factor binding motifs in human cell lines. AB - The enhancer-promoter interactions (EPIs) with strong tissue-specificity play an important role in cis-regulatory mechanism of human cell lines. However, it still remains a challenging work to predict these interactions so far. Due to that these interactions are regulated by the cooperativeness of diverse functional genomic signatures, DNA spatial structure and DNA sequence elements. In this paper, by adding DNA structure properties and transcription factor binding motifs, we presented an improved computational method to predict EPIs in human cell lines. In comparison with the results of other group on the same datasets, our best accuracies by cross-validation test were about 15%-24% higher in the same cell lines, and the accuracies by independent test were about 11%-15% higher in new cell lines. Meanwhile, we found that transcription factor binding motifs and DNA structure properties have important information that would largely determine long range EPIs prediction. From the distribution comparisons, we also found their distinct differences between interacting and non-interacting sets in each cell line. Then, the correlation analysis and network models for relationships among top-ranked functional genomic signatures indicated that diverse genomic signatures would cooperatively establish a complex regulatory network to facilitate long range EPIs. The experimental results provided additional insights about the roles of DNA intrinsic properties and functional genomic signatures in EPIs prediction. PMID- 29476834 TI - Novel proteins that regulate cell extension formation in fibroblasts. AB - Cell extensions are critical structures that enable matrix remodeling in wound healing and cancer invasion but the regulation of their formation is not well defined. We searched for new proteins that mediated cell extension formation over collagen by tandem mass tagged mass spectrometry analysis of purified extensions in 3T3 fibroblasts. Unexpectedly, importin-5, ENH isoform 1b (PDLIM5) and 26 S protease regulatory subunit 6B (PSMC4) were more abundant (> 10-fold) in membrane penetrating cell extensions than cell bodies, which was confirmed by immunostaining and immunoblotting and also observed in human gingival fibroblasts. After siRNA knockdown of these proteins and plating cells on grid supported floating collagen gels for 6 h, formation of cell extensions and collagen remodeling were examined. Knockdown of importin-5 reduced collagen compaction (1.9-fold), pericellular collagen degradation (~ 1.8-fold) and number of cell extensions (~ 69%). Knockdown of PSMC4 reduced collagen compaction (~ 1.5 fold), pericellular collagen degradation (~ 1.7-fold) and number of cell extensions (~ 42%). Knockdown of PDLIM5 reduced collagen compaction (~ 1.6-fold) and number of cell extensions (~ 21%). Inhibition of the TGF-beta RI kinase, Smad3 or ROCK-II signaling pathways reduced the abundance of PDLIM5 in cell extensions but PSMC4 and importin-5 were reduced only by Smad3 or ROCK-II inhibitors. We conclude that these novel proteins are required for cell extension formation and their recruitment into extensions involves the Smad3 and ROCK signaling pathways. PMID- 29476835 TI - CD18-mediated adhesion is required for the induction of a proinflammatory phenotype in lung epithelial cells by mononuclear cell-derived extracellular vesicles. AB - Extracellular vesicles are submicron vesicles that upregulate the synthesis of proinflammatory mediators by lung epithelial cells. We investigated whether these structures adhere to lung epithelial cells, and whether adhesion is a prerequisite for their proinflammatory activity. Extracellular vesicles were generated by stimulation of normal human mononuclear cells with the calcium ionophore A23187, and labelled with carboxyfluorescein diacetate succinimidyl ester. Adhesion of vesicles to monolayers of immortalized bronchial epithelial (16HBE) and alveolar (A549) cells was analyzed by fluorescence microscopy. The role of candidate adhesion receptors was evaluated with inhibitory monoclonal antibodies and soluble peptides. The synthesis of proinflammatory mediators was assessed by ELISA. Transmission electron microscopy confirmed the generation of closed vesicles with an approximate size range between 50 and 600 nm. Adhesion of extracellular vesicles to epithelial cells was upregulated upon stimulation of the latter with tumor necrosis factor-alpha. Adhesion was blocked by an anti-CD18 antibody, by peptides containing the sequence RGD and, to a lesser extent, by an antibody to ICAM-1. The same molecules also blocked the upregulation of the synthesis of interleukin-8 and monocyte chemotactic protein-1 induced by extracellular vesicles. CD18-mediated adhesion of extracellular vesicles is a prerequisite for their proinflammatory activity. PMID- 29476836 TI - Human serum alters cell culture behavior and improves spheroid formation in comparison to fetal bovine serum. AB - BACKGROUND: The use of fetal bovine serum (FBS) as growth supplement for human cell and tissue culture is widely spread in basic research as well as in clinical approaches, although several limitations must be considered, such as unstable composition and availability, biosafety and ethical aspects. Regarding interspecies differences, xenogeneic growth factors may evoke incompatibilities and non-desired interactions with human cells resulting in imprecise outcome of human-relevant data. METHODS: In this study the functionality of human serum (HS) has been investigated in comparison to FBS by assessing proliferation, migration and invasion of the human cervical cancer cell lines SiHa and HeLa. The effects of both sera on spheroid formation were analyzed microscopically. RESULTS: Both, FBS and HS, stimulate cell proliferation and migration similarly, whereas HS significantly enhanced cell invasion. The spheroid formation assay revealed remarkable differences between both sera, especially for SiHa cells. While in FBS supplemented medium cells only formed loose aggregates, HS induced regularly shaped spheroids under all tested conditions. CONCLUSION: We were able to demonstrate that HS and FBS differently influence behavior of cells in culture which may have an impact on experimental results, especially in 3D cultures. PMID- 29476837 TI - Enhanced photocatalytic activity of Bi12O17Cl2 nano-sheets via surface modification of carbon nanotubes as electron carriers. AB - A novel carbon nanotubes modified Bi12O17Cl2 composite (CNTs/Bi12O17Cl2) was prepared via hydrothermal method. The chemical structures, morphologies, optical properties of the synthesized samples were revealed by XRD, XPS, SEM, TEM, BET and UV-vis DRS measurements. The photocatalytic activity of the CNTs/Bi12O17Cl2 composite was evaluated with degradation reaction of rhodamine B (RhB) under visible light. CNTs/Bi12O17Cl2 exhibited improved photocatalytic activity in comparison with pure Bi12O17Cl2, and kept favorable stability and recyclability in the reaction. The relatively high photocatalytic activity of CNTs/Bi12O17Cl2 resulted from the enhanced separation efficiency of photo-induced charges, which were revealed by the photoluminescence spectra and transient photocurrent measurements. CNTs loaded at the surface of Bi12O17Cl2 sheets acted as electron carriers to efficiently transfer the photoinduced electrons, namely to promote the separation of photoinduced electrons and holes, thus improving the photocatalytic activity of the composite materials. At last, a possible photocatalytic reaction mechanism over the CNTs/Bi12O17Cl2 composite was proposed based on the results of trapping experiment, ESR measurements and the band energy analysis. PMID- 29476838 TI - Flexible and transparent films consisting of lanthanide complexes for ratiometric luminescence thermometry. AB - Herein, a flexible and transparent film consisting Eu3+/Tb3+ lanthanide complexes and poly(methylmethacrylate) was constructed via solution casting method, and further developed as a ratiometric luminescent thermometer with an excellent linear response to temperature variation from 77 to 297 K. The thermometer displays higher photo- and thermostability than corresponding pure complexs. Based on that the emission intensity ratio of 5D4 -> 7F5 transition (Tb3+) to 5D0 -> 7F2 transition (Eu3+) can be linearly related to the temperature, the resulting thermometer is not only more reliable than single Eu3+(or Tb3+) material based on one emission, and but also has higher sensitivity than other types of luminescent thermometers. This work highlights the practical applications of luminescent films in temperature-sensing fields. PMID- 29476839 TI - Brain responses associated with different hierarchical effects on cues and targets during rule shifting. AB - Numerous studies have explored the neural mechanisms related to task switching or rule shifting, but few have revealed the neural substrates related to rule shifting at different hierarchical levels. The purpose of this study is to explore the different event-related potentials (ERPs) elicited by higher and lower hierarchical levels of rule shifting in a cue-target task. In the task, participants were presented with Arabic digits (1-9, excluding 5), and performed a parity or magnitude judgment according to the preceding cues, a letter R. The rules were constructed in a hierarchical set, and the rule was either repeated or shifted between neighboring trials. Importantly, the rule shifting would be at a higher or lower hierarchical level. The results showed that, for the cues, the higher hierarchical shifting evoked increased P2, P3, late positive component (LPC), and decreased N2 relative to lower hierarchical shifting, reflecting the increased demand in selective attention, rule processing, and proactive control during the rule acquisition stage. For the targets, the hierarchical effects were reversed, and emerged later than the rule shift effect. These findings imply that, in the cue-target rule-shifting task, the brain responds differently to different hierarchical levels of rule shifting. PMID- 29476840 TI - Methylphenidate selectively modulates one sub-component of the no-go P3 in pediatric ADHD medication responders. AB - Methylphenidate (MPH) has been shown to modulate the amplitude of the no-go P3 component of the event-related potential (ERP; Ogrim, Aasen, & Brunner, 2016). Using group independent component analysis, the no-go P3 from a cued go/no-go task has been separated into two sub-components (Brunner et al., 2013). This study investigated whether sub-components of the no-go P3 could be identified in children with ADHD, and how MPH modulates their amplitudes. ERPs were registered twice (on/off MPH) in 57 children with ADHD classified as medication responders in a four-week medication trial. Two no-go P3 sub-components were identified. In the MPH session, the amplitude of one sub-component, the IC P3no-goearly (mean latency 378 ms, with a central distribution), was significantly larger than at baseline, whereas the other sub-component, the IC P3no-golate (mean latency 428 ms, with a centro-frontal distribution), was not significantly affected. These results add to the literature documenting that the no-go P3 consists of two overlapping phenomena with different functional correlates. PMID- 29476841 TI - A vanishing superficial depressed colorectal lesion in a patient with ulcerative colitis. PMID- 29476842 TI - Endoscopic valvectomy of ileocecal valve stricture resulting in resolution of ileitis in Crohn's disease. PMID- 29476843 TI - Collagenous gastritis: a rare disease with distinctive endoscopic findings. PMID- 29476844 TI - Impact of cleaning monitoring combined with channel purge storage on elimination of Escherichia coli and environmental bacteria from duodenoscopes. AB - BACKGROUND AND AIMS: We aimed to determine whether monitoring of duodenoscope cleaning by rapid adenosine triphosphate (ATP) combined with channel-purge storage could eliminate high-concern microorganisms. METHODS: In a simulated-use study, suction channels, as well as lever recesses, from 2 duodenoscopes models and the unsealed elevator guidewire (EGW) channel from 1 of these 2 duodenoscopes (the other model has a sealed EGW) were perfused with ATS2015 containing approximately 8 Log10 colony-forming units (CFU)/mL of both Enterococcus faecalis and Escherichia coli. Pump-assisted cleaning was monitored by rapid ATP testing. Duodenoscopes exceeding 200 relative light units (RLUs) were recleaned. Clean duodenoscopes were processed through an automated endoscope reprocessor and then stored in a channel-purge storage cabinet for 1 to 3 days. Cultures of EGW channel and instrument channel combined with the lever recess (IC-LR) were taken after storage. The impacts of extended cleaning and alcohol flush were evaluated. RESULTS: E coli was reliably eliminated in IC-LR and EGW channels of 119 duodenoscope tests (59 with sealed EGW and 60 with nonsealed EGW). However, actionable levels of E faecalis and environmental bacteria persisted. Neither alcohol flush nor extended cleaning resulted in a reduction of actionable levels for these organisms. Identification of isolates indicated that residual organisms in duodenoscope channels were hardy Gram-positive bacteria (often spore formers) that likely originated from environmental sources. CONCLUSIONS: These data indicate that high-concern Gram-negative bacteria but not E faecalis or environmental bacteria can be reliably eliminated by use of the manufacturer's instructions for reprocessing with ATP monitoring of cleaning and channel-purge storage conditions. PMID- 29476845 TI - Gastric mucosal devitalization is safe and effective in reducing body weight and visceral adiposity in a porcine model. AB - BACKGROUND AND AIMS: The early improvement in metabolic profile after sleeve gastrectomy (SG) indicates that the significant benefits of metabolic surgery are gastric in origin. We have previously demonstrated that devitalization of the gastric mucosa (without a reduction in gastric volume) in metabolically disturbed obese rats results in an improvement of obesity and its associated comorbidities. The aims of this study were to assess the technical feasibility, efficacy, and safety of gastric mucosal devitalization (GMD) in a large animal (porcine) model. METHODS: A 3-arm (GMD versus SG versus sham [SH]) prospective randomized controlled trial with an 8-week follow-up period was performed. The primary endpoint was relative weight loss. Secondary endpoints were absolute body weight, abdominal visceral adiposity, abdominal subcutaneous adiposity, organ lipid content, and serum ghrelin level. RESULTS: GMD resulted in a significant relative weight loss of 36% over SH at 8 weeks (P < .05). There was no significant difference in relative weight loss between GMD and SG at 4 weeks; however, SG resulted in a 29% superior relative weight loss at 8 weeks (P < .05). With regard to visceral adiposity, there was a significant benefit of GMD over SH at 8 weeks. Despite differences in relative weight loss, there was no significant difference in visceral adiposity between SG and GMD at 8 weeks. Significant improvements in GMD over SH were noted with regard to skeletal and heart muscle lipid content. GMD pigs at 8 weeks demonstrated regeneration of the gastric mucosa without ulceration or significant scarring. Despite mucosal regeneration, the abundance of serum ghrelin was significantly lower in the GMD cohort compared with the SG and SH cohorts. CONCLUSIONS: GMD was technically feasible and resulted in relative weight loss and an improvement in visceral adiposity. The benefits noted were out of proportion to what would be expected with weight loss alone. PMID- 29476846 TI - Optimizing duodenoscope reprocessing: rigorous assessment of a culture and quarantine protocol. AB - BACKGROUND AND AIMS: Iatrogenic infections related to duodenoscopes remain a top concern for medical centers where ERCP is performed. We assessed the long-term results and impact of key interventions in the optimization of a rigorous "culture and quarantine" program for duodenoscope reprocessing. METHODS: We reviewed a prospectively collected, quality assurance database of all duodenoscope cultures (n = 4307) obtained for the initial 3-year duration of culture and quarantine from 2014 to 2017 in a single U.S.-based, high-volume endoscopy center. All duodenoscopes were subject to manual cleaning and automated reprocessing and drying, followed by sampling using a modified protocol developed by the Centers for Disease Control and Prevention. Duodenoscopes were cultured per-use. RESULTS: A total of 4307 duodenoscope cultures were obtained during the study period. High-concern organisms were isolated from 33 of these cultures, resulting in a .697% high-level disinfection defect rate. Statistically significant interventions included withdrawal of a high-frequency culture positive duodenoscope (scope A) from clinical service in addition to implementation of new manufacturer-recommended cleaning protocols. Withdrawal of a second high-frequency culture-positive duodenoscope (scope B) and a mandatory device retrofit had no effect on the observed rate of positive duodenoscope cultures. CONCLUSIONS: Withdrawal of duodenoscopes with a high rate of culture positivity and optimizing manual cleaning practices have contributed to an overall decline in the high-level disinfection defect rate. A stringent culture and quarantine protocol allowed identification of the culprit endoscopes. There remains a much-needed role for an inexpensive and highly reliable method to check on the adequacy of reprocessing given the inherent complexity of these tasks. PMID- 29476847 TI - A randomized trial of single versus double high-level disinfection of duodenoscopes and linear echoendoscopes using standard automated reprocessing. AB - BACKGROUND AND AIMS: In a pilot study, we demonstrated that current guidelines for duodenoscope and linear echoendoscope (DLE) reprocessing using a single cycle of high-level disinfection (HLD) in an automated reprocessor may be inadequate. In August 2015, the U.S. Food and Drug Administration offered double HLD as a possible response to address this concern. As a result, Providence Health and Services adopted double HLD as standard procedure for DLEs, but no rigorous clinical studies supported this practice. We undertook a quality improvement study to compare single HLD versus double HLD at 4 of our 34 hospitals. METHODS: HLD of DLE was randomized, separately in each facility, to either single HLD or double HLD on weekdays, with standard double HLD on weekends or holidays. There was 99.7% compliance with the randomization scheme. Daily qualitative surveillance cultures of dried, post-HLD DLEs were collected for 6 months (1 swab sample from the elevator mechanism and 1 combined brush sample from the suction and working channels for each encounter), and each sample was incubated for 48 hours. Positivity rates of any microbial growth and growth of high-concern pathogens (potentially pathogenic enteric flora) were compared between the 2 study arms. RESULTS: Altogether, 5850 surveillance culture specimens were obtained during 2925 encounters from the 45 DLEs in clinical use in the participating hospitals. Of these, 3052 (52.2%) were from endoscopes cleaned by double HLD. Double HLD demonstrated no benefit over single HLD because similar positivity rates were observed (all P > .05). The elevator mechanism was more frequently colonized than the biopsy channel (5.2% vs 2.9%, P < .001). Among the 224 encounters with positive growth, 140 (62.5%) recovered microbes from only the elevator mechanism specimens, 73 (32.6%) recovered microbes from only the channel specimens, and 11 (4.9%) recovered microbes from both types of specimens. Double HLD failed to improve contamination rates for either sample site at any of the 4 endoscopy facilities, although there were significant overall differences in contamination rates among the facilities (P < .001), as observed in our previous study. Only 8 high-concern pathogens were recovered from 5 DLEs, all from the elevator mechanism. Persistent growth was observed on 2 duodenoscopes. One grew Enterococcus spp (not vancomycin-resistant enterococci) on 3 occasions, and Escherichia coli was present on 2 of these occasions, 1 of which was a multidrug resistant organism. The other grew different enteric flora on 2 specimens. CONCLUSIONS: Our prospectively randomized study, involving 4 separate endoscopy facilities and standard automated endoscope reprocessing, showed that double HLD did not reduce culture positivity rates compared with single HLD in facilities with an already low positive culture rate. Alternative risk mitigation strategies will be assessed in an ongoing effort to reduce endoscope contamination. PMID- 29476848 TI - Secondary tumors of the GI tract: origin, histology, and endoscopic findings. AB - BACKGROUND AND AIMS: The GI tract is rarely affected by secondary tumors. Patients often present at an advanced stage of the disease, and prognosis is dismal. This study aimed to analyze the clinical, endoscopic, and pathologic features of secondary tumors that had been diagnosed endoscopically. METHODS: We conducted a retrospective database analysis of 217 patients with secondary tumors of the GI tract. Endoscopic findings and histologic diagnoses were systematically re-evaluated. RESULTS: Malignant melanoma (n = 33, 15%), breast cancer (n = 32, 15%), and pancreatic cancer (n = 27, 12%) were the most common corresponding primaries. About one-third of secondary tumors were detected in the stomach (n = 76, 35%), followed by small intestine (n = 54, 25%) and rectum (n = 53, 24%). The median time between the diagnoses of primary and secondary tumors was 19 months (mean, 31; range, 0-251), and this time was particularly long for renal cell carcinoma and breast cancer (median, 38 and 45 months, respectively). Direct invasion from extra-GI malignancies was more common (56%) than vascular cancer spread (44%) and depended on both sites of tumor involvement and corresponding primary. The lesions presented with various endoscopic patterns. In patients for whom a definitive diagnosis of cancer was known before the examination (n = 168), a secondary tumor was included in the differential diagnosis in only 48% of lesions. It is of note that the remaining cases were diagnosed endoscopically as primary tumors and rarely also as nonneoplastic change. CONCLUSIONS: Secondary tumors may affect all parts of the GI tract. Malignant melanoma and breast and pancreatic cancer represent the most common primaries. Diagnosis based on examination of biopsy specimens is crucial to avoid misclassification. PMID- 29476849 TI - Cryotherapy for persistent Barrett's esophagus after radiofrequency ablation: a systematic review and meta-analysis. AB - BACKGROUND AND AIMS: A small but significant proportion of patients with Barrett's esophagus (BE) have persistent dysplasia or intestinal metaplasia (IM) after treatment with radiofrequency ablation (RFA). Cryotherapy is a cold-based ablative modality that is increasingly being used in this setting. We aimed to better understand the efficacy of second-line cryotherapy in patients with BE who have persistent dysplasia or IM after RFA by conducting a systematic review and meta-analysis. METHODS: We performed a systematic literature search of Pubmed, EMBASE, and Web of Science through September 1, 2017. Articles were included for meta-analysis based on the following inclusion criteria: >=5 patients with BE treated with RFA had persistent dysplasia or IM; they subsequently underwent >=1 session of cryotherapy with follow-up endoscopy; the proportions of patients achieving complete eradication of dysplasia (CE-D) and/or IM (CE-IM) were reported. The main outcomes were pooled proportions of CE-D and CE-IM by using a random effects model. RESULTS: Eleven studies making up 148 patients with BE treated with cryotherapy for persistent dysplasia or IM after RFA were included. The pooled proportion of CE-D was 76.0% (95% confidence interval [CI] 57.7-88.0), with substantial heterogeneity (I2 = 62%). The pooled proportion of CE-IM was 45.9% (95% CI, 32.0-60.5) with moderate heterogeneity (I2 = 57%). Multiple preplanned subgroup analyses did not sufficiently explain the heterogeneity. Adverse effects were reported in 6.7% of patients. CONCLUSION: Cryotherapy successfully achieved CE-D in three fourths and CE-IM in half of patients with BE who did not respond to initial RFA. Considering its favorable safety profile, cryotherapy may be a viable second-line option for this therapeutically challenging cohort of patients with BE, but higher-quality studies validating this remain warranted. PMID- 29476850 TI - Pd(II)/Pd(0) anchored to magnetic nanoparticles (Fe3O4) modified with biguanidine chitosan polymer as a novel nanocatalyst for Suzuki-Miyaura coupling reactions. AB - This article is devoted to synthesis of a new magnetic interphase palladium catalyst that has been immobilized on chitosan-biguanidine coated-magnetic Fe3O4 nanoparticles [Pd(0/II)/CS-bigua@Fe3O4]. Such surface functionalization of magnetic particles is a promising method to bridge the gap between heterogeneous and homogeneous catalysis approaches. The structure, morphology, and physicochemical properties of the particles were characterized through different analytical techniques, including Fourier transformed infrared spectroscopy (FT IR), field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), vibrating sample magnetometer (VSM), wavelength-dispersive X ray spectroscopy (WDX), inductively coupled plasma (ICP), energy dispersive X-ray spectroscopy (EDS) and X-ray photoelectron spectroscopy (XPS). Pd(0/II)/CS bigua@Fe3O4 demonstrated high catalytic activity as a recyclable nanocatalyst toward Suzuki-Miyaura cross-coupling reactions, at room temperature. Furthermore, the catalyst could be recovered and reused several times with no significant palladium leaching or change in its activity. PMID- 29476851 TI - Cyanidin-3-rutinoside reduces insulin fibrillation and attenuates insulin fibrils induced oxidative hemolysis of human erythrocytes. AB - Insulin is able to form amyloid-like fibrils, a misfolding process by which insulin molecules interact with each other to form aggregates and pathological amyloid deposition. Inhibition of amyloid aggregation using natural products is proposed as a new strategy to prohibit the development of amyloid diseases. Herein, we demonstrated the inhibitory effect of cyanidin-3-rutinoside (C3R), a natural anthocyanin with multiple biological activities, against insulin amyloid fibrillation. The results showed that increased insulin concentration resulted in faster growth and higher amounts of insulin fibrils. C3R (10.6-170MUM) concentration dependently decreased insulin fibril growth and increased the duration of lag time of insulin fibril formation. Moreover, C3R directly decreased the secondary structure transition from alpha-helix to beta-sheet structure. C3R (0.31-5MUM) attenuated insulin fibrils-induced oxidative hemolysis of human erythrocytes in a concentration-dependent manner. Moreover, C3R reduced insulin fibrils-induced erythrocyte membrane disruption through the inhibition of reactive oxygen species (ROS) generation. The findings also suggest that C3R reduced fibrils-induced membrane lipid peroxidation by maintaining the catalase activity and oxidized/reduced glutathione content (GSH/GSSH) in erythrocytes. These findings suggest that C3R may serve as a potential inhibitory agent against amyloid fibril formation and insulin fibrils-induced oxidative hemolysis. PMID- 29476852 TI - Comparative study on the physicochemical and functional properties of the mucilage in the carpel of Nymphaea odorata using ultrasonic and classical heating extractions. AB - The cooked carpel of Nymphaea odorata has a large amount of transparent mucilage; however, the basic characteristics of this mucilage have not yet been reported. This study compared the physicochemical and functional properties of this mucilage obtained using conventional hot water extraction (HWM) and ultrasonic assisted extraction (UAM). Neither HWM nor UAM affected the viability of mouse skin fibroblasts (NIH/3 T3) below 100 MUg/mL. UAM had a higher yield production, phenol concentration, and in vitro antioxidant activity, but it had a lower viscosity and water-holding capacity than that of HWM. The Fourier transform infrared spectra revealed that the dialyzed HWM and UAM, named HWMD and UAMD, respectively, appeared to have major spectral differences at 1730 cm-1 and 1605 cm-1, implying that the degree of methylation was different between HWMD and UAMD. Compared to HWMD, UAMD in low-molecular weight polysaccharides increased. Indeed, the basic characteristics of native mucilage in the carpel of N. odorata were greatly changed by various extractions. Nevertheless, sugar analysis indicated that glucuronic acid was the main composition of HWMD and UAMD. PMID- 29476853 TI - Ferulic acid, a natural phenolic compound, as a potential inhibitor for collagen fibril formation and its propagation. AB - Excess accumulation of collagen (fibrosis) is the hallmark of many fibrotic diseases such as keloids, hypertrophic scars, etc. The inhibition of collagen fibrillation during its accumulation is a therapeutic way to limit the fibrosis. Herein, the effect of Ferulic acid (FA), a natural phenolic acid compound, on collagen fibrillation is studied using biophysical methods. Optical density (OD) and microscopic analysis indicate that FA inhibits collagen self-association, and the inhibitory efficiency depends on the concentration and temperature. The absence of an increase in OD for matured collagen fibrillar solution upon addition of FA followed by collagen solution indicates that FA could also terminates the progression of preformed collagen fibrils. Spectroscopic measurements indicate that collagen retains its unique triple helical structure in the presence of FA. Saturation Transfer Difference NMR suggests that FAs are in proximity to collagen while fluorescence quenching upon addition of FA proposes that FA most likely binds to the telopeptide regions of collagen. Enzymatic studies suggest that FA protects collagen from enzymatic degradation. The current study demonstrates that FA is a potential inhibitor of collagen fibrillation and its propagation and thus it can be considered for therapeutic studies to make FA as a remedy for the plaques related to collagen deposition. PMID- 29476854 TI - Synthesis, characterization and adsorption properties of microcrystalline cellulose based nanogel for dyes and heavy metals removal. AB - Recently, naturally occurring biopolymers have attracted the attention as potential adsorbents for the removal of water contaminants. In this work, we present the development of microcrystalline cellulose (MCC)-based nanogel grafted with acrylamide and acrylic acid in the presence of methylene bisacrylamide and potassium persulphate as a crosslinking agent and initiator, respectively. World class facilities such as X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), surface analysis, field emission scanning electron microscopy (FE-SEM), high resolution transmission electron microscopy (HR-TEM) and zeta sizer were used to characterize the synthesized MCC based nanogel. The prepared nanogel was applied to remove reactive red 195 (RR195) dye and Cd (II) from aqueous medium at different operational conditions. The adsorption experiments showed that the feed concentration of monomers has a significant effect on the removal of RR195 which peaked (93% removal) after 10min of contact time at pH2 and a dose of 1.5g/L. On contrary, the feed concentration has insignificant effect on the removal of Cd (II) which peaked (97% removal) after 30min of contact time at pH6 and a dose of 0.5g/L. The adsorption equilibrium data of RR195 and Cd (II) was best described by Freundlich and Langmuir, respectively. Conclusively, the prepared MCC based nanogels were proved as promising adsorbents for the removal of organic pollutants as well as heavy metals. PMID- 29476855 TI - Construction of size-controllable gold nanoparticles immobilized on polysaccharide nanotubes by in situ one-pot synthesis. AB - A green method for in situ one-pot synthesis of size-controlled gold nanoparticles (AuNPs) was provided in this work. In our findings, a beta-1,3-D glucan, AF1, extracted from black fungus was used as a support of AuNPs. The AuNPs were dispersed in the AF1 aqueous solution without additional reducing and stabilizing or dispersing agents. The infrared spectrum (FT-IR), thermogravimetry (TG), X-ray photoelectron spectra (XPS) and atomic force microscope (AFM) results indicated that the AuNPs synthesized by AF1 were immobilized on the AF1 nanotubes with controllable shape and size of 5-45nm. The hydroxyl groups on AF1 nanotubes not only acted as reducing agents but also were able to stabilize AuNPs by the strong interaction between the surface Au atoms of AuNPs and oxygen atoms of AF1 nanotubes. The AuNPs exhibited a good catalytic activity for the rapid reduction from 4-nitrophenol (4-NP) to 4-aminophenol (4-AP) by excess borohydride, further confirming the dispersion of AuNPs in water. PMID- 29476856 TI - Characteristics of starch isolated from microwave heat treated lotus (Nelumbo nucifera) seed flour. AB - The present study aimed to investigate the influence of microwave irradiation on the physical and functional properties of starch extracted from Nelumbo nucifera seed flour. The seed flour was obtained by manual grinding of seeds and irradiated at different microwave treatment time, i.e., 1, 2, 3, 4 and 5min at the low-medium intensity. The starch was extracted in distilled water and dried at room temperature using a vacuum desiccator. The morphology, crystal structure, and surface parameters of starch granules were analyzed using scanning electron microscopy, X-ray diffraction, Fourier transform infra-red spectroscopy and Brunauer, Emmett and Teller surface analysis techniques. The functional properties of starch were also determined in terms of water and oil holding capacity, swelling capacity, emulsifying activity and gelling ability. Evidently, crystallinity, surface area and pore volume of starch granules were found to be increased, while particle size and average pore size were decreased as a function of microwave treatment time. The microwave-induced variations in physical parameters significantly affected the functional properties of starch. A significant (p>0.05) exponential decrease in extraction yield and gelling ability, while an exponential increase in the functional properties of starch with increase in the microwave treatment time (R2=0.915-0.985) was recorded. PMID- 29476857 TI - Effect of guar gum coatings containing essential oils on shelf life and nutritional quality of green-unripe mangoes during low temperature storage. AB - This study investigated the effect of treatment of guar gum coating coupled with essential oils. Harvested unripe green mangoes (UGM) were preserved using edible coatings containing essential oils of Nigella sativa, Coriandrum sativum, Foeniculum vulgare and Laurus nobilis derived using two different solvents (methanol and ethanol) and stored at refrigeration temperature (10 degrees C, 80 85% relative humidity). Physiological and biochemical parameters that assess the quality of fruits were determined. Microbiological analysis was also performed at the start and end of shelf life. Generally, it was observed that ethanolic essential oils supplemented coatings conferred a greater retention of fruit quality as compared to both controls. Bacterial counts were significantly reduced in fruits that were coated with ethanolic essential oil edible coatings. Secondly, the coatings supplemented with ethanolic and methanolic essential oils extended shelf life up to 24days whereas treated and untreated control decayed after 10 and 6days respectively (P<0.05). These results suggested the application of these edible coatings for preservation of unripe green mangoes during cold storage. PMID- 29476858 TI - Antioxidant activity of purified ulvan in hyperlipidemic mice. AB - Several studies have reported that ulvan from the alga Ulva pertusa (Chlorophyta) exhibits substantial antioxidant and antihyperlipidemic activities; however, which group of heteropolysaccharides play roles in these activities remains unknown. In this study, three purified ulvan (PU1, PU2 and PU3) have been obtained by DEAE-Sepharose fast-flow column. The antioxidant activity was detected via the model of hyperlipidemic Kunming mice, including malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in liver. PU3, which possessed the highest uronic acid content (24.09%) and sulfate content (23.99%) as well as the lowest average molecular weight (83,094 Da), exhibited the stronger antioxidant activity than other examples. It significantly decreased MDA (29.2%; P < 0.05), increased SOD (36.4%; P < 0.05) and CAT (43.6%; P < 0.05) compared with hyperlipidemia group. In conclusion, PU3 may be potential sources of natural antioxidant to protecting against the liver damage of oxidative stress induced by cholesterol-rich diet. PMID- 29476859 TI - Stoichiometric Zn2+ interferes with the self-association of Abeta42: Insights from size distribution analysis. AB - The abnormal aggregation of amyloid beta (Abeta) peptides in the brain has been recognized as a central event in Alzheimer's disease (AD). Divalent metal ions such as Zn2+ have been shown to be closely involved in modulating Abeta self association. Although the link between Zn2+ dyshomeostasis and brain Abeta deposition has been established, the effect of Zn2+ on the aggregation of Abeta is still incompletely clarified. By combining analytical ultracentrifugation (AUC), circular dichroism (CD) spectroscopy, thioflavin T (ThT) assay and atomic force microscopy (AFM) imaging, we analyzed the impact of stoichiometric Zn2+ on the aggregation process of Abeta42, the main toxic isoform of Abeta species in the brain. Abeta42 aggregates found in the presence of Zn2+ were smaller in size, non-fibrillary and showed less beta-sheet structures than aggregates formed in absence of Zn2+. AUC showed that Zn2+ was capable of retaining monomeric Abeta42 in solution. Zn2+ chelation by EDTA totally reversed the inhibitory effect of Zn2+ on Abeta42 fibrillation. Our results provide further evidence that Zn2+ shifts the self-association of Abeta42 toward a non-fibrillary pathway by interfering with the aggregation process at multiple levels. PMID- 29476860 TI - Improvement of chitosan solubility and bactericidity by synthesis of N benzimidazole-O-acetyl-chitosan and its electrodeposition. AB - Chitosan solubility and its antibacterial activity have been improved first of all with a chemical synthesis of N-benzimidazole-O-acetyl-chitosan in acetic medium and foremost through a potentiodynamic electrodeposition of this derivative. An association of one benzimidazole and three acetyl moieties per two units of the biopolymer chain was evidenced by FTIR and 1H NMR, pH-metric titration and TG analysis. Cyclic voltammetry study of the modified polymer in acetonitrile solution reveals its anodic oxidation at a platinum disk and a progressive growing of a thin film, through the cycling of potential. An enhancement of the solubility of the biopolymer as well as its antibacterial activity against Salmonella typhimurium, Escherichia coli, Staphylococcus aureus and Pseudomoenas aeruginosa bacteria have been observed with these chemical and after electrochemical modifications. PMID- 29476861 TI - Thimerosal changes protein conformation and increase the rate of fibrillation in physiological conditions: Spectroscopic studies using bovine serum albumin (BSA). AB - The interaction between bovine serum albumin (BSA) and thimerosal (TM), an organomercury compound widely employed as a preservative in vaccines, was investigated simulating physiological conditions and using different spectroscopic techniques. The results, employing molecular fluorescence showed the interaction occurs by static quenching through electrostatic forces (DeltaH < 0 and DeltaS > 0), spontaneously (DeltaG = -4.40 kJ mol-1) and with a binding constant of 3.24 * 103 M-1. Three-dimensional fluorescence studies indicated that TM causes structural changes in the polypeptide chain of the BSA, confirmed by circular dichroism that showed an increase in alpha-helix (from 43.9 to 47.8%) content after interaction process. Through synchronized fluorescence and employing bilirubin as a protein site marker, it was confirmed the preferential interaction of TM in the subdomain IB of BSA. The interaction mechanism proposed in this work is based on the reaction of TM with BSA through of free Cys34 residue, forming the adduct BSA-HgEt with the thiosalicylic acid release, which possibly interacts electrostatically with positive side chain amino acids of the modified protein. Finally, it was proven that both TM and EtHgCl accelerate the protein fibrillation kinetics in 42 and 122%, respectively, indicating the toxicity of these compounds in biological systems. PMID- 29476862 TI - The effect of ultrasound on the properties and conformation of glucoamylase. AB - In this study, the effects of ultrasonic treatment on the enzyme activity of glucoamylase were investigated and the mechanism of the effect was explored by determining their conformational changes. The enzyme activity was increased by 21.07% over the control with ultrasound at 420W for 10min at 60 degrees C, and Vmax and Km values of glucoamylase were also increased. After ultrasonic treatment at 420W, thermodynamic experiments of glucoamylase showed that Ea, DeltaG, DeltaH decreased but slight increase in DeltaS was observed. In addition, after the treatment, the UV spectra showed that the number of tryptophan and tyrosine on glucoamylase surface increased, and the contents of alpha-helix and random coil increased by 17.8%, 12.41%, respectively, through the circular dichroism spectrum scanning. Besides, fluorescence spectra indicated that the absorption of tryptophan has a red shift. Furthermore, fourier transform infrared spectra suggested that the glucoamylase was significantly influenced by ultrasound. The results indicated that the activity of glucoamylase could be modified by ultrasonic treatment mainly in terms of the variation of their conformation. PMID- 29476863 TI - Time course of polyhexamethyleneguanidine phosphate-induced lung inflammation and fibrosis in mice. AB - Pulmonary fibrosis is a chronic progressive disease with unknown etiology and has poor prognosis. Polyhexamethyleneguanidine phosphate (PHMG-P) causes acute interstitial pneumonia and pulmonary fibrosis in humans when it exposed to the lung. In a previous study, when rats were exposed to PHMG-P through inhalation for 3 weeks, lung inflammation and fibrosis was observed even after 3 weeks of recovery. In this study, we aimed to determine the time course of PHMG-P-induced lung inflammation and fibrosis. We compared pathological action of PHMG-P with that of bleomycin (BLM) and investigated the mechanism underlying PHMG-P-induced lung inflammation and fibrosis. PHMG-P (0.9 mg/kg) or BLM (1.5 mg/kg) was intratracheally administered to mice. At weeks 1, 2, 4 and 10 after instillation, the levels of inflammatory and fibrotic markers and the expression of inflammasome proteins were measured. The inflammatory and fibrotic responses were upregulated until 10 and 4 weeks in the PHMG-P and BLM groups, respectively. Immune cell infiltration and considerable collagen deposition in the peribronchiolar and interstitial areas of the lungs, fibroblast proliferation, and hyperplasia of type II epithelial cells were observed. NALP3 inflammasome activation was detected in the PHMG-P group until 4 weeks, which is suspected to be the main reason for the persistent inflammatory response and exacerbation of fibrotic changes. Most importantly, the pathological changes in the PHMG-P group were similar to those observed in humidifier disinfectant-associated patients. A single exposure of PHMG-P led to persistent pulmonary inflammation and fibrosis for at least 10 weeks. PMID- 29476864 TI - A systems biology approach to predictive developmental neurotoxicity of a larvicide used in the prevention of Zika virus transmission. AB - The need to prevent developmental brain disorders has led to an increased interest in efficient neurotoxicity testing. When an epidemic of microcephaly occurred in Brazil, Zika virus infection was soon identified as the likely culprit. However, the pathogenesis appeared to be complex, and a larvicide used to control mosquitoes responsible for transmission of the virus was soon suggested as an important causative factor. Yet, it is challenging to identify relevant and efficient tests that are also in line with ethical research defined by the 3Rs rule (Replacement, Reduction and Refinement). Especially in an acute situation like the microcephaly epidemic, where little toxicity documentation is available, new and innovative alternative methods, whether in vitro or in silico, must be considered. We have developed a network-based model using an integrative systems biology approach to explore the potential developmental neurotoxicity, and we applied this method to examine the larvicide pyriproxyfen widely used in the prevention of Zika virus transmission. Our computational model covered a wide range of possible pathways providing mechanistic hypotheses between pyriproxyfen and neurological disorders via protein complexes, thus adding to the plausibility of pyriproxyfen neurotoxicity. Although providing only tentative evidence and comparisons with retinoic acid, our computational systems biology approach is rapid and inexpensive. The case study of pyriproxyfen illustrates its usefulness as an initial or screening step in the assessment of toxicity potentials of chemicals with incompletely known toxic properties. PMID- 29476865 TI - Strategies to improve the regulatory assessment of developmental neurotoxicity (DNT) using in vitro methods. AB - Currently, the identification of chemicals that have the potential to induce developmental neurotoxicity (DNT) is based on animal testing. Since at the regulatory level, systematic testing of DNT is not a standard requirement within the EU or USA chemical legislation safety assessment, DNT testing is only performed in higher tiered testing triggered based on chemical structure activity relationships or evidence of neurotoxicity in systemic acute or repeated dose toxicity studies. However, these triggers are rarely used and, in addition, do not always serve as reliable indicators of DNT, as they are generally based on observations in adult rodents. Therefore, there is a pressing need for developing alternative methodologies that can reliably support identification of DNT triggers, and more rapidly and cost-effectively support the identification and characterization of chemicals with DNT potential. We propose to incorporate mechanistic knowledge and data derived from in vitro studies to support various regulatory applications including: (a) the identification of potential DNT triggers, (b) initial chemical screening and prioritization, (c) hazard identification and characterization, (d) chemical biological grouping, and (e) assessment of exposure to chemical mixtures. Ideally, currently available cellular neuronal/glial models derived from human induced pluripotent stem cells (hiPSCs) should be used as they allow evaluation of chemical impacts on key neurodevelopmental processes, by reproducing different windows of exposure during human brain development. A battery of DNT in vitro test methods derived from hiPSCs could generate valuable mechanistic data, speeding up the evaluation of thousands of compounds present in industrial, agricultural and consumer products that lack safety data on DNT potential. PMID- 29476867 TI - Physiological, but not fitness, effects of two interacting haemoparasitic infections in a wild rodent. AB - In contrast to the conditions in most laboratory studies, wild animals are routinely challenged by multiple infections simultaneously, and these infections can interact in complex ways. This means that the impact of a parasite on its host's physiology and fitness cannot be fully assessed in isolation, and requires consideration of the interactions with other co-infections. Here we examine the impact of two common blood parasites in the field vole (Microtus agrestis): Babesia microti and Bartonella spp., both of which have zoonotic potential. We collected longitudinal and cross-sectional data from four populations of individually tagged wild field voles. This included data on biometrics, life history, ectoparasite counts, presence/absence of microparasites, immune markers and, for a subset of voles, more detailed physiological and immunological measurements. This allowed us to monitor infections over time and to estimate components of survival and fecundity. We confirm, as reported previously, that B. microti has a preventative effect on infection with Bartonella spp., but that the reverse is not true. We observed gross splenomegaly following B. microti infection, and an increase in IL-10 production together with some weight loss following Bartonella spp. infection. However, these animals appeared otherwise healthy and we detected no impact of infection on survival or fecundity due to the two haemoparasite taxa. This is particularly remarkable in the case of B. microti which induces apparently drastic long-term changes to spleen sizes, but without major adverse effects. Our work sheds light on the ecologies of these important zoonotic agents, and more generally on the influence that interactions among multiple parasites have on their hosts in the wild. PMID- 29476868 TI - A new LAMP-based assay for the molecular diagnosis of toxoplasmosis: comparison with a proficient PCR assay. AB - Toxoplasmosis is generally a benign infection caused by the protozoan parasite Toxoplasma gondii but can have severe consequences in fetuses of mothers infected during pregnancy (congenital toxoplasmosis) and immunocompromised individuals. PCR-based diagnostic tests have become crucial for its diagnosis. However, this molecular diagnosis essentially relies upon laboratory-developed methods and suffers from a lack of standardization, leading to great variation in methods and performance among laboratories. With the need for accreditation of clinical microbiological laboratories, the use of commercial PCR kits has become an attractive alternative; but thorough evaluation of newly commercialized kits by proficient groups is necessary before any recommendation can be made to parasitology laboratories by health authorities or learned societies. Here, we compared the performance of an original commercial method, the Iam TOXO Q-LAMP (DiaSorin(r)), using Loop-mediated isothermal amplification (LAMP) technology, with our reference laboratory-developed method using real-time PCR. The kit was first tested using amniotic fluid (AF) and plasma samples (either negative or spiked with live T. gondii tachyzoites at different concentrations (from 7 to 105 tachyzoites/mL)). It was then assessed using a cohort of 11 AF, five placental and 32 blood clinical samples preserved at -20 degrees C. For the processing of placental/blood samples, a pretreatment step was used, which did not strictly follow the manufacturer's recommendations. The practical ease of use and compliance with good laboratory practices were also evaluated. Although the LAMP assay was less sensitive than the laboratory-developed method at very low parasite concentrations (0.1 T. gondii genome equivalents/mL), the two methods yielded identical results qualitatively and, in some instances, quantitatively, particularly for AF samples. PMID- 29476866 TI - Investigating zoonotic infection barriers to ape Plasmodium parasites using faecal DNA analysis. AB - African apes are endemically infected with numerous Plasmodium spp. including close relatives of human Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae. Although these ape parasites are not believed to pose a zoonotic threat, their ability to colonise humans has not been fully explored. In particular, it remains unknown whether ape parasites are able to initiate exo-erythrocytic replication in human hepatocytes following the bite of an infective mosquito. Since animal studies have shown that liver stage infection can result in the excretion of parasite nucleic acids into the bile, we screened faecal samples from 504 rural Cameroonians for Plasmodium DNA. Using pan Laverania as well as P. malariae- and P. vivax-specific primer sets, we amplified human P. falciparum (n = 14), P. malariae (n = 1), and P. ovale wallikeri (n = 1) mitochondrial sequences from faecal DNA of 15 individuals. However, despite using an intensified PCR screening approach we failed to detect ape Laverania, ape P. vivax or ape P. malariae parasites in these same subjects. One faecal sample from a hunter-gatherer contained a sequence closely related to the porcupine parasite Plasmodium atheruri. Since this same faecal sample also contained porcupine mitochondrial DNA, but a matching blood sample was Plasmodium-negative, it is likely that this hunter-gatherer consumed Plasmodium-infected bushmeat. Faecal Plasmodium detection was not secondary to intestinal bleeding and/or infection with gastrointestinal parasites, but indicative of blood parasitaemia. Quantitative PCR identified 26-fold more parasite DNA in the blood of faecal Plasmodium-positive than faecal Plasmodium-negative individuals (P = 0.01). However, among blood-positive individuals only 10% - 20% had detectable Plasmodium sequences in their stool. Thus, faecal screening of rural Cameroonians failed to uncover abortive ape Plasmodium infections, but detected infection with human parasites, albeit with reduced sensitivity compared with blood analysis. PMID- 29476869 TI - Advances in Fasciola hepatica research using 'omics' technologies. AB - The liver fluke Fasciola hepatica is an economically important pathogen of livestock worldwide, as well as being an important neglected zoonosis. Parasite control is reliant on the use of drugs, particularly triclabendazole, which is effective against multiple parasite stages. However, the spread of parasites resistant to triclabendazole has intensified the pursuit for novel control strategies. Emerging 'omics' technologies are helping advance our understanding of liver fluke biology, specifically the molecules that act at the host-parasite interface and are central to infection, virulence and long-term survival within the definitive host. This review discusses the technological sequencing advances that have facilitated the unbiased analysis of liver fluke biology, resulting in an extensive range of 'omics' datasets. In addition, we highlight the 'omics' studies of host responses to F. hepatica infection that, when combined with the parasite datasets, provide the opportunity for integrated analyses of host parasite interactions. These extensive datasets will form the foundation for future in-depth analysis of F. hepatica biology and development, and the search for new drug or vaccine interventions. PMID- 29476870 TI - High frequency oscillations in epileptic rodents: Are we doing it right? AB - BACKGROUND: The detection of high-frequency oscillations (HFOs, ripples: 80-200 Hz, fast ripples: 250-500 Hz) is often based on considering ripples or fast ripples in isolation; overlapping ripples and fast ripples are excluded from further analysis. Here, we studied overlapping HFOs during spontaneous seizures in pilocarpine-treated animals. NEW METHOD: Spontaneous seizures (n = 6 animals) presented with either hypersynchronous- (HYP, n = 18) or low-voltage fast-onset (LVF, n = 21) pattern. Ripples and fast ripples overlapping by more than 30% were analysed. RESULTS: Overlapping HFOs could show a unimodal power spectrum between 80-500 Hz (n = 188, 58.9%) or a bimodal power spectrum, with peaks in power between 80 and 200 Hz and between 250 and 500 Hz (n = 131, 41.1%,). Overlapping HFOs occurred at higher rates during HYP seizures compared to the pre-ictal period in seizure onset zones (p < 0.001) and regions of secondary spread (p < 0.001). When comparing HYP and LVF seizures, we found that overlapping HFOs occurred at higher rates before LVF seizures (p < 0.05) compared to HYP seizures but, during the ictal period, HYP seizures showed higher rates of overlapping HFOs than LVF seizures (p < 0.001). COMPARISON WITH EXISTING METHODS: We have analysed overlapping ripples and fast ripples shortly before and during seizures. CONCLUSIONS: Although overlapping ripples and fast ripples represent a minority of HFOs, they may provide additional information on the excitability of neuronal networks that generate seizures in animal models and patients presenting with mesial temporal lobe epilepsy. PMID- 29476871 TI - Designing GABA-edited magnetic resonance spectroscopy studies: Considerations of scan duration, signal-to-noise ratio and sample size. AB - BACKGROUND: The relationships between scan duration, signal-to-noise ratio (SNR) and sample size must be considered and understood to design optimal GABA-edited magnetic resonance spectroscopy (MRS) studies. NEW METHOD: Simulations investigated the effects of signal averaging on SNR, measurement error and group level variance against a known ground truth. Relative root mean square errors (measurement error) and coefficients of variation (group-level variance) were calculated. GABA-edited data from 18 participants acquired from five voxels were used to examine the relationships between scan duration, SNR and quantitative outcomes in vivo. These relationships were then used to determine the sample sizes required to observe different effect sizes. RESULTS: In both simulated and in vivo data, SNR increased with the square root of the number of averages. Both measurement error and group-level variance were shown to follow an inverse-square root function, indicating no significant impact of cumulative artifacts. Comparisons between the first two-thirds of the data and the full dataset showed no statistical difference in group-level variance. There was, however, some variability across the five voxels depending on SNR, which impacted the sample sizes needed to detect group differences in specific brain regions. COMPARISON WITH EXISTING METHODS: Typical scan durations can be reduced if taking into account a statistically acceptable amount of variance and the magnitudes of predicted effects. CONCLUSIONS: While scan duration in GABA-edited MRS has typically been considered in terms of SNR, it is more appropriate to think in terms of the amount of measurement error and group-level variance that provides sufficient statistical power. PMID- 29476872 TI - Aberrant resting-state functional brain networks in dyslexia: Symbolic mutual information analysis of neuromagnetic signals. AB - Neuroimaging studies have identified a variety of structural and functional connectivity abnormalities in students experiencing reading difficulties. The present study adopted a novel approach to assess the dynamics of resting-state neuromagnetic recordings in the form of symbolic sequences (i.e., repeated patterns of neuromagnetic fluctuations within and/or between sensors). Participants were 25 students experiencing severe reading difficulties (RD) and 27 age-matched non-impaired readers (NI) aged 7-14 years. Sensor-level data were first represented as symbolic sequences in eight conventional frequency bands. Next, dominant types of sensor-to-sensor interactions in the form of intra and cross-frequency coupling were computed and subjected to graph modeling to assess group differences in global network characteristics. As a group RD students displayed predominantly within-frequency interactions between neighboring sensors which may reflect reduced overall global network efficiency and cost-efficiency of information transfer. In contrast, sensor networks among NI students featured a higher proportion of cross-frequency interactions. Brain-reading achievement associations highlighted the role of left hemisphere temporo-parietal functional networks, at rest, for reading acquisition and ability. PMID- 29476873 TI - Exploring the switching of the focus of attention within working memory: A combined event-related potential and behavioral study. AB - Working memory enables humans to maintain selected information for cognitive processes and ensures instant access to the memorized contents. Theories suggest that switching the focus of attention between items within working memory realizes the access. This is reflected in object-switching costs in response times when the item for the task processing is to be changed. Another correlate of attentional allocation in working memory is the P3a-component of the human event-related potential. The aim of this study was to demonstrate that switching of attention within working memory is a separable processing step. Participants completed a cued memory-updating task in which they were instructed to update one memory item at a time out of a memory list of four digits by applying a mathematical operation indicated by a target sign. The hypotheses predicted (1) prolonged updating times in switch (different item compared to previous trial) versus repetition trials (same item), (2) an influence of cues (valid/neutral) presented before the mathematical target on switching costs, and (3) that the P3a component is more pronounced in the cue-target interval in the valid cue condition and more pronounced in the post-target interval in the neutral cue condition. A student's t-test verified the first hypothesis, repeated-measurement analyses of variance demonstrated that hypotheses 2 and 3 should be rejected. Results suggest that switching of attention within working memory could not be separated from further processing steps and retro-cue benefits are not due to a head start of retrieval as well as that switch costs represent internal processes. PMID- 29476874 TI - Glutamate-dependent regulation of food intake is altered with age through changes in NMDA receptor phenotypes on vagal afferent neurons. AB - Compared to younger individuals, older human subjects have significantly lower food intakes and an increased satiety response. N-methyl-d-aspartate (NMDA) receptors expressed by vagal afferent neurons originating from nodose ganglia (NG) are involved in modulating the satiety response. The present study investigated how NMDA receptor subunit phenotypes in NG neurons change with age and how these age-related alterations in food intake are modulated by presynaptic NMDA receptors in the NG of male Sprague Dawley rats (six week-old and sixty week old). Food intake was measured at 30-, 60-, and 120-min following intraperitoneal administration of cholecystokinin (CCK) or the non-competitive NMDA receptor antagonist MK-801. Immunofluorescence was used to determine NMDA receptor subunit expression (NR1, NR2B, NR2C, and NR2D) in the NG. The results showed that, CCK reduced food intake at 30-, 60-, and 120-min post injection in both young and the middle-age animals, with no statistical difference between the groups at 30- and 60-min. In contrast, MK-801 produced an increase in food intake that was significantly higher in middle-age rats compared to young animals at all time points studied. NR1 subunit was expressed by almost all NG neurons in both age groups. In young rats, NR2B, NR2C, and NR2D subunits were expressed in 56.1%, 49.3%, and 13.9% of NG neurons, respectively. In contrast, only 30.3% of the neuronal population in middle-aged rats expressed NR2B subunit immunoreactivity, NR2C was present in 34.1%, and only 10.6% of total neurons expressed the NR2D subunit. In conclusion, glutamate-dependent regulation of food intake is altered with age and one of the potential mechanisms through which this age-related changes in intake occur is changes in NMDA receptor phenotypes on vagal afferent neurons located in NG. PMID- 29476875 TI - Ultrasound Fissure Observation: Assessment of Lung by Pleural-Hub Affiliates. AB - BACKGROUND: Lung ultrasound examination is becoming an even more important part of pulmonologists' clinical routine. As indicated in the literature, the coordinates of any findings on lung parenchyma are based on surface landmarks or conventional quadrants. In our experience we have noticed that lung fissures are clearly detectable as interruptions of the pleural line, but this has never been investigated previously. The aim of this study was to evaluate whether lung fissures are detectable under normal conditions in routine clinical practice. METHODS: Ten operators were enrolled from Pleural-Hub, a scientific discussion group. After compiling a prestudy survey to investigate whether they had observed fissures previously, they were asked to note if the following fissures were detectable: posterior right (PR) and left (PL), lateral right (LR) and left (LL), anterior right (AR), and anterolateral left (AL). Enrollment was competitive, aiming to reach 100 case subjects. RESULTS: We found that general fissure detection was 61.3%, in particular: PR, 59%; LR, 75%; AR, 69%; PL, 45%; LL, 64%; AL, 56%. Single operators yielded different detection rates ranging from 90% to 25%, showing strong operator dependency. Before being made aware of general results operators indicated operator's skill and rib shadow artifacts as the principal factors affecting fissure detection. CONCLUSIONS: Lung fissures may be detected with ultrasound once adequate training is provided. This may allow the clinician a more precise anatomical delineation of pathology identified by lung ultrasound. PMID- 29476876 TI - Changes and Clinical Consequences of Smoking Cessation in Patients With COPD: A Prospective Analysis From the CHAIN Cohort. AB - BACKGROUND: Despite the existing evidence-based smoking cessation interventions, chances of achieving that goal in real life are still low among patients with COPD. We sought to evaluate the clinical consequences of changes in smoking habits in a large cohort of patients with COPD. METHODS: CHAIN (COPD History Assessment in Spain) is a Spanish multicenter study carried out at pulmonary clinics including active and former smokers with COPD. Smoking status was certified by clinical history and co-oximetry. Clinical presentation and disease impact were recorded via validated questionnaires, including the London Chest Activity of Daily Living (LCADL) and the Hospital Anxiety and Depression Scale (HADS). No specific smoking cessation intervention was carried out. Factors associated with and clinical consequences of smoking cessation were analyzed by multivariate regression and decision tree analyses. RESULTS: One thousand and eighty-one patients with COPD were included (male, 80.8%; age, 65.2 [SD 8.9] years; FEV1, 60.2 [20.5]%). During the 2-year follow-up time (visit 2, 906 patients; visit 3, 791 patients), the majority of patients maintained the same smoking habit. Decision tree analysis detected chronic expectoration as the most relevant variable to identify persistent quitters in the future, followed by an LCADL questionnaire (cutoff 9 points). Total anxiety HADS score was the most relevant clinical impact associated with giving up tobacco, followed by the LCADL questionnaire with a cutoff value of 10 points. CONCLUSIONS: In this real-life prospective COPD cohort with no specific antismoking intervention, the majority of patients did not change their smoking status. Our study also identifies baseline expectoration, anxiety, and dyspnea with daily activities as the major determinants of smoking status in COPD. TRIAL REGISTRY: ClinicalTrials.gov; No. NCT01122758; URL: www.clinicaltrials.gov. PMID- 29476877 TI - Targeted inhibition of sclerostin for post-menopausal osteoporosis therapy: A critical assessment of the mechanism of action. AB - Promising news in the treatment of osteoporosis is that sequestering sclerostin from circulation with antibodies stimulates robust bone formation. Pre-clinical studies on rodents and monkeys have confirmed that treatment with anti-sclerostin monoclonal antibody (Scl-Ab) increases bone mass, improves bone strength and enhances fracture repair. Clinical trials show that bone gain (anabolic effect) is transient and are primarily at central (spine and hips) than peripheral (wrist) sites. Interestingly Scl-Ab also inhibited bone resorption. Thus Scl-Ab is being regarded as the pharmacologic agent with dual properties - stimulating bone formation and decreasing bone resorption. Sclerostin neutralization transiently increases bone formation markers in post-menopausal women and like parathyroid hormone (PTH) activates osteoblasts and lining cells resulting in bone anabolic effect. However, unlike PTH, sclerostin antibody also decreases bone resorption (anti-catabolic). Although, the U.S. Food and Drug Administration have accepted the Biologics License Application for one of the monoclonal antibodies against sclerostin (romosozumab) for review, many questions remain before romosozumab can be introduced as a skeletal anabolic agent to clinical practice. For example, neutralizing sclerostin alters calcium homeostasis and increases PTH. In addition, sclerostin depletion in preclinical studies has been reported to severely compromises B cell depletion in bone marrow. We have reviewed the currently available evidences that support the use of sclerostin antibody in treating osteoporosis and compare its efficacy and mechanism of action with the currently available anabolic drug, human PTH. PMID- 29476878 TI - Low systemic exposure and calcemic effect of calcipotriol/betamethasone ointment in rats with imiquimod-induced psoriasis-like dermatitis. AB - Vitamin D3 (VD3) analogues-containing ointments are known to occasionally cause hypercalcemia in psoriasis patients, and the frequency of hypercalcemia is suggested to vary based on the VD3 analogue used. In this study, to address the differences in calcemic effects of VD3-containing ointments, the calcemic effects of marketed VD3-containing ointments, including calcipotriol (Cal), maxacalcitol (Max), tacalcitol (Tac), calcipotriol/betamethasone dipropionate (Cal/BDP) and maxacalcitol/betamethasone butyrate propionate (Max/BBP) ointments, were evaluated in a rat model of imiquimod-induced dermatitis. The topical application of Tac, Max and Max/BBP ointments, but not Cal and Cal/BDP ointments, to the imiquimod-induced skin lesions significantly induced an increase in the serum calcium level compared with the vaseline-treated group. Calcemic effect of VD3 analogues in rats treated with VD3-containing ointments was analyzed by evaluating the expression of vitamin D receptor target genes, such as Cyp24a1, Trpv5 and CalbindinD28k, in the intestine and kidney. Real-time reverse transcription PCR (RT-PCR) analysis showed that the renal and intestinal Cyp24a1 expressions in the Cal- and Cal/BDP-treated groups were significantly lower than those in the Tac-, Max- and Max/BBP-treated groups, suggesting that systemic exposure of VD3 analogues in the Cal- and Cal/BDP-treated groups were lower than those in the other ointment-treated groups. In addition, the renal Trpv5 and CalbindinD28k expressions, calcium-transporting genes, were increased in the Max- and Max/BBP-treated groups compared with the Cal- and Cal/BDP-treated groups. Thus, because of the low systemic exposure of VD3 analogues, Cal and Cal/BDP ointments have lower calcemic effect than the other VD3-containing ointments in rats with psoriasis-like dermatitis. PMID- 29476879 TI - A novel PPARalpha/gamma agonist, propane-2-sulfonic acid octadec-9-enyl-amide, ameliorates insulin resistance and gluconeogenesis in vivo and vitro. AB - Peroxisome proliferator-activated receptor alpha/gamma (PPARalpha/gamma) agonists have emerged as important pharmacological agents for improving insulin action. Propane-2-sulfonic acid octadec-9-enyl-amide (N15) is a novel PPARalpha/gamma dual agonist synthesized in our laboratory. The present study investigates the efficacy and safety of N15 on insulin resistance regulation in high fat diet (HFD)-and streptozotocin (STZ)-induced diabetic mice and in palmitic acid (PA) induced HepG2 cells. Our results showed that N15 remarkably ameliorated insulin resistance and dyslipidemia in vivo, as well as rectified the glucose consumption and gluconeogenesis in vitro. Moreover, the glucose-lowering effect of N15 was associated with PPARgamma mediated up-regulation of hepatic glucose consumption and down-regulation of gluconeogenesis. Meanwhile, N15 exerted advantageous effects on glucose and lipid metabolism without triggering weight gain and hepatotoxicity in mice. In conclusion, our data demonstrated that by alleviating glucose and lipid abnormalities, N15 could be used as a potential prophylactic and therapeutic agent against type 2 diabetes and related metabolic disorders. PMID- 29476880 TI - Downregulation of estrogen-related receptor alpha inhibits human cutaneous squamous cell carcinoma cell proliferation and migration by regulating EMT via fibronectin and STAT3 signaling pathways. AB - Estrogen-related receptor alpha (ERRalpha), one of orphan nuclear receptors, has been recently revealed as an oncogenic regulator in a variety of cancers. However, the linking gain of ERRalpha expression and cancer progression in cutaneous squamous cell carcinoma (cSCC) is largely unknown. Here, we showed that the mRNA and protein expression levels of ERRalpha were markedly higher in A431 cells compared with human keratinocyte cell line HaCaT, and targeted inhibition of ERRalpha by shRNA or its inverse agonist XCT790 significantly suppressed A431 cells proliferation and migration, while overexpression of ERRalpha promoted cell proliferation and migration. In addition, the data revealed that ERRalpha downregulation markedly inhibited the epithelial mesenchymal transition (EMT) of A431 cells with increasing the expression of E-cadherin and decreasing fibronectin (FN) and vimentin. Results from further experiments using Western blot suggested that ERRalpha suppression inhibited signal transducer and activator of transcription (STAT3) protein expression. In contrast, overexpression of ERRalpha promoted EMT and the activation of STAT3 pathway. Moreover, treatment with specific STAT3 inhibitor reversed EMT markers in ERRalpha-overexpressing A431 cells. In tumor xenografts of A431 cells, we further showed that ERRalpha depletion inhibited cSCC tumor growth in vivo. Taken together, these results demonstrate, for the first time, that ERRalpha may function as an oncoprotein in cSCC to accelerate tumor aggressiveness by promoting EMT via FN and STAT3 pathway, and it could be a novel target for cSCC therapy. PMID- 29476881 TI - Increased permeability of blood vessels after reversible electroporation is facilitated by alterations in endothelial cell-to-cell junctions. AB - Delivery of electric field pulses, i.e. electroporation (EP), to tissues has been shown to have a blood flow modifying effect. Indeed, the diameter of blood vessels exposed to EP is immediately reduced resulting in blood flow abrogation, followed by an increase in vascular permeability. The main cause of the increased permeability remains unknown. The aim of this study was to determine whether the in vivo effects of EP on permeability of blood vessels are linked to the permeabilization of endothelial cells' membrane (EC) and/or disruption of cell-to cell junctions. We used a dorsal window chamber model in C57Bl/6 mice coupled with multiphoton microscopy and fluorescently labelled antibodies against PECAM-1 (CD31) to visualize endothelial cell-to-cell junctions. Clinically validated EP parameters were used and behavior of cell-to-cell junctions, in combination with leakage of 70 kDa fluorescein isothiocyanate labelled dextran (FD), was followed in time. After EP, a constriction of blood vessels was observed and correlated with the change in the shape of ECs. This was followed by an increase in permeability of blood vessels for 70 kDa FD and a decrease in the volume of labelled cell-to-cell junctions. Both parameters returned to pre-treatment values in 50% of mice. For the remaining 50%, we hypothesize that disruption of cell-to cell junctions after EP may trigger the platelet activation cascade. Our findings show for the first time in vivo that alterations in cell-to-cell junctions play an important role in the response of blood vessels to EP and explain their efficient permeabilization. PMID- 29476882 TI - Surfactant-free solubilization and systemic delivery of anti-cancer drug using low molecular weight methylcellulose. AB - Docetaxel, an advanced taxoid, has been widely used as an anti-mitotic agent, but further augmentation of its properties is still required, including improvement in low aqueous solubility. Herein, we report the development of bio-eliminable low molecular weight methylcellulose-based surfactant-free injectable formulation for the delivery of docetaxel. Crude methylcellulose, a hydrophobically modified cellulose derivative, was hydrolyzed by an enzymatic degradation method to obtain low molecular weight methylcellulose (LMwMC). Docetaxel was successfully loaded in micelles with small particle sizes high drug loading and sustained release profile. The in vivo anti-cancer effects of intravenously injected nanoparticle systems in B16F10 melanoma xenograft mice were evaluated and demonstrated a significantly enhanced therapeutic effect with the docetaxel-LMwMC micellar aggregates compared to a commercially available docetaxel, Taxotere(r). Surfactant-free solubilization of docetaxel could be a promising delivery method for effective insoluble drug delivery for anti-tumor efficacy. PMID- 29476884 TI - Characterization and reproducibility of HepG2 hanging drop spheroids toxicology in vitro. AB - Hepatotoxicity remains a major challenge in drug development despite preclinical toxicity screening using hepatocytes of human origin. To overcome some limitations of reproducing the hepatic phenotype, more structurally and functionally authentic cultures in vitro can be introduced by growing cells in 3D spheroid cultures. Characterisation and reproducibility of HepG2 spheroid cultures using a high-throughput hanging drop technique was performed and features contributing to potential phenotypic variation highlighted. Cultured HepG2 cells were seeded into Perfecta 3D(r) 96-well hanging drop plates and assessed over time for morphology, viability, cell cycle distribution, protein content and protein-mass profiles. Divergent aspects which were assessed included cell stocks, seeding density, volume of culture medium and use of extracellular matrix additives. Hanging drops are advantageous due to no complex culture matrix being present, enabling background free extractions for downstream experimentation. Varying characteristics were observed across cell stocks and batches, seeding density, culture medium volume and extracellular matrix when using immortalized HepG2 cells. These factors contribute to wide-ranging cellular responses and highlights concerns with respect to generating a reproducible phenotype in HepG2 hanging drop spheroids. PMID- 29476883 TI - Active surveillance for carbapenem-resistant Enterobacteriaceae, vancomycin resistant enterococci and toxigenic Clostridium difficile among patients transferred from long-term care facilities in Korea. AB - A 10-month active surveillance study was conducted to assess carriage of carbapenemase-producing Enterobacteriaceae (CPE), vancomycin-resistant enterococci (VRE) and toxigenic Clostridium difficile colonization among patients transferred to hospital from long-term care facilities (LTCFs). Four (1.4%) patients with carbapenem-resistant Enterobacteriaceae (none of which were CPE), 59 (21%) patients with VRE and 20 (7.1%) patients colonized with toxigenic C. difficile were identified from 282 rectal specimens. There was no outbreak of VRE infection during the study period. The low prevalence of CPE carriage suggests that screening all admissions from LTCFs for CPE would not be cost-effective, and that screening and use of contact precautions for VRE should be reconsidered. PMID- 29476885 TI - Antiparasitic, structural, pharmacokinetic, and toxicological properties of riparin derivatives. AB - Schistosomiasis, caused by helminth flatworms of the genus Schistosoma, is one of the most important parasitic diseases in the world, affecting over 200 million people in developing countries. Riparins are natural alkamides found in Aniba riparia (Lauraceae) fruits that possess several pharmacological properties. In this study, we reported the synthesis, characterization and structural analysis of six riparin derivatives (A-F), as well as their schistosomicidal activity against S. mansoni worms together with a biological, pharmacokinetic and toxicological in silico evaluation. Firstly, these compounds were synthesized, purified and characterized by elemental analysis, FT-IR spectroscopy, X-ray diffraction and theoretical calculations to evaluate their stability and conformation. Next, the schistosomicidal activity of the riparins was tested against S. mansoni worms. Bioassays revealed that Riparins E and F were the most active compounds, showing half-maximum inhibitory concentration at low micromolar ranges (IC50 values ~10 MUM). Also, confocal laser scanning microscopy studies revealed tegumental damage in parasites after exposition with Riparins B, E and F. Additionally, based on MTT assay, all tested riparins showed no cytotoxic potential toward mammalian cells. Finally, in silico analyses were used to predict the absorption, distribution, metabolism, elimination and toxicity (ADMET) of the compounds. Taken together, the results revealed a promising ADMET profile and suggested that riparins could be starting points for lead optimization programs for natural products with antischistosomal properties. PMID- 29476886 TI - The functional genomic studies of resveratrol in respect to its anti-cancer effects. AB - Resveratrol has anti-cancer effects in vitro, and hypothetical chemopreventive effects in vivo. Effects are pleiotropic, mediated by changes in expression of many genes and epigenetic reprogramming. Thus, they are well suited for functional genomic studies. We carried out systematic review of such studies (reflecting also on technological progress). Differentially expressed genes commonly linked to resveratrol treatment were linked to cell cycle, proliferation, and apoptosis. However, it is unclear if these are primary and specific targets of resveratrol. We conclude by discussing areas where additional functional genomic studies are desirable, including experiments that better model in vivo effects of dietary intake. PMID- 29476887 TI - Trends and disparities in statin use and low-density lipoprotein cholesterol levels among US patients with diabetes, 1999-2014. AB - AIMS: The 2013 American College of Cardiology/American Heart Association Guideline defined patients with diabetes aged 40-75 years as a major statin benefit group. We explored the temporal trends and disparities in statin utilization and LDL-C levels among patients with diabetes aged 40-75 years. METHODS: A total of 4860 patients from the National Health and Nutrition Examination Survey 1999 to 2014 were included in this study. Differences in statin use and LDL-C levels were explored by patient characteristics. RESULTS: From 1999-2002 to 2011-2014, the prevalence of statin use increased from 26.2% to 49.5% (Ptrend < 0.001). This was accompanied by a continuous decrease in the mean LDL-C level (from 115.8 mg/dL to 103.3 mg/dL, Ptrend < 0.001). The use of guideline-defined high-potency statin medications (atorvastatin and rosuvastatin) remained largely unchanged (from 14.0% to 17.9%, Ptrend = 0.55). Statin utilization increased with age. Women and blacks were 10% and 16% less likely to receive statin treatment compared with men and whites, respectively. In comparison with other statin treatment, use of atorvastatin or rosuvastatin was associated with average LDL-C reduction of 8.0 mg/dL. LDL-C levels were significantly higher among women and black patients. After adjustment for potential confounders, age and Hispanic-white differences in statin use and LDL-C levels were substantially attenuated. CONCLUSIONS: Despite a steady increase in statin use during the 16-year study period, statin therapy remains underutilized in certain subgroups of patients. Confounding factors related to healthcare utilization account for some of the disparities in statin use and LDL-C levels. PMID- 29476888 TI - Effective translation of a type-2 diabetes primary prevention programme into routine primary care: The PreDE cluster randomised clinical trial. AB - AIMS: We assessed the effectiveness of a Type 2 diabetes mellitus (T2D) prevention programme in routine primary health care (PHC) in high-risk patients. METHODS: Phase IV cluster clinical trial involving 14 PHC centres in the Basque Health Service were randomised to the DE-PLAN educational healthy lifestyle promotion programme or standard care. All non-diabetic 45- to 70-year-old PHC attendees considered at high risk of T2D (FINDRISC >= 14 points) were eligible. The primary outcome was the 24-month cumulative incidence of T2D confirmed by oral glucose tolerance testing. Secondary outcomes were self-reported physical activity and dietary changes at 12 months in a subsample. RESULTS: Of the 4170 patients screened, 2128 (51%) were considered high risk, but 355 (33%) and 459 (43.6%) refused to participate in the control and intervention groups, respectively. Of all eligible non-diabetic patients, 634 and 454 were included in the control and intervention arms, 545 (85.9%) and 411 (90.5%) completed the follow-up. Intention-to-treat cumulative incidences of T2D were 12.1% (77/634) in the control group and 8.4% (38/454) in intervention group, with an absolute difference of 3.8% (95% CI: 0.18%-7.4%, p = 0.045) and a relative risk reduction of 32% (0.68; 95% CI: 0.47-0.99, p = 0.048) in favour of the intervention. Intervention patients were 1.83-fold more likely to meet recommended physical activity levels at 12 months (95% CI: 1.06-3.17, p = 0.03). CONCLUSIONS: The DE PLAN programme was effective in reducing T2D incidence in PHC high-risk patients. Research on implementation strategies to improve its feasible and sustainable adoption, reach and public health impact is warranted. PMID- 29476889 TI - Targeted Nrf2 activation therapy with RTA 408 enhances regenerative capacity of diabetic wounds. AB - AIMS: Though unmitigated oxidative stress in diabetic chronic non-healing wounds poses a major therapeutic challenge, currently, there are no effective pharmacological agents. We targeted the cytoprotective Nrf2/Keap1 pathway, which is dysfunctional in diabetic skin and the regenerative environment in the diabetic wound. We assessed the efficacy of a potent Nrf2-activator, RTA 408, a semi-synthetic oleanane triterpenoid, on accelerating diabetic wound healing. METHODS: Using Leprdb/dbmice, we made 10 mm-diameter excisional humanized wounds in dorsal skin. We administered RTA 408 formulations daily, and used ANOVA for comparison of time to closure, in vivo real-time ROS, histology, molecular changes. RESULTS: We found that RTA 408, specifically a 0.1% formulation, significantly reduced wound healing time and increased wound closure rate. While either systemic or topical administration of RTA 408 is effective, wound closure time with the latter was far superior. RTA 408-treated diabetic wounds upregulated Nrf2 and downstream antioxidant genes, and exhibited well vascularized granulation tissue that aided in re-epithelialization. Reintroduction of redox mechanisms via RTA 408-induced Nrf2 resulted in reduction of the oxidative status of wounds, to coordinate successful wound closure. CONCLUSIONS: This preclinical study shows that promoting Nrf2-mediated antioxidant activity in the localized regenerative milieu of a diabetic wound markedly improves the molecular and cellular composition of diabetic wound beds. RTA 408 treats and corrects the irregularity in redox balance mechanisms involving Nrf2, in an avenue not explored previously for treatment of diabetic wounds and tissue regeneration. Our study supports development of RTA 408 as a therapeutic modality for chronic diabetic wounds. PMID- 29476890 TI - Chest compression-only versus conventional cardiopulmonary resuscitation for bystander-witnessed out-of-hospital cardiac arrest of medical origin: A propensity score-matched cohort from 143,500 patients. AB - BACKGROUND: Current cardiopulmonary resuscitation (CPR) guidelines do not define the optimal type of CPR (chest compression-only CPR [CCCPR] or conventional CPR with rescue breathing [CCRB]) to be performed by bystanders when they witness someone collapse. METHODS: Using a nationwide database of 1.17 million patients who underwent out-of-hospital cardiac arrest (OHCA) in Japan, we enrolled consecutive bystander-witnessed OHCAs of medical origin with resuscitation attempts from January 2005 through December 2014. Multivariable logistic regression analysis was used to assess the association between the type of bystander CPR and the OHCA outcome after one-to-one propensity score matching for CCCPR versus CCRB. The primary outcome measure was one-month survival with a favorable neurological outcome, defined as a cerebral performance category of 1 or 2. RESULTS: Among 143,500 eligible patients with bystander-witnessed OHCAs receiving bystander-initiated CPR, 71.4% received CCCPR and 28.6% received CCRB. In the univariate analysis, the proportion of one-month survival cases with favorable neurological outcome was lower in the CCCPR group than the CCRB group (5.6% [5749/102,487] vs. 6.5% [2682/41,013], odds ratio [OR]; 0.85 [95% confidence interval {CI}; 0.81-0.89]). However, in the multivariate analysis, the CCCPR group showed a more favorable neurological outcome than the CCRB group (adjusted OR 1.12, 95% CI; 1.06-1.19). In the propensity-matched cohort, the CCCPR group also showed a more favorable neurological outcome than the CCRB group (7.2% [2894/40,096] vs. 6.5% [2610/40,096], adjusted OR 1.14, 95% CI; 1.09-1.22). CONCLUSIONS: CCCPR is an acceptable resuscitation technique for lay-rescuers responding to bystander witnessed OHCA of presumed medical origin. PMID- 29476891 TI - Post-arrest therapeutic hypothermia in pediatric patients with congenital heart disease. AB - BACKGROUND: While therapeutic hypothermia (TH) is an effective neuroprotective therapy for neonatal hypoxic-ischemic encephalopathy, TH has not been demonstrated to improve outcome in other pediatric populations. Patients with acquired or congenital heart disease (CHD) are at high risk of both cardiac arrest and neurodevelopmental impairments, and therapies are needed to improve neurologic outcome. The primary goal of our study was to compare safety/efficacy outcomes in post-arrest CHD patients treated with TH versus controls not treated with TH. METHODS: Patients with CHD treated during the first 18 months after initiation of a post-arrest TH protocol (temperature goal: 33.5 degrees C) were compared to historical and contemporary post-arrest controls not treated with TH. Post-arrest data, including temperature, safety measures (e.g. arrhythmia, bleeding), neurodiagnostic data (EEG, neuroimaging), and survival were compared. RESULTS: Thirty arrest episodes treated with TH and 51 control arrest episodes were included. The groups did not differ in age, duration of arrest, post-arrest lactate, or use of ECMO-CPR. The TH group's post-arrest temperature was significantly lower than control's (33.6 +/- 0.2 degrees C vs 34.7 +/- 0.5 degrees C, p < 0.001). There was no difference between the groups in safety/efficacy measures, including arrhythmia, infections, chest-tube output, or neuroimaging abnormalities, nor in hospital survival (TH 61.5% vs control 59.1%, p = NS). Significantly more controls had seizures than TH patients (26.1% vs. 4.0%, p = 0.04). Almost all seizures were subclinical and occurred more than 24 h post-arrest. CONCLUSION: Our data show that pediatric CHD patients who suffer cardiac arrest can be treated effectively and safely with TH, which may decrease the incidence of seizures. PMID- 29476892 TI - Reply to: 'Cardiac arrest and breathing, why bother?' Because it's too late if we wait for a definitive diagnosis. PMID- 29476893 TI - How long should we wait for patients to wake up when they undergo targeted temperature management? PMID- 29476895 TI - Inhibition of NF-kappaB-dependent HIV-1 replication by the marine natural product bengamide A. AB - HIV-1 inhibitors that act by mechanisms distinct from existing antiretrovirals can provide novel insights into viral replication and potentially inform development of new therapeutics. Using a multi-cycle HIV-1 replication assay, we screened 252 pure compounds derived from marine invertebrates and microorganisms and identified 6 (actinomycin Z2, bastadin 6, bengamide A, haliclonacyclamine A + B, keramamine C, neopetrosiamide B) that inhibited HIV-1 with 50% effective concentrations (EC50s) of 3.8 MUM or less. The most potent inhibitor, bengamide A, blocked HIV-1 in a T cell line with an EC50 of 0.015 MUM and in peripheral blood mononuclear cells with an EC50 of 0.032 MUM. Bengamide A was previously described to inhibit NF-kappaB signaling. Consistent with this mechanism, bengamide A suppressed reporter expression from an NF-kappaB-driven minimal promoter and an HIV-1 long terminal repeat (LTR) with conserved NF-kappaB response elements, but lacked activity against an LTR construct with mutation of these elements. In single-cycle HIV-1 infection assays, bengamide A also suppressed viral protein expression when viruses encoded an intact LTR but exhibited minimal activity against those with mutated NF-kappaB elements. Finally, bengamide A did not inhibit viral DNA accumulation, indicating that it likely acts downstream of this step in HIV-1 replication. Our study identifies multiple new antiviral compounds including an unusually potent inhibitor of HIV-1 gene expression. PMID- 29476894 TI - Sex Differences in the Neuroadaptations of Reward-related Circuits in Response to Subchronic Variable Stress. AB - Women are twice as likely to be diagnosed with major depressive disorder. However, fewer studies in rodent models of depression have used female animals, leading to a relative lack of understanding of the female brain's response to stress, especially at a neural circuit level. In this study, we utilized a 6-day subchronic variable stress (SCVS) mouse model and measured novelty suppressed feeding as behavioral criteria to evaluate susceptibility to SCVS in male and female mice. First, we showed that SCVS induced a decrease in latency to eat (susceptible phenotype) in female mice, but not in males (resilient phenotype). After determining behavioral phenotypes, we investigated the firing activities of dopamine (DA) neurons in the ventral tegmental area (VTA), as well as the neurons that project from lateral habenula (LHb) to the VTA and from locus coeruleus (LC) to the VTA. Utilizing retrograding lumafluor fluorescent tracers and electrophysiology techniques, we performed cell type- and circuit-specific measures of neuronal firing rates. Our data show that SCVS significantly increased the firing rate of LHb-VTA circuit neurons in female mice when compared to that of their female controls, an effect that was absent in SCVS-exposed males. Interestingly, SCVS did not induce significant firing alterations in VTA DA neurons and LC-VTA circuit neurons in either female mice or male mice when compared to their stress-naive controls. Overall, our data show sex differences in the LHb-VTA circuit responses to SCVS, and implicates a potential role of this projection in mediating vulnerability of female mice to stress-induced depression. PMID- 29476896 TI - Systemic administration of guanfacine improves food-motivated impulsive choice behavior primarily via direct stimulation of postsynaptic alpha2A-adrenergic receptors in rats. AB - Impulsive choice behavior, which can be assessed using the delay discounting task, is a characteristic of various psychiatric disorders, including attention deficit/hyperactivity disorder (ADHD). Guanfacine is a selective alpha2A adrenergic receptor agonist that is clinically effective in treating ADHD. However, there is no clear evidence that systemic guanfacine administration reduces impulsive choice behavior in the delay discounting task in rats. In the present study, we examined the effect of systemic guanfacine administration on food-motivated impulsive choice behavior in rats and the neuronal mechanism underlying this effect. Repeated administration of either guanfacine, methylphenidate, or atomoxetine significantly enhanced impulse control, increasing the number of times the rats chose a large but delayed reward in a dose-dependent manner. The effect of guanfacine was significantly blocked by pretreatment with an alpha2A-adrenergic receptor antagonist. Furthermore, the effect of guanfacine remained unaffected in rats pretreated with a selective noradrenergic neurotoxin, consistent with a post-synaptic action. In contrast, the effect of atomoxetine on impulsive choice behavior was attenuated by pretreatment with the noradrenergic neurotoxin. These results provide the first evidence that systemically administered guanfacine reduces impulsive choice behavior in rats and that direct stimulation of postsynaptic, rather than presynaptic, alpha2A-adrenergic receptors is involved in this effect. PMID- 29476897 TI - Sex-dependent modification by chronic caffeine of acute methamphetamine effects on anxiety-related behavior in rats. AB - For fourteen days, male and female PVG/c hooded rats were provided continuously with either pure drinking water, or water containing caffeine in a quantity approximating a daily dose of 31.1 mg/kg. Then at intervals of 3 days, they were administered 1, 2 mg/kg methamphetamine (MA) or saline before being tested for anxiety-related behavior in a zero maze or a light/dark box, or their short-term spatial memory was assessed in a Y maze following introduction of a novel brightness change in one of the arms. Each rat experienced each type of apparatus with the same acute MA or saline treatment while still exposed to chronic caffeine or pure drinking water. While chronic caffeine on its own did not affect any behavioral measure, acute MA was anxiolytic for male rats suggested by increased entries and occupancy of zero-maze enclosed areas, and decreased emergence latencies and increased entries into the light/dark-box light compartment. Females were less affected than males by MA in both types of apparatus unless they also consumed caffeine. For male rats, choices of the Y maze novel arm were affected by neither caffeine nor MA, but for females provided with unadulterated water, such choices were reduced by 1 mg/kg MA but increased for those exposed to caffeine, thereby suggesting either impaired or improved memory respectively. However, changes in anxiety could also explain these results. Overall, results generated in the three types of apparatus supported potentiation by caffeine of any effects of MA on anxiety for females only. PMID- 29476899 TI - Lucio's phenomenon: A life-threatening medical emergency. PMID- 29476898 TI - Influence of multidrug resistant organisms on the outcome of diabetic foot infection. AB - OBJECTIVES: We described the clinical outcomes of the diabetic patients who had foot infections with multidrug resistant organisms. METHODS: We included the patients with diabetic foot infections (DFI) from 19 centers, between May 2011 and December 2015. Infection was defined according to IDSA DFI guidelines. Patients with severe infection, complicated moderate infection were hospitalized. The patients were followed-up for 6 months after discharge. RESULTS: In total, 791 patients with DFI were included, 531(67%) were male, median age was 62 (19 90). Severe infection was diagnosed in 85 (11%) patients. Osteomyelitis was diagnosed in 291(36.8%) patients. 536 microorganisms were isolated, the most common microorganisms were S. aureus (20%), P. aeruginosa (19%) and E. coli (12%). Methicillin resistance (MR) rate among Staphylococcus aureus isolates was 31%. Multidrug resistant bacteria were detected in 21% of P. aeruginosa isolates. ESBL (+) Gram negative bacteria (GNB) was detected in 38% of E. coli and Klebsiella isolates. Sixty three patients (8%) were re-hospitalized. Of the 791 patiens, 127 (16%) had major amputation, and 24 (3%) patients died. In multivariate analysis, significant predictors for fatality were; dialysis (OR: 8.3, CI: 1.82-38.15, p=0.006), isolation of Klebsiella spp. (OR:7.7, CI: 1.24 47.96, p=0.028), and chronic heart failure (OR: 3, CI: 1.01-9.04, p=0.05). MR Staphylococcus was detected in 21% of the rehospitalized patients, as the most common microorganism (p<0.001). CONCLUSION: Among rehospitalized patients, methicillin resistant Staphylococcus infections was detected as the most common agent, and Klebsiella spp. infections were found to be significantly associated with fatality. PMID- 29476900 TI - Patient-reported outcomes in daily clinical practise in HIV outpatient care. AB - INTRODUCTION: The use of patient-reported outcomes (PROs) in outpatient care holds promise as a tool to enhance the quality of care. The management of chronic HIV infection is multidimensional, and clinical assessment includes broad screening to identify complications. With growing constraints on time and resources, the use of PROs may provide a much-needed tool to ensure optimal HIV care. The aim of this study was to evaluate the clinical implementation and use of a Web-based tool to collect PROs in a cohort of HIV-infected individuals. METHODS: In December 2015, the PRO system AmbuFlex, a Web-based tool for self reporting of clinical symptoms, was implemented in HIV outpatient care at Aarhus University Hospital. The HIV-specific questionnaire was designed to cover items in the European AIDS Clinical Society guidelines. Patients responded through a Web-based system from home. Based on an HIV-specific algorithm, responses were automatically assigned a green, yellow, or red colour code reflecting the severity of the symptom. HIV-related data from the electronic hospital management system were used to compare respondents and non-respondents. For cognitive and red symptoms, patient records were accessed to address whether PRO provided new information. Furthermore, it was sought to determine whether implementing PROs in clinical care can help focus the consultation on current needs. This was done by checking if a flagged symptom was assessed clinically at the following consultation. RESULTS: Five hundred and five HIV patients were invited to participate and 277 (55%) accepted the invitation. Compared to respondents, non respondents were significantly younger and more often female, born outside Denmark, newly diagnosed, and with a plasma viral load >50 copies/ml. Among the 262 correctly received PRO questionnaires, 104 (39%) had solely green colour coded responses, whereas 59 (23%) had one or more red colour-coded responses. Of 69 red symptoms, 28 (41%) led to a specific clinical assessment. In many cases, PROs appeared to provide new information on cognitive (76%) and red-coded symptoms (42%). CONCLUSIONS: The use of PROs identified several cases where physical or cognitive symptoms appeared to have been unnoticed. A substantial proportion of patients reported no symptoms requiring medical attention, suggesting a potential to individualize outpatient care and redistribute resource utilization. PMID- 29476901 TI - Evaluation of a tuberculosis active case finding project in peri-urban areas, Myanmar: 2014-2016. AB - OBJECTIVES: We assessed the effect of an active case finding (ACF) project on tuberculosis (TB) case notification and the yields from a household and neigbourhood intervention (screening contacts of historical index TB patients diagnosed >24months ago) and a community intervention (screening attendants of health education sessions/mobile clinics). DESIGN: Cross-sectional analysis of project records, township TB registers and annual TB reports. RESULTS: In the household and neigbourhood intervention, of 56,709 people screened, 1,076 were presumptive TB and 74 patients were treated for active TB with a screening yield of 0.1% and a yield from presumptive cases of 6.9%. In the community intervention, of 162,881 people screened, 4,497 were presumptive TB and 984 were treated for active TB with a screening yield of 0.6% and yield from presumptive cases of 21.9%. Of active TB cases, 94% were new, 89% were pulmonary, 44% were bacteriologically-confirmed and 5% had HIV. Case notification rates per 100,000 in project townships increased from 142 during baseline (2011-2013) to 148 during intervention (2014-2016) periods. CONCLUSIONS: The yield from household and neigbourhood intervention was lower than community intervention. This finding highlights reconsidering the strategy of screening of contacts from historical index cases. Strategies to reach high-risk groups should be explored for future ACF interventions to increase yield of TB. PMID- 29476902 TI - Comorbidity is more common and occurs earlier in persons living with HIV than in HIV-uninfected matched controls, aged 50 years and older: A cross-sectional study. AB - OBJECTIVES: At present, data are limited on the comorbidity profiles associated with aging people with HIV in the developing world, where most such people live. The aim of this study was to compare the disease burden between older HIV positive subjects and HIV-negative matched controls in Brazil. METHODS: This was a cross-sectional analysis of the South Brazilian HIV Cohort. Individuals aged 50 years and older were enrolled at Hospital de Clinicas de Porto Alegre and matched with HIV-negative controls from the primary practice unit of the same hospital. Multimorbidity (the presence of two or more comorbid conditions) and the number of non-infectious comorbidities were compared. Poisson regression was used to identify factors associated with multimorbidity. RESULTS: A total of 208 HIV positive subjects were matched to 208 HIV-negative controls. Overall, the median age was 57 years and 56% were male. The prevalence of multimorbidity was higher in HIV-positive subjects than in HIV-negative controls (63% vs. 43%, p<0.001), and the median number of comorbidities was 2, compared to 1 in controls (p<0.001). The duration of HIV infection (p=0.02) and time on treatment in years (p=0.015) were associated with greater multimorbidity in HIV-positive persons. CONCLUSIONS: In this large cohort from the developing world, multimorbidity was found to be more common in HIV-positive subjects than in HIV-negative controls. The duration of HIV and time on antiretrovirals were associated with multimorbidity. PMID- 29476903 TI - Retrospective review of 65 atrioesophageal fistulas post atrial fibrillation ablation. AB - BACKGROUND: Although a rare complication of catheter based ablation for atrial fibrillation (AF), atrioesophageal fistula (AEF) is a serious and fatal event [1 5]. Most reports of AEF are single cases or small case series. OBJECTIVE: The purpose of this study was to perform a comprehensive literature search of all published atrioesophageal fistula following catheter ablation for AF in order to identify the mortality rates associated with therapeutic modalities and suggest the most definitive management in reducing mortality. METHODS: A comprehensive literature review of reported observational cases of atrioesophageal fistula post catheter based ablation for atrial fibrillation was performed. RESULTS: Sixty five cases of AEF post atrial fibrillation ablation were reviewed. The mean age was 55 years old. 73.8% (48/65) of the identified cases occurred in males (p < 0.001). Of the 65 cases, 13 underwent surgical radiofrequency ablation (RFA) and 52 underwent percutaneous RFA. Mortality resulted in 53.8% of those who underwent surgical RFA and in 55.8% of those who underwent percutaneous RFA (p = .888). The time range interval from procedure to onset of symptoms was 1-60 days. The most prevalent symptom, fever, occurred in 52 of the 65 cases, followed by neurological symptoms (n = 44). CT of the chest (n = 37), transthoracic echocardiogram (n = 21), and CT of the head (n = 18) were the preferred diagnostic modalities. Patients who underwent surgical correction with esophageal repair for treatment were more likely to survive, in comparison to patients who were treated with non-surgical interventions, such as antibiotic therapy, anticoagulation therapy or esophageal stenting. Of the total 34 patients who were treated surgically, 27 survived (79.4%). Of the total 31 patients who were treated non-surgically, only 2 survived (6.5%), reflecting significantly lower mortality with surgical versus non-surgical therapy (p < 0.001). CONCLUSION: Atrioesophageal fistula is an uncommon but potentially fatal complication of atrial fibrillation ablation. Patients who underwent surgical repair were twelve times more likely to survive than those treated with stenting, antibiotic therapy or no intervention. Based on the observation that patients are 12 times more likely to survive an AEF with surgery than without, the authors believe that prompt surgical correction of AEF should be considered as standard of care when dealing with this dreaded complication. PMID- 29476904 TI - Impact of the third generation cryoballoon on atrial fibrillation ablation: An useful tool? AB - BACKGROUND: Third-generation cryoballoon (CB3) is characterized by a 40% shorter distal tip designed to increase the rate of pulmonary veins real-time signal recording in order to measure time necessary to isolate veins, the "Time to effect" (TTE). Few data are currently available on clinical follow up of CB3 treated patients. METHODS: Sixtyeight consecutive patients (mean age 57.8 +/- 9.6 years, 48 male) with paroxysmal or persistent atrial fibrillation (AF) were enrolled. Thirthyfour (25 paroxysmal AF) underwent to a 28 mmCB3 pulmonary veins isolation and were compared to 34 treated (21 paroxysmal AF) with 28 mmCB2. RESULTS: CB3 use was correlated to significant increase of the possibility to measure TTE in every treated veins (left superior 82,35% vs 23,53%, left inferior 70,59% vs 38,24%, right superior 58,82% vs 14,71%, right inferior 52,94% vs 17,65%). When it is measured, TTE wasn't different between two groups. Higher nadir temperature was observed in CB3 patients (-39.4 +/- 5.2 degrees C vs -43.0 +/- 7.2 degrees C, p = 0.03). CB3 procedures were shorter (91.4 +/- 21.7 vs 110.9 +/- 31.8 min, p = 0.018), with a significant reduction in cryoenergy delivery time (24.2 +/- 8.5 vs 20.3 +/- 6.7 min, p < 0.05), and a significant reduction in left atrium dwell time (59.3 +/- 9.8 vs 69.3 +/- 10.8 min, p = 0.02, p < 0.05). At one year follow up period the Kaplan-Meier curve didn't show any significant difference in AF-free survival (Log p = 0,49). CONCLUSIONS: Novel CB3 is a useful tool in order to simplify AF cryoballoon ablation when compared to second generation cryoballoon, as observed in our experience. Follow up data seem confirm a clinical CB3 efficacy at least comparable CB2. PMID- 29476905 TI - TAX1BP1 overexpression attenuates cardiac dysfunction and remodeling in STZ induced diabetic cardiomyopathy in mice by regulating autophagy. AB - Diabetic cardiomyopathy is associated with suppressed autophagy and augmented inflammation in the heart. The effects of Tax1 binding protein 1 (TAX1BP1) on both autophagy and inflammation suggest that it may participate in the progression of diabetic cardiomyopathy. Mice were injected with streptozotocin (STZ) to induce experimental diabetes. An adenovirus system was used to induce heart specific TAX1BP1 overexpression 12 weeks after STZ injection. TAX1BP1 expression was significantly decreased in STZ-induced diabetic mouse hearts. TAX1BP1 overexpression in the heart alleviated cardiac hypertrophy and fibrosis, attenuated inflammation, oxidative stress, and apoptosis, and improved cardiac function in STZ-induced diabetic mice. Diabetic mice exhibited decreased autophagy. By contrast, increased autophagy was observed in diabetic mice overexpressing TAX1BP1. TAX1BP1 overexpression promoted autophagic flux, as demonstrated by increased LC3-RFP fluorescence in vitro. Furthermore, the autophagy inhibitor 3-MA abolished the protective effects of TAX1BP1 in vivo. Interestingly, we found that TAX1BP1 increased autophagy via the activation of a non-canonical NF-kappaB signaling pathway. Conversely, RelB knockdown disrupted the protective effects of TAX1BP1 in cardiomyocytes. TAX1BP1 thus restores the decreased autophagy level, leading to decreased inflammatory responses and oxidative stress and reduced apoptosis in cardiomyocytes. PMID- 29476907 TI - Flexible colour patterns obscure identification and mimicry in Indo-Pacific Chromodoris nudibranchs (Gastropoda: Chromodorididae). AB - Chromodoris is a genus of colourful nudibranchs that feed on sponges and is found across the Indo-Pacific. While this was once the most diverse chromodorid genus, recent work has shown that the genus should be restricted to a monophyletic lineage that contains only 22 species, all of which exhibit black pigmentation and planar spawning behaviour. Earlier phylogenies of this group are poorly resolved and thus additional work is needed to clarify species boundaries within Chromodoris. This study presents a maximum-likelihood phylogeny based on mitochondrial loci (COI, 16S) for 345 Chromodoris specimens, including data from 323 new specimens and 22 from GenBank, from across the Indo-Pacific. Species hypotheses and phylogenetic analysis uncovered 39 taxa in total containing 18 undescribed species, with only five of 39 taxa showing stable colour patterns and distinct morphotypes. This study also presents the first evidence for regional mimicry in this genus, with C. colemani and C. joshi displaying geographically based variation in colour patterns which appear to match locally abundant congenerics, highlighting the flexibility of these colour patterns in Chromodoris nudibranchs. The current phylogeny contains short branch lengths, polytomies and poor support at interior nodes, which is indicative of a recent radiation. As such, future work will employ a transcriptome-based exon capture approach for resolving the phylogeny of this group. In all, this study included 21 of the 22 described species in the Chromodoris sensu stricto group with broad sampling coverage from across the Indo-Pacific, constituting the most comprehensive sampling of this group to date. This work highlights several cases of undocumented diversity, ultimately expanding our knowledge of species boundaries in this group, while also demonstrating the limitations of colour patterns for species identification in this genus. PMID- 29476908 TI - What happened in the South American Gran Chaco? Diversification of the endemic frog genus Lepidobatrachus Budgett, 1899 (Anura: Ceratophryidae). AB - The Chaco is one the most neglected and least studied regions of the world. This highly-seasonal semiarid biome is an extensive continuous plain without any geographic barrier, and in spite of its high species diversity, the events and processes responsible have never been assessed. Miocene marine introgressions and Pleistocene glaciations have been mentioned as putative drivers of diversification for some groups of vertebrates in adjacent biomes of southern South America. Here we used multilocus data (one mitochondrial and six nuclear loci) from the three species of the endemic frog genus Lepidobatrachus (Lepidobatrachus asper, Lepidobatrachus laevis, and Lepidobatrachus llanensis) to determine if any of the historical events suggested as drivers of vertebrate diversification in southern South America are related to the diversification of the genus and if the Chaco is indeed a biome without barriers. Using fossil calibration in a coalescent framework we estimated that the genus diversified in the second half of the Miocene, coinciding with marine introgressions. Genetic patterns and historical demography suggest an important role of old archs and cratons as refuges during floods. In one species of the genus, L. llanensis, genetic structure reveals some breaks along the landscape, the main one of which corresponds to an area of the central Chaco that may act as a climatic barrier. Additionally, we found differential effects of the main Chacoan rivers on species of Lepidobatrachus that could be related to the time of persistence of populations in the areas influenced by these rivers. PMID- 29476909 TI - Developing a framework to model the primary drying step of a continuous freeze drying process based on infrared radiation. AB - The continuous freeze-drying concept based on spinning the vials during freezing and on non-contact energy transfer via infrared (IR) radiation during drying, improves process efficiency and product quality (uniformity) compared to conventional batch freeze-drying. Automated control of this process requires the fundamental mechanistic modelling of each individual process step. Therefore, a framework is presented for the modelling and control of the continuous primary drying step based on non-contact IR radiation. The IR radiation emitted by the radiator filaments passes through various materials before finally reaching the spin frozen vial. The energy transfer was computed by combining physical laws with Monte Carlo simulations and was verified with experimental data. The influence of the transmission properties of various materials on the emitted IR radiation profile was evaluated. These results assist in the selection of proper materials which could serve as IR window in the continuous freeze-drying prototype. The modelling framework presented in this paper fits the model-based design approach used for the development of this prototype and shows the potential benefits of this design strategy by establishing the desired engineering parameters and by enabling the engineer to assess mechanical tolerances and material options. PMID- 29476910 TI - Differences in travel-related incidence of chlamydia by age groups, gender and destination: Sweden 2000-2013. AB - BACKGROUND: The absolute number of travel-related Chlamydia cases in Sweden has consistently increased between 2000 and 2013. Given the growth in international travel, we aimed to study the trends of travel-related Chlamydia incidence to determine differences and identify high-risk groups and destinations. METHODS: For 2000-2013 we calculated annual Chlamydia incidence per 100,000 travels by dividing the number of notified travel-related cases by the number of travels; the latter were collected from a yearly survey among Swedish residents. For specific destinations 95% confidence intervals were calculated and monotonic yearly trends tested. RESULTS: The overall median annual travel-related Chlamydia incidence was higher for women than for men, but the opposite was true in age groups >25 years. For men, Thailand had the highest incidence, which was 3-7 times higher than the next highest destination in each age group. Spain, Turkey and Thailand had the highest incidence among women, but differences between countries were smaller than for men. For most destinations the yearly trends were stable. CONCLUSIONS: We showed different profiles for men and women and age groups in terms of high incidence destinations. This specific information could allow to better tailor safe sex messages and advocate post-travel Chlamydia testing to target groups travelling to certain destinations. PMID- 29476906 TI - The IASLC Lung Cancer Staging Project: A Renewed Call to Participation. AB - Over the past two decades, the International Association for the Study of Lung Cancer (IASLC) Staging Project has been a steady source of evidence-based recommendations for the TNM classification for lung cancer published by the Union for International Cancer Control and the American Joint Committee on Cancer. The Staging and Prognostic Factors Committee of the IASLC is now issuing a call for participation in the next phase of the project, which is designed to inform the ninth edition of the TNM classification for lung cancer. Following the case recruitment model for the eighth edition database, volunteer site participants are asked to submit data on patients whose lung cancer was diagnosed between January 1, 2011, and December 31, 2019, to the project by means of a secure, electronic data capture system provided by Cancer Research And Biostatistics in Seattle, Washington. Alternatively, participants may transfer existing data sets. The continued success of the IASLC Staging Project in achieving its objectives will depend on the extent of international participation, the degree to which cases are entered directly into the electronic data capture system, and how closely externally submitted cases conform to the data elements for the project. PMID- 29476911 TI - Disambiguating brain functional connectivity. AB - Functional connectivity (FC) analyses of correlations of neural activity are used extensively in neuroimaging and electrophysiology to gain insights into neural interactions. However, analyses assessing changes in correlation fail to distinguish effects produced by sources as different as changes in neural signal amplitudes or noise levels. This ambiguity substantially diminishes the value of FC for inferring system properties and clinical states. Network modelling approaches may avoid ambiguities, but require specific assumptions. We present an enhancement to FC analysis with improved specificity of inferences, minimal assumptions and no reduction in flexibility. The Additive Signal Change (ASC) approach characterizes FC changes into certain prevalent classes of signal change that involve the input of additional signal to existing activity. With FMRI data, the approach reveals a rich diversity of signal changes underlying measured changes in FC, suggesting that it could clarify our current understanding of FC changes in many contexts. The ASC method can also be used to disambiguate other measures of dependency, such as regression and coherence, providing a flexible tool for the analysis of neural data. PMID- 29476913 TI - Stress affects the neural ensemble for integrating new information and prior knowledge. AB - Prior knowledge, represented as a schema, facilitates memory encoding. This schema-related learning is assumed to rely on the medial prefrontal cortex (mPFC) that rapidly integrates new information into the schema, whereas schema incongruent or novel information is encoded by the hippocampus. Stress is a powerful modulator of prefrontal and hippocampal functioning and first studies suggest a stress-induced deficit of schema-related learning. However, the underlying neural mechanism is currently unknown. To investigate the neural basis of a stress-induced schema-related learning impairment, participants first acquired a schema. One day later, they underwent a stress induction or a control procedure before learning schema-related and novel information in the MRI scanner. In line with previous studies, learning schema-related compared to novel information activated the mPFC, angular gyrus, and precuneus. Stress, however, affected the neural ensemble activated during learning. Whereas the control group distinguished between sets of brain regions for related and novel information, stressed individuals engaged the hippocampus even when a relevant schema was present. Additionally, stressed participants displayed aberrant functional connectivity between brain regions involved in schema processing when encoding novel information. The failure to segregate functional connectivity patterns depending on the presence of prior knowledge was linked to impaired performance after stress. Our results show that stress affects the neural ensemble underlying the efficient use of schemas during learning. These findings may have relevant implications for clinical and educational settings. PMID- 29476914 TI - Impact of global signal regression on characterizing dynamic functional connectivity and brain states. AB - Recently, resting-state functional magnetic resonance imaging (fMRI) studies have been extended to explore fluctuations in correlations over shorter timescales, referred to as dynamic functional connectivity (dFC). However, the impact of global signal regression (GSR) on dFC is not well established, despite the intensive investigations of the influence of GSR on static functional connectivity (sFC). This study aimed to examine the effect of GSR on the performance of the sliding-window correlation, a commonly used method for capturing functional connectivity (FC) dynamics based on resting-state fMRI and simultaneous electroencephalograph (EEG)-fMRI data. The results revealed that the impact of GSR on dFC was spatially heterogeneous, with some susceptible regions including the occipital cortex, sensorimotor area, precuneus, posterior insula and superior temporal gyrus, and that the impact was temporally modulated by the mean global signal (GS) magnitude across windows. Furthermore, GSR substantially changed the connectivity structures of the FC states responding to a high GS magnitude, as well as their temporal features, and even led to the emergence of new FC states. Conversely, those FC states marked by obvious anti-correlation structures associated with the default model network (DMN) were largely unaffected by GSR. Finally, we reported an association between the fluctuations in the windowed magnitude of GS and the time-varying EEG power within subjects, which implied changes in mental states underlying GS dynamics. Overall, this study suggested a potential neuropsychological basis, in addition to nuisance sources, for GS dynamics and highlighted the need for caution in applying GSR to sliding-window correlation analyses. At a minimum, the mental fluctuations of an individual subject, possibly related to ongoing vigilance, should be evaluated during the entire scan when the dynamics of FC is estimated. PMID- 29476912 TI - Simulating laminar neuroimaging data for a visual delayed match-to-sample task. AB - Invasive electrophysiological and neuroanatomical studies in nonhuman mammalian experimental preparations have helped elucidate the lamina (layer) dependence of neural computations and interregional connections. Noninvasive functional neuroimaging can, in principle, resolve cortical laminae (layers), and thus provide insight into human neural computations and interregional connections. However human neuroimaging data are noisy and difficult to interpret; biologically realistic simulations can aid experimental interpretation by relating the neuroimaging data to simulated neural activity. We illustrate the potential of laminar neuroimaging by upgrading an existing large-scale, multiregion neural model that simulates a visual delayed match-to-sample (DMS) task. The new laminar-based neural unit incorporates spiny stellate, pyramidal, and inhibitory neural populations which are divided among supragranular, granular, and infragranular laminae (layers). We simulated neural activity which is translated into local field potential-like data used to simulate conventional and laminar fMRI activity. We implemented the laminar connectivity schemes proposed by Felleman and Van Essen (Cerebral Cortex, 1991) for interregional connections. The hemodynamic model that we employ is a modified version of one due to Heinzle et al. (Neuroimage, 2016) that incorporates the effects of draining veins. We show that the laminar version of the model replicates the findings of the existing model. The laminar model shows the finer structure in fMRI activity and functional connectivity. Laminar differences in the magnitude of neural activities are a prominent finding; these are also visible in the simulated fMRI. We illustrate differences between task and control conditions in the fMRI signal, and demonstrate differences in interregional laminar functional connectivity that reflect the underlying connectivity scheme. These results indicate that multi-layer computational models can aid in interpreting layer specific fMRI, and suggest that increased use of laminar fMRI could provide unique and fundamental insights to human neuroscience. PMID- 29476915 TI - Genic C-Methylation in Soybean Is Associated with Gene Paralogs Relocated to Transposable Element-Rich Pericentromeres. AB - Most plants are polyploid due to whole-genome duplications (WGD) and can thus have duplicated genes. Following a WGD, paralogs are often fractionated (lost) and few duplicate pairs remain. Little attention has been paid to the role of DNA methylation in the functional divergence of paralogous genes. Using high resolution methylation maps of accessions of domesticated and wild soybean, we show that in soybean, a recent paleopolyploid with many paralogs, DNA methylation likely contributed to the elimination of genetic redundancy of polyploidy-derived gene paralogs. Transcriptionally silenced paralogs exhibit particular genomic features as they are often associated with proximal transposable elements (TEs) and are preferentially located in pericentromeres, likely due to gene movement during evolution. Additionally, we provide evidence that gene methylation associated with proximal TEs is implicated in the divergence of expression profiles between orthologous genes of wild and domesticated soybean, and within populations. PMID- 29476916 TI - Precise A.T to G.C Base Editing in the Rice Genome. PMID- 29476917 TI - Time Bomb for Pollen Tubes: Peptide RALF-Mediated Signaling. PMID- 29476918 TI - Highly Efficient A.T to G.C Base Editing by Cas9n-Guided tRNA Adenosine Deaminase in Rice. PMID- 29476919 TI - Double the Genome, Double the Fun: Genome Duplications in Angiosperms. PMID- 29476921 TI - Pathways crossing mammalian and plant sulfenomic landscapes. AB - Reactive oxygen species (ROS) and especially hydrogen peroxide, are potent signaling molecules that activate cellular defense responses. Hydrogen peroxide can provoke reversible and irreversible oxidative posttranslational modifications on cysteine residues of proteins that act in diverse signaling circuits. The initial oxidation product of cysteine, sulfenic acid, has emerged as a biologically relevant posttranslational modification, because it is the primary sulfur oxygen modification that precedes divergent series of additional adaptations. In this review, we focus on the functional consequences of sulfenylation for both mammalian and plant proteins. Furthermore, we created compendia of sulfenylated proteins in human and plants based on mass spectrometry experiments, thereby defining the current plant and human sulfenomes. To assess the evolutionary conservation of sulfenylation, the sulfenomes of human and plants were compared based on protein homology. In total, 185 human sulfenylated proteins showed homology to sulfenylated plant proteins and the conserved sulfenylation targets participated in specific biological pathways and metabolic processes. Comprehensive functional studies of sulfenylation remains a future challenge, with multiple candidates suggested by mass spectrometry awaiting scrutinization. PMID- 29476922 TI - The search and selection for primary studies in systematic reviews published in dental journals indexed in MEDLINE was not fully reproducible. AB - OBJECTIVES: To evaluate whether the reporting of search strategies and the primary study selection process in dental systematic reviews is reproducible. STUDY DESIGN AND SETTING: A survey of systematic reviews published in MEDLINE indexed dental journals from June 2015 to June 2016 was conducted. Study selection was performed independently by two authors, and the reproducibility of the selection process was assessed using a tool consisting of 12 criteria. Regression analyses were implemented to evaluate any associations between degrees of reporting (measured by the number of items positively answered) and journal impact factor (IF), presence of meta-analysis, and number of citations of the systematic review in Google Scholar. RESULTS: Five hundred and thirty systematic reviews were identified. Following our 12 criteria, none of the systematic reviews had complete reporting of the search strategies and selection process. Eight (1.5%) systematic reviews reported the list of excluded articles (with reasons for exclusion) after title and abstract assessment. Systematic reviews with more positive answers to the criteria were significantly associated with higher journal IF, number of citations, and inclusion of meta-analysis. CONCLUSION: Search strategies and primary study selection process in systematic reviews published in MEDLINE-indexed dental journals may not be fully reproducible. PMID- 29476920 TI - Analysis of eicosanoid oxidation products in Alzheimer brain by LC-MS with uniformly 13C-labeled internal standards. AB - The quantitative analysis of polyunsaturated fatty acyl (PUFA) chain oxidation products in tissue samples by mass spectrometry is hindered by the lack of durable internal standards for the large number of possible products. To address this problem in a study of oxidative PUFA degradation in Alzheimer's disease (AD) brain, uniformly 13C-labeled arachidonic acid (ARA) was produced biosynthetically, and allowed to oxidize under controlled conditions into a mixture of U-13C-labeled ARA oxidation products. The components of this mixture were characterized with respect to their partitioning behavior during lipid extraction, their durability during saponification, trends in mouse brain tissue concentrations during post mortem intervals, and their overall suitability as internal standards for multiple-reaction monitoring tandem mass spectrometry. This mixture has now been used as a set of internal standards to determine the relative abundance of ARA and 54 non-stereospecific oxidation products in milligram samples of brain tissue. Many of these oxidation products were recovered from both healthy mouse and healthy human brain, although some of them were unique to each source, and some have not heretofore been described. The list of oxidation products detected in AD brain tissue was the same as in healthy human brain, although simple hydroxy-eicosanoids were significantly increased in AD brain. while more complex oxidation products were not. These results are consistent with an increased level of chemically-mediated oxidative ARA degradation in Alzheimer's disease. However, they also point to the existence of processes that selectively produce or eliminate specific oxidation products, and those processes may account for some of the inconsistencies in previously reported results. PMID- 29476923 TI - Component network meta-analysis identifies the most effective components of psychological preparation for adults undergoing surgery under general anesthesia. AB - OBJECTIVES: To apply component network meta-analysis (CNMA) models to an existing Cochrane review of psychological preparation interventions for adults undergoing surgery and to extend the models to account for covariates to identify the most effective components for improving postoperative outcomes. STUDY DESIGN AND SETTING: Interventions consisted of between one and four components of psychological preparation: procedural information (P), sensory information (S), behavioral instruction (B), cognitive interventions (C), relaxation (R), and emotion-focused techniques (E). We used CNMA models to assess the effect of each component for three outcomes: length of stay, pain, and negative affect. RESULTS: We found evidence that the most effective component for reducing length of stay depends on the type of surgery and that R may improve pain. There was insufficient evidence that individual components contributed to the overall reduction in negative affect, but P and S emerged as the most likely beneficial components. Overall, we were unable to identify any one component as the most effective across all three outcomes. CONCLUSION: The CNMA method allowed us to address questions about the effects of specific components that could not be answered using standard Cochrane methodology. PMID- 29476925 TI - Mucoceles of the lesser salivary glands in neonates demonstrate a particular clinicopathological pattern and mandate urgent management. AB - Mucoceles of the lesser salivary glands are common benign lesions affecting all ages, most commonly appearing on the lower lip. However, mucoceles in neonates demonstrate a different clinicopathological pattern than in older children or adults and mandate urgent management. We present a case of a large mucocele on the tongue of a neonate, which impaired feeding and could block the airway. The lesion was resected on the 3rd day of life. We describe a surgical technique that facilitates this procedure. Our literature review revealed 13 neonatal lesser salivary gland mucocele cases, 7 of which were located on the tongue. All tongue cysts were large, impaired feeding and sometimes blocked the airway. Early treatment is usually imperative. Inclusion cysts outnumbered extravasation cysts. Prenatal diagnosis is important in order to arrange delivery in an organized center. Resection is the preferable procedure. PMID- 29476924 TI - Branched polyrotaxane hydrogels consisting of alpha-cyclodextrin and low molecular-weight four-arm polyethylene glycol and the utility of their thixotropic property for controlled drug release. AB - In this work, we developed a new class of branched polyrotaxane hydrogel made of 4-arm polyethylene glycol (4-PEG) and alpha-cyclodextrin (alpha-CD) using supramolecular host-guest interactions as a cross-linking strategy. Because of the dynamic nature of the non-covalent host-guest cross-linking, the resulting supramolecular alpha-CD/4-PEG hydrogels show thixotropic behavior and undergo a reversible gel-sol transition in response to shear stress change. We loaded the antiglaucoma drug brimonidine into the alpha-CD/4-PEG gel and found the drug release kinetics was controlled by shear stress. This thixotropic shear thinning property makes the supramolecular hydrogels highly attractive in drug delivery applications and suitable for preparation of injectable drug formulations. PMID- 29476926 TI - Current status of surgical planning and transfer methods in orthognathic surgery. AB - Since the advent of orthognathic surgery major efforts have been made to render these surgical procedures more reliable, accurate, reproducible, and shorter. Such improvements imply the enhancement of surgical planning (SP) techniques and optimization of SP transfer tools. Most widespread current SP methods are based on physical examination/anthropometric measurements combined with cephalometric analysis. Most surgeons currently use handmade acrylic surgical splints or sometimes freehand surgery as transfer tool. The emergence of virtual surgical planning (VSP) procedures gave birth to several modern transfer tools, such as computer-assisted design and manufactured (CAD/CAM) splints, CAD/CAM splints with extra-oral bone support, customized miniplates, and surgical navigation. This article classifies and describes these emerging transfer tools, therewith underlining their advantages and drawbacks. PMID- 29476927 TI - Double resonance calibration of g factor standards: Carbon fibers as a high precision standard. AB - The g factor of paramagnetic defects in commercial high performance carbon fibers was determined by a double resonance experiment based on the Overhauser shift due to hyperfine coupled protons. Our carbon fibers exhibit a single, narrow and perfectly Lorentzian shaped ESR line and a g factor slightly higher than gfree with g=2.002644=gfree.(1+162ppm) with a relative uncertainty of 15ppm. This precisely known g factor and their inertness qualify them as a high precision g factor standard for general purposes. The double resonance experiment for calibration is applicable to other potential standards with a hyperfine interaction averaged by a process with very short correlation time. PMID- 29476928 TI - Real-time optimization of nuclear magnetic resonance experiments. AB - Nuclear Magnetic Resonance (NMR) experiments are typically performed with predetermined pulse sequences and acquisition parameters, and are oftentimes sub optimal for individual samples under investigation. Here we explore a class of real-time optimization methods that conducts stochastic analyses on the acquired data and in turn updates and optimizes the subsequent measurements. We show superiority of the method to static approaches, both in the efficiency and quality of data acquisition, for a wide range of experiments. PMID- 29476929 TI - An investigation into the effects of pore connectivity on T2 NMR relaxation. AB - Nuclear Magnetic Resonance (NMR) is a powerful technique used to characterize fluids and flow in porous media. The NMR relaxation curves are closely related to pore geometry, and the inversion of the NMR relaxometry data is known to give useful information with regards to pore size distribution (PSD) through the relative amplitudes of the fluids stored in the small and large pores. While this information is crucial, the main challenge for the successful use of the NMR measurements is the proper interpretation of the measured signals. Natural porous media patterns consist of complex pore structures with many interconnected or "coupled" regions, as well as isolated pores. This connectivity along the throats changes the relaxation distribution and in order to properly interpret this data, a thorough understanding of the effects of pore connectivity on the NMR relaxation distribution is warranted. In this paper we address two main points. The first pertains to the fact that there is a discrepancy between the relaxation distribution obtained from experiments, and the ones obtained from solving the mathematical models of diffusion process in the digitized images of the pore space. There are several reasons that may attribute to this such as the lack of a proper incorporation of surface roughness into the model. However, here we are more interested in the effects of pore connectivity and to understand why the typical NMR relaxation distribution obtained from experiments are wider, while the numerical simulations predict that a wider NMR relaxation distribution may indicate poor connectivity. Secondly, by not taking into account the pore coupling effects, from our experience in interpreting the data, we tend to underestimate the pore volume of small pores and overestimate the amplitudes in the large pores. The role of pore coupling becomes even more prominent in rocks with small pore sizes such as for example in shales, clay in sandstones, and in the microstructures of carbonates. PMID- 29476930 TI - 3D hyperpolarized C-13 EPI with calibrationless parallel imaging. AB - With the translation of metabolic MRI with hyperpolarized 13C agents into the clinic, imaging approaches will require large volumetric FOVs to support clinical applications. Parallel imaging techniques will be crucial to increasing volumetric scan coverage while minimizing RF requirements and temporal resolution. Calibrationless parallel imaging approaches are well-suited for this application because they eliminate the need to acquire coil profile maps or auto calibration data. In this work, we explored the utility of a calibrationless parallel imaging method (SAKE) and corresponding sampling strategies to accelerate and undersample hyperpolarized 13C data using 3D blipped EPI acquisitions and multichannel receive coils, and demonstrated its application in a human study of [1-13C]pyruvate metabolism. PMID- 29476931 TI - Vitamin D receptor (VDR) non-synonymous single nucleotide polymorphisms (nsSNPs) affect the calcitriol drug response - A theoretical insight. AB - Pharmacogenetics and pharmacogenomics have become presumptive with advancements in next-generation sequencing technology. In complex diseases, distinguishing the feasibility of pathogenic and neutral disease-causing variants is a time consuming and expensive process. Recent drug research and development processes mainly rely on the relationship between the genotype and phenotype through Single nucleotide polymorphisms (SNPs). The SNPs play an indispensable role in elucidating the individual's vulnerability to disease and drug response. The understanding of the interplay between these leads to the establishment of personalized medicine. In order to address this issue, we developed a computational pipeline of vitamin D receptor (VDR) for SNP centered study by application of elegant molecular docking and molecular dynamics simulation approaches. In a few SNPs the volume of the binding cavities has increased in mutant structures when compared to the wild type, indicating a weakening in interaction (699.1 A3 in wild type Vs. 738.8 in Leu230Val, 820.7 A3 in Arg247Leu). This also differently reflected in the H-bond interactions and binding free energies -169.93 kcal/mol (wild type) Vs -156.43 kcal/mol (R154W), 105.49 kcal/mol (R274L) in Leu230Val and Arg247Leu respectively. Although we could not find noteworthy changes in the binding free energies and binding pocket in the remaining mutations, the H-bond interactions made these SNPs deleterious. Thus, we further analyzed the H-bond interactions and distances using molecular dynamics (MD) simulation studies. PMID- 29476932 TI - Satisfaction and long-term use of orthopedic shoes in people with chronic stroke. PMID- 29476933 TI - Rehabilitation improves walking kinematics in children with a knee varus: Randomized controlled trial. AB - BACKGROUND: Previous studies have demonstrated increased medial stresses in knee varus alignment. Selecting a suitable treatment strategy for individuals with knee malalignment should be a priority. OBJECTIVES: We aimed to investigate the effects of a 16-week corrective exercise continuum (CEC) program on 3-D joint angles of the dominant and non-dominant lower limbs in children with genu varus during walking. METHODS: Overall, 28 male children with genu varus (age range 9 14 years) volunteered to participate in this study. They were randomly divided into 2 equal groups (experimental and control). The participants of the experimental group received CEC for 16 weeks. 3-D gait analysis involved using a Vicon Motion System. Paired and independent sample t-tests were used for within- and between-group comparisons, respectively. RESULTS: For the experimental group, comparison of pre- and post-test joint kinematics of the dominant lower limb revealed that CEC decreased the peak ankle dorsiflexion angle by 26% (P=0.020), peak foot internal rotation angle by 53% (P=0.001), peak knee internal rotation angle by 40% (P=0.011), peak hip abduction by 47% (P=0.010), and peak hip external rotation angle by 60% (P=0.001). In contrast, peak knee external rotation angle of the dominant limb was increased after the training program by 46% (P=0.044). For the non-dominant lower limb, CEC decreased the peak ankle inversion by 63% (P<0.01), peak ankle eversion by 91% (P<0.01), peak foot internal rotation by 50% (P<0.01), peak knee internal rotation by 29%; P=0.042), peak hip abduction angle by 38% (P<0.01), and peak hip external rotation angle by 60% (P<0.01). CONCLUSIONS: CEC therapy reduced excessive foot and knee internal rotations as well as excessive hip external rotation during walking in children with genu varus. PMID- 29476934 TI - Accuracy of intraoperative pathological diagnosis using frozen sections of spinal cord lesions. AB - OBJECTIVES: Frozen sections are used to provide gross and rapid microscopic pathological information for guidance on intraoperative management and therapeutic decision-making. Many studies have shown the accuracy of frozen section diagnosis for intracranial lesions, but there are no studies focusing on spinal cord lesions. The purpose of this study is to evaluate the accuracy of intraoperative rapid diagnosis using frozen sections and to investigate limitations of this approach for spinal cord lesions. PATIENTS AND METHODS: We performed intraoperative pathological diagnosis using frozen sections in 67 cases in which it was difficult to determine malignancy in preoperative images. The lesions were extradural (ED) in 13 cases, intradural extramedullary (IDEM) in 27 cases, and intramedullary (IM) in 27 cases. Metastatic tumors were excluded. The accuracy of intraoperative pathological diagnosis and the patterns of incorrect diagnosis were examined. RESULTS: Comparison of the intraoperative and final diagnoses gave an overall diagnostic sensitivity of 86.6% (58/67), with 100% (13/13) for ED lesions, 96% (26/27) for IDEM lesions, and 70% (19/27) for IM lesions. The diagnostic accuracy for IM lesions was significantly lower than those for ED and IDEM lesions (p < 0.05). Cases with small specimen sizes were frequently incorrectly diagnosed and inflammatory processes were common incorrect diagnoses using frozen specimens. CONCLUSION: Among all spinal cord lesions, low diagnostic accuracy in intraoperative diagnosis using frozen sections is most likely for intramedullary lesions. The results of intraoperative rapid diagnosis should be interpreted with understanding of the limitations of this procedure. PMID- 29476935 TI - Outcomes following minimally invasive lateral transpsoas interbody fusion for degenerative low grade lumbar spondylolisthesis: A systematic review. AB - A variety of surgical approaches have been described to treat low grade lumbar degenerative spondylolisthesis (DS). Minimally invasive spinal fusion techniques were first introduced to minimize morbidities associated with invasive surgical treatments. Minimally invasive lateral transpsoas interbody fusion, also known as lateral lumbar interbody fusion (LLIF), is a relatively new method of lumbar arthrodesis that avoids various approach related complications compared to its posterior and anterior counterparts. A systematic and critical review of recent literature was conducted in accordance with PRISMA guidelines. The sources of the data were PubMed, MEDLINE, Embase, Cochrane and Scopus. Key search terms were "transpsoas", "interbody fusion", "LLIF", "XLIF" and "spondylolisthesis". Papers included in the review were original research articles in peer-reviewed journals. The articles were thoroughly examined and compared on the basis of study design, outcomes, and results. Only studies which met the eligibility criteria were included. Eight studies were included in the qualitative and quantitative analysis (three retrospective, four prospective, one randomized controlled trial). A total of 308 patients (227 females) (pooled age 64.5 years) and a total of 353 operated levels were analyzed. Mean follow up time ranged from 6.2 to 24 months. There were no reported cases of durotomies or pseudarthrosis in any study. All neurologic complications were reported to be transient with no permanent deficits. Mean improvement in ODI scores ranged between 19.5 (38.6%) to 36 (54.5%). Mean improvement in slip ranged from 47 to 67.5%. Three studies also reported that patient satisfaction and willingness to undergo the procedure again approached 90%. Minimally invasive transpsoas interbody fusion possibly leads to favorable clinical and radiological outcomes while avoiding the possible complications of its more traditional open and minimally invasive counterparts. Further studies are needed to better establish its role in the management of low grade degenerative lumbar spondylolisthesis. PMID- 29476936 TI - An educational initiative to improve medical student awareness about brain death. AB - OBJECTIVE: Medical student knowledge about brain death determination is limited. We describe an educational initiative to improve medical student awareness about brain death and assess the impact of this initiative. SUBJECTS AND METHODS: Beginning in July 2016, students at our medical school were required to attend a 90-min brain death didactic and simulation session during their neurology clerkship. Students completed a test immediately before and after participating in the initiative. RESULTS: Of the 145 students who participated in this educational initiative between July 2016 and June 2017, 124 (86%) consented to have their data used for research purposes as part of a medical education registry. Students correctly answered a median of 53% of questions (IQR 47-58%) on the pretest and 86% of questions (IQR 78-89%) on the posttest (p < .001). Comfort with both performing a brain death evaluation and talking to a family about brain death improved significantly after this initiative (18% of students were comfortable performing a brain death evaluation before the initiative and 86% were comfortable doing so after the initiative, p < .001; 18% were comfortable talking to a family about brain death before the initiative and 76% were comfortable doing so after the initiative, p < .001). CONCLUSIONS: Incorporation of simulation in undergraduate medical education is high-yield. At our medical school, knowledge about brain death and comfort performing a brain death exam or talking to a family about brain death was limited prior to development of this initiative, but awareness and comfort dealing with brain death improved significantly after this initiative. PMID- 29476937 TI - Biosimilar switching and related medical liability. AB - Unlike generics, biosimilars are similar, but not equivalent, to the reference biological medicinal product. Therefore, if a patient experiences an adverse event, or a loss of efficacy, when transitioned to a biosimilar, the distribution of medical liability will be different from the case of both the originator and generics. Moreover, the case of naive patients is different from that of non naive patients. In the case of naive patients, physicians make their choice from a range of medicinal products that pose the same risk, since it is not possible to know with any certainty the patients' response to each therapeutic option until they have taken the drug. If physicians, instead, switch to a biosimilar for a patient already in treatment with the originator, they are switching from an option where the individual response is known, to an option where it is unknown. Given the evolving framework of biosimilar legislation, sharing choices with patients and obtaining their informed consent when switching to a biosimilar could represent an effective approach on the part of the prescribing physician. Moreover, a supranational database containing real-life data about patients in treatment with biological medicines, including information on the actual biological medicinal products administered, could complement the data obtained from clinical studies. PMID- 29476939 TI - Effectiveness of regional anaesthesia for treatment of facial and hand wounds by emergency physicians: A 9-month prospective study. AB - OBJECTIVE: We compared the effectiveness of nerve blocks (regional anaesthesia, [RA]) versus local anaesthesia (LA) to treat face and hand wounds. Emergency physicians who had not previously used nerve blocks administered the anaesthesia based on anatomic landmarks. METHODS: This prospective observational open study was conducted at a military teaching hospital emergency department (ED) between May 1, 2013 and January 31, 2014. All patients requiring treatment of facial or hand wounds were included. The primary outcome was anaesthesia effectiveness 15minutes post-administration. We also recorded the number of injections sites, injected volume, pain of administration, operator comfort, and complications. Lidocaine anaesthesia without epinephrine was used. RESULTS: Of the 1090 treated patients, 617 patients were included in the analysis: 316 with hand wounds and 301 with facial wounds. Overall, 130 wrist blocks and 63 facial blocks were performed. RA effectiveness was comparable to that of LA: for facial wounds, RA=88.9% versus LA=89% (P=0.86); for hand wounds, RA=82.2% versus LA=90.1% (P=0.15). RA groups had significantly fewer injections than the LA groups, and less anesthetic was injected in the facial RA group. The pain of anaesthesia administration and operator comfort was similar. There was no complication during the 9-month data collection period. CONCLUSION: Facial and wrist nerve blocks are easy to administer and as efficient as local infiltrations, plus they require fewer injection sites, and, for facial RA, less anesthetic. Their teaching and use should be more widespread in EDs. PMID- 29476938 TI - Estimation of postmortem interval (PMI) based on empty puparia of Phormia regina (Meigen) (Diptera: Calliphoridae) and third larval stage of Necrodes littoralis (L.) (Coleoptera: Silphidae) - Advantages of using different PMI indicators. AB - On 16 July 2015, a body of a 64-year-old man in advanced decomposition was found in an open area of the suburb of Srem (western Poland). Postmortem interval (PMI) was estimated by forensic pathologist for 3-6 weeks. Insects were sampled from the cadaver and the soil from below the cadaver. Empty puparia of Phormia regina were the most developmentally advanced specimens of blowflies. Moreover, third instar larva of Necrodes littoralis was collected directly from the cadaver. For the estimation of minimum PMI from puparia of P. regina, thermal summation method was used to estimate the total immature development interval of this species. In the case of larval N. littoralis, the pre-appearance interval (PAI) was estimated using temperature method and the development interval (DI) using thermal summation method. Average daily temperatures from the nearby weather station were used, as well as the weather station temperatures corrected by 1 degrees C and 2 degrees C. The estimates were as follows: 36-38 days using empty puparia of P. regina and 37-40 days using larva of N. littoralis (for the uncorrected temperatures), 31-34 days using both P. regina and N. littoralis (temperatures corrected by +1 degrees C), 24-27 days using P. regina and 28-29 days using N. littoralis (temperatures corrected by +2 degrees C). It was concluded that death occurred 24-40 days before the body was found and most probably 24-34 days before the body was found. This is the first report when PMI was approximated by the age estimates combined with the PAI estimates. Moreover, the case demonstrates the advantages of using different entomological indicators and an urgent need for the more robust developmental model for N. littoralis, as it proved to be highly useful for the estimation of PMI. PMID- 29476940 TI - Anxiety during inhalation induction in paediatrics: Sitting versus supine position, a randomised trial. AB - STUDY OBJECTIVE: We evaluated if the sitting or supine positions affect anxiety levels induced by the application of a facemask in children. DESIGN: Prospective, randomised study. SETTING: Paediatric hospital, operating room. PATIENTS: Two to twelve years old children, 1-3 ASA status, undergoing inhalation anaesthesia for elective surgery. INTERVENTION: Children were randomly assigned to a sitting or supine position. After monitoring equipment was established, inhalation was inducted by the application of the mask. MEASUREMENTS: Child anxiety was then assessed with the modified Yale Preoperative Anxiety Scale (mYPAS) before the application of the facemask and following mask application. MAIN RESULTS: Overall, 99 children in the sitting group and 103 in the supine group were analysed. The mYPAS score was not different in both groups before the application of facemask (40 [28-51] versus 40 [28-53]; P=0.99). It increased (P=0.005) to a similar extent in both groups following mask application without difference between groups (48 [38-60] versus 48 [35-63]; P=0.95). Side effects were not different between both groups. CONCLUSION: In children undergoing inhalation induction, sitting or supine positions did not modify anxiety induced by the application of a facemask, nor adverse effects; therefore, children should be allowed to choose their preferred position. PMID- 29476941 TI - Postoperative serum levels of Endocan are associated with the duration of norepinephrine support after coronary artery bypass surgery. AB - BACKGROUND: Cardiopulmonary bypass (CPB) is associated with a systemic inflammatory response and an endothelial dysfunction, whose qualitative assessment appears to be a major issue. Endocan (ESM-1, endothelial cell specific molecule-1) is a protein preferentially expressed by the endothelium and previously associated with prognosis of septic shock or acute respiratory distress syndrome. In this pilot study, we investigated the kinetic of Endocan in planned coronary artery bypass grafting (CABG) surgery with CPB. PATIENTS AND METHODS: We conducted an observational, prospective, mono centre study. All adult patients with left systolic ejection fraction>50%, undergoing planned on-pump CABG, were screened for inclusion. A written informed consent was obtained. Measurements and main results Serum Endocan concentrations were respectively 2.4 [2.1-3.0] ng. mL-1, 10.4 [7.4-13.9] ng.mL-1, 5.7 [4.4-8.2] ng.mL-1, and 5.4 [4.1 7.5] ng.mL-1 at day 0, day 1, day 3 and day 5. Endocan concentrations increased at day 1, day 3, and day 5 in comparison with preoperative concentration (P<0.001). In the multivariate analysis, age (P=0.002), history of acute coronary syndrome (P=0.024) and the catecholamine-free days at day 28 (P=0.007) were associated to the increase of perioperative Endocan concentrations. CONCLUSION: Serum Endocan concentration increases after CABG surgery with CPB until day 1. The norepinephrine support increases the risk of Endocan release, suggesting a relationship between the kinetic of Endocan and the vasoplegic syndrome. At day 3, Endocan concentration decreases slowly but is not normalised at day 5. Further studies should investigate the prognostic value of the magnitude of postoperative Endocan concentration after cardiac surgery. PMID- 29476942 TI - Adherence to the law in brain death diagnosis: A national survey. PMID- 29476943 TI - Evolution and organisation of trauma systems. AB - Over the last 20 years, numerous studies have fairly consistently reported an improvement in the prognosis of patients with severe trauma after the establishment of a trauma network. These systems can be either exclusive, in which all patients are referred only to a small number of specifically designated centres that meet strict criteria, or inclusive, in which patients may be referred to any hospital of a particular area according to capacity, which is observed in France. Hospitals are classified (level 1 to level 3) according to their technical facilities and the number of patients admitted for severe trauma, knowing that studies have also shown an improvement of the outcome for the most severely injured patients (haemorrhagic shock, severe head trauma), in hospitals with the greatest technical facilities and the most important activity. The triage of the patients to a suitable centre must be done after careful prehospital evaluation, which is made on clinical criteria (mechanism, injury, medical history), measurement of vital signs, calculation of scores (RTS, MGAP) or based on classifications. According to this assessment, the patients will then be triaged to a centre that has the capacity for the optimal and definitive management of these injuries. The goal is then to avoid under triage which is synonymous of retransfer, loss of time, and probably also prognosis worsening, and to avoid over triage that may induce an inadequate use of resources, activity overload and cost increase. Thus, it seems essential to develop trauma networks to improve mortality and morbidity of patients that undergone a severe injury. These trauma networks will then have to be evaluated and a register set up. PMID- 29476944 TI - Resonance analysis of a high temperature piezoelectric disc for sensitivity characterization. AB - Ultrasonic transducers for high temperature (200 degrees C+) applications are a key enabling technology for advanced nuclear power systems and in a range of chemical and petro-chemical industries. Design, fabrication and optimization of such transducers using piezoelectric materials remains a challenge. In this work, experimental data-based analysis is performed to investigate the fundamental causal factors for the resonance characteristics of a piezoelectric disc at elevated temperatures. The effect of all ten temperature-dependent piezoelectric constants (epsilon33, epsilon11, d33, d31, d15, s11, s12, s13, s33, s44) is studied numerically on both the radial and thickness mode resonances of a piezoelectric disc. A sensitivity index is defined to quantify the effect of each of the temperature-dependent coefficients on the resonance modes of the modified lead zirconium titanate disc. The temperature dependence of s33 showed highest sensitivity towards the thickness resonance mode followed by epsilon33, s11, s13, s12, d31, d33, s44, epsilon11, and d15 in the decreasing order of the sensitivity index. For radial resonance modes, the temperature dependence of epsilon33 showed highest sensitivity index followed by s11, s12 and d31 coefficient. This numerical study demonstrates that the magnitude of d33 is not the sole factor that affects the resonance characteristics of the piezoelectric disc at high temperatures. It appears that there exists a complex interplay between various temperature dependent piezoelectric coefficients that causes reduction in the thickness mode resonance frequencies which is found to be agreement in with the experimental data at an elevated temperature. PMID- 29476945 TI - Ultrasound parametric imaging of hepatic steatosis using the homodyned-K distribution: An animal study. AB - Hepatic steatosis is an abnormal state where excess lipid mass is accumulated in hepatocyte vesicles. Backscattered ultrasound signals received from the liver contain useful information regarding the degree of steatosis in the liver. The homodyned-K (HK) distribution has been demonstrated as a general model for ultrasound backscattering. The estimator based on the first three integer moments (denoted as "FTM") of the intensity has potential for practical applications because of its simplicity and low computational complexity. This study explored the diagnostic performance of HK parametric imaging based on the FTM method in the assessment of hepatic steatosis. Phantom experiments were initially conducted using the sliding window technique to determine an appropriate window size length (WSL) for HK parametric imaging. Subsequently, hepatic steatosis was induced in male Wistar rats fed a methionine- and choline-deficient (MCD) diet for 0 (i.e., normal control), 1, 2, 4, 6, and 8 weeks (n = 36; six rats in each group). After completing the scheduled MCD diet, ultrasound B-mode and HK imaging of the rat livers were performed in vivo and histopathological examinations were conducted to score the degree of hepatic steatosis. HK parameters MU (related to scatterer number density) and k (related to scatterer periodicity) were expressed as functions of the steatosis stage in terms of the median and interquartile range (IQR). Receiver operating characteristic (ROC) curve analysis was conducted to assess the diagnostic performance levels of the MU and k parameters. The results showed that an appropriate WSL for HK parametric imaging is seven times the pulse length of the transducer. The median value of the MU parameter increased monotonically from 0.194 (IQR: 0.18-0.23) to 0.893 (IQR: 0.64-1.04) as the steatosis stage increased. Concurrently, the median value of the k parameter increased from 0.279 (IQR: 0.26-0.31) to 0.5 (IQR: 0.41-0.54) in the early stages (normal to mild) and decreased to 0.39 (IQR: 0.29-0.45) in the advanced stages (moderate to severe). The areas under the ROC curves obtained using (MU, k) were (0.947, 0.804), (0.914, 0.575), and (0.813, 0.604) for the steatosis stages of >=mild, >=moderate, and >=severe, respectively. The current findings suggest that ultrasound HK parametric imaging based on FTM estimation has great potential for future clinical diagnoses of hepatic steatosis. PMID- 29476946 TI - Development of an approach to correcting MicroPEM baseline drift. AB - BACKGROUND: Fine particulate matter (PM2.5) is associated with various adverse health outcomes. The MicroPEM (RTI, NC), a miniaturized real-time portable particulate sensor with an integrated filter for collecting particles, has been widely used for personal PM2.5 exposure assessment. Five-day deployments were targeted on a total of 142 deployments (personal or residential) to obtain real time PM2.5 levels from children living in New York City and Baltimore. Among these 142 deployments, 79 applied high-efficiency particulate air (HEPA) filters in the field at the beginning and end of each deployment to adjust the zero level of the nephelometer. However, unacceptable baseline drift was observed in a large fraction (> 40%) of acquisitions in this study even after HEPA correction. This drift issue has been observed in several other studies as well. The purpose of the present study is to develop an algorithm to correct the baseline drift in MicroPEM based on central site ambient data during inactive time periods. METHOD: A running baseline & gravimetric correction (RBGC) method was developed based on the comparison of MicroPEM readings during inactive periods to ambient PM2.5 levels provided by fixed monitoring sites and the gravimetric weight of PM2.5 collected on the MicroPEM filters. The results after RBGC correction were compared with those using HEPA approach and gravimetric correction alone. Seven pairs of duplicate acquisitions were used to validate the RBGC method. RESULTS: The percentages of acquisitions with baseline drift problems were 42%, 53% and 10% for raw, HEPA corrected, and RBGC corrected data, respectively. Pearson correlation analysis of duplicates showed an increase in the coefficient of determination from 0.75 for raw data to 0.97 after RBGC correction. In addition, the slope of the regression line increased from 0.60 for raw data to 1.00 after RBGC correction. CONCLUSIONS: The RBGC approach corrected the baseline drift issue associated with MicroPEM data. The algorithm developed has the potential for use with data generated from other types of PM sensors that contain a filter for weighing as well. In addition, this approach can be applied in many other regions, given widely available ambient PM data from monitoring networks, especially in urban areas. PMID- 29476947 TI - In vivo maternal and in vitro BPA exposure effects on hypothalamic neurogenesis and appetite regulators. AB - In utero exposure to the ubiquitous plasticizer, bisphenol A (BPA) is associated with offspring obesity. As food intake/appetite is one of the critical elements contributing to obesity, we determined the effects of in vivo maternal BPA and in vitro BPA exposure on newborn hypothalamic stem cells which form the arcuate nucleus appetite center. For in vivo studies, female rats received BPA prior to and during pregnancy via drinking water, and newborn offspring primary hypothalamic neuroprogenitor (NPCs) were obtained and cultured. For in vitro BPA exposure, primary hypothalamic NPCs from healthy newborns were utilized. In both cases, we studied the effects of BPA on NPC proliferation and differentiation, including putative signal and appetite factors. Maternal BPA increased hypothalamic NPC proliferation and differentiation in newborns, in conjunction with increased neuroproliferative (Hes1) and proneurogenic (Ngn3) protein expression. With NPC differentiation, BPA exposure increased appetite peptide and reduced satiety peptide expression. In vitro BPA-treated control NPCs showed results that were consistent with in vivo data (increase appetite vs satiety peptide expression) and further showed a shift towards neuronal versus glial fate as well as an increase in the epigenetic regulator lysine-specific histone demethylase1 (LSD1). These findings emphasize the vulnerability of stem-cell populations that are involved in life-long regulation of metabolic homeostasis to epigenetically-mediated endocrine disruption by BPA during early life. PMID- 29476948 TI - Cx36 in the mouse hippocampus during and after pilocarpine-induced status epilepticus. AB - Gap junctions play an important role in the synchronization activity of coupled cells. Hippocampal inhibitory interneurons are involved in epileptogenesis and seizure activity, and express gap junction protein connexin (Cx) 36. Cx36 is also localized in the axons (mossy fibers) of granule cells in the dentate gyrus. While it has been documented that Cx36 is involved in epileptogenesis, there are still controversies regarding the expression levels of Cx36 at different developmental stages of human and animal models of epileptogenesis. In this study, the expression of Cx36 was investigated in the mouse hippocampus at 1 h, 4 h during pilocarpine-induced status epilepticus (PISE) and 1 week, 2 months after PISE. We found that Cx36 was down-regulated in neurons at different time points during and after PISE, whereas it was increased significantly in the stratum lucidum of CA3 area at 2 months after PISE. Double immunofluorescence indicated that Cx36 was localized in parvalbumin (PV) immunopositive interneuron in CA1 area and in mossy fibers and their terminals in the stratum lucidum of CA3 area. It suggests that decreased expression of Cx36 in interneurons may be related to less effective inhibitory control of excitatory activity of hippocampal principal neurons. However, the increased Cx36 immunopositive product in mossy fibers at the chronic stage after PISE may enhance the contacts between granule cells in the dentate gyrus and pyramidal neurons in CA3 area. The two different changes of Cx36 may be implicated in the epileptogenesis. PMID- 29476949 TI - High obsessive-compulsive individuals may have attenuated access to internal cues associated with active movement: Evidence from a head repositioning study. AB - BACKGROUND AND OBJECTIVES: The Seeking Proxies for Internal States model of OCD posits that obsessive-compulsive (OC) individuals have attenuated access to their internal states. Consequently, they seek and rely on discernible substitutes for these internal states. Previous research has supported these conjectures. Other studies, using a variety of measures, reported a reduced sense of agency (SoA) in OCD. The current study aimed to connect these two bodies of research by focusing on internal signals associated with active movement, which are related to the SoA. We hypothesized that the performance accuracy of high OC participants would be similar for active and passive movements, while that of low OC participants would be higher when the movement is acquired actively. METHOD: Participants with high vs. low OC tendencies were asked to reposition their head to a target angle that was acquired actively or passively. This was repeated with eyes blindfolded to evaluate reliance on visual information. Accuracy of repositioning was measured with a cervical range-of-motion device. RESULTS: As predicted, while low OC participants presented a significant decrease in their accuracy after passive (compared to active) acquisition, high OC participants' accuracy did not differ between acquisition types. Contrary to our predictions, reliance on vision was similar across groups. LIMITATIONS: The generalization of our findings to OCD requires replication with a clinical sample. CONCLUSIONS: This study implies that high OC individuals have a deficient access to internal cues involved in active movement. This might contribute to their doubt regarding their actions and to their reduced SoA. PMID- 29476950 TI - Post partum depression-It's time to pay attention. PMID- 29476952 TI - Promising Outcome of Umbilical Cord Blood Transplantation in Patients with Multiple Comorbidities. AB - The hematopoietic cell transplantation-specific comorbidity index (HCT-CI) has been recently proposed to predict the probability of nonrelapse mortality (NRM) and overall survival (OS) in allogeneic hematopoietic stem cell transplantation (HSCT). However, the usefulness of the HCT-CI in single-unit umbilical cord blood transplantation (UCBT) remains unclear. We investigated the impact of the HCT-CI on the clinical outcomes of allogeneic HSCT in a single-center retrospective study including 53 recipients of UCBT (UCBT group) and 90 recipients of other HSCT (non-UCBT group). In the non-UCBT group 2-year OS rates for HCT-CI score < 3 and >=3 were 67% (n = 74; 95% confidence interval [CI], 54% to 78%) and 26% (n = 16; 95% CI, 7% to 51%), respectively (P = .001). In the UCBT group these rates were 66% (n = 39; 95% CI, 48% to 79%) and 69% (n = 14; 95% CI, 36% to 87%), respectively (P = .73). In the non-UCBT group 1-year NRM rates for HCT-CI score < 3 and >=3 were 14% (95% CI, 6.4% to 22%) and 37% (95% CI, 14% to 61%), respectively (P = .02). In the UCBT group these rates were 6.1% (95% CI, 3.4% to 24%) and 7.7% (95% CI, .4% to 29%), respectively (P = .78). Using multivariate analysis we showed that HCT-CI score >= 3 was significantly associated with lower OS (hazard ratio, 3.06; 95% CI, 1.47 to 6.38; P = .003) and higher NRM (hazard ratio, 2.87; 95% CI, 1.18 to 6.96; P = .02) for the non-UCBT group. UCBT showed good OS with low incidence of NRM, even in patients with high HCT-CI scores. Altogether, we propose single-unit UCB to be a promising stem cell source for improving survival in patients with multiple comorbidities. PMID- 29476951 TI - Current status of vaccines in psychiatry-A narrative review. AB - INTRODUCTION: Vaccines are one of the newer therapeutic modalities being researched in psychiatric illnesses with limited role of pharmacological interventions. Preclinical studies on vaccines have shown favorable results in conditions like Substance use Disorders and Alzheimer's Dementia. However, the utility of Mumps Measles Rubella vaccine has been overshadowed by controversy linked to causation of Autism. With this background, the current narrative review aimed to comprehensively and critically evaluate the current status of vaccines in Psychiatric illnesses. METHODS: Preliminary literature search using the electronic databases of MEDLINE and Google Scholar between May 1967 and May 2017 using the search terms "Vaccines" and "Psychiatry" was carried out and articles were found in the following areas of research: Substance use, Alzheimer Dementia, Autism, Human Immunodeficiency Virus and Human Papilloma Virus Further, the refined search was done using combinations of search terms "Vaccine", "Nicotine", "Cocaine", "Opioid", "Alzheimer Dementia", "Autism", and "Pervasive Developmental Disorders" and peer - reviewed original articles published in English conducted among human subjects and published in English language were included for review. RESULTS: A total of 31 articles found eligible were organized into appropriate sections synthesizing the literature on role of vaccines in specific disorders such as Substance Use Disorders, Alzheimer Dementia and Pervasive Developmental Disorders. DISCUSSION: The therapeutic potential of vaccines in Substance Use Disorders and Alzheimer Dementia was found to be limited in comparison to the results from animal studies. Safety profile of the immunogens and the adjuvants in humans is possibly the most important limitation. No causal association between Measles Mumps Rubella vaccine and Autism was found. PMID- 29476953 TI - Refractory Graft-Versus-Host Disease-Free, Relapse-Free Survival as an Accurate and Easy-to-Calculate Endpoint to Assess the Long-Term Transplant Success. AB - The aim of this study was to develop a new composite endpoint that accurately reflects the long-term success of allogeneic hematopoietic stem cell transplantation (allo-HSCT), as the conventional graft-versus-host disease (GVHD) free, relapse-free survival (GRFS) overestimates the impact of GVHD. First, we validated current GRFS (cGRFS), which recently was proposed as a more accurate endpoint of long-term transplant success. cGRFS was defined as survival without disease relapse/progression or active chronic GVHD at a given time after allo HSCT, calculated using 2 distinct methods: a linear combination of a Kaplan-Meier estimates approach and a multistate modelling approach. Next, we developed a new composite endpoint, refractory GRFS (rGRFS). rGRFS was calculated similarly to conventional GRFS treating grade III to IV acute GVHD, chronic GVHD requiring systemic treatment, and disease relapse/progression as events, except that GVHD that resolved and did not require systemic treatment at the last evaluation was excluded as an event in rGRFS. The 2 cGRFS curves obtained using 2 different approaches were superimposed and both were superior to that of conventional GRFS, reflecting the proportion of patients with resolved chronic GVHD. Finally, the curves of cGRFS and rGRFS overlapped after the first 2 years of post-transplant follow-up. These results suggest that cGRFS and rGRFS more accurately reflect transplant success than conventional GRFS. Especially, rGRFS can be more easily calculated than cGRFS and analyzed with widely used statistical approaches, whereas cGRFS more accurately represents the burden of GVHD-related morbidity in the first 2 years after transplantation. PMID- 29476954 TI - Design and Patient Characteristics of the Chronic Graft-versus-Host Disease Response Measures Validation Study. AB - In 2014, the National Institutes of Health sponsored the second Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease (GVHD). The purpose was to update recommendations about key elements of chronic GVHD research, including definitions for diagnosis, severity scoring, and response measures, based on empirical data published since the first 2005 Consensus Conference. The most significant modifications were to the response assessments, based on studies demonstrating difficulty with the first consensus definitions. The Response Measures Validation Study is a multicenter, prospective cohort study of patients who are starting initial or subsequent treatments for chronic GVHD. The aim of the study is to evaluate the performance of the 2014 response measures and determine whether any other combination of assessments is superior. Clinical data, clinician assessments, patient-reported outcomes, and research samples are collected at enrollment and 3, 6, and 18 months later, and whenever another chronic GVHD systemic treatment is added. The target enrollment of 368 evaluable patients from 12 transplantation centers has been reached. This report describes the rationale, design, and methods of the Chronic GVHD Response Measures Validation Study, and invites other investigators to collaborate with the Consortium to analyze data or specimens. PMID- 29476955 TI - Volatilization and oxidative artifacts of PM bound PAHs collected at low volume sampling (1): Laboratory and field evaluation. AB - Laboratory and field studies were carried out to assess the effects of oxidative degradation and volatilization on PM10 bound polycyclic aromatic hydrocarbons (PAHs), collected at low volume condition according to the EU sampling reference method EN12341:2014 (flow rate 2.3 m3 h-1), on 47 mm quartz filters. For the laboratory experiments, pairs of twin samples were collected in field and, after treatments favoring decomposition or/and volatilization of PAHs on one sample, the PAH amount was compared with that of the corresponding untreated sample. Ozone exposure caused a general PAHs decay with more marked effects on benzo [a]pyrene, perylene and benz [a]anthracene; these compounds showed, similarly to benzo [ghi]perylene, correlations between ozone dose and losses. Treatments with zero air exhibited losses due to volatilization even for 5-ring PAHs up to benzo [a]pyrene, whereas a linear dependence was observed between filter PAH load and losses for benzo [a]anthracene, chrysene and benzofluoranthenes. Concentrations on samples collected simultaneously over 48, 24, 12 and 6 h were compared. Results confirmed a lack of temporal auto-consistency in the PAHs sampling methodology here adopted. In particular higher atmospheric PAH concentrations were ascertained on samples constituted by cumulative filters exposed over shorter sampling times. When 24-h and 2 * 12-h samples were compared, comparable losses were evaluated in the hot and cold seasons. This finding shows that, although in summer meteorology conditions favor sampling artifacts, the effectiveness of these phenomena continue in the winter, probably due to the larger amount of PAH available on the sampling filter (total PAHs ~ 10 vs 0.5 ng m-3). PMID- 29476956 TI - Occurrence and distribution of perfluoroalkyl substances (PFASs) in the water dissolved phase and suspended particulate matter of the Dalian Bay, China. AB - In the present study, the contamination level and spatial distribution of PFASs in the water dissolved phase and suspended particulate matter (SPM) phase of the Dalian Bay, and the SPM-water partition behavior were investigated. The total concentrations of PFASs (?PFASs) in the water dissolved phase ranged from 6.9 to 17.1 ng L-1, with perfluorooctanoic acid (PFOA), perfluorobutanoic acid, and perfluorobutane sulfonate (PFBS) as the predominant PFASs, while ?PFASs in SPM ranged from 1.7 to 27.5 ng g-1 dw with higher contributions from PFBS, perfluorooctane sulfonic acid and PFOA. As for the pollution distribution, the concentrations of PFASs inside the Dalian Bay were higher than those outside the bay. For perfluoroalkyl carboxylic acid (PFCAs) and perfluoroalkane sulfonic acids (PFSAs), the suspended particulate matter-water partition coefficient (log Kd) values ranged from 2.62 to 3.76, and from 3.39 to 3.56, respectively. The log Kd values of PFASs generally increased with the increasing perfluorinated carbon chain length. Short-chain PFCAs were mostly detected in the water dissolved phase, while long-chain PFCAs and PFSAs appeared to bind more strongly to SPM phase. The contamination level of long-chain PFCAs and PFSAs could be underestimated if only the water dissolved phase were measured. Therefore, further investigations should consider the role of SPM on the environmental behavior and fate of PFASs in the aquatic environment. PMID- 29476957 TI - Anaerobic biodegradation of 8:2 fluorotelomer alcohol in anaerobic activated sludge: Metabolic products and pathways. AB - The anaerobic biodegradability and metabolic pathways of 8:2 fluorotelomer alcohol (8:2 FTOH) were investigated in anaerobic activated sludge. The biodegradation was well described by a double exponential decay model. 8:2 FTOH was biodegraded to poly- and perfluorinated metabolites with the release of fluoride ion. All polyfluorinated metabolites were intermediate metabolic products and could be further transformed to other metabolites, while perfluorinated metabolites were terminal products. 2H-perfluoro-2-decenoic acid (8:2 FTUA) and perfluorooctanoic acid (PFOA) were verified as the most abundant poly- and perfluorinated metabolites, respectively. Two shorter-chain perfluorinated metabolites, perfluoropentanoic acid (PFPeA) and perfluorobutyric acid (PFBA), were first reported in the biodegradation of 8:2 FTOH. However, the total molar recovery of 8:2 FTOH decreased with increasing incubation time, indicating that there might be some unknown metabolites. Thus, the anaerobic biodegradation pathways were proposed as follows: 8:2 FTOH was oxidized to 8:2 FTUA and 2-perfluorooctyl ethanoic acid (8:2 FTCA) via 2-perfluorooctyl acetaldehyde (8:2 FTAL), and then 8:2 FTUA and 8:2 FTCA were further transformed to 1-perfluoroheptyl ethanol (7:2 sFTOH) via 3-perfluoroheptyl propionic acid (7:3 acid) or/and 3-perfluoroheptyl acrylic acid (7:3 Uacid), and eventually 7:2 sFTOH was further biodegraded to PFOA and other perfluorocarboxylates containing less than eight carbons. PMID- 29476958 TI - Boundaries between professional nursing and midwifery academics and scholarly research activities: Transitioning through communities of practice. PMID- 29476959 TI - The 360-degree evaluation model: A method for assessing competency in graduate nursing students. A pilot research study. AB - BACKGROUND: The 360 Degree Evaluation Model is one means to provide a comprehensive view of clinical competency and readiness for progression in an online nursing program. OBJECTIVES: This pilot project aimed to evaluate the effectiveness of implementing a 360 Degree Evaluation of clinical competency of graduate advanced practice nursing students. DESIGN: The 360 Degree Evaluation, adapted from corporate industry, encompasses assessment of student knowledge, skills, behaviors and attitudes and validates student's progression from novice to competent. SETTINGS: Cohort of advanced practice nursing students in four progressive clinical semesters. PARTICIPANTS: Graduate advanced practice nursing students (N = 54). METHODS: Descriptive statistics and Jonckheere's Trend Test were used to evaluate OSCE's scores from graded rubric, standardized patient survey scores, student reflection and preceptor evaluation. RESULTS: We identified all students passed the four OSCEs during a first attempt or second attempt. Scaffolding OSCE's over time allowed faculty to identify cohort weakness and create subsequent learning opportunities. Standardized patients' evaluation of the students' performance in the domains of knowledge, skills and attitudes, showed high scores of 96% in all OSCEs. Students' self-reflection comments were a mix of strengths and weaknesses in their self-evaluation, demonstrating themes as students progressed. Preceptor evaluation scores revealed the largest increase in knowledge and learning skills (NONPF domain 1), from an aggregate average of 90% in the first clinical course, to an average of 95%. CONCLUSIONS: The 360 Degree Evaluation Model provided a comprehensive evaluation of the student and critical information for the faculty ensuring individual student and cohort data and ability to analyze cohort themes. PMID- 29476960 TI - Situated teaching improves empathy learning of the students in a BSN program: A quasi-experimental study. AB - BACKGROUND: Empathy is an important clinical skill for nursing students, but it is a characteristic difficult to teach and assess. OBJECTIVE: To evaluate the effect of situated teaching on empathy learning among undergraduate nursing students. DESIGN: A cohort study with pre-post-test quasi-experimental design. PARTICIPANTS AND SETTING: The 2nd-year students were enrolled from two BSN programs. METHODS: The teaching program was completed over 4 months on the basis of experiential learning theory which integrated the following four elements: classroom-based role play, self-reflection, situated learning and acting. The Jefferson Scale of Empathy-Health Profession-Student version was administered before and after the program. Objective Structure Clinical Examination (OSCE) was administered at the end of program and a rubrics scale was used to measure empathy. A generalized estimation equation was used to identify the effect of subjective empathy, and an independent t-test was used for the objective assessment between two groups. RESULTS: A total of 103 students were enrolled. The results showed that subjective empathy increased significantly in experimental group. In the Objective Structured Clinical Examination, examiners and standard patients gave significantly higher empathy scores to the situated teaching group than the control group. CONCLUSIONS: The present study indicated that situated teaching can improve empathy learning of the nursing students. However different methods of assessment of empathy produce different results. We therefore recommend that multiple measurements from difference perspectives are preferable in the assessment of empathy. PMID- 29476963 TI - LPS-mediated cell surface expression of CD74 promotes the proliferation of B cells in response to MIF. AB - Macrophage migration inhibitory factor (MIF) is a chemokine-like inflammatory cytokine, which plays a pivotal role in the pathogenesis of inflammatory and cardiovascular diseases as well as cancer. We previously identified MIF as a novel B cell chemokine that promotes B cell migration through non-cognate interaction with the CXC chemokine receptor CXCR4 and CD74, the surface form of MHC class II invariant chain. In this study, we have analyzed the regulation of the MIF receptors under inflammatory conditions by investigating the impact of lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-alpha) and interleukin 1beta (IL-1beta) on CD74 and CXCR4 expression in B lymphocytes. We found that both LPS and TNF-alpha stimulation of primary B cells and the human B myeloma cell line RPMI-8226 enhanced protein expression as well as mRNA levels of CD74 in a time- and dose-dependent manner. By contrast, no effect on CXCR4 expression was observed. Selective inhibition of IkappaBalpha phosphorylation significantly attenuated LPS-induced expression of CD74, suggesting the contribution of NF kappaB signaling pathways to the regulation of CD74 expression. Importantly, individual or simultaneous blockade of MIF or CD74 using specific neutralizing antibodies markedly affected B cell proliferation after LPS exposure. Taken together, our findings unveil a connection between the pro-proliferative activity of MIF/CD74 signaling in B cells and inflammation, offering novel target mechanisms in inflammatory cardiovascular or autoimmune pathogenesis. PMID- 29476962 TI - Induction of apoptosis and cell cycle arrest by ethyl acetate fraction of Phoenix dactylifera L. (Ajwa dates) in prostate cancer cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Phoenix dactylifera L. (Ajwa date) has high nutritive value and are consumed in Arabian Peninsula as an essential diet. Phoenix dactylifera L. have been mentioned in folk remedies of traditional Egyptian medicine and alternative medicine, for numerous health benefits including cancer treatment. The aim of the study is to evaluate the anticancer effects of the extract of Ajwa Date on human Prostate cancer cell line (PC3). MATERIALS AND METHODS: Antiproliferative effect was measured using MTT assay. The long-term effect of EAFAD was determined using colony assay. Different stains like Giemsa and fluorescent stains (DAPI and acridine orange / Ethidium bromide) measured morphological changes. Loss of mitochondrial membrane potential and increased oxidative stress were measured using JC-1 and DCFH-DA dyes. DNA degradation was analyzed by comet assay. Cell cycle distribution was measured by flow cytometer. The apoptotic cell was quantified by annexin V-FITC and Propidium iodide dual staining using flow cytometer. RESULTS: PC3 cell line was treated with ethyl acetate fractions of Ajwa dates (EAFAD) to study their morphological and cellular changes and induction of apoptosis. MTT assay showed the strong inhibitory effect of EAFAD on PC3 cells. Loss of mitochondrial membrane potential and increased oxidative stress were observed in EAFAD treated cells, which suggested mitochondrial involvement in apoptosis. Comet assay proved DNA fragmentation induced by EAFAD. Flow Cytometer results demonstrated that Annexin V-FITC and propidium iodide staining showed that EAFAD induced apoptosis and arrest the cell cycle in S phase. CONCLUSION: Our results suggested EAFAD has potential therapeutics properties for prostate cancer. PMID- 29476961 TI - Anti-inflammatory action of Athyrium multidentatum extract suppresses the LPS induced TLR4 signaling pathway. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The aerial part of Athyrium multidentatum (Doll.) Ching (AM) is widely used in the northeastern region of China as an edible wild herb, but its medicinal value, especially its anti-inflammatory effect, has not been fully explored. AIM OF THE STUDY: To investigate the anti-inflammatory activity of AM and clarify the anti-inflammatory mechanism involving the TLR4 signaling pathway using a lipopolysaccharide (LPS)-induced inflammatory model. MATERIALS AND METHODS: AM ethanol extract was used as the experimental material to investigate the effect that the extract has on the production of pro inflammatory mediators (NO, PGE2, TNF-alpha, IL-1beta and IL-6); changes in LPS induced peritoneal macrophages (PMs); and TLR4-mediated intracellular events, including MAPKs (ERK, JNK, and p38) and IkappaB-alpha in the MyD88-dependant pathway and IRF3, STAT1, and STAT3 in the TRIF-dependent pathway. In in vivo experiments, we established an LPS-induced acute lung injury (ALI) model and investigated the cell count and cytokine (TNF-alpha, IL-1beta and IL-6) levels in bronchoalvelar lavage fluid (BALF) of C57BL6 mice. Histological changes in the lung tissues were observed with H&E staining. RESULTS: AM extract inhibited NO and PGE2 by suppressing their synthetase (iNOS and COX-2) gene expression in LPS induced PMs; the secretion of IL-6, IL-1beta, and TNF-alpha also deceased via the down-regulation of mRNA levels. Furthermore, the TLR4-mediated intracellular events involved the phosphorylated forms of MAPKs (ERK, JNK) and IkappaB-alpha in the MyD88-dependent pathway and the TRIF-dependent pathway (IRF3, STAT1, STAT3), and the relevant proteins were expressed at low levels in the AM extract groups. In in vivo experiments, the cell count and cytokine (TNF-alpha, IL-1beta and IL 6) levels in BALF decreased significantly in a dose-dependent manner in the AM extract groups. The lung tissue structure exhibited dramatic damage in the LPS group, and the damaged area decreased in the AM extract groups; in particular, the effect of 10 mg/kg extract was similar to that of the positive control dexamethasone (DEX). CONCLUSION: The findings demonstrate that AM protects against LPS-induced acute lung injury by suppressing TLR4 signaling, provide scientific evidence to support further study of the safety of anti-inflammatory drugs and indicate that AM can be used as an anti-inflammatory and anti-injury agent to prevent pneumonia caused by microbial infection. PMID- 29476964 TI - Pro-inflammatory cytokine and high doses of ionizing radiation have similar effects on the expression of NF-kappaB-dependent genes. AB - The NF-kappaB transcription factors are activated via diverse molecular mechanisms in response to various types of stimuli. A plethora of functions associated with specific sets of target genes could be regulated differentially by this factor, affecting cellular response to stress including an anticancer treatment. Here we aimed to compare subsets of NF-kappaB-dependent genes induced in cells stimulated with a pro-inflammatory cytokine and in cells damaged by a high dose of ionizing radiation (4 and 10 Gy). The RelA-containing NF-kappaB species were activated by the canonical TNFalpha-induced and the atypical radiation-induced pathways in human osteosarcoma cells. NF-kappaB-dependent genes were identified using the gene expression profiling (by RNA-Seq) in cells with downregulated RELA combined with the global profiling of RelA binding sites (by ChIP-Seq), with subsequent validation of selected candidates by quantitative PCR. There were 37 NF-kappaB-dependent protein-coding genes identified: in all cases RelA bound in their regulatory regions upon activation while downregulation of RELA suppressed their stimulus-induced upregulation, which apparently indicated the positive regulation mode. This set of genes included a few "novel" NF-kappaB dependent species. Moreover, the evidence for possible negative regulation of ATF3 gene by NF-kappaB was collected. The kinetics of the NF-kappaB activation was slower in cells exposed to radiation than in cytokine-stimulated ones. However, subsets of NF-kappaB-dependent genes upregulated by both types of stimuli were essentially the same. Hence, one should expect that similar cellular processes resulting from activation of the NF-kappaB pathway could be induced in cells responding to pro-inflammatory cytokines and in cells where so-called "sterile inflammation" response was initiated by radiation-induced damage. PMID- 29476965 TI - Garlic, green tea and turmeric extracts-mediated green synthesis of silver nanoparticles: Phytochemical, antioxidant and in vitro cytotoxicity studies. AB - Phyto-synthesis of silver nanoparticles (AgNPs) was achieved using aqueous garlic, green tea and turmeric extracts, and characterized by different spectroscopic techniques. Phytochemical analysis revealed the presence of rich amount of biochemicals in these extracts, which serve as reducing and capping agents for converting silver nitrate into AgNPs. FT IR spectroscopy confirmed the role of biomolecules in the bioreduction and efficient stabilization of AgNPs. UV Vis DRS spectra showed a band around 450 nm characteristics of AgNPs. XRD patterns revealed the crystalline nature of the synthesized AgNPs with fcc structure. SEM and TEM analysis revealed the spherical shape of the synthesized AgNPs with an average particle size of 8 nm. EDX analysis confirmed the purity of the synthesized AgNPs with a strong signal at 3.2 keV. The antioxidant activity was assessed by ABTS, DPPH, p-NDA, H2O2 and DMSO scavenging assays, in which the AgNPs synthesized using green method showed remarkable activity with respect to the standard antioxidants ascorbic acid and rutin. In vitro cytotoxicity activity was tested on four cancer cell lines such as human breast adenocarcinoma (MCF-7), cervical (HeLa), epithelioma (Hep-2) and lung (A549) along with one normal human dermal fibroblasts (NHDF) cell line. The AgNPs synthesized using turmeric extract exhibits excellent antioxidant and cytotoxicity activity compared to that synthesized using other extracts. PMID- 29476966 TI - Keratin-chitosan/n-ZnO nanocomposite hydrogel for antimicrobial treatment of burn wound healing: Characterization and biomedical application. AB - In the Present-day medicinally applied wound bandages have many drawbacks for, instance, rigidity, non-porosity, low mechanical potency, also an affinity for bandages to stick onto the injury exterior; additionally, a greater part of the bandages did not secure bactericidal activity. Hydrogel derived injury bandages would be supportive to afford a chill feeling with a humidity atmosphere, in addition, to performing as an obstruction to bacteria. To overcome these drawbacks, we have fabricated porous keratin-chitosan/n-ZnO nanocomposite (KCBZNs) bandages via the inclusion of nano-ZnO into the keratin-chitosan hydrogel. The functional group and surface of as-fabricated bandages were characterized using Fourier transform infrared spectroscopy (FT-IR), X-ray diffractometry (XRD), and scanning electron microscopy with energy-dispersive X ray spectroscopy (SEM-EDX) and transmission electron microscopy with selected area diffraction (TEM-SAD). Moreover, mechanical, swelling, bactericidal, bio compatibility of nanocomposite was assessed to exhibit its efficacy for biological applications. The nanocomposite illustrated increased swelling, and bactericidal activity. Bio-compatibility of the nanocomposite has been investigated in normal human fibroblast cells. Also, the in vivo assessments in SD rats exposed that as-fabricated nanocomposite bandages increased the wound curing with assisted for quicker skin cell construction along with collagen development. Hence, the acquired information strongly supports to utilize of this nanocomposite hydrogels for burn wounds. PMID- 29476967 TI - Electronic health record case studies to advance environmental public health tracking. AB - Data from traditional public health surveillance systems can have some limitations, e.g., timeliness, geographic level, and amount of data accessible. Electronic health records (EHRs) could present an opportunity to supplement current sources of routinely collected surveillance data. The National Environmental Public Health Tracking Program (Tracking Program) sought to explore the use of EHRs for advancing environmental public health surveillance practices. The Tracking Program funded four state/local health departments to obtain and pilot the use of EHR data to address several issues including the challenges and technical requirements for accessing EHR data, and the core data elements required to integrate EHR data within their departments' Tracking Programs. The results of these pilot projects highlighted the potential of EHR data for public health surveillance of rare diseases that may lack comprehensive registries, and surveillance of prevalent health conditions or risk factors for health outcomes at a finer geographic level. EHRs therefore, may have potential to supplement traditional sources of public health surveillance data. PMID- 29476968 TI - Acute compartment syndrome of the hand secondary to propofol extravasation. PMID- 29476969 TI - Direct determination of surfactant effects on the uptake of gaseous parent and alkylated PAHs by crop leaf surfaces. AB - The partitioning of atmospheric polycyclic aromatic hydrocarbons (PAHs) into crop systems raises concerns about their potential harm to ecosystem and human health. To assess parent and alkylated PAHs accumulation accurately, the uptake of individual 7-isopropyl-1-methylphenanthrene (Retene), 3-methyl-phenanthrene (3 MP) and phenanthrene (Phe) by living maize, soybean and potato leaf surfaces, as well as the effects of cationic cetyltrimethylammonium bromide (CTMAB) and anionic sodium dodecyl benzene sulfonate (SDBS), were examined in situ using fiber-optic fluorimetry. For each of three PAH chemicals, the uptake achieved equilibrium between the air and living crop leaf surfaces within the 120-h monitoring period. There is inter-chemical and inter-species variability in terms of both the time required reaching equilibrium, the equilibrated adsorption concentration (EAC) and the overall air-surfaces mass transfer coefficient (kAS). The EAC of the three PAHs for each of the three crops' leaf surfaces increased with the number of alkyl substitutions on the aromatic ring. For any given PAHs, the EAC values followed the sequence of potato > soybean > maize, which was dominantly controlled by their leaf surface polarity index ((O+N)/C). The presence of CTMAB and SDBS increased the EAC of PAHs in the three crops' leaf surfaces by 6.5-17.1%, due to the plasticizing effect induced by the surface sorbed surfactants, and the enhancement degree was closely associated with leaf wax content and lg KOW values of PAHs. In addition, the two surfactants promoted the kAS values of the three chemicals by 7.7-23.3%. These results demonstrated that surfactants promoted the uptake of PAHs onto the crop leaf surfaces, potentially threatening the agricultural product safety. PMID- 29476970 TI - Investigation of pharmaceutically active compounds in an urban receiving water: Occurrence, fate and environmental risk assessment. AB - Pharmaceutically active compounds (PhACs) recently have been recognized to constitute a health risk for aquatic ecosystems. The major pathways of PhACs to enter the aquatic environment are excretion and discharge of effluents through sewage treatment plants (STPs). The occurrence, bioaccumulation and risk assessment of lipophilic PhACs, including erythromycin, ketoconazole, indomethacin, diclofenac, gemfibrozil, bezafibrate, propranolol, carbamazepine, sertraline and 17alpha-ethinylestradiol were investigated in a river that receives effluents from STP. The results indicate that the PhACs were extensively existed in fish, sediment, suspended particulate matter (SPM), colloidal phase (5 kDa to 1 um) and truly dissolved phase (< 5 kDa) water, with total concentration of ten PhACs (Sigma10PhACs) of ND-19.6 ng/g, 7.3-11.2 ng/g, 25.3-101.5 ng/g, 10.1 27.7 ng/L and 67.0-107.6 ng/L, respectively. The Sigma10PhACs for particulate and water samples collected from STP's outfall site were higher than those collected from upstream and downstream, indicating that the STP is an important PhACs source of river. However, the Sigma10PhACs in sediment showed no significant statistical differences in the sampling area, and which was 3.5-9.5 times lower than those in SPM samples. The colloidal phase contributed 2.5-28.5% of erythromycin, 5.8-45.6% of ketoconazole, 8.4-32.2% of indomethacin, 7.0-21.4% of diclofenac, 11.6-36.9% of gemfibrozil, 10.2-45.9% of bezafibrate, 5.9-16.8% of propranolol, 1.9-11.1% of carbamazepine and 1.1-23.8% of sertraline in the aquatic environment. This suggests that aquatic particulates (e.g., colloids and SPM) maybe an important carrier for PhACs in the aquatic system. In general, the Sigma10PhACs in the tissues of fish were in order as follows: kidney > brain > liver > gill > muscle. Based on truly dissolved concentrations of PhACs in the water, bioaccumulation factors were between 3.7 and 2727.3 in the fish tissues, sertraline exhibited bioaccumulation potential. In all the risk assessments, erythromycin could cause most harmful adverse health effects for the most sensitive algae group based on the acute and chronic data. In addition, the risk quotient values for diclofenac toward fish were higher than 1. These results indicate that the PhACs pose a potential risk to the aquatic organisms, especially for chronic risk. PMID- 29476971 TI - Prenatal exposure to ambient temperature variation increases the risk of common cold in children. AB - BACKGROUND: Common cold is a frequent upper respiratory tract infection, but the role of ambient temperature in the infection is unclear. OBJECTIVE: We investigated the role of prenatal exposure to diurnal temperature variation (DTV), the difference between the daily maximal and minimal temperatures, in the risk of common cold in children. METHODS: We conducted a cohort study of 2598 preschool children in Changsha, China. Occurrence of common cold during the past year was surveyed using questionnaire. We then estimated each child's prenatal exposure to DTV during pregnancy. Multivariate logistic regression model was used to examine the association between occurrence of common cold and prenatal exposure to DTV in terms of odds ratios (OR) and 95% confidence interval (CI). RESULTS: About 45% children have common cold (>=3 times) during the past year. We found that common cold in children was associated with maternal DTV exposure during pregnancy, particularly during the first trimester with adjusted OR (95% CI) = 1.27 (1.10-1.46). Male and atopic children were more susceptible to the effect of DTV during pregnancy. The risk of common cold due to DTV is higher in children living in the suburban areas and the bigger houses and in those exposed to environmental tobacco smoke, mold/dampness, new furniture and redecoration. We observed that the risk of common cold in children has been increased in recent years due to increasing DTV. CONCLUSIONS: Common cold in children was associated with maternal exposure to temperature variation during pregnancy, suggesting that the risk of common cold may originate in pregnancy. PMID- 29476972 TI - Response of PXR signaling pathway to simvastatin exposure in mosquitofish (Gambusia affinis) and its histological changes. AB - As a widely used lipid lowering agent, simvastatin recently has been frequently detected in aquatic environment and the potential adverse effects from simvastatin exposure to non-target organisms such as fish is worthy of more attention. The aim of this study was to reveal the responses of detoxification system in fish to simvastatin exposure. In this investigation a ubiquitous small freshwater fish, mosquito fish (Gambusia affinis), was employed as test organism, and the transcriptional expression of nucleus transcriptional factor pregnane X receptor (PXR) and its downstream genes, including P-glycoprotein (P-gp), cytochrome 3A (CYP3A), multidrug resistance protein 2 (MRP2), UDP-glucuronosyl transferase (UGT) in mosquito fish were investigated by qRT-PCR methods under the exposure of concentrations of simvastatin (0.5 MUg L-1, 5 MUg L-1, 50 MUgL-1, 500 MUg L-1) for 24 h, 72 h and 168 h. The related enzyme activity (Erythromycin-N Demethylase, ERND), the protein expression of PXR and the histological changes of liver tissues in fish were also determined via west blotting and transmission electron microscope approaches in the same conditions. Results showed that the mRNA expression of PXR, CYP3A and P-gp showed significantly changes under simvastatin exposure, exhibiting an obvious time/dose-effect relationship with the prolong of exposure time. ERND activity also showed time-effect at 24 h, and western blotting showed PXR protein displaying a dose-effect relationship to some extent. Hepatocyte cellular of mosquito fish exposed to simvastatin (5 MUg L-1, 168 h) exhibited obvious histological changes in form of swelling, incomplete fragmentary structure etc. Overall, simvastatin altered the expression of PXR signaling pathway and subsequently bring about changes in high-levels of mosquito fish. PMID- 29476973 TI - Ecofriendly nanotechnologies and nanomaterials for environmental applications: Key issue and consensus recommendations for sustainable and ecosafe nanoremediation. AB - The use of engineered nanomaterials (ENMs) for environmental remediation, known as nanoremediation, represents a challenging and innovative solution, ensuring a quick and efficient removal of pollutants from contaminated sites. Although the growing interest in nanotechnological solutions for pollution remediation, with significant economic investment worldwide, environmental and human risk assessment associated with the use of ENMs is still a matter of debate and nanoremediation is seen yet as an emerging technology. Innovative nanotechnologies applied to water and soil remediation suffer for a proper environmental impact scenario which is limiting the development of specific regulatory measures and the exploitation at European level. The present paper summarizes the findings from the workshop: "Ecofriendly Nanotechnology: state of the art, future perspectives and ecotoxicological evaluation of nanoremediation applied to contaminated sediments and soils" convened during the Biannual ECOtoxicology Meeting 2016 (BECOME) held in Livorno (Italy). Several topics have been discussed and, starting from current state of the art of nanoremediation, which represents a breakthrough in pollution control, the following recommendations have been proposed: (i) ecosafety has to be a priority feature of ENMs intended for nanoremediation; ii) predictive safety assessment of ENMs for environmental remediation is mandatory; (iii) greener, sustainable and innovative nano-structured materials should be further supported; (iii) those ENMs that meet the highest standards of environmental safety will support industrial competitiveness, innovation and sustainability. The workshop aims to favour environmental safety and industrial competitiveness by providing tools and modus operandi for the valorization of public and private investments. PMID- 29476974 TI - Assessment of gonadal and thyroid histology in Gulf killifish (Fundulus grandis) from Barataria Bay Louisiana one year after the Deepwater Horizon oil spill. AB - We examined gonads and thyroid glands of Gulf killifish (Fundulus grandis) 1yr after the Deepwater Horizon oil spill. F. grandis were trapped from two impacted sites in Barataria Bay (Bayou St. Denis, Bay Jimmy) and an un-impacted site in East Texas (Sabine Pass). The greatest number of F. grandis were collected at Sabine Pass. F. grandis collected at Bayou St. Denis were smaller and had smaller Fulton condition factor scores than fish collected at Sabine Pass. Sex ratios were biased roughly 2:1 in favor of females at Sabine Pass and Bayou St. Denis. Gonad-somatic index (GSI) in males from Sabine Pass was double that of fish from Bay Jimmy while germinal epithelium thickness of the testes was 2.7 fold smaller in males from the impacted site. GSI and oocyte diameters in females from Bayou St. Denis were significantly smaller than females from Bay Jimmy or the reference site. There were no differences in thyroid follicle cell height. While total polyaromatic hydrocarbons at the impacted sites were no different from the reference site, the impacted sites did have greater concentrations of benzo[a]pyrene in sediment pore water. The finding of smaller GSI and testicular germinal epithelium in males from an impacted site suggest that exposure to a combination of oil and dispersants may adversely impact testicular function. PMID- 29476975 TI - Ecological risk assessment of polymetallic sites using weight of evidence approach. AB - Ecological risk assessment (ERA) of polymetallic contamination in soils has caused extensive solicitude. However, objective and feasible methods suitable for soil ERA are limited. Therefore, in this study, a multidisciplinary and quantitative weight of evidence approach (WOE) specific to soil ecosystems was developed based on the previous WOE for aquatic ecosystems. The framework consisted of four lines of evidence (LOEs): DTPA-extractable heavy metal in soils, bioaccumulation in earthworms, integration of biomarker responses and expected community effect (multi-substance Potentially Affected Fraction, msPAF). These four LOEs were initially evaluated by each hazard quotient (HQ) of them based on the ratio to the reference (RTR) of each parameter. Then, Environmental risk index (EnvRI) integrated by HQs with different weights was calculated. At last, three sites, one for reference (N1) and two for contaminated soils (N2 and N3) were chosen to apply the modified WOE approach. Results showed that heavily contaminated site, N3 had higher HQ classification for each LOE and its EnvRI was classified as Major levels, while the EnvRI of N2 was assigned into Moderate. What's more, HQ of biomarker response (HQbiomarker) integrated by RTRs of biomarkers increased gradiently with the increase of heavy metal levels in soils though irregular changes were observed for most of those biomarkers. Overall, our results indicated that the quantitative WOE framework specific to soil ERA had the advantage of obtaining a comprehensive and objective risk assessment. PMID- 29476976 TI - Heavy metal concentrations in bovine tissues (muscle, liver and kidney) and their relationship with heavy metal contents in consumed feed. AB - Toxic (lead, cadmium and mercury) and essential trace (copper and zinc) metals were measured in muscle, liver and kidney samples of bovine and their relationships with heavy metal concentrations in consumed feed were studied. A total of 216 tissue samples from 72 cows and 216 feed samples from 18 farms were collected during four seasons and analyzed for heavy metals by inductively coupled plasma-optical emission spectrometry after wet digestion. The arithmetic mean concentrations (mg/Kg wet weight) of lead (Pb), cadmium (Cd) and mercury were respectively, 0.221, 0.028 and 0.003 in muscle, 0.273, 0.047 and 0.002 in liver and 0.244, 0.114 and 0.003 in kidney. All measured concentrations (with the exception of Pb in muscle) were below the European Union maximum residual limits (MRL). The Cd contents of the kidney were significantly higher than which observed in other tissues. Although, copper (Cu) and zinc (Zn) levels in all of samples were below MRL, but results showed that many cattles may be suffering from Cu and/or Zn deficiency. Significant and positive correlations between Pb (p < 0.05, r = 0.163) and Cd (p < 0.01, r = 0.303) concentrations in feed and studied organs were observed. As a considerable amount of metals above MRL were noticed in our study, continuous monitoring of these metals is recommended to avoid hazardous transfer to human through the food of animal origin. PMID- 29476977 TI - Secreted Clusterin protein inhibits osteoblast differentiation of bone marrow mesenchymal stem cells by suppressing ERK1/2 signaling pathway. AB - Secreted Clusterin (sCLU, also known as Apolipoprotein J) is an anti-apoptotic glycoprotein involved in the regulation of cell proliferation, lipid transport, extracellular tissue remodeling and apoptosis. sCLU is expressed and secreted by mouse bone marrow-derived skeletal (stromal or mesenchymal) stem cells (mBMSCs), but its functional role in MSC biology is not known. In this study, we demonstrated that Clusterin mRNA expression and protein secretion in conditioned medium increased during adipocyte differentiation and decreased during osteoblast differentiation of mBMSCs. Treatment of mBMSC cultures with recombinant sCLU protein increased cell proliferation and exerted an inhibitory effect on the osteoblast differentiation while stimulated adipocyte differentiation in a dose dependent manner. siRNA-mediated silencing of Clu expression in mBMSCs reduced adipocyte differentiation and stimulated osteoblast differentiation of mBMSCs. Furthermore, the inhibitory effect of sCLU on the osteoblast differentiation of mBMSCs was mediated by the suppression of extracellular signal-regulated kinase (ERK1/2) phosphorylation. In conclusion, we identified sCLU as a regulator of mBMSCs lineage commitment to osteoblasts versus adipocytes through a mechanism mediated by ERK1/2 signaling. Inhibiting sCLU is a possible therapeutic approach for enhancing osteoblast differentiation and consequently bone formation. PMID- 29476979 TI - Bone and blood interactions in human health and disease. AB - Under physiologic conditions hematopoiesis takes place in the bone marrow, and the skeleton provides the structural and supportive network necessary for normal hematopoiesis. Chronic disorders affecting hematopoiesis such as sickle cell anemia and thalassemia demonstrate striking skeletal phenotypes including bone loss and increased fracture risk. There is mounting evidence that anemia in older populations may also be associated with bone fragility. Given the interconnectedness of bone and hematopoietic cells, it is important to review the potential clinical implications and opportunities for therapeutic intervention. There are recognized associations between blood-borne and solid tissue malignancy and skeletal health, but our review will focus on non-malignant disease. PMID- 29476978 TI - Prolonged high force high repetition pulling induces osteocyte apoptosis and trabecular bone loss in distal radius, while low force high repetition pulling induces bone anabolism. AB - We have an operant rat model of upper extremity reaching and grasping in which we examined the impact of performing a high force high repetition (High-ForceHR) versus a low force low repetition (Low-ForceHR) task for 18weeks on the radius and ulna, compared to age-matched controls. High-ForceHR rats performed at 4 reaches/min and 50% of their maximum voluntary pulling force for 2h/day, 3days/week. Low-ForceHR rats performed at 6% maximum voluntary pulling force. High-ForceHR rats showed decreased trabecular bone volume in the distal metaphyseal radius, decreased anabolic indices in this same bone region (e.g., decreased osteoblasts and bone formation rate), and increased catabolic indices (e.g., microcracks, increased osteocyte apoptosis, secreted sclerostin, RANKL, and osteoclast numbers), compared to controls. Distal metaphyseal trabeculae in the ulna of High-ForceHR rats showed a non-significant decrease in bone volume, some catabolic indices (e.g., decreased trabecular numbers) yet also some anabolic indices (e.g., increased osteoblasts and trabecular thickness). In contrast, the mid-diaphyseal region of High-ForceHR rats' radial and ulnar bones showed few to no microarchitecture differences and no changes in apoptosis, sclerostin or RANKL levels, compared to controls. In further contrast, Low ForceHR rats showed increased trabecular bone volume in the radius in the distal metaphysis and increased cortical bone area its mid-diaphysis. These changes were accompanied by increased anabolic indices, no microcracks or osteocyte apoptosis, and decreased RANKL in each region, compared to controls. Ulnar bones of Low ForceHR rats also showed increased anabolic indices, although fewer than in the adjacent radius. Thus, prolonged performance of an upper extremity reaching and grasping task is loading-, region-, and bone-dependent, with high force loads at high repetition rates inducing region-specific increases in bone degradative changes that were most prominent in distal radial trabeculae, while low force task loads at high repetition rates induced adaptive bone responses. PMID- 29476981 TI - Hitchhikers, highway tolls and roadworks: the interactions of plant viruses with the phloem. AB - The phloem is of central importance to plant viruses, providing the route by which they spread throughout their host. Compared with virus movement in non vascular tissue, phloem entry, exit, and long-distance translocation usually involve additional viral factors and complex virus-host interactions, probably, because the phloem has evolved additional protection against these molecular 'hitchhikers'. Recent progress in understanding phloem trafficking of endogenous mRNAs along with observations of membranous viral replication 'factories' in sieve elements challenge existing conceptions of virus long-distance transport. At the same time, the central role of the phloem in plant defences against viruses and the sophisticated viral manipulation of this host tissue are beginning to emerge. PMID- 29476980 TI - Apoptosis Reversal Promotes Cancer Stem Cell-Like Cell Formation. AB - It has long been a puzzle in cancer treatment that despite the initial appearance of apoptosis, the process could be reversed in some cancer cells and often results in more aggressive tumors and metastasis. The mechanism for this recurrence is yet unknown. Here we report that human mammary carcinoma cells induced to undergo apoptosis could recover with increased tumorigenicity in vitro and in vivo, and induced lymph node metastasis. Specifically, the reversed cells underwent epithelial-to-mesenchymal transitions in the primary tumors in situ, and mesenchymal-to-epithelial transitions in the metastatic cells. Flow cytometry confirmed an elevated percentage of cells carrying cancer stem cells (CSCs) markers (CD44+/CD24-) in the reversed breast cancer cell population, with hypomethylated CD44 promoters and hypermethylated CD24 promoters. More importantly, CSCs were generated anew from non-stem cancer cells after apoptosis reversal possibly through epigenetic modifications. The results from this study can open doors to discovering more effective cancer treatments by suppressing apoptosis reversal. PMID- 29476982 TI - Atlas selection for hippocampus segmentation: Relevance evaluation of three meta information parameters. AB - Current state-of-the-art methods for whole and subfield hippocampus segmentation use pre-segmented templates, also known as atlases, in the pre-processing stages. Typically, the input image is registered to the template, which provides prior information for the segmentation process. Using a single standard atlas increases the difficulty in dealing with individuals who have a brain anatomy that is morphologically different from the atlas, especially in older brains. To increase the segmentation precision in these cases, without any manual intervention, multiple atlases can be used. However, registration to many templates leads to a high computational cost. Researchers have proposed to use an atlas pre-selection technique based on meta-information followed by the selection of an atlas based on image similarity. Unfortunately, this method also presents a high computational cost due to the image-similarity process. Thus, it is desirable to pre-select a smaller number of atlases as long as this does not impact on the segmentation quality. To pick out an atlas that provides the best registration, we evaluate the use of three meta-information parameters (medical condition, age range, and gender) to choose the atlas. In this work, 24 atlases were defined and each is based on the combination of the three meta-information parameters. These atlases were used to segment 352 vol from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Hippocampus segmentation with each of these atlases was evaluated and compared to reference segmentations of the hippocampus, which are available from ADNI. The use of atlas selection by meta-information led to a significant gain in the Dice similarity coefficient, which reached 0.68 +/- 0.11, compared to 0.62 +/- 0.12 when using only the standard MNI152 atlas. Statistical analysis showed that the three meta-information parameters provided a significant improvement in the segmentation accuracy. PMID- 29476983 TI - Draft genome sequence of a KPC-2-producing Klebsiella pneumoniae ST340 carrying blaCTX-M-15 and blaCTX-M-59 genes: a rich genome of mobile genetic elements and genes encoding antibiotic resistance. AB - OBJECTIVES: Klebsiella pneumoniae is considered an opportunistic pathogen and an important agent of nosocomial and community infections. It presents the ability to capture and harbour several antimicrobial resistance genes and, in this context, the extensive use of carbapenems to treat serious infections has been responsible for the selection of several resistance genes. This study reports the draft genome sequence of a KPC-2-producing K. pneumoniae strain (Kp10) simultaneously harbouring blaCTX-M-15 and blaCTX-M-59 genes isolated from urine culture of a patient with Parkinson's disease. METHODS: Classical microbiological methods were applied to isolate and identify the strain, and PCR and sequencing were used to identify and characterise the genes and the genetic environment. Whole-genome sequencing (WGS) was performed using a Nextera XT DNA library and a NextSeq platform. RESULTS: WGS analysis revealed the presence of 5915 coding genes, 46 RNA-encoding genes and 255 pseudogenes. Kp10 belonged to sequence type 340 (ST340) of clonal complex 258 (CC258) and carried 20 transferable genes associated with antimicrobial resistance, comprising seven drug classes. Although the simultaneous presence of different blaCTX-M genes in the same strain is rarely reported, the blaKPC-2, blaCTX-M-15 and blaCTX-M-59 genes were not associated with the same genetic mobile structure in Kp10. CONCLUSIONS: These results confirm the capacity of K. pneumoniae to harbour several antimicrobial resistance genes. Thus, this draft genome could help in future epidemiological studies regarding the dissemination of clinically relevant resistance genes. PMID- 29476984 TI - Isolation of a mcr-1-harbouring Escherichia coli isolate from a human clinical setting in Sapporo, Japan. PMID- 29476985 TI - Extensively drug-resistant community-acquired Acinetobacter baumannii sequence type 2 in a dog with urinary tract infection in Thailand. PMID- 29476986 TI - Antituberculosis drug prescribing for inpatients in a national tuberculosis hospital in China, 2011-2015. AB - OBJECTIVES: This study aimed to describe trends in antituberculosis drug prescribing for inpatients from 2011-2015 in a Chinese national tuberculosis (TB) hospital. METHODS: This retrospective study, performed in March 2016, reviewed the medical records of all inpatients from Beijing Chest Hospital diagnosed with TB between 2011-2015. Medication used for TB treatment during the inpatient period was recorded. RESULTS: A total of 11465 inpatients were enrolled in the study. The most frequently prescribed drug for inpatients was isoniazid (71.2%; 8164/11465), followed by ethambutol (67.5%; 7738/11465), pyrazinamide (59.7%; 6839/11465) and rifampicin (40.0%; 4589/11465). In addition, amikacin (16.5%; 1889/11465), levofloxacin (33.0%; 3789/11465), para-aminosalicylic acid (12.4%; 1422/11465) and clarithromycin (3.5%; 406/11465) were the most common drugs used in the treatment of inpatients for Group II, III, IV and V drugs, respectively. A significant increasing trend in prescribing was found for rifampicin, pyrazinamide, capreomycin, moxifloxacin, prothionamide, para-aminosalicylic acid, cycloserine, clofazimine and linezolid, respectively, whilst there was a significant decreasing trend in the rate of prescribing of ethambutol, amikacin, levofloxacin, amoxicillin/clavulanic acid and clarithromycin during the 5-year study period (Ptrend<0.01). CONCLUSIONS: These data demonstrate that prescription of anti-TB drugs varied greatly across clinical diagnostic categories, treatment history and drug susceptibility profiles of TB patients. The World Health Organization (WHO)-endorsed standard regimen should be more extensively employed under conditions where drug susceptibility testing is unavailable in order to guide clinicians to formulate a suitable treatment regimen for TB patients. PMID- 29476987 TI - Isoprenoids and tau pathology in sporadic Alzheimer's disease. AB - The mevalonate pathway has been described to play a key role in Alzheimer's disease (AD) physiopathology. Farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) are nonsterol isoprenoids derived from mevalonate, which serve as precursors to numerous human metabolites. They facilitate protein prenylation; hFPP and hGGPP synthases act as gateway enzymes to the prenylation of the small guanosine triphosphate (GTP)ase proteins such as RhoA and cdc42 that have been shown to facilitate phospho-tau (p-Tau, i.e., protein tau phosphorylated) production in the brain. In this study, a significant positive correlation was observed between the synthases mRNA prevalence and disease status (FPPS, p < 0.001, n = 123; GGPPS, p < 0.001, n = 122). The levels of mRNA for hFPPS and hGGPPS were found to significantly correlate with the amount of p-Tau protein levels (p < 0.05, n = 34) and neurofibrillary tangle density (p < 0.05, n = 39) in the frontal cortex. Interestingly, high levels of hFPPS and hGGPPS mRNA prevalence are associated with earlier age of onset in AD (p < 0.05, n = 58). Together, these results suggest that accumulation of p-Tau in the AD brain is related, at least in part, to increased levels of neuronal isoprenoids. PMID- 29476989 TI - Continuous exploration of parameters derived from multiple electrode platelet aggregometry is warranted. PMID- 29476988 TI - Assessment of coexisting deep vein thrombosis for risk stratification of acute pulmonary embolism. AB - BACKGROUND: In patients with acute pulmonary embolism (PE), studies have shown an association between coexisting deep vein thrombosis (DVT) and short-term prognosis. It is not known whether complete compression ultrasound testing (CCUS) improves the risk stratification of their disease beyond the recommended prognostic models. METHODS: We included patients with normotensive acute symptomatic PE and prognosticated them with the European Society of Cardiology (ESC) risk model for PE. Subsequently, we determined the prognostic significance of coexisting DVT in patients with various ESC risk categories. The primary endpoint was a complicated course after the diagnosis of PE, defined as death from any cause, haemodynamic collapse, or adjudicated recurrent PE. RESULTS: According to the ESC model, 37% of patients were low-risk, 56% were intermediate low risk, and 6.7% were intermediate-high risk. CCUS demonstrated coexisting DVT in 375 (44%) patients. Among the 313 patients with low-risk PE, coexisting DVT (46%) did not show a significant increased risk of complicated course (2.8%; 95% confidence interval [CI], 0.8%-7.0%), compared with those without DVT (0.6%; 95% CI, 0%-3.2%), (P = 0.18). Of the 478 patients with intermediate-low risk PE, a complicated course was 14% and 6.8% for those with and without DVT, respectively (P = 0.01). Of the 57 patients that had intermediate-high risk PE, a complicated course occurred in 17% and 18% for those with and without DVT, respectively (P = 1.0). CONCLUSIONS: In normotensive patients with PE, testing for coexisting DVT might improve risk stratification of patients at intermediate-low risk for short term complications. PMID- 29476990 TI - The effect of oral versus intravenous tranexamic acid in reducing blood loss after primary total hip arthroplasty: A randomized clinical trial. AB - BACKGROUND: The purpose of this study was to determine whether the administration of multiple boluses of oral and intravenous tranexamic acid (TXA) postoperatively was equivalent in reducing blood loss in primary THA. METHODS: A total of 108 patients were randomized into two groups: oral TXA group (54 patients receiving 1 dose of 20 mg/kg intravenous TXA 5-10 min before skin incision and 3 doses of 2 g oral TXA 4 h, 10 h and 16 h postoperatively) and intravenous TXA group (54 patients receiving 1 dose of 20 mg/kg intravenous TXA 5-10 min before skin incision and 3 doses of 1 g intravenous TXA 6 h, 12 h and 18 h postoperatively). The primary outcomes were total blood loss, hidden blood loss, length of hospital stay, hemoglobin (Hb) and hematocrit (Hct) drop. The secondary outcomes were the level of inflammation markers and complications. RESULTS: There was no difference in the mean total blood loss or hidden blood loss [728.4 (645.8-806.9) mL vs 703.6 (576.9-832.8) mL, p = 0.745; 634.6 (552.0-715.7) mL vs 606.4 (480.1-734.5) mL, p = 0.710] and length of hospital stay was similar between the two groups. No patients received allogenic blood transfusion. The Hb and Hct drop on the first and second postoperative days were similar (p > 0.05). The level of inflammation markers did not reach statistical significance. The incidence of complications did not differ significantly between the two groups. CONCLUSIONS: Multiple boluses of oral TXA and intravenous TXA postoperatively are equivalent in reducing blood loss, Hb and Hct drop in primary THA without increasing the risk of thromboembolic diseases and wound complications. PMID- 29476991 TI - beta-L-Arabinofuranosylation Conducted by 5-O-(2-pyridinecarbonyl)-L arabinofuranosyl Trichloroacetimidate. AB - We describe a beta-L-arabinofuranosylation method by employing the 5-O-(2 pyridinecarbonyl)-L-arabinofuranosyl trichloroacetimidate 10 as a donor. This approach allows a wide range of acceptor substrates, especially amino acid acceptors, to be used. Stereoselective synthesis of beta-(1,4)-L-arabinofuranosyl (2S, 4R)-4-hydroxy-L-proline (beta-L-Araf-L-Hyp4) and its dimer is achieved readily by this method. Both the stereoselectivities and yields of the reactions are excellent. To demonstrate the utility of this methodology, the preparation of a trisaccharide in a one-pot manner was carried out. PMID- 29476992 TI - Preparation and structural characterization of regioselective 4-O/6-O-desulfated chondroitin sulfate. AB - The sulfation pattern plays a crucial role in chondroitin sulfate (CS) biological activity, and preparation of CS with defined structure is essential for accurate pharmacological study. In this study, we focused on the preparation of regioselective 4-O/6-O-desulfated CS derived from porcine, employing a dimethyl sulfoxide-methanol (DMSO-MeOH) method and an N-methyl-N-(trimethylsilyl) trifluoroacetamide (MTSTFA) method CS, respectively. Results showed that the sulfate at C4 position (4-O-S) of N-acetylgalactosamine (GalNAc) was selectively removed by the DMSO-MeOH method, and the sulfate at C6 position (6-O-S) of GalNAc was selectively removed by the MTSTFA method. Structures of desulfated CS were characterized by means of FT-IR, NMR and disaccharide composition analysis. The preparations of regioselective 4-O/6-O-desulfated CS are powerful for the study of structure-activity relationship of CS. PMID- 29476993 TI - Multimodal Image-Based Virtual Reality Presurgical Simulation and Evaluation for Trigeminal Neuralgia and Hemifacial Spasm. AB - OBJECTIVE: To address the feasibility and predictive value of multimodal image based virtual reality in detecting and assessing features of neurovascular confliction (NVC), particularly regarding the detection of offending vessels, degree of compression exerted on the nerve root, in patients who underwent microvascular decompression for nonlesional trigeminal neuralgia and hemifacial spasm (HFS). METHODS: This prospective study includes 42 consecutive patients who underwent microvascular decompression for classic primary trigeminal neuralgia or HFS. All patients underwent preoperative 1.5-T magnetic resonance imaging (MRI) with T2-weighted three-dimensional (3D) sampling perfection with application optimized contrasts by using different flip angle evolutions, 3D time-of-flight magnetic resonance angiography, and 3D T1-weighted gadolinium-enhanced sequences in combination, whereas 2 patients underwent extra experimental preoperative 7.0 T MRI scans with the same imaging protocol. Multimodal MRIs were then coregistered with open-source software 3D Slicer, followed by 3D image reconstruction to generate virtual reality (VR) images for detection of possible NVC in the cerebellopontine angle. Evaluations were performed by 2 reviewers and compared with the intraoperative findings. RESULTS: For detection of NVC, multimodal image-based VR sensitivity was 97.6% (40/41) and specificity was 100% (1/1). Compared with the intraoperative findings, the kappa coefficients for predicting the offending vessel and the degree of compression were >0.75 (P < 0.001). The 7.0-T scans have a clearer view of vessels in the cerebellopontine angle, which may have significant impact on detection of small-caliber offending vessels with relatively slow flow speed in cases of HFS. CONCLUSIONS: Multimodal image-based VR using 3D sampling perfection with application-optimized contrasts by using different flip angle evolutions in combination with 3D time-of-flight magnetic resonance angiography sequences proved to be reliable in detecting NVC and in predicting the degree of root compression. The VR image-based simulation correlated well with the real surgical view. PMID- 29476994 TI - Relationship Between Cervical Sagittal Alignment and Patient Outcomes After Anterior Cervical Fusion Surgery Involving 3 or More Levels. AB - BACKGROUND: T1 slope minus C2-7 lordosis (TS-CL) and cervical sagittal alignment reportedly affect health-related quality of life (HRQOL) scores after multilevel posterior cervical fusion surgery. There are no reports of a relationship between cervical alignment and patient outcomes after anterior cervical discectomy and fusion (ACDF) involving 3 or more levels. This study aimed to investigate the relationship between cervical sagittal alignment and patient-reported HRQOL after ACDF involving 3 or more levels. METHODS: Thirty-three patients underwent ACDF involving 3 or more levels for cervical stenosis, cervical degenerative disorder, or ossification of the posterior longitudinal ligament (February 2006-April 2015). Mean follow-up duration was 57.6 +/- 33.2 months. Radiographic measurements included C0-2 lordosis, C2-7 lordosis, C2-7 sagittal vertical axis (SVA), T1 slope, and T1 slope minus cervical lordosis (TS-CL). Clinical outcomes were evaluated by Neck Disability Index (NDI) and visual analog scale (VAS) scores. RESULTS: There were significant correlations between C2-7 lordosis and T1 slope (r = 0.581, P = 0.004), and between C2-7 lordosis and TS-CL (r = -0.579, P = 0.004). C2-7 lordosis, C2-7 SVA, and TS-CL had no significant correlations with NDI or VAS score after surgery. C2-7 SVA was not significantly different before and after surgery. Postoperative TS-CL (P = 0.01) and changes in T1 slope (P = 0.028) and TS-CL (P = 0.01) were significantly correlated with changes in NDI. CONCLUSIONS: ACDF surgery involving 3 or more levels under neutral supine position did not significantly change the postoperative cervical alignment, and thus may not significantly affect cervical alignment or HRQOL. PMID- 29476995 TI - A Systematic Review and Meta-Analysis on Economic Comparison Between Endovascular Coiling Versus Neurosurgical Clipping for Ruptured Intracranial Aneurysms. AB - OBJECTIVE: Healthcare expenditures and cost reduction have been under critical surveillance in all countries and are critical for policymakers. This review aims at qualitatively and quantitatively analyzing the difference of hospital costs and length of stay between endovascular coiling versus neurosurgical clipping in ruptured intracranial aneurysms (RAs). METHODS: MEDLINE, the Cochrane database, Embase, and the Web of Science database were searched and evaluated independently by 2 authors according to the Newcastle-Ottawa Scale for cohort studies describing economic hospital cost or length of stay in patients with RAs. RESULTS: A total of 8 studies were included, describing 24,219 RAs treated with neurosurgical clipping and 24,962 RAs with endovascular coiling. Meta-analysis revealed that the total hospital costs (THCs) were similar between coiling versus clipping in RAs (standard mean difference [SMD], -0.05; 95% confidence interval [CI], -0.12 to 0.22; I2 = 99%; P = 0.50). Subgroup analysis showed that THCs of clipping and coiling were similar in ruptured aneurysms in the United States. However, in South Korea, the THCs of coiling were significantly higher than clipping. In the long run, 1-year medical costs of endovascular treatment were significantly lower than that of clipping in RAs (SMD, 0.15; 95% CI, 0.05-0.25; I2 = 66%; P = 0.005). In addition, the length of stay of coiled patients was significantly shorter than clipped patients (SMD, 0.29; 95% CI, 0.13-0.45; I2 = 96%; P < 0.001). CONCLUSIONS: Medical costs were region-specified. In the United States, total hospital costs and 1-year medical costs were similar in RA patients treated with endovascular coiling and neurosurgical clipping. However, in countries like South Korea and China, coiling was more expensive. The length of stay was much shorter in coiled patients in all countries. PMID- 29476996 TI - Advantages and Disadvantages of Combined Chemotherapy with Carmustine Wafer and Bevacizumab in Patients with Newly Diagnosed Glioblastoma: A Single-Institutional Experience. AB - OBJECTIVE: To retrospectively determine the safety and efficacy of combined chemotherapy with carmustine (BCNU) wafer, bevacizumab, and temozolomide plus radiotherapy in patients with newly diagnosed glioblastoma (GBM). METHODS: A total of 54 consecutive newly diagnosed GBMs were resected at our institution between 2010 and 2016. Twenty-nine patients underwent BCNU wafer implantation into the resection cavity followed by standard radiochemotherapy with temozolomide (TMZ, Stupp regimen) plus additional bevacizumab treatment between 2013 and 2016. Twenty-five patients who underwent resection without BCNU implantation between 2010 and 2012 were enrolled as a control group; these patients were treated with the Stupp regimen and did not receive bevacizumab. This retrospective study included evaluation of progression-free survival and overall survival, plus comparisons between the combined therapy group and the control group. RESULTS: There were no significant differences in age, sex, Karnofsky Performance Status on admission, isocitrate dehydrogenase 1/2 mutation ratio, or resection rate between the combined and standard therapy groups. The median overall survival in the combined therapy group and control group was 24.2 months and 15.30, respectively (P = 0.027). The median progression-free survival was 16.8 months and 7.30 months, respectively (P = 0.009). Overall, the incidence of adverse events leading to discontinuation of the study drug was similar between the treatment groups, except for infection, which was more common in the combined treatment group and required repeat surgery. CONCLUSIONS: The combined therapy showed higher efficacy compared with standard therapy in patients with GBM. Therefore, combined therapy seems to be effective with an acceptable toxicity profile. PMID- 29476997 TI - A Novel Anterior Revision Surgery for the Treatment of Cervical Ossification of Posterior Longitudinal Ligament: Case Report and Review of the Literature. AB - PURPOSE: A 62-year-old blind man with severe ossification of the posterior longitudinal ligament was presented. The patient underwent posterior laminectomy and fixation. After surgery, the patient was not satisfied with the recovery of his upper limbs although his Japanese Orthopedic Association (JOA) score had increased from 9 to 12 points. Because the tactile sensation of his hands was especially important to his daily life, the patient asked for further treatment after 6 months. This report describes the novel revision surgery we invented and the outcome in the patient after the surgery. METHODS: We performed the revision surgery using an anterior approach from C3 to C7 with a novel technique, anterior controllable antedisplacement and fusion (ACAF). The patient was followed up for 6 months. The clinical data, including JOA score and radiologic images, were collected and analyzed. RESULTS: After the revision surgery, the patient had improved sensation in both hands, and his JOA score increased to 14 points. Satisfactory decompression was assessed by magnetic resonance imaging after operation. Bone fusion was confirmed by computed tomography 3 months after operation. No specific complications related to this surgery were observed. CONCLUSIONS: The application of such an operative procedure in revision surgery for OPLL has not been reported earlier and might be an alternative choice for patients with an unsatisfactory outcome from previous posterior surgery. PMID- 29476998 TI - Improved Bone Graft Method for Upper Cervical Surgery with Posterior Approach: Technical Description and Report of 52 Cases. AB - PURPOSE: We sought to report a minimum 12 months' follow-up results of our improved bone graft method for upper cervical surgery with the posterior approach. METHODS: Among 52 consecutive cases, odontoid nonunion occurred in 33 patients, atlantoaxial instability in 11 patients, and occipitocervical deformity in 8 patients who underwent posterior C1-C2 transarticular screw/screw-rod internal fixation (41 cases) and occipitocervical fusion (11 cases) with the improved bone graft technique. Each surgical procedure was performed by the same senior spine surgeon. We took lateral cervical standing roentgenograms before surgery and immediately after surgery. Then we conducted craniocerebral computed tomography examination with reconstruction at 3, 6, 12, and 24 months and annually thereafter. The postoperative follow-up times are about 12-38 months. RESULTS: All cases showed satisfactory screw fixation by radiographic examination, and there were no postoperative neurologic complications. One case had postoperative retropharyngeal infection after the transoral release and posterior reduction by pedicle screw instrumentation. All patients got solid fusions, and no pseudarthrosis occurred. All cases had solid fusions at the 3 month follow-up. CONCLUSION: Good bone graft bed, enough bone graft material, solid local fixation, and effective bone graft method are prerequisites for a successful bone graft. By analyzing postoperative follow-up in the consecutive cases in this study, our bone graft method describing a new bone graft structure is a reliable posterior fusion technique. It is worth considering, and further research is needed. PMID- 29476999 TI - The Impact of Different Postgraduate Year Training in Neurosurgery Residency on 30-Day Return to Operating Room: A National Surgical Quality Improvement Program Study. AB - OBJECTIVE: Because of the health care initiative on quality improvement projects in academic medicine, this study explores the impact of different postgraduate years (PGYs) on unexpected re-operation rates. METHODS: Using the National Surgical Quality Improvement Program 2005-2014, adult neurosurgical cases were divided into subspecialties: spine, open vascular, cranial, and functional. Comparison groups were cases involving junior residents (PGY 1-PGY 3), mid-level residents (PGY 4 + PGY 5), and senior residents (PGY 6 + PGY 7). Comorbidity disease burden was measured by frailty index. The primary outcome measure was 30 day unintended return to the operating room. RESULTS: Of the 9782 cases, re operations were higher for those cases featuring a senior resident (5.6%) compared with mid-level resident (4.1%) and junior resident (3.8%) (P = 0.001). Although senior residents operated on patients with a statistically significantly higher neurologic disease burden, greater relative value units, longer operative times, and more 30-day postoperative adverse events, the level of resident training did not have an impact on revision surgery after multivariable logistical regression. The strongest predictors of return to the operating room included the frailty index (adjusted odds ratio [ORadj] = 5.18, P < 0.001), functional subspecialty (ORadj = 2.65, P < 0.001), and Wound Class 4 - dirty/infected wound (ORadj = 2.33, P = 0.016). CONCLUSIONS: Resident participation in neurosurgical cases does not affect 30-day unplanned re operation rates, which were affected by frailty index, functional subspecialty, and wound class. PMID- 29477000 TI - Bilateral Spontaneous Regression of Vestibular Schwannoma in Neurofibromatosis Type 2. AB - BACKGROUND: Patients with neurofibromatosis type 2 and bilateral vestibular schwannoma (VS) are frequently treated surgically for any tumor progression, and often repeated surgery or radiation treatment is even considered. Some VS progression occurs without the development of new clinical symptoms, or it does not progress in size over many years, even in the absence of any specific treatment. CASE DESCRIPTION: A 61-year-old male patient with neurofibromatosis type 2 presented with bilateral VS. In a long-term follow-up, both had increased in size but also showed bilateral spontaneous regression during an 11-year follow up period with a "watch-and-wait" strategy. CONCLUSIONS: We emphasize conservative treatment ("watch and wait") in older patients even with long-term tumor progression without significant compression-related clinical symptoms. PMID- 29477001 TI - Microvascular Decompression for Treatment of Trigeminal Neuralgia in Patient with Facial Nerve Schwannoma. AB - BACKGROUND: Secondary trigeminal neuralgia (TN) is uncommon. When a space occupying lesion with mass effect is identified, the associated TN is often exclusively attributed to the tumor. This report illustrates the importance of considering coexistent actionable pathology when surgically treating secondary TN. CASE DESCRIPTION: A 51-year-old woman presented with abrupt-onset TN of the V2 and V3 nerve divisions with hypesthesia. She denied changes in hearing, balance, or facial nerve dysfunction. Magnetic resonance imaging revealed a 1.6 cm contrast-enhancing cerebellopontine angle tumor that effaced the trigeminal nerve, consistent with a vestibular schwannoma. In addition, a branch of the superior cerebellar artery abutted the cisternal segment of the trigeminal nerve on T2-weighted thin-slice magnetic resonance imaging. Intraoperative electrical stimulation of the tumor elicited a response from the facial nerve at low threshold over the entire accessible tumor surface, indicating that the tumor was a facial nerve schwannoma. Considering the patient's lack of facial nerve deficit and that the tumor exhibited no safe entry point for intracapsular debulking, tumor resection was not performed. Working between the tumor and tentorium, a branch of the superior cerebellar artery was identified and decompressed with a Teflon pad. At last follow-up, the patient exhibited resolution of her TN. Her hearing and facial nerve function remained intact. CONCLUSIONS: Despite obstruction from a medium-sized tumor, it is still possible to achieve microvascular decompression of the fifth cranial nerve. This emphasizes the importance of considering other actionable pathology during surgical management of presumed tumor-induced TN. Further, TN is relatively uncommon with medium sized vestibular schwannomas and coexistent causes should be considered. PMID- 29477002 TI - Effect of Lumbar Lordosis on the Adjacent Segment in Transforaminal Lumbar Interbody Fusion: A Finite Element Analysis. AB - OBJECTIVE: We used a finite element (FE) analysis to investigate the biomechanical changes caused by transforaminal lumbar interbody fusion (TLIF) at the L4-L5 level by lumbar lordosis (LL) degree. METHODS: A lumbar FE model (L1 S5) was constructed based on computed tomography scans of a 30-year-old healthy male volunteer (pelvic incidence,= 50 degrees ; LL, 52 degrees ). We investigated the influence of LL on the biomechanical behavior of the lumbar spine after TLIF in L4-L5 fusion models with 57 degrees , 52 degrees , 47 degrees , and 40 degrees LL. The LL was defined as the angle between the superior end plate of L1 and the superior end plate of S1. A 150-N vertical axial preload was imposed on the superior surface of L3. A 10-N/m moment was simultaneously applied on the L3 superior surface along the radial direction to simulate the 4 basic physiologic motions of flexion, extension, lateral bending, and torsion in the numeric simulations. The range of motion (ROM) and intradiscal pressure (IDP) of L3-L4 were evaluated and compared in the simulated cases. RESULTS: In all motion patterns, the ROM and IDP were both increased after TLIF. In addition, the decrease in lordosis generally increased the ROM and IDP in all motion patterns. CONCLUSIONS: This FE analysis indicated that decreased spinal lordosis may evoke overstress of the adjacent segment and increase the risk of the pathologic development of adjacent segment degeneration; thus, adjacent segment degeneration should be considered when planning a spinal fusion procedure. PMID- 29477003 TI - Effects of Treatment of Cervical Spinal Cord Injury without Fracture and Dislocation in A Medium-to Long-Term Follow-Up Study. AB - OBJECTIVES: The purpose of this study is to evaluate the clinical effects of cervical spinal cord injury without fracture and dislocation (CSCIWFD) treatment in a medium-to long-term follow-up study. The clinical treatment of CSCIWFD is also discussed. METHODS: A consecutive series of 42 CSCIWFD patients with complete follow-up data were retrospectively analyzed. Among these patients, 9 received conservative treatment and 33 underwent surgical treatment from June 2009 to March 2013. Neurologic functional recovery was evaluated according to the Japanese Orthopaedic Association (JOA) scoring system and the Frankel grade on admission, during hospital discharge, and at final follow-up. The average follow up time was 49.6 months (range, 36-68 months). RESULTS: The 33 cases with surgical treatment showed significantly higher JOA scores at the final follow-up than those with conservative treatment. In addition, statistically significant differences were found in all of the follow-up visits between patients whose operations were performed within 7 days after injury and those performed after 7 days (P < 0.05). Early surgery promoted spinal cord recovery. However, JOA scores at 49.6 months postsurgery were not significantly different between patients treated via the anterior approach and those treated via the posterior approach (P > 0.05). On the basis of Frankel functional classification, differences were also significant between surgical treatment and conservative treatment at all of the follow-up visits. CONCLUSIONS: Early surgical treatment for CSCIWFD can directly relieve spinal cord compression. The medium-to long-term follow-up revealed that surgery clearly promotes decompression. PMID- 29477004 TI - Variations in Treatment of C2 Fractures by Time, Age, and Geographic Region in the United States: An Analysis of 4818 Patients. AB - BACKGROUND: The optimal form of treatment for C2 spine fractures is controversial. This investigation analyzed the variations in treatment of C2 fractures over time, by age group, and by geographic location. METHODS: The Nationwide Emergency Department Sample database was queried to identify patients 18 years and older who sustained C2 fracture without neurologic injury from 2006 to 2012. Subsequently, patients were further filtered based on the intervention they received: collar, halo, and surgery. Regions of hospital used in analysis were defined as Northeast, Midwest, South, and West. Linear regression models were used to analyze trends for C2 incidence rates and treatment type. Analysis of variance tests were used to determine differences among procedure groups when stratified by regions and age groups. RESULTS: Surgical intervention for C2 fracture increased from 36.5% in 2006 to 55.7% in 2012 (r = 0.116, P < 0.001). In contrast, the rate of halo use decreased from 57.8% in 2006 to 37.1% in 2012 (r = -0.139, P < 0.001). Surgery displayed increasing trend across all age groups. A greater proportion of patients in the Northeast were treated by collar compared with all other regions (P < 0.001). In contrast, halo use was significantly lower in the Northeast than the other 3 regions (P < 0.001). CONCLUSIONS: This investigation demonstrated that surgical management of C2 fractures is increasing in frequency over time and at all age groups. Furthermore, the treatment of these fractures varies by region-the Northeast had the highest incidence of collar use and lowest rate of halo use. PMID- 29477005 TI - Computed Tomography Cisternography for Evaluation of Trigeminal Neuralgia When Magnetic Resonance Imaging Is Contraindicated: Case Report and Review of the Literature. AB - BACKGROUND: Trigeminal neuralgia (TGN) causes severe unilateral facial pain. The etiology is hypothesized to be segmental demyelination of the trigeminal nerve root via compression by the superior cerebellar artery (SCA). Microvascular decompression (MVD) allows immediate and long-term pain relief. Preoperative evaluation includes magnetic resonance imaging (MRI) and/or magnetic resonance angiography of the brain. Having a pacemaker is a contraindication for MRI. There have been isolated reports of using computed tomography (CT) cisternography scans for radiation planning for TGN. CASE DESCRIPTION: A 75-year-old male with a permanent pacemaker who had refractory TGN in the V2 (maxillary) distribution of the trigeminal nerve underwent CT cisternography to prepare for MVD. CT angiography with Isovue 370 intravenous contrast injection and 0.625-mm axial images were obtained from the skull base across the posterior fossa. An intrathecal injection of Isovue 180 was performed at the L2/3 level. Imaging revealed the right SCA abutting the medial margin of the proximal right trigeminal nerve. In surgery (K.D.), a standard retrosigmoid suboccipital craniotomy was performed to access the cerebellopontine angle and separate the abutting SCA and trigeminal nerve. The patient had immediate pain relief. CONCLUSIONS: MRI is the preferred method of evaluating for TGN because it offers excellent visualization of vasculature in relation to the trigeminal nerve without accompanying radiation exposure. However, for patients who have contraindications to MRI, CT cisternography is shown to also be an effective method for visualizing the trigeminal root entry zone and nearby vasculature in preparation for MVD of the trigeminal nerve. PMID- 29477006 TI - Electronic Residency Application Service Application Characteristics Associated with Successful Residency Matching in Neurosurgery in 2009-2016. AB - BACKGROUND: Resident applicants in neurosurgery often wonder what factors impact their chances of successfully matching. Using data published by the National Residency Match Program for 2009-2016, we examined which components of the Electronic Residency Application Service application correlated with successful residency matching. METHODS: Data were collected from the National Residency Match Program publication Charting Outcomes in the Match from all years it was available for neurosurgery (2009, 2011, 2014, 2016). Individual factors reported (number of contiguous ranks, research projects, publications and presentations, work experiences, volunteer experiences, United States Medical Licensing Examination Step 1 and 2 score deciles, categorical data about Alpha Omega Alpha status, Ph.D. degree, other degree, and strength of medical school National Institutes of Health funding) were aggregated for all 3 years. Categorical data were available only for U.S. seniors. Spearman correlation and chi2 were used for ranked data and categorical data, respectively. Separate analyses were run for U.S. seniors and independent applicants. RESULTS: For U.S. seniors applying to neurosurgery, number of contiguous ranks, United States Medical Licensing Examination Step 1 and 2 scores, research projects, Alpha Omega Alpha status, and medical school top 40 National Institutes of Health funding were significantly associated with successful matching of applicants. Number of volunteer experiences was nearly statistically significant. For independent applicants, only United States Medical Licensing Examination Step 1 and 2 scores and number of research projects were statistically significant. CONCLUSIONS: This is the first study to analyze National Residency Match Program data for predictors of success in neurosurgical matching. Students applying to neurosurgery residency and their mentors should be aware of which baseline objective factors are associated with match success. PMID- 29477008 TI - Opening New Window in Upper Clival Region: Results from Anatomic Study. PMID- 29477007 TI - Genetic Variations of COL4A1 Gene and Intracerebral Hemorrhage Outcome: A Cohort Study in a Chinese Han Population. AB - OBJECTIVE: To investigate the relationship between single nucleotide polymorphisms or haplotypes of COL4A1 gene and the outcome of intracerebral hemorrhage (ICH). METHODS: In our study, 181 patients with hypertensive ICH were enrolled and followed up at 3 and 6 months. Outcome data included any cause of death and disability. Genomic DNA was extracted by DNA extraction kit, and the 6 single nucleotide polymorphism genotyping of the COL4A1 gene was detected through MassARRAY Analyzer. Unphased 3.1.4 and SPSS 19.0 were used to analyze the association between alleles, genotypes, and haplotypes of the COL4A1 gene and the outcomes of ICH. RESULTS: Of the 181 patients with hypertensive ICH, 12 were lost in follow-up, which accounted for 6.6%. Our association analysis showed that the rs532625 AA genotype of the COL4A1 gene may increase risk of disability at 3 months; the rs532625 A allele and AA genotype were association factors of the risk of disability at 6 months; the rs532625 AA genotype was an association factor of the risk of death/disability at 6 months. After adjusting for gender, age, coma, and severe neurologic deficits, only the rs532625 AA genotype was independently associated with the risk of disability at 3 and 6 months and the risk of death/disability at 6 months. CONCLUSIONS: Our study found that the rs532625 AA genotype in the COL4A1 gene was independently associated with the risk of disability at 3 and 6 months and death/disability at 6 months in a Chinese Han population. These conclusions need to be verified in future studies with larger samples. PMID- 29477009 TI - Converging operations and the role of perceptual and decisional influences on the perception of faces: Neural and behavioral evidence. AB - Theoretical analyses suggest that the regularities indicative of holistic processing can be obtained by combinations of perceptual and decisional factors. Kuefner and colleagues used electrophysiological results to suggest that the composite face effect is driven solely by perceptual factors. Two limitations of their approach are (a) it did not involve behavioral measures of perceptual sensitivity or bias, and (b) it is unclear how the measures used in that study are consistent with other measures of perceptual and decisional processing. Eight observers completed three tasks involving the stimuli used by Kuefner et al.. The first was a direct replication. The second was a complete identification task, associated with the perceptual and decisional distinctions formalized in general recognition theory. The third was an implementation of the Eriksen fianker task, which allows for a pattern of results that have been interpreted in terms of perceptual and decisional influences. While the empirical distinctions used by Kuefner et al. were not consistent with either the EEG data from the other tasks or the established behavioral measures of perceptual sensitivity and decisional bias, the inferences drawn from the EEG and behavioral data from those tasks were consistent with one another, underscoring the importance of converging operations. PMID- 29477010 TI - Impaired detection and differentiation of briefly presented facial emotions in adults with high-functioning autism and asperger syndrome. AB - Although deficits in the recognition of emotional facial expressions are considered a hallmark of autism spectrum disorder (ASD), characterization of abnormalities in the differentiation of emotional expressions (e.g., sad vs. angry) has been rather inconsistent, especially in adults without intellectual impairments who may compensate for their deficits. In addition, previous research neglected the ability to detect emotional expressions (e.g., angry vs. neutral). The present study used a backward masking paradigm to investigate, a) the detection of emotional expressions, and b) the differentiation of emotional expressions in adults diagnosed with high functioning autism or Asperger syndrome (n = 23) compared to neurotypical controls (n = 25). Compensatory strategies were prevented by shortening the stimulus presentation time (33, 67, and 100 ms). In general, participants with ASD were significantly less accurate in detecting and differentiating emotional expressions compared to the control group. In the emotion differentiation task, individuals with ASD profited significantly less from an increase in presentation time. These results reinforce theoretical models that individuals with ASD have deficits in emotion recognition under time constraints. Furthermore, first evidence was provided that emotion detection and emotion differentiation are impaired in ASD. PMID- 29477011 TI - Adapting a memory fMRI research protocol in clinical routine: Feasibility and results. AB - OBJECTIVE: The objective of this study was to test the reliability of functional magnetic resonance imaging (fMRI) evaluation of memory function in clinical practice to predict postoperative memory decline in patients with refractory medial temporal lobe epilepsy (MTLE) candidate to surgery. METHODS: Twenty-six consecutive patients with MTLE who underwent a complete presurgical evaluation were included. All patients underwent fMRI memory study and complete neuropsychological assessment. Lesions consisted in hippocampal sclerosis in 18 patients (12 right and 6 left), dysembryoplastic neuroepithelial tumor (DNET) in 5 cases (4 right, 1 left), epidermoid cyst in one patient (right). Two patients had no lesion (2 left). RESULTS: Nineteen patients (73%) underwent surgery. The other seven patients (27%) declined surgery, mainly because of the risk of memory deficit. The fMRI procedure correctly predicted both verbal and nonverbal memory postoperative outcome in 13 of the patients (72%), failed to predict a postoperative memory worsening in only two patients (12%), and predicted worsening in three patients (17%) that remained stable (versus 44%, 39%, and 17% with the sole neuropsychological testing). The reliability of the fMRI procedure was not influenced by the type of lesion, the side of the epileptic focus, or the type of preoperative memory profile (typical or atypical). SIGNIFICANCE: Appearing as a valuable clinical tool to predict postoperative memory outcome, fMRI may add information over and above other available tests. PMID- 29477012 TI - Treg and NK cells related cytokines are associated with deep rectosigmoid endometriosis and clinical symptoms related to the disease. AB - The aim of this study was to evaluate Treg and NK cells related cytokines in deep infiltrating endometriosis lesions and its relationship with clinical symptoms of the disease. mRNA expression of Transforming Growth Factor Beta (TGFB), Interleukin (IL)10, Interferon Gamma (IFNG), IL7, and IL15 was analyzed by Real Time PCR in eutopic endometrium and rectosigmoid lesions from 11 women with deep infiltrating endometriosis and in eutopic endometrium from 11 healthy women. IL10, IFNG, and IL7 expression was significantly higher in endometriotic bowel lesions than in eutopic endometrium from women with endometriosis. IL10 and TGFB expression was significantly higher in endometriotic bowel lesions than in eutopic endometrium from healthy women. In addition, TGFB and IL15 levels correlated positively with deep dyspareunia and cyclic dyschezia, respectively, while IL7 levels correlated negatively with dysmenorrhea. Deep infiltrating rectosigmoid endometriosis displays alterations in Treg and NK cells related cytokine, and TGFB, IL7 and IL15 expression is related with dyspareunia, dysmenorrhea and cyclic dyschezia, respectively, in patients with the disease. PMID- 29477013 TI - Maternal and child human leukocyte antigens in congenital cytomegalovirus infection. AB - Congenital Cytomegalovirus infection (cCMV) is the most common cause of congenital infections worldwide causing permanent long-term impairment (LTI). cCMV immunopathogenesis remains largely unknown due to the complex interplay between viral, maternal, placental and child factors. The aim of this study was to determine the possible role of particular HLA antigens, of the number of HLA mismatches (mm) and non-inherited maternal antigens (NIMAs) in a large retrospective nation-wide cohort of children with cCMV and their mothers. HLA Class I (HLA-A, HLA-B and HLA-C) and HLA Class II (HLA-DR and HLA-DQ) were assessed in 96 mother-child pairs in relation to a control group of 5604 Dutch blood donors, but no significant differences were observed. Next, although these HLA antigens could not be assessed in relation to symptoms at birth, nor to LTI, due to the low number of cases, they could be evaluated in relation to CMV viral load. HLA-DRB1*04, and potentially HLA-B*51, was shown to have a protective role in the children as its frequency was increased in the low viral load group compared to the high viral load group, and this remained significant after correction. The number of HLA mm and of NIMAs were not associated to symptoms at birth nor to LTI or viral load. In conclusion, although none of the HLA alleles could be put forward as prognostic marker for long-term outcome, our findings give useful insights into cCMV pathogenesis, and identify potential HLAs that correlate with a better viral control. PMID- 29477014 TI - Glial cell line-derived neurotrophic factor supplementation promotes bovine in vitro oocyte maturation and early embryo development. AB - Paracrine factors such as glial cell line-derived neurotrophic factor (GDNF), which was originally derived from the supernatants of a rat glioma cell line, play pivotal roles in oocyte maturation and early embryo development in mammals, such as mice, rats, pigs, sheep, and even humans. However, whether GDNF facilitates in vitro oocyte maturation or early embryo development in bovines is not yet known. We show for the first time that GDNF and its receptor, GDNF family receptor alpha-1 (GFRA1), are presented in ovarian follicles at different stages as well as during oocyte maturation and early embryo development. Immunostaining results revealed the subcellular localizations of GDNF and GFRA1 in oocytes throughout follicle development, first in germinal vesicles and during blastocyst embryo stages. The ability of exogenously applied GDNF to promote oocyte maturation and early embryo development was evaluated in culture, where we found that an optimal concentration of 50 ng/mL promotes the maturation of cumulus oocyte complexes and the nuclei of denuded oocytes as well as the development of embryos after IVF. To further investigate the potential mechanism by which GDNF promotes oocyte maturation, bovine oocytes were treated with morpholinos targeting Gfra1. The suppression of GFRA1 presence blocked endogenous and exogenous GDNF functions, indicating that the effects of GDNF that are essential and beneficial for bovine oocyte maturation and early embryo development occur through this receptor. Furthermore, we show that supplementation with GDNF improves the efficiency of bovine IVF embryo production. PMID- 29477015 TI - Emotion differentiation mediates the association between emotion regulation difficulties and caloric intake. AB - Emotion differentiation is the ability to identify and label emotional experiences into discrete categories. The present study examined the influence of emotion regulation difficulties, emotion differentiation, and emotional state specifically sad versus positive mood-on caloric intake in a laboratory setting. Undergraduate participants completed a series of questionnaires, including measures of emotion regulation difficulties and emotion differentiation, and then underwent a randomly assigned sad or positive mood induction. Afterwards, they participated in a taste test. Food was counted before and after the taste test to determine total caloric intake. Results showed that negative emotion differentiation was significantly inversely associated with overall caloric intake, such that low negative emotion differentiators ate more regardless of mood induction group. Positive emotion differentiation was not associated with caloric intake. Additional analysis found that negative emotion differentiation mediated the relation between emotion regulation difficulties and caloric intake. An alternative model found that emotion regulation difficulties did not mediate the relation between negative emotion differentiation and caloric intake. Our results suggest that reducing caloric intake among individuals with emotion regulation difficulties may involve incorporating strategies to specifically target the ability to differentiate between emotions. PMID- 29477016 TI - The unique effects of angry and depressive rumination on eating-disorder psychopathology and the mediating role of impulsivity. AB - Negative affect and maladaptive emotion regulation strategies are associated with eating-disorder (ED) psychopathology. Depressive rumination is a maladaptive cognitive style associated with the onset, maintenance, and severity of ED psychopathology among both clinical and nonclinical samples. However, although anger is also strongly associated with ED behaviors, the associations between angry rumination and ED psychopathology, as well as mechanisms of the relationships between rumination and ED psychopathology, remain largely unknown. The current study sought to examine the unique influences of trait depressive and angry rumination on ED psychopathology and whether trait negative urgency (i.e., responding rashly to negative affect) mediated these relationships. Study 1 sampled undergraduate students (N = 119) cross-sectionally and longitudinally (five months), and Study 2 sampled patients with eating disorders (N = 85). All participants completed questionnaires assessing angry rumination, depressive rumination, ED psychopathology, and negative urgency. Angry rumination had consistent indirect effects on ED psychopathology via negative urgency among both clinical and nonclinical samples. However, there was mixed support for the influence of depressive rumination: whereas depressive rumination showed total and indirect effects on ED psychopathology in Study 1 cross-sectional analyses, no total or indirect effects emerged in Study 1 longitudinal analyses or in Study 2. Associations between depressive rumination and ED psychopathology may reflect the strong overlap between angry and depressive rumination. Interventions targeting angry rumination and negative urgency may enhance prevention and treatment of disordered eating across eating disorder diagnosis and severity. PMID- 29477017 TI - Long-term trends and health impact of PM2.5 and O3 in Tehran, Iran, 2006-2015. AB - The main objectives of this study were (1) investigation of the temporal variations of ambient fine particulate matter (PM2.5) and ground level ozone (O3) concentrations in Tehran megacity, the capital and most populous city in Iran, over a 10-year period from 2006 to 2015, and (2) estimation of their long-term health effects including all-cause and cause-specific mortality. For the first goal, the data of PM2.5 and O3 concentrations, measured at 21 regulatory monitoring network stations in Tehran, were obtained and the temporal trends were investigated. The health impact assessment of PM2.5 and O3 was performed using the World Health Organization (WHO) AirQ+ software updated in 2016 by WHO European Centre for Environment and Health. Local baseline incidences in Tehran level were used to better reveal the health effects associated with PM2.5 and O3. Our study showed that over 2006-2015, annual mean concentrations of PM2.5 and O3 varied from 24.7 to 38.8 MUg m-3 and 35.4 to 76.0 MUg m-3, respectively, and were significantly declining in the recent 6 years (2010-2015) for PM2.5 and 8 years (2008-2015) for O3. However, Tehran citizens were exposed to concentrations of annual PM2.5 exceeding the WHO air quality guideline (WHO AQG) (10 MUg m-3), U.S. EPA and Iranian standard levels (12 MUg m-3) during entire study period. We estimated that long-term exposure to ambient PM2.5 contributed to between 24.5% and 36.2% of mortality from cerebrovascular disease (stroke), 19.8% and 24.1% from ischemic heart disease (IHD), 13.6% and 19.2% from lung cancer (LC), 10.7% and 15.3% from chronic obstructive pulmonary disease (COPD), 15.0% and 25.2% from acute lower respiratory infection (ALRI), and 7.6% and 11.3% from all-cause annual mortality in the time period. We further estimated that deaths from IHD accounted for most of mortality attributable to long-term exposure to PM2.5. The years of life lost (YLL) attributable to PM2.5 was estimated to vary from 67,970 to 106,706 during the study period. In addition, long-term exposure to O3 was estimated to be responsible for 0.9% to 2.3% of mortality from respiratory diseases. Overall, long-term exposure to ambient PM2.5 and O3 contributed substantially to mortality in Tehran megacity. Air pollution is a modifiable risk factor. Appropriate sustainable control policies are recommended to protect public health. PMID- 29477018 TI - Issues about the findings in the Silver et al. (2017) publication regarding Naled. PMID- 29477019 TI - Dependence of future mortality changes on global CO2 concentrations: A review. AB - The heterogeneity among previous studies of future mortality projections due to climate change has often hindered comparisons and syntheses of resulting impacts. To address this challenge, the present study introduced a novel method to normalize the results from projection studies according to different baseline and projection periods and climate scenarios, thereby facilitating comparison and synthesis. This study reviewed the 15 previous studies involving projected climate change-related mortality under Representative Concentration Pathways. To synthesize their results, we first reviewed the important study design elements that affected the reported results in previous studies. Then, we normalized the reported results by CO2 concentration in order to eliminate the effects of the baseline period, projection period, and climate scenario choices. For twenty-five locations worldwide, the normalized percentage changes in temperature attributable mortality per 100 ppm increase in global CO2 concentrations ranged between 41.9% and 330%, whereas those of total mortality ranged between 0.3% and 4.8%. The normalization methods presented in this work will guide future studies to provide their results in a normalized format and facilitate research synthesis to reinforce our understanding on the risk of climate change. PMID- 29477020 TI - Autonomy declared by primary cilia through compartmentalization of membrane phosphoinositides. AB - The primary cilium is a cell surface projection from plasma membrane which transduces external stimuli to diverse signaling pathways. To function as an independent signaling organelle, the molecular composition of the ciliary membrane has to be distinct from that of the plasma membrane. Here, we review recent findings which have deepened our understanding of the unique yet dynamic phosphoinositide profile found in the primary cilia. PMID- 29477021 TI - Factors associated with excessive sitting time in multiple sclerosis. AB - OBJECTIVE: The objective of this study was to examine the sociodemographic, clinical, and behavioral factors associated with excessive sitting time in persons with multiple sclerosis (MS). METHODS: Useful data were obtained from 6483 persons with MS who completed the semi-annual survey of the North American Research Committee on Multiple Sclerosis registry conducted in the spring of 2015. Sociodemographic, clinical, and behavioral data were collected using self report questionnaires. Sitting time per day was determined using the International Physical Activity Questionnaire. We conducted data analyses in May June 2017 and defined those classified above the 75th percentile of sitting time as excessive sitters. Multivariate binary logistic regression was used to calculate the odds ratios for being an excessive sitter for sociodemographic, clinical, and behavioral variables. RESULTS: The results indicated that participants who were moderately disabled, severely disabled but ambulatory, or severely disabled but non-ambulatory were 1.57, 2.62, and 8.70 times more likely to be excessive sitters than those reporting mild disability. Persons with MS who were insufficiently active were 2.61 times more likely to be excessive sitters than persons who were sufficiently active. CONCLUSION: This study identified disability status and physical activity levels as two prominent factors associated with the likelihood of being an excessive sitter in MS and this will inform the design of future interventions for reducing sedentary behavior in this population. PMID- 29477022 TI - Marine microbes in 4D-using time series observation to assess the dynamics of the ocean microbiome and its links to ocean health. AB - Microbial observation is of high relevance in assessing marine phenomena of scientific and societal concern including ocean productivity, harmful algal blooms, and pathogen exposure. However, we have yet to realise its potential to coherently and comprehensively report on global ocean status. The ability of satellites to monitor the distribution of phytoplankton has transformed our appreciation of microbes as the foundation of key ecosystem services; however, more in-depth understanding of microbial dynamics is needed to fully assess natural and anthropogenically induced variation in ocean ecosystems. While this first synthesis shows that notable efforts exist, vast regions such as the ocean depths, the open ocean, the polar oceans, and most of the Southern Hemisphere lack consistent observation. To secure a coordinated future for a global microbial observing system, existing long-term efforts must be better networked to generate shared bioindicators of the Global Ocean's state and health. PMID- 29477023 TI - Iron overload in lower international prognostic scoring system risk patients with myelodysplastic syndrome receiving red blood cell transfusions: Relation to infections and possible benefit of iron chelation therapy. AB - BACKGROUND: An increased incidence of infections and infectious mortality has been reported in myelodysplastic syndromes (MDS) patients receiving red blood cell (RBC) transfusions. METHODS: We examined incidence of infections requiring antibiotics, antifungal or antiviral medications in transfused lower International Prognostic Scoring System (IPSS) risk MDS patients and whether this differed with iron chelation therapy (ICT). RESULTS: 138 transfused MDS patients were lower IPSS risk. 59 received ICT; median duration was 13 months. There was no significant difference between groups in neutrophil count at first RBC transfusion or first infection. Infections included: bacterial, n = 88; viral; fungal; and mycobacterial; n = 2 each. In ICT and non-ICT patients, respectively, infections were (number [%]): patients, 23 (40.0%) and 22 (27.8%); episodes (median [range]), 2 (1-6) and 2 (1-5); hospitalizations, 16 (27.1%) and 8 (10.1%); and deaths, 0 (0%) and 1 (1.3%), p = NS for all. Median overall survival (OS) from first RBC transfusion was superior in ICT patients, p = 0.01, and remained significant in a multivariate analysis (MVA), p = 0.003. Median time to first infection (TTI) was 27 and 7.8 months, respectively, p < 0.0001, and ICT remained significant for TTI in an MVA, p = 0.02, hazard ratio 0.3. For ICT patients with blast count <5%, TTI was significantly superior (p = 0.004). CONCLUSIONS: In this retrospective analysis, for lower IPSS risk MDS patients receiving RBC transfusions, though number and type of infections were similar between groups and despite similar neutrophil counts, time to first infection was significantly longer in ICT patients (p < 0.0001). These results should be confirmed in larger, prospective analyses. PMID- 29477024 TI - The impact of the neutrophil:lymphocyte ratio in response and survival of patients with de novo diffuse large B-cell lymphoma. AB - The neutrophil:lymphocyte ratio (NLR) has emerged as prognostic in patients with hematological malignancies. We aimed at evaluating the NLR as predictive for complete response (CR) and prognostic for progression-free (PFS) and overall survival (OS) in a study cohort of 121 Peruvian patients with diffuse large B cell lymphoma (DLCBL) treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Patients with an NLR >=6 (n = 28) were more likely to have a performance status ECOG >=2 (74% vs. 23%; p < 0.001). NLR >=6 was associated with lower CR rate to R-CHOP (46% vs. 74%; p = 0.02) and there was a trend towards significance in multivariate regression analyses (OR 0.36, 95% CI 0.11-1.00; p = 0.05). Patients with NLR >=6 had lower 5-year PFS rate (39% vs. 72%; p < 0.001) and lower 5-year OS rate (46% vs. 75%; p = 0.001) than patients with NLR <6 and was an independent adverse factor for PFS (HR 2.43, 95% CI 1.21 4.87; p = 0.01) and OS (HR 2.68, 95% CI 1.31-5.47; p = 0.007) in multivariate Cox regression analyses. NLR >=6 was prognostic of PFS and OS after adjusting for the International Prognostic Index and the NCCN-IPI scores. In conclusion, the NLR could add predictive and prognostic value to well established prognostic tools in DLBCL. PMID- 29477025 TI - Stability and efficacy of combined nystatin and chlorhexidine against suspensions and biofilms of Candida albicans. AB - OBJECTIVE: Nystatin and chlorhexidine are extensively used in oral medicine; however, there is some controversy about the possibility of these drugs showing antagonism. To clarify this issue, this study investigated the efficacy and stability of nystatin and chlorhexidine in combination. DESIGN: An in vitro study was conducted to analyze the effect of nystatin and chlorhexidine combined on Candida albicans ATCC 18804, using the drugs mixed as a single formulation and as independent formulations used sequentially with different time intervals between them. The minimum inhibitory concentration (MIC) and effects on C. albicans suspensions and biofilms were evaluated. Also, the stability of nystatin and chlorhexidine in a mixture was tested by high performance liquid chromatography (HPLC). RESULTS: When nystatin and chlorhexidine were mixed in a single formulation, there was no significant difference in MIC compared to that of the drugs used alone (as the only treatment). However, when these drugs were used as independent formulations, sequentially with time intervals in between, their MICs were higher than the respective MIC of the drug used alone, except for the MIC of chlorhexidine with a 10-min interval. Nystatin/chlorhexidine combinations showed lower activity against C. albicans biofilms, except for that with a 30-min interval. The drugs when combined showed high percentages of degradation at all the times evaluated. CONCLUSIONS: The combination of nystatin and chlorhexidine seems to interfere with the efficacy of the drugs and to increase their rate of degradation. PMID- 29477026 TI - A case series of closed head trauma with pituitary stalk disruption resulting in hypopituitarism. AB - INTRODUCTION: Traumatic brain injury (TBI) is one of the main causes of morbidity and mortality in young trauma patients with resultant multi-organ effects. Hypopituitarism following TBI can be debilitating and life threatening. TBI which causes hypopituitarism may be characterized by a single head injury, such as from a motor vehicle accident, or by chronic repetitive head trauma, as seen in combative supports including boxing, kick-boxing, and football. In the majority of cases, a diagnosis of hypopituitarism can be entirely missed resulting in severe neuro-endocrine dysfunction. We present a case series of two patients diagnosed with hypopituitarism after TBI and treated appropriately with favorable outcome. CASE PRESENTATIONS: The first case is a 34 year-old male, who presented to the emergency department with blunt head trauma after a motor vehicle accident while riding his bicycle. He suffered from severe cranio-facial injuries, resulting in multifocal hemorrhagic contusions, epidural hematoma, and extensive cranio-facial fractures involving the sinuses. The patient developed persistent hypotension with a blood pressure as low as 60/40 mmHg on hospital day three. The second case is a 56 year-old male with a history of schizophrenia, who suffered traumatic brain injury after he was hit by a train. The patient sustained multiple facial fractures, pneumocephalus and C2/7 transverse processes fractures. He also had persistent hypotension, unresponsive to standard treatment. Investigation revealed a deficiency of anterior pituitary hormones resulting from pituitary axis disruption. DISCUSSION: Hypopituitarism is becoming an increasingly recognized complication following TBI, ranging from total to isolated deficiencies. Traumatic Brain Injury is a major public health problem and is one of the leading causes of disability. Understanding and recognizing pituitary dysfunction after TBI can lead to better outcomes and improved quality of life. CONCLUSION: Patients with major head injury and, in particular, those with fractures of the base of the skull, must be closely monitored for signs and symptoms of endocrine dysfunction. Appropriate dynamic pituitary-function screening should be performed. PMID- 29477027 TI - Strength and fracture mechanism of iron reinforced tricalcium phosphate cermet fabricated by spark plasma sintering. AB - The present work studies the microstructure and mechanical performance of tricalcium phosphate (TCP) based cermet toughened by iron particles. A novelty arises by the employment of spark plasma sintering for fabrication of the cermet. Results showed partial transformation of initial alpha TCP matrix to beta phase and the absence of oxidation of iron particles, as well as a lack of chemical reaction between TCP and iron components during sintering. The values of compressive and tensile strength of TCP/Fe cermet were 3.2 and 2.5 times, respectively, greater than those of monolithic TCP. Fracture analysis revealed the simultaneous action of crack-bridging and crack-deflection microstructural toughening mechanisms under compression. In contrast, under tension the reinforcing mechanism was only crack-bridging, being the reason for smaller increment of strength. Elastic properties of the cermet better matched values reported for human cortical bone. Thereby the new TCP/Fe cermet has potential for eventual use as a material for bone fractures fixation under load-bearing conditions. PMID- 29477028 TI - Metabolic heterogeneity in clonal microbial populations. AB - In the past decades, numerous instances of phenotypic diversity were observed in clonal microbial populations, particularly, on the gene expression level. Much less is, however, known about phenotypic differences that occur on the level of metabolism. This is likely explained by the fact that experimental tools probing metabolism of single cells are still at an early stage of development. Here, we review recent exciting discoveries that point out different causes for metabolic heterogeneity within clonal microbial populations. These causes range from ecological factors and cell-inherent dynamics in constant environments to molecular noise in gene expression that propagates into metabolism. Furthermore, we provide an overview of current methods to quantify the levels of metabolites and biomass components in single cells. PMID- 29477029 TI - Corrigendum to "Hippocampus and amygdala volumes from magnetic resonance images in children: Assessing accuracy of FreeSurfer and FSL against manual segmentation"[NeuroImage 129 (2016) 1-14]. PMID- 29477030 TI - Association between alcoholism and the gene encoding the endocannabinoid synthesizing enzyme diacylglycerol lipase alpha in the Japanese population. AB - The endocannabinoid system has been recognized to be involved in neuropsychiatric diseases. 2-arachidonoyl glycerol (2-AG) is one of the two main endocannabinoids, and their regulation could play roles in disorders under environmental influence. This study investigated the involvement of the 2-AG biosynthesizing enzyme diacylglycerol lipase alpha (DAGLA) in the pathogenesis of alcoholism. We investigated a possible association between alcoholism and single nucleotide polymorphisms (SNPs) of the human DAGLA gene in the Japanese population. To discern any environmental influences on Dagla function in an animal study, the Dagla gene expression in the brain from stressed model mice was analyzed. The SNPs, including missense polymorphism Pro899Leu in the DAGLA gene, showed associations with alcoholism in the Japanese population. Dagla expression in mice was found to be influenced by chronic mild stress and by the acquisition of alcohol preference. Our findings indicated the involvement of DAGLA in alcoholism, possibly by its genetic dysfunction and also by the influence of stress. PMID- 29477031 TI - Follow-up with computed tomography after spontaneous isolated dissection of the splanchnic artery. AB - The aim of this study was to evaluate radiological changes after spontaneous isolated dissection of the superior mesenteric artery (SIDSMA) and spontaneous isolated dissection of the celiac artery (SIDCA) using computed tomography (CT). This single-center retrospective study was approved by the hospital institutional review board. We reviewed the medical records and morphological CT findings of 33 consecutive patients with SIDSMA or SIDCA who were diagnosed between January 2001 and February 2016. We analyzed changes on follow-up CT images including length of the dissection, presence of a thrombus in the false lumen, maximal outer diameter, degree of luminal stenosis, patency of distal flow, and end-organ injury. We classified short-term (within the first week) and long-term (between the first week and sixth month) follow-up groups and analyzed differences in radiological changes over time using Wilcoxon signed-rank tests (continuous variables) and Fisher exact probability tests (categorical variables). Additionally, we examined patients who completed follow-up CT within 3 days after symptomatic changes. Comparing initial and final CT findings, a majority of patients with SIDSMA and SIDCA showed no significant changes in most CT parameters, including dissection length, thrombus presence, dissection diameter, stenosis degree, and extended distal branch. Between the short-term and long-term CT follow-up groups, there were no significant differences in radiological changes except for in the degree of luminal stenosis at the dissected segment in SIDSMA (P = 0.043). Only 10 patients completed follow-up CT within 3 days after symptomatic changes (progression or regression); of these, 1 patient had radiological findings that matched symptom progression, showing an increase in the degree of luminal stenosis and end-organ injury. There was no splanchnic artery dissection-related mortality, symptom progression, or event recurrence. In conclusion, CT follow-up of SIDSMA and SIDCA was mainly useful in the acute phase of dissection, with no significant radiological changes occurring in the long term. Accordingly, we question the utility of long-term follow-up CT after spontaneous isolated arterial dissection, especially in the absence of symptom progression. PMID- 29477032 TI - 3D-3-culture: A tool to unveil macrophage plasticity in the tumour microenvironment. AB - The tumour microenvironment (TME) shapes disease progression and influences therapeutic response. Most aggressive solid tumours have high levels of myeloid cell infiltration, namely tumour associated macrophages (TAM). Recapitulation of the interaction between the different cellular players of the TME, along with the extracellular matrix (ECM), is critical for understanding the mechanisms underlying disease progression. This particularly holds true for prediction of therapeutic response(s) to standard therapies and interrogation of efficacy of TME-targeting agents. In this work, we explored a culture platform based on alginate microencapsulation and stirred culture systems to develop the 3D-3 culture, which entails the co-culture of tumour cell spheroids of non-small cell lung carcinoma (NSCLC), cancer associated fibroblasts (CAF) and monocytes. We demonstrate that the 3D-3-culture recreates an invasive and immunosuppressive TME, with accumulation of cytokines/chemokines (IL4, IL10, IL13, CCL22, CCL24, CXCL1), ECM elements (collagen type I, IV and fibronectin) and matrix metalloproteinases (MMP1/9), supporting cell migration and promoting cell-cell interactions within the alginate microcapsules. Importantly, we show that both the monocytic cell line THP-1 and peripheral blood-derived monocytes infiltrate the tumour tissue and transpolarize into an M2-like macrophage phenotype expressing CD68, CD163 and CD206, resembling the TAM phenotype in NSCLC. The 3D-3 culture was challenged with chemo- and immunotherapeutic agents and the response to therapy was assessed in each cellular component. Specifically, the macrophage phenotype was modulated upon treatment with the CSF1R inhibitor BLZ945, resulting in a decrease of the M2-like macrophages. In conclusion, the crosstalk between the ECM and tumour, stromal and immune cells in microencapsulated 3D-3-culture promotes the activation of monocytes into TAM, mimicking aggressive tumour stages. The 3D-3-culture constitutes a novel tool to study tumour-immune interaction and macrophage plasticity in response to external stimuli, such as chemotherapeutic and immunomodulatory drugs. PMID- 29477033 TI - Involvement of thromboxane A2 in interleukin-31-induced itch-associated response in mice. AB - BACKGROUND: Atopic dermatitis is a chronic and severe pruritic skin disease. Interlukin-31 (IL-31) has been recently demonstrated to be one of the key pruritogens in atopic dermatitis. However, the mechanisms underlying IL-31 induced itching remains unclear. In our previous study, we have shown that thromboxane (TX) A2 is involved in itch-associated responses in mice with atopy like skin diseases. METHODS: IL-31 was given intradermally into the rostral back of ICR mice and the hind-paw scratching to the injection site were counted. Expression of TX synthase and IL-31 receptors were analyzed using immunohistochemical staining or RT-PCR in mouse skin or primary cultures of mouse keratinocytes. The concentration of TXB2, a metabolite of TXA2, in the skin and the culture medium of primary cultures of mouse keratinocytes was measured using enzyme immunoassay. The concentration of intracellular Ca2+ ions in mouse keratinocytes was measured using the calcium imaging method. RESULTS: An intradermal injection of IL-31 elicited scratching, an itch-related response, in mice. The scratching was inhibited by TP TXA2 receptor antagonist DCHCH. The distribution of TX synthase and IL-31RA receptor was mainly epidermal keratinocytes in the skin. The primary cultures of keratinocytes expressed the mRNAs of TX synthase and IL-31 receptors. IL-31 increased the concentration of TXB2, which was inhibited by TX synthase inhibitor sodium ozagrel and EGTA, in the skin and the culture medium of primary cultures of keratinocytes. IL-31 increased the concentration of intracellular Ca2+ ions in mouse keratinocytes. CONCLUSION: It is suggested that IL-31 elicits itch-associated responses through TXA2 produced from keratinocytes. PMID- 29477034 TI - Alpinumisoflavone rescues glucocorticoid-induced apoptosis of osteocytes via suppressing Nox2-dependent ROS generation. AB - BACKGROUND: Long term use of glucocorticoids is one of the most common causes of secondary osteoporosis. Osteocyte, the most abundant cell type in bone, coordinates the function of osteoblast and osteoclast. This study evaluates the protective effect of alpinumisoflavone (AIF), a naturally occurring flavonoid compound, on dexamethasone (Dex)-induced apoptosis of osteocytes. METHODS: MLO-Y4 cell was used as a cell model. The effect of AIF on the cell viability was assessed by MTT assay. Apoptosis of MYL-Y4 cells was determined by DNA fragment detection ELISA kit and flow cytometry. Intracellular ROS level was determined by DCFH-DA staining. mRNA and protein expression of target genes were determined by qRT-PCR and western blot, respectively. RESULTS: AIF effectively protected MLO-Y4 cells against Dex-induced apoptosis, which was associated with attenuation of Dex induced ROS generation in MLO-Y4 cells. Furthermore, our data indicated that the expression of NAD(P)H oxidase 2 (Nox2) was suppressed by AIF, which in turn mediated the attenuating effect on Dex-induced ROS generation and apoptosis in MLO-Y4 cells. Moreover, our results showed that AIF modulated the expression of Nox2 by activating AMPK signaling. CONCLUSION: AIF activated AMPK-dependent Nox2 signaling pathway to suppress Dex-induced ROS production in cultured osteocytes, which might explain its anti-apoptotic effect. These results indicate that activation of AMPK pathway by AIF could have beneficial effects on bone damage induced by excessive oxidative stress and osteocyte apoptosis. PMID- 29477035 TI - Quinaldic acid in synovial fluid of patients with rheumatoid arthritis and osteoarthritis and its effect on synoviocytes in vitro. AB - BACKGROUND: Previously, we have demonstrated that kynurenic acid (KYNA), an endogenous metabolite of tryptophan formed along kynurenine pathway, is present in synovial fluid of rheumatoid arthritis (RA) and osteoarthritis (OA) patients. In this study, the goal was to investigate the presence of quinaldic acid (QUDA), a putative metabolite of KYNA, in synovial fluid of RA and OA patients. METHODS: The effect of QUDA on proliferation and motility of synovial fibroblasts and its interaction with KYNA were determined in vitro. The study was conducted on synovial fluid obtained from 38 patients with RA and 15 patients with OA. QUDA was identified and quantified using the gas chromatography-mass spectrometry (GC MS) method. In vitro experiments were conducted on rabbit synoviocyte cell line HIG-82. RESULTS: Presence of QUDA was detected in all 53 samples of synovial fluid. The concentration of QUDA in synovial fluid obtained from patients with RA was 28.6 +/- 14.9 pmol/ml, which was lower in comparison with OA 42.3 +/- 10.0 pmol/ml. QUDA content positively correlated with the number of tender joints and negatively with the total cell counts determined in synovial fluid of RA patients. It did not correlate with KYNA content. QUDA reduced both proliferation and motility of synoviocytes in a dose-dependent manner. The enhancement of antiproliferative action of QUDA by KYNA was evidenced. CONCLUSIONS: Data show a local deficit of QUDA in RA patients and suggest its potential role as an endogenous substance controlling synoviocyte viability. PMID- 29477036 TI - Mechanisms of epileptogenesis and preclinical approach to antiepileptogenic therapies. AB - The prevalence of epilepsy is estimated 5-10 per 1000 population and around 70% of patients with epilepsy can be sufficiently controlled by antiepileptic drugs (AEDs). Epileptogenesis is the process responsible for converting normal into an epileptic brain and mechanisms responsible include among others: inflammation, neurodegeneration, neurogenesis, neural reorganization and plasticity. Some AEDs may be antiepileptiogenic (diazepam, eslicarbazepine) but the correlation between neuroprotection and inhibition of epileptogenesis is not evident. Antiepileptogenic activity has been postulated for mTOR ligands, resveratrol and losartan. So far, clinical evidence gives some hope for levetiracetam as an AED inhibiting epileptogenesis in neurosurgical patients. Biomarkers for epileptogenesis are needed for the proper selection of patients for evaluation of potential antiepileptogenic compounds. PMID- 29477038 TI - Post-irradiation protective effects of ectoine on brain and testicles in male mice. AB - BACKGROUND: The present study aimed to investigate the possible post-irradiation protective effects of ectoine on CNS and testes of male mice. METHODS: The study included thirty male Swiss albino mice (20-22 gm). Mice were divided into five groups (six each); controls (injected intraperitoneally with 0.2ml saline), irradiated group 1 (received six Gy whole body x-irradiation single dose, injected with saline, and sacrificed after one day), irradiated group 2 (x irradiated, injected with saline, and sacrificed after one week), ectoine group 1 (x-irradiated, injected with 200mg/kg ectoine, and sacrificed after one day), and ectoine group 2 (x-irradiated, injected daily with 200mg/kg ectoine, and sacrificed after one week). IL-1beta, IL-6, IL-10, PGE2, MDA, GSH, GSSG, and GSH/GSSG ratio were evaluated in CNS and testes. RESULTS: IL-1beta, IL-6, IL-10, PGE2, and MDA are significantly elevated in the CNS and testes of x-irradiated groups when compared with controls. IL-1beta, IL-6, IL-10, and PGE2 significantly elevated at one week than one day while MDA significantly decreased. A significant decrease in the concentration of GSH and in the GSH/GSSG ratios coupled with an opposite effect on GSSG was noted. Ectoine treatment significantly ameliorated the biochemical effects induced by whole body x irradiation. All the tested parameters tended to go back to near control values. It was noted that the modulating action was dependent on the accumulation of ectoine as it was more effective after repeated administration. CONCLUSION: Ectoine has post-irradiation protective effects on CNS and testes via its action on inflammatory and oxidative stress pathways. PMID- 29477037 TI - Evaluation of the neonatal streptozotocin model of diabetes in rats: Evidence for a model of neuropathic pain. AB - BACKGROUND: The purpose of this study was to evaluate the participation of satellite glial cells (SGC), microglia and astrocytes in a model of streptozotocin-induced diabetes initiated in neonatal rats (nSTZ) and to determine the pharmacological profile for pain relief. METHODS: nSTZ was used to induce experimental diabetes. Von Frey filaments were used to assess tactile allodynia. Drugs were given by systemic administration. Western blotting and immunohistochemistry were used to determine protein expression and cellular localization. RESULTS: nSTZ produced mild hyperglycemia, weight loss, glucose intolerance, and reduction of nerve conduction velocity of C fibers. Moreover, nSTZ enhanced activating transcription factor 3 (ATF3) immunoreactivity in dorsal root ganglia (DRG) and sciatic nerve of adult rats. ATF3 was found in SGC (GFAP+ cells) surrounding DRG at week 16. Late changes in ATF3 immunoreactivity in DRG correlated with up-regulation of ATF3 and GFAP protein expression. nSTZ increased GFAP and OX-42 immunoreactivity and percentage of hypertrophied and ameboid microglia in the spinal dorsal horn. These changes correlated with the presence of mechanical hypersensitivity (tactile allodynia). Administration of gabapentin (30-100mg/kg, po) and metformin (200mg/kg/day, po for 2 weeks) alleviated tactile allodynia, whereas morphine (1-3mg/kg, ip) had a modest effect. CONCLUSIONS: Results suggest that nSTZ leads to activation of SGC, microglia and astrocytes in DRG and spinal cord. Pharmacological profile in the nSTZ model resembles diabetic neuropathic pain in humans. Our findings support the conclusion that the nSTZ rat model has utility for the study of a long-lasting diabetic neuropathic pain. PMID- 29477039 TI - Repositioning of molsidomine for its efficacy in diabetes induced erectile dysfunction in rats: In silico, in vitro and in vivo approach. AB - BACKGROUND: Well known risk factors for diabetic erectile dysfunction include impaired nitric oxide synthesis and endothelial dysfunction. We proposed to evaluate the efficacy of nitric oxide donor, molsidomine in rat model of diabetic erectile dysfunction. METHODS: Streptozotocin (52mg/kg, ip) induced diabetic male rats were treated with molsidomine (5 and 10mg/kg, po) for 8 weeks. The sexual behaviour of male rat in presence of the female rat in oestrous phase was observed at the end of study. The effect of treatment on serum testosterone level, sperm parameters and penile tissue histopathology was also evaluated. Further anti-inflammatory activity and antioxidant potential of molsidomine was evaluated by in vitro method. In silico docking study was carried out to appreciate binding conformation of the molsidomine to its plausible target, phosphodiesterase enzyme. RESULTS: Molsidomine significantly and dose dependently increased sexual behaviour, sperm count and serum testosterone level in diabetic rats. Further, the protective effect of molsidomine was also substantiated by pathological changes in the architect of the penile tissue. Molsidomine showed good membrane stability accounting for its significant anti-inflammatory action and also significantly scavenged DPPH radical activity showing its antioxidant action. Molsidomine was found to settle well in the active site of PDE-5 enzyme with less binding affinity than the standard drug sildenafil. CONCLUSION: The results highlight the rationale behind the repositioning of molsidomine therapy for the management of diabetic erectile dysfunction. PMID- 29477040 TI - Effects of creatine supplementation on nociception in young male and female mice. AB - BACKGROUND: The objective of this study was to evaluate creatine as an anti nociceptive compound in an animal model of thermal and inflammatory pain. Creatine has the structural potential to interact with acid-sensing ion channels (ASIC), which have been involved in pain sensation modulation. The hypothesis evaluated in this study was that creatine will interact with ASICs leading to decreased nociception. METHODS: Male and female C57BL/6J mice were fed with either a control diet or the control diet supplemented with creatine (6.25 g/kg diet). After one week on the diet, the mice were tested for thermal hyperalgesia and inflammatory pain response. RESULTS: The latency to withdraw the tail during the thermal hyperalgesia test was unaffected by sex or diet. During the formalin test, males and females responded differently to the stimulus, and the female mice supplemented with creatine seemed to recover faster than the controls. To determine whether ASICs mediate the action of creatine, GMQ, an ASIC3 agonist, was injected in one paw and pain response was quantified. Females responded more strongly to GMQ injections, and all mice fed creatine had a decreased response to GMQ. CONCLUSIONS: These preliminary data suggest a potential effect of creatine on inflammation-based nociception that may be mediated via ASIC3. While preliminary, this study warrants further research on the potential of creatine as an analgesic and can serve as a stepping stone for the development of ASIC-based therapeutics. PMID- 29477041 TI - Mitochondrial proteomics investigation of frontal cortex in an animal model of depression: Focus on chronic antidepressant drugs treatment. AB - BACKGROUND: Alteration in the brain mitochondrial functions have been suggested to participate, as a relevant factor, in the development of mental disorders. Therefore, the brain mitochondria may be a crucial therapeutic target in the course of depression. METHODS: Our goal was to find out the impact of two antidepressant drugs with various mechanisms of action - imipramine and fluoxetine, on the frontal cortex mitochondria-enriched fraction in an animal model of depression based on the prenatal stress procedure. RESULTS: Our results confirmed that the prenatal stress caused depressive-like disturbances in the adult offspring rats, which were normalized by the chronic imipramine and fluoxetine administration. For the first time, using 2D-LC-MS/MS, we demonstrated nine differentially expressed proteins after the imipramine administration. Of these proteins, the up-regulation of the 2',3'-cyclic-nucleotide 3' phosphodiesterase enzyme and down-regulation of the Hypoxanthine-guanine phosphoribosyltransferase (HPRT), Ras-related proteins (Rap-1A and Rap-1B) and Transgelin-3 (NP25) were the most striking. In contrast, after the chronic fluoxetine treatment, we observed differential expression in five proteins, including the enhanced expression of component of pyruvate dehydrogenase complex and diminished of Glutathione S-transferase P (Gstp-1), as well as Maleylacetoacetate isomerase. CONCLUSIONS: These results overcome the interesting data that brain mitochondria in the frontal cortex may constitute the target for pharmacotherapy. The multifaceted profile of both antidepressant drugs action makes difficult to elucidate the exact mechanism of imipramine and fluoxetine action in the brain mitochondria. Further study of mitochondrial dysfunction in psychiatric disorders will be base to know the possible biological consequences of our observations. PMID- 29477042 TI - Anti-angiogenic and anti-inflammatory effects of long-circulating liposomes co encapsulating curcumin and doxorubicin on C26 murine colon cancer cells. AB - BACKGROUND: Emerging treatment options for colon cancer are needed to overcome the limitations regarding the side effects of current chemotherapeutics and drug resistance. The goal of this study was to assess the antitumor actions of PEGylated long-circulating liposomes (LCL) co-delivering curcumin (CURC) and doxorubicin (DOX) on murine colon carcinoma cells (C26). METHODS: The cytotoxicity of CURC and DOX, administered alone or in combination, either in free or LCL form, was evaluated with regard to antiproliferative effects on C26 cells and to protumor processes that might be affected. RESULTS: Our results indicated that PEGylated LCL-CURC-DOX exerted strong antiproliferative effects on C26 cells, slightly exceeding those induced by free CURC-DOX, but higher than either agent administered alone in their free form. These effects of LCL-CURC-DOX were due to the inhibition of the production of angiogenic/inflammatory proteins in a NF-kappaB-dependent manner, but were independent of ROS production or AP-1 c Jun activation. Notable, the anti-angiogenic actions of LCL-CURC-DOX appeared to be much stronger than those induced by the co-administration of CURC and DOX in their free form, on C26 colon cancer cells. CONCLUSION: LCL-CURC-DOX demonstrated enhanced cytotoxicity on C26 murine colon cancer cells by inhibiting the production of the majority of factors involved in tumor-associated angiogenesis and inflammation and is now being evaluated in vivo regarding its efficacy towards tumor growth in colon cancer. PMID- 29477044 TI - Activation of phosphoinositide 3-kinase delta by antipsychotic drugs: Preliminary results. AB - BACKGROUND: Catalytic subunit delta of phosphoinositide 3-kinase, p110delta, encoded by the PIK3CD gene, was recently proposed as a target for pharmacological treatment of schizophrenia. Current antipsychotic drugs were found to decrease the mRNA expression of PIK3CD, but the mechanism of this process is not known. The aim of the study was to elucidate the mechanism by which antipsychotic drugs affect the mRNA expression of PIK3CD. METHODS: The direct effect of haloperidol, clozapine, olanzapine, quetiapine and amisulpride on p110delta enzymatic activity was tested with a kinase assay, and the results were referenced against data on the mRNA expression of PIK3CD. RESULTS: Haloperidol, clozapine, olanzapine and quetiapine, but not amisulpride, at the concentration of 20-80 MUM, were found to significantly increase enzymatic activity of p110delta by up to two times in a dose-dependent manner. Linear regression analysis revealed that more than 40% of the variance in antipsychotic drugs-induced changes in the expression of PIK3CD mRNA was explained only by changes in antipsychotic drug-regulated p110delta enzymatic activity (p = 0.011). CONCLUSIONS: Antipsychotic drugs differentially increase the enzymatic activity of p110delta. This effect is associated with that of mRNA expression of the PIK3CD gene. Drug-enzyme interaction may explain the effect of antipsychotic drugs on the expression of PIK3CD mRNA, however, further studies are needed to investigate this hypothesis. PMID- 29477043 TI - The beneficial effects of ozone therapy in acetaminophen-induced hepatotoxicity in mice. AB - BACKGROUND: The aim of the present study was to determine the therapeutic effects of medical ozone therapy on acute acetaminophen (APAP)-induced hepatotoxicity which were not clearly demonstrated in prior studies. METHOD: Twenty-four mice were randomly assigned into three equal groups: Group 1 (control), Group 2 (APAP) and Group 3 (APAP +ozone). Hepatotoxicity was induced by APAP given as a single dose of 300mg/kg intraperitoneally in Groups 2 and 3. Additionally, Group 3 received 20mcg/0.5mL ozone intraperitoneal twice a day for the remaining of the study. Other groups received saline injections. On the fourth day of the study, biochemical variables (AST, ALT, ALP) and liver histopathology was assessed. RESULTS: Intraperitoneal administration of a single dose of APAP induced hepatocellular damage that was shown by both liver enzymes and histopathological changes (p<0.001). AST, ALT, ALP levels were elevated in both groups 2 and 3 and the difference from group 1 was statistically significant (p<0.01).Mean ALT and AST levels of group 2 were statistically significantly higher versus group 3 (p<0.01). In histopathological examinations; necrosis and inflammation were more prominent in Group 2 compared to Group 3 (p<0.01). CONCLUSION: Ozone showed beneficial effects on APAP hepatotoxicity at a statistically significant level. It is known that ozone has therapeutic effects in various diseases owing to its antioxidant effects. The present study suggests that ozone may be utilized as a routine supplementary therapy in acute APAP hepatotoxicity. PMID- 29477045 TI - Effects of the delta opioid receptor agonist KNT-127 on electroencephalographic activity in mice. AB - BACKGROUND: We previously reported that the novel selective delta opioid receptor (DOP) agonist KNT-127 did not cause convulsions in mice, whereas the prototype DOP agonist SNC80 did. Previous studies have reported that SNC80 caused electroencephalographic (EEG) disturbances in rodents. However, whether KNT-127 affects EEG responses is unknown. Therefore, the present study aimed to compare the effect of KNT-127 on EEG responses with that of SNC80 in mice. METHODS: For behavioral experiments, male C57BL6/J mice were injected intraperitoneally with either KNT-127 (30 mg/kg) or SNC80 (30 mg/kg) and monitored for convulsions and subsequent catalepsy-like behavior for 10 min immediately after drug treatment. For EEG recording experiments, EEG electrodes were implanted into the right hemisphere. EEG signals exceeding twice the baseline amplitude were defined as seizure spikes. RESULTS: KNT-127 did not induce convulsive or catalepsy-like behaviors in mice and did not result in seizure spikes, while significantly higher EEG power density was observed at 2 Hz. In contrast, SNC80 administration resulted in convulsive behaviors, seizure spikes, and significantly higher EEG power density between 2 and 10 Hz in mice. CONCLUSIONS: In this study, we clearly demonstrated that KNT-127 administration induces neither convulsive effects nor seizure spikes in mice. We propose that KNT-127 should be considered a candidate compound for the development of improved DOP-based psychotropic drug that lack the convulsive properties. PMID- 29477047 TI - New developments in force fields for biomolecular simulations. AB - Biomolecular force field development has been instrumental in improving the predictive power of molecular simulations over the past four decades. More recently, the era of large quantitative experimental datasets and ubiquitous high performance computing power has enabled rapid progress in the field. In this review we summarize recent developments in all-atom protein, nucleic acid, and small molecule force fields, paying specific attention to developments in parameterization methods and improvements in the representations of nonbonded interactions that are critical for solving the challenging biophysical problems of the present. We also sketch out new avenues for force field development and grand challenge applications for the near future. PMID- 29477048 TI - Simulations meet machine learning in structural biology. AB - Classical molecular dynamics (MD) simulations will be able to reach sampling in the second timescale within five years, producing petabytes of simulation data at current force field accuracy. Notwithstanding this, MD will still be in the regime of low-throughput, high-latency predictions with average accuracy. We envisage that machine learning (ML) will be able to solve both the accuracy and time-to-prediction problem by learning predictive models using expensive simulation data. The synergies between classical, quantum simulations and ML methods, such as artificial neural networks, have the potential to drastically reshape the way we make predictions in computational structural biology and drug discovery. PMID- 29477049 TI - Anomalous decrease in groundwater radon before 2016 Mw 6.4 Meinong earthquake and its application in Taiwan. AB - Recurrent groundwater radon anomalies were observed at the Paihe spring (P1) in southwestern Taiwan prior to the Mw 6.3 Jiasian and Mw 6.4 Meinong earthquakes that occurred on March 4, 2010 and February 5, 2016, respectively. Specifically, the concentration of groundwater radon decreased from background levels of 144 +/ 7 and 137 +/- 8 pCi/L to minima of 104 +/- 8 and 97 +/- 9 pCi/L prior to the 2010 Jiasian and 2016 Meinong earthquakes, respectively. The Paihe spring (P1) is located 46 km and 45 km, respectively, from the epicenters of the 2010 Mw 6.3 Jiasian and 2016 Mw 6.4 Meinong earthquakes. The above radon anomalies observed at the Paihe limestone spring corroborated that a small fractured aquifer can be used as an effective natural strain meter by applying radon as a tracer for earthquake warning in southwestern Taiwan. There are scientific difficulties and uncertainties in earthquake prediction. Nonetheless, a long-term monitoring of precursory declines in groundwater radon can provide useful data for forecasting local disastrous earthquakes. PMID- 29477050 TI - A Styrofoam-nano manganese oxide based composite: Preparation and application for the treatment of wastewater. AB - Nano-composites were synthesized by the reaction of waste polystyrene (PS) and KMnO4. The structure of the composite was controlled by the solvent/non-solvent system and the concentration of KMnO4. The FTIR spectra indicated the functionalization of PS and the attachment of NMO with the polymer chains. The maximum adsorption capacities (qmax) were 10,000 and 5000 Bq g-1, for U and Th respectively. Different but controllable sorption/desorption behaviours were noted between Th and U, which could be promising in the separation of Th and U from their mixture. PMID- 29477046 TI - Redox control of cancer cell destruction. AB - Redox regulation has been proposed to control various aspects of carcinogenesis, cancer cell growth, metabolism, migration, invasion, metastasis and cancer vascularization. As cancer has many faces, the role of redox control in different cancers and in the numerous cancer-related processes often point in different directions. In this review, we focus on the redox control mechanisms of tumor cell destruction. The review covers the tumor-intrinsic role of oxidants derived from the reduction of oxygen and nitrogen in the control of tumor cell proliferation as well as the roles of oxidants and antioxidant systems in cancer cell death caused by traditional anticancer weapons (chemotherapeutic agents, radiotherapy, photodynamic therapy). Emphasis is also put on the role of oxidants and redox status in the outcome following interactions between cancer cells, cytotoxic lymphocytes and tumor infiltrating macrophages. PMID- 29477051 TI - Determination of transmission factors in beta radiation beams. AB - In beta emitters, in order to evaluate the absorbed dose rate at different tissue depths, it is necessary to determine the transmission factors. In this work, the transmission factors determined in beta secondary standard radiation beams are presented. For this purpose, an extrapolation chamber was used. The results obtained were considered acceptable, and they are within the uncertainties in comparison with the values provided by the source calibration certificate. The maximum differences between the results obtained in this work and those from the calibration certificate were 3.3%, 3.8% and 5.9% for 90Sr/90Y, 85Kr and 147Pm sources respectively. PMID- 29477052 TI - Kinetochore assembly and disassembly during mitotic entry and exit. AB - Faithful chromosome segregation during mitosis in eukaryotes requires a large protein complex, kinetochore, formed on the centromere of each chromosome, to attach to spindle microtubules. Among the kinetochore proteins, Constitutive Centromere-Associated Network (CCAN) and KMN-network proteins form the base of the vertebrate kinetochore architecture. The CCAN proteins constitutively localize to the centromere throughout the cell cycle, whereas KMN-network proteins are recruited to the CCAN only during mitosis. Recent studies in cellular and structural biology, as well as biochemical reconstitutions, have revealed that mitotic phosphorylation of kinetochore proteins has critical roles in kinetochore organization. Here, we discuss the molecular processes of kinetochore assembly during mitotic entry and its disassembly during mitotic exit. PMID- 29477053 TI - Budget impact of a program for safely reducing caesarean sections in Canada. AB - INTRODUCTION: audits of indications for cesarean section (CS), feedback for health professionals, and implementation of best practices, as compared with usual care (QUARISMA study), resulted in a small reduction in the rate of CS in Quebec and important cost savings from a health care payer perspective. Determining the budget impact would enable estimation of the financial consequences if the program is extended nationwide. MATERIAL AND METHODS: a retrospective pre-post study design was used to estimate cost prior to and after the implementation of QUARISMA in Quebec (105,351 subjects). A prospective analysis was performed to measure the budget impact in Canada's provinces. The primary analytic perspective was that of the Minister of Health, for a 4-year time horizon. Data were taken from the trial for Quebec and extrapolated to Canada's provinces. A sensitivity analysis was conducted by varying more than one probability at a time. FINDINGS: over 4 years, there was a decrease of more than $7.8 million in CS burden in Quebec, $11.9 million in vaginal birth and $9.8 million for neonatal complications. The impact on high-risk women was lower than that on low-risk. In years 1 and 2, the provinces would have to cover the cost of program implementation. CONCLUSIONS: QUARISMA led to savings of $27 million in Quebec over 4 years. In the short to medium term, extending the QUARISMA program nationwide could lead to savings of $150.5 million. PMID- 29477054 TI - TRIM37 inhibits PDGF-BB-induced proliferation and migration of airway smooth muscle cells. AB - Tripartite motif 37 (TRIM37) belongs to the TRIM family of proteins and has been reported to be involved in the progression of asthma. However, the effects of TRIM37 on airway smooth muscle cells (ASMCs) proliferation and migration are still unknown. This study aimed to investigate the effects of TRIM37 on cell proliferation and migration in platelet-derived growth factor BB (PDGF-BB) stimulated ASMCs, and the potential molecular mechanisms was also explored. Our data demonstrated that the expression of TRIM37 was significantly decreased in ASMCs stimulated with PDGF-BB. In addition, overexpression of TRIM37 efficiently suppressed PDGF-BB-induced ASMCs proliferation and migration. Furthermore, overexpression of TRIM37 obviously inhibited the protein expression levels of beta-catenin, c-Myc and cyclinD1 in PDGF-BB-stimulated ASMCs. The Wnt/beta catenin pathway activator LiCl significantly reversed the inhibitory effects of TRIM37 on cell proliferation and migration in PDGF-BB-stimulated ASMCs. Taken together, these results demonstrate that TRIM37 inhibits the proliferation and invasion of ASMCs cultured with PDGF-BB through suppressing the Wnt/beta-catenin signaling pathway. PMID- 29477055 TI - Effect of gallic acid on purinergic signaling in lymphocytes, platelets, and serum of diabetic rats. AB - Diabetes Mellitus (DM) is associated with an increased susceptibility to various infections, which might be attributed to changes in immune response owing to chronic hyperglycemia. Nucleoside triphosphate diphosphohydrolase (NTPDase), 5' nucleotidase, and adenosine deaminase (ADA) are important enzymes involved in the generation of anti-aggregant and anti-inflammatory microenvironments. The aim of this study was to evaluate the effect of gallic acid (GA) on the hematological parameters and ectonucleotidase activities in platelets, lymphocytes, and serum of diabetic rats. Experimental rats were categorized into 4 groups: (i) control saline, (ii) control - GA, (iii) diabetic -saline, and (iv) diabetic - GA. One week after induction of DM using streptozotocin (65 mg/kg), GA (30 mg/kg) or saline was orally administered to the rats for 21 days. Our results demonstrated that the concentration of mean corpuscular hemoglobin was decreased, whereas that of red cell distribution was increased in the diabetic group, however, GA could revert these alterations. Moreover, in diabetic rats, GA reverted the increase in ATP and ADP hydrolysis and ADA activity in lymphocytes, and it prevented the increase in NTPDase and ADA activities in platelets. A decrease in ATP hydrolysis and an increase in ADP and AMP hydrolysis were observed in the serum of diabetic rats; however, GA treatment could solely revert changes in ATP hydrolysis. Our study suggests that GA exhibits beneficial effects on immuno- and thrombo regulatory responses in DM and that these effects may be related to the modulation of purinergic signaling. PMID- 29477056 TI - The chemistry and pharmacology of Cleome genus: A review. AB - BACKGROUND: Since ancient times, species of Cleome genus are used to cure various ailments in human beings and same is stated in traditional treatises. Each part of the plant has its own significance, therefore, in background of its significance, upto date information in systematic manner is required. PURPOSE: The present review embarks on variety of naturally occurring compounds that have been isolated from various species of Cleome genus. The present study furnishes an overview of all naturally isolated compounds diterpenes, triterpenoids, trinorterpenoids, flavonol glycoside, coumarinolignoids, dipyridodiazepinone, essential oils, sesquiterpenes, flavonoids, carboxylic acid derivatives, lactone derivatives, sterols and pharmacological activities of various species of Cleome genus. These plants of Cleome genus are often used as conventional drugs to treat several ailments therefore information on analgesic, anti-inflammatory, antifungal, antimicrobial, anti-diarrheal, anticancer, anti-arthritic, hepatoprotective, antinociceptive, wound healing and psychopharmacological activity etc were compiled. METHOD: Literature regarding the compounds isolated and pharmacological studies performed by various researchers in the last 40 years who worked on different species belonging to genus Cleome was summarized in the present review. RESULTS: On the basis of references, this review covers the phytochemistry and pharmacology of Cleome species, describing compounds previously reported current trends and future prospects. CONCLUSION: From a wellbeing point of view, species belonging toCleome genus presents an excellent option for curing variety of ailments in human beings due to its isolated phytocompounds that reveal significant biological activities or for developing a variety of new pharmaceutical products. FUTURE PERSPECTIVE: The observed pharmacological activities and no toxicity profile of extracts obtained from species of Cleome genus support the statement that these extracts might be used in the formation of new formulations that can be beneficial to treat various ailments. PMID- 29477057 TI - Maintenance proton pump inhibition therapy and risk of oesophageal cancer. AB - BACKGROUND: The association of long-term use of proton pump inhibitors (PPIs) with oesophageal adenocarcinoma has been poorly defined. Our aim was to assess the risk of oesophageal cancer assessing confounding by indication. METHODS: This population-based cohort study included all 796,492 adults exposed to maintenance therapy with PPIs in Sweden in 2005-2012. Standardised incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated to assess the risk of oesophageal adenocarcinoma (and squamous cell carcinoma as a comparison) among long-term PPI users relative to the corresponding background population. The different indications for maintenance PPI therapy were analysed separately. RESULTS: Among all individuals using maintenance PPI therapy, the overall SIR of oesophageal adenocarcinoma was 3.93 (95% CI 3.63-4.24). The SIRs of adenocarcinoma were increased also among individuals without gastro-oesophageal reflux disease who used PPIs for indications not associated with any increased risk of oesophageal adenocarcinoma. For example, the SIRs among participants using maintenance PPI therapy because of maintenance treatment with non-steroidal anti-inflammatory drugs and aspirin were 2.74 (95% CI 1.96-3.71) and 2.06 (95% CI 1.60-2.60), respectively. The SIRs of oesophageal squamous cell carcinoma were increased for most investigated indications, but to a lesser degree than for oesophageal adenocarcinoma. CONCLUSION: In conclusion, the long term use of PPIs is associated with increased risk of oesophageal adenocarcinoma in the absence of other risk factors. Long term use of PPIs should be addressed with caution. PMID- 29477058 TI - Disparity in breast cancer mortality by age and geography in 10 racially diverse US cities. AB - OBJECTIVES: Assess geographic variation in breast cancer racial mortality disparity by age cohorts in US and ten cities with large African American populations. METHODS: Non-Hispanic Black (NHB) and Non-Hispanic White (NHW) female breast cancer mortality rates and NHB:NHW rate ratio (RR) (disparity) were calculated by four age group categories: <40, 40-49, 50-64 and 65+ with time period 1999-2013. RESULTS: In all 10 cities and the US, the most pronounced breast cancer disparities, measured by RR, were seen among younger women. In age group <40, the RR ranges from 1.71 in Houston to 5.37 in Washington, DC. For age group 50-64, the disparity was less pronounced, ranging from 1.24 in New York to 1.72 in Chicago. For 65+ age group, there was wide city to city variation in breast cancer mortality disparity. Three cities had higher mortality for NHW compared to NHB; Baltimore 0.78, Washington DC 0.94 and New York 0.98. One city had no statistically significant racial variation in breast cancer mortality in this age group and six cities had increased NHB: NHW mortality disparities. CONCLUSIONS: While the mortality rate for breast cancer is lower among younger women, the NHB:NHW disparities, as measured by rate ratios, are most pronounced in these age groups. Given the absence of available data regarding incidence, stage and subtypes, further research is necessary and such research is important, given the possible policy implications of these results with respect to screening guidelines and coverage for mammography and breast cancer treatment in particular for younger NHB women. PMID- 29477059 TI - Microbial community characterization of ozone-biofiltration systems in drinking water and potable reuse applications. AB - Microbial community structure in the ozone-biofiltration systems of two drinking water and two wastewater treatment facilities was characterized using 16S rRNA gene sequencing. Collectively, these datasets enabled comparisons by facility, water type (drinking water, wastewater), pre-oxidation (ozonation, chlorination), media type (anthracite, activated carbon), media depth, and backwash dynamics. Proteobacteria was the most abundant phylum in drinking water filters, whereas Bacteroidetes, Chloroflexi, Firmicutes, and Planctomycetes were differentially abundant in wastewater filters. A positive correlation was observed between media depth and relative abundance of Cyanobacteria in drinking water filters, but there was only a slight increase in one alpha diversity metric with depth in the wastewater filters. Media type had a significant effect on beta but not alpha diversity in drinking water and wastewater filters. Pre-ozonation caused a significant decrease in alpha diversity in the wastewater filters, but the effect on beta diversity was not statistically significant. An evaluation of backwash dynamics resulted in two notable observations: (1) endosymbionts such as Neochlamydia and Legionella increased in relative abundance following backwashing and (2) nitrogen-fixing Bradyrhizobium dominated the microbial community in wastewater filters operated with infrequent backwashing. Bradyrhizobium is known to generate extracellular polymeric substances (EPS), which may adversely impact biofilter performance and effluent water quality. These findings have important implications for public health and the operation and resiliency of biofiltration systems. PMID- 29477060 TI - Lindane degradation by electrooxidation process: Effect of electrode materials on oxidation and mineralization kinetics. AB - This study focuses on the effect of electrode materials on abatement of lindane (an organochlorine pesticide) by electrooxidation process. Comparative performances of different anodic (platinum (Pt), dimensionally stable anode (DSA) and boron-doped diamond (BDD)) and cathodic (carbon sponge (CS), carbon felt (CF) and stainless steel (SS)) materials on lindane electrooxidation and mineralization were investigated. Special attention was paid to determine the role of chlorine active species during the electrooxidation process. The results showed that better performances were obtained when using a BDD anode and CF cathode cell. The influence of the current density was assessed to optimize the oxidation of lindane and the mineralization of its aqueous solution. A quick (10 min) and complete oxidation of 10 mg L-1 lindane solution and relatively high mineralization degree (80% TOC removal) at 4 h electrolysis were achieved at 8.33 mA cm-2 current density. Lindane was quickly oxidized by in-situ generated hydroxyl radicals, (M(*OH)), formed from oxidation of water on the anode (M) surface following pseudo first-order reaction kinetics. Formation of chlorinated and hydroxylated intermediates and carboxylic acids during the treatment were identified and a plausible mineralization pathway of lindane by hydroxyl radicals was proposed. PMID- 29477061 TI - Development of biochemical sulfide potential (BSP) test for sulfidogenic biotechnology application. AB - The determination of organics biodegradability and corresponding biodegradation kinetics provides valuable information on the optimal design and operation of anaerobic biotechnology especially for sulfidogenesis. This study proposes a deterministic method, i.e. a biochemical sulfide potential (BSP) test, and compares it to the conventional biochemical methane potential (BMP) test in terms of their ability to characterize sulfate-laden organic waste biodegradability. It demonstrated 1.48 times higher degradation of volatile suspended solids (VSS) and 2.60 times more chemical oxygen demand (COD) conversion in its major metabolites than the BMP test. Moreover, it required only four days to complete, compared to the 35 days required by the BMP test. Through the two-substrate first-order hydrolysis model, it was revealed that the shortened time was attributed to the enhanced degradation rates from both readily (eight times) and slowly (nearly 10 times) biodegradable organic substrates in the BSP test compared with the BMP test for the same sulfate-laden organic waste. The findings highlight the inappropriateness of the BMP test to sulfidogenic applications due to the underestimated predictions of organic waste biodegradability and excessive time requirements. Furthermore, the ability of the BSP test to identify the average elemental composition (CxHyOzNaPbSc) of substrate biodegradable particulate organics (BPO) is explored and verified using a casein-based validation test. Using BPO elemental composition as the input variable, a BSP biochemical kinetic model is thereby developed to predict BSR performance and possible dynamic process control. Overall, this study demonstrates the applicability and advantages of the BSP test in sulfidogenic applications for characterization of organics biodegradability and identification of BPO average elemental composition, furthermore develops a process model utilizing the derived BPO average elemental composition to provide optimized reactor retention time and substrates feed mixture for optimum performance. PMID- 29477062 TI - Bioaugmentation of sidestream nitrifying-denitrifying phosphorus-accumulating granules in a low-SRT activated sludge system at low temperature. AB - Sidestream granular activated sludge grown on anaerobic digester dewatering centrate was bioaugmented and selectively retained to enable high nitrification performance of a 2.5-day aerobic SRT non-nitrifying flocculent activated sludge system at 12 degrees C. Sidestream-grown granules performed enhanced biological phosphorus removal (EBPR) and short-cut nitrogen removal via nitrite. After bioaugmentation, EBPR continued in the mainstream but ammonia oxidation was eventually to nitrate. Low effluent NH3-N concentrations from 0.6 to 1.7 mg/L were achieved with nitrification solely by granules, thus enabling denitrification and nitrogen removal. Molecular microbial analyses of flocs and granules also suggested that nitrifying organisms persisted on granules with minimal nitrifier loss to flocs. Mainstream granule mass at the end of bioaugmentation testing was 1.7 times the amount of sidestream granules added, indicating mainstream granular growth. Nitrite and nitrate availability during the unaerated feeding period encouraged significant growth of ordinary heterotrophs in mainstream granules, but nevertheless mainstream nitrification capacity was sustained. PMID- 29477063 TI - Characterization of a new continuous gas-mixing sulfidogenic anaerobic bioreactor: Hydrodynamics and sludge granulation. AB - Continuous gas recirculation (CGR) was demonstrated in this study to be an effective method to mitigate the persistent problem of sludge flotation in high rate sulfate-reducing upflow sludge bed (SRUSB) reactors that do not produce much gas. The effects of hydraulic- and CGR-mixing on the mixing regime of the SRUSB reactors were investigated over a period of 45 d at the average shear rates of 0.9, 1.5, 2.7, 4.2 and 7.2 s-1 (Phase I). CGR-mixing at 4.2 s-1 resulted in the smallest reactor short-circuiting flow of 1.3 +/- 0.1% and the smallest dead zone volume of 0.2 +/- 0.01% at a lower power consumption (0.0007 W) than hydraulic mixing. In Phase II, the SRUSB reactor with CGR-mixing at 4.2 s-1 was re inoculated and operated for 150 days. Within the first 65 days, the sludge transformed into micro-granules (300-350 MUm) with a high sulfate-reducing bacteria (SRB) activity (0.62 +/- 0.05 g COD/(g MLVSS.day)), a low sludge flotation potential (<20%) and a high settleability (SVI5/SVI30 < 1.3). These results are attributed to the following sludge properties: (i) a low ratio of loosely-bound to tightly-bound extracellular polymeric substances (0.06-0.1), (ii) weakly adhesive surface properties as demonstrated by a strongly negative zeta potential (-23 +/- 2 mV), a low hydrophobicity (37 +/- 3%) and a low viscosity (0.7 +/- 0.1 mPa s), and (iii) small size granules resulting in strong mass transfer (sulfate and COD penetration into the granule core) and a homogeneous structure (SRB detected throughout the granule). PMID- 29477064 TI - A UPLC-ESI-Q-TOF method for rapid and reliable identification and quantification of major indole alkaloids in Catharanthus roseus. AB - We developed a novel ultra performance liquid chromatography-quadrupole time-of flight (UPLC-Q-TOF) mass spectrometry method that allows sensitive, rapid, and reliable detection and identification of six representative indole alkaloids (vincristine, vinblastine, ajmalicine, catharanthine, serpentine, and vindoline) that exhibit physiological activity in Catharanthus roseus (C. roseus). The alkaloids were eluted on a C18 column with acetonitrile and water containing 0.1% formic acid and 10 mM ammonium acetate, and separated with good resolution within 13 min. Electrospray ionization-Q-TOF (ESI-Q-TOF) analysis was performed to characterize the molecules and their fragment ions, and the characteristic ions and fragmentation patterns were used as to identify the alkaloids. The proposed analytical method was verified in reference to the ICH guidelines and the results showed excellent linearity (R2 > 0.9988), limit of detection (1 ng/mL to 10 ng/mL), limit of quantification (3 ng/mL to 30 ng/mL), intra-day and inter-day precisions, and extraction recovery rates (92.8% to 104.1%) for all components. The validated UPLC-Q-TOF method was applied to the analysis of extracts from the root, stem, and leaves of C. roseus, allowing the identification of six alkaloids by comparison of retention times, molecular ions, and fragmentation patterns with those of reference compounds. Sixteen additional indole alkaloids were tentatively identified by comparison of chromatograms to chemical databases and literature reports. The contents of bis-indole alkaloids (vincristine and vinblastine) were high in the aerial parts, while the contents of mono-indole alkaloids (ajmalicine, catharanthine, serpentine, and vindoline) were high in the roots. The present results demonstrate that the proposed UPLC-Q-TOF method can be useful for the investigation of phytochemical constituents of medicinal plants. PMID- 29477065 TI - Characterization of an antibody-drug conjugate by hydrophilic interaction chromatography coupled to mass spectrometry. AB - Brentuximab vedotin (Adcetris) is a cysteine-linked antibody-drug conjugate (ADC) used in the treatment of Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL). In this study, the drug payload and glycan modifications of this ADC were simultaneously characterized using a unique LC-MS middle-up analysis, involving hydrophilic interaction chromatography (HILIC). This work demonstrates that HILIC is an effective and complementary analytical technique to reversed phase liquid chromatography (RPLC) for subunit-level characterization of immuno conjugates. PMID- 29477066 TI - Supercritical fluid chromatography-photodiode array detection-electrospray ionization mass spectrometry as a framework for impurity fate mapping in the development and manufacture of drug substances. AB - Impurity fate and purge studies are critical in order to establish an effective impurity control strategy for approval of the commercial filing application of new medicines. Reversed phase liquid chromatography-diode array-mass spectrometry (RPLC-DAD-MS) has traditionally been the preferred tool for impurity fate mapping. However, separation of some reaction mixtures by LC can be very problematic requiring combination LC-UV for area % analysis and a different LC-MS method for peak identification. In addition, some synthetic intermediates might be chemically susceptible to the aqueous conditions used in RPLC separations. In this study, the use of supercritical fluid chromatography-photodiode array electrospray ionization mass spectrometry (SFC-PDA-ESIMS) for fate and purge of two specified impurities in the 1-uridine starting material from the synthesis of a bis-piv 2'keto-uridine, an intermediate in the synthesis of uprifosbuvir, a treatment under investigation for chronic hepatitis C infection. Readily available SFC instrumentation with a Chiralpak IC column (4.6 * 150 mm, 3 MUm) and ethanol: carbon dioxide based mobile phase eluent enabled the separation of closely related components from complex reaction mixtures where RLPC failed to deliver optimal chromatographic performance. These results illustrate how SFC combined with PDA and ESI-MS detection can become a powerful tool for direct impurity fate mapping across multiple reaction steps. PMID- 29477067 TI - Development of an immunoaffinity column for the highly sensitive analysis of bisphenol A in 14 kinds of foodstuffs using ultra-high-performance liquid chromatography tandem mass spectrometry. AB - An immunoaffinity clean-up material based on a monoclonal antibody (mAb) has been prepared for concentrating and purifying bisphenol A (BPA) in 14 kinds of foodstuffs at trace level. Haptens and immunogen of bisphenol A have been synthesized and comprehensively characterized. An mAb towards BPA was prepared and cross-reactivities with 14 BPA analogues were below 5%. The prepared antibody was coupled to N-hydroxysuccinimide-activated Sepharose 4B to manufacture an immunoaffinity column (IAC), which was applied to purify BPA in 14 kinds of foodstuffs. The analyte was then detected by means of ultra-high-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Under the optimized conditions, compared with two traditional SPE clean-up methods, the IAC showed better selectivity (matrix effect <16.8%) and higher sensitivity. The limits of detection for BPA in 14 kinds of foodstuffs ranged from 0.001 MUg L-1 to 0.01 MUg kg-1, and the limits of quantification were in the range from 0.003 MUg L-1 to 0.04 MUg kg-1. The recoveries of BPA from spiked samples ranged from 82.0% to 104.9%, with RSDs below 13.8%. Besides, the IAC exhibited good reusability, with 40% column capacity remaining and no significant loss of recovery after 25 application cycles in real sample detection. These results demonstrated that the developed IAC-UPLC-MS/MS approach has wide applicability for purifying and detecting BPA in various foodstuffs. PMID- 29477068 TI - Targeted and untargeted-metabolite profiling to track the compositional integrity of ginger during processing using digitally-enhanced HPTLC pattern recognition analysis. AB - Tracking the impact of commonly applied post-harvesting and industrial processing practices on the compositional integrity of ginger rhizome was implemented in this work. Untargeted metabolite profiling was performed using digitally-enhanced HPTLC method where the chromatographic fingerprints were extracted using ImageJ software then analysed with multivariate Principal Component Analysis (PCA) for pattern recognition. A targeted approach was applied using a new, validated, simple and fast HPTLC image analysis method for simultaneous quantification of the officially recognized markers 6-, 8-, 10-gingerol and 6-shogaol in conjunction with chemometric Hierarchical Clustering Analysis (HCA). The results of both targeted and untargeted metabolite profiling revealed that peeling, drying in addition to storage employed during processing have a great influence on ginger chemo-profile, the different forms of processed ginger shouldn't be used interchangeably. Moreover, it deemed necessary to consider the holistic metabolic profile for comprehensive evaluation of ginger during processing. PMID- 29477069 TI - LC-MS determination of steroidal glycosides from Dioscorea deltoidea Wall cell suspension culture: Optimization of pre-LC-MS procedure parameters by Latin Square design. AB - In this paper, the ultrasound assisted extraction method for isolation of steroidal glycosides from D. deltoidea plant cell suspension culture with a subsequent HPLC-MS determination was developed. After the organic solvent was selected via a two-factor experiment the optimization via Latin Square 4 * 4 experimental design was carried out for the following parameters: extraction time, organic solvent concentration in extraction solution and the ratio of solvent to sample. It was also shown that the ultrasound assisted extraction method is not suitable for isolation of steroidal glycosides from the D. deltoidea plant material. The results were double-checked using the multiple successive extraction method and refluxing extraction. Optimal conditions for the extraction of steroidal glycosides by the ultrasound assisted extraction method were: extraction time, 60 min; acetonitrile (water) concentration in extraction solution, 50%; the ratio of solvent to sample, 400 mL/g. Also, the developed method was tested on D. deltoidea cell suspension cultures of different terms and conditions of cultivation. The completeness of the extraction was confirmed using the multiple successive extraction method. PMID- 29477070 TI - A network analysis of eating disorder symptoms and characteristics in an inpatient sample. AB - Eating disorders (EDs) are characterized by symptoms that reflect disturbed eating habits. Available data on EDs largely reflects a traditional latent variable model, whereby symptoms reflect an underlying entity. The network model is an alternative approach where ED symptoms do not reflect an inferred, unobservable category or dimension, but rather are themselves constitutive of the disorder. In the present study, data from ED patients (n = 5193) that completed the Eating Disorders Inventory - 2 (EDI-2; Garner, 1991) before and after inpatient treatment were used to identify symptoms (i.e., body dissatisfaction) and characteristics (i.e., perfectionism) central to EDs. Results revealed that interoceptive awareness and ineffectiveness, but not body dissatisfaction and drive for thinness, were central to the ED network at admission and discharge. Although effect sizes were small, multiple regression analyses revealed that ineffectiveness at admission predicted discharge BMI (over and above interoceptive awareness and BMI at admission) and discharge depression (over and above interoceptive awareness and depression at admission), but not discharge anxiety. These findings suggest that interoceptive awareness and ineffectiveness are central symptoms of EDs that may have implications for treatment outcome. The implications of these findings for conceptualizing the nature and treatment of EDs are discussed. PMID- 29477071 TI - Gender differences in temporal relationships between gambling urge and cognitions in treatment-seeking adults. AB - Many gambling-specific CBT programs seek to target either gambling-related urge or cognitions or both. However, little is known of the influence of one symptom type on another across time and whether these differ for men and women help seeking problem gamblers. The aim of this study was threefold: to determine presence of measurement invariance for urge and cognition measures over time; to investigate the effect of baseline urge on end-of-treatment gambling-related cognitions - and the reciprocal relationship; and, identify whether these pathways differ across gender. Self-reported gambling urge (GUS), and gambling related cognitions (GRCS) data from treatment-seeking problem gamblers prior to and post treatment (N = 223; 62% men) were analyzed with cross-lagged panel models, moderated by gender. Conceptualization of urge and cognitions were found to be temporally stable. There was no significant association between baseline GUS scores and post-treatment GRCS scores, nor the reverse relationship. Putatively, this infers that coexisting urge and gambling-related cognition components of problem gambling operate independently over time. Analyses revealed gambling urge had a significantly stronger tracking correlation across time for men than women when adjusting for cognition paths. This investigation provides early evidence for tailoring CBT in response to sub-population gambling-related characteristics, demonstrated across men and women. PMID- 29477072 TI - Family-wide analysis of aminoacyl-sulfamoyl-3-deazaadenosine analogues as inhibitors of aminoacyl-tRNA synthetases. AB - Aminoacyl-tRNA synthetases (aaRSs) are enzymes that precisely attach an amino acid to its cognate tRNA. This process, which is essential for protein translation, is considered a viable target for the development of novel antimicrobial agents, provided species selective inhibitors can be identified. Aminoacyl-sulfamoyl adenosines (aaSAs) are potent orthologue specific aaRS inhibitors that demonstrate nanomolar affinities in vitro but have limited uptake. Following up on our previous work on substitution of the base moiety, we evaluated the effect of the N3-position of the adenine by synthesizing the corresponding 3-deazaadenosine analogues (aaS3DAs). A typical organism has 20 different aaRS, which can be split into two distinct structural classes. We therefore coupled six different amino acids, equally targeting the two enzyme classes, via the sulfamate bridge to 3-deazaadenosine. Upon evaluation of the inhibitory potency of the obtained analogues, a clear class bias was noticed, with loss of activity for the aaS3DA analogues targeting class II enzymes when compared to the equivalent aaSA. Evaluation of the available crystallographic structures point to the presence of a conserved water molecule which could have importance for base recognition within class II enzymes, a property that can be explored in future drug design efforts. PMID- 29477073 TI - Discovery and optimization of ATX inhibitors via modeling, synthesis and biological evaluation. AB - Autotaxin (ATX) is a potential target for the treatment of various cancers. A new series of ATX inhibitors was rationally designed and synthesized based on our previous study. Biological evaluation and structure-activity relationship (SAR) of this series are discussed. Among fourteen synthesized derivatives, six compounds (2, 3, 4, 12, 13 and 14) exhibited enhanced ATX inhibitory activities with IC50 values in the low nanomolar range. Molecular interactions of all the synthesized compounds within the active site of ATX were studied through molecular docking studies. Herein, we describe our lead optimization efforts that resulted in the identification of a potent ATX inhibitor (compound 4 with IC50 = 1.23 nM, FS-3 and 2.18 nM, bis-pNPP). Furthermore, pharmacokinetic properties of this most promising compound are profiled. PMID- 29477074 TI - Benzomorphan scaffold for opioid analgesics and pharmacological tools development: A comprehensive review. AB - Benzomorphan, derived by morphine skeleton simplification, has been the subject of exploration in medicinal chemistry for the development of new drugs and pharmacological tools to explore opioid pharmacology in vitro and in vivo. Building upon these evidences, the design and synthesis of benzomorphan-based compounds, appropriately modified at the basic nitrogen and/or the phenolic hydroxyl (8-OH) group, represent a valid and versatile strategy to obtain analgesics. In this review, to improve the body of information in this field, we report structure activity-relationships (SARs) of benzomorphan-based compounds analysing data literature of last 25 years. Collectively, SARs data highlighted that the benzomorphan nucleus represents a template in the achievement of a specific functional profile, by modifying N-substituent or 8-OH group. PMID- 29477075 TI - Precise structures of fucosylated glycosaminoglycan and its oligosaccharides as novel intrinsic factor Xase inhibitors. AB - Selective inhibition of the endogenous coagulation pathway is a promising strategy for developing new anticoagulants. Fucosylated glycosaminoglycan (FG), a structurally complex glycosaminoglycan, has distinct anticoagulant properties, especially the strong intrinsic factor Xase inhibitory activity that is recognized as a new target with potential physiological and therapeutic applications. Detailed knowledge of FG structures is necessary for developing a clinically effective intrinsic FXase inhibitor. However, challenges remain to elucidate FG structures as a basis for pharmaceutical development. Herein, using the highly selective beta-elimination method, oligosaccharides with regular structures were prepared from the depolymerization products. Analysis of oligosaccharides further confirmed the precise structural sequence of the FG. Furthermore, biological activity assay suggested that these pure homogeneous oligosaccharides, particularly an octasaccharide, exhibit strong inhibition of the intrinsic coagulation pathway by inhibiting human intrinsic factor Xase. Our finding is significant for discovery of a new class of anticoagulant agents as intrinsic factor Xase inhibitors. PMID- 29477076 TI - Secretase inhibitors for the treatment of Alzheimer's disease: Long road ahead. AB - : Alzheimer's disease (AD) is a neurodegenerative disease, characterized by progressive loss of memory which is associated with other cognitive deficits. The two protein structures in the brain i.e. neurofibrillary tangles and senile plaques are considered to hamper the normal cognitive activity of the brain. There are various therapeutic interpolations under investigation to thwart and treat AD. Secretases inhibitors are important agents that inhibit the development of senile plaques. beta-secretase (BACE) inhibitors are in lime light for the drug development of AD. BACE initiates the production of Abeta, so its inhibition provides a valid target for the AD. BACE inhibitors viz. LY2811376, LY2886721, E2609 are in different phases of clinical trials. However, chemical study of MK8931 was discontinued due to lack of chances of finding a positive clinical effect. AREAS COVERED: The review incorporates exhaustive literature reports on secretase inhibitors, gamma-secretase modulators (GSMs) and alpha-secretase enhancers. The recent studies on the natural products as GSMs have also been included. PMID- 29477077 TI - Pan-NS3 protease inhibitors of hepatitis C virus based on an R3-elongated pyrazinone scaffold. AB - Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors and show that elongated R3 urea substituents were associated with increased inhibitory potencies over several NS3 protein variants. The inhibitors are believed to rely on beta-sheet mimicking hydrogen bonds which are similar over different genotypes and current drug resistant variants and correspond to the beta-sheet interactions of the natural peptide substrate. Inhibitor 36, for example, with a urea substituent including a cyclic imide showed balanced nanomolar inhibitory potencies against genotype 1a, both wild type (Ki = 30 nM) and R155K (Ki = 2 nM), and genotype 3a (Ki = 5 nM). PMID- 29477078 TI - Polycyclic aromatic hydrocarbon-emulsifier protein produced by Aspergillus brasiliensis (niger) in an airlift bioreactor following an electrochemical pretreatment. AB - An emulsifier protein (EP) was produced and easily separated from oil contaminated water as an economical substrate when Aspergillus brasiliensis, pretreated in a solid state culture with a controlled electric field, was used in an airlift bioreactor. The hydrocarbon-EP comprised 19.5% of the total protein, its purification enhanced the specific emulsifying activity (EA) seven times. The influence of operational conditions (pH and salt concentration) on the EA were assessed to characterise the emulsion stability. The EA was increased by 19% in alkaline environments (pH 7-11), but it was not affected by the presence of salt (0-35 g L-1). On the other hand, preheating the EP samples (60 degrees C) enhanced the EA by 2.5 times. Based on analysis of its EA, this EP can be applied as a bioremediation enhancer in contaminated soils. PMID- 29477079 TI - Effect of tetracycline on microbial community structure associated with enhanced biological N&P removal in sequencing batch reactor. AB - The presence of antibiotics in wastewater has raised serious concerns about its potential impacts on biological nitrogen and phosphorus (N&P) removal. This study investigated the long-term process performance and microbial structures in response to tetracycline in the enhanced N&P removal process. Results showed that trace tetracycline (20 and 50 MUg/L) had no obvious effect on the N&P removal, while the relative abundances of Nitrospira and poly-phosphate accumulating organisms (PAOs) were found to increase. Moreover, the decreased abundance of ammonia oxidizing bacteria (AOB) was observed. When the tetracycline concentrations were further increased to 2 and 5 mg/L, initially the N&P removal was seriously inhibited, but gradually recovered with the restored abundances of Nitrospira and PAOs. However, AOB, Nitrobacter and denitrifiers were found to be more vulnerable to high-concentration tetracycline with slow activity recovery. Consequently, this study offered useful information about long-term microbial responses to tetracycline in enhanced biological nutrient removal process. PMID- 29477080 TI - Application of growth-phase based light-feeding strategies to simultaneously enhance Chlorella vulgaris growth and lipid accumulation. AB - Considering the variations of optimal light intensity required by microalgae cells along with growth phases, growth-phase light-feeding strategies were proposed and verified in this paper, aiming at boosting microalgae lipid productivity from the perspective of light conditions optimization. Experimental results demonstrate that under an identical time-averaged light intensity, the light-feeding strategies characterized by stepwise incremental light intensities showed a positive effect on biomass and lipid accumulation. The lipid productivity (235.49 mg L-1 d-1) attained under light-feeding strategy V (time averaged light intensity: 225 MUmol m-2 s-1) was 52.38% higher over that obtained under a constant light intensity of 225 MUmol m-2 s-1. Subsequently, based on light-feeding strategy V, microalgae lipid productivity was further elevated to 312.92 mg L-1 d-1 employing a two-stage based light-feeding strategy V560 (time averaged light intensity: 360 MUmol m-2 s-1), which was 79.63% higher relative to that achieved under a constant light intensity of 360 MUmol m-2 s-1. PMID- 29477081 TI - An improved predictive model to determine the thermal degradation of lignocellulosic materials at low temperature (Torrefaction) ranges. AB - This study introduces an improved computational procedure to determine the thermal degradation of biomasses when submitted to a torrefaction process. The novelty consists in integrating a summative kinetic model approach with an enhanced finite difference scheme. This is achieved by defining timing updated parameters to account for both the extent of conversion and the evolution of the fibers composition. As main result, the proposed method enhances the exploitation of the summative assumption considering that the predictive accuracy of the model sets within 5% as maximum error. Furthermore, the adopted discrete approach contributes to generalize the TGA set up going beyond the conventional heating programs usually limited to isothermal and constant heating rate constrains. Due to these constitutive improvements, the proposed computational approach looks promising for investigations involving both kinetic analysis and thermal processes design including torrefaction. PMID- 29477082 TI - High monomeric sugar yields from enzymatic hydrolysis of soybean meal and effects of mild heat pretreatments with chelators. AB - Defatted soybean meal has 30-35% oligo-/polymeric carbohydrates and approximately 50% proteins. Enzymatic carbohydrate monomerization enables easy separation to enrich protein content, reduces indigestibility concerns, and facilitates use of carbohydrate as fermentation feedstock. Among soybean carbohydrates, pectin and glucan are more recalcitrant to hydrolyze. To destabilize Ca2+-bridged junctures in pectin, effects of 3 chelators ethylenediaminetetraacetic acid (EDTA), sodium hexametaphosphate (HMP) and citric acid under 2-h 90 degrees C pretreatments were investigated here. Citric acid was the most effective while EDTA decreased enzymatic hydrolysis. In a 3-factor 2-level factorial study, heat (90 degrees C, 2 h) and citric acid (10 g/L) pretreatments and cellulase supplementation (10 FPU/g) were found to increase yields of all monosaccharides, to 86.8 +/- 5.2% glucose, 98.1 +/- 1.6% xylose, 87.5 +/- 5.2% galactose, 83.6 +/- 1.6% arabinose, and 91.4 +/- 3.1% fructose + mannose. The largest percentage improvements were for arabinose (382%), mannose (113%) and glucose (51%). Achieving high monosaccharide yields greatly increases value of soybean carbohydrate as fermentation feedstock. PMID- 29477083 TI - A comparative study on the quality of bio-oil derived from green macroalga Enteromorpha clathrata over metal modified ZSM-5 catalysts. AB - The green macroalga Enteromorpha clathrata was pyrolyzed with or without catalysts at the temperature of 550 degrees C for producing high-quality bio oil. The ZSM-5 and 1,2,3 mmol Mg-Ce/ZSM-5 catalysts were introduced to investigate the yields and components distribution of bio-oil. Increase of bio oil production was obtained with the use of ZSM-5 and 1,2,3 mmol Mg-Ce/ZSM-5 catalysts. The 1 mmol Mg-Ce/ZSM-5 catalyst exhibited more promising property for promoting the relative content of C5-C7 compounds, and decreasing the relative content of acids in bio-oil. The results suggested that E. clathrata had potential as pyrolysis feedstocks for producing the high-quality bio-oil with large amounts of C5-C7 compounds and low relative content of acids when the 1 mmol Mg-Ce/ZSM-5 catalyst was used. Furthermore, the physicochemical properties of ZSM-5 and 1 mmol Mg-Ce/ZSM-5 catalysts were investigated by scanning electron microscopy, transmission electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy and temperature-programmed desorption of ammonia. PMID- 29477085 TI - Crystal methamphetamine use and its correlates in women engaged in sex work in a developing country setting. AB - BACKGROUND: Worldwide, crystal methamphetamine (CM) use and associated high-risk sexual behaviors are a concern, but they are less studied among female sex workers (FSW) in developing countries. This study aimed to characterize the prevalence and individual, interpersonal, and structural correlates of self reported past-month CM use among FSW in Iran. METHODS: FSW aged >= 18 years who reported penetrative sex with more than one client in the last year were recruited (analytic sample: 1295). Data were collected in one-on-one interviews using a standardized behavioral questionnaire. Poisson regression model was used to assess the correlated of past-month self-reported CM use by crude and adjusted prevalence ratio (APR) and 95% confidence intervals (CI). RESULTS: Non-injecting and injecting CM use was reported by 15.0% (95% CI: 8.7, 24.7) and 0.9% (95% CI: 0.4, 2.1) of participants. CM use was positively associated with concurrent use of opioids (APR from 2.08 to 3.84, P-value < 0.01), higher number of sexual partners (APR: 2.05, P-value: 0.018), housing instability (APR: 3.54, P-value: 0.001), and history of forced sex (APR: 1.47, P-value: 0.050). CONCLUSIONS: A considerable number of FSWs use CM along with opioids, have a higher number of sexual partners, forced sex, and housing instability. Both prevention strategies as well as strategies to reduce harm associated with CM need to be added to current programs that predominantly focus on opioid dependency and male drug injectors. PMID- 29477084 TI - Differences in time to injection onset by drug in California: Implications for the emerging heroin epidemic. AB - BACKGROUND: Heroin use is increasing in the US. Heroin use may predispose users towards injection routes of drug administration as compared to other illicit substances. OBJECTIVE: To explore the relationship between heroin use and drug injection, we compared time from first use to first injection (referred to as time to injection onset by drug [TTIOD]) of heroin, methamphetamine/speed, cocaine, and crack cocaine among people who inject drugs (PWID). METHODS: Age of first use and first injection by drug was collected from 776 PWID. Survival analyses were used to determine TTIOD and to examine demographic factors associated with TTIOD. Cox regression analysis was used to determine demographic factors associated with drug-specific injection onset. RESULTS: The eventual injection onset rate by the drug was 99% for participants who used heroin, 85% for participants who used methamphetamine/speed, 80% for participants who used powder cocaine, and 38% for participants who used crack cocaine. Hazard ratios for injection use within one year of first use by drug were: 1.37 (median survival time [MST] = 0.61 years) for heroin, 0.66 (MST = 1.10 years) for methamphetamine/speed, 0.50 (MST = 2.93 years) for powder cocaine, and 0.12 (MST = 39.59 years) for crack cocaine. Demographic differences in TTIOD were found for each drug. Demographic differences were found for eventual injection by drug for all substances except heroin. CONCLUSION: Among PWID, heroin use was associated with a more rapid transition to injection and a higher rate of eventual heroin injection regardless of demographics. More robust, innovative efforts to reduce heroin use and prevent injection initiation are urgently needed. PMID- 29477086 TI - Addressing the public health concerns of Fetal Alcohol Spectrum Disorder: Impact of stigma and health literacy. AB - BACKGROUND: Fetal alcohol spectrum disorders (FASD) are a group of developmental disabilities that may result from the mother's consumption of alcohol during pregnancy. The present study examined the effects of health literacy and stigma on the public health agenda for preventing FASD. METHODS: Three hundred and forty one participants were sampled to ascertain levels of endorsement of the public health priorities of FASD, and FASD health literacy. Stigma towards women who consume alcohol during pregnancy, and towards biological mothers of children with FASD were operationalized using ratings of difference and disdain. RESULTS: Public stigma towards women who consume alcohol during pregnancy was greater than stigma towards biological mothers of children with FASD. Research participants with higher FASD literacy were more likely to endorse the prevention priorities of FASD, but also more likely to endorse greater stigma towards biological mothers of children with FASD. Interestingly, those who endorsed greater stigma supported the public health priorities of FASD more strongly. Female research participants more strongly supported the prevention priorities of FASD than male participants. Male participants were more likely to endorse stigma than female participants. CONCLUSIONS: Stigma experienced by biological mothers of children with FASD generalizes to women who consume alcohol while pregnant. Some results were contrary to expectations: stigma was positively associated with health literacy and endorsement of prevention priorities of FASD. Reasons for these findings are speculated and should be tested in future research. PMID- 29477087 TI - Vulnerability of photosynthesis and photosystem I in Jerusalem artichoke (Helianthus tuberosus L.) exposed to waterlogging. AB - Jerusalem artichoke (Helianthus tuberosus L.) is an important energy crop for utilizing coastal marginal land. This study was to investigate waterlogging tolerance of Jerusalem artichoke through photosynthetic diagnose with emphasis on photosystem II (PSII) and photosystem I (PSI) performance. Potted plants were subjected to severe (liquid level 5 cm above vermiculite surface) and moderate (liquid level 5 cm below vermiculite surface) waterlogging for 9 days. Large decreased photosynthetic rate suggested photosynthesis vulnerability upon waterlogging. After 7 days of severe waterlogging, PSII and PSI photoinhibition arose, indicated by significant decrease in the maximal photochemical efficiency of PSII (Fv/Fm) and PSI (?MR/MR0), and PSI seemed more vulnerable because of greater decrease in ?MR/MR0 than Fv/Fm. In line with decreased ?MR/MR0 and unchanged Fv/Fm after 9 days of moderate waterlogging, the amount of PSI reaction center protein rather than PSII reaction center protein was lowered, confirming greater PSI vulnerability. According to positive correlation between ?MR/MR0 and efficiency that an electron moves beyond primary quinone and negative correlation between ?MR/MR0 and PSII excitation pressure, PSI inactivation elevated PSII excitation pressure by depressing electron transport at PSII acceptor side. Thus, PSI vulnerability induced PSII photoinhibition and endangered the stability of whole photosynthetic apparatus under waterlogging. In agreement with photosystems photoinhibition, elevated H2O2 concentration and lipid peroxidation in the leaves corroborated waterlogging-induced oxidative stress. In conclusion, Jerusalem artichoke is a waterlogging sensitive species in terms of photosynthesis and PSI vulnerability. Consistently, tuber yield was tremendously reduced by waterlogging, confirming waterlogging sensitivity of Jerusalem artichoke. PMID- 29477088 TI - Inorganic Hg toxicity in plants: A comparison of different genotoxic parameters. AB - Inorganic Mercury (Hg) contamination persists an environmental problem, but its cyto- and genotoxicity in plants remains yet unquantified. To determine the extent of Hg-induced cyto- and genotoxicity, and assess most sensitive endpoints in plants, Pisum sativum L. seedlings were exposed for 14 days to different HgCl2 concentrations up to 100 MUM. Shoots and roots from hydroponic exposure presented growth impairment and/or morphological disorders for doses >1 MUM, being the roots more sensitive. Plant growth, ploidy changes, clastogenicity (HPCV), cell cycle dynamics (G1-S-G2), Comet-tail moment (TM), Comet-TD, Mitotic-index (MI) and cell proliferation index (CPI) were used to evaluate Hg-induced cyto/genotoxicity. Both leaf and root DNA-ploidy levels, assessed by flow cytometry (FCM), remained unaltered after exposure. Root cell cycle impairment occurred at lower doses (>=1 MUM) than structural DNA damages (>=10 MUM). Cytostatic effects depended on the Hg concentration, with delays during S-phase at lower doses, and arrests at G1 at higher ones. This arrest was paralleled with decreases of both mitotic index (MI) and cell proliferation index (CPI). DNA fragmentation, assessed by the Comet assay parameters of TD and TM, could be visualized for conditions >=10 MUM, while FCM-clastogenic parameter (FPCV) and micronuclei (MNC) were only altered in roots exposed to 100 MUM. We demonstrate that inorganic-Hg induced cytostaticity is detectable even at 1 MUM (a value found in contaminated sites), while structural DNA breaks/damage are only visualized in plants at concentrations >=10 MUM. We also demonstrate that among the different techniques tested for cyto- and genotoxicity, TD and TM Comet endpoints were more sensitive than FPCV or MNC. Regarding cytostatic effects, cell cycle analysis by FCM, including the difference in % cell cycle phases and CPI were more sensitive than MI or MNC frequency. Our data contribute to better understand Hg cyto- and genotoxicity in plants and to understand the information and sensitivity provided by each of the genotoxic techniques used. PMID- 29477089 TI - MiR17 improves insulin sensitivity through inhibiting expression of ASK1 and anti inflammation of macrophages. AB - OBJECTIVES: MicroRNAs (miRNAs) are involved in the pathological progression of various disease including type 2 diabetes (T2D). Chronic inflammation in adipose tissue is a cause of insulin resistance and T2D. MiR-17 palys an anti inflammatory role in many biological processes. We hypothesized that miR-17 suppressed inflammatory macrophage that is related to insulin resistance in patients with T2D. METHODS: Macrophage migration and secretion of inflammatory cytokines including TNF-alpha, IL-6 and IL-1beta were detected through transwell migration assay and enzyme-linked immunosorbent assay, respectively. Insulin stimulated glucose uptake was tested by the radioactivity of tritium-labeled glucose in 3T3-L1 adipocytes. Dual luciferase reporter gene assay was employed to evaluate the interaction between miR-17 and 3'UTR of ASK1. RESULTS: Our results showed that miR-17 inhibited macrophage infiltration and secretion of TNF-alpha, IL-6 and IL-1beta. Moreover, insulin-stimulated glucose uptake of 3T3-L1 was suppressed by treatment with LPS-induced macrophage conditioned media (CM), whereas the opposite effect was showed after treatment with the CM of macrophages transfected with miR-17. Furthermore, we found that miR-17 directly prevented expression of ASK1 by binding to its 3'UTR. CONCLUSION: miR-17 improved inflammation-induced insulin resistance by suppressing ASK1 expression in macrophages. These results indicated that miR-17 had an anti-diabetic acitivity by its anti-inflammation effect on macrophage. PMID- 29477090 TI - Cardioprotective effect of resistance training and Crataegus oxyacantha extract on ischemia reperfusion-induced oxidative stress in diabetic rats. AB - Discovering an effective approach to limit infarction size after ischemia reperfusion has a clinical importance in diabetics. We investigated the anti myocardial ischemia-reperfusion injury effect of resistance training and Crataegus oxyacantha extract on diabetic rats. To this end, 50 male Wistar rats were randomly divided into 5 groups: the sedentary control (SC), sedentary diabetic (SD), resistance trained diabetic (RD), diabetic plus C. oxyacantha extract treatment (CD) and resistance trained diabetic plus C. oxyacantha extract treatment (RCD) groups. Animals in trained groups were subjected to progressive resistance training program with the use of a ladder (5 days/week, for 10 weeks). C. oxyacantha extract rats were treated with 100 mg/kg body weight of the extract using a gavage every day for 10 weeks. After treatments, rats were subjected to ischemia via LAD artery ligation for 30 min followed by 90 min reperfusion. The heart was collected following the ischemia-reperfusion and analyzed for oxidative stress and ischemia-reperfusion injury. Compared to the SC group, LDH, CK-MB and infarction size in the SD group were significantly higher, whereas injury indices in the RCD group were significantly lower than those in the SD group. GPx and MPO levels after reperfusion increased and decreased, respectively in response to training and C. oxyacantha. These findings suggest that 10 weeks resistance training and C. oxyacantha can synergistically decrease ischemia-reperfusion injury, and this mechanism may be related to a reduction in oxidative stress which is normally associated with ischemia-reperfusion. PMID- 29477091 TI - Prediction of parental posttraumatic stress, anxiety and depression after a child's critical hospitalization. AB - OBJECTIVE: To study the role of parental resilience, emotions accessed during admission and perceived stress in predicting the degree of parental posttraumatic stress disorder (PTSD), anxiety and depression symptoms after a child's treatment in intensive care. METHODS: This was prospective longitudinal cohort study. A total of 196 parents of pediatric intensive care survivors completed questionnaires assessing resilience, perceived stress, emotions experienced during admission, 48h post-discharge (T0). Sociodemographic and medical data were also collected. Main outcomes were anxiety, depression and PTSD, three (T1) and six (T2) months later. RESULTS: At T2, 23% of parents reported clinically significant levels of symptoms of PTSD, 21% reported moderate-severe anxiety, and 9% reported moderate-severe depression. These rates were not statistically different to rates at T1. Path analyses indicated that 47% of the variance in psychopathology symptoms at T2 could be predicted from the variables assessed at T0. Resilience was a strong negative predictor of psychopathology symptoms, but this effect was mostly indirect, mediated by the stress that parents perceive during their child's critical hospitalization. CONCLUSIONS: Mobilizing coping in order to maintain resilience and to decrease their perceived stress levels could improve parents' mental health outcomes following their child's intensive care treatment. PMID- 29477092 TI - Evaluation of three statistical prediction models for forensic age prediction based on DNA methylation. AB - DNA methylation is a promising biomarker for forensic age prediction. A challenge that has emerged in recent studies is the fact that prediction errors become larger with increasing age due to interindividual differences in epigenetic ageing rates. This phenomenon of non-constant variance or heteroscedasticity violates an assumption of the often used method of ordinary least squares (OLS) regression. The aim of this study was to evaluate alternative statistical methods that do take heteroscedasticity into account in order to provide more accurate, age-dependent prediction intervals. A weighted least squares (WLS) regression is proposed as well as a quantile regression model. Their performances were compared against an OLS regression model based on the same dataset. Both models provided age-dependent prediction intervals which account for the increasing variance with age, but WLS regression performed better in terms of success rate in the current dataset. However, quantile regression might be a preferred method when dealing with a variance that is not only non-constant, but also not normally distributed. Ultimately the choice of which model to use should depend on the observed characteristics of the data. PMID- 29477093 TI - In vitro and in silico evaluation of Centaurea saligna (K.Koch) Wagenitz-An endemic folk medicinal plant. AB - Centaurea saligna (K.Koch) Wagenitz is an endemic plant used in Turkish folk medicine as antibacterial, tonic, astringent, choleretic, anti-rheumatic, diuretic, and antipyretic. This study attempts for the first time to assess the possible enzyme inhibitory potential, antioxidant activity, and determine the phytochemical profile of the ethyl acetate, methanol, and water extracts of C. saligna. The water extract had the highest phenolic content (30.18 mg GAE/g extract) and the most potent oxidant scavenging activity ((120.53, 111.90, 68.43, and 157.88 mg TE/g extract, for CUPRAC [cupric reducing antioxidant capacity], FRAP [ferric reducing antioxidant power], DPPH [2,2-diphenyl-1-picrylhydrazyl], and ABTS [2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid] assays respectively)). The water extract (4.16 mg KAE/g extract) also inhibited tyrosinase and contained high level of catechin (214 MUg/g extract). Ethyl acetate extract showed potent inhibitory capacity against cholinesterases (2.22 and 2.21 mg GALAE/g extract for acetyl and butyryl cholinesterase, respectively) and alpha-glucosidase (23.80 mmol ACAE/g extract). High concentration of apigenin (2472 MUg/g extract) was identified in the ethyl acetate extract. In silico studies showed that apigenin binds to the enzymatic pocket of alpha-glucosidase and is stabilised by a network of hydrogen bonds and pi-pi stacking. Data collected in the present study advocates the need for further investigation geared towards validation of C. saligna for the management of complications related to the target enzymes, such as diabetes type II, Alzheimer's disease, and epidermal hyperpigmentation. PMID- 29477094 TI - Children's use of comparison and function in novel object categorization. AB - Although young children often rely on salient perceptual cues, such as shape, when categorizing novel objects, children eventually shift towards deeper relational reasoning about category membership. This study investigates what information young children use to classify novel instances of familiar categories. Specifically, we investigated two sources of information that have the potential to facilitate the classification of novel exemplars: (1) comparison of familiar category instances, and (2) attention to function information that might direct children's attention to functionally relevant perceptual features. Across two experiments, we found that comparing two perceptually similar category members-particularly when function information was also highlighted-led children to discover non-obvious relational features that supported their categorization of novel category instances. Together, these findings demonstrate that comparison may aid in novel object categorization by heightening the salience of less obvious, yet functionally relevant, relational structures that support conceptual reasoning. PMID- 29477095 TI - Vocabulary matters! The relationship between verbal fluency and measures of inhibitory control in monolingual and bilingual children. AB - The role of early bilingual experience in the development of skills in the general cognitive and linguistic domains remains poorly understood. This study investigated the link between these two domains by assessing inhibitory control processes in school-aged monolingual and bilingual children with similar English receptive vocabulary size. The participants, 8-year-old monolinguals and bilinguals, completed two Verbal Fluency Tasks (VFTs), letter and category, and two measures of inhibitory control. Results showed that bilinguals outperformed monolinguals on the VFTs, but performance was similar on the inhibitory control measures approaching ceiling for both monolingual and bilingual children. Importantly, it was shown that both vocabulary proficiency and general inhibitory control skills underlie monolingual and bilingual children's performance on VFTs. These results demonstrate that vocabulary proficiency plays a fundamental role in comparing monolingual and bilingual VFT performance. The bilingual advantage found in this study seems to have escaped previous studies that did not account for vocabulary size in populations of bilingual and monolingual school-aged children. PMID- 29477096 TI - The PHQ-9 Item 9 based screening for suicide risk: a validation study of the Patient Health Questionnaire (PHQ)-9 Item 9 with the Columbia Suicide Severity Rating Scale (C-SSRS). AB - BACKGROUND: Item 9 of the Patient Health Questionnaire (PHQ) evaluates passive thoughts of death or self-injury within the last two weeks, and is often used to screen depressed patients for suicide risk. We aimed to validate the PHQ-9 item 9 with a brief electronic version of the Columbia Suicide Severity Rating Scale (eC SSRS). METHODS: We analyzed data from 841 patients enrolled in the National Network of Depression Centers Clinical Care Registry. We performed a validation analysis of PHQ-9 item 9 for suicide risk and ideation, using the eC-SSRS as a gold standard (defined as positive response to suicidal ideation with intent to act or recent suicidal behavior). RESULTS: Of the 841 patients, 13.4% and 41.1% were assessed as being positive for suicide risk by the eC-SSRS and PHQ-9 item 9, respectively. For the overall cohort, sensitivity was 87.6% (95%CI 80.2-92.5%), specificity was 66.1% (95%CI 62.6-69.4%), PPV was 28.6% (95%CI 24.1-33.6%), and NPV was 97.2% (95%CI 95.3-98.3%) for the PHQ-9 suicide item. These performance measures varied within subgroups defined by demographic and clinical characteristics. In addition, the validity of PHQ-9 item 9 (cutoff score of 1) with eC-SSRS-defined suicide ideation showed overall poor results. LIMITATIONS: The gold standard used in our study was a surrogate measure of suicidality based on eC-SSRS scores. CONCLUSIONS: The results of our study suggest that item 9 of the PHQ-9 is an insufficient assessment tool for suicide risk and suicide ideation, with limited utility in certain demographic and clinical subgroups that requires further investigation. PMID- 29477097 TI - Emotional dysregulation is a primary symptom in adult Attention Deficit/Hyperactivity Disorder (ADHD). AB - BACKGROUND: Clinical observations suggest that adults have more diverse deficits than children with Attention Deficit/Hyperactivity Disorder (ADHD). These seem to entail difficulties with emotionality, self-concept and emotion regulation in particular, along with the cardinal symptoms of inattention, impulsivity, and hyperactivity for adult patients. Here, we probed a model that explicitly distinguished positive and negative affect, problems with self-concept and emotion regulation skills as distinct but correlating factors with the symptom domains of inattention, hyperactivity, and impulsivity. METHODS: Participants were 213 newly diagnosed adults with ADHD (62.9% male, mean age 33.5 years). Symptoms were assessed via self-report on the Conners' Adult ADHD Rating Scales, a modified version of the Positive and Negative Affect Scale and the Emotion Regulation Skill Questionnaire. A confirmatory factor analysis with the R package lavaan, using a robust Maximum Likelihood estimator (MLR) for non-normal data, was conducted to test our new non-hierarchical 7-factor model. RESULTS: All calculated model-fit statistics revealed good model-fit (chi2/df ratio = 2.03, robust RMSEA = .07). The SRMR in our model reached .089, indicating an acceptable model fit. Factor loadings on the postulated factors had salient loadings >= .31 except for one item on the hyperactivity factor. Latent factor associations were especially salient between emotional dysregulation and problems with self concept, and also partially with impulsivity/emotional lability. LIMITATIONS: The three models of ADHD and emotion regulation as suggested by Shaw et al. (2014) could not be disentangled in this study, though the overall results support the model with shared neurocognitive deficits. Further, we did not separately analyze ADHD with or without comorbid disorders. As our sample of clinical cases with ADHD is highly comorbid (47.9%), other disorders than ADHD might account for the emotion regulation deficits, though a sensitivity analysis revealed no such differences. CONCLUSIONS: Our model adequately characterizes the relations between and among clinically and therapeutically relevant symptoms in adult ADHD, thus potentially informing future therapeutic interventions by targeting the successful and flexible use of adaptive emotion regulation skills. PMID- 29477098 TI - The effects of low-intensity narrow-band blue-light treatment compared to bright white-light treatment in seasonal affective disorder. AB - BACKGROUND: Ever since a new photoreceptor was discovered with a highest sensitivity to 470-490 nm blue light, it has been speculated that blue light has some advantages in the treatment of Seasonal Affective Disorder (SAD) over more traditional treatments. In this study we compared the effects of exposure to narrow-band blue light (BLUE) to those of broad-wavelength white light (BLT) in the treatment of SAD. METHODS: In a 15-day design, 45 patients suffering from SAD completed 30-min sessions of light treatment on 5 consecutive days. 21 subjects received white-light treatment (BLT, broad-wavelength without UV, 10 000 lx, irradiance 31.7 W/m2), 24 subjects received narrow-band blue light (BLUE, 100 lx, irradiance 1.0 W/m2). All participants completed weekly questionnaires concerning mood and energy levels, and were also assessed by means of the SIGH-SAD, which is the primary outcome measure. RESULTS: On day 15, SIGH-SAD ratings were significantly lower than on day 1 (BLT 73.2%, effect size 3.37; BLUE 67%, effect size 2.63), which outcomes were not statistically significant different between both conditions. LIMITATIONS: Small sample size. CONCLUSIONS: Light treatment is an effective treatment for SAD. The use of narrow-band blue light is equally effective as a treatment using bright white-light. PMID- 29477099 TI - An exploratory study on differences in cumulative plantar tissue stress between healing and non-healing plantar neuropathic diabetic foot ulcers. AB - BACKGROUND: Mechanical stress is important in causing and healing plantar diabetic foot ulcers, but almost always studied as peak pressure only. Measuring cumulative plantar tissue stress combines plantar pressure and ambulatory activity, and better defines the load on ulcers. Our aim was to explore differences in cumulative plantar tissue stress between people with healing and non-healing plantar diabetic foot ulcers. METHODS: We analyzed a subgroup of 31 patients from a randomized clinical trial, treated with a removable offloading device for their plantar diabetic forefoot ulcer. We measured in-device dynamic plantar pressure and daily stride count to calculate cumulative plantar tissue stress at the ulcer location and associated this with ulcer healing and ulcer surface area reduction at four weeks (Student's t and chi-square test for significance, Cohen's d for effect size). FINDINGS: In 12 weeks, 68% (n = 21) of the ulcers healed and 32% (n = 10) did not. No statistically significant differences were found for cumulative plantar tissue stress, plantar pressure or ambulatory activity between people with healed and not-healed ulcers. Cumulative plantar tissue stress was 25% lower for people with healed ulcers (155 vs. 207 MPa.s/day; P = 0.71; Effect size: d = 0.29). Post-hoc analyses in the 27 patients who self-reported to be adherent to wearing the device showed that cumulative plantar tissue stress was 49% lower for those who reached >=75% ulcer surface area reduction at four weeks (140 vs. 275 MPa.s/day; P = 0.09; d = 0.76); smaller differences and effect sizes were found for peak pressure (24%), peak pressure time integral (30%) and ambulatory activity (26%); (P-value range: 0.14-0.97; Cohen's d range: 0.14-0.70). INTERPRETATION: Measuring cumulative plantar tissue stress may provide insight beyond that obtained from plantar pressure or ambulatory activity alone, with regard to diabetic foot ulcer healing using removable offloading devices. These explorative findings provide baseline data for further studies on this relevant topic. PMID- 29477100 TI - Diversity of brain metastases screening and management in non-small cell lung cancer in Europe: Results of the European Organisation for Research and Treatment of Cancer Lung Cancer Group survey. AB - BACKGROUND: Brain metastases (BM) are frequent in non-small cell lung cancer (NSCLC) patients, but there is a lack of evidence-based management of this patient group. We aimed to capture a snapshot of routine BM management in Europe to identify relevant research questions for future clinical trials. METHODS: An EORTC Lung Cancer Group (LCG) online survey containing questions on NSCLC BM screening and treatment was distributed between 16/02/17 and 15/06/17 to worldwide EORTC LCG members, and through several European scientific societies in the thoracic oncology field. RESULTS: A total of 462 European physician responses (394 institutions) were analysed (radiation oncologist: 53% [n = 247], pulmonologist: 26% [n = 119], medical oncologist: 18% [n = 84]; 84% with >5 years' experience in NSCLC). Italy (18%, n = 85), Netherlands (15%, n = 68), UK (14%, n = 66), and France (12%, n = 55) contributed most. 393 physicians (85%) screened neurologically asymptomatic patients for BM at diagnosis (52% using magnetic resonance imaging). Most often screened patients were those with a driver mutation (MUT+; 51%, n = 234), stage III (63%, n = 289), and IV (43%, n = 199). 158 physicians (34%) used a prognostic classification to guide initial treatment decisions, and in 50%, lowest prognostic-score threshold to receive treatment differed between MUT+ and non-driver mutation (MUT-) patients. MUT+ patients with >4 BM were more likely to receive stereotactic radiosurgery (SRS) compared with MUT- (27% versus. 21%; p < 0.01). Most physicians (90%) had access to SRS. After single BM surgery, 50% systematically prescribed SRS or WBRT, and 45% only in case of incomplete resection. The preferred treatment in neurologically asymptomatic treatment-naive patients diagnosed with >5 BM was systemic treatment (79%). Of all, 45%/49% physicians stated that all tyrosine kinase inhibitors and immune checkpoint blockers were discontinued (timing varied) during SRS/WBRT, respectively. Drugs most often continued during SRS/WBRT were erlotinib (44%/40%), gefitinib (39%/34%), afatinib (29%/25%), crizotinib (33%/26%) and anti-PD-(L)-1 (28%/22%). CONCLUSION: BM management is highly variable in Europe: screening is not uniform, prognostic classifications are not often used and MUT+ NSCLC patients generally receive more intensive local treatment. Prospective assessment of BM management in MUT+ NSCLC patients is required. PMID- 29477101 TI - Blood classification and blood response criteria in mycosis fungoides and Sezary syndrome using flow cytometry: recommendations from the EORTC cutaneous lymphoma task force. AB - Our current mycosis fungoides (MF) and Sezary Syndrome (SS) staging system includes blood-classification from B0-B2 for patch/plaque/tumour or erythroderma based on manual Sezary counts but results from our EORTC survey confirm these are rarely performed in patch/plaque/tumour MF, and there is a trend towards using flow cytometry to measure blood-class. Accurately assigning blood-class effects overall stage and the 'global response' used to measure treatment responses in MF/SS and hence impacts management. The EORTC Cutaneous Lymphoma Task Force Committee have reviewed the literature and held a Workshop (June 2017) to agree a definition of blood-class according to flow cytometry. No large study comparing blood-class as defined by Sezary count with flow cytometry has been performed in MF/SS. The definition of blood-class by flow cytometry varies between publications. Low-level blood involvement occurs in patch/plaque/tumour much less than erythroderma (p < 0.001). The prognostic relevance of blood involvement (B1 or B2) in patch/plaque/tumour is not known. Studies have not shown a statistically worse difference in prognosis in erythrodermic MF patients with low level blood involvement (IIIB) versus those without (IIIA), but Sezary patients who by definition have a leukaemic blood picture (staged IVA1 or higher) have a worse prognosis. For consistency flow, definition for blood-class must be an objective measurement. We propose absolute counts of either CD4+CD7-or CD4+CD26 where B0<250/MUL, B1 = 250/MUl-<1000/MUL and B2>=1000/MUL plus a T-cell blood clone. Fluctuations between B0 and B1 should not be considered in the treatment response criteria until further prognostic information is known. PMID- 29477103 TI - Idiopathic scrotal calcinosis - A case report. AB - INTRODUCTION: Idiopathic scrotal calcinosis is a rare benign condition which presents with asymptomatic multiple nodules on the scrotal skin. PRESENTATION OF CASE: Our patient, a 64-year-old Indian male with Fitzpatrick skin type 4, presented with multiple nodules, which were completely surgically excised with no complications. Histological examination reveals extensive intradermal deposition of calcium surrounded by histiocytes and without cystic structure. DISCUSSION: Numerous theories about the pathogenesis have been proposed and the evidence presented suggests this is a continuum. CONCLUSION: The nature of idiopathic scrotal calcinosis is still unknown and it is up to debate whether the term "idiopathic" is appropriate for the condition. PMID- 29477104 TI - Presentation of a Hemangioblastoma in cavernous sinus: An extremely rare case report. AB - INTRODUCTION: Hemangioblastoma (HB) is a benign vascular tumor that accounts for about 2% of intracranial neoplasms. HB of the cavernous sinus (CS) is extremely rare. Only one report was found in the literature. PRESENTATION OF CASE: We present a 29-year-old female with progressive headache and she had right ptosis and right mild oculomotor nerve palsy. The brain Magnetic Resonance Imaging (MRI) revealed a right extra-axial 4 * 4 cm in right CS position. The patient was operated upon microscopically via sub-temporal approach through a right temporal craniotomy. After the subtotal removal of a highly vascular tumor, the patient was referred for adjuvant therapy with Gamma-knife surgery. DISCUSSION: Surgical removal of HB is the most effective treatment of the central nervous system (CNS) HBs. Tumors invading the CS could cause severe bleeding during surgery and HB because of its vascular origin-had more risk for severe intraoperative bleeding, and in some cases resulted in surgery stop with subtotal resection of tumor. CONCLUSION: It was recommended to perform a pre-operative brain angiography and selective embolization of these highly vascular lesions that it could result in subsequent complete surgical removal. PMID- 29477102 TI - Treatment strategies, outcomes and prognostic factors in 291 patients with secondary CNS involvement by diffuse large B-cell lymphoma. AB - PURPOSE: Secondary CNS involvement (SCNS) is a profoundly adverse complication of diffuse large B-cell lymphoma. Evidence from older series indicated a median overall survival (OS) < 6 months; however, data from the immunochemotherapy era are limited. METHODS: Patients diagnosed with SCNS during or after first-line immunochemotherapy were identified from databases and/or regional/national registries from three continents. Clinical information was retrospectively collected from medical records. RESULTS: In total, 291 patients with SCNS were included. SCNS occurred as part of first relapse in 254 (87%) patients and 113 (39%) had concurrent systemic relapse. With a median post-SCNS follow-up of 48 months, the median post-SCNS OS was 3.9 months and 2-year OS rate was 20% (95% CI: 15-25). In multivariable analysis of 173 patients treated with curative/intensive therapy (such as high-dose methotrexate [HDMTX] or platinum containing regimens), age <=60 years, performance status 0-1, absence of combined leptomeningeal and parenchymal involvement, and SCNS occurring after completion of first-line therapy were associated with superior outcomes. Patients <=60 years with performance status 0-1 and treated with HDMTX-based regimens for isolated parenchymal SCNS had a 2-year OS of 62% (95% CI: 36-80). In patients with isolated SCNS, the addition of rituximab to HDMTX-based regimens was associated with improved OS. Amongst patients with isolated SCNS in CR following intensive treatment, high-dose chemotherapy and autologous stem cell transplantation did not improve OS (P = 0.9). CONCLUSIONS: In this large international cohort of patients treated with first-line immunochemotherapy, outcomes following SCNS remain poor. However, a moderate proportion of patients with isolated SCNS who received intensive therapies achieved durable remissions. PMID- 29477105 TI - Hepatic portal venous gas associated with transcathete cardiac defibrillator implantation: A case report. AB - INTRODUCTION: Hepatic Portal Venous Gas (HPVG) is a rare pathological condition that may be caused by iatrogenic factors. CASE REPORT: A 66-year-old Chinese male patient with HPVG underwent laparotomy for chronic bowel ischemia. Transcathete cardiac defibrillator was implanted via left subclavian vein for ventricular tachycardia. DISCUSSION: There are many hypotheses about how gas runs through the intestine into the mesenteric portal venous system. HPVG patients can be improved through comprehensive management. Patients with mesenteric ischemia should be observed in hospital and after discharge, and need surgical intervention if chronic bowel ischemia recurs. CONCLUSION: This case proves the usefulness of comprehensive management in treating HPVG. Prognosis of HPVG should consider the pathological changes contributing to HPVG. PMID- 29477106 TI - A galling disease? Dieulafoy's lesion of the gallbladder. AB - INTRODUCTION: Dieulafoy's lesion is a rare vascular anomaly characterized by an abnormally large and tortuous submucosal arteriole leading to an area of mucosal defect with minimal inflammation. It is most often seen in the stomach but could occur anywhere along the gastrointestinal tract. Only five cases of gallbladder Dieulafoy's lesion have been published so far. PRESENTATION OF CASE: We report a case of Dieulafoy's lesion in the gallbladder in a 44 year-old patient who presented with calculous cholecystitis. DISCUSSION: The clinical, radiologic and histologic findings are discussed in light of the existing literature on Dieulafoy's lesions of the gallbladder. CONCLUSION: Gallbladder Dieulafoy's lesion has potentially serious complications and emergency surgery is often required. Due to the rarity of the entity, the diagnosis is often not considered. PMID- 29477107 TI - Evolution of mechanotransduction via YAP/TAZ in animal epithelia. AB - Mechanical stretch forces can control the growth of epithelial tissues such as mammalian skin, whose surface area is precisely coordinated with body size. In skin keratinocytes cultured in vitro, mechanical forces acting via Integrin adhesions and the actin cytoskeleton have been shown to induce nuclear translocation of YAP/TAZ co-activators to induce cell proliferation. Furthermore, conditional knockouts of both YAP (also called YAP1) and TAZ (also called WWTR1) in mouse skin resemble the phenotype of skin-specific loss of Integrin beta1 (ITGB1), indicating that this signalling mechanism is important in vivo. Curiously, Integrins are dispensable in Drosophila to activate the sole YAP/TAZ homolog Yorkie (Yki), which has lost the C-terminal PDZ-binding motif needed to promote nuclear localization of YAP/TAZ in mammalian cells. Differences in the structure of the epidermis between deuterostomes (e.g.: stratified squamous skin of mammals) and protostomes (e.g.: monolayered columnar epidermis of Drosophila) may explain this evolutionary divergence. Monolayered columnar epithelia feature a well-differentiated apical membrane domain, where proteins such as Crumbs, Expanded, Merlin and Kibra activate the Hippo pathway to repress Drosophila Yki. Stratified squamous epithelia lack an apical domain and thus depend primarily on basal Integrin adhesions to activate YAP/TAZ in basal layer stem cells via multiple postulated signalling mechanisms. Finally, YAP and TAZ retain the ability to sense the apical domain in the columnar epithelial cells lining internal organs such as the lung bronchus, where YAP/TAZ localize to the nucleus in proliferating basal layer stem cells but translocate to the cytoplasm in differentiated columnar cells. PMID- 29477108 TI - Lymphocyte-Related Inflammation and Immune-Based Scores Predict Prognosis of Chordoma Patients After Radical Resection. AB - The inflammatory microenvironment plays a critical role in the development and progression of malignancies. In the present study, we aimed to evaluate the prognostic value of lymphocyte-related inflammation and immune-based prognostic scores in patients with chordoma after radical resection, including the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte lymphocyte ratio (MLR), and systemic immune-inflammation index (SII). A total of 172 consecutive patients with chordoma who underwent radical resection were reviewed. R software was used to randomly select 86 chordoma patients as a training set and 86 chordoma patients as a validation set. Potential prognostic factors were also identified, including age, sex, tumor localization, KPS, Enneking stage, tumor size, and tumor metastasis. Overall survival (OS) was calculated using the Kaplan-Meier method and multivariate Cox regression analyses. NLR, PLR, SII, Enneking stage, tumor differentiation and tumor metastasis were identified as significant factors from the univariate analysis in both the training and validation sets and were subjected to multivariate Cox proportional hazards analysis. The univariate analysis showed that NLR >=1.65, PLR >=121, and SII >=370*109/L were significantly associated with poor OS. In the multivariate Cox proportional hazard analysis, SII, Enneking stage and tumor metastasis were significantly associated with OS. As noninvasive, low-cost, reproducible prognostic biomarkers, NLR, PLR and SII could help predict poor prognosis in patients with chordoma after radical resection. This finding may contribute to the development of more effective tailored therapy according to the characteristics of individual tumors. PMID- 29477109 TI - Diverse and abundant antibiotic resistance genes from mariculture sites of China's coastline. AB - With the rapid development of mariculture in China, large amounts of antibiotics are being discharged into the aquatic environment. Little information is available regarding antibiotics and corresponding antibiotic resistance genes (ARGs) associated with maricultural environments in China. Sediments from eleven typical mariculture areas along the whole coastline of China were collected, and the sediment in Meijijiao in southern China was used as a non-mariculture control. The results revealed that antibiotics and their corresponding ARGs were widely distributed in most maricultural sediments, and present at low concentrations in samples from Meijijiao. The sulfonamide-resistance genes were prevalent, and the sul1 and sul2 in Penglai were the highest detected by using quantitative PCR. Moreover, remarkable differences in ARGs among different sites were observed. Due to the limited availability of primers to detect ARGs, illumina high-throughput sequencing was also used for profiling ARGs, and the results showed that the abundance of bacA in all samples was the highest compared to other ARGs, followed by mexF and mexB. This is the first study to comprehensively investigate the antibiotic resistance profile in typical mariculture areas along the whole coast of China. This study provides insights into the impacts of mariculture on the profiles of bacterial and ARG compositions in China. PMID- 29477110 TI - Tropical land-sea couplings: Role of watershed deforestation, mangrove estuary processing, and marine inputs on N fluxes in coastal Pacific Panama. AB - We review data from coastal Pacific Panama and other tropical coasts with two aims. First, we defined inputs and losses of nitrogen (N) mediating connectivity of watersheds, mangrove estuaries, and coastal sea. N entering watersheds-mainly via N fixation (79-86%)-was largely intercepted; N discharges to mangrove estuaries (3-6%), small compared to N inputs to watersheds, nonetheless significantly supplied N to mangrove estuaries. Inputs to mangrove estuaries (including watershed discharges, and marine inputs during flood tides) were matched by losses (mainly denitrification and export during ebb tides). Mangrove estuary subsidies of coastal marine food webs take place by export of forms of N [DON (62.5%), PN (9.1%), and litter N (12.9%)] that provide dissimilative and assimilative subsidies. N fixation, denitrification, and tidal exchanges were major processes, and DON was major form of N involved in connecting fluxes in and out of mangrove estuaries. Second, we assessed effects of watershed forest cover on connectivity. Decreased watershed forest cover lowered N inputs, interception, and discharge into receiving mangrove estuaries. These imprints of forest cover were erased during transit of N through estuaries, owing to internal N cycle transformations, and differences in relative area of watersheds and estuaries. Largest losses of N consisted of water transport of energy-rich compounds, particularly DON. N losses were similar in magnitude to N inputs from sea, calculated without considering contribution by intermittent coastal upwelling, and hence likely under-estimated. Pacific Panama mangrove estuaries are exposed to major inputs of N from land and sea, which emphasizes the high degree of bi directional connectivity in these coupled ecosystems. Pacific Panama is still lightly affected by human or global changes. Increased deforestation can be expected, as well as changes in ENSO, which will surely raise watershed-derived loads of N, as well as significantly change marine N inputs affecting coastal coupled ecosystems. PMID- 29477111 TI - Discrepant responses of methane emissions to additions with different organic compound classes of rice straw in paddy soil. AB - Crop straw incorporation has become a prevailing agricultural practice that guarantees the food production and security. There is a significant body of work on the effects of straw incorporation on the methane (CH4) emissions in paddy fields. However, it is unclear whether there are diverse links between CH4 emission dynamics and incorporations of different organic compound classes of straw to paddy fields. In this study, soil incubations were conducted to assess the respective effect of incorporations of hydrolysable amino acid (HAA), dilute acid extractable carbohydrate (DAC), lipid and acid-insoluble organic matter (AIOM) fractions of rice straw on the CH4 emission in paddy soil. It is revealed that incorporations of HAA and DAC fractions exert the greatest intensities to stimulate the CH4 emissions, which mainly takes place in the early period of incubation; on contrary, the incorporation of lipid fraction exerts the lowest intensity and mainly takes place in the late period. The pattern of CH4 emission after incorporation of AIOM fraction occurs peaks both in the early and late periods of incubation. Our findings highlight that the time of occurrence and intensity of effects of rice straw incorporation on CH4 emissions vary significantly depending on the different organic compound classes of rice straw, which may be key to proposing a promising management strategy for mitigating CH4 emissions in paddy fields in the context of straw incorporation. PMID- 29477112 TI - Microcolumn-based speciation analysis of thallium in soil and green cabbage. AB - Thallium (Tl) is a toxic trace metal, whose geochemical behavior and biological effects are closely controlled by its chemical speciation in the environment. However, little tends to be known about this speciation of Tl in soil and plant systems that directly affect the safety of food supplies. In this context, the objective of the present study was to elaborate an efficient method to separate and detect Tl(I) and Tl(III) species for soil and plant samples. This method involves the selective adsorption of Tl(I) on microcolumns filled with immobilized oxine, in the presence of DTPA (diethylenetriaminepentaacetic acid), followed by DTPA-enhanced ultrasonic and heating-induced extraction, coupled with ICP-MS detection. The method was characterized by a LOD of 0.037 MUg/L for Tl(I) and 0.18 MUg/L for Tl(III) in 10 mL samples. With this method, a second objective of the research was to assess the speciation of Tl in pot and field soils and in green cabbage crops. Experimental results suggest that DTPA extracted Tl was mainly present as Tl(I) in soils (>95%). Tl in hyperaccumulator plant green cabbage was also mainly present as Tl(I) (>90%). With respect to Tl uptake in plants, this study provides direct evidence that green cabbage mainly takes up Tl(I) from soil, and transports it into the aboveground organs. In soils, Tl(III) is reduced to Tl(I) even at the surface where the chemical environment promotes oxidation. This observation is conducive to understanding the mechanisms of Tl isotope fractionation in the soil-plant system. Based on geochemical fraction studies, the reducible fraction was the main source of Tl getting accumulated by plants. These results indicate that the improved analytical method presented in this study offers an economical, simple, fast, and sensitive approach for the separation of Tl species present in soils at trace levels. PMID- 29477114 TI - The distribution and accumulation of phosphate flame retardants (PFRs) in water environment. AB - Phosphate flame retardants (PFRs) were measured in surface water (n=11), suspended particle matter (SPM, n=11), sediment (n=11), and fish samples (n=26) from the Pearl River Delta located in South China. Triethyl phosphate (TEP), tri(2-chloroethyl) phosphate (TCEP), tris(chloroisopropyl) phosphate (TCIPP), tri n-butyl phosphate (TNBP), triphenyl phosphate (TPHP), and tricresyl phosphate (TMPP) were detected in more than half of surface water, SPM, and sediment samples. The median SigmaPFR levels were 837ng/L, 54.6ng/g dry weight (dw), and 37.1ng/g dw in surface water, SPM, and sediment samples, respectively. No significant correlations were found between the concentrations of most PFRs and organic carbon contents in SPM and sediment (p>0.05). In surface water samples, tris(2-butoxyethyl) phosphate (TBOEP, 27% of SigmaPFRs) and TEP (23% of SigmaPFRs) were the predominant chemicals, while TNBP (38% of SigmaPFRs) and TCEP (32% of SigmaPFRs) dominated in SigmaPFRs in SPM samples, and TCEP (48% of SigmaPFRs) and TCIPP (25% of SigmaPFRs) dominated in SigmaPFRs in sediment samples. The proportions of phenyl-PFRs and chlorinated-PFRs in SigmaPFRs increased from surface water to SPM and sediment. The distribution ratios of PFRs between water and organic carbon in SPM (or observed KOC) were generally 2-3 orders of magnitude higher than the predicted KOC. TNBP (nd-2.42ng/g wet weight (ww)), TCEP (nd-4.96ng/g ww), and TCIPP (nd-2.42ng/g ww) were detected in 27%, 35%, and 23% of all fish samples, respectively. The log bioaccumulation factors (BAFs) ranged 2.56-2.78, 2.15-3.11, and 2.61-3.10 for TNBP, TCEP, and TCIPP, respectively. The biota-sediment accumulation factors (BSAFs) of TNBP, TCEP, and TCIPP were generally lower than 1 except for the BSAF of TCIPP in common carp. The results indicate the species-specific bioaccumulation of PFRs in fish species. PMID- 29477113 TI - Traditional and novel halogenated flame retardants in urban ambient air: Gas particle partitioning, size distribution and health implications. AB - Urban ambient air samples, including gas-phase (PUF), total suspended particulates (TSP), PM10, PM2.5 and PM1 airborne particle fractions were collected to evaluate gas-particle partitioning and size particle distribution of traditional and novel halogenated flame retardants. Simultaneously, passive air samplers (PAS) were deployed in the same location. Analytes included 33 polybrominated diphenyl ether (PBDE), 2,2',4,4',5,5'-hexabromobiphenyl (BB-153), hexabromobenzene (HBB), pentabromoethylbenzene (PBEB), 1,2-bis(2,4,6 tribromophenoxy)ethane (BTBPE), decabromodiphenyl ethane (DBDPE), dechloranes (Dec 602, 603, 604, 605 or Dechorane plus (DP)) and chlordane plus (CP). Clausius Clapeyron equation, gas-particle partition coefficient (Kp), fraction partitioned onto particles (phi) and human respiratory risk assessment were used to evaluate local or long-distance transport sources, gas-particle partitioning sorption mechanisms, and implications for health, respectively. PBDEs were the FR with the highest levels (13.9pgm-3, median TSP+PUF), followed by DP (1.56pgm-3), mirex (0.78pgm-3), PBEB (0.05pgm-3), and BB-153 (0.04pgm-3). PBDE congener pattern in particulate matter was dominated by BDE-209, while the contribution of more volatile congeners, BDE-28, -47, -99, and -100 was higher in gas-phase. Congener contribution increases with particle size and bromination degree, being BDE-47 mostly bounded to particles<=PM1, BDE-99 to > PM1 and BDE-209 to > PM2.5. No significant differences were found for PBDE and DP concentrations obtained with passive and active samplers, demonstrating the ability of the formers to collect particulate material. Deposition efficiencies and fluxes on inhaled PBDEs and DP in human respiratory tract were calculated. Contribution in respiratory track was dominated by head airway (2.16 and 0.26pgh-1, for PBDE and DP), followed by tracheobronchial (0.12 and 0.02pgh-1) and alveoli (0.01-0.002pgh-1) regions. Finally, hazard quotient values on inhalation were proposed (6.3*10-7 and 1.1*10 8 for PBDEs and DP), reflecting a low cancer risk through inhalation. PMID- 29477115 TI - Effects of thinning intensity on understory vegetation and soil microbial communities of a mature Chinese pine plantation in the Loess Plateau. AB - Thinning can effectively improve forest production and maintain ecological stability. However, the changes in soil microbial community compositions after thinning are still not well understood. In this study, we investigated the changes in the soil microbial community of mature Chinese pine (Pinus tabuliformis) plantations in the Loess Plateau after 11years of four different thinning intensity treatments. Furthermore, the responses of the soil microbial community to changes in understory plants and soil properties were analyzed. The ratios of wood removal investigated were 0 (CK), 15% (LIT), 30% (MIT) and 45% (HIT). Compared with the CK, thinning significantly increased the Shannon index, species richness, coverage and biomass of the understory plants, and these values were highest for the HIT. The soil organic carbon (SOC), total nitrogen (TN), total phosphorus (TP), nitrate nitrogen (NO3--N) and available phosphorus (AP) concentrations increased with increasing thinning intensity. Thinning intensity did not significantly affect soil microbial community diversity indices. With respect to the dominant bacterial groups, the relative abundance of Proteobacteria was much higher in the HIT, while that of Acidobacteria was much higher in the LIT and CK. For the dominant fungal groups, the relative abundance of Basidiomycota was lowest in the HIT, while that of Ascomycota was highest in the same treatment. Redundancy analysis (RDA) showed that SOC, TN, and AP significantly correlated with soil bacterial communities and that SOC, TN, TP, AP and NO3--N significantly correlated with soil fungal communities. The understory vegetation influenced soil fungal communities rather than soil bacterial communities. These findings suggest that the aboveground vegetation diversity and soil nutrients were improved with the increased thinning intensity after 11years. The copiotrophic groups (e.g. Proteobacteria) and oligotrophic groups (e.g. Acidobacteria) differed significantly among the four thinning treatments, indicating a dependence of the soil microbial community composition on soil nutrients. PMID- 29477116 TI - Individual and combined effects of multiple global change drivers on terrestrial phosphorus pools: A meta-analysis. AB - Human activity-induced global change drivers have dramatically changed terrestrial phosphorus (P) dynamics. However, our understanding of the interactive effects of multiple global change drivers on terrestrial P pools remains elusive, limiting their incorporation into ecological and biogeochemical models. We conducted a meta-analysis using 1751 observations extracted from 283 published articles to evaluate the individual, combined, and interactive effects of elevated CO2, warming, N addition, P addition, increased rainfall, and drought on P pools of plant (at both single-plant and plant-community levels), soil and microbial biomass. Our results suggested that (1) terrestrial P pools showed the most sensitive responses to the individual effects of warming and P addition; (2) P pools were consistently stimulated by P addition alone or in combination with simultaneous N addition; (3) environmental and experimental setting factors such as ecosystem type, climate, and latitude could significantly influence both the individual and combined effects; and (4) the interactive effects of two-driver pairs across multiple global change drivers are more likely to be additive rather than synergistic or antagonistic. Our findings highlighting the importance of additive interactive effects among multiple global change drivers on terrestrial P pools would be useful for incorporating P as controls on ecological processes such as photosynthesis and plant growth into ecosystem models used to analyze effects of multiple drivers under future global change. PMID- 29477117 TI - Sub-inhibitory concentrations of heavy metals facilitate the horizontal transfer of plasmid-mediated antibiotic resistance genes in water environment. AB - Although widespread antibiotic resistance has been mostly attributed to the selective pressure generated by overuse and misuse of antibiotics, recent growing evidence suggests that chemicals other than antibiotics, such as certain metals, can also select and stimulate antibiotic resistance via both co-resistance and cross-resistance mechanisms. For instance, tetL, merE, and oprD genes are resistant to both antibiotics and metals. However, the potential de novo resistance induced by heavy metals at environmentally-relevant low concentrations (much below theminimum inhibitory concentrations [MICs], also referred as sub inhibitory) has hardly been explored. This study investigated and revealed that heavy metals, namely Cu(II), Ag(I), Cr(VI), and Zn(II), at environmentally relevant and sub-inhibitory concentrations, promoted conjugative transfer of antibiotic resistance genes (ARGs) between E. coli strains. The mechanisms of this phenomenon were further explored, which involved intracellular reactive oxygen species (ROS) formation, SOS response, increased cell membrane permeability, and altered expression of conjugation-relevant genes. These findings suggest that sub-inhibitory levels of heavy metals that widely present in various environments contribute to the resistance phenomena via facilitating horizontal transfer of ARGs. This study provides evidence from multiple aspects implicating the ecological effect of low levels of heavy metals on antibiotic resistance dissemination and highlights the urgency of strengthening efficacious policy and technology to control metal pollutants in the environments. PMID- 29477118 TI - Transformation of arsenic-rich copper smelter flue dust in contrasting soils: A 2 year field experiment. AB - Dust emissions from copper smelters processing arsenic-bearing ores represent a risk to soil environments due to the high levels of As and other inorganic contaminants. Using an in situ experiment in four different forest and grassland soils (pH 3.2-8.0) we studied the transformation of As-rich (>50 wt% As) copper smelter dust over 24 months. Double polyamide bags with 1 g of flue dust were buried at different depths in soil pits and in 6-month intervals; then those bags, surrounding soil columns, and soil pore waters were collected and analysed. Dust dissolution was relatively fast during the first 6 months (5-34%), and mass losses attained 52% after 24 months. The key driving forces affecting dust dissolution were not only pH, but also the water percolation/retention in individual soils. Primary arsenolite (As2O3) dissolution was responsible for high As release from the dust (to 72%) and substantial increase of As in the soil (to a 56 * increase; to 1500 mg kg-1). Despite high arsenolite solubility, this phase persisted in the dust after 2 years of exposure. Mineralogical investigation indicated that mimetite [Pb5(AsO4)3(Cl,OH)], unidentified complex Ca-Pb-Fe-Zn arsenates, and Fe oxyhydroxides partly controlled the mobility of As and other metal(loid)s. Compared to As, other less abundant contaminants (Bi, Cu, Pb, Sb, Zn) were released into the soil to a lesser extent (8-40% of total). The relatively high mobility of As in the soil can be seen from decreases of bulk As concentrations after spring snowmelt, high water-extractable fractions with up to ~50% of As(III) in extracts, and high As concentrations in soil pore waters. Results indicate that efficient controls of emissions from copper smelters and flue dust disposal sites are needed to prevent extensive contamination of nearby soils by persistent As. PMID- 29477119 TI - Effects of benzo[a]pyrene on the blood and liver of Physalaemus cuvieri and Leptodactylus fuscus (Anura: Leptodactylidae). AB - Benzo[a]pyrene (BaP) is a bio-accumulative toxic compound found in the atmosphere, water, and soil that may affect the life cycle of amphibians. In this study, a few contamination biomarkers, such as hepatic melanomacrophages (MMs), mast cells, erythrocyte micronuclei (MN) and white blood cells were used to determine how BaP acts in these cells in the anurans Physalaemus cuvieri and Leptodactylus fuscus. Animals of both species were divided into three treatment groups: 1 day, 7 days and 13 days, subcutaneously injected 2 mg/kg BaP diluted in mineral oil and control group with only mineral oil. After 7 days, BaP caused the frequency of MN to increase in both species while reducing melanin area. The micronucleus frequency increased due to the genotoxicity of BaP, while the decreasing melanin area may be related to the inhibition of tyrosinase activity, an enzyme responsible for regulating melanogenesis, decreasing the synthesis of melanin. The mast cell density increased in all groups and in both species as a response to the inflammatory action of BaP. These cells respond to nonspecific inflammatory effects leading, therefore, to this response in all treatments. The percentage of leukocytes remained unchanged probably due to great intraspecific variability. Additionally, the leukocyte profiles of both species were characterized and the differences were attributed to extrinsic factors. In short, BaP can affect the integrity of several organs and tissues, and cell functions leading to the conclusion that this compound is hepatotoxic, genotoxic and immunotoxic for anurans. PMID- 29477120 TI - Biodegradation of atrazine from wastewater using moving bed biofilm reactor under nitrate-reducing conditions: A kinetic study. AB - In this study employed an anoxic moving bed biofilm reactor (AnMBBR) to evaluate the effects of hydraulic and toxic shocks on performance reactor. The results indicated a relatively good resistance of system against exercised shocks and its ability to return to steady-state conditions. In optimal conditions when there was the maximum rate of atrazine and soluble chemical oxygen demand (COD) removal were 74.82% and 99.29% respectively. Also, atrazine biodegradation rapidly declines in AnMBBR from 74% +/- 0.05 in the presence of nitrate to 9.12% only 3 days after the nitrate was eliding from the influent. Coefficients kinetics was studied and the maximum atrazine removal rate was determined by modified Stover & Kincannon model (Umax = 9.87 gATZ/m3d). Results showed that AnMBBR is feasible, easy, affordable, so suitable process for efficiently biodegrading toxic chlorinated organic compounds such as atrazine. Also, its removal mechanism in this system is co-metabolism. PMID- 29477122 TI - Recent advances in viral vectors in veterinary vaccinology. AB - Viral vectored vaccines, particularly using vectors such as adenovirus, herpesvirus and poxviruses, are used widely in veterinary medicine, where this technology has been adopted much more quickly than in human medicine. There are now a large number of programmes to develop viral vector vaccine platforms for humans and very similar or identical vectors are being developed for veterinary medicine. The shared experiences of developing these new vaccine platforms across the two disciplines is accelerating progress, a striking example of the value of a 'One Health' approach. In particular, there is growing use of adenoviruses, either replicating or replication-incompetent, to create new vaccines for use in livestock or companion animals. Live replicating avian herpesvirus vectors are increasingly used as vaccines against poultry diseases. PMID- 29477121 TI - Ultrastructure of the actin cytoskeleton. AB - The actin cytoskeleton is the primary force-generating machinery in the cell, which can produce pushing (protrusive) forces using energy of actin polymerization and pulling (contractile) forces via sliding of bipolar filaments of myosin II along actin filaments, as well as perform other key functions. These functions are essential for whole cell migration, cell interaction with the environment, mechanical properties of the cell surface and other key aspects of cell physiology. The actin cytoskeleton is a highly complex and dynamic system of actin filaments organized into various superstructures by multiple accessory proteins. High resolution architecture of functionally distinct actin arrays provides key clues for understanding actin cytoskeleton functions. This review summarizes recent advance in our understanding of the actin cytoskeleton ultrastructure. PMID- 29477123 TI - Hierarchical CuInS2-based heterostructure: Application for photocathodic bioanalysis of sarcosine. AB - In this study, on the basis of hierarchical CuInS2-based heterostructure, a novel cathodic photoelectrochemical (PEC) enzymatic bioanalysis of the sarcosine detection was reported. Specifically, heterostructured CuInS2/NiO/ITO photocathode was prepared and sarcosine oxidases (SOx) were integrated for the construction of the enzymatic biosensor. In the bioanalysis, the O2-dependent suppression of the cathodic photocurrent can be observed due to the competition between the as-fabricated O2-sensitive photocathode and the SOx-catalytic event toward O2 reduction. Based on the sarcosine-controlled O2 concentration, a novel photocathodic enzymatic biosensor could be realized for the sensitive and specific sarcosine detection. This work manifested the great potential of CuInS2 based heterostructure as a novel platform for future PEC bioanalytical development and also a PEC method for sarcosine detection, which could be easily extended to numerous other enzymatic systems and to our knowledge has not been reported. This work is expected to stimulate more interest in the design and implementation of numerous CuInS2-based heterostructured photocathodic enzymatic sensing. PMID- 29477124 TI - Silver-dendrimer nanocomposites as oligonucleotide labels for electrochemical stripping detection of DNA hybridization. AB - Silver-dendrimer nanocomposites were synthesized and used as oligonucleotide labels for electrochemical stripping detection of DNA hybridization. The synthesized silver-dendrimer nanocomposites were characterized by UV-vis spectrophotometry, X-ray photoelectron spectroscopy (XPS) and transmission electron microscopy (TEM). Ratios of silver/dendrimer were optimized in order to obtain stable nanocomposites with maximal silver loading in the interior of a polymeric shell. The silver-dendrimer nanocomposites were attached to sequence known DNA probes specific to colitoxin, and used to detect probe hybridization by dissolution of the silver nanoparticles in the interior of dendrimer in a diluted nitric acid, followed by measurement of Ag+ ions by anodic stripping voltammetry (ASV). Use of differential pulse voltammetry for the stripping step, along with optimization of the ASV conditions, enabled a detection limit of 0.78 pM. The present strategy, in combination with dendrimer-encapsulated copper labeled oligonucleotides probe reported previously, could potentially be used to detect single or multiple DNA targets in one sample. PMID- 29477125 TI - Enantiomeric lignans with anti-beta-amyloid aggregation activity from the twigs and leaves of Pithecellobium clypearia Benth. AB - To develop potential agents for slowing the progression of Alzheimer's disease, two pairs of new enantiomeric lignans, including a couple of rarely 8',9'-dinor 3',7-epoxy-8,4'-oxyneolignanes named (7S, 8S)- and (7R, 8R)-pithecellobiumin A (1a/1b) and a pair of 2',9'-epoxy-arylnaphthalenes named (7R, 8R, 8'R)- and (7S, 8S, 8'S)-pithecellobiumin B (2a/2b) were separated by chiral high performance liquid chromatography (HPLC). Their planar structures were elucidated by spectroscopic data analyses. The absolute configurations were determined by comparing of experimental and calculated electronic circular dichroism (ECD). The inhibitory activity on Abeta aggregation of all optical pure compounds was tested by ThT assay. Interestingly, enantiomeric inhibitors 1a (62.1%) and 1b (81.6%) exhibited different degrees of anti-Abeta aggregation activity. However, 2a (65.4%) and 2b (68.4%) showed similar inhibition rate. The different inhibition profiles were explained by molecular dynamics and docking simulation studies. PMID- 29477126 TI - Synthesis, alpha-glucosidase inhibition and molecular docking study of coumarin based derivatives. AB - We have synthesized seventeen Coumarin based derivatives (1-17), characterized by 1HNMR, 13CNMR and EI-MS and evaluated for alpha-glucosidase inhibitory potential. Among the series, all derivatives exhibited outstanding alpha-glucosidase inhibition with IC50 values ranging between 1.10 +/- 0.01 and 36.46 +/- 0.70 MUM when compared with the standard inhibitor acarbose having IC50 value 39.45 +/- 0.10 MUM. The most potent derivative among the series is derivative 3 having IC50 value 1.10 +/- 0.01 MUM, which are many folds better than the standard acarbose. The structure activity relationship (SAR) was mainly based upon by bring about difference of substituent's on phenyl part. Molecular docking studies were carried out to understand the binding interaction of the most active compounds. PMID- 29477127 TI - The effects of an expected twofold perturbation on able-bodied gait: Trunk flexion and uneven ground surface. AB - BACKGROUND: Although alteration in trunk orientation and ground level potentially affects gait pattern individually, it is plausible to examine the interaction effects of such factors. OBJECTIVE: The interaction effects between trunk-flexed gait and uneven ground on able-bodied gait pattern. METHODS: For twelve able bodied participants, we compared the adaptive mechanisms in kinematics, kinetics and spatial-temporal parameters of gait (STPG) with bent postures (30 degrees and 50 degrees of sagittal trunk flexion) across uneven surface (10-cm visible drop at the sight of the second ground contact) with that of upright posture on even ground surface. RESULTS: Significant between-posture changes on the uneven surface included a decreased peak ankle dorsiflexion angle and vertical ground reaction force (GRF) 2nd peak as trunk flexion increased. Moreover, significant between-ground surface changes for each individual gait posture were a decreased peak ankle dorsiflexion angle and ankle range of motion irrespective of trunk posture and a reduced trailing step duration and vertical GRF 2nd peak in upright walking. The spatial parameters of gait remained unchanged across uneven surface, but at the expense of pronounced adjustments in temporal parameters, i.e., a more conservative gait strategy, indicating a distinct contribution from spatial and temporal strategies in trunk-flexed gaits. This was associated with greater peak flexion angles across lower limb joints regardless of trunk posture, alongside with an exertion of greater forces at faster rates earlier in stance and attenuated forces at lower rates at the end of the stance (i.e., early-skewed vertical GRF). When considering the main effect of posture, a more crouched gait was executed with reduced temporal parameters (except for cadence) and an early skewed vertical GRF patterns with increasing trunk flexion. SIGNIFICANCE: These results may have implications for understanding the nature of compensatory mechanisms in gait pattern of older adults and/or patients with altered trunk orientations while accommodating uneven ground. PMID- 29477128 TI - Development of a diagnostic method for Parkinson's disease by reverse-phase high performance liquid chromatography coupled with integrated pulsed amperometric detection. AB - We developed a diagnostic method for Parkinson's disease by simultaneously analyzing biogenic amines and their metabolites using reverse-phase high performance liquid chromatography coupled with integrated pulsed amperometric detection (RP-HPLC-IPAD) method. Dopamine (DA), 3, 4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT), 5-hydroxyindolacetic acid (5-HIAA), and homovanillic acid (HVA) were used as biomarkers to diagnose Parkinson's disease. All target components were detected with good sensitivity using sodium hydroxide (as a post column eluent). The limit of detection (S/N = 3) and limit of quantification (S/N = 10) of the target components ranged from 0.020 to 2.400 ng and from 0.080 to 8.000 ng, respectively. The coefficients of linear regression ranged from 0.9996 to 1.0000, all inter-day and intra-day precision values were <3.43%, and the average recovery and RSD ranged from 97.55 to 103.60% and 0.22 to 4.79% for mice striatum samples. This method exhibited good selectivity, sensitivity, and reproducibility and can be used directly without any pretreatment steps. Our method will be useful as a tool to diagnose Parkinson's disease. PMID- 29477129 TI - Development of an analytical method for separation of phenolic acids by ultra performance convergence chromatography (UPC2) using a column packed with a sub-2 MUm particle. AB - Phenolic acids are important active components of certain Traditional Chinese Medicines (TCM) and have a wide range of biological effects. Separation and purification of phenolic acids remains challenging due to difficulties with quality control using existing chromatographic methods The purpose of this study was to compare the effects of different chromatographic columns and conditions for the separation of phenolic acids. The BEH column was determined to be optimal, providing efficient separation in the shortest time (17.00 min) using gradient elution with carbon dioxide as the mobile phase, methanol/acetonitrile (70:30, v/v) with 1% TFA as the modifier, and a flow rate of 0.8 mL/min. Good peak shapes were obtained, and the peak asymmetry values were close to 1.00 for all phenolic acids. The resolution was more than 2.83 for all separated peaks. The developed method was subsequently applied to the determination of phenolic acids in Xanthii Fructus. These results are beneficial for quality control and standardization of herbal drugs using UPC2, providing an efficient, rapid and environmentally friendly scientific basis for future analysis of phenolic acids. PMID- 29477130 TI - Fate of selected pathogens in spiked "SALAME NOSTRANO" produced without added nitrates following the application of NONITTM technology. AB - This study evaluated the effect of a novel formulation for starter culture associated with specific ripening conditions (NoNitTM technology) vs. a commercial" starter on the fate of selected pathogens and hygiene indicators during the fermentation and ripening of experimentally spiked salame nostrano (Italian dry sausage). Selected strains of Staphylococcus aureus 27R, Escherichia coli CSH26 K 12, Listeria innocua ATCC 33090 and Salmonella Derby 27 were inoculated into salami batter and challenged with two formulations of starter cultures (a commercial formulation and the NoNitTM formulation, consisting of Lactococcus lactis ssp. lactis, strain 340; L. lactis ssp. lactis, strain 16; Lactobacillus casei ssp. casei, strain 208 and Enterococcus faecium strain 614) with ripening at a low temperature. The proposed technology (NoNitTM) performed better than the commercial formulation and limited the growth of spiked Escherichia coli, Staphylococcus aureus (including the production of enterotoxin), Salmonella Derby and Listeria innocua, yet maintained the basic product appearance and texture. PMID- 29477131 TI - Progress in defining the genetic contribution to type 2 diabetes susceptibility. AB - Candidate gene, genome-wide association, exome array and sequencing studies have identified more than 140 loci associated with type 2 diabetes (T2D) susceptibility. In this review, progress in understanding the genetic architecture of T2D susceptibility across diverse populations and in localising potential causal variants for the disease through fine-mapping studies is discussed. The additional insights gained from these genetic studies into novel molecular mechanisms and pathophysiology underlying T2D susceptibility are described, and the prospects for future genomic investigations of the disease are considered. PMID- 29477132 TI - In vitro sensitivity of human parainfluenza 3 clinical isolates to ribavirin, favipiravir and zanamivir. AB - BACKGROUND: Human parainfluenza type 3 (HPIV3) is an important respiratory pathogen. Although a number of potential therapeutic candidates exist, there is currently no licensed therapy or vaccine. Ribavirin (RBV), favipiravir (FVP) and zanamivir (ZNV) are inhibitors with proven activity against influenza and with potential inhibitory activity against HPIV3 laboratory adapted strains in vitro. OBJECTIVES: To evaluate RBV, FVP and ZNV as inhibitors of minimally passaged UK clinical strains of HPIV3 as well as a laboratory adapted strain MK9 in vitro. STUDY DESIGN: The inhibitory action of RBV, FVP and ZNV was evaluated against nine minimally passaged clinical strains and a laboratory adapted strain MK9 using plaque reduction and growth curve inhibition in a cell culture model. RESULTS: Clinical isolates were found to be at least as susceptible as the laboratory adapted strains to RBV and FVP and significantly more susceptible to ZNV. However the inhibitory concentrations achieved by ZNV against clinical strains remain prohibitively high in vivo. CONCLUSIONS: RBV, FVP and ZNV were found to be effective inhibitors of HPIV3 in vitro. The lack of efficacy of RBV in vivo may be due to inability to reach required therapeutic levels. FVP, on the other hand, is a good potential therapeutic agent against HPIV3. Further studies using wild type clinical strains, as well as better formulation and delivery mechanisms may improve the utility of these three inhibitors. PMID- 29477133 TI - Randomized, Controlled Trial: Efficacy of Ultrasound and Exercise in Patients With Ankylosing Spondylitis. AB - Context * The aim in treating ankylosing spondylitis (AS) is to reduce patients' symptoms, including pain, stiffness, and fatigue; to correct their posture; and to improve their quality of life. Currently, no definitive therapy is available for treating AS. Previous studies have reported positive results regarding the efficacy of exercise. Objective * This study aimed to assess the efficacy of ultrasound, combined with exercise, in patients with AS. Design * The research team designed a randomized, double-blind, 2-arm parallel-group, placebo controlled trial. Setting * The study took place at the Affiliated Hongqi Hospital of Mudanjiang Medical University (Mudanjiang, China). Participants * Participants were 62 individuals with AS who were patients at the hospital. Intervention * Participants were randomly assigned to one of 2 groups: (1) the intervention group, who received exercise and ultrasound therapy; or (2) the control group, who received exercise and placebo ultrasound therapy, without an active probe, both for 8 wk. Outcome Measures * The outcome measures included (1) the numerical rating scale (NRS), (2) the Bath ankylosing spondylitis metrology index (BASMI), (3) the Bath ankylosing spondylitis disease activity index (BASDAI), (4) the Bath ankylosing spondylitis functional index (BASFI), and (5) the ankylosing spondylitis quality of life (ASQoL) questionnaire. All outcomes were measured at baseline and at the end of 4 and 8 wk of treatment. Results * Fifty-seven patients fulfilled the requirements of the study. Ultrasound and exercise therapy showed greater efficacy than the placebo ultrasound and exercise in decreasing the scores for the NRS, daily and at night; the BASMI; the BASDAI; the BASFI; and the ASQoL, at the end of both 4 and 8 wk of treatment. No adverse events were noted in either group. Conclusions * The study demonstrated that 8 wk of ultrasound and exercise therapy was efficacious in patients with AS. PMID- 29477134 TI - A Novel Combination Therapy for Patients With Dry Eye Disease: A Pilot Study. AB - Context * Approximately 25% of the US population suffers from dry eyes or some abnormality of the exposed ocular surface. Investigation of effective modalities for their management is needed. Objective * The study intended to examine the efficacy of a proprietary, daily, Dry Eye Protocol consisting of daily use of a moist, heated, ocular compress and intake of an omega-3 dietary supplement in treatment of ocular surface disease. Design * The research team designed a 4-wk, clinically based, open-label, multicenter cohort study. Setting * The study took place at 6 private eye care practices throughout the United States: Beverly Hills, CA, USA; San Diego, CA, USA; Sunnyvale, CA, USA; Park City, UT, USA; Tarpon Spring, FL, USA; and Kennewick, WA, USA. Participants * Participants were adults between 18 and 75 y of age who had established ocular surface disease based on clinical findings and the results of testing using the ocular surface disease index (OSDI). Intervention * For period of 30 d, participants used a combined daily protocol that included (1) application of a moist, heated, eye compress and (2) a nutritional therapy via an omega-3 supplement in an oral triglyceride form. Outcome Measures * Measures included the OSDI and a test of tear break-up time (TBUT). Results * Of the original 35 participants, 33 completed the 4-wk protocol. The participants using the proprietary Dry Eye Protocol showed significant improvements from baseline, demonstrated by a 49% decrease in OSDI scores (P = .0015); and 46% of participants reported becoming asymptomatic of dry eye symptoms. A significant improvement was also observed in TBUT, increasing from 3.0 to 5.4 s. Conclusions * Daily use of the proprietary Dry Eye Protocol that included a high dosage of triglyceride omega-3 and use of a moist, heated, compress daily showed significant improvement for participants in OSDI and TBUT and should be considered to be a first-line therapy for patients with dry eye disease. PMID- 29477135 TI - Potential of Anthocyanin to Prevent Cardiovascular Disease in Diabetes. AB - Context * Type 2 diabetes mellitus is an independent precipitating factor for cardiovascular disease (CVD). Heart disease is one of the leading causes of mortality in patients with diabetes, mainly due to macrovascular complications, such as atherosclerosis. Although aspirin is a frequently used therapy for the inhibition of platelet hyperactivity, many studies suggest that aspirin resistance is rising. Objective * The study intended to investigate the benefits of anthocyanin (AC) as an antioxidant with inhibitory effects on platelets and, consequently, its potential usefulness as complementary antiplatelet therapy to attenuate the negative effects of atherosclerosis and CVD in patients with diabetes. Design * The research team performed a literature review. The team conducted a database search from 2007 to 2017 using Library of Congress, LISTA, PubMed, and Web of Science Core Collection databases, using the following keywords: anthocyanins, platelet, cardiovascular disease, and diabetes. Setting * The study took place at the School of Medical Sciences at Griffith University's Gold Coast campus (Southport, Australia). Results * Platelets have a major pathophysiological role of atherosclerosis and consequently CVD in diabetes. Antiplatelet drugs have a potent inhibitory effect of thrombotic and CVD risks in diabetes. Dietary antioxidants including ACs have a potential platelet inhibitory effect. Hence, ACs may act as complementary therapy to reduce CVD in diabetes. Conclusions * Although antiplatelet drugs such as aspirin provide significant action in the management of CVD, aspirin has limited benefits in diabetes. An AC antioxidant has a potential effect as an antiplatelet agent that subsequently can prevent atherosclerosis and CVD and, therefore, AC may be an alternative to other antiplatelet drugs such as aspirin. However, more interventional studies and large-scale clinical trials are necessary to prove the efficiency of AC as an alternative to other platelet-inhibitory drugs. PMID- 29477136 TI - Canine-assisted Therapy as an Adjunct Tool in the Care of the Surgical Patient: A Literature Review and Opportunity for Research. AB - The use of canine-assisted therapy (CAT) in healthcare is expanding and the purpose of this review is to highlight its potential use in the surgical patient. While CAT literature to date has detailed widespread benefits in blood pressure control and improving pain, anxiety, and stress, little research has been performed specifically in surgical patients who may benefit significantly from CAT interventions. Critical points highlighted herein are as follows: (1) Hypertension is common and significantly increases morbidity and mortality associated with elective surgery. Pet ownership and brief CAT interventions (5-20 min) have demonstrated significant reductions in blood pressure and blood pressure variability in both adult and pediatric populations. (2) Pain management is of utmost importance in hospitalized, surgical patients and unfortunately the growing opioid addiction epidemic has complicated our ability to treat postoperative pain. CAT interventions have been shown to reduce self-reported pain. Therefore, CAT represents a cost-effective, safe, and noninvasive approach to pain management. (3) Patient satisfaction is of growing concern as reimbursement by Medicare, Medicaid, and other insurers is now linked to patient reported satisfaction with their hospital stay. While very limited data is available on this subject, some studies have showed that CAT intervention, specifically, improved patient reported satisfaction in multiple categories of the HCAHPS survey compared with patients who did not receive CAT. Overall, this is a novel narrative review detailing the therapeutic efficacy of CAT, highlighting the specific indications of CAT in the surgical patient, and urging further research of CAT in the surgical patient. PMID- 29477137 TI - Taiwanofungus camphoratus Combined With Amphotericin B for Metastatic Cancer Patients Unresponsive to or Unwilling to Undergo Chemotherapy: A Pilot Study. AB - Context * Taiwanofungus camphoratus is a parasitic mushroom found in the heartwood of Cinnamomum kanehirai and is used as a nutritional supplement. It has an anticancer action, both alone and synergistically with amphotericin B (AmB). Objective * The study intended to assess the efficacy of a T camphoratus ethanol extract (TCEE) combined with AmB for patients with metastatic cancer whose cancer did not respond to multiline chemotherapy or who were unwilling to receive chemotherapy. Design * The research team performed a retrospective analysis as a pilot study. Setting * The study took place at a single hospital (Taipei Medical University Hospital, Taipei, Taiwan). Participants * Participants were 9 patients at the hospital who were terminally ill with metastatic cancer. Interventions * The participants had received daily doses of 2-3 g of the TCEE in combination with a weekly dose of 20-25 mg of AmB in 500 cc of 5% glucose water, given intravenously in 4-6 h. Outcome Measures * Outcome measures included (1) a primary evaluation index measuring the efficacy of the treatment; (2) a measure of tumor burden that was estimated using the response evaluation criteria in solid tumors (RECIST 1.1), (3) a secondary evaluation index measuring survival duration, and (4) safety. Results * The mean treatment time was 54.4 +/- 18.3 wk. At the end of the study, 2 patients showed a continued complete response, 1 patient had a continued partial response, and 1 patient showed a stable disease. The other 5 participants had times to progression ranging from 24 to 48 wk, with a mean of 35.6 wk. The mean survival time was 57.8 +/- 18.5 wk, and 5 patients were still alive at the end of the study. Conclusions * For patients whose metastatic cancer did not respond to multiline chemotherapy or who were unwilling to receive chemotherapy, the use of TCEE as an adjuvant therapy to AmB resulted in tumor suppression and a delay in time to disease progression. The preliminary results reported here can be used to guide a future, more extensive clinical study of the combination. PMID- 29477138 TI - Yoga Aids Blood Pressure Recovery After Exposure of Forehead to Cold: A Pilot Study. AB - Context * Hypotension that occurs after a single bout of aerobic exercise also attenuates the vascular response to discrete stressors, an effect that can last for hours. It is unknown whether the hypotensive benefits of traditional exercise extend to alternative forms of mindful exercise, such as yoga, to confer transient protection against neurovascular challenges that increase blood pressure (BP). Objectives * The study intended to examine the effects of acute exercise on neurovascular responses to exposure of the forehead of female yoga practitioners to vasoconstrictive cold (ie, to cold pressor stress). Design * The research team designed a study with 3 conditions (ie, with participants' participation in 3 activities on separate days in a repeated-measures design). Participants were randomly assigned to perform the activities in 1 of 3 orders across successive visits. Participants * Participants were 9 females, 20 to 33 y old, who had regularly practiced Hatha yoga from 6 mo to 12 y before the start of the study. All participants were normotensive at entry to the study and had normal body weights for their heights. Interventions * All participants performed 3 activities: (1) self-directed yoga practice, the intervention; (2) cycling exercise at a self-selected intensity, a positive control; and (3) quiet rest, a negative control. Outcome Measures * Postintervention, participants' foreheads were exposed to cold. Their systolic blood pressures (SBPs), diastolic blood pressures (DBPs), pulse rates, and forearm oxygenation were assessed using near infrared spectroscopy. Results * Participants' SBPs and DBPs increased during cold pressor stress under all conditions, concurrent with decreased forearm oxygenation. During recovery from the cold, participants' BPs declined to near precold pressor baseline levels after yoga and cycling but remained elevated after quiet rest. Conclusions * The enhanced recovery of BP from cold applied to the forehead after yoga practice or cycling exercise suggests that both types of exercise promote a hypotensive response, which could indicate lowered cardiovascular risk. PMID- 29477139 TI - Effects of Thymol, a Natural Phenolic Compound, on Human Gastric Adenocarcinoma Cells In Vitro. AB - Context * Alternative and complementary medicine has gained importance in anticancer treatment, reflecting a movement toward an integrated approach to treating various diseases. Natural products originating from plants can contain biologically active substances. Thymol is a major component of many plants from the family Lamiaceae that are often used for medicinal and culinary purposes in Mediterranean countries. Objective * The purpose of the present study was to investigate thymol's cytotoxic, genotoxic, apoptotic effects on gastric adenocarcinoma (AGS) cells, including measurement of reactive oxygen species (ROS) and glutathione (GSH) levels at the same time. Design * The research team studied thymol's anticancer potential in vitro. Setting * The research was conducted at the Laboratory of Biochemistry of the Faculty of Medicine at Bezmialem Vakif University (Istanbul, Turkey). Intervention * Caucasian human AGS cells were exposed to 7 concentrations of thymol-10, 20, 30, 50, 100, 200, and 400 MUM-prepared from a stock solution of 600 MUM of thymol in dimethyl sulfoxide (DMSO), and after 24 h of incubation, the results were analyzed. The thymol was obtained commercially. The study used a negative control prepared in a concentration of 1:1000 from the stock solution of DMSO. Outcome Measures * Cytotoxicity was determined using (1) the adenosine 5'-triphosphate cell viability assay; (2) the dichloro-dihydro-fluorescein diacetate assay to evaluate the generation of ROS; (3) the luminescence-based, total GSH assay to determine the GSH levels; and (4) the comet assay to study genotoxicity. Apoptotic induction of thymol was detected (5) by acridine orange/ethidium bromide staining and (6) by Western blotting using a value below the half maximal inhibitory concentration (IC50). Results * Thymol showed significant cytotoxic, genotoxic, apoptotic, ROS-generating, and GSH-reducing effects, in a dose-dependent manner (P <= .001). A close negative relationship existed between cell viability and the ROS level. Conclusions * After researchers have confirmed thymol's anticarcinogenic effects in vitro on healthy cell lines and in vivo, it may be found to be a novel and strong therapeutic agent against gastric cancer. The study's results suggest that thymol may have therapeutic power when developed from natural components of the diet for treatment of the disease. PMID- 29477140 TI - AURKA Suppresses Leukemic THP-1 Cell Differentiation through Inhibition of the KDM6B Pathway. AB - Aberrations in histone modifications are being studied in mixed-lineage leukemia (MLL)-AF9-driven acute myeloid leukemia (AML). In this study, we focused on the regulation of the differentiation of the MLL-AF9 type AML cell line THP-1. We observed that, upon phorbol 12-myristate 13-acetate (PMA) treatment, THP-1 cells differentiated into monocytes by down-regulating Aurora kinase A (AURKA), resulting in a reduction in H3S10 phosphorylation. We revealed that the AURKA inhibitor alisertib accelerates the expression of the H3K27 demethylase KDM6B, thereby dissociating AURKA and YY1 from the KDM6B promoter region. Using Flow cytometry, we found that alisertib induces THP-1 differentiation into monocytes. Furthermore, we found that treatment with the KDM6B inhibitor GSK-J4 perturbed the PMA-mediated differentiation of THP-1 cells. Thus, we discovered the mechanism of AURKA-KDM6B signaling that controls the differentiation of THP-1 cells, which has implications for biotherapy for leukemia. PMID- 29477141 TI - Increased Primary Cilia in Idiopathic Pulmonary Fibrosis. AB - Primary cilia are solitary, non-motile, axonemal microtubule-based antenna-like organelles that project from the plasma membrane of most mammalian cells and are implicated in transducing hedgehog signals during development. It was recently proposed that aberrant SHH signaling may be implicated in the progression of idiopathic pulmonary fibrosis (IPF). However, the distribution and role of primary cilia in IPF remains unclear. Here, we clearly observed the primary cilia in alveolar epithelial cells, fibroblasts, and endothelial cells of human normal lung tissue. Then, we investigated the distribution of primary cilia in human IPF tissue samples using immunofluorescence. Tissues from six IPF cases showed an increase in the number of primary cilia in alveolar cells and fibroblasts. In addition, we observed an increase in ciliogenesis related genes such as IFT20 and IFT88 in IPF. Since major components of the SHH signaling pathway are known to be localized in primary cilia, we quantified the mRNA expression of the SHH signaling components using qRT-PCR in both IPF and control lung. mRNA levels of SHH, the coreceptor SMO, and the transcription factors GLI1 and GLI2 were upregulated in IPF compared with control. Furthermore, the nuclear localization of GLI1 was observed mainly in alveolar epithelia and fibroblasts. In addition, we showed that defective KIF3A-mediated ciliary loss in human type II alveolar epithelial cell lines leads to disruption of SHH signaling. These results indicate that a significant increase in the number of primary cilia in IPF contributes to the upregulation of SHH signals. PMID- 29477142 TI - HDAC4 preserves skeletal muscle structure following long-term denervation by mediating distinct cellular responses. AB - BACKGROUND: Denervation triggers numerous molecular responses in skeletal muscle, including the activation of catabolic pathways and oxidative stress, leading to progressive muscle atrophy. Histone deacetylase 4 (HDAC4) mediates skeletal muscle response to denervation, suggesting the use of HDAC inhibitors as a therapeutic approach to neurogenic muscle atrophy. However, the effects of HDAC4 inhibition in skeletal muscle in response to long-term denervation have not been described yet. METHODS: To further study HDAC4 functions in response to denervation, we analyzed mutant mice in which HDAC4 is specifically deleted in skeletal muscle. RESULTS: After an initial phase of resistance to neurogenic muscle atrophy, skeletal muscle with a deletion of HDAC4 lost structural integrity after 4 weeks of denervation. Deletion of HDAC4 impaired the activation of the ubiquitin-proteasome system, delayed the autophagic response, and dampened the OS response in skeletal muscle. Inhibition of the ubiquitin-proteasome system or the autophagic response, if on the one hand, conferred resistance to neurogenic muscle atrophy; on the other hand, induced loss of muscle integrity and inflammation in mice lacking HDAC4 in skeletal muscle. Moreover, treatment with the antioxidant drug Trolox prevented loss of muscle integrity and inflammation in in mice lacking HDAC4 in skeletal muscle, despite the resistance to neurogenic muscle atrophy. CONCLUSIONS: These results reveal new functions of HDAC4 in mediating skeletal muscle response to denervation and lead us to propose the combined use of HDAC inhibitors and antioxidant drugs to treat neurogenic muscle atrophy. PMID- 29477143 TI - Utility of eButton images for identifying food preparation behaviors and meal related tasks in adolescents. AB - BACKGROUND: Food preparation skills may encourage healthy eating. Traditional assessment of child food preparation employs self- or parent proxy-reporting methods, which are prone to error. The eButton is a wearable all-day camera that has promise as an objective, passive method for measuring child food preparation practices. PURPOSE: This paper explores the feasibility of the eButton to reliably capture home food preparation behaviors and practices in a sample of pre and early adolescents (ages 9 to 13). METHODS: This is a secondary analysis of two eButton pilot projects evaluating the dietary intake of pre- and early adolescents in or around Houston, Texas. Food preparation behaviors were coded into seven major categories including: browsing, altering food/adding seasoning, food media, meal related tasks, prep work, cooking and observing. Inter-coder reliability was measured using Cohen's kappa and percent agreement. RESULTS: Analysis was completed on data for 31 participants. The most common activity was browsing in the pantry or fridge. Few participants demonstrated any food preparation work beyond unwrapping of food packages and combining two or more ingredients; actual cutting or measuring of foods were rare. CONCLUSIONS: Although previous research suggests children who "help" prepare meals may obtain some dietary benefit, accurate assessment tools of food preparation behavior are lacking. The eButton offers a feasible approach to food preparation behavior measurement among pre- and early adolescents. Follow up research exploring the validity of this method in a larger sample, and comparisons between cooking behavior and dietary intake are needed. PMID- 29477144 TI - The curse of angiopoietin-2 in ARDS: on stranger TI(E)des. AB - Pulmonary inflammation and vascular leakage are hallmarks of acute respiratory distress syndrome (ARDS), a life-threatening condition, for which there is no specific pharmacologic treatment.Recent literature suggests that leaky vessels in pulmonary infection and ARDS may be mediated through dysregulation of a non redundant endothelial control pathway, the Tie2 receptor and its ligands, the angiopoietins.This Viewpoint summarizes results from cell-based experiments, animal models and clinical studies underlining the potential of Tie2 targeted interventions in reducing infection-mediated pulmonary hyperpermeability. PMID- 29477146 TI - Long-term visit-to-visit glycemic variability as predictor of micro- and macrovascular complications in patients with type 2 diabetes: The Rio de Janeiro Type 2 Diabetes Cohort Study. AB - BACKGROUND: Long-term visit-to-visit glycemic variability is an additional measure of glycemic control. We aimed to evaluate the prognostic value of several measures of glycemic variability for the occurrence of micro- and macrovascular complications, and all-cause mortality in patients with type 2 diabetes. METHODS: 654 individuals were followed-up over a median of 9.3 years. Glycemic variability (SDs and coefficients of variation of HbA1c and fasting glycaemia) was measured during the first 12- and 24-months. Multivariate Cox analysis, adjusted for risk factors and mean HbA1c and fasting glycaemia levels, examined the associations between glycemic variability and the occurrence of microvascular (retinopathy, microalbuminuria, renal function deterioration, peripheral neuropathy) and macrovascular complications [total cardiovascular events (CVE), major adverse CVEs (MACE) and cardiovascular mortality], and of all-cause mortality. RESULTS: During follow-up, 128 patients had a CVE (96 MACE), and 158 patients died (67 from cardiovascular diseases); 152 newly-developed or worsened diabetic retinopathy, 183 achieved the renal composite outcome (89 newly developed microalbuminuria and 91 deteriorated renal function), and 96 newly-developed or worsened peripheral neuropathy. Glycemic variability, particularly the 24-month parameters either estimated by HbA1c or by fasting glycemia, predicted all endpoints, except for retinopathy and peripheral neuropathy development/progression, and was a better predictor than mean HbA1c. Glycemic variability predicted retinopathy development/progression in patients with good glycemic control (HbA1c <= 7.5%, 58 mmol/mol) and predicted new-incident peripheral neuropathy. CONCLUSIONS: Long-term visit-to-visit glycemic variability is an additional and frequently a better glycemic parameter than mean HbA1c levels for assessing the risk of future development of micro- and macrovascular complications in patients with type 2 diabetes. PMID- 29477145 TI - Hemodynamic effects of acute hyperoxia: systematic review and meta-analysis. AB - BACKGROUND: In clinical practice, oxygen is generally administered to patients with the intention of increasing oxygen delivery. Supplemental oxygen may, however, cause arterial hyperoxia, which is associated with hemodynamic alterations. We performed a systematic review and meta-analysis of the literature to determine the effect of hyperoxia on central hemodynamics and oxygen delivery in healthy volunteers and cardiovascular-compromised patients. METHODS: PubMed and EMBASE were searched up to March 2017. Studies with adult humans investigating changes in central hemodynamics or oxygen delivery induced by acute normobaric hyperoxia were included. Studies focusing on lung, retinal, or brain parameters were not included. We extracted subject and oxygen exposure characteristics, indexed and unindexed values for heart rate, stroke volume, cardiac output, mean arterial pressure (MAP), systemic vascular resistance, and oxygen delivery during normoxia and hyperoxia. For quantitative synthesis of the data, a random-effects ratio of means (RoM) model was used. RESULTS: We identified 33 studies with 42 datasets. Study categories included healthy volunteers (n = 22 datasets), patients with coronary artery disease (CAD; n = 6), heart failure (HF; n = 6), coronary artery bypass graft (CABG; n = 3) and sepsis (n = 5). Hyperoxia (arterial oxygen tension of 234-617 mmHg) reduced cardiac output (CO) by 10-15% in both healthy volunteers (-10.2%, 95% confidence interval (CI) -12.9% to -7.3%) and CAD (-9.6%, 95% CI -12.3% to -6.9%) or HF patients ( 15.2%, 95% CI -21.7% to -8.2%). No significant changes in cardiac output were seen in CABG or septic patients (-3%). Systemic vascular resistance increased remarkably in patients with heart failure (24.6%, 95% CI 19.3% to 30.1%). In healthy volunteers, and those with CAD and CABG, the effect was smaller (11-16%) and was virtually absent in patients with sepsis (4.3%, 95% CI -3.2% to 12.3%). No notable effect on MAP was found in any group (2-3%). Oxygen delivery was not altered by hyperoxia. Considerable heterogeneity existed between study results, likely due to methodological differences. CONCLUSIONS: Hyperoxia may considerably decrease cardiac output and increase systemic vascular resistance, but effects differ between patient categories. Heart failure patients were the most sensitive while no hemodynamic effects were seen in septic patients. There is currently no evidence supporting the notion that oxygen supplementation increases oxygen delivery. PMID- 29477147 TI - MicroRNA-19a contributes to the epigenetic regulation of tissue factor in diabetes. AB - BACKGROUND: Diabetes mellitus is characterized by chronic vascular disorder and presents a main risk factor for cardiovascular mortality. In particular, hyperglycaemia and inflammatory cytokines induce vascular circulating tissue factor (TF) that promotes pro-thrombotic conditions in diabetes. It has recently become evident that alterations of the post-transcriptional regulation of TF via specific microRNA(miR)s, such as miR-126, contribute to the pathogenesis of diabetes and its complications. The endothelial miR-19a is involved in vascular homeostasis and atheroprotection. However, its role in diabetes-related thrombogenicity is unknown. Understanding miR-networks regulating procoagulability in diabetes may help to develop new treatment options preventing vascular complications. METHODS AND RESULTS: Plasma of 44 patients with known diabetes was assessed for the expression of miR-19a, TF protein, TF activity, and markers for vascular inflammation. High miR-19a expression was associated with reduced TF protein, TF-mediated procoagulability, and vascular inflammation based on expression of vascular adhesion molecule-1 and leukocyte count. We found plasma expression of miR-19a to strongly correlate with miR-126. miR-19a reduced the TF expression on mRNA and protein level in human microvascular endothelial cells (HMEC) as well as TF activity in human monocytes (THP-1), while anti-miR 19a increased the TF expression. Interestingly, miR-19a induced VCAM expression in HMEC. However, miR-19a and miR-126 co-transfection reduced total endothelial VCAM expression and exhibited additive inhibition of a luciferase reporter construct containing the F3 3'UTR. CONCLUSIONS: While both miRs have differential functions on endothelial VCAM expression, miR-19a and miR-126 cooperate to exhibit anti-thrombotic properties via regulating vascular TF expression. Modulating the post-transcriptional control of TF in diabetes may provide a future anti-thrombotic and anti-inflammatory therapy. PMID- 29477148 TI - Gene-diet interaction effects on BMI levels in the Singapore Chinese population. AB - BACKGROUND: Recent genome-wide association studies (GWAS) have identified 97 body mass index (BMI) associated loci. We aimed to evaluate if dietary intake modifies BMI associations at these loci in the Singapore Chinese population. METHODS: We utilized GWAS information from six data subsets from two adult Chinese population (N = 7817). Seventy-eight genotyped or imputed index BMI single nucleotide polymorphisms (SNPs) that passed quality control procedures were available in all datasets. Alternative Healthy Eating Index (AHEI)-2010 score and ten nutrient variables were evaluated. Linear regression analyses between z score transformed BMI (Z-BMI) and dietary factors were performed. Interaction analyses were performed by introducing the interaction term (diet x SNP) in the same regression model. Analysis was carried out in each cohort individually and subsequently meta analyzed using the inverse-variance weighted method. Analyses were also evaluated with a weighted gene-risk score (wGRS) contructed by BMI index SNPs from recent large-scale GWAS studies. RESULTS: Nominal associations between Z-BMI and AHEI 2010 and some dietary factors were identified (P = 0.047-0.010). The BMI wGRS was robustly associated with Z-BMI (P = 1.55 * 10- 15) but not with any dietary variables. Dietary variables did not significantly interact with the wGRS to modify BMI associations. When interaction analyses were repeated using individual SNPs, a significant association between cholesterol intake and rs4740619 (CCDC171) was identified (beta = 0.077, adjPinteraction = 0.043). CONCLUSIONS: The CCDC171 gene locus may interact with cholesterol intake to increase BMI in the Singaporean Chinese population, however most known obesity risk loci were not associated with dietary intake and did not interact with diet to modify BMI levels. PMID- 29477149 TI - Laparoscopic repair of vesicovaginal fistulae with a transperitoneal approach at Universitas Gadjah Mada Urological Institute: a case report. AB - BACKGROUND: A vesicovaginal fistula is an abnormal fistulous tract extending between the bladder and the vagina that allows the continuous involuntary discharge of urine into the vaginal vault. In addition, the sequelae from these fistulae have a profound effect on the patients in view of their physical, psychological, and social dimensions. The treatment of vesicovaginal fistula is surgical in most cases and the choice of the repair technique is controversial. We evaluated the benefits of a laparoscopic approach in a patient with vesicovaginal fistulae. Here, we present our first experience using a simplified laparoscopic approach technique to repair vesicovaginal fistulae in our country. CASE PRESENTATION: A 46-year-old Javanese woman presented with urinary incontinence following an abdominal hysterectomy 3 months earlier and received laparoscopic repair. A cystoscopy was performed to confirm the fistula orifice and a stent was inserted into the fistula tract from her bladder to her vagina. A tamponade was inserted into her vagina up to the vaginal apex, to be able to identify the vagina. She had adhesions; therefore, adhesiolysis was performed using a combination of sharp and blunt dissection to expose the vaginal stump and the superior aspect of her bladder. A simple cystotomy was performed and extended to include the fistulae site, and then the defect was repaired by using a running stitch. A second layer of closure was performed in an imbricating fashion with the same suture. The vagina defect was not closed separately but covered with an omental flap. This procedure takes approximately 2.5 hours; estimated blood loss was minimal and there were no intraoperative complications. She had no recurrent symptoms 6 months after surgery. CONCLUSION: Our case report concludes that the simplified laparoscopic approach to vesicovaginal fistulae is a viable option for successful repair and that it reduces the size of bladder opening, causes minimal bleeding, and gives successful relief. PMID- 29477150 TI - ASSOCIATION BETWEEN SINGLE-PARENT FAMILY STRUCTURE AND AGE OF SEXUAL DEBUT AMONG YOUNG PERSONS IN JAMAICA. AB - There is a high and increasing proportion of single-parent families in Jamaica. This has raised concerns about the potential impact of single-parent families on the social, cognitive and behavioural development of children, including their sexual relationships. The aim of this study was to investigate the association between being raised in a single-parent family and age of sexual debut among young people in Jamaica. The study was cross-sectional in design, and based on a multi-stage sampling procedure. The study was conducted in July/September 2016. The study sample comprised 233 respondents (110 males and 123 females) aged from 18 to 35 years (mean 26.37 years; SD 5.46). Respondents completed a self administered questionnaire with questions on socio-demographic characteristics, family structure, sexual debut and current sexual behaviour. Ninety-seven (41.7%) respondents grew up in single-parent families. A total of 201 (86.3%) had had sex (102 males and 99 females). Their mean age of sexual debut was 15.51 years (SD 3.41). Sixty-five (32.3%) had early sexual debut (<16 years). Respondents from single-parent families were more likely to have had early sexual debut (56.9%; n=37) compared with those from two-parent families (43.1%, n=28; p=0.004). Only 44.6% (n=29) of those who experienced early sexual debut used a condom during their first sexual encounter compared with 73% (n=100) of those who had a later sexual debut (>=16 years; p=<0.001). A single-father family structure was a significant predictor of early sexual debut (AOR 5.5; 95%CI: 1.1-25.8). The study found a significant association between single-parent family structure and age of sexual debut. PMID- 29477151 TI - Calcium propionate supplementation improves development of rumen epithelium in calves via stimulating G protein-coupled receptors. AB - In the present study, calcium propionate (CaP) was used as feed additive in the diet of calves to investigate their effects on rumen fermentation and the development of rumen epithelium in calves. To elucidate the mechanism in which CaP improves development of calf rumen epithelium via stimulating the messenger RNA (mRNA) expression of G protein-coupled receptors, a total of 54 male Jersey calves (age=7+/-1 days, BW=23.1+/-1.2 kg) were randomly divided into three treatment groups: control without CaP supplementation (Con), 5% CaP supplementation (5% CaP) and 10% CaP supplementation (10% CaP). The experiment lasted 160 days and was divided into three feeding stages: Stage 1 (days 0 to 30), Stage 2 (days 31 to 90) and Stage 3 (days 91 to 160). Calcium propionate supplementation percentages were calculated on a dry matter basis. In total, six calves from each group were randomly selected and slaughtered on days 30, 90 and 160 at the conclusion of each experimental feeding stage. Rumen fermentation was improved with increasing concentration of CaP supplementation in calves through the first 30 days (Stage 1). No effects of CaP supplementation were observed on rumen fermentation in calves during Stage 2 (days 31 to 90). Supplementation with 5% CaP increased propionate concentration, but not acetate and butyrate in calves during Stage 3 (days 91 to 160). The rumen papillae length of calves in the 5% CaP supplementation group was greater than that of Con groups in calves after 160 days feeding. The mRNA expression of G protein-coupled receptor 41 (GPR41) and GPR43 supplemented with 5% CaP were greater than the control group and 10% CaP group in feeding 160 days calves. 5% CaP supplementation increased the mRNA expression of cyclin D1, whereas did not increase the mRNA expression of cyclin dependent kinase 4 compared with the control group in feeding 160-day calves. These results indicate that propionate may act as a signaling molecule to improve rumen epithelium development through stimulating mRNA expression of GPR41 and GPR43. PMID- 29477152 TI - Effect of starter diet supplementation on rumen epithelial morphology and expression of genes involved in cell proliferation and metabolism in pre-weaned lambs. AB - Starter feeding is usually used in lamb production to improve rumen development and to facilitate the weaning process, but molecular mechanism of which is not well understood. Therefore, the objective of this study is to investigate the effect of starter feeding on the expression of ruminal epithelial genes involved in cell proliferation, apoptosis and metabolism in pre-weaned lambs. We selected eight pairs of 10-day-old lamb twins. One twin was fed ewe milk (M, n=8), while the other was fed ewe milk plus starter (M+S, n=8). The lambs were sacrificed at 56 days age. Results showed that the lambs fed M+S had lower pH in the rumen and a higher concentration of acetate, propionate, butyrate and total volatile fatty acid (VFA). Compared with the M group, the concentration of beta-hydroxybutyric acid in plasma had an increased trend, and the concentration of IGF-1 in plasma had an decreased trend in the M+S group. The length, width and surface of rumen papillae increased in the M+S group compared with the M group; this was associated with increased cell layers in the stratum corneum, stratum granulosum and total epithelia. Messenger RNA (mRNA) expression of proliferative genes of cyclin A, cyclin D1 and cyclin-dependent kinase 2 in the ruminal epithelia of M+S lambs was increased compared with M only lambs. The mRNA expression of apoptosis genes of caspase-3, caspase-8, B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax) in the M+S group was decreased compared with M group, but the ratio of Bcl-2 to Bax were not changed between the two groups. Expression of IGF-1 mRNA was decreased, but the mRNA expression of IGF-1 receptor was higher in ruminal epithelia in the M+S group. Furthermore, the mRNA expression of VFA absorption and metabolism genes of beta-hydroxybutyrate dehydrogenase isoforms 1 and 3 hydroxy-3-methylglutaryl-CoA lyase had an increased trend in the M+S group than in the M group, but the mRNA expression of 3-hydroxy-3-methylglutaryl-CoA synthase isoform 1, monocarboxylate transporter isoform 1 and putative anion transporter isoform 1 had a decreased trend in the M+S group than in the M group. These results suggest that starter feeding increased proliferation and inhibited apoptosis of ruminal epithelial cells, and may promote the VFA metabolism in ruminal epithelium in pre-weaned lambs. These findings provide new insights into improving rumen development by nutritional intervention strategies in pre-weaned lambs. PMID- 29477153 TI - Effects of topical anaesthetic and buccal meloxicam on average daily gain, behaviour and inflammation of unweaned beef calves following surgical castration. AB - Although the pain caused by castration of calves is a significant animal welfare issue for the beef industry, analgesia is not always used for this procedure, largely because of practical limitations associated with injectable forms of pain relief. Novel analgesic formulations have now been developed for livestock to allow topical and buccal administration, offering practical options to improve cattle welfare if shown to be effective. To assess the effects of topical anaesthetic (TA) and buccal meloxicam (BM) on average daily gain (ADG), behaviour and inflammation following surgical castration of beef calves, a total of 50 unweaned bull calves were randomly allocated to: (1) sham castration (SHAM, n=10); (2) surgical castration (C, n=10); (3) surgical castration with pre operative buccal meloxicam (CBM, n=10); (4) surgical castration with post operative topical anaesthetic (CTA, n=10); and (5) surgical castration with pre operative buccal meloxicam and post-operative topical anaesthetic (CBMTA, n=10). Calves were recorded on video for 5 h following treatment and the frequency and duration of specific behaviours displayed by each animal was later observed for 5 min every hour (total of 25 min). Average daily gain was calculated 1, 2 and 6 days following treatment. Scrotal diameter measurements and photographs of wounds were collected from all castrated calves 1, 2 and 6 days following treatment to evaluate inflammation and wound healing. Infrared photographs were used to identify maximum scrotal temperature. Digital photographs were used to visually score wounds on a numerical rating scale of 1 to 5, with signs of inflammation increasing and signs of healing decreasing with progressive scores. Sham castration calves displayed significantly less, and C calves displayed significantly more foot stamps than all other calves (P=0.005). Observations on the duration of time that calves displayed a hypometric 'stiff gait' locomotion, indicated that SHAM calves tended to spend no time, C calves tended to spend the greatest time and all other calves tended to spend an intermediate time displaying this behaviour (P=0.06). Maximum scrotal temperatures were lower in CBM and CBMTA calves than C and CTA calves 2 days following treatment (P=0.004). There was no significant effect of treatment on ADG (P=0.7), scrotal diameter (P=0.09) or wound morphology score (P=0.5). These results suggest that TA and BM, alone or in combination, reduced pain and BM reduced inflammation following surgical castration of calves. PMID- 29477154 TI - Review: Sperm-oocyte interactions and their implications for bull fertility, with emphasis on the ubiquitin-proteasome system. AB - Fertilization is an intricate cascade of events that irreversibly alter the participating male and female gamete and ultimately lead to the union of paternal and maternal genomes in the zygote. Fertilization starts with sperm capacitation within the oviductal sperm reservoir, followed by gamete recognition, sperm-zona pellucida interactions and sperm-oolemma adhesion and fusion, followed by sperm incorporation, oocyte activation, pronuclear development and embryo cleavage. At fertilization, bull spermatozoon loses its acrosome and plasma membrane components and contributes chromosomes, centriole, perinuclear theca proteins and regulatory RNAs to the zygote. While also incorporated in oocyte cytoplasm, structures of the sperm tail, including mitochondrial sheath, axoneme, fibrous sheath and outer dense fibers are degraded and recycled. The ability of some of these sperm contributed components to give rise to functional zygotic structures and properly induce embryonic development may vary between bulls, bearing on their reproductive performance, and on the fitness, health, fertility and production traits of their offspring. Proper functioning, recycling and remodeling of gamete structures at fertilization is aided by the ubiquitin proteasome system (UPS), the universal substrate-specific protein recycling pathway present in bovine and other mammalian oocytes and spermatozoa. This review is focused on the aspects of UPS relevant to bovine fertilization and bull fertility. PMID- 29477155 TI - Canine visceral leishmaniasis diagnosis: a comparative performance of serological and molecular tests in symptomatic and asymptomatic dogs. AB - Although serological assays have been widely used for the diagnosis of canine visceral leishmaniasis (CVL), they present different performances depending on the clinical profile of the dogs. This study evaluated the accuracy of serological tests, immunochromatographic (Dual Path Platform: DPP(r)) and enzyme linked immunosorbent (ELISA EIE(r)), for CVL in relation to the detection of Leishmania DNA through real-time polymerase chain reaction (real-time PCR) in samples from symptomatic and asymptomatic dogs from a non-endemic area in the state of Rio Grande do Sul, Southern Brazil. Serum from 140 dogs (39 symptomatic and 101 asymptomatic) was tested by DPP and ELISA followed by real-time PCR. From a total of 140 samples evaluated, Leishmania DNA was detected by real-time PCR in 41.4% (58/140). Moreover, 67.2% of samples positive in real-time PCR were positive in both DPP and ELISA (39/58), showing moderate agreement between methods. In the symptomatic group, one sample non-reactive in both serological assays was positive in real-time PCR, whereas in the asymptomatic group, 17.8% non-reactive or undetermined samples in serological assays were positive in the molecular method. Leishmania DNA was not detected in 17.9% reactive samples by serological assays from the symptomatic group, and in 3.9% from asymptomatic dogs. Real-time PCR demonstrated greater homogeneity between symptomatic and asymptomatic groups compared with DPP and ELISA. The molecular method can help to establish the correct CVL diagnosis, particularly in asymptomatic dogs, avoiding undesirable euthanasia. PMID- 29477156 TI - An outbreak of Norovirus infections associated with recreational lake water in Western Finland, 2014. AB - In July 2014, an outbreak of gastroenteritis occurred among visitors to lakes in Tampere, Finland. We conducted a retrospective cohort study using an internet based survey, solicited by public announcement, to identify source of infection and to implement control measures. Of 1453 persons enrolled in the study, 244 met the case definition (attack rate, 17%). In the pooled univariate analysis, risk factors for gastroenteritis included getting water in the mouth while swimming (Risk ratio (RR) 3.32; 95% Confidence interval (CI), 2.36-4.68) and playing on the wet sand at the beach (RR 1.90; 95% CI 1.50-2.41). In a multivariable analysis (logistic regression), the source of the infection was likely at two lakes (lake A Odds ratio (OR) 1.66; 95% CI 1.15-2.39 and lake B, OR 2.35; 95% CI 1.49-3.72). Norovirus (NoV) was found in 19 stool samples. All water samples from implicated beaches had acceptable values of fecal indicator bacteria and were negative for NoV. The likely source of the outbreak was lake-water contaminated with NoV at two popular lakes. Closure of swimming beaches, advice on hygienic precautions and rapid outbreak alerts were efficient in controlling the outbreak. Results suggest a need for new indicators of water quality and development of evidence-based recommendations regarding timing of safe reopen of recreational water venues associated with outbreaks. PMID- 29477158 TI - Retraction notice to "Synthesis and characterization of composite polymer, polyethylene glycol grafted flower-like cupric nano oxide for solid phase microextraction of ultra-trace levels of benzene, toluene, ethyl benzene and o xylene in human hair and water samples" [J. Chromatogr. A 1418 (2015) 21-28]. PMID- 29477157 TI - US Renal Data System 2017 Annual Data Report: Epidemiology of Kidney Disease in the United States. PMID- 29477159 TI - Introduction. PMID- 29477160 TI - The Regulative Nature of Mammalian Embryos. AB - The striking developmental plasticity of early mammalian embryos has been known since the classical experiments performed in the 1950s and 1960s. There are many lines of evidence that the mammalian embryo is able to continue normal development even when exposed to severe experimental manipulations of the number and position of cells within the embryo. These observations have raised the question about the mechanisms involved in emergence, maintenance, and progressive restriction of this plasticity. Only recently, we have begun to understand these mechanisms. In this review, in order to explain the molecular and cellular events underlying the remarkable plasticity of the early mammalian embryo, we discuss results of classical experiments demonstrating developmental potential of mammalian embryos and link them with the novel data provided by contemporary experimental approaches. We also show how developmental flexibility of mammalian embryos is manifested in nature, and discuss its implications for basic research and medicine. PMID- 29477161 TI - Cell Polarity-Dependent Regulation of Cell Allocation and the First Lineage Specification in the Preimplantation Mouse Embryo. AB - During the first few days in the mouse preimplantation embryo, two types of cells, polar and apolar cells are generated from spherical totipotent blastomeres. Sequential morphogenetic events, polarization, compaction, and asymmetric division, are essential for the generation of the first distinct cell populations, polar and apolar cells, which establish the outer/inner configuration within the embryo. This leads to position-dependent activation of the Hippo signaling pathway and lineage-specific gene expression to form the trophectoderm and inner cell mass in a blastocyst. It is still unknown how each morphogenetic event is initiated and how it influences subsequent events. In this chapter, we briefly review the two classic models of mouse preimplantation development and discuss recent studies providing novel insights into the self organizing ability of the preimplantation mouse embryo. Advances in live cell imaging and mathematical modeling contribute a greater understanding to lineage specification and cell fate commitment at the single cell level. Differential molecular and mechanistic characteristics created by the presence and absence of the apical domain in polar and apolar cells, respectively, dictate cell allocation, divisional orientation, and differential activation of the Hippo signaling pathway. PMID- 29477162 TI - States and Origins of Mammalian Embryonic Pluripotency In Vivo and in a Dish. AB - Mouse embryonic stem cells (ESC), derived from preimplantation embryos in 1981, defined mammalian pluripotency for many decades. However, after the derivation of human ESC in 1998, comparative studies showed that different types of pluripotency exist in early embryos and that these can be captured in vitro under various culture conditions. Over the past decade much has been learned about the key signaling pathways, growth factor requirements, and transcription factor profiles of pluripotent cells in embryos, allowing improvement of derivation and culture conditions for novel pluripotent stem cell types. More recently, studies using single-cell transcriptomics of embryos from different species provided an unprecedented level of resolution of cellular interactions and cell fate decisions that are informing new ways to understand the emergence of pluripotency in different organisms. These new approaches enhance knowledge of species differences during early embryogenesis and will be instrumental for improving methodologies for generating intra- and interspecies chimeric animals using pluripotent stem cells. Here, we discuss the recent developments in our understanding of early embryogenesis in different mammalian species. PMID- 29477163 TI - Capturing and Interconverting Embryonic Cell Fates in a Dish. AB - Cells of the early embryo are totipotent because they will differentiate to produce the fetus and its surrounding extraembryonic tissues. By contrast, embryonic stem (ES) cells are considered to be merely pluripotent because they lack the ability to efficiently produce extraembryonic cell types. The relatively limited developmental potential of ES cells can be explained by the observation that ES cells are derived from the embryo after its cells have already begun to specialize and lose totipotency. Meanwhile, at the time that pluripotent ES cell progenitors are specified, so are the multipotent progenitors of two extraembryonic stem cell types: trophoblast stem (TS) cells and extraembryonic endoderm stem (XEN) cells. Notably, all three embryo-derived stem cell types are capable of either self-renewing or differentiating in a lineage-appropriate manner. These three types of embryo-derived stem cell serve as paradigms for defining the genes and pathways that define and maintain unique stem cell identities. Remarkably, some of the mechanisms that maintain the specific developmental potential of each stem cell line do so by preventing conversion to another stem cell fate. This chapter highlights noteworthy studies that have identified the genes and pathways that normally limit the interconversion of stem cell identities. PMID- 29477164 TI - From Germline to Soma: Epigenetic Dynamics in the Mouse Preimplantation Embryo. AB - When reflecting about cell fate commitment we think of differentiation. Be it during embryonic development or in an adult stem cell niche, where cells of a higher potency specialize and cell fate decisions are taken. Under normal circumstances this process is definitive and irreversible. Cell fate commitment is achieved by the establishment of cell-type-specific transcriptional programmes, which in turn are guided, reinforced, and ultimately locked-in by epigenetic mechanisms. Yet, this plunging drift in cellular potency linked to epigenetically restricted access to genomic information is problematic for reproduction. Particularly in mammals where germ cells are not set aside early on like in other species. Instead they are rederived from the embryonic ectoderm, a differentiating embryonic tissue with somatic epigenetic features. The epigenomes of germ cell precursors are efficiently reprogrammed against the differentiation trend, only to specialize once more into highly differentiated, sex-specific gametes: oocyte and sperm. Their differentiation state is reflected in their specialized epigenomes, and erasure of these features is required to enable the acquisition of the totipotent cell fate to kick start embryonic development of the next generation. Recent technological advances have enabled unprecedented insights into the epigenetic dynamics, first of DNA methylation and then of histone modifications, greatly expanding the historically technically limited understanding of this processes. In this chapter we will focus on the details of embryonic epigenetic reprogramming, a cell fate determination process against the tide to a higher potency. PMID- 29477165 TI - Pre-gastrula Development of Non-eutherian Mammals. AB - Marsupials and monotremes differ from eutherian mammals in many features of their reproduction and development. Some features appear to be representative of transitional stages in evolution from therapsid reptiles to humans and mice, particularly with respect to the extraembryonic tissues that have undergone remarkable modifications to accommodate reduced egg size and quantity of yolk/deutoplasm, and increasing emphasis on viviparity and placentation. Trophoblast and hypoblast contribute the epithelial layers in most of the extraembryonic membranes and are the first two lineages to differentiate from the embryonic lineage. How they are specified varies greatly among mammals, perhaps largely due to heterochrony in the stage at which they must function. Differences probably also exist in the stage at which lineages are specified relative to the stage at which they fully commit to differentiation. The dogma of sequential commitment to trophoblast and hypoblast with progressive loss of potency may not be a fundamental feature of early mammalian development, but merely a recently acquired developmental pattern in eutherians, or at least mice. PMID- 29477166 TI - Pre-implantation Development of Domestic Animals. AB - During the first days following fertilization, cells of mammalian embryo gradually lose totipotency, acquiring distinct identity. The first three lineages specified in the mammalian embryo are pluripotent epiblast, which later gives rise to the embryo proper, and two extraembryonic lineages, hypoblast (also known as primitive endoderm) and trophectoderm, which form tissues supporting development of the fetus in utero. Most of our knowledge regarding the mechanisms of early lineage specification in mammals comes from studies in the mouse. However, the growing body of evidence points to both similarities and species specific differences. Understanding molecular and cellular mechanisms of early embryonic development in nonrodent mammals expands our understanding of basic mechanisms of differentiation and is essential for the development of effective protocols for assisted reproduction in agriculture, veterinary medicine, and for biomedical research. This review summarizes the current state of knowledge on key events in epiblast, hypoblast, and trophoblast differentiation in domestic mammals. PMID- 29477167 TI - Human Pre-gastrulation Development. AB - Understanding the progression of early human embryonic development prior to implantation is of fundamental biological importance. Greater insights into early developmental events may lead to clinical improvements, not only via the establishment of novel stem cell models with increased potential or more physiological relevance, but also by uncovering some underlying causes of infertility, miscarriages, and developmental disorders. The majority of human embryos available for study are those donated to research once they are surplus to family building following in vitro fertilization, though in some countries it is also possible to create embryos using donated gametes. As human embryo development is surprisingly inefficient, with only 40% reaching the blastocyst stage in vitro (French, Sabanegh, Goldfarb, & Desai, 2010; Gardner, Lane, Stevens, Schlenker, & Schoolcraft, 2000), many embryos may not develop to a stage suitable for study. Where legally permitted, the oversight of human embryo research is subject to either ethics approval from a local institutional review board (i.e., China and the United States) or both a national regulator as well as a regional research ethics committee (i.e., the United Kingdom). The study of human development has historically been by necessity comparative, relying on model organisms and stem cell lines to inform analyses. Preimplantation mouse and human embryos in particular exhibit remarkably similar gross morphologies at these early stages of development, although key differences have been identified in gene expression patterns and developmental timing. While recent advances in high-resolution transcriptomic analyses at the single cell level have improved our capability to interrogate expression patterns directly in the human embryo, we still lack an understanding of basic molecular events in the human embryo, including how the first cell lineages become specified. Here, we present a current overview of the major developmental events during human preimplantation development, from fertilization to delineation of the embryonic and extraembryonic lineages prior to implantation. Comparisons to both the mouse and alternative models are included where these have formed the basis for similar investigations in a human context. PMID- 29477168 TI - The Mitochondria and the Regulation of Cell Fitness During Early Mammalian Development. AB - From fertilization until the onset of gastrulation the early mammalian embryo undergoes a dramatic series of changes that converts a single fertilized cell into a remarkably complex organism. Much attention has been given to the molecular changes occurring during this process, but here we will review what is known about the changes affecting the mitochondria and how they impact on the energy metabolism and apoptotic response of the embryo. We will also focus on understanding what quality control mechanisms ensure optimal mitochondrial activity in the embryo, and in this way provide an overview of the importance of the mitochondria in determining cell fitness during early mammalian development. PMID- 29477169 TI - The Head's Tale: Anterior-Posterior Axis Formation in the Mouse Embryo. AB - The establishment of the anterior-posterior (A-P) axis is a fundamental event during early development and marks the start of the process by which the basic body plan is laid down. This axial information determines where gastrulation, that generates and positions cells of the three-germ layers, occurs. A-P patterning requires coordinated interactions between multiple tissues, tight spatiotemporal control of signaling pathways, and the coordination of tissue growth with morphogenetic movements. In the mouse, a specialized population of cells, the anterior visceral endoderm (AVE) undergoes a migration event critical for correct A-P pattern. In this review, we summarize our understanding of the generation of anterior pattern, focusing on the role of the AVE. We will also outline some of the many questions that remain regarding the mechanism by which the first axial asymmetry is established, how the AVE is induced, and how it moves within the visceral endoderm epithelium. PMID- 29477170 TI - Cell Fate Decisions During Preimplantation Mammalian Development. AB - The early mouse embryo offers a phenomenal system to dissect how changes in the mechanisms controlling cell fate are integrated with morphogenetic events at the single-cell level. New technologies based on live imaging have enabled the discovery of dynamic changes in the regulation of single genes, transcription factors, and epigenetic mechanisms directing early cell fate decision in the early embryo. Here, we review recent progress in linking molecular dynamic events occurring at the level of the single cell in vivo, to some of the key morphogenetic changes regulating early mouse development. PMID- 29477171 TI - Our First Choice: Cellular and Genetic Underpinnings of Trophectoderm Identity and Differentiation in the Mammalian Embryo. AB - The trophectoderm (TE) is the first cell population to appear in the mammalian preimplantation embryo, as the result of the differentiation of totipotent blastomeres located on the outer surface of the late morula. Trophectodermal cells arrange in a monolayer covering the expanding blastocyst and acquire an epithelial phenotype with distinct apicobasal polarity and a basal lamina placed toward the blastocyst interior. During later development through the periimplantation and gastrulation stages, the TE gives rise to extraembryonic membranes and cell types that will eventually form most of the fetal placenta, the specialized organ through which the embryo obtains maternal nourishment necessary for subsequent exponential growth. The specification of the TE is controlled by the combination of morphological cues arising from cell polarity with differential activity of signaling pathways such as Hippo and Notch, and the restriction to outer cells of lineage specifiers such as CDX2. This is possibly the first symmetry-breaking decision undertaken by the uncommitted cells produced by a handful of mitosis divisions from the newly fertilized zygote. Understanding how this cell lineage is specified will therefore provide unique information about development, differentiation, and how the interplay between cellular morphology and signaling and regulatory factors results in a correctly 3D patterned embryo. PMID- 29477173 TI - Management of Oral and Maxillofacial Infections. PMID- 29477172 TI - Primitive Endoderm Differentiation: From Specification to Epithelialization. AB - At the time of implantation, the mouse blastocyst has developed three cell lineages: the epiblast (Epi), the primitive endoderm (PrE), and the trophectoderm (TE). The PrE and TE are extraembryonic tissues but their interactions with the Epi are critical to sustain embryonic growth, as well as to pattern the embryo. We review here the cellular and molecular events that lead to the production of PrE and Epi lineages and discuss the different hypotheses that are proposed for the induction of these cell types. In the second part, we report the current knowledge about the epithelialization of the PrE. PMID- 29477174 TI - Tacrolimus Formulations and African American Kidney Transplant Recipients: When Do Details Matter? PMID- 29477175 TI - Assessing Fatigue in the ESRD Patient: A Step Forward. PMID- 29477176 TI - Dialysis Modality Survival Comparison: Time to End the Debate, It's a Tie. PMID- 29477177 TI - A Peculiar Case of Paraproteinemia and Elevated Creatinine. PMID- 29477178 TI - Inner tooth morphology of Homo erectus from Zhoukoudian. New evidence from an old collection housed at Uppsala University, Sweden. AB - Locality 1, in the Lower Cave of the Zhoukoudian cave complex, China, is one of the most important Middle Pleistocene paleoanthropological and archaeological sites worldwide, with the remains of c. 45 Homo erectus individuals, 98 mammalian taxa, and thousands of lithic tools recovered. Most of the material collected before World War II was lost. However, besides two postcranial elements rediscovered in China in 1951, four human permanent teeth from the 'Dragon Bone Hill,' collected by O. Zdansky between 1921 and 1923, were at the time brought to the Paleontological Institute of Uppsala University, Sweden, where they are still stored. This small sample consists of an upper canine (PMU 25719), an upper third molar (PMU M3550), a lower third premolar crown (PMU M3549), and a lower fourth premolar (PMU M3887). Some researchers have noted the existence of morpho dimensional differences between the Zhoukoudian and the H. erectus dental assemblage from Sangiran, Java. However, compared to its chrono-geographical distribution, the Early to Middle Pleistocene dental material currently forming the Chinese-Indonesian H. erectus hypodigm is quantitatively meager and still poorly characterized for the extent of its endostructural variation. We used micro-focus X-ray tomography techniques of virtual imaging coupled with geometric morphometrics for comparatively investigating the endostructural conformation (tissue proportions, enamel thickness distribution, enamel-dentine junction morphology, pulp cavity shape) of the four specimens stored in Uppsala, all previously reported for their outer features. The results suggest the existence of time-related differences between continental and insular Southeast Asian dental assemblages, the Middle Pleistocene Chinese teeth apparently retaining an inner signature closer to the likely primitive condition represented by the Early Pleistocene remains from Java, while the Indonesian stock evolved toward tooth structural simplification. PMID- 29477179 TI - Understanding climate's influence on the extinction of Oreopithecus (late Miocene, Tusco-Sardinian paleobioprovince, Italy). AB - Despite its long history of scientific study, the causes underlying the extinction of the insular hominoid Oreopithecus bambolii are still a matter of ongoing debate. While some authors consider intense tectonism and invading species the cause of its extinction ca. 6.7 Ma, others propose climatic change as the main contributing factor. We rely on long-term patterns of tooth wear and hypsodonty of the Baccinello and Fiume Santo herbivore-faunas to reconstruct changes in habitat prior to, during and after the extinction. While a mosaic of habitats was represented in Baccinello V1 (as shown by a record of browsers, mixed feeders and species engaged in grazing), more closed forests (higher proportion of browsers, shortage of mixed feeders and lack of grazers) characterised Baccinello V2. Finally, there was a partial loss of canopy cover and development of open-patches and low-abrasive grasses in Baccinello V3 (as denoted by new records of taxa involved in grazing)-although still dominated by a forested habitat (since browse was a component in all diets). Our results provide evidence for two perceptible shifts in climate, one between 8.1 and 7.1 Ma and other ca. 6.7 Ma, though this latter was not drastic enough to lead to intensive forest loss, substantially alter the local vegetation or affect Oreopithecus lifestyle-especially if considering the growing evidence of its versatile diet. Although the disappearance of Oreopithecus is complex, our data reject the hypothesis of environmental change as the main factor in the extinction of Oreopithecus and Maremma fauna. When our results are analysed together with other evidence, faunal interaction and predation by invading species from mainland Europe seems to be the most parsimonious explanation for this extinction event. This contrasts with European hominoid extinctions that were associated with major climatic shifts that led to environmental uniformity and restriction of the preferred habitats of Miocene apes. PMID- 29477180 TI - Lahar inundated, modified, and preserved 1.88 Ma early hominin (OH24 and OH56) Olduvai DK site. AB - Archaeological excavations at the DK site in the eastern Olduvai Basin, Tanzania, age-bracketed between ~1.88 Ma (Bed I Basalt) and ~1.85 Ma (Tuff IB), record the oldest lahar inundation, modification, and preservation of a hominin "occupation" site yet identified. Our landscape approach reconstructs environments and processes at high resolution to explain the distribution and final preservation of archaeological materials at the DK site, where an early hominin (likely Homo habilis) assemblage of stone tools and bones, found close to hominin specimens OH24 and OH56, developed on an uneven heterogeneous surface that was rapidly inundated by a lahar and buried to a depth of 0.4-1.2 m (originally ~1.0-2.4 m pre-compaction). The incoming intermediate to high viscosity mudflow selectively modified the original accumulation of "occupation debris," so that it is no longer confined to the original surface. A dispersive debris "halo" was identified within the lahar deposit: debris is densest immediately above the site, but tails off until not present >150 m laterally. Voorhies indices and metrics derived from limb bones are used to define this dispersive halo spatially and might indicate a possible second assemblage to the east that is now eroded away. Based upon our new data and prior descriptions, two possibilities for the OH24 skull are suggested: it was either entrained by the mudflow from the DK surface and floated due to lower density toward its top, or it was deposited upon the solid top surface after its consolidation. Matrix adhering to material found in association with the parietals indicates that OH56 at least was relocated by the mudflow. PMID- 29477181 TI - A computer simulation to investigate the association between gene-based gifting and pair-bonding in early hominins. AB - This article describes simulation research based on the Hamiltonian theory of gene-based altruism. It investigates the origin of semipermanent breeding bonds during hominin evolution. The research framework is based on a biologically detailed, ecologically situated, multi-agent microsimulation of emergent sociality. The research question tested is whether semipermanent breeding bonds (an emergent homoplastic social construct) might emerge among primate-like agents as the consequence of a mutation capable of supporting involuntary prosocial behavior. The research protocol compared several, single independent-variable longitudinal studies wherein hundreds of generations of autonomous, initially promiscuous, biologically detailed, hominin-like artificial life software agents were born, allowed to forage, reproduce, and die during experimental intervals lasting several simulated millennia. The temporal setting of the experiment was roughly contemporaneous with, or slightly after the time of, the Pan-Homo split. The simulation investigated what would happen if, within a population, a single gene for prosocial behavior (the independent variable in the experiment) was either switched on or switched-off. The null hypothesis predicted that, if the gene was switched off, then semipermanent breeding bonds (the dependent variable) would nonetheless emerge within the population. The results of the simulation rejected this null hypothesis, by showing that semipermanent breeding bonds would reliably emerge among the experimental populations but not among the control groups. Moreover, it was found that, across all experimental settings having constrained population numbers, the portion of each population having no prosocial trait would die out early, whereas the portion with the prosocial trait would survive. Large control populations had no discernible loss. The results of this research imply that, during the early stages of hominin evolution, there might have been a set of initially gene-based, altruistic excess forage-sharing social traits that contributed to the onset of morphological and additional complex social changes characteristic of this group. This work also demonstrates that modern computational technologies can extend our ability to test 'what if' hypotheses appropriate to the study of early hominin evolution. PMID- 29477182 TI - Craniomandibular form and body size variation of first generation mouse hybrids: A model for hominin hybridization. AB - Hybridization occurs in a number of mammalian lineages, including among primate taxa. Analyses of ancient genomes have shown that hybridization between our lineage and other archaic hominins in Eurasia occurred numerous times in the past. However, we still have limited empirical data on what a hybrid skeleton looks like, or how to spot patterns of hybridization among fossils for which there are no genetic data. Here we use experimental mouse models to supplement previous studies of primates. We characterize size and shape variation in the cranium and mandible of three wild-derived inbred mouse strains and their first generation (F1) hybrids. The three parent taxa in our analysis represent lineages that diverged over approximately the same period as the human/Neanderthal/Denisovan lineages and their hybrids are variably successful in the wild. Comparisons of body size, as quantified by long bone measurements, are also presented to determine whether the identified phenotypic effects of hybridization are localized to the cranium or represent overall body size changes. The results indicate that hybrid cranial and mandibular sizes, as well as limb length, exceed that of the parent taxa in all cases. All three F1 hybrid crosses display similar patterns of size and form variation. These results are generally consistent with earlier studies on primates and other mammals, suggesting that the effects of hybridization may be similar across very different scenarios of hybridization, including different levels of hybrid fitness. This paper serves to supplement previous studies aimed at identifying F1 hybrids in the fossil record and to introduce further research that will explore hybrid morphologies using mice as a proxy for better understanding hybridization in the hominin fossil record. PMID- 29477183 TI - Subdecadal phytolith and charcoal records from Lake Malawi, East Africa imply minimal effects on human evolution from the ~74 ka Toba supereruption. AB - The temporal proximity of the ~74 ka Toba supereruption to a putative 100-50 ka human population bottleneck is the basis for the volcanic winter/weak Garden of Eden hypothesis, which states that the eruption caused a 6-year-long global volcanic winter and reduced the effective population of anatomically modern humans (AMH) to fewer than 10,000 individuals. To test this hypothesis, we sampled two cores collected from Lake Malawi with cryptotephra previously fingerprinted to the Toba supereruption. Phytolith and charcoal samples were continuously collected at ~3-4 mm (~8-9 yr) intervals above and below the Toba cryptotephra position, with no stratigraphic breaks. For samples synchronous or proximal to the Toba interval, we found no change in low elevation tree cover, or in cool climate C3 and warm season C4 xerophytic and mesophytic grass abundance that is outside of normal variability. A spike in locally derived charcoal and xerophytic C4 grasses immediately after the Toba eruption indicates reduced precipitation and die-off of at least some afromontane vegetation, but does not signal volcanic winter conditions. A review of Toba tuff petrological and melt inclusion studies suggest a Tambora-like 50 to 100 Mt SO2 atmospheric injection. However, most Toba climate models use SO2 values that are one to two orders of magnitude higher, thereby significantly overestimating the amount of cooling. A review of recent genetic studies finds no support for a genetic bottleneck at or near ~74 ka. Based on these previous studies and our new paleoenvironmental data, we find no support for the Toba catastrophe hypothesis and conclude that the Toba supereruption did not 1) produce a 6-year-long volcanic winter in eastern Africa, 2) cause a genetic bottleneck among African AMH populations, or 3) bring humanity to the brink of extinction. PMID- 29477184 TI - Evidence for rapid faunal change in the early Miocene of East Africa based on revised biostratigraphic and radiometric dating of Bukwa, Uganda. AB - Field expeditions to Bukwa in the late 1960s and early 1970s established that the site had a small but diverse early Miocene fauna, including the catarrhine primate Limnopithecus legetet. Initial potassium-argon radiometric dating indicated that Bukwa was 22 Ma, making it the oldest of the East African early Miocene fossil localities known at the time. In contrast, the fauna collected from Bukwa was similar to other fossil localities in the region that were several million years younger. This discrepancy was never resolved, and due to the paucity of primate remains at the site, little subsequent research took place. We have collected new fossils at Bukwa, reanalyzed the existing fossil collections, and provided new radiometric dating. 40Ar/39Ar incremental heating ages on lavas bracketing the site indicate that the Bukwa fossils were deposited ~19 Ma, roughly 3 Ma younger than the original radiometric age. Our radiometric dating results are corroborated by a thorough reanalysis of the faunal assemblage. Bukwa shares taxa with both stratigraphically older localities (Tinderet, Napak) and with stratigraphically younger localities (Kisingiri, Turkana Basin) perfectly corresponding to our revised radiometric age. This revised age for Bukwa is important because it indicates that significant faunal turnover may have occurred in East Africa between 20 and 19 Ma. Bukwa samples immigrant taxa such as large suids, large ruminants, and ochotonids that are absent from stratigraphically older but well-sampled localities in the region, such as Tinderet (~20 Ma) and Napak (20 Ma). Further age refinements for Bukwa and the entire East African early Miocene sequence will help to constrain the timing of this faunal turnover event, of particular importance in paleoanthropology since this temporal sequence also provides us with what is currently our best window into the early evolution of cercopithecoid and hominoid primates. PMID- 29477185 TI - Through Disaster Relief, Serving the Communities We Love. PMID- 29477186 TI - Practice Paper of the Academy of Nutrition and Dietetics: Nutrition Intervention and Human Immunodeficiency Virus Infection. AB - Nutrition is an integral component of medical care for people living with human immunodeficiency virus (HIV)/autoimmune deficiency syndrome (AIDS) (PLWHA). The Academy of Nutrition and Dietetics supports integration of medical nutrition therapy into routine care for this population. Fewer PLWHA experience wasting and undernutrition, while the prevalence of obesity and other chronic diseases has increased significantly. Improved understanding of HIV infection's impact on metabolism and chronic inflammation has only increased the complexity of managing chronic HIV infection. Nutrition assessment should encompass food insecurity risk, changes in body composition, biochemical indices, and clinical indicators of comorbid disease. Side effects from current antiretroviral therapy regimens are less prevalent than with previous generations of therapy. However, micronutrient deficiencies and chronic anemia also remain significant nutritional risks for PLWHA, making vitamin and mineral supplementation necessary in cases of acute deficiency or food insecurity. Additional factors can impact HIV-related nutrition care among the pediatric population, older adults, minority groups, those co-infected with tuberculosis or hepatitis, and PLWHA in rural or underserved areas. Registered dietitian nutritionists and nutrition and dietetic technicians, registered should participate in multidisciplinary care to incorporate nutrition into the medical management of PLWHA. PMID- 29477187 TI - Compensation and Benefits Survey 2017. PMID- 29477188 TI - A Life Full of Surprises and Excitement through Science in Dermatology. PMID- 29477189 TI - Adipose and Hair Function: An aPPARent Connection. AB - Adipose tissue plays essential roles in various aspects of skin physiology, from regulating hair follicle morphogenesis to wound healing. Peroxisome proliferator activated receptor gamma is important for the maintenance of adipose tissue and has been implicated in some types of hair loss; however, its function during the hair cycle is still unclear. Sardella et al. investigate the role of peroxisome proliferator-activated receptor gamma in hair follicle morphogenesis using a novel global peroxisome proliferator-activated receptor gamma-null mouse. PMID- 29477190 TI - Hot Stuff: Thermal Imaging Aids in Cellulitis Diagnosis. AB - Cellulitis is commonly misdiagnosed, with resultant health care expenditures and complications from antibiotic overprescription. Ko et al. evaluate the use of thermal imaging to aid in the diagnosis of cellulitis, with promising results. Limitations include a small sample size and questionable applicability to bilateral leg findings, where cellulitis is unlikely regardless of temperature differential. Nevertheless, this technology has potential to improve patient care. PMID- 29477191 TI - Shining a Light on Black Holes in Keratinocytes. AB - The mechanisms by which melanins are transferred from melanocytes and stored within keratinocytes to generate skin pigmentation are hotly debated. Correia et al. and Hurbain et al. provide evidence that melanin cores of melanosomes are secreted from melanocytes and taken up and stored within non-degradative membranous organelles in keratinocytes in the basal epidermis of human skin. PMID- 29477193 TI - SnapshotDx Quiz: March 2018. PMID- 29477192 TI - Research Techniques Made Simple: Using Genome-Wide Association Studies to Understand Complex Cutaneous Disorders. AB - Complex cutaneous disorders result from the combined effect of many different genes and environmental factors, with individual genetic variants often having only a modest effect on disease risk. The ability to examine large numbers of samples is required for correlating genetic variants with diseases/traits. Technological advances in high-throughput genotyping, along with mapping of the human genome and its associated inter-individual variation, have allowed genetic variants to be analyzed at high density in large case-control cohorts for many diseases, including several major skin diseases. These genome-wide association studies focus on showing differences in the frequencies of variants between case and control groups, rather than co-transmission of a variant and disease through a family, as is done in linkage studies. In this review, we provide overall guidance for genome-wide association study analysis and interpreting the results. Additionally, we discuss challenges and future directions for genome-wide association studies, focusing on translation of findings to provide biological and clinical implications for dermatology. PMID- 29477194 TI - Cells to Surgery Quiz: March 2018. PMID- 29477195 TI - Kudos to Professor Paul Tam. PMID- 29477196 TI - Invited commentary. PMID- 29477197 TI - Invited commentary. PMID- 29477198 TI - Invited commentary. PMID- 29477199 TI - Invited commentary. PMID- 29477200 TI - Invited commentary. PMID- 29477201 TI - Invited commentary. PMID- 29477202 TI - Invited commentary. PMID- 29477203 TI - Invited commentary. PMID- 29477204 TI - MicroRNA-155 promotes neointimal hyperplasia through smooth muscle-like cell derived RANTES in arteriovenous fistulas. AB - OBJECTIVE: Arteriovenous fistula (AVF) suffers from a high number of failures caused by insufficient outward remodeling and venous neointimal hyperplasia formation. The aim was to investigate the exact mechanism by which microRNA-155 (miR-155) in the outflow vein of AVF is regulated. METHODS: AVFs between the branch of the jugular vein and carotid artery in an end-to-end manner were created in C57BL/6 and miR-155-/- mice with a C57BL/6 background. The venous segments were harvested at day 7, 14, 21, and 28, and the AVFs were analyzed histologically and at a messenger RNA level using real-time quantitative polymerase chain reactions. The outflow vein of AVF and the normal great saphenous vein, collected from patients with chronic kidney disease and coronary artery bypass surgery, were analyzed by histologic and molecular biologic approaches. RESULTS: Venous neointimal hyperplasia is significantly alleviated in miR-155-/- mice, and the expression of several chemokines and cytokines in the vessel wall, including regulated on activation, normal T-cell expressed and secreted factor (RANTES), monocyte chemoattractant protein 1, and vascular endothelial growth factor, was inhibited. miR-155 promoted the RANTES expression of smooth muscle-like cells, which in turn facilitated cell proliferation and extracellular matrix production. CONCLUSIONS: miR-155 enhances venous neointima formation through the autocrine and paracrine effects of smooth muscle-like cell derived RANTES in a nuclear factor kappaB-dependent manner during the entire AVF process, especially at the advanced stage. PMID- 29477205 TI - Impending rupture of an abdominal aortic aneurysm and aortoenteric fistula formation. PMID- 29477206 TI - Level of clinical evidence presented at the Society for Vascular Surgery Annual Meeting during a 5-year period (2012-2016). AB - OBJECTIVE: During the past decades, there has been an increasing emphasis on the use of high-quality evidence to inform clinical decision-making. The purpose of our study was to assess trends in the level of evidence (LOE) of abstracts presented at the Vascular Annual Meeting from 2012 to 2016. METHODS: All Vascular Annual Meeting abstracts for 2012 to 2016 were obtained through the Journal of Vascular Surgery. Two reviewers independently screened abstracts for eligibility. Research with a nonclinical focus was excluded from the study. Data extracted from eligible abstracts included study type (therapeutic, prognostic, diagnostic), study size, country of academic institution of primary author, presentation type, and whether the sample was recruited or from a database. Abstracts were assigned an LOE using the 2011 Oxford Centre for Evidence-Based Medicine classification scheme based on study design (eg, case series, randomized controlled trial). A chi2 test and analysis of variance test were conducted to assess nonrandom changes in LOE during the study period. RESULTS: Of the 1403 abstracts screened, 1147 were included. Inter-rater agreement was high (kappa value for abstract screening was 0.93; kappa value for data extraction was 0.89). Therapeutic studies were the most common study type (58%), followed by prognostic studies (37%), then diagnostic studies (5%). The majority of abstracts (75.0%) were submitted from North American institutions. Overall, 0.35% of the presentations were level I evidence, 3.1% level II, 52.8% level III, 38.0% level IV, and 5.7% level V. The average LOE per year fluctuated between 3.54 and 3.32, with a mean LOE of 3.45. The proportion of high-quality evidence (level I and level II) increased in the years 2015 and 2016, representing 78% of all level I and level II abstracts presented in the 5-year period. A chi2 test between LOE and year yielded a P value of .0084, indicating significant nonrandom change in LOE between 2012 and 2016. The majority of high LOE research was presented in poster sessions (37.5%), plenary sessions (27.5%), and international forum sessions/talks (25%) at the meeting. CONCLUSIONS: Overall, average LOE remained relatively consistent between 2012 and 2016, with most abstracts classified as level III or level IV. There was a gradual, albeit minor, increase in the proportion of level I and level II evidence in 2015 and 2016, potentially indicating the increasing commitment to producing and disseminating high-level research in vascular surgery. Furthermore, a lack of a classification tool specific to vascular surgery research occasionally presented a challenge in assigning LOE, perhaps indicating a need for such a tool in this specialty. PMID- 29477207 TI - Quality Payment Program year 2. PMID- 29477208 TI - Rivaroxaban in peripheral artery disease: The new kid on the block? PMID- 29477209 TI - Regarding "A 10-year institutional experience with open branched graft reconstruction of aortic aneurysms in connective tissue disorders versus degenerative disease". PMID- 29477210 TI - Regarding "A registry-based rationale for discrete intervention thresholds for open and endovascular elective abdominal aortic aneurysm repair in female patients". PMID- 29477211 TI - Reply. PMID- 29477212 TI - Regarding "Updated Society for Vascular Surgery guidelines for management of extracranial carotid disease". PMID- 29477213 TI - Reply. PMID- 29477214 TI - Correction. PMID- 29477215 TI - Influence of ethnic background on left atrial markers of inflammation, endothelial function and tissue remodelling. AB - BACKGROUND: It has been suggested that ethnicity can make a significant difference to the likelihood of thromboembolic stroke related to atrial fibrillation. Ethnic differences have been shown to alter inflammatory and haemostatic factors; however, this may all be confounded by differences in cardiovascular risk factors between different ethnicity. The impact of different ethnicities on the thrombogenic profile is not known. The aim of this study was to investigate differences in markers of inflammation, endothelial function and tissue remodelling between Caucasian and Indian populations with supraventricular tachycardia (SVT). METHODS: Patients with structurally normal hearts undergoing catheter ablation for SVT were studied. This study included 23 Australian (Caucasian) patients from the Royal Adelaide Hospital, Adelaide, Australia and 24 Indian (Indian) patients from the Christian Medical College, Vellore, India. Blood samples were collected from the femoral vein, and right and left atria. Blood samples were analysed for the markers of endothelial function (ADMA, ET-1), inflammation (CD40L, VCAM-1, ICAM-1), and tissue remodelling (MMP-9, TIMP-1) using ELISA. RESULTS: The study populations were well matched for cardiovascular risk factors and the absence of structural heart disease. No difference in the echocardiographic measurements between the two ethnicities was found. In this context, there was no difference in markers of inflammation, endothelial function or tissue remodelling between the two SVT populations. CONCLUSION: Caucasian and Indian populations demonstrate similar inflammatory, endothelial function or tissue remodelling profiles. This study suggests a lack of an impact of different ethnicity in these populations in terms of thrombogenic risk. PMID- 29477217 TI - Importance of including harms as well as benefits in all clinical trials. PMID- 29477218 TI - Foreword: Update on the Treatment of Depression and Pharmacogenomics Testing in Children and Adolescents: Dr. Strawn and Colleagues. PMID- 29477216 TI - Trends in atrial fibrillation hospitalizations in the United States: A report using data from the National Hospital Discharge Survey. AB - AIMS: Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice. Patients presenting with AF are often admitted to hospital for rhythm or rate control, symptom management, and/or anticoagulation. We investigated temporal trends in AF hospitalizations in United States from 1996 to 2010. METHODS: Data were obtained from the National Hospital Discharge Survey (NHDS), a national probability sample survey of discharges conducted annually by National Center for Health Statistics. Because of the survey design, sampling weights were applied to the raw NHDS data to produce national estimates. Hospitalizations with a primary diagnosis of AF were identified using International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) code of 427.31. Weighted least squares regression was used to test for linear trends in the number of AF admissions, length of stay, and inpatient mortality. We further stratified AF admissions based on patients' age, gender, and race. RESULTS: Admissions for a primary diagnosis of AF increased from approximately 286,000 in 1996 to about 410,000 in 2010 with a significant linear trend (beta = 9470 additional admissions per year, p < 0.001). The trend of increased AF admissions was uniform across patient sub-groups. Overall, mean length of stay for AF admissions was 3.75 days, and this remained relatively stable over time (beta = 0.002 days, p = 0.884). Inpatient mortality was 0.96% and also remained stable over time (beta = 0.031%, p = 0.181). CONCLUSION: Our data demonstrate an increase in the number of AF admissions but constant length of stay and mortality over time. PMID- 29477219 TI - Commentary: Recent Advances in Pediatric Psychopharmacology. PMID- 29477220 TI - Thiamin. AB - Starting with a brief history of beriberi and the discovery that thiamin deficiency is its cause, the symptoms and signs are reviewed. None are pathognomonic. The disease has a low mortality and a long morbidity. The appearance of the patient can be deceptive, often being mistaken for psychosomatic disease in the early stages. The chemistry of thiamin and the laboratory methodology for depicting its deficiency are outlined. The diseases associated with thiamin deficiency, apart from malnutrition, include a number of genetically determined conditions where mutations, either in the cofactor relationship or a transporter, provide the etiology. It is emphasized that such mutations are often epigenetically responsive to megadoses of thiamin or one of its derivatives. The use of thiamin in clinical practice requires a high index of suspicion on the part of the clinician since it has a part to play in eating disorders, diabetes, neurodegenerative disease, and cancer. A high rate of critical illness and postsurgery thiamin deficiency have been reported, particularly those associated with gastrointestinal bypass. Emphasis is placed on thiamin deficiency as a major cause of asymmetric dysautonomia, because of the high degree of sensitivity to thiamin deficiency in the brainstem, cerebellum, and hypothalamus. The relationship of thiamin with regional pain syndrome, eosinophilic esophagitis, its analgesic capacity, and its preventive use in obstetrics is raised as a potential issue. The role of thiamin in SIDS and autism is outlined. It is emphasized that megadose thiamin is being used as a drug, either in stimulating the damaged cofactor/enzyme combination, or mitochondria. PMID- 29477221 TI - The Emerging Role of Vitamin B6 in Inflammation and Carcinogenesis. AB - Vitamin B6 serves as a coenzyme catalyzing more than 150 enzymes regulating metabolism and synthesis of proteins, carbohydrates, lipids, heme, and important bioactive metabolites. For several years vitamin B6 and its vitamers (B6) were recognized as antioxidant and antiinflammatory and in modulating immunity and gene expression. During the last 10 years, there were growing reports implicating B6 in inflammation and inflammation-related chronic illnesses including cancer. It is unclear if the deficiency of B6 or additional intake of B6, above the current requirement, should be the focus. Whether the current recommended daily intake for B6 is adequate should be revisited, since B6 is important to human health beyond its role as a coenzyme and its status is affected by many factors including but not limited to age, obesity, and inflammation associated with chronic illnesses. A link between inflammation B6 status and carcinogenesis is not yet completely understood. B6-mediated synthesis of H2S, a gasotransmitter, and taurine in health and disease, especially in maintaining mitochondrial integrity and biogenesis and inflammation, remains an important area to be explored. Recent developments in the molecular role of B6 and its direct interaction with inflammasomes, and nuclear receptor corepressor and coactivator, receptor-interacting protein 140, provide a strong impetus to further explore the multifaceted role of B6 in carcinogenesis and human health. PMID- 29477222 TI - Recent Developments in Folate Nutrition. AB - The term folate (vitamin B9) refers to a group of water-soluble compounds that are nutritionally essential for the support of optimal human health and development. Folates participate in numerous one-carbon transfer reactions, including the methylation of important biomolecules (lipids, amino acids, DNA). A deficiency of folate leads to pathological outcomes including anemia and impairments in reproductive health and fetal development. Due to the linkage of impaired folate status with an increased prevalence of neural tube defects (NTDs) in babies, several jurisdictions required the fortification of the food supply with folic acid, a synthetic and stable form of folate. Data from the postfortification era have provided strong evidence for the reduction of NTDs due to folic acid fortification. However, concern is now growing with respect to the amount of synthetic folic acid within the human food supply. Excess folic acid intake has been linked to a masking of vitamin B12 deficiency, and concerns regarding the promotion of folate-sensitive cancers, including colorectal cancer. New strategies to ensure the supply of optimal folate to at-risk populations may be needed, including the use of biofortification approaches, in order to address recent concerns. PMID- 29477223 TI - Vitamin B12. AB - The biosynthesis of B12, involving up to 30 different enzyme-mediated steps, only occurs in bacteria. Thus, most eukaryotes require an external source of B12, and yet the vitamin appears to have only two functions in eukaryotes: as a cofactor for the enzymes methionine synthase and methylmalonylCoA mutase. These two functions are crucial for normal health in humans, and in particular, the formation of methionine is essential for providing methyl groups for over 100 methylation processes. Interference with the methionine synthase reaction not only depletes the body of methyl groups but also leads to the accumulation of homocysteine, a risk factor for many diseases. The syndrome pernicious anemia, characterized by lack of intrinsic factor, leads to a severe, sometimes fatal form of B12 deficiency. However, there is no sharp cutoff for B12 deficiency; rather, there is a continuous inverse relationship between serum B12 and a variety of undesirable outcomes, including neural tube defects, stroke, and dementia. The brain is particularly vulnerable; in children, inadequate B12 stunts brain and intellectual development. Suboptimal B12 status (serum B12<300pmol/L) is very common, occurring in 30%-60% of the population, in particular in pregnant women and in less-developed countries. Thus, many tens of millions of people in the world may suffer harm from having a poor B12 status. Public health steps are urgently needed to correct this inadequacy. PMID- 29477224 TI - Dietary Vitamin C in Human Health. AB - Vitamin C is essential to prevent scurvy in humans and is implicated in the primary prevention of common and complex diseases such as coronary heart disease, stroke, and cancer. This chapter reviews the latest knowledge about dietary vitamin C in human health with an emphasis on studies of the molecular mechanisms of vitamin C maintenance as well as gene-nutrient interactions modifying these relationships. Epidemiological evidence indicates 5% prevalence for vitamin C deficiency and 13% prevalence for suboptimal status even in industrialized countries. The daily intake (dose) and the corresponding systemic concentrations (response) are related in a saturable relationship, and low systemic vitamin C concentrations in observational studies are associated with negative health outcomes. However, there is no evidence that vitamin C supplementation impacts the risks for all-cause mortality, impaired cognitive performance, reduced quality of life, the development of eye diseases, infections, cardiovascular disease, and cancers. This might be related to the fact that prevention would not be realized by supplementation in populations already adequately supplied through dietary sources. Recent genetic association studies indicate that the dietary intake might not be the sole determinant of systemic concentrations, since variations in genes participating in redox homeostasis and vitamin C transport had been associated with lowered plasma concentrations. However, impact sizes are generally low and these phenomena might only affect individual of suboptimal dietary supply. PMID- 29477225 TI - Water-Soluble Vitamin E-Tocopheryl Phosphate. AB - The hydrophobicity of vitamin E poses transport and metabolic challenges to regulate its bioavailability and to prevent its accumulation in lipid-rich tissues such as adipose tissue, brain, and liver. Water-soluble precursors of vitamin E (alpha-tocopherol, alphaT), such as its esters with acetate (alphaTA), succinate (alphaTS), or phosphate (alphaTP), have increased solubility in water and stability against reaction with free radicals, but they are rapidly converted during their uptake into the lipid-soluble vitamin E. Therefore, the bioavailability of these precursors as intact molecules is low; nevertheless, at least for alphaTS and alphaTP, the recent research has revealed unique regulatory effects on signal transduction and gene expression and the modulation of cellular events ranging from proliferation, survival/apoptosis, lipid uptake and metabolism, phagocytosis, long term potentiation, cell migration, telomere maintenance, and angiogenesis. Moreover, water-soluble derivatives of vitamin E including some based on alphaTP are increasingly used as components of nanocarriers for enhanced and targeted delivery of drugs and other molecules (vitamins, including alphaT and alphaTP itself, vitamin D3, carnosine, caffeine, docosahexaenoic acid (DHA), insulin) and cofactors such as coenzyme Q10. In this review, the chemical characteristics, transport, metabolic pathways, and molecular mechanisms of action of alphaTP in cells and tissues are summarized and put into perspective with its possible role in the prevention of a number of diseases. PMID- 29477226 TI - Riboflavin in Human Health: A Review of Current Evidences. AB - Riboflavin is a water-soluble vitamin, which was initially isolated from milk. There are two coenzyme forms of riboflavin, flavin mononucleotide and flavin adenine dinucleotide, in which riboflavin plays important roles in the enzymatic reactions. Riboflavin is found in a wide variety of animal and plant foods. Meat and dairy products are the major contributors of riboflavin dietary intake. In this chapter, the latest evidence on the relationship between riboflavin status and specific health risks will be reviewed. Also, some of the mechanisms by which riboflavin exerts its roles will be discussed. The evidence accrued suggests that riboflavin is an antioxidant nutrient which may prevent lipid peroxidation and reperfusion oxidative injury. Moreover, riboflavin deficiency may increase the risk of some cancers. Riboflavin may also exert a neuroprotective effects in some neurological disorders (e.g., Parkinson disease, migraine, and multiple sclerosis) through its role in some pathways that are hypothesized to be impaired in neurological disorders such as antioxidation, myelin formation, mitochondrial function, and iron metabolism. PMID- 29477227 TI - Niacin. AB - Nicotinic acid and nicotinamide, collectively referred to as niacin, are nutritional precursors of the bioactive molecules nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). NAD and NADP are important cofactors for most cellular redox reactions, and as such are essential to maintain cellular metabolism and respiration. NAD also serves as a cosubstrate for a large number of ADP-ribosylation enzymes with varied functions. Among the NAD-consuming enzymes identified to date are important genetic and epigenetic regulators, e.g., poly(ADP-ribose)polymerases and sirtuins. There is rapidly growing knowledge of the close connection between dietary niacin intake, NAD(P) availability, and the activity of NAD(P)-dependent epigenetic regulator enzymes. It points to an exciting role of dietary niacin intake as a central regulator of physiological processes, e.g., maintenance of genetic stability, and of epigenetic control mechanisms modulating metabolism and aging. Insight into the role of niacin and various NAD-related diseases ranging from cancer, aging, and metabolic diseases to cardiovascular problems has shifted our view of niacin as a vitamin to current views that explore its potential as a therapeutic. PMID- 29477228 TI - Preface. PMID- 29477229 TI - [Virus and cancer: Still hot topic]. PMID- 29477230 TI - Laparoscopic common bile duct exploration versus endoscopic retrograde cholangiopancreatography for choledocholithiasis found at time of laparoscopic cholecystectomy. PMID- 29477231 TI - Emerging leaders in practice: Identifying and developing them. PMID- 29477232 TI - Mindfulness and the work of the academy. PMID- 29477233 TI - [Behaviour of stroke volume variation in hemodynamic stable patients during thoracic surgery with one-lung ventilation periods]. AB - INTRODUCTION: In last few years, emphasis was placed in goal-directed therapy in order to optimize patient's hemodynamic status and improve their prognosis. Parameters based on the interaction between heart and lungs have been questioned in situations like low tidal volume and open chest surgery. The goal of the study was to analyze the changes that one-lung ventilation can produce over stroke volume variation and to assess the possible impact of airway pressures and lung compliance over stroke volume variation. METHODS: Prospective observational study, 112 patients undergoing lung resection surgery with one-lung ventilation periods were included. Intravenous fluid therapy with crystalloids was set at 2mL.kg-1.h-1. Hypotension episodes were treated with vasoconstrictive drugs. Two lung ventilation was implemented with a TV of 8mL.kg-1 and one-lung ventilation was managed with a TV of 6mL.kg-1. Invasive blood pressure was monitored. We recorded the following cardiorespiratory values: heart rate, mean arterial pressure, cardiac index, stroke volume index, airway peak pressure, airway plateau pressure and static lung compliance at 3 different times during surgery: immediately after lung collapse, 30minutes after initiating one-lung ventilation and after restoration of two-lung ventilation. RESULTS: Stroke volume variation values were influenced by lung collapse (before lung collapse14.6 (DS) vs. OLV 9.9% (DS), p < 0.0001); or after restoring two-lung ventilation (11.01 (DS), p < 0.0001). During two-lung ventilation there was a significant correlation between airwaypressures and stroke volume variation, however this correlation lacks during one-lung ventilation. CONCLUSION: The decrease of stroke volume variation values during one-lung ventilation with protective ventilatory strategies advices not to use the same threshold values to determine fluid responsiveness. PMID- 29477234 TI - Tumor Heterogeneity: An Important Determinant for Efficacy and Safety in Nanoparticle Anticancer Gene Therapy. AB - Models of tumor heterogeneity should mimic perfusion in the tumor mass and consider cancer stem cell hierarchy and convertibility. Other important factors include epigenomic alterations, enhanced permeation and retention effects, and the reticuloendothelial system. New stimuli-responsive delivery systems, active targeting-based methods, and corona characterization strategies can deliver genes more precisely. PMID- 29477235 TI - Bioanalysis of underivatized amino acids in non-invasive exhaled breath condensate samples using liquid chromatography coupled with tandem mass spectrometry. AB - Exhaled breath condensate (EBC) is receiving increased attention as a novel, entirely non-invasive technique for collecting biomarker samples. This increased attention is due to the fact that EBC is simple, effort independent, rapid, can be repeated frequently, and can be performed on young children and patients suffering from a variety of diseases. By having a subject breathe tidally through a cooling system for 15-20 min, a sufficient amount of condensate is collected for analysis of biomarkers in clinical studies. However, bioanalysis of EBC involves an unavoidable sample preparation step due to the low concentration of its components. Thus, there is a need for a new and more sensitive analytical method of assessing EBC samples. While researchers have considered analyses of single and small quantities of amino acids - for example, those connected with leukemia - no one has previously attempted to simultaneously analyze a panel of 23 amino acids. Moreover, the present study is well-justified, as prior studies focusing on single amino acids and leukemia at the moment of diagnosis and during chemotherapy (33 days of treatment) are inconsistent. In the present study, amino acids were separated using an XBridge Amide column (3 mm * 100 mm, 3.5 MUm). The mobile phase consisted of 10 mM of ammonium buffer in water with a pH of 3 (Phase A) and 10 mM ammonium buffer in acetonitrile (Phase B) under gradient program elution. The analytes were detected in electrospray positive ionization mode. Under optimal conditions, the proposed method exhibited limits of quantification (LOQ) in the range of 0.05-0.5 ng/mL, and good linearity, with the determination coefficient (R2) falling between 0.9904 and 0.9998. The accuracy in human exhaled breath condensate samples ranged between 93.3-113.3% for the 23 studied amino acids, with intra- and inter-day coefficient of variation (CVs) of 0.13-9.92% and 0.17-10.53%, respectively. To demonstrate the liquid chromatography with hydrophilic interaction with electrospray source coupled to tandem mass spectrometry (LC-HILIC-ESI-MS/MS) method's applicability for biomedical investigations, it was verified and applied to determine amino acids in pediatric patients with leukemia. These tests confirmed that glutamine, arginine, homoarginine, asparagine, histidine, methionine, proline, hydroxyproline, threonine, tyrosine, and valine were present in significantly higher levels in pediatric leukemia patients than in the healthy control group. The developed assay is an attractive alternative to standard analytical methods, because it allows for the non-invasive, fast, sensitive, and reliable analysis of amino acids without derivatization in EBC. PMID- 29477236 TI - Initialization of active contours for segmentation of breast cancer via fusion of ultrasound, Doppler, and elasticity images. AB - Active contours (snakes) are an efficient method for segmentation of ultrasound (US) images of breast cancer. However, the method produces inaccurate results if the seeds are initialized improperly (far from the true boundaries and close to the false boundaries). Therefore, we propose a novel initialization method based on the fusion of a conventional US image with elasticity and Doppler images. The proposed fusion method (FM) has been tested against four state-of-the-art initialization methods on 90 ultrasound images from a database collected by the Thammasat University Hospital of Thailand. The ground truth was hand-drawn by three leading radiologists of the hospital. The reference methods are: center of divergence (CoD), force field segmentation (FFS), Poisson Inverse Gradient Vector Flow (PIG), and quasi-automated initialization (QAI). A variety of numerical tests proves the advantages of the FM. For the raw US images, the percentage of correctly initialized contours is: FM-94.2%, CoD-0%, FFS-0%, PIG-26.7%, QAI 42.2%. The percentage of correctly segmented tumors is FM-84.4%, CoD-0%, FFS-0%, PIG-16.67%, QAI-22.44%. For reduced field of view US images, the percentage of correctly initialized contours is: FM-94.2%, CoD-0%, FFS-0%, PIG-65.6%, QAI 67.8%. The correctly segmented tumors are FM-88.9%, CoD-0%, FFS-0%, PIG-48.9%, QAI-44.5%. The accuracy, in terms of the average Hausdorff distance, is respectively 2.29 pixels, 33.81, 34.71, 7.7, and 8.4, whereas in terms of the Jaccard index, it is 0.9, 0.18, 0.19, 0.63, and 0.48. PMID- 29477237 TI - Potential benefits and harms of offering ultrasound surveillance to men aged 65 years and older with a subaneurysmal (2.5-2.9 cm) infrarenal aorta. AB - OBJECTIVE: The objective of this review was to perform a rapid evidence summary to determine the prevalence of subaneurysmal aortic aneurysms, growth rates, and risk factors that modulate growth in average-risk men aged 65 years and older. Secondary objectives were to evaluate benefits and harms of lifelong ultrasound (US) surveillance and treatment outcomes for any large aneurysms that develop in the screened population. METHODS: We searched multiple databases (eg, Ovid MEDLINE, Embase Classic and Embase, and the Cochrane Library) on February 16, 2016. Using a liberal accelerated method, two reviewers screened titles and abstracts for relevance and subsequently screened full-text studies. General study characteristics (eg, country, study design, number of participants) and data (eg, number of men with subaneurysmal aortas, quality of life [QoL], mortality) were extracted. One reviewer performed data extraction and risk of bias assessments, and a second reviewer verified 100% of studies. Any disagreements were resolved by consensus. RESULTS: The search identified 37 relevant studies ranging in size from 3 to 52,690 participants. Prevalence of subaneurysmal aortas ranged from 1.14% to 8.53%, and 55% to 88% of these men progressed to a 3.0-cm aneurysm by 5 years of follow-up. Risk factors for growth included the infrarenal aortic diameter at age 65 years, having a subaneurysmal aorta at age 65 years, and current smoking. The 36-Item Short Form Health Survey was the most commonly used tool to measure QoL, and QoL was typically lower in people with abdominal aortic aneurysm. Anxiety and depression levels did not differ significantly between comparison groups in any studies. Four studies reported on the number of men whose aorta was subaneurysmal on initial US who went on to surgery. Overall, 10% (57/547) of men initially measuring in the subaneurysmal range progressed to abdominal aortic aneurysm >5.4 cm and received elective surgery; 1% (6/547) received emergency surgery because of a ruptured aorta. Among those who did, mortality rates were much lower for elective (9.5%) vs emergency surgery (50%). Risk of bias was usually low for studies measuring prevalence and moderate and high for studies measuring psychological harms of screening and harms and benefits of surgery. Overall, using the Grading of Recommendations Assessment, Development, and Evaluation framework as guidance, the quality of the evidence was generally very low. CONCLUSIONS: Because of the limited evidence and the low quality of the existing evidence, it is not possible to determine confidently whether men with abdominal aortas measuring 2.5 to 2.9 cm should be observed in a lifelong US surveillance program. PMID- 29477238 TI - Vascular access of last resort. AB - Exhausted vasculature is not uncommon in patients receiving long-term hemodialysis treatment. Certain patients exhaust their peripheral veins and do not retain the venous capital necessary for fistula creation. Others suffer from severe peripheral arterial disease and despite the presence of adequate venous capital are not able to receive an arteriovenous access successfully. Most importantly, in the case of occluded central veins, the creation of an arteriovenous access in the arms or thighs would be futile, even if peripheral veins and/or arteries were available. Because renal transplant is not readily available, such patients virtually face death in the absence of dialysis therapy. Hence, it is critically important that vascular access options be available to successfully receive renal replacement therapy. This article describes accesses of last resort and provides information vital to nephrologists for discussion with their patients and to surgeons in choosing an optimal option. PMID- 29477239 TI - Advanced glycation end products in the pathogenesis of chronic kidney disease. AB - Advanced glycation end products (AGEs) are stable posttranslational modifications of proteins formed by the spontaneous reaction with glucose and related metabolites. Important AGEs quantitatively are methylglyoxal (MG)-derived hydroimidazolone MG-H1, Nepsilon-carboxymethyl-lysine (CML), and glucosepane. They contribute to the development of chronic kidney disease (CKD). Cellular proteolysis of AGE-modified proteins forms AGE free adducts, glycated amino acids, which are cleared by the kidneys and excreted in urine. Dietary AGEs mainly supplement the endogenous flux of AGE free adduct formation. AGE free adducts accumulate markedly in plasma with decline in glomerular filtration rate. A key precursor of AGEs is the dicarbonyl metabolite MG, which is metabolized by glyoxalase 1 (Glo1) of the cytoplasmic glyoxalase system. Proteins susceptible to MG modification are collectively called the dicarbonyl proteome. Abnormal increase of MG dicarbonyl stress is a characteristic of CKD, driven by down regulation of renal Glo1, increasing flux of MG-H1 formation. Protein inactivation and dysfunction linked to the dicarbonyl proteome contributes to CKD development. The receptor for AGEs, RAGE, is important in development of CKD, but its interaction with AGEs in vivo remains enigmatic; other ligands and ternary complexation may be influential. Prevention of diabetic kidney disease (DKD) by overexpression of Glo1 in transgenic animal models has stimulated the development of small-molecule inducers of Glo1 expression, Glo1 inducers, to prevent AGE formation. trans-Resveratrol-hesperetin combination therapy is a Glo1 inducer. In clinical trial it demonstrated a profound improvement in insulin resistance and vascular inflammation. It may find future therapeutic application for treatment of DKD. PMID- 29477241 TI - Point-of-care ultrasound in the practice of nephrology. AB - Sonography is increasingly being performed by clinicians and has applications throughout the spectrum of nephrology, including acute and chronic renal failure, urinary obstruction, cystic disease, pain, hematuria, transplantation, kidney biopsy, temporary and permanent vascular access, and assessment of fluid status. The skill is relatively easily acquired, expedites patient care, and enhances the practice of nephrology. However, the lack of exposure in most training programs remains a major obstacle. PMID- 29477240 TI - Increased podocyte Sirtuin-1 function attenuates diabetic kidney injury. AB - Podocyte injury and loss contribute to the progression of glomerular diseases, including diabetic kidney disease. We previously found that the glomerular expression of Sirtuin-1 (SIRT1) is reduced in human diabetic glomeruli and that the podocyte-specific loss of SIRT1 aggravated albuminuria and worsened kidney disease progression in diabetic mice. SIRT1 encodes an NAD-dependent deacetylase that modifies the activity of key transcriptional regulators affected in diabetic kidneys, including NF-kappaB, STAT3, p53, FOXO4, and PGC1-alpha. However, whether the increased glomerular SIRT1 activity is sufficient to ameliorate the pathogenesis of diabetic kidney disease has not been explored. We addressed this by inducible podocyte-specific SIRT1 overexpression in diabetic OVE26 mice. The induction of SIRT1 overexpression in podocytes for six weeks in OVE26 mice with established albuminuria attenuated the progression of diabetic glomerulopathy. To further validate the therapeutic potential of increased SIRT1 activity against diabetic kidney disease, we developed a new, potent and selective SIRT1 agonist, BF175. In cultured podocytes BF175 increased SIRT1-mediated activation of PGC1 alpha and protected against high glucose-mediated mitochondrial injury. In vivo, administration of BF175 for six weeks in OVE26 mice resulted in a marked reduction in albuminuria and in glomerular injury in a manner similar to podocyte specific SIRT1 overexpression. Both podocyte-specific SIRT1 overexpression and BT175 treatment attenuated diabetes-induced podocyte loss and reduced oxidative stress in glomeruli of OVE26 mice. Thus, increased SIRT1 activity protects against diabetes-induced podocyte injury and effectively mitigates the progression of diabetic kidney disease. PMID- 29477242 TI - Investigating microplastic trophic transfer in marine top predators. AB - Microplastics are highly bioavailable to marine organisms, either through direct ingestion, or indirectly by trophic transfer from contaminated prey. The latter has been observed for low-trophic level organisms in laboratory conditions, yet empirical evidence in high trophic-level taxa is lacking. In natura studies face difficulties when dealing with contamination and differentiating between directly and indirectly ingested microplastics. The ethical constraints of subjecting large organisms, such as marine mammals, to laboratory investigations hinder the resolution of these limitations. Here, these issues were resolved by analysing sub-samples of scat from captive grey seals (Halichoerus grypus) and whole digestive tracts of the wild-caught Atlantic mackerel (Scomber scombrus) they are fed upon. An enzymatic digestion protocol was employed to remove excess organic material and facilitate visual detection of synthetic particles without damaging them. Polymer type was confirmed using Fourier-Transform Infrared (FTIR) spectroscopy. Extensive contamination control measures were implemented throughout. Approximately half of scat subsamples (48%; n = 15) and a third of fish (32%; n = 10) contained 1-4 microplastics. Particles were mainly black, clear, red and blue in colour. Mean lengths were 1.5 mm and 2 mm in scats and fish respectively. Ethylene propylene was the most frequently detected polymer type in both. Our findings suggest trophic transfer represents an indirect, yet potentially major, pathway of microplastic ingestion for any species whose feeding ecology involves the consumption of whole prey, including humans. PMID- 29477243 TI - Increased auditory cortex neural response amplitude in adults with chronic unilateral conductive hearing impairment. AB - Animal studies have demonstrated that unilateral hearing loss can induce changes in neural response amplitude of the mature central auditory system (CAS). However, there is limited physiological evidence of these neural gain changes in the auditory cortex of human adults. The present study investigated the impact of chronic, unilateral conductive hearing impairment on cortical auditory evoked potentials (CAEPs) recorded from 15 adults (21-65 years old) in response to a 1 kHz tone (80 ms duration) presented to the impaired ear via a bone conduction transducer. The amplitude and latency of the main CAEP components were compared to those obtained from normal hearing age-matched control participants. Both P1 N1 and N1-P2 amplitudes were significantly larger in the hearing impaired relative to the control participants. Differences between groups in the mean latencies of P1, N1, and P2 were not statistically significant. These results are the first to provide direct evidence of increased neural response amplitude in the adult human auditory cortex in the presence of unilateral conductive hearing loss. Importantly, the study shows that central gain changes are a direct result of deprivation of sound rather than cochlear or neural pathology. PMID- 29477244 TI - Iberian consensus on cow's milk allergy: The CIBAL Study. AB - BACKGROUND: The present study explores the professional opinion of a wide range of experts from the Iberian Peninsula (Spain and Portugal) and their degree of consensus about CMPA's prevention, diagnosis, treatment and progression. MATERIAL AND METHODS: A 57-item survey divided in four blocks: Prevention (14 items), Diagnosis (10 items), Treatment (19 items) and Progression (14 items) was completed by 160 panellists, experts in CPMA management (116 Spain, 44 Portugal). Each one answered the questionnaire, formulated in Portuguese and Spanish, by individually accessing an online platform in two consecutive rounds. Five possible answers were possible: "completely agree", "agree", "neither agree nor disagree", "disagree" and "completely disagree". A modified Delphi method was used. RESULTS: Consensus (more than 66% agree) was reached in 39 items (68.4%) and Discrepancy (less than 50% agree) in nine items (15.7%). Block separated analysis offers valuable differences regarding consensus. The Prevention block only reached 50%; the Diagnosis block 90%; the Treatment block 73.68%, showing a high degree of agreement on dietary treatment (15/16 items), and discrepancy or less agreement on immunotherapy treatments. The Progression block reached 71.4% consensus with discrepancy with regard to the time to perform oral food challenge and negatives prognosis consequences of accidental milk ingestion. CONCLUSIONS: This study displays the current opinions of a wide group of experts on CMPA from the Iberian Peninsula and evidence discussion lines in CMPA management. The questions on which there were situations of discrepancy, provide us with very useful information for promoting new, rigorous research enabling us to draw conclusions on these controversial aspects. PMID- 29477245 TI - Psychotic experiences among police officers working in high-stress situations. PMID- 29477246 TI - Neuromelanin magnetic resonance imaging of the substantia nigra in first episode psychosis patients consumers of illicit substances. PMID- 29477247 TI - Metabolic screening for patients with second-generation antipsychotic medication: A population-based study from 2004 to 2016. PMID- 29477248 TI - Association of insurance status and spinal fusion usage in the United States during two decades. AB - OBJECTIVE: This study examined the distribution of spinal fusion usage among payer groups in the United States. METHODS: Using the National Inpatient Sample (NIS) database, total discharges, length of stay, and mean hospital charges of patients who underwent spinal fusion from 1997 to 2014 in the United States were determined and analyzed. RESULTS: 5,715,625 total discharges with spinal fusion were reported. Among them, 2,875,188 (50.3%) were covered by private insurance, 1,710,182 by Medicare (29.9%), 342,638 (6.0%) by Medicaid, and 91,990 (1.6%) were uninsured. A statistically significant increase in spinal fusion usage occurred within each payer group over the study period (P < 0.001). For every year of the study period, private insurance patients had the most number and uninsured patients had the least number of total discharges with spinal fusion. Furthermore, annual growth in spinal fusion usage was greatest among private insurance patients, and smallest among uninsured patients. CONCLUSIONS: Total discharges with spinal fusion increased significantly across all payer groups between 1997 and 2014, but not equally. Further inquiry is indicated to determine the etiology of spinal fusion usage discrepancies between payer groups. PMID- 29477249 TI - More data, more answers: picking the optimal antidepressant. PMID- 29477250 TI - Chronic lymphocytic leukaemia. AB - Important advances in understanding the pathogenesis of chronic lymphocytic leukaemia in the past two decades have led to the development of new prognostic tools and novel targeted therapies that have improved clinical outcome. Chronic lymphocytic leukaemia is the most common type of leukaemia in developed countries, and the median age at diagnosis is 72 years. The criteria for initiating treatment rely on the Rai and Binet staging systems and on the presence of disease-related symptoms. For many patients with chronic lymphocytic leukaemia, treatment with chemotherapy and anti-CD20 monoclonal antibodies is the standard of care. The impressive efficacy of kinase inhibitors ibrutinib and idelalisib and the BCL-2 antagonist venetoclax have changed the standard of care in specific subsets of patients. In this Seminar, we review the recent progress in the management of chronic lymphocytic leukaemia and highlight new questions surrounding the optimal disease management. PMID- 29477252 TI - Prevalence and clinical characteristics of fatty pancreas in Yangzhou, China: A cross-sectional study. AB - OBJECTIVE: The aim of this study was to investigate the prevalence and risk factors of fatty pancreas in Yangzhou, China. METHODS: This was a cross-sectional study. Initially, 2093 subjects were included in the study. After the exclusion of 865 subjects based on incomplete information, a total of 1228 subjects were selected for further analysis. The subjects were stratified into two groups (the fatty pancreas group and the non-fatty pancreas group) based on the results. Anthropometric and biochemical findings were compared between the groups. RESULTS: Among the 2093 study subjects, 56 (2.7%) had fatty pancreas. Overall, 53 out of 1228 subjects were diagnosed with fatty pancreas and included into the fatty pancreas group. Univariate analysis showed significant differences in age and the prevalence of general obesity, central obesity, alcohol consumption, metabolic syndrome and fatty liver between the two groups (all p < 0.01). The fatty pancreas group had higher levels of aspartate aminotransferase, alanine aminotransferase, serum uric acid, fasting blood glucose, total cholesterol, triglycerides and low-density lipoprotein, and lower levels of high-density lipoprotein than did the non-fatty pancreas group (all p < 0.05). Multivariate logistic regression analysis showed that age (p = 0.007), central obesity (p = 0.002) and fatty liver (p = 0.006) were independent risk factors for fatty pancreas, with odds ratios (ORs) of 1.034 (95% confidence interval (CI): 1.009 1.059), 5.364 (95% CI: 1.890-15.227), and 2.666 (95% CI: 1.332-5.338), respectively. CONCLUSION: The prevalence of fatty pancreas in the examined population is approximately 2.7%. Increased age, central obesity and fatty liver disease are independent risk factors for fatty pancreas. PMID- 29477251 TI - Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. AB - BACKGROUND: Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide in adults. Pharmacological and non pharmacological treatments are available; however, because of inadequate resources, antidepressants are used more frequently than psychological interventions. Prescription of these agents should be informed by the best available evidence. Therefore, we aimed to update and expand our previous work to compare and rank antidepressants for the acute treatment of adults with unipolar major depressive disorder. METHODS: We did a systematic review and network meta analysis. We searched Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, PsycINFO, the websites of regulatory agencies, and international registers for published and unpublished, double-blind, randomised controlled trials from their inception to Jan 8, 2016. We included placebo-controlled and head-to-head trials of 21 antidepressants used for the acute treatment of adults (>=18 years old and of both sexes) with major depressive disorder diagnosed according to standard operationalised criteria. We excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment resistant depression; or patients with a serious concomitant medical illness. We extracted data following a predefined hierarchy. In network meta-analysis, we used group-level data. We assessed the studies' risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions, and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Primary outcomes were efficacy (response rate) and acceptability (treatment discontinuations due to any cause). We estimated summary odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with PROSPERO, number CRD42012002291. FINDINGS: We identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2.13 (95% credible interval [CrI] 1.89-2.41) for amitriptyline and 1.37 (1.16-1.63) for reboxetine. For acceptability, only agomelatine (OR 0.84, 95% CrI 0.72-0.97) and fluoxetine (0.88, 0.80-0.96) were associated with fewer dropouts than placebo, whereas clomipramine was worse than placebo (1.30, 1.01-1.68). When all trials were considered, differences in ORs between antidepressants ranged from 1.15 to 1.55 for efficacy and from 0.64 to 0.83 for acceptability, with wide CrIs on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1.19-1.96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0.51-0.84). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0.43 0.77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates (1.30-2.32). 46 (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low; and the certainty of evidence was moderate to very low. INTERPRETATION: All antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants. FUNDING: National Institute for Health Research Oxford Health Biomedical Research Centre and the Japan Society for the Promotion of Science. PMID- 29477253 TI - Central RANK signalling in NPY neurons alters bone mass in male mice. AB - RANKL signalling known to be important for the control of bone mass, has recently also been implicated in the brain to control thermoregulation, however, it is not known which neuronal pathways are involved and whether other aspects of energy homeostasis are also affected. Here we show that selective deletion of RANK from NPY neurons down-regulated NPY mRNA expression in the hypothalamus. While comprehensive phenotyping of germline-induced NPY neuron specific RANK deficient mice revealed no significant changes in physical or metabolic parameters, adult onset deletion of RANK from NPY neurons led to a significant increase in fat mass and a decrease in whole body bone mineral content and bone mineral density. Intriguingly, when these conditional knockout mice were placed on a high fat diet, body weight and fat mass did not differ to control mice. However, they were able to significantly increase their bone mass to match their increased body weight, an ability that was lacking in control mice. Taken together, results from this study demonstrate that RANK signalling in NPY neurons is involved in modulating NPY levels and through that matching bone mass to body weight. PMID- 29477254 TI - Clinical outcomes and rates of aortic growth and reoperation after 1-stage repair of extensive chronic thoracic aortic dissection. AB - OBJECTIVE: The study objective was to analyze clinical outcomes, distal segmental aortic growth, and aortic reoperation rates after 1-stage open repair of extensive chronic thoracic aortic dissection via bilateral anterior thoracotomy. METHODS: Eighty patients underwent extensive 1-stage repair of chronic aortic dissection that included the ascending aorta, the entire aortic arch, and the varying lengths of the descending thoracic aorta. One half or more of the descending thoracic aorta was replaced in 62 (78%) of the 80 patients. Hospital mortality was 2.5% (2 patients). Stroke occurred in 1 patient (1.2%), spinal cord ischemic injury occurred in 1 patient (1.2%), and renal failure requiring long term dialysis occurred in 2 patients (2.5%). Sixty-five of the 78 hospital survivors (83%) had serial imaging studies suitable for calculation of growth rates of the remaining dissected thoracic and abdominal aorta. Forty-seven patients were followed for more than 5 years, and 21 patients were followed for more than 10 years. RESULTS: The mean annual growth rate for the distal contiguous aorta was 1.7 mm/y. Forty aortas increased in diameter, 16 aortas remained unchanged, and 9 aortas decreased in diameter. Five patients required reoperation on the contiguous thoracic or abdominal aorta 8, 27, 34, 51, and 174 months postoperatively for progressive enlargement. Actuarial freedom from reoperation on the contiguous aorta at 5 and 10 years was 95.4% and 93%, respectively. Actuarial freedom from any aortic reoperation at 5 and 10 years was 89.2% and 84.4%, respectively. Actuarial survival for the entire cohort at 5 and 10 years was 76.4% and 52.6%, respectively, and survival free of any aortic operation was 68.6% and 43.9%, respectively. No patient whose cause of death was known died of aortic rupture. CONCLUSIONS: Our extended experience with the 1 stage open procedure confirms its safety and durability for treatment of chronic aortic dissection with enlargement confined to the thoracic aorta. The procedure is associated with low operative risk and a low incidence of reoperation on the contiguous aorta. It represents a suitable alternative to the 2-stage, frozen elephant trunk, and hybrid procedures that are also used to treat this condition. PMID- 29477255 TI - Discussion. PMID- 29477256 TI - Frequency of abnormal findings on routine chest radiography before cardiac surgery. AB - OBJECTIVE: Preoperative chest radiograph screening is widely used before cardiac surgery. The objective of this study was to investigate the frequency of abnormal findings on a routine chest radiograph before cardiac surgery. METHODS: In this retrospective cohort study, 1136 patients were included. Patients were scheduled for cardiac surgery and underwent a preoperative chest radiograph. The primary outcome was the frequency of abnormalities on the chest radiograph. Secondary outcome was the effect of those abnormalities on surgery. RESULTS: One half of the patients (570/1136; 50%) had 1 or more abnormalities on the chest radiograph. Most frequent abnormalities were cardiomegaly, aortic elongation, signs of chronic obstructive pulmonary disease, vertebral fractures or height loss, possible pulmonary or mediastinal mass, pleural effusion, and atelectasis. In 2 patients (2/1136; 0.2%), the chest radiograph led to postponement of surgery, whereas in none of the patients the surgery was cancelled. In 1 patient (1/1136; 0.1%) the surgical approach was altered and in 15 patients (15/1136; 1.3%) further analysis was performed without having an impact on the planned surgical approach. CONCLUSIONS: Although abnormalities are frequently found on preoperative chest radiographs before cardiac surgery, change in clinical management with regard to planned surgery or surgical approach occurs infrequently. PMID- 29477257 TI - Therapeutic R2 resection for pleural mesothelioma. PMID- 29477258 TI - Developmental dosing with a MEK inhibitor (PD0325901) rescues myopathic features of the muscle-specific but not limb-specific Nf1 knockout mouse. AB - Neurofibromatosis Type 1 (NF1) is a common autosomal dominant genetic disorder While NF1 is primarily associated with predisposition for tumor formation, muscle weakness has emerged as having a significant impact on quality of life. NF1 inactivation is linked with a canonical upregulation Ras-MEK-ERK signaling. This in this study we tested the capacity of the small molecule MEK inhibitor PD0325901 to influence the intramyocellular lipid accumulation associated with NF1 deficiency. Established murine models of tissue specific Nf1 deletion in skeletal muscle (Nf1MyoD-/-) and limb mesenchyme (Nf1Prx1-/-) were tested. Developmental PD0325901 dosing of dams pregnant with Nf1MyoD-/- progeny rescued the phenotype of day 3 pups including body weight and lipid accumulation by Oil Red O staining. In contrast, PD0325901 treatment of 4 week old Nf1Prx1-/- mice for 8 weeks had no impact on body weight, muscle wet weight, activity, or intramyocellular lipid. Examination of day 3 Nf1Prx1-/- pups showed differences between the two tissue-specific knockout strains, with lipid staining greatest in Nf1MyoD-/- mice, and fibrosis higher in Nf1Prx1-/- mice. These data show that a MEK/ERK dependent mechanism underlies NF1 muscle metabolism during development. However, crosstalk from Nf1-deficient non-muscle mesenchymal cells may impact upon muscle metabolism and fibrosis in neonatal and mature myofibers. PMID- 29477259 TI - A visco-hyperelastic constitutive model and its application in bovine tongue tissue. AB - Material properties of the human tongue tissue have a significant role in understanding its function in speech, respiration, suckling, and swallowing. Tongue as a combination of various muscles is surrounded by the mucous membrane and is a complicated architecture to study. As a first step before the quantitative mechanical characterization of human tongue tissues, the passive biomechanical properties in the superior longitudinal muscle (SLM) and the mucous tissues of a bovine tongue have been measured. Since the rate of loading has a sizeable contribution to the resultant stress of soft tissues, the rate dependent behavior of tongue tissues has been investigated via uniaxial tension tests (UTTs). A method to determine the mechanical properties of transversely isotropic tissues using UTTs and inverse finite element (FE) method has been proposed. Assuming the strain energy as a general nonlinear relationship with respect to the stretch and the rate of stretch, two visco-hyperelastic constitutive laws (CLs) have been proposed for isotropic and transversely isotropic soft tissues to model their stress-stretch behavior. Both of them have been implemented in ABAQUS explicit through coding a user-defined material subroutine called VUMAT and the experimental stress-stretch points have been well tracked by the results of FE analyses. It has been demonstrated that the proposed laws make a good description of the viscous nature of tongue tissues. Reliability of the proposed models has been compared with similar nonlinear visco-hyperelastic CLs. PMID- 29477260 TI - Control of cellular adhesion and myofibroblastic character with sub-micrometer magnetoelastic vibrations. AB - The effect of sub-cellular mechanical loads on the behavior of fibroblasts was investigated using magnetoelastic (ME) materials, a type of material that produces mechanical vibrations when exposed to an external magnetic AC field. The integration of this functionality into implant surfaces could mitigate excessive fibrotic responses to many biomedical devices. By changing the profiles of the AC magnetic field, the amplitude, duration, and period of the applied vibrations was altered to understand the effect of each parameter on cell behavior. Results indicate fibroblast adhesion depends on the magnitude and total number of applied vibrations, and reductions in proliferative activity, cell spreading, and the expression of myofibroblastic markers occur in response to the vibrations induced by the ME materials. These findings suggest that the subcellular amplitude mechanical loads produced by ME materials could potentially remotely modulate myofibroblastic activity and limit undesirable fibrotic development. PMID- 29477261 TI - Radiography used to measure internal spinal cord deformation in an in vivo rat model. AB - Little is known about the internal mechanics of the in vivo spinal cord during injury. The objective of this study was to develop a method of tracking internal and surface deformation of in vivo rat spinal cord during compression using radiography. Since neural tissue is radio-translucent, radio-opaque markers were injected into the spinal cord. Two tantalum beads (260 um) were injected into the cord (dorsal and ventral) at C5 of nine anesthetized rats. Four beads were glued to the lateral surface of the cord, caudal and cranial to the injection site. A compression plate was displaced 0.5 mm, 2 mm, and 3 mm into the spinal cord and lateral X-ray images were taken before, during, and after each compression for measuring bead displacements. Potential bead migration was monitored for by comparing displacements of the internal and glued surface beads. Dorsal beads moved significantly more than ventral beads with a range in averages of 0.57-0.71 mm and 0.31-0.35 mm respectively. Bead displacements during 0.5 mm compressions were significantly lower than 2 mm and 3 mm compressions. There was no statistically significant migration of the internal beads. The results indicate the merit of this technique for measuring in vivo spinal cord deformation. The pattern of bead displacements illustrates the complex internal and surface deformations of the spinal cord during transverse compression. This information is needed for validating physical and finite element spinal cord surrogates and to define relationships between loading parameters, internal cord deformation, and biological and functional outcomes. PMID- 29477262 TI - Predictive value of Type D personality for impaired endothelial function in patients with coronary artery disease. AB - BACKGROUND: Type D personality (high negative affectivity and social inhibition) is associated with cardiovascular events and coronary plaque severity. Whether Type D is also related to functional vasomotion abnormalities is unknown. We examined concurrent and predictive associations of Type D with endothelial dysfunction in patients with coronary artery disease (CAD). METHODS: At baseline, 180 CAD patients (90% men; M = 58.0 years) completed Type D (DS14) and depression scales, and entered a 12-week exercise program. Flow-mediated dilation (FMD) of the brachial artery and circulating CD34+/KDR+/CD45+dim endothelial progenitor cells (EPCs) were assessed at baseline, 3 months, and 12 months. Logistic regression and linear mixed models were used to analyze endothelial function. RESULTS: Type D personality was associated with decreased FMD across baseline, 3 months, and 12 months (mixed model analysis, p = 0.04), after adjustment for clinical characteristics, exercise training and depression. There was no significant association between Type D and decreased EPCs (p = 0.07). Age and smoking were other significant correlates of FMD and EPCs. Using a FMD <5.5% cut off, Type D patients more often had endothelial dysfunction at baseline (24/37 = 65%) than non-Type Ds (63/143 = 44%); OR = 3.03, 95% CI 1.04-8.80. This significant Type D effect was confirmed in prospective analyses of endothelial dysfunction at 12 months (OR = 3.43, 95% CI 1.01-11.64), and in subgroup analyses of male patients. CONCLUSIONS: Type D personality was associated with impaired endothelial function in men with CAD. This association was robust across time, independent from depressive symptoms, and supports the notion that Type D has an adverse effect on cardiovascular health in patients with CAD. PMID- 29477263 TI - High-sensitivity cardiac troponin T is superior to troponin I in the prediction of mortality in patients without acute coronary syndrome. AB - BACKGROUND: Differences in prevalence and prognostic information of cardiac troponin T (cTnT) and I (cTnI) concentrations in patients without acute coronary syndrome (ACS) are insufficiently investigated. High-sensitivity assays (hs-cTn) have led to an increased interest in hs-cTn for risk stratification. Here, we compare hs-cTnT and hs-cTnI in prediction of mortality patients without ACS. METHOD AND RESULTS: Patients aged >18 years, consecutively admitted to an emergency department (ED) were included. Blood was collected at admission and later analyzed with high-sensitivity assays for cTnT (Roche) and cTnI (Siemens). Troponin concentrations were reported as normal or increased according to the clinical cut-off value of 99th percentile as defined by the manufacturer. The primary outcome was all-cause mortality. Of the 822 participants (median, 65 years [48-77]; 428 female [52%]), 239 patients died. Median follow-up time was 3.0 years [2.1-3.0]. Elevation of hs-cTn was observed in 40% (n = 345) for hs cTnT and 8% (n = 64) for hs-cTnI, p < 0.001. The relationship between elevated hs cTn and mortality was strong for both hs-cTnT and hs-cTnI [HR 6.0 (95%CI: 2.9 12.6) vs. 5.1 (95%CI: 1.9-13.6)].There was no difference in prognostic accuracy for short-term mortality (30 days) between hs-cTnT and hs-cTnI. However, the prognostic accuracy for long-term mortality (1080 days) was superior for hs-cTnT than for hs-cTnI [area under the receivers operating curve (AUC) 0.81 vs 0.74, p < 0.001]. CONCLUSION: Both hs-cTnI and hs-cTnT were predictive for all-cause mortality. Notably, hs-cTnT measurement showed superior prognostic performance in predicting long-term all-cause mortality compared with hs-cTnI. PMID- 29477264 TI - Patient Knowledge Regarding Colorectal Cancer Risk, Opinion of Screening, and Preferences for a Screening Test. AB - AIMS: To assess patient knowledge about colorectal cancer incidence and prognosis as well as willingness to undergo screening with various tests (eg, optical colonoscopy, stool-based tests, computed tomographic colonography (CTC)). MATERIALS AND METHODS: A survey was administered to consecutive patients of a general academic-based internal medicine clinic. RESULTS: Survey response rate was 86.3%. A majority of respondents (55%) reported being aware of general information about colorectal cancer, and 99% indicated a belief that colorectal cancer screening was a good idea. A majority of respondents (73%) were willing to undergo optical colonoscopy, and some were willing to undergo stool-based tests (48%), or CT colonography CTC (40%). A majority reported being more willing to undergo a colorectal cancer screening test if the test did not involve radiation (86%), did not involve insertion of a tube or device into the rectum (78%), did not involve a pre-proceduralpreprocedural bowel cleansing regimen (73%), or did not involve sedation (60%). CONCLUSION: Improved patient education about the negligible radiation risk associated with CTC or development of a non-invasive imaging test that did not involve a preprocedural bowel cleansing regimen may increase rates of colorectal cancer screening. PMID- 29477265 TI - Convolutional Neural Networks: The Possibilities are Almost Endless. PMID- 29477266 TI - Is flucloxacillin monotherapy sufficient for the treatment of skin and soft tissue infections in plastic surgery? PMID- 29477267 TI - Should platelet-rich plasma be activated in fat grafts? An animal study. AB - BACKGROUND: The adjunction of platelet-rich plasma with graft fat has been the subject of a few clinical trials which have demonstrated its value in adipocyte survival. The aim of this study was to assess the different efficacies between activated and non-activated PRP on adipose cells in vitro and for adipose tissue graft survival in vivo. METHODS: The in vitro study assessed the effects of PRP on both the proliferation and adipocyte differentiation of adipose cells. For the in vivo study, 8 nude rats received 3 human fat injections as follows: 0.8 mL of fat + 0.2 mL of normal saline; 0.8 mL of fat + 0.2 mL of non-activated PRP; and 0.8 mL of fat + 0.2 mL of PRP activated with calcium chloride (CaCl2). The quantitative assessment of adipocyte survival was implemented after 3 months using histomorphometric analysis. Histological and immunohistochemical analysis were also performed to evaluate angiogenesis, inflammation and quality of adipocytes in the grafted tissue. RESULTS: We showed that activated PRP stimulated, in vitro, proliferation and differentiation of adipose cells. In vivo experiments indicated that CaCl2-activated PRP was more efficient than non activated to prolong the survival of fat grafts in nude rats. The mean percentage areas occupied by viable adipocytes in the PRP-free group, non-activated PRP group and activated PRP group were 13%, 14% and 24% (p = 0.05%), respectively. Histological and immunohistochemical analysis revealed protective effect of activated PRP on inflammation and adipocyte death. CONCLUSION: This study showed that activation by CaCl2 improves the beneficial effects of PRP for fat graft maintenance. PMID- 29477268 TI - Diagnostic utilities of tracheal ultrasound and USB-endoscope for the confirmation of endotracheal tube placement: A cadaver study. AB - OBJECTIVES: Confirmation of the endotracheal tube placement (CoETP) has the utmost importance in the management of an airway. Visualization of tracheal rings or carina with a fiber-optical bronchoscope (FOB) has considered to be a reliable method for the CoETP. However, FOB is expensive, time-consuming, and not always practical. Inexpensive endoscopic USB-cameras were shown to aid intubation successfully and reliably. On the other hand, there have been no studies investigating their use for the CoETP. Tracheal ultrasonography (TUS) is also a new, inexpensive and widely available alternative. A cadaver study has planned to evaluate the diagnostic utility of TUS and a USB-camera. METHODS: This study was conducted in the Anatomy Lab of a University on a fresh frozen female cadaver. Three senior Emergency Physicians have intubated the cadaver, and performed TUS or USB-endoscopy. We have prepared a randomized intubation list (n=96) in three blocks (3 times 32) as to include equal number of esophageal and tracheal intubations (48 for each). Each EP is performed all three interventions (intubation, TUS and USB-endoscopy) in consecutive blocks of 32 intubations, in turn. The position of the tube has been verified from a 2cm wide ostium on the proximal trachea. RESULTS: In this study, all intubations (n=96, 100%) were correctly identified as tracheal or esophageal with both TUS and USB-camera. Both the sensitivity and specificity of TUS and USB-endoscopy for the CoETP were 100.0%. CONCLUSION: The perfect accuracy of TUS and USB-endoscopy, have placed those techniques in a unique position as an alternative in resource-poor situations. PMID- 29477269 TI - Quality of Life, Behaviour and Attitudes towards Actinic Keratosis in Spain: The PIQA Study. AB - OBJECTIVE: This study was aimed to examine patients' knowledge, behaviours and attitudes regarding actinic keratosis (AK) lesions and the impact of the disease on patients' quality of life (QoL). METHODS: Observational study of patients with AK lesions in Spain. QoL was evaluated with the validated version of Spanish AKQoL questionnaire. Skin self-examination, sun-exposure, habits and attitudes towards AK's treatment were recorded using different questionnaires. The adherence was assessed by means of the Morisky-Green test. Among other variables, QoL and adherence to treatment were compared by using Pearson's chi2 test and one way ANOVA tests. Inferential analysis regarding such factors and length of treatment were also performed. RESULTS: A total of 1240 patients (73.6 [10.5] years old) were recruited. Overall, patients that showed higher levels of concern were also showed a higher impairment on QoL. AK had greater effects on women's QoL and those who performed skin self-examination, think that AK is a disease and/or believe that moisturizers can prevent skin aging (P<.05). Adherence and length of treatment were strongly related, since patients with treatments intended for <1week were more likely to show good adherence and complete remission of AK (Odds Ratio [95%CI]: 6.25 [4.55-8.33] and 2.63 [1.96-3.45]), respectively). CONCLUSIONS: Concerns due to AK are mainly related to sex and to the consideration of AK as a disease. More concerned patients tend to have lower QoL and good adherence to treatment. Short length of treatment was associated with better adherence and complete remission of AK lesions. PMID- 29477270 TI - Application of Topical Sevoflurane Before Cleaning Painful Skin Ulcers. PMID- 29477272 TI - Experiences of Women Who Donated Human Milk. AB - OBJECTIVE: To examine the experiences of women who donated breast milk to a hospital-based milk bank regulated under the policies and procedures set forth by the Human Milk Banking Association of North America (HMBANA). DESIGN: Qualitative, phenomenological design. SETTING: The Mothers' Milk Bank in a children's hospital in the Northeastern region of the United States. PARTICIPANTS: Twelve HMBANA-approved milk donors older than 21 years with infants hospitalized in the NICU. METHODS: Edmund Husserl's design of interpretive phenomenology and Colaizzi's method of data analysis were used for this study. Participants were interviewed using a face-to-face, semistructured interview format. RESULTS: Four themes represented the experience of donating breast milk: Ripple of Hope and Help, Dynamic Interplay of Nurturance, Standing on the Shoulders of Others, and Sharing Their Stories. Donors felt proud and accomplished to provide hope for other infants and families. Nurses were crucial in facilitating and motivating donors and making donation achievable in a supportive environment. Donors felt compelled to share their experiences to teach and motivate others to donate. CONCLUSION: For our participants, donation of human milk was a positive, valuable, and nurturing experience. Donors reported feelings of increased self-esteem during donation that motivated them to "give back" and continue. The support of a well-trained nursing staff is essential for donors to meet their personal goals. PMID- 29477271 TI - Virtual target screening reveals rosmarinic acid and salvianolic acid A inhibiting metallo- and serine-beta-lactamases. AB - Rosmarinic acid (RA), a polyphenolic phytochemical, has broad-spectrum biological and pharmacological activity. A virtual target screening method termed IFPTarget combined with enzyme inhibition assays led to the identification of the clinically relevant metallo-beta-lactamase (MBL) VIM-2 as one of unexploited targets of RA. The enzyme kinetic studies indicated that RA is a fully reversible, substrate-competitive VIM-2 inhibitor. The isothermal titration calorimetry (ITC) analyses revealed that the initial binding of RA to VIM-2 is mainly due to enthalpy contribution. Further inhibition assays with RA related compounds revealed that salvianolic acid A, a derivative of RA, manifests potent inhibition to VIM-2, more interestingly, which shows inhibitory activity against the NDM-1, another clinically relevant MBL subtype, and the serine-beta-lactamase TEM-1 that is structurally and mechanistically distinct from the VIM-2 and NDM-1. PMID- 29477273 TI - Hepatitis C virus core antigen for screening organ donors and recipients. AB - Organ donors and recipients are routinely screened for hepatitis C virus (HCV) infection, typically via anti-HCV detection. We analyze the utility of an alternative HCV core antigen (HCV-Ag) quantification system, the ARCHITECT HCV Ag Assay, in this setting. We simultaneously tested 315 samples from potential organ donors and recipients using two chemiluminescent microparticle immunoassays: ARCHITECT Anti-HCV and HCV Ag (Abbott, Germany). HCV-Ag was detected in 81 of the serum samples (25.71%) and anti-HCV in 87 (27.62%). Seventy-five of the HCV-Ag positive samples were positive for anti-HCV (92.59%). Overall concordance between the two assays was 94.29%. Of the six HCV-Ag-positive/anti-HCV-negative patients, five had HCV-Ag values <32 fmol/L, and the sixth had a concentration of 477.50 fmol/L (viral load, 137,000 IU/mL). The HCV AG Assay detects HCV infections missed by the Anti-HCV Assay. Both markers should be used to screen for HCV infection in potential organ donors and recipients. PMID- 29477274 TI - Is the risk of early neurologic Lyme borreliosis reduced by preferentially treating patients with erythema migrans with doxycycline? AB - Doxycycline is highly effective treatment for early neurologic Lyme borreliosis (NLB). Nineteen studies were reviewed to determine if treatment of patients with erythema migrans with other oral antibiotics would increase the risk for developing NLB. In the eight studies that directly compared doxycycline to another antibiotic, the pooled difference indicated a 0.2% greater risk of developing NLB in doxycycline-treated patients (95% CI: -1.0%, +1.4%; P = 0.77), with an estimated heterogeneity of 0.0%, P = 0.58. Overall, in the 19 studies, NLB was reported in 8/828 (1.0%; 95% CI: 0.42%, 1.89%) doxycycline-treated patients versus 6/1022 (0.6%; 95% CI: 0.22%, 1.27%) patients treated with other antibiotics (P = 0.42). Based on the 95% CI calculation (-0.5%, +1.40%), patients receiving nondoxycycline treatment regimens collectively might have at most a 0.5% greater risk for developing NLB. Available data suggest that oral doxycycline is not superior to comparators for preventing NLB in patients receiving treatment for erythema migrans. PMID- 29477275 TI - Characterization of pEncl-30969cz, a novel ColE1-like plasmid encoding VIM-1 carbapenemase, from an Enterobacter cloacae sequence type 92 isolate. AB - A VIM-1-producing ST92 Enterobacter cloacae was isolated in a Czech hospital. blaVIM-1 was part of the class 1 integron In110 carried by a Tn1721-like transposon. Tn1721-like was located on a ColE1-like plasmid, pEncl-30969cz (33,003 bp). Target site duplications at the boundaries of Tn1721-like suggested its transposition into the pEncl-30969cz backbone. PMID- 29477276 TI - Real world experience of BRAFV600E mutation specific immunohistochemistry in colorectal carcinoma. PMID- 29477277 TI - Two-year management after renal transplantation in 2013 in France: Input from the French national health system database. AB - The objective of this study was to describe the management of patients undergoing renal transplantation in 2013 and over the following two years on the basis of healthcare consumption data. The National Health Insurance Information System was used to identify 1876 general scheme beneficiaries undergoing a first isolated renal transplantation (median age: 53 years; men 63%). Overall, 1.2% of patients died during the transplantation hospital stay (>65 years 3.3%) and 87% of patients had a functional graft at 2 years. Thirty-three percent of patients were readmitted to hospital for 1 day or longer during the first month, 73% the first year and 55% the second year. At least 10% of patients were hospitalised for antirejection treatment during the first quarter after renal transplantation, 16% the first year and 9% the second year. The first year, 32% of patients were hospitalised for renal disease (12% the second year), 14% were hospitalised for cardiovascular disease (9% the second year), 13% for infectious disease (5% the second year) and 2% for a malignant tumour (2% the second year). Almost 80% of patients consulted their general practitioner each year (almost 50% consulted every quarter). During the second year, 83% of patients were taking antihypertensives, 45% lipid-lowering drugs, 26% antidiabetic drugs, 77% tacrolimus, 18% ciclosporin, 88% mycophenolic acid and 69% corticosteroids. This study highlights the important contribution of healthcare consumption data to a better understanding of the modalities of management of renal transplant recipients in France, allowing improvement of this management in line with guidelines. PMID- 29477278 TI - [Initiation of first dialysis and three months quality of life of patients with end stage renal disease in the French territories of Guadeloupe and Guyane]. AB - End stage renal disease is a major public health problem in the French Departments of Guadeloupe and Guiana because of the high prevalence of both type 2 diabetes and hypertension. We investigated factors associated with an emergency start of dialysis, 3 months' quality of life for patients starting a first replacement therapy in Guadeloupe and French Guiana using the data of the Reseau epidemiologie et information en nephrologie network, completed with data from the quality of life questionnaires SF-36 and KDQoL. A total of 242 patients (184 in Guadeloupe and 58 in Guiana) were included. An emergency start was found for 112 (46.5%) patients (Guiana: 74.1%; Guadeloupe: 37.7%). In the multivariate model, an emergency start was associated with the number of nephrology consultations in the year before dialysis and the creation of an arteriovenous fistula prior to the first dialysis. The quality of life scores did not differ between the groups emergency start or not but were higher than those measured in mainland French studies on dialyzed population. Lack of nephrology consultations and dialysis preparation are the main factors associated with an emergency start of the first dialysis, highlighting the need to adapt the provision of care for chronic kidney disease in these departments. PMID- 29477279 TI - [Clinical pharmacist and medication reconciliation in kidney transplantation]. AB - INTRODUCTION: Drug related problems (DRP) can lead to severe consequences in kidney recipients. The aim of the study was to assess the impact of the clinical pharmacist interventions on the incidence of DRP. METHOD: The number of DRP were evaluated according to 3periods: Without intervention, with medication reconciliation at admission, and with medication reconciliation at admission associated with an interview with the clinical pharmacist at discharge. RESULTS: Patients concerned were mainly men, 55years old (median age), stage3 of CKD, transplanted for less than 3months or more than 1year, with cardiovascular risk factors and receiving an average of 9drugs/day. Among the DRP, 20% were avoidable and severe in most cases. In period1, 27.7% patients had at least 1DRP, in period2, 21.3% patients had at least 1DRP, and in period3, 17.4% of patients had at least 1DRP (P=0.03). One hundred and ten patients had medication reconciliation at admission with a mean of 0.6unintentional discrepancies per patient (omission in 81% of cases). The main drugs involved concerned the digestive-metabolic (24.5%), cardiovascular (23%), and nervous (23%) system. Sixty-eight interviews at discharge were realized and revealed self-medication habits. CONCLUSION: Our study shows that medication reconciliation at admission associated with an interview with the clinical pharmacist at discharge can help to reduce DRP in kidney recipients. Further studies are needed to confirm our results. PMID- 29477280 TI - Dynamic properties of human incudostapedial joint-Experimental measurement and finite element modeling. AB - The incudostapedial joint (ISJ) is a synovial joint connecting the incus and stapes in the middle ear. Mechanical properties of the ISJ directly affect sound transmission from the tympanic membrane to the cochlea. However, how ISJ properties change with frequency has not been investigated. In this paper, we report the dynamic properties of the human ISJ measured in eight samples using a dynamic mechanical analyzer (DMA) for frequencies from 1 to 80 Hz at three temperatures of 5, 25 and 37 degrees C. The frequency-temperature superposition (FTS) principle was used to extrapolate the results to 8 kHz. The complex modulus of ISJ was measured with a mean storage modulus of 1.14 MPa at 1 Hz that increased to 3.01 MPa at 8 kHz, and a loss modulus that increased from 0.07 to 0.47 MPa. A 3-dimensional finite element (FE) model consisting of the articular cartilage, joint capsule and synovial fluid was then constructed to derive mechanical properties of ISJ components by matching the model results to experimental data. Modeling results showed that mechanical properties of the joint capsule and synovial fluid affected the dynamic behavior of the joint. This study contributes to a better understanding of the structure-function relationship of the ISJ for sound transmission. PMID- 29477281 TI - Hypothalamic Sensing of Bile Acids, a Gut Feeling. AB - Bile acids facilitate dietary fat absorption upon release into the small intestine after a meal. A recent study by Liu and colleagues identifies a gut brain axis wherein bile acids signal an energy-replete state to hypothalamic AgRP neurons via activation of neuronal FGF receptors, which orchestrate whole-body glucose metabolism. PMID- 29477282 TI - FISH-ing Novel Dynamic Modes of Glucocorticoid-Induced Chromatin Reorganization. AB - In a recent study, Jubb et al. used 3D DNA FISH to assess glucocorticoid-induced 'chromatin decompaction' at multiple loci. Determinants of the specificity, speed, and duration of this phenomenon further enhance our understanding of how the glucocorticoid receptor (GR) dynamically alters chromatin accessibility during acute-phase transcriptional regulation and beyond. PMID- 29477283 TI - Genetic diversity and population structure of a protected species: Polygala tenuifolia Willd. AB - Polygala tenuifolia Willd. is an important protected species used in traditional Chinese medicine. In the present study, amplified fragment length polymorphism (AFLP) markers were employed to characterize the genetic diversity in wild and cultivated P. tenuifolia populations. Twelve primer combinations of AFLP produced 310 unambiguous and repetitious bands. Among these bands, 261 (84.2%) were polymorphic. The genetic diversity was high at the species level: percentage of polymorphic loci (PPL)=84.2%, Nei's gene diversity (h)=0.3296 and Shannon's information index (I)=0.4822. Between the two populations, the genetic differentiation of 0.1250 was low and the gene flow was relatively high, at 3.4989. The wild population (PPL=81.9%, h=0.3154, I=0.4635) showed a higher genetic diversity level than the cultivated population (PPL=63.9%, h=0.2507, I=0.3688). The results suggest that the major factors threatening the persistence of P. tenuifolia resources are ecological and human factors rather than genetic. These results will assist with the design of conservation and management programs, such as in natural habitat conservation, setting the excavation time interval for resource regeneration and the substitution of cultivated for wild plants. PMID- 29477285 TI - Australian community sport extreme heat policies: Limitations and opportunities for improvement. PMID- 29477284 TI - Early striatal amyloid deposition distinguishes Down syndrome and autosomal dominant Alzheimer's disease from late-onset amyloid deposition. AB - INTRODUCTION: The objective of this study was to evaluate amyloid beta (Abeta) deposition patterns in different groups of cerebral beta amyloidosis: (1) nondemented with amyloid precursor protein overproduction (Down syndrome); (2) nondemented with abnormal processing of amyloid precursor protein (preclinical autosomal dominant Alzheimer disease); (3) presumed alteration in Abeta clearance with clinical symptoms (late-onset AD); and (4) presumed alterations in Abeta clearance (preclinical AD). METHODS: We performed whole-brain voxelwise comparison of cerebral Abeta between 23 Down syndrome, 10 preclinical autosomal dominant Alzheimer disease, 17 late-onset AD, and 16 preclinical AD subjects, using Pittsburgh Compound B-positron emission tomography. RESULTS: We found both Down syndrome and preclinical autosomal dominant Alzheimer disease shared a distinct pattern of increased bilateral striatal and thalamic Abeta deposition compared to late-onset AD and preclinical AD. CONCLUSION: Disorders associated with early-life alterations in amyloid precursor protein production or processing are associated with a distinct pattern of early striatal fibrillary Abeta deposition before significant cognitive impairment. A better understanding of this unique pattern could identify important mechanisms of Abeta deposition and possibly important targets for early intervention. PMID- 29477286 TI - Effective Research Mentoring of Radiology Residents. PMID- 29477287 TI - Fostering Diversity and Inclusion: A Summary of the 2017 Intersociety Summer Conference. AB - The 39th radiology Intersociety Committee reviewed the current state of diversity among trainees and in our workplaces and addressed future strategies for fostering diversity through inclusion. The assembled participants addressed the imperatives and drivers for diversity and developed a road map to foster diversity. Themes included the need to be proactive in increasing awareness of our own biases and their potential impact on workplace decisions, overcoming blind spots, and being culturally sensitive. The need to identify and eliminate barriers to diversity was discussed at both the organizational and practice level and included efforts to break down structural and clinical barriers, such as training in multicultural awareness. Additional strategies that were addressed included building inclusive work environments; facilitating debate, conversations, and community building; and pipelining medical students through mentoring pathways. The conference ended with a call to action to develop toolkits with effective resources to support the necessary diversity and inclusion initiatives we must all undertake. PMID- 29477288 TI - Facing the Guilt and Commemorating the Victims: German Radiology and Radiation Oncology During National Socialism. AB - Whereas the scientific community is aware of atrocities committed by medical doctors like Mengele, the specifics of radiology and radiation oncology during National Socialism remain largely unknown. Starting in 2010, the German Radiology Association and the German Association of Radiation Oncology coordinated a national project looking into original archival material. A national committee convened in 2013 to discuss the project's findings, which were also the subject of a symposium at the University of Tuebingen in 2016 on radiology under National Socialism. The project identified approximately 160 radiologists who were victimized because of their Jewish descent, among them Gustav Bucky (known for the Bucky factor in x-ray diagnostics). Radiologists throughout Germany took part in forced sterilizations. The "Schutzstaffel," commonly known as SS, had a special radiology unit that was established for tuberculosis screening. Radiation was also used for sterilization experiments in the Auschwitz concentration camp with subsequent surgical procedures to enable histological analysis of the irradiated tissue. Reflection on medicine during the Holocaust will be strengthened by specific facts related to the respective medical field. Radiologists were involved in atrocious medical experiments as well as in supporting Nazi policies in Germany. These facts provoke ethical considerations about marginalized patient groups and doctor-patient communication. They also raise questions about "evidence-based" medicine as sole justification for medical procedures. In summary, historical studies will be able to help in the professional identity formation of radiologists gaining awareness to ethical issues of today. PMID- 29477289 TI - The Role of Artificial Intelligence in Diagnostic Radiology: A Survey at a Single Radiology Residency Training Program. AB - PURPOSE: Advances in artificial intelligence applied to diagnostic radiology are predicted to have a major impact on this medical specialty. With the goal of establishing a baseline upon which to build educational activities on this topic, a survey was conducted among trainees and attending radiologists at a single residency program. METHODS: An anonymous questionnaire was distributed. Comparisons of categorical data between groups (trainees and attending radiologists) were made using Pearson chi2 analysis or an exact analysis when required. Comparisons were made using the Wilcoxon rank sum test when the data were not normally distributed. An alpha level of 0.05 was used. RESULTS: The overall response rate was 66% (69 of 104). Thirty-six percent of participants (n = 25) reported not having read a scientific medical article on the topic of artificial intelligence during the past 12 months. Twenty-nine percent of respondents (n = 12) reported using artificial intelligence tools during their daily work. Trainees were more likely to express doubts on whether they would have pursued diagnostic radiology as a career had they known of the potential impact artificial intelligence is predicted to have on the specialty (P = .0254) and were also more likely to plan to learn about the topic (P = .0401). CONCLUSIONS: Radiologists lack exposure to current scientific medical articles on artificial intelligence. Trainees are concerned by the implications artificial intelligence may have on their jobs and desire to learn about the topic. There is a need to develop educational resources to help radiologists assume an active role in guiding and facilitating the development and implementation of artificial intelligence tools in diagnostic radiology. PMID- 29477290 TI - Out-of-Pocket Costs for Advanced Imaging Across the US Private Insurance Marketplace. AB - PURPOSE: The aim of this study was to characterize out-of-pocket patient costs for advanced imaging across the US private insurance marketplace. METHODS: Using the 2017 CMS Health Insurance Marketplace Benefits and Cost Sharing Public Use File, which details coverage policies for qualified health plans on federally facilitated marketplaces, measures of out-of-pocket costs for advanced imaging and other essential health benefits were analyzed for all 18,429 plans. RESULTS: Independent of deductibles, 48.0% of plans required coinsurance (percentage fees) for advanced imaging, 9.7% required copayments (flat fees), and 8.0% required both; 34.3% required neither. For out-of-network services, 91.5% required coinsurance, 0.1% copayments, and 1.0% both; only 7.4% required neither. In the presence of deductibles, patient coinsurance burdens for advanced imaging in and out of network were 27.7% and 47.7%, respectively, and average in- and out-of network copayments were $319 and $630, respectively. In the presence of deductibles, patients' average coinsurance ranged from 10.0% to 40.9% in network and from 29.1% to 75.0% out of network by state; these tended to be higher in lower income states (r = -0.332). For no-deductible policies, patients' average out-of-network coinsurance burden for advanced imaging was 99.9%. Among assessed benefits, advanced imaging had the highest in-network and second highest out-of network copayments. CONCLUSIONS: In the US private insurance marketplace, patients very commonly pay coinsurance when undergoing advanced imaging, both in and out of network. But out-of-network services usually involve drastically higher patient financial responsibilities (potentially 100% of examination cost). To more effectively engage patients in shared decision making and mitigate the hardships of surprise balance billing, radiologists should facilitate transparent communication of advanced imaging costs with patients. PMID- 29477291 TI - Head and Neck Tumor Control Probability: Radiation Dose-Volume Effects in Stereotactic Body Radiation Therapy for Locally Recurrent Previously-Irradiated Head and Neck Cancer: Report of the AAPM Working Group. AB - PURPOSE: Stereotactic body radiation therapy (SBRT) has emerged as a viable reirradiation strategy for locally recurrent previously-irradiated head and neck cancer. Doses in the literature have varied, which challenges clinical application of SBRT as well as clinical trial design. MATERIAL & METHODS: A working group was formed through the American Association of Physicists in Medicine to study tumor control probabilities for SBRT in head and neck cancer. We herein present a systematic review of the available literature addressing the dose/volume data for tumor control probability with SBRT in patients with locally recurrent previously-irradiated head and neck cancer. Dose-response models are generated that present tumor control probability as a function of dose. RESULTS: Data from more than 300 cases in 8 publications suggest that there is a dose response relationship, with superior local control and possibly improved overall survival for doses of 35 to 45 Gy (in 5 fractions) compared with <30 Gy. CONCLUSION: Stereotactic body radiation therapy doses equivalent to 5-fraction doses of 40 to 50 Gy are suggested for retreatment. PMID- 29477292 TI - Qualitative Assessment of Academic Radiation Oncology Department Chairs' Insights on Diversity, Equity, and Inclusion: Progress, Challenges, and Future Aspirations. AB - PURPOSE: A lack of diversity has been observed in radiation oncology (RO), with women and certain racial/ethnic groups underrepresented as trainees, faculty, and practicing physicians. We sought to gain a nuanced understanding of how to best promote diversity, equity, and inclusion (DEI) based on the insights of RO department chairs, with particular attention given to the experiences of the few women and underrepresented minorities (URMs) in these influential positions. METHODS AND MATERIALS: From March to June 2016, we conducted telephone interviews with 24 RO department chairs (of 27 invited). Purposive sampling was used to invite all chairs who were women (n = 13) or URMs (n = 3) and 11 male chairs who were not URMs. Multiple analysts coded the verbatim transcripts. RESULTS: Five themes were identified: (1) commitment to DEI promotes quality health care and innovation; (2) gaps remain despite some progress with promoting diversity in RO; (3) women and URM faculty continue to experience challenges in various career domains; (4) solutions to DEI issues would be facilitated by acknowledging realities of gender and race; and (5) expansion of the career pipeline is needed. CONCLUSIONS: The chairs' insights had policy-relevant implications. Bias training should broach tokenism, blindness, and intersectionality. Efforts to recruit and support diverse talent should be deliberate and proactive. Bridge programs could engage students before their application to medical school. PMID- 29477293 TI - Regional Nodal Control for Head and Neck Alveolar Rhabdomyosarcoma. AB - PURPOSE: To assess clinical outcomes and patterns of failure, particularly regional nodal control, for pediatric patients treated with proton beam therapy (PBT) for head and neck alveolar rhabdomyosarcoma (HN-ARMS). MATERIALS AND METHODS: Between 2006 and 2015, 14 patients with HN-ARMS were enrolled in a prospective registry protocol and treated with PBT at a single institution. Of the patients, 8 (57%) presented with localized disease and 6 (43%) with regional nodal metastases. All patients were treated with systemic therapy per accepted cooperative group regimens. All patients received PBT to the primary site and involved nodal disease with a median dose of 50.4 Gy (relative biological effectiveness). Elective nodal irradiation was not delivered. RESULTS: The median follow-up period for surviving patients was 4.3 years. The 5-year overall survival and disease-free survival rates for the cohort (N = 14) were 45% and 25%, respectively. There were 10 relapses in the cohort: 7 regional nodal, 1 combination local and regional nodal, and 2 leptomeningeal. In 6 of 8 patients (75%) with no nodal disease at diagnosis, isolated regional nodal relapse developed. All nodal relapses occurred in first-echelon draining lymph node basins relative to the primary tumor site. Of 6 patients who presented with nodal metastases, 2 had regional nodal relapse; both of these nodal relapses occurred in the same nodal basin that was initially involved by disease but was not completely targeted as part of the primary treatment plan. CONCLUSIONS: High rates of regional nodal relapse are observed for HN-ARMS patients, including patients with no nodal disease at diagnosis. These data suggest that HN-ARMS patients may benefit from elective nodal irradiation to treat at-risk draining lymph node stations relative to the primary tumor site. We further recommend coverage of the entire nodal level for any sites of initial nodal disease at diagnosis, given the high risk of failure at these sites. PMID- 29477294 TI - Sensitization of Hypoxic Tumors to Radiation Therapy Using Ultrasound-Sensitive Oxygen Microbubbles. AB - PURPOSE: Much of the volume of solid tumors typically exists in a chronically hypoxic microenvironment that has been shown to result in both chemotherapy and radiation therapy resistance. The purpose of this study was to use localized microbubble delivery to overcome hypoxia prior to therapy. MATERIALS AND METHODS: In this study, surfactant-shelled oxygen microbubbles were fabricated and injected intravenously to locally elevate tumor oxygen levels when triggered by noninvasive ultrasound in mice with human breast cancer tumors. Changes in oxygen and sensitivity to radiation therapy were then measured. RESULTS: In this work, we show that oxygen-filled microbubbles successfully and consistently increase breast tumor oxygenation levels in a murine model by 20 mmHg, significantly more than control injections of saline solution or untriggered oxygen microbubbles (P < .001). Using photoacoustic imaging, we also show that oxygen delivery is independent of hemoglobin transport, enabling oxygen delivery to avascular regions of the tumor. Finally, we show that overcoming hypoxia by this method immediately prior to radiation therapy nearly triples radiosensitivity. This improvement in radiosensitivity results in roughly 30 days of improved tumor control, providing statistically significant improvements in tumor growth and animal survival (P < .03). CONCLUSIONS: Our findings demonstrate the potential advantages of ultrasound-triggered oxygen delivery to solid tumors and warrant future efforts into clinical translation of the microbubble platform. PMID- 29477295 TI - Erratum to "Efficacy of elastic memory chains versus nickel-titanium coil springs in canine retraction : A two-center split-mouth randomized clinical trial" [International Orthodontics 2017 ;15 :561-74]. PMID- 29477296 TI - Comparison of Basophil Activation Test and Skin Testing Performances in NMBA Allergy. AB - BACKGROUND: Neuromuscular blocking agents (NMBAs) are the main agents involved during perioperative immediate hypersensitivity. The etiological diagnosis (IgE mediated allergy vs nonallergy) is linked to the clinical presentation together with tryptase and histamine levels and skin test results. The role of basophil activation test (BAT) needs to be better defined in this setting. OBJECTIVES: To assess the role of BAT compared with the results of skin testing in 31 patients experiencing immediate NMBA hypersensitivity and compare skin test results and BAT performances in the identification of alternative NMBAs. METHODS: Histamine and tryptase levels were quantified. Anesthetic drugs, including NMBAs, were skin tested. Basophil CD63 and CD203c expressions were measured in response to serial dilutions of the different NMBAs. RESULTS: Allergy and Nonallergy groups involved 19 and 12 patients, respectively. Circulating histamine and tryptase levels were significantly increased in allergic patients. In the Allergy group, while skin test results were positive in 100% (19 of 19) of the cases, BAT positivity to the culprit NMBA reached 78.9% (15 of 19) when combining CD63 and CD203c. NMBAs cross reactivity was identified through skin testing and BAT in 36.8% (7 of 19) and 26.3% (5 of 19) of the cases, respectively. The concordance (culprit and cross reactive NMBAs) between skin tests and BATs was between 73.6% (14 of 19) and 100% (19 of 19) for each NMBA. Negative skin-tested NMBAs were uneventfully used in 7 NMBA-allergic patients. In the Nonallergy group, skin test results were negative in 100% of the cases while BAT result was positive once (CD63 upregulation). CONCLUSION: In our technical conditions, BAT does not replace skin testing in the assessment of NMBA allergy. PMID- 29477297 TI - Chronic Lymphocytic Leukemia: A Review of Front-line Treatment Options, With a Focus on Elderly CLL Patients. AB - Chronic lymphocytic leukemia (CLL) remains the most prevalent form of leukemia in the Western world, with no cure to date. Ongoing and essential research into this heterogeneous disease has led to a number of new treatment options becoming available to CLL patients in the past decade. The present review presents the recent developments in the field of CLL treatment, with the main focus on elderly patients and CLL patients with coexisting comorbidities. The review discusses the current treatment regimens that provide the most promising outcomes for patients in this subgroup, with a number of important clinical trials summarized. These clinical trials, which have investigated promising single-agent therapies or combination therapies, are discussed, with an emphasis on the efficacy and tolerability for patients aged >= 65 years. Also, the misrepresentation of the true CLL population in many clinical trials and the need for better guidelines for participant inclusion criteria to provide a more realistic and accurate study population are noted. PMID- 29477298 TI - Novel approaches to alcohol rehabilitation: Modification of stress-responsive brain regions through environmental enrichment. AB - Relapse remains the most prominent hurdle to successful rehabilitation from alcoholism. The neural mechanisms underlying relapse are complex, but our understanding of the brain regions involved, the anatomical circuitry and the modulation of specific nuclei in the context of stress and cue-induced relapse have improved significantly in recent years. In particular, stress is now recognised as a significant trigger for relapse, adding to the well-established impact of chronic stress to escalate alcohol consumption. It is therefore unsurprising that the stress-responsive regions of the brain have also been implicated in alcohol relapse, such as the nucleus accumbens, amygdala and the hypothalamus. Environmental enrichment is a robust experimental paradigm which provides a non-pharmacological tool to alter stress response and, separately, alcohol-seeking behaviour and symptoms of withdrawal. In this review, we examine and consolidate the preclinical evidence that alcohol seeking behaviour and stress-induced relapse are modulated by environmental enrichment, and these are primarily mediated by modification of neural activity within the key nodes of the addiction circuitry. Finally, we discuss the limited clinical evidence that stress-reducing approaches such as mindfulness could potentially serve as adjunctive therapy in the treatment of alcoholism. PMID- 29477299 TI - Serotonin 5-HT3 receptor antagonism potentiates the antidepressant activity of citalopram. AB - Activation of serotonin 5-HT3 receptor (5HT3R) in the locus coeruleus (LC), the principal somatodendritic noradrenergic area, decreases LC firing activity and noradrenaline (NA) release in prefrontal cortex (PFC). Blockade of 5HT3R in coadministration with selective serotonin reuptake inhibitors (SSRIs) has been proposed as a potential strategy to accelerate the onset of action of SSRIs. Dual probe microdialysis in rats was used to evaluate the involvement of 5HT3R in the in vivo effect exerted by the SSRI citalopram on NA release. Besides, forced swimming test (FST) was carried out in mice to evaluate the antidepressant-like effect of citalopram in combination with a 5HT3R antagonist (Y25130). Systemic administration of the 5HT3R agonist SR57227 (10 mg/kg i.p.) increased NA in LC (Emax = 200 +/- 27%) and PFC (Emax = 133 +/- 2%). The increase in PFC was enhanced in local presence into LC of Y25130 (50 MUM) (Emax = 296 +/- 41%) suggesting an inhibitory function on NA release exerted by the activation of 5HT3R located in somatodendritic areas. Citalopram administration (10 mg/kg i.p.) increased NA in LC (Emax = 185 +/- 11%) and decreased it in PFC (Emax = -35 +/- 7%). Intra-LC (50 MUM) or systemic co-administration of Y25130 (10 mg/kg i.p.) with citalopram (10 mg/kg i.p.) switched NA release in the PFC from an inhibition to a stimulatory effect. In mice FST, systemic coadministration of citalopram (2.5 mg/kg i.p.) and Y25130 (10 mg/kg i.p.) potentiated the decrease of immobility time through the increase of both swimming and climbing behaviours. These results suggest that the addition of a 5HT3R antagonist to SSRIs could represent a feasible strategy to improve antidepressant response. PMID- 29477300 TI - Maternal stress and the MPOA: Activation of CRF receptor 1 impairs maternal behavior and triggers local oxytocin release in lactating rats. AB - Maternal behavior and anxiety are potently modulated by the brain corticotropin releasing factor (CRF) system postpartum. Downregulation of CRF in limbic brain regions is essential for appropriate maternal behavior and an adaptive anxiety response. Here, we focus our attention on arguably the most important brain region for maternal behavior, the hypothalamic medial preoptic area (MPOA). Within the MPOA, mRNA for CRF receptor subtype 1 (protein: CRFR1, gene: Crhr1) was more abundantly expressed than for subtype 2 (protein: CRFR2, gene: Crhr2), however expression of Crhr1, Crhr2 and CRF-binding protein (protein: CRFBP, gene: Crhbp) mRNA was similar between virgin and lactating rats. Subtype-specific activation of CRFR, predominantly CRFR1, in the MPOA decreased arched back nursing and total nursing under non-stress conditions. Following acute stressor exposure, only CRFR1 inhibition rescued the stress-induced reduction in arched back nursing while CRFR1 activation prolonged the decline in nursing. Furthermore, inhibition of CRFR1 strongly increased maternal aggression in the maternal defense test. CRFR1 activation had anxiogenic actions and reduced locomotion on the elevated plus-maze, however neither CRFR1 nor R2 manipulation affected maternal motivation. In addition, activation of CRFR1, either centrally or locally in the MPOA, increased local oxytocin release. Finally, inhibition of CRFBP (a potent regulator of CRFR activity) in the MPOA did not affect any of the maternal parameters investigated. In conclusion, activity of CRFR in the MPOA, particularly of subtype 1, needs to be dampened during lactation to ensure appropriate maternal behavior. Furthermore, oxytocin release in the MPOA may provide a regulatory mechanism to counteract the negative impact of CRFR activation on maternal behavior. PMID- 29477301 TI - Physical exercise prevents cognitive impairment by enhancing hippocampal neuroplasticity and mitochondrial function in doxorubicin-induced chemobrain. AB - Although chemotherapy increases the survival rate of patients with various cancers, such treatment can induce acute or long-term cognitive dysfunction a phenomenon known as post-chemotherapy cognitive impairment (PCCI) or "chemobrain." Exercise is known to positively affect brain function. Thus, the present study aimed to determine whether symptoms of chemobrain and disruptions in the neuroplasticity and functioning of hippocampal mitochondria can be prevented or relieved by exercise. Wistar rats were separated into the following groups: control, control plus exercise, chemobrain, and chemobrain plus exercise. For chemobrain induction, 2 mg/kg of doxorubicin (DOX) a widely utilized chemotherapeutic agent among patients with breast cancer was dissolved in saline and directly injected to the abdomen once every 4 weeks. The exercise groups were subjected to low-intensity treadmill, 6 days per week for 4 weeks. The Morris water maze and step-down avoidance tests were conducted to evaluate cognitive function, while neuroplasticity and mitochondrial function were assessed in the hippocampus and dentate gyrus. Decreased cognitive function were observed in the chemobrain group, along with decreases in levels of neurogenesis, brain derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB), Ca2+ retention in hippocampus. Rats of the chemobrain group also exhibited an increase in apoptosis, H2O2 emission and permeability transition pore by hippocampal mitochondria. However, exercise attenuated impairments in cognitive function, neuroplasticity, and mitochondrial function induced by DOX treatment. Therefore, the findings of the present study indicate that low-intensity exercise may assist in preventing cognitive dysfunction during or after chemotherapy in patients with various cancers, including breast cancer. PMID- 29477303 TI - Identification of volumetric laser endomicroscopy features of colon polyps with histologic correlation. AB - BACKGROUND AND AIMS: There are limited data on the use of volumetric laser endomicroscopy (VLE) for imaging colon polyps. Our aim was to identify VLE features of colon polyps. METHODS: A total of 45 patients were included; 43 underwent endoscopic mucosal resection of colorectal polyps 2 cm or greater. These polyps were then scanned with VLE immediately after resection. Two patients who underwent partial colonic resection served as controls. RESULTS: Forty-three polyps were included with review of matching histology: 3 intramucosal cancer (IMCA), 5 tubular adenoma (TAs)/tubulovillous adenoma (TVA) with high-grade dysplasia (HGD), 9 TVA with only low-grade dysplasia (LGD), 5 serrated adenoma, and 21 TA with LGD. All TAs and TVAs were hyper-reflective compared with normal tissue. Effacement occurred in 82.4% (14/17) of the colonic polyps with advanced pathology (TVA with HGD/IMCA) compared with 11.6% (3/26) with non-advanced pathology (TA with LGD and serrated adenoma) (P < .0001). Forty-seven percent (8/17) of polyps with advanced pathology had greater than 5 glands on VLE compared with none in the non-advanced pathology group (P = .0001). An irregular surface mainly occurred in polyps with high-grade pathology (HGD/IMCA) versus TAs. Eighty-eight percent of polyps with HGD/IMC had an irregular surface (7/8) versus 6% (2/35) of TAs (P < .0001). CONCLUSIONS: In this ex vivo clinicopathologic study, we show that there are distinct VLE features of colon polyps that may help identify polyps or features of a higher-grade lesion. This may have implications for possible in vivo application to aid in dysplasia or polyp detection. PMID- 29477302 TI - Adherence to colorectal cancer screening measured as the proportion of time covered. AB - BACKGROUND AND AIMS: Colorectal cancer (CRC) screening can reduce CRC incidence and mortality, but measuring screening adherence over time is challenging. We examined adherence using a novel measure characterizing the proportion of time covered (PTC) by screening tests. METHODS: Eligible patients were age 50 to 60 years and followed at a large, safety-net health care system between January 2010 and September 2014. We estimated PTC as the number of days up to date with screening divided by the number of days from cohort entry until study end, CRC diagnosis, or death. We estimated mean and median PTC and used least-significant difference tests to assess differences in adherence by patient characteristics. RESULTS: Of 18,257 patients, most were non-Hispanic black (40.5%) or Hispanic (34.9%) and/or female (62.4%). Approximately 40% (n = 7559) were never screened during the study period; the remaining 10,698 patients completed 19,105 screening examinations (14,481 fecal immunochemical tests [FITs], 4393 colonoscopies, 94 sigmoidoscopies, and 137 barium enemas). Overall, the mean PTC was 29.1% (95% confidence interval [CI], 28.6%-29.5%). Among those who completed at least one screening test (n = 10,698), the mean PTC was 49.0% (95% CI, 48.5%-49.5%). The most common reasons for non-adherence were lack of repeat FIT and no diagnostic colonoscopy after abnormal results for the FIT. The mean PTC increased with the number of primary care visits (0 visits, 21%; 1 visit, 29%; 2-3 visits, 35%; >=4 visits, 37%; all P < .05). CONCLUSIONS: PTC provides a reliable estimate of screening adherence, capturing breakdowns in the CRC screening process amenable to intervention. Repeat FIT and diagnostic colonoscopy are important intervention targets that may increase adherence in underserved populations. PMID- 29477304 TI - Radiotherapy of relapse-refractory follicular lymphoma. AB - PURPOSE: To assess the efficacy of treatment and outcomes of patients with relapsed or refractory follicular lymphoma treated with external beam irradiation. PATIENTS AND METHODS: Fifteen patients who received external beam radiotherapy for relapsed or refractory follicular lymphoma were studied. The median age was 68.3 years (range: 37.9-87.08 years) with four men and 11 women. Seven patients had early stage (I or II); eight advanced stage (III or IV). Median FLIPI score was 2. Two patients had high tumour bulk disease. Six patients had extranodal invasion, with five patients having bone marrow invasion. RESULTS: The median time of follow-up after relapse or first-line treatment in case of refractory disease was 61.9 months (range: 9.1-119.7 months). Complete response after external beam radiotherapy was seen in 11 cases (73%) and partial response in two (13%), with a median dose of 30Gy (range: 2-40Gy) and median number of fractions of 15 (range: 2-20). Eight patients (53%) relapsed after external beam radiation therapy in a median of 20.2 months, mostly out of irradiated volumes. Most patients (66%) had a disease control after one or two courses of external beam radiation therapy. At last follow-up, 86% of patients were in remission including those with salvage chemotherapy. The toxicity profile was favourable with toxicity higher than grade 1. In univariate analysis, a Follicular Lymphoma International Prognostic Index (FLIPI) score above 2 was the only predicting factor for non-control disease. CONCLUSION: For relapsed and refractory follicular lymphoma, external beam radiotherapy should be considered as an effective modality when integrated in a multimodality approach. Randomised studies are warranted to validate this strategy. PMID- 29477305 TI - A metabolomic approach to identify anti-hepatocarcinogenic compounds from plants used traditionally in the treatment of liver diseases. AB - Liver cancer is a major health burden in Southeast Asia, and most patients turn towards the use of medicinal plants to alleviate their symptoms. The aim of this work was to apply to Southeast Asian plants traditionally used to treat liver disorders, a successive ranking strategy based on a comprehensive review of the literature and metabolomic data in order to relate ethnopharmacological relevance to chemical entities of interest. We analyzed 45 publications resulting in a list of 378 plant species, and our point system based on the frequency of citation in the literature allowed the selection of 10 top ranked species for further collection and extraction. Extracts of these plants were tested for their in vitro anti-proliferative activities on HepG2 cells. Ethanolic extracts of Andrographis paniculata, Oroxylum indicum, Orthosiphon aristatus and Willughbeia edulis showed the highest anti-proliferative effects (IC50 = 195.9, 64.1, 71.3 and 66.7 MUg/ml, respectively). A metabolomic ranking model was performed to annotate compounds responsible for the anti-proliferative properties of A. paniculata (andrographolactone and dehydroandrographolide), O. indicum (baicalein, chrysin, oroxylin A and scutellarein), O. aristatus (5 desmethylsinensetin) and W. edulis (parabaroside C and procyanidin). Overall, our dereplicative approach combined with a bibliographic scoring system allowed us to rapidly decipher the molecular basis of traditionally used medicinal plants. PMID- 29477306 TI - Crustacean cardioactive peptide (CCAP) of the oriental fruit fly, Bactrocera dorsalis (Diptera: Tephritidae): Molecular characterization, distribution and its potential roles in larva-pupa ecdysis. AB - Insects must undergo ecdysis for successful development and growth, and the crustacean cardioactive peptide (CCAP) is one of the most important hormone in this process. Here we reported a cDNA encoding for the CCAP precursor cloned from the oriental fruit fly, Bactrocera dorsalis, a most destructive insect pest of agriculture. The CCAP mature peptide (PFCNAFTGC-NH2) of B. dorsalis was generated by post-translational processing and found to be highly comparable with other insects. RT-qPCR showed that mRNA of CCAP in B. dorsalis (BdCCAP) was predominantly expressed in the central nervous system (CNS) and midgut of 3rd instar larvae. By using immunohistochemical analysis, we also localized the endocrine cells that produce CCAP in the CNS, ring gland and midgut of 3rd-instar larvae of B. dorsalis. The synthetic CCAP mature peptide could induce the expression of mRNA of adipokinetic hormone (AKH), the metabolic neuropeptides in insects. The expression of BdCCAP mRNA in the CNS, but not in the midgut, could be upregulated in the response to the challenge of insect molting hormone, 20 hydroxyecdysone. PMID- 29477307 TI - Evaluation of vaccine derived poliovirus type 2 outbreak response options: A randomized controlled trial, Karachi, Pakistan. AB - BACKGROUND: Outbreaks of circulating vaccine derived polioviruses type 2 (cVDPV2) remain a risk to poliovirus eradication in an era without live poliovirus vaccine containing type 2 in routine immunization. We evaluated existing outbreak response strategies recommended by the World Health Organization (WHO) for control of cVDPV2 outbreaks. METHODS: Seronegative children for poliovirus type 2 (PV2) at 22 weeks of life were assigned to one of four study groups and received respectively (1) one dose of trivalent oral poliovirus vaccine (tOPV); (2) monovalent OPV 2 (mOPV2); (3) tOPV together with a dose of inactivated poliovirus vaccine (IPV); or (4) mOPV2 with monovalent high-potency IPV type 2. Stool and blood samples were collected and assessed for presence of PV2 (stool) and anti polio antibodies (sera). RESULTS: We analyzed data from 265 children seronegative for PV2. Seroconversion to PV2 was achieved in 48, 76, 98 and 100% in Groups 1-4 respectively. mOPV2 was more immunogenic than tOPV alone (p < 0.001); and OPV in combination with IPV was more immunogenic than OPV alone (p < 0.001). There were 33%, 67%, 20% and 43% PV2 excretors in Groups 1-4 respectively. mOPV2 resulted in more prevalent shedding of PV2 than when tOPV was used (p < 0.001); and tOPV together with IPV resulted in lower excretion of PV2 than tOPV alone (p = 0.046). CONCLUSION: mOPV2 was a more potent vaccine than tOPV. Adding IPV to OPV improved immunological response; adding IPV also seemed to have shortened the duration of PV2 shedding. mIPV2 did not provide measurable improvement of immune response when compared to conventional IPV. WHO recommendation to use mOPV2 as a vaccine of first choice in cVDPV2 outbreak response was supported by our findings. Clinical Trial registry number: NCT02189811. PMID- 29477308 TI - Post-licensure safety monitoring of quadrivalent human papillomavirus vaccine in the Vaccine Adverse Event Reporting System (VAERS), 2009-2015. AB - BACKGROUND: The Food and Drug Administration (FDA) approved quadrivalent human papillomavirus vaccine (4vHPV) for use in females and males aged 9-26 years, since 2006 and 2009 respectively. We characterized reports to the Vaccine Adverse Event Reporting System (VAERS), a US spontaneous reporting system, in females and males who received 4vHPV vaccination. METHODS: We searched VAERS for US reports of adverse events (AEs) following 4vHPV from January 2009 through December 2015. Signs and symptoms were coded using Medical Dictionary for Regulatory Activities (MedDRA). We calculated reporting rates and conducted empirical Bayesian data mining to identify disproportional reports. Clinicians reviewed available information, including medical records, and reports of selected pre-specified conditions. FINDINGS: VAERS received 19,760 reports following 4vHPV; 60.2% in females, 17.2% in males, and in 22.6% sex was missing. Overall, 94.2% of reports were non-serious; dizziness, syncope and injection site reactions were commonly reported in both males and females. Headache, fatigue and nausea were commonly reported serious AEs. More than 60 million 4vHPV doses were distributed during the study period. Crude AE reporting rates were 327 reports per million 4vHPV doses distributed for all reports, and 19 per million for serious reports. Among 29 verified reports of death, there was no pattern of clustering of deaths by diagnosis, co-morbidities, age, or interval from vaccination to death. INTERPRETATION: No new or unexpected safety concerns or reporting patterns of 4vHPV with clinically important AEs were detected. Safety profile of 4vHPV is consistent with data from pre-licensure trials and postmarketing safety data. PMID- 29477309 TI - Successful percutaneous retrieval of unusually knotted temporary pacemaker lead. AB - Implantation of temporary pacemaker lead is commonly performed procedure and is usually safe, but can sometimes develop rare and serious complication like intracardiac lead knotting which may require challenging retrieval techniques. We report a case of successful percutaneous retrieval of unusually knotted right internal jugular venous temporary pacing lead via left femoral transvenous approach using snare over a long sheath after cutting the electrode proximally and thus avoiding any surgical intervention. PMID- 29477310 TI - Cause of the "power-on reset" phenomenon other than electric magnetic interference in a patient with a pacemaker. AB - A 67-year old male with a dual-chamber pacemaker visited for a regular check-up. An unfamiliar message emerged on the display just after placing the programmer wand. We could recognize that the pacemaker had already been in the safe back-up mode of DDI, and the programmer prompted a re-initialization request. We are so surprised because there was no indication of device malfunction the day before in daily monitoring and a 12-lead electrocardiogram revealed normally working in the DDD mode just before checking the device. The pacemaker was immediately re programmed to the former setting. This phenomenon has not recurred for 12 months. PMID- 29477311 TI - Re: Halstuch et al.: Transplant Kidney Retrograde Ureteral Stent Placement and Exchange: Overcoming the Challenge (Urology 2018;111:220-224). PMID- 29477312 TI - Reply by the Authors. PMID- 29477313 TI - Which Patients Report That Their Urologists Advised Them to Forgo Initial Treatment for Prostate Cancer? AB - OBJECTIVE: To examine how frequently patients report that their urologist recommended forgoing definitive treatment and assess the impact of these recommendations on treatment choice and perceived quality of cancer care. METHODS: We mailed surveys to men newly diagnosed with localized prostate cancer between 2014 and 2015 (adjusted response rate of 51.3%). Men reported whether their urologist recommended forgoing definitive treatment. Using logistic regression models, we assessed patient-level predictors of receiving a recommendation to forgo definitive treatment and estimated associations of receiving this recommendation with receipt of definitive treatment and perceived quality of cancer care among men with low-risk tumors and limited life expectancies. RESULTS: Nearly two-thirds (62.2%) of men with low-risk tumors and 46.4% with limited life expectancies received recommendations from their urologists to forgo definitive treatment. Among men with limited life expectancies, those with low-risk tumors were more likely to receive this recommendation compared with men with high-risk tumors (odds ratio [OR] 3.41; 95% confidence interval [CI] 2.17-5.37). Men with low-risk tumors who were recommended to forgo definitive treatment were less likely to receive definitive treatment (OR 0.48; 95% CI 0.32-0.73) but did not report lower perceived quality of care (OR 0.97; 95% CI 0.63-1.48). CONCLUSION: In this population-based study, a majority of men with low-risk prostate cancer report receiving recommendations from their urologists to forgo definitive treatment. Our results suggest that urologists have a strong influence on patient treatment choice and could increase active surveillance uptake in men eligible for expectant management without patients perceiving lower quality of cancer care. PMID- 29477314 TI - Comparison of Percutaneous Nephrolithotomy and Retrograde Intrarenal Surgery for the Treatment of Lower Calyceal Calculi of 2-3 cm in Patients With Solitary Kidney. AB - OBJECTIVE: To compare percutaneous nephrolithotomy (PCNL) and retrograde intrarenal surgery (RIRS) for the treatment of lower calyceal calculi with diameter of 2-3 cm in patients with solitary kidney. METHODS: We retrospectively analyzed 76 cases of calculi in solitary kidney from 3 medical centers in China between April 2013 and October 2016. Among them, 42 cases underwent PCNL, and 34 cases underwent RIRS. RESULTS: The operation time of the PCNL group (82.0 +/- 27.9 minutes) was shorter than the RIRS group (117.2 +/- 23.1 min, P <.001). The intraoperative decrease in hemoglobin of the PCNL group was 5.4 +/- 2.3 g/L, which was significantly higher than the RIRS group (1.8 +/- 0.5 g/L, P <.001). The postoperative hospital stay was 13.9 +/- 1.6 days for PCNL, which was longer than the RIRS group (7.3 +/- 1.2 days, P < .001). PCNL achieved 85.7% (36 of 42) on 1-session stone-free rate, whereas RIRS group was 58.8% (20 of 34, P = .008). The overall stone-free rates were 92.86% (39 of 42) and 85.29% (29 of 34) for PCNL and RIRS, respectively (P >.05). The postoperative complication rate was similar between the RIRS group and the PCNL group. CONCLUSION: For patients with solitary kidney, PCNL achieved a higher 1-session stone-free rate than RIRS in the treatment of lower calyceal calculi within 2-3 cm in diameter. However, RIRS, with less bleeding and shorter postoperative hospital stay, may be an alternative. PMID- 29477315 TI - Emotional and cognitive influences in air traffic controller tasks: An investigation using a virtual environment? AB - Air traffic controllers are required to perform complex tasks which require attention and high precision. This study investigates how the difficulty of such tasks influences emotional states, cognitive workload and task performance. We use quantitative and qualitative measurements, including the recording of pupil dilation and changes in affect using questionnaires. Participants were required to perform a number of air traffic control tasks using the immersive human accessible Virtual Reality space in the "eXperience Induction Machine". Based on the data collected, we developed and validated a model which integrates personality, workload and affective theories. Our results indicate that the difficulty of an air traffic control task has a direct influence on cognitive workload as well as on the self-reported mood; whereas both mood and workload seem to change independently. In addition, we show that personality, in particular neuroticism, affects both mood and performance of the participants. PMID- 29477316 TI - The effect of parallax on eye fixation parameter in projection-based stereoscopic displays. AB - The promising technology of stereoscopic displays is interesting to explore because 3D virtual applications are widely known. Thus, this study investigated the effect of parallax on eye fixation in stereoscopic displays. The experiment was conducted in three different levels of parallax, in which virtual balls were projected at the screen, at 20 cm and 50 cm in front the screen. The two important findings of this study are that parallax has significant effects on fixation duration, time to first fixation, number of fixations, and accuracy. The participant had more accurate fixations, fewer fixations, shorter fixation durations, and shorter times to first fixation when the virtual ball was projected at the screen than when it was projected at the other two levels of parallax. PMID- 29477317 TI - Putting into practice error management theory: Unlearning and learning to manage action errors in construction. AB - Error management theory is drawn upon to examine how a project-based organization, which took the form of a program alliance, was able to change its established error prevention mindset to one that enacted a learning mindfulness that provided an avenue to curtail its action errors. The program alliance was required to unlearn its existing routines and beliefs to accommodate the practices required to embrace error management. As a result of establishing an error management culture the program alliance was able to create a collective mindfulness that nurtured learning and supported innovation. The findings provide a much-needed context to demonstrate the relevance of error management theory to effectively address rework and safety problems in construction projects. The robust theoretical underpinning that is grounded in practice and presented in this paper provides a mechanism to engender learning from errors, which can be utilized by construction organizations to improve the productivity and performance of their projects. PMID- 29477318 TI - Impact of SCBA size and firefighting work cycle on firefighter functional balance. AB - Slips, trips and falls are leading causes of fireground injuries. A functional balance test (FBT) was used to investigate the effects of self-contained breathing apparatus (SCBA) size and design, plus firefighting work cycle. During the FBT, subjects walked along a narrow platform and turned in defined spaces, with and without an overhead obstacle. Thirty firefighters wore three varying sized standard SCBAs and a low-profile prototype SCBA during three simulated firefighting work/rest cycles. Firefighters were tested pre- and post firefighting activity (one bout, two bouts with a 5-min break, or back-to-back bouts with no break). Subjects committed more errors and required longer completion times with larger SCBAs. Use of the prototype SCBA lead to lower times and fewer errors. Performing a second bout of firefighting increased completion time. Firefighters need to consider how SCBA and amount of physical activity on the fireground may influence balance in order to reduce the risk of injury. PMID- 29477319 TI - Cue utilisation reduces effort but increases arousal during a process control task. AB - Process control environments are characterised by rapid changes in work demands, the successful response to which is dependent upon the availability of cognitive resources. Since high cue utilisation is associated with a reduction in cognitive load and a consequent release of residual resources, it was hypothesised that participants with high cue utilisation would experience lower subjective arousal and lower physiological effort in response to increases in the work demands associated with a simulated rail control task. A total of 41 participants completed a 10 min, low work demand period, followed by a 10 min, high work demand condition. High cue utilisation was associated with a reduction in systolic blood pressure and the maintenance of sustained, superior performance in response to high work demands. However, an increase in subjective arousal was also evident. The outcomes have implications for the selection and assessment of operators of high reliability, dynamic, process control environments. PMID- 29477320 TI - Musculoskeletal discomfort and use of computers in the university environment. AB - This cross-sectional study investigated musculoskeletal discomfort and computer use in university staff, through the use of online questionnaires. Results showed a high prevalence of staff reported musculoskeletal discomfort during the preceding year (80%), with neck (60%), shoulder (53%) and lower back discomfort (47%) being the most common. Most believed discomfort was caused by work, although neck discomfort was significantly less in those reporting excellent mental health (OR 0.44, p < 0.01). Computer navigation was performed primarily by mouse (77%); however, using a touch pad increased the odds (OR 1.17, p < 0.01) of wrist discomfort and the belief it was caused by work (OR 1.19, p < 0.01). Few staff attended ergonomic training (16%) or requested workstation assessments (26%). However, high rates of staff reporting musculoskeletal discomfort sought professional treatment (range: 35.2% wrist/hand to 65.0% shoulder). Strategies are needed to address uptake of preventive measures and reduce reliance on medical treatments following musculoskeletal discomfort in universities. PMID- 29477321 TI - The effect of navigation display clutter on performance and attention allocation in presentation- and simulator-based driving experiments. AB - Display clutter can have differential effects based on environmental factors, such as workload, stress, and experiment paradigm. The objectives of the current study were to assess the effects of display clutter on driver performance and attention allocation and compare results across two experimental paradigms. Forty two participants searched high- and low-clutter in-car navigation displays for routine information either during a static, presentation-based experiment or in a dynamic, driving simulator experiment. Results revealed display clutter to significantly alter attention allocation and degrade performance in the presentation experiment, but had little to no effect on driver performance or attention allocation in the driving simulator experiment. Results suggest that display clutter may have its greatest effect on performance and attention allocation in domains requiring extended attention to the cluttered display compared to tasks in which the cluttered display acts as a support tool for secondary tasks. PMID- 29477322 TI - The effect of task type and perceived demands on postural movements during standing work. AB - This study investigated how task demands affect postural behaviour during standing. Twenty-four participants completed three different 12-min tasks: (1) a cognitive task that involved answering questions based on a written passage; (2) a light manual assembly task; and (3) standing quietly with no secondary task. The manual task was associated with the lowest amount of postural movement and a more static pose than the other two conditions. Specifically, postural variability of the lumbar (F = 5.8; p = 0.01) and thoracic (F = 4.2; p = 0.03) spine, and fidgets and shifts of the spine (F = 3.2; p = 0.048), were lowest in the manual task. Additionally, individuals perceiving tasks to be more demanding regardless of task type-tended to move less (p = 0.049) than those perceiving lower demands. These findings provide important initial evidence that the type and perceived demands of standing work tasks can affect postural movement. PMID- 29477323 TI - Immersion of virtual reality for rehabilitation - Review. AB - Virtual reality (VR) shows promise in the application of healthcare and because it presents patients an immersive, often entertaining, approach to accomplish the goal of improvement in performance. Eighteen studies were reviewed to understand human performance and health outcomes after utilizing VR rehabilitation systems. We aimed to understand: (1) the influence of immersion in VR performance and health outcomes; (2) the relationship between enjoyment and potential patient adherence to VR rehabilitation routine; and (3) the influence of haptic feedback on performance in VR. Performance measures including postural stability, navigation task performance, and joint mobility showed varying relations to immersion. Limited data did not allow a solid conclusion between enjoyment and adherence, but patient enjoyment and willingness to participate were reported in care plans that incorporates VR. Finally, different haptic devices such as gloves and controllers provided both strengths and weakness in areas such movement velocity, movement accuracy, and path efficiency. PMID- 29477324 TI - Go Deeper, Go Deeper: Understanding submarine command and control during the completion of dived tracking operations. AB - This is a world's first-of-a-kind study providing empirical evidence for understanding submarine control room performance when completing higher and lower demand Dived Tracking (DT) scenarios. A submarine control room simulator was built, using a non-commercial version of Dangerous Waters as the simulation engine. The creation of networked workstations allowed a team of nine operators to perform tasks completed by submarine command teams during DT. The Event Analysis of Systemic Teamwork (EAST) method was used to model the social, task and information networks and describe command team performance. Ten teams were recruited for the study, affording statistical comparisons of how command team roles and level of demand affected performance. Results indicate that command teams can covertly DT a contact differently depending on demand (e.g. volume of contacts). In low demand it was possible to use periscope more often than in high demand, in a 'duck-and-run' fashion. Therefore, the type of information and frequency of particular task completion, was significantly different between the higher and lower demand conditions. This resulted in different operators in the command team experiencing greater demand depending on how the DT mission objective was completed. Potential bottlenecks in the command team were identified and implications are discussed alongside suggestions for future work. PMID- 29477326 TI - Real time relationship between individual finger force and grip exertion on distal phalanges in linear force following tasks. AB - Individual finger force (FF) in a grip task is a vital concern in rehabilitation engineering and precise control of manipulators because disorders in any of the fingers will affect the stability or accuracy of the grip force (GF). To understand the functions of each finger in a dynamic grip exertion task, a GF following experiment with four individual fingers without thumb was designed. This study obtained four individual FFs from the distal phalanges with a cylindrical handle in dynamic GF following tasks. Ten healthy male subjects with similar hand sizes participated in the four-finger linear GF following tasks at different submaximal voluntary contraction (SMVC) levels. The total GF, individual FF, finger force contribution, and following error were subsequently calculated and analyzed. The statistics indicated the following: 1) the accuracy and stability of GF at low %MVC were significantly higher than those at high SMVC; 2) at low SMVC, the ability of the fingers to increase the GF was better than the ability to reduce it, but it was contrary at high SMVC; 3) when the target wave (TW) was changing, all four fingers strongly participated in the force exertion, but the participation of the little finger decreased significantly when TW remained stable; 4) the index finger and ring finger had a complementary relationship and played a vital role in the adjustment and control of GF. The middle finger and little finger had a minor influence on the force control and adjustment. In conclusion, each of the fingers had different functions in a GF following task. These findings can be used in the assessment of finger injury rehabilitation and for algorithms of precise control. PMID- 29477325 TI - The effect of wearing a lumbar belt on biomechanical and psychological outcomes related to maximal flexion-extension motion and manual material handling. AB - Workers with low back pain (LBP) may benefit from wearing a lumbar belt (LB), but the biomechanical and psychological mechanisms involved are not fully understood. Two types of flexible LB (extensible and non-extensible) were compared to a control condition (no LB) regarding pain-related (pain, fear of pain and catastrophizing) and biomechanical (range of motion - ROM) outcomes related to two tasks: maximal trunk flexion-extension and manual material handling. Healthy controls and participants with LBP were tested. During both tasks, the two LBs reduced the lumbar ROM in participants with LBP in the same way as healthy controls. This was observed even at the beginning of the trunk flexion movement, allowing generalization to many work tasks, that is to say tasks performed with small or deep trunk flexion. The two LBs reduced pain, fear of pain and catastrophizing in subjects with LBP. That may help a gradual re-exposure to physical work activities (disability prevention perspective), or maintaining these activities (secondary prevention perspective), following a LBP episode. PMID- 29477327 TI - Paper-cutting operations using scissors in Drury's law tasks. AB - Human performance modeling is a core topic in ergonomics. In addition to deriving models, it is important to verify the kinds of tasks that can be modeled. Drury's law is promising for path tracking tasks such as navigating a path with pens or driving a car. We conducted an experiment based on the observation that paper cutting tasks using scissors resemble such tasks. The results showed that cutting arc-like paths (1/4 of a circle) showed an excellent fit with Drury's law (R2 > 0.98), whereas cutting linear paths showed a worse fit (R2 > 0.87). Since linear paths yielded better fits when path amplitudes were divided (R2 > 0.99 for all amplitudes), we discuss the characteristics of paper-cutting operations using scissors. PMID- 29477328 TI - Tablet form factors and swipe gesture designs affect thumb biomechanics and performance during two-handed use. AB - Tablet computers' hardware and software designs may affect upper extremity muscle activity and postures. This study investigated the hypothesis that forearm muscle activity as well as wrist and thumb postures differ during simple gestures across different tablet form factors and touchscreen locations. Sixteen adult (8 female, 8 male) participants completed 320 tablet gestures across four swipe locations, with various tablet sizes (8" and 10"), tablet orientations (portrait and landscape), swipe orientations (vertical and horizontal), and swipe directions (medial and radial). Three-dimensional motion analysis and surface electromyography measured wrist and thumb postures and forearm muscle activity, respectively. Postures and muscle activity varied significantly across the four swipe locations (p < .0001). Overall, swipe location closest to the palm allowed users to swipe with a more neutral thumb and wrist posture and required less forearm muscle activity. Greater thumb extension and abduction along with greater wrist extension and ulnar deviation was required to reach the target as the target moved farther from the palm. Extensor Carpi Radialis, Extensor Carpi Ulnaris, Flexor Carpi Ulnaris, Extensor Policis Brevis, and Abductor Pollicis Longus muscle activity also increased significantly with greater thumb reach (p < 001). Larger tablet size induced greater Extensor Carpi Radialis, Extensor Carpi Ulnaris, Flexor Carpi Ulnaris, Flexor Carpi Radialis, and Abductor Pollicis Longus muscle activity (p < .0001). The study results demonstrate the importance of swipe locations and suggest that the tablet interface design can be improved to induce more neutral thumb and wrist posture along with lower forearm muscle load. PMID- 29477329 TI - Corrigendum to "Living with an autonomous spatiotemporal home heating system: Exploration of the user experiences (UX) through a longitudinal technology intervention-based mixed-methods approach" [Appl. Ergon. 65 (2017) 286-308]. PMID- 29477330 TI - Fixation distance and fixation duration to vertical road signs. AB - The distance of first-fixation to vertical road signs was assessed in 22 participants while driving a route of 8.34 km. Fixations to road signs were recorded by a mobile eye-movement-tracking device synchronized to GPS and kinematic data. The route included 75 road signs. First-fixation distance and fixation duration distributions were positively skewed. Median distance of first fixation was 51 m. Median fixation duration was 137 ms with a modal value of 66 ms. First-fixation distance was linearly related to speed and fixation duration. Road signs were gazed at a much closer distance than their visibility distance. In a second study a staircase procedure was used to test the presentation-time threshold that lead to a 75% accuracy in road sign identification. The threshold was 35 ms, showing that short fixations to a road signs could lead to a correct identification. PMID- 29477331 TI - Influence of folding mechanism of bicycles on their usability. AB - In this study, foldable bicycles were evaluated in terms of their usability. Four types of folding mechanisms were identified depending on the number of pivots and the pivot axis direction: single lateral pivot (SLP), single vertical pivot, dual lateral pivot, and combined vertical-lateral pivot. Next, four bicycles-one each of these four types-were selected as test specimens. Ten subjects performed folding and unfolding tasks on each of these bicycles, and three-dimensional body motions and ground reaction forces were measured. The maximum trunk flexion angles and maximum increments in the ground reaction force were used as governing parameters for evaluating the comfort level for each bicycle type. The SLP type provided the lowest upper body flexion and ground reaction force and was hence judged to be the most comfortable folding system. Hence, a promising type of easily foldable bicycle was proposed, thereby encouraging its incorporation into public transit systems. PMID- 29477332 TI - Virtual reality sickness questionnaire (VRSQ): Motion sickness measurement index in a virtual reality environment. AB - This study aims to develop a motion sickness measurement index in a virtual reality (VR) environment. The VR market is in an early stage of market formation and technological development, and thus, research on the side effects of VR devices such as simulator motion sickness is lacking. In this study, we used the simulator sickness questionnaire (SSQ), which has been traditionally used for simulator motion sickness measurement. To measure the motion sickness in a VR environment, 24 users performed target selection tasks using a VR device. The SSQ was administered immediately after each task, and the order of work was determined using the Latin square design. The existing SSQ was revised to develop a VR sickness questionnaire, which is used as the measurement index in a VR environment. In addition, the target selection method and button size were found to be significant factors that affect motion sickness in a VR environment. The results of this study are expected to be used for measuring and designing simulator sickness using VR devices in future studies. PMID- 29477333 TI - Measuring mental workload and physiological reactions in marine pilots: Building bridges towards redlines of performance. AB - This paper investigates the effects of shiphandling manoeuvres on mental workload and physiological reactions in ten marine pilots. Each pilot performed four berthings in a ship simulator. Those berthings were differentiated by two factors, level of difficulty and familiarity with the port. Each berthing could also be divided into five phases, three during the execution and two resting periods, one before and one after the execution (dedicated to baseline physiological data collection). Mental workload was measured through two self assessment scales: the NASA TLX and a Likert scale. Power spectral densities on Beta bands 1 and 2 were obtained from EEG. Heart rate and heart rate variability were obtained from ECG. Pupil dilation was obtained from eye tracking. Workload levels were higher as berthings increased in difficulty level and/or the pilots completed the berthings in unfamiliar ports. Responses differed across specific phases of the berthings. Physiological responses could indirectly monitor levels of mental workload, and could be adopted in future applications to evaluate training improvements and performance. This study provides an example of an applied methodology aiming to define an upper redline of task demands in the context of marine pilotage. PMID- 29477334 TI - Inter-rater reliability of direct observations of the physical and psychosocial working conditions in eldercare: An evaluation in the DOSES project. AB - The aim of the study was to develop and evaluate the reliability of the "Danish observational study of eldercare work and musculoskeletal disorders" (DOSES) observation instrument to assess physical and psychosocial risk factors for musculoskeletal disorders (MSD) in eldercare work. During 1.5 years, sixteen raters conducted 117 inter-rater observations from 11 nursing homes. Reliability was evaluated using percent agreement and Gwet's AC1 coefficient. Of the 18 examined items, inter-rater reliability was excellent for 7 items (AC1>0.75) fair to good for 7 items (AC1 0.40-0.75) and poor for 2 items (AC1 0-0.40). For 2 items there was no agreement between the raters (AC1 <0). The reliability did not differ between the first and second half of the data collection period and the inter-rater observations were representative regarding occurrence of events in eldercare work. The instrument is appropriate for assessing physical and psychosocial risk factors for MSD among eldercare workers. PMID- 29477336 TI - Elucidation of the mechanism of changes in the antioxidant function with the aging in the liver of the senescence-accelerated mouse P10 (SAMP10). AB - Senescence-accelerated mice are known to display a variety of deficits and signs of accelerated aging, but the specific mechanisms involved in this process are still unclear. In this study, we examined the expression levels of antioxidant enzymes, transcription factors responsible for the regulation of expression of these enzymes, and mitochondrial proteins in the liver of SAMP10 and SAMR1 mice at 3 and 12 months of age using western blotting analysis. To investigate the amount of oxidative damage to DNA, levels of 8-OHdG were measured in the liver of these mice. At 3 months of age, the levels of catalase, Mn-SOD, GPx, UQCRC2 and COXIV were significantly upregulated in SAMP10 mice compared with that in SAMR1 mice. However, NDUFS3 levels were not significantly different at this young age. In contrast, the expression level of catalase was significantly lower, and the levels of phosphorylated FoxO-1a and UQCRC2 were significantly higher in SAMP10 mice compared to those in SAMR1 mice; however, at 12 months of age, there were no significant differences in Mn-SOD, GPx, total -FoxO-1a, COXIV, and NDUFS3 expression between the two groups of mice. The levels of 8-OHdG in the liver were markedly higher in 12-month-old SAMP10 mice than those in 3-month-old SAMP10 and SAMR1 mice. These results suggest that an increase in number of mitochondria or a collapse in the balance between the levels of complexes I and III results in an increase in the amount of ROS and induces the expression of antioxidant enzymes in the liver of SAMP10 mice at 3 months of age. Although young SAMP10 mice produce a large amount of ROS, they also produce suitable levels of antioxidant enzymes that decompose ROS; consequently accelerated aging does not occur in young SAMP10 mice. In addition to excessive ROS production which is an important cause of aging, the level of catalase was significantly lower in SAMP10 than that in SAMR1 mice. These results suggested that overexpression of ROS and a decrease in the levels of catalase resulted in the accelerated aging observed in older SAMP10 mice. Moreover, the level of phosphorylated FoxO-1a was increased in SAMP10 compared to that in SAMR1 mice though the total amount of FoxO-1a was not significantly different between the two groups in old age. These results suggest that some impairment in the regulation mechanism of FoxO-1a phosphorylation is responsible for abnormal catalase expression and that a significant decrease in the level of catalase with aging decisively affects the metabolic balance of ROS; thus, ROS that cannot be metabolized contributes to the accelerated aging of SAMP10 mice. PMID- 29477335 TI - Out of the Randomness: Correlating Noise in Biological Systems. AB - The study of the dynamics of biological systems requires one to follow relaxation processes in time with micron-size spatial resolution. This need has led to the development of different fluorescence correlation techniques with high spatial resolution and a tremendous (from nanoseconds to seconds) temporal dynamic range. Spatiotemporal information can be obtained even on complex dynamic processes whose time evolution is not forecast by simple Brownian diffusion. Our discussion of the most recent applications of image correlation spectroscopy to the study of anomalous sub- or superdiffusion suggests that this field still requires the development of multidimensional image analyses based on analytical models or numerical simulations. We focus in particular on the framework of spatiotemporal image correlation spectroscopy and examine the critical steps in getting information on anomalous diffusive processes from the correlation maps. We point out how a dual space-time correlative analysis, in both the direct and the Fourier space, can provide quantitative information on superdiffusional processes when these are analyzed through an empirical model based on intermittent active dynamics. We believe that this dual space-time analysis, potentially amenable to mathematical treatment and to the exact fit of experimental data, could be extended to include the rich phenomenology of subdiffusive processes, thereby quantifying relevant parameters for the various motivating biological problems of interest. PMID- 29477337 TI - Fuzziness in Protein Interactions-A Historical Perspective. AB - The proposal that coupled folding to binding is not an obligatory mechanism for intrinsically disordered (ID) proteins was put forward 10 years ago. The notion of fuzziness implies that conformational heterogeneity can be maintained upon interactions of ID proteins, which has a functional impact either on regulated assembly or activity of the corresponding complexes. Here I review how the concept has evolved in the past decade, via increasing experimental data providing insights into the mechanisms, pathways and regulatory modes. The effects of structural diversity and transient contacts on protein assemblies have been collected and systematically analyzed (Fuzzy Complexes Database, http://protdyn-database.org). Fuzziness has also been exploited as a framework to decipher molecular organization of higher-order protein structures. Quantification of conformational heterogeneity opens exciting future perspectives for drug discovery from small molecule-ID protein interactions to supramolecular assemblies. PMID- 29477338 TI - The Cancer Mutation D83V Induces an alpha-Helix to beta-Strand Conformation Switch in MEF2B. AB - MEF2B is a major target of somatic mutations in non-Hodgkin lymphoma. Most of these mutations are non-synonymous substitutions of surface residues in the MADS box/MEF2 domain. Among them, D83V is the most frequent mutation found in tumor cells. The link between this hotspot mutation and cancer is not well understood. Here we show that the D83V mutation induces a dramatic alpha-helix to beta-strand switch in the MEF2 domain. Located in an alpha-helix region rich in beta-branched residues, the D83V mutation not only removes the extensive helix stabilization interactions but also introduces an additional beta-branched residue that further shifts the conformation equilibrium from alpha-helix to beta-strand. Cross database analyses of cancer mutations and chameleon sequences revealed a number of well-known cancer targets harboring beta-strand favoring mutations in chameleon alpha-helices, suggesting a commonality of such conformational switch in certain cancers and a new factor to consider when stratifying the rapidly expanding cancer mutation data. PMID- 29477339 TI - Rapid progression through the cell cycle ensures efficient migration of primordial germ cells - The role of Hsp90. AB - Zebrafish primordial germ cells (PGCs) constitute a useful in vivo model to study cell migration and to elucidate the role of specific proteins in this process. Here we report on the role of the heat shock protein Hsp90aa1.2, a protein whose RNA level is elevated in the PGCs during their migration. Reducing Hsp90aa1.2 activity slows down the progression through the cell cycle and leads to defects in the control over the MTOC number in the migrating cells. These defects result in a slower migration rate and compromise the arrival of PGCs at their target, the region where the gonad develops. Our results emphasize the importance of ensuring rapid progression through the cell cycle during single-cell migration and highlight the role of heat shock proteins in the process. PMID- 29477340 TI - spe-43 is required for sperm activation in C. elegans. AB - Successful fertilization requires that sperm are activated prior to contacting an oocyte. In C. elegans, this activation process, called spermiogenesis, transforms round immobile spermatids into motile, fertilization-competent spermatozoa. We describe the phenotypic and genetic characterization of spe-43, a new component of the spe-8 pathway, which is required for spermiogenesis in hermaphrodites; spe 43 hermaphrodites are self-sterile, while spe-43 males show wild-type fertility. When exposed to Pronase to activate sperm in vitro, spe-43 spermatids form long rigid spikes radiating outward from the cell periphery instead of forming a motile pseudopod, indicating that spermiogenesis initiates but is not completed. Using a combination of recombinant and deletion mapping and whole genome sequencing, we identified F09E8.1 as spe-43. SPE-43 is predicted to exist in two isoforms; one isoform appears to be a single-pass transmembrane protein while the other is predicted to be a secreted protein. SPE-43 can bind to other known sperm proteins, including SPE-4 and SPE-29, which are known to impact spermiogenesis. In summary, we have identified a membrane protein that is present in C. elegans sperm and is required for sperm activation via the hermaphrodite activation signal. PMID- 29477341 TI - Fibrillarin is essential for S-phase progression and neuronal differentiation in zebrafish dorsal midbrain and retina. AB - Fibrillarin (Fbl) is a highly conserved protein that plays an essential role in ribosome biogenesis and more particularly in the methylation of ribosomal RNAs and rDNA histones. In cellular models, FBL was shown to play an important role in tumorigenesis and stem cell differentiation. We used the zebrafish as an in vivo model to study Fbl function during embryonic development. We show here that the optic tectum and the eye are severely affected by Fbl depletion whereas ventral regions of the brain are less impacted. The morphogenesis defects are associated with impaired neural differentiation and massive apoptosis. Polysome gradient experiments show that fbl mutant larvae display defects in ribosome biogenesis and activity. Strikingly, flow cytometry analyses revealed different S-phase profiles between wild-type and mutant cells, suggesting a defect in S-phase progression. PMID- 29477342 TI - Robotic resection of the liver caudate lobe: technical description and initial consideration. AB - INTRODUCTION: Firstly described in 2002, the robotic liver surgery has not spread widely due to its high cost and the lack of a standardized training program. Still being considered as a 'development in progress' technique, it has however a potential to overcome the traditional limitations of the laparoscopic approach in liver interventions. METHODS: We analyzed the postoperative outcomes of 10 patients who had undergone robotic partial resection of the caudate lobe (Spiegel lobe) from March 2014 to May 2016 in order to evaluate the advantages of robotic technique in hands of a young surgeon. RESULTS: The mean operative time was 258min (150-522) and the estimated blood loss 137ml (50-359), in none of the cases a blood transfusion was required. No patient underwent a conversion to open surgery; the overall morbidity was 2/10 (20%) and all the complications occurred (biliary fistula and pleural effusion) did not require a surgical revision. At histological examination, the mean tumour size was 2.63cm and we achieved R0 resection rate of 100%. The 90-day mortality rate was null. The 1-year overall and disease free-survival rates were 100% and 80%, respectively. CONCLUSIONS: Despite several concerns regarding the cost-effectiveness, a fully robotic partial resection of caudate lobe is an advantageous, implementable technique providing promising short-term postoperative outcomes with acceptable benefit risk profile. PMID- 29477343 TI - T cell exhaustion characterized by compromised MHC class I and II restricted cytotoxic activity associates with acute B lymphoblastic leukemia relapse after allogeneic hematopoietic stem cell transplantation. AB - Acute B lymphoblastic leukemia (B-ALL) relapse contributes predominantly to the mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the mechanism of B-ALL relapse after allo-HSCT remains unknown. The eradication of leukemia after allo-HSCT largely relies on graft-versus-leukemia (GVL) effects mediated by donor T cells. T cell exhaustion, characterized by the increased expression of inhibitory receptors and impaired function, may suppress GVL effects. In this study, we evaluated whether T cell exhaustion was involved in B-ALL relapse after allo-HSCT. The results showed that CD4+ and CD8+ T cells exhibited increased coexpression of PD-1 and Tim-3, and compromised proliferative capacity, cytokine production and cytotoxic potentials in relapsed patients. Additionally, T cells at the tumor site were more easily exhausted than T cells in the peripheral blood. Moreover, the reversal of T cell exhaustion might correlate with effective anti-leukemic responses after reinduction. These results suggested that T cell exhaustion was associated with B-ALL relapse after allo HSCT as well as its treatment outcome. PMID- 29477344 TI - Androst-5-ene-3beta,7alpha/beta,17beta-triols, their plasma levels and dependence on the hypothalamic-pituitary-adrenal axis. AB - Androst-5-ene-triols are metabolites of dehydroepiandrosterone, the most abundant steroid hormone in human circulation. Many observations in rodents have demonstrated the anti-inflammatory and immune modulating activity of 7beta hydroxy-androst-5-enes, and on the basis of these experiments androst-5-ene 3beta,7beta,17beta-triol is considered as a potential agent in the treatment of autoimmune diseases. In contrast to the fairly abundant information on the levels and effects of androst-5-ene-triols in experimental animals and of their the pharmacological perspective, little is known about androst-5-ene 3beta,7alpha/beta,17beta-triols circulating in human blood, their regulation by the hypothalamo-pituitary-adrenal axis, or their daily concentration variability. Here we provide some data on androst-5-ene-3beta,7alpha/beta,17beta-triol concentrations under various conditions in men and women. PMID- 29477345 TI - Effects of stanozolol on apoptosis mechanisms and oxidative stress in rat cardiac tissue. AB - Stanozolol is a widely used 17alpha-alkylated anabolic androgenic steroid (AAS) derivative. Despite stanozolol's adverse effects, its effect on oxidative stress parameters and mitochondrial apoptosis pathway is not clearly defined. In our study, thirty four male Sprague-Dawley rats were divided into 5 groups as control (C), vehicle control (VC), steroid (ST), vehicle control-exercise (VCE), and steroid-exercise (STE). Animals were subcutaneously administered stanozolol 5 mg/kg in steroid groups and propylene glycol 1 ml/kg in the vehicle-control groups. On the 28th day-after sacrification, oxidative stress (MDA, GSH, PC, SOD, CAT) and apoptosis parameters (TUNEL, Cytochrome-c) in cardiac tissue were evaluated. Also, blood vessel morphology of cardiac tissue was evaluated with Verhoeff-van Giesen staining. It has been demonstrated that stanozolol administration triggers apoptosis by using TUNEL assay and cytochrome-c immunohistochemical staining intensity, while this effect is significantly reduced in the presence of exercise. In conclusion, the present study demonstrated that stanozolol administration induces apoptosis with increasing PC and CAT levels, while GSH, MDA and SOD parameters do not reveal any significant change. Exercise has a protective role in stanozolol induced oxidative stress and apoptosis. According to Verhoeff-van Giesen staining results for blood vessel morphology assessment, it has been seen that exercise has a protective role on cardiac blood vessels. This mechanism needs further investigations with long term exposure studies for clarifying possible pathways. PMID- 29477346 TI - Role of the ERp57 protein (1,25D3-MARRS receptor) in murine mammary gland growth and development. AB - The protein disulfide isomerase ERp57 (GRp58/PDIA3/1,25D3-MARRS) has been implicated in a multitude of signaling pathways throughout the entire body. Most thoroughly studied for its protein-folding role, ERp57 has also been found to have multiple binding partners, and have significant effects on cellular growth. ERp57 has been studied n the context of several neurodegenerative disorders, metabolic conditions, and can be used as a prognosis marker in certain cancers. One role, as an alternate vitamin D binding receptor, has prompted research in tissues with known vitamin D activity, such as the intestine and bone. Vitamin D has been studied in relation to mammary gland growth and development, but it is not yet known if ERp57 plays an independent role in this tissue. In this study, ERp57 was knocked out in murine mammary gland epithelial cells of 30 4-week old mice. Several markers of mammary gland growth were measured, including number of terminal end buds (TEB), ductal coverage of the fat pad, and ductal extension. It was found the knockout animals had decreased numbers of TEBs (p = 0.019), and decreased ductal extension (p = 0.018) compared to wildtype animals, with no differences in gross body weight. Immunohistochemistry analysis of mammary glands showed ERp57 localized to the apical side of alveolar branches, and on leading edges of TEBs. These results provide further evidence for ERp57 functioning separately to the VDR, and further insights into the roles of ERp57. PMID- 29477347 TI - Performance of a new histology needle for EUS-guided fine needle biopsy: A retrospective multicenter study. AB - OBJECTIVE: Procurement of tissue core biopsy may overcome some of the limitations of EUS-FNA. We aimed at assessing the safety, core procurement yield and diagnostic accuracy of two novel available histology needles. METHODS: Data from consecutive patients with solid lesions who underwent EUS-FNB using the 25G-22G SharkCoreTM needles were retrieved from 4 tertiary-care centers database. RESULTS: 146 patients (mean age 64 +/- 12 years; M/F, 76/68) with 156 lesions (114 pancreatic) were identified. In 83 cases the 22G needle was used. 3.6 +/- 1.2 passes per lesion were performed, without any major complications. A core biopsy was procured in 89.1% of cases. Considering malignant vs. non-malignant disease, the sensitivity, specificity, negative likelihood ratio, positive likelihood ratio, and diagnostic accuracy were 90.2% (95% CI, 83.7-94.3), 100% (95% CI, 87.2-100), 0.099 (95% CI, 0.058-0.170), 60.4 (95% CI, 3.86-947.4), and 92.3% (95% CI, 88.1-96.5). Procurement yield was significantly higher for the 22G (95.2% vs. 82.2%, p = 0.011), despite the fact that more needle passes were performed with the 25G needle (3.8 +/- 1.3 vs. 3.4 +/- 1.0, p = 0.028). CONCLUSIONS: EUS-FNB using the 25G-22G SharkCoreTM needles is able to reach a very good procurement yield and diagnostic accuracy. The 22G-size needle showed superior core procurement and diagnostic capabilities. Large prospective studies are warranted to further evaluate the use of these types of needles. PMID- 29477348 TI - NAFLD and risk of cardiac arrhythmias: Is hyperuricemia a neglected pathogenic mechanism? PMID- 29477349 TI - Long-term outcomes of combined endoscopic resection and chemoradiotherapy for esophageal squamous cell carcinoma with submucosal invasion. AB - BACKGROUND: For esophageal squamous cell carcinoma (ESCC) with submucosal (SM) invasion, surgery is the standard treatment. Definitive chemoradiotherapy (D-CRT) is a less invasive alternative option, but sometimes results in locoregional failure. AIM: To examine whether endoscopic resection for primary lesion removal combined with chemoradiotherapy (ER-CRT) reduces locoregional failure rates in cases of ESCC with SM invasion. METHODS: We retrospectively compared clinical outcomes between ER-CRT and D-CRT in patients diagnosed with ESCC with SM invasion between 2003 and 2014. Twenty-one patients underwent ER-CRT based on a pathological diagnosis, and 43 patients underwent D-CRT based on a clinical diagnosis. RESULTS: Locoregional failure developed in 26% of patients in the D CRT group, and in no patients in the ER-CRT group (p < 0.01). Thus, the 5-year relapse-free survival in the ER-CRT group was significantly more favorable than that in the D-CRT group (85.1% vs 59.2%; p < 0.05), although there was no difference in overall survival (85.1% vs 79.1%) nor in cause-specific survival (90.5% vs 87.2%) between the groups. There were no instances of perforation or hemorrhage associated with ER. CONCLUSION: ER-CRT is a safe and effective treatment strategy and can be considered as a new minimally invasive treatment option for patients with ESCC with SM invasion. PMID- 29477350 TI - Surgical treatment of hip ankylosis due to heterotopic ossification secondary to spinal cord injury. AB - OBJECTIVES: To expose our experience in the diagnostic and surgical treatment of neurogenic heterotopic ossification of the hip. MATERIAL AND METHODS: We designed an observational retrospective descriptive study including 20 patients (30 hips) with neurogenic heterotopic ossification of the hip secondary to spinal cord injury attended in our institution in the last 10 years, with a minimum of one year follow-up. Medical files and imaging studies were reviewed. The study variables analyzed were: type and localization of neurogenic heterotopic ossification, pre-post excision range of motion, level and aetiology of spinal cord injury, ASIA score, smoking history, surgical approach and complications associated with surgery. RESULTS: A total of 20 patients were treated with resection of heterotopic ossification in 30 hips. 16 patients presented ASIA A spinal cord injury and 4 ASIA B spinal cord injury. Preoperatively all the patients had severe ankylosis in the hip that made sitting in a wheel chair and activities such as repositioning and hygiene difficult. The average postoperative motion at the follow-up evaluation was 90 degrees in flexion, 20 degrees of internal rotation and 40 degrees of external rotation. Immediately after surgery all the patients followed a specific intensive physiotherapy regime for the hip and celecoxib 200 mg was administrated daily orally for a month to prevent recurrence of heterotopic bone formation. None of the patients reviewed suffered a recurrence of heterotopic bone formation. CONCLUSIONS: Surgical excision of hip ossification in order to achieve functional ROM of the hip is the best treatment for patients with neurogenic heterotopic ossification of the hip. PMID- 29477351 TI - In situ biomolecule production by bacteria; a synthetic biology approach to medicine. AB - The ability to modify existing microbiota at different sites presents enormous potential for local or indirect management of various diseases. Because bacteria can be maintained for lengthy periods in various regions of the body, they represent a platform with enormous potential for targeted production of biomolecules, which offer tremendous promise for therapeutic and diagnostic approaches for various diseases. While biological medicines are currently limited in the clinic to patient administration of exogenously produced biomolecules from engineered cells, in situ production of biomolecules presents enormous scope in medicine and beyond. The slow pace and high expense of traditional research approaches has particularly hampered the development of biological medicines. It may be argued that bacterial-based medicine has been "waiting" for the advent of enabling technology. We propose that this technology is Synthetic Biology, and that the wait is over. Synthetic Biology facilitates a systematic approach to programming living entities and/or their products, using an approach to Research and Development (R&D) that facilitates rapid, cheap, accessible, yet sophisticated product development. Full engagement with the Synthetic Biology approach to R&D can unlock the potential for bacteria as medicines for cancer and other indications. In this review, we describe how by employing Synthetic Biology, designer bugs can be used as drugs, drug-production factories or diagnostic devices, using oncology as an exemplar for the concept of in situ biomolecule production in medicine. PMID- 29477352 TI - Aspen Plus process-simulation model: Producing biogas from VOC emissions in an anaerobic bioscrubber. AB - A process-simulation model for a novel process consisted of an anaerobic bioscrubber was developed in Aspen Plus(r). A novel approach was performed to implement the anaerobic reactor in the simulation, enabling it to be connected to the scrubber. The model was calibrated and validated using data from an industrial prototype that converted air emissions polluted with volatile organic compounds with an average daily concentration of 1129 mgC Nm-3 into bioenergy for more than one year. The scrubber, which showed a removal efficiency within 83 93%, was successfully predicted with an average absolute relative error of 5.2 +/ 0.08% using an average height-to-theoretical-plate value of 1.05 +/- 0.08 m and 1.37 +/- 0.11 m for each of the two commercial packing materials used, respectively. The anaerobic reactor, which treated up to 24 kg of chemical oxygen demand m-3 d-1 with efficiencies of about 93%, was accurately simulated, both in effluent-stream characteristics and in the biogas stream. For example, the average absolute error between the experimental biogas production and the model values was 19.6 +/- 18.9%. The model proved its capability as a predictive tool and an aid in design, resulting in savings of time and money for practitioners. In addition, the approach proposed can be expanded to other bioprocesses that include unit operations. PMID- 29477353 TI - Full-scale agricultural biogas plant metal content and process parameters in relation to bacterial and archaeal microbial communities over 2.5 year span. AB - A start-up of 4 MW agricultural biogas plant in Vucja vas, Slovenia, was monitored from 2011 to 2014. The start-up was carried out in 3 weeks with the intake of biomass from three operating full-scale 1-2 MW donor agricultural biogas plants. The samples were taken from donor digesters and from two serial digesters during the start-up over the course of 2.5 years. Bacterial and Archaeal microbial communities progressively diverged from the composition of donor digesters during the start-up phase. The rate of change of Bacterial community decreased exponentially over the first 2.5 years as dynamics within the first 70 days was comparable to that of the next 1.5 years, whereas approximately constant rate was observed for Archaea. Despite rearrangements, the microbial communities remained functionally stable and produced biogas throughout the whole 2.5 years of observation. All systems parameters measured were ordered according to their Kernel density (Gaussian function) ranging from the most dispersed (substrate categories used as cosubstrates, quantities of each cosubstrate, substate dry and volatile matter, process parameters) towards progressively least dispersed (trace metal and ion profiles, aromatic-polyphenolic compounds, biogas plant functional output (energy)). No deficiency was detected in trace metal content as the distribution of metals and elements fluctuated within the suggested limits for biogas over 2.5 year observation. In contrast to the recorded process variables, Bacterial and Archaeal microbial communities exhibited directed changes oriented in time. Variation partitioning showed that a large fraction of variability in the Bacterial and Archaeal microbial communities (55% and 61%, respectively) remained unexplained despite numerous measured variables (n = 44) and stable biogas production. Our results show that the observed reorganization of microbial communities was not directly associated with impact on the full-scale biogas reactor performance. Novel parameters need to be determined to elucidate the variables directly associated with the reorganization of microbial communities and those relevant for sustained function such as the more in-depth interaction between TSOC, trace metal profiles, aromatic polyphenolic compounds and ionic strength (e.g. electrical conductivity). PMID- 29477354 TI - Cytokine expression and cytokine-based T-cell profiling in occupational medicamentosa-like dermatitis due to trichloroethylene. AB - Early diagnosis and treatment of occupational medicamentosa-like dermatitis due to trichloroethylene (OMLDT) are absence of specific and reliable diagnostic/therapeutic biomarkers. This study was conducted on 30 cases of OMLDT, 58 workers exposed to trichloroethylene (TCE) and 40 unexposed controls in order to identify any cytokine signatures that give an index to CD4+T cell differential and serve as biomarkers of OMLDT. Expression profiles of Th1, Th2, Th17 and Treg cell type-specifying transcription factors and cytokines were analyzed using real time quantitative PCR (RT-qPCR) assay. To explore whether such expression profiles reflected their steady state plasma levels, a Luminex liquid fluorescence analysis was conducted. We found that the expression of transcription factors FoxP3 transcription factors (P = 0.006 and P < 0.0001) and IL-10 cytokine (P = 0.0008 and P < 0.0001) of the Treg subset were significantly higher in patients than TCE exposure workers and unexposed controls, suggesting that Treg cells were active after the occurrence of OMLDT. The transcript levels of IL-6 were significantly lower in the TCE exposure groups including patients and exposure workers as compared to the unexposed controls (P < 0.0001 and P = 0.0008). Circulating levels of assessed cytokines of IL-6 (P = 0.001 and P = 0.011) and TFN-alpha (P = 0.005 and P < 0.0001) were lower in the exposure groups than in the unexposed controls. Compared to the controls, the levels of IL-10 in patients were higher (P = 0.001 and P = 0.0008). There was a significantly positive correlation between the plasma levels IL-6 and IL-10 in TCE exposed workers. These alterations in the expression of transcription factors and cytokines highlight the underlying dysregulation of T cell subsets in OMLDT that reflect an immune tolerance or immune inhibition. Therefore, the elevation of IL 10 level may be a kind of pathogenesis indicator, and the decline in IL-6 level may be a kind of TCE exposure biomarker. These biomarkers need additional longitudinal follow-up studies to warrant to clinically useful biomarkers of OMLDT. PMID- 29477355 TI - Histopathological differences in patients with biopsy-proven non-alcoholic fatty liver disease with and without type 2 diabetes. AB - BACKGROUND AND AIMS: Prevalence of non-alcoholic fatty liver disease (NAFLD) in developed countries is 30% in the general population and 50% in patients with type 2 diabetes mellitus (T2DM). The aim of this study was to compare the severity of NAFLD, as assessed by liver biopsy and using the non-invasive index NAFLD Fibrosis Score (NFS), in subjects with and without T2DM. PATIENTS AND METHODS: The study sample consisted of 217 patients with biopsy-proven NAFLD. Anthropometric assessments, laboratory tests, histological criteria established by the Non-alcoholic Steatohepatitis Clinical Research Network (NASH CRN), and the NFS were recorded. RESULTS: Patients with T2DM (n=36; 16.5%) had higher HOMA IR values (6.3+/-3.6 vs. 3.3+/-2.4; p<0.0001), GGT levels (125.2+/-102.3 vs. 82.5+/-70.6IU/l; p<005), and NFS index (-0.6+/-0.2 vs. -1.8+/-0.1; p<0.001) than subjects with no T2DM. Patients with T2DM were found higher rates of NASH (72.2% vs. 48.6%; p<0.05), advanced steatosis (80.6% vs. 63%; p<0.05), and liver fibrosis (75% vs. 43.1%, p<0.05) than patients with no T2DM. Patients with T2DM also had higher NFS values (-0.6+/-1.2 vs. -1.8+/-1.8: p=0.01). A logistic regression analysis adjusting for age, gender and BMI showed a significant independent association between NASH and presence of T2DM (OR=4.2: 95% CI: 1.4 12.1; p=0.007). A second model adjusting for the same covariates showed T2DM to be an independent factor associated to advanced fibrosis (OR=4.1; 95% CI: 1.7 9.7). CONCLUSION: Patients with T2DM have more advanced degrees of NAFLD and advanced fibrosis as assessed by liver biopsy and the NFS index. Particular attention should be paid to the study and monitoring of NASH in patients with T2DM. PMID- 29477356 TI - Simultaneous controlled iontophoretic delivery of pramipexole and rasagiline in vitro and in vivo: Transdermal polypharmacy to treat Parkinson's disease. AB - Effective treatment of Parkinson's disease (PD) involves administration of therapeutic agents with complementary mechanisms of action in order to replenish, sustain or substitute endogenous dopamine. The objective of this study was to investigate anodal co-iontophoresis of pramipexole (PRAM; dopamine agonist) and rasagiline (RAS; MAO-B inhibitor) in vitro and in vivo. Passive permeation of PRAM and RAS (20 mM each) across porcine skin after 6 h was 15.7 +/- 1.9 and 16.0 +/- 2.9 ug/cm2, respectively. Co-iontophoresis at 0.15, 0.3 and 0.5 mA/cm2 resulted in statistically significant increases in delivery of PRAM and RAS; at 0.5 mA/cm2, cumulative permeation of PRAM and RAS was 613.5 +/- 114.6 and 441.1 +/- 169.2 ug/cm2, respectively - corresponding to 38- and 27-fold increases over passive diffusion. Electromigration was the dominant mechanism for both molecules (>80%) and there was no effect on convective solvent flow. Statistically equivalent delivery was observed with human skin. The co-iontophoretic system showed high delivery efficiency with 29% and 35% of the applied amounts of PRAM and RAS being delivered. Preliminary pharmacokinetics studies in rats confirmed that the input rate in vivo was such that therapeutic amounts of the two drugs could be co-administered to humans by transdermal iontophoresis using reasonably sized patches and moderate current densities. PMID- 29477357 TI - In-situ determination of crystallization kinetics in ASDs via water sorption experiments. AB - Amorphous solid dispersions (ASD) are intended to improve the bioavailability of poorly water-soluble active pharmaceutical ingredients. However, the development of long-term stable ASDs is often limited by the unwanted crystallization of the incorporated active pharmaceutical ingredient. Robust detection and quantification of crystal formation - especially at temperatures and humidites relevant for long-term storage tests - are essential for understanding crystallization phenomena. In this work, the crystallization kinetics in spray dried nifedipine/poly (vinyl acetate) ASDs was investigated by measuring the time dependent water sorption behavior at constant storage conditions. By coupling these experiments with thermodynamic predictions of the water sorption in amorphous and crystallized ASDs using the Perturbed-Chain Statistical Associating Fluid Theory, the amount of crystallized nifedipine as function of time could be determined in-situ just by weighing the ASD samples and without any calibration. The experimental findings were validated by X-ray diffraction measurements. Metastable ASDs with nifedipine contents between 70 wt% and 90 wt% were investigated at relative humidities between 60% RH and 90% RH and in a temperature range between 30 degrees C and 40 degrees C. Storage at high temperature and at high RH, and high nifedipine contents dramatically increased the crystallization rates. PMID- 29477360 TI - mROS-TXNIP axis activates NLRP3 inflammasome to mediate renal injury during ischemic AKI. AB - Ischemia/reperfusion (I/R) is a critical risk factor for acute kidney injury (AKI). Recent studies provided evidence that tubular epithelial cells (TEC) associated inflammation aggravates kidney injury and impairs tissue repair after I/R injury. Here we demonstrated that the Nod-like receptor protein 3 (NLRP3) inflammasome is activated by mitochondrial reactive oxygen species (mROS) during I/R injury via direct interactions between the inflammasome and thioredoxin interacting protein (TXNIP). Firstly, we found that NLRP3 inflammasome activation was induced by I/R injury, peaking at day 3 after reperfusion. Consistent with this observation, NLRP3 deletion significantly attenuated I/R-induced kidney damage and markers of inflammasome activation. Then, we observed mitochondrial dysfunction, characterized by ultrastructural changes and cytochrome C (Cyt c) redistribution. Mitochondria-targeted antioxidant MitoTEMPO prevented mROS overproduction and the decline in mitochondrial membrane potential (MMP) in vitro. MitoTEMPO treatment also inhibited NLRP3 inflammasome activation and co localization of NLRP3 and TXNIP after simulated ischemia/reperfusion (SI/R) injury. Finally, we transfected HK-2 cells with TXNIP siRNA to explore the role of TXNIP in mROS-induced NLRP3 inflammasome activation. We found that TXNIP siRNA significantly inhibited NLRP3 inflammasome activation. These results demonstrate that NLRP3 inflammasome is activated through the mROS-TXNIP-NLRP3 pathway and provide a potential therapeutic target in ischemic AKI. PMID- 29477359 TI - Contribution of membrane receptor signalling to chronic visceral pain. AB - Irritable bowel syndrome and inflammatory bowel disease are major forms of chronic visceral pain, which affect over 15% of the global population. In order to identify new therapies, it is important to understand the underlying causes of chronic visceral pain. This review provides recent evidence demonstrating that inflammation or infection of the gastrointestinal tract triggers specific changes in the neuronal excitability of sensory pathways responsible for the transmission of nociceptive information from the periphery to the central nervous system. Specific changes in the expression and function of a variety of ion channels and receptors have been documented in inflammatory and chronic visceral pain conditions relevant to irritable bowel syndrome and inflammatory bowel disease. An increase in pro-nociceptive mechanisms enhances peripheral drive from the viscera and provides an underlying basis for enhanced nociceptive signalling during chronic visceral pain states. Recent evidence also highlights increases in anti-nociceptive mechanisms in models of chronic visceral pain, which present novel targets for pharmacological treatment of this condition. PMID- 29477358 TI - Exposure of the HIV-1 broadly neutralizing antibody 10E8 MPER epitope on the membrane surface by gp41 transmembrane domain scaffolds. AB - The 10E8 antibody achieves near-pan neutralization of HIV-1 by targeting the remarkably conserved gp41 membrane-proximal external region (MPER) and the connected transmembrane domain (TMD) of the HIV-1 envelope glycoprotein (Env). Thus, recreating the structure that generates 10E8-like antibodies is a major goal of the rational design of anti-HIV vaccines. Unfortunately, high-resolution information of this segment in the native Env is lacking, limiting our understanding of the behavior of the crucial 10E8 epitope residues. In this report, two sequences, namely, MPER-TMD1 (gp41 residues 671-700) and MPER-TMD2 (gp41 residues 671-709) were compared both experimentally and computationally, to assess the TMD as a potential membrane integral scaffold for the 10E8 epitope. These sequences were selected to represent a minimal (MPER-TMD1) or full-length (MPER-TMD2) TMD membrane anchor according to mutagenesis results reported by Yue et al. (2009) J. Virol. 83, 11,588. Immunochemical assays revealed that MPER TMD1, but not MPER-TMD2, effectively exposed the MPER C-terminal stretch, harboring the 10E8 epitope on the surface of phospholipid bilayers containing a cholesterol concentration equivalent to that of the viral envelope. Molecular dynamics simulations, using the recently resolved TMD trimer structure combined with the MPER in a cholesterol-enriched model membrane confirmed these results and provided an atomistic mechanism of epitope exposure which revealed that TMD truncation at position A700 combined with N-terminal addition of lysine residues positively impacts epitope exposure. Overall, these results provide crucial insights into the design of effective MPER-TMD derived immunogens. PMID- 29477361 TI - Antioxidant responses of edible and model plant species subjected to subtoxic zinc concentrations. AB - Zinc (Zn) is a common heavy metal in polluted soils, as it is a widespread pollutant deriving both from natural sources and anthropogenic activities. The antioxidant tolerance/defence mechanisms against oxidative stress induced by subtoxic concentrations of Zn (50 and 150 MUM ZnSO4) were studied in a widespread edible plant (lettuce; Lactuca sativa L.) and in an important model plant (Arabidopsis thaliana (L.) Heynh.). After 10 days (Arabidopsis) and 20 days (lettuce) of Zn exposure, Zn uptake/translocation was evaluated in both roots and shoots, while indicators of oxidative stress and stress intensity, total antioxidant capacity, and enzymatic and non-enzymatic antioxidative defence were measured in leaves. From an overall comparison of the two species, Zn root uptake in Arabidopsis subjected to 50 and 150 MUM ZnSO4 was approximately 3- and 5-fold lower than in lettuce, while Zn translocation from roots to apical leaves was more efficient in Arabidopsis (23.7 vs 21.3% at 50 MUM ZnSO4 and 19.3 vs 12.9% at 150 MUM ZnSO4). Generally, a higher degree of Zn-induced oxidative stress (863.8 vs 21.3 MUg g-1 FW H2O2 and 1.33 vs 0.75 MUM g-1 FW MDAeq at 150 MUM ZnSO4) and antioxidant response (441.2 vs 258.5 mM g-1 FW TEAC and 91.0 vs 54.9% RSA at 150 MUM ZnSO4) were found in lettuce. The aim of this study is understanding (a) if subtoxic Zn levels can affect Zn uptake and translocation in the studied species and (b) if this eventual Zn absorption can influence plant oxidative status/antioxidant response. Considering that soil contamination by Zn can affect crop production and quality, the results of this research could be important for environmental, nutritional and human health issues. PMID- 29477362 TI - Evaluating guideline adherence regarding empirical vancomycin use in patients with neutropenic fever. AB - OBJECTIVE: The purpose of this study was to evaluate the use of empirical vancomycin for patients with neutropenic fever (NF) with regard to adherence to treatment guidelines. METHODS: Adult patients with a diagnosis of neutropenia, who met the definition of NF as per treatment guidelines, were identified. Use of vancomycin was evaluated as part of empirical therapy and again after 72h. Outcomes were assessed using descriptive statistics, the Chi-square or Fisher's exact test, and univariate exact logistic regression analyses. RESULTS: Sixty four patients were included. Overall, inappropriate empirical vancomycin use was observed in more than 30% of patients. Of 35 patients with indications for empirical vancomycin, only 68% received it. At 72h, appropriate vancomycin continuation, de-escalation, or discontinuation occurred in 21 of 33 patients. On univariate regression, hematological malignancy was associated with appropriate empirical vancomycin prescribing, whether initiating or withholding (odds ratio 4.0, 95% confidence interval 1.31-12.1). No variable was independently associated with inappropriate continuation at 72h. CONCLUSIONS: There is poor guideline adherence to vancomycin prescribing as empirical therapy and at 72-h reassessment in patients with NF. Further efforts are needed to foster a more rational use of vancomycin in patients with NF. PMID- 29477363 TI - A case-report of a pulmonary tuberculosis with lymphadenopathy mimicking a lymphoma. AB - Clinical and radiological manifestations of tuberculosis (TB) are heterogeneous, and differential diagnosis can include both benign and malignant diseases (e.g., sarcoidosis, metastatic diseases, and lymphoma). Diagnostic dilemmas can delay appropriate therapy, favoring Mycobacterium tuberculosis transmission. We report on a case of TB in an immunocompetent, Somalian 22-year-old boy admitted in the respiratory unit of an Italian university hospital. His symptoms and clinical signs were thoracic pain, weight loss, latero-cervical, mediastinal, and abdominal lymphadenopathy. Smear microscopy and PCR were negative for Mycobacterium tuberculosis. The unclear histological pattern, the unusual clinical presentation, the CT scan signs, the BAL lymphocytes suggested the suspicion a lymphoma. Culture conversion proved Mycobacterium tuberculosis infection. This case report highlights the risk of misdiagnosis in patients with generalized lympho-adenopathy and pulmonary infiltrates, particularly in Africans young patients. PMID- 29477364 TI - Ghrelin protects against depleted uranium-induced bone damage by increasing osteoprotegerin/RANKL ratio. AB - Depleted uranium (DU) is widely used in military and civil activities, and bone is the main target organ of chronic DU toxicity. The aim of this study was to evaluate the effects of ghrelin on rats implanted with DU and explore the underlying mechanisms. The results showed that ghrelin could increase the expression of ghrelin receptor in bone tissue, thus alleviate the apoptosis of bone tissue after 3 months of 0.3 g DU embedded in the tibia. Micro-computed tomography examination showed that after DU implantation, the density of cortical bone showed no significant difference, but the trabecular bone decreased in amount, density and connectivity. Ghrelin treatment can significantly reduce the changes caused by DU. Moreover, ghrelin can inhibit the increase of serum tartrate resistant acid phosphatase and the decrease of alkaline phosphatase and osteocalcin. Furthermore, ghrelin can also significantly reduce the receptor activator of nuclear factor kappaB ligand (RANKL) and phosphorylated p38-MAPK expression, and increase the level of osteoprotegerin (OPG) in tissues after exposure to DU. Based on cell experimental research, p38-MAPK specific agonist can reverse the function of ghrelin, significantly inhibit the level of OPG and increase the level of RANKL. On the contrary, the use of p38-MAPK specific inhibitor or p38-MAPK siRNA can enhance the function of ghrelin. These results suggest that ghrelin may inhibit p38 MAPK activation induced by DU, and increase the OPG/RANKL ratio caused by DU exposure, hence alleviating the bone damage caused by long-term DU exposure. PMID- 29477365 TI - Best Response According to RECIST During First-line EGFR-TKI Treatment Predicts Survival in EGFR Mutation-positive Non-Small-cell Lung Cancer Patients. AB - INTRODUCTION: The association between the response to first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and survival in EGFR mutation-positive non-small-cell lung cancer (NSCLC) remains unclear. We studied the association between the response to first-line EGFR-TKIs and survival using Response Evaluation Criteria In Solid Tumors (RECIST) and maximal tumor shrinkage. MATERIALS AND METHODS: We analyzed data from patients with advanced EGFR mutation-positive NSCLC enrolled in first-line gefitinib and afatinib trials. A total of 98 patients who achieved a response or stable disease and had >= 1 measurable target lesion were included. The association between the best response by RECIST or maximal tumor shrinkage and survival was analyzed in Kaplan Meier and Cox regression models with the landmark method. The specified landmark time points were 8 weeks, the median time to maximal tumor shrinkage (16.5 weeks), and median progression-free survival (PFS; 56 weeks). RESULTS: A total of 76 patients (77%) responded to gefitinib or afatinib. Of these 76 patients, 49 (64%) and 75 (99%) had achieved a response at 8 and 16.5 weeks, respectively. All responders had achieved a response by 56 weeks. The responders had a significantly longer PFS and overall survival (OS) compared with those with stable disease at 16.5 weeks (PFS, P = .003; OS, P < .001) and 56 weeks (PFS, P = .026; OS, P = .016) but not at 8 weeks (PFS, P = .104; OS, P = .313). Among the responders, greater tumor shrinkage was not associated with longer PFS or OS. CONCLUSION: Those with a response to first-line gefitinib or afatinib had more favorable PFS and OS compared with those with stable disease. A sufficient observation period was required for the response to occur and predict outcomes. Greater maximal tumor shrinkage in the responders was not predictive of survival. PMID- 29477366 TI - Pathogenic mechanism of a catecholaminergic polymorphic ventricular tachycardia causing-mutation in cardiac calcium release channel RyR2. AB - Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a condition that is characterized by an abnormal heart rhythm in response to physical or emotional stress. The majority CPVT patients carry mutations in the RYR2 gene that encodes the calcium release channel/ryanodine receptor (RyR2) in cardiomyocytes. The pathogenic mechanisms that account for the clinical phenotypes of CPVT are still elusive. We have identified a de novo mutation, A165D, from a CPVT patient. We found that CPVT phenotypes are recapitulated in A165D knock-in mice. The mutant RyR2 channels enhanced sarcoplasmic reticulum Ca2+ release, triggered delayed afterdepolarization in cardiomyocytes. Structural analysis revealed that the A165D mutation is located in a loop that is involved in inter-subunit interactions in the RyR2 tetrameric structure, it disrupted conformational stability of the RyR2, which favored a closed-to-open state transition, resulting in a leaky channel. The loop also harbors several other CPVT mutations, which suggests a common pathogenic molecular mechanism of CPVT-causing mutations. Our data illustrated disease-relevant functional defects and provide a deeper mechanistic understanding of a life-threatening cardiac arrhythmia. PMID- 29477367 TI - Dose-dependent toxicity of ipilimumab in metastatic melanoma. PMID- 29477368 TI - Concurrent radiotherapy and nivolumab in metachronous metastatic primary adenosquamous-cell carcinoma of the prostate. PMID- 29477369 TI - Medicinal plants used by the people of Nsukka Local Government Area, south eastern Nigeria for the treatment of malaria: An ethnobotanical survey. AB - ETHNOBOTANICAL RELEVANCE: Malaria is a serious public health problem especially in sub-Saharan African countries such as Nigeria. The causative parasite is increasingly developing resistance to the existing drugs. There is urgent need for alternative and affordable therapy from medicinal plants which have been used by the indigenous people for many years. AIM OF STUDY: This study was conducted to document the medicinal plant species traditionally used by the people of Nsukka Local Government Area in south-eastern Nigeria for the treatment of malaria. METHODS: A total of 213 respondents, represented by women (59.2%) and men (40.8%), were interviewed using a semi-structured questionnaire. The results were analysed and discussed in the context of previously published information on anti-malarial and phytochemical studies of the identified plants. RESULTS: The survey revealed that 50 plant species belonging to 30 botanical families were used in this region for the treatment of malaria. The most cited families were Apocynaceae (13.3%), Annonaceae (10.0%), Asteraceae (10.0%), Lamiaceae (10.0%), Poaceae (10.0%), Rubiaceae (10.0%) and Rutaceae (10.0%). The most cited plant species were Azadirachta indica (11.3%), Mangifera indica (9.1%), Carica papaya (8.5%), Cymbopogon citratus (8.5%) and Psidium guajava (8.5%). CONCLUSION: The present findings showed that the people of Nsukka use a large variety of plants for the treatment of malaria. The identified plants are currently undergoing screening for anti-malarial, toxicity and chemical studies in our laboratory. PMID- 29477370 TI - The BMP pathway: A unique tool to decode the origin and progression of leukemia. AB - The microenvironment (niche) governs the fate of stem cells (SCs) by balancing self-renewal and differentiation. Increasing evidence indicates that the tumor niche plays an active role in cancer, but its important properties for tumor initiation progression and resistance remain to be identified. Clinical data show that leukemic stem cell (LSC) survival is responsible for disease persistence and drug resistance, probably due to their sustained interactions with the tumor niche. Bone morphogenetic protein (BMP) signaling is a key pathway controlling stem cells and their niche. BMP2 and BMP4 are important in both the normal and the cancer context. Several studies have revealed profound alterations of the BMP signaling in cancer SCs, with major deregulations of the BMP receptors and their downstream signaling elements. This was illustrated in the hematopoietic system by pioneer studies in chronic myelogenous leukemia that may now be expanded to acute myeloid leukemia and lymphoid leukemia, as reviewed here. At diagnosis, cells from the leukemic microenvironment are the major providers of soluble BMPs. Conversely, LSCs display altered receptors and downstream BMP signaling elements accompanied by altered functional responses to BMPs. These studies reveal the role of BMPs in tumor initiation, in addition to their known effects in later stages of transformation and progression. They also reveal the importance of BMPs in fueling cell transformation and expansion by overamplifying a natural SC response. This mechanism may explain the survival of LSCs independently of the initial oncogenic event and therefore may be involved in resistance processes. PMID- 29477371 TI - Venetoclax: A new wave in hematooncology. AB - Inhibitors of antiapoptotic proteins of the BCL2 family can successfully restart the deregulated process of apoptosis in malignant cells. Whereas nonselective agents have been limited by their affinity to different BCL2 members, thus inducing excessive toxicity, the highly selective BCL2 inhibitor venetoclax (ABT 199, VenclextaTM) has an acceptable safety profile. To date, it has been approved in monotherapy for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) with 17p deletion. Extension of indications can be expected in monotherapy and in combination regimens. Sensitivity to venetoclax is not common in lymphomas, but promising outcomes have been achieved in the mantle cell lymphoma group. Venetoclax is also active in multiple myeloma patients, especially in those with translocation t(11;14), even if high-risk features such as del17p are also present. Surprisingly, positive results are being obtained in elderly acute myeloid leukemia patients, in whom inhibition of BCL2 is able to substantially increase the efficacy of low-dose cytarabine or hypomethylating agents. Here, we provide a summary of available results from clinical trials and describe a specific mechanism of action that stands behind the efficacy of venetoclax in hematological malignancies. PMID- 29477372 TI - Computer-assisted cognitive rehabilitation in persons with multiple sclerosis: Results of a multi-site randomized controlled trial with six month follow-up. AB - BACKGROUND: The effects of multiple sclerosis (MS) on cognition have gained increasing recognition as one of the major disabling symptoms of the disease. Despite the prevalence of these symptoms and their impact on quality of life, limited attention has been given to strategies that might help manage the cognitive changes commonly experienced by persons with MS. OBJECTIVE: The primary purpose of this study was to determine the effectiveness of a novel computer assisted cognitive rehabilitation intervention MAPSS-MS (Memory, Attention, Problem Solving Skills in MS) in a multi-site trial with persons with MS. METHODS: Persons with MS (N = 183) with cognitive concerns were randomly assigned to either the 8-week MAPSS-MS intervention or usual care plus freely available computer games. Participants completed self-report and performance measures of cognitive functioning, compensatory strategies and depression at baseline, immediately after the MAPSS-MS intervention, and three and six months post intervention. Changes in study outcomes were analyzed using intention to treat methodology, ANOVA with repeated measures, and ANCOVA. RESULTS: Both groups improved significantly on all outcome measures. The intervention group outperformed the comparison group on all measures, and there were statistically significant differences on selected measures. CONCLUSION: Findings suggest that MAPSS-MS is a feasible intervention that could be broadly implemented in community settings. It has been shown to be modestly successful in improving cognitive functioning. PMID- 29477373 TI - Comparing SGLT-2 inhibitors to DPP-4 inhibitors as an add-on therapy to metformin in patients with type 2 diabetes: A systematic review and meta-analysis. AB - AIMS: Our aim was to compare Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) to Dipeptidyl peptidase-4 inhibitors (DPP-4i) as add-on therapy to metformin. METHODS: We searched for randomized trials comparing SGLT-2i to DPP-4i as add-on therapy to metformin in Type 2 diabetes.We pooled trials reporting outcomes between 12 and 26 weeks together while trials reporting results >=52 weeks were pooled together. The primary outcomes were the change in haemoglobin A1c (A1c) at <=26 and >=52 weeks. Sensitivity analyses were performed according to the dose of SGLT-2i and according to baseline A1c for the primary outcomes. RESULTS: Seven trials met our inclusion criteria. There was a statistically significant reduction in A1c at >=52 weeks favouring SGLT-2i compared to DPP-4i (MD [95% CI]= 0.11% [-0.20, -0.03]) but no significant difference at <=26 weeks (MD [95% CI]= 0.05% [-0.16, 0.05]). SGLT-2i caused significantly more weight loss compared to DPP-4i at <=26 weeks and >=52 weeks (MD [95% CI]=-2.31kg [-2.66, -1.96] and 2.45kg [-2.83, -2.07], respectively). SGLT-2i treated patients had a significantly more genital infection compared to DPP-4i. On restricting the analysis according to the SGLT-2i FDA-approved dose, only higher doses at >=52 weeks showed a statistically significant reduction in A1c compared to DPP-4i. On restricting the analysis according to baseline A1c, results favoured DPP-4i if baseline A1c was<8.5%, but favoured SGLT-2i if >=8.5%. CONCLUSION: While both SGLT-2i and DPP-4i can reduce A1c, SGLT-2i causes a more robust A1c reduction and more weight loss but with more genital infections. Higher doses of SGLT-2i showed more efficacy when compared to DPP-4i; however, this data should be interpreted cautiously given the limited number of trials. PMID- 29477374 TI - Comment on: effect of bariatric surgery on urinary sphingolipids in adolescents with severe obesity. PMID- 29477375 TI - Comment on: the incidence of complications associated with loop duodeno-ileostomy after single-anastomosis duodenal switch procedures among 1328 patients: a multicenter experience. PMID- 29477376 TI - Is preoperative gastroscopy necessary before sleeve gastrectomy and Roux-en-Y gastric bypass? AB - BACKGROUND: Consensus on the necessity of esophagogastroduodenoscopy (EGD) before bariatric surgery is lacking. Recommendations and practices vary by country and unit. Several reports have expressed concerns on gastroesophageal reflux disease (GERD) and its consequences after sleeve gastrectomy (SG) and the risk of leaving a premalignant lesion in the excluded stomach after Roux-en-Y gastric bypass (RYGB). OBJECTIVES: We explored the number and types of clinically significant findings in preoperative EGDs and how they associate with preexisting GERD symptoms (SG) and premalignant lesions (RYGB). We also studied how many reoperations were performed due to postoperative GERD in SG-patients. SETTING: University hospital. METHODS: We investigated preoperative EGD-findings and gastrointestinal symptoms before bariatric surgery in all patients with a primary bariatric operation in our unit between December 2007 and May 2016. RESULTS: We performed 1474 operations: 1047 (71.0%) RYGB, 407 (27.6%) SG, and 20 (1.4%) others. One thousand two hundred seventy-five (86.5%) preoperative EGD reports were analyzed: 647 (50.7%) EGDs were completely normal. Altogether, 294 patients (23.0% of total) had a clinically significant finding that was relevant for SG (hiatal hernia, esophagitis, Barrett's esophagus, esophageal dysplasia), 144 (49.0%) of whom reported gastrointestinal symptoms. Twenty patients (1.6%) had a significant finding relevant for RYGB (peptic ulcer, atrophic gastritis, gastrointestinal stromal tumor), and 6 (30%) reported gastrointestinal symptoms. Thirteen (3.2%) SGs were converted into RYGB due to GERD. CONCLUSIONS: Preoperative EGD is indicated before SG but not before RYGB for asymptomatic patients without a risk for gastric pathology. PMID- 29477377 TI - A first phylogenetic analysis of the pill millipedes of the order Glomerida, with a special assessment of mandible characters (Myriapoda, Diplopoda, Pentazonia). AB - The pill millipedes of the order Glomerida are a moderately diverse group with a classical Holarctic distribution pattern. Their classification is based on a typological system utilizing mainly a single character complex, the male telopods. In order to infer the apomorphies of the Glomerida, to elucidate its position in the Pentazonia, and to test the monophyly of its families and subfamilies, we conduct the first phylogenetic analysis of the order. To provide additional characters, we comparatively analyze the mandible using scanning electron microscopy. The final character matrix consists of 69 characters (11 mandible characters) and incorporates 22 species from 20 of the 34 pill millipede genera, representing all families and subfamilies, except the monotypic Mauriesiinae. Two species from each of the two other Pentazonian orders Sphaerotheriida and Glomeridesmida, as well as two Spirobolida, are included as outgroup taxa. The Glomerida are recovered as monophyletic and are supported by five apomorphies. Within the Pentazonia, the Glomeridesmida are recovered as the sister group to the classical Oniscomorpha (Sphaerotheriida + Glomerida) with weak support. The analysis provides little resolution within the Glomerida, resulting in numerous polytomies. Further morphological characters and/or the addition of molecular analyses are needed to produce a robust phylogenetic classification of the Glomerida. PMID- 29477379 TI - Haploidentical IL-15/41BBL activated and expanded natural killer cell infusion therapy after salvage chemotherapy in children with relapsed and refractory leukemia. AB - : Primary refractory or relapsed pediatric leukemia yield significant morbidity and mortality, with long-term survival rates <40%. Here we present a post-hoc analysis assessing safety and efficacy of infusing activated and expanded Natural Killer cells (NKAE) from haploidentical donors in patients from 2 clinical trials. In total, 18 children, adolescents and young adults with relapse or refractory acute leukemia were treated with two cycles of rescue chemotherapy followed by fresh NKAE cells infusions and low doses of IL-2. The overall response rate, complete remission achievement at the end of the study, was 72% (13 of 18). We infused 52 NKAE cell products containing a median of 6.76 * 106 NK cells/kg (0.7-34.16) and 0.49 * 106 T cells/kg (0-11). All infusions were well tolerated with no graft versus host disease nor other serious adverse events. Among the 14 patients who completed treatment, 4 of them are alive and leukemia free more than 750 days post-transplant. We conclude that infusion of fresh NKAE cell therapy is feasible and safe in heavily pretreated pediatric population, and should be further investigated in advanced-phase clinical trials as well as a consolidation therapy to decrease relapse in patients with high-risk leukemia. TRIALS REGISTRATION: Registered at www.clinicaltrials.gov as NCT01944982 and NCT02074657. PMID- 29477378 TI - ICAM3 mediates inflammatory signaling to promote cancer cell stemness. AB - In this study, we present a medium throughput siRNA screen platform to identify inflammation genes that regulate cancer cell stemness. We identified several novel candidates that decrease OCT4 expression and reduce the ALDH + subpopulation both of which are characteristic of stemness. Furthermore, one of the novel candidates ICAM3 up-regulates in the ALDH + subpopulation, the side population and the developed spheres. ICAM3 knockdown reduces the side population, sphere formation and chemo-resistance in MDA-MB-231 human breast cancer cells and A549 lung cancer cells. In addition, mice bearing MDA-MB-231 shICAM3 cells develop smaller tumors and fewer lung metastases versus control. Interestingly, ICAM3 recruits and binds to Src by the YLPL motif in its intracellular domain which further activates the PI3K-AKT phosphorylation cascades. The activated p-AKT enhances SOX2 and OCT4 activity and thereby maintains cancer cell stemness. Meanwhile, the p-AKT facilitated p50 nuclear translocation/activation enhances p50 feedback and thereby promotes ICAM3 expression by binding to the ICAM3 promoter region. On this basis, Src and PI3K inhibitors suppress ICAM3-mediated signaling pathways and reduce chemo-resistance which results in tumor growth suppression in vitro and in vivo. In summary, we identify a potential CSC regulator and suggest a novel mechanism by which ICAM3 governs cancer cell stemness and inflammation. PMID- 29477381 TI - CD74-ROS1 G2032R mutation transcriptionally up-regulates Twist1 in non-small cell lung cancer cells leading to increased migration, invasion, and resistance to crizotinib. AB - The c-ros oncogene 1 (ROS1) is a receptor tyrosine kinase, which has been identified as an oncogene driver of non-small-cell lung cancer (NSCLC). Although crizotinib has a prominent effect on ROS1, resistance is inevitable. Development of the acquired ROS1 G2032R mutation has been reported as a resistant mechanism to ROS1 inhibitors in ROS1-rearranged (ROS1+) NSCLC patients. To explore the mechanism of drug resistance, we constructed the crizotinib resistance cell line, A549-CD74-ROS1 G2032R mutation cells, by the methods of fusion polymerase chain reaction (PCR), plasmid construction and cell transfection in vitro. The results showed that the expression of CD74-ROS1 or CD74-ROS1 G2032R mutation in A549 cells induced epithelial-mesenchymal transition (EMT), dramatically enhanced the ability of invasion and migration, and increased expression of matrix metalloproteinase (MMP)-9 and Twist1 transcription factor. Moreover, we found that inhibition of Twist1 could reverse EMT induced by CD74-ROS1 G2032R mutation. Combination of Twist1 siRNA and crizotinib significantly reduced cell vitality, inhibited cell invasion and migration, and promoted apoptosis in A549-CD74-ROS1 G2032R mutation cells. Taken together, these results suggested that CD74-ROS1 G2032R mutation mediated EMT phenotype by increasing the expression of Twist1, resulting in drug resistance. Combination of Twist1 silence and ROS1 inhibitor may provide a potent strategy to treat the ROS1+ NSCLC patients with crizotinib resistance. PMID- 29477380 TI - Nuclear EGFR-PKM2 axis induces cancer stem cell-like characteristics in irradiation-resistant cells. AB - Radiation therapy has become an important tool in the treatment of cancer patients, but most patients relapse within 5 years. Relapse is due to the presence of cancer stem cells (CSCs), but the molecular mechanism of radioresistance in CSCs remains largely elusive. Here, we found that irradiation resistant (IR) cells exhibited increased stem cell-like properties together with elevated anchorage-independent growth and metastasis ability. EGFR not only leads to increased acquisition of endometrial cancer stem cell markers in radioresistant sublines but is critical for the cancer stem-cell phenotype and tumorigenicity. Moreover, PKM2 functions as an interacting partner of EGFR, which induces the EMT phenotype and stem cell-like properties in IR cells. Finally, we found that the regulatory function of the EGFR-PKM2 axis is dependent on nuclear EGFR. In sum, our study indicated that EGFR and PKM2 directly interact and bind with each other to regulate the transcription of stemness-related genes and promote the stem-like phenotype, thus promoting invasion and metastasis. PMID- 29477382 TI - miR-501 is upregulated in cervical cancer and promotes cell proliferation, migration and invasion by targeting CYLD. AB - BACKGROUND: Cervical cancer is the common gynecological deadly malignancy worldwide. Here we attempted to evaluate the effects and mechanisms of microRNA 501-5p (miR-501) on the cell proliferation, migration, invasion and the clinical significance in the cervical cancer. METHODS: Cervical cancer HeLa cells were transfected with miR-501 mimic or inhibitor or siRNA against Cylindromatosis (CYLD) using Lipofectamine 2000. miR-501 expression was assessed in HeLa cells and cervical cancer specimens by real-time qRT-PCR. The functional roles of miR 501 were determined by CCK-8, colony formation, scratch wound healing and transwell assays. The apoptosis rate was detected by flow cytometry assay. CYLD, BCL-2, BAX, NF-kappaB p65 and phosphorylated p65 (p-p65) proteins were examined by Western blotting. CYLD expression was evaluated by immunohistochemistry in cervical cancer tissues. RESULTS: miR-501 was upregulated, whereas CYLD protein was downregulated in cervical cancer tissues compared to normal cervical tissues. miR-501 overexpression and CYLD protein downregulation were positively correlated with poor differentiation, tumor size, International Federation of Gynecology and Obstetrics (FIGO) stage and lymph node metastasis. CYLD was downregulated by miR 501 at both mRNA and protein levels in HeLa cells. miR-501 promoted cell proliferation, migration and invasion in cervical cancer, while inhibited the apoptosis. This is possibly due to the downregulation of CYLD and subsequent activation of NF-kappaB p65. CONCLUSIONS: miR-501 upregulation and CYLD downregulation are associated with the development and progression of cervical cancer. miR-501 promotes cervical cancer cell proliferation, migration and invasion possibly via downregulating CYLD and subsequently activating NF-kappaB p65. miR-501 might be a potential therapeutic target for cervical cancer. PMID- 29477383 TI - Inferring phylogenetic structure, hybridization and divergence times within Salmoninae (Teleostei: Salmonidae) using RAD-sequencing. AB - Phylogenetic studies focusing on Salmonidae have revealed significant obstacles in trying to clarify some interspecific relationships within the Salmoninae subfamily, due to a limited number of markers typed, conflicting phylogenetic signals and ancient hybridization events. To infer reliable phylogenetic relationships, evaluate several putative scenarios of ancient hybridization, and estimate divergence times within Salmoninae, we applied restriction-site associated DNA sequencing (RAD-seq) to 43 samples, including 26 genetic lineages across 21 species, largely representing the subfamily, with an emphasis on the genus Salvelinus. We identified 28,402 loci and 28,363 putatively unlinked SNPs, which were used in downstream analyses. Using an iterative k-means partitioned dataset and a Maximum Likelihood approach; we generated a well-supported phylogeny, providing clear answers to several previous phylogenetic uncertainties. We detected several significant introgression signals, presumably ancient, in the genus Salvelinus. The most recent common ancestor of Salmonidae dates back to approximately 58.9MY ago (50.8-64 MY) and the crown age of Salmoninae was estimated to be 37.7 MY (35.2-40.8 MY) using a Bayesian molecular dating analysis with a relaxed molecular clock. The divergence among genera of the subfamily occurred between the late Eocene and middle of the Miocene (~38-11 MY) such as the divergence between the genus Oncorhynchus and Salvelinus, which we estimated to 21.2 MY ago (95% HPD: 19.8-23.0 MY), while species diversification took place mainly during the Neogene (~22-1.5 MY), with more than half of these events occurring in the last 10 MY. PMID- 29477385 TI - Corrigendum. PMID- 29477384 TI - Corrigendum. PMID- 29477386 TI - Visualisation of intracellular production bottlenecks in suspension-adapted CHO cells producing complex biopharmaceuticals using fluorescence microscopy. AB - With the advance of complex biological formats such as bispecific antibodies or fusion proteins, mammalian expression systems often show low performance. Described determining factors may be accumulation or haltering of heterologous proteins within the different cellular compartments disturbing transport or secretion. In case of the investigated bispecific antibody (bsAb)-producing Chinese hamster ovary (CHO) cell line neither impaired transcription nor decreased translation processes were identified and thus satisfactorily explained its low production capacity. Hence, we established a streamlined confocal microscopy-based methodology for CHO production cells investigating the distribution of the recombinant protein within the respective organelles of the secretory pathway and visualised the structure of the endoplasmic reticulum (ER) to be affected pinpointing towards an intra-ER bottleneck putatively hampering or limiting efficient secretion. The ER displayed not only a heavily altered morphology in comparison to a high immunoglobulin G (IgG)-producing cell line with a possibly inflated or overloaded structure, but the recombinant protein was also completely absent in the Golgi apparatus. Notably, the results obtained using an automated microscopy approach suggest the possible application of this methodology in cell line development and engineering. PMID- 29477387 TI - A Health Economics Approach to US Value Frameworks: Serving the Needs of Decision Making. PMID- 29477388 TI - A Health Economics Approach to US Value Assessment Frameworks-Introduction: An ISPOR Special Task Force Report [1]. AB - Concerns about rising spending on prescription drugs and other areas of health care have led to multiple initiatives in the United States designed to measure and communicate the value of pharmaceuticals and other technologies for decision making. In this section we introduce the work of the International Society for Pharmacoeconomics and Outcomes Research Special Task Force on US Value Assessment Frameworks formed to review relevant perspectives and appropriate approaches and methods to support the definition and use of high-quality value frameworks. The Special Task Force was part of the International Society for Pharmacoeconomics and Outcomes Research Initiative on US Value Assessment Frameworks, which enlisted the expertise of leading health economists, concentrating on what the field of health economics can provide to help inform the development and use of value assessment frameworks. We focus on five value framework initiatives: the American College of Cardiology/American Heart Association, the American Society of Clinical Oncology, the Institute for Clinical and Economic Review, the Memorial Sloan Kettering Cancer Center, and the National Comprehensive Cancer Network. These entities differ in their missions, scope of activities, and methodological approaches. Because they are gaining visibility and some traction in the United States, it is essential to scrutinize whether the frameworks use approaches that are transparent as well as conceptually and methodologically sound. Our objectives were to describe the conceptual bases for value and its use in decision making, critically examine existing value frameworks, discuss the importance of sound conceptual underpinning, identify key elements of value relevant to specific decision contexts, and recommend good practice in value definition and implementation as well as areas for further research. PMID- 29477389 TI - An Overview of Value, Perspective, and Decision Context-A Health Economics Approach: An ISPOR Special Task Force Report [2]. AB - The second section of our Special Task Force builds on the discussion of value and perspective in the previous article of the report by 1) defining a health economics approach to the concept of value in health care systems; 2) discussing the relationship of value to perspective and decision context, that is, how recently proposed value frameworks vary by the types of decisions being made and by the stakeholders involved; 3) describing the patient perspective on value because the patient is a key stakeholder, but one also wearing the hat of a health insurance purchaser; and 4) discussing how value is relevant in the market based US system of mixed private and public insurance, and differs from its use in single-payer systems. The five recent value frameworks that motivated this report vary in the types of decisions they intend to inform, ranging from coverage, access, and pricing decisions to those defining appropriate clinical pathways and to supporting provider-clinician shared decision making. Each of these value frameworks must be evaluated in its own decision context for its own objectives. Existing guidelines for cost-effectiveness analysis emphasize the importance of clearly specifying the perspective from which the analysis is undertaken. Relevant perspectives may include, among others, 1) the health plan enrollee, 2) the patient, 3) the health plan manager, 4) the provider, 5) the technology manufacturer, 6) the specialty society, 7) government regulators, or 8) society as a whole. A valid and informative cost-effectiveness analysis could be conducted from the perspective of any of these stakeholders, depending on the decision context. PMID- 29477390 TI - Defining Elements of Value in Health Care-A Health Economics Approach: An ISPOR Special Task Force Report [3]. AB - The third section of our Special Task Force report identifies and defines a series of elements that warrant consideration in value assessments of medical technologies. We aim to broaden the view of what constitutes value in health care and to spur new research on incorporating additional elements of value into cost effectiveness analysis (CEA). Twelve potential elements of value are considered. Four of them-quality-adjusted life-years, net costs, productivity, and adherence improving factors-are conventionally included or considered in value assessments. Eight others, which would be more novel in economic assessments, are defined and discussed: reduction in uncertainty, fear of contagion, insurance value, severity of disease, value of hope, real option value, equity, and scientific spillovers. Most of these are theoretically well understood and available for inclusion in value assessments. The two exceptions are equity and scientific spillover effects, which require more theoretical development and consensus. A number of regulatory authorities around the globe have shown interest in some of these novel elements. Augmenting CEA to consider these additional elements would result in a more comprehensive CEA in line with the "impact inventory" of the Second Panel on Cost-Effectiveness in Health and Medicine. Possible approaches for valuation and inclusion of these elements include integrating them as part of a net monetary benefit calculation, including elements as attributes in health state descriptions, or using them as criteria in a multicriteria decision analysis. Further research is needed on how best to measure and include them in decision making. PMID- 29477391 TI - Objectives, Budgets, Thresholds, and Opportunity Costs-A Health Economics Approach: An ISPOR Special Task Force Report [4]. AB - The fourth section of our Special Task Force report focuses on a health plan or payer's technology adoption or reimbursement decision, given the array of technologies, on the basis of their different values and costs. We discuss the role of budgets, thresholds, opportunity costs, and affordability in making decisions. First, we discuss the use of budgets and thresholds in private and public health plans, their interdependence, and connection to opportunity cost. Essentially, each payer should adopt a decision rule about what is good value for money given their budget; consistent use of a cost-per-quality-adjusted life-year threshold will ensure the maximum health gain for the budget. In the United States, different public and private insurance programs could use different thresholds, reflecting the differing generosity of their budgets and implying different levels of access to technologies. In addition, different insurance plans could consider different additional elements to the quality-adjusted life year metric discussed elsewhere in our Special Task Force report. We then define affordability and discuss approaches to deal with it, including consideration of disinvestment and related adjustment costs, the impact of delaying new technologies, and comparative cost effectiveness of technologies. Over time, the availability of new technologies may increase the amount that populations want to spend on health care. We then discuss potential modifiers to thresholds, including uncertainty about the evidence used in the decision-making process. This article concludes by discussing the application of these concepts in the context of the pluralistic US health care system, as well as the "excess burden" of tax-financed public programs versus private programs. PMID- 29477392 TI - Approaches to Aggregation and Decision Making-A Health Economics Approach: An ISPOR Special Task Force Report [5]. AB - The fifth section of our Special Task Force report identifies and discusses two aggregation issues: 1) aggregation of cost and benefit information across individuals to a population level for benefit plan decision making and 2) combining multiple elements of value into a single value metric for individuals. First, we argue that additional elements could be included in measures of value, but such elements have not generally been included in measures of quality adjusted life-years. For example, we describe a recently developed extended cost effectiveness analysis (ECEA) that provides a good example of how to use a broader concept of utility. ECEA adds two features-measures of financial risk protection and income distributional consequences. We then discuss a further option for expanding this approach-augmented CEA, which can introduce many value measures. Neither of these approaches, however, provide a comprehensive measure of value. To resolve this issue, we review a technique called multicriteria decision analysis that can provide a comprehensive measure of value. We then discuss budget-setting and prioritization using multicriteria decision analysis, issues not yet fully resolved. Next, we discuss deliberative processes, which represent another important approach for population- or plan-level decisions used by many health technology assessment bodies. These use quantitative information on CEA and other elements, but the group decisions are reached by a deliberative voting process. Finally, we briefly discuss the use of stated preference methods for developing "hedonic" value frameworks, and conclude with some recommendations in this area. PMID- 29477393 TI - Review of Recent US Value Frameworks-A Health Economics Approach: An ISPOR Special Task Force Report [6]. AB - The sixth section of our Special Task Force (STF) report reviews and comments on recent US-oriented value assessment frameworks, specifically those published by the American College of Cardiology/American Heart Association, the Institute for Clinical and Economic Research, the American Society of Clinical Oncology, the National Comprehensive Cancer Network, and the Memorial Sloan Kettering Cancer Center. We review published commentaries that address the validity, reliability, and conceptual underpinnings of these frameworks. We find common themes of critique regarding the strengths and limitations across frameworks. Particular shortcomings of some frameworks pose greater threats to their face validity and utility compared with others. The most significant limitations include lack of clear perspective (e.g., patient vs. health plan) and poor transparency in accounting for costs and benefits. We then review how each framework adheres to core STF recommendations, with particular emphasis on whether the framework can be used to support coverage decisions by health insurers, and whether it adheres to core principles of cost-effectiveness analysis. The Institute for Clinical and Economic Research framework most closely adheres to core STF recommendations. Others have significant limitations that vary widely from framework to framework. We also review how the frameworks follow STF recommendations for addressing potentially relevant issues beyond cost-effectiveness analysis - for example, equity in resource allocation and patient heterogeneity. Finally, we review whether and how each framework uses value thresholds and addresses affordability concerns. We conclude with suggestions for further research, particularly in the areas of testing the measurement and use of novel elements of value and deliberative processes. PMID- 29477394 TI - A Health Economics Approach to US Value Assessment Frameworks-Summary and Recommendations of the ISPOR Special Task Force Report [7]. AB - This summary section first lists key points from each of the six sections of the report, followed by six key recommendations. The Special Task Force chose to take a health economics approach to the question of whether a health plan should cover and reimburse a specific technology, beginning with the view that the conventional cost-per-quality-adjusted life-year metric has both strengths as a starting point and recognized limitations. This report calls for the development of a more comprehensive economic evaluation that could include novel elements of value (e.g., insurance value and equity) as part of either an "augmented" cost effectiveness analysis or a multicriteria decision analysis. Given an aggregation of elements to a measure of value, consistent use of a cost-effectiveness threshold can help ensure the maximization of health gain and well-being for a given budget. These decisions can benefit from the use of deliberative processes. The six recommendations are to: 1) be explicit about decision context and perspective in value assessment frameworks; 2) base health plan coverage and reimbursement decisions on an evaluation of the incremental costs and benefits of health care technologies as is provided by cost-effectiveness analysis; 3) develop value thresholds to serve as one important input to help guide coverage and reimbursement decisions; 4) manage budget constraints and affordability on the basis of cost-effectiveness principles; 5) test and consider using structured deliberative processes for health plan coverage and reimbursement decisions; and 6) explore and test novel elements of benefit to improve value measures that reflect the perspectives of both plan members and patients. PMID- 29477395 TI - ISPOR's Initiative on US Value Assessment Frameworks: The Use of Cost Effectiveness Research in Decision Making among US Insurers. PMID- 29477396 TI - ISPOR's Initiative on US Value Assessment Frameworks: A Missed Opportunity for ISPOR and Patients. PMID- 29477397 TI - ISPOR's Initiative on US Value Assessment Frameworks: Seeking a Role for Health Economics. PMID- 29477398 TI - ISPOR's Initiative on US Value Assessment Frameworks: An Industry Perspective. PMID- 29477399 TI - Basal Insulin Regimens for Adults with Type 1 Diabetes Mellitus: A Systematic Review and Network Meta-Analysis. AB - OBJECTIVE: To assess the relative efficacy and safety of basal insulin regimens in adults with type 1 diabetes mellitus (T1DM). METHODS: A systematic review and Bayesian network meta-analysis (NMA) of randomized controlled trials comparing two or more basal insulin regimens were conducted. The following basal insulin regimens were included: Neutral Protamine Hagedorn (iNPH) (once [od], twice [bid], and four times daily [qid]), insulin detemir (iDet) (od and bid), insulin glargine 100 IU (iGlarg) (od), and insulin degludec (iDegl) (od). We searched the following databases: MEDLINE via OVID, Embase via OVID, and the Cochrane Library (Wiley). Study quality was appraised using Cochrane risk-of-bias checklist for randomized controlled trials. Two outcomes (change in hemoglobin A1c [HbA1c] and rate of severe/major hypoglycemia [SH]) were analyzed. Network inconsistency was assessed using Bucher and chi-square tests. RESULTS: Thirty studies met the eligibility criteria. Twenty-five were included in the HbA1c network and 16 in the SH network. All studies were of moderate quality. No network inconsistency was evident in the HbA1c network. Of the seven regimens of interest, iDet (bid) had the highest probability of being best (mean change in HbA1c -0.48; 95% credible interval -0.69 to -0.29). In contrast, the SH network demonstrated both considerable uncertainty and significant network inconsistency (chi2 test, P = 0.003). CONCLUSIONS: Of the specified frequency regimens, iDet (bid) had the highest probability of being the best basal insulin regimen in terms of reduction in HbA1c. Ranking of the regimens in terms of the SH rate was highly uncertain and no clear conclusion could be made. PMID- 29477400 TI - A Comparison of Different Approaches for Costing Medication Use in an Economic Evaluation. AB - BACKGROUND: Estimating individual-level medication costs in an economic evaluation can involve extensive data collection and handling. Implications of detailed versus general approaches are unclear. OBJECTIVES: To compare costing approaches in a trial-based economic evaluation. METHODS: We applied four costing approaches to prescribed medication data from the Tumour necrosis factor inhibitors Against Combination Intensive Therapy randomized controlled trial. A detailed micro-costing approach was used as a base case, against which other approaches were compared: costing medications used by at least 1.5% of patients; costing medications on the basis of only chemical name; applying a generic prescription charge rather than a medication-specific cost. We quantitatively examined resulting estimates of prescribed medication and total care costs, and qualitatively examined trial conclusions. RESULTS: Medication costs made up 6% of the total health and social care costs. There was good agreement in prescribed medication costs (concordance correlation coefficient [CCC] 0.815, 0.819, and 0.989) and excellent agreement in total costs (CCC 0.990, 0.995, and 0.995) between approaches 1 and 2. Approaches 3 and 4 had poor agreement with approach 1 on prescribed medication costs (CCC 0.246-0.700 and 0.033-0.333, respectively), but agreement on total care costs remained good (CCC 0.778-0.993 and 0.729-0.986, respectively). CONCLUSIONS: Because medication costs comprised only a small proportion of total costs, the less resource-intensive approaches had substantial impacts on medication cost estimates, but had little impact on total care costs and did not significantly impact the trial's cost-effectiveness conclusions. There is room for research efficiencies without detriment to an evaluation in which medication costs are likely to form a small proportion of total costs. PMID- 29477401 TI - Cost-Effectiveness Analysis of Abatacept Compared with Adalimumab on Background Methotrexate in Biologic-Naive Adult Patients with Rheumatoid Arthritis and Poor Prognosis. AB - OBJECTIVES: To assess cost effectiveness of abatacept versus adalimumab, each administered with methotrexate, in treating patients with rheumatoid arthritis (RA) stratified according to baseline anticitrullinated protein antibody (ACPA) levels (marker of poor prognosis in RA). METHODS: A payer-perspective cost effectiveness model simulated disease progression in patients with RA who had previously failed conventional disease-modifying antirheumatic drugs and were starting biologic therapy. Patients commenced treatment with abatacept or adalimumab plus methotrexate and were evaluated after 6 months. Therapy continuation was based on the European League Against Rheumatism treatment response; disease progression was based on the Health Assessment Questionnaire Disability Index score. These score changes were used to estimate health state utilities and direct medical costs. Quality-adjusted life-years (QALYs) and incremental cost per QALY gained were calculated by baseline ACPA groups (Q1, 28 234 AU/ml; Q2, 235-609 AU/ml; Q3, 613-1045 AU/ml; and Q4, 1060-4894 AU/ml). Scenario analysis and one-way and probabilistic sensitivity analyses were used to evaluate robustness of model assumptions. RESULTS: Abatacept resulted in QALY gain versus adalimumab in ACPA Q1, Q3, and Q4; between-treatment difference (difference: Q1, -0.115 Q2, -0.009 Q3, 0.045; and Q4, 0.279). Total lifetime discounted cost was higher for abatacept versus adalimumab in most quartiles (Q2, L77,612 vs. L77,546; Q3, L74,441 vs. L73,263; and Q4, L78,428 vs. L76,696) because of longer time on treatment. Incremental cost per QALY for abatacept (vs. adalimumab) was the lowest in the high ACPA titer group (Q4, L6200/QALY), followed by the next lowest titer group (Q3, L26,272/QALY). CONCLUSIONS: Abatacept is a cost effective alternative to adalimumab in patients with RA with high ACPA levels. PMID- 29477402 TI - The Impact of Decision Makers' Constraints on the Outcome of Value of Information Analysis. AB - BACKGROUND: When proven effective, decision making regarding reimbursement of new health technology typically involves ethical, social, legal, and health economic aspects and constraints. Nevertheless, when applying standard value of information (VOI) analysis, the value of collecting additional evidence is typically estimated assuming that only cost-effectiveness outcomes guide such decisions. OBJECTIVES: To illustrate how decision makers' constraints can be incorporated into VOI analyses and how these may influence VOI outcomes. METHODS: A simulation study was performed to estimate the cost-effectiveness of a new hypothetical technology compared with usual care. Constraints were defined for the new technology on 1) the maximum acceptable rate of complications and 2) the maximum acceptable additional budget. The expected value of perfect information (EVPI) for the new technology was estimated in various scenarios, both with and without incorporating these constraints. RESULTS: For a willingness-to-pay threshold of ?20,000 per quality-adjusted life-year, the probability that the new technology was cost-effective equaled 57%, with an EVPI of ?1868 per patient. Applying the complication rate constraint reduced the EVPI to ?1137. Similarly, the EVPI reduced to ?770 when applying the budget constraint. Applying both constraints simultaneously further reduced the EVPI to ?318. CONCLUSIONS: When decision makers explicitly apply additional constraints, beyond a willingness-to pay threshold, to reimbursement decisions, these constraints can and should be incorporated into VOI analysis as well, because they may influence VOI outcomes. This requires continuous interaction between VOI analysts and decision makers and is expected to improve both the relevance and the acceptance of VOI outcomes. PMID- 29477404 TI - Investigating the Heterogeneity in Women's Preferences for Breast Screening: Does the Communication of Risk Matter? AB - BACKGROUND: The relative benefits and risks of screening programs for breast cancer have been extensively debated. OBJECTIVES: To quantify and investigate heterogeneity in women's preferences for the benefits and risks of a national breast screening program (NBSP) and to understand the effect of risk communication format on these preferences. METHODS: An online discrete choice experiment survey was designed to elicit preferences from female members of the public for an NBSP described by three attributes (probability of detecting a cancer, risk of unnecessary follow-up, and out-of-pocket screening costs). Survey respondents were randomized to one of two surveys, presenting risk either as percentages only or as icon arrays and percentages. Respondents were required to choose between two hypothetical NBSPs or no screening in 11 choice sets generated using a Bayesian D-efficient design. The trade-offs women made were analyzed using heteroskedastic conditional logit and scale-adjusted latent class models. RESULTS: A total of 1018 women completed the discrete choice experiment (percentages-only version = 507; icon arrays and percentages version = 511). The results of the heteroskedastic conditional logit model suggested that, on average, women were willing-to-accept 1.72 (confidence interval 1.47-1.97) additional unnecessary follow-ups and willing-to-pay L79.17 (confidence interval L66.98-L91.35) for an additional cancer detected per 100 women screened. Latent class analysis indicated substantial heterogeneity in preferences with six latent classes and three scale classes providing the best fit. The risk communication format received was not a predictor of scale class or preference class membership. CONCLUSIONS: Most women were willing to trade-off the benefits and risks of screening, but decision makers seeking to improve uptake should consider the disparate needs of women when configuring services. PMID- 29477403 TI - Reliability, Validity, and Responsiveness of InFLUenza Patient-Reported Outcome (FLU-PRO(c)) Scores in Influenza-Positive Patients. AB - OBJECTIVES: To assess the reliability, validity, and responsiveness of InFLUenza Patient-Reported Outcome (FLU-PRO(c)) scores for quantifying the presence and severity of influenza symptoms. METHODS: An observational prospective cohort study of adults (>=18 years) with influenza-like illness in the United States, the United Kingdom, Mexico, and South America was conducted. Participants completed the 37-item draft FLU-PRO daily for up to 14 days. Item-level and factor analyses were used to remove items and determine factor structure. Reliability of the final tool was estimated using Cronbach alpha and intraclass correlation coefficients (2-day reliability). Convergent and known-groups validity and responsiveness were assessed using global assessments of influenza severity and return to usual health. RESULTS: Of the 536 patients enrolled, 221 influenza-positive subjects comprised the analytical sample. The mean age of the patients was 40.7 years, 60.2% were women, and 59.7% were white. The final 32 item measure has six factors/domains (nose, throat, eyes, chest/respiratory, gastrointestinal, and body/systemic), with a higher order factor representing symptom severity overall (comparative fit index = 0.92; root mean square error of approximation = 0.06). Cronbach alpha was high (total = 0.92; domain range = 0.71 0.87); test-retest reliability (intraclass correlation coefficient, day 1-day 2) was 0.83 for total scores and 0.57 to 0.79 for domains. Day 1 FLU-PRO domain and total scores were moderately to highly correlated (>=0.30) with Patient Global Rating of Flu Severity (except nose and throat). Consistent with known-groups validity, scores differentiated severity groups on the basis of global rating (total: F = 57.2, P < 0.001; domains: F = 8.9-67.5, P < 0.001). Subjects reporting return to usual health showed significantly greater (P < 0.05) FLU-PRO score improvement by day 7 than did those who did not, suggesting score responsiveness. CONCLUSIONS: Results suggest that FLU-PRO scores are reliable, valid, and responsive to change in influenza-positive adults. PMID- 29477405 TI - Choice Defines Value: A Predictive Modeling Competition in Health Preference Research. AB - OBJECTIVE: To identify which specifications and approaches to model selection better predict health preferences, the International Academy of Health Preference Research (IAHPR) hosted a predictive modeling competition including 18 teams from around the world. METHODS: In April 2016, an exploratory survey was fielded: 4074 US respondents completed 20 out of 1560 paired comparisons by choosing between two health descriptions (e.g., longer life span vs. better health). The exploratory data were distributed to all teams. By July, eight teams had submitted their predictions for 1600 additional pairs and described their analytical approach. After these predictions had been posted online, a confirmatory survey was fielded (4148 additional respondents). RESULTS: The victorious team, "Discreetly Charming Econometricians," led by Michal Jakubczyk, achieved the smallest chi2, 4391.54 (a predefined criterion). Its primary scientific findings were that different models performed better with different pairs, that the value of life span is not constant proportional, and that logit models have poor predictive validity in health valuation. CONCLUSIONS: The results demonstrated the diversity and potential of new analytical approaches in health preference research and highlighted the importance of predictive validity in health valuation. PMID- 29477406 TI - Examining the Heterogeneity and Cost Effectiveness of a Complex Intervention by Segmentation of Patients with Chronic Obstructive Pulmonary Disease. AB - OBJECTIVES: To examine the heterogeneity in cost-effectiveness analyses of patient-tailored complex interventions. METHODS: Latent class analysis (LCA) was performed on data from a randomized controlled trial evaluating a patient tailored case management strategy for patients suffering from chronic obstructive pulmonary disease (COPD). LCA was conducted on detailed process variables representing service variation in the intervention group. Features of the identified latent classes were compared for consistency with baseline demographic, clinical, and economic characteristics for each class. Classes for the control group, corresponding to the identified latent classes for the intervention group, were identified using multinomial logistic regression. Cost utility analyses were then conducted at the class level, and uncertainty surrounding the point estimates was assessed by probabilistic sensitivity analysis. RESULTS: The LCA identified three distinct classes: the psychologically care class, the extensive COPD care class, and the limited COPD care class. Patient baseline characteristics were in line with the features identified in the LCA. Evaluation of cost-effectiveness revealed highly disparate results, and case management for only the extensive COPD care class appeared cost-effective with an incremental cost-effectiveness ratio of L26,986 per quality-adjusted life-year gained using the threshold value set by the National Institute of Health and Care Excellence. CONCLUSIONS: Findings indicate that researchers evaluating patient tailored complex interventions need to address both supply-side variation and demand-side heterogeneity to link findings with outcome. The article specifically proposes the use of LCA because it is believed to have the potential to enable more appropriate targeting of complex care strategies. PMID- 29477407 TI - ERRATUM. PMID- 29477408 TI - The trabecular bone index: a new tool for assessing osteoporosis. PMID- 29477409 TI - Androgen deprivation therapy-induced epithelial-mesenchymal transition of prostate cancer through downregulating SPDEF and activating CCL2. AB - The chemokine CC motif ligand 2 (CCL2) is important in recruiting tumor associated macrophages and is involved in the development of castration resistance prostate cancer (CRPC) after androgen-deprivation therapy (ADT); however, the underlying mechanism remains unclear. We found that inactivation of the androgen receptor (AR) reduces a transcriptional repressor (SAM pointed domain-containing ETS transcription factor, SPDEF) of CCL2, which mediates epithelial-to-mesenchymal transition (EMT) of prostate tumor cells. Cell lines derived from a prostate-specific Pten/Trp53-null mouse and capable of a spontaneous EMT were utilized for identification of CCL2, and showed that reduced SPDEF expression was associated with an elevated CCL2-activated EMT. AR signaling inhibits CCL2 through a SPDEF-mediated mechanism in that the SPDEF recognizes the CCL2 promoter and transcriptionally represses its activity. Ectopically expressed SPDEF reduced the EMT and rescued expression of CCL2 in SPDEF-expressing cells, which induced the EMT and promotes malignant functions of prostate cancer cells. In tissues from prostate cancer patients with ADT, low SPDEF levels were correlated with high CCL2 expression compared to patients without ADT. We present a novel mechanism that contributes to the EMT and metastatic phenotype observed in a subset of ADT-resistant prostate cancer, where the CCL2 is stimulated through the inactivated of AR-mediated SPDEF. PMID- 29477410 TI - Role of heme oxygenase-1 in potentiation of phagocytic activity of macrophages by taurine chloramine: Implications for the resolution of zymosan A-induced murine peritonitis. AB - Phagocytosis of pathogens by macrophages is crucial for the successful resolution of inflammation induced by microbial infection. Taurine chloramine (TauCl), an endogenous anti-inflammatory and antioxidative substance, is produced by reaction between taurine and hypochlorous acid by myeloperoxidase activity in neutrophils under inflammatory conditions. In the present study, we investigated the effect of TauCl on resolution of acute inflammation caused by fungal infection using a zymosan A-induced murine peritonitis model. TauCl administration reduced the number of the total peritoneal leukocytes, while it increased the number of peritoneal monocytes. Furthermore, TauCl promoted clearance of pathogens remaining in the inflammatory environment by macrophages. When the macrophages isolated from thioglycollate-treated mice were treated with TauCl, their phagocytic capability was enhanced. In the murine macrophage-like RAW264.7 cells treated with TauCl, the proportion of macrophages clearing the zymosan A particles was also increased. TauCl administration resulted in elevated expression of heme oxygenase-1 (HO-1) in the peritoneal macrophages. Pharmacologic inhibition of HO-1 activity or knockdown of HO-1 in the murine macrophage RAW264.7 cells abolished the TauCl-induced phagocytosis, whereas the overexpression of HO-1 augmented the phagocytic ability of macrophages. Moreover, peritoneal macrophages isolated from HO-1 null mice failed to mediate TauCl induced phagocytosis. Our results suggest that TauCl potentiates phagocytic activity of macrophages through upregulation of HO-1 expression. PMID- 29477411 TI - Effect of Rear Wheel Suspension on Tilt-in-Space Wheelchair Shock and Vibration Attenuation. AB - BACKGROUND: Suspension systems are designed to reduce shock and vibration exposure. An aftermarket rear-wheel suspension system is now available for manual tilt-in-space wheelchairs. OBJECTIVE: To compare quantifiable shock and vibration on a rigid manual tilt-in-space wheelchair to published data on manual wheelchairs and to determine whether aftermarket rear suspension system will significantly decrease shock exposure when traversing common obstacles. DESIGN: Cross-sectional. SETTING: Research laboratory. PARTICIPANTS: Ten healthy non wheelchair users. METHODS: Subjects seated in a manual tilt-in-space wheelchair were pushed over 4 different obstacles (an exterior door threshold, truncated domes, 2-cm descent, and 2-cm ascent) with the chair as manufactured and with the suspension system installed. MAIN OUTCOME MEASUREMENTS: Superior/inferior and anterior/posterior accelerations were assessed at the seat pan with and without the use of ISO 2631-1 standards. Peak accelerations were analyzed from the door threshold, 2-cm descent and 2-cm ascent. Root mean square acceleration (RMSa) values were analyzed from the truncated domes, and vibration dose value (VDV) was analyzed for all surfaces. RESULTS: There were no differences in time spent over the 4 obstacles between rigid and suspended conditions (P>=.064). Suspension decreased the peak acceleration at the rear wheel when it initially impacted the door threshold, and when the rear wheel traversed the 2-cm descent and ascent (P<=.043). ISO 2631-1 frequency weighting, placing emphasis on frequencies most harmful to humans, also supports suspension reducing peak accelerations at the rear wheel both when it initially impacted and left the door threshold, and when the rear wheel descended 2 cm (P<=.049). Suspension also reduced the truncated dome RMSa as well as the door threshold, 2-cm descent, and total VDV (P<=.041). CONCLUSIONS: The results indicate that rigid manual tilt-in-space wheelchairs respond to rough surfaces in a similar fashion to previously studied rigid wheelchairs. Furthermore, the aftermarket suspension system reduces some aspects of shock and vibration exposure, also consistent with previously studied suspension systems. LEVEL OF EVIDENCE: NA. PMID- 29477412 TI - Safety, Tolerability, and Effectiveness of Dextromethorphan/Quinidine for Pseudobulbar Affect Among Study Participants With Traumatic Brain Injury: Results From the PRISM-II Open Label Study. AB - BACKGROUND: Dextromethorphan 20 mg / quinidine 10 mg (DM/Q) was approved to treat pseudobulbar affect (PBA) based on phase 3 trials conducted in participants with amyotrophic lateral sclerosis or multiple sclerosis. PRISM II evaluated DM/Q effectiveness, safety, and tolerability for PBA following stroke, dementia, or traumatic brain injury (TBI). OBJECTIVE: To report results from the TBI cohort of PRISM II, including a TBI-specific functional scale. DESIGN: Open-label trial evaluating twice-daily DM/Q over 90 days. STUDY PARTICIPANTS: Adults (n = 120) with a clinical diagnosis of PBA secondary to nonpenetrating TBI; stable psychiatric medications were allowed. METHODS: PRISM II was an open-label, 12 week trial enrolling adults with PBA secondary to dementia, stroke, or TBI (NCT01799941). All study participants received DM/Q 20/10 mg twice daily. Study visits occurred at baseline and at day 30 and day 90. SETTING: 150 U.S. centers. MAIN OUTCOME MEASUREMENTS: Primary endpoint was change in Center for Neurologic Study-Lability Scale (CNS-LS) score from baseline to day 90. Secondary outcomes included PBA episode count, Clinical and Patient Global Impression of Change (CGI C; PGI-C), Quality of Life-Visual Analog Scale (QOL-VAS), treatment satisfaction, Neurobehavioral Functioning Inventory (NFI), Patient Health Questionnaire (PHQ 9), and Mini Mental State Examination (MMSE). RESULTS: DM/Q-treated participants showed significant mean (SD) reductions in CNS-LS from baseline (day 30, -5.6 [5.2]; day 90, -8.5 [5.2]; both, P<.001). Compared with baseline, PBA episodes were reduced by 61.3% and 78.5% at days 30 and 90 (both, P<.001). At day 90, 78% and 73% of study participants had "much improved" or "very much improved" on the CGI-C and PGI-C. QOL-VAS scores were significantly reduced from baseline (-3.7 [3.3], P<.001). Mean (SD) PHQ-9 scores improved compared to baseline at day 30 ( 3.2 [5.3], P<.001) and 90 (-5.2 [6.4], P<.001). NFI T scores were significantly improved (P<.001), whereas MMSE scores were unchanged. Adverse events (AEs) were consistent with the known DM/Q safety profile; the most common AE was diarrhea (8.3%). CONCLUSIONS: DM/Q was well tolerated, and it significantly reduced PBA episodes in study participants with TBI. Changes in CNS-LS and PBA episode count were similar to changes with DM/Q in phase 3 trials. LEVEL OF EVIDENCE: II. PMID- 29477413 TI - Male rats treated with subchronic PCP show intact olfaction and enhanced interest for a social odour in the olfactory habituation/dishabituation test. AB - The olfactory system participates in many sensory processes, and olfactory endophenotypes appear in a variety of neurological disorders such as Alzheimer's and Parkinson's disease, depression and schizophrenia. Social withdrawal is a core negative symptom of schizophrenia and animal models have proven to be invaluable for studying the neurobiological mechanisms and cognitive processes behind the formation of social relationships. The subchronic phencyclidine (PCP) rat model is a validated model for negative symptoms of schizophrenia, such as impaired sociability. However, the complete range of social behaviour and deficits in the model are still not fully understood. Intact rodent olfaction is essential for a wide range of social behaviour and disrupted olfactory function could have severe effects on social communication and recognition. In order to examine the olfactory ability of male rats treated with subchronic PCP, we conducted an olfactory habituation/dishabituation test including both non-social and social odours. The subchronic PCP-treated rats successfully recognized and discriminated among the odours, indicative of intact olfaction. Interestingly, the subchronic PCP-treated rats showed greater interest for a novel social odour compared to the saline-treated rats and the rationale remains to be elucidated. Our data indicate that subchronic PCP treatment does not disrupt olfactory function in male rats. By ruling out impaired olfaction as cause for the poor social interaction performance in subchronic PCP-treated rats, our data supports the use of NMDA receptor antagonists to model the negative symptoms of schizophrenia. PMID- 29477414 TI - Acute stress negatively affects object recognition early memory consolidation and memory retrieval unrelated to state-dependency. AB - It is well known that stress affects memory performance. However, there still appears to be inconstancy in literature about how acute stress affects the different stages of memory: acquisition, consolidation and retrieval. In this study, we exposed rats to acute stress and measured the effect on memory performance in the object recognition task as a measure for episodic memory. Stress was induced 30 min prior to the learning phase to affect acquisition, directly after the learning phase to affect consolidation, or 30 min before the retrieval phase to affect retrieval. Additionally, we induced stress both 30 min prior to the learning phase and 30 min prior to the retrieval phase to test whether the effects were related to state-dependency. As expected, we found that acute stress did not affect acquisition but had a negative impact on retrieval. To our knowledge, we are the first to show that early consolidation was negatively affected by acute stress. We also show that stress does not have a state-dependent effect on memory. PMID- 29477415 TI - Strength of resting-state functional connectivity associated with performance adjustment ability. AB - Erroneous behavior is usually, although not always, inhibited following a negative outcome (e.g., a penalty), although this adjusting behavior is highly varied. Here we aimed to identify brain regions associated with successful behavioral adjustment to negative feedback, and the intrinsic functional connectivity associated with individual variability in such adjustments, using combined task-based and resting-state functional magnetic resonance imaging (MRI). Functional MRI data were obtained from 28 young adults performing a visuomotor associative learning task, wherein participants learned by trial and error to make one of four key responses to each of 24 English letters. All preceding error response trials were sorted post hoc, based on whether the error response was repeated (Error-Repeated) or not (Error-Changed) for the subsequent trial with the same stimulus, and the rate of error adjustment for each individual was computed as the number of Error-Changed trials divided by all error trials. We identified two brain regions, the right dorsal anterior cingulate cortex (dACC) and dorsolateral prefrontal cortex (DLPFC), whose brain response was significantly greater for Error-Changed than Error-Repeated trials. Stronger anti-correlation between the right dACC seed and right amygdala and between the DLPFC seed and the paracentral gyrus and inferior temporal region extending to the hippocampus was associated with better adjustment ability. These results suggest that the stronger anticorrelated relationship between the error monitoring region and emotional processing and that between the executive control region with those involved in memory or default mode network reflect individual variability in error adjustment. PMID- 29477416 TI - Predictors of health-related quality of life in korean patients with myocardial infarction: a longitudinal observational study. AB - BACKGROUND: Experience of myocardial infarction (MI) negatively affects different aspects of health-related quality of life (HRQoL). OBJECTIVES: This study aimed to examine trends in HRQoL of MI patients and to identify demographic, clinical and psychosocial predictors of HRQoL at three months. METHODS: A total of 150 patients in South Korea were completed the study questionnaires at baseline. After three months from discharge, 136 participants completed follow-up questionnaires, including the Korean version of the MacNew Quality of Life after Myocardial Infarction Questionnaire (MacNew). RESULTS: HRQoL significantly improved over three months. Younger age, ST-elevation MI, and higher LVEF, lower level of depression, better understanding of the illness and higher perceived social support at baseline were associated with better HRQoL at three months. CONCLUSION: Providing adequate information about the illness and social support as well as reducing negative psychological experiences in early days after MI may improve HRQoL of MI patients. PMID- 29477417 TI - Intradialytic hypotension related episodes identification based on the most effective features of photoplethysmography signal. AB - BACKGROUND AND OBJECTIVE: One of the most adverse conditions facing the hemodialysis patient is repetitive hypotension during their dialysis session. Different factors can be used to monitor patient conditions and prevent Intradialytic Hypotension (IDH) during hemodialysis. These factors include blood pressure, blood volume, and electrical Impedance factors. In this paper, pre-IDH and IDH episodes were recognized and classified by using the features of the finger photoplethysmography (PPG) signal. In other words, the goal of present study is to use PPG signal features to predict the risk of acute hypotension. METHODS: Since the PPG signal is non-stationary in nature, the main signal was divided in five-minute intervals with no overlap and then each interval was analyzed separately and fifteen PPG signal features in time and seven features in the frequency domain were extracted. Then different feature selection and classification methods were applied on the normalized feature matrix to select the best features and detect IDH and pre-IDH episodes in dialysis sessions. RESULTS: The best results were achieved from a genetic algorithm and AdaBoost. The obtained results on our developed database indicated that the mean and maximum accuracy of the proposed algorithm were 94.5 +/- 1.0 and 96.6 respectively. CONCLUSION: Some PPG signal features can be useful during hemodialysis session for hypotension management. PMID- 29477418 TI - Tuberculosis diagnosis support analysis for precarious health information systems. AB - BACKGROUND AND OBJECTIVE: Pulmonary tuberculosis is a world emergency for the World Health Organization. Techniques and new diagnosis tools are important to battle this bacterial infection. There have been many advances in all those fields, but in developing countries such as Colombia, where the resources and infrastructure are limited, new fast and less expensive strategies are increasingly needed. Artificial neural networks are computational intelligence techniques that can be used in this kind of problems and offer additional support in the tuberculosis diagnosis process, providing a tool to medical staff to make decisions about management of subjects under suspicious of tuberculosis. MATERIALS AND METHODS: A database extracted from 105 subjects with precarious information of people under suspect of pulmonary tuberculosis was used in this study. Data extracted from sex, age, diabetes, homeless, AIDS status and a variable with clinical knowledge from the medical personnel were used. Models based on artificial neural networks were used, exploring supervised learning to detect the disease. Unsupervised learning was used to create three risk groups based on available information. RESULTS: Obtained results are comparable with traditional techniques for detection of tuberculosis, showing advantages such as fast and low implementation costs. Sensitivity of 97% and specificity of 71% where achieved. CONCLUSIONS: Used techniques allowed to obtain valuable information that can be useful for physicians who treat the disease in decision making processes, especially under limited infrastructure and data. PMID- 29477419 TI - An expert system design to diagnose cancer by using a new method reduced rule base. AB - BACKGROUND AND OBJECTIVES: A Medical Expert System (MES) was developed which uses Reduced Rule Base to diagnose cancer risk according to the symptoms in an individual. A total of 13 symptoms were used. With the new MES, the reduced rules are controlled instead of all possibilities (213= 8192 different possibilities occur). By controlling reduced rules, results are found more quickly. The method of two-level simplification of Boolean functions was used to obtain Reduced Rule Base. Thanks to the developed application with the number of dynamic inputs and outputs on different platforms, anyone can easily test their own cancer easily. METHODS: More accurate results were obtained considering all the possibilities related to cancer. Thirteen different risk factors were determined to determine the type of cancer. The truth table produced in our study has 13 inputs and 4 outputs. The Boolean Function Minimization method is used to obtain less situations by simplifying logical functions. Diagnosis of cancer quickly thanks to control of the simplified 4 output functions. RESULTS: Diagnosis made with the 4 output values obtained using Reduced Rule Base was found to be quicker than diagnosis made by screening all 213= 8192 possibilities. With the improved MES, more probabilities were added to the process and more accurate diagnostic results were obtained. As a result of the simplification process in breast and renal cancer diagnosis 100% diagnosis speed gain, in cervical cancer and lung cancer diagnosis rate gain of 99% was obtained. CONCLUSIONS: With Boolean function minimization, less number of rules is evaluated instead of evaluating a large number of rules. Reducing the number of rules allows the designed system to work more efficiently and to save time, and facilitates to transfer the rules to the designed Expert systems. Interfaces were developed in different software platforms to enable users to test the accuracy of the application. Any one is able to diagnose the cancer itself using determinative risk factors. Thereby likely to beat the cancer with early diagnosis. PMID- 29477420 TI - Machine learning techniques for medical diagnosis of diabetes using iris images. AB - BACKGROUND AND OBJECTIVE: Complementary and alternative medicine techniques have shown their potential for the treatment and diagnosis of chronical diseases like diabetes, arthritis etc. On the same time digital image processing techniques for disease diagnosis is reliable and fastest growing field in biomedical. Proposed model is an attempt to evaluate diagnostic validity of an old complementary and alternative medicine technique, iridology for diagnosis of type-2 diabetes using soft computing methods. METHODS: Investigation was performed over a close group of total 338 subjects (180 diabetic and 158 non-diabetic). Infra-red images of both the eyes were captured simultaneously. The region of interest from the iris image was cropped as zone corresponds to the position of pancreas organ according to the iridology chart. Statistical, texture and discrete wavelength transformation features were extracted from the region of interest. RESULTS: The results show best classification accuracy of 89.63% calculated from RF classifier. Maximum specificity and sensitivity were absorbed as 0.9687 and 0.988, respectively. CONCLUSION: Results have revealed the effectiveness and diagnostic significance of proposed model for non-invasive and automatic diabetes diagnosis. PMID- 29477421 TI - ECG fiducial point extraction using switching Kalman filter. AB - In this paper, we propose a novel method for extracting fiducial points (FPs) of the beats in electrocardiogram (ECG) signals using switching Kalman filter (SKF). In this method, according to McSharry's model, ECG waveforms (P-wave, QRS complex and T-wave) are modeled with Gaussian functions and ECG baselines are modeled with first order auto regressive models. In the proposed method, a discrete state variable called "switch" is considered that affects only the observation equations. We denote a mode as a specific observation equation and switch changes between 7 modes and corresponds to different segments of an ECG beat. At each time instant, the probability of each mode is calculated and compared among two consecutive modes and a path is estimated, which shows the relation of each part of the ECG signal to the mode with the maximum probability. ECG FPs are found from the estimated path. For performance evaluation, the Physionet QT database is used and the proposed method is compared with methods based on wavelet transform, partially collapsed Gibbs sampler (PCGS) and extended Kalman filter. For our proposed method, the mean error and the root mean square error across all FPs are 2 ms (i.e. less than one sample) and 14 ms, respectively. These errors are significantly smaller than those obtained using other methods. The proposed method achieves lesser RMSE and smaller variability with respect to others. PMID- 29477422 TI - Visuospatial working memory assessment using a digital tablet in adolescents with attention deficit hyperactivity disorder. AB - BACKGROUND AND OBJECTIVE: Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder hypothesized to involve impaired visuospatial working memory (VSWM). However, there are few studies utilizing neuropsychological tests to measure VSWM in ADHD adolescents. The Rey-Osterrieth complex figure test (ROCF) is commonly used as a neuropsychological test to assess visuospatial working memory for individuals with ADHD. We assessed working memory using the ROCF test on a digital Galaxy tablet with the technically new Gaussian filter method. METHODS: Thirty adolescents with ADHD and 30 healthy control adolescents were recruited for participation in the current study. All adolescents were assessed with K-WISC-IV, Children's depression inventory, and the Korean ADHD rating scale. All adolescents were asked to copy the ROCF from paper onto a Galaxy tablet screen using a wireless pen. RESULTS: There was a significant difference in representative value of the deviation of the original images from template images (R-value) in copy and delayed recall between ADHD adolescents and healthy adolescents. There was no significant difference in R-value of immediate recall between ADHD adolescents and healthy adolescents. In all adolescents (ADHD and healthy) and ADHD adolescents, the R-value of copy was negatively correlated with visuospatial index and working memory index, and the R-value of delayed recall was negatively correlated with WMI. The R-value of copy and delayed recall was positively correlated with K-ARS in all adolescents and ADHD adolescents. CONCLUSIONS: ADHD adolescents showed differences in the R-values of copy and delayed recall in the digital ROCF version compared to healthy adolescents. The digital ROCF assessment tool can represent different patterns of visuospatial working memory abilities in ADHD adolescents compared to healthy adolescents. PMID- 29477423 TI - Using computational support in motor ability analysis of individuals with Down syndrome: Literature review. AB - BACKGROUND: The lack of motor ability is one of the main Down syndrome (DS) effects. However, there are several types of motor disorders that can be attenuated or corrected if they are early identified and properly analyzed. OBJECTIVES: The aim of our study is to support the local Physical Activity research group, which works with about 25 DS children, by means of computational resources for motor analysis. To that end, we first needed to identify the main computational approaches that support the motor analysis of DS individuals, if they are already connected to intervention programs, and potential opportunities to extend the current state of the art. METHOD: We carried out a systematic review that identified 28 papers from the current literature. These papers were then analyzed to answer the research questions defined in our study. RESULTS: Our main findings were: (1) the temporal distribution of papers shows this area is new and it is starting to create a body of knowledge that in fact supports motor treatments of DS individuals; (2) there is a diversity of studies that consider different research directions such as comparisons of motor features of DS with non-DS individuals, characterization of DS motor features, and approaches for intervention programs to improve DS motor abilities; (3) there are several types of sensing hardware that enables the development of studies from different perspectives; (4) spatial monitoring is performed but only in laboratory conditions; (5); mathematical tools are largely used while strategies based on artificial intelligence for automated analysis are ignored; and (6) proposals for DS post-intervention monitoring are not found in the literature. CONCLUSION: DS motor analysis is still a new research area and it is not mature yet. Thus, the use of computational resources is very pragmatic and focused only on mathematical tools that support the numerical analysis of the acquired data. The main proposals for motor analysis are performed in laboratory, so that there are several opportunities to create computational resources to obtain real-time data on the move. The integration of this data with intervention strategies is also a potential area for future researches. PMID- 29477424 TI - Analysis of methods commonly used in biomedicine for treatment versus control comparison of very small samples. AB - BACKGROUND AND OBJECTIVE: A rough estimate indicated that use of samples of size not larger than ten is not uncommon in biomedical research and that many of such studies are limited to strong effects due to sample sizes smaller than six. For data collected from biomedical experiments it is also often unknown if mathematical requirements incorporated in the sample comparison methods are satisfied. METHODS: Computer simulated experiments were used to examine performance of methods for qualitative sample comparison and its dependence on the effectiveness of exposure, effect intensity, distribution of studied parameter values in the population, and sample size. The Type I and Type II errors, their average, as well as the maximal errors were considered. RESULTS: The sample size 9 and the t-test method with p = 5% ensured error smaller than 5% even for weak effects. For sample sizes 6-8 the same method enabled detection of weak effects with errors smaller than 20%. If the sample sizes were 3-5, weak effects could not be detected with an acceptable error; however, the smallest maximal error in the most general case that includes weak effects is granted by the standard error of the mean method. The increase of sample size from 5 to 9 led to seven times more accurate detection of weak effects. Strong effects were detected regardless of the sample size and method used. CONCLUSIONS: The minimal recommended sample size for biomedical experiments is 9. Use of smaller sizes and the method of their comparison should be justified by the objective of the experiment. PMID- 29477425 TI - dfpk: An R-package for Bayesian dose-finding designs using pharmacokinetics (PK) for phase I clinical trials. AB - BACKGROUND AND OBJECTIVE: Dose-finding, aiming at finding the maximum tolerated dose, and pharmacokinetics studies are the first in human studies in the development process of a new pharmacological treatment. In the literature, to date only few attempts have been made to combine pharmacokinetics and dose finding and to our knowledge no software implementation is generally available. In previous papers, we proposed several Bayesian adaptive pharmacokinetics-based dose-finding designs in small populations. The objective of this work is to implement these dose-finding methods in an R package, called dfpk. METHODS: All methods were developed in a sequential Bayesian setting and Bayesian parameter estimation is carried out using the rstan package. All available pharmacokinetics and toxicity data are used to suggest the dose of the next cohort with a constraint regarding the probability of toxicity. Stopping rules are also considered for each method. The ggplot2 package is used to create summary plots of toxicities or concentration curves. RESULTS: For all implemented methods, dfpk provides a function (nextDose) to estimate the probability of efficacy and to suggest the dose to give to the next cohort, and a function to run trial simulations to design a trial (nsim). The sim.data function generates at each dose the toxicity value related to a pharmacokinetic measure of exposure, the AUC, with an underlying pharmacokinetic one compartmental model with linear absorption. It is included as an example since similar data-frames can be generated directly by the user and passed to nsim. CONCLUSION: The developed user friendly R package dfpk, available on the CRAN repository, supports the design of innovative dose-finding studies using PK information. PMID- 29477426 TI - Automated coronary artery tree segmentation in X-ray angiography using improved Hessian based enhancement and statistical region merging. AB - BACKGROUND AND OBJECTIVE: Coronary artery segmentation is a fundamental step for a computer-aided diagnosis system to be developed to assist cardiothoracic radiologists in detecting coronary artery diseases. Manual delineation of the vasculature becomes tedious or even impossible with a large number of images acquired in the daily life clinic. A new computerized image-based segmentation method is presented for automatically extracting coronary arteries from angiography images. METHODS: A combination of a multiscale-based adaptive Hessian based enhancement method and a statistical region merging technique provides a simple and effective way to improve the complex vessel structures as well as thin vessel delineation which often missed by other segmentation methods. The methodology was validated on 100 patients who underwent diagnostic coronary angiography. The segmentation performance was assessed via both qualitative and quantitative evaluations. RESULTS: Quantitative evaluation shows that our method is able to identify coronary artery trees with an accuracy of 93% and outperforms other segmentation methods in terms of two widely used segmentation metrics of mean absolute difference and dice similarity coefficient. CONCLUSIONS: The comparison to the manual segmentations from three human observers suggests that the presented automated segmentation method is potential to be used in an image based computerized analysis system for early detection of coronary artery disease. PMID- 29477427 TI - Deep Convolutional Neural Networks for breast cancer screening. AB - BACKGROUND AND OBJECTIVE: Radiologists often have a hard time classifying mammography mass lesions which leads to unnecessary breast biopsies to remove suspicions and this ends up adding exorbitant expenses to an already burdened patient and health care system. METHODS: In this paper we developed a Computer aided Diagnosis (CAD) system based on deep Convolutional Neural Networks (CNN) that aims to help the radiologist classify mammography mass lesions. Deep learning usually requires large datasets to train networks of a certain depth from scratch. Transfer learning is an effective method to deal with relatively small datasets as in the case of medical images, although it can be tricky as we can easily start overfitting. RESULTS: In this work, we explore the importance of transfer learning and we experimentally determine the best fine-tuning strategy to adopt when training a CNN model. We were able to successfully fine-tune some of the recent, most powerful CNNs and achieved better results compared to other state-of-the-art methods which classified the same public datasets. For instance we achieved 97.35% accuracy and 0.98 AUC on the DDSM database, 95.50% accuracy and 0.97 AUC on the INbreast database and 96.67% accuracy and 0.96 AUC on the BCDR database. Furthermore, after pre-processing and normalizing all the extracted Regions of Interest (ROIs) from the full mammograms, we merged all the datasets to build one large set of images and used it to fine-tune our CNNs. The CNN model which achieved the best results, a 98.94% accuracy, was used as a baseline to build the Breast Cancer Screening Framework. To evaluate the proposed CAD system and its efficiency to classify new images, we tested it on an independent database (MIAS) and got 98.23% accuracy and 0.99 AUC. CONCLUSION: The results obtained demonstrate that the proposed framework is performant and can indeed be used to predict if the mass lesions are benign or malignant. PMID- 29477428 TI - Cloud-assisted mutual authentication and privacy preservation protocol for telecare medical information systems. AB - BACKGROUND AND OBJECTIVE: With the rapid development of wireless communication technologies and the growing prevalence of smart devices, telecare medical information system (TMIS) allows patients to receive medical treatments from the doctors via Internet technology without visiting hospitals in person. By adopting mobile device, cloud-assisted platform and wireless body area network, the patients can collect their physiological conditions and upload them to medical cloud via their mobile devices, enabling caregivers or doctors to provide patients with appropriate treatments at anytime and anywhere. In order to protect the medical privacy of the patient and guarantee reliability of the system, before accessing the TMIS, all system participants must be authenticated. METHODS: Mohit et al. recently suggested a lightweight authentication protocol for cloud-based health care system. They claimed their protocol ensures resilience of all well-known security attacks and has several important features such as mutual authentication and patient anonymity. In this paper, we demonstrate that Mohit et al.'s authentication protocol has various security flaws and we further introduce an enhanced version of their protocol for cloud assisted TMIS, which can ensure patient anonymity and patient unlinkability and prevent the security threats of report revelation and report forgery attacks. RESULTS: The security analysis proves that our enhanced protocol is secure against various known attacks as well as found in Mohit et al.'s protocol. Compared with existing related protocols, our enhanced protocol keeps the merits of all desirable security requirements and also maintains the efficiency in terms of computation costs for cloud-assisted TMIS. CONCLUSIONS: We propose a more secure mutual authentication and privacy preservation protocol for cloud-assisted TMIS, which fixes the mentioned security weaknesses found in Mohit et al.'s protocol. According to our analysis, our authentication protocol satisfies most functionality features for privacy preservation and effectively cope with cloud assisted TMIS with better efficiency. PMID- 29477429 TI - Efficient computational model for classification of protein localization images using Extended Threshold Adjacency Statistics and Support Vector Machines. AB - BACKGROUND AND OBJECTIVE: Discriminative and informative feature extraction is the core requirement for accurate and efficient classification of protein subcellular localization images so that drug development could be more effective. The objective of this paper is to propose a novel modification in the Threshold Adjacency Statistics technique and enhance its discriminative power. METHODS: In this work, we utilized Threshold Adjacency Statistics from a novel perspective to enhance its discrimination power and efficiency. In this connection, we utilized seven threshold ranges to produce seven distinct feature spaces, which are then used to train seven SVMs. The final prediction is obtained through the majority voting scheme. The proposed ETAS-SubLoc system is tested on two benchmark datasets using 5-fold cross-validation technique. RESULTS: We observed that our proposed novel utilization of TAS technique has improved the discriminative power of the classifier. The ETAS-SubLoc system has achieved 99.2% accuracy, 99.3% sensitivity and 99.1% specificity for Endogenous dataset outperforming the classical Threshold Adjacency Statistics technique. Similarly, 91.8% accuracy, 96.3% sensitivity and 91.6% specificity values are achieved for Transfected dataset. CONCLUSIONS: Simulation results validated the effectiveness of ETAS SubLoc that provides superior prediction performance compared to the existing technique. The proposed methodology aims at providing support to pharmaceutical industry as well as research community towards better drug designing and innovation in the fields of bioinformatics and computational biology. The implementation code for replicating the experiments presented in this paper is available at: https://drive.google.com/file/d/0B7IyGPObWbSqRTRMcXI2bG5CZWs/view?usp=sharing. PMID- 29477430 TI - Assessing mechanical ventilation asynchrony through iterative airway pressure reconstruction. AB - BACKGROUND AND OBJECTIVE: Respiratory mechanics estimation can be used to guide mechanical ventilation (MV) but is severely compromised when asynchronous breathing occurs. In addition, asynchrony during MV is often not monitored and little is known about the impact or magnitude of asynchronous breathing towards recovery. Thus, it is important to monitor and quantify asynchronous breathing over every breath in an automated fashion, enabling the ability to overcome the limitations of model-based respiratory mechanics estimation during asynchronous breathing ventilation. METHODS: An iterative airway pressure reconstruction (IPR) method is used to reconstruct asynchronous airway pressure waveforms to better match passive breathing airway waveforms using a single compartment model. The reconstructed pressure enables estimation of respiratory mechanics of airway pressure waveform essentially free from asynchrony. Reconstruction enables real time breath-to-breath monitoring and quantification of the magnitude of the asynchrony (MAsyn). RESULTS AND DISCUSSION: Over 100,000 breathing cycles from MV patients with known asynchronous breathing were analyzed. The IPR was able to reconstruct different types of asynchronous breathing. The resulting respiratory mechanics estimated using pressure reconstruction were more consistent with smaller interquartile range (IQR) compared to respiratory mechanics estimated using asynchronous pressure. Comparing reconstructed pressure with asynchronous pressure waveforms quantifies the magnitude of asynchronous breathing, which has a median value MAsyn for the entire dataset of 3.8%. CONCLUSION: The iterative pressure reconstruction method is capable of identifying asynchronous breaths and improving respiratory mechanics estimation consistency compared to conventional model-based methods. It provides an opportunity to automate real-time quantification of asynchronous breathing frequency and magnitude that was previously limited to invasively method only. PMID- 29477431 TI - Data mart construction based on semantic annotation of scientific articles: A case study for the prioritization of drug targets. AB - BACKGROUND AND OBJECTIVES: Semantic text annotation enables the association of semantic information (ontology concepts) to text expressions (terms), which are readable by software agents. In the scientific scenario, this is particularly useful because it reveals a lot of scientific discoveries that are hidden within academic articles. The Biomedical area has more than 300 ontologies, most of them composed of over 500 concepts. These ontologies can be used to annotate scientific papers and thus, facilitate data extraction. However, in the context of a scientific research, a simple keyword-based query using the interface of a digital scientific texts library can return more than a thousand hits. The analysis of such a large set of texts, annotated with such numerous and large ontologies, is not an easy task. Therefore, the main objective of this work is to provide a method that could facilitate this task. METHODS: This work describes a method called Text and Ontology ETL (TOETL), to build an analytical view over such texts. First, a corpus of selected papers is semantically annotated using distinct ontologies. Then, the annotation data is extracted, organized and aggregated into the dimensional schema of a data mart. RESULTS: Besides the TOETL method, this work illustrates its application through the development of the TaP DM (Target Prioritization data mart). This data mart has focus on the research of gene essentiality, a key concept to be considered when searching for genes showing potential as anti-infective drug targets. CONCLUSIONS: This work reveals that the proposed approach is a relevant tool to support decision making in the prioritization of new drug targets, being more efficient than the keyword-based traditional tools. PMID- 29477432 TI - Fast modified Self-organizing Deformable Model: Geometrical feature-preserving mapping of organ models onto target surfaces with various shapes and topologies. AB - BACKGROUND AND OBJECTIVE: This paper proposes a new method for mapping surface models of human organs onto target surfaces with the same genus as the organs. METHODS: In the proposed method, called modified Self-organizing Deformable Model (mSDM), the mapping problem is formulated as the minimization of an objective function which is defined as the weighted linear combination of four energy functions: model fitness, foldover-free, landmark mapping accuracy, and geometrical feature preservation. Further, we extend mSDM to speed up its processes, and call it Fast mSDM. RESULTS: From the mapping results of various organ models with different number of holes, it is observed that Fast mSDM can map the organ models onto their target surfaces efficiently and stably without foldovers while preserving geometrical features. CONCLUSIONS: Fast mSDM can map the organ model onto the target surface efficiently and stably, and is applicable to medical applications including Statistical Shape Model. PMID- 29477433 TI - Automatic energy expenditure measurement for health science. AB - BACKGROUND AND OBJECTIVE: It is crucial to predict the human energy expenditure in any sports activity and health science application accurately to investigate the impact of the activity. However, measurement of the real energy expenditure is not a trivial task and involves complex steps. The objective of this work is to improve the performance of existing estimation models of energy expenditure by using machine learning algorithms and several data from different sensors and provide this estimation service in a cloud-based platform. METHODS: In this study, we used input data such as breathe rate, and hearth rate from three sensors. Inputs are received from a web form and sent to the web service which applies a regression model on Azure cloud platform. During the experiments, we assessed several machine learning models based on regression methods. RESULTS: Our experimental results showed that our novel model which applies Boosted Decision Tree Regression in conjunction with the median aggregation technique provides the best result among other five regression algorithms. CONCLUSIONS: This cloud-based energy expenditure system which uses a web service showed that cloud computing technology is a great opportunity to develop estimation systems and the new model which applies Boosted Decision Tree Regression with the median aggregation provides remarkable results. PMID- 29477434 TI - Computer assisted gastric abnormalities detection using hybrid texture descriptors for chromoendoscopy images. AB - BACKGROUND AND OBJECTIVE: The early diagnosis of stomach cancer can be performed by using a proper screening procedure. Chromoendoscopy (CH) is an image-enhanced video endoscopy technique, which is used for inspection of the gastrointestinal tract by spraying dyes to highlight the gastric mucosal structures. An endoscopy session can end up with generating a large number of video frames. Therefore, inspection of every individual endoscopic-frame is an exhaustive task for the medical experts. In contrast with manual inspection, the automated analysis of gastroenterology images using computer vision based techniques can provide assistance to endoscopist, by finding out abnormal frames from the whole endoscopic sequence. METHODS: In this paper, we have presented a new feature extraction method named as Gabor-based gray-level co-occurrence matrix (G2LCM) for computer-aided detection of CH abnormal frames. It is a hybrid texture extraction approach which extracts a combination both local and global texture descriptors. Moreover, texture information of a CH image is represented by computing the gray level co-occurrence matrix of Gabor filters responses. Furthermore, the second-order statistics of these co-occurrence matrices are computed to represent images' texture. RESULTS: The obtained results show the possibility to correctly classifying abnormal from normal frames, with sensitivity, specificity, accuracy, and area under the curve as 91%, 82%, 87% and 0.91 respectively, by using a support vector machine classifier and G2LCM texture features. CONCLUSION: It is apparent from results that the proposed system can be used for providing aid to the gastroenterologist in the screening of the gastric tract. Ultimately, the time taken by an endoscopic procedure will be sufficiently reduced. PMID- 29477435 TI - Kidney segmentation in ultrasound, magnetic resonance and computed tomography images: A systematic review. AB - BACKGROUND AND OBJECTIVE: Segmentation is an essential step in computer-aided diagnosis and treatment planning of kidney diseases. In recent years, several researchers proposed multiple techniques to segment the kidney in medical images from distinct imaging acquisition systems, namely ultrasound, magnetic resonance, and computed tomography. This article aims to present a systematic review of the different methodologies developed for kidney segmentation. METHODS: With this work, it is intended to analyze and categorize the different kidney segmentation algorithms, establishing a comparison between them and discussing the most appropriate methods for each modality. For that, articles published between 2010 and 2016 were analyzed. The search was performed in Scopus and Web of Science using the expressions "kidney segmentation" and "renal segmentation". RESULTS: A total of 1528 articles were retrieved from the databases, and 95 articles were selected for this review. After analysis of the selected articles, the reviewed segmentation techniques were categorized according to their theoretical approach. CONCLUSIONS: Based on the performed analysis, it was possible to identify segmentation approaches based on distinct image processing classes that can be used to accurately segment the kidney in images of different imaging modalities. Nevertheless, further research on kidney segmentation must be conducted to overcome the current drawbacks of the state-of-the-art methods. Moreover, a standardization of the evaluation database and metrics is needed to allow a direct comparison between methods. PMID- 29477436 TI - Supervised learning based multimodal MRI brain tumour segmentation using texture features from supervoxels. AB - BACKGROUND: Accurate segmentation of brain tumour in magnetic resonance images (MRI) is a difficult task due to various tumour types. Using information and features from multimodal MRI including structural MRI and isotropic (p) and anisotropic (q) components derived from the diffusion tensor imaging (DTI) may result in a more accurate analysis of brain images. METHODS: We propose a novel 3D supervoxel based learning method for segmentation of tumour in multimodal MRI brain images (conventional MRI and DTI). Supervoxels are generated using the information across the multimodal MRI dataset. For each supervoxel, a variety of features including histograms of texton descriptor, calculated using a set of Gabor filters with different sizes and orientations, and first order intensity statistical features are extracted. Those features are fed into a random forests (RF) classifier to classify each supervoxel into tumour core, oedema or healthy brain tissue. RESULTS: The method is evaluated on two datasets: 1) Our clinical dataset: 11 multimodal images of patients and 2) BRATS 2013 clinical dataset: 30 multimodal images. For our clinical dataset, the average detection sensitivity of tumour (including tumour core and oedema) using multimodal MRI is 86% with balanced error rate (BER) 7%; while the Dice score for automatic tumour segmentation against ground truth is 0.84. The corresponding results of the BRATS 2013 dataset are 96%, 2% and 0.89, respectively. CONCLUSION: The method demonstrates promising results in the segmentation of brain tumour. Adding features from multimodal MRI images can largely increase the segmentation accuracy. The method provides a close match to expert delineation across all tumour grades, leading to a faster and more reproducible method of brain tumour detection and delineation to aid patient management. PMID- 29477437 TI - Simultaneous detection and classification of breast masses in digital mammograms via a deep learning YOLO-based CAD system. AB - BACKGROUND AND OBJECTIVE: Automatic detection and classification of the masses in mammograms are still a big challenge and play a crucial role to assist radiologists for accurate diagnosis. In this paper, we propose a novel Computer Aided Diagnosis (CAD) system based on one of the regional deep learning techniques, a ROI-based Convolutional Neural Network (CNN) which is called You Only Look Once (YOLO). Although most previous studies only deal with classification of masses, our proposed YOLO-based CAD system can handle detection and classification simultaneously in one framework. METHODS: The proposed CAD system contains four main stages: preprocessing of mammograms, feature extraction utilizing deep convolutional networks, mass detection with confidence, and finally mass classification using Fully Connected Neural Networks (FC-NNs). In this study, we utilized original 600 mammograms from Digital Database for Screening Mammography (DDSM) and their augmented mammograms of 2,400 with the information of the masses and their types in training and testing our CAD. The trained YOLO-based CAD system detects the masses and then classifies their types into benign or malignant. RESULTS: Our results with five-fold cross validation tests show that the proposed CAD system detects the mass location with an overall accuracy of 99.7%. The system also distinguishes between benign and malignant lesions with an overall accuracy of 97%. CONCLUSIONS: Our proposed system even works on some challenging breast cancer cases where the masses exist over the pectoral muscles or dense regions. PMID- 29477438 TI - Fully automatic cervical vertebrae segmentation framework for X-ray images. AB - The cervical spine is a highly flexible anatomy and therefore vulnerable to injuries. Unfortunately, a large number of injuries in lateral cervical X-ray images remain undiagnosed due to human errors. Computer-aided injury detection has the potential to reduce the risk of misdiagnosis. Towards building an automatic injury detection system, in this paper, we propose a deep learning based fully automatic framework for segmentation of cervical vertebrae in X-ray images. The framework first localizes the spinal region in the image using a deep fully convolutional neural network. Then vertebra centers are localized using a novel deep probabilistic spatial regression network. Finally, a novel shape-aware deep segmentation network is used to segment the vertebrae in the image. The framework can take an X-ray image and produce a vertebrae segmentation result without any manual intervention. Each block of the fully automatic framework has been trained on a set of 124 X-ray images and tested on another 172 images, all collected from real-life hospital emergency rooms. A Dice similarity coefficient of 0.84 and a shape error of 1.69 mm have been achieved. PMID- 29477439 TI - Communication and diagnosis: Cornerstones for achieving precision medicine. PMID- 29477440 TI - Cross-modal and non-monotonic representations of statistical regularity are encoded in local neural response patterns. AB - Current neurobiological models assign a central role to predictive processes calibrated to environmental statistics. Neuroimaging studies examining the encoding of stimulus uncertainty have relied almost exclusively on manipulations in which stimuli were presented in a single sensory modality, and further assumed that neural responses vary monotonically with uncertainty. This has left a gap in theoretical development with respect to two core issues: (i) are there cross modal brain systems that encode input uncertainty in way that generalizes across sensory modalities, and (ii) are there brain systems that track input uncertainty in a non-monotonic fashion? We used multivariate pattern analysis to address these two issues using auditory, visual and audiovisual inputs. We found signatures of cross-modal encoding in frontoparietal, orbitofrontal, and association cortices using a searchlight cross-classification analysis where classifiers trained to discriminate levels of uncertainty in one modality were tested in another modality. Additionally, we found widespread systems encoding uncertainty non-monotonically using classifiers trained to discriminate intermediate levels of uncertainty from both the highest and lowest uncertainty levels. These findings comprise the first comprehensive report of cross-modal and non-monotonic neural sensitivity to statistical regularities in the environment, and suggest that conventional paradigms testing for monotonic responses to uncertainty in a single sensory modality may have limited generalizability. PMID- 29477441 TI - Ghost interactions in MEG/EEG source space: A note of caution on inter-areal coupling measures. AB - When combined with source modeling, magneto- (MEG) and electroencephalography (EEG) can be used to study long-range interactions among cortical processes non invasively. Estimation of such inter-areal connectivity is nevertheless hindered by instantaneous field spread and volume conduction, which artificially introduce linear correlations and impair source separability in cortical current estimates. To overcome the inflating effects of linear source mixing inherent to standard interaction measures, alternative phase- and amplitude-correlation based connectivity measures, such as imaginary coherence and orthogonalized amplitude correlation have been proposed. Being by definition insensitive to zero-lag correlations, these techniques have become increasingly popular in the identification of correlations that cannot be attributed to field spread or volume conduction. We show here, however, that while these measures are immune to the direct effects of linear mixing, they may still reveal large numbers of spurious false positive connections through field spread in the vicinity of true interactions. This fundamental problem affects both region-of-interest-based analyses and all-to-all connectome mappings. Most importantly, beyond defining and illustrating the problem of spurious, or "ghost" interactions, we provide a rigorous quantification of this effect through extensive simulations. Additionally, we further show that signal mixing also significantly limits the separability of neuronal phase and amplitude correlations. We conclude that spurious correlations must be carefully considered in connectivity analyses in MEG/EEG source space even when using measures that are immune to zero-lag correlations. PMID- 29477443 TI - Towards a Comparable Quantification of Resilience. AB - Resilience is a key concept in ecology and describes the capacity of an ecosystem to maintain its state and recover from disturbances. Numerous metrics have been applied to quantify resilience over a range of ecosystems. However, the way resilience is quantified affects the degree to which different trajectories of ecosystem recovery from disturbance are represented as 'resilient', precluding a comparison of disturbance responses across ecosystems and their properties and functions. To approach a broadly comparable assessment of resilience we suggest using a bivariate framework that jointly considers the disturbance impact and the recovery rate, both normalized to the undisturbed state of a system. We demonstrate the potential of the framework for attribution and integration across the various components underlying resilience. PMID- 29477442 TI - An fMRI study of coherent visual motion processing in children and adults. AB - There is a large corpus of brain imaging studies examining the dorsal visual pathway, especially area V5/MT during visual motion perception. However, despite evidence suggesting a protracted development of the dorsal visual stream, and a role of this pathway in neurodevelopmental disorders, V5/MT has not been characterized developmentally. Further, experiential factors such as reading acquisition may play a modulating role in any age-dependent changes. Here we used a coherent visual motion detection task to examine V5/MT activity and connectivity in typical participants in two studies: a Cross- Sectional Study comparing adults and children; and a Longitudinal Study of 2nd graders followed into 3rd grade. In the Cross-Sectional Study, a whole-brain analysis revealed no differences between the two groups, whereas a region of interest (ROI) approach identified greater activation in left (right trending) V5/MT in adults compared to children. However, when we measured V5/MT activation individually for each participant, children and adults showed no difference in the location or intensity of activation, although children did exhibit relatively larger extent of V5/MT activation bilaterally. There was also relatively greater functional connectivity in the children between left and right occipitotemporal cortex, including V5/MT. The Longitudinal Study revealed no changes in V5/MT activation for any measures of activation or functional connectivity from 2nd to 3rd grade. Finally, there was no evidence of an association between reading and V5/MT over time, nor predictive power of V5/MT activity for later reading. Together, our results indicate similar V5/MT activity across age groups, with relatively greater extent of V5/MT activation and functional connectivity in children relative to adults, bilaterally. These differences were not apparent over the time course of one year, suggesting that these developmental changes occur over a more protracted period. PMID- 29477444 TI - The value of patient registries in advancing pediatric surgical care. AB - Pediatric surgeons treat a variety of conditions that are distinguished by their low occurrence rate, complexity, and need for integrated multidisciplinary care. Although randomized controlled trials (RCTs) are considered the gold standard for generating evidence to inform best practice, they are poorly suited to rare diseases based on the variability of illness severity, unpredictability in clinical course, and the impact limitations of studying a single intervention at a time. An alternative to RCTs for comparative effectiveness research for rare diseases in pediatric surgery is the patient registry, which collects detailed and condition-specific patient level data related to illness severity, treatment, and outcome, and allows a large, disease-specific database to be created for the dual purposes of collaborative research and quality improvement across participating sites. This review discusses the various functions of a patient registry in fulfilling its mandate of evidence-based practice and outcome improvement using examples from a variety of existing pediatric surgical registries. The value proposition of patient registries as sources of knowledge, facilitators of practice standardization, and enablers of continuous quality improvement is discussed. PMID- 29477445 TI - Laparoscopic repair of inguinal hernia in infants: Comparison with open hernia repair. AB - PURPOSE: This study aimed to evaluate the usefulness of laparoscopic repair of inguinal hernia (LR) in infants in comparison with open hernia repair (OR). METHODS: We retrospectively analyzed the clinical data of 465 infants treated for inguinal hernia from January 2006 to December 2015. Among them, 124 underwent LR and 341 underwent OR. RESULTS: In the OR group, 16.1% (55/341) primarily underwent bilateral inguinal hernia repair and 13.6% (42/308) subsequently developed metachronous contralateral inguinal hernia during follow-up. In the LR group, 75.8% (94/124) underwent primary bilateral inguinal hernia repair and only 1.6% (2/123) developed metachronous contralateral inguinal hernia. The mean operation times of unilateral inguinal hernia repair showed no statistical differences between LR and OR. However, the mean operation times of bilateral inguinal hernia repair were shorter in LR (39.8+/-10.4 vs. 51.1+/-14.4min, p<0.001). Postoperative recurrence and wound infection showed no statistical differences between the groups, but postoperative scrotal swelling was more common in OR (0.0% vs. 4.0%, p=0.006). CONCLUSION: LR in infants showed a lower incidence of metachronous hernia, shorter operation times, and better postoperative course than OR. LR could be considered the primary operation method in infants with inguinal hernia. LEVELS OF EVIDENCE: Prognosis Study, Retrospective Study, Level III. PMID- 29477446 TI - Estrogen-induced neuroimmunomodulation as facilitator of and barrier to reproductive aging in brain and lymphoid organs. AB - Reproductive aging in females is marked by alterations in gonadal hormones, estrogen and progesterone, that facilitate cessation of reproductive cycles and onset of female-specific diseases such as autoimmune and neurodegenerative diseases, hormone-dependent cancers, and osteoporosis. Bidirectional communication between the three homeostatic systems, nervous system, endocrine system, and immune system, is essential for the maintenance of health and any dysfunction in the cross-talk promotes the development of diseases and cancer. The pleiotropic effects of estrogen on neural-immune interactions may promote either neuroprotection or inflammatory conditions depending on the site of action, dose and duration of treatment, type of estrogen receptors and its influence on intracellular signaling pathways, etc. Our studies involving treatment of early middle-aged female rats with low and high doses of estrogen and examining the brain areas, thymus, spleen, and lymph nodes revealed that estrogen-induced changes in neural-immune interactions are markedly affected in thymus followed by spleen and lymph nodes while it confers neuroprotection in the brain areas. These alterations are determined by antioxidant enzyme status, growth factors, intracellular signaling pathways involved in cell survival and inflammation, and metabolic enzymes and thus, may regulate the various stages in female reproductive aging. It is imperative that detailed longitudinal studies are carried out to understand the mechanisms of neuroendocrine-immune interactions in reproductive aging to facilitate healthy aging and for the development of better treatment strategies for female-specific diseases. PMID- 29477447 TI - Delay-dependent dynamical analysis of complex-valued memristive neural networks: Continuous-time and discrete-time cases. AB - This paper considers the delay-dependent stability of memristive complex-valued neural networks (MCVNNs). A novel linear mapping function is presented to transform the complex-valued system into the real-valued system. Under such mapping function, both continuous-time and discrete-time MCVNNs are analyzed in this paper. Firstly, when activation functions are continuous but not Lipschitz continuous, an extended matrix inequality is proved to ensure the stability of continuous-time MCVNNs. Furthermore, if activation functions are discontinuous, a discontinuous adaptive controller is designed to acquire its stability by applying Lyapunov-Krasovskii functionals. Secondly, compared with techniques in continuous-time MCVNNs, the Halanay-type inequality and comparison principle are firstly used to exploit the dynamical behaviors of discrete-time MCVNNs. Finally, the effectiveness of theoretical results is illustrated through numerical examples. PMID- 29477448 TI - Effect of lung deflation with indacaterol plus glycopyrronium on ventricular filling in patients with hyperinflation and COPD (CLAIM): a double-blind, randomised, crossover, placebo-controlled, single-centre trial. AB - BACKGROUND: Pulmonary hyperinflation in chronic obstructive pulmonary disease (COPD) is associated with reduced biventricular end-diastolic volumes and increased morbidity and mortality. The combination of a long-acting beta agonist (LABA) and a muscarinic antagonist (LAMA) is more effective in reducing hyperinflation than LABA-inhaled corticosteroid combination therapy but whether dual bronchodilation improves cardiac function is unknown. METHODS: We did a double-blind, randomised, two-period crossover, placebo-controlled, single-centre study (CLAIM) at the Fraunhofer Institute of Toxicology and Experimental Medicine (Hannover, Germany), a specialty clinic. Eligible participants were patients aged at least 40 years with COPD, pulmonary hyperinflation (defined by a baseline residual volume >135% of predicted), a smoking history of at least ten pack years, and airflow limitation (FEV1 <80% predicted and post-bronchodilator FEV1: forced vital capacity <0.7). Patients with stable cardiovascular disease were eligible, but those with arrhythmias, heart failure, unstable ischaemic heart disease, or uncontrolled hypertension were not. We randomly assigned participants (1:1) to either receive a combined inhaled dual bronchodilator containing the LABA indacaterol (110 MUg as maleate salt) plus the LAMA glycopyrronium (50 MUg as bromide salt) once per day for 14 days, followed by a 14-day washout, then a matched placebo for 14 days, or to receive the same treatments in reverse order. The randomisation was done using lists and was concealed from patients and investigators. The primary endpoint was the effect of indacaterol-glycopyrronium versus placebo on left-ventricular end-diastolic volume measured by MRI done on day 1 (visit 4) and day 15 (visit 5) in treatment period 1 and on day 29 (visit 6) and day 43 (visit 7) in treatment period 2 in the per-protocol population. Left-ventricular end-diastolic volume was indexed to body surface area. Safety was assessed in all participants who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02442206. FINDINGS: Between May 18, 2015, and April 20, 2017, we randomly assigned 62 eligible participants to treatment; 30 to indacaterol-glycopyrronium followed by placebo and 32 to placebo followed by indacaterol-glycopyrronium. The 62 randomly assigned patients were included in the intent-to-treat analysis. There were two protocol violations and therefore 60 were included in the per-protocol analysis. 57 patients completed both treatment periods. After indacaterol-glycopyrronium treatment, left-ventricular end-diastolic volume increased from a mean 55.46 mL/m2 (SD 15.89) at baseline to a least-squares (LS) mean of 61.76 mL/m2 (95% CI 57.68-65.84), compared with a change from 56.42 mL/m2 at baseline (13.54) to 56.53 mL/m2 (52.43-60.62) after placebo (LS means treatment difference 5.23 mL/m2 [95% CI 3.22 to 7.25; p<0.0001]). The most common adverse events reported with indacaterol-glycopyrronium were cough (in nine patients [15%] of 59) and throat irritation (in seven [12%]). With placebo, the most common adverse events reported were headache (in five patients [8%] of 61) and upper respiratory tract infection (in four [7%]). Two patients had serious adverse events: one (2%) after indacaterol-glycopyrronium (endometrial cancer) and one (2%) after placebo (myocardial infarction); these were not thought to be treatment related. No patients died during the study. INTERPRETATION: This is the first study to analyse the effect of LABA-LAMA combination therapy on cardiac function in patients with COPD and lung hyperinflation. Dual bronchodilation with indacaterol glycopyrronium significantly improved cardiac function as measured by left ventricular end-diastolic volume. The results are important because of the known association of cardiovascular impairment with COPD, and support the early use of dual bronchodilation in patients with COPD who show signs of pulmonary hyperinflation. FUNDING: Novartis Pharma GmbH. PMID- 29477449 TI - Prediction of ARDS outcome: what tool should I use? PMID- 29477450 TI - Deciphering COPD and associated cardiovascular impairment. PMID- 29477451 TI - The Adaptation and Psychometric Properties of the Kid-KINDLR for Hospitalized Children in Chile. PMID- 29477452 TI - Incidence, Management, and Implications of Visceral Thrombosis in Pancreatic Ductal Adenocarcinoma. AB - BACKGROUND: Visceral or splanchnic thrombosis is defined as thrombi within the hepatoportal venous system, including portal (PV), mesenteric (MV), and splenic vein (SV), as well as thrombi in renal or gonadal veins. There are limited data to evaluate the prognostic significance, incidence, and clinical management of visceral thromboses in patients with pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: We conducted an analysis of 95 patients treated at Memorial Sloan Kettering Cancer Center with PDAC who had a visceral thrombosis. RESULTS: A total of 153 visceral thromboses (VsT) were identified in 95 patients (n = 51, 54% woman). A total of 36 patients (37%) had locally advanced disease, and n = 59 (62%) had metastatic disease. Systemic therapies received included FOLFIRINOX (n = 57, 60%) and GC/PTX (n = 27, 28%). All VsT events were incidentally detected. Overall survival of cohort was 12.3 months (range, 10.2-14.4 months). Visceral thrombosis incidence in the cohort was as follows: portal vein (PV) (45%), MV (26%), SV (17%), and gonadal veins (8%). Time to develop first VsT was 4.3 months (range, 3-5.6 months), and time to death from VsT development was 1.87 months (range, 0.8-2.8 months). Forty-five patients (47%) developed a second VsT. Sixty percent had a Khorana risk score of > 3. Thirty-nine patients (41%) were treated with short-term anticoagulation (AC) (< 1 month) (low-molecular-weight heparin, n = 34). Forty-five patients (47%) were treated with long-term AC (> 1 month) (low molecular-weight heparin, n = 32; 23 were transitioned to an oral anticoagulant). Twenty-two patients (23%) were not treated with AC. Eight patients (8%) had a bleeding complication from AC. Portal vein thrombosis had the shortest overall survival at 3.6 months (range, 2.3-4.8 months). CONCLUSION: In PDAC, VsT can frequently present as an incidental finding on routine abdominal imaging. The most common location is PV, followed by MV and SV. We observed that AC is underutilized in this setting despite a low bleeding complication rate. PV was associated with the least overall survival of the VsT. Future large prospective studies should explore the role of AC and value in this setting. PMID- 29477453 TI - Normalization of connexin 43 protein levels prevents cellular and functional signs of dystrophic cardiomyopathy in mice. AB - Duchenne muscular dystrophy (DMD) associated cardiomyopathy remains incurable. Connexin 43 (Cx43) is upregulated and remodeled in the hearts of mdx mice, a mouse model of DMD. Hearts from Wild Type, mdx, and mdx:Cx43(+/-) mice were studied before (4-6 months) and after (10-15 months) the onset of cardiomyopathy to assess the impact of decreasing Cx43 levels on cardiac pathology in dystrophic mice. Increased connexin 43 protein levels in mdx hearts were not observed in mdx:Cx43(+/-) hearts. Cx43 remodeling in mdx hearts was attenuated in mdx:Cx43(+/ ) hearts. At time-point 4-6 months, isolated cardiomyocytes from mdx hearts displayed enhanced ethidium bromide uptake, augmented intracellular calcium signals and increased production of reactive oxygen species. These pathological features were improved in mdx:Cx43(+/-) cardiomyocytes. Isoproterenol-challenged mdx:Cx43(+/-) mice did not show arrhythmias or acute lethality observed in mdx mice. Likewise, isoproterenol-challenged mdx:Cx43(+/-) isolated hearts were also protected from arrhythmogenesis. At time-point 10-15 months, mdx:Cx43(+/-) mice showed decreased cardiac fibrosis and improved ventricular function, relative to mdx mice. These results suggest that normalization of connexin 43 protein levels in mdx mice reduces overall cardiac pathology. PMID- 29477454 TI - The three-dimensional arrangement of the mineralized collagen fibers in elephant ivory and its relation to mechanical and optical properties. AB - : Elephant tusks are composed of dentin or ivory, a hierarchical and composite biological material made of mineralized collagen fibers (MCF). The specific arrangement of the MCF is believed to be responsible for the optical and mechanical properties of the tusks. Especially the MCF organization likely contributes to the formation of the bright and dark checkerboard pattern observed on polished sections of tusks (Schreger pattern). Yet, the precise structural origin of this optical motif is still controversial. We hereby address this issue using complementary analytical methods (small and wide angle X-ray scattering, cross-polarized light microscopy and scanning electron microscopy) on elephant ivory samples and show that MCF orientation in ivory varies from the outer to the inner part of the tusk. An external cohesive layer of MCF with fiber direction perpendicular to the tusk axis wraps the mid-dentin region, where the MCF are oriented mainly along the tusk axis and arranged in a plywood-like structure with fiber orientations oscillating in a narrow angular range. This particular oscillating-plywood structure of the MCF and the birefringent properties of the collagen fibers, likely contribute to the emergence of the Schreger pattern, one of the most intriguing macroscopic optical patterns observed in mineralized tissues and of great importance for authentication issues in archeology and forensic sciences. STATEMENT OF SIGNIFICANCE: Elephant tusks are intriguing biological materials as they are composed of dentin (ivory) like teeth but have mineralized collagen fibers (MCF) similarly arranged to the ones of lamellar bones and function as bones or antlers. Here, we showed that ivory has a graded structure with varying MCF orientations and that MCF of the mid-dentin are arranged in plywood like layers with fiber orientations oscillating in a narrow angular range around the tusk axis. This organization of the MCF may contribute to ivory's mechanical properties and, together with the collagen fibers birefringence properties, strongly relates to its optical properties, i.e. the emergence of a macroscopic checkerboard pattern, well known as the Schreger pattern. PMID- 29477455 TI - Characterizing viscoelastic mechanical properties of highly compliant polymers and biological tissues using impact indentation. AB - : Precise and accurate measurement of viscoelastic mechanical properties becomes increasingly challenging as sample stiffness decreases to elastic moduli <1 kPa, largely due to difficulties detecting initial contact with the compliant sample surface. This limitation is particularly relevant to characterization of biological soft tissues and compliant gels. Here, we employ impact indentation which, in contrast to shear rheology and conventional indentation, does not require contact detection a priori, and present a novel method to extract viscoelastic moduli and relaxation time constants directly from the impact response. We first validate our approach by using both impact indentation and shear rheology to characterize polydimethylsiloxane (PDMS) elastomers of stiffness ranging from 100 s of Pa to nearly 10 kPa. Assuming a linear viscoelastic constitutive model for the material, we find that the moduli and relaxation times obtained from fitting the impact response agree well with those obtained from fitting the rheological response. Next, we demonstrate our validated method on hydrated, biological soft tissues obtained from porcine brain, murine liver, and murine heart, and report the equilibrium shear moduli, instantaneous shear moduli, and relaxation time constants for each tissue. Together, our findings provide a new and straightforward approach capable of probing local mechanical properties of highly compliant viscoelastic materials with millimeter scale spatial resolution, mitigating complications involving contact detection or sample geometric constraints. STATEMENT OF SIGNIFICANCE: Characterization and optimization of mechanical properties can be essential for the proper function of biomaterials in diverse applications. However, precise and accurate measurement of viscoelastic mechanical properties becomes increasingly difficult with increased compliance (particularly for elastic moduli <1 kPa), largely due to challenges detecting initial contact with the compliant sample surface and measuring response at short timescale or high frequency. By contrast, impact indentation has highly accurate contact detection and can be used to measure short timescale (glassy) response. Here, we demonstrate an experimental and analytical method that confers significant advantages over existing approaches to extract spatially resolved viscoelastic moduli and characteristic time constants of biological tissues (e.g., brain and heart) and engineered biomaterials. PMID- 29477456 TI - Incidence, risk factors, and clinical implications of post-operative delirium in lung transplant recipients. AB - BACKGROUND: Delirium significantly affects post-operative outcomes, but the incidence, risk factors, and long-term impact of delirium in lung transplant recipients have not been well studied. METHODS: We analyzed 155 lung transplant recipients enrolled in the Lung Transplant Outcomes Group (LTOG) cohort at a single center. We determined delirium incidence by structured chart review, identified risk factors for delirium, determined whether plasma concentrations of 2 cerebral injury markers (neuron-specific enolase [NSE] and glial fibrillary acidic protein [GFAP]) were associated with delirium, and determined the association of post-operative delirium with 1-year survival. RESULTS: Fifty-seven (36.8%) patients developed post-operative delirium. Independent risk factors for delirium included pre-transplant benzodiazepine prescription (relative risk [RR] 1.82; 95% confidence interval [CI] 1.08 to 3.07; p = 0.025), total ischemic time (RR 1.10 per 30-minute increase; 95% CI 1.01 to 1.21; p = 0.027), duration of time with intra-operative mean arterial pressure <60 mm Hg (RR 1.07 per 15-minute increase; 95% CI 1.00 to 1.14; p = 0.041), and Grade 3 primary graft dysfunction (RR 2.13; 95% CI 1.27 to 3.58; p = 0.004). Ninety-one (58.7%) patients had plasma available at 24 hours. Plasma GFAP was inconsistently detected, whereas NSE was universally detectable, with higher NSE concentrations associated with delirium (risk difference 15.1% comparing 75th and 25th percentiles; 95% CI 2.5 to 27.7; p = 0.026). One-year mortality appeared higher among delirious patients, 12.3% compared with 7.1%, but the difference was not significant (p = 0.28). CONCLUSIONS: Post-operative delirium is common in lung transplant recipients, and several potentially modifiable risk factors deserve further study to determine their associated mechanisms and predictive values. PMID- 29477457 TI - Immunohistochemical localization of 3beta-Hydroxysteroid dehydrogenase and progesterone receptors in the ovary and placenta during gestation of the placentotrophic lizard Mabuya sp (Squamata: Scincidae). AB - In squamates, progesterone (P) plays a key role in the inhibition of uterine mobility during egg retention in oviparous species, and during gestation in viviparous species. The corpus luteum (CL) is the main organ responsible for the production of P; however, in some species, the CL degenerates early and the P needed for gestation maintenance should be produced in other tissues. Mabuya sp (Scincidae) is a viviparous lizard with a prolonged gestation, it produces microlecithal eggs and, consequently, has an obligate placentotrophy related with a highly complex placenta. Its CL degenerates at early stages of gestation and therefore, other sources of P should exist. The aim of this study was to determine and localize by immunohistochemistry the production of P by detection of the enzyme 3beta-Hydroxysteroid dehydrogenase (3beta-HSD) and P receptors (PR) during gestation in the ovary and placenta of Mabuya sp. Positive and negative control sections were used. The ovary of this species localizes 3beta-HSD and PR in the same tissues. The CL of the ovaries of females at early stages of gestation were positive for both molecules, whereas they did not localize from mid gestation to the end of pregnancy. Previtellogenic and vitellogenic follicles labelled for both molecules in the follicular epithelium and thecae. The placenta of Mabuya sp. demonstrated the potential for P production from mid gestation to the end of gestation in the uterine and chorionic tissues. PR were located in the uterine tissues throughout gestation, with a decrease towards its completion. Western blot analysis confirmed the presence of 3beta-HSD mainly in the ovary of early pregnant females and in the placental tissues at mid gestation stages. Therefore, the chorioallantoic placenta of Mabuya sp. has an endocrine function producing the P needed for gestation and replacing the CL from mid gestation to the end of pregnancy. PMID- 29477458 TI - Apraxia of gait- or apraxia of postural transitions? AB - "Apraxia of gait" is not a useful concept and freezing of gait should also not be considered an apraxia. The concept of apraxia may, however, be applied to distortions of postural transitions that can accompany fronto-parietal lesions. PMID- 29477459 TI - Substantia nigra fractional anisotropy changes confirm the PD at-risk status of patients with idiopathic smell loss. AB - INTRODUCTION: Individuals with unexplained smell loss constitute an at-risk population for the development of Parkinson's disease (PD). Currently, no specific MRI patterns are known for early PD diagnosis. In this study, we measured the fractional anisotropy (FA) in the substantia nigra (SN) in PD patients, in patients with idiopathic smell loss, and in healthy controls. METHODS: All subjects underwent extensive olfactory testing and MR imaging data were obtained to explore SN diffusion characteristics. The SN regions were manually identified by two independent raters on the individual imaging data. RESULTS: FA measurements in the SN revealed significant group differences, with reduced values clearly distinguishing PD patients and patients with idiopathic smell loss from healthy controls. CONCLUSION: These findings indicate a reduced intrinsic integrity of the SN in PD at-risk subjects and support the risk status of patients with idiopathic smell loss. PMID- 29477460 TI - Impact of provincial characteristics on the number of traffic accident victims on interurban roads in Spain. AB - This study has two aims. The first is to determine how various factors impact on the number of fatalities, serious injuries and slight injuries adjusted for the level of traffic on interurban roads in Spain. The second is to establish the number of victims per million vehicle-kilometres (veh-km) travelled on interurban roads in each province resulting from the effect of its specific characteristics. To this end, we developed six fixed effect panel data models with panel corrected standard errors for the 1999-2015 period. Our results show that while the proportion of high capacity roads, the unemployment rate and the motorization rate contribute to a reduction in the number of fatalities, serious injuries and slight injuries adjusted for level of traffic, the penalty-points licence system is effective in reducing the number of fatalities and serious injuries but not the number of slight injuries. Furthermore, the specific conditions in Avila, Toledo, Madrid, Santa Cruz de Tenerife, Las Palmas de Gran Canaria, the Balearic Islands, Lleida and all the provinces on the Mediterranean coast cause a higher number of victims per million veh-km travelled than in the remaining provinces. Thus, greater public investment and more socially responsible behaviour are essential tools for reducing the number of traffic accident victims on Spanish interurban roads. Moreover, the provincial institutions emerge as key agents in improving road safety, due to their greater knowledge of the specific conditions and factors affecting each province. PMID- 29477461 TI - Practice makes better - Learning effects of driving with a multi-stage collision warning. AB - Advanced driver assistance systems like (forward) collision warnings can increase traffic safety. As safety-critical situations (especially in urban traffic) can be diverse, integrated adaptive systems (such as multi-stage warnings) need to be developed and examined in a variety of use cases over time instead of the more common approach of testing only one-time effectiveness in the most relevant use case. Thus, this driving simulator experiment investigated a multi-stage collision warning in partially repetitive trials (T) of various safety-critical situations (scenarios confronting drivers with hazards in form of pedestrians, obstacles or preceding vehicles). Its output adapted according to the drivers' behavior in two warning stages (W1 - warning for moderate deceleration in less critical situations; W2 - urgent warning for strong, fast braking in more critical situations). To analyze how much drivers benefit from the assistance when allowed practice with it, the driving behavior and subjective ratings of 24 participants were measured over four trials. They comprised a baseline without assistance (T1) and three further trials with assistance - a learning phase repeating the scenarios from T1 twice (T2 + T3) and a concluding transfer drive with new scenarios (T4). As expected, the situation criticality in the urgent warning (W2) scenarios was rated higher than in the warning (W1) scenarios. While the brake reaction time differed more between the W1 scenarios, the applied brake force differed more between the W2 scenarios. However, the scenario factor often interacted with the trial factor. Since in later warning stages reaction time reductions become finite, the reaction strength gains importance. Overall the drivers benefited from the assistance. Both warning stages led to faster brake reactions (of similar strength) in all three assisted trials compared to the baseline, which additionally improved successively over time (T1-T3, T1 vs. T4, T2 vs. T4). Moreover, the drivers applied the gained knowledge from the learning phase to various new situations (transfer: faster brake reactions in T4 compared to T1 or T2). The well accepted and positively rated (helpful and understandable) two-stage collision warning can thus be recommended as it facilitates accident mitigation by earlier decelerations. Practice with advanced driver assistance systems (even in driving simulators) should be endorsed to maximize their benefits for traffic safety and accident prevention. PMID- 29477462 TI - Spatial analysis of macro-level bicycle crashes using the class of conditional autoregressive models. AB - The objective of this study was to investigate the relationship between bicycle crash frequency and their contributing factors at the census block group level in Florida, USA. Crashes aggregated over the census block groups tend to be clustered (i.e., spatially dependent) rather than randomly distributed. To account for the effect of spatial dependence across the census block groups, the class of conditional autoregressive (CAR) models were employed within the hierarchical Bayesian framework. Based on four years (2011-2014) of crash data, total and fatal-and-severe injury bicycle crash frequencies were modeled as a function of a large number of variables representing demographic and socio economic characteristics, roadway infrastructure and traffic characteristics, and bicycle activity characteristics. This study explored and compared the performance of two CAR models, namely the Besag's model and the Leroux's model, in crash prediction. The Besag's models, which differ from the Leroux's models by the structure of how spatial autocorrelation are specified in the models, were found to fit the data better. A 95% Bayesian credible interval was selected to identify the variables that had credible impact on bicycle crashes. A total of 21 variables were found to be credible in the total crash model, while 18 variables were found to be credible in the fatal-and-severe injury crash model. Population, daily vehicle miles traveled, age cohorts, household automobile ownership, density of urban roads by functional class, bicycle trip miles, and bicycle trip intensity had positive effects in both the total and fatal-and-severe crash models. Educational attainment variables, truck percentage, and density of rural roads by functional class were found to be negatively associated with both total and fatal-and-severe bicycle crash frequencies. PMID- 29477463 TI - Corrections. PMID- 29477464 TI - The eyes have it: influenza virus infection beyond the respiratory tract. AB - Avian and human influenza A viruses alike have shown a capacity to use the eye as a portal of entry and cause ocular disease in human beings. However, whereas influenza viruses generally represent a respiratory pathogen and only occasionally cause ocular complications, the H7 virus subtype stands alone in possessing an ocular tropism. Clarifying what confers such non-respiratory tropism to a respiratory virus will permit a greater ability to identify, treat, and prevent zoonotic human infection following ocular exposure to influenza viruses; especially those within the H7 subtype, which continue to cause avian epidemics on many continents. PMID- 29477465 TI - 1H NMR metabolic signature of cerebrospinal fluid following repetitive lower-limb remote ischemia preconditioning. AB - : Background OBJECTIVE: The cerebral ischemia/reperfusion greatly influences brain metabolism. Remote ischemia preconditioning (RIPC) is reported to confer neuroprotective effects against cerebral ischemia in animal models and human. This study aims to investigate the metabolomic profiles of cerebrospinal fluid (CSF) in patients treated with repetitive lower limb RIPC and provides an insight into possible mechanism underlying RIPC-induced neuroprotection. METHOD: Fifty healthy patients undergoing minor surgery under spinal anesthesia were randomly allocated to 2 groups: control group (Group C, n = 25) and RIPC treatment group (Group T,n = 25). Repetitive limb RIPC were performed 3 sessions, consisting of three 5-min cycles per session from the day before surgery to the morning on the surgery day. The CSF samples were collected from 48 patients before intrathecal injection of local anesthetic. A proton nuclear magnetic resonance (1H NMR)-based metabonomics approach was used to obtain the CSF metabolic profiles of the samples (n = 24 each). The acquired data were processed with MestReNova and followed by statistical analysis with SIMCA-P. RESULTS: The model obtained with the orthogonal partial least-squares discriminant analysis (OPLS-DA) identified difference of metabolite profiles between two groups. The validation of the discriminant analysis showed that the accuracy of the OPLS-DA model was 81.3%. Sixteen metabolites including glucose, amino-acids and organic acids et al. were identified as the most influential CSF biomarkers for the discrimination between two groups, which are involved in pathways of energy metabolism and amino-acids metabolism. CONCLUSION: 1H NMR spectra combined with pattern recognition analysis offers a new and promising platform to investigate metabolic signatures in patients treated with RIPC. Our results suggest repetitive RIPC mainly changes energy metabolism and amino-acid metabolism in brain, which provides a potential mechanistic understanding of RIPC-induced tolerance to cerebral ischemia. PMID- 29477466 TI - Role of temperature on growth and metabolic rate in the tenebrionid beetles Alphitobius diaperinus and Tenebrio molitor. AB - Insects are increasingly used as a dietary source for food and feed and it is therefore important to understand how rearing conditions affect growth and development of these agricultural animals. Temperature is arguably the most important factor affecting metabolism and growth rate in insects. Here, we investigated how rearing temperature affected growth rate, growth efficiency and macronutrient composition in two species of edible beetle larvae: Alphitobius diaperinus and Tenebrio molitor. Growth rates of both species were quantified at temperatures ranging from 15.2 to 38.0 degrees C after which we measured protein and lipid content of the different treatment groups. Metabolic rate was measured in a similar temperature range by measuring the rate of O2 consumption (V.O2) and CO2 production (V.CO2) using repeated measures closed respirometry. Using these measurements, we calculated the growth efficiency of mealworms by relating the energy assimilation rate to the metabolic rate. Maximum daily growth rates were 18.3% and 16.6% at 31 degrees C, for A. diaperinus and T. molitor respectively, and we found that A. diaperinus was better at maintaining growth at high temperatures while T. molitor had superior growth at lower temperatures. Both species had highest efficiencies of energy assimilation in the temperature range of 23.3-31.0 degrees C, with values close to 2 J assimilated/J metabolised in A. diaperinus and around 4 J assimilated/J metabolised in T. molitor. Compared to "conventional" terrestrial livestock, both species of insects were characterised by high growth rates and very high energy conversion efficiency at most experimental temperatures. For A. diaperinus, lipid content was approximately 30% of dry mass and protein content approximately 50% of dry mass across most temperatures. Temperature had a greater influence on the body composition of T. molitor. At 31.0 degrees C the lipid and protein content was measured to 47.4% and 37.9%, respectively but lipid contents decreased, and protein contents increased when temperatures were higher or lower than 31.0 degrees C. In summary, rearing temperature had large and independent effects on growth rate, energy assimilation efficiency and protein/lipid content. Accordingly, temperature is a critical parameter to control in commercial insect rearing regardless if the producer wants to optimise production speed, production efficiency or product quality. PMID- 29477468 TI - Turning the corner from observation to intervention in human genetics. PMID- 29477467 TI - First extensive characterization of the venom gland from an egg parasitoid: structure, transcriptome and functional role. AB - The venom gland is a ubiquitous organ in Hymenoptera. In insect parasitoids, the venom gland has been shown to have multiple functions including regulation of host immune response, host paralysis, host castration and developmental alteration. However, the role played by the venom gland has been mainly studied in parasitoids developing in larval or pupal hosts while little is known for parasitoids developing in insect eggs. We conducted the first extensive characterization of the venom of the endoparasitoid Ooencyrtus telenomicida (Vassiliev), a species that develops in eggs of the stink bug Nezara viridula (L.). In particular we investigated the structure of the venom apparatus, its functional role and conducted a transcriptomic analysis of the venom gland. We found that injection of O. telenomicida venom induces: 1) a melanized-like process in N. viridula host eggs (host-parasitoid interaction), 2) impairment of the larval development of the competitor Trissolcus basalis (Wollaston) (parasitoid-parasitoid interaction). The O. telenomicida venom gland transcriptome reveals a majority of digestive enzymes (peptidases and glycosylases) and oxidoreductases (laccases) among the most expressed genes. The former enzymes are likely to be involved in degradation of the host resources for the specific benefit of the O. telenomicida offspring. In turn, alteration of host resources caused by these enzymes may negatively affect the larval development of the competitor T. basalis. We hypothesize that the melanization process induced by venom injection could be related to the presence of laccases, which are multicopper oxidases that belong to the phenoloxidases group. This work contributed to a better understanding of the venom in insect parasitoids and allowed to identify candidate genes whose functional role can be investigated in future studies. PMID- 29477469 TI - Biological effects of kojic acid on human monocytes in vitro. AB - Monocytes are mononuclear phagocytes in peripheral blood that can differentiate into macrophages and dendritic cells. Macrophages play a specific role in the inflammatory process and are essential for the innate response. Given the important role of monocytes/macrophages in the immune response, this study aimed to evaluate the activity of kojic acid (KA), a natural product of certain fungal species, on human peripheral blood monocytes in vitro. Purified monocytes isolated from human blood were incubated with KA (50 MUg/mL for 48 h) and analyzed by light microscopy, scanning electron microscopy, transmission electron microscopy and flow cytometry. Host cell cytotoxicity was measured by the colorimetric MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. KA treatment induced morphological alterations in monocytes, such as increased cell size, as well as numerous cellular projections. Furthermore, flow cytometry revealed increased labeling of cell surface EMR1-F4/80 but decreased labeling of CD11b and CD14. KA also promoted increased IL-6 cytokine production but did not cause cytotoxic effects in monocytes. In conclusion, our results show that KA promotes the differentiation of monocytes into macrophages and can act as an immunomodulatory agent. PMID- 29477470 TI - alpha-Hederin inhibits interleukin 6-induced epithelial-to-mesenchymal transition associated with disruption of JAK2/STAT3 signaling in colon cancer cells. AB - Colon cancer is the third most frequently diagnosed malignancy and has high morbidity worldwide. Epithelial-mesenchymal transition (EMT) has been increasingly implicated in colon cancer progression and metastasis. The present study was aimed to evaluate the potential antitumor activity of alpha-hederin, a monodesmosidic triterpenoid saponin isolated from Hedera helix, in human SW620 colon cancer cells stimulated with interleukin 6 (IL-6) for mimicking the tumor inflammatory microenvironment in vivo. Cell viability assay showed that IL-6 at 6.25 ng/ml significantly enhanced viability of SW620 cells, and thus this concentration was used to stimulate SW620 cells throughout this study. We observed that alpha-hederin concentration-dependently inhibited cell viability, migration and invasion in IL-6-treated SW620 cells. Moreover, alpha-hederin significantly restored IL-6-induced decrease in E-cadherin expression and abolished IL-6-induced increase in N-cadherin, vimentin, fibronectin, twist and snail at both mRNA and protein levels in SW620 cells. These data suggested that alpha-hederin suppressed IL-6-indcued EMT in colon cancer cells. Further molecular examinations showed that alpha-hederin inhibited phosphorylation of Janus Kinase 2 (JAK2) and Signal Transducer and Activator of Transcription 3(STAT3), and halted the nuclear translocation of phosphorylated STAT3 in IL-6 treated SW620 cells. In addition, JAK2/STAT3 signaling inhibitor AG490 not only produced similar inhibitory effects on EMT markers as alpha-hederin, but also synergistically enhanced alpha-hederin's inhibitory effects on EMT markers in IL 6-treated SW620 cells. Altogether, we demonstrated that alpha-hederin suppressed IL-6-induced EMT associated with disruption of JAK2/STAT3 signaling in colon cancer cells. Our data strongly suggested alpha-hederin as a promising candidate for intervention of colon cancer and metastasis. PMID- 29477471 TI - Ruscogenin suppressed the hepatocellular carcinoma metastasis via PI3K/Akt/mTOR signaling pathway. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the third-leading cause of cancer related mortality with poor prognosis and treatment. More effective strategies should be studied in HCC. METHODS: After treated with ruscogenin, the cell proliferation was assessed by CCK-8 method. Cell migration and invasion were estimated using wound healing and transwell assays. Pathological changes of lung tissue were observed by HE staining and IHC methods. MMP-2, MMP-9, uPA, VEGF and HIF-1alpha levels were measured using ELISA, RT-qPCR and WB tests. PI3K/Akt/mTOR pathway related molecules were detected using WB analysis. RESULTS: The results indicated the hypotoxicity of ruscogenin. Meanwhile, ruscogenin showed obvious interruption on the cancer cell migration and invasion, and inhibition on the metastatic foci in pulmonary tissue. Significantly, ruscogenin decreased the levels of MMP-2, MMP-9, uPA, VEGF and HIF-1alpha, down-regulated the phosphorylation of Akt, mTOR. CONCLUSION: The present study indicated a novel use of ruscogenin in suppressing HCC metastasis by reducing the expression of MMP-2, MMP-9, uPA, VEGF and HIF-1alpha via regulating the PI3K/Akt/mTOR signaling pathway. PMID- 29477472 TI - Silymarin and caffeine combination ameliorates experimentally-induced hepatic fibrosis through down-regulation of LPAR1 expression. AB - AIMS: Lysophosphatidic acid is a lipid mediator that is supposed to be implicated in hepatic fibrosis. Silymarin and caffeine are natural compounds known for their anti-inflammatory and antioxidant effects. Our study aimed to explore the effect of silymarin, caffeine, and their combination on lysophosphatidic acid receptor 1 (LPAR1) pathway in thioacetamide (TAA)-induced hepatic fibrosis. MAIN METHODS: Hepatic fibrosis was induced in male Sprague-Dawley rats by intraperitoneal injection of 200 mg/kg of TAA twice a week for 8 weeks. Silymarin (50 mg/kg), caffeine (50 mg/kg), and their combination (50 mg/kg silymarin + 50 mg/kg caffeine) were orally given to rats every day for 8 weeks along with TAA injection. Liver functions were measured. Histopathological examination of liver tissues was performed using hematoxylin and eosin and Masson's trichrome staining. mRNA expressions of LPAR1, transforming growth factor beta 1 (TGF beta1), connective tissue growth factor (CTGF), and alpha smooth muscle actin (alpha-SMA) were measured using RT-PCR. LPAR1 tissue expression was scored using immunohistochemistry. KEY FINDINGS: Silymarin, caffeine, and their combination significantly improved liver function. They caused significant decrease in fibrosis and necro-inflammatory scores. Combination of silymain and caffeine caused a significant decrease in the necro-inflammatory score than the single treatment with silymarin or caffeine. In addition, silymarin, caffeine, and their combination significantly decreased hepatic LPAR1, TGF-beta1, CTGF, and alpha-SMA gene expressions and LPAR1 tissue expression. SIGNIFICANCE: Silymarin, caffeine, and their combination protect against liver fibrosis through down-regulation of LPAR1, TGF-beta1, and CTGF. PMID- 29477473 TI - Quercetin and low level laser therapy promote wound healing process in diabetic rats via structural reorganization and modulatory effects on inflammation and oxidative stress. AB - This study aimed to evaluate the effect of quercetin and the photo-stimulatory effect of low energy 632.8 nm laser irradiation on excisional wound healing in non-diabetic and diabetic rats. Streptozotocin (45 mg/kg body weight) was intraperitoneally applied for diabetes induction. A full-thickness skin wound (2 * 2 cm2) was aseptically created with a scalpel in non-diabetic and diabetic rats on the shaved back of the animals. The wounded non-diabetic and diabetic rats were treated every other day with quercetin by oral gavage at dose 25 mg/kg body weight and/or with low level laser therapy (LLLT) for 14 days. The wound closure percent calculated during the course of the experiment at days 1, 7 and 14 was remarkably increased as a result of treatment of non-diabetic and diabetic wounded rats with quercetin and LLLT; the treatment with both was the most potent. The elevated blood glucose and the lowered serum insulin levels were significantly improved in diabetic wounded rats treated with quercetin and LLLT as compared to the diabetic wounded control. The histological findings indicated that the wounded skin showed a marked increase in collagen fibers which become well oriented in sub-epidermal tissue, intact epidermis and presence of hyperplasia covering well-developed granulation tissue in the wounded rats treated with quercetin and LLLT as compared to the corresponding wounded control. The elevated levels of serum pro-inflammatory cytokines, IL-1beta and TNF-alpha, as well as PGE-2 and LTB-4 were decreased in non-diabetic and diabetic wounded rats with quercetin and LLLT while the lowered level of serum anti-inflammatory cytokine, IL-10, was increased. The augmented oxidative stress represented by increased serum lipid peroxides level was decreased and the serum level of non enzymatic anti-oxidant glutathione was increased as a result of treatment with quercetin and LLLT. Thus, it can be suggested that the improvements in glycemic state, cytokines involved in inflammation and antioxidant defense system as well as structural reorganization after treatment with quercetin and LLLT may play pivotal roles in promoting the wound healing process. The study also concluded that the treatment with quercetin in association with LLLT was better in improving wound healing in non-diabetic and diabetic rats than the use of either of each. PMID- 29477474 TI - The emerging use of bioluminescence in medical research. AB - Bioluminescence is the light produced by a living organism and is commonly emitted by sea life with Ca2+-regulated photoproteins being the most responsible for bioluminescence emission. Marine coelenterates provide important functions involved in essential purposes such as defense, feeding, and breeding. In this review, the main characteristics of marine photoproteins including aequorin, clytin, obelin, berovin, pholasin and symplectin from different marine organisms will be discussed. We will focused on the recent use of recombinant photoproteins in different biomedical research fields including the measurement of Ca2+ in different intracellular compartments of animal cells, as labels in the design and development of binding assays. This review will also outline how bioluminescent photoproteins have been used in a plethora of analytical methods including ultra sensitive assays and in vivo imaging of cellular processes. Due to their unique properties including elective intracellular distribution, wide dynamic range, high signal-to-noise ratio and low Ca2+-buffering effect, recombinant photoproteins represent a promising future analytical tool in several in vitro and in vivo experiments. PMID- 29477475 TI - Nepetin inhibits IL-1beta induced inflammation via NF-kappaB and MAPKs signaling pathways in ARPE-19 cells. AB - BACKGROUNDS: Chronic inflammation in retinal pigment epithelial (RPE) cells is related to the pathogenesis of retinal inflammatory blind causing diseases such as age-related macular degeneration (AMD) and diabetic retinopathy (DR). Nepetin, a natural flavonoid compound, has shown potent anti-inflammatory activities but has not been studied on ocular resident cells yet. Here, we assess the ability of Nepetin to alleviate the inflammatory responses of ARPE-19 cells induced by interleukin (IL)-1beta. METHODS: The secretion and mRNA expression of inflammatory cytokines IL-6, IL-8 and monocyte chemoattractant protein-1 (MCP-1) induced by IL-1beta are measured by enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (RT-PCR) respectively. To clarify the underlying action mechanism, we examine the effect of Nepetin on activation of nuclear factor of kappa B (NF-kappaB) and mitogen-activated protein kinase (MAPK) signaling pathways using Western blot. RESULTS: Nepetin can significantly decrease the three inflammatory mediators at both protein and mRNA level in a dose-dependent manner. Western blot results show that Nepetin can decrease the nuclear translocation of p65 through suppressing phosphorylation of inhibitor of nuclear factor kappa B (IkappaB) and IkappaB kinase (IKK). Also, Nepetin can decrease the phosphorylation of extracellular signal-regulated kinases (ERK) 1/2, c-Jun N-terminal kinase (JNK) and p38 MAPK. CONCLUSIONS: Taken together, Nepetin abolishes IL-1beta-induced IL-6, IL-8 and MCP-1 secretion and mRNA expression by repressing the activation of NF-kappaB and MAPKs. These results indicate that Nepetin shows potential to be used for prevention and treatment of inflammatory retinal diseases or as a lead compound. PMID- 29477476 TI - The impact of polyunsaturated fatty acids on DNA methylation and expression of DNMTs in human colorectal cancer cells. AB - Growing evidence suggests a role of polyunsaturated fatty acids (PUFA) in the prevention of various types of malignancy, including colorectal cancer (CRC). No published studies have yet examined the direct effect of PUFA treatment on DNA methylation in CRC cells. In this study, 5 human CRC cells were treated with 100 MUM DHA, EPA, and LA for 6 days and changes in their global- and gene-specific DNA methylation status as well as expression of DNA methyl transferases (DNMT) were investigated. Cell-type specific differences in DNA methylation and expression of DNMTs were observed in PUFA-treated cells. DHA and EPA treatment induced global hypermethylation in HT29/219 and HCT116 cells, but reduced methylation in Caco2 cells (p < 0.05). Among 10 tumor related genes tested in 5 CRC cell lines, DHA and EPA induced promoter demethylation of Cox2 in HT29/219, p14 and PPARgamma in HCT116, and ECAD in SW742 cells. Cell-type specific differences in expression of DNMT1, DNMT3a, and 3b genes were also observed between PUFA-treated and control cells (p < 0.05). Overall, treatment of PUFAs coordinately induced the expression of DNMTs in HT29/219, but suppressed in other 4 cell lines investigated in this study. PMID- 29477477 TI - Stomal construction: Technical tricks for difficult situations, prevention and treatment of post-operative complications. AB - The creation of a digestive stoma, whether it is a lateral stoma or a terminal stoma, is an essential gesture in colorectal surgery, but that may result in post operative complications in 35% of patients. Surgeons are aware of the situations at the origin of complications, although there is little factual data in the literature to discriminate them. They are related to patient-specific factors (obesity, cirrhosis, portal hypertension) or to the underlying pathology (colon obstruction) or the conditions under which the intervention is performed (emergency). The aim of this review is to describe these different situations and the data from the literature that may allow reduction of the risk of an unsatisfactory or even complicated stoma. PMID- 29477478 TI - Preliminary evidence for physiological markers of implicit memory. AB - The Concealed Information Test (CIT) aims to detect concealed knowledge and is known to be sensitive to explicit memory. In two experiments, we examined whether the CIT is also sensitive to implicit memory using skin conductance, respiration and heart rate measures. For each participant, previously studied items were either categorized as explicitly remembered, implicitly remembered or forgotten. The two experiments differed in the strength of memory encoding, the type of implicit memory test, the delay between study and test and the number of critical CIT items. The results of Experiment 1 revealed that CIT detection efficiency was weak and significant only in the explicit memory condition. In Experiment 2, however, CIT detection efficiency was stronger and significant in both the explicit and implicit memory conditions as indexed by skin conductance and respiration. Altogether, our results provide initial evidence that the CIT may be sensitive to implicit memory. Theoretical and practical implications are discussed. PMID- 29477480 TI - Dehydroevodiamine and hortiamine, alkaloids from the traditional Chinese herbal drug Evodia rutaecarpa, are IKr blockers with proarrhythmic effects in vitro and in vivo. AB - Evodiae fructus is a widely used herbal drug in traditional Chinese medicine. Evodia extract was found to inhibit hERG channels. The aim of the current study was to identify hERG inhibitors in Evodia extract and to investigate their potential proarrhythmic effects. Dehydroevodiamine (DHE) and hortiamine were identified as IKr (rapid delayed rectifier current) inhibitors in Evodia extract by HPLC-microfractionation and subsequent patch clamp studies on human embryonic kidney cells. DHE and hortiamine inhibited IKr with IC50s of 253.2+/-26.3nM and 144.8+/-35.1nM, respectively. In dog ventricular cardiomyocytes, DHE dose dependently prolonged the action potential duration (APD). Early afterdepolarizations (EADs) were seen in 14, 67, 100, and 67% of cells after 0.01, 0.1, 1 and 10MUM DHE, respectively. The proarrhythmic potential of DHE was evaluated in 8 anesthetized rabbits and in 8 chronic atrioventricular block (cAVB) dogs. In rabbits, DHE increased the QT interval significantly by 12+/-10% (0.05mg/kg/5min) and 60+/-26% (0.5mg/kg/5min), and induced Torsade de Pointes arrhythmias (TdP, 0.5mg/kg/5min) in 2 rabbits. In cAVB dogs, 0.33mg/kg/5min DHE increased QT duration by 48+/-10% (P<0.05*) and induced TdP in 2/4 dogs. A higher dose did not induce TdP. In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), methanolic extracts of Evodia, DHE and hortiamine dose-dependently prolonged APD. At 3MUM DHE and hortiamine induced EADs. hERG inhibition at submicromolar concentrations, APD prolongation and EADs in hiPSC CMs and dose-dependent proarrhythmic effects of DHE at micromolar plasma concentrations in cAVB dogs should increase awareness regarding proarrhythmic effects of widely used Evodia extracts. PMID- 29477479 TI - Engineered nanomaterial applications in perinatal therapeutics. AB - Engineered nanomaterials (ENM) are widely used in commercial, domestic, and more recently biomedical applications. While the majority of exposures to ENM are unintentional, biomedical platforms are being evaluated for use in individualized and/or tissue-targeted therapies. Treatments are often avoided during prenatal periods to reduce adverse effects on the developing fetus. The placenta is central to maternal-fetal medicine. Perturbation of placental functions can limit transfer of necessary nutrients, alter production of hormones needed during pregnancy, or allow undesired passage of xenobiotics to the developing fetus. The development of therapeutics to target specific maternal, placental, or fetal tissues would be especially important to reduce or circumvent toxicities. Therefore, this review will discuss the potential use of ENM in perinatal medicine, the applicable physiochemical properties of ENM in therapeutic use, and current methodologies of ENM testing in perinatal medicine, and identify maternal, fetal, and offspring concerns associated with ENM exposure during gestation. As potential nanoparticle-based therapies continue to develop, so does the need for thorough consideration and evaluation for use in perinatal medicine. PMID- 29477482 TI - Benefits of Medical Home Care Reaching Beyond Chronically Ill Teens: Exploring Parent Health-Related Quality of Life. AB - BACKGROUND: Caring for teens with special health care needs places physical and mental health burdens on parents, which can be exacerbated by the stresses of transitions to independence. Medical homes can improve teen transitions to greater self-management and reduce health care-related time and financial burdens for families. We examined the association between parent-reported teen medical home status and caregiver health-related quality of life (HRQOL). METHODS: The study sample included parents or caregivers of teens with special health care needs aged 15 to 18 recruited from a pediatric Medicaid accountable care organization who participated in a survey (response rate, 40.5%). The primary outcome was parent HRQOL scores (0-100 points) measured using the Pediatric Quality of Life Inventory Family Impact Module. Medical home status was based on parent report of teen's health care meeting medical home criteria. Linear regression models were used to estimate HRQOL scores, adjusted for demographic characteristics, health literacy, and teen functional limitation. RESULTS: Among 488 parents, 27% reported their teen received care consistent with a medical home. Adjusted parent HRQOL scores were significantly higher among those whose teens had a medical home (74.40; 95% confidence interval, 71.31-77.48), relative to those whose teens did not (65.78; 95% confidence interval, 63.92-67.65). Medical home subscale analyses showed HRQOL scores had significant positive associations with family-centered care and coordinated care, but not other subscales. CONCLUSIONS: Teen medical home status was positively associated with caregiver HRQOL, suggesting that the medical home may benefit overall caregiver well-being. In particular, receiving care that was family centered and coordinated appeared to be the most beneficial. PMID- 29477481 TI - PCORnet Antibiotics and Childhood Growth Study: Process for Cohort Creation and Cohort Description. AB - OBJECTIVES: The National Patient-Centered Clinical Research Network (PCORnet) supports observational and clinical research using health care data. The PCORnet Antibiotics and Childhood Growth Study is one of PCORnet's inaugural observational studies. We sought to describe the processes used to integrate and analyze data from children across 35 participating institutions, the cohort characteristics, and prevalence of antibiotic use. METHODS: We included children in the cohort if they had at least one same-day height and weight measured in each of 3 age periods: 1) before 12 months, 2) 12 to 30 months, and 3) after 24 months. We distributed statistical queries that each institution ran on its local version of the PCORnet Common Data Model, with aggregate data returned for analysis. We defined overweight or obesity as age- and sex-specific body mass index >=85th percentile, obesity >=95th percentile, and severe obesity >=120% of the 95th percentile. RESULTS: A total of 681,739 children met the cohort inclusion criteria, and participants were racially/ethnically diverse (24.9% black, 17.5% Hispanic). Before 24 months of age, 55.2% of children received at least one antibiotic prescription; 21.3% received a single antibiotic prescription; 14.3% received 4 or more; and 33.3% received a broad-spectrum antibiotic. Overweight and obesity prevalence was 27.6% at age 4 to <6 years (n = 362,044) and 36.2% at 9 to <11 years (n = 58,344). CONCLUSIONS: The PCORnet Antibiotics and Childhood Growth Study is a large national longitudinal observational study in a diverse population that will examine the relationship between early antibiotic use and subsequent growth patterns in children. PMID- 29477483 TI - Effects of DDT and permethrin on rat hepatocytes cultivated in microfluidic biochips: Metabolomics and gene expression study. AB - Dichlorodiphenyl-trichloroethane (DDT) and permethrin (PMT) are amongst most prevalent pesticides in the environment. Although their toxicity has been extensively studied, molecular mechanisms and metabolic effects remain unclear, including in liver where their detoxification occurs. Here, we used metabolomics, coupled to RT-qPCR analysis, to examine effects of DDT and PMT on hepatocytes cultivated in biochips. At 150 MUM, DDT caused cell death, cytochrome P450 induction and modulation of estrogen metabolism. Metabolomics analysis showed an increase in some lipids and sugars after 6 h, and a decrease in fatty acids (tetradecanoate, octanoate and linoleate) after 24 h exposure. We also found a change in expression associated with genes involved in hepatic estrogen, lipid, and sugar metabolism. PMT at 150 MUM perturbed lipid/sugar homeostasis and estrogen signaling pathway, between 2 and 6 h. After 24 h, lipids and sugars were found to decrease, suggesting continuous energy demand to detoxify PMT. Finally, at 15 MUM, DDT and PMT appeared to have a small effect on metabolism and were detoxified after 24 h. Our results show a time-dependent perturbation of sugar/lipid homeostasis by DDT and PMT at 150 MUM. Furthermore, DDT at high dose led to cell death, inflammatory response and oxidative stress. PMID- 29477484 TI - Nitric oxide and related factors linked to oxidation and inflammation as possible biomarkers of heart failure. AB - As a prevalent cardiovascular disease, heart failure is one of the leading causes of morbidity and premature mortality. Therefore, there is a special interest in the study of efficient markers associated with risk and / or prediction of cardiovascular events. Multiple candidates are proposed, especially those involved in oxidative and inflammatory processes typical of cardiovascular disease, such as superoxide anion, nitric oxide, and peroxynitrite. There is a lack of knowledge on the potential usefulness of these systems as biomarkers. This review aims to contribute to a better understanding of these systems, as well as an improved patient profile. Furthermore, a deep knowledge of these complex systems would also allow proposing new lines of research for the development of new therapeutic tools as a promising start for new approaches to this disease. PMID- 29477485 TI - A methodological approach for the thermal stability and stress exposure studies of a model antibody. AB - The anti-horseradish peroxidase (HRP) antibody is conventionally used in immunohistochemistry. More recently, it has been used as the key element in a gold standard method to evaluate the functionality of antibody-based materials. However, few information are available about its melting temperature and its stability after exposition to laboratory stress conditions including freeze drying and freeze-thawing cycles. The aim of this study was to evaluate the effects of these environmental constraints on the anti-HRP antibody in order to further use it as a reference in quality control and in the development of new antibody-based materials. In the developed method, the anti-HRP antibody is covalently immobilized onto a solid surface. After the direct recognition of its antigen HRP, the signal is proportional to the number of antibody active binding sites. The method was successfully utilized to accurately evaluate the anti-HRP antibody melting temperature (Tm was 73.5 +/- 0.2 degrees C). The method is a rapid and reliable tool with minimal cost for studying the anti-HRP antibody stability to solvent stress, freeze-thawing cycles, and freeze-drying process. The obtained information may be useful for routine analysis or in the development of antibody-based materials. This can be also proposed as an easy way to control antibody freeze-drying process. PMID- 29477486 TI - Turning negative memories around: Contingency versus devaluation techniques. AB - BACKGROUND AND OBJECTIVES: It is assumed that fear responses can be altered by changing the contingency between a conditioned stimulus (CS) and an unconditioned stimulus (US), or by devaluing the present mental representation of the US. The aim of the present study was to compare the efficacy of contingency- and devaluation-based intervention techniques on the diminishment in - and return of fear. We hypothesized that extinction (EXT, contingency-based) would outperform devaluation-based techniques regarding contingency measures, but that devaluation based techniques would be most effective in reducing the mental representation of the US. Additionally, we expected that incorporations of the US during devaluation would result in less reinstatement of the US averseness. METHODS: Healthy participants received a fear conditioning paradigm followed by one of three interventions: extinction (EXT, contingency-based), imagery rescripting (ImRs, devaluation-based) or eye movement desensitization and reprocessing (EMDR, devaluation-based). A reinstatement procedure and test followed the next day. RESULTS: EXT was indeed most successful in diminishing contingency-based US expectancies and skin conductance responses (SCRs), but all interventions were equally successful in reducing the averseness of the mental US representation. After reinstatement EXT showed lowest expectancies and SCRs; no differences were observed between the conditions concerning the mental US representation. LIMITATIONS: A partial reinforcement schedule was used, resulting in a vast amount of contingency unaware participants. Additionally, a non-clinical sample was used, which may limit the generalizability to clinical populations. CONCLUSION: EXT is most effective in reducing conditioned fear responses. PMID- 29477487 TI - Age-related validity and reliability of the Dutch Little Developmental Coordination Disorder Questionnaire (LDCDQ-NL). AB - BACKGROUND: Early recognition of children at risk of Developmental Coordination Disorder (DCD) is important, but variability in motor development in preschool children affects the validity of instruments to reliably detect children at risk of DCD. AIMS: To investigate the age-related validity and reliability of the Dutch version of the Little Developmental Coordination Disorder Questionnaire (LDCDQ-NL). METHODS AND PROCEDURES: Two hundred and sixty 3- to 5-year old children were recruited in the Netherlands. Parents filled out the LDCDQ-NL and children were assessed with the Movement Assessment Battery for Children-2 Test (MABC-2 Test). Internal consistency of the LDCDQ-NL was determined by Cronbach's alpha. Construct validity was investigated using factor analysis. Concurrent validity was measured by calculating correlations between the LDCDQ-NL and MABC 2. Receiver Operating Characteristics (ROC) were calculated to assess discriminant validity. OUTCOMES AND RESULTS: Internal consistency of the LDCDQ-NL was 0.91. Factor analysis resulted in three factors (Fine motor skills, Locomotor skills, Ball skills). Correlation between the LDCDQ-NL and MABC-2 Test increased with increasing age. With a sensitivity of 80%, specificity increased with age. CONCLUSIONS AND IMPLICATIONS: The LDCDQ-NL is a reliable and valid screening instrument for 4- and 5-year old Dutch children; concurrent and discriminant validity are low for 3-year olds. PMID- 29477488 TI - Effect of Optimizing Guideline-Directed Medical Therapy Before Discharge on Mortality and Heart Failure Readmission in Patients Hospitalized With Heart Failure With Reduced Ejection Fraction. AB - Guideline-directed medical therapy (GDMT) is recommended for patients with heart failure with reduced ejection fraction (HFrEF). However, the prognostic impact of medication optimization at the time of discharge in patients hospitalized with heart failure (HF) is unclear. We analyzed 534 patients (73 +/- 13 years old) with HFrEF. The status of GDMT at the time of discharge (prescription of angiotensin converting enzyme inhibitor [ACE-I]/angiotensin receptor blocker [ARB] and beta blocker [BB]) and its association with 1-year all-cause mortality and HF readmission were investigated. Patients were divided into 3 groups: those treated with both ACE-I/ARB and BB (Both group: n = 332, 62%), either ACE-I/ARB or BB (Either group: n = 169, 32%), and neither ACE-I/ARB nor BB (None group: n = 33, 6%), respectively. One-year mortality, but not 1-year HF readmission rate, was significantly different in the 3 groups, in favor of the Either and Both groups. A favorable impact of being on GDMT at the time of discharge on 1-year mortality was retained even after adjustment for covariates (Either group: hazard ratio [HR] 0.44, 95% confidence interval [CI] 0.21 to 0.90, p = 0.025 and Both group: HR 0.29, 95% CI 0.13-0.65, p = 0.002, vs None group). For 1-year HF readmission, no such association was found. In conclusion, optimization of GDMT before the time of discharge was associated with a lower 1-year mortality, but not with HF readmission rate, in patients hospitalized with HFrEF. PMID- 29477489 TI - Transition zone and anterior stromal prostate cancers: Evaluation of discriminant location criteria using multiparametric fusion-guided biopsy. AB - PURPOSE: The purpose of this study was to evaluate precise location criteria on magnetic resonance imaging (MRI) to improve detection of transition zone (TZ) and anterior stroma (AS) prostate cancers using targeted MRI/transrectal ultrasound fusion biopsies as a reference standard. MATERIAL AND METHODS: Ninety-six men (mean age: 65 years+/-7.7 [SD] [range: 46-83 years]) with an elevated prostate specific antigen (PSA) (PSA>=4ng/mL) who underwent standard and targeted biopsies on a TZ/AS suspicious lesion were included. The database was reviewed to assess topographical and morphological features of each suspicious lesion on MR images (T2-weighted anatomical images on 1.5T MRI or 3T) including PI-RADS score assessed by a senior radiologist. Histopathological examination of MRI transrectal ultrasound fusion biopsy specimens was used as the reference standard. RESULTS: Ninety patients had a positive targeted biopsy with a median [IQR] lesion size of 16mm [13-20mm]. Homogeneous hypointensity on T2-weighted mages, lenticular shape, lack of capsule and indistinct margins were present in 77/90 (85%) patients. All TZ/AS prostate cancers were located in the anterior half of the prostate: 3% at the base, 69% in the mid gland and 28% at the apex. Lesions were mainly located close to or within the AS (74%) and more rarely laterally compressed close to the peripheral anterior horn. CONCLUSION: Our results suggest that specific topographic criteria of TZ and AS prostate cancers could add independent information to the usual diagnostic criteria in prostate MRI. Transrectal ultrasound fusion-targeted biopsies based on these specific criteria improve volume estimation of prostate cancers with substantial impact for prognosis and treatment planning. PMID- 29477490 TI - CT-texture analysis of subsolid nodules for differentiating invasive from in-situ and minimally invasive lung adenocarcinoma subtypes. AB - PURPOSE: The purpose of this study was to evaluate the usefulness of computed tomography-texture analysis (CTTA) in differentiating between in-situ and minimally-invasive from invasive adenocarcinomas in subsolid lung nodules (SSLNs). MATERIAL AND METHODS: Two radiologists retrospectively reviewed 49 SSLNs in 44 patients. There were 27 men and 17 women with a mean age of 63+/-7 (SD) years (range: 47-78years). For each SSLN, type (pure ground-glass or part-solid) was assessed by consensus and CTTA was conducted independently by each observer using a filtration-histogram technique. Different filters were used before histogram quantification: no filtration, fine, medium and coarse, followed by histogram quantification using mean intensity, standard deviation (SD), entropy, mean positive pixels (MPP), skewness and kurtosis. RESULTS: We analyzed 13 pure ground-glass and 36 part-solid nodules corresponding to 16 adenocarcinomas in situ (AIS), 5 minimally invasive adenocarcinomas (MIA) and 28 invasive adenocarcinomas (IVA). At uni- and multivariate analysis CTTA allowed discriminating between IVAs and AIS/MIA (P<0.05 and P=0.025, respectively) with the following histogram parameters: skewness using fine textures and kurtosis using coarse filtration for pure ground-glass nodules, and SD without filtration for part-solid nodules. CONCLUSION: CTTA has the potential to differentiate AIS and MIA from IVA among SSLNs. However, our results require further validation on a larger cohort. PMID- 29477491 TI - Secondary sinus lift: viable technique for when a membrane is raised without a graft, and fails. PMID- 29477492 TI - Clustering of Health Behaviors and Cardiorespiratory Fitness Among U.S. Adolescents. AB - PURPOSE: Decreased cardiorespiratory fitness (CRF) is associated with an increased risk of cardiovascular disease. However, little is known how the interaction of diet, physical activity (PA), and sedentary time (ST) affects CRF among adolescents. By using a nationally representative sample of U.S. adolescents, we used cluster analysis to investigate the interactions of these behaviors with CRF. We hypothesized that distinct clustering patterns exist and that less healthy clusters are associated with lower CRF. METHODS: We used 2003 2004 National Health and Nutrition Examination Survey data for persons aged 12-19 years (N = 1,225). PA and ST were measured objectively by an accelerometer, and the American Heart Association Healthy Diet Score quantified diet quality. Maximal oxygen consumption (VO2max) was measured by submaximal treadmill exercise test. We performed cluster analysis to identify sex-specific clustering of diet, PA, and ST. Adjusting for accelerometer wear time, age, body mass index, race/ethnicity, and the poverty-to-income ratio, we performed sex-stratified linear regression analysis to evaluate the association of cluster with VO2max. RESULTS: Three clusters were identified for girls and boys. For girls, there was no difference across clusters for age (p = .1), weight (p = .3), and BMI (p = .5), and no relationship between clusters and VO2max. For boys, the youngest cluster (p < .01) had three healthy behaviors, weighed less, and was associated with a higher VO2max compared with the two older clusters. CONCLUSIONS: We observed clustering of diet, PA, and ST in U.S. adolescents. Specific patterns were associated with lower VO2max for boys, suggesting that our clusters may help identify adolescent boys most in need of interventions. PMID- 29477493 TI - The Relationship Between COPD and Frailty: A Systematic Review and Meta-Analysis of Observational Studies. AB - BACKGROUND: Frailty is common in seniors and is characterized by diminished physiological reserves and increased vulnerability to stressors. Frailty can change the prognosis and treatment approach of several chronic diseases, including COPD. The association between frailty and COPD has never been systematically reviewed. OBJECTIVES: The goal of this study was to conduct a systematic review and meta-analysis assessing the association of COPD with frailty and pre-frailty. METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used when reporting this review. We searched PubMed, Web of Science, and Embase from January 1, 2002, to October 6, 2017. The quality of the studies was evaluated by using the Newcastle Ottawa Scale. Two assessors independently rated each study: scores > 7 were considered a low risk of bias; 5 to 7, a moderate risk of bias; and < 5, a high risk of bias. Pooled estimates were obtained through random effect models and Mantel-Haenszel weighting. Homogeneity (I2) and publication bias were assessed. RESULTS: A total of 27 studies were selected: 23 cross-sectional, three longitudinal, and one both. The pooled prevalence of pre-frailty in individuals with COPD was 56% (95% CI, 52-60; I2 = 80.8%); it was 19% (95% CI, 14-24; I2 = 94.4%) for frailty. Patients with COPD had a two-fold increased odds of frailty (pooled OR, 1.97 [95% CI, 1.53-2.53]; I2 = 0.0%). Three longitudinal studies, presenting heterogeneous aims and methods, suggested a bidirectional association between COPD and frailty. CONCLUSIONS: Frailty and pre-frailty are common in individuals with COPD. Older subjects with COPD have a two-fold increased odds of frailty. These results may have clinical implications, as they identify the need to assess frailty in individuals with COPD and to further investigate any potential negative effects associated with the co-occurrence of these conditions. Longitudinal research that examines temporal associations between COPD and frailty are needed to further clarify this relationship and to assess if treatment of COPD may prevent the onset of frailty. TRIAL REGISTRY: PROSPERO registration No.: 58302; URL: https://www.crd.york.ac.uk/prospero/. PMID- 29477494 TI - Working With a Mentor: Effective Strategies During Fellowship and Early Career. PMID- 29477495 TI - Gene Editing of Human Embryos with CRISPR/Cas9: Great Promise Coupled with Important Caveats. PMID- 29477496 TI - Molecular cloning, characterization and expression profiling of galectin-9 gene from Labeo rohita (Hamilton, 1822). AB - Galectin-9 is a b-galactoside-binding tandem repeat galectin that regulates many cellular functions, ranging from cell adhesion to pathogen recognition. In spite of extensive study of mammalian galectin importance in immune system, little is known about that of fish. To study the normal expression and immune response of Labeo rohita to pathogens, a tandem-repeat galectin-9 from Labeo rohita was identified and named LrGal-9. Its full-length cDNA was 1534 bp encoded 291 amino acids (35.12 KDa), shared the highest 81% identity with the galectin-9 of Danio rerio. LrGal-9 identified in this study lacked signal peptide and a transmembrane domain like galectin-9 members reported in other fishes. Quantitative PCR showed that LrGal-9 was lowly expressed in gill, muscle, heart, highly expressed in tested immune tissues (intestine, kidney, liver, spleen) in normal body. After Aeromonas hydrophila challenge, LrGal-9 was remarkably increased in all tested immune tissues in a time-dependent manner. These results suggest that LrGal-9 plays a role in innate immunity in Labeo rohita. PMID- 29477499 TI - Comparing Guidelines for Surgical Management of Stones-What Do We Learn? PMID- 29477498 TI - Efficient resistance to grass carp reovirus infection in JAM-A knockout cells using CRISPR/Cas9. AB - The hemorrhagic disease of grass carp (Ctenopharyngodon idellus) induced by grass carp reovirus (GCRV) leads to huge economic losses in China and currently, there are no effective methods available for prevention and treatment. The various GCRV genotypes may be one of the major obstacles in the pursuit of an effective antiviral treatment. In this study, we exploited CRISPR/Cas9 gene editing to specifically knockout the DNA sequence of the grass carp Junctional Adhesion Molecule-A (gcJAM-A) and evaluated in vitro resistance against various GCRV genotypes. Our results show that CRISPR/Cas9 effectively knocked out gcJAM-A and reduced GCRV infection for two different genotypes in permissive grass carp kidney cells (CIK), as evidenced by suppressed cytopathic effect (CPE) and GCRV progeny production in infected cells. In addition, with ectopic expression of gcJAM-A in cells, non-permissive cells derived from Chinese giant salamander (Andrias davidianus) muscle (GSM) could be highly infected by both GCRV-JX0901 and Hubei grass carp disease reovirus (HGDRV) strains that have different genotypes. Taken together, the results demonstrate that gcJAM-A is necessary for GCRV infection, implying a potential approach for viral control in aquaculture. PMID- 29477497 TI - The inhibition of GSK-3beta promotes the production of reactive oxygen species via beta-catenin/C/EBPalpha signaling in the spleen of zebrafish (Danio rerio). AB - In this study, the mechanism that the inhibition of glycogen synthase kinase 3beta (GSK-3beta) promotes the production of reactive oxygen species (ROS) via beta-catenin/CCAAT/enhancer binding protein alpha (C/EBPalpha) signaling was investigated in the spleen of zebrafish (Danio rerio). The results demonstrated that the inhibition of GSK-3beta induced the mRNA expression of beta-catenin and C/EBPalpha by lithium (Li) treatments or GSK-3beta RNA interference. The levels of hydrogen peroxide (H2O2), superoxide anion (O2.-), and hydroxy radical (.OH) as well as the activity of superoxide dismutase (SOD) were increased, while the activities of catalase (CAT) and glutathione peroxidase (GSH-PX) were decreased in the spleen and ZF4 cells of zebrafish by Li+ treatments. In addition, GSK 3beta RNA interference increased ROS levels and decreased the activities of CAT and GSH-PX in the spleen. The fluorescence intensity of ROS was increased but the mitochondrial membrane potential (MMP) was decreased by Li+ treatments in ZF4 cells labeled with 2',7'-dichlorofluorescein diacetate (DCFH-DA) and Rhodamine 123, respectively. The results of present study indicated that the inhibition of GSK-3beta promoted the ROS production via beta-catenin/C/EBPalpha signaling in the spleen of zebrafish, and the balance between ROS and antioxidants could be destroyed by the GSK-3beta/beta-catenin/C/EBPalpha signaling. The results may be a valuable contribution to understanding the modulatory mechanism of GSK 3beta/beta-catenin/C/EBPalpha signaling on the antioxidant system in fish species. PMID- 29477500 TI - Editorial Comment. PMID- 29477501 TI - Evaluation of ventricular repolarization features with Tp-e, Tp-e/QTc, JTc and JTd during electroconvulsive therapy. AB - OBJECTIVE: The purpose of this study was to investigate the influence of electrical stimulation transmitted through the body during electroconvulsive therapy on traditional and relatively new ventricular repolarization parameters (Rate corrected QT interval (QTc), QT dispersion (QTd), rate corrected JT interval (JTc), JT dispersion (JTd), T-peak to T-end interval (Tp-e) and Tp-e/QTc ratio) under propofol anaesthesia. METHODS: Twenty-two patients (aged 18-50 years) who were each scheduled for ECT for major depression, bipolar disorder or schizophrenia enrolled to the study. Electrocardiography (ECG) recordings were obtained before anaesthesia and within 3-5 min after electrical stimulus of ECT for measurements. QTc, QTd, JTc, JTd, Tp-e and Tp-e/QTc were measured as repolarization indices. RESULTS: The study included twenty-two patients, 9(40.9%) females and 13(59.1%) males, and the mean age accounted for 33.57 +/- 9.95 years. The comparison of the measured parameters before and after ECT, which were not statistically different, were as follows: QTc (416.52 +/- 46.64 vs 430.00 +/- 34.00msn; p = 0.18), JTc (308.09 +/- 25.09 vs 315.47 +/- 26.89msn; p = 0.30), QTd (22.27 +/- 11.51 vs 20.45 +/- 9.9msn; p = 0.52) and JTd (22.72 +/- 11.2 vs 17.72 +/- 10.20msn; p = 0.06). Also, no significant difference was detected at the following parameters Tp-e (80.0 +/- 13.45 vs 78.63 +/- 15.21msn; p = 0.65) and Tp e/QTc ratio (0.19 +/- 0.03 vs 0.18 +/- 0.07; p = 0.08). On the other hand, HR showed a significant increase after ECT at 88.13 +/- 13.74 vs 93.0 +/- 15.2 bpm; p = 0.03. CONCLUSION: QTc, QTd, JTc, JTd, Tp-e interval and Tp-e/QTc ratio, which are thought to be potential repolarisation markers for ventricular arrhythmias, did not demonstrate significant change within 3-5 min of electrical stimulation during ECT. PMID- 29477502 TI - Alternans during fascicular ventricular tachycardia due to digitalis toxicity. AB - This report describes a digitalis-induced regular fascicular ventricular tachycardia characterized by marked QRS alternans a manifestation not usually associated with this arrhythmia. The striking alternation of QRS configuration suggested alternating ventricular activation from either a single focus with two exits in distal branches of the left anterior fascicle or 2 different foci localized in the Purkinje-myocardial network of the left anterior fascicle. PMID- 29477503 TI - Physical activity and exercise on diabetic foot related outcomes: A systematic review. AB - BACKGROUND: Diabetic foot is one of the most common complications of diabetes. It has the potential risk of pathologic consequences including infection, ulceration and amputation, but a growing body of evidence suggests that physical activity and exercise may improve diabetic foot outcomes. OBJECTIVE: To analyze de effects of exercise and physical activity interventions on diabetic foot outcomes. METHODS: A comprehensive and systematic search was conducted according to PRISMA recommendations. Only controlled clinical trials with patients with diabetes were included. RESULTS: Six studies, involving 418 patients with diabetes, were included. Two studies used only aerobic exercise; two studies combined aerobic, resistance and balance exercise; and two studies combined aerobic and balance exercise by Thai Chin Chuan methods. Physical activity and exercise significantly improved nerve velocity conduction, peripheral sensory function and foot peak pressure distribution. Moreover, the ulcers incidence rate per year was lower in the intervention groups, compared with the controls [0.02 vs. 0.12]. CONCLUSION: This review suggests evidence that physical activity and exercise is an effective non-pharmacological intervention to improve diabetic foot related outcomes. Combined multi-disciplinary treatments are more effective in the prevention of foot complications in patients with diabetes. PMID- 29477505 TI - Increasing understanding of encephalitis. PMID- 29477504 TI - Use of parenteral glucocorticoids and the risk of new onset type 2 diabetes mellitus: A case-control study. AB - BACKGROUND: Use of oral glucocorticoids (GCs) has been associated with hyperglycaemia and type 2 diabetes mellitus (T2DM). However, unlike oral GCs, there is minimal or no data on the effect of parenteral GC use on T2DM. OBJECTIVE: To assess the association between use of parenteral GCs and the risk of receiving a first prescription of a non-insulin antidiabetic drug (NIAD) as a proxy for new onset of T2DM. METHODS: A population based case-control study was performed using the Clinical Practice Research Datalink (CPRD). Cases (n = 177,154) were defined as patients >18 years of age who had their first ever NIAD prescription between January 1987 and October 2013. Controls were matched by age, gender and general practitioner practice. Conditional logistic regression analyses were used to estimate the risk of NIAD prescription and use of parenteral GCs. Our analyses were statistically adjusted for lifestyle factors, comorbidities and concomitant drug use. RESULTS: Although this study confirmed that oral GCs increases the risk of receiving a first prescription of a NIAD (OR 2.63 [95% CI 2.53-2.73]), there was no association between the use of parenterally administered GCs and the risk of receiving a first prescription of a NIAD (OR 0.88 [95% CI 0.76-1.02]). The number of GC prescriptions was not associated with risk of new onset T2DM compared to no parenteral GCs use; neither the type of GC. CONCLUSION: Our study does not demonstrate an association between the use of parenteral GCs and the risk of new onset of T2DM. PMID- 29477506 TI - Advances in the diagnosis and treatment of fungal infections of the CNS. AB - Fungal infections of the CNS are challenging to treat and their optimal management requires knowledge of their epidemiology, host characteristics, diagnostic criteria, and therapeutic options. Aspergillus and Cryptococcus species predominate among fungal infections of the CNS. Most of these fungi are ubiquitous, but some have restricted geographical distribution. Fungal infections of the CNS usually originate from primary sites outside the CNS (eg, fungal pneumonia) or occur after inoculation (eg, invasive procedures). Most patients with these infections have immunodeficiencies, but immunocompetent individuals can also be infected through heavy exposure. The infecting fungi can be grouped into moulds, yeasts, and dimorphic fungi. Substantial progress has been made with new diagnostic approaches and the introduction of novel antifungal drugs, but fungal infections of the CNS are frequently lethal because of diagnostic delays, impaired drug penetration, resistance to antifungal treatments, and inadequate restoration of immune function. To improve outcomes, future research should advance diagnostic methods (eg, molecular detection and fungus identification), develop antifungal compounds with enhanced CNS-directed efficacy, and further investigate crucial host defence mechanisms. PMID- 29477507 TI - Transcranial direct current stimulation unveils covert consciousness. PMID- 29477508 TI - Sphingolipid Turnover Turns Over the Fate of Aneuploid Cells. AB - Aneuploidy, or unbalanced chromosome number, is a hallmark of cancer. Recently established model systems revealed that aneuploidy affects many aspects of cellular physiology, among them sphingolipid metabolism. The new finding that the proliferation of aneuploid cells depends on sphingolipid homeostasis offers an appealing opportunity for cancer treatment. PMID- 29477509 TI - Aortic Reconstruction With Duplicated Femoral Veins. PMID- 29477510 TI - One Year Outcomes of 101 BeGraft Stent Grafts Used as Bridging Stents in Fenestrated Endovascular Repairs: A Bridge Too Far for Some? PMID- 29477511 TI - Technical note: Evaluation of fine needle aspiration cytology for the diagnosis of fatty liver in dairy cattle. AB - Fatty liver is a common condition affecting dairy cattle during the periparturient period, characterized by a pathological accumulation of triglycerides (TG) in the hepatocytes. The objective of this study was to evaluate the diagnostic potential of fine needle aspiration cytology in fresh liver specimens using liver TG concentrations as a gold standard. Fifty-seven liver samples from Holstein cows were collected during processing at a slaughterhouse. Tissue and fine needle aspirate samples were obtained from the parietal upper portion of the caudate lobe. Two samples of liver tissue were collected with a 16 gauge * 15 cm biopsy needle for histological and TG concentration assessment. A third sample was collected for cytology using an 18 gauge * 5.08 cm needle. The contents of the needle were transferred to a glass slide, spread, and air-dried. Liver samples were assayed by colorimetry/fluorimetry to determine TG concentrations. Concentrations of TG <2% were considered normal. Histological and cytological evaluations were conducted by 2 different pathologists blind to the visual classification. Sensitivity (Se) and specificity (Sp) were calculated. Cytology had a Se and Sp of 73 and 85%, respectively. Histopathology had a Se and Sp of 45.9 and 100%, respectively. The likelihood of having higher scores for histopathology and cytology increased as a function of liver TG content (mg/g). PMID- 29477512 TI - Effect of high-pressure-jet processing on the viscosity and foaming properties of pasteurized whole milk. AB - The processing of milk using high-pressure technologies has been shown to dissociate casein micelles, denature whey proteins, and change the appearance and rheological properties of milk. A novel high-pressure processing technology called high-pressure-jet (HPJ) processing is currently being investigated for use in the food industry. Few studies have evaluated the effects of HPJ technology on dairy foods. The present study investigated the physicochemical and foaming properties of homogenized pasteurized whole milk processed at pressures from 0 to 500 MPa using HPJ processing. The apparent particle size exhibited a monomodal distribution in whole milk samples processed up to 125 MPa and a bimodal distribution for samples processed at 250, 375, and 500 MPa. The viscosity increased from approximately 2 to 5 mPa.s when whole milk was processed using HPJ at 375 MPa, and foam expansion increased from approximately 80 to 140% after processing at >125 MPa. Foam stability was limited to pressures in the 375 to 500 MPa range. We hypothesized that the increase in apparent particle size was due to the dissociation of casein micelles into surface-active casein protein monomers, and the formation of casein-casein and casein-fat particles. Ultracentrifugation of samples into 3 milk fractions (supernatant, serum, and precipitate), and subsequent fat and protein analysis on the 3 fractions, showed that a strong interaction between casein proteins and fat triglycerides occurred, evidenced by the increase in fat content associated with the precipitate fraction with increasing pressure. This suggests that stable casein-fat aggregates are formed when whole milk is processed using HPJ at pressure >125 MPa. PMID- 29477513 TI - Technical note: Method for isolation of the bovine sweat gland and conditions for in vitro culture. AB - Apocrine sweat glands in bovine skin are involved in thermoregulation. Human, horse, and sheep sweat gland epithelial cells have been isolated and grown in vitro. The present study was conducted to identify a method to isolate bovine sweat glands and culture apocrine bovine sweat gland epithelial cells in vitro. Mechanical shearing, collagenase digestion, centrifugation, and neutral red staining were used to identify and isolate the apocrine glands from skin. Bovine sweat glands in situ and after isolation comprised 2 major cell types consisting of a single layer of cuboidal epithelial cells resting on a layer of myoepithelial cells. In situ, the glands were embedded in a collagen matrix primarily comprising fibroblasts, and some of these cells were also present in the isolated material. The isolated material was transferred to complete medium (keratinocyte serum-free medium, bovine pituitary extract, and human recombinant epidermal growth factor + 2.5% fetal bovine serum) in a T 25 flask (Falcon, Franklin Lakes, NJ) with media film and then incubated at 37 degrees C for 24 h. After sweat glands adhered to the bottom of the flask, an additional 2 mL of complete medium was added and the medium was changed every 3 d. Isolated apocrine sweat glands and bovine sweat gland epithelial cells were immunostained for cytokeratin and fibroblast specific protein, indicating fibroblast-free cultures. PMID- 29477514 TI - Exotoxin diversity of Staphylococcus aureus isolated from milk of cows with subclinical mastitis in Central Russia. AB - Mastitis, a major veterinary problem widespread in many regions, is caused mainly by Staphylococcus spp. However, there is no current reliable information about the role of Staphylococcus aureus and their toxins in the development of mastitis in cows in the territory of the Russian Federation. The aim of this investigation was to determine the profile of exotoxins of S. aureus from cow milk from farms of Central Russia. A total of 60 isolates of S. aureus were obtained from milk samples of cows with the subclinical form of mastitis. The exotoxin genes were identified using 2 types of PCR assays. The diversity of enterotoxin genes was studied by multiplex PCR. The percentage occurrence of enterotoxin genes was as follows: sea, 53.3%; seb, 3.3%; sec, 50%; sed, 4%; see, 46.6%; seg, 70%; sei, 10%; selp, 3.3%; and tsst1, 1.6%. The seh gene was not detected. The genes of pore-forming toxins and phenol-soluble modulins were identified by singleplex PCR and consisted of the following: hlA, 70%; lucS, 46.6%; psmA, 81.6%; psmB, 95%; and hld, 78.3%. The most abundant genes were psm (psmB, 95%), which codes for pore-forming toxins, and seg (70%), which codes for enterotoxins. The production of some enterotoxins in bacterial culture medium was detected by ELISA. The level of toxin production was near 1 ng/mL for SEA, SEE, SEG, SEI, SELP, and TSST-1 and reached a maximal level of 18 ng/mL for SEE. In the present work, we show that subclinical mastitis in cows is associated with S. aureus in the central region of the Russian Federation. Most of the isolates containing enterotoxin genes also had cytotoxin genes. PMID- 29477515 TI - The effects of feeding mixed tocopherol oil on whole-blood respiratory burst and neutrophil immunometabolic-related gene expression in lactating dairy cows. AB - The 4 major tocopherol isoforms differ in their biochemical reactivity and cellular effects due to basic chemical structural differences. Alpha-tocopherol has been well studied regarding effects on bovine polymorphonuclear leukocyte (PMN) function and its involvement in respiratory burst. However, no studies to date have identified the effects of supplementing a mixed tocopherol oil (Tmix) particularly enriched in non-alpha tocopherol isoforms (i.e., gamma- and delta isoforms) on fundamental immunometabolic changes in dairy cows. Therefore, the objectives of this study were to determine whether short-term feeding of vegetable oil-derived Tmix alters specific biomarkers of metabolism, whole-blood leukocyte populations, respiratory burst, immunometabolic-related gene expression of PMN, or gene expression of isolated PMN when challenged with lipopolysaccharides (LPS). Clinically healthy multiparous lactating Holstein cows (n = 12; 179 +/- 17 d in milk, 40.65 +/- 3.68 kg of milk yield) were fed Tmix (620 g/d) for 7 consecutive days. Jugular blood (EDTA anticoagulant) was collected from all cows on d 0 before treatment initiation and again on d 7 after Tmix feeding. Total stimulated respiratory burst activity (RBA) and leukocyte populations were assessed in whole blood, and tocopherol isoform concentrations, metabolites, and hormones were measured in plasma. For gene expression analysis, isolated PMN from cows before and after Tmix feeding were incubated with LPS at a final concentration of either 0.0 or 1.5 ug/mL. Feeding of Tmix for 7 d increased the concentrations of alpha- and gamma-tocopherol. The Tmix did not alter plasma insulin but decreased cholesterol. The Tmix did not alter whole-blood RBA or the leukocyte populations. The LPS challenge increased the expression of proinflammatory genes TNFA and IL6. However, Tmix treatment did not alter the patterns of LPS-affected expression of genes (e.g., TNFA, ITGB2, PPARA, and RXRA) associated with the immune or metabolic response. In conclusion, short-term feeding of Tmix may have no negative effect on animal health as Tmix increased alpha- and gamma-tocopherol concentrations in blood and did not impair whole blood RBA or alter leukocyte populations. The data provide further support that the alpha- and gamma-tocopherol isoforms do not interfere with normal immune or metabolic function. PMID- 29477516 TI - Technical note: The development of a reliable 5-point gait scoring system for use in dairy goats. AB - Numerical rating scales are frequently used in gait scoring systems as indicators of lameness in dairy animals. The gait scoring systems commonly used in dairy goats are based on 4-point scales that focus on detecting and judging the severity of a definite limp. An uneven gait, such as a shortened stride or not "tracking up," is arguably the precursor to the development of a limp; thus, identifying such changes in gait could provide opportunity for early treatment. The objectives of this study were (1) to develop a 5-point gait scoring system that included an "uneven gait" category and compare the distribution of gait scores generated using this system to scores generated using a 4-point system, and (2) to determine whether this system could be reliably used. Forty-eight Saanen cross 2- and 3-yr-old lactating does were enrolled from a commercial dairy goat farm. Two observers carried out weekly live gait scoring sessions for 7 wk using the developed 5-point scoring system. The first 2 wk were used as training sessions (training sessions 1-2), with the subsequent 5 wk completed as gait assessments (assessments 1-5). In addition to training session 1 being lived scored, the goats were also video-recorded. This allowed observer 1 to re-score the session 4 times: twice using the developed 5-point system and twice using the previously used 4-point system. Comparisons of score distributions could then be made. Using the 4-point system, 81% of the goats were assigned score 1 (normal gait). Using the 5-point system, only 36% of the goats were assigned score 1 (normal gait), with 50% assigned score 2 (uneven gait). High levels of intra observer reliability were achieved by observer 1 using both gait scoring systems [weighted kappa (kappaw) = 1.00: 4-point, kappaw = 0.96: 5-point]. At training session 1 (wk 1), inter-observer reliability was only moderate (kappaw = 0.54), but this was improved during the subsequent training session 2 (kappaw = 0.89). Inter-observer reliability was high among assessments 1 to 5 (kappaw = 0.90 1.00). During the training sessions, sensitivity for gait scores 1 and 2 was 77 and 65% (training session 1) and 89 and 94% (training session 2), respectively. Sensitivity was high among assessments 1 to 5 (score 1: 83-100%, score 2: 97 100%). This highlights the likely reason why existing gait scoring systems for dairy goats do not include an "uneven gait" category, as distinguishing it from a normal gait was challenging without training. In conclusion, with training, a 5 point gait scoring system could be reliably used. The 5-point system was found to be more sensitive than the 4-point system, allowing for a potential precursor to lameness to be identified. Further work is needed to determine whether the score can be reliably used in an on-farm setting. PMID- 29477517 TI - Invited review: Bioactive compounds produced during cheese ripening and health effects associated with aged cheese consumption. AB - Traditionally, cheese is manufactured by converting fluid milk to a semisolid mass through the use of a coagulating agent, such as rennet, acid, heat plus acid, or a combination thereof. Cheese can vary widely in its characteristics, including color, aroma, texture, flavor, and firmness, which can generally be attributed to the production technology, source of the milk, moisture content, and length of aging, in addition to the presence of specific molds, yeast, and bacteria. Among the most important bacteria, lactic acid bacteria (LAB) play a critical role during the cheese-making process. In general, LAB contain cell envelope proteinases that contribute to the proteolysis of cheese proteins, breaking them down into oligopeptides that can be subsequently taken up by cells via specific peptide transport systems or further degraded into shorter peptides and amino acids through the collaborative action of various intracellular peptidases. Such peptides, amino acids, and their derivatives contribute to the development of texture and flavor in the final cheese. In vitro and in vivo assays have demonstrated that specific sequences of released peptides exhibit biological properties including antioxidant, antimicrobial, anti-inflammatory, immunomodulatory, and analgesic/opioid activity, in addition to angiotensin converting enzyme inhibition and antiproliferative activity. Some LAB also produce functional lipids (e.g., conjugated linoleic acid) with anti-inflammatory and anticarcinogenic activity, synthesize vitamins and antimicrobial peptides (bacteriocins), or release gamma-aminobutyric acid, a nonprotein amino acid that participates in physiological functions, such as neurotransmission and hypotension induction, with diuretic effects. This review provides an overview of the main bioactive components present or released during the ripening process of different types of cheese. PMID- 29477518 TI - Maintenance of plasma branched-chain amino acid concentrations during glucose infusion directs essential amino acids to extra-mammary tissues in lactating dairy cows. AB - The objectives of this study were to investigate the effects of branched-chain AA (BCAA) supplementation when glucose is infused postruminally into lactating dairy cows consuming a diet low in crude protein (CP) and to test the hypothesis that low BCAA concentrations are responsible for the poor stimulation of milk protein yield by glucose. Twelve early-lactation Holstein cows were randomly assigned to 15% and 12% CP diets in a switchback design of 6-wk periods. Cows consuming the 12% CP diet received 96-h continuous jugular infusions of saline and 1 kg/d of glucose with 0, 75, or 150 g/d of BCAA in a Latin square sequence of treatments. Compared with saline, glucose infusion did not affect dry matter intake but increased milk yield by 2.2 kg/d and milk protein and lactose yields by 63 and 151 g/d, respectively. Mammary plasma flow increased 36% during glucose infusion compared with saline infusion, possibly because of a 31% decrease in total acetate plus beta-hydroxybutyrate concentrations. Circulating concentrations of total essential AA and BCAA decreased 19 and 31%, respectively, during infusion of glucose, yet net mammary uptakes of AA remained unchanged compared with saline infusion. The addition of 75 and 150 g/d of BCAA to glucose infusions increased arterial concentrations of BCAA to 106 and 149%, respectively, of the concentrations in saline-infused cows, but caused a decrease in concentrations of non-branched-chain essential AA in plasma, as well as their mammary uptakes and milk protein yields. Plasma urea concentration was not affected by BCAA infusion, indicating no change in catabolism of AA. The lack of mammary and catabolic effects leads us to suggest that BCAA exerted their effects on plasma concentrations of the other essential AA by stimulating utilization in skeletal muscle for protein accretion. Results indicate that the glucose effect on milk protein yield was not limited by low BCAA concentrations, and that a stimulation of extra-mammary use of non-branched-chain essential amino acids by BCAA led to a decrease in milk protein yield. PMID- 29477519 TI - Behavioral changes before metritis diagnosis in dairy cows. AB - Metritis is common in the days after calving and can reduce milk production and reproductive performance. The aim of this study was to identify changes in feeding and social behavior at the feed bunk, as well as changes in lying behavior before metritis diagnosis. Initially healthy Holstein cows were followed from 3 wk before to 3 wk after calving. Behaviors at the feed bunk were recorded using an electronic feeding system. Lying behavior was recorded using data loggers. Metritis, based upon the characteristics of vaginal discharge at d 3, 6, 9, 12 and 15 after calving, was diagnosed in 74 otherwise healthy cows. Behavior of these cows, beginning 2 wk before calving until the day of diagnosis, was compared with 98 healthy cows (never diagnosed with any health disorder, including ketosis, mastitis, and lameness) during the transition period. During the 2 wk before calving, cows later diagnosed with metritis had reduced lying time and fewer lying bouts compared with healthy cows. In the 3 d before clinical diagnosis, cows that developed metritis ate less, consumed fewer meals, were replaced more often at the feed bunk, and had fewer lying bouts of longer duration compared with healthy cows. We concluded that changes in feeding as well as social and lying behavior could contribute to identification of cows at risk of metritis. PMID- 29477520 TI - Performance and methane emissions in dairy cows fed oregano and green tea extracts as feed additives. AB - Plant extracts have been proposed as substitutes for chemical feed additives due to their potential as rumen fermentation modifiers and because of their antimicrobial and antioxidant activities, possibly reducing methane emissions. This study aimed to evaluate the use of oregano (OR), green tea extracts (GT), and their association as feed additives on the performance and methane emissions from dairy between 28 and 87 d of lactation. Thirty-two lactating dairy cows, blocked into 2 genetic groups: 16 Holstein cows and 16 crossbred Holstein-Gir, with 522.6 +/- 58.3 kg of body weight, 57.2 +/- 20.9 d in lactation, producing 27.5 +/- 5.0 kg/cow of milk and with 3.1 +/- 1.8 lactations were evaluated (means +/- standard error of the means). Cows were allocated into 4 treatments: control (CON), without plant extracts in the diet; oregano extract (OR), with the addition of 0.056% of oregano extract in the dry matter (DM) of the diet; green tea (GT), with the addition of 0.028% of green tea extract in the DM of the diet; and mixture, with the addition of 0.056% oregano extract and 0.028% green tea extract in the DM of the diet. The forage-to-concentrate ratio was 60:40. Forage was composed of corn silage (94%) and Tifton hay (6%); concentrate was based on ground corn and soybean meal. Plant extracts were supplied as powder, which was previously added and homogenized into 1 kg of concentrate in natural matter, top dressed onto the total mixed diet. No treatment by day interaction was observed for any of the evaluated variables, but some block by treatment interactions were significant. In Holstein cows, the mixture treatment decreased gross energy and tended to decrease the total-tract apparent digestibility coefficient for crude protein and total digestible nutrients when compared with OR. During the gas measurement period, GT and OR increased the digestible fraction of the ingested DM and decreased CH4 expressed in grams per kilogram of digestible DMI compared with CON. The use of extracts did not change rumen pH, total volatile fatty acid concentration, milk yield, or most milk traits. Compared with CON, oregano addition decreased fat concentration in milk. The use of plant extracts altered some milk fatty acids but did not change milk fatty acids grouped according to chain length (short or long), saturation (unsaturated or saturated), total conjugated linoleic acids, and n-3 and n-6 contents. Green tea and oregano fed separately reduced gas emission in cows during the first third of lactation and have potential to be used as feed additives for dairy cows. PMID- 29477521 TI - Changes in feeding, social, and lying behaviors in dairy cows with metritis following treatment with a nonsteroidal anti-inflammatory drug as adjunctive treatment to an antimicrobial. AB - Dairy cows with metritis display sickness behaviors, and nonsteroidal anti inflammatory drugs (NSAID) have the potential to reduce these responses. The objective of this study was to investigate changes in feeding, social, and lying behaviors in dairy cows with metritis that had been treated with the NSAID meloxicam. After parturition, cows were housed in a dynamic, mixed-parity group of 20 animals with access to 12 electronic feed bins, 2 electronic water bins, and 24 lying stalls in a freestall pen. Every third day after parturition, vaginal discharge was evaluated to diagnose metritis based on the presence of foul smell and characteristic visual appearance. When diagnosed with metritis, animals (n = 87) were randomly allocated to receive either a single dose of meloxicam (0.5 mg/kg of body weight subcutaneously) or a placebo solution. All metritic animals received an antimicrobial (ceftiofur) for 5 d. We measured feeding and social behaviors at the feed bunk, as well as lying behaviors, and assessed within-cow changes from the day before to the day of (d 0) NSAID treatment, and from the day before to d 1 to 5 after treatment. Generally, behaviors changed around the day of diagnosis of metritis. Compared with the placebo group, cows that received meloxicam had a greater increase in the number of visits to the feeder, but tended to show less of an increase in dry matter intake and feeding time. These differences did not persist beyond 24 h after NSAID treatment. We observed no differences in changes in number of meals and feeding rate on d 0, but from d 1 to 5 cows treated with meloxicam had a lesser decrease in the number of meals and tended to have a greater decrease in feeding rate than did placebo-treated cows. In multiparous cows on d 0 and from d 1 to 5, meloxicam treatment was associated with decreased lying times. In primiparous cows, lying time changes were similar between treatments on d 0, but lying times increased more on d 1 to 5 for meloxicam than for placebo cows. Overall, cows changed the number of lying bouts on d 0, and this increase tended to be smaller for the meloxicam cows. There were no treatment differences in changes of social behavior. In summary, we observed inconsistent and generally small effects of a single dose of meloxicam in addition to antimicrobial therapy on the behavior of cows with metritis. PMID- 29477522 TI - Comparison of antioxidant capacity of cow and ewe milk kefirs. AB - This research aimed to evaluate the effects of using either grain or commercial starter culture on the antioxidative capacity of cow and ewe milk kefirs. The antioxidant capacity of kefir samples during fermentation and 21 d of storage was assessed by using 3 assays: 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) radical cation decolorization; 2,2-diphenyl-1-picrylhydrazyl (DPPH*) radical scavenging activity assay; and Fe+3-reducing power (ferric reducing antioxidant power assay, FRAP). Vitamin E and beta-carotene contents were also quantified. All kefir samples exhibited varying values for DPPH, ABTS, and FRAP assays depending on the starter culture and milk type. Vitamin E and beta carotene contents were similar in all kefir samples during storage. The results of this study suggest that milk type (cow or ewe) and culture type (kefir grains or commercial starter) were the significant parameters for the antioxidative activity of kefir. PMID- 29477523 TI - Predicting blood beta-hydroxybutyrate using milk Fourier transform infrared spectrum, milk composition, and producer-reported variables with multiple linear regression, partial least squares regression, and artificial neural network. AB - Prediction of postpartum hyperketonemia (HYK) using Fourier transform infrared (FTIR) spectrometry analysis could be a practical diagnostic option for farms because these data are now available from routine milk analysis during Dairy Herd Improvement testing. The objectives of this study were to (1) develop and evaluate blood beta-hydroxybutyrate (BHB) prediction models using multivariate linear regression (MLR), partial least squares regression (PLS), and artificial neural network (ANN) methods and (2) evaluate whether milk FTIR spectrum (mFTIR) based models are improved with the inclusion of test-day variables (mTest; milk composition and producer-reported data). Paired blood and milk samples were collected from multiparous cows 5 to 18 d postpartum at 3 Wisconsin farms (3,629 observations from 1,013 cows). Blood BHB concentration was determined by a Precision Xtra meter (Abbot Diabetes Care, Alameda, CA), and milk samples were analyzed by a privately owned laboratory (AgSource, Menomonie, WI) for components and FTIR spectrum absorbance. Producer-recorded variables were extracted from farm management software. A blood BHB >=1.2 mmol/L was considered HYK. The data set was divided into a training set (n = 3,020) and an external testing set (n = 609). Model fitting was implemented with JMP 12 (SAS Institute, Cary, NC). A 5 fold cross-validation was performed on the training data set for the MLR, PLS, and ANN prediction methods, with square root of blood BHB as the dependent variable. Each method was fitted using 3 combinations of variables: mFTIR, mTest, or mTest + mFTIR variables. Models were evaluated based on coefficient of determination, root mean squared error, and area under the receiver operating characteristic curve. Four models (PLS-mTest + mFTIR, ANN-mFTIR, ANN-mTest, and ANN-mTest + mFTIR) were chosen for further evaluation in the testing set after fitting to the full training set. In the cross-validation analysis, model fit was greatest for ANN, followed by PLS and MLR. Diagnostic strength after cross validation was poorest for MLR and was similar for ANN and PLS. Models that used mTest + mFTIR variables performed marginally better than models that used only mFTIR or mTest variables. These results suggest that blood BHB prediction models that use mFTIR + mTest variables may be useful additions to existing HYK diagnostic and management programs. PMID- 29477524 TI - Effects of dietary leucine and phenylalanine on pancreas development, enzyme activity, and relative gene expression in milk-fed Holstein dairy calves. AB - This study aimed to investigate the effect of dietary supplementation with leucine and phenylalanine on pancreas development, enzyme activity, and related gene expression in male Holstein calves. Twenty male Holstein calves [1 d of age, 38 +/- 3 kg of body weight (BW)] were randomly assigned to 1 of the following 4 treatment groups with 5 calves in each group: control, leucine supplementation (1.435 g/L of milk), phenylalanine supplementation (0.725 g/L of milk), and leucine and phenylalanine (1.435 + 0.725 g/L of milk). The diets were made isonitrogenous with the inclusion of alanine in each respective treatment. The feeding trial lasted for 8 wk, including 1 wk for adaption and 7 wk for the feeding experiment. Leucine tended to increase the concentration of total pancreatic protein (mg/kg of BW). Phenylalanine increased the concentrations of plasma insulin, cholecystokinin, and pancreatic DNA (mg/g) and the expression of trypsin gene but decreased the pancreatic protein:DNA ratio and tended to decrease the pancreas weight (g/kg of BW). No differences were observed in total pancreatic DNA (mg/pancreas and mg/kg of BW), pancreatic protein (mg/pancreas), or activities of alpha-amylase, trypsin, and lipase. The relative expression levels of the genes encoding alpha-amylase and lipase did not differ among the 4 groups. The supplementation of both leucine and phenylalanine showed an interaction on the pancreas weight (g and g/kg of BW) and a tendency of an interaction on the pancreatic protein concentration (mg/g of pancreas and mg/kg of BW) and the plasma glucose concentration. Leucine tended to increase the size of the pancreatic cells, whereas phenylalanine tended to increase the number of pancreatic cells. However, neither AA affected the activities of the pancreatic enzymes of the calves. These results indicate that leucine and phenylalanine supplementation in milk-fed Holstein calves differentially affect pancreatic growth and development. PMID- 29477525 TI - Effects of preweaning total plane of milk intake and weaning age on intake, growth performance, and blood metabolites of dairy calves. AB - The objective of this study was to evaluate the effects of preweaning total plane of milk intake and weaning age on intake, growth performance, and blood metabolites of dairy calves. A total of 48 Holstein calves (40 +/- 1.6 kg of body weight) were used in a 2 * 2 factorial arrangement with the factors of weaning age (d 60 vs. 75) and the total plane of milk intake (medium vs. high) during the preweaning period. Calves were assigned to 1 of 4 treatments: (1) calves fed medium plane of milk (MPM) intake and weaned on d 60 of age (MPM-60d, 4 L/d of milk from d 3 to 10, 6 L/d of milk from d 11 to 55, and 3 L/d of milk from d 56 to 60 of age; total milk intake = 317 L), (2) calves fed MPM intake and weaned on d 75 of age (MPM-75d, 4 L/d of milk from d 3 to 10 and 4.5 L/d of milk from d 11 to 70 of age followed by feeding 2.25 L/d of milk from d 71 to 75 of age; total milk intake = 313 L), (3) calves fed high plane of milk (HPM) intake and weaned on d 60 of age (HPM-60d, 4 L/d of milk from d 3 to 10, 6 L/d of milk from d 11 to 20, and 8.5 L/d of milk from d 21 to 55 followed by feeding 4.25 L/d of milk from d 56 to 60 of age; total milk intake = ~411 L); and (4) calves fed HPM intake and weaned on d 75 (HPM-75d, 4 L/d of milk from d 3 to 10, and 6 L/d of milk from d 11 to 70 of age followed by feeding 3 L/d of milk from d 71 to 75 of age; total milk intake = 407 L) with no milk refusals. All of the calves were monitored up to d 90 of age. Regardless of weaning age, starter feed intake and dry matter intake (% of body weight) were lower in calves fed HPM compared with those receiving MPM. A tendency for the plane of milk intake * weaning age interaction was observed for metabolizable energy intake with the highest value was recorded with the HPM-75d calves. The lowest efficiency of metabolizable energy intake and average feed efficiency was observed in HPM-60d calves throughout the experimental period as compared with the other groups. An interaction was found between the total plane of milk intake and weaning age regarding effects on total average daily gain, average daily gain/metabolizable energy intake, feed efficiency, final body weight, and plasma beta-hydroxybutyrate levels with the highest values measured in HPM-75d calves. Weaning on d 75 versus d 60 improved wither height and hip width, which tended to increase body length at the end of the trial. The results suggest that calves fed high amounts of milk during their preweaning period benefit from extending the time of weaning from 60 to 75 d of age based on average daily gain, feed efficiency, and final body weight. PMID- 29477526 TI - Short communication: Cheese supplemented with Thymus algeriensis oil, a potential natural food preservative. AB - The essential oil of Thymus algeriensis was analyzed as a potential preservative in soft cheese. We developed a novel method to test the preserving properties of essential oil in soft cheese. Contamination incidence of Penicillium aurantiogriseum was absent after 30 d of storage at 4 degrees C with 25 uL of essential oil added. The antimicrobial activity was tested against 8 bacteria and 8 fungi. Thymus algeriensis oil showed inhibitory activity against tested bacteria at 0.03 to 0.09 mg/mL, and bactericidal activity was achieved at 0.05 to 0.15 mg/mL. For antifungal activity, minimum inhibitory concentrations ranged between 0.01 and 0.04 mg/mL and minimum fungicidal concentrations between 0.01 and 0.04 mg/mL. Furthermore, the oil was also screened for antiradical activity using the 1,1-diphenyl-2-picrylhydrazyl assay. The results showed that the oil was active and achieved half-maximal inhibitory activity at 0.132 mg/mL. We used gas chromatography, gas chromatography-mass spectrometry, and nuclear magnetic resonance spectrometry to investigate the volatile compounds from the oil. Carvacrol was identified as the main compound in the oil, represented by 80.9% of the total constituents, followed by p-cymene (7.7%). PMID- 29477528 TI - Effects of repeated subacute ruminal acidosis challenges on the adaptation of the rumen bacterial community in Holstein bulls. AB - We investigated the effect of repeated subacute ruminal acidosis (SARA) challenges on the pH, fermentative function, and bacterial community in the rumen. Four rumen-cannulated Holstein bulls were fed a high-forage diet for 7 d (HF period) followed by a high-grain diet for 7 d (HG period). Four SARA challenges were carried out consecutively (first, second, third, and fourth challenges). The ruminal pH was measured continuously during the experiment, and rumen fluid samples during the first to fourth challenges were collected at 0800, 1400, and 2000 h on the last days of each feeding period for analysis; volatile fatty acid components, NH3-N, and lactic acid concentrations were measured. Bacterial community structure was analyzed at 0800 h during the first and fourth challenges on the last days of each period. The 24-h mean ruminal pH was decreased during the transition from high-forage to high-grain diet and tended to differ between the HF and HG periods. During the HG period, ruminal pH <5.6 was maintained for a longer period in the first and second challenges (350 and 405 min/d, respectively) than in the third and fourth challenges (both 120 min/d). A marked increase in total volatile fatty acid and NH3-N concentrations during the HG period was observed in the later challenges. In addition, lower and higher proportions of acetic and butyric acids, respectively, were observed during the HG period than during the HF period. A total of 37 core bacterial genera were found in all samples; however, the relative abundance of several genera differed significantly between the HF and HG periods (Prevotella, Ruminococcus, Eubacterium, and Oscillibacter) and between the first and fourth challenges (Eubacterium and unclassified Clostridiaceae). During the HG period, lower relative abundances of Prevotella, Eubacterium, and Oscillibacter and higher relative abundance of Ruminococcus were detected compared with during the HF period. The relative abundances of Eubacterium and unclassified Clostridiaceae were lower in the first challenge than in the fourth challenge. Bacterial diversity was greater during the HF period than during the HG period and was greater during the fourth challenge than during the first challenge. Interestingly, diversity indices during the HG period of the fourth challenge were higher than those during the HF period of the first challenge. These results suggested that rumen fermentation in Holstein cattle can adapt to repeated SARA challenges by minimizing the adverse changes in ruminal pH. Moreover, the composition and diversity of the ruminal bacterial community may be affected by ruminal pH and vice versa. PMID- 29477527 TI - A randomized controlled trial on the effect of incomplete milking during early lactation on ketonemia and body condition loss in Holstein dairy cows. AB - Limiting milk production for a short period of time in early lactation could be a relevant strategy to prevent hyperketonemia (HYK). From December 2013 to March 2015, 838 multiparous Holstein cows from 13 herds were enrolled in a randomized controlled trial evaluating the effect of incomplete milking in early lactation on ketonemia and its effect on body condition score (BCS) loss. Cows were randomly assigned 4 wk before expected calving date to 1 of 2 treatment groups, (1) a conventional milking protocol (CON) for which cows were completely milked or (2) an incomplete milking protocol (INC) for which a maximum of 10 to 14 kg of milk/d were withdrawn during the first 5 d in milk (DIM). beta-Hydroxybutyrate (BHB) concentrations were measured from blood samples collected on each cow 3 times at weekly intervals. Hyperketonemia was defined as BHB >=1.4 mmol/L. Body condition score variation in the postcalving period was calculated by subtracting BCS assessed at wk 7 from BCS assessed at first week after calving. Effect of treatment on ketonemia and prevalence of HYK were evaluated for 4 specific time periods: 1 to 3, 4 to 7, 8 to 17, and 18 to 26 DIM. Effect of treatment on ketonemia was investigated using linear mixed models with natural logarithm of BHB measurements as outcome and treatment groups as fixed effect. Generalized linear mixed models with HYK as outcome, using logit link, and treatment groups as fixed effect were used to investigate effect of treatment on odds of HYK. A logistic regression model with BCS loss (<0.75 or >=0.75) as outcome and treatment groups and herd as fixed effects was used to study effect of INC on odds of having BCS loss >=0.75. A total of 813 lactations had complete data and were used for statistical analysis of ketonemia and HYK. A total of 709 lactations had complete data and were used for analysis of BCS loss. Geometric means of blood BHB concentrations during the 1 to 3, 4 to 7, 8 to 17, and 18 to 26 DIM periods were, respectively, 0.72 (95% confidence interval = 0.66, 0.80), 0.66 (0.60, 0.73), 0.90 (0.80, 1.01), and 0.93 (0.83, 1.05) mmol/L for INC, and 0.65 (0.59, 0.72), 0.79 (0.72, 0.87), 0.94 (0.84, 1.06), and 0.92 (0.82, 1.04) mmol/L for CON. Cows in INC group had lower ketonemia during the 4 to 7 DIM period. Predicted prevalence of HYK during the 1 to 3, 4 to 7, 8 to 17, and 18 to 26 DIM periods were, respectively, 2.8 (3.2, 15.1), 4.6 (2.0, 10.0), 13.4 (8.4, 20.0), and 23.0% (17.4, 29.7) for INC and 2.6 (2.5, 13.8), 10.7 (5.6, 19.3), 19.4 (13.0, 27.9), and 21.3% (16.0, 27.8) for CON. The INC treatment reduced the prevalence of HYK during the 4 to 7 and 8 to 17 DIM periods. No association was observed between INC and BCS loss in the postcalving period. Overall, the incomplete milking protocol was effective for reducing ketonemia and prevalence of HYK during the early postpartum period. PMID- 29477530 TI - Vibration-induced particle formation during yogurt fermentation-Effect of frequency and amplitude. AB - Machinery such as pumps used for the commercial production of fermented milk products cause vibrations that can spread to the fermentation tanks. During fermentation, such vibrations can disturb the gelation of milk proteins by causing texture defects including lumpiness and syneresis. To study the effect of vibrations on yogurt structure systematically, an experimental setup was developed consisting of a vibration exciter to generate defined vibrational states and accelerometers for monitoring. During the fermentation of skim milk, vibrations (frequency sweep: 25 to 1,005 Hz) were introduced at different pH (5.7 to 5.1, step width 0.1 units) for 200 s. Physical properties of set gels (syneresis, firmness) and resultant stirred yogurts (visible particles, rheology, laser diffraction) were analyzed. Vibrational treatments at pH 5.5 to 5.2 increased syneresis, gel firmness, and the number of large particles (d > 0.9 mm); hence, this period was considered critical. The particle number increased from 34 +/- 5 to 242 +/- 16 particles per 100 g of yogurt due to vibrations at pH 5.4. In further experiments, yogurts were excited with fixed frequencies (30, 300, and 1,000 Hz). All treatments increased syneresis, firmness, and particle formation. As the strongest effect was observed by applying 30 Hz, the amplitude was set to vibration accelerations of a = 5, 10, 15, 20, and 25 m/s2 in the final experiments. The number of large particles was increased due to each treatment and a positive correlation with the amplitude was found. We concluded that vibrations during gelation increase the collision probability of aggregating milk proteins, resulting in a compressed set gel with syneresis. Resultant stirred yogurts exhibit large particles with a compact structure leading to a reduced water-holding capacity and product viscosity. PMID- 29477529 TI - A randomized controlled trial on the effect of incomplete milking during the first 5 days in milk on culling hazard and on milk production and composition of dairy cows. AB - An incomplete milking in early lactation could help limit negative energy balance in dairy cattle, but its potential effects on culling hazard and on milk production and composition throughout the entire lactation are unknown. The objective of this study was to evaluate the effect of an incomplete milking during the first 5 d in milk on culling hazard, milk weight, milk fat and protein concentrations, and energy-corrected milk (ECM) yield during the whole lactation. A randomized controlled trial was conducted in 13 dairy farms near St-Hyacinthe, Quebec, Canada. Approximately 1 mo before expected calving, Holstein multiparous cows calving between December 2013 and March 2015 (n = 846 cow lactations) were randomly assigned to a control or a treatment group. Cows in the control group were milked conventionally, whereas cows in the treatment group were submitted to an incomplete milking protocol (maximum of 10, 12, and 14 L/d of milk was collected on days in milk 1-3, 4, and 5, respectively). All farms were registered on Dairy Herd Improvement Association, which was used to obtain records on culling, monthly milk yield, and milk fat and protein concentrations. In addition, daily milk yield records were available for 6 farms. A Cox proportional hazards model with a herd frailty term was fitted to the data to compare culling hazard among treatment groups. Regarding milk production and composition, 4 linear mixed models with herd as a fixed effect, cow as a random effect, and using an autoregressive covariance structure were used to study the effect of the incomplete milking on (1) milk weight, (2) milk fat concentration, (3) milk protein concentration, and (4) ECM yield. Culling hazard did not differ among treatment groups (hazard ratio = 1.0; 95% CI = 0.82, 1.3). We observed no differences in milk weight, milk fat, or protein concentration among treatment groups between weeks in milk (WIM) 2 and 44 (the studied period). We noted a difference in ECM between treatment groups for WIM 38, with incompletely milked cows producing less milk than conventionally milked cows (-2.7 kg/d; 95% CI = 0.02, -5.2 kg/d), but no differences were found for any of the other WIM. These results suggest that this strategy for controlling the negative energy balance has negligible effect on cow productivity. PMID- 29477531 TI - Effects of forage source and forage particle size as a free-choice provision on growth performance, rumen fermentation, and behavior of dairy calves fed texturized starters. AB - We investigated the interactive effects of forage source and forage particle size (PS) as a free-choice provision on growth performance, rumen fermentation, and behavior of dairy calves fed texturized starters. Forty-eight Holstein calves (42 +/- 3 kg of body weight) were randomly assigned (n = 12 calves per treatment) in a 2 * 2 factorial arrangement of treatments with the factors of forage source [alfalfa hay (AH) and wheat straw (WS)] and forage PS [(AH: medium = 1.96 mm or long = 3.93 mm) and (WS: medium = 2.03 mm or long = 4.10 mm), as geometric mean diameters]. The treatments were (1) AH with medium PS (AH-MPS), (2) AH with long PS (AH-LPS), (3) WS with medium PS (WS-MPS), and (4) WS with long PS (WS-LPS). Regardless of forage PS, the preweaning starter intake, dry matter intake, metabolizable energy intake, weaning body weight, and forage intake were greater for AH calves than WS calves. Average daily gain, average daily gain/metabolizable energy intake, feed efficiency, and final body weight of the calves did not differ among groups. An interaction of forage source and forage PS influenced acetate, propionate, and acetate-to-propionate ratio in the rumen on d 35, with the greatest acetate proportion and acetate-to-propionate ratio, but the least propionate proportion for AH-MPS calves than the other calves. The total volatile fatty acid concentration and the rumen proportions of propionate (d 70), butyrate (d 35), and valerate (d 35) were greater in AH-MPS calves than in AH-LPS calves. Calves fed AH had greater total volatile fatty acid concentration (d 35 and 70) and propionate proportion (d 70), but lesser ruminal proportions of butyrate (d 35 and 70), valerate (d 35 and 70), and acetate-to-propionate ratio (d 70) compared with calves fed WS. The ruminal valerate proportion (d 70) was greatest in WS-MPS calves than the other calves. An interaction of forage source and forage PS influenced preweaning standing time and starter eating time, with the least standing time for WS-MPS calves and the greatest eating starter time for AH-LPS calves. Calves fed AH spent less time for rumination, but devoted more time to non-nutritive oral behaviors than WS calves. Calves fed forage with long PS spent more time for rumination, eating forage, and spent less time lying and non-nutritive oral behaviors than medium PS. In conclusion, forage source and PS interacted, affecting behavior and rumen fermentation when calves were fed texturized starters. In addition, a desirable ruminal pH in dairy calves can be obtained with texturized starters. PMID- 29477532 TI - Protective effect of bovine milk against HCl and ethanol-induced gastric ulcer in mice. AB - The purpose of this study was to investigate the gastroprotective effects of bovine milk on an acidified ethanol (HCl-ethanol) mixture that induced gastric ulcers in a mouse model. Mice received different doses of commercial fresh bovine milk (5, 10, and 20 mL/kg of body weight) by oral gavage once a day for 14 d. One hour after the last oral administration of bovine milk, the HCl-ethanol mixture was orally intubated to provoke severe gastric damage. Our results showed that pretreatment with bovine milk significantly suppressed the formation of gastric mucosa lesions. Pretreatment lowered gastric myeloperoxidase and increased gastric mucus contents and antioxidant enzymes catalase and superoxide dismutase. Administration of bovine milk increased nitrate/nitrite levels and decreased the malondialdehyde levels and the expression of proinflammatory genes, including transcription factor nuclear factor-kappaB, cyclooxygenase-2, and inducible nitric oxide synthase in the stomach of mice. These results suggest that bovine milk can prevent the development of gastric ulcer caused by acid and alcohol in mice. PMID- 29477533 TI - Genetic background in partitioning of metabolizable energy efficiency in dairy cows. AB - The main objective of this study was to assess the genetic differences in metabolizable energy efficiency and efficiency in partitioning metabolizable energy in different pathways: maintenance, milk production, and growth in primiparous dairy cows. Repeatability models for residual energy intake (REI) and metabolizable energy intake (MEI) were compared and the genetic and permanent environmental variations in MEI were partitioned into its energy sinks using random regression models. We proposed 2 new feed efficiency traits: metabolizable energy efficiency (MEE), which is formed by modeling MEI fitting regressions on energy sinks [metabolic body weight (BW0.75), energy-corrected milk, body weight gain, and body weight loss] directly; and partial MEE (pMEE), where the model for MEE is extended with regressions on energy sinks nested within additive genetic and permanent environmental effects. The data used were collected from Luke's experimental farms Rehtijarvi and Minkio between 1998 and 2014. There were altogether 12,350 weekly MEI records on 495 primiparous Nordic Red dairy cows from wk 2 to 40 of lactation. Heritability estimates for REI and MEE were moderate, 0.33 and 0.26, respectively. The estimate of the residual variance was smaller for MEE than for REI, indicating that analyzing weekly MEI observations simultaneously with energy sinks is preferable. Model validation based on Akaike's information criterion showed that pMEE models fitted the data even better and also resulted in smaller residual variance estimates. However, models that included random regression on BW0.75 converged slowly. The resulting genetic standard deviation estimate from the pMEE coefficient for milk production was 0.75 MJ of MEI/kg of energy-corrected milk. The derived partial heritabilities for energy efficiency in maintenance, milk production, and growth were 0.02, 0.06, and 0.04, respectively, indicating that some genetic variation may exist in the efficiency of using metabolizable energy for different pathways in dairy cows. PMID- 29477534 TI - A method for the inline measurement of milk gel firmness using an optical sensor. AB - At present, selection of cutting time during cheesemaking is made based on subjective methods, which has effects on product homogeneity and has prevented complete automation of cheesemaking. In this work, a new method for inline monitoring of curd firmness is presented. The method consisted of developing a model that correlates the backscatter ratio of near infrared light during milk coagulation with the rheological storage modulus. The model was developed through a factorial design with 2 factors: protein concentration (3.4 and 5.1%) and coagulation temperature (30 and 40 degrees C). Each treatment was replicated 3 times; the model was calibrated with the first replicate and validated using the remaining 2 replicates. The coagulation process was simultaneously monitored using an optical sensor and small-amplitude oscillatory rheology. The model was calibrated and successfully validated at the different protein concentrations and coagulation temperatures studied, predicting the evolution of storage modulus during milk coagulation with coefficient of determination values >0.998 and standard error of prediction values <3.4 Pa. The results demonstrated that the proposed method allows inline monitoring of curd firming in cheesemaking and cutting the curd at a proper firmness to each type of cheese. PMID- 29477535 TI - Automated body weight prediction of dairy cows using 3-dimensional vision. AB - The objectives of this study were to quantify the error of body weight prediction using automatically measured morphological traits in a 3-dimensional (3-D) vision system and to assess the influence of various sources of uncertainty on body weight prediction. In this case study, an image acquisition setup was created in a cow selection box equipped with a top-view 3-D camera. Morphological traits of hip height, hip width, and rump length were automatically extracted from the raw 3-D images taken of the rump area of dairy cows (n = 30). These traits combined with days in milk, age, and parity were used in multiple linear regression models to predict body weight. To find the best prediction model, an exhaustive feature selection algorithm was used to build intermediate models (n = 63). Each model was validated by leave-one-out cross-validation, giving the root mean square error and mean absolute percentage error. The model consisting of hip width (measurement variability of 0.006 m), days in milk, and parity was the best model, with the lowest errors of 41.2 kg of root mean square error and 5.2% mean absolute percentage error. Our integrated system, including the image acquisition setup, image analysis, and the best prediction model, predicted the body weights with a performance similar to that achieved using semi-automated or manual methods. Moreover, the variability of our simplified morphological trait measurement showed a negligible contribution to the uncertainty of body weight prediction. We suggest that dairy cow body weight prediction can be improved by incorporating more predictive morphological traits and by improving the prediction model structure. PMID- 29477536 TI - Roles of outer membrane protein W (OmpW) on survival, morphology, and biofilm formation under NaCl stresses in Cronobacter sakazakii. AB - Cronobacter sakazakii is an important foodborne pathogen associated with rare but severe infections through consumption of powdered infant formula. Tolerance to osmotic stress in Cronobacter has been described. However, the detailed factors involved in tolerance to osmotic stress in C. sakazakii are poorly understood. In this study, roles of outer membrane protein W (OmpW) on survival rates, morphologic changes of cells, and biofilm formation in C. sakazakii under different NaCl concentrations between wild type (WT) and OmpW mutant (DeltaOmpW) were determined. The survival rates of DeltaOmpW in Luria-Bertani medium with 3.5% or 5.5% NaCl were reduced significantly, and morphological injury of DeltaOmpW was significantly increased compared with survival and morphology of WT. Compared with biofilm formation of the WT strain, biofilms in DeltaOmpW were significantly increased in Luria-Bertani with 3.5% or 5.5% NaCl using crystal violet staining assay after 48 and 72 h of incubation. Detection of biofilms using confocal laser scanning microscopy and scanning electron microscopy further confirmed the changes of biofilm formation under different NaCl stresses. This study demonstrates that OmpW contributes to survival of cells in planktonic mode under NaCl stresses, and biofilm formation is increased in DeltaOmpW in response to NaCl stress. PMID- 29477537 TI - Genetic correlations of mid-infrared-predicted milk fatty acid groups with milk production traits. AB - The objective of this research was to estimate the genetic correlations between milk mid-infrared-predicted fatty acid groups and production traits in first parity Canadian Holsteins. Contents of short-chain, medium-chain, long-chain, saturated, and unsaturated fatty acid groupings in milk samples can be predicted using mid-infrared spectral data for cows enrolled in milk recording programs. Predicted fatty acid group contents were obtained for 49,127 test-day milk samples from 10,029 first-parity Holstein cows in 810 herds. Milk yield, fat and protein yield, fat and protein percentage, fat-to-protein ratio, and somatic cell score were also available for these test days. Genetic parameters were estimated for the fatty acid groups and production traits using multiple-trait random regression test day models by Bayesian methods via Gibbs sampling. Three separate 8- or 9-trait analyses were performed, including the 5 fatty acid groups with different combinations of the production traits. Posterior standard deviations ranged from <0.001 to 0.01. Average daily genetic correlations were negative and similar to each other for the fatty acid groups with milk yield (-0.62 to -0.59) and with protein yield (-0.32 to -0.25). Weak and positive average daily genetic correlations were found between somatic cell score and the fatty acid groups (from 0.25 to 0.36). Stronger genetic correlations with fat yield, fat and protein percentage, and fat-to-protein ratio were found with medium-chain and saturated fatty acid groups compared with those with long-chain and unsaturated fatty acid groups. Genetic correlations were very strong between the fatty acid groups and fat percentage, ranging between 0.88 for unsaturated and 0.99 for saturated fatty acids. Daily genetic correlations from 5 to 305 d in milk with milk, protein yield and percentage, and somatic cell score traits showed similar patterns for all fatty acid groups. The daily genetic correlations with fat yield at the beginning of lactation were decreasing for long-chain and unsaturated fatty acid groups and increasing for short-chain fatty acids. Genetic correlations between fat percentage and fatty acids were increasing at the beginning of lactation for short- and medium-chain and saturated fatty acids, but slightly decreasing for long-chain and unsaturated fatty acid groups. These results can be used in defining fatty acid traits and breeding objectives. PMID- 29477538 TI - Effect of atmospheric carbon dioxide concentration on the cultivation of bovine Mycoplasma species. AB - Recommendations for bovine mycoplasma culture CO2 concentrations are varied and were not empirically derived. The objective of this study was to determine whether the growth measures of bovine mycoplasma isolates differed when incubated in CO2 concentrations of 10 or 5% or in candle jars (2.7 +/- 0.2% CO2). Growth of Mycoplasma bovis (n = 22), Mycoplasma californicum (n = 18), and other Mycoplasma spp. (n = 10) laboratory isolates was evaluated. Isolate suspensions were standardized to approximately 108 cfu/mL and serially diluted in pasteurized whole milk to achieve test suspensions of 102 and 106 cfu/mL. One hundred microliters of each test dilution was spread in duplicate onto the surface of a modified Hayflick's agar plate. Colony growth was enumerated on d 3, 5, and 7 of incubation. A mixed linear model included the fixed effects of CO2 treatment (2.7, 5, or 10%), species, day (3, 5, or 7), and their interactions, with total colony counts as the dependent variable. Carbon dioxide concentration did not significantly affect overall mycoplasma growth differences, but differences between species and day were present. Colony counts (log10 cfu/mL) of M. bovis were 2.6- and 1.6-fold greater than M. californicum and other Mycoplasma spp., respectively. Growth at 7 d of incubation was greater than d 3 and 5 for all species. These findings were confirmed using field isolates (n = 98) from a commercial veterinary diagnostic laboratory. Binary growth responses (yes/no) of the field isolates were not different between CO2 treatments but did differ between species and day of incubation. On average, 57% of all field isolates were detected by 3 d of incubation compared with 93% on d 7. These results suggest that the range of suitable CO2 culture conditions and incubation times for the common mastitis-causing Mycoplasma spp. may be broader than currently recommended. PMID- 29477539 TI - Androgen receptor mediated epigenetic regulation of CRISP3 promoter in prostate cancer cells. AB - Cysteine-rich secretory protein 3 (CRISP3) is one of the most upregulated genes in prostate cancer. Androgen receptor (AR) plays an important role not only in initial stages of prostate cancer development but also in the advanced stage of castration-resistant prostate cancer (CRPC). Role of AR in regulation of CRISP3 expression is not yet known. In order to understand the regulation of CRISP3 expression, various overlapping fragments of CRISP3 promoter were cloned in pGL3 luciferase reporter vector. All constructs were transiently and stably transfected in PC3 (CRISP3 negative) and LNCaP (CRISP3 positive) cell lines and promoter activity was measured by luciferase assay. Promoter activity of LNCaP stable clones was significantly higher than PC3 stable clones. Further in CRISP3 negative PC3 and RWPE-1 cells, CRISP3 promoter was shown to be silenced by histone deacetylation. Treatment of LNCaP cells with DHT resulted in increase in levels of CRISP3 transcript and protein. AR dependency of CRISP3 promoter was also evaluated in LNCaP stable clones by luciferase assay. To provide molecular evidence of epigenetic regulation of CRISP3 promoter and its response to DHT, ChIP PCR was performed in PC3 and LNCaP cells. Our results demonstrate that CRISP3 expression in prostate cancer cells is androgen dependent and in AR positive cells, CRISP3 promoter is epigenetically regulated by AR. PMID- 29477540 TI - In vitro DNA binding studies of therapeutic and prophylactic drug citral. AB - The study of drug-DNA interactions is of great importance, as it paves the way towards the design of better therapeutic agents. Here, the interaction of DNA with a therapeutic and prophylactic drug citral has been studied. We have attempted to ascertain the mode of binding of citral with calf thymus DNA (Ct DNA) through various biophysical techniques. Analysis of the UV-visible absorbance spectra and fluorescence spectra indicated the formation of a complex between citral and Ct-DNA. Competitive binding assays with ethidium bromide (EB), acridine orange (AO) and Hoechst 33258 reflected that citral possibly intercalates within the Ct-DNA. These observations were further confirmed by circular dichroism (CD) spectral analysis, viscosity measurements, DNA melting and molecular docking studies. This study is expected to contribute to a better understanding of molecular mechanisms of citral, and design of new drugs in the future. PMID- 29477541 TI - Surface modification and evaluation of bacterial cellulose for drug delivery. AB - The current study was designed to prepare surface modified BC matrices loaded with model drugs selected on the basis of their aqueous solubility, i.e., poorly water soluble famotidine and highly water soluble tizanidine. Fourier transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), scanning electron microscopy (SEM) and thermogravimetric analysis (TGA) confirmed the successful drug loading and thermal stability of the BC matrices. In-vitro dissolution studies using USP type-II dissolution apparatus showed that most of the drug was released in 0.5-3h from famotidine loaded matrices and in 0.25-0.5h from tizanidine loaded matrices. The chemical structure, concentration of the loaded drug, concentration of the surface modifier, and pre- and post-drug loading modifications altered the physicochemical properties of BC matrices, which in turn affected the drug release behavior. In general, surface modification of the BC matrices enhanced the drug release retardant properties in pre-modification drug loading. Surface modification was found to be effective for controlling the drug release properties of BC. Therefore, these modified BC matrices have the potential for applications in modified drug delivery systems. PMID- 29477542 TI - Differences in the energetics of collagen denaturation in connective tissue from two muscles. AB - The thermal denaturation of collagen the perimysium of intramuscular connective tissue isolated from bovine Semitendinosus (ST) and Perctoralis profundus (PP) muscles was investigated using a range of heating rates in differential scanning calorimetry (DSC) and analyzed by application of the Kissinger-Akahira-Sunose (KAS) and Lumry-Eyring models. Thermograms showed a broadening of endotherms and a shift towards higher temperatures as the thermal scanning rate increased. These features are consistent with the two-step process of a reversible transition between native and unfolded collagen molecules followed by an irreversible transition between unfolded and denatured states. There were small differences between muscles in the onset temperatures of the thermal transitions at heating rates of 0.5 K min-1, while both the KAS and Lumry-Eyring models yielded similar values for the effective activation energy of the whole two-step process, the Lumry-Eyring model allowed a greater insight into differences in the reversible and irreversible steps between the perimysium both muscles. Reversible unwinding of the triple-helical collagen molecules in the perimysium from ST muscle required more energy than in PP muscle. It is speculated that the presence of large amounts of elastin in the perimysium of ST muscles may influence this due to a protein crowding mechanism, or by affecting the covalent cross-linking of the collagen. PMID- 29477543 TI - Inhibitory effect of raspberry ketone on alpha-glucosidase: Docking simulation integrating inhibition kinetics. AB - Inhibition of alpha-glucosidase is directly associated with treatment of type 2 diabetes. In this regard, we conducted enzyme kinetics integrated with computational docking simulation to assess the inhibitory effect of raspberry ketone (RK) on alpha-glucosidase. RK bound to the active site of alpha glucosidase and interacted with several key residues such as ASP68, TYR71, HIS111, PHE157, PHE158, PHE177, GLN181, ASP214, THR215, ASP349, ASP408, and ARG439, as detected by protein-ligand docking simulation. Subsequently, we confirmed the action of RK on alpha-glucosidase as the non-competitive type of inhibition in a reversible and rapidly binding manner. The relevant kinetic parameters were IC50=6.17+/-0.46mM and Ki=7.939+/-0.211mM. Regarding the structure-activity relationship, the higher concentration of RK induced slight modulation of the shape of the active site as monitored by hydrophobic exposure. The tertiary conformational change was linked to RK inhibition, and mostly involved regional changes of the active site. Our study provides insight into the functional role of RK due to its structural property of a hydroxyphenyl ring that interacts with the active site of alpha-glucosidase. We suggest that similar hydroxyphenyl ring compounds targeting the key residues of the active site might be potential alpha-glucosidase inhibitors. PMID- 29477544 TI - Cerebral microvascular abnormalities in patients with idiopathic intracranial hypertension. AB - AIM: Idiopathic intracranial hypertension (IIH) is characterized by symptoms indicative of increased intracranial pressure (ICP), such as headache and visual impairment. We have previously reported that brain biopsies from IIH patients show patchy astrogliosis and increased expression of the water channel aquaporin 4 (AQP4) at perivascular astrocytic endfeet. METHODS: The present study was undertaken to investigate for ultrastructural changes of the cerebral capillaries in individuals with IIH. We examined by electron microscopy (EM) biopsies from the cortical parenchyma of 10 IIH patients and 8 reference subjects (patients, not healthy individuals), in whom tissue was retrieved from other elective and necessary brain surgeries (epilepsy, tumors or vascular diseases). IIH patients were diagnosed on the basis of typical clinical symptoms and abnormal intracranial pressure wave amplitudes during overnight ICP monitoring. RESULTS: All 10 IIH patients underwent shunt surgery followed by favorable clinical outcome. EM revealed abnormal pericyte processes in IIH. The basement membrane (BM) showed more frequently evidence of degeneration in IIH, but neither the BM dimensions nor the pericyte coverage differed between IIH and reference tissue. The BM thickness increased significantly with increasing age. Reference individuals were older than IIH cases; observations may to some extent be age related. CONCLUSION: The present study disclosed marked changes of the cerebral cortical capillaries in IIH patients, suggesting that microvascular alterations are involved in the evolvement of IIH. PMID- 29477545 TI - Neurosteroid metabolites of testosterone and progesterone differentially inhibit ERK phosphorylation induced by amyloid beta in SH-SY5Y cells and primary cortical neurons. AB - Gonadal steroid hormones exert neurotrophic and neuroprotective effects on the brain. Recent work suggests potential neuroprotective roles for the 3alpha hydroxy, 5alpha-reduced metabolites of these hormones. Two such metabolites are 5alpha-androstane-3alpha,17beta-diol (3alpha-diol) and 5alpha-pregnan-3alpha-ol 20-one (allopregnanolone; Allo), which may contribute to the overall protection conferred by their precursors (testosterone and progesterone, respectively) through mechanisms including potentiation of gamma-aminobutyric acid (GABA)A receptor (GABAAR) activity. We have previously demonstrated that physiological concentrations of 3alpha-diol inhibit prolonged phosphorylation of extracellular signal-regulated kinase (ERK) and the associated neurotoxicity resulting from amyloid beta peptide 1-42 (Abeta42) exposure in vitro. In the present study, we sought to characterize the GABAAR-dependency of 3alpha-diol's effects, compared to those of Allo, in SH-SY5Y human female neuroblastoma cells and primary cortical neurons isolated from postnatal day 0-1 mice. Both 3alpha-diol and Allo prevented Abeta42-mediated ERK phosphorylation in SH-SY5Y cells, with substantially different concentration requirements (10 nM for 3alpha-diol, 100 nM for Allo). Pharmacological inhibition of GABAAR with picrotoxin did not prevent this effect, indicating that neurosteroid-mediated ERK inhibition in SH-SY5Y cells may be GABAAR-independent. While 10 nM and 100 nM concentrations of both neurosteroids inhibited ERK phosphorylation induced by Abeta42 in primary cortical neurons, which have high expression levels of GABAARs, only the effects of Allo were significantly inhibited by picrotoxin. These results suggest that neurosteroid metabolites of testosterone and progesterone may contribute to neuroprotection by suppressing ERK phosphorylation through both GABAAR-dependent and -independent mechanisms. PMID- 29477546 TI - [Efficacy of the strategy to improve the quality indicators of Diabetes Mellitus 2 Care Process in Advanced Diabetes Centre Macarena]. AB - INTRODUCTION: The assessment of the Diabetes Mellitus 2 Care Process (PAI-DM2) through the assessment tool for the chronic illness' care models (IEMAC-Diabetes) allows the design of health interventions for the improvement of medical care. OBJECTIVE: Analysing the quality of healthcare provided to DM2 patients. DESIGN: Quasiexperimental study before and after intervention with a not randomised control group. LOCATION: Health care district of primary care Sevilla. PARTICIPANTS: 12 groups of ascribed patients, 5 Primary Care Healthcenter, chosen in a discretionary way. INTERVENTION: Physicians and nurses from the 12 intervention groups took part in a training program, including an external rotation in the Diabetes Daycare Hospital. MAIN MEASUREMENTS: Number of included patients, glycated hemoglobin, feet exploration (FE), and ocular fundus (OF). RESULTS: 1,475 DM-2 patients were analysed. The proportion of included patients per group was 8.5%, 45.5% were women. At the beginning of the study, the rate of patients with HbA1c<7% were 38.9% in 2013 against 47.7% in 2014 and 40.2% in 2016; 33% of the patients had an OF in 2013 against 41.77% in 2014; 51.6% of patients had an EF against 54.7% in 2014. After the intervention, statistically significant differences were reached in HbA1c (p=0.01) and retinography requested (p=0.01). CONCLUSIONS: IEMAC-Diabetes allows spotting improvement areas in the PAI-DM2. The absence of statistically significant differences may be the result of contamination in the sample and/or Hawthorne effect. PMID- 29477547 TI - Challenge and threat states: examining cardiovascular, cognitive and affective responses to two distinct laboratory stress tasks. AB - BACKGROUND: The theory of challenge and threat states in athletes (TCTSA) proposes psychological antecedents will predict psychological and cardiovascular responses to stress. The present study investigated this theory in two contextually different stress tasks. METHOD: 78 males completed a computerised competition and a public speaking task. Cardiovascular activity was measured with impedance cardiography and a blood pressure monitor. Challenge and threat antecedents, indicators of challenge and threat and emotions were assessed pre- and post-tasks. RESULTS: Both tasks induced significant perturbations in cardiovascular activity and were perceived as highly challenging. Reported perceived threat was higher in the public speaking task compared to the competition task. Associations between the proposed antecedents, self-report and cardiovascular indices of challenge and threat and emotions support the TCTSA for the competition task, but less so for the public speaking task. CONCLUSION: The TCTSA is supported during competitive stress, however during social stress there is dissociation between self-report appraisals and cardiovascular reactivity. PMID- 29477548 TI - Gene function prediction based on Gene Ontology Hierarchy Preserving Hashing. AB - Gene Ontology (GO) uses structured vocabularies (or terms) to describe the molecular functions, biological roles, and cellular locations of gene products in a hierarchical ontology. GO annotations associate genes with GO terms and indicate the given gene products carrying out the biological functions described by the relevant terms. However, predicting correct GO annotations for genes from a massive set of GO terms as defined by GO is a difficult challenge. To combat with this challenge, we introduce a Gene Ontology Hierarchy Preserving Hashing (HPHash) based semantic method for gene function prediction. HPHash firstly measures the taxonomic similarity between GO terms. It then uses a hierarchy preserving hashing technique to keep the hierarchical order between GO terms, and to optimize a series of hashing functions to encode massive GO terms via compact binary codes. After that, HPHash utilizes these hashing functions to project the gene-term association matrix into a low-dimensional one and performs semantic similarity based gene function prediction in the low-dimensional space. Experimental results on three model species (Homo sapiens, Mus musculus and Rattus norvegicus) for interspecies gene function prediction show that HPHash performs better than other related approaches and it is robust to the number of hash functions. In addition, we also take HPHash as a plugin for BLAST based gene function prediction. From the experimental results, HPHash again significantly improves the prediction performance. The codes of HPHash are available at: http://mlda.swu.edu.cn/codes.php?name=HPHash. PMID- 29477549 TI - Antimicrobial susceptibilities and molecular typing of neisseria gonorrhoeae isolates at a medical centre in Taiwan, 2001-2013 with an emphasis on high rate of azithromycin resistance among the isolates. AB - A high prevalence of gonococcal resistance to various antimicrobials and Neisseria gonorrhoeae isolates exhibiting resistance to extended-spectrum cephalosporins have been reported in the past few decades. A total of 226 N. gonorrhoeae isolates obtained from the National Taiwan University Hospital from 2001 to 2013 were evaluated. The minimum inhibitory concentrations (MICs) of the isolates to antimicrobials were determined by the agar dilution method and interpreted using the 2017 clinical breakpoints or epidemiological cut-off values recommended by the Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST). The genetic relatedness of these isolates was determined by multilocus sequence typing. None of the isolates was resistant to ceftriaxone and cefotaxime, and the resistance rates to cefixime, spectinomycin, cefpodoxime, ciprofloxacin, and penicillin were 0.4%, 0.4%, 13.3%, 91.6%, and 87.6%, respectively. The rate of isolates resistant to azithromycin was 14.6% (EUCAST criteria), which is higher than in previous surveillance studies. A total of 57 sequence types (ST) were identified, and ST1901, ST7365, and ST1927 prevailed. Isolates of ST8143 emerged after 2011. ST1901 isolates had relatively higher MIC values for ceftriaxone and azithromycin than those of the other STs. In conclusion, ceftriaxone remains an effective drug of choice for gonorrhoeal management in Taiwan. High rates of azithromycin resistance among N. gonorrhoeae isolates were found. The circulating ST1901 strains with high MIC values for ceftriaxone and azithromycin and the emerging ST8143 strains were alarming. PMID- 29477550 TI - Molecular evolution of H1N1 swine influenza in Guangdong, China, 2016-2017. AB - Swine are the main host of the H1N1 swine influenza virus (SIV), however, H1N1 can also infect humans and occasionally cause serious respiratory disease. To trace the evolution of the SIV in Guangdong, China, we performed an epidemic investigation during the period of 2016-2017. Nine H1N1 influenza viruses were isolated from swine nasal swabs. Antigenic analysis revealed that these viruses belonged to two distinct antigenic groups, represented by A/Swine/Guangdong/101/2016 and A/Swine/Guangdong/52/2017. Additionally, three genotypes, known as GD52/17-like, GD493/17-like and GD101/16-like, were identified by phylogenetic analysis. Importantly, the genotypes including a minimum of 4 pdm/09-origin internal genes have become prevalent in China in recent years. A total of 2966 swine serum samples were used to perform hemagglutination inhibition (HI) tests, and the results showed that the seroprevalence values of SW/GD/101/16 (32.2% in 2016, 32.1% in 2017) were significantly higher than the seroprevalence values of SW/GD/52/17 (18.0% in 2016, 16.7% in 2017). Our study showed that the three reassortant genotypes of H1N1 SIV currently circulating in China are stable, but H1N1pdm09 poses challenges to human health by the introduction of internal genes into these reassortant genotypes. Strengthening SIV surveillance is therefore critical for SIV control and minimizing its potential threat to public health. PMID- 29477551 TI - Recombination in the rabies virus and other lyssaviruses. AB - Recombination is a common event in RNA viruses; however, in the rabies virus there have been only a few reports of isolated recombination events. Comprehensive analysis found traces of recent recombination events within Arctic, Arctic-like and Africa 1b rabies virus groups, as well as recombination between distinct lyssaviruses. Recombination breakpoints were not linked to gene boundaries and could be detected all over the genome. However, there was no evidence that recombination is an important factor in the genetic variability of the rabies virus. It is therefore likely that recombination in the rabies virus is limited by ecological factors (e.g., rare co-circulation of distinguishable lineages and a narrow window for productive coinfection in most carnivore hosts), rather than molecular barriers (e.g., incompatibility of genome fragments). PMID- 29477552 TI - Double Opposing Zplasty with VY Advancement of the perineum: Long-term results of a new technique as an alternative to Fenton's operation for narrowing and splitting of the skin at the posterior vaginal fourchette. AB - OBJECTIVE: To assess the long-term results of our experience with this technique which we have developed as an alternative to Fenton's procedure. STUDY DESIGN: A retrospective questionnaire study of all patients undergoing the procedure in our department from Jan. 2006 to Dec. 2013. The main outcome measure was the change in sexual satisfaction scores, using a visual analogue scale, before and after the procedure. RESULTS: There was a statistically significant improvement in sexual satisfaction scores in the majority of patients. This was particularly marked in patients who had previously undergone an unsuccessful Fenton's operation. CONCLUSIONS: Double opposing Z plasty with VY advancement of the perineum (The Plymouth Procedure)should be offered to all patients in whom Fenton's operation has been unsuccessful,and considered as an alternative to Fenton's as a primary procedure. PMID- 29477553 TI - Does a human chorionic gonadotropin level of over 20,000 IU/L four weeks after uterine evacuation for complete hydatidiform mole constitute an indication for chemotherapy for gestational trophoblastic neoplasia? AB - OBJECTIVE: To evaluate whether a human chorionic gonadotropin (hCG) level >=20,000 IU/L four weeks after uterine evacuation for complete hydatidiform mole (CHM) is an appropriate indicator for initiating chemotherapy for the treatment of gestational trophoblastic neoplasia (GTN). STUDY DESIGN: Historical database review of 1228 women with CHM who received treatment and follow-up between January 2000 and June 2013 at four Brazilian trophoblastic disease centers. The primary outcome measure was the progression from CHM to GTN. The secondary outcomes were the occurrence of uterine perforation, staging of GTN, WHO/FIGO risk score, and treatment (use of single- or multiagent chemotherapy). RESULTS: An hCG level >=20,000 IU/L four weeks after uterine evacuation for CHM, while occurring in only 6.1% of women, was the most important risk factor for the development of postmolar GTN (adjusted RR = 5.83; p < 0.01; CI: 3.47-9.79), with a sensitivity of 36.8%, a specificity of 98.6%, a positive predictive value of 80%, and a negative predictive value of 91.1%. On the other hand, there were no differences in postmolar GTN stage, prognostic score, or need for multiagent chemotherapy relative to hCG level >=20,000 IU/L versus <20,000 IU/L. CONCLUSIONS: Although hCG level >=20,000 IU/L four weeks after uterine evacuation for CHM was very predictive of development of post-molar GTN, delay in treatment until hCG plateau or increase did not affect outcomes, with no uterine perforations or treatment failures. PMID- 29477554 TI - Blood Flow Restriction Training After Achilles Tendon Rupture. AB - Blood flow restriction (BFR) training is a technique shown to be safe and effective at increasing muscular strength and endurance in healthy fitness populations and is under study for its use in postinjury rehabilitation. BFR stimulates muscular strength and hypertrophy gains at much lower loads than traditional methods, allowing patients to begin the rehabilitation process much sooner. We report on 2 patients who incorporated BFR training into their traditional rehabilitation program after Achilles tendon ruptures. Patient 1 was a 29-year-old active duty soldier who sustained a left Achilles tendon rupture while playing competitive football. After operative repair and traditional rehabilitative measures, he was unable to ambulate without assistive devices owing to persistent weakness. The patient subsequently started a 5-week "return to run" program using BFR training. He experienced plantarflexion peak torque improvements of 522% and 108.9% and power gains of 4475% and 211% at 60 degrees /s and 120 degrees /s, respectively. He was able to ambulate without assistive devices at the 5-week follow-up examination. Patient 2 was a 38-year-old male soldier who experienced a complete left Achilles tendon rupture while exercising. After nonoperative treatment with an accelerated rehabilitation program, the patient still experienced significant strength and functional deficits. He was subsequently enrolled in a 6-week course of BFR training. He experienced plantarflexion strength improvements of 55.8% and 47.1% and power gains of 68.8% and 78.7% at 60 degrees /s and 120 degrees /s, respectively. He was able to return to running and sports on completion of 6 weeks of BFR-assisted therapy. Incorporating tourniquet-assisted blood flow restriction with rehabilitation programs can improve strength, endurance, and function after Achilles tendon rupture. PMID- 29477555 TI - HtrA3 is a cellular partner of cytoskeleton proteins and TCP1alpha chaperonin. AB - : The human HtrA3 protease is involved in placentation, mitochondrial homeostasis, stimulation of apoptosis and proposed to be a tumor suppressor. Molecular mechanisms of the HtrA3 functions are poorly understood and knowledge concerning its cellular targets is very limited. There are two HtrA3 isoforms, the long (HtrA3L) and short (HtrA3S). Upon stress, their N-terminal domains are removed, resulting in the more active DeltaN-HtrA3. By pull down and mass spectrometry techniques, we identified a panel of putative DeltaN-HtrA3L/S substrates. We confirmed that DeltaN-HtrA3L/S formed complexes with actin, beta tubulin, vimentin and TCP1alpha in vitro and in a cell and partially co-localized with the actin and vimentin filaments, microtubules and TCP1alpha in a cell. In vitro, both isoforms cleaved the cytoskeleton proteins, promoted tubulin polymerization and displayed chaperone-like activity, with DeltaN-HtrA3S being more efficient in proteolysis and DeltaN-HtrA3L - in polymerization. TCP1alpha, essential for the actin and tubulin folding, was directly bound by the DeltaN HtrA3L/S but not cleaved. These results indicate that actin, beta-tubulin, vimentin, and TCP1alpha are HtrA3 cellular partners and suggest that HtrA3 may influence cytoskeleton dynamics. They also suggest different roles of the HtrA3 isoforms and a possibility that HtrA3 protease may also function as a co chaperone. SIGNIFICANCE: The HtrA3 protease stimulates apoptosis and is proposed to be a tumor suppressor and a therapeutic target, however little is known about its function at the molecular level and very few HtrA3 physiological substrates have been identified so far. Furthermore, HtrA3 is the only member of the HtrA family of proteins which, apart from the long isoform possessing the PD and PDZ domains (HtrA3L), has a short isoform (HtrA3S) lacking the PDZ domain. In this work we identified a large panel (about 150) of the tentative HtrA3L/S cellular partners which provides a good basis for further research concerning the HtrA3 function. We have shown that the cytoskeleton proteins actin, beta-tubulin and vimentin, and the TCP1alpha chaperonin are cellular partners of both HtrA3 isoforms. Our findings indicate that HtrA3 may promote destabilization of the actin and vimentin cytoskeleton and suggest that it may influence the dynamics of the microtubule network, with the HtrA3S being more efficient in cytoskeleton protein cleavage and HtrA3L - in tubulin polymerization. Also, we have shown for the first time that HtrA3 has a chaperone-like, holdase activity in vitro - activity typical for co-chaperone proteins. The proposed HtrA3 influence on the cytoskeleton dynamics may be one of the ways in which HtrA3 promotes cell death and affects cancerogenesis. We believe that the results of this study provide a new insight into the role of HtrA3 in a cell and further confirm the notion that HtrA3 should be considered as a target of new anti-cancer therapies. PMID- 29477556 TI - Stochastic cellular automata model of neurosphere growth: Roles of proliferative potential, contact inhibition, cell death, and phagocytosis. AB - Neural stem and progenitor cells isolated from the central nervous system form, under specific culture conditions, clonal cell clusters known as neurospheres. The neurosphere assay has proven to be a powerful in vitro system to study the behavior of such cells and the development of their progeny. However, the theory of neurosphere growth has remained poorly understood. To overcome this limitation, we have, in the present paper, developed a cellular automata model, with which we examined the effects of proliferative potential, contact inhibition, cell death, and clearance of dead cells on growth rate, final size, and composition of neurospheres. Simulations based on this model indicated that the proliferative potential of the founder cell and its progenitors has a major influence on neurosphere size. On the other hand, contact inhibition of proliferation limits the final size, and reduces the growth rate, of neurospheres. The effect of this inhibition is particularly dramatic when a stem cell becomes encapsulated by differentiated or other non-proliferating cells, thereby suppressing any further mitotic division - despite the existing proliferative potential of the stem cell. Conversely, clearance of dead cells through phagocytosis is predicted to accelerate growth by reducing contact inhibition. A surprising prediction derived from our model is that cell death, while resulting in a decrease in growth rate and final size of neurospheres, increases the degree of differentiation of neurosphere cells. It is likely that the cellular automata model developed as part of the present investigation is applicable to the study of tissue growth in a wide range of systems. PMID- 29477557 TI - Central line-associated bloodstream infections and catheter dwell-time: A theoretical foundation for a rule of thumb. AB - Many clinicians know from experience and medical epidemiological literature that the risk of central line-associated bloodstream infections (CLABSI) increases rapidly with a prolonged catheter dwell-time, but how this infection risk increases over time remains obscure. In this manuscript, a clinically useful rule of thumb is derived, stating that the risk of CLABSI increases in a quadratic fashion with the increase in catheter dwell-time. The proposed rule of thumb could be considered a quick and effortless clinical tool to rationally predict the pattern of CLABSI risk with an increasing catheter dwell-time. PMID- 29477558 TI - Homeostasis in a feed forward loop gene regulatory motif. AB - The internal state of a cell is affected by inputs from the extra-cellular environment such as external temperature. If some output, such as the concentration of a target protein, remains approximately constant as inputs vary, the system exhibits homeostasis. Special sub-networks called motifs are unusually common in gene regulatory networks (GRNs), suggesting that they may have a significant biological function. Potentially, one such function is homeostasis. In support of this hypothesis, we show that the feed-forward loop GRN produces homeostasis. Here the inputs are subsumed into a single parameter that affects only the first node in the motif, and the output is the concentration of a target protein. The analysis uses the notion of infinitesimal homeostasis, which occurs when the input-output map has a critical point (zero derivative). In model equations such points can be located using implicit differentiation. If the second derivative of the input-output map also vanishes, the critical point is a chair: the output rises roughly linearly, then flattens out (the homeostasis region or plateau), and then starts to rise again. Chair points are a common cause of homeostasis. In more complicated equations or networks, numerical exploration would have to augment analysis. Thus, in terms of finding chairs, this paper presents a proof of concept. We apply this method to a standard family of differential equations modeling the feed-forward loop GRN, and deduce that chair points occur. This function determines the production of a particular mRNA and the resulting chair points are found analytically. The same method can potentially be used to find homeostasis regions in other GRNs. In the discussion and conclusion section, we also discuss why homeostasis in the motif may persist even when the rest of the network is taken into account. PMID- 29477559 TI - Hearing loss is associated with increased CHD risk and unfavorable CHD-related biomarkers in the Dongfeng-Tongji cohort. AB - BACKGROUND AND AIMS: The association between hearing loss and coronary heart disease (CHD) is inconsistent. We aimed to investigate the association of hearing loss with prevalent CHD and CHD-related biomarkers among a middle aged and elderly Chinese population. METHODS: We included 14,755 Chinese aged 64.6 years from the Dongfeng-Tongji Cohort in 2013. Hearing loss was classified into normal, mild, moderate or greater levels by the pure tone average (PTA) at low frequency and high frequency, respectively. Logistic regression models were used to estimate the odds ratios (ORs) of CHD risk in relation to hearing loss. Linear regression models were used to evaluate the effect of hearing loss on CHD-related biomarkers. RESULTS: The adjusted ORs for prevalent CHD increased gradually with the increasing hearing loss levels. Compared with normal hearing, individuals having mild- and moderate or greater-hearing loss had a higher CHD risk of 19% and 20% at low frequency, and 33% and 41% at high frequency, respectively (all p for trend < 0.05). The associations were more evident among subjects who were females, overweight, exposed to occupational noise and with hyperglycemia, hypertension or dyslipidemia at low frequency, and those with hyperglycemia at high frequency. Meanwhile, moderate or greater hearing loss combined with overweight, hyperglycemia, hypertension or dyslipidemia had joint effects on CHD. In addition, the majority of CHD-related biomarkers worsened with increasing hearing loss levels. CONCLUSIONS: There may be a dose-response relationship between hearing loss and CHD prevalence, and the association could partially be explained by intermediate CHD-related biomarkers. PMID- 29477561 TI - ? PMID- 29477560 TI - Atherosclerosis imaging to refine cardiovascular risk assessment in diabetic patients: Computed tomography and positron emission tomography applications. AB - The lifetime cardiovascular risk of a diabetic patient is approximately 4-5 times higher than that of an age and sex matched individual without diabetes mellitus. Despite the well-publicized cardiovascular risk equivalence of diabetes mellitus, it has become apparent that not all diabetic patients are equally at high-risk and many patients may have a level of risk similar to that of the general population. Cardiovascular imaging has been employed to address the dilemma of a more accurate risk stratification of diabetic patients. Two randomized clinical trials aiming at uncovering the presence of unknown obstructive coronary artery disease (CAD) gave disappointing results. In fact, the number of patients with inducible myocardial ischemia and/or severe obstructive disease was lower than expected and the overall outcome was not improved after having brought the existence of CAD to light. Other techniques that may help identify a diabetic patient susceptible to suffer future events have therefore being explored. In this review we discuss two imaging tools that provide anatomical and functional information on pre-clinical coronary atherosclerosis: computed tomography for calcium scoring, and plaque characterization and myocardial ischemia detection and positron emission tomography using tracers to identify functionally unstable plaques. Despite the availability of several imaging techniques there remain numerous questions as to the utility of imaging to define risk in diabetes mellitus and an optimal approach has yet to be found. PMID- 29477562 TI - Location-allocation model for external beam radiotherapy as an example of an evidence-based management tool implemented in healthcare sector in Poland. AB - BACKGROUND AND PURPOSE: External beam radiotherapy (EBRT) is one of three key treatment modalities of cancer patients. Its utilisation and outcomes depend on a plethora of variables, one of which is the distance a patient must travel to undergo the treatment. The relation between distance and utilisation is clearly visible in Poland. At the same time no strategic investment plan is observed. This work proposes a method of resolving these two issues. MATERIALS AND METHODS: We propose a mixed-integer linear programming model that aims to optimise the distribution of linear accelerators among selected locations in such a way that a patient's journey to the nearest EBRT is as short as possible. The optimisation is done with observance of international guidelines concerning EBRT capacity. With the use of proposed theoretical framework, we develop a national, strategic plan for linear accelerator investments. RESULTS: According to model assumptions decentralisation of EBRT, together with new equipment purchases, is required to ensure optimal access to EBRT. CONCLUSIONS: The results were incorporated into Healthcare Needs Maps for Poland. The plan based on the results of this study, implemented by 2025, should deal with the most pressing concerns of Polish EBRT. PMID- 29477563 TI - A field-based model of the relationship between extirpation of salt-intolerant benthic invertebrates and background conductivity. AB - Field-collected measures of dissolved salts and occurrences of aquatic invertebrates have been used to develop protective levels. However, sufficiently large field data sets of exposures and biota are often not available. Therefore, a model was developed to predict the exposure extirpating 5% of benthic invertebrate genera using only measures of specific conductivity (SC) as the independent variable. The model is based on 3 assumptions: (1) a genus will rarely occur where the background exceeds its upper physiological limit; (2) the lowest possible tolerance limit of a genus in a region is defined by the natural background; and (3) as a result, there will be a regular association between natural background SC and the SC at which salt-intolerant genera are present. Three steps were used to develop the model. First, background SC was characterized as the 25th centile of sampled sites for each of 24 areas in the United States with streams dominated by bicarbonate and sulfate ions. Second, the extirpation concentration (XC95), an estimate of the upper tolerance limit with respect to SC, was calculated for genera in 24 data sets. Next, the lower 5th centile of each set of XC95 values (XCD05) was identified for the most salt intolerant members in each data set. Finally, the relationship between the 24 background SC and the 24 XCD05 values was empirically modeled to develop a background-to-criterion model. The least squares regression of XCD05 values on log background SC (log Y = 0.658logX + 1.071) yields a strong linear relationship (r = 0.93). The regression model makes it possible to use SC background to predict the SC likely to extirpate the most salt-intolerant genera in an area. The results also suggest that species distribute along natural background gradients of SC and that this relationship can be used to develop criteria for ionic concentration. PMID- 29477564 TI - Comparison of laboratory and ambulatory measures of central blood pressure and pulse wave reflection: hitting the target or missing the mark? AB - Prior studies demonstrating clinical significance of noninvasive estimates of central blood pressure (BP) and pulse wave reflection have relied primarily on discrete resting measures. The aim of this study was to compare central BP and pulse wave reflection measures sampled during a single resting laboratory visit against those obtained under ambulatory conditions. The secondary aim was to investigate the reproducibility of ambulatory central BP and pulse wave reflection measurements. Forty healthy participants (21 males; 24 +/- 3 years) completed three measurements of brachial artery pulse wave analysis (Oscar 2 with SphygmoCor Inside) in the laboratory followed by 24 hours of ambulatory monitoring. Seventeen participants repeated the 24-hour ambulatory monitoring visit after at least 1 week. Ambulatory measures were divided into daytime (9 AM 9 PM), nighttime (1 AM-6 AM), and 24-hour periods. Compared with laboratory measurements, central systolic BP, augmentation pressure, and augmentation index (with and without heart rate normalization) were higher (all P < .01) during daytime and 24-hour periods but lower during the nighttime period (all P < .001). The drop in nighttime brachial systolic BP was larger than central systolic pressure (Delta -20 +/- 6 vs. -15 +/- 6 mm Hg; P < .0001). Repeat ambulatory measurements of central BP and pulse wave reflection displayed good-to-excellent intraclass correlation coefficients (r = 0.58-0.86; all P < .01), although measures of pulse wave reflection had higher coefficients of variation (14%-41%). The results highlight absolute differences in central BP and pulse wave reflection between discrete laboratory and ambulatory conditions. The use of ambulatory measures of central BP and pulse wave reflection warrant further investigation for clinical prognostic value. PMID- 29477565 TI - Best to Clarify to Avoid Misunderstandings in the Biomechanics of Ross Operation: Parentheses Matter. PMID- 29477566 TI - Proposal of a New Electrode and Modality of Electrical Stimulation for Diaphragmatic Pacemakers. AB - PURPOSE: This report describes the implantation of a new design of intramuscular electrode to the diaphragm and introduces a new modality of electroventilation for diaphragmatic pacemaker. DESCRIPTION: We used 22 Large White female pigs to test 68 electrodes that were implanted in the abdominal portion of the diaphragm by videolaparoscopy. Animals were submitted to a new protocol of electroventilation with an unpolarized current and a single-channel mode with 1 electrode for each hemidiaphragm during 3 hours. EVALUATION: The electrodes were easily fixed to the diaphragm with the help of a deployment device designed for this purpose. There was no evidence of clinical complications such as pneumothorax or bleeding. No significant differences were observed in arterial blood gas analysis and serum lactate levels. CONCLUSIONS: The designed electrodes provided an excellent performance in connection between the electrical stimulator and the muscle tissue. The proposal for using an unpolarized current proved to be effective in stimulating both hemidiaphragms simultaneously with only a single channel of the electrical stimulator. PMID- 29477567 TI - [Outdoor moulds and respiratory health]. AB - Mould spores constitute the largest portion of biologic particulate matter suspended in the outdoor atmosphere. There is no universal method for collecting airborne mould spores. The most used sampler, Hirst's apparatus, operates continuously and gives results in individual spores per cubic metre of air. Spore concentrations depend on available substrates, human activities such as agriculture, season, diurnal meteorological variations and climate changes. Under natural conditions, concentrations of over 100,000 spores per cubic metre are not exceptional. Cladosporium is the most commonly identified outdoor mould. The association between respiratory health and outdoor mould spore exposure has been assessed in clinical studies, and also by cross-sectional, and less often longitudinal, epidemiological studies. The relationship between asthma exacerbations and specific mould spores has been demonstrated in longitudinal studies. Cross sectional studies have related measurements of mould spore concentrations to severity of bronchial symptoms, drug consumption and peak-flow measurements in groups of asthmatic subjects. Ecological time-series studies use daily indicators of asthma exacerbations (emergency room visits, hospitalizations) within the general population. The moulds mainly incriminated are Cladosporium and Alternaria. They are associated with seasonal, but also perennial, asthma and rhinitis. Further studies are needed to better assess the impact of outdoor moulds on health, particularly basidiomycetes. Studies with molecular biology tools are probably a way forward. PMID- 29477568 TI - Asthma Phenotypes Defined From Parameters Obtained During Recovery From a Hospital-Treated Exacerbation. AB - BACKGROUND: Asthma is a heterogeneous disease with diverse clinical manifestations and inflammatory pathologies that is punctuated by exacerbations. OBJECTIVE: To describe the clinical and inflammatory characteristics of patients with asthma treated in hospital for an acute exacerbation. METHODS: Data from 320 adult patients receiving treatment for an acute exacerbation of asthma were obtained. In 218 patients with complete data, we used the Ward hierarchical clustering to obtain clusters. Pulmonary function, blood cell counts, sputum cell counts, serum IgE levels, and fractional exhaled nitric oxide were measured on hospital admission. We selected 13 variables with which we performed the Ward minimum-variance hierarchical clustering. RESULTS: Four clusters were defined. Clusters 1 (24.5%) and 3 (36.7%) were characterized by predominantly female patients with asthma with sputum neutrophilia, with cluster 1 associated with a small degree of airflow obstruction and early-onset asthma and cluster 3 with a moderate degree of reduction in FEV1. Clusters 2 (22.0%) and 4 (16.5%) were associated with high sputum eosinophilia and severe airflow obstruction. Cluster 4 was made exclusively of male smoking subjects, whereas cluster 2 was made up of predominantly female nonsmoking subjects with the worst FEV1, forced expiratory flow at 25% to 75% of forced vital capacity (% predicted), and partial pressure of oxygen in arterial blood on admission. There were no differences between clusters in terms of atopy, serum IgE, prevalence of nasal disease, dose of maintenance inhaled corticosteroids, or oral/systemic corticosteroid use and asthma exacerbations. CONCLUSIONS: The clusters during recovery from an exacerbation of asthma were distinguished by airflow obstruction and a neutrophilic, eosinophilic, or mixed inflammation. Eosinophilic inflammation was found in smoking and nonsmoking patients with asthma during an exacerbation. PMID- 29477569 TI - A Multicenter Evaluation of Diagnosis and Management of Omega-5 Gliadin Allergy (Also Known as Wheat-Dependent Exercise-Induced Anaphylaxis) in 132 Adults. AB - BACKGROUND: Omega-5 gliadin allergy (also known as wheat-dependent exercise induced anaphylaxis) is a rare allergy to wheat that often presents with intermittent severe anaphylaxis in the context of a cofactor, such as exercise. OBJECTIVE: To undertake a detailed clinical characterization of the largest cohort of patients with omega-5 gliadin allergy to date. METHODS: We retrospectively analyzed the demographic characteristics, presentation, investigation, and management of 132 patients presenting with omega-5 gliadin allergy in 4 UK centers. RESULTS: There were significant delays in diagnosis of 1 to 5 years (40% of patients) and more than 5 years (29% of patients). The commonest cofactors were exercise (80%), alcohol (25%), and nonsteroidal anti inflammatory drugs (9%). A minority of patients (11%) had no identifiable cofactor. The level of specific IgE to omega-5 gliadin does not predict the severity of allergic reactions. Patients who adhered to a gluten-free diet and those who avoided wheat in combination with exercise achieved the largest reductions in subsequent allergic reactions of 67% and 69%, respectively. CONCLUSION: Omega-5 gliadin allergy is a rare wheat allergy that presents with severe anaphylaxis. The diagnosis is frequently delayed, and therefore we recommend that all adult patients presenting with anaphylaxis of unclear cause should have omega-5 gliadin specific IgE tested. A gluten-free diet or avoidance of wheat-based meals in combination with exercise (if the cofactor is exercise) helps to significantly decrease the risk of future allergic reactions. However, antihistamines and an epinephrine autoinjector must always be prescribed because one-third of patients continue to have allergic reactions despite dietary advice. PMID- 29477571 TI - [The biplane microlift. Principles, technic, results]. AB - There has been a growing number of patients asking for a lighter face lift than the classical biplane procedure with wide undermining; This explains the popularity of medical threads lifts. A surgical approach is nevertheless possible by performing a new technique, derived from minilfts, but with a dissection elevating skin and SMAS layers together, preserving as much retaining ligaments as possible, and allowing a predesigned skin excision. Thirty-two patients have been operated this way since 2014; 3 asked and sustained for a redo because of skin relapse at one year postoperatively. Few complications have occurred, mostly limited hematomas, or skin problems because of suture threads rejection. The best indications seemed to be young patients presenting a jowl ptosis or cervical skin laxity, and patients who require a secondary facelift as a lighter procedure. PMID- 29477570 TI - Persistent organic pollutants and risk of type 2 diabetes: A prospective investigation among middle-aged women in Nurses' Health Study II. AB - BACKGROUND: Exposure to persistent organic pollutants (POPs) may predispose to the development of type 2 diabetes (T2D), but prospective human evidence is scarce. OBJECTIVES: We investigated the association between plasma-POP concentrations in the late 1990s and incident T2D over 11 years of follow-up in the Nurses' Health Study II. DISCUSSION: Three organochlorine pesticides and 20 polychlorinated biphenyls (PCBs) were measured in banked plasma from 793 case control pairs of T2D. In a multiviarate-adjusted model, T2D ORs (95%CIs) comparing extreme POP tertiles (high vs. low) were 1.67 (1.24, 2.23; Ptrend < 0.001) for hexachlorobenzene (HCB), 3.62 (2.57, 5.11; Ptrend < 0.001) for beta hexachlorocyclohexane (beta-HCH), 1.55 (1.13, 2.13; Ptrend = 0.05) for p,p' dichlorodiphenyldichloroethylene (p,p'-DDE), and 1.95 (1.42, 2.69; Ptrend < 0.001) for total dioxin-like PCBs (DL-PCBs) which included 5 mono-ortho congeners, PCB-105, 118, 156, 157, and 167. Adjustment for previous weight change and body mass index (BMI) at blood draw attenuated these associations, but that for DL-PCBs remained (OR[95% CI] = 1.78[1.14, 2.76]; Ptrend = 0.006). Age, breastfeeding history, previous weight change and BMI at blood draw were significant predictors of plasma POP concentrations. In addition, we found significant interactions of POPs and weight change before blood draw on T2D risk. ORs (95%CIs) of T2D comparing extreme (high vs. low) POP groups were 2.00 (1.02, 3.92; Ptrend = 0.01) for HCB, 2.69 (1.34, 5.40; Ptrend < 0.001) for beta-HCH, and 2.41 (1.22, 4.77; Ptrend < 0.001) for DL-PCBs in the lowest weight gain group, whereas these values were 1.29 (0.73, 2.28; Ptrend = 0.46; Pinteraction = 0.04) for HCB, 1.41 (0.77, 2.60; Ptrend = 0.24; Pinteraction = 0.003) for beta-HCH, and 0.90 (0.50, 1.63; Ptrend = 0.61; Pinteraction = 0.01) for DL-PCBs in the highest weight-gain group. CONCLUSIONS: Our findings suggest that elevated POP exposure may have diabetogenic potential. These data also highlight the impact of lifestyle factors, especially history of weight gain, on circulating POP concentrations and their associations with subsequent T2D risk. PMID- 29477572 TI - Multiple regulatory actions of 2-guanidine-4-methylquinazoline (GMQ), an agonist of acid-sensing ion channel type 3, on ionic currents in pituitary GH3 cells and in olfactory sensory (Rolf B1.T) neurons. AB - GMQ (2-guanidine-4-methylquinazoline or N-(4-methyl-2-quinazolinyl)-guanidine hydrochloride), an agonist of acid-sensing ion channel type 3, has been increasingly used for in vivo studies of alternations in nociceptic behavior. In this study, we tried to investigate whether GMQ has any possible effect on other types of ion channels. Addition of GMQ to pituitary GH3 cells raised the amplitude of Ca2+-activated K+ currents (IK(Ca)), which was reversed by verruculogen or PF1022A, but not by TRAM-39. Under inside-out current recordings, addition of GMQ into bath enhanced the probability of large-conductance Ca2+ activated K+ (BKCa) channels with an EC50 value of 0.95 uM. The activation curve of BKCa channels during exposure to GMQ shifted to a lower depolarized potential, with no change in the gating charge of the curve; however, there was a reduction of free energy for channel activation in its presence. As cells were exposed to GMQ, the amplitude of ion currents were suppressed, including delayed rectifying K+ current, voltage-gated Na+ and L-type Ca2+ currents. In Rolf B1.T olfactory sensory neuron, addition of GMQ was able to induce inward current and to suppress peak INa. Taken together, findings from these results indicated that in addition to the activation of ASIC3 channels, this compound might directly produce additional actions on various types of ion channels. Caution should be taken in the interpretation of in vivo experimental results when GMQ or other structurally similar compounds are used as targets to characterize the potential functions of ASIC3 channels. PMID- 29477573 TI - Objective Assessments of Peyronie's Disease. AB - INTRODUCTION: Penile deformity is the most obvious manifestation of Peyronie's disease (PD) and key to determining the optimal method of treatment. Other aspects of PD to consider include plaque size, location, and density; amount of calcification; erection quality; disease progression; and penile anatomy. Few standards exist for the objective assessment of these parameters. AIM: To describe current options and new trends in the objective evaluation of PD with a focus on penile curvature and imaging modalities. METHODS: A literature review was performed through PubMed from 1990 to 2017 regarding objective parameters in PD, including imaging modalities, measurements of deformity, and serum markers. Non-English-language articles were excluded. MAIN OUTCOME MEASURES: We sought to assess various objective measurements obtained in patients with PD and to evaluate their usefulness in the evaluation, treatment, and counseling of patients with PD. RESULTS: Measurement of penile curvature is most accurately performed with in-office goniometric angle measurement of a pharmacologically induced erection. However, new methods of assessing penile curvature using 3 dimensional photography and smartphone and tablet applications can aid clinicians in describing and treating PD. Ultrasound and ultrasound adjuncts provide excellent plaque characterization and assessment of penile vasculature, which can be useful for treatment planning and research. Presence of inflammation can be evaluated using magnetic resonance imaging or nuclear scintigraphy. CONCLUSION: Current guidelines only recommend obtaining measurements of penile length and penile curvature in the erect state. However, many other options exist for the objective evaluation of PD. These options can have a role in treatment decision making and help standardize results in PD research. Chen JY, Hockenberry MS, Lipshultz LI. Objective Assessments of Peyronie's Disease. Sex Med Rev 2018;6:438 445. PMID- 29477574 TI - Cost-effectiveness of hepatitis C screening and treatment linkage intervention in US methadone maintenance treatment programs. AB - BACKGROUND: We evaluated the cost-effectiveness of a hepatitis C (HCV) screening and active linkage to care intervention in US methadone maintenance treatment (MMT) patients using data from a randomized trial conducted in New York City and San Francisco. METHODS: We used a decision analytic model to compare 1) no intervention; 2) HCV screening and education (control); and 3) HCV screening, education, and care coordination (active linkage intervention). We also explored an alternative strategy wherein HCV/HIV co-infected participants linked elsewhere. Trial data include population characteristics (67% male, mean age 48, 58% HCV infected) and linkage rates. Data from published sources include treatment efficacy and HCV re-infection risk. We projected quality-adjusted life years (QALYs) and lifetime medical costs using an established model of HCV (HEP CE). Incremental cost-effectiveness ratios (ICERs) are in 2015 US$/QALY discounted 3% annually. RESULTS: The control strategy resulted in a projected 35% linking to care within 6 months and 31% achieving sustained virologic response (SVR). The intervention resulted in 60% linking and 54% achieving SVR with an ICER of $24,600/QALY compared to no intervention from the healthcare sector perspective and was a more efficient use of resources than the control strategy. The intervention had an ICER of $76,500/QALY compared to the alternative strategy. From a societal perspective, the intervention had a net monetary benefit of $511,000-$975,600. CONCLUSIONS: HCV care coordination interventions that include screening, education and active linkage to care in MMT settings are likely cost-effective at a conventional $100,000/QALY threshold for both HCV mono infected and HIV co-infected patients. PMID- 29477575 TI - Correlates of prescription opioid misuse among Black adults: Findings from the 2015 National Survey on Drug Use and Health. AB - BACKGROUND: Prescription drug misuse, especially opioid misuse, has become a public health crisis in the US. While much research attention has been focused on prescription drug misuse, a number of notable gaps in the literature remain. The current research addresses one of these gaps by examining racial/ethnic variation in prescription opioid misuse among adults. METHODS: We use data from the 2015 NSDUH to identify correlates of prescription opioid misuse among Black respondents aged 18 and older. The NSDUH defines prescription drug misuse as the use of prescription drugs in any way a doctor did not direct respondents to use them, including (a) without a prescription of their own; (b) in greater amounts, more often, or longer than told to use; or (c) in any other way a doctor did not tell respondents to use the drug. RESULTS: Findings indicate that Black respondents have a very similar prevalence rate of prescription opioid misuse compared to White respondents. A number of factors (i.e., gender, socioeconomic status, educational attainment) were significantly correlated with prescription opioid misuse only among Black respondents. In addition, many factors (i.e., depression, general health, other illicit drug use, being approached by a drug dealer) were significantly associated with prescription opioid misuse among both Black and White respondents. CONCLUSIONS: The current research identified a number of unique correlates of prescription opioid misuse among Black adults. To more effectively deal with the current public health crisis, research must identify risk factors among various groups within the population. PMID- 29477576 TI - Sodium-glucose cotransporter-2 inhibitors induced eu-glycemic diabetic ketoacidosis: The first report in a type 2 diabetic (T2D) Taiwanese and literature review of possible pathophysiology and contributing factors. AB - Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are the newest class of oral antidiabetic drugs (OADs), approved to be a second-line OAD for type 2 diabetes in Taiwan since 2016. The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) had both released statements associating the use of SGLT-2 inhibitors may increase the risk of eu-glycemic diabetic ketoacidosis (euDKA). This review reveals the possible pathophysiology with a chain of metabolic adaptions to decrease plasma glucose and increase plasma ketone bodies through pancreas, kidney, liver and adipose tissue. Moreover, euDKA is a potential and rare complication of treatment with SGLT-2 inhibitors when coexisting with triggering factors. It is an emerging challenge for clinical physicians and patients treated with SGLT-2 inhibitors. Therefore, first report of SGLT-2 inhibitor induced euDKA in a T2D Taiwanese and literature review of possible pathophysiology and contributing factors are presented in order to make more attentions in public. PMID- 29477577 TI - Similarities and differences between the responses induced in human phagocytes through activation of the medium chain fatty acid receptor GPR84 and the short chain fatty acid receptor FFA2R. AB - GPR84 is a recently de-orphanized member of the G-protein coupled receptor (GPCR) family recognizing medium chain fatty acids, and has been suggested to play important roles in inflammation. Due to the lack of potent and selective GPR84 ligands, the basic knowledge related to GPR84 functions is very limited. In this study, we have characterized the GPR84 activation profile and regulation mechanism in human phagocytes, using two recently developed small molecules that specifically target GPR84 agonistically (ZQ16) and antagonistically (GLPG1205), respectively. Compared to our earlier characterization of the short chain fatty acid receptor FFA2R which is functionally expressed in neutrophils but not in monocytes, GPR84 is expressed in both cell types and in monocyte-derived macrophages. In neutrophils, the GPR84 agonist had an activation profile very similar to that of FFA2R. The GPR84-mediated superoxide release was low in naive cells, but the response could be significantly primed by TNFalpha and by the actin cytoskeleton disrupting agent Latrunculin A. Similar to that of FFA2R, a desensitization mechanism bypassing the actin cytoskeleton was utilized by GPR84. All ZQ16-mediated cellular responses were sensitive to GLPG1205, confirming the GPR84-dependency. Finally, our data of in vivo transmigrated tissue neutrophils indicate that both GPR84 and FFA2R are involved in neutrophil recruitment processes in vivo. In summary, we show functional similarities but also some important differences between GPR84 and FFA2R in human phagocytes, thus providing some mechanistic insights into GPR84 regulation in blood neutrophils and cells recruited to an aseptic inflammatory site in vivo. PMID- 29477578 TI - Association of free-living physical activity measures with metabolic phenotypes in type 2 diabetes at the time of diagnosis. The Verona Newly Diagnosed Type 2 Diabetes Study (VNDS). AB - BACKGROUND AND AIM: Lifestyle is considered a major determinant of risk of type 2 diabetes (T2D). We investigated whether daily physical activity (DPA) is associated with beta-cell function (BF) and/or insulin sensitivity (IS) in patients with T2D at the time of diagnosis. METHODS AND RESULTS: In 41 subjects enrolled in the Verona Newly-Diagnosed Type 2 Diabetes Study we assessed: (1) IS, by euglycaemic insulin clamp; (2) BF, estimated by prolonged-OGTT minimal modeling and expressed as derivative and proportional control; (3) DPA and energy expenditure (EE), assessed over 48-h monitoring by a validated wearable armband system. Study participants (median [IQR]; age: 62 [53-67] years, BMI: 30.8 [26.5 34.3] Kg m-2, HbA1c: 6.7 [6.3-7.3]%; 49.7 [45.4-56.3] mmol/mol) were moderately active (footsteps/day: 7773 [5748-10,927]; DPA>=3MET: 70 [38-125] min/day), but none of them exercised above 6 metabolic equivalents (MET). EE, expressed as EETOT (total daily-EE) and EE>=3MET (EE due to DPA>=3MET) were 2398 [2226-2801] and 364 [238-617] Kcal/day, respectively. IS (M-clamp 630 [371-878] MUmol/min/m2) was positively associated with DPA and EE, independent of age, sex and BMI (p < 0.05). Among the DPA and EE parameters assessed, DPA>=3MET and EETOT were independent predictors of IS in multivariable regression analyses, adjusted for age, sex, BMI (R2 = 16%, R2 = 19%, respectively; p < 0.01). None of model-derived components of BF was significantly associated with DPA or accompanying EE. CONCLUSIONS: Our study highlighted moderate levels of DPA and total EE as potential determinants of IS, but not BF, in T2D at the time of diagnosis. Intervention studies are needed to conclusively elucidate the effect of DPA on these features. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. UNIQUE IDENTIFIER: NCT01526720. PMID- 29477579 TI - Critical role of plasmacytoid dendritic cells in induction of oral tolerance. AB - BACKGROUND: Exposure to dietary constituents through the mucosal surface of the gastrointestinal tract generates oral tolerance that prevents deleterious T cell mediated immunity. Although oral tolerance is an active process that involves emergence of CD4+ forkhead box p3 (Foxp3)+ regulatory T (Treg) cells in gut associated lymphoid tissues (GALTs) for suppression of effector T (Teff) cells, how antigen-presenting cells initiate this process remains unclear. OBJECTIVE: We sought to determine the role of plasmacytoid dendritic cells (pDCs), which are known as unconventional antigen-presenting cells, in establishment of oral tolerance. METHODS: GALT-associated pDCs in wild-type mice were examined for their ability to induce differentiation of CD4+ Teff cells and CD4+Foxp3+ Treg cells in vitro. Wild-type and pDC-ablated mice were fed oral antigen to compare their intestinal generation of CD4+Foxp3+ Treg cells and induction of oral tolerance to protect against Teff cell-mediated allergic inflammation. RESULTS: GALT-associated pDCs preferentially generate CD4+Foxp3+ Treg cells rather than CD4+ Teff cells, and such generation requires an autocrine loop of TGF-beta for its robust production. A deficiency of pDCs abrogates antigen-specific de novo generation of CD4+Foxp3+ Treg cells occurring in GALT after antigenic feeding. Furthermore, the absence of pDCs impairs development of oral tolerance, which ameliorates the progression of delayed-type hypersensitivity and systemic anaphylaxis, as well as allergic asthma, accompanied by an enhanced antigen specific CD4+ Teff cell response and antibody production. CONCLUSION: pDCs are required for establishing oral tolerance to prevent undesirable allergic responses, and they might serve a key role in maintaining gastrointestinal immune homeostasis. PMID- 29477580 TI - Reply. PMID- 29477581 TI - Myocardial dysfunction is frequent in systemic capillary-leak syndrome (Clarkson disease) severe episodes. PMID- 29477582 TI - Sleeping well and staying in rhythm to stave off dementia. PMID- 29477583 TI - The sharp phase of respiratory inhibition during amino acid starvation in Escherichia coli is RelA-dependent and associated with regulation of ATP synthase activity. AB - Amino acid starvation causes an RelA-dependent increase in the regulatory nucleotide (p)ppGpp that leads to pleiotropic changes in Escherichia coli metabolism, but the role of (p)ppGpp in regulation of respiration remains unclear. Here we demonstrate that amino acid starvation is accompanied by sharp RelA-dependent inhibition of respiration. The sharp phase of inhibition is absent in relA mutants, and can be prevented by translation inhibitors chloramphenicol and tetracycline, which abolish accumulation of (p)ppGpp. Single knockouts of any components of the respiratory chain do not affect inhibition of respiration. Studies of dO2 changes in various atp mutants indicate that ATP synthase is probably the primary target of (p)ppGpp-mediated respiratory control. Inhibition of respiration induced by amino acid starvation is followed by transient perturbations in the membrane potential (Deltapsi) and K+ fluxes and leads to transient acceleration of superoxide production and H2O2 accumulation in the medium. High levels of H2O2 and superoxide formation and induced activity of antioxidant systems in the atpC mutant indicate the important role of ATP synthase in controlling the production of reactive oxygen species. The new function of (p)ppGpp, discovered here, expands the understanding of its role in metabolic reprogramming during the adaptive response to stresses. PMID- 29477584 TI - The influence of comorbid anxiety on the effectiveness of Cognitive Therapy and Interpersonal Psychotherapy for Major Depressive Disorder. AB - BACKGROUND: Anxious depression is an important subtype of Major Depressive Disorder (MDD) defined by both syndromal (anxiety disorders) and dimensional (anxiety symptoms) criteria. A debated question is how anxiety affects MDD treatment. This study examined the impact of comorbid anxiety disorders and symptoms on the effectiveness of and dropout during Cognitive Therapy (CT) and Interpersonal Psychotherapy (IPT) for MDD. METHODS: Depressed individuals were randomized to CT (n = 76) or IPT (n = 75). Outcome was depression severity measured with the Beck Depression Inventory-II (BDI-II) at the start of each therapy session, post treatment, and monthly up to five months follow-up. Anxiety disorders were assessed with the Structured Clinical Interview for DSM-IV Axis I disorders, (phobic) anxiety symptoms were assessed with Brief Symptom Inventory subscales. RESULTS: Approximately one third of participants had a comorbid anxiety disorder. Comorbid anxiety disorders and anxiety symptoms were associated with less favorable depression change during IPT as compared to CT in the treatment phase, but not in the trial follow-up phase. Individuals with a comorbid anxiety disorder had significantly higher treatment dropout during both treatments. LIMITATIONS: Not all therapists and participants were blind to the assessment of comorbid anxiety disorders and the assessments were performed by one rater. CONCLUSIONS: A preference for CT over IPT for MDD is justifiable when comorbid anxiety is present, although long-term differences are not established and replication of this finding is needed. Clinicians should be aware of the risk of dropout for depressed individuals with an anxiety disorder. PMID- 29477585 TI - Association between abnormal serum myelin-specific protein levels and white matter integrity in first-episode and drug-naive patients with major depressive disorder. AB - BACKGROUND: Although the structural abnormalities of white matter (WM) have been described in patients with major depressive disorder (MDD), the neuropathological changes remain unclear. The current study aimed to investigate the myelin oligodendrocyte glycoprotein (MOG) and myelin-associated glycoprotein (MAG) levels and their correlations with WM integrity in first-episode, drug-naive MDD patients. METHODS: We obtained diffusion tensor images of 102 first-episode, drug naive MDD patients and 81 age- and sex-matched controls. Serum MOG and MAG levels of all participants were measured and compared between the two groups. The correlations between WM integrity and MOG and MAG levels were examined. RESULTS: MOG and MAG serum levels were significantly higher in MDD patients than in controls. Patients with MDD also showed decreased fractional anisotropy (FA) and axial diffusivity in the WM of the bilateral thalamus, right hippocampus, right temporal lobe, and left pulvinar. At the whole-brain level, no regions showed any correlations of diffusivity parameters with MOG or MAG levels in healthy subjects. However, we observed two-way correlations between the MOG and MAG levels and the FA and mean diffusivity values in the WM of the left middle frontal lobe, right inferior parietal lobe, and right supplementary motor area in MDD patients. LIMITATIONS: Further investigation with a larger sample size and longitudinal studies are required to better understand the neuropathology of WM integrity in MDD. CONCLUSIONS: Our findings represent the first evidence of a relationship between abnormal serum myelin-specific protein levels and impaired WM integrity, which may help to better understand the neurobiological mechanisms of MDD. PMID- 29477586 TI - Evidence for association between familial bipolar risk and ventral striatal volume. AB - BACKGROUND: Recent genome-wide association studies (GWAS) of striatal volumes and bipolar disorder (BD) indicate these traits are heritable and share common genetic architecture, however little independent work has been conducted to help establish this relationship. METHODS: Subcortical volumes (mm3) of young, healthy offspring of BD (N= 32) and major depressive disorder (MDD) patients (N= 158) were compared to larger healthy control sample (NRANGE= 925-1052) adjusting for potential confounds, using data from the latest release (S1200) of the Human Connectome Project. Based on recent GWAS findings, it was hypothesised that the accumbens and caudate would be smaller in offspring of BD, but not MDD patients. RESULTS: After multiple comparison correction, there was a regional and BD specific relationship in the direction expected (Accumbens: F2,1067= 6.244, PFDR CORRECTED= 0.014). DISCUSSION: In line with recent GWAS, there was evidence supporting the hypothesis that reduced striatal volume may be part of the genetic risk for BD, but not MDD. LIMITATIONS: It cannot be concluded whether this association was specific to BD or consistent with a broader psychosis phenotype, due to a small sample size for offspring of schizophrenia patients. Furthermore, one cannot rule out potential shared environmental influences of parental BD. CONCLUSIONS: The common genetic architecture of BD may confer susceptibility via inherited genetic factors that affect striatal volume. Future work should establish how this relationship relates to specific BD symptomology. This work may also help to dissect clinical heterogeneity and improve diagnosis nosology. PMID- 29477587 TI - Factors affecting time to remission for inpatients with bipolar mania - A naturalistic Taiwanese study. AB - BACKGROUND: Bipolar disorder is a complicated and chronic mental disorder. This study investigated factors affecting time to remission for inpatients with bipolar mania after 4 weeks of acute treatment. METHODS: This naturalistic study recruited inpatients with bipolar mania for acute treatment. Symptom severity was assessed using the Young Mania Rating Scale (YMRS) at weeks 0, 1, 2, 3, and 4. Patients were included if they had had assessments at weeks 0 and 1 Remission was defined as an YMRS score <= 12. The Cox regression analysis was used to analyze factors associated with time to remission after 4 weeks of acute treatment. RESULTS: Four hundred and forty-nine patients entered the analysis. Seventy-one of the 449 subjects (15.8%) reached symptomatic remission within 4 weeks of acute treatment. Using forward multivariate Cox regression analysis, comorbid substance use disorders, earlier age at onset, and greater manic symptom severity at baseline found to be statistically significant predictors of a longer time to reach remission after 4 weeks of treatment. LIMITATIONS: As a retrospective chart review and naturalistic design, placebo effect and potentially confounding factors such as the possibility of missing records may have limited our results. CONCLUSIONS: Early identification and intervention with integrated therapy is considered to shorten time to remission for patients at high risk of poor treatment outcome. More studies are needed in other real-world settings to generalize our results. PMID- 29477588 TI - Exploring alternative rTMS strategies in non-responders to standard high frequency left-sided treatment: A switching study. AB - BACKGROUND: High-frequency left-sided repetitive transcranial magnetic stimulation (rTMS) is now commonly used treatment for patients with depression. However, there are several other forms of rTMS (low-frequency right-sided and sequential bilateral rTMS) which have also been shown to be effective. No information has been systematically gathered on the likelihood of response to alternative forms of rTMS in patients who do not improve after an initial course of left-sided treatment. OBJECTIVE: To evaluate whether there are differences in antidepressant response between switching to either low-frequency right sided or sequential bilateral stimulation or continuing high-frequency left-sided TMS following non-response to an initial course of high-frequency left-sided rTMS. METHODS: 113 rTMS naive patients were provided with an initial three-week course of high-frequency left-sided rTMS. Non-responders were then randomised to receive another three weeks of left-sided treatment (n = 21), right-sided low frequency stimulation (n = 18) or sequential bilateral rTMS (n = 20). RESULTS: Although there was an overall improvement in depressive symptoms in the randomised phase of the study, no significant differences in response was seen between the three treatment groups on Montgomery Asberg Depression Rating Scale or Hamilton Depression Rating Scale scores. LIMITATIONS: The main limitation of the study was the duration of treatment provided in both the lead in and random treatment phases. CONCLUSION: This study does not provide evidence for differences in response to different forms of rTMS in initial non-responders to left-sided stimulation. However, further studies with longer periods of treatment and a larger sample size are required to definitively establish or exclude between group differences in rTMS response in initial non-responders to treatment. PMID- 29477589 TI - The role of affective temperaments assessed by the Temperament Evaluation of Memphis, Pisa and San Diego-Autoquestionnaire (TEMPS-A) in the relationship between morningness-eveningness and bipolarity. AB - BACKGROUND: Growing number of studies indicates a link between eveningness chronotype, affective temperaments and bipolarity, both in patients with mood disorders and in general population. Given these tripartite associations, we hypothesized that the effect of circadian preferences on the bipolarity may be mediated by the temperamental traits. METHODS: The study included 1449 subjects (402 men and 1047 women). They all fulfilled a web-based questionnaire, consisting of the Composite Scale of Morningness (CSM), Mood Disorder Questionnaire (MDQ), Hypomania Checklist-32 (HCL-32) and the Temperament Evaluation of the Memphis, Pisa and San Diego-Autoquestionnaire (TEMPS-A). The role of temperamental traits in the relationship between morningness-eveningness and bipolarity was assessed using mediation analysis. RESULTS: Morningness is correlated with lower bipolarity measured by the MDQ and HCL-32, and to lower scores of depressive, cyclothymic, irritable and anxious temperaments of the TEMPS-A. There is no significant association between morningness and hyperthymic traits. Cyclothymic and irritable traits are full mediators of the association between chronotype and bipolarity, influencing bipolarity independently from circadian preferences. Depressive and anxious traits are partial mediators of this association, increasing the effect of eveningness on bipolarity. LIMITATIONS: The indirectness of the findings in the web-based study and disproportion of participants' gender. CONCLUSIONS: Our study confirmed that eveningness is associated with bipolarity. In case of depressive and anxious temperaments, bipolarity is associated stronger with eveningness than with the TEMPS-A scores. On the other hand, cyclothymic and irritable temperaments were associated with bipolarity independently from circadian preferences. PMID- 29477590 TI - Clinical pilot study of transcranial direct current stimulation combined with Cognitive Emotional Training for medication resistant depression. AB - BACKGROUND: While the clinical results from transcranial direct current stimulation (tDCS) for the treatment of depression have been promising, antidepressant effects in patients with medication resistance have been suboptimal. There is therefore a need to further optimise tDCS for medication resistant patients. In this clinical pilot study we examined the feasibility, safety, and clinical efficacy of combining tDCS with a psychological intervention which targets dysfunctional circuitry related to emotion regulation in depression, Cognitive Emotional Training (CET). METHODS: tDCS was administered during CET three times a week for a total of 18 sessions over 6 weeks. Mood, cognition and emotion processing outcomes were examined at baseline and after 3 and 6 weeks of treatment. RESULTS: Twenty patients with medication resistant depression participated, of whom 17 were study completers. tDCS combined with CET was found to be feasible, safe, and associated with significant antidepressant efficacy at 6 weeks, with 41% of study completers showing treatment response (>= 50% improvement in depression score). There were no significant cognitive enhancing effects with the exception of improved emotion recognition. Responders demonstrated superior recognition for the emotions fear and surprise at pre treatment compared to non-responders, suggesting that better pre-treatment emotion recognition may be associated with antidepressant efficacy. LIMITATIONS: This was an open label study. CONCLUSIONS: tDCS combined with CET has potential as a novel method for optimising the antidepressant efficacy of tDCS in medication resistant patients. Future controlled studies are required to determine whether tDCS combined with CET has greater antidepressant efficacy compared to either intervention alone. PMID- 29477591 TI - Generation of a human induced pluripotent stem cell (iPSC) line from a 51-year old female with attention-deficit/hyperactivity disorder (ADHD) carrying a duplication of SLC2A3. AB - Fibroblasts were isolated from a skin biopsy of a clinically diagnosed 51-year old female attention-deficit/hyperactivity disorder (ADHD) patient carrying a duplication of SLC2A3, a gene encoding neuronal glucose transporter-3 (GLUT3). Patient fibroblasts were infected with Sendai virus, a single-stranded RNA virus, to generate transgene-free human induced pluripotent stem cells (iPSCs). SLC2A3 D2-iPSCs showed expression of pluripotency-associated markers, were able to differentiate into cells of the three germ layers in vitro and had a normal female karyotype. This in vitro cellular model can be used to study the role of risk genes in the pathogenesis of ADHD, in a patient-specific manner. PMID- 29477592 TI - Induced pluripotent stem cells line (UNIPDi003-A) from a patient affected by EEC syndrome carrying the R279H mutation in TP63 gene. AB - Oral mucosa epithelial stem cells from a patient affected by Ectrodactyly Ectodermal dysplasia-Clefting (EEC) syndrome carrying the R279H mutation in the TP63 gene were reprogrammed into human induced pluripotent stem cells (hiPSCs) with episomal vectors. The generated UNIPDi003-A-hPSC line retained the mutation of the parental cells and showed a normal karyotype upon long term culture. Analysis of residual transgenes expression showed that the episomal vectors were eliminated from the cell line. UNIPDi003-A-hiPSCs expressed the undifferentiated state marker alkaline phosphatase along with a panel of pluripotency markers, and formed embryoid bodies capable of expressing markers belonging to all the three germ layers. PMID- 29477593 TI - Sleep spindle activity in children with obstructive sleep apnea as a marker of neurocognitive performance: A pilot study. AB - STUDY OBJECTIVES: To assess spindle activity as possible markers for neurocognitive consequences in children with mild obstructive sleep apnea. METHODS: Children aged 6-11 years diagnosed with mild OSA (i.e., an apnea hypopnea index <5.0) were recruited and compared with age and gender-matched healthy controls. Polysomnographic recordings were analyzed for sleep microstructure and spindle activity. All children completed also an intelligence test battery (i.e., the Wechsler intelligence test for children, 4th version). RESULTS: Nineteen children with OSA (13 boys, mean age 7.1 +/- 1.4 y), and 14 controls (7 boys, mean age 8.1 +/- 1.9 y) were included. Mean IQ was 110 +/- 12 for the complete sample, in children with OSA 111 +/- 13, and in controls 108 +/- 12 (p = 0.602). Controls showed a higher spindle index in N2 stage than children with OSA: 143.0 +/- 42.5 vs 89.5 +/- 56.9, respectively (p = 0.003). Spindle index in NREM was strongly and significantly correlated with Verbal Comprehension Index (VCI), Working Memory Index (WMI), Processing Speed Index (PSI), and total IQ in children with OSA. CONCLUSIONS: Children with mild OSA demonstrate a different pattern of sleep spindle activity that seems to be linked with neurocognitive performance, especially concerning memory. Sleep spindle activity seems to be involved with mechanisms related with neurocognitive consequences in children with OSA. PMID- 29477594 TI - Morphological changes in the cerebellum as a result of ethanol treatment and cigarette smoke exposure: A study on astrogliosis, apoptosis and Purkinje cells. AB - The link between Ethanol (EtOH) and tobacco (TOB) has potentially important implications for people involved in alcohol treatment; many alcoholics smoke, putting them at high risk of tobacco-related complications. The present study investigates the effect of chronic exposure to cigarette smoke, EtOH consumption and the combination of both on astrogliosis and apoptosis in the cerebellum of rats. Adult male Wistar rats were divided into 4 groups (8 animals per group): vehicle (glucose 3%, 10 mL/kg, twice a day), EtOH treated (EtOH 2 g/kg, twice a day), exposure to cigarette smoke (TOB, smoke of 6 cigarettes, twice a day) and a combination of EtOH and cigarette smoke (TOB + EtOH, twice a day). The treatment period was 57 days, after which the animals were euthanized, the cerebellum removed and subjected to immunohistochemical studies focusing on glial fibrillary acidic protein (GFAP), cleaved caspase-3, and S100. We also counted the number of Purkinje cells (PC) present following treatment. The combination of both EtOH and TOB exposure induced an increase in GFAP immunoreactivity, whilst TOB alone increased apoptosis in the white matter of the cerebellum. In addition, EtOH consumption reduced the number of PC and TOB tempered this effect. Overall, the present study opens up relevant perspectives for the consequences on human health of the combined use of alcohol and smoking, by demonstrating the biological mechanisms and cerebellar function vulnerabilities to combined use and dependence of licit drugs. PMID- 29477595 TI - Effects of food exposure on food-related inhibitory control in restrained eaters: An ERP study. AB - Restrained eaters are likely to overeat when pre-exposed to cues such as the sight, smell, thought or taste of palatable food whereas unrestrained eaters remain unaffected. However, the neurocognitive correlates of inhibitory control to food stimuli after food exposure have not been examined. This study examined food-related and food-unrelated inhibitory control with two variants of Go/No-go task by means of event-related potentials (ERPs) before and after food exposure among restrained and unrestrained eaters. Results revealed that there was a reduction of food-related no-go N2a neural response strength in frontal/frontal central among restrained eaters compared to unrestrained eaters. Meanwhile, for restrained eaters, food-related no-go P3 amplitude increased significantly after exposure in comparison with baseline, but for unrestrained eaters there was no difference. Importantly, the exposure-induced difference in inhibition between restrained and unrestrained eaters was specific for food-related responses. Results indicated that restrained eaters may be less efficient in monitoring conflict over food-related stimuli and require more cognitive resources to inhibit food-specific responses when exposed to cues of attractive food. PMID- 29477596 TI - Nicotine facilitates synaptic depression in layer V pyramidal neurons of the mouse insular cortex. AB - The insular cortex is known to play a pivotal role in addiction to nicotine. Long term depression (LTD) in the central nervous system is a major form of synaptic plasticity which is involved in learning and memory and in various pathological conditions such as nicotine addiction. Until now, effects of nicotine on LTD were mainly examined in the hippocampus and striatum, and there is no report showing the effects of nicotine on LTD in the insular cortex. In the present study, I show for the first time that nicotine facilitates LTD which is induced by combination of presynaptic stimulation with postsynaptic depolarization (paired training) in layer 5 pyramidal neurons of the mouse insular cortex using whole cell patch-clamp recordings. The facilitatory effect of nicotine on LTD was blocked by GABAA receptor antagonists, bicuculline and picrotoxin. Furthermore, blockade of beta2-containing nicotinic acetylcholine receptors (nAChRs) prevented the effects of nicotine on LTD. Taken together, these results suggest that in layer 5 pyramidal neurons of the insular cortex, nicotine facilitates LTD through enhancement of GABAergic synaptic transmission, presumably mediated by activation of beta2-containing nAChRs. These findings may provide the crucial synaptic basis for the insular cortical changes in nicotine addiction. PMID- 29477598 TI - RAGE and its emerging role in the pathogenesis of Parkinson's disease. AB - Receptor for advanced glycation end products (RAGE) is a multiligand receptor belonging to the immunoglobulin superfamily and plays crucial roles in the development of many human diseases such as neurodegenerative diseases, diabetes, cardiovascular diseases, osteoarthritis and cancer. RAGE involves in a number of cell processes such as neuroinflammation, apoptosis, proliferation and autophagy. In CNS, RAGE was primarily expressed in neurons, microglia and vascular endothelial cells. Interacting with ligands, RAGE induces a series of signal transduction cascades and leads to the activation of transcription factor NF kappaB as well as increased expression of cytokines like TNF-alpha, IL-1. Moreover, binding to RAGE can also stimulate the generation of reactive oxygen species (ROS), which is implicated in neuron death. It was reported that RAGE were highly expressed in PD patients when compared to age-matched controls. And RAGE ablation protected nigral dopaminergic neurons against cell death in MPTP treated mice. Here we review this article to elucidate the role of RAGE in PD pathogenesis and highlight the anti-RAGE strategies in the treatment of PD. PMID- 29477597 TI - N1-Nonyl-1,4-diaminobutane ameliorates brain infarction size in photochemically induced thrombosis model mice. AB - Inhibitors for polyamine oxidizing enzymes, spermine oxidase (SMOX) and N1 acetylpolyamine oxidase (PAOX), were designed and evaluated for their effectiveness in a photochemically induced thrombosis (PIT) mouse model. N1-Nonyl 1,4-diaminobutane (C9-4) and N1-tridecyl-1,4-diaminobutane (C13-4) competitively inhibited the activity of PAOX and SMOX in a manner comparable to N1,N4-bis(2,3 butadienyl)-1,4-butanediamine (MDL72527), an irreversible inhibitor of both enzymes. The two compounds were then tested for their effects in the PIT model. Both intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administration of C9-4 decreased infarct volumes significantly. By contrast, C13-4 reduced the volume of brain infarction by i.c.v. administration, but no reduction was observed after i.p. administration. C9-4 administered by i.p. injection reduced the volume of brain infarction significantly at doses of more than 3 mg/kg, and the dosage of 5 mg/kg or 10 mg/kg demonstrated the most potent effect and were more effective than equivalent doses of the other inhibitors such as MDL72527 and N-benzylhydroxylamine. I.P. injection of 5 mg/kg of C9-4 provided a therapeutic time window of longer than 12 h. This report demonstrates that C9-4 is a potent inhibitor of the polyamine oxidizing enzymes and is useful lead compound for candidate drugs with a long therapeutic time window, to be used in the treatment of ischemic stroke. PMID- 29477599 TI - Rosa hybrida orcinol O-methyl transferase-mediated production of pterostilbene in metabolically engineered grapevine cell cultures. AB - Stilbenes are naturally scarce high-added-value plant compounds with chemopreventive, pharmacological and cosmetic properties. Bioproduction strategies include engineering the metabolisms of bacterial, fungal and plant cell systems. Strikingly, one of the most effective strategies consists in the elicitation of wild grapevine cell cultures, which leads to vast stilbene resveratrol accumulation in the extracellular medium. The combination of both cell culture elicitation and metabolic engineering strategies to produce resveratrol analogs proved more efficient for the hydroxylated derivative piceatannol than for the dimethylated derivative pterostilbene, for which human hydroxylase HsCYP1B1- and grapevine O-methyltransferase VvROMT-transformed cell cultures were respectively used. Rose orcinol O-methyltransferase (OOMT) displays enzymatic properties, which makes it an appealing candidate to substitute VvROMT in the combined strategy to enhance the pterostilbene production level by engineered grapevine cells upon elicitation. Here we cloned a Rosa hybrida OOMT gene, and created a genetic construction suitable for Agrobacterium-mediated plant transformation. OOMT's ability to catalyze the conversion of resveratrol into pterostilbene was first assessed in vitro using protein extracts of agroinfiltrated N. benthamiana leaves and transformed grapevine callus. The grapevine cell cultures transformed with RhOOMT produced about 16 mg/L culture of pterostilbene and reached an extracellular distribution of up to 34% of total production at the best, which is by far the highest production reported to date in a plant system. A bonus large resveratrol production of ca. 1500-3000 mg/L was simultaneously obtained. Our results demonstrate a viable successful metabolic engineering strategy to produce pterostilbene, a resveratrol analog with enhanced pharmacological properties. PMID- 29477600 TI - Improved continuous fumaric acid production with immobilised Rhizopus oryzae by implementation of a revised nitrogen control strategy. AB - A novel fermentation system was employed whereby the mycelial mat of Rhizopus oryzae was attached to a polypropylene tube. Batch operation was used for growth, while continuous operation was employed during the fumaric acid production phase. A clear decrease in respiration, fumaric acid (FA) and ethanol production was observed when zero nitrogen was fed in the production phase, with FA productivity decreasing from an initial 0.7 g L-1 h-1 to 0.3 g L-1 h-1 after 150 h. With the addition of 0.625 mg L-1 h-1 of urea FA productivity dropped to only 0.4 g L-1 h 1 after 150 h and 0.3 g L-1 h-1 after 400 h. Under these conditions it was observed that the ethanol production rate decreased 20 times faster compared with the FA production rate, therefore resulting in high FA yields towards the end of the fermentation (instantaneous 0.96 g g-1 and average 0.81 g g-1 after 400 h). Increasing the urea feed rate to 1.875 mg L-1 h-1 resulted in a clear increase in FA production and respiration rates. This condition also resulted in a 25% increase in biomass after 150 h, while the decline in the ethanol production rate was seven times lower than in the 0.625 mg L-1 h-1 urea fermentation, resulting in lower FA yields. PMID- 29477601 TI - Mechanochemical depolymerization of inulin. AB - Although chemical reactions driven by mechanical force is emerging as a promising tool in the field of physical sciences, its applications in the area of food sciences are not reported. In this paper, we propose ball milling as an efficient tool for the controlled generation of fructooligosaccharide (FOS) mixtures from inulin with a degree of polymerization (dp) ranging between 4 and 7. The addition of catalytic amounts of AlCl3 together with ball milling (30 min, at 30 Hz) generated mixtures rich in dehydrated disaccharides such as di-D-fructose dianhydrides. Based on anion exchange chromatography in conjunction with ESI/qTOF/MS/MS analysis, catalysis increased the overall content of mono-, di-, and tri-saccharides by around 30 fold compared to un-catalyzed milling. In addition, dialysis results of the untreated and treated samples have indicated that under catalysis the percent of depolymerization (dp < 12) reached 73.4% from the starting value of 27.6% in the untreated sample. Both processes resulted in mixtures of prebiotic value. The use of mechanical energy may be suitable for a fast, cost-efficient and green conversion of inulin to value-added food ingredients. PMID- 29477602 TI - Foreword: Aerodigestive Disorders-Part I. PMID- 29477603 TI - Orofacial granulomatosis: an unsuccessful response to weekly azithromycin pulse therapy. AB - Treatment of orofacial granulomatosis (OFG) is difficult and unpredictable, and currently there is not a treatment with guaranteed success. Macrolides have been suggested to give dramatic improvements in idiopathic OFG; however, this was not our experience. Following on from remarkable findings with weekly azithromycin pulse therapy reported in JAMA Dermatology, 2015, we treated 5 male patients with idiopathic OFG with the same regimen. Case 1 had a slight improvement but stopped treatment after 5 weeks due to gastrointestinal upset. Cases 2 and 3 had an initial improvement; however, symptoms returned once treatment had ceased. Case 3 received a second course of azithromycin with no improvement. Cases 4 and 5 did not have any improvement at all. We concluded that weekly azithromycin pulse therapy was not a successful treatment for idiopathic OFG. It may provide some short-term improvement in symptoms but does not dramatically resolve symptoms. PMID- 29477604 TI - Differentiation between benign and malignant palatal tumors using conventional MRI: a retrospective analysis of 130 cases. AB - OBJECTIVES: To evaluate the discriminative value of conventional magnetic resonance imaging between benign and malignant palatal tumors. STUDY DESIGN: Conventional magnetic resonance imaging features of 130 patients with palatal tumors confirmed by histopathologic examination were retrospectively reviewed. Clinical data and imaging findings were assessed between benign and malignant tumors and between benign and low-grade malignant salivary gland tumors. The variables that were significant in differentiating benign from malignant lesions were further identified using logistic regression analysis. Moreover, imaging features of each common palatal histologic entity were statistically analyzed with the rest of the tumors to define their typical imaging features. RESULTS: Older age, partially defined and ill-defined margins, and absence of a capsule were highly suggestive of malignant palatal tumors, especially ill-defined margins (beta = 6.400). The precision in determining malignant palatal tumors achieved a sensitivity of 92.8% and a specificity of 85.6%. In addition, irregular shape, ill-defined margins, lack of a capsule, perineural spread, and invasion of surrounding structures were more often associated with low-grade malignant salivary gland tumors. CONCLUSION: Conventional magnetic resonance imaging is useful for differentiating benign from malignant palatal tumors as well as benign salivary gland tumors from low-grade salivary gland malignancies. PMID- 29477605 TI - There Is a Significant Discrepancy Between "Big Data" Database and Original Research Publications on Hip Arthroscopy Outcomes: A Systematic Review. AB - PURPOSE: The purpose of this study was to compare (1) major complication, (2) revision, and (3) conversion to arthroplasty rates following hip arthroscopy between database studies and original research peer-reviewed publications. METHODS: A systematic review was performed using PRISMA guidelines. PubMed, SCOPUS, SportDiscus, and Cochrane Central Register of Controlled Trials were searched for studies that investigated major complication (dislocation, femoral neck fracture, avascular necrosis, fluid extravasation, septic arthritis, death), revision, and hip arthroplasty conversion rates following hip arthroscopy. Major complication, revision, and conversion to hip arthroplasty rates were compared between original research (single- or multicenter therapeutic studies) and database (insurance database using ICD-9/10 and/or current procedural terminology coding terminology) publishing studies. RESULTS: Two hundred seven studies (201 original research publications [15,780 subjects; 54% female] and 6 database studies [20,825 subjects; 60% female]) were analyzed (mean age, 38.2 +/- 11.6 years old; mean follow-up, 2.7 +/- 2.9 years). The database studies had a significantly higher age (40.6 + 2.8 vs 35.4 +/- 11.6), body mass index (27.4 +/- 5.6 vs 24.9 +/- 3.1), percentage of females (60.1% vs 53.8%), and longer follow up (3.1 +/- 1.6 vs 2.7 +/- 3.0) compared with original research (P < .0001 for all). Ninety-seven (0.6%) major complications occurred in the individual studies, and 95 (0.8%) major complications occurred in the database studies (P = .029; relative risk [RR], 1.3). There was a significantly higher rate of femoral neck fracture (0.24% vs 0.03%; P < .0001; RR, 8.0), and hip dislocation (0.17% vs 0.06%; P = .023; RR, 2.2) in the database studies. Reoperations occurred at a significantly higher rate in the database studies (11.1% vs 7.3%; P < .001; RR, 1.5). There was a significantly higher rate of conversion to arthroplasty in the database studies (8.0% vs 3.7%; P < .001; RR, 2.2). CONCLUSIONS: Database studies report significantly increased major complication, revision, and conversion to hip arthroplasty rates compared with original research investigations of hip arthroscopy outcomes. LEVEL OF EVIDENCE: Level IV, systematic review of Level I IV studies. PMID- 29477606 TI - Are Self-Reported Medication Allergies Associated With Worse Hip Outcome Scores Prior to Hip Arthroscopy? AB - PURPOSE: To determine if there are significant differences in preoperative patient-reported outcome (PRO) scores in patients with and without self-reported medication allergies undergoing hip arthroscopy. METHODS: Consecutive subjects undergoing hip arthroscopy for femoroacetabular impingement (FAI) syndrome by a single surgeon were retrospectively reviewed. PROs were collected within 6 weeks of the date of surgery. PROs included International Hip Outcome Tool (iHOT-12), Hip Outcome Score (HOS), and Short-Form (SF-12) scores. Allergies to medications were self-reported preoperatively within 6 weeks of the date of surgery. Patient demographics were recorded. Bivariate correlations and multivariate regression models were calculated to identify associations with baseline hip outcome scores. RESULTS: Two hundred twelve subjects were analyzed (56% female, mean age 35.1 +/- 13.2 years). Seventy-two subjects (34%) self-reported allergies (range 1-10; 41 subjects had 1 allergy; 14 subjects had 2; 8 subjects had 3; 2 subjects had 4; 7 subjects had 5 or more). The most commonly reported allergies included penicillin (18), sulfa (13), and codeine (11). Female gender was significantly correlated with number of allergies (Pearson correlation coefficient, 0.188; P < .001). SF 12 Mental Component Score (MCS) was significantly correlated with HOS-ADL (Pearson correlation coefficient, 0.389; P < .001), HOS-SSS (Pearson correlation coefficient, 0.251; P < .001), and iHOT-12 (Pearson correlation coefficient, 0.385; P < .001). There was no significant correlation between number of allergies and all hip PROs. In all multivariate models, the SF-12 MCS had the strongest association with HOS-ADL, HOS-SSS, and iHOT-12 (P < .001 for all). Allergies were not significantly associated with any hip PROs. CONCLUSIONS: In patients undergoing hip arthroscopy for FAI syndrome, self-reported medication allergies are not significantly associated with preoperative patient-reported hip outcome scores. LEVEL OF EVIDENCE: Level III, retrospective comparative case series. PMID- 29477608 TI - Mushroom body glycolysis is required for olfactory memory in Drosophila. AB - Glucose catabolism, also known as glycolysis, is important for energy generation and involves a sequence of enzymatic reactions that convert a glucose molecule into two pyruvate molecules. The glycolysis process generates adenosine triphosphate as a byproduct. In this study, we investigated whether glycolysis plays a role in maintaining neuronal functions in the Drosophila mushroom bodies (MBs), which are generally accepted to be an olfactory learning and memory center. Our data showed that individual knockdown of glycolytic enzymes in the MBs, including hexokinase (HexA), phosphofructokinase (Pfk), or pyruvate kinase (PyK), disrupts olfactory memory. Whole-mount brain immunostaining indicated that pyruvate kinase is strongly expressed in the MB alphabeta, alpha'beta', and gamma neuron subsets. We conclude that HexA, Pfk, and PyK are required in each MB neuron subset for olfactory memory formation. Our data therefore indicates that glucose catabolism in the MBs is important for olfactory memory formation in Drosophila. PMID- 29477607 TI - Trends in the Surgical Management of Acromioclavicular Joint Arthritis Among Board-Eligible US Orthopaedic Surgeons. AB - PURPOSE: (1) Define the epidemiologic trend of distal clavicle excision (DCE) for acromioclavicular (AC) joint arthritis among board-eligible orthopaedic surgeons in the United States, (2) describe the rates and types of reported complications of open and arthroscopic DCE, and (3) evaluate the effect of fellowship training on preferred technique and reported complication rates. METHODS: The American Board of Orthopaedic Surgery (ABOS) database was used to identify DCE cases submitted by ABOS Part II Board Certification examination candidates. Inclusion criteria were predetermined using a combination of ICD-9 and CPT codes. Cases were dichotomized into 2 groups: open or arthroscopic DCE. The 2 groups were then analyzed to determine trends in annual incidence, complication rates, and surgeon fellowship training. RESULTS: From April 2004 to September 2013, there were 3,229 open and 12,782 arthroscopic DCE procedures performed and submitted by ABOS Part II Board Eligible candidates. Overall, the annual incidence of open DCE decreased (78-37 cases per 10,000 submitted cases, P = .023). Although the annual number of arthroscopic DCE remained steady (1160-1125, P = .622), the percentage of DCE cases performed arthroscopically increased (65%-79%, P = .033). Surgeons without fellowship training were most likely to perform a DCE via an open approach (31%) whereas surgeons with sports medicine training were more likely to perform DCE arthroscopically compared with other fellowship groups (88%, P < .001). Open DCE was associated with a higher surgical complication rate overall when compared with arthroscopic DCE (9.4% vs 7.6%, respectively; P < .001). When compared with other fellowship-trained surgeons, sports medicine surgeons maintained a lower reported surgical complication rate whether performing open or arthroscopic DCE (5.5%, P = .027). CONCLUSIONS: In recent years, open management of AC joint arthritis has declined among newly trained, board-eligible orthopaedic surgeons, possibly because of an increased complication rate associated with open treatment. Fellowship training was significantly associated with the type of treatment (open vs arthroscopic) rendered and complication rates. LEVEL OF EVIDENCE: Level IV, case series. PMID- 29477609 TI - Learning what to expect and when to expect it involves dissociable neural systems. AB - Two experiments with Long-Evans rats examined the potential independence of learning about different features of food reward, namely, "what" reward is to be expected and "when" it will occur. This was examined by investigating the effects of selective reward devaluation upon responding in an instrumental peak timing task in Experiment 1 and by exploring the effects of pre-training lesions targeting the basolateral amygdala (BLA) upon the selective reward devaluation effect and interval timing in a Pavlovian peak timing task in Experiment 2. In both tasks, two stimuli, each 60 s long, signaled that qualitatively distinct rewards (different flavored food pellets) could occur after 20 s. Responding on non-rewarded probe trials displayed the characteristic peak timing function with mean responding gradually increasing and peaking at approximately 20 s before more gradually declining thereafter. One of the rewards was then independently paired repeatedly with LiCl injections in order to devalue it whereas the other reward was unpaired with these injections. In a final set of test sessions in which both stimuli were presented without rewards, it was observed that responding was selectively reduced in the presence of the stimulus signaling the devalued reward compared to the stimulus signaling the still valued reward. Moreover, the timing function was mostly unaltered by this devaluation manipulation. Experiment 2 showed that pre-training BLA lesions abolished this selective reward devaluation effect, but it had no impact on peak timing functions shown by the two stimuli. It appears from these data that learning about "what" and "when" features of reward may entail separate underlying neural systems. PMID- 29477610 TI - How patient experience informed the SafeMed Program: Lessons learned during a Health Care Innovation Award to improve care for super-utilizers. PMID- 29477611 TI - Willingness to disclose child maltreatment: CSA vs other forms of child abuse in relation to gender. AB - The aim of the study was to examine the role of gender in willingness to disclose childhood sexual abuse (CSA) compared to other forms of abuse (physical, emotional and neglect) in young adolescents. Willingness was examined through two terms: reluctance- the level of unwillingness or disinclination to disclose, and urge-the need to share in order to get rid of unbearable feelings. The sample consisted of 3,156 boys (n = 1,544) and girls (n = 1,612) between the ages of 11 16 who reported having been abused at least once during their life. Participants were divided into three groups: experiencing other than CSA, sexual abuse with no physical contact, and sexual abuse with physical contact. Regarding measures, a self-report questionnaire incorporating the following instruments was administered: Demographics, the Juvenile Victimization Questionnaire (JVQ), and the Disclosure of Trauma Questionnaire (DTQ). Study results indicated that CSA victims were more reluctant to disclose than victims of other than CSA forms of abuse. The more severe the CSA (physical contact) the lower was the willingness to disclose. Boys were more reluctant than girls to disclose sexual abuse whether or not it involved physical contact. Reluctance to disclose was positively associated with emotional reactions to disclosure while urge to talk was negatively correlated with emotional reactions to disclosure. PMID- 29477612 TI - Individual-level factors related to better mental health outcomes following child maltreatment among adolescents. AB - Research on factors associated with good mental health following child maltreatment is often based on unrepresentative adult samples. To address these limitations, the current study investigated the relationship between individual level factors and overall mental health status among adolescents with and without a history of maltreatment in a representative sample. The objectives of the present study were to: 1) compute the prevalence of mental health indicators by child maltreatment types, 2) estimate the prevalence of overall good, moderate, and poor mental health by child maltreatment types; and 3) examine the relationship between individual-level factors and overall mental health status of adolescents with and without a history of maltreatment. Data were from the National Comorbidity Survey of Adolescents (NCS-A; n = 10,123; data collection 2001-2004); a large, cross-sectional, nationally representative sample of adolescents aged 13-17 years from the United States. All types of child maltreatment were significantly associated with increased odds of having poor mental health (adjusted odds ratios ranged from 3.2 to 9.5). The individual-level factors significantly associated with increased odds of good mental health status included: being physically active in the winter; utilizing positive coping strategies; having positive self-esteem; and internal locus of control (adjusted odds ratios ranged from 1.7 to 38.2). Interventions targeted to adolescents with a history of child maltreatment may want to test for the efficacy of the factors identified above. PMID- 29477613 TI - Hallmarks of Cellular Senescence. AB - Cellular senescence is a permanent state of cell cycle arrest that promotes tissue remodeling during development and after injury, but can also contribute to the decline of the regenerative potential and function of tissues, to inflammation, and to tumorigenesis in aged organisms. Therefore, the identification, characterization, and pharmacological elimination of senescent cells have gained attention in the field of aging research. However, the nonspecificity of current senescence markers and the existence of different senescence programs strongly limit these tasks. Here, we describe the molecular regulators of senescence phenotypes and how they are used for identifying senescent cells in vitro and in vivo. We also highlight the importance that these levels of regulations have in the development of therapeutic targets. PMID- 29477614 TI - Recent Advances in Lgr5+ Stem Cell Research. AB - The discovery of leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) as both a marker of adult stem cells and a critical modulator of their activity via its role as an effector of Wnt/R-spondin (Rspo) signaling has driven major advances in our understanding of stem cell biology during homeostasis, regeneration, and disease. Exciting new mouse and organoid culture models developed to study the endogenous behavior of Lgr5-expressing cells in health and disease settings have revealed the existence of facultative stem cell populations responsible for tissue regeneration, cancer stem cells (CSCs) driving metastasis in the gut, and Lgr5+ niche cells in the lung. Here we review these recent advances and discuss their impact on efforts to harness the therapeutic potential of adult stem cells and their cancer counterparts in the clinic. PMID- 29477615 TI - GCN5L1/BLOS1 Links Acetylation, Organelle Remodeling, and Metabolism. AB - General control of amino acid synthesis 5 (GCN5) like-1 (GCN5L1) was identified as a novel gene with sequence homology to the histone acetyltransferase Gcn5. Subsequent protein-interaction studies identified GCN5L1 as a subunit of the multiprotein lysosome biogenesis complex, resulting in an alternative designation as biogenesis of lysosome-related organelle complex 1 subunit 1 (BLOS1 or BLOC1S1). Despite the distinct nomenclatures, GCN5L1/BLOS1 has been shown to play crucial roles in mitochondria, endosomes, lysosomes, and synaptic vesicle precursors (SVPs). GCN5L1/BLOS1 controls mitochondrial protein acetylation, modulates metabolic pathways, and orchestrates retrograde mitochondria-to-nucleus signaling. It also contributes to endosome-lysosome and vesicle trafficking and to endolysosomal function. Here we discuss the intracellular roles of GCN5L1/BLOS1 in the hope of linking mitochondria-centric effects to cytosolic vesicle biology. PMID- 29477617 TI - Sleep in adults with ADHD: Systematic review and meta-analysis of subjective and objective studies. AB - Sleep alterations associated with adulthood ADHD are poorly understood. Here, we conducted the first meta-analysis of sleep studies in adults with ADHD. Based on a pre-registered protocol (PROSPERO-CRD42017065407), we searched Pubmed, Ovid and Web of Knowledge databases through August 3rd, 2017, with no language or publication type restrictions, and contacted study authors for unpublished data/information. From a pool of 8812 references, we retained 13 studies. Random effects models were performed and study quality was rated using the Newcastle Ottawa Scale. Compared to adults without ADHD, those with ADHD significantly differed in seven out of nine subjective parameters (Standardized Mean Difference, SMD, ranging from 0.56 to 1.55) and two out of five actigraphic parameters [SMD (95% CI): sleep onset latency: 0.80 (0.46-1.14); sleep efficiency: -0.68 (-1.03, -0.34)]. No significant differences were detected for polysomnographic parameters. We conclude that, whereas subjectively reported sleep problems are significantly associated with ADHD in adults and should be systematically screened during the clinical interview, additional research is needed to understand if they are underpinned by objective sleep alterations. PMID- 29477616 TI - The role of the cerebellum in multiple sclerosis-150 years after Charcot. AB - Despite its functional importance and well known clinical impact in Multiple Sclerosis (MS), the cerebellum has only received significant attention over the past few years. It is now established that the cerebellum plays a key role not only in various sensory-motor networks, but also in cognitive-behavioural processes, domains primarily affected in patients with MS. Evidence from histopathological and magnetic resonance imaging (MRI) studies on cerebellar involvement in MS is increasingly available, however linking these pathological findings with clinical dysfunction remains challenging. There are promising advances in technology that are likely to improve the detection of pathological changes within the cerebellum, which may elucidate how pathology relates to disability. PMID- 29477618 TI - Overexpression of COPS3 promotes clear cell renal cell carcinoma progression via regulation of Phospho-AKT(Thr308), Cyclin D1 and Caspase-3. AB - The third subunit of the COP9 signalosome (COPS3) is associated with cell proliferation and tumorigenesis process in cancer. The present study showed that the expression level of COPS3 was upregulated in malignant cell lines and COPS3 overexpression was related with clinical stage, T stage, historical grade. Kaplan Meier survival curves showed that COPS3 may function as a prognostic factor for overall survival. CCK-8 and colony formation assays revealed that knockdown of COPS3 in ACHN and 786-O significantly impacted proliferation in vitro. In addition, flow cytometry showed that inhibition of COPS3 induced G0/G1 arrest and promoted apoptosis. COPS3 may promote kidney cancer progression by altering Phospho-AKT(Thr308), Cyclin D1 and Caspase-3 expression. Collectively, Our findings suggest that COPS3 may be a new potential target of ccRCC. PMID- 29477619 TI - Transarterial Chemoembolization within First 3 Months of Sorafenib Initiation Improves Overall Survival in Hepatocellular Carcinoma: A Retrospective, Multi Institutional Study with Propensity Matching. AB - PURPOSE: The impact of transarterial chemoembolization after initiation of sorafenib (SOR) has not been prospectively compared with SOR alone in unresectable hepatocellular carcinoma (HCC). The objective of this study was to assess whether SOR + transarterial chemoembolization provides benefit over SOR alone in this setting. MATERIALS AND METHODS: A retrospective cohort study with propensity matching using data from patients prescribed SOR for HCC at Veterans Health Administration hospitals from 2007 to 2015. The primary outcome was overall survival from the time of SOR prescription and stratified by receipt of transarterial chemoembolization within 90 days of SOR initiation. RESULTS: A total of 4,896 patients received SOR for HCC, of whom 232 (4.7%) underwent transarterial chemoembolization within 90 days. Patients receiving transarterial chemoembolization + SOR were highly selected, being younger and with less significant hepatic dysfunction, earlier Barcelona Clinic Liver Cancer stage (P < .0001), and fewer tumors with lower rates of macrovascular invasion (MVI) and metastases (all P < .0001) than SOR-alone patients. In unadjusted analysis, SOR + transarterial chemoembolization was associated with reduced mortality (hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.53-0.71; P < .0001). After propensity matching, SOR + transarterial chemoembolization continued to show significant associations with reduced mortality with HR 0.75 (95% CI 0.62-0.92; P = .0005). Subgroup analysis suggests that the addition of transarterial chemoembolization to SOR improves outcomes in most patients, particularly those with Model for End-Stage Liver Disease score <15, platelets >50,000/MUL, and >3 tumors with or without macrovascular invasion, without local invasion or metastases. CONCLUSIONS: Patients with unresectable HCC started on systemic therapy with SOR appear to benefit from adjuvant transarterial chemoembolization. Optimal application of multimodal therapy in this setting should be prospectively investigated. PMID- 29477620 TI - Isolated Arteries Originating from the Intrahepatic Arteries: Anatomy, Function, and Importance in Intervention. AB - Isolated hepatic arteries are defined as hepatic terminal arterioles that are not accompanied by portal venules or bile ductules and penetrate the liver parenchyma and distribute to the hepatic capsule and intrahepatic hepatic veins. Abundant communications exist between intra- and extrahepatic arteries through isolated arteries and capsular arterial plexus. They play a principal role in the development of subcapsular hemorrhage and arterial collateral formation following transcatheter arterial chemoembolization for liver cancers. The anatomy, function, and clinical importance of isolated hepatic arteries in interventional radiology, especially regarding subcapsular hemorrhage and arterial collateral formation, are highlighted in this article. PMID- 29477621 TI - Early Results of Transcatheter Arterial Embolization for Relief of Chronic Shoulder or Elbow Pain Associated with Tendinopathy Refractory to Conservative Treatment. AB - PURPOSE: To evaluate the effectiveness and safety of transcatheter arterial embolization to relieve pain associated with shoulder and elbow tendinopathy refractory to conservative treatment. MATERIALS AND METHODS: This study included 13 patients (15 cases) who underwent embolization between November 2015 and December 2016 to treat chronic shoulder pain (6 with rotator-cuff tendinopathy, 2 with calcific tendinitis) or elbow pain (7 with lateral epicondylitis) refractory to conservative treatment. Microspheres were used in the first 4 cases, and imipenem/cilastatin sodium was used in the remaining 11. Visual analog scale (VAS) score changes were recorded. Decrease in VAS score and degree of enhancement on digital subtraction angiography were compared. RESULTS: The technical and clinical success rates were 100% (15/15) and 73% (11/15), respectively. The mean VAS scores at baseline, 1 day, 1 week, 1 month, and 4 months after embolization were 6.1, 5.8, 5.1, 4.3, and 2.5, respectively (P < .05 after 1 wk). Pain improved in 9 of 10 cases (90%) with "evident" enhancement and 3 of 5 cases (60%) with no evident enhancement. The VAS scores in the evident enhancement group decreased more than those in patients with no evident enhancement (4.5 vs 1.8; P < .05). Forearm cutaneous erythema was noted in 1 patient treated with microspheres. CONCLUSIONS: Transcatheter arterial embolization may be an option for relieving pain associated with chronic shoulder and elbow tendinopathy refractory to conservative treatment. The degree of angiographic enhancement might be a possible factor affecting the degree of pain relief after embolization. PMID- 29477622 TI - Safety and Efficacy of Repeat Embolization for Recurrent Hemoptysis: A 16-Year Retrospective Study Including 223 Patients. AB - PURPOSE: To assess safety, efficacy, and long-term outcome of repeat bronchial artery embolization (BAE) for recurrent hemoptysis. MATERIALS AND METHODS: This was a retrospective study of patients referred for repeat BAE to manage recurrent hemoptysis after initial successful embolization. BAE was performed in 223 patients; 36 (16.1%) of these patients underwent 59 repeat BAE procedures because of recurring symptoms. The most frequent underlying lung diseases were bronchiectasis (n = 8; 22%), cystic fibrosis (n = 7; 19%), and idiopathic hemoptysis (n = 7; 19%). RESULTS: Most patients (64%) underwent 2 embolization procedures owing to vessel recanalization (71%) as the most frequent pathophysiologic mechanism of recurrent hemoptysis. No serious adverse events requiring prolonged hospital stay were noted. Risk for relapse of hemoptysis was significantly lower for bronchiectasis compared with other chronic infections (P = .0022) and cystic fibrosis (P = .0004). Overall survival after 3-year and 5 year follow-up was 92% and 84%, respectively. CONCLUSIONS: Repeat BAE for recurrent hemoptysis after initial successful BAE is safe and efficacious, especially in patients with bronchiectasis as the underlying lung disease. PMID- 29477623 TI - Uterine Artery Embolization for Pedunculated Subserosal Leiomyomas: Evidence of Safety and Efficacy. AB - PURPOSE: To evaluate safety and efficacy of uterine artery embolization (UAE) for pedunculated subserosal (PS) leiomyomas. MATERIALS AND METHODS: Of 1,069 patients who underwent UAE for symptomatic leiomyomas or adenomyosis from 2007 to 2016, 55 patients (mean age 40.3 y +/- 4.8) with 66 PS leiomyomas (mean diameter 6.61 cm +/- 2.04) were enrolled. Each PS leiomyoma was categorized into 1 of 2 groups: high-risk PS leiomyoma (stalk diameter < 25% of diameter of leiomyoma) and low risk PS leiomyoma (stalk diameter 25%-50% of diameter of leiomyoma). MR imaging was performed 3 months after UAE. Rates of infarction and volume reduction were compared between PS leiomyomas and non-PS dominant leiomyomas and between high risk and low-risk PS leiomyomas. Complications related to PS leiomyomas were assessed. RESULTS: At a median follow-up of 96 days (range, 36-348 d) after UAE, none of the patients (0%) had complications related to PS leiomyomas, even among high-risk cases. Mean volume reductions of 38.2% and 38.4% were achieved for PS leiomyomas and non-PS dominant leiomyomas, respectively (P = .953). There were 3 (5.5%) minor adverse events, but none were related to PS leiomyoma. There was no significant difference in volume reduction and infarction rates between low-risk and high-risk PS leiomyomas. CONCLUSIONS: UAE is safe and effective in patients with PS leiomyomas even for high-risk cases (stalk diameter < 25% of diameter of leiomyoma). PS leiomyoma should not be considered a contraindication for UAE. PMID- 29477624 TI - Endovascular Removal of Inferior Vena Cava Filters with Arterial Penetration. AB - PURPOSE: To evaluate the safety and outcomes of endovascular percutaneous removal of inferior vena cava filters (IVCFs) with elements penetrating an artery. MATERIALS AND METHODS: From an IVCF retrieval database, computerized tomographic scans of patients who underwent IVCF retrieval from 2011 to 2017 were reviewed for IVCF elements penetrating through the caval wall and into an adjacent arterial wall (AW) or penetrating into an adjacent arterial lumen (AL). Forty-two patients were identified, including 20 with elements penetrating into an AW and 22 with elements penetrating into an AL; 30 of these IVCFs were tip embedded. RESULTS: All of the filters in both groups were removed. Of the arterial interacting filters, 9 were removed with the use of standard techniques and 33 with the use of endobronchial forceps. Arterial access was obtained before removal in 3 patients (7%) with post-removal arteriography revealing no abnormalities, such as extravasation, pseudoaneurysm, or new fractured components. There was no significant difference between groups in tip embedding, retrieval technique, or fluoroscopy time. CONCLUSIONS: Endovascular removal of IVCFs with elements that have penetrated into adjacent arterial walls or lumens can be performed safely in the majority of patients. PMID- 29477625 TI - Chitosan-Based Hydrogel Microparticles for Treatment of Carcinoma in a Rabbit VX2 Liver Tumor Model. AB - PURPOSE: To investigate potential of chitosan hydrogel microparticles (CHI) for treatment of VX2 carcinoma. MATERIALS AND METHODS: Two weeks after liver VX2 implantation, contrast-enhanced computerized tomographic scanning was conducted. Rabbits (n = 2) with successful tumor growth were treated with different sizes of 99mTc-labeled CHI (60-80 MUm and 100-120 MUm) via intra-arterial hepatic catheterization. Liver distribution of 99mTc-labeled CHI was determined by means of autoradiography, a radiation-based photographic technique. In the next part of this study, therapeutic effectiveness was examined with the use of CHI with the size range of 60-80 MUm (n = 11). Tumor growth response and levels of blood liver enzymes were studied at baseline and 1 and 2 weeks after CHI treatment. RESULTS: Successful tumor growth was confirmed in all rabbits (24/24). Intrahepatic CHI with the size range of 60-80 MUm resulted in liver localization in more close proximity to tumor nodule versus 100-120 MUm. Baseline tumor volume was 1,909 +/- 575 mm3 in animals receiving CHI versus 1,831 +/- 249 mm3 in control animals (P = .342). In control animals, tumor volume markedly increased by 1,544 +/- 512% at 2 weeks after sham operation versus baseline. In animals receiving CHI, tumor volume remained relatively unchanged (54 +/- 6% increase; P = .007 vs control). Levels of blood aspartate transaminase (AST) and alanine transaminase (ALT) in animals receiving CHI increased 1 week after treatment (P = .032 vs control for AST; P = .000 vs control for ALT), but returned to control levels at 2 weeks. CONCLUSIONS: CHI embolization suppressed tumor growth without appreciable damages in liver function. PMID- 29477626 TI - Towards a complete characterisation of guaiacwood oil. AB - Guaiacwood oil is a common perfume ingredient used in modern compositions for its suave woody-rosy scent. This essential oil is a byproduct of the timber industry obtained by hydrodistillation of the heartwood of Bulnesia sarmientoi, a tree native from Latin America. Despite being widely used in perfumery, guaiacwood oil has been poorly described in the past. This study aims at giving an in-depth characterisation of its chemical composition as well as disclosing the odorant compounds responsible for its characteristic fragrance. Our methodology was based on a combination of fractionation and analytical techniques, including comprehensive two-dimensional gas chromatography coupled to mass spectrometry and preparative capillary-gas chromatography. The entire analytical work led to the isolation of 20 constituents among which 14 have never been reported so far in natural extracts. Each isolated compound was fully characterised by spectroscopic methods. Finally, the accurate knowledge of the chemical composition permitted the identification of the odour-active constituents by gas chromatography olfactometry. PMID- 29477627 TI - Tyrosine biosynthesis, metabolism, and catabolism in plants. AB - L-Tyrosine (Tyr) is an aromatic amino acid (AAA) required for protein synthesis in all organisms, but synthesized de novo only in plants and microorganisms. In plants, Tyr also serves as a precursor of numerous specialized metabolites that have diverse physiological roles as electron carriers, antioxidants, attractants, and defense compounds. Some of these Tyr-derived plant natural products are also used in human medicine and nutrition (e.g. morphine and vitamin E). While the Tyr biosynthesis and catabolic pathways have been extensively studied in microbes and animals, respectively, those of plants have received much less attention until recently. Accumulating evidence suggest that the Tyr biosynthetic pathways differ between microbes and plants and even within the plant kingdom, likely to support the production of lineage-specific plant specialized metabolites derived from Tyr. The interspecies variations of plant Tyr pathway enzymes can now be used to enhance the production of Tyr and Tyr-derived compounds in plants and other synthetic biology platforms. PMID- 29477628 TI - Corrigendum to "Barhl1 is required for the differentiation of inner ear hair cell like cells from mouse embryonic stem cells" [Int. J. Biochem. Cell Biol. 96 (2018) 79-89]. PMID- 29477629 TI - The use of a low-literacy version of the Medicaid sterilization consent form to assess sterilization-related knowledge in Spanish-speaking women: results from a randomized controlled trial. AB - OBJECTIVE: To learn whether a version of the Medicaid Sterilization Consent Form (SCF) adapted for populations of low-literacy can help Spanish-speaking women better understand the process and consequences of tubal sterilization. STUDY DESIGN: We randomly assigned Spanish-speaking women, ages 21-45 years, to review either a "standard" or "low-literacy" version of the Medicaid SCF. We assessed sterilization-related knowledge using items from the Postpartum Tubal Sterilization Knowledge questionnaire, using as the primary outcome correct identification of least four or more knowledge items and as secondary outcome participants' preferred version of the SCF. RESULTS: Overall sterilization related knowledge was low in both groups, with 33% of women (n=100) who reviewed the standard SCF form and 42% of those who reviewed the low-literacy form (n=100) correctly identifying four or more knowledge-related items (p=.19). Regarding specific items, women in the low-literacy SCF group were more likely than those in the standard SCF group to understand the permanence of sterilization (69% versus 49%, p<.01) and the time requirement between signing the consent document and undergoing sterilization (79% versus 59%, p<.01). The groups were similar in appreciating availability of equally effective nonpermanent contraceptive options (71% versus 64%, p=.29), time from signing to expiration (33% versus 38%, p=.46), or non-binding nature of sterilization consent (55% versus 62%, p=.32). Overall, 71% of participants from both groups preferred the low-literacy form. CONCLUSION: In our patient population, characterized by low educational attainment and inadequate health literacy skills, a low-literacy SCF did not improve overall sterilization-related knowledge when compared to the standard SCF. The low literacy version did improve understanding of the permanence of sterilization and time requirements to undergo the procedure. IMPLICATIONS: Neither form conveyed an adequate level of knowledge to this vulnerable Spanish-speaking population. Therefore, a considerable need persists for detailed education regarding availability of equally effective reversible contraceptive options, procedure related risks, and permanence of sterilization throughout the process of informed consent. PMID- 29477630 TI - A qualitative study of digoxin injection before dilation and evacuation. AB - OBJECTIVE: We sought to qualitatively understand patients' experiences with digoxin as a step before dilation and evacuation (D&E). STUDY DESIGN: We recruited English-speaking women from one abortion health center where digoxin is routinely used before D&E. We interviewed participants one to three weeks after the D&E about physical and emotional experiences with digoxin and understanding of its purpose. Using grounded theory, we analyzed transcripts iteratively, identifying themes from interviews; we stopped recruitment when we reached thematic saturation. RESULTS: We conducted 20 interviews and participants described mixed experiences. Three overarching themes from the qualitative interviews were: (1) physical and emotional discomfort; (2) varied understanding of digoxin's purpose and effects; and (3) reassurance. Most participants described significantly negative experiences with digoxin; however, many participants also described positive aspects of the injection intermingled with those negative experiences. CONCLUSIONS: Participants' experiences with digoxin before D&E were both polarized and nuanced. While participants were largely clear about digoxin's action, they were much less clear about the reason for its use. IMPLICATIONS: Both the clinical purpose for and patients' experiences with digoxin before D&E are complicated. Providers who continue to use digoxin should consider patient preferences in how they offer digoxin, and consider tools to ensure patient understanding. PMID- 29477631 TI - What are people looking for when they Google "self-abortion"? AB - OBJECTIVE: To examine the motivations and circumstances of individuals seeking information about self-abortion on the Internet. STUDY DESIGN: We identified 26 terms that we anticipated someone might use to find information about self abortion on the internet. Users who entered these terms into the Google search engine were provided with a link to our survey via Google AdWords. We fielded the survey over a 32-day period; users were eligible if accessing the survey from a US-based device. We examined demographic characteristics of the sample, reasons for searching for information on self-abortion, knowledge of the legality of abortion and of nearby providers, and top performing keywords. RESULTS: Our Google AdWords campaign containing the survey link was shown approximately 210,000 times, and clicked 9,800 times; 1,235 respondents completed the survey. The vast majority of the sample was female (96%), and 41% were minors. Almost three-quarters (73%) indicated that they were searching for information because they were pregnant and did not or may not want to be. Eleven percent had ever attempted to self-abort. One-third of respondents did not know if abortion was legal in their state of residence, and knowledge of legality did not differ by age. CONCLUSIONS: There is interest in learning more about self-abortion on the Internet. Our findings suggest that, among those who participated in our survey, online searches for information on self-abortion may be driven by adolescents and young adults facing an unintended pregnancy. IMPLICATIONS: Young women, in particular, may have an unmet need for information about safe and accessible abortion options. PMID- 29477632 TI - Effect of counseling quality on anxiety, grief, and coping after second-trimester abortion for pregnancy complications. AB - OBJECTIVE: We sought to explore the relationship between counseling quality, measured by shared decision making and decision satisfaction, and psychological outcomes (anxiety, grief, and posttraumatic stress) after second-trimester abortion for pregnancy complications. STUDY DESIGN: We conducted a cross sectional study of women who underwent second-trimester abortion for complications. We recruited participants from Facebook and online support groups and surveyed them about counseling experiences and psychosocial issues. We used multivariate linear regression to evaluate relationships between counseling quality and psychological outcomes. RESULTS: We analyzed data from 145 respondents. Shared decision making and decision satisfaction scores were positively and strongly correlated in bivariate analysis (r=0.7, p<.0001), as were posttraumatic stress and grief scores (r=0.7, p<.0001). In the adjusted analysis, higher decision satisfaction was associated with lower grief and posttraumatic stress scores (p=.02 and p=.01, respectively) and higher shared decision making was associated with lower posttraumatic stress scores (p=.01). CONCLUSIONS: Decision satisfaction and shared decision making have a positive effect on psychological outcomes after second-trimester abortion for pregnancy complications. Counseling quality may be especially important in this setting given the sensitive nature of decisions regarding pregnancy termination for complications. IMPLICATION: These results highlight the importance of patient centered counseling for women seeking pregnancy termination. PMID- 29477633 TI - Heavy menstrual bleeding: is tranexamic acid a safe adjunct to combined hormonal contraception? PMID- 29477634 TI - Clearance of carbapenem-resistant Enterobacteriaceae vs vancomycin-resistant enterococci carriage after faecal microbiota transplant: a prospective comparative study. AB - BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE) and vancomycin resistant enterococci (VRE) carriage are increasing worldwide. Faecal microbiota transplantation (FMT) appears to be an attractive option for decolonization. This study aimed to evaluate CRE vs VRE clearance by FMT among carriers. METHODS: A multi-centre trial was undertaken on patients with CRE or VRE digestive tract colonization who received FMT between January 2015 and April 2017. Adult patients with CRE or VRE colonization, confirmed by three consecutive rectal swabs at weekly intervals, including one in the week prior to FMT, were included in the study. Patients with immunosuppression or concomitant antibiotic prescription at the time of FMT were excluded. Successful decolonization was determined by at least two consecutive negative rectal swabs [polymerase chain reaction (PCR) and culture] on Days 7, 14, 21 and 28, and monthly for three months following FMT. RESULTS: Seventeen patients were included, with a median age of 73 years [interquartile range (IQR) 64.3-79.0]. Median duration of carriage of CRE or VRE before FMT was 62.5 days (IQR 57.0-77.5). One week after FMT, three of eight patients were free of CRE colonization and three of nine patients were free of VRE colonization. After three months, four of eight patients were free of CRE colonization and seven of eight patients were free of VRE colonization. Qualitative PCR results were concordant with culture. Six patients received antibiotics during follow-up, three in each group. No adverse events were reported. CONCLUSION: CRE and VRE clearance rates were not significantly different in this study, possibly due to the small sample size, but a trend was observed. These data should be confirmed by larger cohorts and randomized trials. PMID- 29477635 TI - What Can Immunologists Learn from Systems Approaches? PMID- 29477638 TI - Mixed Hinfinity and passive filtering for switched Takagi-Sugeno fuzzy systems with average dwell time. AB - This paper investigates the mixed Hinfinity and passive filtering problem for switched Takagi-Sugeno (T-S) fuzzy systems with average dwell time (ADT) in both continuous-time and discrete-time contexts. To deal with this problem, a new performance index is proposed for switched systems. This new performance index can be viewed as the mixed weighted Hinfinity and passivity performance index. Based on this new performance index, the weighted Hinfinity filtering problem and the passive filtering problem for switched T-S fuzzy systems can be solved in a unified framework. Combining the multiple Lyapunov functions approach with a matrix decoupling technique, new sufficient conditions for the existence of mixed weighted Hinfinity and passive filters are obtained for switched T-S fuzzy systems. All these conditions are expressed in terms of linear matrix inequalities (LMIs). The desired filters can be constructed by solving these LMIs. Finally, numerical examples and practical examples are provided. PMID- 29477637 TI - Prognostic Value of Molecular Breast Cancer Subtypes based on Her2, ESR1, PGR and Ki67 mRNA-Expression in Muscle Invasive Bladder Cancer. AB - INTRODUCTION: Gene expression analyses have identified similarities between bladder and breast cancer, where clinical risk stratification is based on Her2, ESR1, PGR and Ki67 expression. The aim of the study was to assess the respective marker gene expression in patients treated with radical cystectomy for muscle invasive bladder cancer (MIBC) and to evaluate the applicability of breast cancer subtypes for MIBC risk stratification. MATERIALS & METHODS: 102 patients treated with radical cystectomy for MIBC were assessed. Using routine FFPE tissue and an IVD validated kit, mRNA expression was measured by single step RT-qPCR. Partition test were employed to define cut-off values for high or low marker gene expression. Association of expression with outcome was assessed using Kaplan Meier analysis and multivariate cox regression analysis. Finally, we performed validation of our results in the MD-Anderson cohort (n=57). RESULTS: Cancer specific survival (CSS) was impaired in patients with high gene expression of Her2 (P=0.0009) and ESR1 (P=0.04). In the multivariate regression model Her2 expression remained significant for the prediction of CSS (HR=2.11, CI 1.11-4.21, P=0.024). Furthermore, molecular stratification by breast cancer subgroups was significant (P=0.023) for CSS prediction. Especially the differentiation between Her2-positive and Luminal A (HR=4.41, CI 1.53-18.71, P=0.004) and Luminal B (HR=1.96, CI 0.99-4.08, P=0.053) respectively was an independent prognostic parameter for CSS. External validation resulted in comparable risk stratification with differences in fractional subgroups distribution. CONCLUSION: Gene expression of Her2, ESR1, PGR, Ki67 and corresponding breast cancer subtypes allow a risk-stratification in MIBC, whereby Her2 overexpressing tumors reveal a particularly poor prognosis. PMID- 29477636 TI - Preclinical Analysis of JAA-F11, a Specific Anti-Thomsen-Friedenreich Antibody via Immunohistochemistry and In Vivo Imaging. AB - The tumor specificity of JAA-F11, a novel monoclonal antibody specific for the Thomsen-Friedenreich cancer antigen (TF-Ag-alpha linked), has been comprehensively studied by in vitro immunohistochemical (IHC) staining of human tumor and normal tissue microarrays and in vivo biodistribution and imaging by micro-positron emission tomography imaging in breast and lung tumor models in mice. The IHC analysis detailed herein is the comprehensive biological analysis of the tumor specificity of JAA-F11 antibody performed as JAA-F11 is progressing towards preclinical safety testing and clinical trials. Wide tumor reactivity of JAA-F11, relative to the matched mouse IgG3 (control), was observed in 85% of 1269 cases of breast, lung, prostate, colon, bladder, and ovarian cancer. Staining on tissues from breast cancer cases was similar regardless of hormonal or Her2 status, and this is particularly important in finding a target on the currently untargetable triple-negative breast cancer subtype. Humanization of JAA F11 was recently carried out as explained in a companion paper "Humanization of JAA-F11, a Highly Specific Anti-Thomsen-Friedenreich Pancarcinoma Antibody and In Vitro Efficacy Analysis" (Neoplasia 19: 716-733, 2017), and it was confirmed that humanization did not affect chemical specificity. IHC studies with humanized JAA F11 showed similar binding to human breast tumor tissues. In vivo imaging and biodistribution studies in a mouse syngeneic breast cancer model and in a mouse human xenograft lung cancer model with humanized 124I- JAA-F11 construct confirmed in vitro tumor reactivity and specificity. In conclusion, the tumor reactivity of JAA-F11 supports the continued development of JAA-F11 as a targeted cancer therapeutic for multiple cancers, including those with unmet need. PMID- 29477639 TI - Critical challenges and emerging opportunities in hepatitis C virus research in an era of potent antiviral therapy: Considerations for scientists and funding agencies. AB - The development and clinical implementation of direct-acting antivirals (DAAs) has revolutionized the treatment of chronic hepatitis C. Infection with any hepatitis C virus (HCV) genotype can now be eliminated in more than 95% of patients with short courses of all-oral, well-tolerated drugs, even in those with advanced liver disease and liver transplant recipients. DAAs have proven so successful that some now consider HCV amenable to eradication, and continued research on the virus of little remaining medical relevance. However, given 400,000 HCV-related deaths annually important challenges remain, including identifying those who are infected, providing access to treatment and reducing its costs. Moreover, HCV infection rarely induces sterilizing immunity, and those who have been cured with DAAs remain at risk for reinfection. Thus, it is very unlikely that global eradication and elimination of the cancer risk associated with HCV infection can be achieved without a vaccine, yet research in that direction receives little attention. Further, over the past two decades HCV research has spearheaded numerous fundamental discoveries in the fields of molecular and cell biology, immunology and microbiology. It will continue to do so, given the unique opportunities afforded by the reagents and knowledge base that have been generated in the development and clinical application of DAAs. Considering these critical challenges and new opportunities, we conclude that funding for HCV research must be sustained. PMID- 29477641 TI - NLRP3-dependent synaptic plasticity deficit in an Alzheimer's disease amyloidosis model in vivo. AB - Pro-inflammatory mechanisms have recently emerged as an important component of early Alzheimer's disease (AD) pathogenesis. A particularly attractive therapeutic strategy is to selectively prevent the disruptive effects of activation of the innate immune system in the brain at an early transitional stage by reducing the production or directly neutralizing pro-inflammatory cytokines, in particular IL-1beta and TNF-alpha. Here we tested their in vivo effects on synaptic plasticity deficits, which provide sensitive and robust measures of synaptic failure, in a rat model of AD amyloidosis. Using electrophysiological techniques we longitudinally studied the effects of the NLRP3 inflammasome inhibitor Mcc950, the IL-1 receptor antagonist (anakinra) and an anti-TNF-alpha agent (etanercept) in awake freely moving transgenic rats overexpressing AD associated beta-amyloid precursor protein at a pre-plaque stage of amyloidosis. Repeated treatment with Mcc950 reversibly abrogated the inhibition of long-term potentiation. The IL-1 receptor antagonist and etanercept also had a similar beneficial effect on the deficit in synaptic plasticity. Our findings support the clinical development of Mcc950 and clinically available IL-1 and TNF-alpha-neutralizing agents in early AD. PMID- 29477642 TI - Determination of cesium transfer factors by instrumental neutron activation analysis. AB - Food-chain models are used to predict radionuclide ingestion after fallout deposition. These models include those transfer processes (soil-to-plant transfer factor(s) [TF], plant-to-animal transfer coefficient(s) [TC] and concentration ratio [CR]) that are likely to be important for radiological assessment. The range of variability for transfer factors for the same plant groups is great, about 4-5 orders of magnitude, which limits their applicability. A better way to determine the best estimate the factors for radiocaesium and other important radionuclides is if the site-specific data are available. Soil, plant and animal samples were collected from a pasture area in Hungary during the vegetation period in 2016. Stable 133Cs concentration was analysed by comparative method with neutron activation analysis (NAA). The comparator and the samples were irradiated in thermal neutron flux 2.55 * 1012 ncm-2s-1 for 2 h (soil) and 6 h (vegetation, animal samples) in the TRIGA Mark II research reactor at the Nuclear Engineering Teaching Laboratory. After an appropriate decay time (12 days) the samples were measured by gamma-spectrometry and analysed. The observed stable caesium TCpm (0.48-0.53) and CRpm (0.41-0.45) were very close to 137Cs factors in the IAEA 2009 Report of 0.49 and 0.54, respectively. This methodology is particularly suitable for the simultaneous study of natural caesium in ecosystem compartments. Consequently, the transfer of stable caesium in a pasture field may be regarded as a useful analogy in predicting the long-term changes of 137Cs affected by site-specific environmental factors. PMID- 29477643 TI - Paclitaxel controlled delivery using a pH-responsive functional-AuNP/block copolymer vesicular nanocarrier composite system. AB - Paclitaxel (PTX)-loaded gold nanoparticles functionalized with mercaptooctanoic acid (MOA) and folic acid (FA) (AuMOA-FA) were encapsulated within pH-sensitive poly(2-vinylpyridine)-b-poly(ethylene oxide) (P2VP-PEO) vesicles with the aim to develop a more selective injectable nano-formulation for PTX, lacking the side effects of the conventional PTX delivery system. The size of the resulting composite vesicles was lower than 200 nm, i.e. it is suitable for tumor targeting applications taking advantage of the enhanced permeability and retention (EPR) effect. The vesicles did not aggregate in the presence of high electrolyte concentrations, indicating the colloidal stability of the vesicles. The vesicles did not leak their AuMOA-FA or PTX content at physiological pH of 7.4. However, AuMOA-FA and PTX release were significantly accelerated at acidic pHs resembling tumor environment and acidic intracellular compartments. PTX release from the vesicles at acidic pH apparently follows AuMOA-FA release from the vesicles. Flow cytometry measurements and confocal laser scanning microscopy images showed that the vesicles could enter A549 cancer cells in culture and that cellular uptake increased with time. Blank vesicles did not exhibit cytotoxicity and did not induce apoptosis in A549 cancer cells. The PTX currying vesicles exhibited comparable or a little higher cytotoxicity than free PTX. Both the PTX currying vesicles and free PTX induced A549 cells apoptosis, however the vesicle encapsulated PTX induced a higher percentage of late apoptotic cells than free PTX. PMID- 29477640 TI - Differential effect of amyloid beta peptides on mitochondrial axonal trafficking depends on their state of aggregation and binding to the plasma membrane. AB - Inhibition of mitochondrial axonal trafficking by amyloid beta (Abeta) peptides has been implicated in early pathophysiology of Alzheimer's Disease (AD). Yet, it remains unclear whether the loss of motility inevitably induces the loss of mitochondrial function, and whether restoration of axonal trafficking represents a valid therapeutic target. Moreover, while some investigations identify Abeta oligomers as the culprit of trafficking inhibition, others propose that fibrils play the detrimental role. We have examined the effect of a panel of Abeta peptides with different mutations found in familial AD on mitochondrial motility in primary cortical mouse neurons. Peptides with higher propensity to aggregate inhibit mitochondrial trafficking to a greater extent with fibrils inducing the strongest inhibition. Binding of Abeta peptides to the plasma membrane was sufficient to induce trafficking inhibition where peptides with reduced plasma membrane binding and internalization had lesser effect on mitochondrial motility. We also found that Abeta peptide with Icelandic mutation A673T affects axonal trafficking of mitochondria but has very low rates of plasma membrane binding and internalization in neurons, which could explain its relatively low toxicity. Inhibition of mitochondrial dynamics caused by Abeta peptides or fibrils did not instantly affect mitochondrial bioenergetic and function. Our results support a mechanism where inhibition of axonal trafficking is initiated at the plasma membrane by soluble low molecular weight Abeta species and is exacerbated by fibrils. Since trafficking inhibition does not coincide with the loss of mitochondrial function, restoration of axonal transport could be beneficial at early stages of AD progression. However, strategies designed to block Abeta aggregation or fibril formation alone without ensuring the efficient clearance of soluble Abeta may not be sufficient to alleviate the trafficking phenotype. PMID- 29477644 TI - Improvement of Tenofovir vaginal release from hydrophilic matrices through drug granulation with hydrophobic polymers. AB - Sustained-release vaginal microbicides hold out great hope for the prevention of sexual transmission of HIV from men to women. Tenofovir (TFV) -an antiretroviral drug- sustained-release vaginal compacts combining two release control systems (by drug-loading granules with hydrophobic polymers and incorporating them in a hydrophilic matrix) are proposed in this work as a possible microbicide. The polymers used for the drug granules are Eudragit(r) RS (ERS), an acrylic derivative, and Zein, a maize protein. The hydrophilic matrix is composed of a mixture of hydroxypropylmethyl cellulose (HPMC) and chitosan (CH). The thermal, microscopic, spectrophotometric and X-ray diffraction analysis showed that the drug was not altered during the granulation process. Studies of TFV release, swelling and ex vivo mucoadhesion were subsequently performed on simulated vaginal fluid. The formulation whereby TFV is granulated using twice its weight in ERS, and then including these granules in a matrix in which the CH predominates over HPMC, allows the sustained release of TFV for 144 h, mucoadhesion to the vaginal mucosa for 150 h and a moderate swelling, making it the most suitable formulation of all those studied. These compacts would therefore offer women protection against the sexual acquisition of HIV. PMID- 29477645 TI - Marrow adiposity and bone: Review of clinical implications. AB - There is growing interest in the relationship between bone marrow fat (BMF) and skeletal health. Progress in clinical studies of BMF and skeletal health has been greatly enhanced by recent technical advances in our ability to measure BMF non invasively. Magnetic resonance imagery (MRI) with or without spectroscopy is currently the standard technique for evaluating BMF content and composition in humans. This review focuses on clinical studies of marrow fat and its relationship with bone. The amount of marrow fat is associated with bone mineral density (BMD). Several studies have reported a significant negative association between marrow fat content and BMD in both healthy and osteoporotic populations. There may also be a relationship between marrow fat and fracture (mostly vertebral fracture), but data are scarce and further studies are needed. Furthermore, a few studies suggest that a lower proportion of unsaturated lipids in vertebral BMF may be associated with reduced BMD and greater prevalence of fracture. Marrow fat might be influenced by metabolic diseases associated with bone loss and fractures, such as diabetes mellitus, obesity and anorexia nervosa. An intriguing aspect of bariatric (weight loss) surgery is that it induces bone loss and fractures, but with different impacts on marrow fat depending on diabetic status. In daily practice, the usefulness for clinicians of assessing marrow fat using MRI is still limited. However, the perspectives are exciting, particularly in terms of improving the diagnosis and management of osteoporosis. Further studies are needed to better understand the regulators involved in the marrow fat-bone relationship and the links between marrow fat, other fat depots and energy metabolism. PMID- 29477646 TI - Persistence of pain quality in community-dwelling older adults with chronic non cancer pain. AB - Longitudinal assessment of chronic geriatric pain is complicated by an age associated plateau in pain severity and increase in widespread pain, calling for innovative measures such as pain quality descriptors that characterize how pain may feel. We characterized persistence of pain quality and its relation to severity, activity interference and distribution of sites, in a population-based sample of adults aged>=70 years with chronic pain (n = 398). Persistent pain quality was defined as reporting descriptors within the same category: sensory, cognitive/affective, or neuropathic at baseline and 18 months. A count variable indicated number of persistent categories. Pain quality was highly persistent. Adjusted for baseline covariates, individuals endorsing 3 persistent categories were 2-2.5x more likely to experience more widespread pain at 18 months compared to fewer persistent categories. No associations were noted in changes in pain severity or interference. A comprehensive pain assessment that includes diverse pain quality descriptors may improve individualized pain management. PMID- 29477647 TI - Restorative activities among bereaved caregivers of nursing home patients. AB - This prospective study examined predictors and correlates of restorative activities in recently bereaved caregivers and their relation to post-bereavement adjustment, namely complicated grief. Participants included 89 caregivers (CGs) age 32-87 (M age - 63 years) whose care recipients recently died in a long-term care facility (M time since loss = 107 days). Our findings show that being prepared prior to death enables CGs the opportunity to engage in restorative activities post death. Restorative activities partially mediated the relationship between preparedness prior to death and complicated grief, but this association was attenuated in multivariable models. It is possible that being prepared prior to death allows CGs to engage in restorative activities post-death, which in turn decreases complicated grief. More research is needed in diverse populations of CGs to determine how restorative activities may impact post-bereavement adjustment. PMID- 29477648 TI - Hybrid process, electrocoagulation-biofiltration for landfill leachate treatment. AB - Landfill leachates are known for their high and complex composition of organic, inorganic and microbial pollutants. As a result, it is quite challenging to treat these effluents by using only one treatment process. A combining approach is generally required to treat efficiently these wastewaters and comply with the discharge standards. In this present study, electrocoagulation (EC) and biofiltration (BF) processes were sequentially used to treat landfill leachate. EC process has been able to remove 37 +/- 2% of the initial total COD. A fractionation of organic compounds showed that EC was particularly efficient to remove insoluble COD and humic acids. In addition, other pollutants such as turbidity, true color, Zn and phosphorus were significantly reduced by EC with 82 +/- 2.7%, 60 +/- 13%, 95 +/- 2.6% and 82 +/- 5.5% of removal respectively. The subsequent treatment by BF process led to completely removal of ammonia pollution (>99% of NH4 removal) and a partial removal of dissolved organic compounds (42 +/ 7% of COD removal). The hybrid process EC/BF could form the basis of a process capable of removing organic and inorganic pollutants from many refractory wastewaters (mature landfill leachates, industrial and municipal wastewaters). PMID- 29477649 TI - Anaerobic digestion of thermal pre-treated emulsified slaughterhouse wastes (TESW): Effect of trace element limitation on process efficiency and sludge metabolic properties. AB - Slaughterhouse solid wastes, characterized by a high lipid content, are considered a valuable resource for energy production by means of anaerobic digestion technologies. Aim of this study was to examine the effect of trace element limitation on the mesophilic anaerobic digestion of thermally pre-treated emulsified slaughterhouse wastes (TESW). Under two distinct experimental periods (Period I - low and Period II - high trace element dosage respectively) a CSTR with sludge recirculation was operated at increasing organic loading rate (OLR) from 1.5 to 10 g L-1 d-1. Under optimum conditions, COD removal was higher than 96%, biogas yield equal to 0.53 L g-1 COD feed and the biogas methane content 77%. Trace element limitation however, resulted in a dramatic decline in process efficiency, with VFA accumulation and events of extreme sludge flotation, despite that the soluble concentration of Ni, Co and Mo were between 12 and 28 MUg L-1. This is indicative of mass transfer limitations caused by lipids adsorption onto the anaerobic biomass. PMID- 29477650 TI - A comparison of on-line and off-line bioaerosol measurements at a biowaste site. AB - An air measurement campaign was carried out at a green-waste composting site in the South of Ireland during Spring 2016. The aim was to quantify and identify the levels of Primary Biological Aerosol Particles (PBAP) that were present using the traditional off-line, impaction/optical microscopy method alongside an on-line, spectroscopic approach termed WIBS (Wideband Integrated Bioaerosol Sensor), which can provide number concentrations, sizes and "shapes" of airborne PBAP in real time by use of Light Induced Fluorescence (LIF). The results from the two techniques were compared in order to validate the use of the spectroscopic method for determining the releases of the wide-range of PBAP present there as a function of site activity and meteorological conditions. The seven-day monitoring period undertaken was much longer than any real-time studies that have been previously performed and allowed due comparison between weekday (working) activities at the site and weekend (closed) releases. The time-span also allowed relationships between site activities like turning, agitation or waste delivery and the WIBS data to be determined in a quantitative manner. This information cannot be obtained with the Andersen Sampling methods generally employed at green waste management sites. Furthermore, few specific bioaerosol types other than Aspergillus fumigatus, are identified using the traditional protocols employed for site licensing purposes. Here though the co-location of WIBS with the impaction instrument made it possible to identify the real-time release behaviour of a specific plant pathogenic spore, Ustilago maydis, present after green-waste deliveries were made by a local distillery. PMID- 29477651 TI - Effect of chemical pretreatment on pyrolysis of non-metallic fraction recycled from waste printed circuit boards. AB - The non-metallic fraction from waste printed circuit boards (NMF-WPCB) generally consists of plastics with high content of Br, glass fibers and metals (e.g. Cu), which are normally difficult to dispose. This work aims to study the chemical pretreatments by using alkalis, acids and alkali-earth-metal salts on pyrolysis of NMF-WPCB. Char (60-79%) and volatile matter (21-40%) can be produced via the pyrolysis process. In particular, the ash content can reach up to 42-56%, which was attributed to the high content of glass fibers and other minerals. Copper (Cu, 2.5%), calcium (Ca, 28.7%), and aluminum (Al, 6.9%) were the main metal constituents. Meanwhile, silicon (Si, 28.3%) and bromine (Br, 26.4%) were the predominant non-metallic constituents. The heavy metals such as Cu were significantly reduced by 92.4% with the acid (i.e. HCl) pretreatment. It has been proved that the organic Br in the plastics (e.g. BFR) can be transformed into HBr via the pyrolysis process at relatively high temperature. It was noteworthy that the alkali pretreatment was more benefit for the Br fixation in the solid char. Particularly, the Br fixation efficiency can reach up to 53.6% by the sodium hydroxide (NaOH) pretreatment with the pyrolysis process. The formed HBr can react with NaOH to generate NaBr. PMID- 29477652 TI - A review of the fate of engineered nanomaterials in municipal solid waste streams. AB - Significant knowledge and data gaps associated with the fate of product-embedded engineered nanomaterials (ENMs) in waste management processes exist that limit our current ability to develop appropriate end-of-life management strategies. This review paper was developed as part of the activities of the IWWG ENMs in Waste Task Group. The specific objectives of this review paper are to assess the current knowledge associated with the fate of ENMs in commonly used waste management processes, including key processes and mechanisms associated with ENM fate and transport in each waste management process, and to use that information to identify the data gaps and research needs in this area. Literature associated with the fate of ENMs in wastes was reviewed and summarized. Overall, results from this literature review indicate a need for continued research in this area. No work has been conducted to quantify ENMs present in discarded materials and an understanding of ENM release from consumer products under conditions representative of those found in relevant waste management process is needed. Results also indicate that significant knowledge gaps associated with ENM behaviour exist for each waste management process investigated. There is a need for additional research investigating the fate of different types of ENMs at larger concentration ranges with different surface chemistries. Understanding how changes in treatment process operation may influence ENM fate is also needed. A series of specific research questions associated with the fate of ENMs during the management of ENM-containing wastes have been identified and used to direct future research in this area. PMID- 29477653 TI - The diagnosis of chronic endometritis in infertile asymptomatic women: a comparative study of histology, microbial cultures, hysteroscopy, and molecular microbiology. AB - BACKGROUND: Chronic endometritis is a persistent inflammation of the endometrial mucosa caused by bacterial pathogens such as Enterobacteriaceae, Enterococcus, Streptococcus, Staphylococcus, Mycoplasma, and Ureaplasma. Although chronic endometritis can be asymptomatic, it is found in up to 40% of infertile patients and is responsible for repeated implantation failure and recurrent miscarriage. Diagnosis of chronic endometritis is based on hysteroscopy of the uterine cavity, endometrial biopsy with plasma cells being identified histologically, while specific treatment is determined based on microbial culture. However, not all microorganisms implicated are easily or readily culturable needing a turnaround time of up to 1 week. OBJECTIVE: We sought to develop a molecular diagnostic tool for chronic endometritis based on real-time polymerase chain reaction equivalent to using the 3 classic methods together, overcoming the bias of using any of them alone. STUDY DESIGN: Endometrial samples from patients assessed for chronic endometritis (n = 113) using at least 1 or several conventional diagnostic methods namely histology, hysteroscopy, and/or microbial culture, were blindly evaluated by real-time polymerase chain reaction for the presence of 9 chronic endometritis pathogens: Chlamydia trachomatis, Enterococcus, Escherichia coli, Gardnerella vaginalis, Klebsiella pneumoniae, Mycoplasma hominis, Neisseria gonorrhoeae, Staphylococcus, and Streptococcus. The sensitivity and specificity of the molecular analysis vs the classic diagnostic techniques were compared in the 65 patients assessed by all 3 recognized classic methods. RESULTS: The molecular method showed concordant results with histological diagnosis in 30 samples (14 double positive and 16 double negative) with a matching accuracy of 46.15%. Concordance of molecular and hysteroscopic diagnosis was observed in 38 samples (37 double positive and 1 double negative), with an accuracy of 58.46%. When the molecular method was compared to microbial culture, concordance was present in 37 samples (22 double positive and 15 double negative), a matching rate of 56.92%. When cases of potential contamination and/or noncultivable bacteria were considered, the accuracy increased to 66.15%. Of these 65 patients, only 27 patients had consistent histological + hysteroscopic diagnosis, revealing 58.64% of nonconcordant results. Only 13 of 65 patients (20%) had consistent histology + hysteroscopy + microbial culture results. In these cases, the molecular microbiology matched in 10 cases showing a diagnostic accuracy of 76.92%. Interestingly, the molecular microbiology confirmed over half of the isolated pathogens and provided additional detection of nonculturable microorganisms. These results were confirmed by the microbiome assessed by next generation sequencing. In the endometrial samples with concordant histology + hysteroscopy + microbial culture results, the molecular microbiology diagnosis demonstrates 75% sensitivity, 100% specificity, 100% positive and 25% negative predictive values, and 0% false-positive and 25% false-negative rates. CONCLUSION: The molecular microbiology method describe herein is a fast and inexpensive diagnostic tool that allows for the identification of culturable and nonculturable endometrial pathogens associated with chronic endometritis. The results obtained were similar to all 3 classic diagnostic methods together with a degree of concordance of 76.92% providing an opportunity to improve the clinical management of infertile patients with a risk of experiencing this ghost endometrial pathology. PMID- 29477654 TI - [Metastatic colorectal cancer: To stop or not to stop?] AB - The introduction of new regimens and targeted therapies has prolonged survival in metastatic colorectal cancer from 1 year during the fluoropyrimidines-only era to more than 30 months today. Avoiding the cumulative toxicity of oxaliplatin, but also the physical or psychological asthenia of prolonged chemotherapy, is currently a worthwhile management goal. Data from randomized controlled trials indicate that a formalized stop-and-go approach to the delivery of oxaliplatin does not compromise efficacy. This paper presents also a critical review of the randomized trials evaluating the place of bevacizumab and cetuximab as maintenance therapy. To conclude we recommend chemotherapy holidays only after 4 to 6 months of chemotherapy and only in the population of very good responders to the induction treatment. PMID- 29477655 TI - The HDAC1/c-JUN complex is essential in the promotion of nerve injury-induced neuropathic pain through JNK signaling. AB - Histone deacetylase inhibitors (HDACIs) interfere with the epigenetic process of histone acetylation and are known to have analgesic properties in models of chronic inflammatory pain. Administration of a selective HDAC1 inhibitor (LG325) in SNI-subjected mice significantly attenuated behavior related to injury-induced pain. Understanding the HDAC1 pathway in epigenetic regulation of pathological pain is of great medical relevance. Spared nerve injury (SNI) mice showed a significant increase in the HDAC1 protein levels within spinal cord in coincidence with the nociceptive phenotype at 1 and 3 weeks after nerve injury. No variation in HDAC3, DNMT3a, AcH3, MBD3 and MeCP2 levels was detected. Increased expression of HDAC1 is accompanied by activation of the JNK-c-Jun signaling pathway. A robust spinal JNK-1 overphosphorylation was observed post nerve-injury along with a selective JNK-dependent increase in p-c-Jun and HDAC1 protein levels. Co-immunoprecipitation experiments showed the presence of a heterodimeric complex between HDAC1 and c-Jun in SNI mice indicating that these transcription factors can act together to regulate transcription through heterodimerization. Stimulation of c-Jun phosphorylation was prevented by the selective HDAC1 inhibitor LG325. We found that HDAC1 was associated with c-Jun in nuclei of spinal dorsal horn astrocytes expressing JNK. On the other hand, the presence of HDAC1 and c-Jun interaction was not detected in control mice. These findings provide new insights into the mechanisms underlying the anti-nociceptive activity of HDAC inhibitors. Taken together, these data support a role for histone deacetylase in the emergence of neuropathic pain. PMID- 29477656 TI - Unusual modes of action of the repellent DEET in insects highlight some human side effects. AB - N,N-diethyl-m-toluamide (DEET) induces favorable repellency against insects by acting on the sensory nervous system. According to emerging literature reports, DEET side effects in humans involve new molecular targets including the cholinergic system, acetylcholinesterase (AChE), muscarinic M1 and M3 receptor and the participation of the second messenger nitric oxide (NO). Most of these molecular events targeted by DEET have previously been characterized in insects while they have been considered as marginal compared to classical repellent properties. Despite these uncommon actions in insects, there is no consensus on the effects in human. Based on these data, this review provides new insights on side effects in human and more largely in mammals by identifying the unusual properties of DEET in insects, which seem to be correlated with adverse effects in mammals. These data will be very helpful to understand better the toxicological effects observed in order to protect non-target organisms from the toxicity. PMID- 29477657 TI - Berberine induces miR-373 expression in hepatocytes to inactivate hepatic steatosis associated AKT-S6 kinase pathway. AB - Berberine is a Chinese herbal medicine extracted from rhizoma coptidis that functions to improve insulin resistance, hyperlipidemia, hepatosteatosis and inflammation. Berberine can modify the activity of cell metabolism and signaling pathways by regulating expression of genes. However, the roles and effects of differential microRNA (miRNA) expression induced by berberine treatment are largely unexplored. It is believed that miRNAs expression modified by berberine contributes to its therapeutic effects to diseases such as hepatosteatosis and non-alcoholic fatty liver disease. By identifying novel miRNAs and their putative gene targets associated with abnormal hepatic lipid deposition, the underlying mechanism of these diseases could be established and effective therapies against the diseases could be developed. Here, we used the immortalized hepatocyte cell line MIHA as a model to study the effect of berberine on global miRNA expression profile of hepatocytes. Global miRNA expression levels were measured in berberine treated MIHA cells by quantitative reverse transcription PCR miRNA panel, and the potential berberine regulated miRNAs were then validated in MIHA and HepG2 cells. MicroRNA-373 (MiR-373) was consistently upregulated in both cell lines upon berberine treatments. Gene expression microarray showed that berberine upregulated Early Growth Response 1 (EGR1) level which functioned to transactivate miR-373 expression. Subsequently, we showed that upregulation of miR-373 depleted its target gene AKT serine/threonine kinase 1 (AKT1) mRNA level, which led to the inhibition of AKT-mTOR-S6K signaling pathway in hepatocytes that was critical in the development of hepatosteatosis. Study of the therapeutic effect of manipulating miR-373 against abnormal lipid deposition in liver is warranted. PMID- 29477659 TI - Fever-Induced Paroxysmal Weakness and Encephalopathy (FIPWE)-Part of a Phenotypic Continuum in Patients With ATP1A3 Mutations? PMID- 29477660 TI - Moving forward with actionable therapeutic targets and opportunities in endometrial cancer: A NCI clinical trials planning meeting report. AB - The incidence of endometrial cancer (EC) in the U.S. has been rising, from an estimated annual incidence of 49,560 in 2013 to 61,380 in 2017. Meanwhile, the SEER-based relative survival of women with EC in the U.S. has remained flat [82.3% from 1987 to 1989, 82.8% from 2007 to 2013] and our recent increased understanding of EC biology and subtypes has not been translated into therapeutic advances. The U.S. National Cancer Institute (NCI) therefore convened a Uterine Clinical Trials Planning Meeting in January 2016 to initiate and accelerate design of molecularly-targeted EC trials. Prior to the meeting a group of experts in this field summarized available data, emphasizing data on human samples, to identify potentially actionable alterations in EC, and the results of their work has been separately published. The Clinical Trials Meeting planners focused on discussion of (1) novel trial designs, including window-of opportunity trials and appropriate control groups for randomized trials, (2) targets specific to serous carcinoma and promises and pitfalls of separate trials for women with tumors of this histology (3) specific recommendations for future randomized trials. PMID- 29477658 TI - The potential role of glucokinase activator SHP289-04 in anti-diabetes and hepatic protection. AB - Glucokinase was glucose sensor in hepatocytes and islet beta cells. It not only promoted glucose metabolism, but also advanced glucose-stimulated insulin secretion. Glucokinase activators had been reported as one kind of new potential drugs for treatment of type 2 diabetes. Compound 6-(5-(3-fluorobenzyloxy)-2 ethoxybenzamido) pyridine-3-carboxylic acid (SHP289-04) was found to increase glucokinase activity effectively by our lab. In order to demonstrate its effect of anti-diabetes, in vitro, human liver carcinoma cell line HepG2 was used to glucose consumption test, and pancreatic cell line NIT-1 was used to assess insulin secretion in response to different concentration of glucose (5 mmol/l and 20 mmol/l). Type 2 diabetes model KKAy mice were chose to evaluate the pharmacodynamics of SHP289-04 in vivo. In hepatocytes, SHP289-04 could accelerate glucose consuming. In NIT cell line, it promoted glucose-stimulated insulin secretion at the 20 mmol/l of glucose. Moreover, it normalized oral glucose tolerance test and down-regulated blood lipid level in KKAy mice. At the same time, it ameliorated function of islets and accelerated the ratio of beta cell/alpha cell mass, and also alleviated the fatty liver of KKAy mice. Therefore, SHP289-04 as a glucokinase activator had the potential effect of diabetes treatment. PMID- 29477661 TI - Ash fusion characteristics during co-gasification of biomass and petroleum coke. AB - In this study, the effect of biomass ash on petroleum coke ash fusibility was investigated at a reducing atmosphere. Some analytical methods, such as ash fusion temperatures (AFTs) analysis, X-ray diffraction (XRD), FactSage and scanning electron microscopy (SEM), were applied to determine the characteristics of ash fusion and transformation of mineral matters. The results indicated that AFTs were closely associated with ash mineral compositions. It was found that the formations of high melting point calcium silicate, vanadium trioxide and coulsonite resulted in the high AFTs of Yanqing petroleum coke (YQ). When blending with certain proportional pine sawdust (PS), corn stalk (CS), the AFTs of mixture could be decreased significantly. For PS addition, the formations of low-melting point calcium vanadium oxide should be responsible for the reduction of AFTs, whereas for CS addition the reason was ascribed to the formation of low melting point leucite and the disappearance of high-melting V2O3. PMID- 29477662 TI - Bioremediation of Cephalexin with non-living Chlorella sp., biomass after lipid extraction. AB - In this work, the removal of the Cephalexin by Chlorella sp., nonliving modified by extraction of lipids was evaluated. First, the microalga was grown to completing 20 days and later, the biomass of crop was centrifuged and the extraction of lipids was performed. Two adsorption experiments were performed: (1) with nonliving Chlorella sp. (control), and (2) the obtained biomass after lipid extraction. The high antibiotic removal, 71.19% and 82.77% (control), were obtained at the lowest initial concentration. The contact time between the biosorbent and the antibiotic was 2 h. The adsorption isotherm follows the Freundlich model and the obtained maximum absorption capacity was 63.29 mg of antibiotic/g of biosorbent for lipid-extracted biomass, while the control follows best to the Langmuir model with 129.87 mg/g in maximum absorption capacity. In summary, this biosorbent provides a potential alternative in the removal of Cephalexin. PMID- 29477663 TI - New insight into sludge reduction induced by different substrate allocation strategy between oxygen and nitrate/nitrite as terminal electron acceptor. AB - Sludge reduction based on regulating substrate allocation between catabolism and anabolism as a strategy is proposed to reduce energy and chemicals consumption during wastewater treatment. The results indicated that a sludge reduction of 14.8% and excellent nutrient removal were simultaneously achieved in the low dissolved oxygen (LDO) activated sludge system with a hydraulic retention time of 24 h at 25 degrees C. Denitrifiers comprised nearly 1/4 of all microorganisms in the system. These denitrifiers converted NOx- to N2 obtaining a lower biomass yield. The oxidoreductase activity proteins in the LDO sample was more than twice that of the normal DO sample, indicating that catabolism was stimulated by NOx- when replacing O2 as electron acceptor. Less substrate was used for cell synthesis in the LDO system. Stable sludge reduction without extra energy and chemicals inputs was achieved by regulating the substrate allocation by inducing the bacteria to utilize NOx- instead of O2. PMID- 29477664 TI - The brim of uncertainty in adjuvant treatment of melanoma. PMID- 29477666 TI - Evaluation of resistance gene transfer from heat-treated Escherichia coli. AB - Antimicrobial-resistant Escherichia coli may be present in various foods. The aim of this study was to evaluate the impact of heat treatment, simulating food preparation, on the possibility of antimicrobial resistance genes being transferred from E. coli cells. The study was performed on antimicrobial resistant E. coli cells in suspension in a sterile saline solution. The stability of resistance genes and the possibility of their transfer by transformation or conjugation were analyzed. Results showed that antimicrobial-resistant E. coli cells managing to survive after a few minutes at 60 degrees C retained their antimicrobial resistance. No plasmid could be transferred by conjugation from antimicrobial-resistant E. coli cells heated to 60 degrees C for ten or more minutes. Twelve electroporation experiments were performed using a bacterial suspension heated to 70 degrees C for 30 min. Genes coding for resistance to extended-spectrum cephalosporins, tetracycline or sulfonamides were transferred to an E. coli DH5alpha recipient on two occasions. In conclusion we showed that heat-treated E. coli may occasionally transfer resistance genes. PMID- 29477667 TI - Coracoid graft union: a quantitative assessment by computed tomography in primary and revision Latarjet procedure. AB - BACKGROUND: The goal of the Latarjet procedure is restoration of shoulder stability enabled by accurate graft positioning and union. This study aimed to establish a reproducible method of quantitatively assessing coracoid graft osseous union percentage (OUP) using computed tomography (CT) scans and to determine the effect of other factors on the OUP. MATERIALS AND METHODS: Postoperative CT scans of 41 consecutive patients treated with the open Latarjet procedure (37% primary, 63% revision) for anterior glenohumeral instability were analyzed for the OUP, position of the graft, and screw type and angle. Two musculoskeletal radiologists independently examined the images 2 times, and intraobserver and interobserver reliability was calculated using intraclass correlation coefficient (ICC). RESULTS: Mean OUP was 66% (range, 0%-94%) using quantitate methods, with good intraobserver reliability (ICC = 0.795) and interobserver reliability (ICC = 0.797). Nonunion and significant graft resorption was found in 2 patients. No significant difference was found in the mean OUP in the primary (63%) vs. revision Latarjet procedure (67%). Grafts were flush in 39%, medial in 36%, and lateral in 8%. The medial and neutral graft position was associated with slightly higher OUP (72% and 69%) compared with lateral (65%). OUP was higher when the superior screw angle was less than 17 degrees and the inferior screw angle was less than 24 degrees . This difference did not reach statistical significance. Screw type was not associated with significant difference in OUP. CONCLUSION: Quantitative assessment of osseous union of the graft using a reproducible method that we introduced showed similar OUP in the primary and revision Latarjet procedure. PMID- 29477668 TI - Variation in stress distribution patterns across the radial head fovea in osteochondritis dissecans: predictive factors in radiographic findings. AB - BACKGROUND: Predictive factors for the development of osteoarthritis in adolescent osteochondritis dissecans (OCD) of the humeral capitellum remain unclear. The objectives of this study were to assess subchondral bone density in the radial head fovea of patients with OCD and to evaluate stress distribution in the radiocapitellar joint. The relationship between radiologic classification and stress distribution, according to multivariate ordinal regression analysis, was also investigated. METHODS: Computed tomography (CT) imaging data from 54 male patients with OCD (mean age, 13.1 years) were collected. Stress in the radial head fovea was measured using CT osteoabsorptiometry. A stress map was constructed and divided into 4 sections, and percentages of high-density regions in each section were quantitatively analyzed. Multivariate ordinal regression analyses were performed of bone density, incorporating the stage, location, and size of the OCD lesion and the presence of medial elbow disturbance in the radiographic images. RESULTS: The percentage of high-density area in the anteromedial, posteromedial, and the anterolateral sections of the radial head fovea were significantly increased compared with the posterolateral section. Multivariate ordinal regression analysis revealed that the location and size of the lesion and a history of excessive valgus stress were associated with imbalances in the radial head fovea. CONCLUSIONS: When the OCD lesion is large and located laterally and a medial epicondyle disturbance is apparent on radiographs, the risk for developing advanced radiocapitellar osteoarthritis should be considered. These findings can be useful in the decision-making process for treating OCD. PMID- 29477665 TI - Adjuvant vemurafenib in resected, BRAFV600 mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. AB - BACKGROUND: Systemic adjuvant treatment might mitigate the high risk of disease recurrence in patients with resected stage IIC-III melanoma. The BRIM8 study evaluated adjuvant vemurafenib monotherapy in patients with resected, BRAFV600 mutation-positive melanoma. METHODS: BRIM8 was a phase 3, international, double blind, randomised, placebo-controlled study that enrolled 498 adults (aged >=18 years) with histologically confirmed stage IIC-IIIA-IIIB (cohort 1) or stage IIIC (cohort 2) BRAFV600 mutation-positive melanoma that was fully resected. Patients were randomly assigned (1:1) by an interactive voice or web response system to receive twice-daily adjuvant oral vemurafenib 960 mg tablets or matching placebo for 52 weeks (13 * 28-day cycles). Randomisation was done by permuted blocks (block size 6) and was stratified by pathological stage and region in cohort 1 and by region in cohort 2. The investigators, patients, and sponsor were masked to treatment assignment. The primary endpoint was disease-free survival in the intention-to-treat population, evaluated separately in each cohort. Hierarchical analysis of cohort 2 before cohort 1 was prespecified. This trial is registered with ClinicalTrials.gov, number NCT01667419. FINDINGS: The study enrolled 184 patients in cohort 2 (93 were assigned to vemurafenib and 91 to placebo) and 314 patients in cohort 1 (157 were assigned to vemurafenib and 157 to placebo). At the time of data cutoff (April 17, 2017), median study follow-up was 33.5 months (IQR 25.9-41.6) in cohort 2 and 30.8 months (25.5-40.7) in cohort 1. In cohort 2 (patients with stage IIIC disease), median disease-free survival was 23.1 months (95% CI 18.6-26.5) in the vemurafenib group versus 15.4 months (11.1-35.9) in the placebo group (hazard ratio [HR] 0.80, 95% CI 0.54-1.18; log-rank p=0.026). In cohort 1 (patients with stage IIC-IIIA-IIIB disease) median disease-free survival was not reached (95% CI not estimable) in the vemurafenib group versus 36.9 months (21.4-not estimable) in the placebo group (HR 0.54 [95% CI 0.37-0.78]; log rank p=0.0010); however, the result was not significant because of the prespecified hierarchical prerequisite for the primary disease-free survival analysis of cohort 2 to show a significant disease-free survival benefit. Grade 3 4 adverse events occurred in 141 (57%) of 247 patients in the vemurafenib group and 37 (15%) of 247 patients in the placebo group. The most common grade 3-4 adverse events in the vemurafenib group were keratoacanthoma (24 [10%] of 247 patients), arthralgia (17 [7%]), squamous cell carcinoma (17 [7%]), rash (14 [6%]), and elevated alanine aminotransferase (14 [6%]), although all keratoacanthoma events and most squamous cell carcinoma events were by default graded as grade 3. In the placebo group, grade 3-4 adverse events did not exceed 2% for any of the reported terms. Serious adverse events were reported in 40 (16%) of 247 patients in the vemurafenib group and 25 (10%) of 247 patients in the placebo group. The most common serious adverse event was basal cell carcinoma, which was reported in eight (3%) patients in each group. One patient in the vemurafenib group of cohort 2 died 2 months after admission to hospital for grade 3 hypertension; however, this death was not considered to be related to the study drug. INTERPRETATION: The primary endpoint of disease-free survival was not met in cohort 2, and therefore the analysis of cohort 1 showing a numerical benefit in disease-free survival with vemurafenib versus placebo in patients with resected stage IIC-IIIA-IIIB BRAFV600 mutation-positive melanoma must be considered exploratory only. 1 year of adjuvant vemurafenib was well tolerated, but might not be an optimal treatment regimen in this patient population. FUNDING: F Hoffman-La Roche Ltd. PMID- 29477669 TI - The Chytrid-like Parasites of Algae Amoeboradix gromovi gen. et sp. nov. and Sanchytrium tribonematis Belong to a New Fungal Lineage. AB - Fungi encompass, in addition to classically well-studied lineages, an ever expanding diversity of poorly known lineages including zoosporic chytrid-like parasites. Here, we formally describe Amoeboradix gromovi gen. et sp. nov. comprising a set of closely related strains of chytrid-like parasites of the yellow-green alga Tribonema gayanum unusually endowed with amoeboid zoospores. Morphological and ultrastructural features of A. gromovi observed by light and transmission electron microscopy recall previous descriptions of Rhizophydium anatropum. A. gromovi exhibits one of the longest kinetosomes known in eukaryotes, composed of microtubular singlets or doublets. To carry out molecular phylogenetic analysis and validate the identification of different life cycle stages, we amplified 18S rRNA genes from three A. gromovi strains infecting T. gayanum cultures, single sporangia and single zoospores. Molecular phylogenetic analyses of 18S+28S rRNA concatenated genes of the type strain revealed that A. gromovi is closely related to the recently described species Sanchytrium tribonematis, another parasite of Tribonema that had been tentatively classified within Monoblepharidomycetes. However, our phylogenetic analysis with an extended taxon sampling did not show any particular affinity of Amoeboradix and Sanchytrium with described fungal taxa. Therefore, Amoeboradix gromovi and Sanchytrium tribonematis likely represent a new divergent taxon that remains incertae sedis within Fungi. PMID- 29477670 TI - Assessing three fish species ecological status in Colorado River, Grand Canyon based on physical habitat and population models. AB - Colorado River is a unique ecosystem and provides important ecological services such as habitat for fish species as well as water power energy supplies. River management for this ecosystem requires assessment and decision support tools for fish which involves protecting, restoring as well as forecasting of future conditions. In this paper, a habitat and population model was developed and used to determine the levels of fish habitat suitability and population density in Colorado River between Lees Ferry and Lake Mead. The short term target fish populations are also predicted based on native fish recovery strategy. This model has been developed by combining hydrodynamics, heat transfer and sediment transport models with a habitat suitability index model and then coupling with habitat model into life stage population model. The fish were divided into four life stages according to the fish length. Three most abundant and typical native and non-native fish were selected as target species, which are rainbow trout (Oncorhynchus mykiss), brown trout (Salmo trutta) and flannelmouth sucker (Catostomus latipinnis). Flow velocity, water depth, water temperature and substrates were used as the suitability indicators in habitat model and overall suitability index (OSI) as well as weight usable area (WUA) was used as an indicator in population model. A comparison was made between simulated fish population alteration and surveyed fish number fluctuation during 2000 to 2009. The application of this habitat and population model indicates that this model can be accurate present habitat situation and targets fish population dynamics of in the study areas. The analysis also indicates the flannelmouth sucker population will steadily increase while the rainbow trout will decrease based on the native fish recovery scheme. PMID- 29477671 TI - Structural and practical identifiability analysis of outbreak models. AB - Estimating the reproduction number of an emerging infectious disease from an epidemiological data is becoming more essential in evaluating the current status of an outbreak. However, these studies are lacking the fundamental prerequisite in parameter estimation problem, namely the structural identifiability of the epidemic model, which determines the possibility of uniquely determining the model parameters from the epidemic data. In this paper, we perform both structural and practical identifiability analysis to classical epidemic models such as SIR (Susceptible-Infected-Recovered), SEIR (Susceptible-Exposed-Infected Recovered) and an epidemic model with the treatment class (SITR). We performed structural identifiability analysis on these epidemic models using a differential algebra approach to investigate the well-posedness of the parameter estimation problem. Parameters of these models are estimated from different data types, namely prevalence, cumulative incidences and treated individuals. Furthermore, we carried out practical identifiability analysis on these models using Monte Carlo simulations and Fisher's Information Matrix. Our study shows that the SIR model is both structurally and practically identifiable from the prevalence data. It is also structurally identifiable to cumulative incidence observations, but due to high correlations of the parameters, it is practically unidentifiable from the cumulative incidence data. Furthermore, we found that none of these simple epidemic models are practically identifiable from the cumulative incidence data which is the standard type of epidemiological data provided by CDC or WHO. Our analysis with simple SIR model suggest that the health agencies, if possible, should report prevalence rather than incidence data. PMID- 29477672 TI - Emotional reactivity: Beware its involvement in traffic accidents. AB - BACKGROUND: Reducing risk attributable to traffic accidents is a public health challenge. Research into risk factors in the area is now moving towards identification of the psychological factors involved, particularly emotional states. The aim of this study was to evaluate the link between emotional reactivity and responsibility in road traffic accidents. We hypothesized that the more one's emotional reactivity is disturbed, the greater the likelihood of being responsible for a traffic accident. METHODS: This case-control study was based on a sample of 955 drivers injured in a motor vehicle crash. Responsibility levels were determined with a standardized method adapted from the quantitative Robertson and Drummer crash responsibility instrument. Emotional reactivity was assessed with the MATHYS. RESULTS: Hierarchical cluster analysis discriminated four distinctive driver's emotional reactivity profiles: basic emotional reactivity (54%), mild emotional hyper-reactivity (29%), emotional hyper reactivity (11%) and emotional hypo-reactivity (6%). Drivers who demonstrated emotional hypo-reactivity had a 2.3-fold greater risk of being responsible for a traffic accident than those with basic emotional reactivity. CONCLUSION: Drivers' responsibility in traffic accidents depends on their emotional status. The latter can change the ability of drivers, modifying their behavior and thus increasing their propensity to exhibit risk behavior and to cause traffic accidents. PMID- 29477673 TI - Childhood adversities, bonding, and personality in social anxiety disorder with alcohol use disorder. AB - Social anxiety disorder (SAD) is frequently associated with alcohol use disorders (abuse/dependence). However, there has been little research on the characteristics of this subgroup so far. In the current study we investigated individuals with SAD and comorbid alcohol use disorder (AUD) with regard to socialization experiences and personality. The sample comprised 410 individuals diagnosed with SAD by the Structured Clinical Interview of DSM-IV. 108 participants with comorbid AUD were compared to 302 participants without comorbid AUD concerning traumatic experiences during childhood and adolescence (Adverse Childhood Experiences Questionnaire; ACE), parental bonding (Parental Bonding Instrument; PBI), and personality (Temperament and Character Inventory; TCI). MANCOVA with covariates sex and depression displayed that individuals with SAD plus AUD reported significantly more traumatic events during childhood and adolescence, lower levels of maternal care, as well as lower cooperativeness. Our results highlight that adverse childhood experiences and unfavourable maternal bonding characterize individuals suffering from SAD plus AUD. These experiences might be reflected in a personality-based tendency to distance themselves from others, which corresponds to low scores on the character dimension cooperativeness. A deeper understanding of personality and specific socialization experiences is necessary to develop new treatment options in this clinically challenging subgroup. PMID- 29477674 TI - Preoperative Antibiotics for Dialysis Access Surgery: Are They Necessary? AB - BACKGROUND: Current guidelines recommend preoperative antibiotics in all vascular surgery cases. However, we hypothesize that patients undergoing arteriovenous fistula (AVF) and arteriovenous graft (AVG) creation have low rates of postoperative surgical site infection (SSI) and that preoperative antibiotic prophylaxis in these patients may not be necessary. METHODS: This is a retrospective review of all patients who underwent AVF and AVG creation from November 2014 through July of 2016 at a single institution. At our institution, preoperative antibiotic use is surgeon dependent. Patients who received preoperative antibiotics were compared with those who did not. The primary outcome measured was the development of postoperative SSI. RESULTS: There were 304 patients identified and 294 patients with 30 day postoperative follow-up. Of the 294 patients, 23 (7.8%) received an AVG, and 271 (92.2%) received an AVF. There were 244 (83%) patients who received preoperative antibiotics and 50 (17%) who did not. Overall, there were 2 (0.68%) SSIs identified. Both patients with postoperative SSI underwent AVF creation and received preoperative antibiotics. There was no statistically significant difference in SSI rate between antibiotic and nonantibiotic groups (P = 1.0), and no difference when comparing patients that received AVG (0%) and AVF (0.73%) (P = 1.0). CONCLUSIONS: The rate for postoperative SSI following hemodialysis access surgery is very low both for patients undergoing AVF and AVG. Furthermore, there was no difference in SSI rate between antibiotic and nonantibiotic groups. Given these findings, we conclude that preoperative antibiotics for AVF creation may not be necessary. PMID- 29477676 TI - A National Study Evaluating Hospital Volume and Inpatient Mortality after Open Abdominal Aortic Aneurysm Repair in Vulnerable Populations. AB - BACKGROUND: There is a large body of evidence documenting better outcomes for abdominal aortic aneurysm (AAA) repairs performed in high-volume centers. However, it remains unknown if the strength of this volume-outcome relationship is moderated by race or socioeconomic status (SES). METHODS: This is a cross sectional retrospective cohort study evaluating 60,618 Medicare fee-for-service beneficiaries undergoing open AAA repair across 1,649 hospitals between 2005 and 2009. We selected, a priori, black race and low SES as vulnerable populations based on previous reports showing each is independently associated with higher mortality. Next, we divided hospitals into quintiles of procedural volume and used logistic regression to compare risk-adjusted rates of inpatient mortality across volume quintiles for the overall study population and separately by race (black versus nonblack) and SES (low, middle, and high). RESULTS: Overall, patients treated in the lowest-volume hospitals (LVHs) had higher risk-adjusted inpatient mortality rates than patients treated in the highest-volume hospitals (HVHs) (15.3% vs. 10.6%, P < 0.001). Higher mortality was associated with black versus nonblack race (12.9% vs. 11.7%, P < 0.001) and low SES versus high SES (12.2% vs. 11.6% P < 0.001). While nonblack patients treated in LVHs had higher odds of mortality (versus HVHs, adjusted odds ratio (aOR) 1.83 [1.59-2.11]), this volume-outcome effect was greater for black patients (aOR 2.60 [1.63-4.16]). In contrast, high and low SES patients experienced similar differences in mortality when treated in LVHs (aOR 1.79 [1.49-2.12]; aOR 1.72 [1.28-2.30], respectively). CONCLUSIONS: While a volume-outcome effect was observed in all patients, black patients appeared to derive a disproportionate benefit from undergoing open AAA repair in HVHs. The mechanism underlying these disparate outcomes remains unclear but warrants further evaluation of contributing hospital and patient factors. PMID- 29477675 TI - Factors Associated with Early Thrombosis after Arteriovenous Fistula Creation. AB - BACKGROUND: Arteriovenous fistulas (AVF) are the preferred modality for hemodialysis access. Early thrombosis hampers development of a working AVF. We endeavored to determine the incidence and identify factors associated with early thrombosis of AVF and to determine salvage rates following thrombosis, at a high volume hemodialysis access center. METHODS: Retrospective review of autologous AVF was created between November 2014 and July 2016 at a single center. Early thrombosis was defined as thrombosis that occurred within 30 days of surgery. RESULTS: There were 291 AVFs. The median age was 54.7 years, and 192 patients (66%) were male. Early postoperative AVF thrombosis was noted in 5 (1.7%) cases. Factors associated with early thrombosis on univariate analysis included previous access surgery (P = 0.02) and absence of a good intraoperative thrill (P = 0.006). Intraoperative protamine use trended toward significance (P = 0.06). Factors that were not significant included gender, diabetes, dialysis at time of surgery, fistula configuration, and systemic heparin use. None of the thrombosed fistulas were salvaged. CONCLUSIONS: Early thrombosis is a relatively rare complication of AVF creation at a high-volume center. Previous access surgery and absence of good thrill at conclusion of the procedure are associated with early thrombosis. PMID- 29477677 TI - Ultrasound Vein and Artery Mapping by General Surgery Residents During Initial Consult Can Decrease Time to Dialysis Access Creation. AB - BACKGROUND: Formal preoperative ultrasound (US) mapping of vascular anatomy by radiology is recommended before hemodialysis access surgery. We hypothesized that US performed by general surgery residents in place of formal US would decrease the time from initial consult to creation of dialysis access without affecting patient outcomes. METHODS: This is a retrospective review of all patients who underwent dialysis access surgery from November 2014 to July 2016 and received preoperative upper extremity US vein and artery evaluation by either radiology or general surgery residents. The primary endpoints were days from initial consult to dialysis access creation, rate of arteriovenous fistula (AVF) creation, fistula maturation, and 1-year primary assisted patency. RESULTS: Of 242 patients, 167 (69%) had formal US, and 75 (31%) had only a resident US. The resident US group had 100% AVF creation compared with the formal US group with 92.2% AVF creation (P = 0.01). There was no difference between the groups in rate of fistula maturation (P = 0.1) and 1-year assisted patency (P = 0.9). Of the resident US 90.7% occurred in the outpatient setting. On multivariable analysis controlling for outpatient consult, the average time to the operating room was 13.7 days longer for the formal US group in the outpatient setting (P = 0.0006). CONCLUSIONS: Ultrasound vein and artery evaluation at the time of the initial consult by general surgery residents can decrease the time to dialysis access creation by bypassing the need for formal US with a higher rate of AVF creation and no difference in fistula maturation or 1-year primary assisted patency. PMID- 29477678 TI - Prognostic Factors for Arteriovenous Fistula Maturation. AB - BACKGROUND: Recent studies have reported successful arteriovenous (AV) fistula maturation rates between 40% and 80%, with older age, distal fistula location, and small vein diameter associated with greater failure rates. Our objective is to determine if these findings are consistent with the outcomes at our institution. METHODS: A retrospective chart review was performed on patients who underwent upper extremity AV fistula creation at a single institution. Patient demographics and risk factors were analyzed, as well as fistula location and vein diameter based on preoperative ultrasound. Veins less than 2.5 mm were not used for fistula creation. Successful fistula maturation was defined as the fistula serving as the primary access for hemodialysis for 3 months or greater. Pearson Chi-Square, Fisher's Exact Test, and Mann-Whitney U-tests were used to determine significant associations. RESULTS: Between January 2012 and December 2013, 146 fistulas were created in 136 patients. The median age was 68. Median body mass index (BMI) was 27.8. Ninety-one fistulas were created in men and 55 in women. Ninety-two percent of patients had hypertension, 57% had diabetes, and 33% had coronary artery disease. Sixty percent of fistulas created were brachiocephalic, 24% were basilic vein transpositions, and 16% were radiocephalic. Median vein diameter was 3.7 (range 2.5-8.8). Eighty-four percent of patients were on hemodialysis at the time of fistula creation, and 21% had a prior fistula. One hundred five fistulas were accessed for 3 months or more, resulting in a successful overall maturation rate of 72%. BMI greater than 29.5 (P = 0.026) negatively impacted successful fistula maturation, whereas age, fistula location, and vein size did not. CONCLUSIONS: We noted a successful overall maturation rate of 72% at our institution when veins at least 2.5 mm in diameter were used. Our sole negative significant predictor for fistula maturation was BMI greater than 29.5. Therefore, in our experience, age, sex, and fistula location should not be used to preclude patients with a vein diameter of at least 2.5 mm from consideration for AV fistula creation. PMID- 29477679 TI - Flow Rates at Thirty Days after Construction of Radiocephalic Arteriovenous Fistula Predict Hemodialysis Function. AB - BACKGROUND: Construction of radiocephalic arteriovenous fistula (RC-AVF) results in successful hemodialysis (HD) in approximately 40% of end-stage renal disease patients. We investigated whether RC-AVF flow measured by ultrasound 30 days postoperative predicted successful HD. METHODS: In this prospective study, color Doppler ultrasound was used to measure cephalic vein outflow volume at 3 forearm sites at 1 and 3 months postoperatively. RESULTS: Of 45 consecutive patients screened for feasibility of RC-AVF by physical examination and US arterial and vein mapping, 41 were considered suitable for construction of RC-AVF. Mean age was 70 (60-78) years. Of the 41 patients who had a forearm RC-AVF, 25 (61%) proceeded to successful AVF dialysis, 4 (10%) had HD via central venous catheter, and 12 (29%) ceased function within the first 30 days postoperatively. The mean flow at 30 days for patent fistulas was 629 +/- 305 ml/min and by the third month had increased to 663 +/- 367 mL/min. At 1 month, 8/29 (27.6%) patients had a flow rate <400 mL/min. Two (25%) of these clotted, 2 of 3 with closed revisions went on to HD, and 1 died. Of the 21 patients with a flow rate >=400 mL/min, 19 (90%) functioned for HD, and 2 (10%) AVF occluded before 1 year, resulting in 17 functioning at 1 year (81% 1-year patency). Sixty-two percent of the low-flow fistulas had successful patency within 1 year. CONCLUSIONS: An RC-AVF flow rate of >=400 mL/min in the first month predicted more successful HD than low flow (<400 mL/min) (81% vs. 62%). Without intervention, low flow rates do not improve significantly and maturation is unlikely. We recommend imaging for all patients at 30 days to identify and promptly correct stenosis in those with low flow rates. PMID- 29477680 TI - The Importance of Profunda Femoris Artery Justifies Further the Endovascular Approach in Critical Limb Ischemia. PMID- 29477681 TI - Surgical Missteps in the Management of Venous Thoracic Outlet Syndrome Which Lead to Reoperation. AB - BACKGROUND: Surgical management of spontaneous subclavian thrombosis due to venous thoracic outlet syndrome (vTOS) results in durable relief of symptoms. The need to reoperate is rare. We report our experience with reoperation for vTOS. METHODS: Patients evaluated for vTOS between 1996 and 2016 were identified in a prospective database. Data recorded included demographics, initial presentation, initial surgery, recurrent presentation, reoperation, and final outcomes. RESULTS: In all, 261 patients were evaluated for vTOS, of these, 246 patients underwent first rib resections. Ten (3.8%) patients required evaluation for recurrent vTOS symptoms. Prior management included thrombolysis (4) and anticoagulation alone (6). Prior surgical approaches included infraclavicular (2), supraclavicular (2) and transaxillary (6). One operation was complicated by a hemothorax, and one a brachial plexus injury. Indication for reoperation included congestive symptoms (6) and recurrent thrombosis (4). Evaluation included chest X-rays (10), venogram (8), intra-venous ultrasound (2), and computed tomography venography (3). Significant compression by remaining rib segments were identified in all: inadequate resection of the anterior first rib (7), inadequate resection of posterior rib segment (1), and erroneous resection of second rib (2). Reoperations include 7 transaxillary approaches, 1 medial claviculectomy, and 1 paraclavicular decompression. One phrenic nerve palsy occurred following paraclavicular decompression. All underwent postoperative venography and angioplasty. At final evaluation, 8 veins are patent and congestive symptoms resolved, and 1 crushed stent could not be reopened despite decompression. CONCLUSIONS: The incidence of reoperation for first rib resection in cases of vTOS is low and appears largely due to missteps during the initial operation. Awareness of potential errors including inadequacy of resection, intraoperative disorientation, and misunderstanding of the limitations of surgical approaches will result in fewer reoperations. PMID- 29477683 TI - Carotid Artery Angioplasty and Stenting for Atherosclerotic Plaque with Mobile Intimal Flap. AB - Atherosclerotic carotid stenosis associated with a mobile carotid plaque (MCP) is a relatively rare entity, observed in less than 1 in 2,000 carotid ultrasound examinations. As such, the natural history of this lesion and risk for neurological thromboembolic complications are not well defined. Small case reports have described treatment varying from medical management with anticoagulation, to carotid endarterectomy, and more recently, carotid stenting. We present two patients with carotid stenosis associated with a MCP. A distinct MCP component that varied with the cardiac cycle was clearly delineated on ultrasound in both patients. Intravascular ultrasound (IVUS) at the time of carotid stenting confirmed the MCP. Successful carotid angioplasty and stenting was performed in both patients with resolution of the MCP documented on IVUS and follow-up duplex ultrasound. Although the definitive treatment method remains uncertain, carotid stenting is a viable option for treatment in patients with MCPs. PMID- 29477682 TI - Perioperative Outcomes are Adversely Affected by Poor Pretransfer Adherence to Acute Limb Ischemia Practice Guidelines. AB - BACKGROUND: The accepted treatment for acute limb ischemia (ALI) is immediate systemic anticoagulation and timely reperfusion to restore blood flow. In this study, we describe the retrospective assessment of pretransfer management decisions by referring hospitals to an academic tertiary care facility and its impact on perioperative adverse events. METHODS: A retrospective analysis of ALI patients transferred to us via our Level I Vascular Emergency Program from 2010 to 2013 was performed. Patient demographics, comorbidities, Rutherford ischemia classification, time to anticoagulation, and time to reperfusion were tabulated and analyzed for correlation to incidence of major adverse limb events (MALEs), mortality, and bypass patency in the perioperative period (30-day postoperative). All intervals were calculated from the onset of symptoms and categorized into 3 subcohorts (<6 hr, 6-48 hr, and >48 hr). RESULTS: Eighty-seven patients with an average age of 64.0 (+/-16.2) years presented to outlying hospitals and were transferred to us with lower extremity ALI. The mean delay from symptom onset to initial referring physician evaluation was 18.3 hr. At that time of evaluation, 53.8% had Rutherford class IIA ischemia and 36.3% had class IIB ischemia. Seventy six patients (87.4%) were started on heparin previous to transfer. However, only 44 patients (57.9%) reached therapeutic levels as measured by activated partial thromboplastin time before definitive revascularization. A delay of anticoagulation initiation >48 hr from symptom onset was associated with increased 30-day reintervention rates compared with the <6 hr group (66.7% vs. 23.5%; P < 0.05). However, time to reperfusion had no statistically significant impact on MALE, 30-day mortality, or 30-day interventional patency in our small cohorts. Additionally, patients with a previous revascularization had a higher 30 day reintervention rate (46.5%; P < 0.05). CONCLUSIONS: The practice of timely therapeutic anticoagulation of patients referred for ALI from community facilities occurs less frequently than expected and is associated with an increased perioperative reintervention rate. PMID- 29477685 TI - Hypothenar Hammer Syndrome: Surgical Approach in Patients Presenting with Ulnar Artery Aneurysm. AB - Hypothenar hammer syndrome is an uncommon condition but of high clinical importance due to ischemia-related complications. In this article, we discuss about our surgical approach to deal with hypothenar hammer syndrome patients suffering from ulnar artery aneurysm, which is surgical exploration and end-to end anastomosis of the ulnar artery. PMID- 29477684 TI - Frailty Is Associated with an Increased Risk of Major Adverse Cardiac Events in Patients with Stable Claudication. AB - BACKGROUND: Frailty, a syndrome characterized by decreased physiologic reserves and resistance to stressors, is associated with disability, poor surgical outcomes, and mortality. We evaluated the impact of frailty on cardiovascular disease (CVD) events in peripheral arterial disease (PAD) patients with intermittent claudication. METHODS: We conducted a retrospective review of patients with stable intermittent claudication enrolled in the OMEGA-PAD study between 2010 and 2015. The modified frailty index (mFI) is a retrospectively validated index of frailty derived from the Canadian Study of Health and Aging and was used in this study to categorize frailty as low, medium, or high. Our outcome was time to occurrence of a major adverse cardiac event (MACE), defined as a composite endpoint of myocardial infarction, coronary revascularization, stroke, or CVD-related death. Cox proportional hazards models were used to calculate relative hazards ratio. RESULTS: There were 129 subjects with a mean age of 67 years, 97% were men, 36% were diabetic, and 33% had known coronary heart disease. When the mFI criteria were applied, 38 subjects were "low" frailty, 72 were "medium" frailty, and 19 were "high" frailty. During the median follow-up period of 34 months (interquartile range: 25-43), 29 subjects experienced a MACE. When compared to the lowest mFI, patients with medium frailty were 2.8 times more likely to have an event (95% confidence interval [CI]: 0.95 8.46, P = 0.06), whereas patients with a high mFI were 4.8 times as likely (95% CI: 1.43-15.8, P = 0.01). In a model adjusted for age, smoking status, and presence of diabetes, those with a medium mFI were 4.3 times more likely to have an event (95% CI: 1.37-13.7, P = 0.01) and those with a high mFI were 9.2 times as likely (95% CI: 2.6-32.4, P = 0.001). CONCLUSIONS: Higher mFI category is associated with a significantly increased risk of MACE in PAD patients with stable claudication. Frailty may serve as a useful adjunct for assessment of overall cardiac risk, particularly as treatment options are being contemplated. PMID- 29477686 TI - Changes in Arterial Stiffness and N-Terminal Pro-Brain Natriuretic Peptide Levels after Endovascular Repair of Descending Thoracic Aorta. PMID- 29477687 TI - Postoperative Development of Abdominal Compartment Syndrome among Patients Undergoing Endovascular Aortic Repair for Ruptured Abdominal Aortic Aneurysms. AB - BACKGROUND: Abdominal compartment syndrome (ACS) has a reported incidence of 9% 14% among trauma patients. However, in patients with similar hemodynamic changes, the incidence of ACS remains unclear. Our aim was to determine the incidence of ACS among patients undergoing endovascular aortic repair (EVAR) for ruptured abdominal aortic aneurysms (rAAAs) and to identify associated risk factors. METHODS: A retrospective review was performed for consecutive patients who underwent EVAR for rAAA from March 2010 to November 2016 at our institution. The development of ACS was diagnosed based on a variety of factors, including bladder pressure, laboratory abnormalities, hemodynamic monitoring, and clinical evaluation. Previously validated risk factors for ACS development in trauma and EVAR patients (preoperative hypotension, aggressive fluid resuscitation, postoperative anemia, use of an aorto-uniiliac graft, and placement of an aortic occlusive balloon) were analyzed. Association between patient characteristics and ACS development was analyzed using the Fisher's exact test. RESULTS: During the study period, 25 patients had image-confirmed rAAA and underwent emergent EVAR. Mortality rate was 28% (n = 7), and ACS incidence was 12% (n = 3). Of the analyzed risk factors, hypotension on arrival (P = 0.037), transfusion of 3 or more units of packed red blood cells (P = 0.037), and postoperative anemia (P = 0.02) were all significantly associated with postoperative ACS development. In addition, having greater than 3 of the studied risk factors was associated with increased odds of developing ACS (P = 0.015), and having greater than 4 of the studied risk factors showed the strongest association with ACS development (P = 0.0017). CONCLUSIONS: Overresuscitation should be avoided in patients with rAAA. In addition, patients who present with multiple risk factors for ACS should be monitored very closely with serial bladder pressures and may require decompression laparotomy immediately after EVAR. PMID- 29477689 TI - Endophthalmitis after Intravitreal Injection of Vascular Endothelial Growth Factor Inhibitors: Management and Visual Outcomes. AB - PURPOSE: We describe the presentation of patients developing endophthalmitis after intravitreal injection with vascular endothelial growth factor (VEGF) inhibitors. Moreover, we evaluate the management by comparing the outcomes of immediate tap and injection of intravitreal antibiotics (TAI) versus initial surgical pars plana vitrectomy (PPV). Finally, we analyze the predictive factors of visual outcomes at 6-month follow-up. DESIGN: Retrospective, single-center, nonrandomized interventional study. PARTICIPANTS: Patients developing endophthalmitis after receiving an intravitreal injection of anti-VEGF agent between 2006 and 2016. METHODS: All patients received a vitreous biopsy sent for cultures before the initiation of treatment: TAI group versus PPV with intravitreal antibiotics (PPV group). MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA) at 6-month follow-up after treatment for endophthalmitis. RESULTS: A total of 258 357 intravitreal injections occurred over the course of the 10-year period, of which 40 patients (0.016%) had endophthalmitis within 3 weeks after injection. In total, 34 patients (85.0%) had pain and 25 patients (62.5%) had hypopyon on initial examination. Among 24 culture-positive cases, 66.7% of the causative organisms were coagulase-negative Staphylococcus, followed by Streptococcus species (10.0%). The best-corrected visual acuity (BCVA) (logarithm of the minimum angle of resolution [logMAR]) at 6-month follow-up was significantly worse for patients who had a positive culture for Streptococcus species (4.0; standard deviation [SD], 0.8) (approximately light perception) compared with those who had a positive culture for coagulase-negative Staphylococcus (0.4; SD, 0.3) (~20/50) (P < 0.0001). Compared with the TAI group, a higher proportion of samples were culture-positive in the PPV group (90.9% vs. 48.3%, P = 0.03). There was no statistically significant difference in BCVA at 6 month follow-up between the TAI and PPV groups. Younger age (<85 years) and lower intraocular pressure (IOP) (<=25 mmHg) at presentation were predictive of achieving a BCVA of 20/400 or better at 6-month follow-up after treatment. Initial management (TAI vs. PPV), duration of symptoms, presence of pain, presence of hypopyon, presenting BCVA, and culture status (positive vs. negative) were not found to be predictive of visual outcomes at 6-month follow-up. CONCLUSIONS: No significant difference in BCVA at 6-month follow-up was detected between the TAI and PPV groups. Younger age and lower IOP at presentation were associated with better visual outcomes at 6-month follow-up. PMID- 29477690 TI - Vision-Related Quality of Life Associated with Unilateral and Bilateral Ocular Conditions. AB - PURPOSE: To present ophthalmic patient time-tradeoff vision utilities for quantifying vision-related quality-of-life when the fellow eye still has good vision. These utilities are important for performing reliable cost-utility analyses. DESIGN: Consecutive time-tradeoff vision utilities were obtained from ophthalmic patients with good vision (20/20-20/25) in one eye and vision ranging from 20/20 to no light perception in the fellow eye over a 15-year period from 2000 through 2014. PARTICIPANTS: Five hundred eighty-six ophthalmic participant interviews from Wills Eye Hospital, New York Eye and Ear Hospital, and ophthalmology office practices in Pennsylvania and New Jersey. METHODS: Participants underwent a full ophthalmic examination, after which time-tradeoff vision utilities were obtained by personal interview by the authors using a standardized, validated instrument. MAIN OUTCOME MEASURES: Time-tradeoff vision utilities. RESULTS: Mean time-tradeoff vision utilities were as follows in participants with good vision (20/20-20/25) in at least one eye and the following visions in the fellow eyes: no light perception, 0.79; counting fingers to light perception, 0.87; 20/200 to 20/400, 0.88; 20/60 to 20/100, 0.88; 20/30 to 20/50, 0.87; and 20/20 to 20/25, 0.94. CONCLUSIONS: In people with good vision (20/20 20/25) in one eye, the associated mean time-tradeoff vision utility is a remarkably consistent 0.87 to 0.88 when vision in the fellow eye ranges from 20/30 to light perception. Vision of 20/20 to 20/25 in the fellow eye results in a significantly higher associated utility of 0.94 (P < 0.01), whereas vision of no light perception in the fellow eye results in a significantly lower utility of 0.079 (P < 0.01). These utilities are important for calculating reliable patient value (quality-adjusted life-year) gains in ophthalmic cost-utility analysis populations in which there is unilateral and bilateral disease involvement. PMID- 29477688 TI - Treatment Outcomes in the Primary Tube Versus Trabeculectomy Study after 1 Year of Follow-up. AB - PURPOSE: To report 1-year treatment outcomes in the Primary Tube Versus Trabeculectomy (PTVT) Study. DESIGN: Multicenter, randomized clinical trial. PARTICIPANTS: Two hundred forty-two eyes of 242 patients with medically uncontrolled glaucoma and no previous incisional ocular surgery, including 125 in the tube group and 117 in the trabeculectomy group. METHODS: Patients were enrolled at 16 clinical centers and assigned randomly to treatment with a tube shunt (350-mm2 Baerveldt glaucoma implant) or trabeculectomy with mitomycin C (MMC; 0.4 mg/ml for 2 minutes). MAIN OUTCOME MEASURES: Intraocular pressure (IOP), glaucoma medical therapy, visual acuity, visual fields, surgical complications, and failure (IOP of more than 21 mmHg or reduced by less than 20% from baseline, IOP of 5 mmHg or less, reoperation for glaucoma, or loss of light perception vision). RESULTS: The cumulative probability of failure during the first year of follow-up was 17.3% in the tube group and 7.9% in the trabeculectomy group (P = 0.01; hazard ratio, 2.59; 95% confidence interval, 1.20 5.60). Mean +/- standard deviation IOP was 13.8+/-4.1 mmHg in the tube group and 12.4+/-4.4 mmHg in the trabeculectomy group at 1 year (P = 0.01), and the number of glaucoma medications was 2.1+/-1.4 in the tube group and 0.9+/-1.4 in the trabeculectomy group (P < 0.001). Postoperative complications developed in 36 patients (29%) in the tube group and 48 patients (41%) in the trabeculectomy group (P = 0.06). Serious complications requiring reoperation or producing a loss of 2 Snellen lines or more occurred in 1 patient (1%) in the tube group and 8 patients (7%) in the trabeculectomy group (P = 0.03). CONCLUSIONS: Trabeculectomy with MMC had a higher surgical success rate than tube shunt implantation after 1 year in the PTVT Study. Lower IOP with use of fewer glaucoma medications was achieved after trabeculectomy with MMC compared with tube shunt surgery during the first year of follow-up. The frequency of serious complications producing vision loss or requiring reoperation was lower after tube shunt surgery relative to trabeculectomy with MMC. PMID- 29477691 TI - Characterizing Anterior Segment OCT Angle Landmarks of the Trabecular Meshwork Complex. AB - PURPOSE: To identify the presence or absence of 3 identifiable landmarks: trabecular meshwork (TM), Schlemm's canal (SC), and a novel landmark termed the band of extracanalicular limbal lamina (BELL), which is a landmark adjacent to SC visible on anterior segment (AS) OCT. These landmarks also were analyzed pathologically to identify all 3 landmarks. DESIGN: Retrospective review. PARTICIPANTS: One eye per participant from prior institutional review board approved studies in which AS OCT imaging was performed. METHODS: Horizontal images from 2-dimensional angle analysis scans using a CASIA SS-1000 (Tomey, Nagoya, Japan) AS OCT were evaluated by masked readers. Logistic regression was used to analyze the potential factors of age, gender, race, intraocular pressure, gonioscopy grade, angle location, and history or presence of surgery on the visibility of these structures. Pathologic correlation on 5 previously enucleated eyes also was performed. MAIN OUTCOME MEASURES: Presence or absence of angle landmarks-TM, SC, and BELL-using Anterior Chamber Analysis and Interpretation software (ACAI, Houston, TX). RESULTS: Three hundred three angles of 153 horizontal images were included in this study. The mean age was 51.5+/-16.0 years, with 98 women (64%) and 100 white persons (66%). The outer border of the BELL was observed in 288 angles (95%), TM was found in 220 angles (73%), and SC was seen in 120 angles (40%). The outer border of the BELL was more visible in white persons (P = 0.02) than Asians and in eyes with a Spaeth gonioscopy grade of E than those with a grade of A (P = 0.02). Both TM (P = 0.001) and SC (P = 0.001) were more visible in temporal angles (81% for TM, 49% for SC) than in nasal angles (64% for TM, 30% for SC). Additionally, SC was more visible in open angles (43%) than in narrow angles (27%; P = 0.02). These 3 structures were verified in a pathologic study. CONCLUSIONS: We identified a novel AS OCT landmark adjacent to SC. This structure also was identified on pathologic samples from enucleated eyes. Further study is needed to determine the pathophysiologic relevance of these findings. PMID- 29477692 TI - Macular Atrophy in the HARBOR Study for Neovascular Age-Related Macular Degeneration. AB - PURPOSE: To evaluate macular atrophy (MA) presence in the 24-month HARBOR study (NCT00891735) for neovascular age-related macular degeneration (AMD). DESIGN: Post hoc analysis of a phase 3 multicenter, prospective, randomized, double masked, active treatment-controlled clinical trial. PARTICIPANTS: Evaluable subjects (N = 1095) with subfoveal choroidal neovascularization (CNV) secondary to neovascular AMD treated with ranibizumab 0.5 mg or 2.0 mg monthly or pro re nata (PRN). METHODS: Fluorescein angiograms (FAs) and color fundus photographs at baseline and months 3, 12, and 24 were retrospectively graded by masked graders for MA: well-defined areas of depigmentation with increased choroidal vessel visibility, diameter >=250 MUm, corresponding to flat areas of well-demarcated staining on FA, excluding atrophy associated with retinal pigment epithelium tears. Atrophy immediately within, adjacent, and nonadjacent to CNV lesions was included. MAIN OUTCOME MEASURES: Macular atrophy incidence, best-corrected visual acuity (BCVA). RESULTS: At baseline, MA was detected in 11.2% (123/1095) of study eyes. At month 24, 29.4% (229/778) of eyes without baseline atrophy had detectable MA. Eyes with and without baseline MA had significant mean BCVA gains from baseline at month 24 (letters [95% confidence interval]: +6.7 [4.1-9.3]; +9.1 [8.0-10.2], respectively). Among eyes with and without MA at month 24, mean month 24 BCVA was 62.0 [60.3-63.7] and 64.7 [63.2-66.3] letters, respectively. Baseline risk factors for month 24 MA presence included intraretinal cysts (hazard ratio [HR], 2.45 [1.76-3.42]) and fellow eye atrophy (HR, 2.02 [1.42 2.87]); subretinal fluid was associated with a lower MA risk (HR, 0.50 [0.33 0.74]). Ranibizumab dose was not associated with MA development. Monthly versus PRN treatment trended toward an association with MA (HR, 1.29 [0.99-1.68]), but was not statistically significant. CONCLUSIONS: New MA was detected in 29% of study eyes after 24 months of treatment. Clinically significant BCVA gains were achieved with MA present over 24 months. Baseline subretinal fluid absence, intraretinal cyst presence, and fellow eye atrophy presence were associated with month 24 MA presence. With existing data, the benefits of ranibizumab for neovascular AMD outweighed the risk of MA development over 24 months in HARBOR, although outcomes >2 years were not evaluated. PMID- 29477693 TI - Adolescent varicocele: Efficacy of indication-to-treat protocol and proposal of a grading system for postoperative hydroceles. AB - BACKGROUND: Varicocele is a common urologic anomaly in adolescent males; however, evidence-based treatment guidelines do not exist. Hydroceles are known to be a common complication after surgical therapy, with a wide variation in the reported incidence between 1 and 40%. AIM: This study aimed to introduce a standardized indication-to-treat protocol and prove its efficacy by analyzing the outcome of patients. Secondly, it aimed to better define postoperative hydroceles because the wide variation of reported incidence is attributed to a lack of definition. METHODS: Our standardized treatment protocol included an initial assessment with clinical grading of varicoceles, ultrasound evaluation of testicular volume, and calculation of the atrophy index. Indications for surgical treatment were testicular volume asymmetry >20%, discomfort and pain, or bilateral varicocele. The Palomo procedure (laparoscopically since 2005) was the standard procedure. Postoperative hydroceles were graded according to clinical findings and symptoms: Grade I, sonographic chance finding without clinical correlate; Grade II, palpable but clinically insignificant; Grade III, symptomatic. All patients treated according to the defined protocol were prospectively monitored between January 2001 and December 2015. RESULTS: A total of 129 patients with left varicocele were referred to our institution; 70 fulfilled the indication criteria for surgical treatment. Twenty-eight of these patients were treated for volume asymmetry, 26 of these showed catch-up growth. Forty-two patients were treated for discomfort and pain; the symptoms subsided in all of them. Postoperative hydroceles were detected in 36 patients (51%). In 29 patients this was a sonographic chance finding (Grade I). Three patients showed a palpable but clinically insignificant postoperative hydrocele (Grade II) and four patients (5.7%) showed symptomatic hydrocele (Grade III) where treatment was recommended. DISCUSSION: The treatment protocol allowed judicious indication for surgery and postoperative outcomes similar to previous reports. The high rate of catch-up growth in operated cases represents a proxy for successful treatment in cases where more precise parameters, like semen quality or paternity rate, were not yet detectable. The introduced grading system for postoperative hydroceles provs to be a valid and appropriate instrument, and promises to be a standardized method for comparing outcomes in future studies. CONCLUSION: The indication-to-treat protocol proved to be easily applicable, highly efficient, and have outcomes comparable to international literature. The necessity for a standardized grading of postoperative hydroceles was underscored in the data. PMID- 29477694 TI - Ethical issues in research: Human and animal experimentation. PMID- 29477696 TI - Calpain-2 Regulates TNF-alpha Expression Associated with Neuropathic Pain Following Motor Nerve Injury. AB - Both calpain-2 (CALP2) and tumor necrosis factor-alpha (TNF-alpha) contribute to persistent bilateral hypersensitivity in animals subjected to L5 ventral root transection (L5-VRT), a model of selective motor fiber injury without sensory nerve damage. However, specific upstream mechanisms regulating TNF-alpha overexpression and possible relationships linking CALP2 and TNF-alpha have not yet been investigated in this model. We examined changes in CALP2 and TNF-alpha protein levels and alterations in bilateral mechanical threshold within 24 h following L5-VRT model injury. We observed robust elevation of CALP2 and TNF alpha in bilateral dorsal root ganglias (DRGs) and bilateral spinal cord neurons. CALP2 and TNF-alpha protein induction by L5-VRT were significantly inhibited by pretreatment using the calpain inhibitor MDL28170. Administration of CALP2 to rats without nerve injury further supported a role of CALP2 in the regulation of TNF-alpha expression. Although clinical trials of calpain inhibition therapy for alleviation of neuropathic pain induced by motor nerve injury have not yet shown success, our observations linking CALP2 and TNF-alpha provide a framework of a systems' approach based perspective for treating neuropathic pain. PMID- 29477695 TI - Prefrontal-limbic Functional Connectivity during Acquisition and Extinction of Conditioned Fear. AB - This study is a new analysis to obtain novel metabolic data on the functional connectivity of prefrontal-limbic regions in Pavlovian fear acquisition and extinction of tone-footshock conditioning. Mice were analyzed with the fluorodeoxyglucose (FDG) autoradiographic method to metabolically map regional brain activity. New FDG data were sampled from the nuclei of the habenula and other regions implicated in aversive conditioning, such as infralimbic cortex, amygdala and periaqueductal gray regions. The activity patterns among these regions were inter-correlated during acquisition, extinction or pseudorandom training to develop a functional connectivity model. Two subdivisions of the habenular complex showed increased activity after acquisition relative to extinction, with the pseudorandom group intermediate between the other two groups. Significant acquisition activation effects were also found in centromedial amygdala, dorsomedial and ventrolateral periaqueductal gray. FDG uptake increases during extinction were found only in dorsal and ventral infralimbic cortex. The overall pattern of activity correlations between these regions revealed extensive but differential functional connectivity during acquisition and extinction training, with less functional connectivity found after pseudorandom training. Interestingly, habenula nuclei showed a distinct pattern of inter-correlations with amygdala nuclei during extinction. The functional connectivity model revealed changing interactions among infralimbic cortex, amygdala, habenula and periaqueductal gray regions through the stages of Pavlovian fear acquisition and extinction. This study provided new data on the contributions of the habenula to fear conditioning, and revealed previously unreported infralimbic-amygdala-habenula-periaqueductal gray interactions implicated in acquisition and extinction of conditioned fear. PMID- 29477697 TI - Persistent hair cell malfunction contributes to hidden hearing loss. AB - Noise exposures that result in fully reversible changes in cochlear neural threshold can cause a reduced neural output at supra-threshold sound intensity. This so-called "hidden hearing loss" has been shown to be associated with selective degeneration of high threshold afferent nerve fiber-inner hair cell (IHC) synapses. However, the electrophysiological function of the IHCs themselves in hidden hearing loss has not been directly investigated. We have made round window (RW) measurements of cochlear action potentials (CAP) and summating potentials (SP) after two levels of a 10 kHz acoustic trauma. The more intense acoustic trauma lead to notch-like permanent threshold changes and both CAP and SP showed reductions in supra-threshold amplitudes at frequencies with altered thresholds as well as from fully recovered regions. However, the interpretation of the results in normal threshold regions was complicated by the likelihood of reduced contributions from adjacent regions with elevated thresholds. The milder trauma showed full recovery of all neural thresholds, but there was a persistent depression of the amplitudes of both CAP and SP in response to supra-threshold sounds. The effect on SP amplitude in particular shows that occult damage to hair cell transduction mechanisms can contribute to hidden hearing loss. Such damage could potentially affect the supra-threshold output properties of surviving primary afferent neurons. PMID- 29477698 TI - Serum Malondialdehyde Levels and Mortality in Patients with Spontaneous Intracerebral Hemorrhage. AB - OBJECTIVE: Oxidative stress has been associated with secondary brain injury after spontaneous intracerebral hemorrhage (SIH). Malondialdehyde (MDA) appears in blood during lipid oxidation. Higher serum MDA levels have been found in patients with SIH than in healthy controls; however, we have not found data indicating an association between elevated serum MDA and early mortality in this population. This was the main objective of our study. METHODS: MDA levels were measured in serum samples obtained from 100 patients at diagnosis of severe SIH (Glasgow Coma Scale score <=8) and 80 healthy controls. The endpoint of the study was mortality at 30 days. RESULTS: Serum MDA levels were significantly higher in patients with severe SIH than in healthy controls (1.46 [1.18-2.2] vs. 1.11 [0.72-1.51]; P < 0.001), and in nonsurviving (n = 46) than in surviving (n = 54) patients (1.68 [1.23-4.02] vs. 1.37 [0.99-1.92]; P = 0.002). The area under the receiving operating characteristic curve of serum MDA levels to predict 30-day mortality was 0.68 (95% CI, 0.58-0.77; P < 0.001). Serum MDA levels were associated with 30 day mortality (OR, 6.279; 95% CI, 1.940-20.319; P = 0.002). CONCLUSIONS: The most important new finding of our study is that there is an association between serum MDA levels at diagnosis of severe SIH and early mortality. PMID- 29477699 TI - Acute Deafness: A Rare Complication of Shunting. AB - BACKGROUND: Mild hearing loss following shunting has been described; however, severe auditory impairment associated with ventriculoperitoneal (VP) shunt is an uncommon, rarely reported phenomenon. Treatment options and pathophysiologic considerations are discussed in this case report. CASE DESCRIPTION: A 27-year-old man who was treated for an eighth cranial nerve schwannoma with complete resection and a VP shunt 10 years previously presented to the emergency department with acute severe hearing loss and headache. Imaging showed diminished size of the ventricles and dural contrast enhancement. The previous shunt was replaced with a programmable antisiphoning VP shunt. The patient's hearing and headache improved 48 hours later, as demonstrated in serial audiograms. CONCLUSIONS: Hearing loss is an underestimated complication of shunting that in some cases may progress to severe impairment and deafness. Patients with a VP shunt who experience hearing loss should undergo further evaluation and possibly adjustment of shunt settings. PMID- 29477700 TI - The Nuchal Lines as Anatomic Landmarks to Dissect the Muscles in the Far Lateral Approach. AB - BACKGROUND: A critical step in the far lateral approach (FLA) is exposure of the V3 segment of the vertebral artery, located deep in the suboccipital triangle (SOT). Safe exposure of the SOT is achieved by means of a plane-by-plane dissection, which carries the risk of devascularization. A suitable alternative is to lift a cutaneous muscle flap including the 3 first muscle planes and leave the deepest plane (SOT) attached to the skull base. To achieve this, it is necessary to have superficial anatomic landmarks to help identify the cleavage site. We describe the use of the nuchal lines as a safe, effective, and reproducible method to dissect the muscles to expose the SOT and vertebral artery. METHODS: Eight adult cadaveric heads, fixed with formaldehyde and injected, were studied. On both sides, FLA was simulated by using the nuchal lines as anatomic landmarks to expose the SOT. This technique was later applied on 10 patients requiring FLA. RESULTS: Anatomic dissections confirmed identification, by means of the nuchal lines, of a cleavage site, which made it possible to separate the deepest muscle plane from the rest of the flap. This technique was successfully applied in 10 patients undergoing FLA. CONCLUSIONS: The nuchal lines allow dissection of muscles in 2 groups, one superficial and the other deep (SOT), which remains attached to the skull base. The V3 segment of the vertebral artery is easily exposed. PMID- 29477701 TI - The Role of Angiotensin-Converting Enzyme Inhibitors in Patients with Chronic Subdural Hematoma: A Scandinavian Population-Based Multicenter Study. AB - OBJECTIVE: To investigate the role of angiotensin converting enzyme (ACE) inhibitors in the recurrence of chronic subdural hematoma (cSDH) after burr hole surgery. METHODS: A retrospective review was conducted of a Scandinavian multicenter, population-based cohort of 1252 adults with cSDH who underwent with burr hole surgery between January 1, 2005, and December 31, 2010. The risk of cSDH recurrence was assessed in users of ACE inhibitors, users of angiotensin II receptor blockers (ARBs), and those without ACE inhibitor treatment (no ACE inhibitor group) using univariable and multivariable regression analyses. RESULTS: The cohort included 98 (7.8%) ACE inhibitor users and 63 (5%) ARB-only users. The recurrence rate was 16.3% (n = 16) in the ACE inhibitor group, compared with 13.3% (n = 153) in the no ACE inhibitor group (P = 0.39) and 14.3% (n = 9) in the ARB group (P = 0.73). When comparing groups, age (P = 0.01), Charlson Comorbidity Index (P = 0.01), use of platelet inhibitors (P = 0.001) and use of anticoagulants (P = 0.01) differed between the ACE inhibitor and no ACE inhibitor groups. Only age differed significantly between the ACE inhibitor and ARB groups (P = 0.03). In the analyses adjusted for differences in baseline characteristics, ACE inhibitor treatment did not influence the risk of recurrence (odds ratio, 1.2; 95% confidence interval, 0.7-2.2; P = 0.46). CONCLUSION: In this population-based study, the use of ACE inhibitors was not associated with the risk of recurrence following burr hole surgery for cSDH. PMID- 29477702 TI - Immediate Flow Disruption as a Prognostic Factor After Flow Diverter Treatment: Long-Term Experience with the Pipeline Embolization Device. AB - OBJECTIVE: To report long-term results after Pipeline Embolization Device (PED) implantation, characterize complex and standard aneurysms comprehensively, and introduce a modified flow disruption scale. METHODS: We retrospectively reviewed a consecutive series of 40 patients harboring 59 aneurysms treated with 54 PEDs. Aneurysm complexity was assessed using our proposed classification. Immediate angiographic results were analyzed using previously published grading scales and our novel flow disruption scale. RESULTS: According to our new definition, 46 (78%) aneurysms were classified as complex. Most PED interventions were performed in the paraophthalmic and cavernous internal carotid artery segments. Excellent neurologic outcome (modified Rankin Scale 0 and 1) was observed in 94% of patients. Our data showed low permanent procedure-related mortality (0%) and morbidity (3%) rates. Long-term angiographic follow-up showed complete occlusion in 81% and near-total obliteration in a further 14%. Complete obliteration after deployment of a single PED was achieved in all standard aneurysms with 1-year follow-up. Our new scale was an independent predictor of aneurysm occlusion in a multivariable analysis. All aneurysms with a high flow disruption grade showed complete occlusion at follow-up regardless of PED number or aneurysm complexity. CONCLUSIONS: Treatment with the PED should be recognized as a primary management strategy for a highly selected cohort with predominantly complex intracranial aneurysms. We further show that a priori assessment of aneurysm complexity and our new postinterventional angiographic flow disruption scale predict occlusion probability and may help to determine the adequate number of per-aneurysm devices. PMID- 29477703 TI - Latent Toxoplasma gondii infection is associated with decreased serum triglyceride to high-density lipoprotein cholesterol ratio in male patients with schizophrenia. AB - BACKGROUND: Previous studies suggested a complex association between Toxoplasma gondii (TG) infection and host lipid metabolism. Both TG infection and metabolic disturbances are very common in patients with schizophrenia, but this relationship is not clear. METHODS: In this cross-sectional study, we evaluated the association between TG seropositivity, serum lipid levels, body mass index (BMI) and metabolic syndrome (MetS) in 210 male inpatients with schizophrenia. RESULTS: In our sample of schizophrenia patients, with the mean age of 43.90 +/- 12.70 years, the rate of TG seropositivity was 52.38% and the prevalence of MetS was 17%. Patients with the TG antibodies had lower serum triglyceride levels and body weight compared to TG seronegative patients, despite having more frequently received antipsychotics (clozapine, olanzapine risperidone and quetiapine), which are well known to induce weight gain and metabolic abnormalities. However, the only significant change in metabolic parameters, observed in TG seropositive patients with schizophrenia, was decreased serum triglyceride to high-density lipoprotein cholesterol (HDL-C) ratio. No associations were observed between TG seropositivity and serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and glucose levels, waist circumference, BMI and the rate of MetS. CONCLUSION: This is the first report of the association between TG infection and decreased serum triglyceride to HDL-C ratio in a sample of carefully selected men with chronic schizophrenia. PMID- 29477704 TI - The role of expressive suppression in hallucinatory-like and delusion-like experiences. Findings in a non-clinical sample. AB - INTRODUCTION: Previous works concerning emotion regulation in psychosis highlighted the relationship between expressive suppression and negative psychotic symptoms, as well as between expressive suppression and auditory hallucinations. However, a direct association between suppression and delusions has not been observed. In the study we examined whether expressive suppression is associated with psychotic-like experiences and whether it may influence delusion like experiences by changing the impact of cognitive biases on delusional beliefs. METHODS: Two hundred and twenty-one healthy individuals never diagnosed with psychiatric disorders completed self-report questionnaires measuring: delusion-like experiences, hallucinatory-like experiences, cognitive biases and expressive suppression. Regression and moderation analyses were performed. RESULTS: Regression analyses revealed that the overall level of suppression predicts hallucinatory-like experiences, but not delusion-like experiences. Suppression of anxiety and suppression of sadness were significant predictors of hallucinatory-like experiences, whereas suppression of anxiety predicted delusion like experiences. A moderation analysis indicated that both the overall level of suppression and suppression of sadness moderate the relationship between belief inflexibility and delusion-like experiences in such a way that belief inflexibility increases delusion-like experiences only among individuals reporting a low level of suppression. CONCLUSIONS: Our findings confirmed that expressive suppression has a direct impact on hallucinatory-like experiences and suggest that the use of suppression may influence delusion-like experiences by moderating the impact of belief inflexibility on delusional thinking. PMID- 29477705 TI - Restrictive eating and nonsuicidal self-injury in a nonclinical sample: Co occurrence and associations with emotion dysregulation and interpersonal problems. AB - Disordered eating frequently co-occurs with nonsuicidal self-injury (NSSI), and evidence suggests that the co-occurrence of these behaviors is associated with heightened emotion dysregulation. However, little is known about the relationship between restrictive eating and NSSI, and the significance of their co-occurrence. This study examined cross-sectional associations between self-reported restrictive eating, NSSI, and putative mechanisms of emotion regulation and interpersonal problems in a non-clinical sample of undergraduate students (N = 98, 80.6% female), using the Dietary Restriction Screener (Haynos & Fruzzetti, 2015), Deliberate Self-Harm Inventory (Gratz, 2001), Difficulties in Emotion Regulation Scale (Gratz & Roemer, 2006), and Inventory of Interpersonal Problems Personality Disorders-25 (Kim & Pilkonis, 1999). Hierarchical logistic regression analyses indicated that restrictive eating was associated with NSSI above and beyond the influence of binge eating, purging, and relevant covariates (B = 2.04, p < 0.001). In addition, multivariate analyses of variance revealed that the co occurrence of restrictive eating and NSSI was associated with greater difficulties accessing and implementing effective, rather than impulsive, emotion regulation strategies when distressed than either behavior alone (p < 0.001). Findings highlight the seriousness of restrictive eating even within a nonclinical sample, as it is associated with heightened probability of NSSI and clinical severity among those who engage in co-morbid NSSI. Healthcare providers are encouraged to screen for NSSI among individuals with restrictive eating. In addition, a focus on improving emotion regulation and interpersonal skills may enhance prevention and intervention efforts for individuals with co-occurring restrictive eating and NSSI behaviors. PMID- 29477706 TI - The relationship between distress tolerance regulation, counterfactual rumination, and PTSD symptom clusters. PMID- 29477708 TI - Biodegradable near-infrared-photoresponsive shape memory implants based on black phosphorus nanofillers. AB - In this paper, we propose a new shape memory polymer (SMP) composite with excellent near-infrared (NIR)-photoresponsive shape memory performance and biodegradability. The composite is fabricated by using piperazine-based polyurethane (PU) as thermo-responsive SMP incorporated with black-phosphorus (BP) sheets as NIR photothermal nanofillers. Under 808 nm light irradiation, the incorporated BP sheets with concentration of only 0.08 wt% enable rapid temperature increase over the glass temperature of PU and trigger the shape change of the composite with shape recovery rate of ~100%. The in vitro and in vivo toxicity examinations demonstrate the good biocompatibility of the PU/BP composite, and it degrades naturally into non-toxic carbon dioxide and water from PU and non-toxic phosphate from BP. By implanting PU/BP columns into back subcutis and vagina of mice, they exhibit excellent shape memory activity to change their shape quickly under moderate 808 nm light irradiaiton. Such SMP composite enable the development of intelligent implantable devices, which can be easily controlled by the remote NIR light and degrade gradually after performing the designed functions in the body. PMID- 29477709 TI - An Unexpected Finding on Digital Rectal Examination. PMID- 29477710 TI - Do Most Obese People with Exercise Intolerance and a Normal Ejection Fraction Have Treatable Heart Failure? PMID- 29477707 TI - Blood brain barrier (BBB)-disruption in intracortical silicon microelectrode implants. AB - Chronically implanted microelectrodes in the neural tissue elicit inflammatory responses that are time varying and have been shown to depend on multiple factors. Among these factors, blood brain barrier (BBB)-disruption has been hypothesized as one of the dominant factors resulting in electrode failure. A series of events that includes BBB and cell-membrane disruption occurs during electrode implantation that triggers multiple biochemical cascades responsible for microglial and astroglial activation, hemorrhage, edema, and release of pro inflammatory neurotoxic cytokines that causes neuronal degeneration and dysfunction. Typically, microwire arrays and silicon probes are inserted slowly into the neural tissue whereas the silicon Utah MEAs (UMEA) are inserted at a high speed using a pneumatic inserter. In this work, we report the sequelae of electrode-implant induced cortical injury at various acute time points in UMEAs implanted in the brain tissue by quantifying the expression profile for key genes mediating the inflammatory response and tight junction (TJ) and adherens junction (AJ) proteins that form the BBB and are critical to the functioning of the BBB. Our results indicated upregulation of most pro-inflammatory genes relative to naive controls for all time points. Expression levels for the genes that form the TJ and AJ were downregulated suggestive of BBB-dysfunction. Moreover, there was no significant difference between stab and implant groups suggesting the effects of UMEA insertion-related trauma in the brain tissue. Our results provide an insight into the physiological events related to neuroinflammation and BBB disruption occurring at acute time-points following insertion of UMEAs. PMID- 29477711 TI - Serine proteases in schistosomes and other trematodes. AB - Trematodes, also known as flukes, are phylogenetically ancient parasitic organisms. Due to their importance as human and veterinary parasites, their proteins have been investigated extensively as drug and vaccine targets. Among those, proteases, as crucial enzymes for parasite survival, are considered candidate molecules for anti-parasitic interventions. Surprisingly however, trematode serine proteases, in comparison with other groups of proteases, are largely neglected. Genes encoding serine proteases have been identified in trematode genomes in significant abundance, but the biological roles and biochemical functions of these proteases are poorly understood. However, increasing volumes of genomic and proteomic studies, and accumulated experimental evidence, indicate that this class of proteases plays a substantial role in host parasite interactions and parasite survival. Here, we discuss in detail serine proteases at genomic and protein levels, and their known or hypothetical functions. PMID- 29477712 TI - Surgical management of fibroids: Putting morcellation into perspective. PMID- 29477713 TI - In-host microevolution of Aspergillus fumigatus: A phenotypic and genotypic analysis. AB - In order to survive, Aspergillus fumigatus must adapt to specific niche environments. Adaptation to the human host includes modifications facilitating persistent colonisation and the development of azole resistance. The aim of this study is to advance understanding of the genetic and physiological adaptation of A. fumigatus in patients during infection and treatment. Thirteen A. fumigatus strains were isolated from a single chronic granulomatous disease patient suffering from persistent and recurrent invasive aspergillosis over a period of 2 years. All strains had identical microsatellite genotypes and were considered isogenic. Whole genome comparisons identified 248 non-synonymous single nucleotide polymorphisms. These non-synonymous mutations have potential to play a role in in-host adaptation. The first 2 strains isolated were azole susceptible, whereas later isolates were itraconazole, voriconazole and/or posaconazole resistant. Growth assays in the presence and absence of various antifungal stressors highlighted minor changes in growth rate and stress resistance, with exception of one isolate showing a significant growth defect. Poor conidiation was observed in later isolates. In certain drug resistant isolates conidiation was restored in the presence of itraconazole. Differences in virulence were observed as demonstrated in a Galleria mellonella infection model. We conclude that the microevolution of A. fumigatus in this patient has driven the emergence of both Cyp51A-independent and Cyp51A-dependent, azole resistance mechanisms, and additional phenotypes that are likely to have promoted fungal persistence. PMID- 29477715 TI - My Path from Hiroshima to Houston. PMID- 29477714 TI - "Call for Standardization of RILD Toxicity Reporting and Multi-institutional Collaboration". PMID- 29477716 TI - Gender Specific Differences in Disease-Free, Cancer Specific and Overall Survival after Radical Cystectomy for Bladder Cancer: A Systematic Review and Meta Analysis. AB - PURPOSE: We summarize the evidence on gender specific differences in disease free, cancer specific and overall survival after radical cystectomy for bladder cancer. MATERIALS AND METHODS: We performed a systematic literature search of MEDLINE(r), Embase(r) and the Cochrane Library in July 2017. Studies evaluating gender specific differences in disease-free, cancer specific or overall survival after radical cystectomy for bladder cancer were included in study. Analyses included random effect meta-analysis, subgroup analyses, meta-influence and cumulative meta-analyses. Funnel plots and the Egger test were used to assess publication bias. RESULTS: Of the 3,868 studies identified during the literature search 59 published between 1998 and 2017 were included in analysis. Of the studies 30 in a total of 38,321 patients evaluated disease-free survival, 44 in a total of 69,666 evaluated cancer specific survival and 26 in a total of 30,039 evaluated overall survival. Random effect meta-analyses revealed decreased disease-free, cancer specific survival and overall survival in female patients than in their male counterparts. Pooled estimates showed a HR of 1.16 (95% CI 1.06-1.27, p = 0.0018) for disease-free survival, 1.23 (95% CI 1.15-1.31, p <0.001) for cancer specific survival and 1.08 (95% CI 1.03-1.12, p = 0.0004) for overall survival. Subgroup analyses confirmed impaired disease-free, cancer specific and overall survival in female patients in all strata. Publication bias was evident only for studies of cancer specific survival (Egger test p = 0.0029). After adjusting for publication bias by the trim and fill method the corrected pooled estimated HR of cancer specific survival was 1.13 (95% CI 1.05-1.21, p = 0.0012). CONCLUSIONS: Female patients who underwent radical cystectomy for bladder cancer demonstrated worse disease-free, cancer specific and overall survival than their male counterparts. The multifactorial etiology might include epidemiological differences, gender specific health care discrepancies and hormonal influences. PMID- 29477717 TI - A Single Center Evaluation of the Diagnostic Accuracy of Multiparametric Magnetic Resonance Imaging against Transperineal Prostate Mapping Biopsy: An Analysis of Men with Benign Histology and Insignificant Cancer following Transrectal Ultrasound Biopsy. AB - PURPOSE: In this study we evaluated the diagnostic performance of transrectal ultrasound guided biopsy and multiparametric magnetic resonance imaging to detect prostate cancer against transperineal prostate mapping biopsy as the reference test. MATERIALS AND METHODS: Transrectal ultrasound guided biopsy, multiparametric magnetic resonance imaging and transperineal prostate mapping biopsy were performed in 426 patients between April 2012 and January 2016. Patients initially underwent systematic 12 core transrectal ultrasound guided biopsy followed 3 months later by 1.5 Tesla, high resolution T2, diffusion weighted, dynamic contrast enhanced multiparametric magnetic resonance imaging. Two specialist uroradiologists blinded to the results of transperineal prostate mapping biopsy allocated a PI-RADSTM (Prostate Imaging-Reporting and Data System) score to each multiparametric magnetic resonance imaging study. Transperineal prostate mapping biopsy with 5 mm interval sampling, which was performed within 6 months of multiparametric magnetic resonance imaging, served as the reference test. RESULTS: Transrectal ultrasound guided biopsy identified 247 of 426 patients with prostate cancer and 179 of 426 with benign histology. Transperineal prostate mapping biopsy detected prostate cancer in 321 of 426 patients. On transperineal prostate mapping biopsy 94 of 179 patients with benign transrectal ultrasound guided biopsy had prostate cancer and 95 of 247 with prostate cancer on transrectal ultrasound guided biopsy were identified with cancer of higher grade. Using a multiparametric magnetic resonance imaging PI-RADS score of 3 or greater to detect significant prostate cancer, defined as any core containing Gleason 4 + 3 or greater prostate cancer on transperineal prostate mapping biopsy, the ROC AUC was 0.754 (95% CI 0.677-0.819) with 87.0% sensitivity (95% CI 77.3-97.0), 55.3% specificity (95% CI 50.2-60.4) and 97.1% negative predictive value (95% CI 94.8-99.4). CONCLUSIONS: Multiparametric magnetic resonance imaging is a more accurate diagnostic test than transrectal ultrasound guided biopsy. However, a significant proportion of ISUP (International Society of Urological Pathology) Grade Group 2 prostate cancer remained undetected following multiparametric magnetic resonance imaging. Although multiparametric magnetic resonance imaging could avoid unnecessary biopsy in many patients with ISUP Grade Group 3 or greater prostate cancer, at less stringent definitions of significant cancer a substantial proportion of prostate cancer would remain undetected after multiparametric magnetic resonance imaging. PMID- 29477719 TI - Low Intensity Shock Wave Treatment for Erectile Dysfunction-How Long Does the Effect Last? AB - PURPOSE: We studied the long-term efficacy of penile low intensity shock wave treatment 2 years after an initially successful outcome. MATERIALS AND METHODS: Men with a successful outcome of low intensity shock wave treatment according to the minimal clinically important difference on the IIEF-EF (International Index of Erectile Function-Erectile Function) questionnaire were followed at 6, 12, 18 and 24 months. Efficacy was assessed by the IIEF-EF. Failure during followup was defined as a decrease in the IIEF-EF below the minimal clinically important difference. RESULTS: We screened a total of 156 patients who underwent the same treatment protocol but participated in different clinical studies. At 1 month treatment was successful in 99 patients (63.5%). During followup a gradual decrease in efficacy was observed. The beneficial effect was maintained after 2 years in only 53 of the 99 patients (53.5%) in whom success was initially achieved. Patients with severe erectile dysfunction were prone to earlier failure than those with nonsevere erectile dysfunction. During the 2-year followup the effect of low intensity shock wave treatment was lost in all patients with diabetes who had severe erectile dysfunction at baseline. On the other hand, patients with milder forms of erectile dysfunction without diabetes had a 76% chance that the beneficial effect of low intensity shock wave treatment would be preserved after 2 years. CONCLUSIONS: Low intensity shock wave treatment is effective in the short term but treatment efficacy was maintained after 2 years in only half of the patients. In patients with milder forms of erectile dysfunction the beneficial effect is more likely to be preserved. PMID- 29477718 TI - Prevalence and Characteristics of Urinary Incontinence in a Treatment Seeking Male Prospective Cohort: Results from the LURN Study. AB - PURPOSE: Male urinary incontinence is thought to be infrequent. We sought to describe the prevalence of urinary incontinence in a male treatment seeking cohort enrolled in the LURN (Symptoms of Lower Urinary Tract Dysfunction Research Network). MATERIALS AND METHODS: Study inclusion and exclusion criteria, including men with prostate cancer or neurogenic bladder, were previously reported. LURN participants prospectively completed questionnaires regarding lower urinary tract symptoms and other clinical variables. Men were grouped based on incontinence type, including 1) no urinary incontinence, 2) post-void dribbling only and 3) urinary incontinence. Comparisons were made using ANOVA and multivariable regression. RESULTS: Of the 477 men 24% reported no urinary incontinence, 44% reported post-void dribbling only and 32% reported urinary incontinence. African American men and those with sleep apnea were more likely to be in the urinary incontinence group than in the no urinary incontinence group (OR 3.2, p = 0.02 and OR 2.73, p = 0.003, respectively). Urinary incontinence was associated with significantly higher bother compared to men without leakage (p <0.001). Compared to men without urinary incontinence and men with only post-void dribbling those with urinary incontinence were significantly more likely to report higher scores (more severe symptoms) on the PROMIS (Patient-Reported Outcomes Measurement Information System) questionnaires regarding bowel issues, depression and anxiety than men without urinary incontinence (p <0.01). CONCLUSIONS: Urinary incontinence is common among treatment seeking men. This is concerning because the guideline recommended questionnaires to assess male lower urinary tract symptoms do not query for urinary incontinence. Thus, clinicians may be missing an opportunity to intervene and improve patient care. This provides a substantial rationale for a new or updated symptom questionnaire which provides a more comprehensive symptom assessment. PMID- 29477720 TI - Impact of Androgen Deprivation Therapy on Self-Reported Cognitive Function in Men with Prostate Cancer. AB - PURPOSE: Although androgen deprivation therapy is widely used to treat prostate cancer, its effects on cognitive function are unclear. To our knowledge no prior report has examined the impact of androgen deprivation therapy on self-reported cognitive function. MATERIALS AND METHODS: Three groups of men 50 years old or older who were matched on age and education were enrolled in the study, including 81 with prostate cancer starting on continuous androgen deprivation therapy, 84 controls with prostate cancer not receiving androgen deprivation therapy and 85 healthy controls. Two scales from the FACT-Cog (Functional Assessment of Cancer Therapy-Cognitive subscale) version 3 were used to assess self-reported cognitive function. Changes in cognitive scores with time were analyzed by 2 approaches, including 1) multivariable regression and 2) calculation of the proportion of subjects per group with a decrease of 1 SD or more. Multivariable regression was applied to assess predictors of a decline in self-reported cognitive function. We also examined relationships between the FACT-Cog and a neuropsychological battery of 15 tests. RESULTS: Mean participant age was 69 years (range 50 to 87). The mean educational level was 15 years (range 8 to 24). FACT-Cog scores were similar at baseline across the cohorts. Neither analytical approach revealed that androgen deprivation therapy was associated with changes in self-reported cognitive function on either FACT-Cog scale. Mood and fatigue correlated with changes in self-reported cognitive function. The relationship between self reported and objective cognitive measures was weak (maximum Spearman correlation coefficient 0.14) and only 2 of 30 correlations were statistically significant. CONCLUSIONS: A total of 12 months of androgen deprivation therapy were not associated with self-reported cognitive function changes in older men with nonmetastatic prostate cancer. PMID- 29477722 TI - Feasibility and Safety of Ultrasonography Guidance and Flank Position during Percutaneous Nephrolithotomy. AB - PURPOSE: Percutaneous nephrolithotomy is generally performed using fluoroscopy, which is associated with exposure to radiation. Another drawback of fluoroscopic guided percutaneous nephrolithotomy is the prone position, which is not suitable for all patients. In this study we evaluated the feasibility, safety and efficacy of ultrasound guided percutaneous nephrolithotomy with the patient in the flank position. MATERIALS AND METHODS: A total of 603 patients with a mean +/- SD age of 50.9 +/- 13 years were included in this study from December 2010 to July 2016. Access to the collecting system and tract dilation were performed under ultrasound guidance. Perioperative data on the stone-free rate, operative time, length of stay and complication rates were recorded. RESULTS: Successful access was achieved in all but 1 patient. Mean operative time was 56.6 +/- 6.5 minutes. Complete stone clearance was achieved in 529 patients (87.7%) and Clavien-Dindo grade 3 complications were noted in 17 (2.8%). Blood transfusion was necessary in 43 patients (7.1%). However, bleeding was self-limited in all cases and did not require angioembolization. CONCLUSIONS: To our knowledge this is the largest series of ultrasound guided percutaneous nephrolithotomy with the patient in the flank position. Unlike in other studies we used this procedure in all patients irrespective of stone burden, renal anomaly and body habitus. Ultrasound guided percutaneous nephrolithotomy has outcomes comparable to those of conventional percutaneous nephrolithotomy and it is not associated with radiation exposure. Furthermore, anesthesia while in the flank position might be less harmful in some patients, including those with obesity or cardiopulmonary comorbidities. PMID- 29477721 TI - Quality Indicators for Global Benchmarking of Localized Prostate Cancer Management. AB - PURPOSE: We sought to develop a core set of clinical indicators to enable international benchmarking of localized prostate cancer management using data available in the TrueNTH Global Registry. MATERIALS AND METHODS: An international expert panel completed an online survey and participated in a face-to-face meeting. Participants included 3 urologists, 3 radiation oncologists, 2 psychologists, 1 medical oncologist, 1 nurse and 1 epidemiologist with prostate cancer expertise from a total of 7 countries. Current guidelines on prostate cancer treatment and potential quality indicators were identified from a literature review. These potential indicators were refined and developed through a modified Delphi process during which each panelist independently and repeatedly rated each indicator based on importance (satisfying the indicator demonstrated a provision of high quality care) and feasibility (the likelihood that data used to construct the indicator could be collected at a population level). The main outcome measure was items with panel agreement indicated by a disagreement index less 1, median importance 8.5 or greater and median feasibility 9 or greater. RESULTS: The expert panel endorsed 33 indicators. Seven of these 33 prostate cancer quality indicators assessed care relating to diagnosis, 7 assessed primary treatment, 1 assessed salvage treatment and 18 assessed health outcomes. CONCLUSIONS: We developed a set of quality indicators to measure prostate cancer care using numerous international evidence-based clinical guidelines. These indicators will be pilot tested in the TrueNTH Global Registry. Reports comparing indicator performance will subsequently be distributed to groups at participating sites with the purpose of improving the consistency and quality of prostate cancer management on a global basis. PMID- 29477723 TI - Pharmacological inhibition of caspase-8 suppresses inflammation-induced lymphangiogenesis and allograft rejection in the cornea. PMID- 29477725 TI - Mast cell-derived plasminogen activator inhibitor type 1 promotes airway inflammation and remodeling in a murine model of asthma. PMID- 29477726 TI - Personalized and rapid test for food-related allergy. PMID- 29477727 TI - Role of lipid mediators and control of lymphocyte responses in type 2 immunopathology. AB - Type 2 immunopathology is a cardinal feature of allergic diseases and involves cooperation between adaptive immunity and innate effector responses. Virtually all cell types relevant to this pathology generate leukotriene and/or prostaglandin mediators that derive from arachidonic acid, express receptors for such mediators, or both. Recent studies highlight prominent functions for these mediators in communication between the innate and adaptive immune systems, as well as amplification or suppression of type 2 effector responses. This review focuses on recent advances and insights, and highlights existing and potential therapeutic applications of drugs that target these mediators or their receptors, with a special emphasis on their regulation of the innate and adaptive lymphocytes relevant to type 2 immunopathology. PMID- 29477729 TI - Slow VO2 kinetics in acute hypoxia are not related to a hyperventilation-induced hypocapnia. AB - We examined whether slower pulmonary O2 uptake (VO2p) kinetics in hypoxia is a consequence of: a) hypoxia alone (lowered arterial O2 pressure), b) hyperventilation-induced hypocapnia (lowered arterial CO2 pressure), or c) a combination of both. Eleven participants performed 3-5 repetitions of step changes in cycle ergometer power output from 20W to 80% lactate threshold in the following conditions: i) normoxia (CON; room air); ii) hypoxia (HX, inspired O2 = 12%; lowered end-tidal O2 pressure [PETO2] and end-tidal CO2 pressure [PETCO2]); iii) hyperventilation (HV; increased PETO2 and lowered PETCO2); and iv) normocapnic hypoxia (NC-HX; lowered PETO2 and PETCO2 matched to CON). Ventilation was increased (relative to CON) and matched between HX, HV, and NC-HX conditions. During each condition VO2p was measured and phase II VO2p kinetics were modeled with a mono-exponential function. The VO2p time constant was different (p < 0.05) amongst all conditions: CON, 26 +/- 11s; HV, 36 +/- 14s; HX, 46 +/- 14s; and NC HX, 52 +/- 13s. Hypocapnia may prevent further slowing of VO2p kinetics in hypoxic exercise. PMID- 29477730 TI - Host Cell Targeting by Enteropathogenic Bacteria T3SS Effectors. AB - Microbial pathogens possess a diversity of weapons that disrupt host homeostasis and immune defenses, thus resulting in the establishment of infection. The best characterized system mediating bacterial protein delivery into target eukaryotic cells is the type III secretion system (T3SS) expressed by Gram-negative bacteria, including the human enteric pathogens Shigella, Salmonella, Yersinia, and enteropathogenic/enterohemorragic Escherichia coli (EPEC/EHEC). The emerging global view is that these T3SS-bearing pathogens share similarities in their ability to target key cellular pathways such as the cell cytoskeleton, trafficking, cell death/survival, and the NF-kappaB and MAPK signaling pathways. In particular, multiple host proteins are targeted in a given pathway, and different T3SS effectors from various pathogens share functional similarities. PMID- 29477728 TI - Prevalence and clinical challenges among adults with primary immunodeficiency and recombination-activating gene deficiency. PMID- 29477731 TI - Neighborhood characteristics, bystander automated external defibrillator use, and patient outcomes in public out-of-hospital cardiac arrest. AB - BACKGROUND: Automated external defibrillators (AEDs) can be used by bystanders to provide rapid defibrillation for patients with out-of-hospital cardiac arrest (OHCA). Whether neighborhood characteristics are associated with AED use is unknown. Furthermore, the association between AED use and outcomes has not been well characterized for all (i.e. shockable and non-shockable) public OHCAs. METHODS: We included public, non-911-responder witnessed OHCAs registered in the Cardiac Arrest Registry to Enhance Survival (CARES) between 2013 and 2016. The primary patient outcome was survival to hospital discharge with a favorable functional outcome. We first assessed the association between neighborhood characteristics and bystander AED use using logistic regression and then assessed the association between bystander AED use and patient outcomes in a propensity score matched cohort. RESULTS: 25,182 OHCAs were included. Several neighborhood characteristics, including the proportion of people living alone, the proportion of white people, and the proportion with a high-school degree or higher, were associated with bystander AED use. 5132 OHCAs were included in the propensity score-matched cohort. Bystander AED use was associated with an increased risk of a favorable functional outcome (35% vs. 25%, risk difference: 9.7% [95% confidence interval: 7.2%, 12.2%], risk ratio: 1.38 [95% confidence interval: 1.27, 1.50]). This was driven by increased favorable functional outcomes with AED use in patients with shockable rhythms (58% vs. 39%) but not in patients with non shockable rhythms (10% vs. 10%). CONCLUSIONS: Specific neighborhood characteristics were associated with bystander AED use in OHCA. Bystander AED use was associated with an increase in favorable functional outcome. PMID- 29477724 TI - Loss-of-function nuclear factor kappaB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans. AB - BACKGROUND: The genetic cause of primary immunodeficiency disease (PID) carries prognostic information. OBJECTIVE: We conducted a whole-genome sequencing study assessing a large proportion of the NIHR BioResource-Rare Diseases cohort. METHODS: In the predominantly European study population of principally sporadic unrelated PID cases (n = 846), a novel Bayesian method identified nuclear factor kappaB subunit 1 (NFKB1) as one of the genes most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense, and gene deletion variants. This accounted for 4% of common variable immunodeficiency (CVID) cases (n = 390) in the cohort. Amino acid substitutions predicted to be pathogenic were assessed by means of analysis of structural protein data. Immunophenotyping, immunoblotting, and ex vivo stimulation of lymphocytes determined the functional effects of these variants. Detailed clinical and pedigree information was collected for genotype-phenotype cosegregation analyses. RESULTS: Both sporadic and familial cases demonstrated evidence of the noninfective complications of CVID, including massive lymphadenopathy (24%), unexplained splenomegaly (48%), and autoimmune disease (48%), features prior studies correlated with worse clinical prognosis. Although partial penetrance of clinical symptoms was noted in certain pedigrees, all carriers have a deficiency in B-lymphocyte differentiation. Detailed assessment of B-lymphocyte numbers, phenotype, and function identifies the presence of an increased CD21low B-cell population. Combined with identification of the disease causing variant, this distinguishes between healthy subjects, asymptomatic carriers, and clinically affected cases. CONCLUSION: We show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID, which results in a temporally progressive defect in the formation of immunoglobulin-producing B cells. PMID- 29477732 TI - Isotretinoin therapy: A retrospective cohort analysis of completion rates and factors associated with nonadherence. PMID- 29477733 TI - Shortage of lidocaine with epinephrine: Causes and solutions. PMID- 29477735 TI - The "dermatologist recommended" label: Is it meaningful? PMID- 29477736 TI - Medicare Part D payments for brand and generic drugs prescribed by dermatologists. PMID- 29477734 TI - CARD14-associated papulosquamous eruption: A spectrum including features of psoriasis and pityriasis rubra pilaris. AB - BACKGROUND: Heterozygous mutations in caspase recruitment domain family member 14 gene (CARD14) have been shown to be associated with psoriasis and familial pityriasis rubra pilaris (PRP). Many subjects with CARD14 mutations display features of both disorders, which can result in diagnostic uncertainty. In addition, these eruptions are often recalcitrant to conventional psoriasis therapies such as methotrexate, oral retinoids, and tumor necrosis factor-alpha inhibitors. OBJECTIVE: We sought to describe the clinical characteristics, family history, and response to therapy in subjects with papulosquamous eruptions due to mutations in CARD14. METHODS: Subjects were referred for genetic testing as part of a registry of subjects with inherited disorders of keratinization. DNA was isolated from blood or saliva, and multiplex targeted sequencing or whole exome sequencing was performed. Clinical histories of subjects with CARD14 mutations were reviewed. RESULTS: We identified 15 kindreds with CARD14-associated papulosquamous eruption (CAPE). Characteristic features of CAPE include early age of onset; prominent involvement of the cheeks, chin, and ears; family history of psoriasis or PRP; minimal response to conventional topical and systemic psoriasis therapies; and improvement with ustekinumab. LIMITATIONS: Relatively small sample size. CONCLUSIONS: Many subjects with CARD14 mutations display characteristics of both psoriasis and PRP. We propose the term CARD14-associated papulosquamous eruption to describe this spectrum of disease. Subjects with clinical features suggestive of CAPE should undergo CARD14 sequencing and may benefit from treatment with ustekinumab. PMID- 29477737 TI - Vitamin D deficiency in patients with chronic and acute urticaria: A systematic review and meta-analysis. PMID- 29477738 TI - Simple mixing technique of triamcinolone acetonide solution by air bubble movement. PMID- 29477739 TI - Atopic dermatitis is not a risk factor for keratoconus: A population-based cohort study. PMID- 29477740 TI - Interleukin 17, inflammation, and cardiovascular risk in patients with psoriasis. AB - In addition to being recognized as a chronic inflammatory disease that manifests in the skin, psoriasis is increasingly understood to be a systemic disease that causes immune dysregulation throughout the body. The systemic nature of psoriasis is evidenced by the higher burden of comorbidities and shorter life expectancies of patients with psoriasis, particularly those with early-onset and severe disease. Notably, psoriasis is associated with an increased risk for cardiovascular disease, which is the most common cause of morbidity and mortality in patients with psoriasis. In this review, we examine the association between psoriasis and cardiovascular disease and specifically focus on the role of interleukin 17-mediated inflammation as a potential mechanistic link between psoriasis and cardiovascular disease. Moreover, we describe potential treatment approaches to reduce the burden of cardiovascular disease in patients with psoriasis and discuss the clinical importance of the association of these 2 diseases with respect to patient management and education. PMID- 29477741 TI - Pregnancy outcomes in patients with vitiligo: A nationwide population-based cohort study from Korea. AB - BACKGROUND: Vitiligo is a chronic autoimmune skin disorder affecting 1% of populations worldwide. Few large-scale studies have explored adverse pregnancy outcomes in patients with vitiligo. OBJECTIVE: To investigate adverse pregnancy outcomes in patients with vitiligo. METHODS: We performed a retrospective cohort study on 4738 pregnancies of women with vitiligo and 47,380 pregnancies of age matched controls without vitiligo using the Korean National Health Insurance Claims database from 2007 to 2016. Multivariate logistic regression models were used to evaluate the associations between vitiligo and pregnancy outcomes, including live births, spontaneous abortion, cesarean delivery, preterm delivery, gestational diabetes mellitus, stillbirth, pre-eclampsia/eclampsia, and intrauterine growth retardation. RESULTS: Patients with vitiligo exhibited a significantly lower live birth rate (odds ratio, 0.870; 95% confidence interval, 0.816-0.927) and a higher incidence of spontaneous abortion (odds ratio, 1.250; 95% confidence interval, 1.148-1.362) than the control group. LIMITATION: The Korean National Health Insurance Claims database lacks detailed clinical information on individual patients. CONCLUSION: Vitiligo was significantly associated with an increased risk of spontaneous abortion. Further studies are needed to determine whether systemic autoimmunity explains our finding. PMID- 29477742 TI - Gastrointestinal colonisation and systemic spread of Candida albicans in mice treated with antibiotics and prednisolone. AB - Normally, Candida albicans is a commensal microbe that resides in the human oral cavity, gut and vagina. However, the fungus can cause mucosal and systemic infections in immunocompromised individuals. The mechanism by which local mucosal infections progress to systemic candidiasis is poorly understood. Here, a murine model of gastrointestinal (GI) candidiasis was developed by inoculation of the oral cavity, followed by treatment with tetracycline (TC) and prednisolone (PSL). Temporal progression from a local infection of the oral cavity to a systemic infection was then monitored. Histological analysis of tissues from mice treated with both TC and PSL revealed massive infiltration of the tongue and stomach by hyphae. PSL increased the fungal burden in the tongue, stomach and small intestine, and facilitated dissemination to the spleen, kidney and liver within 3 days post-infection. Treatment with both TC and PSL supressed interferon (IFN) gamma and interleukin (IL)-17 (cytokines that play key roles in host defence against fungal infection) levels in the tongue, which were induced by C. albicans infection. In addition, the mucosal layer of the small intestine of mice treated with both TC and PSL was almost destroyed by the fungal infection; this may be a critical event that allows passage of the fungus across the mucosa and into the systemic circulation. Thus, this mouse model is useful for studying mechanisms underlying progression of C. albicans from a local infection of the oral cavity to a systemic infection in immunocompromised individuals. PMID- 29477743 TI - Alterations of the human gut Methanobrevibacter smithii as a biomarker for inflammatory bowel diseases. AB - It is hypothesized that direct and indirect homeostasis between gut microbiota plays a key role in different intestine disorders. Archaea methanogens, an ancient domain of single-celled organism, are major archaea in the digestive system. Recent evidence has shown that the variable prevalence of methanogens in different individuals could have certain effects on inflammatory bowel diseases (IBD). We aimed to assess the prevalence of Methanobrevibacter smithii between Iranian patients suffering from IBD and healthy control subjects. Stool DNA extracts from 47 healthy controls and 61 IBD patients were investigated. Quantitative real time PCR was performed for detecting Mbb. smithii load. We found a significantly decreased the Mbb. smithii load between IBD patients and healthy subjects. It is assumed that there is a reverse association between Mbb. smithii bacterial load and susceptibility to IBD, and this association could be extended to IBD patients in remission as we found that Mbb. smithii bacterial load is markedly higher among healthy subjects in comparison to IBD patients. PMID- 29477744 TI - Comparison of Two Different Ultrasound Devices Using Strain Elastography Technology in the Diagnosis of Breast Lesions Related to the Histologic Results. AB - This study was conducted to provide evidence that elastograms of two different devices and different manufacturers using the same technical approach provide the same diagnoses. A total of 110 breast lesions were prospectively analysed by two experts in ultrasound, using the strain elastography function from two different manufacturers (Hitachi HI-RTE, Hitachi Medical Systems, Wiesbaden, Germany; and Siemens eSie Touch, Siemens Medical Systems, Erlangen, Germany). Results were compared with the histopathologic results. Applying the Bowker test of symmetry, no statistically significant difference between the two elastography functions of these two devices was found (p = 0.120). The Cohen's kappa of k = 0.591 showed moderate strength of agreement between the two elastograms. The two examiners yielded moderate strength of agreement analysing the elastograms (Hitachi HI-RTE, k = 0.478; Siemens eSie Touch, k = 0.441). In conclusion, evidence is provided that elastograms of the same lesion generated by two different ultrasound devices equipped with a strain elastography function do not significantly differ. PMID- 29477745 TI - Shear Wave Speed Estimation Using Reverberant Shear Wave Fields: Implementation and Feasibility Studies. AB - Elastography is a modality that estimates tissue stiffness and, thus, provides useful information for clinical diagnosis. Attention has focused on the measurement of shear wave propagation; however, many methods assume shear wave propagation is unidirectional and aligned with the lateral imaging direction. Any deviations from the assumed propagation result in biased estimates of shear wave speed. To address these challenges, directional filters have been applied to isolate shear waves with different propagation directions. Recently, a new method was proposed for tissue stiffness estimation involving creation of a reverberant shear wave field propagating in all directions within the medium. These reverberant conditions lead to simple solutions, facile implementation and rapid viscoelasticity estimation of local tissue. In this work, this new approach based on reverberant shear waves was evaluated and compared with another well-known elastography technique using two calibrated elastic and viscoelastic phantoms. Additionally, the clinical feasibility of this technique was analyzed by assessing shear wave speed in human liver and breast tissues, in vivo. The results indicate that it is possible to estimate the viscoelastic properties in each scanned medium. Moreover, a better approach to estimation of shear wave speed was obtained when only the phase information was taken from the reverberant waves, which is equivalent to setting all magnitudes within the bandpass equal to unity: an idealization of a perfectly isotropic reverberant shear wave field. PMID- 29477746 TI - Orthogonal B-Mode Evaluation of Common Carotid Artery Plaques Reveals the Absence of Outward Remodeling. AB - To properly assess morphologic and dynamic parameters of arteries and plaques, we propose the concept of orthogonal distance measurements, that is, measurements made perpendicular to the local lumen axis rather than along the ultrasound beam (vertical direction for a linear array). The aim of this study was to compare orthogonal and vertical artery and lumen diameters at the site of a plaque in the common carotid artery (CCA). Moreover, we investigated the interrelationship of orthogonal diameters and plaque size and the association of artery parameters with plaque echogenicity. In 29 patients, we acquired a longitudinal B-mode ultrasound recording of plaques at the posterior CCA wall. After semi-automatic segmentation of end-diastolic frames, diameters were extracted orthogonally along the lumen axis. To establish inter-observer variability of diameters obtained at the location of maximal plaque thickness, a second observer repeated the analysis (subset N = 21). Orthogonal adventitia-adventitia and lumen diameters could be determined with good precision (coefficient of variation: 1%-5%. However, the precision of the change in lumen diameter from diastole to systole (distension) at the site of the plaque was poor (21%-50%). The orthogonal lumen diameter was significantly smaller than the vertical lumen diameter (p <0.001). Surprisingly, the plaques did not cause outward remodeling, that is, a local increase in adventitia-adventitia distance at the site of the plaque. The intra- and inter observer precision of diastolic-systolic plaque compression was poor and of the same order as the standard deviation of plaque compression. The orthogonal relative lumen distension was significantly lower for echogenic plaques, indicating a higher stiffness, than for echolucent plaques (p <0.01). In conclusion, we illustrated the feasibility of extracting orthogonal CCA and plaque dimensions, albeit that the proposed approach is inadequate to quantify plaque compression. PMID- 29477747 TI - The Roman high- and low-avoidance rats differ in the sensitivity to shock-induced suppression of drinking and to the anxiogenic effect of pentylenetetrazole. AB - The Roman high- (RHA) and low-avoidance (RLA) outbred rat lines are selected for respectively rapid vs. poor acquisition of active avoidant behavior. Emotional reactivity appears to be the most prominent behavioral difference between the two lines, with RLA rats being more fearful/anxious than their RHA counterparts. Accordingly, here we show that shock-induced inhibition of drinking behavior in the Vogel's test is significantly more pronounced in RLA than RHA rats. Thus, unpunished drinking activity is similar in both lines (38.1 +/- 0.9 and 36.4 +/- 0.6 licking periods/3 min in RLA and RHA rats, respectively), whereas under punished conditions (0.05-1.00 mA electric shocks delivered through the drinking tube) a more robust decrease in drinking behavior is observed in RLA vs. RHA rats. Moreover, fear-related behaviors like freezing and self-grooming are more frequent in RLA than RHA rats throughout the test. Similar results are obtained with the inbred RHA-I and RLA-I rats, which have been selected and bred through brother/sister mating of the outbred lines. In keeping with the above findings, we also show that, compared with their RHA counterparts, the outbred RLA rats are similarly responsive to the anticonflict effect of diazepam but more responsive to the proconflict effect of pentylenetetrazole in the Vogel's test. Collectively, these results reveal another behavioral trait distinguishing RHA from RLA rats and add experimental support to the view that the Roman lines/strains are a valid genetic model for the study of the neural underpinnings of fear/anxiety- and stress-related behaviors. PMID- 29477750 TI - Early preparation during turn-taking: Listeners use content predictions to determine what to say but not when to say it. AB - During conversation, there is often little gap between interlocutors' utterances. In two pairs of experiments, we manipulated the content predictability of yes/no questions to investigate whether listeners achieve such coordination by (i) preparing a response as early as possible or (ii) predicting the end of the speaker's turn. To assess these two mechanisms, we varied the participants' task: They either pressed a button when they thought the question was about to end (Experiments 1a and 2a), or verbally answered the questions with either yes or no (Experiments 1b and 2b). Predictability effects were present when participants had to prepare a verbal response, but not when they had to predict the turn-end. These findings suggest content prediction facilitates turn-taking because it allows listeners to prepare their own response early, rather than because it helps them predict when the speaker will reach the end of their turn. PMID- 29477749 TI - Functional characterization and FTIR-based 3D modeling of full length and truncated forms of Scorpio maurus venom phospholipase A2. AB - BACKGROUND: Heterodimeric phospholipase A2 from venom glands of Tunisian scorpion Scorpio maurus (Sm-PLGV) had been purified. It contains long and short chains linked by a disulfide bridge. Sm-PLGV exhibits hemolytic activity towards human erythrocytes and interacts with phospholipid monolayers at high surface pressure. The investigation of structure-function relationships should provide new clues to understand its activity. METHODS: Molecular cloning of Sm-PLGV and heterologous expression in Escherichia coli of three recombinant forms was used to determine the role of the short chain on enzymatic activity. Infrared spectroscopy assisted 3D model building of the three recombinant constructs (phospholipases with and without the penta-peptide and Long chain only) allowed us to propose an explanation of the differences in specific activities and their interaction with various phospholipids. RESULTS: Nucleotide sequence of Sm-PLGV encodes 129 residues corresponding to the Long chain, the penta-peptide and the short chain. Although recombinant phospholipases without and with the penta-peptide have different specific activities, they display a similar substrate specificity on various phospholipid monolayers and similar bell-shaped activity profiles with maxima at high surface pressure. The absence of the short chain reduces significantly enzymatic and hemolytic activities. The 3D models pointed to an interaction of the short chain with the catalytic residues, what might explain the difference in activities of our constructs. CONCLUSION: Infrared spectroscopy data and 3D modeling confirm the experimental findings that highlight the importance of the short chain for the Sm-PLGV activity. GENERAL SIGNIFICANCE: New informations are given to further establish the structure-function relationships of the Sm-PLGV. PMID- 29477748 TI - Transforming growth factor-beta modulates pancreatic cancer associated fibroblasts cell shape, stiffness and invasion. AB - BACKGROUND: Tumor microenvironment consists of the extracellular matrix (ECM), stromal cells, such as fibroblasts (FBs) and cancer associated fibroblasts (CAFs), and a myriad of soluble factors. In many tumor types, including pancreatic tumors, the interplay between stromal cells and the other tumor microenvironment components leads to desmoplasia, a cancer-specific type of fibrosis that hinders treatment. Transforming growth factor beta (TGF-beta) and CAFs are thought to play a crucial role in this tumor desmoplastic reaction, although the involved mechanisms are unknown. METHODS: Optical/fluorescence microscopy, atomic force microscopy, image processing techniques, invasion assay in 3D collagen I gels and real-time PCR were employed to investigate the effect of TGF-beta on normal pancreatic FBs and CAFs with regard to crucial cellular morphodynamic characteristics and relevant gene expression involved in tumor progression and metastasis. RESULTS: CAFs present specific myofibroblast-like characteristics, such as alpha-smooth muscle actin expression and cell elongation, they also form more lamellipodia and are softer than FBs. TGF-beta treatment increases cell stiffness (Young's modulus) of both FBs and CAFs and increases CAF's (but not FB's) elongation, cell spreading, lamellipodia formation and spheroid invasion. Gene expression analysis shows that these morphodynamic characteristics are mediated by Rac, RhoA and ROCK expression in CAFs treated with TGF-beta. CONCLUSIONS: TGF-beta modulates CAFs', but not FBs', cell shape, stiffness and invasion. GENERAL SIGNIFICANCE: Our findings elucidate on the effects of TGF-beta on CAFs' behavior and stiffness providing new insights into the mechanisms involved. PMID- 29477751 TI - Immune complexome analysis of antigens in circulating immune complexes from patients with acute cellular rejection after living donor liver transplantation. AB - Liver transplantation is a life-saving procedure for many end-stage liver diseases; however, rejection after transplantation is still occurs in some recipients. The most common form of rejection is T cell-related acute cellular rejection (ACR). To understand the mechanism of rejection, it is necessary to identify immune targets. Since the development of B cell immunity depends upon concordant T cell immunity, we hypothesized that rejection-specific antigens in circulating immune complexes (CICs) may be present in the sera of recipients experiencing rejection, and as such, may be useful as diagnostic biomarkers for ACR. The purpose of this study was to investigate rejection-specific antigens in CICs (CIC-antigens) in serum of ACR patients. We applied immune complexome analysis, in which CICs are separated from whole serum and then subjected to direct tryptic digestion and identification of CIC-antigens by nano-liquid chromatography-tandem mass spectrometry, to sera of 32 living donor liver transplant recipients (10 recipients experienced ACR and the others did not experience). CIC-antigens were compared between rejection and non-rejection groups to elucidate those that were only detected in the rejection group. We identified 11 CIC-antigens that were only detected in patients who experienced rejection, 4 of which (thrombospondin-1, apolipoprotein E, apolipoprotein C-III, and complement factor H) were only detected during ACR. PMID- 29477752 TI - Persistent accumulation of circulating monocytic myeloid-derived suppressor cells contributes to post-infectious immunosuppression in renal transplant recipients with bacterial infection: A pilot study. AB - INTRODUCTION: Post-infectious immunosuppression is disadvantageous to patients' long-term outcomes, especially in transplant recipients receiving large doses of immunosuppressants. A growing body of evidence indicates the immunoregulatory ability of myeloid-derived suppressor cells (MDSCs). We herein investigate the characteristics of monocytic-MDSCs (M-MDSCs) in a cohort of renal transplant recipients with/without infection to clarify the potential involvement in post infectious immunosuppression. METHODS: The study prospectively included 28 adult recipients who underwent allogeneic ABO-compatible renal transplant. Blood samples were drawn at day 0, 7, 14, 28, 60 and 90 postoperation. The incidence of infection and treatment strategies were recorded. The frequency and absolute number of peripheral blood M-MDSCs as well as other immune cells were determined by flow cytometry. Immnosuppressive functions of M-MDSCs were analyzed by inhibition of T cells proliferation. mRNA levels of immunosuppressive molecules in sorted M-MDSCs were also examined. RESULTS: 7 recipients were diagnosed with bacterial (n = 5) or viral (n = 2) infection and 3/5 of bacterial-infected recipients suffered from secondary infection during further follow-up. In the non infected group, M-MDSCs numbers increased transiently during the early postoperative period, however, bacterial but not viral infection led to significant and persistent accumulation of M-MDSCs that remained at high levels after anti-infective treatments. M-MDSCs from infected recipients demonstrated potent ability to suppress T cells proliferation in vitro and negatively correlated with lymphocytes in vivo, yet not in the non-infected group. Inducible nitric oxide synthase (iNOS) mRNA levels were higher in sorted M-MDSCs when compared with monocytes, and suppressive activity was reversed by addition of a NOS inhibitor. CONCLUSIONS: Circulating M-MDSCs underwent significant and persistent increases after bacterial infection in renal transplant recipients, contributing to post-infectious immunodeficiency. Therefore, special attention should be given to M-MDSCs during the monitoring of immune status and infection management. PMID- 29477753 TI - Orientation and property of fibers of the myodural bridge in humans. AB - BACKGROUND CONTEXT: Studies over the past 20 years have revealed that there are fibrous connective tissues between the suboccipital muscles, nuchal ligament, and cervical spinal dura mater (SDM). This fibrous connection with the SDM is through the posterior atlanto-occipital or atlantoaxial interspaces and is called the myodural bridge (MDB). Researchers have inferred that the MDB might have important functions. It was speculated that the function of MDB might be related to proprioception transmission, keeping the subarachnoid space and the cerebellomedullary cistern unobstructed, and affecting the dynamic circulation of the cerebrospinal fluid. In addition, clinicians have found that the pathologic change of the MDB might cause cervicogenic or chronic tension-type headache. Previous gross anatomical and histologic studies only confirmed the existence of the MDB but did not reveal the fiber properties of the MDB. This is important to further mechanical and functional research on the MDB. PURPOSE: Multiple histologic staining methods were used in the present study to reveal the various origin and fiber properties of the MDB. Muscles and ligaments participating in forming the MDB at the posterior atlanto-occipital or atlantoaxial interspaces were observed, and the fiber properties of the MDB were confirmed. The present study provides a basis for speculating the tensile force values of the MDB on the SDM and a morphologic foundational work for exploring the physiological functions and clinical significances of the MDB. STUDY DESIGN: Anatomical and histologic analyses of suboccipital structures that communicate with the SDM at the posterior atlanto-occipital or atlantoaxial interspaces were carried out. METHODS: Multiple histologic staining methods were used to evaluate the histologic properties and composition of the MDB at the posterior atlanto occipital or atlantoaxial interspaces in five formalin-fixed head-neck human specimens. RESULTS: The results show that the MDB traversing the atlanto occipital interspace originated from the rectus capitis posterior minor (RCPmi). The MDB traversing the atlantoaxial interspace originated mainly from the RCPmi, rectus capitis posterior major, and obliquus capitis inferior. These fibers form the vertebral dural ligament in the atlantoaxial interspace and connect with SDM. The MDB is mainly formed by parallel running type I collagen fibers; thus, suboccipital muscle could pull SDM strongly through the effective force propagated by the MDB during head movement. CONCLUSIONS: Myodural bridge is mainly formed by parallel running type I collagen fibers; thus, it can transmit the strong pull from the diverse suboccipital muscles or ligaments during head movement. The results of the present study will serve as a basis for further biomechanical and functional MDB research. PMID- 29477754 TI - Introduction to the TSJ special collection on interdisciplinary spine. PMID- 29477755 TI - A new standardized data collection system for interdisciplinary thyroid cancer management: Thyroid COBRA. AB - The big data approach offers a powerful alternative to Evidence-based medicine. This approach could guide cancer management thanks to machine learning application to large-scale data. Aim of the Thyroid CoBRA (Consortium for Brachytherapy Data Analysis) project is to develop a standardized web data collection system, focused on thyroid cancer. The Metabolic Radiotherapy Working Group of Italian Association of Radiation Oncology (AIRO) endorsed the implementation of a consortium directed to thyroid cancer management and data collection. The agreement conditions, the ontology of the collected data and the related software services were defined by a multicentre ad hoc working-group (WG). Six Italian cancer centres were firstly started the project, defined and signed the Thyroid COBRA consortium agreement. Three data set tiers were identified: Registry, Procedures and Research. The COBRA-Storage System (C-SS) appeared to be not time-consuming and to be privacy respecting, as data can be extracted directly from the single centre's storage platforms through a secured connection that ensures reliable encryption of sensible data. Automatic data archiving could be directly performed from Image Hospital Storage System or the Radiotherapy Treatment Planning Systems. The C-SS architecture will allow "Cloud storage way" or "distributed learning" approaches for predictive model definition and further clinical decision support tools development. The development of the Thyroid COBRA data Storage System C-SS through a multicentre consortium approach appeared to be a feasible tool in the setup of complex and privacy saving data sharing system oriented to the management of thyroid cancer and in the near future every cancer type. PMID- 29477756 TI - Advances in kinome research of parasitic worms - implications for fundamental research and applied biotechnological outcomes. AB - Protein kinases are enzymes that play essential roles in the regulation of many cellular processes. Despite expansions in the fields of genomics, transcriptomics and bioinformatics, there is limited information on the kinase complements (kinomes) of most eukaryotic organisms, including parasitic worms that cause serious diseases of humans and animals. The biological uniqueness of these worms and the draft status of their genomes pose challenges for the identification and classification of protein kinases using established tools. In this article, we provide an account of kinase biology, the roles of kinases in diseases and their importance as drug targets, and drug discovery efforts in key socioeconomically important parasitic worms. In this context, we summarise methods and resources commonly used for the curation, identification, classification and functional annotation of protein kinase sequences from draft genomes; review recent advances made in the characterisation of the worm kinomes; and discuss the implications of these advances for investigating kinase signalling and developing small-molecule inhibitors as new anti-parasitic drugs. PMID- 29477757 TI - Metabolic regulation in solventogenic clostridia: regulators, mechanisms and engineering. AB - Solventogenic clostridia, a group of important industrial microorganisms, have exceptional substrate and product diversity, capable of producing a series of two carbon and even long-chain chemicals and fuels by using various substrates, including sugars, cellulose and hemicellulose, and C1 gases. For the sake of in depth understanding and engineering these anaerobic microorganisms for broader applications, studies on metabolic regulation of solventogenic clostridia had been extensively carried out during the past ten years, based on the rapid development of various genetic tools. To date, a number of regulators that are essential for cell physiological and metabolic processes have been identified in clostridia, and the relevant mechanisms have also been dissected, providing a wealth of valuable information for metabolic engineering. Here, we reviewed the latest research progresses on the metabolic regulation for chemical production and substrate utilization in solventogenic clostridia, by focusing on three typical Clostridium species, the saccharolytic C. acetobutylicum and C. beijerinckii, as well as the gas-fermenting C. ljungdahlii. On this basis, future directions in the study and remodeling of clostridial regulation systems, were proposed for effective modification of these industrially important anaerobes. PMID- 29477758 TI - An automated workflow for segmenting single adult cardiac cells from large-volume serial block-face scanning electron microscopy data. AB - This paper presents a new algorithm to automatically segment the myofibrils, mitochondria and nuclei within single adult cardiac cells that are part of a large serial-block-face scanning electron microscopy (SBF-SEM) dataset. The algorithm only requires a set of manually drawn contours that roughly demarcate the cell boundary at routine slice intervals (every 50th, for example). The algorithm correctly classified pixels within the single cell with 97% accuracy when compared to manual segmentations. One entire cell and the partial volumes of two cells were segmented. Analysis of segmentations within these cells showed that myofibrils and mitochondria occupied 47.5% and 51.6% on average respectively, while the nuclei occupy 0.7% of the cell for which the entire volume was captured in the SBF-SEM dataset. Mitochondria clustering increased at the periphery of the nucleus region and branching points of the cardiac cell. The segmentations also showed high area fraction of mitochondria (up to 70% of the 2D image slice) in the sub-sarcolemmal region, whilst it was closer to 50% in the intermyofibrillar space. We finally demonstrate that our segmentations can be turned into 3D finite element meshes for cardiac cell computational physiology studies. We offer our large dataset and MATLAB implementation of the algorithm for research use at www.github.com/CellSMB/sbfsem-cardiac-cell-segmenter/. We anticipate that this timely tool will be of use to cardiac computational and experimental physiologists alike who study cardiac ultrastructure and its role in heart function. PMID- 29477759 TI - Unusual cystic lesion of the eyebrow: A case report of malignant chondroid syringoma. AB - INTRODUCTION: Malignant chondroid syringomas, also known as cutaneous malignant mixed tumors, are rare neoplasms that most frequently occur on the torso or extremities of women. Here, we present an illustrated case of a facial malignant chondroid syringoma. MATERIALS AND METHODS: A 32-year-old female patient with no notable medical history presented with an approximately 1cm-wide, painless, palpably-mobile subcutaneous nodule, suggestive of a sebaceous cyst, just above the middle third of the right eyebrow. The nodule had grown steadily over six months. She had no palpable cervical lymphadenopathies. RESULTS: Anatomic pathology of the enucleated nodule found an adnexal sudoriparous tumor measuring 6*10mm and indicative of a malignant chondroid syringoma. Cervicofacial computed tomography and positron emission tomography scans showed no near or distant lymph node involvement. A second intervention for wide excision around the original enucleation lesion (+1cm) was validated in a multidisciplinary, cancerology dermatology consultation. The eyebrow was reconstructed with a temporally harvested fasciocutaneous island flap. DISCUSSION: Malignant chondroid syringomas are very rare and thus no standardized treatment has been established for them. Only 12 craniofacial localizations have been described to date. Radiation therapy and chemotherapy have not been shown effective for this malignancy, leaving only wide excision as a therapeutic option. A high and sustained (as much as 20 years after the initial diagnosis) risk of recurrence or metastasis necessitates prolonged patient follow-up. PMID- 29477760 TI - Motor-Evoked Pain Increases Force Variability in Chronic Jaw Pain. AB - : Musculoskeletal pain changes how people move. Although experimental pain is associated with increases in the variability of motor output, it is not clear whether motor-evoked pain in clinical conditions is also associated with increases in variability. In the current study, we measured jaw force production during a visually guided force paradigm in which individuals with chronic jaw pain and control subjects produced force at 2% of their maximum voluntary contraction (low target force level) and at 15% of their maximum voluntary contraction (high target force level). State measures of pain were collected before and after each trial. Trait measures of pain intensity and pain interference, self-report measures of jaw function, and measures of depression, anxiety, and fatigue were also collected. We showed that the chronic jaw pain group exhibited greater force variability compared with controls irrespective of the force level, whereas the accuracy of force production did not differ between groups. Furthermore, predictors of force variability shifted from trait measures of pain intensity and pain interference at the low force level to state measures of pain intensity at the high force level. Our observations show that motor evoked jaw pain is associated with increases in force variability that are predicted by a combination of trait measures and state measures of pain intensity and pain interference. PERSPECTIVE: Chronic jaw pain is characterized by increases in variability during force production, which can be predicted by pain intensity and pain interference. This report could help clinicians better understand the long-term consequences of chronic jaw pain on the motor system. PMID- 29477761 TI - Concurrent Assessment of the Antinociceptive and Behaviorally Disruptive Effects of Opioids in Squirrel Monkeys. AB - : Although the clinical application of opioids for pain management is often hindered by undesired behavioral impairment, preclinical assays of antinociception typically do not provide information regarding the behaviorally disruptive effects of opioids that may accompany their antinociceptive effects. To address this, we modified a warm water tail withdrawal procedure to determine concurrently the effects of opioids on tail withdrawal latency (antinociception) and indices of food-maintained operant behavior (rates of responding and reinforcement density) in squirrel monkeys. Six opioid agonists were tested, and all produced dose-dependent antinociception and impairment of operant behavior. The ratio of median effective dose (ED50) values for both measures (behavioral impairment:antinociception) was used as a quantitative measure of therapeutic index. Nalbuphine had the highest ED50 ratio (4.88), reflecting antinociception with minimal behavioral disruption. Oxycodone, heroin, buprenorphine, and methadone all produced similar ED50 ratios (.82-1.14), whereas butorphanol yielded a significantly lower ED50 ratio (.17) reflecting behavioral disruption at doses producing only minimal antinociception. The antinociceptive and behaviorally disruptive effects of oxycodone and buprenorphine were further characterized using Schild analysis to calculate apparent pA2 values for antagonism of the 2 drugs by naltrexone. These analyses suggest that u-receptor mechanisms likely mediate the antinociceptive as well as behaviorally disruptive effects of oxycodone (pA2 values: 8.13 and 8.57) and buprenorphine (pA2 values: 8.6 and 7.9). PERSPECTIVE: This article presents an assay that allows for the concurrent assessment of the antinociceptive and behaviorally disruptive effects of opioids. Our results show that the tail withdrawal assay in squirrel monkeys can provide a useful index of the behavioral selectivity with which opioids produce antinociception. PMID- 29477762 TI - Occurrence, distribution, and seasonality of emerging contaminants in urban watersheds. AB - The widespread occurrence of natural and synthetic organic chemicals in surface waters can cause ecological risks and human health concerns. This study measured a suite of contaminants of emerging concern (CECs) in water samples collected by the U.S. Environmental Protection Agency Region 8 around the Denver, Colorado, metropolitan area. The results showed that 109 of 144 analyzed pharmaceutical compounds, 42 of 55 analyzed waste-indicator compounds (e.g., flame retardants, hormones, and personal care products), and 39 of 72 analyzed pesticides were detected in the water samples collected monthly between April and November in both 2014 and 2015. Pharmaceutical compounds were most abundant in the surface waters and their median concentrations were measured up to a few hundred nanograms per liter. The CEC concentrations varied depending on sampling locations and seasons. The primary source of CECs was speculated to be wastewater effluent. The CEC concentrations were correlated to streamflow volume and showed significant seasonal effects. The CECs were less persistent during spring runoff season compared with baseflow season at most sampling sites. These results are useful for providing baseline data for surface CEC monitoring and assessing the environmental risks and potential human exposure to CECs. PMID- 29477763 TI - The effects of oil induced respiratory impairment on two indices of hypoxia tolerance in Atlantic croaker (Micropogonias undulatus). AB - The Gulf of Mexico was home to the Deepwater Horizon oil spill, and is also known to exhibit seasonal declines in oxygen availability. Oil exposure in fish is known to impact oxygen uptake through cardiac impairment, which raises questions about the additive effects of these two stressors. Here we explore this question on the Atlantic croaker using two measures of hypoxia tolerance: critical oxygen threshold (Pcrit), and time to loss of equilibrium (LOE). We first demonstrated that 24 h exposure to 10.1 and 23.2 MUg l-1 SigmaPAH50 significantly impaired oxygen uptake. There was no effect of exposure on Pcrit or LOE. Exposure did result in significantly different repeatability between pre- and post-exposure Pcrit, suggesting that hypoxia tolerant individual may see greater impacts following exposure. These results suggest oil exposure does not have wide scale detrimental outcomes for hypoxia tolerance in fish, yet there may be fine scale impairments of ecological significance. PMID- 29477764 TI - Effects of Cd accumulation on cutworm Spodoptera litura larvae via Cd treated Chinese flowering cabbage Brassica campestris and artificial diets. AB - By exposing herbivorous cutworm Spodoptera litura (Lepidoptera: Noctuidae) larvae to Cadmium (Cd) stress via Cd treated cabbages Brassica campestris and artificial diets, we investigated effects of Cd accumulation in larvae on their survival and food utilization. The results showed that Cd transferred from soils contaminated with different Cd concentrations through cabbages-larvae, and be mainly accumulated in larvae guts. There was a dose-response relationship between Cd accumulations in larvae cuticle, head, guts and Cd concentrations in artificial diets, and the highest one was found in the guts, regardless of generations. High Cd stress (10 mg kg-1 Cd in soil, 40.6, 81.2 mg kg-1 Cd in artificial diets) had inhibited effects on larvae growth and food utilization, whereas low Cd stress (Lvbao 701 planted in 2.5 mg kg-1 Cd soil, 4.06 mg kg-1 Cd in artificial diets) showed stimulated effect. Cd accumulations in the guts were significantly negative correlated with efficiency of conversion of ingested food (ECI) and relative growth rate (RGR) of larvae feeding on Cd treated diets or cabbages while were significantly positive correlated with relative consumption rate (RCR). Therefore, after S. litura larvae feed on Cd treated natural food or artificial diets, Cd could be transferred to different tissues, and mainly accumulated in the guts, which significantly affected growth and food utilization. Additionally, Cd stress via Cd treated artificial diets presented less detrimental effects on S. litura larvae than via Cd treated cabbages. PMID- 29477765 TI - Transformation of aqueous sulfonamides under horseradish peroxidase and characterization of sulfur dioxide extrusion products from sulfadiazine. AB - The potential of horseradish peroxidase (HRP) to catalyze the removal of sulfonamides from water and the effects of different H2O2 and HRP concentrations were investigated. Six sulfonamides, each with a five- or six-membered heterocyclic group, including sulfamethoxazole (SMX), sulfathiazole (STZ), sulfapyridine (SPD), sulfadiazine (SDZ), sulfamerazine (SMR) and sulfamethoxypyridazine (SMP) were selected as target compounds. All sulfonamides exhibit a pseudo-first-order dependence of the concentration versus the reaction time. The decay rate (k, h-1) of the six sulfonamides spiked individually exhibit a trend following the order of STZ > SMP, SPD > SMR > SDZ " SMX. When spiked together, the coexistent sulfonamides might act as mediators for the enhancement of SMX removal and as competitors for the decreased removal of most sulfonamides. Moreover, six transformation products of SDZ are identified by the Thermo Scientific LTQ Orbitrap Elite technique. SDZ transformation involves two steps: one is the Smiles re-arrangement of the structure, and the other is oxidation and sulfur dioxide extrusion. This study is the first to report the removal dynamics of sulfonamides in HRP-catalyzed reactions and the identified products of SDZ. PMID- 29477766 TI - A novel biosorbent prepared by immobilized Bacillus licheniformis for lead removal from wastewater. AB - Magnetic polyving akohol (PVA) immobilized the endogenous bacterium Bacillus licheniformis with sodium alginate to get a novel biosorbent. The optimum preparation and adsorption conditions were studied. The optimal preparation conditions was the fraction of magnetic PVA was 9%, the fraction of sodium alginate was 0.8%, the fraction of microbial suspensions was 5% and the crosslinking time was 20 h. The best adsorption conditions were listed as follows: pH was 6, the biosorbent dosage was 0.7 g L-1, the initial concentration of lead ions was 200 mg L-1 and the optimal adsorption time was 12 h. The results of SEM and FTIR spectroscopy analysis displayed this novel biosorbents had good structure and the functional groups on the surface was abundant. The VSM analysis confirmed the novel biosorbents had good magnetic magnetization and were easily separated from aqueous medium. Under the optimum conditions, the removal rate of lead ions from waste water could reach 98%, the calculated maximum adsorption capacity could be up to 113.84 mg g-1. The whole adsorption process was well fit by the pseudo-second order kinetic and it was also a Langmuir monolayer adsorption. The desorption experiments showed the biosorbent had good re usability. PMID- 29477767 TI - Coupling electrochemistry and TIRF-microscopy with the fluorescent false neurotransmitter FFN102 supports the fluorescence signals during single vesicle exocytosis detection. AB - Applications of the Fluorescent False Neurotransmitter FFN102, an analog of biogenic neurotransmitters and a suitable probe for coupled amperometry and TIRFM (total internal reflexion fluorescence microscopy) investigations of exocytotic secretion, were considered here. The electroactivity of FFN102 was shown to very likely arise from the oxidation of its phenolic group through a CE (Chemical Electrochemical) mechanism. Evidences that the aminoethyl group of FFN102 is the key recognition element by BON N13 cells were also provided. Amperometric measurements were then performed at the single cell level with carbon fiber electrode (CFE) or Indium Tin Oxide (ITO) surfaces. It proved the disparity of kinetic and quantitative parameters of FFN102-stained cells acquired either at cell top and bottom. Moreover, coupled analyses of FFN102 loaded vesicles allowed us to classify three types of optical signals that probably arise from secretion releases thanks to their concomitant detection with an electrochemical spike. Finally, preliminary benefits from the coupling involving FFN102 were reported in terms of origins of overlapped amperometric spikes or assignment of fluorescence extinctions to real exocytotic events. PMID- 29477769 TI - 15(V/K) kinetic isotope effect and steady-state kinetic analysis for the transglutaminase 2 catalyzed deamidation and transamidation reactions. AB - The Ca2+-dependent deamidation and transamidation activities of transglutaminase 2 (TG2) are important to numerous physiological and pathological processes. Herein, we have examined the steady-state kinetics and 15(V/K) kinetic isotope effects (KIEs) for the TG2-catalyzed deamidation and transamidation of N Benzyloxycarbonyl-l-Glutaminylglycine (Z-Gln-Gly) using putrescine as the acyl acceptor substrate. Kinetic parameters determined from initial velocity plots are consistent with previously proposed mechanisms. Significant differences in the 15(V/K) KIEs on NH3 release determined for the deamidation (0.2%) and the transamidation (2.3%) of Z-Gln-Gly suggest the rate-limiting steps of TG2 active site acylation are dependent on the presence of the acyl acceptor. We propose a plausible mechanistic explanation where substrate-induced conformational changes may play a role in promoting catalysis. PMID- 29477768 TI - Inhibition of amyloid fibrillation of lysozyme by bisdemethoxycurcumin and diacetylbisdemethoxycurcumin. AB - Amyloid deposition, arising from the fibrillogenesis of proteins in organs and tissues of the body, causes several neurodegenerative disorders. One therapeutic approach is based on the use of polyphenols and their derivatives for suppressing and inhibiting the accumulation of these toxic fibrils in tissues. In the present study, the anti-amyloidogenic activities of bisdemethoxycurcumin (BDMC), a natural polyphenolic compound, and diacetylbisdemethoxycurcumin (DABC), a synthetic derivative of curcumin, on the amyloid fibrillation of hen egg white lysozyme (HEWL) is studied in depth using thioflavin T (ThT) fluorescence, atomic force microscopy (AFM), circular dichroism spectroscopy (CD), molecular docking and Ligplot calculations. The binding parameters such as binding constants and the number of substantive binding sites were obtained experimentally. It could be shown from docking simulation that four hydrogen bonds via the two phenolic OH groups of BDMC and two beta-diketone moiety of BDMC are formed with the Asp-101, Trp-63, Asn-59 and Glu-35 of HEWL, whereas, two hydrogen bonds formed via two beta-diketone moiety of DABC with Asn-39 and Trp-63 of HEWL. The short Forster's distance (r) between donor and acceptor, the binding constant values and also the nature of interaction, demonstrate strong interaction between these two curcuminoids and lysozyme. According to amyloid fibrillation and binding results, the interaction of BDMC with HEWL is stronger than that of DABC and amyloid fibrillation of HEWL was inhibited more effectively by BDMC than DABC. It can be suggested that the more inhibitory activity of BDMC than DABC is correlated to the stronger interaction of BDMC with HEWL. These natural polyphenolic compounds are thus good candidates for inhibiting of amyloid formation. The inhibitory activities of BDMC and DABC can be used in drug formulation against the dangerous amyloid-related diseases and provide health promotion for organs and tissues of the body. PMID- 29477770 TI - Glucuronoxylan recognition by GH 30 xylanases: A study with enzyme and substrate variants. AB - XynA from Erwinia chrysanthemi (EcXyn30A), belonging to glycoside hydrolase family 30 subfamily 8, is specialized for hydrolysis of 4-O-methylglucuronoxylan (GX). Carboxyl group of 4-O-methylglucuronic acid serves as a substrate recognition element interacting ionically with positively charged Arg293 of the enzyme. We determined kinetic parameters of EcXyn30A on GX, its methyl ester (GXE) and 4-O-methylglucoxylan (GXR) and compared them with behavior of the enzyme variant in which Arg293 was replaced by Ala. The modifications of the substrate carboxyl groups resulted in several thousand-fold decrease in catalytic efficiency of EcXyn30A. In contrast, the R293A replacement reduced catalytic efficiency on GX only 18-times. The main difference was in catalytic rate (kcat) which was much lower for EcXyn30A acting on the modified substrates than for the variant which exhibited similar kcat values on all three polymers. The R293A variant cleaved GX, GXE and GXR on the second glycosidic bond from branch towards the reducing end, similarly to EcXyn30A. The R293A replacement caused 15-times decrease in specific activity on MeGlcA3Xyl4, but it did not influence low activity on linear xylooligosaccharides. Docking experiments showed that MeGlcA3Xyl4 and its esterified and reduced forms were bound to both enzymes in analogous way but with different binding energies. PMID- 29477771 TI - Resveratrol suppresses migration, invasion and stemness of human breast cancer cells by interfering with tumor-stromal cross-talk. AB - Cancer-associated fibroblasts (CAFs) constitute a major compartment of the tumor microenvironment. CAFs produce a variety of cytokines, growth factors and extracellular matrix proteins, thereby stimulating tumor progression. CAFs are distinct from normal fibroblasts for their overexpression of alpha-smooth muscle actin. Recent studies suggest that CAFs play an important role in proliferation and migration of cancer cells through cross-talk with them. Resveratrol (trans 3,4'5,-trihydroxystilbene), a phytoalexin present in grapes, has been reported to possess chemopreventive and chemotherapeutic activities. In the present study, we examined the effects of resveratrol on CAF-induced migration, invasion and self renewal activity of breast cancer cells. Resveratrol inhibited proliferation, migration and invasion of human breast cancer cells treated with CAF-conditioned media (CAF-CM). Resveratrol treatment suppressed the CAF-CM-induced expression of Cyclin D1, c-Myc, MMP-2 and MMP-9. In addition, resveratrol inhibited Sox2 expression as well as activation of Akt and STAT3 induced by CAF-CM in breast cancer cells. Further, resveratrol abrogated stemness properties and reduced the expression of self-renewal signaling molecules in stem-like breast cancer cells. Taken together, the present study provides insights into the role of resveratrol in tumor microenvironment with focus on interaction between cancer cells and the hosting niche. PMID- 29477772 TI - It's Not a Small World After All. PMID- 29477773 TI - Effects of Psychosocial Interventions for Behavioral and Psychological Symptoms in Dementia on the Prescription of Psychotropic Drugs: A Systematic Review and Meta-Analyses. AB - BACKGROUND: Dementia is often accompanied by neuropsychiatric symptoms. Psychotropic drugs for the treatment of neuropsychiatric symptoms are frequently used to manage these problems, but they are of limited effectiveness and can have serious side effects. Psychosocial interventions are advocated as first line treatment and may help to reduce psychotropic drug use. AIMS: To assess the effect of multidisciplinary psychosocial interventions in nursing homes on the psychotropic drug prescription rate. METHODS: Literature obtained from searches in 9 electronic databases was systematically reviewed. In addition, the pooled effects of specific psychosocial interventions in homogenous subgroups were analyzed (meta-analysis). RESULTS: Eleven randomized controlled studies that investigated multiple psychotropic drugs interventions (psychotropic drugs in 3, antipsychotics in 9, and antidepressants in 5 studies) as well as different types of psychosocial interventions were included. We separately analyzed interventions directed at the care staff level (educational programs in 3, in-reach services or consultation in 1, cultural or process change in 6 studies) and the individual resident level in 1 study. In 7 out of 9 studies reporting on antipsychotic drug use, the physician was actively involved. Nine studies in which antipsychotic drug use was specified reported a significant decrease in prescription rate as a result of psychosocial interventions [relative risk (RR) 0.71, 95% confidence interval (CI) 0.59-0.88], whereas meta-analysis of 5 studies investigating antidepressant drug use failed to show a significant effect (RR 0.82, 95% CI 0.64 1.02). Pooled effect sizes of 6 studies investigating cultural change, showed a significant decrease in antipsychotic drug use (RR 0.65, 95% CI 0.57-0.73). Effect sizes of 2 studies on educational programs on antipsychotic use were nonsignificant (RR 1.50, 95% CI 0.49-4.64). Sensitivity analysis of 7 studies reporting on antipsychotic drug use involving prescribing physicians showed a more robust decrease (RR 0.66, 95% CI 0.54-0.80). CONCLUSIONS: The results of this study show that psychosocial interventions may lead to a substantial reduction of antipsychotic drug prescription, especially in studies that reported on cultural change and that involved prescribing physicians. Conspicuously, a profound lack of information was observed in many studies as to what exactly constituted the care-as-usual treatment in the control group. PMID- 29477774 TI - Screening Sarcopenia in Community-Dwelling Older Adults: SARC-F vs SARC-F Combined With Calf Circumference (SARC-CalF). AB - OBJECTIVES: To compare the diagnostic value of the 5-component questionnaire that measures strength, assistance walking, rise from a chair, climb stairs, and falls (SARC-F) and SARC-F combined with calf circumference (SARC-CalF) for screening sarcopenia in community-dwelling older adults. DESIGN: A diagnostic accuracy study. SETTING: A community in Chengdu, China. PARTICIPANTS: Older adults aged 60 years or older. MEASUREMENTS: Muscle mass, muscle strength, and physical performance were estimated using a bioimpedance analysis device, handgrip strength, and gait speed, respectively. Four commonly used diagnostic criteria [European Working Group on Sarcopenia in Older People (EWGSOP), Asian Working Group for Sarcopenia (AWGS), International Working Group on Sarcopenia (IWGS), and Foundation for the National Institutes of Health (FNIH) criteria] were applied as the reference standard, separately. The sensitivity/specificity analyses of the SARC-F and SARC-CalF methods were evaluated. The receiver operating characteristics curves and the area under the receiver operating characteristics curves were used to compare the overall diagnostic accuracy of the SARC-F and SARC-CalF for identifying sarcopenia. RESULTS: We included 160 men and 224 women. Based on the 4 diagnostic criteria, the prevalence of sarcopenia ranged from 11.7% to 25.0%. Using the AWGS criteria as the reference standard, the SARC-CalF had a sensitivity of 60.7% and a specificity of 94.7% in the whole study population, whereas the SARC-F had a sensitivity of 29.5% and a specificity of 98.1%. The area under the receiver operating characteristics curves for SARC CalF and SARC-F were 0.92 (95% confidence interval 0.89-0.94) and 0.89 (95% confidence interval 0.86-0.92), respectively (P = .003). We obtained similar results when using the other 3 criteria as the reference standard. Subgroup analyses revealed similar results in both men and women. CONCLUSIONS: SARC-CalF significantly improves the sensitivity and overall diagnostic accuracy of SARC-F for screening sarcopenia in community-dwelling older adults. PMID- 29477775 TI - Clarifying the Conceptualization, Dimensionality, and Structure of Emotion: Response to Barrett and Colleagues. AB - We present a mathematically based framework distinguishing the dimensionality, structure, and conceptualization of emotion-related responses. Our recent findings indicate that reported emotional experience is high-dimensional, involves gradients between categories traditionally thought of as discrete (e.g., 'fear', 'disgust'), and cannot be reduced to widely used domain-general scales (valence, arousal, etc.). In light of our conceptual framework and findings, we address potential methodological and conceptual confusions in Barrett and colleagues' commentary on our work. PMID- 29477776 TI - The Effort Paradox: Effort Is Both Costly and Valued. AB - According to prominent models in cognitive psychology, neuroscience, and economics, effort (be it physical or mental) is costly: when given a choice, humans and non-human animals alike tend to avoid effort. Here, we suggest that the opposite is also true and review extensive evidence that effort can also add value. Not only can the same outcomes be more rewarding if we apply more (not less) effort, sometimes we select options precisely because they require effort. Given the increasing recognition of effort's role in motivation, cognitive control, and value-based decision-making, considering this neglected side of effort will not only improve formal computational models, but also provide clues about how to promote sustained mental effort across time. PMID- 29477777 TI - Cord Blood Unit Dominance Analysis and Effect of the Winning Unit on Outcomes after Double-Unit Umbilical Cord Blood Transplantation in Adults with Acute Leukemia: A Retrospective Study on Behalf of Eurocord, the Cord Blood Committee of Cellular Therapy, Immunobiology Working Party, and the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. AB - Usually, after double umbilical cord blood transplantation (DUCBT), only 1 of the transplanted units persists in the long term. The characteristics of the winning cord blood unit (W-CBU) that determine unit dominance and how they influence the outcomes of DUCBT remain unclear. We retrospectively analyzed 347 patients with acute leukemia transplanted with a DUCBT (694 CBU) from 2005 to 2013 who had documented neutrophil engraftment and a W-CBU identified by chimerism analysis, to identify unit characteristics impacting on dominance. Median age at DUCBT was 40 years and median follow-up was 35 months. Among W-CBUs, 41% were >=5/6 HLA matched to the recipient and 59% were <=4/6. Multivariate analysis indicated that <=4/6 HLA-matched W-CBUs led to lower leukemia-free survival (44% versus 56%; hazard ratio [HR], 1.5; P = .032) and overall survival (49% versus 62%; HR, 1.5; P = .028), increased nonrelapse mortality (26% versus 18%; HR, 1.9; P = .027), and acute graft-versus-host disease (46% versus 35%; HR, 1.7; P = .013). We were unable to predict unit dominance, but we demonstrated that outcomes were strongly influenced by the degree of HLA mismatch between W-CBU and recipient. Therefore, selection of both units with the lower number of HLA mismatches with the recipient is indicated. PMID- 29477780 TI - "Needs More Research"-Implications of the Proteus Effect for Researchers and Evidence Adopters. PMID- 29477778 TI - Cohort-Controlled Comparison of Umbilical Cord Blood Transplantation Using Carlecortemcel-L, a Single Progenitor-Enriched Cord Blood, to Double Cord Blood Unit Transplantation. AB - Umbilical cord blood (UCB) transplantation has a high early mortality rate primarily related to transplanted stem cell dose. To decrease early mortality and enhance engraftment, a portion of selected cord blood units (20% to 50%) was expanded with cytokines and the copper chelator tetraethylenepentamine (carlecortemcel-L) and transplanted with the unmanipulated fraction after myeloablative conditioning. The primary endpoint was 100-day survival, which was compared with a contemporaneous double-unit cord blood transplantation (DUCBT) group. We enrolled 101 patients at 25 sites; the DUCBT comparison (n = 295) was selected from international registries using study eligibility criteria. Baseline carlecortemcel-L study group unit nucleated cell (NC) and CD34+ were 3.06 * 107 cell dose/kg and 1.64 * 105 cell dose/kg. Median NC and CD34+ fold expansion were 400 and 77, with a mean total CD34 infused of 9.7 * 105/kg. The 100-day survival was 84.2% for the carlecortemcel-L study group versus 74.6% for the DUCBT group (odds ratio, .50; 95% CI, .26 to .95; P = .035). Survival at day 180 was similar for the 2 groups; the major cause of death after day 100 was opportunistic infections. Faster median neutrophil (21 days versus 28 days; P < .0001), and platelet (54 days versus 105 days; P = .008) engraftment was seen in the carlecortemcel-L study group; acute and chronic graft-versus-host disease rates were similar. In this multinational comparative study, transplanting expanded CD34+ stem cells from a portion of a single UCB unit, with the remaining unmanipulated fraction improved 100-day survival compared with DUCBT control patients while facilitating myeloid and platelet engraftment. This trial was registered at www.clinicaltrials.gov as #NCT00469729. PMID- 29477779 TI - Defibrotide for Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease Prophylaxis in High-Risk Adult Patients: A Single-Center Experience Study. AB - Sinusoidal obstruction syndrome (SOS), also known as hepatic veno-occlusive disease (VOD), is a serious complication after hematopoietic stem cell transplantation (HSCT). SOS/VOD usually occurs within 3 weeks of HSCT, but the 2016 European Society for Blood and Marrow Transplantation diagnosis criteria have been revised to include late forms. Prophylactic use of defibrotide is recommended in the pediatric setting, but its value remains uncertain in the adult population. We report here a single-center series of 63 adult patients considered at high risk for SOS/VOD who received defibrotide prophylaxis in combination with ursodeoxycholic acid between May 2012 and August 2016. The median duration of defibrotide therapy was 23 days. Bleeding occurred in 14 patients (21.5%). Defibrotide prophylaxis was discontinued in 7 patients (10.8%): 4 cases (6.3%) due to bleeding and 3 cases (4.6%) because of the need for antithrombotic therapy. Overall, SOS/VOD occurred in 4 cases (6.3%) within 21 days after HSCT (days 13 and 14) in 2 cases and late-onset SOS/VOD (days 57 and 58) in the other 2 cases. SOS/VOD was moderate in 1 case, very severe in 3 cases, with 2 deaths related to SOS/VOD. Cumulative incidence of grades II to IV acute graft-versus-host disease and transplant-associated thrombotic microangiopathy were 22.2% and 3.2%, respectively. With a median follow-up of 31 months (range, 10.7 to 60.3), the rates of 2-year overall survival, progression-free survival, incidence of relapse, and nonrelapse mortality were 56.5%, 49%, 28.7%, and 22.3%, respectively. In our experience defibrotide prophylaxis is associated with a low incidence of SOS/VOD after allogeneic HSCT in a high-risk adult population with an acceptable safety profile. PMID- 29477781 TI - Treatment Effect in Earlier Trials of Patients With Chronic Medical Conditions: A Meta-Epidemiologic Study. AB - OBJECTIVE: To determine whether the early trials in chronic medical conditions demonstrate an effect size that is larger than that in subsequent trials. METHODS: We identified randomized controlled trials (RCTs) evaluating a drug or device in patients with chronic medical conditions through meta-analyses (MAs) published between January 1, 2007, and June 23, 2015, in the 10 general medical journals with highest impact factor. We estimated the prevalence of having the largest effect size or heterogeneity in the first 2 published trials. We evaluated the association of the exaggerated early effect with several a priori hypothesized explanatory variables. RESULTS: We included 70 MAs that had included a total of 930 trials (average of 13 [range, 5-48] RCTs per MA) with average follow-up of 24 (range, 1-168) months. The prevalence of the exaggerated early effect (ie, proportion of MAs with largest effect or heterogeneity in the first 2 trials) was 37%. These early trials had an effect size that was on average 2.67 times larger than the overall pooled effect size (ratio of relative effects, 2.67; 95% CI, 2.12-3.37). The presence of exaggerated effect was not significantly associated with trial size; number of events; length of follow-up; intervention duration; number of study sites; inpatient versus outpatient setting; funding source; stopping a trial early; adequacy of random sequence generation, allocation concealment, or blinding; loss to follow-up or the test for publication bias. CONCLUSION: Trials evaluating treatments of chronic medical conditions published early in the chain of evidence commonly demonstrate an exaggerated treatment effect compared with subsequent trials. At the present time, this phenomenon remains unpredictable. Considering the increasing morbidity and mortality of chronic medical conditions, decision makers should act on early evidence with caution. PMID- 29477782 TI - ? AB - Endophthalmitis is a rare infection of the vitreous and/or aqueous. It can be bacterial or fungal. Exogenous endophthalmitis is the most common form and results from direct inoculation of a pathogen after eye surgery or penetrating trauma. Endophthalmitis can also be endogenous, secondary to disseminated infection. Fungal endophthalmitis is associated with poor prognosis and treatment is difficult given the low penetration of most of the antifungal agents available and the emergence of resistant filamentous fungi like Fusarium. To our knowledge, we describe the first endogenous fungal endophthalmitis due to Fusarium dimerum, a ubiquitous pathogen found in soil and plants. A 71-year-old woman, diagnosed with acute myeloid leukemia, was hospitalized for surveillance after induction chemotherapy. Prophylaxis by antibiotics and posaconazole was ongoing when she complained of pain and decreased vision in the left eye. A voluminous chorioretinal abscess developed and after multiple sterile aqueous humour samples, only vitrectomy allowed diagnosis with fungal hyphae seen on May Grunwald Giemsa stained smear and positive cultures. The fungus was identified as Fusarium dimerum. The treatment, that included intravitreal injections of voriconazole and amphotericin B associated with systemic administration of voriconazole, allowed complete control of the infection. The source of this infection could not be confirmed despite the discovery of several possible infection sites including a periungual whitlow on the left hand and a lesion on a nail, from which samples were negative in microbiology laboratories. Unfortunately, damages of the retina were too important and the patient did not recover sight of her left eye. PMID- 29477783 TI - Chemical composition, antioxidant activity and antifungal effects of five Iranian essential oils against Candida strains isolated from urine samples. AB - Systemic candidiasis has become an emerging fungal infection in recent years. Anti-Candida resistance to conventional antifungal agents has subsequently increased. This study reported the chemical composition, antioxidant and anti Candida activity of Origanum majorana, Artemisia dracunculus, Cymbopogon citrate, Cinnamomum verum and Caryophyllus aromaticus essential oils. Different Candida species, from urine tracts of hospitalized patients, were included to be challenged with understudied essential oils. Chemical compositions were determined using gas chromatography/mass spectroscopy (GC/MS) analysis and antioxidant activity was measured using DDPH assay. MIC of these essential oils was evaluated using broth micro-dilution test. Caryophyllus aromaticus had the highest antioxidant activity while the lowest antioxidant activity was for Artemisia dracunculus. MICs of Cinnamomum verum, Caryophillium aromaticus, Artemisia dracunculus, Origanum vulgare and Cymbopogon citratus essential oils ranged from 125 to 175MUg/mL (mean value: 147.7+/-25.5MUg/mL), 700 to 1000MUg/mL (mean value: 740.9+/-105.4MUg/mL), 1000 to 2000MUg/mL (mean value: 1454.5+/ 509.6MUg/mL), 173 to 350MUg/mL (mean value: 208+/-55.8MUg/mL) and 125 to 175MUg/mL (mean value: 156.8+/-24.6MUg/mL) for different Candida species, respectively. In general, natural compounds are suitable to be used as anti Candida and antioxidant agents. However in this stage, these compounds could be applied as supplementary agents along with conventional antifungal drugs. PMID- 29477784 TI - Dracorhodin perchlorate inhibits biofilm formation and virulence factors of Candida albicans. AB - OBJECTIVE: The aim of this study was to investigate the antifungal activity of dracorhodin perchlorate (DP) against planktonic growth and virulence factors of Candida albicans. METHODS: Microdilution method based on CLSI-M27-A3 was used to test the antifungal susceptibility of DP. The activity of DP against biofilm formation and development of C. albicans was quantified by XTT assay and visualized by confocal laser scanning microscope. The effect of DP on the morphological transition of C. albicans induced by four kinds of hyphal-inducing media at 37 degrees C for 4hours was observed under microscope. The rescue experiment by adding exogenous cAMP analog was performed to investigate the involvement of cAMP in the yeast to hyphal transition and biofilm formation of C. albicans. Egg yolk emulsion agar was used to determine the inhibition of DP on the phospholipase production of C. albicans. Human JEG-3 and HUVEC cell lines, as well as the nematode Caenorhabditis elegans was used to assess the toxicity of DP. RESULTS: The minimum inhibitory concentration (MIC) of DP is 64MUM while the antifungal activity was fungistatic. As low as a concentration at 16MUM, DP could inhibit the yeast to hyphal transition in liquid RPMI-1640, Spider, GlcNAc and 10% FBS-containing Sabouroud Dextrose medium, as well as on the solid spider agar. Exogenous cAMP analog could rescue part of biofilm viability of C. albicans. DP could inhibit the production of phospholipase. The toxicity of DP against human cells and C. elegans is low. CONCLUSION: DP could inhibit the planktonic growth and virulent factors in multiple stages, such as yeast to hyphal transition, adhesion, biofilm formation and production of phospholipase of C. albicans. PMID- 29477785 TI - Interpretation of statistical results. AB - The appropriate interpretation of the statistical results is crucial to understand the advances in medical science. The statistical tools allow us to transform the uncertainty and apparent chaos in nature to measurable parameters which are applicable to our clinical practice. The importance of understanding the meaning and actual extent of these instruments is essential for researchers, the funders of research and for professionals who require a permanent update based on good evidence and supports to decision making. Various aspects of the designs, results and statistical analysis are reviewed, trying to facilitate his comprehension from the basics to what is most common but no better understood, and bringing a constructive, non-exhaustive but realistic look. PMID- 29477786 TI - National survey: Room for improvement. PMID- 29477787 TI - Self-perceived level of competitiveness, tension, and dependency and lifestyles in the 'Seguimiento Universidad de Navarra' cohort study. AB - OBJECTIVE: The objective of this study is to assess the differences in lifestyles according to levels of self-perceived competitiveness, psychological tension, and dependency in a Mediterranean cohort of university graduates. STUDY DESIGN: Levels of personality traits, food consumption, nutrient intake, eating attitudes, physical activity, sedentary lifestyle, and alcohol and tobacco consumption were assessed through a questionnaire administered at baseline. This was a cross-sectional study in the context of the Seguimiento Universidad de Navarra cohort. Participants are 15,346 Spanish adults. RESULTS: Participants with a high level of self-perceived competitiveness consumed more vegetables and fish but less refined grains; they had higher protein intake and healthier eating attitudes. They were more physically active and less likely to be smokers. Participants with a high level of tension or dependency were less physically active, and participants more dependent also had poorer adherence to the Mediterranean diet. CONCLUSIONS: Self-perceived personality traits, especially the trait of competitiveness, are likely to be associated with healthier dietary patterns, better nutrient profile, better eating attitudes, physical activity, and less exposure to smoking. The use of short questions about self-perceived levels of competitiveness, psychological tension, and dependency can contribute to add additional information when assessing lifestyles and diet in adults. PMID- 29477788 TI - Projected diabetes prevalence and related costs in three North American urban centres (2015-2040). AB - OBJECTIVES: To explore the future implications of diabetes for urban centres, we projected the prevalence and cost of diabetes from 2015 to 2040 in three very different North American cities: Houston, Mexico City and Vancouver. STUDY DESIGN: We use a simple demographic transition model using existing sources to project future prevalence and financial burden of diabetes. METHODS: Based on data from each individual city, projections of the diabetes prevalence and financial burden were created through a three-stage transition model where the likelihood of moving across stages is based on incidence rates for age and gender groups. RESULTS: According to our projections from 2015 to 2040, diabetes prevalence will approximately double in Houston to 1,051,900 people and in Vancouver to 379,778 people and increase by >1 million to 3,080,013 people in Mexico City. Prevalence rates will increase from 8.5% to 11.7% in Houston, from 9.1% to 11.9% in Mexico City and from 7.2% to 11.3% in Vancouver. Associated costs will rise 1.9-fold to $11.5 billion (in US dollars) in Houston, 1.6-fold to $2.8 billion in Mexico City and 2.1-fold to $2.6 billion in Vancouver. CONCLUSIONS: Unless actions are taken to decrease its incidence, diabetes is expected to increasingly contribute to the societal and financial burden, particularly for urban areas. Resources and policy actions are needed immediately to promote healthy lifestyles and to implement secondary prevention of diabetes complications. PMID- 29477789 TI - Evaluation of websites that contain information relating to malaria in pregnancy. AB - OBJECTIVES: The study identified available websites on malaria in pregnancy on the World Wide Web and sought to evaluate their readability and information quality. STUDY DESIGN: A purposeful sample of websites were selected which provided information on Malaria in pregnancy. METHODS: A total of 31 websites were identified from searches using Google, Yahoo and Bing search engines. Two generic tools (Discern and HON), one specific tool designed to assess information quality of malaria in pregnancy and readability tests (Flesch Reading Ease and Flesh-Kincaid Grade level) were used to evaluate the websites. RESULTS: Most of the websites scored below 50% with the HON Code tool, with most lacking information on the symptoms. One website scored over 70 with the reading ease with two (2) achieving a score of 7 for the reading level test. The readability of the websites was too advanced for an ordinary consumer. CONCLUSION: The results of this study indicated that the information quality of malaria in pregnancy websites varied from fair to medium. It was also found that the readability of the websites was too advanced for an ordinary consumer. These findings suggest that most websites are not comprehensive in addressing all the relevant aspects of malaria in pregnancy. PMID- 29477790 TI - Bivalirudin versus unfractionated heparin in peripheral vascular interventions. AB - BACKGROUND: A number of studies suggest that bivalirudin (BIV) is associated with similar efficacy but reduced bleeding when compared with unfractionated heparin (UFH) in patients undergoing peripheral vascular interventions (PVI). METHODS: A comprehensive literature search was conducted with the electronic databases MEDLINE, EMBASE and CENTRAL. These were queried to identify studies comparing BIV with UFH in PVI. Study endpoints included total bleeding events, major and minor bleeding events and procedural success. Random-effects meta-analysis method was used to pool endpoint odds ratios (OR) for both UFH and BIV with 95% confidence intervals (CI). RESULTS: A total of 12,335 patients (70.6 years; 59.7% male) were included from seven observational cohort studies (two prospective and five retrospective) comparing outcomes between BIV and UFH during PVI between January 2000 and May 2017. Compared with BIV, UFH was associated with significantly higher total bleeding, (OR 1.52 with 95% CI 1.11 to 2.09, p = 0.009), major bleeding (OR 1.38 with 95% CI 1.13 to 1.68, p = 0.002), and minor bleeding (OR 1.51 with 95% CI 1.09 to 2.08, p = 0.01). Procedural success rates were not different between the two groups (BIV vs HEP: OR 0.90 with 95% CI 0.49 to 1.64, p = 0.72) CONCLUSION: Compared with BIV, UFH was associated with more bleeding when used during PVI. There was no significant difference in procedural success between the two anticoagulation strategies. PMID- 29477791 TI - A review of bio-based materials for oil spill treatment. AB - Being cost-effective, synthetic materials were initially used abundantly for the removal of oil. Gradually, however, awareness of the use of dispersants like Corexit, which makes water resources more toxic than oil, has changed the scenario for the treatment of spilled oil. The removal of spilled oil from water resources is still a very topical issue. An eco-friendly and sustainable approach towards the environment has introduced many low-cost, non-toxic and biodegradable materials along with different biomasses to make micro-to nano-sized materials, membranes, sponges/aerogel, etc. for the removal and recovery of oil from water resources. Additionally, the reusability of these materials after the recovery of oils has added one more step towards sustainability. This review comprises the work conducted by various researchers in the field of the removal and recovery of spilled oils using various biomasses and polymers, either in the form of sorbents or separators. PMID- 29477792 TI - The performance and membrane fouling rate of a pilot-scale anaerobic membrane bioreactor for treating antibiotic solvent wastewater under different cross flow velocity. AB - The performance of a pilot-scale anaerobic membrane bioreactor (AnMBR) for treating antibiotic solvent wastewater under different cross flow velocities (CFV) was investigated. Effects of mixed liquid suspended solids (MLSS), colloid total organic carbon (TOC) and CFV on membrane fouling rate (RMF) were also explored in this paper. Throughout 341 days of experiment, the average total removal rate of N, N-Dimethylformamide (DMF) was 98.5% which hardly affected by the variation of CFV, and the compliance rate of DMF was 92% according to the Chinese standard (<25 mg/L). However, the relevant high total removal rate of M cresol (MC) was achieved as 97.5%, the content of effluent failed to meet the national level emission standard (<0.1 mg/L). The biogas yield and the methane content of the biogas increased gradually with the increase of CFV, and the average methane content were over 70%. There were four kinds of methanogens in AnMBR, Methanosaeta spp was the largest methanogenic community, with an area of 45-70% of the archae. There was a linear relationship between colloid TOC and RMF at different MLSS concentrations. Then a universal mathematical model for the changes of RMF with influence factors was established. The result showed that model well fitted the laboratory data. It is suggested that the model proposed could reflect and manage the membrane fouling of AnMBR treating antibiotic solvent wastewater. PMID- 29477793 TI - Improved sulfide mitigation in sewers through on-line control of ferrous salt dosing. AB - Water utilities worldwide spend annually billions of dollars to control sulfide induced corrosion in sewers. Iron salts chemically oxidize and/or precipitate dissolved sulfide in sewage and are especially used in medium- and large-size sewers. Iron salt dosing rates are defined ad hoc, ignoring variation in sewage flows and sulfide levels. This often results in iron overdosing or poor sulfide control. Online dosing control can adjust the chemical dosing rates to current (and future) state of the sewer system, allowing high-precision, stable and cost effective sulfide control. In this paper, we report a novel and robust online control strategy for the dosing of ferrous salt in sewers. The control considers the fluctuation of sewage flow, pH, sulfide levels and also the perturbation from rainfall. Sulfide production in the pipe is predicted using auto-regressive models (AR) based on current flow measurements, which in turn can be used to determine the dose of ferrous salt required for cost-effective sulfide control. Following comprehensive model-based assesment, the control was successfully validated and its effectiveness demonstrated in a 3-week field trial. The online control algorithm controlled sulfide below the target level (0.5 mg S/L) while reducing chemical dosing up to 30%. PMID- 29477794 TI - Clonal evolution and heterogeneity in metastatic head and neck cancer-An analysis of the Austrian Study Group of Medical Tumour Therapy study group. AB - BACKGROUND: Tumour heterogeneity and clonal evolution within a cancer patient are deemed responsible for relapse in malignancies and present challenges to the principles of targeted therapy, for which treatment modality is often decided based on the molecular pathology of the primary tumour. Nevertheless, the clonal architecture in distant relapse of head and neck cancer is fairly unknown. PATIENTS AND METHODS: For this project, we analysed a cohort of 386 patients within the Austrian Registry of head and neck cancer. We identified 26 patients with material from the primary tumour, the distant metastasis after curative first-line treatment and a germline sample for analysis of clonal evolution. After pathological analyses, these samples were analysed using a targeted massively parallel sequencing (MPS) panel of 257 genes known to be recurrently mutated in head and neck cancer plus a genome-wide SNP-set. RESULTS: Despite histological diagnosis of distant metastasis, no corresponding mutation in the supposed metastases was found in two of 23 (8.6%) evaluable patients suggesting a primary tumour of the lung instead of a distant metastasis of head and neck cancer. We observed a branched pattern of evolution in 31.6% of the analysed patients. This pattern was associated with a shorter time to distant metastasis, compared with a pattern of punctuated evolution. Structural genomic changes over time were also present in 7 of 12 (60%) evaluable patients with metachronous metastases. CONCLUSION: Targeted MPS demonstrated substantial heterogeneity at the time of diagnosis and a complex pattern of evolution during disease progression in head and neck cancer. Copy number analyses revealed additional changes that were not detected by mutational analyses. Mutational and structural changes contribute to tumour heterogeneity at diagnosis and progression. PMID- 29477795 TI - Health-related quality of life of adjuvant chemotherapy with S-1 versus gemcitabine for resected pancreatic cancer: Results from a randomised phase III trial (JASPAC 01). AB - BACKGROUND: Adjuvant chemotherapy with S-1 for resected pancreatic cancer demonstrated survival benefits compared with gemcitabine in the JASPAC 01 trial. We investigated the effect of these agents on health-related quality of life (HRQOL) of patients in the JASPAC 01 trial. METHODS: Patients with resected pancreatic cancer were randomly assigned to receive gemcitabine (1000 mg/m2 weekly for three of four weeks for up to six cycles) or S-1 (40, 50, or 60 mg twice daily for four of six weeks for up to four cycles). HRQOL was assessed using the EuroQol-5D-3L (EQ-5D) questionnaire at baseline, months three and six, and every 6 months thereafter. HRQOL end-points included change in EQ-5D index from baseline, responses to five items in the EQ-5D, and quality-adjusted life months up to 24 months. RESULTS: Of randomised 385 patients, 354 patients were included in HRQOL analysis. Mean change in the EQ-5D index was similar in the S-1 and gemcitabine groups within 6 months from treatment initiation (difference, 0.024; P = 0.112), whereas corresponding mean from 12 to 24 months was better in the S-1 group than in the gemcitabine group (difference, 0.071; P < 0.001). Problems in mobility and pain/discomfort were also less frequent in the S-1 group than in the gemcitabine group in that period. Quality-adjusted life months were longer in the S-1 group than in the gemcitabine group (P < 0.001). CONCLUSION: Adjuvant chemotherapy with S-1 does not improve HRQOL within 6 months from treatment initiation but does improve HRQOL thereafter and quality-adjusted life months. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000000655 at UMIN CTR. PMID- 29477796 TI - The use of intensive radiological assessments in routine surveillance after treatment for head and neck cancer: An economic evaluation. AB - BACKGROUND: There is uncertainty around the optimal surveillance of head and neck cancer patients after the primary curative treatment. This study aims at assessing the cost-effectiveness of a post-treatment programme of frequent radiological assessments (maximal approach) compared with a symptom-driven surveillance (minimal approach). MATERIALS AND METHODS: A decision-analytic Markov model is developed to assess the cost utility of two alternative follow-up programmes with a lifetime horizon. The two interventions differ in the number of radiological assessments (i.e. magnetic resonance imaging, computed tomography and positron-emission tomography) performed over a 5-year period. Clinical and utility parameters are derived from published and unpublished literature and expert opinion. The cost analysis is conducted from the perspective of a major Italian region's health care system. Cost-effectiveness results are expressed as incremental cost per life year gained (LYG) and per quality-adjusted life year (QALY) and checked against a cost-effectiveness threshold of ?25,000-40,000 per QALY. One-way, two-way and probabilistic sensitivity analyses are carried out. RESULTS: In the base-case analysis, an intensive programme of radiological investigations leads to 0.10 additional QALYs (0.15 LYG) and an increase in costs of ?1903 per patient compared with those of a minimal option, resulting in an incremental cost of ?19,951/QALY gained (?13,123/LYG). In probabilistic sensitivity analysis, 72% of the results lie below the ?40,000 threshold (55% below ?25,000). CONCLUSIONS: An intensive post-treatment follow-up with scheduled radiological assessments over time might be cost-effective compared with symptom driven surveillance in head and neck cancer patients. Further research is needed to check these results in empirical studies or real-world settings. PMID- 29477797 TI - Adjuvant recMAGE-A3 Immunotherapy After Cystectomy for Muscle-invasive Bladder Cancer: Lessons Learned from the Phase 2 MAGNOLIA Clinical Trial. AB - The MAGNOLIA study, investigating the concept of perioperative immunotherapy in muscle- invasive bladder cancer, was prematurely terminated. The lessons learned that should be considered before initiating and conducting future clinical trials in this field are highlighted. PMID- 29477798 TI - Seat belt and child restraint use in a developing country metropolitan city. AB - Seat belt and child restraint use is noted to be poor in developing countries such as Ghana. An unobstructive observational survey guided by the Theory of Planned Behaviour was therefore conducted to assess seat belt and child restraint use in the Cape Coast Metropolis, Ghana. The observational survey was carried out at the entrances of four nursery schools in medium and high class residential areas in the Metropolis to determine seat belt use by drivers and accompanied child being transported/dropped off in school. The results revealed that a total of 1922 vehicles comprising 826(43.0%) cars, 350(18.2%) SUV, 644(33.5%) taxis and 102(5.3%) mini buses with 3844 vehicle occupants comprising 1922 drivers and child apiece were successively observed. The majority of the drivers (53.1%) did not use the seat belt with 13.2% of the children been restrained. The gender of the driver has a relationship with the seat belt use. The vehicle type has a relationship with the child restraint use and the gender of the driver has a significant relationship with child restraint use. The enforcement of the Road Traffic Act 2004 and Road Traffic Regulation 2180 by the officials of Motor Transport and Traffic Department(MTTD) of the Ghana Police Service in collaboration with National Road Safety Commission (NRSC) can establish social norms that may have a greater potential to enhance seat belt and child restraint use in the Metropolis. PMID- 29477799 TI - Erratum to "Overcoming multiple gastrointestinal barriers by bilayer modified hollow mesoporous silica nanocarriers" [Acta Biomater. 65 (2017) 405-416]. PMID- 29477800 TI - Development of a new screening tool for neuromotor development in children aged two - the neuromotor 5 min exam 2-year-old version (N5E2). AB - OBJECTIVE: As a new screening tool for neuromotor development in children aged two, we developed the Neuromotor 5 min Exam 2-year-old version (N5E2), which can be easily administered by pediatricians or primary care physicians. In this study, as an initial attempt to examine the utility of the N5E2, the inter-rater reliability on scoring for the individual items in this scale was assessed. METHODS: The participants of the study were 29 children (aged 1-5 years, mean age = 2.79) diagnosed with a variety of neuromotor/developmental disorders/high-risk conditions. Inter-rater reliability was examined on the following 11 items in the N5E2: (1) Retrieving a rolling ball, (2) Gait, (3) Toe-walking, (4) Asymmetries of posture and/or movement, (5) Age at unsupported walking, (6) Speaking in two word understandable sentences, (7) Hypotonus, (8) Hypertonus, (9) Eye movement, (10) Vision problem, (11) Hearing problem. The items were administered to children by two pediatricians with different expertise and clinical experience, separately. RESULTS: The results showed that among the eleven items in the N5E2 examined, a high level of agreement (kappa >= 0.60) was found on 4 items, and a moderate level of agreement (0.40 <= kappa < 0.60) was found on 5 items. The level of agreement somewhat improved after the dichotomization of the score; using this format, a high level of rater agreement (kappa >= 0.60) was found on 6 out of 11 items. The analyses also revealed high inter-rater reliability on the sum score of the 11 items (r = 0.84). CONCLUSIONS: The results suggest the possibility that this brief screening tool could be feasible in settings where clinicians' experience varies, based on its inter-rater reliability on individual items between the clinicians with different expertise and amount of clinical experiences. PMID- 29477801 TI - The assessment of sniff nasal inspiratory pressure in patients with Duchenne muscular dystrophy in China. AB - OBJECTIVE: Progressive weakness of respiratory muscles remains one of the leading causes of death among patients with Duchenne muscular dystrophy (DMD). Currently, there are few pulmonary function data among Chinese DMD patients. This study was carried out to evaluate the sniff nasal inspiratory pressure (SNIP) change among a group of Chinese DMD patients, and compare it with the SNIP value of patients with neuromuscular disorders in other countries. METHODS: SNIP data were collected in three research groups that consists of 581 subjects: 125 DMD boys who have taken steroid (Age 5.0-13.3, DMD-steroid group), 145 DMD steroid-naive boys (Age 5.0-13.9, DMD-nonsteroid group), and 311 healthy controls (Age 5.0 14.0, Control group). RESULTS: The SNIP for DMD-nonsteroid group, DMD-steroid group and Control group were: 56.5 (+/-14.3) cm H2O,66.4 (+/-15.5) cm H2O and 78.9 (+/-21.5) respectively. The SNIP in the DMD-nonsteroid group became significantly different from that of the healthy controls since age 7.0-8.9. The significant difference of SNIP between DMD-steroid group and DMD-nonsteroid group at age 7.0-10.9. The peak value of SNIP in the DMD-nonsteroid group appeared at age 8.7, and decreased dramatically thereafter, while in DMD-steroid group and the Control group peaked at 10.2 years and 12.2 years respectively. There was a bit difference between SNIP in this group and that in previous researches which may be due to geographical distribution and ethnic backgrounds. CONCLUSION: This study strengthens the previous findings that SNIP can be used to evaluate respiratory dysfunction during the early stage of young patients with neuromuscular disorders, and demonstrates that steroid is effective in slowing the decrease of SNIP in this group of Chinese DMD boys. PMID- 29477802 TI - Mortality due to KPC carbapenemase-producing Klebsiella pneumoniae infections: Systematic review and meta-analysis: Mortality due to KPC Klebsiella pneumoniae infections. AB - INTRODUCTION: KPC carbapenemase-producing Klebsiella pneumoniae (KPC-KP) has become a major public health challenge. Accordingly, this study sought to use a systematic review of the scientific literature to ascertain the mortality of KPC KP infection, and analyze such mortality by country, year of publication, hospital ward, and type of interpretation used to define carbapenem resistance. METHODOLOGY: A search without language restrictions was made of the MEDLINE, CENTRAL, EBSCO, LILACS and EMBASE databases from 1996 through June 2017, to locate all studies which had determined the existence of KPC-KP infection. We then performed a meta-analysis of all studies that reported KPC-KP infection related mortality, and analyzed mortality by subgroup in accordance with standard methodology. RESULTS: A total of 51 papers were included in the systematic review. From 2005 through 2017, data on KPC-KP infection were reported in 5124 patients, with an average of 465 patients per year. The most widely studied type of infection was bacteremia (28?0%). The meta-analysis showed that overall mortality for the 37 studies was 41.0% (95%CI 37.0-44.0), with the highest mortality rates being observed in oncology patients, 56.0% (95%CI 38.1-73.0), and Brazil, 51.3% (95%CI 43.0-60.0). CONCLUSION: KPC-KP infection-related mortality is high, is manifested differently in some countries, and is highest among oncology patients. PMID- 29477803 TI - Prevalence and distribution of human papillomavirus genotypes in Chinese women between 1991 and 2016: A systematic review. AB - BACKGROUND: Human papillomavirus (HPV) associated cervical cancer is one of the most common cancers and ranked as the eighth most common killer for Chinese women. A dozen of HPV vaccines are being developed in China without a solid China specific distribution of carcinogenic HPV types, thus, we performed this systematic review to explore the China-specific spectrum of high-risk types causing cancer. METHODS: Studies on HPV infection among Chinese women were searched. All retrieved articles were screened and reviewed by a standardized algorithm. Distribution of carcinogenic HPV types and age-specific prevalence were analyzed using random-effects model. RESULTS: A total of 303 articles were included in the final analysis. The top 10 common HPV types detected in ICC patients, in descending order of frequency, were HPV 16 (62.5%), 18 (12.4%), 58 (8.6%), 52 (5.7%), 33 (4.6%), 31 (3.5%), 55 (2.4%), 68 (2.4%), 53 (2.2%) and 45 (2.0%) respectively. Similar spectrum was found in women with precancer. The prevalence of HPV infection peaked between 20 and 24 years with a rate of 24.3%, thereafter declined substantially and stabilized at middle-ages. Compared to women living in the developed provinces, the second peak was observed among women aged 45-55 years in less developed regions. CONCLUSION: In general, the spectrum of HPV types in women with precancer/cancer and the pattern of age-specific prevalence were consistent with that of elsewhere worldwide. However, some distinguished characteristics could also be concluded, and these imprinting should be considered and integrated when developing vaccines and strategy for disease control in China. PMID- 29477804 TI - Placental CpG methylation of HPA-axis genes is associated with cognitive impairment at age 10 among children born extremely preterm. PMID- 29477805 TI - Role of cell surface composition and lysis in static biofilm formation by Lactobacillus plantarum WCFS1. AB - Next to applications in fermentations, Lactobacillus plantarum is recognized as a food spoilage organism, and its dispersal from biofilms in food processing environments might be implicated in contamination or recontamination of food products. This study provides new insights into biofilm development by L. plantarum WCFS1 through comparative analysis of wild type and mutants affected in cell surface composition, including mutants deficient in the production of Sortase A involved in the covalent attachment of 27 predicted surface proteins to the cell wall peptidoglycan (DeltasrtA) and mutants deficient in the production of capsular polysaccharides (CPS1-4, Deltacps1-4). Surface adhesion and biofilm formation studies revealed none of the imposed cell surface modifications to affect the initial attachment of cells to polystyrene while biofilm formation based on Crystal Violet (CV) staining was severely reduced in the DeltasrtA mutant and significantly increased in mutants lacking the cps1 cluster, compared to the wild-type strain. Fluorescence microscopy analysis of biofilm samples pointed to a higher presence of extracellular DNA (eDNA) in cps1 mutants and this corresponded with increased autolysis activity. Subsequent studies using Deltaacm2 and DeltalytA derivatives affected in lytic behaviour revealed reduced biofilm formation measured by CV staining, confirming the relevance of lysis for the build-up of the biofilm matrix with eDNA. PMID- 29477806 TI - Metabolite profiling of Listeria innocua for unravelling the inactivation mechanism of electrolysed water by nuclear magnetic resonance spectroscopy. AB - Bactericidal effects of low concentration electrolysed water (LcEW) on microorganisms are previously well reported; however, the inactivation mechanism of EW is not understood. The lethal and sublethal injuries of L. monocytogenes and L. innocua by EW treatments were determined and the metabolic profile changes for L. innocua were characterised using nuclear magnetic resonance (NMR). Microbial metabolomics approach combined with multivariate data analyses was used to interpret the cellular chemical fingerprints of L. innocua. The relative amount of intracellular reactive oxygen species (ROS) was assayed using 2',7 dichlorodihydrofluorescein diacetate (H2DCFDA). The results showed that the proportion of the sublethally injured microbial cells L. monocytogenes and L. innocua increased from 40% to 70% and from 35% to 65%, respectively, when the free available chlorine (FAC) of LcEW increased from 2 to 8 mg/L. Overall, 36 low molecular-weight metabolic compounds in L. innocua extracts were characterised by NMR spectroscopy. EW perturbation resulted in a drastic and multitude disruption across a wide range of biochemical process including peptidoglycan synthesis, nucleotides biosynthesis and amino acid metabolism. Elevated levels of alpha ketoglutarate and succinate implicated the enhanced glutamate decarboxylase (GAD) system and gamma-aminobutyric acid (GABA) shunt for the protection against oxidative stress. These findings provided the comprehensive insights into the metabolic response of Listeria to EW oxidative stress and can serve as a basis for better utilisation for sanitisation. PMID- 29477807 TI - Bacteriophages reduce Yersinia enterocolitica contamination of food and kitchenware. AB - Yersinia enterocolitica, the primary cause of yersiniosis, is one of the most important foodborne pathogens globally and is associated with the consumption of raw contaminated pork. In the current study, four virulent bacteriophages (phages), one of Podoviridae (fHe-Yen3-01) and three of Myoviridae (fHe-Yen9-01, fHe-Yen9-02, and fHe-Yen9-03), capable of infecting Y. enterocolitica were isolated and characterized. fHe-Yen9-01 had the broadest host range (61.3% of strains, 65/106). It demonstrated a latent period of 35 min and a burst size of 33 plaque-forming units/cell, and was found to have a genome of 167,773 bp with 34.79% GC content. To evaluate the effectiveness of phage fHe-Yen9-01 against Y. enterocolitica O:9 strain Ruokola/71, we designed an experimental model of the food market environment. Phage treatment after bacterial inoculation of food samples, including raw pork (4 degrees C, 72 h), ready-to-eat pork (26 degrees C, 12 h), and milk (4 degrees C, 72 h), prevented bacterial growth throughout the experiments, with counts decreasing by 1-3 logs from the original levels of 2 4 * 103 CFU/g or ml. Similarly, when artificially contaminated kitchen utensils, such as wooden and plastic cutting boards and knives, and artificial hands, were treated with phages for 2 h, bacterial growth was effectively inhibited, with counts decreasing by 1-2 logs from the original levels of ca 104 CFU/cm2 or ml. To the best of our knowledge, this is the first report of the successful application of phages for the control of Y. enterocolitica growth in food and on kitchen utensils. PMID- 29477808 TI - Safety of diclofenac use during early pregnancy: A prospective observational cohort study. AB - Diclofenac is a widely used analgesic so that exposure during pregnancy may frequently occur. Most publications have evaluated the safety of NSAIDs on pregnancy outcome as a group of substances. Specific data on diclofenac are rare. This observational cohort study used the German Embryotox pharmacovigilance database to assess the risk of major birth defects and spontaneous abortion after first trimester exposure to diclofenac. A group of 260 women who took diclofenac during first trimester was compared to 778 non-exposed pregnancies. In the diclofenac exposed cohort 4 major birth defects were observed among 220 live-born infants and 25 spontaneous abortions occurred. Neither the rate of major birth defects (1.8% vs. 3.1%; OR adjusted 0.59; 95% CI 0.17-2.08) nor the risk of spontaneous abortion (HR adjusted 0.90; 95% CI 0.56-1.46) was increased. The study results do not indicate that diclofenac exposure during first trimester is associated with a teratogenic risk. PMID- 29477809 TI - Pictorial review: Renal ultrasound. AB - Ultrasound (US) is the first-line imaging modality for evaluating azotemic patients for urinary obstruction and renal size. US is also valuable for distinguishing congenital variants and simple cystic lesions from renal masses. Doppler US is effective in detection of renal calculi and evaluation of vascular pathology. Unfortunately, renal US is limited in distinguishing causes of medical renal disease. The kidneys have a complex internal architecture with a highly variable appearance on US. This article illustrates non-neoplastic renal conditions, including normal and embryological variants, parenchymal, cystic, and vascular diseases. Renal infections, calcifications, and trauma and fluid collections are also discussed, with an emphasis on distinguishing US features and pathophysiology. PMID- 29477811 TI - Ultrasonic investigation of granular materials subjected to compression and crushing. AB - Ultrasonic wave propagation measurement has been used as a suitable technique for studying the granular materials and investigating the soil fabric structure, the grain contact stiffness, frictional strength, and inter-particle contact area. Previous studies have focused on the variations of shear and compressional wave velocities with effective stress and void ratio, and lesser effort has been made in understanding the variation of amplitude and dominant frequency of transmitted compressional waves with deformation of soil packing. In this study, continuous compressional wave transmission measurements during compaction of unconsolidated quartz sand are used to investigate the impact of soil layer deformation on ultrasonic wave properties. The test setup consisted of a loading machine to apply constant loading rate to a sand layer (granular quartz) of 6 mm thickness compressed between two forcing blocks, and an ultrasonic wave measurement system to continuously monitor the soil layer during compression up to 48 MPa normal stress. The variations in compressional wave attributes such as wave velocity, transmitted amplitude, and dominant frequency were studied as a function of the applied normal stress and the measured normal strain as well as void ratio and particle size. An increasing trend was observed for P-wave velocity, transmitted amplitude and dominant frequency with normal stress. In specimen with the largest particle size (D50 = 0.32 mm), the wave velocity, amplitude and dominant frequency were found to increase about 230%, 4700% and 320% as the normal stress reached the value of 48 MPa. The absolute values of transmitted wave amplitude and dominant frequency were greater for specimens with smaller particle sizes while the normalized values indicate an opposite trend. The changes in the transmitted amplitude were linked to the changes in the true contact area between the particles with a transitional point in the slope of normalized amplitude, coinciding with the yield stress of the granular soil layer. The amount of grain crushing as a result of increase in the normal stress was experimentally measured and a linear correlation was found between the degree of grain crushing and the changes in the normalized dominant frequency of compressional waves. PMID- 29477810 TI - Renal and hepatic effects following neonatal exposure to low doses of Bisphenol-A and 137Cs. AB - 137-Cesium (137Cs) is one of the most important distributed radionuclides after a nuclear accident. Humans are usually co-exposed to various environmental toxicants, being Bisphenol-A (BPA) one of them. Exposure to IR and BPA in early life is of major concern, due to the higher vulnerability of developing organs. We evaluate the renal and hepatic effects of low doses of ionizing radiation (IR) and BPA. Sixty male mice (C57BL/6J) were randomly assigned to six experimental groups (n=10) and received a single subcutaneous dose of 0.9% saline solution, 137Cs and/or BPA on postnatal day 10: control, BPA (25 MUg/kgbw), Cs4000 (4000 Bq 137Cs/kgbw), Cs8000 (8000 Bq 137Cs/kgbw), BPA/Cs4000 and BPA/Cs8000. At the age of two months, urines (24h) and blood samples were collected from animals of each group to determine biochemical parameters. Finally, kidneys and liver were removed to quantify DNA damage (8-OHdG), as well as to determine CYP1A2 mRNA expression. Data suggest that both BPA and 137Cs induced renal and liver damage evidenced by oxidative stress. However, when there is a co-exposure, it seems that there are compensatory mechanisms that may reverse the damage induced by each toxic itself. Notwithstanding, more studies are necessary to better understand the synergistic mechanisms behind. PMID- 29477812 TI - Picosecond ultrasonic study of surface acoustic waves on periodically patterned layered nanostructures. AB - We have used the ultrafast pump-probe technique known as picosecond ultrasonics to generate and detect surface acoustic waves on a structure consisting of nanoscale Al lines on SiO2 on Si. We report results from ten samples with varying pitch (1000-140 nm) and SiO2 film thickness (112 nm or 60 nm), and compare our results to an isotropic elastic calculation and a coarse-grained molecular dynamics simulation. In all cases we are able to detect and identify a Rayleigh like surface acoustic wave with wavelength equal to the pitch of the lines and frequency in the range of 5-24 GHz. In some samples, we are able to detect additional, higher frequency surface acoustic waves or independent modes of the Al lines with frequencies close to 50 GHz. We also describe the effects of probe beam polarization on the measurement's sensitivity to the different surface modes. PMID- 29477813 TI - Targeting RORs nuclear receptors by novel synthetic steroidal inverse agonists for autoimmune disorders. AB - Designing novel inverse agonists of NR RORgammat still represents a challenge for the pharmaceutical community to develop therapeutics for treating immune diseases. By exploring the structure of NRs natural ligands, the representative arotenoid ligands and RORs specific ligands share some chemical homologies which can be exploited to design a novel molecular structure characterized by a polycyclic core bearing a polar head and a hydrophobic tail. Compound MG 2778 (8), a cyclopenta[a]phenantrene derivative, was identified as lead compound which was chemically modified at position 2 in order to obtain a small library for preliminary SARs. Cell viability and estrogenic activity of compounds 7, 8, 19a, 30, 31 and 32 were evaluated to attest selectivity. The selected 7, 8, 19a and 31 compounds were assayed in a Gal4 UAS-Luc co-transfection system in order to determine their ability to modulate RORgammat activity in a cellular environment. They were evaluated as inverse agonists taken ursolic acid as reference compound. The potency of compounds was lower than that of ursolic acid, but their efficacy was similar. Compound 19a was the most active, significantly reducing RORgammat activity at low micromolar concentrations. PMID- 29477815 TI - How to choose among the multiple options to enhance the penetration of topically applied methyl aminolevulinate prior to photodynamic therapy. PMID- 29477814 TI - Multifunctional manganese-doped Prussian blue nanoparticles for two-photon photothermal therapy and magnetic resonance imaging. AB - Here we demonstrate for the first time that Mn2+-doped Prussian blue nanoparticles of c.a. 70 nm act as effective agents for photothermal therapy under two-photon excitation with an almost total eradication of malignant cells (97 and 98%) at a concentration of 100 MUg mL-1 24 h after NIR excitation. This effect combined with interesting longitudinal NMR relaxivity values offer new perspectives for effective imaging and cancer treatment. PMID- 29477816 TI - The yin and yang of solubilization and stabilization for wild-type and full length membrane protein. AB - Membrane proteins (MP) are stable in their native lipid environment. To enable structural and functional investigations, MP need to be extracted from the membrane. This is a critical step that represents the main obstacle for MP biochemistry and structural biology. General guidelines and rules for membrane protein solubilization remain difficult to establish. This review aims to provide the reader with a comprehensive overview of the general concepts of MP solubilization and stabilization as well as recent advances in detergents innovation. Understanding how solubilization and stabilization are intimately linked is key to facilitate MP isolation toward fundamental structural and functional research as well as drug discovery applications. How to manage the tour de force of destabilizing the lipid bilayer and stabilizing MP at the same time is the holy grail of successful isolation and investigation of such a delicate and fascinating class of proteins. PMID- 29477817 TI - Prognostic impact of elevated serum uric acid levels on long-term outcomes in patients with chronic heart failure: A post-hoc analysis of the GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca-Heart Failure) trial. AB - BACKGROUND: The prognostic impact of hyperuricemia on long-term clinical outcomes in patients with chronic heart failure (HF) has been investigated in observational registries and clinical trials, but the results have been often inconclusive. We examined the prognostic impact of elevated serum uric acid levels on long-term clinical outcomes in the GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca-Heart Failure) trial. CLINICAL TRIAL REGISTRATION: CLINICALTRIALS. GOV IDENTIFIER: NCT00336336. METHODS: We assessed the rates of all-cause death, cardiovascular death, cardiovascular hospitalization and the composite of all-cause death or cardiovascular hospitalization over a median follow-up of 3.9 years among 6683 ambulatory patients with chronic HF. RESULTS: Patients in the 3rd serum uric acid tertile (>7.2 mg/dl) had a nearly 1.8-fold increased risk of both all-cause death and cardiovascular death, and a nearly 1.5-fold increased risk of cardiovascular hospitalization and of the composite endpoint compared to those in the 1st uric acid tertile (<5.7 mg/dl). Beyond serum uric acid >= 7 mg/dl the risk of outcomes increased sharply and linearly. The significant association between elevated serum uric acid levels and adverse outcomes persisted after adjustment for multiple established cardiovascular risk factors, HF etiology, left ventricular ejection fraction, medication use and other potential confounders, with an adjusted hazard ratio of 1.37 (95% CI 1.22-1.55) for all-cause death, 1.48 (1.29 1.69) for cardiovascular death, 1.19 (1.09-1.30) for cardiovascular hospitalization and 1.21 (1.11-1.31) for the composite endpoint, respectively. CONCLUSIONS: Elevated serum uric acid levels are independently associated with poor long-term survival and increased risk of cardiovascular hospitalization in patients with chronic HF. PMID- 29477818 TI - Effects of submarine mine tailings on macrobenthic community structure and ecosystem processes. AB - A mesocosm experiment with intact benthic communities was conducted to evaluate the effects of mine tailings on benthic community structure and biogeochemical processes. Two types of tailings were supplied from process plants using flotation and flocculation chemicals, while a third type was absent of added chemicals. All tailings impacted the sediment community at thin layers, and through more mechanisms than merely hypersedimentation. In general, the strongest impact was observed in a very fine-grained tailings containing flotation chemicals. The second strongest occurred in tailings with no process chemicals. The tailings with flocculation chemicals initiated the weakest response. Fluxes of oxygen, nitrate and ammonium provided some indications on biodegradation of organic phases. Release of phosphate and silicate decreased with increasing layer thickness of all three tailings. A threshold level of 2cm was identified both for faunal responses and for fluxes of phosphate and silicate. The particular impact mechanisms should receive more attention in future studies in order to minimize the environmental risk associated with tailings disposal. PMID- 29477819 TI - Anthropogenic deposition of heavy metals and phosphorus may reduce biological N2 fixation in boreal forest mosses. AB - A study was undertaken to test the effects of molybdenum (Mo) and phosphorus (P) amendments on biological nitrogen (N) fixation (BNF) by boreal forest moss associated cyanobacteria. Feather moss (Pleurozium schreberi) samples were collected on five sites, on two dates and at different roadside distances (0 100m) corresponding to an assumed gradient of reactive N deposition. Potential BNF of Mo and P amended moss samples was measured using the acetylene reduction assay. Total N, P and heavy metal concentrations of mosses collected at 0 and 100m from roadsides were also measured. Likewise, the needles from Norway spruce trees (Picea abies) at different roadside distances were collected in late summer and analyzed for total N, P and heavy metals. There was a significant increase in BNF with roadside distance on 7-of-10 individual Site*Date combinations. We found no clear evidence of an N gradient across roadside distances. Elemental analyses of feather moss and Norway spruce needle tissues suggested decreasing deposition of heavy metals (Mo-Co-Cr-Ni-V-Pb-Ag-Cu) as well as P with increasing distance from the roadside. The effects of Mo and P amendments on BNF were infrequent and inconsistent across roadside distances and across sites. One particular site, however, displayed greater concentrations of heavy metals near the roadside, as well as a steeper P fertility gradient with roadside distance, than the other sites. Here, BNF increased with roadside distance only when moss samples were amended with P. Also at this site, BNF across all roadside distances was higher when mosses were amended with both Mo and P, suggesting a co-limitation of these two nutrients in controlling BNF. In summary, our study showed a potential for car emissions to increase heavy metals and P along roadsides and underscored the putative roles of these anthropogenic pollutants on BNF in northern latitudes. PMID- 29477820 TI - Assessing sea-level rise impact on saltwater intrusion into the root zone of a geo-typical area in coastal east-central Florida. AB - Saltwater intrusion (SWI) into root zone in low-lying coastal areas can affect the survival and spatial distribution of various vegetation species by altering plant communities and the wildlife habitats they support. In this study, a baseline model was developed based on FEMWATER to simulate the monthly variation of root zone salinity of a geo-typical area located at the Cape Canaveral Barrier Island Complex (CCBIC) of coastal east-central Florida (USA) in 2010. Based on the developed and calibrated baseline model, three diagnostic FEMWATER models were developed to predict the extent of SWI into root zone by modifying the boundary values representing the rising sea level based on various sea-level rise (SLR) scenarios projected for 2080. The simulation results indicated that the extent of SWI would be insignificant if SLR is either low (23.4cm) or intermediate (59.0cm), but would be significant if SLR is high (119.5cm) in that infiltration/diffusion of overtopping seawater in coastal low-lying areas can greatly increase root zone salinity level, since the sand dunes may fail to prevent the landward migration of seawater because the waves of the rising sea level can reach and pass over the crest under high (119.5cm) SLR scenario. PMID- 29477821 TI - Bioaccessibility-corrected risk assessment of urban dietary methylmercury exposure via fish and rice consumption in China. AB - The role of seafood consumption for dietary methylmercury (MeHg) exposure is well established. Recent studies also reveal that rice consumption can be an important pathway for dietary MeHg exposure in some Hg-contaminated areas. However, little is known about the relative importance of rice versus finfish in MeHg exposure for urban residents in uncontaminated areas. Especially, the lack of data on MeHg bioaccessibility in rice hinders accurately assessing MeHg exposure via rice consumption, and its importance compared to fish. By correcting commonly used risk models with quantified MeHg bioaccessibility, we provide the first bioaccessibility-corrected comparison on MeHg risk in rice and fish for consumers in non-contaminated urban areas of China, on both city- and province-scales. Market-available fish and rice samples were cooked and quantified for MeHg bioaccessibility. Methylmercury bioaccessibility in rice (40.5+/-9.4%) was significantly (p<0.05) lower than in fish (61.4+/-14.2%). This difference does not result from selenium content but may result from differences in protein or fiber content. Bioaccessibility-corrected hazard quotients (HQs) were calculated to evaluate consumption hazard of MeHg for consumers in Nanjing city, and Monte Carlo Simulations were employed to evaluate uncertainty and variability. Results indicate that MeHg HQs were 0.14 (P50) and 0.54 (P90). Rice consumption comprised 27.2% of the overall dietary exposure to MeHg in Nanjing, while fish comprised 72.8%. Employing our bioaccessibility data combined with literature parameters, calculated relative contribution to MeHg exposure from rice (versus fish) was high in western provinces of China, including Sichuan (95.6%) and Guizhou (81.5%), and low to moderate in eastern and southern provinces (Guangdong: 6.6%, Jiangsu: 17.7%, Shanghai: 15.1%, Guangxi: 20.6%, Jiangxi: 22.8% and Hunan: 25.9%). This bioaccessibility-corrected comparison of rice versus fish indicates that rice consumption can substantively contribute to dietary MeHg exposure risk for urban populations in Asia, and should be regularly included in dietary MeHg exposure assessment. PMID- 29477822 TI - Supercritical water gasification of microalgae over a two-component catalyst mixture. AB - Supercritical water gasification (SCWG) of the microalga Chlorella pyrenoidosa was examined with a catalyst mixture of Ru/C and Rh/C in a mass ratio of 1:1. The influences of temperature (380-600 degrees C), water density (0-0.197g/cm3), and catalyst loading (0-20wt%) on the yields and composition of the gaseous products and the gasification efficiency were examined. The temperature and water density significantly affected the SCWG of the microalgae. The hydrogen gasification efficiency was more dependent on the temperature, while the carbon gasification efficiency was more dependent on the water density. The gaseous products mainly consisted of CH4, H2, CO, and CO2, with smaller amounts of C2-C3 hydrocarbons. CH4 made up half of the mole fraction of the gaseous products under most reaction conditions. A synergistic effect between Ru/C and Rh/C existed during the SCWG of the microalgae, and this effect favored the production of CH4. The role of the catalyst mixture became indistinct at higher temperatures. Hydrogen atoms from the water were transferred to the gaseous products during the SCWG, leading to hydrogen gasification efficiencies that exceeded 100%. The main components of the bio-oil were aromatics and nitrogen-containing compounds, and the main aromatics consisted of azulene and anthracene. The nitrogen-containing compounds are potential poisons to the catalyst mixture. PMID- 29477823 TI - Effects of grazing exclusion on the grassland ecosystems of mountain meadows and temperate typical steppe in a mountain-basin system in Central Asia's arid regions, China. AB - Grazing exclusion has been proposed as a method of restoring degraded grassland ecosystems. However, its effectiveness remains poorly understood in mountain basin grasslands in arid regions. Thus, we investigated the plant community characteristics, C and N storage levels, and soil organic carbon and total nitrogen concentrations and storage within the upper 0-40 cm soil layer in a grazed grassland (GG) and a fenced grassland (FG) with grazing exclusion in mountain meadow (MM) and temperate typical steppe (TTS) habitats in a mountain basin ecosystem in an arid region of Central China, which are both vital grassland resources for livestock grazing and ecological conservation. In MM, our investigation revealed that grazing exclusion was beneficial to the productivity, coverage, height, diversity, and C and N storage of aboveground plants. However, grazing exclusion was not an effective option for soil C and N sequestration. In TTS, grazing exclusion effectively improved the plant productivity, coverage, height, plant and soil C and N sequestration, although it was not beneficial for maintaining plant diversity. Our findings suggest that reduced or rotational grazing may be a better choice than grazing exclusion in MM. In addition, considering the trade-off between biomass productivity and species diversity in TTS, short-term grazing exclusion should be considered. Additionally, grazing exclusion should be combined with other appropriate measures rather than operating on a standalone basis. PMID- 29477824 TI - A spatial assessment of urban waterlogging risk based on a Weighted Naive Bayes classifier. AB - Urban waterlogging occurs frequently and often causes considerable damage that seriously affects the natural environment, human life, and the social economy. The spatial evaluation of urban waterlogging risk represents an essential analytic step that can be used to prevent urban waterlogging and minimize related losses. The Weighted Naive Bayes (WNB) classifier is a powerful method for knowledge discovery and probability inference under conditions of uncertainty; a WNB classifier can be applied to estimate the likelihood of hazards. Six spatial factors were considered to be added to the WNB, which may improve the efficiency in predicting urban waterlogging risk during analysis. As such, a spatial framework integrating WNB with GIS was developed to assess the risk of urban waterlogging using the primary urban area of Guangzhou in China as an example. The results show that 1) the rationality of six spatial factors was determined according to the Conditional Probability Tables and weights; 2) the Most Accurate Sampling Table has objectivity; and 3) the areas with a high likelihood of waterlogging risk were mainly located in the southwestern part of the study area. The northeastern zones are relatively free of waterlogging risk. The results reveal a more accurate spatial pattern of urban waterlogging risk that can be used to identify risk "hot spots". The resulting gridded estimates provide a realistic reference for decision making related to urban waterlogging. PMID- 29477825 TI - Assessing the agromining potential of Mediterranean nickel-hyperaccumulating plant species at field-scale in ultramafic soils under humid-temperate climate. AB - Nickel (Ni) agromining of ultramafic soils has been proposed as an eco-friendly option for metal recovery, which can also improve the fertility and quality of these low productive soils. The selection of adequate plant species and the analysis of their performance under the different climatic conditions are of interest for optimising the process and evaluating its full viability. A one-year field experiment was carried out to evaluate the viability of the two Ni hyperaccumulating Mediterranean species, Alyssum murale and Leptoplax emarginata, for agromining purposes in ultramafic soils under a humid-temperate climate. Field plots of 50 m2 were established and the soil was fertilised with gypsum and inorganic NPK fertilisers prior to cropping. Alyssum murale produced a slightly higher Ni yield than L. emarginata, but Ni bioaccumulation was dependent on the plant phenological stage for both species, being maximal at mid-flowering (4.2 and 3.0 kg Ni ha-1, respectively). In both species, Ni was mainly stored in the leaves, especially in leaves of vegetative stems, but also in flowers and fruits in the case of L. emarginata. The main contributors to Ni yield of A. murale were flowering stems and their leaves, while for L. emarginata they were flowering stems and fruits. Implementing the agromining system increased soil nutrient availability, and modified microbial community structure and metabolic activity (due to fertilisation and plant root activity). The soil bacterial communities were dominated by Proteobacteria, Actinobacteria, Acidobacteria and Chloroflexi, and the agromining crops modified the relative abundance of some phyla (increasing Proteobacteria, Bacteroidetes and Nitrospirae and reducing Acidobacteria and Planctomycetes). Cultivating A. murale increased the densities of total culturable bacteria, while L. emarginata selected Ni-tolerant bacteria in its rhizosphere. In summary, both species showed great potential for their use in Ni agromining systems, although optimising soil and crop management practices could improve the phytoextraction efficiency. PMID- 29477826 TI - Multi-scale variability of storm Ophelia 2017: The importance of synchronised environmental variables in coastal impact. AB - Low frequency, high magnitude storm events can dramatically alter coastlines, helping to relocate large volumes of sediments and changing the configuration of landforms. Increases in the number of intense cyclones occurring in the Northern Hemisphere since the 1970s is evident with more northward tracking patterns developing. This brings added potential risk to coastal environments and infrastructure in northwest Europe and therefore understanding how these high energy storms impact sandy coasts in particular is important for future management. This study highlights the evolution of Storm (formally Hurricane) Ophelia in October 2017 as it passed up and along the western seaboard of Ireland. The largest ever recorded Hurricane to form in the eastern Atlantic, we describe, using a range of environmental measurements and wave modelling, its track and intensity over its duration whilst over Ireland. The impact on a stretch of sandy coast in NW Ireland during Storm Ophelia, when the winds were at their peak, is examined using terrestrial laser scanning surveys pre- and post storm to describe local changes of intertidal and dune edge dynamics. During maximum wind conditions (>35 knots) waves no >2m were recorded with an oblique to parallel orientation and coincident with medium to low tide (around 0.8m). Therefore, we demonstrate that anticipated widespread coastal erosion and damage may not always unfold as predicted. In fact, around 6000m3 of net erosion occurred along the 420m stretch of coastline with maximum differences in beach topographic changes of 0.8m. The majority of the sediment redistribution occurred within the intertidal and lower beach zone with some limited dune trimming in the southern section (10% of the total erosion). Asynchronous high water (tide levels), localised offshore winds as well as coastline orientation relative to the storm winds and waves plays a significant role in reducing coastal erosional impact. PMID- 29477827 TI - Transfer of arsenic from poultry feed to poultry litter: A mass balance study. AB - Roxarsone (rox), an arsenic (As) containing organic compound, is a common feed additive used in poultry production. To determine if As present in rox is excreted into the poultry litter without any retention in chicken meat for safe human consumption, the transference of As from the feed to poultry excreta was assessed using two commercial chicken strains fed with and without dietary rox. The results revealed that both the strains had similar behaviour in growth (chicken weight; 2.17-2.25kg), feed consumption (282-300kgpen-1 initially containing 102 chicken) and poultry litter production (73-81kgpen-1) during the growth phase of 35days. Our mass balance calculations showed that chickens ingested 2669-2730mg As with the feed and excreted out 2362-2896mg As in poultry litter during the growth period of 28days when As containing feed was used, yielding As recovery between 86 and 108%. Though our complementary studies show that residual arsenic species in rox-fed chicken meat may have relevance to human exposure, insignificant retention of total As in the chicken meat substantiates our mass balance results. The results are important in evaluating the fate of feed additive used in poultry production and its potential environmental implications if As containing poultry litter is applied to soil for crop production. PMID- 29477828 TI - Acid pretreatment of three-dimensional graphite cathodes enhances the hydrogen peroxide synthesis in bioelectrochemical systems. AB - Graphite is a potential catalyst for hydrogen peroxide (H2O2) synthesis in bioelectrochemical systems (BESs) because of its high performance and low cost. In this study, acidic pretreatment method was performed on raw graphite powder to optimize the performance of three-dimensional graphite cathode and increase the H2O2 yield. Through this method, the production rate of H2O2 increased by 46.9% after 20% nitric acid (HNO3) pretreatment and reached up to 1.55 mg.L-1.h-1, while the chemical oxygen demand (COD) removal efficiency increased by 54%. The high micropore surface area of the acid-pretreated graphite cathode (23.32 m2.g) enhanced the oxygen reduction reaction (ORR) in the electrode and subsequently increased the Faradic efficiency and maximum power density by 25% and 45%, respectively. Thus, this approach has potential for H2O2 synthesis. PMID- 29477829 TI - Air monitoring at large public electronic cigarette events. AB - BACKGROUND: Electronic cigarette (e-cigarette) conventions bring hundreds to thousands of e-cigarette users together socially regularly across the world. E cigarette secondhand exposures to chemicals in this environment, likely the public setting with the highest concentration of e-cigarette secondhand aerosol, have not been characterized. METHODS: Air sampling for formaldehyde, acetaldehyde, acrolein, nicotine, and propylene glycol was conducted at three e cigarette conventions and one smaller event from April 2016 to March 2017 in three states in the Southeastern United States. Volunteers attended the events as members of the public and wore backpacks containing air sampling pumps. Control sampling was conducted when venues were crowded for non-e-cigarette events. Additional control sampling was conducted in two venues when they were empty. RESULTS: Formaldehyde and acetaldehyde concentrations during e-cigarette events were comparable to background concentrations. The median formaldehyde concentrations during events, crowded control events, and empty control events were 12.0, 10.5, and 12.5 MUg/m3, respectively. The median acetaldehyde concentrations during events, crowded control events, and empty control events were 9.7, 15.5, and 3.5 MUg/m3, respectively. Propylene glycol and nicotine were not detected during control sampling. The median nicotine concentration during events was 1.1 MUg/m3. The median propylene glycol concentration during events was 305.5 MUg/m3. CONCLUSION: Results indicate e-cigarette secondhand exposures are sources of elevated nicotine and propylene glycol exposures. Secondhand exposures to e-cigarettes did not contain consistently elevated concentrations of formaldehyde or acetaldehyde. Additional research is needed to characterize exposures via inhalation to propylene glycol at concentrations measured in this study. PMID- 29477830 TI - Real-world comparison of HbA1c reduction at 6-, 12- and 24-months by primary care provider type. AB - AIMS: To assess differences in hemoglobin A1c (HbA1c) over time in diabetics treated by internal medicine physicians using the chronic care model (IMP ancillary) or an advanced practice nurse (APN-IMP). METHODS: Retrospective, 2 group comparative design using administrative databases and matching of IMP ancillary and APN-IMP subjects 2:1 based on patient age (+/-3years), gender and race. Subjects were diabetics treated >=2 times during 2007-2010, had >=1 follow up visit 6-months from baseline and >=2 HbA1c levels. HbA1c levels were assessed longitudinally using linear mixed effect models. Pearson chi-square and two sample t-tests compared groups on patient characteristics. RESULTS: A total of 774 patients were identified. After matching 93 APN-IMP patients with 176 IMP ancillary patients (N=269), there were no differences between groups in demographics; however, baseline mean (SD) HbA1c was higher in APN-IMP group, p<0.001. Compared to baseline, at follow-up there were no between-group differences in HbA1c levels at 6 and 12 months; at 24month follow-up, APN-IMP tended to have a large decrease in HbA1c compared to the IMP-ancillary group; mean difference (95% CI), -0.26 (-0.56, 0.05) p=0.097. CONCLUSION: Compared to baseline HbA1c, patients treated by APN-IMP and IMP-ancillary provider groups had equivalent reductions in HbA1c. PMID- 29477831 TI - Two-Year Course of Quality of Life in Nursing Home Residents with Dementia. AB - OBJECTIVE: To assess the course of quality of life (QoL) in nursing home residents with dementia and to study its predictors. METHODS: This longitudinal, multicenter, observational cohort study with a 2-year follow-up looked at 290 residents with dementia, who lived in 14 dementia special care units in nine nursing homes in the Netherlands. QoL was assessed with the Qualidem, providing a total score and QoL profile with nine subscales. Residents were assessed at five assessments: every 6 months during 2 years. A linear mixed model was used for data analysis. RESULTS: No change was found in the Qualidem total score (range: 0 111) over 2 years. However, a significant increase of QoL over time was seen in the subscales "Care relationship," "Negative affect," "Restless tense behavior," "Positive self-image," "Social isolation," and "Feeling at home." A significant decrease of QoL was seen in the subscales "Positive affect," "Social relations," and "Having something to do." Most predictors of the course of Qol were found for the subscales "Positive self-image" (sex, Global Deterioration Scale, Severe Impairment Battery, Activities of Daily Living, and Neuropsychiatric Inventory) and "Having something to do" (Global Deterioration Scale, Severe Impairment Battery, and Activities of Daily Living). Sex and Neuropsychiatric Inventory at baseline were the predictors found most frequently. CONCLUSION: The total QoL score was stable over a 2-year period. However, QoL subscales showed multidirectional changes. The largest QoL decline in the subscale "Having something to do" suggests that more attention should be given to useful activities in nursing home care. PMID- 29477832 TI - Effect of Simulated Patient Practice on the Self-Efficacy of Japanese Undergraduate Dietitians in Nutrition Care Process Skills. AB - OBJECTIVE: To examine the effect of an adapted simulated patient (SP) intervention on self-efficacy in nutrition care process skills. DESIGN: A repeated-measures design using a 25-item survey divided into 7 nutrition professional practice competencies (PPCs) employing a 5-point self-efficacy scale (1 = lowest to 5 = highest) administered immediately before and after the intervention. SETTING: A private Japanese university. PARTICIPANTS: Ninety Japanese third-year dietetics undergraduates aged 20-38 years. INTERVENTION: An adapted SP activity practicing nutrition care process skills for the infirm elderly population. MAIN OUTCOME MEASURES: Pre- to postintervention self-efficacy response scores and feedback. ANALYSIS: Mean preintervention survey scores were used to divide participants into statistical quartiles (Q1 indicated lowest mean scores and Q3, highest mean scores). Wilcoxon signed-rank tests compared each PPC's pre- and postintervention means. Kruskal-Wallis tests examined changes in quartiles' scores within each PPC. RESULTS: Self-efficacy improved significantly in PPCs relating to application of appropriate medical ethics and interpersonal skills (P = .02), appropriate nutrition assessment (P = .04), and creation of a nutrition management plan and nutrition intervention (P = .03). Self-efficacy of Q1 and Q2 rose significantly in most PPCs, although not for acting as a dietitian within a medical care team, whereas that of Q3 decreased for all PPCs. CONCLUSIONS AND IMPLICATIONS: Among initially low self-efficacy dietetics undergraduates, the SP intervention enhanced self-efficacy in 3 of the 6 PPCs practiced directly and may facilitate more realistic self-views among initially high self-efficacy students. However, further research in the design, implementation, and efficacy of this type of training is recommended to gauge its effects on the quality of related professional practice. PMID- 29477833 TI - Epidemiology and seasonality of acute respiratory infections in hospitalized children over four consecutive years (2012-2016). AB - BACKGROUND: Acute respiratory infections are a principal cause of illness and mortality especially in young children worldwide. OBJECTIVES: To study the epidemiology and seasonality of viral respiratory infections in hospitalized children (under the age of 16) between September 2012 and August 2016. STUDY DESIGN: Nasopharyngeal swabs or aspirates were collected from 3199 symptomatic patients and then screened with a routine multiplex PCR assay. RESULTS: Respiratory viruses were detected for 1624 (50.8%) of the 3199 children in the study population. Of these, 210 (13.3%) were positive for two viruses, 28 (1.7%) were positive for three, and 3 (0.2%) were positive for four. The viral profile varied with age. Some viruses were significantly more frequent in children under the age of 1 month (such as human respiratory syncytial virus (p < 0.0001)), whereas others were significantly more frequent in children over that age (such as influenza viruses (p < 0.0001) and adenoviruses (p = .0006)). The distribution of viruses is variable over the year depending on the species. However, the atmospheric temperature was rarely found to be a limiting factor in the circulation of respiratory viruses. CONCLUSIONS: our results constitute a detailed description of the distribution of respiratory viruses among hospitalized children over four consecutive years. Our data notably highlight the persistence of non-enveloped viruses and some enveloped viruses throughout the year-regardless of temperature variations. PMID- 29477834 TI - Enriched housing promotes post-stroke neurogenesis through calpain 1-STAT3/HIF 1alpha/VEGF signaling. AB - Enriched environment (EE) has been shown to promote neurogenesis and functional recovery after ischemic stroke. However, the underlying molecular mechanisms are not fully understood. In this study, C57BL/6 mice underwent middle cerebral artery occlusion (60 min) followed by reperfusion, after which mice were housed in either standard environment (SE) or EE and allowed to survive for 3, 4, 6 or 10 weeks. Ipsilateral subventricular zone (SVZ) or striatum cells were dissociated from ischemic hemispheric brains of enriched mice at 14 days post ischemia (dpi) and cultured in vitro. Our data showed that post-ischemic EE inhibited calpain 1 activity, and increased the expression of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in the ischemic hemisphere of enriched mice at 21 dpi. Calpain 1-specific inhibitor PD151746 further increased p-STAT3 expression and augmented the promoting effects of EE on post-stroke SVZ neural precursor cells (NPCs) proliferation and functional recovery. EE also increased the expression of hypoxia-inducible factor 1-alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) in the ischemic hemisphere at 21 dpi. Inhibition of the JAK/STAT3 pathway with AG490 decreased the expression of HIF-1alpha and VEGF. Furthermore, inhibition of HIF-1alpha with 2-methoxyestradiol robustly abolished EE-induced elevation of VEGF l expression. Furthermore, VEGF-A promoted the production and secretion of high mobility group box-1 protein (HMGB1) from reactive astrocytes in vitro. Culture supernatant from reactive astrocytes treated with VEGF-A promoted the proliferation and differentiation of NPCs. Glycyrrhizin reversed the promoting effects of EE on post-stroke neurorepair and functional recovery in vivo. Taken together, our data indicate that EE promotes post-stroke functional recovery through the inhibition of calpain 1 activity, and subsequent STAT3-HIF-1alpha-VEGF-mediated neurogenesis. PMID- 29477836 TI - Mechanism of noradrenaline-induced alpha1-adrenoceptor mediated regulation of Na K ATPase subunit expression in Neuro-2a cells. AB - Rapid eye movement sleep (REMS) plays an important role in maintaining brain excitability by regulating noradrenaline (NA) level and Na-K ATPase activity. We showed earlier that REMS deprivation (REMSD) associated elevated NA increased neuronal, while decreased glial Na-K ATPase activity. However, our knowledge was insufficient on how the REMSD-associated effect is sustained particularly under chronic condition. Using Neuro-2a cells as a model, we investigated the molecular mechanism of NA-induced increase in mRNA expression of Na-K ATPase subunit and the enzyme activity. The cells were treated with NA in the presence or absence of either alpha1- or beta-adrenoceptor (AR) antagonists, Ca++-channel blocker or SERCA-inhibitor, and PKA or PKC inhibitor. We observed that NA acting on alpha1 AR increased Na-K ATPase activity and mRNA expression of the catalytic alpha1- and alpha3-Na-K ATPase subunits in the Neuro-2a cells. Further, PLC and PKC mediated modulation of intracellular Ca++ played a critical role in inducing the mRNA expression. On the other hand NA, acting on beta-AR up-regulated expression of the regulatory beta1-subunit of Na-K ATPase. The involvement of SP1 as well as phospho-CREB transcription factors in the NA-mediated increased expression of various subunit isoforms was established. The results of this study along with that of earlier reports support our proposed working model of NA-induced increase in mRNA expression of specific Na-K ATPase subunit leading to increased Na-K ATPase activity. The findings help us understand the molecular mechanism of NA induced increased brain excitability, for example, upon REMSD including under chronic condition. PMID- 29477837 TI - A survey of antiepileptic drug responses identifies drugs with potential efficacy for seizure control in Wolf-Hirschhorn syndrome. AB - Seizures are present in over 90% of infants and children with Wolf-Hirschhorn syndrome (WHS). When present, they significantly affect quality of life. The goal of this study was to use caregiver reports to describe the comparative efficacies of commonly used antiepileptic medications in a large population of individuals with WHS. A web-based, confidential caregiver survey was developed to capture seizure semiology and a chronologic record of seizure treatments as well as responses to each treatment. Adverse events for each drug were also cataloged. We received 141 complete survey responses (47% response rate) describing the seizures of individuals ranging in age from 4months to 61years (90 females: 51 males). Using the Early Childhood Epilepsy Severity Scale (E-Chess), WHS associated seizures are demonstrably severe regardless of deletion size. The best performing antiepileptic drugs (AEDs) for controlling seizures in this cohort were broad spectrum drugs clobazam, levetiracetam, and lamotrigine; whereas, the three commonly used carboxamide class drugs: carbamazepine, phenytoin, and oxcarbazepine, were reported to have little effect on, or even exacerbate, seizures. The carboxamide class drugs, along with phenobarbital and topiramate, were also associated with the highest rate of intolerance due to cooccurrence of adverse events. Levetiracetam, clobazam, and clonazepam demonstrated higher tolerability and comparatively less severe adverse events (Wilcoxon rank sum comparison between performance of levetiracetam and carboxamide class drugs gives a p<0.0001 after multiple comparison adjustment). This is the largest survey to date assessing WHS seizures. This study design is susceptible to possible bias, as the data are largely drawn from caregiver report and investigators had limited access to medical records. Despite this, our data suggest that the genetic etiology of seizures, together with an accurate electroclinical delineation, are important components of drug selection, even in contiguous gene syndromes which may have complex seizure etiologies. PMID- 29477835 TI - Epigenetic regulation of Fgf1 transcription by CRTC1 and memory enhancement. AB - Recent evidence demonstrates that epigenetic regulation of gene transcription is critically involved in learning and memory. Here, we discuss the role of histone acetylation and DNA methylation, which are two best understood epigenetic processes in memory processes. More specifically, we focus on learning-strength dependent changes in chromatin on the fibroblast growth factor 1 (Fgf1) gene and on the molecular events that modulate regulation of Fgf1 transcription, required for memory enhancement, with the specific focus on CREB-regulated transcription coactivator 1 (CRTC1). PMID- 29477838 TI - Dissociable components of spatial neglect associated with frontal and parietal lesions. AB - Spatial neglect is a complex neuropsychological disorder, in which patients fail to detect and respond to contralesional stimuli. Recent studies suggest that these symptoms may reflect a combination of different component deficits, associated with different lesion substrates. Thus, damage to right lateral prefrontal and inferior parietal regions produce different degrees of left neglect on cancellation and line bisection tasks, respectively. Here we tested for dissociable behaviors across two tasks designed to assess distinct cognitive processes possibly mediating such components, in 14 patients with right focal lesion in either the frontal or parietal lobe. In the "distractor filtering" task, patients had to respond to a visual target presented centrally, with or without a lateralized distractor. Only frontal-lesioned patients showed a marked slowing of reaction times when a central target appeared with a simultaneous right distractor (compared to center and left distractor). In the "spatial coding" task, patients had to detect a target among successive visual stimuli presented horizontally with three sequence conditions (regular/predictive or irregular/non-predictive). Only parietal-lesioned patients were unable to benefit from the predictability of the target position, with similar reaction times across all sequence conditions. By contrast, frontal patients showed faster reaction times on trials with a regular succession of stimuli (compared to random order). Taken together, these results suggest that frontal damage may contribute to left inattention by disrupting top-down control and resistance to distractors on the ipsilesional side, whereas parietal damage may disrupt the maintenance of stable locations in space across gaze shifts or time. This further supports the notion that left neglect may arise as a combined breakdown or impaired connectivity between frontal and parietal mechanisms involved (respectively) in the selective control and memory storage components of spatial attention. PMID- 29477839 TI - How distributed processing produces false negatives in voxel-based lesion-deficit analyses. AB - In this study, we hypothesized that if the same deficit can be caused by damage to one or another part of a distributed neural system, then voxel-based analyses might miss critical lesion sites because preservation of each site will not be consistently associated with preserved function. The first part of our investigation used voxel-based multiple regression analyses of data from 359 right-handed stroke survivors to identify brain regions where lesion load is associated with picture naming abilities after factoring out variance related to object recognition, semantics and speech articulation so as to focus on deficits arising at the word retrieval level. A highly significant lesion-deficit relationship was identified in left temporal and frontal/premotor regions. Post hoc analyses showed that damage to either of these sites caused the deficit of interest in less than half the affected patients (76/162 = 47%). After excluding all patients with damage to one or both of the identified regions, our second analysis revealed a new region, in the anterior part of the left putamen, which had not been previously detected because many patients had the deficit of interest after temporal or frontal damage that preserved the left putamen. The results illustrate how (i) false negative results arise when the same deficit can be caused by different lesion sites; (ii) some of the missed effects can be unveiled by adopting an iterative approach that systematically excludes patients with lesions to the areas identified in previous analyses, (iii) statistically significant voxel-based lesion-deficit mappings can be driven by a subset of patients; (iv) focal lesions to the identified regions are needed to determine whether the deficit of interest is the consequence of focal damage or much more extensive damage that includes the identified region; and, finally, (v) univariate voxel-based lesion-deficit mappings cannot, in isolation, be used to predict outcome in other patients. PMID- 29477840 TI - One-way traffic: The inferior frontal gyrus controls brain activation in the middle temporal gyrus and inferior parietal lobule during divergent thinking. AB - Contrary to earlier approaches that focused on the contributions of isolated brain regions to the emergence of creativity, there is now growing consensus that creative thought emerges from the interaction of multiple brain regions, often embedded within larger brain networks. Specifically, recent evidence from studies of divergent thinking suggests that kernel ideas emerge in posterior brain regions residing within the semantic system and/or the default mode network (DMN), and that the prefrontal cortex (PFC) regions within the executive control network (ECN) constrain those ideas for generating outputs that meet task demands. However, despite knowing that regions within these networks exhibit interaction, to date the direction of the relationship has not been tested directly. By applying Dynamic Causal Modeling (DCM) to fMRI data collected during a divergent thinking task, we tested the hypothesis that the PFC exerts unidirectional control over the middle temporal gyrus (MTG) and the inferior parietal lobule (IPL), vs. the hypothesis that these two sets of regions exert bidirectional control over each other (in the form of feedback loops). The data were consistent with the former model by demonstrating that the right inferior frontal gyrus (IFG) exerts unidirectional control over MTG and IPL, although the evidence was somewhat stronger in the case of the MTG than the IPL. Our findings highlight potential causal pathways that could underlie the neural bases of divergent thinking. PMID- 29477841 TI - ZSCAN4 is negatively regulated by the ubiquitin-proteasome system and the E3 ubiquitin ligase RNF20. AB - Zscan4 is an early embryonic gene cluster expressed in mouse embryonic stem and induced pluripotent stem cells where it plays critical roles in genomic stability, telomere maintenance, and pluripotency. Zscan4 expression is transient, and characterized by infrequent high expression peaks that are quickly down-regulated, suggesting its expression is tightly controlled. However, little is known about the protein degradation pathway responsible for regulating the human ZSCAN4 protein levels. In this study we determine for the first time the ZSCAN4 protein half-life and degradation pathway, including key factors involved in the process, responsible for the regulation of ZSCAN4 stability. We demonstrate lysine 48 specific polyubiquitination and subsequent proteasome dependent degradation of ZSCAN4, which may explain how this key factor is efficiently cleared from the cells. Importantly, our data indicate an interaction between ZSCAN4 and the E3 ubiquitin ligase RNF20. Moreover, our results show that RNF20 depletion by gene knockdown does not affect ZSCAN4 transcription levels, but instead results in increased ZSCAN4 protein levels. Further, RNF20 depletion stabilizes the ZSCAN4 protein half-life, suggesting that RNF20 negatively regulates ZSCAN4 stability. Due to the significant cellular functions of ZSCAN4, our results have important implications in telomere regulation, stem cell biology, and cancer. PMID- 29477842 TI - Cell endogenous activities of fukutin and FKRP coexist with the ribitol xylosyltransferase, TMEM5. AB - Dystroglycanopathies are a group of muscular dystrophies that are caused by abnormal glycosylation of dystroglycan; currently 18 causative genes are known. Functions of the dystroglycanopathy genes fukutin, fukutin-related protein (FKRP), and transmembrane protein 5 (TMEM5) were most recently identified; fukutin and FKRP are ribitol-phosphate transferases and TMEM5 is a ribitol xylosyltransferase. In this study, we show that fukutin, FKRP, and TMEM5 form a complex while maintaining each of their enzyme activities. Immunoprecipitation and immunofluorescence experiments demonstrated protein interactions between these 3 proteins. A protein complex consisting of endogenous fukutin and FKRP, and exogenously expressed TMEM5 exerts activities of each enzyme. Our data showed for the first time that endogenous fukutin and FKRP enzyme activities coexist with TMEM5 enzyme activity, and suggest the possibility that formation of this enzyme complex may contribute to specific and prompt biosynthesis of glycans that are required for dystroglycan function. PMID- 29477843 TI - Oncogene RPA1 promotes proliferation of hepatocellular carcinoma via CDK4/Cyclin D pathway. AB - As the sixth most prevalent cancer, hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Human replication protein A (RPA), a three-subunit protein, plays a central role in eukaryotic DNA replication, homologous recombination, and excision repair, including RPA1, RPA2 and RPA3. Recently, some studies focusing on the relation between RPA1 and carcinogenesis have demonstrated that RPA1 is a candidate oncogene and influences tumor biological behaviors in many cancers such as esophageal carcinoma, colon cancer, urothelial carcinomas, etc. However, the characteristic role of RPA1 in HCC and the detailed potential mechanism remain unknown. To identify the real effects of RPA1 on HCC and its potential pathway participating in the changes of liver cancer cells, we have conducted this study and demonstrated that RPA1 is up regulated both in liver cancer cell lines and HCC tissues, which is associated with poorer prognosis, advanced TNM stage and larger tumor size. Stable knock down of RPA1 by specific small hairpin RNA (shRNA) contributes to the impaired proliferate ability of SK-HEP-1 cells both in vitro and vivo. Consistently, upregulation of RPA1 in HuH-7 cells by specific adenovirus promotes tumor cells' proliferation. Furthermore, cyclin-dependent-kinase 4(CDK4)/Cyclin-D pathway is found to be well associated with RPA1 induced proliferation. In conclusion, RPA1 plays a pivotal role as a potential oncogene in HCC and promotes tumor proliferation via CDK4/Cyclin-D pathway. PMID- 29477844 TI - Comparison of the bone regeneration ability between stem cells from human exfoliated deciduous teeth, human dental pulp stem cells and human bone marrow mesenchymal stem cells. AB - Cleft lip and palate is the most common congenital anomaly in the orofacial region. Autogenous iliac bone graft, in general, has been employed for closing the bone defect at the alveolar cleft. However, such iliac bone graft provides patients with substantial surgical and psychological invasions. Consequently, development of a less invasive method has been highly anticipated. Stem cells from human exfoliated deciduous teeth (SHED) are a major candidate for playing a significant role in tissue engineering and regenerative medicine. The aim of this study was to elucidate the nature of bone regeneration by SHED as compared to that of human dental pulp stem cells (hDPSCs) and bone marrow mesenchymal stem cells (hBMSCs). The stems cells derived from pulp tissues and bone marrow were transplanted with a polylactic-coglycolic acid barrier membrane as a scaffold, for use in bone regeneration in an artificial bone defect of 4 mm in diameter in the calvaria of immunodeficient mice. Three-dimensional analysis using micro CT and histological evaluation were performed. Degree of bone regeneration with SHED relative to the bone defect was almost equivalent to that with hDPSCs and hBMSCs 12 weeks after transplantation. The ratio of new bone formation relative to the pre-created bone defect was not significantly different among groups with SHED, hDPSCs and hBMSCs. In addition, as a result of histological evaluation, SHED produced the largest osteoid and widely distributed collagen fibers compared to hDPSCs and hBMSCs groups. Thus, SHED transplantation exerted bone regeneration ability sufficient for the repair of bone defect. The present study has demonstrated that SHED is one of the best candidate as a cell source for the reconstruction of alveolar cleft due to the bone regeneration ability with less surgical invasion. PMID- 29477845 TI - Storying energy consumption: Collective video storytelling in energy efficiency social marketing. AB - Despite calls for more socio-technical research on energy, there is little practical advice to how narratives collected through qualitative research may be melded with technical knowledge from the physical sciences such as engineering and then applied in energy efficiency social action strategies. This is despite established knowledge in the environmental management literature about domestic energy use regarding the utility of social practice theory and narrative framings that socialise everyday consumption. Storytelling is positioned in this paper both as a focus for socio-technical energy research, and as one potential practical tool that can arguably enhance energy efficiency interventions. We draw upon the literature on everyday social practices, and storytelling, to present our framework called 'collective video storytelling' that combines scientific and lay knowledge about domestic energy use to offer a practical tool for energy efficiency management. Collective video storytelling is discussed in the context of Energy+Illawarra, a 3-year cross-disciplinary collaboration between social marketers, human geographers, and engineers to target energy behavioural change within older low-income households in regional NSW, Australia. PMID- 29477846 TI - Enhancing arsenic removal from arsenic-contaminated water by Echinodorus cordifolius-endophytic Arthrobacter creatinolyticus interactions. AB - In this study, Echinodorus cordifolius was the best plant for arsenic removal compared to Cyperus alternifolius, Acrostichum aureum and Colocasia esculenta. Under arsenic stress, the combination of E. cordifolius with microbes (Bacillus subtilis and Arthrobacter creatinolyticus) was investigated. It was found that A. creatinolyticus, a native microbe, can endure arsenic toxicity, produce higher indole-3 acetic acid (IAA) and ammonium production better than B. subtilis. Interestingly, E. cordifolius-endophytic A. creatinolyticus interactions showed that dipping plant roots in A. creatinolyticus suspension for 5 min had the highest arsenic removal efficiency compared to dipping plant roots in A. creatinolyticus suspension for 2 h and inoculating A. creatinolyticus with E. cordifolius directly. Our findings indicated that under this inoculation condition, the inoculum could colonize from the roots to the shoots of the host tissues in order to avoid arsenic toxicity and favored arsenic removal by the host through plant growth-promoting traits, such as IAA production. Highest levels of IAA were found in plant tissues and the plants exhibited higher root elongation than other conditions. Moreover, low level of reactive oxygen species (ROS) was related to low arsenic stress. In addition, dipping E. cordifolius roots in A. creatinolyticus for 5 min was applied in a constructed wetland, the result showed higher arsenic removal than conventional method. Therefore, this knowledge can be applied at a real site for improving plant tolerance stress, plant growth stimulation, and enhancing arsenic remediation. PMID- 29477847 TI - Correlation between pH and molar iron/ligand ratio during ciprofloxacin degradation by photo-Fenton process: Identification of the main transformation products. AB - Ciprofloxacin has been determined with high frequency in studies involving environmental waters matrixes. However, no study evaluating the correlation between the initial pH and molar iron/organic ligand ratio has been published. This paper describes the degradation of the antibiotic ciprofloxacin by the photo Fenton process using different sources of iron (Fe2+, Fe3+ and Fe3+-citrate and Fe3+-oxalate, named FeCit and FeOx, respectively) and molar iron/organic ligand ratios at initial pH values of 2.5 and 6.5. The best results at initial pH 2.5 were achieved using FeCit and FeOx at molar iron/organic ligand ratios of 1:1 and 1:3 respectively, when the ciprofloxacin concentration reached values below the quantitation limit of the HPLC after 20 min of treatment. However, at initial pH 6.5, improvements in the results (15% for FeCit, and 46% for FeOx) were achieved by increasing the molar iron/organic ligand ratios to 1:4 (FeCit) and 1:9 (FeOx), respectively. Three transformation products, (C17H19FN3O4, m/z 348; C17H21FN3O5, m/z 366; and C13H12FN2O3, m/z 263) of ciprofloxacin degradation were identified, one of them not yet being reported in the literature (C17H21FN3O5, m/z 366). Their formation and degradation was monitored and the initial steps of their formation and degradation were proposed. The results show that the piperazine ring is more susceptible to hydroxyl radical attack than the quinolone ring, which persists in the intermediates identified. Therefore, this process can be a good alternative for the treatment of this type of pollutant at near-neutral conditions. PMID- 29477848 TI - Assessment of dynamic membrane filtration for biological treatment of old landfill leachate. AB - This study investigated the behaviour of dynamic membrane (DM) filtration for the treatment of stabilised landfill leachate in a bench-scale pre-anoxic and aerobic submerged dynamic membrane bioreactor (DMBR). Four meshes with different openings (10, 52, 85 and 200 MUm) were tested to support the development of DM. Differences were observed among the meshes in supporting the development of the cake layer constituting the DM. The treatment of landfill leachate had an impact on sludge characteristics resulting in deteriorated filtration performance of the DM. Effluent turbidity was often higher than 100 NTU for larger mesh pore size (85 and 200 MUm). Low effluent turbidity was achieved with meshes with 10 and 52 MUm (13 +/- 2 and 26 +/- 4 NTU, respectively) although at membrane fluxes lower than 10 L m- 2 h-1. The bioreactor exhibited a moderate organics removal of 50 60% and an ammonia oxidation between 80 and 90%. Incomplete nitrification was observed due to increased concentrations of free ammonia and free nitrous acid, with nitrite effluent concentrations up to 1062 mgNO2--N L-1. Due to the large presence of refractory organic matter in landfill leachate, denitrification was limited resulting in a total nitrogen removal of approximately 20%. PMID- 29477849 TI - Granulation of drinking water treatment residuals as applicable media for phosphorus removal. AB - Recycling drinking water treatment residuals (DWTR) show promise as a strategy for phosphorus (P) removal; however, powdered DWTR is not an ideal practical medium due to clogging. This study granulates DWTR by entrapping powdered DWTR in alginate beads. Results show that granular DWTR has an appreciable amount of mesopores along with a Brunauer-Emmett-Teller (BET) surface area of 43.8 m2/g and total pore volume of 0.049 cm3/g. Most metals (e.g., Al, Ba, Be, Cd, Co, Cr, Mn, Ni, Pb, and Zn) in granular DWTR became more stable and granular DWTR could be considered non-hazardous material. Further analysis indicates that the granular DWTR has strong P adsorption capability with a maximum adsorption capacity of 19.70 mg/g as estimated by the Langmuir model. Good P adsorption may be attributed to the formation of Fe-PO4 and Al-PO4 associated with the amorphous state of enormous iron and aluminum in granular DWTR. More importantly, granular DWTR exhibits good mechanical stability and maintained its shape with weight loss below 12.49% after three recycling rounds. Overall, granular DWTR appears to serve as better media for phosphorus removal in water treatment structures such as wetlands. PMID- 29477850 TI - PM2.5 mitigation in China: Socioeconomic determinants of concentrations and differential control policies. AB - Elucidating the key impact factors on PM2.5 concentrations is crucial to formulate effective mitigation policies. In this study, we employed an extended Stochastic Impacts by Regression on Population Affluence and Technology (STIRPAT) model to identify the socioeconomic determinants of PM2.5 concentrations for 12 different regions and across China. The evaluation was based on a balanced panel dataset integrating long-term satellite-derived PM2.5 concentrations and socio economic data in China from 1999 to 2011. Empirical results indicate that the influencing factors can be ranked in descending order of importance as: proportion of secondary sector of the economy, GDP per capita, urbanization, population, energy intensity, and proportion of tertiary sector. Proportion of secondary sector is the greatest contribution to increasing PM2.5 concentrations, especially for heavily polluted regions. GDP per capita is secondary in importance, and its impact is weakened by the existence of an EKC relationship between GDP per capita and PM2.5 concentrations. Therefore, PM2.5 pollution is an economic development mode problem, rather than a general economic development problem. The impact of urbanization varies across regions; while promoting urbanization will be conducive to decreased PM2.5 concentrations in Northwest China and Northeast China, it will contribute to increased PM2.5 concentrations in other regions. Population and energy intensity are significant in most regions, but neither are decisive factors because of the small absolute value of their coefficients. Finally, different combinations of mitigation policies are proposed for different regions in this study to meet the mitigation targets. PMID- 29477851 TI - A Ti-doped gamma-Fe2O3/SDS nano-photocatalyst as an efficient adsorbent for removal of methylene blue from aqueous solutions. AB - Synthetic dyes are among the most important environmental pollutants in wastewaters. Consequently, elimination of the synthetic dyes from wastewaters using non-toxic materials and eco-friendly technologies has been of considerable interests. In this study, magnetically separable Ti-doped gamma-Fe2O3 photocatalysts were synthesized for the removal of methylene blue (MB) from a dye contaminated aqueous solution (as a model of dye-polluted wastewaters). Compared to the pristine gamma-Fe2O3, the 1.78 v% Ti-doped gamma-Fe2O3 significantly increased the adsorption of MB by 57% in the dark condition as a result of the improved BET surface area in this photocatalyst. Moreover, the contact time required for the photocatalytic degradation of MB by the 1.78 v% Ti-doped gamma Fe2O3 decreased due to the higher concentration of charge carriers in this photocatalyst than that of the pristine gamma-Fe2O3. The effect of different experimental parameters on the adsorption property and photocatalytic activity of the 1.78 v% Ti-doped gamma-Fe2O3 photocatalyst showed that the solution pH had a remarkable influence on the removal performance of this photocatalyst. Surface treatment of the 1.78 v% Ti-doped gamma-Fe2O3 with sodium dodecyl sulfate (SDS) resulted in the formation of a negatively charged Ti-doped gamma-Fe2O3/SDS photocatalyst, which showed a higher tendency for the adsorption and removal of MB than the untreated photocatalyst. Moreover, the MB removal efficiency of this photocatalyst was among the best performances that have been reported for the gamma-Fe2O3-based photocatalysts. The synthesized photocatalysts were characterized by various techniques, and a plausible mechanism for the removal of MB from aqueous solutions by the Ti-doped gamma-Fe2O3/SDS photocatalyst was purposed. PMID- 29477852 TI - Removal of mercury from contaminated saline wasters using dithiocarbamate functionalized-magnetic nanocomposite. AB - In this study, an efficient adsorbent was proposed for the removal of mercury from saline water contaminated with mercury ions. Fe3O4 nanoparticles were modified using tetraethylenepentamine and carbon disulfide to incorporate dithiocarbamate functional group on the surface of the adsorbent. CHNS analysis confirmed successful modification of magnetic nanoparticles. The XRD pattern of adsorbent indicated a proper match with the standard XRD pattern of cubic Fe3O4. The saturation magnetization of final adsorbent was 27 emu g-1. The morphology of bare and silica-coated Fe3O4 and final product were investigated using FE-SEM analysis. For optimizing the adsorption process, response surface methodology was applied, which was resulted in a significant quadratic model. The effect of adsorbent dosage and initial concentration of Hg (II) was much more significant than that of pH. Different concentrations of dissolved solids up to 2000 mg L-1 had no adverse effect on the adsorption process due to the strong interaction between dithiocarbamate functional group of adsorbent and Hg (II). The least values of RMSE (0.0950) and chi2 (0.0009) were observed for Radke-Prausnitz, Redlich-Peterson, and UT isotherms. Maximum adsorption capacities calculated using Langmuir and UT models were 109.5 and 95.07 mg g-1, respectively. The investigation of adsorption isotherm was conducted at the pH range of 2.0-6.5. The results showed an increase in the adsorption capacity by increasing pH. Thermodynamic studies demonstrated that the nature of the adsorption process was spontaneous and endothermic. Recovery of adsorbent was successfully carried out using HCl 0.5 mol L-1. The prepared adsorbent was successfully applied for mercury removal from a real groundwater. PMID- 29477853 TI - How do large-scale agricultural investments affect land use and the environment on the western slopes of Mount Kenya? Empirical evidence based on small-scale farmers' perceptions and remote sensing. AB - Africa has been heavily targeted by large-scale agricultural investments (LAIs) throughout the last decade, with scarcely known impacts on local social ecological systems. In Kenya, a large number of LAIs were made in the region northwest of Mount Kenya. These large-scale farms produce vegetables and flowers mainly for European markets. However, land use in the region remains dominated by small-scale crop and livestock farms with less than 1 ha of land each, who produce both for their own subsistence and for the local markets. We interviewed 100 small-scale farmers living near five different LAIs to elicit their perceptions of the impacts that these LAIs have on their land use and the overall environment. Furthermore, we analyzed remotely sensed land cover and land use data to assess land use change in the vicinity of the five LAIs. While land use change did not follow a clear trend, a number of small-scale farmers did adapt their crop management to environmental changes such as a reduced river water flows and increased pests, which they attributed to the presence of LAIs. Despite the high number of open conflicts between small-scale land users and LAIs around the issue of river water abstraction, the main environmental impact, felt by almost half of the interviewed land users, was air pollution with agrochemicals sprayed on the LAIs' land. Even though only a low percentage of local land users and their household members were directly involved with LAIs, a large majority of respondents favored the presence of LAIs nearby, as they are believed to contribute to the region's overall economic development. PMID- 29477854 TI - Cost comparison of centralized and decentralized wastewater management systems using optimization model. AB - There is a growing interest in decentralized wastewater management (DWWM) as a potential alternative to centralized wastewater management (CWWM) in developing countries. However, the comparative cost of CWWM and DWWM is not well understood. In this study, the cost of cluster-type DWWM is simulated and compared to the cost of CWWM in Alibag, India. A three-step model is built to simulate a broad range of potential DWWM configurations with varying number and layout of cluster subsystems. The considered DWWM scheme consists of cluster subsystems, that each uses simplified sewer and DEWATS (Decentralized Wastewater Treatment Systems). We consider CWWM that uses conventional sewer and an activated sludge plant. The results show that the cost of DWWM can vary significantly with the number and layout of the comprising cluster subsystems. The cost of DWWM increased nonlinearly with increasing number of comprising clusters, mainly due to the loss in the economies of scale for DEWATS. For configurations with the same number of comprising cluster subsystems, the cost of DWWM varied by +/-5% around the mean, depending on the layout of the cluster subsystems. In comparison to CWWM, DWWM was of lower cost than CWWM when configured with fewer than 16 clusters in Alibag, with significantly less operation and maintenance requirement, but with higher capital and land requirement for construction. The study demonstrates that cluster-type DWWM using simplified sewer and DEWATS may be a cost-competitive alternative to CWWM, when carefully configured to lower the cost. PMID- 29477855 TI - Directed combinatorial mutagenesis of Escherichia coli for complex phenotype engineering. AB - Strain engineering for industrial production requires a targeted improvement of multiple complex traits, which range from pathway flux to tolerance to mixed sugar utilization. Here, we report the use of an iterative CRISPR EnAbled Trackable genome Engineering (iCREATE) method to engineer rapid glucose and xylose co-consumption and tolerance to hydrolysate inhibitors in E. coli. Deep mutagenesis libraries were rationally designed, constructed, and screened to target ~40,000 mutations across 30 genes. These libraries included global and high-level regulators that regulate global gene expression, transcription factors that play important roles in genome-level transcription, enzymes that function in the sugar transport system, NAD(P)H metabolism, and the aldehyde reduction system. Specific mutants that conferred increased growth in mixed sugars and hydrolysate tolerance conditions were isolated, confirmed, and evaluated for changes in genome-wide expression levels. We tested the strain with positive combinatorial mutations for 3-hydroxypropionic acid (3HP) production under high furfural and high acetate hydrolysate fermentation, which demonstrated a 7- and 8 fold increase in 3HP productivity relative to the parent strain, respectively. PMID- 29477856 TI - Copper homeostasis as a target to improve Saccharomyces cerevisiae tolerance to oxidative stress. AB - The yeast Saccharomyces cerevisiae is widely used as a cell factory for the biotechnological production of various industrial products. During these processes, yeasts meet different kinds of stressors that often cause oxidative stress and thus impair cell growth. Therefore, the development of robust strains is indispensable to improve production, yield and productivity of fermentative processes. Copper plays a key role in the response to oxidative stress, as cofactor of the cytosolic superoxide dismutase (Sod1) and being contained in metallochaperone and metallothioneines with antioxidant properties. In this work, we observed a higher naturally copper internalization in a robust S. cerevisiae strain engineered to produce the antioxidant l-ascorbic acid (L-AA), compared with the wild type strain. Therefore, we investigated the effect of the alteration of copper homeostasis on cellular stress tolerance. CTR1 and FRE1 genes, codifying for a plasma membrane high-affinity copper transporter and for a cell-surface ferric/cupric reductase, respectively, were overexpressed in both wild type and L-AA cells. Remarkably, we found that the sole FRE1 overexpression was sufficient to increase copper internalization leading to an enhanced stress tolerance toward H2O2 exposure, in both strains under investigation. These findings reveal copper homeostasis as a target for the development of robust cell factories. PMID- 29477857 TI - Balancing the carbon flux distributions between the TCA cycle and glyoxylate shunt to produce glycolate at high yield and titer in Escherichia coli. AB - The glyoxylate shunt is a branch of the tricarboxylic acid (TCA) cycle which directly determines the synthesis of glycolate, and the balance between the glyoxylate shunt and TCA cycle is very important for the growth of Escherichia coli. In order to accumulate glycolate at high yield and titer, strategies for over-expressing glycolate pathway enzymes including isocitrate lyase (AceA), isocitrate dehydrogenase kinase/phosphatase (AceK) and glyoxylate reductase (YcdW) were analyzed. The genes encoding these three enzymes were transcribed under the control of promoter pTrc on pTrc99A, to form pJNU-3, which was harbored by strain Mgly1, resulting in strain Mgly13. Strain Mgly13 produced glycolate with 0.385 g/g-glucose yield (45.2% of the theoretical yield). Citrate synthase (GltA) converted excess acetyl-CoA and oxaloacetate to citrate and was over expressed by pJNU-4 (pCDFDuet-1 backbone). Thus, the resulting strain Mgly134 produced glycolate with a 0.504 g/g-glucose yield (59.3% of the theoretical yield). We then eliminated the pathways involved in the degradation of glycolate, resulting in strain Mgly434, which produced glycolate with 92.9% of the theoretical yield. Following optimization of fermentation, the maximum glycolate titer from strain Mgly434 was 65.5 g/L. PMID- 29477858 TI - Engineered cyanobacteria with enhanced growth show increased ethanol production and higher biofuel to biomass ratio. AB - The Calvin-Benson-Bassham (CBB) cycle is the main pathway to fix atmospheric CO2 and store energy in carbon bonds, forming the precursors of most primary and secondary metabolites necessary for life. Speeding up the CBB cycle theoretically has positive effects on the subsequent growth and/or the end metabolite(s) production. Four CBB cycle enzymes, ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO), fructose-1,6/sedoheptulose-1,7-bisphosphatase (FBP/SBPase), transketolase (TK) and aldolase (FBA) were selected to be co overexpressed with the ethanol synthesis enzymes pyruvate decarboxylase (PDC) and alcohol dehydrogenase (ADH) in the cyanobacterium Synechocystis PCC 6803. An inducible promoter, PnrsB, was used to drive PDC and ADH expression. When PnrsB was induced and cells were cultivated at 65 umol photons m-2 s-1, the RuBisCO-, FBP/SBPase-, TK-, and FBA-expressing strains produced 55%, 67%, 37% and 69% more ethanol and 7.7%, 15.1%, 8.8% and 10.1% more total biomass (the sum of dry cell weight and ethanol), respectively, compared to the strain only expressing the ethanol biosynthesis pathway. The ethanol to total biomass ratio was also increased in CBB cycle enzymes overexpressing strains. This study experimentally demonstrates that using the cells with enhanced carbon fixation, when the product synthesis pathway is not the main bottleneck, can significantly increase the generation of a product (exemplified with ethanol), which acts as a carbon sink. PMID- 29477859 TI - Bioamination of alkane with ammonium by an artificially designed multienzyme cascade. AB - Biocatalytic C-H amination is one of the most challenging tasks. C-H amination reaction can hardly be driven efficiently by solely one enzyme so far. Thus, enzymatic synergy represents an alternative strategy. Herein, we report an "Artificially Bioamination Pathway" for C-H amination of cyclohexane as a model substrate. Three enzymes, a monooxygenase P450BM3 mutant, an alcohol dehydrogenase ScCR from Streptomyces coelicolor and an amine dehydrogenase EsLeuDH from Exiguobacterium sibiricum, constituted a clean cascade reaction system with easy product isolation. Two independent cofactor regeneration systems were optimized to avoid interference from the endogenous NADH oxidases in the host E. coli cells. Based on a stepwise pH adjustment and ammonium supplement strategy, and using an in vitro mixture of cell-free extracts of the three enzymes, cyclohexylamine was produced in a titer of 14.9 mM, with a product content of up to 92.5%. Furthermore, designer cells coexpressing the three required enzymes were constructed and their capability of alkane bio-amination was examined. This artificially designed bioamination paves an attractive approach for enzymatic synthesis of amines from accessible and cheap alkanes. PMID- 29477860 TI - High-level production of valine by expression of the feedback inhibition insensitive acetohydroxyacid synthase in Saccharomyces cerevisiae. AB - Valine, which is one of the branched-chain amino acids (BCAAs) essential for humans, is widely used in animal feed, dietary supplements and pharmaceuticals. At the commercial level, valine is usually produced by bacterial fermentation from glucose. However, valine biosynthesis can also proceed in the yeast Saccharomyces cerevisiae, which is a useful microorganism in fermentation industry. In S. cerevisiae, valine biosynthesis is regulated by valine itself via the feedback inhibition of acetohydroxyacid synthase (AHAS), which consists of two subunits, the catalytic subunit Ilv2 and the regulatory subunit Ilv6. In this study, to improve the valine productivity of yeast cells, we constructed several variants of Ilv6 by introducing amino acid substitutions based on a protein sequence comparison with the AHAS regulatory subunit of E. coli. Among them, we found that the Asn86Ala, Gly89Asp and Asn104Ala variants resulted in approximately 4-fold higher intracellular valine contents compared with those in cells with the wild-type Ilv6. The computational analysis of Ilv6 predicted that Asn86, Gly89 and Asn104 are located in the vicinity of a valine-binding site, suggesting that amino acid substitutions at these positions induce conformational change of the valine-binding site. To test the effects of these variants on AHAS activity, both recombinant Ilv2 and Ilv6 were purified and reconstituted in vitro. The Ilv6 variants were much less sensitive to feedback inhibition by valine than the wild-type Ilv6. Only a portion of the amino acid changes identified in the E. coli AHAS regulatory subunit IlvH enhanced the valine synthesis, suggesting structural and/or functional differences between the S. cerevisiae and E. coli AHAS regulatory subunits. It should also be noted that these amino acid substitutions did not affect the intracellular pools of the other BCAAs, leucine and isoleucine. The approach described here could be a practical method for the development of industrial yeast strains with high-level production of valine or isobutanol. PMID- 29477861 TI - Schistosoma mansoni venom allergen-like protein 18 (SmVAL18) is a plasminogen binding protein secreted during the early stages of mammalian-host infection. AB - Schistosomiasis is a neglected tropical disease caused by trematodes of the genus Schistosoma which have a complex life cycle characterized by an asexual multiplication phase in the snail intermediate host and a sexual reproduction phase in the mammalian definitive host. The initial steps of the human host infection involve the secretion of proteins contained in the acetabular glands of cercariae that promote parasite adhesion and proteolysis of the skin layers. Herein, we performed a functional analysis of SmVAL18, identified as one of the three SCP/TAPS proteins constituent of cercarial secretions. We evaluated the SmVAL18 binding to immobilized macromolecules of the extracellular matrix (ECM) and to plasma components. Recombinant protein, expressed in E. coli, was found to maintain an ordered secondary structure typical of the SCP/TAPS domain after purification. Expression of native SmVAL18 protein was verified to be restricted to cercariae and 3-h schistosomula stages; furthermore, the protein was observed in the corresponding secretions, confirming that SmVAL18 is secreted during the first 3 h of in vitro culture. rSmVAL18 was able to interact specifically with plasminogen (PLG) and enhance its conversion into plasmin in the presence of the urokinase-type plasminogen activator (uPA). Protein homology modelling suggested that the PLG-rSmVAL18 interaction was mediated by lysine residues of the protein. This was supported by in vitro data using the lysine analogue, 6-aminocaproic acid (ACA), which abolished the interaction. Finally, our results showed that both cercariae and 3-h schistosomula, as well as their corresponding secretions, exhibited the capacity to bind PLG and enhance its conversion into plasmin in vitro in the same way as observed for the recombinant protein. In conclusion, our findings show that SmVAL18 is a novel PLG-binding protein secreted during the early stages of the mammalian-host infection. PMID- 29477862 TI - The Brain-Lung-Thyroid syndrome (BLTS): A novel deletion in chromosome 14q13.2 q21.1 expands the phenotype to humoral immunodeficiency. AB - Genetic defects of NKX2-1 are classically associated with hypothyroidism, benign chorea and neonatal respiratory distress. The purpose of this study was to identify the genetic pathogenesis of the "NKX2-1 triad" in a 10 year-old female presenting additional features barely described in the disorder. In the neonatal period, she presented with generalized hypotonia and respiratory distress, with later episodes of frequent wheezing. At 3 month-age developmental dysplasia of the hip was diagnosed and at 10 months, primary hypothyroidism was detected and treated. Subsequently, delayed achievement of developmental milestones and then subtle choreic movements of extremities were identified at 2 years of age. Furthermore, delayed teeth eruption and agenesis of some dental pieces, short stature and joint hyperlaxity were also noticed. At 10 years, a poor immune response to polysaccharide antigens and hypogammaglobulinemia, including all IgG subclasses were detected. Surprisingly, no mutations were identified in the complete coding region of NKX2-1 by PCR and Sanger sequencing. MLPA showed a de novo loss of gene dosage in all 3 probes located in NKX2-1 exons. A CGH-array identified a deletion of 3.32 Mb in chromosome 14q13.2-q21.1 containing 20 genes, including NKX2-1, PAX9 and two candidate genes (NFKB1A and PPP2R3C) involved in immune response. The Brain-Lung-Thyroid syndrome (OMIM#610978; ORPHA:209905) associated with other clinical phenotypes should suggest monoallelic deletions of chromosome 14 causing haploinsufficiency of NKX2-1, and other contiguous genes like PAX9 (hypodontia) or other dosage-sensitive genes in the chromosomal vicinity that emerge as candidates for hypogammaglobulinemia, mainly NFKBIA. PMID- 29477864 TI - An endocrine-disrupting agricultural contaminant impacts sequential female mate choice in fish. AB - The environmental impact of endocrine-disrupting chemicals (EDCs)-compounds that interfere with endocrine system function at minute concentrations-is now well established. In recent years, concern has been mounting over a group of endocrine disruptors known as hormonal growth promotants (HGPs), which are natural and synthetic chemicals used to promote growth in livestock by targeting the endocrine system. One of the most potent compounds to enter the environment as a result of HGP use is 17beta-trenbolone, which has repeatedly been detected in aquatic habitats. Although recent research has revealed that 17beta-trenbolone can interfere with mechanisms of sexual selection, its potential to impact sequential female mate choice remains unknown, as is true for all EDCs. To address this, we exposed female guppies (Poecilia reticulata) to 17beta trenbolone at an environmentally relevant level (average measured concentration: 2 ng/L) for 21 days using a flow-through system. We then compared the response of unexposed and exposed females to sequentially presented stimulus (i.e., unexposed) males that varied in their relative body area of orange pigmentation, as female guppies have a known preference for orange colouration in males. We found that, regardless of male orange pigmentation, both unexposed and exposed females associated with males indiscriminately during their first male encounter. However, during the second male presentation, unexposed females significantly reduced the amount of time they spent associating with low-orange males if they had previously encountered a high-orange male. Conversely, 17beta-trenbolone exposed females associated with males indiscriminately (i.e., regardless of orange colouration) during both their first and second male encounter, and, overall, associated with males significantly less than did unexposed females during both presentations. This is the first study to demonstrate altered sequential female mate choice resulting from exposure to an endocrine disruptor, highlighting the need for a greater understanding of how EDCs may impact complex mechanisms of sexual selection. PMID- 29477863 TI - Nature and kinetics of redox imbalance triggered by respiratory and skin chemical sensitizers on the human monocytic cell line THP-1. AB - Low molecular weight reactive chemicals causing skin and respiratory allergies are known to activate dendritic cells (DC), an event considered to be a key step in both pathologies. Although generation of reactive oxygen species (ROS) is considered a major danger signal responsible for DC maturation, the mechanisms leading to cellular redox imbalance remain poorly understood. Therefore, the aim of this study was to unveil the origin and kinetics of redox imbalance elicited by 1-fluoro-2,4-dinitrobenzene (DNFB) and trimellitic anhydride chloride (TMAC), two golden standards of skin and chemical respiratory allergy, respectively. To track this goal, we addressed the time course modifications of ROS production and cellular antioxidant defenses as well as the modulation of MAPKs signaling pathways and transcription of pathophysiological relevant genes in THP-1 cells. Our data shows that the thiol-reactive sensitizer DNFB directly reacts with cytoplasmic glutathione (GSH) causing its rapid and marked depletion which results in a general increase in ROS accumulation. In turn, TMAC, which preferentially reacts with amine groups, induces a delayed GSH depletion as a consequence of increased mitochondrial ROS production. These divergences in ROS production seem to be correlated with the different extension of intracellular signaling pathways activation and, by consequence, with distinct transcription kinetics of genes such as HMOX1, IL8, IL1B and CD86. Ultimately, our observations may help explain the distinct DC phenotype and T-cell polarizing profile triggered by skin and respiratory sensitizers. PMID- 29477866 TI - PTEN negative correlates with miR-181a in tumour tissues of non-obese endometrial cancer patients. AB - The effects of microRNAs on PTEN levels are characteristic for many types of cancer. However, the picture of the correlation between the expression levels of PTEN and its targeting microRNAs in endometrial cancer is not fully presented. Our study investigated and analysed the expression levels of PTEN and PTEN targeting miR-21, miR-181a, miR-214, miR-301a, and miR-1908 in total of 78 samples, out of which 26 samples were from normal endometrium, whereas the 52 samples were from endometrial cancer samples. Our results demonstrated a high variability of individual endometrial cancer samples in the levels of PTEN. The level of miR-181a showed significant increment in endometrial cancer tissues in comparison with normal endometrium. We did not observe any statistically significant correlation between levels of microRNAs and PTEN in a heterogeneous cohort of patients. At the same time, in samples collected from endometrial cancer patients, it was found out that the relationship between PTEN expression and body mass index had significant positive correlation. Moreover, our data demonstrated that the expression of PTEN was significantly decreased, whereas expression of miR-181a was significantly over-expressed in non-obese compared to obese endometrial cancer patients. Additionally, we observed the relationship between PTEN levels and miR-181a related to the cancerous tissues for non-obese patients was established to be negatively correlated. Our findings suggest that decrease of PTEN via increase of miR-181a may be important contributor to endometrial cancer in non-obese patients. PMID- 29477865 TI - Bioaccumulation of organic pollutants in Indo-Pacific humpback dolphin: A review on current knowledge and future prospects. AB - Indo-Pacific humpback dolphin (Sousa chinensis) are chronically exposed to organic pollutants since they inhabit shallow coastal waters that are often impacted by anthropogenic activities. The aim of this review was to evaluate existing knowledge on the occurrence of organic pollutants in Indo-Pacific humpback dolphins, identify knowledge gaps, and offer recommendations for future research directions. We discussed the trends in the bioaccumulation of organic pollutants in Indo-Pacific humpback dolphins focusing on sources, physicochemical properties, and usage patterns. Furthermore, we examined factors that influence bioaccumulation such as gender, age, dietary intake and tissue-specific distribution. Studies on bioaccumulation in Indo-Pacific humpback dolphin remain scarce, despite high concentrations above 13,000 ng/g lw we previously detected for PFOS, ?PBDE and chlorinated paraffins. The maximum concentration of organochlorines detected was 157,000 ng/g wt. Furthermore, variations in bioaccumulation were shown to be caused by factors such as usage patterns and physicochemical properties of the pollutant. However, restrictions in sampling inhibit investigations on exposure pathway and toxicity of organic pollutants in Indo-Pacific humpback dolphin. We proposed the use of biopsy sampling, predictive bioaccumulation and toxicity modeling, and monitoring other emerging contaminants such as microplastics and pharmaceuticals for future health risk assessment on this critically endangered marine mammal species. PMID- 29477867 TI - Decreased neutrophil-associated miRNA and increased B-cell associated miRNA expression during tuberculosis. AB - MicroRNAs are short non-coding RNAs that regulate gene expression by binding to, and suppressing the expression of genes. Research show that microRNAs have potential to be used as biomarkers for diagnosis, treatment response and can be used for therapeutic interventions. Furthermore, microRNA expression has effects on immune cell functions, which may lead to disease. Considering the important protective role of neutrophils and B-cells during M.tb infection, we evaluated the expression of microRNAs, known to alter function of these cells, in the context of human TB. We utilised real-time PCR to evaluate the levels of microRNA transcripts in the peripheral blood of TB cases and healthy controls. We found that neutrophil-associated miR-197-3p, miR-99b-5p and miR-191-5p transcript levels were significantly lower in TB cases. Additionally, B-cell-associated miR 320a, miR-204-5p, miR331-3p and other transcript levels were higher in TB cases. The miRNAs differentially expressed in neutrophils are predominantly implicated in signalling pathways leading to cytokine productions. Here, the decreased expression in TB cases may imply a lack of suppression on signalling pathways, which may lead to increased production of pro-inflammatory cytokines such as interferon-gamma. Furthermore, the miRNAs differentially expressed in B-cells are mostly involved in the induction/suppression of apoptosis. Further functional studies are however required to elucidate the significance and functional effects of changes in the expression of these microRNAs. PMID- 29477868 TI - miR-519b-3p promotes responsiveness to preoperative chemoradiotherapy in rectal cancer patients by targeting ARID4B. AB - Recent evidences demonstrate that preoperative chemoradiotherapy (pCRT) followed by mesorectal excision is an effective therapy for patients with locally advanced rectal cancer (LARC). Nevertheless, the predictive molecular biomarkers for the response of patients to CRT remain largely unknown. Here we showed that the expression of miR-519b-3p was correlated with the responsiveness to pCRT in patients with LARC. We found that miR-519b-3p was highly expressed in responsive LARC samples. And we showed that miR-519b-3p may serve as a novel predictive marker by ROC analysis. In addition, overexpression of miR-519b-3p enhanced responsiveness to chemoradiation in vitro. Mechanistically, we found that miR 519b-3p directly bond to the 3' UTR of ARID4B mRNA whose expression was inversely correlated with miR-519b-3p expression. Finally, we performed functional experiments and showed that miR-519b-3p was directly involved in response to pCRT in rectal cancer patients in an ARID4B-dependent way. PMID- 29477869 TI - The role of BKCa in endometrial cancer HEC-1-B cell proliferation and migration. AB - BKCa is a large conductance calcium activated potassium channel ubiquitously expressed in various cell types. Accumulating evidence demonstrates that BKCa is aberrantly expressed in many malignancies, involving in cancerous behaviors such as cell proliferation and migration. In this study, we investigated the functional role of BKCa in endometrial cancer HEC-1-B cells. Overexpression of BKCa by plasmid transfection enhanced endometrial cancer cell proliferation and migration. Conversely, silence of BKCa by lentivirus mediated RNAi system not only inhibited proliferation and migration but also impaired tumor growth in vivo. Patch clamp assay identified the BKCa currents in HEC-1-B cells, which was supported by the observation of channel activation or inhibition in response to the specific opener (NS1619) or blocker (IBTX) of BKCa. Moreover, NS1619 significantly increased cell proliferation and migration while IBTX exhibited the opposite effects. In summary, these data suggested an important role of BKCa in proliferation and migration of endometrial cancer HEC-1-B cells. Thus, BKCa may be established as a potential therapeutic target in endometrial cancer. PMID- 29477870 TI - Association of CCL11 promoter polymorphisms with schizophrenia in a Korean population. AB - BACKGROUND: Immunological alterations and dysregulation of the inflammatory response have been suggested to play a crucial role in schizophrenia pathophysiology. Growing evidence supports the involvement of chemokines in brain development, thus many chemokines have been studied in relation with schizophrenia. The C-C motif chemokine ligand 11 (CCL11) has been shown to be related with synaptic plasticity and neurogenesis. Moreover, altered levels of CCL11 have been observed in schizophrenia patients. Therefore, we examined whether single nucleotide polymorphisms (SNPs) of the CCL11 in the promoter region contribute to susceptibility to schizophrenia. METHODS: Four promoter SNPs [rs17809012 (-384T>C), rs16969415 (-426C>T), rs17735961 (-488C>A), and rs4795896 (576G>A)] were genotyped in 254 schizophrenia patients and 405 control subjects using Fluidigm SNPtype assays. RESULTS: The genotype frequency of CCL11 rs4795896 (-576G>A) showed significant association with schizophrenia in a recessive model (AA vs. GG/AG, p < 0.0001) and in a log-additive model (AG vs. AA vs. GG, p < 0.0001). The allele frequency of rs4795896 also showed a significant association with schizophrenia (p < 0.0001). Furthermore, haplotype analysis revealed that GCT, ACT, and GCC haplotypes containing rs4795896, rs17735961 and rs17809012 were significantly associated with schizophrenia (p = 0.0044, p < 0.0001, and p < 0.0001, respectively). CONCLUSION: Our results suggest that CCL11 promotor polymorphism is associated with increased risk for the development of schizophrenia in a Korean population. PMID- 29477871 TI - Identification of two novel PCDHA9 mutations associated with Hirschsprung's disease. AB - Hirschsprung's disease (HSCR) is a complex disorder with multiple pathogenic gene mutations. Protocadherin alpha 9 (PCDHA9) was identified as a potential candidate gene for HSCR by whole-exome sequencing in a Chinese family. Sanger sequencing in 298 HSCR cases revealed two sporadic Chinese patients with a novel missence PCDHAlpha9 mutation (NM_031857; c.1280C > T[p.Ala427Val]) and one sporadic Chinese patient with another novel missence PCDHAlpha9 mutation (c.1425C > G[p.Phe475Leu]).The silico predictions and 3D modeling suggest the deleterious effect of identified mutations on protein function. Immunohistochemistry analysis showed PCDHAlpha9 was predominantly expressed in the myenteric plexus of human colon tissues. For mouse embryos, PCDHAlpha9 was expressed in the stomach but rarely seen in the intestine during E10.5-12.5, then obviously expressed in the intestinal mucosa at E13.5 and extensively expressed in intestinal muscularis and mucosa at E14.5. Moreover, the down-regulation of PCDHAlpha9 in the SH-SY5Y cell line promoted the proliferation and migration rate but inhibited the apoptotic rate. In summary, PCDHAlpha9 is potentially related to HSCR and the clustered protocadherins (Pcdhs) may involve in the enteric nervous system (ENS) ontogeny. PMID- 29477872 TI - MicroRNA-216b actively modulates diabetic angiopathy through inverse regulation on FZD5. AB - BACKGROUND: In this work, we examined the angiogenic function of microRNA-216b in an in vitro rat diabetic model of myocardial microvascular endothelial cells (MMECs). METHODS: MMECs were extracted from Wistar rats (MMEC(WI)) or diabetic Goto-Kakizaki (GK) rats (MMEC(GK)) and cultured in vitro. QRT-PCR was applied to compare miR-216b between MMEC(WI) and MMEC(GK). MiR-216b was downregulated in MMEC(GK). Its effects on angiogenic development, including invasion and proliferation, were evaluated. In MMEC(GK), putative miR-216b downstream target gene, frizzled class receptor 5 (FZD5), was evaluated by dual-luciferase reporter, qRT-PCR and western blot assays, respectively. FZD5 was further downregulated in MMEC(GK) with stable miR-216b downregulation to evaluate its functional role in regulating diabetic angiogenesis. RESULTS: MiR-216b was markedly overexpressed in MMEC(GK). MiR-216b downregulation significantly enhanced angiogenesis in MMEC(GK) by promoting invasion and proliferation. FZD5 was inversely upregulated in miR-216b-downregulated MMEC(GK). Subsequently, FZD5 downregulation suppressed angiogenic development, by inhibiting invasion and proliferation in miR-216b-downregulated MMEC(GK). CONCLUSION: MicroRNA-216b was overexposed in diabetic MMECs and its downregulation may actively enhance angiogenesis in diabetic angiopathy through inverse regulation on FZD5. PMID- 29477873 TI - Clinical and genetic characterization of a patient with SOX5 haploinsufficiency caused by a de novo balanced reciprocal translocation. AB - Lamb-Shaffer syndrome (OMIM: 616803) is a neurodevelopmental disorder characterized by developmental delay, mild to moderate intellectual disability, speech delay, and mild characteristic facial appearance caused by SOX5 haploinsufficiency on chromosome 12p12.1. There are clinical variabilities among the patients with genomic alterations, such as intragenic deletions, a point mutation, and a chromosomal translocation of t(11;12)(p13;p12.1), in SOX5. We report herein a 5-year-old Japanese male with a de novo balanced reciprocal translocation t(12;20)(p12.1;p12.3) presenting a mild intellectual disability, speech delay, characteristic facial appearance, and autistic features. We determined the translocation breakpoints of the patient to be in intron 4 of SOX5 and the intergenic region in 20p12.3 via FISH and nucleotide sequence analyses. Thus, the present patient has SOX5 haploinsufficiency affecting 2 long forms of SOX5 and is the second reported case of Lamb-Shaffer syndrome caused by a de novo balanced reciprocal translocation. This report confirmed that haploinsufficiency of the 2 long forms of SOX5 presents common clinical features, including mild intellectual disability and autistic features, which could be useful for the clinical diagnosis of Lamb-Shaffer syndrome. PMID- 29477874 TI - Molecular characterization of alpha- and beta-thalassemia in the Yulin region of Southern China. AB - Thalassemia is one of the most common hereditary blood disorders. Epidemiological data regarding the prevalence and distribution of mutations is important for planning a thalassemia control program. To reveal the prevalence of thalassemia and mutation spectrum in the Yulin region of southern China, we screened 130,318 individuals from Yulin region by hematological and genetic analysis. Totally, 24,886 (19.10%) subjects were diagnosed with thalassemia, including 16,308 (12.51%) subjects with alpha-thalassemia alone, 6658 (5.11%) subjects with beta thalassemia alone and 1920 (1.47%) subjects with both alpha- and beta thalassemia. Ten alpha-thalassemia mutations were identified in the alpha thalassemia subjects, with the common alpha-thalassemia mutations being --SEA mutation (51.91%), -alpha3.7 (19.90%), alphaCSalpha (10.58%), -alpha4.2 (8.13%), alphaWSalpha (7.67%). Thirteen beta-thalassemia mutations and 31 genotypes were characterized in the beta-thalassemia subjects. The seven common mutations [CD41 42 (-CTTT) (43.31%), CD17 (A > T) (34.58%), CD26 (G > A) (6.86%), CD71-72 (+A) (4.25%), -28 (A > G) (3.90%), IVS-II-654 (C > T) (3.53%) and IVS-I-1 (G > T) (2.22%)] accounted for 98.65% of all beta-thalassemia defects. Furthermore, 6 cases of alpha-triplication and 3 cases of mutation -alpha2.4 were first identified in this region. Our data illustrated that there was great heterogeneity and extensive spectrum of thalassemias in the Yulin populations. The findings will contribute an available reference for prevention of thalassemia in this region. PMID- 29477875 TI - Mortality among rescue and recovery workers and community members exposed to the September 11, 2001 World Trade Center terrorist attacks, 2003-2014. AB - BACKGROUND: Multiple chronic health conditions have been associated with exposure to the September 11, 2001 World Trade Center (WTC) terrorist attacks (9/11). We assessed whether excess deaths occurred during 2003-2014 among persons directly exposed to 9/11, and examined associations of 9/11-related exposures with mortality risk. MATERIALS AND METHODS: Deaths occurring in 2003-2014 among members of the World Trade Center Health Registry, a cohort of rescue/recovery workers and lower Manhattan community members who were exposed to 9/11, were identified via linkage to the National Death Index. Participants' overall levels of 9/11-related exposure were categorized as high, intermediate, or low. We calculated standardized mortality ratios (SMR) using New York City reference rates from 2003 to 2012. Proportional hazards were used to assess associations of 9/11-related exposures with mortality, accounting for age, sex, race/ethnicity and other potential confounders. RESULTS: We identified 877 deaths among 29,280 rescue/recovery workers (3.0%) and 1694 deaths among 39,643 community members (4.3%) during 308,340 and 416,448 person-years of observation, respectively. The SMR for all causes of death was 0.69 [95% confidence interval (CI) 0.65-0.74] for rescue/recovery workers and 0.86 (95% CI 0.82-0.90) for community members. SMRs for diseases of the cardiovascular and respiratory systems were significantly lower than expected in both groups. SMRs for several other causes of death were significantly elevated, including suicide among rescue recovery workers (SMR 1.82, 95% CI 1.35-2.39), and brain malignancies (SMR 2.25, 95% CI 1.48-3.28) and non-Hodgkin's lymphoma (SMR 1.79, 95% CI 1.24-2.50) among community members. Compared to low exposure, both intermediate [adjusted hazard ratio (AHR) 1.36, 95% CI 1.10-1.67] and high (AHR 1.41, 95% CI 1.06-1.88) levels of 9/11-related exposure were significantly associated with all-cause mortality among rescue/recovery workers (p-value for trend 0.01). For community members, intermediate (AHR 1.13, 95% CI 1.01-1.27), but not high (AHR 1.14, 95% CI 0.94 1.39) exposure was significantly associated with all-cause mortality (p-value for trend 0.03). AHRs for associations of overall 9/11-related exposure with heart disease- and cancer-related mortality were similar in magnitude to those for all cause mortality, but with 95% CIs crossing the null value. CONCLUSIONS: Overall mortality was not elevated. Among specific causes of death that were significantly elevated, suicide among rescue/recovery workers is a plausible long term consequence of 9/11 exposure, and is potentially preventable. Elevated mortality due to other causes, including non-Hodgkin's lymphoma and brain cancer, and small but statistically significant associations of 9/11-related exposures with all-cause mortality hazard warrant additional surveillance. PMID- 29477876 TI - Enhanced sensitivity of CpG island search and primer design based on predicted CpG island position. AB - DNA methylation has important biological roles, such as gene expression regulation, as well as practical applications in forensics, such as in body fluid identification and age estimation. DNA methylation often occurs in the CpG site, and methylation within the CpG islands affects various cellular functions and is related to tissue-specific identification. Several programs have been developed to identify CpG islands; however, the size, location, and number of predicted CpG islands are not identical due to different search algorithms. In addition, they only provide structural information for predicted CpG islands without experimental information, such as primer design. We developed an analysis pipeline package, CpGPNP, to integrate CpG island prediction and primer design. CpGPNP predicts CpG islands more accurately and sensitively than other programs, and designs primers easily based on the predicted CpG island locations. The primer design function included standard, bisulfite, and methylation-specific PCR to identify the methylation of particular CpG sites. In this study, we performed CpG island prediction on all chromosomes and compared CpG island search performance of CpGPNP with other CpG island prediction programs. In addition, we compared the position of primers designed for a specific region within the predicted CpG island using other bisulfite PCR primer programs. The primers designed by CpGPNP were used to experimentally verify the amplification of the target region of markers for body fluid identification and age estimation. CpGPNP is freely available at http://forensicdna.kr/cpgpnp/. PMID- 29477877 TI - Massively parallel sequencing of 165 ancestry informative SNPs in two Chinese Tibetan-Burmese minority ethnicities. AB - The Tibeto-Burman language, one subfamily of the Sino-Tibetan languages, is spoken by over 60 million people all over East Asia. Yet the ethnic origin and genetic architecture of Tibeto-Burman speaking populations remain largely unexplored. In the present study, 169 Chinese individuals from Tibeto-Burman speaking populations (two ethnic groups: Tibetan and Yi) in four different geographic regions in western China were analyzed using the Precision ID Ancestry Panel (165 AISNPs) and the Ion PGM System. The performance and corresponding forensic statistical parameters of this AISNPs panel were investigated. Comprehensive population genetic comparisons (143 populations based on Kidd' SNPs, 92 populations on the basis of Seldin' SNPs and 31 populations based on the Precision ID Ancestry Panel) and ancestry inference were further performed. Sequencing performance demonstrated that the Precision ID Ancestry Panel is effective and robust. Forensic characteristics suggested that this panel not only can be used for ancestry estimation of Tibeto-Burman populations but also for individual identification. Tibetan and Yi shared a common genetic ancestry origin but experienced the complex history of gene flow, local adaptation, and isolation, and constructed the specific genetic landscape of human genetic diversity of Highlander and Lowlander populations. Tibetan-Burman populations and other East Asian populations showed sufficient genetic difference and could be distinguished into three distinct groups. Furthermore, analysis of population structure revealed that significant genetic difference was existed inter continent populations and strong genetic affinity was observed within-continent populations. Additional population-specific AISNPs and a relatively more comprehensive database with sufficient reference population data remain necessary to get better-scale resolution within a geographically proximate populations in East Asia. PMID- 29477878 TI - Zika virus in Thailand. AB - This review examines the historic reports of the presence of Zika virus (ZIKV) in Thailand, as well as collates such information as exists on the current situation in Thailand with regards to ZIKV. We suggest that considerable caution must be applied in interpreting early serological studies, but that ZIKV is presently circulating over much of Thailand, with increasing numbers of cases being reported. PMID- 29477879 TI - Fatty acid composition of several muscles and adipose tissues of pigs fed n-3 PUFA rich diets. AB - During two months, sixty Pietrain*(Landrace*Large White) finishing pigs (50.7 to 115.2kg live weight) received diets containing various levels of C18:3n-3 from linseed and C22:6n-3 from Schizochytrium microalgae to increase the content of these fatty acids (FA) in their lean and fat tissues. Samples of tissues have been extracted from the carcass at the slaughterhouse. Tissues of pigs fed linseed had the highest C18:3n-3 and C20:3n-3 contents, while the C20:4, C20:5 and C22:6n-3 contents increased in tissues with microalgae diets. Diaphragm was fatter, but contained less monounsaturated FA, total n-6 and n-3 polyunsaturated FA (PUFA) than longissimus thoracis et lumborum and semimembranosus muscles due to their different roles. The leaf fat was the most saturated and monounsaturated tissue, regardless of the diet. Adipose tissues located in extremities contained more n-3 and n-6 PUFA than adipose tissues located in the middle of the carcass. This study showed the existence of a PUFA gradient depending on tissue location. PMID- 29477880 TI - Effectiveness of pneumatically powered penetrating and non-penetrating captive bolts in stunning cattle. AB - This study assessed the effectiveness of penetrating (PCB; 190 psi; N = 363) and non-penetrating captive bolt guns (NPCB; 210-220 psi; N = 92) to stun a total of 455 cattle (Zebu and Zebu Cross). Physical bolt parameters (momentum, kinetic energy and energy density) were evaluated. Clinical indicators of brain function were recorded after stunning (GR), after being hoisted (HO) and at the bleeding rail (BL). Physical bolt parameters (bolt velocity, momentum, kinetic energy, energy density and sectional density) were significantly higher (P < 0.001) for PCB. The need for two or more shots was more frequent for NPCB (210-220 psi; 29% vs. 12%, P < 0.001). Cattle were more likely to collapse at first shot with PCB (190 psi; 99%) compared to NPCB (91%; P < 0.002) which can be attributed to the higher values of bolt physical parameters. Incidence of eyeball rotation (5% vs. 1%) and righting behaviour (7% vs. 1%) were higher (P < 0.001) for NPCB (210-220 psi) at GR than PCB. The NPCB with 210-220 psi had a higher frequency of response to nostril stimulation (2% vs. 0%; P < 0.001) than PCB. Rhythmic respiration was more frequently found for NPCB with 210-220 psi at GR, HO and BL. Therefore, PCB with 190 psi was more effective in ensuring unconsciousness in cattle. PMID- 29477881 TI - A comprehensive review on nano-molybdenum disulfide/DNA interfaces as emerging biosensing platforms. AB - The development of nucleic acid-based portable platforms for the real-time analysis of diseases has attracted considerable scientific and commercial interest. Recently, 2D layered molybdenum sulfide (2D MoS2 from here on) nanosheets have shown great potential for the development of next-generation platforms for efficient signal transduction. Through combination with DNA as a biorecognition medium, MoS2 nanostructures have opened new opportunities to design and construct highly sensitive, specific, and commercially viable sensing devices. The use of specific short ssDNA sequences like aptamers has been proven to bind well with the unique transduction properties of 2D MoS2 nanosheets to realize aptasensing devices. Such sensors can be operated on the principles of fluorescence, electro-cheumuluminescence, and electrochemistry with many advantageous features (e.g., robust biointerfacing through various conjugation chemistries, facile sensor assembly, high stability with regard to temperature/pH, and high affinity to target). This review encompasses the state of the art information on various design tactics and working principles of MoS2/DNA sensor technology which is emerging as one of the most sought-after and valuable fields with the advent of nucleic acid inspired devices. To help achieve a new milestone in biosensing applications, great potential of this emerging technique is described further with regard to sensitivity, specificity, operational convenience, and versatility. PMID- 29477882 TI - Risk stratification of heart failure from one drop of blood using hand-held biosensor for BNP detection. AB - Continued risk assessment by evaluating cardiac biomarkers in healthy and unhealthy individuals can lower the mortality rate of cardiovascular diseases (CVDs). In this research, we have developed a hand-held biosensor system to rapidly screen for brain natriuretic peptide (BNP) from a single drop of whole blood. The sensor methodology is based on extended gate design of electrical double layer (EDL) field effect transistor (FET), that can directly detect BNP in whole blood, without extensive sample pre-treatments, thereby eliminating the limitations of charge screening in high ionic strength solutions. A simple sensor array chip is fabricated to integrate with the MOSFET sensor system. Sensing characteristics are elucidated using purified BNP samples in 1 * PBS (with 4% BSA), spiked BNP samples in whole blood and clinical whole blood samples. The blood cells can be gravitationally separated without the use of any external actuation. The sensor exhibits very high sensitivity over wide dynamic range of detection. The sensing characteristics are not adversely affected by the presence of background proteins or blood cells, even without gravitational blood cell separation. Thus, the biosensor system can allow users to perform rapid whole blood diagnostics with minimal user protocols, in 5 min. The features of high sensitivity, cost-effectiveness and convenience of usage empower this technology to revolutionize the mobile diagnostics and healthcare industry. PMID- 29477884 TI - Brouers-Sotolongo fractal kinetics versus fractional derivative kinetics: A new strategy to analyze the pollutants sorption kinetics in porous materials. AB - This study presents a detailed comparison of the two most popular fractal theories used in the field of kinetics sorption of pollutants in porous materials: the Brouers-Sotolongo model family of kinetics based on the BurrXII statistical distribution and the fractional kinetics based on the Riemann Liouville fractional derivative theory. Using the experimental kinetics data of several studies published recently, it can be concluded that, although these two models both yield very similar results, the Brouers-Sotolongo model is easier to use due to its simpler formal expression and because it enjoys all the properties of a well-known family of distribution functions. We use the opportunity of this study to comment on the information, in particular, the sorption strength, the half-life time, and the time dependent rate, which can be drawn from a complete analysis of measured kinetics using a fractal model. This is of importance to characterize and classify sorbent-sorbate couples for practical applications. Finally, a generalization form of the Brouers-Sotolongo equation is presented by introducing a time dependent fractal exponent. This improvement, which has a physical meaning, is necessary in some cases to obtain a good fit of the experimental data. PMID- 29477883 TI - Portable and quantitative point-of-care monitoring of Escherichia coli O157:H7 using a personal glucose meter based on immunochromatographic assay. AB - Here we innovate a portable and quantitative immunochromatographic assay (ICA) with a personal glucose meter (PGM) as readout for the detection of Escherichia coli O157:H7 (E. coli O157:H7). The carboxyl group coated Fe3O4 nanoparticles (MNPs) were synthesized by a one pot method and used as carriers of invertase and monoclonal antibody against E. coli O157:H7. Initially, the invertase and antibody double functionalized MNPs (Invertase-MNPs-IgG) conjugates were prepared and used as label probe in this assay system. Before laminating onto the baking card, the absorbent pad was soaked in sucrose solution and desiccated. MNPs produced brown band at the detection zone of the ICA when acting as direct labels. As they were also coupled with invertase, the invertase catalyzed the hydrolysis of sucrose on the absorbent pad into glucose, which was detected by the PGM. To increase the sensitivity, antibody functionalized MNPs were used to enrich E. coli O157:H7 from sample solution. The innovative aspect of this approach lies in the visualization and quantification of E. coli O157:H7 through Invertase-MNPs-IgG and the detection of glucose concentration using PGM. Although the feasibility is demonstrated using E. coli O157:H7 as a model analyte, this approach can be easily developed to be a universal analysis system and applied to detection of a wide variety of foodborne pathogens and protein biomarkers. This study proposed a qualitative and quantitative analysis device for the clinic diagnostics and food safety analysis. PMID- 29477885 TI - A new resin embedded with chelating motifs of biogenic methionine for the removal of Hg(II) at ppb levels. AB - Cyclopolymerization of N,N-diallylmethionine hydrochloride, derived from the biogenic amino acid methionine, (90 mol%) and cross-linker tetraallylpiperazinium dichloride (10 mol%) in presence of an azo-initiator afforded pH-responsive cross linked polyzwitterion (CPZ). The structural morphology of the resin (i.e. CPZ) was examined by the BET and FESEM-EDX analyses. The methionine embedded resin demonstrated remarkable efficacies for the removal of Hg(II) ions at ppb levels. A 50 mg-dose of the resin immersed in aqueous medium (18 mL) could reduce the concentration of Hg(II) from 200 and 400 ppb to 1.8 and 4.4 ppb, respectively, within 15 min. The resin has also proven to be remarkably effective in the removal of several toxic and priority metal pollutants from industrial wastewater. The Hg(II) adsorption followed pseudo second-order process with Ea of 48.1 kJ mol-1. The initial rapid adsorption of metal ions and subsequent slower adsorption was attributed to film and intraparticle diffusion, respectively. The SEM-EDX analyses revealed the attachment of Hg(II) ions onto the resin. The favorability of the endothermic adsorption was ensured by the negative DeltaGo values. The efficient adsorption/desorption process confirmed the recyclability of the resin. The current resin demonstrated superior metal removal capacities as compared to several other adsorbents in recent works. PMID- 29477886 TI - Aerobic biodegradation kinetics for 1,4-dioxane under metabolic and cometabolic conditions. AB - Biodegradation of 1,4-dioxane has been studied extensively, however, there is insufficient information on the kinetic characteristics of cometabolism by propanotrophs and a lack of systematic comparisons to metabolic biodegradation. To fill in these gaps, experiments were performed with suspended growth cultures to determine 16 Monod kinetic coefficients that describe metabolic consumption of 1,4-dioxane by Pseudonocardia dioxanivorans CB1190 and cometabolism by the propanotrophic mixed culture ENV487 and the propanotroph Rhodococcus ruber ENV425. Maximum specific growth rates were highest for ENV425, followed by ENV487 and CB1190. Half saturation constants for 1,4-dioxane for the propanotrophs were one-half to one-quarter those for CB1190. Propane was preferentially degraded over 1,4-dioxane, but the reverse did not occur. A kinetic model was used to simulate batch biodegradation of 1,4-dioxane. Propanotrophs decreased 1,4-dioxane from 1000 to 1 MUg/L in less time than CB1190 when the initial biomass concentration was 0.74 mg COD/L; metabolic biodegradation was favored at higher initial biomass concentrations and higher initial 1,4-dioxane concentrations. 1,4 Dioxane biodegradation was inhibited when oxygen was below 1.5 mg/L. The kinetic model provides a framework for comparing in situ biodegradation of 1,4-dioxane via bioaugmentation with cultures that use the contaminant as a growth substrate to those that achieve biodegradation via cometabolism. PMID- 29477887 TI - Discovery of carbazole carboxamides as novel RORgammat inverse agonists. AB - A novel series of carbazole carboxamides was discovered as potent RORgammat inverse agonists using a scaffold hybridization strategy. Structure-activity relationship exploration on the amide linker, carbazole ring and arylsulfone moiety of the hybrid amide 3a led to identification of potent RORgammat inverse agonists. Compound 6c was found to have a good RORgammat activity with an IC50 of 58.5 nM in FRET assay, and reasonable inhibitory activity in mouse Th17 cell differentiation assay (58.8% inhibition at 0.3 MUM). The binding mode of carbazole carboxamides in RORgammat ligand binding domain was discussed. PMID- 29477888 TI - Synthesis and molecular docking of new roflumilast analogues as preferential selective potent PDE-4B inhibitors with improved pharmacokinetic profile. AB - In the present work, we designed and synthesized new roflumilast analogues with preferential-selective PDE-4B inhibition activity and improved pharmacokinetic properties. The unsubstituted benzo[d]thiazol-2-yl and -6-yl benzamide derivatives (4a and 6a) showed both good potency and preferential selectivity for PDE-4B. More remarkably, 6c revealed 6 times preferential PDE-4B/4D selectivity with a significant increase of in vitro cAMP and good % inhibition of TNF-alpha concentration. In addition, the in vitro pharmacokinetics of 6c showed good metabolic stability with in vitro CLint (5.67 mL/min/kg) and moderate % plasma protein binding (53.71%). This was reflected onto increased in vivo exposure with a half-life greater than roflumilast by 3 folds (21 h) and a Cmax value of 113.958 ng/mL. Molecular docking attributed its good activity to its key binding interactions in PDE-4B active site with additional hydrogen bonding with amino acids lining the metal pocket. Summing up, 6c can be considered as suitable candidate for further investigation for the treatment of COPD. PMID- 29477889 TI - Novel indanone derivatives as MAO B/H3R dual-targeting ligands for treatment of Parkinson's disease. AB - The design of multi-targeting ligands was developed in the last decades as an innovative therapeutic concept for Parkinson's disease (PD) and other neurodegenerative disorders. As the monoamine oxidase B (MAO B) and the histamine H3 receptor (H3R) are promising targets for dopaminergic regulation, we synthetized dual-targeting ligands (DTLs) as non-dopaminergic receptor approach for the treatment of PD. Three series of compounds were developed by attaching the H3R pharmacophore to indanone-related MAO B motifs, leading to development of MAO B/H3R DTLs. Among synthesized indanone DTLs, compounds bearing the 2 benzylidene-1-indanone core structure showed MAO B preferring inhibition capabilities along with nanomolar hH3R affinity. Substitution of C5 and C6 position of the 2-benzylidene-1-indanones with lipophilic substituents revealed three promising candidates exhibiting inhibitory potencies for MAO B with IC50 values ranging from 1931 nM to 276 nM and high affinities at hH3R (Ki < 50 nM). Compound 3f ((E)-5-((4-bromobenzyl)oxy)-2-(4-(3-(piperidin-1 yl)propoxy)benzylidene)-2,3-dihydro-1H-inden-1-one, MAO B IC50 = 276 nM, hH3R Ki = 6.5 nM) showed highest preference for MAO B over MAO A (SI > 36). Interestingly, IC50 determinations after preincubation of enzyme and DTLs revealed also nanomolar MAO B potency for 3e (MAO B IC50 = 232 nM), a structural isomer of 3f, and 3d (MAO B IC50 = 541 nM), suggesting time-dependent inhibition modes. Reversibility of inhibition for all three compounds were confirmed by dilution studies in excess of substrate. Thus, indanone-substituted derivatives are promising lead structures for the design of MAO B/hH3R DTLs as novel therapeutic approach of PD therapy. PMID- 29477890 TI - A meta-analysis of dropout rates in acceptance and commitment therapy. AB - Many psychotherapies, including cognitive behavioral therapy and acceptance and commitment therapy (ACT), have been found to be effective interventions for a range of psychological and behavioral health concerns. Another aspect of treatment utility to consider is dropout, as interventions only work if clients are engaged in them. To date, no research has used meta-analytic methods to examine dropout in ACT. Thus, the objectives of the present meta-analysis were to (1) determine the aggregate dropout rate for ACT in randomized controlled trials, (2) compare dropout rates in ACT to those in other psychotherapies, and (3) identify potential moderators of dropout in ACT. Our literature search yielded 68 studies, representing 4,729 participants. The weighted mean dropout rates in ACT exclusive conditions and ACT inclusive conditions (i.e., those that included an ACT intervention) were 15.8% (95% CI: 11.9%, 20.1%) and 16.0% (95% CI: 12.5%, 19.8%), respectively. ACT dropout rates were not significantly different from those of established psychological treatments. In addition, dropout rates did not vary by client characteristics or study methodological quality. However, master's level clinicians/therapists (weighted mean = 29.9%, CI: 17.6%, 43.8%) were associated with higher dropout than psychologists (weighted mean = 12.4%, 95% CI: 6.7%, 19.4%). More research on manipulable, process variables that influence dropout is needed. PMID- 29477891 TI - Green synthesis of zero-valent Fe-nanoparticles: Catalytic degradation of rhodamine B, interactions with bovine serum albumin and their enhanced antimicrobial activities. AB - Biomimetic method was used for the synthesis of Fe-nanoparticles (FeNPs). FeCl3 and Hibiscus sabdariffa, Roselle flower aqueous extract (HBS) were employed in the present studies. The FeNPs have been characterized by using UV-visible spectroscopy, transmission electron microscope (TEM), and energy dispersion X-ray spectroscopy (EDS). The average particles diameter was found to be 18 nm. The as prepared FeNPs were used as a catalyst to the oxidative degradation of rhodamine B (RB) in presence of NaBH4. The effects of various quencher on the degradation rates were examined by employing ammonium oxalate (AO), benzoquinone (BQ), isopropyl alcohol (IPA), and potassium iodide (KI). The interactions of FeNPs with bovine serum albumin (BSA) have been determined and discussed. Adsorption of FeNPs into the core of BSA changes the tryptophan environment from hydrophobic to hydrophilic (from folding to partially folded and/or unfolded). Tryptophan residues, indole moieties of BSA were responsible to complex formation with FeNPs in excited states via electrostatic, van der Waals, hydrogen bonding, hydrophobic and hydrophilic interactions with static quenching. The antimicrobial activities of FeNPs have been determined against human pathogens. Hibiscus sabdariffa flower extract shows mild antimicrobial activities against all target pathogenic organisms. FeNPs have potential antimicrobial activity against both bacterial strains and candida fungus even at low concentration, and retains potential application in biomedical industries. PMID- 29477892 TI - Investigating the scavenging of reactive oxygen species by antioxidants via theoretical and experimental methods. AB - Reactive oxygen (hydroxyl OH, hydroperoxyl OOH) species are highly unstable to be studied experimentally under normal conditions. The present study reports the antioxidant potential of the vitamins namely ascorbic acid, riboflavin and nicotinic acid against these reactive oxygen species (ROS) using the predictive power of Density Functional Theory (DFT) (B3LYP with 6311G basis set) calculations. The order of reactivity of aforementioned vitamins was assessed by determining the bond dissociation enthalpy (BDE) of the OH bond, which is the controlling factor, if hydrogen atom transfer (HAT) mechanism is considered. Transition state calculations were also carried out to determine the reaction barrier for the radical scavenging reaction of vitamins by calculating the forward and the backward activation energies using the same level of theory as mentioned above. The theoretical methodology was first validated by taking a model stable free radical, 2, 2-diphenyl-1, picrylhydrazyl radical (DPPH) and applying the proposed approach followed by the experimental studies using UV visible spectroscopy and cyclic voltammetry. The close agreement between the theoretical prediction and experimental observations proved the authenticity of theoretical approach. PMID- 29477893 TI - Titanium surface bio-functionalization using osteogenic peptides: Surface chemistry, biocompatibility, corrosion and tribocorrosion aspects. AB - Titanium (Ti) is widely used in biomedical devices due to its recognized biocompatibility. However, implant failures and subsequent clinical side effects are still recurrent. In this context, improvements can be achieved by designing biomaterials where the bulk and the surface of Ti are independently tailored. The conjugation of biomolecules onto the Ti surface can improve its bioactivity, thus accelerating the osteointegration process. Ti was modified with TiO2, two different spacers, 3-(4-aminophenyl) propionic acid (APPA) or 3-mercaptopropionic acid (MPA) and dentin matrix protein 1 (DMP1) peptides. X-ray photoelectron spectroscopy analysis revealed the presence of carbon and nitrogen for all samples, indicating a success in the functionalization process. Furthermore, DMP1 peptides showed an improved coverage area for the samples with APPA and MPA spacers. Biological tests indicated that the peptides could modulate cell affinity, proliferation, and differentiation. Enhanced results were observed in the presence of MPA. Moreover, the immobilization of DMP1 peptides through the spacers led to the formation of calcium phosphate minerals with a Ca/P ratio near to that of hydroxyapatite. Corrosion and tribocorrosion results indicated an increased resistance to corrosion and lower mass loss in the functionalized materials, showing that this new type of functional material has attractive properties for biomaterials application. PMID- 29477895 TI - The effect of mood on integration of information in a multi-attribute decision task. AB - The exact effect of different moods on choosing strategies in multi-attribute decision tasks is yet unknown since previous work has found apparently contradicting results. Furthermore, different theoretical accounts lead to opposite expectations. While the "mood-as-information" theory states that a positive mood leads to heuristic processing of information and application of non compensatory strategies, the "broaden-and-build" theory expects more non compensatory decision-making in a negative mood. To test the predictions of those two theories, we conducted two experimental studies, in which both the mood and the type of information search were manipulated. The results rather support "mood as-information" theory, so participants in the positive mood made non compensatory choices more often than participants in the negative mood. The effect was only present in the open information board, where the information was presented simultaneously, but not in the closed Mouselab, where the information had to be searched in a sequential manner. PMID- 29477896 TI - Impact of the strategy adopted for drug loading in nonporous silica nanoparticles on the drug release and cytotoxic activity. AB - Nanoparticles are normally classified as "hard", mainly consisting of metal or metal oxide cores, or "soft", including polymer-based, liposomes and biomimetic nanoparticles. Soft nanoparticles have been studied in depth for drug formulation and therapeutic delivery applications, albeit hard nanoparticles may offer easier synthesis, smaller size and more effective tumor penetration. Among them, silica nanoparticles maintain excellent biocompatibility and biodegradability and can be finely adjusted in size and shape, easily produced in a large scale and functionalized or loaded with active molecules. To help filling the gap of a poor clinical translation of hard nanoparticles, we have designed and developed three different nonporous silica nanocarriers loading the chemotherapeutic doxorubicin within the core matrix, on the surface or both inside and outside, respectively. A comparative study was performed on drug loading and drug release, silica matrix degradation and nanodrug cytotoxic activity, highlighting unexpected correlation between the strategy adopted for drug incorporation and nanoparticle behavior in a physiological environment. This study offers a new insight on the impact of the choice of the prodrug nanoparticles on the kinetics and efficacy of drug delivery, which may encourage the scientific community in developing a new generation of drug delivery systems based on hard nanocarriers. PMID- 29477894 TI - Locomotor differences in mice expressing wild-type human alpha-synuclein. AB - Parkinson's disease manifests as a progressive movement disorder with underlying degeneration of dopaminergic neurons in the substantia nigra, consequent depletion of dopamine levels, and the accumulation of Lewy bodies in the brain. Because alpha-synuclein (alpha-Syn) protein is the major component of Lewy bodies, mouse models expressing wild-type or mutant SNCA/alpha-Syn genes provide a useful tool to investigate canonical characteristics of the disease. We evaluated a mouse model (denoted M20) that expresses human wild-type SNCA gene. The M20 mice showed abnormal locomotor behavior and reduced species-specific home cage activity. However, the direction of behavioral changes was task specific. In comparison with their control littermates, the M20 mice exhibited shorter grip endurance, and longer times to traverse elevated beams, but they descended the vertical pole faster and stayed longer on the accelerated rod than the control mice. The M20 mice were also impaired in burrowing and nest building activities. These results indicate a possible role of alpha-Syn in motor coordination and the motivation to perform species-specific behaviors in the presymptomatic model of synucleinopathy. PMID- 29477897 TI - Interfacial rheology of low interfacial tension systems using a new oscillating spinning drop method. AB - When surfactants adsorb at liquid interfaces, they not only decrease the surface tension, they confer rheological properties to the interfaces. There are two types of rheological parameters associated to interfacial layers: compression and shear. The elastic response is described by a storage modulus and the dissipation by a loss modulus or equivalently a surface viscosity. Various types of instruments are available for the measurements of these coefficients, the most common being oscillating pendent drops instruments and rheometers equipped with bicones. These instruments are applicable to systems with large enough interfacial tensions, typically above a few mN/m. We use a new type of instrument based on spinning drop oscillations, allowing to extend the interfacial rheology studies to low and ultralow interfacial tension systems. We present examples of measurements with systems of high and low tension, discuss the possible artifacts and demonstrate the capability of this new technique. We emphasize that the data shown for low interfacial tensions are the first reported in the literature. The instrument is potentially interesting for instance in enhanced oil recovery or demulsification studies. PMID- 29477898 TI - Hydrothermal preparation of hierarchical ZIF-L nanostructures for enhanced CO2 capture. AB - A zeolitic imidazolate framework (ZIF-L) with hierarchical morphology was synthesized through hydrothermal method. The hierarchical product consists of ZIF L leaves with length of several micrometers, width of 1 ~ 2 MUm and thickness of ~300 nm cross connected symmetrically. It was found that the hydrothermal temperature is crucial for the formation of such hierarchical nanostructure. The formation mechanism was investigated to be a secondary crystal growth process. The hierarchical ZIF-L has larger surface area compared with the two-dimensional (2D) ZIF-L leaves. Subsequently, the hierarchical ZIF-L exhibited enhanced CO2 adsorption capacity (1.56 mmol.g-1) as compared with that of the reported two dimensional ZIF-L leaves (0.94 mmol.g-1). This work not only reveals a new strategy for the formation of hierarchical ZIF-L nanostructures, but also supplies a potential material for CO2 capture. PMID- 29477899 TI - Comparative study of quality of life and metabolic syndrome in schizophrenia patients who are receiving treatment versus antipsychotic naive, first episode patients from a tertiary care hospital. PMID- 29477900 TI - Novel methods to identify and address mental health issues among adolescents. PMID- 29477901 TI - Evaluative conditioning: A brief computer-delivered intervention to reduce college student drinking. AB - BACKGROUND: Recent research suggests that a brief computer-delivered intervention based on evaluative conditioning (EC) can change the implicit evaluation of alcohol and reduce drinking behaviors among college students. We tested whether we could obtain similar findings in a high-powered preregistered study and whether hazardous drinking moderates these effects. METHOD: Before the intervention, 122 French college students were screened for hazardous drinking using the Alcohol Use Disorder Identification Test (AUDIT). Implicit evaluation of alcohol was assessed before and immediately after the intervention using an Implicit Association Test (IAT). Drinking behavior was assessed before the intervention and approximately two weeks after using the TimeLine Follow Back (TLFB) method. The EC consisted of 120 trials of words (related to alcoholic beverages, soft drinks or neutral) paired with pictures (neutral, positive or negative). In the EC condition, alcohol-related words were systematically paired with negative pictures. In the control condition, alcohol-related words were systematically paired with neutral pictures. RESULTS: The EC did not change the implicit evaluation of alcohol, Cohen's d = 0.01, 95CI [-0.35, 0.35]. However, the EC reduced drinking behavior, Cohen's d = 0.37, 95CI [0.01, 0.72]. This effect was independent of hazardous drinking behavior, but it was especially pronounced among participants with the most positive implicit evaluation of alcohol before the intervention. CONCLUSION: This preregistered study suggests that evaluative conditioning can successfully reduce drinking behavior among college students by 31% (compared to 4% in the control condition) without causing an immediate change in the implicit evaluation of alcohol. PMID- 29477902 TI - Parental smoking, rejection of parental smoking, and smoking susceptibility and behaviors in Hong Kong adolescents. AB - INTRODUCTION: We explored the role of rejection of parental smoking in the association between parental smoking and smoking in adolescents. METHODS: In 2010 11 cross-sectional survey, 61,810 Hong Kong secondary school students (mean age 14.6 years, 50.5% boys) reported their smoking (never, not susceptible; never, susceptible; ever, not current; current), paternal and maternal smoking, and whether they accepted paternal and maternal smoking (acceptance/rejection). We used multinomial logistic regression to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) of students' smoking in relation to acceptance and rejection of parental smoking, compared with no parental smoking. RESULTS: The OR (95% CI) of "never, susceptible", "ever, not current", and "current", compared with "never, not susceptible", in relation to acceptance of paternal smoking was 1.81 (1.67-1.96), 2.46 (2.25-2.69), and 2.79 (2.51-3.10), respectively. The corresponding ORs for rejection were 0.70 (0.64-0.76), 1.23 (1.13-1.35), and 0.47 (0.40-0.56). The OR (95% CI) of "never, susceptible", "ever, not current", and "current", compared with "never, not susceptible", in relation to acceptance of maternal smoking was 2.05 (1.80-2.33), 2.57 (2.29-2.88), and 6.33 (5.39-7.44), respectively. The corresponding ORs for rejection were 0.85 (0.69-1.05), 1.59 (1.39-1.81), and 2.14 (1.71-2.68). No overlapping was observed between the 95% CIs for acceptance and rejection of paternal or maternal smoking. CONCLUSIONS: While adolescent smoking was associated with parental smoking, especially in those who accepted parental smoking, the association was attenuated or reversed in those who rejected parental smoking. PMID- 29477904 TI - The Hip Hop peer crowd: An opportunity for intervention to reduce tobacco use among at-risk youth. AB - INTRODUCTION: Peer crowds, peer groups with macro-level connections and shared norms that transcend geography and race/ethnicity, have been linked to risky health behaviors. Research has demonstrated that Hip Hop peer crowd identification, which is common among multicultural youth, is associated with increased risk of tobacco use. To address this, the FDA Center for Tobacco Products created Fresh Empire, the first national tobacco education campaign tailored for Hip Hop youth aged 12-17 who are multicultural (Hispanic, African American, Asian-Pacific Islander, or Multiracial). As part of campaign development, peer crowd (Hip Hop, Mainstream, Popular, Alternative, Country) and cigarette smoking status were examined for the first time with a nationally recruited sample. METHODS: Youth were recruited via targeted social media advertisements. Participants aged 13-17 (n = 5153) self-reported peer crowd identification via the I-Base SurveyTM and cigarette smoking status. Differences in smoking status by peer crowd were examined using chi-square and followed up with z-tests to identify specific differences. RESULTS: Alternative youth were most at risk of cigarette smoking, followed by Hip Hop. Specifically, Hip Hop youth were significantly less likely to be Non-susceptible Non-triers than Popular, Mainstream, and Country youth, and more likely to be Experimenters than Popular and Mainstream youth. CONCLUSIONS: Representative studies show that Alternative is relatively small compared to other high-risk crowds, such as the Hip Hop peer crowd. The current research underscores the potential utility of interventions tailored to larger at-risk crowds for campaigns like Fresh Empire. PMID- 29477903 TI - Student engagement and comfort during a web-based personalized feedback intervention for alcohol and sexual assault. AB - INTRODUCTION: The purpose of this study was to investigate individual engagement and comfort during a web-based intervention for alcohol and sexual assault risk reduction. METHODS: Participants were 264 college women (aged 18-20) who reported engaging in heavy episodic drinking in the past month. Participants were randomized to either an intervention condition (alcohol, sexual assault risk reduction, or combined) or a control condition (full or minimal assessment). Participants rated their experiences during the procedures following the assessment or receipt of the intervention depending on condition. Survey usage information (e.g., time data, completion of intervention) was automatically recorded. RESULTS: Most participants completed the intervention as intended (in a reasonable amount of time, in private, without consuming substances). Women with a sexual assault history were most comfortable in the sexual assault risk reduction intervention, whereas women who frequently engaged in heavy episodic drinking were least comfortable in the alcohol intervention condition. Self reported distraction was not impacted by personal relevance of the intervention, but was associated with setting of participation. CONCLUSIONS: Results suggest that most college women completed web-based personalized feedback interventions as designed, despite minimal discomfort. PMID- 29477905 TI - Comparative analyses of polyphenolic composition of Fragaria spp. color mutants. AB - White-fruited mutants of Fragaria vesca, and one of F. x ananassa, were studied to determine the identity and quantity of major flavonols (FVLs), flavan-3-ols (FV3Ls), hydroxycinnamic acids (HCAs), and ellagic acid (EA)-derived compounds, by using HPLC-MS. The content of 22 compounds across the major groups were used to assess the possibility of unique mutations among the mutant gentoypes. Total HCAs were lower in the white than the red cultivars of both species, except for 2 white F. vesca cultivars. Total FVLs were comparable in white fruit of both species, although a red F. x ananassa had more than a red F. vesca. Total FV3Ls were higher in red than white cultivars of both species. Total EA-derived content was generally higher in white than in red F. vesca. Principal component analysis and a combined heatmap and hierarchical cluster analysis clearly discriminated among the five white F. vesca genotypes. PMID- 29477906 TI - Cognitive phenotypes of sequential staging in amyotrophic lateral sclerosis. AB - Sequential spread of TDP-43 load in the brain may be a pathological characteristic of amyotrophic lateral sclerosis (ALS). Diffusion tensor imaging (DTI) is a magnetic resonance imaging (MRI) based marker of this pathological feature. Cognitive deficits known to be present in a subset of ALS patients might act as an additional in vivo clinical marker of disease spread. N = 139 patients with ALS were tested with the Edinburgh Cognitive and Behavioural ALS screen (ECAS) in addition to DTI brain measures of pathological spread. Executive function, memory and disinhibited behaviour were selected for Cognitive-Staging criteria, as these cognitive functions are attributed to cerebral areas analogous to the pattern of MRI markers of TDP-43 pathology. ROC curve analyses were performed to define cut-off scores for cognitive stages 2 (executive function), stage 3 (disinhibited behaviour) and stage 4 (memory), and staging was performed according to the cognitive profile subsequently. Associations of Cognitive Staging (stage 2-4) and MRI-Staging measures were determined. In total, 77 patients (55%) performed below ROC cut-off scores in either executive function or memory or both and/or were reported to have disinhibited behaviour which permitted Cognitive-Staging. The cognitive profile of patients with discrete MRI stages 2-4 correlated significantly with DTI parameters. For those patients with cognitive impairment, there was a high congruency between MRI and Cognitive Staging with high specificity and sensitivity of executive functions for MRI stage 2, disinhibited behaviour for MRI stage 3 and moderate of memory for MRI stage 4. Cognitive impairment follows specific patterns in ALS and these patterns can be used for Cognitive-Staging with a high specificity compared to MRI Staging. For the individual, cognitive screening is a fast and easy to apply measurement of cerebral function giving valuable information in a clinical context. PMID- 29477907 TI - Spherical aberration correction with an in-lens N-fold symmetric line currents model. AB - In our previous works, we have proposed N-SYLC (N-fold symmetric line currents) models for aberration correction. In this paper, we propose "in-lens N-SYLC" model, where N-SYLC overlaps rotationally symmetric lens. Such overlap is possible because N-SYLC is free of magnetic materials. We analytically prove that, if certain parameters of the model are optimized, an in-lens 3-SYLC (N = 3) doublet can correct 3rd order spherical aberration. By computer simulation, we show that the required excitation current for correction is less than 0.25 AT for beam energy 5 keV, and the beam size after correction is smaller than 1 nm at the corrector image plane for initial slope less than 4 mrad. PMID- 29477908 TI - Heat stress responses in spermatozoa: Mechanisms and consequences for cattle fertility. AB - Currently, the world is facing the negative impact of global warming on all living beings. Adverse effects of global warming are also becoming obvious in dairy cattle breeding. In dairy bulls, low fertility has frequently been reported during summer season especially in tropical or subtropical conditions. Typically, spermatozoa at post-meiotic stages of development are more susceptible to heat stress. During this period extensive incorporation of histone modifications and hyperacetylation turns the chromatin into an unstable conformation. These unstable forms of chromatin are thought to be more vulnerable to heat stress, which may have an effect on chromatin condensation of spermatozoa. Spermatozoa with altered chromatin condensation perturb the dynamics of DNA methylation reprogramming in the paternal pronucleus resulting in disordered active DNA demethylation followed by de novo methylation patterns. In addition, there was a tendency of decreased size in both paternal and maternal pronuclei after fertilization of oocytes with heat-stressed spermatozoa, leading to lower fertilization rates. In this review, we will focus on the mechanisms of heat stress-induced sperm defects and provide more detailed insights into sperm-borne epigenetic regulations. PMID- 29477909 TI - Exogenous ascorbic acid enhances vitrification survival of porcine in vitro developed blastocysts but fails to improve the in vitro embryo production outcomes. AB - In this study, the effects of addition of the antioxidant ascorbic acid (AsA) were evaluated during porcine in vitro embryo production (IVP) and vitrification. In experiment 1, the effects of AsA supplementation during IVM, IVF and IVC were evaluated, using a total of 2744 oocytes in six replicates. The IVM, IVF and embryo IVC media were supplemented or not (control) with 50 MUg/mL AsA in all possible combinations. No significant effects of AsA were detected in any of the maturation, fertilization or embryo development parameters assessed. In experiment 2, we evaluated the effects of adding AsA to vitrification-warming media on the post-warming survival and quality of blastocysts. Day-6 in vitro produced blastocysts (N = 588) from six replicates were randomly divided in two groups, with vitrification and warming media either supplemented with 50 MUg/mL AsA (VW + group) or un-supplemented (VW- control). Addition of AsA increased (P < 0.05) blastocyst survival rate after vitrification compared with that of VW- control embryos. Vitrification and warming increased (P < 0.05) the production of oxygen species (ROS) and reduced (P < 0.05) the glutathione levels in blastocysts. Although VW + blastocysts displayed higher (P < 0.05) ROS levels than those of fresh control blastocysts, the levels were lower (P < 0.05) than those found in VW- control blastocysts. In conclusion, under the experimental conditions, supplementation of IVM/IVF/IVC media with AsA did not improve the embryo production in vitro. By contrast, the addition of AsA to chemically defined vitrification and warming media increased the survival of in vitro produced porcine blastocysts by decreasing ROS production. PMID- 29477910 TI - Chlorogenic acid attenuates glucotoxicity in H9c2 cells via inhibition of glycation and PKC alpha upregulation and safeguarding innate antioxidant status. AB - A series of cardiovascular complications associated with hyperglycemia is a critical threat to the diabetic population. Here we elucidate the link between hyperglycemia and cardiovascular diseases onset, focusing on oxidative stress and associated cardiac dysfunctions. The contribution of advanced glycation end products (AGE) and protein kinase C (PKC) signaling is extensively studied. For induction of hyperglycemia, H9c2 cells were incubated with 33 mM glucose for 48 h to simulate the diabetic condition in in vitro system. Development of cardiac dysfunction was confirmed with the significant increase of lactate dehydrogenase (LDH) release to the medium and associated decrease in cell viability. Various parameters like free radical generation, alteration in innate antioxidant system, lipid peroxidation, AGE production and PKC alpha -ERK axis were investigated during hyperglycemia and with chlorogenic acid. Hyperglycemia has significantly enhanced reactive oxygen species (ROS- 4 fold) generation, depleted SOD activity (1.3 fold) and expression of enzymes particularly CuZnSOD (SOD1) and MnSOD (SOD2), increased production of AGE (2.18 fold). Besides, PKC alpha dependent ERK signaling pathway was found activated (1.43 fold) leading to cardiac dysfunction during hyperglycemia. Chlorogenic acid (CA) was found beneficial against hyperglycemia most probably through its antioxidant mediated activity. The outcome of this preliminary study reveals the importance of integrated approach emphasizing redox status, glycation and signaling pathways like PKC alpha - ERK axis for control and management of diabetic cardiomyopathy (DCM) and potential of bioactives like CA. PMID- 29477911 TI - Angiogenic potential of YKL-40 in the dynamics of tumor niche. AB - A multitude of clinical studies showed the elevation of YKL-40 in subjects with different kinds of tumors. It is predicted that an inherent correlation exists between survivals of cancer patients with total YKL-40 serum levels, making this factor as a potential novel biomarker. However, the crucial role of YKL-40 in the dynamics of cancers, especially angiogenesis, has not yet been completely addressed. In this review, we highlighted the various facets of YKL-40 and its importance in cancer biology as a bio-shuttle in gene therapy. PMID- 29477912 TI - Bavachin induces the apoptosis of multiple myeloma cell lines by inhibiting the activation of nuclear factor kappa B and signal transducer and activator of transcription 3. AB - Bavachin is a phytoestrogen purified from natural herbal plants such as Psoralea corylifolia. In this study, we examined the effect of bavachin in multiple myeloma (MM) cell lines. We found that bavachin decreased the viability of MM cell lines, but was not cytotoxic towards normal cells. It inhibited the activation of nuclear factor kappa B (NF-kappaB) and signal transducer and activator of transcription 3 (STAT3). Furthermore, bavachin increased the expression of p53 and NOXA, and decreased the expression of X-linked inhibitor of apoptosis protein (XIAP), survivin, B cell lymphoma-extra large (Bcl-xL), and Bcl 2. Additionally, bavachin induced apoptosis by the activation of caspase-3 and caspase-9, implicating the involvement of the mitochondrial pathway. Our results suggest that bavachin induces apoptosis through the inhibition of NF-kappaB and STAT3 activation in MM cell lines. Most importantly, few NF-kappaB and STAT3 inhibitors with high efficiency, specificity, and safety are currently available for clinical cancer therapy. Hence, bavachin, which targets NF-kappaB and STAT3, is a potential anticancer agent for the treatment of MM. PMID- 29477913 TI - Oral administration effects of beta-d-mannuronic acid (M2000) on Th17 and regulatory T cells in patients with ankylosing spondylitis. AB - BACKGROUND: To explore the effects of beta-d-mannuronic acid (M2000) on levels of Th17, regulatory T (Treg) cells and their related cytokines in patients with ankylosing spondylitis (AS). METHODS: 30 AS patients and 15 age and sex-matched healthy individuals were enrolled in this study. The frequencies of Th17 and Treg cells and serum levels of related cytokines were measured by flow cytometry analysis and ELISA respectively, before (baseline) and 3 months after M2000 therapy. RESULTS: Significantly higher baseline Th17 cells and serum IL-17, TNF alpha and IL-6 were observed in AS patients than in normal controls, whereas baseline levels of Treg cells and serum IL-10 were not significantly different between AS patients and healthy controls. After M2000 therapy, frequencies of Th17 and serum levels of IL-17 and IL-6 significantly decreased in AS patients. The frequencies of Treg cells and serum level of IL-10 were not significantly changed, in comparison to before therapy. Moreover, the correlation analysis showed that frequencies of Th17 and levels of IL-17, TNF-alpha and IL-6 were positively correlated with Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) scores, whereas Treg cells were revealed to be negatively correlated with BASDAI and BASFI scores. CONCLUSIONS: It can be concluded that the oral administration of M2000 as a novel NSAID with the immunosuppressive property that down-regulates Th17 and Th17-related cytokines and facilitates the correction of the Th17/Treg imbalance can be effective in the process of AS treatment. PMID- 29477914 TI - A novel limonin derivate modulates inflammatory response by suppressing the TLR4/NF-kappaB signalling pathway. AB - In our previous studies, we have demonstrated that a novel water-soluble derivative of limonin, (12S,12aS,Z)-8-((2-(diethylamino)ethoxy)imino)-12-(furan-3 yl)-6,6,8a,12a-tetramethyldodecahydro-1H,3H-oxireno[2,3 d]pyrano[4',3':3,3a]isobenzofuro[5,4-f]isochromene-3,10(9aH)-dione (V-A-4), exhibited strong anti-inflammatory activity both in vitro and in vivo. The purpose of this study was to further explore the underlying mechanisms of such activity demonstrated by V-A-4. The protective effect of V-A-4 on the alleviation of xylene-induced ear swelling and carrageenan-induced subcutaneous air pouch model was detected in vivo. Furthermore, the in vitro effects of V-A-4 and its mechanisms of action were determined by colorimetric COX (ovine) inhibitor screening assay and in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. This study showed that V-A-4 does not exert anti-inflammatory effect through the inhibition of COX-1 or COX-2. Rather, it is exerted through the suppression of the secretion of nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha), as well as through the infiltration of inflammatory cells. V-A-4 demonstrated strong inhibition of NF-kappaB activation through repression of IKKalpha and IKKbeta phosphorylations, which in turn leads to the phosphorylation and degradation of IkappaBalpha in LPS-induced RAW264.7 cells. Moreover, toll-like receptor 4 (TLR4) pathway was involved in the anti-inflammatory effect of V-A-4, which also played an important role in the down-regulation of LPS-mediated miR 146a and miR-155 expressions. These results encourage further development of V-A 4 as a potential candidate for the treatment of inflammatory diseases. PMID- 29477915 TI - Prediction of neurodevelopment at one year of age using the General Movements assessment in the neonatal surgical population. AB - BACKGROUND: Recent evidence indicates neonatal surgery is associated with an increased risk of neurodevelopmental disability, including cerebral palsy (CP). Despite evidence for prediction of CP there is limited information on use of the General Movements Assessment (GMA) with this population. AIM: To investigate the utility of the GMA for prediction of neurodevelopment in an infant surgical population. STUDY DESIGN: Prospective cohort study Subjects: 278 infants following cardiac surgery (n = 149), non-cardiac surgery (n = 123) or both surgeries (n = 6). OUTCOME MEASURES: GMA at three months of age (mean 12 weeks, SD 1.6) rated by three assessors, two blinded to clinical details. Follow-up at one year of age (mean 372 days, SD 13) using Bayley Scales of Infant and Toddler Development III (BSID-III), clinical and neurological examination. RESULTS: At one year, none of the 248 (89%) infants with normal fidgety movements had a diagnosis of CP, however a large proportion (n = 118, 48%) demonstrated delayed development. Infants who had absent fidgety movements (n = 25, 9%) showed a significant difference on all subtests of the BSID-III (p > 0.05). For prediction of CP there was 100% sensitivity and 96% specificity. CONCLUSIONS: The GMA is a valid complementary assessment tool to enhance prediction of neurodevelopment, specifically CP, following early neonatal surgery and should be incorporated into routine follow-up for this population. PMID- 29477916 TI - Max-plus and min-plus projection autoassociative morphological memories and their compositions for pattern classification. AB - Autoassociative morphological memories (AMMs) are robust and computationally efficient memory models with unlimited storage capacity. In this paper, we present the max-plus and min-plus projection autoassociative morphological memories (PAMMs) as well as their compositions. Briefly, the max-plus PAMM yields the largest max-plus combination of the stored vectors which is less than or equal to the input. Dually, the vector recalled by the min-plus PAMM corresponds to the smallest min-plus combination which is larger than or equal to the input. Apart from unlimited absolute storage capacity and one step retrieval, PAMMs and their compositions exhibit an excellent noise tolerance. Furthermore, the new memories yielded quite promising results in classification problems with a large number of features and classes. PMID- 29477917 TI - Measurement of the 100 MHz EMF radiation in vivo effects on zebrafish D. rerio embryonic development: A multidisciplinary study. AB - The augmented exposure of both environment and human being to electromagnetic waves and the concomitant lack of an unequivocal knowledge about biological consequences of these radiations, raised public interest on electromagnetic pollution. In this context, the present study aims to evaluate the biological effects on zebrafish (ZF) embryos of 100 MHz radiofrequency electromagnetic field (RF-EMF) exposure through a multidisciplinary protocol. Because of the shared synteny between human and ZF genomes that validated its use in biomedical research, toxicology and developmental biology studies, ZF was here selected as experimental model and a measurement protocol and biological analyses have been set up to clearly discriminate between RF-EMF biological and thermal effects. The results showed that a 100 MHz EMF was able to affect ZF embryonic development, from 24 to 72 h post fertilization (hpf) in all the analyzed pathways. Particularly, at the 48 hpf stage, a reduced growth, an increased transcription of oxidative stress genes, the onset of apoptotic/autophagic processes and a modification in cholesterol metabolism were detected. ZF embryos faced stress induced by EMF radiation by triggering detoxification mechanisms and at 72 hpf they partially recovered from stress reaching the hatching time in a comparable way respect to the control group. Data here obtained showed unequivocally the in vivo effects of RF-EMF on an animal model, excluding thermal outcomes and thus represents the starting point for more comprehensive studies on dose response effects of electromagnetic fields radiations consequences. PMID- 29477918 TI - Tracing source, distribution and health risk of potentially harmful elements (PHEs) in street dust of Durgapur, India. AB - Street dust samples from Durgapur, the steel city of eastern India, were collected from five different land use patterns, i.e., national highways, urban residential area, sensitive area, industrial area and busy traffic zone during summer, monsoon, and winter to analyze the pollution characteristics, chemical fractionation, source apportionment and health risk of heavy metals (HMs). The samples were fractionated into <= 53 um and analyzed for potentially harmful elements (PHEs) viz. Cd, Cr, Cu, Fe, Mn, Ni, Pb, and Zn. Summer season indicated higher concentrations of PHEs when compared to the other two seasons. Mean enrichment factor (EF), geo-accumulation index (Igeo), and contamination factor (CF) were high for Cd followed by Pb during all the three season in Durgapur. Chemical fractionation was executed in order to obtain distribution patterns of PHEs and to evaluate their bioavailable fractions in street dust samples. Mn was found to be highly bioavailable and bioavailability of the PHEs were in the order of Mn > Zn > Pb > Ni > Cd > Cu > Fe > Cr. Principal Component Analysis (PCA), cluster analysis, correlation analysis indicated the main sources of PHEs could be industrial, especially coal powered thermal plant, iron and steel industries and cement industries and vehicular. Multivariate analysis of variance (MANOVA) indicated that sites, seasons and their interaction were significantly affected by different PHEs as a whole. The health risk was calculated with total metal as well as mobile fraction of PHEs, which indicated that the actual non-carcinogenic risk due to bioavailable PHEs was less (HI < 1) when compared to total concentrations of PHEs. Carcinogenic risk was observed for total Cr in street dust (Child: 4.6E-06; Adult: 3.6E-06). PMID- 29477919 TI - Reproductive endpoints of Rhinella arenarum (Anura, Bufonidae): Populations that persist in agroecosystems and their use for the environmental health assessment. AB - Degradation of the environment by agriculture affects the persistence and health of the amphibian populations. Characteristics related to reproduction of anuran can be used to evaluate the status of populations and as endpoints in environmental health assessment. In this in situ study the aspects related to the amplexus and ovipositions of the bioindicator species Rhinella arenarum that inhabits agroecosystems were analyzed. The hypothesis of this study is that perturbations of agroecosystems have a negative impact on the size of reproductive adults, on the size of ovipositions and eggs, and on the survival of eggs and embryos. Study area is located in the rural landscape of central Argentina. Four sampling sites were selected: C1, C2 and C3 are ponds on agroecosystems; and SM is a reference site that is not affected by agriculture or livestock. Abundance of amplexus pairs, oviposition and tadpoles per site was recorded. Individuals' snout-vent length (SVL) in amplexus was measured. The fecundity was calculated like number of eggs per oviposition. The eggs' Gosner stage, the diameter eggs and the frequency of dead and abnormal eggs were recorded by oviposition. Killing-power between egg-embryo and egg-tadpole was calculated. The higher phosphate concentration was detected in all agroecosystems and nitrate was detected in C1 and C2. Conductivity, salinity and SDT were higher in C1 site Male SVL from the SM site was lower than the other sites while the largest SVL was of female from the C3 site. The higher frequencies of sprouted eggs and of dead eggs were recorded in the C2 site. Egg diameter was associated with SM and correlated negatively to SVL of the male and female. No correlation between female SVL and oviposition size was recorded. Killing-power in the passage from egg to tadpole classes was higher in the three agroecosystems. The hypothesis of this study was corroborated in part. Reproductive adults in agroecosystems did not have smaller body size. However, in the agroecosystem ponds, the eggs with smaller diameter were registered, the oviposition had higher frequency of abnormal eggs and the higher mortality was registered. This confirms the high sensitivity of the early stages to environmental disturbances and sustains their use as endpoints for the environmental health assessment. PMID- 29477920 TI - Sand smelt ability to cope and recover from ocean's elevated CO2 levels. AB - Considered a major environmental concern, ocean acidification has induced a recent research boost into effects on marine biodiversity and possible ecological, physiological, and behavioural impacts. Although the majority of literature indicate negative effects of future acidification scenarios, most studies are conducted for just a few days or weeks, which may be insufficient to detect the capacity of an organism to adjust to environmental changes through phenotypic plasticity. Here, the effects and the capacity of sand smelt larvae Atherina presbyter to cope and recover (through a treatment combination strategy) from short (15 days) and long-term exposure (45 days) to increasing pCO2 levels (control: ~515 MUatm, pH = 8.07; medium: ~940 MUatm, pH = 7.84; high: ~1500 MUatm, pH = 7.66) were measured, addressing larval development traits, behavioural lateralization, and biochemical biomarkers related with oxidative stress and damage, and energy metabolism and reserves. Although behavioural lateralization was not affected by high pCO2 exposure, morphometric changes, energetic costs, and oxidative stress damage were impacted differently through different exposures periods. Generally, short-time exposures led to different responses to either medium or high pCO2 levels (e.g. development, cellular metabolism, or damage), while on the long-term the response patterns tend to become similar between them, with both acidification scenarios inducing DNA damage and tending to lower growth rates. Additionally, when organisms were transferred to lower acidified condition, they were not able to recover from the mentioned DNA damage impacts. Overall, results suggest that exposure to future ocean acidification scenarios can induce sublethal effects on early life-stages of fish, but effects are dependent on duration of exposure, and are likely not reversible. Furthermore, to improve our understanding on species sensitivity and adaptation strategies, results reinforce the need to use multiple biological endpoints when assessing the effects of ocean acidification on marine organisms. PMID- 29477922 TI - Corrigendum to "Application of wavelet and Fourier transforms as powerful signal processing tools for determination of naltrexone and bupropion in their binary mixture" [Spectrochim. Acta A Mol. Biomol. Spectrosc. 191 (2018) 365-371]. PMID- 29477921 TI - Reduced expression of purinergic P2X4 receptors increases voluntary ethanol intake in C57BL/6J mice. AB - Purinergic P2X4 receptors (P2X4Rs) belong to the P2X superfamily of ionotropic receptors that are gated by adenosine 5'-triphosphate (ATP). Accumulating evidence indicates that P2X4Rs play an important role in regulation of ethanol intake. At the molecular level, ethanol's inhibitory effects on P2X4Rs are antagonized by ivermectin (IVM), in part, via action on P2X4Rs. Behaviorally, male mice deficient in the p2rx4 gene (P2X4R knockout [KO]) have been shown to exhibit a transient increase in ethanol intake over a period of 4 days, as demonstrated by social and binge drinking paradigms. Furthermore, IVM reduced ethanol consumption in male and female rodents, whereas male P2X4R KO mice were less sensitive to the anti-alcohol effects of IVM, compared to wildtype (WT) mice, further supporting a role for P2X4Rs as targets of IVM's action. The current investigation extends testing the hypothesis that P2X4Rs play a role in regulation of ethanol intake. First, we tested the response of P2X4R KO mice to ethanol for a period of 5 weeks. Second, to gain insights into the changes in ethanol intake, we employed a lentivirus-shRNA (LV-shRNA) methodology to selectively knockdown P2X4R expression in the nucleus accumbens (NAc) core in male C57BL/6J mice. In agreement with our previous study, male P2X4R KO mice exhibited higher ethanol intake than WT mice. Additionally, reduced expression of P2X4Rs in the NAc core significantly increased ethanol intake and preference. Collectively, the findings support the hypothesis that P2X4Rs play a role in regulation of ethanol intake and that P2X4Rs represent a novel drug target for treatment of alcohol use disorder. PMID- 29477923 TI - Gastrothorax: A case of mistaken identity. AB - INTRODUCTION: Acute wrap failure post fundoplication is a rare but recognized complication and can be due to patient factors, disease factors and surgical factors. Herniation of the stomach into the thorax can mimic a pneumothorax clinically and radiologically and thus lead to bad outcomes for patients. PRESENTATION OF CASE: We report the case of a 20-year-old male who presented to the emergency department with progressively worsening upper abdominal pain, nausea and vomiting followed by acute onset dyspnoea, six days post a laparoscopic repair of a small hiatus hernia and a Nissen fundoplication. His chest x-ray was consistent with that of a left sided pneumothorax and was therefore, appropriately resuscitated and treated with an intercostal catheter (ICC). A subsequent CT scan of the chest revealed a left gastrothorax. The patient was taken to theatre for the surgical reduction of the paraoesophageal hernia. DISCUSSION: Patients with a recent history of anti-reflux surgery, who present with a pneumothorax and respiratory distress or a tension pneumothorax should always be treated with an ICC. However, follow up imaging with a CT scan is essential to confirm diagnosis. Good control of post- operative nausea and vomiting is essential in avoiding wrap failure and ensuing complications. CONCLUSION: A high index of suspicion for a gastrothorax mimicking a pneumothorax is important in the setting of recent anti-reflux surgery. PMID- 29477924 TI - Three-stage management of complex pancreatic trauma with gastroduodenopancreatectomy: A case report. AB - INTRODUCTION: Severe injuries of the pancreatic head and duodenum in haemodynamically unstable patients are complex management. The purpose of this study is to report a case of complex pancreatic trauma induced by gunshot and managed with surgical approaches at three different times. PRESENTATION OF CASE: Exploratory laparotomy was indicated after initial emergency room care, with findings of cloudy blood-tinged fluid and blood clots on the mesentery near the hepatic angle, on the region of the 2nd portion of the duodenum and at the pancreatic head. Gastroduodenopancreatectomy was performed with right hemicolectomy and the peritoneal cavity was temporarily closed by a vacuum peritoneostomy. Surgical reopening occurred on the fifth postoperative day, and the patient was subjected to single-loop reconstruction of the intestinal transit with telescoping pancreaticojejunal anastomosis, biliodigestive anastomosis with termino-lateral hepaticojejunal anastomosis with a Kehr drain and gastroenteroanastomosis in 2 planes. The terminal ileostomy was maintained. After 2 days, the patient was subjected to abdominal wall closure without complications, which required relaxing Gibson incisions and wound closure with polypropylene mesh placement in a pre-aponeurotic position closed with multiple stitches. RESULTS: The patient was discharged on the 40th post-trauma day without drains, with a functioning ileostomy and with a scheduled reconstruction of intestinal transit. CONCLUSION: In the presence of multiple associated injuries, hemodynamic instability and the need for an extensive surgical procedure such as duodenopancreatectomy, damage control surgery performed in stages as reported here enables the clinical stabilization of the patient for definitive treatment, achieving better survival results. PMID- 29477925 TI - Intestinal obstruction caused by endometriosis: Endoscopic stenting and expedited laparoscopic resection avoiding stoma. A case report and review of the literature. AB - INTRODUCTION: Endometriosis is the growth of endometrium outside the uterine cavity. In 5-15% of cases the disease can affect the colon and small bowel, causing complete obstruction and requiring resection in about 1% of cases. CASE SUMMARY: We describe a case of sigmoid obstruction due to endometriosis in a 38 years old woman with personal history of endometriosis. She was admitted for abdominal pain and constipation. The patient was treated with endoscopic stenting and subsequent laparoscopic sigmoidectomy. DISCUSSION: Bowel obstruction caused by endometriosis is a rare event. Its diagnosis can thus be a clinical and radiological challenge but it may be suspected in all young woman with colonic obstruction. At present, the management of endometriosis is an integrate approach of both medical and surgical therapy. In case of irreversible colonic obstruction surgery is mandatory. The treatment of choice is usually an emergency procedure (either Hartmann procedure or resection and anastomosis with stoma placement). This approach entails all the risks related to emergency procedures and can have important psychological and biological drawbacks. CONCLUSION: Endoscopic prosthesis placement as bridge to surgery is a feasible therapeutic strategy in colonic obstruction due to endometriosis. It brings about all the advantages of an expedited one step laparoscopic surgical procedure. Laparoscopic elective resection has a lower rate of stoma placement and has a postoperative pregnancy rate grater than open surgery. PMID- 29477926 TI - Colorectal intussusception secondary to primary rectal melanoma: A novel case report. AB - INTRODUCTION: Intussusception in adults is a rare condition, accounting for just 5% of all cases. Approximately 50% of cases of large intestine intussusception occur due to a malignant neoplasm. We present here a novel case report of colo rectal intussusception arising secondary to a primary rectal melanoma. PRESENTATION OF CASE: We present the case of an 85 year-old patient, who underwent a colonoscopy for investigation of weight loss and altered bowel habit. At colonoscopy, a pigmented polypoid mass was visualised in the upper third of the rectum. The lesion was causing colo-rectal intussusception. Initial biopsies of the specimen stained positive for S-100. The patient had an MRI (magnetic resonance imaging) pelvis, which demonstrated a mass at the rectosigmoid junction, which was diffusely high signal on the fat sat T1 weighted sequence. The patient proceeded to a laparoscopic anterior resection and had an uncomplicated post-operative course. The resected specimen was sent for pathological analysis. The morphological and immunohistochemical profile was consistent with malignant melanoma. There was no evidence of cutaneous melanoma following a full skin examination. DISCUSSION: Rectal melanoma is a rare condition. We present a novel case report of colo-rectal intussusception arising secondary to rectal melanoma. CONCLUSION: This is a rare entity. This patient's pre-operative MRI and biopsy samples suggested this lesion was a rectal melanoma, which was subsequently confirmed on analysis of the resected specimen. Surgical resection of such neoplasms should be attempted where possible. PMID- 29477927 TI - Current perspectives on the application of N-damo and anammox in wastewater treatment. AB - The efficient treatment of wastewater for the removal of nitrogen is of key importance to prevent eutrophication and deoxygenation of receiving water bodies. In addition, ineffective wastewater treatment can be a source of greenhouse gasses. The application of newly discovered microbial processes, such as nitrite/nitrate-dependent methane oxidation (N-damo), can make wastewater treatment systems more sustainable; especially when they are combined with anaerobic ammonium oxidation (anammox). A treatment system based on these microbial processes will need oxygen supply for the production of nitrite. This oxygen may inhibit N-damo and anammox and careful regulation of the oxygen supply is of key importance for the success of the application of N-damo in wastewater treatment. PMID- 29477928 TI - New-generation bar adsorptive microextraction (BAMUE) devices for a better eco user-friendly analytical approach-Application for the determination of antidepressant pharmaceuticals in biological fluids. AB - The present contribution aims to design new-generation bar adsorptive microextraction (BAMUE) devices that promote an innovative and much better user friendly analytical approach. The novel BAMUE devices were lab-made prepared having smaller dimensions by using flexible nylon-based supports (7.5 * 1.0 mm) coated with convenient sorbents (~ 0.5 mg). This novel advance allows effective microextraction and back-extraction ('only single liquid desorption step') stages as well as interfacing enhancement with the instrumental systems dedicated for routine analysis. To evaluate the achievements of these improvements, four antidepressant agents (bupropion, citalopram, amitriptyline and trazodone) were used as model compounds in aqueous media combined with liquid chromatography (LC) systems. By using an N-vinylpyrrolidone based-polymer phase good selectivity and efficiency were obtained. Assays performed on 25 mL spiked aqueous samples, yielded average recoveries in between 67.8 +/- 12.4% (bupropion) and 88.3 +/- 12.1% (citalopram), under optimized experimental conditions. The analytical performance also showed convenient precision (RSD < 12%) and detection limits (50 ng L-1), as well as linear dynamic ranges (160-2000 ng L-1) with suitable determination coefficients (r2 > 0.9820). The application of the proposed analytical approach on biological fluids showed negligible matrix effects by using the standard addition methodology. From the data obtained, the new generation BAMUE devices presented herein provide an innovative and robust analytical cycle, are simple to prepare, cost-effective, user-friendly and compatible with the current LC autosampler systems. Furthermore, the novel devices were designed to be disposable and used together with negligible amounts of organic solvents (100 MUL) during back-extraction, in compliance with the green analytical chemistry principles. In short, the new-generation BAMUE devices showed to be an eco-user-friendly approach for trace analysis of priority compounds in biological fluids and a versatile alternative over other well stablished sorption-based microextraction techniques. PMID- 29477929 TI - Comparative evaluation of ICP sample introduction systems to be used in the metabolite profiling of chlorine-containing pharmaceuticals via HPLC-ICP-MS. AB - A systematic evaluation of four different ICP sample introduction systems to be used in the context of metabolite profiling of chlorine-containing pharmaceuticals via HPLC-ICP-MS was carried out using diclofenac and its major metabolite, 4'-hydroxy-diclofenac, as model compounds. The strict requirements for GMP validation of chromatographic methods in the pharmaceutical industry were adhered to in this context. The final aim of this investigation is an extension of the applicability and validatability of HPLC-ICP-MS in the field of pharmaceutical R&D. Five different gradient programmes were tested while the baseline peak width (wb), peak capacity (P), USP tailing factor (As) and USP signal-to-noise ratio (USP S/N) were determined as major indicators of the chromatographic performance and the values obtained were compared to the corresponding FDA recommendations (if applicable). Four different ICP-MS sample introductions systems were investigated involving two units typically working at higher flow rates (~1.0 mL min-1) and another two systems working at lower flow rates (~0.1 mL min-1). Optimal conditions with potential for applicability under GMP conditions were found at a mobile phase flow rate of 1.0 mL min-1 by using a pneumatic micro-flow LC nebulizer mounted onto a Peltier-cooled cyclonic spray chamber cooled to -1 degrees C for sample introduction. Under these conditions, HPLC-ICP-MS provided a chromatographic performance similar to that of HPLC with UV detection. The peak shape (USP tailing factor = 1.1-1.4) was significantly improved compared to that obtained with the Peltier-cooled Scott-type spray chamber. Two alternative sample introduction systems - a POINT(r) and a High Temperature Torch-Integrated Sample Introduction System (hTISIS) - were also tested at a flow rate of 0.1 mL min-1 using a chromatographic column with 1.0 mm ID. Although these systems allowed the peak shape to be improved compared to that obtained with the traditional Scott-type spray chamber, the limits of detection and of quantification achievable were strongly compromised due to the significantly lower sensitivity observed for Cl. In addition to a comparison of the aforementioned sample introduction systems, also the effect of spray chamber temperature was evaluated and it was demonstrated that proper temperature control plays an essential role in the optimization of HPLC-ICP-MS methods. PMID- 29477930 TI - Acquired resistance to EGFR targeted therapy in non-small cell lung cancer: Mechanisms and therapeutic strategies. AB - The tyrosine kinase inhibitors (TKIs) directed at sensitizing mutations in the epidermal growth factor receptor (EGFR) gene represents a critical pillar in non small cell lung cancer treatment. Despite the excellent disease control with initial EGFR TKI therapy, acquired resistance is ubiquitous and remains a key challenge. Investigations into the mechanisms which foster resistance to EGFR TKIs has led to the discovery of novel biomarkers and drug targets, and in turn has enabled the development of third-generation TKIs and proposals for rational therapeutic combinations. The threonine-to-methionine substitution mutation at position 790 (T790M) is clinically validated to engender refractoriness to first- and second-generation TKIs, and is a standard-of-care predictive biomarker used in therapeutic stratification. Clinical use of liquid biopsy approaches for assessment of T790M mutations continues to increase, with growing advocacy for serial monitoring of tumor evolution. For patients who are T790M-negative, cytotoxic chemotherapy or protracted EGFR TKI treatment are acceptable treatment standards after disease progression, although combinations of targeted therapies and checkpoint blockade immunotherapy may offer promising alternatives in the future. Among T790M-positive patients, the third-generation EGFR TKI, osimertinib, has shown superiority over both platinum-doublet chemotherapy and 1st generation EGFR TKI in randomized clinical trials, and exhibits enhanced in vitro selectivity for mutant EGFR receptors and pharmacokinetics compared to earlier-generation TKIs. This article appraises the key literature on the contemporary management of non-small cell lung cancer patients with acquired resistance to EGFR TKIs, and envisions future directions in translational and clinical research. PMID- 29477931 TI - Self-Management Interventions for Women With Cardiac Pain: A Systematic Review and Meta-analysis. AB - BACKGROUND: Cardiac pain is considered the primary indicator of coronary artery disease (CAD). Existing reviews lack appropriate numbers of women or sex-based subgroup analyses, or both; thus, the benefits of self-management (women with cardiac pain actively participating in their own care and treatment) remain uncertain. METHODS: Using methods described by the Evidence for Policy and Practice Information and Co-ordinating Centre at the Institute of Education, 7 databases were systematically searched to examine and synthesize the evidence on self-management interventions for women with cardiac pain and cardiac pain equivalents, such as fatigue, dyspnea, and exhaustion. RESULTS: Our search yielded 22,402 article titles and abstracts. Of these, 57 randomized controlled trials were included in a final narrative synthesis, comprising data from 13,047 participants, including 5299 (41%) women. Self-management interventions targeting cardiac pain in women compared with a control population reduced (1) cardiac pain frequency and cardiac pain proportion (obstructive and nonobstructive CAD), (2) fatigue at 12 months, and (3) dyspnea at 2 months. There was no evidence of group differences in postprocedural (percutaneous coronary intervention or cardiac surgery) pain. Results indicated that self-management interventions for cardiac pain were more effective if they included a greater proportion of women (standardized mean difference [SMD], -0.01; standard error, 0.003; P = 0.02), goal setting (SMD, -0.26; 95% confidence interval [CI], -0.49 to -0.03), and collaboration/support from health care providers (SMD, -0.57; 95% CI, -1.00 to 0.14). CONCLUSIONS: The results of this review suggest that self-management interventions reduce cardiac pain and cardiac pain equivalents. PMID- 29477932 TI - Comments on Etiological Classification of Stroke in Patients with Chagas Disease Using TOAST, Causative Classification System TOAST, and ASCOD Phenotyping. PMID- 29477933 TI - Immunological network analysis in HPV associated head and neck squamous cancer and implications for disease prognosis. AB - Human papillomavirus-positive (HPV+) head and neck squamous cell cancer (HNSCC) exhibits a better prognosis than HPV-negative (HPV-) HNSCC. This difference may in part be due to enhanced immune activation in the HPV+ HNSCC tumor microenvironment. To characterize differences in immune activation between HPV+ and HPV- HNSCC tumors, we identified and annotated differentially expressed genes based upon mRNA expression data from The Cancer Genome Atlas (TCGA). Immune network between immune cells and cytokines was constructed by using single sample Gene Set Enrichment Analysis and conditional mutual information. Multivariate Cox regression analysis was used to determine the prognostic value of immune microenvironment characterization. A total of 1673 differentially expressed genes were functionally annotated. We found that genes upregulated in HPV+ HNSCC are enriched in immune-associated processes. And the up-regulated gene sets were validated by Gene Set Enrichment Analysis. The microenvironment of HPV+ HNSCC exhibited greater numbers of infiltrating B and T cells and fewer neutrophils than HPV- HNSCC. These findings were validated by two independent datasets in the Gene Expression Omnibus (GEO) database. Further analyses of T cell subtypes revealed that cytotoxic T cell subtypes predominated in HPV+ HNSCC. In addition, the ratio of M1/M2 macrophages was much higher in HPV+ HNSCC. The infiltration of these immune cells was correlated with differentially expressed cytokine associated genes. Enhanced infiltration of B cells and CD8+ T cells were identified as independent protective factors, while high neutrophil infiltration was a risk enhancing factor for HPV+ HNSCC patients. A schematic model of immunological network was established for HPV+ HNSCC to summarize our findings. PMID- 29477934 TI - Recent advances in the selection and identification of antigen-specific nanobodies. AB - Nanobodies represent the next-generation antibody-derived biologics with significant advances over conventional antibodies. Several rapid and robust techniques for isolating highly specific nanobodies have been developed. Antigen specific nanobodies are selected from constructed nanobody libraries, which can be classified into 3 main types: immune library, naive library, and semisynthetic/synthetic library. The immune library is the most widely used strategy for nanobody screening. Target specific nanobodies are highly enriched in immune libraries than in non-immune libraries; however, it is largely limited by the natural antigenicity of antigens. The naive library is thus developed. Despite the lack of somatic maturation, protein engineering can be employed to significantly increase the affinities of selected binders. However, a substantial amount of blood samples collected from a large number of individual animals is a prerequisite to ensure the diversity of the naive library. With this issue considered, the semisynthetic/synthetic library may be a promising path toward obtaining a limitless source of nanobodies against a variety of antigens without the need of animals. In this review, we summarize the state-of-the-art screening technologies with different libraries. The approaches presented here can further boost the diverse applications of nanobodies in biomedicine and biotechnology. PMID- 29477935 TI - Biocatalysts based on nanozeolite-enzyme complexes: Effects of alkoxysilane surface functionalization and biofuel production using microalgae lipids feedstock. AB - Nanozeolites with different crystallographic structures (Nano/TS1, Nano/GIS, Nano/LTA, Nano/BEA, Nano/X, and Nano-X/Ni), functionalized with (3 aminopropyl)trimethoxysilane (APTMS) and crosslinked with glutaraldehyde (GA), were studied as solid supports for Thermomyces lanuginosus lipase (TLL) immobilization. Physicochemical characterizations of the surface-functionalized nanozeolites and nanozeolite-enzyme complexes were performed using XRD, SEM, AFM, ATR-FTIR, and zeta potential measurements. The experimental enzymatic activity results indicated that the nanozeolitic supports functionalized with APTMS and GA immobilized larger amounts of enzymes and provided higher enzymatic activities, compared to unfunctionalized supports. Correlations were observed among the nanozeolite surface charges, the enzyme immobilization efficiencies, and the biocatalyst activities. The catalytic performance and reusability of these enzyme nanozeolite complexes were evaluated in the ethanolysis transesterification of microalgae oil to fatty acid ethyl esters (FAEEs). TLL immobilized on the nanozeolite supports functionalized with APTMS and GA provided the most efficient biocatalysis, with FAEEs yields above 93% and stability during five reaction cycles. Lower FAEEs yields and poorer catalytic stability were found for nanozeolite-enzyme complexes prepared only by physical adsorption. The findings indicated the viability of designing highly efficient biocatalysts for biofuel production by means of chemical modulation of nanozeolite surfaces. The high biocatalyst catalytic efficiency observed in ethanolysis reactions using a lipid feedstock that does not compete with food production is an advantage that should encourage the industrial application of these biocatalysts. PMID- 29477936 TI - Nano-scale characterization of nano-hydroxyapatite incorporated chitosan particles for bone repair. AB - In this study, injectable porous spherical particles were fabricated using chitosan (CS) biopolymer, sodium tripolyphosphate (TPP), and nano-hydroxyapatite (nHA). TPP was primarily used as an ionic crosslinker to crosslink 2% (w/v) CS droplets. 2% (w/v) nHA was used to prepare nHA incorporated particles. The surface morphological properties and nanomechanical properties such as topography, deformation, adhesion, and dissipation of CS particles with and without nHA were studied using contact mode and peakforce quantitative nanomechanical property mapping mode in atomic force microscopy. The nHA spots have higher density than CS which leads to higher forces acting on the probe tip and higher energy dissipation to lift the tip from nHA areas. The cumulative release data showed that about 87% of total BMP-2 encapsulated within the particles was released by third week of experiment period. Degradation study was conducted to understand how the particles degradation occurs in the presence of phosphate buffered saline with continues shaking in an incubator at 37 degrees C. In addition, BMP-2 release from the 2% nHA/CS particles was studied over a three weeks period and found that BMP-2 release was governed by the simple diffusion rather than the degradation of particles. PMID- 29477937 TI - Porous epoxy phenolic novolac resin polymer microcapsules: Tunable release and bioactivity controlled by epoxy value. AB - Microcapsules (MCs) prepared with diverse wall material structures may exhibit different properties. In this study, MCs were fabricated with three kinds of epoxy phenolic novolac resins (EPNs), which possessed unique epoxy values as wall forming materials by interfacial polymerization. The effects of the EPN types on the surface morphology, particle size distribution, encapsulation efficiency, thermal stability as well as release behavior and bioactivity of the MCs were investigated. In all three samples, the MCs had nearly spherical shapes with fine monodispersities and sizes in the range of 7-30 MUm. Scanning electron microscopy (SEM) images showed that some small pores (ranging from 50 nm to 400 nm) appeared on the microcapsule surfaces and that the porosity decreased with an increasing of epoxy value. The X-ray diffractometer (XRD) analysis indicated that the cured EPN shells had larger degrees of crosslinking with higher epoxy values, leading to better thermal stabilities. Moreover, the release rate of the core material (pendimethalin) decreased with an increasing of epoxy value and thus resulted in a lower herbicidal control efficacy. The results of our research will enhance the potential application of EPNs as smart wall-forming materials to prepare porous MCs for controlled release. PMID- 29477938 TI - Genetic syndromes of severe insulin resistance. AB - Insulin resistance underpins the link between obesity and most of its associated metabolic disorders including type 2 diabetes, fatty liver disease, dyslipidaemia and cardiovascular disease. Despite its importance and extensive scientific endeavour, its precise molecular pathogenesis remains unclear. Monogenic syndromes of extreme insulin resistance, whilst rare in themselves, can provide unique insights into the pathogenesis of human insulin resistance. Severe insulin resistance syndromes are broadly classified into three categories: lipodystrophies, primary insulin signalling defects or complex syndromes including severe insulin resistance. Genetically confirmed classification has facilitated the identification of robust diagnostic biochemical features accelerating accurate clinical diagnosis. Interestingly the biochemical features of lipodystrophies are far more closely aligned to what is seen in prevalent forms of insulin resistance than those of primary insulin signalling defects, suggesting that lipodystrophy could be a relevant model for common disease. This assertion is supported by genome-wide association data indicating that SNPs associated with fasting hyperinsulinemia and metabolic dyslipidaemia, are strongly associated with a subtle reduction in hip fat, suggesting that subtle forms of lipodystrophy are likely to be a significant contributor to prevalent insulin resistance. PMID- 29477939 TI - Successful weaning from continuous renal replacement therapy. Associated risk factors. AB - PURPOSE: To identify risk factors of successful continuous renal replacement therapy (CRRT) weaning and to evaluate the effect of furosemide in the recovery of urine output after CRRT stop. MATERIALS AND METHODS: Retrospective, observational study of critical patients treated with CRRT. Weaning tests (WT) were classified in two groups: successful (urine output was recovered and CRRT was not required again) and failed (CRRT was required again). A multiple logistic regression model was used to identify risk factors of successful CRRT WT. The prediction ability was assessed with the area under the receiver operating characteristic curves (AUC-ROC). RESULTS: Eighty-six patients underwent 101 CRRT WT. The multivariate model identified that the risk factors of successful CRRT weaning were sex and 6h-urine output after CRRT stop. The AUC-ROC was 0.81 (0.72 0.90) for 6h-urine output before and 0.91 (0.84-0.96) for 6h-urine output after CRRT stop. The AUC-ROC for 6h-urine output after WT to predict successful CRRT weaning were 0.94 (0.88-1.0) in patients who received furosemide and 0.85 (0.72 0.99) in patients who did not. CONCLUSIONS: Urine output after CRRT stop was the main risk factor of successful CRRT weaning. Administration of furosemide increased the strength of this association. PMID- 29477940 TI - Fingerprints of single nuclear spin energy levels using STM - ENDOR. AB - We performed STM-ENDOR experiments where the intensity of one of the hyperfine components detected in ESR-STM is recorded while an rf power is irradiated into the tunneling junction and its frequency is swept. When the latter frequency is near a nuclear transition a dip in ESR-STM signal is observed. This experiment was performed in three different systems: near surface SiC vacancies where the electron spin is coupled to a next nearest neighbor 29Si nucleus; Cu deposited on Si(111)7x7 surface, where the unpaired electron of the Cu atom is coupled to the Cu nucleus (63Cu, 65Cu) and on Tempo molecules adsorbed on Au(111), where the unpaired electron is coupled to a Nitrogen nucleus (14N). While some of the hyperfine values are unresolved in the ESR-STM data due to linewidth we find that they are accurately determined in the STM-ENDOR data including those from remote nuclei, which are not detected in the ESR-STM spectrum. Furthermore, STM-ENDOR can measure single nuclear Zeeman frequencies, distinguish between isotopes through their different nuclear magnetic moments and detect quadrupole spectra. We also develop and solve a Bloch type equation for the coupled electron-nuclear system that facilitates interpretation of the data. The improved spectral resolution of STM - ENDOR opens many possibilities for nanometric scale chemical analysis. PMID- 29477941 TI - The management of hyperleukocytosis in 2017: Do we still need leukapheresis? AB - Hyperleukocytosis is defined as a white blood cell count greater than 100.000/MUL in patients affected by acute or chronic leukemias. Hyperleukocytosis is more common in acute leukemias than in chronic leukemias. Risk factors include younger age, acute myeloid leukemia, the microgranular variant of acute promyelocytic leukemia, acute lymphoblastic leukemia and some cytogenetic abnormalities. Although it can affect any organ system, symptoms usually arise from involvement of the cerebral, pulmonary and renal microvasculature. The term "leukostasis" refers to 'symptomatic hyperleukocytosis' which is a medical emergency that needs prompt recognition and initiation of therapy to prevent renal and respiratory failure or intracranial haemorrhage. The underlying mechanisms of hyperleukocytosis and leukostasis are poorly understood. The management of hyperleukocytosis and leukostasis involves supportive measures and reducing the number of circulating leukemic blast cells by induction chemotherapy, hydroxyurea, low-dose chemotherapy, and leukapheresis. The measures such as hydroxyurea, low-dose chemotherapy, and leukapheresis shouldn't be considered to correct the laboratory abnormalities in patients with hyperleukocytosis who have no signs or symptoms. Also, neither hydroxyurea nore leukapheresis is able to show benefit on short and long term outcomes in patients with symptomatic hyperleukocytosis. The optimal management of symptomatic hyperleukocytosis is still uncertain, and there are no randomized studies demonstrating one is superior to each other. Therefore, it is recommended that intensive chemotherapy should be implemented as quickly as possible in treatment-eligible patients, in parallel with supportive measures for DIC and TLS. PMID- 29477942 TI - Reflections on the usefulness of extracorporeal photopheresis in renal transplant rejection: A concise review of the involved mechanisms and therapeutic perspectives. AB - Renal rejection clinically represents a major cause of graft dysfunction and sadly the loss of the renal transplant. This is despite the considerable progress in immunosuppressive therapy. It is strongly believed that the complex immunologic network underlying the response against major histocompatibility molecules (MHC) is responsible for rejection, an unresolved issue that is, in part, not inhibited by the current prophylactic and therapeutic strategies. Extracorporeal photopheresis (ECP) is an effective cell therapy approach that was successfully used in immunomodulating heart rejection, acute and chronic GvHD, lung rejection and some selected autoimmune diseases. In this concise report we provide a brief review on the mechanisms of action and the use of ECP in acute and chronic renal allograft rejection. PMID- 29477943 TI - The use of emergency apheresis in the management of plasma cell disorders. AB - Hyperviscosity syndrome (HVS) develops most commonly in Waldenstrom's macroglobulinemia (WM) and multiple myeloma (MM). Plasmapheresis is the immediate therapy and very effective at relieving symptoms by removing paraprotein. The most commonly used replacement fluid is 4%-5% human albumin in physiologic saline. FFP may be used in patients with coagulation abnormalities. Plasmapheresis should be continued until acute symptoms abate. Hyperviscosity impairs the circulation in the retina and causes hemorrhages around the small retinal vessels. Early diagnosis and urgent plasmapheresis may reduce blindness caused by retinal hemorrhages and/or retinal detachment. In HCV related mixed cryoglobulinemias, plasmapheresis is indicated if rapidly evolving life threatening disease with immunosuppressive agent exists. In non-infectious mixed cryoglobulinemia plasmapheresis is indicated when the disease manifestations are severe, as a second line option. In WM patients with hyperviscosity symptoms and IgM > 4 g/dL, preemptive plasmapheresis is recommended to prevent an IgM flare with rituximab. Certain IgG/A MGUS-associated neuropathy patients may benefit from plasmapheresis. For cast nephropathy (suspected or biopsy proven), plasmapheresis is recommended when the sFLC >= 500 mg/l and as early as possible (<1 month with kidney injury). Theoretically, extracorporeal removal alone, without efficient tumor killing, could not reduce sFLC due to high production by the tumor mass and rapid rebound between compartments. PMID- 29477944 TI - The role of Cortistatin-14 in the gastrointestinal motility in mice. AB - BACKGROUND: This study aimed to investigate the functional roles of Cortistatin 14 (CST-14) in the gastrointestinal (GI) motility. METHODS: For in vivo study, mice were randomly divided into control, ip injected CST-14 (0.1, 0.5, 1, 5, 10mg/kg)+control group, icv injected CST-14 (5MUg)+control group, dextran sulfate sodium-induced colitis group, CST-14+colitis group, castor oil-induced diarrhea group, CST-14+diarrhea group. We carried out these experiments by quantitative real-time PCR, GI transit, bead expulsion and fecal pellet output. For in vitro study, effects of CST-14 were investigated in the longitudinal and circular muscle contractions of jejum, ileum, and colon. RESULTS: In vivo, the expression of CST-14 mRNA was significantly decreased in the colon of colitis mice and CST 14 significantly inhibited GI transit rate in colitis mice, and delayed the emergence of liquid feces in castor oil-induced diarrhea mouse model. Additionally, ip injection of CST-14, but not icv injected, remarkably inhibited GI transit, bead expulsion and fecal pellet output in mice. In vitro assays, CST 14 (10-6M) could relax the rhythms of the longitudinal muscles and circular muscles of the jejunum, ileum and colon of mice. The further study indicated that the roles of CST-14 in mouse GI motility were significantly reversed by c-SOM (sstr1-5 antagonist), especially sstr2 and sstr3 and propranolol (beta adrenoceptor blocker), suggesting that somatostatin system and noradrenaline system were involved in the inhibiting effects of CST-14 in GI. CONCLUSION: Such inhibiting effects imply that CST-14 system in gastrointestinal motility might be a new target for treatment of GI tract disorder. PMID- 29477945 TI - Subtle improvement of seizure susceptibility by atorvastatin treatment during epileptogenesis. AB - BACKGROUND: The process by which a brain insult elicits epilepsy is termed epileptogenesis and it is characterized by numerous molecular and functional alterations. Statins are first-line drugs for hypercholesterolemia and related diseases, and display neuroprotective properties in clinical and experimental studies. Considering the importance in developing therapeutic strategies to prevent or modify epileptogenesis, we aimed the present study to test the hypothesis that atorvastatin modifies seizure susceptibility of mice after status epilepticus (SE). METHODS: Male and female C57BL/6 mice were submitted to the pilocarpine-induced SE and then treated with atorvastatin (10 or 100mg/kg, once daily by gavage) for 14days. At days 7 and 14 post SE we evaluated the susceptibility of mice to the convulsant effects of a low dose of PTZ (30mg/kg). Cell loss in the hilus of dentate gyrus was evaluated by Giemsa staining. RESULTS: Latencies to myoclonic jerks and to tonic-clonic seizures decreased between baseline (before SE) and days 7 and 14 after SE, confirming the development of seizure susceptibility. Atorvastatin protected against PTZ-induced tonic-clonic seizures in both sexes at day 14 post-SE. Protective effects were similar in both female and male mice, except that a high dose of atorvastatin was required for females (protection at 100mg/kg versus 10mg/kg in males). Giemsa staining did not reveal neuroprotective effects of atorvastatin. CONCLUSIONS: Atorvastatin treatment during epileptogenesis had slight beneficial effects on seizure susceptibility. These seem not related to neuroprotection. Further studies are needed to determine the disease-modifying potential of atorvastatin in epilepsy. PMID- 29477946 TI - In vitro antiglycating effect and in vivo neuroprotective activity of Trigonelline in d-galactose induced cognitive impairment. AB - BACKGROUND: Alzheimer's disease (AD) is characterized by amyloid beta (Abeta) plaques, neurofibrillary tangles (NFTs) and cognitive impairment. Literature cites the role of advanced glycation end products (AGEs) in AD due to increased cytotoxicity via oxidative stress. d-galactose (d-gal) induced amnesia stimulates Abeta overproduction via increased oxidative stress and AGEs. Trigonelline (TRG), a naturally occurring alkaloid has been reported to have neuroprotective and antidiabetic properties. METHODS: Present study assessed the protective effect of TRG against in vitro AGEs formation. Since chronic administration of d-gal increases AGEs, we subsequently investigated the neuroprotective role of TRG (50 and 100 mg/kg as per body weight) against d-gal induced amnesia. Mice were subcutaneously (sc) injected with d-gal (150 mg/kg) for 6 weeks. Behavioral assessments in Morris water maze (MWM) and Y-maze were performed, followed by biochemical estimations to deduce the probable mechanism of action. RESULTS: In vitro experiments demonstrated that TRG stalled early and late AGEs formation. Chronic d-gal administration significantly impaired cognitive performance in MWM and Y maze, caused marked oxidative damage, elevated the AGEs levels and significantly increased the acetylcholinesterase levels as compared to sham group. TRG (50 and 100 mg/kg) treatment significantly ameliorated cognitive performance, reversed the oxidative damage, decreased AGE levels and caused significant decline in acetylcholine esterase levels as compared to d-gal group. CONCLUSION: Present study highlights the neuroprotective role of TRG against d gal induced amnesia due to the antioxidant, antiglycative and anticholinesterase properties. PMID- 29477947 TI - Cardioprotective effect of N-methylnicotinamide salt of pyruvate in experimental model of cardiac hypoxia. AB - BACKGROUND: Pyruvate improves contractility of normal, hypoxic, and post-ischemic myocardium. However, sodium overload is a major problem with its therapeutic application if sodium pyruvate is used. Development of alternative forms such as N-1-methylnicotinamide (MNA) pyruvate may help to overcome this problem. The aim of the study was to investigate the effect of MNA pyruvate in a murine model of cardiac ischemia. METHODS: Seven month old male ApoE-/-LDLr-/- mice that develop myocardial infarction when exposed to hypoxic stress, were used in this study. Hypoxia (8% O2 in inspired air) was maintained for 8min and was followed by reoxygenation (21% O2 in inspired air). Four groups of mice were treated 10min before the hypoxic event by intravenous injection of MNA, MNA pyruvate, sodium pyruvate, and saline as control. The myocardial ischemia and damage was recorded by ECG. Four hours following the hypoxic episode serum troponin T and creatine kinase activity were measured. RESULTS: Significant hypernatremia was found in the sodium pyruvate group. During hypoxia, control and MNA group developed profound STU depressions on ECG while no changes were observed in MNA pyruvate and sodium pyruvate group. Creatine kinase activity and troponin T content in the mice plasma were significantly higher in the control and MNA group as compared to the MNA pyruvate and sodium pyruvate group. CONCLUSIONS: This study demonstrated that administration of MNA pyruvate prior to a hypoxia-induced cardiac event was cardioprotective. This intervention did not cause hypernatremia in contrast to sodium pyruvate. PMID- 29477948 TI - Antinociceptive and pronociceptive effect of levetiracetam in tonic pain model. AB - BACKGROUND: Levetiracetam (LEV) is a novel anticonvulsant with proven antinociceptive properties. However, the antinociceptive and pronociceptive effect of this drug has not yet been fully elucidated in a tonic pain model. METHODS: Thirty-six male rats (Wistar) were randomized into six groups and underwent the formalin test as follows: rats in the control group were administered 50MUL of 1% formalin in the paw; sham-group rats were administered 50MUL of saline in the paw to mimick the application of formalin; the four experimental groups were administered LEV intragastrically (ig) (50, 100, 200 and 300mg/kg), and 40min later 50MUL of 1% formalin was injected in the paw. RESULTS: LEV exhibited antinociceptive effect in the 300mg/kg LEV group (p<0.05) and a pronociceptive effect in the 100mg/kg LEV group (p<0.05) and in the 50mg/kg LEV group (p<0.001). CONCLUSIONS: The antinociceptive and pronociceptive effect of LEV in a tonic pain model is dose-dependent. PMID- 29477949 TI - The association between lifestyle and overall health, using the frailty index. AB - OBJECTIVE: To evaluate the associations of four individual lifestyle factors with frailty. METHODS: We used cross-sectional data from 11,539 participants of the Rotterdam Study, a population-based cohort, running from 1990 till now. A frailty index was used with a range from 0 to 100 (higher values indicating increasing frailty). We examined physical activity, dietary quality, alcohol intake, and smoking and calculated a sum-score of these, with a range from 0 (lowest) to 8 (highest). The associations between each lifestyle factor and the lifestyle score with frailty were evaluated. RESULTS: Each lifestyle factor was independently associated with frailty. Participants with high physical activity levels had lower frailty scores than participants with low physical activity (beta = 4.70,95%CI = -5.10,-4.30). High diet quality, compared to low diet quality was associated with less frailty (beta=-0.88,95%CI = -1.35,-0.42). Low alcohol intake was associated more frailty (beta = 0.84, 95%CI = 0.39, 1.29). Never-smokers or former smokers had on average 1.15 (95%CI = -1.60,-0.69) and 1.28 (95%CI = -1.78, 0.79) better frailty scores than smokers. A one-unit increment of the lifestyle score was associated with lower frailty (beta = -0.62;95%CI = -0.84,-0.53). CONCLUSIONS: The prevention of frailty can lead to lower health care costs and a higher quality of life among the growing group of elderly people. Our results emphasize that there is an urgent need for preventions that combine several lifestyle factors to improve healthy ageing. PMID- 29477950 TI - Barriers and enablers to ongoing exercise for people with chronic health conditions: Participants' perspectives following a randomized controlled trial of two interventions. AB - BACKGROUND: At present there is no clear evidence to support any one particular intervention for engaging adults with chronic health issues in ongoing exercise. An understanding of consumer perceptions and preferences is important, because low rates of exercise adherence are likely to limit any benefits obtained. OBJECTIVE: To identify and compare participants' perceptions about their own motivation, capacity and opportunity to adhere to an allocated exercise program during either a gym-based or a home-based exercise program with telephone follow up. METHOD/DESIGN: This qualitative study used convenience sampling to recruit participants (adults with chronic health issues) immediately after a randomised controlled trial comparing gym-and home-based exercise programs conducted for 12 months. Ten people, five from each intervention group, attended face-to- face semi-structured interviews at a local Community Health Service. Thematic analysis methods were used to analyse the dataset. RESULTS: Improved social interaction in the gym-based program was seen to contribute to adherence, however home-based programs were perceived as more convenient and easily integrated into daily routines. Individualized exercise prescription by a health professional with regular follow up (in person or by telephone) promoted an active practitioner participant relationship. Health coaching combined with exercise was perceived to improve self-efficacy and assisted with the removal of intrinsic and extrinsic exercise barriers. CONCLUSION: This research presented many common and different themes in participant's motivation, capacity and opportunity in sustained adherence to a gym or home-based exercise program. However, this study found no superior intervention or individual preference to improve ongoing exercise adherence. PMID- 29477951 TI - Can amputation save the hospital? The impact of the Medicare Rural Flexibility Program on demand and welfare. AB - This paper seeks to understand the impact of the Medicare Rural Hospital Flexibility (Flex) Program on hospital choice and consumer welfare for rural residents. The Flex Program created a new class of hospital, the Critical Access Hospital (CAH), which receives more generous Medicare reimbursements in return for limits on capacity and length of stay. We find that conversion to CAH status resulted in a 4.7 percent drop in inpatient admissions to participating hospitals, almost all of which was driven by factors other than capacity constraints. The Flex Program increased consumer welfare if it prevented the exit of at least 6.5 percent of randomly selected converting hospitals. PMID- 29477952 TI - The effects of immigration on NHS waiting times. AB - This paper analyzes the effects of immigration on waiting times for the National Health Service (NHS) in England. Linking administrative records from Hospital Episode Statistics (2003-2012) with immigration data drawn from the UK Labour Force Survey, we find that immigration reduced waiting times for outpatient referrals and did not have significant effects on waiting times in accident and emergency departments (A&E) and elective care. The reduction in outpatient waiting times can be explained by the fact that immigration increases natives' internal mobility and that immigrants tend to be healthier than natives who move to different areas. Finally, we find evidence that immigration increased waiting times for outpatient referrals in more deprived areas outside of London. The increase in average waiting times in more deprived areas is concentrated in the years immediately following the 2004 EU enlargement and disappears in the medium term (e.g., 3-4 years). PMID- 29477953 TI - Age moderates the association between social integration and diurnal cortisol measures. AB - Social integration is defined as the degree to which an individual participates in a broad range of social relationships. Although measures of social integration vary across studies, it is often assessed as the number of social roles (e.g., parent, friend, student, volunteer) that an individual reports actively participating in. More socially integrated individuals tend to be healthier than those less socially integrated, but the biological mechanisms through which this occurs remain unclear. One possibility is that social integration might alter the function of the hypothalamic-pituitary-adrenal axis, of which cortisol is a key product, and in turn influence a broad range of health outcomes. This study examined the association between social integration and two indices of cortisol in a community sample of 680 healthy men and women aged 18-55. Because the social roles held by younger individuals may be more numerous yet superficial than those held by older individuals, this study also tested the hypothesis that these associations could be moderated by age such that lower levels of integration would be associated with cortisol dysregulation for older but not younger individuals in our sample. Participants provided salivary cortisol samples during waking hours on three days that were used to calculate diurnal cortisol levels and slopes. Increased social integration was associated with lower cortisol AUC among older (ages 35-55) but not younger (ages 18-34) individuals in our sample. Moreover, while increased social integration was associated with steeper diurnal cortisol slopes regardless of age, this association was strongest among older individuals. Differences in health behaviors, affect, and psychological stress did not mediate these associations. The results of this study support cortisol as a candidate biological mechanism through which increased social integration is associated with better physical health among older individuals. PMID- 29477954 TI - Corticotrophin releasing factor receptor 1 antagonists prevent chronic stress induced behavioral changes and synapse loss in aged rats. AB - Mounting evidence suggests that chronic stress can alter brain structure and function and promote the development of neuropsychiatric disorders, such as depression and Alzheimer's disease. Although the results of several studies have indicated that aged brains are more vulnerable to chronic stress, it remains unknown whether antagonists of a key stress regulator, the corticotrophin releasing factor receptor 1 (CRF1), can prevent stress-induced anxiety and memory deficits in animal models. In this study, we evaluated the potential benefits of two CRF1 antagonists, R121919 and antalarmin, for preventing stress-induced anxiety-related behavioral and memory deficits and neurodegeneration in aged rats. We stressed rats using isolation-restraint for 3 months starting from the 18 months of age. Subsets of animals were administrated either R121919 or antalarmin through food chow for 3 months, followed by a series of behavioral, biochemical and morphological analyses. We found that stressed aged rats displayed body weight losses and increased corticosterone levels, as well as anxiety-related behaviors and memory deficits. Additionally, chronic stress induced a loss of cortical dendritic spines and synapses. However, R121919 and antalarmin both prevented stress-induced behavioral changes including anxiety related behaviors and memory deficits and prevented synapse loss, perhaps through reversing HPA axis dysfunction. These results suggest that CRF1 antagonists may hold promise as a potential therapy for preventing stress-induced anxiety and memory deficits in aged individuals. PMID- 29477956 TI - An (un)desirable trade of harms? How elite athletes might react to medically supervised 'doping' and their considerations of side-effects in this situation. AB - BACKGROUND: The zero-tolerance approach to doping in sport has long been criticised. Legalising 'doping' under medical supervision has been proposed as a better way of protecting both athletes' health and fair competition. This paper investigates how elite athletes might react if specific doping substances were permitted under medical supervision and explore athletes' considerations about side-effects in this situation. The results are interpreted using a framework, which views elite sport as an exceptional and risky working environment. METHODS: 775 elite athletes (mean age: 21.73, SD = 5.52) representing forty sports completed a web-based questionnaire (response rate: 51%) presenting a scenario of legalised, medically supervised 'doping'. RESULTS: 58% of athletes reported an interest in one or more of the 13 proposed substances/methods. Athletes' interest in a specific product was linked to its capacity to enhance performance levels in the athletes' particular sport and depended on gender and age. 23% showed interest in either one or more of erythropoietin (EPO), anabolic-androgenic steroids (AAS), blood transfusions and/or Growth Hormone if permitted and provided under qualified medical supervision. Male speed and power sports athletes of increasing age had the highest likelihood of being interested in AAS (41%, age 36), female motor-skill sports athletes had the lowest (<1%, age 16). 59% feared side-effects. This fear kept 39% of all athletes from being interested in specific substances/methods whereas 18% declared their interest despite fearing the side-effects. CONCLUSION: Interpreting results with the understanding of sport as an exceptional and risky working environment suggests that legalising certain 'doping' substances under medical supervision would create other/new types of harms, and this 'trade-off of harms and benefits' would be undesirable considering the occupational health, working conditions and well-being of most athletes. Assessing the risks and harms produced/reduced by specific drugs when considering sport as a precarious occupation may prove useful in composing the Prohibited List and reducing drug-related harm in sport. PMID- 29477955 TI - Preconception and prenatal urinary concentrations of phenols and birth size of singleton infants born to mothers and fathers from the Environment and Reproductive Health (EARTH) study. AB - BACKGROUND: Although pregnancy concentrations of some phenols have been associated with infant size at birth, there is limited data on the effect of preconception exposure. OBJECTIVE: We aimed to examine paternal and maternal preconception and maternal prenatal urinary phenol concentrations in relation to birth weight and head circumference. METHODS: We evaluated 346 singletons born to 346 mothers and 184 fathers (184 couples) from a prospective preconception cohort of subfertile couples from the Environment and Reproductive Health (EARTH) Study in Boston, USA. We used multiple urine samples collected before the index pregnancy in both men and women to estimate mean preconception urinary benzophenone-3, triclosan, butylparaben, propylparaben, methylparaben, or ethylparaben concentrations. We also estimated mean maternal prenatal urinary phenol concentrations by averaging trimester-specific urine samples. Birth weight and head circumference were abstracted from delivery records. We estimated the association of natural log-phenol concentrations with birth outcomes using multivariable linear regression models, adjusting for known confounders. RESULTS: In adjusted models, each log-unit increase in paternal preconception benzophenone 3 concentration was associated with a 137 g increase in birth weight (95% CI: 60, 214). Additional adjustment for prenatal benzophenone-3 concentration strengthened this association. None of the maternal preconception phenol concentrations were associated with birth weight. However, maternal prenatal triclosan concentrations were associated with a 38 g decrease in birth weight (95% CI: -76, 0). Few associations were observed between phenols and head circumference except for a decrease of 0.27 cm (95% CI: -54, 0) in relation to maternal preconception methylparaben concentration. CONCLUSIONS: Although our findings should be interpreted in light of inherent study limitations, these results suggest potential evidence of associations between some paternal or maternal phenol concentrations and birth size. PMID- 29477957 TI - Effect of synergists on ivermectin resistance in field populations of Rhipicephalus (Boophilus) microplus from Punjab districts, India. AB - The status of ivermectin resistance in Rhipicephalus (Boophilus) microplus collected from various districts of the Punjab state, India was determined using larval immersion test (LIT). Regression graphs of probit mortality of larval ticks of various field isolates were plotted against log values of increasing concentrations of technical grade ivermectin for determination of slopes of mortality, lethal concentrations for 50% (LC50) and resistance factors (RF). Values for the coefficient of determination (R2) in LIT assay ranged from 0.82 to 0.98 indicating the model to be a good fit. The RF values against ivermectin ranged from 1.65 to 9.07 revealing resistance status in all the field isolates. Pre-exposure to a single pre-determined sub-lethal concentration of ATP-binding cassette transporter inhibitors (cyclosporin-A, MK571) and p-glycoprotein inhibitor (verapamil) lead to reduction in LC50 values of ivermectin in different field tick isolates. Among the various field isolates, the highest synergistic factor for MK571 and verapamil was recorded in the Moga isolate as 4.97 and 3.21, respectively whereas for cyclosporin-A, the highest value was recorded in the Mansa isolate as 2.81. Among the three synergists used in the current study, MK571 caused the highest increase in toxicity against ivermectin in the field ticks. Therefore, combination products of ivermectin with the above synergists could prolong the useful life of this drug for effective control of ticks. PMID- 29477958 TI - Evidence of multiple mechanisms of alphacypermethrin and deltamethrin resistance in ticks Rhipicephalus microplus in Benin, West Africa. AB - Ticks are obligate haematophagous arthropods, causing heavy losses in affected livestock. The objective of this study is to investigate phenotypic and genotypic resistance in Rhipicephalus microplus populations from Benin. Engorged female adult ticks were collected from cattle in two districts of Benin. Bioassays, biochemical and molecular tests were carried out on these ticks to determine the phenotypic, enzymatic and genetic status of resistance. Results of bioassays showed high resistance factors (RF > 41). The molecular tests showing the presence of the domain II mutation and absence of the domain III mutation in the voltage-gated sodium channel gene. Biochemical tests showed increased activity of esterases, multifunction oxidases and glutathione transferases in resistant samples. Genotyping the samples showed high levels of heterozygous genotypes (73.36% and 63.30%) as compared to homozygous susceptible and resistant genotypes (23.3% and 10%) respective at Samiondji and Betecoucou. A correlation between phenotype resistance and presence of the domain II mutation at the voltage gated sodium channel gene was observed suggesting that this could be associated with resistance. Target site mutation and metabolic detoxification are mechanisms of resistance to pyrethroids in R. microplus tick populations from Benin. PMID- 29477959 TI - Molecular surveillance of novel tick-borne organisms in Madagascar's lemurs. AB - The discovery and characterization of emerging tick-borne organisms are critical for global health initiatives to improve animal and human welfare (One Health). It is possible that unknown tick-borne organisms underlie a subset of undiagnosed illness in wildlife, domesticated species, and humans. Our study lends support to the One Health concept by highlighting the prevalence of three blood-borne organisms in wild lemurs living in close proximity to domesticated species and humans. Previously, our team identified three novel, presumably tick-borne, intravascular organisms, belonging to the genera Babesia, Borrelia, and Neoehrlichia, circulating in two of Madagascar's lemur species. Here, we extend our previous observation by developing a targeted molecular surveillance approach aimed at determining the prevalence of these organisms in lemurs. Using quantitative PCR, we provide Babesia, Borrelia, and Neoehrlichia prevalence data for 76 individuals comprising four lemur species located in eastern Madagascar. Our results indicate a high prevalence (96%) of Babesia across sampled individuals with lower prevalences for Neoehrlichia (36%) and Borrelia (14.5%). In light of our results, we recommend additional studies of these tick-borne organisms to determine pathogenicity and assess zoonotic potency to other animals and humans in Madagascar. PMID- 29477960 TI - A five-year survey of tick species and identification of tick-borne bacteria in Sardinia, Italy. AB - Sardinia is a hotspot for studying tick-borne diseases in the Mediterranean region, where cases of notifiable tick-borne diseases are increasing. The aim of this study was to determine the presence of tick-borne bacteria of medical and veterinary importance in ixodid ticks collected from domestic and wild animals, humans, and vegetation from different collection sites in Sardinia. Using standard PCR and sequencing techniques, the presence of Rickettsia, Anaplasma, Ehrlichia, and Bartonella species, as well as Coxiella burnetii was evaluated. A total of 1619 ticks were morphologically identified as Rhipicephalus sanguineus sensu lato, R. bursa, R. annulatus, Dermacentor marginatus, Haemaphysalis punctata, Ha. sulcata, Hyalomma lusitanicum, H. marginatum, Ixodes festai (sometimes referred to erroneously as I. ventalloi), and Argas reflexus. Results indicated the presence of several circulating pathogens in Sardinian ticks. DNA of Rickettsia species was detected in 58 out of 1619 (4%) belonging to R. sanguineus s.l., D. marginatus, Ha. punctata, H. marginatum, and I. festai species. Ehrlichia canis DNA was detected in 33 out of 1619 ticks (2%) belonging to R. sanguineus s.l., R. bursa, and Ha. punctata species. A total of 61 out of 1619 (4%) ticks (R. sanguineus s. l., R. bursa, Ha. punctata, and I. festai) tested positive for Anaplasma spp. Coxiella burnetii was detected in 21 out of 1619 (1%) ticks belonging to R. sanguineus s.l., R. bursa, R. annulatus, and H. marginatum species. Five R. sanguineus s.l. and one R. bursa ticks were positive for the presence of Bartonella sp. 16S rRNA gene. Our findings expand the knowledge on tick-borne microorganism repertoires and tick distribution in Sardinia. Tick distribution should be monitored for effective control of these arthropods and the infections they transmit. PMID- 29477961 TI - Influences of knee osteoarthritis and walking difficulty on knee kinematics and kinetics. AB - BACKGROUND: Self-reported walking difficulty is a problem among patients with knee osteoarthritis (OA), however, these patients have never been studied as a subgroup population. OBJECTIVE: The purpose of this study is to examine known knee OA gait mechanics among those with knee OA, with (Diff) and without (NoDiff) self-reported walking difficulty, as compared to age- and sex-matched controls without knee OA. METHODS: A total of 39 subjects in three groups of 13 individuals walked at a controlled gait speed during instrumented gait analysis. Gait mechanics were compared between a priori determined groups using the independent t-test. RESULTS: The results of the study found that among those with knee OA, knee excursion angles were not significantly different between the Diff and NoDiff groups. Whereas, external knee moments were significantly different between the Diff and NoDiff groups but not between the NoDiff and the control groups. The lack of difference between the NoDiff and control groups were especially interesting because of the moderate to severe OA in the NoDiff group. Therefore, the findings of this study suggest the importance of considering self reported walking difficulty among those with knee OA. Perhaps patients with knee OA-related walking difficulties use alternative gait parameters that may need to be clinically addressed. Strengths of the study included a matched design and controlled walking speed, whereas limitations were the small sample size and cross-sectional design. CONCLUSIONS: Given the relationships found among self reported walking difficulty, OA presence, and gait parameters, addressing gait parameters specifically related to walking difficulty may be indicated in this sub-group knee OA population. PMID- 29477962 TI - Teaching respectful maternity care using an intellectual partnership model in Tanzania. AB - OBJECTIVE: to develop and deliver a two-day Respectful Maternity Care workshop for midwives using Intellectual Partnership Model principles SETTING: rural Tanzania BACKGROUND: respectful Maternity Care is an objective, measurable indicator of quality maternal newborn care INTERVENTIONS: using the Intellectual Partnership Model, educators facilitated cocreation of solutions alongside learners for complex ethical and logistic problems in the workplace FINDINGS: the mean scores on a 10-item multiple choice test increased by 20% on average following completion of the interventions; however 2-year certificate learners were less prepared for critical thinking work and social innovations than those midwives who had 3 or 4 year formal training KEY CONCLUSIONS: the implementation of the Intellectual Partnership Model revealed that midwife learners were creative, innovative, context specific in their social innovation creations related to Respectful Maternity Care when supported by respectful facilitators. IMPLICATIONS FOR PRACTICE: the Intellectual Partnership Model should be considered along with problem-based learning in the Global South, for pre and post-service education. PMID- 29477963 TI - Lived experiences of Asian fathers during the early postpartum period: Insights from qualitative inquiry. AB - OBJECTIVE: this study aims to understand fathers' expectations, needs, and experiences in infant care during the early postpartum period in Singapore. DESIGN: a descriptive qualitative study design was adopted. SETTING: the study was conducted in a tertiary public hospital in Singapore. PARTICIPANTS: fifty participants (first-time as well as experienced fathers) were recruited from postnatal wards of a public hospital. FINDINGS: thematic analysis was used to analyze the interviews data. Four main themes emerged from the analysis: (1) support system of fathers, (2) paternal involvement in childcare, (3) challenges of fatherhood, and (4) recommendations by fathers. KEY CONCLUSION: this study found that the postpartum period is a stressful period for both first-time and experienced fathers. Fathers desired to be involved but were hindered in many ways, such as maternal gatekeeping, work commitments, and a lack of infant care skills. Experienced fathers faced difficulty in assimilating older children with the newborn. IMPLICATIONS FOR PRACTICE: fathers' needs to be involved in the infant and maternal care activities in the postpartum period. Necessary help from healthcare professionals and policymakers are needed for fathers to assimilate to fatherhood. PMID- 29477965 TI - Image features dependant correlation-weighting function for efficient PRNU based source camera identification. AB - For source camera identification (SCI), photo response non-uniformity (PRNU) has been widely used as the fingerprint of the camera. The PRNU is extracted from the image by applying a de-noising filter then taking the difference between the original image and the de-noised image. However, it is observed that intensity based features and high-frequency details (edges and texture) of the image, effect quality of the extracted PRNU. This effects correlation calculation and creates problems in SCI. For solving this problem, we propose a weighting function based on image features. We have experimentally identified image features (intensity and high-frequency contents) effect on the estimated PRNU, and then develop a weighting function which gives higher weights to image regions which give reliable PRNU and at the same point it gives comparatively less weights to the image regions which do not give reliable PRNU. Experimental results show that the proposed weighting function is able to improve the accuracy of SCI up to a great extent. PMID- 29477964 TI - Visual Function Metrics in Early and Intermediate Dry Age-related Macular Degeneration for Use as Clinical Trial Endpoints. AB - PURPOSE: To evaluate and quantify visual function metrics to be used as endpoints of age-related macular degeneration (AMD) stages and visual acuity (VA) loss in patients with early and intermediate AMD. DESIGN: Cross-sectional analysis of baseline data from a prospective study. METHODS: One hundred and one patients were enrolled at Duke Eye Center: 80 patients with early AMD (Age-Related Eye Disease Study [AREDS] stage 2 [n = 33] and intermediate stage 3 [n = 47]) and 21 age-matched, normal controls. A dilated retinal examination, macular pigment optical density measurements, and several functional assessments (best-corrected visual acuity, macular integrity assessment mesopic microperimety, dark adaptometry, low-luminance visual acuity [LLVA] [standard using a log 2.0 neutral density filter and computerized method], and cone contrast test [CCT]) were performed. Low-luminance deficit (LLD) was defined as the difference in numbers of letters read at standard vs low luminance. Group comparisons were performed to evaluate differences between the control and the early and intermediate AMD groups using 2-sided significance tests. RESULTS: Functional measures that significantly distinguished between normal and intermediate AMD were standard and computerized (0.5 cd/m2) LLVA, percent reduced threshold and average threshold on microperimetry, CCTs, and rod intercept on dark adaptation (P < .05). The intermediate group demonstrated deficits in microperimetry reduced threshhold, computerized LLD2, and dark adaptation (P < .05) relative to early AMD. CONCLUSIONS: Our study suggests that LLVA, microperimetry, CCT, and dark adaptation may serve as functional measures differentiating early-to-intermediate stages of dry AMD. PMID- 29477966 TI - The Mastery Matrix for Integration Praxis: The development of a rubric for integration practice in addressing weight-related public health problems. AB - In response to the limitations of siloed weight-related intervention approaches, scholars have called for greater integration that is intentional, strategic, and thoughtful between researchers, health care clinicians, community members, and policy makers as a way to more effectively address weight and weight-related (e.g., obesity, diabetes, cardiovascular disease, cancer) public health problems. The Mastery Matrix for Integration Praxis was developed by the Healthy Eating and Activity across the Lifespan (HEAL) team in 2017 to advance the science and praxis of integration across the domains of research, clinical practice, community, and policy to address weight-related public health problems. Integrator functions were identified and developmental stages were created to generate a rubric for measuring mastery of integration. Creating a means to systematically define and evaluate integration praxis and expertise will allow for more individuals and teams to master integration in order to work towards promoting a culture of health. PMID- 29477967 TI - Dietary patterns and risk of advanced colorectal neoplasms: A large population based screening study in Germany. AB - Specific components of the diet such as red and processed meat have been associated with the risk of developing colorectal cancer. However, evidence on the association of dietary patterns with colorectal neoplasms is sparse. The aim of this study was to analyze the association of dietary patterns with prevalence of advanced colorectal neoplasms among older adults in Germany. A cross-sectional study was conducted among participants of screening colonoscopy in Saarland, Germany, who were enrolled in the KolosSal study (Effektivitat der Fruherkennungs Koloskopie: eine Saarland-weite Studie) from 2005 to 2013. Information on diet and lifestyle factors was obtained through questionnaires and colonoscopy results were extracted from physicians' reports. Associations of a priori defined dietary patterns (vegetarian or adapted versions of the Healthy Eating Index [HEI] and the Dietary Approaches to Stop Hypertension [DASH] index) with the risk of advanced colorectal neoplasms were assessed by multiple logistic regression analyses with comprehensive adjustment for potential confounders. A total of 14,309 participants were included (1561 with advanced colorectal neoplasms). Healthier eating behavior was associated with lower prevalence of advanced colorectal neoplasms in a dose-response manner. Adjusted odds ratios (95% confidence intervals) comparing the highest with the lowest categories of adapted HEI and DASH were 0.61 (0.50, 0.76) and 0.70 (0.55, 0.89), respectively. No significant associations were observed for a vegetarian eating pattern (adjusted OR 0.80 (0.55, 1.17)). Healthy dietary patterns, as described by a high HEI or DASH score, but not a vegetarian diet alone, are associated with reduced risk of advanced colorectal neoplasms. PMID- 29477968 TI - Implementation of Medical Assistance in Dying: A Scoping Review of Health Care Providers' Perspectives. AB - RESEARCH AIMS: With the growing interest in Medical Assistance in Dying (MAiD), understanding health care professionals' roles and experiences in handling requests is necessary to evaluate the quality, consistency, and efficacy of current practices. This scoping review sought to map the existing literature on health care providers' perspectives of their involvement in MAiD. METHODS: A scoping review was conducted to address the following: 1) What are the roles of diverse health care professionals in the provision of MAiD? and 2) What professional challenges arise when confronted with MAiD requests? A literature search in electronic databases and gray literature sources was performed. Articles were screened, and a thematic content analysis synthesized key findings. RESULTS: After evaluating 1715 citations and 148 full-text papers, 33 articles were included. Perspectives of nurses (n = 10), physicians (n = 7), mental health providers (n = 7), pharmacists (n = 4), social workers (n = 3), and medical examiners (n = 1) were explored. Professional roles included consulting/supporting patients and/or other staff members with requests, assessing eligibility, administering/dispensing the lethal drugs, providing aftercare to bereaved relatives, and regulatory oversight. Challenges included lack of clear guidelines/protocols, role ambiguity, evaluating capacity/consent, conscientious objection, and lack of interprofessional collaboration. CONCLUSION: Evidence from various jurisdictions highlighted a need for clear guidelines and protocols that define each profession's role, scope of practice, and legal boundaries for MAiD. Comprehensive models of care that incorporate multidisciplinary teams alongside improved clinician education may be effective to support MAiD implementation. Little is known about health care providers' perspectives in handling requests, especially outside physician practice and nursing. PMID- 29477970 TI - Weight bias internalization across weight categories among school-aged children. Validation of the Weight Bias Internalization Scale for Children. AB - Anti-fat bias is widespread and is linked to the internalization of weight bias and psychosocial problems. The purpose of this study was to examine the internalization of weight bias among children across weight categories and to evaluate the psychometric properties of the Weight Bias Internalization Scale for Children (WBIS-C). Data were collected from 1484 primary school children and their parents. WBIS-C demonstrated good internal consistency (alpha = .86) after exclusion of Item 1. The unitary factor structure was supported using exploratory and confirmatory factor analyses (factorial validity). Girls and overweight children reported higher WBIS-C scores in comparison to boys and non-overweight peers (known-groups validity). Convergent validity was shown by significant correlations with psychosocial problems. Internalization of weight bias explained additional variance in different indicators of psychosocial well-being. The results suggest that the WBIS-C is a psychometrically sound and informative tool to assess weight bias internalization among children. PMID- 29477969 TI - Humoral immune responses to infection: common mechanisms and unique strategies to combat pathogen immune evasion tactics. AB - Humoral immune responses are crucial for protection against invading pathogens and are the underlying mechanism of protection for most successful vaccines. Our understanding of how humoral immunity develops is largely based on animal models utilizing experimental immunization systems. While these studies have made enormous progress for the field and have defined many of the fundamental principles of B cell differentiation and function, we are only now beginning to appreciate the complexities of humoral immune responses induced by infection. Co evolution of the adaptive immune system and the pathogenic world has created a diverse array of B cell responses to infections, with both shared and unique strategies. In this review, we consider the common mechanisms that regulate the development of humoral immune responses during infection and highlight recent findings demonstrating the evolution of unique strategies used by either host or pathogen for survival. PMID- 29477971 TI - In vitro uptake of oligomannose-coated liposomes leads to differentiation of inflammatory monocytes into mature antigen-presenting cells that can activate T cells. AB - Oligomannose-coated liposomes (OMLs), containing entrapped antigens, serve as effective antigen delivery vehicles and as a novel adjuvant to induce antigen specific cellular immune responses. However, in vitro activation of antigen presenting cells (APCs) by OMLs has not yet been demonstrated. In this paper, we found that OMLs can deliver the antigens and the stimulatory signals into inflammatory monocytes in vitro, leading to differentiation of the cells to mature APCs. When OMLs were co-cultured with peripheral blood mononuclear cells from C57BL/6 mice in the presence of mouse serum, OMLs were preferentially incorporated into both Ly6Chigh monocytes and Ly6Clow monocytes, which are referred to as murine inflammatory and resident monocytes, respectively. The expression of CD11c, CD80, CD86, CCR7, and MHC class II on the Ly6Chigh monocytes was significantly enhanced during the 24 h after OML uptake, whereas upregulation of these molecules on the Ly6Clow monocytes was limited. In addition, the antigenic peptide of OVA encased in OMLs was presented on MHC class I of only Ly6Chigh monocytes. Furthermore, OVA-encasing OML-ingesting monocytes can activate CD8+ T cells from OT-1 mice, suggesting that antigens encapsulated in OMLs were cross-presented in inflammatory monocytes. Adoptive transfer of the monocytes that engulf OVA-encasing OMLs led to induction of an antigen-specific Th1 immune response in mice. Taken together, mature APCs can be generated from inflammatory monocytes in peripheral blood by ex vivo treatment of the cells with OMLs without any additional stimuli. PMID- 29477973 TI - Mechanical function of the left atrium is improved with epicardial ligation of the left atrial appendage: Insights from the LAFIT-LARIAT Registry. AB - BACKGROUND: Left atrial (LA) strain (epsilon) and epsilon rate (SR) analysis by 2 dimensional speckle tracking echocardiography is a novel method for functional assessment of the LA. OBJECTIVE: The purpose of this study was to determine the impact of left atrial appendage (LAA) exclusion by Lariat epicardial ligation on mechanical function of the LA by performing epsilon and SR analysis before and after the procedure. METHODS: A total of 66 patients who underwent successful LAA exclusion were included in the study. Of these 66 patients, 32 had adequate paired data for epsilon and SR analysis. SR during ventricular systole (LA-SRs) represents LA reservoir function, and SR during early ventricular diastole (LA SRe) represents LA conduit function. epsilon and SR were determined from apical 4 and 2-chamber views using the electrocardiographic QRS as a reference point. LA volume index as surrogate for LA remodeling was measured from apical views. RESULTS: Mean patient age was 70 +/- 9.2 years. LAA ligation resulted in improved reservoir function (LA-SRs: pre 0.72, confidence interval [CI] 0.63-0.83 vs post 0.81, CI 0.73-0.98; P = .043) and conduit function (LA-SRe: pre 0.74, CI 0.67 0.99 vs post 0.89, CI 0.82-1.07; P = .025). LA volume index improved significantly with the Lariat (pre 35.4, CI 29.4-37.2 vs post 29.2, CI 28.2-35.9; P <.023). CONCLUSION: LAA exclusion seems to improve mechanical function of the LA and results in reverse LA remodeling. PMID- 29477972 TI - Regulation of fetal hemoglobin expression during hematopoietic stem cell development and its importance in bone metabolism and osteoporosis. AB - We have shown that an altered tissue redox environment in mice lacking either murine beta Hemoglobin major (HgbbetamaKO) or minor (HgbbetamiKO) regulates inflammation. The REDOX environment in marrow stem cell niches also control differentiation pathways. We investigated osteoclastogenesis (OC)/osteoblastogenesis (OB), in bone cultures derived from untreated or FSLE treated WT, HgbbetamaKO or HgbbetamiKO mice. Marrow mesenchymal cells from 10d pre-cultures were incubated on an osteogenic matrix for 21d prior to analysis of inflammatory cytokine release into culture supernatants, and relative OC:OB using (TRAP:BSP, RANKL:OPG) mRNA expression ratios and TRAP or Von Kossa staining. Cells from WT and HgbbetamaKO mice show decreased IL-1beta,TNFalpha and IL-6 production and enhanced osteoblastogenesis with altered mRNA expression ratios and increased bone nodules (Von Kossa staining) in vitro after in vivo stimulation of mRNA expression of fetal Hgb genes (Hgbepsilon and Hgbbetami) by a fetal liver extract (FSLE). Marrow from HgbbetamiKO showed enhanced cytokine release and preferential enhanced osteoclastogenesis relative to similar cells from WT or HgbbetamaKO mice, with no increased osteoblastogenesis after mouse treatment with FSLE. Pre-treatment of WT or HgbbetamaKO, but not HgbbetamiKO mice, with other molecules (rapamycin; hydroxyurea) which increase expression of fetal Hgb genes also augmented osteoblastogenesis and decreased cytokine production in cells differentiating in vitro. Infusion of rabbit anti- Hgbepsilon or anti- Hgbbetami, but not anti-Hgbalpha or anti- Hgbbetama into WT mice from day 13 gestation for 3 weeks led to attenuated osteoblastogenesis in cultured cells. We conclude that increased fetal hemoglobin expression, or use of agents which improve fetal hemoglobin expression, increases osteoblast bone differentiation in association with decreased inflammatory cytokine release. PMID- 29477974 TI - Does the CHA2DS2-VASc score reliably predict atrial arrhythmias? Analysis of a nationwide database of remote monitoring data transmitted daily from cardiac implantable electronic devices. AB - BACKGROUND: CHA2DS2-VASc is a validated score for predicting stroke in patients with atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to assess whether the CHA2DS2-VASc score can predict new-onset AF in a cohort of patients with a cardiac implantable electronic device (CIED) followed with remote monitoring. METHODS: Using the database of the Home Monitoring Expert Alliance project, we selected 2410 patients with no documented AF who had received a CIED with diagnostics on atrial high rate episodes (AHREs). The primary endpoint was time to first day with cumulative AHRE burden >=15 minutes, 5 hours, 24 hours, and >=7 consecutive days. RESULTS: During a median duration of 24.1(11.5-42.9) months, the incidence of AHRE increased with increasing CHA2DS2-VASc. At 6 years, occurrence of >=15-minute AHRE was 80.2% (CHA2DS2-VASc <=1) vs 93.7% (CHA2DS2 VASc >=5), whereas >=5-hour AHRE incidence was 68.4% (CHA2DS2-VASc <=1) vs 92.5% (CHA2DS2-VASc >=5). Occurrence of >=24-hour and >=7-day AHREs also increased with increasing CHA2DS2-VASc: 9.1% and 3.9% (CHA2DS2-VASc <=1) vs 40.4% and 28.7% (CHA2DS2-VASc >=5), respectively. Adjusted hazard ratio for unitary CHA2DS2-VASc increase ranged from 1.09 (confidence interval 1.04-1.14; P <.001) with AHRE burden >=15 minutes to 1.26 (confidence interval 1.11-1.42; P <.001) with AHRE burden >=7 days. At receiver operating curve analysis, CHA2DS2-VASc >=2 was estimated to predict persistent forms of AHREs with 95.8% sensitivity but 11.7% specificity at 3 years. CHA2DS2-VASc >=5 had 77.0% specificity but 34.6% sensitivity. CONCLUSION: In a CIED population with no previous diagnosis of clinical AF, AHRE incidence increased with increasing CHA2DS2-VASc score. The association was stronger with longer AHREs, but the accuracy of CHA2DS2-VASc as AHRE predictor was moderate. PMID- 29477975 TI - Cardiac electrical dyssynchrony is accurately detected by noninvasive electrocardiographic imaging. AB - BACKGROUND: Poor identification of electrical dyssynchrony is postulated to be a major factor contributing to the low success rate for cardiac resynchronization therapy. OBJECTIVE: The purpose of this study was to evaluate the sensitivity of body surface mapping and electrocardiographic imaging (ECGi) to detect electrical dyssynchrony noninvasively. METHODS: Langendorff-perfused pig hearts (n = 11) were suspended in a human torso-shaped tank, with left bundle branch block (LBBB) induced through ablation. Recordings were taken simultaneously from a 108 electrode epicardial sock and 128 electrodes embedded in the tank surface during sinus rhythm and ventricular pacing. Computed tomography provided electrode and heart positions in the tank. Epicardial unipolar electrograms were reconstructed from torso potentials using ECGi. Dyssynchrony markers from torso potentials (eg, QRS duration) or ECGi (total activation time, interventricular delay [D-LR], and intraventricular markers) were correlated with those recorded from the sock. RESULTS: LBBB was induced (n = 8), and sock-derived activation maps demonstrated interventricular dyssynchrony (D-LR and total activation time) in all cases (P < .05) and intraventricular dyssynchrony for complete LBBB (P < .05) compared to normal sinus rhythm. Only D-LR returned to normal with biventricular pacing (P = .1). Torso markers increased with large degrees of dyssynchrony, and no reduction was seen during biventricular pacing (P > .05). Although ECGi-derived markers were significantly lower than recorded (P < .05), there was a significant strong linear relationship between ECGi and recorded values. ECGi correctly diagnosed electrical dyssynchrony and interventricular resynchronization in all cases. The latest site of activation was identified to 9.1 +/- 0.6 mm by ECGi. CONCLUSION: ECGi reliably and accurately detects electrical dyssynchrony, resynchronization by biventricular pacing, and the site of latest activation, providing more information than do body surface potentials. PMID- 29477976 TI - Tension pneumopericardium after pericardiocentesis: Useful echocardiographic obscured heart sign and effective postural change during air aspiration. PMID- 29477977 TI - Formation of Cys-heme cross-link in K42C myoglobin under reductive conditions with molecular oxygen. AB - The structure and function of heme proteins are regulated by diverse post translational modifications including heme-protein cross-links, with the underlying mechanisms not well understood. In this study, we introduced a Cys (K42C) close to the heme 4-vinyl group in sperm whale myoglobin (Mb) and solved its X-ray crystal structure. Interestingly, we found that K42C Mb can partially form a Cys-heme cross-link (termed K42C Mb-X) under dithiothreitol-induced reductive conditions in presence of O2, as suggested by guanidine hydrochloride induced unfolding and heme extraction studies. Mass spectrometry (MS) studies, together with trypsin digestion studies, further indicated that a thioether bond is formed between Cys42 and the heme 4-vinyl group with an additional mass of 16 Da, likely due to hydroxylation of the alpha-carbon. We then proposed a plausible mechanism for the formation of the novel Cys-heme cross-link based on MS, kinetic UV-vis and electron paramagnetic resonance (EPR) studies. Moreover, the Cys-heme cross-link was shown to fine-tune the protein reactivity toward activation of H2O2. This study provides valuable insights into the post-translational modification of heme proteins, and also suggests that the Cys-heme cross-link can be induced to form in vitro, making it useful for design of new heme proteins with a non-dissociable heme and improved functions. PMID- 29477978 TI - XRCC1 phosphorylation affects aprataxin recruitment and DNA deadenylation activity. AB - Aprataxin (APTX) is a DNA-adenylate hydrolase that removes 5'-AMP blocking groups from abortive ligation repair intermediates. XRCC1, a multi-domain protein without catalytic activity, interacts with a number of known repair proteins including APTX, modulating and coordinating the various steps of DNA repair. CK2 phosphorylation of XRCC1 is thought to be crucial for its interaction with the FHA domain of APTX. In light of conflicting reports, the importance of XRCC1 phosphorylation and APTX function is not clear. In this study, a phosphorylation mutant of XRCC1 designed to eliminate APTX binding was stably expressed in Xrcc1 /- cells. Analysis of APTX-GFP accumulation at micro-irradiation damage confirmed that phosphorylated XRCC1 is required for APTX recruitment. APTX-mediated DNA deadenylation activity (i.e., 5'-AMP removal) was measured in extracts of cells expressing wild-type XRCC1 or the XRCC1 phosphorylation mutant, and compared with activity in APTX-deficient and APTX-complemented human cells. APTX activity was lower in extracts from Xrcc1-/- and XRCC1 phosphorylation mutant cells compared to the robust activity in extract from wild-type XRCC1 expressing cells. Taken together, results verify that interaction with phosphorylated XRCC1 is a requirement for significant APTX recruitment to cellular DNA damage and enzymatic activity in cell extracts. PMID- 29477979 TI - Functional ultrasound neuroimaging: a review of the preclinical and clinical state of the art. AB - In the last decade, ultrasound imaging has gained new capabilities and produced new insights in the field of neuroscience. The development of new concepts, such as ultrafast ultrasound, has enhanced Doppler sensitivity by orders of magnitude and has paved the way for ultrasonic functional neuroimaging. In this review, we position ultrasound in the field of neuroimaging and discuss how it complements current tools available to neurobiologists and clinicians. PMID- 29477980 TI - Sodium-potassium pump assessment by submaximal electrical nerve stimulation. AB - OBJECTIVE: Sodium-potassium pump dysfunction in peripheral nerve is usually assessed by determining axonal hyperpolarization following maximal voluntary contraction (MVC) or maximal electrical nerve stimulation. As MVC may be unreliable and maximal electrical stimulation too painful, we assessed if hyperpolarization can also be induced by submaximal electrical nerve stimulation. METHODS: In 8 healthy volunteers different submaximal electrical stimulus trains were given to the median nerve at the wrist, followed by 5 min assessment of thresholds for compound muscle action potentials of 20%, 40% or 60% of maximal. RESULTS: Threshold increase after submaximal electrical nerve stimulation was most prominent after an 8 Hz train of at least 5 min duration evoking submaximal CMAPs of 60%. It induced minimal discomfort and was not painful. Threshold increase after MVC was not significantly higher than this stimulus train. CONCLUSIONS: Submaximal electrical stimulation evokes activity dependent hyperpolarization in healthy test subjects without causing significant discomfort. SIGNIFICANCE: Sodium-potassium pump function may be assessed using submaximal electrical stimulation. PMID- 29477981 TI - A novel, fast and efficient single-sensor automatic sleep-stage classification based on complementary cross-frequency coupling estimates. AB - OBJECTIVE: Limitations of the manual scoring of polysomnograms, which include data from electroencephalogram (EEG), electro-oculogram (EOG), electrocardiogram (ECG) and electromyogram (EMG) channels have long been recognized. Manual staging is resource intensive and time consuming, and thus considerable effort must be spent to ensure inter-rater reliability. As a result, there is a great interest in techniques based on signal processing and machine learning for a completely Automatic Sleep Stage Classification (ASSC). METHODS: In this paper, we present a single-EEG-sensor ASSC technique based on the dynamic reconfiguration of different aspects of cross-frequency coupling (CFC) estimated between predefined frequency pairs over 5 s epoch lengths. The proposed analytic scheme is demonstrated using the PhysioNet Sleep European Data Format (EDF) Database with repeat recordings from 20 healthy young adults. We validate our methodology in a second sleep dataset. RESULTS: We achieved very high classification sensitivity, specificity and accuracy of 96.2 +/- 2.2%, 94.2 +/- 2.3%, and 94.4 +/- 2.2% across 20 folds, respectively, and also a high mean F1 score (92%, range 90-94%) when a multi-class Naive Bayes classifier was applied. High classification performance has been achieved also in the second sleep dataset. CONCLUSIONS: Our method outperformed the accuracy of previous studies not only on different datasets but also on the same database. SIGNIFICANCE: Single-sensor ASSC makes the entire methodology appropriate for longitudinal monitoring using wearable EEG in real-world and laboratory-oriented environments. PMID- 29477982 TI - Indemnity bonds for MBBS students: Need for a change of perspective. AB - Compulsory service programmes for MBBS students have existed for many years in India and other parts of the world. Such programmes have been referred to differently as "obligatory", "mandatory", "requisite" and "compulsory" service. Governments look at these programmes as a means to deploy and retain the health workforce even as health professionals are lost to opportunities in other countries. Though these programmes have been successful, they have been carried out by enforcement on medical students to finish a rural bond. PMID- 29477983 TI - The social value of research: interrogating the paradoxes. AB - The relation between science and society is, simply put, very complex. In the history of global bioethics, it is the Code of Nuremberg which foregrounded the acute ways in which biomedical/scientific research could (negatively) impact society; this 1947 Code became the point of reference for subsequent research concerning humans. The Code "required that medical experiments on human beings must have the potential to yield fruitful results for the good of society". The Declaration of Helsinki (DoH), 1964 reinstated this concern by stressing that "clinical research cannot be legitimately carried out unless the risks to participants are justified by the importance of the research" - invoking the idea of the "social value" of research. However, in these initial days, "social value" of research was interpreted more in terms of the moral balance of research, a balance to ensure that the benefits of research unambiguously outweighed its risks as far as its participants were concerned. PMID- 29477984 TI - The HIV Act - better late than never. AB - Although over 15 years in the making, the HIV legislation has recently been passed in India. This Act is unique in many respects, and hopefully a precursor to broader health sector legislation. The process of law making in this instance included a robust consultative process with civil society and other stakeholders involved with HIV. Some of the unique aspects of the Act, as it was eventually passed, include an anti-discrimination provision to cover violations by the private sector, and concrete provisions to ensure informed consent while seeking HIV-related testing and treatment, and confidentiality of HIV status. However, the law fails to recognise the enhanced vulnerability to HIV that some people - sex workers, transgender people, men who have sex with men, and people who use drugs - face, which should have been addressed by extending anti-discrimination guarantees to these communities, thereby providing a legal tool to access health, employment, educational, and other sectors; while also serving public health imperatives to encourage marginalised people towards health-seeking behaviour without fear of stigma and mistreatment. Yet, at least the legislation does protect these criminalised communities from punishment when they access or are provided HIV-related services and commodities, which could otherwise be tantamount to a crime. Another drawback of the law is the diluted obligation of the State to provide antiretroviral treatment to those in need. The legislation also provides options to redress grievances, which are localised, less formal and intimidating, and more accessible than courts, thereby recognising that implementation and actualisation of rights is critical to the success of the law, and efforts to control HIV. PMID- 29477985 TI - Menstruation: a complex saga. PMID- 29477986 TI - The brand of generic prescriptions. PMID- 29477987 TI - Declarations of conflict of interest are still inadequate. AB - Declaration of conflicts of interest (COI, understood mainly as financial) in medical publications is long established. Most journals refer only to the guidelines of the International Committee of Medical Journal Editors (ICMJE) but not to those of the WAME (World Association of Medical Editors). We surveyed 17 journals and found only one (BJOG), which explicitly mentioned "religious interest" as an example of a possible COI and one other journal included "personal belief" (Journal of Obstetrics and Gynaecology of India) as a COI. Of the other 15 journals, 10 used the ICJME as their COI model. They were the general journals, NEJM, JAMA, Lancet, BMJ and JIM (Journal of Internal Medicine); the pediatric/neonatology journals Pediatrics and Journal of Pediatrics (this also mentions WAME) but not Acta Paediatrica, which mentions COPE; the obstetrics/gynaecology journals AJOG and IJOG; and the British Journal of Haematology but not Blood, which uses the American Society of Hematology's own COI model. Neither EJOG, JOG, IndianObs Gyn, nor J Obstet Gynaecol India clearly specified a COI model. Yet the ICMJE COI guidelines fail to include involvement in religious and/or secular groups which take sides on the subject being discussed, while the WAME guidelines specifically do so. Instead the ICMJE uses the vaguer phrase "intellectual beliefs". The actual ICJME COI-form does not itemise religion. To maintain their scientific credibility, medical journals must start requiring disclosure of such ties. A typical example where current ICMJE rules fall short is the ongoing heated debates over the ethics of prenatology and of physician assisted suicide. PMID- 29477988 TI - Futility and appropriateness: challenging words, important concepts. AB - The provision of healthcare is being challenged by a 'perfect storm' of forces including an increasing population with multiple comorbidities, high expectations and resource limitations, and in the background, the pre-eminence of the 'curative medical model'. Non-beneficial (futile) treatments are wasteful and costly. They have a negative impact on quality of life especially in the last year of life. Among professionals, frequent encounters with futility cause moral distress and demoralisation. The factors that drive non-beneficial treatments include personal biases, patient-related pressures and institutional imperatives. Breaking loose from the perceived necessity to deliver non-beneficial treatment is a major challenge. Curative intent should give way to appropriateness such that curative and palliative interventions are valued equally. Goals of treatment should be shaped by illness trajectory, the risk of harms as well as potential benefits and patient preferences. This strategy should be reflected in professional training and the design of acute services. PMID- 29477989 TI - Stability of ARDS subphenotypes over time in two randomised controlled trials. AB - RATIONALE: Two distinct acute respiratory distress syndrome (ARDS) subphenotypes have been identified using data obtained at time of enrolment in clinical trials; it remains unknown if these subphenotypes are durable over time. OBJECTIVE: To determine the stability of ARDS subphenotypes over time. METHODS: Secondary analysis of data from two randomised controlled trials in ARDS, the ARMA trial of lung protective ventilation (n=473; patients randomised to low tidal volumes only) and the ALVEOLI trial of low versus high positive end-expiratory pressure (n=549). Latent class analysis (LCA) and latent transition analysis (LTA) were applied to data from day 0 and day 3, independent of clinical outcomes. MEASUREMENTS AND MAIN RESULTS: In ALVEOLI, LCA indicated strong evidence of two ARDS latent classes at days 0 and 3; in ARMA, evidence of two classes was stronger at day 0 than at day 3. The clinical and biological features of these two classes were similar to those in our prior work and were largely stable over time, though class 2 demonstrated evidence of progressive organ failures by day 3, compared with class 1. In both LCA and LTA models, the majority of patients (>94%) stayed in the same class from day 0 to day 3. Clinical outcomes were statistically significantly worse in class 2 than class 1 and were more strongly associated with day 3 class assignment. CONCLUSIONS: ARDS subphenotypes are largely stable over the first 3 days of enrolment in two ARDS Network trials, suggesting that subphenotype identification may be feasible in the context of clinical trials. PMID- 29477990 TI - Incorporating polysomnography into obstructive sleep apnoea phenotyping: moving towards personalised medicine for OSA. PMID- 29477991 TI - Severe hypophosphataemia: a rare cause of postoperative muscle weakness. AB - We report a case of severe generalised muscle weakness in a 66-year-old man who underwent revision of left knee arthroplasty. On postoperative day 1, he developed non-focal muscle weakness and shortness of breath which progressed over a 6-hour period. Serum phosphorus level was severely low at 0.5 mg/dL, along with mild degree of hypokalaemia, hypocalcaemia and hypomagnesaemia. His symptoms completely resolved after emergent phosphorus replacement. The authors believe this case is of educational interest to physicians as generalised muscle weakness is an uncommon presentation of severe hypophosphataemia. In a postoperative setting, hypophosphataemia is often multifactorial, thought to result from combination of perioperative catecholamine surge, administration of saline, diuretics, glucose and antacids, poor oral intake and respiratory alkalosis secondary to pain. We report this case to raise awareness among physicians on severe phosphate imbalance as the primary aetiology for acute generalised muscle weakness and respiratory failure, especially after a surgery. PMID- 29477992 TI - Role Of Conservative Management In Emphysematous Gastritis. AB - Emphysematous gastritis (EG) is a rare disease of the stomach that is caused by gas-forming bacteria, and it can be lethal. There have been <70 reported cases in the English literature of this disease which carries a mortality rate up to 60%. Early recognition and treatment through conservative management have been a popular and successful choice in today's medicine. Studies have shown that surgical intervention does not confer a statistical benefit on mortality in this condition. We present another case of EG in a 33-year-old woman who was successfully managed conservatively. PMID- 29477993 TI - First case of acute granulomatous interstitial nephritis with immune reconstitution inflammatory syndrome in a patient with HIV coinfected with disseminated Mycobacterium kansasii. AB - Restoration of immune response by highly active antiretroviral therapy (HAART) effectively improved the overall prognosis of HIV infection. However, 25%-31.7% of patients experience paradoxical worsening of pre-existing infections or unmasking of subclinical infections after starting HAART therapy, which is termed as immune reconstitution inflammatory syndrome (IRIS). Acute granulomatous interstitial nephritis as a consequence of IRIS has never been reported with Mycobacteriumkansasiicoinfection. Here, we describe an HIV/AIDS patient coinfected with disseminated M. kansasii infection, who presented with acute kidney injury 4.5 months after initiation of HAART. The diagnostic workup revealed IRIS was the cause of acute kidney injury. Short-term course of prednisone (1 mg/kg/day) along with antimycobacterial and HAART regimen achieved significant improvement. PMID- 29477994 TI - Recurrent postinfectious glomerulonephritis: an unusual evolution compatible with C3 glomerulopathy. AB - Acute endocapillary glomerulonephritis, as its name suggests, is a one-time process, which usually resolves within weeks. However, in a small percentage of patients, the disease becomes chronic. In these cases, a deregulation in the alternative complement pathway, which can be caused by mutations or autoantibodies, has been proposed as a pathophysiological mechanism. As a result, the alternative complement pathway remains active after resolution of infection. We report a patient with two episodes of acute renal failure, both times diagnosed by renal biopsy of acute endocapillary glomerulonephritis, with slow recovery after two episodes of low-serum complement C3, haematuria and proteinuria. PMID- 29477995 TI - Postoperative epidural abscess after spinal anaesthesia for a circumcision necessitated by phimosis. AB - A 70-year-old man was admitted to our hospital for a penile circumcision due to phimosis using continuous dose spinal anaesthesia. On postoperative day 10 he came to the emergency department with a superficial abscess localised at the injection site of the spinal catheter. He was treated with intravenous antibiotics for 10 days, and the superficial abscess was incised and drained. Ten days later, the patient was readmitted to the emergency department with complaints of back pain and fever. A repeat MRI scan of his lumbar sacral area was done and showed epidural abscesses without any compression of the medulla or the myelum. The patient did not have any signs of spinal cord or nerve root compression at that time. He was treated with intravenous antibiotics with resolution of symptoms. PMID- 29477996 TI - Nail to the heart: no big deal. A rare case of post-traumatic pericarditis. AB - This is a unique case report of a 32-year-old man who presented with pneumatic nail gun injury to his right chest at work. He removed the nail and continued to work through the day. With continued chest pain, he presented to the emergency room and an echocardiogram revealed moderate-size pericardial effusion. He was managed conservatively as he was haemodynamically stable. Serial echocardiograms revealed slow resolution of the effusion over 3 days. At his 3-month follow-up appointment, there was complete resolution of his effusion. This case highlights the importance of obtaining imaging studies in penetrating chest wall injuries and utilisation of medications to prevent expected complications. PMID- 29477997 TI - A rare case of right pulmonary segmental artery dissection following pacemaker insertion. PMID- 29477998 TI - Stimming behaviour in a 4-year-old girl with autism spectrum disorder. PMID- 29477999 TI - Portomesenteric vein thrombosis following laparoscopic sleeve gastrectomy: are underlying haematological disorders the culprit? PMID- 29478000 TI - Incidental presentation of a button battery within a pharyngeal pouch: the first reported case. PMID- 29478001 TI - Attenuated form of type II mucopolysaccharidoses (Hunter syndrome): pitfalls and potential clues in diagnosis. PMID- 29478002 TI - Gunshot victimisations resulting from high-volume gunfire incidents in Minneapolis: findings and policy implications. AB - Laws restricting large ammunition magazines for semiautomatic weapons are intended to reduce firearm deaths and injuries by preventing gun attacks involving high numbers of shots. However, data on shootings from high-volume gunfire (HVG) incidents are extremely limited. This study examined gunshot victimisations resulting from HVG attacks (>10 shots fired) using police data on shootings in Minneapolis, Minnesota from January through August 2014 (n=135 to 167). Shots fired estimates were generated from police reports based on physical evidence recovered, reported gunshot victims, and accounts of witnesses and actors. HVG incidents accounted for 20%-28% of victims and were more likely to involve multiple victims. Most HVG cases seemed likely to have involved a gun with a large capacity magazine though these data were limited. Restricting large ammunition magazines may have greater potential for preventing shootings than previously estimated, but further studies of this issue are needed. PMID- 29478003 TI - I did NOT feel like this at all before the accident: do men and women report different health and life consequences of a road traffic injury? AB - BACKGROUND: Worldwide, injuries represent one of the leading causes of mortality, and nearly one-quarter of all injuries are road traffic related. In many high income countries, the burden of road traffic injuries (RTIs) has shifted from premature death to injury and disability with long-term consequences; therefore, it is important to assess the full burden of an RTI on individual lives. OBJECTIVE: To describe how men and women with minor and moderate injuries reported the consequences of an RTI on their health and lives. METHODS: The study was designed as an explorative qualitative study, in which the answers to an open ended question concerning the life and health consequences following injury were analysed using systematic text condensation. PARTICIPANTS: A total of 692 respondents with a minor or a moderate injury were included. RESULTS: The respondents reported the consequences of the crash on their health and lives according to four categories: physical consequences, psychological consequences, everyday life consequences and financial consequences. The results show that medically classified minor and moderate injuries have detrimental long-term health and life consequences. Although men and women report some similar consequences, there are substantial differences in their reported psychological and everyday life consequences following an injury. Women report travel anxiety and PTSD-like symptoms, being life altering for them compared with men, for whom these types of reports were missing. CONCLUSION: These differences emphasise the importance of considering gender-specific physical and psychological consequences following an RTI. PMID- 29478004 TI - Herpes simplex virus (HSV) encephalitis in a young man: an unusual course. AB - We present a case of cerebral venous sinus thrombosis (CVST) as a rare complication of herpes simplex virus (HSV) encephalitis. A young man with no pertinent medical history was diagnosed with HSV encephalitis. After initial treatment, he showed improvement in symptomatology until day 6 when he acutely developed new neurological deficits. An urgent MRI brain showed changes in left temporal lobe consistent with HSV encephalitis and lack of flow void in superior sagittal sinus. Subsequent magnetic resonance venography confirmed the diagnosis of superior sagittal sinus thrombosis along with thrombosis of bilateral frontoparietal cortical draining veins. Anticoagulation was immediately initiated and oral anticoagulation was continued for 1 year. He made complete recovery subsequently. Our case serves as a reminder for the treating clinicians to consider CVST in patients with HSV encephalitis who develop an unexpected new neurological deficits during early phase of appropriate treatment. PMID- 29478006 TI - Blueberry eye: acquired total anterior staphyloma. PMID- 29478005 TI - Pleuroparenchymal fibroelastosis with positive MPO-ANCA diagnosed with a CT guided percutaneous needle biopsy. AB - A 67-year-old woman was referred to our hospital because of gradually increasing dyspnoea on exertion for 6 months. Chest CT scan showed subpleural parenchymal fibrotic opacities with traction bronchiectasis in the bilateral upper lung fields. Serum rheumatoid factor and myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) were positive. There was no evident reason to suspect connective tissue disease such as ANCA-associated vasculitis or rheumatoid arthritis. We performed a CT-guided percutaneous needle biopsy of the subpleural lesion that showed slight uptake on the fluorodeoxyglucose-positron emission tomography (FDG-PET) CT scan. This specimen showed subpleural fibrosis as evidenced by an abnormal increase of elastic tissue and minimal collagen deposition, which indicated pleuroparenchymal fibroelastosis (PPFE). Although PPFE can be associated with a variety of causes, its association with MPO-ANCA is unknown. A CT-guided transthoracic lung biopsy caused no adverse events and was useful in the diagnosis of PPFE in our patient. PMID- 29478007 TI - Maternal veterinary occupation and adverse birth outcomes in Washington State, 1992-2014: a population-based retrospective cohort study. AB - OBJECTIVE: Women in veterinary occupations are routinely exposed to potential reproductive hazards, yet research into their birth outcomes is limited. We conducted a population-based retrospective cohort study of the association between maternal veterinary occupation and adverse birth outcomes. METHODS: Using Washington State birth certificate, fetal death certificate and hospital discharge data from 1992 to 2014, we compared birth outcomes of mothers in veterinary professions (n=2662) with those in mothers in dental professions (n=10 653) and other employed mothers (n=8082). Relative risks (RRs) and 95% CIs were estimated using log binomial regression. Outcomes studied were premature birth (<37 weeks), small for gestational age (SGA), malformations and fetal death (death at >=20 weeks gestation). Subgroup analyses evaluated risk of these outcomes among veterinarians and veterinary support staff separately. RESULTS: While no statistically significant associations were found, we noted a trend for SGA births in all veterinary mothers compared with dental mothers (RR=1.16, 95% CI 0.99 to 1.36) and in veterinarians compared with other employed mothers (RR=1.37, 95% CI 0.96 to 1.96). Positive but non-significant association was found for malformations among children of veterinary support staff. CONCLUSIONS: These results support the need for further study of the association between veterinary occupation and adverse birth outcomes. PMID- 29478008 TI - Vitamin D status in prepubertal children with isolated idiopathic growth hormone deficiency: effect of growth hormone therapy. AB - Few studies, and with controversial results, analyzed vitamin D status in children before and after growth hormone (GH) treatment. Thus, we aimed to assess vitamin D status in prepubertal children with idiopathic growth hormone deficiency (GHD), and to evaluate the effect of GHD and GH treatment on vitamin D levels. Fifty prepubertal children with isolated GHD were compared with 50 controls. All were subjected to history, anthropometric assessment and measurement of 25 hydroxyvitamin D (25(OH)D), serum calcium, phosphorous, alkaline phosphatase and parathyroid hormone (PTH) at diagnosis and 1 year after GH therapy. Serum 25(OH)D levels <30 ng/mL and 20 ng/mL were defined as vitamin D insufficiency and deficiency, respectively. 25(OH)D was lower in cases than controls. Forty per cent of children with GHD were 25(OH)D insufficient and 44% deficient, while 16% were sufficient at baseline. There was a positive correlation between 25(OH)D and peak GH levels. Peak GH was a significant predictor of 25(OH)D levels. After 1 year of GH therapy, 25(OH)D increased (18.42+/-5.41 vs 34.5+/-10.1 ng/mL; P<0.001). Overall, 22% of cases remained insufficient and 24% deficient, with an increase in prevalence of children with normal levels (54%; P<0.001). 25(OH) correlated negatively with PTH (r=-0.71, P=0.01). In conclusion, hypovitaminosis D is prevalent in children with GHD and significantly improved 1 year after GH therapy. 25(OH)D should be assessed in children with GHD at diagnosis and during follow-up. PMID- 29478009 TI - New insights into SERCA2a gene therapy in heart failure: pay attention to the negative effects of B-type natriuretic peptides. AB - Sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a) is a target of interest in gene therapy for heart failure with reduced ejection fraction (HFrEF). However, the results of an important clinical study, the Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) trial, were controversial. Promising results were observed in the CUPID 1 trial, but the results of the CUPID 2 trial were negative. The factors that caused the controversial results remain unclear. Importantly, enrolled patients were required to have a higher plasma level of B-type natriuretic peptide (BNP) in the CUPID 2 trial. Moreover, BNP was shown to inhibit SERCA2a expression. Therefore, it is possible that high BNP levels interact with treatment effects of SERCA2a gene transfer and accordingly lead to negative results of CUPID 2 trial. From this point of view, effects of SERCA2a gene therapy should be explored in heart failure with preserved ejection fraction, which is characterised by lower BNP levels compared with HFrEF. In this review, we summarise the current knowledge of SERCA2a gene therapy for heart failure, analyse potential interaction between BNP levels and therapeutic effects of SERCA2a gene transfer and provide directions for future research to solve the identified problems. PMID- 29478010 TI - Insulin analogues use in pregnancy among women with pregestational diabetes mellitus and risk of congenital anomaly: a retrospective population-based cohort study. AB - OBJECTIVES: To evaluate the risk of major congenital anomaly associated with first-trimester exposure to insulin analogues compared with human insulin in offspring of women with pregestational diabetes. DESIGN AND SETTING: A population based cohort of women with pregestational diabetes (n=1661) who delivered between 1996 and 2012 was established retrospectively from seven European regions covered bythe European Surveillance of Congenital Anomalies (EUROCAT) congenital anomaly registries. PRIMARY OUTCOME MEASURES: The risk of non-chromosomal major congenital anomaly in live births, fetal deaths and terminations for a fetal anomaly exposed to insulin analogues in the first trimester of pregnancy was compared with the risk in those exposed to human insulin only. RESULTS: During the first trimester, 870 fetuses (52.4%) were exposed to human insulin only, 397 fetuses (23.9%) to insulin analogues only and 394 fetuses (23.7%) to both human insulin and insulin analogues. The risk of major congenital anomaly in fetuses exposed to insulin analogues only was lower than those exposed to human insulin only; the relative risk adjusted for glycaemic control and region was 0.56 (95% CI 0.29 to 1.06). The significantly lower risk related to exposure of insulin analogues only was observed in congenital heart defects: adjusted relative risk 0.14 (95% CI 0.03 to 0.62). CONCLUSIONS: In this retrospective population-based cohort study across Europe, first-trimester exposure to insulin analogues did not increase the risk of major congenital anomaly compared with exposure to human insulin. A possible lower risk of congenital heart defects among fetuses exposed to insulin analogues only deserves further investigation. PMID- 29478011 TI - SecurAstaP trial: securement with SecurAcath versus StatLock for peripherally inserted central catheters, a randomised open trial. AB - OBJECTIVES: To assess the effect on needed nursing time for dressing change. DESIGN, SETTING, PARTICIPANTS: A parallel-group, open-label, randomised controlled trial in patients who are in need for a peripherally inserted central catheter insertion in one teaching hospital in Belgium. The follow-up lasted 180 days or until catheter removal, whatever came first. A computer generated table was used to allocate devices. Randomised patients were 105 adults (StatLock, n=53; SecurAcath, n=52) and primary analysis was based on all patients (n=92) with time measurements (StatLock, n=43; SecurAcath, n=49). INTERVENTIONS: StatLock which has to be changed weekly versus SecurAcath which could remain in place for the complete catheter dwell time. MAIN OUTCOME MEASURE: Needed time for the dressing change at each dressing change (SecurAcath) or at each dressing change combined with the change of the securement device (StatLock). RESULTS: Median time needed for dressing change was 7.3 min (95% CI 6.4 min to 8.3 min) in the StatLock group and in the SecurAcath group 4.3 min (95% CI 3.8 min to 4.9 min) (P<0.0001). The time in the SecurAcath group was reduced with 41% (95% CI 29% to 51%). Incidence rates of migration, dislodgement and catheter-related bloodstream infection were comparable across groups. Pain scores were higher with SecurAcath than with StatLock at insertion (P=0.02) and at removal (P<0.001) and comparable during dressing change (P=0.38) and during dwell time (P=0.995). User friendliness was scored at insertion and removal. All statements regarding the user-friendliness were scored significantly higher for StatLock than for SecurAcath (P<0.05). Only for the statement regarding the recommending routine use of the device, which was asked at removal, no difference was found between the two devices (P=0.32). CONCLUSION: Use of SecurAcath saves time during dressing change compared with StatLock. Training on correct placement and removal of SecurAcath is critical to minimise pain. TRIAL REGISTRATION NUMBER: NCT02311127; Pre-results. PMID- 29478012 TI - Effectiveness of a complex intervention on Prioritising Multimedication in Multimorbidity (PRIMUM) in primary care: results of a pragmatic cluster randomised controlled trial. AB - OBJECTIVES: Investigate the effectiveness of a complex intervention aimed at improving the appropriateness of medication in older patients with multimorbidity in general practice. DESIGN: Pragmatic, cluster randomised controlled trial with general practice as unit of randomisation. SETTING: 72 general practices in Hesse, Germany. PARTICIPANTS: 505 randomly sampled, cognitively intact patients (>=60 years, >=3 chronic conditions under pharmacological treatment, >=5 long term drug prescriptions with systemic effects); 465 patients and 71 practices completed the study. INTERVENTIONS: Intervention group (IG): The healthcare assistant conducted a checklist-based interview with patients on medication related problems and reconciled their medications. Assisted by a computerised decision support system, the general practitioner optimised medication, discussed it with patients and adjusted it accordingly. The control group (CG) continued with usual care. OUTCOME MEASURES: The primary outcome was a modified Medication Appropriateness Index (MAI, excluding item 10 on cost-effectiveness), assessed in blinded medication reviews and calculated as the difference between baseline and after 6 months; secondary outcomes after 6 and 9 months' follow-up: quality of life, functioning, medication adherence, and so on. RESULTS: At baseline, a high proportion of patients had appropriate to mildly inappropriate prescriptions (MAI 0-5 points: n=350 patients). Randomisation revealed balanced groups (IG: 36 practices/252 patients; CG: 36/253). Intervention had no significant effect on primary outcome: mean MAI sum scores decreased by 0.3 points in IG and 0.8 points in CG, resulting in a non-significant adjusted mean difference of 0.7 (95% CI 0.2 to 1.6) points in favour of CG. Secondary outcomes showed non-significant changes (quality of life slightly improved in IG but continued to decline in CG) or remained stable (functioning, medication adherence). CONCLUSIONS: The intervention had no significant effects. Many patients already received appropriate prescriptions and enjoyed good quality of life and functional status. We can therefore conclude that in our study, there was not enough scope for improvement. TRIAL REGISTRATION NUMBER: ISRCTN99526053. NCT01171339; Results. PMID- 29478013 TI - Associations between birth weight, obesity, fat mass and lean mass in Korean adolescents: the Fifth Korea National Health and Nutrition Examination Survey. AB - OBJECTIVE: Previous studies on the relationship between birth weight and obesity in adolescents have mostly been conducted within Western populations and have yielded inconsistent results. We aimed to investigate the association between birth weight, obesity, fat mass and lean mass in Korean adolescents using the fifth Korea National Health and Nutritional Examination Survey (KNHANES V). METHODS: The study population consisted of a total of 1304 (693 men and 611 women) participants aged between 12 and 18 years. Adjusted ORs and 95% CIs were calculated by multivariable logistic regression analyses to determine the association between birth weight and being overweight or obese. Furthermore, adjusted mean values for body mass index (BMI), fat mass index (FMI) and lean mass index (LMI) according to birth weight were calculated by multiple linear regression analyses. RESULTS: Individuals within the highest 25th percentile in birth weight were more likely to be overweight (adjusted OR (aOR) 1.75, 95% CI 1.11 to 2.76) compared with adolescents within the 25th and 75th percentile in birth weight. Female adolescents who were in the highest 25th percentile in birth weight were more likely to be obese (aOR 2.13, 95% CI 1.03 to 4.41) compared with those within the 25th and 75th percentile in birth weight. Increasing FMI, but not LMI was associated with increasing birth weight (P for trend: 0.03). This tendency remained only in female population in sex-stratified analysis (P for trend: 0.03). CONCLUSIONS: High birth weight may lead to obesity and increased fat mass, but not lean mass. Adolescents born with high birth weight may benefit from close weight monitoring and early intervention against obesity. PMID- 29478015 TI - Prevalence, causes and mental health impact of workplace bullying in the Neonatal Intensive Care Unit environment. AB - OBJECTIVES: The aim of this study is to examine the prevalence, to report barriers and mental health impact of bullying behaviours and to analyse whether psychological support at work could affect victims of bullying in the healthcare workplace. DESIGN: Self-administered questionnaire survey. SETTING: 20 in total neonatal intensive care units in 17 hospitals in Greece. PARTICIPANTS: 398 healthcare professionals (doctors, nurses). MAIN OUTCOME MEASURES: The questionnaire included information on demographic data, Negative Act Questionnaire-Revised (NAQ-R) behaviour scale, data on sources of bullying, perpetrators profile, causal factors, actions taken and reasons for not reporting bullying, psychological support and 12-item General Health Questionnaire (GHQ-12) scores to investigate psychological distress. RESULTS: Prevalence of bullying measured by the NAQ-R was 53.1% for doctors and 53.6% for nurses. Victims of bullying differed from non-bullied in terms of gender and job experience, among demographic data. Crude NAQ-R score was found higher for female, young and inexperienced employees. Of those respondents who experienced bullying 44.9% self labelled themselves as victims. Witnessing bullying of others was found 83.2%. Perpetrators were mainly females 45-64 years old, most likely being a supervisor/senior colleague. Common reasons for not reporting bullying was self dealing and fear of consequences. Bullying was attributed to personality trait and management. Those who were bullied, self-labelled as a victim and witnessed bullying of others had higher GHQ-12 score. Moreover, psychological support at work had a favour effect on victims of bullying. CONCLUSIONS: Prevalence of bullying and witnessing were found extremely high, while half of victims did not consider themselves as sufferers. The mental health impact on victims and witnesses was severe and support at work was necessary to ensure good mental health status among employees. PMID- 29478014 TI - Association between perceived stress, multimorbidity and primary care health services: a Danish population-based cohort study. AB - OBJECTIVES: Mental stress is common in the general population. Mounting evidence suggests that mental stress is associated with multimorbidity, suboptimal care and increased mortality. Delivering healthcare in a biopsychosocial context is key for general practitioners (GPs), but it remains unclear how persons with high levels of perceived stress are managed in primary care. We aimed to describe the association between perceived stress and primary care services by focusing on mental health-related activities and markers of elective/acute care while accounting for mental-physical multimorbidity. DESIGN: Population-based cohort study. SETTING: Primary healthcare in Denmark. PARTICIPANTS: 118 410 participants from the Danish National Health Survey 2010 followed for 1 year. Information on perceived stress and lifestyle was obtained from a survey questionnaire. Information on multimorbidity was obtained from health registers. OUTCOME MEASURES: General daytime consultations, out-of-hours services, mental health related services and chronic care services in primary care obtained from health registers. RESULTS: Perceived stress levels were associated with primary care activity in a dose-response relation when adjusted for underlying conditions, lifestyle and socioeconomic factors. In the highest stress quintile, 6.8% attended GP talk therapy (highest vs lowest quintile, adjusted incidence rate ratios (IRR): 4.96, 95% CI 4.20 to 5.86), 3.3% consulted a psychologist (IRR: 6.49, 95% CI 4.90 to 8.58), 21.5% redeemed an antidepressant prescription (IRR: 4.62, 95% CI 4.03 to 5.31), 23.8% attended annual chronic care consultations (IRR: 1.22, 95% CI 1.16 to 1.29) and 26.1% used out-of-hours services (IRR: 1.47, 95% CI 1.51 to 1.68). For those with multimorbidity, stress was associated with more out-of-hours services, but not with more chronic care services. CONCLUSION: Persons with high stress levels generally had higher use of primary healthcare, 4 6 times higher use of mental health-related services (most often in the form of psychotropic drug prescriptions), but less timely use of chronic care services. PMID- 29478016 TI - Interactive voice response interventions targeting behaviour change: a systematic literature review with meta-analysis and meta-regression. AB - OBJECTIVE: A number of promising automated behaviour change interventions have been developed using advanced phone technology. This paper reviewed the effectiveness of interactive voice response (IVR)-based interventions designed to promote changes in specific health behaviours. METHODS: A systematic literature review of papers published between January 1990 and September 2017 in MEDLINE, CINAHL, Embase, PsycINFO, SCOPUS and the Cochrane Central Register of Controlled Trials (CENTRAL) was conducted. From the total of 2546 papers identified, 15 randomised control trials (RCTs) met the eligibility criteria and were included in a random effects meta-analysis. Meta-regression analysis was used to explore whether behaviour change techniques (BCTs) that were used in the interventions were associated with intervention effectiveness. RESULTS: Meta-analysis of 15 RCTs showed that IVR-based interventions had small but significant effects on promoting medication adherence (OR=1.527, 95% CI 1.207 to 1.932, k=9, p=0.000) and physical activity (Hedges' g=0.254, 95% CI 0.068 to 0.439, k=3, p=0.007). No effects were found for alcohol (Hedges' g=-0.077, 95% CI -0.162 to 0.007, k=4, p=0.073) or diet (Hedges' g=0.130, 95% CI -0.088 to 0.347, k=2, p=0.242). In the medication adherence studies, multivariable meta-regression including six BCTs explained 100% of the observed variance in effect size, but only the BCT 'information about health consequences' was significantly associated with effect size (beta=0.690, SE=0.199, 95% CI 0.29 to 1.08, p=0.000). CONCLUSION: IVR-based interventions appear promising in changing specific health behaviours, such as medication adherence and physical activity. However, more studies are needed to elucidate further the combination of active components of IVR interventions that make them effective and test their feasibility and effectiveness using robust designs and objective outcome measures. PMID- 29478017 TI - What resources are used in emergency departments in rural sub-Saharan Africa? A retrospective analysis of patient care in a district-level hospital in Uganda. AB - OBJECTIVES: To determine the most commonly used resources (provider procedural skills, medications, laboratory studies and imaging) needed to care for patients. SETTING: A single emergency department (ED) of a district-level hospital in rural Uganda. PARTICIPANTS: 26 710 patient visits. RESULTS: Procedures were performed for 65.6% of patients, predominantly intravenous cannulation, wound care, bladder catheterisation and orthopaedic procedures. Medications were administered to 87.6% of patients, most often pain medications, antibiotics, intravenous fluids, antimalarials, nutritional supplements and vaccinations. Laboratory testing was used for 85% of patients, predominantly malaria smears, rapid glucose testing, HIV assays, blood counts, urinalyses and blood type. Radiology testing was performed for 17.3% of patients, including X-rays, point-of-care ultrasound and formal ultrasound. CONCLUSION: This study describes the skills and resources needed to care for a large prospective cohort of patients seen in a district hospital ED in rural sub-Saharan Africa. It demonstrates that the vast majority of patients were treated with a small formulary of critical medications and limited access to laboratories and imaging, but providers require a broad set of decision-making and procedural skills. PMID- 29478018 TI - Evaluation of Mediterranean diet adherence scores: a systematic review. AB - OBJECTIVE: The aim of this review was to evaluate the conceptual suitability, applicability and psychometric properties of scores used internationally to measure adherence to the Mediterranean diet (MD). DESIGN: This was a systematic review to identify original articles that examined some aspects of the conceptual suitability, applicability or psychometric properties of the MD adherence score. Electronic searches were carried out on the international databases MEDLINE, Scopus, Web of Science and EMBASE (from January 1980 to 31 December 2015). ELIGIBILITY CRITERIA FOR SELECTING STUDIES: The study included original articles that examined some aspects of the conceptual suitability, applicability or psychometric properties of the MD adherence score. The studies where MD adherence scores were administered but did not bring forward any evidence about their performance related to conceptual suitability, applicability or psychometric properties were excluded. DATA EXTRACTION: Information relating to the scales was extracted in accordance with the quality criteria defined by the Scientific Advisory Committee of the Medical Outcomes Trust for measurement of health results and the quality criteria recommended by Terwee: (1) conceptual, (2) applicability and (3) psychometric properties. Three authors independently extracted information from eligible studies. RESULTS: Twenty-seven studies were identified as meeting the inclusion criteria, yielding 28 MD adherence scores. The results showed that evidence is scarce and that very few scores fulfilled the applicability parameters and psychometric quality. The scores developed by Panagiotakos et al, Buckland et al and Sotos-Prieto et al showed the highest levels of evidence. CONCLUSIONS: Scores measuring adherence to MD are useful tools for identifying the dietary patterns of a given population. However, further information is required regarding existing scores. In addition, new instruments with greater conceptual and methodological rigour should be developed and evaluated for their psychometric properties. PMID- 29478019 TI - Targeting strategies of mHealth interventions for maternal health in low and middle-income countries: a systematic review protocol. AB - INTRODUCTION: Recently, there has been a steady increase in mobile health (mHealth) interventions aimed at improving maternal health of women in low-income and middle-income countries. While there is evidence indicating that these interventions contribute to improvements in maternal health outcomes, other studies indicate inconclusive results. This uncertainty has raised additional questions, one of which pertains to the role of targeting strategies in implementing mHealth interventions and the focus on pregnant women and health workers as target groups. This review aims to assess who is targeted in different mHealth interventions and the importance of targeting strategies in maternal mHealth interventions. METHODS AND ANALYSIS: We will search for peer-reviewed, English-language literature published between 1999 and July 2017 in PubMed, Web of Knowledge (Science Direct, EMBASE) and Cochrane Central Registers of Controlled Trials. The study scope is defined by the Population, Intervention, Comparison and Outcomes framework: P, community members with maternal or reproductive needs; I, electronic health or mHealth programmes geared at improving maternal or reproductive health; C, other non-electronic health or mHealth-based interventions; O, maternal health measures including family planning, antenatal care attendance, health facility delivery and postnatal care attendance. ETHICS AND DISSEMINATION: This study is a review of already published or publicly available data and needs no ethical approval. Review results will be published in a peer-reviewed journal and presented at international conferences. PROSPERO REGISTRATION NUMBER: CRD42017072280. PMID- 29478020 TI - Chinese observational prospective study of ageing population with chronic kidney disease (C-OPTION): a study protocol. AB - INTRODUCTION: The proportion of elderly people is steadily rising worldwide, especially in low-income and middle-income countries, including China. Chronic kidney disease (CKD) is a common disorder in older people. However, little is known about the epidemiology of CKD and its consequences among the elderly. Improvements on clinical guidelines and healthcare policies for this population are required. This study aims to examine the risk factors for progression of CKD among the elderly and develop models to identify subgroups who are at high risk. METHODS AND ANALYSIS: This is a prospective, multicentre, cohort study. The study population comprises ~3000 patients with predialysis CKD, aged >=65 years, recruited between March 2016 and December 2017. After the baseline assessments, these patients will be followed for 5 years or until the occurrence of primary outcomes. Assessments that include anthropomorphic measures, laboratory tests, questionnaires, and blood and urine specimen collection will be performed at baseline and at follow-ups. Data on demographic information, cognitive function, depression, risk of malnutrition, physical activity and quality of life will be collected. The primary outcomes are incidence of end-stage renal disease, loss of renal function (>=40% decline in glomerular filtration rate from baseline), and death. The secondary outcomes are acute coronary syndrome, hospitalisation for heart failure or unstable angina, cerebrovascular events, and peripheral arterial disease. ETHICS AND DISSEMINATION: This study protocol has been approved by the ethics committees of the Chinese People's Liberation Army General Hospital and the participating centres. All the participants gave written informed consent before data collection. The findings of the study will be published in peer reviewed journals and will be presented at national or international conferences. TRIAL REGISTRATION NUMBER: NCT03246204; Pre-results. PMID- 29478022 TI - Physical Activity Measured by Implanted Devices Predicts Atrial Arrhythmias and Patient Outcome: Results of IMPLANTED (Italian Multicentre Observational Registry on Patients With Implantable Devices Remotely Monitored). AB - BACKGROUND: To determine whether daily physical activity (PA), as measured by implanted devices (through accelerometer sensor), was related to the risk of developing atrial arrhythmias during long-term follow-up in a population of heart failure (HF) patients with an implantable cardioverter defibrillator (ICD). METHODS AND RESULTS: The study population was divided into 2 equally sized groups (PA cutoff point: 3.5 h/d) according to their mean daily PA recorded by the device during the 30- to 60-day period post-ICD implantation. Propensity score matching was used to compare 2 equally sized cohorts with similar characteristics between lower and higher activity patients. The primary end point was time free from the first atrial high-rate episode (AHRE) of duration >=6 minutes. Secondary end points were: first AHRE >=6 hours, first AHRE >=48 hours, and a combined end point of death or HF hospitalization. Data from 770 patients (65+/-15 years; 66% men; left ventricular ejection fraction 35+/-12%) remotely monitored for a median of 25 months were analyzed. A PA >=3.5 h/d was associated with a 38% relative reduction in the risk of AHRE >=6 minutes (72-month cumulative survival: 75.0% versus 68.1%; log rank P=0.025), and with a reduction in the risk of AHRE >=6 hours, AHRE >=48 hours, and the combined end point of death or HF hospitalization (all P<0.05). CONCLUSIONS: In HF patients with ICD, a low level of daily PA was associated with a higher risk of atrial arrhythmias, regardless of the patients' baseline characteristics. In addition, a lower daily PA predicted death or HF hospitalization. PMID- 29478023 TI - High-Sensitivity Troponin T and C-Reactive Protein Have Different Prognostic Values in Hemo- and Peritoneal Dialysis Populations: A Cohort Study. AB - BACKGROUND: Dialysis patients have an exceedingly high mortality rate. Biomarkers may be useful tools in risk stratification of this population. We evaluated the prognostic value of high-sensitivity cardiac troponin T (hs-cTnT) and CRP (C reactive protein) in predicting adverse outcomes in stable hemodialysis and peritoneal dialysis (PD) patients. Variability in hs-cTnT was also examined. METHODS AND RESULTS: A retrospective cohort study included 574 dialysis patients (hemodialysis 347, PD 227). Outcomes examined included mortality and major adverse cardiovascular events, with median follow-up of 3.5 years. hs-cTnT was an independent predictor of both outcomes in hemodialysis and PD patients. Increased risk only became significant when hs-cTnT reached quintile 3 (>49 ng/L). Area under the receiver operating curve analysis showed that the addition of hs-cTnT to clinical parameters significantly improved its prognostic performance for mortality in PD patients (P=0.002). CRP was an independent predictor of both outcomes in PD patients only. Only CRP in the highest quintile (>16.8 mg/L) was associated with increased risk. hs-cTnT remained relatively stable for the whole follow-up period for hemodialysis patients, whereas for PD patients, hs-cTnT increased by 23.63% in year 2 and 29.13% in year 3 compared with baseline (P<0.001). CONCLUSIONS: hs-cTnT and CRP are useful tools in predicting mortality and major adverse cardiovascular events in hemodialysis and PD patients. Given that hs-cTnT levels increase over time in PD patients, interval monitoring may be valuable for risk assessment. In contrast, hs-cTnT in hemodialysis patients has little interval change and progress monitoring is not indicated. PMID- 29478021 TI - 2018 International Olympic Committee consensus statement on prevention, diagnosis and management of paediatric anterior cruciate ligament (ACL) injuries. AB - In October 2017, the International Olympic Committee hosted an international expert group of physiotherapists and orthopaedic surgeons who specialise in treating and researching paediatric ACL injuries. Representatives from the American Orthopaedic Society for Sports Medicine, European Paediatric Orthopaedic Society, European Society for Sports Traumatology, Knee Surgery & Arthroscopy, International Society of Arthroscopy Knee Surgery and Orthopaedic Sports Medicine, Pediatric Orthopaedic Society of North America and Sociedad Latinoamericana de Artroscopia, Rodilla y Deporte attended. Physiotherapists and orthopaedic surgeons with clinical and research experience in the field, and an ethics expert with substantial experience in the area of sports injuries also participated. Injury management is challenging in the current landscape of clinical uncertainty and limited scientific knowledge. Injury management decisions also occur against the backdrop of the complexity of shared decision making with children and the potential long-term ramifications of the injury. This consensus statement addresses six fundamental clinical questions regarding the prevention, diagnosis and management of paediatric ACL injuries. The aim of this consensus statement is to provide a comprehensive, evidence-informed summary to support the clinician, and help children with ACL injury and their parents/guardians make the best possible decisions. PMID- 29478024 TI - Slow Gait Speed and Cardiac Rehabilitation Participation in Older Adults After Acute Myocardial Infarction. AB - BACKGROUND: Lack of participation in cardiac rehabilitation (CR) and slow gait speed have both been associated with poor long-term outcomes in older adults after acute myocardial infarction (AMI). Whether the effect of CR participation on outcomes after AMI differs by gait speed is unknown. METHODS AND RESULTS: We examined the association between gait speed and CR participation at 1 month after discharge after AMI, and death and disability at 1 year, in 329 patients aged >=65 years enrolled in the TRIUMPH (Translational Research Investigating Underlying Disparities in Recovery From Acute Myocardial Infarction: Patients' Health Status) registry. Among these patients, 177 (53.7%) had slow gait speed (<0.8 m/s) and 109 (33.1%) participated in CR. Patients with slow gait speed were less likely to participate in CR compared with patients with normal gait speed (27.1% versus 40.1%; P=0.012). In unadjusted analysis, CR participants with normal gait speed had the lowest rate of death or disability at 1 year (9.3%), compared with those with slow gait speed and no CR participation (43.2%). After adjustment for cardiovascular risk factors and cognitive impairment, both slow gait speed (odds ratio, 2.30; 95% confidence interval, 1.30-4.06) and non-CR participation (odds ratio, 2.34; 95 confidence interval, 1.22-4.48) were independently associated with death or disability at 1 year. The effect of CR on the primary outcome did not differ by gait speed (P=0.70). CONCLUSIONS: CR participation is associated with reduced risk for death or disability after AMI. The beneficial effect of CR participation does not differ by gait speed, suggesting that slow gait speed alone should not preclude referral to CR for older adults after AMI. PMID- 29478025 TI - Hypoxia Inducible Factor 1alpha Plays a Key Role in Remote Ischemic Preconditioning Against Stroke by Modulating Inflammatory Responses in Rats. AB - BACKGROUND: Limb remote ischemic preconditioning (RIPC) protects against brain injury induced by stroke, but the underlying protective mechanisms remain unknown. As hypoxia inducible factor 1alpha (HIF-1alpha) is neuroprotective in stroke and mediates neuroinflammation, we tested the hypothesis that HIF-1alpha is a key factor of RIPC against stroke by mediating inflammation. METHODS AND RESULTS: Stroke was induced by transient middle cerebral artery occlusion in rats, and RIPC was conducted in both hind limbs. The HIF-1alpha mRNA was examined by quantitative reverse transcription polymerase chain reaction after RIPC. In addition, inflammatory cytokines in the peripheral blood and brain were measured using the AimPlex multiplex immunoassays. Data showed that RIPC reduced the infarct size, improved neurological functions, and increased HIF-1alpha mRNA levels, interleukin (IL)-4, and IL-10 protein levels in the peripheral blood. Intraperitoneal injection of the HIF activator, dimethyloxaloylglycine, reduced the infarct size and inhibited interferon-gamma protein levels, while promoting IL-4 and IL-10 protein levels, while decreasing interferon-gamma protein levels in both the peripheral blood and ischemic brain. In addition, injection of dimethyloxaloylglycine had a synergistic effect with RIPC on reducing infarction and improving neurological functions, as well as decreasing interferon-gamma in the peripheral blood and ischemic brain. In contrast, injection of the HIF inhibitor, acriflavine hydrochloride, abolished the protective effects of RIPC on infarction, and reduced IL-4 and IL-10 protein levels in both the peripheral blood and ischemic brain. CONCLUSIONS: We conclude that HIF-1alpha plays a key role in RIPC, likely mediated by a systemic modulation of the inflammatory response. PMID- 29478027 TI - Patient-Reported Outcomes in Relation to Continuously Monitored Rhythm Before and During 2 Years After Atrial Fibrillation Ablation Using a Disease-Specific and a Generic Instrument. AB - BACKGROUND: Atrial fibrillation (AF) ablation improves patient-reported outcomes, irrespective of mode of intermittent rhythm monitoring. We evaluated the use of an AF-specific and a generic patient-reported outcomes instrument during continuous rhythm monitoring 2 years after AF ablation. METHODS AND RESULTS: Fifty-four patients completed the generic 36-Item Short-Form Health Survey and the AF-specific AF6 questionnaires before and 6, 12, and 24 months after AF ablation. All patients underwent continuous ECG monitoring via an implantable loop recorder. The generic patient-reported outcomes scores were compared with those of a Swedish age- and sex-matched population. After ablation, both summary scores reached normative levels at 24 months, while role-physical and vitality remained lower than norms. Responders to ablation (AF burden <0.5%) reached the norms in all individual 36-Item Short-Form Health Survey domains, while nonresponders (AF burden >0.5%) reached norms only in social functioning and mental component summary. All AF6 items and the sum score showed moderate to large improvement in both responders and nonresponders, although responders showed significantly greater improvement in all items except item 1 from before to 24 months after ablation. Higher AF burden was independently associated with poorer physical component summary and AF6 sum score. CONCLUSIONS: The AF-specific AF6 questionnaire was more sensitive to changes related to AF burden than the generic 36-Item Short-Form Health Survey. Patients improved as documented by both instruments, but a higher AF burden after ablation was associated with poorer AF specific patient-reported outcomes and poorer generic physical but not mental health. Our results support the use of an AF-specific instrument, alone or in combination with a generic instrument, to assess the effect of ablation. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00697359. PMID- 29478026 TI - Genome-Wide Association Approach Identified Novel Genetic Predictors of Heart Rate Response to beta-Blockers. AB - BACKGROUND: For many indications, the negative chronotropic effect of beta blockers is important to their efficacy, yet the heart rate (HR) response to beta blockers varies. Herein, we sought to use a genome-wide association approach to identify novel single nucleotide polymorphisms (SNPs) associated with HR response to beta-blockers. METHODS AND RESULTS: We first performed 4 genome-wide association analyses for HR response to atenolol (a beta1-adrenergic receptor blocker) as: (1) monotherapy or (2) add-on therapy, in 426 whites and 273 blacks separately from the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) study. A meta-analysis was then performed between the genome-wide association analysis performed in PEAR atenolol monotherapy and add-on therapy, in each race separately, using the inverse variance method assuming fixed effects. From this analysis, SNPs associated with HR response to atenolol at a P<1E-05 were tested for replication in whites (n=200) and blacks (n=168) treated with metoprolol (a beta1-adrenergic receptor blocker). From the genome-wide association meta-analyses, SNP rs17117817 near olfactory receptor family10 subfamily-p-member1 (OR10P1), and SNP rs2364349 in sorting nexin-9 (SNX9) replicated in blacks. The combined studies meta-analysis P values for the rs17117817 and rs2364349 reached genome-wide significance (rs17117817G-allele; Meta-beta=5.53 beats per minute, Meta-P=2E-09 and rs2364349 A-allele; Meta beta=3.5 beats per minute, Meta-P=1E-08). Additionally, SNPs in the OR10P1 and SNX9 gene regions were also associated with HR response in whites. CONCLUSIONS: This study highlights OR10P1 and SNX9 as novel genes associated with changes in HR in response to beta-blockers. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00246519. PMID- 29478028 TI - Diabetes adversely affects phospholipid profiles in human carotid artery endarterectomy plaques. AB - Patients with diabetes are at higher risk of developing carotid artery stenosis and resultant stroke. Arachidonoyl phospholipids affect plaque inflammation and vulnerability, but whether diabetic patients have unique carotid artery phospholipidomic profiles is unknown. We performed a comprehensive paired analysis of phospholipids in extracranial carotid endarterectomy (CEA) plaques of matched diabetic and nondiabetic patients and analyzed mass spectrometry-derived profiles of three phospholipids, plasmenyl-phosphatidylethanolamine (pPE), phosphatidylserine (PS), and phosphatidylinositol (PI), in maximally (MAX) and minimally (MIN) diseased CEA segments. We also measured levels of arachidonic acid (AA), produced by pPE hydrolysis, and choline-ethanolamine phosphotransferase 1 (CEPT1), responsible for most pPE de novo biosynthesis. In paired analysis, MIN CEA segments had higher levels than MAX segments of pPE (P < 0.001), PS (P < 0.001), and PI (P < 0.03). MIN diabetic plaques contained higher levels than MAX diabetic plaques of arachidonoyl pPE38:4 and pPE38:5 and CEPT1 was upregulated in diabetic versus nondiabetic plaques. AA levels were relatively greater in MIN versus MAX segments of all CEA segments, and were higher in diabetic than nondiabetic plaques. Our findings suggest that arachidonoyl phospholipids are more likely to be abundant in the extracranial carotid artery plaque of diabetic rather than nondiabetic patients. PMID- 29478029 TI - Treatment of blood blister aneurysms of the internal carotid artery with flow diversion. AB - BACKGROUND: Blood blister aneurysms (BBA) are a rare subset of intracranial aneurysms that represent a therapeutic challenge from both a surgical and endovascular perspective. OBJECTIVE: To report multicenter experience with flow diversion exclusively for BBA, located at non-branching segments along the anteromedial wall of the supraclinoidal internal carotid artery (ICA). METHODS: Consecutive cases of BBA located at non-branching segments along the anteromedial wall of the supraclinoidal ICA treated with flow diversion were included in the final analysis. RESULTS: 49 patients with 51 BBA of the ICA treated with devices to achieve the flow diversion effect were identified. 43 patients with 45 BBA of the ICA were treated with the pipeline embolization device and were included in the final analysis. Angiographic follow-up data were available for 30 patients (32 aneurysms in total); 87.5% of aneurysms (28/32) showed complete obliteration, 9.4% (3/32) showed reduced filling, and 3.1% (1/32) persistent filling. There was no difference between the size of aneurysm (<=2 mm vs >2 mm) or the use of adjunct coiling and complete occlusion of the aneurysm on follow-up (P=0.354 and P=0.865, respectively). Clinical follow-up data were available for 38 of 43 patients. 68% of patients (26/38) had a good clinical outcome (modified Rankin scale score of 0-2) at 3 months. There were 7 (16%) immediate procedural and 2 (5%) delayed complications, with 1 case of fatal delayed re-rupture after the initial treatment. CONCLUSIONS: Our data support the use of a flow diversion technique as a safe and effective therapeutic modality for BBA of the supraclinoid ICA. PMID- 29478030 TI - Immunohistochemical evaluation of stress-responsive protein sestrin2 and its correlation with p53 mutational status in eyelid sebaceous gland carcinoma. AB - BACKGROUND: p53 is a stress-activated tumour suppressor gene, and its mutation has been associated with solid tumours including non-melanoma skin cancers. Sestrin2 expression is associated with DNA damage and oxidative stress and has been described as a downstream target of p53 network. However, its role in sebaceous gland carcinoma (SGC) remains unexplored. OBJECTIVES: To determine the role of p53 and its downstream target gene sestrin2 expression and p53 gene mutation status in SGC. METHODS: Twenty cases of eyelid SGC tumour and circulating cell-free DNA (ccfDNA) were subjected to mutational analysis of p53 gene. p53 and sesrin2 expression was evaluated by immunohistochemistry. Results were correlated with the clinicopathological features of eyelid SGC. RESULTS: p53 gene mutations was detected in 25% of the SGC cases. A C>T transition was identified in exon 6 in a single patient in both tumour and ccfDNA. A G>T transversion leading to amino acid change D259Y was seen in four patients. A splice site mutation affected a single case in exon 6. p53 expression was observed in 55% SGC. Loss of sestrin2 in 55% SGC cases correlated with poor tumour differentiation (P=0.0001), upper eyelid involvement (P=0.004), p53 mutation (P=0.039) and with mutant p53 expression (P=0.0001). CONCLUSION: Sestrin2 expression was found to be significantly reduced in p53 mutated SGC cases and in cases with strong p53 nuclear immunopositivity, suggesting that loss of sestrin2 may be of biological significance in the development of SGC and as a key downstream component of p53 tumour suppression network in eyelid SGC. PMID- 29478031 TI - Obituary of Harvey Lincoff. PMID- 29478032 TI - Face transplantation for the blind: more than being blind in a sighted world. AB - Face transplantation (FT) is a landmark in reconstructive surgery involving vascularised composite allotransplantation. A recent issue of FT for patients who are blind has arisen. Some bioethicists recommend not excluding a patient who is blind, as this may amount to discrimination. From an ethical standpoint, FT for those with blindness is appropriate in selected candidates. This article seeks to add to the clinical evidence supporting FT for those with blindness by detailing a complementary psychosocial perspective. Currently, there is little relevant research about the subjectivity of the blind. This is critical since the arguments against FT for the blind refer to their inability to see their face and to view the reaction of others to their disfigured faces. We begin with a brief look at examples of FT involving blindness and associated arguments. The next part is a multidisciplinary investigation of the experiences of the blind. These are gleaned from a close reading of the literature and drawing inferences, as direct studies are rare. The discussion analyses identity themes of the blind in relation to their faces: as they experience it; the face they wish to show to the world; and how others perceive and react to their face in a saturated environment of imagery and visual communication. Disability and the blind person's experience of faces are well-founded considerations for medical practitioners and ethics boards in the process of FT decision-making. PMID- 29478033 TI - Who calls the shots? The ethics of adolescentself-consent for HPV vaccination. AB - While the human papillomavirus (HPV) vaccine is medically indicated to reduce the risk of genital warts and certain types of cancer, rates of HPV vaccination repeatedly fall short of public health goals. Individual-level factors contributing to low vaccination rates are well documented. However, system-level barriers, particularly the need for parental consent, have been less explored. To date, there is no legal or ethical consensus in the USA regarding whether adolescents might permissibly self-consent to the HPV vaccine. Consequently, there is considerable variability in medical practice at the provider and state level. In this essay, we explore the ethical acceptability of vaccinating adolescents for HPV without parental consent. We argue that the same ethical considerations that justify permitting minors to consent to treatment for sexual and reproductive health care-namely, public health benefit and adolescents' developing autonomy-similarly justify permitting minors to consent to HPV vaccination. Based on this analysis, we conclude that allowing adolescents to self-consent to the HPV vaccine is ethically justifiable and should be reflected in US state policies. PMID- 29478035 TI - Neurosyphilis in patients with HIV. AB - Syphilis is a resurgent sexually transmitted infection in the UK that is disproportionately diagnosed in patients living with HIV, particularly in men who have sex with men. Syphilis appears to present differently in patients with HIV, particularly in those with severe immunosuppression. Progression to neurosyphilis is more common in HIV coinfection and can be asymptomatic, often for several years. The presentations of neurosyphilis vary but can include meningitis, meningovascular disease, general paresis and tabes dorsalis. There is debate about the circumstances in which to perform a lumbar puncture, and the current gold standard diagnostics have inadequate sensitivity. We recommend a pragmatic approach to lumbar punctures, interpreting investigations and deciding when to consider treatment with a neuropenetrative antibiotic regimen. PMID- 29478036 TI - Communication technology and healthcare. AB - EBN Perspectives bring together key issues from the commentaries in one of our nursing topic themes. PMID- 29478037 TI - Response to: 'Congenital tricuspid valve disease can masquerade as primary idiopathic TR' by Rajpal. PMID- 29478039 TI - The natural history of autoimmune Addison's disease with a non-classical presentation: a case report and review of literature. AB - Autoimmune Addison's disease (AAD) is the most frequent cause of adrenocortical insufficiency. The natural history of AAD usually comprises five consecutive stages with the first stage characterized by the increase of plasma renin consistent with the impairment of pars glomerulosa, which is usually the first affected layer of the adrenal cortex. We describe a 19-year-old female with Hashimoto's thyroiditis (HT) who underwent an autoantibody screening due to having the personal and family history of other autoimmune diseases in the absence of relevant clinical manifestations. She was positive for adrenal cortex autoantibodies (ACA) and steroid 21-hydroxylase autoantibodies (21-OH Ab) at high titers. She had increased basal levels of ACTH with normal basal cortisol not responding to ACTH stimulation, reduced levels of dehydroepiandrosterone-sulfate but normal levels of orthostatic renin and aldosterone. This scenario was consistent with a subclinical AAD presenting with first impairments in pars fasciculata and reticularis and conserved pars glomerulosa function. Only subsequently, progressive deficiency in pars glomerulosa function has become evident. Review of the literature showed that there was only one case, reported to date, with a similar atypical natural history of AAD. The strategies for screening for ACA/21-OH Ab in patients with HT are discussed. PMID- 29478038 TI - Long-term recording performance and biocompatibility of chronically implanted cylindrically-shaped, polymer-based neural interfaces. AB - Stereo-electroencephalography depth electrodes, regularly implanted into drug resistant patients with focal epilepsy to localize the epileptic focus, have a low channel count (6-12 macro- or microelectrodes), limited spatial resolution (0.5-1 cm) and large contact area of the recording sites (~mm2). Thus, they are not suited for high-density local field potential and multiunit recordings. In this paper, we evaluated the long-term electrophysiological recording performance and histocompatibility of a neural interface consisting of 32 microelectrodes providing a physical shape similar to clinical devices. The cylindrically-shaped depth probes made of polyimide (PI) were chronically implanted for 13 weeks into the brain of rats, while cortical or thalamic activity (local field potentials, single-unit and multi-unit activity) was recorded regularly to monitor the temporal change of several features of the electrophysiological performance. To examine the tissue reaction around the probe, neuron-selective and astroglia selective immunostaining methods were applied. Stable single-unit and multi-unit activity were recorded for several weeks with the implanted depth probes and a weak or moderate tissue reaction was found around the probe track. Our data on biocompatibility presented here and in vivo experiments in non-human primates provide a strong indication that this type of neural probe can be applied in stereo-electroencephalography recordings of up to 2 weeks in humans targeting the localization of epileptic foci providing an increased spatial resolution and the ability to monitor local field potentials and neuronal spiking activity. PMID- 29478040 TI - Reference standards for the detection of anti-mitochondrial and anti-rods/rings autoantibodies. PMID- 29478034 TI - UK guidelines on oesophageal dilatation in clinical practice. AB - These are updated guidelines which supersede the original version published in 2004. This work has been endorsed by the Clinical Services and Standards Committee of the British Society of Gastroenterology (BSG) under the auspices of the oesophageal section of the BSG. The original guidelines have undergone extensive revision by the 16 members of the Guideline Development Group with representation from individuals across all relevant disciplines, including the Heartburn Cancer UK charity, a nursing representative and a patient representative. The methodological rigour and transparency of the guideline development processes were appraised using the revised Appraisal of Guidelines for Research and Evaluation (AGREE II) tool.Dilatation of the oesophagus is a relatively high-risk intervention, and is required by an increasing range of disease states. Moreover, there is scarcity of evidence in the literature to guide clinicians on how to safely perform this procedure. These guidelines deal specifically with the dilatation procedure using balloon or bougie devices as a primary treatment strategy for non-malignant narrowing of the oesophagus. The use of stents is outside the remit of this paper; however, for cases of dilatation failure, alternative techniques-including stents-will be listed. The guideline is divided into the following subheadings: (1) patient preparation; (2) the dilatation procedure; (3) aftercare and (4) disease-specific considerations. A systematic literature search was performed. The Grading of Recommendations Assessment, Develop-ment and Evaluation (GRADE) tool was used to evaluate the quality of evidence and decide on the strength of recommendations made. PMID- 29478041 TI - Processing multisource feedback during residency under the guidance of a non medical coach. AB - Objectives: The present study aimed to investigate residents' preferences in dealing with personal multi-source feedback (MSF) reports with or without the support of a coach. Methods: Residents employed for at least half a year in the study hospital were eligible to participate. All 43 residents opting to discuss their MSF report with a psychologist-coach before discussing results with the program director were included. Semi-structured interviews were conducted following individual coaching sessions. Qualitative and quantitative data were gathered using field notes. Results: Seventy-four percent (n= 32) preferred sharing the MFS report always with a coach, 21% (n= 9) if either the feedback or the relationship with the program director was less favorable, and 5% (n=2) saw no difference between discussing with a coach or with the program director. In the final stage of training residents more often preferred the coach (82.6%, n=19) than in the first stages (65%, n=13). Reasons for discussing the report with a coach included her neutral and objective position, her expertise, and the open and safe context during the discussion. Conclusions: Most residents preferred discussing multisource feedback results with a coach before their meeting with a program director, particularly if the results were negative. They appeared to struggle with the dual role of the program director (coaching and judging) and appreciated the expertise of a dedicated coach to navigate this confrontation. We encourage residency programs to consider offering residents neutral coaching when processing multisource feedback. PMID- 29478043 TI - Prenatal Diagnosis of Hydro(metro)colpos: A Series of 20 Cases. AB - BACKGROUND: Hydrocolpos and hydrometrocolpos are rare malformations caused by accumulation of secretion due to congenital obstruction of the vagina. Hydro(metro)colpos may be isolated or can be combined with other malformations as part of a syndromic disorder. We report on a series of 20 cases with hydro(metro)colpos diagnosed prenatally, delineate the differential diagnoses, and illustrate the spectrum of associated malformations. SUBJECTS AND METHODS: This was a retrospective study involving 20 fetuses with hydro(metro)colpos at two large tertiary referral centers in Germany over an 18-year period (2000 2017). RESULTS: The median diagnosis was made at 30+4 weeks of gestation, the earliest at 20+6 weeks, the latest at 37+2 weeks. All 20 fetuses presented with the typical cystic structure behind the fetal bladder. Additional malformations included urogenital malformations, hexadactyly, and heart defects. Postnatal follow-up revealed that hydro(metro)colpos was associated with anorectal malformation in 11/20 fetuses, McKusick-Kaufman syndrome or Bardet-Biedl syndrome in 4/20 fe tuses, Mayer-Rokitansky-Kuster-Hauser syndrome in 3/20 fetuses, and Herlyn-Werner-Wunderlich syndrome in 1/20. In 1 fetus pressure from an intraabdominal teratoma resulted in prenatal hydro(metro)colpos. CONCLUSION: Hydro(me tro)colpos is a rare prenatal sonographic feature. Multidisciplinary prenatal counseling should include all potential syndromes that can present with hydro(metro)colpos in the prenatal setting. PMID- 29478042 TI - Blended learning in quality improvement training for healthcare professionals in Qatar. PMID- 29478044 TI - Relationships between Neighborhood Walkability and Objectively Measured Physical Activity Levels in Hemodialysis Patients. AB - BACKGROUND/AIMS: Neighborhood walkability is associated with indicators of health in the general population. We explored the association between neighborhood walkability and daily steps in hemodialysis (HD) patients. METHODS: We measured daily steps over 5 weeks using Fitbit Flex (Fitbit, San Francisco, CA, USA) and retrieved Walk Score(r) (WS) data by patient's home ZIP code (www.walkscore.com; 0 = poorest walkability; 100 = greatest walkability). RESULTS: HD patients took a mean of 6,393 +/- 3,550 steps/day (n = 46). Median WS of the neighborhood where they resided was 28. Patients in an above-median WS (n = 27) neighborhood took significantly more daily steps compared to those (n = 19) in a below-median WS neighborhood (7,514 +/- 3,900 vs. 4,800 +/- 2,228 steps/day; p < 0.001, t test). Daily steps and WS were directly correlated (R = 0.425; p = 0.0032, parametric test; R = 0.359, p = 0.0143, non-parametric test). CONCLUSION: This is the first study conducted among HD patients to indicate a direct relationship between neighborhood walkability and the actual steps taken. These results should be considered when designing initiatives to increase and improvise exercise routines in HD populations. PMID- 29478045 TI - IGICS: JGA Keynote Program. The 10th International Gastrointestinal Consensus Symposium (IGICS). Advanced Technology for Diagnosis and Treatment of Gastroenterological Diseases. February 18, 2017, Nagoya Congress Center, Aichi, Japan: Abstracts. PMID- 29478046 TI - Management of Elderly Patients with Rapidly Progressive Glomerulonephritis. AB - BACKGROUND: Rapidly progressive glomerulonephritis (RPGN) is characterized by a rapid deterioration of renal function and by extracapillary proliferation in >50% of glomeruli. The most common type of RPGN is "pauci-immune" glomerulonephritis caused by anti-neutrophil cytoplasmic antibodies-associated vasculitis (AAV). SUMMARY: The incidence of AAV increases with age and pauci-immune glomerulonephritis is the most common diagnosis found in renal biopsies in the elderly population. Age was identified as an independent negative risk factor for both death and end-stage renal disease in AAV, and the mortality of older patients was uniformly higher than in younger patients in all retrospective studies. Early diagnosis may be difficult particularly in elderly patients with renal-limited disease but is important for the good outcome of the patients. Immunosuppressive treatment options include cyclophosphamide or rituximab combined with corticosteroids with or without plasma exchange in case of severe disease. Data from randomized trials are completely missing for patient aged >75 years. Based on retrospective studies, elderly patients seem to respond to immunosuppressive drugs just as younger patients are able to, but they are at a higher risk of adverse events. Key Messages: RPGN is relatively common in the elderly patients. Immunosuppressive treatment in older patients with AAV or RPGN may be useful but needs to be strictly individualized with all the risks taken into consideration. Further studies are needed to examine the role of novel therapeutic options in the elderly population with RPGN. PMID- 29478047 TI - Arterial Stiffness in Chronic Kidney Disease and End-Stage Renal Disease. AB - Accelerated ageing is observed in patients with chronic kidney disease (CKD)/end stage renal disease. Premature vascular aging and arterial stiffening are the most characteristic features of this "progeria" that is already observed in those with the early stages of CKD. Aortic stiffening is associated with high characteristic impedance, left ventricular hypertrophy, decreased coronary perfusion, and is a strong prognostic marker of mortality and cardiovascular morbidity. With aging, the arterial stiffening is more pronounced in the aorta and central arteries than in peripheral conduit arteries. This leads to progressive decrease and inversion of the arterial stiffness gradient and systemic reflection coefficient, leading to less protection of the microcirculation in the event of high-pressure transmission towards it Arterial stiffening is multifactorial with systemic microinflammation being one of the most important associated factors primarily associated with vascular calcifications. PMID- 29478048 TI - Association between Heights of Dialysis Patients and Outcomes: Results from a Retrospective Cohort Study of the International MONitoring Dialysis Outcomes (MONDO) Database Initiative. AB - BACKGROUND: Tall people have improved metabolic profiles and better cardiovascular outcomes, a relationship inverted in dialysis patients. We investigated the relationship between height and outcomes in incident hemodialysis (HD) patients commencing treatment in an analysis of the international Monitoring Dialysis Outcomes (MONDO) database. METHODS: In this retrospective cohort study, we included incident HD patients commencing treatment between -January 1, 2006 and December 31, 2010 and investigated the association between height and mortality using the MONDO database. A 6-months baseline period preceded 2.5 years of follow-up, during which we recorded patient mortality. Patients were stratified in region-specific deciles of the respective database's population (Asia Pacific, North and South America, and Europe) and we developed Cox-proportional hazard models (additionally adjusted for age, gender, post dialysis weight, eKt/V, albumin, interdialytic weight gain, phosphorus, and predialysis systolic blood pressure) for each database. RESULTS: We studied 23,353 patients (62 +/- 15 years old, 42% female, body mass index 26 +/- 6 kg/m2, height 165 +/- 10 cm). We found a trend of increasing hazard ratio of death (HR) with increasing height for Asia Pacific, Europe, and South America. In the fully adjusted models, for South America, we found a trend of increasing HR without significance among deciles >5. In Europe, deciles 8-10 had significantly increased HR. No clear trend was found in North America. CONCLUSION: We found an increasing risk of death with increasing height in all regions, except North America. While the reasons remain unclear, further research may be warranted. PMID- 29478049 TI - Interpreting Poisson Regression Models in Dental Caries Studies. AB - Oral epidemiology involves studying and investigating the distribution and determinants of dental-related diseases in a specified population group to inform decisions in the management of health problems. In oral epidemiology studies, the hypothesis is typically followed by a cogent study design and data collection. Appropriate statistical analysis is essential to demonstrate the scientific association between the independent factors and the target variable. Analysis also helps to develop and build a statistical model. Poisson regression and its extensions have gained more attention in caries epidemiology than other working models such as logistic regression. This review discusses the fundamental principles and basic knowledge of Poisson regression models. It also introduces the use of a robust variance estimator with a focus on the "robust" interpretation of the model. In addition, extensions of regression models, including the zero-inflated model, hurdle model, and negative binomial model, and their interpretation in caries studies are reviewed. Principles of model fitting, including goodness-of-fit measures, are also discussed. Clinicians and researchers should pay attention to the statistical context of the models used and interpret the models to improve the oral and general health of the communities in which they live. PMID- 29478050 TI - Sodium Intake and Blood Pressure in Patients with Chronic Kidney Disease: A Salty Relationship. AB - BACKGROUND: Hypertension affects almost all chronic kidney disease patients and is related to poor outcomes. Sodium intake is closely related to blood pressure (BP) levels in this population and decreasing its intake consistently improves the BP control particularly in short-term controlled trials. However, most patients struggle in following a controlled diet on sodium according to the guidelines recommendation due to several factors and barriers discussed in this article. SUMMARY: This review article summarizes the current knowledge related to the associations between sodium consumption, BP, and the risk of cardiovascular disease and chronic kidney disease (CKD); it also provides recommendations of how to achieve sodium intake lowering. Key Messages: Evidences support the benefits in decreasing sodium intake on markers of cardiovascular and renal outcomes in CKD. Trials had shorter follow-up and to maintain long-term sodium intake control is a major challenge. Larger studies with longer follow-up looking at hard endpoints will be important to drive future recommendations. PMID- 29478052 TI - Predicting Acute Kidney Injury in Intensive Care Unit Patients: The Role of Tissue Inhibitor of Metalloproteinases-2 and Insulin-Like Growth Factor-Binding Protein-7 Biomarkers. AB - BACKGROUND: Acute kidney injury (AKI) diagnosis is based on a rise in serum creatinine and/or fall in urine output. It has been shown that there are patients that fulfill AKI definition but do not have AKI, and there are also patients with evidence of renal injury who do not meet any criteria for AKI. Recently the innovative and emerging proteomic technology has enabled the identification of novel biomarkers that allow improved risk stratification. METHODS: Tissue inhibitor of metalloproteinases-2 (TIMP-2), insulin-like growth factor-binding protein 7 (IGFBP7) were measured to a cohort of 719 consecutive patients admitted to Intensive Care Unit (ICU). The primary endpoint was the evaluation of clinical performances of the biomarkers focusing on the probability do develop AKI in the first 7 days. RESULTS: The Kaplan-Meier analysis considering the first 7 days of ICU stay suggested a lower risk of developing AKI (p < 0.0001) for patients with a negative (<0.3; TIMP-2*IGFBP7) test. CONCLUSION: (TIMP-2*IGFBP7) at ICU admission has a good performance in predicting AKI, especially in the first 4 days in ICU. PMID- 29478053 TI - Acid-Base and Electrolyte Managements in Chronic Kidney Disease and End-Stage Renal Disease: Case-Based Discussion. AB - Acid-base and electrolyte alterations are common in patients with chronic kidney disease (CKD) and end-stage kidney failure (ESRD). The alterations become more complex as CKD advances to ESRD, leading to morbidity and mortality. Three cases are presented illustrating some key prototypic features in CKD and ESRD. Each is accompanied by discussion of pathophysiology, diagnosis, and treatment options. Newer investigational results are integrated into the existing body of knowledge. Although rigorous assessment of various dialysis prescriptions is scanty, in its current state, instituting a well thought-out, multi-pronged management plan to minimize CKD/ESRD and dialysis-related electrolyte and acid-base disruptions is appropriate. There is a pressing need for prospective interventional trials in the future. PMID- 29478054 TI - Bringing Home The Bacon: Update on The State of Kidney Xenotransplantation. AB - BACKGROUND: There is a continuing critical shortage of organs from deceased human donors for transplantation, particularly for patients awaiting kidney transplantation. Efforts are being made to resolve the donor kidney shortage by the transplantation of kidneys from genetically-engineered pigs. SUMMARY: This review outlines the pathobiological barriers to pig organ xenotransplantation in primates, which include (i) antibody-dependent complement-mediated rejection, (ii) a T cell-mediated elicited antibody and cellular response, (iii) coagulation dysregulation between pigs and primates, and (iv) a persistent inflammatory response. As a result of increasing genetic manipulation of the pig and the introduction of novel immunosuppressive agents, pig kidney graft survival has increased from minutes to months, and even to >1 year in some cases. Aspects of the selection of the patients for a first clinical trial are discussed. Although there would appear to be some cross-reactivity between anti-human leukocyte antigen (HLA) antibodies and swine leukocyte antigens expressed in pigs, some HLA sensitized patients will be at no disadvantage if they receive a pig kidney. Furthermore, the current limited evidence is that, even if the patient becomes sensitized to pig antigens (after a pig organ transplant), this would not be detrimental to a subsequent allotransplant. The potential risk of infection with a pig microorganism, and the function of a pig kidney in a primate are also discussed. Key Message: The recent encouraging results of pig kidney transplantation in nonhuman primates suggest the likelihood of a successful (and safe) initial clinical trial, with graft survival for months or possibly years. PMID- 29478055 TI - Perfluorocarbons Prevent Lung Injury and Promote Development during Artificial Placenta Support in Extremely Premature Lambs. AB - BACKGROUND: Extremely premature neonates suffer high morbidity and mortality. An artificial placenta (AP) using extracorporeal life support (ECLS) is a promising therapy. OBJECTIVES: We hypothesized that intratracheal perfluorocarbon (PFC) instillation during AP support would reduce lung injury and promote lung development relative to intratracheal amniotic fluid or crystalloid. METHODS: Lambs at an estimated gestational age (EGA) 116-121 days (term 145 days) were placed on venovenous ECLS with jugular drainage and umbilical vein reinfusion and intubated. Airways were managed by the instillation of amniotic fluid and tracheal occlusion (TO; n = 4), or lactated Ringer's (LR; n = 4) or perfluorodecalin (a PFC) without occlusion (n = 4). After 7 days, the animals were sacrificed. Early (EGA 116-121 days) and late (EGA 125-131 days) tissue control lambs were delivered and sacrificed. Lungs were formalin-inflated to 30 cm H2O and sectioned for histology. Injury was scored by an unbiased pathologist. Slides were immunostained for PDGFR-alpha and alpha-actin; development was quantified by the area fraction of double-positive tips. Surfactant protein-C (SP C) concentration in bronchoalveolar lavage fluid was quantified using ELISA. RESULTS: Total injury scores were lower in PFC lungs (1.8 +/- 1.7) than in TO (6.5 +/- 2.1; p = 0.01) and LR lungs (5.5 +/- 2.4; p = 0.01). The area fraction of double-positive alveolar tips appeared higher in PFC lungs than in TO lungs (0.18 +/- 0.007 vs. 0.008 +/- 0.004; p = 0.07). SP-C concentration was higher in PFC lungs than in TO lungs (37.9 +/- 7.6 vs. 20.0 +/- 5.4 pg/mL; p = 0.005), and both early (12.4 +/- 1.7 g/mL; p = 0.007) and late tissue control lungs (15.1 +/- 5.0 pg/mL; p = 0.0008). CONCLUSION: During AP support, intratracheal PFC prevents lung injury and promotes normal lung development better than crystalloid or amniotic fluid with TO. PMID- 29478056 TI - Choosing Home Hemodialysis: A Critical Review of Patient Outcomes. AB - BACKGROUND/AIM: Home hemodialysis (HHD) has been associated with improved clinical outcomes vs. in-center HD (ICHD). The prevalence of HHD in the United States is still very low at 1.8%. This critical review compares HHD and ICHD outcomes for survival, hospitalization, cardiovascular (CV), nutrition, and quality of life (QoL). METHODS: Of 545 publications identified, 44 were not selected after applying exclusion criteria. A systematic review of the identified publications was conducted to compare HHD to ICHD outcomes for survival, hospitalization, CV outcomes, nutrition, and QoL. RESULTS: Regarding mortality, 10 of 13 trials reported 13-52% reduction; three trials found no differences. According to 6 studies, blood pressure and left ventricular size measurements were generally lower in HHD patients compared to similar measurements in ICHD patients. Regarding nutritional status, conflicting results were reported (8 studies); some found improved muscle mass, total protein, and body mass index in HHD vs. ICHD patients, while others found no significant differences. There were no significant differences in the rate of hospitalization between HHD and ICHD in the 6 articles reviewed. Seven studies on QoL demonstrated positive trends in HHD vs. ICHD populations. CONCLUSIONS: Despite limitations in the current data, 66% of the publications reviewed (29/44) demonstrated improved clinical outcomes in patients who chose HHD. These include improved survival, CV, nutritional, and QoL parameters. Even though HHD may not be preferred in all patients, a review of the literature suggests that HHD should be provided as a modality choice for substantially more than the current 1.8% of HHD patients in the United States. PMID- 29478058 TI - Visions in a Crystal Ball: The Future of Peritoneal Dialysis. AB - BACKGROUND: Peritoneal dialysis (PD) is one of the corner stones of renal replacement therapy and should be strongly considered if preemptive kidney transplantation is not available. SUMMARY: There are several initiatives that may help the growth in the use of PD around the world. First, PD is an underused and valuable option in patients with heart failure and the chronic cardiorenal syndrome, especially in those with frequent hospitalizations despite optimal medical therapy. To identify these patients, an interdisciplinary approach of nephrologists and cardiologists is needed. These patients and other CKD patients with significant residual kidney function may do well with a regimen employing fewer than the usual number of bag exchanges, referred to as "incremental" dialysis. Second, acute kidney injury (AKI) is a worldwide burden with high morbidity and mortality, especially in low income countries. To reach the goal of zero preventable deaths caused by AKI by 2025 endorsed by the International Society of Nephrology, PD is the therapy of choice for treatment in this setting. Third, although dextrose has served well as the osmotic agent in PD solutions, there has been a continuous search for alternative agents. Hyperbranched polyglycerol might be such an osmole. Finally, to obviate the need for production and delivery of bags of PD solution, the development of home-generated dialysate is of interest. Key Message: The future of PD lies not only in accruing experience from the past decades, but also in staying open to other uses. PMID- 29478057 TI - Neuroinflammation in Response to Intracerebral Injections of Different HMGB1 Redox Isoforms. AB - BACKGROUND: Neuroinflammation triggered by infection or trauma is the cause of central nervous system dysfunction. High-mobility group box 1 protein (HMGB1), released from stressed and dying brain cells, is a potent neuroinflammatory mediator. The proinflammatory functions of HMGB1 are tightly regulated by post translational redox modifications, and we here investigated detailed neuroinflammatory responses induced by the individual redox isoforms. METHODS: Male Dark Agouti rats received a stereotactic injection of saline, lipopolysaccharide, disulfide HMGB1, or fully reduced HMGB1, and were accessed for blood-brain barrier modifications using magnetic resonance imaging (MRI) and inflammatory responses by immunohistochemistry. RESULTS AND CONCLUSIONS: Significant blood-brain barrier disruption appeared 24 h after injection of lipopolysaccharide, disulfide HMGB1, or fully reduced HMGB1 compared to controls, as assessed in post-gadolinium T1-weighted MRI images and confirmed by increased uptake of FITC-conjugated dextran. Immunohistochemistry revealed that both HMGB1 isoforms also induced a local production of IL-1beta. Additionally, disulfide HMGB1 increased major histocompatibility complex class II expression and apoptosis. Together, the results demonstrate that extracellular, cerebral HMGB1 causes significant blood-brain barrier disruption in a redox-independent manner and activates several components of neuroinflammation. Blocking HMGB1 might potentially improve clinical outcome in conditions such as stroke and traumatic brain injury. PMID- 29478059 TI - Skin Examination: An Important Diagnostic Tool in Renal Failure Patients. AB - Renal failure is common in the United States with an estimated prevalence of 660,000 treated end-stage renal disease patients in 2015 [1]. Causes of renal failure are many, and complications from renal failure, underlying disease, and treatment are not infrequent. Examples of common skin manifestations include xerosis, pigmentary change, and nail dystrophies. Frequent disease-specific skin changes may be helpful in the diagnosis of primary disorders leading to renal disease or severity of disease including bullosis diabeticorum, sclerodactyly, or leukoctoclastic vasculitis. Some cutaneous changes, such as the multiple angiokeratomas of Fabry disease or the plexiform neurofibromas of neurofibromatosis, are pathognomonic of genetic disorders, which often lead to renal failure. Careful examination of the skin can provide crucial clues to diagnosis of renal failure causation and aid in monitoring complications. PMID- 29478060 TI - Standardized Protocol for Hemodialysis Vascular Access Assessment: The Role of Ultrasound and ColorDoppler. AB - INTRODUCTION: Ultrasound and colorDoppler technique, which is relatively inexpensive, rapid, non-invasive and repeatable is a powerful tool used for early diagnosis of vascular access (VA) complications in hemodialysis patients. To date a standard and widely comprehensible echocolorDoppler (ECD) protocol is not available. MATERIALS AND METHODS: A simple step-by-step protocol based on anatomical and hemodynamic parameters of VA has been developed during a 3-years VA ECD follow-up. It consists of an ECD study scheme. The algorithm created involves the calculation of brachial artery flow, description of artero-venous and/or graft-vascular anastomosis and efferent vessel and/or graft. RESULTS: The algorithm allows to formulate a medical report that takes into account both anatomic and hemodynamic parameters of the VA. Reduction of complications and the prevention of chronic complications as well as the early detection of acute problems were achieved. DISCUSSION AND CONCLUSION: The creation of a step-by-step protocol may simplify the multidisciplinary management of VA, its monitoring and the early diagnosis of its complications. PMID- 29478061 TI - Fluid Overload and Inflammation Axis. AB - Extracellular fluid overload (FO), which is assessed using bioimpedance technologies, is an important predictor of outcome in dialysis patients and in patients with early stages of chronic kidney disease. While traditional cardiovascular abnormalities are assumed to mediate this risk, recently also, the importance of noncardiovascular factors, such as systemic inflammation and malnutrition has been shown. While both FO and inflammation are independent risk factors for mortality, recent studies have shown that their combined presence can lead to a cumulative risk profile. From a pathophysiologic viewpoint, FO and inflammation can also be mutually reinforcing. Inflammation could contribute to FO by hypoalbuminemia, capillary leakage, and a (unnoticed) decline in lean and/or fat tissue mass resulting in incorrect estimation of dry weight. Reciprocally, FO could lead to inflammation by the translocation of endotoxins through a congested bowel wall or by a proinflammatory effect of tissue sodium. The relative importance of these putative factors is, however, not clear yet and epidemiological studies have shown no clear temporal direction regarding the relationship between FO and inflammation. FO and inflammation appear to be part of (dynamic) clusters of risk factors, including malnutrition and hyponatremia. Technology-guided fluid management of the often vulnerable dialysis patient with FO and inflammation cannot yet be based on evidence from randomized controlled trials, in which these specific patients were in general not included. In the absence of those trials, treatment should be based on identifying actionable causes of inflammation and on the judicious removal of excess volume based on frequent clinical reassessment. PMID- 29478062 TI - Novel Insights into the Pathogenesis and Prevention of Intradialytic Hypotension. AB - BACKGROUND: Intradialytic hypotension (IDH) is a common complication of haemodialysis (HD) and associated with adverse outcomes, especially when a nadir definition (systolic blood pressure <90 mm Hg) is used. The pathogenesis of IDH is directly linked to the discontinuous nature of the HD treatment, in combination with patient-related factors such as age, diabetes mellitus and cardiac failure. SUMMARY: Although the decline in blood volume due to removal of fluid by ultrafiltration is the prime mover, thermally induced reflex vasodilation compromises the haemodynamic response to hypovolemia. Recent studies have stressed the relevance of changes in tissue perfusion during HD, which may translate in long-term organ damage. Monitoring changes in tissue perfusion, for which emerging evidence becomes available, appears to have great promise in the fine-tuning of the dialysis procedure. Key Messages: While it is unlikely that IDH can be completely prevented, reduction in inter-dialytic weight gain, prevention of an increase in core temperature by adjusting the dialysate temperature and more frequent or prolonged dialysis treatment remain cornerstones in providing a more comfortable and safe treatment. PMID- 29478063 TI - Epigenetics, Early Adversity and Child and Adolescent Mental Health. AB - Epigenetic modification, such as DNA methylation (DNAm), is a mechanism that can help explain how early adversities can engender long-term vulnerability for mental health problems. At present, there is preliminary evidence to support the possibility of epigenetic mediation: environmental factors are reported to influence offspring DNAm, which in turn associate with child and adolescent psychopathology. However, all analyses have been correlational in nature and, as these studies have focussed on children and adolescents, DNAm has been based on peripheral tissue (cord blood, whole blood, buccal cells). Therefore, the extent to which DNAm could represent a causal mechanism (e.g., a surrogate of central nervous system function) or a biomarker (i.e., an indicator of the pathological process leading to disease) is unclear. This short report has 2 main components. First, 2 studies are summarized, one a candidate gene study and the other an epigenome-wide association study in which DNAm was reported to (partially) mediate the link between adversity and child development. Second, there is a discussion of (1) the "tissue issue," (2) maximizing the interpretability of candidate gene and epigenome-wide approaches, and (3) the need for examining DNAm as a potential biomarker for mental health. It is argued that advances within these 3 areas will make clearer the role of DNAm in the link between adversity and child and adolescent mental health. PMID- 29478064 TI - Preface - Advances in CKD 2018. PMID- 29478065 TI - Pregnancy and End-Stage Renal Disease. AB - Pregnancy is uncommon in women with end-stage renal disease (ESRD). Fertility rates are low in women on dialysis, and physicians still frequently counsel women with ESRD against pregnancy. Advancements in the delivery of dialysis and obstetric care have led to improved live birth rates in women on dialysis, so pregnancy for young women with ESRD is now more feasible and safer. However, these pregnancies remain high-risk for both maternal and fetal complications, necessitating experienced multidisciplinary care. In this article, we review fertility issues in women with ESRD, discuss pregnancy outcomes in women on dialysis, and provide an approach for management of pregnant women with ESRD. PMID- 29478066 TI - Acute Kidney Injury in Sub-Sahara Africa: A Single-Center Experience from Khartoum, Sudan. AB - BACKGROUND: The burden of acute kidney injury (AKI) is high in Africa. While there are no reliable statistics about AKI in Africa, the Global Snapshot Study of the 0by25 initiative of the International Society of Nephrology has determined dehydration, infections, animal envenomation, and complications during pregnancy as the main causes. METHODS: This study was conducted at the Soba University Hospital (SUH), Khartoum, Sudan, a tertiary referral center. We included all hemodialysis patients treated for AKI at SUH between -January 1, 2013 and December 31, 2014 in the study. We reviewed patients' hospital records and characterized pathogenesis, treatment, and patient outcomes. In addition, we investigated survival by Kaplan-Meier and Cox regression analysis. RESULTS: Out of 520 patients who received emergency HD, 71 patients (14%) had AKI (age 40.6 +/ 17.3 years, 56.5% were males). Glomerular and tubular-interstitial diseases were the leading cause of AKI, followed by envenomation and intoxication by hair dye. Patients received a median of 5 dialysis sessions for a median of 8 days. In 32 patients (45%) renal function recovered, 10 patients (14%) died, and 29 patients (41%) remained dialysis-dependent. Mortality was significantly higher in females compared to men (hazard ratio 4.1 [95% CI 1.02-16.67]). Outcomes were worse in patients with pre-renal AKI and intoxications. CONCLUSION: Our results indicate a higher mortality in females and in patients with pre-renal AKI and intoxications. Awareness of factors associating with poor outcomes is central to diagnostic and therapeutic efforts, and must be considered in the design of initiatives to reduce risk factors and improve outcomes of AKI in developing countries. PMID- 29478067 TI - What We Do and Do Not Know about Women and Kidney Diseases; Questions Unanswered and Answers Unquestioned: Reflection on World Kidney Day and International Woman's Day. AB - Chronic kidney disease affects approximately 10% of the world's adult population: it is within the top 20 causes of death worldwide, and its impact on patients and their families can be devastating. World Kidney Day and International Women's Day in 2018 coincide, thus offering an opportunity to reflect on the importance of women's health and specifically their kidney health, on the community and the next generations, as well as to strive to be more curious about the unique aspects of kidney disease in women so that we may apply those learnings more broadly. Girls and women, who make up approximately 50% of the world's population, are important contributors to society and their families. Gender differences continue to exist around the world in access to education, medical care, and participation in clinical studies. Pregnancy is a unique state for women, offering an opportunity for diagnosis of kidney disease, but also a state where acute and chronic kidney diseases may manifest, and which may impact future generations with respect to kidney health. There are various autoimmune and other conditions that are more likely to have an impact on women, with profound consequences for child bearing, and on the fetus. Women have different complications on dialysis than men, and are more likely to be donors than recipients of kidney transplants. In this editorial, we focus on what we do and do not know about women, kidney health, and kidney disease, and what we might learn in the future to improve outcomes worldwide. PMID- 29478068 TI - Fistula Cannulation with a Novel Fistula Cannula: A Review of Cannulation Devices and Procedures. AB - Arteriovenous fistula cannulation for dialysis treatments in Europe has traditionally been done by metal needles. In -Japan, plastic cannulas have been available for many years and are used in the majority of the dialysis patients. The mechanical structure and the cannulation procedure of the plastic cannulas differ from those of the metal needles. These differences are particularly beneficial for patients with delicate fistulas, tortuous vessels, metal allergies, oligophrenic patients, and also for the safety of the medical staff. In this paper, we present the main features of a novel fistula plastic cannula and the innovations introduced by it compared to the traditional metal needles. PMID- 29478069 TI - Magnesium in Chronic Kidney Disease: Should We Care? AB - BACKGROUND: Magnesium (Mg) is an essential cation for multiple processes in the body. The kidney plays a major role in regulating the Mg balance. In a healthy individual, total-body Mg content is kept constant by interactions among intestine, bones and the kidneys. SUMMARY: In case of chronic kidney disease (CKD), renal regulatory mechanisms may be insufficient to balance intestinal Mg absorption. Usually Mg remains normal; however, when glomerular filtration rate declines, changes in serum Mg are observed. Patients with end-stage renal disease on dialysis are largely dependent on the dialysate Mg concentration for maintaining serum Mg and Mg homeostasis. A low Mg is associated with several complications such as hypertension, and vascular calcification, and also associated with an increased risk for both cardiovascular disease (CVD) and non CVD mortality. Severe hypermagnesaemia is known to cause cardiac conduction defects, neuromuscular effects and muscle weakness; a slightly elevated Mg has been suggested to be beneficial in patients with end-stage renal disease. Key Messages: The role of both low and high Mg, in general, but especially in relation to CKD and dialysis patients is discussed. PMID- 29478071 TI - Prevalence of Iron Deficiency and Iron Deficiency Anemia in Strenuously Training Male Army Recruits. AB - OBJECTIVES: The objectives of our study were to determine the effect of strenuous physical training on the prevalence of iron deficiency anemia (IDA), iron deficiency (ID) with normal hemoglobin (Hb), and anemia without ID. METHODS: Our study was a prospective observational study. We followed 115 healthy male recruits in the Israel Defense Forces elite units during 15 months of training. Blood samples were collected at recruitment and at 6-, 9- and 15-month follow ups. RESULTS: Upon recruitment, anemia (Hb < 14 g/dL), ID, and ID anemia (IDA) were diagnosed in 28, 31, and 9% of individuals, respectively. Sixty-three subjects (54%) were followed for 6 months; 9 of them (14%) developed new-onset IDA. Among them, the prevalence of anemia rose from 19 to 52%, and ID from 33 to 35%. At the 15-month follow-up, 29% had developed new-onset IDA and 65% showed evidence of ID. CONCLUSION: We report a high prevalence of anemia, ID, and IDA among young healthy males participating in prolonged strenuous training programs. These findings can be partly explained by the physiological changes associated with strenuous physical activity. Further investigations aiming to develop specific diagnostic guidelines for this unique population are warranted. PMID- 29478072 TI - Treatment of Rapidly Progressive Glomerulonephritis in the Elderly. AB - As the population worldwide ages, the epidemic of kidney disease will also increase. Anti-neutrophil cytoplasmic antibodies (ANCA) positive rapidly progressive positive glomerulonephritis (RPGN) is the most common etiology for biopsied patients among the very elderly. Its pathological features and clinical course are well described, though there is still debate about the mechanism of injury involved in individual patients. From very ancient times, the cornerstone of treatment historically has been high-dose cyclophosphamide and a lengthy course of high-dose corticosteroids. Although this regimen has diminished the immediate mortality rate of RPGN, its intermediate and long-term adverse effects are not insignificant. Attempts to minimize toxicity and improve efficacy have been made through the years to allow physicians some options for therapy. Lower cumulative cyclophosphamide regimens, shorter corticosteroid courses, and the introduction of rituximab have modified the armamentarium for treatment of ANCA positive RPGN. As progress is made in understanding the molecular pathogenesis of this disease, new targets will be found for potential therapeutic attack. The complement system is an area of active interest for all glomerular diseases at this time. Indeed, animal studies and preliminary human studies suggest that targeting the complement system can ameliorate the course of ANCA-positive RPGN. Hopefully, as the population ages, we will see more and safer therapeutic options to treat this once rapidly fatal disease. PMID- 29478073 TI - Assessment of Screw Length of Proximal Humerus Internal Locking System (PHILOS) Plate for Proximal Humeral Fractures Using Three-Dimensional Computed Tomography Scan. AB - BACKGROUND Screw perforation and varus collapse are common complications of treatment with a PHILOS (proximal humerus internal locking system) plate for proximal humerus fractures, which are associated with improper screw length selection and lack of medial column support. The purposes of this study were: (1) to measure the proper length of periarticular screws of the PHILOS plate in the humeral head, and (2) to determine what factors influence the screw length and implantation of the inferomedial support screw. MATERIAL AND METHODS Computed tomography (CT) images of the normal proximal humerus in 134 cases were retrospectively reviewed. The length of periarticular screws was measured using three-dimensional (3D) techniques. Intraobserver and interobserver reliability of measurement were evaluated using intraclass correlation coefficients (ICCs). Sex and body height influences on screw length and implantation of the inferomedial screw were analyzed. RESULTS All measurements had excellent agreement (ICC>0.75). The screw length and implantation rate of the inferomedial screw were greater in males than in females. Positive correlations were observed between body height and screw length and implantation of the inferomedial screw (all P<0.001). CONCLUSIONS The screws were longer and the implantation rate was higher for inferomedial screws in males than in females, and were positively correlated with body height. Our data can be used as a reference for surgeons to reduce the number of times screws are changed intraoperatively and to reduce operation duration and minimize use of intraoperative fluoroscopy for proximal humerus fractures treated with the PHILOS plate. PMID- 29478074 TI - Comparison of Cytotoxic Effects of Intra-Articular Use of Tranexamic Acid versus Epinephrine on Rat Cartilage. AB - BACKGROUND Adequate visualization is known to be essential to perform arthroscopic procedures effectively and efficiently. We hypothesized that tranexamic acid may be considered as an alternative agent to reduce intra articular bleeding during arthroscopic procedures, after comparing its potential chondrotoxicity with that of epinephrine. MATERIAL AND METHODS Seventy-two rats were randomized into 3 groups with 24 rats each. The injections were performed in the right knees, as follows: Group 1: 0.25 mL of tranexamic acid solution, Group 2: 0.25 mL of epinephrine solution, and Group 3: 0.25 mL of 0.9% saline, serving as control. One week after the injections, the animals were euthanized. Samples were evaluated histologically based on the Osteoarthritis Research Society International (OARSI) Histopathology Grading and Staging System and the "live/dead" staining technique to determine chondrocyte viability. RESULTS Comparison of epinephrine and tranexamic acid revealed significantly higher OARSI scores in the epinephrine group (epinephrine: 3.42+/-1.31, TA: 0.92+/-0.90; P<0.001). The most significant difference between the 2 groups was in the number of joints diagnosed with OARSI grade III. The percentage of viability was significantly higher in the tranexamic acid group when compared with the epinephrine group (tranexamic acid: 79.74+/-3.343; epinephrine: 63.81+/-1.914; P<0.05). CONCLUSIONS Based on the histologic parameters and chondrocyte viability, tranexamic acid is less cytotoxic than epinephrine in rat chondrocytes at the doses typically used in irrigation fluid, and may be a good alternative to epinephrine in arthroscopic surgery. PMID- 29478075 TI - Cancer evolution, mutations, and clonal selection in relapse neuroblastoma. AB - The notion of cancer as a complex evolutionary system has been validated by in depth molecular analyses of tumor progression over the last years. While a complex interplay of cell-autonomous programs and cell-cell interactions determines proliferation and differentiation during normal development, intrinsic and acquired plasticity of cancer cells allow for evasion of growth factor limitations, apoptotic signals, or attacks from the immune system. Treatment induced molecular selection processes have been described by a number of studies already, but understanding of those events facilitating metastatic spread, organ specific homing, and resistance to anoikis is still in its early days. In principle, somatic events giving rise to cancer progression should be easier to follow in childhood tumors bearing fewer mutations and genomic aberrations than their counterparts in adulthood. We have previously reported on the genetic events accompanying relapsing neuroblastoma, a solid tumor of early childhood. Our results indicated significantly higher single nucleotide variants in relapse tumors, gave hints for branched tumor evolution upon treatment and clonal selection as deduced from shifts in allelic frequencies between primary and relapsing neuroblastoma. Here, we will review these findings and give an outlook on dealing with intratumoral heterogeneity and sub-clonal diversity in neuroblastoma for future targeted treatments. PMID- 29478076 TI - Commentary on ''European status on temporal bone training: a questionnaire study''. PMID- 29478077 TI - Airwayplasty: long-term outcome of nasal wall lateralisation. AB - BACKGROUND: There are a variety of surgical techniques which can be used to treat structural nasal obstruction. Airwayplasty is a procedure, combining septoplasty, turbinate surgery, and nasal wall lateralization. The article reports the long term result of this novel approach. METHODOLOGY: Patients who have evidence of structural nasal obstruction were offered the option to have airwayplasty under the senior surgeon. Patients were asked to quantify the severity and the impact of their nasal obstruction using the Visual Analogue Scale (VAS) and the validated Sino-Nasal Outcome Test (SNOT-22) pre-operatively and post-operatively. RESULTS: The mean total SNOT-22 score and VAS score showed a reduction of more than 50% with significant p value at 6 and 12 months post-operatively. CONCLUSIONS: This novel approach to nasal obstruction can provide good long-term functional results for patients suffering from nasal obstruction. PMID- 29478078 TI - Health-related quality of life in patients with major salivary gland carcinoma. AB - PURPOSE: To evaluate the health-related quality of life (QOL) in patients with major salivary gland carcinoma (MSGC). METHODS: 45 patients with MSGC completed the University of Washington Quality of Life (UWQOL) questionnaire. Results and factors influencing quality of life were analyzed using Mann-Whitney U test. RESULTS: 24 patients were male, 21 patients were female, and median age was 57 years. 33 patients presented with early stage (UICC stage I or II) cancer. All patients had surgery as initial therapy. The UWQOL domains with the worst results were 'appearance', 'activity' and 'anxiety'. Factors influencing QOL were sex, tumor stage, comorbidities, follow-up time, tumor grade, postoperative radiation therapy and facial nerve dysfunction. CONCLUSIONS: Diagnosis and treatment of MSGC has influence on overall QOL. Postoperative radiation has the greatest impact on QOL. This is one of the largest study evaluating QOL in patients with salivary gland carcinoma using the UWQOL. PMID- 29478079 TI - The role of interim 18F-FDG PET/CT in prediction of response to ipilimumab treatment in metastatic melanoma. AB - PURPOSE: The aim of the present study was to assess the value of interim 18F-FDG PET/CT performed after the first two cycles of ipilimumab treatment in the prediction of the final clinical response to this type of immunotherapy. METHODS: The study group comprised 41 patients with unresectable metastatic melanoma scheduled for ipilimumab therapy. Whole-body 18F-FDG PET/CT was performed before the start of ipilimumab treatment (baseline PET/CT) and after the initial two cycles of ipilimumab treatment (interim PET/CT). Evaluation of patient response to treatment was based on the European Organization for Research and Treatment of Cancer (EORTC) 1999 criteria for PET as well as the recently proposed PET Response Evaluation Criteria for Immunotherapy (PERCIMT). The patients' best clinical response, assessed at a median of 21.4 months (range 6.3-41.9 months) was used as reference. RESULTS: According to their best clinical response, the patients were divided into two groups: those showing clinical benefit (CB) including stable disease, partial response and complete response (31 patients), and those showing no clinical benefit (no-CB including progressive disease (10 patients). According to the EORTC criteria, interim PET/CT demonstrated progressive metabolic disease (PMD) in 20 patients, stable metabolic disease (SMD) in 11 patients, partial metabolic response (PMR) in 8 patients, and complete metabolic response (CMR) in 2 patients. According to the PERCIMT, interim PET/CT demonstrated PMD in 9 patients, SMD in 24 patients, PMR in 6 patients and CMR in 2 patients. On the basis of the interim PET, the patients were divided in a similar manner to the division according to clinical response into those showing metabolic benefit (MB) including SMD, PMR and CMR, and those showing no metabolic benefit (no-MB) including PMD. According to this dichotomization, the EORTC criteria showed a sensitivity (correctly predicting CB) of 64.5%, a specificity (correctly predicting no-CB) of 90.0%, a positive predictive value (PPV) of 95.2%, a negative predictive value (NPV) of 45.0% and an accuracy of 70.7% in predicting best clinical response. The PERCIMT showed a sensitivity of 93.6%, a specificity of 70.0%, a PPV of 90.6%, a NPV of 77.8% and an accuracy of 87.8%. The McNemar test showed that the PERCIMT had a significantly higher sensitivity than EORTC criteria (p = 0.004), while there was no significant difference in specificity (p = 0.5). The agreement between the two sets of criteria was poor (McNemar test p = 0.001, and accordingly kappa = 0.46). CONCLUSION: The application of the recently proposed PERCIMT to interim 18F-FDG PET/CT provides a more sensitive predictor of final clinical response to immunotherapy than the application of the EORTC criteria in patients with metastatic melanoma. PMID- 29478080 TI - FDG-PET/CT for treatment response assessment in head and neck squamous cell carcinoma: a systematic review and meta-analysis of diagnostic performance. AB - PURPOSE: 18-fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG-PET/CT) is increasingly used to evaluate treatment response in head and neck squamous cell carcinoma (HNSCC). This analysis assessed the diagnostic value of FDG-PET/CT in detecting nodal disease within 6 months after treatment, considering patient and disease characteristics. METHODS: A systematic review was performed using the MEDLINE and Web of Knowledge databases. The results were pooled using a bivariate random effects model of the sensitivity and specificity. RESULTS: Out of 22 identified studies, a meta-analysis of 20 studies (1293 patients) was performed. The pooled estimates of sensitivity, specificity and diagnostic odds ratio (with 95% CI) were 85% (76-91%), 93% (89 96%) and 76 (35-165), respectively. With the prevalence set at 10%, the positive and negative predictive values were 58% and 98%. There was significant heterogeneity between the trials (p < 0.001). HPV positive tumors were associated with lower sensitivity (75% vs 89%; p = 0.01) and specificity (87% vs 95%; p < 0.005). CONCLUSION: FDG-PET/CT within 6 months after (chemo)radiotherapy in HNSCC patients is a reliable method for ruling out residual/recurrent nodal disease and obviates the need for therapeutic intervention. However, FDG-PET/CT may be less reliable in HPV positive tumors and the optimal surveillance strategy remains to be determined. PMID- 29478081 TI - Hybrid MR-PET of brain tumours using amino acid PET and chemical exchange saturation transfer MRI. AB - PURPOSE: PET using radiolabelled amino acids has become a promising tool in the diagnostics of gliomas and brain metastasis. Current research is focused on the evaluation of amide proton transfer (APT) chemical exchange saturation transfer (CEST) MR imaging for brain tumour imaging. In this hybrid MR-PET study, brain tumours were compared using 3D data derived from APT-CEST MRI and amino acid PET using O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET). METHODS: Eight patients with gliomas were investigated simultaneously with 18F-FET PET and APT-CEST MRI using a 3-T MR-BrainPET scanner. CEST imaging was based on a steady-state approach using a B1 average power of 1MUT. B0 field inhomogeneities were corrected a Prametric images of magnetisation transfer ratio asymmetry (MTRasym) and differences to the extrapolated semi-solid magnetisation transfer reference method, APT# and nuclear Overhauser effect (NOE#), were calculated. Statistical analysis of the tumour-to-brain ratio of the CEST data was performed against PET data using the non-parametric Wilcoxon test. RESULTS: A tumour-to-brain ratio derived from APT# and 18F-FET presented no significant differences, and no correlation was found between APT# and 18F-FET PET data. The distance between local hot spot APT# and 18F-FET were different (average 20 +/- 13 mm, range 4-45 mm). CONCLUSION: For the first time, CEST images were compared with 18F-FET in a simultaneous MR-PET measurement. Imaging findings derived from18F-FET PET and APT CEST MRI seem to provide different biological information. The validation of these imaging findings by histological confirmation is necessary, ideally using stereotactic biopsy. PMID- 29478082 TI - Japanese multicenter database of healthy controls for [123I]FP-CIT SPECT. AB - PURPOSE: The aim of this multicenter trial was to generate a [123I]FP-CIT SPECT database of healthy controls from the common SPECT systems available in Japan. METHODS: This study included 510 sets of SPECT data from 256 healthy controls (116 men and 140 women; age range, 30-83 years) acquired from eight different centers. Images were reconstructed without attenuation or scatter correction (NOACNOSC), with only attenuation correction using the Chang method (ChangACNOSC) or X-ray CT (CTACNOSC), and with both scatter and attenuation correction using the Chang method (ChangACSC) or X-ray CT (CTACSC). These SPECT images were analyzed using the Southampton method. The outcome measure was the specific binding ratio (SBR) in the striatum. These striatal SBRs were calibrated from prior experiments using a striatal phantom. RESULTS: The original SBRs gradually decreased in the order of ChangACSC, CTACSC, ChangACNOSC, CTACNOSC, and NOACNOSC. The SBRs for NOACNOSC were 46% lower than those for ChangACSC. In contrast, the calibrated SBRs were almost equal under no scatter correction (NOSC) conditions. A significant effect of age was found, with an SBR decline rate of 6.3% per decade. In the 30-39 age group, SBRs were 12.2% higher in women than in men, but this increase declined with age and was absent in the 70-79 age group. CONCLUSIONS: This study provided a large-scale quantitative database of [123I]FP CIT SPECT scans from different scanners in healthy controls across a wide age range and with balanced sex representation. The phantom calibration effectively harmonizes SPECT data from different SPECT systems under NOSC conditions. The data collected in this study may serve as a reference database. PMID- 29478083 TI - Recovering normal networks from shortest inter-taxa distance information. AB - Phylogenetic networks are a type of leaf-labelled, acyclic, directed graph used by biologists to represent the evolutionary history of species whose past includes reticulation events. A phylogenetic network is tree-child if each non leaf vertex is the parent of a tree vertex or a leaf. Up to a certain equivalence, it has been recently shown that, under two different types of weightings, edge-weighted tree-child networks are determined by their collection of distances between each pair of taxa. However, the size of these collections can be exponential in the size of the taxa set. In this paper, we show that, if we have no "shortcuts", that is, the networks are normal, the same results are obtained with only a quadratic number of inter-taxa distances by using the shortest distance between each pair of taxa. The proofs are constructive and give cubic-time algorithms in the size of the taxa sets for building such weighted networks. PMID- 29478084 TI - Enhanced laccase-mediated transformation of diclofenac and flufenamic acid in the presence of bisphenol A and testing of an enzymatic membrane reactor. AB - The inadequate removal of pharmaceuticals and other micropollutants in municipal wastewater treatment plants, as evidenced by their detection of these substances in the aquatic environment has led to the need for sustainable remediation strategies. Laccases possess a number of advantages including a broad substrate spectrum. To identify promoting or inhibitory effects of reaction partners in the remediation processes we tested not only single compounds-as has been described in most studies-but also mixtures of pollutants. The reaction of diclofenac (DCF) and flufenamic acid (FA), mediated by Trametes versicolor laccase resulted in the formation of products, which were more hydrophilic than the respective reactant (reactant concentration of 0.1 mM; laccase activity 0.5 U/ml). Analyses (HPLC, LC/MS) showed that the product 1a and 1b for DCF and FA, respectively, to be a para-benzoquinone imine derivative. The formation of 1a was enhanced by the addition of bisphenol A (BPA). After 6 days 97% more product was formed in the mixture of DCF and BPA compared with DCF tested alone. Product 1a was also detected in experiments with micropollutant-supplemented secondary effluent. Within 24 h 67% and 100% of DCF and BPA were transformed, respectively (25 U/ml). Experiments with a membrane reactor (volume 10 l; phosphate buffer, pH 7) were in good agreement with the results of the laboratory scale experiments (50 ml). EC50 values were also determined. The data support the use of laccases for the removal or detoxification of recalcitrant pollutants. Thus, the enzyme laccase may be a component of an additional environmentally friendly process for the treatment stage of wastewater remediation. PMID- 29478085 TI - Transradial Artery Access in Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction and Cardiogenic Shock. AB - Early revascularization is the gold standard for management of patients with ST elevation myocardial infarction (STEMI) and cardiogenic shock (CS). The use of transradial artery access (TRA) in percutaneous coronary intervention (PCI) has increased in recent years and has emerged as a safe and effective approach to PCI in high-risk patients, with advantages in reduced major bleeding events, other peri-procedural complications, and all-cause mortality when compared with transfemoral artery access (TFA). Multiple randomized clinical trials have demonstrated these advantages of TRA vs. TFA PCI in STEMI patients. Although there remains a lack of dedicated randomized trials in CS, observational data suggest benefits on the same endpoints as in STEMI with TRA vs. TFA PCI in CS. This review summarizes the existing literature on the use of TRA compared to TFA for STEMI and CS patients; the reduction of major bleeding events, other peri procedural complications, and mortality associated with TRA in STEMI and CS; and technical considerations and challenges in the care of these high-risk patient populations. PMID- 29478086 TI - Modeling interactions between saturated and un-saturated zones by Hydrus-1D in semi-arid regions (plain of Kairouan, Central Tunisia). AB - In semi-arid areas like the Kairouan region, salinization has become an increasing concern because of the constant irrigation with saline water and over use of groundwater resources, soils, and aquifers. In this study, a methodology has been developed to evaluate groundwater contamination risk based on the unsaturated zone hydraulic properties. Two soil profiles with different ranges of salinity, one located in the north of the plain and another one in the south of plain (each 30 m deep) and both characterized by direct recharge of the aquifer, were chosen. Simulations were conducted with Hydrus-1D code using measured precipitation data for the period 1998-2003 and calculated evapotranspiration for both chosen profiles. Four combinations of initial conditions of water content and salt concentration were used for the simulation process in order to find the best match between simulated and measured values. The success of the calibration of Hydrus-1D allowed the investigation of some scenarios in order to assess the contamination risk under different natural conditions. The aquifer risk contamination is related to the natural conditions where it increased while facing climate change and temperature increase and decreased in the presence of a clay layer. Hydrus-1D was a useful tool to predict the groundwater level and quality in the case of a direct recharge and in the absence of any information related to the soil layers except for the texture. PMID- 29478087 TI - Journal of clinical monitoring and computing 2017 end of year summary: anesthesia. PMID- 29478088 TI - The use of Data Envelopment Analysis (DEA) in healthcare with a focus on hospitals. AB - The healthcare sector in general and hospitals in particular represent a main application area for Data Envelopment Analysis (DEA). This paper reviews 262 papers of DEA applications in healthcare with special focus on hospitals and therefore closes a gap of over ten years that were not covered by existing review articles. Apart from providing descriptive statistics of the papers, we are the first to examine the research purposes of the publications. These research goals can be grouped into four distinct clusters according to our proposed framework. The four clusters are (1) "Pure DEA efficiency analysis", i.e. performing a DEA on hospital data, (2) "Developments or applications of new methodologies", i.e. applying new DEAy approaches on hospital data, (3) "Specific management question", i.e. analyzing the effects of managerial specification, such as ownership, on hospital efficiency, and (4) "Surveys on the effects of reforms", i.e. researching the impact of policy making, such as reforms of health systems, on hospital efficiency. Furthermore, we analyze the methodological settings of the studies and describe the applied models. We analyze the chosen inputs and outputs as well as all relevant downstream techniques. A further contribution of this paper is its function as a roadmap to important methodological literature and publications, which provide crucial information on the setup of DEA studies. Thus, this paper should be of assistance to researchers planning to apply DEA in a hospital setting by providing information on a) what has been published between 2005 and 2016, b) possible pitfalls when setting up a DEA analysis, and c) possible ways to apply the DEA analysis in practice. Finally, we discuss what could be done to advance DEA from a scientific tool to an instrument that is actually utilized by managers and policymakers. PMID- 29478089 TI - Serum/glucocorticoid-regulated kinase 1 as a novel transcriptional target of bone morphogenetic protein-ALK1 receptor signaling in vascular endothelial cells. AB - Bone morphogenetic protein 9 (BMP9)/BMP10-ALK1 receptor signaling is essential for endothelial differentiation and vascular morphogenesis. Mutations in ALK1/ACVRL1 and other signal-related genes are implicated in human vascular diseases, and the Alk1/Acvrl1 deletion in mice causes severe impairment of vascular formation and embryonic lethality. In the microarray screen to search for novel downstream genes of ALK1 signaling, we found that the mRNA and protein expression of serum/glucocorticoid-regulated kinase 1 (SGK1) was rapidly up regulated by the BMP9 stimulation of cultured human endothelial cells. The increase in SGK1 mRNA was completely blocked by the transcriptional inhibitor actinomycin D and significantly suppressed by the siRNA treatment against the co SMAD transcription factor SMAD4. Upon the BMP9 treatment of endothelial cells, phosphorylated SMAD1/5/9 bound to a consensus site upstream of the SGK1 gene, which was necessary for BMP9-dependent increment of the luciferase reporter activity driven by the SGK1 proximal enhancer. The Sgk1 mRNA expression in mouse embryos was enriched in vascular endothelial cells at embryonic day 9.0-9.5, at which Sgk1 null mice showed embryonic lethality due to abnormal vascular formation, and its mRNA as well as protein expression was clearly reduced in Alk1/Acvrl1 null embryos. These results indicate that SGK1 is a novel target gene of BMP9/BMP10-ALK1 signaling in endothelial cells and further suggest a possibility that down-regulation of the Sgk1 expression may be involved in the mechanisms of vascular defects by the ALK1 signaling deficiency. PMID- 29478090 TI - Species- and density-dependent induction of volatile organic compounds by three mite species in cassava and their role in the attraction of a natural enemy. AB - Upon damage by herbivores, plants induce an array of volatile organic compounds (VOCs) that mediate ecological interactions involving communication with organisms of the second and third trophic levels. VOC-mediated tritrophic interactions have largely been studied in various systems, including cassava (Manihot esculenta), but little is known about the chemical nature of herbivore induced VOCs in this crop and the response they evoke in natural enemies. Several tetranychid and predatory mites are associated with cassava. Here, VOC emissions from uninfested plants and plants infested with 200 or 400 Mononychellus tanajoa, a specialist herbivore on cassava, and the generalists Tetranychus urticae and T. gloveri were measured. Dual-choice experiments were also conducted to assess the preference of inexperienced (reared on prey-infested bean plants) and experienced (adapted on prey-infested cassava plants) predatory mites, Neoseiulus idaeus (Phytoseiidae), between odors of uninfested plants versus odors of plants infested with M. tanajoa, T. urticae or T. gloveri. Two hundred individuals significantly increased the emissions of (Z)-3-hexen-1-ol, (E)-beta-ocimene, beta caryophyllene, alloaromadendrene and (E)-geranyl acetone in T. urticae-infested plants, and (E)-beta-ocimene and methyl salicylate (MeSA) in T. gloveri-infested plants. Four hundred individuals significantly increased the emissions of (Z)-3 hexen-1-ol, MeSA, alpha-pinene and D-limonene in M. tanajoa-infested plants. In addition, T. urticae at this density induced (E)-beta-ocimene, D-limonene, (E) geranyl acetone and six compounds that were not detected in other treatments. Tetranychus gloveri-infested plants induced the emissions of (E)-2-hexenal and D limonene. Regardless of the infesting species, inexperienced N. idaeus did not discriminate between uninfested or infested plants. Upon experience, they discriminated between the odors of uninfested and T. urticae-damaged plants. Our findings reveal that mite infestations in cassava result in density-dependent and species-specific emission of VOCs, and that N. idaeus relies on associative learning to forage for its prey. PMID- 29478091 TI - 2016 PREP attitudes in Germany: high awareness and acceptance in MSM at risk of HIV. AB - PRUPOSE: To examine current risk behavior, awareness, experience, and attitudes towards pre-exposure-prophylaxis (PrEP), and to estimate a potential impact on the prevention of HIV transmission among HIV-negative MSM in Germany. PrEP was not officially licensed at the time of survey. METHODS: Web-based questionnaire from 03-06/2016. Potential participants were informed through social media, flyers, and advertisements. Risk contacts were defined as unprotected sexual intercourse under the influence of recreational drugs in the past 6 months. RESULTS: In total, 1208 subjects participated, 342 subjects were excluded for being HIV-infected or non-MSM, leaving 866 subjects to be evaluated in this analysis. Mean age was 37.0 +/- 10.4 years. 593 participants (68.5%) were tested for HIV within the past 12 months. A total of 206 STDs in the past 6 months were reported by 144 (16.6%). Aware of PrEP was 748 (86.4%) respondents, while 65.1% reported willingness to use it. Risk behavior was significantly associated with higher PrEP acceptance (OR 2.90, 95% CI 2.14-3.90), as was a history of STDs (OR 1.85, 95% CI 1.17-2.91). The use of condoms would forgo 52.3% of subjects if taking PrEP. Sixty-five respondents (7.5%) reported PrEP use. Only 19 (29.2%) had accessed PrEP under medical supervision. PrEP use was reported by 14.8% with > 5 risk contacts in the past 6 months, compared to 6.3% with one risk contact (p < 0.001). CONCLUSION: We found a high PrEP awareness and acceptance, especially among subgroups of MSM at highest risk of HIV infection. Structured access and availability of PrEP to this population may have an important impact on the HIV epidemic in Germany. PMID- 29478092 TI - Structural atlas of dynein motors at atomic resolution. AB - Dynein motors are biologically important bio-nanomachines, and many atomic resolution structures of cytoplasmic dynein components from different organisms have been analyzed by X-ray crystallography, cryo-EM, and NMR spectroscopy. This review provides a historical perspective of structural studies of cytoplasmic and axonemal dynein including accessory proteins. We describe representative structural studies of every component of dynein and summarize them as a structural atlas that classifies the cytoplasmic and axonemal dyneins. Based on our review of all dynein structures in the Protein Data Bank, we raise two important points for understanding the two types of dynein motor and discuss the potential prospects of future structural studies. PMID- 29478093 TI - New geranyl flavonoids from the leaves of Artocarpus communis. AB - Four new geranyl flavonoids 1-4 and four known flavonoids 5-8 were obtained from the leaves of Artocarpus communis collected in Indonesia. The planar structures of flavonoids were elucidated by analyses of MS and NMR spectroscopic data. Absolute configurations of 1 and 2 were determined by ECD spectroscopy. Analyses by HPLC with a chiral-phase column and ECD spectra confirmed that 3 and 4 were stereoisomeric mixtures and 7 and 8 were racemic mixtures. The compounds obtained in this study inhibited the enzymatic activities of ubiquitin-specific protease 7 (USP7) and the chymotrypsin-like activity of the proteasome. Among the geranyl flavonoids tested in this experiment, the USP7 inhibitory activity of 6 (IC50 value, 0.094 MUM) was 55 times more potent than the commercially available positive control, P5091 (IC50 value, 5.2 MUM). PMID- 29478094 TI - The utility of plastinates in court: a case of firearm homicide. AB - Plastination is a technique renowned for its use in the preservation of human tissues or organs, and is mainly employed in anatomical training and in research regarding various scientific fields. The advantages of this method are related to the natural appearance, absence of odor, and easy-handling of the plastinated products. The use of plastinates in forensic sciences, their potential role in personal identification, and their usefulness in interpretation of post-mortem findings has been described, although literature on this topic is poor. The present paper is the first report of a firearm homicide where the brain of the victim was plastinated and presented in court as documentary evidence. Three dimensional examination of the brain during the trial allowed the judge to directly evaluate the pathway of the projectile and to compare it with the information that was presented based on depositions, post mortem data and police investigations, in a more straightforward manner. The important role played by plastination in the reported case in assisting with the final verdict could be a catalyst to extend the use of this technique to other criminal cases. PMID- 29478095 TI - "The pen is mightier than the sword" - suicidal trans-orbital intracranial penetrating injury from a pencil. AB - A 40-year-old drug addict, who was being treated with methadone and occupational therapy, committed suicide by striking a wooden pencil into his right eye socket. While still conscious, he hit his head hard against a table, jamming the pencil even deeper into his head. The autopsy showed that the pencil missed the globe and lodged in the inner part of the right eye socket. It pierced the orbital part of the right ethmoid bone, the right ethmoid cells, and the right superior nasal concha, then passed through the body of the sphenoid bone and the clivus of the occipital bone before stopping in the brain tissue. The basilar artery was transected at the pontomedullary junction, where the tip of the pencil had lodged. Also, at the pontomedullary junction, an approximately 3 mm deep laceration of the brainstem was evident together with flecks of green paint. Histological examination revealed that laceration at the pontomedullary junction was even deeper than the macroscopic appearance had suggested, with several small lateral cracks, focal deep hemorrhage, and disruption of both gray and white matter of the brainstem. Fragments of cellulose originating from the wooden pencil could also be clearly distinguished. Toxicological analysis was performed using liquid chromatography with mass spectrometry, and it showed traces of methadone in the blood and humor vitreous samples. The cause of death was damage to the vital structures in the brainstem, resulting from a penetrating injury to the head by a pencil. Herein, we present a self-inflicted trans-orbital penetrating injury by a non-missile, low-velocity object - a pencil, with a rather unusual, immediately incapacitating outcome. PMID- 29478096 TI - Impact of long-term air pollution exposure on metabolic control in children and adolescents with type 1 diabetes: results from the DPV registry. AB - AIMS/HYPOTHESIS: Studies on the association between air pollution and metabolic control in children and adolescents with type 1 diabetes are rare and findings are inconsistent. We examined the relationship between air pollution variables (particulate matter with an aerodynamic diameter <10 MUm [PM10], NO2 and accumulated ozone exposure [O3-AOT]) and metabolic variables (HbA1c and daily insulin dose [U/kg body weight]) in children and adolescents with type 1 diabetes. METHODS: We investigated 37,372 individuals with type 1 diabetes aged <21 years, documented between 2009 and 2014 in 344 German centres of the prospective diabetes follow-up registry (Diabetes-Patienten-Verlaufsdokumentation [DPV]). Long-term air pollution exposure (annual and quinquennial means) data were linked to participants via the five-digit postcode areas of residency. Cross sectional multivariable regression analysis was used to examine the association between air pollution and metabolic control. RESULTS: After comprehensive adjustment, an interquartile range increase in O3-AOT was associated with a lower HbA1c (-3.7% [95% CI -4.4, -3.0]). The inverse association between O3-AOT and HbA1c persisted after additional adjustment for degree of urbanisation or additional adjustment for PM10. Moreover, the inverse association remained stable in further sensitivity analyses. No significant associations between HbA1c and PM10 or NO2 were found. No association was observed between any of the three air pollutants and insulin dose. CONCLUSIONS/INTERPRETATION: The inverse association between O3-AOT and HbA1c could not be explained by regional differences in diabetes treatment or by other differences between urban and rural areas. Furthermore, our results remained stable in sensitivity analyses. Further studies on the association between air pollution and HbA1c in children and adolescents with type 1 diabetes are needed to confirm our observed association and to elucidate underlying mechanisms. PMID- 29478097 TI - Impact of type 1 diabetes on maternal long-term risk of hospitalisation and mortality: a nationwide combined clinical and register-based cohort study (The EPICOM study). AB - AIMS/HYPOTHESIS: The aims of this study were to examine long-term mortality and morbidity rates in mothers with type 1 diabetes, both overall and according to the level of albuminuria prior to pregnancy, the presence of hypertension, pre eclampsia and periconceptional HbA1c. METHODS: This study was a part of the EPICOM (Environmental Versus Genetic and Epigenetic Influences on Growth, Metabolism and Cognitive Function in Offspring of Mothers with Type 1 Diabetes) study, which is a prospective follow-up study focusing on pregnancies complicated by maternal type 1 diabetes. We carried out a nationwide combined clinical and register-based cohort study of mortality rates and hospital admissions in mothers with diabetes (n = 986) who gave birth between 1992 and 2000. Control mothers (n = 91,441) were women from the background population, matched according to age and year of childbirth. Age at follow-up was 32-66 years. RESULTS: Mortality rate was increased threefold in mothers with diabetes compared with control mothers (HR 3.41 [95% CI 2.42, 4.81]; p < 0.0001), and was also increased with pre gestational kidney dysfunction (normoalbuminuria, HR 2.17 [95% CI 1.28, 3.68]; microalbuminuria, HR 3.36 [95% CI 0.82, 13.8]; macroalbuminuria, HR 12.9 [95% CI 5.45, 30.7]). Moreover, the presence of hypertension prior to or at any time during pregnancy and of pre-eclampsia also increased mortality rate (hypertension, HR 4.34 [95% CI 2.13, 8.84]; pre-eclampsia, HR 5.55 [95% CI 2.71, 11.4]). Mortality rate also increased with higher levels of HbA1c in early pregnancy (HbA1c <=75 mmol/mol [<=9%], HR 2.15 [95% CI 1.31, 3.53]; HbA1c >75 mmol/mol [>9%], HR 6.10 [95% CI 2.67, 14.0]). However, in mothers with diabetes and HbA1c <64 mmol/mol (<8%) in the first trimester and normal pre-gestational urinary albumin excretion rate (n = 517), mortality rate was comparable with that of control mothers. Among mothers with diabetes, mortality rate was associated with HbA1c level: per 11 mmol/mol (1 percentage point) increase in HbA1c, HR was 1.52 (95% CI 1.19, 1.94; p = 0.001). In mothers with diabetes, the overall incidence of hospital admissions was more than double (incidence rate ratio [IRR] 2.69 [95% CI 2.59, 2.80]; p < 0.0001) that of control mothers, as were admissions with various diagnoses from 14 out of 19 ICD-10 chapters. Among mothers with diabetes, the IRR for hospital admissions increased with the level of HbA1c: per 11 mmol/mol (1 percentage point) increase in HbA1c, HR was 1.07 (95% CI 1.04, 1.10; p < 0.0001). CONCLUSIONS/INTERPRETATION: Overall, mothers with type 1 diabetes have a two- to threefold increase in mortality and morbidity rates. HbA1c levels, level of albuminuria around the time of conception, and the presence of hypertension and pre-eclampsia are important risk factors for mortality/morbidity in this cohort. However, it is reassuring that mothers with type 1 diabetes without kidney complications and with HbA1c <64 mmol/mol (<8%) in early pregnancy have a similar survival potential during the period where they are raising their children to that of control mothers from the background population. PMID- 29478098 TI - Clinically meaningful and lasting HbA1c improvement rarely occurs after 5 years of type 1 diabetes: an argument for early, targeted and aggressive intervention following diagnosis. AB - AIMS/HYPOTHESIS: Our objectives were to explore whether the phenomenon of HbA1c 'tracking' occurs in individuals with type 1 diabetes, how long after diagnosis does tracking take to stabilise, and whether there is an effect of sex and age at diagnosis on tracking. METHODS: A total of 4525 individuals diagnosed with type 1 diabetes between 1 January 1995 and 1 May 2015 were identified from The Health Improvement Network (THIN) database. Mixed models were applied to assess the variability of HbA1c levels over time with random effects on general practices (primary care units) and individuals within practices. RESULTS: 4525 individuals diagnosed with type 1 diabetes were identified in THIN over the study period. The greatest difference in mean HbA1c measurement (-7.0 [95% CI -8.0, -6.1] mmol/mol [0.6%]) was seen when comparing measurements made immediately after diagnosis (0 1 year since diagnosis) with those at 10 or more years (the reference category). The mean difference in HbA1c for the successive periods compared with 10 or more years after diagnosis declined and was no longer statistically significant after 5 years. In the stratified analysis using sex and age group there was considerable heterogeneity with adult onset type 1 diabetes appearing to track earlier and at a lower mean HbA1c. CONCLUSIONS/INTERPRETATION: In individuals with type 1 diabetes, glycaemic control measured by HbA1c settles onto a long term 'track' and this occurs on average by 5 years following diagnosis. Age at diagnosis modifies both the rate at which individuals settle into their track and the absolute HbA1c tracking level for the next 10 years. PMID- 29478099 TI - Increased Ifi202b/IFI16 expression stimulates adipogenesis in mice and humans. AB - AIMS/HYPOTHESIS: Obesity results from a constant and complex interplay between environmental stimuli and predisposing genes. Recently, we identified the IFN activated gene Ifi202b as the most likely gene responsible for the obesity quantitative trait locus Nob3 (New Zealand Obese [NZO] obesity 3). The aim of this study was to evaluate the effects of Ifi202b on body weight and adipose tissue biology, and to clarify the functional role of its human orthologue IFI16. METHODS: The impact of Ifi202b and its human orthologue IFI16 on adipogenesis was investigated by modulating their respective expression in murine 3T3-L1 and human Simpson-Golabi-Behmel syndrome (SGBS) pre-adipocytes. Furthermore, transgenic mice overexpressing IFI202b were generated and characterised with respect to metabolic traits. In humans, expression levels of IFI16 in adipose tissue were correlated with several variables of adipocyte function. RESULTS: In mice, IFI202b overexpression caused obesity (Delta body weight at the age of 30 weeks: 10.2 +/- 1.9 g vs wild-type mice) marked by hypertrophic fat mass expansion, increased expression of Zfp423 (encoding the transcription factor zinc finger protein [ZFP] 423) and white-selective genes (Tcf21, Tle3), and decreased expression of thermogenic genes (e.g. Cidea, Ucp1). Compared with their wild-type littermates, Ifi202b transgenic mice displayed lower body temperature, hepatosteatosis and systemic insulin resistance. Suppression of IFI202b/IFI16 in pre-adipocytes impaired adipocyte differentiation and triacylglycerol storage. Humans with high levels of IFI16 exhibited larger adipocytes, an enhanced inflammatory state and impaired insulin-stimulated glucose uptake in white adipose tissue. CONCLUSIONS/INTERPRETATION: Our findings reveal novel functions of Ifi202b and IFI16, demonstrating their role as obesity genes. These genes promote white adipogenesis and fat storage, thereby facilitating the development of obesity-associated insulin resistance. PMID- 29478100 TI - Certain BCG-reactive responses are associated with bladder cancer prognosis. AB - A subset of bladder patients does not respond to BCG treatment effectively and the underlying reason behind this observation is currently unclear. CD4+ T cells are composed of various subsets that each expresses a distinctive set of cytokines and can potently shift the immune response toward various directions. In this study, we examined the CD4+ T-cell cytokine response in bladder cancer patients toward BCG stimulation. We found that bladder cancer patients presented a variety of responses toward BCG, with no uniform characteristics. Those patients with high IFN-gamma and IL-21 expression in CD4+ T cells presented significantly better prognosis than patients with low cytokine secretion in CD4+ T cells. Tumor-infiltrating CD4+ T cells were significantly less potent in expressing IFN-gamma, IL-4, and IL-17, and more potent in expressing IL-10 than circulating CD4+ T cells. In addition, we found no difference in CD80, CD86, or MHC II expression by macrophages from patients with different IFN-gamma and IL-21 levels. However, the secretion of IL-12, a Th1-skewing cytokine, was released at significantly higher level by macrophages from patients with high IFN-gamma or high IL-21 secretion. We also identified that modulating monocytes/macrophages by GM-CSF-mediated polarization resulted in significantly elevated expression of IFN gamma and IL-21 from CD4+ T cells. Overall, these results suggested that the specific types of responses mounted by CD4+ T cells were critical to the final outcome of bladder cancer patients and can be influenced by monocyte/macrophage polarization. PMID- 29478101 TI - Local air gap thickness and contact area models for realistic simulation of human thermo-physiological response. AB - To evaluate the quality of new energy-saving and performance-supporting building and urban settings, the thermal sensation and comfort models are often used. The accuracy of these models is related to accurate prediction of the human thermo physiological response that, in turn, is highly sensitive to the local effect of clothing. This study aimed at the development of an empirical regression model of the air gap thickness and the contact area in clothing to accurately simulate human thermal and perceptual response. The statistical model predicted reliably both parameters for 14 body regions based on the clothing ease allowances. The effect of the standard error in air gap prediction on the thermo-physiological response was lower than the differences between healthy humans. It was demonstrated that currently used assumptions and methods for determination of the air gap thickness can produce a substantial error for all global, mean, and local physiological parameters, and hence, lead to false estimation of the resultant physiological state of the human body, thermal sensation, and comfort. Thus, this model may help researchers to strive for improvement of human thermal comfort, health, productivity, safety, and overall sense of well-being with simultaneous reduction of energy consumption and costs in built environment. PMID- 29478102 TI - Is intrauterine device a risk factor for failure of conservative management in patients with tubo-ovarian abscess? An observational retrospective study. AB - PURPOSE: Tubo-ovarian abscess (TOA) is a serious and potentially life-threatening complication of pelvic inflammatory disease (PID). TOA formation may be an uncommon, but serious complication associated with the use of an intrauterine device (IUD). While the majority of TOA respond to antibiotic therapy, in approximately 25% of cases surgery or drainage is indicated. In the present study, we compared the failure rate of conservative management in patients with and without IUD, who were admitted with a diagnosis of TOA. METHODS: In this retrospective case-control study, 78 women were diagnosed with TOA. All patients were treated initially by broad-spectrum intravenous antibiotics. The failure of conservative management after 72 h was followed by surgical intervention. RESULTS: The patients were divided into two groups: 24 patients were IUD carriers, and 54 did not use IUD. There was no significant difference in surgical intervention rate between IUD group (50%) and no-IUD group (43%), p = 0.32. The WBC count was significantly higher in IUD-carriers diagnosed with TOA than in patients without IUD (16.5 +/- 6.6 vs. 13.1 +/- 4.6, p = 0.001). The patients with IUD had significantly larger abscesses as revealed by ultrasound than patients without IUD (61.6 +/- 21.4 vs. 49.6 +/- 20.6 mm, p = 0.02). CONCLUSION: The surgical intervention rate in TOA patients with and without IUD was similar. PMID- 29478104 TI - Benton visual form discrimination test in healthy children: normative data and qualitative analysis. AB - The attention evaluation may be considered a crucial phase in neuropsychological assessment. It must take into account the systemic nature of the attentional functions and must use different reliable tests in relation to the neurological and attentional problems to be addressed. The aim of the study was to offer the clinician an effective tool for attention assessment and provide the normative data and performance analysis on the Benton Visual Form Discrimination Test on an Italian sample (number 323) of healthy school children, from ages 5 to 11. Performance on Visual Form Discrimination Test (VFDT) significantly increased with growing age. Performances were significantly different when the test was divided into four sets. All groups, especially the younger ones, showed some difficulty in maintenance and sustained attention. The correct answers were significantly more numerous when they were placed at the top quadrants. This effect was more marked in the younger groups. Sex was never a significantly influencing performance. Our data seem to indicate that the higher attentional frontoparietal network becomes more functionally organized around 9-10 years. VFDT appears as a discriminative task. In clinical practice, our normative data can be used both on complex visual attention skill evaluation in children and on the ability to maintain visual attention in time. PMID- 29478103 TI - Investigation of polar organic chemical integrative sampler (POCIS) flow rate dependence for munition constituents in underwater environments. AB - Munition constituents (MC) are present in aquatic environments throughout the world. Potential for fluctuating release with low residence times may cause concentrations of MC to vary widely over time at contaminated sites. Recently, polar organic chemical integrative samplers (POCIS) have been demonstrated to be valuable tools for the environmental exposure assessment of MC in water. Flow rate is known to influence sampling by POCIS. Because POCIS sampling rates (Rs) for MC have only been determined under quasi-static conditions, the present study evaluated the uptake of 2,4,6-trinitrotoluene (TNT), RDX (hexahydro-1,3,5 trinitro-1,3,5-triazine), and 2,4- and 2,6-dinitrotoluenes (DNT), by POCIS in a controlled water flume at 7, 15, and 30 cm/s in 10-day experiments using samplers both within and without a protective cage. Sampling rate increased with flow rate for all MC investigated, but flow rate had the strongest impact on TNT and the weakest impact on RDX. For uncaged POCIS, mean Rs for 30 cm/s was significantly higher than that for 7 cm by 2.7, 1.9, 1.9, and 1.3 folds for TNT, 2,4-DNT, 2,6 DNT, and RDX, respectively. For all MC except RDX, mean Rs for caged POCIS at 7 cm/s were significantly lower than for uncaged samplers and similar to those measured at quasi-static condition, but except for 2,6-DNT, no caging effect was measured at the highest flow rate, indicating that the impact of caging on Rs is flow rate-dependent. When flow rates are known, flow rate-specific Rs should be used for generating POCIS-derived time-averaged concentrations of MC at contaminated sites. PMID- 29478105 TI - Cardiogenic Shock: Recent Developments and Significant Knowledge Gaps. AB - PURPOSE OF REVIEW: Patients with cardiogenic shock (CS) continue to have high rates of morbidity and mortality. We aimed to describe current principles in the management of CS including coronary revascularization, medical management, mechanical circulatory support, and supportive care. RECENT FINDINGS: Revascularization is still recommended, but trials have not found a benefit in the revascularization of nonculprit artery lesions. New mechanical circulatory support options are available, but optimal use remains uncertain. Overall improvement in outcomes appears to have plateaued. There remain substantial knowledge gaps about the management of CS. The ideal timing and selection criteria for mechanical support remain under-developed. There has been little systematic study to inform medical management or supportive care of this patient population. A more expansive research focus is necessary to improve the care of CS. PMID- 29478106 TI - Hypothesis: the hospital learning environment impedes students' acquisition of reflectivity and medical professionalism. AB - Undergraduate clinical education follows the "bedside" tradition that exposes students to inpatients. However, the hospital learning environment has two main limitations. First, most inpatients require acute care, and students may complete their training without seeing patients with frequent non-emergent and chronic diseases that are managed in outpatient settings. Second, students rarely cope with diagnostic problems, because most inpatients are diagnosed in the community or the emergency room. These limitations have led some medical schools to offer longitudinal integrated clerkships in community settings instead of hospital block clerkship rotations. In this paper, I propose the hypothesis that the hospital learning environment has a third limitation: it causes students' distress and delays their development of reflectivity and medical professionalism. This hypothesis is supported by evidence that (a) the clinical learning environment, rather than students' personality traits, is the major driver of students' distress, and (b) the development of attributes, such as moral reasoning, empathy, emotional intelligence and tolerance of uncertainty that are included in the definitions of both reflectivity and medical professionalism, is arrested during undergraduate medical training. Future research may test the proposed hypothesis by comparing students' development of these attributes during clerkships in hospital wards with that during longitudinal clerkships in community settings. PMID- 29478107 TI - Substitution analysis in nutritional epidemiology: proceed with caution. PMID- 29478108 TI - The case for medicinal cannabis. PMID- 29478109 TI - Prediction efficiency of serum cystatin C for clinical outcome in patients with cardiac resynchronization therapy. AB - BACKGROUND: Since only 60-70% of select patients with chronic heart failure (CHF) are responders in cardiac resynchronization therapy (CRT), this study aimed to investigate whether serum cystatin C (Cys C) can be used to evaluate the effectiveness of CRT in patients with CHF. METHODS: Seventy-six patients implanted with CRT were retrospectively enrolled. The concentration of serum Cys C was detected and echocardiography was performed before and after 15 days, 1 month, and 6 months of CRT. RESULTS: There were 52 patients (68.4%) who responded to CRT during the follow-up. In the responding group, compared with the pre-CRT, the cardiac function, QRS interval, left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), and left ventricular ejection fraction (LVEF) were significantly improved at 6 months after implantation (P < 0.05), but the level of serum Cys C decreased significantly from 1 month after CRT. There was no change of all the parameters in the non responding group during the follow-up. In the responding group, the DeltaCys C% is significantly related to the DeltaLVEDV%, DeltaLVESV%, and DeltaLVEF%. Multivariate linear analysis shows that the DeltaCys C% is significantly related to the DeltaLVEDV%. The level of serum Cys C before CRT implantation could predict the response to CRT (AUC = 0.78, P < 0.05). Univariate analysis and multivariate analysis demonstrated that the level of Cys C remained independent predictor for CRT (P = 0.028, 95% CI 0.919-1.348). CONCLUSIONS: The level of serum Cys C before CRT implantation is valuable in predicting the response to CRT. PMID- 29478110 TI - An efficient synthetic protocol for amide derivatives of Boc-2-aminoisobutyrate. AB - Aminoisobutyric acid (AIB) is an important building block widely incorporated by medicinal chemists in molecular design. Owing to the steric challenge, elaborating AIB's carboxylic acid using conventional amidation protocols is often problematic. We discovered that an amidation protocol utilizing methyl Boc aminoisobutyrate and magnesium amidates of various reactivities produces the corresponding amide derivatives in good to excellent yields. PMID- 29478111 TI - Evaluation of intra-individual test-re-test variability of uroflowmetry in healthy women and women suffering from stress, urge, and mixed urinary incontinence. AB - INTRODUCTION AND HYPOTHESIS: The objective was to evaluate the intra-individual variability of uroflowmetry (UFM) in healthy control subjects and women suffering from stress, urge, and mixed urinary incontinence. METHODS: A total of 35 healthy controls (group A) and 105 women suffering from urinary incontinence were enrolled in the study. Thirty-five women suffered from stress urinary incontinence (group B), 35 women suffered from mixed urinary incontinence (group C), and 35 women with overactive bladder both dry and wet (group D). All participants were asked to perform UFM measurement three times. The following parameters were analyzed: voided volume (VV), peak flow (Qmax), average flow (Qave), volume-corrected peak flow cQmax (cQmax = Qmax/2? VV), volume-corrected average flow (cQave = Qave/2? VV), and postvoid residual volume (PVR). Statistical analysis was performed using the analysis of variance on repeated measurements. Relative error was calculated using variation coefficients reported as a percentage of the average. All descriptive characteristics were reported as means +/- standard deviation (SD). p values <=0.05 were considered statistically significant. RESULTS: No statistically significant intra-individual difference in any of the recorded parameters was identified among the three UFM recordings in groups A, C, and D. The intra-individual variability of the following parameters reached statistical significance in patients suffering from stress urinary incontinence (group B): Qmax (p = 0.0016), Qave (p = 0.0005), and cQave (p = 0.0389). A significant difference was only observed in comparison between the first and second consecutive recordings. CONCLUSIONS: This study provides evidence supporting the high yield and good intra-individual reproducibility of UFM. PMID- 29478112 TI - Effect of generalized anxiety disorders on the success of pessary treatment for pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: Our aim was to evaluate the impact of generalized anxiety disorders (GAD) on the effectiveness of pessary treatment for pelvic organ prolapse (POP) in postmenopausal women. METHODS: One-hundred and ten women with symptomatic POP who underwent pessary treatment were enrolled in this prospective study. Subjective evaluations of pelvic floor symptoms were assessed using the Pelvic Floor Distress Inventory (PFDI-20) and the Pelvic Floor Impact Questionnaire-7 (PFIQ-7), both at baseline and at the 3-month follow-up visit after pessary use. GAD was measured by the Generalized Anxiety Disorder-7 (GAD 7). Independent samples t tests, Mann-Whitney U test, chi-square test, Fisher's exact test, and Wilcoxon signed rank test were used to analyze data. RESULTS: Twenty-one patients (20.6%) had GAD at baseline. After 3 months of pessary use, PFIQ-7, PFDI-20, and GAD scores were significantly improved in all participants (P < 0.001). In the GAD-negative group, total PFIQ-7 and PFDI-20 scores, including all subscales scores, were significantly decreased from baseline to posttreatment (P < 0.05). However, in the GAD-positive group, both PFIQ-7 and PFDI-20 scores, including subscales, were also significantly decreased from baseline to posttreatment (P < 0.05), except for subscale Colorectal-Anal Impact Questionnaire (CRAIQ-7) of PFIQ-7 (P = 0.225), which represented the impact on quality of life (QoL) from bowel dysfunction. CONCLUSIONS: Both groups of women with or without GAD showed significant improvement in QoL scores after 3 months of pessary treatment. GAD had no influence on the success of pessary treatment for POP. PMID- 29478113 TI - Video of the laparoscopic repair of a vesico-uterine fistula. AB - AIM: Vesico-uterine fistulas (VUFs) are rare in modern gynecological practice. We aim to demonstrate with a video the surgical techniques involved in laparoscopic repair of a vesico-uterine fistula (Youssef's syndrome). METHODS: A 37-year-old woman, para 2 and otherwise healthy, was referred to the Urogynaecology Unit 4 months following a vaginal birth after a previous cesarean, with ongoing pink colored vaginal watery discharge. Cystoscopy and hysteroscopy confirmed the findings of a well-granulated fistulous tract connecting the base of the bladder and anterior uterine wall just above the level of the internal os. She underwent an uncomplicated laparoscopic repair of VUF. RESULTS: She has remained asymptomatic with resumption of normal menses and no clinical evidence of fistula recurrence at 6-week and 6-month post-operative reviews. CONCLUSION: This video demonstrates the surgical techniques involved in the laparoscopic repair of a VUF, a rare case in modern gynecological practice where there are few surgical videos demonstrating techniques. PMID- 29478114 TI - Effectiveness of a continuous-use ring-shaped vaginal pessary without support for advanced pelvic organ prolapse in postmenopausal women. AB - INTRODUCTION AND HYPOTHESIS: There is considerable variation in the clinical management of pessaries. This study was aimed at exploring the efficacy of the continuous use of ring pessaries without support for the treatment of advanced pelvic organ prolapse (POP) in nonhysterectomized postmenopausal women. METHODS: We conducted this prospective study of fitted pessaries between January 2013 and June 2015 in the Department of Obstetrics and Gynecology at Macarena Hospital, Seville University, Spain. A total of 171 nonhysterectomized postmenopausal patients with symptomatic POP (stages III and IV) were counseled for two treatment options: either surgery or vaginal pessary. A total of 94 patients who agreed to use the vaginal ring pessary were included. A successful fitting was defined as the continued use of the device until the end of the study (a median 27-month follow-up). The data were analyzed with continuity correction tests, Mann-Whitney U tests, and Fisher's exact test. RESULTS: Pessary use was continued by 80.8% of the patients. Most discontinuations (50.0%) occurred within the first week after device insertion. The adverse events rate was 31.6%, and all adverse events were Clavien-Dindo grade I. The complications were extrusion of the pessary (18.4%), bleeding or excoriation (10.5%), and pain or vaginal discharge (2.6%). No major complications occurred. CONCLUSIONS: The ring pessary without support was successfully fitted in patients with advanced POP, resulting in a high success rate. There were few side effects and complications associated with continuous use of this pessary without periodic removal or replacement. PMID- 29478115 TI - Correction to: Olaratumab in Combination with Doxorubicin for the Treatment of Advanced Soft Tissue Sarcoma: An Evidence Review Group Perspective of a National Institute for Health and Clinical Excellence Single Technology Appraisal. AB - Page 41, Column 1, Section 3.1, paragraph 2, 1st sentence which. PMID- 29478116 TI - The Australian Managed Entry Scheme: Are We Getting it Right? AB - In 2010, the Australian Government introduced the managed entry scheme (MES) to improve patient access to subsidised drugs on the Pharmaceutical Benefits Scheme and enhance the quality of evidence provided to decision makers. The aim of this paper was to critically review the Australian MES experience. We performed a comprehensive review of publicly available Pharmaceutical Benefits Advisory Committee online documents from January 2010 to July 2017. Relevant information on each MES agreement was systematically extracted, including its rationale, the conditions that guided its implementation and its policy outcomes. We identified 11 drugs where an MES was considered. Most of the identified drugs (75%) were antineoplastic agents and the main uncertainty was the overall survival benefit. More than half of the MES proposals were made by sponsors and most of the schemes were considered after previous rejected/deferred submissions for reimbursement. An MES was not established in 8 of 11 drugs (73%) despite the high evidence uncertainty. Nevertheless, six of these eight drugs were listed after the sponsors reduced their prices. Three MESs were established and implemented by Deeds of Agreement. The three cases were concluded and the required data were submitted within the agreed time frames. The need for feasibility and value of an MES should be carefully considered by stakeholders before embarking on such an agreement. It is essential to engage major stakeholders, including patient representatives, in this process. The conditions governing MESs should be clear, transparent and balanced to address the expectations of various stakeholders. PMID- 29478118 TI - Contemporary Tools and Techniques for Substrate Ablation of Ventricular Tachycardia in Structural Heart Disease. AB - As we have witnessed in other arenas of catheter-based therapeutics, ventricular tachycardia (VT) ablation has become increasingly anatomical in its execution. Multi-modality imaging provides anatomical detail in substrate characterization, which is often complex in nonischemic cardiomyopathy patients. Patients with intramural, intraseptal, and epicardial substrates provide challenges in delivering effective ablation to the critical arrhythmia substrate due to the depth of origin or the presence of adjacent critical structures. Novel ablation techniques such as simultaneous unipolar or bipolar ablation can be useful to achieve greater lesion depth, though at the expense of increasing collateral damage. Disruptive technologies like stereotactic radioablation may provide a tailored approach to these complex patients while minimizing procedural risk. Substrate ablation is a cornerstone of the contemporary VT ablation procedure, and recent data suggest that it is as effective and more efficient that conventional activation guided ablation. A number of specific targets and techniques for substrate ablation have been described, and all have shown a fairly high success in achieving their acute procedural endpoint. Substrate ablation also provides a novel and reproducible procedural endpoint, which may add predictive value for VT recurrence beyond conventional programmed stimulation. Extrapolation of outcome data to nonischemic phenotypes requires caution given both the variability in substrate nonischemic distribution and the underrepresentation of these patients in previous trials. PMID- 29478117 TI - Modified posterior percutaneous endoscopic cervical discectomy for lateral cervical disc herniation: the vertical anchoring technique. AB - PURPOSE: During the long-term practice of percutaneous endoscopic cervical discectomy (PECD) at our institution, we have modified the protocol to include the vertical anchoring technique (VAT), which we will describe in detail in this article. The objective of this study was to compare the clinical outcomes associated with the conventional posterior PECD technique with that associated with the modified technique to determine the safety and efficacy of the latter technique. METHODS: From December 2014 to January 2016, a total of 44 patients with single cervical disc herniation were randomly divided into two groups. One group underwent conventional posterior PECD, and the other group underwent posterior PECD combined with VAT. The operative time, fluoroscopy times and perioperative complications were recorded. The visual analog scale (VAS) for neck and arm pain and the modified MacNab criteria at 1 day, 3, 6, and 12 months after surgery were used to evaluate the postoperative outcomes. RESULTS: All patients underwent surgery successfully without severe complications. The operative time and intraoperative fluoroscopy times were significantly less in patients treated with VAT than in those who underwent conventional posterior PECD (P < 0.05). Both types of surgery significantly improved the symptoms of patients. According to the results of the follow-up period, there were no significant differences in VAS scores for neck and arm pain or the modified MacNab criteria between the two groups (P > 0.05). There was no recurrence in either group during the follow-up period. CONCLUSIONS: Although the clinical outcomes of the two surgical techniques were similar, the VAT decreased the operative time and intraoperative fluoroscopy times in posterior PECD surgery. The learning curve for posterior PECD could be shortened by using the VAT. These slides can be retrieved under Electronic Supplementary Material. PMID- 29478119 TI - A review of split-bolus single-pass CT in the assessment of trauma patients. AB - PURPOSE: The purpose of this study was to review and compare the image quality and radiation dose of split-bolus single-pass computed tomography(CT) in the assessment of trauma patients in comparison to standard multi-phase CT techniques. METHODS: An online electronic database was searched using the MESH terms "split-bolus," "dual phase," and "single pass." Inclusion criteria required the research article to compare a split contrast bolus protocol in a single-pass scan in the assessment of trauma patients. Studies using split-bolus CT technique in non-traumatic injury assessment were excluded. Six articles met the inclusion criteria. CONCLUSIONS: Parenchymal and vascular image qualities, as well as subjective image quality assessments, were equal or superior in comparison to non split-bolus multi-phase trauma CT protocols. Split-bolus single-pass CT decreased radiation exposure in all studies. Further research is required to determine the superior split-bolus protocol and the specificity and sensitivity of detecting blunt cerebrovascular injury screening, splenic parenchymal vascular lesions, and characterization of pelvic vascular extravasation. PMID- 29478120 TI - Callous-Unemotional Traits and Effortful Control Mediate the Effect of Parenting Intervention on Preschool Conduct Problems. AB - Parenting intervention (PI) is an effective treatment for children's conduct problems (CP) that has been shown to be mediated by improved parenting practices and parenting self-efficacy. Recently, Hitkashrut's randomized controlled trial demonstrated that ineffective parenting (IP) mediated effects on callous unemotional (CU) traits and effortful control (EC), while controlling for more general treatment effects on CP. These temperament and personality-based features predict the formation of early-onset antisocial trajectories with poor long-term prognosis. The objective of this study was to use Hitkashrut's 3-wave dataset to test posttreatment EC and CU mediation of treatment effect on 1-year follow-up CP, and to determine whether mediation by each child-level potential mediator remains significant when tested concurrently with the parenting mediator. Parents of 209 3-5 year-old preschoolers (163 boys; 46 girls), with subclinical-clinical range CP were assigned to 14-session co-parent training groups (n = 140 couples), or to minimal intervention control groups (n = 69 couples). Assessments were based on both parents' questionnaires. An intent-to-treat analysis showed that EC and CU traits simultaneously mediated treatment effects on CP in one EC/CU mediational model. The concurrent testing of child- and parent-level mediators showed mediation by IP and CU traits in the CU/IP model, and IP mediation in the EC/IP model. Similar results were obtained in mediational analyses that controlled for the shared variance between the mediators and CP at T2. Overall, the findings support an intervention model of coaching parents of high-CP children to promote moral self-regulatory competencies while concurrently applying behavioral methods that directly target CP. PMID- 29478121 TI - Contributions to our modern understanding of spina bifida: Camille Dareste (1822 1899). PMID- 29478122 TI - IcmF and DotU are required for the virulence of Acidovorax oryzae strain RS-1. AB - Acidovorax oryzae (Ao) cause bacterial brown stripe in rice that result in great economic loss. However, the pathogenic mechanism of this rice bacterial pathogen still remains unclear. Interestingly, transcriptomic and proteomic analysis of in vivo infection indicate that the pathogenicity of Ao strain RS-1 may be associated with the type six secretion system (T6SS), which was identified by in silico comparative genomic analysis in our previous studies. This makes it necessary to further examine the role of each core component of T6SS in the pathogenicity of Ao strain RS-1 to rice plants. Results from this study highlight the mutual interaction between IcmF and DotU, which was determined by bacterial two-hybrid and bimolecular fluorescence complementation assays. Furthermore, a difference was observed in bacterial pathogenicity, biofilm formation, secreted proteins identified by LC-MS/MS analysis and the expression of T6SS other genes examined by quantitative real-time PCR between the wild-type and both single-gene knockout mutants, which were respectively constructed based on the insertional mutagenesis of Ao strain RS-1 in this study. Overall, our results clearly revealed the importance of T6SS icmF and dotU in pathogenicity of Ao strain RS-1 to rice plants. PMID- 29478124 TI - Optimizing Hypertensive Acute Heart Failure Management with Afterload Reduction. AB - PURPOSE OF REVIEW: In spite of advances in our understanding of acute heart failure (AHF) and its different phenotypic expressions, AHF management is still centered on volume removal with intravenous diuretics. This narrative review describes the pathophysiology underlying hypertensive AHF and appraises therapies targeting these mechanisms. RECENT FINDINGS: Vascular redistribution rather than volume overload may be the primary determinant of elevated cardiac filling pressures and subsequent pulmonary congestion in patients with hypertensive AHF; in these patients, vasodilators should be the predominant treatment. Additional therapy with diuretics in hypertensive AHF should be relegated to the treatment of overt volume overload or persistent congestion in spite of optimized hemodynamics. Intravenous nitroglycerin at high doses can rapidly achieve pulmonary decongestion and reduce downstream critical care needs in these patients. The therapeutic role for synthetic peptides with vasodilator properties has yet to be defined. Evidence supporting both old and new vasodilator therapies is limited by a paucity of well-designed studies and failure to demonstrate improvement in long-term outcomes. Targeted study of this phenotype of AHF is needed before vasodilator therapies become incorporated into treatment guidelines. PMID- 29478123 TI - Physical exercise mitigates high-fat diet-induced adiposopathy and related endocrine alterations in an animal model of obesity. AB - The dysregulation of adipokine secretion owing to adiposopathy can contribute to the pathogenesis of obesity-related disorders. Being that exercise is an advised strategy against obesity-induced adiposopathy, we aimed to analyze the role of physical exercise as a preventive and therapeutic strategy against high-fat diet (HFD)-induced adipokine and ghrelin alterations. Rats were pair-fed the Lieber De Carli standard diet (S, 35 Kcal% fat) or HFD (71 Kcal% fat) over 17 weeks. Animals were assigned into four groups as follows: standard diet sedentary (SS), standard diet voluntary physical activity (SVPA), high-fat diet sedentary (HS), and high-fat diet voluntary physical activity (HVPA). After 9 weeks of dietary treatment, half of the SS and HS animals were submitted to an 8-week endurance training program, standard diet endurance training (SET), and high-fat-diet endurance training (HET) groups, maintaining the respective diets. Although there were no changes in body weight, HFD increased visceral adiposity, percentage of large adipocytes, hypoxia inducible factor (HIF)-1alpha, and leptin contents in epididymal adipose tissue (eWAT) and decreased plasma content of adiponectin (AdipQ). Both VPA and ET decreased visceral adiposity and percentage of large adipocytes in HFD-fed animals, but ET also increased the percentage of small- to medium-sized adipocytes. VPA increased plasma growth hormone secretagogue receptor (GHS-R) and decreased leptin protein in HVPA group. ET decreased plasma insulin and leptin levels and eWAT HIF-1alpha and leptin expression in HET group. Moreover, ET improved insulin sensitivity, plasma high molecular weight, and AdipQ and ghrelin levels and increased eWAT and GHS-R expression. Our data suggest that exercise, particularly ET, reverted adiposopathy and related endocrine alterations induced by an isocaloric HFD pair-fed diet. PMID- 29478126 TI - Colorectal cancer spheroid biobanks: multi-level approaches to drug sensitivity studies. AB - Biobanking of molecularly characterized colorectal cancer stem cells (CSCs) generated from individual patients and growing as spheroids in defined serum-free media offer a fast, feasible, and multi-level approach for the screening of targeted therapies and drug resistance molecular studies. By combining in vitro and in vivo analyses of cetuximab efficacy with genetic data on an ongoing collection of stem cell-enriched spheroids, we describe the identification and preliminary characterization of microsatellite stable (MSS) CSCs that, despite the presence of the KRAS (G12D) mutation, display epidermal growth factor (EGF) dependent growth and are strongly inhibited by anti-EGF-receptor (EGFR) treatment. In parallel, we detected an increased resistance to anti-EGFR therapy of microsatellite instable (MSI) CSC lines irrespective of KRAS mutational status. MSI CSC lines carried mutations in genes coding for proteins with a role in RAS and calcium signaling, highlighting the role of a genomically unstable context in determining anti-EGFR resistance. Altogether, these results argue for a multifactorial origin of anti-EGFR resistance that emerges as the effect of multiple events targeting direct and indirect regulators of the EGFR pathway. An improved understanding of key molecular determinants of sensitivity/resistance to EGFR inhibition will be instrumental to optimize the clinical efficacy of anti EGFR agents, representing a further step towards personalized treatments. PMID- 29478125 TI - Detection of the antiviral activity of epicatechin isolated from Salacia crassifolia (Celastraceae) against Mayaro virus based on protein C homology modelling and virtual screening. AB - Mayaro fever, caused by Mayaro virus (MAYV) is a sub-lethal disease with symptoms that are easily confused with those of dengue fever, except for polyarthralgia, which may culminate in physical incapacitation. Recently, outbreaks of MAYV have been documented in metropolitan areas, and to date, there is no therapy or vaccine available. Moreover, there is no information regarding the three dimensional structure of the viral proteins of MAYV, which is important in the search for antivirals. In this work, we constructed a three-dimensional model of protein C of MAYV by homology modelling, and this was employed in a manner similar to that of receptors in virtual screening studies to evaluate 590 molecules as prospective antiviral agents. In vitro bioassays were utilized to confirm the potential antiviral activity of the flavonoid epicatechin isolated from Salacia crassifolia (Celastraceae). The virtual screening showed that six flavonoids were promising ligands for protein C. The bioassays showed potent antiviral action of epicatechin, which protected the cells from almost all of the effects of viral infection. An effective concentration (EC50) of 0.247 MUmol/mL was observed with a selectivity index (SI) of 7. The cytotoxicity assay showed that epicatechin has low toxicity, with a 50% cytotoxic concentration (CC50) greater than 1.723 umol/mL. Epicatechin was found to be twice as potent as the reference antiviral ribavirin. Furthermore, a replication kinetics assay showed a strong inhibitory effect of epicatechin on MAYV growth, with a reduction of at least four logs in virus production. Our results indicate that epicatechin is a promising candidate for further testing as an antiviral agent against Mayaro virus and other alphaviruses. PMID- 29478127 TI - Impact of RAS/BRAF mutation status in locally advanced rectal cancer treated with preoperative chemotherapy. AB - PURPOSE: Our sincere hope is to establish the predictive factors of neoadjuvant chemotherapy (NAC) response and provide patients with greater certainty regarding treatment outcomes. The aim of this study was to assess the response to NAC and survival in patients with locally advanced rectal cancer (LARC) according to their RAS/BRAF mutation status. METHODS: Data on 57 patients with LARC who received NAC between 2009 and 2016 were analyzed retrospectively. The patients were classified into two groups based on their mutation status: wild-type in both RAS and BRAF (WT) or mutant-type in either RAS or BRAF (MT). RESULTS: Twenty three patients were classified as WT, and the remaining 34 patients were MT. Histological response to NAC was similar in both groups. In responders, the 3 year relapse-free survival (RFS) was better compared with the non-responders (92 and 66%, respectively). In the WT group, the 3-year RFS was 95% which was significantly better than that in the MT group (59%, p = 0.011). The MT group was further subdivided into the following 2 groups by the pathological response; the MT responders (n = 10) and MT non-responders (n = 24). The 3-year RFS was 50% in the MT non-responders, which was significantly worse compared to that in the remaining patients (92%, p = 0.001). CONCLUSION: RAS/BRAF mutations did not affect the response to NAC. However, the RFS was likely to be poor for those in the MT group who did not achieve favorable pathological response. In contrast, the RFS was favorable in the WT group regardless of the pathological response. PMID- 29478128 TI - Combining oral anticoagulation and antiplatelet therapies: appropriate patient selection. AB - Anticoagulant therapy and antiplatelet therapy are used regularly for prevention of arterial and venous thrombosis, and combinations of the two drug classes are seen with relative frequency in clinical practice. While co-prescribing is as high as 39-55% in some real-world cohort studies, the number of patients that meet criteria for combination therapy based on the overall body of evidence is likely much lower. This may not always be realized by prescribers, and many patients may be continued on long term combination therapies that provide little additional benefit, and carry significant risk for harm. Given the heightened bleeding risk with combination therapies, prescribers should readily reassess the risk: benefit ratio in all patients on combination therapies. Combined antiplatelet and anticoagulant therapy should be used only in those with a low risk of bleeding who have a higher risk of thromboembolic disease events. Most patients with coronary artery disease, atrial fibrillation, peripheral arterial disease, or bioprosthetic cardiac valves will not benefit from combining antiplatelet and anticoagulant therapies. Conversely, patient populations more likely to derive benefit from antiplatelet-anticoagulant combinations include those with mechanical cardiac valves, patients undergoing percutaneous cardiac intervention who have another indication for anticoagulant therapy, and patients with recurrent thrombotic events while being treated with a single agent. This article will attempt to provide readers with a framework to assess which patient populations are likely to derive the greatest benefit with combination anticoagulant-antiplatelet therapies relative to the weighted risk for bleeding. PMID- 29478129 TI - Gene polymorphisms in dual antiplatelet therapy and the presence of hypo attenuated leaflet thickening after transcatheter aortic valve replacement. AB - The imaging finding of hypo-attenuated leaflet thickening (HALT) on bioprosthesis after transcatheter aortic valve replacement (TAVR) has been reported. The underlying mechanism is not clear, but leaflet thrombosis is speculated to be the cause. Heterogeneous antiplatelet responses may play a role in the process. This is a prospective, single-center pilot study in patients who received successful TAVR from June 2012 to November 2016. HALT on post-procedural multi-detector computed tomography. We thoroughly genotyped 34 SNPs and 8 SNPs that have been reported for clopidogrel and aspirin resistance. A total of 148 patients were enrolled. There were 15 patients demonstrating signs of HALT. Patients with HALT had a higher rate of atrial fibrillation (AF) pre-TAVR (33.3 vs. 7.5%, P = 0.01). We found that rs4244285 G>A polymorphism of the CYP2C19 gene was associated with the risk of HALT in the overdominant model (OR 4.00 [1.15-13.97], P = 0.02 for GA vs. GG+AA) adjusted by sex and the presence of pre-TAVR AF. Antiplatelet drug resistance is a reasonable possibility involved in HALT. Potential directions were suggested in polymorphisms of the CYP2C19 gene. PMID- 29478130 TI - CCL2 Induces the Production of beta2 Adrenergic Receptors and Modifies Astrocytic Responses to Noradrenaline. AB - The decline in brain noradrenaline levels is associated with the progression of certain neurodegenerative diseases. This seems to be due, at least in part, to the ability of noradrenaline to limit glial activation and to reduce the damage associated with it. Our previous studies of the mechanisms involved in this process indicate that noradrenaline induces the production of the chemokine CCL2 in astrocytes. While CCL2 can protect neurons against certain injuries, its overproduction has also proven to be harmful and to prevent noradrenaline neuroprotective effects. Therefore, in this study, we analyze if the modifications caused to astrocytes by an excessive production of CCL2 may alter their response to noradrenaline. Using primary cultures of rat cortical astrocytes, we observed that CCL2 enhances the production of beta 2 adrenergic receptors in these cells. While this potentiates noradrenaline signaling through cAMP, the activation of the transcription factor CREB is inhibited by CCL2. Furthermore, although CCL2 potentiates noradrenaline induction of glycogenolysis, this does not translate into an augmented release of lactate, one of the processes through which astrocytes help support neurons. Additionally, other neuroprotective actions of noradrenaline, such as the production of brain derived neurotrophic factor and the inhibition of the inducible nitric oxide synthase in astrocytes were modified by CCL2. These data suggest that some of the central nervous system alterations related to CCL2 could be due to its effects on adrenergic receptors and its interference with noradrenaline signaling. PMID- 29478131 TI - Influence of changes in the Spanish labor market during the economic crisis (2007 2011) on perceived health. AB - PURPOSE: We analyze the influence of the dramatic changes in the Spanish labor market during the crisis on the perceived health of the Spanish population. METHODS: We use the longitudinal Living Conditions Survey database and multilevel longitudinal logistic models between 2007 and 2011, before and during the economic crisis in one of the European countries most affected by its consequences. RESULTS: Unemployment (OR 1.75; p < 0.001), job insecurity (OR 1.38; p < 0.001), and being part of a household with severe material deprivation (OR 1.87; p = 0.004) increase the risk of having worsened perceived health. Available income, on the other hand, is a protective factor (OR 0.72; p < 0.001). Public expenditure policies have little impact on the perceived health. Labor market reforms reducing the degree of job insecurity and unemployment, together with income transfers to those at greater risk of social deprivation, can be more effective in improving the health of the population than the increase of aggregated social or health care expenditure. CONCLUSIONS: This study provides evidence of the influence that unemployment, job insecurity, and poverty exert on the perceived health of individuals, with data collected in Spain after the onset of the financial crisis. In addition, after analyzing public social expenditure, only expenditure on FPS seems to influence self-reported health, although to a very limited degree. PMID- 29478132 TI - The impact of caregiver's role preference on decisional conflicts and psychiatric distresses in decision making to help caregiver's disclosure of terminal disease status. AB - PURPOSE: The objective of this study was to investigate the impact of caregivers' role preference in decision making on conflicts and psychiatric distresses. METHODS: The responses of 406 caregivers of terminal cancer patients enrolled in a trial determining the efficacy of a decision aid focused on the disclosure of terminal disease status were included in this secondary analysis. The outcomes include the change scores of the Decision Conflict Scale (DCS) and depression and anxiety subscales of the Hospital Anxiety and Depression Scale (HADS) at the 1 and 3 months from baseline. The linear mixed model was employed to discover the impact of caregivers' decisional role preference on the outcomes. FINDINGS: Of the 406, 137 (33.7%) showed an active role preference and 269 (66.3%) showed a passive role preference. In the post hoc analysis of the adjusted differences of change scores between passive caregivers who received decision aid (passive decision aid) and active caregivers with decision aid (active-decision aid), non significant differences were observed in the DCS. However, at the 3-month, the change scores of the HADS depression subscale increased by 4.43 (effect size, 0.71) and those of the HADS anxiety subscale increased by 4.14 (effect size, 0.61) in the passive-decision aid group than in active-decision aid group, showing moderate to large difference. CONCLUSIONS: These findings suggest that information might be ethically recommended in a format that is interactive and tailored to how much an individual wishes to be involved in the decision-making process. PMID- 29478134 TI - Ex Vivo Imaging and Genetic Manipulation of Mouse Hair Follicle Bulge Stem Cells. AB - Stem cells that reside in the bulge of adult mouse hair follicles are a leading model of tissue stem cell research. Ex vivo culturing, molecular and cell biological characterizations, as well as genetic manipulation of fluorescence activated cell sorting-isolated bulge stem cells offer a useful experimental pipeline to complement in vivo studies. Here we describe detailed methods for culturing, immunostaining, live cell imaging, and adenoviral infection of bulge stem cells for downstream applications such as in vitro clonal and in vivo patch assays. PMID- 29478133 TI - Sympathomimetic Toxidromes and Other Pharmacological Causes of Acute Hypertension. AB - PURPOSE OF REVIEW: Acute drug-induced hypertension, sympathomimetic toxicity, and other hyperadrenergic states can be caused by both xenobiotic toxicity and withdrawal. This manuscript is a selective review of the recent literature regarding pharmacologic causes of hypertensive emergencies and other hyperadrenergic states. RECENT FINDINGS: We will discuss designer stimulants, alpha2 and baclofen agonist withdrawal, and the clinical entity known as posterior reversible encephalopathy syndrome (PRES). Additionally, we examine the controversial "unopposed alpha" phenomenon which may result from use of beta adrenergic antagonist in the presence of stimulant toxicity. These topics encompass clinical situations and disease entities that are increasingly encountered and are often either unanticipated or under-recognized. PMID- 29478135 TI - One-Step Simple Isolation Method to Obtain Both Epidermal and Dermal Stem Cells from Human Skin Specimen. AB - Stem cells play a crucial role in maintaining and repairing tissues during homeostasis and following injury. The efficient procurement of high quantity and quality of skin stem cells is important for both laboratory studies and clinical applications. Here, we describe a one-step isolation procedure to efficiently obtain both epidermal and dermal cell population from human skin specimen, based on the different influence of the Rho kinase inhibitor Y27632 on the growth of epidermal and dermal cells during the initial culture. Compared with the conventional methods, our protocol shows that it is simpler and less time consuming and can efficiently obtain the high quality of skin stem cells and can maintain the stem cell features after culture expansion. PMID- 29478136 TI - A Spanish laborer with the most severe iodine deficiency disorder. PMID- 29478137 TI - Phylogeography of the Macaronesian Lettuce Species Lactuca watsoniana and L. palmensis (Asteraceae). AB - The phylogenetic relationships and phylogeography of two relatively rare Macaronesian Lactuca species, Lactuca watsoniana (Azores) and L. palmensis (Canary Islands), were, until this date, unclear. Karyological information of the Azorean species was also unknown. For this study, a chromosome count was performed and L. watsoniana showed 2n = 34. A phylogenetic approach was used to clarify the relationships of the Azorean endemic L. watsoniana and the La Palma endemic L. palmensis within the subtribe Lactucinae. Maximum parsimony, Maximum likelihood and Bayesian analysis of a combined molecular dataset (ITS and four chloroplast DNA regions) and molecular clock analyses were performed with the Macaronesian Lactuca species, as well as a TCS haplotype network. The analyses revealed that L. watsoniana and L. palmensis belong to different subclades of the Lactuca clade. Lactuca watsoniana showed a strongly supported phylogenetic relationship with North American species, while L. palmensis was closely related to L. tenerrima and L. inermis, from Europe and Africa. Lactuca watsoniana showed four single-island haplotypes. A divergence time estimation of the Macaronesian lineages was used to examine island colonization pathways. Results obtained with BEAST suggest a divergence of L. palmensis and L. watsoniana clades c. 11 million years ago, L. watsoniana diverged from its North American sister species c. 3.8 million years ago and L. palmensis diverged from its sister L. tenerrima, c. 1.3 million years ago, probably originating from an African ancestral lineage which colonized the Canary Islands. Divergence analyses with *BEAST indicate a more recent divergence of the L. watsoniana crown, c. 0.9 million years ago. In the Azores colonization, in a stepping stone, east-to-west dispersal pattern, associated with geological events might explain the current distribution range of L. watsoniana. PMID- 29478138 TI - Genetic Variation and Association Analysis of the SSR Markers Linked to the Major Drought-Yield QTLs of Rice. AB - Drought is one of the major abiotic stresses, which hampers the production of rice worldwide. Informative molecular markers are valuable tools for improving the drought tolerance in various varieties of rice. The present study was conducted to evaluate the informative simple sequence repeat (SSR) markers in a diverse set of rice genotypes. The genetic diversity analyses of the 83 studied rice genotypes were performed using 34 SSR markers closely linked to the major quantitative trait loci (QTLs) of grain yield under drought stress (qDTYs). In general, our results indicated high levels of polymorphism. In addition, we screened these rice genotypes at the reproductive stage under both drought stress and nonstressful conditions. The results of the regression analysis demonstrated a significant relationship between 11 SSR marker alleles and the plant paddy weight under stressful conditions. Under the nonstressful conditions, 16 SSR marker alleles showed a significant correlation with the plant paddy weight. Finally, four markers (RM279, RM231, RM166, and RM231) demonstrated a significant association with the plant paddy weight under both stressful and nonstressful conditions. These informative-associated alleles may be useful for improving the crop yield under both drought stress and nonstressful conditions in breeding programs. PMID- 29478139 TI - Phospholipase D1 Signaling: Essential Roles in Neural Stem Cell Differentiation. AB - Phospholipase D1 (PLD1) is generally accepted as playing an important role in the regulation of multiple cell functions, such as cell growth, survival, differentiation, membrane trafficking, and cytoskeletal organization. Recent findings suggest that PLD1 also plays an important role in the regulation of neuronal differentiation of neuronal cells. Moreover, PLD1-mediated signaling molecules dynamically regulate the neuronal differentiation of neural stem cells (NSCs). Rho family GTPases and Ca2+-dependent signaling, in particular, are closely involved in PLD1-mediated neuronal differentiation of NSCs. Moreover, PLD1 has a significant effect on the neurogenesis of NSCs via the regulation of SHP-1/STAT3 activation. Therefore, PLD1 has now attracted significant attention as an essential neuronal signaling molecule in the nervous system. In the current review, we summarize recent findings on the regulation of PLD1 in neuronal differentiation and discuss the potential role of PLD1 in the neurogenesis of NSCs. PMID- 29478140 TI - Biosynthesis of nervonic acid and perspectives for its production by microalgae and other microorganisms. AB - Nervonic acid (NA) is a major very long-chain monounsaturated fatty acid found in the white matter of mammalian brains, which plays a critical role in the treatment of psychotic disorders and neurological development. In the nature, NA has been synthesized by a handful plants, fungi, and microalgae. Although the metabolism of fatty acid has been studied for decades, the biosynthesis of NA has yet to be illustrated. Generally, the biosynthesis of NA is considered starting from oleic acid through fatty acid elongation, in which malonyl-CoA and long chain acyl-CoA are firstly condensed by a rate-limiting enzyme 3-ketoacyl-CoA synthase (KCS). Heterologous expression of kcs gene from high NA producing species in plants and yeast has led to synthesis of NA. Nevertheless, it has also been reported that desaturases in a few plants can catalyze very long-chain saturated fatty acid into NA. This review highlights recent advances in the biosynthesis, the sources, and the biotechnological aspects of NA. PMID- 29478141 TI - Anaerobic degradation of a mixture of MtBE, EtBE, TBA, and benzene under different redox conditions. AB - The increasing use of biobased fuels and fuel additives can potentially change the typical fuel-related contamination in soil and groundwater. Anaerobic biotransformation of the biofuel additive ethyl tert-butyl ether (EtBE), as well as of methyl tert-butyl ether (MtBE), benzene, and tert-butyl alcohol (TBA, a possible oxygenate metabolite), was studied at an industrially contaminated site and in the laboratory. Analysis of groundwater samples indicated that in the field MtBE was degraded, yielding TBA as major product. In batch microcosms, MtBE was degraded under different conditions: unamended control, with medium without added electron acceptors, or with ferrihydrite or sulfate (with or without medium) as electron acceptor, respectively. Degradation of EtBE was not observed under any of these conditions tested. TBA was partially depleted in parallel with MtBE. Results of microcosm experiments with MtBE substrate analogues, i.e., syringate, vanillate, or ferulate, were in line with the hypothesis that the observed TBA degradation is a cometabolic process. Microcosms with ferulate, syringate, isopropanol, or diethyl ether showed EtBE depletion up to 86.5% of the initial concentration after 83 days. Benzene was degraded in the unamended controls, with medium without added electron acceptors and with ferrihydrite, sulfate, or chlorate as electron acceptor, respectively. In the presence of nitrate, benzene was only degraded after addition of an anaerobic benzene degrading community. Nitrate and chlorate hindered MtBE, EtBE, and TBA degradation. PMID- 29478142 TI - A practical approach for the optimization of channel integrity in the sealing of shallow microfluidic devices made from cyclic olefin polymer. AB - A reduced channel height in microfluidic Lab-on-a-Chip (LOC) devices enables a reduction in the required volume of sample and reagents. LOC devices are most often manufactured by microstructuring a planar substrate and subsequently sealing it with a cover film. However, shallow chip designs, made from polymers, are sensitive to channel deformation during the sealing of the microfluidic device. Inappropriate bonding conditions often result in the loss of the microfluidic functionality. A systematic and practical approach for the identification of suitable bonding process parameters is missing. In this article, a straightforward approach for the optimization of channel integrity in the sealing of shallow microfluidic devices made from Cyclic Olefin Polymer (COP) is presented. Two COP materials were tested: COP Zeonex 690R (Glass transition temperature Tg = 135 degrees C) both as a cover film and substrate material, and COP ZF14 (Tg = 135 degrees C) as a film material. A mechanical analysis using microstructured Zeonex 690R substrates was performed to generate a matrix of low distortion bonding parameters, including temperature, pressure and time. The well established method of solvent-assisted bonding was used to enhance the characteristically low bond strengths of the native COP material. In addition, plasma-assisted bonding was tested and compared. The optimization approach was validated by the manufacture of a microfluidic test device, the demonstration of its microfluidic functionality, and the quantitative evaluation of the achieved channel integrity. PMID- 29478143 TI - Response priming with motion primes: negative compatibility or congruency effects, even in free-choice trials. AB - How actions are chosen, and what they are influenced by, has been the focus of several research traditions. Influences on actions are often studied using compatibility paradigms, such as response priming. Here, a first stimulus (i.e., the prime) is presented shortly before a second stimulus (i.e., the target) which has to be classified. Reaction times to the target are often reduced when primes and targets are compatible compared to incompatible primes and targets-i.e., a positive compatibility effect (PCE). There are, however, some conditions in which reliably negative compatibility effects (NCEs), with faster reactions to incompatible targets, are found. Actions in real life are often influenced by perceived motion and are less determined by following (target) stimuli as it is the case in typical response priming studies with predetermined stimulus-response mappings. Thus, in the current experiment we used motion primes in forced-choice trials (with >> and << as targets) as well as in free-choice trials (with <> and >< as targets). Essentially, we found PCEs in the short-SOA condition and NCEs in the long-SOA condition. The pattern was not qualified by task (i.e., forced choice/free choice). The results provide evidence that NCEs with motion primes are found even without strong links between target stimuli and responses and that especially PCEs can be found with simpler and smaller targets than have been used in previous experiments. PMID- 29478144 TI - Integration of transcriptomic and cytoarchitectonic data implicates a role for MAOA and TAC1 in the limbic-cortical network. AB - Decoding the chain from genes to cognition requires detailed insights how areas with specific gene activities and microanatomical architectures contribute to brain function and dysfunction. The Allen Human Brain Atlas contains regional gene expression data, while the JuBrain Atlas offers three-dimensional cytoarchitectonic maps reflecting interindividual variability. To date, an integrated framework that combines the analytical benefits of both scientific platforms towards a multi-level brain atlas of adult humans was not available. We have, therefore, developed JuGEx, a new method for integrating tissue transcriptome and cytoarchitectonic segregation. We investigated differential gene expression in two JuBrain areas of the frontal pole that we have structurally and functionally characterized in previous studies. Our results show a significant upregulation of MAOA and TAC1 in the medial area frontopolaris which is a node in the limbic-cortical network and known to be susceptible for gray matter loss and behavioral dysfunction in patients with depression. The MAOA gene encodes an enzyme which is involved in the catabolism of dopamine, norepinephrine, serotonin, and other monoaminergic neurotransmitters. The TAC1 locus generates hormones that play a role in neuron excitations and behavioral responses. Overall, JuGEx provides a new tool for the scientific community that empowers research from basic, cognitive and clinical neuroscience in brain regions and disease models with regard to gene expression. PMID- 29478145 TI - MHC class I diversity of olive baboons (Papio anubis) unravelled by next generation sequencing. AB - The olive baboon represents an important model system to study various aspects of human biology and health, including the origin and diversity of the major histocompatibility complex. After screening of a group of related animals for polymorphisms associated with a well-defined microsatellite marker, subsequent MHC class I typing of a selected population of 24 animals was performed on two distinct next-generation sequencing (NGS) platforms. A substantial number of 21 A and 80 B transcripts were discovered, about half of which had not been previously reported. Per animal, from one to four highly transcribed A alleles (majors) were observed, in addition to ones characterised by low transcripion levels (minors), such as members of the A*14 lineage. Furthermore, in one animal, up to 13 B alleles with differential transcription level profiles may be present. Based on segregation profiles, 16 Paan-AB haplotypes were defined. A haplotype encodes in general one or two major A and three to seven B transcripts, respectively. A further peculiarity is the presence of at least one copy of a B*02 lineage on nearly every haplotype, which indicates that B*02 represents a separate locus with probably a specialistic function. Haplotypes appear to be generated by recombination-like events, and the breakpoints map not only between the A and B regions but also within the B region itself. Therefore, the genetic makeup of the olive baboon MHC class I region appears to have been subject to a similar or even more complex expansion process than the one documented for macaque species. PMID- 29478146 TI - Psychiatric Illness, Substance Use, and Viral Suppression Among HIV-Positive Men of Color Who Have Sex with Men in Los Angeles. AB - For individuals living with human immunodeficiency virus (HIV), viral suppression positively affects quality and length of life and reduces risks for HIV transmission. Men of color who have sex with men (MoCSM) who have been diagnosed with HIV have disproportionately low rates of viral suppression, with concomitant increases in incidence. We identified specific social, structural, and psychiatric factors associated with viral suppression among a sample of 155 HIV positive MoCSM. Cigarette smoking and biological markers of recent drug use were significantly associated with detectable viral load. In contrast, individuals reporting a history of psychiatric illness during medical examination were more likely to be virally suppressed. Further analyses demonstrated that psychiatric illness may affect virologic outcomes through increased probability of being prescribed HIV medications. Alternatively, cigarette smoking and drug use appear to negatively affect subsequent HIV Care Continuum milestones such as medication adherence. Findings provide support for comprehensive intervention programs that emphasize prevention and treatment of cigarette, methamphetamine, and other drug use, and promote improved connection to psychiatric care. Continual achievement of this goal may be a crucial step to increase rates of viral suppression and slow HIV incidence in communities of MoCSM in Los Angeles and other urban areas. PMID- 29478148 TI - A new treatment of female stress urinary incontinence with vaginal antetheca retropubic space mesh repair surgery: a clinical trial. AB - PURPOSE: To investigate the short- and medium-term effect of vaginal antetheca submucosal-retropubic space with mesh repair through the implantation of organic patch (shortly as new-style vaginal mesh repair) in the treatment of patients with stress urinary incontinence (SUI). METHODS: This was a clinical prospective single arm study in a tertiary grade hospital (General Hospital of Jinan Military Region, Jinan, China). From January 2009 to December 2014, 316 female patients were enrolled. 316 female patients with stress urinary incontinence (SUI) underwent the surgery. The treatment effect was evaluated using the urinary incontinence questionnaire (ICIQ-SF), urine pad test and coughing test. The perioperative and postoperative complications were also evaluated. The results were compared with 1-year cure rates of Burch retropubic urethropexy (Burch) and tension-free vaginal tape (TVT) procedure. RESULTS: The mean follow-up period was 25 +/- 12 months. The success rate of the new surgical technique was 94.0% (297/316) at 1 month, and 91.5% (289/316) at 1-year postoperation. The ICIQ-SF score significantly decreased at the 1-year follow-up (P < 0.01). There was no significant difference in the 1-year cure rate when compared with the Burch and TVT procedures (P > 0.05). The rates of perioperative urinary tract irritation and mesh exposure were 9.5% (30/316) and 5.38% (17/316), respectively, and no serious complications were found. CONCLUSIONS: The surgery demonstrated favorable short-term and medium-term treatment effects. Given its advantages of being minimally invasive, cost efficient and requiring only local anesthesia, this new surgical technique has a potential for broader clinical application. CLINICALTRIALS. GOV ID: NCT02934490. PMID- 29478147 TI - Community Savings Groups, Financial Security, and HIV Risk Among Female Sex Workers in Iringa, Tanzania. AB - This study assessed the association between community savings group participation and consistent condom use (CCU) among female sex workers (FSW) in Iringa, Tanzania. Using cross-sectional data from a survey of venue-based FSW (n = 496), logistic regression was used to examine the associations between financial indicators including community savings group participation and CCU. Over one third (35%) of the women participated in a savings group. Multivariable regression results indicated that participating in a savings group was significantly associated with nearly two times greater odds of CCU with new clients in the last 30 days (aOR = 1.77, 95% CI 1.10-2.86). Exploratory mediation analysis indicated that the relationship between savings group participation and CCU was partially mediated by financial security, as measured by monthly income. Findings indicate that community savings groups may play an important role in reducing sexual risk behaviors of FSW and hold promise as part of comprehensive, community-led HIV prevention strategies among FSW. PMID- 29478150 TI - Cardiac Rehabilitation: Current Review of the Literature and Its Role in Patients with Heart Failure. AB - PURPOSE OF REVIEW: Cardiovascular (CV) disease remains the leading cause of death in the USA despite major advances in its treatment. With time, cardiac rehabilitation (CR) programs have gathered interest to help increase CV health and improve functional status after a CV event. Patients with heart failure have also been shown to benefit. In this review, we will evaluate the current literature showcasing the benefits of CR, particularly in patients with heart failure, discuss current limitations, and avenues for future investigation. RECENT FINDINGS: Studies have shown that CR is beneficial in reducing morbidity, mortality, hospitalizations, activity-related symptoms, and increasing quality of life. Similar findings have also been observed in patients with heart failure who underwent CR in addition to optimal medical management. The positive effects of CR are well established in patients with coronary disease. Recent literature is also showing a trend to benefit in patients with heart failure, though much of the evidence is limited to patients with systolic dysfunction. Despite recommendations by professional societies, the use of CR remains underutilized. Further investigation is needed to better understand the impact of CR in heart failure. Moreover, strategies to increase CR utilization must be explored. PMID- 29478149 TI - Botulinum Toxin Treatment of Movement Disorders. AB - Botulinum neurotoxins (BoNTs) are now among the most widely used therapeutic agents in clinical medicine with indications applied to the fields of movement disorders, pain disorders, and autonomic dysfunction. In this literature review, the efficacy and utility of BoNTs in the field of movement disorders are assessed using the criteria of the Guideline Development Subcommittee of the American Academy of Neurology. The literature supports a level A efficacy (established) for BoNT therapy in cervical dystonia and a level B efficacy (probably effective) for blepharospasm, hemifacial spasm, laryngeal dystonia (spasmodic dysphonia), task-specific dystonias, essential tremor, and Parkinson rest tremor. It is the view of movement disorder experts, however, that despite the level B efficacy, BoNTs should be considered treatment of first choice for blepharospasm, hemifacial spasm, laryngeal, and task-specific dystonias. The emerging data on motor and vocal tics of Tourette syndrome and oromandibular dystonias are encouraging but the current level of efficacy is U (undetermined) due to lack of published high-quality studies. PMID- 29478151 TI - Theoretical study on p-type D-pi-A sensitizers with modified pi-spacers for dye sensitized solar cells. AB - Based on a prototype sensitizer W2, we designed triarylamine-based p-type sensitizers W2-1 to W2-7 that contain modified pi-spacers (pi'), a pi-spacer and two anchors. For W2-1 to W2-4, instead of 2,1,3-benzothiadiazole in W2, thieno[3,4-b]-1,4-dioxin, thiophene, thieno[3,4-c][1,2,5]thiadizole, thiazolo[5,4 d]thiazole are pi' and thiophene as pi-spacer. For W2-5 to W2-8, pi' and pi are same, with 2,1,3-benzothiadiazole, thieno[3,4-b]-1,4-dioxin, thieno[3,4 c][1,2,5]thiadiazo, thiazolo[5,4-d]thiazole, respectively, as the pi'-spacers. Structure optimization, electronic level and absorption characters were calculated with density functional theory (DFT) and time-dependent DFT (TDDFT) at the CAM-B3LYP/6-311G (d,p). The solvent effect was involved using a polarized continuum model in chloroform. The results showed that the highest occupied molecular orbital and the lowest unoccupied molecular orbital guarantee sufficient hole injection (lower than -0.2 eV), and dye regeneration (lower than 0.2 eV). W2-4 has higher light-harvesting efficiency (LHE) (0.994) and larger overlap with the visible light from 400 nm to 600 nm. Finally, the results suggest that the driving force of hole injection, dye regeneration and charge recombination (DeltaGinj, DeltaGreg and DeltaGCR) of W2-4 are the best, with more negative DeltaGinj (-4.33), DeltaGreg (-1.74) and more positive DeltaGCR (1.92). Replacing 2,1,3-benzothiadiazole with thiazolo[5,4-d]thiazole as pi'-spacers is a effective way to improve the performance of the dyes. An introduction of thiazolo[5,4-d]thiazole group can improve the absorption ability and hinder charge recombination. Graphical abstract Absorption spectra of p-type D-pi-A sensitizers with modified pi-spacers. PMID- 29478152 TI - The Role of Integrin alpha4beta7 in HIV Pathogenesis and Treatment. AB - PURPOSE OF REVIEW: Acute HIV infection is characterized by high-level viral replication throughout the body's lymphoid system, particularly in gut-associated lymphoid tissues resulting in damage to structural components of gut tissue. This damage is irreversible and believed to contribute to the development of immune deficiencies. Antiretroviral therapy (ART) does not restore gut structure and function. Studies in macaques point to an alternative treatment strategy that may ameliorate gut damage. Integrin alpha4beta7 mediates the homing of lymphocytes to gut tissues. Vedolizumab, a monoclonal antibody (mAb) antagonist of alpha4beta7, has demonstrated efficacy and has been approved for the treatment of inflammatory bowel disease in humans. Here, we describe our current knowledge, and the gaps in our understanding, of the role of alpha4beta7 in HIV pathogenesis and treatment. RECENT FINDINGS: When administered to macaques prior to infection, a nonhuman primate analogue of vedolizumab prevents transmission of SIV. In combination with ART, this mAb facilitates durable virologic control following treatment interruption. Targeting alpha4beta7 represents a novel therapeutic approach to prevent and treat HIV infection. PMID- 29478153 TI - The Interactions of the Immune System and the Brain in Hypertension. AB - PURPOSE OF REVIEW: Hypertension still represents a huge health problem, causing death and disability and rising at epidemic levels worldwide. The availability of a vast array of antihypertensive therapeutic strategies still fails to adequately treat significant fractions of refractory patients. The possible explanation to this disappointing evidence should be ascribed to the fact that myriad of mechanisms contribute to onset and maintenance of hypertension. Although we have been able to develop strategies aimed at counteracting the single mechanisms identified as master regulators of blood pressure, we still lack strategies capable to approach at the complex interactions established among the different pathophysiological mechanisms. RECENT FINDINGS: One of the most intriguing pathophysiological interactions in hypertension emerged in the very last years is the one established between the autonomic nervous system and immunity. Here we briefly review the most important contributions revealing neural modulation of immunity in hypertension and how this novel concept is integrated in the already known multitude of regulations exerted by the autonomic nervous system in typical organs involved in blood pressure regulation. PMID- 29478155 TI - Brief Report: Impact of Challenging Behavior on Parenting Stress in Mothers and Fathers of Children with Autism Spectrum Disorders. AB - Challenging behaviors are a known predictor of high parenting stress in families of children with autism spectrum disorders. However, few studies have evaluated the effect of reducing challenging behaviors on parenting stress. The purpose of our study was to (a) examine the impact of reducing the frequency and severity of challenging behaviors on parenting stress and (b) compare the effects of family centered support and parent education on changes in parenting stress. Both high severity of autistic symptoms and of challenging behaviors were predictors of parenting stress. Furthermore, receiving family-centered support were associated with larger reductions in parenting stress. Overall, our results suggest that reducing challenging behaviors with family-centered support may be preferable to produce collateral reductions in parenting stress. PMID- 29478156 TI - Comparing Mobile Technologies for Teaching Vocational Skills to Individuals with Autism Spectrum Disorders and/or Intellectual Disabilities Using Universally Designed Prompting Systems. AB - The purpose of this study was to compare mobile technologies with universally designed prompting systems to improve the independent vocational performance of four adolescents with ASD and/or ID in school-based employment settings. Specific aims were to (1) compare the effectiveness of universally-designed prompting systems presented on iPads and HP Slates that involved participant-selection and participant-fading of available on-screen media prompts; (2) compare the usability of different mobile devices; and (3) determine if built-in decision prompts could improve problem-solving behavior during task completion. Results indicated that both devices resulted in immediate and substantial increases in independent responding for three of the four participants. All participants performed better with their preferred device and all self-faded reliance on instructional prompts as skill acquisition increased. PMID- 29478154 TI - Vessel radius mapping in an extended model of transverse relaxation. AB - OBJECTIVES: Spin dephasing of the local magnetization in blood vessel networks can be described in the static dephasing regime (where diffusion effects may be ignored) by the established model of Yablonskiy and Haacke. However, for small capillary radii, diffusion phenomena for spin-bearing particles are not negligible. MATERIAL AND METHODS: In this work, we include diffusion effects for a set of randomly distributed capillaries and provide analytical expressions for the transverse relaxation times T2* and T2 in the strong collision approximation and the Gaussian approximation that relate MR signal properties with microstructural parameters such as the mean local capillary radius. RESULTS: Theoretical results are numerically validated with random walk simulations and are used to calculate capillary radius distribution maps for glioblastoma mouse brains at 9.4 T. For representative tumor regions, the capillary maps reveal a relative increase of mean radius for tumor tissue towards healthy brain tissue of [Formula: see text] (p < 0.001). CONCLUSION: The presented method may be used to quantify angiogenesis or the effects of antiangiogenic therapy in tumors whose growth is associated with significant microvascular changes. PMID- 29478157 TI - Expression of the 5-enoylpyruvylshikimate-3-phosphate synthase domain from the Acremonium sp. aroM complex enhances resistance to glyphosate. AB - OBJECTIVE: To discover and isolate a glyphosate-resistant gene from a microorganism through gene mining. RESULTS: The full aroM gene from Acremonium sp. (named aroMA.sp.) was cloned using rapid amplification of cDNA ends. The transcriptional expression level of each domain increased significantly after glyphosate treatment in the aroMA.sp. complex and reached its maximum at 48 h. The aroA domain of the aroMA.sp. (named aroA A.sp.) was expressed in Escherichia coli BL21 (DE3) and the product was purified through Ni-NTA affinity chromatography. Furthermore, 45 KDa was indicated by SDS-PAGE and its enzyme activity was optimal at 30 degrees C and PH 7.0. The Ki/Km value of aroAA.sp. was 0.106, and the E. coli BL21 harboring aroAA.sp. could grow in the M9 minimal medium with 100 mM glyphosate. CONCLUSION: The aroAA.sp. from the aroMA.sp. complex had high enzyme activity and glyphosate resistance. Therefore, this research offers a new strategy for improving glyphosate resistance using the aroA domain of the aroM complex in the fungi. PMID- 29478158 TI - The patient who fell off a skyscraper. PMID- 29478159 TI - Genomics of Salmonella phage PhiStp1: candidate bacteriophage for biocontrol. AB - Multidrug-resistant Salmonella causing Salmonellosis is a food-borne pathogen and hence a public health hazard. Alternatives to antibiotics, such as phages, are possible solutions to this increasing drug resistance. In this context, several Salmonella phages were isolated and characterized. This paper describes the physiochemical and whole genome characterization of one such bacteriophage, PhiStp1, which efficiently infects serovars Salmonella Enteritidis and Salmonella Typhimurium. Morphological observations by transmission electron microscopy and phylogenetic analysis using terminase gene classified PhiStp1 to family Siphoviridae, closely resembling 'T5 like phage' morpho-types. With a maximum adsorption time of 50 min, PhiStp1 latent period was 30 min with 37 phages/cell burst size. PhiStp1 draft genome sequenced by shotgun method comprised 112,149 bp in 3 contigs with 37.99% GC content, 168 predicted ORFs, and 15 tRNAs. Genes involved in host shut down, DNA replication, regulation, nucleotide metabolism, lysis, and morphogenesis were also noted. The study not only provided an insight into the characteristics of phage genome, but also information about proteins encoded by bacteriophages, therefore contributing to understanding phage diversity. Sequence analysis also proved the absence of virulence and lysogeny related genes, which only went to confirm PhiStp1 as a promising therapeutic agent against Salmonella infections. PMID- 29478160 TI - An update of the Worldwide Integrated Assessment (WIA) on systemic insecticides. Part 3: alternatives to systemic insecticides. AB - Over-reliance on pesticides for pest control is inflicting serious damage to the environmental services that underpin agricultural productivity. The widespread use of systemic insecticides, neonicotinoids, and the phenylpyrazole fipronil in particular is assessed here in terms of their actual use in pest management, effects on crop yields, and the development of pest resistance to these compounds in many crops after two decades of usage. Resistance can only be overcome in the longterm by implementing methods that are not exclusively based on synthetic pesticides. A diverse range of pest management tactics is already available, all of which can achieve efficient pest control below the economic injury level while maintaining the productivity of the crops. A novel insurance method against crop failure is shown here as an example of alternative methods that can protect farmer's crops and their livelihoods without having to use insecticides. Finally, some concluding remarks about the need for a new framework for a truly sustainable agriculture that relies mainly on natural ecosystem services instead of chemicals are included; this reinforcing the previous WIA conclusions (van der Sluijs et al. Environ Sci Pollut Res 22:148-154, 2015). PMID- 29478161 TI - Kinetic release of arsenic after exogenous inputs into two different types of soil. AB - The mobility of arsenic (As) in soil depends on its sorption/desorption processes on soil particles. Plant uptake locally lowers As concentration in soil pore water, which would trigger resupplies of As from soil solid phase. To better understand the fate of As in soil system after its inputs into soil and its subsequent dynamic processes, diffusive gradients in thin films (DGT) technique along with DGT-induced fluxes in soils (DIFS) model were introduced to study the kinetic information of As in soils, including its response time (TC) and resupply rate constant (k-1). To achieve a series of soils with gradient As level, two different types of soils with similar As level (total As in soil JL is 7.4 mg kg 1, while in soil BJ is 6.5 mg kg-1) were collected and amended with exogenous As. Then, DGT deployments were carried out following a period of 90-day soil incubation. The simulated TC values in non-amended soil JL and soil BJ were 0.036 and 0.001 s-1, respectively. The difference may due to the properties of these two soils, including pH values and contents of adsorption materials, such as Fe and Al compounds. After As inputs into soils, the intrinsic rate of As release from the solid phase to the solution phase in As-amended JL soil was much higher than that in non-amended soil. While for soil BJ, a decreasing trend was observed after As spiking. The redistribution of As may responsible for the different variation trends of As kinetics in these two soils after As spiking. The results indicated that the distribution coefficient of As (Kd) in soil was mainly affected by soil Olsen-P content due to an ubiquitous competition between P and As on soil particles. PMID- 29478162 TI - Intermittent flux from a sand filter for household wastewater and integrated solute transfer to the vadose zone. AB - Depending on the actual number of soil-based on-site wastewater treatment system (OWTS) in an area, on-site sanitation may be a significant source of pollutants and a threat to groundwater. Even in the case of a system functioning correctly, here, a sand filter substituted for the in-situ soil, as the treated effluent may reach to the water table, it is necessary evaluating in situ how much the sand and underneath soil respectively contribute to pollutant removal. On the plot of a household in a small rural community, the functioning of a real scale OWTS was monitored for 1.5 years. This system, composed of a septic tank connected to a 5 * 5 m2 and 0.7-m thick aerobic sand filter was equipped with soil hydrodynamic probes (water content and matrix potential) during construction. By using the instantaneous profile method of water content, the intermittent infiltrated flux was determined across the sand-pack according to position and time. Treated water infiltrates into underneath soil acting as post-treatment. Quality of interstitial liquid from the sand and the soil was analysed each month on a 12-h pumping sample obtained through porous plates. Results of water fluxes and concentrations provide an estimate of the annual flux to the vadose zone and groundwater of metals, nutrients and some organic micro-pollutants (parabens and triclosan) through the OWTS and subsoil. PMID- 29478163 TI - Removal of helminth eggs by centralized and decentralized wastewater treatment plants in South Africa and Lesotho: health implications for direct and indirect exposure to the effluents. AB - Wastewater may contain contaminants harmful to human health; hence, there is the need for treatment before discharge. Centralized wastewater treatment systems are the favored treatment options globally, but these are not necessarily superior in reduction of pathogens as compared to decentralized wastewater treatment systems (collectively called DEWATS). This study was therefore undertaken to assess the soil-transmitted helminth (STH) and Taenia sp. egg reduction efficiency of selected anaerobic baffled reactors and planted gravel filters compared to centralized wastewater treatment plants in South Africa and Lesotho. The risk of ascariasis with exposure to effluents from the centralized wastewater treatment plants was also assessed using the quantitative microbial risk assessment (QMRA) approach. Eggs of Ascaris spp., hookworm, Trichuris spp., Taenia spp., and Toxocara spp. were commonly detected in the untreated wastewater. The DEWATS plants removed between 95 and 100% of the STH and Taenia sp. eggs, with centralized plants removing between 67 and 100%. Helminth egg concentrations in the final effluents from the centralized wastewater treatment plants were consistently higher than those in the WHO recommended guideline (<= 1 helminth egg/L) for agricultural use resulting in higher risk of ascariasis. Therefore, in conclusion, DEWATS plants may be more efficient in reducing the concentration of helminth eggs in wastewater, resulting in lower risks of STH infections upon exposure. PMID- 29478164 TI - Effect of water motion and microhabitat preferences on spatio-temporal variation of epiphytic communities: a case study in an artificial rocky reef system, Laoshan Bay, China. AB - Epiphytic fauna community structure is mainly determined by macro-scale environmental characteristics (e.g., water motion), whereas the influences of, and interaction with, micro-scale habitat-forming species are not well known. In order to explore the effects of water motion and functional macroalgal group on the community structure of epiphytic faunas, macroalgae and epiphytic faunas from four isolated artificial rocky reefs with different levels of hydrodynamic conditions were investigated in Laoshan Bay of China. A total of 32 macroalgal species and 22 faunal species were recorded on the surveys. The biomass and abundance of macroalgae and epiphytic faunas showed significant variations among stations and months. The biomass and abundance of epiphytic faunas were highest at outer Huangshankou station (H1) with medium hydrodynamic force. The lowest biomass of epiphytic faunas occurred at inner Huangshankou station (H3) with highest level of water motion, while the lowest abundance of epiphytic faunas occurred at Liepo station (L) with lowest level of water motion. Results showed that medium water motion level contributed to increasing biodiversity of epiphytic faunas. Epiphytic communities generally presented higher biomass and abundance in summer than in spring or autumn, which indicated temperature could be the ecological driver for temporal variation of epiphytic communities. The epiphytic faunas showed distinct preferences to structural morphology of macroalgae which forms suitable habitat for these organisms. This study suggests that artificial rocky reefs are of great significance to restore and maintain coastal biodiversity, and appropriate physical disturbance promote community reestablishment. PMID- 29478165 TI - Effects of high fluoride content in livestock drinking water on milk samples of different cattle in endemic area of Pakistan: risk assessment for children. AB - Fluoride in trace quantity is beneficial for human beings, serving to strengthen the apatite matrix of skeletal tissues and teeth, whereas high intake causes adverse impacts. In the present study, the effect of fluoride-contaminated drinking water of livestock on the milk samples of different cattle, belonging to a fluoride-endemic area (Tharparkar, Pakistan), was studied. In milk samples of different cattle (cows, camels, sheep, and goats), free and bound fluoride forms and its total (free (F-) + bound (F-)) contents were measured by ion-selective electrode. The concentration of fluoride in drinking water of livestock was also analyzed, as found in the range of 11.8-33.5 mg/L. The concentration of total fluoride in the milk samples of sheep, goats, cows, and camels were observed in the range of 1.72-2.43, 1.40-2.03, 0.835-1.41, and 0.425-0.897 mg/L, respectively. The resulted data indicated that the concentration of fluoride was higher in the milk samples of smaller cattle (sheep and goat), as compared to cow and camel. The fluoride in milk samples of all cattle appeared dominantly in free form. The percentage values of bound fluoride in the milk samples of sheep, goats, and cows were found to be 6.76, 11.6, and 19.7% in total, respectively, while in camel milk, the percentage was below the detection limit. The estimated daily intake of fluoride contents on consuming different types of milk by children age ranged 1.0 to 3.0 years was evaluated. Graphical abstract ?. PMID- 29478167 TI - Behavioral and mutagenic biomarkers in tadpoles exposed to different abamectin concentrations. AB - It is known that pesticides such as abamectin (ABA) present cytotoxic effects on target organisms; however, the effects from ABA on non-target organisms such as amphibians are poorly understood. The aim of the current study is to investigate whether the exposure of Lithobates catesbeianus tadpoles to different abamectin concentrations [12.5, 25, and 50% of the median lethal concentration (LC50)] leads to behavioral and morphological changes and/or generates possible cytotoxic effects. The aggregation test showed that tadpoles exposed to the highest ABA concentrations did not respond to the stimulus from non-familial and unrelated co specific species. On the other hand, there was no difference in the total number of crossings in the central line of the herein adopted apparatus between groups; it suggests that ABA did not affect animal locomotion in the aforementioned test, although changes in the normal swimming pattern of tadpoles exposed to the pesticide were recorded in the swimming activity test. In addition, the herein exposed animals did not respond to the predatory stimulus in the antipredator response test; this result suggests defensive response deficit caused by the pesticide. With respect to their oral morphology, tadpoles exposed to ABA presented the lowest scores for mandibular pigmentation and structures, as well as for dentition condition. Finally, it was possible seeing that the exposure to ABA, even at the lowest concentration (12.5% of the LC50), resulted in nuclear changes in the erythrocytes of the animals; these changes became evident in the increased number of micronuclei and in other nuclear abnormalities. Thus, besides confirming the cytotoxic potential of ABA in amphibians, the current study corroborates the hypothesis that the exposure to the herein investigated pesticide leads to behavioral and morphological changes in tadpoles, fact that may negatively reflect on the survival, as well as on natural populations of these individuals. PMID- 29478166 TI - Associations between respiratory health and ambient air quality in Canakkale, Turkey: a long-term cohort study. AB - Few epidemiological studies investigating the association between air pollution and health are available in Turkey. The aim of this cohort-type study is to examine the relationships between ambient air quality, respiratory diseases, and decreases in pulmonary function over a year in three different towns in Canakkale: Canakkale Central town (region I), Lapseki town center (region II), and Can town (region III). Region III had four different sub-regions, which were Can town center (region III-A), and the villages located around Can town, namely Durali (region III-B), Kulfal (region III-C), and Yuvalar (region III-D). In the first stage of the study, a detailed questionnaire was completed by the participants (n = 1152) in face-to-face interviews and pulmonary function test (PFT) was performed. In the second stage of the study, PFT measurements were repeated 1 year after the first stage. Particulate matter, SO2, NO2, and ozone were gathered from air quality monitoring stations located in the centers of the three regions. The most polluted area was region III, while region I and region II were the least polluted areas. The risk of pulmonary function decline throughout a year was 2.1 times higher in region III, 2.4 times higher both in regions III-B and III-C, and 1.6 times higher for smokers in all regions. In the present study, ambient air quality was worse in region III (industrialized region), which influenced PFT scores and the prognostics for chronic respiratory diseases. The findings of this study should be considered for future investment plans in this region related to human and environmental health needs. PMID- 29478168 TI - Probabilistic risk assessment of the effect of acidified seawater on development stages of sea urchin (Strongylocentrotus droebachiensis). AB - Growing evidence indicates that ocean acidification has a significant impact on calcifying marine organisms. However, there is a lack of exposure risk assessments for aquatic organisms under future environmentally relevant ocean acidification scenarios. The objective of this study was to investigate the probabilistic effects of acidified seawater on the life-stage response dynamics of fertilization, larvae growth, and larvae mortality of the green sea urchin (Strongylocentrotus droebachiensis). We incorporated the regulation of primary body cavity (PBC) pH in response to seawater pH into the assessment by constructing an explicit model to assess effective life-stage response dynamics to seawater or PBC pH levels. The likelihood of exposure to ocean acidification was also evaluated by addressing the uncertainties of the risk characterization. For unsuccessful fertilization, the estimated 50% effect level of seawater acidification (EC50 SW ) was 0.55 +/- 0.014 (mean +/- SE) pH units. This life stage was more sensitive than growth inhibition and mortality, for which the EC50 values were 1.13 and 1.03 pH units, respectively. The estimated 50% effect levels of PBC pH (EC50 PBC ) were 0.99 +/- 0.05 and 0.88 +/- 0.006 pH units for growth inhibition and mortality, respectively. We also predicted the probability distributions for seawater and PBC pH levels in 2100. The level of unsuccessful fertilization had 50 and 90% probability risks of 5.07-24.51 (95% CI) and 0 6.95%, respectively. We conclude that this probabilistic risk analysis model is parsimonious enough to quantify the multiple vulnerabilities of the green sea urchin while addressing the systemic effects of ocean acidification. This study found a high potential risk of acidification affecting the fertilization of the green sea urchin, whereas there was no evidence for adverse effects on growth and mortality resulting from exposure to the predicted acidified environment. PMID- 29478169 TI - Mytilus galloprovincialis (Lamarck, 1819) spermatozoa: hsp70 expression and protamine-like protein property studies. AB - In this work, we describe results of the reproductive health monitoring studies in Mytilus galloprovincialis following spermatozoa hsp70 expression and protamine like protein properties. Mussels control (ctr) were released within cages for 30 days in three different marine sites near Naples (Campania, Italy): Bagnoli south (BAs) and Bagnoli north (BAn), both close to a disposal metallurgical factory and in Capo Miseno (CM). Studies of hsp70 gene expression carried out, by RT-qPCR, in mussel spermatozoa have shown varied expression levels, particularly 5, 13, and 15-fold more than ctr in CM, BAs, and BAn, respectively, indicating highest involvement of stress proteins in spermatozoa of mussels in Bagnoli. In order to evaluate the possible risk on Mytilus galloprovincialis sustainability loss, electrophoretic analyses were performed on protamine-like proteins (PL) of collected spermatozoa. The results showed that CM PL were apparently unaltered with respect to ctr PL, while BAs and BAn PL appeared in part in the form of peptides and in part as bands with low mobility. Further, CM and BAs PL showed, by electrophoretic mobility shift assay, a decrease in DNA binding ability and a change in their DNA binding mode. The results of this investigation show the usefulness of the study of alterations of spermatozoa hsp70 expression and protamine-like protein properties for eco-toxicological evaluation using Mytilus galloprovincialis as a bioindicator. PMID- 29478170 TI - Arsenite removal from contaminated water by precipitation of aluminum, ferrous and ferric (hydr)oxides. AB - Several methods to remove arsenic from water have been considered, including co precipitation with Fe and Al (hydr)oxides. Such compounds are considered very effective to remove As from contaminated water due to strong bindings between them. Three Fe:Al molar ratios (100:0, 80:20, and 60:40) were used to synthesize aluminum, ferrous, and ferric (hydr)oxides by precipitation in water highly contaminated with arsenite (50 and 500 mg L-1). The method was very efficient for all treatments (> 93%) at the beginning of the incubation period, excepted the one with 60:40 Fe(II):Al molar ratio at the higher As concentration (500 mg L-1) in which gibbsite was identified in precipitated phases. In spite of the high efficiency, however, the threshold for drinking water was not attained, mainly to the higher As concentration, even 84 days after precipitation. At this high concentration of arsenite, even the required threshold for effluent discharge was not attained in some treatments. The sludge resulting from treatments with higher As concentration were considered hazardous according to results from leaching test and corroborated by BCR extractions. Arsenic associated with Al and adsorbed phases were also assessed by extractions with NH4F and KH2PO4, respectively. In general, the presence of Al increased the efficiency as well as the stability of the sludge resulting from Fe (II) treatments, but did not affect Fe (III) treatments, which were more efficient for As removal. PMID- 29478171 TI - Interferon-alpha Silencing by Small Interference RNA Increases Adenovirus Transduction and Transgene Expression in Huh7 Cells. AB - Adenoviruses are the most common vectors used in clinical trials of gene therapy. In 2017, 21.2% of clinical trials used rAds as vectors. Systemic administration of rAds results in high tropism in the liver. Interferon types alpha and beta are the major antiviral cytokines which orchestrate the host's immune response against rAd, limiting therapeutic gene expression and preventing subsequent vector administration. siRNA is small double-strand RNAs that temporally inhibit the expression of a specific gene. The aim is to evaluate the effect of IFN-alpha blocking by a specific siRNA on Ad-GFP transduction and on transgene expression in Huh7 cells in culture. Huh7 cells were cultured in DMEM and transfected with 70 nM of siRNA-IFN-alpha. Six hours later, the cells were exposed to 1 * 109 vp/ml of rAd-GFP for 24 h. Expression of IFN-alpha, TNF-alpha and the PKR gene was determined by RT-qPCR. Percentage of transduction was analyzed by flow cytometry and by qPCR. GFP expression was determined by western blot. 70 nM of siRNA-IFN-alpha inhibited 96% of IFN-alpha and 65% of TNF-alpha gene expression compared to an irrelevant siRNA. Percentage of transduction and transgene expression increased in these cells compared to an irrelevant siRNA. Inhibition of IFN-alpha expression by siRNA-IFN-alpha enabled a higher level of transduction and transgene expression GFP, highlighting the role of IFN-alpha in the elimination of adenovirus in transduced cells and thus suggesting that its inhibition could be an important strategy for gene therapy in clinical trials using adenovirus as a vector directed to liver diseases. PMID- 29478173 TI - Retrospective review of Arctic Front Advance Cryoballoon Ablation: a multicenter examination of second-generation cryoballoon (RADICOOL trial). AB - BACKGROUND: Pulmonary vein isolation (PVI) via catheter ablation is an approved therapy for patients with drug-refractory and symptomatic atrial fibrillation (AF). Furthermore, cryoballoon is now considered to be as effective as focal radiofrequency catheter ablation. This study examines the second-generation cryoballoon performance in a US multicenter review of real-world practices. METHODS: By retrospective chart collections, the long-term efficacy and safety of the cryoballoon procedure were assessed in 15 US centers. All patients had a history of drug-refractory symptomatic paroxysmal AF and were treated with a cryoballoon PVI strategy at the index ablation. RESULTS: Four hundred fifty-two patients were evaluated, and acute PVI was achieved in 99% of patients by cryoballoon catheter ablation. In 0.88% of patients (4/452), an additional focal ablation catheter was used to achieve acute PVI during the ablation procedure. Average procedure time was 128 (range 82 to 260) min, using an average of 17 (range 1 to 19) min of fluoroscopy. The most frequent adverse event was transient phrenic nerve injury (1.5%; 7/452 patients) which all resolved by the end of the procedure with no diaphragmatic dysfunction at discharge. There were no strokes, transient ischemic attacks, cardiac tamponade, atrioesophageal fistulas, or deaths during the study. At the 12-month efficacy endpoint, single-procedure success of freedom from atrial arrhythmia was 87% (393/452 patients). CONCLUSIONS: This real-world examination of the US practice demonstrates that second-generation cryoballoon ablation by PVI strategy is safe and effective among patients with paroxysmal AF. PMID- 29478174 TI - Efficacy of advanced pace-mapping technology for idiopathic premature ventricular complexes ablation. AB - PURPOSE: Catheter ablation is an effective treatment for premature ventricular complexes (PVCs). Activation mapping is accurate but requires PVCs at the time of the ablation. Pace-mapping correlation (PMC) is a supplemental tool recently developed as an integrated module for an electro-anatomical mapping platform. Our study sought to investigate whether pace-mapping technology provides similar ablation results in patients with low versus high idiopathic PVC burden at the time of ablation and the relationship between sites with the highest PMC and the earliest local activation time (LAT). METHODS: A total of 59 consecutive patients undergoing catheter ablation for idiopathic PVCs were enrolled. Twelve out of 59 patients (20%) were classified in the low PVC burden group (defined as < 2 PVCs/min) and 47/59 (80%) in the high PVC burden group. RESULTS: The most common origin of PVCs was the right ventricular outflow tract (RVOT) followed by aortic cusps, coronary sinus, parahisian region, and aorto-mitral continuity. Procedural and 1-month success rate were 95 and 87% respectively. PVC burden at the time of ablation did not influence the success rate. The median distance between the earliest LAT points and the highest PMC points was 6.4 (4.9-10.6) mm. CONCLUSIONS: Pace-mapping correlation is useful and accurate in localizing the origin of idiopathic PVCs irrespective of the initial PVC burden. It provides optimal ablation results when combined with LAT. Success rate at mid-term follow up is higher when the origin of PVCs is located in the RVOT as compared to other locations. PMID- 29478175 TI - Asymptomatic carriers of Leishmania infantum in patients infected with human immunodeficiency virus (HIV) in Morocco. AB - In Morocco, visceral leishmaniasis (VL) is a parasitic disease caused by the flagellated protozoan parasite Leishmania infantum. L. infantum is transmitted by the bite of female phlebotomine sandflies, and its main reservoir hosts are domestic dogs. Asymptomatic infection with L. infantum is more frequent than clinically apparent disease. In HIV-infected patients, the risk of clinical VL is increased due to immunosuppression that may reactivate latent infections. However, coinfected subjects do not necessarily develop VL and may remain as asymptomatic carriers depending on their immune status. The present study investigates the asymptomatic carriers of L. infantum in HIV-infected patients in central Morocco, where human cases of visceral leishmaniasis by L. infantum have been reported. A total of 200 HIV-infected patients attending the Infectious Diseases Unit of the Ibn Zohar Hospital of Marrakech participated in the study. Parasitological and serological blood analyses included a direct microscopic examination (DME), culture in Novy-McNeal-Nicolle (NNN) medium, and serology by indirect immunofluorescence (IFI). We found prevalence rates of 5% (10/200) by IFI, 3% (6/200) by DME, and 2.5% (5/200) by culture. The parasite was identified as L. infantum by PCR from positive cultures. PMID- 29478176 TI - Synthesis and antibacterial activity of iron-hexacyanocobaltate nanoparticles. AB - This paper deals with the synthesis and characterization of iron hexacyanocobaltate (FeHCC) and its antibacterial properties. The nanoparticles were prepared by a facile co-precipitation technique. Crystal structure, particle morphology, and elemental composition were determined using X-ray Powder Diffraction, X-ray fluorescence spectroscopy, Transmission Electron Microscopy (TEM), and Infrared Spectroscopy (IR). The antibacterial activity of the FeHCC nanoparticles was tested against Escherichia coli and Staphylococcus aureus as models for Gram-negative and Gram-positive bacteria, respectively, by bacterial counting method and microscopic visualization (TEM, FEG-SEM, and fluorescence microscopy). The results showed that the FeHCC nanoparticles bind to the bacterial cells, inhibit bacterial growth in a dose- and time-dependent manner, inducing a loss of the membrane potential, the production of reactive oxygen species and the release of macromolecules (nucleic acids and proteins) in the extracellular environment. To the best of our knowledge, this is the first study reporting the antimicrobial effects of metal-hexacyanometallates suggesting practical uses of these materials in different areas, such as self-cleaning surfaces or food packaging. PMID- 29478177 TI - Waterborne outbreaks in diarrhoea endemic foci of India: a longitudinal exploration and its implications. AB - Diarrhoea remains a global public health enigma raising deep concerns for the health planners since contaminated potable water often spoils the community health structure. We hereby report a 6-year odd continuing outbreak surveillance report based on potable water indices, during which 264 water samples were screened from different districts of West Bengal, India. Samples were analysed for the presence of different enteropathogenic bacterial species by conventional molecular tools and their sensitivity to antibiotics. 78.03% samples were positive for enteropathogenic bacterial organisms and 75% samples harbored Coliform. 45.45, 12.12, and 4.16% samples were positive for E.coli, V. cholerae, and V. mimicus, respectively. Diarrhoeagenic E.coli 7 EPEC, 10 ETEC, and 2 EIEC were isolated along with 2 V. cholerae O1 Ogawa (ctxA and tcpA ElTor positive), one each from tube well and pond. Interestingly, 4 V.cholerae non-O1/non-O139 also harbored hlyA gene. The detection of toxin genes among this bacterial pool of sampled water indicates the fallout of the potable water sources, thus enabling us to establish that it is none other than the contaminated potable water system which often wreaks havoc in the south Bengal diarrhoeal menace. The consequences are further complicated by the presence of drug-resistant pathogenic bacterial pool to fluoroquinolone, beta-lactams, and cephalosporins, in the accessible potable water, with threats of outbreaks exploding into an epidemic, given suitable environment, poor sanitation, and unhygienic practices. Therefore, we strongly recommend re-modelling of 'point-of-use water disinfection' measures and adequate personal hygiene for healthier community life. PMID- 29478178 TI - Modified Finney enteroplasty: a bowel sparing damage control stapled technique for penetrating jejunal and ileal injuries. AB - The rise in gun violence and other penetrating trauma constitutes one of the main challenges in the modern practice of Acute Care Surgery. Expertise in the emergency management of this type of injuries is needed if one is to avoid preventable complications, such as short bowel syndrome. Revisiting and sometimes repurposing old surgical techniques may facilitate this task. The use of a modified Finney enteroplasty as a bowel sparing damage control technique for penetrating jejunal and ileal injuries was studied on 87 gunshot wound victims. The results show this to be a safe and efficient bowel sparing approach to the management of these injuries. PMID- 29478179 TI - Participation in the convention on migratory species: A biogeographic assessment. AB - The Convention on the Conservation of Migratory Species of Wild Animals (CMS) is a Multilateral Environmental Agreement (MEA) focused on species that regularly travel across international borders. Despite covering an important group of species, CMS is under-utilized compared to other conservation-focused MEAs. CMS suffers from a lack of participation across North America and most of Asia. Our goal is to illustrate differences in species richness and average range-size across signatory and nonsignatory nation-states using range-diversity plots. We also show differences in the cost of CMS membership relative to species patterns to highlight which countries may be discouraged from becoming CMS signatories. Despite containing many CMS species, large economies such as the United States, Russia, and China are not members of the convention. To facilitate migratory species conservation into the future, CMS should seek to fill gaps in participation, potentially directing recruitment efforts toward nonsignatory states that would receive the largest benefit at the lowest relative cost. PMID- 29478180 TI - Influence of solid waste and topography on urban floods: The case of Mexico City. AB - Floods in cities are increasingly common as a consequence of multifactor watershed dynamics, including geomorphology, land-use changes and land subsidence. However, urban managers have focused on infrastructure to address floods by reducing blocked sewage infrastructure, without significant success. Using Mexico City as a case study, we generated a spatial flood risk model with geomorphology and anthropogenic variables. The results helped contrast the implications of different public policies in land use and waste disposal, and correlating them with flood hazards. Waste disposal was only related to small floods. 58% of the city has a high risk of experiencing small floods, and 24% of the city has a risk for large floods. Half of the population with the lowest income is located in the high-risk areas for large floods. These models are easy to build, generate fast results and are able to help to flood policies, by understanding flood interactions in urban areas within the watershed. PMID- 29478181 TI - Ecological changes and local knowledge in a giant honey bee (Apis dorsata F.) hunting community in Palawan, Philippines. AB - One of the traditional livelihood practices of indigenous Tagbanuas in Palawan, Philippines is wild honey hunting and gathering from the giant honey bee (Apis dorsata F.). In order to analyze the linkages of the social and ecological systems involved in this indigenous practice, we conducted spatial, quantitative, and qualitative analyses on field data gathered through mapping of global positioning system coordinates, community surveys, and key informant interviews. We found that only 24% of the 251 local community members surveyed could correctly identify the giant honey bee. Inferential statistics showed that a lower level of formal education strongly correlates with correct identification of the giant honey bee. Spatial analysis revealed that mean NDVI of sampled nesting tree areas has dropped from 0.61 in the year 1988 to 0.41 in 2015. However, those who correctly identified the giant honey bee lived in areas with high vegetation cover. Decreasing vegetation cover limits the presence of wild honey bees and this may also be limiting direct experience of the community with wild honey bees. However, with causality yet to be established, we recommend conducting further studies to concretely model feedbacks between ecological changes and local knowledge. PMID- 29478182 TI - Managing flood risks in the Mekong Delta: How to address emerging challenges under climate change and socioeconomic developments. AB - Climate change and accelerating socioeconomic developments increasingly challenge flood-risk management in the Vietnamese Mekong River Delta-a typical large, economically dynamic and highly vulnerable delta. This study identifies and addresses the emerging challenges for flood-risk management. Furthermore, we identify and analyse response solutions, focusing on meaningful configurations of the individual solutions and how they can be tailored to specific challenges using expert surveys, content analysis techniques and statistical inferences. Our findings show that the challenges for flood-risk management are diverse, but critical challenges predominantly arise from the current governance and institutional settings. The top-three challenges include weak collaboration, conflicting management objectives and low responsiveness to new issues. We identified 114 reported solutions and developed six flood management strategies that are tailored to specific challenges. We conclude that the current technology centric flood management approach is insufficient given the rapid socioecological changes. This approach therefore should be adapted towards a more balanced management configuration where technical and infrastructural measures are combined with institutional and governance resolutions. Insights from this study contribute to the emerging repertoire of contemporary flood management solutions, especially through their configurations and tailoring to specific challenges. PMID- 29478184 TI - Correction to: Visualization of microaneurysms using optical coherence tomography angiography: comparison of OCTA en face, OCT B-scan, OCT en face, FA, and IA images. AB - In the original publication, the yellow circles in Figures 2a, 2b, 3a and 3b are placed incorrectly. The corrected figures are given in this Erratum. PMID- 29478183 TI - Bird on the wire: Landscape planning considering costs and benefits for bird populations coexisting with power lines. AB - Power-line grids are increasingly expanding worldwide, as well as their negative impacts on avifauna, namely the direct mortality through collision and electrocution, the reduction of breeding performance, and the barrier effect. On the other hand, some bird species can apparently benefit from the presence of power lines, for example perching for hunting purposes or nesting on electricity towers. In this perspective essay, we reviewed the scientific literature on both costs and benefits for avifauna coexisting with power lines. Overall, we detected a generalized lack of studies focusing on these costs or benefits at a population level. We suggest that a switch in research approach to a larger spatio-temporal scale would greatly improve our knowledge about the actual effects of power lines on bird populations. This research approach would facilitate suitable landscape planning encompassing both mitigation of costs and promotion of benefits for bird populations coexisting with power lines. For example, the strategic route planning of electricity infrastructures would limit collision risk or barrier effects for threatened bird populations. Concurrently, this strategic route planning would promote the range expansion of threatened populations of other bird species, by providing nesting structures in treeless but potentially suitable landscapes. We suggest establishing a collaborative dialogue among the scientific community, governments, and electricity companies, with the aim to produce a win-win scenario in which both biodiversity conservation and infrastructure development are integrated in a common strategy. PMID- 29478185 TI - Effects of 1-Alkyl-3-Methylimidazolium Nitrate on Soil Physical and Chemical Properties and Microbial Biomass. AB - Ionic liquids (ILs), also called room temperature ILs, are widely applied in many fields on the basis of their unique physical and chemical properties. However, numerous ILs may be released into and gradually accumulate in the environment due to their extensive use and absolute solubility. The effects of 1-alkyl-3 methylimidazolium nitrate ([Cnmim]NO3, n = 4, 6, 8) on soil pH, conductivity, cation exchange capacity, microbial biomass carbon, and microbial biomass nitrogen were examined at the doses of 1, 10, and 100 mg/kg on days 10, 20, 30, and 40. The results demonstrated that the soil pH decreased and the conductivity increased with increasing IL doses. No significant differences were observed in the soil cation-exchange capacity. All three of the tested ILs decreased the soil microbial biomass carbon and nitrogen. Additionally, there were few differences among the ILs with different alkyl chain lengths on the tested indicators except for the microbial biomass nitrogen. The present study addressed a gap in the literature regarding the effects of the aforementioned ILs with different alkyl side chains on the physicochemical properties of soil, and the results could provide the basic data for future studies on their toxicity to soil organisms, such as earthworms and soil microbes. PMID- 29478186 TI - Aneuploidization under segmental allotetraploidy in rice and its phenotypic manifestation. AB - KEY MESSAGE: We report a repertoire of diverse aneuploids harbored by a newly synthesized segmental allotetraploid rice population with fully sequenced sub genomes and demonstrate their retention features and phenotypic consequences. Aneuploidy, defined as unequal numbers of different chromosomes, is a large effect genetic variant and may produce diverse cellular and organismal phenotypes. Polyploids are more permissive to chromosomal content imbalance than their diploid and haploid counterparts, and therefore, may enable more in-depth investigation of the phenotypic consequences of aneuploidy. Based on whole-genome resequencing, we identify that ca. 40% of the 312 selfed individual plants sampled from an early generation rice segmental allotetraploid population are constitutive aneuploids harboring 55 distinct aneuploid karyotypes. We document that gain of a chromosome is more prevalent than loss of a chromosome, and the 12 rice chromosomes have distinct tendencies to be in an aneuploid state. These properties of aneuploidy are constrained by multiple factors including the number of genes residing on the chromosome and predicted functional connectivity with other chromosomes. Two broad categories of aneuploidy-associated phenotypes are recognized: those shared by different aneuploids, and those associated with aneuploidy of a specific chromosome. A repertoire of diverse aneuploids in the context of a segmental allotetraploid rice genome with fully sequenced sub genomes provides a tractable resource to explore the roles of aneuploidy in nascent polyploid genome evolution and helps to decipher the mechanisms conferring karyotypic stabilization on the path to polyploid speciation and towards artificial construction of novel polyploid crops. PMID- 29478187 TI - Efficacy and safety of American ginseng (Panax quinquefolius L.) extract on glycemic control and cardiovascular risk factors in individuals with type 2 diabetes: a double-blind, randomized, cross-over clinical trial. AB - PURPOSE: Despite the lack of evidence, a growing number of people are using herbal medicine to attenuate the burden of diabetes. There is an urgent need to investigate the clinical potential of herbs. Preliminary observations suggest that American ginseng (Panax quinquefolius [AG]) may reduce postprandial glycemia. Thus, we aimed to evaluate the efficacy and safety of AG as an add-on therapy in individuals with type 2 diabetes (T2DM) controlled by conventional treatment. METHODS: 24 individuals living with T2DM completed the study (F:M = 11:13; age = 64 +/- 7 year; BMI = 27.8 +/- 4.6 kg/m2; HbA1c = 7.1 +/- 1.2%). Utilizing a double-blind, cross-over design, the participants were randomized to receive either 1 g/meal (3 g/day) of AG extract or placebo for 8 weeks while maintaining their original treatment. Following a >= 4-week washout period, the participants were crossed over to the opposite 8-week treatment arm. The primary objective was HbA1c, and secondary endpoints included fasting blood glucose and insulin, blood pressure, plasma lipids, serum nitrates/nitrites (NOx), and plasominogen-activating factor-1 (PAI-1). Safety parameters included liver and kidney function. RESULTS: Compared to placebo, AG significantly reduced HbA1c (- 0.29%; p = 0.041) and fasting blood glucose (- 0.71 mmol/L; p = 0.008). Furthermore, AG lowered systolic blood pressure (- 5.6 +/- 2.7 mmHg; p < 0.001), increased NOx (+ 1.85 +/- 2.13 umol/L; p < 0.03), and produced a mean percent end difference of - 12.3 +/- 3.9% in LDL-C and - 13.9 +/- 5.8% in LDL-C/HDL. The safety profiles were unaffected. CONCLUSIONS: AG extract added to conventional treatment provided an effective and safe adjunct in the management of T2DM. Larger studies using physiologically standardized ginseng preparations are warranted to substantiate the present findings and to demonstrate therapeutic effectiveness of AG. CLINICALTRIALS. GOV IDENTIFIER: NCT02923453. PMID- 29478188 TI - Palliative care in Swiss pediatric oncology settings: a retrospective analysis of medical records. AB - PURPOSE: This study examined the provision of palliative care and related decision-making in Swiss pediatric oncology settings. The aim was to determine if and when children who died from cancer received palliative care, whether there were differences by cancer diagnosis, and inclusion of children in decision making regarding palliative care. METHODS: Using a standardized data extraction form, a retrospective review of medical records of deceased pediatric patients was conducted. The form captured information on demographics, diagnosis, relapse(s), treatments, decision-making during palliative care, and circumstances surrounding a child's death. RESULTS: For 170 patients, there was information on whether the child received palliative care. Among those, 38 cases (22%) did not receive palliative care. For 16 patients, palliative care began at diagnosis. The mean duration of palliative care was 145 days (Mdn = 89.5, SD = 183.4). Decision to begin palliative care was discussed solely with parent(s) in 60.9% of the cases. In 39.1%, the child was involved. These children were 13.6 years of age (SD = 4.6), whereas those not included were 7.16 years old (SD = 3.9). Leukemia patients were less likely to receive palliative care than the overall sample, and patients with CNS neoplasms received palliative care for a longer time than other patients. CONCLUSIONS: There are still high numbers of late or non-referrals, and even children older than 12 years were not involved in decision-making regarding palliative care. These results do not align with international organizational guidelines which recommend that palliative care should begin at diagnosis. PMID- 29478189 TI - Maximizing patient adherence to prehabilitation: what do the patients say? AB - PURPOSE: Multimodal prehabilitation programs (exercise, nutrition, and anxiety reduction) have been shown to be successful for enhancing patients' physical function prior to surgery, although adherence remains a challenge. Given the short pre-operative period, maintaining adherence is critical to maximize program effectiveness. This study was designed to better understand patients' perspectives of prehabilitation and to identify factors related to program adherence. METHODS: A qualitative descriptive study was conducted based on 52 cancer patients enrolled in a prehabilitation program at the Montreal General Hospital, Montreal, Canada. Data was collected with a structured questionnaire designed to evaluate the program. RESULTS: Patients enjoyed their experience in prehabilitation, especially the exercise program and training sessions. The primary motivating factor for participation was to be physically prepared for the surgery. The most challenging exercise component was resistance training, while the most enjoyed was the aerobic training. Approximately 50% of patients were interested in group fitness classes as opposed to supervised individual training sessions for reasons related to social support. The preferred methods for exercise program delivery were home-based and one supervised exercise session per week. The biggest barrier to participation was related to transportation. CONCLUSIONS: These findings highlight the need to make prehabilitation programs more patient-centered. This is critical when designing more effective therapeutic strategies tailored to meet patients' specific needs while overcoming program non adherence. PMID- 29478190 TI - The Geropathology Grading Platform demonstrates that mice null for Cu/Zn superoxide dismutase show accelerated biological aging. AB - The Geropathology Grading Platform (GGP) that is being developed by the Geropathology Research Network provides a grading system that allows investigators to assess biological aging in mice by measuring the pathological status of a wide range of tissues in a standardized scoring system. The GGP is a grading system that generates a numerical score for the total lesions in each tissue, which when averaged over the mice in the cohort provides a composite lesion score (CLS) for each tissue and mouse. In this study, we tested ability of the GGP to predict accelerated aging in mice null for Cu/Zn-superoxide dismutase (Sod1KO mice), which have been shown to have reduced lifespan and healthspan. Using the GGP, we evaluated the pathological status of 11 tissues from male and female wild-type (WT) and Sod1KO mice at 9 to 10 months of age. The whole animal CLS was 2- to 3.5-fold higher for both male and female Sod1KO mice compared to WT mice. The tissues most affected in the Sod1KO mice were the liver, lung, and kidney. These data demonstrate that the GGP is able to predict the accelerated aging phenotype observed in the Sod1KO mice and correlates with the changes in healthspan that have been reported for Sod1KO mice. Thus, the GGP is a new paradigm for evaluating the effect of an intervention on the pathological status of an animal as well as the healthspan of the mice. PMID- 29478192 TI - Neural Mechanisms of Swallowing Dysfunction and Apraxia of Speech in Acute Stroke. AB - Speech and swallowing utilize overlapping anatomy and are thus inherently related processes. We sought to identify common neural mechanisms between risk of swallowing dysfunction and apraxia of speech (AOS). This was a retrospective analysis using data from a prospectively collected cohort. Left hemisphere stroke patients (68 subjects) tested with the Apraxia Battery for Adults II, a swallow screen, and MRI were included in the study. Main outcome measure was the presence of AOS or aspiration risk after stroke. We identified a significant association between AOS measures and increased aspiration risk (defined by failed swallow screen; p = 0.04; OR 5.2). Lesions in pars opercularis of Broca's area (BA 44) were associated with both AOS (p = 0.044; OR 9.7) and increased aspiration risk (p = 0.04; OR 5) but deficits rarely co-occurred in the same cases. Lesions in left premotor cortex (BA 6) were not significantly associated with increased aspiration risk (p = 0.06; OR 3.3) but were significantly associated with AOS (p = 0.008; OR 7). Impaired swallowing function was also associated with lesions in Wernicke's area (BA 22; p = 0.05; OR 3.5) and pars triangularis (BA 45; p = 0.02; OR 6.8). AOS and risk of aspiration are associated in patients with acute left hemisphere stroke. Acute infarct in the pars opercularis of Broca's area is associated with both deficits, though they rarely co-occur in the same individual. The co-occurrence of AOS and risk of aspiration likely reflects dependence on closely related neural structures. PMID- 29478191 TI - Using the Dutch multi-informant Strengths and Difficulties Questionnaire (SDQ) to predict adolescent psychiatric diagnoses. AB - Knowledge on the validity of the Strengths and Difficulties Questionnaire (SDQ) among adolescents is limited but essential for the interpretation of SDQ scores preceding the diagnostic process. This study assessed the predictive and discriminative value of adolescent- and parent-rated SDQ scores for psychiatric disorders, diagnosed by professionals in outpatient community clinics, in a sample of 2753 Dutch adolescents aged 12-17. Per disorder, the predictive accuracy of the SDQ scale that is contentwise related to that particular disorder and the SDQ impact scale was assessed. That is, 24 logistic regression analyses were performed, for each combination of DSM-IV diagnosis [4: Attention Deficit/Hyperactivity Disorder (ADHD), Conduct/Oppositional Defiant Disorder (CD/ODD), Anxiety/Mood disorder, Autism Spectrum Disorder (ASD)], informant (3: adolescent, parent, both), and SDQ scale(s) (2; related scale only, related scale and impact scale). Additional logistic regression analyses were performed to assess the discriminative strength of the SDQ scales. The results show both fair predictive strength and fair discriminative strength for the adolescent- and parent-reported hyperactivity scales, the parent-reported conduct scale, and the parent-reported social and prosocial scales, indicating that these scales provide useful information about the presence of ADHD, CD/ODD, and ASD, respectively. The SDQ emotional scale showed to be insufficiently predictive. The findings suggest that parent-rated SDQ scores can be used to provide clinicians with a preliminary impression of the type of problems for ADHD, CD/ODD, and ASD, and adolescent for ADHD. PMID- 29478193 TI - Balloon Pulmonary Angioplasty in Patients With Thromboembolic Pulmonary Hypertension. AB - PURPOSE OF REVIEW: Chronic thromboembolic pulmonary hypertension (CTEPH) is the only potentially curable form of precapillary pulmonary hypertension. Although pulmonary endarterectomy (PEA) is the preferred management strategy, a significant number of CTEPH patients will have an inoperable disease. As drug therapy is not expected to offer relief from the mechanical component of the disease, the novel technique of balloon pulmonary angioplasty (BPA) has provided a new therapeutic option for patients with inoperable CTEPH. This review will discuss the contemporary use of BPA technique in inoperable CTEPH patients highlighting the effectiveness and safety of this therapeutic option. RECENT FINDINGS: Data supporting the role of BPA in inoperable CTEPH are limited to observational studies. However, these observational studies report consistent findings that BPA results in marked improvements in pulmonary hemodynamics and exercise capacity indicating its efficacy and safety as a treatment strategy in inoperable CTEPH patients. Summarizing, BPA is an emerging treatment option providing marked improvements in parameters affecting the outcome of CTEPH patients, but multicenter studies are needed to confirm the safety and the long term efficacy of the procedure, before BPA can be recommended as an established treatment for CTEPH. PMID- 29478194 TI - Numerical study of the effect of head and eye movement on progression of retinal detachment. AB - Rhegmatogenous retinal detachment (RD) is a sight threatening condition. In this type of RD a break in the retina allows retrohyaloid fluid to enter the subretinal space. The prognosis concerning the patients' visual acuity is better if the RD has not progressed to the macula. The patient is given a posturing advice of bed rest and semi-supine positioning (with the RD as low as possible) to allow the utilisation of gravity and immobilisation in preventing progression of the RD. It is, however, unknown what external loads on the eye contribute the most to the progression of a RD. The goal of this exploratory study is to elucidate the role of eye movements caused by head movements and saccades on the progression of an RD. A finite element model is produced and evaluated in this study. The model is based on geometric and material properties reported in the literature. The model shows that a mild head movement and a severe eye movement produce similar traction loads on the retina. This implies that head movements and not eye movements-are able to cause loads that can trigger and progress an RD. These preliminary results suggest that head movements have a larger effect on the progression of an RD than saccadic eye movements. This study is the first to use numerical analysis to investigate the development and progression of RD and shows promise for future work. PMID- 29478195 TI - Contribution of left ventricular residual stress by myocytes and collagen: existence of inter-constituent mechanical interaction. AB - We quantify the contribution of myocytes, collagen fibers and their interactions to the residual stress field found in the left ventricle (LV) using both experimental and theoretical methods. Ring tissue samples extracted from normal rat, male and female, LV were treated with collagenase and decellularization to isolate myocytes and collagen fibers, respectively. Opening angle tests were then performed on these samples as well as intact tissue samples containing both constituents that served as control. Our results show that the collagen fibers are the main contributor to the residual stress fields found in the LV. Specifically, opening angle measured in collagen-only samples (106.45[Formula: see text] +/- 23.02[Formula: see text]) and myocytes-only samples (21.00[Formula: see text] +/- 4.37[Formula: see text]) was significantly higher and lower than that of the control (57.88[Formula: see text] +/- 12.29[Formula: see text]), respectively. A constrained mixture (CM) modeling framework was then used to infer these experimental results. We show that the framework cannot reproduce the opening angle found in the intact tissue with measurements made on the collagen only and myocytes-only samples. Given that the CM framework assumes that each constituent contributes to the overall mechanics simply by their mere presence, this result suggests the existence of some myocyte-collagen mechanical interaction that cannot be ignored in the LV. We then propose an extended CM formulation that takes into account of the inter-constituent mechanical interaction in which constituents are deformed additionally when they are physically combined into a mixture. We show that the intact tissue opening angle can be recovered in this framework. PMID- 29478196 TI - Development of a novel shrouded impeller pediatric blood pump. AB - The aim of this work was to analyze a shrouded impeller pediatric ventricular assist device (SIP-VAD). This device has distinctive design characteristics and parameter optimizations for minimization of recirculation flow and reduction in high-stress regions that cause blood damage. Computational Fluid Dynamics (CFD) simulations were performed to analyze the optimized design. The bench-top prototype of SIP-VAD was manufactured with biocompatible stainless steel. A study on the hydrodynamic and hemodynamic performance of the SIP-VAD was conducted with predictions from CFD and actual experimentation values, and these results were compared. The CFD analysis yielded a pressure range of 29-90 mmHg corresponding to flow rates of 0.5-3 L/min over 9000-11000 rpm. The predicted value of the normalized index of hemolysis (NIH) was 0.0048 g/100 L. The experimental results with the bench-top prototype showed a pressure rise of 30-105 mmHg for the flow speed of 8000-12000 rpm and flow rate of 0.5-3.5 L/min. The maximum difference between CFD and experimental results was 4 mmHg pressure. In addition, the blood test showed the average NIH level of 0.00674 g/100 L. The results show the feasibility of shrouded impeller design of axial-flow pump for manufacturing the prototype for further animal trials. PMID- 29478197 TI - The use of high-throughput sequencing to investigate an outbreak of glycopeptide resistant Enterococcus faecium with a novel quinupristin-dalfopristin resistance mechanism. AB - High-throughput sequencing (HTS) has successfully identified novel resistance genes in enterococci and determined clonal relatedness in outbreak analysis. We report the use of HTS to investigate two concurrent outbreaks of glycopeptide resistant Enterococcus faecium (GRE) with an uncharacterised resistance mechanism to quinupristin-dalfopristin (QD). Seven QD-resistant and five QD-susceptible GRE isolates from a two-centre outbreak were studied. HTS was performed to identify genes or predicted proteins that were associated with the QD-resistant phenotype. MLST and SNP typing on HTS data was used to determine clonal relatedness. Comparative genomic analysis confirmed this GRE outbreak involved two distinct clones (ST80 and ST192). HTS confirmed the absence of known QD resistance genes, suggesting a novel mechanism was conferring resistance. Genomic analysis identified two significant genetic determinants with explanatory power for the high level of QD resistance in the ST80 QD-resistant clone: an additional 56aa leader sequence at the N-terminus of the lsaE gene and a transposon containing seven genes encoding proteins with possible drug or drug-target modification activities. However, HTS was unable to conclusively determine the QD resistance mechanism and did not reveal any genetic basis for QD resistance in the ST192 clone. This study highlights the usefulness of HTS in deciphering the degree of relatedness in two concurrent GRE outbreaks. Although HTS was able to reveal some genetic candidates for uncharacterised QD resistance, this study demonstrates the limitations of HTS as a tool for identifying putative determinants of resistance to QD. PMID- 29478198 TI - Transurethral en bloc resection with bipolar button electrode for non-muscle invasive bladder cancer. AB - PURPOSE: Transurethral resection of bladder tumor (TURBT) using a wire loop is considered the gold standard for staging and treating non-muscle invasive bladder cancer (NMIBC). TURBT is associated with serious disadvantages that facilitate tumor recurrence. The present study evaluated the safety and efficacy of the bipolar button electrode for en bloc resection of NMIBC. METHODS: From January 2013 to July 2016, 82 consecutive patients newly diagnosed with NMIBC received transurethral en bloc resection with bipolar button electrode. Operative details, pathological result, and intraoperative and postoperative complications regarded as safety outcomes were documented. Each patient was followed up for >= 18 months. RESULTS: A total of 118 neoplasms were removed en bloc from 82 patients. The mean tumor diameter was 2.42 +/- 1.34 cm. The average operation time was 35 +/- 14 min. No complications such as bladder bleeding, vesicle perforation, and obturator nerve reflex occurred during the treatment. Pathological evaluations showed urothelial carcinoma with stage Ta low grade in 26 patients, T1 high grade in 51 patients, and T2 high grade in 5 patients. In addition, the bladder detrusor muscle layer was provided in all cases. The 18-month recurrence-free survival was 88.5% (23/26) and 74.5% (38/51) for Ta and T1 patients, respectively. CONCLUSIONS: The current results demonstrated that transurethral en bloc resection with bipolar button electrode is an effective, feasible, and safe treatment for NMIBC. PMID- 29478200 TI - pH after the first session of direct hemoperfusion with polymyxin B-immobilized fibers predicts mortality in patients with sepsis and septic shock. AB - BACKGROUND: The definition of sepsis was updated to sepsis-3 in February 2016. Currently, direct hemoperfusion therapy using the polymyxin B-immobilized fiber cartridge (PMX-DHP) is widely performed to treat sepsis and septic shock. However, the prognostic factors of PMX-DHPs in patients with sepsis using the new definition are unclear. We retrospectively assessed prognostic factors in patients who had received PMX-DHP therapy for sepsis and septic shock. METHODS: We included 71 patients with severe infection who underwent PMX-DHP treatment from January 2006 to August 2015 in this study. Participants were re-evaluated according to the criteria of sepsis-3. The patients were divided into two groups based on having survived (n = 59) or not survived (n = 12) for 28 days after PMX DHP treatment. Clinical data before and after PMX-DHP treatment were compared between the two groups. RESULTS: Non-survivors showed a lower Glasgow Coma Scale (GCS) score before PMX-DHP treatment compared with 28-day survivors [12 (6-14) vs 14 (12-15), P < 0.01]. Furthermore, pH after the first PMX-DHP session was significantly lower in non-survivors than in survivors (7.28 +/- 0.23 vs 7.39 +/- 0.06, P = 0.03). Multivariate logistic regression analysis showed that only lower pH after the first PMX-DHP session was a predictor of 28-day mortality independent of age, sex, GCS score, and mean arterial pressure (odds ratio per pH of 0.01, 0.93; 95% confidence interval, 0.83-0.99; P = 0.02). CONCLUSION: The pH after the first PMX-DHP session is an independent risk factor for mortality in patients receiving PMX-DHP for sepsis and septic shock. PMID- 29478199 TI - Inhibition of miR-219 Alleviates Arsenic-Induced Learning and Memory Impairments and Synaptic Damage Through Up-regulating CaMKII in the Hippocampus. AB - Epidemiological investigations and experimental studies indicate that chronic arsenic exposure can reduce learning and memory function. However, the underlying mechanism of this effect remains largely unknown. Emerging evidence suggests that microRNA (miRNA) play an important role in toxicant exposure and a regulatory role in cognitive function. In this study, we observed that subchronic arsenic exposure induced impairment of learning and memory and significantly up-regulated miRNA-219 (miR-219) expression in the mouse hippocampus. Furthermore, the expression of CaMKII, an experimentally validated target of miR-219, was decreased in the mice exposed to arsenic. Suppression of miR-219 by adeno associated viral (AAV)-delivered anti-miR-219 prevented the arsenic-induced impairment of learning and memory and relieved the pathological changes in the synaptic structure of the hippocampus. Furthermore, we observed that the NMDA receptor subunit 2 (NR2) and the memory-related proteins c-Fos and c-Jun were up regulated by inhibition of miR-219 in the mouse hippocampus. Taken together, the results of this study indicate that inhibition of miR-219 regulates arsenic induced damage in the structure of the hippocampus and impairment of learning and memory, possibly by targeting CaMKII. Suppression of miR-219 may be a potential strategy to ameliorate arsenic-induced neurotoxicity. PMID- 29478201 TI - Is low pre-transplant parathyroid hormone a risk marker for cardiovascular disease in long-term follow-up of renal transplant recipients? AB - BACKGROUND: Secondary hyperparathyroidism and altered levels of parathyroid hormone (PTH) are associated with vascular events in chronic kidney disease. After renal transplantation, this association is not clear. Pre-transplant parathyroidectomy (PTX) is common, but post-transplant data are scarce. We aimed to study the effect of PTH at the time of transplantation on risk of post transplant vascular events in renal transplant recipients with and without pre transplant PTX. METHODS: 258 patients from two Swedish transplant units were followed for 6 years. Separate analyses were made for patients with or without pre-transplant PTX. Patients with no pre-transplant PTX were stratified by quartiles of PTH at time of transplantation and patients with pre-transplant PTX were stratified by above and below median levels of PTH at time of transplantation. Hazard ratios for vascular events, mortality, and graft failure were calculated in adjusted Cox regression models. RESULTS: In patients with no pre-transplant PTX, the lowest quartile of PTH at transplantation had a higher risk of cardiovascular events compared to quartile 3 with an adjusted hazard ratio (95% CI) of 2.63 (1.04-6.67). In patients with pre-transplant PTX, the group below median of PTH had a higher risk of cardiovascular events with an adjusted hazard ratio (95% CI) of 18.15 (1.62-203.82) compared to patients above median of PTH. CONCLUSION: Low levels of parathyroid hormone before transplantation were associated with increased risk of post-transplant vascular events both in patients with and without pre-transplant parathyroidectomy. Any conclusions on causal or direct effect of PTH on outcome cannot be drawn from this observational study. PMID- 29478204 TI - Transradial PCI and Same Day Discharge. AB - PURPOSE OF REVIEW: The evolution of cardiac catheterization has led to the development of well-refined, more effective, and safer devices that allow cardiovascular interventionalists to deliver high-quality percutaneous interventions (PCI). Transradial PCI (TRI) has gained more popularity in the USA over the past 10 years, and as experience and volume of TRI grow, studies adopting same day radial PCI protocols have emerged and are showing promising results. We sought to review the current literature on TRI and same day discharge (SDD). RECENT FINDINGS: This literature review was performed to evaluate the studies that were published over the last 17 years regarding TRI and SDD. A literature search using PubMed, Cochran database, Google Scholar, and Embase was performed for studies evaluating TRI and SDD from January 1, 2000, to August 1, 2017. Observational studies, randomized clinical trials, meta-analyses, and consensus statements were included in our review. We used the following terms in our search: "same day," "same day discharge," "outpatient," and "ambulatory radial PCI." Articles with data pertinent to the subject matter were included. We did not limit our searches to specific journals. The available literature supports SDD for selected radial PCI patients. The advancement in PCI devices and pharmacology has enhanced the safety of post-PCI disposition leading to the evolution from traditional overnight stays to the development of same day discharge programs. We conclude that outpatient TRI for appropriately selected patients will be the standard of care in the future. This will lead to increased patient satisfaction, improved hospital throughput, and reduced hospital costs, without increased procedural complications. PMID- 29478202 TI - Activation of AQP2 water channels without vasopressin: therapeutic strategies for congenital nephrogenic diabetes insipidus. AB - Congenital nephrogenic diabetes insipidus (NDI) is characterized by defective urine concentrating ability. Symptomatic polyuria is present from birth, even with normal release of the antidiuretic hormone vasopressin by the pituitary. Over the last two decades, the aquaporin-2 (AQP2) gene has been cloned and the molecular mechanisms of urine concentration have been gradually elucidated. Vasopressin binds to the vasopressin type II receptor (V2R) in the renal collecting ducts and then activates AQP2 phosphorylation and trafficking to increase water reabsorption from urine. Most cases of congenital NDI are caused by loss-of-function mutations to V2R, resulting in unresponsiveness to vasopressin. In this article, we provide an overview of novel therapeutic molecules of congenital NDI that can activate AQP2 by bypassing defective V2R signaling with a particular focus on the activators of the calcium and cAMP signaling pathways. PMID- 29478203 TI - Co-regulation of photosynthetic processes under potassium deficiency across CO2 levels in soybean: mechanisms of limitations and adaptations. AB - Plants photosynthesis-related traits are co-regulated to capture light and CO2 to optimize the rate of CO2 assimilation (A). The rising CO2 often benefits, but potassium (K) deficiency adversely affects A that contributes to the majority of plant biomass. To evaluate mechanisms of photosynthetic limitations and adaptations, soybean was grown under controlled conditions with an adequate (control, 5.0 mM) and two K-deficient (moderate, 0.50 and severe, 0.02 mM) levels under ambient (aCO2; 400 umol mol-1) and elevated CO2 (eCO2; 800 umol mol-1). Results showed that under severe K deficiency, pigments, leaf absorption, processes of light and dark reactions, and CO2 diffusion through stomata and mesophyll were down co-regulated with A while light compensation point increased and photorespiration, alternative electron fluxes, and respiration were up regulated. However, under moderate K deficiency, these traits were well co regulated with the sustained A without any obvious limitations amid ~ 50% reduction in leaf K level. Primary mechanism of K limitation to A was either biochemical processes (Lb ~ 60%) under control and moderate K deficiency or the CO2 diffusion limitations (DL ~ 70%) with greater impacts of mesophyll than stomatal pathways under severe K deficiency. The eCO2 increased DL while lessened the Lb under K deficiency. Adaptation strategies to severe K deficiency included an enhanced K utilization efficiency (KUE), and reduction of photosystem II excitation pressure by decreasing photosynthetic pigments, light absorption, and photochemical quenching while increasing photorespiration and alternative electron fluxes. The eCO2 also stimulated A and KUE when K deficiency was not severe. Thus, plants responded to K deficiency by a coordinated regulation of photosynthetic processes to optimize A, and eCO2 failed to alleviate the DL in severely K-deficient plants. PMID- 29478205 TI - Digestibility, productive performance, and egg quality of laying hens as affected by dried cassava pulp replacement with corn and enzyme supplementation. AB - Two experiments were conducted to investigate the potential use of dried cassava pulp (DCP) supplemented with enzymes as an alternative feed ingredient in laying hen diets. In experiment 1, 45 laying hens (Isa Brown) aged 45 weeks were placed in individual cages to measure nutrient digestibility for 10 days. Nine dietary treatments were control and DCP as a replacement for corn at 20, 25, 30, and 35% supplemented with mixed enzymes (cellulase, glucanase, and xylanase) at 0.10 and 0.15%. Results showed that the use of DCP at 20-35% added with mixed enzymes had no negative effects on dry matter digestibility, while organic matter digestibility and nitrogen retention decreased with increased DCP up to 30-35% in diets. Both enzyme levels (0.10 and 0.15%) showed similar results on nutrient digestibility and retention. In experiment 2, a total of 336 laying hens aged 32 weeks were randomly allocated to seven dietary treatments (control and DCP substituted diets at 20, 25, and 30%) supplemented with mixed enzymes (0.10 and 0.15%). Diets incorporated with 20-30% of DCP and supplemented with mixed enzymes at both levels had no significant effects on egg production, egg weight, feed intake, egg mass, feed conversion ratio, protein efficiency ratio, or egg quality, except for egg yolk color being decreased with an increase of DCP in diets (P < 0.05). In conclusion, it is suggested that DCP supplemented with enzymes can be used as an energy source in laying hen diets up to 30% without showing negative effects on nutrient digestibility, productive performance, or egg quality. PMID- 29478206 TI - Effect of ambient management interventions on the production and physiological performance of lactating Sahiwal cattle during hot dry summer. AB - During summer season, increase in the environmental temperature in the subtropical regions of Pakistan is negatively affecting the performance of dairy animals. The study objective was to determine the effect of ambient management (90 days) on productive and physiological performance of lactating Sahiwal cows during hot dry summer season. Fifteen lactating cows during the early lactation stage, having similar parity (3), daily milk production (6.2 l), were randomly allocated to three treatments, 5 cows each, i.e., (1) kept under roof shade only, (2) provision of fans along with roof shade, and (3) provision of roof shade, fans, and sprinklers designated as S, SF, and SFS, respectively. The fans were of 360-rpm capacity and showers were on for 40 min after every 90-min interval from 9:00 to 21:00 h. THI values were 81.1 +/- 0.7, 80.5 +/- 0.7, and 77.7 +/- 0.4 under S, SF, and SFS treatments, respectively. Cows were milked twice daily. Respiration rate (RR) and rectal temperature (RT) data were collected at 14:00 h on daily basis. The daily milk production was significantly higher in cows under SF (7.9 +/- 1 kg) followed by SFS (6.9 +/- 1.2 kg) and S (6.1 +/- 0.9 kg) treatments. The mean RT (101.0 +/- 0.04 degrees F) was significantly lower in cows under SFS than that on SF and S treatments and similarly mean RR was also lower (21.2 breaths/min) in cows under SFS followed by SF and S treatments. It is concluded that milk production and physiological performance in Sahiwal cows can be improved by fan-assisted ventilation during hot dry summer in subtropical regions. PMID- 29478207 TI - Correction to: Early Life Stress and Childhood Aggression: Mediating and Moderating Effects of Child Callousness and Stress Reactivity. AB - The article "Early Life Stress and Childhood Aggression: Mediating and Moderating Effects of Child Callousness and Stress Reactivity", written by Dominika A. Winiarski, Melissa L. Engel, Niranjan S. Karnik and Patricia A. Brennan, was originally published electronically on the publisher's internet portal (https://link.springer.com/article/10.1007/s10578-018-0785-9) on 13 February 2018 without open access. PMID- 29478208 TI - Prominent and fruitful development of orthopaedic research in China. PMID- 29478209 TI - Muscle pedicle bone grafting using the anterior one-third of the gluteus medius attached to the greater trochanter for treatment of Association Research Circulation Osseous stage II osteonecrosis of the femoral head. AB - PURPOSE: The aim of this study was to evaluate the effectiveness of our technique on further collapse of the femoral head in Association Research Circulation Osseous (ARCO) stage II, patient's functional improvements, and analyze the survival rate of the affected hip. METHODS: Between June 2007 and March 2015, 24 hips diagnosed with osteonecrosis of the femoral head (ONFH) were treated with our muscle pedicle bone grafting (MPBG) technique using anterior one-third of gluteus medius attached to the greater trochanter. The group was consisted of 15 men and eight women, mean age of 36 years at the time of surgery. Mean follow-up was 6.2 years. RESULTS: Four hips showed regeneration, 11 hips showed no progression, and nine hips showed slight extent of the lesion. But during the follow-up, three hips underwent total hip arthroplasty at the mean follow-up of 5.8 years after the surgery. The survival rate at the last follow-up was approximately 87.5%. Excluding the three failed cases, the mean total Harris hip score was improved from 57.2 to 82.3 points (p < 0.05). We had no case of complications such as limping, numbness, wound infection, heterotopic ossification, nor intra- and post-operative fracture. CONCLUSION: We showed 87.5% of survival rate by average of 6.2-year follow-up, maximum of 10.1 years. And compared to other reports, our technique showed relatively good results. In the short term, our modified MPBG technique seems to be effective in ARCO stage II ONFH. We, therefore, suggest this technique as one of the promising treatments of choices for patients with ARCO stage II ONFH. PMID- 29478210 TI - Comparison between uncemented and cemented fixation for the tibial component in distal femoral replacement: a clinical and radiological study. AB - PURPOSES: We performed a retrospective, cohort study to compare uncemented tibial fixation with cemented tibial fixation in distal femoral replacement (DFR). METHODS: Sixty-two cases with uncemented tibial fixation and 58 cases with cemented tibial fixation were included. Inter-group comparisons were performed for baseline data, oncological and prosthetic outcomes, and changes of cortical thickness of tibial diaphysis. Radiological signs of bone adaptations around the uncemented tibial stem were identified through evaluation of plain films during follow-up. RESULTS: Uncemented tibial fixation shortened operative duration by 26 minutes, achieved equivalent oncological and prosthetic outcomes, and helped preserve anterior cortical thickness of tibia compared with the cemented counterpart after a mean follow-up of over 40 months. Radiological signs of osseointegration and reactive line were observed in 64.3 and 17.9% cases with uncemented tibial fixation. The two signs had different patterns of distribution and no significant predisposing factors could be identified. CONCLUSIONS: For DFR, the uncemented tibial fixation was safe and effective in functional reconstruction and in preservation of anterior cortex of tibial diaphysis. It could achieve osseointegration and might permit adaptive micromotion of the tibial stem post-operatively. LEVEL OF EVIDENCE: level III Therapeutic. PMID- 29478211 TI - Anterior cervical corpectomy and fusion versus discectomy and fusion for the treatment of two-level cervical spondylotic myelopathy: analysis of sagittal balance and axial symptoms. AB - PURPOSE: To compare the postoperative sagittal balance and occurrence of axial symptoms between anterior cervical corpectomy and fusion (ACCF) and anterior cervical discectomy and fusion (ACDF) for the treatment of two-level cervical spondylotic myelopathy (CSM). METHODS: A total of 71 consecutive patients who underwent ACCF or ACDF for two-level CSM in our institution from January 2014 to December 2016 were retrospectively reviewed. Of these patients, 30 (17 males, 13 females) were subjected to ACCF, and 41 (20 males, 21 females) were treated with ACDF. Perioperative data, radiographic parameters, clinical outcomes, and axial symptom occurrence were compared between the two groups. RESULTS: The average follow-up durations were 13.7 +/- 3.9 months in the ACCF group and 13.4 +/- 3.3 months in the ACDF group. The volume of blood loss was significantly lower in the ACDF group than in the ACCF group, and the operation time of the former was significantly shorter than that of the latter. The postoperative global lordotic angle and T1 slope were significantly larger in the ACCF group than in the ACDF group in each follow-up. The occurrence of postoperative axial symptoms was significantly lower in the ACDF group than in the ACCF group. CONCLUSION: The volume of blood loss was lower and the operation time was shorter in ACDF than in ACCF for the treatment of two-level CSM. Sagittal balance was better in the ACDF group than in the ACCF group, and this observation may lead to a reduced occurrence of axial symptoms. PMID- 29478212 TI - Correction to: The Effect of a Change Agent on Use of Evidence-Based Mental Health Practices. AB - The original version of this article unfortunately contained a mistake. PMID- 29478213 TI - Concomitant use of polarization and negative phase contrast microscopy for the study of microorganisms. AB - A simultaneous application of negative phase contrast and polarization microscopy was used to study the internal structure of microbial cells. Negative phase contrast allowed us to display the fine cell structures with a refractive index of light approaching that of the environment, e.g., the cytoplasm, and converted an invisible phase image to a visible amplitude one. In the polarizing microscope, cross-polarizing filters, together with first-order quartz compensator and a turntable, showed maximum birefringence of individual structures. Material containing algae was collected in ponds in the villages Sykorice and Zbecno (Protected Landscape Area Krivoklatsko). Objects were studied in a laboratory microscope (Carl Zeiss Jena, type NfpK), equipped with a basic body In Ph 160 with an exchangeable module Ph, LOMO St. Petersburg turntable mounted on a centering holder of our own construction and a Nikon D 70 digital SLR camera. Anisotropic granules were found only in the members of two orders of algae (Euglenales, Euglenophyceae and Chlorococcales, Chlorophyceae). They always showed strong birefringence and differed in both number and size. An important finding concerned thin pellicles in genus Euglena (Euglenales, Euglenophyceae) which exhibited weak birefringence. In genus Pediastrum (Chlorococcales, Chlorophyceae), these granules were found only in living coenobium cells. In contrast, dead coenobium cells contained many granules without birefringence-an important finding. Another important finding included birefringent lamellar structure of the transverse cell wall and weak birefringence of pyrenoids in filamentous algae of genus Spirogyra (Zygnematales, Conjugatophyceae). It was clearly displayed by the negative phase contrast and has not been documented by other methods. This method can also record the very weak birefringence of the frustule of a diatom of genus Pinnularia (Naviculales, Bacillariophyceae), which was further reinforced by the use of quartz compensator-an important finding. Simultaneous use of negative phase contrast and polarization microscopy allowed us to study not only birefringent granules of storage substances in microorganisms, but also the individual lamellae of the cell walls of filamentous algae and very thin frustule walls in diatoms. These can be visualized only by this contrast method, which provides a higher resolution (subjective opinion only) than other methods such as positive phase contrast or relief contrast. PMID- 29478214 TI - The role of weather conditions and normal level of air pollution in appearance of stroke in the region of Southeast Europe. AB - We investigated correlation between the normal level of air pollution, weather conditions and stroke occurrence in the region of Southeast Europe with a humid continental climate. This retrospective study included 1963 patients, 1712 (87.2%) with ischemic (IS) and 251 (12.8%) with hemorrhagic stroke (HS) admitted to emergency department. The number of patients, values of weather condition (meteorological parameters) [air temperature ( degrees C), atmospheric pressure (kPa), relative humidity (%)] and concentrations of air pollutants [particulate matter (PM10), nitrogen dioxide (NO2), ozone (O3)], were recorded and evaluated for each season (spring, summer, autumn, winter) during 2 years (July 2008-June 2010). The highest rate of IS was observed during spring (28.9%) (p = 0.0002) and HS in winter (33.9%) (p = 0.0006). We have found negative Spearman's correlations (after Bonferroni adjustment for the multiple correlations) of the number of males with values of relative humidity (%) (day 0, rho = - 0.15), the total number of strokes (day 2, rho = - 0.12), females (day 2, rho = - 0.12) and IS (day 2, rho = - 0.13) with concentrations of PM10 (ug/m3), as well as negative correlations of the number of females (day 2, rho = - 0.12) and IS (day 2, rho = 0.12) with concentrations of NO2 (ug/m3) (for all p < 0.002). In winter, the number of HS (day 0, rho = 0.25, p = 0.001) positively correlated with concentrations of O3 (ug/m3). The appearance of stroke has seasonal variations, with the highest rates during spring and winter. Positive correlation between the number of HS and values of O3 requires an additional reduction of the legally permitted pollutants concentrations. PMID- 29478215 TI - Additions of neural monitoring for thyroid surgery. PMID- 29478217 TI - Normal Growth in PKU Patients Under Low-Protein Diet in a Single-Center Cross Sectional Study. AB - Dietary phenylalanine restriction in phenylketonuria (PKU) patients is usually mandatory in order to prevent cognitive impairment. The influence of a low protein diet on growth has raised concerns in families and caregivers. This paper aims to investigate the growth in PKU patients treated with a low-protein diet including supplementation of amino acids and other nutrients according to standard protocols.We performed a single-center, cross-sectional study on growth in pediatric PKU patients (n = 51) treated with low-protein diet over a 20-month period. Height of healthy siblings (n = 44) and target height, calculated based on parents' height, served as controls.No statistically significant differences were found comparing mean height z-scores between patients and siblings (p = 0.261). Patients <12 years showed a reduction in mean height z-scores compared to the target height (p = 0.020), whereas postpubertal patients >=12 years did not differ significantly in height z-scores compared to the target height (p = 0.071). Healthy siblings' height did not differ from target height in neither age group (p = 0.100/p = 0.301).Our results suggest that PKU patients treated with low-protein diet can achieve normal growth with patients making up the leeway after puberty. While prepubertal patients were shorter than expected based on their target height, older patients were within their expected target height. This study indicates that current practice of low-protein diet in PKU patients allows normal growth. PMID- 29478218 TI - Mitochondrial Encephalopathy: First Portuguese Report of a VARS2 Causative Variant. AB - INTRODUCTION: Combined oxidative phosphorylation deficiency 20 (COXPD20) is a mitochondrial respiratory chain complex (RC) disorder, caused by disease-causing variants in the VARS2 gene, which encodes a mitochondrial aminoacyl-tRNA synthetase. Here we describe a patient with fatal mitochondrial encephalopathy caused by a homozygous VARS2 gene missense variant. CASE REPORT: We report the case of a girl, the first child of non-consanguineous and healthy parents, born from an uneventful term pregnancy, who presented, in the neonatal period, major hypotonia and microcephaly. At 4 months of age she showed poor eye contact, nystagmus, global psychomotor development delay and failure to thrive, without dysmorphic features. Focal seizures started at 24 months which evolved to a severe epileptic encephalopathy and finally to super refractory status epilepticus, leading to her death at 28 months of age. Etiologic investigation encompassing metabolic and genetic causes failed to disclose a diagnosis. Post mortem exome sequencing allowed the identification of a pathogenic variant in VARS2 gene in the homozygous state (c.1100C > T, p.Thr367Ile) in the patient, inherited from her heterozygous parents, leading to the diagnosis of COXPD2. CONCLUSION: To the best of our knowledge, this is the fifth case described in the literature of a child with disease-causing variant in VARS2. With this report we expand the knowledge about the phenotype associated with this very rare mitochondrial defect, further emphasizing the use of exome sequencing as a very powerful diagnostic tool. PMID- 29478216 TI - The feasibility of 18F-FES and 18F-FDG microPET/CT for early monitoring the effect of fulvestrant on sensitizing docetaxel by downregulating ERalpha in ERalpha+ breast cancer. AB - OBJECTIVE: Our study aimed to investigate the feasibility of PET/CT for monitoring the influence of fulvestrant on sensitizing docetaxel by downregulating ERalpha in ERalpha+ breast cancer. METHODS: Docetaxel-insensitive ERalpha+ breast cancer cells (DIS-ZR751) were established, identified and cultured. ERalpha expression, toxicity and viability of DIS-ZR751 were analyzed before and after treatment in vitro. DIS-ZR751-bearing nude mice were randomly divided into four groups according to different treatments: blank (DIS-ZR751), docetaxel (DIS-ZR751+DOC), fulvestrant (DIS-ZR751+FUL), and combination treatment (DIS-ZR751+DOC+FUL). 18F-FES and 18F-FDG microPECT/CT scans were performed before and 7, 14 days after treatment. Absolute %ID/gmax was calculated. RESULTS: ERalpha expression level and growth rate of DIS-ZR751 were higher than control group and decreased dramatically after docetaxel and fulvestrant combination treatment. 18F-FES and 18F-FDG PET/CT imaging in vivo revealed that ERalpha expression in DIS-ZR751 treated with fulvestrant, and tumor activity in DIS-ZR751 treated with combination drugs decreased as early as 7 days after treatment. CONCLUSIONS: 18F-FES and 18F-FDG PET/CT were feasible for early monitoring the effect of fulvestrant on sensitizing docetaxel by downregulation of ERalpha in ERalpha+ breast cancer noninvasively. PMID- 29478219 TI - Serial Magnetic Resonance Imaging and 1H-Magnetic Resonance Spectroscopy in GABA Transaminase Deficiency: A Case Report. AB - Gamma-aminobutyric acid transaminase (GABA-T) deficiency is a rare, autosomal recessive disorder characterized by severe psychomotor retardation, early-onset epileptic encephalopathy, intractable seizures, hypotonia, and hyperreflexia. The disease is caused by mutation in the 4-aminobutyrate aminotransferase (ABAT) gene, which encodes an enzyme involved in GABA catabolism. In this chapter, a 10 year follow-up of GABA-T deficiency in a rare case of a long-term survivor patient is discussed. The patient showed a progression of clinical phases with increasing age. In infancy, the patient developed psychomotor retardation and recurrent encephalopathic episodes associated with febrile illness. In early childhood, the patient presented with refractory involuntary and hyperkinetic movements and dystonic hypertonicity. In childhood, the patient gradually progressed into the chronic stable phase of the condition. Magnetic resonance imaging demonstrated high signal intensity on diffusion-weighted images involving the internal and external capsules and cerebral white matter in infancy which disappeared gradually by the age of 3 years, and showed subsequently diffuse brain atrophy in childhood. Using proton magnetic resonance spectroscopy, GABA levels in the basal ganglia were shown to be markedly elevated at the age of 1-2 years, and subsequently decreased with increasing age (toward 5 years). These findings suggest that the encephalopathic episodes in infancy and clinical severity of involuntary and hyperkinetic movements may be correlated with levels of GABA in the basal ganglia. The high levels of GABA in the cerebrospinal fluid remained unaltered, whereas levels of GABA in the serum decreased during childhood. Further investigation of long-term clinical surveillance may improve the understanding of GABA-T deficiency. PMID- 29478220 TI - Biofilm formation and antimicrobial sensitivity of lactobacilli contaminants from sugarcane-based fuel ethanol fermentation. AB - Industrial ethanol fermentation is subject to bacterial contamination that causes significant economic losses in ethanol fuel plants. Chronic contamination has been associated with biofilms that are normally more resistant to antimicrobials and cleaning efforts than planktonic cells. In this study, contaminant species of Lactobacillus isolated from biofilms (source of sessile cells) and wine (source of planktonic cells) from industrial and pilot-scale fermentations were compared regarding their ability to form biofilms and their sensitivity to different antimicrobials. Fifty lactobacilli were isolated and the most abundant species were Lactobacillus casei, Lactobacillus fermentum and Lactobacillus plantarum. The majority of the isolates (87.8%) were able to produce biofilms in pure culture. The capability to form biofilms and sensitivity to virginiamycin, monensin and beta-acids from hops, showed inter- and intra-specific variability. In the pilot-scale fermentation, Lactobacillus brevis, L. casei and the majority of L. plantarum isolates were less sensitive to beta-acids than their counterparts from wine; L. brevis isolates from biofilms were also less sensitive to monensin when compared to the wine isolates. Biofilm formation and sensitivity to beta-acids showed a positive and negative correlation for L. casei and L. plantarum, respectively. PMID- 29478221 TI - Mild cognitive impairment in Parkinson's disease: the Parkinson's disease cognitive study (PACOS). AB - Approximately 30% of Parkinson's disease (PD) patients show impaired cognitive performance, which is suggestive of Mild Cognitive Impairment (MCI), representing a predictor of dementia, especially when present at diagnosis. The objective of the study was to evaluate the frequency and clinical predictors of MCI in a large hospital-based cohort of PD patients. We collected cross-sectional data from the Parkinson's disease cognitive impairment study (PACOS), a multicenter study involving two Movement Disorder centers, which are located in south Italy. The PD subjects were diagnosed according to the UK Brain Bank criteria and they underwent an extensive neuropsychological assessment. PD-MCI was diagnosed according to the Movement Disorder Society task force criteria for MCI. PD severity was evaluated in accordance with the Unified PD Rating Scale-Motor Examination (UPDRS-ME) and the Hoehn and Yahr scales. The study included 659 PD patients (57.5% men; mean age 67.0 +/- 9.7 years), with a mean disease duration of 3.8 +/- 4.6 years and a mean UPRDS-ME score of 25.8 +/- 12.3. PD-MCI was diagnosed in 261 (39.6%) subjects and in 82 (31.7%) of 259 newly diagnosed patients (disease duration <= 1 year). An amnestic MCI multidomain phenotype was the most frequent MCI subtype (39.1% of the overall sample and 43.9% in newly diagnosed PD). A positive significant association between MCI, age and motor scores was found at multivariate logistic regression analysis, while a negative association was observed between educational level and MCI. In conclusion and in agreement with the literature data, the prevalence of MCI recorded in the PACOS sample was approximately 40 and 32% amongst newly diagnosed patients. PMID- 29478222 TI - Growing older with drug-resistant epilepsy: cognitive and psychosocial outcomes. AB - We aimed to investigate the cognitive and psychosocial outcomes of patients older than 50 with drug-resistant temporal lobe epilepsy as compared to a younger cohort. One hundred and thirty-one patients with temporal lobe epilepsy (47% age >= 50) who underwent comprehensive neuropsychological testing were retrospectively identified. A comparison of percentage of Z scores < - 1.5 between the older and younger cohort on Trail Making Tests A and B, Boston Naming Test, Rey Auditory Verbal Learning Test (RAVLT) delayed recall, and Rey Osterrieth complex figure test delayed recall was performed as well as the presence of disability due to epilepsy and depression scores. Grading of white matter hyperintensities on MRI was also performed. Older patients with epilepsy were more likely to score Z < - 1.5 on the RAVLT (54.1 vs 32.8%) and were more likely to be on disability due to their seizures (23.0 vs 5.7%). A higher grade of white matter hyperintensities correlated with worse performance on Trail Making Test A, while a higher number of anti-epileptic drugs (AEDs) correlated with worse performance on Trail Making Test B regardless of age. The results of this study reveal that older patients with drug-resistant epilepsy are a vulnerable population with an impaired cognitive profile. In addition, limiting the number of AEDs and addressing markers of small vessel disease should also be prioritized by clinicians. PMID- 29478223 TI - University education and cervical artery dissection. AB - BACKGROUND AND PURPOSE: We investigated whether university education is more likely in cervical artery dissection (CeAD)-patients than in age- and sex-matched patients with ischemic stroke (IS) due to other causes (non-CeAD-IS-patients). METHODS: Patients from the Cervical Artery Dissection and Ischemic Stroke Patients study with documented self-reported profession before onset of IS due to CeAD (n = 715) or non-CeAD causes (n = 631) were analyzed. In the reported profession, the absence or presence of university education was assessed. Professions could be rated as academic or non-academic in 518 CeAD and 456 non CeAD patients. Clinical outcome at 3 months was defined as excellent if modified Rankin Scale was 0-1. RESULTS: University education was more frequent in CeAD patients (100 of 518, 19.3%) than in non-CeAD-IS-patients (61 of 456, 13.4%, p = 0.008). CeAD-patients with and without university education differed significantly with regard to smoking (39 vs. 57%, p = 0.001) and excellent outcome (80 vs. 66%, p = 0.004). In logistic regression analysis, university education was associated with excellent outcome in CeAD-patients (OR 2.44, 95% CI 1.37-5.38) independent of other outcome predictors such as age (OR 0.97, 95% CI 0.84-0.99), NIHSS (OR 0.80, 95% CI 0.76-0.84) and local signs (OR 2.77, 95% CI 1.37-5.57). CONCLUSION: We observed a higher rate of university education in patients with CeAD compared with non-CeAD patients in our study population. University education was associated with favorable outcome in CeAD-patients. The mechanism behind this association remains unclear. PMID- 29478224 TI - Robotic-Assisted Percutaneous Coronary Intervention. AB - PURPOSE OF REVIEW: The goal of this review is to describe the benefits and limitations of robotic-assisted percutaneous coronary intervention (PCI), the most important and recent clinical data, and the future applications as robotic technology continues to develop. RECENT FINDINGS: Robotic-assisted PCI can reduce occupational hazards of ionizing radiation exposure and orthopedic injury to the interventional cardiologist while offering increased precision and fine control that may confer benefit to the patient. Recent studies have suggested the efficacy and safety of robotic-assisted PCI, yet widespread use of the technology has not been fully adopted due to limitations of the current technology and high costs. Robotic-assisted PCI has potential to benefit both the operator and the patient. Despite some limitations of robotic-assisted PCI, it can safely and effectively be used in many patients with coronary artery disease requiring PCI. The value proposition for robotic-assisted PCI will depend on the evolution of robotic systems and its applicability to more complex coronary lesions, peripheral arterial interventions, and telemedicine. PMID- 29478225 TI - Tear Martix Metalloproteinase-9 and Tissue Inhibitor of Metalloproteinase-1 in Post-Lasik Ectasia. AB - PURPOSE: To estimate the concentrations of matrix metalloproteinase-9 (MMP-9) and tissue inhibitors of metalloproteinase-1 (TIMP-1) in the tear film of cases with post-Lasik ectasia (PLE) to spot any role of these mediators. SETTINGS: Ophthalmology department, Benha University hospitals, Egypt. METHODS: Twelve eyes of 12 patients with PLE, 30 eyes of 30 patients with KC, 25 eyes of 25 subjects with uncomplicated Lasik and finally 25 eyes of 25 healthy subjects as a control group were studied. Subjects with ocular surface diseases, previous ocular surgeries except for Lasik in PLE group and Lasik group, were excluded. All subjects had full ophthalmic examination and Pentacam imaging. The concentration of tear MMP-9 and TIMP-1 was measured by ELISA. RESULTS: Our results showed a significant elevation in the level of MMP-9 and a significant reduction in the level of TIMP-1 in tear samples from PLE cases (MMP-9 was 59.17 +/- 28.15 ng/ml, and TIMP-1 was 110.3 +/- 50.6 ng/ml) and also in KC cases (MMP-9 was 53.12 +/- 17.35 ng/ml, and TIMP-1 was 105.8 +/- 56.3 ng/ml) when compared to post-Lasik group (MMP-9 was 35.65 +/- 17.32 ng/ml, and TIMP-1 was 155.2 +/- 39.4 ng/ml) and control group (MMP-9 was 31.92 +/- 20.78 ng/ml, and TIMP-1 was 162.5 +/- 48.2 ng/ml). CONCLUSION: The results pointed to potential role of MMP-9 in the pathogenesis of PLE and also referred to a biochemical similarity between PLE and KC. More studies are needed in the future to investigate larger number of tear mediators. PMID- 29478227 TI - Heat Adaptation Improved Cell Viability of Probiotic Enterococcus faecium HL7 upon Various Environmental Stresses. AB - The production of viable functional probiotics presupposes stability of strain features in the final product. In previous studies, Enterococcus faecium HL7 was found to have relatively higher cell viability after freeze-drying and the long lasting resistance to heat (60 degrees C) as well as higher antimicrobial activities against some of fish and human pathogens among isolated strains. For heat adaptation, E. faecium HL7 cells were exposed to 52 degrees C for 15 min. After adaption, slight decreases of unsaturated membrane fatty acid ratios were confirmed through fatty acid analysis. Upon subsequent exposure to various stress conditions such as H2O2 (0.01%), ethanol (20%), acid (pH 3), and alkali (pH 12), the survival rate of heat-adapted HL7 was 103-105-fold higher than that of non adapted one. These results highlight the potential of preconditioning treatments for maximizing survival of probiotic bacteria during development of probiotic functional foods. The cross-protection afforded by acid against thermal stress may indicate that certain common protective mechanisms are induced by both heat and acid stress. These results can be applied to enhancing the cell viability during live cell formulation of E. faecium HL7 to be used as a potential probiotics in aquaculture. PMID- 29478226 TI - Reverse Pupillary Block After Retinal Detachment Surgery in an Eye with Toric Implantable Collamer Lens. AB - PURPOSE: To report an interesting phenomenon, after vitreoretinal surgery, in an eye with toric implantable collamer lens (ICL). METHODS: A 20-year-old male presented with raised intraocular pressure (IOP) after the retinal detachment surgery in the left eye. He had toric ICL in both the eyes, and left eye showed shallow peripheral anterior chamber depth (ACD), narrow iridocorneal angle (ICA), increased ICL vault and pigments debris blocking central hole. After dilation, peripheral ACD deepened, ICL vault decreased and ICA increased, with posterior bowing of iris. RESULTS: Patient was managed with topical steroids and antiglaucoma medications. A month later, after inflammation subsided, central hole of ICL became patent, peripheral ACD deepened, ICA increased and IOP was normal without medications, however, after dilation, posterior bowing of iris persisted. He was speculated to have unusual presentation of reverse pupillary block in the left eye after mydriasis. This phenomenon was not observed in the right eye. CONCLUSION: Reverse pupillary block, after dilation is an unusual phenomenon, which was seen in a silicone-filled eye with toric ICL implant. In cases of inflammatory debris blocking Aquaport opening of ICL, conservative management with topical steroids and antiglaucoma medications can help reduce inflammation and IOP, alleviating need for any intervention, such as laser iridotomy. PMID- 29478228 TI - High Dietary Iron Differentially Influences the Iron Distribution in the Livers and the Spleens of Laying Hens After Salmonella Typhimurium Infection. AB - Salmonella and the host battle for iron (Fe), due to its importance for fundamental cellular processes. To investigate Fe redistribution of Salmonella infected hens and the effects of high dietary Fe on it, Salmonella-free hens were randomly assigned to 1 of 4 treatments in 2 (two dietary Fe level) * 2 (Salmonella-inoculation or -noninoculation) factorial assignment. After feeding a basal diet supplemented with 60 (adequate, control) or 300 mg Fe/kg (high-Fe) for 4 weeks, 59-week-old Salmonella-free hens were orally inoculated with 5 * 107 colony-forming units of Salmonella Typhimurium (infection) or PBS (vehicle). Blood, spleen, and liver samples (n = 8) were collected at 14 days post inoculation to determine Fe concentration and Fe transporters expression. Salmonella infection decreased (P < 0.05) hematocrit, serum Fe concentration, and splenic Fe concentration regardless of high-Fe or control hens, whereas increased (P < 0.05) Fe centration in the livers of high-Fe-treated hens. High dietary Fe increased hematocrit and serum Fe concentration, but did not affect (P = 0.11) splenic Fe concentration in Salmonella-infected hens. Salmonella infection did not influence (P = 0.31) liver Fe centration in control hens, but increased (P = 0.04) it in high-Fe-treated hens. High dietary Fe decreased (P < 0.01) the mRNA abundance of divalent metal transporter 1 and transferrin receptor, but increased (P < 0.02) ferroportin-1 (FPN1) mRNA and protein in the spleens and the livers regardless of Salmonella-infected or vehicle hens. Salmonella infection increased (P < 0.02) FPN1 mRNA and protein expression in the spleens, but did not influence its expression in the livers. These results suggested Salmonella infection and high dietary Fe differently influence the Fe distribution in the spleen and the liver of Salmonella-infected hens. PMID- 29478229 TI - Pregnancy Alters Renal and Blood Burden of Mercury in Females. AB - Methylmercury (CH3Hg+), a common environmental toxicant, has serious detrimental effects in numerous organ systems. We hypothesize that a significant physiological change, like pregnancy, can alter the disposition and accumulation of mercury. To test this hypothesis, pregnant and non-pregnant female Wistar rats were exposed orally to CH3Hg+. The amount of mercury in blood and total renal mass was significantly lower in pregnant rats than in non-pregnant rats. This finding may be due to expansion of plasma volume in pregnant rats and dilution of mercury, leading to lower levels of mercury in maternal blood and kidneys. PMID- 29478230 TI - Trace Element Concentrations in Beef Cattle Related to the Breed Aptitude. AB - Animal feed has traditionally been supplemented with trace elements at dietary concentrations well above physiological needs. However, environmental concerns have led to calls for better adjustment of mineral supplementation to actual physiological needs and, in this context, consideration of breed-related differences in trace element requirements. The aim of this study was to analyze trace element concentrations in the main breeds used for intensive beef production in northern Spain (Holstein-Friesian [HF], Galician Blonde [GB], and GB * HF cross). Samples of blood, internal organs, and muscle were obtained at slaughter from 10 HF, GB, and GB * HF cross calves in the same feedlot. Overall, trace element concentrations in serum and internal organs were within adequate ranges and did not differ between those of breeds, suggesting that trace mineral supplementation was adequate in all groups. The only exception to this was copper, and hepatic copper concentrations were above adequate levels in all calves. This was particularly evident in the HF calves, and the maximum recommended level for human consumption was exceeded in 90% of these animals. Copper, iron, manganese, selenium, and zinc concentrations in muscle were significantly higher in the HF than those in the GB calves, with intermediate values for the crosses. These breed-related differences in trace element concentrations in the muscle may be related to lower muscle mass and/or higher hepatic activity in the HF (dairy) calves than in GB (beef) calves. As meat is an essential source of highly available trace elements in human diets, breed-related differences in trace element concentrations in meat deserve further investigation. PMID- 29478231 TI - Correction to: Release of an enantioselective nitrilase from Alcaligenes faecalis MTCC 126: a comparative study. AB - In the original version of our paper entitled "Release of an enantioselective nitrilase from Alcaligenes faecalis MTCC 126: a comparative study" (2005) 27:415 424, some references to already published articles were inadvertently left out. PMID- 29478232 TI - Biodegradation of decabromodiphenyl ether (BDE 209) by a newly isolated bacterium from an e-waste recycling area. AB - Polybrominated diphenyl ethers (PBDEs) have become widespread environmental pollutants all over the world. A newly isolated bacterium from an e-waste recycling area, Stenotrophomonas sp. strain WZN-1, can degrade decabromodiphenyl ether (BDE 209) effectively under aerobic conditions. Orthogonal test results showed that the optimum conditions for BDE 209 biodegradation were pH 5, 25 degrees C, 0.5% salinity, 150 mL minimal salt medium volume. Under the optimized condition, strain WZN-1 could degrade 55.15% of 65 MUg/L BDE 209 under aerobic condition within 30 day incubation. Moreover, BDE 209 degradation kinetics was fitted to a first-order kinetics model. The biodegradation mechanism of BDE 209 by strain WZN-1 were supposed to be three possible metabolic pathways: debromination, hydroxylation, and ring opening processes. Four BDE 209 degradation genes, including one hydrolase, one dioxygenase and two dehalogenases, were identified based on the complete genome sequencing of strain WZN-1. The real-time qPCR demonstrated that the expression level of four identified genes were significantly induced by BDE 209, and they played an important role in the degradation process. This study is the first to demonstrate that the newly isolated Stenotrophomonas strain has an efficient BDE 209 degradation ability and would provide new insights for the microbial degradation of PBDEs. PMID- 29478233 TI - Improvement of L-ornithine production by attenuation of argF in engineered Corynebacterium glutamicum S9114. AB - L-Ornithine, a non-essential amino acid, has enormous industrial applications in food, pharmaceutical, and chemical industries. Currently, L-ornithine production is focused on microorganism fermentation using Escherichia coli or Corynebacterium glutamicum. In C. glutamicum, development of high L-ornithine producing C. glutamicum was achieved by deletion of argF, but was accompanied by growth deficiency and arginine auxotrophy. L-Arginine has been routinely added to solve this problem; however, this increases production cost and causes feedback inhibition of N-acetyl-L-glutamate kinase activity. To avoid the drawbacks of growth disturbance due to disruption of ArgF, strategies were adopted to attenuate its expression. Firstly, ribosome binding site substitution and start codon replacement were introduced to construct recombinant C. glutamiucm strains, which resulted in an undesirable L-ornithine production titer. Then, we inserted a terminator (rrnB) between argD and argF, which significantly improved L ornithine production and relieved growth disturbance. Transcription analysis confirmed that a terminator can be used to downregulate expression of argF and simultaneously improve the transcriptional level of genes in front of argF. Using disparate terminators to attenuate expression of argF, an optimal strain (CO-9) with a T4 terminator produced 6.1 g/L of L-ornithine, which is 42.8% higher than that produced by strain CO-1, and is 11.2-fold higher than that of the parent CO strain. Insertion of terminators with gradient termination intensity can be a stable and powerful method to exert precise control of the expression level of argF in the development of L-ornithine producing strains, with potential applications in metabolic engineering and synthetic biology. PMID- 29478234 TI - CMP Honors Byron J. Good in 2018. PMID- 29478235 TI - New Feature for CMP: Noted Author's Question Period. PMID- 29478236 TI - Les Bons Mots: Wisdom in Words for CMP and Millennial Medical Anthropology. PMID- 29478237 TI - Risky Driving Behaviors for Older Adults: Differences by Veteran's Status. AB - Veterans are at an increased risk of being injured or killed in motor vehicle crashes, potentially due to their proclivity to engage in risky driving behaviors. However, most research in this area has focused on driving behaviors of veterans who have recently returned home after deployment. No research has focused on risky driving behaviors of older veterans (aged 65 or older) and if risky driving behaviors extend beyond the time period immediately following return from deployment. The purpose of this research is to determine if differences exist in risky driving behaviors of veterans and non-veterans aged 65 or older. This study used data from the 2011 National Health and Aging Trend Study (NHATS), a nationally representative, longitudinal survey of community dwelling, Medicare beneficiaries aged 65 or older. Binary logistic regression analyses were conducted in 2017 to determine if veteran's status was predictive of specific risky driving behaviors. Veteran's status was found to be predictive of specific driving behaviors for adults aged 65 and older, with non-veterans significantly more likely than veterans to: not currently drive; avoid driving at night; avoid driving alone; avoid driving on busy roads or highways; and avoid driving in bad weather. The results of this study highlight the need to further understand the effects of veteran's status on risky driving behaviors among older adults, specifically, whether veteran's status compounds driving-related risks associated with aging-related physical and mental changes. PMID- 29478238 TI - Safety of Intravenous Diltiazem in Reduced Ejection Fraction Heart Failure with Rapid Atrial Fibrillation. AB - BACKGROUND AND OBJECTIVE: Diltiazem is a nondihydropyridine calcium channel blocker that is used to control rapid ventricular response in patients who have atrial fibrillation or flutter. Diltiazem has a negative inotropic effect and may cause hemodynamic decompensation in patients with reduced ejection fraction. This study evaluated outcomes in patients who had low ejection fraction and were treated with diltiazem. METHODS: This was a retrospective chart review in 635 patients who were hospitalized because of rapid atrial fibrillation and who were treated with intravenous diltiazem. Outcomes were evaluated for patients in two groups based on ejection fraction (EF): normal (EF >= 50%) and low EF (EF < 50%). RESULTS: There were no differences in frequency of hypotension, intensive care unit transfer, or in-hospital mortality between the two groups. There was a significantly higher frequency of acute kidney injury within 48 h after starting diltiazem in patients who had low (16 patients [10%]) compared with normal EF (17 patients [3.6%] P = 0.002). CONCLUSIONS: Intravenous diltiazem in patients who have decreased EF may be associated with increased risk of acute kidney injury, but not increased risk of hypotension, intensive care unit transfer, or in hospital mortality. PMID- 29478239 TI - A Phase I Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel Dopamine D1 Receptor Partial Agonist, PF-06669571, in Subjects with Idiopathic Parkinson's Disease. AB - BACKGROUND AND OBJECTIVES: There is an unmet medical need for additional treatment options for Parkinson's disease. This was a Phase I, double-blind clinical trial assessing safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of the novel dopamine D1 receptor partial agonist, PF-06669571, in subjects with idiopathic Parkinson's disease on a stable dose of L-DOPA. METHODS: Subjects received PF-06669571 (or matching placebo) titrated from 1 mg to 3 mg over 7 days. The primary pharmacodynamic endpoint was the change from baseline in Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III total motor score at the pharmacodynamic time of maximum change from baseline on day 7. RESULTS: Twenty subjects were randomized and 19 completed the study. Maximum plasma concentrations (Cmax) of PF-06669571 were reached 3.35 and 3.19 h post-dose on day 1 and day 7. Geometric mean Cmax and area under the plasma concentration-time profile from time 0 to 24 h post-dose on day 7 were 92.51 ng/mL and 1626 ng.h/mL, respectively. The primary pharmacodynamic endpoint did not meet the pre-specified criteria for significant improvement; however, the criteria were met in a sensitivity analysis excluding data from a L-DOPA outlier (L-DOPA dose of 2550 mg/d). The most common adverse events (AEs) were nausea (experienced by 2 subjects each in the PF-06669571 and placebo groups). There were no permanent discontinuations or dose reductions due to AEs. DISCUSSION: Multiple daily doses of PF-06669571 were safe and well tolerated with no notable safety concerns. The pharmacodynamic endpoint did not meet the pre-specified criteria for significant improvement. CLINICALTRIALS. GOV IDENTIFIER: NCT02565628. PMID- 29478240 TI - Cardioprotection by Metformin: Beneficial Effects Beyond Glucose Reduction. AB - Metformin is a biguanide that is widely used as an insulin-sparing agent to treat diabetes. When compared with the general population, diabetics are twice as likely to die from fatal myocardial infarction and congestive heart failure (CHF). There has been a significant concern regarding the use of metformin in patients with CHF because of their higher tendency to develop lactic acidosis. However, large epidemiological trials have reported better cardiovascular prognosis with metformin compared to other glucose-lowering agents among diabetics. Additionally, metformin has reduced the risk of reinfarction and all cause mortality in patients with coronary artery disease and CHF, respectively. The protection against cardiovascular diseases appears to be independent of the anti-hyperglycemic effects of metformin. These effects are mediated through an increase in 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and by increased phosphorylation of endothelial nitric oxide synthase (eNOS) in cardiomyocytes with an increased production of nitric oxide (NO). Metformin preconditions the heart against ischemia-reperfusion injury and may improve myocardial remodeling after an ischemic insult. The preponderance of evidence currently suggests that metformin is safe in patients with CHF, prompting the Food and Drug Administration to remove CHF as a contraindication from the package insert of all generic metformin preparations. In this narrative, along with a limited meta-analysis of available studies, we have reviewed the pleiotropic (non-glucose-lowering) effects of metformin that potentially contribute to its cardioprotective properties. Additionally, we have reviewed issues surrounding the safety of metformin in patients with cardiac diseases. PMID- 29478241 TI - Acinetobacter soli SP2 Capable of High-Efficiency Degradation of Food Emulsifier Polysorbate 80. AB - Emulsifiers like polysorbate family, carboxymethyl cellulose are widely used in the preparation of drugs, vaccines, food, cosmetics, and skin care products. In this study, strain SP2 is isolated for the high-efficiency utilization of emulsifier as its sole carbon and energy source. Strain grows on the polysorbate family with generation time ranging from 0.8 to 2.2 h. It is sensitive to ampicillin, gentamicin, imipenem, penicillin, and vancomycin, but resistant to amikacin, cefoxitin, erythromycin, kanamycin, nalidixic acid, and tetracycline. Based on 16S rRNA gene, strain is identified as Acinetobacter soli. Compared to M. pamicella, which is capable of degrading 50% polysorbate 80 within 3 days, isolate PS2 could dispose 51.6% polysorbate 80 within only 8 h. Using cell crude extract from strain SP2, the liberation of free fatty acid in the reaction mixture containing polysorbate 80 suggests that the mechanism for polysorbate utilization belongs to the beta-oxidation. PMID- 29478242 TI - Unique clinical and serological features of bullous pemphigoid associated with dipeptidyl peptidase-4 inhibitors. PMID- 29478243 TI - Effectiveness of systemic treatments for pyoderma gangrenosum: a systematic review of observational studies and clinical trials. AB - BACKGROUND: Pyoderma gangrenosum (PG) is a neutrophilic dermatosis with substantial morbidity. There is no consensus on gold-standard treatments. OBJECTIVES: To review the effectiveness of systemic therapy for PG. METHODS: We searched six databases for 24 systemic therapies for PG. Primary outcomes were complete healing and clinical improvement; secondary outcomes were time to healing and adverse effects. RESULTS: We found 3326 citations and 375 articles underwent full-text review; 41 studies met the inclusion criteria. There were 704 participants in 26 retrospective cohort studies, three prospective cohort studies, seven case series, one case-control study, two open-label trials and two randomized controlled trials (RCTs). Systemic corticosteroids were the most studied (32 studies), followed by ciclosporin (21 studies), biologics (16 studies) and oral dapsone (11 studies). One RCT (STOP-GAP, n = 121) showed that prednisolone and ciclosporin were similar: 15-20% of patients showed complete healing at 6 weeks and 47% at 6 months. Another RCT (n = 30) found that infliximab was superior to placebo at 2 weeks (46% vs. 6% response), with a 21% complete healing rate at 6 weeks. Two uncontrolled trials showed 60% and 37% healing within 4 months for canakinumab and infliximab, respectively; other data suggest that patients with concurrent inflammatory bowel disease may benefit from biologics. The remaining studies were poor quality and had small sample sizes but supported the use of corticosteroids, ciclosporin and biologics. CONCLUSIONS: Systemic corticosteroids, ciclosporin, infliximab and canakinumab had the most evidence in treating PG. However, current literature is limited to small and lower-quality studies with substantial heterogeneity. PMID- 29478244 TI - Tanning addiction: conceptualization, assessment and correlates. AB - BACKGROUND: Research into problematic tanning (or 'tanning addiction') has markedly increased over the past few years. Although several instruments exist to measure excessive tanning, most of these are psychometrically poor, are not theoretically anchored, and have been used mainly on small samples. OBJECTIVES: To develop a new tanning addiction scale based on a specific theoretical approach utilizing core addiction criteria. METHODS: A scale comprising seven items (salience/craving, tolerance, mood modification, relapse/loss of control, withdrawal, conflict and problems) was administered online to a cross-sectional convenience sample of 23 537 adults (mean +/- SD age 35.8 +/- 13.3 years). There was also assessment of demographic factors, the five-factor model of personality, and symptoms of obsessive-compulsive disorder, anxiety and depression. RESULTS: A confirmatory factor analysis showed that a one-factor model gave an optimal fit with the data collected [root mean square error of approximation = 0.050, 90% confidence interval (CI) 0.047-0.053; comparative fit index = 0.99; Tucker-Lewis index = 0.99]. High factor loadings (0.78-0.91, all P < 0.001) and coefficient omega indicator of reliability (omega = 0.94, 95% CI 0.94-0.94) were also found using the new scale. In a multiple linear regression analysis, tanning addiction was positively associated with being female, not being in a relationship, extraversion, neuroticism, anxiety and obsessive-compulsiveness. It was also found that educational level, intellect/openness and depression were inversely associated with tanning addiction. CONCLUSIONS: The new scale, the Bergen Tanning Addiction Scale (BTAS), showed good psychometric properties, and is the first scale to conceptualize tanning addiciton fully within a contemporary addiction framework. Given this, the BTAS may potentially assist future clinical practice in providing appropriate patient care, prevention and disease management. PMID- 29478245 TI - Prevalence of vertical root fractures in teeth planned for apical surgery. A retrospective cohort study. AB - AIM: To evaluate retrospectively the prevalence of vertical root fractures (VRFs) in a cohort of patients during apical surgery and the factors possibly associated with VRF. METHODOLOGY: The sample consisted of 944 root filled teeth belonging to 768 patients (49.3% males and 50.7% females; mean age 43.5 +/- 11.2 years, range 22-68 years), consecutively referred for endodontic surgery over a six-year period. All patients underwent a clinical assessment of their signs and symptoms. Periapical radiographs of teeth that were candidates for endodontic surgery were taken. Sixty-eight teeth with VRF were identified. Vertical root fractures were identified in pre-surgical screenings in 32 cases (47.1%), and these did not undergo surgery. Another 36 cases of VRF were noted during the intervention for root-end resection. The influence of posts, post type, tooth type, periodontal probing defects, spontaneous pain, sinus tract and follow-up duration was assessed using a logistic regression analysis. RESULTS: Vertical root fractures occurred significantly more frequently (P < 0.001) when a post was present (61 VRF out of 377 teeth with post, prevalence 16.2%) than in teeth without a post (1.2%). Threaded posts and cast posts were significantly more involved in VRF than fibre, silica or carbide posts (P < 0.001). Most fractures (80.9%) occurred 1-5 years after root canal treatment. Sinus tracts, probing defects and spontaneous pain were significantly more associated with VRF cases than with nonfractured teeth. CONCLUSIONS: In the present group of teeth, the major risk for VRF was represented by posts retained by actively engaging the canal via mechanical design (thread) or by frictional fit (cast). PMID- 29478246 TI - Psychogenic pseudosyncope: Not always a diagnosis of exclusion. AB - BACKGROUND: Psychogenic pseudosyncope (PPS) frequently mimics syncope. The aim of this study was to assess the prevalence and clinical features of PPS and its relationship to vasovagal syncope (VVS). METHODS: We examined retrospectively the medical records of 1,401 consecutive patients referred to a syncope unit. We identified patients who had the final diagnosis of PPS. In these patients, we retrieved the initial diagnosis made during their first visit and the subsequent tests performed leading to the final diagnosis. RESULTS: Fourteen (1.0%) patients (mean age 35 +/- 14; 11 females) were diagnosed as having PPS: seven had a diagnosis of PPS alone and seven had both VVS and PPS. High frequency of attacks (53 +/- 35 attacks during the previous year), prolonged loss of consciousness (minutes to > 1 hour), and a history of psychiatric disorders characterized PPS patients. Tilt test reproduced a PPS attack in the presence of normal blood pressure and heart rate in seven patients (50%), and induced VVS in another three patients who had the final diagnosis of both PPS and VVS. In two patients, one or more events occurred during the clinic visits and were directly witnessed by the clinic personnel. CONCLUSIONS: We have shown that 1% of referrals to a syncope unit have the final diagnosis of PPS and that up to 50% of cases presented with a different initial diagnosis, namely VVS. Our findings suggest that causality between syncope and psychiatric disorders is likely bidirectional. The presence of a multidisciplinary team is important to address this often unrecognized relationship. PMID- 29478247 TI - Comparison of cyclic fatigue resistance and bending properties of two reciprocating nickel-titanium glide path files. AB - AIM: To compare the cyclic fatigue resistance and bending properties of R-Pilot and WaveOne Gold (WOG) Glider files, at intracanal temperature (35 degrees C). METHODOLOGY: Forty R-Pilot and 40 WOG Glider files were subjected to a cyclic fatigue resistance test (n = 20), calculating the time to fracture (TTF) in an artificial stainless steel canal. The length of the fractured file tips (FL) was also measured. The fracture surface of fragments was examined with a scanning electron microscope, and the cross-sectional area of the fractured surfaces was measured. Flexibility of the tested files (n = 20) was determined using 45 degrees bending test. Data were analysed statistically using the Mann-Whitney U test at 5% significance level. RESULTS: Time to fracture was significantly higher in the R-Pilot group compared to the WOG Glider (P < 0.05). There was no significant difference between groups for fracture length. The bending resistance of R-Pilot files was significantly greater than WOG Glider files (P < 0.05). CONCLUSIONS: A significant greater cyclic fatigue resistance was observed for R Pilot files compared to WOG Glider instruments, although the bending resistance of WOG Glider files was lower. PMID- 29478248 TI - Histopathology of 460 liver allografts removed at retransplantation: A shift in disease patterns over 27 years. AB - BACKGROUND AND AIM: Approximately 10%-19% of liver transplant recipients develop irreversible graft failure requiring retransplantation. We reviewed the histology of failed grafts removed at retransplantation in our center over 27 years. METHODS: Two hundred and seventy-six adults and 118 children underwent retransplantation from 1987 to 2014, receiving 321 and 139 liver grafts, respectively. We analyzed graft histology, recipient demographics, indications and time interval to retransplantation. We divided retransplantation in 3 eras: A (1987-1994), B (1995-2001), and C (2002-2014). RESULTS: A total of 3298 adult and 938 pediatric primary liver transplants were conducted in our center, and 8.4% of adults and 12.6% of children experienced retransplantation. Considering the changes throughout the eras, the proportion of chronic rejection declined, while that of unexplained chronic fibrosing hepatitis increased steadily, representing the main reason for retransplantation conducted >10 years after primary transplant in children, and second in adults in the most recent era. This chronic hepatitis of the graft might correspond to a slowly evolving form of rejection, possibly with a humoral component, associated with progressive graft fibrosis and eventually failure. CONCLUSIONS: We observed a shift in histopathology of failed liver grafts, with increasing relevance of chronic idiopathic hepatitis associated with progressive fibrosis and graft failure. PMID- 29478249 TI - CYLD mutations differentially affect splicing and mRNA decay in Brooke-Spiegler syndrome. PMID- 29478250 TI - High prevalence of hypogonadism determined by serum free testosterone level in Japanese testicular cancer survivors. AB - OBJECTIVE: Hypogonadism is a major complication in testicular cancer survivors, but its prevalence varies among studies. In Japan, free testosterone has been used for diagnosis of late-onset hypogonadism syndrome. In the present study, we evaluated the hormone level of testicular cancer survivors and its impact on their quality of life. METHODS: Overall, 50 testicular cancer survivors treated from 1990 to 2013 were enrolled. The median age was 44 years. The serum levels of free testosterone, total testosterone and luteinizing hormone were measured. All patients completed the Aging Males' Symptom scale and International Index of Erectile Function-15. The hormone levels of 337 healthy volunteers were used as the control. RESULTS: A total of 32 (64%) patients showed free testosterone levels <8.5 pg/mL. In contrast, just 26% of 50 patients showed total testosterone levels <3.5 ng/mL. Testicular cancer survivors had significantly lower free testosterone and higher luteinizing hormone compared with healthy controls. In contrast, there was no difference in total testosterone between patients and controls. The prevalence of late-onset hypogonadism symptoms of any grade (Aging Males' Symptom total score >=27) was 60%. Overall, 64% were defined as having moderate erectile dysfunction (International Index of Erectile Function-Erectile Function domain score <17). However, Aging Males' Symptom, International Index of Erectile Function-15 and Erectile Function domain scores did not differ by free testosterone or total testosterone level. CONCLUSIONS: This is the first report on the prevalence of hypogonadism determined by free testosterone level in Japanese testicular cancer survivors. Because Aging Males' Symptom and International Index of Erectile Function-15 scores do not necessarily reflect the hormone level, measuring free testosterone is also important in the follow up of these patients. PMID- 29478251 TI - Horizontal bone-augmentation procedures in implant dentistry: prosthetically guided regeneration. AB - The rehabilitation of partially or totally edentulous patients with implant supported prostheses has become routine, with excellent long-term outcome. A proper implant position is mandatory to achieve good functional and esthetic outcome and may require an adequate amount of alveolar bone and surrounding soft tissue. When this is lacking because of atrophy, sequelae of periodontal disease, traumas or congenital malformations, increased bone volume and/or keratinized mucosa can be obtained by guided bone regeneration, bone-grafting techniques and alveolar bone expansion. This article presents an evidence-based, prosthetically driven approach for the treatment of edentulous ridges with horizontal defects. The classification of bony defects, the main augmentation techniques, the selection criteria among different surgical procedures for different types of bony defects, and the advantages, disadvantages and limitations of each technique, are described in detail. PMID- 29478252 TI - Vertical ridge augmentation in the esthetic zone. AB - The reconstruction of deficient alveolar ridges using vertical and/or horizontal guided bone regeneration techniques allows for ideal implant placement, which is crucial for function and also for esthetically successful outcomes. Unlike in the past, when meeting a patient's functional demands was sufficient, many patients now have greater expectations from their implant restoration. Hence, it is no longer enough simply to restore the edentulous space with a functioning tooth or teeth. It has been suggested that patients now measure their final restoration using the contralateral natural tooth as the gold standard. Both subjective and objective levels of patient information on dental implants have increased significantly in the last decade. As a result of this demand, implant literature has inherited and developed specific esthetic parameters and patient-centered outcomes from studies in the restorative field. Unfortunately, studies reporting on guided bone regeneration in the esthetic zone entirely lack such parameters and outcomes. Currently, there is a strong need for a consensus on objective and well-defined parameters to assess the esthetics in bone regeneration and subsequently on implant dentistry. PMID- 29478253 TI - Blood vessel occlusion with erythrocyte aggregates causes burn injury progression microvasculature dilation as a possible therapy. AB - Burns are dynamic injuries characterized by progressive tissue death and continuous severe pain over the course of several days. The extent of burn injury progression determines the ultimate patient outcome. Initial burns result in a central zone of necrosis surrounded by a potentially viable zone of ischemia. Several mechanisms have been proposed to explain injury progression, including oxidant and cytokine stress resulting from either ischemia/reperfusion and/or inflammation, but no proven therapy has emerged. To address the unmet need to limit burn injury progression, the root cause of this process must be delineated. For this reason, we have recently focused on post-burn blood vessel occlusion, currently ascribed to microthrombi. We have found that blood vessel occlusion is initially, mainly and persistently caused by erythrocyte aggregation. Although thermal-induced cell necrosis is the immediate cause of cell death, apoptotic cells from persistent ischemia/anoxia, admixed with inflammatory cells, form a band between viable and nonviable tissue 24 hours later. The delayed cell death by apoptosis appears to be the main attractant for inflammatory cells. Finally, we posit that fibrinogen elevation arising from inflammation provides stimulus for additional erythrocyte aggregation, further extending blood vessel occlusion. In our view this persistent occlusion with resultant prolonged tissue ischemia/anoxia, not ischemia/reperfusion, is the root cause of burn injury progression concomitant with associated severe and persistent pain. Epiviosamines, a new class of peptides, appear to selectively dilate microvasculature, and may provide therapy for burn injury progression. PMID- 29478254 TI - Editorial Comment to Urological laparoendoscopic single-site and reduced port surgery: A nationwide survey in Japan. PMID- 29478255 TI - Use of glucagon-like peptide-1 receptor agonists among individuals on basal insulin requiring treatment intensification. AB - As Type 2 diabetes progresses, treatment is intensified with additional therapies in an effort to manage hyperglycaemia effectively and therefore avoid complications. When greater efficacy is required, options for injectable treatments include glucagon-like peptide-1 receptor agonists and insulin, which may be added on to oral glucose-lowering treatments. Among individuals receiving long-acting basal insulin as their first injectable treatment, ~40-60% are unable to achieve or maintain their target HbA1c goals. For these people, treatment intensification options are relatively limited and include the addition of short acting prandial insulin or a glucagon-like peptide-1 receptor agonist. Glucagon like peptide-1 receptor agonists vary in their effects, with short- and long acting agents having a greater impact on postprandial and fasting hyperglycaemia, respectively. Studies comparing treatment intensification options have found both glucagon-like peptide-1 receptor agonists and prandial insulin to be effective in reducing HbA1c concentrations; however, recipients of glucagon-like peptide-1 receptor agonists lost weight and had a greater frequency of gastrointestinal adverse events, whereas those receiving prandial insulin gained weight and had a greater incidence of hypoglycaemia. In addition to the separate administration of a glucagon-like peptide-1 receptor agonist and basal insulin, fixed-ratio combinations of a glucagon-like peptide-1 receptor agonist and basal insulin offer a single administration for both treatments but have less flexibility in dose titration than treatment with their individual components. For individuals who require treatment intensification beyond basal insulin, use of these various options allows physicians to target the individual needs of their patients for the achievement of optimal long-term glycaemic control. PMID- 29478256 TI - Impact of early reoperation on graft survival after liver transplantation: Univariate and multivariate analysis. AB - BACKGROUND: Data on rate, risk factors, and consequences of early reoperation after liver transplantation are still limited. STUDY DESIGN: Single-center retrospective analysis of data of 428 patients, who underwent liver transplantation in period between January 2009 and December 2014. Univariate and multivariate analysis were used to study the risk factors of early reoperation and its impact on graft survival. RESULTS: Of 428 patients, 74 (17.3%) underwent early reoperation. Of them, 46 (62.2%) underwent reoperation within the first week and 28 (37.8%) underwent reoperation later than 1 week after transplantation. With multivariate analysis, significant risk factors of early reoperation included pretransplant ICU admission, previous abdominal surgery and diabetes. Early reoperation itself was not found to be an independent predictor of graft loss. However, early reoperation later than 7 days from transplant was found to be independent predictor of graft loss (odds ratio [OR] = 5.125; 95% CI, 1.358-19.552; P = .016). In our series, other independent predictors of graft loss were MELD score (P = .010) and operative time (P = .048). CONCLUSIONS: This analysis demonstrates that early reoperations later than a week appear to negatively impact the graft survival. The timing of early reoperation should be a focus of additional studies. PMID- 29478258 TI - Treatment of hepatitis C virus leads to economic gains related to reduction in cases of hepatocellular carcinoma and decompensated cirrhosis in Japan. AB - Hepatocellular carcinoma (HCC) is a serious complication of hepatitis C virus (HCV) infection. Sustained virologic response (SVR) for HCV is associated with a reduction in cirrhosis, HCC and mortality and their associated costs. Japanese HCV patients are older with higher prevalence of HCC. Here we used a decision analytic Markov model to estimate the economic benefit of HCV cure by reducing HCC and DCC burden in Japan. A cohort of 10 000 HCV genotype 1b (GT1b) Japanese patients was modelled with a hybrid decision tree and Markov state-transition model capturing natural history of HCV over a lifetime horizon. Treatment options were approved all-oral direct-acting anti-virals (DAAs) vs no treatment. Treatment efficacy was based on clinical trials and transition rates and costs obtained from Japan-specific data. Cases of HCC, decompensated cirrhosis (DCC) and quality-adjusted life years (QALYs) were projected for patients treated with DAAs vs NT. QALYs were monetized using a willingness-to-pay threshold of Y4-to-Y6 million. Incremental savings with treatment were calculated by adding the projected cost of complications avoided to the monetized gains in QALYs. The model showed that DAA treatment vs no treatment, reduces 2057 cases of HCC and 1478 cases of decompensated cirrhosis and saves Y850 446.73 and Y338 229.90 per patient (ppt). Additionally, treatment can lead to additional 2.64 QALYs gained per patient. The indirect economic gains associated with treatment-related QALY improvements were Y10 576 000, Y13 220 000 and Y15 864 000 ppt (willingness-to pay thresholds of Y4 million, Y5 million and Y6 million). Total economic savings of treatment with DAAs (vs no treatment) was Y7 526 372.63, Y10 170 372.63 and Y12 814 372.63, at these different willingness-to-pay thresholds. In conclusion treatment of HCV GT1b with all-oral DAAs in Japan can lead to significant direct and indirect savings related to avoidance of HCC and DCC. PMID- 29478259 TI - Maybe ECD kidneys aren't as bad as I thought? PMID- 29478260 TI - Personal strengths reported by people with chronic illness: A qualitative study. AB - BACKGROUND: Self-management of chronic illness can be highly demanding and people need to mobilize their personal strengths to live well with their condition. More knowledge is needed about how people with chronic illness perceive and use their personal strengths as a basis for better integrating empowering person-centred approaches into health care. OBJECTIVE: To explore what people with chronic illness describe as their strengths relevant to their health and well-being. SETTING AND PARTICIPANTS: Thirty-nine participants (11 men) from 4 outpatient self-management programmes were recruited to individual or group interviews. Participants included patients with chronic respiratory disease (n = 7), chronic pain (n = 18) and morbid obesity (n = 14). Interviews were analysed using content analysis. RESULTS: A number of personal strengths were reported and categorized into 3 domains: (i) Internal strengths, (ii) External strengths and (iii) Self management strategies. Internal strengths included being persistent, having a positive outlook, being kind and caring, experiencing positive emotions, being kind towards oneself, reconciling oneself with the situation, having courage and having knowledge and insight. External strengths included support from family, friends, peers and health-care providers. Self-management strategies included being active, planning and prioritizing, reducing stress, goal setting and seeking knowledge and help. DISCUSSION AND CONCLUSION: The study provides insights into personal strengths as reported by people with chronic illness. The results complement prior findings on strengths in people with health challenges and can aid in incorporating person-centred approaches into health care. PMID- 29478257 TI - Bortezomib plus dexamethasone vs thalidomide plus dexamethasone for relapsed or refractory multiple myeloma. AB - A randomized phase II selection design study (JCOG0904) was carried out to evaluate the more promising regimen between bortezomib (Bor) plus dexamethasone (Dex; BD) and thalidomide (Thal) plus Dex (TD) in Bor and Thal-naive patients with relapsed or refractory multiple myeloma (RRMM). Patients >=20 and <80 years old with a documented diagnosis of symptomatic multiple myeloma (MM) who received one or more prior therapies were randomized to receive BD (Bor 1.3 mg/m2 ) or TD (Thal 200 mg/d). In both arms, 8 cycles of induction (3-week cycle) were followed by maintenance phase (5-week cycle) until disease progression, unacceptable toxicity, or patient refusal. The primary end-point was 1-year progression-free survival (PFS). Forty-four patients were randomized and assigned to receive BD and TD (n = 22, each group). At a median follow-up of 34.3 months, the 1-year PFS in the BD and TD arms were 45.5% (95% confidence interval (CI), 24.4%-64.3%) and 31.8% (95% CI, 14.2%-51.1%), respectively, and the overall response rates were 77.3% and 40.9%, respectively. The 3-year overall survival (OS) was 70.0% (95% CI, 44.9%-85.4%) in the BD, and 48.8% (95% CI, 25.1%-69.0%) in the TD arm. Among grade 3/4 adverse events, thrombocytopenia (54.5% vs 0.0%) and sensory peripheral neuropathy (22.7% vs 9.1%) were more frequent in BD when compared with the TD arm. Patients treated with BD had better outcomes than those treated with TD with regard to 1-year PFS and 3-year OS. Thus, BD was prioritized over TD for further investigations in Bor and Thal-naive RRMM patients. (Clinical trial registration no. UMIN000003135.). PMID- 29478261 TI - Myocardial infarction stabilization by cell-based expression of controlled Vascular Endothelial Growth Factor levels. AB - Vascular Endothelial Growth Factor (VEGF) can induce normal or aberrant angiogenesis depending on the amount secreted in the microenvironment around each cell. Towards a possible clinical translation, we developed a Fluorescence Activated Cell Sorting (FACS)-based technique to rapidly purify transduced progenitors that homogeneously express a desired specific VEGF level from heterogeneous primary populations. Here, we sought to induce safe and functional angiogenesis in ischaemic myocardium by cell-based expression of controlled VEGF levels. Human adipose stromal cells (ASC) were transduced with retroviral vectors and FACS purified to generate two populations producing similar total VEGF doses, but with different distributions: one with cells homogeneously producing a specific VEGF level (SPEC), and one with cells heterogeneously producing widespread VEGF levels (ALL), but with an average similar to that of the SPEC population. A total of 70 nude rats underwent myocardial infarction by coronary artery ligation and 2 weeks later VEGF-expressing or control cells, or saline were injected at the infarction border. Four weeks later, ventricular ejection fraction was significantly worsened with all treatments except for SPEC cells. Further, only SPEC cells significantly increased the density of homogeneously normal and mature microvascular networks. This was accompanied by a positive remodelling effect, with significantly reduced fibrosis in the infarcted area. We conclude that controlled homogeneous VEGF delivery by FACS-purified transduced ASC is a promising strategy to achieve safe and functional angiogenesis in myocardial ischaemia. PMID- 29478262 TI - Roles of protein kinase R in cancer: Potential as a therapeutic target. AB - Double-stranded (ds) RNA-dependent protein kinase (PKR) is a ubiquitously expressed serine/threonine protein kinase. It was initially identified as an innate immune antiviral protein induced by interferon (IFN) and activated by dsRNA. PKR is recognized as a key executor of antiviral host defense. Moreover, it contributes to inflammation and immune regulation through several signaling pathways. In addition to IFN and dsRNA, PKR is activated by multiple stimuli and regulates various signaling pathways including the mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells pathways. PKR was initially thought to be a tumor suppressor as a result of its ability to suppress cell growth and interact with major tumor suppressor genes. However, in several types of malignant disease, such as colon and breast cancers, its role remains controversial. In hepatocellular carcinoma, hepatitis C virus (HCV) is the main cause of liver cancer, and PKR inhibits HCV replication, indicating its role as a tumor suppressor. However, PKR is overexpressed in cirrhotic patients, and acts as a tumor promoter through enhancement of cancer cell growth by mediating MAPK or signal transducer and activator of transcription pathways. Moreover, PKR is reportedly required for the activation of inflammasomes and influences metabolic disorders. In the present review, we introduce the multifaceted roles of PKR such as antiviral function, tumor cell growth, regulation of inflammatory immune responses, and maintaining metabolic homeostasis; and discuss future perspectives on PKR biology including its potential as a therapeutic target for liver cancer. PMID- 29478264 TI - Incidence and prevalence of rosacea: a systematic review and meta-analysis. AB - BACKGROUND: The exact prevalence and incidence of rosacea remain unknown, although it is a common condition associated with severe noncutaneous diseases. OBJECTIVES: To perform a systematic review of the published literature to examine the global incidence and prevalence of rosacea. METHODS: A systematic review of population-based and dermatological outpatient studies reporting the incidence and/or prevalence of rosacea was performed using three electronic medical databases: PubMed, Embase and Web of Science. Data were extracted and a proportion meta-analysis was performed to obtain pooled proportions. RESULTS: In total 32 studies were included examining a total of 41 populations with 26 519 836 individuals. Twenty-two populations were from Europe, three from Africa, four from Asia, nine from North America and three from South America. The pooled proportion of individuals with rosacea was 5.46% [95% confidence interval (CI) 4.91-6.04] in the general population and 2.39% (95% CI 1.56-3.39) among dermatological outpatients. Self-reported rosacea gave higher prevalence estimates than rosacea diagnosed by clinical examination, suggesting a low specificity of questionnaires based on symptoms. Rosacea affected both women (5.41%, 95% CI 3.85-7.23) and men (3.90%, 95% CI 3.04-4.87), and mostly those aged 45-60 years. CONCLUSIONS: We estimated the global prevalence of rosacea based on published data and found that 5.46% of the adult population is affected. However, the prevalence of rosacea depended on the diagnostic method, with higher estimates in questionnaire studies of rosacea symptoms and lower estimates in health registries with International Classification of Diseases codes. PMID- 29478263 TI - Impact of sustained virologic response on risk of type 2 diabetes among hepatitis C patients in the United States. AB - Data regarding the impact of hepatitis C (HCV) therapy on incidence of type 2 diabetes mellitus are limited. We used the data from the longitudinal Chronic Hepatitis Cohort Study-drawn from four large US health systems-to investigate how response to HCV treatment impacts the risk of subsequent diabetes. Among HCV patients without a history of type 2 diabetes mellitus or hepatitis B, we investigated the incidence of type 2 diabetes from 12 weeks post-HCV treatment through December 2015. Cox proportional hazards models were used to test the effect of treatment status (sustained virologic response [SVR] or treatment failure) and baseline risk factors on the development of diabetes, considering any possible risk factor-by-SVR interactions, and death as a competing risk. Among 5127 patients with an average follow-up of 3.7 years, diabetes incidence was significantly lower among patients who achieved SVR (231/3748; 6.2%) than among patients with treatment failure (299/1379; 21.7%; adjusted hazard ratio [aHR] = 0.79; 95% CI: 0.65-0.96). Risk of diabetes was higher among African American and Asian American patients than White patients (aHR = 1.82 and 1.75, respectively; P < .05), and among Hispanic patients than non-Hispanics (aHR = 1.86). Patients with BMI >= 30 and 25-30 (demonstrated higher risk of diabetes aHR = 3.62 and 1.72, respectively; P < .05) than those with BMI < 25; patients with cirrhosis at baseline had higher risk than those without cirrhosis (aHR = 1.47). Among a large US cohort of patients treated for HCV, patients who achieved SVR demonstrated a substantially lower risk for the development of type 2 diabetes mellitus than patients with treatment failure. PMID- 29478266 TI - Treatment for superficial thrombophlebitis of the leg. AB - BACKGROUND: The optimal treatment of superficial thrombophlebitis (ST) of the legs remains poorly defined. While improving or relieving the local painful symptoms, treatment should aim at preventing venous thromboembolism (VTE), which might complicate the natural history of ST. This is the third update of a review first published in 2007. OBJECTIVES: To assess the efficacy and safety of topical, medical, and surgical treatments for ST of the leg in improving local symptoms and decreasing thromboembolic complications. SEARCH METHODS: For this update, the Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register (March 2017), CENTRAL (2017, Issue 2), and trials registries (March 2017). We handsearched the reference lists of relevant papers and conference proceedings. SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating topical, medical, and surgical treatments for ST of the legs that included people with a clinical diagnosis of ST of the legs or objective diagnosis of a thrombus in a superficial vein. DATA COLLECTION AND ANALYSIS: Two authors assessed the trials for inclusion in the review, extracted the data, and assessed the quality of the studies. Data were independently extracted from the included studies and any disagreements resolved by consensus. We assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: We identified three additional trials (613 participants), therefore this update considered 33 studies involving 7296 people with ST of the legs. Treatment included fondaparinux; rivaroxaban; low molecular weight heparin (LMWH); unfractionated heparin (UFH); non-steroidal anti-inflammatory drugs (NSAIDs); compression stockings; and topical, intramuscular, or intravenous treatment to surgical interventions such as thrombectomy or ligation. Only a minority of trials compared treatment with placebo rather than an alternative treatment and many studies were small and of poor quality. Pooling of the data was possible for few outcomes, and none were part of a placebo-controlled trial. In one large, placebo controlled RCT of 3002 participants, subcutaneous fondaparinux was associated with a significant reduction in symptomatic VTE (risk ratio (RR) 0.15, 95% confidence interval (CI) 0.04 to 0.50; moderate-quality evidence), ST extension (RR 0.08, 95% CI 0.03 to 0.22; moderate-quality evidence), and ST recurrence (RR 0.21, 95% CI 0.08 to 0.54; moderate-quality evidence) relative to placebo. Major bleeding was infrequent in both groups with very wide CIs around risk estimate (RR 0.99, 95% CI 0.06 to 15.86; moderate-quality evidence). In one RCT on 472 high-risk participants with ST, fondaparinux was associated with a non significant reduction of symptomatic VTE compared to rivaroxaban 10 mg (RR 0.33, 95% CI 0.03 to 3.18; low-quality evidence). There were no major bleeding events in either group (low-quality evidence). In another placebo-controlled trial, both prophylactic and therapeutic doses of LMWH (prophylactic: RR 0.44, 95% CI 0.26 to 0.74; therapeutic: RR 0.46, 95% CI 0.27 to 0.77) and NSAIDs (RR 0.46, 95% CI 0.27 to 0.78) reduced the extension (low-quality evidence) and recurrence of ST (low quality evidence) in comparison to placebo, with no significant effects on symptomatic VTE (low-quality evidence) or major bleeding (low-quality evidence). Overall, topical treatments improved local symptoms compared with placebo, but no data were provided on the effects on VTE and ST extension. Surgical treatment combined with elastic stockings was associated with a lower VTE rate and ST progression compared with elastic stockings alone. However, the majority of studies that compared different oral treatments, topical treatments, or surgery did not report VTE, ST progression, adverse events, or treatment adverse effects. AUTHORS' CONCLUSIONS: Prophylactic dose fondaparinux given for 45 days appears to be a valid therapeutic option for ST of the legs for most people. The evidence on topical treatment or surgery is too limited and does not inform clinical practice about the effects of these treatments in terms of VTE. Further research is needed to assess the role of rivaroxaban and other direct oral factor-X or thrombin inhibitors, LMWH, and NSAIDs; the optimal doses and duration of treatment in people at various risk of recurrence; and whether a combination therapy may be more effective than single treatment. Adequately designed and conducted studies are required to clarify the role of topical and surgical treatments. PMID- 29478265 TI - Prevalence and correlates of depressive disorders in people with Type 2 diabetes: results from the International Prevalence and Treatment of Diabetes and Depression (INTERPRET-DD) study, a collaborative study carried out in 14 countries. AB - AIMS: To assess the prevalence and management of depressive disorders in people with Type 2 diabetes in different countries. METHODS: People with diabetes aged 18-65 years and treated in outpatient settings were recruited in 14 countries and underwent a psychiatric interview. Participants completed the Patient Health Questionnaire and the Problem Areas in Diabetes scale. Demographic and medical record data were collected. RESULTS: A total of 2783 people with Type 2 diabetes (45.3% men, mean duration of diabetes 8.8 years) participated. Overall, 10.6% were diagnosed with current major depressive disorder and 17.0% reported moderate to severe levels of depressive symptomatology (Patient Health Questionnaire scores >9). Multivariable analyses showed that, after controlling for country, current major depressive disorder was significantly associated with gender (women) (P<0.0001), a lower level of education (P<0.05), doing less exercise (P<0.01), higher levels of diabetes distress (P<0.0001) and a previous diagnosis of major depressive disorder (P<0.0001). The proportion of those with either current major depressive disorder or moderate to severe levels of depressive symptomatology who had a diagnosis or any treatment for their depression recorded in their medical records was extremely low and non-existent in many countries (0 29.6%). CONCLUSIONS: Our international study, the largest of this type ever undertaken, shows that people with diabetes frequently have depressive disorders and also significant levels of depressive symptoms. Our findings indicate that the identification and appropriate care for psychological and psychiatric problems is not the norm and suggest a lack of the comprehensive approach to diabetes management that is needed to improve clinical outcomes. PMID- 29478267 TI - A Bayesian nonparametric approach to causal inference on quantiles. AB - We propose a Bayesian nonparametric approach (BNP) for causal inference on quantiles in the presence of many confounders. In particular, we define relevant causal quantities and specify BNP models to avoid bias from restrictive parametric assumptions. We first use Bayesian additive regression trees (BART) to model the propensity score and then construct the distribution of potential outcomes given the propensity score using a Dirichlet process mixture (DPM) of normals model. We thoroughly evaluate the operating characteristics of our approach and compare it to Bayesian and frequentist competitors. We use our approach to answer an important clinical question involving acute kidney injury using electronic health records. PMID- 29478268 TI - Long non-coding RNA RP11-552M11.4 promotes cells proliferation, migration and invasion by targeting BRCA2 in ovarian cancer. AB - The present study aimed to investigate the effect of long non-coding RNA (lncRNA) RP11-552M11.4 on cell proliferation, apoptosis, migration and invasion as well as its targeting genes in epithelial ovarian cancer (EOC) cells. LncRNA RP11 552M11.4 expression was detected in 67 tumor tissues and paired adjacent tissues obtained from EOC patients. lncRNA RP11-552M11.4 mimic/inhibitor plasmids were transferred into ovarian cancer cells (SKOV3, A-2780) and normal ovarian epithelial cells (IOSE80 cells). In addition, rescue experiment was carried out by transferring BRCA2 inhibitor&lncRNA RP11-552M11.4 inhibitor plasmids into SKOV3 and A-2780 cells. qPCR, western blot, CKK-8, Annexin V/propidium iodide (AV/PI), wound-healing and Matrigel invasion assays were carried out to detect RNA expression, protein expression, cell proliferation, apoptosis, migration, and invasion, respectively. LncRNA RP11-552M11.4 expression was elevated in tumor tissues compared with paired adjacent tissues and correlated with higher pathological grade, International Federation of Gynecology and Obstetrics stage and worse overall survival in EOC patients. LncRNA RP11-552M11.4 promoted SKOV3 cell proliferation, migration and invasion whereas it inhibited apoptosis. Rescue experiment and luciferase reporter assay showed that lncRNA RP11-552M11.4 regulated SKOV3 cells functions through binding BRCA2. Further experiments in A 2780 cells also validated that lncRNA RP11-552M11.4 induced A-2780 cell proliferation while repressing apoptosis by targeting BRCA2. In addition, upregulation of lncRNA RP11-552M11.4 increased IOSE80 cell proliferation, migration and invasion while decreasing apoptosis. In conclusion, lncRNA RP11 552M11.4 correlates with worse prognosis, and promotes cell proliferation, migration, invasion, and inhibits cell apoptosis by down-regulating BRCA2 in EOC. PMID- 29478269 TI - Tolerance of triazole-based fungicides by biocontrol agents used to control Fusarium head blight in wheat in Argentina. AB - : Fusarium head blight (FHB) caused by Fusarium graminearum species complex is a devastating disease that causes extensive yield and quality losses to wheat around the world. Fungicide application and breeding for resistance are among the most important tools to counteract FHB. Biological control is an additional tool that can be used as part of an integrated management of FHB. Bacillus velezensisRC 218, Brevibacillus sp. RC 263 and Streptomyces sp. RC 87B were selected by their potential to control FHB and deoxynivalenol production. The aim of this work was to test the tolerance of these biocontrol agents to triazole based fungicides such as prothioconazole, tebuconazole and metconazole. Bacterial growth was evaluated in Petri dishes using the spread plating technique containing the different fungicides. Bacillus velezensisRC 218 and Streptomyces sp. RC 87B showed better tolerance to fungicides than Brevibacillus sp. RC 263. Complete growth inhibition was observed at concentrations of 20 MUg ml-1 for metconazole, 40 MUg ml-1 for tebuconazole and 80 MUg ml-1 for prothioconazole. The results obtained indicate the possibility of using these biocontrol agents in combination with fungicides as part of an integrated management to control FHB of wheat. SIGNIFICANCE AND IMPACT OF THE STUDY: This study evaluates the possibility to use biocontrol agents (Bacillus velezensisRC 218, Brevibacillus sp. RC 263 and Streptomyces sp. RC 87B) in combination with triazole-based fungicides to control Fusarium head blight in wheat. The evaluation of biocontrol agents' growth under in vitro conditions was carried out in Petri dishes containing either prothioconazole, tebuconazole or metconazole. Viability studies demonstrated that B. velezensisRC 218 and Streptomyces sp. RC 87B were more tolerant to the fungicides evaluated. Results obtained reflect the possibility to use fungicides at low doses combined with biocontrol agents. PMID- 29478271 TI - Dysplastic features relevant to malignant transformation in atrophic epithelium of oral submucous fibrosis: A preliminary study. AB - BACKGROUND: The grading of oral epithelial dysplasia (OED) is not applicable to oral submucous fibrosis (OSMF) cases due to the presence of atrophic epithelium. The mucosal margins associated with resected OSCC specimens are often closely related to transformed cells. In this study, we compared the histomorphological alterations (dysplastic features) in the atrophic epithelium of OSMF patients with the mucosal margins of OSCC associated with OSMF (OSCC-OSMF). METHODS: We evaluated 17 dysplastic features in 37 patients with OSMF (biopsy site: buccal mucosa) and 37 patients with OSCC-OSMF (mucosal margins involving buccal mucosa) using histopathological staining. RESULTS: Dysplastic features, such as keratin pearls within rete ridges, nuclear pleomorphism, and atypical mitotic figures, were not observed in the epithelium of the OSMF or OSCC-OSMF groups. Basal cell hyperplasia (P = .016), abnormal superficial mitosis (P = .010), increased nuclear-cytoplasmic ratio (P = .034), and hyperchromasia (P = .031) were predominantly seen in the OSCC-OSMF group. We found no statistically significant differences in the following parameters: irregular epithelial stratification (P = 1.00), loss of basal cell polarity (P = .237), presence of drop-shaped rete ridges (P = .077), increased number of mitotic figures (P = .154), premature keratinization in single cells (P = .499), anisonucleosis (P = .289), anisocytosis (P = .079), cellular pleomorphism (P = .317), and increased number and size of nucleoli (P = .129). CONCLUSION: Increased basal cell layer hyperplasia, abnormal superficial mitosis, increased nuclear-cytoplasmic ratio, and hyperchromasia are high-risk features for OSMF, and affected patients should be followed on a priority basis for the early detection of OSCC. PMID- 29478270 TI - Enhanced heat stable antifungal factor production by Lysobacter enzymogenes OH11 with cheap feedstocks: medium optimization and quantitative determination. AB - : Heat stable antifungal factor (HSAF) is considered to be a potential biological pesticide due to its broad antifungal activity and novel mode of action. However, few studies have reported on HSAF production during fermentation. Thus, this work was executed to optimize the medium composition to maximize HSAF production by Lysobacter enzymogenes OH11, with soybean flour, glucose and CaCl2 identified as suitable nutrients with concentrations of 8.00, 7.89 and 0.72 g l-1 respectively. Simultaneously, the quantitative analysis of HSAF production was established by eliminating the emulsification problem, and the highest HSAF production was determined to be 356.34 +/- 13.86 mg l-1 using the optimized medium, 12-fold higher than when using the 10% TSB medium (29.34 +/- 2.57 mg l-1 ). Furthermore, the cost of this medium was assessed and nearly 31-fold lower than that of 10% TSB. This study suggests that the optimized medium is not only effective but also economical for HSAF production. SIGNIFICANCE AND IMPACT OF THE STUDY: Significance and Impact of the Study: Heat stable antifungal factor (HSAF) exhibits a potent and broad antifungal activity with a novel mode of action. Increased production and reduced cost of raw materials are particularly important for the future production of HSAF, however, no report was involved in these studies. This study aimed to improve the production of HSAF with cheap raw materials through the medium optimization, which would lay the foundation for the application of HSAF in biological control. PMID- 29478272 TI - Fates of Evolutionarily Distinct, Plastid-type Glyceraldehyde 3-phosphate Dehydrogenase Genes in Kareniacean Dinoflagellates. AB - The ancestral kareniacean dinoflagellate has undergone tertiary endosymbiosis, in which the original plastid is replaced by a haptophyte endosymbiont. During this plastid replacement, the endosymbiont genes were most likely flowed into the host dinoflagellate genome (endosymbiotic gene transfer or EGT). Such EGT may have generated the redundancy of functionally homologous genes in the host genome-one has resided in the host genome prior to the haptophyte endosymbiosis, while the other transferred from the endosymbiont genome. However, it remains to be well understood how evolutionarily distinct but functionally homologous genes were dealt in the dinoflagellate genomes bearing haptophyte-derived plastids. To model the gene evolution after EGT in plastid replacement, we here compared the characteristics of the two evolutionally distinct genes encoding plastid-type glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in Karenia brevis and K. mikimotoi bearing haptophyte-derived tertiary plastids: "gapC1h" acquired from the haptophyte endosymbiont and "gapC1p" inherited from the ancestral dinoflagellate. Our experiments consistently and clearly demonstrated that, in the two species examined, the principal plastid-type GAPDH is encoded by gapC1h rather than gapC1p. We here propose an evolutionary scheme resolving the EGT derived redundancy of genes involved in plastid function and maintenance in the nuclear genomes of dinoflagellates that have undergone plastid replacements. Although K. brevis and K. mikimotoi are closely related to each other, the statuses of the two evolutionarily distinct gapC1 genes in the two Karenia species correspond to different steps in the proposed scheme. PMID- 29478273 TI - Temporal trends of in-hospital complications associated with catheter ablation of atrial fibrillation in the United States: An update from Nationwide Inpatient Sample database (2011-2014). AB - BACKGROUND: Catheter ablation is widely accepted intervention for atrial fibrillation (AF) refractory to antiarrhythmic drugs, but limited data are available regarding contemporary trends in major complications and in-hospital mortality due to the procedure. This study was aimed at exploring the temporal trends of in-hospital mortality, major complications, and impact of hospital volume on frequency of AF ablation-related outcomes. METHODS: The Nationwide Inpatient Sample database was utilized to identify the AF patients treated with catheter ablation. In-hospital death and common complications including vascular access complications, cardiac perforation and/or tamponade, pneumothorax, stroke, and transient ischemic attack, were identified using International Classification of Disease (ICD-9-CM) codes. RESULT: In-hospital mortality rate of 0.15% and overall complication rate of 5.46% were noted among AF ablation recipients (n = 50,969). Significant increase in complications during study period (relative increase 56.37%, P-trend < 0.001) was observed. Cardiac (2.65%), vascular (1.33%), and neurological (1.05%) complications were most common. On multivariate analysis (odds ratio [OR]; 95% confidence interval [95% CI]; P value), significant predictors of complications were female sex (OR = 1.40; CI = 1.17 1.68; P value < 0.001), high burden of comorbidity as indicated by Charlson Comorbidity Index >=2 (OR = 2.84; CI = 2.29-3.52; P value < 0.001), and low hospital volume (< 50 procedures). CONCLUSION: Our study noted a decline in AF ablation-related hospitalizations and complications associated with the procedure. These findings largely reflect shifting trends of outpatient performance of the procedure and increasing safety profile due to improved institutional expertise and catheter techniques. PMID- 29478275 TI - Editorial Comment to Summary of the UAA-AAUS guidelines for urinary tract infections. PMID- 29478274 TI - Microbiological quality of spinach irrigated with reclaimed wastewater and roof harvest water. AB - AIMS: The effect of reclaimed wastewater (RCW) and roof-harvest rainwater (RHW) on the microbiological quality of irrigated spinach was investigated. METHODS AND RESULTS: Spinach grown in the controlled environment chamber was irrigated by RCW, RHW or creek water (CW; control water) for 4 weeks, and then six replicate spinach samples from each treatment were collected weekly at 0 h and 24 h postirrigation. Spinach samples were analysed for populations of faecal bacterial indicators and pathogens. Bacterial populations in alternative irrigation water samples were determined by the membrane filtration technique. The RCW samples contained the highest faecal bacterial indicator populations, followed by the CW and RHW throughout the entire study. Irrigation waters containing higher populations of total and faecal coliforms did not necessarily result in higher populations of these bacteria on the irrigated spinach. Higher numbers of E. coli positive spinach samples were reported from RCW-irrigated spinach, especially with repeated irrigation. Pathogens were not detected from any water or spinach samples. CONCLUSIONS: Spinach irrigated with RHW did not significantly affect the populations of faecal indicator bacteria when compared with CW-irrigated spinach. Repeat irrigation with RCW is not recommended due to the increased contamination of E. coli on spinach leaves. SIGNIFICANCE AND IMPACT OF THE STUDY: RHW may potentially be used as alternative irrigation water without deleteriously affecting the microbiological safety of the spinach. PMID- 29478276 TI - Response to Re: Impact of metabolic syndrome on early recovery of continence after robot-assisted radical prostatectomy. PMID- 29478278 TI - Impact of the access tunnel engineering on catalysis is strictly ligand-specific. AB - The traditional way of rationally engineering enzymes to change their biocatalytic properties utilizes the modifications of their active sites. Another emerging approach is the engineering of structural features involved in the exchange of ligands between buried active sites and the surrounding solvent. However, surprisingly little is known about the effects of mutations that alter the access tunnels on the enzymes' catalytic properties, and how these tunnels should be redesigned to allow fast passage of cognate substrates and products. Thus, we have systematically studied the effects of single-point mutations in a tunnel-lining residue of a haloalkane dehalogenase on the binding kinetics and catalytic conversion of both linear and branched haloalkanes. The hotspot residue Y176 was identified using computer simulations and randomized through saturation mutagenesis, and the resulting variants were screened for shifts in binding rates. Strikingly, opposite effects of the substituted residues on the catalytic efficiency toward linear and branched substrates were observed, which was found to be due to substrate-specific requirements in the critical steps of the respective catalytic cycles. We conclude that not only the catalytic sites, but also the access pathways must be tailored specifically for each individual ligand, which is a new paradigm in protein engineering and de novo protein design. A rational approach is proposed here to address more effectively the task of designing ligand-specific tunnels using computational tools. PMID- 29478277 TI - Higher than reported adolescent and young adult clinical trial enrollment during the "Golden Age" of melanoma clinical trials. AB - Clinical trial enrollments in adolescents and young adults (AYA) with cancer have historically been lower than those in pediatric and older adult populations. We sought to examine therapeutic trial enrollment rates at our cancer center. We performed a retrospective evaluation of AYA patients treated before and after the first checkpoint inhibitor trial opened at our cancer center in 2007. We examined gender, stage at presentation and insurance status in terms of trial enrollment. We compared the trial participation rate of AYA patients with that of older adults. In this adult facility, 12.7% (1,831) of total patients were between age 15 and 39. Overall therapeutic clinical trial rate was 17.6% which increased to 19.8% since 2007. Both nodal disease or metastatic disease at presentation was associated with increasing odds of trial enrollment (OR = 5.36 and P < 0.001 for nodal disease and OR = 7.96 and P < 0.001 for metastatic disease). There was a nonstatistically significant trend toward improved 3-year overall survival in the AYA patients with advanced presentation that enrolled on clinical trials compared with those not enrolled on trials since 2007. AYA clinical trial enrollment at a comprehensive care center melanoma program was higher than reported in the literature overall for AYA patients. This 1,831 patient cohort may provide a foundation for more detailed investigation toward quantifying the effects of clinical trial enrollment in terms of age-specific benefits and toxicities for AYA patients with malignancies that have their peak incidence in older adults. PMID- 29478279 TI - Novel in vivo observations of scrotal Nannizzia gypsea infection. PMID- 29478281 TI - Frequency of unsatisfactory cervical cytology smears in cancer screening of Japanese women: A systematic review and meta-analysis. AB - The Bethesda system (TBS) has been used for cervical cytological diagnosis in Japan since 2008. Evaluation of specimen adequacy is the most important aspect of quality assurance and for precise diagnosis in TBS. A systematic review and meta analysis were carried out to assess the unsatisfactory specimen rate in the primary cervical cancer screening setting in Japan. Ovid Medline and Ichushi-Web databases were searched from inception through to May 2017. Prospective and retrospective studies that reported the proportion of unsatisfactory specimens in healthy asymptomatic Japanese women in a cervical cancer screening program were eligible for inclusion; 17 studies were included in the meta-analysis. The random effects model meta-analysis calculated summary estimates of the unsatisfactory rate of 0.60% (95% confidence interval [CI], 0.18-1.96%; I2 = 99%) for conventional cytology and 0.04% (95% CI, 0.00-0.35%; I2 = 99%) for liquid-based cytology (LBC). However, comparative results between conventional and liquid based cytology, based on four direct and nine comparative studies, showed no significant difference (summary odds ratio = 3.5 * 10-2 favoring LBC [95% CI, 6.9 * 10-4 -1.7]; I2 = 98%). In the subgroup analyses and meta-regressions, use of non-cotton devices for conventional cytology and use of a particular platform for LBC were associated with lower unsatisfactory rates. Meta-regression also suggested chronological improvement in unsatisfactory rates for both tests. In Japanese cervical cancer screening programs, conventional cytology remains prevalent. Future research needs to focus on evaluating the impact of screening programs using LBC by comparing the accuracy, performance, and cost-effectiveness with conventional cytology in the Japanese population. PMID- 29478282 TI - Purinergic signalling and TRPV1 receptors are associated with the carotid body plasticity induced by an apnoea-like stimulus. PMID- 29478280 TI - The miR-139-5p regulates proliferation of supratentorial paediatric low-grade gliomas by targeting the PI3K/AKT/mTORC1 signalling. AB - AIMS: Paediatric low-grade gliomas (pLGGs) are a heterogeneous group of brain tumours associated with a high overall survival: however, they are prone to recur and supratentorial lesions are difficult to resect, being associated with high percentage of disease recurrence. Our aim was to shed light on the biology of pLGGs. METHODS: We performed microRNA profiling on 45 fresh-frozen grade I tumour samples of various histological classes, resected from patients aged <=16 years. We identified 93 microRNAs specifically dysregulated in tumours as compared to non-neoplastic brain tissue. Pathway analysis of the microRNAs signature revealed PI3K/AKT signalling as one of the centrally enriched oncogenic signalling. To date, activation of the PI3K/AKT pathway in pLGGs has been reported, although activation mechanisms have not been fully investigated yet. RESULTS: One of the most markedly down-regulated microRNAs in our supratentorial pLGGs cohort was miR 139-5p, whose targets include the gene encoding the PI3K's (phosphatidylinositol 3-kinase) catalytic unit, PIK3CA. We investigated the role of miR-139-5p in regulating PI3K/AKT signalling by the use of human cell cultures derived from supratentorial pLGGs. MiR-139-5p overexpression inhibited pLGG cell proliferation and decreased the phosphorylation of PI3K target AKT and phosphorylated-p70 S6 kinase (p-p70 S6K), a hallmark of PI3K/AKT/mTORC1 signalling activation. The effect of miR-139-5p was mediated by PI3K inhibition, as suggested by the decrease in proliferation and phosphorylation of AKT and p70 S6K after treatment with the direct PI3K inhibitor LY294002. CONCLUSIONS: These findings provide the first evidence that down-regulation of miR-139-5p in supratentorial pLGG drives cell proliferation by derepressing PI3K/AKT signalling. PMID- 29478283 TI - Parasitized Natural Killer cells do not facilitate the spread of Toxoplasma gondii to the brain. AB - Toxoplasma gondii is a protozoan parasite capable of invading immune cells and co opting their migratory pathways to disseminate through the host. Natural Killer (NK) cells can be directly invaded by the parasite and this invasion alters NK cell migration, producing a hypermotile phenotype. However, the consequences of this hypermotile phenotype for the dissemination of T. gondii to the brain remain unknown. To address this, C57BL6/J mice were infected with freshly egressed tachyzoites (type IIPrugniaud strain) or with parasitized NK cells. Under both conditions, parasite loads in the brain were comparable, indicating that parasitized NK cells were not able to facilitate spread of T. gondii to the brain. Consistent with this, we found no evidence for the recruitment of endogenous NK cells to the brain at early time points post-infection, nor any changes in the expression of alpha4beta1 integrin, involved in recruitment of NK cells to the brain. We therefore found no evidence for a role for hypermotile NK cells in delivery of parasites to the brain during acute infection with T. gondii. PMID- 29478284 TI - Immediate implant placement and provisionalization of maxillary anterior single implants. AB - An inevitable loss of soft and hard tissue after tooth extraction often results in a compromised site for anterior implant esthetics in both vertical and horizontal dimensions. Immediate implant placement and provisionalization has been a viable option for replacing failing maxillary anterior teeth as it preserves the vertical existing osseous and gingival architecture. With the simultaneous addition of soft- and hard-tissue grafts, the peri-implant horizontal tissue topography can also be maintained. The esthetic success of immediate implant placement and provisionalization procedures is influenced by a number of factors that can be identified as patient-dependent or clinician dependent. This article describes in detail the process of patient selection, indications, contraindications, diagnosis, treatment planning and treatment execution required to achieve functional and esthetic success with immediate implant placement and provisionalization. PMID- 29478285 TI - Incidence of sexual dysfunction among patients with hidradenitis suppurativa: a population-based retrospective analysis. PMID- 29478286 TI - Key role of hydrogen peroxide in antimicrobial activity of spring, Honeydew maquis and chestnut grove Corsican honeys on Pseudomonas aeruginosa DNA. AB - : In honeys, several molecules have been known for their antibacterial or wound healing properties. Corsican honeys just began to be tested for their antimicrobial activity with promising results on Pseudomonas aeruginosa. So, identification of active molecules and their mode of action was determined. Hydrogen peroxide concentrations were evaluated and, in parallel, the minimal inhibitory concentrations (MIC) values were performed with and without catalase. More, the quantity of phenolic compounds and ORAC assay were measured. Observation of antibacterial action was done using scanning electron microscopy (SEM) followed by plasmidic DNA extraction. MIC values of chestnut grove and honeydew maquis honeys vary between 7 and 8%, showing a strong antimicrobial capacity, associated with a plasmidic DNA degradation. When catalase is added, MIC values significatively increase (25%) without damaging DNA, proving the importance of H2 O2 . This hypothesis is confirmed by SEM micrographies which did not show any morphological damages but a depletion in bacterial population. Although, such low concentrations of H2 O2 (between 23 MUmol l-1 and 54 MUmol l-1 ) cannot explain antimicrobial activity and might be correlated with phenolic compounds concentration. Thus, Corsican honeys seem to induce DNA damage when H2 O2 and phenolic compounds act in synergy by a putative pro-oxidant effect. SIGNIFICANCE AND IMPACT OF THE STUDY: We started to determine the antibacterial efficiency of Corsican chestnut grove and honeydew maquis honeys on Pseudomonas aeruginosa. No morphological alteration of the bacterial surface was observed. Antimicrobial action seems to be related to the synergy between hydrogen peroxide and phenolic compounds. The exerted pro-oxidant activity leads to a degradation of P. aeruginosa plasmidic DNA. This is the first study that investigate the primary antibacterial mechanism of Corsican honeys. PMID- 29478287 TI - Altered epigenetic pathways and cell cycle dysregulation in healthy appearing skin of patients with koebnerized squamous cell carcinomas following skin surgery. AB - BACKGROUND: Koebnerized non-melanoma skin cancer following skin trauma represents a rare and obscure event. OBJECTIVES: To study molecular pathological parameters in koebnerized squamous cell carcinomas (K-SCCs) occurring after complete tumour removal. METHODS: We assessed two patients with multiple sclerosis who were on treatment with dimethylfumarate (DMF) preceded by long-term azathioprine therapy. Both patients rapidly developed several K-SCCs following histopathologically proven complete excision of cutaneous SCCs. We performed immunohistochemistry for p53, p16, Ki-67, TET-2, IDH-2, 5-hmc and 5-mc. PCR was carried out for the detection of human papilloma viruses. Mutation analysis was performed for BRAF, K RAS and EGFR. RESULTS: All lesions investigated were negative for HPV DNA. Mutations were not detected. Healthy appearing skin of both patients showed relatively high Ki-67, p16 and p53 expression which was comparable to the expression observed in primary SCCs as well as K-SCCs. Protein expression of Ki 67, p16 and mutant p53 was barely detected in the specimens of the healthy controls. A decreased protein expression of TET-2 enzyme was seen in all tumours and healthy appearing skin when compared to the skin of healthy controls. CONCLUSIONS: We observed two patients with K-SCCs developing under DMF treatment. In healthy appearing skin of patients with K-SCCs, wound healing processes, including induction of proliferation and growth factor release, might promote the growth of preneoplastic keratinocytes and cancer formation on the basis of pre existing altered epigenetic pathways and cell cycle dysregulation. Although fumarates can reduce TET-2 expression, the role of DMF intake in the development of K-SCCs remains unclear. PMID- 29478288 TI - Response to Lee et al. PMID- 29478289 TI - Alternative test models for skin ageing research. AB - Increasing ethical concerns regarding animal experimentation have led to the development of various alternative methods based on the 3Rs (Refinement, Reduction and Replacement), first described by Russell and Burch in 1959. Cosmetic research and skin ageing research are particularly susceptible to concerns related to animal testing. In addition to animal welfare reasons, there are scientific and economic reasons to reduce and avoid animal experiments. Importantly, animal experiments may not reflect findings in humans mainly because of the differences in architectures and immune responses between animal skin and human skin. Here, we review the shift from animal testing to the development and application of alternative non-animal-based methods and the necessity and benefits of this shift. Some specific alternatives to animal models are discussed, including biochemical approaches, 2-dimensional and 3-dimensional cell cultures and volunteer studies, as well as future directions, including genome based research and the development of in silico computer simulations of skin models. Among the in vitro methods, 3-dimensional reconstructed skin models are highly popular and useful alternatives to animal models however still have many limitations. With careful selection and skilful handling, these alternative methods will become indispensable for modern dermatology and skin ageing research. PMID- 29478291 TI - Subclinical atrial fibrillation in patients with recent transient ischemic attack. AB - BACKGROUND: Atrial fibrillation (AF) is a major risk factor of stroke, but the association between AF and transient ischemic attack (TIA) is less clear. Despite this, patients with TIA are included in stroke trials. AIMS: To determine the 1 year incidence of AF in TIA patients using an insertable cardiac monitor (ICM); second, to determine factors associated with incident AF in these patients. METHODS: Prospective cohort study of patients with TIA with normal standard electrocardiogram (ECG) and 72-hour Holter monitoring (HM). Exclusion criteria were as follows: age < 18 or > 81 years; prior AF/stroke; ongoing oral anticoagulation therapy or contraindication for it; significant carotid artery stenosis; uncertain TIA diagnosis. Eligible patients received an ICM and were followed for 12 months. RESULTS: From November 2013 to October 2015, 809 patients were diagnosed with TIA. In total, 235 patients were eligible. Nine (3.8%) of these had AF on standard ECG or HM. Of the remaining patients, 121 refused ICM implantation. In total, 105 patients (median age 65.4 years [range 27.1-80.8], 46% males) received an ICM, which revealed AF in 7 (6.7%). Factors associated with new-onset AF were a history of recurrent TIA (odds ratio [OR] 11.5, 95% confidence interval [CI] 2.1-63.6) and heart failure (OR 12.7, 95% CI 1.71 96.83). CONCLUSIONS: The 1-year incidence of AF in TIA patients with normal ECG and HM was 6.7% using an ICM. Factors associated with development of AF were recurrent TIA and heart failure. PMID- 29478290 TI - Two-Year Follow-Up Magnetic Resonance Imaging and Spectroscopy Findings and Cerebrospinal Fluid Analysis of a Dog with Sandhoff's Disease. AB - A 13-month-old female Toy Poodle was presented for progressive ataxia and intention tremors of head movement. The diagnosis of Sandhoff's disease (GM2 gangliosidosis) was confirmed by deficient beta-N-acetylhexosaminidase A and B activity in circulating leukocytes and identification of the homozygous mutation (HEXB: c.283delG). White matter in the cerebrum and cerebellum was hyperintense on T2-weighted and fluid-attenuated inversion recovery magnetic resonance images. Over the next 2 years, the white matter lesions expanded, and bilateral lesions appeared in the cerebellum and thalamus, associated with clinical deterioration. Magnetic resonance spectroscopy showed progressive decrease in brain N acetylaspartate, and glycine-myo-inositol and lactate-alanine were increased in the terminal clinical stage. The concentrations of myelin basic protein and neuron specific enolase in cerebrospinal fluid were persistently increased. Imaging and spectroscopic appearance correlated with histopathological findings of severe myelin loss in cerebral and cerebellar white matter and destruction of the majority of cerebral and cerebellar neurons. PMID- 29478293 TI - Reply to 'Comments on a new classification, treatment algorithm and prognosis estimating system for sigmoid volvulus: patient determination for elective surgery'. PMID- 29478292 TI - The measurement of drug-induced interferon gamma-releasing cells and lymphocyte proliferation in severe cutaneous adverse reactions. AB - BACKGROUND: The lymphocyte transformation test (LTT) is a standard laboratory method to identify culprit drugs in patients with a history of drug-induced non immediate hypersensitivity and is mainly performed during the recovery phase. The measurement of drug-specific interferon gamma (IFN-gamma)-releasing cells has been introduced to confirm culprit drugs, even during the acute phase of drug allergy. OBJECTIVES: This study aimed to evaluate the capability of the enzyme linked immunospot assay (ELISpot) to detect drug-specific IFN-gamma-releasing cells during the acute phase and the capability of LTT to identify culprit drugs during the recovery phase in patients presenting with severe cutaneous adverse reactions (SCARs). METHODS: Peripheral blood mononuclear cells (PBMCs) from 23 SCAR patients were collected during the acute and recovery phases and assayed for drug-specific IFN-gamma-releasing cells and lymphocyte proliferation, respectively. RESULTS: Drug-specific IFN-gamma-releasing cells were detectable in 73.9% of SCAR subjects (55.6% and 85.7% in patients who were and were not taking systemic steroids, respectively), whereas LTT results were positive in 52.2% of SCAR subjects. The frequencies of drug-specific IFN-gamma-releasing cells were significantly higher in patients with positive LTT than in those with negative LTT (260.1 +/- 110.0 and 46.6 +/- 20.7 cells/106 PBMCs, P = 0.01). A significant correlation between the results of the IFN-gamma ELISpot assay and LTT was demonstrated (r = 0.65, P value <0.01). CONCLUSION: The IFN-gamma ELISpot assay could be a useful tool to identify culprit drugs in SCAR patients when culprit drug identification is urgently needed during the acute phase of drug allergy. PMID- 29478295 TI - Association between childhood atopic dermatitis and cutaneous, extracutaneous and systemic infections. PMID- 29478294 TI - Tricyclic antidepressant use and the risk of fibrosis progression in hepatitis C infected persons: Results from ERCHIVES. AB - Recent preclinical studies have suggested an antifibrotic role for tricyclic antidepressants (TCA). Using the Electronically Retrieved Cohort of hepatitis C virus (HCV) Infected Veterans, we aimed to evaluate the impact of TCA use on fibrosis progression and development of hepatocellular carcinoma (HCC) among HCV infected persons. Subjects were categorized according to use of TCAs, selective serotonin reuptake inhibitors (SSRI) or no antidepressants. TCAs or selective serotonin uptake inhibitors use was defined according to cumulative defined daily dose (cDDD), and categories were mutually exclusive. Subjects with HIV coinfection, hepatitis B surface antigen (HbsAg) positivity, cirrhosis or HCC at baseline were excluded. Outcomes were liver fibrosis progression measured by APRI scores and incident HCC. We utilized Cox proportional hazards regression to determine predictors of cirrhosis, defined as APRI > 2, and incident hepatocellular carcinoma (iHCC). Among 128 201 eligible HCV+ persons, 4% received TCAs, 43% received selective serotonin uptake inhibitors, and 53% received no antidepressants. Fewer TCAs users had drug abuse (34% and 43%) and alcohol abuse (32% vs 42%) compared to selective serotonin uptake inhibitor users. After adjusting for age, baseline APRI score, diabetes, hypertension, alcohol use, drug abuse and HCV RNA levels, TCAs use was associated with decreased risk of cirrhosis (hazard ratio [HR] = 0.77, 95% CI = 0.60, 0.99) and delayed time to development of cirrhosis, but not with decreased iHCC. In conclusion among a large cohort of HCV-positive Veterans, TCAs use was associated with decreased fibrosis progression and lower risk of developing cirrhosis. These data provide supportive evidence for the beneficial effects of TCAs on progression of liver fibrosis in patients with chronic HCV infection. PMID- 29478296 TI - Cardiac electroporation: The promise of the unknown. PMID- 29478297 TI - Laparoscopic adrenalectomy using the lateral retroperitoneal approach: Is it a safe and feasible treatment option for pheochromocytomas larger than 6 cm? AB - OBJECTIVES: To evaluate the surgical feasibility of laparoscopic adrenalectomy using the lateral retroperitoneal approach for the treatment of large pheochromocytomas, and to identify the preoperative risk factors for intraoperative hypertension. METHODS: We retrospectively reviewed 51 patients who underwent laparoscopic adrenalectomy using the lateral retroperitoneal approach for the treatment of pheochromocytomas. Patient characteristics and perioperative outcomes were analyzed and compared between the two study groups based on tumor size: group A (n = 27, <=6 cm) and group B (n = 24, ?6 cm). RESULTS: There was no significant difference in preoperative characteristics between the two groups except for tumor size (P = 0.001) and urinary metanephrine (P = 0.011). Group B patients required longer operating time (P = 0.008), had a greater estimated blood loss (P = 0.001) and hemoglobin change (P = 0.002). However, no significant differences were observed in perioperative complications and mortality. Multivariate analysis showed that symptomatic pheochromocytomas (P = 0.004) and tumor size (P = 0.007) were significant risk factors for intraoperative hypertension. CONCLUSIONS: Laparoscopic adrenalectomy using the lateral retroperitoneal approach for pheochromocytomas can be regarded as a treatment option, even for tumors measuring >6 cm. Symptomatic pheochromocytomas and large tumor size seem to represent risk factors for intraoperative hypertension. PMID- 29478299 TI - Everlasting memories of Alina Szczesniak and Malcolm Bourne. PMID- 29478298 TI - Functional Fc gamma receptor gene polymorphisms and donor-specific antibody triggered microcirculation inflammation. AB - Fc-dependent effector mechanisms may contribute to antibody-mediated rejection (ABMR), and distinct gene polymorphisms modifying the function of Fc gamma receptors (FcgammaRs) may influence the capability of donor-specific antibodies (DSAs) to trigger inflammation. To evaluate the relevance of functional FcgammaR variants in late ABMR, 85 DSA-positive kidney allograft recipients, who were recruited upon antibody screening of 741 prevalent patients, were genotyped for polymorphisms in FcgammaRIIA (FCGR2A-H/R131 ; rs1801274), FcgammaRIIIA (FCGR3A V/F158 ; rs396991), and FcgammaRIIIB (FCGR3B-neutrophil antigen 1 ([NA1]/NA2; rs35139848). Individuals with high-affinity FCGR3A-V158 alleles (V/V158 or V/F158 ) showed a higher rate (and extent) of peritubular capillaritis (ptc) in protocol biopsies than homozygous carriers of the lower-affinity allele (ptc score >=1: 53.6% vs 25.9%; P = .018). Associations were independent of C1q-binding to DSA or capillary C4d. In parallel, there was a trend toward increased macrophage- and injury-repair response-associated transcript subsets. Kidney function over 24 months, however, was not different. In support of a functional role of FcgammaRIIIA polymorphism, NK92 cells expressing FCGR3A-V158 produced >2 times as much interferon gamma upon incubation with HLA antibody-coated cells as those expressing FCGR3A-F158 . FcgammaRIIA and FcgammaRIIIB polymorphisms were not associated with allograft morphology. Our data suggest that the presence of high affinity FcgammaRIIIA variants may favor DSA-triggered microcirculation inflammation. PMID- 29478300 TI - The passing of the baton. PMID- 29478302 TI - Influence of cigarette smoking on pemphigus - a systematic review and pooled analysis of the literature. AB - Epidemiological evidence suggests that smoking cigarettes may be beneficial in pemphigus, but no systematic evaluation exists to corroborate this assumption. Therefore, a systematic literature review with pooled data analysis of the smoking status in patients with pemphigus was conducted. Electronic searches using PubMed from inception to November 2017 identified 13 reports meeting predetermined inclusion and exclusion criteria. Most were case-control studies partly reporting that pemphigus vulgaris and foliaceus occurred less frequently in current and former smokers. Studies also indicated that duration of smoking and number of cigarettes smoked were lower in patients with pemphigus than controls and that remission may be achieved sooner in those who smoke. However, although a generally low prevalence of smoking was demonstrated in patients with pemphigus, which was lower than in controls by pooled analysis, some investigations found no difference regarding the smoking status compared with non pemphigus subjects. One study demonstrated more severe mucosal involvement in non smoking patients with pemphigus, whereas another observed no difference in the rate of cutaneous or mucosal lesions between smokers and non-smokers with pemphigus. This review indicates that smoking may be a possible protective factor in pemphigus, although some compromised study methodologies yet hinder any firm conclusion. Further investigations with a refined quality design are required to resolve the so far partly conflicting results in this area. PMID- 29478301 TI - Papulopustular rosacea and rosacea-like demodicosis: two phenotypes of the same disease? AB - BACKGROUND: Papulopustular rosacea and rosacea-like demodicosis have numerous similarities, but they are generally considered as two distinct entities, mainly because the causal role of the Demodex mite in the development of rosacea is not yet widely accepted. Several clinical characteristics are traditionally considered to differentiate the two conditions; for example, papulopustular rosacea is typically characterized by central facial papulopustules and persistent erythema, whereas small superficial papulopustules and follicular scales rather suggest rosacea-like demodicosis. However, none of these characteristics is exclusive to either entity. OBJECTIVE: To explore differences in Demodex densities according to clinical characteristics traditionally associated with these two conditions. METHODS: Retrospective, observational, case control study of 242 patients with central face papulopustules. Demodex densities were measured on two consecutive standardized skin surface biopsies. RESULTS: In the whole cohort, Demodex densities were greater in patients with persistent erythema than in those without. In 132 patients without recent treatment or other facial dermatoses, 120 (91%) had persistent erythema, 119 (90%) small superficial papulopustules and 124 (94%) follicular scales; 116 (88%) simultaneously had clinical characteristics traditionally associated with both papulopustular rosacea and rosacea-like demodicosis. Higher Demodex densities were linked to the presence of follicular scales, but not to papulopustules size, nor to the presence/absence of persistent erythema. CONCLUSION: Our observations highlight the difficulty differentiating between these entities and suggest that rosacea like demodicosis and papulopustular rosacea should no longer be considered as two separate entities, but rather as two phenotypes of the same disease. PMID- 29478303 TI - The opinions of Turkish mental health nurses on physical health care for individuals with mental illness: A qualitative study. AB - WHAT IS KNOWN ON THE SUBJECT: Individuals with mental illness have significantly higher mortality and morbidity than the general population due to physical illnesses. Mental health nurses play a key role in providing care for common physical problems and protecting and promoting healthy lifestyles. Little is known from previous studies in the international literature about the attitudes, behaviours and thoughts of mental health nurses on providing physical health care. WHAT THIS PAPER ADDS TO THE EXISTING KNOWLEDGE: Mental health nurses mostly focus on the existing physical health problems of individuals with mental illness. However, mental health nurses do not include practices of disease prevention and physical health promotion for individuals with mental illness. The desire to see positive changes in individuals with mental illness, receiving positive feedback, feeling useful and happy, and feeling satisfied with their profession motivate mental health nurses in terms of providing physical health care. WHAT ARE THE IMPLICATIONS FOR PRACTICE: The knowledge and skill required of mental health nurses to provide physical health care need to be increased. Institutions should employ expert nurses who are able to guide mental health nurses to provide physical health care. It is important to provide adequate physical infrastructure and human resources to provide better physical health care in mental health services. ABSTRACT: Background Mental health nurses play an important role in improving the physical health of individuals with mental illnesses. However, there are limited studies of their attitudes and practices about physical health. Therefore, there is a need for qualitative studies to clarify the issue. AIM: The aim of this study was to determine mental health nurses' opinions about physical health care for individuals with mental illness. METHODS: This study was carried out in Turkey. A qualitative descriptive approach was taken in the study. The sample consisted of twelve mental health nurses selected by purposeful sampling. In-depth interviews were conducted using a semi structured interview format. A thematic analysis was used to evaluate the interviews. RESULTS: Four main themes were determined. (1) The barriers to physical healthcare theme included barriers related to patients, illness and treatment, barriers related to patients' caregivers, barriers related to health professionals and barriers related to the healthcare system. (2) The physical healthcare practices theme included common physical health problems and current nursing practices. (3) Motivators theme included the desire to see positive changes in a patient, receiving positive feedback, feeling useful and happy, having a sense of conscience and feeling satisfied with their profession. (4) The needs for better physical healthcare theme included the nurses' recommendations for better physical health care. CONCLUSION: Mental health nurses believe that the physical health care provided to individuals with mental illness is not adequate. Many barriers to providing care for physical health, such as having psychiatric symptoms that are not seen as a priority by patients and health personnel, were determined. IMPLICATIONS FOR PRACTICE: Mental health nurses should integrate physical healthcare practices into their routine care. In addition, mental health nurses' knowledge and skills about physical health care should be improved. PMID- 29478304 TI - Use of emollients and topical glucocorticoids among adolescents with eczema: data from the population-based birth cohort BAMSE. AB - BACKGROUND: Knowledge regarding how adolescents treat their eczema is sparse. OBJECTIVES: To explore the use of emollients and topical glucocorticoids in adolescents with eczema in relation to sex and disease severity, and to study dispensing patterns of topical glucocorticoids. METHODS: Questionnaire-based data on symptoms of eczema, eczema severity and treatment with emollients and topical glucocorticoids were obtained from 3108 adolescents in the Swedish population based birth cohort BAMSE. Severity of reported eczema was evaluated with the BAMSE Eczema Severity Score (BESS) in a questionnaire and with the Patient Oriented Eczema Measure in clinically examined patients with current eczema (n = 247). Information on dispensed topical glucocorticoids was obtained from the Swedish Prescribed Drug Register. RESULTS: In all, 10% of the adolescents reported eczema in the preceding year: 73% mild, 17% moderate and 10% severe according to BESS. Almost all used emollients, whereas use of topical glucocorticoids was reported by 55%, with no significant difference between sexes. The likelihood of treatment with emollients and topical glucocorticoids increased when the adolescents had symptoms of current eczema [adjusted odds ratio (OR) 5.95, 95% confidence interval (CI) 1.90-18.8], but not if they had more severe eczema compared with mild eczema (adjusted OR 1.57, 95% CI 0.58 4.25). Among those with reported eczema, 24% had a topical glucocorticoid dispensed in the preceding year, and among those with moderate-to-severe current eczema 24% had a dispensed potent topical glucocorticoid. CONCLUSIONS: This population-based study indicates that adolescents with eczema are undertreated or completely untreated, even those with severe eczema. PMID- 29478305 TI - Both sarcopenia and frailty determine suitability of patients for liver transplantation-A systematic review and meta-analysis of the literature. AB - Liver grafts are allocated based on both urgency and utility. Due to a tremendous shortage of suitable organs for liver transplantation (LT), a careful selection of suitable recipients is of utmost importance. While the sickest first principle for organ allocation based on MELD score goes along with poor utility, other parameters reflecting the general health condition like frailty and sarcopenia might be essential to detect suitable patients for the waiting list. Thus, this study was designed to evaluate both frailty and sarcopenia in LT. A systematic review of the literature on sarcopenia and frailty measurements in liver transplant recipients was performed. Thirteen of 238 studies were selected for full paper review. Six of the studies investigating the impact of frailty on waitlist mortality were subjected to a meta-analysis. Despite the different methodologies to assess sarcopenia, reports showed that sarcopenia was highly related to waitlist mortality with a sum of all that highly favored negative outcome in case of sarcopenia. The existing literature clearly underlines that frailty and sarcopenia are important to determine in LT candidates. One unique index for transplant candidates reflecting frailty should be developed and be used as a standard in all transplant centers to facilitate comparability. PMID- 29478306 TI - Impact of electronic reminder systems on hepatitis C screening in primary care. AB - Screening for hepatitis C virus (HCV) was recommended in 2012 by the Centers for Disease Control (CDC) for the population born between 1946 and 1965. Reminder systems are effective at promoting HCV screening, but the yield of positive tests among various population subgroups and the linkage to specialty HCV treatment is not well understood. We sought to determine: (i) the effect of the CDC recommendation alone, and the effect of an electronic medical record (EMR) reminder on the proportion of the population screened; (ii) the yield of positive HCV tests as screening strategies have evolved, and according to a patient's history of serum aminotransferase testing; (iii) the proportion of positive cases followed up for HCV treatment. This retrospective cohort study included 60 000 primary care patients at a northeast US academic medical centre serving an urban and rural population in which an EMR reminder was instituted in 2014. Results demonstrated an increase in proportion tested for HCV from 12% prior to the CDC recommendation to 37% after the reminder system. The yield of positive HCV antibody (HCV Ab) tests decreased from 7% in the "case-finding" era to 1.6% after the EMR reminder prompted screening of a lower risk population (P < .001). Patients with a history of abnormal aminotransferase tests had a fivefold higher rate of positive HCV Ab testing (6.7% vs 1.5%, P < .001). Ninety per cent of patients with confirmed HCV infection were seen in specialty care. PMID- 29478307 TI - Magnifying Endoscopy for Esophageal Ectopic Sebaceous Glands. AB - Ectopic sebaceous glands are found very rarely in the esophagus; heretofore, several cases have been reported. The sebaceous gland is originally a source of an endodermal origin; however, there have been controversies regarding whether the origin of the esophageal ectopic sebaceous gland is ectodermal or endodermal. Ectopic sebaceous glands of the esophagus usually do not cause symptoms; thus, they are often found incidentally on endoscopy for routine health screening. Endoscopic findings are characterized by single or multiple yellow patches or nodular lesions of various sizes, sometimes with small central openings. We report two cases of esophageal ectopic sebaceous glands found incidentally during endoscopy with magnifying endoscopic findings. The lesions were in the mid esophagus and lower esophagus, respectively, and both endoscopic findings were similar as multiple yellowish patches or plaques. Magnifying endoscopy revealed the openings of the excretory ducts surrounded by circular microvessels in both cases. PMID- 29478308 TI - Encapsulated peritoneal sclerosis: a single center, retrospective analysis of clinical manifestations, risk factors and prognosis. AB - BACKGROUND: Encapsulated peritoneal sclerosis (EPS) is a multifactorial chronic intra-abdominal inflammatory disorder affecting the peritoneum diffusely. The aim of this study was to evaluate the rates of EPS in our peritoneal dialysis (PD) population, to perform a general assessment of the clinical presentation and to determine the outcome of affected patients and risk factors. METHODS: The medical records of consecutive 384 patients who started PD therapy between January 2001 and November 2016 were evaluated. Socio-demographic characteristics, comorbidities, PD therapy details and infectious complications were recorded. Medical records were examined to make sure that the cases met the ISPD criteria for EPS diagnosis including clinical features and either radiological and/or histopathological confirmation. Patients diagnosed with EPS were identified, and the incidence, clinical presentation, treatments and recent status of the patients were reviewed. Factors that might be associated with EPS formation and mortality were investigated. RESULTS: Two hundred one of 384 patients were female, mean age was 45.9+/-15.6 years and mean PD follow up time were 42.6+/-35 months. EPS was developed in 26 patients and EPS development rate was 6.7%. PD follow-up period and duration of hypertonic solution usage were longer in patients with EPS (P<0.001 and P=0.017 respectively). Patients with and without EPS were similar in terms of modality (P=0.21) but treatment duration with APD modality was longer in patients with EPS (P<0.001). The PD follow-up period was found to be a predictor of EPS formation (P<0.001, RR:1.034 [95% CI: 1.020 1.047]). Age (P<0.001, RR:1.039 (95% CI: 1.024-1.053) and use of hypertonic dialysis solution (P=0.007, RR:0.979 (95% CI: 0.965-0.994)) were the factors affecting survival in EPS patients. CONCLUSIONS: EPS is a relatively rare but fatal complication of peritoneal dialysis and extension of PD duration is a risk for EPS formation. Younger age and usage of hypertonic dialysis solution affects mortality in patients with EPS. PMID- 29478309 TI - Moderate-to-high cardiovascular risk is associated with increased lower urinary tract storage symptoms in patients with benign prostatic enlargement. AB - BACKGROUND: To assess the association between cardiovascular risk (CVR) and lower urinary tract symptoms (LUTS) in men with benign prostatic enlargement (BPE). METHODS: We enrolled a consecutive series of men with LUTS/BPE. International Prostate Symptom Score (IPSS), voiding (vIPSS) and storage (sIPSS) subscore and prostate volume were evaluated. We defined CVR according to the European Association of Cardiologist Guidelines, and metabolic syndrome (MetS) according to the Adult Treatment Panel III (ATP III). RESULTS: A total of 509 patients were enrolled. Median age was 66 years (IQR: 60-72), IPSS 9 (IQR: 5-15), vIPSS 5 (IQR: 2-9), sIPSS 4 (IQR: 2-7), Prostate volume was 54 cc (IQR: 40-73). Overall 309/509 (60.7%) patients had a moderate/high CVR and 128/509 presented MetS (25.1%). 297/509 (58.3%) men had an IPSS>7 and 282/509 (55.4%) a sIPSS>3. Men with moderate-to-severe CVR had higher IPSS (9; IQR: 4-14 vs. 10; IQR: 5-16; P=0.01), higher vIPSS (6; IQR: 2-9 vs. 4; IQR: 2-8; P=0.06) and higher sIPSS (4; IQR: 2-8 vs. 3; IQR: 1-6; P=0.005) when compared with no/low CVR patients. On multivariate analysis CVR was associated with an increased risk of IPSS>7 (OR=1.794; 95% CI: 1.111-2.888; P=0.01) and sIPSS>3 (OR=1.593; 95% CI: 1.101-2.555; P=0.04). CONCLUSIONS: A moderate/high CVR is associated with an increased risk of LUTS, particularly storage LUTS. Although the pathophysiology is yet to be understood, it can be assumed that an increased CVR may be associated with LUTS/BPE presence. PMID- 29478310 TI - Isolation of Exosome-Like Nanoparticles and Analysis of MicroRNAs Derived from Coconut Water Based on Small RNA High-Throughput Sequencing. AB - In this study, the presence of microRNAs in coconut water was identified by real time polymerase chain reaction (PCR) based on the results of high-throughput small RNA sequencing. In addition, the differences in microRNA content between immature and mature coconut water were compared. A total of 47 known microRNAs belonging to 25 families and 14 new microRNAs were identified in coconut endosperm. Through analysis using a target gene prediction software, potential microRNA target genes were identified in the human genome. Real-time PCR showed that the level of most microRNAs was higher in mature coconut water than in immature coconut water. Then, exosome-like nanoparticles were isolated from coconut water. After ultracentrifugation, some particle structures were seen in coconut water samples using 1,1'-dioctadecyl-3,3,3',3' tetramethylindocarbocyanine perchlorate fluorescence staining. Subsequent scanning electron microscopy observation and dynamic light scattering analysis also revealed some exosome-like nanoparticles in coconut water, and the mean diameters of the particles detected by the two methods were 13.16 and 59.72 nm, respectively. In conclusion, there are extracellular microRNAs in coconut water, and their levels are higher in mature coconut water than in immature coconut water. Some exosome-like nanoparticles were isolated from coconut water, and the diameter of these particles was smaller than that of animal-derived exosomes. PMID- 29478312 TI - Straightforward and Ultrastable Surface Modification of Microfluidic Chips with Norepinephrine Bitartrate Improves Performance in Immunoassays. AB - Polymers are commonly used materials for microfluidic chip fabrication, because they are standardized in fabrication and low in cost. However, most polymeric materials that are readily fabricated on the industrial scale are hydrophobic, which is inconvenient for the injection and flow of the aqueous solution, resulting in poor analytical performance for biochemical assays. In this work, we present a straightforward and ultrastable surface modification process for polymeric chips. A one-step modification by using norepinephrine bitartrate monohydrate as a modification reagent is completed at room temperature. The hydrophilicity of the polymeric surfaces increases dramatically. Surface modification is stable for at least 2.5 years, allowing for autoinjection of aqueous solution into the channels. The chips are applied in the immunoassay of alpha-fetoprotein (AFP). The low nonspecific adsorption after modification results in significantly decreased background noise, optimized signal-to-noise ratios (SNR), and dramatically enhanced reproducibility of the immunoassay. Thirty clinical human serum samples are analyzed; these results strongly correlated with the values obtained using commercial test kits. We anticipate that this surface modification method can be used for immunoassay devices in analytical and biosensing technology. PMID- 29478311 TI - Synthesis of 1,1'-Diarylethanes and Related Systems by Displacement of Trichloroacetimidates with Trimethylaluminum. AB - Benzylic trichloroacetimidates are readily displaced by trimethylaluminum under Lewis acid promoted conditions to provide the corresponding methyl substitution product. This method is a convenient way to access 1,1'-diarylethanes and related systems, which play a significant role in medicinal chemistry, with a number of systems owing their biological activity to this functionality. Most benzylic substrates undergo ready displacement, with electron deficient systems being the exception. The use of an enantiopure imidate showed significant racemization, implicating the formation of a cationic intermediate. PMID- 29478313 TI - Revealing Biotic and Abiotic Controls of Harmful Algal Blooms in a Shallow Subtropical Lake through Statistical Machine Learning. AB - Harmful algal blooms are a growing human and environmental health hazard globally. Eco-physiological diversity of the cyanobacteria genera that make up these blooms creates challenges for water managers tasked with controlling the intensity and frequency of blooms, particularly of harmful taxa (e.g., toxin producers, N2 fixers). Compounding these challenges is the ongoing debate over the efficacy of nutrient management strategies (phosphorus-only versus nitrogen and phosphorus), which increases decision-making uncertainty. To improve our understanding of how different cyanobacteria respond to nutrient levels and other biophysical factors, we analyzed a unique 17 year data set comprising monthly observations of cyanobacteria genera and zooplankton abundances, water quality, and flow in a bloom-impacted, subtropical, flow-through lake in Florida (United States). Using the Random Forests machine learning algorithm, an ensemble modeling approach, we characterized and quantified relationships among environmental conditions and five dominant cyanobacteria genera. Results highlighted nonlinear relationships and critical thresholds between cyanobacteria genera and environmental covariates, the potential for hydrology and temperature to limit the efficacy of cyanobacteria bloom management actions, and the importance of a dual nutrient management strategy for reducing bloom risk in the long term. PMID- 29478315 TI - Rapid Sample Preparation for Alpha Spectroscopy with Ultrafiltration Membranes. AB - This contribution describes a rapid, fieldable alpha spectroscopy sample preparation technique that minimizes consumables and decreases the nuclear forensics timeline. Functional ultrafiltration membranes are presented that selectively concentrate uranium directly from pH 6 groundwater and serve as the alpha spectroscopy substrate. Membranes were prepared by ultraviolet grafting of uranium-selective polymer chains from the membrane surface. Membranes were characterized by Fourier-transform infrared spectroscopy before and after modification to support functionalization. Membrane performance was evaluated using uranium-233 or depleted uranium in both deionized and simulated groundwater at pH 6. Functionalized membranes achieved peak energy resolutions of 31 +/- 2 keV and recoveries of 81 +/- 4% when prepared directly from pH 6 simulated groundwater. For simulated groundwater spiked with depleted uranium, baseline energy resolution was achieved for both isotopes (uranium-238 and uranium-234). The porous, uranium-selective substrate designs can process liters per hour of uranium-contaminated groundwater using low-pressure (<150 kPa) filtration and a 45 mm diameter membrane filter, leading to a high-throughput, one-step concentration, purification, and sample mounting process. PMID- 29478314 TI - CO Oxidation Kinetics over Au/TiO2 and Au/Al2O3 Catalysts: Evidence for a Common Water-Assisted Mechanism. AB - The mechanism of CO oxidation over supported gold catalysts has long been debated, with two prevailing mechanisms dominating the discussion: a water assisted mechanism and a mechanism involving O-defect sites. In this study, we directly address this debate through a kinetic and mechanistic investigation of the role of water in CO oxidation over Au/TiO2 and Au/Al2O3 catalysts; the results clearly indicate a common water-assisted mechanism to be at work. Water adsorption isotherms were determined with infrared spectroscopy; the extracted equilibrium constant was essentially the same for both catalysts. Added water decreases CO adsorption on Au/TiO2, likely by blocking CO binding sites at the metal-support interface. Reaction kinetics (CO, O2, and H2O reaction orders) were essentially the same for both catalysts, as were measured O-H(D) kinetic isotope effects. These data indicate that the two catalysts operate by essentially the same mechanism under the conditions of these experiments (ambient temperature, significant amounts of water available). A reaction mechanism incorporating the kinetic and thermodynamic data and accounting for different CO and O2/COOH binding sites is proposed. The mechanism and kinetic data are treated with an active site (Michaelis-Menten) approach. This indicated that water adsorption does not significantly affect reaction rate constants, only the number of active sites available at a given water pressure. Extracted water and O2 binding constants are similar on both catalysts and consistent with previous DFT calculations. Water adsorption constants are also similar to independently determined equilibrium constants measured by IR spectroscopy. The likely roles of water, surface carbonates, and oxygen vacancies at the metal-support interface are discussed. The results definitively show that, at least in the presence of added water, O vacancies cannot play an important role in the room-temperature catalysis, and that the water-assisted mechanism is far more consistent with the preponderance of the kinetic data. PMID- 29478316 TI - Photochemical Reaction Cascade from O-Pent-4-enyl-Substituted Salicylates to Complex Multifunctional Scaffolds. AB - The arene ring of the title compounds is cleaved by a reaction cascade which is initiated by an intramolecular ortho photocycloaddition reaction. Tricyclic products were obtained in a highly regio- and diastereoselective fashion via a cyclooctatriene intermediate. The facial diastereoselectivity exerted by a stereogenic center in the tether is moderate to good (dr = 65/35 to 82/18). Yields were acceptable (44-87%) except for a single substrate which had a geminal dimethyl substitution in the tether and which gave the respective product in only 14% yield. The reaction is stereoconvergent with regard to the olefin configuration ( E or Z) in agreement with a triplet mechanism of the ortho photocycloaddition step. PMID- 29478317 TI - Optimization of the Production of Covalently Circularized Nanodiscs and Their Characterization in Physiological Conditions. AB - Lipid nanodiscs are widely used platforms for studying membrane proteins in a near-native environment. Lipid nanodiscs made with membrane scaffold proteins (MSPs) in the linear form have been well studied. Recently, a new kind of nanodisc made with MSPs in the circular form, referred to as covalently circularized nanodiscs (cNDs), has been reported to have some possible advantages in various applications. Given the potential of nanodisc technology, researchers in the field are very interested in learning more about this new kind of nanodisc, such as its reproducibility, production yield, and the possible pros and cons of using it. However, research on these issues is lacking. Here, we report a new study on nanodiscs made with circular MSPs, which are produced from a method different from the previously reported method. We show that our novel production method, detergent-assisted sortase-mediated ligation, can effectively avoid high-molecular-weight byproducts and also significantly improve the yield of the target proteins up to around 80% for larger circular MSP constructs. In terms of the application of circular MSPs, we demonstrate that they can be used to assemble nanodiscs using both synthetic lipids and native lipid extract as the source of lipids. We also show that bacteriorhodopsin can be successfully incorporated into this new kind of cND. Moreover, we found that cNDs have improved stability against both heat and high-concentration-induced aggregations, making them more beneficial for related applications. PMID- 29478318 TI - Gold/Periodic Mesoporous Organosilicas with Controllable Mesostructure by Using Compressed CO2. AB - Gold nanoparticles confined into the walls of periodic mesoporous organosilicas (PMOs) with controllable morphology have been successfully fabricated through a one-pot method by using different CO2 pressures. The synthesis can be easily conducted in a mixed aqueous solution by using HAuCl4 as gold source and bis[3 (triethoxysilyl)propyl] tetrasulfide and tetramethoxysilane as the organosilica precursor. P123 and compressed CO2 served as the template and catalytic/regulative agent, respectively. Transmission electron microscopy, N2 adsorption, and X-ray diffraction were employed to characterize the structure of the obtained composite materials. To further investigate the formation mechanism, a series of ordered PMOs with one-dimensional nanotube, two-dimensional hexagonal, vesicle-like, and cellular foam structures were obtained by using different CO2 pressures without the gold source. The mechanism for mesostructure evolution of PMOs with different CO2 pressures was proposed and discussed in detail. The catalytic performance of Au-based PMOs was evaluated for the reduction of 4-nitrophenol (4-NP). These obtained composites with different mesostructures not only exhibit excellent catalytic activity, high conversion rate, and remarkable thermal stability, but they also exhibit morphology dependent reaction properties in the reduction of 4-NP. The possible reaction pathway of the reactants to embedded Au active sites was proposed and schemed. PMID- 29478319 TI - Efficient Construction of Energetic Materials via Nonmetallic Catalytic Carbon Carbon Cleavage/Oxime-Release-Coupling Reactions. AB - The exploitation of C-C activation to facilitate chemical reactions is well-known in organic chemistry. Traditional strategies in homogeneous media rely upon catalyst-activated or metal-mediated C-C bonds leading to the design of new processes for applications in organic chemistry. However, activation of a C-C bond, compared with C-H bond activation, is a more challenging process and an underdeveloped area because thermodynamics does not favor insertion into a C-C bond in solution. Carbon-carbon bond cleavage through loss of an oxime moiety has not been reported. In this paper, a new observation of self-coupling via C-C bond cleavage with concomitant loss of oxime in the absence of metals (either metal complex mediation or catalysis) results in dihydroxylammonium 5,5-bistetrazole 1,10-diolate (TKX-50) as well as N, N'-([3,3'-bi(1,2,4-oxadiazole)]-5,5' diyl)dinitramine, a potential candidate for a new generation of energetic materials. PMID- 29478320 TI - Combinatorial in Vitro and in Silico Approach To Describe Shear-Force Dependent Uptake of Nanoparticles in Microfluidic Vascular Models. AB - In the present work, we combine experimental and computational methods to define the critical shear stress as an alternative parameter for nanotoxicological and nanomedical evaluations using an in vitro microfluidic vascular model. We demonstrate that our complementary in vitro and in silico approach is well suited to assess the fluid flow velocity above which clathrin-mediated (active) nanoparticle uptake per cell decreases drastically although higher numbers of nanoparticles per cell are introduced. Results of our study revealed a critical shear stress of 1.8 dyn/cm2, where maximum active cellular nanoparticle uptake took place, followed by a 70% decrease in uptake of 249 nm nanoparticles at 10 dyn/cm2, respectively. The observed nonlinear relationship between flow velocity and nanoparticle uptake strongly suggests that fluid mechanical forces also need to be considered in order to predict potential in vivo distribution, bioaccumulation, and clearance of nanomaterials and novel nanodrugs. PMID- 29478321 TI - Metabolites of Dietary Acteoside: Profiles, Isolation, Identification, and Hepatoprotective Capacities. AB - In recent years, cistanche tea has been increasingly used as a major herbal supplement in functional drinks, and it has attracted a growing number of consumers because of its excellent tonic effects and medicinal properties. Acteoside (ACT), which is the principal bioactive component of Chinese cistanche tea, possesses various pharmacological effects. This study profiled, isolated, identified, and investigated the hepatoprotective capacities of metabolites in rat urine after the administration of ACT. Eleven metabolites, including one new compound (M8), were obtained and identified by nuclear magnetic resonance (NMR) spectroscopy for the first time. Compared with native ACT, ACT metabolites such as hydroxytyrosol (HT), 3-hydroxyphenylpropionic acid (3-HPP), and caffeic acid (CA) exhibited higher hepatoprotective activities by regulating oxidative stress, lipid peroxidation, and inflammatory responses in a GalN/LPS-induced-acute hepatic-injury mouse model. The HT treatment markedly reduced the levels of TNF alpha to 280 +/- 14.3 ng/L compared with the model group (429 +/- 9.20 ng/L, p < 0.01). The results obtained indicated that cistanche tea could be developed as a functional drink for the prevention of hepatic injuries and that ACT metabolites could be responsible for the potent hepatoprotective activity as well as the other therapeutic effects. PMID- 29478322 TI - PMIDA-Modified Fe3O4 Magnetic Nanoparticles: Synthesis and Application for Liver MRI. AB - The surface modification of Fe3O4-based magnetic nanoparticles (MNPs) with N (phosphonomethyl)iminodiacetic acid (PMIDA) was studied, and the possibility of their use as magnetic resonance imaging contrast agents was shown. The effect of the added PMIDA amount, the reaction temperature and time on the degree of immobilization of this reagent on MNPs, and the hydrodynamic characteristics of their aqueous colloidal solutions have been systematically investigated for the first time. It has been shown that the optimum condition for the modification of MNPs is the reaction at 40 degrees C with an equimolar amount of PMIDA for 3.5 h. The modified MNPs were characterized by X-ray diffraction, transmission electron microscopy, Fourier transform infrared spectroscopy, thermogravimetric, and CHN elemental analyses. The dependence of the hydrodynamic characteristics of the MNP colloidal solutions on the concentration and pH of the medium was studied by the dynamic light scattering method. On the basis of the obtained data, we can assume that the PMIDA molecules are fixed on the surface of the MNPs as a monomolecular layer. The modified MNPs had good colloidal stability and high magnetic properties. The calculated relaxivities r2 and r1 were 341 and 102 mmol 1 s-1, respectively. The possibility of using colloidal solutions of PMIDA modified MNPs as a T2 contrast agent for liver studies in vivo (at a dose of 0.6 mg kg-1) was demonstrated for the first time. PMID- 29478323 TI - Identification and Quantification of Avenanthramides and Free and Bound Phenolic Acids in Eight Cultivars of Husked Oat ( Avena sativa L) from Finland. AB - Finland is the second largest oat producer in Europe. Despite the existing knowledge of phenolics in oat, there is little information on the phenolic composition of oats from Finland. The aim of the study was to investigate the concentrations of free and bound phenolic acids, as well as avenanthramides in eight Finnish cultivars of husked oat ( Avena sativa L.). Seven phenolic acids and one phenolic aldehyde were identified, including, in decreasing order of abundance: p-coumaric, ferulic, cinnamic, syringic, vanillic, 2,4 dihydroxybenzoic, and o-coumaric acids and syringaldehyde. Phenolic acids were mostly found as bound compounds. Significant varietal differences ( p < 0.05) were observed in the cumulative content of phenolic acids, with the lowest level found in cv. 'Viviana' (1202 +/- 52.9 mg kg-1) and the highest in cv. 'Akseli' (1687 +/- 80.2 mg kg-1). Avenanthramides (AVNs) 2a, 2p, and 2f were the most abundant. Total AVNs levels ranged from 26.7 +/- 1.44 to 185 +/- 12.5 mg kg-1 in cv. 'Avetron' and 'Viviana', respectively. PMID- 29478324 TI - Brownian Translational Dynamics on a Flexible Surface: Nuclear Spin Relaxation of Fluid Membrane Phases. AB - A general model for nuclear magnetic resonance (NMR) relaxation studies of fluid bilayer systems is introduced, combining a mesoscopic Brownian dynamics description of the bilayer with atomistic molecular dynamics (MD) simulations. An example is given for dipalmitoylphosphatidylcholine in 2H2O solvent and compared with the experiment. Experimental agreement is within a factor of 2 in the water relaxation rates, based on a postulated model with fixed parameters, which are largely available from the MD simulation. Relaxation rates are particularly sensitive to the translational diffusion of water perturbed by the interface dynamics and structure. Simulation results suggest that a notable deviation in the relaxation rates may follow from the commonly used small-angle approximation of bilayer undulation. The method has the potential to overcome the temporal and spatial limitations in computing NMR relaxation with atomistic MD, as well as the shortcomings of continuum models enabling a consistent description of experiments performed on a solvent lipid and added spin probes. This work opens for possibilities to understand relaxation processes involving systems such as micelles, multilamellar vesicles, red blood cells, and so forth at biologically relevant timescales in great detail. PMID- 29478325 TI - Carcinogenesis and Reactive Oxygen Species Signaling: Interaction of the NADPH Oxidase NOX1-5 and Superoxide Dismutase 1-3 Signal Transduction Pathways. AB - SIGNIFICANCE: Reduction/oxidation (redox) balance could be defined as an even distribution of reduction and oxidation complementary processes and their reaction end products. There is a consensus that aberrant levels of reactive oxygen species (ROS), commonly observed in cancer, stimulate primary cell immortalization and progression of carcinogenesis. However, the mechanism how different ROS regulate redox balance is not completely understood. Recent Advances: In the current review, we have summarized the main signaling cascades inducing NADPH oxidase NOX1-5 and superoxide dismutase (SOD) 1-3 expression and their connection to cell proliferation, immortalization, transformation, and CD34+ cell differentiation in thyroid, colon, lung, breast, and hematological cancers. CRITICAL ISSUES: Interestingly, many of the signaling pathways activating redox enzymes or mediating the effect of ROS are common, such as pathways initiated from G protein-coupled receptors and tyrosine kinase receptors involving protein kinase A, phospholipase C, calcium, and small GTPase signaling molecules. FUTURE DIRECTIONS: The clarification of interaction of signal transduction pathways could explain how cells regulate redox balance and may even provide means to inhibit the accumulation of harmful levels of ROS in human pathologies. Antioxid. Redox Signal. 00, 000-000. PMID- 29478326 TI - A Pilot Study of the Snap & Sniff Threshold Test. AB - OBJECTIVES: The Snap & Sniff(r) Threshold Test (S&S) has been recently developed to determine the olfactory threshold. The aim of this study was to further evaluate the validity and test-retest reliability of the S&S. METHODS: The olfactory thresholds of 120 participants were determined using both the Smell Threshold Test (STT) and the S&S. The participants included 30 normosmic volunteers and 90 patients (60 hyposmic, 30 anosmic). The normosmic participants were retested using the STT and S&S at an intertest interval of at least 1 day. RESULTS: The mean olfactory threshold determined with the S&S was -6.76 for the normosmic participants, -3.79 for the hyposmic patients, and -2 for the anosmic patients. The olfactory thresholds were significantly different across the 3 groups ( P < .001). Snap & Sniff-based and STT-based olfactory thresholds were correlated weakly in the normosmic group (correlation coefficient = 0.162, P = .391) but more strongly correlated in the patient groups (hyposmic: correlation coefficient = 0.376, P = .003; anosmic: correlation coefficient = 1.0). The test retest correlation for the S&S-based olfactory thresholds was 0.384 ( P = .036). CONCLUSION: Based on validity and test-retest reliability, we concluded that the S&S is a proper test for olfactory thresholds. PMID- 29478327 TI - Preoperative Imaging Findings and Cost in Adults With Postlingual Deafness Prior to Cochlear Implant. AB - OBJECTIVE: To assess the imaging findings of computed topography (CT) and magnetic resonance imaging (MRI) in adults with postlingual deafness and otherwise normal clinical history and physical exam. Additionally, determine the influence and implications of these findings with respect to surgical outcomes and cost. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral hospital. PATIENTS: Adults with postlingual deafness with no history of prior ear surgery, chronic ear disease, meningitis, otosclerosis, or head trauma. INTERVENTIONS: Cochlear implantation of 1 or both ears, with preoperative CT, MRI, or both. MAIN OUTCOME MEASURES: Imaging results were classified as normal, abnormal affecting surgery, incidental requiring follow-up, or incidental not requiring follow-up. Average cost of each imaging modality was determined. RESULTS: A total of 128 patients met the inclusion criteria. Of these, 82 (64.1%) had both CT and MRI performed, 33 (25.8%) had CT, and 13 (10.2%) had MRI prior to cochlear implant (CI). Scans were normal in 125 (97.7%) of cases. Of the remaining 3 (2.3%) patients, there were incidental findings requiring follow-up. All implants were placed successfully, and in no instance did the results of the scan influence the surgery. The average cost of imaging per patient was $4707. CONCLUSION: In adults with postlingual deafness with an otherwise benign clinical history, CT and MRI are unlikely to affect or preclude surgery. With new MRI safe cochlear implants, imaging can be performed safely postoperatively if needed. PMID- 29478328 TI - A Simple Endoscopic Technique for Measuring the Cross-Sectional Area of the Upper Airway in a Rabbit Model. AB - OBJECTIVE: Validate an accurate and reproducible method of measuring the cross sectional area (CSA) of the upper airway. SUBJECTS AND METHODS: This is a prospective animal study done at a tertiary care medical treatment facility. Control images were obtained using endotracheal tubes of varying sizes. In vivo images were obtained from various timepoints of a concurrent study on subglottic stenosis. Using a 0 degrees rod telescope, an instrument was placed at the level of interest, and a photo was obtained. Three independent and blinded raters then measured the CSA of the narrowest portion of the airway using open source image analysis software. RESULTS: Each blinded rater measured the CSA of 79 photos. The t testing to assess for accuracy showed no difference between measured and known CSAs of the control images ( P = .86), with an average error of 1.5% (SD = 5.5%). All intraclass correlation (ICC) values for intrarater agreement showed excellent agreement (ICC > .75). Interrater reliability among all raters in control (ICC = .975; 95% CI, .817-.995) and in vivo (ICC = .846;, 95% CI, .780-.896) images showed excellent agreement. CONCLUSIONS: We validate a simple, accurate, and reproducible method of measuring the CSA of the airway that can be used in a clinical or research setting. PMID- 29478330 TI - Carbonic anhydrase activators. AB - Mammalian carbonic anhydrases (CAs; EC 4.2.1.1) of which 16 isoforms are known, are involved in important physiological functions. Their inhibition is exploited pharmacologically for the treatment of many diseases (glaucoma, edema, epilepsy, obesity, hypoxic tumors, neuropathic pain, etc.) but the activators were less investigated till recently. A review on the CA activation is presented, with the activation mechanism, drug design approaches of activators and comparison of the various isoforms activation profiles being discussed. Some CAs, which are abundant in the brain, were recently demonstrated to be activatable by drug-like compounds, affording the possibility to design agents that enhance cognition, with potential therapeutic applications in aging and neurodegenerative diseases as well as tissue engineering. PMID- 29478329 TI - Single tablet HIV regimens facilitate virologic suppression and retention in care among treatment naive patients. AB - Newer HIV regimens are typically taken once daily but vary in the number of pills required. Whether the number of pills in a once-daily HIV regimen affects clinical outcomes is unknown. We retrospectively compared adherence, retention in care, and virologic outcomes between patients starting a once daily single-tablet regimen (STR) to patients starting a once-daily multi-tablet regimen (MTR) in a publicly funded clinic in the United States. Outcomes were measured in the year after starting ART and included retention in care, virologic suppression, and medication possession ratio of at least 80%. Data from patients initiating therapy from 1 January 2008 to 31 December 2011 were analyzed with both unadjusted and propensity-score adjusted regression. Overall, 622 patients started with an STR (100% efavirenz-based) and 406 with an MTR (65% atazanavir based and 35% darunavir-based) regimen. Retention in care was achieved in 80.7% of STR patients vs. 72.7% of MTR patients (unadjusted OR 1.57, 95% CI 1.17-2.11; adjusted OR 1.49, 95% CI 1.10-2.02). Virologic suppression occurred among 84.4% of STR patients vs. 77.6% of MTR patients (unadjusted OR 1.56; 95% CI 1.14-2.15; adjusted OR 1.41; 95% CI 1.02-1.96). There was no difference in the proportion of patients achieving at least 80% adherence, as measured by medication possession ratio (33.0% of STR patients and 30.1% of MTR patients; unadjusted OR 1.14; 95% CI 0.87-1.50; adjusted OR 1.04, CI 0.79-1.38). While it is difficult to eliminate confounding in this observational study, retention in care and virologic outcomes were better in patients prescribed STRs. PMID- 29478331 TI - Transitioning from learning healthcare systems to learning health care communities. AB - The learning healthcare system (LHS) model framework has three core, foundational components. These include an infrastructure for health-related data capture, care improvement targets and a supportive policy environment. Despite progress in advancing and implementing LHS approaches, low levels of participation from patients and the public have hampered the transformational potential of the LHS model. An enhanced vision of a community-engaged LHS redesign would focus on the provision of health care from the patient and community perspective to complement the healthcare system as the entity that provides the environment for care. Addressing the LHS framework implementation challenges and utilizing community levers are requisite components of a learning health care community model, version two of the LHS archetype. PMID- 29478332 TI - An image analysis-aided method for redundancy reduction in differentiation of identical Actinobacterial strains. AB - AIM: To simplify the recognition of Actinobacteria, at different stages of the growth phase, from a mixed culture to facilitate the isolation of novel strains of these bacteria for drug discovery purposes. MATERIALS & METHODS: A method was developed based on Gabor transform, and machine learning using k-Nearest Neighbors and Naive Bayes classifier, Logitboost, Bagging and Random Forest to automatically categorize the colonies. RESULTS: A signature pattern was inferred by the model, making the differentiation of identical strains possible. Additionally, higher performance, compared with other classification methods was achieved. CONCLUSION: This automated approach can contribute to the acceleration of the drug discovery process while it simultaneously can diminish the loss of budget due to the redundancy occurred by the inexperienced researchers. PMID- 29478333 TI - Global Dietary Surveillance: Data Gaps and Challenges. AB - BACKGROUND: Detailed information on global individual-level consumption patterns is imperative for informed policy making. However, such data are dispersed and incomplete. OBJECTIVE: To review and discuss the methodologies, observed data availability, challenges, and opportunities pertaining to global dietary surveillance. METHODS: This investigation provides an extensive review of global dietary assessment methodologies and challenges, including at the survey level, the dietary collection and assessment level, and the dietary data processing and analysis level. The focus is on nationally representative individual-level data, and additional types of dietary data, such as dietary biomarkers, household assessment, and food availability, are reviewed as alternatives. Practical guidance is provided to inform key decisions when designing dietary surveys and collecting, analyzing, and using dietary data. This article further identifies and describes existing global and regional dietary initiatives/data sets. RESULTS: Harmonized and standardized primary individual-level dietary data collection, processing, and analysis worldwide are currently not available. Evaluation and decision-making should be based on best available data, that is, secondary nonharmonized yet to the extent possible, standardized individual-level dietary data. Existing initiatives differ substantially in methodologies, including survey design/representativeness, coverage, diet assessment, and dietary metric standardization and processing. Data gaps have been identified that were more profound for certain countries, certain dietary indicators across countries, population subgroups, representativeness, or time periods. CONCLUSIONS: Optimizing worldwide dietary habits to improve population health requires systematically identified and evaluated data on a continuing basis. Leveraging existing available dietary data and efforts is an indispensable prerequisite for informed priority setting targeting the intersections between diet and disease. PMID- 29478334 TI - The V-to-Y Advancement Flap for Distal Nasal Reconstruction: Our Experience With 39 Patients. AB - BACKGROUND AND OBJECTIVE: The V-to-Y advancement flap, also known as the island pedicle flap, is a single-stage repair option that can be used for defects on the distal nose. We report our experience using this flap for nasal defects following Mohs micrographic surgery, as well as describe optimal patient selection and flap design. MATERIALS AND METHODS: A retrospective review was conducted of all patient charts and operative photographs of nasal V-to-Y advancement flaps performed over 6 years at the Universtiy of Texas Southwestern Medical Center. Charts were reviewed for age, sex, tumour type and location, defect size, anticoagulation, immunosuppression, postoperative complications, revisions, and outcomes. RESULTS: Thirty-nine patients with defects ranging from 0.7 to 1.7 cm in size (median of 1 cm) were included. Most defects involved the inferior, paramedian nose, and after accounting for 7 postrepair interventions on 6 (15%) patients, 38 (97%) patients were noted to have good to excellent cosmetic outcomes while 1 patient experienced a persistent trapdoor effect. CONCLUSION: The V-to-Y advancement flap is an excellent single-stage option that can reliably provide good to excellent cosmetic results when used to repair small- to medium size sized defects on the distal half of the nose. PMID- 29478335 TI - Calciphylaxis in a Patient With Non-Hodgkin Lymphoma: Case Report and Literature Review. AB - BACKGROUND: Calciphylaxis is a well-known entity in end-stage kidney disease and after renal transplant. Cases of nonuremic calciphylaxis (NUC) have also been reported, but data on this rare condition are mainly empirical. OBJECTIVE: We discuss a case of NUC secondary to spontaneous tumour lysis syndrome in a patient who had chemotherapy for non-Hodgkin lymphoma and present a review of the literature to better characterize malignancy-associated NUC. METHODS: We identified 12 published cases of malignancy-associated NUC. RESULTS: This systematic review of malignancy-associated NUC did not show a relationship between the type of malignancy, the distribution of skin lesions, or mortality. However, distal more than proximal involvement seems to be more frequently associated with calcium phosphate imbalance. CONCLUSION: Clinicians must maintain a high index of suspicion for calciphylaxis when evaluating patients with cutaneous lesions developed in the setting of malignancy. PMID- 29478336 TI - Carbapenemase-producing Enterobacteriaceae in South Korea: a report from the National Laboratory Surveillance System. AB - AIM: To assess the epidemiology of carbapenemase-producing Enterobacteriaceae (CPE) in South Korea. MATERIALS & METHODS: From 2011 to 2015, 2487 carbapenem nonsusceptible Enterobacteriaceae were collected through the Korean National Laboratory Surveillance System. Disk-diffusion for antimicrobial susceptibility, PCR/sequencing to detect carbapenemase genes and multilocus sequence typing for molecular epidemiology were carried out. RESULTS: The number of carbapenem nonsusceptible Enterobacteriaceae was increasing approximately 1.5-fold per year and the proportion of CPEs was exponentially confirmed from 2014. KPC was the most dominant, mostly associated with Klebsiella pneumoniae ST11 and ST307, NDM was the second and OXA-48-like was the third dominant carbapenemases. The IMP, VIM and GES-5 CPEs were identified sporadically. CONCLUSION: The nation-wide spreads of KPC, NDM and OXA-48-like CPEs were in an alarming epidemiological stage. PMID- 29478337 TI - Do Men Produce Higher Quality Ejaculates When Primed With Thoughts of Partner Infidelity? AB - Sperm competition theory can be used to generate the hypothesis that men alter the quality of their ejaculates as a function of sperm competition risk. Using a repeated measures experimental design, we investigated whether men produce a higher quality ejaculate when primed with cues to sperm competition (i.e., imagined partner infidelity) relative to a control prime. Men ( n = 45) submitted two masturbatory ejaculates-one ejaculate sample for each condition (i.e., sperm competition and control conditions). Ejaculates were assessed on 17 clinical parameters. The results did not support the hypothesis: Men did not produce higher quality ejaculates in the sperm competition condition relative to the control condition. Despite the null results of the current research, there is evidence for psychological and physiological adaptations to sperm competition in humans. We discuss methodological limitations that may have produced the null results and present methodological suggestions for research on human sperm competition. PMID- 29478338 TI - Local Network-Level Integration Mediates Effects of Transcranial Alternating Current Stimulation. AB - Transcranial alternating current stimulation (tACS) has been proposed as a tool to draw causal inferences on the role of oscillatory activity in cognitive functioning and has the potential to induce long-term changes in cerebral networks. However, effectiveness of tACS underlies high variability and dependencies, which, as previous modeling works have suggested, may be mediated by local and network-level brain states. We used magnetoencephalography to record brain activity from 17 healthy participants at rest as they kept their eyes open (EO) or eyes closed (EC) while being stimulated with sham, weak, or strong alpha tACS using a montage commonly assumed to target occipital areas. We reconstructed the activity of sources in all stimulation conditions by means of beamforming. The analysis of resting-state brain activity revealed an interaction of the external stimulation with the endogenous alpha power increase from EO to EC. This interaction was localized to the posterior cingulate, a region remote from occipital cortex. This suggests state-dependent (EO vs. EC) long-range effects of tACS. In a follow-up analysis of this online-tACS effect, we find evidence that this state-dependency effect is mediated by functional network changes: connection strength from the precuneus was significantly correlated with the state-dependency effect in the posterior cingulate during tACS. No analogous correlation could be found for alpha power modulations in occipital cortex. Altogether, this is the first strong evidence to illustrate how functional network architectures can shape tACS effects. PMID- 29478339 TI - [Screening, diagnosis, treatment, and follow up of hepatitis C virus related liver disease. National consensus guideline in Hungary from 22 September 2017]. AB - The treatment of hepatitis C is based on a national consensus guideline updated six-monthly according to local availability and affordability of approved therapies through a transparent allocation system in Hungary. This updated guideline incorporates some special new aspects, including recommendations for screening, diagnostics, use and allocation of novel direct acting antiviral agents. The indication of therapy in patients with no contraindication is based on the demonstration of viral replication with consequent inflammation and/or fibrosis in the liver. Non-invasive methods (elastographies and biochemical methods) are preferred for liver fibrosis staging. The budget allocated for these patients is limited. Interferon-based or interferon-free therapies are available for the treatment. Due to their limited success rate as well as to their (sometimes severe) side-effects, the mandatory use of interferon-based therapies as first line treatment can not be accepted from the professional point of view. However, they can be used as optional therapy in treatment-naive patients with mild disease. As of interferon-free therapies, priority is given to those with urgent need based on a pre-defined scoring system reflecting mainly the stage of the liver disease, but considering also additional factors, i.e., hepatic decompensation, other complications, activity and progression of liver disease, risk of transmission and other special issues. Approved treatments are restricted to the most cost-effective combinations based on the cost per sustained virological response value in different patient categories with consensus amongst treating physicians, the National Health Insurance Fund of Hungary and patients' organizations. Interferon-free treatments and shorter therapy durations are preferred. Orv Hetil. 2018; 159(Suppl 1): 3-23. PMID- 29478340 TI - [Diagnosis and treatment of chronic hepatitis B and D. National consensus guideline in Hungary from 22 September 2017]. AB - Diagnosis and treatment of hepatitis B virus (HBV) and hepatitis D virus infection mean for the patient to be able to maintain working capacity, to increase quality of life, to prevent cancer, and to prolong life expectancy, while the society benefits from eliminating the chances of further transmission of the viruses, and decreasing the overall costs of serious complications. The guideline delineates the treatment algorithms from 22 September 2017 set by a consensus meeting of physicians involved in the treatment of these diseases. The prevalence of HBV infection in the Hungarian general population is 0,5-0,7%. The indications of treatment are based upon viral examinations (including viral nucleic acid determination), determinations of disease activity and stage (including biochemical, pathologic, and/or non-invasive methods), and excluding contraindications. To avoid unnecessary side effects and for a cost-effective approach, the guideline stresses the importance of quick and detailed virologic evaluations, the applicability of transient elastography as an acceptable alternative of liver biopsy in this regard as well as the relevance of appropriate consistent follow-up schedule for viral response during therapy. The first choice of therapy in chronic HBV infection can be pegylated interferon for 48 weeks or continuous entecavir or tenofovir therapy. The latter two must be continued for at least 12 months after hepatitis B surface antigen seroconversion. Lamivudine is no longer the first choice; patients currently taking lamivudine must switch if the response is inadequate. Appropriate treatment of patients taking immunosuppressive medications is highly recommended. Pegylated interferon based therapy is recommended for the treatment of concomitant hepatitis D infection. Orv Hetil. 2018; 159(Suppl 1): 24-37. PMID- 29478341 TI - The role of pleurodesis in respiratory diseases. AB - INTRODUCTION: Pleurodesis is used to obliterate the pleural space, most commonly in patients with symptomatic malignant pleural effusions but also in patients with benign effusions or pneumothorax. Areas covered: Traditionally, chemical pleurodesis has been undertaken at thoracoscopy or using instillation of a slurry through a chest drain. The optimum method of achieving pleurodesis, whether surgical or medical, has yet to be proven. Evidence in the different disease areas will be reviewed, along with ongoing trial evidence, which may change practice. Expert commentary: Newer methods of achieving pleurodesis are being introduced. Studies have shown that instilling sclerosing agents via an indwelling pleural catheter or introducing drug-eluting catheters are safe and effective ways of inducing pleurodesis. There is evidence that pleurodesis might increase in survival, especially after pleural infection, possibly due to activation of the immune system. Multiple studies are currently underway to answer some of these questions and the future landscape may be very different from the present. PMID- 29478342 TI - Outcomes in patients with early-onset fetal growth restriction without fetal or genetic anomalies. AB - OBJECTIVE: Early-onset fetal growth restriction is associated with poor pregnancy outcomes, but frequently is due to fetal structural or chromosomal abnormalities. The objective of this study was to determine outcomes in patients with early onset fetal growth restriction without diagnosed fetal or genetic anomalies and to identify additional risk factors for poor outcomes in these patients. METHODS: This was retrospective cohort study of singleton pregnancies in women with early onset growth restriction defined as a sonographic estimated fetal weight <10% diagnosed between 16-28 weeks' gestation. We excluded all women with a fetal structural or chromosomal abnormality diagnosed prenatally. Data on pregnancy characteristics and outcomes were collected and analyzed for estimated fetal weight <10% and <=5%. A nested case-control study within the cohort of patients with ongoing pregnancies was then performed to identify risk factors associated with poor pregnancy outcome using chi-squared test. RESULTS: One hundred forty two patients were identified who met inclusion and exclusion criteria and 20 patients were found to have fetal structural or chromosomal abnormalities. In the remaining 122 patients, the incidence of intrauterine fetal demise was 5.7% and there were high rates of preterm birth <37 weeks (20%), birth weight <10% (59.3%), and gestational hypertension (14.1%). Later gestational age at diagnosis and the presence of echogenic bowel and abnormal initial umbilical artery Dopplers were associated with poor pregnancy outcome (22.56 versus 20.86 weeks, p = .046), (17.4 versus 2.2%, OR 9.68, 95%CI 1.65-56.73), and (35.3 versus 0%, OR 4.46, 95%CI 2.65-7.50) respectively. CONCLUSIONS: Patients with early-onset fetal growth restriction with no fetal structural or genetic abnormality have a high risk of poor pregnancy outcomes. Gestational age at diagnosis and certain ultrasound findings are associated with poor pregnancy outcome. PMID- 29478343 TI - PD-L1 inhibition with avelumab for metastatic Merkel cell carcinoma. AB - INTRODUCTION: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer that lacks durable responses to traditional chemotherapy. Areas covered: After MCC was shown to be an immunogenic tumor, small trials revealed high objective response rates to PD-1/PD-L1 checkpoint inhibitors. The JAVELIN Merkel 200 (NCT02155647) trial tested the use of avelumab, a human IgG1 monoclonal antibody against PD-L1, in metastatic MCC. Avelumab recently became the first approved drug for metastatic MCC. Expert commentary: By conducting broad phase I studies assessing the safety of avelumab and a small phase II study demonstrating efficacy in this rare orphan tumor type, avelumab gained accelerated approval for the treatment of metastatic MCC. Additional studies are needed to determine how the antibody-dependent cellular cytotoxicity (ADCC) competent Fc region of avelumab contributes to disease control. Remaining questions: Longer follow-up will determine the durability of checkpoint blockade in controlling metastatic MCC. Additional studies will assess the utility and safety of adjuvant checkpoint blockade in patients with excised MCC. How to increase response rates by combining PD-1/PD-L1 blockade with other treatment approaches needs to be explored. In addition, treatment options for MCC patients who fail or do not respond to avelumab need to be identified. PMID- 29478344 TI - Guselkumab for the treatment of moderate-to-severe plaque psoriasis. AB - INTRODUCTION: Guselkumab is a human monoclonal antibody targeting the p19 subunit of IL-23 that has been approved for the treatment of adult patients with moderate to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. This medication blocks the IL-23/IL-17 axis, which has been implicated in playing a key role in the pathogenesis of psoriasis. Areas covered: This review outlines the pharmacologic properties, safety, and efficacy of guselkumab for the treatment of plaque psoriasis. Expert commentary: Guselkumab is the first IL-23 specific inhibitor to be approved for the treatment of plaque psoriasis. Phase II and III clinical trial results have demonstrated excellent safety and efficacy of guselkumab. IL-23 inhibitors may offer potential benefits over existing therapies for moderate-to-severe plaque psoriasis in terms of safety, frequency of administration, and efficacy. Long-term safety data will be critical in evaluating the role of guselkumab in the treatment of psoriasis. PMID- 29478345 TI - Cardiovascular magnetic resonance imaging in heart failure. AB - INTRODUCTION: Heart failure is a complex clinical syndrome resulting from heart structural remodeling and impaired function in ejecting blood; its incidence is increasing markedly worldwide. The observed variations in the structure and function of the heart are attributable to differences in etiology of heart failure. Cardiac magnetic resonance imaging (CMR) can characterize myocardial tissue, assess myocardial viability, and help diagnose specific cardiomyopathies. The emergence of T1 mapping techniques further improves our knowledge and the clinical assessment of myocardial diffuse fibrosis. Physicians, therefore, must identify the variations using CMR to improve patient's symptoms, survival, and quality of life. Area covered: Current reports regarding CMR and the evidence for heart failure diagnosis and therapy as a potential marker of therapeutic response, including low- and high-risk patients, were reviewed. Literature search was performed using PubMed and Google Scholar for literature relevant to CMR, late gadolinium enhancement, T1 mapping, assessment of fibrosis and remodeling, coronary artery, myocardial infarction, heart failure, and its outcomes. Expert commentary: The authors review current evidence and discuss the potential ability of CMR to guide, diagnose, plan risk strategies, and treat patients with heart failure. PMID- 29478346 TI - Perceptions and attitudes towards the implementation of a disability evaluation system based on the international classification of functioning, disability, and health among people with disabilities in Taiwan. AB - PURPOSE: To explore the perceptions and attitudes among people with disabilities towards the newly implemented International Classification of Functioning, Disability and Health-based disability evaluation system (the new system) in Taiwan. METHOD: Using a self-administered questionnaire, we conducted a nationwide survey. The questionnaire focused on the domains of quality, satisfaction, and revision of the new system. In total, 1073 persons (age, >=18 years) with disabilities or their primary caregivers, who experienced both the old and the new system, responded to the questionnaire. RESULTS: Most participants were satisfied with the new system overall (58.7%) and the subscale of quality of structure (91.3%) and quality of outcome (63.6%). However, only 20.5% of the participants were favourable to the quality of process. The probability of being satisfied with the system overall was low for the quality of process subscale (adjusted odds ratio range, 0.3 ~ 0.4) and its item of long interval (0.2 ~ 0.6). Contrariwise, the probability was high for the other subscales (3.9 ~ 13.7) and the item of identifying needs (21.9 ~ 23.4). CONCLUSIONS: Persons with disabilities and their primary caregivers have positive attitudes towards the new system. It is important to simplify the assessment tools and procedures to improve the system's quality of process and facilitate its usability. IMPLICATIONS FOR REHABILITATION Persons with disabilities have positive attitudes towards the newly implemented International Classification of Functioning, Disability, and Health-based disability evaluation system in Taiwan. The system that provides comprehensive information about functioning and disability of persons with disabilities is able to capture the difficulties and needs of those individuals in their daily lives. The system hence helps people to mitigate the effects of disability and guide rehabilitation. The assessment items and processes of the system, however, were perceived to be complicated, time consuming, and inconvenient. Simplifying the assessment items and processes, such as developing a short form version of the assessment tool and increasing the service time, may facilitate the usability of the system. PMID- 29478347 TI - Waning immunity of one-dose measles-mumps-rubella vaccine to mumps in children from kindergarten to early school age: a prospective study. AB - BACKGROUND: In China, one dose measles-mumps-rubella vaccine (MMR) was administered to children aged 18-24 months. The mumps incidence was still high. Data on the waning immunity to mumps after MMR vaccination are limited. This study aimed to describe the waning immunity to mumps in kindergarten and primary school children to provide a scientific basis for confirming an optimal age for a second dose. METHODS: An observational, prospective study on one-dose MMR in children in kindergarten and primary school was conducted from 2015 to 2016. Waning immunity to mumps in terms of seropositivity and geometric antibody concentration (GMC) with time was analyzed. RESULTS: In total, 7436 eligible subjects in kindergarten (3435) and primary school (4001) were included in 2015. The overall GMC (201.7 U/ml) and seropositivity (75.4%) to mumps antibodies in 2016 were significantly lower compared to those in 2015 (218.7 U/ml, 78.4%). Asymptomatic infection occurred within one year in 8.8% of children who received one-dose MMR. CONCLUSIONS: Children who received one-dose MMR in kindergarten and primary school were at high risk of mumps infection, and waning immunity occurred with time. Determining the optimal age for the second dose of MMR in children should be prioritized to prevent mumps epidemics. PMID- 29478348 TI - Cardiovascular benefits and risks of testosterone replacement therapy in older men with low testosterone. AB - Many studies have shown that low testosterone (T) levels have been associated with increased risk for cardiovascular (CV) events, type 2 diabetes mellitus (T2DM), and strokes. In contrast, many other studies have demonstrated that normal T levels or the normalization of low T levels with testosterone replacement therapy (TRT) is associated with decreased incidence of CV events, T2DM, and strokes, besides improving sexual function and the quality of life. However, recent studies have indicated that TRT could lead to increased incidence of CV events and strokes. These latter studies have created a great controversy among physicians regarding these findings, who question the validity of their results. In order to get a better perspective on the current status of TRT in hypogonadal men, a focused Medline and EMBASE search of the English language literature was conducted between 2010 and 2017 using the terms hypogonadism, low Testosterone, cardiovascular disease, testosterone replacement therapy, benefits, risks, older men, mechanism of action, and 58 papers with pertinent information were selected and 48 papers were rejected. The selected papers will be discussed in this review. In conclusion, based on the current status of TRT, the majority of studies indicate that TRT is safe and is associated with prevention of CVD and strokes in hypogonadal men. However, the evidence is not uniform and the therefore, decision to administer TRT should be discussed with the patient till more definitive information becomes available. PMID- 29478349 TI - Utilization of conventional radiography in a regional neonatal intensive care unit in Ireland. AB - OBJECTIVE: To audit the demand and radiation exposure of conventional radiography in a regional neonatal intensive care unit (NICU) in Ireland. METHODS: A retrospective study of radiographs performed on all admissions to the NICU in University Maternity Hospital Limerick (UMHL) over 2 years. RESULTS: A total of 1405 radiographs were performed on 506 infants. 153.5 radiographs per 1000 live births was the observed demand and 44% of radiographs were done out of hours. 47% of all radiographs were performed on infants <1500 g. Median number of radiographs per infant was one (IQR 1-2; range 1-39). Significant negative correlation was observed between number of radiographs and gestational age. Mean lung radiation doses estimated using published values for normal weight (>2500 g), very low birth weight (VLBW), and extremely low birth weight (ELBW) infants based on the median number of chest X-rays were 31.7 uGym, 84.66 and 232.75 uGy, respectively. CONCLUSIONS: Conventional radiography remains a key diagnostic tool in neonatology particularly in VLBW and ELBW infants and is invaluable in supporting timely clinical decision making. Clinicians should be aware of the cost and potential hazards of neonatal radiography and is recommend that the cumulative radiation exposure among the ELBW and VLBW infants is monitored. Increasing awareness and standardisation of point-of-care ultrasonography could decrease the reliance on conventional radiography in neonatal units. PMID- 29478350 TI - Integrated Cancer Treatment in the Course of Metastatic Pancreatic Cancer: Complete Resolution in 2 Cases. AB - Pancreatic cancer (PC) has a very low average survival, but its prognosis is further reduced in the case of metastatic spread. Medical therapy in these cases is the only applicable methodology in the international guidelines. During anticancer treatments, common side effects are nausea, vomiting, arthralgia, neuropathy, and alopecia as well as a myelosuppressive effect. The toxicity of various drugs not only affects the quality of life of the patient, but often its severity requires a reduction in if not the termination of drug administration. Scientific studies have shown that a combined use of chemotherapy and certain natural substances, in the form of standardized extracts, can lead to an enhancement of the action of the chemotherapy. Here, we describe 2 cases of metastatic PC. The first case concerns the integrated treatment of a patient with cancer of the pancreas tail with metastatic involvement ab initio of peripancreatic lymph nodes and liver parenchyma, with numerous secondary lesions greater than 9.5 cm. The second case concerns the integrated treatment of a patient with cancer of the pancreatic body with metastatic involvement of the liver parenchyma, with a small secondary lesion. In both cases, an integrated cancer treatment approach, combining chemotherapy with natural remedies, extracts, and hyperthermia, induced a notable remission of primary and metastatic lesions. PMID- 29478351 TI - Proteasome inhibitors for the treatment of multiple myeloma. AB - INTRODUCTION: Multiple Myeloma (MM) management is rapidly evolving, with a spectrum of novel treatments that have changed our approach to the therapy. Proteasome inhibitors (PIs) have revolutionized the scenario of both relapsed/refractory and newly diagnosed patients. The efficacy of bortezomib, the first PI approved, followed by carfilzomib and, the oral ixazomib, have been tested in several trials as single agents or in combination. Areas covered: In this review, the authors summarize mechanism of action, efficacy and safety of proteasome inhibitors in MM and focus on data derived from clinical trials, analyzing adverse events and their relative management. Expert opinion: The authors believe that, currently, the best course of action in the treatment of MM is to use PIs in combination with immunomodulatory drugs (IMiDs) and/or with monoclonal antibodies for all patients. However, based on the patient-specific characteristics, it is important to avoid inappropriate discontinuation by knowing the single side effects of every agent in order to balance their efficacy and safety. PMID- 29478352 TI - Adjuvant therapy for resected colon cancer 2017, including the IDEA analysis. AB - INTRODUCTION: Oxaliplatin-based adjuvant chemotherapy has been the standard of care for resected early colon cancer for over a decade. Recent results from the IDEA meta-analysis attempt to address the question of whether 3 or 6 months of adjuvant chemotherapy is preferable in Stage III colon cancer. Areas covered: A review of the literature and recent conference presentations was undertaken on the topic of adjuvant therapy for resected early colon cancers. This article reviews the current evidence for adjuvant treatment of Stage II and III colon cancer, as well as up-to-date data regarding optimal duration of therapy. This article reviews the evidence for lifestyle modifications in the management of early colorectal cancer and other future directions for research in early colon cancer. Expert commentary: In recent years, there have been no advances in the development of novel agents for adjuvant therapy in colorectal cancer. Although the IDEA meta-analysis was negative for its primary non-inferiority endpoint, the detailed results provide valuable information that allows personalisation of treatment regimen and duration. PMID- 29478354 TI - When Trust Is Not Enough: A Serial Mediation Model Explaining the Effect of Race Identity, eHealth Information Efficacy, and Information Behavior on Intention to Participate in Clinical Research. AB - Black participants remain significantly underrepresented in clinical research. Mistrust in medical researchers has been named a key barrier to the successful enrollment of minority study participants. However, trust is a social interactional construct, and its effects on behavior are complex. This study hypothesized that intention to participate in clinical research is mediated by trust in medical researchers, eHealth literacy, and information seeking behavior. The data were collected through an online survey ( N = 340) and analyzed to identify serial mediation. The model showed insignificant direct effect of race identity on behavioral intention, c' = -0.19, t(335) = -1.22, p = .22, but a significant total effect, c = -0.44, t(335) = -2.59, p < .01. The indirect effect of race identity on behavioral intention was also significant. The positive effect of trust in medical researchers on decisions to participate in clinical research can be amplified by stronger eHealth literacy and active information seeking, which can be supported through focused strategic health education and communication interventions. A focus on the development of information literacy that could provide prospective minority research volunteers with skills for informed decision making should be explored as an option for increasing mindful, informed participation in clinical research among currently underrepresented racial and ethnic groups. PMID- 29478353 TI - Predictors of Long-Term Adherence to Multiple Health Behavior Recommendations for Weight Management. AB - BACKGROUND: We have demonstrated previously that patterns of behavioral adherence in the first 6 months of behavioral lifestyle interventions were associated with significant weight loss at 18 months. In this article, we extend this work to examine patterns of behavioral adherence over 18 months and to explore baseline demographic and psychosocial predictors. METHOD: Latent class analysis was applied separately to the Weight Loss Maintenance and PREMIER trials data to examine patterns of adherence to the following recommendations: (1) consuming >=9 servings of fruits and vegetables per day, (2) <=25% of energy from total fat, (3) <=7% energy from saturated fat, and (4) >=180 minutes of moderate-to-vigorous physical activity per week. Multinomial logistic regression was used to test demographic and psychosocial predictors of latent class membership. RESULTS: Four distinct subgroups with common patterns of behavioral adherence were identified in each trial including, Behavioral Maintainers, who maintained adherence to all behavioral recommendations for 1 year, Nonresponders, who did not adhere to the recommendations at any time point, and latent classes that reflected patterns of adherence to one or two behaviors or behavioral relapse. A significantly higher proportion of Behavioral Maintainers sustained >=5% weight loss for 1 year compared with Nonresponders. Participants with higher vitality scores at baseline were more likely to belong to a latent class with long-term adherence to one or more recommendations than the Nonresponders class. CONCLUSIONS: Regular assessment of health behaviors and psychosocial measures such as vitality may help identify nonresponders and inform treatment tailoring to improve long-term behavioral and weight outcomes. PMID- 29478355 TI - Treating breakthrough pain in oncology. AB - INTRODUCTION: Breakthrough cancer pain (BTcP) is an episode of severe intensity in patients receiving an adequate treatment with opioids able to provide at least mild analgesia. BTcP is a heterogeneous condition as episodes vary between individuals. The aim of this article is to review the pharmacologic options for the management of BTcP. Areas covered: Recent reviews revealed that transmucosal preparations of fentanyl provided superior and more rapid pain relief as compared to placebo and oral morphine within the first 30 min after dosing. Few comparison studies among fentanyl products have been performed. Although dose titration has been recommended for years, a meaningful dosing, according to the level of opioid tolerance, may enhance the advantages of such products Expert commentary: BTcP represents a relevant problem reported by many cancer patients despite receiving regular use of opioids. Different modalities of pharmacological interventions are available. In comparison with oral opioids, fentanyl preparations appear to have a short onset and offset of analgesic effect, fitting the temporal characteristics of BTcP. Further studies are warranted to assess the net benefit of these drugs to assist decision-making by patients, clinicians, and payers, according to individual clinical conditions. PMID- 29478356 TI - Reliability of one-repetition maximum performance in people with chronic heart failure. AB - PURPOSE: Evaluate intra-rater and inter-rater reliability of the one-repetition maximum strength test in people with chronic heart failure. DESIGN: Intra-rater and inter-rater reliability study. SETTING: A public tertiary hospital in northern metropolitan Melbourne. PARTICIPANTS: Twenty-four participants (nine female, mean age 71.8 +/- 13.1 years) with mild to moderate heart failure of any aetiology. METHODS: Lower limb strength was assessed by determining the maximum weight that could be lifted using a leg press. Intra-rater reliability was tested by one assessor on two separate occasions . Inter-rater reliability was tested by two assessors in random order. STATISTICAL ANALYSES: Intra-class correlation coefficients and 95% confidence intervals were calculated. Bland and Altman analyses were also conducted, including calculation of mean differences between measures ([Formula: see text]) and limits of agreement . RESULTS: Ten intra-rater and 21 inter-rater assessments were completed. Excellent intra-rater (intra-class correlation coefficient2,1 0.96) and inter-rater (intra-class correlation coefficient2,1 0.93) reliability was found. Intra-rater assessment showed less variability (mean difference 4.5 kg, limits of agreement -8.11 to 17.11 kg) than inter-rater agreement (mean difference -3.81 kg, limits of agreement -23.39 to 15.77 kg). CONCLUSION: One-repetition maximum determined using a leg press is a reliable measure in people with heart failure. Given its smaller limits of agreement, intra-rater testing is recommended. Implications for Rehabilitation Using a leg press to determine a one-repetition maximum we were able to demonstrate excellent inter-rater and intra-rater reliability using an intra class correlation coefficient. The Bland and Altman levels of agreement were wide for inter-rater reliability and so we recommend using one assessor if measuring change in strength within an individual over time. PMID- 29478357 TI - Insights into thermal stress in Japanese quail (Coturnix coturnix): dynamics of immunoendocrine and biochemical responses during and after chronic exposure. AB - Avian require comfortable temperatures for optimal development and heat stress is a high concern in warm weather countries. We aimed to assess the dynamics of immunoendocrine and biochemical variables responses of birds exposed to a heat stressor applied during daylight hours, during the chronic stress and the recovery periods. We hypothesize that variables involved in the birds response will be differentially and gradually modified during those periods. Female quail (n = 210) were housed in six rearing boxes. At 29 days of age, the temperature in three boxes was increased from 24 to 34 degrees C during the light period throughout the nine days (Stress Treatment). The other three boxes remained at 24 degrees C and were used as controls. The subsequent 12 days were considered as recovery period. Different sets of 12 birds/treatment were blood-sampled at 29 (basal), 32, 35, 38 (stress), 41, 44, 47, and 50 (recovery) days of age, respectively. Immunoendocrine (corticosterone, lymphoproliferation, heterophil/lymphocyte ratio (H/L), and antibody response) and biochemical (glucose, total proteins, globulins, and albumin) variables were assessed. During stress, progressive corticosterone and H/L increments, and antibody titers and lymphoproliferation decreases were detected. No clear pattern of changes was found in biochemical variables. During recovery, while corticosterone and lymphoproliferation had recovered three days after the stressor ended, H/L and antibody responses required respectively nine and 12 days to recover to their basal levels, respectively. Findings suggest that immunity is already threatened when heat stress is sustained for three or more days. However, the system appears resilient, needing six to 12 days to recover to their basal responses. PMID- 29478358 TI - Body temperatures of very low birth weight infants on admission to a neonatal intensive care unit. AB - OBJECTIVE: Hypothermia occurs frequently in the first minutes after birth in preterm infants. Hyperthermia also occurs, often as a consequence of efforts to provide thermal support. Both hypothermia and hyperthermia are potentially harmful. Our objective was to examine the distribution of admission temperatures of very low birth weight (VLBW) infants, the effect of gestational age on admission temperatures, and the time required for correction of low temperatures. METHODS: Admission axillary temperatures were retrieved from the medical records for all VLBW infants born in our hospital during a 5-year period. The temperatures were classified as severe (<35.0 degrees C), moderate (35.0-35.9 degrees C), or mild (36.0-36.4 degrees C) hypothermia, normothermia (36.5-37.4 degrees C), or hyperthermia (>=37.5 degrees C). The relationship between gestational age and admission temperature was examined. In addition, we analyzed the time required for normalization of low temperatures. RESULTS: Overall, 12% of infants were severely hypothermic, 40% moderately hypothermic, 27% mildly hypothermic, 19% normothermic, and 2% hyperthermic. Gestational age was inversely related to hypothermia risk and to the time required for recovery to normothermia. CONCLUSION: Admission hypothermia is common among VLBW infants and is affected by gestational age. PMID- 29478359 TI - Trends in comorbidity, acuity, and maternal risk associated with preeclampsia across obstetric volume settings. AB - OBJECTIVE: The objective of this study was to characterize morbidity, acuity, and maternal risks associated with preeclampsia across hospitals with varying obstetric volumes. METHODS: This retrospective cohort analysis used a large administrative data source, the Perspective database, to characterize the risk for preeclampsia from 2006 to 2015. Hospitals were classified as having either low (<=1000), moderate (1001-2000), or high (>=2000) delivery volume. The primary outcomes included preeclampsia, antihypertensive administration, comorbidity, and related severe maternal morbidity. Severe maternal morbidity was estimated using criteria from the Centers for Disease Control and Prevention. Comorbidity was estimated using an obstetric comorbidity index. Univariable comparisons were made with Chi-squared test. Adjusted log linear regression models were fit to assess factors associated with severe morbidity with risk ratios with 95% confidence intervals as the measures of effect. Population weights were applied to create national estimates. RESULTS: Of 36,985,729 deliveries included, 1,414,484 (3.8%) had a diagnosis of preeclampsia. Of these, 779,511 (2.1%) had mild, 171,109 (0.5%) superimposed, and 463,864 (1.3%) severe preeclampsia. The prevalence of mild, superimposed, and severe preeclampsia each increased over the study period with severe and superimposed preeclampsia as opposed to mild preeclampsia increasing the most proportionately (53.2 and 102.5 versus 10.8%, respectively). The use of antihypertensives used to treat severe range hypertension increased with use of intravenous labetalol increasing 31.5%, 43.2%, and 36.1% at low-, medium-, and high-volume hospitals. Comorbid risk also increased across hospital volume settings as did risk for severe maternal morbidity. CONCLUSIONS: Preeclampsia is increasing across obstetric care settings with preeclamptic patients demonstrating increasing comorbid risk, increased risk for severe morbidity, and more frequent need for treatment of acute hypertension. PMID- 29478360 TI - The elite player performance plan: the impact of a new national youth development strategy on injury characteristics in a premier league football academy. AB - The objective of this study was to investigate the injury incidence and patterns in elite youth football at a category 1 Premier League Academy before and after the introduction of a new development strategy, the Elite Player Performance Plan (EPPP). A prospective study was performed over six consecutive seasons encompassing three years before and after the introduction of the EPPP. The findings revealed a most likely moderate increase in total exposure per player per season when the post-EPPP football exposure (640.86 +/- 83.25 hours per player per year) was compared with the pre-EPPP football exposure (539.08 +/- 71.59). The total injury incidence pre-EPPP was 3.0/1000 hours compared to 2.1/1000 hours post-EPPP (rate ratio 1.43). 6% of all injuries were re-injuries (20.24 +/- 33.43 days) but did not result in a substantially longer absence (16.56 +/- 15.77 days). The injury burden decreased for the U12-U15 from pre- to post-EPPP, whereas the injury burden increased for the U16-U18 (respectively 125 and 47% higher). These findings suggest that following the introduction of the EPPP there has been a reduction in injuries in the younger age groups U12-U15 but in the older age groups U16-U18 there has been an increase in the severity of the injuries sustained at this club. PMID- 29478361 TI - Hepatic rupture associated with preeclampsia, report of three cases and literature review. AB - BACKGROUND: Hepatic rupture is a complication during pregnancy that, although rare, accounts for high morbidity and mortality rates. It is mainly associated with severe preeclampsia and HELLP syndrome. Incidence is estimated to be at one per 67,000 births or one per 2000 patients with preeclampsia/eclampsia/HELLP, mainly in multiparous women; women in their 40s; after 32 weeks of gestation; and during the first 15 h postpartum. CASES: This article exposes the institutional experience at Fundacion Valle del Lili in Cali, Colombia, in managing and treating hepatic rupture associated with severe preeclampsia and HELLP syndrome in three patients in the 30th, the 26th, and the 27th week of gestation, not resulting in maternal death. DISCUSSION: A search in Pubmed, Embase, and Ovid from 2000 to 2017 resulted in 35 cases reported in either pregnant or puerperal women. Hepatic rupture is a rare complication in pregnancy associated with preeclampsia and HELLP syndrome. Its pathophysiology is attributed to the presence of vasospasm due to an increase in concentration and sensitivity to circulating vasopressors during pregnancy. There is no standard management, but surgery reduces mortality significantly. It includes endovascular management, partial hepatectomy, or transplant (only one patient required a liver transplant in our search). The most used techniques have been ligation of the hepatic artery, embolization of the hepatic artery, and examination, packing, and drainage of hepatic lesion for bleeding control (27 cases were treated with laparotomy with evacuation of hematoma and hemostasis and four cases were treated with embolization of the hepatic artery). Hepatic artery occlusion both by surgery ligation and by embolization through interventional radiology has reported successful and failing results during pregnancy Conclusion: Management of pathologies as hepatic rupture associated with severe preeclampsia and HELLP syndrome has to be clearly protocolized for prompt diagnosis and early management. Furthermore, it has to be carried out through multidisciplinary teams in high-complexity obstetrics scenarios. PMID- 29478362 TI - Dispensing Naloxone Without a Prescription: Survey Evaluation of Ohio Pharmacists. AB - BACKGROUND: The Centers for Disease Control and Prevention (CDC) reports a 200% escalation in the rate of opioid overdose deaths in the United States. Unfortunately, Ohio has been deemed the epicenter of the nation's opioid epidemic. In 2015, Ohio passed a bill that permits a pharmacist to distribute naloxone without a prescription. OBJECTIVES: This survey was aimed to discover pharmacists' knowledge of naloxone and Ohio law, perceived barriers that may prohibit naloxone dispensing, and Ohio pharmacists' general confidence, comfort, perception, and experience dispensing naloxone per physician protocol. METHODS: Pharmacists' knowledge of naloxone and Ohio law pertaining to dispensing naloxone; perceived barriers to naloxone distribution; and overall experience, willingness, comfort, and perceptions of personally supplying naloxone were assessed using multiple-choice and Likert-type scale questions through an e-mail survey. RESULTS: Overall, Ohio pharmacists were knowledgeable about naloxone and displayed confidence in their training and ability to provide patient education on naloxone. Pharmacists were less certain about Ohio law pertaining to naloxone distribution, especially those who have been in practice longer. Pharmacists indicated several barriers to dispensing naloxone and the need for more training. Younger pharmacists were more likely to report a concern with clientele who would frequent their pharmacy and moral and ethical concerns as barriers to dispensing naloxone. CONCLUSION: Additional educational programs should be delivered to Ohio pharmacists to inform them of the state law and policies. Continuing education programs that review substance abuse and attempt to reduce social stigma may assist with increasing naloxone distribution to those in need, especially, if directed toward younger pharmacists in Ohio. PMID- 29478363 TI - Fetal biacromial diameter as a new ultrasound measure for prediction of macrosomia in term pregnancy: a prospective observational study. AB - OBJECTIVE: The current study aims to evaluate a simple method for sonographic measurement of the fetal biacromial diameter for prediction of fetal macrosomia in term pregnancy. MATERIALS AND METHODS: The current study was a single center prospective observational study conducted in a tertiary University Hospital from January 2015 to May 2017. We included all consecutive term (37-42 weeks) pregnant women presented to the labor ward for delivery. Ultrasound parameters were measured as biparietal diameter, head circumference, transverse thoracic diameter, mid arm diameter, abdominal circumference, femur length, estimated fetal weight, and amniotic fluid index. The proposed ultrasound formula "Youssef's formula" to measure the fetal biacromial diameter is: [Transverse thoracic diameter +2 * midarm diameter]. The accuracy of proposed formula was compared to the actual biacromial diameter of the newborn after delivery. The primary outcome of the study was accuracy of sonographic measurement of fetal biacromial diameter in prediction of fetal macrosomia in terms of sensitivity and specificity Results: The study included 600 participants; 49 (8.2%) of them delivered a macrosomic neonates and 551 (91.8%) delivered average weight neonates. There was no statistical significant difference between the proposed fetal biacromial diameter measured by ultrasound and the actual neonatal biacromial diameter measured after birth (p = .192). The area under the curve (AUC) for prediction of macrosomia at birth based on the fetal biacromial diameter and the abdominal circumference was 0.987 and 0.989, respectively, on receiver operating characteristic (ROC) curve analysis. Using the biacromial diameter cutoff of 15.4 cm has a PPV for prediction of macrosomia (88.4%) and 96.4% sensitivity with overall accuracy of 97%. Similarly, with the abdominal circumference (AC) cutoff of 35.5 cm, the PPV for prediction of macrosomia (87.7%) and 96.4% sensitivity with overall accuracy of 96.83%. No statistical significant difference between both of them was observed for prediction of fetal macrosomia (p = .841) Conclusions: The sonographic measurement of fetal biacromial diameter seems to be a new simple and accurate method for prediction of fetal macrosomia and shoulder dystocia at birth. PMID- 29478364 TI - What constitutes evidence that fear appeals have positive effects on health behaviour? Commentary on Kok, Peters, Kessels, ten Hoor, and Ruiter (2018). PMID- 29478365 TI - Validity of cardiometabolic index, lipid accumulation product, and body adiposity index in predicting the risk of hypertension in Chinese population. AB - OBJECTIVES: Adiposity, defined by higher cardiometabolic index (CMI), lipid accumulation product (LAP), and body adiposity index (BAI), has conferred increased metabolic risk. However, the incremental utility of CMI, LAP, and BAI in association with prevalent hypertension has not been well described in a population-based setting. We hypothesized that CMI, LAP, and BAI would provide important insight into hypertension risk. METHODS: Blood pressure (BP), fasting lipid profiles, and anthropometric parameters were recorded in a cross-sectional study of 11,400 participants (mean age, 54 years; 53% women) from China. Logistic regression models were used to assess associations of CMI, LAP, and BAI with prevalent hypertension. BAI was evaluated according to hip (cm)/[height (m)1.5] 18; LAP was calculated separately for men [(WC-65) * TG] and women [(WC-58) * TG]; and CMI was defined by TG/HDL-C * waist-to-height ratio. RESULTS: CMI, LAP, and BAI were independently correlated with higher SBP and DBP, with nonstandardized (B) coefficients ranging from 1.827 to 4.590 mmHg and 1.475 to 2.210 mmHg (all P < 0.001). After adjustment for hypertension risk factors and potential confounders, CMI, LAP, and BAI, modeled as continuous measures, carried hypertension odds (95% CI) of 1.356 (1.259-1.459), 1.631 (1.501-1.771), and 1.555 (1.454-1.662) in women, respectively, per SD increment. In men, each SD increase in CMI, LAP, and BAI experienced a 31%, 65%, and 53% higher hypertension risk, respectively. Moreover, among women, the odds ratio (95% CI) for hypertension were 2.318 (1.956-2.745), 3.548 (2.985-4.217), and 3.004 (2.537-3.557) in the 4th quartile vs the first quartile of CMI, LAP, and BAI, respectively. For men, the corresponding figures were 2.200 (1.838-2.635), 3.892 (3.238-4.677), and 3.288 (2.754-3.927), respectively. CONCLUSION: Measurements of CMI, LAP, and BAI provide a more complete understanding of hypertension risk related to variation in body fat distribution and pinpoint hypertensive participants in great risk of cardiovascular disease in the future. PMID- 29478366 TI - Misinterpreting theory and ignoring evidence: fear appeals can actually work: a comment on Kok et al. (2018). PMID- 29478367 TI - MicroRNA-30a Mediates Cell Migration and Invasion by Targeting Metadherin in Colorectal Cancer. AB - MicroRNAs play critical roles in the occurrence and progression in various cancers including colorectal cancer. Here, we found that microRNA-30a expression was significantly downregulated in colorectal cancer tissues compared to adjacent noncancerous tissues, and the suppression levels of microRNA-30a were significantly associated with tumor differentiation and lymph node metastasis. We also discovered that the expression level of microRNA-30a was inversely proportional to the invasive potential of several colorectal cancer cell lines. Moreover, overexpression of microRNA-30a in colorectal cancer cells inhibited activity of cell migration and invasion. Luciferase reporter assay confirmed metadherin could be a direct target of microRNA-30a, as the overexpression of microRNA-30a decreased metadherin expression at both the protein and messenger RNA levels. Furthermore, the knockdown of metadherin expression in SW620 significantly decreased cell metastasis and invasion. The upregulation of metadherin at the protein level negatively correlated with the expression of microRNA-30a in colorectal cancer tissues, and this upregulation could partially attenuate the effect induced by microRNA-30a. These findings indicate that microRNA-30a may act as a tumor suppressor in colorectal cancer and that microRNA 30a represses cell migration and invasion by decreasing metadherin, highlighting the therapeutic potential of microRNA-30a and metadherin in colorectal cancer treatment. PMID- 29478368 TI - Identification of the Differential Expression Profiles of Serum and Tissue Proteins During Rat Hepatocarcinogenesis. AB - The pathogenesis of hepatocellular carcinoma is complex and not fully known yet. This study aims to screen and identify the differentially expressed proteins in peripheral blood and liver tissue samples from rat hepatocellular carcinoma and to further clarify the pathogenesis and discover the specific tumor markers and molecular targets of hepatocellular carcinoma. The hepatocellular carcinoma model of Wistar rats were induced by chemical carcinogen. The serum and liver tissue samples were obtained after induction for 2, 4, 8, 14, 18, and 21 weeks. The results showed that the clusterin (IPI00198667), heat shock protein a8 (IPI00208205), and N-myc downstream-regulated gene-2 (IPI00382069) being closely related to hepatocarcinogenesis were eventually identified from the 30 different proteins. As the time progressed, the serum levels of clusterin and heat shock protein a8 increased gradually during induced liver cancer in rats. However, the serum N-myc downstream-regulated gene 2 level in induced liver cancer in rats underwent biphasic changes, and the serum N-myc downstream-regulated gene 2 level decreased at the 8th week, increased at the 14th week, and then decreased significantly. Statistical difference occurred in protein expression of clusterin and heat shock protein a8 in liver tissues at the different time points. In the liver tissues, the N-myc downstream-regulated gene 2 level decreased gradually at the 8th week, increased gradually at the 14th week, and then decreased significantly after 14 weeks. The study demonstrated that heat shock protein a8, clusterin, and N-myc downstream-regulated gene 2 participated in the process of abnormal cell division, proliferation, and carcinogenesis of liver cells during hepatocarcinogenesis. PMID- 29478369 TI - The growth and pluripotency of mesenchymal stem cell on the biodegradable polyurethane synthesized with ferric catalyst. AB - Polyurethane (PU) is a class of polymers that have been applied for tissue engineering scaffolds. Cross-linked poly(ester urethane) (CPU), synthesized with ferric catalyst in our laboratory, was modified by silk fibroin (SF) grafting using our aminolysis and glutaradehyde crosslinking method. The physical and chemical properties of the materials were investigated by scanning electron microscope (SEM), atomic force microscope (AFM) and tensile tester. The results showed that SF grafted CPU possessed good strain and strength (4.29 +/- 0.18 MPa/382.38 +/- 0.71%). Its surface chemistry and roughness were fine to well support the growth of bone marrow mesenchymal stem cells (BMSC). The cells were verified to maintain the pluripotency after they were cultured in vitro for 2 weeks, which supplied us a good technology to keep cell's stemness but proliferate cell's number. These results are valuable for us to further study esophageal tissue engineering with BMSC and polyurethane materials as the components. PMID- 29478371 TI - Pictorial cigarette pack warnings increase quitting: a comment on Kok et al. PMID- 29478370 TI - Parallel detection of lactobacillus and bacterial vaginosis-associated bacterial DNA in the chorioamnion and vagina of pregnant women at term. AB - BACKGROUND: The majority of early preterm births are associated with intrauterine infections, which are thought to occur when microbes traffic into the uterus from the lower genital tract and seed the placenta. Bacterial vaginosis (BV) is associated with heterogeneous bacterial communities in the vagina and is linked to preterm birth. The extent to which trafficking into the uterus of normal and BV-associated vaginal bacteria occurs is unknown. The study objective was to characterize in parallel the distribution and quantities of bacteria in the vagina, uterus, and placental compartments. METHODS: Pregnant women at term (>=37 weeks) presenting for delivery were recruited prospectively. Swabs were collected in parallel from the vagina, chorioamnion. Choriodecidual swabs were collected if a cesarean section was performed. Samples were analyzed by culture, broad-range 16S rRNA gene PCR, and bacterial species-specific quantitative PCR (qPCR) for DNA from Lactobacillus and a panel of BV-associated bacteria. Results were correlated with placental histopathology. RESULTS: Of the 23 women enrolled, 15 were delivered by cesarean section (N = 10 without labor; N = 5 in labor) and eight were delivered vaginally. BV was diagnosed in two women not in labor. Placental histopathology identified chorioamnionitis or funisitis in six cases [1/10 (10%) not in labor; 5/13 (38%) in labor]. Among non-laboring women, broad-range 16S qPCR detected bacteria in the chorioamnion and the choriodecidua (4/10; 40%). Among laboring women, Lactobacillus species were frequently detected in the chorioamnion by qPCR (4/13; 31%). In one case, mild chorioamnionitis was associated with qPCR detection of similar microbes in the chorioamnion and vagina (e.g. Leptotrichia/Sneathia, Megasphaera), along a quantitative gradient. CONCLUSIONS: Microbial trafficking of lactobacilli and fastidious bacteria into the chorioamniotic membranes and choriodecidua occurs at term in normal pregnancies. In one case, we demonstrated a quantitative gradient between multiple bacterial species in the lower genital tract and placenta. Not all bacterial colonization is associated with placental inflammation and clinical sequelae. Further studies of the role of placental colonization with Lactobacillus in normal pregnancy and fastidious bacteria in chorioamnionitis may improve prevention and treatment approaches for preterm labor. PMID- 29478372 TI - Age-Related Differences in Spatiotemporal Variables and Ground Reaction Forces During Sprinting in Boys. AB - PURPOSE: We aimed to elucidate age-related differences in spatiotemporal and ground reaction force variables during sprinting in boys over a broad range of chronological ages. METHODS: Ground reaction force signals during 50-m sprinting were recorded in 99 boys aged 6.5-15.4 years. Step-to-step spatiotemporal variables and mean forces were then calculated. RESULTS: There was a slower rate of development in sprinting performance in the age span from 8.8 to 12.1 years compared with younger and older boys. During that age span, mean propulsive force was almost constant, and step frequency for older boys was lower regardless of sprinting phase. During the ages younger than 8.8 years and older than 12.1 years, sprint performance rapidly increased with increasing mean propulsive forces during the middle acceleration and maximal speed phases and during the initial acceleration phase. CONCLUSION: There was a stage of temporal slower development of sprinting ability from age 8.8 to 12.1 years, being characterized by unchanged propulsive force and decreased step frequency. Moreover, increasing propulsive forces during the middle acceleration and maximal speed phases and during the initial acceleration phase are probably responsible for the rapid development of sprinting ability before and after the period of temporal slower development of sprinting ability. PMID- 29478374 TI - Ignoring theory and evidence: commentary on Kok et al. (2018). PMID- 29478373 TI - Gamma irradiation of aloe-emodin induced structural modification and apoptosis through a ROS- and caspase-dependent mitochondrial pathway in stomach tumor cells. AB - PURPOSE: The changes in molecular structure and the physiological properties of a gamma-irradiated aloe-emodin were examined. MATERIALS AND METHODS: Aloe-emodin was gamma-irradiated at doses ranging from 0 to 150 kGy, and the molecular structure was then analyzed using high-performance liquid chromatography (HPLC). AGS cells were cultured in RPMI medium and treated gamma irradiated aloe-emodin. Cell viability was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Apoptosis efficiency was investigated by cell cycle arrest, cell morphology, and signaling pathway. The structure of new radiolytic peak was identified by the hydrogen-nuclear magnetic resonance (1H NMR). RESULTS: HPLC results showed that gamma irradiation induced new radiolytic peaks that were distinguishable from the aloe-emodin standard, and the area of new peaks was increased as the radiation dose increased. Gamma-irradiated aloe emodin treatment significantly increased the cytotoxicity in AGS tumor cells. We also found that 150 kGy aloe-emodin increased the expression of Bax, cytosolic cytochrome c, PARP cleavage, and the activation of caspases-8, -9, -3, Bid, and Bcl-2. Treatment of 150 kGy aloe-emodin induced ROS production, DNA fragmentation, alterations of cell morphology, and the migration in AGS cells. Gamma-irradiated aloe-emodin induced an increase of sub-G1 phase and depolarization of mitochondrial membrane potential in AGS cells. We also confirmed that fractionated AEF1 (new radiolytic peak) induce the cell death, migration, an increase of sub-G1 phase and cytochrome c in a ROS-dependent manner. CONCLUSIONS: The radiolysis product (AEF1) of aloe-emodin transformed by gamma-irradiation strongly induced apoptotic cell death in AGS cells, indicating AEF1 is a potential candidate drug for use in anti-cancer drug. PMID- 29478375 TI - Engineering the Second Generation of Therapeutic Cells with Enhanced Targeting of Injured Tissues. AB - Experimental approaches to improving tissue repair utilize cells and growth factors needed to restore the architecture and function of damaged tissues and organs. Key limitations of these approaches include poor delivery of therapeutic cells and growth factors into injury sites, as well as their short-term retention in target areas. In our earlier studies, we demonstrated that artificial collagen specific anchor (ACSA) expressed on the surface of therapeutic cells directs them into collagen-rich sites of injury. Moreover, we demonstrated that the ACSA improves the retention of these cells in target sites, thereby promoting tissue repair. To advance the ACSA-based technology, we engineered the second generation of the ACSA-expressing cells able to deliver growth factors to target sites. In this study, we specifically focused on insulin growth factor 1 (IGF1), which enhances the repair of a number of collagen-rich connective tissues, including ligament and tendon. Utilizing gene engineering, we produced IGF1 in the ACSA expressing cells. Using relevant experimental models, we demonstrated that recombinant IGF1 secreted by these cells maintains its specificity and biological activity. Moreover, our studies show that IGF1 produced by the ACSA-expressing cells cultured in three-dimensional environment promotes the formation of the collagen-rich fibrillar matrix. Furthermore, the engineered cells integrated well with the native collagen-rich tendon tissue. Our study provides strong evidence for the great potential of cells with rationally engineered target-specific receptors to restore damaged connective tissues. Future studies in relevant animal models will determine the utility of these cells in vivo. PMID- 29478376 TI - RPPAware: A software suite to preprocess, analyze and visualize reverse phase protein array data. AB - Reverse Phase Protein Arrays (RPPA) is a high-throughput technology used to profile levels of protein expression. Handling the large datasets generated by RPPA can be facilitated by appropriate software tools. Here, we describe RPPAware, a free and intuitive software suite that was developed specifically for analysis and visualization of RPPA data. RPPAware is a portable tool that requires no installation and was built using Java. Many modules of the tool invoke R to utilize the statistical features. To demonstrate the utility of RPPAware, data generated from screening brain regions of a mouse model of Down syndrome with 62 antibodies were used as a case study. The ease of use and efficiency of RPPAware can accelerate data analysis to facilitate biological discovery. RPPAware 1.0 is freely available under GNU General Public License from the project website at http://downsyndrome.ucdenver.edu/iddrc/rppaware/home.htm along with a full documentation of the tool. PMID- 29478377 TI - Design of functionalized folic acid-chitosan nanoparticles for delivery of tetracycline, doxorubicin, and tamoxifen. PMID- 29478379 TI - Can We Talk About It Now? Recognizing the Optimal Time to Initiate End-of-Life Care Discussions with Older Chinese Americans and Their Families. AB - INTRODUCTION: Older Chinese Americans often defer end-of-life care discussions. Researchers sought to explore how to engage older Chinese Americans and their families in end-of-life care discussions and to understand the optimal timing to initiate such discussions. METHODS: Individual, semistructured interviews were conducted with 14 community-dwelling older Chinese Americans, 9 adult children, and 7 clinicians. The data were collected and analyzed using focused ethnographic methodology. RESULTS: Older Chinese Americans and their families would discuss end-of-life care when introduced at "optimal times," which included after triggering events (e.g., death of loved ones, fall accidents), changes in health status, or advanced age. DISCUSSION: Adult children are not expected to initiate end-of-life care discussions with their parents. Thus, culturally congruent health care that could better engage Chinese Americans in such discussions would be optimized by having clinicians proactively assess their patients' readiness and initiate such discussion at optimal times. PMID- 29478378 TI - The Effects of 3-Month Skill-Based and Plyometric Conditioning on Fitness Parameters in Junior Female Volleyball Players. AB - PURPOSE: This study compared the effects of skill-based and plyometric conditioning (both performed in addition to regular volleyball training twice a week for 12 wk) on fitness parameters in female junior volleyball players. METHODS: The participants [n = 47; age: 16.6 (0.6) y; mass: 59.4 (8.1) kg; height: 175.1 (3.0) cm] were randomized into a plyometric (n = 13), a skill-based (n = 17), and a control (n = 17) groups. The variables included body height, body mass, calf girth, calf skinfold, corrected calf girth, countermovement jump, 20-m sprint, medicine ball toss, and sit-and-reach test. RESULTS: Two-way analysis of variance (time * group) effects for time were significant (P < .05) for all variables except body mass. Significant group * time interactions were observed for calf skinfold [eta2 = .14; medium effect size (ES)], 20-m sprint (eta2 = .09; small ES), countermovement jump (eta2 = .29; large ES), medicine ball (eta2 = .58; large ES), with greater gains (reduction of skinfold) for plyometric group, and sit-and-reach (eta2 = .35; large ES), with greater gains in plyometric and skill-based groups. The magnitude-based inference indicated positive changes in 1) medicine ball toss and countermovement jump for all groups; 2) sit-and-reach for the plyometric and skill-based groups; and 3) 20-m sprint, calf girth, calf skinfold, and corrected calf girth for plyometric group only. CONCLUSION: Selected variables can be improved by adding 2 plyometric training sessions throughout the period of 12 weeks. Additional skill-based conditioning did not contribute to improvement in the studied variables compared with regular volleyball training. PMID- 29478380 TI - An Emerging Integrated Middle-Range Theory on Asian Women's Leadership in Nursing. AB - INTRODUCTION: Asian cultures reflect patriarchal cultural values and attitudes, which likely have influenced women leaders in their countries differently from women in Western cultures. However, virtually no leadership theories have been developed to reflect the experiences and development of nursing leaders from Asian cultures. The purpose of this article is to present an emerging integrated middle-range theory on Asian women's leadership in nursing. METHODOLOGY: Using an integrative approach, the theory was developed based on three major sources: the leadership frames of Bolman and Deal, literature reviews, and exemplars/cases from five different countries. RESULTS: The theory includes two main domains (leadership frames and leadership contexts). The domain of leadership frames includes human resources/networks, structure/organization, national/international politics, and symbols. The domain of leadership contexts includes cultural contexts, sociopolitical contexts, and gendered contexts. DISCUSSION: This theory will help understand nursing leadership in Asian cultures and provide directions for future nurse leaders in this ever-changing globalized world. PMID- 29478382 TI - A (Re)defining moment for fear appeals: a comment on Kok et al. (2018). PMID- 29478381 TI - Relationships Between Training Load, Sleep Duration, and Daily Well-Being and Recovery Measures in Youth Athletes. AB - PURPOSE: To assess the relationships between training load, sleep duration, and 3 daily well-being, recovery, and fatigue measures in youth athletes. METHODS: Fifty-two youth athletes completed 3 maximal countermovement jumps (CMJs), a daily well-being questionnaire (DWB), the perceived recovery status scale (PRS), and provided details on their previous day's training loads (training) and self reported sleep duration (sleep) on 4 weekdays over a 7-week period. Partial correlations, linear mixed models, and magnitude-based inferences were used to assess the relationships between the predictor variables (training and sleep) and the dependent variables (CMJ, DWB, and PRS). RESULTS: There was no relationship between CMJ and training (r = -.09; +/-.06) or sleep (r = .01; +/-.06). The DWB was correlated with sleep (r = .28; +/-.05, small), but not training (r = -.05; +/-.06). The PRS was correlated with training (r = -.23; +/-.05, small), but not sleep (r = .12; +/-.06). The DWB was sensitive to low sleep (d = -0.33; +/-0.11) relative to moderate; PRS was sensitive to high (d = -0.36; +/-0.11) and low (d = 0.29; +/-0.17) training relative to moderate. CONCLUSIONS: The PRS is a simple tool to monitor the training response, but DWB may provide a greater understanding of the athlete's overall well-being. The CMJ was not associated with the training or sleep response in this population. PMID- 29478383 TI - Relationship between skeletal muscle contractile properties and power production capacity in female Olympic rugby players. AB - This study aimed to determine which contractile properties measured by tensiomyography (TMG) could better differentiate athletes with high- and low power values, as well as to analyse the relationship between contractile properties and power production capacity. The contractile properties of the vastus medialis (VM), rectus femoris (RF) and vastus lateralis (VL) of an Olympic women's Rugby Sevens team (n = 14) were analysed before a Wingate test in which their peak power output (PPO) was determined. Athletes were then divided into a high-power (HP) and a low-power (LP) group. HP presented an almost certainly higher PPO (9.8 +/- 0.3 vs. 8.9 +/- 0.4 W kg-1, ES = 3.00) than LP, as well as a very likely lower radial displacement (3.39 +/- 1.16 vs. 5.65 +/- 1.50 mm, ES = 1.68) and velocity of deformation (0.08 +/- 0.02 vs. 0.13 +/- 0.03 mm ms-1, ES = 1.87) of the VL. A likely lower time of delay was observed in HP for all analysed muscles (ES > 0.60). PPO was very largely related to the radial displacement (r = -0.75, 90% CI = -0.90 to -0.44) and velocity of deformation (r = -0.70, 90% CI = 0.87 to -0.34) of the VL. A large correlation was found between PPO and the time of delay of the VL (r = -0.61, 90% CI = -0.84 to -0.22). No correlations were found for the contractile properties of RF or VM. These results highlight the importance of VL contractile properties (but not so much those of RF and VM) for maximal power production and suggest TMG as a practical technique for its evaluation. PMID- 29478384 TI - In Vitro Detection System to Evaluate the Immunogenic Potential of Xenografts. AB - Tissue antigenicity represents the main limitation for the use of xenografts in clinical practice. To eliminate xenoantigens and avoid graft rejection in human, decellularization is often used to remove all immunoreactive components from the extracellular matrix (ECM). After decellularization, acellular scaffolds are required to be investigated regarding the presence of antigens, but commonly used detection methods solely focus on known xenoantigens such as alpha Gal (Galalpha1,3-Galbeta1-4GlcNAc-R) or major histocompatibility complex-I (MHC-I). However, there are unknown xenoantigens that escape the standard methods. To evaluate the immunological potential of xenogenic tissues, new in vitro methods need to be developed. Therefore, we established a novel human serum-based approach, including dot blot, Western blot, immunohistochemistry, and enzyme linked immunosorbent assay (ELISA). With these methods, we analyzed protein extracts and tissue samples of native and decellularized bovine carotid arteries. All methods verified an effective removal of potential immunogens from the ECM through decellularization, and relative quantification with ELISA showed that 99.9% (p < 0.01) of antigenic components were successfully eliminated. We compared our human serum-based methods with commonly used assays for the detection of alpha Gal and MHC-I. Our results showed highly increased sensitivity for xenoantigens using the human serum antibody pool. This novel in vitro detection system allows the direct determination of the immunogenic potential of xenografts and is a vast improvement in comparison to the methods used so far. That way, it is possible to optimize the decellularization process to prevent hyperacute graft rejection in patients. PMID- 29478385 TI - A Comparison of Bone Marrow and Cord Blood Mesenchymal Stem Cells for Cartilage Self-Assembly. AB - Joint injury is a common cause of premature retirement for the human and equine athlete alike. Implantation of engineered cartilage offers the potential to increase the success rate of surgical intervention and hasten recovery times. Mesenchymal stem cells (MSCs) are a particularly attractive cell source for cartilage engineering. While bone marrow-derived MSCs (BM-MSCs) have been most extensively characterized for musculoskeletal tissue engineering, studies suggest that cord blood MSCs (CB-MSCs) may elicit a more robust chondrogenic phenotype. The objective of this study was to determine a superior equine MSC source for cartilage engineering. MSCs derived from bone marrow or cord blood were stimulated to undergo chondrogenesis through aggregate redifferentiation and used to generate cartilage through the self-assembling process. The resulting neocartilage produced from either BM-MSCs or CB-MSCs was compared by measuring mechanical, biochemical, and histological properties. We found that while BM constructs possessed higher tensile properties and collagen content, CB constructs had superior compressive properties comparable to that of native tissue and higher GAG content. Moreover, CB constructs had alkaline phosphatase activity, collagen type X, and collagen type II on par with native tissue suggesting a more hyaline cartilage-like phenotype. In conclusion, while both BM MSCs and CB-MSCs were able to form neocartilage, CB-MSCs resulted in tissue more closely resembling native equine articular cartilage as determined by a quantitative functionality index. Therefore, CB-MSCs are deemed a superior source for the purpose of articular cartilage self-assembly. PMID- 29478386 TI - Spontaneous Findings in the Eyes of Cynomolgus Monkeys ( Macaca fascicularis) of Mauritian Origin. AB - Spontaneous findings noted in the eyes of Mauritian cynomolgus monkeys are described and descriptions are supplemented with illustrations. Findings observed after extensive histopathologic examinations (20 to 44 sections per eye) from 20 control, 17 treatment-naive stock monkeys, and 2 findings noted in drug-treated monkeys that were considered to be spontaneous are included. Also included are findings from 361 control monkeys of routine toxicity studies performed at our laboratories, for most of which a standard histopathological examination of 1 section per eye was conducted. Common observations in monkeys examined extensively and in historical controls were limited to lymphocytic or mononuclear cell infiltrations of the uvea and/or conjunctiva/sclera and, less commonly observed, melanocytoma of the ciliary body or iris. Findings noted only in monkeys examined extensively consisted of inflammation of the conjunctiva, ora serrata cysts, glial nodules, focal degeneration of the retina, cystoid degeneration of the central retina, ballooning degeneration of the ciliary epithelium, cyst of the ciliary body, and decreased pigmentation of the retinal pigment epithelium. Changes recorded only in historical controls included retinal atrophy and nuclear displacement in the retina. Lesions are discussed and compared with pertinent literature. PMID- 29478387 TI - The effect of vitamin B6 on dexamethasone-induced depression in mice model of despair. AB - OBJECTIVE: Glucocorticoid receptors (GRs) have an important role in mediating the effects of glucocorticoids (GCs) on brain plasticity and mood. GC drugs and elevated cortisol level can cause psychiatric disorders including depression. The B-vitamins have numerous benefits on general health as well as mood, and cognition. The aim was evaluating the effect of vitamin B6 following dexamethasone (DEX)-induced depression in mice, to see if it can be proposed as a remedy for psychiatric problems following GC therapy. METHODS: Male mice were housed by six. The immobility time was measured, in the forced swimming test as an animal model of despair and sucrose preference was measured in order to test anhedonia (<65% was taken as a criterion for anhedonia). DEX was administered either single dose (15, 60, 250 mcg/kg) or 15 mcg/kg for 7 consecutive days, vitamin B6 (100 mg/kg) was administered for 7 days. RESULTS: DEX dose dependently increased immobility time that denoted animal depression; as it was 177.5 seconds +/- 3 following 60 mcg/kg and 188.3 seconds +/- 5 following 250 mcg/kg administration (vs. control animals 164 seconds +/- 6, P < 0.01). Premedication with vitamin B6 prevented DEX-induced depression and demonstrated antidepressant effect. It also reduced the immobility time following 7days DEX injection (192.5 seconds +/- 6) to 100 seconds +/- 5.5; sucrose preference escalated from 50%+/-3 to 87%+/-4. CONCLUSION: Vitamin B6 prevented DEX-induced depression possibly by altering the GR function. Thus Vitamin B6 could be promising in patients suffering from GC-induced psychiatric adverse effects and probably controlling stress and preventing its affective disorder out comes. PMID- 29478389 TI - Chinese Female Drug Users' Experiences and Attitudes With Institutional Drug Treatment. AB - With its rapid economic growth and the increased influence of Western culture, China has become a drug-consuming country. Forty-six semistructured interviews were conducted in a compulsory drug treatment institution to document Chinese female drug users' experiences with and attitudes toward two mandated treatment modalities: vocational training and educational activities. Detainees required to participate in first institutional treatment showed enthusiasm and had more positive attitudes; those who had entered the compulsory treatment facilities 2 or more times generally had a negative outlook on their pursuit of abstinence. Although female detainees achieved detoxification in the institution, many relapsed upon release to their community, indicating the institutional compulsory treatment model's failure to ensure long-term abstinence. By revealing four main flaws of the current institutional compulsory treatment, this study indicates the need for a comprehensive treatment system that combines improvements to institutional treatment and development of community-based treatment to address different stages of abstinence. PMID- 29478388 TI - Freezing Responses in DMSO-Based Cryopreservation of Human iPS Cells: Aggregates Versus Single Cells. AB - Inadequate preservation methods of human induced pluripotent stem cells (hiPSCs) have impeded efficient reestablishment of cell culture after the freeze-thaw process. In this study, we examined roles of the cooling rate, seeding temperature, and difference between cell aggregates (3-50 cells) and single cells in controlled rate freezing of hiPSCs. Intracellular ice formation (IIF), post thaw membrane integrity, cell attachment, apoptosis, and cytoskeleton organization were evaluated to understand the different freezing responses between hiPSC single cells and aggregates, among cooling rates of 1, 3, and 10 degrees C/min, and between seeding temperatures of -4 degrees C and -8 degrees C. Raman spectroscopy images of ice showed that a lower seeding temperature (-8 degrees C) did not affect IIF in single cells, but significantly increased IIF in aggregates, suggesting higher sensitivity of aggregates to supercooling. In the absence of IIF, Raman images showed greater variation of dimethyl sulfoxide concentration across aggregates than single cells, suggesting cryoprotectant transport limitations in aggregates. The ability of cryopreserved aggregates to attach to culture substrates did not correlate with membrane integrity for the wide range of freezing parameters, indicating inadequacy of using only membrane integrity-based optimization metrics. Lower cooling rates (1 and 3 degrees C/min) combined with higher seeding temperature (-4 degrees C) were better at preventing IIF and preserving cell function than a higher cooling rate (10 degrees C/min) or lower seeding temperature (-8 degrees C), proving the seeding temperature range of -7 degrees C to -12 degrees C from literature to be suboptimal. Unique f-actin cytoskeletal organization into a honeycomb-like pattern was observed in postpassage and post-thaw colonies and correlated with successful reestablishment of cell culture. PMID- 29478390 TI - Beyond Circles of Support: "Fearless"-An Open Peer-to-Peer Mutual Support Group for Sex Offense Registrants and Their Family Members. AB - The term sex offender carries expectations that include a continuous level of sexual criminal risk and untreatable mental health conditions that govern sex offending behaviors. These role expectations by the public can socially isolate individuals who have been convicted of a crime and the people who love them. This is likely to contribute to negative self-images that can result in loneliness, isolation, and depression, and, subsequently, contribute to discontinuing support for sex offender's loved ones and reoffending. This article highlights the creation and maintenance of a peer-to-peer social support group for registered sex offenders and their family members that helps combat the effects of "sex offender" labels. This group differs from formal organized circles of support model and traditional self-help groups such as Alcohol (AA) or Narcotic (NA) Anonymous. We review this group's creation, processes and procedures, and outcomes, including changes in cognition, mood, and affect over time for members in the group. PMID- 29478391 TI - Prisoners' Perception of Legitimacy of the Prison Staff: A Qualitative Study in Slovene Prisons. AB - The purpose of this article is to explore prisoners' perception of legitimacy of prison staff and examine the compliance of prisoners with the authority of prison staff to highlight the differences between instrumental and normative compliance of prisoners. This study draws on data collected from a random sample of 193 prisoners in all Slovene prisons. Using a qualitative approach based on structured interviews, our findings suggest that distributive justice, procedural justice, the quality of relations with prison staff, and the effectiveness of prison staff influence prisoners' perception of legitimacy in a prison environment. Several prisoners comply with prison rules because they fear sanctions, which indicates their instrumental compliance, while normative compliance was reported by prisoners who perceived the legitimacy of prison staff in a more positive manner. Overall findings indicate that both instrumental and normative compliance of prisoners can be observed in Slovene prisons. PMID- 29478392 TI - Comparing the Central Eight Risk Factors: Do They Differ Across Age Groups of Sex Offenders? AB - Following the risk-need-responsivity (RNR) model, cognitive-behavioral therapy is considered most effective in reducing recidivism when based on dynamic risk factors. As studies have found differences of these factors across age, exploring this seems beneficial. The current study investigates the Central Eight (C8) risk factors across six age groups of outpatient sex offenders ( N = 650). Results showed that recidivism rates and age were inversely related from 19 years and up. Half of the C8 did not predict general recidivism at all, substance abuse, antisocial cognition, antisocial associates, and history of antisocial behavior in only one or several age groups. However, factors differed between age groups, with the youngest group demonstrating the most dysfunction in several areas and the oldest group the least. It is concluded that the C8 risk factors seem to lose significance in the older age groups. Results may benefit targeting treatment goals. PMID- 29478393 TI - The Impact of Juvenile Educational Measures, Confinement Centers, and Probation on Adult Recidivism. AB - This study aimed to examine the impact of the educational measure of confinement in juvenile detention center versus probation, on adult recidivism. Participants were 264 youths with a disciplinary record in the Juvenile Court ( M = 16.5), who were sentenced to custody in a juvenile closed detention center or to probation. The risk levels were assessed using the YLS/CMI Inventory (Youth Level of Service/Case Management). A follow-up period for studying these two groups into adulthood was carried out to register possible adult recidivism. The results showed that probation was more effective in reducing subsequent adult offences than the deprivation of liberty. The variable risk level also appears to be a significant factor, improving the predictive model of adult recidivism. PMID- 29478395 TI - News & Views. PMID- 29478394 TI - Don't throw the baby out with the bath water: commentary on Kok, Peters, Kessels, ten Hoor, and Ruiter (2018). PMID- 29478396 TI - Ciclosporin and the cat: Current understanding and review of clinical use. AB - : Practical relevance: Ciclosporin (CsA) is a systemic immuno-modulatory drug widely used to treat immune-mediated diseases in humans and veterinary species. CsA was registered for use in cats in the USA and Europe in 2011, and is indicated for the treatment of chronic allergic dermatitis at a recommended daily dose of 7 mg/kg PO. AUDIENCE: This review will be of interest to all veterinarians working with cats, given the wide range of potential applications of CsA and its safety profile. Although the drug is currently only licensed to treat chronic allergic dermatitis in cats, a small number of reports describe its use in non-dermatological conditions. Evidence base: This article reviews the mechanism of action, pharmacokinetics, drug interactions, adverse effects and clinical use of CsA, both for the licensed indication and for off-label use in the feline patient. Information presented has been summarised from the existing literature on CsA, with specific interest in studies carried out in cats. For its licensed indication, chronic allergic dermatitis, evidence provided includes randomised, placebo or prednisolone-controlled studies (EBM grade I) and prospective or retrospective open trials. PMID- 29478397 TI - Diagnosis of feline infectious peritonitis: Update on evidence supporting available tests. AB - Practical relevance: Feline coronavirus (FCoV) infection is very common in cats, usually causing only mild intestinal signs such as diarrhoea. Up to 10% of FCoV infections, however, result in the fatal disease feline infectious peritonitis (FIP). Clinical challenges: Obtaining a definitive diagnosis of FIP based on non invasive approaches is difficult. Confirmation of the disease relies on finding appropriate cytological or histopathological changes in association with positive immunostaining for FCoV antigen. In FIP cases with effusions, cytology and immunostaining on effusion samples can be relatively easy to perform; otherwise obtaining diagnostic samples is more challenging and collection of biopsies from tissues with gross lesions is necessary. In the absence of a definitive diagnosis, a high index of suspicion of FIP may be obtained from the cat's signalment and history, combined with findings on clinical examination and laboratory test results. If largely consistent with FIP, these can be used as a basis for discussion with the owner about whether additional, more invasive, diagnostic tests are warranted. In some cases it may be that euthanasia is discussed as an alternative to pursuing a definitive diagnosis ante-mortem, especially if financial limitations exist or where there are concerns over a cat's ability to tolerate invasive diagnostic procedures. Ideally, the diagnosis should be confirmed in such patients from samples taken at post-mortem examination. Global importance: FIP occurs wherever FCoV infection is present in cats, which equates to most parts of the world. Evidence base: This review provides a comprehensive overview of how to approach the diagnosis of FIP, focusing on the tests available to the veterinary practitioner and recently published evidence supporting their use. PMID- 29478398 TI - Mesenchymal stem cell therapy in cats: Current knowledge and future potential. AB - : Practical relevance: Stem cell therapy is an innovative field of scientific investigation with tremendous potential for clinical application in veterinary medicine. Based on the known desirable immunomodulatory properties of mesenchymal stem cells, this therapy holds promise for the treatment of a variety of inflammatory diseases in cats. AIMS: This review details our current understanding of feline stem cell biology and proposed mechanism of action. Studies performed in feline clinical trials for diseases including gingivostomatitis, chronic enteropathy, asthma and kidney disease are summarized, with the goal of providing an overview of the current status of this treatment modality and its potential for the future. PMID- 29478399 TI - Hepatic lipidosis: Clinical review drawn from collective effort. AB - : Practical relevance: Hepatic lipidosis (HL) is the most common form of liver dysfunction in cats. If recognized early and treated appropriately, the prognosis is good; if not, the prognosis is grave. Clinical challenges: Distinguishing HL as idiopathic or secondary is critical since the presence of a concurrent disease affects the therapeutic plan and the prognosis. AUDIENCE: Despite the unique and severe nature of a cat's response to anorexia and the complexity of the metabolic changes underlying this condition, the clinical acumen and technical ability to effectively diagnose and treat HL are readily available to all small animal practitioners. Patient group: Although many species develop a 'fatty liver', the cat is one of relatively few species that suffer from HL. The classic presentation is that of an overweight cat that stops eating for days to weeks, losing weight in the process. Equipment: Abdominal ultrasound is frequently employed in the diagnostic work-up of an anorectic cat; ultrasonographic findings often support a presumptive diagnosis, provide samples for cytology and, perhaps most importantly, help identify concurrent conditions that must be addressed for therapeutic success. All of the equipment necessary for essential nutritional intervention in an anorectic cat is readily available and easily affordable. Evidence base: The material for this review draws heavily on a relatively large number of original studies, excellent reviews by recognized experts, and informative communication with experienced clinicians, hence the term 'collective effort'. PMID- 29478400 TI - Haemoplasmosis in cats: European guidelines from the ABCD on prevention and management. AB - OVERVIEW: Haemoplasmas are haemotropic bacteria that can induce anaemia in a wide range of mammalian species. Infection in cats: Mycoplasma haemofelis is the most pathogenic of the three main feline haemoplasma species known to infect cats. ' Candidatus Mycoplasma haemominutum' and ' Candidatus Mycoplasma turicensis' are less pathogenic but can result in disease in immunocompromised cats. Male, non pedigree cats with outdoor access are more likely to be haemoplasma infected, and ' Candidatus M haemominutum' is more common in older cats. All three haemoplasma species can be carried asymptomatically. Transmission: The natural mode of transmission of haemoplasma infection is not known, but aggressive interactions and vectors are possibilities. Transmission by blood transfusion can occur and all blood donors should be screened for haemoplasma infection. DIAGNOSIS AND TREATMENT: PCR assays are the preferred diagnostic method for haemoplasma infections. Treatment with doxycycline for 2-4 weeks is usually effective for M haemofelis-associated clinical disease (but this may not clear infection). Little information is currently available on the antibiotic responsiveness of ' Candidatus M haemominutum' and ' Candidatus M turicensis'. PMID- 29478401 TI - Intimate Partner Violence Against Women in Northwestern Botswana: The Maun Women's Study. AB - Factors characterizing intimate partner violence (IPV) against women vary according to setting and must be understood in localized environments if effective interventions are to be identified. This 2009-2010 exploratory study in Maun, Botswana, used semistructured interviews to elicit information from 469 women about their experiences with IPV. Characteristics found to be important included suicide attempts, childhood exposure to familial violence, access to and control over certain tangible assets, number of children, household location and monthly income, controlling behavior by a partner, and alcohol consumption. Controlling behavior by a partner was the single greatest predictor of physical or psychological IPV. PMID- 29478402 TI - A Meta-Study of Qualitative Research Examining Sport and Recreation Experiences of Indigenous Youth. AB - Participation in sport and recreation may contribute to various holistic benefits among Indigenous youth in Canada. However, there is a need for a consolidated evidence base to support the development of sport and recreation opportunities that could facilitate such holistic benefits. The purpose of this research was to produce a meta-study of qualitative research examining sport and recreation experiences of Indigenous youth in Canada. Following record identification and screening, 20 articles were retained for analysis and synthesis. Strengths and weaknesses of included studies were identified through the meta-method and meta theory analysis. The meta-data analysis revealed five themes that represent the sport and recreation experiences of Indigenous youth. Working collaboratively with community members, our final meta-synthesis situated these five themes within the integrated Indigenous ecological model. This review consolidates the qualitative evidence base, and provides direction for future research and practice. PMID- 29478403 TI - Strategizing and Fatalizing: Self and Other in the Trauma Narratives of Justice Involved Women. AB - Jail admissions in the United States number nearly 1 million women annually. Many have limited access to public support and must seek assistance from family, friends, and strangers to maintain health and safety after release. This study sought to learn more about how women with a history of interpersonal trauma and criminal justice involvement perceive and manage social relationships. In-depth, story-eliciting interviews were conducted over 12 months with 10 participants who were selected from the convenience sample of an ongoing parent study in a Midwestern urban jail. Embedded trauma narratives were analyzed for self presentation, form, and theme. The trauma narratives registered a continuum of agency, anchored at either end by patterns of strategizing talk and fatalizing talk. Providers and advocates can improve support for justice-involved women post incarceration by becoming familiar with and responding to patterns of strategizing and fatalizing in their personal narratives. PMID- 29478404 TI - Barriers to Family Caregivers' Coping With Patients With Severe Mental Illness in Iran. AB - The broad spectrum of problems caused by caring for a patient with mental illness imposes a high burden on family caregivers. This can affect how they cope with their mentally ill family members. Identifying caregivers' experiences of barriers to coping is necessary to develop a program to help them overcome these challenges. This qualitative content analysis study explored barriers impeding family caregivers' ability to cope with their relatives diagnosed with severe mental illness (defined here as schizophrenia, schizoaffective disorders, and bipolar affective disorders). Sixteen family caregivers were recruited using purposive sampling and interviewed using a semi-structured in-depth interview method. Data were analyzed by a conventional content analytic approach. Findings consisted of four major categories: the patient's isolation from everyday life, incomplete recovery, lack of support by the mental health care system, and stigmatization. Findings highlight the necessity of providing support for caregivers by the mental health care delivery service system. PMID- 29478405 TI - Using Positive Organizational Scholarship in Healthcare and Video Reflexive Ethnography to Examine Positive Deviance to New Public Management in Healthcare. AB - Following increased interest in and use of new public management (NPM), greater regulation has been introduced into many Western health systems. Yet, the effects have revealed the negative aspects of NPM. Positive organizational scholars have argued that adversity can give rise to positive deviance. Yet as a form of noncompliance, positive deviance can be difficult to examine. This methodological article demonstrates how the combined methodologies of positive organizational scholarship in healthcare (POSH) and video reflexive ethnography (VRE) can help examine positive deviance. This study illustrates the methodological utility of POSH VRE to respectfully study the impact of NPM-inspired expectations on public health clinicians, positively reframe how clinicians constructively respond to and manage obstruction, and reveal the unintended effects of NPM-inspired expectations. As a participatory methodology, POSH VRE can promote trust between researchers and clinicians, thereby unveiling instances of positive deviance to NPM in healthcare. PMID- 29478407 TI - Multiple Researcher Roles in Video-Reflexive Ethnography. AB - Hospital-based video-reflexive ethnography (VRE) is a collaborative visual methodology used by researchers and/or health professionals to understand, interpret, and optimize health professionals' work practices and patients' experiences. For more than a decade, the VRE methodology has spread throughout (research) institutions and hospitals internationally, and VRE has evolved and broadened. Different ways of doing VRE have implications for the role of the researcher. A thorough examination of the consequences for the researcher's position is the central focus of this article. We outline three typical styles of researcher engagement with VRE: clinalyst, affect-as-method, and planned obsolescence. We argue that by examining these different styles of doing VRE research, academic researchers can then critically review and carefully choose which styles of VRE research best meet the needs of their research questions, their field relationships, their disciplinary background, and the expectations of their clinical research collaborators. PMID- 29478406 TI - An Exploration of Syndemic Factors That Influence Engagement in HIV Care Among Black Men. AB - Syndemic theory seeks to understand the interactions and clustering of disease and social conditions and explain racial disparities in HIV. Traditionally applied to HIV risk, this study characterizes the syndemic challenges of engagement in care among Black men living with HIV and provides insight into potential HIV treatment interventions to retain vulnerable individuals in care. Interviews were conducted with 23 HIV-positive men who were either out-of-care or nonadherent to antiretroviral therapy (ART). Interviews were audio recorded, transcribed verbatim, and coded using MAXQDA qualitative software. Researchers analyzed data using thematic content analysis to identify syndemic factors associated with disengagement in care or suboptimal ART adherence among Black men. Analyses revealed the syndemic nature of four themes: intersectional stigma, depression, substance use, and poverty. Findings from this study offer numerous opportunities for intervention including social and structural-level interventions to address syndemic processes and the influence of stigma and poverty on engagement in care. PMID- 29478408 TI - Effect of oral nut supplementation on endothelium-dependent vasodilation - a meta analysis. AB - BACKGROUND: An inverse association was found between nut supplementation and the risk of cardiovascular disease. Identifying the direct effect of nut supplementation on endothelium-dependent vasodilation may partly explain that association. METHODS: Human intervention studies were identified by systematic electronic search of the databases EMBASE, MEDLINE, Pubmed, and Web of Science through January 2017 and by manually searching related articles. Subgroup analyses were performed to identify the source of heterogeneity among studies. RESULTS: In total, 11 eligible articles involving 468 participants were included in the meta-analysis. Overall, the results of the 13 trials showed that nut supplementation significantly increased flow-mediated dilation [weighted mean differences (WMD): 1.03 %; 95 % CI: 0.26-1.79 %, P = 0.008]. There was significant heterogeneity among studies (P = 0.006) that might partly be explained by the different types of nuts. No significant association between nut supplementation and endothelium-independent vasodilatation was observed in a fixed effect model (WMD: 1.10 %, 95 % CI: -0.19-2.38 %, P = 0.09). CONCLUSIONS: Supplementation of nuts significantly improves the vascular endothelial function without affecting endothelium-independent vasodilatation. PMID- 29478409 TI - "I Must Be Silent Because of Residency": Barriers to Escaping Domestic Violence in the Context of Insecure Immigration Status in England and Sweden. AB - This article draws on qualitative research examining domestic violence against women with insecure immigration status in England and Sweden. Empirical data were collected through in-depth semistructured interviews with 31 survivors from 14 non-European Union (EU) countries, and 57 professional stakeholders including 19 support service providers. This article reveals a multilayered process of actualizing women's right to live free from violence, with survivors required to be formally eligible for services according to their immigration status, having to prove their eligibility, overcome informal barriers including the fear of deportation, and gain access to accurate information about their rights and services. PMID- 29478410 TI - Psychotropic medications in older people in residential care facilities and associations with quality of life: a cross-sectional study. AB - BACKGROUND: Psychotropic medications have been associated with many adverse outcomes in older people living in residential care. Home-like models of residential care may be preferable to traditional models of care and we hypothesized that this model may impact on the prevalence of psychotropic medications. The objectives were to: 1) examine associations between psychotropic medications and quality of life in older adults living in residential care facilities with a high prevalence of cognitive impairment and dementia and 2) determine if there was a difference in prevalence of psychotropic medications in facilities which provide a small group home-like model of residential care compared to a 'standard model' of care. METHODS: Participants included 541 residents from 17 residential aged care facilities in the Investigating Services Provided in the Residential Environment for Dementia (INSPIRED) study. Cross sectional analyses were completed to examine the above objectives. Quality of life was measured with the dementia quality of life questionnaire (DEMQOL) and the EQ-5D-5L completed by the resident or a proxy. RESULTS: Overall, 70.8% (n = 380) of the population had been prescribed/dispensed at least one psychotropic medication in the 100 days prior to recruitment. An increased number of psychotropic medications was associated with lower quality of life according to DEMQOL-Proxy-Utility scores (beta (SE): - 0.012 (0.006), p = 0.04) and EQ-5D-5L scores (- 0.024 (0.011), p = 0.03) after adjustment for resident-level and facility-level characteristics. Analysis of the individual classes of psychotropic medications showed antipsychotics were associated with lower DEMQOL Proxy-Utility scores (- 0.030 (0.014), p = 0.03) and benzodiazepines were associated with lower EQ-5D-5L scores (- 0.059 (0.024), p = 0.01). Participants residing in facilities which had a home-like model of residential care were less likely to be prescribed psychotropic medications (OR (95% CI): 0.24 (0.12, 0.46), p < 0.001). CONCLUSIONS: An increased number of psychotropic medications were associated with lower quality of life scores. These medications have many associated adverse effects and the use of these medications should be re-examined when investigating approaches to improve quality of life for older people in residential care. Home-like models of residential care may help to reduce the need for psychotropic medications, but further research is needed to validate these findings. PMID- 29478412 TI - Nivolumab induced remitting seronegative symmetrical synovitis with pitting edema in a patient with melanoma: a case report. AB - BACKGROUND: Novel immune checkpoint inhibitors have been often utilized for different types of malignancies as salvage therapy with varying success. One obstacle to immune checkpoint inhibitor use is the higher incidence of immune mediated side effects that can prompt discontinuation of therapy. Remitting seronegative symmetrical synovitis with pitting edema has been described with immune checkpoint inhibitors only once previously. We report a case of a patient who developed remitting seronegative symmetrical synovitis with pitting edema related to immune checkpoint inhibitor therapy and stress that these symptoms can be managed without cessation of immune checkpoint inhibitor therapy. CASE PRESENTATION: We present a 70-year-old white man who presented with 4 months of progressive inflammatory arthritis with pitting edema. He had been started on nivolumab therapy for his metastatic melanoma with excellent response prior to symptom onset. The symptoms started in his knees and subsequently involved both hands and feet. On evaluation, he was wheelchair bound and completely dependent for all activities of daily living. Evaluation revealed negative serological testing and plain film imaging. Ultrasound demonstrated diffuse flexor tenosynovitis and soft tissue swelling, and a diagnosis of remitting seronegative symmetrical synovitis with pitting edema was made. He was treated with orally administered corticosteroids (0.5 mg/kg per day) which improved his symptoms significantly and allowed him to regain prior independent functioning. His corticosteroids were tapered (0.15 mg/kg per day) but not discontinued and his nivolumab treatment was not interrupted. In follow up he continued to have stable control of his melanoma as well as his remitting seronegative symmetrical synovitis with pitting edema. CONCLUSIONS: In conclusion we present the first case of nivolumab-induced remitting seronegative symmetrical synovitis with pitting edema that is controlled by maintenance low-dose orally administered corticosteroids allowing for continuation of nivolumab therapy. Clinicians who encounter mild-to-moderate immune checkpoint inhibitor immune-mediated adverse effects can consider maintaining immune checkpoint inhibitor therapy with concomitant low-dose corticosteroids rather than abrupt cessation of the immune checkpoint inhibitor. PMID- 29478413 TI - Is waist-to-height ratio the best predictive indicator of hypertension incidence? A cohort study. AB - BACKGROUND: The best anthropometric indicator to verify the association between obesity and hypertension (HTN) has not been established. We conducted this study to evaluate and compare the discriminatory power of waist-to-height ratio (WHtR) in relation to body mass index (BMI) and waist circumference (WC) in predicting HTN after 13 years of follow-up. METHODS: This study was an observational prospective cohort study performed in the city of Firminopolis, in Brazilian's midwest. The cohort baseline (phase 1) was initiated in 2002 with the evaluation of a representative sample of the normotensive population (>= 18 years of age). The incidence of HTN was evaluated as the outcome (phase 2). Sociodemographic, dietary and lifestyle variables were used to adjust proportional hazards models and evaluate risk of HTN according to anthropometric indices. The areas under the receiver operating characteristic (ROC) curves were used to compare the predictive capacity of these indices. The best HTN predictor cut-offs were obtained based on sensitivity and specificity. RESULTS: A total of 471 patients with a mean age of 38.9 +/- 12.3 years were included in phase 1. The mean follow up was 13.2 years, and 207 subjects developed HTN. BMI, WC and WHtR were associated with risk of HTN incidence and had similar power in predicting the disease. However, the associations were only significant for women. The cut-off points with a better HTN predictive capacity were in agreement with current recommendations, except for the WC in men. CONCLUSIONS: The results suggest that both overall obesity (BMI) and central obesity (WC and WHtR) anthropometric indicators can be used in this population to evaluate the risk of developing hypertension. PMID- 29478411 TI - Observation weights unlock bulk RNA-seq tools for zero inflation and single-cell applications. AB - Dropout events in single-cell RNA sequencing (scRNA-seq) cause many transcripts to go undetected and induce an excess of zero read counts, leading to power issues in differential expression (DE) analysis. This has triggered the development of bespoke scRNA-seq DE methods to cope with zero inflation. Recent evaluations, however, have shown that dedicated scRNA-seq tools provide no advantage compared to traditional bulk RNA-seq tools. We introduce a weighting strategy, based on a zero-inflated negative binomial model, that identifies excess zero counts and generates gene- and cell-specific weights to unlock bulk RNA-seq DE pipelines for zero-inflated data, boosting performance for scRNA-seq. PMID- 29478414 TI - Feasibility and reliability of frailty assessment in the critically ill: a systematic review. AB - BACKGROUND: For healthcare systems, an ageing population poses challenges in the delivery of equitable and effective care. Frailty assessment has the potential to improve care in the intensive care setting, but applying assessment tools in critical illness may be problematic. The aim of this systematic review was to evaluate evidence for the feasibility and reliability of frailty assessment in critical care. METHODS: Our primary search was conducted in Medline, Medline In process, EMBASE, CINAHL, PsycINFO, AMED, Cochrane Database of Systematic Reviews, and Web of Science (January 2001 to October 2017). We included observational studies reporting data on feasibility and reliability of frailty assessment in the critical care setting in patients 16 years and older. Feasibility was assessed in terms of timing of evaluation, the background, training and expertise required for assessors, and reliance upon proxy input. Reliability was assessed in terms of inter-rater reliability. RESULTS: Data from 11 study publications are included, representing 8 study cohorts and 7761 patients. Proxy involvement in frailty assessment ranged from 58 to 100%. Feasibility data were not well reported overall, but the exclusion rate due to lack of proxy availability ranged from 0 to 45%, the highest rate observed where family involvement was mandatory and the assessment tool relatively complex (frailty index, FI). Conventional elements of frailty phenotype (FP) assessment required modification prior to use in two studies. Clinical staff tended to use a simple judgement-based tool, the clinical frailty scale (CFS). Inter-rater reliability was reported in one study using the CFS and although a good level of agreement was observed between clinician assessments, this was a small and single-centre study. CONCLUSION: Though of unproven reliability in the critically ill, CFS was the tool used most widely by critical care clinical staff. Conventional FP assessment required modification for general application in critical care, and an FI-based assessment may be difficult to deliver by the critical care team on a routine basis. There is a high reliance on proxies for frailty assessment, and the reliability of frailty assessment tools in critical care needs further evaluation. PROSPERO REGISTRATION NUMBER: CRD42016052073 . PMID- 29478415 TI - Development and evaluation of novel tumor-targeting paclitaxel-loaded nano carriers for ovarian cancer treatment: in vitro and in vivo. AB - BACKGROUND: Ovarian cancer is the most leading cause of death and the third most common gynecologic malignancy in women. Traditional chemotherapy has inevitable drawbacks of nonspecific tumor targeting, high toxicity, and poor therapeutic efficiency. In order to overcome such shortcomings, we prepared a novel nano carrier drug-delivery system to enhance the anti-tumor efficiency. METHODS: In vitro characterizations of nano-carriers were determined by TEM, DLS. Cell viability was measured by MTT method. RT-PCR was performed to measure the expression of FARalpha in three ovarian cancer cell lines. The drug-release study and the uptaken study were measured in vitro. The pharmacokinetic and the drug distribution study were verified by HPLC methods in vivo. The enhanced anti-tumor efficiency of FA-NP was evaluated by the tumor inhibitory rate in vivo. RESULTS: Paclitaxel (PTX)-loaded nanoparticles (NPs) (PTX-PEG-PLA-NP and PTX-PEG-PLA-FA NP) were prepared successfully, and the drug-release study showed that the cumulative release rates of NP groups were much less than free PTX group. The pharmacokinetic study showed that the elimination phase of two kinds of NP groups were much longer than that of PTX group. The drug distribution in different tissues showed that the peak-reach time was 2 h in the PTX group and 6 h in both NP groups. All of these results confirmed the excellent slow-release effects of both kinds of nano-carriers. More importantly, we confirmed that PTX-PEG-PLA-FA NP had greater uptake by SK-OV-3 cells than PTX-PEG-PLA-NP and free PTX in vitro. A drug-distribution study of tumor-bearing mice demonstrated that the PTX concentration of tumor tissues in the PTX-PEG-PLA-FA-NP group was 3 times higher than the other two groups. PTX-PEG-PLA-FA-NP was uptaken much more by SK-OV-3 cells than PTX-PEG-PLA-NP and free PTX. Eventually, based on the slow-release effect and tumor-targeting characteristics of PTX-PEG-PLA-FA-NP, a cytotoxicity test indicated that PTX-PEG-PLA-FA-NP was much more toxic to SK-OV-3 cells than the controls. The tumor inhibitory rate in the PTX-PEG-PLA-FA-NP group of tumor bearing mice was about 1.5 times higher than the controls. The tumor targeting and anti-tumor efficiency of PTX-PEG-PLA-FA-NP were confirmed both in vitro and in vivo. CONCLUSIONS: We developed an ovarian cancer targeting nano-carrier drug delivery system successfully, which showed perfect ovarian cancer targeting and anti-tumor effect, thus have the potential to be a new therapy strategy for ovarian cancer patients. PMID- 29478416 TI - Salmonella osteomyelitis in a previously healthy neonate: a case report and review of the literature. AB - BACKGROUND: Acute osteomyelitis, which is uncommon in neonates, needs to be quickly diagnosed and treated to avoid devastating sequelae. Therefore, it is important to maintain a high index of suspicion and be aware of the evolving epidemiology and of the emergence of antibiotic resistant and aggressive strains requiring careful monitoring and targeted therapy. The most frequently isolated bacterium in neonates with osteomyelitis is Staphylococcus aureus, while Salmonella is an unusual organism causing osteomyelitis and is exceedingly rare in non-sickle cell disease children. CASE PRESENTATION: We report an extremely rare case of neonatal osteomyelitis caused by Salmonella in a neonate, who was previously healthy. We report this case because it was caused by a rare pathogenic germ in newborns and by its non-specific presentation. CONCLUSIONS: Salmonella should be kept in mind in the differential diagnosis of neonatal osteomyelitis. It is important to start antibiotic therapy as soon as possible and to adjust therapy in relation to the susceptibility of the bacterial strain. PMID- 29478417 TI - Development and Evaluation of a Cognitive Behavioural Intervention for Chronic Post-Stroke Insomnia. AB - BACKGROUND: Cognitive behavioural therapy for insomnia (CBTI) has been successfully applied to those with chronic illness. However, despite the high prevalence of post-stroke insomnia, the applicability of CBTI for this population has not been substantially researched or routinely used in clinical practice. AIMS: The present study developed a 'CBTI+' protocol for those with post-stroke insomnia and tested its efficacy. The protocol also incorporated additional management strategies that considered the consequences of stroke. METHOD: A single-case experimental design was used with five community-dwelling individuals with post-stroke insomnia. Daily sleep diaries were collected over 11 weeks, including a 2-week baseline, 7-week intervention and 2-week follow-up. The Insomnia Severity Index, Dysfunctional Attitudes and Beliefs About Sleep Scale, Epworth Sleepiness Scale, Fatigue Severity Scale and Stroke Impact Scale were administered pre- and post-treatment, as well as at 2-week follow-up. RESULTS: At post-treatment, three participants no longer met diagnostic criteria for insomnia and all participants showed improvements on two or more sleep parameters, including sleep duration and sleep onset latency. Three participants showed a reduction in daytime sleepiness, increased quality of life and reduction in unhelpful beliefs about sleep. CONCLUSIONS: This study provides initial evidence that CBTI+ is a feasible and acceptable intervention for post-stroke insomnia. Furthermore, it indicates that sleep difficulties in community-dwelling stroke populations are at least partly maintained by unhelpful beliefs and behaviours. The development and delivery of the CBTI+ protocol has important clinical implications for managing post-stroke insomnia and highlights directions for future research. PMID- 29478419 TI - Psychological morbidity in family caregivers of people living with terminal cancer: Prevalence and predictors. AB - OBJECTIVE: The issues surrounding a patient's terminal phase of cancer and the imminent death of the individual represent a major family crisis affecting all its members. The goal of this study was to assess the prevalence of psychological morbidity in family caregivers of persons with terminal cancer in terms of psychological distress, depression, anxiety, somatization, and complicated anticipatory grief, and to determine which factors may influence these responses. METHOD: One hundred and twelve family caregivers of individuals with terminal cancer completed an assessment protocol comprising the Brief Symptom Inventory (depression, anxiety, somatization, and a computed score for global distress), the Marwit-Meuser Caregiver Grief Inventory - Short Form (anticipatory grief), the Family Inventory of Needs (importance and satisfaction of needs), and the Systemic Clinical Outcome Routine Evaluation -15 (family functioning). Prevalence of psychological morbidity was determined through descriptive and frequency statistics. Predictors of psychological morbidity were ascertained through structural equation modelling methods. Result Regarding the prevalence of psychological morbidity in family caregivers, 66.1% reported high levels of distress, 68.8% showed high risk of depression, 72.3% showed high risk of anxiety, 50.9% reported high levels of somatization, and 25.9% showed high risk of complicated anticipatory grief. It was found that the predictors of age, gender, relationship to the family member with terminal cancer, the caregiving role played (i.e., primary vs. nonprimary), the satisfaction of needs by healthcare professionals, and family functioning play an important role in terms of one's risk of developing psychological morbidity. Significance of results This study revealed an alarming prevalence of psychological morbidity in family caregivers of individuals living with terminal cancer, making it crucial to move forward from a patient-centered approach to a family-centrad approach to reduce the risk of family maladjustment when facing the imminent death of a family member and to prevent postdeath unadjusted responses. PMID- 29478418 TI - What life course theoretical models best explain the relationship between exposure to childhood adversity and psychopathology symptoms: recency, accumulation, or sensitive periods? AB - BACKGROUND: Although childhood adversity is a potent determinant of psychopathology, relatively little is known about how the characteristics of adversity exposure, including its developmental timing or duration, influence subsequent mental health outcomes. This study compared three models from life course theory (recency, accumulation, sensitive period) to determine which one(s) best explained this relationship. METHODS: Prospective data came from the Avon Longitudinal Study of Parents and Children (n = 7476). Four adversities commonly linked to psychopathology (caregiver physical/emotional abuse; sexual/physical abuse; financial stress; parent legal problems) were measured repeatedly from birth to age 8. Using a statistical modeling approach grounded in least angle regression, we determined the theoretical model(s) explaining the most variability (r2) in psychopathology symptoms measured at age 8 using the Strengths and Difficulties Questionnaire and evaluated the magnitude of each association. RESULTS: Recency was the best fitting theoretical model for the effect of physical/sexual abuse (girls r2 = 2.35%; boys r2 = 1.68%). Both recency (girls r2 = 1.55%) and accumulation (boys r2 = 1.71%) were the best fitting models for caregiver physical/emotional abuse. Sensitive period models were chosen alone (parent legal problems in boys r2 = 0.29%) and with accumulation (financial stress in girls r2 = 3.08%) more rarely. Substantial effect sizes were observed (standardized mean differences = 0.22-1.18). CONCLUSIONS: Child psychopathology symptoms are primarily explained by recency and accumulation models. Evidence for sensitive periods did not emerge strongly in these data. These findings underscore the need to measure the characteristics of adversity, which can aid in understanding disease mechanisms and determining how best to reduce the consequences of exposure to adversity. PMID- 29478420 TI - Transmission of respiratory and gastrointestinal infections in German households with children attending child care. AB - Transmission of acute respiratory infections (ARI) and acute gastroenteritis (AGE) often occurs in households. The aim of this study was to assess which proportion of ARI and AGE is introduced and transmitted by children in German households with children attending child care. We recruited families with children aged 0-6 years in Braunschweig (Germany), for a 4 months prospective cohort study in the winter period 2014/2015. Every household member was included in a health diary and used nasal swabs for pathogen identification in case of ARI. We defined a transmission if two persons had overlapping periods with symptoms and used additional definitions for sensitivity analyses. In total, 77 households participated with 282 persons. We observed 277 transmission events for ARI and 23 for AGE. In most cases, the first infected person in a household was a child (ARI: 63%, AGE: 53%), and the risk of within-household transmission was two times higher when the index case was a child. In 26 ARI-transmission events, pathogens were detected for both cases; hereof in 35% (95% confidence interval (17-56%)) the pathogens were different. Thus, symptomatic infections in household members, apparently linked in time, were in 2/3 associated with the same pathogens. PMID- 29478421 TI - MtDNA allows the sensitive detection and haplotyping of the crayfish plague disease agent Aphanomyces astaci showing clues about its origin and migration. AB - The oomycete Aphanomyces astaci, the causative agent of crayfish plague, is listed as one of the 100 worst invasive species in the world, destroying the native crayfish populations throughout Eurasia. The aim of this study was to examine the potential of selected mitochondrial (mt) genes to track the diversity of the crayfish plague pathogen A. astaci. Two sets of primers were developed to amplify the mtDNA of ribosomal rnnS and rnnL subunits. We confirmed two main lineages, with four different haplogroups and five haplotypes among 27 studied A. astaci strains. The haplogroups detected were (1) the A-haplogroup with the a haplotype strains originating from Orconectes sp., Pacifastacus leniusculus and Astacus astacus; (2) the B-haplogroup with the b-haplotype strains originating from the P. leniusculus; (3) the D-haplogroup with the d1 and d2-haplotypes strains originating from Procambarus clarkii; and (4) the E-haplogroup with the e haplotype strains originating from the Orconectes limosus. The described markers are stable and reliable and the results are easily repeatable in different laboratories. The present method has high applicability as it allows the detection and characterization of the A. astaci haplotype in acute disease outbreaks in the wild, directly from the infected crayfish tissue samples. PMID- 29478422 TI - Lower vitamin D intake is associated with low HDL cholesterol and vitamin D insufficiency/deficiency in Brazilian children. AB - OBJECTIVE: To evaluate the association of vitamin D intake with dyslipidaemia and vitamin D insufficiency/deficiency in Brazilian children and identify the main food group sources of this nutrient in the sample. DESIGN: A cross-sectional study carried out with a representative sample. Blood was collected after 12 h of fasting. Laboratory tests were performed to determine total cholesterol, HDL cholesterol (HDL-C), LDL cholesterol, TAG, apoB, apoA1, 25-hydroxyvitamin D and parathyroid hormone. Dietary intake was evaluated by a 24 h recall. SETTING: Vicosa, Minas Gerais, Brazil. SUBJECTS: Children between 8 and 9 years old enrolled in urban schools (n 378). RESULTS: We found an elevated prevalence of inadequate vitamin D intake (91.3 %), dyslipidaemia (72.8 %) and vitamin D insufficiency/deficiency (56.2 %). The food groups that contributed the most to vitamin D intake were dairy products and fish. Lower vitamin D intake was associated with increased prevalence of both low HDL-C (prevalence ratio=2.51; 95 % CI 1.02, 6.18; P<0.05) and vitamin D insufficiency/deficiency (prevalence ratio=1.61; 95 % CI 1.01, 2.58; P<0.05). CONCLUSIONS: Given the elevated prevalence of inadequate vitamin D intake and its association with low HDL-C and vitamin D insufficiency/deficiency, it is important to develop specific actions in food and nutritional education as well as programmes that stimulate and facilitate access to vitamin D food sources, such as dairy products and fish. PMID- 29478423 TI - Early detection and successful treatment of Wernicke's encephalopathy in outpatients without the complete classic triad of symptoms who attended a psycho oncology clinic. AB - OBJECTIVE: Wernicke's encephalopathy (WE) is a neuropsychiatric disorder caused by a thiamine deficiency. Although WE has been recognized in cancer patients, it can be overlooked because many patients do not exhibit symptoms that are typical of WE, such as delirium, ataxia, or ocular palsy. Furthermore, outpatients with WE who intermittently present at psycho-oncology clinics have not been described as far as we can ascertain. METHOD: This report describes two patients who did not exhibit the complete classic triad of symptoms among a series with cancer and WE, and who attended a psycho-oncology outpatient clinic.ResultCase 1, a 76-year old woman with pancreatic cancer and liver metastasis, periodically attended a psycho-oncology outpatient clinic. She presented with delirium and ataxia as well as appetite loss that had persisted for 8 weeks. We suspected WE, which was confirmed by low serum thiamine levels and the disappearance of delirium after thiamine administration. Case 2, a 79-year-old man with advanced stomach cancer, was referred to a psycho-oncology outpatient clinic with depression that had persisted for about 1 month. He also had appetite loss that had persisted for several weeks. He became delirious during the first visit to the outpatient clinic. Our initial suspicion of WE was confirmed by low serum thiamine levels and the disappearance of delirium after thiamine administration. The key indicator of a diagnosis of WE in both patients was appetite loss.Significance of resultsThis report emphasizes awareness of WE in the outpatient setting, even when patients do not exhibit the classical triad of WE. Appetite loss might be the key to a diagnosis of WE in the absence of other causes of delirium. PMID- 29478424 TI - Mustard and cumin seeds improve feed utilisation, milk production and milk fatty acids of Damascus goats. AB - The experiments reported in this Research Paper aimed to study the effects of mustard and cumin seeds inclusion on feed utilisation, milk production, composition, and profile of milk fatty acids in lactating Damascus goats. The study was a completely randomised design with repeated measurements in time using fifteen goats (6 +/- 2 d of lactation) divided into 3 treatments (5 goats per treatment). Goats were offered a control diet of berseem clover and concentrates (1 : 1 dry matter (DM) basis) or the control diet supplemented with either 10 g/d of dried mustard seeds (mustard treatment) or 10 g/d of cumin seeds (cumin treatment) for 12 weeks. Treatments had no effect (P > 0.05) on feed intake, but enhanced (P < 0.05) digestibility of DM, organic matter, non-structural carbohydrates, and fibre fractions. Digestibility was greater (P < 0.001) with cumin treatment compared with mustard treatment. Mustard and cumin seeds had greater (P < 0.05) ruminal total short chain fatty acids (SCFA) production, and molar proportion of propionate, with greater (P < 0.001) SCFA production for cumin vs. mustard treatment. Mustard and cumin seeds increased (P < 0.05) concentrations of serum total proteins, globulin, and glucose and lowered (P < 0.05) serum cholesterol concentration. Mustard and cumin seeds inclusion elevated milk production (P = 0.007), while cumin increased milk contents (P < 0.05) of fat and lactose. Cumin treatment lowered (P < 0.05) milk saturated fatty acids (SFA) and had greater total unsaturated fatty acids (UFA) and total conjugated linoleic acid (CLA) contents. Overall, supplementing diets of Damascus goats with mustard or cumin seeds at 10 g/daily enhanced feed digestion, ruminal fermentation, milk yield (actual production by 6.8 and 11.1%, and energy corrected milk yield by 10.1 and 15.4%, respectively) and positively modified milk fatty acid profile with a 3.9% decrease in milk individual and total SFA, and an increase in individual and total UFA by about 9.7%, and total CLA by about 23.1%. PMID- 29478425 TI - Day hospital mentalization-based treatment v. specialist treatment as usual in patients with borderline personality disorder: randomized controlled trial. AB - BACKGROUND: Day hospital mentalization-based treatment (MBT-DH) is a promising treatment for borderline personality disorder (BPD) but its evidence base is still limited. This multi-site randomized trial compared the efficacy of MBT-DH delivered by a newly set-up service v. specialist treatment as usual (S-TAU) tailored to the individual needs of patients, and offered by a well-established treatment service. METHODS: Two mental healthcare institutes in The Netherlands participated in the study. Patients who met DSM-IV criteria for BPD and had a score of ?20 on the borderline personality disorder severity index (BPDSI) were randomly allocated to MBT-DH (N = 54) or S-TAU (N = 41). The primary outcome variable was the total score on the BPDSI. Secondary outcome variables included symptom severity, quality of life, and interpersonal functioning. Data were collected at baseline and every 6 months until 18-month follow-up, and were analyzed using multilevel analyses based on intention-to-treat principles. RESULTS: Both treatments were associated with significant improvements in all outcome variables. MBT-DH was not superior to S-TAU on any outcome variable. MBT DH was associated with higher acceptability in BPD patients compared v. S-TAU, reflected in significantly higher early drop-out rates in S-TAU (34%) v. MBT-DH (9%). CONCLUSIONS: MBT-DH delivered by a newly set-up service is as effective as specialist TAU in The Netherlands in the treatment of BPD at 18-month follow-up. Further research is needed to investigate treatment outcomes in the longer term and the cost-effectiveness of these treatments. PMID- 29478426 TI - Effects of in ovo feeding of l-arginine on breast muscle growth and protein deposition in post-hatch broilers. AB - In ovo feeding (IOF) of l-arginine (Arg) can affect growth performance of broilers, but the response of IOF of Arg on breast muscle growth is unclear, and the mechanism involved in protein deposition remains unknown. Hense, this experiment was conducted to evaluate the effects of IOF of Arg on breast muscle growth and protein-deposited signalling in post-hatch broilers. A total of 720 fertile eggs were collected from 34-week-old Arbor Acres breeder hens and distributed to three treatments: (1) non-injected control group; (2) 7.5 g/l (w/v) NaCl diluent-injected control group; (3) 0.6 mg Arg/egg solution-injected group. At 17.5 days of incubation, fertile eggs were injected 0.6 ml solutions into the amnion of the injected groups. Upon hatching, 80 male chicks were randomly assigned to eight replicates of 10 birds each and fed ad libitum for 21 days. The results indicated that IOF of Arg increased relative breast muscle weight compared with those of control groups at hatch, 3-, 7- and 21-day post hatch (P<0.05). In the Arg-injected group, the plasma total protein and albumen concentrations were higher at 7- and 21-day post-hatch than those of control groups (P<0.05). The alanine aminotransferase activity in Arg group was higher at hatch than that of control groups (P<0.05). The levels of triiodothyronine at four time points and thyroxine hormones at hatch, 7- and 21-day post-hatch in Arg group were higher than those of control groups (P<0.05). In addition, IOF of Arg increased the amino acid concentrations of breast muscle at hatch, 7- and 21-day post-hatch (P<0.05). In ovo feeding of Arg also enhanced mammalian target of rapamycin, ribosomal protein S6 kinase-1 and eIF4E-bindingprotein-1 messenger RNA expression levels at hatch compared with those of control groups (P<0.05). It was concluded that IOF of Arg treatment improved breast muscle growth, which might be associated with the enhancement of protein deposition. PMID- 29478427 TI - What factors may contribute to sex differences in childhood obesity prevalence in China? AB - OBJECTIVE: Previous studies in China showed large sex differences in childhood overweight and obesity (OW/OB) rates. However, limited research has examined the cause of these sex differences. The present study aimed to examine individual and parental/familial factors associated with sex differences in childhood OW/OB rates in China. DESIGN: Variables associated with child weight status, beliefs and behaviours, and obesity-related parenting practices were selected to examine their sex differences and association with a sex difference in child OW/OB outcomes using logistic regression analysis. SETTING: Cross-sectional data analysis using the 2011 China Health and Nutrition Survey. SUBJECTS: Children aged 6-17 years (n 1544) and their parents. RESULTS: Overall child OW/OB prevalence was 16.8 %. Adolescent boys (AB; 12-17 years) were about twice as likely to be overweight/obese as adolescent girls (AG; 15.5 v. 8.4 %, P<0.05). AB more likely had energy intake exceeding recommendations, self-perceived underweight, underestimated their body weight and were satisfied with their physical activity level than AG. AG more likely practised weight-loss management through diet and self-perceived overweight than AB. Mothers more likely identified AG's weight accurately but underestimated AB's weight. Stronger associations with risk of childhood OW/OB were found in boys than girls in dieting to lose weight (OR=6.7 in boys v. 2.6 in girls) and combined maternal and child perception of the child's overweight (OR=35.4 in boys v. 14.2 in girls). CONCLUSIONS: Large sex differences in childhood obesity may be related to the sex disparities in weight-related beliefs and behaviours among children and their parents in China. PMID- 29478428 TI - 'To know before hand is to freeze and kill' Commentary on... Should psychiatrists write fiction? AB - In this article I argue that fictional accounts of mental illness should be unethically unobliged. I suggest that art is not generated with conscious ethical intent and provide evidence that art proceeding from an ethical agenda is more likely to be poor art. I also consider ways in which a writer-doctor might need to compromise what they articulate to maintain a professional ethical integrity. Declaration of interest None. PMID- 29478429 TI - Milk production and composition, and progeny performance in young ewes with high merit for rapid growth and muscle and fat accumulation. AB - In ewe lambs, acceleration of growth and accumulation of both muscle and fat leads to earlier sexual maturity and better reproductive performance. The next stage in the development of this theme is to test whether these aspects of growth in young ewes affect milk production in their first lactation and the growth of their first progeny. We studied 75 young Merino ewes that had known phenotypic values for depth of eye muscle (EMD) and fat (FAT), and known Australian Sheep Breeding Values for post-weaning weight (PWT) and depths of eye muscle (PEMD) and fat (PFAT). They lambed for the first time at 1 year of age. Their lambs were weighed weekly from birth to weaning at 10 weeks to determine live weight gain and weaning weight. Progeny birth weight was positively associated with live weight gain and weaning weight (P0.05). The PWT of the sire was positively associated with live weight gain (P0.05). The concentrations of fat, protein, lactose and total solids in the milk were not affected by the phenotype or genotype of the mothers or of the sires of the mothers, or by the sex of the progeny (P>0.05). We conclude that selection of young Merino ewes for better growth, and more rapid accumulation of muscle and fat, will lead to progeny that are heavier at birth, grow faster and are heavier at weaning. Moreover, milk production and composition do not seem to be affected by the genetic merit of the mother for post-weaning live weight or PEMD or PFAT. Therefore, Merino ewes can lamb at 1 year of age without affecting the production objectives of the Merino sheep industry. PMID- 29478431 TI - What is mood? A computational perspective. AB - The neurobiological understanding of mood, and by extension mood disorders, remains elusive despite decades of research implicating several neuromodulator systems. This review considers a new approach based on existing theories of functional brain organisation. The free energy principle (a.k.a. active inference), and its instantiation in the Bayesian brain, offers a complete and simple formulation of mood. It has been proposed that emotions reflect the precision of - or certainty about - the predicted sensorimotor/interoceptive consequences of action. By extending this reasoning, in a hierarchical setting, we suggest mood states act as (hyper) priors over uncertainty (i.e. emotions). Here, we consider the same computational pathology in the proprioceptive and interoceptive (behavioural and autonomic) domain in order to furnish an explanation for mood disorders. This formulation reconciles several strands of research at multiple levels of enquiry. PMID- 29478430 TI - Weight, physical activity and breast cancer survival. AB - Weight, weight change and physical activity may affect prognosis among women who are diagnosed with breast cancer. Observational studies show associations between overweight/obesity and weight gain with several measures of reduced prognosis in women with breast cancer, and some suggestions of lower survival in women who are underweight or who experience unexplained weight loss after diagnosis. Observational studies have also shown an association between higher levels of physical activity and reduced breast cancer-specific and all-cause mortality, although a dose-response relationship has not been established. The effects of purposive dietary weight loss and increase in physical activity on survival or recurrence in breast cancer are not yet established, and randomised controlled trials are needed for definitive data. This paper presents the epidemiologic evidence on weight status, weight change, and physical activity and breast cancer survival; suggests potential mediating mechanisms; summarises evidence on weight loss interventions in breast cancer survivors; describes ongoing randomised clinical trials designed to test the effects of weight loss or physical activity on breast cancer survival; and provides information on available guidelines on weight and physical activity for cancer survivors. PMID- 29478432 TI - Fitness and eco-physiological response of a chytrid fungal parasite infecting planktonic cyanobacteria to thermal and host genotype variation. AB - Understanding how individual parasite traits contribute to overall fitness, and how they are modulated by both external and host environment, is crucial for predicting disease outcome. Fungal (chytrid) parasites of phytoplankton are important yet poorly studied pathogens with the potential to modulate the abundance and composition of phytoplankton communities and to drive their evolution. Here, we studied life-history traits of a chytrid parasite infecting the planktonic, bloom-forming cyanobacterium Planktothrix spp. under host genotype and thermal variation. When expressing parasite fitness in terms of transmission success, disease outcome was largely modulated by temperature alone. Yet, a closer examination of individual parasite traits linked to different infection phases, such as (i) the establishment of the infection (i.e. intensity of infection) and (ii) the exploitation of host resources (i.e. size of reproductive structures and propagules), revealed differential host genotype and temperature * host genotype modulation, respectively. This illustrates how parasite fitness results from the interplay of individual parasite traits that are differentially controlled by host and external environment, and stresses the importance of combining multiple traits to gain insights into underlying infection mechanisms. PMID- 29478434 TI - Progress in Recognizing and Treating Polyneuropathy. PMID- 29478435 TI - Rumpel-Leede Sign After Coronary Angiography. PMID- 29478437 TI - Nonspecific Lower Abdominal Pain? PMID- 29478433 TI - Psychotic experiences and general medical conditions: a cross-national analysis based on 28 002 respondents from 16 countries in the WHO World Mental Health Surveys. AB - BACKGROUND: Previous work has identified associations between psychotic experiences (PEs) and general medical conditions (GMCs), but their temporal direction remains unclear as does the extent to which they are independent of comorbid mental disorders. METHODS: In total, 28 002 adults in 16 countries from the WHO World Mental Health (WMH) Surveys were assessed for PEs, GMCs and 21 Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) mental disorders. Discrete-time survival analyses were used to estimate the associations between PEs and GMCs with various adjustments. RESULTS: After adjustment for comorbid mental disorders, temporally prior PEs were significantly associated with subsequent onset of 8/12 GMCs (arthritis, back or neck pain, frequent or severe headache, other chronic pain, heart disease, high blood pressure, diabetes and peptic ulcer) with odds ratios (ORs) ranging from 1.3 [95% confidence interval (CI) 1.1-1.5] to 1.9 (95% CI 1.4-2.4). In contrast, only three GMCs (frequent or severe headache, other chronic pain and asthma) were significantly associated with subsequent onset of PEs after adjustment for comorbid GMCs and mental disorders, with ORs ranging from 1.5 (95% CI 1.2-1.9) to 1.7 (95% CI 1.2-2.4). CONCLUSIONS: PEs were associated with the subsequent onset of a wide range of GMCs, independent of comorbid mental disorders. There were also associations between some medical conditions (particularly those involving chronic pain) and subsequent PEs. Although these findings will need to be confirmed in prospective studies, clinicians should be aware that psychotic symptoms may be risk markers for a wide range of adverse health outcomes. Whether PEs are causal risk factors will require further research. PMID- 29478436 TI - Polyneuropathies. AB - BACKGROUND: Polyneuropathies (peripheral neuropathies) are the most common type of disorder of the peripheral nervous system in adults, and specifically in the elderly, with an estimated prevalence of 5-8%, depending on age. The options for treatment depend on the cause, which should therefore be identified as precisely as possible by an appropriate diagnostic evaluation. METHODS: This review is based on the current guidelines and on large-scale cohort studies and randomized, controlled trials published from 2000 to 2017, with an emphasis on non-hereditary types of polyneuropathy, that were retrieved by a selective search in PubMed. RESULTS: Diabetes is the most common cause of polyneuropathy in Europe and North America. Alcohol-associated polyneuropathy has a prevalence of 22-66% among persons with chronic alcoholism. Because of the increasing prevalence of malignant disease and the use of new chemotherapeutic drugs, chemotherapy-induced neuropathies (CIN) have gained in clinical importance; their prevalence is often stated to be 30-40%, with high variation depending on the drug(s) and treatment regimen used. Polyneuropathy can also arise from genetic causes or as a consequence of vitamin deficiency or overdose, exposure to toxic substances and drugs, and a variety of immunological processes. About half of all cases of polyneu - ropathy are associated with pain. Neuropathic pain can be treated symptomatically with medication. Exercise, physiotherapy, and ergotherapy can also be beneficial, depending on the patient's symptoms and functional deficits. CONCLUSION: A timely diagnosis of the cause of polyneuropathy is a prerequisite for the initiation of appropriate specific treatment. Patients with severe neuropathy of unidentified cause should be referred to a specialized center for a thorough diagnostic evaluation. PMID- 29478439 TI - Oxygen-Resistant "Cyanosis" After Sun Exposure. PMID- 29478440 TI - Additional Information. PMID- 29478441 TI - In Reply. PMID- 29478438 TI - Hereditary Neuropathies. AB - BACKGROUND: Hereditary peripheral neuropathies constitute a large group of genetic diseases, with an overall prevalence of 1:2500. In recent years, the use of so-called next-generation sequencing (NGS) has led to the identification of many previously unknown involved genes and genetic defects that cause neuropathy. In this article, we review the procedures and utility of genetic evaluation for hereditary neurop - athies, while also considering the implications of the fact that causally directed treatment of these disorders is generally unavailable. METHODS: This review is based on pertinent publications retrieved by a PubMed search employing the search terms "hereditary neuropathy," "Charcot-Marie-Tooth disease," "hereditary sensory neuropathy," and "hereditary motor neuropathy." RESULTS: With rare exceptions, the diagnostic evaluation for hereditary neuropathies proceeds in stepwise fashion, beginning with the study of individual genes. If this fails to detect any abnormality, NGS analysis, which involves the sequencing of many different genes in parallel and has now become available for routine diagnosis, should be performed early on in the diagnostic work-up. Exome and genome analyses are currently performed only when considered to be indicated in the individual case. Whenever a hereditary neuropathy is suspected, other (including potentially treatable) causes of neuropathy should be ruled out. Mutations in neurop athy-associated genes may also be associated with other clinical entities such as spastic paraplegia or myopathy. Thus, interdisciplinary assessment is necessary. CONCLUSION: The molecular diagnosis of neuropathies has become much more successful through the use of NGS. Although causally directed treatment approaches still need to be developed, the correct diagnosis puts an end to the often highly stressful search for a cause and enables determination of the risk of disease in other members of the patient's family. PMID- 29478442 TI - Our dental care system is stuck: And here is what to do about it. PMID- 29478443 TI - Authors' response. PMID- 29478444 TI - Letters. PMID- 29478445 TI - Correction. PMID- 29478446 TI - Correction. PMID- 29478447 TI - Correction. PMID- 29478449 TI - Oral rigidity and xerostomia in a 46-year-old man. PMID- 29478448 TI - Periodontal status of current methamphetamine users. AB - BACKGROUND: Methamphetamine (MA) use is associated with extensive dental caries. The purpose of this study was to determine the prevalence and severity of periodontal disease in a convenience sample of MA users. METHODS: In this cross sectional survey, MA users were recruited with a combination of snowball sampling and street outreach techniques. Three dentists, trained and calibrated to the oral assessments used in the National Health and Nutrition Survey, measured and recorded the participants' attachment loss, probing depth, and gingival recession. Concomitant interviews elicited psychological, substance use, medication, and dietary habits associated with MA use. RESULTS: Periodontal assessments were completed on 546 adults. More than 69% were cigarette smokers, and more than 55% were medium to high MA users. Classifying prevalence by means of the Centers for Disease Control and Prevention and the American Academy of Periodontology definitions, cigarette smokers and medium to high MA users had a high prevalence of periodontal disease. The defining features of the participants were being 30 years and older (average, 42.2 years) and having severe and moderate periodontitis. CONCLUSION: This is the first study to the authors' knowledge to systematically examine periodontal disease in a large population of current MA users. MA users in a Los Angeles urban setting had a high prevalence and severity of destructive periodontal disease. The frequency of MA use had a minimal impact on the severity of periodontal disease. PRACTICAL IMPLICATIONS: An MA user can be at high risk of developing periodontal disease. Knowing that behavioral factors, such as smoking and consuming sugary beverages, are more important than MA use will assist the clinician in managing the treatment of MA users. PMID- 29478450 TI - Facial pain associated with cardiac origin. AB - BACKGROUND: Ischemic heart disease manifests as pain on the left side, in the retrosternal or the precordial region, with subsequent radiation to the ipsilateral shoulder, face, and cervical region. Less frequently, it may manifest solely as face pain. CASE DESCRIPTION: A 57-year-old man sought care at the Massachusetts General Hospital Oral and Maxillofacial Pain Center with a symptom of pain in the mandibular left posterior region, in the medial aspect of the ipsilateral eye, and in the left side of the neck. The pain had started approximately 8 months previously as a mild, constant dull ache in the mandibular left posterior region. However, it became severe in intensity and sharp in quality and radiated toward the medical aspect of the ipsilateral eye and lateral neck region after intense physical activity. Results from comprehensive diagnostic evaluation and a series of diagnostic tests suggested that the facial pain was associated with cardiovascular disease. There was complete resolution of pain symptoms after the patient received appropriate pharmacotherapy. PRACTICAL IMPLICATIONS: Association of pain with exercise and termination of pain with rest and the presence of risk factors for cardiovascular disease necessitate a thorough investigation of rare and fatal causes of facial pain. PMID- 29478451 TI - Dental Public Health Practice, Infrastructure, and Workforce in the United States. AB - Dental public health is a unique specialty of dentistry that focuses on prevention of oral diseases among populations rather than individual patients. It encompasses several complementary disciplines and greatly varies in its functions and activities. Several federal, state, local, and nonpublic entities operationalize the mission of dental public health to improve population oral health through a diverse and vibrant workforce. PMID- 29478452 TI - Oral Health Disparities Across the Life Span. AB - Despite improvements in the oral health status of the US population as a whole, a disproportionately higher burden of oral diseases and disorders are borne by those individuals from low-income and racial and ethnic minority groups. These differences in health status, health outcomes, or health care use between distinct socially disadvantaged and advantaged groups are well documented and known as health disparities. It is vital that members of the dental profession understand the distribution of oral health and disease across different populations and the life span and participate in developing innovative and sustainable approaches to eliminate oral health disparities. PMID- 29478453 TI - The Expanding Dental Workforce: The Impact of Nondental Providers. AB - This article describes the evolution of nondental health providers engaging in oral health and the influences that have played a role. This discussion is followed by a review of why oral health is a natural fit for medical care, an examination of the current trends and successes in oral health education and practice in the health professions, and the need for a comprehensive approach. The article concludes by reviewing the impact these efforts are having and defining roles for each profession in the future with thoughts about what will be required to obtain these goals. PMID- 29478455 TI - Infant Oral Health: An Emerging Dental Public Health Measure. AB - Infant oral health (IOH) is a preventive service advocated by major medical and dental organizations. IOH aims to prevent early childhood caries (ECC) and impart health strategies to families for continued oral health and prevention of future caries. IOH reaches across disciplines, is low cost, and is covered by Medicaid and many private dental payers. Increasing evidence points to immediate and long term positive oral health outcomes of reduced disease, reduction in costly care, and reduction in ECC-associated morbidities. PMID- 29478456 TI - Dental Care for Geriatric and Special Needs Populations. AB - This article reviews considerations for oral health care associated with the most common causes of mortality and morbidity in older adults. Many of these diseases result in functional or cognitive impairments that must be considered in treatment planning to ensure appropriate, safe, and effective care for patients. Many of these considerations parallel those of adults who have lived with developmental disabilities over a lifetime and similar principles can be applied. Systemic diseases, conditions, and their treatments can pose significant risks to oral health, which requires prevention, treatment, and advocacy for oral health care as integral to chronic disease management. PMID- 29478457 TI - Providing Health Screenings in a Dental Setting to Enhance Overall Health Outcomes. AB - Data suggest that providers and patients have a favorable attitude toward chairside screening in the dental setting and are willing to participate in these activities. Likewise, efficacy studies indicate this strategy can effectively identify patients who are at increased risk of disease or have the presence of disease risk factors and could benefit from medical follow-up. Studies suggest it is feasible to conduct these screenings in the dental setting. Although the American Dental Association has established screening treatment codes, challenges to widespread implementation still exist, including developing a provider reimbursement strategy and the need for adequate provider training. PMID- 29478454 TI - Fluorides and Other Preventive Strategies for Tooth Decay. AB - We focus on scalable public health interventions that prevent and delay the development of caries and enhance resistance to dental caries lesions. These interventions should occur throughout the life cycle, and need to be age appropriate. Mitigating disease transmission and enhancing resistance are achieved through use of various fluorides, sugar substitutes, mechanical barriers such as pit-and-fissure sealants, and antimicrobials. A key aspect is counseling and other behavioral interventions that are designed to promote use of disease transmission-inhibiting and tooth resistance-enhancing agents. Advocacy for public water fluoridation and sugar taxes is an appropriate dental public health activity. PMID- 29478458 TI - Role of Dentists in Prescribing Opioid Analgesics and Antibiotics: An Overview. AB - Opioid analgesics and antibiotics prescribed by dentists is a useful and cost effective measure when prescribed appropriately. Common dental conditions are best managed by extracting the offending tooth, restoring the tooth with an appropriate filling material, performing root canal therapy, and/or fabricating a prosthesis for the edentulous space. Unnecessary prescription of opioid analgesics and antibiotics to treat dental pain and bacterial infection is a growing public health concern. This article highlights the state of the literature on opioid analgesic and antibiotic prescribing practices in dentistry, the impact of opioid analgesic overdose, and prevention strategies to reduce opioid analgesics and antibiotic overprescription. PMID- 29478459 TI - Trends in Pediatric Dental Care Use. AB - This article explores trends in 3 areas of dental services use for children less than 21 years of age. First, it examines the change in access to prevention, diagnostic, and treatment services over time among Medicaid-enrolled children and how access to care is affected by state-level factors. Second, it evaluates trends and health care costs associated with the treatment of oral health conditions in the operating room of pediatric hospitals. Third, it examines the trends in use of emergency departments for dental needs among children in the United States. PMID- 29478461 TI - A Public Health Perspective on Paying for Dentistry, the Affordable Care Act, and Looking to the Future. AB - Health care costs have traditionally been provider generated whereas payment has been split between public and private sources. There has been little pressure on health care providers to demonstrate value. The quest for value in health care financing is now widely evident as demonstrated by governmental and private sector pursuits of a 3-part aim: better health outcomes at lower cost with improved patient and population experience. Value-based approaches involve payment innovation with its attendant constraints and opportunities for innovation. This contribution posits a growing role for dental public health by exploring interfaces with these forces within the contexts of US dental care financing. PMID- 29478460 TI - Innovative Models of Dental Care Delivery and Coverage: Patient-Centric Dental Benefits Based on Digital Oral Health Risk Assessment. AB - Innovative models of dental care delivery and coverage are emerging across oral health care systems causing changes to treatment and benefit plans. A novel addition to these models is digital risk assessment, which offers a promising new approach that incorporates the use of a cloud-based technology platform to assess an individual patient's risk for oral disease. Risk assessment changes treatment by including risk as a modifier of treatment and as a determinant of preventive services. Benefit plans are being developed to use risk assessment to predetermine preventive benefits for patients identified at elevated risk for oral disease. PMID- 29478462 TI - The Intersection of Clinical Practice and Dental Public Health. PMID- 29478464 TI - [Pharmacovigilance, our ally in daily practice]. PMID- 29478463 TI - [Personalized medicine in primary care]. PMID- 29478465 TI - The democratisation of health in the real world. PMID- 29478466 TI - Hats On: Why Hair Must Be Covered, an Infection Prevention Perspective. PMID- 29478467 TI - Out of Sight, but Not Out of Mind: Covering Hair in the Operating Room Is Not Effective If the Hat Is Suboptimal: In Reply to Fabre and Colleagues. PMID- 29478468 TI - Checklist for Surgeons Engaged in Global Surgery. PMID- 29478469 TI - A Potential Definitive Solution Is Preferable: In reply to Toro and colleagues. PMID- 29478470 TI - Does Converted Open Subtotal Cholecystectomy Definitively Cure a Diseased Gallbladder? PMID- 29478471 TI - Delayed Gastric Emptying after Pancreaticoduodenectomy: The Hunt Continues. PMID- 29478472 TI - Flange Gastroenterostomy: In Reply to Limongelli and Colleagues. PMID- 29478473 TI - Assessing Emergency Surgical Procedures for Life-Threatening Illness in Randomized Clinical Trials. PMID- 29478474 TI - Randomized Clinical Trial (DIVERTI) and Ethical Considerations: In reply to Fujita. PMID- 29478475 TI - Epidural Analgesia after Colorectal Surgery Within an Enhanced Recovery Program. PMID- 29478476 TI - March 2018 Featured Articles, Volume 226. PMID- 29478477 TI - Correction. PMID- 29478478 TI - Cost-Effectiveness Analysis and the Foot and Ankle Surgeon. PMID- 29478479 TI - Appraisal of Biofilm Formation in Diabetic Foot Infections by Comparing Phenotypic Methods With the Ultrastructural Analysis. AB - Diabetic patients are more prone to the development of foot ulcers, because their underlying tissues are exposed to colonization by various pathogenic organisms. Hence, biofilm formation plays a vital role in disease progression by antibiotic resistance to the pathogen found in foot infections. The present study has demonstrated the correlation of biofilm assay with the clinical characteristics of diabetic foot infection. The clinical characteristics such as the ulcer duration, size, nature, and grade were associated with biofilm production. Our results suggest that as the size of the ulcer with poor glycemic control increased, the organism was more likely to be positive for biofilm formation. A high-degree of antibiotic resistance was exhibited by the biofilm-producing gram positive isolates for erythromycin and gram-negative isolates for cefpodoxime. Comparisons of biofilm production using 3 different conventional methods were performed. The strong producers with the tube adherence method were able to produce biofilm using the cover slip assay method, and the weak producers in tube adherence method had difficulty in producing biofilm using the other 2 methods, indicating that the tube adherence method is the best method for assessing biofilm formation. The strong production of biofilm with the conventional method was further confirmed by scanning electron microscopy analysis, because bacteria attached as a distinct layer of biofilm. Thus, the high degree of antibiotic resistance was exhibited by biofilm producers compared with nonbiofilm producers. The tube adherence and cover slip assay were found to be the better method for biofilm evaluation. PMID- 29478480 TI - Percutaneous Kirschner Wire Versus Commercial Implant for Hammertoe Repair: A Cost-Effectiveness Analysis. AB - Hammertoe deformities are one of the most common foot deformities, affecting up to one third of the general population. Fusion of the joint can be achieved with various devices, with the current focus on percutaneous Kirschner (K)-wire fixation or commercial intramedullary implant devices. The purpose of the present study was to determine whether surgical intervention with percutaneous K-wire fixation versus commercial intramedullary implant is more cost effective for proximal interphalangeal joint arthrodesis in hammertoe surgery. A formal cost effectiveness analysis using a decision analytic tree model was conducted to investigate the healthcare costs and outcomes associated with either K-wire or commercial intramedullary implant fixation. The outcomes assessed included long term costs, quality-adjusted life-years (QALYs), and incremental cost per QALY gained. Costs were evaluated from the healthcare system perspective and are expressed in U.S. dollars at a 2017 price base. Our results found that commercial implants were minimally more effective than K-wires but carried significantly higher costs. The total cost for treatment with percutaneous K-wire fixation was $5041 with an effectiveness of 0.82 QALY compared with a commercial implant cost of $6059 with an effectiveness of 0.83 QALY. The incremental cost-effectiveness ratio of commercial implants was $146,667. With an incremental cost-effectiveness ratio of >$50,000, commercial implants failed to justify their proposed benefits to outweigh their cost compared to percutaneous K-wire fixation. In conclusion, percutaneous K-wire fixation would be preferred for arthrodesis of the proximal interphalangeal joint for hammertoes from a healthcare system perspective. PMID- 29478481 TI - Arthroscopy of the First Metatarsophalangeal Joint. AB - Arthroscopic treatments for the first metatarsophalangeal joint have not spread fully owing to a number of factors. First, in the common arthroscopic view, the joint is observed from above, which makes the structures difficult to grasp and the dorsal aspect of the joint difficult to visualize and treat. Second, techniques for widening the view have not yet been reported. Third, the portals necessary for observation and treatment with hallux sesamoids have not yet been established. Finally, techniques for detecting the sesamoids have not been previously reported. We have developed a method for first metatarsophalangeal joint arthroscopy by treating 14 patients with hallux rigidus and 9 patients with hallux sesamoid disorders. We report a new method that combines a variety of arthroscopic techniques. Our study has 4 novel points. First, in our arthroscopic technique, the joint can be examined from the medial side because traction is directly and horizontally applied to the great toe using an adjustable traction device with the surgeon standing on the unoperated side. The technique enables observation of the dorsal aspect of the metatarsal head and proximal phalanx and makes the structures easier to grasp. Second, the coagulator technique as an arthroscopic aid is demonstrated. Third, all aspects of the joint, including the sesamoids, can be observed through our 4 portals. Finally, techniques for detecting the sesamoids are identified. We believe our novel method will ensure that arthroscopy of the first metatarsophalangeal joint is easier than previously described methods. PMID- 29478482 TI - Acute Compartment Syndrome of the Foot Due To Frostbite: Literature Review and Case Report. AB - Acute compartment syndrome of the foot and ankle is a relatively rare clinical finding. Lower extremity compartment syndrome is customarily due to vascular or orthopedic traumatic limb-threatening pathologic issues. Clinical correlation and measurement of intracompartmental pressure are paramount to efficient diagnosis and treatment. Delayed treatment can lead to local and systemically adverse consequences. Frostbite, a comparatively more common pathologic entity of the distal extremities, occurs when tissues are exposed to freezing temperatures. Previously found in military populations, frostbite has become increasingly prevalent in the general population, leading to more clinical presentations to foot and ankle specialists. We present a review of the published data of acute foot compartment syndrome and pedal frostbite, with pathogenesis, treatment, and subsequent sequelae. A case report illustrating 1 example of bilateral foot, atraumatic compartment syndrome, is highlighted in the present report. The patient presented with changes consistent with distal bilateral forefoot frostbite, along with gangrenous changes to the distal tuft of each hallux. At admission and evaluation, the patient had increasing rhabdomyolysis with no other clear etiology. Compartment pressures were measured in the emergency room and were >100 mm Hg in the medial compartment and 50 mm Hg dorsally. The patient was taken to the operating room urgently for bilateral pedal compartment release. Both pathologic entities have detrimental outcomes if not treated in a timely and appropriate manner, with amputation rates increasing with increasing delay. PMID- 29478483 TI - The Doctor Is In! Diagnostic Analysis. AB - To make meaningful inferences based on our regression models, we must ensure that we have met the necessary assumptions of these tests. In this commentary, we review these assumptions and those for the t-test and analysis of variance, and introduce a variety of methods, formal and informal, numeric and visual, for assessing conformity with the assumptions. PMID- 29478484 TI - Retraction Notice to: Amniotic Band Syndrome with Pseudoarthrosis of Tibia and Fibula: A Case Report [J Foot Ankle Surg. 56 (2017) 1121-1124]. PMID- 29478485 TI - Retraction Notice to: Posterior Arthroscopic Tibiotalar Arthrodesis: Anatomic Feasibility Study [J Foot Ankle Surg. 56 (2017) 704-707]. PMID- 29478486 TI - Erratum to 'Ligands for the Nuclear Peroxisome Proliferator-Activated Receptor Gamma': [Trends in Pharmacological Sciences 36 (2015) 688-704]. PMID- 29478487 TI - Corrigendum to "Influence of ionic strength and polyelectrolyte concentration on the electrical conductivity of suspensions of soft colloidal polysaccharides" [J. Colloid Interface Sci. 459 (2015) 212-217]. PMID- 29478489 TI - Fertile ground for education on fertility preservation. PMID- 29478488 TI - Corrigendum to "Covalent immobilization of molecularly imprinted polymer nanoparticles on a gold surface using carbodiimide coupling for chemical sensing" [J. Colloid Interface Sci. 461 (2016) 1-8]. PMID- 29478490 TI - Negative consequences of corporal punishment of children are unequivocal. PMID- 29478491 TI - 50 Years Ago in The Journal of Pediatrics: Detailing Ipecac; Report on the Committee on Poison Control, Rocky Mountain Pediatric Society. PMID- 29478493 TI - 50 Years Ago in The Journal of Pediatrics: A Study of "Total Therapy" of Acute Lymphocytic Leukemia in Children. PMID- 29478492 TI - Frailty in Children with Liver Disease: A Prospective Multicenter Study. AB - OBJECTIVE: To assess frailty, a measure of physiologic declines in multiple organ systems, in children with chronic liver disease using a novel pediatric frailty tool. STUDY DESIGN: We performed a prospective cross-sectional multicenter study at 17 liver transplantation (LT) centers. 71 children (5-17 years of age), 36 with compensated chronic liver disease (CCLD) and 35 with end-stage liver disease (ESLD) and listed for LT, were assessed for frailty using validated pediatric tools to assess the 5 classic Fried Frailty Criteria-slowness, weakness, exhaustion, diminished physical activity, and shrinkage. Test scores were translated to age- and sex-dependent z scores, generating a maximum frailty score of 10. RESULTS: The median frailty score of the cohort was 4 (IQR 3, 5). Subjects with ESLD had significantly higher frailty scores (median 5; IQR 4, 7) than subjects with CCLD (median 3; IQR 2, 4); (P < .0001). Area under the curve receiver operating characteristic for frailty scores to discriminate between ESLD and CCLD was 0.83 (95% CI 0.73, 0.93). Forty-six percent of children with ESLD were frail and there was no correlation between pediatric frailty scores and physician's global assessments (r = -0.24, 95% CI -0.53, 0.10). CONCLUSIONS: A novel frailty tool assessed additional dimensions of health, not captured by standard laboratory measures and identified the sickest individuals among a cohort of children with chronic liver disease. This tool may have applicability to other children with chronic disease. PMID- 29478494 TI - Safety of Oats in Children with Celiac Disease: A Double-Blind, Randomized, Placebo-Controlled Trial. AB - OBJECTIVE: To evaluate the long-term validity and safety of pure oats in the treatment of children with celiac disease. STUDY DESIGN: This noninferiority clinical trial used a double-blind, placebo-controlled, crossover design extended over 15 months. Three hundred six children with a biopsy-proven diagnosis of celiac disease on a gluten-free diet for >=2 years were randomly assigned to eat specifically prepared gluten-free food containing an age-dependent amount (15-40 g) of either placebo or purified nonreactive varieties of oats for 2 consecutive 6-month periods separated by washout standard gluten-free diet for 3 months. Clinical (body mass index, Gastrointestinal Symptoms Rating Scale score), serologic (IgA antitransglutaminase antibodies, and IgA anti-avenin antibodies), and intestinal permeability data were measured at baseline, and after 6, 9, and 15 months. Direct treatment effect was evaluated by a nonparametric approach using medians (95% CI) as summary statistic. RESULTS: After the exclusion of 129 patients who dropped out, the cohort included 177 children (79 in the oats placebo and 98 in the placebo-oats group; median, 0.004; 95% CI, -0.0002 to 0.0089). Direct treatment effect was not statistically significant for clinical, serologic, and intestinal permeability variables (body mass index: median, -0.5; 95% CI, -0.12 to 0.00; Gastrointestinal Symptoms Rating Scale score: median, 0; 95% CI, -2.5 to 0.00; IgA antitransglutaminase antibodies: median, -0.02; 95% CI, -0.25 to 0.23; IgA anti-avenin antibodies: median, -0.0002; 95% CI, -0.0007 to 0.0003; intestinal permeability test: median, 0.004; 95% CI, -0.0002 to 0.0089). CONCLUSIONS: Pure nonreactive oat products are a safe dietary choice in the treatment of children with celiac disease. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00808301. PMID- 29478495 TI - 50 Years Ago in The Journal of Pediatrics: Human Cell Culture: An Important Tool for the Diagnosis and Understanding of Disease. PMID- 29478496 TI - 50 Years Ago in The Journal of Pediatrics: Successful Treatment of Juvenile Hemangiomas with Prednisone. PMID- 29478497 TI - Up or down? PMID- 29478498 TI - Not all emergency departments are alike. PMID- 29478499 TI - Magnesium sulfate prevents cerebral palsy in premature infants. PMID- 29478500 TI - English language acquisition is delayed in bilingual homes. PMID- 29478501 TI - Phone app detects hyperbilirubinemia. PMID- 29478502 TI - Focused update on cardiopulmonary resuscitation: Utility of rescue breaths. PMID- 29478504 TI - Recognition of Kingella kingae as a major cause of osteoarticular infections in young children. PMID- 29478503 TI - Low 40-year incidence of end-stage renal disease in childhood-onset diabetes. PMID- 29478505 TI - In search of biomarkers for HIE. PMID- 29478506 TI - 50 Years Ago in The Journal of Pediatrics: Familial Granulocytopenia and Associated Immunoglobulin Abnormality: Report of 3 Cases in Young Brothers. PMID- 29478507 TI - Jerold Francis Lucey, MD (1926-2017). PMID- 29478508 TI - Fostering the Career Development of Future Educational Leaders: The Success of the Association of Pediatric Program Directors Leadership in Educational Academic Development Program. PMID- 29478509 TI - 50 Years Ago in The Journal of Pediatrics: Alveolar Arterial Oxygen Gradient in Premature Infants Breathing 100% Oxygen. PMID- 29478511 TI - Biomarkers for atypical Parkinsonism: Some progress, but much work remains. PMID- 29478510 TI - Plasma Biomarkers of Brain Injury in Neonatal Hypoxic-Ischemic Encephalopathy. AB - OBJECTIVES: To evaluate plasma brain specific proteins and cytokines as biomarkers of brain injury in newborns with hypoxic-ischemic encephalopathy (HIE) and, secondarily, to assess the effect of erythropoietin (Epo) treatment on the relationship between biomarkers and outcomes. STUDY DESIGN: A study of candidate brain injury biomarkers was conducted in the context of a phase II multicenter randomized trial evaluating Epo for neuroprotection in HIE. Plasma was collected at baseline (<24 hours) and on day 5. Brain injury was assessed by magnetic resonance imaging (MRI) and neurodevelopmental assessments at 1 year. The relationships between Epo, brain-specific proteins (S100B, ubiquitin carboxy terminal hydrolase-L1 [UCH-L1], total Tau, neuron specific enolase), cytokines (interleukin [IL]-1beta, IL-6, IL-8, IL-10, IL-12P70, IL-13, interferon-gamma [IFN-gamma], tumor necrosis factor alpha [TNF-alpha], brain-derived neurotrophic factor [BDNF], monocyte chemoattractant protein-1), and brain injury were assessed. RESULTS: In 50 newborns with encephalopathy, elevated baseline S100B, Tau, UCH-L1, IL-1beta, IL-6, IL-8, IL-10, IL-13, TNF-alpha, and IFN-gamma levels were associated with increasing brain injury severity by MRI. Higher baseline Tau and lower day 5 BDNF were associated with worse 1 year outcomes. No statistically significant evidence of Epo treatment modification on biomarkers was detected in this small cohort. CONCLUSIONS: Elevated plasma brain-specific proteins and cytokine levels in the first 24 hours of life are associated with worse brain injury by MRI in newborns with HIE. Only Tau and BDNF levels were found to be related to neurodevelopmental outcomes. The effect of Epo treatment on the relationships between biomarkers and brain injury in HIE requires further study. TRIAL REGISTRATION: ClinicalTrials.gov: 01913340. PMID- 29478512 TI - Protein Carbamylation: Chemistry, Pathophysiological Involvement, and Biomarkers. AB - Protein carbamylation refers to a nonenzymatic modification, which consists in the binding of isocyanic acid on protein functional groups. This reaction is responsible for the alteration in structural and functional properties of proteins, which participate in their molecular aging. Protein molecular aging is now considered a molecular substratum for the development of chronic and inflammatory diseases, including atherosclerosis, chronic kidney disease, or rheumatoid arthritis. As a consequence, carbamylation-derived products have been proposed as interesting biomarkers in various pathological contexts and appropriate analytical methods have been developed for their quantification in biological fluids. The purpose of this review is (i) to describe the biochemical bases of the carbamylation reaction, (ii) to explain how it contributes to protein molecular aging, (iii) to provide evidence of its involvement in aging and chronic diseases, and (iv) to list the available biomarkers of carbamylation process and the related analytical methods. PMID- 29478514 TI - Uncertainty in Measurement: Procedures for Determining Uncertainty With Application to Clinical Laboratory Calculations. AB - The "Guide to the Expression of Uncertainty in Measurement" (GUM) is the foundational document of metrology. Its recommendations apply to all areas of metrology including metrology associated with the biomedical sciences. When the output of a measurement process depends on the measurement of several inputs through a measurement equation or functional relationship, the propagation of uncertainties in the inputs to the uncertainty in the output demands a level of understanding of the differential calculus. This review is intended as an elementary guide to the differential calculus and its application to uncertainty in measurement. The review is in two parts. In Part I, Section 3, we consider the case of a single input and introduce the concepts of error and uncertainty. Next we discuss, in the following sections in Part I, such notions as derivatives and differentials, and the sensitivity of an output to errors in the input. The derivatives of functions are obtained using very elementary mathematics. The overall purpose of this review, here in Part I and subsequently in Part II, is to present the differential calculus for those in the medical sciences who wish to gain a quick but accurate understanding of the propagation of uncertainties. PMID- 29478513 TI - Blood Glucose Determination: Effect of Tube Additives. AB - The measurement of fasting plasma glucose may be biased by a time-dependent decrease of glucose in blood tubes, mainly attributable to blood cell metabolism when glycolysis is not rapidly inhibited or blood cells cannot be rapidly separated from plasma. Although glycolysis inhibitors such as sodium fluoride (NaF) in combination with potassium oxalate (KOx) are currently used for overcoming this drawback, their efficacy for stabilizing blood glucose is seemingly limited, and probably lower than that of newer additives such as the citrate buffer. Therefore, we performed a critical analysis of the current scientific literature aimed to generate evidence-based information about the advantages of using citrate buffer in blood tubes compared to the more conventional NaF additive. The results of our systematic overview of the literature show that citrate blood tubes represent a considerable step forward in achieving more accurate and reliable plasma glucose measurements, thereby limiting the risk of underdiagnosing diabetes due to spurious decrease of glucose concentration in uncentrifuged blood specimens, ensuring higher stability of glucose levels over time, while simultaneously producing less hemolysis compared to NaF blood tubes. Therefore, we suggest that the use of this new mixture should be encouraged for achieving a higher degree of accuracy and standardization of plasma glucose measurements. PMID- 29478515 TI - Distribution of Fatty Acids and Lipids During Pregnancy. AB - Maternal fatty acid and lipid metabolism undergoes changes during pregnancy to facilitate fetal growth and development. Different types of fatty acids have different roles in maintaining a successful pregnancy and they are incorporated into different forms of lipids for the purpose of storage and transport. This chapter aims to provide an understanding of the distribution and metabolism of fatty acids and lipids in the maternal, placental, and fetal compartments. We further describe how this distribution is altered in maternal obesity, preterm birth, and pregnancy complications such as gestational diabetes mellitus, preeclampsia, and intrauterine growth restriction. PMID- 29478516 TI - Inflammatory Response During Myocardial Infarction. AB - The occlusion of a coronary artery by a thrombus generated on a ruptured atherosclerotic plaque has been pursued in the last decades as a determining event for the clinical outcome after myocardial infarction (MI). Yet, MI causes a cell death wave front, which triggers an inflammatory response to clear cellular debris, and which in excess can double the myocardial lesion and influence the clinical prognosis in the short and long term. Accordingly, proper, timely regulated inflammatory response has now been considered a second pivotal player in cardiac recovery after MI justifying the search for pharmacological strategies to modulate inflammatory effectors. This chapter reviews the key events and the main effectors of inflammation after myocardial ischemic insult, as well as the contribution of this phenomenon to the progression of atherosclerosis. PMID- 29478517 TI - Metabolomics of Major Depressive Disorder and Bipolar Disorder: Overview and Future Perspective. AB - Major depressive disorder (MDD) and bipolar disorder (BD) are the most common mood disorders. They are etiologically related, but clinically distinct psychiatric illnesses. Their shared clinical features result in high rates of misdiagnosis due to a lack of biomarkers that allow their differentiation. BD is more frequently misdiagnosed as MDD because of overlapping symptomology, often later onset of mania, and frequent occurrence of depressive episodes in patients with BD. Misdiagnosis is also increased when patients with BD present symptoms indicative of a clinically significant depressive episode, but are premorbid for manic symptoms, or previous manic states not recognized. Therefore, the development of specific biomarkers for these disorders would be invaluable for establishing the correct diagnosis and treatment of MDD and BD. This chapter presents an overview and future perspective of the identification of biomarkers for mood disorders using metabolomics. PMID- 29478518 TI - Preface. PMID- 29478519 TI - Effect of heating and ionic strength on the interaction of bovine serum albumin and the antinutrients tannic and phytic acids, and its influence on in vitro protein digestibility. AB - Bioavailability of food nutrients can be reduced in the presence of antinutrients such as phytates and tannins. This work aimed to study bovine serum albumin binding to phytic acid and tannic acid, and its influence on in vitro protein digestibility. The effect of autoclaving and boiling on protein digestibility and the microstructure of complexes was also evaluated. Results showed that high ionic strength promotes greater affinity between tannic acid and bovine serum albumin, and decreases in vitro protein digestibility. For phytic acid and bovine serum albumin, the opposite behavior is observed because interactions are governed by electrostatic forces. A rise in temperature above that causing denaturation of the protein favors its interaction with phytic acid, and disfavors that with tannic acid, probably due to different protein binding site exposure. For both antinutrients, heating treatment increased protein hydrolysis, the size of complexes and their fragility. PMID- 29478520 TI - Emulsifying properties development of pork myofibrillar and sacroplasmic protein irradiated at different dose: A combined FT-IR spectroscopy and low-field NMR study. AB - The present study investigated the effect of different irradiation dose (0, 3, 5 and 7 kGy) on the emulsifying properties development of pork myofibrillar protein (MP) and sacroplasmic protein (SP). The results showed that emulsifying activities of SP was significantly impaired by the increasing irradiation dose, while that of MP were only observed to be significantly improved at 3 kGy irradiation (P < .05). The increasing irradiation dose caused the increase of SP carbonyl groups and the decrease of its sulfhydryl groups (P < .05), while 3 kGy irradiation decreased the carbonyl groups of MP and increased zeta-potential significantly (P < .05). LF-NMR results revealed that the water hydration in MP structure was dose-dependent. FT-IR data displayed that irradiation caused minor change of SP in the amide I region from 1700 to 1600 cm-1, while >=5 kGy irradiation significantly contributed to the denatured aggregated beta-sheet components of MP. PMID- 29478521 TI - Slowly digestible properties of lotus seed starch-glycerine monostearin complexes formed by high pressure homogenization. AB - Starch-lipid complexes were prepared using lotus seed starch (LS) and glycerin monostearate (GMS) via a high-pressure homogenization process, and the effect of high pressure homogenization (HPH) on the slow digestion properties of LS-GMS was investigated. The digestion profiles showed HPH treatment reduced the digestive rate of LS-GMS, and the extent of this change was dependent on homogenized pressure. Scanning electron microscopy displayed HPH treatment change the morphology of LS-GMS, with high pressure producing more compact block-shape structure to resist enzyme digestion. The results of Gel-permeation chromatography and Small-angle X-ray scattering revealed high homogenization pressure impacted molecular weight distribution and semi-crystalline region of complexes, resulting in the formation of new semi-crystalline with repeat unit distance of 16-18 nm and molecular weight distribution of 2.50-2.80 * 105 Da, which displayed strong enzymatic resistance. Differential scanning calorimeter results revealed new semi-crystalline lamellar may originate from type-II complexes that exhibited a high transition temperature. PMID- 29478522 TI - Effect of processing on aggregation mechanism of egg white proteins. AB - Egg white proteins (EWPs) are important components of many food products. To obtain optimal functionality, EWP aggregation needs to be controlled. Different treatments can lead to the formation of aggregates in diverse ways, depending on the parameters of the treatments. Recent articles on the effects of processing (heat treatment, alkali treatment, pulsed electric field, high pressure, ultraviolet irradiation, and high intensity ultrasound) on the aggregation of EWPs are reviewed. The relationships between the processing parameters and the aggregation mechanisms are discussed. The information may be helpful in controlling the aggregation mechanisms during the processing. PMID- 29478523 TI - Effects of a novel chitosan formulation treatment on quality attributes and storage behavior of harvested litchi fruit. AB - The effects of Kadozan (a novel chitosan formulation) treatment on physiological attribute, nutritional quality and storage behavior of harvested "Wuye" litchi fruit were studied. Compared with control litchis, Kadozan treatment significantly decreased fruit respiration rate, retarded the increase of pericarp cell membrane permeability, maintained higher contents of anthocyanins and flavonoids and higher values of L*, a* and b* in litchi pericarp, and reduced the decreases of titratable acidity, total soluble solids, total soluble sugars, and vitamin C contents in litchi pulp, maintaining better quality of litchis. Furthermore, Kadozan treatment decreased browning index and disease index of litchis, kept higher rate of commercially acceptable fruit, and reduced fruit weight loss, showing better storage behavior of litchis under ambient temperature. The optimal Kadozan treatment for litchis was the 1:100 (VKadozan: VKadozan + Water) dilution, which might be a promising method for keeping quality and prolonging shelf-life of harvested "Wuye" litchi fruit. PMID- 29478524 TI - The inhibitory potential of Montmorency tart cherry on key enzymes relevant to type 2 diabetes and cardiovascular disease. AB - The inhibitory potential of Montmorency tart cherry on glycemia regulation and other enzymes relevant to inflammation were evaluated. Tart cherry has superior inhibitory potential against key enzymes associated with carbohydrate digestion linked to hypertension. In particular, alpha-amylase activity was significantly inhibited (IC50 = 3.46 +/- 0.06 mg/ml), whereas we observed mild inhibition of alpha-glucosidase (IC50 = 11.64 +/- 0.65 mg/ml). Angiotensin I-converting enzyme inhibition was also strong by about 89%. Tart cherry extract showed strong to moderate inhibitions of cyclooxygenase-1 (65%), lipoxygenase (64%), cyclooxygenase-2 (38%) and xanthine oxidase (26%), respectively. Anthocyanins, cyanidin 3-rutinoside and cyanidin 3-glucoside, were strong inhibitors of alpha amylase and alpha-glucosidase. Kaempferol showed relatively potent inhibition on COX and XO. It was revealed that some pairs of metabolites manifest positive or negative interactions against XO enzyme inhibition. Inhibition of all these enzymes provides a strong biochemical basis for management of type 2 diabetes and cardiovascular disease by controlling glucose absorption, reducing associated hypertension and inflammation. PMID- 29478525 TI - Development and validation of an HPLC-MS/MS method with QuEChERS extraction using isotopic dilution to simultaneously analyze chlordecone and chlordecol in animal livers. AB - A QuEChERS extraction method followed by HPLC-MS/MS analysis was developed to simultaneously analyze chlordecone and its metabolite chlordecol in animal livers. The overall method was validated with accuracy profiles according to the French Standard NF V03-110 and European Union guidelines. The validation was performed on bovine, ovine and porcine liver samples. Linearity, matrix effect, accuracy, within-laboratory repeatability, specificity, LOQ, Q/q relative ion intensities, and uncertainty were reported. Recoveries were between 70% and 120%. LOQs of 1.36 ug chlordecone kg-1 and 2.50 ug chlordecol kg-1 of fresh liver were found. Twelve contaminated livers of bovine, ovine and porcine origin from the French West Indies or samples from in vivo studies were analyzed. In these liver samples from contaminated animals, chlordecone was quantified at concentrations higher than the maximum residue limit and chlordecol in very low amounts in all the samples. In addition, these results confirm that chlordecone can be metabolized in ruminant species. PMID- 29478526 TI - Evaluation of triacylglycerol composition in commercial infant formulas on the Chinese market: A comparative study based on fat source and stage. AB - Triacylglycerol (TAG) composition in 180 commercial infant, follow-on and growing up formulas with different fat sources (plant oil, cow's milk and goat's milk) were analyzed and compared with mature human milk (MHM). TAGs in formulas were greatly affected by fat source. Formulas contained higher proportions of TAGs with short-chain/medium-chain saturated fatty acids, OOO and acyl carbon number (ACN) 54, and lower proportions of ACN 52 than MHM. There were significant differences in the content and stereochemical structure of OPL and OPO between formulas and MHM. Although there were no significant differences in the OPO contents between formulas with OPO and MHM, it is not enough to reach the abundance of palmitic acid (PA) at the sn-2 position in MHM. These results indicated that it is more suitable for Chinese infants to supplement the formulas with not only OPO, but also other TAGs containing PA mainly at the sn-2 position (such as OPL). PMID- 29478527 TI - Chemical imaging of protein hydrogels undergoing alkaline dissolution by CARS microscopy. AB - Hydrogels swell, shrink and degrade depending on the solution they are in contact which, strongly affecting their performance. The minimum information needed to validate many published simulations would be the spatial quantification of the solute material with time. In this study we develop a simple methodology to quantify the protein content in heat induced protein hydrogels using a commercial Coherent anti-Stokes Raman Spectroscopy (CARS) microscope. The system is used to quantify the whey protein isolate (WPI) concentration in hydrogels undergoing dissolution at alkaline pH. Quantitative measurements were performed in hydrogels up to depths of ~600 um, with an average accuracy of ~1 wt%. Results show that the protein concentration within the swollen layer is constant with time, confirming the existence of steady state conditions during dissolution. The methodology presented can easily be implemented to other biopolymer hydrogels and foods. PMID- 29478528 TI - Combined spectroscopic, molecular docking and quantum mechanics study of beta casein and p-coumaric acid interactions following thermal treatment. AB - The molecular nature of interactions between beta-casein and p-coumaric acid was studied following exposure of their solutions to ultra-high temperature (UHT at 145 degrees C). Interactions were characterised by employing multi-spectroscopic methods, molecular docking and quantum mechanics calculations. FTIR demonstrates that the ligand lies in the vicinity of the protein, hence inverting the absorbance spectrum of the complex. This outcome changes the conformational characteristics of the protein leading to a flexible and open structure that accommodates the phenolic microconstituent. Results are supported by UV-vis, CD and fluorescence quenching showing considerable shifts in spectra with complexation. Molecular docking indicates that there is at least a hydrogen bond between p-coumaric acid and the peptide backbone of isoleucine (Ile27). Quantum mechanics calculations further argue that changes in experimental observations are also due to a covalent interaction in the protein-phenolic adduct, which according to the best predicted binding pose involves the side chain of lysine 47. PMID- 29478529 TI - NMR-driven identification of anti-amyloidogenic compounds in green and roasted coffee extracts. AB - To identify food and beverages that provide the regular intake of natural compounds capable of interfering with toxic amyloidogenic aggregates, we developed an experimental protocol that combines NMR spectroscopy and atomic force microscopy, in vitro biochemical and cell assays to detect anti-Abeta molecules in natural edible matrices. We applied this approach to investigate the potential anti-amyloidogenic properties of coffee and its molecular constituents. Our data showed that green and roasted coffee extracts and their main components, 5-O-caffeoylquinic acid and melanoidins, can hinder Abeta on-pathway aggregation and toxicity in a human neuroblastoma SH-SY5Y cell line. Coffee extracts and melanoidins also counteract hydrogen peroxide- and rotenone-induced cytotoxicity and modulate some autophagic pathways in the same cell line. PMID- 29478530 TI - Emulsion stability and dilatational viscoelasticity of ovalbumin/chitosan complexes at the oil-in-water interface. AB - The contribution of the emulsion rheological properties and the viscoelastic of the interface adsorbed layer to the emulsification mechanism of ovalbumin (OVA) chitosan (CS) mixtures were investigated. In comparison to the treatment with OVA alone and OVA/CS mixtures at pH 4.0, the addition of CS at pH 5.5 increased the size distribution of emulsion droplets with significant flocculation through polyelectrolyte bridging, remarkably enhancing the emulsions stability against gravity creaming after storage at 25 degrees C for 14 days. The dynamic rheological properties indicated that the formation of the complex at pH 5.5 increased the elastic modulus (G') and apparent viscosity (eta*) of the emulsions, which is useful for inhibiting creaming. Moreover, the complexation of OVA and CS at pH 5.5 increased the dilatational modulus (E), especially the elastic modulus (Ed), of the oil/water interfacial absorbed layer, which could reduce the droplet coalescence and therefore inhibit the growth of emulsion droplets. PMID- 29478531 TI - Rapid detection of illegal colorants on traditional Chinese pastries through mass spectrometry with an interchangeable thermal desorption electrospray ionization source. AB - Ambient mass spectrometry using an interchangeable thermal desorption/electrospray ionization source (TD-ESI) is a relatively new technique that has had only a limited number of applications to date. Nevertheless, this direct-analysis technique has potential for wider use in analytical chemistry (e.g., in the rapid direct detection of contaminants, residues, and adulterants on and in food) when operated in dual-working mode (pretreatment-free qualitative screening and conventional quantitative confirmation) after switching to a TD-ESI source from a conventional ESI source. Herein, we describe the benefits and challenges associated with the use of a TD-ESI source to detect adulterants on traditional Chinese pastries (TCPs), as a proof-of-concept for the detection of illegal colorants. While TD-ESI can offer direct (i.e., without any sample preparation) qualitative screening analyses for TCPs with adequate sensitivity within 30 s, the use of TD-ESI for semi-quantification is applicable only for homogeneous matrices (e.g., tang yuan). PMID- 29478533 TI - Swertiajaponin as an anti-browning and antioxidant flavonoid. AB - Enzymatic browning is a major issue that needs to be solved in the food industry. Although swertiajaponin is a flavonoid rich in the whole herb of Swertia japonica that has been clinically used, its biological functions and application in the foods have not been fully elucidated. Here, we showed that swertiajaponin efficiently blocked enzymatic browning in potatoes possibly by direct binding to and inactivating polyphenol oxidase. Furthermore, swertiajaponin showed potent antioxidant activity proven by markedly suppressed reactive oxygen species. Swertiajaponin significantly increased antioxidant properties of potato extract when it is added since it additively elevated total flavonoid content. Considering numerous beneficial effects of antioxidants, swertiajaponin may be used as a functional food additive to suppress enzymatic browning and elevate the antioxidant capacity of foods including beverages and soups by fortification of flavonoids. PMID- 29478532 TI - FTIR studies of gluten matrix dehydration after fibre polysaccharide addition. AB - FTIR spectroscopy was used to determine changes in secondary structure, as well as water state, in gluten and model doughs supplemented by four fibre polysaccharides (microcrystalline cellulose, inulin, apple pectin and citrus pectin). The gluten and model doughs were obtained from commercially available wheat gluten and model flour, respectively. The polysaccharides were used in five concentrations: 3%, 6%, 9%, 12% and 18%. Analysis of the FTIR spectra indicated that polysaccharides could be divided into two groups: first - microcrystalline cellulose and inulin, second - apple and citrus pectins that induced opposite structural changes. Changes in secondary structure concern mainly beta-sheets and beta-turns that form aggregated beta-structures, suggesting dehydration of the gluten matrix as a result of competition for water between gluten proteins and polysaccharides. Moreover, the positive band at ca. 1226 cm-1 in the spectra of pectin-modified samples indicates formation of 'ether' type hydrogen bonds between gluten proteins and pectins. PMID- 29478534 TI - Activation of membrane-located Ca2+ channels by hop beta acids and their tricyclic transformation products. AB - Beta-bitter acids of hops (lupulones) revealed sedative and antidepressant-like effects in animal studies. Transformation of beta-acids during beer brewing leads to the formation of tricyclic transformation products, which have a close structural analogy to hyperforin. The latter compound is responsible for the antidepressant activity of St. John's wort by activation of TRPC6 cation channels in neuronal-like cells leading to Ca2+ influx. In this study, nortricyclolupones, dehydrotricyclolupones, and tricyclolupones were isolated from a wort-boiling model and their structures were elucidated by UHPLC-DAD, UHPLC-ESI--MS/MS and 1D/2D-NMR spectroscopy. Beta-bitter acids and their transformation products induced Ca2+ influx in PC12 cells to the same extent as hyperforin. Application of a Ca2+-free environment abolished the Ca2+ elevation, indicating that the increase is mediated by influx across the plasma membrane. Thus, activation of neuronal-like Ca2+-channels by lupulones and tricyclolupones represent a novel mechanism contributing to the antidepressant activity of hops. PMID- 29478535 TI - Fast quantification of bovine milk proteins employing external cavity-quantum cascade laser spectroscopy. AB - Analysis of proteins in bovine milk is usually tackled by time-consuming analytical approaches involving wet-chemical, multi-step sample clean-up procedures. The use of external cavity-quantum cascade laser (EC-QCL) based IR spectroscopy was evaluated as an alternative screening tool for direct and simultaneous quantification of individual proteins (i.e. casein and beta lactoglobulin) and total protein content in commercial bovine milk samples. Mid IR spectra of protein standard mixtures were used for building partial least squares (PLS) regression models. A sample set comprising different milk types (pasteurized; differently processed extended shelf life, ESL; ultra-high temperature, UHT) was analysed and results were compared to reference methods. Concentration values of the QCL-IR spectroscopy approach obtained within several minutes are in good agreement with reference methods involving multiple sample preparation steps. The potential application as a fast screening method for estimating the heat load applied to liquid milk is demonstrated. PMID- 29478536 TI - Determination of toxigenic fungi and aflatoxins in nuts and dried fruits using imaging and spectroscopic techniques. AB - Nuts and dried fruits contain rich nutrients and are thus highly vulnerable to contamination with toxigenic fungi and aflatoxins because of poor weather, processing and storage conditions. Imaging and spectroscopic techniques have proven to be potential alternative tools to wet chemistry methods for efficient and non-destructive determination of contamination with fungi and toxins. Thus, this review provides an overview of the current developments and applications in frequently used food safety testing techniques, including near infrared spectroscopy (NIRS), mid-infrared spectroscopy (MIRS), conventional imaging techniques (colour imaging (CI) and hyperspectral imaging (HSI)), and fluorescence spectroscopy and imaging (FS/FI). Interesting classification and determination results can be found in both static and on/in-line real-time detection for contaminated nuts and dried fruits. Although these techniques offer many benefits over conventional methods, challenges remain in terms of heterogeneous distribution of toxins, background constituent interference, model robustness, detection limits, sorting efficiency, as well as instrument development. PMID- 29478537 TI - Biochemical properties, antibacterial and cellular antioxidant activities of buckwheat honey in comparison to manuka honey. AB - The biochemical properties of buckwheat honey, including contents of sugars, proteins, total phenols, methylglyoxal (MGO), minerals and phenolic compounds, were determined in comparison with those of manuka honey. Buckwheat honey has higher contents of sugars, proteins and total phenols but a lower content of MGO than manuka honey. Buckwheat honey contains abundant minerals involved in a number of vital functions of the human body as does manuka honey, and has even higher contents of Fe, Mn and Zn. In buckwheat honey, p-hydroxybenzoic acid, chlorogenic acid and p-coumaric acid are the dominant phenolic compounds. Moreover, the antibacterial and cellular antioxidant activities of buckwheat honey were compared with those of manuka honey. Buckwheat honey exhibits antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa, comparable with manuka honey, and the cellular antioxidant activity of buckwheat honey is higher than that of manuka honey. Our results suggest that buckwheat honey has great nutritional and commercial potentials. PMID- 29478538 TI - Influence of controlled deficit irrigation on tomato functional value. AB - The effect of controlled deficit irrigation (CDI) on the accumulation of carotenoids, polyphenols and l-ascorbic acid was studied in conventional and high lycopene tomato cultivars. Plants were initially irrigated to cover 100%ETc and after the fruit set phase, the dose was reduced to 75% or 50% of ETc. CDI had no significant effect on the accumulation of carotenoids, while it increased the levels of the hydroxycinnamic acids chlorogenic and ferulic acids, the flavonoid rutin and l-ascorbic acid. Nevertheless, there were important interactions and this effect was highly dependent on the year and site of cultivation. Certain growing areas would be more favorable to supply high quality markets, and, fortunately, CDI would maximize polyphenol (100-75%ETc) and l-ascorbic acid (100 50%ETc) in these areas. A combination of the best genotype and growing area with CDI would offer high quality products, preserving a scarce resource: water. PMID- 29478539 TI - Essential micronutrient and toxic trace element concentrations in gluten containing and gluten-free foods. AB - For individuals following a gluten-free (GF) diet, rice is commonly the major grain. People following a GF diet have a higher arsenic burden than the general population. We conducted a multielemental market basket study of GF and gluten containing ingredients and prepared foods (Mn, Fe, Ni, Cu, Zn, Cr, Co, Se, Cd, Sb, Pb, total As, As species, total Hg and methylmercury). Foods containing rice were significantly higher in As, Hg and Pb and lower in Se, Fe, Cu and Zn. Wheat based foods were higher in Cd. Mercury concentrations were low (<3.5 ng/g); speciation was predominantly methylmercury. Arsenic and mercury in rice were correlated. GF foods contained significantly more As and Hg. Eating a wide variety of GF grains may reduce contaminant exposure and increase micronutrient status compared to a rice-based GF diet. PMID- 29478540 TI - Taste and chemical characteristics of low molecular weight fractions from tofuyo Japanese fermented soybean curd. AB - Tofuyo, a Japanese traditional food, is a fermented soybean curd manufactured in Okinawa region. Due to its original cheese-like flavor, the current study was designed to evaluate the sensory and chemical characteristics of three stepwise ultrafiltration fractions, using 10,000, 3000 and 500 Da membranes and further chromatographic fractions from tofuyo. The results showed that umami, sweet and salty were the characteristic tastes of all fractions, with umami intensity evaluated for the fraction with MW less than 500 Da (F-500) as the most prominent among the three fractions. Subsequent Sephadex G-25 SF fractions and RP-HPLC fractions were subjected to sensory and chemical analyses. The tastiest fraction contained sodium chloride, sugars, organic acids, umami and sweet free amino acids, at concentrations above their thresholds. The abundant presence of umami and sweet free amino acids with certain concentrations of sodium chloride and glucose might provide the typical savory taste of tofuyo. PMID- 29478541 TI - Pectin characterisation using size exclusion chromatography: A comparison of ELS and RI detection. AB - A high-performance size-exclusion chromatography (HPSEC) method coupled to Evaporative Light Scattering (ELS) and Refractive Index (RI) detectors were evaluated and compared for the molecular mass (Mw) estimation of pectin in a wide range (0.342-805 kDa). Instrumental parameters of the ELSD were optimised by Response Surface Methodology (RSM) being 73 degrees C the evaporator temperature and 0.9 mL/min the air flow rate. The linear range for the ELSD concentration response was wider (10-2250 mg/L) and better (R2 = 0.985) than RID (10-1500 mg/L; R2 = 0.875). The limits of detection (LOD) and quantitation (LOQ) for all pullulans hardly changed in ELSD (LOD: 1.22-1.99 mg/L; LOQ: 4.07-6.63 mg/L); however, RID showed huge variations (LOD: 0.49-10.41 mg/L; LOQ: 1.64-34.70 mg/L), which increased with the Mw. In general, responses of both detectors were similar for the Mw estimation, although pectin characterisation with HPSEC-ELSD exhibited better results in the lowest Mw compounds. PMID- 29478542 TI - Enhancing stability of echium seed oil and beta-sitosterol by their coencapsulation by complex coacervation using different combinations of wall materials and crosslinkers. AB - Intake of omega-3 fatty acids and phytosterols aids in the reduction of cholesterol and serum triglycerides. However, both fatty acids and phytosterols are susceptible to oxidation. This work coencapsulated echium oil (source of stearidonic and alpha-linolenic fatty acids) and beta-sitosterol (phytosterol) by complex coacervation using different combinations of wall materials, and sinapic acid (SA) and transglutaminase as crosslinkers. High encapsulation yields were obtained (29-93% for SA; 68-100% for the mixture of oil and phytosterols) and retention of 49-99% and 16% for encapsulated and free SA, at 30 days-storage. Treatment with gelatin-arabic gum and 0.075 g SA/g gelatin showed the best results: 0.07 mg MDA/g capsule, and retention of 96, 90 and 74% for alpha linolenic, stearidonic acid and beta-sitosterol at 30 days of storage, respectively. Thus, coencapsulation of echium oil and phytosterol using SA as the crosslinker was possible, obtaining effective vehicles for protection and application of these compounds in foods. PMID- 29478543 TI - The prooxidant activity of salts on the lipid oxidation of lecithin-stabilized oil-in-water emulsions. AB - Salts reduction/substitution have gained a lot interest from food industry since the US Food and Drug Administration (FDA) has issued a draft guidance for salt reduction. However how changes of salts in food formulation could influence lipid oxidation is still not fully understood. Using oil-in-water emulsions stabilized by a natural emulsifier - lecithin at pH 7.0 as a model system, this study evaluated how salts affect the physical parameters of the emulsion, the chelating activity of lecithin and thus the lipid oxidation of these emulsions. Results showed that salts increased the particle size, the negative charge of the oil droplets, and the amount of iron chelated by lecithin. Lipid oxidation lag phases were shortened by addition of salts, by 1 day and 2 days for lipid hydroperoxides and thiobarbituric acid reactive substances measurements respectively. These results provide some new insights on the mechanisms of how salts could affect the lipid oxidation of food emulsions. PMID- 29478544 TI - Interaction of divalent minerals with liposoluble nutrients and phytochemicals during digestion and influences on their bioavailability - a review. AB - Several divalent minerals, including the macroelements calcium and magnesium, are essential nutrients for humans. However, their intake, especially via high-dose supplements, has been suspected to reduce the availability of lipophilic dietary constituents, including lipids, liposoluble vitamins, and several phytochemicals such as carotenoids. These constituents require emulsification in order to be bioavailable, and high divalent mineral concentrations may perturb this process, due to precipitations of free fatty acids or bile salt complexation, both pivotal for mixed micelle formation. Though in part based on in vitro or indirect evidence, it appears likely that high-dose supplements of divalent minerals around or even below their recommended dietary allowance perturb the availability of certain liposoluble miroconstituents, in addition to reducing absorption of dietary lipids/cholesterol. In this review, we investigate possible negative influences of divalent minerals, including trace elements (iron, zinc), on the digestion and intestinal uptake of lipophilic dietary constituents, with a focus on carotenoids. PMID- 29478545 TI - Simple and rapid determination of 5-nitroimidazoles and metabolites in fish roe samples by salting-out assisted liquid-liquid extraction and UHPLC-MS/MS. AB - A novel multiresidue method is proposed for the determination of 12 5 nitroimidazoles and their metabolites in fish roe samples using UHPLC-MS/MS. A salting-out assisted liquid-liquid extraction procedure was performed prior to sample analysis. The separation of compounds was accomplished using a C18 Zorbax Eclipse Plus column (50 mm * 2.1 mm, 1.8 um) at 25 degrees C and a mobile phase consisting of 0.025% (v/v) aqueous formic acid and pure MeOH at a flow rate of 0.5 mL/min. Parameters involved in ionization and fragmentation were also optimized. The method was characterized in terms of linearity (R2 >= 0.9992), extraction efficiency (>=68.9%), repeatability (RSD <= 9.8%), reproducibility (RSD <= 13.9%) and trueness (recoveries >=81.4%). Decision limits (CCalpha) and detection capabilities (CCbeta) were obtained in the ranges 0.1-1.0 and 0.2-1.7 ug/kg, respectively. PMID- 29478546 TI - A casein hydrolysate increases GLP-1 secretion and reduces food intake. AB - In an effort to control weight gain, much attention has focused on the identification of bioactive peptides from food sources that induce satiety hormone secretion and increase the feeling of fullness. In this study, a screening platform identified a sodium caseinate hydrolysate, LFC25, that significantly increased calcium signalling in the enteroendocrine cell line, STC 1, and as a result increased secretion of the satiety hormone, GLP-1, in a dose dependent manner. Administration of this hydrolysate to mice reduced the cumulative food intake over an eight hour period. To determine the feasibility of LFC25 as a food ingredient, production was scaled up to 10 L and spray-dried or freeze-dried without loss of bioactivity. PMID- 29478547 TI - Maillard induced glycation behaviour of individual milk proteins. AB - This paper set out to differentiate the Maillard induced glycation reactivity of individual milk proteins using different saccharides under well-defined reaction conditions. alpha-Lactalbumin, beta-lactoglobulin and beta-casein were incubated with mono-, di- and trisaccharides in the dry state under standardised buffered conditions and glycation was expressed relative to the available reactive groups per protein (DG). Protein reactivity, described by the DGmax and initial speed of glycation (v), followed the same order for each protein-saccharide incubation: alpha-lactalbumin > beta-lactoglobulin ? beta-casein. Glycation of whey proteins by different monosaccharides was double that of beta-casein. Differences in DG between whey proteins and beta-casein decreased with increased saccharide size. A two-fold difference was found for glycation in the presence of the dimers lactose and maltose for beta-casein but not for the whey proteins. The percentage of glycated lysines increased with increased lysine to protein size ratio. PMID- 29478548 TI - Lowering greening of cookies made from sunflower butter using acidic ingredients and effect on reducing capacity, tryptophan and protein oxidation. AB - Lowering of greening formed from oxidized chlorogenic acid (CGA) and amino groups, and favoured at alkaline pH, was investigated using acidic ingredients (sour cream, buttermilk, yoghurt, and honey) in sunflower butter cookies. Cookies with maple syrup added were used as a positive control. Changes in greening intensity, greening reactants (total phenols, CGA, protein), antioxidant capacity, tryptophan and Schiff base fluorescence were measured. Percentage greening, pH and aw of cookies followed the same order: maple syrup > sour cream >= buttermilk > yoghurt > honey. pH was positively correlated with greening intensity (r = 0.77) and negatively correlated with CGA (r = -0.96). Total phenolic content, antioxidant capacity, tryptophan and Schiff bases were similar among cookies. The results suggest it is possible to decrease greening by minimizing storage time and using acidic ingredients. Minimal greening with acidic ingredients can extend the application of sunflower butter as a baking ingredient without loss of free radical-scavenging capacity, or higher protein oxidation. PMID- 29478549 TI - Application of Fourier-transform mid infrared spectroscopy for the monitoring of pound cakes quality during storage. AB - The aim of the present study was to investigate the ability of MIR and texture analyzer to evaluate the quality of pound cake samples produced with palm oil and rapeseed oil throughout storage. The MIR spectra analyzed by using principal component analysis (PCA) showed a clear separation of pound cakes as a function of the storage time and the nature of the used oil in the recipe. By applying partial least square regression (PLSR), excellent prediction was obtained for hardness (R2 = 0.91; RPD = 2.26), while an approximate qualitative prediction was found for springiness (R2 = 0.73; RPD = 2.07), cohesiveness (R2 = 0.67; RPD = 1.31) and resilience (R2 = 0.65; RPD = 1.24). It could be concluded that the MIR spectroscopy could be used as a rapid and non-destructive technique for monitoring texture of pound cakes throughout storage as well as for the prediction of their hardness. PMID- 29478550 TI - Phosphorylation regulated by protein kinase A and alkaline phosphatase play positive roles in MU-calpain activity. AB - This study was aimed to determine the effect of phosphorylation/dephosphorylation regulated by protein kinase A (PKA) and alkaline phosphatase (AP) on MU-calpain activity at different Ca2+ concentrations. MU-Calpain was treated with AP or PKA at 0.01, 0.05, 0.1 and 1 mM Ca2+. The pH value decreased in the AP group but remained stable in the control and PKA groups during incubation. Except samples incubated at 0.01 and 0.1 mM Ca2+ for more than 20 min, MU-calpain incubated with PKA showed a higher degree of autolysis than control, but lower than the AP group. The content of alpha-helix structure of MU-calpain increased as phosphorylation level rose. Phosphorylation of MU-calpain at serine 255, 256, 476, 417 and 420 was identified. PKA catalyzed MU-calpain phosphorylation at serine 255, 256 and 476, located at domains II and III, positively regulated MU calpain activity. These data demonstrated that dephosphorylation and PKA phosphorylation positively regulated MU-calpain activity, which was limited by increased Ca2+ concentration. PMID- 29478551 TI - Establishment of a spectral database for classification of edible oils using matrix-assisted laser desorption/ionization mass spectrometry. AB - In this study, we aim to establish a comprehensive spectral database for analysis of edible oils using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). More than 900 edible oil samples, including 30 types of edible oils, were analyzed and compared, and the characteristic peaks and spectral features of each edible oil were obtained. Edible oils were divided into eight groups based on their characteristic spectral patterns and principal component analysis results. An overall correct rate of 97.2% (98.1% for testing set) was obtained for classification of 435 edible oil products using partial least square-discriminant analysis, with nearly 100% correct rate for commonly used edible oils. Differentiation of counterfeit edible oils, repeatedly cooked edible oils and gutter oils from normal edible oils could also be achieved based on the MALDI-MS spectra. The establishment of this spectral database provides reference spectra for spectral comparison and allows rapid classification of edible oils by MALDI-MS. PMID- 29478552 TI - The effect of processing on the glucosinolate profile in mustard seed. AB - Brassica juncea mustard seed are used to make mustard paste or condiment. Mustard seed contains glucosinolates which are converted to isothiocyanates following cell disruption by the enzyme, myrosinase. Isothiocyanates are sulphur-containing compounds which give a pungent flavour to the mustard condiment. Three mustard seed cultivars from two seasons were processed into Dijon- and wholegrain-style mustard and glucosinolates and isothiocyanates analysed. Canadian cv. Centennial tended to contain higher glucosinolates compared with the French cv. AZ147 and Ukrainian cv. Chorniava. Conversion of the mustard seed into a wholegrain condiment had a lesser effect on total isothiocyanates and sinigrin content compared with the Dijon-style preparation. The Canadian mustard cultivars produced wholegrain-style mustard with higher total isothyocyantes and sinigrin compared with the French and Ukrainian cultivars. In summary, results herein suggest that Canadian mustard seed cvs. Centennial and Forge, and wholegrain processing may result in a condiment with greater bioactive composition. PMID- 29478553 TI - Changes in phenolic profiles of red-colored pellicle walnut and hazelnut kernel during ripening. AB - In studies of secondary metabolites in nuts, many constituents in the kernel remain unidentified due to a high content of phenolic compounds in the pellicle. In the present study, we focused on the investigation of the phenolic and dicarboxylic acid profiles of walnut and hazelnut pellicle-less kernels. High performance liquid chromatography with diode array and mass spectrometric detection (HPLC-DAD-MSn) was used to carry out the determination of individual phenolics and dicarboxylic acids in brown and red-pellicle walnut and hazelnut. Results show that hexahydroxydiphenic acid (HHDP) di-galloyl hexose isomer, vanillic acid hexoside, quinic acid derivative and catechin are the main constituents of the phenolic profile of walnut, while galloylquinic derivative, caffeoyl hexoside and catechin are the main constituents of the hazelnut kernel. Even though both walnut and hazelnut kernels have a considerably lower content of phenolic compounds and dicarboxylic acids in comparison to the pellicles, when calculated as a percentage of the total mass, the kernel makes a significant contribution to the total phenolic content of the whole nut. PMID- 29478554 TI - Phenolic compounds and antioxidant activity of lingonberry (Vaccinium vitis-idaea L.) leaf, stem and fruit at different harvest periods. AB - Fruits and aerial parts of lingonberry could be better developed as dietary supplements if the composition in bioactive phenolic compounds and the best period for collection were known. UPLC/MS analysis revealed the predominant presence of arbutin in leaf and that of flavanols in stems harvested in May, July and September. Anthocyanins, flavanols and benzoic acid derivatives were equally present in fruits. Stem and leaf are highly homologous with (+)-catechin, A- and B-type dimers/trimers, and two quercetin glycosides as major contributors. No or only weak seasonal variations were highlighted for all phenolic classes. Additionally, flavanol oligomers showed a lower mDP for fruit (3-4) than for stem and leaf (4-6). The rate of A-type linkage was 3-5% with A-type subunits in extension mainly. Finally, the content in phenolic compounds (UPLC) correlated well with TPC and the DPPH radical scavenging activity although leaf and stem constituents reacted differently in both antioxidant tests. PMID- 29478555 TI - Interlaboratory comparison of liquid chromatography-tandem mass spectrometry quantification of diarrhetic shellfish toxins in scallop midgut glands. AB - An interlaboratory comparison (ILC) was organized as a measure of the analytical competency in the liquid chromatography-tandem mass spectrometry quantification of okadaic acid (OA) and dinophysistoxin-1 (DTX1) in scallop midgut gland samples. The test sample was prepared using boiled midgut glands of naturally contaminated scallops with DTX1 and its esters by spiking with OA, and homogeneity and stability of this test sample was assessed to be appropriate. Twenty laboratories participated in the ILC based on the Japanese official testing method; they submitted two sets of analytical concentrations of target analytes along with the details of their analytical protocols. For assessing these data, assigned values were established from another ILC where ten participants quantified the target analytes by the standard addition method. The mean analytical results of the former ILC showed good agreement with the assigned values, and the corresponding relative reproducibility standard deviations met the criterion of CODEX STAN 292. Meanwhile, the results of more than half of the participants were out of the uncertainty range of the assigned values; these participants were encouraged to investigate their protocols to improve their analytical capability. PMID- 29478557 TI - Development and characterization of a green procedure for apigenin extraction from Scutellaria barbata D. Don. AB - This study compared the use of ultrasound-assisted supercritical CO2 (USC-CO2) extraction to obtain apigenin-rich extracts from Scutellaria barbata D. Don with that of conventional supercritical CO2 (SC-CO2) extraction and heat-reflux extraction (HRE), conducted in parallel. This green procedure yielded 20.1% and 31.6% more apigenin than conventional SC-CO2 extraction and HRE, respectively. Moreover, the extraction time required by the USC-CO2 procedure, which used milder conditions, was approximately 1.9 times and 2.4 times shorter than that required by conventional SC-CO2 extraction and HRE, respectively. Furthermore, the theoretical solubility of apigenin in the supercritical fluid system was obtained from the USC-CO2 dynamic extraction curves and was in good agreement with the calculated values for the three empirical density-based models. The second-order kinetics model was further applied to evaluate the kinetics of USC CO2 extraction. The results demonstrated that the selected model allowed the evaluation of the extraction rate and extent of USC-CO2 extraction. PMID- 29478556 TI - Chemical composition of the edible flowers, pansy (Viola wittrockiana) and snapdragon (Antirrhinum majus) as new sources of bioactive compounds. AB - The nutritional composition - including total and individual phenolic compounds, carotenoids, and the antioxidant capacity - of two commercially available edible flowers, pansy and snapdragon, was studied. The edible flowers did not differ in their carbohydrates, fat, or ash contents, or in total energy, but pansy had higher values of moisture, protein, and total dietary fiber than snapdragon. Phenolic compounds were more abundant in pansy than in snapdragon, and flavonoids were the major compounds, followed by anthocyanins. The phenolic profile of pansy included flavonols, such as quercetin and isorhamnetin glycosides, flavones, such as apigenin glycosides, and anthocyanins, such as cyanidin and delphinidin glycosides; in snapdragon it included flavonol glycosides (e.g. quercetin and kaempferol glycosides) and anthocyanins, such as cyanidin and pelargonidin glycosides. The contents of total carotenoids were 146 and 29 ug/mg for pansy and snapdragon, respectively, and lutein was the dominant compound. PMID- 29478558 TI - Development and evaluation of rapid screening detection methods for genetically modified crops using loop-mediated isothermal amplification. AB - We developed new loop-mediated isothermal amplification (LAMP)-based detection methods for the screening of genetically modified (GM) maize and soybean events. The LAMP methods developed targeted seven sequences: cauliflower mosaic virus 35S promoter; 5-enolpyruvylshikimate-3-phosphate synthase gene from Agrobacterium tumefaciens strain CP4 (cp4epsps); phosphinothricin acetyltransferase (pat) gene; mannose-6-phosphate isomerase gene; Pisum sativum ribulose 1, 5-bisphosphate carboxylase terminator; a common sequence between Cry1Ab and Cry1Ac genes; and a GA21 construct-specific sequence. We designed new specific primer sets for each target, and the limit of detection (LOD) was evaluated using authorized GM maize and soybean events. LODs for each target were <= 0.5%. To make the DNA extraction process simple and rapid, we also developed a direct LAMP detection scheme using crude cell lysates. The entire process, including pretreatments and detection, could be completed within 1 h. PMID- 29478559 TI - Corrigendum to "The addition of inulin and Lactobacillus casei 01 in sheep milk ice cream" [Food Chem. 246 (2018) 464-472]. PMID- 29478560 TI - Erratum to "Effect of maize bran feruloylated oligosaccharides on the formation of endogenous contaminants and the appearance and textural properties of biscuits" [Food Chem. 245 (2018) 974-980]. PMID- 29478561 TI - Corrigendum to "Physicochemical properties, nutritional value and techno functional properties of goldenberry (Physalis peruviana) waste powder concise title: Composition of goldenberry juice waste" [Food Chem., 248 (2018) 1-7]. PMID- 29478562 TI - Simultaneous determination of clanobutin, dichlorvos, and naftazone in pork, beef, chicken, milk, and egg using liquid chromatography-tandem mass spectrometry. AB - A chromatographic method involving a single run was validated for the quantification of clanobutin, dichlorvos, and naftazone in products of animal origin. Pork, beef, chicken, milk, and egg samples were extracted with a solution of 0.1% formic acid in acetonitrile, defatted with n-hexane, centrifuged, and filtered prior to analysis using liquid chromatography-tandem mass spectrometry (LC-/MS/MS). The analytes were separated on a C18 column using a solution of 0.1% formic acid and 10 mM ammonium formate (A) and acetonitrile (B) as the mobile phase. A good linearity over 5-50 ng/g concentration range was obtained with coefficients of determination (R2) >= 0.9807. The intra- and interday accuracy (recovery %) calculated from 3 fortification levels (5, 10, and 20 ng/g) were 73.2-108.1% and 71.4-109.8%, and the precisions (expressed relative standard deviations (RSDs)) were 0.9-12.9% and 1.8-10.6%, respectively, for the 3 tested analytes in animal originated foods. The limits of quantification (LOQs) ranged between 0.1 and 1 ng/g, thus enabling the quantification of residual levels below the uniform maximum residue limit (MRL) of 0.01 mg/kg set for compounds having no MRL. The designated methodology was successfully applied to monitor various samples collected from Seoul; the tested analytes were not quantified in any of the market samples. Conclusively, the developed method is simple, sensitive, and accurate, and could be used for the detection of pharmaceuticals in various animal food matrices with variable protein and fat contents. PMID- 29478563 TI - Development and validation of an UHPLC-HRMS protocol for the analysis of flavan-3 ol metabolites and catabolites in urine, plasma and feces of rats fed a red wine proanthocyanidin extract. AB - This study developed, optimized and validated an ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) method to identify and quantify metabolites and microbial-derived catabolites in urine, plasma and feces of rats following ingestion of 50 mg of a red wine proanthocyanidin-rich extract. The method was validated for specificity, linearity, limit of detection (LD) and quantification (LQ), intra-day and inter-day precision, recovery and matrix effects, which were determined for 34 compounds in the three biological matrices. After method validation, three parent flavan-3-ols, four 5-carbon side chain ring fission metabolites, and 27 phenolic acid and aromatic catabolites were quantified in plasma, urine and feces after red wine proanthocyanidin intake. These results establish the value of the UHPLC-HRMS protocol in obtaining a detailed picture of proanthocyanidin metabolites and their microbial-derived catabolites, along with their phase II metabolites, in biological fluids of rat, and potentially in human clinical studies designed to evaluate the bioavailability of dietary flavan-3-ols. PMID- 29478564 TI - Flavonols and ellagic acid derivatives in peels of different species of jabuticaba (Plinia spp.) identified by HPLC-DAD-ESI/MSn. AB - Extracts of jabuticaba peels show complex chromatographic profiles at 360 nm, with some peaks presenting UV-Vis spectra resembling those of flavonol glycosides and others resembling that of ellagic acid. The presence and tentative identification of these phenolic compounds were comprehensively studied in four species of Brazilian jabuticaba fruit - Plinia trunciflora, variety 'jabuticaba de cabinho'; P. caulifora, varieties 'jabuticaba paulista' and 'jabuticaba canaa acu'; P. jaboticaba, variety 'jabuticaba sabara'; and P. phitrantha, variety 'jabuticaba branca-vinho' - using HPLC-DAD-ESI-MSn. Seventeen flavonols derived from quercetin and three from myricetin and eighteen derivatives of ellagic acid and eleven of methyl ellagic acid were detected. Most of them were newly described and mainly occurred in glycosylated and acylglycosylated forms. Some compounds were missing in one variety, such as the absence of methyl ellagic acid derivatives in 'jabuticaba branca-vinho', and others only appeared in one variety, thus suggesting potential capacity for varietal differentiation. PMID- 29478566 TI - Detection and identification of furan fatty acids from fish lipids by high performance liquid chromatography coupled to electrospray ionization quadrupole time-of-flight mass spectrometry. AB - Using high-performance liquid chromatography coupled to high-resolution electrospray ionization quadrupole time-of-flight mass spectrometry (HPLC/ESI-Q TOF-MS), we have developed a new method for detection and identification of furan fatty acids (F-acids), which are widely distributed in living organisms and foods as minor lipid components and are known to have antioxidant and anti-inflammatory effects. For this purpose, total fatty acids prepared from the testis lipids of Japanese chum salmon (Oncorhynchus keta) were examined without any concentration or isolation of F-acids. In negative ESI mode, F-acids gave a prominent [M-H]- ion, by which individual F-acids could be detected and identified. High resolution extracted ion chromatograms clearly showed the occurrence of five major F-acid homologs as already reported by GC/MS. The method was successfully applied to several fish samples and revealed the occurrence of F-acids for the first time in the two New Zealand fish, hoki (Macruronus novaezelandiae) and school shark (Galeorhinus galeus). PMID- 29478565 TI - Response of nutrients, minerals, antioxidant leaf pigments, vitamins, polyphenol, flavonoid and antioxidant activity in selected vegetable amaranth under four soil water content. AB - Four selected vegetable amaranths were grown under four soil water content to evaluate their response in nutrients, minerals, antioxidant leaf pigments, vitamins, polyphenol, flavonoid and total antioxidant activity (TAC). Vegetable amaranth was significantly affected by variety, soil water content and variety * soil water content interactions for all the traits studied. Increase in water stress, resulted in significant changes in proximate compositions, minerals (macro and micro), leaf pigments, vitamin, total polyphenol content (TPC), and total flavonoid content (TFC) of vegetable amaranth. Accessions VA14 and VA16 performed better for all the traits studied. Correlation study revealed a strong antioxidant scavenging activity of leaf pigments, ascorbic acid, TPC and TFC. Vegetable amaranth can tolerate soil water stress without compromising the high quality of the final product in terms of nutrients and antioxidant profiles. Therefore, it could be a promising alternative crop in semi-arid and dry areas and also during dry seasons. PMID- 29478567 TI - Exploring the effects of selenium treatment on the nutritional quality of tomato fruit. AB - In this work, the effects of selenium (Se) on the nutritional quality of tomato fruit were investigated. The results showed that application of 1 mg L-1 sodium selenate foliar spray increased Se content in the fruit without affecting other concentrations of other metals. Se treatment elevated the contents of soluble sugars (glucose and fructose), amino acids, and bioactive compounds, such as flavanoids, glutathione, vitamin C, and vitamin E, in pink tomato fruit. Proteomic analysis using isobaric tags for relative and absolute quantification was performed on tomato fruit at the commercial harvest stage. When comparing Se enriched tomato fruit with the control group, we identified an aggregate of 269 differentially expressed proteins. Proteins involved in carbohydrate metabolism, amino acids metabolism, and secondary metabolism were highly affected by Se treatment. The results help elucidate the mechanism of Se treatment on improved nutritional quality of tomato fruit. PMID- 29478568 TI - Interaction between lactoferrin and whey proteins and its influence on the heat induced gelation of whey proteins. AB - In this paper, the influence of lactoferrin (LF) on the structural development of whey protein isolate (WPI) gels during heating was investigated. The results demonstrated that the presence of sufficient LF could improve the strength and elasticity of WPI gels. When 30% LF was added, the elastic modulus of WPI gels increased from 254 +/- 31 and 413 +/- 58 Pa to 3222 +/- 105 and 2730 +/- 131 Pa at pH 6.7 and 5.8, respectively. The addition of LF improved the water holding capacity (WHC) of WPI gels at pH 6.7, while no improvement was observed at pH 5.8. LF interacted with whey proteins differently at pH 6.7 and 5.8 during heating. The LF/whey proteins complexes formed at pH 6.7 had smaller sizes and narrower size distributions than those formed at pH 5.8. PMID- 29478569 TI - Investigation into allergenicity reduction and glycation sites of glycated beta lactoglobulin with ultrasound pretreatment by high-resolution mass spectrometry. AB - Ultrasound treatment could change the conformation of beta-lactoglobulin (beta Lg) and improve the glycation reaction in aqueous solution under neutral condition. However, the effect of ultrasound pretreatment on glycation of beta-Lg with pentose at dry-state remains ambiguous, and the relationship between glycation and allergenicity of beta-Lg with ultrasound pretreatment is unclear. This study aimed to evaluate the effect of ultrasound pretreatment on glycation and allergenicity of beta-Lg. Markedly decreased allergenicity of beta-Lg was observed after glycation with ribose before and after ultrasound pretreatment with the minimum found at 400 W. Orbitrap LC-MS/MS showed that the glycation degree of some peptides in glycated beta-Lg with and without ultrasound pretreatment were different although the content of free amino group and molecular mass were insignificantly different. Therefore, ultrasound pretreatment promoted the reduction in allergenicity by improving the glycation extent of some glycation sites although it hardly enhanced the whole glycation degree of beta Lg. PMID- 29478571 TI - An Interview with Vsevolod "Seva" Katritch. PMID- 29478570 TI - Subcellular Organization of GPCR Signaling. AB - G protein-coupled receptors (GPCRs) comprise a large and diverse class of signal transducing receptors that undergo dynamic and isoform-specific membrane trafficking. GPCRs thus have an inherent potential to initiate or regulate signaling reactions from multiple membrane locations. This review discusses emerging insights into the subcellular organization of GPCR function in mammalian cells, focusing on signaling transduced by heterotrimeric G proteins and beta arrestins. We summarize recent evidence indicating that GPCR-mediated activation of G proteins occurs not only from the plasma membrane (PM) but also from endosomes and Golgi membranes and that beta-arrestin-dependent signaling can be transduced from the PM by beta-arrestin trafficking to clathrin-coated pits (CCPs) after dissociation from a ligand-activated GPCR. PMID- 29478572 TI - [Refusal of treatments by an adult cancer patient]. AB - INTRODUCTION: Refusal of treatment questions the treatment's adequacy as well as the quality of the care relationship. A rigorous analysis of these situations is necessary in order to respect the patient's fundamental right to decide for him/herself while preventing a potential loss of chance. This paper proposes practical guidelines for assessment and management of the refusal of treatment by adult cancer patients. METHODS: The French Association for Supportive Care in Cancer and the French Society for Psycho-Oncology formed a task force that applied a consensus methodology to draft guidelines. RESULTS: We propose five guidelines: (1) be informed of the conditions most often associated with refusal of treatment so as to reinforce adequate support measures; (2) understand the complexity of the process of refusal and accurately identify what is precisely refused; (3) apply an approach of systematic analysis to refusal, to try and increase the possibilities of finding an agreement while reinforcing the respect of the patient's position; (4) establish a legal procedure to address refusal of treatment that safeguards the stakeholders when no accord can be found; and (5) know the indications for ethical collective decision-making. CONCLUSION: A systematic assessment procedure of treatment refusal is necessary in order to ensure that all the physical, psychological and contextual aspects of it are taken into account, and to provide patients with the best treatment possible. The setting of good care relationship, the improvement of communication skills training and of comprehensive multidisciplinary care are all crucial elements in the prevention of these situations. PMID- 29478573 TI - Systolic Blood Pressure Threshold for HEMS-Witnessed Arrests. AB - OBJECTIVE: Defining vital sign thresholds has focused on mortality, which may be delayed for hours, days, or weeks after injury. This limits the immediate clinical significance in guiding therapy to avoid arrest. The aim of this study was to identify a systolic blood pressure (SBP) threshold indicating imminent cardiopulmonary arrest. METHODS: This was a retrospective, observational study analyzing physiological data from air medical patients suffering witnessed arrest. We limited the analysis to a subgroup of adult (> 14 years) patients with hypoperfusion-related arrest. Prearrest SBP values were plotted over time, with arrest defined as "time zero." Multiple linear regression was used to define a best fit curve to identify an inflection point beyond which arrest was imminent. RESULTS: A total of 53 eligible patients were identified; 33 (62%) were trauma victims. A fifth-degree equation showed appropriate goodness of fit (r = -.66, P < .0001). An inflection point was identified at an SBP of 78 mm Hg, with arrest occurring approximately 3 minutes later. CONCLUSION: An inflection point below SBP 80 mm Hg was identified, suggesting a predictable physiological pattern for perfusion-related deterioration. This may help guide therapy to reverse deterioration and prevent arrest. PMID- 29478574 TI - Canceled to Be Called Back: A Retrospective Cohort Study of Canceled Helicopter Emergency Medical Service Scene Calls That Are Later Transferred to a Trauma Center. AB - INTRODUCTION: In our trauma system, helicopter emergency medical services (HEMS) can be requested to attend a scene call for an injured patient before arrival by land paramedics. Land paramedics can cancel this response if they deem it unnecessary. The purpose of this study is to describe the frequency of canceled HEMS scene calls that were subsequently transferred to 2 trauma centers and to assess for any impact on morbidity and mortality. METHODS: Probabilistic matching was used to identify canceled HEMS scene call patients who were later transported to 2 trauma centers over a 48-month period. Registry data were used to compare canceled scene call patients with direct from scene patients. RESULTS: There were 290 requests for HEMS scene calls, of which 35.2% were canceled. Of those canceled, 24.5% were later transported to our trauma centers. Canceled scene call patients were more likely to be older and to be discharged home from the trauma center without being admitted. CONCLUSION: There is a significant amount of undertriage of patients for whom an HEMS response was canceled and later transported to a trauma center. These patients face similar morbidity and mortality as patients who are brought directly from scene to a trauma center. PMID- 29478575 TI - In-Flight Pharmacological Management of Patients with Acute Mental Health Disturbance. AB - OBJECTIVE: Patients can be transferred many hundreds of kilometers with acute mental health disturbance for specialist mental health services in Western Australia. METHODS: A retrospective notes review of Royal Flying Doctor Service Western Operations records was undertaken over a 4-month period. Patients were identified from the transfer database by mental health diagnosis. Benzodiazepine and antipsychotic doses were converted into a reference drug per class for comparison. RESULTS: One hundred ten patients underwent air transfer in a total of 130 flights. Over 80% of patients were involuntary patients being transferred for specialist psychiatric evaluation and management in an inpatient mental health unit. Over half of the patients required no in-flight sedation, and around 80% of patients were managed with standard doses of first-line agents (haloperidol, midazolam, and diazepam). A small number of patients required alternative agents for refractory sedation, most commonly ketamine and propofol. There were no statistically significant differences for in-flight medication by sex, ethnicity, or substance misuse status. CONCLUSIONS: The rate of in-flight incidents including violence remained low. Transfers of patients with acute mental health disturbance are challenging, and quality preflight assessment and in-flight care are required to minimize the associated risks. PMID- 29478576 TI - Safe Interfacility Transport of Pediatric Patients: Medical Control Training, an Interdisciplinary Approach. AB - INTRODUCTION: Critically ill children who require transfer to tertiary care centers often require transport by specialized transport teams (TT). These interfacility transports require a medical control physician (MCP). Traditionally this role is assigned to fellows who are taught "on-the-job", but achieving competency in communication for those trained this way may not be optimal. We sought to close this curriculum gap by developing a MCP training program immersing emergency medicine (EM) and critical care (CC) fellows together with TT members to manage a simulated patient. METHODS: Pilot curriculum from 2014-2016 involving 1st year fellows. A case is presented initially with a referral call. By phone the fellow is to communicate with and guide the TT, who is in a separate room managing the "sick" patient using high-fidelity simulation. Each MCP and TT communication is evaluated by faculty and peers. An immediate debriefing session provided formative feedback. RESULTS: 11 fellows participated and 10 completed a post-simulation survey (91%). The fellows and TT members rated the curriculum as "highly important" and positively viewed the interprofessional collaboration. Respondents were neutral when asked if communication skills improved. CONCLUSION: The MCP training curriculum was viewed favorably and participants reported that this formalized training is needed. PMID- 29478578 TI - Helicopter Emergency Medical Services Literature 2014 to 2016: Lessons and Perspectives, Part 2-Nontrauma Transports and General Issues. PMID- 29478577 TI - Should Helicopters Transport Patients Who Become Sick After a Chemical, Biological, Radiological, Nuclear, and Explosive Attack? AB - The local fire department executed a training simulation for chemical and explosive incidents at a large sports facility. In this training simulation, a physician-staffed helicopter arrived at the request of the fire department and landed just outside the cold zone in the parking area. The doctor and nurse of the helicopter were escorted to a red area in the cold zone, which was selected based on the results of postdecontamination triage. After the patients had been treated, they were air medically evacuated to the base hospital. In the Tokyo subway sarin attack in 1995, St Luke's International Hospital admitted over 600 victims. During this incident, 23.2% of medical staff suffered secondary injury from sarin exposure. If air medial crews respond with subsequent postexposure effects during flight, an affected pilot could lose control of the helicopter, resulting in a fatal crash. Based on potential safety concerns for air medical and ground personnel, our recommendation would be that air medical helicopters not be dispatched to sites of chemical, biological, radiological, nuclear, and explosive incidents. PMID- 29478579 TI - Air Medical Simulation Training: A Retrospective Review of Cost and Effectiveness. AB - OBJECTIVE: Simulation training is an integral part of the training of medical personnel. However, there are limited data on the use of simulation in the training of helicopter emergency medical services (HEMS). METHODS: In this study, we retrospectively compared the number of orientation flights needed to be released to a full crewmember and the cost of training in an air medical flight academy before and after implementation of a high-fidelity air medical simulator. A total of 13 participants in the air medical services flight academy were analyzed. Four of these participants went through the standard academy. Nine participants went through the standard academy but had additional training using the simulator. RESULTS: There was no statistical difference in the number of orientation flights before release from training (P = .35). Also, although there was a trend that the simulator decreased the overall cost of training, there was no significant difference between the groups (P = .16). CONCLUSION: This study found that the use of a high-fidelity simulator when training HEMS personnel does not significantly reduce the number of orientation flights needed to become a full crewmember. There was a trend toward a significant reduction in the total cost of training. PMID- 29478580 TI - CAMTS in 2018. PMID- 29478581 TI - A 70 Year-Old Woman with Postoperative Hypotension. PMID- 29478582 TI - Burn Care: Transfers and Toxins. PMID- 29478583 TI - Articles That May Change Your Practice: Mechanical Chest Compressions. PMID- 29478584 TI - Forum. PMID- 29478585 TI - Corrigendum to "Pediatric Extracorporeal Cardiopulmonary Resuscitation Patient with Traumatic Subarachnoid Hemorrhage and Takotsubo Syndrome" [Air Medical Journal 37 (2018) 64-66]. PMID- 29478586 TI - The Role of the Paramedic in Transport Medicine and Crew Resource Management. PMID- 29478587 TI - Exploration of a Preflight Acuity Scale for Fixed Wing Air Ambulance Transport. AB - INTRODUCTION: Despite the prevalence of fixed wing medical flights for specialized care and repatriation, few acuity rating scales exist aimed at the prediction of adverse in-flight medical events. An acuity scoring system can provide information to flight crews, allowing for staffing enhancements, protocol modifications, and flight planning, with the aim of improving patient care, outcomes, and preventing losses to providers because of costly diversions. METHODS: Our medical crew developed an acuity scale, which was applied retrospectively to 296 patients transported between January 2016 and March 2017. Patients received scores based on conditions identified during the preflight medical report, the initial patient assessment, demographics, and flight factors. RESULTS: Five patients were identified as high-risk transports based on our scale. Three patients suffered adverse events according to our defined criteria, 2 of which occurred before transport and 1 during transport. The 3 patients suffering adverse events did not receive a score that indicated adverse events in flight. CONCLUSION: Our scale was not predictive of adverse events in flight. However, it did illuminate factors worthy of consideration. Consideration of these factors may have prevented adverse events. PMID- 29478588 TI - Concern Network. PMID- 29478589 TI - A case-control study of GRIN2B polymorphisms and major depressive disorder in the Chinese Han population. PMID- 29478590 TI - The genetic landscape of Alzheimer disease. AB - Alzheimer disease (AD), a progressive and neurodegenerative disease, is the most common form of dementia with high incidence in elderly people. Neuropathologically the disease is defined by the combined presence of extracellular amyloid-beta (Abeta) plaques and intracellular neurofibrillary tangles of phosphorylated tau protein. Genetically, the first clues were provided by genetic linkage studies that led to the identification of APP, PSEN1, and PSEN2 mutations as the main causes of autosomal-dominant early-onset AD. Another important hallmark was the identification of the APOE E4 allele as a risk factor for late-onset AD. Over the last 20 years the development and implementation of new genetic and genomic technologies have allowed the identification of other genetic players in this disease. Genome-wide association studies identified more than 20 loci with common variability having small contributions to the susceptibility of AD. The majority of the genes mapped in these loci are known to be involved in specific biologic pathways: cholesterol metabolism, immune response, and endocytosis. More recently, the application of next-generation sequencing (mainly whole-exome sequencing) has begun to reveal the contribution of rarer variants with medium effects on risk for AD. This area of research has come a long way with many and important results allowing a better understanding of the disease. More efforts are still needed, however, to fully understand the etiology of this disease in order to establish reliable individual predictive models and put us closer to the development of a curative, preventive, or modulator drug. PMID- 29478591 TI - Frontotemporal dementia. AB - Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by progressive changes in behavior, personality, and language with involvement of the frontal and temporal regions of the brain. About 40% of FTD cases have a positive family history, and about 10% of these cases are inherited in an autosomal-dominant pattern. These gene defects present with distinct clinical phenotypes. As the diagnosis of FTD becomes more recognizable, it will become increasingly important to keep these gene mutations in mind. In this chapter, we review the genes with known associations to FTD. We discuss protein functions, mutation frequencies, clinical phenotypes, imaging characteristics, and pathology associated with these genes. PMID- 29478592 TI - The genetics of dementia with Lewy bodies. AB - Dementia with Lewy bodies (DLB), the most common non-AD neurodegenerative disease has in the past several decades attracted the attention of the neurological scientific community due to its highly negative impact on the quality of life of both the affected individuals and those caring for them. The strong hereditary component in related conditions such as PD and AD and the description of a number of DLB families suggest that genetic factors may play a role in the pathogenesis of DLB. This chapter focuses on currently proposed causal and risk genes and their role in the pathophysiology of DLB, discusses the feasibility of genetic therapy and genetic testing in the diagnostic and treatment of DLB and provides directions for future research. While no single mutation is specific enough to support its regular use in the diagnosis/treatment of DLB, identification of combinations of causative gene or single-gene point mutations and risk genes interfering with the pathogenesis of DLB may help elucidate the genetic mechanisms involved in DLB and inform development of gene-specific therapies. PMID- 29478593 TI - Prion disease. AB - Genetic prion diseases (gPrDs) are caused by autosomal-dominant mutations in the prion protein gene (PRNP). Although the first PRNP mutations identified, and most since, are PRNP missense, octapeptide repeat insertions, deletion and nonsense mutations have now also been shown to cause gPrD. Based on clinicopathologic features of familial disease, gPrDs historically have been classified into three forms: familial Jakob-Creutzfeldt disease, Gerstmann-Straussler-Scheinker disease, and fatal familial insomnia. This classification, however, occurred prior to the identification of PRNP, and although these forms are still recognized, classification now is somewhat more complex. Clinical manifestations, and even pathology, are known to be more heterogeneous and varied than the historic three phenotypic classifications. Most gPrDs either present rapidly with progression of dementia, ataxia, myoclonus, and other motor features leading to death in few months or present more slowly, declining over a few years with mild cognitive impairment, ataxia, or parkinsonism and later dementia; a few very rare mutations, however, present over years to decades with neuropsychiatric disorders and systemic symptoms (gastrointestinal disorders and neuropathy). In this chapter, we review the broad phenotypic spectrum of PRNP mutations causing gPrDs. PMID- 29478594 TI - Genetics of epilepsy. AB - Discovery of nearly 200 genes implicated in epilepsy and insights into the molecular and cellular pathways involved are transforming our knowledge of the causes, classifications, diagnosis, and in some cases, treatments for individuals with chronic seizure disorders. Numerous disorders once considered "idiopathic" are now recognized as genetic conditions. Despite these remarkable advances, the cause of epilepsy for most individuals is unknown. We present a clinical approach to patients with epilepsy, presenting an algorithm for clinical and genetic testing, and review genes implicated in epilepsy and their associated syndromes. PMID- 29478595 TI - Genetics of migraine. AB - Genetics of migraine has recently undergone a major shift, moving in the space of a few years from having only a few known genes for rare Mendelian forms to 47 known common variant loci affecting the susceptibility of the common forms of migraine. This has largely been achieved by rapidly increasing sample sizes for genomewide association studies (GWAS), soon to be followed by the first wave of large-scale exome-sequencing studies. The large number of detected loci, chief among them TRPM8, PRDM16, and LRP1, have enabled a number of in silico analyses, which have shed light on the functional and tissue-level aspects of the common risk variants for migraine, including evidence for involvement of both vascular and neuronal mechanisms. Polygenic risk scores and other measures of genetic variance based on GWAS information are further opening the door to dissecting pharmacogenetics, functional etiology, and comorbidity. Heritability-based analyses are demonstrating strong links between migraine and other neuropsychiatric disorders and brain phenotypes, highlighting genetic links between migraine and major depressive disorder and attention-deficit hyperactivity disorder, among others. These recent successes in migraine genetics are starting to be mature enough to provide robust evidence of specific quantifiable genetic factors in common migraine. PMID- 29478596 TI - Periodic paralysis. AB - The periodic paralyses are a group of skeletal muscle channelopathies characterizeed by intermittent attacks of muscle weakness often associated with altered serum potassium levels. The underlying genetic defects include mutations in genes encoding the skeletal muscle calcium channel Cav1.1, sodium channel Nav1.4, and potassium channels Kir2.1, Kir3.4, and possibly Kir2.6. Our increasing knowledge of how mutant channels affect muscle excitability has resulted in better understanding of many clinical phenomena which have been known for decades and sheds light on some of the factors that trigger attacks. Insights into the pathophysiology are also leading to new therapeutic approaches. PMID- 29478597 TI - Episodic ataxias. AB - The familial episodic ataxias (EAs) are prototypical channelopathies in the central nervous system clinically characterized by attacks of imbalance and incoordination variably associated with progressive ataxia and variable interictal features. EA1, EA2, and EA6 are caused by mutations in ion channel- and transporter-encoding genes that regulate neuronal excitability and neurotransmission. PMID- 29478598 TI - Disorders of sleep and circadian rhythms. AB - Sleep is fundamental to the survival of humans. However, knowledge regarding the role of sleep and its regulation is poorly understood. Genetics in flies, mice, and humans has led to a detailed understanding of some aspects of circadian regulation. Sleep homeostasis (the effect of increasing periods of wakefulness on our sleep propensity) is largely not understood. Sleep homeostasis is distinct from, but also linked to, the circadian clock. It is only in the last two decades that our understanding of some sleep disorders has been revealed. These breakthroughs were mostly fueled by intensive investigation using genetic tools. Although modern human genetics has revolutionized scientific research of neurologic disorders beginning ~35 years ago, studies of sleep and sleep disorders have lagged behind those of many neurologic diseases. This is due to the complexity in phenotyping behaviors like sleep and the fact that sleep is strongly influenced by environmental and other factors. We have long been aware that the amount of sleep required by individuals is normally distributed in the general population with small proportions of people being natural short or natural long sleepers. However, it has been less than a decade since Mendelian families of natural short sleepers have been recognized. Recent work has made significant advances and mechanistic insights of several sleep disorders as well as familial natural short sleepers by using ever-improving human genetic and cellular molecular tools. Given recent advances into genetic and biologic understanding of sleep, the hope of understanding this indispensable process is closer. Ultimately, our growing understanding will lead to more effective treatments of human sleep disorders. PMID- 29478599 TI - Facioscapulohumeral muscular dystrophy. AB - Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common forms of muscular dystrophy with a distinctive pattern of skeletal muscle weakness and a wide spectrum of disease severity. The pathophysiologic consequences of the genetic lesion, the loss of a critical number of macrosatellite repeats (D4Z4) in the subtelomeric region of chromosome 4q35, remained unexplained for almost two decades. Recent studies demonstrate that contraction in the number of D4Z4 repeats results in chromatin relaxation and transcriptional de-repression of DUX4, a gene normally expressed only in the germline. In about 5% of individuals with phenotypic FSHD, there is no contraction in the D4Z4 repeats and yet similar chromatin changes are present, resulting in the inappropriate expression of the DUX4 gene. The chromatin changes in this form of FSHD (FSHD2) are the result, in most cases, of mutations in SMCHD1, a gene on chromosome 18 involved in chromatin regulation. The recent identification of aberrant activation of DUX4 transcription in FSHD as the root cause of FSHD now allows for a targeted approach to therapeutic development. PMID- 29478601 TI - Genetic basis and phenotypic features of congenital myasthenic syndromes. AB - The congenital myasthenic syndromes (CMS) are heterogeneous disorders in which the safety margin of neuromuscular transmission is compromised by one or more specific mechanisms. The disease proteins reside in the nerve terminal, the synaptic basal lamina, or in the postsynaptic region, or at multiple sites at the neuromuscular junction as well as in other tissues. Targeted mutation analysis by Sanger or exome sequencing has been facilitated by characteristic phenotypic features of some CMS. No fewer than 20 disease genes have been recognized to date. In one-half of the currently identified probands, the disease stems from mutations in genes encoding subunits of the muscle form of the acetylcholine receptor (CHRNA1, CHRNB, CHRNAD1, and CHRNE). In 10-14% of the probands the disease is caused by mutations in RAPSN, DOK 7, or COLQ, and in 5% by mutations in CHAT. Other less frequently identified disease genes include LAMB2, AGRN, LRP4, MUSK, GFPT1, DPAGT1, ALG2, and ALG 14 as well as SCN4A, PREPL, PLEC1, DNM2, and MTM1. Identification of the genetic basis of each CMS is important not only for genetic counseling and disease prevention but also for therapy, because therapeutic agents that benefit one type of CMS can be harmful in another. PMID- 29478600 TI - The genetics of congenital myopathies. AB - Congenital myopathies are a clinically and genetically heterogeneous group of conditions that most commonly present at or around the time of birth with hypotonia, muscle weakness, and (often) respiratory distress. Historically, this group of disorders has been subclassified based on muscle histopathologic characteristics. There has been an explosion of gene discovery, and there are now at least 32 different genetic causes of disease. With this increased understanding of the genetic basis of disease has come the knowledge that the mutations in congenital myopathy genes can present with a wide variety of clinical phenotypes and can result in a broad spectrum of histopathologic findings on muscle biopsy. In addition, mutations in several genes can share the same histopathologic features. The identification of new genes and interpretation of different pathomechanisms at a molecular level have helped us to understand the clinical and histopathologic similarities that this group of disorders share. In this review, we highlight the genetic understanding for each subtype, its pathogenesis, and the future key issues in congenital myopathies. PMID- 29478602 TI - Spinal muscular atrophy. AB - Autosomal-recessive proximal spinal muscular atrophy (Werdnig-Hoffmann, Kugelberg Welander) is caused by mutation of the SMN1 gene, and the clinical severity correlates with the number of copies of a nearly identical gene, SMN2. The SMN protein plays a critical role in spliceosome assembly and may have other cellular functions, such as mRNA transport. Cell culture and animal models have helped to define the disease mechanism and to identify targets for therapeutic intervention. The main focus for developing treatment has been to increase SMN levels, and accomplishing this with small molecules, oligonucleotides, and gene replacement has been quite. An oligonucleotide, nusinersen, was recently approved for treatment in patients, and confirmatory studies of other agents are now under way. PMID- 29478603 TI - Emerging understanding of the genotype-phenotype relationship in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a progressive, noncurable neurodegenerative disorder of the upper and lower motor neurons causing weakness and death within a few years of symptom onset. About 10% of patients with ALS have a family history of the disease; however, ALS-associated genetic mutations are also found in sporadic cases. There are over 100 ALS-associated mutations, and importantly, several genetic mutations, including C9ORF72, SOD1, and TARDBP, have led to mechanistic insight into this complex disease. In the clinical realm, knowledge of ALS genetics can also help explain phenotypic heterogeneity, aid in genetic counseling, and in the future may help direct treatment efforts. PMID- 29478604 TI - Spinal and bulbar muscular atrophy. AB - Spinal and bulbar muscular atrophy (SBMA) is an adult-onset degenerative disorder of the neuromuscular system resulting in slowly progressive weakness and atrophy of the proximal limb and bulbar muscles. The disease is caused by the expansion of a CAG/glutamine tract in the amino-terminus of the androgen receptor. That SBMA exclusively affects males reflects the fact that critical pathogenic events are hormone-dependent. These include translocation of the polyglutamine androgen receptor from the cytoplasm to the nucleus and unfolding of the mutant protein. Studies of the pathology of SBMA subjects have revealed nuclear aggregates of the mutant androgen receptor, loss of lower motor neurons in the brainstem and spinal cord, and both neurogenic and myopathic changes in skeletal muscle. Mechanisms underlying disease pathogenesis include toxicity in both lower motor neurons and skeletal muscle, where effects on transcription, intracellular transport, and mitochondrial function have been documented. Therapies to treat SBMA patients remain largely supportive, although experimental approaches targeting androgen action or promoting degradation of the mutant androgen receptor protein or the encoding RNA are under active study. PMID- 29478605 TI - Hereditary spastic paraplegia. AB - The hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurologic disorders with the common feature of prominent lower-extremity spasticity, resulting from a length-dependent axonopathy of corticospinal upper motor neurons. The HSPs exist not only in "pure" forms but also in "complex" forms that are associated with additional neurologic and extraneurologic features. The HSPs are among the most genetically diverse neurologic disorders, with well over 70 distinct genetic loci, for which about 60 mutated genes have already been identified. Numerous studies elucidating the molecular pathogenesis underlying HSPs have highlighted the importance of basic cellular functions - especially membrane trafficking, mitochondrial function, organelle shaping and biogenesis, axon transport, and lipid/cholesterol metabolism - in axon development and maintenance. An encouragingly small number of converging cellular pathogenic themes have been identified for the most common HSPs, and some of these pathways present compelling targets for future therapies. PMID- 29478606 TI - Neuropathy. AB - The genetic neuropathies are a clinically and genetically heterogeneous group of diseases that can broadly be classified into two groups: those in which the neuropathy is the sole or primary part of the disorder (Charcot-Marie-Tooth disease, CMT) and those in which the neuropathy is part of a more generalized neurologic or multisystem disorder (e.g., familial amyloid polyneuropathy, neuropathies associated with mitochondrial diseases, with hereditary ataxias, porphyrias). The former is the most common group, with a prevalence of 1 in 2500 people, and this chapter will concentrate on CMT. CMT is, however, an umbrella term that encompasses a wide variety of inherited sensory and/or motor neuropathies. The number of disease genes identified in CMT has expanded rapidly over the past few decades, making an accurate genetic diagnosis more challenging, although increasingly possible. Although no specific therapies are yet available, research into their pathogenesis has increased our understanding of the disease and allowed the development of rational approaches to therapy. In this chapter, the authors review the clinical features of CMT, suggest genetic testing strategies, and provide an update on new-generation sequencing techniques in inherited neuropathies. PMID- 29478608 TI - Alexander disease. AB - Alexander disease is a rare and generally fatal disorder of the central nervous system, originally defined by the distinctive neuropathology consisting of abundant Rosenthal fibers within the cytoplasm and processes of astrocytes. More recently, mutations in GFAP, encoding glial fibrillary acidic protein, the major intermediate filament protein of astrocytes, have been identified in nearly all patients. No other genetic causes have yet been identified. The precise mechanisms by which mutations lead to disease are poorly understood. Despite the genetic homogeneity, there are a wide range of clinical phenotypes. The genetic issues and the approach to diagnosis are the prime consideration in this chapter. PMID- 29478607 TI - The spectrum of adult-onset heritable white-matter disorders. AB - Unique clinical presentations and magnetic resonance imaging patterns can help differentiate the various adult presentations of leukodystrophies and leukoencephalopathies. White-matter disorders are genetically based disorders affecting the central nervous system white matter, with or without peripheral nervous system involvement. These disorders predominantly affect patients in the pediatric population; however, a number of classic leukodystrophies can present in adulthood. Disease progression can be of variable onset with a broad range of symptoms, usually progressing from cognitive dysfunction. Recognition of specific disorders can have important implications for treatment, involvement of multidisciplinary services, and important conversations surrounding social issues the families may face. The focus of this chapter is to highlight the adult presentations of the classic childhood-onset leukodystrophies as well as to describe leukodystrophies which predominantly present in adulthood. PMID- 29478609 TI - Neurogenetics of Pelizaeus-Merzbacher disease. AB - Pelizaeus-Merzbacher disease (PMD) is an X-linked disorder caused by mutations in the PLP1 gene, which encodes the proteolipid protein of myelinating oligodendroglia. PMD exhibits phenotypic variability that reflects its considerable genotypic heterogeneity, but all forms of the disease result in central hypomyelination associated with early neurologic dysfunction, progressive deterioration, and ultimately death. PMD has been classified into three major subtypes, according to the age of presentation: connatal PMD, classic PMD, and transitional PMD, combining features of both connatal and classic forms. Two other less severe phenotypes were subsequently described, including the spastic paraplegia syndrome and PLP1-null disease. These disorders may be associated with duplications, as well as with point, missense, and null mutations within the PLP1 gene. A number of clinically similar Pelizaeus-Merzbacher-like disorders (PMLD) are considered in the differential diagnosis of PMD, the most prominent of which is PMLD-1, caused by misexpression of the GJC2 gene encoding connexin-47. No effective therapy for PMD exists. Yet, as a relatively pure central nervous system hypomyelinating disorder, with limited involvement of the peripheral nervous system and little attendant neuronal pathology, PMD is an attractive therapeutic target for neural stem cell and glial progenitor cell transplantation, efforts at which are now underway in a number of centers internationally. PMID- 29478610 TI - Multiple sclerosis. AB - Multiple sclerosis is a potentially progressive, autoimmune neurologic disorder of the central nervous system, resulting from an autoimmune attack on central nervous system white matter. It is a leading cause of neurologic symptoms in young adults, with no known cure. Emerging disease-modifying therapies aim to control symptoms, with increasingly sophisticated immune function modulation. Though several environmental exposures increase the risk of developing the disease, a large fraction of overall risk is heritable and can be attributed to hundreds of common genetic variants influencing gene regulation in specific immune subsets. Here, we review the history of the disease, the realization that risk is heritable, and the recent revelation of hundreds of genetic variants driving this risk by international consortia studying tens of thousands of patients. Finally, we discuss how these results are revealing the specific pathobiology of multiple sclerosis and how this knowledge is transforming drug discovery. PMID- 29478611 TI - CADASIL. AB - Cerebral small-vessel disease is a prevalent condition that is strongly associated with ischemic stroke and dementia. The most prevalent inherited cause of cerebral small-vessel disease is CADASIL, cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy, a disorder linked to mutations in NOTCH3. The most common symptoms of CADASIL are small ischemic strokes and/or transient ischemic attacks and cognitive impairment, appearing in middle age, that may progress to frank vascular dementia. However, it is increasingly recognized that individual symptom types, onset, and disease severity span a wide spectrum, even among individuals in the same family. Magnetic resonance imaging in CADASIL reveals severe white-matter hyperintensities, evidence of prior subcortical strokes, and, in some cases, microhemorrhages. Several hundred mutations in NOTCH3 have been described worldwide in CADASIL, and virtually all of these mutations alter the cysteine content of the extracellular NOTCH3 gene product. This molecular genetic signature of CADASIL has led to the hypothesis that structural abnormalities in the vascular smooth-muscle protein NOTCH3 trigger arterial degeneration, vascular protein accumulation, and cerebrovascular failure. PMID- 29478613 TI - Genetic susceptibility in obsessive-compulsive disorder. AB - Obsessive-compulsive disorder (OCD) is present in 1.5-2.5% of the population and can result in substantial lifelong disability. It is characterized by intrusive thoughts, sensations, and urges and by repetitive behaviors that are difficult to control despite, in most cases, preserved insight as to their excessive or irrational nature. The causes and underlying pathophysiology of OCD are not well understood, which has limited the development of new treatments and interventions. Despite evidence for a substantial genetic contribution to disease risk, identification and replication of genetic variants associated with OCD have been challenging. Decades of candidate gene association studies have provided little insight. They are now being supplanted by modern genomewide approaches to discover both common and rare sequence and structural variants. Studies to date suggest potential novel therapeutic avenues such as modulators of glutamatergic and immune pathways; however, individual genetic findings are not yet statistically robust or replicated. Further efforts are clearly needed to identify specific risk variants and to confirm vulnerable pathways by studying much larger cohorts of patients with comprehensive variant discovery approaches. Mouse knockout models have already made notable inroads into our understanding of OCD pathology; their utility will only increase as specific risk alleles are identified. PMID- 29478614 TI - Brain cancer genomics and epigenomics. AB - Classically, brain cancers have been graded and diagnosed based on histology and risk stratified by clinical criteria. Recent advances in genomics and epigenomics have ushered in an era of defining cancers based on molecular criteria. These advances have increased our precision of identifying oncogenic driving events and, most importantly, increased our precision at predicting clinical outcome. For the first time in its history, the 2016 revision of the WHO Classification of Tumors of the Central Nervous System included molecular features as tumor classification criteria. Brain tumors can develop in the context of genetic cancer predisposition syndromes, such as Li-Fraumeni or Gorlin syndrome, but by far most commonly arise through the acquisition of somatic mutations and chromosome changes in the malignant cells. By taking a survey across this cancer landscape, certain themes emerge as being common events to drive cancer: DNA damage repair, genomic instability, mechanistic target of rapamycin pathway, sonic hedgehog pathway, hypoxia, and epigenetic dysfunction. Understanding these mechanisms is of paramount importance for improving targeted therapies, and for identifying the right patients for those therapies. PMID- 29478615 TI - Neurofibromatosis type 1. AB - The neurofibromatoses are a group of three heterogeneous disorders that include neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis. NF1 is the most common of these three conditions, and represents one of the most frequently diagnosed cancer predisposition disorders involving the nervous system. While NF1 primarily affects the central and peripheral nervous system, multisystem involvement is the rule, with dermatologic, cardiovascular, gastrointestinal, and orthopedic affectation often reported. Importantly, NF1 is a disorder of heterogeneity, such that affected individuals can be variably affected, even within the same family. This heterogeneity also presents significant challenges to the actualization of effective treatments. However, recent studies aimed at understanding the role of the NF1 protein (neurofibromin) as a tumor suppressor have revealed that this profound level of clinical heterogeneity may reflect tissue and region-specific effects, sexually dimorphic influences, and the contribution of germline genetics and genomics. With the availability of accurate preclinical Nf1 small-animal models, human induced pluripotent stem cells, and an efficient clinical trials consortium, we are now uniquely positioned to identify and efficiently evaluate promising therapies for NF1-related medical problems. PMID- 29478612 TI - Neuroepigenetics and addiction. AB - Drug addiction involves long-term behavioral abnormalities that arise in response to repeated exposure to drugs of abuse in vulnerable individuals. It is a multifactorial syndrome involving a complex interplay between genes and the environment. Evidence suggests that the underlying mechanisms regulating these persistent behavioral abnormalities involve changes in gene expression throughout the brain's reward circuitry, in particular, in the mesolimbic dopamine system. In the past decade, investigations have begun to reveal potential genes involved in the risk for addiction through genomewide association studies. Additionally, a crucial role for epigenetic mechanisms, which mediate the enduring effects of drugs of abuse on the brain in animal models of addiction, has been established. This chapter focuses on recent evidence that genetic and epigenetic regulatory events underlie the changes throughout the reward circuitry in humans, as well as animal models of addiction. While further investigations are necessary, a picture of genetic and epigenetic mechanisms involved in addiction is beginning to emerge and the insight gained from these studies will be key to the identification of novel targets for improved diagnosis and treatment of addiction syndromes in humans. PMID- 29478617 TI - Von Hippel-Lindau disease and Sturge-Weber syndrome. AB - The primary neurologic involvement in both von Hippel-Lindau (VHL) disease and Sturge-Weber syndrome (SWS) is vascular tumor/vascular malformation, but molecular pathogenesis, long-term symptom evolution, and treatment are quite different. VHL is caused by dominant inherited or de novo germline mutations, while SWS is caused by somatic mosaicism. A diagnosis of VHL carries substantial cancer risk, while the clinical issues in SWS are primarily related to the consequences of the intracranial vascular abnormalities. PMID- 29478616 TI - Tuberous sclerosis complex. AB - Tuberous sclerosis complex (TSC) is an autosomal-dominant or sporadic multisystem disorder that results from mutations in either TSC1 or TSC2. The primary organs affected include the brain, skin, lung, kidney, and heart, all with variable frequency, penetrance, and severity. There are over 2000 known allelic variants for TSC, including nonsense and misssense mutation, and all pathogenic mutations are inactivating, leading to loss-of-function effects on the encoded proteins, TSC1 and TSC2. These proteins form a complex to constitutively inhibit the mammalian target of rapamycin (mTOR) signaling cascade, and as a consequence, mTOR signaling is constitutively active within all TSC-associated lesions. The mTOR inhibitors rapamycin (sirolimus) and everolimus have been shown to reduce renal and brain lesion size, and improve pulmonary function in TSC, and these compounds may also decrease seizure frequency. The clinical application of mTOR inhibitors in TSC has provided one of the first examples of precision medicine in a neurodevelopmental disorder. PMID- 29478618 TI - Preface. PMID- 29478619 TI - Foreword. PMID- 29478620 TI - Accuracy of Injection Into the First Dorsal Compartment: A Cadaveric Ultrasound Study. AB - PURPOSE: To determine the accuracy of ultrasound-guided (UG) injections compared with anatomic landmark-guided (AL) injections in the first dorsal compartment (FDC) with the hypothesis that ultrasound guidance would increase the accuracy of injection. METHODS: We randomized 43 above-elbow cadaveric specimens to receive latex dye injections into the FDC via a UG or AL technique. If ultrasound imaging identified a septated FDC, the needle was redirected and a portion of the dye was injected around the extensor pollicis brevis (EPB) tendon. Specimens were dissected and data collected regarding the location of the dye and presence of a septated FDC. Fisher exact test was used to calculate the difference in accuracy rates of injections. RESULTS: All 21 specimens injected via UG and all 22 specimens injected via the AL technique demonstrated dye within the FDC. Eight of 21 specimens in the UG group and 6 of 22 specimens in the AL group demonstrated a septated FDC upon dissection. Ultrasound was able to identify 6 of 8 specimens accurately with a septated FDC, representing a sensitivity of 75% and specificity of 92%. Six of 8 specimens with a septated FDC in the UG group versus 2 of 6 specimens with a septated FDC in the AL group demonstrated dye infiltration around the EPB. Dye was noted in the subcutaneous tissues in 2 of 21 specimens in the UG group versus 2 of 22 specimens in the AL group. CONCLUSIONS: The UG- and AL-based injections both had excellent dye infiltration into a portion of the FDC. Ultrasound-guided injections had a higher observed infiltration rate in EPB subcompartments than the AL technique, but could not be statistically confirmed to be different. CLINICAL RELEVANCE: Ultrasound is unlikely to increase the accuracy of injections into an unseptated FDC. It may aid in injection of a septated FDC; however, that remains to be statistically demonstrated. PMID- 29478621 TI - Unexpected trends in hospital standardized mortality indicate a novel cause. PMID- 29478622 TI - Supplying osteogenesis to dead bone using an osteogenic matrix cell sheet. AB - PURPOSE: To evaluate whether osteogenic matrix cell sheets can supply osteogenesis to dead bone. METHODS: Femur bone fragments (5 mm in length) were obtained from Fisher 344 rats and irradiated by a single exposure of 60 Gy to produce bones that were no longer viable. Osteogenic matrix cell sheets were created from rat bone marrow-derived stromal cells (BMSCs). After wrapping the dead bone with an osteogenic matrix cell sheet, it was subcutaneously transplanted into the back of a rat and harvested after 4 weeks. Bone formation around the dead bone was evaluated by X-ray imaging and histology. Alkaline phosphatase (ALP) and osteocalcin (OC) mRNA expression levels were measured to confirm osteogenesis of the transplanted bone. The contribution of donor cells to bone formation was assessed using the Sry gene and PKH26. RESULTS: After the cell sheet was transplanted together with dead bone, X-ray images showed abundant calcification around the dead bone. In contrast, no newly formed bone was seen in samples that were transplanted without the cell sheet. Histological sections also showed newly formed bone around dead bone in samples transplanted with the cell sheet, whereas many empty lacunae and no newly formed bone were observed in samples transplanted without the cell sheet. ALP and OC mRNA expression levels were significantly higher in dead bones transplanted with cell sheets than in those without a cell sheet (P < 0.01). Sry gene expression and cells derived from cell sheets labeled with PKH26 were detected in samples transplanted with a cell sheet, indicating survival of donor cells after transplantation. CONCLUSION: Our study indicates that osteogenic matrix cell sheet transplantation can supply osteogenesis to dead bone. PMID- 29478623 TI - Selection of posterior spinal osteotomies for more effective periapical segmental vertebral derotation in adolescent idiopathic scoliosis-An in vivo comparative analysis between Ponte osteotomy and inferior facetectomy alone. AB - BACKGROUND: Ponte osteotomy is a useful method in posterior spinal release. However, it is unclear whether Ponte osteotomy itself contributes to vertebral derotation in surgery for adolescent idiopathic scoliosis (AIS) patients compared to inferior facetectomy alone. This study aimed to assess the effect of Ponte osteotomy on the magnitude of periapical vertebral body rotation compared to inferior facetectomy alone. This study was a prospective collected data. METHODS: The study included 63 patients with AIS (Thoracic curve type, 35; thoracolumbar/lumbar curve type, 27), who underwent surgery between August 2011 and January 2015. All AIS patients underwent posterior spinal fusion with uniplanar screws and Ponte osteotomies on three periapical intervertebral segments. We measured and analyzed the flexibility of periapical intervertebral rotation pre- and post-bilateral inferior facetectomy, and post-Ponte osteotomy with our device (three times). The difference in intervertebral rotation between pre- and post-Ponte osteotomy was analyzed. RESULTS: The mean increase in angle was 5.6 degrees for thoracic curves and 6.4 degrees for thoracolumbar curves. The increase in angle for thoracolumbar curves was significantly larger than that for thoracic curves (P < 0.05). The more an apical region of the scoliosis was located at caudal side of spine, the more the flexibility due to Ponte osteotomy increased (P < 0.05). The significant differences of the increase in intervertebral flexibility between inferior facetectomies and Ponte osteotomies were recognized at middle thoracic and thoracolumbar regions (P < 0.005). CONCLUSIONS: Our data suggest that Ponte osteotomy has a loosening effect on periapical scoliotic curvature compared to inferior facetectomy alone. Ponte osteotomy is likely to be associated with an increase in loosening of the middle thoracic and thoracolumbar regions. PMID- 29478625 TI - Traumatic spondyloptosis at the thoracolumbar junction in a patient with diffuse idiopathic skeletal hyperostosis: A case report. PMID- 29478624 TI - Subchondral insufficiency fracture of the femoral head in an elderly woman with symptomatic osteoarthritis of the contralateral hip. PMID- 29478626 TI - Prognostic factors in high grade gliomas. PMID- 29478627 TI - The efficacy of a brief hazard perception interventional program for child bicyclists to improve perceptive standards. AB - INTRODUCTION: Even though child bicyclists are highly vulnerable in traffic only few studies focused on providing child bicyclists with means to enhance their abilities to deal with the complexity of dynamic traffic situations. The current study therefore evaluated whether a brief hazard perception intervention might be effective to improve hazard perception skills in child bicyclists towards a level more comparable to adult bicyclists. METHODS: Eighty children of the fourth grade (9.03 +/- 0.43 years; 34 girls) and forty-six adults (34.67 +/- 14.25 years age; 24 woman) first performed a Hazard Perception test for bicyclists. Response rate, reaction times, first fixation, duration of the first fixation, dwell time and total number of fixations on the events were measured. Next, the children took part in the HP intervention in which video clips of dangerous traffic situations were presented. The intervention comprised two classroom sessions of one hour (1/week). A post-test was performed one day after and the retention-test three weeks after the intervention. RESULTS: Children responded to more covert hazards immediately after the intervention (p < 0.05), but did not improve their response rate for overt hazards. Reaction times for the covert hazards improved on the post-test (p < 0.001) compared to the pre-test but this effect was reduced on the retention test. There was no effect of the intervention for entry time of the first fixation but the duration of the first fixation increased for the covert hazards (p < 0.05). Children made fewer fixations on the event compared to adults (p < 0.001), except for the covert hazards on the retention-test. The training also increased the number of fixations for the overt hazards on the post-test (p < 0.001) and the retention-test (p < 0.001) but only increased on the retention test for the covert hazards (p < 0.001). CONCLUSION: The results demonstrated that a brief intervention for training hazard perception skills in child bicyclists is able to improve children's situation awareness and hazard perception for potential dangerous situations. The training, however, was too short to improve children to higher adult levels. PMID- 29478628 TI - Interaction of polyhydroxy fullerenes with ferrihydrite: adsorption and aggregation. AB - The rapid development of nanoscience and nanotechnology, with thousands types of nanomaterials being produced, will lead to various environmental impacts. Thus, understanding the behaviors and fate of these nanomaterials is essential. This study focused on the interaction between polyhydroxy fullerenes (PHF) and ferrihydrite (Fh), a widespread iron (oxyhydr)oxide nanomineral and geosorbent. Our results showed that PHF were effectively adsorbed by Fh. The adsorption isotherm fitted the D-R model well, with an adsorption capacity of 67.1mg/g. The adsorption mean free energy of 10.72kJ/mol suggested that PHF were chemisorbed on Fh. An increase in the solution pH and a decrease of the Fh surface zeta potential were observed after the adsorption of PHF on Fh; moreover, increasing initial solution pH led to a reduction of adsorption. The Fourier transform infrared spectra detected a red shift of C-O stretching from 1075 to 1062cm-1 and a decrease of Fe-O bending, implying the interaction between PHF oxygenic functional groups and Fh surface hydroxyls. On the other hand, PHF affected the aggregation and reactivity of Fh by changing its surface physicochemical properties. Aggregation of PHF and Fh with individual particle sizes increasing from 2nm to larger than 5nm was measured by atomic force microscopy. The uniform distribution of C and Fe suggested that the aggregates of Fh were possibly bridged by PHF. Our results indicated that the interaction between PHF and Fh could evidently influence the migration of PHF, as well as the aggregation and reactivity of Fh. PMID- 29478629 TI - Large variability in ambient ozone sensitivity across 19 ethylenediurea-treated Chinese cultivars of soybean is driven by total ascorbate. AB - The sensitivity of Chinese soybean cultivars to ambient ozone (O3) in the field is unknown, although soybean is a major staple food in China. Using ethylenediurea (EDU) as an O3 protectant, we tested the gas exchange, pigments, antioxidants and biomass of 19 cultivars exposed to 28ppm.hr AOT40 (accumulated O3 over an hourly concentration threshold of 40ppb) over the growing season at a field site in China. By comparing the average biomass with and without EDU, we estimated the cultivar-specific sensitivity to O3 and ranked the cultivars from very tolerant (<10% change) to highly sensitive (>45% change), which helps in choosing the best-suited cultivars for local cultivation. Higher lipid peroxidation and activity of the ascorbate peroxidase enzyme were major responses to O3 damage, which eventually translated into lower biomass production. The constitutional level of total ascorbate in the leaves was the most important parameter explaining O3 sensitivity among these cultivars. Surprisingly, the role of stomatal conductance was insignificant. These results will guide future breeding efforts towards more O3-tolerant cultivars in China, while strategies for implementing control measures of regional O3 pollution are being implemented. Overall, these results suggest that present ambient O3 pollution is a serious concern for soybean in China, which highlights the urgent need for policy-making actions to protect this critical staple food. PMID- 29478630 TI - Combined and synergistic effects of climate change and urbanization on water quality in the Wolf Bay watershed, southern Alabama. AB - This study investigated potential changes in flow, total suspended solid (TSS) and nutrient (nitrogen and phosphorous) loadings under future climate change, land use/cover (LULC) change and combined change scenarios in the Wolf Bay watershed, southern Alabama, USA. Four Global Circulation Models (GCMs) under three Special Report Emission Scenarios (SRES) of greenhouse gas were used to assess the future climate change (2016-2040). Three projected LULC maps (2030) were employed to reflect different extents of urbanization in future. The individual, combined and synergistic impacts of LULC and climate change on water quantity/quality were analyzed by the Soil and Water Assessment Tool (SWAT). Under the "climate change only" scenario, monthly distribution and projected variation of TSS are expected to follow a pattern similar to streamflow. Nutrients are influenced both by flow and management practices. The variation of Total Nitrogen (TN) and Total Phosphorous (TP) generally follow the flow trend as well. No evident difference in the N:P ratio was projected. Under the "LULC change only" scenario, TN was projected to decrease, mainly due to the shrinkage of croplands. TP will increase in fall and winter. The N:P ratio shows a strong decreasing potential. Under the "combined change" scenario, LULC and climate change effect were considered simultaneously. Results indicate that if future loadings are expected to increase/decrease under any individual scenario, then the combined change will intensify that trend. Conversely, if their effects are in opposite directions, an offsetting effect occurs. Science-based management practices are needed to reduce nutrient loadings to the Bay. PMID- 29478631 TI - Efficient low-temperature soot combustion by bimetallic Ag-Cu/SBA-15 catalysts. AB - In this study, the effects of copper (Cu) additive on the catalytic performance of Ag/SBA-15 in complete soot combustion were investigated. The soot combustion performance of bimetallic Ag-Cu/SBA-15 catalysts was higher than that of monometallic Ag and Cu catalysts. The optimum catalytic performance was acquired with the 5Ag1-Cu0.1/SBA-15 catalyst, on which the soot combustion starts at Tig=225 degrees C with a T50=285 degrees C. The temperature for 50% of soot combustion was lower than that of conventional Ag-based catalysts to more than 50 degrees C (Aneggi et al., 2009). Physicochemical characterizations of the catalysts indicated that addition of Cu into Ag could form smaller bimetallic Ag Cu nanolloy particles, downsizing the mean particle size from 3.7nm in monometallic catalyst to 2.6nm in bimetallic Ag-Cu catalyst. Further experiments revealed that Ag and Cu species elicited synergistic effects, subsequently increasing the content of surface active oxygen species. As a result, the structure modifications of Ag by the addition of Cu strongly intensified the catalytic performance. PMID- 29478632 TI - Effects of TiO2 nanoparticles on the aquatic plant Spirodela polyrrhiza: Evaluation of growth parameters, pigment contents and antioxidant enzyme activities. AB - Plants are essential components of all ecosystems and play a critical role in environmental fate of nanoparticles. However, the toxicological impacts of nanoparticles on plants are not well documented. Titanium dioxide nanoparticles (TiO2-NPs) are produced worldwide in large quantities for a wide range of purposes. In the present study, the uptake of TiO2-NPs by the aquatic plant Spirodela polyrrhiza and the consequent effects on the plant were evaluated. Initially, structural and morphological characteristics of the used TiO2-NPs were determined using XRD, SEM, TEM and BET techniques. As a result, an anatase structure with the average crystalline size of 8nm was confirmed for the synthesized TiO2-NPs. Subsequently, entrance of TiO2-NPS to plant roots was verified by fluorescence microscopic images. Activity of a number of antioxidant enzymes, as well as, changes in growth parameters and photosynthetic pigment contents as physiological indices were assessed to investigate the effects of TiO2-NPs on S. polyrrhiza. The increasing concentration of TiO2-NPs led to the significant decrease in all of the growth parameters and changes in antioxidant enzyme activities. The activity of superoxide dismutase enhanced significantly by the increasing concentration of TiO2-NPs. Enhancement of superoxide dismutase activity could be explained as promoting antioxidant system to scavenging the reactive oxygen species. In contrast, the activity of peroxidase was notably decreased in the treated plants. Reduced peroxidase activity could be attributed to either direct effect of these particles on the molecular structure of the enzyme or plant defense system damage due to reactive oxygen species. PMID- 29478633 TI - Revealing the anaerobic acclimation of microbial community in a membrane bioreactor for coking wastewater treatment by Illumina Miseq sequencing. AB - The dynamic change of microbial community during sludge acclimation from aerobic to anaerobic in a MBR for coking wastewater treatment was revealed by Illumina Miseq sequencing in this study. The diversity of both Bacteria and Archaea showed an increase-decrease trajectory during acclimation, and exhibited the highest at the domestication interim. Ignavibacteria changed from a tiny minority (less than 1%) to the dominant bacterial group (54.0%) along with acclimation. The relative abundance of Betaproteobacteria kept relatively steady, as in this class some species increased coupled with some other species decreased during acclimation. The dominant Archaea shifted from Halobacteria in initial aerobic sludge to Methanobacteria in the acclimated anaerobic sludge. The dominant bacterial and archaeal groups in different acclimation stages were indigenous microorganisms in the initial sludge, though some of them were very rare. This study supported that the species in "rare biosphere" might eventually become dominant in response to environmental change. PMID- 29478634 TI - A comparison of process performance during the anaerobic mono- and co-digestion of slaughterhouse waste through different operational modes. AB - The use of consecutive feeding was applied to investigate the response of the microbial biomass to a second addition of substrates in terms of biodegradation using batch tests as a promising alternative to predict the behavior of the process. Anaerobic digestion (AD) of the slaughterhouse waste (SB) and its co digestion with manure (M), various crops (VC), and municipal solid waste were evaluated. The results were then correlated to previous findings obtained by the authors for similar mixtures in batch and semi-continuous operation modes. AD of the SB failed showing total inhibition after a second feeding. Co-digestion of the SB+M showed a significant improvement for all of the response variables investigated after the second feeding, while co-digestion of the SB+VC resulted in a decline in all of these response variables. Similar patterns were previously detected, during both the batch and the semi-continuous modes. PMID- 29478635 TI - Effects of triclosan on gonadal differentiation and development in the frog Pelophylax nigromaculatus. AB - Previous studies have reported that triclosan (TCS) could possess an androgenic activity. We aimed to investigate the effects of TCS on gonadal differentiation and development in the frog Pelophylax nigromaculatus, a sensitive amphibian species to androgenic chemicals. P. nigromaculatus tadpoles at stage 24 were exposed to TCS (3, 30, and 300nmol/L) to stage 46 in a semi-static exposure system. At the end of exposure, gonadal morphology and histology, sex ratio and gonadal expression of sex-biased genes were examined in P. nigromaculatus. In each TCS treatment group, we found several individuals whose gonads exhibited morphological and/or histological abnormalities. Gonadal histological abnormalities were characterized by few oocytes and many somatic cells. Although the percentage of the individuals with abnormal gonads was low (7.8%) among all animals treated with TCS, statistical test revealed the sex ratios in the 3 and 300nmol/L TCS treatment groups were significantly different from the solvent control. In the 30nmol/L TCS treatment group, abnormal gonads were also observed, although the sex ratio was not changed compared with the solvent control, which was possibly due to the smaller sample size in this group. In all the TCS treatment groups, the sex ratios were not obviously male-biased, but the expression levels of some sex-biased genes were significantly altered by TCS. Altogether, our results suggest that TCS, even at environmentally relevant concentrations, could disrupt gonadal differentiation and development in P. nigromaculatus, but we are not sure whether the disrupting effects were associated with masculinization or feminization. PMID- 29478636 TI - Algae functional group characteristics in reservoirs and lakes with different trophic levels in northwestern semi-humid and semi-arid regions in China. AB - In order to study the differences in algae species and their biomass in water bodies in a region, three reservoirs and two lakes at the center of Guanzhong Plain were chosen to identify algae functional groups, measure biomass, and assess water quality, from January 2013 to December 2014. The water bodies represented different trophic levels: one oligotrophic, three mesotrophic, and one eutrophic. Based on the Reynolds' functional groups, they had 10 groups in common-B, P, D, X1, M, MP, F, S1, J, and G, but the algae biomasses and proportions were different. In the oligotrophic reservoir, functional group B reached a peak biomass of 576*104L-1, which accounted for 31.27%. In the eutrophic lake, functional group D reached a peak biomass of 3227*104L-1, which accounted for only 13.38%. When samples collected from other water bodies with similar trophic levels were compared, we found differences in the algae species functional groups. The potential reasons for the differences in algae functional group characteristics in the different water bodies in the region were water temperature and nutritional states. PMID- 29478637 TI - An integrated theoretical and experimental investigation of insensitive munition compounds adsorption on cellulose, cellulose triacetate, chitin and chitosan surfaces. AB - This manuscript reports results of combined computational chemistry and batch adsorption investigation of insensitive munition compounds, 2,4-dinitroanisole (DNAN), triaminotrinitrobenzene (TATB), 1,1-diamino-2,2-dinitroethene (FOX-7) and nitroguanidine (NQ), and traditional munition compound 2,4,6-trinitrotoluene (TNT) on the surfaces of cellulose, cellulose triacetate, chitin and chitosan biopolymers. Cellulose, cellulose triacetate, chitin and chitosan were modeled as trimeric form of the linear chain of 4C1 chair conformation of beta-d glucopyranos, its triacetate form, beta-N-acetylglucosamine and D-glucosamine, respectively, in the 1?4 linkage. Geometries were optimized at the M062X functional level of the density functional theory (DFT) using the 6-31G(d,p) basis set in the gas phase and in the bulk water solution using the conductor like polarizable continuum model (CPCM) approach. The nature of potential energy surfaces of the optimized geometries were ascertained through the harmonic vibrational frequency analysis. The basis set superposition error (BSSE) corrected interaction energies were obtained using the 6-311G(d,p) basis set at the same theoretical level. The computed BSSE in the gas phase was used to correct interaction energy in the bulk water solution. Computed and experimental results regarding the ability of considered surfaces in adsorbing the insensitive munitions compounds are discussed. PMID- 29478638 TI - Two-dimensional correlation spectroscopic analysis on the interaction between humic acids and aluminum coagulant. AB - In this study, two-dimensional correlation spectroscopy integrated with synchronous fluorescence and infrared absorption spectroscopy was employed to investigate the interaction between humic acids and aluminum coagulant at slightly acidic and neutral pH. Higher fluorescence quenching was produced for fulvic-like and humic-like fractions at pH5. At pH5, the humic-like fractions originating from the carboxylic acid, carboxyl and polysaccharide compounds were bound to aluminum first, followed by the fulvic-like fractions originating from the carboxyl and polysaccharide compounds. This finding also demonstrated that the activated functional groups of HA were involved in forming the Al-HA complex, which was accompanied by the removal of other groups by co-precipitation. Meanwhile, at pH7, almost no fluorescence quenching occurred, and surface complexation was observed to occur, in which the activated functional groups were absorbed on the amorphous Al(OH)3. Two-dimensional FT-IR correlation spectroscopy indicated the sequence of HA structural change during coagulation with aluminum, with IR bands affected in the order of COOH>COO->NH deformation of amide II>aliphatic hydroxyl COH at pH5, and COO->aliphatic hydroxyl COH at pH7. This study provides a promising pathway for analysis and insight into the priority of functional groups in the interaction between organic matters and metal coagulants. PMID- 29478639 TI - Removal of hydrophobic volatile organic compounds with sodium hypochlorite and surfactant in a co-current rotating packed bed. AB - A co-current flow rotating packed bed was applied to remove volatile organic compounds (VOCs) by sodium hypochlorite (NaClO) and surfactant (sodium dodecyl benzene sulfonate, SDBS) from air stream. Xylene was used as a model VOC herein. The effect of pH, concentration of NaClO and SDBS solution, liquid flow rate, gas flow rate and rotational speed on xylene removal efficiency and overall mass transfer coefficient (KGa) were discussed. Then, a correlation for KGa of the co current rotating packed bed was proposed by fitting the experimental data of KGa and independent variables of liquid/gas ratio, rotational speed, pH, NaClO concentration and treatment time, which was in good agreement with the experimental data (the deviation<=+/-30%). PMID- 29478640 TI - Surfactant-enhanced flushing enhances colloid transport and alters macroporosity in diesel-contaminated soil. AB - Soil contamination by diesel has been often reported as a result of accidental spillage, leakage and inappropriate use. Surfactant-enhanced soil flushing is a common remediation technique for soils contaminated by hydrophobic organic chemicals. In this study, soil flushing with linear alkylbenzene sulfonates (LAS, an anionic surfactant) was conducted for intact columns (15cm in diameter and 12cm in length) of diesel-contaminated farmland purple soil aged for one year in the field. Dynamics of colloid concentration in column outflow during flushing, diesel removal rate and resulting soil macroporosity change by flushing were analyzed. Removal rate of n-alkanes (representing the diesel) varied with the depth of the topsoil in the range of 14%-96% while the n-alkanes present at low concentrations in the subsoil were completely removed by LAS-enhanced flushing. Much higher colloid concentrations and larger colloid sizes were observed during LAS flushing in column outflow compared to water flushing. The X-ray micro computed tomography analysis of flushed and unflushed soil cores showed that the proportion of fine macropores (30-250MUm in diameter) was reduced significantly by LAS flushing treatment. This phenomenon can be attributed to enhanced clogging of fine macropores by colloids which exhibited higher concentration due to better dispersion by LAS. It can be inferred from this study that the application of LAS enhanced flushing technique in the purple soil region should be cautious regarding the possibility of rapid colloid-associated contaminant transport via preferential pathways in the subsurface and the clogging of water-conducting soil pores. PMID- 29478641 TI - Inhibitory effect of high phenol concentration in treating coal gasification wastewater in anaerobic biofilter. AB - In this paper, the inhibition of methanogens by phenol in coal gasification wastewater (CGW) was investigated by both anaerobic toxicity tests and a lab scale anaerobic biofilter reactor (AF). The anaerobic toxicity tests indicated that keeping the phenol concentration in the influent under 280mg/L could maintain the methanogenic activity. In the AF treating CGW, the result showed that adding glucose solution as co-substrate could be beneficial for the quick start-up of the reactor. The effluent chemical oxygen demand (COD) and total phenol reached 1200 and 100mg/L, respectively, and the methane production rate was 175mLCH4/gCOD/day. However, if the concentration of phenol was increased, the inhibition of anaerobic micro-organisms was irreversible. The threshold of total phenol for AF operation was 200-250mg/L. The extracellular polymeric substances (EPS) and particle size distribution of anaerobic granular sludge in the different stages were also examined, and the results indicated that the influence of toxicity in the system was more serious than its effect on flocculation of EPS. Moreover, the proportion of small size anaerobic granular sludge gradually increased from 10.2% to 34.6%. The results of high through-put sequencing indicated that the abundance of the Chloroflexi and Planctomycetes was inhibited by the toxicity of the CGW, and some shifts in the microbial community were observed at different stages. PMID- 29478642 TI - Adsorption-oxidation of hydrogen sulfide on Fe/walnut-shell activated carbon surface modified by NH3-plasma. AB - Walnut-shell activated carbon (WSAC) supported ferric oxide was modified by non thermal plasma (NTP), and the removal efficiency for hydrogen sulfide over Fe/WSAC modified by dielectric barrier discharge (DBD) was significantly promoted. The sample modified for 10min and 6.8kV output (30V input voltage) maintained 100% H2S conversion over a long reaction time of 390min. The surface properties of adsorbents modified by NTP under different conditions were evaluated by the methods of X-ray photoelectron spectroscopy (XPS), Brunauer Emmett-Teller (BET) analysis and in-situ Fourier transform infrared spectroscopy (FTIR), to help understand the effect of the NTP treatment. NTP treatment enhanced the adsorption capacity of Fe/WSAC, which could due to the formation of micro-pores with sizes of 0.4, 0.5 and 0.75nm. XPS revealed that chemisorbed oxygen changed into lattice oxygen after NTP treatment, and lattice oxygen is beneficial for H2S oxidation. From the in-situ FTIR result, transformation of the reaction path on Fe/WSAC was observed after NTP modification. The research results indicate that NTP is an effective method to improve the surface properties of the Fe/WSAC catalyst for H2S adsorption-oxidation. PMID- 29478643 TI - Insights into sludge granulation during anaerobic treatment of high-strength leachate via a full-scale IC reactor with external circulation system. AB - In this study, a full-scale internal circulation (IC) reactor coupled with an external circulation system was developed to treat high-strength leachate from a municipal solid waste (MSW) incineration plant, in which anaerobic sludge granulation was intensively investigated. Results showed that the IC reactor achieved excellent treatment performance under high organic loading rates (OLR) of 21.06-25.16kg chemical oxygen demand (COD)/(m3?day). The COD removal efficiency and biogas yield respectively reached 89.4%-93.4% and 0.42 0.50m3/kgCOD. The formation of extracellular polymeric substances (EPS) was closely associated with sludge granulation. Protein was the dominant component in sludge EPS, and its content was remarkably increased from 21.6 to 99.7mg/g Volatile Suspended Solid (VSS) during the reactor operation. The sludge Zeta potential and hydrophobicity positively correlated with the protein/polysaccharide ratio in EPS, and they were respectively increased from 26.2mV and 30.35% to -10.6mV and 78.67%, which was beneficial to microbial aggregation. Three-dimensional fluorescence spectroscopy (3D-EEM) and Fourier transform infrared spectroscopy (FT-IR) analysis further indicated the importance of protein-like EPS substances in the sludge granulation. Moreover, it was also found that the secondary structures of EPS proteins varied during the reactor operation. PMID- 29478644 TI - Environmental risk assessment of selected organic chemicals based on TOC test and QSAR estimation models. AB - Environmental risks of organic chemicals have been greatly determined by their persistence, bioaccumulation, and toxicity (PBT) and physicochemical properties. Major regulations in different countries and regions identify chemicals according to their bioconcentration factor (BCF) and octanol-water partition coefficient (Kow), which frequently displays a substantial correlation with the sediment sorption coefficient (Koc). Half-life or degradability is crucial for the persistence evaluation of chemicals. Quantitative structure activity relationship (QSAR) estimation models are indispensable for predicting environmental fate and health effects in the absence of field- or laboratory-based data. In this study, 39 chemicals of high concern were chosen for half-life testing based on total organic carbon (TOC) degradation, and two widely accepted and highly used QSAR estimation models (i.e., EPI Suite and PBT Profiler) were adopted for environmental risk evaluation. The experimental results and estimated data, as well as the two model-based results were compared, based on the water solubility, Kow, Koc, BCF and half-life. Environmental risk assessment of the selected compounds was achieved by combining experimental data and estimation models. It was concluded that both EPI Suite and PBT Profiler were fairly accurate in measuring the physicochemical properties and degradation half-lives for water, soil, and sediment. However, the half-lives between the experimental and the estimated results were still not absolutely consistent. This suggests deficiencies of the prediction models in some ways, and the necessity to combine the experimental data and predicted results for the evaluation of environmental fate and risks of pollutants. PMID- 29478646 TI - Influence of combustion-originated dioxins in atmospheric deposition on water quality of an urban river in Japan. AB - Bulk (wet and dry) deposition samples were collected in Saitama Prefecture, Japan throughout a year (February 8, 2012 to February 7, 2013) to estimate the influence of dioxins emitting from waste incinerators on river water quality. The annual deposition flux of dioxins was 3.3ng-toxic equivalent (TEQ)/m2/year. Source identification using indicative congeners estimated that 82% of dioxin TEQ in the bulk deposition (2.7ng-TEQ/m2/year) was combustion-originated, indicating that most of the dioxins in the deposition were derived from waste incinerators. In Saitama prefecture the annual flux of combustion-originated dioxins in depositions was apparently consistent with that of dioxin emission into the air from waste incinerators. The TEQ of combustion-originated dioxins in the deposition per rainfall was 2.4pg-TEQ/L on annual average, exceeding the environmental quality standard (EQS) for water in Japan of 1pg-TEQ/L. This suggests there is a possibility that dioxins in atmospheric deposition have a significant influence on the water quality of urban rivers which rainwater directly flows into because of many paved areas in the basins. The influence of combustion-originated dioxin in the deposition on the water quality of Ayase River, an urban river heavily polluted with dioxins, was estimated at 0.29pg TEQ/L on annual average in 2015. It seems that dioxins in atmospheric deposition from waste incinerators have a significant influence on water quality of some urban rivers via rainwater though the dioxins in the ambient air have achieved the EQS for atmosphere at all monitoring sites in Japan. PMID- 29478645 TI - Submicron particle-bound polycyclic aromatic hydrocarbons in the Polish teaching rooms: Concentrations, origin and health hazard. AB - The goal of the work was to investigate the concentrations of the 16 US EPA priority polycyclic aromatic hydrocarbons (PAH) bound to submicrometer particles (particulate matter, PM1) suspended in the air of university teaching rooms and in the atmospheric air outside. Two teaching rooms were selected in two Polish cities, Gliwice, southern Poland, and Warsaw, central Poland, differing with regard to the ambient concentrations and major sources of PM and PAH. The variabilities of indoor and outdoor 24-hr concentrations of PM1-bound PAH, the ratio (I/O) of the indoor to outdoor 24-hr concentrations of PM1-bound PAH, probable sources of PAH and the level of the hazard from the mixture of the 16 PAH (SigmaPAH) to humans at both sites were analyzed. In both Warsaw and Gliwice, the mean concentrations of PM1-bound SigmaPAH were slightly higher in the atmospheric air than in the rooms. The indoor and outdoor concentrations of individual PAH in Gliwice were correlated, in Warsaw - they were not. Most probably, the lack of the correlations in Warsaw was due to the existence of an unidentified indoor source of gaseous PAH enriching PM1 in phenanthrene, fluorene, and pyrene. Although the ambient concentrations of PM1-bound PAH were low compared to the ones observed earlier at both sites, they were much higher than in other urbanized European areas. However, because of low mass share of heavy PAH in SigmaPAH, the various indicators of the health hazard from the 16 PAH mixture were low compared to other regions. PMID- 29478647 TI - Pollutants identification of ambient aerosols by two types of aerosol mass spectrometers over southeast coastal area, China. AB - Two different aerosol mass spectrometers, Aerodyne Aerosol Mass Spectrometer (AMS) and Single Particle Aerosol Mass Spectrometer (SPAMS) were deployed to identify the aerosol pollutants over Xiamen, representing the coastal urban area. Five obvious processes were classified during the whole observation period. Organics and sulfate were the dominant components in ambient aerosols over Xiamen. Most of the particles were in the size range of 0.2-1.0MUm, accounting for over 97% of the total particles measured by both instruments. Organics, as well as sulfate, measured by AMS were in good correlation with measured by SPAMS. However, high concentration of NH4+ was obtained by AMS, while extremely low value of NH4+ was detected by SPAMS. Contrarily, high particle number counts of NO3- and Cl- were given by SPAMS while low concentrations of NO3- and Cl- were measured by AMS. The variations of POA and SOA obtained from SPAMS during event 1 and event 2 were in accordance with the analysis of HOA and OOA given by AMS, suggesting that both of AMS and SPAMS can well identify the organic clusters of aerosol particles. Overestimate or underestimate of the aerosol sources and acidity would be present in some circumstances when the measurement results were used to analyze the aerosol properties, because of the detection loss of some species for both instruments. PMID- 29478648 TI - Synthesis of zinc-carboxylate metal-organic frameworks for the removal of emerging drug contaminant (amodiaquine) from aqueous solution. AB - We herein report the removal of amodiaquine, an emerging drug contaminant from aqueous solution using [Zn2(fum)2(bpy)] and [Zn4O(bdc)3] (fum=fumaric acid; bpy=4,4-bipyridine; bdc=benzene-1,4-dicarboxylate) metal-organic frameworks (MOFs) as adsorbents. The adsorbents were characterized by elemental analysis, Fourier transform infrared (FT-IR) spectroscopy, and powder X-ray diffraction (PXRD). Adsorption process for both adsorbents were found to follow the pseudo first-order kinetics, and the adsorption equilibrium data fitted best into the Freundlich isotherm with the R2 values of 0.973 and 0.993 obtained for [Zn2(fum)2(bpy)] and [Zn4O(bdc)3] respectively. The maximum adsorption capacities foramodiaquine in this study were found to be 0.478 and 47.62mg/g on the [Zn2(fum)2(bpy)] and [Zn4O(bdc)3] MOFs respectively, and were obtained at pH of 4.3 for both adsorbents. FT-IR spectroscopy analysis of the MOFs after the adsorption process showed the presence of the drug. The results of the study showed that the prepared MOFs could be used for the removal of amodiaquine from wastewater. PMID- 29478649 TI - Concurrent catalytic removal of typical volatile organic compound mixtures over Au-Pd/alpha-MnO2 nanotubes. AB - alpha-MnO2 nanotubes and their supported Au-Pd alloy nanocatalysts were prepared using hydrothermal and polyvinyl alcohol-protected reduction methods, respectively. Their catalytic activity for the oxidation of toluene/m-xylene, acetone/ethyl acetate, acetone/m-xylene and ethyl acetate/m-xylene mixtures was evaluated. It was found that the interaction between Au-Pd alloy nanoparticles and alpha-MnO2 nanotubes significantly improved the reactivity of lattice oxygen, and the 0.91wt.% Au0.48Pd/alpha-MnO2 nanotube catalyst outperformed the alpha MnO2 nanotube catalyst in the oxidation of toluene, m-xylene, ethyl acetate and acetone. Over the 0.91wt.% Au0.48Pd/alpha-MnO2 nanotube catalyst, (i) toluene oxidation was greatly inhibited in the toluene/m-xylene mixture, while m-xylene oxidation was not influenced; (ii) acetone and ethyl acetate oxidation suffered a minor impact in the acetone/ethyl acetate mixture; and (iii) m-xylene oxidation was enhanced whereas the oxidation of the oxygenated VOCs (volatile organic compounds) was suppressed in the acetone/m-xylene or ethyl acetate/m-xylene mixtures. The competitive adsorption of these typical VOCs on the catalyst surface induced an inhibitive effect on their oxidation, and increasing the temperature favored the oxidation of the VOCs. The mixed VOCs could be completely oxidized into CO2 and H2O below 320 degrees C at a space velocity of 40,000mL/(g.hr). The 0.91wt.% Au0.48Pd/alpha-MnO2 nanotube catalyst exhibited high catalytic stability as well as good tolerance to water vapor and CO2 in the oxidation of the VOC mixtures. Thus, the alpha-MnO2 nanotube-supported noble metal alloy catalysts hold promise for the efficient elimination of VOC mixtures. PMID- 29478650 TI - Water regime-nitrogen fertilizer incorporation interaction: Field study on methane and nitrous oxide emissions from a rice agroecosystem in Harbin, China. AB - Water regime and nitrogen (N) fertilizer are two important factors impacting greenhouse gases (GHG) emission from paddy field, whereas their effects have not been well studied in cold region. In this study, we conducted a two-year field experiment to study the impacts of water regime and N fertilizer on rice yields and GHG emissions in Harbin, China, a cold region located in high latitudes. Our results showed that intermittent irrigation significantly decreased methane (CH4) emission compared with continuous flooding, however, the decrement was far lower than the global average level. The N2O emissions were very small when flooded but peaked at the beginning of the disappearance of floodwater. The N fertilizer treatments increased CH4 emissions at low level (75kgN/ha). But both CH4 and N2O emissions were uninfluenced at the levels of 150kgN/ha and 225kgN/ha. Rice yields increased under intermittent irrigation and were highest at the level of 150kgN/ha. From our results, we recommended that the intermittent irrigation and 150kgN/ha as the ideal water regime-nitrogen fertilizer incorporation for this area to achieve low GHG emissions without impacting rice yields. PMID- 29478651 TI - Release kinetics of vanadium from vanadium titano-magnetite: The effects of pH, dissolved oxygen, temperature and foreign ions. AB - As part of a broader study of the environmental geochemistry behavior of vanadium (V), the release kinetics of V from the dissolution of natural vanadium titano magnetite under environmentally relevant conditions was investigated. In both the acidic and basic domains, the V release rate was found to be proportional to fractional powers of hydrogen ion and dissolved oxygen activities. The dependence of the rate on dissolved oxygen can also be described in terms of the Langmuir adsorption model. The empirical rate equation is given by: r [Formula: see text] where, alpha=0.099-0.265, k'=3.2*10-6-1.7*10-5, K=2.7*104-3.9*104mol/L in acid solution (pH4.1), and alpha=-0.494-(-0.527), k'=2.0*104-2.5*10-11, and K=4.1*103 6.5*103mol/L in basic solution (pH8.8) at 20 degrees C. Based on the effect of temperature on the release rate of V, the activation energies of minerals at pH8.8 were determined to be 148-235kJ/mol, suggesting that the dissolution of vanadium titano-magnetite is a surface-controlled process. The presence of Na+, Ca2+, Mg2+, K+, NO3-, Cl-, SO42- and CO32- was found to accelerate the V release rates. This study improves the understanding of both the V pollution risk in some mine areas and the fate of V in the environment. PMID- 29478652 TI - Pulsed corona discharge for improving treatability of coking wastewater. AB - Coking wastewater (CW) contains toxic and macromolecular substances that inhibit biological treatment. The refractory compounds remaining in biologically treated coking wastewater (BTCW) provide chemical oxygen demand (COD) and color levels that make it unacceptable for reuse or disposal. Gas-phase pulsed corona discharge (PCD) utilizing mostly hydroxyl radicals and ozone as oxidants was applied to both raw coking wastewater (RCW) and BTCW wastewater as a supplemental treatment. The energy efficiency of COD, phenol, thiocyanate and cyanide degradation by PCD was the subject of the research. The cost-effective removal of intermediate oxidation products with addition of lime was also studied. The energy efficiency of oxidation was inversely proportional to the pulse repetition frequency: lower frequency allows more effective utilization of ozone at longer treatment times. Oxidative treatment of RCW showed the removal of phenol and thiocyanate at 800 pulses per second from 611 to 227mg/L and from 348 to 86mg/L, respectively, at 42kWh/m3 delivered energy, with substantial improvement in the BOD5/COD ratio (from 0.14 to 0.43). The COD and color of BTCW were removed by 30% and 93%, respectively, at 20kWh/m3, showing energy efficiency for the PCD treatment exceeding that of conventional ozonation by a factor of 3-4. Application of lime appeared to be an effective supplement to the PCD treatment of RCW, degrading COD by about 28% at an energy input of 28kWh/m3 and the lime dose of 3.0kg/m3. The improvement of RCW treatability is attributed to the degradation of toxic substances and fragmentation of macromolecular compounds. PMID- 29478654 TI - Spatial and historical distribution of organic phosphorus driven by environment conditions in lake sediments. AB - The chemistry of sedimentary organic phosphorus (OP) and its fraction distribution in sediments are greatly influenced by environmental conditions such as terrestrial inputs and runoffs. The linkage of OP with environmental conditions was analyzed on the basis of OP spatial and historical distributions in lake sediments. The redundancy analysis and OP spatial distribution results suggested that both NaOH-OP (OP extracted by NaOH) and Re-OP (residual OP) in surface sediments from the selected 13 lakes reflected the gradient effects of environmental conditions and the autochthonous and/or allochthonous inputs driven by latitude zonality in China. The lake level and salinity of Lake Hulun and the runoff and precipitation of its drainage basin were reconstructed on the basis of the geochemistry index. This work showed that a gradient in weather conditions presented by the latitude zonality in China impacts the OP accumulation through multiple drivers and in many ways. The drivers are mainly precipitation and temperature, governing organic matter (OM) production, degradation rate and transportation in the watershed. Over a long temporal dimension (4000years), the vertical distributions of Re-OP and NaOH-OP based on a dated sediment profile from HLH were largely regulated by the autochthonous and/or allochthonous inputs, which depended on the environmental and climate conditions and anthropogenic activities in the drainage basin. This work provides useful environmental geochemistry information to understand the inherent linkage of OP fractionation with environmental conditions and lake evolution. PMID- 29478653 TI - Analysis of key microbial community during the start-up of anaerobic ammonium oxidation process with paddy soil as inoculated sludge. AB - A sequencing batch reactor (SBR)-anaerobic ammonium oxidation (anammox) system was started up with the paddy soil as inoculated sludge. The key microbial community structure in the system along with the enrichment time was investigated by using molecular biology methods (e.g., high-throughput 16S rRNA gene sequencing and quantitative PCR). Meanwhile, the influent and effluent water quality was continuously monitored during the whole start-up stage. The results showed that the microbial diversity decreased as the operation time initially and increased afterwards, and the microbial niches in the system were redistributed. The anammox bacterial community structure in the SBR-anammox system shifted during the enrichment, the most dominant anammox bacteria were CandidatusJettenia. The maximum biomass of anammox bacteria achieved 1.68*109copies/g dry sludge during the enrichment period, and the highest removal rate of TN achieved around 75%. PMID- 29478655 TI - Effects of urbanization on heavy metal accumulation in surface soils, Beijing. AB - Urbanization processes affect the accumulation of heavy metals in urban soils. Effects of urbanization on heavy metal accumulation in soils were studied using Beijing as an example. It has been suggested that the ecological function of vegetation covers shifting from natural to agricultural settings and then to urban greenbelts could increase the zinc (Zn) concentrations of soils successively. The Zn concentration of urban soils was significantly correlated to the percentage of the impervious land surface at the 500m*500m spatial scale. For urban parks, the age or years since the development accounted for 80% of the variances of cadmium (Cd) and Zn in soils. The population density, however, did not affect the heavy metal distributions in urban soils. To conclude, the urban age turned out to be a notable factor in quantifying heavy metal accumulation in urban soils. PMID- 29478656 TI - Investigation on mechanism of phosphate removal on carbonized sludge adsorbent. AB - For the removal of phosphate (PO43-) from water, an adsorbent was prepared via carbonization of sewage sludge from a wastewater treatment plant: carbonized sludge adsorbent (CSA). The mechanism of phosphate removal was determined after studying the structure and chemical properties of the CSA and its influence on phosphate removal. The results demonstrate that phosphate adsorption by the CSA can be fitted with the pseudo second-order kinetics and Langmuir isotherm models, indicating that the adsorption is single molecular layer adsorption dominated by chemical reaction. The active sites binding phosphate on the surface are composed of mineral particles containing Si/Ca/Al/Fe. The mineral containing Ca, calcite, is the main factor responsible for phosphate removal. The phosphate removal mechanism is a complex process including crystallization via the interaction between Ca2+ and PO43-; formation of precipitates of Ca2+, Al3+, and PO43-; and adsorption of PO43- on some recalcitrant oxides composed of Si/Al/Fe. PMID- 29478658 TI - Comment. PMID- 29478659 TI - Erratum to "Development of EMC-based empirical model for estimating spatial distribution of pollutant loads and its application in rural areas of Korea" [J. Environ. Sci. 35(1 September 2015) 1-11]. PMID- 29478657 TI - Rapid evaluation of arsenic contamination in paddy soils using field portable X ray fluorescence spectrometry. AB - Arsenic (As) in paddy fields is deteriorating food security and human health through rice ingestion. Rice is the dominant food source of arsenic exposure to half of the world's population. Therefore, an in situ effective method for As risk evaluation in paddy soil is strongly needed to avoid As exposure through rice ingestion. Herein, we developed a rapid analytical methodology for determination of As in plant tissues using field portable X-ray fluorescence spectrometry (FP-XRF). This method was applied to rice roots in order to evaluate the As contamination in paddy soils. The results showed that rice roots with iron plaques were superior to rhizosphere soils for generating FP-XRF signals, especially for field sites with As concentrations lower than the soil detection limit of FP-XRF (30.0mg/kg). Moreover, the strong linear relationships of As concentrations between the rice roots and corresponding leaves and grains proved that the rice root, rather than the soil, is a better predictor of As concentrations in rice grains. The research provides an efficient As monitoring method for As contaminated paddy fields by using wetland plant roots with iron plaques and XRF-based analytical techniques. PMID- 29478660 TI - Simultaneous Fe(III) reduction and ammonia oxidation process in Anammox sludge. AB - In recent years, there have been a number of reports on the phenomenon in which ferric iron (Fe(III)) is reduced to ferrous iron [Fe(II)] in anaerobic environments, accompanied by simultaneous oxidation of ammonia to NO2-, NO3-, or N2. However, studies on the relevant reaction characteristics and mechanisms are rare. Recently, in research on the effect of Fe(III) on the activity of Anammox sludge, excess ammonia oxidization has also been found. Hence, in the present study, Fe(III) was used to serve as the electron acceptor instead of NO2-, and the feasibility and characteristics of Anammox coupled to Fe(III) reduction (termed Feammox) were investigated. After 160days of cultivation, the conversion rate of ammonia in the reactor was above 80%, accompanied by the production of a large amount of NO3- and a small amount of NO2-. The total nitrogen removal rate was up to 71.8%. Furthermore, quantities of Fe(II) were detected in the sludge fluorescence in situ hybridization (FISH) and denaturated gradient gel electrophoresis (DGGE) analyses further revealed that in the sludge, some Anammox bacteria were retained, and some microbes were enriched during the acclimatization process. We thus deduced that in Anammox sludge, Fe(III) reduction takes place together with ammonia oxidation to NO2- and NO3- along with the Anammox process. PMID- 29478661 TI - 17alpha-Ethynylestradiol biodegradation in different river-based groundwater recharge modes with reclaimed water and degradation-associated community structure of bacteria and archaea. AB - This study investigated 17alpha-ethynylestradiol (EE2) biodegradation process and primary metabolic pathways associated with community structures of microorganism during groundwater recharge using reclaimed water. The attenuation rate is 1.58 times higher in wetting and drying alternative recharge (WDAR) than in continual recharge (CR). The primary biotransformation pathways of EE2 in WDAR system began with the oxidation of C-17 on ring D to form a ketone group, and D-ring was subsequently hydroxylated and cleaved. In the CR system, the metabolic pathway changed from the oxidation of C-17 on ring D to hydroxylation of C-4 on ring A, and ring A or B subsequently cleaved; this transition was related to DO, and the microbial community structure. Four hundred fifty four pyrosequencing of 16s rRNA genes indicated that the bacterial communities in the upper layer of the WDAR system were more diverse than those found in the bottom layer of the CR system; this result was reversed for archaea. Unweighted UniFrac and taxonomic analyses were conducted to relate the change in bacterial community structure to the metabolic pathway. Microorganism community diversity and structure were related to the concentrations of dissolved oxygen, EE2 and its intermediates in the system. Five known bacterial classes and one known archaeal class, five major bacterial genera and one major archaeal genus might be involved in EE2 degradation. The findings of this study provide an understanding of EE2 biodegradation in groundwater recharge areas under different recharging modes and can facilitate the prediction of the fate of EE2 in underground aquifers. PMID- 29478662 TI - Application of nanoparticle tracking analysis for characterising the fate of engineered nanoparticles in sediment-water systems. AB - Novel applications of nanotechnology may lead to the release of engineered nanoparticles (ENPs), which result in concerns over their potential environmental hazardous impact. It is essential for the research workers to be able to quantitatively characterise ENPs in the environment and subsequently to assist the risk assessment of the ENPs. This study hence explored the application of nanoparticle tracking system (NTA) to quantitatively describe the behaviour of the ENPs in natural sediment-water systems. The NTA allows the measurement of both particle number concentration (PNC) and particle size distribution (PSD) of the ENPs. The developed NTA method was applied to a range of gold and magnetite ENPs with a selection of surface properties. The results showed that the positively-charged ENPs interacted more strongly with the sediment than neutral and negatively-charged ENPs. It was also found that the citrate coated Au ENPs had a higher distribution percentage (53%) than 11-mercaptoundecanoic acid coated Au ENPs (20%) and citrate coated magnetite ENPs (21%). The principles of the electrostatic interactions between hard (and soft) acids and bases (HSAB) are used to explain such behaviours; the hard base coating (i.e. citrate ions) will interact more strongly with hard acid (i.e. magnetite) than soft acid (i.e. gold). The results indicate that NTA is a complementary method to existing approaches to characterise the fate and behaviour of ENPs in natural sediment. PMID- 29478663 TI - Measurement of hydrogen peroxide and organic hydroperoxide concentrations during autumn in Beijing, China. AB - Gaseous peroxides play important roles in atmospheric chemistry. To understand the pathways of the formation and removal of peroxides, atmospheric peroxide concentrations and their controlling factors were measured from 7:00 to 20:00 in September, October, and November 2013 at a heavily trafficked residential site in Beijing, China, with average concentrations of hydrogen peroxide (H2O2) and methyl hydroperoxide (MHP) at 0.55ppb and 0.063ppb, respectively. H2O2 concentrations were higher in the afternoon and lower in the morning and evening, while MHP concentrations did not exhibit a regular diurnal pattern. Both H2O2 and MHP concentrations increased at dusk in most cases. Both peroxides displayed monthly variations with higher concentrations in September. These results suggested that photochemical activity was the main controlling factor on variations of H2O2 concentrations during the measurement period. Increasing concentrations of volatile organic compounds emitted by motor vehicles were important contributors to H2O2 and MHP enrichment. High levels of H2O2 and MHP concentrations which occurred during the measurement period probably resulted from the transport of a polluted air mass with high water vapor content passing over the Bohai Bay, China. PMID- 29478664 TI - Simultaneous removal of ammonia and N-nitrosamine precursors from high ammonia water by zeolite and powdered activated carbon. AB - When adding sufficient chlorine to achieve breakpoint chlorination to source water containing high concentration of ammonia during drinking water treatment, high concentrations of disinfection by-products (DBPs) may form. If N-nitrosamine precursors are present, highly toxic N-nitrosamines, primarily N nitrosodimethylamine (NDMA), may also form. Removing their precursors before disinfection should be a more effective way to minimize these DBPs formation. In this study, zeolites and activated carbon were examined for ammonia and N nitrosamine precursor removal when incorporated into drinking water treatment processes. The test results indicate that Mordenite zeolite can remove ammonia and five of seven N-nitrosamine precursors efficiently by single step adsorption test. The practical applicability was evaluated by simulation of typical drinking water treatment processes using six-gang stirring system. The Mordenite zeolite was applied at the steps of lime softening, alum coagulation, and alum coagulation with powdered activated carbon (PAC) sorption. While the lime softening process resulted in poor zeolite performance, alum coagulation did not impact ammonia and N-nitrosamine precursor removal. During alum coagulation, more than 67% ammonia and 70%-100% N-nitrosamine precursors were removed by Mordenite zeolite (except 3-(dimethylaminomethyl)indole (DMAI) and 4 dimethylaminoantipyrine (DMAP)). PAC effectively removed DMAI and DMAP when added during alum coagulation. A combination of the zeolite and PAC selected efficiently removed ammonia and all tested seven N-nitrosamine precursors (dimethylamine (DMA), ethylmethylamine (EMA), diethylamine (DEA), dipropylamine (DPA), trimethylamine (TMA), DMAP, and DMAI) during the alum coagulation process. PMID- 29478666 TI - Correction. PMID- 29478665 TI - Limited acid deposition inferred from diatoms during the 20th century - A case study from lakes in the Tatra Mountains. AB - Mountain lakes are usually sensitive to the effects of global and regional environmental changes. Since the second half of the 20th century, surface-water acidification has become a significant ecological problem, and many lakes in Europe and North America have anthropogenically acidified. Additionally, following reduction in emissions of sulfur (S) and nitrogen (N) compounds, recovery from acidification has been observed in many lakes. In this study, we used changes in diatom communities to reconstruct the pH histories based on changes recorded in nine Tatra lakes (Western Carpathians, Poland) since approximately 1850AD. Overall, results indicate that acidic precipitation had little influence on lake-water pH in the Tatra Mountain lakes. Changes in diatom inferred pH (DI-pH) generally were small and showed little evidence of acidification during the time of the highest air pollution (since the 1960s), and have shown little change since the reduction of acidic deposition since the 1990s. Lakes that showed some evidence of acidification included dystrophic lakes with low acid neutralizing capacity. However, as illustrated by the PCA trajectories of the diatom assemblages, the majority of the lakes currently contain diatom assemblages that are unlike the diatom floras that existed ca. 1850. PMID- 29478668 TI - Design of sports clothing for hot environments. AB - The clothing design based on sweat distribution pattern is called as body mapping clothing. Comparisons of three designs of body mapped and one conventional design of T-shirt was done in a wearer testing at a controlled chamber of 33 degrees C and 60% relativity humidity in a treadmill at 12 km/h for 40 min followed by 10 min resting. It is concluded that with the full body mapped T-shirt the increase in skin temperature is reduced in the chest area, shoulder, the body back by 47%,44% and 55% respectively; the increase in skin micro climate relative humidity is reduced in the chest area, shoulder, the body back by 54%,39.2% and 53% respectively; the increase in heart beat rate is reduced by 5.1%; the subjective perceptions of skin temperature, skin moisture and comfort are better; the wearer will be able to improve the running performance due better comfort level in terms lesser increase skin temperature, skin micro climate relative humidity and heart beat rate. PMID- 29478667 TI - Human factors in robotic assisted surgery: Lessons from studies 'in the Wild'. AB - This article reviews studies conducted "in the wild" that explore the "ironies of automation" in Robotic Assisted Surgery (RAS). Workload may be reduced for the surgeon, but increased for other team members, with postural stress relocated rather than reduced, and the introduction of a range of new challenges, for example, in the need to control multiple arms, with multiple instruments; and the increased demands of being physically separated from the team. Workflow disruptions were not compared with other surgeries; however, the prevalence of equipment and training disruptions differs from other types of surgeries. A consistent observation is that communication and coordination problems are relatively frequent, suggesting that the surgical team may need to be trained to use specific verbal and non-verbal cues during surgery. RAS also changes the necessary size of the operating room instrument cleaning processes. These studies demonstrate the value of clinically-based human factors engineers working alongside surgical teams to improve the delivery of RAS. PMID- 29478669 TI - The 'Enfacement' illusion: A window on the plasticity of the self. AB - Understanding how self-representation is built, maintained and updated across the lifespan is a fundamental challenge for cognitive psychology and neuroscience. Studies demonstrate that the detection of body-related multisensory congruency builds bodily and facial self-representations that are crucial to developing self recognition. Studies showing that the bodily self is more malleable than previously believed were mainly concerned with full-bodies and non-facial body parts. Crucially, however, intriguing recent evidence indicates that simple experimental manipulations could even affect self-face representation that has long been considered a stable construct impervious to change. In this review, we discuss how Interpersonal Multisensory Stimulation (IMS) paradigms can be used to temporarily induce Enfacement, i.e., the subjective illusion of looking at oneself in the mirror when in fact looking at another person's face. We show that Enfacement is a subtle but robust phenomenon occurring in a variety of experimental conditions and assessed by multiple explicit and implicit measures. We critically discuss recent findings on i) the role of sensory extero/proprio ceptive (visual, tactile, and motor) and interoceptive (cardiac) signals in self face plasticity, ii) the importance of multisensory integration mechanisms for the bodily self, and iii) the neural network related to IMS-driven changes in self-other face processing, within the predictive coding theoretical framework. PMID- 29478670 TI - Looking for novel, brain-derived, peripheral biomarkers of neurological disorders. AB - The role of blood brain barrier (BBB) is to preserve a precisely regulated environment for proper neuronal signaling. In many of the central nervous system (CNS) pathologies, the function of BBB is altered. Thus, there is a necessity to evaluate a fast, noninvasive and reliable method for monitoring of BBB condition. It seems that revealing the peripheral diagnostic biomarker whose release pattern (concentration, dynamics) will be correlated with clinical symptoms of neurological disorders offers significant hope. It could help with faster diagnosis and efficient treatment monitoring. In this review we summarize the recent data concerning exploration of potential new serum biomarkers appearing in the peripheral circulation following BBB disintegration, with an emphasis on epilepsy, traumatic brain injury (TBI) and stroke. We consider the application of well-known proteins (S100beta and GFAP) as serum indicators in the light of recently obtained results. Furthermore, the utility of molecules like MMP-9, UCHL 1, neurofilaments, BDNF, and miRNA, which are newly recognized as a potential serum biomarkers, will also be discussed. PMID- 29478671 TI - Encapsulation, protection, and delivery of bioactive proteins and peptides using nanoparticle and microparticle systems: A review. AB - There are many examples of bioactive proteins and peptides that would benefit from oral delivery through functional foods, supplements, or medical foods, including hormones, enzymes, antimicrobials, vaccines, and ACE inhibitors. However, many of these bioactive proteins are highly susceptible to denaturation, aggregation or hydrolysis within commercial products or inside the human gastrointestinal tract (GIT). Moreover, many bioactive proteins have poor absorption characteristics within the GIT. Colloidal systems, which contain nanoparticles or microparticles, can be designed to encapsulate, retain, protect, and deliver bioactive proteins. For instance, a bioactive protein may have to remain encapsulated and stable during storage and passage through the mouth and stomach, but then be released within the small intestine where it can be absorbed. This article reviews the application of food-grade colloidal systems for oral delivery of bioactive proteins, including microemulsions, emulsions, nanoemulsions, solid lipid nanoparticles, multiple emulsions, liposomes, and microgels. It also provides a critical assessment of the characteristics of colloidal particles that impact the effectiveness of protein delivery systems, such as particle composition, size, permeability, interfacial properties, and stability. This information should be useful for the rational design of medical foods, functional foods, and supplements for effective oral delivery of bioactive proteins. PMID- 29478672 TI - Spectroscopic methods for aqueous cyclodextrin inclusion complex binding measurement for 1,4-dioxane, chlorinated co-contaminants, and ozone. AB - Recalcitrant organic contaminants, such as 1,4-dioxane, typically require advanced oxidation process (AOP) oxidants, such as ozone (O3), for their complete mineralization during water treatment. Unfortunately, the use of AOPs can be limited by these oxidants' relatively high reactivities and short half-lives. These drawbacks can be minimized by partial encapsulation of the oxidants within a cyclodextrin cavity to form inclusion complexes. We determined the inclusion complexes of O3 and three common co-contaminants (trichloroethene, 1,1,1 trichloroethane, and 1,4-dioxane) as guest compounds within hydroxypropyl-beta cyclodextrin. Both direct (ultraviolet or UV) and competitive (fluorescence changes with 6-p-toluidine-2-naphthalenesulfonic acid as the probe) methods were used, which gave comparable results for the inclusion constants of these species. Impacts of changing pH and NaCl concentrations were also assessed. Binding constants increased with pH and with ionic strength, which was attributed to variations in guest compound solubility. The results illustrate the versatility of cyclodextrins for inclusion complexation with various types of compounds, binding measurement methods are applicable to a wide range of applications, and have implications for both extraction of contaminants and delivery of reagents for treatment of contaminants in wastewater or contaminated groundwater. PMID- 29478673 TI - Interaction Between Depression, Obesity, and Type 2 Diabetes: A Complex Picture. AB - Depression plays an important role in the pathogenesis and treatment of obesity and type 2 diabetes (T2D). However, its relevance is frequently unrecognized by clinicians and researchers. The purpose of this review is to present a critical analysis of the evidence linking depression and metabolic disorders and to highlight the practical implications of this complex relationship. Evidence obtained from epidemiological, basic, clinical and controlled studies demonstrate that the association goes beyond a random phenomenon. Epidemiological studies have rendered controversial results due to the lack of control of the confounding variables and the bidirectional relationship that exists between the outcomes and the conditions that modulate the association (i.e. socioeconomic status). Animal and human studies have been useful to define the anatomic substrates and physiologic processes that participate in the association, but, the evidence is preliminary in many areas (i.e gene * environmental interactions). Controlled studies have shown the strong impact that treatment of depression has on body weight and the large effect that has the correction of excess body weight on the depression-related symptoms. Practical implications of the depression-obesity duet include the training of the health providers to assess and treat these conditions in a concomitant manner, the need for translational medicine projects and the application the systems biology approach to fill the existing gaps of knowledge. PMID- 29478674 TI - Restoring the p53 'Guardian' Phenotype in p53-Deficient Tumor Cells with CRISPR/Cas9. AB - With an increasing prevalence in the human population, cancer has become one of the most investigated fields of medicine. Among the potential targets for cancer therapy is the tumor suppressor gene TP53, which is found in a mutated state in approximately 50% of human cancers and is often associated with poor prognosis. We propose a novel, highly tumor-specific delivery system for TP53, based on the CRISPR/Cas9 genome editing technology. This system will restore the normal p53 phenotype in tumor cells by replacing the mutant TP53 gene with a functional copy, leading to sustained expression of p53 protein and tumor regression. PMID- 29478675 TI - Fluorescent Antibiotics: New Research Tools to Fight Antibiotic Resistance. AB - Better understanding how multidrug-resistant (MDR) bacteria can evade current and novel antibiotics requires a better understanding of the chemical biology of antibiotic action. This necessitates using new tools and techniques to advance our knowledge of bacterial responses to antibiotics, ideally in live cells in real time, to selectively investigate bacterial growth, division, metabolism, and resistance in response to antibiotic challenge. In this review, we discuss the preparation and biological evaluation of fluorescent antibiotics, focussing on how these reporters and assay methods can help elucidate resistance mechanisms. We also examine the potential utility of such probes for real-time in vivo diagnosis of infections. PMID- 29478676 TI - Engineering Biology by Controlling Tissue Folding. AB - Achieving complex self-organization in vitro has remained a fundamental challenge in tissue engineering. A recent study in Developmental Cell by Hughes and colleagues uses computational and experimental approaches to understand and control the morphogenic process of tissue folding. These approaches provide an engineering framework to reproducibly control tissue shape. PMID- 29478677 TI - Variation in Treatment Patterns Correlate With Resource Utilization in the 30-Day Episode of Care of Displaced Femoral Neck Fractures. AB - BACKGROUND: We evaluated which treatment decisions in the management of displaced femoral neck fractures (FNFs) may associate with measures of resource utilization relevant to a value-based episode-of-care model. METHODS: A total of 1139 FNFs treated with hip arthroplasty at 7 hospitals were retrospectively reviewed. Treatment choices were procedure (hemiarthroplasty vs total hip arthroplasty [THA]), surgeon training status, admitting service, and time to surgery. Dependent variables were length of stay, discharge disposition, 30-day readmission, and in-hospital mortality. Variation across hospitals was evaluated with analysis of variance and chi-square tests. Treatment choices were evaluated for the dependent variables of interest with univariable and multivariable regression. RESULTS: There was significant variation between hospitals regarding proportion of cases treated with THA (range = 3.0%-73.2%, P < .001), proportion treated by arthroplasty fellowship-trained surgeons (range = 0%-74.9%, P < .001), proportion admitted to the orthopedic service (range = 2.8%-91.3%, P < .001), mean time to surgery (range = 0.9-2.1 days, P < .001), and proportion of discharge home (range = 63.9%-97.8%, P < .001). Multivariable analysis adjusting for age, gender, and Charlson Comorbidity Index demonstrated correlations between (1) decreased length of stay and admission to orthopedics (B = -1.256, P < .001); (2) lower 30-day readmission and THA (odds ratio [OR] = .376, P = .004), and (3) decreased discharge to a care facility and admission to orthopedics (OR = 0.402, P = <.001), THA (OR = 0.435, P = .002), and treatment by an arthroplasty fellowship-trained surgeon (OR = 0.572, P = .016). None of the treatment variables tested associated with in-hospital mortality. CONCLUSION: We observed significant variation in the treatment of displaced FNF patients across 7 hospitals and identified treatment choices that associated with resource utilization within the episode of care. Future, prospective study is necessary to understand whether care pathways that adapt some combination of these characteristics may result in more value-based care. PMID- 29478678 TI - Implementation of a Total Hip Arthroplasty Care Pathway at a High-Volume Health System: Effect on Length of Stay, Discharge Disposition, and 90-Day Complications. AB - BACKGROUND: Standardized care pathways are evidence-based algorithms for optimizing an episode of care. Despite the theoretical promise of care pathways, there is an inconsistent literature demonstrating improvements in patient care. The authors hypothesized that implementing a care pathway, across 11 hospitals, would decrease hospital length of stay (LOS), decrease postoperative complications at 90 days, and increase discharges to home. METHODS: A multidisciplinary team developed an evidence-based care pathway for total hip arthroplasty (THA) perioperative care. All patients receiving THA in 2013 (pre protocol, historical control), 2014 (transition), and 2015 (full protocol implementation) were included in the analysis. Multivariable regression assessed the relationship of the care pathway to 90-day postoperative complications, LOS, and discharge disposition. Cost savings were estimated using previously published postarthroplasty episode and per diem hospital costs. RESULTS: A total of 6090 primary THAs were conducted during the study period. After adjusting for the covariates, the full protocol implementation was associated with a decrease in LOS (mean ratio, 0.747; 95% confidence interval [CI; 0.727, 0.767]) and an increase in discharges to home (odds ratio, 2.079; 95% CI [1.762, 2.456]). The full protocol implementation was not associated with a change in 90-day complications (odds ratio, 1.023; 95% CI [0.841, 1.245]). Payer-perspective calculated theoretical cost savings, including both index admission and postdischarge costs, were $2533 per patient. CONCLUSION: The THA care pathway implementation was successful in reducing LOS and increasing discharges to home. The care pathway was not associated with a change in 90-day complications; further targeted interventions in this area are needed. Despite care standardization efforts, high-volume hospitals and surgeons had higher performance. Extrapolation of theoretical cost savings indicates that widespread THA care pathway adoption could lead to national healthcare savings of $1.2 billion annually. PMID- 29478679 TI - Gaps in Knowledge About the Association Between Maternal Periodontitis and Adverse Obstetric Outcomes: An Umbrella Review. AB - OBJECTIVES: Scientific literature has established that the periodontal condition during pregnancy could be associated with obstetric/neonatal morbidity, and these effects have an important relationship with problems during childhood and cardiovascular disease in adulthood. This umbrella review aimed to summarize the results about the association between maternal periodontitis and obstetric complications (low birth weight, preterm delivery, and preeclampsia) and identify the gaps in the scientific literature. METHODS: An umbrella review of systematic reviews with or without meta-analysis was performed. Quality evaluation and descriptive analysis of the characteristics of the included studies were conducted. RESULTS: Nineteen systematic reviews/meta-analyses were considered. In total, the systematic reviews included 99 observational studies. Most of the reviews established an association between maternal periodontitis and a higher risk of low birth weight, preterm delivery, and preeclampsia. The magnitude and statistical significance of this relationship are influenced by the context in which the studies have been conducted. Gaps were identified in the definition/evaluation of periodontal disease, criteria of gestational age for study purposes, and potential confounders, among others. CONCLUSIONS: Although scientific literature has established an association among the analyzed pathologies, conceptual and methodological gaps were identified, and they should be considered as integral components when this association is investigated. PMID- 29478680 TI - Clinical Factors Affecting the Accuracy of Guided Implant Surgery-A Systematic Review and Meta-analysis. AB - OBJECTIVES: To systematically review the current dental literature regarding clinical accuracy of guided implant surgery and to analyze the involved clinical factors. MATERIAL AND METHODS: PubMed and Cochrane Central Register of Controlled Trials were searched. Meta-analysis and meta-regression analysis were performed. Clinical studies with the following outcome measurements were included: (1) angle deviation, (2) deviation at the entry point, and (3) deviation at the apex. The involved clinical factors were further evaluated. RESULTS: Fourteen clinical studies from 1951 articles initially identified met the inclusion criteria. Meta regression analysis revealed a mean deviation at the entry point of 1.25 mm (95% confidence interval [CI]: 1.22-1.29), 1.57 mm (95% CI: 1.53-1.62) at the apex, and 4.1 degrees in angle (95% CI: 3.97-4.23). A statistically significant difference (P < .001) was observed in angular deviations between the maxilla and mandible. Partially guided surgery showed a statistically significant greater deviation in angle (P < .001), at the entry point (P < .001), and at the apex (P < .001) compared with totally guided surgery. The outcome of guided surgery with flapless approach indicated significantly more accuracy in angle (P < .001), at the entry point (P < .001), and at apex (P < .001). Significant differences were observed in angular deviation based on the use of fixation screw (P < .001). CONCLUSIONS: The position of guide, guide fixation, type of guide, and flap approach could influence the accuracy of computer-aided implant surgery. A totally guided system using fixation screws with a flapless protocol demonstrated the greatest accuracy. Future clinical research should use a standardized measurement technique for improved accuracy. PMID- 29478681 TI - Skeletal and Dental Effectiveness of Treatment of Class II Malocclusion With Headgear: A Systematic Review and Meta-analysis. AB - OBJECTIVE: To evaluate the skeletal and dental effects of headgear treatment by systematically reviewing the best available scientific evidence. MATERIALS AND METHODS: A survey of articles published up to February 2017 investigating the effects of headgear in the treatment of patients with class II malocclusion was performed using 19 electronic databases. Only randomized clinical trials and prospective controlled clinical trials investigating growing patients with class II malocclusion treated with headgear were included. Two authors performed independently study selection, data extraction, and risk of bias assessment. All pooled data analyses were performed using the random-effect model. Statistical heterogeneity was evaluated. RESULTS: In total, 6 trials were included (4 randomized clinical trials and 2 prospective controlled clinical trials), grouping data from 337 patients (170 treated patients and 167 untreated controls). The ages of the patients varied across the studies, but the majority of the trials had a sample with an age range between 8 and 9 years. The times of daily wear of the appliance varied across studies from 8 to 14 h/d. The significant mean differences in treatment effects compared with the untreated controls were -1.41 degrees per year for SNA angle cephalometric parameter (95% confidence interval [CI]: -2.25 degrees to -0.56 degrees ), -0.57 mm/y for anterior maxillary displacement (95% CI: -0.75 to -0.40 mm), -1.42 degrees per year for ANB angle cephalometric parameter (95% CI: -2.12 degrees to -0.72 degrees ), and -1.31 mm/y for the overjet cephalometric parameter (95% CI: -2.34 to -0.29 mm). CONCLUSION: Headgear treatment is effective in restricting sagittal maxillary growth and reducing the overjet in the short term. PMID- 29478682 TI - In Vivo and In Vitro Effectiveness of Rotary Nickel-Titanium vs Manual Stainless Steel Instruments for Root Canal Therapy: Systematic Review and Meta-analysis. AB - INTRODUCTION: This systematic review evaluated the effectiveness of nickel titanium (NiTi) rotary files compared to stainless-steel (SST) hand files. METHODS: An electronic search was performed on Medline, EMBASE, CENTRAL and Scopus databases up to February 2016. An additional hand searching was performed in 13 journals. The studies were classified according to study type and the outcome variables. Two reviewers independently applied eligibility criteria, extracted data, and three reviewers independently assessed the quality of the evidence of each included study according to The Cochrane Collaboration's procedures. A meta-analysis was performed whenever it was possible. RESULTS: The electronic and hand search strategies yielded 1155 references of studies after removal of duplicates. Four clinical studies (two prospective and two retrospective studies) and 18 in vitro studies (on extracted teeth) were included for the qualitative synthesis after full-text evaluation of the eligible studies. The overall level of methodological quality of the studies included can be considered inadequate. Only one clinical study was judged at low risk of bias, whereas most non-clinical studies had a low risk of bias. Three meta-analyses, based on a very limited number of studies, could be performed. Each meta-analysis contained two studies. Of these, one meta-analysis was based on clinical studies. CONCLUSIONS: The results of this systematic review suggested that NiTi rotary instruments were associated with lower canal transportation and apical extrusion when compared to SST hand files, whereas both groups had similar outcomes in terms of success of therapy, amount of residual bacteria, and cleansing ability after treatment. However, due to the limited evidence available, these results should be interpreted with caution. Consequently, more randomized control trials using standardized protocols are needed in order to provide more solid recommendations. PMID- 29478683 TI - Insufficient Evidence to Compare the Efficacy of Treatments for Medication Related Osteonecrosis of the Jaws. AB - ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Effectiveness of treatments for medication-related osteonecrosis of the jaw: A systematic review and meta analysis. El-Rabbany M, Sgro A, Lam DK, Shah PS, Azarpazhooh A. J Am Dent Assoc 2017; 148(8):584-94. SOURCE OF FUNDING: Nonprofit: Canadian Association of Oral and Maxillofacial Surgeons and the Alpha Omega Foundation of Canada TYPE OF STUDY/DESIGN: Systematic review with meta-analysis of data. PMID- 29478684 TI - Adenotonsillectomy May Have Beneficial Effects on the Dentofacial Development of Children with Adenotonsillar Hypertrophy. AB - ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Impact of adenotonsillectomy on the dentofacial development of obstructed children: a systematic review and meta analysis. Becking BE, Verweij JP, Kalf-Scholte SM, Valkenburg C, Bakker EWP, van Merkesteyn JPR. Eur J Orthod 2017; 39(5):509-18. SOURCE OF FUNDING: The review received no funding TYPE OF STUDY/DESIGN: Systematic review. PMID- 29478685 TI - Survival Rate of Delayed Implants Placed in Healed Extraction Sockets is Significantly Higher Than That of Immediate Implants Placed in Fresh Extraction Sockets. AB - ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Immediate implant placement into fresh extraction sockets versus delayed implants into healed sockets: a systematic review and meta-analysis. Mello CC, Lemos CAA, Verri FR, Dos Santos DM, Goiato MC, Pellizzer EP. Int J Oral Maxillofac Surg 2017; 46(9):1162-77. SOURCE OF FUNDING: None TYPE OF STUDY/DESIGN: Systematic review with meta analysis of data. PMID- 29478686 TI - Limited Evidence Suggests that a History of Suboptimal Breastfeeding May Increase the Risk of Developing Anterior Open Bite, Posterior Crossbite, and Class II Canine Relationship. AB - ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Malocclusion in young children. Does breast-feeding really reduce the risk? A systematic review and meta-analysis. Dogramaci EJ, Rossi-Fedele G, Dreyer CW. J Am Dent Assoc 2017; 148(8):566-74. SOURCE OF FUNDING: Australian Government Research Training Program Scholarship TYPE OF STUDY/DESIGN: Systematic review with meta-analysis of data. PMID- 29478687 TI - Limited Longitudinal Evidence Suggests That Socioeconomic Position May Influence Periodontal Diseases Over the Course of Life. AB - ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Socioeconomic position during life and periodontitis in adulthood: a systematic review. Schuch HS, Peres KG, Singh A, Peres MA, Do LG. Community Dent Oral Epidemiol 2017; 45(3):201-8. SOURCE OF FUNDING: Brazilian Government Agency-CAPES: Coordination for the Improvement of Higher Education Personnel for the PhD Scholarship (HSS-Process 13374-13-1) TYPE OF STUDY/DESIGN: Systematic review. PMID- 29478688 TI - Limited Evidence Suggests That Alveolar Ridge Preservation is More Favorable Than Unassisted Socket Healing in Minimizing Alveolar Ridge Dimensional Changes After Extraction. AB - ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Alveolar ridge preservation after tooth extraction: a Bayesian Network meta-analysis of grafting materials efficacy on prevention of bone height and width reduction. Iocca O, Farcomeni A, Pardinas Lopez S, Talib HS. J Clin Periodontol 2017; 44(1):104-14. SOURCE OF FUNDING: Self funded by the authors and their institutions TYPE OF STUDY/DESIGN: Meta-analysis and Bayesian network meta-analysis. PMID- 29478689 TI - Silver Diamine Fluoride Arrests Caries in Primary Teeth. AB - ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Silver Diamine Fluoride Has Efficacy in Controlling Caries Progression in Primary Teeth: A Systematic Review and Meta Analysis. Chibinski AC, Wambier LM, Feltrin J, Loguercio AD, Wambier DS, Reis A. Caries Res 2017;51(5):527-41. SOURCE OF FUNDING: This study was partially supported by the Brazilian Government Organization-National Council for Scientific and Technological Development (CNPq)-under grants 304105/2013-9 and 305588/2014-1 TYPE OF STUDY/DESIGN: Systematic review and meta-analysis. PMID- 29478690 TI - Multiple Disconnections/Reconnections of Implant Abutment May Induce Recession of Peri-implant Mucosa. AB - ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Abutment Disconnection/Reconnection Affects Peri-implant Marginal Bone Levels: A Meta-Analysis. Koutouzis T, Gholami F, Reynolds J, Lundgren T, Kotsakis GA. Int J Oral Maxillofac Implants 2017;32(3):575-81. SOURCE OF FUNDING: The authors declared no conflict of interest TYPE OF STUDY/DESIGN: Systematic review with meta-analysis of data. PMID- 29478691 TI - Silver Diamine Fluoride Staining is Acceptable for Posterior Primary Teeth and Is Preferred Over Advanced Pharmacologic Behavior Management by Many Parents. AB - ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Parental perceptions and acceptance of silver diamine fluoride staining. Crystal YO, Janal MN, Hamilton DS, Niederman R. J Am Dent Assoc 2017; 148(7):510-8. SOURCE OF FUNDING: Grant from the National Institute on Minority Health and Health Disparities (NIMHD), National Institutes of Health; New York University Clinical and Translational Science Award; and National Center for Advancing Translational Science, National Institutes of Health TYPE OF STUDY/DESIGN: Cross-sectional. PMID- 29478692 TI - Inflammatory myofibroblastic tumours of the head and neck. PMID- 29478693 TI - Incidental single-organ vasculitis of the appendix. PMID- 29478694 TI - Breastfeeding Recommended Despite HIV Infection. PMID- 29478695 TI - Inadequate Production of H2 by Gut Microbiota and Parkinson Disease. AB - Dysbiosis of the gut flora accompanies Parkinson disease (PD), yet no specific cause-effect link has been identified so far. The gut microbiota produce molecular hydrogen (H2), a ubiquitous molecule recently recognized as a biologically active gas with antioxidant, antiapoptotic, anti-inflammatory, cytoprotective, and signaling properties. Here, we discuss an idea that an impaired production of endogenous H2 by intestinal microbiota might play a role in PD pathogenesis, with supplemental H2 debated as a possible therapy for this progressive neurodegenerative disease. PMID- 29478696 TI - Validation of imaging-based quantification of glenohumeral joint kinematics using an unmodified clinical biplane fluoroscopy system. AB - Model-based tracking, using CT and biplane fluoroscopy, allows highly accurate quantification of glenohumeral motion and changes in the subacromial space. Previous investigators have used custom-built biplane fluoroscopes designed specifically for kinematic applications, which are available at few institutions and require FDA approval prior to clinical use. The aim of this study was to demonstrate the utility of an off-the-shelf clinical biplane fluoroscope for kinematic applications by validating model-based tracking for measurement of glenohumeral motion using an unmodified clinical system. Biplane images of each shoulder of a cadaver torso were acquired at various joint positions and during simulated movements along anatomical planes of motion. The pose of each humerus and scapula was determined using model-based tracking and compared to a bead based gold standard. Error due to a temporal-offset between corresponding biplane images, characteristic of clinical biplane systems, was determined by comparison of measured and known relative position of 2 bead clusters of a phantom that was imaged while moved throughout the fluoroscopy image volume. Model-based tracking had global kinematic mean absolute errors of 0.27 mm and 0.29 degrees (static), and 0.22-0.32 mm and 0.12-0.45 degrees (dynamic). Glenohumeral mean absolute errors were 0.39 mm and 0.45 degrees (static), and 0.36-0.42 mm and 0.41-0.48 degrees (dynamic). The temporal-offset was predicted to add errors of 0.06-0.85 mm and 0.05-0.28 degrees for cadaveric trials for the speeds examined. For defined speeds, sub-millimeter and sub-degree kinematic accuracy and precision were achieved using an unmodified clinical biplane fluoroscope for quantification of glenohumeral motion. PMID- 29478697 TI - The fluid dynamics of Balanus glandula barnacles: Adaptations to sheltered and exposed habitats. AB - Suspension feeders use a wide range of appendages to capture particles from the surrounding fluid. Their functioning, either as a paddle or a sieve, depends on the leakiness, or amount of fluid that passes through the gaps between the appendages. Balanus glandula is the most common species of barnacle distributed along the Pacific coast of North America. It shows a strong phenotypic response to water flow velocity. Individuals from exposed, high flow sites have short and robust cirral filters, whereas those from sheltered, low velocity sites have long, spindly appendages. Computational fluid dynamics (CFD) simulations of these two ecophenotypes were done using a finite volume method. Leakiness was determined by simulating flow velocity fields at increasing Reynolds numbers, results that have been unattainable at higher velocities by observation. CFD also allowed us to characterize flow in hard to see regions of the feeding legs (rami). Laser-illumination experiments were performed at low to medium flow velocities in a flume tank and corroborated results from CFD. Barnacle filters from a sheltered site become completely leaky at Re=2.24(0.16m/s), well above the maximum habitat velocity, suggesting that this ecophenotype is not mechanically optimized for feeding. Barnacles from exposed environments become fully leaky within the range of habitat velocities Re=3.50(0.18m/s). Our CFD results revealed that the drag force on exposed barnacles feeding appendages are the same as the sheltered barnacles feeding appendages despite their shape difference and spacing ratio. PMID- 29478699 TI - alpha-Synuclein Oligomers Induce a Unique Toxic Tau Strain. AB - BACKGROUND: The coexistence of alpha-synuclein and tau aggregates in several neurodegenerative disorders, including Parkinson's disease and Alzheimer's disease, raises the possibility that a seeding mechanism is involved in disease progression. METHODS: To further investigate the role of alpha-synuclein in the tau aggregation pathway, we performed a set of experiments using both recombinant and brain-derived tau and alpha-synuclein oligomers to seed monomeric tau aggregation in vitro and in vivo. Brain-derived tau oligomers were isolated from well-characterized cases of progressive supranuclear palsy (n = 4) and complexes of brain-derived alpha-synuclein/tau oligomers isolated from patients with Parkinson's disease (n = 4). The isolated structures were purified and characterized by standard biochemical methods, then injected into Htau mice (n = 24) to assess their toxicity and role in tau aggregation. RESULTS: We found that alpha-synuclein induced a distinct toxic tau oligomeric strain that avoids fibril formation. In vivo, Parkinson's disease brain-derived alpha-synuclein/tau oligomers administered into Htau mouse brains accelerated endogenous tau oligomer formation concurrent with increasing cell loss. CONCLUSIONS: Our findings provide evidence, for the first time, that alpha-synuclein enhances the harmful effects of tau, thus contributing to disease progression. PMID- 29478698 TI - Genome-wide Association Study Identifies a Regulatory Variant of RGMA Associated With Opioid Dependence in European Americans. AB - BACKGROUND: Opioid dependence (OD) is at epidemic levels in the United States. Genetic studies can provide insight into its biology. METHODS: We completed an OD genome-wide association study in 3058 opioid-exposed European Americans, 1290 of whom met criteria for a DSM-IV diagnosis of OD. Analysis used DSM-IV criterion count. RESULTS: By meta-analysis of four cohorts, Yale-Penn 1 (n = 1388), Yale Penn 2 (n = 996), Yale-Penn 3 (n = 98), and SAGE (Study of Addiction: Genetics and Environment) (n = 576), we identified a variant on chromosome 15, rs12442183, near RGMA, associated with OD (p = 1.3 * 10-8). The association was also genome wide significant in Yale-Penn 1 taken individually and nominally significant in two of the other three samples. The finding was further supported in a meta analysis of all available opioid-exposed African Americans (n = 2014 [1106 meeting DSM-IV OD criteria]; p = 3.0 * 10-3) from three cohorts; there was nominal significance in two of these samples. Thus, of seven subsamples examined in two populations, one was genome-wide significant, and four of six were nominally (or nearly) significant. RGMA encodes repulsive guidance molecule A, which is a central nervous system axon guidance protein. Risk allele rs12442183*T was correlated with higher expression of a specific RGMA transcript variant in frontal cortex (p = 2 * 10-3). After chronic morphine injection, the homologous mouse gene (Rgma) was upregulated in C57BL/6J striatum. Coexpression analysis of 1301 brain samples revealed that RGMA messenger RNA expression was associated with that of four genes implicated in other psychiatric disorders, including GRIN1. CONCLUSIONS: This is the first study to demonstrate an association of RGMA with OD. It provides a new lead into our understanding of OD pathophysiology. PMID- 29478700 TI - Effective Use of Animal Models for Therapeutic Development in Psychiatric and Substance Use Disorders. AB - Athina Markou and others argue forcefully for the adoption of a "translational back translational strategy" for central nervous system drug discovery involving novel application of drugs with established safety profiles in proof-of-principle studies in humans, which in turn encourage parallel studies using experimental animals to provide vital data on the neural systems and neuropharmacological mechanisms related to the actions of the candidate drugs. Encouraged by the increasing adoption of drug-development strategies involving reciprocal information exchange between preclinical animal studies and related clinical research programs, this review presents additional compelling examples related to the following: 1) the treatment of cognitive deficits that define attention deficit/hyperactivity disorder; 2) the development of fast-acting antidepressants based on promising clinical effects with low doses of the anesthetic ketamine; and 3) new and effective medications for the treatment of substance misuse. In the context of addressing the unmet medical need for new and effective drugs for treatment of mental ill health, now may be the time to launch major new academic industry consortia committed to open access of all preclinical and clinical data generated by this research. PMID- 29478703 TI - Can diabetes affect my oral health? PMID- 29478702 TI - Relationship between community-level variables and number of general dentists. AB - BACKGROUND: In this study, the authors used observational data from 2014 to evaluate the association between the number of general dentists and several community characteristics. METHODS: The authors collected community-level characteristics from secondary sources for all 947 Iowa incorporated communities to study their relationships with the mean number of general dentists per 1,000 population per square mile (population density), the dependent variable. The authors used zero-inflated negative binomial models to examine the association between the dependent and predictor variables. RESULTS: Only 22.8% of communities had a dentist. Urban, young, well-educated, fluoridated communities with at least 1 elementary school had the highest estimated mean concentration of dentists. Isolated communities with older, less educated adults and lacking fluoridation and an elementary school had the fewest dentists. CONCLUSIONS: Although population is an important determinant for where a dentist practices, other variables such as urbanization, demographic characteristics, fluoridation status, and presence of at least 1 elementary school are also predictors of the number of dentists in a community. PRACTICAL IMPLICATIONS: These findings provide dental students and young practitioners useful information by highlighting community characteristics that are associated with office locations. PMID- 29478701 TI - Dopamine D1 Receptor-Positive Neurons in the Lateral Nucleus of the Cerebellum Contribute to Cognitive Behavior. AB - BACKGROUND: Studies in humans and nonhuman primates have identified a region of the dentate nucleus of the cerebellum, or the lateral cerebellar nucleus (LCN) in rodents, activated during performance of cognitive tasks involving complex spatial and sequential planning. Whether such a subdivision exists in rodents is not known. Dopamine and its receptors, which are implicated in cognitive function, are present in the cerebellar nuclei, but their function is unknown. METHODS: Using viral and genetic strategies in mice, we examined cellular phenotypes of dopamine D1 receptor-positive (D1R+) cells in the LCN with whole cell patch clamp recordings, messenger RNA profiling, and immunohistochemistry to examine D1R expression in mouse LCN and human dentate nucleus of the cerebellum. We used chemogenetics to inhibit D1R+ neurons and examined behaviors including spatial navigation, social recognition memory, prepulse inhibition of the acoustic startle reflex, response inhibition, and working memory to test the necessity of these neurons in these behaviors. RESULTS: We identified a population of D1R+ neurons that are localized to an anatomically distinct region of the LCN. We also observed D1R+ neurons in human dentate nucleus of the cerebellum, which suggests an evolutionarily conserved population of dopamine receptive neurons in this region. The genetic, electrophysiological, and anatomical profile of mouse D1R neurons is consistent with a heterogeneous population of gamma-aminobutyric acidergic, and to a lesser extent glutamatergic, cell types. Selective inhibition of D1R+ LCN neurons impairs spatial navigation memory, response inhibition, working memory, and prepulse inhibition of the acoustic startle reflex. CONCLUSIONS: Collectively, these data demonstrate a functional link between genetically distinct neurons in the LCN and cognitive behaviors. PMID- 29478705 TI - [Comparison of transverse short-axis classic and oblique long-axis "Syringe-Free" approaches for internal jugular venous catheterization under ultrasound guidance]. AB - BACKGROUND AND OBJECTIVES: There are different ultrasound probe positions used for internal jugular venous catheter placement. Also, in-plane or out of plane needle approach may be used for catheterization. Transverse short-axis classic approach is the most popular performed approach in literature. "Syringe-Free" is a new described technique that is performed with oblique long-axis approach. We aimed to compare performance of these two approaches. METHODS: This study was conducted as a prospective and randomized study. 80 patients were included the study and divided into two groups that were named Group C (transverse short-axis classic approach) and Group SF (oblique long-axis syringe-free approach) by a computer-generated randomization. The primary outcome was mean time that guidewire is seen in the internal jugular vein (performing time). The secondary outcomes were to compare number of needle pass, number of skin puncture and complications between two groups. RESULTS: Demographic and hemodynamic data were not significantly different. The mean performing time was 54.9+/-19.1s in Group C and 43.9+/-15.8s in Group SF. Significant differences were found between the groups (p=0.006). Mean number of needle pass was 3.2(+/-2.1) in Group C and 2.1(+/-1.6) in Group SF. There were statistically significant differences between two groups (p=0.002). The number of skin puncture was 1.6(+/-0.8) and 1.2(+/-0.5) in Group C and SF, respectively (p=0.027). CONCLUSION: "Syringe-Free" technique has lower performing time, number of needle pass and skin puncture. Also, it allows to follow progress of guide-wire under continuous ultrasound visualization and the procedure does not need assistance during catheter insertion. Namely, "Syringe-Free" is effective, safe and fast technique that may be used to place internal jugular venous catheter. PMID- 29478704 TI - Synthesis and biological evaluation of polyhydroxylated oxindole derivatives as potential antileishmanial agent. AB - The devastating appearance of numerous drug-unresponsive strains of Leishmania donovani and severe toxic side effects of conventional antileishmanial therapy necessitates the search for novel leads, to treat visceral leishmaniasis efficiently. The current study deals with the synthesis and biological evaluation of a unique C-5 functionalized oxindole based polyphenol to ascertain its activities against L. donovani infection, in vitro. The polyhydroxylated oxindole derivative (1) was generated by coupling styrene derivatives with 5-bromo bis arylidene oxindole using Heck coupling reaction. The synthesized molecule 1 was tested for its antileishmanial activity using both promastigote and amastigote stages of L. donovani. Molecule 1 showed promising anti-promastigote and anti amastigote activities with IC50 values 15 uM and 1 uM, respectively, with no cytotoxicity towards host splenocytes. The results revealed that this compound induced parasite death by promoting oxidative stress, thereby triggering apoptosis. PMID- 29478708 TI - Emotion Recognition From Singing Voices Using Contemporary Commercial Music and Classical Styles. AB - OBJECTIVES: This study examines the recognition of emotion in contemporary commercial music (CCM) and classical styles of singing. This information may be useful in improving the training of interpretation in singing. STUDY DESIGN: This is an experimental comparative study. METHODS: Thirteen singers (11 female, 2 male) with a minimum of 3 years' professional-level singing studies (in CCM or classical technique or both) participated. They sang at three pitches (females: a, e1, a1, males: one octave lower) expressing anger, sadness, joy, tenderness, and a neutral state. Twenty-nine listeners listened to 312 short (0.63- to 4.8 second) voice samples, 135 of which were sung using a classical singing technique and 165 of which were sung in a CCM style. The listeners were asked which emotion they heard. Activity and valence were derived from the chosen emotions. RESULTS: The percentage of correct recognitions out of all the answers in the listening test (N = 9048) was 30.2%. The recognition percentage for the CCM-style singing technique was higher (34.5%) than for the classical-style technique (24.5%). Valence and activation were better perceived than the emotions themselves, and activity was better recognized than valence. A higher pitch was more likely to be perceived as joy or anger, and a lower pitch as sorrow. Both valence and activation were better recognized in the female CCM samples than in the other samples. CONCLUSIONS: There are statistically significant differences in the recognition of emotions between classical and CCM styles of singing. Furthermore, in the singing voice, pitch affects the perception of emotions, and valence and activity are more easily recognized than emotions. PMID- 29478707 TI - ? AB - The constant development of health technologies, combined with the increase in the cost of treatment, means that States must continually make choices about the introduction of new technologies into their healthcare system and how they are to be funded. In France, the systematic participation of patients in these processes is one of the targets to be met in terms of healthcare democracy. Although, on an international level, patient involvement in these assessments is constantly growing, it is difficult to define due to the presence of unstabilised elements in terms of both terminology and assessment methods. As a result, patient and public involvement in health technology assessments varies considerably from one country to the next, from one field to the next and even from one type of technology to the next. Several types of involvement exist, ranging from studies conducted to collect patient "insight" (experience, perception, needs, preferences, attitudes to treatment and health, etc.) to processes aimed at including patients in assessments (as individuals, as representatives of associations, etc.). Given the scope and complexity of the subject, and the difficulty involved in understanding all the different aspects of health technologies and innovations, the members of the Round Table chose to concentrate on health technology assessments (medicinal products and medical devices) to develop national recommendations on all possible types of patient involvement in the health technology assessment processes conducted by the health authorities in France. PMID- 29478706 TI - Using connected objects in clinical research. AB - Connected objects (CO), whether medical devices or not, are used in clinical research for data collection, a specific activity (communication, diagnosis, effector, etc.), or several functions combined. Their validation should be based on three approaches: technical and clinical reliability, data protection and cybersecurity. Consequently, the round table recommends that the typology of COs, their uses and limitations, be known and shared by all, particularly for implementing precise specifications. COs are used in clinical research during observational studies (assessment of the device itself or data collection), randomized studies, where only one group has a CO (assessment of its impact on patient follow-up or management), or randomized studies where both groups have a CO, which is then used as a tool to help with assessment. The benefits of using COs in clinical research includes: improved collection and quality of data, compliance of patients and pharmacovigilance, easier implementation of e-cohorts and a better representative balance of patients. The societal limits and risks identified relate to the sometimes intrusive nature of certain collected parameters and the possible misuse of data. The round table recommends the following on this last point: anticipation, by securing transmission methods, the qualification of data hosts, and assessment of the object's vulnerability. For this, a risk analysis appears necessary for each project. It is also necessary to accurately document the data flow, in order to inform both patients and healthcare professionals and to ensure adequate security. Anticipating regulatory changes and involving users starting from the study design stage are also recommended. PMID- 29478709 TI - Evaluation of Surgical Strategies for Bilateral Vocal Fold Paralysis Using Excised Canine Larynges. AB - OBJECTIVE: The objective of this study was to provide a theoretical basis for the selection of optimal surgical procedures in ex vivo simulated bilateral vocal fold paralysis (BVFP). STUDY DESIGN: Four surgical stages were sequentially performed on 10 excised canine larynges with simulated BVFP: (1) transverse cordotomy, (2) medial arytenoidectomy, (3) subtotal arytenoidectomy, and (4) total arytenoidectomy. MATERIALS AND METHODS: The sound pressure level, the signal-to-noise ratio, the glottal resistance, the glottal airflow (GF), the maximal glottal area (MGA), and spectrograms were measured after each stage. For comparative analysis of variance, a randomized block design and the Student Newman-Keuls test were performed. RESULTS: Under stable phonation, the sound pressure level showed no significant differences among the four stages. The signal-to-noise ratio was significantly different between the preoperative period and stage 1, as well as between stages 2 and 3. Glottal resistance was significantly different between the preoperative period and stage 1 and between stages 1 and 2. GF and MGA were significantly different among all stages, compared with those between stages 3 and 4 for GF and the preoperative period and stage 1 for MGA. The spectrograms indicated that the degree of disorder in the acoustic signals gradually increased. CONCLUSIONS: Based on a comprehensive analysis of GF and voice quality in excised canine larynges, which simulated BVFP, our results suggest that the optimal surgical choice for BVFP is either medial or subtotal arytenoidectomy. PMID- 29478710 TI - Seafood spoilage microbiota and associated volatile organic compounds at different storage temperatures and packaging conditions. AB - Seafood comprising of both vertebrate and invertebrate aquatic organisms are nutritious, rich in omega-3 fatty acids, essential vitamins, proteins, minerals and form part of healthy diet. However, despite the health and nutritional benefits, seafood is highly perishable. Spoilage of seafood could be as a result of microbial activity, autolysis or chemical oxidation. Microbial activity constitutes more spoilage than others. Spoilage bacteria are commonly Gram negative and produce off odours and flavours in seafood as a result of their metabolic activities. Storage temperature, handling and packaging conditions affect microbial growth and thus the shelf-life of seafood. Due to the complexity of the microbial communities in seafood, culture dependent methods of detection may not be useful, hence the need for culture independent methods are necessary to understand the diversity of microbiota and spoilage process. Similarly, the volatile organic compounds released by spoilage bacteria are not fully understood in some seafood. This review therefore highlights current knowledge and understanding of seafood spoilage microbiota, volatile organic compounds, effects of storage temperature and packaging conditions on quality of seafood. PMID- 29478711 TI - Possible X chromosome-linked transmission of ovarian cancer. PMID- 29478712 TI - Ultra-processed foods might increase cancer risk. PMID- 29478713 TI - Tokishakuyakusan ameliorates spatial memory deficits induced by ovariectomy combined with beta-amyloid in rats. AB - Previously, we reported that ovariectomy (OVX) combined with beta-amyloid peptide (Abeta) impaired spatial memory by decreasing extracellular acetylcholine (ACh) levels in the dorsal hippocampus. Here, we investigated the effect of tokishakuyakusan (TSS), a Kampo medicine, on the impairment of spatial memory induced by OVX combined with Abeta in rats. Repeated administration of TSS (300 mg/kg, p.o.) significantly decreased the number of errors in the eight-arm radial maze test. Though TSS had no effect on extracellular ACh levels at baseline, TSS significantly increased extracellular ACh levels in the dorsal hippocampus. These results suggest that TSS improves the impairment of spatial memory induced by OVX combined with Abeta by (at least in part) increasing extracellular ACh levels in the dorsal hippocampus. PMID- 29478714 TI - Transient receptor potential vanilloid 1 and transient receptor potential ankyrin 1 contribute to the progression of colonic inflammation in dextran sulfate sodium induced colitis in mice: Links to calcitonin gene-related peptide and substance P. AB - Transient receptor potential (TRP) vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1), which are non-selective cation channels, play important roles in the sensation of pain. This study investigated the roles of TRPV1 and TRPA1 in dextran sulfate sodium (DSS)-induced murine colitis. DSS (2%) administered for 7 days caused severe colitis that was significantly less severe in TRPV1-deficient (TRPV1KO) and TRPA1-deficient (TRPA1KO) mice than that in wild-type (WT) mice. Similar colitis attenuations were observed in TRPV1KO and TRPA1KO mice but not in WT mice that had been transplanted with bone marrow cells from WT, TRPA1KO, or TRPV1KO mice. DSS treatment upregulated calcitonin gene-relative peptide (CGRP)- and substance P (SP)-positive nerve fibers in the colonic mucosa of WT mice. TRPV1KO and TRPA1KO mice showed significant reductions in the DSS-induced upregulation of SP, but the DSS-induced upregulation of CGRP was not reduced. Sensory deafferentation evoked by pretreatment with high doses of capsaicin markedly exacerbated DSS-induced colitis with reductions in DSS-induced upregulation of SP and CGRP-positive nerve fibers. These findings suggest that neuronal TRPV1 and TRPA1 contribute to the progression of colonic inflammation. While these responses may be mediated by the upregulation of SP-mediated deleterious mechanisms, CGRP may be associated with protective mechanisms. PMID- 29478715 TI - Validated chromatographic method for the simultaneous determination of eight drugs (morphine, ropivacaine, bupivacaine, baclofen, clonidine, sufentanil, fentanyl and ziconotide) for intrathecal analgesia. AB - Intrathecal analgesia has increased over the past two decades in various indications: chronic refractory pain from cancerous or non-cancerous origins, spasticity. These different indications involve the use of different molecules alone or in combination such as morphine, ropivacaine, bupivacaine, fentanyl, sufentanil, clonidine, baclofen and ziconotide. Pump refills are prepared at the pharmacy under a laminar flow hood. An analytical control should be carried out before release of the preparation. A new method of analytical control by chromatography has been developed and validated according to the International Conference on Harmonization guideline in order to secure the production process. PMID- 29478716 TI - [Study of the deadlines for the use after sterilization of hot-sealable bags and sheaths]. AB - INTRODUCTION: The choice of packaging is crucial for the sterility of a reusable medical device. The use-by dates for sterile barrier systems (SBSs) are currently determined solely on the basis of an empirical rating scale developed in 1985. The objective of our work is to validate in a scientific way this deadline for the use of SBS for heat-sealable sleeves and bags, with protective packaging. MATERIALS AND METHODS: Thirty SBSs were tested after different storage periods ; six, nine and twelve months. They contained five different types of medical devices, followed the different sterilization steps and were stored in the operating room. The SBSs have or have not been folded in order to analyze this practice in our unit as well. Various tests were carried out on the paper side of the SBS, the plastic side and the welds. RESULTS: After 6 months of storage, SBS are still sterile. After 9 and 12 months, the results are more moderate. Folding the SBS will affect the weld, regardless of the storage time. DISCUSSION: This study allowed us to extend all our expiration dates up to 6 months, to stop the habit of folding the SBS and to become aware of the importance of having a size of SBS adapted to the different devices to be packaged and lastly, to protect the ends. CONCLUSION: Each sterilization unit must carry out its own study and risk analysis because the determination of shelf life periods depends on many factors. PMID- 29478717 TI - Propafenone for supraventricular arrhythmias in septic shock-Comparison to amiodarone and metoprolol. PMID- 29478719 TI - Social and Individual Influences on Tractor Operating Practices of Young Adult Agricultural Workers. AB - PURPOSE: Tractor-related incidents are the leading cause of agricultural-related fatalities in the United States. Injuries from rollovers can be prevented by equipping tractors with rollover protective structures (ROPS, an engineering approach) and by using seatbelts (a behavior-based approach). While adult farmers report low seatbelt use and frequent use of tractors without ROPS, it is unknown whether the young adult population has adopted similar tractor driving practices. This study was designed to identify tractor operating practices among young adult agricultural workers and the influence of supervisors, peers, and parents on their safety behaviors. METHODS: An online survey was conducted among college students enrolled in agricultural science classes in four Midwestern colleges and universities. Participants answered questions about their tractor operating practices, the influence of supervisors, peers, parents, and individual risk taking tendencies on their workplace practices. A tractor operation safety score was estimated from participants' responses. Linear regression was used to examine the association of these influences and the tractor operation safety score. RESULTS: Of the 193 respondents, most (78.8%) reported that they never or rarely wear a seatbelt when operating a tractor with a ROPS. Supervisory influences, such as being negatively evaluated by a supervisor, were found to be more strongly associated with tractor operating behaviors than peer or parent influence. CONCLUSIONS: Young adult agricultural workers frequently reported unsafe tractor operating behaviors. Supervisors were found to have the most influence over reported behaviors of young adult agricultural workers. PMID- 29478718 TI - Determination of neurotensin projections to the ventral tegmental area in mice. AB - Pharmacologic treatment with the neuropeptide neurotensin (Nts) modifies motivated behaviors such as feeding, locomotor activity, and reproduction. Dopamine (DA) neurons of the ventral tegmental area (VTA) control these behaviors, and Nts directly modulates the activity of DA neurons via Nts receptor 1. While Nts sources to the VTA have been described in starlings and rats, the endogenous sources of Nts to the VTA of mice remain incompletely understood, impeding determination of which Nts circuits orchestrate specific behaviors in this model. To overcome this obstacle we injected the retrograde tracer Fluoro Gold into the VTA of mice that express GFP in Nts neurons. Identification of GFP Nts cells that accumulate Fluoro-Gold revealed the Nts afferents to the VTA in mice. Similar to rats, most Nts afferents to the VTA of mice arise from the medial and lateral preoptic areas (POA) and the lateral hypothalamic area (LHA), brain regions that are critical for coordination of feeding and reproduction. Additionally, the VTA receives dense input from Nts neurons in the nucleus accumbens shell (NAsh) of mice, and minor Nts projections from the amygdala and periaqueductal gray area. Collectively, our data reveal multiple populations of Nts neurons that provide direct afferents to the VTA and which may regulate specific aspects of motivated behavior. This work lays the foundation for understanding endogenous Nts actions in the VTA, and how circuit-specific Nts modulation may be useful to correct motivational and affective deficits in neuropsychiatric disease. PMID- 29478721 TI - MC4R Agonists: Structural Overview on Antiobesity Therapeutics. AB - The melanocortin-4 receptor (MC4R) regulates adipose tissue formation and energy homeostasis, and is believed to be a monogenic target for novel antiobesity therapeutics. Several research efforts targeting this receptor have identified potent and selective agonists. While viable agonists have been characterized in vitro, undesirable side effects frequently appeared during clinical trials. The most promising candidates have diverse structures, including linear peptides, cyclic peptides, and small molecules. Herein, we present a compilation of potent MC4R agonists and discuss the pivotal structural differences within those molecules that resulted in good selectivity for MC4R over other melanocortins. We provide insight on recent progress in the field and reflect on directions for development of new agonists. PMID- 29478722 TI - Spontaneous dissection in the left main coronary artery. AB - We present two cases of spontaneous left main stem coronary artery dissection. One was underdiagnosed with suboptimal percutaneous coronary artery intervention followed by acute vessel occlusion again during the hospitalization. The other one was identified and confirmed by intravascular ultrasound, followed by conservative medical treatment, with completed healing of SCAD during two-month follow up. PMID- 29478720 TI - Cellphone Legislation and Self-Reported Behaviors Among Subgroups of Adolescent U.S. Drivers. AB - PURPOSE: The relationship between cellphone use while driving legislation and self-reported adolescent driver behavior is poorly understood, especially across demographic subgroups. This study investigated the relationship between statewide cellphone legislation and cellphone use behaviors across adolescent driver subgroups, including age (16/17 vs. 18), sex, race/ethnicity (white non-Hispanic and others), and rurality (urban or rural). METHODS: Data from the 2011-2014 Traffic Safety Culture Index Surveys were combined with state legislation. The outcomes were self-reported texting and handheld cellphone conversations. The exposure was the presence of a texting or handheld cellphone ban applicable to all drivers (i.e., universal) in the drivers' state of residence. A multilevel, modified Poisson regression model was used to estimate the risk of engaging in these behaviors. RESULTS: Approximately 34% of respondents reported to have driven while conversing, and 37% texted and drove in the 30 days before the survey. Universal handheld calling bans were associated with lower occurrences of cellphone conversations across all groups except rural drivers. Overall, handheld cellphone bans were associated with 55% lower (adjusted risk ratio .45, 95% confidence interval .32-.63) occurrences of cellphone conversations. However, universal texting bans were not associated with fewer texting behaviors in any subgroup. CONCLUSIONS: Universal handheld calling bans may discourage adolescents from engaging in handheld phone conversations, whereas universal texting bans may not fully discourage texting behaviors. More interventional or educational work is necessary, particularly addressing texting while driving. PMID- 29478723 TI - Nasal oxygenation cannula during noninvasive positive pressure ventilation: Two things better than one? PMID- 29478724 TI - Airway ultrasound for the confirmation of endotracheal tube placement in cadavers by military flight medic trainees - A pilot study. AB - OBJECTIVE: Confirming correct endotracheal tube (ETT) placement is a key component of successful airway management. Ultrasound (US) as a tool for the confirmation of ETT placement has been investigated in the hospital setting but not in the pre-hospital setting. We hypothesized that after a short educational session, military flight medic trainees would be able to accurately identify ETT placement in a cadaver model. METHODS: We conducted a prospective, randomized trial in a human cadaver model. Participants received a brief didactic and hands on presentation on airway US techniques. Each participant then performed transtracheal US on cadaver models which were randomly assigned to tracheal or esophageal intubation; time to verbalize ETT location was also recorded. Participants were then asked whether they felt airway US would be a useful adjunctive skill in their practice. RESULTS: Thirty-two military flight medic trainees were enrolled. US had a sensitivity of 66.7% and a specificity of 76.4% for identification of esophageal intubations. The positive predictive value was 71.4% and the negative predictive value was 72.2%. Mean time to report ETT placement was 47.3s. Time did not vary between medics with accurate identification versus inaccurate identification (p=0.176). 83% of participants felt airway US would be a useful adjunctive skill for the confirmation of ETT placement. CONCLUSIONS: Military flight medic trainees can rapidly use airway US to identify ETT placement after a short educational session with moderate sensitivity and specificity. These advanced military medics are interested in learning and implementing this skill into their practice. PMID- 29478725 TI - Oxytocin promotes face-sensitive neural responses to infant and adult faces in mothers. AB - Research utilizing intranasal oxytocin (OT) administration has shown that OT may increase attention and sensitivity to social cues, such as faces. Given the pivotal role of OT in parental behaviors across mammals, the paucity of intranasal OT research investigating responses to social cues in parents and particularly mothers of young children is a critical limitation. In the current study, we recorded cortical event-related potentials (ERPs) to investigate whether intranasal OT affects the early neural responses to emotional faces in mothers of 1-year-old infants. Using a double-blind, within-subjects design, mothers (n = 38) were administered intranasal OT and placebo on separate sessions and presented with happy and sad infant and adult faces while ERP components reflecting face-sensitive brain activation and attention allocation were measured. We hypothesized that ERP responses to faces would be larger in the OT condition and that the effects of OT on ERP responses would be more pronounced for infant faces. The amplitudes of the face-sensitive N170 ERP component were larger in the OT condition to infant and adult faces, but no clear support was found for the hypothesis that the responses to infant faces would be more susceptible to OT effects than the responses to adult faces. The attention sensitive late positive potential (LPP) component was not modulated by intranasal substance condition. The results are in line with the view that OT acts to enhance the perceptual salience of social and emotional stimuli. Demonstrating such effects in mothers of young children encourages further investigation of the potential of intranasal OT to affect the perception of social cues relevant for parent-child interaction. PMID- 29478727 TI - A comparison of pediatric and adult neuromyelitis optica spectrum disorders: A review of clinical manifestation, diagnosis, and treatment. AB - Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disorder of the central nervous system (CNS). Serum immunoglobulin G autoantibodies (NMO-IgG) are identified in the majority of NMOSD patients. The Pediatric form presents before 18 years. Based on the similarity of clinical, neuroimaging, and laboratory characteristics of pediatric NMOSD to those of the adult form, the international panel suggested that adult criteria of NMOSD also are appropriate in pediatric patients. However, the proposed criteria need validation in pediatric patients. This strategy poses challenges to the study design in clinical trials in pediatric NMOSD patients. PMID- 29478726 TI - Influence of gender on delays and early mortality in ST-segment elevation myocardial infarction: Insight from the first French Metaregistry, 2005-2012 patient-level pooled analysis. AB - BACKGROUND: Women show greater mortality after acute myocardial infarction. We decided to investigate whether gender affects delays and impacts in-hospital mortality in a large population. METHODS AND RESULTS: We performed a patient level analysis of 7 French MI registries from different regions from January 2005 to December 2012. All patients with acute STEMI were included within 12 h from symptom onset and a first medical contact with a mobile intensive care unit an emergency department of a hospital with percutaneous coronary intervention facility. Primary study outcomes were STEMI, patient and system, delays. Secondary outcome was in-hospital mortality. 16,733 patients were included with 4021 females (24%). Women were significantly older (mean age 70.6 vs 60.6), with higher diabetes (19.6% vs 15.4%) and hypertension rates (58.7% vs 38.8%). Patient delay was longer in women with adjusted mean difference of 14.4 min (p < 0.001); system delay did not differ. In-hospital death occurred 3 times more in women. This disadvantage persisted strongly adjusting for age, therapeutic strategy and delay with a 1.85 (1.32-2.61) adjusted hazard ratio. CONCLUSIONS: This overview of 16,733 real-life consecutive STEMI patients in prospective registries over an extensive period strongly indicates gender-related discrepancies, highlighting clinically relevant delays in seeking medical attention. However, higher in hospital mortality was not totally explained by clinical characteristics or delays. Dedicated studies of specific mechanisms underlying this female disadvantage are mandatory to reduce this gender gap. PMID- 29478728 TI - Neuromyelitis optica spectrum disorder in the very young: An in depth review of the present data. PMID- 29478729 TI - Pre-existing Immunity to Oncolytic Virus Potentiates Its Immunotherapeutic Efficacy. AB - Anti-viral immunity presents a major hurdle for systemically administered oncolytic viruses (OV). Intratumoral OV therapy has a potential to overcome this problem through activation of anti-tumor immune response, with local and abscopal effects. However, the effects of anti-viral immunity in such a setting are still not well defined. Using Newcastle Disease Virus (NDV) as a model, we explore the effects of pre-existing anti-viral immunity on therapeutic efficacy in syngeneic mouse tumor models. Unexpectedly, we find that while pre-existing immunity to NDV limits its replication in tumors, tumor clearance, abscopal anti-tumor immune effects, and survival are not compromised and, on the contrary, are superior in NDV-immunized mice. These findings demonstrate that pre-existing immunity to NDV may increase its therapeutic efficacy through potentiation of systemic anti-tumor immunity, which provides clinical rationale for repeated therapeutic dosing and prompts investigation of such effects with other OVs. PMID- 29478730 TI - [Contraception in the Roma population living in two low-income neighborhoods of Barcelona (Spain)]. AB - OBJECTIVE: To describe the knowledge and use of contraceptive methods and health services in the Roma population (Kale/Spanish Gitanos) of two low-income neighbourhoods of Barcelona (2011-2015). METHOD: Mixed. Community setting. 1) Descriptive cross-sectional study. We interviewed with a questionnaire a sample of residents of childbearing age. We compared the knowledge and use of contraception and services by ethnic self-identification and sex with adjusted logistic regression models to obtain adjusted odds ratio (ORa) and 95% confidence interval (95%CI). 2) Qualitative descriptive study with ethnographic method. We interviewed 10 Roma residents and three health professionals to explore aspects of contraception, family and roles. We performed a narrative analysis of discourse from the recorded texts. RESULTS: 834 people participated, with an 11.8% self-identified Roma population. With regard to the non-Roma population, more Roma women used tubal ligation (ORa: 3.0; 95%CI: 1.3-7)] and implant (ORa:4.9; 95%CI: 3.1-72), and had better knowledge of IUD (ORa: 2,4; 95%CI: 1,4 4,1), tubal obstruction (ORa: 3,3; 95%CI: 1,1-9,9) and injectables (ORa: 2,4; 95%CI: 1.3-4.4). Roma men used withdrawal more frequently (ORa: 3.6; 95%CI: 1.3 10), a practice confirmed in the qualitative study. Both communities used emergency contraception and health services. In the Roma population, contraception and reproduction are in the hands of women. As abortion is culturally penalized in the Roma population, women use it, but they face it alone. CONCLUSIONS: Gender emerged as a cross-cutting determinant in all issues explored. In the Roma population reproductive control and contraception remain the responsibility of women. Once the family is complete, Roma women use long term contraception. Both populations use health services. PMID- 29478731 TI - An exploratory study of whether pregnancy outcomes influence maternal self reported history of child maltreatment. AB - Childhood maltreatment is common and has been increasingly studied in relation to perinatal outcomes. While retrospective self-report is convenient to use in studies assessing the impact of maltreatment on perinatal outcomes, it may be vulnerable to bias. We assessed bias in reporting of maltreatment with respect to women's experiences of adverse perinatal outcomes in a cohort of 230 women enrolled in studies of maternal mental illness. Each woman provided a self reported history of childhood maltreatment via the Childhood Trauma Questionnaire at two time points: 1) the preconception or prenatal period and 2) the postpartum period. While most women's reports of maltreatment agreed, there was less agreement for physical neglect among women experiencing adverse perinatal outcomes. Further, among women who discrepantly reported maltreatment, those experiencing adverse pregnancy outcomes tended to report physical neglect after delivery but not before, and associations between physical neglect measured after delivery and adverse pregnancy outcomes were larger than associations that assessed physical neglect before delivery. There were larger associations between post-delivery measured maltreatment and perinatal outcomes among women who had not previously been pregnant and in those with higher postpartum depressive symptoms. Although additional larger studies in the general population are necessary to replicate these findings, they suggest retrospective reporting of childhood maltreatment, namely physical neglect, may be prone to systematic differential recall bias with respect to perinatal outcomes. Measures of childhood maltreatment reported before delivery may be needed to validly estimate associations between maternal exposure to childhood physical neglect and perinatal outcomes. PMID- 29478732 TI - Feasibility of Dose-escalated Hypofractionated Chemoradiation in Human Papilloma Virus-negative or Smoking-associated Oropharyngeal Cancer. AB - AIMS: Oropharyngeal squamous cell carcinoma (OPSCC) can be divided into favourable and poor prognostic groups by association with human papilloma virus (HPV) and smoking. This study prospectively investigated a dose-intensified schedule in poor/intermediate prognosis OPSCC. MATERIALS AND METHODS: Patients with p16/HPV-negative or p16-positive N2b OPSCC with a greater than 10 pack-year smoking history were eligible. Patients were planned to receive 64 Gy in 25 fractions with cisplatin. The primary end point was absence of grade 3 mucositis at 3 months. RESULTS: Fifteen patients were recruited over 14 months. All patients completed a minimum of 2 years of follow-up. All patients completed full dose radiotherapy within a median treatment time of 32 days (31-35). Grade 3 mucositis was absent in all patients at 3 months. There was one grade 4 toxicity event due to cisplatin (hypokalaemia). Complete response rates at 3 months were 100% and 93% for local disease and lymph nodes, respectively. One patient developed metastatic disease and subsequently died. Overall survival at 2 years was 93% (95% confidence interval 61-99%). CONCLUSIONS: The schedule of 64 Gy in 25 fractions with concomitant chemotherapy is tolerable in patients with poor and intermediate prognosis OPSCC. PMID- 29478733 TI - Response to a Request for Clarification Regarding the Advanced Radiotherapy Technologies Network (ART-NET). PMID- 29478734 TI - Lupus: The microbiome angle. AB - Microbiota consists of more than 1014 microorganisms that inhabit different areas of the body including the gastrointestinal tract, mainly the mouth and gut. It includes viruses, fungi, protozoa, archaea and bacteria. The microbiota interacts closely with host leading to a dynamic relationship that results in the biological effects observed. Its diverse genetic material (microbiome) interacts closely with the host immune system and cells, and therefore is closely associated with inflammation, immune tolerance, adaptive immunity and autoimmune diseases. Bacterial microbiota, which is the mostly studied lives in harmony with the host and maintains a symbiotic relationship. Therefore it plays an important role in immunological, metabolic, and neurological aspects and thereby the well being of the host. Alteration of the homeostatic environment or the dynamic balance of microorganisms can result in dysbiosis or disease. However, does dysbiosis cause disease, aggravate disease or is the result of the disease remains to be defined, it could be a bit of all three factors. More recently, a number of studies demonstrate that these microorganisms could contribute to disease. Alteration of the tightly balanced composition of bacterial microbiota (dysbiosis) leads to exacerbation, rapid progression and worsening of disease states. It is important to identify the 'healthy' microbes that maintain a healthy environment, the 'sensitive' microbes that go awry with disease, the 'bad' microbes that cause disease and the 'therapeutic' microbes that can help rectify the changes. Increased relative abundance of certain bacterial species has been linked to triggering autoimmune diseases. Despite the burgeoning literature in the field, the molecular mechanisms by which the microbiota impacts the body in health and disease remain largely unknown. In this review, we will discuss recent advancements in our understanding of the gut bacterial microbiota associated with inflammatory and immunological processes and the role they play in the autoimmune disease, systemic lupus erythematosus. PMID- 29478735 TI - Atezolizumab in Platinum-treated Locally Advanced or Metastatic Urothelial Carcinoma: Clinical Experience from an Expanded Access Study in the United States. AB - BACKGROUND: Atezolizumab (anti-programmed death-ligand 1) was approved in the USA, Europe, and elsewhere for treatment-naive and platinum-treated locally advanced/metastatic urothelial carcinoma (mUC). OBJECTIVE: To report efficacy and safety from an atezolizumab expanded access study. DESIGN, SETTING, AND PARTICIPANTS: This single-arm, open-label study enrolled 218 patients at 36 US sites. Key eligibility criteria included progression during/following >=1 platinum-based chemotherapy for mUC or in perioperative setting (progression within 12 mo) and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2. INTERVENTION: Patients received atezolizumab1200mg intravenously every 3 wk until loss of clinical benefit, unacceptable toxicity, consent withdrawal, decision to discontinue, death, atezolizumab commercial availability, or study closure. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Key end points reported herein included Response Evaluation Criteria in Solid Tumors v1.1 objective response rate and duration, disease control rate (DCR; response or stable disease), and safety. RESULTS AND LIMITATIONS: All patients received prior systemic therapy (68% mUC; 27% adjuvant; and 26% neoadjuvant). At baseline, 57% of 214 treated patients had ECOG PS >=1, 19% had hemoglobin <10g/dl, and 25% had liver metastases. Median treatment duration was 9 wk (interquartile range [IQR], 6-12 wk). Median follow-up duration was 2.3 mo (IQR, 1.6-3.4 mo) overall and 2.7 mo (IQR, 2.0-3.5 mo) in patients not known to have died. Seventeen of 114 evaluable patients (15%) had objective responses (16 ongoing at study termination). DCR was 49%. Treatment-related adverse events (mostly fatigue) occurred in 98 of 214 treated patients. CONCLUSIONS: The benefit/risk profile of atezolizumab was consistent with that observed in previous studies, despite pretreatment and poor prognostic factors. These results suggest a potential role for atezolizumab in a broader patient range than typically eligible for phase 1-3 studies. PATIENT SUMMARY: In this expanded access study, atezolizumab was active and tolerable in a range of patients with platinum-treated metastatic urothelial carcinoma. PMID- 29478736 TI - Clinical and Genomic Characterization of Low-Prostate-specific Antigen, High grade Prostate Cancer. AB - BACKGROUND: The consequences of low prostate-specific antigen (PSA) in high-grade (Gleason 8-10) prostate cancer are unknown. OBJECTIVE: To evaluate the clinical implications and genomic features of low-PSA, high-grade disease. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective study of clinical data for 494 793 patients from the National Cancer Data Base and 136 113 patients from the Surveillance, Epidemiology, and End Results program with cT1-4N0M0 prostate cancer (median follow-up 48.9 and 25.0 mo, respectively), and genomic data for 4960 patients from the Decipher Genomic Resource Information Database. Data were collected for 2004-2017. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable Fine-Gray and Cox regressions were used to analyze prostate cancer specific mortality (PCSM) and all-cause mortality, respectively. RESULTS AND LIMITATIONS: For Gleason 8-10 disease, using PSA 4.1-10.0ng/ml (n=38 719) as referent, the distribution of PCSM by PSA was U-shaped, with an adjusted hazard ratio (AHR) of 2.70 for PSA <=2.5ng/ml (n=3862, p<0.001) versus 1.97, 1.36, and 2.56 for PSA of 2.6-4.0 (n=4199), 10.1-20.0 (n=17 372), and >20.0ng/ml (n=16 114), respectively. By contrast, the distribution of PCSM by PSA was linear for Gleason <=7 (using PSA 4.1-10.0ng/ml as the referent, n=359 898), with an AHR of 0.41 (p=0.13) for PSA <=2.5ng/ml (n=37 812) versus 1.38, 2.28, and 4.61 for PSA of 2.6-4.0 (n=54 152), 10.1-20.0 (n=63 319), and >20.0ng/ml (n=35 459), respectively (pinteraction<0.001). Gleason 8-10, PSA <=2.5ng/ml disease had a significantly higher PCSM than standard high-risk/very high-risk disease with PSA >2.5ng/ml (AHR 2.15, p=0.002; 47-mo PCSM 14% vs 4.9%). Among Gleason 8-10 patients treated with radiotherapy, androgen deprivation therapy was associated with a survival benefit for PSA >2.5ng/ml (AHR 0.87; p<0.001) but not <=2.5ng/ml (AHR 1.36; p=0.084; pinteraction=0.021). For Gleason 8-10 tumors, PSA <=2.5ng/ml was associated with higher expression of neuroendocrine/small-cell markers compared to >2.5ng/ml (p=0.046), with no such relationship for Gleason <=7 disease. CONCLUSIONS: Low-PSA, high-grade prostate cancer has very high risk for PCSM, potentially responds poorly to androgen deprivation therapy, and is associated with neuroendocrine genomic features. PATIENT SUMMARY: In this study, we found that low-prostate-specific antigen, high-grade prostate cancer has a very high risk for prostate cancer death, may not respond well to androgen deprivation therapy, and is associated with neuroendocrine genomic features. These findings suggest that current nomograms and treatment paradigms may need modification. PMID- 29478738 TI - Startles, Stiffness, and SLC6A5: Do You Know the Condition? PMID- 29478737 TI - Sequential drain amylase to guide drain removal following pancreatectomy. AB - BACKGROUND: Although used as criterion for early drain removal, postoperative day (POD) 1 drain fluid amylase (DFA) <= 5000 U/L has low negative predictive value for clinically relevant postoperative pancreatic fistula (CR-POPF). It was hypothesized that POD3 DFA <= 350 could provide further information to guide early drain removal. METHODS: Data from a pancreas surgery consortium database for pancreatoduodenectomy and distal pancreatectomy patients were analyzed retrospectively. Those patients without drains or POD 1 and 3 DFA data were excluded. Patients with POD1 DFA <= 5000 were divided into groups based on POD3 DFA: Group A (<=350) and Group B (>350). Operative characteristics and 60-day outcomes were compared using chi-square test. RESULTS: Among 687 patients in the database, all data were available for 380. Fifty-five (14.5%) had a POD1 DFA > 5000. Among 325 with POD1 DFA <= 5000, 254 (78.2%) were in Group A and 71 (21.8%) in Group B. Complications (35 (49.3%) vs 87 (34.4%); p = 0.021) and CR-POPF (13 (18.3%) vs 10 (3.9%); p < 0.001) were more frequent in Group B. CONCLUSIONS: In patients with POD1 DFA <= 5000, POD3 DFA <= 350 may be a practical test to guide safe early drain removal. Further prospective testing may be useful. PMID- 29478739 TI - Role of neoadjuvant chemoradiotherapy in clinical T2N0M0 esophageal cancer: A population-based cohort study. AB - BACKGROUND: The aim of this population-based cohort study was to determine whether the addition of neoadjuvant chemoradiotherapy (nCRT) to surgery is associated with improved pathologic outcomes and survival in patients with cT2N0M0 esophageal cancer. METHODS: Patients who underwent nCRT followed by surgery or surgery alone for cT2N0M0 esophageal cancer were identified from The Netherlands Cancer Registry database (2005-2014). Accuracy of clinical staging was assessed using the resection specimen as gold standard. After propensity score matching, influences of both treatment strategies on radical resection (R0) rates and overall survival were compared. RESULTS: In total 533 patients were included; 353 underwent nCRT followed by surgery and 180 underwent surgery alone. In the nCRT group 32% of patients achieved a pathologic complete response. Clinical understaging was observed in 62% of the patients in the surgery alone group based on pT-stage (n = 30, 27%), pN-stage (n = 26, 23%), or both (n = 55, 50%). Propensity score matching resulted in 78 patients who underwent nCRT plus surgery versus 78 who underwent surgery alone. In the nCRT group radical resections were more frequently observed (99% vs. 89% p = 0.031) and resulted in improved 5-year overall survival (46% vs. 33%, p = 0.017). CONCLUSION: In this population-based study, clinical staging of cT2N0M0 esophageal cancer was highly inaccurate. Compared to surgery alone, neoadjuvant chemoradiotherapy was associated with higher radical resection rates and improved overall survival. PMID- 29478740 TI - Optimisation of breast MRI compatibility after sentinel node biopsy with paramagnetic tracers. PMID- 29478742 TI - Clinical and pathological features of "small" GIST (<=2 cm). What is their prognostic value? AB - INTRODUCTION: Small GIST (<2 cm) are tumors whose biological behavior is benign and frequently involutes. Despite their increasing incidence, few studies have addressed the characteristics of these GIST. The aim of this work is to clarify the management of this entity. PATIENTS AND METHOD: The characteristics of <=2 cm GIST were initially described, and then compared with those >2 cm. This series comprises 104 patients and they were divided according to tumor size in 4 groups: tumors which are <=2 cm (group 1, G1), >2 and <= 5 cm (G2), >5 and <= 10 cm (G3) and >10 cm (G4). RESULTS AND DISCUSSION: Most of small GIST were asymptomatic and incidental, and were located in the stomach. There is an association between patients with associated tumors and asymptomatic GIST. A high overall mortality rate of up to 40% is observed being disease-specific mortality 4.5%. The disease specific mortality increases proportionally with size. The overall survival (OS) at 5 years are lower for both <2 cm (61%) and >10 cm (53%) than the rest (85 91%). When analyzing the impact of tumor association on <2 cm GIST, we observed that the OS of patients with non-associated tumors was much higher than in the associated ones (90% vs 32% at 5 years, respectively), while no differences were observed in the disease specific survival. CONCLUSIONS: Small GIST are tumors that are very often incidentally discovered in the course of complementary examinations. Its prognosis is very good, but it depends on the associated tumor. PMID- 29478743 TI - The neutrophil-to-lymphocyte ratio (NLR) predicts short-term and long-term outcomes in gastric cancer patients. AB - BACKGROUND: The preoperative neutrophil-to-lymphocyte ratio (NLR) is a well-known prognostic marker for gastric cancer patients. However, the utility of the NLR in predicting short-term outcomes in gastric cancer patients remains unclear. Here, we investigated whether the preoperative NLR is a predictor of short-term outcomes in gastric cancer patients. METHODS: We retrospectively evaluated 154 consecutive gastric cancer patients. We compared the perioperative outcomes and median survival times (MSTs). In particular, for stage II/III (UICC, 7th edition) gastric cancer patients, we compared median disease-free survival time (MDFST) between the low- and high-NLR groups. RESULTS: Between the low-NLR group (n = 110) and the high-NLR group (n = 44), significant differences were observed in perioperative outcomes, including postoperative complications (3 (2.7%) vs. 5 (11.3%); p = 0.015), intraoperative blood loss (158 +/- 168 g vs. 232 +/- 433 g; p = 0.022), and intraoperative blood transfusions (0 vs. 3 (6.8%); p = 0.042). MSTs and MDFSTs were also significantly different (812 vs. 594 days, p = 0.04; and 848 vs. 475 days, p = 0.03, respectively). Multivariate analysis identified the NLR (hazard ratio [HR], 2.015; p = 0.004), Glasgow Prognostic Score (GPS) (HR, 1.533; p = 0.012), and presence of stage III/IV disease (HR, 5.488; p < 0.001), preoperative symptoms (HR, 3.412; p = 0.008), or postoperative complications (HR, 2.698; p < 0.001) as independent prognostic factors. CONCLUSIONS: We suggest that the preoperative NLR is an additional useful predictor of both long-term and short-term outcomes in gastric cancer patients. PMID- 29478744 TI - Tricuspid annulus diameter does not predict the development of tricuspid regurgitation after mitral valve repair for mitral regurgitation due to degenerative diseases. AB - BACKGROUND: Heart valve surgery guidelines suggest that tricuspid valve annuloplasty may be beneficial in patients with a tricuspid annulus (TA) >=40 mm even in the absence of functional tricuspid regurgitation (TR) at the time of surgery for left-sided valve lesions (class 2a). Given the broad spectrum of degenerative diseases that affect the atrioventricular valves, we hypothesize that this measurement might not be predictive of TR after mitral valve (MV) repair. METHODS: The diameter of the TA was measured preoperatively in a cohort of 312 consecutive patients who had isolated MV repair for degenerative diseases. The mean TA diameter was 36 mm (95% confidence interval [CI], 35-37 mm). TA >=40 mm was present in 80 patients. The median duration of echocardiographic follow-up was 6.7 years (interquartile range, 5.4-8.4 years), and was 100% complete. The main study endpoint was postoperative TR of moderate or greater degree. RESULTS: Thirty patients had new or persistent TR at some point during follow-up. The probability of postoperative TR at 7 years was 6.6% (95% CI, 4.6%-9.4%) for all patients, 6.8% (95% CI, 4.6%-10.4%) for TA <40 mm, and 6.0% (95% CI, 2.9%-12.2%) for TA >=40 mm. Preoperative TA diameter was not associated with the odds of postoperative TR in either the univariable or multivariable regression models. In these analyses, preoperative TR was the strongest predictor of postoperative TR. CONCLUSIONS: TA >=40 mm is not predictive of the development of postoperative TR after MV repair for degenerative diseases. PMID- 29478745 TI - Maternal separation increases alcohol-drinking behaviour and reduces endocannabinoid levels in the mouse striatum and prefrontal cortex. AB - Childhood adversity is associated with an increased risk of mood, anxiety and substance use disorders. Maternal separation is a reliable rodent model of early life adversity that leads to depression-like symptoms, which may increase the vulnerability to alcohol consumption during adolescence. However, the specific alterations in the pattern of alcohol consumption induced by maternal separation and the underlying molecular mechanisms are still unclear. The purpose of this study is to evaluate the long-term effects of maternal separation with early weaning (MSEW) on emotional and social behaviour, alcohol rewarding properties, and alcohol consumption, abstinence and relapse in adolescent male C57BL/6 mice. In addition, endocannabinoid and monoamine levels were analysed in discrete brain areas. Results showed that MSEW mice presented emotional alterations related to depressive-like behaviour and modified endocannabinoid levels in the striatum and the prefrontal cortex. MSEW mice also showed impairments in alcohol-induced conditioned place preference and higher alcohol intake in a model of binge drinking. Moreover, MSEW animals displayed a higher propensity to relapse in the two-bottle choice paradigm following a period of alcohol abstinence associated with reduced monoamine levels in the striatum. Such results indicate that exposure to early life stress increased the vulnerability to alcohol binge drinking during adolescence, which may be partially explained by decreased sensitivity to alcohol rewarding properties and the ability to potentiate alcohol intake following a period of abstinence. PMID- 29478746 TI - Methylphenidate alters monoaminergic and metabolic pathways in the cerebellum of adolescent rats. AB - Abnormalities in the cerebellar circuitry have been suggested to contribute to some of the symptoms associated with attention deficit hyperactivity disorder (ADHD). The psychostimulant methylphenidate (MPH) is the major drug for treating this condition. Here, the effects of acute (2.0 mg/kg and 5.0 mg/kg) and chronic (2.0 mg/kg, twice daily for 15 days) MPH treatments were investigated in adolescent (35-40 days old) rats on monoaminergic and metabolic markers in the cerebellum. Data acquired indicates that acute MPH treatment (2.0 mg/kg) decreased cerebellar vesicular monoamine transporter (VMAT2) density, while chronic treatment caused an increase. In contrast, protein levels of tyrosine hydroxylase (TH) and the dopamine D1 receptor were not significantly altered by neither acute nor chronic MPH treatment. In addition, while chronic but not acute MPH treatment significantly enhanced dopamine turnover (DOPAC/dopamine) in the cerebellum, levels of dopamine and homovanillic acid (HVA) were not altered. Acute MPH (5.0 mg/kg) significantly modified levels of a range of cerebellar metabolites with similar trends also detected for the lower dose (2.0 mg/kg). In this regard, acute MPH tended to decrease cerebellar metabolites associated with energy consumption and excitatory neurotransmission including glutamate, glutamine, N-acetyl aspartate, and inosine. Conversely, levels of some metabolites associated with inhibitory neurotransmission, including GABA and glycine were reduced by acute (5.0 mg/kg) MPH, together with acetate, aspartate and hypoxanthine. In conclusion, this study demonstrated that MPH alters cerebellar biochemistry, and that this effect depends on both dose and duration of treatment. The therapeutic significance of these results requires further investigation. PMID- 29478741 TI - Treatment challenges in and outside a network setting: Head and neck cancers. AB - Head and neck cancer (HNC) is a rare disease that can affect different sites and is characterized by variable incidence and 5-year survival rates across Europe. Multiple factors need to be considered when choosing the most appropriate treatment for HNC patients, such as age, comorbidities, social issues, and especially whether to prefer surgery or radiation-based protocols. Given the complexity of this scenario, the creation of a highly specialized multidisciplinary team is recommended to guarantee the best oncological outcome and prevent or adequately treat any adverse effect. Data from literature suggest that the multidisciplinary team-based approach is beneficial for HNC patients and lead to improved survival rates. This result is likely due to improved diagnostic and staging accuracy, a more efficacious therapeutic approach and enhanced communication across disciplines. Despite the benefit of MTD, it must be noted that this approach requires considerable time, effort and financial resources and is usually more frequent in highly organized and high-volume centers. Literature data on clinical research suggest that patients treated in high-accrual centers report better treatment outcomes compared to patients treated in low-volume centers, where a lower radiotherapy-compliance and worst overall survival have been reported. There is general agreement that treatment of rare cancers such as HNC should be concentrated in high volume, specialized and multidisciplinary centers. In order to achieve this goal, the creation of international collaboration network is fundamental. The European Reference Networks for example aim to create an international virtual advisory board, whose objectives are the exchange of expertise, training, clinical collaboration and the reduction of disparities and enhancement of rationalize migration across Europe. The purpose of our work is to review all aspects and challenges in and outside this network setting planned for the management of HNC patients. PMID- 29478747 TI - Congenital generalized lipodystrophy in Taiwan. AB - BACKGROUND: Congenital generalized lipodystrophy (CGL) is a rare disorder characterized by scarce adipose tissue. This disease is distributed worldwide, but little is known about these patients in the Chinese population. Here, we delineate the phenotype and prognosis of CGL in our cohort. METHODS: Patients diagnosed with CGL from 8 medical centers were reviewed. The initial presentation, laboratory findings, and molecular testing were retrospectively analyzed. RESULTS: A total of 16 patients were analyzed, and the current median age was 3.5 years (range, 9 months-17.5 years). In all patients, molecular results confirmed BSCL2 mutation. c.782dupG (p.Ile262Hisfs*12) was the most common genotype identified. All patients had triangular faces and muscular hypertrophy. In addition, 75% presented with hepatomegaly, 19% had cardiomegaly, and 44% exhibited acanthosis nigricans. Developmental delay was noted in 5 out of 9 patients (56%) with a median developmental quotient (DQ)/intelligence quotient (IQ) of 61. Thirteen patients (81.3%) had high triglyceride levels. Eight patients received leptin analysis, and 7 of them (88%) had low leptin levels. One patient exclusively received a lipid-lowering drug, 4 patients were exclusively placed on a fat-restricted diet, 5 patients were administered combination therapy, and 5 patients received no treatment. Three patients (19%) who developed diabetes mellitus received both oral hypoglycemic agents and insulin. Three patients (19%) experienced loss of ambulation and died prematurely. CONCLUSIONS: Our findings highlight the uniqueness of the genotype and phenotype in our cohort. Further long-term surveillance for comorbidities is necessary for early detection and management of these patients. PMID- 29478748 TI - Synchronization of multiple 3-DOF helicopters under actuator faults and saturations with prescribed performance. AB - The distributed cooperative control strategy is proposed to make the networked nonlinear 3-DOF helicopters achieve the attitude synchronization in the presence of actuator faults and saturations. Based on robust adaptive control, the proposed control method can both compensate the uncertain partial loss of control effectiveness and deal with the system uncertainties. To address actuator saturation problem, the control scheme is designed to ensure that the saturation constraint on the actuation will not be violated during the operation in spite of the actuator faults. It is shown that with the proposed control strategy, both the tracking errors of the leading helicopter and the attitude synchronization errors of each following helicopter are bounded in the existence of faulty actuators and actuator saturations. Moreover, the state responses of the entire group would not exceed the predesigned performance functions which are totally independent from the underlaying interaction topology. Simulation results illustrate the effectiveness of the proposed control scheme. PMID- 29478749 TI - Internal model control for industrial wireless plant using WirelessHART hardware in-the-loop simulator. AB - The emergence of wireless technologies such as WirelessHART and ISA100 Wireless for deployment at industrial process plants has urged the need for research and development in wireless control. This is in view of the fact that the recent application is mainly in monitoring domain due to lack of confidence in control aspect. WirelessHART has an edge over its counterpart as it is based on the successful Wired HART protocol with over 30 million devices as of 2009. Recent works on control have primarily focused on maintaining the traditional PID control structure which is proven not adequate for the wireless environment. In contrast, Internal Model Control (IMC), a promising technique for delay compensation, disturbance rejection and setpoint tracking has not been investigated in the context of WirelessHART. Therefore, this paper discusses the control design using IMC approach with a focus on wireless processes. The simulation and experimental results using real-time WirelessHART hardware-in-the loop simulator (WH-HILS) indicate that the proposed approach is more robust to delay variation of the network than the PID. PMID- 29478750 TI - Adaptive output-feedback control for switched stochastic uncertain nonlinear systems with time-varying delay. AB - This paper addresses the problem of adaptive output-feedback control for a class of switched stochastic time-delay nonlinear systems with uncertain output function, where both the control coefficients and time-varying delay are unknown. The drift and diffusion terms are subject to unknown homogeneous growth condition. By virtue of adding a power integrator technique, an adaptive output feedback controller is designed to render that the closed-loop system is bounded in probability, and the state of switched stochastic nonlinear system can be globally regulated to the origin almost surely. A numerical example is provided to demonstrate the validity of the proposed control method. PMID- 29478751 TI - YBX1 at the crossroads of non-coding transcriptome, exosomal, and cytoplasmic granular signaling. AB - YBX1 (Y box binding protein 1) is an RNA-/DNA-binding multifunctional protein harboring the classical cold shock protein (CSD) domain, an A/P domain, and a long C-terminal domain with alternating positively and negatively charged amino acids. It is a well-established oncogenic transcriptional factor, and regulates apoptosis, translation, cell proliferation, mRNA splicing, repair, differentiation, and stress response. The non-coding transcriptome has added yet another layer of complexity to the YBX1-mediated master regulation of cellular functions. Interestingly, YBX1 has been shown to localize to cytoplasmic granules such as P granules and stress granules. These granules regulate the non-coding transcriptome profile as well as mRNA translation and degradation. In this review, we discuss the recent findings on YBX1 signaling as mediated by various classes of non-coding RNAs, and on the functions of YBX1 at P granules, stress granules, exosomes, and mitochondria. YBX1 is a well-established target for cancer therapy and understanding its functions at organelles and ncRNA transcriptomes will shed new insights for devising organelle based anti-cancer therapies. PMID- 29478752 TI - Towards the introduction of pneumococcal conjugate vaccines in Bhutan: A cost utility analysis to determine the optimal policy option. AB - BACKGROUND: Due to competing health priorities and limited resources, many low income countries, even those with a high disease burden, are not able to introduce pneumococcal conjugate vaccines. OBJECTIVE: To determine the cost utility of 10- and 13-valent pneumococcal conjugate vaccines (PCV10 and PCV13) compared to no vaccination in Bhutan. METHODS: A model-based cost-utility analysis was performed in the Bhutanese context using a government perspective. A Markov simulation model with one-year cycle length was used to estimate the costs and outcomes of three options: PCV10, PCV13 and no PCV programmes for a lifetime horizon. A discount rate of 3% per annum was applied. Results are presented using an incremental cost-effectiveness ratio (ICER) in United State Dollar per quality adjusted life year (QALY) gained (USD 1 = Ngultrum 65). A one-way sensitivity analysis and a probabilistic sensitivity analysis were conducted to assess uncertainty. RESULTS: Compared to no vaccination, PCV10 and PCV13 gained 0.0006 and 0.0007 QALYs with additional lifetime costs of USD 0.02 and USD 0.03 per person, respectively. PCV10 and PCV13 generated ICERs of USD 36 and USD 40 per QALY gained compared to no vaccination. In addition, PCV13 produced an ICER of USD 92 compared with PCV10. When including PCV into the Expanded Programme on Immunization, the total 5-year budgetary requirement is anticipated to increase to USD. 3.77 million for PCV10 and USD 3.75 million for PCV13. Moreover, the full time equivalent (FTE) of one health assistant would increase by 2.0 per year while the FTE of other health workers can be reduced each year, particularly of specialist (0.6-1.1 FTE) and nurse (1-1.6 FTE). CONCLUSION: At the suggested threshold of 1xGDP per capita equivalent to USD 2708, both PCVs are cost effective in Bhutan and we recommend that they be included in the routine immunization programme. PMID- 29478753 TI - Recurrent intussusception among infants less than 2 years of age in Vietnam. AB - In some settings, rotavirus vaccines have been associated with a low-level risk of intussusception, the most common cause of bowel obstruction in infants. As Vietnam prepares to introduce rotavirus vaccine into the national immunization program, we sought to better characterize the epidemiology of recurrent intussusception. We enrolled children <2 years of age who were hospitalized for intussusception retrospectively from January 2013 through December 2014 and prospectively from January 2015 through December 2016 at 2 hospitals in Vietnam. We enrolled 2477 children. Nearly all children were successfully treated by enema with low surgery rate (1%). We found 10% of children (n = 254) experienced at least once recurrence (range: 1-6) and 57% of first recurrences happened within the first 12 weeks after treatment of the first episode. The median age at first intussusception was 13 months for children without a recurrent episode and 10 months for children with a recurrence. The symptoms of the recurrent cases were milder with less vomiting (67%), bloody stool (7%) and fever (10%) compared to the initial cases (p < 0.01). We found the rate of recurrences following enema reduction of intussusception to be similar to that reported from other countries. Due to the high rate of intussusception and recurrent episodes in Vietnam, a better understanding of the cause of recurrent intussusception will be critical in assessing intussusception cases after rotavirus introduction. PMID- 29478756 TI - Continued research into nonverbal language in chest pain of coronary origin. PMID- 29478755 TI - New insights into physiopathology of immunodeficiency-associated vaccine-derived poliovirus infection; systematic review of over 5 decades of data. AB - Widespread administration of oral poliovirus vaccine (OPV) has decreased global incidence of poliomyelitis by ~99.9%. However, the emergence of vaccine-derived polioviruses (VDPVs) is threatening polio-eradication program. Primary immunodeficiency (PID) patients are at higher risks of vaccine-associated paralytic poliomyelitis (VAPP) and prolonged excretion of immunodeficiency associated VDPV (iVDPV). We searched Embase, Medline, Science direct, Scopus, Web of Science, and CDC and WHO databases by 30 September 2016, for all reports of iVDPV cases. Patient-level data were extracted form eligible studies. Data on immunization coverage and income-level of countries were extracted from WHO/UNICEF and the WORLD BANK databases, respectively. We assessed bivariate associations between immunological, clinical, and virological parameters, and exploited multivariable modeling to identify independent determinants of poliovirus evolution and patients' outcomes. Study protocol was registered with PROSPERO (CRD42016052931). 4329 duplicate-removed titles were screened. A total of 107 iVDPV cases were identified from 68 eligible articles. The majority of cases were from higher income countries with high polio-immunization coverage. 74 (69.81%) patients developed VAPP. Combined immunodeficiency patients showed lower rates of VAPP (p < .001) and infection clearance (p = .02), compared to humoral immunodeficiency patients. The rate of poliovirus genomic evolution was higher at early stages of replication, decreasing over time until reaching a steady state. Independent of replication duration, higher extent (p = .04) and rates (p = .03) of genome divergence contributed to a less likelihood of virus clearance. PID type (p < .001), VAPP occurrence (p = .008), and income-level of country (p = .04) independently influenced patients' survival. With the use of OPV, new iVDPVs will emerge independent of the rate of immunization coverage. Inherent features of PIDs contribute to the clinical course of iVDPV infection and virus evolution. This finding could shed further light on poliomyelitis pathogenesis and iVDPV evolution pattern. It also has implications for public health, the polio eradication effort and the development of effective antiviral interventions. PMID- 29478754 TI - Reduced nontypeable Haemophilus influenzae lower airway infection in children with chronic endobronchial suppuration vaccinated with the 10-valent pneumococcal H. influenzae protein D conjugate vaccine. AB - BACKGROUND: Nontypeable Haemophilus influenzae (NTHi), the most common bacterial lower airway infection in children with protracted bacterial bronchitis, is associated with progression to bronchiectasis. We determined whether vaccination with 10-valent pneumococcal NTHi protein-D conjugate vaccine (PHiD-CV) reduced NTHi lower airway infection compared to children not PHiD-CV-vaccinated. Our unique childhood vaccination schedule and prospective 9-year bronchoalveolar lavage (BAL) collection provided an exclusive opportunity to examine this hypothesis. METHODS: Paired BAL fluids and nasopharyngeal (NP) swabs were collected from 543 children (2007-2016) undergoing bronchoscopy for chronic cough. Children who received a primary course of >=2 doses of one pneumococcal conjugate vaccine (PCV) and <2 doses of another PCV were included in each vaccine group. Logistic regression determined associations between NTHi lower airway infection (>=104 colony-forming units/mL BAL) and age, sex, Indigenous status, antibiotic exposure, and PHiD-CV vaccination. RESULTS: Of 262 PCV7-vaccinated, 53 PHiD-CV-vaccinated and 166 PCV13-vaccinated children (62 had mixed schedules, <2 PCV doses or missing vaccination data), NTHi lower airway infection was detected in 89 (34%), 9 (17%) and 47 (28%), respectively. On multivariate regression, significant independent factors associated with reduced NTHi lower airway infection were PHiD-CV vaccination (ORadjusted = 0.42, 95%CI 0.19-0.93), macrolide use (ORadjusted = 0.57, 95%CI 0.35-0.93) and increasing age (ORadjusted = 0.88, 95%CI 0.80-0.96). PHiD-CV vaccination had no impact on NTHi NP carriage. CONCLUSIONS: PHiD-CV-vaccinated children were significantly less likely to have NTHi lower airway infection than children not PHiD-CV-vaccinated. PHiD-CV is likely an effective intervention for reducing NTHi endobronchial infection in children at risk of chronic suppurative lung diseases. PMID- 29478757 TI - [Invasive pulmonary aspergillosis]. AB - INTRODUCTION: Invasive pulmonary aspergillosis (IPA) is an important cause of morbidity and mortality in a wide range of patients. Early recognition and diagnosis have become a major focus in improving the management and outcomes of this life-threatening disease. BACKGROUND: IPA typically occurs during a period of severe and prolonged neutropenia. However, solid organ transplant recipients, patients under immunosuppressive therapy or hospitalized in intensive care units are also at risk. The diagnosis is suspected in the presence of a combination of clinical, biological and CT scan evidence. The microbiological diagnostic strategy should be adapted to the patient's profile. Conventional methods with culture and species identification remain the standard but early diagnosis has been improved by the use of biomarkers such as galactomannan antigen in serum or in bronchoalveolar lavage. OUTLOOK: The epidemiology of IPA should change with the increased use of antifungal prophylactic regimens and the arrival of targeted therapies. Other microbiological tools, such as PCR and other biomarkers, are currently being assessed. CONCLUSIONS: IPA must be considered in a wide range of patients. Its prognosis remains poor despite progress in the microbiological diagnosis and therapeutic management. PMID- 29478758 TI - The National Healthcare Safety Network Long-term Care Facility Component early reporting experience: January 2013-December 2015. AB - BACKGROUND: In 2012, the Centers for Disease Control and Prevention launched the Long-term Care Facility (LTCF) Component of the National Healthcare Safety Network (NHSN) designed for LTCFs to monitor Clostridium difficile infections (CDIs), urinary tract infections (UTIs), infections due to multidrug-resistant organisms, including methicillin-resistant Staphylococcus aureus (MRSA), and infection prevention process measures. METHODS: We describe characteristics and reporting patterns of facilities enrolled in the first 3 years of the surveillance system and rate estimates for CDI, UTI, and MRSA data submitted between 2013 and 2015. RESULTS: From 2013-2015, 279 LTCFs were enrolled and eligible to report to the NHSN with variability in reporting from year to year. Crude rate estimates pooled over these 3 years from reporting facilities were 0.98 incident LTCF-onset CDI cases per 10,000 resident days, 0.59 UTI cases per 1,000 resident days, and 0.10 LTCF-onset MRSA cases per 1,000 resident days. CONCLUSIONS: These initial data demonstrate the capability of the NHSN LTCF Component as a national surveillance system for monitoring infections in LTCFs. Further investigation is needed to understand factors associated with successful enrollment and reporting. As participation increases, data from a larger group of LTCFs will be used to establish national baselines and track prevention goals. PMID- 29478759 TI - Adherence to surgical hand antisepsis: Barriers and facilitators in a tertiary care hospital. AB - Although surgical hand antisepsis is paramount to surgical infection prevention, adherence to correct technique may be suboptimal. We conducted direct observations and semistructured interviews to identify barriers and facilitators to appropriate surgical hand antisepsis in a tertiary care hospital. Only 18% (9 out of 50) surgical hand antisepsis observations were fully compliant with the recommended application techniques. Most surgical staff members considered lack of organizational oversight, monitoring, and direct hands-on training as important barriers to adherence. PMID- 29478760 TI - The attributable cost of catheter-associated urinary tract infections in the United States: A systematic review. AB - BACKGROUND: Catheter-associated urinary tract infections (CAUTIs) are the most common healthcare-acquired condition. The attributable cost of CAUTIs is frequently cited to be approximately $1,000. However, there is a paucity of recent literature that confirms this estimate. The purpose of this study was to perform a systematic review of the literature that estimates the attributable cost of CAUTIs in the United States. METHODS: A systematic review was conducted using Pubmed. Studies conducted between the years 2000 and 2017, conducted at a facility within the United States, and that used novel patient-level cost data were included. Attributable cost estimates were adjusted for inflation to 2016 U.S. dollars using the medical care component of the Consumer Price Index. RESULTS: Only 4 articles met our inclusion criteria. Adjusted to 2016 U.S. dollars, the attributable costs of a CAUTI as reported in these studies were: $876 (inpatient cost to the hospital for additional diagnostic tests and medications); $1,764 (inpatient cost to Medicare for non-intensive care unit [ICU] patients); $7,670 (inpatient and outpatient costs to Medicare); $8,398 (inpatient cost to the hospital for pediatric patients); and $10,197 (inpatient cost to Medicare for ICU patients). CONCLUSIONS: The cost of a CAUTI ranges widely depending on population, patient acuity, and cost perspective. Attributable costs likely exceed $1,000. Additional research is needed to assess the full economic effect of CAUTIs. PMID- 29478761 TI - Parallel effect of 4-octylphenol and cyclic adenosine monophosphate (cAMP) alters steroidogenesis, cell viability and ROS production in mice Leydig cells. AB - Over the last decade, there is growing incidence of male reproductive malfunctions. It has been documented that numerous environmental contaminants, such as endocrine disruptors (EDs) may adversely affect the reproductive functions of humans as well as wildlife species. The aim of this in vitro study was to examine the effects of 4-octylphenol (4-OP) on the steroidogenesis in mice Leydig cells. We evaluated the impact of this endocrine disruptor on the cholesterol levels and hormone secretion in a primary culture. Subsequently, we determined the cell viability and generation of reactive oxygen species (ROS) following 4-OP treatment. Isolated mice Leydig cells were cultured in the presence of different 4-OP concentrations (0.04-5.0 MUg/mL) and 1 mM cyclic adenosine-monophosphate during 44 h. Cholesterol levels were determined from the culture medium using photometry. Quantification of steroid secretion was performed by enzyme-linked immunosorbent assay. The cell viability was assessed using the metabolic activity assay, while ROS production was assessed by the chemiluminescence technique. Slightly increased cholesterol levels were recorded following exposure to the whole applied range of 4-OP, without significant changes (P>0.05). In contrast, the secretion of steroid hormones, specifically dehydroepiandrosterone, androstenedione, and testosterone was decreased following exposure to 4-OP. Experimental doses of 4-OP did not affect cell viability significantly; however a moderate decrease was recorded following the higher doses (2.5 and 5.0 MUg/mL) of 4-OP. Furthermore, relative treatment of 4-OP (5.0 MUg/mL) caused a significant (P < 0.001) ROS overproduction in the exposed cells. PMID- 29478762 TI - Do radiation oncology outreach clinics affect the use of radiotherapy? AB - BACKGROUND AND PURPOSE: The scope and effect of radiation oncology (RO) outreach activities within centralized radiotherapy (RT) systems is poorly defined. The purpose of this study was to describe the outreach activities of Ontario's regional cancer centres, and to explore the relationship between radiation oncology (RO) outreach clinics and rates of radiotherapy (RT) utilization at hospitals without RT on site (HWOS-RT). MATERIALS AND METHODS: Ontario RO centres' outreach activities were identified by semi-structured interview. A multivariate analysis determined the association between on-site RT facilities, or presence of RO clinic at HWOS-RT, and RT utilization within one year of diagnosis (RT1Y), for all patients diagnosed with cancer in Ontario in 2011-2012. RESULTS: RO outreach varied widely by region. Of the largest 58 diagnosing hospitals, 14 had RT on-site, 19 had no RT but RO outreach clinic(s) and 25 had no RT or RO clinic. RT was used more frequently for patients diagnosed at hospitals with on-site RT compared to those at HWOS-RT (RT1Y = 35% vs. 29%, RR = 1.32 [95% CI 1.27-1.38]). For HWOS-RT, RT was used more frequently if there was an RO clinic (RT1Y = 31% vs. 29%, RR = 1.06 [95% CI 1.02-1.10]). CONCLUSIONS: RO outreach clinics were associated with a small but significant increase in RT utilization. There is opportunity to improve access to RT by optimizing the effectiveness of RO outreach. PMID- 29478764 TI - Environmental and phenotypic heterogeneity of populations at the trailing range edge of the habitat-forming macroalga Fucus serratus. AB - Empirical work on the dynamics of range limits of species distributions often lack replications of edge populations. We compared the local environment and performance of two groups of geographically peripheral populations of the foundation intertidal alga Fucus serratus L. at its southern range boundary in the NW Iberian Peninsula. Two populations were located on the Western Galician coast in large embayments or rias, and the other two on a Northern open coastal stretch in Lugo province. Sharp differences were detected in the local environment and performance of the two groups of populations. While recruitment was quite consistent throughout the year in rias, it was very limited and variable in Lugo. Furthermore, thalli from rias were severely damaged following their transplantation in Lugo, and poor conditions of local adult plants were detected there in subsequent years. These results suggest a higher vulnerability of Lugo populations under new climate conditions, while western rias, strongly influenced by upwelling events, feasibly act as contemporary refugia for this species. If sustained over time, these refugia may mitigate the retreat of the seaweed' rear-edge predicted by large spatial scale models. PMID- 29478763 TI - Esophagus toxicity after stereotactic and hypofractionated radiotherapy for central lung tumors: Normal tissue complication probability modeling. AB - PURPOSE: To correlate esophagus toxicity and dose-volume histogram (DVH) parameters in order to assess risks, and derive a Normal Tissue Complication Probability (NTCP) model. METHODS AND MATERIALS: Patients with a central lung tumor from 2 centers, who underwent stereotactic or hypofractionated radiotherapy (<=12 fractions), were analyzed. Doses were recalculated to an equivalent dose of 2 Gy with an alpha/beta ratio of 10 (EQD210). The esophagus was manually delineated and DVH-parameters (Dmax,EQD2, D1cc,EQD2, D2cc,EQD2, D5cc,EQD2) were analyzed and used for NTCP modeling based on logistic regression analysis. RESULTS: Two-hundred-and-thirty-one patients with 252 tumors were eligible. No acute or late grade 3-5 esophageal toxicity was reported. Acute grade 1-2 esophagus toxicity was recorded in 38 patients (17%). All DVH-parameters were significantly higher in patients with toxicity. NTCP models showed a 50% probability of acute grade 1-2 toxicity at a Dmax of 67 Gy EQD210 and D1cc of 42 Gy EQD210. No difference in overall survival was observed between patients with and without toxicity (p = 0.428). CONCLUSION: As no grade 3-5 esophageal toxicity was observed in our cohort, a Dmax of 56 Gy EQD210 and a D5cc of 35.5 Gy EQD210 could be delivered without high risks of severe toxicity. The NTCP models of this study might be used as practical guidelines for the treatment of central lung tumors with stereotactic radiotherapy. PMID- 29478765 TI - Macroalgal response to a warmer ocean with higher CO2 concentration. AB - Primary production and respiration rates were studied for six seaweed species (Cystoseira abies-marina, Lobophora variegata, Pterocladiella capillacea, Canistrocarpus cervicornis, Padina pavonica and Corallina caespitosa) from Subtropical North-East Atlantic, to estimate the combined effects of different pH and temperature levels. Macroalgal samples were cultured at temperature and pH combinations ranging from current levels to those predicted for the next century (19, 21, 23, 25 degrees C, pH: 8.1, 7.7 and 7.4). Decreased pH had a positive effect on short-term production of the studied species. Raised temperatures had a more varied and species dependent effect on short term primary production. Thermophilic algae increased their production at higher temperatures, while temperate species were more productive at lower or present temperature conditions. Temperature also affected algal respiration rates, which were higher at low temperature levels. The results suggest that biomass and productivity of the more tropical species in coastal ecosystems would be enhanced by future ocean conditions. PMID- 29478766 TI - Physiological acclimation of the green tidal alga Ulva prolifera to a fast changing environment. AB - To aid early warning and prevent the outbreak of green tides in the Yellow Sea, both the growth and photosynthetic performance of Ulva prolifera were studied after culture in different temperatures (18, 22, and 26 degrees C) and light intensities (44, 160, and 280 MUmol m-2.s-1). Furthermore, their instantaneous net photosynthetic performance (INPP) was studied to determine the resulting environmental acclimation. The relative growth rates of U. prolifera significantly decreased in response to increasing temperature, while they increased with increasing light intensity. Culture at higher light intensities significantly increased INPP, while higher temperatures decreased the INPP. Culture at lower temperatures lowered INPP, while increased growth temperature increased the effect. These results suggest that high temperatures during the cold season inhibited U. prolifera growth. However, low temperatures during the warm season increase biomass and may cause a large-scale green tide. These results help to understand the correlation between U. prolifera blooms and extreme weather. PMID- 29478767 TI - Food availability on the shore: Linking epilithic and planktonic microalgae to the food ingested by two intertidal gastropods. AB - Research on the interaction of primary producers and consumers is crucial for understanding trophic transfer in intertidal food webs. This study explores the association between epilithic and planktonic microalgae, and gut contents of two targeted intertidal gastropods, the periwinkle Echinolittorina radiata (splash zone) and the limpet Cellana toreuma (mid-intertidal zone). With the application of gut fluorescence technique and metabarcoding, this study investigates the quantity and composition of two different sources of microalgae (epilithic and planktonic) and the food ingested by the gastropods. The results suggest the following findings: 1) The planktonic microalgae have higher compositional similarity to the gut contents of grazing gastropods. 2) Increased gut pigment content in C. toreuma is observed with increasing abundance of epilithic and planktonic microalgae. However, there was no such pattern observed for E. radiata. This difference could be attributed to potentially divergent foraging behaviours of the two species that inhabit different shore heights. PMID- 29478768 TI - Effects of shrimp effluents on mudskippers (Gobiidae: Oxudercinae) in the northern Persian Gulf. AB - Shrimp effluents can affect environmental conditions of the receiving ecosystems, and cause noticeable alterations in the residing communities. Mudskippers, as benthic fish with limited movement, could be affected by aquaculture-induced changes in environmental factors. These changes and subsequent responses of mudskipper assemblage to them, in the northern Persian Gulf, were studied. Some physicochemical and biological characteristics of the environment in addition to density, length, weight, and condition (i.e., Fulton's condition factor) of the residing mudskipper species (i.e., Boleophthalmus dussumieri and Periophthalmus waltoni) were measured in the control and impact sites. The results showed significant increases in the organic content (TOM and BOD), chlorophyll a, pH, total nitrogen and phosphorus, and fine particle fraction of sediments and decrease in DO due to shrimp effluent discharge. Furthermore, significant increases in the studied mudskippers' biological properties, except density of P. waltoni, in the sites receiving effluents were observed. It appears that increases in the fauna and flora of the impact sites have provided mudskippers with more food sources, and increased their lengths, weights, and densities (i.e., the overall environmental changes seem to be desirable for the mudskippers). The higher condition factors of the individuals inhabiting polluted sites indicate that not only these species can endure adverse changes in environmental circumstances, but also are in healthy physical conditions. PMID- 29478769 TI - Study on the in situ aggregation of liposomes with negatively charged phospholipids for use as injectable depot formulation. AB - Compared to conventional parenteral formulations injectable depot formulations, owing to a sustained drug release, offer several advantages, such as a reduced dosing frequency - and consequent improved compliance - or a predictable release profile. Additionally, fluctuations in the drug blood level may be smoothened and consequently side effects reduced. Because of their capability to encapsulate water soluble drugs and their very low toxicity profile liposomes comprising phospholipids, most certainly represent a vehicle of choice for subcutaneous (s.c.) or intramuscular (i.m.) administration typical for depot injections too. In the past, especially liposomes containing negatively charged phosphatidylserines were investigated regarding their aggregation and fusion behavior upon addition of calcium ions. Liposomes need to have a large size to prevent fast removal from the s.c. or i.m. injection site to make them useful as depot vehicle. In order to obtain such large liposomes, aggregation of smaller liposomes may be considered. Aim of the present study was to induce and investigate controlled aggregation of vesicles containing other negatively charged phospholipids besides phosphatidylserines upon mixing with a solution of divalent cations. L-alpha-phosphatidylcholine from egg (EPC) liposomes formulated with 25 mol% of 1,2-dipalmitoyl-sn-glycero-3-phosphate (DPPA) or 1,2-distearoyl sn-glycero-3-phospho-(1'-rac-glycerol) (DSPG) proved to be possible lipid-based depot candidates due to their strong aggregation induced by calcium and magnesium cations. Different aggregation profiles with both cations could be observed. Morphological investigations of the aggregates showed that individual liposomes remain stable in the aggregates and no fusion occurred. A fluorescence-based fusion assay confirmed these results. Differential scanning calorimetry measurements supported the findings of the diverse aggregation profiles with calcium or magnesium owing to different binding sites of the cations to the lipid molecules. PMID- 29478770 TI - Natural Killer Cells Detect a Tumor-Produced Growth Factor: A Vestige of Antiviral Resistance? AB - In addition to exogenous ligands derived from pathogens, natural killer (NK) and other innate cells can recognize endogenous ligands that often act as markers of stress or damage. A recent study reports that one of these receptors, human NKp44, recognizes PDGF-DD, providing a rare example of the recognition of a soluble growth factor as a stress signal. The recognition of PDGF-DD induces the secretion of cytokines with antitumor activity. PMID- 29478771 TI - Lipid Droplets as Immune Modulators in Myeloid Cells. AB - Lipid droplets (LDs) were initially described as fat storage organelles in adipocytes, but are increasingly recognized as dynamic players in lipid metabolism, with important roles not only in diseases such as diabetes and cancer, but also in immune regulation. Alterations in immune cell function, such as myeloid cell activation, are connected to profound changes in LD numbers and LD protein composition. Thus, these organelles appear to be essential to metabolically support immune responses, and have a vital role in antigen crosspresentation, interferon (IFN) responses, production of inflammatory mediators, and pathogen clearance. Here, we review recent studies that report on the role of LDs in the modulation of immune cell function, primarily focusing on myeloid cells, such as macrophages and dendritic cells (DCs). PMID- 29478772 TI - Skin Commensal Antigens: Taking the Road Less Traveled. AB - Although our knowledge of host-commensal interactions has increased exponentially, the mechanisms linking a specific commensal, its detection by the immune system, and its impact on tissue function are still often poorly understood. In a recent study in Cell, Linehan et al. dissect one of these interactions in the context of the skin, and demonstrate that Staphylococcus epidermidis antigens, presented through a non-classical pathway, drive the accumulation of CD8+ T cells that promote wound healing. PMID- 29478773 TI - In Vitro Culture, Drug Sensitivity, and Transcriptome of Plasmodium Vivax Hypnozoites. AB - The unique relapsing nature of Plasmodium vivax infection is a major barrier to malaria eradication. Upon infection, dormant liver-stage forms, hypnozoites, linger for weeks to months and then relapse to cause recurrent blood-stage infection. Very little is known about hypnozoite biology; definitive biomarkers are lacking and in vitro platforms that support phenotypic studies are needed. Here, we recapitulate the entire liver stage of P. vivax in vitro, using a multiwell format that incorporates micropatterned primary human hepatocyte co cultures (MPCCs). MPCCs feature key aspects of P. vivax biology, including establishment of persistent small forms and growing schizonts, merosome release, and subsequent infection of reticulocytes. We find that the small forms exhibit previously described hallmarks of hypnozoites, and we pilot MPCCs as a tool for testing candidate anti-hypnozoite drugs. Finally, we employ a hybrid capture strategy and RNA sequencing to describe the hypnozoite transcriptome and gain insight into its biology. PMID- 29478774 TI - Commensal Microbes Induce Serum IgA Responses that Protect against Polymicrobial Sepsis. AB - Serum immunoglobulin A (IgA) antibodies are readily detected in mice and people, but the mechanisms underlying the induction of serum IgA and its role in host protection remain uncertain. We report that select commensal bacteria induce several facets of systemic IgA-mediated immunity. Exposing conventional mice to a unique but natural microflora that included several members of the Proteobacteria phylum led to T cell-dependent increases in serum IgA levels and the induction of large numbers of IgA-secreting plasma cells in the bone marrow. The resulting serum IgA bound to a restricted collection of bacterial taxa, and antigen specific serum IgA antibodies were readily induced after intestinal colonization with the commensal bacterium Helicobacter muridarum. Finally, movement to a Proteobacteria-rich microbiota led to serum IgA-mediated resistance to polymicrobial sepsis. We conclude that commensal microbes overtly influence the serum IgA repertoire, resulting in constitutive protection against bacterial sepsis. PMID- 29478775 TI - Dampened STING-Dependent Interferon Activation in Bats. AB - Compared with terrestrial mammals, bats have a longer lifespan and greater capacity to co-exist with a variety of viruses. In addition to cytosolic DNA generated by these viral infections, the metabolic demands of flight cause DNA damage and the release of self-DNA into the cytoplasm. However, whether bats have an altered DNA sensing/defense system to balance high cytosolic DNA levels remains an open question. We demonstrate that bats have a dampened interferon response due to the replacement of the highly conserved serine residue (S358) in STING, an essential adaptor protein in multiple DNA sensing pathways. Reversing this mutation by introducing S358 restored STING functionality, resulting in interferon activation and virus inhibition. Combined with previous reports on bat specific changes of other DNA sensors such as TLR9, IFI16, and AIM2, our findings shed light on bat adaptation to flight, their long lifespan, and their unique capacity to serve as a virus reservoir. PMID- 29478776 TI - Cerebral blood vessel damage in traumatic brain injury. AB - Traumatic brain injury is a devastating cause of death and disability. Although injury of brain tissue is of primary interest in head trauma, nearly all significant cases include damage of the cerebral blood vessels. Because vessels are critical to the maintenance of the healthy brain, any injury or dysfunction of the vasculature puts neural tissue at risk. It is well known that these vessels commonly tear and bleed as an immediate consequence of traumatic brain injury. It follows that other vessels experience deformations that are significant though not severe enough to produce bleeding. Recent data show that such subfailure deformations damage the microstructure of the cerebral vessels, altering both their structure and function. Little is known about the prognosis of these injured vessels and their potential contribution to disease development. The objective of this review is to describe the current state of knowledge on the mechanics of cerebral vessels during head trauma and how they respond to the applied loads. Further research on these topics will clarify the role of blood vessels in the progression of traumatic brain injury and is expected to provide insight into improved strategies for treatment of the disease. PMID- 29478777 TI - Assessment of hip abductors by MRI after total hip arthroplasty and effect of fatty atrophy on functional outcome. AB - OBJECTIVES: The aim of this study was to evaluate how fatty atrophy (FA) of the hip abductors in operated and non-operated hips affected the functional outcome following arthroplasty. METHODS: Forty-four hips of 22 patients (8 males and 14 females; mean age: 60 +/- 14.4 (range: 24-84)) who matched the inclusion criteria and willing to participate in the study were retrospectively evaluated. The mean follow-up was 13.8 +/- 2.3 (range: 10-18) months Magnetic resonance imaging (MRI) and Harris Hip Score (HHS) were used to evaluate muscle degeneration and functional outcome after unilateral THA through a posterolateral approach. The FA grade was evaluated using Goutallier grading system. Non-operated hips of subjects were used as the control. Age, duration after the operation, gluteal muscle FA, and the relationships with HHS were evaluated. RESULTS: FA was more evident in the operated hip (p < 0.05), and was more in the gluteus minimus than in the gluteus medius in both hips (p < 0.05). Patients' age was not correlated with gluteal muscle FA in the operated hip (p > 0.05), whereas there was a positive correlation with the contra-lateral hip (p < 0.05). Duration after surgery did not affect gluteal muscle FA in the operated hip. Older age and FA of either the operated or healthy hip resulted in poorer HHS (p < 0.05). HHS had the strongest correlations with patient age (p < 0.001) and FA (p = 0.026) of the gluteus minimus of contralateral hip. CONCLUSION: Following THA, there was marked FA in the operated hip compared to that in the contralateral hip. In these cases, degree of FA in the replaced hip did not correlate with patients' age. Fatty atrophy of the gluteus minimus precedes that of gluteus medius. FA of the contralateral gluteus minimus and patient age are strongly correlated with lower HHS. LEVEL OF EVIDENCE: Level IV, diagnostic study. LEVEL OF EVIDENCE: Level IV, diagnostic study. PMID- 29478778 TI - Surgical correction of hallux valgus deformity in children with cerebral palsy. AB - OBJECTIVE: This study aimed to present a treatment algorithm for the correction of the hallux valgus deformity in Cerebral Palsy (CP) patients and to discuss the outcomes based on our clinical and radiological results. METHODS: 29 patients (45 feet) were included in the study. The mean age of the patients at the time of the surgery was 14 (range 6-22) years. The mean follow-up was 33 (range 22-59) months. A reconstructive procedure was performed on 19 patients (27 feet); a soft tissue surgery and exostectomy of the bunion in six patients (11 feet); and MTP joint arthrodesis in four patients (7 feet). The hallux valgus angle (HVA) and the anteroposterior intermetatarsal angle (IMA) were used for radiologic evaluation and the DuPont Bunion Rating Score was used for clinical evaluation. RESULTS: The follow-up period was 36 (range 22-59) months in reconstructive group, 27 (range 24-29) months in soft tissue group, and 29 (range 23-41) months in MTP arthrodesis group. Significant improvements were detected in hallux valgus angle in three groups postoperatively but in soft tissue group correction loss was observed during follow up. Best results were achieved in arthrodesis group and worse in soft tissue group in terms of clinical evaluation. CONCLUSION: According to our results isolated soft tissue procedures are ineffective in CP patients. Soft tissue procedure combined with metatarsal osteotomy has satisfactory results. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 29478779 TI - Loss of Function of the Nuclear Receptor NR2F2, Encoding COUP-TF2, Causes Testis Development and Cardiac Defects in 46,XX Children. AB - Emerging evidence from murine studies suggests that mammalian sex determination is the outcome of an imbalance between mutually antagonistic male and female regulatory networks that canalize development down one pathway while actively repressing the other. However, in contrast to testis formation, the gene regulatory pathways governing mammalian ovary development have remained elusive. We performed exome or Sanger sequencing on 79 46,XX SRY-negative individuals with either unexplained virilization or with testicular/ovotesticular disorders/differences of sex development (TDSD/OTDSD). We identified heterozygous frameshift mutations in NR2F2, encoding COUP-TF2, in three children. One carried a c.103_109delGGCGCCC (p.Gly35Argfs*75) mutation, while two others carried a c.97_103delCCGCCCG (p.Pro33Alafs*77) mutation. In two of three children the mutation was de novo. All three children presented with congenital heart disease (CHD), one child with congenital diaphragmatic hernia (CDH), and two children with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). The three children had androgen production, virilization of external genitalia, and biochemical or histological evidence of testicular tissue. We demonstrate a highly significant association between the NR2F2 loss-of-function mutations and this syndromic form of DSD (p = 2.44 * 10-8). We show that COUP-TF2 is highly abundant in a FOXL2-negative stromal cell population of the fetal human ovary. In contrast to the mouse, these data establish COUP-TF2 as a human "pro-ovary" and "anti-testis" sex-determining factor in female gonads. Furthermore, the data presented here provide additional evidence of the emerging importance of nuclear receptors in establishing human ovarian identity and indicate that nuclear receptors may have divergent functions in mouse and human biology. PMID- 29478780 TI - Inherited DNA-Repair Defects in Colorectal Cancer. AB - Colorectal cancer (CRC) heritability has been estimated to be around 30%. However, mutations in the known CRC-susceptibility genes explain CRC risk in fewer than 10% of affected individuals. Germline mutations in DNA-repair genes (DRGs) have recently been reported in CRC, but their contribution to CRC risk is largely unknown. We evaluated the gene-level germline mutation enrichment of 40 DRGs in 680 unselected CRC individuals and 27,728 ancestry-matched cancer-free adults. Significant findings were then examined in independent cohorts of 1,661 unselected CRC individuals and 1,456 individuals with early-onset CRC. Of the 680 individuals in the discovery set, 31 (4.56%) individuals harbored germline pathogenic mutations in known CRC-susceptibility genes, and another 33 (4.85%) individuals had DRG mutations that have not been previously associated with CRC risk. Germline pathogenic mutations in ATM and PALB2 were enriched in both the discovery (OR = 2.81 and p = 0.035 for ATM and OR = 4.91 and p = 0.024 for PALB2) and validation (OR = 2.97 and adjusted p = 0.0013 for ATM and OR = 3.42 and adjusted p = 0.034 for PALB2) sets. Biallelic loss of ATM was evident in all individuals with matched tumor profiling. CRC individuals also had higher rates of actionable mutations in the HR pathway, which can substantially increase the risk of developing cancers other than CRC. Our analysis provides evidence for ATM and PALB2 as CRC-risk genes, underscoring the importance of the homologous recombination pathway in CRC. In addition, we identified frequent complete homologous recombination deficiency in CRC tumors, representing a unique opportunity to explore targeted therapeutic interventions such as poly-ADP ribose polymerase inhibitor (PARPi). PMID- 29478782 TI - Controlling the cleavage of the inter- and intra-molecular linkages in lignocellulosic biomass for further biorefining: A review. AB - The abundant intermolecular linkages among cellulose, hemicellulose and lignin significantly limit the utilization of the most promising renewable biomass. Process control with solvents, catalysts and temperature is of significant importance providing ways to break the above linkages, and benefiting to the further conversion of the main biomass components to small molecular products. This article discusses the effect of catalyst under hydrothermal and organosolv treatment emphasizing the cleavage of the intermolecular linkage. Acidic catalysts show good performance on cleaving the linkages between carbohydrates and lignin. Basic catalysts promoted the dissolution of lignin component. Hydrogenolysis assisted conversion of lignin can efficiently break the intermolecular linkages to yield lignin-derived bio-oil, especially in co-solvent reaction system. Besides, the effects of single solvent and co-solvent systems, as well as the cleavage of the intramolecular linkages to yield target chemicals are also included. Several further study strategies are proposed. PMID- 29478783 TI - Biodiesel production by various oleaginous microorganisms from organic wastes. AB - Biodiesel is a biodegradable and renewable fuel. A large amount of research has considered microbial oil production using oleaginous microorganisms, but the commercialization of microbial lipids produced in this way remains uncertain due to the high cost of feedstock or low lipid yield. Microbial lipids can be typically produced by microalgae, yeasts, and bacteria; the lipid yields of these microorganisms can be improved by using sufficient concentrations of organic carbon sources. Therefore, combining low-cost organic compounds contained in organic wastes with cultivation of oleaginous microorganisms can be a promising approach to obtain commercial viability. However, to achieve effective bioconversion of low-cost substrates to microbial lipids, the characteristics of each microorganism and each substrate should be considered simultaneously. This article discusses recent approaches to developing cost-effective microbial lipid production processes that use various oleaginous microorganisms and organic wastes. PMID- 29478784 TI - Characterization of the promising poly(3-hydroxybutyrate) producing halophilic bacterium Halomonas halophila. AB - This work explores molecular, morphological as well as biotechnological features of the highly promising polyhydroxyalkanoates (PHA) producer Halomonas halophila. Unlike many other halophiles, this bacterium does not require expensive complex media components and it is capable to accumulate high intracellular poly(3 hydroxybutyrate) (PHB) fractions up to 82% of cell dry mass. Most remarkably, regulating the concentration of NaCl apart from PHB yields influences also the polymer's molecular mass and polydispersity. The bacterium metabolizes various carbohydrates including sugars predominant in lignocelluloses and other inexpensive substrates. Therefore, the bacterium was employed for PHB production on hydrolysates of cheese whey, spent coffee grounds, sawdust and corn stover, which were hydrolyzed by HCl; required salinity of cultivation media was set up during neutralization by NaOH. The bacterium was capable to use all the tested hydrolysates as well as sugar beet molasses for PHB biosynthesis, indicating its potential for industrial PHB production. PMID- 29478785 TI - Electrokinetic analyses in biofilm anodes: Ohmic conduction of extracellular electron transfer. AB - This review explores electron transfer kinetics from an electron donor to the anode in electrically conductive biofilm anodes. Intracellular electron transfer (IET) from the donor to the anode is well described with the Monod equation. In comparison, mechanisms of extracellular electron transfer (EET) conduction are unclear yet, complicating EET kinetics. However, in biofilm anodes where potential gradient to saturated current density is less than ~300 mV, Ohmic conduction successfully describe conductive EET mainly with biofilm conductivity (Kbio) and biofilm thickness (Lf). High Kbio essential for production of high current density is found in Geobacter pure or enriched biofilm anodes, but other exoelectrogens could make biofilms electrically conductive. IET is rate-limiting for current density in conductive biofilms, and biofilm density of active exoelectrogens and Lf are operating parameters that can be optimized further to improve current density. PMID- 29478786 TI - Quantitative Evaluation of Hepatic Microvascular Perfusion after Ischemia Reperfusion Injury in Rabbits by Contrast-Enhanced Ultrasound Perfusion Imaging. AB - The aim of this study was to evaluate microvascular perfusion after liver ischemia-reperfusion injury (IRI) in rabbits using the "flash-replenishment" method of contrast-enhanced ultrasound (CEUS) perfusion imaging. Twenty-eight rabbits underwent either 30, 60 or 90 min of ischemia and 120 min of reperfusion. CEUS perfusion imaging was performed using the "flash-replenishment" model, and hepatic microvascular perfusion parameters, including peak intensity (PI), area under the curve (AUC), and hepatic artery-to-vein transit time (HA-HVTT), were calculated. Prolonged ischemia upregulated intracellular adhesion molecule-1 (ICAM-1), alanine transaminase (ALT) and aspartate transaminase (AST) levels. Longer ischemia decreased PI and AUC, but increased HA-HVTT. The perfusion parameters were significantly correlated with Suzuki's pathology scores and ALT and AST levels. The "flash-replenishment" method of CEUS perfusion imaging is an accurate and non-invasive method for evaluating hepatic microvascular perfusion and provides a valuable experimental basis for early prediction of liver IRI damage after liver transplantation or liver resection. PMID- 29478787 TI - Full-Field-of-View Time-Harmonic Elastography of the Native Kidney. AB - The purpose of this study was to analyze full-field-of-view maps of renal shear wave speed (SWS) measured by time-harmonic elastography (THE) in healthy volunteers in terms of reproducibility, regional variation and physiologic effects. The kidneys of 37 healthy volunteers were investigated by multifrequency THE. The complete renal parenchyma, as well as cortex and medulla, was analyzed. A subgroup was investigated to test reproducibility (n = 3). Significant differences between SWS in cortex, medulla and full parenchyma were observed (2.10 +/- 0.17, 1.35 +/- 0.11 and 1.71 +/- 0.16 m/s, all p values < 0.001) with mean intra-volunteer standard deviations of repeated measurements of 0.04 m/s (1.6%), 0.06 m/s (4.0%) and 0.08 m/s (4.5%), respectively. No effects of kidney anatomy, age, body mass index, blood pressure and heart rate on SWS were observed. THE allows generation of full-field-of-view SWS maps of native kidneys with high reproducibility. PMID- 29478788 TI - National Partnership for Maternal Safety: Consensus Bundle on Safe Reduction of Primary Cesarean Births-Supporting Intended Vaginal Births. AB - Cesarean births and associated morbidity and mortality have reached near epidemic proportions. The National Partnership for Maternal Safety under the guidance of the Council on Patient Safety in Women's Health Care responded by developing a patient safety bundle to reduce the number of primary cesarean births. Safety bundles outline critical practices to implement in every maternity unit. This National Partnership for Maternity Safety bundle, as with other bundles, is organized into four domains: Readiness, Recognition and Prevention, Response, and Reporting and Systems Learning. Bundle components may be adapted to individual facilities, but standardization within an institution is advised. Evidence-based resources and recommendations are provided to assist implementation. PMID- 29478789 TI - [Thoracoabdominal aneurysms]. AB - Endovascular treatment of thoracoabdominal aneurysms: what's new? Thoracoabdominal aneurysms (T-AAA) are aortic aneurysms that involve both the thoracic and abdominal segments of the aorta and its associated visceral branches. Although the first successful open repair was reported over 50 years ago, the risks of treatment remain considerable. As the first generations of devices available for endovascular aneurysm repair (EVAR) were relatively simple tubes or bifurcated grafts, initial attempts to extend the benefits of EVAR to patients with T-AAA lead to "hybrid solution". Good results with hybrid repairs have not been universal and the approach does not exploit all of the potential advantages of a "pure" endovascular approach (lesser surgical insult). This unmet need, together with rapid technological advances, has encouraged the development of custom-made endografts with fenestrations and/or branches (F-BEVAR) for extension into the visceral vessel ostia. F-BEVAR requires considerably more complex device design and planning than conventional EVAR. Deployment is more technically demanding and takes longer to complete. Thus, patient, aneurysm anatomy and surgical team selection is paramount. Favorable outcomes have been widely reported following T-AAA repair with F-BEVAR in expert centers; more complex aortic lesions such as T-AAA in the context of chronic dissection or arch aneurysms are thus now also offered endovascular repair with F-BEVAR. PMID- 29478781 TI - Biallelic Mutations in ATP5F1D, which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder. AB - ATP synthase, H+ transporting, mitochondrial F1 complex, delta subunit (ATP5F1D; formerly ATP5D) is a subunit of mitochondrial ATP synthase and plays an important role in coupling proton translocation and ATP production. Here, we describe two individuals, each with homozygous missense variants in ATP5F1D, who presented with episodic lethargy, metabolic acidosis, 3-methylglutaconic aciduria, and hyperammonemia. Subject 1, homozygous for c.245C>T (p.Pro82Leu), presented with recurrent metabolic decompensation starting in the neonatal period, and subject 2, homozygous for c.317T>G (p.Val106Gly), presented with acute encephalopathy in childhood. Cultured skin fibroblasts from these individuals exhibited impaired assembly of F1FO ATP synthase and subsequent reduced complex V activity. Cells from subject 1 also exhibited a significant decrease in mitochondrial cristae. Knockdown of Drosophila ATPsyndelta, the ATP5F1D homolog, in developing eyes and brains caused a near complete loss of the fly head, a phenotype that was fully rescued by wild-type human ATP5F1D. In contrast, expression of the ATP5F1D c.245C>T and c.317T>G variants rescued the head-size phenotype but recapitulated the eye and antennae defects seen in other genetic models of mitochondrial oxidative phosphorylation deficiency. Our data establish c.245C>T (p.Pro82Leu) and c.317T>G (p.Val106Gly) in ATP5F1D as pathogenic variants leading to a Mendelian mitochondrial disease featuring episodic metabolic decompensation. PMID- 29478790 TI - Cost-effectiveness analysis of strategies using new immunological diagnostic tests of latent tuberculosis infection before TNF-blockers therapy. AB - : Several tests have been proposed to detect latent tuberculosis (LTB). OBJECTIVE: To evaluate the cost-effectiveness of different interferon-gamma release assays based strategies used to screen LTB before tumour necrosis factor (TNF) blockers initiation. METHODS: Consecutive patients with rheumatoid arthritis, spondyloarthritis or Crohn's disease for whom TNF-blockers were considered, were recruited in 15 tertiary care centres. All were screened for LTB with tuberculin skin test (TST), QuantiFERON TB Gold(r) in tube (QFT) and T SPOT.TB(r) (TSpot) on the same day. Cost-minimization and cost-effectiveness analysis, testing 8 screening test combinations, were conducted. Effectiveness was defined as the percentage of LTB treatment avoided and compared with TST alone. Cost were elicited in the payer perspective, included all the costs related to the screening procedure. RESULTS: No tuberculosis reactivation was observed after TNF-blocker initiation. TST followed by QFT if TST was positive was found as the best screening strategy, i.e. the less costly (-54? compared to reference) and most effective (effectiveness 0.93), resulting in an incremental cost-effectiveness ratio of -192? per treatment avoided. A probabilistic sensitivity analysis confirmed this result in 72.3% of simulations. CONCLUSION: TST followed by QFT if TST was positive is the most cost-effective strategy in screening for LTB in patients before starting anti-TNF therapy. TRIALREGNO: NCT00811343. PMID- 29478791 TI - Bullous systemic lupus erythematosus. PMID- 29478792 TI - ? AB - Any doctor may be required to take care of patients with psychiatric disorders and be confronted with the necessity of imposing hospitalization in a psychiatric facility. In view of the increase in hands raised by the Judge of Freedoms and Detention, it is important to adopt a rigorous approach in the drafting of certificates for psychiatric care without consent. We will remember: the importance of conscientious fulfilment of the first certificates; the reassessment of the patient within 24hours, by a psychiatrist; a review by the judge of freedoms and detention; the information given to the patient. PMID- 29478793 TI - [Spontaneous coronary dissection, an unusual suspect]. AB - Under-diagnosed pathology. Especially in women under 60 without cardiovascular risk factor. Conventional coronary angiography without lesion. Association with fibrodysplasia being evaluated. Impact of IVUS and OCT. Conservative therapy. PMID- 29478794 TI - Acceptability and feasibility of HIV testing in general medicine by ELISA or rapid test from finger-stick whole blood. AB - OBJECTIVES: Guidelines recommend routine universal HIV testing in adults to reduce the pool of infected patients unaware of their status, without specific recommendations concerning the method. We compared acceptability and feasibility of HIV testing by ELISA tests or rapid tests from finger-stick whole blood. METHODS: Prospective randomized multi-center study comparing acceptability and feasibility of routine universal HIV testing by ELISA tests, with a charge, subsequently reimbursed by Social Security for affiliated patients, or rapid tests from finger-stick whole blood, without any charge from the patients or the general practitioner for the study. A single investigator performed all interventions. After consent, all adults (18-70 years old) consulting their general practitioner in Paris, France, unaware of their status, were enrolled. Testing was performed immediately for the patients in the rapid test arm; a prescription was given for testing in a lab for the patients in the ELISA arm. The primary endpoint was acceptability of each method. The secondary endpoint was feasibility of each method, assessed one month after the consultation. RESULTS: Two hundred and seventy patients were enrolled: 133 patients in the ELISA arm, 137 in the rapid test arm. Acceptability of the rapid test (92%) was higher than that of the ELISA (63.9%), P<0.0001. Feasibility of the rapid test (100%) was higher than that of the ELISA (50.5%), P<0.0001. A center effect was shown concerning feasibility of ELISA but not concerning feasibility of rapid tests. CONCLUSION: Rapid testing from finger-stick whole blood is more acceptable and feasible than ELISA for routine universal HIV testing. A larger use of rapid tests, ideally free of charge, by general practitioners could reduce the pool of infected patients unaware of their status. PMID- 29478795 TI - Outpatient Transarterial Chemoembolization of Hepatocellular Carcinoma: Review of a Same-Day Discharge Strategy. AB - PURPOSE: To test the hypothesis that same-day discharge of selected transarterial chemoembolization patients would not increase 30-day readmission rate compared with overnight observation. MATERIALS AND METHODS: With institutional review board approval, 193 hepatocellular carcinoma patients who underwent transarterial chemoembolization from July 2013 to June 2016 were reviewed. Treatment was conventional/lipiodol transarterial chemoembolization with 50 mg doxorubicin/10 mg mitomycin-c/particles or drug-eluting embolics transarterial chemoembolization with 50-75 mg doxorubicin/vial. At 3 hours, patients tolerating oral intake and not requiring intravenous analgesics were considered for discharge. The primary outcome measure was 30-day readmission for observation versus discharge using chi squared (chi2) analysis. The secondary aim was to identify baseline or treatment variables independently associated with readmission, including Child-Pugh class, medically managed encephalopathy or ascites, patient age (<65 vs >=65), tumor number (1 or >1), and level of embolization (segmental vs lobar). RESULTS: Patients underwent 261 transarterial chemoembolization procedures. The 30-day readmission rate was not significantly different between observed patients (n = 179, 9.0%) and discharged patients (n = 82, 13.8%; P = .33). Readmission was not related to the selected agent (conventional/lipiodol-transarterial chemoembolization, 11.0% vs drug-eluting embolics transarterial chemoembolization, 7.5%; P = .36). Baseline variables associated with readmission were Child-Pugh B/C (chi2 = 7.9, P < .01), history of encephalopathy (chi2 = 15.4, P < 0.01), and ascites (chi2 = 4.4, P < .05). Patient age (<65 vs >=65), tumor number (1 vs >1), and level of embolization (segmental vs lobar) were not predictive of readmission (all P > .05). CONCLUSIONS: Same-day discharge after transarterial chemoembolization does not increase the risk of 30-day readmission. Child-Pugh B/C patients, as well as those with ascites or encephalopathy, have the highest risk of readmission. PMID- 29478796 TI - Clinical IR in Canada: The Evolution of a Revolution. AB - PURPOSE: To investigate the current status and evolution of both the interventional radiologist's role as a clinician and the practice of interventional radiology (IR) over the past decade in Canada. MATERIALS AND METHODS: In 2015, an online survey was e-mailed to 210 interventional radiologists, including all Canadian active members of the Canadian Interventional Radiology Association (CIRA) and nonmembers who attended CIRA's annual meeting. Comparisons were made between interventional radiologists in academic versus community practice. The results of the 2015 survey were compared with CIRA's national surveys from 2005 and 2010. RESULTS: A total of 102 interventional radiologists responded (response rate 49%). Significantly more academic versus community interventional radiologists performed chemoembolization, transjugular intrahepatic portosystemic shunt, aortic interventions, and arteriovenous malformation embolization (P < .05). Ninety percent of respondents were involved in longitudinal patient care, which had increased by 42% compared with 2005; 46% of interventional radiologists had overnight admitting privileges, compared with 39% in 2010 and 29% in 2005. Eighty six percent of interventional radiologists accepted direct referrals from family physicians, and 83% directly referred patients to other consultants. Sixty-three percent participated in multidisciplinary tumor board. The main challenges facing interventional radiologists included a lack of infrastructure, inadequate remuneration for IR procedures, and inadequate funding for IR equipment. Significantly more community versus academic interventional radiologists perceived work volume as an important issue facing the specialty in 2015 (60% vs 34%; P = .02). CONCLUSIONS: Over the past decade, many Canadian interventional radiologists have embraced the interventional radiologist-clinician role. However, a lack of infrastructure and funding continue to impede more widespread adoption of clinical IR practice. PMID- 29478797 TI - Multisociety Consensus Quality Improvement Revised Consensus Statement for Endovascular Therapy of Acute Ischemic Stroke: From the American Association of Neurological Surgeons (AANS), American Society of Neuroradiology (ASNR), Cardiovascular and Interventional Radiology Society of Europe (CIRSE), Canadian Interventional Radiology Association (CIRA), Congress of Neurological Surgeons (CNS), European Society of Minimally Invasive Neurological Therapy (ESMINT), European Society of Neuroradiology (ESNR), European Stroke Organization (ESO), Society for Cardiovascular Angiography and Interventions (SCAI), Society of Interventional Radiology (SIR), Society of NeuroInterventional Surgery (SNIS), and World Stroke Organization (WSO). PMID- 29478798 TI - Therapeutic plasma exchange for hyperviscosity syndrome secondary to high rheumatoid factor. AB - Hyperviscosity syndrome (HVS) is most commonly associated with Waldenstrom's macroglobulinemia, where it may be life-threatening. HVS may also occur in autoimmune diseases; data pertaining to efficacy of therapeutic plasma exchange (TPE) in HVS arising in non-malignant gammopathy are limited. We report a case of 71-year-old female with erosive rheumatoid arthritis with profoundly elevated rheumatoid factor (57,400 IU/ml; normal <35) who presented with findings consistent with HVS: profound weakness, headache, epistaxis and plasma viscosity (8.5 centipoise). She was successfully treated with pulsed high-dose steroids and TPE. Her symptoms of HVS have not recurred and the plasma viscosity has remained less than 3 centipoise. Given a slow onset of non-specific symptoms, HVS may be missed, incurring high risk of adverse effect. In symptomatic patients with high RF activity, a high index of suspicion for HVS is necessary to ensure timely identification and treatment with TPE, a safe and effective therapy. PMID- 29478799 TI - Therapeutic apheresis in the treatment of catastrophic antiphospholipid syndrome. AB - Catastrophic thrombotic syndrome is characterized by occurrence of several thromboembolic occlusions which affect a variety of vascular beds over a short period of time. Catastrophic Antiphospholipid syndrome (CAPS) (1%) is regarded as a rare but severe variant of Antiphospholipid Syndrome. Treatment with anticoagulants, steroids and therapeutic plasma exchange has been shown to give the best results. However, to treat CAPS, the best substitute for plasma is still a debatable issue because there are no standard methods. PMID- 29478800 TI - Granulocyte transfusions in the management of neutropenic fever: A pediatric perspective. AB - Severe neutropenia-associated invasive bacterial or fungal infections are still the major cause of mortality and morbidity in children receiving cancer chemotherapy. Granulocyte transfusion therapy has been used for many years in the management of neutropenic patients with severe infections in whom the clinical condition deteriorated despite appropriate antimicrobial treatment. Transfused granulocytes can increase the recipient's blood neutrophil count and accumulation of them into the site of infection. There are some data obtained from retrospective or prospective observational studies in pediatric granulocyte transfusion therapy, but results are not conclusive. This review appraises the potential benefits and risks of the use of granulocyte transfusion in children with neutropenic fever. PMID- 29478801 TI - PET probe detecting non-small cell lung cancer susceptible to epidermal growth factor receptor tyrosine kinase inhibitor therapy. AB - Tyrosine kinase inhibitors for epidermal growth factor receptor (EGFR-TKIs) are used as molecular targeted therapy for non-small cell lung cancer (NSCLC) patients. The therapy is applied to the patients having EGFR-primary L858R mutation, but drug tolerance caused by EGFR-secondary mutation is occurred within one and half years. For the non-invasive detection of the EGFR-TKIs treatment positive patients by positron emission tomograpy (PET) imagaing, fluorine-18 labeled thienopyrimidine derivative, [18F]FTP2 was newly synthesized. EGFR inhibition assay, cell uptake study, and blocking study indicated [18F]FTP2 binds with high and selective affinity for EGFR with L858R mutation, and not with L858R/T790M dual mutations. On animal PET study using tumor bearing mice, H3255 cells expressing L858R mutated EGFR was more clearly visualized than H1975 cells expressing L858R/T790M dual mutated EGFR. [18F]FTP2 has potential for detecting NSCLC which is susceptible to EGFR-TKI treatment. PMID- 29478803 TI - Design and synthesis of 1-(1-benzothiophen-7-yl)-1H-pyrazole, a novel series of G protein-coupled receptor 52 (GPR52) agonists. AB - G-protein-coupled receptor 52 (GPR52) is classified as an orphan Gs-coupled G protein-coupled receptor. GPR52 cancels dopamine D2 receptor signaling and activates dopamine D1/N-methyl-d-aspartate receptors via intracellular cAMP accumulation. Therefore, GPR52 agonists are expected to alleviate symptoms of psychotic disorders. A novel series of 1-(benzothiophen-7-yl)-1H-pyrazole as GPR52 agonists was designed and synthesized based on compound 1b. Compound 1b has been reported by our group as the first orally active GPR52 agonist, but high lipophilicity and poor aqueous solubility still remained as issues for candidate selection. To resolve these issues, replacement of the benzene ring at the 7 positon of compound 1b with heterocylic rings, such as pyrazole and pyridine, was greatly expected to reduce lipophilicity to levels for which calculated logD values were lower than that of compound 1b. While evaluating the pyrazole derivatives, introduction of a methyl substituent at the 3-position of the pyrazole ring led to increased GPR52 agonistic activity. Moreover, additional methyl substituent at the 5-position of the pyrazole and further introduction of hydroxy group to lower logD led to significant improvement of solubility while maintaining the activity. As a result, we identified 3-methyl-5-hydroxymethyl-1H pyrazole derivative 17 (GPR52 EC50 = 21 nM, Emax = 103%, logD = 2.21, Solubility at pH 6.8 = 21 MUg/mL) with potent GPR52 agonistic activity and good solubility compared to compound 1b. Furthermore, this compound 17 dose-dependently suppressed methamphetamine-induced hyperlocomotion in mice. PMID- 29478802 TI - Pharmacophore requirements for HIV-1 reverse transcriptase inhibitors that selectively "Freeze" the pre-translocated complex during the polymerization catalytic cycle. AB - Reverse transcriptase (RT) is responsible for replicating the HIV-1 genome and is a validated therapeutic target for the treatment of HIV infections. During each cycle of the RT-catalyzed DNA polymerization process, inorganic pyrophosphate is released as the by-product of nucleotide incorporation. Small molecules were identified that act as bioisosteres of pyrophosphate and can selectively freeze the catalytic cycle of HIV-1 RT at the pre-translocated stage of the DNA- or RNA template-primer-enzyme complex. PMID- 29478805 TI - Biomonitoring of selenoprotein P in human serum by fast affinity chromatography coupled to ICP-MS. AB - Most of the Se in human serum is bound to selenoprotein P (SEPP1) in which Se is present in form of selenocysteine. The SEPP1 is a new possible biomarker for the Se status and for this reason we developed a fast, simple and reliable method for the quantitative determination of SEPP1 in serum by affinity chromatography coupled to ICP-MS. It is possible to separate SEPP1 from other selenoproteins in serum in only 5 min, which allows high sample throughput in clinical laboratories. Measured and certified concentrations of total Se and Se(SEPP1) are in good agreement for the reference material SRM 1950. The SEPP1 concentration was stable in serum samples of 3 persons for a minimum of 2 weeks. Further results of method validation were described including internal and external quality assurance. The analytical method was applied for a biomonitoring study of the SEPP1 and total Se concentration in human serum of 50 occupationally non exposed persons living in northern Germany. Concentration ranges and mean concentrations for Se(SEPP1) are 31.1-59.7 and 46.2 MUg/L, respectively. The corresponding values for total Se are 62-120 and 83.5 MUg/L. The mean percentage of total Se in serum present as SEPP1 is 58%. PMID- 29478804 TI - A case of Wolff-Parkinson-White syndrome presenting spontaneous mutual frequent transition between atrioventricular reciprocating tachycardia and atrioventricular nodal re-entrant tachycardia. AB - Atrioventricular reciprocating tachycardia (AVRT) and atrioventricular nodal re entrant tachycardia (AVNRT) can coexist and present unidirectional transition (from AVRT to AVNRT, or from AVNRT to AVRT) in a single patient. Actually, such cases have already been reported previously. However, a case with spontaneous bidirectional transition of both tachycardias during supraventricular tachycardia has never been reported. This article describes a case with spontaneous, mutual, and frequent transition between AVRT and AVNRT. PMID- 29478806 TI - Prenatal exposure to organophosphate pesticides and risk of autism spectrum disorders and other non-typical development at 3 years in a high-risk cohort. AB - INTRODUCTION: Organophosphates are widely used pesticides that have been shown to affect child neurodevelopment. Previous studies that explored their potential effects on Autism Spectrum Disorder (ASD) relied either on proxies of external exposure or on questionnaires completed by the parents to identify autism-like behaviors but did not provide a clinical diagnosis of ASD. AIMS: We studied the associations between prenatal biologic markers for exposure to organophosphate pesticides and the risk of having a child with ASD or other developmental concerns (ODC). METHOD: We analyzed 203 mother-child pairs of the ongoing MARBLES (Markers of Autism Risk in Babies - Learning Early Signs) mother-child cohort, which enrolls mothers who are either pregnant or planning a pregnancy and whose expected child has an elevated risk to develop ASD. Seven metabolites of organophosphate pesticides were assessed in repeated urine samples collected during pregnancy. At 36 months, children were assessed with intruments measuring cognitive function and adaptive behaviors, and with two gold-standard diagnostic instruments for ASD: the Autism Diagnostic Observation Schedule and the Autism Diagnostic Interview-Revised. Children were classified in one of the following groups: ASD (n = 46), ODC (n = 55) and typically developing (TD, n = 102). RESULTS: After adjustment for potential confounders, organophosphate metabolite concentrations were not associated with an increased risk of ASD or ODC when boys and girls were studied together. After stratification by sex, dimethylthiophosphate (DMTP) pregnancy concentration tended to be associated with an increased ASD risk among girls (OR for a doubling in the DMTP concentration: 1.64 (95%CI, 0.95; 2.82)) but not among boys (OR: 0.84, 95%CI: 0.63; 1.11). DISCUSSION: This is the first study of clinically confirmed diagnoses of ASD that utilized repeated measurements of organophosphate metabolites during pregnancy to explore the associations between these pesticides and ASD risk in children. The association we observed among girls, as well as the lack of association in boys, need to be replicated in further studies with similar design and larger sample size. In light of the higher baseline risk for ASD in this cohort, generalizability to children lacking a first degree relative affected by ASD is unknown. PMID- 29478807 TI - The Histone Chaperones ASF1 and CAF-1 Promote MMS22L-TONSL-Mediated Rad51 Loading onto ssDNA during Homologous Recombination in Human Cells. AB - The access-repair-restore model for the role of chromatin in DNA repair infers that chromatin is a mere obstacle to DNA repair. However, here we show that blocking chromatin assembly, via knockdown of the histone chaperones ASF1 or CAF 1 or a mutation that prevents ASF1A binding to histones, hinders Rad51 loading onto ssDNA during homologous recombination. This is a consequence of reduced recruitment of the Rad51 loader MMS22L-TONSL to ssDNA, resulting in persistent RPA foci, extensive DNA end resection, persistent activation of the ATR-Chk1 pathway, and cell cycle arrest. In agreement, histones occupy ssDNA during DNA repair in yeast. We also uncovered DNA-PKcs-dependent DNA damage-induced ASF1A phosphorylation, which enhances chromatin assembly, promoting MMS22L-TONSL recruitment and, hence, Rad51 loading. We propose that transient assembly of newly synthesized histones onto ssDNA serves to recruit MMS22L-TONSL to efficiently form the Rad51 nucleofilament for strand invasion, suggesting an active role of chromatin assembly in homologous recombination. PMID- 29478809 TI - PRDM9 Methyltransferase Activity Is Essential for Meiotic DNA Double-Strand Break Formation at Its Binding Sites. AB - The programmed formation of hundreds of DNA double-strand breaks (DSBs) is essential for proper meiosis and fertility. In mice and humans, the location of these breaks is determined by the meiosis-specific protein PRDM9, through the DNA binding specificity of its zinc-finger domain. PRDM9 also has methyltransferase activity. Here, we show that this activity is required for H3K4me3 and H3K36me3 deposition and for DSB formation at PRDM9-binding sites. By analyzing mice that express two PRDM9 variants with distinct DNA-binding specificities, we show that each variant generates its own set of H3K4me3 marks independently from the other variant. Altogether, we reveal several basic principles of PRDM9-dependent DSB site determination, in which an excess of sites are designated through PRDM9 binding and subsequent histone methylation, from which a subset is selected for DSB formation. PMID- 29478808 TI - Allosteric Effector ppGpp Potentiates the Inhibition of Transcript Initiation by DksA. AB - DksA and ppGpp are the central players in the stringent response and mediate a complete reprogramming of the transcriptome. A major component of the response is a reduction in ribosome synthesis, which is accomplished by the synergistic action of DksA and ppGpp bound to RNA polymerase (RNAP) inhibiting transcription of rRNAs. Here, we report the X-ray crystal structures of Escherichia coli RNAP in complex with DksA alone and with ppGpp. The structures show that DksA accesses the template strand at the active site and the downstream DNA binding site of RNAP simultaneously and reveal that binding of the allosteric effector ppGpp reshapes the RNAP-DksA complex. The structural data support a model for transcriptional inhibition in which ppGpp potentiates the destabilization of open complexes by DksA. This work establishes a structural basis for understanding the pleiotropic effects of DksA and ppGpp on transcriptional regulation in proteobacteria. PMID- 29478811 TI - Non-competitive antagonists of NMDA and AMPA receptors decrease seizure-induced c fos protein expression in the cerebellum and protect against seizure symptoms in adult rats. AB - The aim of the present study was to examine the role of ionotropic glutamate receptors in the cerebellum during generalized seizures. Epileptic neuronal activation was evaluated through the immunohistochemical detection of c-fos protein in the cerebellar cortex. Generalized seizures were precipitated by the intraperitoneal injection of 4-aminopyridine. The animals were pretreated with the NMDA receptor antagonists MK-801 (2 mg/kg), amantadine (50 mg/kg), and the AMPA receptor antagonist GYKI 52466 hydrochloride (50 mg/kg). Two hours after 4 aminopyridine injection, the number of c-fos immunostained cell nuclei was counted in serial immunohistochemical sections of the cerebellar vermis. The number of c-fos immunostained cell nuclei in the granular layer decreased significantly in animals pretreated with the glutamate receptor antagonists compared to the untreated animals having convulsion. We can conclude that mossy fiber stimulation exerts its seizure-generating action mainly through the ionotropic glutamate receptors of the mossy fiber synapses. Both NMDA and AMPA receptor antagonists are effective in reducing glutamate-mediated postsynaptic effects in the cerebellar cortex. PMID- 29478810 TI - Temporal trends in clinical characteristics and management according to sex in patients with cardiogenic shock after acute myocardial infarction: The FAST-MI programme. AB - BACKGROUND: Cardiogenic shock (CS) complicating acute myocardial infarction (AMI) occurs more frequently in women, but little is known about its potential specificities according to sex. AIMS: To analyse the incidence, management and 1 year mortality of CS according to sex using the FAST-MI programme. METHODS: The FAST-MI programme consists of four nationwide French surveys carried out 5 years apart from 1995 to 2010, including consecutive patients with AMI over a 1-month period, and with a 1-year follow-up. RESULTS: Among the 10,610 patients included in the surveys, the incidence of CS was 4.8% in men and 8.2% in women (P<0.001). Absolute incidence of CS decreased from 1995 to 2010 in both sexes. Mean age in patients with CS tended to decrease in men (from 72+/-12 to 69+/-13 years) and to increase in women (from 78+/-10 to 80+/-9 years). One-year mortality decreased significantly in men (from 70% in 1995 to 48% in 2010) and in women (from 81% to 54%). Using Cox multivariable analysis, female sex was not an independent correlate of 1-year mortality [hazard ratio (HR): 0.98, 95% confidence interval (CI): 0.78-1.22]. Early use of percutaneous coronary intervention was, however, an independent predictor of 1-year survival in women (HR: 0.55, 95% CI: 0.37 0.81), but showed only a non-significant trend in men (HR: 0.85, 95% CI: 0.61 1.19). CONCLUSIONS: The incidence of CS-AMI has decreased in both men and women, but remains higher in women. One-year mortality has significantly decreased for both men and women, and the role of early percutaneous coronary intervention as a potential mediator of decreased mortality seems greater in women than in men. PMID- 29478812 TI - Sleep evaluation in patients with myasthenia gravis. PMID- 29478813 TI - The effect of increasing tertiles of waist circumference on cardio-metabolic risk, adipokines and biomarkers of inflammation and oxidative stress in nascent metabolic syndrome. AB - AIMS: The effect of waist circumference (WC) on cardio-metabolic features and biomarkers of oxidative stress and inflammation and adipose tissue dysregulation is poorly defined in Metabolic Syndrome (MetS). Hence the aim of this study was to examine the effect of increasing tertiles of WC on the cardio metabolic risk profile, pro-oxidant state, pro-inflammatory state and adipose tissue dysregulation in nascent MetS patients (n = 59) without diabetes or CVD. METHODS AND RESULTS: None of the main cardio-metabolic features including blood pressure, blood glucose, HDL-cholesterol, triglycerides, HOMA-IR, and free fatty acids increased with increasing WC tertiles except for hsCRP. In addition, none of the biomarkers of oxidative stress increased with increasing WC. Other circulating and cellular bio-mediators of inflammation and adipokines did not show significant increase with increasing WC. Using the waist to height ratio (WHtR) also did not reveal any major findings with increasing tertiles. CONCLUSION: In conclusion, in a well-defined cohort of MetS we failed to show any superiority of either WC or WHtR compared to BMI in capturing the cardio-metabolic cluster, adipose tissue dysregulation and the increased burden of oxidative stress and inflammation in this pilot study. These observations need confirmation in larger studies. PMID- 29478814 TI - Clustering of microvascular complications in Type 1 diabetes mellitus. AB - AIMS: To describe to what extent microvascular complications exhibit clustering in persons with Type 1 diabetes, and to assess whether the presence of one complication modified the strength of the association between the other two. METHODS: We conducted a cross-sectional analysis of the electronic medical records of 2276 persons with Type 1 diabetes treated in a specialized care hospital in Denmark in 2013. We used log-linear analysis to describe associations between diabetic kidney disease, neuropathy and retinopathy and logistic regression models to quantify the magnitude of associations adjusting for potential confounders. RESULTS: The median duration of diabetes was 24 years and median HbA1c was 63 mmol/mol (7.9%). We found strong indication of clustering and found no evidence that presence of one complication modified the association between the other two. In models adjusted for diabetes duration and HbA1c, persons with neuropathy had an OR of 2.15 (95% CI: 1.73-2.66) for concurrent diabetic kidney disease. Those with retinopathy had an OR of 2.49 (1.92-3.24) for diabetic kidney disease and of 2.66 (1.94-3.64) for neuropathy. CONCLUSIONS: Microvascular complications in persons with Type 1 diabetes exhibit strong clustering. However, the association between any pair of complications is not modified by the presence of the third. PMID- 29478815 TI - Paired editorial: rate of revisions or conversions after bariatric surgery over 10 years in the state of New York. PMID- 29478816 TI - Comment on: impact of age on risk of complications after gastric bypass: a cohort study from the Scandinavian Obesity Surgery Registry (SOReg). PMID- 29478817 TI - Functional assessment of creatine transporter in control and X-linked SLC6A8 deficient fibroblasts. AB - Creatine transporter is currently the focus of renewed interest with emerging roles in brain neurotransmission and physiology, and the bioenergetics of cancer metastases. We here report on amendments of a standard creatine uptake assay which might help clinical chemistry laboratories to extend their current range of measurements of creatine and metabolites in body fluids to functional enzyme explorations. In this respect, short incubation times and the use of a stable isotope-labeled substrate (D3-creatine) preceded by a creatine wash-out step from cultured fibroblast cells by removal of fetal bovine serum (rich in creatine) from the incubation medium are recommended. Together, these measures decreased, by a first order of magnitude, creatine concentrations in the incubation medium at the start of creatine-uptake studies and allowed to functionally discriminate between 4 hemizygous male and 4 heterozygous female patients with X-linked SLC6A8 deficiency, and between this cohort of eight patients and controls. The functional assay corroborated genetic diagnosis of SLC6A8 deficiency. Gene anomalies in our small cohort included splicing site (c.912G > A [p.Ile260_Gln304del], c.778-2A > G and c.1495 + 2 T > G), substitution (c.407C > T) [p.Ala136Val] and deletion (c.635_636delAG [p.Glu212Valfs*84] and c.1324delC [p.Gln442Lysfs*21]) variants with reduced creatine transporter function validating their pathogenicity, including that of a previously unreported c.1324delC variant. The present assay adaptations provide an easy, reliable and discriminative manner for exploring creatine transporter activity and disease variations. It might apply to drug testing or other evaluations in the genetic and metabolic horizons covered by the emerging functions of creatine and its transporter, in a way, however, requiring and completed by additional studies on female patients and blood-brain barrier permeability properties of selected compounds. As a whole, the proposed assay of creatine transporter positively adds to currently existing measurements of this transporter activity, and determining on a large scale the extent of its exact suitability to detect female patients should condition in the future its transfer in clinical practice. PMID- 29478818 TI - ACE phenotyping in Gaucher disease. AB - BACKGROUND: Gaucher disease is characterized by the activation of splenic and hepatic macrophages, accompanied by dramatically increased levels of angiotensin converting enzyme (ACE). To evaluate the source of the elevated blood ACE, we performed complete ACE phenotyping using blood, spleen and liver samples from patients with Gaucher disease and controls. METHODS: ACE phenotyping included 1) immunohistochemical staining for ACE; 2) measuring ACE activity with two substrates (HHL and ZPHL); 3) calculating the ratio of the rates of substrate hydrolysis (ZPHL/HHL ratio); 4) assessing the conformational fingerprint of ACE by evaluating the pattern of binding of monoclonal antibodies to 16 different ACE epitopes. RESULTS: We show that in patients with Gaucher disease, the dramatically increased levels of ACE originate from activated splenic and/or hepatic macrophages (Gaucher cells), and that both its conformational fingerprint and kinetic characteristics (ZPHL/HHL ratio) differ from controls and from patients with sarcoid granulomas. Furthermore, normal spleen was found to produce high levels of endogenous ACE inhibitors and a novel, tightly-bound 10-30 kDa ACE effector which is deficient in Gaucher spleen. CONCLUSIONS: The conformation of ACE is tissue-specific. In Gaucher disease, ACE produced by activated splenic macrophages differs from that in hepatic macrophages, as well as from macrophages and dendritic cells in sarcoid granulomas. The observed differences are likely due to altered ACE glycosylation or sialylation in these diseased organs. The conformational differences in ACE may serve as a specific biomarker for Gaucher disease. PMID- 29478819 TI - A novel Blind Start study design to investigate vestronidase alfa for mucopolysaccharidosis VII, an ultra-rare genetic disease. AB - BACKGROUND: Drug development for ultra-rare diseases is challenging because small sample sizes and heterogeneous study populations hamper the ability of randomized, placebo-controlled trials with a single primary endpoint to demonstrate valid treatment effects. METHODS: To overcome these challenges, a novel Blind Start design was utilized in a study of vestronidase alfa in mucopolysaccharidosis VII (Sly syndrome), an ultra-rare lysosomal disease, that demonstrates the strengths of this approach in a challenging drug-development setting. Twelve subjects were randomized to 1 of 4 blinded groups, each crossing over to active treatment in a blinded fashion at different timepoints with efficacy analysis comparing the last assessment before cross over to after 24 weeks of treatment. Study assessments included: Percentage change from baseline in urinary GAG (uGAG); a Multi-Domain Responder Index (MDRI) using prespecified minimal important differences (6-Minute Walk Test, Forced Vital Capacity, shoulder flexion, visual acuity, and Bruininks-Oseretsky Test of Motor Proficiency); fatigue as assessed by the Pediatric Quality of Life InventoryTM Multidimensional Fatigue Scale; and safety. RESULTS: Vestronidase alfa treatment for 24 weeks significantly reduced uGAG excretion (dermatan sulfate: 64.8%, p < 0.0001). Most subjects (10/12) had a clinically meaningful improvement in at least one MDRI domain with an overall mean change (+/-SD) of +0.5 (+/-0.8) at Treatment Week 24 (p = 0.0527). Exposure-adjusted incidence rates of adverse events were similar between groups. CONCLUSIONS: The Blind Start study and MDRI design improve statistical power that enhances detection of a positive treatment effect in this rare heterogeneous disease and could be utilized for other ultra rare diseases. PMID- 29478820 TI - Fluxomic assay-assisted diagnosis orientation in a cohort of 11 patients with myopathic form of CPT2 deficiency. AB - Carnitine palmitoyltransferase type 2 (CPT2) deficiency, a mitochondrial fatty acid oxidation disorder (MFAOD), is a cause of myopathy in its late clinical presentation. As for other MFAODs, its diagnosis may be evocated when blood acylcarnitine profile is abnormal. However, a lack of abnormalities or specificity in this profile is not exclusive of CPT2 deficiency. Our retrospective study reports clinical and biological data in a cohort of 11 patients with circulating acylcarnitine profile unconclusive enough for a specific diagnosis orientation. In these patients, CPT2 gene studies was prompted by prior fluxomic explorations of mitochondrial beta-oxidation on intact whole blood cells incubated with pentadeuterated ([16-2H3, 15-2H2])-palmitate. Clinical indication for fluxomic explorations was at least one acute rhabdomyolysis episode complicated, in 5 of 11 patients, by acute renal failure. Major trigger of rhabdomyolysis was febrile infection. In all patients, fluxomic data indicated deficient CPT2 function showing normal deuterated palmitoylcarnitine (C16-Cn) formation rates associated with increased ratios between generated C16-Cn and downstream deuterated metabolites (Sigma deuterated C2-Cn to C14-Cn). Subsequent gene studies showed in all patients pathogenic gene variants in either homozygous or compound heterozygous forms. Consistent with literature data, allelic frequency of the c.338C > T[p.Ser113Leu] mutation amounted to 68.2% in our cohort. Other missense mutations included c.149C > A[p.Pro50His] (9%), c.200C > G[p.Ala200Gly] (4.5%) and previously unreported c.1171A > G[p.ser391Gly] (4.5%) and c.1420G > C[p.Ala474Pro] (4.5%) mutations. Frameshift c.1666 1667delTT[p.Leu556val*16] mutation (9%) was observed in two patients unknown to be related. PMID- 29478821 TI - Disease Variants of FGFR3 Reveal Molecular Basis for the Recognition and Additional Roles for Cdc37 in Hsp90 Chaperone System. AB - Receptor tyrosine kinase FGFR3 is involved in many signaling networks and is frequently mutated in developmental disorders and cancer. The Hsp90/Cdc37 chaperone system is essential for function of normal and neoplastic cells. Here we uncover the mechanistic inter-relationships between these proteins by combining approaches including NMR, HDX-MS, and SAXS. We show that several disease-linked mutations convert FGFR3 to a stronger client, where the determinant underpinning client strength involves an allosteric network through the N-lobe and at the lobe interface. We determine the architecture of the client kinase/Cdc37 complex and demonstrate, together with site-specific information, that binding of Cdc37 to unrelated kinases induces a common, extensive conformational remodeling of the kinase N-lobe, beyond localized changes and interactions within the binary complex. As further shown for FGFR3, this processing by Cdc37 deactivates the kinase and presents it, in a specific orientation established in the complex, for direct recognition by Hsp90. PMID- 29478822 TI - Conservation of Dynamics Associated with Biological Function in an Enzyme Superfamily. AB - Enzyme superfamily members that share common chemical and/or biological functions also share common features. While the role of structure is well characterized, the link between enzyme function and dynamics is not well understood. We present a systematic characterization of intrinsic dynamics of over 20 members of the pancreatic-type RNase superfamily, which share a common structural fold. This study is motivated by the fact that the range of chemical activity as well as molecular motions of RNase homologs spans over 105 folds. Dynamics was characterized using a combination of nuclear magnetic resonance experiments and computer simulations. Phylogenetic clustering led to the grouping of sequences into functionally distinct subfamilies. Detailed characterization of the diverse RNases showed conserved dynamical traits for enzymes within subfamilies. These results suggest that selective pressure for the conservation of dynamical behavior, among other factors, may be linked to the distinct chemical and biological functions in an enzyme superfamily. PMID- 29478823 TI - Characteristics of testicular tumors in prepubertal children (age 5-12 years). AB - INTRODUCTION: Testicular tumors in children have two peaks with different types of tumors; in the first 4 years of life a third to half are benign with increased risk of malignancy during puberty. The pathology of testicular tumors between these peaks, at the age of 5-12 years, is not known. We hypothesized that because of the low level of testosterone at this time, the incidence of malignant tumors is very low. OBJECTIVE: To compare malignancy risk of primary testicular tumors in children in the prepubertal period (5-12 years) compared with younger (0-4 years) and pubertal (13-18 years) children. STUDY DESIGN: We retrospectively (2002-2016) identified patients <18 years with surgery for primary testicular tumor. Patients with testicular tumor risk were excluded. Ultrasound studies were reviewed for contralateral testis volume, tumor morphology, and tumor maximal diameter, for three age groups: 0-4, 5-12, and 13-18 years. The Freeman-Halton extension of the Fisher exact probability test was adopted for categorical outcomes, and one-way ANOVA for continuous outcomes. RESULTS: Fifty-two patients (mean age 11.0 years, range 6 days-18 years) were identified. Malignant tumor prevalence significantly differed (p < 0.01) among age groups (Fig).: 0-4 (72.7%, 8/11), 5-12 (0%, 0/16), and 13-18 years (44.0%, 11/25). The most common tumor types in 5-12 years were epidermoid cyst (31.3%, 5/16) and tumor mimics (37.5%, 6/16). Prevalence of cystic tumors in 5-12 year olds was not significantly different compared with other age groups. Contralateral testicular volume >4 mL (pubertal surge) significantly (p < 0.01) differed among groups: 0-4 years (0/11), 5-12 years (3/16), and 13-18 years (19/20). In children aged 13-18 years the mean tumor maximal diameter (29.8 +/- 4.4 mm) was significantly larger (p < 0.01) compared with children 5-12 years (9.3 +/- 5.5 mm) and all malignant tumors had contralateral testicular volume >4 mL. DISCUSSION: We found that preadolescent children between the ages of 5 and 12 years have distinctive characteristics compared with the other age groups. Most importantly, no malignant testicular tumors were found in this age group. About a third of the children presented with an incidental testicular mass. The testicular tumors were significantly smaller (9.3 +/- 6.7 mm) compared with those in children aged 13-18 years (29.8 +/- 4.4 mm). There were limitations because of the retrospective nature of the study. CONCLUSION: We found no malignant testicular tumors in children aged 5-12 years with no risk factors and prior to pubertal surge. Our study suggests use of more conservative treatment in this group of patients. PMID- 29478824 TI - An unexpected player in Gaucher disease: The multiple roles of complement in disease development. AB - The complement system is well appreciated for its role as an important effector of innate immunity that is activated by the classical, lectin or alternative pathway. C5a is one important mediator of the system that is generated in response to canonical and non-canonical C5 cleavage by circulating or cell derived proteases. In addition to its function as a chemoattractant for neutrophils and other myeloid effectors, C5a and its sister molecule C3a have concerted roles in cell homeostasis and surveillance. Through activation of their cognate G protein coupled receptors, C3a and C5a regulate multiple intracellular pathways within the mitochondria and the lysosomal compartments that harbor multiple enzymes critical for protein, carbohydrate and lipid metabolism. Genetic mutations of such lysosomal enzymes or their receptors can result in the compartmental accumulation of specific classes of substrates in this organelle summarized as lysosomal storage diseases (LSD). A frequent LSD is Gaucher disease (GD), caused by autosomal recessively inherited mutations in GBA1, resulting in functional defects of the encoded enzyme, acid beta-glucosidase (glucocerebrosidase, GCase). Such mutations promote excessive accumulation of beta-glucosylceramide (GC or GL1) in innate and adaptive immune cells frequently associated with chronic inflammation. Recently, we uncovered an unexpected link between the C5a and C5a receptor 1 (C5aR1) axis and the accumulation of GL1 in experimental and clinical GD. Here, we will review the pathways of complement activation in GD, its role as a mediator of the inflammatory response, and its impact on glucosphingolipid metabolism. Further, we will discuss the potential role of the C5a/C5aR1 axis in GL1-specific autoantibody formation and as a novel therapeutic target in GD. PMID- 29478825 TI - Early postoperative and late metabolic morbidity after pancreatic resections: An old and new challenge for surgeons - A review. AB - The metrics for measuring early postoperative morbidity after resection of pancreatic neoplastic tumors are overall morbidity, severe surgery-related morbidity, frequency of reoperation and reintervention, in-hospital, 30-day and 90-day mortality and length of hospital stay. Thirty-day readmission after discharge is additionally an indispensable criterion to assess quality of surgery. The metrics for surgery-associated long-term results after pancreatic resections are survival times, new onset of diabetes (DM), impaired glucose tolerance, exocrine pancreatic insufficiency, body mass index and GI motility dysfunctions. Following pancreaticoduodenectomy (PD) performed on pancreatic normo-glycemic patients for malignant and benign tumors, 4-30% develop postoperative new onset of diabetes. Long-term persistence of diabetes mellitus is observed after surgery for benign tumors in 14% and in 15.5% of patients after cancer resection. Pancreatic exocrine insufficiency after PD is observed in the early postoperative period in 23-80% of patients. Persistence of exocrine dysfunctions exists in 25% and 49% of patients. Following left-sided pancreatic resection, new onset DM is observed in 14% of cases; an exocrine insufficiency persisting in the long-term outcome is observed in 16-28% of patients. PMID- 29478826 TI - Non-Technical Skills for Surgeons (NOTSS): Critical appraisal of its measurement properties. AB - BACKGROUND: To critically appraise the development and measurement properties, including sensibility, reliability, and validity of the Non-Technical Skills of Surgeons (NOTSS) system. DATA SOURCES: Articles that described development process of the NOTSS system were identified. Relevant primary studies that presented evidence of reliability and validity were identified through a comprehensive literature review. RESULTS: NOTSS was developed through robust item generation and reduction strategies. It was shown to have good content validity, acceptability, and feasibility. Inter-rater reliability increased with greater expertise and number of assessors. Studies demonstrated evidence of cross sectional construct validity, in that the tool was able to differentiate known groups of varied non-technical skill levels. Evidence of longitudinal construct validity also existed to demonstrate that NOTSS detected changes in non-technical skills before and after targeted training. CONCLUSION: In populations and settings presented in our critical appraisal, NOTSS provided reliable and valid measurements of intraoperative non-technical skills of surgeons. PMID- 29478827 TI - Social media in the mentorship and networking of physicians: Important role for women in surgical specialties. AB - BACKGROUND: Social media may be a useful supplement to physician and trainee interactions; however, its role in enhancing mentorship has not been described. METHODS: A 35-item survey investigating trainee and physician social media use was distributed. Responses were analyzed using descriptive statistics. RESULTS: 282 respondents completed the survey, among whom 136 (48.2%) reported careers in surgical specialties. Women in surgical specialties were more likely to describe the specialty as being dominated by the opposite sex (p < 0.001) and to be mentored by the opposite sex though wish to be mentored by individuals of the same sex (p < 0.001). Respondents in surgical specialties were also more likely to report using social media to build a network of same-sex mentorship (p = 0.031). CONCLUSIONS: Social media serves as a valuable tool to enhance the networking and mentorship of surgeons, particularly for women in surgical specialties who may lack exposure to same-sex mentors at their own institution. PMID- 29478828 TI - Primary pancreatic perivascular epithelioid cell tumor (PEComa): A surgical enigma. A systematic review of the literature. AB - BACKGROUND: Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal tumor, with distinctive morphology and expression of myo-melanocytic markers. Current scientific literature reported just 24 cases of pancreatic PEComas. With our systematic review, we aimed at improving our understanding of the disease, focusing on the knowledge gained on epidemiology, etiology, clinical presentation, diagnosis, treatment and prognosis. METHODS: Based on the PRISMA guidelines, a systematic research was carried out on PubMed/MEDLINE, Web of Science, Scopus, EMBASE, and EBSCO using the search terms: ("perivascular epithelioid cell tumor" OR "PEComa") and ("pancreas "OR" pancreatic"). RESULTS: The 4th-6th decades of life and female sex (86.9%) turned out as the most affected. Pancreatic head was the most involved site (50%), with a single lesion in almost all cases. The diagnosis was only obtained after histopathological examination (70.8%). The clinical presentation was non-specific, abdominal pain being the main symptom (60.9%). At immunohistochemistry, PEComa showed benign epithelioid predominance and a strong positivity for HMB-45, Melan-A, and alpha SMA. Surgical resection was performed in almost all cases, while for one patient the multidisciplinary group chose just endoscopic and imaging follow-up, based on the benign nature of the lesion. CONCLUSIONS: The biological characteristics of pancreatic PEComa remain an enigma. Its prognosis seems to depend on whether atypical ("worrisome") histological features are available or not. Surgery turned out as the most appropriate treatment, without reaching any agreement on surgery timing. Further studies on larger population are needed to better understand the biological features of pancreatic PEComa, in order to set up guidelines in the diagnosis, treatment and follow-up. PMID- 29478829 TI - Electrospun UiO-66/polyacrylonitrile nanofibers as efficient sorbent for pipette tip solid phase extraction of phytohormones in vegetable samples. AB - In this work, metal-organic framework particles incorporated fibers (UiO-66/PAN nanofibers) were used as adsorbent in pipette tip solid phase extraction (PT-SPE) for the first time. The UiO-66/PAN nanofibers were fabricated by a facile electrospinning method and characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, X-ray diffraction and nitrogen adsorption-desorption experiments. The UiO-66/PAN nanofibers were applied to assemble a novel PT-SPE cartridge for determination of four phytohormones followed by high performance liquid chromatography (HPLC). Several experimental parameters such as kinds of UiO-66/PAN nanofibers, the amount of UiO-66/PAN nanofibers, the effect of solution pH, ionic strength and desorption conditions were intensively investigated. Under the optimal conditions, the linear ranges of the phytohormones were in the range of 0.06-60 ng/mL with correlation coefficients above 0.992. The limits of detection were between 0.01 ng/mL to 0.02 ng/mL. The interday and intraday precision (RSD) for three replicate extractions of the four phytohormones (15 ng/mL for each) was in the range of 1.5-5.6%. The established method was successfully applied for the determination of phytohormones in watermelon and mung bean sprouts samples. The results showed that the electrostatic interaction between the positively charged UiO-66 and anionic forms of phytohormones played an important role in the extraction of the phytohormones. PMID- 29478830 TI - Determination of free formaldehyde in cosmetics containing formaldehyde-releasing preservatives by reversed-phase dispersive liquid-liquid microextraction and liquid chromatography with post-column derivatization. AB - An analytical method for the determination of traces of formaldehyde in cosmetic products containing formaldehyde-releasing preservatives has been developed. The method is based on reversed-phase dispersive liquid-liquid microextraction (RP DLLME), that allows the extraction of highly polar compounds, followed by liquid chromatography-ultraviolet/visible (LC-UV/vis) determination with post-column derivatization. The variables involved in the RP-DLLME process were studied to provide the best enrichment factors. Under the selected conditions, a mixture of 500 MUL of acetonitrile (disperser solvent) and 50 MUL of water (extraction solvent) was rapidly injected into 5 mL of toluene sample solution. The extracts were injected into the LC-UV/vis system using phosphate buffer 6 mmol L-1 at pH 2 as mobile phase. After chromatographic separation, the eluate merged with a flow stream of pentane-2,4-dione in ammonium acetate solution as derivatizing reagent and passed throughout a post-column reactor at 85 degrees C in order to derivatize formaldehyde into 3,5-diacetyl-1,4-dihydrolutidine, according to Hantzsch reaction, which was finally measured spectrophotometrically at 407 nm. The method was successfully validated showing good linearity, an enrichment factor of 86 +/- 2, limits of detection and quantification of 0.7 and 2.3 ng mL 1, respectively, and good repeatability (RSD < 9.2%). Finally, the proposed analytical method was applied to the determination of formaldehyde in different commercial cosmetic samples containing formaldehyde-releasing preservatives, such as bronopol, diazolidinyl urea, imidazolidinyl urea, and DMDM hydantoin, with good relative recovery values (91-113%) thus showing that matrix effects were negligible. The good analytical features of the proposed method besides of its simplicity and affordability, make it useful to carry out the quality control of cosmetic products containing formaldehyde-releasing preservatives. PMID- 29478831 TI - Cyclodextrin based polymer sorbents for micro-solid phase extraction followed by liquid chromatography tandem mass spectrometry in determination of endogenous steroids. AB - Sorbents were prepared by cross-linking beta-cyclodextrin (beta-CD) using two different types of cross-linker units at variable reactant mole ratios. The resulting polymers containing beta-CD were evaluated as sorbents in micro-solid phase extraction (MU-SPE) format for the extraction of the endogenous steroids testosterone (T), epitestosterone (E), androsterone (A), etiocholanolone (Etio), 5alpha-androstane-3alpha,17beta-diol (5alphaAdiol) and 5beta-androstane 3alpha,17beta-diol (5betaAdiol). The best sorbent (C1; cyclodextrin polymer) showed superior extraction characteristics compared with commercial sorbents (C18 and Bond Elut Plexa). Parameters influencing the extraction efficiency of the C1 sorbent such as extraction and desorption times, desorption solvent and volume of sample were investigated. The extracts were separated using a Hypersil Gold column (50 * 2.1 mm, 1.9 MUm) under gradient elution coupled to a LC-MS/MS. The compounds were successfully separated within 8 min. The method offers good repeatability (RSD < 10%) and linearity (r2 > 0.995) were within the range of 1 200 ng mL-1 for T and E, 250-4000 ng mL-1 for A and Etio and 25-500 ng mL-1 for 5alphaAdiol and 5betaAdiol, respectively. The method was applied for the determination of steroid profile of urine from volunteers. PMID- 29478832 TI - Systematic review into obesity and weight gain within male prisons. AB - OBJECTIVES: To review current studies on obesity and weight within male prisoners. Including assessment of factors which influence obesity and weight change during imprisonment. STUDY DESIGN: A systematic review. METHODS: The systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. A literature search was conducted using defined exclusion and inclusion criteria for relevant studies published between 2000 and 2016. RESULTS: The findings show the prevalence rates of obesity for prisoners range from 8.1% to 55.6%, with prison population often having lower levels of obesity than the general population. The findings are inconclusive into those factors that influence weight change and obesity during imprisonment, though potential factors and their mechanisms are highlighted. CONCLUSION: Current literature highlights the complex relationship between imprisonment and weight. A significant amount of evidence exists to suggest that obesity levels are similar or lower in prison population compared to the general population. Future research might explore more intensively the various factors influencing prisoners' weight change within prison, including food, diet, activity levels and other relevant factors in relation to weight change, using both quantitative and qualitative methods. PMID- 29478833 TI - Shifting perspectives - Planning for the future of the pharmacy profession taking current labor market trends into consideration. AB - The future of the pharmacy profession and concerns about professional identity have been popular and recurring themes in professional journals and at international pharmacy conferences for more than 30 years. The aim of this paper is to contribute to realistic and viable visions for the future of the pharmacy profession via insights through labor market and work organization theories. These insights provide an understanding of contemporary work patterns and what they mean for the future role of community pharmacists. It appears that an important and influential contemporary trend in work organization today is precarious work, i.e. non-standard employment that promotes and relies on a flexible and fluid work force. Contrary to permanent employment, precarious work is often poorly paid, insecure, unprotected, and in many cases cannot support a household. The growth of precarious work among professionals, including pharmacists has been documented in many countries. In the early 21st century a major concern in the UK was the growth in the number of pharmacists who choose to be self-employed "locums" as opposed to seeking permanent employment. With the spread of precarious work a new, involuntary form of employment appeared a decade later with the spread of "zero-hour contracts" and "exclusivity agreements". Particularly affected by these flexible, precarious work conditions are the highly-educated young health professionals such as pharmacists. The profession needs to be proactive in order to stay abreast of economic/workforce and organizational trends. The way forward is a commitment to a dynamic, knowledge based vision that includes an ongoing analysis of the outside world. The core role of pharmacists in the future includes: 1. engagement in interprofessional education with other healthcare professionals; 2. an acceptance of the contribution that lay knowledge provides to the understanding of health and medicines, and 3.keeping ajour with new and revolutionary treatments, both pharmaceutical and non-pharmacological. PMID- 29478834 TI - Circadian Control of DRP1 Activity Regulates Mitochondrial Dynamics and Bioenergetics. AB - Mitochondrial fission-fusion dynamics and mitochondrial bioenergetics, including oxidative phosphorylation and generation of ATP, are strongly clock controlled. Here we show that these circadian oscillations depend on circadian modification of dynamin-related protein 1 (DRP1), a key mediator of mitochondrial fission. We used a combination of in vitro and in vivo models, including human skin fibroblasts and DRP1-deficient or clock-deficient mice, to show that these dynamics are clock controlled via circadian regulation of DRP1. Genetic or pharmacological abrogation of DRP1 activity abolished circadian network dynamics and mitochondrial respiratory activity and eliminated circadian ATP production. Pharmacological silencing of pathways regulating circadian metabolism and mitochondrial function (e.g., sirtuins, AMPK) also altered DRP1 phosphorylation, and abrogation of DRP1 activity impaired circadian function. Our findings provide new insight into the crosstalk between the mitochondrial network and circadian cycles. PMID- 29478835 TI - A wrinkle in ON-time - A GI structural abnormality confounding levodopa therapy with Duodopa rescue; a case study. PMID- 29478837 TI - Purpose: A Slow Dawning For Us All? PMID- 29478836 TI - Sex differences in progression to mild cognitive impairment and dementia in Parkinson's disease. AB - INTRODUCTION: Identification of factors associated with progression of cognitive symptoms in Parkinson's disease (PD) is important for treatment planning, clinical care, and design of future clinical trials. The current study sought to identify whether prediction of cognitive progression is aided by examining baseline cognitive features, and whether this differs according to stage of cognitive disease. METHODS: Participants with PD in the Pacific Udall Center Clinical Consortium who had longitudinal data available and were nondemented at baseline were included in the study (n = 418). Logistic and Cox regression models were utilized to examine the relationship between cognitive, demographic, and clinical variables with risk and time to progression from no cognitive impairment to mild cognitive impairment (PD-MCI) or dementia (PDD), and from PD-MCI to PDD. RESULTS: Processing speed (OR = 1.05, p = 0.009) and working memory (OR = 1.01, p = 0.03) were associated with conversion to PDD among those with PD-MCI at baseline, over and above demographic variables. Conversely, the primary predictive factor in the transition from no cognitive impairment to PD-MCI or PDD was male sex (OR = 4.47, p = 0.004), and males progressed more rapidly than females (p = 0.01). Further, among females with shorter disease duration, progression was slower than for their male counterparts, and poor baseline performance on semantic verbal fluency was associated with shorter time to cognitive impairment in females but not in males. CONCLUSIONS: This study provides evidence for sex differences in the progression to cognitive impairment in PD, while specific cognitive features become more important indicators of progression with impending conversion to PDD. PMID- 29478838 TI - Molecular characterization, toxin detection and resistance testing of human clinical Clostridium difficile isolates from Lebanon. AB - Clostridium (Clostridioides) difficile is the main cause for nosocomial diarrhoea in industrialised nations. Epidemiologic data on the pathogen's occurrence in other world regions are still scarce. In this context we characterized with phenotypic and molecular genetic methods C. difficile isolates stemming from hospitalised patients with diarrhoea in Lebanon. From 129 stool samples of symptomatic patients at a tertiary care University hospital in Lebanon, a total of 107 C. difficile strains were cultivated and underwent ribotyping, toxin gene detection and antibiotic resistance testing. Ribotype 014 (RT014, 16.8%) predominated, followed by RT002 (9.3%), RT106 (8.4%) and RT070 (6.5%). Binary toxin gene-positive isolates (RT023, RT078 and RT126) were rarely detected and RT027 was absent. Interestingly, within one isolate only the toxin A gene (tcdA) was detected. Multiple-locus variable-number tandem repeat analysis (MLVA) revealed strong strain diversity in most RTs. The isolates were sensitive to metronidazole and vancomycin, and only a small proportion of strains displayed resistance against moxifloxacin, rifampicin, and clarithromycin (5.6%, 1.9%, and 2.8%), respectively. The data indicate that the genetic strain composition of Lebanese strains differs markedly from the situation seen in Europe and North America. Especially the epidemic RTs seen in the latter regions were almost absent in Lebanon. Interestingly, most strains showed almost no resistance to commonly used antibiotics that are suspected to play a major role in the development of C. difficile infection, despite frequent use of these antibiotics in Lebanon. Thus, the role of antimicrobial resistance as a major driving force for infection development remains uncertain in this area. PMID- 29478839 TI - Poor ovarian response as a predictor for live birth in older women undergoing IVF. AB - Women of advanced age present a major challenge for fertility treatments. This study was designed to assess whether poor ovarian response (POR) according to the Bologna criteria is a significant predictor for live birth in women over 40. The outcomes of subsequent IVF cycles were also studied. The results of 1870 fresh IVF cycles in 1212 women were retrospectively analysed. The live birth per cycle was 3.3 times higher (11.61% versus 3.54%, P < 0.001) in good responders with more than three oocytes collected compared with women with less. Ovarian response defined by oocytes collected, but not by the number of follicles, was independently associated with live birth (odds ratio, 2.0; 95% confidence interval, 1.18 to 3.54; P = 0.009). The occurrence of POR in subsequent IVF cycles was only 55%. No differences in live births were found in persistent POR compared with women with at least one good response. A single episode of POR in a first IVF cycle in older women has a limited predictive value for the outcomes of subsequent cycles. POR in women aged 40-43 years, defined by the number of oocytes retrieved, is a predictor for live birth in IVF. PMID- 29478840 TI - Investigation of anti-Mullerian hormone concentrations in relation to natural conception rate and time to pregnancy. AB - The objectives of this study were to investigate whether anti-Mullerian hormone (AMH) concentrations can predict pregnancy rates and time to pregnancy (TTP) in women attempting to conceive naturally/having an unplanned conception, and whether there is a lower AMH threshold compatible with natural conception. This prospective cohort study included 260 women aged 25-42 years in two subcohorts: (A) healthcare workers at Rigshospitalet (2008-2010), and (B) women consulting the Fertility Assessment and Counselling Clinic (2011-2014), Rigshospitalet, Denmark. Pregnancy rates and TTP at 2-year follow-up were stratified into AMH groups: low: < 9.5 pmol/l, intermediate: 9.5-33 pmol/l, high: > 33 pmol/l. Pregnancy rates increased with increasing AMH: 60.1% (low) versus 70.0% (intermediate) versus 78.3% (high) (P = 0.03). The highest pregnancy rate (84.1%) was seen in regular cycling women with high AMH. TTP was reduced in women with high AMH compared with intermediate or low AMH (stepwise trend test P = 0.01). Natural conceptions were observed with AMH concentrations down to 1.2 pmol/l. In conclusion, high AMH, especially in ovulatory women, was associated with higher pregnancy rates. Nonetheless, TTP reflected a large variation in fecundity within similar AMH concentrations and natural conceptions occurred with AMH down to 1.2 pmol/l. PMID- 29478842 TI - CABG the clear choice for patients with diabetes and multivessel disease. PMID- 29478841 TI - Mortality after coronary artery bypass grafting versus percutaneous coronary intervention with stenting for coronary artery disease: a pooled analysis of individual patient data. AB - BACKGROUND: Numerous randomised trials have compared coronary artery bypass grafting (CABG) with percutaneous coronary intervention (PCI) for patients with coronary artery disease. However, no studies have been powered to detect a difference in mortality between the revascularisation strategies. METHODS: We did a systematic review up to July 19, 2017, to identify randomised clinical trials comparing CABG with PCI using stents. Eligible studies included patients with multivessel or left main coronary artery disease who did not present with acute myocardial infarction, did PCI with stents (bare-metal or drug-eluting), and had more than 1 year of follow-up for all-cause mortality. In a collaborative, pooled analysis of individual patient data from the identified trials, we estimated all cause mortality up to 5 years using Kaplan-Meier analyses and compared PCI with CABG using a random-effects Cox proportional-hazards model stratified by trial. Consistency of treatment effect was explored in subgroup analyses, with subgroups defined according to baseline clinical and anatomical characteristics. FINDINGS: We included 11 randomised trials involving 11 518 patients selected by heart teams who were assigned to PCI (n=5753) or to CABG (n=5765). 976 patients died over a mean follow-up of 3.8 years (SD 1.4). Mean Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) score was 26.0 (SD 9.5), with 1798 (22.1%) of 8138 patients having a SYNTAX score of 33 or higher. 5 year all-cause mortality was 11.2% after PCI and 9.2% after CABG (hazard ratio [HR] 1.20, 95% CI 1.06-1.37; p=0.0038). 5 year all-cause mortality was significantly different between the interventions in patients with multivessel disease (11.5% after PCI vs 8.9% after CABG; HR 1.28, 95% CI 1.09-1.49; p=0.0019), including in those with diabetes (15.5% vs 10.0%; 1.48, 1.19-1.84; p=0.0004), but not in those without diabetes (8.7% vs 8.0%; 1.08, 0.86-1.36; p=0.49). SYNTAX score had a significant effect on the difference between the interventions in multivessel disease. 5 year all-cause mortality was similar between the interventions in patients with left main disease (10.7% after PCI vs 10.5% after CABG; 1.07, 0.87-1.33; p=0.52), regardless of diabetes status and SYNTAX score. INTERPRETATION: CABG had a mortality benefit over PCI in patients with multivessel disease, particularly those with diabetes and higher coronary complexity. No benefit for CABG over PCI was seen in patients with left main disease. Longer follow-up is needed to better define mortality differences between the revascularisation strategies. FUNDING: None. PMID- 29478843 TI - A mimetic nesting association between a timid social wasp and an aggressive arboreal ant. AB - In French Guiana, the arboreal nests of the swarm-founding social wasp Protopolybia emortualis (Polistinae) are generally found near those of the arboreal dolichoderine ant Dolichoderus bidens. These wasp nests are typically protected by an envelope, which in turn is covered by an additional carton 'shelter' with structure resembling the D. bidens nests. A few wasps constantly guard their nest to keep D. bidens workers from approaching. When alarmed by a strong disturbance, the ants invade the host tree foliage whereas the wasps retreat into their nest. Notably, there is no chemical convergence in the cuticular profiles of the wasps and ants sharing a tree. The aggressiveness of D. bidens likely protects the wasps from army ant raids, but the ants do not benefit from the presence of the wasps; therefore, this relationship corresponds to a kind of commensalism. PMID- 29478846 TI - Volatile Anesthesia for Carotid Endarterectomy: Friend or Foe for the Brain? PMID- 29478845 TI - The potential of heart rate variability for exploring dental anxiety in mandibular third molar surgery. AB - An objective method to recognize patient psychology using heart rate variability (HRV) has recently been developed and is increasingly being used in medical practice. This study compared the potential of this new method with the use of conventional surveys measuring anxiety levels in patients undergoing impacted third molar (ITM) surgery. Patient anxiety was examined before treatment in 64 adults who required ITM surgery, using two methods: measurement of HRV and conventional questionnaire surveys (state section of the State-Trait Anxiety Inventory (STAI-S) and Dental Fear Survey (DFS)). Both methods were assessed for their respective abilities to determine the impact of personal background, the amount of information provided, and the surgical procedure on patient psychology. Questionnaires and HRV yielded the same finding: dental experience was the single background factor that correlated with patient anxiety; the other factors remain unclear. The STAI-S showed a significant relationship between the information provided to the patient and their anxiety level, while the DFS and HRV did not. In addition, HRV demonstrated its ability to assess the effects of the surgical procedure on patient psychology. HRV demonstrated great potential as an objective method for evaluating patient stress, especially for providing real-time information on the patient's status. PMID- 29478844 TI - Macrophage-Derived Extracellular Succinate Licenses Neural Stem Cells to Suppress Chronic Neuroinflammation. AB - Neural stem cell (NSC) transplantation can influence immune responses and suppress inflammation in the CNS. Metabolites, such as succinate, modulate the phenotype and function of immune cells, but whether and how NSCs are also activated by such immunometabolites to control immunoreactivity and inflammatory responses is unclear. Here, we show that transplanted somatic and directly induced NSCs ameliorate chronic CNS inflammation by reducing succinate levels in the cerebrospinal fluid, thereby decreasing mononuclear phagocyte (MP) infiltration and secondary CNS damage. Inflammatory MPs release succinate, which activates succinate receptor 1 (SUCNR1)/GPR91 on NSCs, leading them to secrete prostaglandin E2 and scavenge extracellular succinate with consequential anti inflammatory effects. Thus, our work reveals an unexpected role for the succinate SUCNR1 axis in somatic and directly induced NSCs, which controls the response of stem cells to inflammatory metabolic signals released by type 1 MPs in the chronically inflamed brain. PMID- 29478847 TI - [Hyperthyroidism and breast cancer: Is there a link?] AB - : The objective of this review was to determine whether there is an association between hyperthyroidism and the risk of developing a breast cancer from the analysis of data in the literature. METHOD: The analyzed articles were extracted from the PUBMED database from 2002 to 2017 using the following keywords "hyperthyroidism AND breast cancer" and "thyroid AND breast cancer". RESULTS: A total of 22 studies were selected, including 8 cohort studies, 12 case-control studies and 2 meta-analyzes. Of these 22 studies, 15 have established a significant epidemiological or biological link between hyperthyroidism and breast cancer. Five of them were particularly interested in Graves' disease, and four demonstrated a positive association between this disease and the onset of breast cancer, especially within three years from the thyropathy diagnosis. These different studies also highlighted the increased risk of breast cancer seen in overweight or postmenopausal women. Contradictions persist over the types of mammary cancers observed and their prognosis. CONCLUSION: This review reveals that women with hyperthyroidism appear to have a moderately high risk of breast cancer (RR<2). These data are corroborated by solid physiopathological hypotheses. Regardless of the type of thyropathy responsible for hyperthyroidism, care should be taken to ensure that these patients receive a clinical examination of the breasts on an annual basis and mammographic screening every 2 years from the age of 50 years. PMID- 29478849 TI - Bridging the Gap: Drug and Alcohol Screening in Adolescent Trauma Patients. PMID- 29478848 TI - A magnetically separable and recyclable Ag-supported magnetic TiO2 composite catalyst: Fabrication, characterization, and photocatalytic activity. AB - In this study, a magnetically separable, highly active, and recyclable photocatalyst was synthesized by physico-chemical incorporation of Ag, TiO2, and Fe3O4 into one structure. The physical and chemical properties of the catalysts were evaluated by X-ray diffraction, X-ray fluorescence spectrometry, scanning electron microscopy, field emission transmission electron microscopy, energy dispersive X-ray spectroscopy, and diffuse reflectance spectroscopy. The Ag supported magnetic TiO2 composite demonstrated desirable properties and features such as a narrow band gap of 1.163 eV, modifiable structure, and high degradation efficiency. The activity and durability of the synthesized photocatalyst in the degradation of methyl orange (MO) in aqueous solutions under visible light irradiation and different experimental conditions were evaluated and compared to those of commercial TiO2 and Ag/TiO2 composites. It was found that the synthesized composite showed a much higher MO photodegradation efficiency than the other composites under visible light irradiation. Moreover, it exhibited a high photocatalytic activity and was recoverable and durable; its photocatalytic efficiency in MO removal was consistently higher than 93.1% after five reuses without any evident signs of deactivation. Thus, the developed photocatalyst is a very promising material for practical applications in environmental pollution remediation. PMID- 29478850 TI - The Impact of Emergency Department RN Staffing on ED Patient Experience. AB - INTRODUCTION: Patient experience ratings are important to health care organizations from both a clinical and financial perspective. Studies examining the relationship between patient experience and nurse staffing are prevalent in the inpatient setting, but not as much is known about how staffing affects these ratings in the emergency department. METHODS: Using responses from 3,120 adult patients who visited the emergency department of a large academic medical center in the southeastern United States between March 1, 2015, and November 30, 2015, this study examined the relationships between ED RN staffing and patient experience ratings. Ordinal logistic regression models were used to examine the relationship between 2 nurse staffing variables and patient ratings of care. RESULTS: Overall, higher levels of RN staffing in the emergency department were associated with better patient ratings of their care experiences, but the strength and significance of this relationship varied as a function of different factors (eg, how staffing is measured, discharge status of the patient). DISCUSSION: Higher levels of ED RNs may enable nurses to better meet the expectations of patients presenting to the emergency department, highlighting a number of opportunities for allocating nursing resources. PMID- 29478851 TI - Drosophila Full-Length Amyloid Precursor Protein Is Required for Visual Working Memory and Prevents Age-Related Memory Impairment. AB - The beta-amyloid precursor protein (APP) plays a central role in the etiology of Alzheimer's disease (AD). However, its normal physiological functions are still unclear. APP is cleaved by various secretases whereby sequential processing by the beta- and gamma-secretases produces the beta-amyloid peptide that is accumulating in plaques that typify AD. In addition, this produces secreted N terminal sAPPbeta fragments and the APP intracellular domain (AICD). Alternative cleavage by alpha-secretase results in slightly longer secreted sAPPalpha fragments and the identical AICD. Whereas the AICD has been connected with transcriptional regulation, sAPPalpha fragments have been suggested to have a neurotrophic and neuroprotective role [1]. Moreover, expression of sAPPalpha in APP-deficient mice could rescue their deficits in learning, spatial memory, and long-term potentiation [2]. Loss of the Drosophila APP-like (APPL) protein impairs associative olfactory memory formation and middle-term memory that can be rescued with a secreted APPL fragment [3]. We now show that APPL is also essential for visual working memory. Interestingly, this short-term memory declines rapidly with age, and this is accompanied by enhanced processing of APPL in aged flies. Furthermore, reducing secretase-mediated proteolytic processing of APPL can prevent the age-related memory loss, whereas overexpression of the secretases aggravates the aging effect. Rescue experiments confirmed that this memory requires signaling of full-length APPL and that APPL negatively regulates the neuronal-adhesion molecule Fasciclin 2. Overexpression of APPL or one of its secreted N termini results in a dominant-negative interaction with the FASII receptor. Therefore, our results show that specific memory processes require distinct APPL products. PMID- 29478852 TI - A Conserved Role of the Unconventional Myosin 1d in Laterality Determination. AB - Anatomical and functional asymmetries are widespread in the animal kingdom [1, 2]. In vertebrates, many visceral organs are asymmetrically placed [3]. In snails, shells and inner organs coil asymmetrically, and in Drosophila, genitalia and hindgut undergo a chiral rotation during development. The evolutionary origin of these asymmetries remains an open question [1]. Nodal signaling is widely used [4], and many, but not all, vertebrates use cilia for symmetry breaking [5]. In Drosophila, which lacks both cilia and Nodal, the unconventional myosin ID (myo1d) gene controls dextral rotation of chiral organs [6, 7]. Here, we studied the role of myo1d in left-right (LR) axis formation in Xenopus. Morpholino oligomer-mediated myo1d downregulation affected organ placement in >50% of morphant tadpoles. Induction of the left-asymmetric Nodal cascade was aberrant in >70% of cases. Expression of the flow-target gene dand5 was compromised, as was flow itself, due to shorter, fewer, and non-polarized cilia at the LR organizer. Additional phenotypes pinpointed Wnt/planar cell polarity signaling and suggested that myo1d, like in Drosophila [8], acted in the context of the planar cell polarity pathway. Indeed, convergent extension of gastrula explant cultures was inhibited in myo1d morphants, and the ATF2 reporter gene for non-canonical Wnt signaling was downregulated. Finally, genetic interference experiments demonstrated a functional interaction between the core planar cell polarity signaling gene vangl2 and myo1d in LR axis formation. Thus, our data identified myo1d as a common denominator of arthropod and chordate asymmetry, in agreement with a monophyletic origin of animal asymmetry. PMID- 29478854 TI - The Auxin-Regulated CrRLK1L Kinase ERULUS Controls Cell Wall Composition during Root Hair Tip Growth. AB - Root hairs facilitate a plant's ability to acquire soil anchorage and nutrients. Root hair growth is regulated by the plant hormone auxin and dependent on localized synthesis, secretion, and modification of the root hair tip cell wall. However, the exact cell wall regulators in root hairs controlled by auxin have yet to be determined. In this study, we describe the characterization of ERULUS (ERU), an auxin-induced Arabidopsis receptor-like kinase, whose expression is directly regulated by ARF7 and ARF19 transcription factors. ERU belongs to the Catharanthus roseus RECEPTOR-LIKE KINASE 1-LIKE (CrRLK1L) subfamily of putative cell wall sensor proteins. Imaging of a fluorescent fusion protein revealed that ERU is localized to the apical root hair plasma membrane. ERU regulates cell wall composition in root hairs and modulates pectin dynamics through negative control of pectin methylesterase (PME) activity. Mutant eru (-/-) root hairs accumulate de-esterified homogalacturonan and exhibit aberrant pectin Ca2+-binding site oscillations and increased PME activity. Up to 80% of the eru root hair phenotype is rescued by pharmacological supplementation with a PME-inhibiting catechin extract. ERU transcription is altered in specific cell wall-related root hair mutants, suggesting that it is a target for feedback regulation. Loss of ERU alters the phosphorylation status of FERONIA and H+-ATPases 1/2, regulators of apoplastic pH. Furthermore, H+-ATPases 1/2 and ERU are differentially phosphorylated in response to auxin. We conclude that ERULUS is a key auxin controlled regulator of cell wall composition and pectin dynamics during root hair tip growth. PMID- 29478853 TI - Remodeling the Specificity of an Endosomal CORVET Tether Underlies Formation of Regulated Secretory Vesicles in the Ciliate Tetrahymena thermophila. AB - In the endocytic pathway of animals, two related complexes, called CORVET (class C core vacuole/endosome transport) and HOPS (homotypic fusion and protein sorting), act as both tethers and fusion factors for early and late endosomes, respectively. Mutations in CORVET or HOPS lead to trafficking defects and contribute to human disease, including immune dysfunction. HOPS and CORVET are conserved throughout eukaryotes, but remarkably, in the ciliate Tetrahymena thermophila, the HOPS-specific subunits are absent, while CORVET-specific subunits have proliferated. VPS8 (vacuolar protein sorting), a CORVET subunit, expanded to 6 paralogs in Tetrahymena. This expansion correlated with loss of HOPS within a ciliate subgroup, including the Oligohymenophorea, which contains Tetrahymena. As uncovered via forward genetics, a single VPS8 paralog in Tetrahymena (VPS8A) is required to synthesize prominent secretory granules called mucocysts. More specifically, Deltavps8a cells fail to deliver a subset of cargo proteins to developing mucocysts, instead accumulating that cargo in vesicles also bearing the mucocyst-sorting receptor Sor4p. Surprisingly, although this transport step relies on CORVET, it does not appear to involve early endosomes. Instead, Vps8a associates with the late endosomal/lysosomal marker Rab7, indicating that target specificity switching occurred in CORVET subunits during the evolution of ciliates. Mucocysts belong to a markedly diverse and understudied class of protist secretory organelles called extrusomes. Our results underscore that biogenesis of mucocysts depends on endolysosomal trafficking, revealing parallels with invasive organelles in apicomplexan parasites and suggesting that a wide array of secretory adaptations in protists, like in animals, depend on mechanisms related to lysosome biogenesis. PMID- 29478856 TI - Electrophysiological Correlates of Semantic Dissimilarity Reflect the Comprehension of Natural, Narrative Speech. AB - People routinely hear and understand speech at rates of 120-200 words per minute [1, 2]. Thus, speech comprehension must involve rapid, online neural mechanisms that process words' meanings in an approximately time-locked fashion. However, electrophysiological evidence for such time-locked processing has been lacking for continuous speech. Although valuable insights into semantic processing have been provided by the "N400 component" of the event-related potential [3-6], this literature has been dominated by paradigms using incongruous words within specially constructed sentences, with less emphasis on natural, narrative speech comprehension. Building on the discovery that cortical activity "tracks" the dynamics of running speech [7-9] and psycholinguistic work demonstrating [10-12] and modeling [13-15] how context impacts on word processing, we describe a new approach for deriving an electrophysiological correlate of natural speech comprehension. We used a computational model [16] to quantify the meaning carried by words based on how semantically dissimilar they were to their preceding context and then regressed this measure against electroencephalographic (EEG) data recorded from subjects as they listened to narrative speech. This produced a prominent negativity at a time lag of 200-600 ms on centro-parietal EEG channels, characteristics common to the N400. Applying this approach to EEG datasets involving time-reversed speech, cocktail party attention, and audiovisual speech in-noise demonstrated that this response was very sensitive to whether or not subjects understood the speech they heard. These findings demonstrate that, when successfully comprehending natural speech, the human brain responds to the contextual semantic content of each word in a relatively time-locked fashion. PMID- 29478855 TI - Insulin Signaling Regulates Oocyte Quality Maintenance with Age via Cathepsin B Activity. AB - A decline in female reproduction is one of the earliest hallmarks of aging in many animals, including invertebrates and mammals [1-4]. The insulin/insulin-like growth factor-1 signaling (IIS) pathway has a conserved role in regulating longevity [5] and also controls reproductive aging [2, 6]. Although IIS transcriptional targets that regulate somatic aging have been characterized [7, 8], it was not known whether the same mechanisms influence reproductive aging. We previously showed that Caenorhabditis elegans daf-2 IIS receptor mutants extend reproductive span by maintaining oocyte quality with age [6], but IIS targets in oocytes had not been identified. Here, we compared the transcriptomes of aged daf 2(-) and wild-type oocytes, and distinguished IIS targets in oocytes from soma specific targets. Remarkably, IIS appears to regulate reproductive and somatic aging through largely distinct mechanisms, although the binding motif for longevity factor PQM-1 [8] was also overrepresented in oocyte targets. Reduction of oocyte-specific IIS targets decreased reproductive span extension and oocyte viability of daf-2(-) worms, and pqm-1 is required for daf-2(-)'s long reproductive span. Cathepsin-B-like gene expression and activity levels were reduced in aged daf-2(-) oocytes, and RNAi against cathepsin-B-like W07B8.4 improved oocyte quality maintenance and extended reproductive span. Importantly, adult-only pharmacological inhibition of cathepsin B proteases reduced age dependent deterioration in oocyte quality, even when treatment was initiated in mid-reproduction. This suggests that it is possible to pharmacologically slow age related reproductive decline through mid-life intervention. Oocyte-specific IIS target genes thereby revealed potential therapeutic targets for maintaining reproductive health with age. PMID- 29478857 TI - Precise Motor Control Enables Rapid Flexibility in Vocal Behavior of Marmoset Monkeys. AB - Investigating the evolution of human speech is difficult and controversial because human speech surpasses nonhuman primate vocal communication in scope and flexibility [1-3]. Monkey vocalizations have been assumed to be largely innate, highly affective, and stereotyped for over 50 years [4, 5]. Recently, this perception has dramatically changed. Current studies have revealed distinct learning mechanisms during vocal development [6-8] and vocal flexibility, allowing monkeys to cognitively control when [9, 10], where [11], and what to vocalize [10, 12, 13]. However, specific call features (e.g., duration, frequency) remain surprisingly robust and stable in adult monkeys, resulting in rather stereotyped and discrete call patterns [14]. Additionally, monkeys seem to be unable to modulate their acoustic call structure under reinforced conditions beyond natural constraints [15, 16]. Behavioral experiments have shown that monkeys can stop sequences of calls immediately after acoustic perturbation but cannot interrupt ongoing vocalizations, suggesting that calls consist of single impartible pulses [17, 18]. Using acoustic perturbation triggered by the vocal behavior itself and quantitative measures of resulting vocal adjustments, we show that marmoset monkeys are capable of producing calls with durations beyond the natural boundaries of their repertoire by interrupting ongoing vocalizations rapidly after perturbation onset. Our results indicate that marmosets are capable of interrupting vocalizations only at periodic time points throughout calls, further supported by the occurrence of periodically segmented phees. These ideas overturn decades-old concepts on primate vocal pattern generation, indicating that vocalizations do not consist of one discrete call pattern but are built of many sequentially uttered units, like human speech. PMID- 29478858 TI - Feeding-State-Dependent Modulation of Temperature Preference Requires Insulin Signaling in Drosophila Warm-Sensing Neurons. AB - Starvation is life-threatening and therefore strongly modulates many aspects of animal behavior and physiology [1]. In mammals, hunger causes a reduction in body temperature and metabolism [2], resulting in conservation of energy for survival. However, the molecular basis of the modulation of thermoregulation by starvation remains largely unclear. Whereas mammals control their body temperature internally, small ectotherms, such as Drosophila, set their body temperature by selecting an ideal environmental temperature through temperature preference behaviors [3, 4]. Here, we demonstrate in Drosophila that starvation results in a lower preferred temperature, which parallels the reduction in body temperature in mammals. The insulin/insulin-like growth factor (IGF) signaling (IIS) pathway is involved in starvation-induced behaviors and physiology and is well conserved in vertebrates and invertebrates [5-7]. We show that insulin-like peptide 6 (Ilp6) in the fat body (fly liver and adipose tissues) is responsible for the starvation induced reduction in preferred temperature (Tp). Temperature preference behavior is controlled by the anterior cells (ACs), which respond to warm temperatures via transient receptor potential A1 (TrpA1) [4]. We demonstrate that starvation decreases the responding temperature of ACs via insulin signaling, resulting in a lower Tp than in nutrient-rich conditions. Thus, we show that hunger information is conveyed from fat tissues via Ilp6 and influences the sensitivity of warm sensing neurons in the brain, resulting in a lower temperature set point. Because starvation commonly results in a lower body temperature in both flies and mammals, we propose that insulin signaling is an ancient mediator of starvation induced thermoregulation. PMID- 29478859 TI - fMRI Reveals a Novel Region for Evaluating Acoustic Information for Mate Choice in a Female Songbird. AB - Selection of sexual partners is among the most critical decisions that individuals make and is therefore strongly shaped by evolution. In social species, where communication signals can convey substantial information about the identity, state, or quality of the signaler, accurate interpretation of communication signals for mate choice is crucial. Despite the importance of social information processing, to date, relatively little is known about the neurobiological mechanisms that contribute to sexual decision making and preferences. In this study, we used a combination of whole-brain functional magnetic resonance imaging (fMRI), immediate early gene expression, and behavior tests to identify the circuits that are important for the perception and evaluation of courtship songs in a female songbird, the zebra finch (Taeniopygia guttata). Female zebra finches are sensitive to subtle differences in male song performance and strongly prefer the longer, faster, and more stereotyped courtship songs to non-courtship renditions. Using BOLD fMRI and EGR1 expression assays, we uncovered a novel region involved in auditory perceptual decision making located in a sensory integrative region of the avian central nidopallium outside the traditionally studied auditory forebrain pathways. Changes in activity in this region in response to acoustically similar but categorically divergent stimuli showed stronger parallels to behavioral responses than an auditory sensory region. These data highlight a potential role for the caudocentral nidopallium (NCC) as a novel node in the avian circuitry underlying the evaluation of acoustic signals and their use in mate choice. PMID- 29478860 TI - Predictor of Isolated Trauma in Head: A New Simple Predictor for Survival of Isolated Traumatic Brain Injury. AB - BACKGROUND: Mortality prediction in patients with brain trauma during initial management in the emergency department (ED) is essential for creating the foundation for a better prognosis. OBJECTIVE: This study aimed to create a simple and useful survival predictive model for patients with isolated blunt traumatic brain injury that is easily available in the ED. METHODS: This is a retrospective study based on the trauma registry data of an academic teaching hospital. The inclusion criteria were age >= 15 years, blunt and not penetrating mechanism of injury, and Abbreviated Injury Scale (AIS) scores between 1 and 6 for head and 0 for all other body parts. The primary outcome was 30-day survival probability. Internal and external validation was performed. RESULTS: After univariate logistic regression analysis based on the derivation cohort, the final Predictor of Isolated Trauma in Head (PITH) model for survival prediction of isolated traumatic brain injury included Glasgow Coma Scale (GCS), age, and coded AIS of the head. In the validation cohort, the area under the curve of the PITH score was 0.970 (p < 0.0001; 95% confidence interval 0.960-0.978). Sensitivity and specificity were 95% and 81.7% at the cutoff value of 0.9 (probability of survival 90%), respectively. CONCLUSIONS: The PITH model performed better than the GCS; Revised Trauma Score; and mechanism of injury, GCS, age, and arterial pressure. It will be a useful triage method for isolated traumatic brain injury in the early phase of management. PMID- 29478861 TI - Impact of the HEART Pathway on Admission Rates for Emergency Department Patients with Chest Pain: An External Clinical Validation Study. AB - BACKGROUND: Chest pain is a common emergency department (ED) chief complaint. Safe discharge mechanisms for low-risk chest pain patients would be useful. OBJECTIVE: To compare admission rates prior to and after implementation of an accelerated disposition pathway for ED patients with low-risk chest pain based upon the HEART (History, ECG, Age, Risk factors, Troponin) score (HEART pathway). METHODS: We conducted an impact analysis of the HEART pathway. Patients with a HEART score >= 4 underwent hospital admission for cardiac risk stratification and monitoring. Patients with a HEART score <= 3 could opt for discharge with 72-h follow-up in lieu of admission. We collected data on cohorts prior to and after implementation of the new disposition pathway. For each cohort, we screened the charts of 625 consecutive chest pain patients. We measured patient demographics, past medical history, vital signs, HEART score, disposition, and 6-week major adverse cardiac events (MACE) using chart review methodology. We compared our primary outcome of hospital admission between the two cohorts. RESULTS: The admission rate for the preintervention cohort was 63.5% (95% confidence interval [CI] 58.7-68.2%), vs. 48.3% (95% CI 43.7-53.0%) for the postintervention cohort. The absolute difference in admission rates was 15.3% (95% CI 8.7-21.8%). The odds ratio of admission for the postintervention cohort in a logistic regression model controlling for demographics, comorbidities, and vital signs was 0.48 (95% CI 0.33-0.66). One postintervention cohort patient leaving the ED against medical advice (HEART Score 4) experienced 6-week MACE. CONCLUSIONS: The HEART pathway may provide a safe mechanism to optimize resource allocation for risk-stratifying ED chest pain patients. PMID- 29478862 TI - An exploratory study of candidate gene(s) for Delirium Tremens: Adding the new cholinergic dimension to the conundrum. AB - BACKGROUND AND AIMS: Delirium Tremens (DT) is the most severe form of alcohol withdrawal syndrome, with a potential risk of mortality. Search for the predictors of DT led to study of candidate genes, with inconsistent and inconclusive results. This study aimed to explore the association of various candidate gene polymorphisms and DT in a case-control design. METHODS: This was a genetic association study with a case control design. Two hundred ten Alcohol dependent (AD) male subjects and 200 age matched controls were recruited. DT was diagnosed with the help of Semi-structured Assessment for Genetics of Alcoholism. SNP genotyping was done using TaqMan assay by real time PCR (q-PCR). RESULTS: T allele carrying status (GT and TT) [rs1824024] of muscarinic cholinergic receptor 2 (CHRM2) was found to be significantly associated with DT. When compared to the general population, this genetic polymorphism was not found to be more common in alcohol dependence per se, which excludes the possibility of spurious association between CHRM2 and DT. Withdrawal seizure was more common in the DT group and came out to be one of the important predictors of DT. However, the genetic association was found to be specific for DT, not related to withdrawal seizures. CONCLUSION: The present research added a new cholinergic dimension in the genetic association and biological mechanism of DT. PMID- 29478863 TI - Virus discovery analyses on post-mortem brain tissue and cerebrospinal fluid of schizophrenia patients. PMID- 29478864 TI - Management of Acute Kidney Injury: Core Curriculum 2018. AB - Acute kidney injury (AKI) is a heterogeneous disorder that is common in hospitalized patients and associated with short- and long-term morbidity and mortality. When AKI is present, prompt workup of the underlying cause should be pursued, with specific attention to reversible causes. Measures to prevent AKI include optimization of volume status and avoidance of nephrotoxic medications. Crystalloids are preferred over colloids for most patients, and hydroxyethyl starches should be avoided. Volume overload in the setting of AKI is associated with adverse outcomes, so attention should be paid to overall fluid balance. Currently there are no targeted pharmacotherapies approved for the treatment of AKI. The optimal timing of renal replacement therapy in critically ill patients with AKI is unclear, but is an area of active investigation. Recent studies suggest that AKI is not a "self-limited" process, but is strongly linked to increased risk for chronic kidney disease, subsequent AKI, and future mortality. PMID- 29478865 TI - How Omics Data Can Be Used in Nephrology. AB - Advances in technology and computing now permit the high-throughput analysis of multiple domains of biological information, including the genome, transcriptome, proteome, and metabolome. These omics approaches, particularly comprehensive analysis of the genome, have catalyzed major discoveries in science and medicine, including in nephrology. However, they also generate large complex data sets that can be difficult to synthesize from a clinical perspective. This article seeks to provide an overview that makes omics technologies relevant to the practicing nephrologist, framing these tools as an extension of how we approach patient care in the clinic. More specifically, omics technologies reinforce the impact that genetic mutations can have on a range of kidney disorders, expand the catalogue of uremic molecules that accumulate in blood with kidney failure, enhance our ability to scrutinize urine beyond urinalysis for insight on renal pathology, and enable more extensive characterization of kidney tissue when a biopsy is performed. Although assay methodologies vary widely, all omics technologies share a common conceptual framework that embraces unbiased discovery at the molecular level. Ultimately, the application of these technologies seeks to elucidate a more mechanistic and individualized approach to the diagnosis and treatment of human disease. PMID- 29478868 TI - Management of Heart Failure in Advancing CKD: Core Curriculum 2018. AB - Heart failure and chronic kidney disease have increasing incidence and prevalence owing in part to the aging population and increasing rates of hypertension, diabetes, and other cardiovascular and kidney disease risk factors. The presence of one condition also has a strong influence on the other, leading to greater risks for hospitalization, morbidity, and death, as well as very high health care costs. Despite the frequent coexistence of heart failure and chronic kidney disease, many of the pivotal randomized trials that guide the management of heart failure have excluded patients with more advanced stages of chronic kidney disease. In this Core Curriculum article, management of a challenging, yet not unusual, case of heart failure with reduced ejection fraction in a patient with stage 4 chronic kidney disease provides an opportunity to review the relevant literature and highlight gaps in our knowledge. PMID- 29478866 TI - Report of the Standardized Outcomes in Nephrology-Hemodialysis (SONG-HD) Consensus Workshop on Establishing a Core Outcome Measure for Hemodialysis Vascular Access. AB - Vascular access outcomes in hemodialysis are critically important for patients and clinicians, but frequently are neither patient relevant nor measured consistently in randomized trials. A Standardized Outcomes in Nephrology Hemodialysis (SONG-HD) consensus workshop was convened to discuss the development of a core outcome measure for vascular access. 13 patients/caregivers and 46 professionals (clinicians, policy makers, industry representatives, and researchers) attended. Participants advocated for vascular access function to be a core outcome based on the broad applicability of function regardless of access type, involvement of a multidisciplinary team in achieving a functioning access, and the impact of access function on quality of life, survival, and other access related outcomes. A core outcome measure for vascular access required demonstrable feasibility for implementation across different clinical and trial settings. Participants advocated for a practical and flexible outcome measure with a simple actionable definition. Integrating patients' values and preferences was warranted to enhance the relevance of the measure. Proposed outcome measures for function included "uninterrupted use of the access without the need for interventions" and "ability to receive prescribed dialysis," but not "access blood flow," which was deemed too expensive and unreliable. These recommendations will inform the definition and implementation of a core outcome measure for vascular access function in hemodialysis trials. PMID- 29478867 TI - Rapidity of Correction of Hyponatremia Due to Syndrome of Inappropriate Secretion of Antidiuretic Hormone Following Tolvaptan. AB - BACKGROUND: Tolvaptan effectively corrects hyponatremia due to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), but undesired overcorrection can occur. We hypothesized that pretherapy parameters can predict the rapidity of response to tolvaptan in SIADH. STUDY DESIGN: Multicenter historical cohort study. SETTING & PARTICIPANTS: Adults with SIADH or congestive heart failure (CHF) treated with tolvaptan for a serum sodium concentration <= 130 mEq/L at 5 US hospitals. PREDICTORS: Demographic and laboratory parameters. OUTCOMES: Rate of change in serum sodium concentration. MEASUREMENTS: Spearman correlations, analysis of variance, and multivariable linear mixed-effects models. RESULTS: 28 patients with SIADH and 39 patients with CHF treated with tolvaptan (mean baseline serum sodium, 120.6 and 122.4 mEq/L, respectively) were studied. Correction of serum sodium concentration > 12 mEq/L/d occurred in 25% of patients with SIADH compared to 3% of those with CHF (P<0.001). Among patients with SIADH, the increase in serum sodium over 24 hours was correlated with baseline serum sodium concentration (r=-0.78; P<0.001), serum urea nitrogen concentration (SUN; r=-0.76; P<0.001), and estimated glomerular filtration rate (r=0.58; P=0.01). Baseline serum sodium and SUN concentrations were identified as independent predictors of change in serum sodium concentration in multivariable analyses. When patients were grouped into 4 categories according to baseline serum sodium and SUN median values, those with both low baseline serum sodium (<=121 mEq/L) and low baseline SUN concentrations (<=10mg/dL) exhibited a significantly greater rate of increase in serum sodium concentration (mean 24 hour increase of 15.4 mEq/L) than the other 3 categories (P<0.05). Among patients with CHF, only baseline SUN concentration was identified as an independent predictor of change in serum sodium concentration over time. LIMITATIONS: Lack of uniformity in serial serum sodium concentration determinations and documentation of water intake. CONCLUSIONS: Baseline serum sodium and SUN values are predictive of the rapidity of hyponatremia correction following tolvaptan use in SIADH. We advise caution when dosing tolvaptan in patients with both low serum sodium and SUN concentrations. PMID- 29478870 TI - Clinical Significance of Reciprocal ST-Segment Changes in Patients With STEMI: A Cardiac Magnetic Resonance Imaging Study. AB - INTRODUCTION AND OBJECTIVES: We sought to determine the association of reciprocal change in the ST-segment with myocardial injury assessed by cardiac magnetic resonance (CMR) in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). METHODS: We performed CMR imaging in 244 patients who underwent primary PCI for their first STEMI; CMR was performed a median 3 days after primary PCI. The first electrocardiogram was analyzed, and patients were stratified according to the presence of reciprocal change. The primary outcome was infarct size measured by CMR. Secondary outcomes were area at risk and myocardial salvage index. RESULTS: Patients with reciprocal change (n=133, 54.5%) had a lower incidence of anterior infarction (27.8% vs 71.2%, P < .001) and shorter symptom onset to balloon time (221.5+/-169.8 vs 289.7+/-337.3min, P=.042). Using a multiple linear regression model, we found that patients with reciprocal change had a larger area at risk (P=.002) and a greater myocardial salvage index (P=.04) than patients without reciprocal change. Consequently, myocardial infarct size was not significantly different between the 2 groups (P=.14). The rate of major adverse cardiovascular events, including all-cause death, myocardial infarction, and repeat coronary revascularization, was similar between the 2 groups after 2 years of follow-up (P=.92). CONCLUSIONS: Reciprocal ST-segment change was associated with larger extent of ischemic myocardium at risk and more myocardial salvage but not with final infarct size or adverse clinical outcomes in STEMI patients undergoing primary PCI. PMID- 29478869 TI - Management of Traditional Cardiovascular Risk Factors in CKD: What Are the Data? AB - Patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) are 10 times more likely to die of cardiovascular (CV) diseases than the general population, and dialysis-dependent patients are at even higher risk. Although traditional CV risk factors are highly prevalent in individuals with CKD, these patients were often excluded from studies targeting modification of these risks. Although treatment of hypertension is beneficial in CKD, the best target blood pressure has not been established. Trial data showed that renin-angiotensin aldosterone blockade may prevent CV events in patients with CKD. The risks of aspirin may equal the benefits in NDD-CKD samples, and there are no trials testing aspirin in dialysis-dependent patients. Lipid-lowering therapy improves CV outcomes in NDD-CKD, but not in dialysis-dependent patients. Strict glycemic control prevents CV events in nonalbuminuric individuals, but showed no benefit in those with baseline albuminuria with albumin excretion > 300mg/g, and there are no data in dialysis-dependent patients. Data for lifestyle modifications, such as weight loss, physical activity, and smoking cessation, are mostly observational and extrapolated from non-CKD samples. This comprehensive review summarizes the best existing evidence and current clinical guidelines for modification of traditional risk factors for the prevention of CV events in patients with CKD and identifies knowledge gaps. PMID- 29478871 TI - Iodide-induced Sialadenitis Related to Coronary Angiogram. PMID- 29478872 TI - Reactive Acyl-CoA Species Modify Proteins and Induce Carbon Stress. AB - In recent years, our understanding of the scope and diversity of protein post translational modifications (PTMs) has rapidly expanded. In particular, mitochondrial proteins are decorated with an array of acyl groups that can occur non-enzymatically. Interestingly, these modifying chemical moieties are often associated with intermediary metabolites from core metabolic pathways. In this Review, we describe biochemical reactions and biological mechanisms that activate carbon metabolites for protein PTM. We explore the emerging links between the intrinsic reactivity of metabolites, non-enzymatic protein acylation, and possible signaling roles for this system. Finally, we propose a model of 'carbon stress', similar to oxidative stress, as an effective way to conceptualize the relationship between widespread protein acylation, nutrient sensing, and metabolic homeostasis. PMID- 29478873 TI - Pathophysiological Characteristics Associated With Epileptogenesis in Human Hippocampal Sclerosis. AB - Mesial temporal lobe epilepsy (MTLE) is the most frequent focal epileptic syndrome in adults, and the majority of seizures originate primarily from the hippocampus. The resected hippocampal tissue often shows severe neuronal loss, a condition referred to as hippocampal sclerosis (HS). In order to understand hippocampal epileptogenesis in MTLE, it seems important to clarify any discrepancies between the clinical and pathological features of affected patients. Here we investigated epileptiform activities ex vivo using living hippocampal tissue taken from patients with MTLE. Flavoprotein fluorescence imaging and local field potential recordings revealed that epileptiform activities developed from the subiculum. Moreover, physiological and morphological experiments revealed possible impairment of K+ clearance in the subiculum affected by HS. Stimulation of mossy fibers induced recurrent trans synaptic activity in the granule cell layer of the dentate gyrus, suggesting that mossy fiber sprouting in HS also contributes to the epileptogenic mechanism. These results indicate that pathophysiological alterations involving the subiculum and dentate gyrus could be responsible for epileptogenesis in patients with MTLE. PMID- 29478875 TI - Variations in non-prescription drug consumption and expenditure: Determinants and policy implications. AB - This paper analyses the determinants of cross-regional variations in expenditure and consumption for non-prescription drugs using the Italian Health Care Service as a case study. This research question has never been posed in other literature contributions. Per capita income, the incidence of elderly people, the presence of distribution points alternative to community pharmacies (para-pharmacies and drug corners in supermarkets), and the disease prevalence were included as possible explanatory variables. A trade-off between consumption of non prescription and prescription-only drugs was also investigated. Correlation was tested through linear regression models with regional fixed-effects. Demand driven variables, including the prevalence of the target diseases and income, were found to be more influential than supply-side variables, such as the presence of alternative distribution points. Hence, the consumption of non prescription drugs appears to respond to needs and is not induced by the supply. The expected trade-off between consumption for prescription-only and non prescription drugs was not empirically found: increasing the use of non prescription drugs did not automatically imply savings on prescription-only drugs covered by third payers. Despite some caveats (the short period of time covered by the longitudinal data and some missing monthly data), the regression model revealed a high explanatory power of the variability and a strong predictive ability of future values. PMID- 29478874 TI - Memory-Focused Cognitive Therapy for Cocaine Use Disorder: Theory, Procedures and Preliminary Evidence From an External Pilot Randomised Controlled Trial. AB - BACKGROUND: Cocaine use disorder (CUD) is a debilitating condition with no NICE recommended medication or specific psychosocial interventions. In the United Kingdom (UK), general counselling (treatment-as-usual; TAU) is widely delivered, but has limited effectiveness. We tested the feasibility, safety and preliminary efficacy of a novel, adjunctive psychosocial intervention for CUD, called 'memory focused cognitive therapy' (MFCT). METHODS: We did a two-arm, external pilot randomised controlled trial at a specialist community National Health Service addictions clinic in London, UK. 30 adults (>=18years), voluntarily seeking treatment for CUD (enrolled >=14days; all with moderate-to-severe DSM5 CUD), were individually randomised (1:1) to a control group (ongoing TAU; 3*90min CUD cognitive conceptualisation assessments; 2*30min cocaine-related cue-induction procedures; and 3*30min research follow-ups); or to an intervention group (ongoing TAU; 3*90min cognitive conceptualisation assessments; 2*30min cocaine related cue-induction procedures; 5*120min, one-to-one, MFCT sessions [in 1week]; and 3*60min research follow-ups and MFCT-relapse prevention). The primary outcome was the total percentage score on the frequency version of the Craving Experiences Questionnaire (CEQ-F) at 1-month follow-up after the intensive intervention week (clinical endpoint; recall period past 2weeks; higher score indicating greater craving). Secondary outcomes at the 1-month follow-up were percentage days abstinent (PDA) from cocaine, and longest period (days) of continuous abstinence (LPA) in the prior 28days. Outcomes were analysed as an unadjusted group mean difference (with Hedge's g effect size [ES]) and a 95% Confidence Interval [CI] for the primary outcome and a 90% CI for the secondary outcomes. Exploratory, multivariable linear (primary outcome) and Poisson regression models (secondary outcomes), with sex, age, months of regular cocaine use, baseline outcome score, and group estimated the effectiveness of the intervention. The trial is registered with the ISCRTN (ISRCTN16462783). FINDINGS: Between July 15, 2015, and November 27, 2016, 58 patients were assessed for eligibility and 30 participants were randomised (14 to the control group and 16 to the intervention). With outcome data collected for all participants at the endpoint, the intervention group mean CEQ-F score (14.77; SD 21.47) was lower than the control group mean (51.75; SD 22.72); ES -1.62; 95% CI -2.45 to -0.80. MFCT was associated with more cocaine abstinence in the intervention group (PDA 85.94; SD 18.96) than the control group (PDA 54.59; SD 30.29); ES 1.19; 90% CI 0.54 to 1.84. There was also greater maximum abstinence in the intervention group (LPA 15.69; SD 10.10) than the control group (6.00; SD 7.36); ES 1.06; 90% CI 0.41 to 1.70. Exploratory, confounder-adjusted regression models for this preliminary effect supported the treatment association for reduced craving experiences (CEQ-F Coef. -28.25; 95% CI -45.15 to -11.35); more abstinence (PDA Incidence Rate Ratio [IRR] 1.56; 95% CI 1.31 to 1.88); and greater maximum abstinence (LPA IRR 2.56; 95% CI 1.96 to 3.35), although relative weak unmeasured confounding could overturn these model-adjusted exposure-outcome associations. There were four serious adverse events (among three participants). None were judged related to study procedures or interventions. INTERPRETATION: In this first external pilot randomised controlled trial of MFCT for CUD, we have shown that the intervention and control procedures and acceptable feasible and safe, and report preliminary evidence that MFCT is associated with reduced craving and increased abstinence. These findings support progression to a substantive trial. FUNDING SOURCE: UK National Institute for Health Research, Biomedical Research Centre. PMID- 29478876 TI - Health systems reforms in Singapore: A qualitative study of key stakeholders. AB - In response to a growing chronic disease burden and ageing population, Singapore implemented Regional Health Systems (RHS) in 2008. In January 2017, the MOH announced that the six RHS clusters would be reorganised into three in 2018. This qualitative study sought to identify the health system challenges, opportunities, and ways forward for the implementation of the RHS. We conducted semi-structured interviews with 35 key informants from RHS clusters, government, academia, and private and voluntary sectors. Integration, innovation, and people-centeredness were identified as the key principles of the RHS. The RHS was described as an opportunity to holistically care for a person across the care continuum, address social determinants of health, develop new models of care, and work with social and community partners. Challenges to RHS implementation included difficulties aligning the goals, values, and priorities of multiple actors, the need for better integration across clusters, differing care capabilities and capacities across partners, healthcare financing structures that may not reflect RHS goals, scalability and evaluation of pilot programmes, and disease-centricity, provider centricity, and medicalisation in health and healthcare. Suggested ways forward included building relationships between actors to facilitate integration; exploring innovative new models of care; clear long-term/scale-up plans for successful pilots; healthcare financing reforms to meet changing patient and population needs; and developing evaluation systems reflective of RHS principles and priorities. PMID- 29478877 TI - Stakeholder views on the role of spiritual care in Australian hospitals: An exploratory study. AB - Research increasingly demonstrates the contribution of spiritual care to patient experience, wellbeing and health outcomes. Responsiveness to spiritual needs is recognised as a legitimate component of quality health care. Yet there is no consistent approach to the models and governance of spiritual care across hospitals in Australia. This is consistent with the situation in other developed countries where there is increased attention to identifying best practice models for spiritual care in health. This study explores the views of stakeholders in Australian hospitals to the role of spiritual care in hospitals. A self completion questionnaire comprising open and closed questions was distributed using a snowball sampling process. Analysis of 477 complete questionnaires indicated high levels of agreement with ten policy statements and six policy objectives. Perceived barriers to spiritual care related to: terminology and roles, education and training, resources, and models of care. Responses identified the issues to inform a national policy agenda including attention to governance and policy structures and clear delineation of roles and scope of practice with aligned education and training models. The inclusion of spiritual care as a significant pathway for the provision of patient-centred care is noted. Further exploration of the contribution of spiritual care to wellbeing, health outcomes and patient experience is invited. PMID- 29478879 TI - Author's reply. PMID- 29478878 TI - A case-vignette based assessment of patient's perspective on coronary revascularization strategies, the OPINION study. AB - BACKGROUND AND AIMS: Significant left main (LM) stem disease is potentially life threatening and mandates revascularization. This study aimed to assess how patients rate the importance of particular features of coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI), how this determines their preference for a particular treatment strategy, and whether particular personality characteristics influence this preference. METHODS AND RESULTS: In total, 1145 patients who visited the outpatient clinic of the Erasmus Medical Center for stable coronary artery disease were asked to complete a case vignette questionnaire on a hypothetical significant LM stenosis amenable to PCI or CABG. To assess the individual's personality disposition and general distress level, each patient had to complete a set of 3 standardized, validated questionnaires with satisfactory psychometric properties. Overall 89% of patients preferred PCI to CABG. PCI was the preferred strategy despite a higher risk for repeat revascularization and need for more medication. Remarkably, the fact that a risk for repeat revascularization is more common in the PCI group is less important for the patients who opt for PCI. Risk for stroke and bleeding were the most important arguments to opt for PCI over CABG. Type D personality, depression, and anxiety were all associated with a relatively higher preference for CABG as revascularization strategy. CONCLUSION: Overall, when given the choice patients seem to have a clear preference for PCI over CABG and consider stroke and bleeding important procedure-related complications. Patients with Type D personality, depression, or anxiety favor CABG. PMID- 29478880 TI - [Body mass index and tri-ponderal mass index of 1,453 healthy non-obese, non undernourished millennial children. The Barcelona longitudinal growth study]. AB - INTRODUCTION: Body mass index-for age (BMI) and tri-ponderal mass index-for-age (TMI) values of healthy non-underweight, non-obese millennial children have not been reported until now. We aimed to obtain these values. SUBJECTS AND METHODS: Longitudinal growth study (1995-2017) of 1,453 healthy non-underweight, non-obese millennial children, from birth (n = 477) or from 4 years of age (n = 976) to 18 years in girls and 19 years in boys (25,851 anthropometric measurements). RESULTS: In each sex, mean BMI-for-age values increased from birth to one year, declined until 5and increased from then onwards. Mean TMI-for-age values decreased abruptly during the first 6years of age and slowly thereafter, in both sexes. Although, at some ages, mean BMI-for age values differed statistically between sexes, differences were scant and of poor clinical significance. The same occurred for TMI-for-age values. BMI-for-age cut-off values to define underweight status (-2 SD) were similar to those proposed by Cole and the WHO for both sexes. However, BMI-for-age cut-off values to define obesity (+2 SD) were lower in both sexes (1.0-5.3) than those proposed by Cole and similar to those proposed by the WHO until 12 in girls and 14 in boys and lower (1.0-4.8) from these ages onwards. CONCLUSIONS: BMI-for-age and TMI-for-age values of healthy non-underweight, non obese millennial children are provided. No clinically relevant differences were observed between sexes. These values may be used to measure underweight status and obesity in present pediatric populations and to evaluate the relationship between BMI-for-age and TMI-for-age in a clinical setting. PMID- 29478881 TI - Paving the way for disorders of consciousness diagnosis and prognosis: The role of cardiac autonomic response and beyond. PMID- 29478882 TI - It takes two to tango: A dyadic approach to understanding the medication dialogue in patient-provider relationships. AB - OBJECTIVE: To describe typologies of dyadic communication exchanges between primary care providers and their hypertensive patients about prescribed antihypertensive medications. METHODS: Qualitative analysis of 94 audiotaped patient-provider encounters, using grounded theory methodology. RESULTS: Four types of dyadic exchanges were identified: Interactive (53% of interactions), divergent-traditional (24% of interactions), convergent-traditional (17% of interactions) and disconnected (6% of interactions). In the interactive and convergent-traditional types, providers adopted a patient-centered approach and used communication behaviors to engage patients in the relationship. Patients in these interactions adopted either an active role in the visit (interactive), or a passive role (convergent-traditional). The divergent-traditional type was characterized by provider verbal dominance, which inhibited patients' ability to ask questions, seek information, or check understanding of information. In the disconnected types, providers used mainly closed-ended questions and terse directives to gather and convey information, which was often disregarded by patients who instead diverted the conversation to psychosocial issues. CONCLUSIONS: This study identified interdependent patient-provider communication styles that can either facilitate or hinder discussions about prescribed medications. PRACTICE IMPLICATIONS: Examining the processes that underlie dyadic communication in patient-provider interactions is an essential first step to developing interventions that can improve the patient-provider relationship and patient health behaviors. PMID- 29478884 TI - Experimental infection by microparasites affects the oxidative balance in their avian reservoir host the blackbird Turdus merula. AB - By draining resources, microparasites can negatively affect the host fitness, which in turn can result in reduced transmission when virulence leads to reductions in host population size. Therefore, for a microparasite to persist in nature, the level of harm it can do to its host is expected to be limited. We tested this hypothesis for tick-borne Borrelia burgdorferi sensu lato (s.l.) infections in the blackbird Turdus merula, one of the most important avian reservoir hosts in Europe. Experimental and observational data were combined to examine the physiological effects caused by B. burgdorferi s.l. infection in blackbirds. Pathogen-free blackbirds were exposed to B. burgdorferi s.l.-infected Ixodes ricinus and I. frontalis nymphs, and compared with a control group (exposed to naive laboratory-derived I. ricinus nymphs). Their physiological status was evaluated before and after infection with B. burgdorferi s.l., through a set of immunological (erythrocyte sedimentation rate, haptoglobin, white blood cell count and heterophil/lymphocyte ratio), oxidative stress (glutathione peroxidase activity, protein carbonyls and nitric oxide) and general body condition variables (body condition, glucose and haematocrit). Infected males showed higher levels of oxidative damage to proteins (increased levels of protein carbonyls), decreased glutathione peroxidase activity and increased body mass. Infected females had higher levels of glutathione peroxidase activity after infection by B. burgdorferi s.l. than the control group. No significant effects of B. burgdorferi s.l. infection were detected on erythrocyte sedimentation rate, haptoglobin, heterophil/lymphocyte ratio, nitric oxide, glucose and haematocrit. The first experimental study on the effects of B. burgdorferi s.l. on its avian reservoir hosts shows that these bacteria may inflict non-negligible physiological costs. We speculate that during energetically demanding periods, these physiological costs may reduce host fitness and affect pathogen transmission. PMID- 29478883 TI - On the possible role of ticks in the eco-epidemiology of Coxiella burnetii in a Mediterranean ecosystem. AB - Ruminant livestock is the main reservoir of Coxiella burnetii (Cb), but little is known about the role of wildlife and ticks in its epidemiology. The Iberian ibex (Capra pyrenaica, Schinz 1838) population of "Ports de Tortosa i Beseit" (NE Spain) suffers intense tick infestations and low reproduction rates. This study aims to (1) assess the relationship between infection in ibexes (detection of serum antibodies and/or of Cb DNA in tissues) and Cb DNA presence in ticks hosted by the same ibexes; and (2) identify Cb associated risk factors. Between 2011 and 2015, serum (n = 130), spleen (n = 72), lymph node (n = 89) and tick (n = 669) samples from 134 hunter-harvested ibexes were collected. Antibody detection was performed by ELISA and Cb DNA presence was assessed by PCR. Potential risk factors were assessed with regression tree models. Although 30% of the ibexes (39/130; 95%CI, [10%-29.8%]) had antibodies, Cb DNA was detected in only 9.8% of the ibexes (11/112; 95%CI [7.6%-27.25%]). The prevalence of Cb-carrier ticks averaged 10% and exceeded 20% for the genus Haemaphysalis. However, lacking correlation between infection in ibexes and their ticks does not support tick-to ibex transmission or vice versa. Tree modelling points to host, population and environmental factors as drivers of Cb infection in ticks and suggests connections with the domestic cycle. The percentage of Cb-carrier ticks detected is noteworthy. Along with heavy tick infestations, it suggests vector potential for these tick species, especially for the genera Rhipicephalus and Haemaphysalis. Since vector competence has not been assessed in these tick species, a classic vector role cannot be proposed nor discarded, but promoter factors of vector capacity occur. In addition, the risk of tick-borne infection through tick excreta should not be neglected. While the airborne route is the preeminent route for Cb infection, ticks' contribution to Cb epidemiology deserves further attention. PMID- 29478885 TI - Combining public participatory surveillance and occupancy modelling to predict the distributional response of Ixodes scapularis to climate change. AB - Ixodes scapularis, a known vector of Borrelia burgdorferi sensu stricto (Bbss), is undergoing range expansion in many parts of Canada. The province of New Brunswick, which borders jurisdictions with established populations of I. scapularis, constitutes a range expansion zone for this species. To better understand the current and potential future distribution of this tick under climate change projections, this study applied occupancy modelling to distributional records of adult ticks that successfully overwintered, obtained through passive surveillance. This study indicates that I. scapularis occurs throughout the southern-most portion of the province, in close proximity to coastlines and major waterways. Milder winter conditions, as indicated by the number of degree days <0 degrees C, was determined to be a strong predictor of tick occurrence, as was, to a lesser degree, rising levels of annual precipitation, leading to a final model with a predictive accuracy of 0.845 (range: 0.828-0.893). Both RCP 4.5 and RCP 8.5 climate projections predict that a significant proportion of the province (roughly a quarter to a third) will be highly suitable for I. scapularis by the 2080s. Comparison with cases of canine infection show good spatial agreement with baseline model predictions, but the presence of canine Borrelia infections beyond the climate envelope, defined by the highest probabilities of tick occurrence, suggest the presence of Bbss carrying ticks distributed by long-range dispersal events. This research demonstrates that predictive statistical modelling of multi-year surveillance information is an efficient way to identify areas where I. scapularis is most likely to occur, and can be used to guide subsequent active sampling efforts in order to better understand fine scale species distributional patterns. PMID- 29478886 TI - The red blood cell proportion of arachidonic acid relates to shorter leukocyte telomeres in Mediterranean elders: A secondary analysis of a randomized controlled trial. AB - BACKGROUND & AIMS: Shortening of leukocyte telomere length (LTL) is a biomarker of aging. Epidemiologic studies of LTL in relation to dietary fatty acids have reported conflicting results. The red blood cell (RBC) fatty acid status is a valid objective biomarker of long-term dietary intake of C18:2n-6, C18:3n-3 and long-chain n-3 polyunsaturated fatty acids (C20:5n-3 and C22:6n-3). In healthy older individuals, we investigated whether LTL relates to the RBC proportions of the main dietary polyunsaturated fatty acids (PUFA), and to the RBC proportion of arachidonic acid (C20:4n-6), a fatty acid that can generate pro-inflammatory lipid mediators once released from cell membranes. DESIGN: Cross-sectional study in 344 subjects (mean age 68.8 y, 68.6% women) who participated in a randomized controlled trial testing whether a diet enriched in walnuts can delay the onset of age-related diseases (https://clinicaltrials.gov/ct2/show/NCT01634841). At baseline, we assessed LTL by high-throughput quantitative fluorescence and determined fatty acids in RBCs by gas chromatography. RESULTS: In multivariate models adjusted for age and gender, the RBC proportions of dietary PUFA were unrelated to LTL. In contrast, the RBC proportion of arachidonic acid inversely related to LTL (regression coefficient [95% confidence interval], -0.10 (-0.19 to -0.01), P = 0.023). CONCLUSION: An increasing proportion of C20:4n-6 in RBCs is associated with shorter telomeres. Further research is needed to investigate the role of this fatty acid and its derived lipid mediators in the aging process. PMID- 29478887 TI - Long term outcomes of intestinal rehabilitation in children with neonatal very short bowel syndrome: Parenteral nutrition or intestinal transplantation. AB - BACKGROUND & AIMS: Intestinal rehabilitation is the preferred treatment for children with short bowel syndrome (SBS) whatever the residual bowel length, and depends on the accurate management of long-term parenteral nutrition (PN). If nutritional failure develops, intestinal transplantation (ITx) should be discussed and may be life-saving. This study aimed to evaluate survival, PN dependency and nutritional status in children with neonatal very SBS on PN or after ITx, in order to define indications and timing of both treatments. PATIENTS AND METHODS: This retrospective cross-sectional study enrolled 36 children with very SBS (<40 cm) who entered our intestinal rehabilitation program from 1987 to 2007. RESULTS: All the children on long-term PN (n = 16) survived with a follow up of 17 years (9-20). Six of them were eventually weaned off PN. Twenty children underwent ITx: eight children died (40%) 29 months (0-127) after Tx. The others 12 patients were weaned off PN 73 days (13-330) after Tx. Follow-up after transplantation was 14 years (6-28). Seven out of 8 (88%) patients with a history of gastroschisis required ITx. Patients who required ITx had longer stoma duration. CONCLUSION: Survival rate of children with very short bowel was excellent if no life-threatening complications requiring transplantation developed. Gastroschisis and delayed ostomy closure are confirmed as risk factor for nutritional failure. Intestinal rehabilitation may allow a total weaning of PN before adulthood. A follow-up by a multidisciplinary team is necessary to avoid PN complications in order to minimize indications for ITx. PMID- 29478888 TI - Reply-Letter to the editor-Lifestyle predictors of obese and non-obese patients with nonalcoholic fatty liver disease: A cross-sectional study. PMID- 29478889 TI - Opioid Prescribing Behavior of Interventional Radiologists Across the United States. AB - PURPOSE: To study opioid prescribing behavior of US interventional radiologists (IRs). METHODS: Using Medicare Physician and Other Supplier Public Use File claims, we identified 2,133 radiologists whose practice in 2015 comprised predominantly interventional radiology. Cross-linking the Medicare Part D Prescriber File, their opioid prescription writing behavior was characterized. RESULTS: Most (52.2%) IRs wrote 10 or fewer prescriptions total for Medicare beneficiaries. Of the 47.8% who wrote >10 prescriptions, 87.4% prescribed an opioid, most commonly hydrocodone with acetaminophen, at least once (71.3%, 1-10 opioid prescriptions; 27.4%, 11-100; 1.3%, >=101). Overall, 23.0% of all prescriptions by those IRs writing >10 were for opioids, with an average 8.0-day prescription. Average opioid prescriptions per IR were significantly (P <= .015) independently associated with their providing clinical evaluation and management (E&M) services (9.7 opioid prescriptions per IR with demonstrable E&M encounters versus 2.2 if not), practice size (12.6 for practices with <= 10 members versus 3.7-4.8 for larger groups), and geography (8.3 in the South versus 3.6-4.0 elsewhere). Rates were highest in Georgia (39.5) and lowest in Delaware (2.0). Higher opioid prescribing rates showed additional univariable associations with more years in practice and nonacademic practices. CONCLUSION: Most IRs write few, if any, prescriptions for Medicare beneficiaries. Of those who do, the large majority writes for opioids, at rates higher than national physician benchmarks. IRs' opioid prescribing varies significantly based on physician and practice characteristics and particularly whether the IR provides clinical E&M services. In light of the nation's opioid epidemic, these observations may guide education, practice improvement, and policy efforts to optimize opioid prescribing. PMID- 29478890 TI - Complex Nature of Radiation Risk in Medical Imaging. PMID- 29478891 TI - Meso-Endothelial Bipotent Progenitors from Human Placenta Display Distinct Molecular and Cellular Identity. AB - The existence of bipotential precursors for both mesenchymal and endothelial stem/progenitor cells in human postnatal life is debated. Here, we hypothesized that such progenitors are present within the human term placenta. From a heterogeneous placental single-cell suspension, a directly flow-sorted CD45 CD34+CD144+CD31Lo population uniquely differentiated into both endothelial and mesenchymal colonies in limiting dilution culture assays. Of interest, these bipotent cells were in vessel walls but not in contact with the circulation. RNA sequencing and functional analysis demonstrated that Notch signaling was a key driver for endothelial and bipotential progenitor function. In contrast, the formation of mesenchymal cells from the bipotential population was not affected by TGFbeta receptor inhibition, a classical pathway for endothelial-mesenchymal transition. This study reveals a bipotent progenitor phenotype in the human placenta at the cellular and molecular levels, giving rise to endothelial and mesenchymal cells ex vivo. PMID- 29478892 TI - Imaging-Based Screen Identifies Laminin 411 as a Physiologically Relevant Niche Factor with Importance for i-Hep Applications. AB - Use of hepatocytes derived from induced pluripotent stem cells (i-Heps) is limited by their functional differences in comparison with primary cells. Extracellular niche factors likely play a critical role in bridging this gap. Using image-based characterization (high content analysis; HCA) of freshly isolated hepatocytes from 17 human donors, we devised and validated an algorithm (Hepatocyte Likeness Index; HLI) for comparing the hepatic properties of cells against a physiological gold standard. The HLI was then applied in a targeted screen of extracellular niche factors to identify substrates driving i-Heps closer to the standard. Laminin 411, the top hit, was validated in two additional induced pluripotent stem cell (iPSC) lines, primary tissue, and an in vitro model of alpha1-antitrypsin deficiency. Cumulatively, these data provide a reference method to control and screen for i-Hep differentiation, identify Laminin 411 as a key niche protein, and underscore the importance of combining substrates, soluble factors, and HCA when developing iPSC applications. PMID- 29478893 TI - Calorie Restriction Governs Intestinal Epithelial Regeneration through Cell Autonomous Regulation of mTORC1 in Reserve Stem Cells. AB - Aging is a complex process associated with a decline in functionality of adult stem cells affecting tissue homeostasis and regeneration. Calorie restriction (CR) is the only experimental manipulation known to extend lifespan and reduce the incidence of age-related disorders across numerous species. These benefits are likely mediated, at least in part, through the preservation of stem cell function. Here, we show that CR enhances the regenerative capacity of the intestinal epithelium through preservation of an injury-resistant reserve intestinal stem cell (ISC) pool. Cell-autonomous activity of mechanistic target of rapamycin complex 1 (mTORC1) governs the sensitivity of reserve ISCs to injury. CR inhibits mTORC1 in these cells, protecting them against DNA damage, while mTORC1 stimulation, either genetically or through nutrient sensing, sensitizes reserve ISCs to injury, thus compromising regeneration of the epithelium. These data delineate a critical role for mTORC1 in epithelial regeneration and inform clinical strategies based on nutrient modulation. PMID- 29478894 TI - Heterogeneity of SOX9 and HNF1beta in Pancreatic Ducts Is Dynamic. AB - Pancreatic duct epithelial cells have been suggested as a source of progenitors for pancreatic growth and regeneration. However, genetic lineage-tracing experiments with pancreatic duct-specific Cre expression have given conflicting results. Using immunofluorescence and flow cytometry, we show heterogeneous expression of both HNF1beta and SOX9 in adult human and murine ductal epithelium. Their expression was dynamic and diminished significantly after induced replication. Purified pancreatic duct cells formed organoid structures in 3D culture, and heterogeneity of expression of Hnf1beta and Sox9 was maintained even after passaging. Using antibodies against a second cell surface molecule CD51 (human) or CD24 (mouse), we could isolate living subpopulations of duct cells enriched for high or low expression of HNF1beta and SOX9. Only the CD24high (Hnfbetahigh/Sox9high) subpopulation was able to form organoids. PMID- 29478895 TI - High-Yield Purification, Preservation, and Serial Transplantation of Human Satellite Cells. AB - Investigation of human muscle regeneration requires robust methods to purify and transplant muscle stem and progenitor cells that collectively constitute the human satellite cell (HuSC) pool. Existing approaches have yet to make HuSCs widely accessible for researchers, and as a result human muscle stem cell research has advanced slowly. Here, we describe a robust and predictable HuSC purification process that is effective for each human skeletal muscle tested and the development of storage protocols and transplantation models in dystrophin deficient and wild-type recipients. Enzymatic digestion, magnetic column depletion, and 6-marker flow-cytometric purification enable separation of 104 highly enriched HuSCs per gram of muscle. Cryostorage of HuSCs preserves viability, phenotype, and transplantation potential. Development of enhanced and species-specific transplantation protocols enabled serial HuSC xenotransplantation and recovery. These protocols and models provide an accessible system for basic and translational investigation and clinical development of HuSCs. PMID- 29478896 TI - Prostaglandin E2 Is Required for BMP4-Induced Mesoderm Differentiation of Human Embryonic Stem Cells. AB - The accurate control of early cell fate specification during differentiation of human embryonic stem cells (hESCs) is critical for acquiring pure therapeutic cell populations of interest. Bone morphogenetic protein 4 (BMP4) is a key mesoderm inducer from ESCs. However, the molecular mechanism of the mesodermal cell fate decision induced by BMP4 remains unclear. Here, we demonstrate the requirement of a bioactive lipid, prostaglandin E2 (PGE2), for the mesoderm specification from hESCs by BMP4 induction. We show that BMP4 directly regulates the expression of the key enzyme for PGE2 synthesis, COX-1, and promotes PGE2 production. More importantly, in the absence of BMP4, forced COX-1 expression or PGE2 treatment is sufficient to initiate mesoderm specification of hESCs by activation of EP2-PKA signaling and modulation of nuclear translocation of beta catenin. Together, our findings provide insights into the critical role of BMP regulation of PGE2 synthesis and its downstream signaling in initiating mesoderm commitment of hESCs. PMID- 29478897 TI - An Adeno-Associated Virus-Based Toolkit for Preferential Targeting and Manipulating Quiescent Neural Stem Cells in the Adult Hippocampus. AB - Quiescent neural stem cells (qNSCs) with radial morphology are the only proven source of new neurons in the adult mammalian brain. Our understanding of the roles of newly generated neurons depends on the ability to target and manipulate adult qNSCs. Although various strategies have been developed to target and manipulate adult hippocampal qNSCs, they often suffer from prolonged breeding, low recombination efficiency, and non-specific labeling. Therefore, developing a readily manufactured viral vector that allows flexible packaging and robust expression of various transgenes in qNSCs is a pressing need. Here, we report a recombinant adeno-associated virus serotype 4 (rAAV4)-based toolkit that preferentially targets hippocampal qNSCs and allows for lineage tracing, functional analyses, and activity manipulation of adult qNSCs. Importantly, targeting qNSCs in a non-Cre-dependent fashion opens the possibility for studying qNSCs in less genetically tractable animal species and may have translational impact in gene therapy by preferentially targeting qNSCs. PMID- 29478898 TI - Loss of MyoD and Myf5 in Skeletal Muscle Stem Cells Results in Altered Myogenic Programming and Failed Regeneration. AB - MyoD and Myf5 are fundamental regulators of skeletal muscle lineage determination in the embryo, and their expression is induced in satellite cells following muscle injury. MyoD and Myf5 are also expressed by satellite cell precursors developmentally, although the relative contribution of historical and injury induced expression to satellite cell function is unknown. We show that satellite cells lacking both MyoD and Myf5 (double knockout [dKO]) are maintained with aging in uninjured muscle. However, injured muscle fails to regenerate and dKO satellite cell progeny accumulate in damaged muscle but do not undergo muscle differentiation. dKO satellite cell progeny continue to express markers of myoblast identity, although their myogenic programming is labile, as demonstrated by dramatic morphological changes and increased propensity for non-myogenic differentiation. These data demonstrate an absolute requirement for either MyoD or Myf5 in muscle regeneration and indicate that their expression after injury stabilizes myogenic identity and confers the capacity for muscle differentiation. PMID- 29478899 TI - Exosome-Mediated Benefits of Cell Therapy in Mouse and Human Models of Duchenne Muscular Dystrophy. AB - Genetic deficiency of dystrophin leads to disability and premature death in Duchenne muscular dystrophy (DMD), affecting the heart as well as skeletal muscle. Here, we report that clinical-stage cardiac progenitor cells, known as cardiosphere-derived cells (CDCs), improve cardiac and skeletal myopathy in the mdx mouse model of DMD. Injection of CDCs into the hearts of mdx mice augments cardiac function, ambulatory capacity, and survival. Exosomes secreted by human CDCs reproduce the benefits of CDCs in mdx mice and in human induced pluripotent stem cell-derived Duchenne cardiomyocytes. Surprisingly, CDCs and their exosomes also transiently restored partial expression of full-length dystrophin in mdx mice. The findings further motivate the testing of CDCs in Duchenne patients, while identifying exosomes as next-generation therapeutic candidates. PMID- 29478901 TI - A Long-Term Follow-Up Study of Allogeneic Mesenchymal Stem/Stromal Cell Transplantation in Patients with Drug-Resistant Systemic Lupus Erythematosus. AB - Allogeneic mesenchymal stem/stromal cells (MSCs) have been widely studied as an alternative cell source for regenerative medicine. Here, we report a long-term follow-up study of allogeneic bone marrow and/or umbilical cord MSC transplantation (MSCT) in severe and drug-refractory systemic lupus erythematosus (SLE) patients. Eighty-one patients were enrolled, and the 5-year overall survival rate was 84% (68/81) after MSCT. At 5-year follow-up, 27% of patients (22/81) were in complete clinical remission and another 7% (6/81) were in partial clinical remission, with a 5-year disease remission rate of 34% (28/81). In total, 37 patients had achieved clinical remission and then 9 patients subsequently relapsed, with 5-year overall rate of relapse of 24% (9/37). SLE Disease Activity Index scores, serum albumin, complement C3, peripheral white blood cell, and platelet numbers, as well as proteinuria levels, continued to improve during the follow-up. Our results demonstrated that allogeneic MSCT is safe and resulted in long-term clinical remission in SLE patients. PMID- 29478900 TI - GDNF/GFRalpha1 Complex Abrogates Self-Renewing Activity of Cortical Neural Precursors Inducing Their Differentiation. AB - The balance between factors leading to proliferation and differentiation of cortical neural precursors (CNPs) determines the correct cortical development. In this work, we show that GDNF and its receptor GFRalpha1 are expressed in the neocortex during the period of cortical neurogenesis. We show that the GDNF/GFRalpha1 complex inhibits the self-renewal capacity of mouse CNP cells induced by fibroblast growth factor 2 (FGF2), promoting neuronal differentiation. While GDNF leads to decreased proliferation of cultured cortical precursor cells, ablation of GFRalpha1 in glutamatergic cortical precursors enhances its proliferation. We show that GDNF treatment of CNPs promoted morphological differentiation even in the presence of the self-renewal-promoting factor, FGF2. Analysis of GFRalpha1-deficient mice shows an increase in the number of cycling cells during cortical development and a reduction in dendrite development of cortical GFRalpha1-expressing neurons. Together, these results indicate that GDNF/GFRalpha1 signaling plays an essential role in regulating the proliferative condition and the differentiation of cortical progenitors. PMID- 29478902 TI - TGF-beta Signaling Accelerates Senescence of Human Bone-Derived CD271 and SSEA-4 Double-Positive Mesenchymal Stromal Cells. AB - It is generally thought that the proliferative capacity and differentiation potential of somatic stem cells, including mesenchymal stromal/stem cells (MSCs) and hematopoietic stem cells, decline with age. We investigated the effects of aging on human bone-derived MSCs expressing CD271 and SSEA-4 (double-positive MSCs [DPMSCs]). The percentages of DPMSCs in bone tissue decreased significantly with age. The DPMSCs from elderly patients (old DPMSCs) showed cellular senescence, which was evidenced by low growth potential, high senescence associated beta-galactosidase activity, and elevated p16 and p21 CDK inhibitor levels. Moreover, old DPMSCs showed weak osteogenic differentiation potential and less hematopoiesis-supporting activity in comparison with young DPMSCs. Interestingly, the addition of transforming growth factor beta2 (TGF-beta2) induced cellular senescence in young DPMSCs. With the exception of the adipogenic differentiation potential, all of the aging phenomena observed in old DPMSCs were reversed by the addition of anti-TGF-beta antibodies. These results suggest that, in part, old DPMSCs accelerate cellular senescence through TGF-beta signaling. PMID- 29478903 TI - Pericardial effusion associated with systemic inflammatory disease in seven dogs (January 2006 - January 2012). AB - Pericardial effusion (PE) is reported in dogs as a consequence of neoplasia, primary cardiac disease or as an idiopathic condition. We describe seven dogs with systemic inflammatory disease, PE without tamponade and increased cardiac troponin I concentrations. Echocardiographic findings and adjunctive testing did not identify other known causes of PE. Resolution of the PE was documented in five of seven dogs in which follow-up echocardiography was performed, often after anti-inflammatory therapy. Resolution of PE was associated with normalisation of cardiac troponin I levels. Clinical signs had not recurred in six dogs with follow-up for more than 12 months and up to 7 years. These findings suggest an association between systemic inflammation and PE in dogs. PMID- 29478904 TI - Anterior cruciate ligament ruptures in German elite soccer players: Epidemiology, mechanisms, and return to play. AB - BACKGROUND: Anterior cruciate ligament ruptures (ACLRs) are severe sports-related injuries with significant consequences for affected players and teams. This study aims to identify the epidemiology and injury-related lay-off after ACLR in professional male soccer players from the first-division German Bundesliga. METHODS: Exposure times and incidence of anterior cruciate ligament ruptures were collected during 7.5 consecutive seasons using two media-based registers. RESULTS: A total of 72 total ACLRs were registered in 66 different players with an incidence of 0.040 per 1000h of exposure (95% CI 0.009-0.12). On average there were 9.6 ACLRs per season and 0.53 per team and season. The mean age of players affected was 24 (standard deviation+/-3.6) years. The number of ACLRs recorded per season fluctuated during the period observed. Goalkeepers are significantly (P<0.05) less prone to suffer an ACLR compared to outfield players. CONCLUSIONS: Understanding ACLR loading mechanisms, knowing risk factors for the injury and mean off time after ACLR are essential information for the coach, the medical staff, the elite soccer players, the insurance and team managers. Our results are in accordance with reports based on information from medical team staff. Therefore, our analysis of ACLR based on media sources may serve as an alternative for injury reports in elite soccer. The information of this study may be helpful for the medical staff taking care of professional soccer players and for orthopedic surgeons performing ACL reconstructions in this patient population. PMID- 29478905 TI - MUB40 Binds to Lactoferrin and Stands as a Specific Neutrophil Marker. AB - Neutrophils represent the most abundant immune cells recruited to inflamed tissues. A lack of dedicated tools has hampered their detection and study. We show that a synthesized peptide, MUB40, binds to lactoferrin, the most abundant protein stored in neutrophil-specific and tertiary granules. Lactoferrin is specifically produced by neutrophils among other leukocytes, making MUB40 a specific neutrophil marker. Naive mammalian neutrophils (human, guinea pig, mouse, rabbit) were labeled by fluorescent MUB40 conjugates (-Cy5, Dylight405). A peptidase-resistant retro-inverso MUB40 (RI-MUB40) was synthesized and its lactoferrin-binding property validated. Neutrophil lactoferrin secretion during in vitro Shigella infection was assessed with RI-MUB40-Cy5 using live cell microscopy. Systemically administered RI-MUB40-Cy5 accumulated at sites of inflammation in a mouse arthritis inflammation model in vivo and showed usefulness as a potential tool for inflammation detection using non-invasive imaging. Improving neutrophil detection with the universal and specific MUB40 marker will aid the study of broad ranges of inflammatory diseases. PMID- 29478906 TI - Identification of the Nicotinamide Salvage Pathway as a New Toxification Route for Antimetabolites. AB - Interest in the modulation of nicotinamide adenine dinucleotide (NAD) metabolome is gaining great momentum because of its therapeutic potential in different human disorders. Suppression of nicotinamide salvage by nicotinamide phosphoribosyl transferase (NAMPT) inhibitors, however, gave inconclusive results in neoplastic patients because several metabolic routes circumvent the enzymatic block converging directly on nicotinamide mononucleotide adenylyl transferases (NMNATs) for NAD synthesis. Unfortunately, NMNAT inhibitors have not been identified. Here, we report the identification of Vacor as a substrate metabolized by the consecutive action of NAMPT and NMNAT2 into the NAD analog Vacor adenine dinucleotide (VAD). This leads to inhibition of both enzymes, as well as NAD dependent dehydrogenases, thereby causing unprecedented rapid NAD depletion, glycolytic block, energy failure, and necrotic death of NMNAT2-proficient cancer cells. Conversely, lack of NMNAT2 expression confers complete resistance to Vacor. Remarkably, Vacor prompts VAD formation and growth suppression in NMNAT2 positive neuroblastoma and melanoma xenografts. Our data show the first evidence of harnessing the entire nicotinamide salvage pathway for antimetabolic strategies. PMID- 29478908 TI - Bronchiectasis: new therapies and new perspectives. AB - European Respiratory Society guidelines for the management of adult bronchiectasis highlight the paucity of treatment options available for patients with this disorder. No treatments have been licensed by regulatory agencies worldwide, and most therapies used in clinical practice are based on very little evidence. Development of new treatments is needed urgently. We did a systematic review of scientific literature and clinical trial registries to identify agents in early-to-late clinical development for bronchiectasis in adults. In this Review, we discuss the mechanisms and potential roles of emerging therapies, including drugs that target airway and systemic inflammation, mucociliary clearance, and epithelial dysfunction. To ensure these treatments achieve success in randomised clinical trials-and therefore reach patients-we propose a reassessment of the current approach to bronchiectasis. Although understanding of the pathophysiology of bronchiectasis is at an early stage, we argue that bronchiectasis is a heterogeneous disease with many different biological mechanisms that drive disease progression (endotypes), and therefore the so called treatable traits approach used in asthma and chronic obstructive pulmonary disease could be applied to bronchiectasis, with future trials targeted at the specific disease subgroups most likely to benefit. PMID- 29478907 TI - SRPKIN-1: A Covalent SRPK1/2 Inhibitor that Potently Converts VEGF from Pro angiogenic to Anti-angiogenic Isoform. AB - The SRPK family of kinases regulates pre-mRNA splicing by phosphorylating serine/arginine (SR)-rich splicing factors, signals splicing control in response to extracellular stimuli, and contributes to tumorigenesis, suggesting that these splicing kinases are potential therapeutic targets. Here, we report the development of the first irreversible SRPK inhibitor, SRPKIN-1, which is also the first kinase inhibitor that forms a covalent bond with a tyrosine phenol group in the ATP-binding pocket. Kinome-wide profiling demonstrates its selectivity for SRPK1/2, and SRPKIN-1 attenuates SR protein phosphorylation at submicromolar concentrations. Vascular endothelial growth factor (VEGF) is a known target for SRPK-regulated splicing and, relative to the first-generation SRPK inhibitor SRPIN340 or small interfering RNA-mediated SRPK knockdown, SRPKIN-1 is more potent in converting the pro-angiogenic VEGF-A165a to the anti-angiogenic VEGF A165b isoform and in blocking laser-induced neovascularization in a murine retinal model. These findings encourage further development of SRPK inhibitors for treatment of age-related macular degeneration. PMID- 29478909 TI - Explanted Vascular and Endovascular Graft Analysis: Where Do We Stand and What Should We Do? AB - OBJECTIVE/BACKGROUND: Since the late 1950s, major advances in vascular surgical practice have been closely associated with the introduction of novel vascular implants. These devices have been constructed from a variety of materials and have been designed to be implanted in several different ways. Despite a rigorous regulatory process, regular failures continue to be observed. A systematic review of the literature and of the Geprovas registry was performed in order to improve understanding of the failures. METHODS: A systematic review was performed via a search of the MEDLINE and Embase databases. Full text, English, German, or French language studies without any chronological limit were included. The reference lists of included studies, as well as the first 20 related items, were scanned for other potentially relevant studies. RESULTS: Data extraction allowed the evaluation of 184 publications; 72 publications met the inclusion criteria. Only 12 publications reported sufficient data for structural, histopathological, and epidemiological analysis. However, explant analysis allowed the understanding of degenerative phenomena: "warp knitted" replaced "weft knitted" polyethylene terephthalate grafts, decreasing the risk of dilatation or rupture; inter-nodal distance was modified in order to improve polytetrafluoroethylene graft incorporation capacities; and index of saturation, endograft fabric/stent interactions, and stent fatigue phenomena have been extensively studied in an attempt to improve endovascular device durability. CONCLUSION: A general lack of depth of reporting of explants remains. Dedicated systematic explant analysis programs are the key to improving the performance of future generations of devices. PMID- 29478910 TI - Ten Year Mortality in Different Peripheral Arterial Disease Stages: A Population Based Observational Study on Outcome. AB - OBJECTIVE: The aim was to determine long-term mortality rates and the underlying cause of death for subjects with different peripheral arterial disease (PAD) stages in a population based setting. METHODS: A randomly selected population sample of 5080 subjects was enrolled in the study in 2004-2005. Participants completed health state questionnaires and underwent ankle brachial index (ABI) measurements for classification into PAD severity stages and reference subjects. A follow-up was conducted by the end of 2015 using data from Swedish governmental national registers for cause of death, which was then compared with PAD stage determined at baseline in 2005. RESULTS: The 10 year all cause mortality was 27% for reference cases, 56% for asymptomatic PAD (APAD), 63% for intermittent claudication (IC), and 75% for severe limb ischaemia (SLI). Among all PAD subjects, cardiovascular (CV) causes were the most common main cause of death (45%) and a CV event was present as either the main or one of the three most common contributing causes of death in 64% of the cases. The age adjusted hazard ratios for a main cause of death by a CV event were 1.9 (95% CI 1.5-2.3) for APAD, 2.6 (95% CI 2.1-3.4) for IC, and 3.5 (95% CI 2.3-5.2) for SLI. CONCLUSION: PAD subjects, including the APAD subjects, are still at high risk of CV death. The mortality risks are more than doubled in symptomatic PAD patients compared with reference subjects and increase by severity of PAD stage. Awareness and improved risk reduction management of PAD are still warranted. PMID- 29478912 TI - Commentary on "The Implications of Non-compliance for Endovascular Aneurysm Repair (EVAR)". PMID- 29478911 TI - An Individualised Strategy and Long-Term Outcomes of Endovascular Treatment of Budd-Chiari Syndrome Complicated by Inferior Vena Cava Thrombosis. AB - OBJECTIVES: The aim was to evaluate individualised treatment and long-term outcomes of endovascular treatment of Budd-Chiari syndrome (BCS) complicated by inferior vena cava (IVC) thrombosis. METHODS: Between April 2005 and December 2015, 108 consecutive patients with BCS complicated by IVC thrombosis underwent endovascular treatment. According to the type, size, extent, and degree of organisation of the thrombus, agitation thrombolysis (n = 7), agitation thrombolysis combined with retrieval stent filter (n = 5), pre-dilation (n = 32), retrieval stent filter (n = 56), or direct large balloon dilation (n = 8) was performed. Peri- and post-operative follow-up data were recorded. RESULTS: The endovascular treatment was technically successful in 107 of the 108 patients (99.1%). The incidence of thrombosis related complications was 7.4% (8/108). Major and minor complications occurred in four patients. The mean follow-up duration was 61.7 +/- 39.3 months (range 3-140 months). The cumulative 1, 2, 5, and 10 year primary patency rates were 91%, 88%, 79%, and 79%, respectively, and the cumulative 1, 2, 5, and 10 year secondary patency rates were 100%, 100%, 97%, and 97%, respectively. The cumulative 1, 5, and 10 year survival rates were 95%, 86%, and 81%, respectively. Serum albumin and total bilirubin values were independent predictors of survival. CONCLUSIONS: For patients with BCS complicated by IVC thrombosis, an individualised endovascular treatment strategy based on the type, size, extent, and degree of organisation of the thrombus is associated with long-term patency of the IVC and favourable survival and complication rates. PMID- 29478913 TI - [Oxygen therapy in the management of acute myocardial infarction: A disappearing practice?] PMID- 29478915 TI - A Hypothalamic Switch for REM and Non-REM Sleep. AB - Rapid eye movement (REM) and non-REM (NREM) sleep are controlled by specific neuronal circuits. Here we show that galanin-expressing GABAergic neurons in the dorsomedial hypothalamus (DMH) comprise separate subpopulations with opposing effects on REM versus NREM sleep. Microendoscopic calcium imaging revealed diverse sleep-wake activity of DMH GABAergic neurons, but the galanin-expressing subset falls into two distinct groups, either selectively activated (REM-on) or suppressed (REM-off) during REM sleep. Retrogradely labeled, preoptic area (POA) projecting galaninergic neurons are REM-off, whereas the raphe pallidus (RPA) projecting neurons are primarily REM-on. Bidirectional optogenetic manipulations showed that the POA-projecting neurons promote NREM sleep and suppress REM sleep, while the RPA-projecting neurons have the opposite effects. Thus, REM/NREM switch is regulated antagonistically by DMH galaninergic neurons with intermingled cell bodies but distinct axon projections. PMID- 29478914 TI - Genome-wide CRISPR-Cas9 Screen Identifies Leukemia-Specific Dependence on a Pre mRNA Metabolic Pathway Regulated by DCPS. AB - To identify novel targets for acute myeloid leukemia (AML) therapy, we performed genome-wide CRISPR-Cas9 screening using AML cell lines, followed by a second screen in vivo. Here, we show that the mRNA decapping enzyme scavenger (DCPS) gene is essential for AML cell survival. The DCPS enzyme interacted with components of pre-mRNA metabolic pathways, including spliceosomes, as revealed by mass spectrometry. RG3039, a DCPS inhibitor originally developed to treat spinal muscular atrophy, exhibited anti-leukemic activity via inducing pre-mRNA mis splicing. Humans harboring germline biallelic DCPS loss-of-function mutations do not exhibit aberrant hematologic phenotypes, indicating that DCPS is dispensable for human hematopoiesis. Our findings shed light on a pre-mRNA metabolic pathway and identify DCPS as a target for AML therapy. PMID- 29478916 TI - Caldendrin Directly Couples Postsynaptic Calcium Signals to Actin Remodeling in Dendritic Spines. AB - Compartmentalization of calcium-dependent plasticity allows for rapid actin remodeling in dendritic spines. However, molecular mechanisms for the spatio temporal regulation of filamentous actin (F-actin) dynamics by spinous Ca2+ transients are still poorly defined. We show that the postsynaptic Ca2+ sensor caldendrin orchestrates nano-domain actin dynamics that are essential for actin remodeling in the early phase of long-term potentiation (LTP). Steep elevation in spinous [Ca2+]i disrupts an intramolecular interaction of caldendrin and allows cortactin binding. The fast on and slow off rate of this interaction keeps cortactin in an active conformation, and protects F-actin at the spine base against cofilin-induced severing. Caldendrin gene knockout results in higher synaptic actin turnover, altered nanoscale organization of spinous F-actin, defects in structural spine plasticity, LTP, and hippocampus-dependent learning. Collectively, the data indicate that caldendrin-cortactin directly couple [Ca2+]i to preserve a minimal F-actin pool that is required for actin remodeling in the early phase of LTP. PMID- 29478917 TI - The Sixth Transmembrane Segment Is a Major Gating Component of the TMEM16A Calcium-Activated Chloride Channel. AB - Calcium-activated chloride channels (CaCCs) formed by TMEM16A or TMEM16B are broadly expressed in the nervous system, smooth muscles, exocrine glands, and other tissues. With two calcium-binding sites and a pore within each monomer, the dimeric CaCC exhibits voltage-dependent calcium sensitivity. Channel activity also depends on the identity of permeant anions. To understand how CaCC regulates neuronal signaling and how CaCC is, in turn, modulated by neuronal activity, we examined the molecular basis of CaCC gating. Here, we report that voltage modulation of TMEM16A-CaCC involves voltage-dependent occupancy of calcium- and anion-binding site(s) within the membrane electric field as well as a voltage dependent conformational change intrinsic to the channel protein. These gating modalities all critically depend on the sixth transmembrane segment. PMID- 29478918 TI - Evidence against a role for NLRP3-driven islet inflammation in db/db mice. AB - OBJECTIVES: Type 2 diabetes (T2D) is associated with chronic, low grade inflammation. Activation of the NLRP3 inflammasome and secretion of its target interleukin-1beta (IL-1beta) have been implicated in pancreatic beta cell failure in T2D. Specific targeting of the NLRP3 inflammasome to prevent pancreatic beta cell death could allow for selective T2D treatment without compromising all IL 1beta-associated immune responses. We hypothesized that treating a mouse model of T2D with MCC950, a compound that specifically inhibits NLRP3, would prevent pancreatic beta cell death, thereby preventing the onset of T2D. METHODS: Diabetic db/db mice were treated with MCC950 via drinking water for 8 weeks from 6 to 14 weeks of age, a period over which they developed pancreatic beta cell failure. We assessed metabolic parameters such as body composition, glucose tolerance, or insulin secretion over the course of the intervention. RESULTS: MCC950 was a potent inhibitor of NLRP3-induced IL-1beta in vitro and was detected at high levels in the plasma of treated db/db mice. Treatment of pre-diabetic db/db mice with MCC950, however, did not prevent pancreatic dysfunction and full onset of the T2D pathology. When examining the NLRP3 pathway in the pancreas of db/db mice, we could not detect an activation of this pathway nor increased levels of its target IL-1beta. CONCLUSIONS: NLRP3 driven-pancreatic IL-1beta inflammation does not play a key role in the pathogenesis of the db/db murine model of T2D. PMID- 29478920 TI - Teaching and Assessing Professionalism in Radiology: Resources and Scholarly Opportunities to Contribute to Required Expectations. AB - Teaching and assessing trainees' professionalism now represents an explicit expectation for Accreditation Council Graduate Medical Education-accredited radiology programs. Challenges to meeting this expectation include variability in defining the construct of professionalism; limits of traditional teaching and assessment methods, used for competencies historically more prominent in medical education, for professionalism; and emerging expectations for credible and feasible professionalism teaching and assessment practices in the current context of health-care training and practice. This article identifies promising teaching resources and methods that can be used strategically to augment traditional teaching of the cognitive basis for professionalism, including role modeling, case-based scenarios, debriefing, simulations, narrative medicine (storytelling), guided discussions, peer-assisted learning, and reflective practice. This article also summarizes assessment practices intended to promote learning, as well as to inform how and when to assess trainees as their professional identities develop over time, settings, and autonomous practice, particularly in terms of measurable behaviors. This includes assessment tools (including mini observations, critical incident reports, and appreciative inquiry) for authentic assessment in the workplace; engaging multiple sources (self-, peer, other health professionals, and patients) in assessment; and intentional practices for trainees to take responsibility for seeking our actionable feedback and reflection. This article examines the emerging evidence of the feasibility and value added of assessment of medical competency milestones, including professionalism, coordinated by the Accreditation Council Graduate Medical Education in radiology and other medical specialties. Radiology has a strategic opportunity to contribute to scholarship and inform policies in professionalism teaching and assessment practices. PMID- 29478919 TI - Intravoxel Incoherent Motion Diffusion-weighted MR Imaging for Early Evaluation of the Effect of Radiofrequency Ablation in Rabbit Liver VX2 Tumors. AB - RATIONALE AND OBJECTIVES: This study aims to investigate the value of intravoxel incoherent motion (IVIM)-derived parameters for early evaluation of the efficiency of radiofrequency ablation (RFA) treatment for rabbit liver VX2 tumor. MATERIALS AND METHODS: Eighteen rabbit liver VX2 tumor models were constructed, and computed tomography-guided RFA was performed. One day before and 7 days after RFA, 18 models underwent magnetic resonance imaging, including contrast-enhanced imaging and IVIM diffusion-weighted imaging with 16 b-factors (0-1000 s/mm2). Post-RFA liver tumors were segmented into viable tumor, inflammatory reaction, and ablation necrotic regions according to gross and histopathologic examinations. Parameters derived from IVIM were calculated. One-way analysis of variance and least significant difference test were used for comparisons among the three regions. The diagnostic performance of parameters was evaluated using receiver operating characteristic (ROC) analysis. RESULTS: ADCtotal, D, and f values were significantly lower in viable tumor than in inflammatory reaction regions (all P < .05), but D* showed no significant difference between the two regions. ADCtotal values of viable tumor regions were significantly lower than that of ablation necrotic regions (P = .007), but D* values of necrotic regions were significantly lower than that of viable tumor regions (P = .045). In ROC analysis, ADC showed the highest area under the ROC curve for differentiating inflammatory reaction from viable tumor region. CONCLUSIONS: ADCtotal, D, and f were valuable discriminating markers for differentiation between regions of viable tumor and inflammatory reaction in post-RFA tumor, especially ADCtotal outperformed the other two parameters with higher diagnostic performance. PMID- 29478921 TI - Canceled MRI-guided Breast Biopsies Due to Nonvisualization: Follow-up and Outcomes. AB - RATIONALE AND OBJECTIVE: The objective of this study was to evaluate breast lesion outcomes in patients after canceled MRI-guided breast biopsy due to lesion nonvisualization. MATERIALS AND METHODS: Electronic medical records (January 2007 December 2014) were searched for patients with canceled magnetic resonance imaging (MRI)-guided breast biopsies due to lesion nonvisualization. A total of 1403 MRI-detected lesions were scheduled for MRI-guided biopsy and 89 were canceled because of nonvisualization. Imaging studies and medical records were reviewed for patient demographics, lesion characteristics, and subsequent malignancy. Patients without adequate MRI follow-up imaging were excluded. Statistical analysis was employed to determine if patient demographics or lesion characteristics were predictive of lesion resolution or lesion biopsy after subsequent follow-up. RESULTS: Eighty-nine (6.3% [89/1403]; 95% confidence interval, 5.2%-7.7%) biopsies in 89 women were canceled because of nonvisualization. Follow-up MRIs greater than 5.5 months were available for 60.7% (54/89) of women. In 74.1% (40/54) of these patients, the lesions completely resolved on follow-up. In 25.9% (14/54) of the patients, the lesion persisted on follow-up; 42.9% (6/14) of these patients underwent biopsy. One case (1.9% [1/54]) yielded ductal carcinoma in situ with microinvasion at the 6-month follow up. No patient demographics or lesion features were associated with lesion resolution or lesion biopsy. CONCLUSIONS: The majority of canceled MRI-guided biopsy lesions resolved on later follow-up; however, because of the small possibility of a missed malignancy, follow-up MRI imaging at 6 months is recommended. PMID- 29478924 TI - ? PMID- 29478925 TI - Is systematic mandibular retention mandatory? A systematic review. AB - INTRODUCTION: Relapse in orthodontics, and particularly, mandibular anterior crowding is an unforeseeable phenomenon and a quite embarrassing situation for the orthodontist, as it may be interpreted by the patient as a treatment failure. Relapse may be inherent to various factors (periodontal, anatomical, muscular, occlusal, residual growth, third molars development...), which must be imperatively acknowledged in order to be managed during orthodontic treatment and therefore ensure an optimal control on the stability of the achieved final outcomes. The aim of this review was to determine, through a systematic analysis based on a Medline PubMed search, the scientific relevant factors involved in the relapse of mandibular anterior crowding. MATERIALS AND METHODS: A systematic research was performed based on an electronic search (between 2005 and December 2016) among various databases. The search was limited to the use of several specific search words expressed in two languages: English and French. Two investigators selected those meeting the exclusion/inclusion criteria. RESULTS AND DISCUSSION: Out of the 1055 references, only 19 studies met our inclusion criteria. The factors addressed by these studies are: extraction or non extraction treatment, residual growth, facial divergence, periodontium, type of retainer, incisor morphology and quality of dental occlusion. Divergence in female patients, thin cortical bone and treatment using aligners were associated with a higher rate of mandibular anterior crowding relapse. However, due to the low level of evidence of the included studies, as well as the heterogeneity of protocols between the studies, it was not possible to determine factors truly involved in mandibular crowding relapse. Future reliable prospective studies are required to provide unbiased and quantifiable results. PMID- 29478923 TI - Innate Immune Response and Off-Target Mis-splicing Are Common Morpholino-Induced Side Effects in Xenopus. AB - Antisense morpholino oligomers (MOs) have been indispensable tools for developmental biologists to transiently knock down (KD) genes rather than to knock them out (KO). Here we report on the implications of genetic KO versus MO mediated KD of the mesoderm-specifying Brachyury paralogs in the frog Xenopus tropicalis. While both KO and KD embryos fail to activate the same core gene regulatory network, resulting in virtually identical morphological defects, embryos injected with control or target MOs also show a systemic GC content dependent immune response and many off-target splicing defects. Optimization of MO dosage and increasing incubation temperatures can mitigate, but not eliminate, these MO side effects, which are consistent with the high affinity measured between MO and off-target sequence in vitro. We conclude that while MOs can be useful to profile loss-of-function phenotypes at a molecular level, careful attention must be paid to their immunogenic and off-target side effects. PMID- 29478926 TI - ? PMID- 29478922 TI - Activation of the Notch Signaling Pathway In Vivo Elicits Changes in CSL Nuclear Dynamics. AB - A key feature of Notch signaling is that it directs immediate changes in transcription via the DNA-binding factor CSL, switching it from repression to activation. How Notch generates both a sensitive and accurate response-in the absence of any amplification step-remains to be elucidated. To address this question, we developed real-time analysis of CSL dynamics including single molecule tracking in vivo. In Notch-OFF nuclei, a small proportion of CSL molecules transiently binds DNA, while in Notch-ON conditions CSL recruitment increases dramatically at target loci, where complexes have longer dwell times conferred by the Notch co-activator Mastermind. Surprisingly, recruitment of CSL related corepressors also increases in Notch-ON conditions, revealing that Notch induces cooperative or "assisted" loading by promoting local increase in chromatin accessibility. Thus, in vivo Notch activity triggers changes in CSL dwell times and chromatin accessibility, which we propose confer sensitivity to small input changes and facilitate timely shut-down. PMID- 29478927 TI - A comparison of mechanical characteristics of four common orthodontic loops in different ranges of activation and angular bends: The concordance between experiment and finite element analysis. AB - PURPOSE: Several methods have been used to analyse different characteristics of orthodontic loops, which are generally divided into two categories: Experimental methods, Analytical and numerical methods such as finite element methods (FEM). The main goal of this study was to compare the results of FEM and experimental methods in determining mechanical characteristics (moment, force and M/F in various ranges of activation and different angular bends) of four common orthodontic loops to find the level of concordance between them. METHODS AND MATERIALS: Experimental method: 60 closing loops were prepared and divided into four groups. Universal testing machine was used for two reasons: tensile tests were performed to check the horizontal force component; compression tests were designed to check the vertical force component. To measure the moment at the two ends of the loops, they were activated by 0.1mm, 0.3mm, 0.7mm, 1mm, 1.25mm and 1.5mm. The vertical component of the force was calculated at the centre of the loops. Each group was divided to three subgroups, depending on the amount of applied angular bend: 0 degrees , 20 degrees , 40 degrees . Finite element method (FEM): three-dimensional model loops were designed by special software. Then, strong meshing software meshed them. Loops were activated in the same range attempted in the experimental method. Then, force, moment and M/F were assessed. RESULTS: It can be understood from the results of both methods that the values of force and moment increase when the activation range and angular bend increase, and M/F increases when the activation range decreases and angular bend increases. The highest concordance between the two methods was related to M/F, force and moment. CONCLUSION: Experimental results and FEM predictions are in good agreement when determining the mechanical characteristics of the loops. PMID- 29478928 TI - ? PMID- 29478929 TI - Effects of fixed orthodontic treatment and two new mouth rinses on gingival health: A prospective cohort followed by a single-blind placebo-controlled randomized clinical trial. AB - INTRODUCTION: Routine brushing protocols might not suffice to reduce the increased plaque accumulation in orthodontic patients. Antimicrobial mouth rinses are favorable in this regard. This two-phase study evaluated the effects of orthodontic treatment and the application of two mouthwashes not studied before on oral health indices. METHODS: In this two-phase study (a prospective cohort followed by a parallel randomized controlled trial), plaque index (PI), gingival index (GI), gingival bleeding index (GBI), and pocket probing depth (PPD) were measured in 54 orthodontic patients before orthodontic treatment and 4 months later. Then patients were randomized into three groups of mouthrinses: Persica (herbal), Ortho-Kin (containing diluted chlorhexidine), and Placebo (n=18*3). The effects of orthodontic treatment and mouthrinses were analyzed statistically (alpha=0.05). RESULTS: All the 4 indices increased between the baseline and 4th month of treatment (P values<0.01, paired t-test). They decreased back to baseline levels or below them, after one month of mouthwash application (P values<0.002). Both mouthwashes showed therapeutic effects compared to placebo in terms of PI and GBI. In the case of GI, only Persica showed significantly better results compared to placebo. Regarding PPD, only Ortho-Kin acted better than placebo (P values<=0.05, Tukey). LIMITATIONS OF THE RANDOMIZED CONTROL TRIAL (RCT) PHASE: Lack of positive control (regular chlorhexidine mouth rinse) and negative control (a group with no mouthwashes, even without the placebo). Lack of sample size predetermination based on a priori power calculations. The difference between the regime of Persica with that of Ortho-Kin and placebo (which had similar application protocols) disallowed perfectly effective blinding of the patients (hence, single-blind). CONCLUSION: Fixed orthodontic treatment might disrupt gingival health. Antimicrobial mouthwashes might reverse this. Both evaluated mouthwashes might have therapeutic effects. PMID- 29478930 TI - ? PMID- 29478931 TI - ? PMID- 29478932 TI - Profile changes following extraction orthodontic treatment: A comparison of first versus second premolar extraction. AB - OBJECTIVE: To determine the change in the soft tissue profile following extraction orthodontic treatment with either first or second premolar extractions. METHODS: This was a retrospective clinical study of 81 consecutive orthodontic patients treated with extraction of four premolars. Patients were divided into two treatment groups according to whether four first premolar teeth (PM1 treatment group, n=48) or four second premolar teeth were removed (PM2 treatment group, n=33) during treatment. Changes in the nasolabial angle and the distance of the upper and lower lips to E-plane were compared pre- and post treatment. Age, sex, upper lip thickness, facial convexity, facial axis, upper and lower arch crowding at pre-treatment, use of molar anchorage and the amount of retrusion of the maxillary and mandibular incisor teeth during treatment were used as explanatory variables. RESULTS: When facial convexity and facial axis at pre-treatment, the use of maxillary anchorage and the amount of retrusion of the maxillary and mandibular incisor teeth achieved as a consequence of treatment were taken into account, there was less than one degree (0.67 degrees ) difference between the change in the nasolabial angle in the PM1 treatment group compared to the PM2 treatment group (P>0.05). The mean change in the upper lip position relative to E-plane and the mean change in lower lip position relative to E-plane were also similar for the two groups. CONCLUSION: The change in soft tissue profile following orthodontic treatment was similar regardless of whether first premolar or second premolar teeth were removed. PMID- 29478933 TI - Clinical comparison of two initial arch wires (A-NiTi and Heat Activated NiTi) for amount of tooth alignment and perception of pain: A randomized clinical trial. AB - OBJECTIVES: The aim of this study was to compare two initial arch wires, 0.014" A NiTi and 0.016" Heat Activated NiTi (HANT), for amount of tooth alignment and perception of pain. MATERIALS AND METHODS: In total, 59 orthodontic patients (21 males and 38 females) from three orthodontic clinics participated in this 2-arm, parallel-group clinical trial and were randomized to 0.014" A-NiTi (n=30) or 0.016" HANT groups (n=29). Patient recruitment commenced in April 2016 and ended in December 2016. Age of the patients was between 12 to 25 years with an average of 17.92+/-3.74 years. Eligibility criteria included permanent dentition, non extraction treatment plan in lower arch, Irregularity Index>2 in lower arch, no systemic disease influencing pain, no chronic Non Steroid Anti Inflammatory Drug (NSAID) therapy, and no history of dental pain, mucosal ulcers or temporomandibular disorders (TMD). Blinding was applicable to the patients and outcome assessment. The primary outcome was to compare the reduction of the Irregularity Index mean from bonding sessions to 4 weeks later in these groups and the secondary outcome was evaluation of the pain according to the modified McGill Pain Questionnaire (MPQ) with Visual Analogue Scale questionnaire (VAS). RESULTS: The mean differences of irregularity indices between the two groups are not statistically significant (95% CI: 0.39-1.03; P=0.36) and according to the questionnaire, there was no significant difference between the two groups in trigger, site, description, duration, beginning, medication, and pain reduction over time. However, the VAS scale of HANT group was significantly higher than that of A-NiTi (P=0.04). CONCLUSION: Results from this investigation suggested that there was no clinical difference in amount of tooth alignment and perception of pain between 0.014" A-NiTi and 0.016" HANT wires. PMID- 29478934 TI - Human evaluation in association to the mathematical analysis of arch forms: Two dimensional study. AB - OBJECTIVES: To evaluate the relationship between human evaluation of the dental arch form, to complete a mathematical analysis via two different methods in quantifying the arch form, and to establish agreement with the fourth-order polynomial equation. MATERIALS AND METHODS: This study included 64 sets of digitised maxilla and mandible dental casts obtained from a sample of dental arch with normal occlusion. For human evaluation, a convenient sample of orthodontic practitioners ranked the photo images of dental cast from the most tapered to the less tapered (square). In the mathematical analysis, dental arches were interpolated using the fourth-order polynomial equation with millimetric acetate paper and AutoCAD software. Finally, the relations between human evaluation and mathematical objective analyses were evaluated. RESULTS: Human evaluations were found to be generally in agreement, but only at the extremes of tapered and square arch forms; this indicated general human error and observer bias. The two methods used to plot the arch form were comparable. CONCLUSION: The use of fourth order polynomial equation may be facilitative in obtaining a smooth curve, which can produce a template for individual arch that represents all potential tooth positions for the dental arch. PMID- 29478935 TI - Evaluation of determinants for the nickel release by the standard orthodontic brackets. AB - AIM: The study was aimed to assess the effect of different pH and immersion time on the amount of nickel release from simulated orthodontic appliance of 3M Unitek company. MATERIAL AND METHOD: Nickel ion release was evaluated after subjecting the brackets to the simulated artificial oral environment. In this study, 90 stainless steel brackets of 3M Unitek Company were tested by immersing them in artificial saliva of pH 4.2, pH 6.5 and pH 7.6 for a time interval of 1hour, 1 week and 1 month (T1 - 1h, T2 - 7 days, T3 - 30 days) respectively. The data was subjected for the one-way ANOVA and the post-hoc test for the statistical comparison. RESULTS: Means of 2.99+/-0.77, 9.53+/-4.26 and 12.65+/-2 .52 ppb (parts per billion by volume) of nickel were released for 4.2 pH at a time interval of 1hour, 7 days and 1 month respectively. Means of 5.37+/-2.26, 10.94+/ 1.51 and 16.92+/-1.69 ppb of nickel were released for 6.5 pH at a time interval of 1hour, 7 days and 1 month respectively. A mean of 2.13+/-0.92, 0.74+/-0.54 and 18.83+/-1.02 ppb of nickel was released for 7.6 pH at a time interval of 1 hr, 7 days and 1 month respectively. CONCLUSION: pH of the artificial saliva significantly affected the amount of nickel release. Acidic pH was found to increase the amount of nickel release in the artificial saliva. Time duration of bracket immersion significantly affected the amount of nickel release. PMID- 29478936 TI - ? PMID- 29478937 TI - ? PMID- 29478938 TI - Calcified Cerebral Embolism Due to a Calcified Amorphous Tumor. AB - A 59-year-old man developed brain embolism in the frontal and parietal cortex. Brain CT showed a high-density spot in the upper branch of the left middle cerebral artery, indicating calcified cerebral embolism. Calcified amorphous tumor attached to the mitral valve was identified as the cause of embolism. After surgical resection, anticoagulation was started and recurrent stroke did not occur. PMID- 29478939 TI - Association between Factor V Gene Polymorphism and Risk of Ischemic Stroke: An Updated Meta-Analysis. AB - BACKGROUND: Ischemic stroke is a complex, multifactorial, and polygenic disease. Reports on relationship between Factor V G1691A single nucleotide gene polymorphism and ischemic stroke have revealed inconsistent results. We conducted an updated meta-analysis to determine the role of Factor V single nucleotide gene polymorphism in ischemic stroke. METHODS: We searched the literature using academic electronic databases that is, PubMed, Trip Data Base, EBSCO, and Google Scholar, last search up to September 2017. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated from fixed or random effects models whichever applicable using software STATA version 13 (StataCorp LP, College Station, TX). RESULTS: Forty case-control studies met the inclusion criteria, which included 6860 cases and 18,025 controls. Altogether, 19 studies in young adults (age < or = 40 years) and 17 studies were conducted in old stroke (age > 40). Four studies did not report the mean age at recruitment. Significant association between Factor V G1691A gene polymorphism and risk of ischemic stroke were observed under dominant model (OR 1.40; 95% CI: 1.22 to 1.62, P value <.001). Stratified analysis suggested substantial association of Factor V gene polymorphism and risk of ischemic stroke in cases with onset at young age (OR 1.84; 95% CI: 1.47 to 2.30), but was not statistical significant in cases at old age (>40 years). CONCLUSIONS: Factor V G1691A single nucleotide gene polymorphism was associated with risk of ischemic stroke mainly in young adults. Further research with adequately powered prospective studies in homogenous subjects are required to determine the nature of association in young stroke. PMID- 29478940 TI - Decline in Hemoglobin during Hospitalization May Be Associated with Poor Outcome in Acute Stroke Patients. AB - BACKGROUND AND PURPOSE: Anemia upon hospital admission is a known predictor of poor functional outcomes in patients with acute cerebral infarction. However, it remains unclear whether reductions in hemoglobin levels during hospitalization influence stroke outcomes. We investigated the association between in-hospital decline in hemoglobin and poor outcomes. MATERIALS AND METHODS: We retrospectively analyzed data from 480 consecutive patients who had experienced acute cerebral infarction and presented without anemia between January 2012 and March 2015. Decline in hemoglobin was taken as the difference between hemoglobin levels upon admission and nadir hemoglobin. Poor outcome was defined as a modified Rankin Scale score 3-6. A multivariate analysis of the relationship between decline in hemoglobin and poor outcome at discharge was conducted for various patient characteristics. RESULTS: The mean hemoglobin level at admission was 14.3 +/- 1.3 g/dL, whereas the mean nadir hemoglobin value was 13.1 +/- 1.9 g/dL, with a mean decline in hemoglobin of 1.3 +/- 1.5 g/dL. In patients with poor outcomes, mean decline in hemoglobin was significantly reduced to 3.1 g/dL (P < .001). The optimal cutoff decline in hemoglobin required to distinguish a poor outcome was 1.5 g/dL whereas the sensitivity and specificity were 62% and 82.3%, respectively, with an area under the curve of .77 (P < .0001). A decline in hemoglobin below 1.5 g/dL was found to be an independent predictor of poor outcome (odds ratio: 2.10; confidence interval: 1.10-3.99; P = .023). CONCLUSION: Decline in hemoglobin in patients hospitalized with acute stroke may be associated with poor outcome. PMID- 29478941 TI - Contribution of Beverage Selection to the Dietary Quality of the Packed Lunches Eaten by Preschool-Aged Children. AB - BACKGROUND: Sweet drinks early in life could predispose to lifelong consumption, and the beverage industry does not clearly define fruit drinks as part of the sweet drink category. OBJECTIVES: To ascertain the relationship between beverage selection and dietary quality of the lunches packed for preschool-aged children evaluated using the Healthy Eating Index-2010. METHODS: Foods packed by parents (n=607) were observed at 30 early care and education centers on two nonconsecutive days. Three-level regression models were used to examine the dietary quality of lunches by beverage selection and the dietary quality of the lunch controlling for the nutrient composition of the beverage by removing it from the analysis. RESULTS: Fruit drinks were included in 25% of parent-packed lunches, followed by 100% fruit juice (14%), milk (14%), and flavored milk (3.7%). Lunches with plain milk had the highest Healthy Eating Index-2010 scores (59.3) followed by lunches with 100% fruit juice (56.9) and flavored milk (53.2). Lunches with fruit drinks had the lowest Healthy Eating Index-2010 scores at 48.6. After excluding the nutrient content of the beverage, the significant difference between lunches containing milk and flavored milk persisted (+5.5), whereas the difference between fruit drinks and 100% fruit juice did not. CONCLUSIONS: Dietary quality is associated with the type of beverage packed and these differences hold when the lunch is analyzed without the nutrient content of the beverage included. PMID- 29478942 TI - The prevalence of rotator cuff pathology in the setting of acute proximal biceps tendon rupture. AB - BACKGROUND: The prevalence and severity of concomitant rotator cuff pathology in the setting of proximal biceps tendon ruptures are poorly understood. Concomitant rotator cuff disease may have important implications in the prognosis and natural history of this shoulder condition. Therefore, an observational cohort of patients with an acute rupture of the long head of the biceps tendon (LHBT) was evaluated to determine the prevalence and severity of concomitant rotator cuff disease. METHODS: Thirty consecutive patients diagnosed with acute proximal biceps tendon rupture were prospectively enrolled. Magnetic resonance imaging of the affected shoulder was obtained in 27 patients and reviewed by a fellowship trained orthopedic surgeon. RESULTS: The cohort consisted of 20 men (74%) and 7 women (26%) (mean age, 61.0 years [range, 42-78 years]). The dominant side was involved in 20 injuries (74%), and a low-energy trauma mechanism of injury was involved in 23 (85%). Of the patients, 11 (41%) reported a history of antecedent shoulder pain. Magnetic resonance imaging assessment revealed that 93% of patients had evidence of rotator cuff disease, including 13 full-thickness tears. Of the full-thickness tears, 3 were small, 6 medium, 2 large, and 2 massive. Pathology of the subscapularis tendon was identified in 7 patients (26%). CONCLUSION: In this cohort, we found LHBT rupture to be highly correlated with the presence of rotator cuff disease, with the majority of patients presenting with full-thickness tears of the supraspinatus. These findings may have important implications in the treatment and prognosis of patients who present with acute LHBT ruptures. PMID- 29478943 TI - Can the contralateral scapula be used as a reliable template to reconstruct the eroded scapula during shoulder arthroplasty? AB - HYPOTHESIS: The contralateral scapula can be used as a reliable template to determine scapular offset, glenoid inclination, and version of the native scapula in view of reconstructing pathologic scapulae. METHODS: Three-dimensional measurements of scapular offset, inclination, and version were performed using data from a set of 50 bilateral computed tomography scans of full scapulae to determine direct side-to-side differences. RESULTS: The scapula pairs had a mean bilateral difference of 2 mm in offset, 2 degrees in inclination, and 2 degrees in version. Ninety percent of the scapula pairs showed an offset difference smaller than 3 mm. In 96% and 94% of the scapula pairs, the inclination difference and version difference, respectively, were smaller than 5 degrees . The maximum bilateral difference for offset, inclination, and version was 6 mm, 6 degrees , and 8 degrees , respectively. DISCUSSION AND CONCLUSION: The anatomic parameters of scapular offset, glenoid inclination, and version are quite symmetrical and fall into the currently technically feasible accuracy of shoulder arthroplasty implantation. The healthy scapula can be used as a template to guide the reconstruction of the glenoid during shoulder arthroplasty planning in the case of unilateral advanced arthropathy. PMID- 29478945 TI - Dachshund 1 is Differentially Expressed Between Male and Female Breast Cancer: A Matched Case-Control Study of Clinical Characteristics and Prognosis. AB - INTRODUCTION: Male breast cancer (MBC) is rare and little is known about its biological behavior. In this study we described clinical characteristics and prognosis of MBC and evaluated roles of different factors between MBC and female breast cancer (FBC). PATIENTS AND METHODS: We retrospectively reviewed 42 MBC patients matched with 84 consecutive FBC patients with similar year, age, tumor, node, metastases (TNM) stage, and estrogen receptor (ER) expression from 2003 to 2016. Their clinical characteristics, treatments, and prognosis were analyzed, and immunohistochemistry for androgen receptor (AR), dachshund 1 (DACH1), sine oculis 1 (SIX1), eyes absent 1, B-cell lymphoma-2, and p53 were performed on paraffin sections. RESULTS: MBC constituted 0.56% (42 of 7561) of consecutive breast cancer and had a median age of 55 years. The 14 paraffin samples from men and 28 from women expressed all the assessed proteins, and DACH1 was significantly higher in women (P = .043). Body mass index (P = .023) and DACH1 (P = .034) were correlated with MBC prognosis, whereas the expression of AR (P = .049), SIX1 (P = .048), surgery (P < .001), and chemotherapy (P = .001) were important for FBC in addition to already known factors: tumor size and location, TNM stage (lymph nodes and organ metastasis), radiotherapy, and ER and human epidermalgrowth factor receptor-2 (HER2) expression. No distinct difference in recurrence was observed between MBC and FBC (P = .667). CONCLUSION: In this study we found that DACH1 was expressed less in MBC and HER2 was expressed more in FBC. They were respectively correlated with MBC and FBC prognosis. Although no significant differences were observed between MBC and FBC prognosis, DACH1, SIX1, and AR expression requires greater attention to develop treatment strategies for MBC and FBC. PMID- 29478944 TI - Scapular kinematic and shoulder muscle activity alterations after serratus anterior muscle fatigue. AB - BACKGROUND: Although the serratus anterior muscle has an important role in scapular movement, no study to date has investigated the effect of serratus anterior fatigue on scapular kinematics and shoulder muscle activity. The purpose of this study was to clarify the effect of serratus anterior fatigue on scapular movement and shoulder muscle activity. METHODS: The study participants were 16 healthy men. Electrical muscle stimulation was used to fatigue the serratus anterior muscle. Shoulder muscle strength and endurance, scapular movement, and muscle activity were measured before and after the fatigue task. The muscle activity of the serratus anterior, upper and lower trapezius, anterior and middle deltoid, and infraspinatus muscles was recorded, and the median power frequency of these muscles was calculated to examine the degree of muscle fatigue. RESULTS: The muscle endurance and median power frequency of the serratus anterior muscle decreased after the fatigue tasks, whereas the muscle activities of the serratus anterior, upper trapezius, and infraspinatus muscles increased. External rotation of the scapula at the shoulder elevated position increased after the fatigue task. CONCLUSION: Selective serratus anterior fatigue due to electric muscle stimulation decreased the serratus anterior endurance at the flexed shoulder position. Furthermore, the muscle activities of the serratus anterior, upper trapezius, and infraspinatus increased and the scapular external rotation was greater after serratus anterior fatigue. These results suggest that the rotator cuff and scapular muscle compensated to avoid the increase in internal rotation of the scapula caused by the dysfunction of the serratus anterior muscle. PMID- 29478946 TI - Outcomes of Adolescents and Young Adults With Acute Myeloid Leukemia Treated in a Single Latin American Center. AB - INTRODUCTION: The outcomes for adolescents and young adults (AYAs) with acute myeloid leukemia (AML) have been poorly characterized in Hispanics in low- to middle-income countries. The results are influenced by biologic and socioeconomic factors. The clinical paths for AYA patients with AML are reported. PATIENTS AND METHODS: A retrospective analysis of AYA and pediatric AML patients aged 1 to 39 years during 2003 to 2016 from a single reference center in Northeast Mexico treated with a 7+3 standard protocol was performed. The 5-year overall survival (OS) and event-free survival (EFS) were estimated using Kaplan-Meier analysis. The hazard ratios for relapse and death were estimated using a Cox regression model. The patients with promyelocytic leukemia were analyzed separately. RESULTS: The study included 110 non-PML AML patients, 39 children and 71 AYAs. No difference in complete remission was found (P = .446), although the overall response rate was greater in the children (87.2% vs. 69% in AYAs; P = .034). The 5-year EFS rate was 33% for the children versus 9.3% in the AYAs at a median follow-up of 22 and 9 months, respectively (P = .008). The 5-year OS rate was 51% in the children and 22% in the AYAs (P = .001). Of the 44 AYAs with complete remission, 29 (65%) developed a relapse. Of the 39 children and 71 AYAs, 20 children (51.3%) and 21 AYAs (29.6%) underwent transplantation (P = .024). Patients with refractory disease had a 1-year OS rate of 14.4%. Older age (hazard ratio [HR], 2.55; P = .002) and white blood cell count > 50 * 109/L (HR, 1.79; P = .023) were significant for death, and transplantation was protective (HR, 0.57; P = .023). CONCLUSION: Low EFS and OS rates were found for AML patients in the AYA group. To improve survival rates, intensified chemotherapy regimens and early hematopoietic stem cell transplantation are needed. PMID- 29478947 TI - Azacitidine Use for Myeloid Neoplasms. AB - Azacitidine and decitabine are hypomethylating agents frequently used interchangeably to treat myeloid neoplasms in different settings. Azacitidine is metabolized intracellularly into decitabine. Hypomethylating agents work by inhibiting DNA methyltransferases, causing demethylation of aberrantly methylated promoter regions of genes involved in the pathogenesis of myeloid neoplasms. Azacitidine was the first agent approved by the US Food and Drug Administration for treatment of myelodysplastic syndrome in 2004, after which, the use of azacitidine in other myeloid neoplasms increased significantly. It is a well tolerated agent and can be safely administered in the outpatient setting, which makes it an attractive choice for patients as well as physicians. In this review we summarize the published literature about the use of azacitidine in myeloid neoplasms, and shed the light on some ongoing trials. PMID- 29478948 TI - Inhibiting HSP90 prevents the induction of myeloid-derived suppressor cells by melanoma cells. AB - Metastatic melanoma is the most dangerous form of skin cancer, with an ever increasing incidence worldwide. Despite encouraging results with immunotherapeutic approaches, long-term survival is still poor. This is likely partly due to tumour-induced immune suppression mediated by myeloid-derived suppressor cells (MDSCs), which were shown to be associated with response to therapy and survival. Thus, identifying pathways responsible for MDSC differentiation may provide new therapeutic targets and improve efficacy of existing immunotherapies. Therefore, we've analysed mechanisms by which tumour cells contribute to the induction of MDSCs. Established melanoma cell lines were pre-treated with inhibitors of different pathways and tested for their capacity to alleviate T cell suppression via MDSC differentiation in vitro. Targeting HSP70/90 in melanoma cells resulted in reduced induction of immune suppressive cells on a phenotypic and functional basis, for which a more potent effect was observed when HSP90 was inhibited under hypoxic conditions. This initial study suggests a novel mechanism in tumour cells responsible for the induction of MDSC in melanoma. PMID- 29478949 TI - Interleukin-1beta, interleukin-1 receptor antagonist, interleukin-6, interleukin 10, and tumor necrosis factor-alpha levels in CSF and serum in relation to the clinical diversity of Parkinson's disease. AB - Several parameters representing the clinical diversity of Parkinson's disease (PD), including severity, phenotypes, cognitive decline, anxiety and depression were analyzed to examine the link with interleukin-1beta (IL-1beta), the interleukin-1 receptor antagonist (IL-1RA), IL-6, IL-10, and tumor necrosis factor-alpha (TNFalpha) and also to determine the relationship between levels of these factors in serum and cerebrospinal fluid (CSF). Significantly elevated serum IL-1beta and IL-6 and reduced IL-1RA levels were found in the PD group. In CSF and serum, inflammatory factors behaved differently, with increased CSF TNFalpha indicating rapid PD progression, and increased IL-1beta in serum. A low level of IL-6 was associated with a longer duration of PD. Anxiety, depression, non-tremor phenotype and late-onset PD correlated with a high serum level of IL 10. The serum TNFalpha level was lower in PD patients with mild cognitive impairment compared to controls. Serum IL-1beta, IL-6 and IL-10 levels correlated with CSF markers. PMID- 29478950 TI - Lay Perceptions of Healthy Eating Styles and Their Health Impacts. AB - OBJECTIVE: This study examined perceptions of healthy eating styles among US respondents to determine whether eating styles are defined as a distinct set of people's healthy eating beliefs and how different aspects of eating styles are perceived to affect health. DESIGN: In-person pile sort activities were used to identify key dimensions of healthy eating beliefs, and online surveys were used to confirm these dimensions and examine perceived health benefits of healthy eating styles. PARTICIPANTS: The pile-sorting activity recruited 48 US participants in the Phoenix metropolitan area via social media and snowball sampling. Online surveys recruited US participants via Amazon Mechanical Turk (survey 1, n = 70; survey 2, n = 283). ANALYSIS: The researchers used an exploratory visualizing technique (multidimensional scaling) to analyze pile sort data; Property Filling (PROFIT) analysis was used to analyze online survey 1; paired sample t test and repeated-measures ANOVA were used to analyze online survey 2. RESULTS: Eating styles are a distinct set of beliefs within lay models of healthful diets (P < .001) viewed as important for a number of health outcomes, including weight management. CONCLUSIONS AND IMPLICATIONS: In addition to educating the public about choosing healthy food characteristics, health and nutrition professionals may need to address people's beliefs regarding healthy eating styles to identify gaps and misconceptions. Future research is needed to examine the relationships between such beliefs and corresponding behaviors, as well as whether these behaviors result in any health benefits. PMID- 29478951 TI - An Evaluation of Washington State SNAP-Ed Farmers' Market Initiatives and SNAP Participant Behaviors. AB - OBJECTIVE: To describe Supplemental Nutrition Assistance Program-Education (SNAP Ed)-supported farmers' market (FM) access activities in Washington State communities and identify associations between participation in these activities and SNAP participants' FM shopping and fruit and vegetable consumption. DESIGN: Descriptive study; data included stakeholder interviews and surveys with FM managers and a stratified clustered random sample of SNAP participants. SETTING: Washington State. PARTICIPANTS: A total of 51 SNAP-Ed stakeholders, 400 SNAP participants, and 94 FM managers participated. MAIN OUTCOME MEASURE(S): Partnership measures and SNAP-Ed FM access activities; SNAP participants' participation in FM access activities, FM shopping frequency, and fruit and vegetable consumption. ANALYSIS: Thematic content analysis, descriptive statistics, and 0-inflated Poisson and ordinary least-squares regression models. RESULTS: A total of 343 FM access activities and strong multi-sector partnerships were identified. Fifty percent of SNAP participants shopped at an FM in the past year, and 30% at least monthly. The SNAP participants participating in FM access activities shopped at FMs more frequently (P=.005). The SNAP participants shopping at FMs ate fruit and vegetables more frequently than did non-FM shoppers (P<.001). CONCLUSIONS AND IMPLICATIONS: Through nutrition education and systems and environmental changes, Washington SNAP-Ed developed effective programming and multi-sector partnerships. These efforts are associated with SNAP participants' FM shopping and fruit and vegetable consumption. PMID- 29478952 TI - Food Purchasing Behaviors and Sugar-Sweetened Beverage Consumption among Canadian Secondary School Students in the COMPASS Study. AB - OBJECTIVES: To examine whether several food purchasing behaviors (ie, sources of meals or snacks) are associated with adolescents' sugar-sweetened beverage (SSB) consumption and whether these associations vary by province. DESIGN: Cross sectional observational study. SETTING: Alberta and Ontario, Canada. PARTICIPANTS: Secondary school students from Alberta (n = 3,300) and Ontario (n = 37,999) participating in year 2 (2013-2014) of the Cannabis Use, Obesity, Mental Health, Physical Activity, Alcohol Use, Smoking, Sedentary Behavior (COMPASS) study. MAIN OUTCOME MEASURES: Participants' self-reported frequency of consuming 3 SSB types (soft drinks, sweetened coffees/teas, and energy drinks) in a typical week. ANALYSIS: Hierarchical Poisson regression analyses. RESULTS: Participants from Alberta had a significantly (P < .05) higher rate of consuming SSBs and purchasing meals or snacks from school food outlets compared with their Ontario counterparts. Most of the food purchasing behaviors were significantly (P < .05) and positively associated with greater rates of SSB consumption. Meal or snack purchases on weekends (vs weekdays) and from food outlets off school property (vs on school property) had a greater association with SSB consumption. Eating a home packed lunch was protective against SSB consumption across models. CONCLUSIONS AND IMPLICATIONS: Adolescents' food purchasing behaviors have a significant impact on their propensity for SSB consumption. These data demonstrate potentially important contexts for SSB consumption and have implications for possible settings and strategies for future interventions to reduce adolescents' SSB intake. PMID- 29478953 TI - The Impact of Exposure to Cartoons Promoting Healthy Eating on Children's Food Preferences and Choices. AB - OBJECTIVE: This study explored whether a cartoon show with healthy eating messages positively affected children's food choices and food preferences. DESIGN: Experimental between-subjects design. SETTING: Four elementary schools in Portugal were investigated. PARTICIPANTS: Children (aged 4-8 years; n = 142) were randomly assigned to 1 of 2 groups: a comparison group (n = 73) was exposed to cartoons with no reference to food and an intervention group (n = 69) was exposed to cartoons with healthy eating messages. After viewing, each child was given the opportunity to eat ad libitum for 10 minutes from a small selection of snack foods. MAIN OUTCOME MEASURE: Number of healthy and unhealthy food items chosen. Food preferences were measured using an adapted version of the Leeds Food Preference Checklist. ANALYSIS: Generalized linear models were used to test for differences between groups. Results were considered significant at P <= .05. RESULTS: Children in the experimental group chose significantly more healthy food items than did those in the comparison group (B = -.600; SE = .19; P < .05). CONCLUSIONS AND IMPLICATIONS: Future studies may address the effect of prolonged exposure to healthy eating cartoons. Cartoons can be used to promote healthy food choices and can be a part of health promotion campaigns. PMID- 29478954 TI - Predictors of Nutrition Quality in Early Child Education Settings in Connecticut. AB - OBJECTIVE: This study assessed the dietary quality of lunches and feeding practices (family-style service, teacher role modeling) in Connecticut child care centers and made comparisons by center participation in the federal Child and Adult Care Food Program (CACFP). DESIGN: Plate waste methods and visual observation of lunches served and consumed. SETTING: A total of 97 randomly selected licensed Connecticut child care centers (53 CACFP and 44 non-CACFP). PARTICIPANTS: A total of 838 preschool-aged children. MAIN OUTCOME MEASURES: Total energy intake, macronutrient intake, and intake by CACFP meal component as well as use of family-style dining, management of additional helpings, and whether and what teachers consumed in view of children. ANALYSIS: Child dietary intake at lunch was compared with dietary and CACFP recommendations using a mixed linear regression model. RESULTS: The CACFP centers were more likely to offer family-style service and have staff eat the same foods as the children. Children in non-CACFP centers consumed more saturated fat (4.1 vs 2.7 g; P < .001) and trans fats (0.1 vs 0.1 g; P = .02) and less milk (3.5 vs 2.7 oz; P < .001) than did children in CACFP centers. Caloric intake and dietary fiber were below recommendations in both groups. Participation in CACFP was a significant predictor of low-fat milk consumption. CONCLUSIONS AND IMPLICATIONS: The CACFP participating centers confer some nutritional advantages in terms of provider behavior during meals, characteristics of food offerings, and child intake. Current feeding practices in child care settings require further exploration in the context of serving children at risk for food insecurity and in light of recent work on responsive feeding. PMID- 29478955 TI - Response to "How to quantify the 'auditory gain' of a bone-conduction device; comment to the systematic review by Bezdjian et al." PMID- 29478956 TI - Experimental and feasibility assessment of biogas production by anaerobic digestion of fruit and vegetable waste from Joburg Market. AB - Substrate-induced instability of anaerobic digestion from fruit and vegetable waste (FVW) results in low biogas yield. In this study, substrate management through fruit to vegetable mix ratio in a two-stage semi-continuous digester was investigated as a pathway for optimality of yield. The experiment conducted over 105 days with 62.52 kg of FVWs sourced from Joburg Market, South Africa showed that a stable process was achieved at a fruit to vegetable waste mix ratio of 2.2:2.8. At this ratio, optimal organic loading rate ranged between 2.68 and 2.97 kg VS/m3-d which resulted in a specific biogas yield of 0.87 Nm3/kg VS with 57.58% methane on average. The results of the experimental study were used as a feasibility assessment for a full-scale 45 tonnes/d plant for Joburg Market considering three energy pathways. The plant will produce 1,605,455 Nm3/y of biogas with the potential for offsetting 15.2% of the Joburg Market energy demand. Conversion of all biogas to biomethane was the most economically attractive energy pathway with a net present value of $2,428,021, an internal rate of return of 16.90% and a simple payback period of 6.17 years. This route avoided the greenhouse gas emission of 12,393 tonnes CO2, eq. The study shows that the anaerobic digestion of FVWs as sole substrate is possible with financial and environmental attractiveness. PMID- 29478957 TI - Thermal treatment and ammoniacal leaching for the recovery of valuable metals from spent lithium-ion batteries. AB - The recycling of spent commercial lithium-ion batteries (LIBs) generates numerous environmental and economic benefits. In this research, a thermal treatment ammoniacal leaching process is proposed to recover valuable metals from cathode active powder. Based on the thermal behavior by TG-DSC analysis, the cathode active powder is calcined at 300 degrees C and 550 degrees C in air atmosphere, and the crystalline phase characterization indicates that a new phase of Co3O4 appears in the cathode active powder calcined at 550 degrees C, which signifies that the layer structure of LiCoO2 collapses. The valence of manganese increases to form Li4Mn5O12 in spinel structure of LiMn2O4. Using calcined cathode powder as feed material, ammoniacal leaching is carried out in (NH4)2SO4 -(NH4)2SO3 solution. Under the optimum conditions, Ni, Co, Mn and Li can be completely leached out with efficiencies of 98%, 81%, 92% and 98%, respectively. However, with the increase of ammonia concentration, the leaching efficiency of Mn decreases dramatically to 4% due to the formation of double salts. It is found that Co and Mn can be precipitated into residues in the form of (NH4)2Co(SO4)2.H2O, (NH4)2Mn(SO3)2.H2O and (NH4)2Mn(SO4)2.6H2O under different leaching parameters. Based on the corresponding relationship between the leaching efficiency and phase evolution of object element, selective leaching can be achieved by controlling the formation of double salts. PMID- 29478958 TI - Quantification of main and trace metal components in the fly ash of waste-to energy plants located in Germany and Switzerland: An overview and comparison of concentration fluctuations within and between several plants with particular focus on valuable metals. AB - The elemental composition of fly ash from six waste-to-energy (WTE) plants in Germany and two WTE plants in Switzerland were analyzed. Samples were taken daily over a period of one month and mixed to a composite sample for each German plant. From two Swiss plants, two and three of these composite samples, respectively, were collected for different months in order to assess temporal differences between these months. In total, 61 elements, including rare earth elements, were analyzed using ICP-OES and ICP-MS. The analysis method was validated for 44 elements either by reference materials (BCR 176R and NIST 1633c) or analysis with both methods. Good recoveries, mostly +/-10%, and high agreements between both methods were achieved. As long as no additives from flue gas cleaning were mixed with the fly ash, quite similar element contents were observed between all of the different incinerators. For most elements, the variations between the different months within the two Swiss plants were lower than differences between various plants. Especially main components show low variations between different months. To get a more detailed insight into temporal fluctuations within the mentioned Swiss plants, the concentrations of Zn, Pb, Cu, Cd, Sb, and Sn are presented over a period of three years (Jan. 2015 - Oct. 2017). The concentration profiles are based on weekly composite samples (consisting of daily taken samples) analyzed by the routine control of these plants using ED-XRF. The standard deviations of the average concentrations were around 20% over the three years for the regarded elements. The fluctuations were comparable at both plants. Due to the relatively low temporal concentration fluctuations observed within the plants, fly ash would be a continuous and constant source of secondary raw materials. Beside Zn, Pb, Cu, and Cd, which were already recovered on an industrial scale, Sb, Sn, and Bi also show a high potential as secondary raw material due to the high concentration of these elements in fly ash. PMID- 29478959 TI - Monitoring foaming potential in anaerobic digesters. AB - Foaming in anaerobic digestion (AD) systems for biogas generation can give serious operational problems. The cause of such foaming events is often unclear, and it is therefore not an easy task to predict and subsequently apply preventative measures. Methods for the measurement of the foaming potential of digester sludge are often implemented, but no standardized method is available. In this study, we investigated parameters influencing the foam formation during experimental aeration tests of full-scale digester sludge, including air flow, time, and total solids concentration, and proposed an optimized method for standard use. In a survey of 16 full-scale AD systems located at wastewater treatment plants in Denmark, all sludge samples were classified into three groups (non-foaming, pre-foaming, and actually foaming) according to their foam height/propensity and stability. Extensive surveillance of plants with the proposed classification system will enable the determination of cut-off values to help to identify foaming or pre-foaming sludge, and to associate these with operational conditions leading to foaming episodes. PMID- 29478960 TI - Platelet component transfusion and alloimmunization: Where do we stand? AB - Platelet transfusion in patients, particularly in onco-haematology, is frequent and can become chronic in some cases. Post-transfusion alloimmunization is often seen, in practice. The risk of this is significantly improved in multitransfused patients. Several classes of antigens binding on platelets (HLA and HPA) are involved and also red blood cell antigens (residual red blood cells in platelet concentrates). Platelet alloimmunization causes a poor transfusion response, refractoriness and, more rarely, post-transfusion purpura. In an alloimmunized recipient, the efficiency of platelet transfusion is based on the selection of compatible products. Significant technical progress means that several methods are currently available to ensure a good post-transfusion platelet count and a satisfactory clinical outcome for the patient. PMID- 29478961 TI - Exposure to Multiple Lines of Treatment and Survival of Patients With Metastatic Renal Cell Carcinoma: A Real-world Analysis. AB - BACKGROUND: The purpose of the present retrospective analysis was to describe the trends in exposure to multiple lines of treatment and overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) who started therapy in 2 different periods (period 1, 2004-2010; and period 2, 2011-2017). PATIENTS AND METHODS: The proportion of patients who received subsequent lines of treatment after disease progression was compared between the 2 groups. OS was measured from the start of first-line treatment for metastatic disease to death or the last follow-up examination. Both univariate and multivariate analyses were performed. RESULTS: A total of 500 patients were included in the study; 274 started treatment in period 1 and 226 in period 2. Of those patients who stopped first line treatment because of disease progression, the patients in period 2 had a greater conditional probability to receive second- and third-line treatment compared with patients in period 1 (77.2% vs. 63.7%; odds ratio [OR], 1.93; 95% confidence interval [CI], 1.20-3.11; P = .0065; and 69.6% vs. 48.1%; OR, 2.48; 95% CI, 1.40-4.40; P = .002, respectively). The median OS improved from 22.8 months for patients in period 1 to 38.2 months for patients in period 2 (univariate analysis: hazard ratio, 0.65; 95% CI, 0.50-0.83; P = .001). CONCLUSION: Patients who started treatment during the past 5 years were exposed to a greater number of treatment lines compared with patients treated before 2011. Our data suggest that the increase of treatment options available and clinician expertise could be associated with better outcomes. PMID- 29478962 TI - Risk of Readmission After Uncomplicated Hospitalization After Radical Cystectomy. AB - BACKGROUND: Enhanced recovery pathways after radical cystectomy attempt to decrease length of hospitalization, but might increase risk of readmission after discharge. We evaluated the relationship between length of stay and readmission after uncomplicated hospitalization for bladder cancer patients treated with radical cystectomy. PATIENTS AND METHODS: Using the American College of Surgeons National Surgical Quality Improvement Program database, we identified bladder cancer patients who were treated with radical cystectomy from 2011 to 2015. We limited this cohort to those who did not have complications captured while in hospital, and assessed the proportion readmitted within 30 days of surgery on the basis of length of stay (ie, < 7, 7-9, >= 10 days). We fit multivariable logistic regression models to estimate odds of readmission after adjusting for potential confounding factors. RESULTS: Among 4624 patients treated with radical cystectomy, 1003 (21.7%) were readmitted within 30 days of surgery. Of 1,003 readmitted patients, 503 (50%) experienced a major complication after discharge. Factors associated with an increased risk of readmission included diversion with neobladder, diabetes, prolonged surgical time, and obesity (all P < .01). Patients with hospitalization < 7 days were not at increased risk of readmission compared with those with prolonged stays (354/1769, 20.0% < 7 days vs. 201/968, 20.8% >= 10 days, adjusted odds ratio, 1.04; 95% confidence interval, 0.90-1.21). CONCLUSION: In the absence of in-hospital complications after radical cystectomy, shorter hospitalizations were not associated with an increased risk of readmission. These findings emphasize the safety and potential cost savings of enhanced recovery pathways after these complex operations. PMID- 29478963 TI - Interleukin-18: a regulator of cancer and autoimmune diseases. AB - Interleukin (IL)-18, structurally similar to IL-1beta, is a member of IL-1 superfamily of cytokines. This cytokine, which is expressed by many human lymphoid and nonlymphoid cells, has an important role in inflammatory processes. The main function of IL-18 is mediated through induction of interferon-gamma (IFN gamma) secretion from T helper (Th1) cells. This cytokine synergistically with IL 12 contributes to Th1 differentiation and, therefore, is important in host defense mechanisms against intracellular bacteria, viruses, and fungi. Recent evidences showing the involvement of IL-18 in Th2 differentiation and ultimately IgE production from B cells have shed a new insight on the dual effects of IL-18 on Th1 and Th2 inflammatory responses. IL-18 in combination with IL-12 can activate cytotoxic T cells (CTLs), as well as natural killer (NK) cells, to produce IFN-gamma and, therefore, may contribute to tumor immunity. The biological activity of IL-18 is not limited to these cells, but it also plays a role in development of Th17 cell responses. IL-18 synergistically with IL-23 can induce IL-17 secretion from Th17 cells. The diverse biological activity of IL-18 on T-cell subsets and other immune cells has made this cytokine a good target for investigating its role in various inflammatory-based diseases. Lately, the discovery of IL-18 binding protein (IL-18BP), a physiological inhibitor of IL-18 and a hallmark of IL-18 biology, made this cytokine an attractive target for studying its pros and cons in the treatment of various diseases. In recent years, the biology, genetics, and pathological role of IL-18 have been studied in a number of diseases. In this article, we aimed to present an updated review on these aspects regarding the contribution of IL-18 to important diseases such as cancer, autoimmunity, and inflammatory-mediated conditions including allergic diseases, metabolic syndrome, and atherosclerosis. Emerging data indicating prognostic, diagnostic, and therapeutic features of IL-18 and its related molecules will also be discussed. PMID- 29478964 TI - Seminal plasma adipokines: involvement in human reproductive functions. AB - Infertility, which increased worldwide over the past few decades, has recently been linked to obesity prevalence. Adipokines, produced by adipose tissue, could be the link between obesity and infertility. The association between circulating adipokines and female infertility has been extensively studied in the last ten years. However, the male aspect has been less investigated, although some adipokines are present in seminal plasma. We have attempted to analyze published studies that measured seminal plasma adipokines and their relationships with semen parameters. Apart from leptin, other seminal adipokines have rarely been studied. Indeed, leptin seems to have a differential role depending on its concentration in the seminal plasma. Thus, it could have a beneficial effect at lower concentrations but a deleterious effect at higher seminal levels. Although some studies are currently available, the roles of leptin and other adipokines in seminal plasma on sperm parameters and their consequences on male fertility remain to be clarified. PMID- 29478965 TI - The prognostic time dependence of intra-tumoural IFNgamma mRNA and protein in patients with breast cancer followed for 14 years after surgery and radiotherapy, without subsequent systemic therapy. AB - There is increasing evidence for the importance of immunity in breast cancer. IFNgamma is expected to have a prognostic value based on its major role in innate and specific cell-mediated immunity. In this retrospective study, based on the 14 year follow-up of 73 patients with breast cancer after surgery and radiotherapy but no subsequent systemic therapy, we investigated the prognostic time dependence of intra-tumoural IFNgamma mRNA and protein levels. Over the entire 14 years of follow-up, neither IFNgamma mRNA nor protein was significantly associated with metastasis outcome by AUC and Cox regression criteria. However, evaluation of the shorter periods has revealed a prognostic significance in the late follow-up period of 7-14 years for IFNgamma mRNA and protein with the maximal respective AUCs of 0.72 and 0.73 and hazard ratios of 6.1 and 5.2, respectively. Interestingly, the opposite prognostic association was discovered for IFNgamma mRNA and protein in the first 7 years of follow-up, possibly due to the negative correlation of IFNgamma protein and mRNA. Moreover, the prognostic association of IFNgamma mRNA has shifted from marking the favourable outcome in the first 7 years to poor outcome thereafter. This study contributes to clarification of the previously inconsistent prognostic performance of IFNgamma by providing the first prognostic evaluation with long follow-up, time-dependence assessment and absence of any chemotherapy influence. PMID- 29478966 TI - Use of health services in the last year of life and cause of death in people with intellectual disability: a retrospective matched cohort study. AB - OBJECTIVE: To describe the cause of death together with emergency department presentations and hospital admissions in the last year of life of people with intellectual disability. METHOD: A retrospective matched cohort study using de identified linked data of people aged 20 years or over, with and without intellectual disability who died during 2009 to 2013 in Western Australia. Emergency department presentations and hospital admissions in the last year of life of people with intellectual disability are described along with cause of death. RESULTS: Of the 63 508 deaths in Western Australia from 2009 to 2013, there were 591 (0.93%) decedents with a history of intellectual disability. Decedents with intellectual disability tended to be younger, lived in areas of more social disadvantage, did not have a partner and were Australian born compared with all other decedents. A matched comparison cohort of decedents without intellectual disability (n=29 713) was identified from the general population to improve covariate balance.Decedents with intellectual disability attended emergency departments more frequently than the matched cohort (mean visits 3.2 vs 2.5) and on average were admitted to hospital less frequently (mean admissions 4.1 vs 6.1), but once admitted stayed longer (average length of stay 5.2 days vs 4.3 days). People with intellectual disability had increased odds of presentation, admission or death from conditions that have been defined as ambulatory care sensitive and are potentially preventable. These included vaccine preventable respiratory disease, asthma, cellulitis and convulsions and epilepsy. CONCLUSION: People with intellectual disability were more likely to experience potentially preventable conditions at the end of their lives. This indicates a need for further improvements in access, quality and coordination of healthcare to provide optimal health for this group. PMID- 29478967 TI - Clinical Outcomes in Patients With Nonobstructive, Labile, and Obstructive Hypertrophic Cardiomyopathy. AB - BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disease characterized by varying degrees of left ventricular outflow tract obstruction. In a large cohort, we compare the outcomes among 3 different hemodynamic groups. METHODS AND RESULTS: We prospectively enrolled patients fulfilling standard diagnostic criteria for HCM from January 2005 to June 2015. Detailed phenotypic characterization, including peak left ventricular outflow tract pressure gradients at rest and after provocation, was measured by echocardiography. The primary outcome was a composite cardiovascular end point, which included new-onset atrial fibrillation, new sustained ventricular tachycardia/ventricular fibrillation, new or worsening heart failure, and death. The mean follow-up was 3.4+/-2.8 years. Among the 705 patients with HCM (mean age, 52+/-15 years; 62% men), 230 with obstructive HCM were older and had a higher body mass index and New York Heart Association class. The 214 patients with nonobstructive HCM were more likely to have a history of sustained ventricular tachycardia/ventricular fibrillation and implantable cardioverter defibrillator implantation. During follow-up, 121 patients experienced a composite cardiovascular end point. Atrial fibrillation occurred most frequently in the obstructive group. Patients with nonobstructive HCM had more frequent sustained ventricular tachycardia/ventricular fibrillation events. In multivariate analysis, obstructive (hazard ratio, 2.80; 95% confidence interval, 1.64-4.80) and nonobstructive (hazard ratio, 1.94; 95% confidence interval, 1.09 3.45) HCM were associated with more adverse events compared with labile HCM. CONCLUSIONS: Nonobstructive HCM carries notable morbidity, including a higher arrhythmic risk than the other HCM groups. Patients with labile HCM have a relatively benign clinical course. Our data suggest detailed sudden cardiac death risk stratification in nonobstructive HCM and monitoring with less aggressive management in labile HCM. PMID- 29478968 TI - MicroRNA-210 Promotes Accumulation of Neural Precursor Cells Around Ischemic Foci After Cerebral Ischemia by Regulating the SOCS1-STAT3-VEGF-C Pathway. AB - BACKGROUND: Neural precursor cell (NPC) migration toward lesions is key for neurological functional recovery. The neovasculature plays an important role in guiding NPC migration. MicroRNA-210 (miR-210) promotes angiogenesis and neurogenesis in the subventricular zone and hippocampus after cerebral ischemia; however, whether miR-210 regulates NPC migration and the underlying mechanism is still unclear. This study investigated the role of miR-210 in NPC migration. METHODS AND RESULTS: Neovascularization and NPC accumulation was detected around ischemic foci in a mouse model of middle cerebral artery occlusion (MCAO) and reperfusion. Bone marrow-derived endothelial progenitor cells (EPCs) were found to participate in neovascularization. miR-210 was markedly upregulated after focal cerebral ischemia/reperfusion. Overexpressed miR-210 enhanced neovascularization and NPC accumulation around the ischemic lesion and vice versa, strongly suggesting that miR-210 might be involved in neovascularization and NPC accumulation after focal cerebral ischemia/reperfusion. In vitro experiments were conducted to explore the underlying mechanism. The transwell assay showed that EPCs facilitated NPC migration, which was further promoted by miR-210 overexpression in EPCs. In addition, miR-210 facilitated VEGF-C (vascular endothelial growth factor C) expression both in vitro and in vivo. Moreover, the luciferase reporter assay demonstrated that miR-210 directly targeted the 3' untranslated region of SOCS1 (suppressor of cytokine signaling 1), and miR-210 overexpression in HEK293 cells or EPCs decreased SOCS1 and increased STAT3 (signal transducer and activator of transcription 3) and VEGF-C expression. When EPCs were simultaneously transfected with miR-210 mimics and SOCS1, the expression of STAT3 and VEGF-C was reversed. CONCLUSIONS: miR-210 promoted neovascularization and NPC migration via the SOCS1-STAT3-VEGF-C pathway. PMID- 29478969 TI - Network of MicroRNAs Mediate Translational Repression of Bone Morphogenetic Protein Receptor-2: Involvement in HIV-Associated Pulmonary Vascular Remodeling. AB - BACKGROUND: Earlier, we reported that the simultaneous exposure of pulmonary arterial smooth muscle cells to HIV proteins and cocaine results in the attenuation of antiproliferative bone morphogenetic protein receptor-2 (BMPR2) protein expression without any decrease in its mRNA levels. Therefore, in this study, we aimed to investigate the micro RNA-mediated posttranscriptional regulation of BMPR2 expression. METHODS AND RESULTS: We identified a network of BMPR2 targeting micro RNAs including miR-216a to be upregulated in response to cocaine and Tat-mediated augmentation of oxidative stress and transforming growth factor-beta signaling in human pulmonary arterial smooth muscle cells. By using a loss or gain of function studies, we observed that these upregulated micro RNAs are involved in the Tat- and cocaine-mediated smooth muscle hyperplasia via regulation of BMPR2 protein expression. These in vitro findings were further corroborated using rat pulmonary arterial smooth muscle cells isolated from HIV transgenic rats exposed to cocaine. More importantly, luciferase reporter and in vitro translation assays demonstrated that direct binding of novel miR-216a and miR-301a to 3'UTR of BMPR2 results in the translational repression of BMPR2 without any degradation of its mRNA. CONCLUSIONS: We identified for the first time miR-216a as a negative modulator of BMPR2 translation and observed it to be involved in HIV protein(s) and cocaine-mediated enhanced proliferation of pulmonary smooth muscle cells. PMID- 29478970 TI - Dipeptidyl Peptidase-4 Inhibition Potentiates Stimulated Growth Hormone Secretion and Vasodilation in Women. AB - BACKGROUND: Diminished growth hormone (GH) is associated with impaired endothelial function and fibrinolysis. GH-releasing hormone is the primary stimulus for GH secretion and a substrate of dipeptidyl peptidase-4. We tested the hypothesis that dipeptidyl peptidase-4 inhibition with sitagliptin increases stimulated GH secretion, vasodilation, and tissue plasminogen activator (tPA) activity. METHODS AND RESULTS: Healthy adults participated in a 2-part double blind, randomized, placebo-controlled, crossover study. First, 39 patients (29 women) received sitagliptin or placebo on each of 2 days separated by a washout. One hour after study drug, blood was sampled and then arginine (30 g IV) was given to stimulate GH. Vasodilation was assessed by plethysmography and blood sampled for 150 minutes. Following a washout, 19 of the original 29 women received sitagliptin alone versus sitagliptin plus antagonist to delineate GH receptor (GHR)- (n=5), nitric oxide- (n=7), or glucagon-like peptide-1 receptor- (n=7) dependent effects. Sitagliptin enhanced stimulated GH secretion (P<0.01 versus placebo, for 30 minutes) and free insulin-like growth factor-1 (P<0.001 versus placebo, after adjustment for baseline) in women. Vasodilation and tPA increased in all patients, but sitagliptin enhanced vasodilation (P=0.01 versus placebo) and increased tPA (P<0.001) in women only. GHR blockade decreased free insulin-like growth factor-1 (P=0.04 versus sitagliptin alone) and increased stimulated GH (P<0.01), but decreased vascular resistance (P=0.01) such that nadir vascular resistance correlated inversely with GH (rs=-0.90, P<0.001). GHR blockade suppressed tPA. Neither nitric oxide nor glucagon-like peptide-1 receptor blockade affected vasodilation or tPA. CONCLUSIONS: Sitagliptin enhances stimulated GH, vasodilation, and fibrinolysis in women. During sitagliptin, increases in free insulin-like growth factor-1 and tPA occur via the GHR, whereas vasodilation correlates with GH but occurs through a GHR-independent mechanism. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01701973. PMID- 29478971 TI - Kidney Mass Reduction Leads to l-Arginine Metabolism-Dependent Blood Pressure Increase in Mice. AB - BACKGROUND: Uninephrectomy (UNX) is performed for various reasons, including kidney cancer or donation. Kidneys being the main site of l-arginine production in the body, we tested whether UNX mediated kidney mass reduction impacts l arginine metabolism and thereby nitric oxide production and blood pressure regulation in mice. METHODS AND RESULTS: In a first series of experiments, we observed a significant increase in arterial blood pressure 8 days post-UNX in female and not in male mice. Further experimental series were performed in female mice, and the blood pressure increase was confirmed by telemetry. l-citrulline, that is used in the kidney to produce l-arginine, was elevated post-UNX as was also asymmetric dimethylarginine, an inhibitor of nitric oxide synthase that competes with l-arginine and is a marker for renal failure. Interestingly, the UNX-induced blood pressure increase was prevented by supplementation of the diet with 5% of the l-arginine precursor, l-citrulline. Because l-arginine is metabolized in the kidney and other peripheral tissues by arginase-2, we tested whether the lack of this metabolic pathway also compensates for decreased l arginine production in the kidney and/or for local nitric oxide synthase inhibition and consecutive blood pressure increase. Indeed, upon uninephrectomy, arginase-2 knockout mice (Arg-2-/-) neither displayed an increase in asymmetric dimethylarginine and l-citrulline plasma levels nor a significant increase in blood pressure. CONCLUSIONS: UNX leads to a small increase in blood pressure that is prevented by l-citrulline supplementation or arginase deficiency, 2 measures that appear to compensate for the impact of kidney mass reduction on l-arginine metabolism. PMID- 29478972 TI - Circulating Concentrations of Redox Biomarkers Do Not Improve the Prediction of Adverse Cardiovascular Events in Patients With Type 2 Diabetes Mellitus. AB - BACKGROUND: Despite pathophysiological relevance and promising experimental data, the usefulness of biomarkers of oxidative stress for cardiac risk prediction is unclear. The aim of our study was to investigate the prognostic value of 6 biomarkers exploring different pathways of oxidative stress for predicting adverse cardiovascular outcomes in patients with type 2 diabetes mellitus beyond established risk factors. METHODS AND RESULTS: The SURDIAGENE (Survie, Diabete de type 2 et Genetique) prospective cohort study consecutively recruited 1468 patients with type 2 diabetes mellitus. Assays were performed at baseline, and incident cases of major adverse cardiovascular events (MACE)-first occurrence of cardiovascular death, nonfatal myocardial infarction, or stroke-were recorded during a median of 64 months. Advanced oxidation protein products, oxidative hemolysis inhibition assay, ischemia-modified albumin, and total reductive capacity of plasma were not associated with the risk of MACE in univariate analyses. Fluorescent advanced glycation end products and carbonyls were associated with MACE (hazard ratio=1.38 per SD, 95% confidence interval 1.24 1.54, P<0.001 and hazard ratio=1.15 per SD, 95% confidence interval 1.04-1.27, P=0.006, respectively) in univariate analysis, but when added to a multivariate predictive model including traditional risk factors for MACE, these markers did not significantly improve c-statistics or integrated discrimination index of the model. CONCLUSIONS: These plasma concentrations of 6 markers, which cover a broad spectrum of oxidative processes, were not significantly associated with MACE occurrence and were not able to improve MACE risk discrimination and classification beyond classical risk factors in type 2 diabetes mellitus patients. PMID- 29478973 TI - efficacy of dry extract of ivy leaves in the treatment of productive cough. AB - OBJECTIVE: Introduction: Coughing is a physiological, spontaneous defense mechanism against irritants that stimulate respiratory mucosa. Productive cough should be not suppressed; instead, mucus-dissolving agents are recommended. One of the expectorants, which increases the excretion volume, is the herbal medicine derived from ivy leaves. The ivy extract contains triterpene saponins, which have secretory properties. The aim of this study was to determine the effectiveness and safety of the treatment with the medicinal product Hedussin(r), containing dry ivy extract, in the therapy of productive cough in the course of the respiratory tract infection. PATIENTS AND METHODS: Material and methods:This was a non-randomized, non-interventional, multicenter, open-label, post-authorization effectiveness study (PAES). The study group consisted of 464 patients aged 2-12 years with productive cough. The study was supported by a questionnaire that included: the type of cough etiological factor, Bronchitis Severity Score (BSS), temperature, and prescription of antibiotic therapy. Effectiveness and safety of the therapy with Hedussin(r) was assessed at the follow-up visit. RESULTS: Results and conclusion: Improvement in cough was reported in 93.3% subjects; improvement in chest pain on coughing was reported in 84.7%, in wheezing - in 90.0%, in dyspnoea - in 88.7%, and in auscultation changes - in 94.8%. In addition, decline or normalization of body temperature was found in 96.0% of subjects. No adverse drug reactions were reported in the study population. The non-antibiotic treated group showed similar proportions. The results of this study support the efficacy of Hedussin(r) prescribed for the treatment of productive cough in the course of respiratory tract infections. Hedussin(r) was well tolerated by sick children aged 2-12 years. PMID- 29478974 TI - Report on the study of spatial organization of the human prostate glands. AB - OBJECTIVE: Introduction: In terms of the spatial organization human prostate is the complex organ due to the fact that it consists of several types of glands, localized in several histotopographic areas, characterized by the heterogeneous structure. On the other hand, most of the prostate glands are characterized by the high degree of adjacency to each other and quite complicated architectonics of both the external and internal contours of their acini and terminal ducts. The aim: The paper was aimed at the study of steromorphological features of the tubuloalveolar secretory elements in the peripheral area of the human prostate. PATIENTS AND METHODS: Material and Methods: 10 isolated postmortem specimens of the prostate gland, urinary bladder, seminal vesicles, fragments of the seminal ducts and urinary tracts which were taken from adult patients, died for the reasons not associated with the pathology of the urogenital system, have been analyzed to study the features of spatial organization of the human prostate glands in its peripheral area. To analyze the secretory components of the prostate stereological and decomposition methods have been used, which allow visualization of its structural and functional elements in all three inter perpendicular planes. RESULTS: Results and Conclusions: The use of the suggested method enables to get the megascopic reconstruction of the acini and terminal ducts of the prostate gland which can be studied from all sides, getting a comprehensive idea about the shape and size, as well as allows to explore the inner topography of the organ's structure, the geometry of the lumen of the epithelial excretory ducts, to determine the changes in the thickness of the wall, to get a visual representation of microtopographic correlation between the different parts of blood microcirculatory flow with the acini and terminal ducts of the prostate gland. PMID- 29478975 TI - combination effect of hypertonic disease with chronic pancreatitis on the processes maintain homeostasis. AB - OBJECTIVE: Introduction: Abnormalities comorbidity - a frequent phenomenon in medical practice. This determines the relevance of research processes maintaining homeostasis with a combination of various diseases. The aim of this study was to examine and compare the character of vegetative, antioxidant, kallikrein-kinin system and parameters of endogenous intoxication disorders in the patients with isolated essential hypertension and with combination of hypertonic disease and chronic pancreatitis. PATIENTS AND METHODS: Materials and Methods: Cardiointervalography was used in the research with definition of standard statistical and spectral heart rate variability. Determination of superoxide dismutase, glutathione, catalase, middle molecular peptides, total proteolytic activity of plasma by the hydrolysis of protamine sulfate, prekallikrein, kallikrein, alpha1 -proteinase inhibitor, alpha2 -macroglobulin and kininase II was conducted by laboratory methods. RESULTS: Results: Sympathicotonia with the moderate tension of adaptation processes, violation of antioxidant protection, kallikrein-kinin system and displays of endogenous intoxication were found in the patients with isolated hypertension. Reduction of sympathicotonia, reducing total power spectrum, increasing the share of humoral-metabolic effects on heart rate, tendency to asympathicotonia autonomic reactivity, lower levels of superoxide dismutase, glutathione, prekallikrein, alpha2 -macroglobulin, kininase II, higher levels of catalase, middle molecular peptides, total proteolytic activity of plasma kallikrein were observed upon accession the concomitant chronic pancreatitis. CONCLUSION: Conclusions: The signs of compensatory mechanisms disruption and increased autonomic nervous system imbalance with a decrease in ductility autonomous processes in the load were determined upon accession the concomitant chronic pancreatitis. The combination of pathologies also accompanied by more severe manifestations of endogenous intoxication, significant violations of antioxidant and kallikrein-kinin systems. PMID- 29478976 TI - Results of mammary glands topometry among yakut women with focus on age and importance of age in augmentation mammoplasty. AB - OBJECTIVE: Introduction: In connection with the development of plastic and aesthetic surgery, there is a steady growth in aesthetic mammoplasty. Modern aesthetics require an emphasis on and accentuation of mammary glands. For our region it is obvious that the physical and sexual development of girls living in the harsh continental climate of Yakutia has its own characteristics. In this regard, the issues of defining a clear standard diagnosis of the regional norm of mammary gland and adjacent topographic layers of the chest wall, as well as its shape, are becoming increasingly relevant. The aim: To identify the individual typological variability of the shape, size, and topometric characteristics of mammary glands of Yakut women with focus on age. PATIENTS AND METHODS: Materials and Methods: Morphometry of the mammary glands was performed in 72 Yakut women. The examined women were divided into the following age groups: group I - IV ( ages 20 -40). The measurements were performed using the Body Logic (Mentor Medical Systems BV - USA) System, where the following indicators were recorded anthropometric characteristics of the body, topometric and organometric characteristics of mammary glands women. RESULTS: Results: The analysis of the obtained data showed that the bodyweight of the women being examined increases by ages 35-40. Dimensional parameters of the transverse diameter of the chest at the level of the submammary fold and at the level of the nipples were also greater in the older age group. Visual asymmetry MG relative to right and left sides is observed in the first age group (ages 26-35). The thickness of the dermal glandular fold at the level of the lateral, medial and upper poles also tends to increase with age, with higher values on the left side in all groups. Submammary fold as anatomical structure is the key structure that determines the aesthetics of the mammary gland during its augmentation and mastopexy, it is the foundation on which the designs of mammoplasty are based. Its asymmetry is less noticeable in the older age group. When analyzing the size of the areola along the vertical and transverse lines, a pronounced tendency to increase in size with age is observed relative to the right and left sides. CONCLUSION: Conclusions: Thus, as a result of the study, we determined the topo-morphometric parameters of the mammary glands of Yakut women of different age groups. It was observed that with sufficient symmetry of the mammary gland shape in most women in the study groups, there is an asymmetry in the structure of the shape of the chest, probably due to rickets-like conditions widespread in our region. The growth in the thickness of the skin-glandular fold is more pronounced in the fourth age group (ages 36-40), which indicates the hypertrophy of the MG tissues, which is an important factor when calculating the volume of the future implant. The index of extensibility in the lower pole of theMG is important for planning surgical intervention, since it indicates the state of the skin pocket for the implant. It is only natural that with age, MG tissues become susceptibleto natural gravitational ptosis, the same happens to the nipple-areolar complex, as evidenced by its largest transverse and vertical dimensions in the fourth age group. Whenplanning the intervention, these dimensions can be reduced using periareolar mastopexy. PMID- 29478977 TI - Sonographic assistance in the process of internal jugular vein catheterization. AB - OBJECTIVE: Introduction: The use of ultrasound assistance of major vessels simplifies and facilitates vascular catheterization under conditions that significantly complicate gaining vascular access and reduces the risk of complications. The aim of the work is technical improvement of catheterization of major vessels, in particular, of the jugular vein, under guidance of ultrasound. PATIENTS AND METHODS: Materials and Methods:The result of catheterization of the internal jugular vein in 126 patients of intensive care unit, was analyzed. In 75 patients Seldinger's catheterization was used, taking into account anatomical markings, in 51 patients a method using ultrasound navigation was applied. RESULTS: Results: The advantages of catheterization of the main vessels under the guidance of ultrasound are established, in particular, control over the procedure and reduction of the time of its carrying out, the possibility of catheterization at the first attempt and the absence of complications associated with the procedure. CONCLUSION: Conclusions: The greatest effectiveness of internal jugular vein catheterization under the guidance of ultrasound assistency has been proved, which reduces the time of the procedure by 23.1%, reduces the number of attempts of catheterization, enables to monitor the progress of the procedure and prevent complications by using ultrasound navigation in 100% of the cases. PMID- 29478978 TI - Specific characteristics of intracardiac hemodynamics and vegetative regulation in healthy young individuals with normal heart geometry and concentric remodeling of left ventricle. AB - OBJECTIVE: Introduction: Heart remodeling is a complex multifactor process determining the prognosis of the patient with any cardio-vascular pathology. There are convincing observations and conclusions in literature about the formation of concentric remodeling of LV prior to the appearance of any changes in AP [4, 5]. But until now there is no common point of view as to the factors involved in remodeling both the myocardium and the vessels, especially in the absence of the major known causative factor - arterial hypertension. From this perspective the study of relationship between cardiac and vascular remodeling as well as the factors involved in their development, especially in young individuals, is urgent. The aim of this work was a comparative study of characteristic features of intracardiac hemodynamics, daily profile of arterial pressure, daily ECG monitoring data and vegetative regulation in young apparently healthy individuals (18-44 years) with normal heart geometry and those with concentric remodeling of left ventricle. PATIENTS AND METHODS: Materials and Methods: Apparently healthy persons aged 18 to 42 years, mean age 25.3+/-0.6 years, were included in the study. There were 56 males (73.7%) and 20 females (26.36%). All participants of the study were divided into two equal groups consisting of 38 persons according to relative wall thickness (RWT) value of the left ventricle: the patients with RWT > 0.42 (concentric remodeling of left ventricle) and those with RWT <= 0.42 (normal geometry of left ventricle). RESULTS: Results and Conclusion: The analysis of obtained findings revealed comparatively larger sizes of left heart cavities, comparatively higher rate of AP morning rise and daily variability of predominantly systolic arterial pressure, decreased activity of parasympathetic nervous system, greater number of supraventricular premature beats mainly at night time as well as the signs of connective tissue dysplasia in the patients with concentric remodeling of left ventricle. More than half of young persons with concentric remodeling of left ventricle showed the signs of connective tissue heart dysplasia, namely prolapse of mitral valve and abnormal left ventricular chords. Those specific characteristics of heart structure, daily profile of arterial pressure and variability of cardiac rhythm can be considered the signs associated with concentric remodeling of left ventricle. CONCLUSION: PMID- 29478979 TI - Comprehensive assessment of autonomic dysfunction in patients with asthma using the regulatory systems activity index. AB - The regulatory systems activity index (RSAI), proposed by RM Bayevsky, can be used as an integral measure of the functional stress of the autonomic nervous system in patients with asthma. RSAI values of 8-10 should be used as a criteria for maladaptive and prognostically unfavorable course of asthma. Autonomic dysfunction at these RSAI levels is characterized by a pronounced reduction in total power of the spectrum of heart rate variability (HRV) (TP<1000ms), significant predominance of humoral-metabolic waves (VLF> 65%), increased activity of the sympathetic nervous system(LF/HF> 3.0), and high index of centralization (IC > 8). PMID- 29478980 TI - Clinico-pathogenic aspects of osteodeficiency in osteoarthritis in combination with chronic pancreatitis. AB - OBJECTIVE: Introduction: Pathology of the musculoskeletal system creates a number of important and complex medical problems affecting the economic situation of society, health and quality of life of individuals and their families. One of these problems and the most common disease of the joints which is diagnosed in 20% of the population of the planet is osteoarthritis (OA). The aim: The article deals with modern views on the problem of comorbidity of osteoarthritis, chronic pancreatitis and osteodefisiency. Dual energy X-ray densitometry data were analyzed, as well as indicators of activation of lipid peroxidation (malonic aldehyde), antioxidant protection system (superoxide dismutase and SH-group, ceruloplasmin, satalase) and tissue destruction (oxyproline). PATIENTS AND METHODS: Materials and Methods:The complex examination of 72 patients was made. Patients were divided into two groups: 30 patients with OA and 42 - with OA in combination with CP. The control group included 20 apparently healthy individuals. Evaluation of CT scan was performed using Dual Energy X-Ray Absorptiometry - DXA by Lunar corp. (Madison, WI) - Lunar DPX-A No. 2589 in the lumbar region of the vertebral column. The evaluation of the indicators was carried out in accordance with WHO recommendations (WHO, Geneva, 1994) [1]. The study of LPO was carried out on the level of malonic aldehyde (MA). To assess AOP, we determined SOD, ceruloplasmin (CPN); SH-groups; catalase. The endogenous intoxication and the level of degradation of the connective tissue in the body was estimated by levels of free oxyproline. The influence of CP on the state of LPO-AOP was established by the following clinical characteristics of CP: age of the patients, structural condition of the pancreas with the help of the method of ultrasound, expressed in points. Excretory function of the pancreas was investigated on the level of fecal alpha-elastase ( by ELISA test using the kits BIOSERV ELASTASE 1-ELISA). RESULTS: Results: During the examination of the mineral bone density by the dual energy X-ray densitometry it was discovered that the presence of CP in patients with OA led to a significant reduction of BMD and deterioration of the bone tissue (BT): the proportion of patients with normal bone decreased from 67% to 16%, the number of patients with osteopenia increased from 10% to 67%; patients with OP appeared - 17%.Besides, the increased degradation of bone tissue in OA with CP was accompanied by strengthening of oxidative changes (by MA-level), weakening of the antioxidant defense (SOD and SH groups), the increase in the severity of inflammation and endotoxemia (levels of catalase and ceruloplasmin), as well as increased degradation of connective and bone tissue in the joints and progression of fibrosis in tissue (the level of oxyproline). CONCLUSION: Conclusions: It was found out that the presence of CP in patients with OA led to a significant reduction of BMD and the deterioration of the bone tissue. It was discovered that during the combined course of OA and CP with osteopenia there occurs the weakening of the AOP (by SOD and SH-groups) and a relatively high level of LPO activation (by MAlevel) as well as the increased deterioration in connective and bone tissue and aggravation of osteopenia which is indicated by the increased levels of oxyproline. PMID- 29478981 TI - Clinical forms of actinic keratosis and levels of dysplasia of the epidermis. AB - OBJECTIVE: Introduction: Actinic keratosis (AK) is precancerous skin lesion that occurs in the sun-exposedskin areas characterized by local intraepidermal dysplasia of different severity (KIN I, KIN II and KIN III). The aim of this research was to study distribution patterns and morphological features of AK histological types. PATIENTS AND METHODS: Materials and Methods: The study included skin biopsy material from 68 patients with different clinical forms of AK. The diagnosis of AK was histologically confirmed in 100% of cases. RESULTS: Results: There were 63.21% of men and 36.8% of women among all patients with AK. The average age of patients was 73.3 +/- 8.3.The most common clinico-histological forms of actinic keratosis were typical (41.2%), hypertrophic (16.2%), atrophic (14.7%) and pigmentary (11.7%), bowenoid (8.8%), acantholytic (7.4%). Among the rate of epidermal dysplasia there diagnosed cases of KIN I (50%), KIN II (36.8%) and KIN III (13.2%). CONCLUSION: Conclusions: It was found a direct correlation between KIN I and typical and pigment forms of AK, KIN II and hypertrophic and bowenoid forms of AK. PMID- 29478982 TI - Symmetry of elements of temporomandibular joint (TMJ). AB - OBJECTIVE: Introduction: Dysfunction of temporomandibular joint is present in 70 75% of orthodontic patients. Evaluation of TMJ and detailed characteristics of its elements with additional methods of examination in children and adults is necessary for clinical definition of proposed disturbances of the structure and functions of the joint. The aim of the investigation is to study morphological symmetry of TMJ in patients with dentofacial abnormalities and with dentofacial abnormalities complicated by secondary edentulism. PATIENTS AND METHODS: Materials and Methods: 57 patients were involved in the examination. Based on gender principle patients' distribution was almost equal: there were 30 women and 27 men. Cone-beam computerized tomography (CBCT) Galileos (SIRONA DENTAL, Germany) was used to all patients. RESULTS: Results: It was done analysis of parameters (height and length) of right and left heads (condyles) of temporomandibular joint in both groups. Asymmetry of parameters of heads' length in saggital area in patients of the second group was defined. It was proved statistically (left 10,38+/-0,76, right 8,16+/-0,78). CONCLUSION: Conclusions: Increase of asymmetry of length of heads of TMJ in saggital area with age was determined. It can be explained by complication of dentofacial abnormalities and the presence of secondary edentulism. Depending on bite type length of condyle, especially at prognathism (in saggital) area peculiar clinical problems with TMJ can be present due to asymmetry of condyles. The size of joint gaps of TMJ due to the presence of dentofacial abnormalities with age demonstrates compensatory ability and saves its. PMID- 29478983 TI - [Behavioral risk factors of chronic non-communicable diseases in medical doctors]. AB - OBJECTIVE: Introdukcion: Group of chronic communicable disease is the main cause of mobility and mortality in industrially and development countries. The same behavioral risk factors are in the basis of these diseases. On the one side medical doctors are completely aware about risk factors management, from the other side, they are mainly unable to maintain healthy life style. The aim of the present study was to assess behavioral risk factors in medical doctors and awareness of need to maintain healthy life style. Fifty one medical doctors of different specialties were included in the study. Anthropometric parameters (high, weight, waist circumference, body mass index, body composition, smoking status, nutrition habits, sleep quality and physical activity were studied. The body composition was assessed with Omron Body Composition Monitor BF511. Physical activity was measurement by pedometer Omron Walking style III step counter HJ-203 EK. The status of smoking, nutrition habits and sleep quality were analyzed with standardized questionnaires. PATIENTS AND METHODS: Materials and Methods:Fifty one medical doctors of different specialties were included in the study. Anthropometric parameters (high, weight, waist circumference, body mass index, body composition, smoking status, nutrition habits, sleep quality and physical activity were studied. The body composition was assessed with Omron Body Composition Monitor BF511. Physical activity was measurement by pedometer Omron Walking style III step counter HJ-203-EK. The status of smoking, nutrition habits and sleep quality were analyzed with standardized questionnaires. RESULTS: Results: very low level of physical activity was found in medical doctors. Median of steps per day in male subjects was8462 [5742/10430] and 7479 [5574/10999] in female. Such physical activity was associated with overweight; low muscular and high fat tissue as well as with increased level of visceral fat. Different sleep disorders and associated day symptoms were detected in investigated medical doctors. Absence of continuous sleep and early awakenings dominated between diagnosed sleep disorders. Fifty three percent of women and 47 percent of men had early awakenings. CONCLUSION: Conclusions: the main part of medical doctors in present study had low physical activity, sleep disorders and unhealthy nutrition behavior. So, special programs designed for medical professionals are needed to correct risk of chronic non-communicable disease related to behavioral factors. PMID- 29478984 TI - [Comparison of execution time and tissue damage by using four ready-to-use percutaneous emergency airway access devices available in Poland]. AB - OBJECTIVE: Objective: Assessment of execution time and tissue damage during providing percutaneous airway access using four ready-to-use sets: Quicktrach I (Q1) and II (Q2), Portex Cricothyroidothomy Kit (PCK) and Surgicric I (SC). PATIENTS AND METHODS: Material and methods:Prospective laboratory test. Each of 54 participants carried out 1 puncture on porcine larynx preparation for each of 4 sets, which resulted in a total of 216 trials. Efficacy was defined as placing a cannula in the tracheal lumen ensuring adequate ventilation. Safety was assessed based on the size and type of laryngeal damage, improper placement of the cannula, perforation of the esophagus and extensive destruction of surrounding tissues. RESULTS: Results: The percentage of effective procedures for respective sets was: PCK - 94.4%; Q1 - 100.0%; Q2 - 96.3%; SC - 96.3%. Differences were not statistically significant. There were significant differences in duration of the procedure: PCK - 59.20 s (20.0-188.0 s, SD +/- 35.25), Q1 - 21.76 s (6.0-61.0 s; SD +/- 10.62), Q2 - 28.36 s (5.0-71.0 s, SD +/- 14.86), SC - 48.71 s (29.0-9.0 s, SD +/- 15.07). The size of the lesions of anterior and posterior walls of the larynx and trachea were significantly different. The mean (SD) lesions of the anterior laryngeal wall for respective sets were: PCK - 11.18 mm +/- 5.11; Q1 - 6.59 mm +/- 2.22; Q2 - 7.71 mm +/- 1.87; SC - 19.85 mm +/- 5.72, and for the posterior wall of the trachea: PCK - 8.29 +/- +/- 8.43; Q1 - 0.44 mm +/- 1.22; Q2 - 0.92 mm +/- 3.79; SC - 0.08 mm +/- 0.27. Percentage of additional damages for respective sets: PCK - 18.5%, Q1 - no damages; Q2 - 5.6% and SC - 3.7%. CONCLUSION: Conclusions: There were no differences in the efficacy of particular sets. Significant differences were demonstrated for the duration and safety of the procedure. The average time as well as the size of posterior wall damage and the amount of additional damage was the highest for PCK and the lowest in case of Q1. PMID- 29478985 TI - [Patient safety in poland according to analysis of medical adverse events]. AB - The paper presents the analysis of rulings from regional commisions on health care malpractice in Poland wiith special attention to patient safety issues. The analysis entails causes, types and consequensence of 469 malpractice claims. In 23,7% of cases the claim was confirmed by commission. The most frequent types of malpractice was body injury. General surgery and othopedis were the major medical specialities when confirmed malpractices took place. PMID- 29478986 TI - [high on-treatment platelet reactivity in patients with chronic renal failure using acetylsalicylic acid]. AB - Cardiovascular diseases (CVD) are the most common cause of mortality in the world. Acetylsalicylic acid (ASA) is a widely used medicine in primary and secondary prevention of cardiovascular diseases. About 1-60% patients taking aspirin have high platelet reactivity (HOPR) despite aspirin treatment. HOPR is significantly more frequent in patients with chronic kidney disease (CKD) and it increases the risk of adverse cardiovascular events in these patients. The cause of HOPR in patients with CKD may be oxidative stress and inflammation. To the risk factors belong diabetes, female sex or decreased HDL cholesterol level. PMID- 29478987 TI - Legal aspects of cancer deseases prophylactics: patients rights context. AB - OBJECTIVE: Introduction: In accordance with Resolution on Cancer Control WHA58.22 Cancer prevention and control The Fifty-eighth World Health Assembly it is obvious technology for diagnosis and treatment of cancer is mature, and that many cases of cancer may be cured, especially if detected earlier Some key points on concept of legal regulation of abovementioned sphere is a base of this study. However, the problems of using an effective mechanism for protecting the rights of patients in certain types of disease, in particular cancer patients, by providing early diagnosis, are not fully developed by medical law specialists. The aim of the article is to determine the means of ensuring the right to health and life of cancer patients in particular through early diagnosis. PATIENTS AND METHODS: Material and Methods: This study is based on regulation acts, World health report (2013), The Fifty-eighth World Health Assembly, WHA58.22 Cancer prevention and control, Universal Declaration of Human Rights, International Covenant on Civil and Political Rights, International Covenant on Economic, Social and Cultural Rights, European Convention for the Protection of Human Rights and Fundamental Freedoms, Charter of Fundamental Rights of the European Union, research papers and views of progressive-minded people in this sphere. Article is grounded on dialectical, comparative, analytic, synthetic and comprehensive research methods. RESULTS: Review: Most countries have declared a compliance of their national legislation with international standards regarding the right to life and health. The analysis of the abovementioned international acts in context of protection of the rights of patients with cancer leads to the conclusion that countries that have undertaken international legal obligations to protect the right to life are required to take the necessary measures to ensure the effective treatment of cancer patients. Taking into account that the lack of such treatment due to the specificity of the disease entails the death of the patient, the state inaction in this area should be regarded as a violation of a human right for life. Absence of state's policy in terms of early detection of cancer brings a huge problem of human rights violation and providing the standards of fundamentally different approach of the European Union countries could become a great solution. CONCLUSION: Conclusions: Individual states do not pay sufficient attention to the need of effective public health policy. In today's world, there are objective prerequisites for changing the system of protection of patients' rights and, consequently, for changing views on health protection in general, especially in the part of functioning of diagnostic procedures system. Formation of a state policy on ensuring the rights of citizens to health and life, taking into account the various consequences of such a policy, cannot be narrowed down only to the proclamation of such rights, but also requires planning and development of relevant state programs. Failure by the state to provide the proper organization of health care through the establishment of early diagnosis for cancer patients, considering wide incidence and mortal danger of cancer in case of late diagnosis, should be considered as a violation of human rights. It also does not conform to ECHR practice in terms of provisions of Articles 2, 3 and 8 of European Convention. PMID- 29478988 TI - Current studies of ukrainian researchers of stress impact on chest organs: literature review. AB - OBJECTIVE: Introduction: Stress reactions allow the body to adapt to the various environmental factors using the universal complex of neurohumoral reactions. Excessive stress reduces adaptability of the body and can initiate the onset and development of various pathologies. In recent years, Ukrainian scientists have completed a series of studies on the analysis of various aspects of the stress effect on the body. Aim: The paper was aimed at the analysis of the national medical publications, devoted to the study of the impact of stress on the chest organs. PATIENTS AND METHODS: Material and Methods: The bibliosemantic method has been used during the study. Findings of the contemporary scientific studies devoted to the effect of stress on the chest organs have been analyzed. RESULTS: Results: The analysis shows that despite a long history of stress-related investigations, the study of the problem of stress remains relevant to date. Scientific researches elicit the new aspects of the impact of stress on the body, particularly on the chest organs. CONCLUSION: Conclusion: Recent investigations of Ukrainian scientists assist in better understanding of the essence of the stress-related morphofunctional changes that occur in the lungs, heart and esophagus. The findings will be helpful in the search for ways to prevent and treat stress-induced pathological processes, since the problem of stress remains to be solved to date. PMID- 29478989 TI - Clinical image of anterior longitudinal ligament syndrome - an interdisciplinary problem. AB - INTRODUCTION: Approximately 1.5-2.5% of all patients treated due to discopathy have anterior longitudinal ligament lesions. An intervertebral disc moving under the anterior longitudinal ligament causes ligament displacement and irritation of the autonomic nervous system structures, resulting in a disturbed function of the organs controlled by this system. Clinical image: Increased sympathetic system activity in the thoracic section may cause symptoms that mimic coronary heart disease while irritation of the autonomic structures in the lumbosacral section of the spine results in a clinical presentation similar to that of gastrointestinal or gynecological disorders. The clinical image of the most common disorders is presented. The diagnosis may be formulated with the use of magnetic resonance imaging. TREATMENT: pharmacotherapy is ineffective. Physiotherapy and rehabilitation constitute a method of choice in the treatment of this syndrome. PMID- 29478990 TI - Protection of children's rights in the health care: problems and legal issues. AB - OBJECTIVE: Introduction: Among all categories of patients children (minors) must be protected first. It is caused so by the specificity of the treatment, their vulnerability, the need of further protection and supervision. Providing of medical care services for children are often connected with the risks of the process of treatment, and of the drug usage. The aim: To identify the problems associated with the protection of the rights of minors and, on the basis of this, the basic guarantees of their rights, as well as mark the trends in the practice of ECHR. PATIENTS AND METHODS: Materials and Methods: The study is based on its own theoretical and empirical basis. The theoretical basis include scientific articles, expert reviews of legislation and communications of non-governmental organisations, and empirical - decisions of the ECHR, international legal acts and directives of the EU. RESULTS: Results: The main violations of the rights of minor children include the following: - legal representatives of children do not take to the account their interests (refusal of medical intervention or the choice of certain method of interference); - medical intervention under the influence of coercion; - providing of unwarranted medical care without the corresponding testimony; - providing of inadequate medical care: when the patient was only examined and ineffective treatment was prescribed, and others. As for mentally ill children, the following rights are usually violated: for life, for a fair trial. It has been proved that defects in the provision of health care are often predetermined by the poor state logistics of hospitals, lack of financing and appropriate pediatric medicines, outdated methods of treatment, and incompetence of some doctors. CONCLUSION: Conclusions: From the point of view of protecting the rights of minors, the rights of children in medicine can be classified into universal and special. The rights correspond not only to the corresponding duties of medical staff, but also of their parents (legal representatives). Violations of their rights are usually related to improper representation of the interests of children and disadvantages of providing medical services (defects in their provision), in particular, regarding the treatment of mentally ill, as well as in clinical trials. It has been proven that the practice of the ECHR on the protection of the rights of the child in the field of health is of particular importance. PMID- 29478991 TI - [Three-month rehabilitation of a patient with the III, IV and VI cranial nerve damage caused by a neurosurgery of the left internal carotid artery aneurysm]. AB - OBJECTIVE: Introduction: Oculomotor nerve palsy is an eye condition resulting from damage to the third cranial nerve or a branch thereof. Third nerve damage weakens the muscles innervated by the nerve . Also adversely affect the fourth and sixth nerve , causing impairment of their activity. Rehabilitation third nerve palsy is rarely described in the available literature . The whole process is very difficult , but the effects of physiotherapy is very beneficial for the patient. The aim:The assessment of the influence of the outpatient rehabilitation on the patient's condition after a three-month treatment and the use of physical therapy. PATIENTS AND METHODS: Material and methods:Case studies of the 38-yerar old patient after having operated a big aneurism of the left ICA, which was clipped. After the procedure, the III, IV and VI cranial nerves were deeply impaired and the amnesic aphasia occurred. The patient started the rehabilitation a month after the incident. To assess the process of rehabilitation, the own movement examination of the eyeball was implemented. Active and passive exercises, Tigger Point therapy, kinesiotaping, laser and electrostimulation were inserted. RESULTS: Results: The significant improvement of the eyeball movement has been proved on the basis of the same own examination. A physiotherapy has had a positive influence on the speech disorder, namely amnesic aphasia, and after the month of the rehabilitation it has been completely removed. The positive influence of the rehabilitation, which has been pointed out, is clinically essential. CONCLUSION: Conclusions: Obtained results have not been described in literature yet, that is why it is essential to widen further research and emphasise the importance of the rehabilitation, which is rarely implemented in an intense way in such medical conditions. PMID- 29478992 TI - [Von Meyenburg complexes. case report]. AB - Von Meyenburg complexes is one of the polycystic liver diseases, characterized by bile duct hamartoma. These cysts come from the biliary tract but the cysts do not communicate with them. Because of asymptomatic course of the lesions usually are diagnosed in the course of diagnostic for another reason. It is not possible to define the entire diagnosis based upon ultrasonography imaging, as cyst could mimic metastasis, micro-abscesses and multiple focal nodular lesions. Because of the small size of the lesion (0.5-15 mm) usually inconclusive is also computed tomography. On the basis of magnetic resonance imaging (MRI) and cholangio-MRI we can determine the diagnosis of the complexes. Liver biopsy is obligatory in case of suspicion of neoplastic process. These complexes do not require treatment, but long-term follow-up is indicated because of the possibility to more frequent cholangiocarcinoma in patient with von Meyenburg complexes. It is probably the first case report of the von Meyenburg complexes described in Poland. PMID- 29478993 TI - Genetic algorithm for making pharmacotherapy decision in the patients with multimorbidity: approaches for clinicians. AB - OBJECTIVE: Purpose of our investigation was to propose and verify the algorithm for making pharmacotherapy decision in the patients with multimorbidity. PATIENTS AND METHODS: Material and methods: Object of investigation: patients with multimorbidity. Observations were conducted according to European Guidelines. We proposed and tested genetic algorithm for making pharmacotherapy decision for such patients. It is necessary to mention, that each person is representing a variant of treating with certain pathology. Chromosome of this variant is composed from genes, where each gene is certain group of drugs. The sequence of solutions of this problem comes down to the selection of drugs for the di-morbid conditions as the descendants of mono-morbidity. At the next stage of selection continues the most successful combinations of drugs for multimorbid conditions as descendants di-morbid and monomorbid conditions. When breeding pairs must take into account the mutual potentiating pathogenic and / or sanogenetic effects. RESULTS: Results: We had optimal patient's treatment as a result of crossing genes, groups of drugs and obtaining their offspring with the best combination without absolute contraindications and minimal relative contraindications. CONCLUSION: Conclusion: Thus, genetic algorithm for making pharmacotherapy decision in the patients with multimorbidity showed effectiveness of drugs choosing. PMID- 29478994 TI - [Diverticulosis of the proximal part of the jejunum causing intestinal obstruction - case report]. AB - Diverticulosis is a rare disease with a multifactorial aetiology, with a large majority in the elderly. It is characterized by a mildly symptomatic and non specific clinical symptom. Unequivocal diagnosis can be difficult and not always possible before intraoperative examination. Delayed diagnosis can result in life threatening consequences such as intestinal perforation or hemorrhage. A case of an 86-year-old patient with abdominal pain, nausea, and vomiting lasting for 2 days was reported. In the physical examination of the deviation from the normal state, general abrasion, flatulence and tenderness were found in the mesogastric abdominal area. In the past 6 months, the patient reported weight loss and a change in bowel movements. In laboratory tests, low leucocytosis, with normal levels of C-reactive protein. Despite intensive treatment, no improvement in general condition was observed. Due to persistent abdominal pain and gastrointestinal symptoms, it was decided to perform reconnaissance laparotomy. Several diverticulae of the initial small intestine were found in the intestine at ca. 20 cm from the Treitz ligament. The intestines were decompress by cutting them. Due to localization of lesions, no inflammation, perforation or haemorrhage, age and general condition of the patient, resection of the diseased segment of the small intestine was rescued. Perioperative and postoperative course without complications. Patient was discharged home in good general condition 10 days after surgery. PMID- 29478995 TI - Philosophy of Deafness: A Perspective. PMID- 29478996 TI - Deaf Education Teacher Preparation: A Phenomenological Case Study of a Graduate Program With a Comprehensive Philosophy. AB - At a time when deaf education teacher preparation programs are declining in number, little is known about their actual effectiveness. A phenomenological case study of a graduate-level comprehensive deaf education teacher preparation program at a midwestern university explored empowered and enabled learning of teacher candidates using the Missouri Department of Elementary and Secondary Education educator pillars: (a) commitment to the profession, (b) proficiency in practice, and (c) learning impact, all deemed critical to developing quality teachers. A strong connection was found between the program's comprehensive philosophy and its practice. Embracing diversity of d/Deafness and differentiated instruction were the most prevalent themes expressed by participants. Teacher candidates displayed outstanding commitment to the profession and high proficiency in practice. The findings suggest that additional consideration should be given to classroom and behavior management, teacher candidate workload, teaching beyond academics, and preparation for navigating the public school system. PMID- 29478997 TI - A Grounded Theory of Effective Reading by Profoundly Deaf Adults. AB - The purpose of the study was to uncover and describe psycholinguistic and sociocognitive factors facilitating effective reading by signing adults who are profoundly deaf and do not use hearing technology. The sample comprised four groups, each consisting of 15 adults, for a total of 60 participants. The four groups were deaf high-achieving, deaf low-achieving, hearing high-achieving, and hearing low-achieving. Measurements included a language background interview and think-aloud reading discussion. Through the lens of a grounded theory approach, the conditions that facilitate effective reading were uncovered-by coding and categorizing themes, relating the codes and categories, and determining a central theme. It was found that there are similarities and differences in how deaf and hearing people process phonological codes and conceptualize language, and that access to varied instructional strategies and meaningful language experiences is an overarching theme in effective reading. PMID- 29478998 TI - Selected Factors in Reading Comprehension for Deaf and Hearing Adults: Phonological Skills and Metacognition. AB - The purpose of the study was to identify factors related to reading comprehension, and to compare similarities and differences in the reading processes of deaf and hearing adults. The sample included four groups, each consisting of 15 adults. The groups were identified as (a) deaf high-achieving readers, (b) deaf low-achieving readers, (c) hearing high-achieving readers, and (d) hearing low-achieving readers. Measurement instruments included a demographic form along with assessments of reading comprehension, phonological skills, and metacognition, the latter of which contained both a making-inferences measure and a think-aloud discussion with a reading strategies checklist. Results indicated that deaf high-achieving readers performed similarly to hearing high-achieving readers, except for phonological skills, and that for all participants, phonological skills and metacognition were related to reading comprehension skills. PMID- 29478999 TI - Exploring the Social Capital of Adolescents Who Are Deaf or Hard of Hearing and Their Parents: A Preliminary Investigation. AB - The study explored the social capital of Australian adolescents who were deaf or hard of hearing (DHH) and their parents, and investigated the relationship between social capital and individual characteristics, language, literacy, and psychosocial outcomes. Sixteen adolescents (ages 11-14 years) and 24 parents enrolled in the Longitudinal Outcomes of Children with Hearing Impairment (LOCHI) study completed an online questionnaire on social capital and psychosocial outcomes. Information about demographics, language, and literacy was retrieved from the LOCHI study database. On average, parent-rated social capital was positively related to adolescent-rated social capital, but not to child outcomes. Aspects of adolescent-reported social capital were significantly related to the adolescents' language and reading skills, but not to psychosocial outcomes. This study gives support to the promotion of social capital in adolescents who are DHH and their families, and considers how social capital promotion could be applied in interventions. PMID- 29479001 TI - Annual Index 2017 - 2018. PMID- 29479000 TI - In the Rearview Mirror: Social Skill Development in Deaf Youth, 1990-2015. AB - Social skills are a vehicle by which individuals negotiate important relationships. The present article presents historical data on how social skills in deaf students were conceptualized and studied empirically during the period 1990-2015. Using a structured literature review approach, the researchers coded 266 articles for theoretical frameworks used and constructs studied. The vast majority of articles did not explicitly align with a specific theoretical framework. Of the 37 that did, most focused on socioemotional and cognitive frameworks, while a minority drew from frameworks focusing on attitudes, developmental theories, or ecological systems theory. In addition, 315 social skill constructs were coded across the data set; the majority focused on socioemotional functioning. Trends in findings across the past quarter century and implications for research and practice are examined. PMID- 29479002 TI - Sex Differences in Birth Weight and Physical Activity in Japanese Schoolchildren. AB - BACKGROUND: Lower birth weight (BW) is associated with increased chronic disease risk later in life. Previous studies suggest that this may be mediated principally via physical activity (PA). However, the association between BW and PA in children has not been clarified. The purpose of this study was to examine the association between BW and PA in school-aged children in Japan. METHODS: Participants were children from a prospective birth cohort study (Project Koshu) who were born from 1996 through 2002 in rural Japan. BWs were obtained from the Maternal and Child Health Handbook. Data on PA during childhood were collected using a self-reported questionnaire when participants were 9-15 years of age in July 2011. Analysis of covariance was used to evaluate exercise duration; Poisson regression analysis was used to evaluate if the recommended PA amount was met. RESULTS: Data from 657 children (boys: 54.8%, follow-up rate: 77.6%) were analyzed. Compared with the normal BW group, only girls in the low-BW group had significantly lower PA level (normal BW, 11.4 [standard error, 1.0] hours/week; low BW, 5.8 [standard error, 3.6] hours/week, P = 0.010), and were more likely to not meet the recommended PA level (prevalence ratio 1.57; 95% CI, 1.14-2.16). CONCLUSION: Low BW was associated with a lower PA level in school-aged girls but not boys. Earlier consideration of BW may be an important public health strategy to prevent physical inactivity in school-aged girls. PMID- 29479004 TI - Neurokinin B receptor agonist and Dynorphin receptor antagonist stimulated luteinizing hormone secretion in fasted male rodents. AB - Kisspeptin/neurokinin B (NKB)/dynorphin (Dyn) (KNDy) neuron in hypothalamic arcuate nucleus plays a key role in GnRH/LH pulsatile secretion. We aimed to determine whether stimulation of NKB/neurokinin 3 receptor (NK3R) signaling and inhibition of Dyn/kappa-opioid receptor (KOR) signaling recover LH secretion that is suppressed by acute fasting in male rats. Furthermore, we determined dose dependent effect of NKB/NK3R signaling on serum LH level under acute fasting condition in male mice. Mature male rats were injected saline (0.1 mL) and senktide (20 MUg/kg), a NK3R agonist, or nor-BNI (800 MUg/kg), a KOR antagonist intraperitoneally (ip) after 72 h fasting. And mature male mice were injected multiple doses of senktide, ip after 48 h fasting. Blood and brain sample were collected 90 min after injections for LH measurement and hypothalamic mRNA expressions. All three studies showed significantly lower LH concentration in fasted groups than non-fasted groups. Senktide did not recover LH suppressed by acute fasting in male rats, whereas nor-BNI injected male rats showed significantly higher LH than 72 h fasted male rats (p < 0.05). Mice study showed significantly higher LH concentration in higher doses senktide groups than 48 h fasted group and one of lower doses senktide group. These results suggest that stimulation of NKB/NK3R signaling and attenuation of Dyn/KOR signaling could recover suppressed LH secretion under acute fasting condition in male rodents. PMID- 29479003 TI - Recent Improvement in the Long-term Survival of Breast Cancer Patients by Age and Stage in Japan. AB - BACKGROUND: Recent improvements in 5-year survival of breast cancer have been reported in Japan and other countries. Though the number of long-term breast cancer survivors has been increasing, recent improvements in 10-year survival have not been reported. Moreover, the degree of improvement according to age and disease stage remains unclear. METHODS: We calculated long-term survival using data on breast cancer diagnosed from 1993 through 2006 from six prefectural population-based cancer registries in Japan. The recent increase in 10-year relative survival was assessed by comparing the results of period analysis in 2002-2006 with the results of cohort analysis in 1993-1997. We also conducted stratified analyses by age group (15-34, 35-49, 50-69, and 70-99 years) and disease stage (localized, regional, and distant). RESULTS: A total of 63,348 patients were analysed. Ten-year relative survival improved by 2.4% (76.9% vs 79.3%) from 1993 through 2006. By age and stage, 10-year relative survival clearly improved in the age 35-49 years (+2.9%; 78.1% vs 81.0%), 50-69 years (+2.8%; 75.2% vs 78.0%) and regional disease (+3.4%; 64.9% vs 68.3%). In contrast, the degree of improvement was small in the age 15-34 years (+0.1%; 68.2% vs 68.3%), 70-99 years (+1.0%; 87.6% vs 88.6%), localized disease (+1.1%; 92.6% vs 93.7%) and distant metastasis (+0.9%; 13.8% vs 14.7%). CONCLUSIONS: These population-based cancer registry data show that 10-year relative survival improved 2.4% over this period in Japan. By age and stage, improvement in the age 15-34 years and distant metastasis was very small, which suggests the need for new therapeutic strategies in these patients. PMID- 29479005 TI - Structural Insights into the Altering Function of CRMP2 by Phosphorylation. AB - Collapsin response mediator protein 2 (CRMP2) regulates neuronal polarity by controlling microtubule dynamics. CRMP2 activity is regulated by semaphorin induced phosphorylation at the C-terminal tail domain. Unphosphorylated CRMP2 induces effective axonal microtubule formation to give the axonal characteristics to a neurite, whereas phosphorylated CRMP2 leads to the apparently opposite effect, growth cone collapse. We have recently characterized the structural detail of CRMP2-induced axonal microtubule formation (Niwa et al. (2017) Sci. Rep., 7: 10681). CRMP2 forms the hetero-trimer with GTP-tubulin to induce effective axonal microtubule formation in the future axon. Phosphorylation of CRMP2 has been reported to decrease the affinity between CRMP2 and the microtubule, albeit the molecular mechanisms of how the phosphorylation of CRMP2 changes the structure to achieve distinct effects from unphosphorylated CRMP2 is not well understood. Here we performed a series of biochemical and structural analyses of phospho-mimic CRMP2. Phosphorylation of CRMP2 undergoes small conformational changes at the C-terminal tail with shifting the surface charge, which not only alters the interactions within the CRMP2 tetramer but also alters the interactions with GTP-tubulin. Consequently, phospho-mimic CRMP2 fails to form a hetero-trimer with GTP-tubulin, thus losing the ability to establish and maintain the axonal microtubules.Key words: CRMP2, phosphorylation, microtubule, axon, crystal structure. PMID- 29479006 TI - Plant Materials are Sustainable Substrates Supporting New Technologies of Plant Only-Based Culture Media for in vitro Culturing of the Plant Microbiota. AB - In order to improve the culturability and biomass production of rhizobacteria, we previously introduced plant-only-based culture media. We herein attempted to widen the scope of plant materials suitable for the preparation of plant-only based culture media. We chemically analyzed the refuse of turfgrass, cactus, and clover. They were sufficiently rich to support good in vitro growth by rhizobacteria isolates representing Proteobacteria and Firmicutes. They were also adequate and efficient to produce a cell biomass in liquid batch cultures. These culture media were as sufficient as artificial culture media for the cultivation and recovery of the in situ rhizobacteria of barley (Hordeum murinum L.). Based on culture-dependent (CFU plate counting) and culture-independent analyses (qPCR), mowed turfgrass, in particular, supported the highest culturable population of barley endophytes, representing >16% of the total bacterial number quantified with qPCR. This accurately reflected the endophytic community composition, in terms of diversity indices (S', H', and D') based on PCR-DGGE, and clustered the plant culture media together with the qPCR root populations away from the artificial culture media. Despite the promiscuous nature of the plant materials tested to culture the plant microbiome, our results indicated that plant materials of a homologous nature to the tested host plant, at least at the family level, and/or of the same environment were more likely to be selected. Plant-only-based culture media require further refinements in order to provide selectivity for the in vitro growth of members of the plant microbiome, particularly difficult-to-culture bacteria. This will provide insights into their hidden roles in the environment and support future culturomic studies. PMID- 29479007 TI - Endocardial Fibrotic Lesions Have a Greater Effect on Peak Longitudinal Strain than Epicardial Fibrotic Lesions in Hypertrophic Cardiomyopathy Patients. AB - Peak longitudinal strain (PLS) of the left ventricular (LV) myocardium by transthoracic echocardiogram (TTE) is useful to detect LV myocardial damage. We hypothesized that myocardial fibrosis (MF) in the LV myocardium may influence PLS. Eighteen hypertrophic cardiomyopathy (HCM) patients (14 males; 58 +/- 17 years old) underwent 1.5 Tesla cardiac magnetic resonance (CMR) and TTE. Patients with previous myocardial infarction were excluded. We used TTE to assess whole layer PLS in an American Heart Association-defined 17-segment LV model. Whole layer PLS was calculated using Echo PAC, version 113 (GE Healthcare). MF was assessed by T1-weighted CMR of the LV endocardial layer, the LV epicardial layer, or both the LV endocardial and epicardial layers for each lesion. Of the 306 segments, MF was detected in the LV endocardial layer only (13 segments), in the LV epicardial layer only (9 segments), or in both LV endocardial and epicardial layers (59 segments). PLS values were significantly lower in segments with MF affecting only the LV endocardial layer (7% +/- 4%) (P < 0.05) and where MF was observed in both the LV endocardial and epicardial layers (9% +/- 5%) (P = 0.001) compared with segments without MF (13% +/- 7%). No significant difference in PLS values was detected between the MF segments for the LV epicardial layer only (10% +/- 6%) and those without MF (13% +/- 7%) (P > 0.05). In HCM patients, fibrotic lesions in the LV endocardium have a greater adverse effect on PLS than those in the LV epicardium. Our results are significant for HCM patients with fibrotic lesions within the LV endocardium. PMID- 29479008 TI - Morphological Determinants of Obstructive Hypertrophic Cardiomyopathy Obtained Using Echocardiography. AB - The morphological determinants of left ventricular outflow tract (LVOT) obstruction in hypertrophic cardiomyopathy (HCM) are not completely understood. We aimed to identify the anatomical risks of the obstruction using echocardiography.Fifty patients with untreated HCM were classified into two groups: those with LVOT pressure gradient (LVOTPG) >= 30 mmHg (obstructive HCM [HOCM] group) and those with LVOTPG < 30 mmHg (HNCM group). The echocardiographic morphological variables were analyzed to determine whether they were predictive of LVOT obstruction. Systolic anterior motions of the mitral valve were observed in 100% of patients in the HOCM group but only in 58% in the HNCM group. There were no significant differences in wall thickness, end-systolic LV dimension (LVDs), or LVOT diameter between the two groups. However, HOCM subjects had a shorter distance from papillary muscles to the inter-ventricular septum (5.97 +/- 2.3 versus 9.20 +/- 1.9 mm, respectively, P < 0.0001) and a longer anterior mitral leaflet (AML) length (24.7 +/- 5.8 versus 20.1 +/- 5.4 mm, respectively, P < 0.01) compared to the HNCM group. The AML length/LVDs ratio was significantly higher in the HOCM group compared to the HNCM group (1.02 +/- 0.34 versus 0.78 +/ 0.26, P < 0.01), and an LVOT obstruction was predicted with an area under the curve of 0.71 (P < 0.05). Multiple linear regression revealed that only the AML length/LVDs ratio was independently associated with LVOTPG (P < 0.01).The AML length/LVDs ratio has a significant predictive value for LVOT obstruction and a strong relationship with LVOTPGs. The AML length/LVDs ratio determines the anatomical risk of LVOT obstruction in HCM. PMID- 29479010 TI - High-Sensitivity C-Reactive Protein Combined with Low-Density Lipoprotein Cholesterol as the Targets of Statin Therapy in Patients with Acute Coronary Syndrome. AB - To investigate the combination of high-sensitivity C-reactive protein (hs-CRP) and Low-density lipoprotein (LDL)-C as the targets for statin treatment in patients with acute coronary syndrome (ACS). This single-center, prospective, randomized study was performed in 400 patients treated with atorvastatin 40 mg/day for 1 month and then with atorvastatin 20 mg/day as maintenance. The patients were randomized to the LDL group (LDL-C target of < 2.07 mmol/L according to the Chinese dyslipidemia guidelines) and to the LDL-CRP group (LDL-C target of < 2.07 mmol/L and hs-CRP target of < 3 mg/L). The patients were followed up for major adverse cardiac events (MACE) at 6, 12, and 18 months. The two groups had similar baseline characteristics and 391 patients completed the follow-up. No differences were found in LDL-C between the two groups, but a difference was found in hs-CRP at 12 and 18 months. There was a significant difference in revascularization (8.7% versus 3.6%, P = 0.04) and MACE (16.8% versus 9.7%; P = 0.04) between the LDL and LDL-CRP groups at 18 months. Compared to LDL-C as the single target, targeting both LDL-C and hs-CRP by statin therapy in patients with ACS could further reduce the incidence of MACE and the residual cardiovascular risk. PMID- 29479009 TI - Utility of Nutritional Screening in Predicting Short-Term Prognosis of Heart Failure Patients. AB - Controlling nutritional status (CONUT) uses 2 biochemical parameters (serum albumin and cholesterol level), and 1 immune parameter (total lymphocyte count) to assess nutritional status. This study examined if CONUT could predict the short-term prognosis of heart failure (HF) patients.A total of 482 (57.5%) HF patients from the Ibaraki Cardiovascular Assessment Study-HF (n = 838) were enrolled (298 men, 71.7 +/- 13.6 years). Blood samples were collected at admission, and nutritional status was assessed using CONUT. CONUT scores were defined as follows: 0-1, normal; 2-4, light; 5-8, moderate; and 9-12, severe degree of undernutrition. Accordingly, 352 (73%) patients had light-to-severe nutritional disturbances. The logarithmically transformed plasma brain natriuretic peptide (log BNP) concentration was significantly higher in the moderate-severe nutritional disturbance group (2.92 +/- 0.42) compared to the normal group (2.72 +/- 0.45, P < 0.01). CONUT scores were significantly higher in the in-hospital death patients [4 (3-8), n = 14] compared with patients who were discharged following symptom alleviation [3 (1-5), n = 446, P < 0.05]. With the exception of transferred HF patients (n = 22), logistic regression analysis that incorporated the CONUT score and the log BNP, showed that a higher CONUT score (P = 0.019) and higher log BNP (P = 0.009) were predictors of in-hospital death, and the median duration of hospital stay was 20 days.Our results demonstrate the usefulness of CONUT scores as predictors of short-term prognosis in hospitalized HF patients. PMID- 29479011 TI - Histopathology of Giant Coronary Artery Aneurysm Associated with Coronary Artery Fistula. AB - Giant coronary artery aneurysms related to coronary fistula are rare, and the precise mechanisms by which they occur are unknown. We present a case of giant coronary artery aneurysm of the left coronary artery to the pulmonary artery fistula with a lack of internal and (or) external elastic lamina and medial degeneration. PMID- 29479012 TI - Crocin Attenuates Oxidative Stress and Myocardial Infarction Injury in Rats. AB - Oxidative stress and excessive nitric oxide (NO) production play considerable roles in infarction-induced injury impairing cardiac functions. Crocin is the active constituent of Crocus sativus (saffron) with antioxidant properties and has protective effects against disturbances induced by ischemia in many organs. The present study aimed to investigate the protective effects and the underlying mechanisms of crocin on myocardial infarction (MI)-induced injury in rats in vivo. MI rats were intraperitoneally injected with crocin at different doses for seven successive days after coronary ligation. Infarct size, hemodynamic studies, and capillary density were evaluated. Levels of oxidative stress, inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), and their corresponding phosphorylation expressions were then measured. Crocin decreased infarct size, left ventricular (LV) end-diastolic pressure, and LV minimum dP/dt while increased LV maximum dP/dt and percentage of LV fractional shortening dose dependently. Capillary density was markedly increased after crocin treatment. Crocin enhanced superoxide dismutase activity and reduced malondialdehyde levels as well as inhibited excessive production of NO through downregulating iNOS as well as upregulating eNOS during MI-induced injury. This study reveals that crocin improves MI-induced impairments in cardiac function, which is associated with its antioxidant properties. PMID- 29479013 TI - Renal Denervation for Ventricular Arrhythmia in Patients with Implantable Cardioverter Defibrillators. AB - To investigate the efficacy of renal denervation (RDN) on the recurrence of ventricular arrhythmia (VA) in Asian patients with implantable cardioverter defibrillators (ICDs).Eight ICD patients with recurrent VA episodes underwent RDN using an off-the-shelf saline-irrigated catheter. The pre- and postprocedural VA episodes were counted via ICD interrogation. All patients underwent successful RDN without any complications related to radiofrequency catheter ablation. The median follow-up was 15 months (range 6-30), and the median VA episodes per month were significantly reduced from 3.17 (range 0.33-15.33) to 0.10 (range 0-5.83) after RDN (P < 0.05).RDN is an effective suppressor of VA in Asian patients with ICDs. PMID- 29479015 TI - Circadian Blood Pressure Variations in Postmenopausal Females with Hypertension. AB - The abnormalities of blood pressure (BP) nocturnal decline have been found to be predictive for carotid plaque and lacunar infarction in patients with hypertension. In this study, BP dipping patterns in postmenopausal females with hypertension were investigated. The nocturnal decline of systolic BP (SBP) was evaluated using 24-hour ambulatory BP monitoring (ABPM). A total of 163 postmenopausal females were eventually included in our study. The prevalence of reverse-dipper BP pattern was 32.3% in females with menopause age in their 40s and 40% in their 50s. However, after multivariate logistic regression analysis, menopause age was shown to be an independent risk factor for BP reverse dipping (Odds ratio [OR] 1.148; 95%CI 1.020 - 1.292; P = 0.020). Moreover, menopause age was negatively correlated with the decline rate of nocturnal SBP (r = -0.159; P < 0.05) and diastolic BP (r = -0.161; P < 0.05). Our study suggested that the menopause age might serve as a risk factor for reverse-dipper BP pattern in postmenopausal females with hypertension. PMID- 29479014 TI - Spontaneous Recanalization of the Obstructed Right Coronary Artery Caused by Blunt Chest Trauma. AB - Blunt chest trauma can cause a wide variety of injuries including acute myocardial infarction (AMI). Although AMI due to coronary artery dissection caused by blunt chest trauma is very rare, it is associated with high morbidity and mortality. In the vast majority of patients with AMI, primary percutaneous coronary interventions (PCI) are performed to recanalize obstructed arteries, but PCI carries a substantial risk of hemorrhagic complications in the acute phase of trauma. We report a case of AMI due to right coronary artery (RCA) dissection caused by blunt chest trauma. The totally obstructed RCA was spontaneously recanalized with medical therapy. We could avoid primary PCI in the acute phase of blunt chest trauma because electrocardiogram showed early reperfusion signs. We performed an elective PCI in the subacute phase when the risk of bleeding subsided. Since the risk of severe hemorrhagic complications is greater in the acute phase of blunt chest trauma as compared with the late phase, deferring emergency PCI is reasonable if signs of recanalization are observed. PMID- 29479016 TI - Asbestos exposure biomarkers in the follow-up of asbestos-exposed workers. AB - Health surveillance of asbestos exposed workers should be stratified according to the exposure level. Unfortunately there is a lack of information regarding asbestos exposure in many working places and markers of asbestos exposure are often needed. The aim of the study was to assess the reliability of different dose and effect biomarkers in the follow up of asbestos-exposed workers. Mineralogical analysis of bronchoalveolar lavage fluid (BALF) as a biomarker of asbestos fibre burden was performed in a population of 307 male subjects occupationally exposed to asbestos. Using nonparametric statistical methods 8 variables were analyzed with respect to asbestos-related diseases and working sectors. The existence of a relationship between serum soluble mesothelin-related peptides (SMRP) and asbestos exposure levels was also investigated. Concentrations of amphiboles, chrysotile and asbestos bodies in BALF were higher in patients with asbestosis as well as in railway industry workers. A correlation between the onset of non malignant asbestos-related diseases and the levels of SMRP concentration was not found. This study confirms that fibre concentration in BALF may be considered as a reliable biomarker of previous asbestos exposure, whereas SMRP does not appear to be influenced by asbestos exposure levels. PMID- 29479017 TI - Japan's healthcare policy for the elderly through the concepts of self-help (Ji jo), mutual aid (Go-jo), social solidarity care (Kyo-jo), and governmental care (Ko-jo). AB - Elderly care is an emerging global issue threatening both developed and developing countries. The elderly in Japan increased to 26.7% of the population in 2015, and Japan is classified as a super-aged society. In this article, we introduce the financial aspects of the medical care and welfare services policy for the elderly in Japan. Japan's universal health insurance coverage system has been in place since 1961. Long-term care includes welfare services, which were separated from the medical care insurance scheme in 2000 when Japan was already recognized as an aging society. Since then, the percentage of the population over 65 has increased dramatically, with the productive-age population on the decrease. The Japanese government, therefore, is seeking to implement "The Community-based Integrated Care System" with the aim of building comprehensive up to-the-end-of-life support services in each community. The system has four proposed elements: self-help (Ji-jo), mutual aid (Go-jo), social solidarity care (Kyo-jo), and government care (Ko-jo). From the financial perspective, as the government struggles against the financial burdens of an aging population, they are considering self-help and mutual aid. Based on Japan's present situation, both elements could lead to positive results. The Japanese government must also entrust the responsibility for implementing preventive support to municipalities through strongly required regional autonomy. As Japan has resolved this new challenge through several discussions over a long period of time, other aging countries could learn from the Japanese experience of solving barriers to healthcare policy for the elderly. PMID- 29479018 TI - Core factors promoting a continuum of care for maternal, newborn, and child health in Japan. AB - Providing a continuum of care (CoC) is important strategy for improving maternal, newborn, and child health (MNCH). Japan's current very low maternal and infant mortality rates suggest that its CoC for MNCH is good. In this paper, we attempt to clarify how CoC and low mortality rates are being maintained in Japan, by examining the entire MNCH service provision system. First, we examine two important tools for integrated service provision, the Maternal and Child Health (MCH) Handbook and registration of pregnant women with local governments, both introduced in 1942. Second, we explore the incentives provided by the MNCH system that prompt actors to participate in it. The three actors identified are service users (e.g., mothers and babies), medical professionals, and local governments. Through system design, all three actors benefit in ways that incentivize them to use MNCH services, which consequently connects service users with resources: all service users regardless of financial status, nationality, and location can receive free MNCH services such as antenatal care, assistance with childbirth, postnatal care, and immunizations; using the handbook, service users obtain health information, and medical professionals obtain the health records of pregnant women and their children as well as access examination fees from the local government by submitting vouchers in the handbook; local governments can then identify pregnant women for follow-up and provide health information and administrative services. As a result, the coverage rate of the MCH Handbook has reached 100% and MNCH services coverage could potentially reach the same level. PMID- 29479019 TI - [JKIMS Joint Symposium]. PMID- 29479020 TI - [Luncheon Seminar]. PMID- 29479021 TI - [Index]. PMID- 29479022 TI - [Workshop]. PMID- 29479023 TI - [International Symposium]. PMID- 29479024 TI - [Poster]. PMID- 29479025 TI - [Symposium]. PMID- 29479026 TI - Histologic comparison of direct pulp capping of rat molars with MTA and different concentrations of simvastatin gel. AB - Previous in vitro studies have suggested that simvastatin can be used as a direct pulp capping material due to its ability to induce odontoblastic differentiation and angiogenesis. The aim of this animal study was to evaluate the pulpal response to mineral trioxide aggregate (MTA) and four concentrations of simvastatin/MTA in combination. The study was conducted in two stages using four different simvastatin concentrations and MTA as a capping material for rat maxillary molars. The grades of inflammation and continuity of dentin formation were evaluated in hematoxylin and eosin (HE)-stained samples. Dentin thickness was determined by histomorphometric analysis, and the data were subjected to statistical analysis. On day 3, mild inflammation was observed in all groups. On day 7, the simvastatin groups showed a slightly higher rate of chronic inflammation. Inflammation was not present on day 30. Discontinuous dentin was present in all methylcellulose (control) samples. Continuous dentin was formed in all of the samples treated with 1.5% simvastatin. The greatest dentin thickness was observed after treatment with 1.5% simvastatin and MTA, followed by 0.5% simvastatin. Statistical analysis demonstrated no significant differences in dentin thickness and continuity between MTA and simvastatin at 0.5% and 1.5% (P > 0.05). PMID- 29479027 TI - A micro-CT study of the greater palatine foramen in human skulls. AB - The greater palatine foramen (GPF) is an important anatomical landmark and has substantial clinical relevance in dental surgery. Knowledge of its precise location and dimensions is required for proper planning of surgical procedures involving the posterior maxilla. We used microfocus computed tomography to determine the location and dimensions of the GPF, and any sex and race variations in those measurements, in 77 human skulls scanned at the South African Nuclear Energy Corporation. Specialized software was used for three-dimensional rendering, segmentation, and visualization of the reconstructed volume data. GPF location ranged from adjacent to the first molar to distal of the third molar. The most common GPF location was near the third molar (66.7% of skulls), and the GPF was as close as 6.31 mm (mean distance 12.75 +/- 3 mm). The mean GPF dimensions were 5.22 mm on the anterior-posterior axis and 2.81 mm on the lateral medial axis. We noted no significant differences in relation to race, sex, or age in the sample. The GPF was adjacent or posterior to the third maxillary molar in most skulls. PMID- 29479028 TI - Effect of collagenase concentration on the isolation of small adipocytes from human buccal fat pad. AB - Dedifferentiated fat (DFAT) cells were isolated from mature adipocytes using the ceiling culture method. Recently, we successfully isolated DFAT cells from adipocytes with a relatively small size (<40 MUm). DFAT cells have a higher osteogenic potential than that of medium adipocytes. Therefore, the objective of this study was to determine the optimal concentration of collagenase solution for isolating small adipocytes from human buccal fat pads (BFPs). Four concentrations of collagenase solution (0.01%, 0.02%, 0.1%, and 0.5%) were used, and their effectiveness was assessed by the number of small adipocytes and DFAT cells isolated. The total number of floating adipocytes that dissociated with 0.02% collagenase was 2.5 times of that dissociated with 0.1% collagenase. The number of floating adipocytes with a diameter of <=29 MUm that dissociated with 0.02% collagenase was thrice of those dissociated with 0.1% and 0.5% collagenase. The number of DFAT cells that dissociated with 0.02% collagenase was 1.5 times of that dissociated with 0.1% collagenase. In addition, DFAT cells that dissociated with 0.02% collagenase had a higher osteogenic differentiation potential than those that dissociated with 0.1% collagenase. These results suggest that 0.02% is the optimal collagenase concentration for isolating small adipocytes from BFPs. PMID- 29479030 TI - Involvement of transient receptor potential vanilloid 1 channel expression in orofacial cutaneous hypersensitivity following tooth pulp inflammation. AB - A study was conducted to evaluate the mechanisms underlying ectopic orofacial pain associated with tooth pulp inflammation in rats. We observed a significant decrease in the head withdrawal threshold (HWT) response to mechanical and heat stimuli applied to the ipsilateral facial skin upon application of complete Freund's adjuvant (CFA) to the upper first molar (M1TP) in comparison to application of vehicle. A large number of trigeminal ganglion (TG) neurons showed transient receptor potential vanilloid 1 (TRPV1) immunoreactivity (IR), and some of them were retrogradely labeled with fluorogold injected into the facial skin. A large number of cells showing IR for glial fibrillary acidic protein (GFAP) were observed in the 2nd compared to the 1st or 3rd branch regions of the TG, and TG cells innervating the facial skin were also surrounded by GFAP-IR cells. After administration of TRPV1 antagonist into the facial skin of M1TP CFA-treated rats, the decrease of HWTs in response to mechanical and heat stimulation of the facial skin was significantly reversed. The present findings suggest that the excitability of TG neurons is enhanced upon tooth pulp inflammation, leading to overexpression of TRPV1 in TG neurons innervating the facial skin, and that satellite glial cells are also activated, resulting in the development of ectopic orofacial pain. PMID- 29479029 TI - Cytogenetic, genomic, and epigenetic characterization of the HSC-3 tongue cell line with lymph node metastasis. AB - Oral carcinoma develops from squamous epithelial cells by the acquisition of multiple (epi) genetic alterations that target different genes and molecular pathways. Herein, we performed a comprehensive genomic and epigenetic characterization of the HSC-3 cell line through karyotyping, multicolor fluorescence in situ hybridization, array comparative genomic hybridization, and methylation-specific multiplex ligation-dependent probe amplification. HSC-3 turned out to be a near-triploid cell line with a modal number of 61 chromosomes. Banding and molecular cytogenetic analyses revealed that nonrandom gains of chromosomal segments occurred more frequently than losses. Overall, gains of chromosome 1, 3q, 5p, 7p, 8q, 9q, 10, 11p, 11q13, 12, 13, 14, 17, 18p, 20, Yp, and Xq were observed. The largest region affected by copy number loss was observed at chromosome 18q. Several of the observed genomic imbalances and their mapped genes were already associated with oral carcinoma and/or adverse prognosis, invasion, and metastasis in cancer. The most common rearrangements observed were translocations in the centromeric/near-centromeric regions. RARB, ESR1, and CADM1 genes were methylated and showed copy number losses, whereas TP73 and GATA5 presented with methylation and copy number gains. Thus, the current study presents a comprehensive characterization of the HSC-3 cell line; the use of this cell line may contribute to enriching the resources available for oral cancer research, especially for the testing of therapeutic agents. PMID- 29479031 TI - Large Non-Bacterial Vegetation Causing Acute Aortic Regurgitation - Unexpected Finding at Autopsy. PMID- 29479032 TI - Mitochondrial damage mediated by ROS incurs bronchial epithelial cell apoptosis upon ambient PM2.5 exposure. AB - Mitochondria can be used as important biomarkers of pollutants on human health, and fine particulate matter (PM2.5) has been documented to cause respiratory damage. However, current studies about the relationship between PM2.5 and mitochondria in respiratory tract are limited and warrant further detailed investigations. Hence, the study was aimed to evaluate effects of PM2.5 on mitochondrial structure, investigate the link between PM2.5-induced mitochondrial disorder and respiratory damage, and delineate the possible mechanisms using both in vitro and in vivo models. PM2.5 exposure resulted in damage of mitochondrial structure, including mitochondrial dynamic, DNA biogenesis and morphological alteration 16HBE cells. Furthermore, PM2.5 elevated ROS formation. However, DPI and NAC (inhibitor of ROS) in supplement restored PM2.5-induced mitochondrial disorder. PM2.5 also contributed to the 16HBE cells apoptosis via mitochondrial pathway. Additionally, the results coincided with the in vivo data which were obtained from bronchial tissues of SD rats exposed to PM2.5 for 30 days. Collectively, this study uncovers that PM2.5 leads to the disorder of mitochondrial structure via ROS generation, and then results in respiratory damage. It provides further understanding about the detrimental effect of PM2.5 on respiratory damage, and reveals a mechanistic basis for preventing outcomes in polluted environments. PMID- 29479033 TI - Carcinogenicity of quinoline by drinking-water administration in rats and mice. AB - The carcinogenicity of quinoline was examined by administrating quinoline in the drinking water to groups of 50 F344/DuCrj rats and 50 Crj: BDF1 mice of each sex. In rats, the doses of quinoline were 0, 200, 400, and 800 ppm for males and 0, 150, 300, and 600 ppm for females. In male rats, administration of quinoline was terminated at week 96 due to high mortality caused by tumors. There were significant increases of hepatocellular adenomas, hepatocellular carcinomas, hepatocellular adenomas and/or carcinomas (combined), and liver hemangiomas, hemangiosarcomas, hemangiomas and/or hemangiosarcomas (combined) in both male and female rats, and nasal esthesioneuroepitheliomas and sarcoma NOS (not otherwise specified) in males. In mice, doses of quinoline were 0, 150, 300 and 600 ppm for both males and females. Administration of quinoline was terminated at week 65 in males and at week 50 in females due to high mortality caused by tumors. There were marked increases of hemangiomas, hemangiosarcomas, and hemangiomas and/or hemangiosarcomas (combined) in the retroperitoneum, mesenterium, and liver in males, and in the retroperitoneum, mesenterium, peritoneum, and subcutis in females. Additionally, histiocytic sarcomas were statistically increased in the livers of female mice. Thus the present studies provided clear evidence of carcinogenic activity of quinoline administered in the drinking water in both rats and mice. PMID- 29479034 TI - Lethal chronotoxicity induced by seven metal compounds in mice. AB - The aim of the present study is to investigate the "chronotoxicity" of seven metal compounds (Hg, Pb, Ni, Cr, Cu, Zn, or Fe) by assessing how their toxicity varies with circadian periodicity. Male ICR mice were injected with each metal compound intraperitoneally at 6 different time points over the course of a day (zeitgeber time [ZT]: ZT2, ZT6, ZT10, ZT14, ZT18 and ZT22). Mortality was then monitored until 14 days after the injection. Our investigation demonstrated that mice were tolerant against Ni toxicity during dark phase, on the other hand, they were tolerant against Cr toxicity during light phase. The chronotoxicity of Hg and Pb seemed to be biphasic. Further, mice were susceptible to toxicities against Cu and Zn in the time zone during which light and dark were reversed. Interestingly, no significant differences were observed for Fe exposure at any time of the day. Our results propose that the chronotoxicology may provide valuable information regarding the importance of injection timing for not only toxicity evaluation tests but also the reproducibility of animal experiments. Furthermore, our data suggests that chronotoxicology may be an important consideration when evaluating the quality of risk assessments for night shift workers who may be exposed to toxic substances at various times of the day. PMID- 29479035 TI - A pharmacologic increase in activity of plasma transaminase derived from small intestine in animals receiving an acyl CoA: diacylglycerol transferase (DGAT) 1 inhibitor. AB - Acyl CoA: diacylglycerol acyltransferase (DGAT) 1 is an enzyme that catalyzes the re-synthesis of triglycerides (TG) from free fatty acids and diacylglycerol. JTT 553 is a DGAT1 inhibitor and exhibits its pharmacological action (inhibition of re-synthesis of TG) in the enterocytes of the small intestine leading to suppression of a postprandial elevation of plasma lipids. After repeated oral dosing JTT-553 in rats and monkeys, plasma transaminase levels were increased but there were neither changes in other hepatic function parameters nor histopathological findings suggestive of hepatotoxicity. Based on the results of exploratory studies for investigation of the mechanism of the increase in transaminase levels, plasma transaminase levels were increased after dosing JTT 553 only when animals were fed after dosing and a main factor in the diet contributing to the increase in plasma transaminase levels was lipids. After dosing JTT-553, transaminase levels were increased in the small intestine but not in the liver, indicating that the origin of transaminase increased in the plasma was not the liver but the small intestine where JTT-553 exhibits its pharmacological action. The increase in small intestinal transaminase levels was due to increased enzyme protein synthesis and was suppressed by inhibiting fatty acid-transport to the enterocytes. In conclusion, the JTT-553-related increase in plasma transaminase levels is considered not to be due to release of the enzymes from injured cells into the circulation but to be phenomena resulting from enhancement of enzyme protein synthesis in the small intestine due to the pharmacological action of JTT-553 in this organ. PMID- 29479036 TI - Arsenite exposure potentiates apoptosis-inducing effects of tumor necrosis factor alpha- through reactive oxygen species. AB - Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine released by immune cells during inflammation process. Sodium arsenite (NaAsO2) is an environmental toxic metal. The effects of excess NaAsO2 on TNF-alpha response and its intracellular signaling are not well understood. We hypothesized that NaAsO2 exposure might affect cellular response to TNF-alpha. Using HeLa cell model, we found that the combination of NaAsO2 and TNF-alpha clearly decreased cell viability and mitochondrial membrane potential, but increased percentage of early and late apoptotic cells and cleaved-poly (ADP-ribose) polymerase (PARP). Moreover, the combination prolonged the phosphorylation of mitogen-activated protein kinase (MAPK) members, including c-Jun-N-terminal kinase (JNK), p38, and extracellular signal related kinases (ERK), and increased intracellular reactive oxygen species (ROS), in comparison to treatment of NaAsO2 or TNF-alpha alone. We further investigated the role of ROS and MAPK signaling on this event by inhibiting ROS production and MAPK. An antioxidant N-acetylcysteine pretreatment diminished the apoptosis-inducing effect of NaAsO2 and TNF-alpha combination and also inhibited MAPK signaling. Using specific inhibitor of p38 (SB203580) and siRNA-p38 surprisingly increased cell apoptosis and this effect was not observed by JNK and ERK inhibition. This study suggests that p38 may possibly be a survival mediator in response to environmental toxicant-related inflammation. In conclusion, NaAsO2 exposure might amplify inflammation-related tissue injury by potentiating the apoptosis-inducing effect of TNF-alpha through ROS-dependent mechanism. PMID- 29479037 TI - Role of cytochrome P450-mediated metabolism and involvement of reactive metabolite formations on antiepileptic drug-induced liver injuries. AB - Several drugs have been withdrawn from the market or restricted to avoid unexpected adverse outcomes. Drug-induced liver injury (DILI) is a serious issue for drug development. Among DILIs, idiosyncratic DILIs have been a serious problem in drug development and clinical uses. Idiosyncratic DILI is most often unrelated to pharmacological effects or the dosing amount of a drug. The number of drugs that cause idiosyncratic DILI continue to grow in part because no practical preclinical tests have emerged that can identify drug candidates with the potential for developing idiosyncratic DILIs. Nevertheless, the implications of drug metabolism-related factors and immune-related factors on idiosyncratic DILIs has not been fully clarified because this toxicity can not be reproduced in animals. Therefore, accumulated evidence for the mechanisms of the idiosyncratic toxicity has been limited to only in vitro studies. This review describes current knowledge of the effects of cytochrome P450 (CYP)-mediated metabolism and its detoxification abilities based on studies of idiosyncratic DILI animal models developed recently. This review also focused on antiepileptic drugs, phenytoin (diphenyl hydantoin, DPH) and carbamazepine (CBZ), which have rarely caused severe adverse reactions, such as fulminant hepatitis, and have been recognized as sources of idiosyncratic DILI. The studies of animal models of idiosyncratic DILIs have produced new knowledge of chronic administration, CYP inductions/inhibitions, glutathione contents, and immune-related factors for the initiation of idiosyncratic DILIs. Considering changes in the drug metabolic profile and detoxification abilities, idiosyncratic DILIs caused by antiepileptic drugs will lead to understanding the mechanisms of these DILIs. PMID- 29479038 TI - Effects of long-term cadmium exposure on urinary metabolite profiles in mice. AB - Cadmium (Cd) is a common environmental pollutant with known toxic effects on the kidney. Urinary metabolomics is a promising approach to study mechanism by which Cd-induced nephrotoxicity. The aim of this study was to elucidate the mechanism of Cd toxicity and to develop specific biomarkers by identifying urinary metabolic changes after a long-term of Cd exposure and with the critical concentration of Cd in the kidney. Urine samples were collected from wild-type 129/Sv mice after 67 weeks of 300 ppm Cd exposure and analyzed by ultra performance liquid chromatography connected with quadrupole time of flight mass spectrometer (UPLC-QTOF-MS) based metabolomics approach. A total of 40 most differentiated metabolites (9 down-regulated and 31 up-regulated) between the control and Cd-exposed group were identified. The majority of the regulated metabolites are amino acids (glutamine, L-aspartic acid, phenylalanine, tryptophan, and D-proline) indicating that amino acid metabolism pathways are affected by long-term exposure of Cd. However, there are also some nucleotides (guanosine, guanosine monophosphate, cyclic AMP, uridine), amino acid derivatives (homoserine, N-acetyl-L-aspartate, N-acetylglutamine, acetyl-phenylalanine, carboxymethyllysine), and peptides. Results of pathway analysis showed that the arginine and proline metabolism, purine metabolism, alanine, aspartate and glutamate metabolism, and aminoacyl-tRNA biosynthesis were affected compared to the control. This study demonstrates that metabolomics is useful to elucidate the metabolic responses and biological effects induced by Cd-exposure. PMID- 29479039 TI - Concomitant Intracranial and Lumbar Chronic Subdural Hematoma Treated by Fluoroscopic Guided Lumbar Puncture: A Case Report and Literature Review. AB - A 40-year-old man presented with a severe headache, lower back pain, and lower abdominal pain 1 month after a head injury caused by falling. Computed tomography (CT) of the head demonstrated bilateral chronic subdural hematoma (CSDH) with a significant amount in the left frontoparietal region. At the same time, magnetic resonance imaging (MRI) of the lumbar spine also revealed CSDH from L2 to S1 level. A simple drainage for the intracranial CSDH on the left side was performed. Postoperatively, the headache was improved; however, the lower back and abdominal pain persisted. Aspiration of the liquefied spinal subdural hematoma was performed by a lumbar puncture under fluoroscopic guidance. The clinical symptoms were dramatically improved postoperatively. Concomitant intracranial and spinal CSDH is considerably rare so only 23 cases including the present case have been reported in the literature so far. The etiology and therapeutic strategy were discussed with a review of the literature. Therapeutic strategy is not established for these two concomitant lesions. Conservative follow-up was chosen for 14 cases, resulting in a favorable clinical outcome. Although surgical evacuation of lumbosacral CSDH was performed in seven cases, an alteration of cerebrospinal fluid (CSF) pressure following spinal surgery should be reminded because of the intracranial lesion. Since CSDH is well liquefied in both intracranial and spinal lesion, a less invasive approach is recommended not only for an intracranial lesion but also for spinal lesion. Fluoroscopic-guided lumbar puncture for lumbosacral CSDH following burr hole surgery for intracranial CSDH could be a recommended strategy. PMID- 29479040 TI - Subarachnoid Hemorrhage from Vertebral Arteriovenous Fistula without Perimedullary Drainage: Rare Stroke Hemorrhagic Event in a Patient of Neurofibromatosis Type 1. AB - Vertebral arteriovenous fistula (VAVF), which can cause subarachnoid hemorrhage (SAH) when having a perimedurally drainage, has been reported as a rare vascular abnormality in patients with neurofibromatosis type 1 (NF-1). In addition, extracranial vertebral aneurysm (EVAn) coexisting with VAVF and NF-1 is considered rare, and further complication with SAH is extremely rare in patients. There is only one reported case of NF-1 complicated with SAH from VAVF with an EVAn. Here, we present a case of a middle-aged patient with NF-1. The VAVF accompanied by an EVAn was detected with an episode of SAH. The VAVF with an EVAn in our case was accompanied with an epidural varix, lacking of perimedullary drainage, which could be a cause for SAH. We speculate the mechanism of SAH from the VAVF with an EVAn lacking of perimedurally drainage, focusing on hemodynamic stress of the VAVF and the tissue fragility related to NF-1. PMID- 29479041 TI - Mechanical Thrombectomy in Anterior Circulation Occlusion Could Be More Effective than Medical Management Even in Low DWI-ASPECTS Patients. AB - The purpose of this study was to investigate whether patients with low preoperative Diffusion-weighted Imaging Alberta Stroke Program Early Computed Tomography Score (DWI-ASPECTS) could benefit from mechanical thrombectomy for acute anterior circulation occlusion. This was a retrospective, non-blinded, cohort study. From September 2012 to August 2016, 83 consecutive patients of acute anterior circulation occlusion were treated with thrombectomy using second generation devices or medical management. The DWI-ASPECTS was scored after the first MRI. Patient characteristics and clinical outcomes were compared between the treatment groups. Significant dependence was defined as a modified Rankin scale score >=3 at 90 days. As a result, 33 patients underwent mechanical thrombectomy and 50 received medical management. In the mechanical thrombectomy group, the variable of lower DWI-ASPECTS (5, 4-6 vs. 8, 7-8, P < 0.001), especially <=6, was significantly associated with poor prognosis. However, compared with patients of DWI-ASPECTS <= 6 who received medical management, there were significantly fewer patients with poor outcomes in thrombectomy (dependent in 11 of 15 vs. 23 of 23, respectively; P = 0.019). Although patients with lower pretreatment DWI-ASPECTS could benefit less from thrombectomy, their outcomes were still better than medical management. Therefore, mechanical thrombectomy could be considered in some patients with low pretreatment DWI-ASPECTS. PMID- 29479043 TI - Sound exposure-induced cytokine gene transcript profile changes in captive bottlenose dolphin (Tursiops truncatus) blood identified by a probe-based qRT PCR. AB - Cetacean health may be potentially affected by anthropogenic sound. We have initiated investigations on the effect of low-frequency underwater sound on immunological gene transcript profiles of captive bottlenose dolphins (Tursiops truncatus) using a probe-based quantitative gene expression assay. Six immunologic genes (IL-2Ralpha, -4, -10, -12, TNFalpha and IFNgamma) were selected for analysis using two validated housekeeping genes (PGK1 and HPRT1) as reference genes. Twenty-four blood samples from six clinically healthy individuals and six blood samples from individuals after sound exposures were available. The gene transcript profile of sound-exposed dolphins was consistent with a stress-induced TH2 shift profile as compared to controls. This study may lead to better understanding of the effects of anthropogenic sound on immune responses of cetaceans. PMID- 29479042 TI - Postoperative Changes in Metabolic Parameters of Patients with Surgically Controlled Acromegaly: Assessment of New Stringent Cure Criteria. AB - The criteria for surgical cure of acromegaly have become more stringent during the past decades and a change from Cortina to new consensus criteria has recently been proposed. However, the superiority of the new consensus over Cortina criteria with respect to postoperative metabolic parameters remains to be ascertained. We retrospectively assessed metabolic parameters, the body habitus, and other health-related parameters of 48 patients with surgically controlled acromegaly who met the Cortina criteria [normalized insulin-like growth factor-1 (IGF-1) level and nadir growth hormone (GH) level <1.0 ng/ml during postoperative oral glucose tolerance test]. The 48 patients were divided into two groups. Group A (n = 33) met the new consensus criteria (normalized IGF-1 and nadir GH level <0.4 ng/ml). Group B (n = 15) met Cortina criteria, but their nadir GH ranged from 0.4 to 1.0 ng/ml. In both groups, the level of triglyceride and homeostasis model assessment-insulin resistance (HOMA-IR) was significantly decreased 1 year after the operation (P < 0.05). High-density lipoprotein cholesterol showed a significant increase only in group B (P = 0.02). However, the two groups did not differ with respect to the postoperative improvement rate of these parameters and the other health-related parameters including body mass index, blood pressure, anterior pituitary function, and self-estimated quality of life scale. In conclusion, our findings show that with respect to changes in metabolic parameters and the body habitus assessed 1 year after surgery, the stricter consensus criteria seemed not to be superior to Cortina criteria. PMID- 29479044 TI - Detection and phylogenetic analysis of phlebovirus, including severe fever with thrombocytopenia syndrome virus, in ticks collected from Tokyo, Japan. AB - Severe fever with thrombocytopenia syndrome (SFTS) was detected for the first time in China in 2011. Since then, human cases have been reported in endemic regions, including Japan. To investigate the presence of tick-borne pathogens in Tokyo, 551 ticks (266 samples) were collected from October 2015 to October 2016. Although the SFTS virus was not detected by RT-PCR, a novel phlebovirus was detected in one sample. In a phylogenetic analysis based on the partial nucleotide sequences of the L and S segments of the virus, the virus clustered with Lesvos virus (Greece), Yongjia tick virus, and Dabieshan tick virus (China). Further studies involving virus isolation are required to characterize this novel phlebovirus and to expand the epidemiological knowledge of related pathogens. PMID- 29479045 TI - Welfare analysis of a zero-smoking policy - A case study in Japan. AB - Smoking cessation efforts in Japan reduce smoking rates. A future zero-smoking policy would completely prohibit smoking (0% rate). We therefore analyzed the social welfare of smokers and non-smokers under a hypothetical zero-smoking policy. The demand curve for smoking from 1990 to 2014 was estimated by defining quantity as the number of cigarettes smoked and price as total tobacco sales/total cigarettes smoked by the two-stage least squares method using the tax on tobacco as the instrumental variable. In the estimation equation (calculated using the ordinary least squares method), the price of tobacco was the dependent variable and tobacco quantity the explanatory variable. The estimated constant was 31.90, the estimated coefficient of quantity was - 0.0061 (both, p < 0.0004), and the determinant coefficient was 0.9187. Thus, the 2015 consumer surplus was 1.08 trillion yen (US$ 9.82 billion) (95% confidence interval (CI), 889 billion yen (US$ 8.08 billion) - 1.27 trillion yen (US$ 11.6 billion)). Because tax revenue from tobacco in 2011 was 2.38 trillion yen (US$ 21.6 billion), the estimated deadweight loss if smoking were prohibited in 2014 was 3.31 trillion yen (US$ 30.2 billion) (95% CI, 3.13 trillion yen (US$ 28.5 billion) - 3.50 trillion yen (US$ 31.8 billion)), representing a deadweight loss about 0.6 trillion yen (US$ 5.45 billion) below the 2014 disease burden (4.10-4.12 trillion yen (US$ 37.3-37.5 billion)). We conclude that a zero-smoking policy would improve social welfare in Japan. PMID- 29479046 TI - Anesthetic activity of plant essential oils on Cyprinus carpio (koi carp). AB - The aims of this study were to investigate the anesthetic and cytotoxic effects of essential oils (EOs) of Ocimum basilicum (OBO), O. canum (OCO), and O. sanctum (OSO) on Cyprinus carpio (koi carp). For anesthetic effect, induction time to surgical anesthesia and recovery time were determined. For cytotoxicity effect, viability of fish peripheral blood nuclear cells (PBMCs) was investigated. Results indicated that increasing oil concentration caused significant (p < 0.01) decrease of induction time. OSO at 100, 200, and 300 mg/L gave the induction time of 169.5 +/- 10.2, 62.8 +/- 2.3, 45.3 +/- 2.2 sec, respectively, significantly shorter than OCO, and OBO. The recovery time of anesthetized fish was dose dependent (p <0.01). Among them, OCO showed the longest recovery time of 313.0 +/ 8.1, 420.7 +/- 12.6, 616.6 +/- 12.1 sec for concentrations of 100, 200, and 300 mg/L, respectively, followed by OSO and OBO, respectively. Within 10 min contact time of the EOs and fish PBMCs, the fish PBMC viability was higher than 80%. Increase contact time and EO concentration caused an increase in cytotoxicity to fish PBMC. OBO showed less toxic than OSO and OCO. Based on the desired induction and recovery times for anesthetizing koi carp, OBO, OCO, and OSO at 300, 200, and 100 mg/L, respectively were suggested to be the most suitable. It was concluded that OBO, OCO, and OSO can be used as natural anesthetics for fish. PMID- 29479047 TI - Long-term use of ipragliflozin improved cardiac sympathetic nerve activity in a patient with heart failure: A case report. AB - Ipragliflozin is the first SGLT2 inhibitor approved in Japan. Reported here is a case where long-term administration of ipragliflozin decreased the rate of re hospitalization due to heart failure (HF). An 83-year-old man with chronic HF and diabetes mellitus (DM) was hospitalized four times in the last five years. He was discharged six months after his last hospitalization, but he continued to have class III HF according to the New York Heart Association classification (NYHA), and his DM was also not properly managed. Therefore, he received ipragliflozin. One year after initiation of ipragliflozin, he lost weight (body weight (BW): 79.0 to 76.2 kg), his levels of brain natriuretic peptide (BNP) decreased (191.4 to 122.5 mg/dL), and the class of his HF improved (class III to class II). The management of DM also improved (fasting blood glucose: 100 to 110 mg/dL; hemoglobin A1C: 6.8 to 6.6%). In addition, cardiac sympathetic nerve function evaluated with 123I-metaiodobenzylguanidine cardiac-scintigraphy (123I-MIBG) also improved (the average of the heart-to-mediastinum ratio in early and delayed phases; 1.44 to 2.17 in the early phase, 1.41 to 1.92 in the delayed phase, washout rate; 43.3 to 35.6). The patient was not re-hospitalized due to HF two years after administration of ipragliflozin started. A reduction in cardiac sympathetic nerve hyperactivity by an SGLT2 inhibitor might be one of the mechanisms of its cardio-protective effect, but clinical studies need to be conducted to verify this finding. PMID- 29479048 TI - Generic selection criteria for safety and patient benefit [VII]: Comparing the physicochemical and pharmaceutical properties of brand-name and generic terbinafine hydrochloride cream. AB - We measured and compared the physicochemical properties (pH, yield value, and squeeze force) of a drug for dermatomycosis, terbinafine hydrochloride-containing cream (brand-name product), and 12 generic products to clarify the characteristics of each product. On pH measurement, the pH value of the brand name product, Lamisil, was 4.8, and those of the generic products ranged from 4.3 to 5.5, showing no marked difference. Furthermore, the yield value of Lamisil, as an index of cream ductility, was 122.2 dyn/cm2, and those of the generic products ranged from 42.1 to 1,621.5 dyn/cm2. In particular, the value of a generic product, Taiyo (42.1 dyn/cm2), was significantly lower, whereas that of another one, Viras (1,621.0 dyn/cm2), was significantly higher. In addition, the squeeze force was measured by attaching a HapLog(r) to the thumb and second finger. The value of Lamisil was 12.9 N, and those of the generic products ranged from 8.0 to 15.4 N. The values of generic products, Mylan (8.6 N), Tebinaceil (9.0 N), and Kelger (8.0 N), were significantly lower, whereas that of another one, Viras (15.4 N), was significantly higher. These results showed that there were marked differences in the pharmaceutical properties between the generic and brand-name products. The above pharmaceutical characteristics of drugs facilitated the presentation of reasons for differences in the sense of use, which characterizes external preparations, suggesting that products appropriate for individual patients can be recommended. PMID- 29479049 TI - Atypical presentation of pyogenic iliopsoas abscess in two cases. AB - Iliopsoas abscess (IPA) is an uncommon diagnosis in medical wards. Herein, we present two unusual cases of IPA. First patient was an elderly diabetic patient who had gas-forming bilateral IPA caused by Escherichia coli. This infection proved fatal and patient succumbed on third day of hospital admission. Second patient was a young boy who had right sided sacroilitis with IPA. Staphylococcus aureus was isolated from the pus culture and patient was successfully treated without any sequelae. PMID- 29479050 TI - CORRIGENDUM: Electrophysiological Characteristics and Radiofrequency Catheter Ablation Treatment of Idiopathic Ventricular Arrhythmias Successfully Ablated From the Ostium of the Coronary Sinus. PMID- 29479053 TI - A Computational Workflow Translates a 58-Gene Signature to a Formalin-Fixed, Paraffin-Embedded Sample-Based Companion Diagnostic for Personalized Treatment of the BRAF-Mutation-Like Subtype of Colorectal Cancers. AB - Colorectal cancer patients with the BRAF(p.V600E) mutation have poor prognosis in metastatic setting. Personalized treatment options and companion diagnostics are needed to better treat these patients. Previously, we developed a 58-gene signature to characterize the distinct gene expression pattern of BRAF-mutation like subtype (accuracy 91.1%). Further experiments repurposed drug Vinorelbine as specifically lethal to this BRAF-mutation-like subtype. The aim of this study is to translate this 58-gene signature from a research setting to a robust companion diagnostic that can use formalin-fixed, paraffin-embedded (FFPE) samples to select patients with the BRAF-mutation-like subtype. BRAF mutation and gene expression data of 302 FFPE samples were measured (mutants = 57, wild-type = 245). The performance of the 58-gene signature in FFPE samples showed a high sensitivity of 89.5%. In the identified BRAF-mutation-like subtype group, 50% of tumours were known BRAF mutants, and 50% were BRAF wild-type. The stability of the 58-gene signature in FFPE samples was evaluated by two control samples over 40 independent experiments. The standard deviations (SD) were within the predefined criteria (control 1: SD = 0.091, SD/Range = 3.0%; control 2: SD = 0.169, SD/Range = 5.5%). The fresh frozen version and translated FFPE version of this 58-gene signature were compared using 170 paired fresh frozen and FFPE samples and the result showed high consistency (agreement = 99.3%). In conclusion, we translated this 58-gene signature to a robust companion diagnostic that can use FFPE samples. PMID- 29479055 TI - Development and Validation of an Ultrasensitive Procalcitonin Sandwich Immunoassay. AB - Procalcitonin (PCT) is well established as a highly specific biomarker for the detection of bacterial infections and sepsis. However, the currently available diagnostic tests are not able to detect very low or very early increases of PCT or even baseline levels in healthy individuals or patients with non-bacterial infections. In order to be able to detect these very low concentrations of PCT, a sandwich immunoassay was developed using high sensitivity Single Molecule Array technology (Simoa). The assay was thoroughly validated and applied to analyze human cerebrospinal fluid (CSF) and serum samples from patients with bacterial or viral meningitis as well as CSF, serum, and K2 EDTA plasma from healthy control subjects. A 50-fold increase in sensitivity compared to the current gold standard assays was achieved, which was sensitive enough for the detection of baseline PCT levels. Both serum and CSF showed significantly elevated PCT levels in patients with bacterial meningitis compared to patients with viral meningitis and the healthy control group. Procalcitonin concentration levels for patients with viral meningitis and the control group could be measured, but were not significantly different. The determination of PCT in the low pg.mL-1 range could help to improve the monitoring of bacterial infectious diseases, as PCT level changes could be detected earlier. PMID- 29479054 TI - Application of High-Throughput Assays to Examine Phospho-Modulation of the Late Steps of Regulated Exocytosis. AB - Abstract: Regulated exocytosis enables a range of physiological functions including neurotransmission, and the late steps (i.e., docking, priming and Ca2+ triggered membrane fusion) are modulated by a highly conserved set of proteins and lipids. Many of the molecular components and biochemical interactions required have been identified; the precise mechanistic steps they modulate and the biochemical interactions that need to occur across steps are still the subject of intense investigation. Particularly, although the involvement of phosphorylation in modulating exocytosis has been intensively investigated over the past three decades, it is unclear which phosphorylation events are a conserved part of the fundamental fusion mechanism and/or serve as part of the physiological fusion machine (e.g., to modulate Ca2+ sensitivity). Here, the homotypic fusion of cortical vesicles was monitored by utilizing new high throughput, cost-effective assays to assess the influence of 17 small molecule phospho-modulators on docking/priming, Ca2+ sensitivity and membrane fusion. Specific phosphatases and casein kinase 2 are implicated in modulating the Ca2+ sensitivity of fusion, whereas sphingosine kinase is implicated in modulating the ability of vesicles to fuse. These results indicate the presence of multiple kinases and phosphatases on the vesicles and critical phosphorylation sites on vesicle membrane proteins and lipids that directly influence late steps of regulated exocytosis. PMID- 29479056 TI - Association of APOE Gene Polymorphisms with Cerebral Infarction in the Chinese Population. AB - BACKGROUND Apolipoprotein E (ApoE) is a multifunctional protein that plays an important role in lipoprotein metabolism. However, the relationship between APOE gene polymorphisms and cerebral infarction in the Chinese population remains unclear. Therefore, we studied the role of APOE gene polymorphisms in patients with cerebral infarction in a Chinese population. MATERIAL AND METHODS This study involved 906 patients with cerebral infarction and 1,141 individuals without cerebral infarction who served as controls. APOE genotypes were identified in all participants who participated in the study. Factors influencing cerebral infarction were also analyzed. RESULTS Statistically significant variances in the distribution and frequencies of the APOE genotypes in the patients were observed (epsilon2/epsilon3 versus epsilon2/epsilon4 versus epsilon3/epsilon3=22.85% versus 7.62% versus 56.95%) and controls (epsilon2/epsilon3 versus epsilon2/epsilon4 versus epsilon3/epsilon3=17.27% versus 2.72% versus 66.87%; p<0.001). Univariate analysis showed that the APOE epsilon3/epsilon3 genotype [OR, 0.393 (95% CI, 0.237-0.653); p<0.001] and epsilon3/epsilon4 genotype [OR, 0.376 (95% CI 0.221-0.637); p<0.001] played a protective role against cerebral infarction in Chinese men. CONCLUSIONS Statistically significant variances in the distribution and frequencies of the APOE genotypes of the patients and controls were observed. The study demonstrated that the APOE epsilon3/epsilon3 and epsilon3/epsilon4 genotypes played a protective role against cerebral infarction in Chinese men, but not women. Additionally, the epsilon2/epsilon4 genotype may be a potential risk factor in men, whereas epsilon3/epsilon4 genotype may play a potential protective role against this disease in women. PMID- 29479057 TI - Osteoid Osteoma Can Occur at the Pars Interarticularis of the Lumbar Spine, Leading to Misdiagnosis of Lumbar Spondylolysis. AB - BACKGROUND Osteoid osteomas are benign bone-forming tumors characterized by local inflammation and pain. They are also characterized by a small osteolytic lesion (nidus). Spondylolysis is a defect of the pars interarticularis, which may lead to stress fractures, and is a common cause of low back pain in adolescence. Osteoid osteoma occurs predominantly in the posterior elements of the spine. Magnetic resonance imaging (MRI) signal abnormality suggesting bone marrow edema is a common finding in osteoid osteoma and early-stage spondylolysis without prominent defect. CASE REPORT An 18-year-old male was suffering from low back pain. He was diagnosed with lumbar spondylolysis on initial MRI and computed tomography (CT). Subsequent thin-slice CT demonstrated a nidus at the pars interarticularis, and variously-sliced MRI could detect widespread bone marrow edema. On the diagnosis of an osteoid osteoma, the nidus and surrounding osteosclerosis were resected. The patient's pain disappeared after surgery. CONCLUSIONS Osteoid osteoma in the pars interarticularis can be difficult to diagnosis, because MRI and CT findings for osteoid osteoma at the pars interarticularis are similar to those of the lumbar spondylolysis. The possibility of osteoid osteoma should be kept in mind when examining adolescents with low back pain. PMID- 29479058 TI - Targeting UDP-alpha-D-glucose 6-dehydrogenase inhibits glioblastoma growth and migration. AB - UDP-glucose 6-dehydrogenase (UGDH) produces UDP-alpha-D-glucuronic acid, the precursors for glycosaminoglycans (GAGs) and proteoglycans of the extracellular matrix. Elevated GAG formation has been implicated in a variety of human diseases, including glioblastoma (GBM). In our previous study, we found that Kruppel-like factor 4 (KLF4) promotes GBM cell migration by binding to methylated DNA, mainly methylated CpGs (mCpG) and transactivating gene expression. We identified UDGH as one of the downstream targets of KLF4-mCpG binding activity. In this study, we show that KLF4 upregulates UGDH expression in a mCpG-dependent manner, and UGDH is required for KLF4-induced cell migration in vitro. UGDH knockdown decreases GAG abundance in GBM cells, as well as cell proliferation and migration in vitro. In intracranial xenografts, reduced UGDH inhibits tumor growth and migration, accompanied by a decrease in the expression of extracellular matrix proteins such as tenascin C, brevican. Our studies demonstrate a novel DNA methylation-dependent UGDH upregulation by KLF4. Developing UGDH antagonists to decrease the synthesis of extracellular matrix components will be a useful strategy for GBM therapy. PMID- 29479059 TI - Phylogeographic analysis suggests two origins for the riparian azalea Rhododendron indicum (L.) Sweet. AB - Ecological speciation is an important factor in the diversification of plants. The distribution of the woody species Rhododendron indicum, which grows along rivers and is able to withstand water flow when rivers flood (i.e. it is a rheophyte), is disjunct, in contrast to the widespread distribution of its relative, Rhododendron kaempferi. This study aimed to elucidate the phylogenetic relationships between R. indicum and R. kaempferi and the evolutionary processes that gave rise to them. The sequences of three non-coding chloroplast DNA regions (total length 1977 bp) were obtained from 21 populations covering the ranges of the two species. In addition, genome-wide SNPs were genotyped from 20 populations using a genotyping by sequencing method. Leaf morphologies were measured for eight representative populations. Two chloroplast DNA haplotypes, which were detected in R. indicum, were shared between the two species. Genome-wide SNPs identified two lineages in R. indicum and these lineages did not constitute a monophyletic group. Each of these two lineages was related to geographically close populations of R. kaempferi. Leaf morphology, which is a characteristic feature in rheophytes, was not differentiated between the two lineages in R. indicum. The morphological similarity between the two heterogeneous lineages may be a result of parallel evolution from R. kaempferi or of introgressive hybridization between the species due to strong selective pressure imposed by flooding. PMID- 29479061 TI - Once-weekly carfilzomib, pomalidomide, and low-dose dexamethasone for relapsed/refractory myeloma: a phase I/II study. PMID- 29479060 TI - A GABAergic cell type in the lateral habenula links hypothalamic homeostatic and midbrain motivation circuits with sex steroid signaling. AB - The lateral habenula (LHb) has a key role in integrating a variety of neural circuits associated with reward and aversive behaviors. There is limited information about how the different cell types and neuronal circuits within the LHb coordinate physiological and motivational states. Here, we report a cell type in the medial division of the LHb (LHbM) in male rats that is distinguished by: (1) a molecular signature for GABAergic neurotransmission (Slc32a1/VGAT) and estrogen receptor (Esr1/ERalpha) expression, at both mRNA and protein levels, as well as the mRNA for vesicular glutamate transporter Slc17a6/VGLUT2, which we term the GABAergic estrogen-receptive neuron (GERN); (2) its axonal projection patterns, identified by in vivo juxtacellular labeling, to both local LHb and to midbrain modulatory systems; and (3) its somatic expression of receptors for vasopressin, serotonin and dopamine, and mRNA for orexin receptor 2. This cell type is anatomically located to receive afferents from midbrain reward (dopamine and serotonin) and hypothalamic water and energy homeostasis (vasopressin and orexin) circuits. These afferents shared the expression of estrogen synthase (aromatase) and VGLUT2, both in their somata and axon terminals. We demonstrate dynamic changes in LHbM VGAT+ cell density, dependent upon gonadal functional status, that closely correlate with motivational behavior in response to predator and forced swim stressors. The findings suggest that the homeostasis and reward related glutamatergic convergent projecting pathways to LHbMC employ a localized neurosteroid signaling mechanism via axonal expression of aromatase, to act as a switch for GERN excitation/inhibition output prevalence, influencing depressive or motivated behavior. PMID- 29479063 TI - High PIM1 expression is a biomarker of T-cell acute lymphoblastic leukemia with JAK/STAT activation or t(6;7)(p21;q34)/TRB@-PIM1 rearrangement. PMID- 29479062 TI - Distinct roles for phosphoinositide 3-kinases gamma and delta in malignant B cell migration. AB - The PI 3-kinases (PI3K) are essential mediators of chemokine receptor signaling necessary for migration of chronic lymphocytic leukemia (CLL) cells and their interaction with tissue-resident stromal cells. While the PI3Kdelta-specific inhibitor idelalisib shows efficacy in treatment of CLL and other B cell malignancies, the function of PI3Kgamma has not been extensively studied in B cells. Here, we assess whether PI3Kgamma has non-redundant functions in CLL migration and adhesion to stromal cells. We observed that pharmaceutical PI3Kgamma inhibition with CZC24832 significantly impaired CLL cell migration, while dual PI3Kdelta/gamma inhibitor duvelisib had a greater impact than single isoform-selective inhibitors. Knockdown of PI3Kgamma reduced migration of CLL cells and cell lines. Expression of the PI3Kgamma subunits increased in CLL cells in response to CD40L/IL-4, whereas BCR cross-linking had no effect. Overexpression of PI3Kgamma subunits enhanced cell migration in response to SDF1alpha/CXCL12, with the strongest effect observed within ZAP70 + CLL samples. Microscopic tracking of cell migration within chemokine gradients revealed that PI3Kgamma functions in gradient sensing and impacts cell morphology and F-actin polarization. PI3Kgamma inhibition also reduced CLL adhesion to stromal cells to a similar extent as idelalisib. These findings provide the first evidence that PI3Kgamma has unique functions in malignant B cells. PMID- 29479064 TI - miR-34c-5p promotes eradication of acute myeloid leukemia stem cells by inducing senescence through selective RAB27B targeting to inhibit exosome shedding. AB - Leukemia stem cells (LSCs) are responsible for acute myeloid leukemia (AML) chemotherapy resistance and relapse. Here, we discovered that miR-34c-5p, a microRNA central to the senescence regulation network, was significantly down regulated in AML (non-acute promyelocytic leukemia, non-APL) stem cells compared to that in normal hematopoietic stem cells (HSCs). The lower expression of miR 34c-5p in LSCs was closely correlated to the adverse prognosis and poor responses to therapy of AML patients. Increased miR-34c-5p expression induced LSCs senescence ex vivo, prevented leukemia development and promoted the eradication of LSCs in immune deficient mice. Mechanistically, forced expression of miR-34-5p induced senescence in LSCs through p53-p21Cip1-Cyclin-dependent kinase (CDK)/Cyclin or p53-independent CDK/Cyclin pathways. Exosome-mediated transfer of miR-34c-5p was one of the reasons for miR-34c-5p deficiency in LSCs. Furthermore, miR-34c-5p could increase its intracellular level by inhibiting exosome-mediated transfer via a positive feedback loop through RAB27B, a molecule that promotes exosome shedding. Overall, this study establishes a new strategy for treatment of AML patients by targeting LSCs to reinitiate senescence via increased miR-34c-5p expression. This miRNA-mediated tumor stem cell senescence could also have important therapeutic value in other malignancies. PMID- 29479066 TI - Utx loss causes myeloid transformation. AB - Recurrent somatic loss-of-function mutations in histone demethylases are frequently detected in cancer. However, whether loss of a histone demethylase can cause cancer has not been determined. Here, we report that knockout of the histone demethylase Utx in mice causes a chronic myelomonocytic leukemia (CMML) like disease with splenomegaly, monocytosis, and extramedullary hematopoiesis. Mutational analysis of patient data indicated that UTX mutations occur simultaneously with TP53 mutations in myeloid malignancies, and combined inactivation of Utx and Trp53 accelerated the development of CMML in a cell autonomous manner. Utx loss caused increased self-renewal of hematopoietic stem cells and predisposed hematopoietic stem cells to differentiate into myeloid derived lineages. Transcriptome and chromatin immunoprecipitation analyses revealed that Utx activates key transcriptional factors required for erythroid differentiation by modulating histone H3 lysine 27 and lysine 4 trimethylation. Our results suggest that Utx suppresses CMML formation by controlling hematopoietic stem cell self-renewal and differentiation. PMID- 29479065 TI - PI3K orchestration of the in vivo persistence of chimeric antigen receptor modified T cells. AB - In vivo persistence of chimeric antigen receptor (CAR)-modified T cells correlates with therapeutic efficacy, yet CAR-specific factors that support persistence are not well resolved. Using a CD33-specific CAR in an acute myeloid leukemia (AML) model, we show how CAR expression alters T cell differentiation in a ligand independent manner. Ex vivo expanded CAR-T cells demonstrated decreased naive and stem memory populations and increased effector subsets relative to vector-transduced control cells. This was associated with reduced in vivo persistence. Decreased persistence was not due to specificity or tumor presence, but to pre-transfer tonic signaling through the CAR CD3zeta ITAMs. We identified activation of the PI3K pathway in CD33 CAR-T cells as responsible. Treatment with a PI3K inhibitor modulated the differentiation program of CAR-T cells, preserved a less differentiated state without affecting T cell expansion, and improved in vivo persistence and reduced tumor burden. These results resolve mechanisms by which tonic signaling of CAR-T cells modulates their fate, and identifies a novel pharmacologic approach to enhance the durability of CAR-T cells for immunotherapy. PMID- 29479067 TI - Sustained long-lasting responses after lenalidomide discontinuation in patients with chronic lymphocytic leukemia. PMID- 29479068 TI - Mutational profiling of isolated myeloid sarcomas and utility of serum 2HG as biomarker of IDH1/2 mutations. PMID- 29479069 TI - Detection of recurrent and of novel fusion transcripts in myeloid malignancies by targeted RNA sequencing. PMID- 29479070 TI - Defining therapy goals for major molecular remission in chronic myeloid leukemia: results of the randomized CML Study IV. AB - Major molecular remission (MMR) is an important therapy goal in chronic myeloid leukemia (CML). So far, MMR is not a failure criterion according to ELN management recommendation leading to uncertainties when to change therapy in CML patients not reaching MMR after 12 months. At monthly landmarks, for different molecular remission status Hazard ratios (HR) were estimated for patients registered to CML study IV who were divided in a learning and a validation sample. The minimum HR for MMR was found at 2.5 years with 0.28 (compared to patients without remission). In the validation sample, a significant advantage for progression-free survival (PFS) for patients in MMR could be detected (p value 0.007). The optimal time to predict PFS in patients with MMR could be validated in an independent sample at 2.5 years. With our model we provide a suggestion when to define lack of MMR as therapy failure and thus treatment change should be considered. The optimal response time for 1% BCR-ABL at about 12 15 months was confirmed and for deep molecular remission no specific time point was detected. Nevertheless, it was demonstrated that the earlier the MMR is achieved the higher is the chance to attain deep molecular response later. PMID- 29479073 TI - Microbiome: Principles of microbiota engraftment. PMID- 29479074 TI - Cellular microbiology: Lysozyme protects bacteria from beta-lactams. PMID- 29479071 TI - Genetic variation in Aquaporin-4 moderates the relationship between sleep and brain Abeta-amyloid burden. AB - The glymphatic system is postulated to be a mechanism of brain Abeta-amyloid clearance and to be most effective during sleep. Ablation of the astrocytic end feet expressed water-channel protein, Aquaporin-4, in mice, results in impairment of this clearance mechanism and increased brain Abeta-amyloid deposition, suggesting that Aquaporin-4 plays a pivotal role in glymphatic function. Currently there is a paucity of literature regarding the impact of AQP4 genetic variation on sleep, brain Abeta-amyloid burden and their relationship to each other in humans. To address this a cross-sectional observational study was undertaken in cognitively normal older adults from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Genetic variants in AQP4 were investigated with respect to self-reported Pittsburgh Sleep Quality Index sleep parameters, positron emission tomography derived brain Abeta-amyloid burden and whether these genetic variants moderated the sleep-Abeta-amyloid burden relationship. One AQP4 variant, rs72878776, was associated with poorer overall sleep quality, while several SNPs moderated the effect of sleep latency (rs491148, rs9951307, rs7135406, rs3875089, rs151246) and duration (rs72878776, rs491148 and rs2339214) on brain Abeta-amyloid burden. This study suggests that AQP4 genetic variation moderates the relationship between sleep and brain Abeta-amyloid burden, which adds weight to the proposed glymphatic system being a potential Abeta-amyloid clearance mechanism and suggests that AQP4 genetic variation may impair this function. Further, AQP4 genetic variation should be considered when interpreting sleep-Abeta relationships. PMID- 29479075 TI - Antimicrobials: Breaking ground for new antibiotics. PMID- 29479072 TI - The spread and evolution of rabies virus: conquering new frontiers. AB - Rabies is a lethal zoonotic disease that is caused by lyssaviruses, most often rabies virus. Despite control efforts, sporadic outbreaks in wildlife populations are largely unpredictable, underscoring our incomplete knowledge of what governs viral transmission and spread in reservoir hosts. Furthermore, the evolutionary history of rabies virus and related lyssaviruses remains largely unclear. Robust surveillance efforts combined with diagnostics and disease modelling are now providing insights into the epidemiology and evolution of rabies virus. The immune status of the host, the nature of exposure and strain differences all clearly influence infection and transmission dynamics. In this Review, we focus on rabies virus infections in the wildlife and synthesize current knowledge in the rapidly advancing fields of rabies virus epidemiology and evolution, and advocate for multidisciplinary approaches to advance our understanding of this disease. PMID- 29479076 TI - Viral infection: CRISPR-Cas enhances HGT by transduction. PMID- 29479078 TI - Correction: The absence that makes the difference: choroidal abnormalities in Legius syndrome. AB - Correction to: Journal of Human Genetics advance online publication 27 July 2017; https://doi.org/10.1038/jhg.2017.78. PMID- 29479080 TI - Hypertension: CLCN2 chloride channel mutations in primary aldosteronism. PMID- 29479081 TI - Hypertension: Role of C3aR and C5aR in Treg cells. PMID- 29479079 TI - Environmental pollution and kidney diseases. AB - The burden of disease and death attributable to environmental pollution is becoming a public health challenge worldwide, especially in developing countries. The kidney is vulnerable to environmental pollutants because most environmental toxins are concentrated by the kidney during filtration. Given the high mortality and morbidity of kidney disease, environmental risk factors and their effect on kidney disease need to be identified. In this Review, we highlight epidemiological evidence for the association between kidney disease and environmental pollutants, including air pollution, heavy metal pollution and other environmental risk factors. We discuss the potential biological mechanisms that link exposure to environmental pollutants to kidney damage and emphasize the contribution of environmental pollution to kidney disease. Regulatory efforts should be made to control environmental pollution and limit individual exposure to preventable or avoidable environmental risk. Population studies with accurate quantification of environmental exposure in polluted regions, particularly in developing countries, might aid our understanding of the dose-response relationship between pollutants and kidney diseases. PMID- 29479077 TI - Pseudomonas syringae: what it takes to be a pathogen. AB - Pseudomonas syringae is one of the best-studied plant pathogens and serves as a model for understanding host-microorganism interactions, bacterial virulence mechanisms and host adaptation of pathogens as well as microbial evolution, ecology and epidemiology. Comparative genomic studies have identified key genomic features that contribute to P. syringae virulence. P. syringae has evolved two main virulence strategies: suppression of host immunity and creation of an aqueous apoplast to form its niche in the phyllosphere. In addition, external environmental conditions such as humidity profoundly influence infection. P. syringae may serve as an excellent model to understand virulence and also of how pathogenic microorganisms integrate environmental conditions and plant microbiota to become ecologically robust and diverse pathogens of the plant kingdom. PMID- 29479083 TI - Gene expression: Developmental enhancers in action. PMID- 29479082 TI - Integrative omics for health and disease. AB - Advances in omics technologies - such as genomics, transcriptomics, proteomics and metabolomics - have begun to enable personalized medicine at an extraordinarily detailed molecular level. Individually, these technologies have contributed medical advances that have begun to enter clinical practice. However, each technology individually cannot capture the entire biological complexity of most human diseases. Integration of multiple technologies has emerged as an approach to provide a more comprehensive view of biology and disease. In this Review, we discuss the potential for combining diverse types of data and the utility of this approach in human health and disease. We provide examples of data integration to understand, diagnose and inform treatment of diseases, including rare and common diseases as well as cancer and transplant biology. Finally, we discuss technical and other challenges to clinical implementation of integrative omics. PMID- 29479085 TI - Humanitarian crisis in the National Health Service of United Kingdom. PMID- 29479086 TI - Assessment of severity of acute gastroenteritis in the paediatric Pakistani population by Modified Vesikari Score. AB - OBJECTIVE: To assess the severity of acute gastroenteritis in paediatric population. METHODS: This observational cross-sectional study was conducted at 93 randomly selected outpatient centres with paediatric practice across Pakistan between July 2014 and January 2015, involving children between 3 to 48 months of age suffering from acute gastroenteritis. The severity of acute gastroenteritis was measured using Modified Vesikari Score. SPSS 18 was used for data analysis. RESULTS: There were 1,756subjects having a mean age of 18.6+/-12.0 months. There were 220(12.52%) children ?6 months out of whom 73(33%) were exclusively breastfed. Most children had moderate 1,041(59.3%) and severe 403(22.9%) acute gastroenteritis. Overall 1,401(79.8%) carers were females, of whom 1,080(77.1%) were mothers with a mean age of 29.7+/-6.7 years. Oral rehydration solution 1,357(77.3%), plain water 1,083(61.7%), antipyretics 783(44.6%) and anti diarrhoeals 645(36.7%) were most common medicines administered at home by the carers. Mean duration between gastroenteritis onset and seeking consultation was 2.7+/-1.7 days. Most common treatment provided by physicians were oral rehydration solution 1,451(82.6%), antibiotic 1,294(73.7%) and probiotic 1,105(62.9%). Worsening of symptoms 1,152(65.6%) was the most common reason for seeking consultation. CONCLUSIONS: Most children assessed with acute gastroenteritis showed moderate to severe disease symptoms.|. PMID- 29479087 TI - Risk factors and molecular epidemiology of HBV and HCV in internally displaced persons (IDPs) of North Waziristan Agency, Pakistan. AB - OBJECTIVE: To investigate the prevalence and transmission risks of hepatitis B virus and hepatitis C virus infections among internally displaced persons. METHODS: This study was conducted in district Bannu, Khyber Pakhtunkhwa, Pakistan, from August 2014 to April 2015, and comprised internally displaced people from North Waziristan Agency residing in camps or settled in towns. Potential subjects were initially screened through immunochromatographic test devices. Samples detected positive were confirmed through enzyme-linked immunosorbent assay. Confirmation of the presence of viral nucleic acids and genotyping was done via real-time polymerase chain reaction. SPSS 21 was used for data analysis. RESULTS: Of the 1,000 participants, 570(57%) were males and 430(43%) females. Seroprevalence of hepatitis B virus among the participants was 45(4.5%) and hepatitis C virus was 52(5.2%). Viral nucleic acids were present in 41(4.1%) participants in case of hepatitis B virus and 39(3.9%) in case of hepatitis C virus. No co-infection with both of these viruses was found. Dominant hepatitis B virus and hepatitis C virus genotypes were genotype-D 19(46.3%) and 3a with 20(51.2%), respectively. CONCLUSIONS: High prevalence of hepatitis B and C virus infections was found among internally displaced people. PMID- 29479088 TI - Short term outcomes following surgery in brain tumours sans neuronavigation. AB - OBJECTIVE: To determine the presentation and frequency of various intracranial neoplasms and assess outcomes for patients who underwent surgery without neuronavigation. METHODS: This retrospective study was conducted at Combined Military Hospital, Peshawar, Pakistan, and comprised medical records related to the period from August 2011 to July 2014. Patient histories, examination reports and preoperative and post-operative radiological scans were reviewed and extent of excision was determined based on these coupled with recurrence rates. Intraoperatively, tumour excision was determined largely by the experience of the surgeon and preoperative planning using bony landmarks and radiological scans as an objective guide to resection. SPSS 21 was used for data analysis. RESULTS: Of the 143 patients, 83(57.9%) were males and 60(42.1%)were females. Gliomas were the most common tumours, occurring in 20(33.3%) females and 35(42.2%) males. One year survival rate for grade 4 astrocytomas was poor (39.4%) and was excellent for meningiomas (100%) and pituitary tumours (100%). CONCLUSIONS: Time-tested methods of careful neurological examination and knowledge of neuroanatomy can allow a surgeon with limited resources to plan and accommodate for accurate tumour resection with adequate margins. PMID- 29479089 TI - Characterisation of breeding sites of anopheline mosquitoes in District Bannu, KPK, Pakistan. AB - OBJECTIVE: To highlight the role of habitat evaluation in reducing the potential transmission risk of malaria. METHODS: This study was conducted from January to June, 2015, in District Bannu in Khyber Pakhtunkhwa, Pakistan, where 64 larval habitats were characterised in 10 villages of the district. The larvae habitat features, like its permanent or temporary nature, artificial or natural, basic type, substrate type and vegetation, anopheline and culicine larval presence and density, were noted. ArcGIS 9.2 was used to map the mosquitoe breeding sites. Data was analysed related to the effect of temperature, rainfall and relative humidity on larval occurrence and density.. RESULTS: Of the 64 breeding habitats characterised, 26(40.6%) were temporary, while the remaining 38(59.4%) were permanent. Anopheline larvae were found in different types of habitats and occurred in man-made and temporary habitats with high population density. The marshlands (rice fields, sugarcane and open drains) were positive for anopheline larvae. The climatic factors like rain and humidity positively affected the larval density. The larval density was high in March and April at temperatures ranging from 16.1Co-23.45oC. CONCLUSIONS: Targeting the man-made and temporary larval habitats could results in the effective anopheline mosquitoes larvae control. PMID- 29479090 TI - MRA-based evaluation of anatomical variation of circle of Willis in adult Pakistanis. AB - OBJECTIVE: To determine the frequency and patterns of normal anatomical variation of Circle of Willis on magnetic resonance angiogram in adults without cerebrovascular disease. METHODS: This descriptive cross-sectional study was conducted at the Radiology Department of Dow University of Health Sciences / Civil Hospital, Karachi, from January to December 2016, and comprised patients referred for magnetic resonance imaging of the brain and magnetic resonance angiogram without any clinical or radiological manifestation of cerebrovascular disease, primarily including those with suspected demyelination, infection, epilepsy or metastases. Three-dimensional time-of-flight magnetic resonance angiography was performed. The Circle of Willis was assessed for its completeness along with anatomical variations of anterior and posterior components of the circle. RESULTS: Of the 135 subjects, 70(51.8%) were males and 65(48.2%) were females with an overall mean age of 49.26+/-9.2 years. Among all the subjects, 30(22.2%) showed a complete circle, while 82 (60.7%) and 23(17.1%) had partially complete and incomplete circles respectively. The anterior part of the circle was completed in 108 (80%) subjects, showing type 'a' as the most common variant in 93(68.9%). The posterior part of the circle was completed in 30 (22.2%) subjects with type 'e' variant in 52(38.5%). CONCLUSIONS: There was a wide variability in the anatomy of the Circle of Willis in Pakistani adults asymptomatic for cerebrovascular disease. PMID- 29479092 TI - Self-reported academic performance in relation to health behaviours among Bahria University students. AB - OBJECTIVE: To find an association between self-reported academic performance with different socio-demographic factors, health behaviours and mental health amongst university students. METHODS: This cross-sectional study was conducted at Bahria University, Karachi, from January 2012 to December 2013, and comprised university students of different disciplines. An anonymous, self-reported questionnaire was distributed among the subjects. Convenient sampling technique was used. Demographic information, including age, gender and field of study, were obtained. Depresion was evaluated via Centre for Epidemiological Studies Depression Scale. SPSS 22 was used to analyse data. RESULTS: Of the 813 respondents, 334(41.1%) were males and 479(58.9%) females. The mean age was 19.9+/-1.8 years. Overall, 126(15.5%) subjects reported excellent, 242(29.8%) very good, 310(38.1%) good, 100(12.3%) satisfactory and 35(4.3%) not satisfactory academic performance. Residential status of students played a significant role on their academic performance (p=0.011). Breakfast eating behaviour depicted a significant association with the academic performance (p=0.04).The proportion of unsatisfactory academic performances among students having severe sleep disorder was the highest, followed by mild/moderate (p=0.01). The depression scale's item 'troubling in mind' was highly associated with academic performance (p<0.05). CONCLUSIONS: A constructive association existed among healthy behaviours and academic performance. . PMID- 29479091 TI - Outbreak investigation report of dengue fever during June-November 2014: A case study of district Swat, Pakistan. AB - OBJECTIVE: To determine the frequency distribution of dengue fever during the 2014 outbreak in a district in northern Pakistan. METHODS: This cross-sectional study was conducted between June and November, 2014, at Saidu Sharif Teaching Hospital, Swat, Pakistan, where patients were screened for dengue virus non structural protein using Dengue Duo strips from Standard Diagnostics (SD). Data was obtained from patient's record, filled forms and through questionnaire. RESULTS: Of the total 812 patients, 290(35.71%) tested positive for dengue virus non-structural protein, of whom 175(60.34%) were males and 115(39.66%) were females. Overall, 146(50.34%), cases were recorded in the 16-30 age group, while 7(2.41%) were reported in those aged >60 years. The highest numbers of cases were recorded from Faizabad 84(28.96%), whereas the lowest numbers of cases 42(14.48%) were reported from Sethi Amankot. CONCLUSIONS: Dengue virus affected male individuals more compared to female. The affected areas had poor drainage and water storage system. PMID- 29479084 TI - Stretching the limits: from homeostasis to stem cell plasticity in wound healing and cancer. AB - Stem cells (SCs) govern tissue homeostasis and wound repair. They reside within niches, the special microenvironments within tissues that control SC lineage outputs. Upon injury or stress, new signals emanating from damaged tissue can divert nearby cells into adopting behaviours that are not part of their homeostatic repertoire. This behaviour, known as SC plasticity, typically resolves as wounds heal. However, in cancer, it can endure. Recent studies have yielded insights into the orchestrators of maintenance and lineage commitment for SCs belonging to three mammalian tissues: the haematopoietic system, the skin epithelium and the intestinal epithelium. We delineate the multifactorial determinants and general principles underlying the remarkable facets of SC plasticity, which lend promise for regenerative medicine and cancer therapeutics. PMID- 29479093 TI - Development, validity and reliability of an URDU version of the International Prostate Symptom Score. AB - OBJECTIVE: To develop and validate the Urdu version of the International Prostate Symptoms Score. METHODS: The prospective study was conducted at Indus Hospital, Karachi, from January to April 2014, and comprised interviews of subjects at baseline and at 2 weeks for assessing the test-retest reliability. Patients presenting with lower urinary track symptoms and who were able to read Urdu were recruited as subjects. The reliability of the Urdu version of the International Prostate Symptoms Score was assessed by determining the internal consistency, and by assessing the test-retest reliability. RESULTS: There were 58 subjects with a mean age of 61.53+/-9.99 years. There was no statistically significant difference in self-administered and assister filling total score (p=0.145) and quality of life (p=0.201). For reliability analysis, Cronbach's alpha coefficient was 0.756 total score and 0.622 for quality of life. CONCLUSIONS: The Urdu version of the International Prostate Symptoms Score stood validated for assessing lower urinary track symptoms. PMID- 29479094 TI - Association between environmental tobacco smoke and dental caries amongst 5-14 years old children in Karachi, Pakistan. AB - OBJECTIVE: To determine the association between environmental tobacco smoke and dental caries. METHODS: This cross-sectional study was conducted in peri-urban and urban areas of Karachi, from February to August 2014, and comprised children aged 5-14 years. A pre-coded questionnaire for environmental tobacco smoke and food frequency questionnaire for dietary habits were used. Dental examination of children was done to detect caries. Cox-proportional hazard algorithm was used to measure the association of environmental tobacco smoke with dental caries at multivariable level. STATA version 12.0 was used for statistical analysis. RESULTS: Of the 500 children, 250(50%) each were from peri-urban and urban localities. The prevalence of dental caries was 336(67.2%).Family members of 154(30.8%) participants reported smoking. After adjusting for junk food intake, in-between meals, age, plaque index, dental visits and socio-economic status, the association between environmental tobacco smoke and dental caries remained statistically significant (p<0.05). Compared to non-exposed children, the adjusted prevalence ratio was 1.25 (95% confidence interval: 1.08-1.46) and 1.36 (95% confidence interval: 1.09-1.70) for children with < 30 minutes and >30 minutes of environmental tobacco smoke exposure, respectively. CONCLUSIONS: Environmental tobacco smoke was found to be associated with dental caries. PMID- 29479095 TI - Determination of the life quality and self-care ability of the mothers in post partum period. AB - OBJECTIVE: To determine the life quality and self-care ability of mothers in the post-partum period. . METHODS: This descriptive study was conducted at a family health centre based in Kars Province of Turkey from May to September 2015, and comprised mothers who were in the post-partum period. Personal information form, maternal post-partum quality of life questionnaire and self-care ability scale were used to collect data. SPSS was used for data analysis. RESULTS: There were 290 participants with a mean age of 26.81+/-6.21 years (range: 16-45 years). Mean scores for sub-dimensions in the maternal post-partum quality of life questionnaire were recorded at 19.00+/-6.23 for affinity/family/friend, 21.05+/ 6.10 for socio-economic, 20.79+/-5.97 for spouse, 20.56+/-6.23 for health, and 19.86+/-6.21 for psychological/baby. The total maternal post-partum quality of life mean score was 20.17+/-5.51. The mean score for the self-care ability scale was 84.56+/-21.39. CONCLUSIONS: The self-care ability and post-partum life quality were substantially affected by educational status, economic condition, family type and post-partum week. PMID- 29479096 TI - Perceptions of nursing students of educational environment at a private undergraduate School of Nursing in Karachi. AB - OBJECTIVE: To assess educational environment at a nursing school.. METHODS: The cross-sectional survey was carried out from May to October 2016 at Aga Khan University School of Nursing and Midwifery, Karachi, using the Dundee Ready Educational Environment Measure tool. The scores were obtained by merging five sub-scales of the inventory. The average scores of the scale and sub-scales were compared in terms of age, year of study, and living status using Mann-Whitney U test, and among years of study by Kruskal Wallis test.. RESULTS: Of the 442 students, 228(51.6%) had age below 20 years. Overall, 131(29.1%) subjects were in the first year, 152(33.8%) second year, 91(20.2%) third year and 76(16.9%) fourth year. The average Dundee Ready Educational Environment Measure score was 129.92+/ 19.97 with reliability of 88.9%. Students aged 20 years and less had more positive perceptions than students over 20 years (p<0.0001). Students living in hostel secured higher scores (p<0.0001). First year nursing students attained significant highest scores in all sub-scales compared to the rest (p<0.0001). CONCLUSIONS: Scores reveal better perception from younger nursing students, as well as those living in the hostel and those who were in their initial years of nursing education. PMID- 29479097 TI - Association of TP53 codon 72 polymorphism in women suffering from endometriosis from Lahore, Pakistan. AB - OBJECTIVE: To investigate TP53 gene codon 72 polymorphism in women with endometriosis and compare it with healthy samples. METHODS: This case-control study was carried out at Jinnah Hospital, Services Hospital and Sheikh Zayed Hospital, Lahore, Pakistan, from 2014 to 2016, and comprised patients with endometriosis and healthy controls. SPSS 21 was used for statistical analysis. RESULTS: Of the 176 participants, 88(50%) were healthy controls and 88(50%) were endometriosis patients. The observed genotype frequencies for controls and patients were 14(15.9%) and 31(35.3%) for proline/proline, 46(52.3%) and 35(39.8%) for proline/arginine, and 28(31.8%) and 22(25%) for arginine/arginine, respectively. The association of different genotypes was not significant in patients with moderate-to-severe endometriosis (p=0.574). The presence of pro/pro genotype enhanced the chances/odds of getting the disease (p<0.05). However, the risk further increased with the advancement of age, particularly in the 27-46 age group (p<0.05). CONCLUSIONS: In Pakistani women the association of TP53 gene codon 72 arginine/proline polymorphism was present.. PMID- 29479098 TI - Frequency of obsessive compulsive symptoms in depression: A hospital-based cross sectional study. AB - OBJECTIVE: To determine the frequency of obsessive compulsive symptoms in patients suffering from depression. METHODS: This cross-sectional study was conducted at the Allama Iqbal Memorial Teaching, Sialkot, Pakistan, from February 2014 to March 2017, and comprised patients suffering from depression. Every patient was examined by a consultant psychiatrist or a senior medical officer in psychiatry, and a psychologist to establish clinical diagnosis of depression according to the tenth revision of the International Statistical Classification of Diseases and Related Health Problems. Adult patients suffering from depression were included. Patients with severe physical illnesses, other psychiatric illnesses, current, past or family history of obsessive compulsive disorder and drug abuse were excluded. Beck Depression Inventory and Yale Brown Obsessive Compulsive Scale were also administered. Data was analysed using SPSS 21. RESULTS: Of the 5,127 patients, 2,318(45.21%) were males and 2,809(54.79%) females. The mean age of the male and female patients was 35.17+/-12.39 years (range: 18-73 years) and 33.67+/-13.27 years (range: 18-70 years), respectively. Besides, 1,991(38.83%) patients had moderate depression, 1,647(32.13%) had mild depression and 1,489(29.04%) had severe depression. Moreover, 1,673(32.63%) patients had obsessive compulsive symptoms, including 497(29.70%) patients with mild depression, 599(35.80%) with moderate depression and 577(34.49%) with severe depression. CONCLUSIONS: Around one-third participants had obsessive compulsive symptoms. PMID- 29479099 TI - A new management strategy for the treatment of streptococcal gingivitis: A pilot study. AB - OBJECTIVE: To demonstrate a supportive treatment option based on microorganism's growth characteristics. METHODS: This study was conducted at Ordu University, Faculty of Dentistry, Turkey, between January and April, 2017, comprising patients whose periodontal parameters and saliva pH scores were measured before and after the treatments. The patients were divided into two equal groups. Group I underwent routine periodontal treatment methods for streptococcal gingivitis, while a supportive treatment that involved an antacid chewing tablet two times a day for a week based on the microorganism's growth characteristics was used on patients in Group II. SPSS 11.5 was used for data analysis. RESULTS: There were 16 patients in the study with an average age of 27.90+/-5.54 years. The periodontal index values progressively decreased for all patients post-treatment. However, the decrease of gingival index values in Group I was significantly higher than Group II (p<0.05). The decrease in the oral pH was statistically significant after the periodontal treatment procedures with supportive method (p<0.001). CONCLUSIONS: The use of antacids in addition to conventional periodontal treatment may be effective in the treatment of oral streptococcal infections.. PMID- 29479100 TI - Evaluation of effectiveness of a paediatric simulation course in procedural skills for paediatric residents - A pilot study. AB - OBJECTIVE: To explore the effects of simulation training on paediatric residents' confidence and skills in managing advanced skills in critical care. METHODS: The study was conducted at Alfaisal University, Riyadh, Saudi Arabia, from March to June 2016, and comprised junior residents in paediatrics. All paediatric residents (years 1 and 2) were recruited into two workshops, held one week apart. The first workshop covered lumbar puncture/ cerebrospinal fluid interpretation, oral intubation, bone marrow aspiration, and critical airway management. The second workshop covered chest tube insertion, pleural tap, insertion of central line, and arthrocentesis. The participants were surveyed using a 5-point Likert scale survey pre- and post-course, assessing their confidence. Their practical skills were assessed using a pre-objective structured clinical examination on the same day and post-course objective structured clinical examination a week later on selected skills. The outcome measures were: (1) pre-/post-course confidence rating, and (2) pre-/post-course objective structured clinical examination results. Data was analysed using SPSS 20. RESULTS: Of the 16 participants, 8(50%) were boys and 8(50%) girls. Besides, 13(81%) residents were in year-1 and 3(19%) in year-2. Median post-course confidence level ranks for all the skills were higher (p<0.05). There was no improvement in mean pre-objective structured clinical examination scores (2.31+/-2.66/ 7.46+/-3.02) and post- objective structured clinical examination scores (22.54+/-4.39/ 31.85+/-6.90) in Year 1 residents (p<0.001). CONCLUSIONS: Simulation course was significantly successful in improving residents' clinical skills and confidence in performing critical tasks. PMID- 29479101 TI - The awareness of childhood autism among residents of neuropsychiatric and other disciplines of a research and training hospital in Istanbul, Turkey. AB - OBJECTIVE: To assess the awareness of childhood autism among physicians undergoing residency training in various disciplines. METHODS: This cross sectional study was conducted at a research and training hospital in Istanbul, Turkey, in February 2013 and comprised physicians undergoing residency training in various disciplines. Data was collected through a self-administered questionnaire. Questions about "awareness on autism" were prepared in the light of "Knowledge about Childhood Autism among Health Workers questionnaire. RESULTS: Of the 128 physicians, 122(95.3%) were aware that the most known characteristic of childhood autism was "failure to build-up friendship". All of the 29(22.66%) physicians at the neuropsychiatric disciplines were aware that "autism can be a genetic disorder", whereas, in other disciplines 69(69.7) physicians had that awareness. Besides, 15(51.7%) of the residents of the neuropsychiatric disciplines thought that "autism can be associated with childhood epilepsy", while 32(32.3%) physicians of other disciplines gave a similar answer (p=0.057). CONCLUSIONS: The awareness on childhood autism of residents belonging to the non- neuropsychiatric disciplines was moderate. PMID- 29479102 TI - Chikungunya virus; an emerging arbovirus in Pakistan. AB - Chikungunya virus (CHIKV), an arbovirus belongs to the family Togaviridae and was discovered in Tanzania in year 953-54. In November 2016, an outbreak occurred in Karachi and approximately 30,000 individuals were infected with CHIKV. More than 4,000 cases were confirmed by qualitative reverse transcriptase polymerase chain reaction. However, actual numbers of cases are expected to rise. For the diagnosis of chikungunya virus, several methods including viral culture, detection of viral antigen, anti-CHIKV immunoglobulin M, immunoglobulin G antibodies and viral nucleic acid can be used. The recommended therapies include use of analgesics, antipyretic, anti-inflammatory medications like paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs). In severe cases, where NSAIDs are not effective, disease modifying anti-rheumatic drugs (DMARDs) can also be used. For prevention, mosquito nets and mosquito repellents are vital and must therefore be used effectively. PMID- 29479103 TI - Robotics in neurosurgery: A literature review. AB - Robotic surgery has been the forte of minimally invasive stereo-tactic procedures for some decades now. Ongoing advancements and evolutionary developments require substantial evidence to build the consensus about its efficacy in the field of neurosurgery. Main obstacle in obtaining successful results in neurosurgery is fine neural structures and other anatomical limitations. Currently, human rationalisation and robotic precision works in symbiosis to provide improved results. We reviewed the current data about recent interventions. Robots are capable of providing virtual data, superior spatial resolution and geometric accuracy, superior dexterity, faster manoeuvring and non-fatigability with steady motion. Robotic surgery also allows simulation of virtual procedures which turn out to be of great succour for young apprentice surgeons to practise their surgical skills in a safe environment. It also allows senior professionals to rehearse difficult cases before involving into considerable risky procedures. PMID- 29479104 TI - Radiation absorbed dose for cobalt-60 gamma source in phantoms for different materials. AB - Current practices in radiation therapy required high doses of radiation to be delivered with increased accuracy. Treatment planning task is exercised till an optimum dose distribution is achieved. The present reported work was performed to compare the various aspects of the cobalt-60 radiation beam therapy with fixed source-surface distance 70cm incident normally. This study was conducted in May 2012 at the Department of Radiation Physics of MD Anderson Cancer Centre, University of Texas, Houston, United States. Radiation doses were calculated in a solid phantom as well as in water phantom at different square field sizes and depths. It was noted that the rate of absorbed dose increased with the increase in the field size and decreased with the increase in depths. The rate of absorbed dose was found to be directly proportional to the increase in the square field size and inversely proportional to the increase in depth. Moreover, the solid phantom demonstrated more absorbed doses as compared to the water phantom. PMID- 29479105 TI - Prognostic significance of optic nerve sheath diameter on computed tomography scan with severity of blunt traumatic brain injury in the emergency department. AB - Optic nerve sheath diameter measurement (ONSD) has been associated with identifying the prognosis of traumatic brain injury (TBI) patients. The study was planned to evaluate the prognostic value of ONSD measured on the initial brain computed tomography (CT) scan performed on patients with blunt TBI in the emergency department(ED). This retrospective cross-sectional study was conducted at the Aga Khan University Hospital, Karachi, and comprised data of moderate and severe TBI patients from January to December 2014. ONSD for each eye on the initial CT scan and Glasgow Coma Scale (GCS) was measured upon patient presentation. Correlation between presentation GCS and ONSD was done through Pearson's correlation. Receiver operator curve (ROC) analysis was done to measure the predictive values of ONSD for mortality. Of the 276 patients, 211(76%) were males and 65(23%) females. ONSD was measured on 160(58%) patients. The mean ONSD measured on CT scan was 3.8+/-1. The Pearson's correlation between the severity of brain injury as per GCS at presentation and ONSD was not significant (-0.182). We concluded that ONSD measured on the initial CT brain scan had good association with the severity of blunt TBI in patients presenting to the ED. PMID- 29479106 TI - Influences on medical career choice and future medical practice plans among women: Perspective from final year students and house officers. AB - There is a growing perception in Pakistan that comparatively more women are gaining admissions and graduating from medical colleges; however these graduates are not practicing medicine. This pilot study provides perspectives on the influences on medical career choice and plans regarding future medical practice among female final-year students and house-officers in Karachi. Using convenience sampling, a study was conducted in August and September 2016, wherein out of 141 women, 95 (67.4%) were final-year medical students and 46 (32.6%) were house officers. Most of the women (n=101; 71.6%) made their own choice to become doctors, while only 18 (12.8%) were compelled by their parents. An overwhelming majority (n=131; 92.9%) planned to do house job upon graduation or complete their ongoing one. Regarding post-graduation, 124 (87.9%) participants intended to acquire post-graduate qualification. Results indicate the need for representative studies to quantify the determinants and correlates of women's choice to study and practice medicine. PMID- 29479107 TI - Self-esteem among eunuchs of Hazara Division, Pakistan. AB - Self-esteem among eunuchs is highly influenced by a variety of factors. The aim of the current study was to investigate the differences in self-esteem of eunuchs on the basis of education, income, age and marital status. The study was conducted at the University of Haripur, Pakistan, from December 2015 to November 2016. A sample of 140 eunuchs was collected from different areas of Hazara division, through purposive and snowball sampling technique. A self-esteem scale with four sub-scales was used to measure the self-esteem of eunuchs. One-way analysis of variance was used to determine education level differences. The t test was applied to find out the impact of demographics differences such as marital status, income level, and age on self-esteem of eunuchs. The scale used was found to be quite reliable with alpha coefficient of 0.85. The outcomes are significant and showed that educated, higher income, younger and unmarried eunuchs had higher self-esteem (p<0.05). PMID- 29479108 TI - The Spatial Scale and Spatial Configuration of Residential Settlement: Measuring Segregation in the Postbellum South. AB - Studies of residential segregation typically focus on its degree without questioning its scale and configuration. We study Southern cities in 1880 to emphasize the salience of these spatial dimensions. Distance-based and sequence indices can reflect spatial patterns but with some limitations, while geocoded 100% population data make possible more informative measures. One improvement is flexibility in spatial scale, ranging from adjacent buildings to whole districts of the city. Another is the ability to map patterns in fine detail. In Southern cities we find qualitatively distinct configurations that include not only black "neighborhoods" as usually imagined, but also backyard housing, alley housing, and side streets that were predominantly black. These configurations represent the sort of symbolic boundaries recognized by urban ethnographers. By mapping residential configurations and interpreting them in light of historical accounts, our intention is to capture meanings that are too often missed by quantitative studies of segregation. PMID- 29479109 TI - Improved Treatment of Nucleosides and Nucleotides in the OPLS-AA Force Field. AB - DFT calculations have been used to develop improved descriptions of the torsional energetics for nucleosides and nucleotides in the OPLS-AA force field. Scans of nucleotide dihedral angles (gamma, chi, and beta) and methyl phosphates provided the bases for the new torsional parameters. In addition, the angle-bending parameters of phosphodiesters and ribose were updated, and adjustments were made to existing carbohydrate torsions to better capture the sugar puckering landscape of ribose. MD simulations of nucleosides with the new parameters demonstrate a significant improvement in the ribose sugar puckering and chi angle distributions. Additionally, energy-minimization of protein-nucleotide crystal structures with the new parameters produced accurate poses. PMID- 29479110 TI - Unordered Monotonicity. AB - This paper defines and analyzes a new monotonicity condition for the identification of counterfactuals and treatment effects in unordered discrete choice models with multiple treatments, heterogenous agents and discrete-valued instruments. Unordered monotonicity implies and is implied by additive separability of choice of treatment equations in terms of observed and unobserved variables. These results follow from properties of binary matrices developed in this paper. We investigate conditions under which unordered monotonicity arises as a consequence of choice behavior. We characterize IV estimators of counterfactuals as solutions to discrete mixture problems. PMID- 29479111 TI - Pregnancy-associated Death - Clarifying the Cause of Death and Medico-legal Assessments in Accusations of Malpractice. AB - Background: Pregnancy-associated deaths are extremely rare in Germany. Most deaths are from natural causes, and a range of causes are possible. Method: The deaths of 22 women who died of pregnancy-associated causes and who were autopsied in the Institute of Forensic Medicine of Justus-Liebig University Giebetaen between 1992 and 2016 were analyzed. Results: The autopsy results and histological examinations for the majority of women who died of pregnancy associated causes between 1992 and 2016 showed that they had died of natural causes, although complications of pregnancy were a leading cause of death. Conclusion: The death of a pregnant woman should not automatically raise the suspicion of malpractice, although the question does arise in cases of bleeding complications only detected at very late stages. Experts must prove that a real mistake was made during treatment and provide evidence of the causality between malpractice and patient death. Particularly when well-known complications of pregnancy were present, this is only the case if poor monitoring resulted in the complication being detected too late or if treatment was not in accordance with accepted standards of care. The majority of pregnancy-associated deaths are from natural causes and the death of a pregnant woman does not mean that medical malpractice was involved, although this accusation is often levelled in cases where rupture was not immediately diagnosed or in cases of fatal postpartum hemorrhage. PMID- 29479112 TI - Help-seeking Following Termination of Pregnancy after Diagnosis of Fetal Anomaly: Women's Intentions and Experiences 1 to 7 Years after the Event. AB - Introduction: Diagnosis of fetal anomaly and the difficult circumstances involved in the decision to terminate an affected pregnancy can go along with severe psychological distress. However, little is known about women's help-seeking for emotional problems following an abortion after diagnosis of fetal anomaly. Methods: 148 women who had been treated for abortion after diagnosis of fetal anomaly at the University Hospital Leipzig responded to self-report questionnaires 1 to 7 years after the event. Main outcomes were help-seeking intentions and actual help-seeking behavior. Logistic regression was used to explore the associations between participants' sociodemographic characteristics and help-seeking intentions. Results: Most women reported that they would seek help from their partner (91.7%), friends/family (82.8%) or the internet (62.2%). With regard to health services, 50.0% of women would seek help from gynecologists and between 43.8 and 47.9% from counseling services and mental health professionals. Intentions to seek help from support groups were lowest (21.7%). Age, income, region, and religion were associated with help-seeking intentions. Among participants with elevated levels of current psychological distress, 23.8% indicated that they had not discussed their emotional problems with a health service ever. Conclusion: Gynecologists are among the most preferred health professionals for women to discuss psychological problems in the aftermath of an abortion after diagnosis of fetal anomaly. They should be actively involved in screening, diagnostic assessment, and referral of affected women. PMID- 29479113 TI - Does an Immigrant Background Affect the Indication, Incidence or Outcome of Emergency Cesarean Section? Results of the Prospective Data Collection of 111 Births. AB - Objectives: Does the incidence and/or indication(s) for emergency cesarean section differ if the pregnant woman has an immigrant background (IB)? Does a lack of language proficiency (communication problems) and a low acculturation level result in a longer decision-to-delivery interval (D-D interval)? Are neonates born to women with IB by emergency cesarean section in a poorer condition post delivery? Patient cohorts and method: Standardized interviews were carried out before or immediately after delivery in three Berlin obstetric hospitals. Questions were asked about the sociodemographic background and care aspects as well as about immigration and level of acculturation. Collected data were linked to information obtained from the expectant mother's antenatal records and to care data and perinatal data routinely recorded by the hospitals. Data was analyzed using regression models which adjusted for age, parity, and socio economic status. Results: The total patient population consisted of 7100 women (rate of response: 89.6%); of these women, 111 required emergency cesarean section (50 women without IB, 61 immigrant women). Risk factors such as late first antenatal check-up, gestational diabetes, pregnancy-induced hypertension, fetal macrosomia, smoking, and weight gain were similar in both patient cohorts. The incidence of and indications for emergency cesarean section and the D-D interval were similar for both groups. Limited German language proficiency and low levels of acculturation among immigrant women did not prolong the D-D interval. There were no statistically relevant differences between immigrant and non-immigrant cohorts with regard to adverse neonatal conditions (5-minute Apgar score <= 7, umbilical cord arterial pH < 7.00) or with regard to immediate transfer of the neonate to a pediatric clinic following emergency cesarean section. Conclusion: The factor "immigrant background" did not affect the indication or obstetric outcome following emergency cesarean section. PMID- 29479114 TI - Use of Bladder Filling to Prevent Urinary System Complications in the Management of Placenta Percreta: a Randomized Prospective Study. AB - Introduction: The aim of our study was to evaluate the effect of filling the bladder on peripartum genitourinary injuries (especially bladder complications) in women with placenta percreta and to compare patient characteristics. Material and Methods: Our prospective cohort study consisted of pregnant women with placenta percreta who underwent planned cesarean hysterectomy at the Department of Obstetrics and Gynecology of Gaziantep University Hospital between January 2015 and July 2016. Bladders were filled with 300 ml saline solution to determine surgical borders better and enable dissection of the lower uterine segment without excessive bleeding or unintended injury. Results: A total of 66 women were included in the study: 32 women whose bladders were filled during surgery (filled-bladder group) and 34 women whose bladders were not filled (not filled bladder group). Comparisons of demographic and obstetrical data, surgical parameters, the need for transfusion, and bladder injury rates revealed no significant differences between the two groups. We did not observe any beneficial effect of filling the bladder on preventing urinary complications compared with the women whose bladders were not filled (p = 0.339). Conclusions: Filling the bladder with saline solution and mobilization of the bladder from the lower uterine segment did not have a statistically significant beneficial effect on preventing complications of the genitourinary system. But although the beneficial effects were not significant, shorter operation times, shorter postoperative hospital stays, and fewer bladder injuries were noted in patients whose bladders were filled. PMID- 29479115 TI - Examination of radio-opacity enhancing additives in shape memory polyurethane foams. AB - Three microparticle additives, tungsten (W), zirconium oxide (ZrO2), and barium sulfate (BaSO4) were selected to enhance the radio-opacity in shape memory polymer (SMP) foam biomaterials. The addition of filler causes no significant alterations of glass transition temperatures, density of the materials increases, pore diameter decreases, and total volume recovery decreases from approximately 70 times in unfilled foams to 20 times (4% W and 10% ZrO2). The addition of W increases time to recovery; ZrO2 causes little variation in time to shape recovery; BaSO4 increases the time to recovery. On a 2.00 mean X-ray density (mean X.D.) scale, a GDC coil standard has a mean X.D. of 0.62; 4% W enhances the mean X.D. to 1.89, 10% ZrO2 to 1.39 and 4% BaSO4 to 0.74. Radio-opacity enhancing additives could be used to produce SMP foams with controlled shape memory kinetics, low density, and enhanced X-ray opacity for medical materials. PMID- 29479116 TI - Who Helps Single Mothers in Nairobi? The Role of Kin Support. AB - Single mothers often turn to their extended kin for financial assistance and to help with child care. Such support may be especially important in areas of high poverty and poor environmental conditions. Using novel kinship data, this paper assesses the extent of support given by over 3,000 relatives to 462 single mothers living in a slum area of Nairobi, Kenya. Contrary to stereotypes about families in sub-Saharan Africa, the active kin network of single mothers is relatively small and nearly a fifth of mothers do not receive any financial or child care assistance. Different types of kin offer different kinds of support according to culturally proscribed roles. However, support also depends heavily on kin's employment status, geographic proximity, and age. These findings offer a nuanced picture of how single women living in slum areas draw upon their kin network to cope with their daily demands as mothers. PMID- 29479118 TI - A familiar Friend: The Impacts of the Master's Thesis over Four Formative Career Phases. AB - Over the course of my career, I have experienced the thesis in different ways. This reflection paper will relay my encounters with, what I am calling, thesis objects (to borrow a concept from object relations). I encountered the thesis objects at different phases of my professional development: when I was a student, a supervisor for Smith MSW students, a PhD applicant, and chair of the Alumni Thesis Award Committee. My relationship with each thesis-object has refined me and granted me new perspective and personal growth. When I was a student, the thesis was a coach helping me develop tools to answer important questions. When I was a supervisor, the thesis was a bridge-builder strengthening my relationships with supervisees. Then, when I was a PhD applicant, the thesis was a door-opener providing me means to access PhD opportunities. Now that I am a chair, the thesis is a teacher opening my eyes to new intellectual terrain and pressing social problems. PMID- 29479117 TI - Odijk excluded volume interactions during the unfolding of DNA confined in a nanochannel. AB - We report experimental data on the unfolding of human and E. coli genomic DNA molecules shortly after injection into a 45 nm nanochannel. The unfolding dynamics are deterministic, consistent with previous experiments and modeling in larger channels, and do not depend on the biological origin of the DNA. The measured entropic unfolding force per friction per unit contour length agrees with that predicted by combining the Odijk excluded volume with numerical calculations of the Kirkwood diffusivity of confined DNA. The time scale emerging from our analysis has implications for genome mapping in nanochannels, especially as the technology moves towards longer DNA, by setting a lower bound for the delay time before making a measurement. PMID- 29479119 TI - Studies toward brevisulcenal F via convergent strategies for marine ladder polyether synthesis. AB - Shortly after the initial isolation of marine ladder polyether natural products, biomimetic epoxide-opening cascade reactions were proposed as an efficient strategy for the synthesis of these compounds. However, difficulties in assembling the cascade precursors have limited the realization of these cascades. In this report, we describe strategies that provide convergent access to cascade precursors via regioselective allylation and efficient fragment coupling. We then investigate epoxide-opening cascades promoted by strong bases for the formation of fused tetrahydropyrans. These strategies are evaluated in the context of the synthesis of rings CDEFG of brevisulcenal F. PMID- 29479120 TI - The Impact of Diesel Oil Pollution on the Hydrophobicity and CO2 Efflux of Forest Soils. AB - The contamination of soil with petroleum products is a major environmental problem. Petroleum products are common soil contaminants as a result of human activities, and they are causing substantial changes in the biological (particularly microbiological) processes, chemical composition, structure and physical properties of soil. The main objective of this study was to assess the impact of soil moisture on CO2 efflux from diesel-contaminated albic podzol soils. Two contamination treatments (3000 and 9000 mg of diesel oil per kg of soil) were prepared for four horizons from two forest study sites with different initial levels of soil water repellency. CO2 emissions were measured using a portable infrared gas analyser (LCpro+, ADC BioScientific, UK) while the soil samples were drying under laboratory conditions (from saturation to air-dry). The assessment of soil water repellency was performed using the water drop penetration time test. An analysis of variance (ANVOA) was conducted for the CO2 efflux data. The obtained results show that CO2 efflux from diesel-contaminated soils is higher than efflux from uncontaminated soils. The initially water repellent soils were found to have a bigger CO2 efflux. The non-linear relationship between soil moisture content and CO2 efflux only existed for the upper soil horizons, while for deeper soil horizons, the efflux is practically independent of soil moisture content. The contamination of soil by diesel leads to increased soil water repellency. PMID- 29479121 TI - Biogeography and genetic diversity of the atlantid heteropods. AB - The atlantid heteropods are regularly encountered, but rarely studied marine planktonic gastropods. Relying on a small (<14 mm), delicate aragonite shell and living in the upper ocean means that, in common with pteropods, atlantids are likely to be affected by imminent ocean changes. Variable shell morphology and widespread distributions indicate that the family is more diverse than the 23 currently known species. Uncovering this diversity is fundamental to determining the distribution of atlantids and to understanding their environmental tolerances. Here we present phylogenetic analyses of all described species of the family Atlantidae using 437 new and 52 previously published cytochrome c oxidase subunit 1 mitochondrial DNA (mtCO1) sequences. Specimens and published sequences were gathered from 32 Atlantic Ocean stations, 14 Indian Ocean stations and 21 Pacific Ocean stations between 35 degrees N and 43 degrees S. DNA barcoding and Automatic Barcode Gap Discovery (ABGD) proved to be valuable tools for the identification of described atlantid species, and also revealed ten additional distinct clades, suggesting that the diversity within this family has been underestimated. Only two of these clades displayed obvious morphological characteristics, demonstrating that much of the newly discovered diversity is hidden from morphology-based identification techniques. Investigation of six large atlantid collections demonstrated that 61% of previously described (morpho) species have a circumglobal distribution. Of the remaining 39%, two species were restricted to the Atlantic Ocean, five occurred in the Indian and Pacific oceans, one species was only found in the northeast Pacific Ocean, and one occurred only in the Southern Subtropical Convergence Zone. Molecular analysis showed that seven of the species with wide distributions were comprised of two or more clades that occupied distinct oceanographic regions. These distributions may suggest narrower environmental tolerances than the described morphospecies. Results provide an updated biogeography and mtCO1 reference dataset of the Atlantidae that may be used to identify atlantid species and provide a first step in understanding their evolutionary history and accurate distribution, encouraging the inclusion of this family in future plankton research. PMID- 29479122 TI - MODELING LEFT-TRUNCATED AND RIGHT-CENSORED SURVIVAL DATA WITH LONGITUDINAL COVARIATES. AB - There is a surge in medical follow-up studies that include longitudinal covariates in the modeling of survival data. So far, the focus has been largely on right censored survival data. We consider survival data that are subject to both left truncation and right censoring. Left truncation is well known to produce biased sample. The sampling bias issue has been resolved in the literature for the case which involves baseline or time-varying covariates that are observable. The problem remains open however for the important case where longitudinal covariates are present in survival models. A joint likelihood approach has been shown in the literature to provide an effective way to overcome those difficulties for right censored data, but this approach faces substantial additional challenges in the presence of left truncation. Here we thus propose an alternative likelihood to overcome these difficulties and show that the regression coefficient in the survival component can be estimated unbiasedly and efficiently. Issues about the bias for the longitudinal component are discussed. The new approach is illustrated numerically through simulations and data from a multi-center AIDS cohort study. PMID- 29479123 TI - Modeling the rheological behavior of thermosonic extracted guava, pomelo, and soursop juice concentrates at different concentration and temperature using a new combination model. AB - : This study has modeled the rheological behavior of thermosonic extracted pink fleshed guava, pink-fleshed pomelo, and soursop juice concentrates at different concentrations and temperatures. The effects of concentration on consistency coefficient (K) and flow behavior index (n) of the fruit juice concentrates was modeled using a master curve which utilized the concentration-temperature shifting to allow a general prediction of rheological behaviors covering a wide concentration. For modeling the effects of temperature on K and n, the integration of two functions from the Arrhenius and logistic sigmoidal growth equations has provided a new model which gave better description of the properties. It also alleviated the problems of negative region when using the Arrhenius model alone. The fitted regression using this new model has improved coefficient of determination, R2 values above 0.9792 as compared to using the Arrhenius and logistic sigmoidal models alone, which presented minimum R2 of 0.6243 and 0.9440, respectively. Practical applications: In general, juice concentrate is a better form of food for transportation, preservation, and ingredient. Models are necessary to predict the effects of processing factors such as concentration and temperature on the rheological behavior of juice concentrates. The modeling approach allows prediction of behaviors and determination of processing parameters. The master curve model introduced in this study simplifies and generalized rheological behavior of juice concentrates over a wide range of concentration when temperature factor is insignificant. The proposed new mathematical model from the combination of the Arrhenius and logistic sigmoidal growth models has improved and extended description of rheological properties of fruit juice concentrates. It also solved problems of negative values of consistency coefficient and flow behavior index prediction using existing model, the Arrhenius equation. These rheological data modeling provide good information for the juice processing and equipment manufacturing needs. PMID- 29479124 TI - Comment. PMID- 29479126 TI - Graffinity: Visualizing Connectivity in Large Graphs. AB - Multivariate graphs are prolific across many fields, including transportation and neuroscience. A key task in graph analysis is the exploration of connectivity, to, for example, analyze how signals flow through neurons, or to explore how well different cities are connected by flights. While standard node-link diagrams are helpful in judging connectivity, they do not scale to large networks. Adjacency matrices also do not scale to large networks and are only suitable to judge connectivity of adjacent nodes. A key approach to realize scalable graph visualization are queries: instead of displaying the whole network, only a relevant subset is shown. Query-based techniques for analyzing connectivity in graphs, however, can also easily suffer from cluttering if the query result is big enough. To remedy this, we introduce techniques that provide an overview of the connectivity and reveal details on demand. We have two main contributions: (1) two novel visualization techniques that work in concert for summarizing graph connectivity; and (2) Graffinity, an open-source implementation of these visualizations supplemented by detail views to enable a complete analysis workflow. Graffinity was designed in a close collaboration with neuroscientists and is optimized for connectomics data analysis, yet the technique is applicable across domains. We validate the connectivity overview and our open-source tool with illustrative examples using flight and connectomics data. PMID- 29479125 TI - Efficient Semiparametric Inference Under Two-Phase Sampling, With Applications to Genetic Association Studies. AB - In modern epidemiological and clinical studies, the covariates of interest may involve genome sequencing, biomarker assay, or medical imaging and thus are prohibitively expensive to measure on a large number of subjects. A cost effective solution is the two-phase design, under which the outcome and inexpensive covariates are observed for all subjects during the first phase and that information is used to select subjects for measurements of expensive covariates during the second phase. For example, subjects with extreme values of quantitative traits were selected for whole-exome sequencing in the National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP). Herein, we consider general two-phase designs, where the outcome can be continuous or discrete, and inexpensive covariates can be continuous and correlated with expensive covariates. We propose a semiparametric approach to regression analysis by approximating the conditional density functions of expensive covariates given inexpensive covariates with B-spline sieves. We devise a computationally efficient and numerically stable EM-algorithm to maximize the sieve likelihood. In addition, we establish the consistency, asymptotic normality, and asymptotic efficiency of the estimators. Furthermore, we demonstrate the superiority of the proposed methods over existing ones through extensive simulation studies. Finally, we present applications to the aforementioned NHLBI ESP. PMID- 29479127 TI - A Horizontal Multi-Purpose Microbeam System. AB - A horizontal multi-purpose microbeam system with a single electrostatic quadruplet focusing lens has been developed at the Columbia University Radiological Research Accelerator Facility (RARAF). It is coupled with the RARAF 5.5 MV Singleton accelerator (High Voltage Engineering Europa, the Netherlands) and provides micrometer-size beam for single cell irradiation experiments. It is also used as the primary beam for a neutron microbeam and microPIXE (particle induced x-ray emission) experiment because of its high particle fluence. The optimization of this microbeam has been investigated with ray tracing simulations and the beam spot size has been verified by different measurements. PMID- 29479130 TI - A space- and time-resolved single photon counting detector for fluorescence microscopy and spectroscopy. AB - We have recently developed a wide-field photon-counting detector having high temporal and high-spatial resolutions and capable of high-throughput (the H33D detector). Its design is based on a 25 mm diameter multi-alkali photocathode producing one photo electron per detected photon, which are then multiplied up to 107 times by a 3-microchannel plate stack. The resulting electron cloud is proximity focused on a cross delay line anode, which allows determining the incident photon position with high accuracy. The imaging and fluorescence lifetime measurement performances of the H33D detector installed on a standard epifluorescence microscope will be presented. We compare them to those of standard single-molecule detectors such as single-photon avalanche photodiode (SPAD) or electron-multiplying camera using model samples (fluorescent beads, quantum dots and live cells). Finally, we discuss the design and applications of future generation of H33D detectors for single-molecule imaging and high throughput study of biomolecular interactions. PMID- 29479129 TI - Factors that influence vital rates of Seaside and Saltmarsh sparrows in coastal New Jersey, USA. AB - As saltmarsh habitat continues to disappear, understanding the factors that influence saltmarsh breeding bird population dynamics is an important step for the conservation of these declining species. Using five years (2011 - 2015) of demographic data, we evaluated and compared Seaside (Ammodramus maritimus) and Saltmarsh (A. caudacutus) sparrow apparent adult survival and nest survival at the Edwin B. Forsythe National Wildlife Refuge, New Jersey, USA. We determined the effect of site management history (unditched vs. ditched marsh) on adult and nest survival to aid in prioritizing future management or restoration actions. Seaside Sparrow apparent adult survival (61.6%, 95% CI: 52.5 - 70.0%) averaged >1.5 times greater than Saltmarsh Sparrow apparent adult survival (39.9%, 95% CI: 34.0 - 46.2%). Nest survival and predation and flooding rates did not differ between species, and predation was the primary cause of failure for both species. Apparent adult survival and nest survival did not differ between unditched and ditched marshes for either species, indicating that marsh ditching history may not affect breeding habitat quality for these species. With predation as the primary cause of nest failure for both species in New Jersey, we suggest that future research should focus on identification of predator communities in salt marshes and the potential for implementing predator-control programs to limit population declines. PMID- 29479131 TI - Development of an ultrafast single photon counting imager for single molecule imaging. AB - We have begun developing an innovative ultra-fast single-photon counting imager which comprises a mega-pixel CMOS array and a newly-designed Image Intensifier. It is expected to have single photon sensitivity with 100 psec time resolution, operational at a total counting rate exceeding 1MHz. The readout is based on dead time-free flash ADC, running at 1-2GS/s, followed by a FPGA for real-time parallel data processing. Such a device has not been realized before and is expected to revolutionize time-resolved fluorescence imaging and spectroscopy from a single-molecule to whole animal level. To evaluate the design principle, an Image Intensifier with a GaAsP photocathode (>40% quantum efficiency at 400 600 nm) followed by double MCP was evaluated together with an existing CMOS camera. In our future design, the image from CMOS Camera will be combined with the MCP output, followed by a set of FPGA and CPU for real time data processing. This stream line method will allow ultra fast single-photon counting with 100 psec time resolution and 20 um position resolution (1M pixel imaging). In this paper, we present the design principle and preliminary results on its performance. Our future plan and the design goals are also described. PMID- 29479132 TI - Farm family effects of adopting improved and hybrid sorghum seed in the Sudan Savanna of West Africa. AB - Uptake of improved sorghum varieties in the Sudan Savanna of West Africa has been limited, despite the economic importance of the crop and long-term investments in sorghum improvement. One reason why is that attaining substantial yield advantages has been difficult in this harsh, heterogeneous growing environment. Release in Mali of the first sorghum hybrids in Sub-Saharan Africa that have been developed primarily from local germplasm has the potential to change this situation. Utilizing plot data collected in Mali, we explain the adoption of improved seed with an ordered logit model and apply a multivalued treatment effects model to measure impacts on farm families, differentiating between improved varieties and hybrids. Since farm families both consume and sell their sorghum, we consider effects on consumption patterns as well as productivity. Status within the household, conferred by gender combined with marital status, generation, and education, is strongly related to the improvement status of sorghum seed planted in these extended family households. Effects of hybrid use on yields are large, widening the range of food items consumed, reducing the share of sorghum in food purchases, and contributing to a greater share of the sorghum harvest sold. Use of improved seed appears to be associated with a shift toward consumption of other cereals, and also to greater sales shares. Findings support on-farm research concerning yield advantages, also suggesting that the use of well-adapted sorghum hybrids could contribute to diet diversification and the crop's commercialization by smallholders. PMID- 29479128 TI - Association of Personality Profiles with Depressive, Anxiety, and Cancer-related Symptoms in Patients Undergoing Chemotherapy. AB - Background: This study identified latent classes of cancer patients based on Big Five personality dimensions and evaluated for differences in demographic and clinical characteristics, depression, anxiety, and cancer-related symptoms. Methods: Patients (n=1248) with breast, gastrointestinal, gynecological, or lung cancer completed the Center for Epidemiological Studies-Depression scale, Spielberger State-Trait Anxiety Inventories, NEO-Five Factor Inventory (NEO-FFI), and Memorial Symptom Assessment Scale (MSAS). Latent class profile analysis of NEO-FFI scores was used to identify patient subgroups. Results: Three latent classes were identified. The "Distressed" class (14.3%) scored highest on neuroticism and lowest on extraversion, agreeableness, and conscientiousness. The "Resilient" class (31.9%) scored lowest on neuroticism and highest on extraversion, agreeableness, and conscientiousness. The "Normative" class (53.8%) was intermediate on all dimensions except openness. Compared to the Resilient class, patients in the Distressed class were younger, less educated, more likely to care for another adult, had more comorbidities, and exercised less. The three classes differed by performance status, marital and employment status, and income, but not by gender, time since diagnosis, or type of prior cancer treatment. The classes differed (Distressed > Normative > Resilient) in depression, anxiety, and cancer symptoms. Conclusions: Personality is associated with psychological and physical symptoms in cancer patients. PMID- 29479133 TI - Parenting Stress and Sexual Satisfaction Among First-time Parents: A Dyadic Approach. AB - The present paper reports on longitudinal associations between parenting stress and sexual satisfaction among 169 heterosexual couples in the first year after the birth of a first child. Actor Partner Interdependence Modeling (APIM) was used to model the effects of the mother's and father's parenting stress at 6 months after birth on sexual satisfaction at one year after birth. Based on social constructivist theory and scarcity theory, two hypotheses were posed: (a) mothers' parenting stress will predict their own later sexual satisfaction whereas fathers' parenting stress will not predict their own later sexual satisfaction (actor effects) and (b) mothers' parenting stress will predict fathers' later sexual satisfaction but fathers' parenting stress will not predict mothers' later sexual satisfaction (partner effects). On average, parents were only somewhat satisfied with their sex life. The first hypothesis was supported as greater parenting stress significantly predicted lower sexual satisfaction for mothers but not for fathers. The second hypothesis was also supported as mothers' greater parenting stress significantly predicted less sexual satisfaction in fathers, whereas fathers' parenting stress did not significantly predict mothers' sexual satisfaction. We discuss how our results may be interpreted considering the social construction of gendered family roles. PMID- 29479134 TI - Assessing the risk of downwind spread of avian influenza virus via airborne particles from an urban wholesale poultry market. AB - Interspecies transmissions of avian influenza viruses (AIV) occur at the human poultry interface, among which the live poultry markets (LPMs) are easily assessed by urban residents. Thousands of live poultry from different farms arrive daily at wholesale markets before being sold to retail markets. We assessed the risk of AIV downwind spread via airborne particles from a representative wholesale market in Guangzhou. Air samples were collected using the cyclone-based NIOSH bioaerosol samplers at different locations inside a wholesale market, and viral RNA and avian 18S RNA were quantified using quantitative real-time RT-PCR. Computational Fluid Dynamics (CFD) modeling was performed to investigate the AIV spread pattern. Viral RNA was readily detected from 19 out of 21 air sampling events, predominantly from particles larger than 1 um. The concentration of viral RNA detected at the poultry holding area was 4.4 * 105 copies/m3 and was as high as 2.6 * 104 copies/m3 100 m downwind. A high concentration of avian 18S RNA (2.5 * 108 copies/m3) detected at the poultry holding area was used for assessing the potential spread of avian influenza virus during outbreak situations. CFD modeling indicated the combined effect of wind direction and surrounding buildings on the spread of virus and a slow decay rate of the virus in the air in the downwind direction. Because of the large volume of poultry trade daily, wholesale markets located in urban areas may pose considerable AIV infection risk to neighboring residents via wind spread, even in the absence of direct contact with poultry. PMID- 29479135 TI - Circulating liver-specific microRNAs in cynomolgus monkeys. AB - Circulating microRNAs (miRNAs) can potentially be used as sensitive and specific biomarkers for tissue injury. However, the usefulness of circulating miRNAs as safety biomarkers in nonclinical toxicological studies using nonhuman primates is debatable owing to the limited information on organ-specific miRNAs. Therefore, a systematic investigation was performed to address this point. We identified organ specific miRNAs from cynomolgus monkeys by next-generation sequencing analysis, which revealed that miR-122 was only abundant in the liver, whereas miR-192 was abundant in the liver, stomach, intestines, and kidney. The sequences of these miRNAs were identical to their human counterparts. Next, the absolute miR-122 and miR-192 levels were qualified by quantitative reverse transcription polymerase chain reaction (RT-qPCR) to determine the circulating levels of the miRNAs. No significant differences in the levels of circulating miRNAs between sexes were noted, and there was greater interindividual variation in miR-122 (20-fold variation) than in miR-192 (8-fold variation), based on their dynamic ranges. Finally, we evaluated the fluctuation in circulating liver-specific miRNAs in a monkey model of acetaminophen-induced hepatotoxicity. Acetaminophen with L buthionine-(S,R)-sulfoximine induced hepatotoxicity in all the animals, which was characterized histopathologically by centrilobular necrosis and vacuolation of hepatocytes. Circulating miR-122 and miR-192 levels increased more than ALT levels after 24 h, indicating that circulating miR-122 and miR-192 may serve as sensitive biomarkers for the detection of hepatotoxicity in cynomolgus monkeys. This review describes the fundamental profiles of circulating liver-specific miRNAs in cynomolgus monkeys and focusses on their organ specificity, circulating levels, and fluctuations in drug-induced hepatotoxicity. PMID- 29479136 TI - Statistical analysis for toxicity studies. AB - Generally, multiple statistical analysis methods can be applied for certain kind of data, and conclusion could differ, depending on the selected statistical method. Therefore, it is necessary to fully understand the performance of each statistical method and to examine which method is appropriate to use and to standardize statistical methods for toxicity studies to be carried out routinely. Several viewpoints for selecting appropriate statistical methods are discussed in this review paper. According to the distribution form, i.e., whether a distribution has a bell shape without outliers or not, either a parametric or a nonparametric approach should be selected. The nonparametric approach is also available for categorical data. Depending on the design and purpose of a study, several forms of statistical analysis are available. Assuming dose dependency, comparisons with a control are conducted by Williams test (nonparametric: Shirley Williams test). When a dose dependent relationship is not expected, comparisons with the control are conducted by Dunnett test (nonparametric: Steel test). All possible pairwise comparisons among groups are conducted by Tukey test (nonparametric: Steel-Dwass test). If we are interested in several specific comparisons among groups, the Bonferroni-adjusted Student's t-test (nonparametric: the Bonferroni-adjusted Wilcoxon test) can be used. PMID- 29479138 TI - Progression process and safety assessment adaptation of endometrial lesions in ENU-induced 2-stage uterine carcinogenicity in a Tg-rasH2 mouse model. AB - Although acotiamide hydrochloride hydrate (acotiamide-HH) has not been reported to have genotoxic findings in any of the genotoxicity studies or treatment related toxicological findings in reproductive and developmental studies, suspicious uterine tumorigenesis was observed in the results of a long-term rat carcinogenicity study. To clarify the uterine tumorigenesis of acotiamide-HH, we performed a 2-stage uterine carcinogenicity model in the transgenic rasH2 mouse initiated by N-Ethyl-N-nitrosourea (ENU). This model facilitated the short-term detection of uterine carcinogenic potential, and it appears to be a very useful testing method for assessing the safety of chemicals that may affect uterine tumorigenesis. However, there have not been many reports on this model, and accumulation of case studies using this model is recommended to support its usability. In this study, we performed this carcinogenesis model to not only confirm uterine tumorigenesis of acotiamide-HH but also to confirm the reliability of the model. The results of this study revealed that the endometrial adenocarcinoma found in the long-term rat carcinogenicity study possibly arose spontaneously. Also, we confirmed early induction of a uterine tumor as in previous reports and confirmed that 26 weeks is the appropriate treatment period for this rasH2 mouse model according to time-course observations of uterine tumor development. PMID- 29479139 TI - Increased hepatic inflammation in a normal-weight mouse after long-term high-fat diet feeding. AB - Among five C57BL/6 mice fed a high-fat diet (HFD) for 12 weeks, one mouse showed a body weight (BW) similar to normal diet (ND)-fed mice. We compared obesity related parameters of three groups (ND-fed mice, one HFD-fed normal-weight mouse, and HFD-fed overweight mice), including visceral fat weight, serum levels of total cholesterol (TC), glucose, and aminotransferases (AST and ALT), adipocyte size, percentage of crown-like structures, severity of hepatic steatosis, and number of inflammatory foci. Compared to ND-fed mice, the HFD-fed normal-weight mouse exhibited a similar visceral fat weight, similar serum levels of glucose and aminotransferases, and a similar percentage of crown-like structures. On the other hand, the serum TC level, adipocyte size, and hepatic steatosis severity of the HFD-fed normal-weight mouse were intermediate between those of ND-fed mice and HFD-fed overweight mice. Interestingly, the number of hepatic inflammatory foci in the HFD-fed normal-weight mouse was remarkably increased compared with those in HFD-fed overweight mice. These results suggest that having BW or serum ALT levels within normal ranges may not guarantee absence of hepatic inflammation and that the HFD-fed normal-weight mouse can be used as an animal model for the study of liver inflammation, particularly in patients with normal BWs and/or serum ALT values. PMID- 29479137 TI - MicroRNAs associated with the development of kidney diseases in humans and animals. AB - Mature microRNAs (miRNAs) are single-stranded RNAs with approximately 18-25 bases, and their sequences are highly conserved among animals. miRNAs act as posttranscriptional regulators by binding mRNAs, and their main function involves the degradation of their target mRNAs. Recent studies revealed altered expression of miRNAs in the kidneys during the progression of acute kidney injury (AKI) and chronic kidney disease (CKD) in humans and experimental rodent models by using high-throughput screening techniques including microarray and small RNA sequencing. Particularly, miR-21 seems to be strongly associated with renal pathogenesis both in the glomerulus and tubulointerstitium. Furthermore, abundant evidence has been gathered showing the involvement of miRNAs in renal fibrosis. Because of the complex morphofunctional organization of the mammalian kidneys, it is crucial both to determine the exact localization of the kidney cells that express the miRNAs, which has been addressed mainly using in situ hybridization methods, and to identify precisely which mRNAs are bound and degraded by these miRNAs, which has been studied mostly through in vitro analysis. To discover novel biomarker candidates, miRNA levels in urine supernatant, sediment, and exosomal fraction were comprehensively investigated in different types of kidney disease, including drug-induced AKI, ischemia-induced AKI, diabetic nephropathy, lupus nephritis, and IgA nephropathy. Recent studies also demonstrated the therapeutic effect of miRNA and/or anti-miRNA administrations. The intent of this review is to illustrate the state-of-the-art research in the field of miRNAs associated with renal pathogenesis, especially focusing on AKI and CKD in humans and animal models. PMID- 29479140 TI - Spontaneous hypertrophic cardiomyopathy in a cynomolgus macaque (Macaca fascicularis). AB - The term cardiomyopathy is used to describe heart disease resulting from an abnormality in the myocardium. It is rare in cynomolgus macaques (Macaca fascicularis). Here, we report a case of hypertrophic cardiomyopathy in an 11 year-old male cynomolgus macaque. Macroscopically, the interventricular septum (IVS) and the left ventricular (LV) and right ventricular (RV) walls of the heart were thickened. Histologically, cardiomyocytes showed hypertrophy and disarray with interstitial fibrosis, and some myocytes showed karyomegaly and vacuoles. On the basis of these morphological characteristics, the present case was diagnosed as hypertrophic cardiomyopathy. Immunohistochemically, the cardiomyocytes in the affected regions were positive for the autophagic markers LC3 and p62/SQSTM1 (p62). The accumulation of autophagosomes in hypertrophied cardiomyocytes was demonstrated. The mechanism of accumulation of autophagosomes seems to be a secondary effect due to stress. To our knowledge, this is the first report of spontaneous hypertrophic cardiomyopathy in a cynomolgus macaque. PMID- 29479141 TI - Minimal change disease of the kidney in a young Sprague Dawley rat. AB - Minimal change disease (MCD) can be experimentally induced in rats, but spontaneous cases have not been reported. Herein, we present a case of MCD in rats that resembled the phenotypes of human MCD. A 9-week-old male Sprague Dawley rat developed continuous albuminuria for 2 weeks and was sacrificed at 11 weeks of age. Histological testing revealed no glomerular or renal tubular abnormalities on light microscopy. Immunofluorescence revealed absence of immunoglobulin G or immunoglobulin M deposition in the glomerulus. Extensive foot process effacement of glomerular podocytes was observed by electron microscopy, with rearrangement of the actin cytoskeleton at the base of the fused foot processes. The rat did not show desmin-positive podocytes, and the nephrin showed a normal liner pattern of distribution along the glomerular capillary loop throughout the glomeruli. These pathological characteristics corresponded to those of human MCD, and the glomerular lesion was considered a rare case of rat MCD. PMID- 29479142 TI - Quality assessment of long-term stored formalin-fixed paraffin embedded tissues for histopathological evaluation. AB - Histopathological examination of formalin-fixed paraffin-embedded (FFPE) tissues that had been stored for 30 years was conducted, and reconstructivity of the results was verified. These FFPE tissues, which were from all organs of male and female rats, were re-sectioned and histopathologically examined using hematoxylin and eosin (HE) staining. In particular, the stainability and morphology of HE sections and reproducibility of microscopic findings in the liver and kidney demonstrated in the original final reports were evaluated. Although the stainability of hematoxylin was slightly weaker and some morphological artifacts were observed in tissues in re-prepared slides, these deteriorations in the quality of HE sections were considered to be permissible for histopathological examination so long as control sections were also prepared. Most microscopic findings recorded in the original final reports were confirmed using re-prepared HE sections in the present study. While some focal findings, which were judged to be either incidental or spontaneous in nature, were not observed in the sections as expected, this was not considered to be a problem in reconstructing the results of the original histopathological examination because most findings related to the test articles were generally observed diffusely or multifocally in each organ. We concluded that results of the original histopathological examinations could be reconstructed using paraffin blocks that had been stored for up to 30 years. PMID- 29479143 TI - Ocular lesions in leptin receptor-deficient medaka (Oryzias latipes). AB - Ocular lesions in leptin receptor-deficient medaka were examined histopathologically at 10, 28, and 37 weeks post hatching. Leptin receptor deficient medaka at 28 and 37 weeks old showed hyperglycemia and hypoinsulinemia. Histopathologically, vacuolation, swelling, fragmentation, and liquefaction of the lens fibers and dilatation of the retinal central veins, retinal capillaries, iridal veins and capillaries, and choroidal veins were observed in leptin receptor-deficient medaka at 28 and 37 weeks old. Thinning of the total retina, pigment epithelial layer, layer of rods and cones, outer granular layer, outer plexiform layer, inner granular layer, and inner plexiform layer was observed in leptin receptor-deficient medaka at 28 and 37 weeks compared with in control medaka. These histopathological characteristics in leptin receptor-deficient medaka are similar to characteristics in ocular lesions of rodent models for type II diabetes mellitus, making leptin receptor-deficient medaka a useful model of diabetic cataract and retinopathy. PMID- 29479144 TI - Size-dependent acute toxicity of silver nanoparticles in mice. AB - In this study, we aimed to evaluate changes in the acute toxicity of intraperitoneally administered silver nanoparticles (AgNPs) of varying sizes in BALB/c mice. Seven-week-old female BALB/c mice were intraperitoneally administered AgNPs measuring 10, 60, or 100 nm in diameter (0.2 mg/mouse) and then sacrificed 1, 3, or 6 h after treatment. In mice administered 10 nm AgNPs, reduced activity and piloerection were observed at 5 h post administration, and lowered body temperature was observed at 6 h post administration, with histopathological changes of congestion, vacuolation, single cell necrosis, and focal necrosis in the liver; congestion in the spleen; and apoptosis in the thymus cortex. These histopathological changes were not evident following administration of either 60 or 100 nm AgNPs. These results suggested that smaller AgNPs, e.g., those measuring 10 nm in diameter, had higher acute toxicity in mice. PMID- 29479145 TI - A simple method for histopathological evaluation of organoids. AB - In vitro-cultured 3D structures called organoids have become important tools for biological research, but there is little information concerning simple and efficient methods to evaluate organoid morphology. To address this issue, we attempted to establish a simple method by applying conventional histopathology that enables observation of multiple organoids on a single cross section, maintains good morphology, and is applicable to various histopathological stains. By centrifugation in unsolidified agarose solution, we were able to accumulate the organoids onto a single plane. The morphology was well preserved, and the various morphological types and sizes of organoid structures were identified. This method was also applicable for special staining, immunohistochemistry, and immunofluorescence staining. This method makes it possible to utilize the advantages of conventional pathological methods when studying organoids. PMID- 29479146 TI - cis Versus trans-Azobenzene: Precise Determination of NMR Parameters and Analysis of Long-Lived States of 15N Spin Pairs. AB - We provide a detailed evaluation of nuclear magnetic resonance (NMR) parameters of the cis- and trans-isomers of azobenzene (AB). For determining the NMR parameters, such as proton-proton and proton-nitrogen J-couplings and chemical shifts, we compared NMR spectra of three different isotopomers of AB: the doubly 15N labeled azobenzene, 15N,15N'-AB, and two partially deuterated AB isotopomers with a single 15N atom. For the total lineshape analysis of NMR spectra, we used the recently developed ANATOLIA software package. The determined NMR parameters allowed us to optimize experiments for investigating singlet long-lived spin states (LLSs) of 15N spin pairs and to measure LLS lifetimes in cis-AB and trans AB. Magnetization-to-singlet-to-magnetization conversion has been performed using the SLIC and APSOC techniques, providing a degree of conversion up to 17 and 24% of the initial magnetization, respectively. Our approach is useful for optimizing the performance of experiments with singlet LLSs; such LLSs can be exploited for preserving spin hyperpolarization, for probing slow molecular dynamics, slow chemical processes and also slow transport processes. PMID- 29479147 TI - Bamboo vs. crops: an integrated emergy and economic evaluation of using bamboo to replace crops in south Sichuan Province, China. AB - Based on long-term monitoring conducted in Chang-ning county, a pilot site of the 'Grain for Green Program' (GFGP), an integrated emergy and economic method was applied to evaluate the dynamic ecological-economic performance of 3 kinds of bamboo systems planted on sloping farmland. The results confirmed the positive effects of all 3 kinds of bamboo systems on water conservation and soil erosion control. The benefits gained progressively increased during the first 8 years after conversion, going from 4639 to 16127 EMyuan/ha/yr on average. All three bamboo plantations were much more sustainable than common agricultural crops planted on sloping land (CP) on both the short and long-term scales with their Emergy Sustainability Index (ESI) and Emergy Index for Sustainable Development (EISD), respectively, being 14.07-325.71 and 80.35-265.80 times that of CP. However, all 3 bamboo plantations had a Net Economic Benefit (NEB) less than that of CP during the first 8 years after conversion. Even with the government mandated ecological compensation applied, the annual NEBECs of the Bambusa rigida (BR) and Phyllostachys pubescense (PP) plantations were, respectively, 3922.03 and 7422.77 yuan/ha/yr lower than the NEB of CP. Emergy-based evaluation of ecosystem services provides an objective reference for applying ecological compensation in strategy-making, but it cannot wholly solve the economic viability problem faced by all bamboo plantations. Inter-planting annual herbs or edible fungus, such as Dictyophora echinovolvata, within bamboo forests, especially in young bamboo plantations, might be a direction for optimizing bamboo cultivation that would improve its economic viability. PMID- 29479148 TI - In vitro potential anthelmintic activity of Biophytum petersianum on Haemonchus contortus. AB - Aim: Haemonchus contortus is a major problem in small ruminants in Indonesia. The frequent use of the anthelmintic drugs has given rise to drug-resistant populations which increase the need for new anthelminthic compounds, particularly from endemic plants. This study evaluated the in vitro effects of Biophytum petersianum crude aqueous extract (BAE) as an anthelmintic compound against H. contortus adult worm isolated from goats. Materials and Methods: Adult worm collected from naturally infected abomasums were obtained from slaughtered goats on the day of slaughter. BAE was prepared in six different concentrations (10, 20, 40, 60, 80, and 100 mg/ml) which were tested for their efficacies on ten actively moving worms. Ivermectin (1 mg/ml) was included as a reference drug, while saline water was included as a control. The dead worms from anthelmintic test then went through sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and scanning electron microscopy (SEM). Results: Highest mean mortality in treatments group both at 2 h and 4 h observations was BAE 10%. The SDS-PAGE analysis revealed the presence of five protein bands with molecular weights 9.3, 17.1, 50.0, 63.2, and 72.7 kDa based on BAE 10%. The SEM changes observed in the in vitro trials revealed the occurrence of interactions between the BAE and the cuticle. Conclusion: The SEM and SDS-PAGE analysis revealed ultrastructural structural changes and the decrease numbers of polypeptides on treated worms when compared to the control worms. It can thus be concluded that the BAE exhibits good anthelmintic activity against H. contortus adult worm. PMID- 29479149 TI - Third wave of African swine fever infection in Armenia: Virus demonstrates the reduction of pathogenicity. AB - Aim: First cases of clinically uncommon African swine fever (ASF), caused by virus genotype II are described in this article. These cases occurred in Armenia, Tavush region, Dilijan municipality in 2011. The aim of this study was to identify and describe the new pathogenic forms of ASF in Armenia. Materials and Methods: The isolation and identification of ASF virus (ASFV) were carried out using conventional techniques. Clinical signs of infection were recorded daily. Gross anatomical pathology characteristics were observed during routine postmortem examinations. Blood and serum were obtained by puncture of the jugular vein using a vacutainer system. Results: The presence of ASFV DNA in the spleens was confirmed by polymerase chain reaction. Sequenced sections of p72 showed phylogenetic identity to genotype 2. The pathology exhibits unusual manifestations of the main disease. The unusual form of ASF demonstrates characteristics of a subacute form of the disease, with the possibility of conversion to a chronic form. Decreased lethality, low level of hemorrhages, and absence of severe pancytopenia in smears from spleen, lymph nodes, and blood are common features of the new form of ASF. Unlike severe thrombocytopenia in the typical ASF, the unusual form exhibited moderate or minor decrease of this feature. Despite a moderate decrease in hemadsorption titers, the unusual pattern of the disease was characterized by viremia and the presence of the virus in the visceral organs, including the brain. Conclusion: Our data allow assuming that new nosological form of ASF (genotype II) may present as a transitional form of the disease with the possibility of chronization. PMID- 29479151 TI - Detection of Ehrlichia, Anaplasma, and Babesia spp. in dogs of Cebu, Philippines. AB - Background: Ehrlichia, Anaplasma, and Babesia spp. are canine pathogens transmitted by the Rhipicephalus sanguineus tick which can cause varied clinical signs. These pathogens have been investigated in the Philippines, but coinfection has not been reported yet. Aim: The aim of this study was to evaluate the presence of Ehrlichia/Anaplasma and Babesia spp. in Philippine dogs. Materials and Methods: A total of 100 dogs from seven different veterinary establishments in Cebu, Philippines, were examined for Ehrlichia/Anaplasma and Babesia spp. infection using peripheral blood smear examination and polymerase chain reaction (PCR). Inclusion criteria included a history or presence of tick infestation, anemia, and/or thrombocytopenia. Clinical signs were recorded. Statistical analyses were performed between PCR positivity and clinical signs and hematological results. Results: A total of 10 and 18 dogs were found to be positive for Ehrlichia/Anaplasma and Babesia spp., respectively. One animal was PCR positive for both pathogens, which is the first report of coinfection in the country. The most common clinical signs observed include inappetence (89%), lethargy (80%), thrombocytopenia (85%), and anemia (74%). Analyses revealed that inappetence (p=0.044) and weight loss (p=0.028) were found statistically significant with Ehrlichia/Anaplasma infection. Basophil (p=0.001) and eosinophil counts (p=0.000) were also found significantly different between Ehrlichia/Anaplasma spp.-positive and -negative dogs. On the other hand, differential monocyte count (p=0.009) was found significantly different between Babesia spp.-positive and -negative dogs. Conclusion: The present study showed low infection rates of canine ehrlichiosis/anaplasmosis and babesiosis and provided additional evidence for the presence of the pathogens in the area. PMID- 29479152 TI - Prevalence and bacterial etiology of subclinical mastitis in goats reared in organized farms. AB - Aim: Assessment of the status of subclinical mastitis (SCM) in Jamunapari and Barbari goats in Indian organized farms, the involvement of bacterial pathogens and their sensitivity to antibiotics. Materials and Methods: A total of 181 composite milk samples were aseptically collected from the apparently healthy Barbari (n=95) and Jamunapari (n=86) goats. The California mastitis test (CMT) and somatic cell count (SCC) were used to diagnose SCM. The milk samples with CMT scores of 0 and +1 were considered as negative, while the samples with the score of +2 or +3 were taken as positive, and further, the positive samples were used for the bacteriological examination. An antibiotic sensitivity test was performed by disk diffusion method using seven commercially available antibiotic discs. Results: All the samples having CMT score of +2 or +3 demonstrated SCC more than 1 million. Overall, the prevalence of SCM in the goats was assessed as 19.89% (36/181). The prevalence of SCM in Barbari and Jamunapari goats was found as 24.21% (23/95) and 15.12% (13/86), respectively. Out of 11 isolates of Staphylococci, 9 isolates were identified as coagulase-negative Staphylococci (CNS), whereas 2 isolates were found as Staphylococcus aureus. The identified bacterial isolates (n=30) did not show antibiotic resistance. Conclusion: The current investigation showed the considerable prevalence of SCM among Jamunapari and Barbari goats which may have a negative impact on quantity and quality of the milk. CNS was found as the most prevalent cause of SCM in the goats. Negligible antibiotic resistance was found among the identified udder pathogens. PMID- 29479153 TI - Anti-inflammatory properties of a wound dressing combination of zinc oxide and turmeric extract. AB - Aim: The aim of this study was to determine the effect of a wound dressing consisting of a zinc oxide with turmeric extract combination as an anti inflammatory on the healing process through the expression of MAC387 and cyclooxygenase-2 (COX-2). Materials and Methods: Forty Wistar rats were divided into four control and four treatment groups (n=5). On day 1, a 6 mm*6 mm square of skin in the area of the vertebralis thoracis was excised from all subjects. The wound was then dressed with a combination of zinc oxide and turmeric extract for the treatment groups, while the control groups were left undressed. Both the control and treatment groups were then sequentially sacrificed on days 3, 5, 7, and 14 to obtain subepithelial excision samples. These samples subsequently underwent immunohistochemistry examination through the expression of MAC387 and COX-2 to ascertain the anti-inflammatory reaction to the wound healing process. Results: The highest expression of MAC387 was found in the treatment group to which a dressing of zinc oxide with turmeric extract had been applied on the day 5 before slowly reducing on days 7 and 14. MAC387 peaked in the undressed control group on day 14. The COX-2 expression results in control groups showed their higher expression on day 3, increased up to day 5, began to decline on day 7 before, and finally, decreasing on day 14. This result was different to those treatment groups which presented a high COX-2 expression on day 3, before gradually decreasing between days 5 and 7 and reaching its lowest point on day 14. Conclusion: A wound dressing consisting of a combination of zinc oxide and turmeric extract has been proven effective as an anti-inflammatory in the healing process. PMID- 29479154 TI - Detection of Schmallenberg virus antibody in equine population of Northern and Northeast of Iran. AB - Aim: Schmallenberg virus (SBV) is a newly emerging virus in Simbu group that 1st time is reported in 2011 in Germany and now spread to Europe. The clinical signs of infection to this virus are fever, loss of appetite, reduced milk yield and in some cases, diarrhea and in pregnant animals congenital malformations in calves, lambs, and kid goats. Materials and Methods: In this study for a serologic survey of SBV, blood samples from 200 horse in different rural areas of the northern and northeast of Iran with the high equine population collected and were analyzed using an indirect ELISA test. Results: Based on our results 5% (n=10) of total 200 samples were positive for SBV antibody and 2% (n=4) was doubtful and 93% (n=186) was negative. There were no significant differences between age and sex and breed properties (p>0.05). Conclusion: This study demonstrated the presence of antibodies against the SBV on horse populations in Iran. The high population and activity of Culicoides biting midges and their proper living conditions, especially the areas of temperate and humid environmental conditions, are the possible causes of arboviruses related diseases seen in this country. PMID- 29479155 TI - Milk amyloid A as a biomarker for diagnosis of subclinical mastitis in cattle. AB - Background and Aim: Mastitis is one of the most vital noteworthy monetary risks to dairy ranchers and affects reproductive performance in dairy cattle. However, subclinical mastitis (SCM) negatively affects milk quality and quantity and associated with economic losses as clinical mastitis. It is recognizable only by additional testing. Somatic cell count (SCC) is currently used worldwide for the screening of intramammary infection (IMI) infections. However, somatic cells (SC) are affected by numerous factors and not always correlate with infection of the udder. Therefore, the aim of the present study was to evaluate the milk amyloid A (MAA) in the milk of normal and SCM cows and compare the sensitivity of both MAA secretion and SCC in response to mammary gland bacterial infection. Materials and Methods: A total of 272 quarter milk samples collected from 68 Friesian cows after clinical examination for detection of clinical mastitis were employed in this study. All quarter milk samples (272) were subjected to bacteriological examination, while SCs were assessed in samples (220). Following SCC estimation and bacteriological examination, the apparently normal quarter milk samples were categorized into 7 groups and MAA concentration was estimated in normal and subclinical mastitic milk samples. Results: Prevalence of clinical mastitis was 19.12 % (52 quarters), while 80.88 % (220 quarters) were clinically healthy with normal milk secretion. Of those 220 clinically healthy quarter milk samples, 72 (32.73%) showed SCM as detected by SCC (SCC >=500,000 cells/ml). The most prevalent bacteria detected in this study were streptococci (48.53%), Staphylococcus aureus (29.41%), Escherichia coli (36.76%), and coagulase-negative staphylococci (11.76%). Results of MAA estimation revealed a strong correlation between MAA secretion level and SCC in agreement with the bacteriological examination. Interestingly, there was a prompt increase in MAA concentration in Group III (G III) (group of milk samples had SCC <=200,000 cells/ml and bacteriologically positive) than Group I (G I) (group of milk samples with SCC <=500,000 cells/ml and bacteriologically negative), as MAA concentration in G III was about 4 times its concentration in G I. Conclusion: Our study provides a strong evidence for the significance of MAA measurement in milk during SCM, and MAA is more sensitive to IMI than SCC. This can be attributed to rapid and sensitive marker of inflammation. The advantage of MAA over other diagnostic markers of SCM is attributed the minute or even undetectable level of MAA in the milk of healthy animals, it is not influenced by factors other than mastitis, and could be estimated in preserved samples. Therefore, we recommend that estimation of MAA concentration in milk is a more useful diagnostic tool than SCC to detect SCM and to monitor the udder health in dairy cattle. PMID- 29479156 TI - Seroprevalence of selected viral pathogens in pigs reared in organized farms of Meghalaya from 2014 to 16. AB - Aim: A pilot study was carried out to find out the seroprevalence of Porcine circovirus 2 (PCV2), classical swine fever virus (CSFV), and Porcine respiratory and reproductive syndrome virus (PRRS) in pig population of Meghalaya. Materials and Methods: Serum samples were collected from piglets of 40-45 days age group, growers, and sows reared under organized and unorganized management in 11 districts of Meghalaya situated in the Khasi, Jaintia, and Garo hills divisions in the time period of 2014-2016 from apparently healthy and suspected pigs. Seroprevalence of PCV2, CSFV, and PRRS specific antibodies was detected by enzyme linked immunosorbent assay (ELISA). Results: A total of 1899 serum samples were collected and screened using antibody ELISA kits specific for PCV2, CSFV, and PRRS. The highest antibody prevalence during the selected time periods was detected for PCV2 (80.8% in 2014, 79.1% in 2015, and 96.2% in 2016) followed by CSFV (76.4% in 2014, 66.09% in 2015, and 25.5% in 2016) and PRRS (2.8% in 2014, 2.7% in 2015, and 3.62% in 2016). The result indicates high seroprevalence for PCV2, which can be considered as an inducement factor due to the immunosuppressive nature of the virus, for animals being susceptible to other pathogens in farms where airborne transmission of PCV2 and postweaning multisystemic wasting syndrome among animals reared in close pens can be a major possibility. Conclusions: The data from this study indicates ubiquitous prevalence of PCV2 antibodies in the farm animals along with the endemic presence of swine fever and emergence of PRRS in an organized farm. There are few reports regarding PCV2 infections/outbreaks in pigs associated with reproductive failure from northern and southern part of India, but till date, there are no reports regarding concomitant infection of CSFV and PCV2 from India. Considerable high seropositivity of PCV2 indicates the need for high impact hygiene practice in farms, routine seromonitoring and implementation the vaccination program. To the author's best knowledge, this is the first documented report on the seroprevalence of PCV2, CSFV, and PRRS from pig population of Meghalaya. PMID- 29479157 TI - Exploring knowledge and management practices on ticks and tick-borne diseases among agro-pastoral communities in Southern Highlands, Tanzania. AB - Aim: The current study was conducted to assess the farmers' knowledge and management practices on ticks and tick-borne diseases (TBDs) through individual interview using a structured questionnaire in Mbarali and Momba districts of Mbeya region. Materials and Methods: A total of 240 households, 120 from each district were asked to mention TBDs of cattle which they thought were the most important in their localities and period of the year when the diseases occurred more frequently. In addition, farmers were asked to describe clinical signs and management practices associated with the common TBDs that they knew. Results: The majority of respondents (46.2%) reported that East Coast fever (ECF) was the most important disease of cattle in the region, followed by anaplasmosis (33.8%), heartwater (15.4%), and babesiosis (4.6%). According to the farmers, ECF and anaplasmosis occurred more frequently during the dry season, while babesiosis and heartwater occurred more frequently during the rainy season. The majority of farmers were able to describe properly the signs of the common TBDs. Most farmers (80.4%) reported that they used acaricide to control ticks at a frequency of after every 2 weeks and a small proportion (15.8%) vaccinated their animals against ECF. Conclusion: It can be concluded that farmers in Mbeya have considerable knowledge on tick species and clinical signs of TBDs affecting their cattle. Based on the findings of the current study, it is recommended that integrated approach to the control of ticks and TBDs be adopted in the study area and many other areas that utilize agro-pastoral and pastoral cattle production systems. PMID- 29479158 TI - Zoonotic intestinal parasites of carnivores: A systematic review in Iran. AB - Aim: Parasitic infections, especially of the zoonotic-parasitic type, are the most important health, economic, and social problems in developing countries, including Iran. The aim of this study was to review systematically the available data on gastrointestinal parasites of carnivores in Iran and their ability to infect humans. Materials and Methods: Studies reporting intestinal parasites of carnivores were systematically collected from nine electronic English and Persian databases and Proceedings of Iranian parasitology and veterinary congresses published between 1997 and 2015. A total of 26 studies issued from 1997 to 2015 met the eligibility criteria. Results: The pooled proportion of intestinal parasites of carnivores was estimated as 80.4% (95% confidence interval=70.2 88.8%). The overall prevalence of gastrointestinal parasites in dogs, cats, foxes, and jackals were 57.89%, 90.62%, 89.17%, and 97.32%, respectively. Dipylidium caninum (20.45%), Toxocara spp. (18.81%), Taenia hydatigena (15.28%), Mesocestoides lineatus (11.83%), Echinococcus granulosus (10%), and Toxascaris leonina (8.69%) were the most frequently observed parasites. Conclusion: High prevalence rates of zoonotic intestinal parasites of carnivores particularly Echinococcus spp. and Toxocara spp. increase the risk of acquiring zoonotic infections such as cystic hydatid, alveolar cysts, and visceral or ocular larva migrants in Iranian people. Therefore, it is essential for public health centers to develop more effective control strategies to decrease infections rates in carnivores' populations. PMID- 29479160 TI - Edible bird's nest impact on rats' uterine histomorphology, expressions of genes of growth factors and proliferating cell nuclear antigen, and oxidative stress level. AB - Aim: This study aimed to evaluate the effect of edible bird's nest (EBN) supplementation on the uteri of rats based on analyses of the morphological and histomorphometric changes, and expressions of epidermal growth factor (EGF) and its receptor (REGF) genes, vascular endothelial growth factor (VEGF), proliferating cell nuclear antigen (PCNA), and steroid receptors. Materials and Methods: Twenty-four: Sprague Dawley rats were equally distributed into the following four groups: G1 (control), G2, G3, and G4 represented the groups treated with EBN at graded concentrations of 0, 30, 60, and 120 mg/kg body weight (BW) per day for 8 weeks, respectively. During the experimental period, the BW of each rat was recorded weekly. At the proestrus stage of estrous cycle, blood samples were collected from the hearts of anesthetized rats that were later sacrificed. The uteri were removed for histological and immunohistochemical analyses. Results: The EBN-treated groups showed an increase in the weights and lengths of uteri as compared to the control. Results showed that relative to G1 and G2, G3 and G4 exhibited proliferation in their uterine luminal and glandular epithelia and uterine glands, and up-regulated expressions of EGF, REGF, VEGF, PCNA, and progesterone receptor, and estrogen receptor in their uteri. The EBN increased the antioxidant (AO) and total AO capacities and reduced the oxidative stress (OS) levels in non-pregnant rats. Conclusion: Findings of this study revealed that EBN promotes proliferation of the uterine structures as evidenced by the upregulation of the expressions of steroid receptors, EGF, REGF, VEGF, and PCNA in the uterus and increased in the plasma concentrations of AO and reduced levels of OS. PMID- 29479159 TI - Seroprevalence of Capripoxvirus infection in sheep and goats among different agro climatic zones of Odisha, India. AB - Aim: The study was undertaken to assess the prevalence of antibodies to Capripoxviruses among small ruminants of Odisha, India. Materials and Methods: A total of 500 random serum samples collected from 214 sheep and 286 goats across 10 agro-climatic zones of Odisha, were screened using whole virus antigen-based indirect ELISA for antibodies against Capripoxviruses. Results were analyzed by suitable statistical methods. Results: Screening of 500 serum samples showed seropositivity of 8.88% and 31.47% in sheep and goats, respectively, for Capripoxviruses. The prevalence rate according to agro-climatic zone ranged from 0% (North Eastern coastal plain zone) to 48.57% (North central plateau zone) for goat pox, and 0% (Western undulating zone and North central plateau) to 22.22% (South Eastern ghat zone) for sheep pox. The difference in prevalence rates among the various agro-climatic zones was statistically significant (p<0.05) for goats, but not for sheep. Antibody prevalence rates among various districts were recorded to be the highest in Jagatsinghpur (30%) for sheep pox and Dhenkanal (80%) for goat pox. Conclusions: The study revealed serological evidence of Capripoxvirus infection in sheep and goat populations in the study area, in the absence of vaccination. Systematic investigation, monitoring, and reporting of outbreaks are necessary to devise control strategies. PMID- 29479161 TI - In vitro immunomodulatory potential of Artemisia indica Willd. in chicken lymphocytes. AB - Aim: Evaluation of the in vitro immunomodulatory potential of Artemisia indica Willd. methanolic extract in chicken lymphocyte culture system through lymphocyte (B and T cells) proliferation assay, after standardizing the maximum non cytotoxic dose (MNCD) in chicken lymphocytes. Materials and Methods: Fresh aerial parts of A. indica Willd. (family: Asteraceae) specimens were collected (altitude 1560 m), gotten authenticated, processed, dried, and Soxhlet extracted to yield methanolic extract (AME). Chicken splenocytes were isolated from spleens collected from healthy birds; lymphocytes were separated by density gradient centrifugation, percentage cell viability determined and final cell count adjusted to 107 cells/ml in RPMI-1640 medium. MNCD of AME in chicken lymphocytes was determined through 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide dye reduction assay. Immunomodulatory potential of AME was evaluated through lymphocytes proliferation or B and T cells blastogenesis assay in the presence of appropriate mitogens, namely, lipopolysaccharide (LPS) and concanavalin A (Con A), respectively. Results: Maximum concentration of AME exhibiting 100% cell viability (MNCD) was 200 MUg/ml and was selected for further in vitro analysis. The in vitro exposure of chicken lymphocytes to 200 ug/ml dose of AME, resulted in significant (p<0.05) upregulation of 11.76% in B cell proliferation in the presence of B cell mitogen (LPS) and a significant (p<0.05) increase of 12.018% T cells proliferation in the presence of the mitogen (Con A), as compared to the control. Conclusion: The significant upregulation in the proliferation of two major cell types modulating the immune system is an indication of the immunostimulatory potential of the plant. It would be worthwhile to further evaluate A. indica on relevant immunomodulatory aspects, especially the in vivo studies in a poultry system. PMID- 29479162 TI - Observations on biotic parameters of Angora rabbit breed under controlled conditions in different housing systems. AB - Aim: The aim of the present study was to compare the body weight (BW) gain and physiological parameters such as temperature, respiratory rate (RR), and heart rate (HR) of Angora rabbit reared in different housing systems. Materials and Methods: A total of 30 angora rabbits (age 4-6 months), weight 1.5 kg in average were divided into three groups, i.e., (outdoor control [OC], indoor in cages [IC], and indoor open [IO]). All rabbits were reared for 10 weeks. Feed and water were given ad libitum. BW gain and physiological parameters such as temperature, RR, and HR were recorded. Results: All parameters showed some degree of variations. The BW differed significantly (p<0.05). The mean BW in kilogram (kg) of OC group was 1.59+/-0.03 obtained during the experimental period, while the BW of IC group shows a decrease of 1.43+/-0.05 and IO group it was 1.49+/-0.06 kg. The body temperature (BT) of the control group was 38.83+/-1.07 degrees C, but IC and IO groups show increased in BT (39.10+/-0.78 degrees C) and (39.33+/-1.24 degrees C), indicated no significant difference among the groups (p=0.05). The RR in breaths/min of OC group recorded was 40.3+/-5.20, but the RR recorded for IC and IO groups was 41.2+/-7.29 and 39.3+/-6.30 breaths/min, respectively, showed less variation. The HR obtained in beat/min of OC group was 136.9+/-15.22, IC group (139.1+/-16.42) and IO group were (139.6+/-19.90 beat/min) showed less substantial variation. Conclusion: The present study clearly indicates that housing rabbits in cages and stress condition is a cause of poor welfare due to movement constraint, it will affect the body biotic parameters such as normal temperature, respiration as well as it can reduce the growth performance of animals significantly but housing system may not affect HR. PMID- 29479163 TI - Effect of dietary supplementation of sea buckthorn and giloe leaf meal on the body weight gain, feed conversion ratio, biochemical attributes, and meat composition of turkey poults. AB - Aim: In the recent past, few studies have been carried out about sea buckthorn (SBT) and giloe in chicken as a part of the quest for suitable alternatives to antibiotics. However, studies in turkeys are lacking. Hence, the present study was conducted to evaluate the effects of SBT and giloe leaf meal by dietary feed supplementation in turkey poults. Materials and Methods: A total of 1-day-old turkey poults (n=84) of small white variety were distributed into four dietary treatments having three replicates each with seven birds. The study was conducted in turkey poults during 0-8 weeks of age. During the experiment, the poults were fed basal ration (28% crude protein [CP], 2800 Kcal/kg ME) T1, T2-basal ration was supplemented with SBT leaf meal powder at 0.5%, T3-basal ration was supplemented with giloe leaf meal powder at 0.5%, and T4-basal ration was fed along with supplementation of both SBT at 0.5% and giloe leaf meal powder at 0.5%. Results: T2 turkey poults had a significantly higher (p<0.01) body weight gain than T3 and T4 at 7th week of age. Weekly body weight gain was significantly higher (p<0.05) in T2 than T3 during 5th-8th week and 0-8th week of the growth phase. Feed conversion ratio (FCR) was significantly better (p<0.01) in T2 than other treatment groups during 4th-8th week phase of growth (2.09 vs. 2.36, 2.29 and 2.31). Further, FCR was significantly better (p<0.01) in T2 group as compared to other treatment groups during 0-8th week of growth phase (1.95 vs. 2.21, 2.21 and 2.12). Plasma uric acid was found significantly increased (p<0.05) in T1 than T3 and T4, and alkaline phosphatase value was significantly higher (p<0.05) in T1 and T3 than T2. Zinc content of breast (pectoralis major) muscles was significantly higher (p<0.05) in T2 and T4 as compared to T1, while ether extract (EE) in thigh (ilio tibialis) muscles was significantly higher (p<0.05) in T2 as compared to the other treatment groups. Conclusion: It may be concluded that supplementation of SBT leaf meal at 0.5% may improve production performance of turkey poults. Supplementation of 0.5% SBT leaf meal may result in higher levels of zinc and EE in the breast and thigh cuts of turkey poults. PMID- 29479164 TI - Multivariate systems of nonexpansive operator equations and iterative algorithms for solving them in uniformly convex and uniformly smooth Banach spaces with applications. AB - We prove some existence theorems for solutions of a certain system of multivariate nonexpansive operator equations and calculate the solutions by using the generalized Mann and Halpern iterative algorithms in uniformly convex and uniformly smooth Banach spaces. The results of this paper improve and extend the previously known ones in the literature. PMID- 29479165 TI - Enhancing the Responsible Conduct of Sexual Health Prevention Research Across Global and Local Contexts: Training for Evidence-Based Research Ethics. AB - The HIV/AIDS pandemic has brought global attention to the ethical challenges of conducting research involving socially vulnerable participants. Such challenges require not only ethical deliberation but also an empirical evidentiary basis for research ethics policies and practices. This need has been addressed through the Fordham University HIV and Drug Abuse Prevention Research Ethics Institute, a National Institute on Drug Abuse-funded program that trains and funds early career scientists in conducting research on HIV/drug abuse research ethics. This article describes the ethical framework guiding Institute training and introduces readers to six empirical articles in this special issue that illuminate and help foster the responsible conduct of research. PMID- 29479166 TI - Ethical Challenges for Piloting Sexual Health Programs for Youth in Hammanskraal, South Africa: Bridging the Gap Between Rights and Services. AB - This article describes challenges of conducting an HIV prevention program involving 40 male and female participants ages 12-18 in Hammanskraal, South Africa, aimed at increasing awareness and knowledge of laws protecting children's sexual health rights and access to services through a culturally based "study circle" format. Challenges highlighted by the project included Institutional Review Board approval of youth consent procedures, cooperation and coordination with local policymakers, the need to modify presentation materials to youths' comprehension levels, availability of youth-based sexual health service providers, and cultural ambiguity over parental involvement in youth health care decisions and laws pertaining to sexual relationships among minors. PMID- 29479167 TI - A likelihood-based time series modeling approach for application in dendrochronology to examine the growth-climate relations and forest disturbance history. AB - A time series intervention analysis (TSIA) of dendrochronological data to infer the tree growth-climate-disturbance relations and forest disturbance history is described. Maximum likelihood is used to estimate the parameters of a structural time series model with components for climate and forest disturbances (i.e., pests, diseases, fire). The statistical method is illustrated with a tree-ring width time series for a mature closed-canopy Douglas-fir stand on the west slopes of the Cascade Mountains of Oregon, USA that is impacted by Swiss needle cast disease caused by the foliar fungus, Phaecryptopus gaeumannii (Rhode) Petrak. The likelihood-based TSIA method is proposed for the field of dendrochronology to understand the interaction of temperature, water, and forest disturbances that are important in forest ecology and climate change studies. PMID- 29479168 TI - The dawn of a new era for Paediatrics & Child Health. PMID- 29479169 TI - Pharmacological treatment of children with gastro-oesophageal reflux. PMID- 29479170 TI - Multiple red-brown macules and papules in a toddler. PMID- 29479171 TI - A 13-year-old girl with fever and limp. PMID- 29479172 TI - It's not all about the honey. PMID- 29479173 TI - A 4-year-old girl with head drops. PMID- 29479174 TI - Severe vitamin D deficiency: A persistent yet preventable problem among Canadian youth. PMID- 29479175 TI - On tides, tennis and determination. PMID- 29479176 TI - We Agree-Psychologists are Needed! Re: M van den Heuvel, T Barozzonio, K Milligan, E Ford-Jones, S Freeman. We need psychologists! Paediatr Child Health 2016;21(1):e1-e3. PMID- 29479177 TI - An irritable newborn with tender red bumps. PMID- 29479178 TI - Fatty liver in a non-obese patient. PMID- 29479179 TI - An unexpected rash. PMID- 29479180 TI - A surprising cause of motor tics. PMID- 29479181 TI - Comment on the CTS 2015 guidelines for asthma in preschoolers. PMID- 29479182 TI - Making it easier to 'choose wisely'. AB - The Choosing Wisely campaign has stimulated many clinicians to think about the appropriateness of various tests and treatments. Most of the recommendations published thus far are adult-focused. In this commentary, we discuss the development and early implementation of a Choosing Wisely 'top 5' list specifically aimed at children being cared for at our tertiary care children's hospital. We hope that this will encourage others involved in the health care of infants and children to engage in further thought and discussion about the appropriateness of current tests and therapies. Despite often focusing on the deficiencies, we are privileged to have a highly developed and well-resourced health care system in Canada which allows us tremendous freedom to order tests and treatments. It is incumbent on us as health care providers to exercise that privilege with the utmost responsibility and strive to choose wisely and thoughtfully when selecting tests and therapies for our patients. PMID- 29479183 TI - Supporting the developmental health of refugee children and youth. AB - The Canadian Government has announced that over 50,000 refugees from the Middle East will be resettled in Canada by 2018. More than one-third of these refugees are expected to be children. The Canadian Paediatric Society has called for the Canadian government to prepare for the influx of these children. This should include addressing developmental, behavioural, and mental health needs. The focus of this paper is the role of paediatricians and family physicians in caring for the developmental health of refugee children, as a means of supporting their developmental and learning potential. The authors suggest the use of EMPOWER (Education, Migration, Parents and Family, Outlook, Words, Experience of Trauma and Resources), a mnemonic checklist they developed for assessing developmental risk factors in refugee children. EMPOWER can be used along with online web resources such as Caring For Kids New to Canada in providing evidence-informed care to these children. PMID- 29479184 TI - Diagnosis and management of infants with congenital cytomegalovirus infection. AB - Congenital cytomegalovirus infection (cCMV) is the most common congenital infection, occurring in approximately 0.5% of live births. Most infected newborns are asymptomatic, but up to 20% develop sensorineural hearing loss or other permanent neurologic sequelae. The presentation of newborns with symptomatic cCMV is highly variable, and the infection is usually not diagnosed in the absence of a screening program. Newborn cCMV screening programs are estimated to be beneficial and cost-effective, and are increasingly being implemented. Diagnosis requires direct detection of virus in a sample obtained before 3 weeks of life, and is best performed by polymerase chain reaction (PCR) of saliva or urine, either of which is more sensitive than dried blood spot. Antiviral treatment of selected newborns with cCMV-related disease appears to improve hearing and neurocognitive outcomes. All infected infants should be evaluated promptly to determine appropriate therapy, and receive close audiologic and developmental follow-up. PMID- 29479185 TI - Long-term follow-up of cardiorespiratory outcomes in children born extremely preterm: Recommendations from a Canadian consensus workshop. AB - Bronchopulmonary dysplasia, the most common pulmonary complication of extremely preterm (EPT) birth, has longstanding multiorgan repercussions, with increasing reports of emphysema and cardiac disease in early adulthood. There are currently no clear recommendations pertaining to best practices for optimal multidisciplinary cardiorespiratory follow-up of EPT children. We report the outcomes of a 2-day consensus workshop involving a Canadian panel of 31 multidisciplinary experts with the goal of improvement and standardization of the cardiopulmonary follow-up care of EPT infants (i.e., born at <28 weeks' gestation), from neonatal discharge to mid childhood. The most relevant and important clinical outcomes to evaluate were identified. Practical aspects of integrating cardiopulmonary follow-up into ambulatory care clinics were explored. This article summarizes the discussions from this workshop and provides the panel's recommendations for clinical follow-up and research priorities. PMID- 29479186 TI - General paediatric inpatient deaths over a 15-year period. AB - Objective: To retrospectively review trends of general paediatric inpatient deaths at a tertiary care children's hospital over a 15-year period. Methods: Data were collected for all patients who died on the general paediatric wards or paediatric intensive care unit (PICU) during 1998, 2005 or 2012 and had a 'general paediatric condition'-an underlying condition or diagnosis that would normally result in admission to a general paediatric ward. Data were related to: demographics, health services utilization, information about provision and orders related to cardiopulmonary resuscitation (CPR) at time of death and involvement of palliative care services. Results: Eighty-five inpatients met inclusion criteria: 35 in 1998, 27 in 2005 and 23 in 2012. Nearly 95% of general paediatric patients who died in 1998 did so in the PICU, 59.3% in 2005 and 69.6% in 2012. The median age of death decreased from 3 years in 1998 to 2 years in 2012. The proportion of patients with 'no CPR' orders at time of death increased from 31.4% in 1998 to 87.0% in 2012. Similarly, the proportion of patients with palliative care team involvement prior to death increased from less than 10% in 1998 to 73.9% in 2012. Conclusions: The absolute number of inpatient general paediatric deaths has decreased from 1998 to 2012 at this hospital. A larger proportion of these deaths are occurring on the general paediatric wards rather than in the PICU over time. 'No CPR' orders and palliative care consultations are becoming more prevalent in these patients prior to death. PMID- 29479187 TI - Sickness presenteeism: The prevalence of coming to work while ill among paediatric resident physicians in Canada. AB - Background: Sickness presenteeism is defined as the act of attending one's job despite ill-health. Recently, physicians and other health care workers have become the focus of sickness presenteeism research, because presenteeism in this population can put patients at risk of infection. There are currently no data on this topic among physicians in Canada. The aim of this study was to investigate sickness presenteeism in paediatric resident physicians in Canada. Methods: We conducted an anonymous, online, cross-sectional survey study in which all paediatric residents in Canada were eligible. Outcomes of interest included prevalences of sickness presenteeism, sickness during the study period and voluntary self-appointed personal protective equipment use when engaging in sickness presenteeism. Results: Response rate was 56.5% (N=323). During the previous 2 months, 61% (95% confidence interval [CI] 55.7 to 66.3) of respondents reported having experienced an illness and 59% (95% CI 53.7 to 64.5) of respondents had come to work sick. Of those who reported becoming ill during the study period, 97.0% (95% CI 94.6 to 99.4) reported coming to work while sick. There was no difference in prevalence when comparing across post-graduate year training levels. Extra personal protective equipment was used by 86% (95% CI 82.1 to 91.7) when engaging in sickness presenteeism. Conclusion: Sickness presenteeism is a common phenomenon among paediatric resident physicians. Our results should influence residents and supervising staff physicians to encourage appropriate self-care at home, rather than presenteeism. PMID- 29479188 TI - Promoting booster seat use for young children: A school-based intervention pilot study. AB - Purpose: Misuse and/or lack of booster seat use are often associated with high rates of injury and death among school-aged children. This pilot study examined the efficacy and the potential effectiveness of a booster seat intervention in the classroom. Methods: Two elementary schools participated (randomly assigned as one intervention school and one control school). At the intervention school, a certified car seat specialist and a police officer held an interactive booster seat session. The height and age for each child were recorded. Children received a certificate indicating whether they met the requirements for booster seat use and a postcard with car seat restraint specifications. Children in the control school received a brochure on car seat safety. Pre- and post-intervention self reports were collected and booster seat use was observed. Results: Observational findings showed a decline in booster seat use at the control school and an increase in use at the intervention school. Self-reports of booster seat use indicated a decline at both schools; however, cell sizes were too small to permit statistical analyses. Conclusion: Anecdotally researchers found the sessions were easy to conduct and were well received by the children and could be easily integrated into programming in schools. Classroom sessions may have the potential to positively influence booster seat use among 6- to 8-year-olds. PMID- 29479189 TI - Literacy promotion at the Montreal Children's Hospital. AB - The foundations for language and literacy are set in utero when babies hear the tone of their mother's voice (1). There is strong evidence of a positive relationship between early literacy experiences and language and academic outcomes (2). Unfortunately, many parents do not know about the benefits of reading to and with young children, and many children enter school without the basic skills needed to learn to read and succeed. Physicians who have contact with young families are in a distinctive position to promote reading, though despite its evidence base, it has not yet become a universal intervention. A short description of the projects at the Montreal Children's Hospital is provided. PMID- 29479190 TI - Tonsillectomy or adenotonsillectomy versus non-surgical treatment for chronic/recurrent acute tonsillitis. PMID- 29479191 TI - Fifty years of research at the Janeway Children's Hospital. PMID- 29479193 TI - A 10-year-old girl with a fluctuating level of consciousness, ataxia and slurred speech. PMID- 29479192 TI - Caring for children and youth from Canadian military families: Special considerations. AB - Military families experience a number of life stressors, such as frequent geographical moves, long periods of separation within the family, geographic isolation from extended family support systems and deployments to high-risk areas of the world. While children and youth in military families experience all the same developmental and motivational trajectories as their civilian counterparts, they must also contend with more unusual developmental pressures and stressors placed on them by the unique demands of military life. The effects of the military life on families and children are beginning to be recognized and characterized more fully. Understanding the unique concerns of children and youth from military families and mobilizing specific resources to support them are critical for meeting the health care needs of this population. PMID- 29479194 TI - Eight-year-old girl with hepatomegaly. PMID- 29479195 TI - A 2-year-old boy with cough and anaemia. PMID- 29479196 TI - Efficacy of minimally invasive surfactant therapy in moderate and late preterm infants: A multicentre randomized control trial. AB - Background: Minimally invasive surfactant therapy (MIST) is a new strategy to avoid mechanical ventilation (MV) in respiratory distress syndrome. The primary aim of this study was to test MIST as a means of avoiding MV exposure and pneumothorax occurrence in moderate and late preterm infants (32 to 36 weeks' gestational age). Methods: This was a randomized controlled trial including three Canadian centres. Patients were randomized to standard management or to the intervention if they required nasal continuous positive airway pressure of 6 cm H2O and 35% FiO2 in the first 24 hours of life. Patients from the intervention group received MIST immediately after inclusion. The primary outcome was either need for MV or development of a pneumothorax requiring a chest tube. To ensure that clinicians were not biased toward delaying intubation in the intervention group, clinical failure criteria were also used as a primary outcome. The primary outcome was analyzed using bivariate and multivariate logistic regressions. Results: Among 45 randomized patients, 24 were assigned to MIST and 21 to standard management. Eight infants (33%) from the intervention group met the primary outcome criteria versus 19 (90%) in the control group (absolute risk reduction 0.57, 95% confidence interval 0.54 to 0.60). One patient in each group reached the primary outcome because of pneumothorax occurrence. The other patients were exposed to MV. None of the patients reached the clinical failure criteria. Conclusion: MIST for respiratory distress syndrome management in moderate and late preterm infants was associated with a significant reduction of MV exposure and pneumothorax occurrence. PMID- 29479198 TI - Cheerleading injuries in children: What can be learned? AB - Introduction: Cheerleading has gradually become more popular in Canada and represents an accessible way for youth to be physically active. Objective: To determine the differences in the injuries encountered by cheerleaders according to their age, in order to propose safety guidelines that take into account the developmental stages of children. Method: Retrospective database review of cheerleading injuries extracted from the Canadian Hospitals Injury Reporting and Prevention Program (CHIRPP) database between 1990 and 2010. The injuries were compared by age group (5 to 11 versus 12 to 19) according to their sex, mechanism of injury and injury severity. Results: Overall, in 20 years, there were 1496 cases of injuries documented secondary to cheerleading (median age 15, 4 (interquartile range [IQR]=2, 2) years); mostly females (1410 [94%]). Of that number, 101 cases were 5 to 11 years old (age group [AG]1), while 1385 were 12 to 19 (AG2). Participants in AG1 were found to have a higher proportion of moderate to-severe injury (46.5% compared with 28.2% in AG2). The odds ratio of moderate/severe injury for AG1 compared with AG2 was found to be 2.217 (95% CI [1.472; 3.339]). No fatalities were known to have occurred. Conclusion: Children's developmental stages affect their ability to participate in sports and the responses of their bodies to impact forces. Our findings concerning cheerleading injuries indicate that younger children (5 to 11 years old) are more likely to suffer moderate-to-severe injuries. Thus, on a local basis, the use of appropriate safety measures including appropriate flooring/safety mats and spotters to catch falling athletes should be mandatory. PMID- 29479197 TI - Prevalence and predictors of low serum 25-hydroxyvitamin D levels in rural Canadian children. AB - Objectives: Studies in Canada have reported varying prevalences of low serum 25 hydroxyvitamin D (25(OH)D) levels, but none have been conducted in rural paediatric populations. The purpose of this study was to determine the prevalence and predictors of low vitamin D levels in rural communities. Methods: We conducted a cross-sectional study of children aged 3 to 15 living in Canadian Hutterite communities. Serum 25(OH)D levels were measured between October 2008 and April 2009 using a chemiluminescence assay. Predictors of vitamin D levels were evaluated using multivariable linear regression. A multilevel model was used to evaluate the impact of individual, household and colony factors on the variation in vitamin D levels. Results: Serum 25(OH)D levels were available on 743 children/adolescents. The median was 62.0 nmol/L (interquartile range 51.0, 74.0). Levels lower than 50 nmol/L and 75 nmol/L were found in 152 (20.5%) and 565 (76%) children, respectively. Adolescents were at highest risk for levels <75 nmol/L (odds ratio 3.38, 95% confidence interval 2.00, 5.80). Age and latitude were negatively correlated with serum 25(OH)D level. In the multilevel model, most of the variation in levels was associated with individual children. Conclusion: Low vitamin D levels are a significant problem in rural Hutterite communities in Canada. Adolescents were at greatest risk for low levels and represent an important target group for supplementation. Variation in serum 25(OH)D levels was explained mostly at the individual level. Additional studies are needed to explore factors associated with individuals (e.g., genetics) leading to lower 25(OH)D levels. PMID- 29479199 TI - The Canadian Hospital Injury Reporting and Prevention Program: Captured versus uncaptured injuries for patients presenting at a paediatric tertiary care centre. AB - Objectives: The Canadian Hospital Injury Reporting and Prevention Program (CHIRPP) is an injury surveillance program that informs prevention policy locally and nationally. It is of import that it is reflective of the underlying population. The objective of this study was to describe differences between those injuries that were captured by the program, and those that were not. Methods: This was a retrospective chart review of patients presenting with an injury to the IWK Health Centre between January 12, 2013 and June 30, 2013. The patients (or their parents/guardians) either completed a CHIRPP form (captured injuries), or did not (non-captured). The probability of receiving a CHIRPP form was modelled using logistic regression using patients' age, gender, disposition, Canadian Triage Assessment Scale (CTAS) score and activity/event at time of injury. Results: A total of 2928 patients presented with an injury during the study period. Of these, 2135 (72.9%) were captured by the CHIRPP program and 793 (27.1%) were not. Patients (or parents) not returning the form to the department (465/793, 58.6%) represented the largest source of non-capture. The likelihood of non-capture increased with increasing CTAS score, the patient being admitted, and the following events at time of injury: drugs or overdoses, self-harm and foreign body involvement. Conclusion: There is an under-representation of seriously injured patients by CHIRPP at the IWK. This data may underestimate the true severity of injuries. It may also under-represent injuries that involve incidents of self-harm or drugs. Effort must be expended to increase the capture rate of CHIRPP. PMID- 29479200 TI - Constipation and paediatric emergency department utilization. AB - Background: Constipation is a common condition in children. Little is known about the acute health care utilization of constipated children, including how many present to the paediatric emergency department (ED), the spectrum of presenting complaints, investigations and treatments used. Methods: We conducted a cross sectional chart review of all 42,875 visits to British Columbia Children's Hospital ED between August 31, 2012 and September 1, 2013. All visits were assessed for a potential diagnosis of constipation and a total of 913 patients were included. We recorded the chief complaints, tests performed and therapies administered in the ED and measures of flow/efficiency including waiting time (WT), length of stay (LOS) and disposition. Results: Constipation-related visits comprised 2.1% of overall visits. Abdominal pain was found to be the most common presenting complaint in 65.6% of patients; however, 11.9% of patients presented with complaints unrelated to the gastrointestinal tract. Abdominal radiographs were obtained in nearly one-third of patients and almost half of the patients received a fleet enema in the ED. Only a quarter of patients were discharged home on longer-term management. Measures of ED flow were similar between groups, with no meaningful difference in WT or LOS. The vast majority of children (99.7%) were discharged home. Conclusions: Constipation can be treated as an out-patient, rather than burdening the paediatric ED unnecessarily. This study demonstrates over utilization of radiologic tests and invasive ED treatments and an under utilization of outpatient medication and dietary counselling that may contribute to unnecessary return ED visits. PMID- 29479201 TI - Ten-year experience of fetal alcohol spectrum disorder; diagnostic and resource challenges in Indigenous children. AB - Background: Although fetal alcohol spectrum disorder (FASD) can have a disproportionate impact in some Indigenous communities, there is a paucity of literature on its epidemiology. Objective: To characterize the epidemiology of Indigenous individuals under the age of 18 years who were diagnosed with FASD at Anishnawbe Health Toronto over a 10-year period. Methods: Children who were assessed at Anishnawbe Health Toronto from 2002 to 2012 and met the 2005 criteria for FASD were included. The multidisciplinary team assessed neurodevelopmental abnormalities, FASD facial features and growth parameters and enquired about maternal alcohol consumption, current custody and involvement with the criminal justice system. Results: Forty-nine children were diagnosed with FASD. None of these had full fetal alcohol syndrome (FAS); 12 were diagnosed as partial FAS and 37 with alcohol-related neurodevelopmental disorder (ARND). Thirty-five were male and the median age at diagnosis was 9 years. Nineteen were wards of children's services, and 8 were living with adoptive parents. All children had abnormalities in psychometric testing. Other issues included: behavioural issues (80%); learning disabilities (63%); attention deficit hyperactivity disorder (43%); developmental delay (14%); involvement with the criminal justice system (12%) and alcohol abuse (10%). The morbidity and impairment for ARND was higher on almost every measurement compared with partial FAS. Conclusions: FASD is a preventable cause of lifelong significant morbidity to Indigenous children with a high proportion of children needing foster-care services and involvement with the criminal justice system at an early age. Although ARND is difficult to diagnose, it can result in significant morbidity. Additional resources for culturally sensitive primary prevention and early diagnosis of FASD for Indigenous families are required. PMID- 29479202 TI - Variations and similarities in clinical management of neonatal abstinence syndrome: Findings of a Canadian survey. AB - Background: There are no evidence-based national guidelines for managing neonatal abstinence syndrome (NAS) and surveys from other countries have demonstrated considerable variations in practice. Objective: To describe NAS management practices in Canada. Method: The directors of all Level 2 and Level 3 neonatal intensive care units (NICUs) were contacted to request their participation in a structured telephone survey. Frequency distributions were generated and associations between practice variations and unit type (Level 2 or 3) and size were examined. Results: Personnel at 65 of 103 sites (63.1%) participated. Most (92.3%) stated their hospital has a written NAS practice guideline. The majority (89.5%) use a version of Finnegan's scoring system to monitor signs. If pharmacological treatment is required, 89.2% admit infants to the NICU and 93.8% routinely use cardiorespiratory monitors when treatment is initiated. Morphine is the first-line medication at most sites (96.9%). There was greater variability in terms of other practices: 44.6% observe at-risk infants in the NICU, while 52.3% allow them to room-in with their mothers; 65.1% use adjunct medications; 36.9% and 38.9% will discharge infants on the first-line and adjunct medications respectively, and 53.8% reported that breastfeeding is always encouraged, while 44.6% discourage breastfeeding if the mother continues to use illicit drugs and 1.5% make recommendations on an individual basis. Few practice variations were associated with unit type or size. Conclusion: While most NICUs surveyed have an NAS practice guideline, there are some notable differences in how NAS is managed. This underscores the need for research that can be translated into best practices. PMID- 29479203 TI - Prevalence of overweight and obesity in Canadian children, 2004 to 2013: Impact of socioeconomic determinants. AB - Background: We recently reported an encouraging decline in the prevalence of overweight (OW) or obesity (OB) in Canadian children from 31% to 27% with stabilization in OB rates at ~13% using national survey data between 2004 and 2013. Although rates were lower for toddlers, girls and those of European (White) race-ethnicity, secular trends persisted after adjustment. In this follow-up study, we explored the ability of socioeconomic status to explain or modify these relationships using the same data set. Methods: We analyzed a decade of anthropometric data from 14,014 children aged 3 to 19 years. We explored the influence of income adequacy, education, immigration status, family type (e.g., single-parent) and geographic region by multivariable logistic regression. Data sets included Canadian Community Health Survey cycle 2.2 and Canadian Health Measures Surveys cycles 2 and 3. Results: Children from higher-income families fared better than their lower-income counterparts in each survey era and demonstrated a significant decline in OW/OB from 29.1% (95% confidence interval [CI]: 27.3 to 30.8) in 2004 to 2005 to 22.2% (95% CI: 19.8 to 24.6) in 2012 to 2013, P<0.001. Regression models confirmed the effects of time, age, sex, race, income, education, immigration and region. Although single-parent families did less well in univariate analyses, this effect vanished after adjustment for other socioeconomic status variables, such as income and education. Regional variations persisted, with lower rates of OB and OW/OB in British Columbia and higher rates in Atlantic Canada. Conclusions: These results confirm that progress is possible against this important public health challenge, underline the need to better understand sociodemographic risk factors and identify groups at higher risk for possible interventions. PMID- 29479204 TI - Time to revisit tummy time: A commentary on plagiocephaly and development. AB - Many centres report receiving more referrals for deformational plagiocephaly since implementation of the Back to Sleep campaign. This commentary combines clinical experience, local quality improvement data and existing literature to highlight three points to help prevent and manage plagiocephaly: (1) communicating 'Back to Sleep, Tummy to Play', (2) the importance of early detection and (3) plagiocephaly as a marker of developmental risk. We recommend: (1) equal emphasis on the messages of Back to Sleep and supervised Tummy to Play, to start this messaging early and reinforce at every opportunity; (2) examination of skull shape and neck range of motion as a routine component of the newborn assessment so that caregivers can implement positioning and handling suggestions immediately and (3) physiotherapy referral for babies who have torticollis, or who show persistent or worsening plagiocephaly despite positioning and handling interventions, for further assessment and management. PMID- 29479205 TI - Patients first: Getting youth mental health right...finally? AB - Service delivery in youth mental health is a top priority for Canadians and their health providers. This synthesizing article describes the magnitude of youth suicide in comparison to other leading causes of mortality in youth, brings together an analysis of current service delivery and proposes an alternate and evidence-based strategy for youth mental health treatment. PMID- 29479206 TI - Missed appointments: More complicated than we think. PMID- 29479207 TI - Up Schmidt's creek: When the right treatment goes wrong. PMID- 29479208 TI - A 6-week-old girl with weak cry and cardiac murmur. PMID- 29479209 TI - A 9-year-old girl presenting with hearing voices. PMID- 29479210 TI - The breastfeeding paradox: Relevance for household food insecurity. AB - Mitigating the harmful effects of adverse social conditions is critical to promoting optimal health and development throughout the life course. Many Canadians worry over food access or struggle with household food insecurity. Public policy positions breastfeeding as a step toward eradicating poverty. Breastfeeding fulfills food security criteria by providing the infant access to sufficient, safe and nutritious food that meets dietary needs and food preferences. Unfortunately, a breastfeeding paradox exists where infants of low income families who would most gain from the health benefits, are least likely to breastfeed. Solving household food insecurity and breastfeeding rates may be best realized at the public policy level. Notably, the health care provider's competencies as medical expert, professional, communicator and advocate are paramount. Our commentary aims to highlight the critical link between breastfeeding and household food insecurity that may provide opportunities to affect clinical practice, public policy and child health outcomes. PMID- 29479211 TI - Goal setting within a tertiary-level early developmental intervention program. AB - Objectives: To determine the domains of parent-therapist collaboratively set goals for intervention within a family-centered, tertiary-level early developmental intervention (EDI) program. To report changes in ratings for performance and satisfaction of performance pre- and postintervention for the set goals. Methods: This study includes all children with complex developmental disabilities (30 +/- 3 months of age, 61% boys) registered in a tertiary-level EDI program from 2009 to 2012 whose parents completed the Canadian Occupational Performance Measure (COPM) to evaluate goal setting. The International Classification of Functioning, Disability and Health: Children & Youth version (ICF-CY) domain for each goal was recorded. Pre- and postintervention ratings for individual and averaged goals per child were calculated. Positive changes in ratings were determined by an increase of <=2 and presented as a proportion and as means (standard deviation). Student t test, Fisher Exact and chi-square tests compared groups. Results: Of 483 individual goals set for 168 children, 65.4% were in the ICF-CY activity domain, 16.4% participation, 10.3% body function, 7.4% environment and 0.4% body structure. Positive changes in ratings for performance occurred in 70%; for satisfaction, 68%, with no difference in relation to domain. Positive changes in average ratings per child showed: performance, 67%; satisfaction, 66%. Conclusion: Intervention goals for disabled children within tertiary-level EDI are primarily those of activity, not participation as ICF-CY recommends; two-thirds of goals show positive change. These results suggest the need for further evaluation of goal setting within EDI programs with the expectation of increasing goals of participation and improving ratings for performance and satisfaction. PMID- 29479212 TI - Physician and parent barriers to the use of oral corticosteroids for the prevention of paediatric URTI-induced acute asthma exacerbations at home. AB - Objectives: Administration of oral corticosteroids at the onset of an upper respiratory tract infection (URTI) can be effective in the management of acute asthma exacerbations in children. This study was designed to identify barriers to parent-initiated implementation of clinical practice guideline-recommended use of oral corticosteroids for prophylaxis against severe asthma exacerbations in children. Methods: Twenty-seven children who presented to BC Children's Hospital with URTI-induced asthma exacerbations were recruited. Parents received a filled prescription for a course of oral corticosteroids to be used at the earliest onset of their child's next URTI. Each family was contacted monthly over a 1-year period to inquire about URTI events, asthma symptoms, medication use and health care utilization. Focus groups were held with family physicians, paediatricians and parents; transcripts were analyzed qualitatively to identify key themes. Results: Incidence of URTI events among participants was high (85%). Uptake of study medication was low; 44% used the medication as directed at their first URTI event. Eleven per cent of the patients who used the study medication also visited the emergency department for an exacerbation. Focus groups identified four main barriers to the effective use of parent-initiated oral corticosteroids: physician resistance and conflicting messages from providers; parent uncertainty about oral corticosteroids; multiple caregivers and relative ease of access to an emergency department. Conclusion: We have identified key barriers to the effective use of parent-administered oral corticosteroids as an asthma management strategy and gained important insights regarding the research that is required to enhance the applicability of the strategy. PMID- 29479213 TI - Temperament and fracture in preschool-aged children. AB - Objectives: Approximately one-half of all children will sustain a fracture before adulthood. Understanding the factors that place a child at increased risk of fracture is necessary to inform effective injury prevention strategies. The purpose of this study was to examine the association between temperament and fracture risk in preschool-aged children. Methods: Children aged 3 to 6 years who were diagnosed with a fracture were recruited from the Hospital for Sick Children Fracture Clinic. Using a retrospective case-control study design, the 148 cases were frequency-matched by age and sex to 426 controls from the TARGet Kids primary care paediatric cohort. The Childhood Behaviour Questionnaire, a 36-item caregiver response questionnaire was used to assess three of the following temperament factors: surgency (e.g., high activity level), negative affect (e.g., anger, fear, discomfort) and effortful control (e.g., attentional focusing). Results: Unadjusted logistic models demonstrated no association between children with previous fracture and higher scores of surgency (unadjusted odds ratio [OR]=1.06, 95% confidence interval [CI]: 0.84, 1.34), negative affect (unadjusted OR=1.15, 95% CI: 0.93, 1.42) or effortful control (unadjusted OR=0.80, 95% CI: 0.63, 1.03). Further, models adjusted for covariates also demonstrated no significant association with surgency (1.00, 95% CI: 0.78, 1.29), negative affect (1.09, 95% CI: 0.86, 1.37) and effortful control (0.80, 95% CI: 0.61, 1.05). Conclusion: None of the three main temperament types identified by the Childhood Behaviour Questionnaire were associated with an increase in fracture risk. PMID- 29479214 TI - Wellness in Canadian paediatric residents and their program directors. AB - Purpose: This study aimed to explore the prevalence of and identify risk factors for depression and burnout in paediatric residents and paediatric program directors (PDs) in Canada. Methods: Residents and PDs completed separate anonymous online surveys consisting of demographic questions, the Maslach Burnout Inventory and the Patient Health Questionnaire-2, which screens for risk of depression. Results: A total of 166 paediatric residents completed the survey representing 14/17 Canadian paediatric residency programs. Participants were 74% female. Twenty-four (14%) were at risk of depression and 69 (42%) met criteria for burnout. Burnout was associated with year of residency (P=0.03), with third year residents at highest risk. Residents who reported unhelpful wellness curricula were at risk of burnout (81.3%) compared with those with no wellness curricula (51.1%) or curricula reported as helpful (29.1%, P=0.01). More than 79% of residents at risk of depression also met criteria for burnout (P=0.01). No associations were identified for risk of depression.Seventeen of 21 Canadian PDs completed the survey. No PDs were identified as at risk for depression. Five PDs (29%) met criteria for burnout. Conclusions: Paediatric PDs in Canada have relatively low rates of burnout and depression. In contrast, a large number of Canadian paediatric residents met criteria for burnout. Residents in programs with wellness curricula described as helpful are at lowest risk of burnout. Future research should include identifying features that define helpful wellness curricula and exploring interventions to help residents at risk of burnout and depression. PMID- 29479215 TI - Assessment of WINROP algorithm as screening tool for preterm infants in Manitoba to detect retinopathy of prematurity. AB - Objective: Developing less invasive methods for early detection of retinopathy of prematurity (ROP) is vital to minimizing blindness in premature infants. Lofqvist and colleagues developed a computer-based ROP risk algorithm (WINROP) (https://winrop.com), which detects downtrends in postnatal weight gain that correlate with the development of sight-threatening ROP. The aim of this study is to investigate the sensitivity and specificity of the WINROP algorithm to detect vision-threatening ROP. Methods: This is a retrospective chart review study between January 2008 and December 2013. This study was conducted in the neonatal intensive care unit in Children's Hospital at Health Sciences Centre, Winnipeg, Manitoba, Canada. The study included preterm infants, less than 32 weeks' gestation, who were admitted to the hospital during the study period. The included 215 infants were eligible for ROP screening and had sufficient data to be entered into the WINROP algorithm. Infants were screened by a paediatric ophthalmologist for retinopathy of prematurity. The body weight of infants was measured weekly and entered into the WINROP algorithm; the sensitivity and the specificity of the WINROP algorithm were assessed. Results: The mean gestational age was 28.6 +/- 1.8 weeks. The mean body weight was 1244 +/- 294 g. The sensitivity of the WINROP algorithm to detect vision-threatening retinopathy of prematurity in our cohort was 90% (P=0.021) with a specificity of 60% (P=0.002). Conclusion: The WINROP algorithm lacks sufficient sensitivity to be used clinically in our population. The algorithm needs to be reassessed in contemporary populations. PMID- 29479216 TI - A qualitative study of the at-home pain experience for children with an arm fracture. AB - Objective: Most children treated in the emergency department (ED) with painful conditions are discharged home to the care of their parents. There is growing evidence that at-home pain management is inadequate. No studies have evaluated the child's report of their at-home pain experience. Our objective was to explore the child's perspective on the pain experience at home after ED discharge. Methods: We performed semistructured interviews with children aged 4 to 14 years discharged from the ED with an arm fracture. Interviews occurred at the child's home and were recorded and transcribed verbatim. Using a narrative analysis, themes were identified. Results: A total of 30 children were interviewed. Overall, three distinct themes regarding the pain experience were identified: (1) issues of communication between children and their parents regarding pain management, (2) issues of communication between children and ED health care personnel and (3) misunderstandings by children about pain and pain medication. Conclusion: Communication is a critical barrier to optimizing the at-home pain experience. This novel information may be used to develop innovative interventions directed at the child and parent to improve the at-home pain experience. PMID- 29479217 TI - Impact of sleep on injury risk among rural children. AB - Objectives: To examine sleep patterns in a large cohort of rural children and explore the association between sleep patterns and injury occurrence. Methods: Cross-sectional analyses of the baseline survey from a prospective cohort study (2012 to 2017) was conducted with 46 rural schools in Saskatchewan, Canada who distributed surveys to parents of 2275 rural dwelling farm and nonfarm children aged 0 to 17 years. Parents reported child sleep characteristics and farm or nonfarm injury in the previous calendar year. Multivariable log-binomial regression examined associations between sleep characteristics and injury risk. Results: There was a significant trend of decreasing sleep duration with increasing age (P-trend < 0.001). Short sleep duration on weekdays (RR: 2.14; 95% CI: 1.25 to 3.66) and sleep debt (RR: 1.89; 95% CI: 1.21 to 2.95) increased injury risk in school-age children (7 to 12 years) but not in teens. A nearly fivefold increase in injury risk was identified among school-age children reporting all sleep problems (RR: 4.99; 95% CI: 1.99 to 12.50). Snoring in teens (13 to 17 years), often a symptom of obstructive sleep apnea, was associated with increased injury risk (RR: 1.98; 95% CI: 1.17 to 3.33). There were no statistically significant associations identified between sleep characteristics and injury risk in preschool children. Conclusion: Injuries to rural children are an important public health concern. This study highlights the impact of sleep problems on risk for injury among rural children. These findings are discussed in light of the recent American Academy of Pediatrics Technical Report on Insufficient Sleep in Adolescents and Young Adults. PMID- 29479218 TI - Parent-led interventions in reducing infant vaccination pain after participation in a longitudinal randomized control trial. PMID- 29479219 TI - Parenting interventions for the prevention of unintentional injuries in childhood. PMID- 29479220 TI - Canada's eight-component vaccine safety system: A primer for health care workers. AB - Concerns about vaccine safety make some parents hesitant about immunization. Health care providers are pivotal in helping parents understand that Canada is a leader in vaccine safety. The present practice point provides an update on the eight components of Canada's vaccine safety system: (1) an evidence-based pre license review and approval process; (2) strong regulations for manufacturers; (3) independent evidence-based vaccine use recommendations; (4) immunization competency training and standards for health care providers; (5) pharmacovigilance programs to detect and (6) determine causality of adverse events following immunization (AEFIs); (7) a program for vaccine safety and efficacy signal detection; and (8) the Canadian Immunization Research Network's special immunization clinics for children who have experienced serious AEFIs. PMID- 29479221 TI - Le systeme d'innocuite vaccinale canadien en huit etapes : des notions pour les travailleurs de la sante. AB - Parce qu'ils s'inquietent de l'innocuite vaccinale, certains parents hesitent a faire vacciner leurs enfants. Les professionnels de la sante jouent un role determinant aupres des parents pour leur faire comprendre que le Canada est un chef de file en matiere d'innocuite vaccinale. Le present point de pratique fournit une mise a jour des huit etapes du systeme d'innocuite vaccinale canadien : 1) une analyse pre-homologation et un processus d'approbation fondes sur des donnees probantes; 2) une reglementation rigoureuse pour les fabricants; 3) des recommandations independantes et fondees sur des donnees probantes a l'egard de l'utilisation des vaccins; 4) la formation et les normes sur les competences en matiere d'immunisation pour les travailleurs de la sante; 5) des programmes de pharmacovigilance pour deceler et 6) determiner la causalite des effets secondaires suivant l'immunisation (ESSI); 7) un programme pour la detection des signaux relatifs a l'innocuite et a l'efficacite vaccinales; et 8) les cliniques de vaccination speciales du Reseau de recherche canadien sur l'immunisation pour les enfants qui ont ete victimes de graves ESSI. PMID- 29479222 TI - Rh sensitization in Canada is not obsolete. PMID- 29479223 TI - Le systeme d'innocuite vaccinale canadien en huit etapes : des notions pour les travailleurs de la sante. AB - Parce qu'ils s'inquietent de l'innocuite vaccinale, certains parents hesitent a faire vacciner leurs enfants. Les professionnels de la sante jouent un role determinant aupres des parents pour leur faire comprendre que le Canada est un chef de file en matiere d'innocuite vaccinale. Le present point de pratique fournit une mise a jour des huit etapes du systeme d'innocuite vaccinale canadien : 1) une analyse pre-homologation et un processus d'approbation fondes sur des donnees probantes; 2) une reglementation rigoureuse pour les fabricants; 3) des recommandations independantes et fondees sur des donnees probantes a l'egard de l'utilisation des vaccins; 4) la formation et les normes sur les competences en matiere d'immunisation pour les travailleurs de la sante; 5) des programmes de pharmacovigilance pour deceler et 6) determiner la causalite des effets secondaires suivant l'immunisation (ESSI); 7) un programme pour la detection des signaux relatifs a l'innocuite et a l'efficacite vaccinales; et 8) les cliniques de vaccination speciales du Reseau de recherche canadien sur l'immunisation pour les enfants qui ont ete victimes de graves ESSI. PMID- 29479224 TI - Congenital molluscum contagiosum. PMID- 29479225 TI - Newborn with bilateral eyelid swelling, rash and erythema. PMID- 29479226 TI - A 7-year-old girl with acute onset esotropia. PMID- 29479227 TI - A 7-year-old boy with dysphagia and proximal muscle weakness. PMID- 29479228 TI - Twenty-four-hour in-house neonatologist coverage and long-term neurodevelopmental outcomes of preterm infants. AB - Objectives: To compare short- and long-term neurodevelopmental outcomes at 3 years of corrected age of preterm infants cared for by 24-hour in-house staff neonatologists and those cared for by staff neonatologists during daytime only. Methods: Retrospective analysis of prospectively collected follow-up data on all nonanomalous preterm infants from 1998 to 2004 excluding year 2001 as a washout period. Infants were divided into two groups based on care provided by staff neonatologists: 24-hour in-house coverage (24-hour coverage 1998-2000) and daytime coverage (day coverage 2002-2004). Short- and long-term outcomes were compared. Results: A total of 387 (78%) of the screened infants were included. Twenty-four-hour coverage (n=179) and day coverage (n=208) groups had a median birth weight (BW) of 875 g (range 470-1250) and 922 g (480-1530; P=0.028), respectively, and both had a median gestational age of 27 weeks. In the day coverage group, a smaller proportion of mothers had chorioamnionitis (20% vs. 30%; P=0.025), received less antibiotics (62% vs. 73%; P=0.023), and infants had fewer cases of confirmed sepsis (14% vs. 23%; P=0.022). In the day coverage group, a larger number of infants had respiratory distress syndrome (87% vs. 77%; P=0.011) and required prolonged mechanical ventilation (median 31 vs. 21 days; P=0.002). The incidence of major neurodevelopmental impairment was not significantly different between the two groups (odds ratio 0.76; 95% confidence interval 0.34-1.65). Conclusions: Duration of mechanical ventilation was reduced with 24-hour in-house coverage by staff neonatologists. However, 24-hour coverage was not associated with any difference in neurodevelopmental (ND) outcomes at 3 year corrected age. PMID- 29479229 TI - Adherence to antimuscarinics in children with overactive bladder. AB - Objectives: Adherence to antimuscarinics for the treatment of overactive bladder is known to be low in adults but there is scarce data on adherence in paediatric patients. Our objectives were to evaluate the adherence of children to antimuscarinics and to identify influencing factors. Methods: Children aged 5 to 18 years and treated with an antimuscarinic agent for at least 6 months were recruited at a routine visit and had to fill out a questionnaire. Their pharmacists were then contacted to inquire about prescription renewals since the beginning of treatment. The medication possession ratio was calculated and grouped by time blocks of 1, 3, 6 and 12 months. The pharmacists were contacted again 6 months after the recruitment visit. A medication possession ratio >= 80% was considered as good adherence. Results: Seventy-two patients were recruited with a mean age of 10.1 years. The self-reported adherence was 93%. Prior to the questionnaire, the medication possession ratio was >= 80% in 36%, 57%, 64% and 74% of cases in blocks of 1, 3, 6 and 12 months, respectively. After the questionnaire, the medication possession ratio improved to 53%, 65% and 71% for blocks of 1, 3 and 6 months, respectively. No influencing factors were identified. Conclusions: Measured adherence to antimuscarinics in children with overactive bladder is higher than in adults but significantly lower than the self reported adherence. Good self-reported adherence must be questioned to avoid unnecessary dose escalation or change of medication. Strategies to increase medication adherence are required to improve treatment efficacy. PMID- 29479230 TI - A nurse-initiated jaundice management protocol improves quality of care in the paediatric emergency department. AB - Background: Hyperbilirubinemia is a common neonatal condition requiring timely management to prevent acute bilirubin encephalopathy. Management protocols allow nonphysicians to initiate designated actions prior to physician assessment. Objective: To assess the effectiveness of a nurse-initiated neonatal jaundice management protocol for serum bilirubin sampling and phototherapy for neonates presenting with hyperbilirubinemia to the Paediatric Emergency Department (PED). Methods: A health records review was performed for jaundiced neonates 12 months prior to the introduction of the management protocol (control period) and 12 months after (intervention period). Randomly selected charts were evaluated for time to serum bilirubin sampling, phototherapy initiation, ED length of stay, admission rate, completion of direct antiglobulin test and nursing documentation. Results: Two hundred and sixty-six neonates (131 control and 135 intervention) were included. Median time to serum bilirubin sampling was reduced by 22% (36 min versus 28 min; P<0.001) with 34 min difference at the 90th percentile (94 min [95% confidence interval (CI) 63.7 to 116.9] versus 60 min [95% CI 49.0 to 78.2]). Statistically significant improvements were found in time to phototherapy initiation (127 min [95% CI 72.0 to 160.7] versus 65 min [95% CI 50.0 to 72.4] at 90th percentile), ED length of stay (267 min [95% CI 180.9 to 292.9] versus 216 min [95% CI 171.1 to 247.4] at 90th percentile) and hospital admissions (36% versus 17%; P<0.001). Improvements were also observed in direct antiglobulin test measurement (P<0.001) and nursing documentation (P=0.017). Conclusions: Implementation of a PED neonatal jaundice management protocol was associated with improved timeliness and standardization of care for this common and important condition. PMID- 29479231 TI - Initiation of passive cooling at referring centre is most predictive of achieving early therapeutic hypothermia in asphyxiated newborns. AB - Objective: To identify factors associated with early initiation and achievement of therapeutic hypothermia (TH) in newborns with hypoxic-ischemic encephalopathy (HIE). Methods: Retrospective cohort study of newborns who received TH according to National Institute of Child Health and Human Development (NICHD) criteria in two academic level 3 Neonatal Intensive Care Units (NICU) between 2009 and 2013. All infants were transported by a neonatal transport team (NNTT). Multivariate linear regression including who initiated cooling and degree of resuscitation in the model was performed. Results: Two hundred and seven infants were included. Waiting for advice from a tertiary care NICU was independently associated with a 50 minute delay in the median time of initiation of TH. The need for extensive resuscitation (cardiopulmonary resuscitation [CPR] or epinephrine) was independently associated with a reduction of 43 minutes in the median time to reach target core temperature. Log-transformed time to initiation of TH was associated with time to reach target core temperature (P<0.001). A doubling of time to initiation of TH corresponds to a 24% (95% CI 18% to 30%) increase in median time to reach target core temperature. Conclusions: Initiating passive cooling at the referring centre, before transfer, is critical to faster achievement of target core temperature in asphyxiated infants. Greater outreach education and development of clinical care pathways are needed to improve optimal delivery of TH to enhance outcome. PMID- 29479232 TI - A shift to placing parents in charge: Does it improve weight gain in youth with anorexia? AB - Family-based treatment (FBT) has emerged as a promising approach for medically stable youth with anorexia nervosa (AN). While there is evidence that therapists embrace the core principles of FBT, most face barriers in implementing the model with fidelity. Little research has been conducted to determine whether adhering to the core methods of placing parents in charge are sufficient in restoring weight in youth with AN. This study involved a chart review of youth under 16 years of age, treated by a Canadian tertiary care health centre-based eating disorders team (EDT). The purpose was to compare the weight gain of youth treated before and after the team was trained in FBT and shifted to empowering parents to be in charge of weight gain. As predicted, youth who participated in family sessions adhering to the 'parents in charge' approach (PIC, N=32) made greater gains in percentage of ideal body weight (%IBW) and were more likely to reach body weights within a healthy range as compared with youth (N=14) who participated in a 'non-specific therapy' (NST) involving expert driven psycho educational family sessions. Youth whose parents were placed in charge of weight gain were also significantly less likely to be hospitalized on the psychiatry unit for weight restoration, had significantly shorter mean duration of stays on this unit, and required tube-feeding less frequently than youth who participated in NST. Collectively, the results suggest that placing parents in charge of refeeding promotes efficient weight gain, while decreasing the need for more intensive intervention. PMID- 29479233 TI - Sleep problems over a year in sexually abused preschoolers. AB - Objectives: The aim of the present study was to explore sleep problems in sexually abused preschoolers over a year. Methods: The sample consisted of 224 abused children and 83 nonabused children aged 3 to 6 years old at enrolment into the study (T1), and 85 abused children and 73 nonabused children at the second evaluation, approximately 1 year later (T2). Sleep problems were assessed using parental reports on the Child Behavior Checklist - Preschool Version. Results: Multivariate analysis of covariance revealed that sexually abused preschoolers presented higher scores of sleep problems than nonabused children on all items related to sleep problems at T1. Results from a regression analysis revealed that sexual abuse remained associated with higher levels of sleep problems after controlling for sociodemographical variables. At T2, abused preschoolers still presented more sleep problems than nonabused children on all but one of the sleep items. Results from a repeated measure one-way analysis of covariance revealed that abused preschoolers presented higher total sleep scores at both measurement times. Time was not associated with levels of sleep problems and sleep problems did not evolve differently for abused and nonabused children. Conclusions: Sexually abused preschoolers are at risk of presenting with sleep problems. These results are worrisome given the negative impacts of sleep problems on child development. Research and clinical implications are discussed. PMID- 29479235 TI - Three hundred babies born to underhoused mothers in Toronto-understanding the problem and how we can help. AB - Little is known about pregnancy in underhoused women, possibly because the number of underhoused mothers with babies in Toronto has been significantly underestimated. Using a novel data collection method, it has been found that there are approximately 300 babies being born each year to underhoused women in Toronto. This finding has significant public health implications, as these women are at increased risk of multiple issues related to physical health, mental health, child protection, poverty and safety. This commentary presents a new data collection strategy, highlights the importance of accurate data collection and offers suggestions for supports for this over-looked population. PMID- 29479234 TI - Health transition experiences of Canadian ventilator-assisted adolescents and their family caregivers: A qualitative interview study. AB - Purpose: No studies have explored the experiences of Canadian mechanical ventilator-assisted adolescents (VAAs) living at home as they transition from paediatric to adult health providers. A better understanding of the needs of this growing population is essential to provide transition services responsive to VAAs and caregiver-identified needs. Methods: We conducted semistructured telephone interviews with adolescents and family caregivers who had recently initiated or completed transition to adult care recruited from three Canadian university affiliated paediatric home ventilation programs. We analyzed transcripts using a theoretical framework for understanding facilitators and barriers to transition. Results: We interviewed 18 individuals representing 14 episodes of paediatric to adult transition. Participants identified early planning, written informational materials and joint paediatric-adult provider-family transition meetings as facilitators of care transition to adult services and providers. Barriers included insufficient information, limited access to interprofessional (nursing and allied health) providers and reduced funding or health services. Barriers resulted in service disruption and a sense of 'medical homelessness'. While most families related a positive transition to a new 'medical home', families caring for VAAs with moderate-to-severe cognitive and/or physical dependence more commonly reported transition difficulties. Conclusions: Important opportunities exist to enable improvements in the transition experiences of VAAs and their family caregivers. To maximize service continuity during paediatric to adult transition, future research should focus on transition navigator roles, interprofessional health outreach and the needs of families caring for VAAs with cognitive and physical deficits. PMID- 29479236 TI - The next vaccine-autism question: Are school-aged youth with autism spectrum disorder undervaccinated and, if so, why? AB - Over the past two decades, the words 'autism' and 'vaccination' have often been linked and mired in controversy. In this commentary, we raise a different question about autism spectrum disorder (ASD) and vaccines: Are school-aged youth with ASD undervaccinated and, if so, why? There are several reasons why youth with ASD might be undervaccinated, including: belief in a vaccine-ASD link, challenges faced by youth with ASD when seeking health care and vaccine hesitancy factors that affect the general population. Possible undervaccination in this group is concerning given the prevalence of ASD and the key role of vaccinations in preventing infectious diseases. More research is needed to establish definitively whether youth with ASD are undervaccinated and to understand facilitators and barriers to vaccination for this population. This would help public health officials to develop and implement targeted policy and practice changes to increase vaccination uptake in youth with ASD, thereby increasing immunization equity. PMID- 29479237 TI - Amphetamines for attention deficit hyperactivity disorder in children and adolescents. PMID- 29479238 TI - Recommandations sur l'utilisation du vaccin antirotavirus chez les nourrissons. AB - Le present document de principes fournit de l'information sur l'infection a rotavirus clinique et les vaccins antirotavirus au Canada. Depuis l'adoption des programmes de vaccination antirotavirus finances par les gouvernements au Canada, les preuves s'accumulent quant a l'efficacite des vaccins antirotavirus pour prevenir la gastroenterite aigue. Selon les donnees a jour, l'efficacite du vaccin serait de l'ordre de 85 % pour prevenir une maladie grave, y compris les hospitalisations et les consultations a l'urgence, lorsque la couverture vaccinale est elevee. De plus, une importante protection collective est attestee chez les enfants plus ages. La surveillance postcommercialisation a permis de deceler une tres legere augmentation du risque d'invagination chez les enfants (un a trois cas sur 100000), qui se manifeste generalement dans la semaine suivant la vaccination. Les nourrissons qui ont une immunodeficience marquee, demontree ou presumee, ne devraient pas recevoir ce vaccin. PMID- 29479239 TI - A 15-year-old boy with acute onset abdominal pain and hypertension. PMID- 29479240 TI - First episode of seizure in a 10-year old. PMID- 29479241 TI - Audit of pulse oximetry screening for critical congenital heart disease (CCHD) in newborns. AB - Objectives: To assess the efficacy of a new screening protocol for critical congenital heart disease (CCHD). Background: In March 2014, the Ontario Provincial Council for Maternal Child Health (PCMCH) recommended screening for CCHD, utilizing pulse oximetry to measure oxygen saturation as part of the newborn examination. However, this is yet to be implemented in all hospitals. Method: An audit of consecutive healthy normal newborn patients in a secondary level centre in Ontario with early adoption of the screening recommendation over a 1-year period was undertaken. Results: The median age of screening was 25 hours (6 to 80 hours). Compliance was 88% (95% if one excludes deliveries by a midwife as they did not agree to comply). Four patients screened positive and were seen by a paediatrician in consultation but did not have CCHD (specificity 99.4%). Conclusions: The current study shows that screening was successfully implemented in a Canadian hospital, with high specificity (99.4%) and good compliance (88%). Reasons for non-acceptance of screening by midwives need to be addressed. PMID- 29479242 TI - Vitamin D levels and influencing predictors in refugee children in Sherbrooke (Quebec), Canada. AB - Background and Objective: Suboptimal vitamin D levels and associated complications are on the rise. Vulnerable populations, like refugee children, are further at risk. Studies on the vitamin D levels in refugee children are limited. The primary objective of this cross-sectional retrospective study was to determine the level of serum 25-hydroxyvitamin D (25-(OH)D) in the paediatric refugee population residing in Sherbrooke, Quebec, Canada. The secondary objective was to determine variables predicting vitamin D levels. Methods: Refugees under the age of 19 years arriving in Sherbrooke, Quebec, Canada, evaluated by the refugee clinic between March 2013 and April 2014, were included in the study. Vitamin D levels upon arrival and variables including age, sex, body mass index, season of arrival and season of test, ethnicity, previous country of residence and duration of stay in Canada from time of arrival were recorded. The protocol was approved by the scientific and ethics board of respective institutions. Results: A total of 138 subjects were included in the study from the Middle East, Central Asia and South East Asia, Africa and South America. The mean 25-(OH)D serum value was 55 nmol/L (insufficient). Fourteen per cent of subjects were vitamin D deficient and 64% were vitamin D insufficient as per Canadian Paediatric Society threshold guidelines. Gender (P=0.022), age (P<0.001), latitude (P<0.001) and season of testing (P=0.022) predict vitamin D status. Conclusions: This study concluded that refugee children have insufficient vitamin D levels. Gender, age, latitude and season of testing have an impact in predicting vitamin D status. PMID- 29479243 TI - Oral health assessment practices and perceptions of North American paediatric cardiologists. AB - Objective: Children with cardiac defects should have good oral health, particularly prior to cardiac surgery to minimize risks of infective endocarditis. The aim of the study was to examine the oral health assessment practices of North American cardiologists. Methods: Online surveys were e-mailed to 1409 cardiologists. Cardiologists without paediatric patients or practicing in centres without cardiac surgical care were excluded. Surveys addressed oral health assessment practices for paediatric cardiac patients, and perceptions of the impact of oral health on cardiac care. Results: The centre response rate was 69%, individual response rate 20%. Most cardiologists (96%) reported oral health was assessed as part of cardiac care. The most common time for assessment was prior to cardiac surgery (44%), with a quarter assessing by age 1 (28%). While most oral assessments involved a dentist (59%), 17% of cardiologists performed the oral assessment without the aid of a dentist. Four-fifths of cardiologists (83%) reported cancellation of cardiac surgery due to oral disease. Cardiologists who deferred assessment until prior to surgery had the highest experience of cancellation (96%). Assessments were delayed despite the common belief (89%) that children on pre-surgical high-calorie diets are at increased risk of oral disease. Conclusion: Assessments of oral health status were often deferred until immediately prior to cardiac surgery despite the cardiologist's perception that children with cardiac defects were at increased risk of oral disease and prior experience of surgical cancellation due to oral disease. Paediatricians may need to facilitate early oral assessment for these children. PMID- 29479245 TI - Training, knowledge, attitudes and practices of Canadian health care providers regarding sleep and sleep disorders in children. AB - Background: Sleep disorders are prevalent in children and are associated with significant comorbidity. Objective: To assess the training, knowledge, attitudes and practices of Canadian health care providers (HCPs) regarding sleep disorders in children. Method: A 42-item survey, designed to collect information on frequency of paediatric sleep disorders-related screening and diagnosis, implementation of evidence-based interventions and related knowledge base, was completed by HCPs. Results: Ninety-seven HCPs completed the survey. One per cent obtained training in paediatric sleep during undergraduate training and 3% obtained such training during their residencies, yet 34.9% estimated that 25 to 50% of their patients suffered from sleep disorders. Most HCPs thought that sleep disorders significantly impacted children's health and daytime function. Most HCPs screened for developmental sleep issues, but not consistently for sleep disorders. Most recommended evidence-based behavioural interventions for behavioural sleep disorders, but some also reported behavioural interventions that were not first-line or recommended. Inadequate knowledge regarding melatonin use was evident. Most participants reported rarely/never ordering a sleep study for a child with suspected obstructive sleep apnea (OSA). Most were familiar with surgical and weight loss management options for OSA; many were unfamiliar with benefits of continuous positive airway pressure. Participants' knowledge scores were highest on developmental and behavioural aspects of sleep, and lowest on sleep disorders. Conclusions: HCPs exhibit significant gaps in their knowledge, screening, evaluation and treatment practices for paediatric sleep disorders. Training at the undergraduate, graduate and postgraduate levels, as well as Continuing Medical Education are needed to optimize recognition, treatment and follow-up of paediatric sleep disorders. PMID- 29479244 TI - Physician perspectives on vaccination and diagnostic testing in children with gastroenteritis: A primary care physician survey. AB - Objectives: Gastroenteritis remains a common paediatric illness. Little is known about physician knowledge of enteric pathogen diagnostic tests. At the time of study conduct, Alberta lacked a publicly funded rotavirus vaccination program and knowledge of primary care physician perspectives was lacking. We sought to ascertain diagnostic testing methods and to understand knowledge and perceptions regarding enteric pathogen vaccination. Methods: A 30-item electronic survey was distributed across Alberta's five health care zones. The survey was developed by virology, microbiology, paediatrics, family medicine and public health experts. Participants were members of Alberta's Primary Care Networks, the TARRANT network and The Society of General Pediatricians of Greater Edmonton. Study outcomes included: (1) physician knowledge of available diagnostic tests, (2) perspectives regarding stool sample collection and (3) support for an enteric vaccine program. Results: Stool culture was reported as the test to identify parasites (47%), viruses (74%) and Clostridium difficile (67%). Although electron microscopy and enzyme immunoassay were used to identify viruses in Alberta during the study period, only 20% and 48% of respondents respectively identified them as tests employed for such purposes. Stool testing was viewed as being inconvenient (62%; 55/89), whereas rectal swabs were thought to have the potential to significantly improve specimen collection rates (82%; 72/88). Seventy-three per cent (66/90) of the respondent physicians support the adoption of future enteric pathogen vaccines. Conclusions: Simplification of diagnostic testing and stool sample collection could contribute to improved pathogen identification rates. Implementation of an enteric vaccine into the routine paediatric vaccination schedule is supported by the majority of respondents. PMID- 29479246 TI - Beach, dogs and itchy foot. PMID- 29479247 TI - Update for Canadian NRP providers: A case-based review. AB - The International Liaison Committee on Resuscitation (ILCOR) Neonatal Task Force reviews available resuscitation science every 5 years and develops guidelines which are integrated into educational programs such as the Neonatal Resuscitation Program (NRP). The most recent ILCOR Neonatal Task Force consensus guidelines were published in October 2015. The Canadian Paediatric Society's NRP Steering Committee has reviewed ILCOR guidelines alongside the 7th edition (2016) NRP materials. Using a case-based approach, this practice point highlights the main changes relating to the delivery of NRP, within the Canadian context. PMID- 29479248 TI - An 18-month-old boy with growth failure and gross motor skill regression. PMID- 29479249 TI - Clinician's Corner: 9-month old with a coagulopathy. PMID- 29479250 TI - Children with medical complexities: Addressing the gaps in respite care during transition from paediatrics to adult health care in Ontario. AB - Respite care is one integral component of the transition process from paediatric to adult health care, and is of particular importance to individuals with medical complexities. Numerous gaps that exist within the current system limit a child and family's ability to access quality respite care during a time when it is often most needed. Identifying and addressing these gaps in a systematic and collaborative way presents an opportunity to improve the quality of life for this vulnerable, ever growing population and their families. PMID- 29479251 TI - Childhood exposures to discarded needles and other objects potentially contaminated with blood-borne pathogens in Toronto, Canada. AB - Background: Exposure to discarded needles or other objects put children at risk for infection with blood-borne pathogens (BBP), including human immunodeficiency virus (HIV), hepatitis B (HBV) and hepatitis C. Objective: The purpose of this study was to retrospectively analyze the epidemiology, management and outcome of children following such exposures in the greater Toronto community setting. Methods: A retrospective study of children <19 years of age who had community based exposure to objects that could contain BBP between January 2001 and December 2014. Sexual and hospital inpatient exposures were excluded. Patients were identified by medical record review of all children who had HIV testing performed. Results: Sixty-six community-based exposures to objects potentially contaminated with BBP were identified (71.2% needlesticks). The median age was 6.3 years (interquartile range 3.8, 7.8). Exposures occurred outdoors in the community (45.5%), in schools (30.3%), homes (15.2%) and community/outpatient clinics (9.0%). Of 11 (16.7%) identified source subjects, 7 were known to be HIV infected. HIV post-exposure prophylaxis was prescribed to 22 (33.3%) children; 15 (71.4%) completed the course. Only 41.2% of previously unvaccinated children were documented to have completed a full HBV vaccine series post-exposure. No blood borne infections were documented, but only 60.6% had documentation of adequate follow-up testing. Conclusions: Enhanced public health interventions in schools and other community settings are needed to reduce childhood risk of exposure to needlesticks or other objects potentially contaminated with BBP. PMID- 29479252 TI - Paediatric emergency department overcrowding and adverse patient outcomes. AB - Background: General emergency department crowding negatively impacts patient care, and increases patient morbidity. Objectives: This study seeks to determine if markers of paediatric emergency department (PED) flow are independently associated with negative outcomes and increased health care utilization. Methods: We conducted a retrospective cohort study of PED visits from 2008 to 2012. Data were pulled from an electronic administrative database. Using multivariate logistic regression models, we measured the association between odds of adverse outcomes (hospital/paediatric intensive care unit [PICU] admission, unscheduled return visits and mortality) with markers of PED flow (shift mean length of stay [LOS] and daily rate of patients leaving without being seen [LWBS]). Results: We found an association between the daily LWBS proportion and the odds of being admitted to the hospital (odds ratio [OR]: 2.1; 95% confidence interval [CI]: 1.2, 3.7), as well as admission to the PICU (OR: 8.9; 95% CI: 1.1, 71.3). We found a statistically significant increase in the odds of admission if seen during shifts in the third or fourth quartile mean shift LOS. We observed lower odds of returning to the PED with increased daily LWBS proportions (OR: 0.4; 95% CI: 0.2, 0.7), but found no association between the odds of returning to the PED and mean shift LOS. Conclusion: While we found an association between our pre defined measures of adverse outcomes and markers of PED flow (or crowding), further studies are needed to determine whether PED overcrowding is the cause or effect of increased hospital and PICU admissions. PMID- 29479253 TI - Changes in the incidence and surgical treatment of ankyloglossia in Canada. AB - Background: Recent reports show increases in rates of ankyloglossia and frenotomy in British Columbia. We carried out a study to determine temporal trends and regional variations in ankyloglossia and frenotomy in Canada. Methods: The study included all hospital-based live births in Canada (excluding Quebec) between April 2002 and March 2015, with information obtained from the Canadian Institute for Health Information. Information on ankyloglossia and frenotomy was obtained from records of hospital admission for childbirth. Temporal trends and provincial/territorial variations were quantified using rate ratios (RR) and 95% confidence intervals (CI). Results: Ankyloglossia rates increased from 6.86 in 2002 to 22.6 per 1000 live births in 2014 (P for trend < 0.001), while frenotomy rates increased from 3.76 in 2002 to 14.7 per 1000 live births in 2014 (P for trend < 0.001). Frenotomy rates among infants with ankyloglossia increased from 54.7% in 2002 to 63.9% in 2014 (RR: 1.18, 95% CI: 1.13-1.24). Compared with British Columbia, rates of ankyloglossia were over three-fold higher in Saskatchewan (RR: 3.40, 95% CI: 3.16-3.67), Alberta (RR: 3.50, 95% CI: 3.29-3.72) and the Yukon (RR: 3.62, 95% CI: 2.67-4.92), while rates of frenotomy were three- to four-fold higher in the Yukon (RR: 3.41, 95% CI: 2.28-5.10), Alberta (RR: 4.01, 95% CI: 3.71-4.33) and Saskatchewan (RR: 4.12, 95% CI: 3.76-4.52). Conclusion: A desire to increase rates of breast feeding initiation and absence of standardized criteria for the diagnosis of ankyloglossia have resulted in runaway rates of frenotomy for newborn infants in some parts of Canada. PMID- 29479254 TI - Family bedside orientations: An innovative peer support model to enhance a culture of family-centred care at the Stollery Children's Hospital. AB - This paper presents family bedside orientations, an innovative bedside peer support model for families of paediatric patients piloted in one unit at the Stollery Children's Hospital in Edmonton, Alberta. The model invites family members of former patients back to the hospital as volunteer peer mentors responsible for meeting one-on-one with current inpatient families to provide a listening presence, discuss patient safety practices and encourage families to participate in their child's care. Using qualitative and quantitative data collection methods, the model was evaluated over 1 year (December 2014 to December 2015). Data sources included peer mentor field notes (from 163 visits) detailing the number of family bedside orientations completed by peer mentors and how they interacted with families, as well as post-visit family (n=35) surveys, Hospital-Child Inpatient Experience Survey data, peer mentor (n=6) questionnaires, focus groups with unit staff (n=10) and interviews with members of the project leadership team (n=5). Our findings indicated that family bedside orientations became an established practice in the pilot unit and positively impacted family care experiences. We attribute these successes to championing and support from unit staff and our multidisciplinary project leadership team. We discuss how our team addressed family privacy and confidentiality while introducing peer mentors in the unit. We also highlight strategies used to integrate peer mentors as part of the staff team and enhance peer support culture in the pilot unit. Practical considerations for implementing this model in other paediatric environments are provided. PMID- 29479255 TI - Updates on early peanut introduction and prevention of peanut allergy. PMID- 29479256 TI - Interventions for Treating Low-Risk Ankle Fractures in Children. PMID- 29479257 TI - A 16 year-old female with shortness of breath and stridor. PMID- 29479258 TI - A 13-year-old boy with fatigue and dizziness. PMID- 29479259 TI - Tiered curriculum in global child health: A novel CanMEDs-based multidisciplinary educational program. AB - Despite the importance of Global Child Health to the practice of 21st century paediatricians, formal comprehensive outcomes-based curricula in this area are lacking. This article describes the development and implementation of a novel, tiered, CanMEDs-based and multidisciplinary curriculum in Global Child Health that was based on a thorough review of the literature. In addition to detailing the steps and results of our literature review, we discuss the three tiers of our curriculum (General Track, Advanced Curriculum and Elective Track) as well as the evidence-informed curricular topics and learning outcomes associated with each tier. Moreover, we highlight the importance of a multidisciplinary approach to Global Child Health education and the potential for this work to help transition Global Child Health training to competency-based models of teaching and learning. This review may help hospitals and residency programs across Canada looking to develop more formal curricula in this often overlooked area. PMID- 29479260 TI - The gap between coverage and care-what can Canadian paediatricians do about access to health services for refugee claimant children? AB - Introduction: In June 2012, the government of Canada severely restricted the scope of the Interim Federal Health Program that had hitherto provided coverage for the health care needs of refugee claimants. The Quebec government decided to supplement coverage via the provincial health program. Despite this, we hypothesized that refugee claimant children in Montreal would continue to experience significant difficulties in accessing basic health care. Objectives: (1) Report the narrative experiences of refugee claimant families who were denied health care services in Montreal following June 2012, (2) describe the predominant barriers to accessing health care services and understanding their impact using thematic analysis and (3) derive concrete recommendations for child health care providers to improve access to care for refugee claimant children. Methods: Eleven parents recruited from two sites in Montreal participated in semi structured interviews designed to elicit a narrative account of their experiences seeking health care. Interviews were recorded, transcribed, coded using NVivo software and subjected to thematic analysis. Results: Thematic analysis of the data revealed five themes concerning barriers to health care access: lack of continuous health coverage, health care administrators/providers' lack of understanding of Interim Federal Health Program coverage, refusal of services or fees charged, refugee claimants' lack of understanding about health care rights and services and language barriers, and four themes concerning the impact of denial of care episodes: potential for adverse health outcomes, psychological distress, financial burden and social stigma. Conclusion: We propose eight action points for advocacy by Canadian paediatricians to improve access to health care for refugee claimant children in their communities and institutions. PMID- 29479261 TI - Overweight and obesity are associated with lower vitamin D status in Canadian children and adolescents. AB - Introduction: There is evidence that 25-hydroxyvitamin D levels are lower in overweight and obese youth. This study examined the relationship between weight status and 25-hydroxyvitamin D, while controlling for confounders, in Canadian youth. Methods: Plasma 25-hydroxyvitamin D from subjects aged 6 to 17 years from the Canadian Health Measures Survey cycles 1 (2007 to 2009) and 2 (2009 to 2011) was used. Sex-specific multiple linear regression and logistic regressions examined the relationship of overweight and obesity (body mass index >= 85th percentile) with 25-hydroxyvitamin D levels and the odds of 25-hydroxyvitamin D <40 nmol/L and <50 nmol/L. Results: The prevalence of risk of vitamin D deficiency (25-hydroxyvitamin D < 30 nmol/L) was 6% (95% confidence interval [CI] 3.26% to 10.12%). Vitamin D inadequacy, estimated by levels <40 nmol/L, was 15% (95% CI 10.34% to 20.39%; 19% [95% CI 13.1 to 25.6] for teenagers). Seventy per cent (95% CI 63.59 to 75.17) had levels >50 nmol/L, consistent with achieving the Recommended Dietary Allowance. In adjusted analyses, overweight/obesity (1/3 of subjects) was independently associated with lower 25-hydroxyvitamin D for both sexes after adjustment for age, race, income, season, vitamin D supplementation and daily milk consumption. For 25-hydroxyvitamin D <40 nmol/L, the overweight/obese odds ratio for males was 2.63 (95% CI 1.34 to 5.18). For 25 hydroxyvitamin D <50 nmol/L, overweight/obese odds ratios were 2.19 (95% CI 1.46 to 3.28) for males and 1.39 (95% CI 1.05 to 1.84) for females. Conclusions: This study confirms the inverse association between adiposity and serum concentrations of 25-hydroxyvitamin D in Canadian youth and the independent association of overweight/obesity to 25-hydroxyvitamin D level and vitamin D status after adjustment for other factors. PMID- 29479263 TI - Drugs for the acute treatment of migraine in children and adolescents. PMID- 29479262 TI - Increasing incidence of optic nerve hypoplasia/septo-optic dysplasia spectrum: Geographic clustering in Northern Canada. AB - Introduction: Owing to the shared embryonic origin, defects in development of optic nerves are often seen in conjunction with defects affecting the surrounding brain and pituitary gland. Optic nerve hypoplasia (ONH) and septo-optic dysplasia (SOD) represent a clinical spectrum associated with visual, pituitary and severe central nervous system structural abnormalities (SODplus). Based on changing clinical patterns, our primary objective was to examine trends in annual incidence of ONH/SOD and geographical clustering in Manitoba. Methods: This was a retrospective 1996 to 2015 chart review with extraction of anthropometric measures, radiologic findings, parental characteristics, endocrinopathies and neurologic symptoms from all involved in care. Postal codes were used to assign map co-ordinates and identify relevant census-based deprivation indices. Results: Ninety-three children were identified in our catchment area; Poisson regression confirmed a striking 1.11-fold annual increase (95% confidence interval 1.07 to 1.16) or ~800% over two decades. The annual incidence (averaged 2010 to 2014 chart data) reached 53.3 per 100,000, affecting 1 in 1875 live births. Most (~55%) had SODplus. Common presenting features were hypoglycemia, nystagmus, seizures and developmental delay; 40% had hormone deficiencies; 80% had reduced visual acuity, typically bilateral. Many were premature with young, primiparous mothers. Unhealthy maternal lifestyles and severe material deprivation were noted. There was disproportionate clustering in individuals from Northern Manitoba at three times the average provincial rate. Conclusion: We noted a dramatic rise in the annual incidence of ONH/SOD, which was strongly associated with poverty and northern communities. The pattern was consistent with environmental or nutritional etiologies. Many children were severely affected with increased morbidity and health care burdens. PMID- 29479264 TI - A mobile yellow nodule under the foreskin of a toddler. PMID- 29479265 TI - Pulse oximetry screening in newborns to enhance detection of critical congenital heart disease. AB - Pulse oximetry screening is safe, noninvasive, easy to perform and proven to enhance detection of critical congenital heart disease in newborns. However, this test has yet to be adopted as routine practice in Canada. The present practice point highlights essential details and recommendations for screening, which research has shown to be highly specific, with low false-positive rates. Optimal screening for critical congenital heart disease should include prenatal ultrasound, physical examination and pulse oximetry screening. Screening should be performed between 24 hours and 36 hours postbirth, using the infant's right hand and either foot to minimize false-positive results. Newborns with abnormal results should undergo a thorough evaluation by the most responsible health care provider. When a cardiac diagnosis cannot be excluded, referral to a paediatric cardiologist for consultation and echocardiogram is advised. PMID- 29479266 TI - Small bite, big problem: Understanding severe microcephaly in Canada. PMID- 29479267 TI - I am green with envy...... PMID- 29479270 TI - Index to Abstracts / Index des Resumes. PMID- 29479268 TI - Response to 'Comment on the CTS 2015 guidelines for asthma in preschoolers'. PMID- 29479271 TI - Medical publishing in 2018. PMID- 29479272 TI - A 17-year-old girl with fever and lymphadenopathy. PMID- 29479273 TI - Literacy promotion by health care professionals: A comprehensive biomedical and psychosocial approach. AB - Literacy is the ability to read, write and understand print. Proficiency in literacy is fundamental to social inclusion and strongly linked to health outcomes. Thus, improving literacy is important for lifelong health promotion. Poverty, inadequate hearing, speech and vision and learning disabilities may challenge literacy development. In our review, we explore these topics and suggest recommendations to: Mitigate the Effects of Poverty, Access Comprehensive Medical Assessments, Promote Early Childhood Education and Advocate for Early Intervention and Remediation Programs. PMID- 29479274 TI - Use and perceived effectiveness of complementary health approaches in children. AB - Background and Objectives: Up to one-half of children may use complementary health approaches (CHA). However, current prevalence in North America, variables associated with CHA use and caregiver perceptions of effectiveness are unclear. We aimed to determine the self-reported use of CHA during the previous 12 months in paediatric patients, demographic variables associated with CHA use and perceptions around effectiveness of CHA. Methods: A cross-sectional survey study of patients aged between 28 days and 18 years who presented to a large paediatric emergency department was conducted between December 2014 and July 2015. Univariate analysis and multivariate logistic regression were used to examine variables associated with CHA use. Results: Of 475 potential participants, 412 (86.7%) responded to the questionnaire, of whom 369 (89.5%) had completed the entire survey. Of these, 61.7% (95% confidence interval [CI] 56.7% to 66.6%) reported using CHA for their child. The most used CHA products were vitamins and minerals (59.2%, 95% CI 52.4% to 65.7%). Among CHA practices, massage (50.0%, 95% CI 15.5% to 30.1%) was most common. Most CHA users perceived effectiveness of the therapy used. Parental education remained statistically significant (P=0.03) in multivariate logistic regression; the odds of CHA use among caregivers with university-level education were 1.65 times higher when compared with those without (95% CI 1.04% to 2.61%). Conclusions: CHA use is higher than previously reported in children. Given the high self-reported perceived effectiveness, paediatricians and family physicians should review CHA use with their patients in an open, non-judgmental manner, exploring both perceptions of safety and efficacy. PMID- 29479276 TI - The path to paediatric donation after circulatory determination of death guidelines. AB - Recently, Canada became the first country to publish paediatric specific guidelines for the practice of donation after circulatory death (pDCD). These guidelines, endorsed by the Canadian Paediatric Society, were created in response to the fact that pDCD in Canada was largely undeveloped even in tertiary care centres, and no national guidelines addressed the practice in children. This article explains what pDCD is and how these recommendations were developed. PMID- 29479277 TI - Intranasal influenza vaccine: Why does Canada have different recommendations from the USA on its use? AB - Canada and the USA differ in their recommendations for the use of live attenuated influenza vaccine (LAIV). The Canadian National Advisory Committee on Immunization (NACI) continues to recommend LAIV as one of the influenza vaccines available for use in children 2 to 17 years of age. The US Advisory Committee on Immunization Practices (ACIP) made an interim recommendation against the use of LAIV for the 2016 to 2017 influenza season in response to low LAIV effectiveness observed in the USA during the 2013 to 2014 to 2015 to 2016 seasons. The recommendation has been continued for the 2017 to 2018 season. In response, NACI undertook a review of available LAIV effectiveness data in children and adolescents from Canada, the USA and a number of European countries. This commentary by Canada's Chief Public Health Officer summarizes the findings of that review and provides the rationale for Canada's current continued recommendation for LAIV use. PMID- 29479275 TI - The Canadian Neuromuscular Disease Registry: Connecting patients to national and international research opportunities. AB - Introduction: Patient registries serve an important role in rare disease research, particularly for the recruitment and planning of clinical trials. The Canadian Neuromuscular Disease Registry was established with the primary objective of improving the future for neuromuscular (NM) patients through the enablement and support of research into potential treatments. Methods: In this report, we discuss design and utilization of the Canadian Neuromuscular Disease Registry with special reference to the paediatric cohort currently enrolled in the registry. Results: As of July 25, 2017, there are 658 paediatric participants enrolled in the registry, 249 are dystrophinopathies (229 are Duchenne muscular dystrophy), 57 are myotonic dystrophy participants, 98 spinal muscular atrophy participants and 65 are limb girdle muscular dystrophy. A total of 175 patients have another NM diagnosis. The registry has facilitated 20 clinical trial inquiries, 5 mail-out survey studies and 5 other studies in the paediatric population. Discussion: The strengths of the registry are discussed. The registry has proven to be an invaluable tool to NM disease research and has increased Canada's visibility as a competitive location for the conduct of clinical trials for NM therapies. PMID- 29479278 TI - The prevention of firearm injuries in Canadian youth. AB - Firearm injuries are a significant and preventable cause of death in Canadian youth. Adolescent and young adult males are disproportionately affected; however, firearm-related deaths occur in youth of all ages. Canada's rate of firearm ownership is lower than that of the USA, but high compared with other upper income countries. The availability of firearms to youth is an important factor in adolescent suicide, unintentional firearm deaths, gang homicide and school shootings. Guns should not be kept in homes or environments where children and adolescents live or play. Screening for the presence of a firearm in the home is an essential part of the safety assessment of a depressed or suicidal youth, and removal of the firearm from the home must be recommended in this situation. Legislative measures to strictly control the acquisition, transport, ownership and storage of firearms, and to reduce smuggling of firearms, are also recommended. PMID- 29479279 TI - Rapid response systems for paediatrics: Suggestions for optimal organization and training. AB - Resuscitation and cardiac arrest events in the paediatric population are rare occurrences. Improving outcomes from such events continues to be a difficult challenge. Rapid response systems and teams have been integrated into many hospitals in an effort to facilitate early identification and management of patients at risk for clinical deterioration. Optimizing education in the form of team training is a major component of successful team performance. Simulation based team training, is a key educational supplement for existing standardized resuscitation courses. This position statement describes the evidence supporting rapid response systems and teams as well as simulation-based team training and provides recommendations for implementation in hospital care for paediatric patients. PMID- 29479280 TI - Cross-cultural communication: Tools for working with families and children. AB - The ability to communicate effectively with patients and families is paramount for good patient care. This practice point reviews the importance of communicating effectively in cross-cultural encounters. The concept of cultural competence is introduced, along with the LEARN (Listen, Explain, Acknowledge, Recommend, Negotiate) model for cross-cultural communication. Three vignettes, one each in Indigenous, global, and newcomer child health, are used to illustrate challenges in cross-cultural communication and effective application of the LEARN model. Practical tips are provided for communicating across cultures. PMID- 29479281 TI - Les communications interculturelles - des outils pour travailler aupres des familles et des enfants. AB - Pour prodiguer de bons soins, il est crucial de communiquer de maniere efficace avec les patients et leur famille. Le present point de pratique traite de l'importance d'une communication transculturelle efficace. Les auteurs exposent le concept de competence culturelle, ainsi que celui du modele LEARN (acronyme anglais des mots ecouter, expliquer, reconnaitre, recommander et negocier), pour faciliter la communication transculturelle. Trois scenarios demontrent les difficultes de la communication transculturelle et l'application efficace du modele LEARN. L'un porte sur un enfant autochtone, le deuxieme sur un enfant a l'etranger et le dernier, sur un nouvel arrivant. Des conseils pratiques sont proposes pour favoriser les communications interculturelles. PMID- 29479282 TI - Update on invasive meningococcal vaccination for Canadian children and youth. AB - Invasive meningococcal disease (IMD) is serious, often resulting in fulminant sepsis or meningitis. IMD in Canada is primarily attributable to serogroups B and C. There are routine programs for serogroup C vaccine at 12 months of age, with some jurisdictions routinely providing additional earlier doses. Adolescents routinely receive a booster dose of serogroup C vaccine or of a quadrivalent (serogroups A, C, W and Y) vaccine. Serogroup B vaccines are not recommended for routine use pending further data on the efficacy and duration of protection from the available vaccine. However, children at increased risk for IMD should start immunization for serogroups B and C as soon as possible, assuming that they are at least 2 months of age. PMID- 29479283 TI - Mise a jour sur la vaccination contre la meningococcie invasive chez les enfants et les adolescents canadiens. AB - La meningococcie invasive (MI) est une maladie grave qui est souvent a l'origine d'un sepsis fulminant ou d'une meningite. Au Canada, elle est surtout attribuable aux serogroupes B et C. Des programmes de vaccination systematique contre le meningocoque du serogroupe C sont prevus a l'age de 12 mois, et dans certaines regions sociosanitaires, le calendrier comprend l'administration de doses supplementaires aux enfants plus jeunes. Les adolescents recoivent systematiquement une dose de rappel du vaccin contre le serogroupe C ou d'un vaccin quadrivalent (serogroupes A, C, W et Y). L'utilisation systematique des vaccins contre le serogroupe B n'est pas recommandee tant qu'on n'aura pas recueilli de donnees supplementaires sur l'efficacite des vaccins sur le marche et la duree de la protection qu'ils conferent. Cependant, les enfants d'au moins deux mois qui courent un risque accru de MI devraient etre vaccines contre les serogroupes B et C dans les plus brefs delais. PMID- 29479284 TI - Vaccine recommendations for children and youth for the 2017/2018 influenza season. AB - The Canadian Paediatric Society continues to encourage annual influenza vaccination for ALL children and youth >=6 months of age. Recommendations from the National Advisory Committee on Immunization (NACI) for the 2017/2018 influenza season are not substantially changed from those of last season. NACI has conducted a review of all available vaccine effectiveness data concerning live attenuated influenza vaccine (LAIV) and concludes that current evidence supports the continued use of LAIV in Canada, although use is not currently recommended in the USA because of concern about efficacy. PMID- 29479285 TI - Les recommandations relatives aux vaccins antigrippaux administres aux enfants et aux adolescents pour la saison 2017-2018. AB - La Societe canadienne de pediatrie continue d'encourager la vaccination antigrippale annuelle de TOUS les enfants et les adolescents, des l'age de six mois. Les recommandations du Comite consultatif national de l'immunisation (CCNI) pour la saison 2017-2018 n'ont pas subi de changements importants par rapport a la saison precedente. Le CCNI a analyse toutes les donnees sur l'efficacite du vaccin vivant attenue contre l'influenza (VVAI) sur le marche et conclut qu'elles en appuient l'utilisation au Canada, meme si les Etats-Unis ne le recommandent pas en raison de doutes quant a son efficacite. PMID- 29479286 TI - Head lice infestations: A clinical update. AB - Head lice (Pediculus humanus capitis) infestations are not a primary health hazard or a vector for disease, but they are a societal problem with substantial costs. Diagnosis of head lice infestation requires the detection of a living louse. Although pyrethrins and permethrin remain first-line treatments in Canada, isopropyl myristate/ST-cyclomethicone solution and dimeticone can be considered as second-line therapies when there is evidence of treatment failure. PMID- 29479287 TI - Les infestations par les poux de tete : une mise a jour clinique. AB - Les infestations par les poux de tete (Pediculus humanus capitis) ne constituent ni un risque sanitaire primaire ni un vecteur de maladie, mais representent plutot un probleme de societe au cout impor- tant. Pour diagnostiquer une infestation, il faut deceler un pou vivant. Meme si les pyrethines et la permethrine demeurent les traitements de premiere intention au Canada, la solution de myristate d'isopropyle et de ST-cyclomethicone et la dimeticone peuvent etre envisagees en deuxieme intention apres un echec therapeutique demontre. PMID- 29479288 TI - Biomimetic hierarchical walnut kernel-like and erythrocyte-like mesoporous silica nanomaterials: controllable synthesis and versatile applications. AB - We developed a facile and controllable strategy to fabricate biomimic walnut kernel-like mesoporous silica nanomaterial (WMSN) and erythrocyte-like mesoporous silica nanomaterial (EMSN). The former possesses unique multi-shell hollow structure and surface wrinkles while the latter has special multi-stack structure and bowl-shaped depression. These hierarchical materials with distinct structures can be finely tuned by changing the molar ratios of two surfactants, cetyltrimethylammonium bromide and 11-mercaptoundecanoic acid. The mechanism of structural formation through intermolecular interactions was revealed and validated experimentally. The promising potential applications of WMSN and EMSN in adsorption, cellular imaging, drug delivery, and cancer theranostics were further identified. PMID- 29479289 TI - Evaluation of infectious and non-infectious complications in patients with primary immunodeficiency. AB - Introduction: Primary immunodeficiency diseases (PIDs) are a heterogeneous group of genetic immune disorders. PID patients suffer from a variety of complications. The aim of this study was to determine the infectious and non-infectious complications among PID patients. Material and methods: This retrospective cohort study was performed on recorded data of 202 PID patients who were diagnosed with eight major categories: common variable immunodeficiency (CVID), X-linked agammaglobulinemia, hyper-IgM syndrome, hyper IgE syndrome, chronic granulomatous disease (CGD), ataxia telangiectasia, hereditary angioedema and leukocyte adhesion deficiency. For all patients, infectious and non-infectious manifestations and laboratory data were collected in a comprehensive questionnaire. Results: Infectious complications were more frequent than non infectious complications. Pneumonia and otitis media were the main infectious problems in PID patients, especially in patients with antibody deficiencies. Among the non-infectious complications, splenomegaly and hepatomegaly were the most common complications in PID patients, and were more commonly seen in CGD patients than others. Splenomegaly, hepatomegaly and autoimmunity were the most common findings in CVID patients. A significant correlation was observed between diagnostic delay and bronchiectasis in CVID patients (p = 0.042). Conclusions: PID patients are at risk of multiple infectious and non-infectious problems. Timely diagnosis of PIDs not only improves their outcome and quality of life, but also helps prevent these troubling complications. PMID- 29479290 TI - Perceived neighborhood ethnic diversity and social outcomes: Context-dependent effects within a postindustrial city undergoing regeneration. AB - This article examines whether perceived neighborhood ethnic diversity is associated with a range of social outcomes in a postindustrial city undergoing regeneration. The research included a survey in 3 types of deprived area in Glasgow: those undergoing regeneration, those directly adjoining regeneration areas, and those further removed from regeneration areas. In areas undergoing regeneration, perceived diversity was positively associated with many residential, cohesion, safety, and empowerment outcomes. This was also true, although to a lesser extent, in deprived areas at some distance from regeneration areas. In areas immediately surrounding the regeneration areas, perceived diversity had mixed associations with residential and safety outcomes and few associations with cohesion and empowerment outcomes. The results suggest that the effects of perceived diversity are context dependent within a city. Moreover, regeneration processes alter neighborhood contexts and therefore enable scale, timing, and duration of diversity to mediate the relationships between perceived diversity and social outcomes. PMID- 29479291 TI - Optimizing mouse models of neurodegenerative disorders: are therapeutics in sight? AB - The genomic and biologic conservation between mice and humans, along with our increasing ability to manipulate the mouse genome, places the mouse as a premier model for deciphering disease mechanisms and testing potential new therapies. Despite these advantages, mouse models of neurodegenerative disease are sometimes difficult to generate and can present challenges that must be carefully addressed when used for preclinical studies. For those models that do exist, the standardization and optimization of the models is a critical step in ensuring success in both basic research and preclinical use. This review looks back on the history of model development for neurodegenerative diseases and highlights the key strategies that have been learned in order to improve the design, development and use of mouse models in the study of neurodegenerative disease. PMID- 29479292 TI - Adherence to gender-typical behavior and high frequency substance use from adolescence into young adulthood. AB - Substance use is prevalent among adolescents in the U.S., especially males. Understanding the cross-sectional and longitudinal associations between gender norms and substance use is necessary to tailor substance use prevention messages and efforts appropriately. This study investigates the relationship between adherence to gender-typical behavior (AGB) and substance use from adolescence into young adulthood. Participants in the National Longitudinal Study of Adolescent to Adult Health completed self-report measures on the frequency of binge drinking, cigarette smoking and marijuana use as well as various behaviors and emotional states that captured the latent construct of AGB. Sex-stratified logistic regression models revealed cross-sectional and longitudinal relationships between AGB and high frequency substance use. For example, an adolescent male who is more gender-adherent, compared to less adherent males, has 75% higher odds of high frequency binge drinking in adolescence and 22% higher odds of high frequency binge drinking in young adulthood. Sex-stratified multinomial logistic regression models also revealed cross-sectional and longitudinal relationships between AGB and patterns of use. For example, a more gender-adherent adolescent male, compared to one who is less adherent, is 256% more likely to use all three substances in adolescence and 66% more likely to use all three in young adulthood. Cross-sectional and longitudinal results for females indicate greater gender-adherence is associated with lower odds of high frequency substance use. These findings indicate adherence to gender norms may influence substance use behaviors across the developmental trajectory, and inform strategies for prevention efforts. PMID- 29479293 TI - Predictors for Gingival Index in Middle-Aged Asian Indians with Type 2 Diabetes from South India: A Cross-Sectional Observational Study. AB - Asian Indians develop type 2 diabetes mellitus (T2DM) much earlier as compared to White Caucasians, due to unique phenotypic and genetic architecture. Periodontitis in T2DM patients is often a neglected clinical feature. This study was conducted to derive predictor variables for gingival index in middle-aged Asian Indians with T2DM in a semiurban population of Dravidian ethnicity from Tamil Nadu, India. T2DM patients (n = 232, mean age: 50.6 +/- 10.4 years) with periodontitis (n = 123, mean age: 54.3 +/- 2.4 years) and without periodontitis (n = 109, mean age: 55.2 +/- 3.1 years) were recruited between 2014 and 2016 by purposive sampling method. Dental examinations for pocket depth (PD) and clinical attachment level (CAL) were performed and gingival index was calculated. Fasting venous blood samples were analysed for measures of glycaemia and cholesterol. Significant positive correlation (p < 0.01) was observed for gingival index with glycosylated haemoglobin (HbA1c), pocket depth, presence of T2DM, and clinical attachment level. Stepwise multiple linear regression analysis derived increased pocket depth (p < 0.01), elevated HbA1c (p < 0.01), clinical attachment level (p < 0.01), and presence of diabetes (p < 0.01) as significant predictors (r2 value = 0.67) for increased gingival index in middle aged patients with T2DM. These variables significantly (p < 0.01) predispose middle-aged T2DM patients to increased gingival index, thus warranting appropriate intervention. PMID- 29479294 TI - Mildly Cross-Linked Dendrimer Hydrogel Prepared via Aza-Michael Addition Reaction for Topical Brimonidine Delivery. AB - In this work, we developed a mildly cross-linked dendrimer hydrogel (mcDH) via aza-Michael addition of polyamidoamine (PAMAM) dendrimer G5 and polyethylene glycol diacrylate (PEG-DA, Mn=575 g/mol). We chose the antiglaucoma drug brimonidine tartrate as a model drug and developed a new antiglaucoma drug formulation on the basis of mcDH. Cytotoxicity of the mcDH formulation to NIH3T3 fibroblasts, in vitro drug release kinetics and ex vivo drug permeability across the rabbit cornea were examined. We also studied interactions between PAMAM dendrimer and the drug using 1H NMR spectroscopy for a mechanistic understanding of brimonidine release from the mcDH. mcDH was found to be efficient unionizing brimonidine tartrate to form and encapsulate brimonidine free base for sustained release and enhanced corneal permeation. PMID- 29479296 TI - Second Update on a Patient With Alzheimer Disease Treated by CT Scans. PMID- 29479295 TI - Biological Entanglement-Like Effect After Communication of Fish Prior to X-Ray Exposure. AB - The phenomenon by which irradiated organisms including cells in vitro communicate with unirradiated neighbors is well established in biology as the radiation induced bystander effect (RIBE). Generally, the purpose of this communication is thought to be protective and adaptive, reflecting a highly conserved evolutionary mechanism enabling rapid adjustment to stressors in the environment. Stressors known to induce the effect were recently shown to include chemicals and even pathological agents. The mechanism is unknown but our group has evidence that physical signals such as biophotons acting on cellular photoreceptors may be implicated. This raises the question of whether quantum biological processes may occur as have been demonstrated in plant photosynthesis. To test this hypothesis, we decided to see whether any form of entanglement was operational in the system. Fish from 2 completely separate locations were allowed to meet for 2 hours either before or after which fish from 1 location only (group A fish) were irradiated. The results confirm RIBE signal production in both skin and gill of fish, meeting both before and after irradiation of group A fish. The proteomic analysis revealed that direct irradiation resulted in pro-tumorigenic proteomic responses in rainbow trout. However, communication from these irradiated fish, both before and after they had been exposed to a 0.5 Gy X-ray dose, resulted in largely beneficial proteomic responses in completely nonirradiated trout. The results suggest that some form of anticipation of a stressor may occur leading to a preconditioning effect or temporally displaced awareness after the fish become entangled. PMID- 29479297 TI - A lost opportunity for science: journals promote data sharing in metabolomics but do not enforce it. AB - Introduction: Data sharing is being increasingly required by journals and has been heralded as a solution to the 'replication crisis'. Objectives: (i) Review data sharing policies of journals publishing the most metabolomics papers associated with open data and (ii) compare these journals' policies to those that publish the most metabolomics papers. Methods: A PubMed search was used to identify metabolomics papers. Metabolomics data repositories were manually searched for linked publications. Results: Journals that support data sharing are not necessarily those with the most papers associated to open metabolomics data. Conclusion: Further efforts are required to improve data sharing in metabolomics. PMID- 29479298 TI - Extending our tools and resources in the non-conventional industrial yeast Xanthophyllomyces dendrorhous through the application of metabolite profiling methodologies. AB - Introduction: Xanthophyllomyces dendrorhous is a non-conventional industrial yeast. It has the unique ability among yeasts to produce geranylgeranyl pyrophosphate derived terpenoids such as carotenoids and in particular the high value pigment astaxanthin. Objective: In order to fully exploit the industrial potential of Xanthophyllomyces using modern industrial biotechnology approaches the further development of "omic" resources in this organism are required to build on the now sequenced and annotated genome. To contribute to this goal, the present study has developed and implemented an efficient metabolite profiling system comprised of, quenching, extraction and associated GC-MS and UPLC analysis. Method: Four quenching methods and five extraction methods compatible with GC-MS and UPLC profiling were tested and validated by analysing steady state metabolite changes of Xanthophyllomyces cultivated at laboratory scale in liquid shake culture at lag, exponential and early and late stationary phases. Results: A customised Automated Mass Spectral Deconvolution and Identification System (AMDIS) library has been created for Xanthophyllomyces, over 400 compounds are present in the library of which 78 are detected and quantified routinely in polar and non-polar derived extracts. A preliminary biochemical network has been constructed. Over a standardised laboratory growth cycle, changes in metabolite levels have been determined to create reference point for future strain improvement approaches and the initial biochemical network construction. Correlation analysis has illustrated that astaxanthin formation correlates positively with different sectors of intermediary metabolism (e.g. the TCA cycle intermediates and amino acid formation), "short" saturated fatty acids and beta carotene, while other metabolites are reduced in response to astaxanthin production. These sectors of intermediary metabolism offer potential future targets for the manipulation resulting in the generation of strains with improved titres of given terpenoids. Discussion: In summary a robust metabolite profiling system for Xanthophyllomyces is in place to further our understanding and potential exploitation of this underutilised industrial yeast. PMID- 29479300 TI - Feature Representations for Neuromorphic Audio Spike Streams. AB - Event-driven neuromorphic spiking sensors such as the silicon retina and the silicon cochlea encode the external sensory stimuli as asynchronous streams of spikes across different channels or pixels. Combining state-of-art deep neural networks with the asynchronous outputs of these sensors has produced encouraging results on some datasets but remains challenging. While the lack of effective spiking networks to process the spike streams is one reason, the other reason is that the pre-processing methods required to convert the spike streams to frame based features needed for the deep networks still require further investigation. This work investigates the effectiveness of synchronous and asynchronous frame based features generated using spike count and constant event binning in combination with the use of a recurrent neural network for solving a classification task using N-TIDIGITS18 dataset. This spike-based dataset consists of recordings from the Dynamic Audio Sensor, a spiking silicon cochlea sensor, in response to the TIDIGITS audio dataset. We also propose a new pre-processing method which applies an exponential kernel on the output cochlea spikes so that the interspike timing information is better preserved. The results from the N TIDIGITS18 dataset show that the exponential features perform better than the spike count features, with over 91% accuracy on the digit classification task. This accuracy corresponds to an improvement of at least 2.5% over the use of spike count features, establishing a new state of the art for this dataset. PMID- 29479299 TI - Recommended strategies for spectral processing and post-processing of 1D 1H-NMR data of biofluids with a particular focus on urine. AB - 1H NMR spectra from urine can yield information-rich data sets that offer important insights into many biological and biochemical phenomena. However, the quality and utility of these insights can be profoundly affected by how the NMR spectra are processed and interpreted. For instance, if the NMR spectra are incorrectly referenced or inconsistently aligned, the identification of many compounds will be incorrect. If the NMR spectra are mis-phased or if the baseline correction is flawed, the estimated concentrations of many compounds will be systematically biased. Furthermore, because NMR permits the measurement of concentrations spanning up to five orders of magnitude, several problems can arise with data analysis. For instance, signals originating from the most abundant metabolites may prove to be the least biologically relevant while signals arising from the least abundant metabolites may prove to be the most important but hardest to accurately and precisely measure. As a result, a number of data processing techniques such as scaling, transformation and normalization are often required to address these issues. Therefore, proper processing of NMR data is a critical step to correctly extract useful information in any NMR-based metabolomic study. In this review we highlight the significance, advantages and disadvantages of different NMR spectral processing steps that are common to most NMR-based metabolomic studies of urine. These include: chemical shift referencing, phase and baseline correction, spectral alignment, spectral binning, scaling and normalization. We also provide a set of recommendations for best practices regarding spectral and data processing for NMR-based metabolomic studies of biofluids, with a particular focus on urine. PMID- 29479301 TI - Homer1a Attenuates Hydrogen Peroxide-Induced Oxidative Damage in HT-22 Cells through AMPK-Dependent Autophagy. AB - Neuronal oxidative stress is involved in diverse neurological disorders. Homer1a, as an important member of the Homer family and localized at the postsynaptic density, is known to protect cells against oxidative injury. However, the exact neuroprotective mechanism of Homer1a has not been fully elucidated. Here, we found that Homer1a promoted cell viability and reduced H2O2-induced LDH release. The overexpression of Homer1a enhanced autophagy after H2O2 treatment, which was confirmed by increased expression of LC3II, Beclin-1, and greater autophagosome formation. In addition, we demonstrated that activating autophagy improved cell survival and reduced H2O2-induced oxidative stress and mitochondrial damage. Moreover, the autophagy inhibitor 3-MA partially prevented the protective effects of Homer1a against oxidative challenge. We also found that the upregulation of Homer1a after H2O2 treatment increased the phosphorylation of AMPK. Furthermore, the AMPK inhibitor compound C inhibited Homer1a-induced autophagy and abolished Homer1a-mediated neuroprotection. All the above data suggests that Homer1a confers protection against H2O2-induced oxidative damage via AMPK-dependent autophagy. PMID- 29479302 TI - Influence of Brain Stem on Axial and Hindlimb Spinal Locomotor Rhythm Generating Circuits of the Neonatal Mouse. AB - The trunk plays a pivotal role in limbed locomotion. Yet, little is known about how the brain stem controls trunk activity during walking. In this study, we assessed the spatiotemporal activity patterns of axial and hindlimb motoneurons (MNs) during drug-induced fictive locomotor-like activity (LLA) in an isolated brain stem-spinal cord preparation of the neonatal mouse. We also evaluated the extent to which these activity patterns are affected by removal of brain stem. Recordings were made in the segments T7, L2, and L5 using calcium imaging from individual axial MNs in the medial motor column (MMC) and hindlimb MNs in lateral motor column (LMC). The MN activities were analyzed during both the rhythmic and the tonic components of LLA, the tonic component being used as a readout of generalized increase in excitability in spinal locomotor networks. The most salient effect of brain stem removal was an increase in locomotor rhythm frequency and a concomitant reduction in burst durations in both MMC and LMC MNs. The lack of effect on the tonic component of LLA indicated specificity of action during the rhythmic component. Cooling-induced silencing of the brain stem reproduced the increase in rhythm frequency and accompanying decrease in burst durations in L2 MMC and LMC, suggesting a dependency on brain stem neuron activity. The work supports the idea that the brain stem locomotor circuits are operational already at birth and further suggests an important role in modulating trunk activity. The brain stem may influence the axial and hindlimb spinal locomotor rhythm generating circuits by extending their range of operation. This may represent a critical step of locomotor development when learning how to walk in different conditions and environments is a major endeavor. PMID- 29479304 TI - The Decrease in Mitochondrial DNA Mutation Load Parallels Visual Recovery in a Leber Hereditary Optic Neuropathy Patient. AB - The onset of Leber hereditary optic neuropathy is relatively rare in childhood and, interestingly, the rate of spontaneous visual recovery is very high in this group of patients. Here, we report a child harboring a rare pathological mitochondrial DNA mutation, present in heteroplasmy, associated with the disease. A patient follow-up showed a rapid recovery of the vision accompanied by a decrease of the percentage of mutated mtDNA. A retrospective study on the age of recovery of all childhood-onset Leber hereditary optic neuropathy patients reported in the literature suggested that this process was probably related with pubertal changes. PMID- 29479303 TI - Representing Diversity in the Dish: Using Patient-Derived in Vitro Models to Recreate the Heterogeneity of Neurological Disease. AB - Neurological diseases, including dementias such as Alzheimer's disease (AD) and fronto-temporal dementia (FTD) and degenerative motor neuron diseases such as amyotrophic lateral sclerosis (ALS), are responsible for an increasing fraction of worldwide fatalities. Researching these heterogeneous diseases requires models that endogenously express the full array of genetic and epigenetic factors which may influence disease development in both familial and sporadic patients. Here, we discuss the two primary methods of developing patient-derived neurons and glia to model neurodegenerative disease: reprogramming somatic cells into induced pluripotent stem cells (iPSCs), which are differentiated into neurons or glial cells, or directly converting (DC) somatic cells into neurons (iNeurons) or glial cells. Distinct differentiation techniques for both models result in a variety of neuronal and glial cell types, which have been successful in displaying unique hallmarks of a variety of neurological diseases. Yield, length of differentiation, ease of genetic manipulation, expression of cell-specific markers, and recapitulation of disease pathogenesis are presented as determining factors in how these methods may be used separately or together to ascertain mechanisms of disease and identify therapeutics for distinct patient populations or for specific individuals in personalized medicine projects. PMID- 29479305 TI - Neuronal Growth and Behavioral Alterations in Mice Deficient for the Psychiatric Disease-Associated Negr1 Gene. AB - Neuronal growth regulator 1 (NEGR1), a member of the immunoglobulin superfamily cell adhesion molecule subgroup IgLON, has been implicated in neuronal growth and connectivity. In addition, genetic variants in or near the NEGR1 locus have been associated with obesity and more recently with learning difficulties, intellectual disability and psychiatric disorders. However, experimental evidence is lacking to support a possible link between NEGR1, neuronal growth and behavioral abnormalities. Initial expression analysis of NEGR1 mRNA in C57Bl/6 wildtype (WT) mice by in situ hybridization demonstrated marked expression in the entorhinal cortex (EC) and dentate granule cells. In co-cultures of cortical neurons and NSC-34 cells overexpressing NEGR1, neurite growth of cortical neurons was enhanced and distal axons occupied an increased area of cells overexpressing NEGR1. Conversely, in organotypic slice co-cultures, Negr1-knockout (KO) hippocampus was less permissive for axons grown from EC of beta-actin-enhanced green fluorescent protein (EGFP) mice compared to WT hippocampus. Neuroanatomical analysis revealed abnormalities of EC axons in the hippocampal dentate gyrus (DG) of Negr1-KO mice including increased numbers of axonal projections to the hilus. Neurotransmitter receptor ligand binding densities, a proxy of functional neurotransmitter receptor abundance, did not show differences in the DG of Negr1 KO mice but altered ligand binding densities to NMDA receptor and muscarinic acetylcholine receptors M1 and M2 were found in CA1 and CA3. Activity behavior, anxiety-like behavior and sensorimotor gating were not different between genotypes. However, Negr1-KO mice exhibited impaired social behavior compared to WT littermates. Moreover, Negr1-KO mice showed reversal learning deficits in the Morris water maze and increased susceptibility to pentylenetetrazol (PTZ)-induced seizures. Thus, our results from neuronal growth assays, neuroanatomical analyses and behavioral assessments provide first evidence that deficiency of the psychiatric disease-associated Negr1 gene may affect neuronal growth and behavior. These findings might be relevant to further evaluate the role of NEGR1 in cognitive and psychiatric disorders. PMID- 29479306 TI - Identification of Chloride Channels CLCN3 and CLCN5 Mediating the Excitatory Cl- Currents Activated by Sphingosine-1-Phosphate in Sensory Neurons. AB - Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid involved in numerous physiological and pathophysiological processes. We have previously reported a S1P induced nocifensive response in mice by excitation of sensory neurons via activation of an excitatory chloride current. The underlying molecular mechanism for the S1P-induced chloride conductance remains elusive. In the present study, we identified two CLCN voltage-gated chloride channels, CLCN3 and CLCN5, which mediated a S1P-induced excitatory Cl- current in sensory neurons by combining RNA seq, adenovirus-based gene silencing and whole-cell electrophysiological voltage clamp recordings. Downregulation of CLCN3 and CLCN5 channels by adenovirus mediated delivery of shRNA dramatically reduced S1P-induced Cl- current and membrane depolarization in sensory neurons. The mechanism of S1P-induced activation of the chloride current involved Rho GTPase but not Rho-associated protein kinase. Although S1P-induced potentiation of TRPV1-mediated ionic currents also involved Rho-dependent process, the lack of correlation of the S1P activated Cl- current and the potentiation of TRPV1 by S1P suggests that CLCN3 and CLCN5 are necessary components for S1P-induced excitatory Cl- currents but not for the amplification of TRPV1-mediated currents in sensory neurons. This study provides a novel mechanistic insight into the importance of bioactive sphingolipids in nociception. PMID- 29479308 TI - The Importance of the Dissociation Rate in Ion Channel Blocking. AB - Understanding the relationships between the rates and dynamics of current wave forms under voltage clamp conditions is essential for understanding phenomena such as state-dependence and use-dependence, which are fundamental for the action of drugs used as anti-epileptics, anti-arrhythmics, and anesthetics. In the present study, we mathematically analyze models of blocking mechanisms. In previous experimental studies of potassium channels we have shown that the effect of local anesthetics can be explained by binding to channels in the open state. We therefore here examine models that describe the effect of a blocking drug that binds to a non-inactivating channel in its open state. Such binding induces an inactivation-like current decay at higher potential steps. The amplitude of the induced peak depends on voltage and concentration of blocking drug. In the present study, using analytical methods, we (i) derive a criterion for the existence of a peak in the open probability time evolution for a model with an arbitrary number of closed states, (ii) derive formula for the relative height of the peak amplitude, and (iii) determine the voltage dependence of the relative peak height. Two findings are apparent: (1) the dissociation (unbinding) rate constant is important for the existence of a peak in the current waveform, while the association (binding) rate constant is not, and (2) for a peak to exist it suffices that the dissociation rate must be smaller than the absolute value of all eigenvalues to the kinetic matrix describing the model. PMID- 29479307 TI - Lpar2b Controls Lateral Line Tissue Size by Regulating Yap1 Activity in Zebrafish. AB - LPA signaling plays important roles during cell migration and proliferation in normal and pathological conditions. However, its role during sensory organ development remains unknown. Here we show a LPA receptor Lpar2b is expressed in the posterior lateral line primordium (pLLP) and mechanosensory organs called neuromasts (NMs) in zebrafish embryos. Lpar2b loss-of-function significantly reduces the number of NMs and hair cells in the posterior lateral line (pLL). Further analysis reveals that Lpar2b regulates the patterning and tissue size of the pLLP. Interestingly, we show that knocking down a Hippo effector Yap1 phenocopies the result of Lpar2b depletion, and Lpar2b regulates the phosphorylation and activity of Yap1 in the pLLP. Importantly, a phosphorylation resistant Yap1 rescues pLLP size and NM number in Lpar2b-depleted embryos. Our results indicate Lpar2b controls primordium size and NM number by regulating Yap1 activity in the lateral line system. PMID- 29479309 TI - The Medial Ventrothalamic Circuitry: Cells Implicated in a Bimodal Network. AB - Previous avian thalamic studies have shown that the medial ventral thalamus is composed of several nuclei located close to the lateral wall of the third ventricle. Although the general connectivity is known, detailed morphology and connectivity pattern in some regions are still elusive. Here, using the intracellular filling technique in the chicken, we focused on two neural structures, namely, the retinorecipient neuropil of the n. geniculatus lateralis pars ventralis (GLv), and the adjacent n. intercalatus thalami (ICT). We found that the GLv-ne cells showed two different neuronal types: projection cells and horizontal interneurons. The projection cells showed variable morphologies and dendritic arborizations with axons that targeted the n. lentiformis mesencephali (LM), griseum tectale (GT), ICT, n. principalis precommissuralis (PPC), and optic tectum (TeO). The horizontal cells showed a widespread mediolateral neural process throughout the retinorecipient GLv-ne. The ICT cells, on the other hand, had multipolar somata with wide dendritic fields that extended toward the lamina interna of the GLv, and a projection pattern that targeted the n. laminaris precommissuralis (LPC). Together, these results elucidate the rich complexity of the connectivity pattern so far described between the GLv, ICT, pretectum, and tectum. Interestingly, the implication of some of these neural structures in visuomotor and somatosensory roles strongly suggests that the GLv and ICT are part of a bimodal circuit that may be involved in the generation/modulation of saccades, gaze control, and space perception. PMID- 29479310 TI - Theta and Alpha Oscillations in Attentional Interaction during Distracted Driving. AB - Performing multiple tasks simultaneously usually affects the behavioral performance as compared with executing the single task. Moreover, processing multiple tasks simultaneously often involve more cognitive demands. Two visual tasks, lane-keeping task and mental calculation, were utilized to assess the brain dynamics through 32-channel electroencephalogram (EEG) recorded from 14 participants. A 400-ms stimulus onset asynchrony (SOA) factor was used to induce distinct levels of attentional requirements. In the dual-task conditions, the deteriorated behavior reflected the divided attention and the overlapping brain resources used. The frontal, parietal and occipital components were decomposed by independent component analysis (ICA) algorithm. The event- and response-related theta and alpha oscillations in selected brain regions were investigated first. The increased theta oscillation in frontal component and decreased alpha oscillations in parietal and occipital components reflect the cognitive demands and attentional requirements as executing the designed tasks. Furthermore, time varying interactive over-additive (O-Add), additive (Add) and under-additive (U Add) activations were explored and summarized through the comparison between the summation of the elicited spectral perturbations in two single-task conditions and the spectral perturbations in the dual task. Add and U-Add activations were observed while executing the dual tasks. U-Add theta and alpha activations dominated the posterior region in dual-task situations. Our results show that both deteriorated behaviors and interactive brain activations should be comprehensively considered for evaluating workload or attentional interaction precisely. PMID- 29479312 TI - EEG Beta Oscillations in the Temporoparietal Area Related to the Accuracy in Estimating Others' Preference. AB - Humans often attempt to predict what others prefer based on a narrow slice of experience, called thin-slicing. According to the theoretical bases for how humans can predict the preference of others, one tends to estimate the other's preference using a perceived difference between the other and self. Previous neuroimaging studies have revealed that the network of dorsal medial prefrontal cortex (dmPFC) and right temporoparietal junction (rTPJ) is related to the ability of predicting others' preference. However, it still remains unknown about the temporal patterns of neural activities for others' preference prediction through thin-slicing. To investigate such temporal aspects of neural activities, we investigated human electroencephalography (EEG) recorded during the task of predicting the preference of others while only a facial picture of others was provided. Twenty participants (all female, average age: 21.86) participated in the study. In each trial of the task, participants were shown a picture of either a target person or self for 3 s, followed by the presentation of a movie poster over which participants predicted the target person's preference as liking or disliking. The time-frequency EEG analysis was employed to analyze temporal changes in the amplitudes of brain oscillations. Participants could predict others' preference for movies with accuracy of 56.89 +/- 3.16% and 10 out of 20 participants exhibited prediction accuracy higher than a chance level (95% interval). There was a significant difference in the power of the parietal alpha (10~13 Hz) oscillation 0.6~0.8 s after the onset of poster presentation between the cases when participants predicted others' preference and when they reported self-preference (p < 0.05). The power of brain oscillations at any frequency band and time period during the trial did not show a significant correlation with individual prediction accuracy. However, when we measured differences of the power between the trials of predicting other's preference and reporting self preference, the right temporal beta oscillations 1.6~1.8 s after the onset of facial picture presentation exhibited a significant correlation with individual accuracy. Our results suggest that right temporoparietal beta oscillations may be correlated with one's ability to predict what others prefer with minimal information. PMID- 29479313 TI - Characteristics of Human Brain Activity during the Evaluation of Service-to Service Brand Extension. AB - Brand extension is a marketing strategy to apply the previously established brand name into new goods or service. A number of studies have reported the characteristics of human event-related potentials (ERPs) in response to the evaluation of goods-to-goods brand extension. In contrast, human brain responses to the evaluation of service extension are relatively unexplored. The aim of this study was investigating cognitive processes underlying the evaluation of service to-service brand extension with electroencephalography (EEG). A total of 56 text stimuli composed of service brand name (S1) followed by extended service name (S2) were presented to participants. The EEG of participants was recorded while participants were asked to evaluate whether a given brand extension was acceptable or not. The behavioral results revealed that participants could evaluate brand extension though they had little knowledge about the extended services, indicating the role of brand in the evaluation of the services. Additionally, we developed a method of grouping brand extension stimuli according to the fit levels obtained from behavioral responses, instead of grouping of stimuli a priori. The ERP analysis identified three components during the evaluation of brand extension: N2, P300, and N400. No difference in the N2 amplitude was found among the different levels of a fit between S1 and S2. The P300 amplitude for the low level of fit was greater than those for higher levels (p < 0.05). The N400 amplitude was more negative for the mid- and high-level fits than the low level. The ERP results of P300 and N400 indicate that the early stage of brain extension evaluation might first detect low-fit brand extension as an improbable target followed by the late stage of the integration of S2 into S1. Along with previous findings, our results demonstrate different cognitive evaluation of service-to-service brand extension from goods-to-goods. PMID- 29479314 TI - Development of the Italian Version of the Near-Death Experience Scale. AB - Near-death experiences (NDEs) have been defined as any conscious perceptual experience occurring in individuals pronounced clinically dead or who came very close to physical death. They are frequently reported by patients surviving a critical injury and, intriguingly, they show common features across different populations. The tool traditionally used to assess NDEs is the NDE Scale, which is available in the original English version. The aim of this study was to develop the Italian version of the NDE Scale and to assess its reliability in a specific clinical setting. A process of translation of the original scale was performed in different stages in order to obtain a fully comprehensible and accurate Italian translation. Later, the scale was administered to a convenience sample of patients who had experienced a condition of coma and were, at the time of assessment, fully conscious and able to provide information as requested by the scale. Inter-rater and test-retest reliability, assessed by the weighted Cohen's kappa (Kw), were estimated. A convenience sample of 20 subjects [mean age +/- standard deviation (SD) 51.6 +/- 17.1, median time from injury 3.5 months, interquartile range (IQR) 2-10] was included in the study. Inter-rater [Kw 0.77 (95% CI 0.67-0.87)] and test-retest reliability [Kw 0.96 (95% CI 0.91-1.00)] showed good to excellent values for the total scores of the Italian NDE Scale and for subanalyses of each single cluster of the scale. An Italian Version of the NDE Scale is now available to investigate the frequency of NDE, the causes for NDE heterogeneity across different life-threatening conditions, and the possible neural mechanisms underlying NDE phenomenology. PMID- 29479315 TI - Dissecting the Potential Roles of Nigella sativa and Its Constituent Thymoquinone on the Prevention and on the Progression of Alzheimer's Disease. AB - Several nutraceuticals have been investigated for preventing or retarding the progression of different neurodegenerative diseases, including Alzheimer's disease (AD). Because Nigella sativa (NS) and its isolated compound thymoquinone (TQ) have significant anti-oxidant and anti-inflammatory proprieties, they could represent effective neuroprotective agents. The purpose of this manuscript is to analyze and to recapitulate the results of in vitro and in vivo studies on the potential role of NS/TQ in AD's prevention and treatment. The level of evidence for each included animal study has been assessed by using a modified CAMARADES (Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies) 10-item checklist. We used MEDLINE and EMBASE databases to screen relevant articles published up to July 2017. A manual search was also performed. The database search yielded 38 studies, of which 18 were included in this manuscript. Results from these approaches suggest that NS or TQ could represent an effective strategy against AD due to the balancing of oxidative processes and the binding to specific intracellular targets. The overall effects mainly regard the prevention of hippocampal pyramidal cell loss and the increased cognitive functions. PMID- 29479311 TI - The Winding Road to Relapse: Forging a New Understanding of Cue-Induced Reinstatement Models and Their Associated Neural Mechanisms. AB - In drug addiction, cues previously associated with drug use can produce craving and frequently trigger the resumption of drug taking in individuals vulnerable to relapse. Environmental stimuli associated with drugs or natural reinforcers can become reliably conditioned to increase behavior that was previously reinforced. In preclinical models of addiction, these cues enhance both drug self administration and reinstatement of drug seeking. In this review, we will dissociate the roles of conditioned stimuli as reinforcers from their modulatory or discriminative functions in producing drug-seeking behavior. As well, we will examine possible differences in neurobiological encoding underlying these functional differences. Specifically, we will discuss how models of drug addiction and relapse should more systematically evaluate these different types of stimuli to better understand the neurobiology underlying craving and relapse. In this way, behavioral and pharmacotherapeutic interventions may be better tailored to promote drug use cessation outcomes and long-term abstinence. PMID- 29479316 TI - PhytoNanotechnology: Enhancing Delivery of Plant Based Anti-cancer Drugs. AB - Natural resources continue to be an invaluable source of new, novel chemical entities of therapeutic utility due to the vast structural diversity observed in them. The quest for new and better drugs has witnessed an upsurge in exploring and harnessing nature especially for discovery of antimicrobial, antidiabetic, and anticancer agents. Nature has historically provide us with potent anticancer agents which include vinca alkaloids [vincristine (VCR), vinblastine, vindesine, vinorelbine], taxanes [paclitaxel (PTX), docetaxel], podophyllotoxin and its derivatives [etoposide (ETP), teniposide], camptothecin (CPT) and its derivatives (topotecan, irinotecan), anthracyclines (doxorubicin, daunorubicin, epirubicin, idarubicin), and others. In fact, half of all the anti-cancer drugs approved internationally are either natural products or their derivatives and were developed on the basis of knowledge gained from small molecules or macromolecules that exist in nature. Three new anti-cancer drugs introduced in 2007, viz. trabectedin, epothilone derivative ixabepilone, and temsirolimus were obtained from microbial sources. Selective drug targeting is the need of the current therapeutic regimens for increased activity on cancer cells and reduced toxicity to normal cells. Nanotechnology driven modified drugs and drug delivery systems are being developed and introduced in the market for better cancer treatment and management with good results. The use of nanoparticulate drug carriers can resolve many challenges in drug delivery to the cancer cells that includes: improving drug solubility and stability, extending drug half-lives in the blood, reducing adverse effects in non-target organs, and concentrating drugs at the disease site. This review discusses the scientific ventures and explorations involving application of nanotechnology to some selected plant derived molecules. It presents a comprehensive review of formulation strategies of phytoconstituents in development of novel delivery systems like liposomes, functionalized nanoparticles (NPs), application of polymer conjugates, as illustrated in the graphical abstract along with their advantages over conventional drug delivery systems supported by enhanced biological activity in in vitro and in vivo anticancer assays. PMID- 29479317 TI - Suanzaoren Formulae for Insomnia: Updated Clinical Evidence and Possible Mechanisms. AB - Insomnia disorder is a widespread and refractory disease. Semen Ziziphi Spinosae, Suanzaoren, a well-known Chinese herbal medicine, has been used for treating insomnia for thousands of years. Here, we aimed to assess the available evidence of Chinese herbal formulae that contains Suanzaoren (FSZR) for insomnia according to high-quality randomized controlled trials (RCTs) and reviewed their possible mechanisms based on animal-based studies. Electronic searches were performed in eight databases from inception to November 2016. The primary outcome measures were polysomnography index and Pittsburgh sleep quality index. The secondary outcome measures were clinical effective rate and adverse events. The methodological quality of RCTs was assessed by Cochrane's collaboration tool, and only RCTs with positive for 4 out of 7 for the Cochrane risk of bias domains were included in analyses. Thirteen eligible studies with 1,454 patients were identified. Meta-analysis of high-quality RCTs showed that FSZR monotherapy was superior to placebo (P < 0.01); FSZR plus Diazepam was superior to Diazepam alone (P < 0.05); there were mixed results comparing FSZR with Diazepam (P > 0.05 or P < 0.05). Furthermore, FSZR caused fewer side effects than that of Diazepam. Suanzaoren contains complex mixtures of phytochemicals including sanjoinine A, Jujuboside A, spinosin and other flavonoids, which has sedative and hypnotic functions primarily mediated by the GABAergic and serotonergic system. In conclusion, the findings of present study supported that FSZR could be an alternative treatment for insomnia in clinic. FSZR exerted sedative and hypnotic actions mainly through the GABAergic and serotonergic system. PMID- 29479318 TI - Circadian Clock Proteins and Melatonin Receptors in Neurons and Glia of the Sapajus apella Cerebellum. AB - Oscillations of brain proteins in circadian rhythms are important for determining several cellular and physiological processes in anticipation of daily and seasonal environmental rhythms. In addition to the suprachiasmatic nucleus, the primary central oscillator, the cerebellum shows oscillations in gene and protein expression. The variety of local circuit rhythms that the cerebellar cortex contains influences functions such as motivational processes, regulation of feeding, food anticipation, language, and working memory. The molecular basis of the cerebellar oscillator has been demonstrated by "clock gene" expression within cells of the cerebellar layers. Genetic and epidemiological evidence suggests that disruption of circadian rhythms in humans can lead to many pathological conditions. Despite this importance, data about clock gene and protein expression in the cerebellum of diurnal (day-active) species, specifically primates, is currently poorly explored, mainly in regard to cellular identity, as well as the relationship with other molecules also involved in cerebellar functions. These studies could contribute to clarification of the possible mechanisms behind cerebellar rhythmicity. Considering that calcium binding proteins (CaBPs) play crucial roles in preserving and modulating cerebellar functions and that clock gene expression can be controlled by afferent projections or paracrine circadian signals such as the hormone melatonin, the present study aimed to describe cellular identities, distribution patterns and day/night expression changes in PER1, PER2, CaBPs, and MT1 and MT2 melatonin receptors in the cerebellar cortex of a diurnal primate using conventional fluorescence and peroxidase antiperoxidase immunocytochemical techniques. PER1 and PER2 immunoreactive (IR) cells were observed in the Purkinje cells of the cerebellum, and MT1 and MT2 receptors were localized around Purkinje cells in the Pj layer in Bergmann cells. This identity was confirmed by the S100beta-IR of these cells. The highest expression of PER seen in the daytime analysis coincided with the highest expression of melatonin receptors. CaBPs showed day/night morphological and density changes in the cerebellar cortex. The presence of the same temporal variations in the expression of PER in the Pj neurons and in MT1 and MT2 receptors in Bergmann cells indicates a possible relation between these cells during the rhythmic processing of the cerebellum, in addition to the CaBP temporal morphological and density changes. PMID- 29479319 TI - High Fat Diet Attenuates the Anticontractile Activity of Aortic PVAT via a Mechanism Involving AMPK and Reduced Adiponectin Secretion. AB - Background and aim: Perivascular adipose tissue (PVAT) positively regulates vascular function through production of factors such as adiponectin but this effect is attenuated in obesity. The enzyme AMP-activated protein kinase (AMPK) is present in PVAT and is implicated in mediating the vascular effects of adiponectin. In this study, we investigated the effect of an obesogenic high fat diet (HFD) on aortic PVAT and whether any changes involved AMPK. Methods: Wild type Sv129 (WT) and AMPKalpha1 knockout (KO) mice aged 8 weeks were fed normal diet (ND) or HFD (42% kcal fat) for 12 weeks. Adiponectin production by PVAT was assessed by ELISA and AMPK expression studied using immunoblotting. Macrophages in PVAT were identified using immunohistochemistry and markers of M1 and M2 macrophage subtypes evaluated using real time-qPCR. Vascular responses were measured in endothelium-denuded aortic rings with or without attached PVAT. Carotid wire injury was performed and PVAT inflammation studied 7 days later. Key results: Aortic PVAT from KO and WT mice was morphologically indistinct but KO PVAT had more infiltrating macrophages. HFD caused an increased infiltration of macrophages in WT mice with increased expression of the M1 macrophage markers Nos2 and Il1b and the M2 marker Chil3. In WT mice, HFD reduced the anticontractile effect of PVAT as well as reducing adiponectin secretion and AMPK phosphorylation. PVAT from KO mice on ND had significantly reduced adiponectin secretion and no anticontractile effect and feeding HFD did not alter this. Wire injury induced macrophage infiltration of PVAT but did not cause further infiltration in KO mice. Conclusions: High-fat diet causes an inflammatory infiltrate, reduced AMPK phosphorylation and attenuates the anticontractile effect of murine aortic PVAT. Mice lacking AMPKalpha1 phenocopy many of the changes in wild-type aortic PVAT after HFD, suggesting that AMPK may protect the vessel against deleterious changes in response to HFD. PMID- 29479320 TI - A microCT Study of Three-Dimensional Patterns of Biomineralization in Pig Molars. AB - Domestic pig molars provide an interesting system to study the biomineralization process. The large size, thick enamel and complex crown morphology make pig molars relatively similar to human molars. However, compared to human molars, pig molars develop considerably faster. Here we use microCT to image the developing pig molars and to decipher spatial patterns of biomineralization. We used mineral grains to calibrate individual microCT-scans, which allowed an accurate measure of the electron density of the developing molars. The microCT results show that unerupted molars that are morphologically at the same stage of development, can be at markedly different stage of enamel biomineralization. Erupted molars show increased electron density, suggesting that mineralization continues in oral cavity. Yet, our comparisons show that human enamel has slightly higher electron density than pig enamel. These results support the relatively low hardness values and calcium level values that have been reported earlier in literature for pig teeth. The mineral calibration was an efficient method for the microCT-absorption models, allowing a relatively robust way to detect scanning artifacts. In conclusions, whereas thin sections remain the preferred way to analyze enamel features, such as incremental lines and crystal orientation, the microCT allows efficient and non-destructive comparisons between different teeth and species. PMID- 29479321 TI - Trypophobia: What Do We Know So Far? A Case Report and Comprehensive Review of the Literature. AB - In this article, we describe the case of a girl who suffers from a phobia to repetitive patterns, known as trypophobia. This condition has not yet been recognised by diagnostic taxonomies such as the Diagnostic and Statistical Manual of Mental Disorders. Trypophobia usually involves an intense and disproportionate fear towards holes, repetitive patterns, protrusions, etc., and, in general, images that present high-contrast energy at low and midrange spatial frequencies. It is commonly accompanied by neurovegetative symptoms. In the case we present here, the patient also suffered from generalised anxiety disorder and was treated with sertraline. After she was diagnosed, she showed symptoms of both fear and disgust towards trypophobic images. After some time following treatment, she only showed disgust towards said images. We finish this case report presenting a comprehensive literature review of the peer reviewed articles we retrieved after an exhaustive search about trypophobia, we discuss how this case report contributes to the understanding of this anxiety disorder, and what questions future studies should address in order to achieve a better understanding of trypophobia. PMID- 29479322 TI - Association between School Membership and Substance Use among Adolescents. AB - Background: Substance use among adolescents is a major problem worldwide, producing many health and economic consequences. Even though there are well-known personal, familial, and social factors associated with drug use, less is known about the effect of school-related factors. School membership is a recognized variable affecting academic performance among students; however, its effect on substance use is less understood. Aims: The primary aim of this study was to explore the association between school membership and cigarette, alcohol, and cannabis use among a representative sample of secondary students from municipal state-funded schools in Santiago of Chile, and secondly, to test the hypothesis that depressive or anxiety symptoms mediate this association. Methods: A total of 2,508 students from 22 state-funded schools in Santiago, Chile, answered a questionnaire. This instrument included an abbreviated version of the psychological sense of school membership (PSSM), questions regarding the use of alcohol, tobacco, and cannabis and scales of psychological functioning (depression, anxiety, self-concept, and problem-solving). The association analyses were performed using adjusted regression models for each outcome using all independent variables while controlling for gender and age. For the mediation effect, a combination of ordinary least square and logistic regression analyses was conducted. Results: There was an association between a strong PSSM and low risk for smoking (OR 0.57; 95% CI 0.46-0.72), drinking (0.65; 95% CI: 0.51-0.83), and cannabis use (0.52; 95% CI 0.37-0.74). We also found that depressive and anxiety symptoms do not fully mediate the association between school membership and any substance use, and 73% of this effect in the case of smoking, 80% in the case of drinking, and 78.5% in the case of cannabis use, was direct. Conclusion: This is the first study in Latin America exploring the association between school membership and substance use among secondary students. School membership seems to be an important and independent factor to be included in preventive interventions. Therefore, these results support future research aiming to test interventions at increasing the sense of school membership to prevent substance use among adolescents. Clinical Trial Registration: ISRCTN19466209. Retrospectively registered. PMID- 29479323 TI - Latent Impulsivity Subtypes in Substance Use Disorders and Interactions with Internalizing and Externalizing Co-Occurring Disorders. AB - This study explored the clinical importance of latent impulsivity subtypes within a sample of individuals with substance use disorders (SUDs) and high rates of co occurring disorders (CODs) receiving residential treatment, aiming to assess the heterogeneity of the associations between SUDs and CODs across such impulsivity subtypes. The abbreviated Barratt impulsiveness scale was used to assess motor and cognitive (attentional and nonplanning) impulsivity, a structured interview for diagnosis of SUD and CODs, and other clinimetric measures for severity of substance use. Latent class analysis was conducted to extract subgroups of impulsivity subtypes and Poisson regression to analyze effects of interactions of classes by CODs on severity of substance use. 568 participants were evaluated. Results featured a four-class model as the best-fitted solution: overall high impulsivity (OHI); overall low impulsivity; high cognitive-low motor impulsivity; and moderate cognitive-low motor impulsivity (MC-LMI). OHI and MC-LMI concentrated on most of the individuals with CODs, and individuals within OHI and MC-LMI showed more severity of substance use. The expression of this severity relative to the impulsivity subtypes was modified by their interaction with internalizing and externalizing CODs in very heterogeneous ways. Our findings suggest that knowing either the presence of trait-based subtypes or CODs in individuals with SUDs is not enough to characterize clinical outcomes, and that the analysis of interactions between psychiatric categories and behavioral traits is necessary to better understand the expressions of psychiatric disorders. PMID- 29479324 TI - Can Robotic Systems Promote Self-Disclosure in Adolescents with Autism Spectrum Disorder? A Pilot Study. AB - Research suggests that many individuals with autism spectrum disorder (ASD) often demonstrate challenges providing appropriate levels of information during conversational interchanges. Considering the preference of individuals with ASD, and recent rapid technological advances, robotic systems may yield promise in promoting certain aspects of conversation and interaction such as self-disclosure of appropriate personal information. In the current work, we evaluated personal disclosures of events with specific emotional content across two differing robotic systems (android and simplistic humanoid) and human interactions. Nineteen participants were enrolled in this study: 11 (2 women and 9 men) adolescents with ASD and 8 (4 women and 4 men) adolescents with TD. Each participant completed a sequence of three interactions in a random order. Results indicated differences regarding comfort level and length of disclosures between adolescents with ASD and typically developing (TD) controls in relation to system interactions. Specifically, adolescents with ASD showed a preference for interacting with the robotic systems compared to TD controls and demonstrated lengthier disclosures when interacting with the visually simple humanoid robot compared to interacting with human interviewer. The findings suggest that robotic systems may be useful in eliciting and promoting aspects of social communication such as self-disclosure for some individuals with ASD. PMID- 29479325 TI - Exposing an "Intangible" Cognitive Skill among Collegiate Football Players: Enhanced Interference Control. AB - American football is played in a chaotic visual environment filled with relevant and distracting information. We investigated the hypothesis that collegiate football players show exceptional skill at shielding their response execution from the interfering effects of distraction (interference control). The performances of 280 football players from National Collegiate Athletic Association Division I football programs were compared to age-matched controls in a variant of the Eriksen flanker task (Eriksen and Eriksen, 1974). This task quantifies the magnitude of interference produced by visual distraction on split second response execution. Overall, football athletes and age controls showed similar mean reaction times (RTs) and accuracy rates. However, football athletes were more proficient at shielding their response execution speed from the interfering effects of distraction (i.e., smaller flanker effect costs on RT). Offensive and defensive players showed smaller interference costs compared to controls, but defensive players showed the smallest costs. All defensive positions and one offensive position showed statistically smaller interference effects when compared directly to age controls. These data reveal a clear cognitive advantage among football athletes at executing motor responses in the face of distraction, the existence and magnitude of which vary by position. Individual differences in cognitive control may have important implications for both player selection and development to improve interference control capabilities during play. PMID- 29479326 TI - Psychometric Comparisons of Benevolent and Corrective Humor across 22 Countries: The Virtue Gap in Humor Goes International. AB - Recently, two forms of virtue-related humor, benevolent and corrective, have been introduced. Benevolent humor treats human weaknesses and wrongdoings benevolently, while corrective humor aims at correcting and bettering them. Twelve marker items for benevolent and corrective humor (the BenCor) were developed, and it was demonstrated that they fill the gap between humor as temperament and virtue. The present study investigates responses to the BenCor from 25 samples in 22 countries (overall N = 7,226). The psychometric properties of the BenCor were found to be sufficient in most of the samples, including internal consistency, unidimensionality, and factorial validity. Importantly, benevolent and corrective humor were clearly established as two positively related, yet distinct dimensions of virtue-related humor. Metric measurement invariance was supported across the 25 samples, and scalar invariance was supported across six age groups (from 18 to 50+ years) and across gender. Comparisons of samples within and between four countries (Malaysia, Switzerland, Turkey, and the UK) showed that the item profiles were more similar within than between countries, though some evidence for regional differences was also found. This study thus supported, for the first time, the suitability of the 12 marker items of benevolent and corrective humor in different countries, enabling a cumulative cross-cultural research and eventually applications of humor aiming at the good. PMID- 29479328 TI - A Chip Off the Old Block: Parents' Subtle Ethnic Prejudice Predicts Children's Implicit Prejudice. AB - The increasing flow of immigrants in many European countries and the growing presence of children from immigrant families in schools makes it relevant to study the development of prejudice in children. Parents play an important role in shaping children's values and their attitudes toward members of other ethnic groups; an intergenerational transmission of prejudice has been found in a number of studies targeting adolescents. The present study aims to investigate the intergenerational transmission of ethnic prejudice in 3- to 9- year-old children and its relations to parenting styles. Parents' blatant and subtle ethnic prejudice and parenting style are measured together with children's explicit and implicit ethnic prejudice in pupils and parents of preschool and primary schools in the region of Rome, Italy (N = 318). Results show that parents' subtle prejudice predicts children's implicit prejudice regardless of the parenting style. Findings indicate that children might acquire prejudice by means of the parents' implicit cognition and automatic behavior and educational actions. Implications for future studies and insights for possible applied interventions are discussed. PMID- 29479327 TI - Type D Personality and Alexithymia: Common Characteristics of Two Different Constructs. Implications for Research and Clinical Practice. AB - In the last few decades, particular attention has been paid to the role of personality specific traits that can affect the loss of health, i.e., Type D personality and Alexithymia. They have been conceptualized in a different period, this means that they are different both for their theoretical positions and their empirical studies. Some authors have speculated that there is a potential conceptual overlap between Type D personality and alexithymia constructs but there is a shortcoming in the literature. The aim of the study was to examine the potential overlap between the constructs of type D personality and alexithymia, replicating previous two studies, to extend these findings to Italian population. The participants were 247 Italian adults (males = 43%), recruited in primary health care practices of Palermo. All participants did not have chronic diseases during tests administration. They ranged in age from 35 to 69 years old (M = 52.34 years, SD = 9.76). Participants were administered Type D Personality Scale (DS-14) and Toronto Alexithymia Scale (TAS-20). A series of confirmatory factor analyses was performed to evaluate the factorial structure underlying the TAS-20 and DS-14 items. Globally results showed that alexithymia and type D personality are distinct constructs, but they are also strictly positively related with each other. Negative affectivity (NA) was highly correlated with Difficulties in identifying feelings and Difficulties in describing feelings, while Social inhibition (SI) was highly correlated with Difficulties in describing feelings. These results are consistent with those of other studies conducted in this area. Future research should consider evaluating the relationship between a deficit of affect regulation and type D personality to improve the effectiveness of interventions of health cure. PMID- 29479329 TI - Childhood Adversity and the Creative Experience in Adult Professional Performing Artists. AB - Childhood adversity is identified as any exposure to abuse, neglect or family dysfunction. Greater exposure to childhood adversity has been strongly identified with increased morbidity and mortality. The aim of this study was to examine differences in creative experiences, fantasy proneness, dispositional flow, exposure to adult traumatic events, and psychopathology (internalized shame, trait anxiety), amongst professional performing artists who experienced no childhood adversity, some adversity, or substantial adversity. This cross-section IRB approved study examined 234 professional performers (dancers, opera singers, actors, directors, musicians). Self-report measurements were included to examine the following psychological factors: adverse childhood experiences (ACEs), experience of creativity questionnaire, dispositional flow, trait anxiety, internalized shame, fantasy, and total adult and childhood traumatic events. The sample was divided into three groups based on ACE scores: 0 ACE (n = 93), 1-3 ACEs (n = 95), >=4 ACEs (n = 42). The MANCOVA (with age and gender as covariates) results revealed no significant (p = 0.280) differences between all three ACE groups for the nine flow scales (optimal performance measurements). Performing artists with >=4 ACEs had significantly stronger creative experiences (p = 0.006) related to distinct creative processing, absorption, and a transformational sense of self and the world. They were also more fantasy prone, shame-based, anxious, and experienced more cumulative past traumatic events (p < 0.001). Although the high ACE group experienced greater negative effects, they also endorsed positive creative performance experiences. PMID- 29479330 TI - Editorial: Music and the Functions of the Brain: Arousal, Emotions, and Pleasure. PMID- 29479331 TI - Right Forceps Minor and Anterior Thalamic Radiation Predict Executive Function Skills in Young Bilingual Adults. AB - Executive function (EF) skills enhance learning across domains, and are particularly linked to the acquisition of a second language. Previous studies have shown that bilingual individuals show enhanced EF skills in cognitive tasks where they attended a targeted dimension of a stimulus while inhibiting other competing cues. Brain imaging revealed that bilingual young adults' performances in the Stroop color-naming task were related to the volume of anterior cingulate cortex (ACC) and inferior frontal lobe. Subjects who had greater white-matter in the frontal cortex showed enhanced performances in the same task, suggesting that brain fiber pathways connecting ACC to the frontal region may be related to the Stroop color-naming task. No studies to date have examined the tissue properties of brain fiber pathways connecting these brain regions and their association with subjects' EF performances. Importantly, there are no data establishing whether bilingual subjects exhibit different reaction times when words are presented in their first versus second language. To study these questions, we used behavioral and unbiased whole-brain analyses, recruiting 21 Chinese students. Using the Stroop color-naming task, we measured subjects' reaction times (RTs) in which color names were displayed using fonts that matched the named color (congruent task) or mismatched the color (incongruent task). Students performed the task twice, first in English, the subjects' second language, then in Chinese, the subjects' primary language. Results from whole-brain analysis showed that students' RTs in both the English and Chinese tasks were significantly correlated with the mode of anisotropy (MO) in a brain cluster containing the forceps minor and anterior thalamic radiation in the right hemisphere. We also found that fractional anisotropy (FA) significantly predicted students' RTs, with higher FA predicting shorter RT. Taken together, our findings demonstrate that right forceps minor and anterior thalamic radiation predict EF skills, suggesting that this brain feature may be important for young bilingual adults using their first and second languages to direct their attention when conflicting cues are present. PMID- 29479332 TI - Parental External Locus of Control in Pregnancy Is Associated with Subsequent Teacher Ratings of Negative Behavior in Primary School: Findings from a British Birth Cohort. AB - The purpose of the present study was to examine whether parents' locus of control (LOC) obtained before the birth of their child predicts the child's behavior at school in School Years 3 (ages 7-8) and 6 (ages 10-11). A modified version of the adult Nowicki-Strickland internal-external locus of control scale was completed by mothers and fathers in their own home during pregnancy. Externality was defined as a score greater than the median and internality as equal to, or less than, the median. Outcomes were the five individual subscales and the total difficulties of Goodman's strengths and difficulties' questionnaire completed by the children's class teachers at the end of School Years 3 and 6. As predicted, it was found that the greater the presence of externality in the parents, the greater the increased risk of the child's adverse behavior as rated by teachers. The risk was generally greatest if both parents were external and lowest if both were internal. There was a consistent relationship at both Year 3 and Year 6 between maternal externality in pregnancy and children's emotional difficulties. However, for other behaviors, the pattern of associations varied depending on whether the mother or father was external, the type of adverse behavior, and the School Year in which children were assessed. Prenatal parental externality appears to be significantly associated with a variety of children's negative behaviors. Of note was the finding that fathers' as well as mothers' LOC was important in determining children's outcomes. Implications of the complexity of the results for the role parents may play in children's personality and adjustment are discussed. PMID- 29479333 TI - The Role of Co-occurring Emotions and Personality Traits in Anger Expression. AB - The main aim of the current study was to examine the role of co-occurring emotions and their interactive effects with the Big Five personality traits in anger expression. Everyday anger expression ("anger-in" and "anger-out" behavior) was studied with the experience-sampling method in a group of 110 participants for 14 consecutive days on 7 random occasions per day. Our results showed that the simultaneously co-occurring emotions that buffer against anger expression are sadness, surprise, disgust, disappointment, and irritation for anger-in behavior, and fear, sadness and disappointment for anger-out reactions. While previous studies have shown that differentiating one's current affect into discrete emotion categories buffers against anger expression (Pond et al., 2012), our study further demonstrated the existence of specific interactive effects between the experience of momentary emotions and personality traits that lead to higher levels of either suppression or expression of anger behavior (or both). For example, the interaction between the trait Openness and co-occurring surprise, in predicting anger-in behavior, indicates that less open people hold their anger back more, and more open people use less anger-in behavior. Co-occurring disgust increases anger-out reactions in people low in Conscientiousness, but decreases anger-out reactions in people high in Conscientiousness. People high in Neuroticism are less likely to engage in anger-in behavior when experiencing disgust, surprise, or irritation alongside anger, but show more anger out in the case of co-occurring contempt. The results of the current study help to further clarify the interactions between the basic personality traits and the experience of momentary co-occurring emotions in determining anger behavior. PMID- 29479334 TI - "I Can Only Work So Hard Before I Burn Out." A Time Sensitive Conceptual Integration of Ideological Psychological Contract Breach, Work Effort, and Burnout. AB - Employees often draw meaning from personal experiences and contributions in their work, particularly when engaging in organizational activities that align with their personal identity or values. However, recent empirical findings have demonstrated how meaningful work can also have a negative effect on employee's well-being as employees feel so invested in their work, they push themselves beyond their limits resulting in strain and susceptibility to burnout. We develop a framework to understand this "double edged" role of meaningful work by drawing from ideological psychological contracts (iPCs), which are characterized by employees and their employer who are working to contribute to a shared ideology or set of values. Limited iPC research has demonstrated employees may actually work harder in response to an iPC breach. In light of these counterintuitive findings, we propose the following conceptual model to theoretically connect our understanding of iPCs, perceptions of breach, increases in work effort, and the potential "dark side" of repeated occurrences of iPC breach. We argue that time plays a central role in the unfolding process of employees' reactions to iPC breach over time. Further, we propose how perceptions of iPC breach relate to strain and, eventually, burnout. This model contributes to our understanding of the role of time in iPC development and maintenance, expands our exploration of ideology in the PC literature, and provides a framework to understanding why certain occupations are more susceptible to instances of strain and burnout. This framework has the potential to guide future employment interventions in ideology infused organizations to help mitigate negative employee outcomes. PMID- 29479336 TI - Acute Motor Axonal Neuropathy in Association with Hepatitis E. AB - Guillain-Barre syndrome (GBS) is an acute peripheral neuropathy that develops as a result of post-infectious immune-mediated nerve injury. It can be classified into classic and variant GBS. Acute motor axonal neuropathy (AMAN) is a subtype of GBS with the key clinical features of pure motor weakness, areflexia, absence of sensory symptoms, and lack of neurophysiologic evidence of demyelination. We reported a case of acute motor axonal neuropathy in association with hepatitis E infection. A young woman was referred to us after a period of nausea, fever, and diarrhea. She had unexplained muscle weakness at admission and has been diagnosed with acute hepatitis E infection. A rigorous clinical neurological assessment revealed bilateral symmetrical weakness, which affects the lower limbs more than the upper limbs, with no evidence of sensory involvement. Neurophysiological measurements indicated acute axonal injury without clues to demyelination. A diagnosis of acute motor axonal neuropathy subtype has been made, to which she only received supportive therapy. The symptoms resolved spontaneously and full recovery of motor function was attained after 35 days of weakness onset with complete normalization of neurophysiologic parameters. PMID- 29479337 TI - Successful Treatment of a Drug-Resistant Epilepsy by Long-term Transcranial Direct Current Stimulation: A Case Report. AB - Transcranial direct current stimulation (tDCS) is a reemerged noninvasive cerebral therapy used to treat patients with epilepsy, including focal cortical dysplasia, with controversial results. We present a case of a 28-year-old female with left frontal cortical dysplasia refractory to antiepileptic drugs, characterized by 10-15 daily right tonic hemi-body seizures. The patient received a total of seven sessions of cathodal tDCS (2 mA, 30 min). The first three sessions were applied over three consecutive days, and the remaining four sessions of tDCS were given each at 2-week intervals. At the 1-year follow-up, the patient reported to have a single seizure per month and only mild adverse events. PMID- 29479338 TI - The Effects of Low-Dose Bisphenol A and Bisphenol F on Neural Differentiation of a Fetal Brain-Derived Neural Progenitor Cell Line. AB - Environmental chemicals are known to disrupt the endocrine system in humans and to have adverse effects on several organs including the developing brain. Recent studies indicate that exposure to environmental chemicals during gestation can interfere with neuronal differentiation, subsequently affecting normal brain development in newborns. Xenoestrogen, bisphenol A (BPA), which is widely used in plastic products, is one such chemical. Adverse effects of exposure to BPA during pre- and postnatal periods include the disruption of brain function. However, the effect of BPA on neural differentiation remains unclear. In this study, we explored the effects of BPA or bisphenol F (BPF), an alternative compound for BPA, on neural differentiation using ReNcell, a human fetus-derived neural progenitor cell line. Maintenance in growth factor-free medium initiated the differentiation of ReNcell to neuronal cells including neurons, astrocytes, and oligodendrocytes. We exposed the cells to BPA or BPF for 3 days from the period of initiation and performed real-time PCR for neural markers such as beta III tubulin and glial fibrillary acidic protein (GFAP), and Olig2. The beta III tubulin mRNA level decreased in response to BPA, but not BPF, exposure. We also observed that the number of beta III-tubulin-positive cells in the BPA-exposed group was less than that of the control group. On the other hand, there were no changes in the MAP2 mRNA level. These results indicate that BPA disrupts neural differentiation in human-derived neural progenitor cells, potentially disrupting brain development. PMID- 29479335 TI - Light and Cognition: Roles for Circadian Rhythms, Sleep, and Arousal. AB - Light exerts a wide range of effects on mammalian physiology and behavior. As well as synchronizing circadian rhythms to the external environment, light has been shown to modulate autonomic and neuroendocrine responses as well as regulating sleep and influencing cognitive processes such as attention, arousal, and performance. The last two decades have seen major advances in our understanding of the retinal photoreceptors that mediate these non-image forming responses to light, as well as the neural pathways and molecular mechanisms by which circadian rhythms are generated and entrained to the external light/dark (LD) cycle. By contrast, our understanding of the mechanisms by which lighting influences cognitive processes is more equivocal. The effects of light on different cognitive processes are complex. As well as the direct effects of light on alertness, indirect effects may also occur due to disrupted circadian entrainment. Despite the widespread use of disrupted LD cycles to study the role circadian rhythms on cognition, the different experimental protocols used have subtly different effects on circadian function which are not always comparable. Moreover, these protocols will also disrupt sleep and alter physiological arousal, both of which are known to modulate cognition. Studies have used different assays that are dependent on different cognitive and sensory processes, which may also contribute to their variable findings. Here, we propose that studies addressing the effects of different lighting conditions on cognitive processes must also account for their effects on circadian rhythms, sleep, and arousal if we are to fully understand the physiological basis of these responses. PMID- 29479340 TI - Pseudomonas orientalis F9: A Potent Antagonist against Phytopathogens with Phytotoxic Effect in the Apple Flower. AB - In light of public concerns over the use of pesticides and antibiotics in plant protection and the subsequent selection for spread of resistant bacteria in the environment, it is inevitable to broaden our knowledge about viable alternatives, such as natural antagonists and their mode of action. The genus Pseudomonas is known for its metabolic versatility and genetic plasticity, encompassing pathogens as well as antagonists. We characterized strain Pseudomonas orientalis F9, an isolate from apple flowers in a Swiss orchard, and determined its antagonistic activity against several phytopathogenic bacteria, in particular Erwinia amylovora, the causal agent of fire blight. P. orientalis F9 displayed antagonistic activity against a broad suite of phytopathogenic bacteria in the in vitro tests. The promising results from this analysis led to an ex vivo assay with E. amylovora CFBP1430Rif and P. orientalis F9 infected detached apple flowers. F9 diminished the fire blight pathogen in the flowers but also revealed phytotoxic traits. The experimental results were discussed in light of the complete genome sequence of F9, which revealed the strain to carry phenazine genes. Phenazines are known to contribute to antagonistic activity of bacterial strains against soil pathogens. When tested in the cress assay with Pythium ultimum as pathogen, F9 showed results comparable to the known antagonist P. protegens CHA0. PMID- 29479339 TI - The Natural History of Metabolic Comorbidities in Turner Syndrome from Childhood to Early Adulthood: Comparison between 45,X Monosomy and Other Karyotypes. AB - Objective: Patients with Turner syndrome (TS) are at increased risk for metabolic disorders. We aimed to delineate the occurrence and evolution of metabolic comorbidities in TS patients and to determine whether these differ in 45,X monosomy and other karyotypes. Methods: A longitudinal and cross-sectional retrospective cohort study was conducted in a tertiary pediatric endocrine unit during 1980-2016. Ninety-eight TS patients, 30 with 45,X monosomy were followed from childhood to early adulthood. Outcome measures included weight status, blood pressure (BP), glucose metabolism, and lipid profile. Results: Longitudinal analysis showed a significant change in body mass index (BMI) percentiles over time [F(3,115) = 4.8, P = 0.003]. Age was associated with evolution of elevated BP [systolic BP: odds ratio (OR) = 0.91, P = 0.003; diastolic BP: OR = 0.93, P = 0.023], impaired glucose metabolism (HbA1c: OR = 1.08, P = 0.029; impaired glucose tolerance: OR = 1.12, P = 0.029), and abnormal lipid profile (cholesterol: OR = 1.06, P = 0.01; low-density lipoprotein cholesterol: OR = 1.07, P = 0.041; high-density lipoprotein cholesterol: OR = 1.07, P = 0.033). The occurrence of metabolic comorbidities was similar in 45,X monosomy and other karyotypes. Coexistence of multiple metabolic comorbidities was significantly higher in 45,X monosomy [F(1,72) = 4.81, P = 0.032]. BMI percentiles were positively correlated with metabolic comorbidities (occurrence and number) in each patient (r = 0.35, P = 0.002 and r = 0.383, P = 0.001, respectively). Conclusion: Our longitudinal study provides unique insights into the evolution of weight gain and metabolic disorders from childhood to early adulthood in TS patients. Since overweight and increasing age aggravate the risk for metabolic comorbidities, careful surveillance is warranted to prevent and control obesity already from childhood. The more prominent clustering of metabolic comorbidities in 45,X monosomy underscores the importance of a more vigorous intervention in this group. PMID- 29479341 TI - Clinically Relevant ESBL-Producing K. pneumoniae ST307 and E. coli ST38 in an Urban West African Rat Population. AB - High-risk ESBL-producing Enterobacteriaceae (ESBL-E) have been described in wild birds and rodents worldwide. Rats are of special interest not only due to their indicator role for environmental pollution with multi-resistant bacteria but also as possible infection source. Data on the presence of high-risk ESBL-E in urban wildlife from Africa remain scarce, however. Twenty-nine animals from three different rat (Rattus) species were captured in the city of Conakry (Guinea, West Africa) in 2015. Rectal swabs were analyzed for ESBL-E using selective media. Species typing and phenotypic antimicrobial resistance analysis to broad-spectrum beta-lactams and other classes of antimicrobials was performed for Enterobacteriaceae-like isolates using the VITEK(r)2 system (BioMerieux, Germany). Confirmed ESBL-producing E. coli and K. pneumoniae were whole-genome sequenced and resistance genes, phylogenetic background and genes related to bacterial fitness and virulence were analyzed. In total, six of twenty-nine rats (20%) carried ESBL-E (K. pneumoniae and E. coli). All ESBL-producers were multi drug resistant with blaCTX-M-15 as the dominating ESBL-type. Interestingly, ESBL associated clonal lineages E. coli ST38 and K. pneumoniae ST307 were found. The ESBL-plasmid in K. pneumoniae ST307 revealed high sequence similarities to pKPN3 307_TypeC, a >200 kbp IncFII plasmid originating from a human clinical ST307 isolate. This was in contrast to the core genome: the rat isolate was distantly related to the human clinical ST307 isolate (27 SNPs/Mbp). In addition, we identified pi-fimbrial, capsule 2, and glycogen synthesis clusters in the rodent ST307 isolate, whose involvement in the adaptation to survival outside the host and in human urinary tracts has been suggested. Our results demonstrate the presence of clinically relevant, ESBL-producing K. pneumoniae ST307 and E. coli ST38 clonal lineages in an urban West African rat population. The human community is likely the initial source of ESBL-E however, rats might function as infection source and transmission hub, accelerated by frequent interactions at a human wildlife interface. PMID- 29479342 TI - Adaptation to Aerobic Environment of Lactobacillus johnsonii/gasseri Strains. AB - Oxygen is considered one of the main factors affecting probiotic bacteria survival due to the induction of oxidative damages caused by the action of reactive oxygen species (ROS). It has been shown that oxidative stress resistance in lactic acid bacteria is strongly dependent on the type of cell metabolism. Shift from fermentative to respiratory metabolism (through the addition of heme and menaquinone and in presence of oxygen) was associated to increase in biomass, long-term survival, and production of antioxidant enzymes. The aim of this work was to investigate the effect of aerobic (presence of oxygen) and respiratory (presence of oxygen, heme, and menaquinone) cultivation on the growth kinetic, catalase production, oxygen uptake, and oxidative stress response of Lactobacillus johnsonii/gasseri strains previously isolated from infant feces. Seven strains showed to consume oxygen under aerobic and respiratory conditions. The strain AL5 showed a catalase activity in both growth conditions, while AL3 showed this activity only in respiratory condition. Respiratory condition improved their tolerance to oxidative compounds (hydrogen peroxide and ROS generators) and further they showed promising probiotic features. The exploration of respiratory competent phenotypes with probiotic features may be extremely useful for the development of competitive starter or probiotic cultures. PMID- 29479343 TI - Specificity and Application of the Lantibiotic Protease NisP. AB - Lantibiotics are ribosomally produced and posttranslationally modified peptides containing several lanthionine residues. They exhibit substantial antimicrobial activity against Gram-positive bacteria, including relevant pathogens. The production of the model lantibiotic nisin minimally requires the expression of the modification and export machinery. The last step during nisin maturation is the cleavage of the leader peptide. This liberates the active compound and is catalyzed by the cell wall-anchored protease NisP. Here, we report the production and purification of a soluble variant of NisP. This has enabled us to study its specificity and test its suitability for biotechnological applications. The ability of soluble NisP to cleave leaders from various substrates was tested with two sets of nisin variants. The first set was designed to investigate the influence of amino acid variations in the leader peptide or variations around the cleavage site. The second set was designed to study the influence of the lanthionine ring topology on the proteolytic efficiency. We show that the substrate promiscuity is higher than has previously been suggested. Our results demonstrate the importance of the arginine residue at the end of the leader peptide and the importance of lanthionine rings in the substrate for specific cleavage. Collectively, these data indicate that NisP is a suitable protease for the activation of diverse heterologously expressed lantibiotics, which is required to release active antimicrobial compounds. PMID- 29479344 TI - Direct and Indirect Effects of Resource P-Limitation Differentially Impact Population Growth, Life History and Body Elemental Composition of a Zooplankton Consumer. AB - One of the central tenets of ecological stoichiometry is that consumer growth rate is strongly determined by food phosphorus (P) content. In planktonic organisms population growth rates of zooplankton have repeatedly been shown to be reduced when fed with P-limited algal food sources. However, P-limitation may also affect other quality-related aspects of algae, such as biochemical composition or palatability. We studied the population growth, detailed life history and body elemental composition of the herbivorous rotifer, Brachionus calyciflorus, in response to three different food quality treatments: algae cultured in high phosphorus conditions (average algal molar C:P ~ 112, 'HP'), algae cultured in low P conditions (molar C:P ~ 631, 'LP') and low-P cultured algae spiked with P just before feeding (molar C:P ~ 113, 'LP+P'). LP+P algae thus combined high P content with a history of growth under P-limited conditions. Total P content and the C:P ratio of rotifers in the LP+P treatment equaled those of rotifers in the HP treatment. Rotifer population growth rates were higher in HP than in LP and intermediate in the LP+P treatment. Similarly, many life history traits observed for animals in the LP+P treatment, such as somatic growth rate, age at maturity, and egg production rate were also intermediate to those observed in the LP and HP treatments. However, there were important deviations from this pattern: size at first reproduction and egg mortality in the LP+P treatment equaled the HP treatment, whereas size and development time of the first eggs equaled those of the LP treatment. Our results indicate that elemental limitation cannot fully explain reduced performance of consumers fed with P limited algae and strongly suggest that indirect, non-stoichiometric effects of P limitation, e.g., via changes in biochemical composition or morphology of the algae also play a major role. Furthermore, our study highlights that such indirect effects have a differential impact on major fitness components and may as such also determine the population dynamics and demographic structure of consumer populations. PMID- 29479345 TI - Membrane Topology and Heme Binding of the Histidine Kinases HrrS and ChrS in Corynebacterium glutamicum. AB - The HrrSA and the ChrSA two-component systems play a central role in the coordination of heme homeostasis in the Gram-positive soil bacterium Corynebacterium glutamicum and the prominent pathogen Corynebacterium diphtheriae, both members of the Corynebacteriaceae. In this study, we have performed a comparative analysis of the membrane topology and heme-binding characteristics of the histidine kinases HrrS and ChrS of C. glutamicum. While the cytoplasmic catalytic domains are highly conserved between HrrS and ChrS, the N-terminal sensing parts share only minor sequence similarity. PhoA and LacZ fusions of the N-terminal sensor domains of HrrS and ChrS revealed that both proteins are embedded into the cytoplasmic membrane via six alpha-helices. Although the overall membrane topology appeared to be conserved, target gene profiling indicated a higher sensitivity of the ChrS system to low heme levels (< 1 MUM). In vitro, solubilized and purified full-length proteins bound heme in a 1:1 stoichiometry per monomer. Alanine-scanning of conserved amino acid residues in the N-terminal sensor domain revealed three aromatic residues (Y112, F115, and F118), which apparently contribute to heme binding of HrrS. Exchange of either one or all three residues resulted in an almost abolished heme binding of HrrS in vitro. In contrast, ChrS mutants only displayed a red shift of the soret band from 406 to 418 nm suggesting an altered set of ligands in the triple mutant. In line with target gene profiling, these in vitro studies suggest distinct differences in the heme-protein interface of HrrS and ChrS. Since the membrane topology mapping displayed no extensive loop regions and alanine-scanning revealed potential heme-binding residues in alpha-helix number four, we propose an intramembrane sensing mechanism for both proteins. Overall, we present a first comparative analysis of the ChrS and HrrS kinases functioning as transient heme sensors in the Corynebacteriaceae. PMID- 29479346 TI - Resource Availability Drives Responses of Soil Microbial Communities to Short term Precipitation and Nitrogen Addition in a Desert Shrubland. AB - Desert microbes are expected to be substantially sensitive to global environmental changes, such as precipitation changes and elevated nitrogen deposition. However, the effects of precipitation changes and nitrogen enrichment on their diversity and community composition remain poorly understood. We conducted a field experiment over 2 years with multi-level precipitation and nitrogen addition in a desert shrubland of northern China, to examine the responses of soil bacteria and fungi in terms of diversity and community composition and to explore the roles of plant and soil factors in structuring microbial communities. Water addition significantly increased soil bacterial diversity and altered the community composition by increasing the relative abundances of stress-tolerant (dormant) taxa (e.g., Acidobacteria and Planctomycetes); however, nitrogen addition had no substantial effects. Increased precipitation and nitrogen did not impact soil fungal diversity, but significantly shifted the fungal community composition. Specifically, water addition reduced the relative abundances of drought-tolerant taxa (e.g., the orders Pezizales, Verrucariales, and Agaricales), whereas nitrogen enrichment decreased those of oligotrophic taxa (e.g., the orders Agaricales and Sordariales). Shifts in microbial community composition under water and nitrogen addition occurred primarily through changing resource availability rather than plant community. Our results suggest that water and nitrogen addition affected desert microbes in different ways, with watering shifting stress-tolerant traits and fertilization altering copiotrophic/oligotrophic traits of the microbial communities. These findings highlight the importance of resource availability in driving the desert microbial responses to short-term environmental changes. PMID- 29479347 TI - Genome Sequencing of Extended-Spectrum beta-Lactamase (ESBL)-Producing Klebsiella pneumoniae Isolated from Pigs and Abattoir Workers in Cameroon. AB - Background and objectives: Extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae is a serious public health issue globally. In this study, the antibiotic resistance genes, virulence factors, mobile genetic elements, and genetic lineages of circulating ESBL-producing K. pneumoniae strains isolated from pigs and humans in Cameroonian abattoirs were investigated using whole genome sequencing (WGS), in order to ascertain zoonotic transmission (viz. from animals to humans and/or vice-versa) in the food chain. Methods: During March October 2016, 288 nasal and rectal pooled samples from 432 pigs as well as nasal and hand swabs from 82 humans were collected from Cameroon and South Africa. Seven ESBL-producing K. pneumoniae circulating in Cameroonian pig abattoirs were selected and their genomic DNA sequenced using an Illumina MiSeq platform. Generated reads were de novo assembled using the Qiagen CLC Genomics Workbench and SPAdes. The assembled contigs were annotated using RAST and antibiotic resistance genes, virulence factors, plasmids, and bacteriophages were identified with ResFinder, Virulence Finder, PlasmidFinder, and PHAST, respectively. Results: ESBL-producing K. pneumoniae were detected in pigs (34/158; 21.52%) and exposed workers (8/71; 11.26%) in Cameroon only. The circulating K. pneumoniae strains were dominated principally by the sequence type (ST) 14 and 39. In addition, the "high-risk" ST307 clone and two novel STs assigned ST2958 and ST2959 were detected. Genomic analysis identified various antibiotic resistance genes associated with resistance to beta-lactams, aminoglycosides, fluoroquinolones, macrolide, lincosamide and streptogramins, rifampicin, sulfonamides, trimethoprim, phenicols and tetracycline. None of the ESBL producing K. pneumoniae harbored virulence genes. Intermingled K. pneumoniae populations were observed between pig- and human-source within and across abattoirs in the country. Conclusion: Our study shows that ESBL-producing K. pneumoniae is actively disseminating in pigs and occupationally exposed workers in Cameroonian pig abattoirs and is probably underestimated in the absence of molecular epidemiological studies. It suggests pigs, abattoir workers and food products as potential reservoirs and sources of zoonotic transmission in Cameroon. Our findings underline the existence of a potential unheeded food safety and public health threat associated with these resistant strains and reinforce the crucial importance of implementing appropriate food safety measures and promoting rational antibiotic use. PMID- 29479348 TI - Vitamin C Fosters the In Vivo Differentiation of Peripheral CD4+ Foxp3- T Cells into CD4+ Foxp3+ Regulatory T Cells but Impairs Their Ability to Prolong Skin Allograft Survival. AB - Regulatory T cells (Tregs) are critical players of immunological tolerance due to their ability to suppress effector T cell function thereby preventing transplant rejection and autoimmune diseases. During allograft transplantation, increases of both Treg expansion and generation, as well as their stable function, are needed to ensure allograft acceptance; thus, efforts have been made to discover new molecules that enhance Treg-mediated tolerance and to uncover their mechanisms. Recently, vitamin C (VitC), known to regulate T cell maturation and dendritic cell-mediated T cell polarization, has gained attention as a relevant epigenetic remodeler able to enhance and stabilize the expression of the Treg master regulator gene Foxp3, positively affecting the generation of induced Tregs (iTregs). In this study, we measured VitC transporter (SVCT2) expression in different immune cell populations, finding Tregs as one of the cell subset with the highest levels of SVCT2 expression. Unexpectedly, we found that VitC treatment reduces the ability of natural Tregs to suppress effector T cell proliferation in vitro, while having an enhancer effect on TGFbeta-induced Foxp3+ Tregs. On the other hand, VitC increases iTregs generation in vitro and in vivo, however, no allograft tolerance was achieved in animals orally treated with VitC. Lastly, Tregs isolated from the draining lymph nodes of VitC-treated and transplanted mice also showed impaired suppression capacity ex vivo. Our results indicate that VitC promotes the generation and expansion of Tregs, without exhibiting CD4+ T cell-mediated allograft tolerance. These observations highlight the relevance of the nutritional status of patients when immune regulation is needed. PMID- 29479349 TI - Adrenergic Signaling: A Targetable Checkpoint Limiting Development of the Antitumor Immune Response. AB - An immune response must be tightly controlled so that it will be commensurate with the level of response needed to protect the organism without damaging normal tissue. The roles of cytokines and chemokines in orchestrating these processes are well known, but although stress has long been thought to also affect immune responses, the underlying mechanisms were not as well understood. Recently, the role of nerves and, specifically, the sympathetic nervous system, in regulating immune responses is being revealed. Generally, an acute stress response is beneficial but chronic stress is detrimental because it suppresses the activities of effector immune cells while increasing the activities of immunosuppressive cells. In this review, we first discuss the underlying biology of adrenergic signaling in cells of both the innate and adaptive immune system. We then focus on the effects of chronic adrenergic stress in promoting tumor growth, giving examples of effects on tumor cells and immune cells, explaining the methods commonly used to induce stress in preclinical mouse models. We highlight how this relates to our observations that mandated housing conditions impose baseline chronic stress on mouse models, which is sufficient to cause chronic immunosuppression. This problem is not commonly recognized, but it has been shown to impact conclusions of several studies of mouse physiology and mouse models of disease. Moreover, the fact that preclinical mouse models are chronically immunosuppressed has critical ramifications for analysis of any experiments with an immune component. Our group has found that reducing adrenergic stress by housing mice at thermoneutrality or treating mice housed at cooler temperatures with beta-blockers reverses immunosuppression and significantly improves responses to checkpoint inhibitor immunotherapy. These observations are clinically relevant because there are numerous retrospective epidemiological studies concluding that cancer patients who were taking beta-blockers have better outcomes. Clinical trials testing whether beta-blockers can be repurposed to improve the efficacy of traditional and immunotherapies in patients are on the horizon. PMID- 29479351 TI - T-Cell Metabolism in Hematopoietic Cell Transplantation. AB - Metabolism, including catabolism and anabolism, is a basic cellular process necessary for cell survival. T lymphocytes have a distinct metabolism that can determine both fate and function. T-cell activation depends on glycolysis to obtain materials and energy for proliferation and effector function. Importantly, T cells utilize different metabolic processes under different conditions and diseases. Allogeneic hematopoietic cell transplantation (allo-HCT) is a classic immunotherapy for hematological malignancies; however, the development of graft versus-host disease (GVHD) is a major factor limiting the success of allo-HCT. T cells in the donor graft drive GVHD by mounting a robust immunological attack against recipient normal tissues. Hence, understanding T-cell metabolism after allo-HCT would provide potential metabolic targets for the control of GVHD and primary tumor relapse. The purpose of the current review is to highlight the key metabolic pathways involved in alloantigen-activated T cells and to discuss how manipulating these pathways can serve as potential new therapeutic strategies to induce immune tolerance after allo-transplantation. We will also summarize the recent progress in regulating T-cell metabolism in bone marrow transplantation by targeting novel metabolic regulators or immune checkpoint molecules. PMID- 29479350 TI - Parallels in Immunometabolic Adipose Tissue Dysfunction with Ageing and Obesity. AB - Ageing, like obesity, is often associated with alterations in metabolic and inflammatory processes resulting in morbidity from diseases characterised by poor metabolic control, insulin insensitivity, and inflammation. Ageing populations also exhibit a decline in immune competence referred to as immunosenescence, which contributes to, or might be driven by chronic, low-grade inflammation termed "inflammageing". In recent years, animal and human studies have started to uncover a role for immune cells within the stromal fraction of adipose tissue in driving the health complications that come with obesity, but relatively little work has been conducted in the context of immunometabolic adipose function in ageing. It is now clear that aberrant immune function within adipose tissue in obesity-including an accumulation of pro-inflammatory immune cell populations plays a major role in the development of systemic chronic, low-grade inflammation, and limiting the function of adipocytes leading to an impaired fat handling capacity. As a consequence, these changes increase the chance of multiorgan dysfunction and disease onset. Considering the important role of the immune system in obesity-associated metabolic and inflammatory diseases, it is critically important to further understand the interplay between immunological processes and adipose tissue function, establishing whether this interaction contributes to age-associated immunometabolic dysfunction and inflammation. Therefore, the aim of this article is to summarise how the interaction between adipose tissue and the immune system changes with ageing, likely contributing to the age-associated increase in inflammatory activity and loss of metabolic control. To understand the potential mechanisms involved, parallels will be drawn to the current knowledge derived from investigations in obesity. We also highlight gaps in research and propose potential future directions based on the current evidence. PMID- 29479352 TI - The Effects of Prednisolone Treatment on Cytokine Expression in Patients with Erythema Nodosum Leprosum Reactions. AB - Erythema nodosum leprosum (ENL) is a systemic inflammatory complication occurring mainly in patients with lepromatous leprosy (LL) and borderline lepromatous leprosy. Prednisolone is widely used for treatment of ENL reactions but clinical improvement varies. However, there is little good in vivo data as to the effect of prednisolone treatment on the pro-inflammatory cytokines in patients with ENL reactions. As a result, treatment and management of reactional and post reactional episodes of ENL often pose a therapeutic challenge. We investigated the effect of prednisolone treatment on the inflammatory cytokines TNF, IFN gamma, IL-1beta, IL-6, and IL-17 and the regulatory cytokines IL-10 and TGF-beta in the skin lesion and blood of patients with ENL and compared with non reactional LL patient controls. A case-control study was employed to recruit 30 patients with ENL and 30 non-reactional LL patient controls at ALERT Hospital, Ethiopia. Blood and skin biopsy samples were obtained from each patient before and after prednisolone treatment. Peripheral blood mononuclear cells from patients with ENL cases and LL controls were cultured with M. leprae whole-cell sonicates (MLWCS), phytohemagglutinin or no stimulation for 6 days. The supernatants were assessed with the enzyme-linked immunosorbent assay for inflammatory and regulatory cytokines. For cytokine gene expression, mRNA was isolated from whole blood and skin lesions and then reverse transcribed into cDNA. The mRNA gene expression was quantified on a Light Cycler using real-time PCR assays specific to TNF, IFN-gamma, IL-beta, TGF-beta, IL-17A, IL-6, IL-8, and IL-10. The ex vivo production of the cytokines: TNF, IFN-gamma, IL-1beta, and IL 17A was significantly increased in untreated patients with ENL. However, IL-10 production was significantly lower in untreated patients with ENL and significantly increased after treatment. The ex vivo production of IL-6 and IL-8 in patients with ENL did not show statistically significant differences before and after prednisolone treatment. The mRNA expression in blood and skin lesion for TNF, IFN-gamma, IL-1beta, IL-6, and IL-17A significantly reduced in patients with ENL after treatment, while mRNA expression for IL-10 and TGF-beta was significantly increased both in blood and skin lesion after treatment. This is the first study examining the effect of prednisolone on the kinetics of inflammatory and regulatory cytokines in patients with ENL reactions before and after prednisolone treatment. Our findings suggest that prednisolone modulates the pro-inflammatory cytokines studied here either directly or through suppression of the immune cells producing these inflammatory cytokines. PMID- 29479354 TI - Withaferin A Associated Differential Regulation of Inflammatory Cytokines. AB - A role of inflammation-associated cytokines/chemokines has been implicated in a wide variety of human diseases. Here, we investigated the regulation of inflammatory cytokines released by monocyte-derived THP-1 cells following treatment with the dietary agent withaferin A (WFA). Membrane-based cytokine array profiling of the culture supernatant from adenosine triphosphate-stimulated WFA-treated THP-1 cells showed differential regulation of multiple cytokines/chemokines. A selected group of cytokines/chemokines [interleukin-1 beta (IL-1beta), CCL2/MCP-1, granulocyte-macrophage colony stimulating factor, PDGF-AA, PTX3, cystatin-3, relaxin-2, TNFRSF8/CD30, and ACRP30] was validated at the transcription level using qPCR. In silico analysis for transcriptional binding factors revealed the presence of nuclear factor-kappa B (NF-kappaB) in a group of downregulated cytokine gene promoters. WFA treatment of THP-1 cells blocks the nuclear translocation of NF-kB and corresponds with the reduced levels of cytokine secretion. To further understand the differential expression of cytokines/chemokines, we showed that WFA alters the nigericin-induced co localization of NLRP3 and ASC proteins, thereby inhibiting caspase-1 activation, which is responsible for the cleavage and maturation of pro-inflammatory cytokines IL-1beta and IL-18. These data suggest that dietary agent WFA concurrently targets NF-kappaB and the inflammasome complex, leading to inhibition of IL-1beta and IL-18, respectively, in addition to differential expression of multiple cytokines/chemokines. Taken together, these results provide a rationale for using WFA to further explore the anti-inflammatory mechanism of cytokines/chemokines associated with inflammatory diseases. PMID- 29479355 TI - Novel CARMIL2 Mutations in Patients with Variable Clinical Dermatitis, Infections, and Combined Immunodeficiency. AB - Combined immunodeficiencies are a heterogeneous collection of primary immune disorders that exhibit defects in T cell development or function, along with impaired B cell activity even in light of normal B cell maturation. CARMIL2 (RLTPR) is a protein involved in cytoskeletal organization and cell migration, which also plays a role in CD28 co-signaling of T cells. Mutations in this protein have recently been reported to cause a novel primary immunodeficiency disorder with variable phenotypic presentations. Here, we describe seven patients from three unrelated, consanguineous multiplex families that presented with dermatitis, esophagitis, and recurrent skin and chest infections with evidence of combined immunodeficiency. Through the use of whole exome sequencing and autozygome-guided analysis, we uncovered two mutations not previously reported (p.R50T and p.L846Sfs) in CARMIL2. Real-time PCR analysis revealed that the biallelic frameshift mutation is under negative selection, likely due to nonsense mediated RNA decay and leading to loss of detectable protein upon immunoblotting. Protein loss was also observed for the missense mutation, and 3D modeling suggested a disturbance in structural stability due to an increase in the electrostatic energy for the affected amino acid and surrounding residues. Immunophenotyping revealed that patient Treg counts were significantly depressed, and that CD4+ T cells were heavily skewed towards the naive status. CD3/CD28 signaling impairment was evidenced by reduced proliferative response to stimulation. This work broadens the allelic heterogeneity associated with CARMIL2 and highlights a deleterious missense alteration located outside the leucine-rich repeat of the protein, where all other missense mutations have been reported to date. PMID- 29479353 TI - Reinforcing the Functionality of Mononuclear Phagocyte System to Control Tuberculosis. AB - The mononuclear phagocyte system (MPS) constitutes dendritic cells, monocytes, and macrophages. This system contributes to various functions that are essential for maintaining homeostasis, activation of innate immunity, and bridging it with the adaptive immunity. Consequently, MPS is highly important in bolstering immunity against the pathogens. However, MPS is the frontline cells in destroying Mycobacterium tuberculosis (Mtb), yet the bacterium prefers to reside in the hostile environment of macrophages. Therefore, it may be very interesting to study the struggle between Mtb and MPS to understand the outcome of the disease. In an event when MPS predominates Mtb, the host remains protected. By contrast, the situation becomes devastating when the pathogen tames and tunes the host MPS, which ultimately culminates into tuberculosis (TB). Hence, it becomes extremely crucial to reinvigorate MPS functionality to overwhelm Mtb and eliminate it. In this article, we discuss the strategies to bolster the function of MPS by exploiting the molecules associated with the innate immunity and highlight the mechanisms involved to overcome the Mtb-induced suppression of host immunity. In future, such approaches may provide an insight to develop immunotherapeutics to treat TB. PMID- 29479356 TI - Elevated Systemic Levels of Eosinophil, Neutrophil, and Mast Cell Granular Proteins in Strongyloides Stercoralis Infection that Diminish following Treatment. AB - Infection with the helminth parasite Strongyloides stercoralis (Ss) is commonly clinically asymptomatic that is often accompanied by peripheral eosinophilia. Granulocytes are activated during helminth infection and can act as immune effector cells. Plasma levels of eosinophil and neutrophil granular proteins convey an indirect measure of granulocyte degranulation and are prominently augmented in numerous helminth-infected patients. In this study, we sought to examine the levels of eosinophil, neutrophil, and mast cell activation-associated granule proteins in asymptomatic Ss infection and to understand their kinetics following anthelmintic therapy. To this end, we measured the plasma levels of eosinophil cationic protein, eosinophil-derived neurotoxin, eosinophil peroxidase, eosinophil major basic protein, neutrophil elastase, myeloperoxidase, neutrophil proteinase-3, mast cell tryptase, leukotriene C4, and mast cell carboxypeptidase-A3 in individuals with asymptomatic Ss infection or without Ss infection [uninfected (UN)]. We also estimated the levels of all of these analytes in infected individuals following definitive treatment of Ss infection. We demonstrated that those infected individuals have significantly enhanced plasma levels of eosinophil cationic protein, eosinophil-derived neurotoxin, eosinophil peroxidase, eosinophil major basic protein, elastase, myeloperoxidase, mast cell tryptase, leukotriene C4, and carboxypeptidase-A3 compared to UN individuals. Following the treatment of Ss infection, each of these granulocyte associated proteins drops significantly. Our data suggest that eosinophil, neutrophil, and mast cell activation may play a role in the response to Ss infection. PMID- 29479357 TI - Arabidopsis Type III Ggamma Protein AGG3 Is a Positive Regulator of Yield and Stress Responses in the Model Monocot Setaria viridis. AB - Heterotrimeric G-proteins are key regulators of a multitude of growth and development pathways in eukaryotes. Along with the conserved G-protein components found in all organisms, plants have certain novel variants with unique architecture, which may be involved in the regulation of plant-specific traits. The higher plant-specific type III (or Class C) Ggamma protein, which possesses a large C terminal extension, represented by AGG3 in Arabidopsis, is one such variant of canonical Ggamma proteins. The type III Ggamma proteins are involved in regulation of many agronomically important traits in plants, including seed yield, organ size regulation, abscisic acid (ABA)-dependent signaling and stress responses, and nitrogen use efficiency. However, the extant data, especially in the monocots, present a relatively complex and sometimes contradictory picture of the regulatory role of these proteins. It remains unclear if the positive traits observed in certain naturally occurring populations are due to the presence of specific allelic variants of the proteins or due to the altered expression of the gene itself. To address these possibilities, we have overexpressed the Arabidopsis AGG3 gene in the model monocot Setaria viridis and systematically evaluated its role in conferring agriculturally relevant phenotypes. Our data show that AtAGG3 is indeed functional in Setaria and suggest that a subset of the traits affected by the type III Ggamma proteins are indeed positively correlated with the gene expression level, while others might have more complex, allele specific regulation. PMID- 29479358 TI - Analysis of Extreme Phenotype Bulk Copy Number Variation (XP-CNV) Identified the Association of rp1 with Resistance to Goss's Wilt of Maize. AB - Goss's wilt (GW) of maize is caused by the Gram-positive bacterium Clavibacter michiganensis subsp. nebraskensis (Cmn) and has spread in recent years throughout the Great Plains, posing a threat to production. The genetic basis of plant resistance is unknown. Here, a simple method for quantifying disease symptoms was developed and used to select cohorts of highly resistant and highly susceptible lines known as extreme phenotypes (XP). Copy number variation (CNV) analyses using whole genome sequences of bulked XP revealed 141 genes containing CNV between the two XP groups. The CNV genes include the previously identified common rust resistant locus rp1. Multiple Rp1 accessions with distinct rp1 haplotypes in an otherwise susceptible accession exhibited hypersensitive responses upon inoculation. GW provides an excellent system for the genetic dissection of diseases caused by closely related subspecies of C. michiganesis. Further work will facilitate breeding strategies to control GW and provide needed insight into the resistance mechanism of important related diseases such as bacterial canker of tomato and bacterial ring rot of potato. PMID- 29479359 TI - A Rice CPYC-Type Glutaredoxin OsGRX20 in Protection against Bacterial Blight, Methyl Viologen and Salt Stresses. AB - Glutaredoxins (GRXs) belong to the antioxidants involved in the cellular stress responses. In spite of the identification 48 GRX genes in rice genomes, the biological functions of most of them remain unknown. Especially, the biological roles of members of GRX family in disease resistance are still lacking. Our proteomic analysis found that OsGRX20 increased by 2.7-fold after infection by bacterial blight. In this study, we isolated and characterized the full-length nucleotide sequences of the rice OsGRX20 gene, which encodes a GRX family protein with CPFC active site of CPYC-type class. OsGRX20 protein was localized in nucleus and cytosol, and its transcripts were expressed predominantly in leaves. Several stress- and hormone-related motifs putatively acting as regulatory elements were found in the OsGRX20 promoter. Real-time quantitative PCR analysis indicated that OsGRX20 was expressed at a significantly higher level in leaves of a resistant or tolerant rice genotype, Yongjing 50A, than in a sensitive genotype, Xiushui 11, exposed to bacterial blight, methyl viologen, heat, and cold. Its expression could be induced by salt, PEG-6000, 2,4-D, salicylic acid, jasmonic acid, and abscisic acid treatments in Yongjing 50A. Overexpression of OsGRX20 in rice Xiushui 11 significantly enhanced its resistance to bacterial blight attack, and tolerance to methyl viologen and salt stresses. In contrast, interference of OsGRX20 in Yongjing 50A led to increased susceptibility to bacterial blight, methyl viologen and salt stresses. OsGRX20 restrained accumulation of superoxide radicals in aerial tissue during methyl viologen treatment. Consistently, alterations in OsGRX20 expression affect the ascorbate/dehydroascorbate ratio and the abundance of transcripts encoding four reactive oxygen species scavenging enzymes after methyl viologen-induced stress. Our results demonstrate that OsGRX20 functioned as a positive regulator in rice tolerance to multiple stresses, which may be of significant use in the genetic improvement of rice resistance. PMID- 29479361 TI - Nanobody-Directed Specific Degradation of Proteins by the 26S-Proteasome in Plants. AB - Here, we present data showing the directed degradation of target proteins recognized by a specific nanobody in transgenic plants. Green fluorescent protein was depleted by a chimeric nanobody fused to a distinct F-box domain, which enables protein degradation via the ubiquitin proteasome pathway. This technique could thus be used to knock out other proteins of interest in planta using specific, high-affinity binding proteins. PMID- 29479363 TI - Mechanisms of Invasion Resistance of Aquatic Plant Communities. AB - Invasive plant species are among the major threats to freshwater biodiversity. Few experimental studies have investigated whether native plant diversity can provide biotic resistance to invaders in freshwater ecosystems. At small spatial scales, invasion resistance may increase with plant species richness due to a better use of available resources, leaving less available for a potential invader (Complementarity effect) and/or the greater probability to have a highly competitive (or productive) native species in the community (Selection effect). In submerged aquatic plant communities, we tested the following hypotheses: (1) invader establishment success is greatest in the absence of a native plant community; (2) lower in plant communities with greater native species richness, due to complementary and/or selection effects; and (3) invader establishment success would be lowest in rooted plant communities, based on the limiting similarity theory as the invader is a rooted submerged species. In a greenhouse experiment, we established mesocosms planted with 0 (bare sediment), 1, 2, and 4 submerged plant species native to NW Europe and subjected these to the South African invader Lagarosiphon major (Ridl.) Moss. We used two rooted (Myriophyllum spicatum L., Potamogeton perfoliatus L.) and two non-rooted native species (Ceratophyllum demersum L., Utricularia vulgaris L.) representing two distinct functional groups considering their nutrient acquisition strategy which follows from their growth form, with, respectively, the sediment and water column as their main nutrient source. We found that the presence of native vegetation overall decreased the establishment success of an alien aquatic plant species. The strength of this observed biotic resistance increased with increasing species richness of the native community. Mainly due to a selection effect, the native biomass of mixed communities overyielded, and this further lowered the establishment success of the invader in our experiment. The strongest biotic resistance was caused by the two native plant species that were of the same functional group, i.e., functionally most similar to the invader. These results support the prediction of Elton's biotic resistance hypothesis in aquatic ecosystems and indicate that both species richness and functional group identity can play an important role in decreasing establishment success of alien plant species. PMID- 29479360 TI - The Chemistry of Plant-Microbe Interactions in the Rhizosphere and the Potential for Metabolomics to Reveal Signaling Related to Defense Priming and Induced Systemic Resistance. AB - Plant roots communicate with microbes in a sophisticated manner through chemical communication within the rhizosphere, thereby leading to biofilm formation of beneficial microbes and, in the case of plant growth-promoting rhizomicrobes/ bacteria (PGPR), resulting in priming of defense, or induced resistance in the plant host. The knowledge of plant-plant and plant-microbe interactions have been greatly extended over recent years; however, the chemical communication leading to priming is far from being well understood. Furthermore, linkage between below- and above-ground plant physiological processes adds to the complexity. In metabolomics studies, the main aim is to profile and annotate all exo- and endo metabolites in a biological system that drive and participate in physiological processes. Recent advances in this field has enabled researchers to analyze 100s of compounds in one sample over a short time period. Here, from a metabolomics viewpoint, we review the interactions within the rhizosphere and subsequent above ground 'signalomics', and emphasize the contributions that mass spectrometric based metabolomic approaches can bring to the study of plant-beneficial - and priming events. PMID- 29479362 TI - The Multiple Functions of the Nucleolus in Plant Development, Disease and Stress Responses. AB - The nucleolus is the most conspicuous domain in the eukaryotic cell nucleus, whose main function is ribosomal RNA (rRNA) synthesis and ribosome biogenesis. However, there is growing evidence that the nucleolus is also implicated in many other aspects of cell biology, such as regulation of cell cycle, growth and development, senescence, telomerase activity, gene silencing, responses to biotic and abiotic stresses. In the first part of the review, we briefly assess the traditional roles of the plant nucleolus in rRNA synthesis and ribosome biogenesis as well as possible functions in other RNA regulatory pathways such as splicing, nonsense-mediated mRNA decay and RNA silencing. In the second part of the review we summarize recent progress and discuss already known and new hypothetical roles of the nucleolus in plant growth and development. In addition, this part will highlight studies showing new nucleolar functions involved in responses to pathogen attack and abiotic stress. Cross-talk between the nucleolus and Cajal bodies is also discussed in the context of their association with poly(ADP ribose)polymerase (PARP), which is known to play a crucial role in various physiological processes including growth, development and responses to biotic and abiotic stresses. PMID- 29479364 TI - Peroxisomal Targeting as a Sensitive Tool to Detect Protein-Small RNA Interactions through in Vivo Piggybacking. AB - Peroxisomes are organelles that play key roles in eukaryotic metabolism. Their protein complement is entirely imported from the cytoplasm thanks to a unique pathway that is able to translocate folded proteins and protein complexes across the peroxisomal membrane. The import of molecules bound to a protein targeted to peroxisomes is an active process known as 'piggybacking' and we have recently shown that P15, a virus-encoded protein possessing a peroxisomal targeting sequence, is able to piggyback siRNAs into peroxisomes. Here, we extend this observation by analyzing the small RNA repertoire found in peroxisomes of P15 expressing plants. A direct comparison with the P15-associated small RNA retrieved during immunoprecipitation (IP) experiments, revealed that in vivo piggybacking coupled to peroxisome isolation could be a more sensitive means to determine the various small RNA species bound by a given protein. This increased sensitivity of peroxisome isolation as opposed to IP experiments was also striking when we analyzed the small RNA population bound by the Tomato bushy stunt virus-encoded P19, one of the best characterized viral suppressors of RNA silencing (VSR), artificially targeted to peroxisomes. These results support that peroxisomal targeting should be considered as a novel/alternative experimental approach to assess in vivo interactions that allows detection of labile binding events. The advantages and limitations of this approach are discussed. PMID- 29479365 TI - Plastid Genome Evolution in the Early-Diverging Legume Subfamily Cercidoideae (Fabaceae). AB - The subfamily Cercidoideae is an early-branching legume lineage, which consists of 13 genera distributed in the tropical and warm temperate Northern Hemisphere. A previous study detected two plastid genomic variations in this subfamily, but the limited taxon sampling left the overall plastid genome (plastome) diversification across the subfamily unaddressed, and phylogenetic relationships within this clade remained unresolved. Here, we assembled eight plastomes from seven Cercidoideae genera and conducted phylogenomic-comparative analyses in a broad evolutionary framework across legumes. The plastomes of Cercidoideae all exhibited a typical quadripartite structure with a conserved gene content typical of most angiosperm plastomes. Plastome size ranged from 151,705 to 165,416 bp, mainly due to the expansion and contraction of inverted repeat (IR) regions. The order of genes varied due to the occurrence of several inversions. In Tylosema species, a plastome with a 29-bp IR-mediated inversion was found to coexist with a canonical-type plastome, and the abundance of the two arrangements of isomeric molecules differed between individuals. Complete plastome data were much more efficient at resolving intergeneric relationships of Cercidoideae than the previously used selection of only a few plastid or nuclear loci. In sum, our study revealed novel insights into the structural diversification of plastomes in an early-branching legume lineage, and, thus, into the evolutionary trajectories of legume plastomes in general. PMID- 29479366 TI - The Hemiparasitic Plant Phtheirospermum (Orobanchaceae) Is Polyphyletic and Contains Cryptic Species in the Hengduan Mountains of Southwest China. AB - Phtheirospermum (Orobanchaceae), a hemiparasitic genus of Eastern Asia, is characterized by having long and viscous glandular hairs on stems and leaves. Despite this unifying character, previous phylogenetic analyses indicate that Phtheirospermum is polyphyletic, with Phtheirospermum japonicum allied with tribe Pedicularideae and members of the Ph. tenuisectum complex allied with members of tribe Rhinantheae. However, no analyses to date have included broad phylogenetic sampling necessary to test the monophyly of Phtheirospermum species, and to place these species into the existing subfamiliar taxonomic organization of Orobanchaceae. Two other genera of uncertain phylogenetic placement are Brandisia and Pterygiella, also both of Eastern Asia. In this study, broadly sampled phylogenetic analyses of nrITS and plastid DNA revealed hard incongruence between these datasets in the placement of Brandisia. However, both nrITS and the plastid datasets supported the placement of Ph. japonicum within tribe Pedicularideae, and a separate clade consisting of the Ph. tenuisectum complex and a monophyletic Pterygiella. Analyses were largely in agreement that Pterygiella, the Ptheirospermum complex, and Xizangia form a clade not nested within any of the monophyletic tribes of Orobanchaceae recognized to date. Ph. japonicum, a model species for parasitic plant research, is widely distributed in Eastern Asia. Despite this broad distribution, both nrITS and plastid DNA regions from a wide sampling of this species showed high genetic identity, suggesting that the wide species range is likely due to a recent population expansion. The Ph. tenuisectum complex is mainly distributed in the Hengduan Mountains region. Two cryptic species were identified by both phylogenetic analyses and morphological characters. Relationships among species of the Ph. tenuisectum complex and Pterygiella remain uncertain. Estimated divergence ages of the Ph. tenuisectum complex corresponding to the last two uplifts of the Qinghai-Tibet Plateau at around 8.0-7.0 Mya and 3.6-1.5 Mya indicated that the development of a hot-dry valley climate during these uplifts may have driven species diversification in the Ph. tenuisectum complex. PMID- 29479368 TI - The Histone Demethylase JMJD2A Modulates the Induction of Hypertrophy Markers in iPSC-Derived Cardiomyocytes. AB - The development of cardiovascular pathologies is partly attributed to epigenetic causes, including histone methylation, which appears to be an important marker in hearts that develop cardiac hypertrophy. Previous studies showed that the histone demethylase JMJD2A can regulate the hypertrophic process in murine cardiomyocytes. However, the influence of JMJD2A on cardiac hypertrophy in a human cardiomyocyte model is still poorly understood. In the present study, cardiomyocytes derived from human induced pluripotent stem cells (iPSCs) were used. Hypertrophy was induced by angiotensin II and endothelin-1 (ET-1), and transfections were performed to overexpress JMJD2A and for small interfering RNA (siRNA)-induced silencing of JMJD2A. Gene expression analyses were determined using RT-PCR and Western blot. The expression levels of B-type natriuretic peptide (BNP), natriuretic peptide A (ANP), and beta myosin heavy chain (beta MHC) were increased by nearly 2-10-fold with ET-1 compared with the control. However, a higher level of JMJD2A and UTX was detected, whereas the level of JMJD2C was lower. When cardiomyocytes were transiently transfected with JMJD2A, an increase close to 150% in BNP was observed, and this increase was greater after treatment with ET-1. To verify the specificity of JMJD2A activity, a knockdown was performed by means of siRNA-JMJD2A, which led to a significant reduction in BNP. The involvement of JMJD2A suggests that histone-specific modifications are associated with genes encoding proteins that are actively transcribed during the hypertrophy process. Since BNP is closely related to JMJD2A expression, we suggest that there could be a direct influence of JMJD2A on the expression of BNP. These results may be studied further to reduce cardiac hypertrophy via the regulation of epigenetic modifiers. PMID- 29479367 TI - The Plant Ribosome-Inactivating Proteins Play Important Roles in Defense against Pathogens and Insect Pest Attacks. AB - Ribosome-inactivating proteins (RIPs) are toxic N-glycosidases that depurinate eukaryotic and prokaryotic rRNAs, thereby arresting protein synthesis during translation. RIPs are widely found in various plant species and within different tissues. It is demonstrated in vitro and in transgenic plants that RIPs have been connected to defense by antifungal, antibacterial, antiviral, and insecticidal activities. However, the mechanism of these effects is still not completely clear. There are a number of reviews of RIPs. However, there are no reviews on the biological functions of RIPs in defense against pathogens and insect pests. Therefore, in this report, we focused on the effect of RIPs from plants in defense against pathogens and insect pest attacks. First, we summarize the three different types of RIPs based on their physical properties. RIPs are generally distributed in plants. Then, we discuss the distribution of RIPs that are found in various plant species and in fungi, bacteria, algae, and animals. Various RIPs have shown unique bioactive properties including antibacterial, antifungal, antiviral, and insecticidal activity. Finally, we divided the discussion into the biological roles of RIPs in defense against bacteria, fungi, viruses, and insects. This review is focused on the role of plant RIPs in defense against bacteria, fungi, viruses, and insect attacks. The role of plant RIPs in defense against pathogens and insects is being comprehended currently. Future study utilizing transgenic technology approaches to study the mechanisms of RIPs will undoubtedly generate a better comprehending of the role of plant RIPs in defense against pathogens and insects. Discovering additional crosstalk mechanisms between RIPs and phytohormones or reactive oxygen species (ROS) against pathogen and insect infections will be a significant subject in the field of biotic stress study. These studies are helpful in revealing significance of genetic control that can be beneficial to engineer crops tolerance to biotic stress. PMID- 29479369 TI - The Circular RNA Profiles of Colorectal Tumor Metastatic Cells. AB - Circular RNAs (circRNAs) have been reported that can be used as biomarkers for colorectal cancers (CRC) and other types of tumors. However, a limited number of studies have been performed investigating the potential role of circRNAs in tumor metastasis. Here, we examined the circRNAs in two CRC cell lines (a primary tumor cell SW480 and its metastasis cell SW620), and found a large set of circRNA (2,919 ncDECs) with significantly differential expression patterns relative to normal cells (NCM460). In addition, we uncovered a set of 623 pmDECs that differ between the primary CRC cells and its metastasis cells. Both differentially expressed circRNA (DEC) sets contain many previously unknown putative CRC-related circRNAs, thereby providing many new circRNAs as candidate biomarkers for CRC development and metastasis. These studies are the first large-scale identification of metastasis-related circRNAs for CRC and provide valuable candidate biomarkers for diagnostic and a starting point for additional investigations of CRC metastasis. PMID- 29479370 TI - Wushenziye Formula Improves Skeletal Muscle Insulin Resistance in Type 2 Diabetes Mellitus via PTP1B-IRS1-Akt-GLUT4 Signaling Pathway. AB - Background. Wushenziye formula (WSZYF) is an effective traditional Chinese medicine in the treatment of type 2 diabetes mellitus (T2DM). Aim. This study aimed to identify the effects and underlying mechanisms of WSZYF on improving skeletal muscle insulin resistance in T2DM. Methods. An animal model of T2DM was induced by Goto-Kakizaki diabetes prone rats fed with high fat and sugar for 4 weeks. Insulin resistance model was induced in skeletal muscle cell. Results. In vivo, WSZYF improved general conditions and decreased significantly fasting blood glucose, glycosylated serum protein, glycosylated hemoglobin, insulin concentration, and insulin resistance index of T2DM rats. In vitro, WSZYF enhanced glucose consumption in insulin resistance model of skeletal muscle cell. Furthermore, WSZYF affected the expressions of molecules in regulating T2DM, including increasing the expressions of p-IRS1, p-Akt, and GLUT4, reducing PTP1B expression. Conclusion. These findings displayed the potential of WSZYF as a new drug candidate in the treatment of T2DM and the antidiabetic mechanism of WSZYF is probably mediated through modulating the PTP1B-IRS1-Akt-GLUT4 signaling pathway. PMID- 29479371 TI - In Vivo Subacute Toxicity and Antidiabetic Effect of Aqueous Extract of Nigella sativa. AB - Context. Nigella sativa seeds are usually used as traditional medicine for a wide range of therapeutic purposes. Objective. To investigate the subacute toxicity of NS aqueous extract and select its lowest dose to study its antidiabetic effect. Methods. 5 AqE.NS doses (2, 6.4, 21, 33, and 60 g/Kg) were daily administered to mice by gavage. Biochemical parameters measurements and histological study of the liver and the kidney were performed after 6 weeks of supplementation. Thereafter, and after inducing diabetes by alloxan, rats were treated by 2 g/Kg of AqE.NS during 8 weeks. Metabolic parameters were measured on sera. A horizontal electrophoresis of plasmatic lipoprotein was conducted. Glycogen, total lipids, and triglycerides were measured in the liver. TBARS were evaluated on adipose tissue, liver, and pancreas. Results. AqE.NS showed no variation in urea and albumin at the 5 doses, but hepatotoxicity from 21 g/Kg was confirmed by histopathological observations of the liver. In diabetic rats, AqE.NS significantly decreased glycemia, TG, T-cholesterol, LDL-c, and TBARS and showed a restored insulinemia and a significant increase in HDL-c. Results on the liver indicated a decrease in lipids and a possible glycogenogenesis. Conclusion. AqE.NS showed its safety at low doses and its evident antihyperglycemic, antihyperlipidemic, and antioxidant effect. PMID- 29479372 TI - The sensitivity of US wildfire occurrence to pre-season soil moisture conditions across ecosystems. AB - It is generally accepted that year-to-year variability in moisture conditions and drought are linked with increased wildfire occurrence. However, quantifying the sensitivity of wildfire to surface moisture state at seasonal lead-times has been challenging due to the absence of a long soil moisture record with the appropriate coverage and spatial resolution for continental-scale analysis. Here we apply model simulations of surface soil moisture that numerically assimilate observations from NASA's Gravity Recovery and Climate Experiment (GRACE) mission with the US Forest Service's historical Fire-Occurrence Database over the contiguous United States. We quantify the relationships between pre-fire-season soil moisture and subsequent-year wildfire occurrence by land-cover type and produce annual probable wildfire occurrence and burned area maps at 0.25-degree resolution. Cross-validated results generally indicate a higher occurrence of smaller fires when months preceding fire season are wet, while larger fires are more frequent when soils are dry. This result is consistent with the concept of increased fuel accumulation under wet conditions in the pre-season. These results demonstrate the fundamental strength of the relationship between soil moisture and fire activity at long lead-times and are indicative of that relationship's utility for the future development of national-scale predictive capability. PMID- 29479373 TI - In vivo cellular-resolution retinal imaging in infants and children using an ultracompact handheld probe. PMID- 29479374 TI - Responding to chemical weapons violations in Syria: legal, health, and humanitarian recommendations. AB - Background: The repeated use of prohibited chemical weapons in the Syrian conflict poses serious health, humanitarian, and security threats to civilians, healthcare personnel, and first responders. Moreover, the use of chemical weapons constitutes a clear and egregious violation of international law-likely amounting to a war crime-for which continued impunity is setting a dangerous precedent in relation to current and future conflicts. This debate article calls upon concerned states, organizations, and individuals to respond urgently and unequivocally to this serious breach of international legal and humanitarian norms. Main Body: Based on health, humanitarian, and legal findings, this article calls for concrete action to: 1) reduce the risk of chemical weapons being used in current and future conflicts; 2) review and support the preparedness equipment and antidote supplies of first responders, humanitarian organizations, and military forces operating in Syria; 3) support international mechanisms for monitoring and enforcing the prohibition on chemical weapons, including through criminal accountability; 4) support civilian victims of chemical weapons attacks, including refugees; and 5) re-commit to the complete elimination of chemical weapons in compliance with the Chemical Weapons Convention (1993), a comprehensive treaty that bans chemical weapons and requires their complete destruction. Conclusion: All involved states and organizations should take urgent steps to ensure the protection of the most vulnerable victims of conflict, including victims of chemical weapons attacks in Syria, and to reinforce international law in the face of such serious violations. PMID- 29479376 TI - Enhancing Clustering by Exploiting Complementary Data Modalities in the Medical Domain. AB - Data Clustering has been an active area of research in many different application areas, with existing clustering algorithms mostly focusing on partitioning one modality or representation of the data. In this study, we delineate and demonstrate a new, enhanced data clustering approach whose innovation is its exploitation of multiple data modalities. We propose BI-NMF, a bi-modal clustering approach based on Non Negative Matrix Factorization (NMF) that clusters two differing data modalities simultaneously. The strength of our approach is its combining of multiple aspects of the data when forming the final clusters. To assess the utility of our approach, we performed several experiments on two distinct biomedical datasets with two modalities each. Comparing the clusters of BI-NMF with NMF clusters of single data modality, we observed consistent performance enhancement across both datasets. Our experimental results suggest that BI-NMF is advantageous for boosting data clustering. PMID- 29479377 TI - The mindful personality: A meta-analysis from a cybernetic perspective. AB - Dispositional mindfulness (DM), or the tendency to attend to present moment experience, may have important implications for the structure of human personality. However, relationships between DM and the Big Five Model of Personality (BF) have not been definitively established. Therefore, the purpose of this meta-analysis was to extend previous investigations of the relationship between DM and the BF, utilizing a larger sample of studies, attending to relational inconsistencies potentially associated with alternative methods of operationalizing DM, conducting the first meta-analysis of the DM subdomains in relation to the BF, and situating the results in a cybernetic model. Results indicate that neuroticism evidenced the strongest, negative relationship with DM and conscientiousness evidenced the strongest, positive relationship with DM, suggesting the mindful personality may be characterized principally by emotional stability and conscientious self-regulation - potentially reflective of an inclination towards the personality metatrait stability. Measurement differences were also observed, with the mindful personality arrived at through the FFMQ differing to some extent from the mindful personality emerging from the MAAS. Broadly, the mindful personality associated with the FFMQ appears to reflect greater personality complexity, with the FFMQ evidencing associations with all five personality factors while the MAAS appears primarily linked with only three personality factors (Neuroticism, Conscientiousness and Agreeableness). Examination of the relationships between the BF and DM at the facet level also suggest unique patterns of association between the DM facets and each of the personality factors. PMID- 29479375 TI - Efficacy and safety of pasireotide-LAR for the treatment of refractory bleeding due to gastrointestinal angiodysplasias: results of the ANGIOPAS multicenter phase II noncomparative prospective double-blinded randomized study. AB - Background: Gastrointestinal angiodysplasias (GIADs) could be responsible for recurrent bleeding and severe anemia. Somatostatin analogs could reduce transfusion requirements in these patients but no randomized controlled study is available. The main objective of the ANGIOPAS phase II double-blinded randomized, noncomparative study was to assess the effectiveness of pasireotide-LAR in reducing transfusion requirements in patients with refractory GIADs bleeding. Methods: A total of 22 patients with transfusion requirements ?6 units of packed red blood cells (pRBCs) during the 6 months prior to inclusion were randomized to receive pasireotide-LAR 60 mg (n = 10) or placebo (n = 12) every 28 days for 6 months. Patients were then followed for an additional 6 months after stopping treatment. Results: The pasireotide-LAR and placebo groups were equivalent for age, sex, comorbidities and transfusion requirement during the reference period (median 13 and 9.5 pRBCs). A 50 and 83% success rate (success defined as a decrease of at least 30% of transfused pRBCs) was observed in the pasireotide-LAR arm in the Intent to Treat (ITT) and per protocol (PP) analysis respectively. The need for transfusion during the intervention period was 3 pRBC units in the pasireotide-LAR group (range 0-26) and 11.5 pRBC units in the placebo group (range 0-23). Overall, three cases with glycemic control impairment were observed in the pasireotide-LAR group including one de novo diabetes. Conclusion: This double-blinded noncomparative randomized phase II study suggests, for the first time, the effectiveness of pasireotide-LAR 60 mg every 28 days to decrease the transfusion requirement in patients with recurrent bleeding due to GIADs. PMID- 29479379 TI - Effects of Preoperative Curcumin on the Inflammatory Response During Mechanical Circulatory Support: A Porcine Model. AB - Background: Curcumin is a polyphenol extracted from the turmeric plant which may have anti-inflammatory properties. We hypothesized that curcumin pretreatment would result in a reduction in inflammatory markers in a large animal model of extracorporeal support. Methods: A total of seven samples were obtained from three swine treated with curcumin and 16 samples were obtained from six swine in the control group (procedure terminated in two swine before last sample could be obtained). Results: Samples for interleukin (IL)-8 and IL-1b had concentrations below the limit of detection at all points and were discarded from further analysis. IL-6, tumor necrosis factor (TNF)-alpha, and intercellular adhesion molecule (ICAM)-1 concentrations were lower in curcumin pretreated animals when compared to control animals. This decrease was statistically significant for TNF alpha, and ICAM-1. Conclusions: This project may provide information for the development of a translational study in humans as we noted that curcumin pretreatment in a large animal model of cardiopulmonary bypass (CPB) and extracorporeal support resulted in a decrease in TNF-alpha and ICAM-1 expression compared to control animals. PMID- 29479378 TI - Are Measures of Left Ventricular Longitudinal Shortening Affected by Left Atrial Enlargement? AB - Background: Even though left atrial (LA) size and function are intimately related to left ventricular (LV) diastolic dysfunction, the role of LA with regard to LV systolic function is less clear. Consequently, we examined the potential association that might exist between measures of longitudinal LV systolic shortening and LA dilation using LA volume index (LAVI). Methods: In this retrospective analysis, data from 75 echocardiograms (mean age 53 +/- 14; range 24 - 89 years; mean body surface area (BSA) 2.0 +/- 0.3) were analyzed. Results: Peak global longitudinal (PGLS) correlated best with LV mass index (LVMI) followed by mitral annular systolic excursion (MAPSE), and age. Similar results were obtained when analyzing the best variables that correlated with LAVI. Finally, MAPSE correlated best with PGLS, then with MA tissue Doppler systolic velocity, BSA, and LAVI in that order. All patients had normal LV ejection fraction (LVEF) and normal sinus rhythm when studied. Conclusions: LAVI does not directly affect LV systolic function and longitudinal measures of LV shortening are mainly dependent on LV mass. Additional studies are now required to determine how these associations vary when different degrees of LV dilatation and systolic dysfunction are included in the analysis. PMID- 29479380 TI - The Severity of Coronary Arterial Stenosis in Patients With Acute ST-Elevated Myocardial Infarction: A Thrombolytic Therapy Study. AB - Background: It is widely believed that ST-elevated myocardial infarction (STEMI) generally occurs at the site of mild to moderate coronary stenosis. The aim of this study was to determine the degree of stenosis of infarct-related artery (IRA) in STEMI patients who underwent coronary angiography (CAG) after successful reperfusion with thrombolytic therapy (TT). Methods: A total of 463 consecutive patients between January 2008 and December 2013 with acute STEMI treated with TT were evaluated retrospectively. The patients in whom reperfusion failed (n = 120), death occurred before CAG (n = 12), IRA cannot be determined (n = 10), and CAG was not performed in index hospitalization (n = 54) were excluded from the study. To determine the severity of stenosis of IRA, two experienced cardiologists who were unaware of each other used quantitative CAG analysis. Significant stenosis was defined as a >= 50% stenosis in the coronary artery lumen. A total of 267 patients who were successfully reperfused with TT and in whom CAG was performed during hospitalization with median 8 (1 - 17) days after myocardial infarction were included in the study. Results: The mean age of patients was 55.7 +/- 10.8 years (85.5% male). Most of the patients had a significant stenosis in IRA ( >= 50%, n = 236, group 1) after successful TT; whereas only 11.6% had stenosis < 50% (n = 31, group 2). In addition, majority of the patients had >= 70.4% (n = 188, 70.4%) stenosis in IRA. Average of stenosis in IRA was 74+/-16%. Conclusions: In contrast to the general opinion, we detected that majority of STEMI patients had a significant stenosis in IRA. PMID- 29479381 TI - Diagnostic Value of D-Dimer in Acute Myocardial Infarction Among Patients With Suspected Acute Coronary Syndrome. AB - Background: The role of D-dimer as a diagnostic marker in myocardial infarction (MI) and acute coronary syndrome (ACS) is still a question. The aim of this study was to evaluate the diagnostic value of D-dimer in the diagnosis of AMI in patients suspected with ACS. Methods: This cross-sectional study was conducted on patients suspected with ACS. Serial standard 12-lead electrocardiogram (ECG), D dimer, and troponin tests were done for all the patients. According to the examinations, ECG changes, and troponin, patients were allocated into two groups of MI and unstable angina (UA). Chi-square, independent t-test, and Pearson correlation test were used by SPSS ver, 17. Cut-off point of D-dimer for MI diagnosis was evaluated by receiver operating characteristic (ROC) curve analysis. Results: Seventy-five patients with a mean age of 63.1 +/- 9.75 years were studied in two groups of MI (n = 34) and UA (n = 41). Patients were homogeneous based on age, gender, and risk factors for diabetes and dyslipidemia. D-dimer in patients with MI patients was higher than in patients with UA (P = 0.001). The optimal cut-off point of D-dimer for diagnosis of MI was 548 mEq/L with sensitivity and specifity of 63.4% and 91.2%, respectively. Conclusions: Based on the results of this study, it seems that the measurement of D-dimer serum level can be appropriate as a marker with high sensitivity and relatively high specificity for differentiating MI from UA in patients with suspected ACS. PMID- 29479382 TI - Early Diagnosis and Treatment of Coronary Heart Disease in Asymptomatic Subjects With Advanced Vascular Atherosclerosis of the Carotid Artery (Type III and IV b Findings Using Ultrasound) and Risk Factors. AB - Background: A study was conducted as to whether the early diagnosis of coronary heart disease in asymptomatic subjects with advanced atherosclerosis of the carotid artery which additionally shows at least one risk factor is successful using ultrasound technology. Methods: Within the scope of an occupational screening program using subjects from diverse employment sectors, people were given the opportunity to determine their risk of heart attack. During the study the total plaque area (TPA), the maximum plaque thickness in the carotid artery and the PROCAM-Scores of 3,748 healthy men and 2,260 healthy women between the ages of 20 and 64 years were determined. During the subsequent follow-up study 94 subjects sickened. An ultrasound examination of the carotid artery of 79 patients revealed a type III or IV b finding. In a pilot study 33 asymptomatic subjects with a type III or IV b finding in the ultrasound examination were assessed using a computed tomography (CT) coronary angiogram. Additional 10 asymptomatic subjects were examined independently to undergo further cardiac examinations. Results: In the final analysis only five patients had entirely smooth coronary arteries, six had coronary sclerosis, eight had a 30% stenosis, one had a 30-50% stenosis and 23 patients had a stenosis >= 50%; and in extreme case, a left main coronary artery stenosis with three-vessel disease. Conclusions: Asymptomatic subjects with advanced atherosclerosis of the carotid artery (type III and type IV b findings) had a high risk for coronary heart disease (CHD). Early treatment of the disease improves the patient's prognosis. A screening consisting in the combination of TPA measurement and determining the maximum plaque thickness is recommended. PMID- 29479383 TI - The Relationship Between Absence Coronary Artery Calcification and Myocardial Perfusion Single Photon Emission Computed Tomography. AB - Background: Coronary artery calcification score (CACS) is well validated prognostic tool in coronary artery disease (CAD). The data on the prevalence of myocardial ischemia on myocardial perfusion single photon emission computed tomography (MPS) in symptomatic patients with zero CACS and low to intermediate risk probability is lacking and controversial. The aim of our study was to evaluate the capability of zero CACS to exclude myocardial ischemia on MPS. Methods: A total of 157 patients ((mean age 53 +/- 10 years), 88 (56%) female patients, 69 (44%) male patients) who were suspected to have CAD and having low to intermediate pretest likelihood for CAD underwent CACS on dedicated computed tomography (CT) scanners. CACS was reported as zero in all patients, subsequently all patients underwent MPS. Patients with abnormal MPS underwent additional imaging with coronary computed tomography angiography (CCTA). Results: All patients had zero CACS, of which 122 (78%) had normal MPS, and 35 (22%) had abnormal MPS. Abnormal MPS included fixed defect in 22 (13%), equivocal in 10 (6%), and reversible defect in four (3%) patients. All patients with abnormal MPS had further imaging with CTCA. CTCA was normal in 30 (85%) patients, one patient had coronary artery stenosis more than 50%, one patient had coronary artery stenosis less than 50%, one patient had anomalous origin coronary artery, and two patients had myocardial bridging. Patients with abnormal MPS and normal coronary artery had dilated cardiomyopathy in 14 (40%), asymmetrical septal hypotrophy in one (3%), and mitral valve disease in three (9%). Conclusions: Zero CACS in stable patients with low or intermediate risk indicated very low likelihood of obstructive CAD, less than 1%. Patients with zero CACS and normal MPS most likely will not benefit from further testing; however, patients with abnormal MPS will need further imaging with CCTA. CCTA is helpful in this group of patients for evaluation of coronary artery and cardiac morphology. PMID- 29479384 TI - A Survey of Coping Strategies With Stress in Patients With Acute Myocardial Infarction and Individuals Without a History of Fixed Myocardial Infarction. AB - Background: This study aimed at investigating the coping strategies with stress in patients with acute myocardial infarction (MI) and individuals without a history of fixed MI and cardiovascular disorders. Methods: This case-control crossover study was conducted from March 2015 to February 2016 on 220 patients with acute MI (MI patients) as case group and 220 patients without any history of MI and cardiovascular diseases as the control group using availability sampling method. To collect the required data, demographic information questionnaire, Holms-Raheh life stress inventory, perceived stress questionnaire, and coping inventory for stressful situations (CISS) were applied. Results: On the basis of our findings, 118 patients (53.6%) with MI used emotion-focused coping strategy. Ninety-seven patients (82.2%) with MI who used emotion-focused coping strategy had negative perceived stress. Additionally, 71 patients (60.2%) with MI who had used emotion-focused coping strategy suffered from very high level of stress. Conclusion: The most MI patients had very high level of stress while most people in control group had high level of stress. Most MI patients that had very high level of stress cope with it in emotion-focused coping strategy and it proves that people with higher levels of stress are more likely to use inefficient coping strategies. PMID- 29479385 TI - Transcatheter Aortic Valve Replacement After Coronary Artery Bypass Graft Is Associated With Increased Pacemaker Implantation but Not Reduced Overall Survival. AB - Background: A history of coronary artery bypass graft (CABG) is a common compelling indication for transcatheter aortic valve replacement (TAVR). However, there is little data on how these patients compare to other TAVR patients. In this study, the short and long-term outcomes of these TAVR patients after CABG are defined. Methods: A retrospective chart review case-control study of 337 consecutive patients who underwent a TAVR for severe aortic stenosis at Sanford Health in Fargo ND was performed to determine if a history of prior CABG was associated with worse outcomes after TAVR as compared to a TAVR cohort without a history of CABG. Results: Despite higher predicted surgical risk, patients with a history of CABG had no significant difference overall survival at 1 month (98% vs. 93%, P = 0.112), 6 months (94% vs. 87%, P = 0.094), 1 year (85% vs. 77%, P = 0.206) or 2 years (70% vs. 57%, P = 0.135) post-TAVR. However, a history of CABG was associated with an increase in post-TAVR permanent pacemaker (PPM) implantation (15% vs. 6%, P = 0.015). Conclusions: This study gives evidence to suggest that patients with a history of prior CABG do not have any difference in overall survival as other TAVR patients, despite higher predicted surgical risk and differences in preprocedural comorbidities. Our study also confirms the safety of TAVR in this specific population in lower volume centers. PMID- 29479386 TI - Critical Management of Severe Hypotension Caused by Amlodipine Toxicity Managed With Hyperinsulinemia/Euglycemia Therapy Supplemented With Calcium Gluconate, Intravenous Glucagon and Other Vasopressor Support: Review of Literature. AB - Calcium channel blocker (CCB ) overdose, whether intentional or accidental, is a common clinical scenario and can be very lethal. Conventional treatments for CCB overdose include intravenous (IV) fluids, calcium salts, dopamine, dobutamine, norepinephrine, phosphodiesterase inhibitors, and glucagon. However, the conventional therapies are unsuccessful in reversing the cardiovascular toxicity of CCB, so they commonly fail to improve the hemodynamic condition of the patient. Blockade of the L-type calcium channels that mediate the antihypertensive effect of CCBs also decreases the release of insulin from pancreatic beta-islet cells and reduces glucose uptake by tissues (insulin resistance). By targeting this insulin-mediated pathway, hyperinsulinemia/euglycemia therapy (HIET) appears to have a distinct role, and its clinical potential is underrecognized in the management of severe CCB toxicity. We present a case of young man with amlodipine toxicity successfully managed with high dose of IV insulin therapy. PMID- 29479387 TI - Use of Sugammadex in a Patient With Myotonic Dystrophy. AB - One of the challenges during the perioperative care of patients with myotonic dystrophy is the reversal of neuromuscular blocking agents. Agents that inhibit acetylcholinesterase, such as neostigmine, may precipitate myotonia, and are therefore relatively contraindicated. Sugammadex is a novel pharmacologic agent, which encapsulates rocuronium or vecuronium, thereby reversing their effect. We report anecdotal experience with the use of sugammadex to reverse neuromuscular blockade in a patient with myotonic dystrophy. Concerns with the reversal of neuromuscular blockade in patients with myotonic dystrophy are presented, previous reports of the use of sugammadex in similar clinical scenarios are reviewed, and its advantages are discussed. PMID- 29479389 TI - Group G Streptococcus Infective Endocarditis in Association With Colon Cancer. AB - Group G streptococcus has been increasingly reported as a cause of bacteremia and infective endocarditis. The association between various groups of streptococcus with malignancy has been well established. Such association is particularly observed in group D Streptococcus bovis which is commonly reported in association with carcinoma of the colon. We herein report a case of a 72-year-old male who presented with severe sepsis, iron deficiency anemia and newly diagnosed cardiac murmur. Further workup confirmed group G streptococcus bacteremia, infective endocarditis and newly diagnosed carcinoma of the colon. This case highlights a unique association between invasive form of group G streptococcus and colon cancer. PMID- 29479388 TI - Successful Surgical Repair and Perioperative Management of 6-Month-Old With Total Anomalous Pulmonary Venous Return in a Developing Country: Considerations for the Treatment of Pulmonary Hypertension. AB - Total anomalous pulmonary venous return (TAPVR) is a rare congenital cardiac defect, accounting for 1.5-3% of cases of congenital heart disease. With prenatal ultrasonography, the majority of these patients are diagnosed in utero with definitive surgery performed during the neonatal period. However, as prenatal screening may not be available in developing countries, patients may present in later infancy. We present successful surgical repair of a 6-month-old infant with TAPVR who presented for medical care at 5 months of age in Lima, Peru. The late presentation of such infants and the limited resources available for the treatment of elevated pulmonary vascular resistance may impact successful surgical correction of such defects. The perioperative care of such infants in developing countries is discussed and strategies for managing postoperative pulmonary hypertension is reviewed. PMID- 29479390 TI - Acute Stent Loss and Its Retrieval of a Long, Tapering Morph Stent in a Tortuous, Calcified Lesion. AB - A 72-year-old male with diabetes and smoking as coronary risk factors was evaluated for chronic stable angina - Canadian Cardiovascular Society III - despite guideline directed medical treatment which revealed a diffuse, tortuous, calcified narrowing (90% stenosis) in left circumflex (LCx) coronary artery. After predilatation, a 3.0 - 2.5 * 60 mm BioMime Morph stent - long tapering stent (Sirolimus eluting stent, Meril life Sciences, India) - was tracked which failed and dislodged to right deep femoral artery during its pullback. It was successfully retrieved by EN snare: 6 - 10 mm (Merit Medical, USA) by contralateral femoral approach. Lesion was further dilated and successfully stented with another 3.0 - 2.5 * 60 mm BioMime Morph stent at 10 atm pressure showing proper stents expansion with TIMI-3 coronary flow. Our case highlights trackibility issues and importance of adequate lesion preparation before stent deployment in a tortuous and calcified vessel especially with very long stent. To the best of our knowledge, this is the first such case report demonstrating dislodgement and successful retrieval of long, tapered Morph stent. PMID- 29479391 TI - Massive Hemorrhagic Pericardial Effusion With Cardiac Tamponade as Initial Manifestation of Mixed Connective Tissue Disease. AB - Mixed connective tissue disease (MCTD) is a distinct entity of connective tissue disorders characterized by overlapping clinical features of various autoimmune diseases along with the presence of antibodies to ribonucleoprotein (anti-RNP). The prevalence of cardiac involvement in MCTD varies from 13% to 65% and accounts for approximately 20% of MCTD related mortality. In this case, we describe an elderly female patient with multiple complaints without a clear etiology on presentation. Echocardiogram revealed severe rapidly accumulating pericardial effusion causing tamponade necessitating pericardial window. Laboratory investigations showed positive ribonucleoprotein antibodies. Biopsy of pericardial tissue revealed fibrinous pericarditis. While pericarditis is commonly associated with MCTD, pericardial tamponade on the other hand is rarely described. This case highlights a very rare complication of the disease. Early recognition, prompt treatment, and regular follow-up with serial echo are essential for treatment. PMID- 29479392 TI - Conversion of Atrial Fibrillation to Sinus Rhythm During Coronary Intervention: Complex Interplay of Arrhythmic and Ischemic Substrate. AB - Atrial fibrillation (AF) can be a manifestation of acute coronary syndrome (ACS). Presence of AF during ACS further adds to complexities in the management issues and prognosis of ACS. We report a case of a 77-year-old male in whom we observed spontaneous conversion of AF to sinus rhythm during percutaneous coronary interventional procedure for critical ostial stenosis of the right coronary artery; and discuss potential electrophysiological mechanisms related to such phenomenon. PMID- 29479393 TI - A comparison of the vending environment among three rural subtypes of secondary schools. AB - The purpose of this study was to further explore the rural school food environment. This study assessed trends in prevalence of vending machines and vending items within and between Minnesota schools located in 3 rural subtypes: town/rural fringe, town/rural distant, and remote rural. Generalized estimating equation models were employed to analyze data from the 2006 through 2012 School Health Profiles Principal's Surveys (Profiles). All 3 rural subtypes had a statistically significant decrease in the prevalence of low nutrient energy dense (LNED) vending items between 2006 and 2012, with the exception of sports drinks. However, different vending practices were observed between rural subtypes, with town/rural fringe schools providing more LNED vending options and experiencing less positive change over time compared to town/rural distant and remote rural schools. Differences in vending machine practices emerge when rural schools are subtyped. PMID- 29479394 TI - A NOVEL AND EFFICIENT ALGORITHM FOR DE NOVO DISCOVERY OF MUTATED DRIVER PATHWAYS IN CANCER. AB - Next-generation sequencing studies on cancer somatic mutations have discovered that driver mutations tend to appear in most tumor samples, but they barely overlap in any single tumor sample, presumably because a single driver mutation can perturb the whole pathway. Based on the corresponding new concepts of coverage and mutual exclusivity, new methods can be designed for de novo discovery of mutated driver pathways in cancer. Since the computational problem is a combinatorial optimization with an objective function involving a discontinuous indicator function in high dimension, many existing optimization algorithms, such as a brute force enumeration, gradient descent and Newton's methods, are practically infeasible or directly inapplicable. We develop a new algorithm based on a novel formulation of the problem as non-convex programming and non-convex regularization. The method is computationally more efficient, effective and scalable than existing Monte Carlo searching and several other algorithms, which have been applied to The Cancer Genome Atlas (TCGA) project. We also extend the new method for integrative analysis of both mutation and gene expression data. We demonstrate the promising performance of the new methods with applications to three cancer datasets to discover de novo mutated driver pathways. PMID- 29479395 TI - The Role of Computational Modeling and Simulation in the Total Product Life Cycle of Peripheral Vascular Devices. AB - The total product life cycle (TPLC) of medical devices has been defined by four stages: discovery and ideation, regulatory decision, product launch, and postmarket monitoring. Manufacturers of medical devices intended for use in the peripheral vasculature, such as stents, inferior vena cava (IVC) filters, and stent-grafts, mainly use computational modeling and simulation (CM&S) to aid device development and design optimization, supplement bench testing for regulatory decisions, and assess postmarket changes or failures. For example, computational solid mechanics and fluid dynamics enable the investigation of design limitations in the ideation stage. To supplement bench data in regulatory submissions, manufactures can evaluate the effects of anatomical characteristics and expected in vivo loading environment on device performance. Manufacturers might also harness CM&S to aid root-cause analyses that are necessary when failures occur postmarket, when the device is exposed to broad clinical use. Once identified, CM&S tools can then be used for redesign to address the failure mode and re-establish the performance profile with the appropriate models. The Center for Devices and Radiological Health (CDRH) wants to advance the use of CM&S for medical devices and supports the development of virtual physiological patients, clinical trial simulations, and personalized medicine. Thus, the purpose of this paper is to describe specific examples of how CM&S is currently used to support regulatory submissions at different phases of the TPLC and to present some of the stakeholder-led initiatives for advancing CM&S for regulatory decision-making. PMID- 29479397 TI - The revival of intrauterine insemination: evidence-based data have changed the picture. AB - According to a number of high quality studies intrauterine insemination (IUI) with homologous semen should be the first choice treatment in case of unexplained and moderate male factor subfertility. IVF and ICSI are clearly over-used in this selected group of infertile couples. The limited value of IUI in infertility treatment as mentioned in the 2013 NICE guidelines was surely a premature statement and should be adapted to the actual literature. More evidence-based data are becoming available on different variables influencing the success rates after IUI. It can be expected that these findings may lead to a better understanding and use of IUI in the near future. PMID- 29479396 TI - Characterization of extracellular vesicles derived from cardiac cells in an in vitro model of preconditioning. AB - Preconditioning is a promising technique to protect the heart from ischaemia reperfusion injury. In this context, the crosstalk between different cardiac cell types and especially the exchange of cardioprotective mediators has come into the focus of current research. Recently, extracellular vesicles (EVs), nano-sized structures, emerged as possible communication mediators. They are taken up by recipient cells and can alter gene expression or activate intracellular signal cascades. It has been shown that all cardiac cell types are able to secrete EVs, but so far the influence of an in vitro preconditioning stimulus on EV concentration and composition has not been investigated. Therefore, we stimulated primary cardiac myocytes and fibroblasts from neonatal rats, as well as H9c2 cells, with two known in vitro preconditioning stimuli: hypoxia or isoflurane. EVs were isolated from cell culture supernatants 48 h after stimulation by differential centrifugation and size exclusion chromatography. They were characterized by transmission electron microscopy, tunable resistive pulse sensing, miRNA array and Western blot analysis. The detected EVs had the typical cup-shaped morphology and a size of about 150 nm. No significant differences in EV concentration were observed between the different groups. The protein and miRNA load was affected by in vitro preconditioning with isoflurane or hypoxia. EV markers like Alix, CD63, flotillin-1 and especially heat shock protein 70 were significantly up-regulated by the treatments. Several miRNAs like miR-92b-3p, miR 761 and miR-101a-5p were also significantly affected. A migration assay confirmed the physiological benefit of these EVs. Taken together, our findings show that a model of in vitro preconditioning of cardiac cells does not influence EV concentration but strongly regulates the EV cargo and affects migration. This might indicate a role for EV-mediated communication in isoflurane- and hypoxia induced in vitro preconditioning. PMID- 29479398 TI - Maternal and neonatal outcomes in a treated versus non- treated cohort of women with Gestational Diabetes Mellitus according to the HAPO 5 and 4 criteria. AB - Background: Our aim was to evaluate the treatment effect of gestational diabetes mellitus (GDM) according to the Hyperglycemia and Adverse Pregnancy Outcome group (HAPO) screening. Results: The prevalence of GDM, using HAPO 5 was 23.8%. Of these, 72.8% were treated. Comparison of outcomes between treated and untreated patients showed no differences. The prevalence of GDM according to HAPO 4 criteria was 16.9%. In the untreated group, there were more cases of (pre)eclampsia (P=0.038), more admissions to neonatal care department (P=0.036), pregnancy duration was shorter (P=0.05), and Apgar score at five minutes was significantly lower (P=0.019). The outcomes didn't differ in the MAGG (midly aberrant glycemic group). Conclusions: Using HAPO 5 criteria in population-based screening doubled the prevalence of GDM. There were no differences between untreated and treated HAPO 5 and MAGG patients, while in the HAPO 4 group there might be a trend of therapy effectiveness. PMID- 29479399 TI - The prognostic value of perifollicular blood flow in the outcome after assisted reproduction: a systematic review. AB - Background: The overall final outcome of assisted reproductive technologies (ART) is still more often a failure than a success. Assessing perifollicular blood flow (PFBF) is one technique to predict and possibly improve this outcome. The aim was to provide a structured review of studies concerning PFBF and its prognostic value in patients undergoing ART, including IUI (intrauterine insemination). Methods: PUBMED, EMBASE and Cochrane Database of Systematic Reviews were searched for relevant studies published until December 2016. As key words 'Perifollicular blood flow', 'IUI', 'IVF' and 'ICSI' were used. Results: A total of 14 articles were included in the current review. The results are very heterogeneous, though there is evidence that measuring PFBF could be a good prognostic marker for oocyte and embryo quality, but even more for pregnancy rate after IVF/ICSI. This finding is not observed in studies concerning IUI. Conclusions: Our results highlight an urgent need to investigate the role for PFBF assessment by Power Doppler in ART in randomised controlled trials. PMID- 29479400 TI - Correlation between follicle dimensions recorded by patients at home (SOET) versus ultrasound performed by professional care providers. AB - Introduction: Serial measurements of the number of follicles and their growth by ultrasound is a standard way of monitoring fertility treatments using controlled ovarian stimulation. This is stressful for both the patient and the professional. Self-operated endovaginal telemonitoring (SOET) is more patient friendly and less time-consuming. Aim of the study: The goal of the study is to see if there's a correlation in the number of follicles and in two- dimensional growth between recordings made using SOET versus measurements performed by a professional sonographer. Results: Three different ultrasound moments were recorded and compared in a total of 15 women. At time A an ultrasound was performed by the patient at home using SOET at the decision time of triggering. At time B an ultrasound was also recorded by the patient, 24 hours later. At time C an ultrasound was performed by a physician using a high end ultrasound device immediately prior to oocyte retrieval, 12 hours later than time B. The correlation in number and two-dimensional size between the different measurement moments was calculated. There is an excellent correlation in follicle count between time B and C. The difference in mean two-dimensional size between different measurement moments was not statistically significant. Conclusion: SOET ultrasound correlates well with ultrasound performed by a professional in number of follicles. SOET is a good alternative for monitoring controlled ovarian stimulation in a well-defined population group of normal responders, especially near the end of the ovarian stimulation. PMID- 29479401 TI - Patients' ideas, expectations and experience with self operated endovaginal telemonitoring: a prospective pilot study. AB - Objective: To examine advantages and disadvantages as perceived by patients and their partners using home sonography for monitoring ovarian stimulation prior to artificial fertility treatment. Method: We interviewed 25 patients and their partners and took 44 online questionnaires. All interviews were written out and the transcripts were coded, based on words patients used to describe their experience. The query consisted mostly of statements, of which the participant had to ascertain whether or not they agreed (1= I absolutely don't agree and 5 = I absolutely agree). The median and mean of agreement scores was calculated. Results: The time saving and practical aspect of self-operated endo-vaginal tele monitoring (SOET) was the most important argument to choose SOET. In addition, the following aspects were considered advantages: more autonomy, no need for leave from work, a better doctor-patient relationship and sometimes more involvement of the partner. The most important disadvantage is a sense of initial insecurity couples experience during the first ultrasound. Almost all couples experience this, but they accept it as part of the process. Conclusion: Using SOET was a pleasant experience for all couples. All patients and partners had positive expectations about SOET. The initial insecurity can be minimized, by improving teaching measures. It would be positive if a legal framework is set up allowing reimbursement of home sonography. PMID- 29479403 TI - Uncommon presentations of an uncommon entity: OHVIRA syndrome with hematosalpinx and pyocolpos. AB - Mullerian malformations result from defective fusion of the Mullerian ducts during development of the female reproductive system. The least common form of these malformations is Herlyn-Werner-Wunderlich syndrome characterized by obstructed hemivagina and ipsilateral renal anomaly (OHVIRA). The most common presentation of this syndrome is a mass secondary to hematocolpos, pain, and dysmenorrhea. Clinical diagnosis is very challenging and requires imaging studies in which ultrasound and MRI play an essential role in the diagnosis, classification and treatment plan. We report two cases of this syndrome, featuring two very rare clinical presentations: hematosalpinx and pyocolpos. The clinical course of the pathology is not standard and each patient is treated accordingly. PMID- 29479402 TI - Mini-laparoscopic hysterectomy for adenocarcinoma in situ of the uterine cervix using interchangeable 5-mm end effectors: a way to cross the line of minimally invasive surgery in gynaecologic oncology. AB - The incidence of adenocarcinoma of the uterine cervix is increasing. It poses the affected women in risk and the definitive treatment requires hysterectomy. Here we describe a case of adenocarcinoma in situ of the uterine cervix successfully managed by minilaparoscopic hysterectomy using interchangeable 5-mm end effectors. PMID- 29479404 TI - Vaginal lichen sclerosus: report of two cases. AB - Background: Lichen sclerosus most commonly affects the genital area. Contrarily to lichen planus, the involvement of the oral or vaginal mucosa is rare. Only four cases of vaginal lichen sclerosus have been described in the literature. Case report: The authors report two cases of postmenopausal women with a history of vulvar pruritus and burning. Both presented with lesions of the vaginal mucosa compatible with lichen sclerosus, and genital prolapse. Vaginal biopsies confirmed the diagnosis. Initial treatment with topical clobetasol was effective in one of the patients, but in the other patient line therapy with pimecrolimus, triamcinolone, and retinoids was needed. Conclusion: Vaginal lichen sclerosus may be underdiagnosed and genital prolapse may favour the development of vaginal lesions. PMID- 29479406 TI - Assessing local adaptation vs. plasticity under different resource conditions in seedlings of a dominant boreal tree species. AB - Under changing climate conditions, understanding local adaptation of plants is crucial to predicting the resilience of ecosystems. We selected black spruce (Picea mariana), the most dominant tree species in the North American boreal forest, in order to evaluate local adaptation vs. plasticity across regions experiencing some of the most extreme climate warming globally. Seeds from three provenances across the latitudinal extent of this species in northwestern Canada were planted in a common garden study in growth chambers. Two levels of two resource conditions were applied (low/high nutrient and ambient/elevated CO2) in a fully factorial design and we measured physiological traits, allocational traits, growth and survival. We found significant differences in height, root length and biomass among populations, with southern populations producing the largest seedlings. However, we did not detect meaningful significant differences among nutrient or CO2 treatments in any traits measured, and there were no consistent population-level differences in physiological traits or allocation patterns. We found that there was greater mortality after simulated winter in the high nutrient treatment, which may reflect an important shift in seedling growth strategies under increased resource availability. Our study provides important insight into how this dominant boreal tree species might respond to the changing climate conditions predicted in this region. PMID- 29479405 TI - Advanced glycation endproducts, dityrosine and arginine transporter dysfunction in autism - a source of biomarkers for clinical diagnosis. AB - Background: Clinical chemistry tests for autism spectrum disorder (ASD) are currently unavailable. The aim of this study was to explore the diagnostic utility of proteotoxic biomarkers in plasma and urine, plasma protein glycation, oxidation, and nitration adducts, and related glycated, oxidized, and nitrated amino acids (free adducts), for the clinical diagnosis of ASD. Methods: Thirty eight children with ASD (29 male, 9 female; age 7.6 +/- 2.0 years) and 31 age matched healthy controls (23 males, 8 females; 8.6 +/- 2.0 years) were recruited for this study. Plasma protein glycation, oxidation, and nitration adducts and amino acid metabolome in plasma and urine were determined by stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry. Machine learning methods were then employed to explore and optimize combinations of analyte data for ASD diagnosis. Results: We found that children with ASD had increased advanced glycation endproducts (AGEs), Nepsilon-carboxymethyl-lysine (CML) and Nomega-carboxymethylarginine (CMA), and increased oxidation damage marker, dityrosine (DT), in plasma protein, with respect to healthy controls. We also found that children with ASD had increased CMA free adduct in plasma ultrafiltrate and increased urinary excretion of oxidation free adducts, alpha aminoadipic semialdehyde and glutamic semialdehyde. From study of renal handling of amino acids, we found that children with ASD had decreased renal clearance of arginine and CMA with respect to healthy controls. Algorithms to discriminate between ASD and healthy controls gave strong diagnostic performance with features: plasma protein AGEs-CML, CMA-and 3-deoxyglucosone-derived hydroimidazolone, and oxidative damage marker, DT. The sensitivity, specificity, and receiver operating characteristic area-under-the-curve were 92%, 84%, and 0.94, respectively. Conclusions: Changes in plasma AGEs were likely indicative of dysfunctional metabolism of dicarbonyl metabolite precursors of AGEs, glyoxal and 3-deoxyglucosone. DT is formed enzymatically by dual oxidase (DUOX); selective increase of DT as an oxidative damage marker implicates increased DUOX activity in ASD possibly linked to impaired gut mucosal immunity. Decreased renal clearance of arginine and CMA in ASD is indicative of increased arginine transporter activity which may be a surrogate marker of disturbance of neuronal availability of amino acids. Data driven combination of these biomarkers perturbed by proteotoxic stress, plasma protein AGEs and DT, gave diagnostic algorithms of high sensitivity and specificity for ASD. PMID- 29479407 TI - The role of ecotypic variation in driving worldwide colonization by a cosmopolitan plant. AB - For almost 100 years now, ecotypic differentiation of plant species has been a major topic of research. In changing environments, the question needs to be answered as to how long it takes to adapt, and which parameters are subject to this fast adaptation. Short-living colonizing plant species are excellent examples, especially when they are selfing. Shepherd's Purse Capsella bursa pastoris (Brassicaceae) is one of the most wide-spread flowering species on earth and avoids only the hot and humid tropics. Many studies demonstrated the ecotypic differentiation of C. bursa-pastoris in various regions of the world but ecotypic differentiation regarding adaptability of anatomy and physiology of rosette leaves so far remained less recognized. However, the leaves are relevant for subsequent seed set; in particular, winter-annual accessions require a robust rosette to survive adverse conditions. Leaf-related traits such as the thickness of the mesophyll and epidermis, stomatal density, photosynthetic capacity and the ability to withstand and even use high light conditions were therefore analysed in provenances from various climatic zones. Photosynthetic capacity depends on leaf anatomy and cellular physiological parameters. In particular, the ability to dynamically adjust the photosynthetic capacity to changing environmental conditions results in higher fitness. Here, we attempt to relate these results to the four Mendelian leaf types according to Shull. PMID- 29479408 TI - Two closely related species differ in their regional genetic differentiation despite admixing. AB - Regional genetic differentiation within species is often addressed in evolutionary ecology and conservation biology. Here, we address regional differentiation in two closely related hybridizing taxa, the perennial sedges Carex flava and C. viridula and their hybrid C. * subviridula in 37 populations in the north and centre of their distribution range in Europe (Estonia, Lowland (<1000 m a.s.l.) and Highland Switzerland) using 10 putative microsatellite loci. We ask whether regional differentiation was larger in the less common taxon C. viridula or whether, possibly due to hybridization, it was similar between taxa. Our results showed similar, low to moderate genetic diversity for the three studied taxa. In total, we found 12 regional species-specific alleles. Analysis of molecular variance (AMOVA), STRUCTURE and multidimensional scaling analysis showed regional structure in genetic variation, where intraspecific differentiation between regions was lower for C. flava (AMOVA: 6.84 %) than for C. viridula (20.77 %) or C. * subviridula (18.27 %) populations. Hybrids differed from the parental taxa in the two regions where they occurred, i.e. in Estonia and Lowland Switzerland. We conclude that C. flava and C. viridula clearly differ from each other genetically, that there is pronounced regional differentiation and that, despite hybridization, this regional differentiation is more pronounced in the less common taxon, C. viridula. We encourage future studies on hybridizing taxa to work with plant populations from more than one region. PMID- 29479410 TI - Intercropping with wheat lowers nutrient uptake and biomass accumulation of maize, but increases photosynthetic rate of the ear leaf. AB - Intercropping is an ancient agricultural practice that provides a possible pathway for sustainable increases in crop yields. Here, we determine how competition with wheat affects nutrient uptake (nitrogen and phosphorus) and leaf traits, such as photosynthetic rate, in maize. In a field experiment, maize was planted as a sole crop, in three different intercrop configurations with wheat (a replacement intercrop and two add-row intercrops), and as a skip-row system with one out of each three maize rows omitted. Nitrogen and phosphorus uptake were determined at flowering and maturity. Specific leaf area, leaf nitrogen concentration, chlorophyll content and photosynthetic rate of the ear leaf were determined at flowering. Nitrogen and phosphorus concentrations were significantly lower in intercropped maize than in sole maize and skip-row maize at flowering, but these differences were smaller at maturity. At flowering, specific leaf area was significantly greater in intercrops than in skip-row maize. Leaf nitrogen concentration was significantly lower in add-row intercrops than in sole maize, skip-row maize or maize in the replacement intercrop. Leaf chlorophyll content was highest in sole and skip-row maize, intermediate in maize in the replacement intercrop and lowest in maize grown in add-row intercrops. On the contrary, photosynthetic rate was significantly higher in the replacement intercrop than in sole maize, skip-row maize and the intercrop with an additional maize row. The findings indicate that competition with intercropped wheat severely constrained nutrient uptake in maize, while photosynthetic rate of the ear leaf was not negatively affected. Possible mechanisms for higher photosynthesis rate at lower leaf nitrogen content in intercropped maize are discussed. PMID- 29479409 TI - Geography, environment and organismal traits in the diversification of a major tropical herbaceous angiosperm radiation. AB - The generation of plant diversity involves complex interactions between geography, environment and organismal traits. Many macroevolutionary processes and emergent patterns have been identified in different plant groups through the study of spatial data, but rarely in the context of a large radiation of tropical herbaceous angiosperms. A powerful system for testing interrelated biogeographical hypotheses is provided by the terrestrial bromeliads, a Neotropical group of extensive ecological diversity and importance. In this investigation, distributional data for 564 species of terrestrial bromeliads were used to estimate variation in the position and width of species-level hydrological habitat occupancy and test six core hypotheses linking geography, environment and organismal traits. Taxonomic groups and functional types differed in hydrological habitat occupancy, modulated by convergent and divergent trait evolution, and with contrasting interactions with precipitation abundance and seasonality. Plant traits in the Bromeliaceae are intimately associated with bioclimatic differentiation, which is in turn strongly associated with variation in geographical range size and species richness. These results emphasize the ecological relevance of structural-functional innovation in a major plant radiation. PMID- 29479412 TI - Amphioxus, motion detection, and the evolutionary origin of the vertebrate retinotectal map. AB - The axonal projection from the retina to the optic tectum maps visual information isomorphically from one to the other and serves as a model for the development of sensory maps more generally in the vertebrate brain. How or why this connection evolved is not known, nor why the midbrain is so important to the processing of visual information. Amphioxus is potentially informative here because its eye homolog, the frontal eye, also has a neural connection to a region of the brain now known to be homologous with the caudal diencephalon and midbrain. The frontal eye has only a one-dimensional receptor array, but simple alterations to the pattern and plane of cell division would have been sufficient to generate a structure more like the vertebrate retina. Accounting for the retinotectal map poses more of a problem. The hypothesis developed here is that this is best explained as a consequence of a prior association between the roof of the anterior nerve cord and an array of rhabdomeric photoreceptors, homologous with the Joseph cells of amphioxus, that were used by the common ancestor of amphioxus and vertebrates for detecting moving shadows. Hence, a rudimentary tectal map could have been present before the evolution of image-forming eyes and been coopted by them secondarily. Assuming the orientation of this map was fixed from the start relative to the external world, its retinal counterpart would have had to adjust to this to accommodate the image reversal that accompanies the conversion of a flat receptor array to a camera-type eye. Exploring this hypothesis further will require more information than is currently available on the Joseph cells, especially as to where and how their neural output is processed. PMID- 29479413 TI - Laparoscopic endoscopic combined surgery for removal of migrated coil after embolization of ruptured splenic artery aneurysm. AB - Splenic artery aneurysm is the most common visceral arterial aneurysm. Rupture of aneurysm is a rare event but associated with a high mortality. Endovascular coil embolization of bleeding splenic artery aneurysm has emerged as a promising minimal invasive treatment and considered safer than open surgery in selected patients. Nevertheless, several complications related to coils have been reported, the rarest being coil migration and erosion. We report a case of splenic artery coil migration into the stomach and its successful removal by laparoscopic endoscopy combined surgery. PMID- 29479411 TI - SoxB2 in sea urchin development: implications in neurogenesis, ciliogenesis and skeletal patterning. AB - Background: Current studies in evolutionary developmental biology are focused on the reconstruction of gene regulatory networks in target animal species. From decades, the scientific interest on genetic mechanisms orchestrating embryos development has been increasing in consequence to the fact that common features shared by evolutionarily distant phyla are being clarified. In 2011, a study across eumetazoan species showed for the first time the existence of a highly conserved non-coding element controlling the SoxB2 gene, which is involved in the early specification of the nervous system. This discovery raised several questions about SoxB2 function and regulation in deuterostomes from an evolutionary point of view. Results: Due to the relevant phylogenetic position within deuterostomes, the sea urchin Strongylocentrotus purpuratus represents an advantageous animal model in the field of evolutionary developmental biology. Herein, we show a comprehensive study of SoxB2 functions in sea urchins, in particular its expression pattern in a wide range of developmental stages, and its co-localization with other neurogenic markers, as SoxB1, SoxC and Elav. Moreover, this work provides a detailed description of the phenotype of sea urchin SoxB2 knocked-down embryos, confirming its key function in neurogenesis and revealing, for the first time, its additional roles in oral and aboral ectoderm cilia and skeletal rod morphology. Conclusions: We concluded that SoxB2 in sea urchins has a neurogenic function; however, this gene could have multiple roles in sea urchin embryogenesis, expanding its expression in non-neurogenic cells. We showed that SoxB2 is functionally conserved among deuterostomes and suggested that in S. purpuratus this gene acquired additional functions, being involved in ciliogenesis and skeletal patterning. PMID- 29479414 TI - A case of chronic left main trunk occlusion treated with off-pump coronary artery bypass grafting. AB - Ischemic heart disease presents with various symptoms, and chest pain is a chief complaint. Occlusion of the left main trunk often results in serious symptoms such as cardiogenic shock. However, while extremely rare, left main trunk occlusion can present with only slight chronic symptoms. In the present case, a 62-year-old woman with few risk factors for ischemic heart disease visited our hospital complaining of exertional chest pain, which had gradually intensified over the past several years. Coronary artery computed tomography revealed total occlusion of the left main trunk, which was examined closely using coronary angiography. Coronary angiography showed that the left coronary artery was perfused by collateral pathways from the right coronary artery. The patient was thus diagnosed with chronic occlusion of the left main trunk. She underwent off pump coronary artery bypass grafting, which proved to be an effective treatment. PMID- 29479415 TI - Solitary pancreatic head metastasis from tibial adamantinoma: a rare indication to pancreaticoduodenectomy. AB - Pancreatic metastases are rare, <2% of all pancreatic neoplasia. This is the first case of pancreatic metastasis from adamantinoma, a rare, low grade and slow growing tumor which is frequently localized in long bones. We describe a case of a 45-year-old woman presenting with increased bilirubin level. Computed tomography and ecoendoscopic ultra sonography revealed a pancreatic head mass. Fine-needle aspiration biopsy was consistent with metastatic adamantinoma. The patient was submitted to a standard pancreaticoduodenectomy. As in the case presented, standard pancreatic resections are safe and feasible options to treat non-pancreatic primary tumor improving patient's survival and quality of life. PMID- 29479416 TI - Need brooks no delay. Peritoneo-cutaneous fistula formation secondary to gallstone dropped at laparoscopic cholecystectomy 20 years previously: a case report. AB - Dropped gallstones, in addition to inadvertent damage to the biliary tree, is a complication seen in laparoscopic cholecystectomy (LC) far more frequently than the open procedure. It can result in symptomatic abscess formation, and given its relative rarity, can present a diagnostic challenge. We present the case of a lady whose dropped gallstone resulted in a peritoneo-cutaneous fistula, over 20 years on from her LC. PMID- 29479417 TI - The role of TEVAR in the management of a recurrent aorto-gastric fistula. AB - An aorto-gastric fistula is a catastrophic and rare cause of an upper gastrointestinal bleed. The diagnosis requires a high index of suspicion and expedient management as any delay in each of these component, will be to the detriment of the patient. We report a case of a patient with two episodes of this rare event, with haemodynamic compromise, 15 years after having had a trans hiatal oesophagectomy for an adenocarcinoma of the oesophagus who presented on both occasions. He had thoracic endo-vascular aortic repair (TEVAR) on both presentations and survived. This case exemplifies the fact that while TEVAR is a good bridging therapy for the management of an aorto-enteric fistula. It however should not be considered as the definitive management for patients who are operable or patients who do not have prohibitive surgical risk. PMID- 29479418 TI - Neurosurgical management of multiple intracranial Nocardia and Enterococcus abscesses in an immunocompetent patient. AB - Nocardia farcinica and Enterococcus faecium are both rare causes of cerebral abscess. The former is associated with high morbidity and mortality. We describe a neurosurgical approach to the management of multiple intracranial abscesses of dual microbial pathology in an immunocompetent patient to achieve a good outcome. PMID- 29479419 TI - Lymphangioma cavernous of the small bowel mesentery, an infrequent cause of acute abdomen in adult. AB - Lymphangioma is a benign mass lesion characterized by numerous thin-walled lymphatic spaces that usually manifests in the first few years of life. They generally appear in the head, neck and axillary regions. Abdominal lymphangiomas have been reported however they are rare 5%. The small bowel mesentery lymphangioma has been described in <1%. Lymphangiomas may remain asymptomatic or present with complications depending on the size and location of the lesion. We present a case of a 71-year-old female, she presented to the emergency with acute abdomen and a palpable mass in the lower abdomen. Computed tomography confirmed a mass within the mesentery of the small bowel. Laparotomy was performed and a cystic mass near the root of the small bowel mesentery was found. Patient underwent full recovery. On follow-up controls, pathology described lymphangioma cavernous. PMID- 29479420 TI - Preoperative radiation in large angiomatosis of the breast, attempting breast conserving surgery: multidisciplinary approach. AB - Angiomatosis of the breast is very rare. The presentations are including breast mass, skin discoloration and breast enlargement that mimic to angiosarcoma. The imaging could suggest non-specific vascular tumors. The histology should be obtained for the certain diagnosis. Surgical excision is the standard treatment. To our knowledge, this is the first case that preoperative radiation is given. Currently, radiation is occasionally used in benign condition. This case shows the successful result of preoperative radiation for achieving breast conserving surgery in large angiomatosis of the breast. PMID- 29479421 TI - Wilkie's syndrome: a case report of favourable minimally invasive surgery. AB - Wilkie's syndrome, or superior mesenteric artery syndrome (SMAS), is a rare clinical entity caused by compression of the third portion of the duodenum between the abdominal aorta and superior mesenteric artery, leading to duodenal obstruction and severe malnutrition. The authors report a case of a female patient with years of chronic intestinal obstruction with abdominal pain, vomits and weight loss. Contrast intestinal series showed dilation of stomach and duodenum. Abdominal computed tomography study revealed findings compatible with SMAS. After initial nutritional support, she was successfully treated by laparoscopic duodenojejunostomy. Surgical treatment of SMAS may be necessary in most cases with chronic symptoms or conservative treatment failure. A minimally invasive approach can be considered a safe surgical option with favourable outcomes. Clinical details, diagnostic studies and treatment are discussed. PMID- 29479422 TI - Abstract Sifter: a comprehensive front-end system to PubMed. AB - The Abstract Sifter is a Microsoft Excel based application that enhances existing search capabilities of PubMed. The Abstract Sifter assists researchers to search effectively, triage results, and keep track of articles of interest. The tool implements an innovative "sifter" functionality for relevance ranking, giving the researcher a way to find articles of interest quickly. The tool also gives researchers a view of the literature landscape for a set of entities such as chemicals or genes. The Abstract Sifter is available as a Microsoft Excel macro enabled workbook application. PMID- 29479424 TI - A SNP resource for studying North American moose. AB - Background: Moose ( Alces alces) colonized the North American continent from Asia less than 15,000 years ago, and spread across the boreal forest regions of Canada and the northern United States (US). Contemporary populations have low genetic diversity, due either to low number of individuals in the original migration (founder effect), and/or subsequent population bottlenecks in North America. Genetic tests based on informative single nucleotide polymorphism (SNP) markers are helpful in forensic and wildlife conservation activities, but have been difficult to develop for moose, due to the lack of a reference genome assembly and whole genome sequence (WGS) data. Methods: WGS data were generated for four individual moose from the US states of Alaska, Idaho, Wyoming, and Vermont with minimum and average genome coverage depths of 14- and 19-fold, respectively. Cattle and sheep reference genomes were used for aligning sequence reads and identifying moose SNPs. Results: Approximately 11% and 9% of moose WGS reads aligned to cattle and sheep genomes, respectively. The reads clustered at genomic segments, where sequence identity between these species was greater than 95%. In these segments, average mapped read depth was approximately 19-fold. Sets of 46,005 and 36,934 high-confidence SNPs were identified from cattle and sheep comparisons, respectively, with 773 and 552 of those having minor allele frequency of 0.5 and conserved flanking sequences in all three species. Among the four moose, heterozygosity and allele sharing of SNP genotypes were consistent with decreasing levels of moose genetic diversity from west to east. A minimum set of 317 SNPs, informative across all four moose, was selected as a resource for future SNP assay design. Conclusions: All SNPs and associated information are available, without restriction, to support development of SNP based tests for animal identification, parentage determination, and estimating relatedness in North American moose. PMID- 29479423 TI - IL-15 enhances cross-reactive antibody recall responses to seasonal H3 influenza viruses in vitro. AB - Background: Recently, several human monoclonal antibodies that target conserved epitopes on the stalk region of influenza hemagglutinin (HA) have shown broad reactivity to influenza A subtypes. Also, vaccination with recombinant chimeric HA or stem fragments from H3 influenza viruses induce broad immune protection in mice and humans. However, it is unclear whether stalk-binding antibodies can be induced in human memory B cells by seasonal H3N2 viruses. Methods: In this study, we recruited 13 donors previously exposed to H3 viruses, the majority (12 of 13) of which had been immunized with seasonal influenza vaccines. We evaluated plasma baseline strain-specific and stalk-reactive anti-HA antibodies and B cell recall responses to inactivated H3N2 A/Victoria/361/2011 virus in vitro using a high throughput multiplex (mPlex-Flu) assay. Results: Stalk-reactive IgG was detected in the plasma of 7 of the subjects. Inactivated H3 viral particles rapidly induced clade cross-reactive antibodies in B cell cultures derived from all 13 donors. In addition, H3 stalk-reactive antibodies were detected in culture supernatants from 7 of the 13 donors (53.8%). H3 stalk-reactive antibodies were also induced by H1 and H7 subtypes. Interestingly, broadly cross-reactive antibody recall responses to H3 strains were also enhanced by stimulating B cells in vitro with CpG 2006 ODN in the presence of IL-15. H3 stalk-reactive antibodies were detected in CpG 2006 ODN + IL-15 stimulated B cell cultures derived from 12 of the 13 donors (92.3%), with high levels detected in cultures from 7 of the 13 donors. Conclusions: Our results demonstrate that stalk-reactive antibody recall responses induced by seasonal H3 viruses and CpG 2006 ODN can be enhanced by IL 15. PMID- 29479425 TI - Positive Mental Health from the perspective of Iranian society: A qualitative study. AB - Background: According to the World Health Organization, mental health relates, not only to the absence of mental disorder, but also to Positive Mental Health. Studies have shown that promoting positive mental health, not only reduces the prevalence and incidence of mental disorders, but also affects the process of treatment and reduces related burden. However, this concept has different interpretations in different cultures, and in many societies, mental health is still considered the absence of mental illness. Thus, the present study was conducted to provide an in-depth understanding of Iranian adults' perspective towards the concept of positive mental health. Materials and Methods: In the present qualitative study, eight focus group discussions (6 to 8 adults in each session) were held consisting of 30 to 60 year-old men and women from Tehran. Data were analyzed in "DeDoose" qualitative software using content analysis. Results: According to the data obtained, participants found no difference between positive mental health and mental health, mostly equating it to the absence of mental disorders and having positive energy, peace in and satisfaction with life. According to the results, positive mental health has four domains of emotional/psychological, spiritual, social, and life skills. Conclusion: Understanding an individual's positive mental health concepts culturally and providing appropriate community based programs can significantly promote the mental health of the community. PMID- 29479427 TI - Enhancing outpatient nephrology experience for internal medicine residents. AB - Interest in nephrology careers continues to remain low in the USA. Educational innovations that enhance interest in nephrology among medical trainees are being actively studied. While internal medicine (IM) residency programs commonly offer the inpatient nephrology elective to the resident, outpatient nephrology experience is lacking. Understanding the provision of care in outpatient and home dialysis and management of patients with glomerular diseases, chronic kidney disease and kidney transplantation are vital components of an outpatient nephrology rotation. In this review article, we share our experiences in incorporating outpatient nephrology to the IM resident's elective time. We also present the structure of the nephrology rotations at our programs and suggest several learning opportunities in outpatient nephrology that the training community can provide to medical residents. Strategies to effectively set up an outpatient nephrology rotation are also described. While more educational research on the impact of outpatient nephrology on resident learning and career choices are needed, we encourage a collaborative effort between faculty members in nephrology and the medicine residency programs to provide this unique learning opportunity to IM residents. PMID- 29479426 TI - The Art of War: harnessing the epigenome against cancer. AB - Histone chaperones are indispensable regulators of chromatin structure and function. Recent work has shown that they are frequently mis-regulated in cancer, which can have profound consequences on tumor growth and survival. Here, we focus on chaperones for the essential H3 histone variants H3.3 and CENP-A, specifically HIRA, DAXX/ATRX, DEK, and HJURP. This review summarizes recent studies elucidating their roles in regulating chromatin and discusses how cancer-specific chromatin interactions can be exploited to target cancer cells. PMID- 29479428 TI - Effect of health education on severe thalassemia prevention and control in communities in Cambodia. AB - Background: Severe thalassemia diseases are a major health problem in Southeast Asia. In Cambodia, there has never been a significant program for prevention or control of severe thalassemia. We, therefore, studied the effect of a health education program on severe thalassemia prevention and control in Phnom Penh, Cambodia. Methods: A quasi-experimental study in several communities around Phnom Penh was done. The respective intervention and control group comprised 124 and 117 people, between 18 and 40 years of age, male and female. Pre- and post-tests using a validated and reliable questionnaire were performed in the intervention group and one test was done in the control group. A health education program was organized to give important information to the intervention group and, at the end of the process, to the control group. The outcomes were evaluations of their knowledge and attitude vis-a-vis severe thalassemia prevention and control, and participating in thalassemia screening. Results: Among participants in the intervention group, 105 (84.7%) considered undergoing blood screening vs. 65 (55.6%) in the control group (p-value < 0.001). In the intervention group, the respective mean scores for knowledge and attitude to a prevention and control program for severe thalassemia before and after health education were 2.6 VS 6.5 (p-value < 0.001) and 4.6 VS 6.5 (p-value < 0.001). Conclusions: The intention to undergo screening was significantly higher in the intervention group than the control group. Knowledge and attitude towards prevention and control of severe thalassemia was significantly improved in the intervention group. Health education clearly heightens awareness and improves consideration of screening for prevention and control of severe thalassemia. PMID- 29479430 TI - Not just fat: investigating the proteome of cetacean blubber tissue. AB - Mammalian adipose tissue is increasingly being recognized as an endocrine organ involved in the regulation of a number of metabolic processes and pathways. It responds to signals from different hormone systems and the central nervous system, and expresses a variety of protein factors with important paracrine and endocrine functions. This study presents a first step towards the systematic analysis of the protein content of cetacean adipose tissue, the blubber, in order to investigate the kinds of proteins present and their relative abundance. Full depth blubber subsamples were collected from dead-stranded harbour porpoises (Phocoena phocoena) (n = 21). Three total protein extraction methods were trialled, and the highest total protein yields with the lowest extraction variability were achieved using a RIPA cell lysis and extraction buffer based protocol. Extracted proteins were separated using 1D Sodium Dodecyl Sulphate Polyacrylamide Gel Electrophoresis (SDS-PAGE), and identified using nanoflow Liquid Chromatography Electrospray Ionization in tandem with Mass Spectrometry (nLC-ESI-MS/MS). A range of proteins were identified (n = 295) and classed into eight functional groups, the most abundant of which were involved in cell function and metabolism (45%), immune response and inflammation (15%) and lipid metabolism (11%). These proteins likely originate both from the various cell types within the blubber tissue itself, and from the circulation. They therefore have the potential to capture information on the cellular and physiological stresses experienced by individuals at the time of sampling. The importance of this proteomic approach is two-fold: Firstly, it could help to assign novel functions to marine mammal blubber in keeping with current understanding of the multi-functional role of adipose tissue in other mammals. Secondly, it could lead to the development of a suite of biomarkers to better monitor the physiological state and health of live individuals though remote blubber biopsy sampling. PMID- 29479429 TI - Impact of Anti-Biofouling Surface Coatings on the Properties of Nanomaterials and Their Biomedical Applications. AB - Understanding and subsequently controlling non-specific interactions between engineered nanomaterials and biological environment have become increasingly important for further developing and advancing nanotechnology for biomedical applications. Such non-specific interactions, also known as the biofouling effect, mainly associate with the adsorption of biomolecules (such as proteins, DNAs, RNAs, and peptides) onto the surface of nanomaterials and the adhesion or uptake of nanomaterials by various cells. By altering the surface properties of nanomaterials the biofouling effect can lead to in situ changes of physicochemical properties, pharmacokinetics, functions, and toxicity of nanomaterials. This review provides discussions on the current understanding of the biofouling effect, the factors that affect the non-specific interactions associated with biofouling, and the impact of the biofouling effect on the performances and functions of nanomaterials. An overview of the development and applications of various anti-biofouling coating materials to preserve and improve the properties and functions of engineered nanomaterials for intended biomedical applications is also provided. PMID- 29479431 TI - Biochemistry and hematology parameters of the San Cristobal Galapagos tortoise (Chelonoidis chathamensis). AB - As part of a planned introduction of captive Galapagos tortoises (Chelonoidis chathamensis) to the San Cristobal highland farms, our veterinary team performed thorough physical examinations and health assessments of 32 tortoises. Blood samples were collected for packed cell volume (PCV), total solids (TS), white blood cell count (WBC) differential, estimated WBC and a biochemistry panel including lactate. In some cases not all of the values were obtainable but most of the tortoises have full complements of results. Despite a small number of minor abnormalities this was a healthy group of mixed age and sex tortoises that had been maintained with appropriate husbandry. This work establishes part of a scientific and technical database to provide qualitative and quantitative information when establishing sustainable development strategies aimed at the conservation of Galapagos tortoises. PMID- 29479432 TI - Artificial light at night causes an unexpected increase in oxalate in developing male songbirds. AB - Artificial light at night (ALAN) is a widespread and increasing environmental pollutant with known negative impacts on animal physiology and development. Physiological effects could occur through sleep disruption and deprivation, but this is difficult to quantify, especially in small developing birds. Sleep loss can potentially be quantified by using oxalate, a biomarker for sleep debt in adult humans and rats. We examined the effect of ALAN on oxalate in free-living developing great tits (Parus major) as effects during early-life could have long lasting and irreversible consequences. Nestlings' physiology was quantified at baseline (= 13 days after hatching) and again after two nights of continued darkness (control) or exposure to ALAN (treatment). We found that ALAN increased oxalate levels but only in male nestlings, rather than decreasing it as was found in sleep-deprived humans and rats. Our results using developing birds differ strongly from those obtained with adult mammals. However, we used ALAN to reduce sleep while in rats forced movement was used. Finally, we used free-living opposed to laboratory animals. Whether oxalate is a reliable marker of sleep loss in developing great tits remains to be examined. Potentially the increase of oxalate in male nestlings was unrelated to sleep debt. Nonetheless, our results substantiate physiological effects of ALAN in developing animals and may provide a foundation for future work with free-living animals. PMID- 29479434 TI - Life's not a cinch for a stressed finch, or is it? PMID- 29479433 TI - Blood analytes of oceanic-juvenile loggerhead sea turtles (Caretta caretta) from Azorean waters: reference intervals, size-relevant correlations and comparisons to neritic loggerheads from western Atlantic coastal waters. AB - Blood analyte reference intervals are scarce for immature life stages of the loggerhead sea turtle (Caretta caretta). The objectives of this study were to (1) document reference intervals of packed cell volume (PCV) and 20 plasma chemistry analytes from wild oceanic-juvenile stage loggerhead turtles from Azorean waters, (2) investigate correlations with body size (minimum straight carapace length: SCLmin) and (3) compare plasma chemistry data to those from older, larger neritic juveniles (<80 cm SCLmin) and adult loggerheads (>=80 cm SCLmin) that have recruited to the West Atlantic in waters around Cape Canaveral, Florida. Twenty eight Azorean loggerhead turtles with SCLmin of 17.6-60.0 cm (mean 34.9 +/- 12.1 cm) were captured, sampled and immediately released. Reference intervals are reported. There were several biologically relevant correlations of blood analytes with SCLmin: positive correlations of PCV, proteins and triglycerides with SCLmin indicated somatic growth, increasing diving activity and/or diet; negative correlations of tissue enzymes with SCLmin suggested faster growth at smaller turtle size, while negative correlations of electrolytes with SCLmin indicated differences in diet, environmental conditions and/or osmoregulation unique to the geographic location. Comparisons of loggerhead turtles from the Azores (i.e. oceanic) and Cape Canaveral (i.e. neritic) identified significant differences regarding diet, somatic growth, and/or environment: in Azorean turtles, albumin, triglycerides and bilirubin increased with SCLmin, while alkaline phosphatase, lactate dehydrogenase and sodium decreased. In larger neritic Cape Canaveral turtles, aspartate aminotransferase increased with SCLmin, while the albumin:globulin ratio, phosphorus and cholesterol decreased. These differences suggest unique physiological disparities between life stage development and migration, reflecting biological and habitat differences between the two populations. This information presents biologically important data that is applicable to stranded individual turtles and to the population level, a tool for the development of conservation strategies, and a baseline for future temporal and spatial investigations of the Azorean loggerhead sea turtle population. PMID- 29479435 TI - A novel method for the measurement of glucocorticoids in dermal secretions of amphibians. AB - Amphibians have been declining in both diversity and abundance due in large part to habitat degradation and the prevalence of emerging diseases. Although stressors can suppress the immune system, affecting an individual's health and susceptibility to pathogens, established methods for directly collecting stress hormones are not suitable for rapid field use or for use on threatened and endangered species. To overcome these challenges, we are developing an innovative method to collect and measure amphibian glucocorticoid secretions using non invasive dermal swabs. We tested this methodology using multiple terrestrial, semi-aquatic and fully aquatic species. We swabbed the dorsal side of each animal six times and then induced a stressor of either hand-restraint, ACTH injection, or saline as a control. We then repeated swab collection immediately after the stressor and at 15, 30, 45, 60, 90 and 120 min intervals. Cortisol enzyme immunoassay detected changes in cortisol post-stressor. We also tested this methodology in the field and were successfully able to detect glucocorticoids from multiple species at varying life stages. When using in the field, capture technique should be considered since it may impact stress levels in certain species. Upon further testing, this novel method may be used to greatly increase our understanding of amphibian health especially as disease and environmental changes continue to impact fragile populations. PMID- 29479436 TI - ZnO nanoparticle preparation route influences surface reactivity, dissolution and cytotoxicity. AB - ZnO nanoparticles (nZnO) are commonly used in nanotechnology applications despite their demonstrated cytotoxicity against multiple cell types. This underscores the significant need to determine the physicochemical properties that influence nZnO cytotoxicity. In this study, we analyzed six similarly sized nZnO formulations, along with SiO2-coated nZnO, bulk ZnO and ZnSO4 as controls. Four of the nZnO samples were synthesized using various wet chemical methods, while three employed high-temperature flame spray pyrolysis (FSP) techniques. X-ray diffraction and optical analysis demonstrated the lattice parameters and electron band gap of the seven nZnO formulations were similar. However, electrophoretic mobility measures, hydrodynamic size, photocatalytic rate constants, dissolution potential, reactive oxygen species (ROS) production and, more importantly, the cytotoxicity of the variously synthesized nZnO towards Jurkat leukemic and primary CD4+ T cells displayed major differences. Surface structure analysis using FTIR, X-ray photoelectron spectroscopies (XPS) and dynamic light scattering (DLS) revealed significant differences in the surface-bound chemical groups and the agglomeration tendencies of the samples. The wet chemical nZnO, with higher cationic surface charge, faster photocatalytic rates, increased extracellular dissolution and ROS generation demonstrated greater cytotoxicity towards both cell types than those made with FSP techniques. Furthermore, principal component analysis (PCA) suggests that the synthesis procedure employed influences which physicochemical properties contribute more to the cytotoxic response. These results suggest that the synthesis approach results in unique surface chemistries and can be a determinant of cellular cytotoxicity and oxidative stress responses. PMID- 29479438 TI - Interventions to improve physical function and prevent adverse events in cirrhosis. AB - Cirrhosis is associated with debilitating complications that significantly impact on a patient's physical function and reduce quality of life. Owing to highly prevalent sarcopenia, malnutrition and hepatic encephalopathy, functional impairment or frailty is a common complication of cirrhosis. Frailty in turn increases the patient's risk of hospitalization, accidental falls and fractures, and death. The management of frailty and its associated adverse effects is imperative in improving the overall prognosis of patients with advanced liver disease. The cornerstone of therapy revolves around optimizing physical function with appropriate nutrition and exercise. Nutritional therapy with protein supplementation has shown significant benefit, while studies on exercise have been controversial. However, newly emerging studies trend towards a beneficial effect of physical exercise with improvement in quality of life. The implementation of technology in liver disease management shows future promise. Fitbits and other wearable devices can be used to help monitor a patient's personal progress in physical exercise and nutritional optimization. Additionally, the progressive development of new smartphone applications to help aid in the diagnosis and monitoring of complications of cirrhosis provides a sophisticated avenue for improving care of patients with cirrhosis. PMID- 29479437 TI - Dysbiosis of gut microbiota in promoting the development of colorectal cancer. AB - Gastrointestinal microbiome, containing at least 100 trillion bacteria, resides in the mucosal surface of human intestine. Recent studies show that perturbations in the microbiota may influence physiology and link to a number of diseases, including colon tumorigenesis. Colorectal cancer (CRC), the third most common cancer, is the disease resulting from multi-genes and multi-factors, but the mechanistic details between gut microenvironment and CRC remain poorly characterized. Thanks to new technologies such as metagenome sequencing, progress in large-scale analysis of the genetic and metabolic profile of gut microbial has been possible, which has facilitated studies about microbiota composition, taxonomic alterations and host interactions. Different bacterial species and their metabolites play critical roles in the development of CRC. Also, microbiota is important in the inflammatory response and immune processes deregulation during the development and progression of CRC. This review summarizes current studies regarding the association between gastrointestinal microbiota and the development of CRC, which provides insights into the therapeutic strategy of CRC. PMID- 29479440 TI - Liver-inclusive intestinal transplantation results in decreased alloimmune mediated rejection but increased infection. AB - Background and aims: A co-transplanted liver allograft has been thought to protect other organs from rejection-mediated injury; however, detailed analyses of co-transplanted liver on intestinal allograft outcomes have not been conducted to date. The aim of the study was to compare immune-mediated injury, causes of graft failure and clinical outcomes between recipients who underwent either a liver-inclusive intestinal transplant (LITx) or liver-exclusive intestinal transplant (LETx). Methods: Between May 2000 and May 2010, 212 adult patients undergoing LITx (n =76) and LETx (n =136) were included. LITx underwent either liver combined intestinal or full multivisceral transplantation. LETx underwent either isolated intestinal or modified multivisceral transplantation. Results: During 44.9 +/- 31.4 months of follow-up, death-censored intestinal graft survival was significantly higher for LITx than LETx (96.9%, 93.2% and 89.9% vs 91.4%, 69.3% and 60.0% at 1, 3 and 5 years; p =0.0001). Incidence of graft loss due to rejection was higher in LETx than in LITx (30.9% vs 6.6%; p <0.0001), while infection was the leading cause of graft loss due to patient death in LITx (25.0% vs 5.1%; p <0.0001). Despite similar immunosuppression, the average number (0.87 vs 1.42, p =0.02) and severity of acute cellular rejection episode (severe grade: 7.9% vs 21.3%; p =0.01) were lower in LITx than in LETx. Incidence of acute antibody-mediated rejection was also significantly lower in LITx than in LETx (3.6% vs 15.2%; p =0.03). Incidence of chronic rejection was reduced in LITx (3.9% vs 24.3%; p =0.0002). Conclusions: Intestinal allografts with a liver component appear to decrease risk of rejection but increase risk of infection. Our findings emphasize that LITx has characteristic immunologic and clinical features. Lower immunosuppression may need to be considered for patients who undergo LITx to attenuate increased risk of infection. PMID- 29479441 TI - Ulcerative Colitis Endoscopic Index of Severity (UCEIS) versus Mayo Endoscopic Score (MES) in guiding the need for colectomy in patients with acute severe colitis. AB - Background: The Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and the Mayo Endoscopic Score (MES) were developed as an objective method of the endoscopic severity in ulcerative colitis (UC); however, it was still unclear whether UCEIS vs MES could guide the need for colectomy in acute severe colitis (ASC). Methods: Consecutive ASC patients between January 2012 and May 2016 were retrospectively evaluated. Demographic data, previous therapy, clinical observations, laboratory parameters, medical therapy and endoscopic assessments were documented. The primary outcome was the need for colectomy during admission and follow-up. Results: Ninety-two patients were enrolled. 37 (40.2%) needed colectomy. UCEIS score is a predictor of requirement for colectomy in multivariate analysis (OR, 3.25; 95% CI, 1.77-5.97; P < 0.001). Receiver-operator characteristic (ROC) area of UCEIS is 0.85, with a sensitivity of 60.3% and specificity of 85.5% using cut-off value of 7, which outperforms MES with the ROC area of 0.65; When UCEIS score >=7, 80% of patients eventually need colectomy. Conclusion: UCEIS outperformed MES as a predictor for need for colectomy in ASC patients. The high probability of medical treatment failure and benefits of early colectomy should be discussed in patients with baseline UCEIS >= 7.Acute severe colitis; colectomy; Ulcerative Colitis Endoscopic Index of Severity; Mayo Endoscopic Score. PMID- 29479439 TI - Treatment of recurrent Clostridium difficile colitis: a narrative review. AB - Clostridium difficile is a gram-positive, spore-forming, obligate anaerobic bacillus that was originally isolated from the stool of a healthy neonate in 1935. In high-income countries, C. difficile is the most common cause of infectious diarrhoea in hospitalized patients. The incidence of C. difficile infection in the USA has increased markedly since 2000, with hospitalizations for C. difficile infections in non-pregnant adults doubling between 2000 and 2010. Between 20% and 35% of patients with C. difficile infection will fail initial antibiotic treatment and, of these, 40-60% will have a second recurrence. Recurrence of C. difficile infection after initial treatment causes substantial morbidity and is a major burden on health care systems. In this article, current treatments for recurrent C. difficile infection are reviewed and future directions explored. These include the use of antibiotics, probiotics, donor faecal transplants, anion resins, secondary bile acids or anti-toxin antibodies. PMID- 29479442 TI - The efficacy of rapid on-site evaluation during endoscopic ultrasound-guided fine needle aspiration of pancreatic masses. AB - Background: Endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) has become the preferred method to diagnose pancreatic masses due to its minimally invasive approach and diagnostic accuracy. Many studies have shown that rapid on site evaluation (ROSE) improves diagnostic yield by 10-30%; however, more recent studies have demonstrated effective diagnostic accuracy rates without ROSE. Our study aims to examine whether the current standard of performing ROSE after each FNA pass adds diagnostic value during EUS-guided FNA of pancreatic masses. Methods: We conducted a retrospective case series on patients who underwent EUS guided FNA of pancreatic masses between February 2011 and October 2014. All cases were performed by one of three endoscopists at Emory University Hospital. Patient demographics, radiologic details of pancreatic masses and pathology reports of the biopsied pancreatic masses were examined. Results: A total of 184 procedures performed in 171 patients were reviewed. The final pathology reports of the biopsied pancreatic masses showed 128 (70%) with confirmed malignancy. Only 64 (50%) of these 128 cases initially showed malignant cells during ROSE. Among these 64 cases, 23% required 5 or more FNA passes to first detect malignant cells. Conclusions: The use of ROSE during EUS-guided FNA of pancreatic masses may increase the diagnostic yield, since malignant cells were often detected during later FNA passes that would otherwise be missed if tissue sampling stopped prematurely. In addition, sample preparation for ROSE may be suboptimal, since malignant cells were only detected in 50% of cases. PMID- 29479444 TI - Comparative analysis of different hepatico-jejunostomy techniques for treating adult type I choledochal cyst. AB - Objective: To compare Roux-en-Y hepatico-jejunostomy with complete resection of the cyst or incomplete resection with 1-cm remnant proximal cyst wall in treating adult type I choledochal cyst (CC). Methods: The medical records of 267 adult patients with type I CC from January 1998 to December 2015 were reviewed retrospectively. Among them, 171 underwent Roux-en-Y hepatico-jejunostomy with complete resection (PBD 0-cm group) and 96 underwent Roux-en-Y hepatico jejunostomy with 1-cm proximal cyst wall left (PBD 1-cm group). The short- and long-term post-operative complications were compared between the two groups. Results: No significant difference was observed in operative time or anastomotic diameter between the two groups. The incidence of perioperative complications was significantly higher in the PBD 1-cm group than that in the PBD 0-cm group (28.1% vs 14.0%, p=0.005), especially post-operative cholangitis (7.3% vs 1.2%, p=0.021). The incidence of long-term post-operative complications was not significantly different, including anastomotic stricture, reflux cholangitis, intra-hepatic bile duct stones and bile leak (all p >0.05). Post-operative intra pancreatic biliary malignancy occurred in one patient in the PBD 0-cm group at 25 months and one patient in the PBD 1-cm group at 5 month, respectively. Anatomical site malignancy was observed in one patient in the PBD 1-cm group at 10 months. Conclusion: Ease of performing anastomosis does not justify retaining a segment of choledochal cyst in type I CC due to its higher risk of post-operative complication and malignancy. A complete excision of the CC with anastomosis to the healthy proximal bile duct is necessary in treatment of type I CC. PMID- 29479443 TI - Effects of lifestyle modification on liver enzyme and Fibroscan in Indian patients with non-alcoholic fatty liver disease. AB - Background and aims: Non-alcoholic fatty liver disease (NAFLD) is remarkably increasing in developing countries like India, in parallel with the increasing incidence of obesity. Lifestyle modification is a recommended treatment for NAFLD. In most of the previous studies, improvement after lifestyle modification was assessed by liver fibrosis through liver biopsy, but we cannot do a serial liver biopsy in every NAFLD patient. Liver fibrosis can also be assessed by fibroscan non-invasively in NAFLD. This study was designed to evaluate the effect of lifestyle modification on liver enzymes and Fibroscan values in a population with NAFLD. Methods: Initially, 50 NAFLD patients were included in this prospective follow-up study; however, after 6 months of lifestyle modification, only 39 participants were studied. During both the first and second consultations, Fibroscan was carried out. All participants underwent a careful interview, anthropometry measurements and radiological and biochemical tests during every consultation. Results: After 6 months of lifestyle modification, Fibroscan values improved significantly (8.31 +/- 0.11kPa vs 7.87 +/- 0.12kPa, p=0.009). Alanine aminotransferase (ALT) values also showed improvement during the second consultation (97.25 +/- 2.62 U/L vs 66.69 +/- 3.95 U/L, p <0.001). Conclusion: Measured by Fibroscan and liver enzymes, it has been found that lifestyle modification is an effective therapy to downgrade hepatic injury in NAFLD patients. Serial Fibroscan can be used to assess the treatment response in NAFLD patients due to its non-invasive nature. PMID- 29479445 TI - Variations in the medical treatment of inflammatory bowel disease among gastroenterologists. AB - Background and aims: With expanding available treatment options and evolving understanding of the risks and benefits of medical therapies for inflammatory bowel disease (IBD), there is the possibility of significant variations in treatment and outcomes. Little is known about the variation in treatment between IBD specialists and other gastroenterology (GI) physicians. Evaluating possible variations is an important first step to help address standardized care and optimize treatment. We studied the differences in use of biologics and immunomodulators in the management of IBD patients at a tertiary care hospital between IBD-trained physicians and other gastroenterologists. Methods: A total of 325 IBD patients were included in the analysis. Of these, 216 patients received care with an IBD physician and 109 had other GI/non-IBD physicians as their main caregivers. Results: The unadjusted use of immunomodulators (35.6% vs 16.5%, p = 0.001), biologics (45.8% vs 22.9%, p =0.001) and dual therapy (biologics and immunomodulator) (14.4% vs 3.7%, p =0.001) was significantly higher in the IBD physician group. These differences in therapy between the two groups remained after adjusting for patient and disease characteristics. Conclusion: There are significant variations in the treatment of patients with IBD by GI physicians. The use of biologics and immunomodulators is higher in GI physicians with dedicated IBD interest and training. PMID- 29479446 TI - Use of acetazolamide in lithium-induced nephrogenic diabetes insipidus: a case report. AB - : Lithium-induced nephrogenic diabetes insipidus (Li-NDI) is a rare and difficult to-treat condition. A study in mice and two recent papers describe the use of acetazolamide in Li-NDI in 7 patients (a case report and a 6 patient series). We describe the case of a 63-year-old woman with bipolar disorder treated with lithium and no previous history of diabetes insipidus. She was hospitalized due to a bowel obstruction and developed severe dehydration after surgery when she was water deprived. After desmopressin administration and unsuccessful thiazide and amiloride treatment, acetazolamide was administrated to control polyuria and hydroelectrolytic disorders without significant side effects. To our knowledge, this is the third publication on acetazolamide use in Li-NDI patients. Learning points: Treatment of lithium-induced nephrogenic diabetes insipidus might be challenging.Vasopressin, amiloride and thiazide diuretics have been used in lithium-induced nephrogenic diabetes insipidus treatment.Acetazolamide might be an option to treat lithium-induced nephrogenic diabetes insipidus patients who fail to respond to standard treatment.The use of acetazolamide in lithium-induced nephrogenic diabetes insipidus must be monitored, including its effects on glomerular filtration rate. PMID- 29479447 TI - Severe bilateral adrenal hemorrhages in a newborn complicated by persistent adrenal insufficiency. AB - : Bilateral adrenal hemorrhages rarely occur during the neonatal period and are often associated with traumatic vaginal deliveries. However, the adrenal gland has highly regenerative capabilities and adrenal insufficiency typically resolves over time. We evaluated a newborn female after experiencing fetal macrosomia and a traumatic vaginal delivery. She developed acidosis and acute renal injury. Large adrenal hemorrhages were noted bilaterally on ultrasound, and she was diagnosed with adrenal insufficiency based on characteristic electrolyte changes and a low cortisol (4.2 ug/dL). On follow-up testing, this patient was unable to be weaned off of hydrocortisone or fludrocortisone despite resolution of hemorrhages on ultrasound. Providers should consider bilateral adrenal hemorrhage when evaluating critically ill neonates after a traumatic delivery. In extreme cases, this may be a persistent process. Learning points: Risk factors for adrenal hemorrhage include fetal macrosomia, traumatic vaginal delivery and critical acidemia.Signs of adrenal hemorrhage include jaundice, flank mass, skin discoloration or scrotal hematoma.Adrenal insufficiency often is a transient process when related to adrenal hemorrhage.Severe adrenal hemorrhages can occur in the absence of symptoms.Though rare, persistent adrenal insufficiency may occur in extremely severe cases of bilateral adrenal hemorrhage.Consider adrenal hemorrhage when evaluating a neonate for shock in the absence of an infectious etiology. PMID- 29479448 TI - A case of allergic bronchopulmonary aspergillosis in a 43-year-old farmer following single high level exposure to organic dust with symptomatic remission and radiological resolution after early diagnosis and treatment. AB - Allergic bronchopulmonary aspergillosis (ABPA) is an uncommon lung condition associated with development or worsening of asthma symptoms, distinctive radiological and serological findings. It is thought to be the consequence of chronic colonization of the airways in individuals with pre-existing atopic conditions. We present a case unique in the literature of the development of ABPA in an individual without pre-existing atopic disease following a single high level exposure to organic dust. Early treatment was associated with complete symptomatic remission and significant resolution of bronchiectatic changes. PMID- 29479449 TI - Meckel Gruber syndrome associated with anencephaly-an unusual reported case. AB - Meckel-Gruber syndrome (MGS) is a rare and lethal ciliopathic disorder, with the incidence ranging between 1 in 13 000-400 000 live births. MGS is characterized by multisystem developmental malformations with the classical features of renal cystic dysplasia, occipital encephalocele and post-axial polydactyly. Except for occipital encephalocele, the CNS abnormalities associated with MGS that are less frequently reported include hydrocephaly, anencephaly or malformation of cerebellum. Our presented case of MGS is associated with anencephaly and other facial abnormalities. This kind of ailment is infrequently reported in literature. PMID- 29479450 TI - Fournier gangrene: a rare case of necrotizing fasciitis of the entire right hemi pelvis in a diabetic female. AB - Fournier's gangrene, a rare polymicrobial infection that affects the genitals and perineum, can present as an insidious onset to a rapid and fulminant course. Early recognition, diagnosis, initiation of broad-spectrum antibiotics and prompt surgical treatment remain the foundation of management. If treatment is not initiated aggressively, the patient will likely rapidly deteriorate, leading to organ failure and death. We present the case of a 58-year-old diabetic female presenting febrile, hypoxic, with severe respiratory distress and evidence of septic shock, found to have necrotizing fasciitis of the entire right hemi pelvis. Despite rapid recognition, IV antibiotics and operative management, the patient went to the intensive-care unit on multiple pressors and died 24 h later. PMID- 29479451 TI - An unexpected diagnosis in a patient with new-onset pulmonary infiltrates during adjuvant therapy for breast cancer. AB - The differential diagnosis of new-onset pulmonary infiltrates during adjuvant therapy in a cancer patient is challenging. Opportunistic infections, pulmonary drug-induced toxicity and metastatic dissemination of the underlying cancer are the most common causes. However, although infrequent, the development of a second primary pulmonary neoplasia should be taken into account. We present the clinical case of a breast cancer patient who developed progressive pulmonary infiltrates during adjuvant therapy, who was finally diagnosed as having a second lung neoplasm of unexpected histology. PMID- 29479452 TI - Fertility preservation in primary brain tumor patients. AB - Background: Fertility preservation (FP) is an infrequently addressed issue for young adults with primary brain tumors. Given the improved prognosis and enhanced technology in reproductive medicine, more primary brain tumor patients see procreation as feasible, making the discussion of FP increasingly important. The goals of this study were to describe patients who received FP counseling by a fertility nurse specialist (FNS) and determine which sociodemographic and disease related factors predict acceptance of referral to a reproductive specialist. Methods: Institutional review board-approved retrospective review of primary brain tumor patients, ages 18 to 45, who were referred for FP counseling with a FNS from 2009 to 2013. Results: Seventy patients were referred for FP counseling: 38 men, 32 women, with a median age of 32 years and median KPS of 90. Eighty-nine percent had gliomas; 58% grade III, 17% grade IV. Sixty-seven percent were referred for counseling at initial diagnosis. Of those referred, 73% accepted referral to a sperm bank (87% of men) or reproductive endocrinologist (56% of women). Patients were more likely to accept referral if they had no prior children (P = .048). There was no statistically significant difference in referral acceptance by age, race/ethnicity, marital status, religion, or tumor grade. After treatment, 3 men conceived naturally, 2 men conceived using banked sperm, and 2 women conceived naturally. Conclusions: Despite the historically poor prognosis of patients with primary brain tumors, there is significant interest in FP among these patients, particularly if they have no prior children. Clinicians should develop strategies to incorporate FP counseling into practice. PMID- 29479454 TI - Serum nitric oxide levels in healthy pregnant women: a case- control study in a tertiary facility in Ghana. AB - Background: Pregnancy is associated with significant changes in maternal cardiovascular system which regulates oxygen and nutrient supply to the growing foetus. Nitric oxide, a physiologic vascular smooth muscle relaxant regulates blood flow and therefore may play a role in the cardiovascular changes in pregnancy. The study aimed to determine the levels and changes in maternal serum nitric oxide levels during healthy pregnancy. Methods: A case-control study was conducted among 32 healthy non-pregnant women as controls and 100 healthy pregnant women (consisting of 33 first trimester, 37 s trimester, and 30 third trimester) as cases. Subjects were consecutively recruited into the study after obtaining an informed consent and meeting the inclusion criteria. Griess Reagent method was used to determine serum nitric oxide levels. Results: There were no statistically significant difference in the ages and parity of recruited cases and controls. Mean arterial blood pressures were significantly lower (p = 0.009) and serum nitric oxide levels were significantly higher (p < 0.001) in healthy pregnant women compared to healthy non-pregnant women. There was a non significant progressive increase in serum nitric oxide levels during healthy normal pregnancy. Conclusions: The finding of a significantly reduced blood pressures and a significant increase in serum nitric oxide levels in healthy pregnancy may suggest a role of nitric oxide in vascular adaptation in pregnancy. PMID- 29479455 TI - Nutrient production from Korean poultry and loading estimations for cropland. AB - Background: Poultry breeding has increased by 306% in Korea, inevitably increasing the production of manure which may contribute to environmental pollution. The nutrients (NP) in the manure are essential for crop cultivation and soil fertility when applied as compost. Excess nutrients from manure can be accumulated on the land and can lead to eutrophication. Therefore, a nutrient load on the finite land should be calculated. Methods: This study calculates the nutrient production from Korean poultry by investigating 11 broiler and 16 laying hen farms. The broiler manure was composted using deep litter composting while for layer deep litter composting, drying, and simple static pile were in practice. The effect of weight reduction and storing period during composting was checked. Three weight reduction cases of compost were constructed to calculate nutrient loading coefficients (NLCs) using data from; i) farm investigation, ii) theoretical P changes (DeltaP = 0), and iii) dry basis. Results: During farm investigation of broiler and layer with deep litter composting, there was a 68 and 21% N loss whereas 77 and 33% P loss was found, respectively. In case of layer composting, a loss of 10-56% N and a 52% P loss was observed. Drying manure increased the P concentrations therefore NLCs calculated using dry basis that showed quite higher reductions (67% N; 53% P). Nutrient loss from farm investigation was much higher than reported by Korean Ministry of Environment (ME). Conclusions: Nutrients in manure are decreased when undergo storing or composting process due to microbial action, drying, and leaching. The nutrient load applied to soil is less than the fresh manure, hence the livestock manure management and conservation of environment would be facilitated. PMID- 29479453 TI - Practice Patterns in the Treatment and Monitoring of Acute T Cell-Mediated Kidney Graft Rejection in Canada. AB - Background: One of the goals of the Canadian National Transplant Research Program (CNTRP) is to develop novel therapies for acute rejection that could positively affect graft outcomes with greater efficacy or less toxicity. To develop innovative management strategies for kidney graft rejection, new modalities need to be compared with current clinical practices. However, there are no standardized practices concerning the management of acute T cell-mediated rejection (TCMR). Objectives: To describe clinicians' practice patterns in the diagnosis, treatment, and monitoring of acute TCMR in Canada. Design: Survey. Setting Patients/Participants: Canadian transplant nephrologists and transplant surgeons involved in the management of acute TCMR. Methods and Measurements: We developed an anonymous, web-based survey consisting of questions related to the diagnosis, treatment, and monitoring of TCMR. The survey was disseminated on 3 occasions between June and October 2016 through the Canadian Society of Transplantation (CST) kidney group electronic mailing list. Results: Forty-seven respondents, mostly transplant nephrologists (97%), originating from at least 18 of the 25 Canadian centers offering adult or pediatric kidney transplantation, participated in the study. Surveillance biopsies were used by 28% of respondents to screen for kidney graft rejection. High-dose steroids were used by most of the respondents to treat clinical and subclinical Banff grade 1A and 1B rejections. Nine percent (95% confidence interval [CI]: 1-17) of practitioners used lymphocyte-depleting agents as the first-line approach for the treatment of Banff grade 1B acute rejection. Eighteen percent (95% CI: 7-29) and 36% (95% CI: 8-65) of respondents reported that they would not use high-dose steroids for treating clinical and subclinical borderline rejections, respectively. Seventy percent (95% CI: 54-83) of respondents answered that there was no indication to assess histological response to treatment independent of the change in kidney function. Limitations: The limitations of this study are its limited sample size and the low representation of pediatric specialists. Conclusions: There is heterogeneity regarding the use of surveillance biopsies, treatment of borderline rejection, and modalities to monitor treatment response among transplant physicians. Our results illustrate the current state of practice patterns across Canada and can be used to inform the design of future trials. PMID- 29479456 TI - Inverted items and validity: A psychobiological evaluation of two measures of psychological resources and one depression scale. AB - Psychological resources and risk factors influence risk of coronary heart disease. We evaluated whether inverted items in the Self-esteem, Mastery, and Center for Epidemiological Studies Depression scales compromise validity in the context of coronary heart disease. In a population-based sample, validity was investigated by calculating correlations with other scales (n = 1004) and interleukin-6 (n = 374), and by analyzing the relationship with 8-year coronary heart disease risk (n = 1000). Negative items did not affect the validity of the resource scales. In contrast, positive items from Center for Epidemiological Studies Depression showed no significant relationships with biological variables. However, they had no major impact on the validity of the original scale. PMID- 29479458 TI - Editorial. PMID- 29479457 TI - A randomized study to evaluate the effect of exercise on fatigue in people with relapsing-remitting multiple sclerosis treated with fingolimod. AB - Background: Fatigue is a major symptom of multiple sclerosis (MS) in patients, and it has been shown to improve with physical exercise. Although fingolimod might lessen fatigue, it is unclear how patients treated with fingolimod react to physical activity regarding fatigue. Objective: This study evaluated the effect of an exercise intervention on fatigue in relapsing-remitting MS patients receiving fingolimod. Methods: People with MS (PwMS) were randomized to either a structured internet-based exercise program (e-training) or no e-training intervention. The primary endpoint was the change in the Modified Fatigue Impact Scale (mFIS) after six months. Results: The primary analysis showed no statistically significant difference between groups in the mFIS change. Subgroup analyses revealed a beneficial effect of physical exercise for PwMS with low aerobic capacity and with low aerobic capacity plus more severe fatigue. The incidence of adverse events was similar in both groups. No cardiovascular events were reported. The majority of PwMS were relapse free. Conclusion: Physical exercise benefits on fatigue may depend on the physical capacity of the patient and requires individualized training. Consistent with previous studies, these results suggest that physical exercise generally does not impose a risk and that this holds true also for patients receiving fingolimod.Trial registration: ClinicalTrials.gov, NCT01490840. PMID- 29479459 TI - Media framing and construction of childhood obesity: a content analysis of Swedish newspapers. AB - Objective: Despite lower prevalence than most European countries, childhood obesity is a Swedish public health priority due to its lasting health impacts and socioeconomic patterning. Mass media content influences public and political perceptions of health issues, and media framing of childhood obesity may influence perceptions of its solutions. This study examines framing of childhood obesity in Swedish morning and evening newspapers from 1996 to 2014. Methods: Content analysis of 726 articles about childhood obesity published in the five most-circulated Swedish newspapers. Article content coded quantitatively and subjected to statistical analysis, describing relationships between themes and trends over time. Results: Childhood obesity was consistently problematised, primarily in health terms, and linked to socio-economic and geographical factors. The yearly frequency of articles peaked in 2004, followed by a decline, corresponding with evidence about prevalence. Childhood obesity was framed as being driven by individual behaviours more frequently than structural or environmental factors. Structural framings increased over time, but constructions of the problem as driven by individual behaviours, particularly parenting, remained prominent. Conclusions: A relative growth in structural framings of causes and solutions over time, combined with prominent coverage of socio economic inequalities, might be indicative of public and political amenability towards societal-level solutions, but individual behaviours remain prominent in framing of the issue. Health advocates might incorporate these insights into media engagement. PMID- 29479460 TI - A new method to visualize obesity prevalence in Seattle-King County at the census block level. AB - Objective: The aim of this study is to map obesity prevalence in Seattle King County at the census block level. Methods: Data for 1,632 adult men and women came from the Seattle Obesity Study I. Demographic, socioeconomic and anthropometric data were collected via telephone survey. Home addresses were geocoded, and tax parcel residential property values were obtained from the King County tax assessor. Multiple logistic regression tested associations between house prices and obesity rates. House prices aggregated to census blocks and split into deciles were used to generate obesity heat maps. Results: Deciles of property values for Seattle Obesity Study participants corresponded to county wide deciles. Low residential property values were associated with high obesity rates (odds ratio, OR: 0.36; 95% confidence interval, CI [0.25, 0.51] in tertile 3 vs. tertile 1), adjusting for age, gender, race, home ownership, education, and incomes. Heat maps of obesity by census block captured differences by geographic area. Conclusion: Residential property values, an objective measure of individual and area socioeconomic status, are a useful tool for visualizing socioeconomic disparities in diet quality and health. PMID- 29479461 TI - Early predictors of weight loss in a 1-year behavioural weight-loss programme. AB - Objective: Identifying early predictors of weight loss is key for developing personalized treatment. However, few individual factors have been identified that predict weight loss during intervention, other than early weight loss itself. Methods: Women with overweight or obesity (n = 186, mean +/- SD age 50.0 +/- 10.6 years, body mass index 34.0 +/- 4.2 kg m-2) participated in the Portion-Control Strategies Trial, a 1-year randomized controlled weight-loss trial with three intervention groups. Early changes in eating behaviours and psychological factors were evaluated by questionnaires at baseline and Month 1. The influence of these early changes on the trajectory of weight loss from baseline to Months 3 and 12 was assessed by random coefficients models. Results: Although there were no differences in weight loss between intervention groups at the end of the trial, certain individual factors were shown to predict both early weight loss at Month 3 and longer-term weight loss at Month 12. Across all participants, increases in dietary restraint and healthy lifestyle ratings in the first month predicted more rapid weight loss from baseline to Month 3 (P < 0.05) and also predicted more rapid weight loss and slower regain from baseline to Month 12 (both P < 0.01). Early attendance and changes in disinhibition were not associated with subsequent weight loss. Conclusions: Changes in psychological and behavioural measures, such as restraint, in the first month of weight loss intervention predicted longer term weight loss in women. Early additional support or tailored treatment could promote long-term success by reinforcing these behaviours. PMID- 29479462 TI - Visual body size norms and the under-detection of overweight and obesity. AB - Objectives: The weight status of men with overweight and obesity tends to be visually underestimated, but visual recognition of female overweight and obesity has not been formally examined. The aims of the present studies were to test whether people can accurately recognize both male and female overweight and obesity and to examine a visual norm-based explanation for why weight status is underestimated. Methods: The present studies examine whether both male and female overweight and obesity are visually underestimated (Study 1), whether body size norms predict when underestimation of weight status occurs (Study 2) and whether visual exposure to heavier body weights adjusts visual body size norms and results in underestimation of weight status (Study 3). Results: The weight status of men and women with overweight and obesity was consistently visually underestimated (Study 1). Body size norms predicted underestimation of weight status (Study 2) and in part explained why visual exposure to heavier body weights caused underestimation of overweight (Study 3). Conclusions: The under detection of overweight and obesity may have been in part caused by exposure to larger body sizes resulting in an upwards shift in the range of body sizes that are perceived as being visually 'normal'. PMID- 29479463 TI - Obesity and healthcare resource utilization: comparative results from the UK and the USA. AB - Objectives: To estimate the differences between individuals with and without obesity on healthcare resource utilization using two large electronic medical record databases. Methods: Data from the UK Clinical Practice Research Datalink and US General Electric Centricity database of adults (>=18 years) with registration date before 01/01/2010. Differences between individuals with and without obesity on 5-year rates of Primary Care Physician (PCP) contacts, prescriptions and hospitalizations were analysed. Results: The study contained 1,878,017 UK and 4,414,883 US individuals. Compared with body mass index (BMI) (18.5-24.9 kg m-2), significant (p < 0.0001) increases in healthcare usage were observed with increasing BMI. Individuals with BMI 30-34.9 kg m-2 had higher PCP contact rate (rate ratios [RR] 1.27 and 1.28 for UK and USA, respectively), higher prescription rate (RR 1.61 and 1.51) and higher hospitalization rate (RR 1.10 and 1.13) than individuals with BMI 18.5-24.9 kg m-2. Individuals with BMI >40 kg m-2 also had higher PCP contact rate (RR 1.56 and 1.64), prescription rate (RR 2.48 and 2.14) and hospitalization rate (RR 1.27 and 1.30) than individuals with BMI 18.5-24.9 kg m-2. Conclusions: The utilization of healthcare resources is significantly higher in individuals with obesity. A similar trend was observed in both the UK and US cohorts. PMID- 29479465 TI - Efficacy and safety of an oral device to reduce food intake and promote weight loss. AB - Objective: Minimal risk weight loss tools are needed. This study's objective was to confirm Food and Drug Administration submissions of the SmartByteTM System's safety and efficacy. Methods: This 16-week, prospective, single-arm, four-centre, observational study assessed the oral device in combination with a video delivered lifestyle programme in adults aged 18-49 years with body mass index 27 to <35 kg m-2. Results: Seventy-six subjects received the device and video lifestyle instruction. The prespecified per protocol (PP) population (N = 40) required sensor-verified use of the device >=7 times per week for 14 of 16 weeks, overall device usage rate of >=33% and study completion. At week 16, 12 (30%) achieved >=5% weight loss, 16 (40%) achieved >=4% and 21 (52.5%) achieved >=3%. Week 16 mean loss for the PP population was 2.93%, and among 36 participants who did not meet PP criteria, it was 1.45%. Among 76 intent-to-treat subjects, two subjects reported three mild to moderate device-related adverse events, resolving spontaneously (one hard palate abrasion and two tongue lacerations). Conclusion: The System, a minimal risk tool, can help individuals achieve meaningful weight loss, when used with a lifestyle video. More frequent device use was associated with more weight loss, on average, and greater chance of achieving >=4% or >=5% weight loss. PMID- 29479464 TI - Evidence of a gap in understanding obesity among physicians. AB - Background: Experience suggests that some physicians view obesity as a purely lifestyle condition rather than a chronic metabolic disease. Physicians may not be aware of the role of biological factors in causing weight regain after an initial weight loss. Methods: A questionnaire was administered at continuing medical education conferences, both primary care and obesity-specific. The questionnaire included items about biological and behavioral factors that predispose to weight regain and general items about treatment of obesity. The sample was separated into primary care physicians (PCPs) and physicians preparing for the obesity medicine (OMs) exam. Results: Among all respondents, behavioral factors were given higher importance ratings, relative to biological factors in causing weight regain. Respondents rated behaviour modification as more effective, relative to medications or surgery to treat obesity. OMs gave higher importance ratings to biological factors, relative to PCPs. OMs also gave higher effectiveness ratings for medications and surgery, relative to PCPs. However, even OMs gave higher effectiveness ratings for behaviour modification, relative to medications or surgery. Respondents who reported a belief in the role of behavioral factors rated lifestyle modification as more effective. Respondents who reported a belief in both behavioral and biological factors rated medications as more effective. Conclusions: Physicians rate biological factors as less important, relative to behavioral factors in causing weight regain. Physicians rate medications and surgery as less effective, relative to lifestyle modification alone. Belief in the importance of behavioral factors correlated with a higher effectiveness rating for lifestyle modification. A better understanding of the biological basis for weight regain may help to increase comfort with the use of biological treatments for obesity. PMID- 29479466 TI - Together Eating & Activity Matters (TEAM): results of a pilot randomized-clinical trial of a spousal support weight loss intervention for Black men. AB - Objectives: The objective of this study is to evaluate the feasibility, participation, preliminary efficacy and retention in a couples-based weight loss intervention among Black men. Design setting participants: Two-arm pilot randomized clinical trial in an academic clinical setting. Forty self-identified Black men and their female cohabitating partners (n = 80) aged 18 to 65 years with body mass index from 25 to 45 kg/m2 were randomized using computer generated tables to allocate treatments. Intervention: Participants were randomized to a standard behavioural weight loss (Standard) programme or the Standard programme plus partner involvement (Enhanced). Both interventions focused on calorie reduction, physical activity and self-monitoring to facilitate weight loss. Enhanced included couples skills training and couple's communication components. Main outcome and measures: Changes in weight from baseline to 3 months among men. Partner weight loss (secondary). Results: Forty Black couples (men mean [SD] age, 47.4[11] years; body mass index, 35.0[6.1]), were recruited. Retention was 100% of the men and 98% of female partners. Attendance at group sessions was 63-73%. Between groups, mean (SD) weight changes among men were -3.4[.04] and -4.7[5.9] kg (p = 0.57) and among women -0.23[4.46] and -2.47[3.62] kg (p = 0.09), in the standard and enhanced groups. Conclusions: Weight losses from an intervention enhanced by partner involvement and an intervention with no partner involvement were not different. Treatment choice can be based on preference rather than outcome as both treatments are effective in producing clinically significant percent weight loss.Trial registration Clinical Trials NCT02458053. PMID- 29479467 TI - Patient-provider relationship and perceived provider weight bias among American Indians and Alaska Natives. AB - Objective: The objective of this study was to examine patient-provider relationships among American Indians and Alaska Native (AI/AN) patients by examining associations between patient activation, perceived provider weight bias and working alliance. Patient activation is generally defined as having the knowledge, skills and confidence to manage one's health. Methods: Among a sample of 87 AI/AN adults presenting for general medical care at an urban clinic in the north-west region of the USA, ordinary least squares regression analysis was completed to examine associations. Results: Better working alliance scores were associated with increased patient activation, while perceived provider weight bias was associated with reduced patient activation. In addition, those with class II obesity had decreased patient activation. Conclusion: These findings point to the importance of a positive patient-provider relationship in AI/ANs. Optimal patient engagement and subsequent health outcomes warrant additional consideration of patients' perceptions of provider weight bias within the context of health promotion and interventions. PMID- 29479468 TI - Association of interleukin-6 polymorphisms with obesity or metabolic traits in young Mexican-Americans. AB - Objective: The objective of the study is to investigate the association of interleukin-6 (IL6) promoter single-nucleotide polymorphisms rs1800797 (-597 G/A) and rs1800796 (-572 G/C) with obesity or metabolic syndrome in Mexican-Americans. Methods: The rs1800797 and rs1800796 single-nucleotide polymorphisms were genotyped in Mexican-Americans (n = 437) from South Texas, and results were correlated with measures of obesity and metabolic syndrome including body mass index, waist circumference, blood pressure, cholesterol, triglycerides, glucose, liver enzymes, plasma IL6 and high-sensitive C-reactive protein (hs-CRP). Results: Significant associations were found for the rs1800796 variant with increased waist circumference, insulin resistance, lower IL6 levels and higher hs CRP levels. The rs1800797 variant showed no associations with metabolic traits but was associated with higher IL6 levels and lower hs-CRP levels. Conclusions: Findings in this study support the anti-inflammatory, anti-obesity and glucose homeostatic roles of IL6 in Mexican-American youth. PMID- 29479469 TI - The relationship of waist circumference and body mass index to grey matter volume in community dwelling adults with mild obesity. AB - Objective: Previous work has shown that high body mass index (BMI) is associated with low grey matter volume. However, evidence on the relationship between waist circumference (WC) and brain volume is relatively scarce. Moreover, the influence of mild obesity (as indexed by WC and BMI) on brain volume remains unclear. This study explored the relationships between WC and BMI and grey matter volume in a large sample of Japanese adults. Methods: The participants were 792 community dwelling adults (523 men and 269 women). Brain magnetic resonance images were collected, and the correlation between WC or BMI and global grey matter volume were analysed. The relationships between WC or BMI and regional grey matter volume were also investigated using voxel-based morphometry. Results: Global grey matter volume was not correlated with WC or BMI. Voxel-based morphometry analysis revealed significant negative correlations between both WC and BMI and regional grey matter volume. The areas correlated with each index were more widespread in men than in women. In women, the total area of the regions significantly correlated with WC was slightly greater than that of the regions significantly correlated with BMI. Conclusions: Results show that both WC and BMI were inversely related to regional grey matter volume, even in Japanese adults with somewhat mild obesity. Especially in populations with less obesity, such as the female participants in current study, WC may be more sensitive than BMI as a marker of grey matter volume differences associated with obesity. PMID- 29479470 TI - Tools for studying growth patterns and chemical dynamics of aggregated Pseudomonas aeruginosa exposed to different electron acceptors in an alginate bead model. AB - In chronic infections, bacterial pathogens typically grow as small dense cell aggregates embedded in a matrix consisting of, e.g., wound bed sludge or lung mucus. Such biofilm growth mode exhibits extreme tolerance towards antibiotics and the immune defence system. The bacterial aggregates are exposed to physiological heterogeneity and O2 limitation due to steep chemical gradients through the matrix, which is are hypothesised to contribute to antibiotic tolerance. Using a novel combination of microsensor and bioimaging analysis, we investigated growth patterns and chemical dynamics of the pathogen Pseudomonas aeruginosa in an alginate bead model, which mimics growth in chronic infections better than traditional biofilm experiments in flow chambers. Growth patterns were strongly affected by electron acceptor availability and the presence of chemical gradients, where the combined presence of O2 and nitrate yielded highest bacterial growth by combined aerobic respiration and denitrification. PMID- 29479471 TI - The VOICE Study: Valuing Opinions, Individual Communication and Experience: building the evidence base for undertaking Patient-Centred Family Meetings in palliative care - a mixed methods study. AB - Background: Despite family meetings being widely used to facilitate discussion among patients, families, and clinicians in palliative care, there is limited evidence to support their use. This study aims to assess the acceptability and feasibility of Patient-Centred Family Meetings in specialist inpatient palliative care units for patients, families, and clinicians and determine the suitability and feasibility of validated outcome measures from the patient and family perspectives. Methods: The study is a mixed-methods quasi-experimental design with pre-planned Patient-Centred Family Meetings at the intervention site. The patient will set the meeting agenda a priori allowing an opportunity for their issues to be prioritised and addressed. At the control site, usual care will be maintained which may include a family meeting. Each site will recruit 20 dyads comprising a terminally ill inpatient and their nominated family member. Pre- and post-test administration of the Distress Thermometer, QUAL-EC, QUAL-E, and Patient Health Questionnaire-4 will assess patient and family distress and satisfaction with quality of life. Patient, family, and clinician interviews post meeting will provide insights into the meeting feasibility and outcome measures. Recruitment percentages and outcome measure completion will also inform feasibility.Descriptive statistics will summarise pre- and post-meeting data generated by the outcome measures. SPSS will analyse the quantitative data. Grounded theory will guide the qualitative data analysis. Discussion: This study will determine whether planned Patient-Centred Family Meetings are feasible and acceptable and assess the suitability and feasibility of the outcome measures. It will inform a future phase III randomised controlled trial. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN12616001083482 on 11 August 2016. PMID- 29479472 TI - Moderate use of alcohol is associated with lower levels of C reactive protein but not with less severe joint inflammation: a cross-sectional study in early RA and healthy volunteers. AB - Objectives: Moderate alcohol consumption is protective against rheumatoid arthritis (RA) development and associated with lower levels of systemic inflammation in RA and in the general population. We therefore hypothesised that moderate alcohol consumption is associated with less severe local inflammation in joints in RA, detected by MRI. Since asymptomatic persons can have low-grade MRI detected inflammation, we also hypothesised that alcohol consumption is associated with the extent of MRI inflammation in asymptomatic volunteers. Methods: 188 newly presenting patients with RA and 192 asymptomatic volunteers underwent a unilateral contrast-enhanced 1.5T MRI of metacarpophalangeal, wrist and metatarsophalangeal joints. The MRIs were scored on synovitis, bone marrow oedema and tenosynovitis; the sum of these yielded the MRI inflammation score. MRI data were evaluated in relation to current alcohol consumption, categorised as non-drinkers, consuming 1-7 drinks/week, 8-14 drinks/week and >14 drinks/week. Association between C reactive protein (CRP) level and alcohol was studied in 1070 newly presenting patients with RA. Results: Alcohol consumption was not associated with the severity of MRI-detected inflammation in hand and foot joints of patients with RA (P=0.55) and asymptomatic volunteers (P=0.33). A J-shaped curve was observed in the association between alcohol consumption and CRP level, with the lowest levels in patients consuming 1-7 drinks/week (P=0.037). Conclusion: Despite the fact that moderate alcohol consumption has been shown protective against RA, and our data confirm a J-shaped association of alcohol consumption with CRP levels in RA, alcohol was not associated with the severity of joint inflammation. The present data suggest that the pathophysiological mechanism underlying the effect of alcohol consists of a systemic effect that might not involve the joints. PMID- 29479473 TI - Response to baricitinib therapy in patients with rheumatoid arthritis with inadequate response to csDMARDs as a function of baseline characteristics. AB - Objective: We analysed the effects of baseline characteristics on the safety and efficacy of baricitinib in patients with rheumatoid arthritis (RA) with inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) from two phase III trials. Methods: In RA-BEAM (NCT01710358), patients with inadequate response to methotrexate were randomised to placebo, baricitinib 4 mg or adalimumab 40 mg. RA-BUILD (NCT01721057) patients had inadequate response to >=1 csDMARDs and were randomised to either placebo or once daily baricitinib (2 or 4 mg). Both study populations were naive to biologic DMARDs (bDMARDs). Primary end point for both studies was American College of Rheumatology 20% improvement (ACR20) response at week 12. Pooled data from the two trials were analysed post hoc based on select subgroups defined by age, previous csDMARD use, baseline RA disease activity, etc, with assessment of clinical and safety outcomes at week 12 and radiographic outcomes at week 24 for the baricitinib 4 mg and placebo-treated patients. Results: Efficacy was observed with baricitinib 4 mg treatment irrespective of patient demographics and baseline disease characteristics. ORs primarily favoured baricitinib over placebo in the ACR20 response. In other outcomes such as Disease Activity Score for 28 joints based on high-sensitivity C reactive protein levels, Simplified Disease Activity Index score <=11 and radiographic progression, baricitinib 4 mg showed better responses than placebo regardless of baseline characteristics. Safety events were more common in patients over 65 years, but similar between baricitinib 4 mg and placebo patients. Conclusion: Baseline characteristics did not substantially affect clinical response to baricitinib 4 mg in patients with RA with inadequate response to csDMARDs. PMID- 29479475 TI - Long-term persistence of TNF-inhibitor treatment in patients with psoriatic arthritis. Data from the British Society for Rheumatology Biologics Register. AB - Background: Long-term effectiveness of tumour necrosis factor alpha inhibitors (TNFi) has mainly been explored in patients with rheumatoid arthritis (RA) and the data available on patients with psoriatic arthritis (PsA) includes limited follow-up. Objective: Investigate long-term effectiveness of first TNFi in a PsA population by describing treatment persistence, identify factors associated with 5-year persistence and further investigate comparative long-term effectiveness of subsequent TNFi treatments through persistence to treatment. Methods: Patients with a rheumatologist diagnosis of PsA receiving their first TNFi registered in the British Society for Rheumatology Biologics Register (BSRBR) (2002-2006) were included. Treatment at different time points was described and factors associated with 5-year treatment persistence were identified by logistic regression. Kaplan Meier analysis was used to assess factors associated with persistence to first TNFi and subsequent TNFi treatments. Results: At 5 years, 46.7% of patients were still on their initial TNFi treatment. Better 5 -year persistence was associated with male gender, use of etanercept or adalimumab rather than infliximab and absence of baseline comorbidity. Five-year persistence estimates (95% CI) of first, second and third TNFi were 53% (49% to 57%), 60% (43% to 57%) and 48% (36% to 59%), respectively. Conclusion: We found good long-term persistence of TNFi in this PsA population both for the first and subsequent TNFi treatments. The relationship between persistence and relevant clinical factors was not strong and demonstrates the difficulties in predicting outcome of TNFi treatment in PsA. PMID- 29479474 TI - MRI for diagnosis of axial spondyloarthritis: major advance with critical limitations 'Not everything that glisters is gold (standard)'. AB - Recognition of axial spondyloarthritis (SpA) remains challenging, as no unique reference standard is available to ascertain diagnosis. Imaging procedures have been used for long in the field, in particular pelvic radiography, to capture structural changes evocative of sacroiliitis, the key feature in SpA. The introduction of MRI of the sacroiliac joints (SIJs) has led to a major shift in recognition of the disorder. MRI has been shown to detect the initial inflammatory processes, in particular osteitis depicted by bone marrow oedema, even in patients having not yet developed structural lesions. In addition, MRI has revealed a previously under-recognised very early clinical phase of the disease where patients have symptomatic axial involvement, but no structural changes. However, what constitutes a 'positive MRI' in SpA remains controversial, since both sensitivity and specificity show limitations, and interpretation of MRI lesions in daily practice is critically dependent on the clinical context. There is growing evidence that integration of the assessment of structural changes on dedicated T1 weighted-sequences on MRI may enhance diagnostic utility. The performance of MRI in detecting structural lesions in the SIJs may even be superior to traditional evaluation by pelvic radiography. These findings launched a debate on imaging in SpA, whether MRI, which is advancing early recognition of disease and shows superiority to detect structural changes, should replace traditional conventional radiography of the SIJs. PMID- 29479476 TI - The binding of DCC-P3 motif and FAK-FAT domain mediates the initial step of netrin-1/DCC signaling for axon attraction. AB - Netrin-1 plays a key role in axon guidance through binding to its receptor, Deleted in Colorectal Cancer (DCC). The initial step of signaling inside the cell after netrin-1/DCC ligation is the binding of DCC cytoplasmic P3 motif to focal adhesion targeting (FAT) domain of focal adhesion kinase (FAK). Here we report the crystal structure of P3/FAT complex. The helical P3 peptide interacts with a helix-swapped FAT dimer in a 2:2 ratio. Dimeric FAT binding is P3-specific and stabilized by a calcium ion. Biochemical studies showed that DCC-P3 motif and calcium ion could facilitate FAT dimerization in solution. Axon guidance assays confirm that the DCC/FAK complex is essential for netrin-1-induced chemoattraction. We propose that netrin-1/DCC engagement creates a small cluster of P3/FAT for FAK recruitment close to the cell membrane, which exerts a concerted effect with PIP2 for FAK signaling. We also compare P3/FAT binding with paxillin/FAT binding and discuss their distinct recognition specificity on a common FAT domain for axon attraction versus integrin signaling, respectively. PMID- 29479477 TI - Clinical testing of BRCA1 and BRCA2: a worldwide snapshot of technological practices. AB - Clinical testing of BRCA1 and BRCA2 began over 20 years ago. With the expiration and overturning of the BRCA patents, limitations on which laboratories could offer commercial testing were lifted. These legal changes occurred approximately the same time as the widespread adoption of massively parallel sequencing (MPS) technologies. Little is known about how these changes impacted laboratory practices for detecting genetic alterations in hereditary breast and ovarian cancer genes. Therefore, we sought to examine current laboratory genetic testing practices for BRCA1/BRCA2. We employed an online survey of 65 questions covering four areas: laboratory characteristics, details on technological methods, variant classification, and client-support information. Eight United States (US) laboratories and 78 non-US laboratories completed the survey. Most laboratories (93%; 80/86) used MPS platforms to identify variants. Laboratories differed widely on: (1) technologies used for large rearrangement detection; (2) criteria for minimum read depths; (3) non-coding regions sequenced; (4) variant classification criteria and approaches; (5) testing volume ranging from 2 to 2.5 * 105 tests annually; and (6) deposition of variants into public databases. These data may be useful for national and international agencies to set recommendations for quality standards for BRCA1/BRCA2 clinical testing. These standards could also be applied to testing of other disease genes. PMID- 29479478 TI - Inverted ILM flap, free ILM flap and conventional ILM peeling for large macular holes. AB - Background: To assess closure rate after a single surgery of large macular holes and their visual recovery in the short term with three different surgical techniques. Methods: Prospective multicenter randomized controlled trial. We included treatment-naive patients with diagnosis of large macular hole (minimum diameter of > 400 um). All patients underwent a comprehensive ophthalmological examination. Before surgery, the patients were randomized into three groups: group A: conventional internal limiting membrane peeling, group B: inverted-flap technique and group C: free-flap technique. All study measurements were repeated within the period of 1 and 3 months after surgery. Continuous variables were assessed with a Kruskal-Wallis test, change in visual acuity was assessed with analysis of variance for repeated measurements with a Bonferroni correction for statistical significance. Results: Thirty-eight patients were enrolled (group A: 12, group B: 12, group C: 14). The closure rate was in group A and B: 91.6%; 95% CI 61.52-99.79%. In group C: 85.71%; 95% CI 57.19-98.22%. There were no differences in the macular hole closure rate between groups (p = 0.85). All groups improved ~ 0.2 logMAR, but only group B reached statistical significance (p < 0.007). Conclusions: Despite all techniques displayed a trend toward visual improvement, the inverted-flap technique seems to induce a faster and more significant recovery in the short term. PMID- 29479479 TI - Mosquito bottlenecks alter viral mutant swarm in a tissue and time-dependent manner with contraction and expansion of variant positions and diversity. AB - Viral diversity is theorized to play a significant role during virus infections, particularly for arthropod-borne viruses (arboviruses) that must infect both vertebrate and invertebrate hosts. To determine how viral diversity influences mosquito infection and dissemination Culex taeniopus mosquitoes were infected with the Venezuelan equine encephalitis virus endemic strain 68U201. Bodies and legs/wings of the mosquitoes were collected individually and subjected to multi parallel sequencing. Virus sequence diversity was calculated for each tissue. Greater diversity was seen in mosquitoes with successful dissemination versus those with no dissemination. Diversity across time revealed that bottlenecks influence diversity following dissemination to the legs/wings, but levels of diversity are restored by Day 12 post-dissemination. Specific minority variants were repeatedly identified across the mosquito cohort, some in nearly every tissue and time point, suggesting that certain variants are important in mosquito infection and dissemination. This study demonstrates that the interaction between the mosquito and the virus results in changes in diversity and the mutational spectrum and may be essential for successful transition of the bottlenecks associated with arbovirus infection. PMID- 29479481 TI - Can civil lawsuits stem the tide of direct-to-consumer marketing of unproven stem cell interventions. AB - The sale of unproven stem cell interventions (SCIs) by commercial entities has proliferated in highly developed countries, most notably in the USA. Yet, there have been few criminal prosecutions and regulatory enforcement actions against providers who have violated laws and best practice standards due to the lack of resources and legal ambiguity. While the stem cell research community has invested much in protecting patients and preventing the growth of this industry, some patients are seeking remedies under civil law to hold stem cell clinics responsible for fraudulent practices. Several patients have filed lawsuits against providers demanding compensation for physical injuries caused by unproven treatments and financial losses due to fraud and false advertising. Lawsuits can be used as a tool not only to compensate plaintiffs but also to achieve positive public health and policy outcomes. In this paper, we explore the value of a public health litigation strategy as a countermeasure against the exploitative practices of the unproven SCI industry by analyzing stem cell lawsuits and comparing them with other major public health litigation efforts. We argue that stem cell lawsuits complement other approaches to reining in unsafe practices. In particular, stem cell lawsuits could intensify publicity and raise awareness of the harms of unproven treatments, set legal precedent, reshape the media narrative from one focused on the right to try or practice to one highlighting the need for adequate safety and efficacy standards, and encourage authorities to turn their attention to policy reform and enforcement. PMID- 29479482 TI - Concomitant mycotic abdominal aortic aneurysm and lumbartuberculous spondylitis with cauda equina syndrome: a rare condition - a case report and literature review. AB - Introduction: Concomitant mycotic abdominal aortic aneurysm and lumbar tuberculous spondylitis with psoas abscess and cauda equina syndrome is extremely rare. This condition can cause serious life-threatening problems if not diagnosed and treated properly. Case presentation: We report an unusual case of a 79-year old Thai male, who was diagnosed with concomitant mycotic abdominal aortic aneurysm and lumbar tuberculous spondylitis at the L2-L3 level with left psoas abscess and cauda equina syndrome. The surgical plan was radical surgical debridement via transpsoas approach and the defect was filled with iliac crest strut graft and posterior decompressive laminectomy and fusion with a pedicle screws and rods system. During the operation, an abdominal aortic aneurysm was iatrogenically ruptured and then was emergently treated with endovascular stent graft implantation. Subsequently, hemostasis was achieved and the patient remained hemodynamically stable. A few days later, he underwent posterior decompressive laminectomy L2-L3, fusion and instrumentation with a pedicle screws and rods system at T11-L5. After surgery, the patient recovered well and his motor power improved gradually. He was continually treated with anti-tuberculous chemotherapy for 12 months. Discussion: Concomitant mycotic aortic aneurysm and lumbar tuberculous spondylitis with psoas abscess and cauda equina syndrome is an extremely rare condition that requires prompt diagnosis and management. Its consequences can lead to serious complications such as permanent neurological damage, paralysis or even death, if left untreated. The aims of the treatment are to eradicate infection, to prevent further neurological compromise, to stabilize the spine and to protect the aortic aneurysm from rupture. PMID- 29479480 TI - Humanizing the mdx mouse model of DMD: the long and the short of it. AB - Duchenne muscular dystrophy (DMD) is a common fatal heritable myopathy, with cardiorespiratory failure occurring by the third decade of life. There is no specific treatment for DMD cardiomyopathy, in large part due to a lack of understanding of the mechanisms underlying the cardiac failure. Mdx mice, which have the same dystrophin mutation as human patients, are of limited use, as they do not develop early dilated cardiomyopathy as seen in patients. Here we summarize the usefulness of the various commonly used DMD mouse models, highlight a model with shortened telomeres like humans, and identify directions that warrant further investigation. PMID- 29479483 TI - Traumatic spinal injury and spinal cord injury: point for active physiological conservative management as compared to surgical management. AB - The controversy about surgical vs conservative treatment of the injured spine with cord damage is centuries old. Until the end of the Second World War the majority of patients died or lived a short miserable life. Subsequently, Guttmann, an experienced neurosurgeon, realised surgery was not beneficial and sometimes detrimental to the person with spinal cord injury. Guttman, Frankel and others demonstrated with expert conservative management of the spine and the multi-system consequences of cord damage most patients made some neurological recovery and most with incomplete cord injury recovered ambulation regardless of X-ray findings. Attention to the non-medical effects of paralysis and post discharge supervision enabled persons with SCIs to enjoy complication free, dignified, productive and even competitive lives in sport and employment. The introduction of CT, MRI and safe anaesthesia led to the beliefs that surgical realignment, stabilisation and/or decompression improved neurologic outcome, facilitated early mobilisation and completion of rehabilitation, shortened hospitalisation, facilitated management and reduced cost. However, there is no supporting evidence for these claims. This manuscript describes the rationale and outcomes of conservative management and the weakness of the arguments for surgical management. PMID- 29479484 TI - The case for surgery of the injured spine in the management of traumatic cord injuries. AB - Spinal cord injury can be a life-altering trauma for patients and can be costly to patients and society alike. Generally recognized as biphasic, these injuries have both primary and secondary drivers. Although the primary insult is largely unavoidable, prevention of secondary injury mechanisms-and the resultant cascade has been a target of substantial research. Continued spinal cord compression has been recognized as one of several deleterious secondary mechanisms, and decompressive and stabilization surgery has been routinely used for neuroprotection in this setting. Numerous biomechanical and animal studies have confirmed its potential utility. More recently, several high-quality randomized trials have concluded that early surgery for spinal cord injury improves rates of recovery when compared with delayed or nonoperative management. Herein, we argue that early surgery for spinal cord injury with continued cord compression offers significant benefit and should be undertaken when not contraindicated. PMID- 29479485 TI - Surgery for spinal injury with neurologic deficit: a matter of opinion? AB - The establishment of a new technology into the mainstream of treatment, such as spinal surgery for traumatic spinal cord injury, only rarely happens after being scrutinized in trials. Usually, a new technology is widely adopted when it offers an easily identifiable advantage over other treatment choices. In the case of spinal fixation, this advantage is the omission of a prolonged immobilization. However, this does not automatically preclude that the final outcome of the treatment is better. It does not imply that associated assumptions, such as the benefit of early decompression toward neurological improvement, are true as well. They need to be established with careful studies. PMID- 29479487 TI - Intravitreal Ziv-Aflibercept in Treatment of Naive Chronic Central Serous Chorioretinopathy Related Choroidal Neovascular Membrane. AB - Purpose. To study the effect and outcome of intravitreal Ziv-Aflibercept (IVZ) in treatment of Chronic Central Serous Chorioretinopathy (CSCR) related Choroidal Neovascular Membrane (CNVM). Methods. A case report of 48-year-old male patient treated with 1.25 mg/0.05 ml IVZ (total 3 doses at monthly intervals) in CSCR related CNVM. Pre- and posttreatment fundus fluorescein angiography (FFA) and Optical Coherence Tomography (OCT) were done to document response along with improvement in visual acuity. Patients. Single eye of a 48-year-old male patient. Results. Regression of CNVM was noted with improvement of macular contour and thickness on OCT and cessation of leakage on FFA. Visual acuity improved from 3/60, Menumbok > Sundar > Weston and supporting the perspective of less/undisturbed vegetation at two former locations. Both remote sensing and ground-truth observations have complementarily represented the distribution of Sonneratia spp. as pioneer vegetation at shallow river mouths, N. fruticans in the areas of strong freshwater discharge, R. apiculata in the areas of strong neritic incursion and X. granatum at interior/elevated grounds. The results from this study would be able to serve as strong baseline data for future mangrove investigations at Brunei Bay, including for monitoring and management purposes locally at present. PMID- 29479501 TI - Comparative genomic analysis of a new tellurite-resistant Psychrobacter strain isolated from the Antarctic Peninsula. AB - The Psychrobacter genus is a cosmopolitan and diverse group of aerobic, cold adapted, Gram-negative bacteria exhibiting biotechnological potential for low temperature applications including bioremediation. Here, we present the draft genome sequence of a bacterium from the Psychrobacter genus isolated from a sediment sample from King George Island, Antarctica (3,490,622 bp; 18 scaffolds; G + C = 42.76%). Using phylogenetic analysis, biochemical properties and scanning electron microscopy the bacterium was identified as Psychrobacter glacincola BNF20, making it the first genome sequence reported for this species. P. glacincola BNF20 showed high tellurite (MIC 2.3 mM) and chromate (MIC 6.0 mM) resistance, respectively. Genome-wide nucleotide identity comparisons revealed that P. glacincola BNF20 is highly similar (>90%) to other uncharacterized Psychrobacter spp. such as JCM18903, JCM18902, and P11F6. Bayesian multi-locus phylogenetic analysis showed that P. glacincola BNF20 belongs to a polyphyletic clade with other bacteria isolated from polar regions. A high number of genes related to metal(loid) resistance were found, including tellurite resistance genetic determinants located in two contigs: Contig LIQB01000002.1 exhibited five ter genes, each showing putative promoter sequences (terACDEZ), whereas contig LIQB1000003.2 showed a variant of the terZ gene. Finally, investigating the presence and taxonomic distribution of ter genes in the NCBI's RefSeq bacterial database (5,398 genomes, as January 2017), revealed that 2,623 (48.59%) genomes showed at least one ter gene. At the family level, most (68.7%) genomes harbored one ter gene and 15.6% exhibited five (including P. glacincola BNF20). Overall, our results highlight the diverse nature (genetic and geographic diversity) of the Psychrobacter genus, provide insights into potential mechanisms of metal resistance, and exemplify the benefits of sampling remote locations for prospecting new molecular determinants. PMID- 29479502 TI - Phylogeny, time divergence, and historical biogeography of the South American Liolaemus alticolor-bibronii group (Iguania: Liolaemidae). AB - The genus Liolaemus comprises more than 260 species and can be divided in two subgenera: Eulaemus and Liolaemus sensu stricto. In this paper, we present a phylogenetic analysis, divergence times, and ancestral distribution ranges of the Liolaemus alticolor-bibronii group (Liolaemus sensu stricto subgenus). We inferred a total evidence phylogeny combining molecular (Cytb and 12S genes) and morphological characters using Maximum Parsimony and Bayesian Inference. Divergence times were calculated using Bayesian MCMC with an uncorrelated lognormal distributed relaxed clock, calibrated with a fossil record. Ancestral ranges were estimated using the Dispersal-Extinction-Cladogenesis (DEC-Lagrange). Effects of some a priori parameters of DEC were also tested. Distribution ranged from central Peru to southern Argentina, including areas at sea level up to the high Andes. The L. alticolor-bibronii group was recovered as monophyletic, formed by two clades: L. walkeri and L. gracilis, the latter can be split in two groups. Additionally, many species candidates were recognized. We estimate that the L. alticolor-bibronii group diversified 14.5 Myr ago, during the Middle Miocene. Our results suggest that the ancestor of the Liolaemus alticolor-bibronii group was distributed in a wide area including Patagonia and Puna highlands. The speciation pattern follows the South-North Diversification Hypothesis, following the Andean uplift. PMID- 29479503 TI - Ovary activation does not correlate with pollen and nectar foraging specialization in the bumblebee Bombus impatiens. AB - Social insect foragers may specialize on certain resource types. Specialization on pollen or nectar among honeybee foragers is hypothesized to result from associations between reproductive physiology and sensory tuning that evolved in ancestral solitary bees (the Reproductive Ground-Plan Hypothesis; RGPH). However, the two non-honeybee species studied showed no association between specialization and ovary activation. Here we investigate the bumblebee B. impatiens because it has the most extensively studied pollen/nectar specialization of any bumblebee. We show that ovary size does not differ between pollen specialist, nectar specialist, and generalist foragers, contrary to the predictions of the RGPH. However, we also found mixed support for the second prediction of the RGPH, that sensory sensitivity, measured through proboscis extension response (PER), is greater among pollen foragers. We also found a correlation between foraging activity and ovary size, and foraging activity and relative nectar preference, but no correlation between ovary size and nectar preference. In one colony non foragers had larger ovaries than foragers, supporting the reproductive conflict and work hypothesis, but in the other colony they did not. PMID- 29479504 TI - How has our knowledge of dinosaur diversity through geologic time changed through research history? AB - Assessments of dinosaur macroevolution at any given time can be biased by the historical publication record. Recent studies have analysed patterns in dinosaur diversity that are based on secular variations in the numbers of published taxa. Many of these have employed a range of approaches that account for changes in the shape of the taxonomic abundance curve, which are largely dependent on databases compiled from the primary published literature. However, how these 'corrected' diversity patterns are influenced by the history of publication remains largely unknown. Here, we investigate the influence of publication history between 1991 and 2015 on our understanding of dinosaur evolution using raw diversity estimates and shareholder quorum subsampling for the three major subgroups: Ornithischia, Sauropodomorpha, and Theropoda. We find that, while sampling generally improves through time, there remain periods and regions in dinosaur evolutionary history where diversity estimates are highly volatile (e.g. the latest Jurassic of Europe, the mid-Cretaceous of North America, and the Late Cretaceous of South America). Our results show that historical changes in database compilation can often substantially influence our interpretations of dinosaur diversity. 'Global' estimates of diversity based on the fossil record are often also based on incomplete, and distinct regional signals, each subject to their own sampling history. Changes in the record of taxon abundance distribution, either through discovery of new taxa or addition of existing taxa to improve sampling evenness, are important in improving the reliability of our interpretations of dinosaur diversity. Furthermore, the number of occurrences and newly identified dinosaurs is still rapidly increasing through time, suggesting that it is entirely possible for much of what we know about dinosaurs at the present to change within the next 20 years. PMID- 29479505 TI - Acute sleep fragmentation does not alter pro-inflammatory cytokine gene expression in brain or peripheral tissues of leptin-deficient mice. AB - Obesity and sleep fragmentation (SF) are often co-occurring pro-inflammatory conditions in patients with obstructive sleep apnea. Leptin is a peptide hormone produced by adipocytes that has anorexigenic effects upon appetite while regulating immunity. The role of leptin in mediating inflammatory responses to SF is incompletely understood. Male C57BL/6j (lean) and ob/ob mice (leptin-deficient mice exhibiting obese phenotype) were subjected to SF or control conditions for 24 h using an automated SF chamber. Trunk blood and tissue samples from the periphery (liver, spleen, fat, and heart) and brain (hypothalamus, prefrontal cortex, and hippocampus) were collected. Quantitative PCR was used to determine relative cytokine gene expression of pro-inflammatory (IL-1beta, TNF-alpha) and anti-inflammatory (TGF-beta1) cytokines. Enzyme-linked immunosorbent assay (ELISA) was used to determine serum corticosterone concentration. Ob/ob mice exhibited elevated cytokine gene expression in liver (TNF-alpha, TGF-beta1), heart (TGF-beta1), fat (TNF-alpha), and brain (hippocampus, hypothalamus, prefrontal cortex: IL-1beta, TNF-alpha) compared with wild-type mice. Conversely, leptin deficiency decreased pro-inflammatory cytokine gene expression in heart (IL-1beta, TNF-alpha). SF significantly increased IL-1beta and TNF-alpha gene expression in fat and TGF-beta1 expression in spleen relative to controls, but only in wild-type mice. SF increased basal serum corticosterone regardless of genotype. Taken together, these findings suggest that leptin deficiency affects cytokine gene expression differently in the brain compared to peripheral tissues with minimal interaction from acute SF. PMID- 29479506 TI - Multi-year composite view of ozone enhancements and stratosphere-to-troposphere transport in dry intrusions of northern hemisphere extratropical cyclones. AB - We examine the role of extratropical cyclones in stratosphere-to-troposphere (STT) exchange with cyclone-centric composites of O3 retrievals from the Microwave Limb Sounder (MLS) and the Tropospheric Emission Spectrometer (TES), contrasting them to composites obtained with the Modern-Era Retrospective analysis for Research and Applications (MERRA and MERRA-2) reanalyses and the GEOS-Chem chemical transport model. We identify 15,978 extratropical cyclones in the northern hemisphere (NH) for 2005-2012. The lowermost stratosphere (261 hPa) and middle troposphere (424 hPa) composites feature a 1,000 km-wide O3 enhancement in the dry intrusion (DI) airstream to the southwest of the cyclone center, coinciding with a lowered tropopause, enhanced potential vorticity, and decreased H2O. MLS composites at 261 hPa show that the DI O3 enhancements reach a 210 ppbv maximum in April. At 424 hPa, TES composites display maximum O3 enhancements of 27 ppbv in May. The magnitude and seasonality of these enhancements are captured by MERRA and MERRA-2, but GEOS-Chem is a factor of two too low. The MERRA-2 composites show that the O3-rich DI forms a vertically aligned structure between 300 and 800 hPa, wrapping cyclonically with the warm conveyor belt. In winter and spring DIs, O3 is enhanced by 100 ppbv or 100-130% at 300 hPa, with significant enhancements below 500 hPa (6-20 ppbv or 15-30%). We estimate that extratropical cyclones result in a STT flux of 119+/-56 Tg O3 yr-1, accounting for 42+/-20 % of the NH extratropical O3 STT flux. The STT flux in cyclones displays a strong dependence on westerly 300 hPa wind speeds. PMID- 29479507 TI - Silver nanoparticles in sewage treatment plant effluents: chronic effects and accumulation of silver in the freshwater amphipod Hyalella azteca. AB - Background: Increasing amounts of engineered nanoparticles (NPs) in wastewater can reach the aquatic environment by passing through the sewage treatment plant (STP). NPs can induce ecotoxicological effects due to their specific chemical properties. However, their bioavailability and toxicity are potentially influenced by transformation processes caused by substances present in the STP, e.g., humic acids or sulfides. Due to the lack of a test system allowing to test NPs under realistic environmental conditions, we coupled two existing test systems, the activated sludge simulation test (OECD TG 303A 2001) and the chronic exposure test with the freshwater amphipod Hyalella azteca (Environment Canada 2013), to gain a test scenario that allows to consider the altered behavior and fate of NPs induced by the STP process. This should improve the environmental realism of the chronic exposure test with Hyalella. In the first study, we tested the STP effluent containing AgNPs. In the second and third study, tap water and control STP effluent were spiked with AgNPs and used as test media. Results: The chronic exposure studies with the freshwater amphipod H. azteca showed that the investigated AgNPs lose most of their toxicity while passing through the STP. Over all studies with total Ag concentrations ranging from 0.85 to 68.70 ug/L, significant effects of the AgNPs were only observed in the survival of test animals exposed to tap water containing the highest Ag concentration (62.59 ug/L). Accumulation of silver in the body of test animals was clearly dependent on the pretreatment of the AgNPs. Silver ions (Ag+) released from AgNPs are supposed to be the major pathway leading to body burden following exposure to test media containing AgNPs. Conclusion: The coupled test system is suitable for testing substances that can reach the environment via the STP effluent. The investigated AgNPs lose most of their toxicity while passing through the STP. Accumulation of silver in the animals exposed to the different treatments was apparent, whereby silver ions (Ag+) released from AgNPs were supposed to be the major pathway leading to body burden. PMID- 29479508 TI - Optimization of silver nanoparticles biosynthesis mediated by Aspergillus niger NRC1731 through application of statistical methods: enhancement and characterization. AB - The fungal-mediated silver nanoparticles (AgNPs) biosynthesis optimization via the application of central composite design (CCD) response surface to develop an effective ecofriendly and inexpensive green process was the aim of the current study. Nanosilver biosynthesis using the Aspergillus niger NRC1731 cell-free filtrate (CFF) was studied through involving the most parameters affecting the AgNPs green synthesis and its interactions effects. The statistical optimization models showed that using 59.37% of CFF in reaction containing 1.82 mM silver nitrate for 34 h at pH 7.0 is the optimum value to optimize the AgNPs biosynthesis. The obtained AgNPs were characterized by means of electron microscopy, UV/visible spectrophotometry, energy dispersive X-ray analysis and infrared spectroscopy to elucidate its almost spherical shape with diameter of 3 20 nm. The produced AgNPs exhibited a considerable antimicrobial activity against Bacillus mycoides, Escherichia coli in addition to Candida albicans. PMID- 29479509 TI - Enrichment of genomic resources and identification of simple sequence repeats from medicinally important Clausena excavata. AB - To broaden and delve into the genomic information of Clausena excavata, an important medicinal plant in many Asian countries, RNA sequencing (RNA-seq) analysis was performed and a total of 16,638 non-redundant unigenes (>= 300 bp) with an average length of 755 bp were generated by de novo assembly from 17,580,456 trimmed clear reads. The functional categorization of the identified unigenes by a gene ontology (GO) term resulted in 2305 genes in the cellular component, 5577 in the biological processes, and 8056 in the molecular functions, respectively. The top sub-category in biological processes was the metabolic process with 4374 genes. Among annotated genes, 3006 were mapped to 123 metabolic pathways by the Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathway analysis tool. The search for simple sequence repeats (SSRs) resulted in 845 SSRs from 749 SSR-containing unigenes and the most abundant SSR motifs was AAG/CTT with 179 occurrences. Twelve SSR markers were tested for cross transferability among five Clausena species; eight of them exhibited polymorphism. Taken together, these data provide valuable resources for genomic or genetic studies of Clausena species and other relative studies. The transcriptome shotgun assembly data have been deposited at DDBJ/EMBL/GenBank under the accession GGEM00000000. PMID- 29479510 TI - Medium composition potentially regulates the anthocyanin production from suspension culture of Daucus carota. AB - In the present study, an effort has been made to optimize various culture conditions for enhanced production of anthocyanin. Nutrient content of MS medium (ammonium to potassium nitrate ratio and phosphate concentration) had a profound influence on the cell biomass and anthocyanin accumulation in cell suspension cultures of Daucus carota. Suspension cultures were carried out in shake flasks for 18 days and examined for cell growth, anthocyanin synthesis, anthocyanin yield and development of pigmented cells in relation to the uptake of total sugar, extracellular phosphate, nitrate and ammonia. The addition of NH4NO3 to KNO3 ratio (20.0 mM: 37.6 mM) in the suspension culture media resulted in a 2.85 fold increase in anthocyanin content at day 3. Similarly, a lower concentration of KH2PO4 (0.45 mM) in the MS medium resulted in 1.63-fold increase in anthocyanin content at day 9. The total sugar uptake was closely associated with a significant increase in anthocyanin accumulation. Total sugar and nitrate were consumed until 9-12 days, while ammonia and phosphate were completely consumed within 3 days after inoculation. After 9 days, cell lysis was observed and resulted in the leakage of intracellular substances. These observations suggest that anthocyanin was synthesized only by viable pigmented cells and degraded rapidly after cell death and lysis. This study signifies the utility of D. carota suspension culture for further up-scaling studies of anthocyanin. PMID- 29479511 TI - Assessment of adulteration in raw herbal trade of important medicinal plants of India using DNA barcoding. AB - A number of studies have shown that there could be widespread substitution and/or adulteration (hereafter referred to as substitution) in raw herbal trade of medicinal plants. Substitution could potentially endanger the health and safety of the consumers. In this study, the extent of adulteration in raw herbal trade of 30 important medicinal plants in South India was analyzed. Biological reference material (BRM) consisting of taxonomically authenticated samples of each of the 30 species along with 14 other co-occurring and congeneric allied species that are likely to be used in adulteration was established. DNA barcode signatures of 124 BRM using two candidate regions, nr-ITS and psbA-trnH were identified. A total of 203 herbal trade samples representing the 30 medicinal plant species were collected from 34 locations in South India. Using the DNA barcode sequences of the BRM as reference, the analysis indicated that the substitution ranged from 20 to 100%. Overall, approximately 12% of the market samples were adulterated. Considering the potential health hazard that such adulteration can cause, the need for a national regulatory framework that can authenticate and regulate raw herbal trade in the country is discussed. PMID- 29479512 TI - Deep sequencing and in silico analysis of small RNA library reveals novel miRNA from leaf Persicaria minor transcriptome. AB - In current era, majority of microRNA (miRNA) are being discovered through computational approaches which are more confined towards model plants. Here, for the first time, we have described the identification and characterization of novel miRNA in a non-model plant, Persicaria minor (P. minor) using computational approach. Unannotated sequences from deep sequencing were analyzed based on previous well-established parameters. Around 24 putative novel miRNAs were identified from 6,417,780 reads of the unannotated sequence which represented 11 unique putative miRNA sequences. PsRobot target prediction tool was deployed to identify the target transcripts of putative novel miRNAs. Most of the predicted target transcripts (mRNAs) were known to be involved in plant development and stress responses. Gene ontology showed that majority of the putative novel miRNA targets involved in cellular component (69.07%), followed by molecular function (30.08%) and biological process (0.85%). Out of 11 unique putative miRNAs, 7 miRNAs were validated through semi-quantitative PCR. These novel miRNAs discoveries in P. minor may develop and update the current public miRNA database. PMID- 29479513 TI - Isolation, identification of a laccase-producing fungal strain and enzymatic properties of the laccase. AB - A new type of thermostable laccase was isolated from Paraphoma sp. GZS18, and its partial enzymatic properties were determined. A strain GZS18 of laccase with high yield was screened from forest soil and identified as Paraphoma sp. GZS18 through morphological characteristics and ITS sequence analysis. The laccase of Paraphoma sp. GZS18 (Lac-P) was obtained through cation-anion exchange chromatography, gel filtration chromatography, and other purification processes. The testing result shows that Lac-P is a single protein of 75 kDa, and the 11 amino acid sequences in the N-terminal are AXaVSVASREMT (Xa was the non-standard protein). The optimum temperature and optimum pH of lac-P activity are substrate-independent. The temperature is in the range of 50-70 degrees C, and pH has high catalytic efficiency in the acidic range. Lac-P has good stability in the temperature and pH. The half time at 70-60 degrees C is 1.5 and 4 h, respectively. At pH 6-9 and room temperature, there is more than 80% activity 24 h later. Lac-P is tolerant of most metal ions and low concentrations of inhibitors but is inhibited by Hg2+, Fe2+ and NaN3. The laccase from Paraphoma sp. GZS18 at high temperature and pH 6 9, with strong stability, has better industrial application characteristics. PMID- 29479514 TI - Combined Open and Endoscopic Endonasal Skull Base Resection of a Rare Endometrial Carcinoma Metastasis. AB - In the absence of significant extracranial disease, patients with solitary brain metastases have shown benefit with resection. Brain lesions due to endometrial cancer are uncommon, and the only described skull base involvement is limited to the pituitary gland. We report the case of a 60-year-old female with endometrial cancer who presented with weeks of right cheek pain and numbness that was accompanied by headaches. We describe the magnetic resonance imaging (MRI) findings and surgical resection of a solitary endometrial metastasis involving the infratemporal fossa, middle fossa, cavernous sinus, trigeminal nerve, and nasal sinuses. Due to extensive nasal and lateral involvement, a combined open and endoscopic approach was planned. The patient was discharged home without complication. She underwent adjuvant radiotherapy. Despite its suspected indolent course, intracranial endometrial adenocarcinoma metastases are gaining higher prevalence. This case report documents the first direct neural spread of an endometrial primary, and highlights the potential for extra-axial sites of metastasis. PMID- 29479515 TI - Current Status of Transcranial Direct Current Stimulation in Posttraumatic Stress and Other Anxiety Disorders. AB - Several empirically supported treatments have been identified for post-traumatic stress disorder (PTSD), yet a sizable number of patients are either unable to tolerate these approaches or remain symptomatic following treatment. Transcranial direct current stimulation (tDCS) is a well-tolerated method of modulating neuronal excitability that may hold promise as a novel intervention in PTSD and related disorders. The current review summarizes literature on the disrupted neural circuitry in PTSD and discusses the rationale for the commonly targeted prefrontal cortex (PFC) as it relates to PTSD. We then review the few prior (case) studies that have evaluated tDCS in patients with PTSD (1 study) and other anxiety disorders (4 studies). There was considerable variability in both the methods/justification for selecting the targeted brain region(s) and the tDCS montage used, which obscured any clear trends in the data. Finally, we describe the rationale for our ongoing study that specifically targets the lateral temporal cortex as a method of treating the symptoms of hyperarousal and re experiencing in PTSD. Overall, it is clear that additional work is needed to establish dosing (e.g., intensity and duration of sessions, number of sessions) and optimal treatment targets as well as to identify synergistic effects with existing treatments. PMID- 29479517 TI - Is the cigarette pack just a wrapper or a characteristic of the product itself? A qualitative study of adult smokers to inform U.S. regulations. AB - Purpose: In the U.S., tobacco products are now regulated by the Food and Drug Administration (FDA). Litigation has quickly followed. One area of controversy is when a change to the design of the cigarette pack requires approval through FDA's rigorous premarket review process. In this paper, we examine how adult U.S. smokers view the connection between the design of cigarette packs and the characteristics of the cigarettes within. Methods: Data for this qualitative study came from six focus groups conducted in March 2017 with adult smokers. Two groups consisted of lesbian, gay, and bisexual (LGB) participants; two groups of participants with less than four years of college education; one group of LGB and straight identity; and, one group of the general population. All groups were selected for regional, gender, and racial/ethnic diversity. Participants (n = 33) represented all nine U.S. Census divisions. We conducted constant comparison qualitative analysis utilizing a grounded theory approach. Results: Participants' views reflected a belief that pack design is clearly a reflection of the cigarettes within and that a change in the pack signaled a change in the cigarettes. However, some participants felt price was the salient characteristic of cigarettes and design mattered more for enticing young people to smoke. Conclusions: Changes in pack design signal changes to the product for smokers. Pack design and changes to pack design are seen as particularly relevant to new and young smokers. These findings provide support for regulations that require assessment of cigarette pack design changes for impacts on public health. PMID- 29479516 TI - Comorbidity, Physical Function, and Quality of Life in Older Adults with Acute Myeloid Leukemia. AB - Purpose of review: To describe the pathology, impact of comorbidities, functional limitations, symptoms, and quality of life (QOL) related to treatment of acute myeloid leukemia (AML) in older adults. Recent findings: AML is a rare aggressive hematologic disease that occurs most often in older adults. The prognosis for older patients with AML is markedly worse due to genetic mutations and patient characteristics such as comorbidities and functional limitations. Patient characteristics may influence treatment decisions, as well as impact symptoms, functional ability, health-related outcomes and (QOL). Summary: As the population continues to age, the number of people diagnosed with AML is expected to increase. Better management of comorbidities is imperative to improving QOL and other treatment related outcomes. Prospective, longitudinal and multi-site studies are warranted to further understand the interaction between these characteristics on symptoms, outcomes and QOL. PMID- 29479518 TI - Environmental Mycobacterium avium subsp. paratuberculosis Hosted by Free-Living Amoebae. AB - Mycobacterium avium subsp. paratuberculosis is responsible for paratuberculosis in animals. This disease, leading to an inflammation of the gastrointestinal tract, has a high impact on animal health and an important economic burden. The environmental life cycle of M. avium subsp. paratuberculosis is poorly understood and several studies suggest that free-living amoebae (FLA) might be a potential environmental host. FLA are protozoa found in water and soil that are described as reservoirs of pathogenic and non-pathogenic bacteria in the environment. Indeed, bacteria able to survive within these amoebae would survive phagocytosis from immune cells. In this study, we assessed the in vitro interactions between several strains of M. avium subsp. paratuberculosis and Acanthamoeba castellanii. The results indicate that the bacteria were able to grow within the amoeba and that they can survive for several days within their host. To explore the presence of M. avium subsp. paratuberculosis in environmental amoebae, we sampled water from farms positive for paratuberculosis. A M. avium subsp. paratuberculosis strain was detected within an environmental amoeba identified as related to the poorly described Rosculus genus. The bacterial strain was genotyped, showing that it was similar to previous infectious strains isolated from cattle. In conclusion, we described that various M. avium subsp. paratuberculosis strains were able to grow within amoebae and that these bacteria could be found on farm within amoebae isolated from the cattle environment. It validates that infected amoebae might be a reservoir and vector for the transmission of M. avium subsp. paratuberculosis. PMID- 29479519 TI - Evaluating Different Virulence Traits of Klebsiella pneumoniae Using Dictyostelium discoideum and Zebrafish Larvae as Host Models. AB - Multiresistant and invasive hypervirulent Klebsiella pneumoniae strains have become one of the most urgent bacterial pathogen threats. Recent analyses revealed a high genomic plasticity of this species, harboring a variety of mobile genetic elements associated with virulent strains, encoding proteins of unknown function whose possible role in pathogenesis have not been addressed. K. pneumoniae virulence has been studied mainly in animal models such as mice and pigs, however, practical, financial, ethical and methodological issues limit the use of mammal hosts. Consequently, the development of simple and cost-effective experimental approaches with alternative host models is needed. In this work we described the use of both, the social amoeba and professional phagocyte Dictyostelium discoideum and the fish Danio rerio (zebrafish) as surrogate host models to study K. pneumoniae virulence. We compared three K. pneumoniae clinical isolates evaluating their resistance to phagocytosis, intracellular survival, lethality, intestinal colonization, and innate immune cells recruitment. Optical transparency of both host models permitted studying the infective process in vivo, following the Klebsiella-host interactions through live-cell imaging. We demonstrated that K. pneumoniae RYC492, but not the multiresistant strains 700603 and BAA-1705, is virulent to both host models and elicits a strong immune response. Moreover, this strain showed a high resistance to phagocytosis by D. discoideum, an increased ability to form biofilms and a more prominent and irregular capsule. Besides, the strain 700603 showed the unique ability to replicate inside amoeba cells. Genomic comparison of the K. pneumoniae strains showed that the RYC492 strain has a higher overall content of virulence factors although no specific genes could be linked to its phagocytosis resistance, nor to the intracellular survival observed for the 700603 strain. Our results indicate that both zebrafish and D. discoideum are advantageous host models to study different traits of K. pneumoniae that are associated with virulence. PMID- 29479520 TI - Tripartite ATP-Independent Periplasmic (TRAP) Transporters and Tripartite Tricarboxylate Transporters (TTT): From Uptake to Pathogenicity. AB - The ability to efficiently scavenge nutrients in the host is essential for the viability of any pathogen. All catabolic pathways must begin with the transport of substrate from the environment through the cytoplasmic membrane, a role executed by membrane transporters. Although several classes of cytoplasmic membrane transporters are described, high-affinity uptake of substrates occurs through Solute Binding-Protein (SBP) dependent systems. Three families of SBP dependant transporters are known; the primary ATP-binding cassette (ABC) transporters, and the secondary Tripartite ATP-independent periplasmic (TRAP) transporters and Tripartite Tricarboxylate Transporters (TTT). Far less well understood than the ABC family, the TRAP transporters are found to be abundant among bacteria from marine environments, and the TTT transporters are the most abundant family of proteins in many species of beta-proteobacteria. In this review, recent knowledge about these families is covered, with emphasis on their physiological and structural mechanisms, relating to several examples of relevant uptake systems in pathogenicity and colonization, using the SiaPQM sialic acid uptake system from Haemophilus influenzae and the TctCBA citrate uptake system of Salmonella typhimurium as the prototypes for the TRAP and TTT transporters, respectively. High-throughput analysis of SBPs has recently expanded considerably the range of putative substrates known for TRAP transporters, while the repertoire for the TTT family has yet to be fully explored but both types of systems most commonly transport carboxylates. Specialized spectroscopic techniques and site-directed mutagenesis have enriched our knowledge of the way TRAP binding proteins capture their substrate, while structural comparisons show conserved regions for substrate coordination in both families. Genomic and protein sequence analyses show TTT SBP genes are strikingly overrepresented in some bacteria, especially in the beta-proteobacteria and some alpha proteobacteria. The reasons for this are not clear but might be related to a role for these proteins in signaling rather than transport. PMID- 29479521 TI - Differential Protein Profiling of Cerebrospinal Fluid in Piglets with Severe Meningoencephalitis Caused by Streptococcus suis Type 2 Compared to Controls. AB - Streptococcus suis serotype 2 (SS2) is a zoonotic pathogen that can cause meningitis both in pigs and in human beings. However, the pathogenesis of central nervous system (CNS) infection caused by SS2 have not yet been elucidated. To find the key molecules in cerebrospinal fluid (CSF) needed for the pathogenesis, a SS2 meningoencephalitic pig model and a SS2 non-meningoencephalitic pig model were established in this study. CSF was collected from infected piglets, and protein profiling was performed with label-free proteomics technology. A total of 813 differential proteins, including 52 up-regulated proteins and 761 down regulated proteins, were found in the CSF of meningoencephalitic pigs compared with both non-meningoencephalitic pigs and healthy pigs. These 813 differential proteins were clustered into three main categories, namely, cellular component, biological process, and molecular function by gene ontology (GO) analysis. The most enriched subclasses of differential proteins in each category were exosome (44.3%), energy pathway (25.0%) and catalytic activity (11.3%), respectively. The most enriched subclasses of upregulated proteins were extracellular (62.1%), protein metabolism (34.5%) and cysteine-type peptidase activity (6.9%), and of downregulated proteins were exosomes (45.0%), energy pathway (24.0%) and catalytic activity (9.4%). Then, the differential proteins were further investigated by using the KEGG database and were found to participate in 16 KEGGs. The most enriched KEGG was citrate cycle (56.6%), and some of these differential proteins are associated with brain diseases such as Huntington's disease (18.6%), Parkinson's disease (23.8%) and Alzheimer's disease (17.6%). Sixteen of the 813 differential proteins, chosen randomly as examples, were further confirmed by enzyme-linked immunosorbent assay (ELISA) to support the proteomic data. To our knowledge, this is the first study to analyze the differential protein profiling of CSF between SS2 meningoencephalitic piglets and non-meningoencephalitic piglets by employing proteomic technology. The discovery and bioinformatics analysis of these differential proteins provides reference data not only for research on pathogenesis of SS2 CNS infection but also for diagnosis and drug therapy research. PMID- 29479522 TI - Genetics of Autosomal Recessive Polycystic Kidney Disease and Its Differential Diagnoses. AB - Autosomal recessive polycystic kidney disease (ARPKD) is a hepatorenal fibrocystic disorder that is characterized by enlarged kidneys with progressive loss of renal function and biliary duct dilatation and congenital hepatic fibrosis that leads to portal hypertension in some patients. Mutations in the PKHD1 gene are the primary cause of ARPKD; however, the disease is genetically not as homogeneous as long thought and mutations in several other cystogenes can phenocopy ARPKD. The family history usually is negative, both for recessive, but also often for dominant disease genes due to de novo arisen mutations or recessive inheritance of variants in genes that usually follow dominant patterns such as the main ADPKD genes PKD1 and PKD2. Considerable progress has been made in the understanding of polycystic kidney disease (PKD). A reduced dosage of disease proteins leads to the disruption of signaling pathways underlying key mechanisms involved in cellular homeostasis, which may help to explain the accelerated and severe clinical progression of disease course in some PKD patients. A comprehensive knowledge of disease-causing genes is essential for counseling and to avoid genetic misdiagnosis, which is particularly important in the prenatal setting (e.g., preimplantation genetic diagnosis/PGD). For ARPKD, there is a strong demand for early and reliable prenatal diagnosis, which is only feasible by molecular genetic analysis. A clear genetic diagnosis is helpful for many families and improves the clinical management of patients. Unnecessary and invasive measures can be avoided and renal and extrarenal comorbidities early be detected in the clinical course. The increasing number of genes that have to be considered benefit from the advances of next-generation sequencing (NGS) which allows simultaneous analysis of a large group of genes in a single test at relatively low cost and has become the mainstay for genetic diagnosis. The broad phenotypic and genetic heterogeneity of cystic and polycystic kidney diseases make NGS a particularly powerful approach for these indications. Interpretation of genetic data becomes the challenge and requires deep clinical understanding. PMID- 29479523 TI - Renal Cell Carcinoma in von Hippel-Lindau Disease-From Tumor Genetics to Novel Therapeutic Strategies. AB - von Hippel-Lindau (VHL) disease is an autosomal dominant syndrome caused by mutations in the VHL tumor-suppressor gene, leading to the dysregulation of many hypoxia-induced genes. Affected individuals are at increased risk of developing recurrent and bilateral kidney cysts and dysplastic lesions which may progress to clear cell renal cell carcinoma (ccRCC). Following the eponymous VHL gene inactivation, ccRCCs evolve through additional genetic alterations, resulting in both intratumor and intertumor heterogeneity. Genomic studies have identified frequent mutations in genes involved in epigenetic regulation and phosphoinositide 3-kinase-AKT-mechanistic target of rapamycin (mTOR) pathway activation. Currently, local therapeutic options include nephron-sparing surgery and alternative ablative procedures. For advanced metastatic disease, systemic treatment, including inhibition of vascular endothelial growth factor pathways and mTOR pathways, as well as immunotherapy are available. Multimodal therapy, targeting multiple signaling pathways and/or enhancing the immune response, is currently being investigated. A deeper understanding of the fundamental biology of ccRCC development and progression, as well as the development of novel and targeted therapies will be accelerated by new preclinical models, which will greatly inform the search for clinical biomarkers for diagnosis, prognosis, and response to treatment. PMID- 29479524 TI - The Acceptability of Pre-Exposure Prophylaxis: Beliefs of Health-Care Professionals Working in Sexually Transmitted Infections Clinics and HIV Treatment Centers. AB - Background: Pre-exposure prophylaxis (PrEP) is highly effective for preventing HIV infections, but is not yet implemented in the Netherlands. As the attitudes of health-care professionals toward PrEP can influence future PrEP implementation, we studied PrEP knowledge and beliefs and their association with PrEP acceptability among professionals in clinics for sexually transmitted infection (STI professionals) and HIV treatment centers (HIV specialists). In addition, we examined preferred regimens, attitudes toward providing PrEP to key populations and to reimbursement of PrEP costs. Methods: An online questionnaire was distributed among 24 public health STI clinics and 27 HIV treatment centers nationwide in the Netherlands between January and August 2015. The acceptability of PrEP was measured on a 7-point Likert scale ranging from 1 = low to 7 = high acceptability. Univariable and multivariable linear regression analyses were used to explore associations between demographic characteristics, PrEP knowledge, beliefs about PrEP, and PrEP acceptability. Results: In total, 209 people (143 STI professionals and 66 HIV specialists) completed the questionnaire. The mean acceptability of PrEP implementation was 4.28 (SD 1.68) among STI professionals and 4.42 (SD 1.67) among HIV specialists. The mean score on self-perceived knowledge related to PrEP efficacy was 3.90 (SD 1.57) among STI professionals and 5.68 (SD 1.08) among HIV specialists (p-value of <0.001). Beliefs associated with lower PrEP acceptability among both groups were the fear that PrEP use will lead to a decrease in condom use and an increase in STI, the high costs of PrEP and ethical issues regarding prescribing antiretroviral medication to healthy individuals. No preference for a daily or an event-driven regimen was detected. Most participants deemed the following groups to be eligible for PrEP: men who have sex with men (MSM) who regularly get post-exposure prophylaxis, MSM who never used condoms with casual partners and MSM with an HIV-positive partner with a detectable viral load. Over half of the participants indicated that PrEP users should partly (54.1%) or fully (35.4%) pay the costs of PrEP. Conclusion: In 2015, PrEP acceptability was only moderate among Dutch STI professionals and HIV specialists, which is far from an optimal setting. Addressing barriers to PrEP acceptability in educational programs for various types of health-care professionals is needed to successfully implement PrEP in the Netherlands. PMID- 29479525 TI - Perspectives on Underlying Factors for Unhealthy Diet and Sedentary Lifestyle of Adolescents at a Kenyan Coastal Setting. AB - Unhealthy diet and physical inactivity are among the key modifiable risk factors for non-communicable diseases, such as diabetes and cardiovascular disease. Although such diseases often only appear in adulthood, these behaviors are typically initiated or reinforced already during adolescence. However, knowledge on underlying factors for adolescents' unhealthy dieting and physical inactivity in sub-Saharan Africa (SSA) is poor. We conducted in-depth interviews and focus group discussions to explore the perceptions of a diverse group of 78 young people of 10-19 years of age, which also included some adolescents living with HIV, as this is an emerging group in the HIV/AIDS epidemic in many parts of SSA. In addition, 10 stakeholders, such as teachers, clinicians, and staff from organizations at the Kenyan coast and seven young adult community representatives informed us on: (a) adolescents' unhealthy food choices and their forms of sedentary behavior; (b) predisposing factors; and (c) protective factors against unhealthy food choices and sedentary behavior of adolescents living in Kilifi County. The findings reveal that adolescents occasionally access nutritious foods, such as fruits, vegetables, and animal protein. However, there is a growing tendency to consume unbalanced diets with high intake of carbohydrates, oily foods, and consumption of sugar dense processed foods and drinks. Sports and domestic chores were found to be major sources of physical activity. Sedentary lifestyles characterized by a long-time sitting and chatting, watching sports games and movies were described. Adolescents living with HIV did not indicate any divergent perceptions from those of other adolescents relating to diet and physical activity, but mentioned health-related conditions, such as medication, asthma, and low body weight, as a risk factors for sedentary lifestyle. Using a Socio-Ecological model, our findings suggest that risk factors are numerous and interrelated, especially at intrapersonal, interpersonal, and community level. The negative influences at an intrapersonal level were as follows: body image concerns, attitudes and misconceptions, substance use behavior, and taste for unhealthy foods. In the interpersonal domain, household poverty and parenting practices that condone unhealthy habits were identified risk factors. Availability of affordable unhealthy foods, high prices for nutritious food, farming practices, gambling, and influx of transportation alternatives in the community were interrelated but also had relationships with intrapersonal and interpersonal risk factors. Modernization and poor implementation of policies were discussed as enabling factors especially by stakeholders from a societal perspective. Seasonality and farming practices, school attendance, community based services, and regulations mitigating adolescents' engagement in gambling were identified as potential protective factors. Our findings provide a unique qualitative insight of the factors underlying adolescents' dietary and sedentary lifestyle and highlight the need for ecological intervention approaches to address these forms of health risk behavior in a rural African setting. PMID- 29479527 TI - Problem Gambling among Young People in Sub-Saharan Africa. AB - Gambling is a cross-cultural and global activity which typically involves the wagering of money or an item of monetary value on an outcome that is governed by chance. Although gambling is positioned as a legitimate recreational and leisure activity within sub-Saharan Africa (SSA), there is widespread recognition among healthcare professionals and policy-makers that gambling has the capacity to become dysfunctional in a minority. Emerging knowledge suggests that problem gambling is rapidly evolving in to a public health concern in SSA, especially among youth. This article focuses on problem gambling among young people in SSA with an emphasis on three key themes: (1) gambling behavior and patterns in SSA; (2) public health and socioeconomic implications of gambling in SSA; and (3) public health policies and interventions for addressing this issue. We believe that collaborative efforts between government, prevention specialists, legislators, researchers, treatment providers, and other stake holders can influence the uptake of research findings necessary to implement social policies and design effective public health intervention options to combat problem gambling and its associated implications among young people in SSA. PMID- 29479526 TI - Increasing Research Capacity in Underserved Communities: Formative and Summative Evaluation of the Mississippi Community Research Fellows Training Program (Cohort 1). AB - Background: The Mississippi Community Research Fellows Training Program (MSCRFTP) is a 15-week program conducted in Jackson, MS, USA consisting of training in the areas of evidence-based public health, research methods, research ethics, and cultural competency. The purpose of the program was to increase community knowledge and understanding of public health research, develop community-based projects that addressed health disparity in the participants' community, increase individual and community capacity, and to engage community members as equal partners in the research process. Methods: A comprehensive evaluation of the MSCRFTP was conducted that included both quantitative and qualitative methods. All participants were asked to complete a baseline, midterm, and final assessment as part of their program requirements. Knowledge gained was assessed by comparing baseline assessment responses to final assessment responses related to 27 key content areas addressed in the training sessions. Assessments also collected participants' attitudes toward participating in research within their communities, their perceived influence over community decisions, and their perceptions of community members' involvement in research, satisfaction with the program, and the program's impact on the participants' daily practice and community work. Results: Twenty-one participants, the majority of which were female and African-American, completed the MSCRFTP. Knowledge of concepts addressed in 15 weekly training sessions improved significantly on 85.2% of 27 key areas evaluated (p < 0.05). Two mini-grant community based participatory research projects proposed by participants were funded through competitive application. Most participants agreed that by working together, the people in their community could influence decisions that affected the community. All participants rated their satisfaction with the overall program as "very high" (76.2%, n = 16) or "high" (23.8%, n = 5). Conclusion: The evaluation of the MSCRFTP demonstrates that participants have the necessary knowledge to engage as research partners, and the pilot projects provided an opportunity for application of this objective to be realized. Overall, the MSCRFTP was an intervention that assisted community members in identifying their communities' strengths and weaknesses, interpret knowledge in a meaningful way, and create a self-reflective community of inquiry for change. PMID- 29479528 TI - Vascular Calcification: Is it rather a Stem/Progenitor Cells Driven Phenomenon? AB - Vascular calcification (VC) has witnessed a surge of interest. Vasculature is virtually an omnipresent organ and has a notably high capacity for repair throughout embryonic and adult life. Of the vascular diseases, atherosclerosis is a leading cause of morbidity and mortality on account of ectopic cartilage and bone formation. Despite the identification of a number of risk factors, all the current theories explaining pathogenesis of VC in atherosclerosis are far from complete. The most widely accepted response to injury theory and smooth muscle transdifferentiation to explain the VC observed in atherosclerosis is being challenged. Recent focus on circulating and resident progenitor cells in the vasculature and their role in atherogenesis and VC has been the driving force behind this review. This review discusses intrinsic cellular players contributing to fate determination of cells and tissues to form ectopic cartilage and bone formation. PMID- 29479530 TI - Environmental Impacts of Plant-Based Diets: How Does Organic Food Consumption Contribute to Environmental Sustainability? AB - Background: Studies investigating diet-related environmental impacts have rarely considered the production method of the foods consumed. The objective of the present study, based on the NutriNet-Sante cohort, was to investigate the relationship between a provegetarian score and diet-related environmental impacts. We also evaluated potential effect modifications on the association between a provegetarian score and the environmental impacts of organic food consumption. Methods: Food intake and organic food consumption ratios were obtained from 34,442 French adults using a food frequency questionnaire, which included information on organic food consumption for each group. To characterize the overall structure of the diets, a provegetarian score was used to identify preferences for plant-based products as opposed to animal-based products. Moreover, three environmental indicators were used to assess diet-related environmental impacts: greenhouse gas (GHG) emissions, cumulative energy demand (CED), and land occupation. Environmental impacts were assessed using production life cycle assessment (LCA) at the farm level. Associations between provegetarian score quintiles, the level of organic food consumption, and environmental indicators were analyzed using ANCOVAs adjusted for energy, sex, and age. Results: Participants with diets rich in plant-based foods (fifth quintile) were more likely to be older urban dwellers, to hold a higher degree in education, and to be characterized by an overall healthier lifestyle and diet. A higher provegetarian score was associated with lower environmental impacts (GHG emissionsQ5vsQ1 = 838/1,664 kg CO2eq/year, -49.6%, P < 0.0001; CEDQ5vsQ1 = 4,853/6,775 MJ/year, -26.9%, P < 0.0001; land occupationQ5vsQ1 = 2,420/4,138 m2/year, -41.5%, P < 0.0001). Organic food consumption was also an important modulator of the relationship between provegetarian dietary patterns and environmental impacts but only among participants with diets rich in plant-based products. Conclusion: Future field studies should endeavor to integrate all the components of a sustainable diet, i.e., both diet composition and production methods. PMID- 29479531 TI - Association of Anthropometric and Lifestyle Parameters with Fitness Levels in Greek Schoolchildren: Results from the EYZHN Program. AB - Objective: The aim of the study was to evaluate physical fitness (PF) and identify its anthropometric and lifestyle determinants in a sample of Greek schoolchildren. Methods: The study sample consisted of 335,810 schoolchildren (?: 51.3%, 6-18 years old). Students' anthropometric parameters and PF levels assessed via the Eurofit test battery-were measured by trained physical education teachers and evaluated according to the available norms, while their lifestyle habits were assessed through a questionnaire. Results: In all applied PF tests, students' performance was negatively associated with the presence of obesity and central obesity, defined through international criteria for body mass index and waist to height ratio, respectively. According to multiple logistic regression analysis, the presence of overweight/obesity [odds ratio (OR): 4.43, 95% confidence interval (CI): 3.98-4.93], low adherence to the MD (KIDMED <= 3) (OR: 1.27, 95% CI: 1.09-1.48), and increased time spent in sedentary activities (>2 h per day) (OR: 1.16, 95% CI: 1.03-1.29) were positively associated with poor PF, after adjusting for age and sex. In contrast, for every 1 day increase in the weekly frequency of engagement in athletic activity, the probability of poor PF decreased by 26% (OR: 0.74, 95% CI: 0.72-0.77). In a similar model, the presence of central obesity emerged as an even stronger possible predictor of poor PF (OR: 5.20, 95% CI: 4.66-5.78), compared to the presence of general obesity. Conclusion: Higher general or abdominal adiposity, as well as the adoption of a low-quality diet and a sedentary lifestyle, is strongly associated with low PF levels during childhood. PMID- 29479533 TI - BIN1 localization is distinct from Tau tangles in Alzheimer's disease. AB - BIN1 is the second most significant Alzheimer's disease (AD) risk factor gene identified through genome-wide association studies. BIN1 is an adaptor protein that can bind to several proteins including c-Myc, clathrin, adaptor protein-2 and dynamin. BIN1 is widely expressed in the brain and peripheral tissue as ubiquitous and tissue-specific alternatively spliced isoforms that regulate membrane dynamics and endocytosis in multiple cell types. The function of BIN1 in the brain and the mechanism(s) by which AD-associated BIN1 alleles increase the risk for the disease are not known. BIN1 has been shown to interact with Tau and two studies reported a positive correlation between BIN1 expression and neurofibrillary tangle pathology in AD. However, an inverse correlation between BIN1 expression and Tau propagation has also been reported. Moreover, there have been conflicting reports on whether BIN1 is present in tangles. A recent study characterized predominant BIN1 expression in mature oligodendrocytes in the gray matter and the white matter in rodent, and the human brain. Here, we have examined BIN1 localization in the brains of patients with AD using immunohistochemistry and immunofluorescence techniques to analyze BIN1 cellular expression in relation to cellular markers and pathological lesions in AD. We report that BIN1 immunoreactivity in human AD is not associated with neurofibrillary tangles or senile plaques. Moreover, our results show that BIN1 is not expressed by resting and activated microglia, astrocytes, or macrophages in human AD. In accordance with a recent report, low-level de novo BIN1 expression can be observed in a subset of neurons in the AD brain. Further investigations are warranted to understand the complex cellular mechanisms underlying the observed correlation between BIN1 expression and the severity of tangle pathology in AD. PMID- 29479532 TI - Previous Sternotomy as a Risk Factor in Minimally Invasive Mitral Valve Surgery. AB - Background: Cardiac redo surgery, especially after a full sternotomy, is considered a high-risk procedure. Minimally invasive mitral valve surgery (MIMVS) is a potential therapeutic approach. However, current developments in interventional cardiology necessitate additional discussion regarding the therapy of choice in high-risk patients. In this context, it is necessary to clarify the perioperative and postoperative risks induced by the factor previous sternotomy in the setting of MIMVS. Thus, we present a comparative study analyzing the outcome of MIMVS after previous sternotomy vs. primary operation. Methods: We identified 19 patients who received isolated or combined mitral valve (MV) surgery via the MIMVS approach after previous full sternotomy (PS group) and compared the results to those of a group of 357 patients who received primary MIMVS (non-PS group). After a propensity score analysis, groups of n = 15 and n = 131, respectively, were subjected to a comparative evaluation. A 1-year follow-up analysis of functional cardiac parameters and clinical symptoms was performed, accompanied by a Kaplan-Meier analysis. Results: Except for the rate of realized MV reconstructions (PS group: 53.8% vs. non-PS group: 85.5%; p = 0.011), no significant differences were to be noted within the intraoperative and early postoperative course. However, patients in the PS group experienced an increased intensive care unit stay length (PS group: 2 days, 95% CI, 1-8 vs. non-PS group: 1 day, 95% CI, 1-2; p = 0.072). The follow-up examinations revealed excellent functional and clinical outcomes for both groups. The Kaplan-Meier analysis displayed no significant difference regarding the postoperative mortality (p = 0.929) related to the patients at risk. Conclusion: A previous sternotomy remains a risk factor for MIMVS and demands special attention in the early postoperative period. Nevertheless, the early- and late-term results concerning the functional and clinical outcomes suggest that the MIMVS procedure is satisfactory, even after a full sternotomy. PMID- 29479535 TI - Influenza news from the frontline: what's happening? AB - Chief Editor Anita Simonds explains what's happening on the frontline of the flu season http://ow.ly/fBW630iiYC5. PMID- 29479534 TI - Do-not-resuscitate orders as part of advance care planning in patients with COPD. AB - There is growing awareness of the need for advance care planning in patients with chronic obstructive pulmonary disease (COPD). However, do-not-resuscitate (DNR) order implementation remains a challenge in clinical practice. We retrospectively analysed an observational cohort of 569 COPD patients with 2.5-8 years of follow up in secondary care, to evaluate potential determinants and the prognostic significance of DNR order implementation and specification. 345 patients (61%) had no DNR order, of whom 27% died during a median (interquartile range (IQR)) follow-up of 1935 (1290-2448) days. 194 (39%) patients had a DNR order, of whom 17 had the order at baseline and 82% died (median (IQR) follow-up 528 (137-901) days), while 177 received an order during follow-up and 76% died (median (IQR) follow-up 1322 (721-2018) days). 88% of DNR orders were implemented during hospitalisation. 58% of the patients with a DNR order died within the first year after admission; of them, 66% died in the hospital. Age, forced expiratory volume in 1 s, chronic oxygen dependency and previous mechanical ventilation were significantly and independently associated with DNR order implementation. DNR order specification was significantly associated with increased mortality, even after adjustment for age and disease severity. These findings identify DNR orders as independent determinants of mortality, mainly implemented just before death. PMID- 29479529 TI - Delineating Crosstalk Mechanisms of the Ubiquitin Proteasome System That Regulate Apoptosis. AB - Regulatory functions of the ubiquitin-proteasome system (UPS) are exercised mainly by the ubiquitin ligases and deubiquitinating enzymes. Degradation of apoptotic proteins by UPS is central to the maintenance of cell health, and deregulation of this process is associated with several diseases including tumors, neurodegenerative disorders, diabetes, and inflammation. Therefore, it is the view that interrogating protein turnover in cells can offer a strategy for delineating disease-causing mechanistic perturbations and facilitate identification of drug targets. In this review, we are summarizing an overview to elucidate the updated knowledge on the molecular interplay between the apoptosis and UPS pathways. We have condensed around 100 enzymes of UPS machinery from the literature that ubiquitinates or deubiquitinates the apoptotic proteins and regulates the cell fate. We have also provided a detailed insight into how the UPS proteins are able to fine-tune the intrinsic, extrinsic, and p53-mediated apoptotic pathways to regulate cell survival or cell death. This review provides a comprehensive overview of the potential of UPS players as a drug target for cancer and other human disorders. PMID- 29479536 TI - Advance care planning in severe COPD: it is time to engage with the future. AB - Advance care planning should be part of our clinical routine in severe COPD http://ow.ly/Cshs30i8FS9. PMID- 29479537 TI - OMNIgene.SPUTUM suppresses contaminants while maintaining Mycobacterium tuberculosis viability and obviates cold-chain transport. AB - Tuberculosis (TB) diagnostics are centralised, requiring long-distance transportation of specimens in most resource-limited settings. We evaluated the ability of OMNIgene.SPUTUM (OM-S) to obviate cold-chain transport of TB specimens. A two-arm (same-day and after 5 days sample processing) study was conducted to assess contamination rates and Mycobacterium tuberculosis viability in OM-S-treated samples against the standard decontamination procedure (SDP) in Mozambique, using Lowenstein Jensen (LJ) and mycobacterial growth indicator tube (MGIT) culture and molecular bacterial load assay. 270 specimens were processed using OM-S and SDP in same-day and 5-day arms. Contamination was lower in OM-S treated than SDP-treated cultures: 12% versus 15% and 2% versus 27% in the same day and 5-day arms, respectively. M. tuberculosis recovery in OM-S-treated LJ cultures was 10% and 56% higher in the same-day and 5-day arms, respectively, than SDP-treated cultures, but lower in MGIT (52% and 28% lower in the same-day and 5-day arms, respectively). M. tuberculosis viable count was 1log estimated CFU.mL-1 lower in 5-day OM-S-treated sputa. OM-S was more effective at liquefying sputum with a shorter sample processing time: 22 min for culture. OM-S is simple to use and has demonstrated a high potency to suppress contaminants, maintenance of viability at ambient temperatures and higher M. tuberculosis recovery, particularly in the solid LJ cultures. Optimisation of OM-S to achieve higher MGIT culture positivity and shorter time to result will increase its application and utility in the clinical management of TB. PMID- 29479538 TI - An educational initiative to improve the team-based care of patients with idiopathic pulmonary fibrosis. AB - A successful initiative to improve best care practice in IPF supported by electronic medical record changes http://ow.ly/ORxi30hBEmy. PMID- 29479539 TI - The Tubular Penetration Depth and Adaption of Four Sealers: A Scanning Electron Microscopic Study. AB - Background. The tubular penetration and adaptation of the sealer are important factors for successful root canal filling. The aim of this study was to evaluate the tubular penetration depth of four different sealers in the coronal, middle, and apical third of root canals as well as the adaptation of these sealers to root canal walls. Materials and Methods. 50 single-rooted teeth were prepared in this study. Forty-eight of them were filled with different sealers (Cortisomol, iRoot SP, AH-Plus, and RealSeal SE) and respective core filling materials. Then the specimens were sectioned and scanning electron microscopy was employed to assess the tubular penetration and adaptation of the sealers. Results. Our results demonstrated that the maximum penetration was exhibited by RealSeal SE, followed by AH-Plus, iRoot SP, and Cortisomol. As regards the adaptation property to root canal walls, AH-Plus has best adaptation capacity followed by iRoot SP, RealSeal SE, and Cortisomol. Conclusion. The tubular penetration and adaptation vary with the different sealers investigated. RealSeal SE showed the most optimal tubular penetration, whereas AH-Plus presented the best adaptation to the root canal walls. PMID- 29479541 TI - Severe Multi-Organ Failure and Hypereosinophilia: When to Call It "Idiopathic"? AB - The hypereosinophilic syndrome is a rare disease characterized by the association between high absolute eosinophil count and eosinophil-mediated organ damage. We describe a case of a 70-year-old male with an absolute eosinophil count of 2130 cells/uL. Clinical symptoms and signs included the following: severe asthenia, axonal sensitive motor neuropathy, basal pleural effusion with signs of hypoventilation on chest radiography, and gastrointestinal symptoms such as severe diarrhea, weight loss (-10 kg in 6 months), abdominal pain, and vomiting. On physical examination he had an urticarial dermatitis on his back, abdomen, and lower limbs. An extensive instrumental and laboratory diagnostic workup was performed. When all causes of primary and secondary hypereosinophilic syndrome were excluded, treatment with solumedrol infusion and oral prednisone was started, with a rapid recover of clinical symptoms and normalization of laboratory parameters. A complete remission of the laboratory and clinical findings was achieved after 2 months and maintained over 1-year follow-up. PMID- 29479542 TI - Giant Condylomata Acuminata of Buschke-Lowenstein Associated With Paraneoplastic Hypercalcemia. AB - Low-risk human papillomavirus types 6 and 11 can manifest as giant condylomata acuminata (GCA) of Buschke-Lowenstein. Up to 50% of GCA can slowly progress over years to fungating, invasive tumors. The malignant potential is attributed to unique immune evading abilities of the human papillomavirus. A 42-year-old male presented with pain and foul-smelling discharge from his genital warts. The histopathological examination of the mass showed invasive squamous cell carcinoma, and it was associated with paraneoplastic hypercalcemia. The timely removal of long-standing GCA in order to prevent a carcinomatous transition is a priority. PMID- 29479540 TI - High Prevalence of Leptotrichia amnionii, Atopobium vaginae, Sneathia sanguinegens, and Factor 1 Microbes and Association of Spontaneous Abortion among Korean Women. AB - Objective. The purpose of this study was to (i) determine the cervical microbial composition in different abortion samples and to (ii) investigate the correlation between spontaneous abortion and cervical microbes in Korean women. Methods. We collected cervical swabs from women who had never undergone abortion (N = 36), had spontaneous abortion (N = 23), and had undergone induced abortion (N = 88) and subjected those samples to 16S rRNA pyrosequencing. Further, factor analysis and correlation between cervical microbiota and spontaneous abortion were evaluated by logistic regression analysis. Results. In spontaneous abortion women, 16 S rRNA gene sequences showed significant increases in Atopobium vaginae, Megasphaera spp., Gardnerella vaginalis, Leptotrichia amnionii, and Sneathia sanguinegens compared to women in nonabortion group. In multivariate logistic regression analysis, A. vaginae (OD = 11.27; 95% = 1.57-81), L. amnionii (OD = 11.47; 95% = 1.22-107.94), S. sanguinegens (OD = 6.89; 95% = 1.07-44.33), and factor 1 microbes (OD = 16.4; 95% = 1.88-42.5) were strongly associated with spontaneous abortion. Conclusions. This study showed a high prevalence of L. amnionii, A. vaginae, S. sanguinegens, and factor 1 microbes in spontaneous abortion and association with spontaneous abortion in Korean women. PMID- 29479543 TI - Chronicity of Anterior Cruciate Ligament Deficiency, Part 2: Radiographic Predictors of Early Graft Failure. AB - Background: Accumulating evidence suggests that long-term anterior cruciate ligament (ACL) deficiency can give rise to an abnormal tibiofemoral relationship and subsequent intra-articular lesions. However, the effects of chronic ACL deficiency (ACLD) on early graft failure after anatomic reconstruction remain unclear. Hypothesis: We hypothesized that patients with long-term ACLD lasting more than 5 years would have a greater rate of early graft failure due to insufficient intraoperative reduction of the tibia and that the preoperative and immediately postoperative abnormal tibiofemoral relationship in the sagittal plane, such as anterior tibial subluxation (ATS), would correlate with the graft status on postoperative magnetic resonance imaging (MRI). Study Design: Cohort study; Level of evidence, 3. Methods: A total of 358 patients who had undergone anatomic ACL reconstruction with hamstring grafts were divided into 5 groups based on chronicity of ACLD: (1) 0 to 6 months, (2) 6 months to 1 year, (3) 1 to 2 years, (4) 2 to 5 years, and (5) longer than 5 years. Preoperatively and immediately postoperatively, lateral radiographs in full extension were taken in all patients to evaluate the tibiofemoral relationship, specifically with regard to ATS, space for the ACL (sACL), and extension angle. All patients underwent MRI at 6 months to reveal graft status. Groups with a high rate of graft failure were further analyzed to compare demographic and radiographic factors between the intact and failure subgroups, followed by multivariate logistic regression analysis to identify predisposing factors. Results: Graft failure without trauma was observed in 4 (1.8%), 0 (0%), 1 (3.7%), 3 (9.7%), and 8 patients (17.7%) in groups 1, 2, 3, 4, and 5, respectively. Of the 76 patients in groups 4 and 5, significant differences were noted between the failure and intact subgroups in preoperative ATS (4.9 vs 2.4 mm, respectively; P < .01), side-to-side differences in sACL (sACL-SSD) (4.7 vs 1.9 mm, respectively; P < .01), extension deficit (4.4 degrees vs 1.3 degrees , respectively; P < .01), and chondral lesions (P = .02), while postoperative ATS and sACL-SSD showed no differences. Multivariate logistic regression analysis revealed that of these factors, preoperative sACL-SSD could be a risk factor for early graft failure (odds ratio, 3.2; 95% CI, 1.37-7.46). Conclusion: Early graft failure at 6 months increased in patients with ACLD longer than 2 years. In this population, preoperative sACL-SSD was the most significant risk factor for early graft failure on MRI. However, immediately postoperative radiographic measurements had no effect on graft failure rates. PMID- 29479544 TI - Ulnar Collateral Ligament Reconstruction Versus Repair With Internal Bracing: Comparison of Cyclic Fatigue Mechanics. AB - Background: Ulnar collateral ligament (UCL) injuries have increased significantly in recent years, and reconstruction has become the preferred treatment for UCL injury over ligament repair. In a recent study, UCL repair with internal bracing demonstrated significantly greater resistance to gap formation in biomechanical tests, even at low cycles of valgus loading. Purpose/Hypothesis: The purpose of this study was to compare the fatigue and failure mechanics of traditional UCL reconstruction with UCL repair and internal bracing. We hypothesized that repaired specimens would have less gap formation, closer return to native gap formation, and greater maximum torque to failure versus traditionally reconstructed specimens. Study Design: Controlled laboratory study. Methods: Ten matched pairs of cadaveric elbows were positioned at 90 degrees of flexion and the native UCL subjected to 500 cycles of subfailure valgus loading. A simulated tear was created, and the 10 cycles were repeated. Each pair of specimens was next given repair with internal bracing on 1 side and a modified Jobe reconstruction on the contralateral side, followed by 100 manual cycles of flexion-extension, 500 cycles of valgus rotation, and, finally, rotation to failure. Results: The specimens that received the repair unexpectedly experienced significantly less gapping in the torn state than did those in the reconstruction group. At the 10th cycle, repaired UCL injuries had significantly less gap formation than the reconstructed UCLs. At the 100th and 500th cycles, repaired UCL injuries continued to experience significantly less gap formation as compared with the reconstructed injuries. Conclusion: When compared with the gold standard reconstruction technique, UCL repair with internal bracing is more resistant to gap formation under fatigue loading. However, the unexpected early difference between the torn states may have confounded this finding. Time-zero failure properties of this repair technique are on par with those of traditional reconstruction, even after 500 cycles of valgus loading. Clinical Relevance: UCL reconstruction has become a common procedure among adolescent and elite-level throwers. Recent data suggest that UCL repair may be a viable option for younger athletes with acute proximal or distal UCL tears, allowing a faster return to play. PMID- 29479545 TI - Central Tendon Injuries of Hamstring Muscles: Case Series of Operative Treatment. AB - Background: As compared with injuries involving muscle only, those involving the central hamstring tendon have a worse prognosis. Limited information is available regarding the surgical treatment of central tendon injuries of the hamstrings. Purpose: To describe the operative treatment and outcomes of central tendon injuries of the hamstrings among athletes. Study Design: Case series; Level of evidence, 4. Methods: Eight athletes (6 top level, 2 recreational) with central hamstring tendon injuries underwent magnetic resonance imaging and surgical treatment. The indication for surgery was recurrent (n = 6) or acute (n = 2) central hamstring tendon injury. All patients followed the same postoperative rehabilitation protocol, and return to play was monitored. Results: Magnetic resonance imaging found a central tendon injury in all 3 hamstring muscles (long head of the biceps femoris, semimembranosus, and semitendinosus) with disrupted tendon ends. In acute and recurrent central tendon injuries, full return to play was achieved at 2.5 to 4 months. There were no adverse events during follow-up. Conclusion: Central tendon injuries of the hamstrings can be successfully repaired surgically after acute and recurrent ruptures. PMID- 29479546 TI - Potential Adverse Effects of Broad-Spectrum Antimicrobial Exposure in the Intensive Care Unit. AB - Background: The potential adverse effects of empiric broad-spectrum antimicrobial use among patients with suspected but subsequently excluded infection have not been fully characterized. We sought novel methods to quantify the risk of adverse effects of broad-spectrum antimicrobial exposure among patients admitted to an intensive care unit (ICU). Methods: Among all adult patients admitted to ICUs at a single institution, we selected patients with negative blood cultures who also received >=1 broad-spectrum antimicrobials. Broad-spectrum antimicrobials were categorized in >=1 of 5 categories based on their spectrum of activity against potential pathogens. We performed, in serial, 5 cohort studies to measure the effect of each broad-spectrum category on patient outcomes. Exposed patients were defined as those receiving a specific category of broad-spectrum antimicrobial; nonexposed were all other patients in the cohort. The primary outcome was 30-day mortality. Secondary outcomes included length of hospital and ICU stay and nosocomial acquisition of antimicrobial-resistant bacteria (ARB) or Clostridium difficile within 30 days of admission. Results: Among the study cohort of 1918 patients, 316 (16.5%) died within 30 days, 821 (42.8%) had either a length of hospital stay >7 days or an ICU length of stay >3 days, and 106 (5.5%) acquired either a nosocomial ARB or C. difficile. The short-term use of broad-spectrum antimicrobials in any of the defined broad-spectrum categories was not significantly associated with either primary or secondary outcomes. Conclusions: The prompt and brief empiric use of defined categories of broad-spectrum antimicrobials could not be associated with additional patient harm. PMID- 29479547 TI - Keratitis due to an Unusual Pathogenic Social Amoeba, Dictyostelium polycephalum. PMID- 29479549 TI - Challenges in Procalcitonin Implementation in the Real-World. PMID- 29479548 TI - Incidence, Etiology, and Outcomes of Community-Acquired Pneumonia: A Population Based Study. AB - Background: The microbial etiology of community-acquired pneumonia (CAP) is often unclear in clinical practice, and previous studies have produced variable results. Population-based studies examining etiology and incidence are lacking. This study examined the incidence and etiology of CAP requiring hospitalization in a population-based cohort as well as risk factors and outcomes for specific etiologies. Methods: Consecutive admissions due to CAP in Reykjavik, Iceland were studied. Etiologic testing was performed with cultures, urine-antigen detection, and polymerase chain reaction analysis of airway samples. Outcomes were length of stay, intensive care unit admission, assisted ventilation, and mortality. Results: The inclusion rate was 95%. The incidence of CAP requiring hospitalization was 20.6 cases per 10000 adults/year. A potential pathogen was detected in 52% (164 of 310) of admissions and in 74% (43 of 58) with complete sample sets. Streptococcuspneumoniae was the most common pathogen (61 of 310, 20%; incidence: 4.1/10000). Viruses were identified in 15% (47 of 310; incidence: 3.1/10000), Mycoplasmapneumoniae were identified in 12% (36 of 310; incidence: 2.4/10000), and multiple pathogens were identified in 10% (30 of 310; incidence: 2.0/10000). Recent antimicrobial therapy was associated with increased detection of M pneumoniae (P < .001), whereas a lack of recent antimicrobial therapy was associated with increased detection of S pneumoniae (P = .02). Symptoms and outcomes were similar irrespective of microbial etiology. Conclusions: Pneumococci, M pneumoniae, and viruses are the most common pathogens associated with CAP requiring hospital admission, and they all have a similar incidence that increases with age. Symptoms do not correlate with specific agents, and outcomes are similar irrespective of pathogens identified. PMID- 29479551 TI - Mycobacterium chimaera Infection After Aortic Valve Replacement Presenting With Aortic Dissection and Pseudoaneurysm. AB - We present a case of Mycobacterium chimaera infection presenting with aortic dissection and pseudoaneuysm in a 22-year-old man with a past history of aortic valve replacement. Clinicians should consider M. chimaera infection in those presenting with aortic dissection as a late complication of cardiovascular surgery. PMID- 29479552 TI - Cryptococcus and Coccidioides in Sarcoidosis. PMID- 29479550 TI - Sexually Transmitted Infections Among HIV-Infected Individuals in the District of Columbia and Estimated HIV Transmission Risk: Data From the DC Cohort. AB - Background: Washington, DC, has one of the highest rates of HIV infection in the United States. Sexual intercourse is the leading mode of HIV transmission, and sexually transmitted infections (STIs) are a risk factor for HIV acquisition and transmission. Methods: We evaluated the incidence and demographic factors associated with chlamydia, gonorrhea, and syphilis among HIV-infected persons enrolled at 13 DC Cohort sites from 2011 to 2015. Using Poisson regression, we assessed covariates of risk for incident STIs. We also examined HIV viral loads (VLs) at the time of STI diagnosis as a proxy for HIV transmission risk. Results: Six point seven percent (451/6672) developed an incident STI during a median follow-up of 32.5 months (4% chlamydia, 3% gonorrhea, 2% syphilis); 30% of participants had 2 or more STI episodes. The incidence rate of any STIs was 3.8 cases per 100 person-years (95% confidence interval [CI], 3.5-4.1); age 18-34 years, 10.8 (95% CI, 9.7-12.0); transgender women, 9.9 (95% CI, 6.9-14.0); Hispanics, 9.2 (95% CI, 7.2-11.8); and men who have sex with men (MSM), 7.7 (95% CI, 7.1-8.4). Multivariate Poisson regression showed younger age, Hispanic ethnicity, MSM risk, and higher nadir CD4 counts to be strongly associated with STIs. Among those with an STI, 41.8% had a detectable VL within 1 month of STI diagnosis, and 14.6% had a VL >=1500 copies/mL. Conclusions: STIs are highly prevalent among HIV-infected persons receiving care in DC. HIV transmission risk is considerable at the time of STI diagnosis. Interventions toward risk reduction, antiretroviral therapy adherence, and HIV virologic suppression are critical at the time of STI evaluation. PMID- 29479555 TI - Validation of the Minority Stress Scale Among Italian Gay and Bisexual Men. AB - The experience of sexual orientation stigma (e.g., homophobic discrimination and physical aggression) generates minority stress, a chronic form of psychosocial stress. Minority stress has been shown to have a negative effect on gay and bisexual men's (GBM's) mental and physical health, increasing the rates of depression, suicidal ideation, and HIV risk behaviors. In conservative religious settings, such as Italy, sexual orientation stigma can be more frequently and/or more intensively experienced. However, minority stress among Italian GBM remains understudied. The aim of this study was to explore the dimensionality, internal reliability, and convergent validity of the Minority Stress Scale (MSS), a comprehensive instrument designed to assess the manifestations of sexual orientation stigma. The MSS consists of 50 items assessing (a) Structural Stigma, (b) Enacted Stigma, (c) Expectations of Discrimination, (d) Sexual Orientation Concealment, (e) Internalized Homophobia Toward Others, (f) Internalized Homophobia toward Oneself, and (g) Stigma Awareness. We recruited an online sample of 451 Italian GBM to take the MSS. We tested convergent validity using the Perceived Stress Questionnaire. Through exploratory factor analysis, we extracted the 7 theoretical factors and an additional 3-item factor assessing Expectations of Discrimination From Family Members. The MSS factors showed good internal reliability (ordinal alpha > .81) and good convergent validity. Our scale can be suitable for applications in research settings, psychosocial interventions, and, potentially, in clinical practice. Future studies will be conducted to further investigate the properties of the MSS, exploring the association with additional health-related measures (e.g., depressive symptoms and anxiety). PMID- 29479554 TI - Molecular Identification of Bacteria in Intra-abdominal Abscesses Using Deep Sequencing. AB - Background: Intra-abdominal abscesses are localized collections of pus, which generally arise from a breach in the normal mucosal defense barrier that allows bacteria from gastrointestinal tract, and less commonly from the gynecologic or urinary tract, to induce inflammation, resulting in an infection. The microbiology of these abscesses is usually polymicrobial, associated with the primary disease process. However, the microbial identity, diversity and richness in intra-abdominal abscesses have not been well characterized, due in part to the difficulty in cultivating commensal organisms using standard culture-based techniques. Methods: We used culture-independent 16S rRNA Illumina sequencing to characterize bacterial communities in intra-abdominal abscesses collected by percutaneous drainage. A total of 43 abscess samples, including 19 (44.2%) Gram stain and culture-negative specimens, were analyzed and compared with results from conventional microbiologic cultures. Results: Microbial composition was determined in 8 of 19 culture-negative samples and 18 of 24 culture-positive samples, identifying a total of 221 bacterial taxa or operational taxonomic units (OTUs) and averaging 13.1 OTUs per sample (interquartile range, 8-16.5 OTUs). Microbial richness for monomicrobial and polymicrobial samples was significantly higher than culture-negative samples (17 and 15.2 OTUs vs 8 OTUs, respectively), with a trend toward a higher microbial diversity (Shannon diversity index of 0.87 and 1.18 vs 0.58, respectively). Conclusions: The bacterial consortia identified by cultures correlated poorly with the microbial composition determined by 16S rRNA sequencing, and in most cases, the cultured isolates were minority constituents of the overall abscess microbiome. Intra-abdominal abscesses were generally polymicrobial with a surprisingly high microbial diversity, but standard culture-based techniques failed to reveal this diversity. These data suggest that molecular-based approaches may be helpful for documenting the presence of bacteria in intra-abdominal abscesses where standard cultures are unrevealing, particularly in the setting of prior antibiotic exposure. PMID- 29479553 TI - Outpatient Antibiotic Stewardship: A Growing Frontier-Combining Myxovirus Resistance Protein A With Other Biomarkers to Improve Antibiotic Use. AB - Background: The majority of oral antibiotics are prescribed in outpatient primary and urgent care clinics for acute respiratory infections. Effective antibiotic stewardship must include proper prescribing for outpatients as well as for those in a hospital or long-term care facility. Methods: Major databases, including MEDLINE and the Cochrane Library, were searched for prospective human clinical studies, including children and/or adults published between January 1966 and November 2017 that evaluated Myxovirus resistance protein A (MxA) as a biomarker for diagnosing viral infections as well as both C-reactive protein (CRP) and procalcitonin (PCT) as potential biomarkers for identifying and differentiating true bacterial upper respiratory infection (URI) from colonization. Results: Ten prospective human studies, totaling 1683 patients, were identified that evaluated MxA as a viral biomarker in children and/or adults. Both systematic review articles, meta-analyses, and randomized controlled clinical trials that examined CRP and/or PCT as a biomarker for identifying clinically significant bacterial infections and supporting antibiotic stewardship were identified. Conclusions: Quick and accurate differentiation between a viral and bacterial respiratory infection is critical to effectively combat antibiotic misuse. MxA expression in peripheral blood is a highly specific marker for viral infection. Combining MxA with other inflammatory biomarkers to test for respiratory infections offers enhanced sensitivity and specificity, forming an excellent tool for antibiotic stewardship in the outpatient setting. PMID- 29479556 TI - Sarcoidosis Manifestion Centered on the Thalamic Pulvinar Leading to Persistent Astasia. AB - View Supplementary Video. PMID- 29479557 TI - Benefits and Barriers to Teaching Medical Students in an Ob-Gyn Clinic. AB - Introduction: As the US health-care system has evolved over the past decade, access to obstetric care in rural communities has declined, and there has been a challenge in retaining obstetrics and gynecology (OB-GYN) providers to train the next generation of physicians. The current pilot study sought to identify the factors that influence faculty who train medical students within the field of OB GYN with the hope of influencing recruitment and retention of providers for the future. Methods: Clinical OB-GYN faculty within the University of Washington School of Medicine regional medical education program were surveyed about practice patterns and beliefs regarding medical student training as part of a pilot study on provider recruitment and retention. Results: Fifty-seven eligible respondents completed the survey. Most (88.9%) reported their hospitals encourage student participation in patient care. Students in their practices participate in many aspects of patient care, including conducting exams (96.2%) and participating in the operating room (94.3%). The majority found the rewarding aspects of teaching medical students to be intellectual stimulation (90.9%), continuing the tradition of medical teaching (87.5%), and the intrinsic satisfaction of teaching (83.6%). Challenging aspects of teaching included reduced reimbursement (40%) and the student/workload (63.6%). Discussion: Medical student education continues to rely on a generation's medical professionals to impart their knowledge to the next. We hope that with a better understanding of the benefits of participation and minimization of the challenges, we can perpetuate this tradition despite the uncertainty in our health-care system. PMID- 29479558 TI - Plasma Menthol Glucuronide as a Biomarker of Acute Menthol Inhalation. AB - Objectives: Menthol is often added to cigarettes and e-cigarette solutions for its cooling and anti-irritant effects, and may contribute to development of nicotine dependence, particularly in vulnerable populations such as adolescents, and among African Americans. Menthol is rapidly metabolized to menthol glucuronide (MG) with little or no unconjugated menthol measurable in venous blood. Human challenge studies of the effects of inhaled menthol, and of its interactions with nicotine, would benefit from a quantitative measure of acute menthol exposure. Our objective was to determine whether plasma MG concentrations might be a suitable quantitative biomarker of acute menthol exposure following its inhalation. Methods: We performed a secondary analysis of plasma MG concentrations obtained during a study of the effects of inhaled menthol on behavioral responses to intravenous nicotine. MG concentrations were followed over time in venous plasma from 48 participants following inhalation of aerosols from e-cigarettes employing solutions containing either of 2 menthol concentrations or placebo. Results: Whereas plasma MG concentrations were variable, they showed a dose-dependent increase following menthol inhalation. Conclusions: Measurement of plasma MG may be useful to assess inter-individual differences in acute menthol exposure in human challenge studies involving menthol inhalation. PMID- 29479559 TI - Thymoma-associated panencephalitis: a newly emerging paraneoplastic neurologic syndrome. AB - Recently, a few case reports of thymoma-associated panencephalitis (TAPE) have brought to light a disease entity that has not been fully characterized. Literature review of TAPE reveals an array of associated neuronal antibodies, with varied responses to thymomectomy with or without immunotherapy. This report describes a case of TAPE and proposes that the GABAA receptor antibody is a potential target antigen driving the immune process in this disease entity. Treatment-wise, early thymomectomy consistently improves the overall course of disease. Further study of such cases will be critical in clarifying the mechanisms of disease, improving early diagnosis, and developing targeted approaches to treatment. PMID- 29479560 TI - Atypical perioperative management for duodenal obstruction in an infant with heterotaxy syndrome: a case report. AB - Background: Heterotaxy syndrome (HS) is characterized by a wide variety of cardiac and extra-cardiac malformations, including pulmonary valve stenosis, interruption of the inferior vena cava, total anomalous pulmonary venous connection (TAPVC), asplenia, polysplenia, intestinal malrotation, and preduodenal portal vein (PDPV). We report the case of a heterotaxic infant with an infracardiac TAPVC and preduodenal portal vein who experienced repetitive hemodynamic instability during urgent laparotomy for duodenal obstruction. Case presentation: A 3-day-old boy with HS was planned to undergo urgent laparotomy for duodenal atresia. Echocardiogram showed an interrupted inferior vena cava, single right ventricle, pulmonary valve stenosis, and infracardiac TAPVC. On exploratory laparotomy, intestinal malrotation characterized by Ladd's band was found. During further exploration, repetitive severe hypotension and hypoxia occurred. Thorough examination revealed a greatly dilated PDPV crossing over and compressing the proximal duodenum externally. Finally, we considered the possibility that surgical manipulation directly compressed the dilated PDPV into which the TAPVC had pulmonary venous drainage, leading to repetitive pulmonary venous obstruction (PVO). Computed tomography, which was examined after laparotomy, indicated that the vertical vein from pulmonary venous confluence drained into the portal vein. Conclusion: PDPV is a rare anomaly associated with HS. In case of intestinal malrotation and duodenal obstruction in HS with infracardiac TAPVC, both the presence of PDPV and the possibility of pulmonary venous drainage into the PDPV should be considered by pediatric surgeons and anesthesiologists performing laparotomy to avoid catastrophic PVO. PMID- 29479561 TI - Using biomimetic polymers in place of noncollagenous proteins to achieve functional remineralization of dentin tissues. AB - In calcified tissues such as bones and teeth, mineralization is regulated by an extracellular matrix, which includes non-collagenous proteins (NCP). This natural process has been adapted or mimicked to restore tissues following physical damage or demineralization by using polyanionic acids in place of NCPs, but the remineralized tissues fail to fully recover their mechanical properties. Here we show that pre-treatment with certain amphiphilic peptoids, a class of peptide like polymers consisting of N-substituted glycines that have defined monomer sequences, enhances ordering and mineralization of collagen and induces functional remineralization of dentin lesions in vitro. In the vicinity of dentin tubules, the newly formed apatite nano-crystals are co-aligned with the c-axis parallel to the tubular periphery and recovery of tissue ultrastructure is accompanied by development of high mechanical strength. The observed effects are highly sequence-dependent with alternating polar and non-polar groups leading to positive outcomes while diblock sequences have no effect. The observations suggest aromatic groups interact with the collagen while the hydrophilic side chains bind the mineralizing constituents and highlight the potential of synthetic sequence-defined biomimetic polymers to serve as NCP mimics in tissue remineralization. PMID- 29479562 TI - Anatomical and Radiological Considerations When Colonic Perforation Leads to Subcutaneous Emphysema, Pneumothoraces, Pneumomediastinum, and Mediastinal Shift. AB - While colonoscopy is generally regarded as a safe procedure, colonic perforation can occur and the risk of this is higher when interventional procedures are undertaken. The presentation may be acute or delayed depending on the extent of the perforation. Extracolonic gas following colonic perforation can migrate to several body compartments that are embryologically related and it has previously been reported in the thorax, mediastinum, neck, scrotum, and lower limbs. This review discusses in detail the anatomical pathways that led to a rare case of widespread subcutaneous emphysema, bilateral pneumothoraces, pneumomediastinum, and mediastinal shift from colonic perforation during a diagnostic colonoscopy. This is further supported by a description of the radiological images. PMID- 29479563 TI - Imaging Lung Cancer by Using Chemical Exchange Saturation Transfer MRI With Retrospective Respiration Gating. AB - Performing chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) in lung tissue is difficult because of motion artifacts. We, therefore, developed a CEST MRI acquisition and analysis method that performs retrospective respiration gating. Our method used an acquisition scheme with a short 200-millisecond saturation pulse that can accommodate the timing of the breathing cycle, and with saturation applied at frequencies in 0.03-ppm intervals. The Fourier transform of each image was used to calculate the difference in phase angle between adjacent pixels in the longitudinal direction of the respiratory motion. Additional digital filtering techniques were used to evaluate the breathing cycle, which was used to construct CEST spectra from images during quiescent periods. Results from CEST MRI with and without respiration gating analysis were used to evaluate the asymmetry of the magnetization transfer ratio (MTRasym), a measure of CEST, for an egg white phantom that underwent cyclic motion, in the liver of healthy patients, as well as liver and tumor tissues of patients diagnosed with lung cancer. Retrospective respiration gating analysis produced more precise measurements in all cases with significant motion compared with nongated analysis methods. Finally, a preliminary clinical study with the same respiration-gated CEST MRI method showed a large increase in MTRasym after radiation therapy, a small increase or decrease in MTRasym after chemotherapy, and mixed results with combined chemoradiation therapy. Therefore, our retrospective respiration-gated method can improve CEST MRI evaluations of tumors and organs that are affected by respiratory motion. PMID- 29479564 TI - Radical Trapping Study of the Relaxation of bis-Fe(IV) MauG. AB - The di-heme enzyme, MauG, utilizes a high-valent, charge-resonance stabilized bis Fe(IV) state to perform protein radical-based catalytic chemistry. Though the bis Fe(IV) species is able to oxidize remote tryptophan residues on its substrate protein, it does not rapidly oxidize its own residues in the absence of substrate. The slow return of bis-Fe(IV) MauG to its resting di-ferric state occurs via up to two intermediates, one of which has been previously proposed by Ma et al. (Biochem J 2016; 473:1769) to be a methionine-based radical in a recent study. In this work, we pursue intermediates involved in the return of high valent MauG to its resting state in the absence of the substrate by EPR spectroscopy and radical trapping. The bis-Fe(IV) MauG is shown by EPR, HPLC, UV Vis, and high-resolution mass spectrometry to oxidize the trapping agent, 5,5 dimethyl-1-pyrroline N-oxide (DMPO) to a radical species directly. Nitrosobenzene was also employed as a trapping agent and was shown to form an adduct with high valent MauG species. The effects of DMPO and nitrosobenzene on the kinetics of the return to di-ferric MauG were both investigated. This work eliminates the possibility that a MauG-based methionine radical species accumulates during the self-reduction of bis-Fe(IV) MauG. PMID- 29479565 TI - Qidong hepatitis B virus infection cohort: a 25-year prospective study in high risk area of primary liver cancer. AB - Qidong hepatitis B virus (HBV) infection cohort (QBC) is a prospective community based study designed to investigate causative factors of primary liver cancer (PLC) in Qidong, China, where both PLC and HBV infection are highly endemic. Residents aged 20-65 years, living in seven townships of Qidong, were surveyed using hepatitis B surface antigen (HBsAg) serum test and invited to participate in QBC from June 1991 to December 1991. A total of 852 and 786 participants were enrolled in HBsAg-positive and HBsAg-negative sub-cohorts in May 1992, respectively. All participants were actively followed up in person, received HBsAg, alanine aminotransferase (ALT), alpha-fetoprotein (AFP) tests and upper abdominal ultrasonic examination, and donated blood and urine samples once or twice a year. The total response rate was 99.6%, and the number of incident PLC was 201 till the end of February 2017. The ratio of incidence rates was 12.32 (95% confidence interval[CI]=7.16-21.21, P < 0.0001) in HBsAg-positive arm compared with HBsAg-negative arm. The relative risk of PLC was 13.25 (95% CI=6.67 26.33, P < 0.0001) and 28.05 (95% CI=13.87-56.73, P < 0.0001) in the HBsAg+/HBeAg group and the HBsAg+/HBeAg+ group, respectively, as compared to the HBsAg-/HBeAg group. A series of novel PLC-related mutations including A2159G, A2189C and G2203W at the C gene, A799G, A987G and T1055A at the P gene of HBV genome were identified by using samples from the cohort. The mutation in hepatitis B virus (HBV) basal core promoter region of HBV genome has an accumulative effect on the occurrence of PLC. In addition, the tripartite relationship of aflatoxin exposure, P53 mutation and PLC was also investigated. Dynamic prediction model for PLC risk by using its long-term follow-up information and serial blood samples for QBC was developed. This model is expected to improve the efficiency of PLC screening in HBV infection individuals. PMID- 29479566 TI - Liquid chromatography-tandem mass spectrometry for the simultaneous quantitation of ceftriaxone, metronidazole and hydroxymetronidazole in plasma from seriously ill, severely malnourished children. AB - We have developed and validated a novel, sensitive, selective and reproducible reversed-phase high-performance liquid chromatography method coupled with electrospray ionization mass spectrometry (HPLC-ESI-MS/MS) for the simultaneous quantitation of ceftriaxone (CEF), metronidazole (MET) and hydroxymetronidazole (MET-OH) from only 50 uL of human plasma, and unbound CEF from 25 uL plasma ultra filtrate to evaluate the effect of protein binding. Cefuroxime axetil (CEFU) was used as an internal standard (IS). The analytes were extracted by a protein precipitation procedure with acetonitrile and separated on a reversed-phase Polaris 5 C18-Analytical column using a mobile phase composed of acetonitrile containing 0.1% (v/v) formic acid and 10 mM aqueous ammonium formate pH 2.5, delivered at a flow-rate of 300 uL/min. Multiple reaction monitoring was performed in the positive ion mode using the transitions m/z555.1-> m/z396.0 (CEF), m/z172.2-> m/z 128.2 (MET), m/z188.0-> m/z125.9 (MET-OH) and m/z528.1-> m/z 364.0 (CEFU) to quantify the drugs. Calibration curves in spiked plasma and ultra-filtrate were linear ( r 2 >= 0.9948) from 0.4-300 ug/mL for CEF, 0.05-50 ug/mL for MET and 0.02 - 30 ug/mL for MET-OH. The intra- and inter- assay precisions were less than 9% and the mean extraction recoveries were 94.0% (CEF), 98.2% (MET), 99.6% (MET-OH) and 104.6% (CEF in ultra-filtrate); the recoveries for the IS were 93.8% (in plasma) and 97.6% (in ultra-filtrate). The validated method was successfully applied to a pharmacokinetic study of CEF, MET and MET-OH in hospitalized children with complicated severe acute malnutrition following an oral administration of MET and intravenous administration of CEF over the course of 72 hours. PMID- 29479567 TI - Variation among cleft centres in the use of secondary surgery for children with cleft palate: a retrospective cohort study. AB - Objectives: To test whether cleft centres vary in their use of secondary cleft palate surgery, also known as revision palate surgery, and if so to identify modifiable hospital- and surgeon-factors that are associated with use of secondary surgery. Design: Retrospective cohort study. Setting: Forty-three paediatric hospitals across the United States. Patients: Children with cleft lip and palate who underwent primary cleft palate repair from 1999 to 2013. Main outcome measures: Time from primary cleft palate repair to secondary palate surgery. Results: We identified 4,939 children who underwent primary cleft palate repair. At ten years after primary palate repair, 44% of children had undergone secondary palate surgery. Significant variation existed among hospitals (p<0.001); the proportion of children undergoing secondary surgery by 10 years ranged from 9% to 77% across hospitals. After adjusting for patient demographics, primary palate repair before nine months of age was associated with an increased hazard of secondary palate surgery (initial hazard ratio 6.74, 95% CI 5.30-8.73). Postoperative antibiotics, surgeon procedure volume, and hospital procedure volume were not associated with time to secondary surgery (p>0.05). Of the outcome variation attributable to hospitals and surgeons, between-hospital differences accounted for 59% (p<0.001), while between-surgeon differences accounted for 41% (p<0.001). Conclusions: Substantial variation in the hazard of secondary palate surgery exists depending on a child's age at primary palate repair and the hospital and surgeon performing their repair. Performing primary palate repair before nine months of age substantially increases the hazard of secondary surgery. Further research is needed to identify other factors contributing to variation in palate surgery outcomes among hospitals and surgeons. PMID- 29479568 TI - Relationship Between Fibrosis Detected on Late Gadolinium-Enhanced Cardiac Magnetic Resonance and Re-Entrant Activity Assessed With Electrocardiographic Imaging in Human Persistent Atrial Fibrillation. AB - OBJECTIVES: This study sought to assess the relationship between fibrosis and re entrant activity in persistent atrial fibrillation (AF). BACKGROUND: The mechanisms involved in sustaining re-entrant activity during AF are poorly understood. METHODS: Forty-one patients with persistent AF (age 56 +/- 12 years; 6 women) were evaluated. High-resolution electrocardiographic imaging (ECGI) was performed during AF by using a 252-chest electrode array, and phase mapping was applied to locate re-entrant activity. Sites of high re-entrant activity were defined as re-entrant regions. Late gadolinium-enhanced (LGE) cardiac magnetic resonance (CMR) was performed at 1.25 * 1.25 * 2.5 mm resolution to characterize atrial fibrosis and measure atrial volumes. The relationship between LGE burden and the number of re-entrant regions was analyzed. Local LGE density was computed and characterized at re-entrant sites. All patients underwent catheter ablation targeting re-entrant regions, the procedural endpoint being AF termination. Clinical, CMR, and ECGI predictors of acute procedural success were then analyzed. RESULTS: Left atrial (LA) LGE burden was 22.1 +/- 5.9% of the wall, and LA volume was 74 +/- 21 ml/m2. The number of re-entrant regions was 4.3 +/- 1.7 per patient. LA LGE imaging was significantly associated with the number of re entrant regions (R = 0.52, p = 0.001), LA volume (R = 0.62, p < 0.0001), and AF duration (R = 0.54, p = 0.0007). Regional analysis demonstrated a clustering of re-entrant activity at LGE borders. Areas with high re-entrant activity showed higher local LGE density as compared with the remaining atrial areas (p < 0.0001). Failure to achieve AF termination during ablation was associated with higher LA LGE burden (p < 0.001), higher number of re-entrant regions (p < 0.001), and longer AF duration (p = 0.008). CONCLUSIONS: The number of re-entrant regions during AF relates to the extent of LGE on CMR, with the location of these regions clustering to LGE areas. These characteristics affect procedural outcomes of ablation. PMID- 29479569 TI - Interaction between SNCA, LRRK2 and GAK increases susceptibility to Parkinson's disease in a Chinese population. AB - PD is a complex disease, and may result from gene-gene and gene-environment interactions. There are limited studies on gene-gene interactions in PD. We and others have previously shown that SNCA rs356219, LRRK2 (rs2046932 and rs7304279) and GAK (rs1564282) are risk factors in sporadic PD. Since the expression of SNCA and neurotoxicity of alpha-synuclein are affected by LRRK2 and GAK, we hypothesize that their genetic risk variants may interact with each other. Here we investigated the interaction of SNCA rs356219, LRRK2rs7304279 and rs2046932 and GAK rs1564282 using the Multifactor Dimensionality Reduction (MDR) in a Chinese PD patient-control series (534 patients and 435 controls) and the cumulative risk effect of SNCA, LRRK2 and GAK. The MDR analysis showed a significant gene-gene interaction between the rs356219 of SNCA, rs2046932 of LRRK2 and rs1564282 of GAK. Moreover, individuals with increasing numbers of variants had an increasing likelihood of having PD, compared with those carrying none of the variants. The estimated OR for developing PD in individuals carrying 3 variants was 5.89. We demonstrated for the first time that SNPs in SNCA, LRRK2 and GAK interacted with each other to confer an increased risk of PD. In addition, PD risk increased cumulatively with the increasing number of variants. PMID- 29479570 TI - A novel A792D mutation in the CSF1R gene causes hereditary diffuse leukoencephalopathy with axonal spheroids characterized by slow progression. AB - Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant white matter disease that causes adult-onset cognitive impairment. The clinical manifestations are a variable combination of personality and behavioral changes, cognitive decline, parkinsonism, spasticity, and epilepsy. In 2012, mutations in the gene encoding colony stimulating factor 1 receptor (CSF1R) were identified as the cause of HDLS. As the numbers of reported mutations are limited, the understanding of whole pathogenesis needs accumulation of disease causing mutations with detailed clinical descriptions. We describe a Japanese family with autosomal dominant adult-onset cognitive impairment and characteristic white matter lesions. Genetic testing revealed a novel p.A792D mutation in the tyrosine kinase domain of CSF1R in two affected family members. The symptom profile of the present cases mostly matched the previously reported cases, with the notable exceptions of late-onset and long disease duration. PMID- 29479571 TI - Income in midlife and dementia related mortality over three decades: A Norwegian prospective study. AB - Studies on midlife income and dementia are scarce, and our main aim was to investigate midlife with later risk of dementia related mortality, adjusting for education and dementia related risk factors. The study population consisted of Norwegian men, aged 40-59 years in 1980 at income assessment, which participated in Norwegian health examination studies in the period 1980-2002 where risk factors such as cholesterol level, hypertension, smoking, cardiovascular disease, and diabetes were assessed. Dementia related mortality was defined as a dementia diagnosis on the death certificate until 2012. Cox regression was used. The study included 45,944 participants and 1062 dementia related deaths. There was no association between midlife income and dementia mortality risk (HR = 1.04, 95% confidence interval (CI) 0.85, 1.28 for the lowest fifth of income compared to those in the highest fifth). For total mortality, there was a strong inverse association with income (HR = 1.61, 95% CI 1.53, 1.69), which was attenuated when adjusting for education and risk factors, but still significant (HR = 1.27, 95% CI 1.20, 1.34). Lower educational attainment was significantly associated with increased dementia mortality risk, also after adjustment for income and other known risk factors (HR = 1.30, 95% CI 1.03, 1.64 comparing low versus high education). Midlife income was not associated with dementia related mortality, but low education was independently linked to increased risk of dementia related mortality. Our results support the cognitive reserve hypothesis suggesting that mental activity and not material resources are related to dementia related mortality. PMID- 29479573 TI - Benefit of ELISpot in early diagnosis of tuberculous meningoencephalitis: Case report and literature review. AB - Tuberculous meningitis and meningoencephalitis are rare and dangerous complications of infections with mycobacteria-complex. Usually these are complications of systemic florid infection with Mycobacterium (M.) tuberculosis. They are most often seen in immune compromised patients. The confirmation of diagnosis can be elaborate and delayed due to long-term culture requirements for M. tuberculosis. We present a female patient, without history of immunosuppression, who was diagnosed with tuberculous meningoencephalitis using ELISpot to detect immune reactivity against mycobacterial antigens with lymphocytes from cerebrospinal fluid (CSF). ELISpot with CSF derived lymphocytes seems to be an appropriate method to diagnose tuberculous meningitis and meningoencephalitis and to make therapeutic decisions easier and earlier in atypical cases of infection with M. tuberculosis. PMID- 29479572 TI - Acute ischemic stroke associated with nephrotic syndrome: Incidence and significance - Retrospective cohort study. AB - We report 10 cases with arterial ischemic stroke (AIS) with nephrotic syndrome (NS), and clarified its incidence and clinical characteristics. The patients having albumin less than 3.0 g/dl and serum cholesterol greater than 250 mg/dl at the same time were retrospectively screened from 11,161 cases of stroke. Furthermore, the patients of AIS showing heavy proteinuria were selected. The 10 cases were diagnosed as AIS with NS. Its incidence was 0.09% of all kinds of stroke and 0.12% of AIS. Their subtypes were 6 large-artery atherosclerosis, 3 small-vessel occlusion, and 1 cardioembolism. We carried out a retrospective cohort study to assess the association between NS and atherosclerosis progression in AIS patients. Seven AIS patients with NS due to diabetic nephropathy (cases; NS group) were compared with patients with AIS and diabetes mellitus (DM) without NS (control group). Control group subjects were matched in a 2:1 ratio to cases by age, sex, use of medications for DM, and hemoglobin A1c (HbA1c) level. The NS group had high cerebral artery atherosclerosis scores, especially in the anterior circulation. The NS group demonstrated atherosclerosis of the internal carotid and lower extremity arteries, although there were no statistical differences between the two groups. Study subjects had high serum fibrinogen and D-dimer levels, suggesting that AIS patients with NS have a greater degree of hypercoagulability than AIS patients without NS. PMID- 29479574 TI - Extensive necrotizing lymphadenitis complicated by an aseptic meningeal reaction. PMID- 29479575 TI - Effective delivery of sonication energy to fast settling and agglomerating nanomaterial suspensions for cellular studies: Implications for stability, particle kinetics, dosimetry and toxicity. AB - Typical in vitro assays used for high throughput toxicological screening and measuring nano-bio interactions are conducted by pipetting suspensions of engineered nanomaterials (ENMs) dispersed in nutrient-rich culture media directly onto cells. In order to achieve fairly monodisperse and stable suspensions of small agglomerates, ultrasonic energy is usually applied to break apart large agglomerates that can form upon suspension in liquid. Lack of standardized protocols and methods for delivering sonication energy can introduce variability in the ENM suspension properties (e.g. agglomerate size, polydispersity, suspension stability over time), and holds significant implications for in vitro dosimetry, toxicity, and other nano-bio interactions. Careful assessment of particle transformations during dispersion preparation and sonication is therefore critical for accurate interpretation of in vitro toxicity studies. In this short communication, the difficulties of preparing stable suspensions of rapidly settling ENMs are presented. Furthermore, methods to optimize the delivery of the critical sonication energy required to break large agglomerates and prepare stable, fairly monodispersed suspensions of fast settling ENMs are presented. A methodology for the efficient delivery of sonication energy in a discrete manner is presented and validated using various rapidly agglomerating and settling ENMs. The implications of continuous vs. discrete sonication on average hydrodynamic diameter, and polydispersity was also assessed for both fast and slow settling ENMs. For the rapidly agglomerating and settling ENMs (Ag15%/SiO2, Ag and CeO2), the proposed discrete sonication achieved a significant reduction in the agglomerate diameter and polydispersity. In contrast, the relatively slow agglomerating and settling Fe2O3 suspension did not exhibit statistically significant differences in average hydrodynamic diameter or polydispersity between the continuous and discrete sonication approaches. Our results highlight the importance of using the proposed material-specific discrete sonication method to effectively deliver the critical sonication energy necessary to reproducibly achieve stable and fairly monodispersed suspensions that are suitable for in vitro toxicity testing. PMID- 29479576 TI - Evidence for the extended de Gennes regime of a semiflexible polymer in slit confinement. AB - We use off-lattice, pruned-enriched Rosenbluth method (PERM) simulations to compute the confinement free energy of a real wormlike chain of effective width w and persistence length lp in a slit of height H. For slit heights much larger than the persistence length of the polymer and much smaller than the thermal blob size, the excess free energy of the confined chain is consistent with a modified version of the scaling theory for the extended de Gennes regime in a channel that reflects the blob statistics in slit confinement. Explicitly, for channel sizes [Formula: see text], the difference between the confinement free energy of the real chain and that of an ideal chain scales like w/H. PMID- 29479577 TI - [18F]Fluorophenylazocarboxylates: Design and Synthesis of Potential Radioligands for Dopamine D3 and MU-Opioid Receptor. AB - 18F-Labeled building blocks from the type of [18F]fluorophenylazocarboxylic-tert butyl esters offer a rapid, mild, and reliable method for the 18F-fluoroarylation of biomolecules. Two series of azocarboxamides were synthesized as potential radioligands for dopamine D3 and the MU-opioid receptor, revealing compounds 3d and 3e with single-digit and sub-nanomolar affinity for the D3 receptor and compound 4c with only micromolar affinity for the MU-opioid receptor, but enhanced selectivity for the MU-subtype in comparison to the lead compound AH 7921. A "minimalist procedure" without the use of a cryptand and base for the preparation of 4-[18F]fluorophenylazocarboxylic-tert-butyl ester [18F]2a was established, together with the radiosynthesis of methyl-, methoxy-, and phenyl substituted derivatives ([18F]2b-f). With the substituted [18F]fluorophenylazocarbylates in hand, two prototype azocarboxylates radioligands were synthesized by 18F-fluoroarylation, namely the methoxy azocarboxamide [18F]3d as the D3 receptor radioligand and [18F]4a as a prototype structure of the MU-opioid receptor radioligand. By introducing the new series of [18F]fluorophenylazocarboxylic-tert-butyl esters, the method of 18F fluoroarylation was significantly expanded, thereby demonstrating the versatility of 18F-labeled phenylazocarboxylates for the design of potential radiotracers for positron emission tomography . PMID- 29479578 TI - N-ethyl-N-nitrosourea-Induced Adaptor Protein 2 Sigma Subunit 1 (Ap2s1) Mutations Establish Ap2s1 Loss-of-Function Mice. AB - The adaptor protein-2 sigma subunit (AP2sigma), encoded by AP2S1, forms a heterotetrameric complex, with AP2alpha, AP2beta, and AP2MU subunits, that is pivotal for clathrin-mediated endocytosis, and AP2sigma loss-of-function mutations impair internalization of the calcium-sensing receptor (CaSR), a G protein-coupled receptor, and cause familial hypocalciuric hypercalcemia type-3 (FHH3). Mice with AP2sigma mutations that would facilitate investigations of the in vivo role of AP2sigma, are not available, and we therefore embarked on establishing such mice. We screened >10,000 mice treated with the mutagen N-ethyl N-nitrosourea (ENU) for Ap2s1 mutations and identified 5 Ap2s1 variants, comprising 2 missense (Tyr20Asn and Ile123Asn) and 3 intronic base substitutions, one of which altered the invariant donor splice site dinucleotide gt to gc. Three dimensional modeling and cellular expression of the missense Ap2s1 variants did not reveal them to alter AP2sigma structure or CaSR-mediated signaling, but investigation of the donor splice site variant revealed it to result in an in frame deletion of 17 evolutionarily conserved amino acids (del17) that formed part of the AP2sigma alpha1-helix, alpha1-beta3 loop, and beta3 strand. Heterozygous mutant mice (Ap2s1+/del17 ) were therefore established, and these had AP2sigma haplosufficiency but were viable with normal appearance and growth. Ap2s1+/del17 mice, when compared with Ap2s1+/+ mice, also had normal plasma concentrations of calcium, phosphate, magnesium, creatinine, urea, sodium, potassium, and alkaline phosphatase activity; normal urinary fractional excretion of calcium, phosphate, sodium, and potassium; and normal plasma parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D (1,25(OH)2) concentrations. However, homozygous Ap2s1del17/del17 mice were non-viable and died between embryonic days 3.5 and 9.5 (E3.5-9.5), thereby indicating that AP2sigma likely has important roles at the embryonic patterning stages and organogenesis of the heart, thyroid, liver, gut, lungs, pancreas, and neural systems. Thus, our studies have established a mutant mouse model that is haplosufficient for AP2sigma. PMID- 29479580 TI - Solifluction rates and environmental controls at local and regional scales in central Austria. AB - Solifluction is a widespread periglacial phenomenon. Little is known about present solifluction rates in Austria. The author monitored five solifluction lobes during a four-year period. Annual rates of surface velocity, vertical velocity profiles, depths of movement, and volumetric velocities were quantified using near-surface markers and painted lines. Environmental conditions were assessed using air temperature, soil texture, and ground temperature-derived parameters. The latter were used to estimate the relevance of needle-ice creep, diurnal frost creep, annual frost creep, and gelifluction. The mean surface velocity rates were 3.5-6.1 cm yr-1 (near-surface markers) and 6.2-8.9 cm yr-1 (painted lines), respectively, indicating a high relevance of needle-ice creep. The mean depth of movement was 32.5-40 cm. The mean volumetric velocities were 71 102 cm3 cm-1 yr-1. Solifluction rates at the five sites did not correlate with each other due to site-specific controls. No statistically significant correlations were quantified between solifluction rates and different environmental parameters due to data gaps and short time series, thus highlighting the importance of long-term monitoring. Nevertheless, the results suggest that longer zero curtain periods, longer seasonal ground thawing periods, later start of the seasonal snow cover, more freeze-thaw cycles, and cooler early summer temperatures promote solifluction. PMID- 29479579 TI - Electromagnetic Simulation of Influence of Metamaterial for Magnetic Resonance Imaging at 3T. AB - This paper presents an approach to investigate the influence of metamaterial to radio-frequency (RF) magnetic field in magnetic resonance imaging (MRI) at 3T. The variety of magnetic fields of RF receiving coil was calculated using the commercial electromagnetic simulation software (CST). The simulation results demonstrate that the transmitting and receiving magnetic field (B1+ and B1-) can be enhanced when the metamaterial is inserted into the RF coil, suggesting that the metamaterial has potential in MRI applications at 3T. PMID- 29479581 TI - PhLeGrA: Graph Analytics in Pharmacology over the Web of Life Sciences Linked Open Data. AB - Integrated approaches for pharmacology are required for the mechanism-based predictions of adverse drug reactions that manifest due to concomitant intake of multiple drugs. These approaches require the integration and analysis of biomedical data and knowledge from multiple, heterogeneous sources with varying schemas, entity notations, and formats. To tackle these integrative challenges, the Semantic Web community has published and linked several datasets in the Life Sciences Linked Open Data (LSLOD) cloud using established W3C standards. We present the PhLeGrA platform for Linked Graph Analytics in Pharmacology in this paper. Through query federation, we integrate four sources from the LSLOD cloud and extract a drug-reaction network, composed of distinct entities. We represent this graph as a hidden conditional random field (HCRF), a discriminative latent variable model that is used for structured output predictions. We calculate the underlying probability distributions in the drug-reaction HCRF using the datasets from the U.S. Food and Drug Administration's Adverse Event Reporting System. We predict the occurrence of 146 adverse reactions due to multiple drug intake with an AUROC statistic greater than 0.75. The PhLeGrA platform can be extended to incorporate other sources published using Semantic Web technologies, as well as to discover other types of pharmacological associations. PMID- 29479582 TI - Modeling of Li diffusion in nanocrystalline Li-Si anode material. AB - To quantify the Li diffusion behavior in nanocrystalline anode materials for lithium-ion batteries (LIBs), a hybrid model of the first principles calculation and diffusion kinetics was developed. The dependence of the Li diffusion on the electronic structure, solute concentration, grain size and temperature was described for the nanocrystalline Li-Si system. In contrast to conventional polycrystalline materials in which the activation barrier for Li diffusion decreases with the increase of concentration before amorphization, there exists a coordination effect of the solute concentration and grain size on the Li diffusion in nanocrystalline materials. A maximum diffusion coefficient can be obtained in the nanocrystalline Li-Si by a combination of the concentration and grain size, which is increased by two orders of magnitude from that in the coarse grained counterpart. The present work advanced the understanding of the Li diffusion mechanisms during lithiation/delithiation of LIBs and may facilitate the development of nanocrystalline anode materials. PMID- 29479583 TI - One-dimensional MoO2-Co2Mo3O8@C nanorods: a novel and highly efficient oxygen evolution reaction catalyst derived from metal-organic framework composites. AB - One-dimensional MoO2-Co2Mo3O8@C nanorods were synthesized by using MoO3@ZIF-67 composites as a precursor for the first time, and it is found that the Co2Mo3O8 species and its composite have excellent OER activities. The MoO2-Co2Mo3O8@C nanorods present favorable electrocatalytic advantages toward OER in alkaline solution, requiring an overpotential of only 320 mV to deliver a current density of 10 mA cm-2. In addition, the catalyst also shows a small Tafel slope of 88 mV dec-1 and relatively good durability. The attractive OER performance can be attributed to the highly active Co2Mo3O8 and MoO2 species and the unique structure of the catalyst. This strategy can be extended to design and synthesize other novel and highly efficient molybdenum based ternary metal oxides as OER catalysts. PMID- 29479584 TI - "Liquid, gel and soft glass" phase transitions and rheology of nanocrystalline cellulose suspensions as a function of concentration and salinity. AB - The colloidal size and rod morphology of nanocrystalline cellulose (NCC) lead to suspensions with useful phase and gelation behaviours as well as complex rheologies. However, these have not been comprehensively evaluated previously. Here we report the detailed phase behaviour of sulphonated NCC aqueous suspensions as a function of concentration and salinity. Four phases - liquid, viscoelastic, repulsive glass and attractive glass/gel - are identified in terms of their distinct rheological behaviours. The liquid-solid transitions (LSTs) are determined rheologically, and these are supported by a simplified model based on the DLVO theory that indicates the importance of charge in determining the phase behaviour. Rheology is also used to investigate the solid-solid transition from a repulsive glass to an attractive gel with increasing salt at high NCC concentrations. A time-dependent aging phenomenon is observed in suspensions with a composition just below the LSTs, and the implications of this on the dynamics occurring during gelation processes are discussed. This work can be directly applied to the development of structure-function relationships and the expanding utilisation of NCC suspensions, whilst also providing a basis for the study of charged colloidal rods more generally and evaluation of theoretical models. PMID- 29479585 TI - Harnessing complexity in molecular self-assembly using computer simulations. AB - In molecular self-assembly, hundreds of thousands of freely-diffusing molecules associate to form ordered and functional architectures in the absence of an actuator. This intriguing phenomenon plays a critical role in biology and has become a powerful tool for the fabrication of advanced nanomaterials. Due to the limited spatial and temporal resolutions of current experimental techniques, computer simulations offer a complementary strategy to explore self-assembly with atomic resolution. Here, we review recent computational studies focusing on both thermodynamic and kinetic aspects. As we shall see, thermodynamic approaches based on modeling and statistical mechanics offer initial guidelines to design nanostructures with modest computational effort. Computationally more intensive analyses based on molecular dynamics simulations and kinetic network models (KNMs) reach beyond it, opening the door to the rational design of self-assembly pathways. Current limitations of these methodologies are discussed. We anticipate that the synergistic use of thermodynamic and kinetic analyses based on computer simulations will provide an important contribution to the de novo design of self assembly. PMID- 29479586 TI - Combined analysis of 1,3-benzodioxoles by crystalline sponge X-ray crystallography and laser desorption ionization mass spectrometry. AB - The crystalline sponge (CS) method, which employs single-crystal X-ray diffraction to determine the structure of an analyte present as a liquid or an oil and having a low melting point, was used in combination with laser desorption ionization mass spectrometry (LDI-MS). 1,3-Benzodioxole derivatives were encapsulated in CS and their structures were determined by combining X-ray crystallography and MS. After the X-ray analysis, the CS was subjected to imaging mass spectrometry (IMS) with an LDI spiral-time-of-flight mass spectrometer (TOF MS). The ion detection area matched the microscopic image of the encapsulated CS. In addition, the accumulated 1D mass spectra showed that fragmentation of the guest molecule (hereafter, guest) can be easily visualized without any interference from the fragment ions of CS except for two strong ion peaks derived from the tridentate ligand TPT (2,4,6-tris(4-pyridyl)-1,3,5-triazine) of the CS and its fragment. X-ray analysis clearly showed the presence of the guest as well as the pi-pi, CH-halogen, and CH-O interactions between the guest and the CS framework. However, some guests remained randomly diffused in the nanopores of CS. In addition, the detection limit was less than sub-pmol order based on the weight and density of CS determined by X-ray analysis. Spectroscopic data, such as UV-vis and NMR, also supported the encapsulation of the guest through the interaction between the guest and CS components. The results denote that the CS LDI-MS method, which combines CS, X-ray analysis and LDI-MS, is effective for structure determination. PMID- 29479587 TI - Non-enzymatic portable optical sensors for microcystin-LR. AB - We present here the development of an all-solid-state optical sensor based on phenyl-substituted diaza-18-crown-6 hydroxyquinoline (DCHQ-Ph) for the indirect selective detection of microcystin-LR (MC-LR), reaching a very low detection limit of 0.05 MUg L-1, well below the World Health Organisation (WHO) guideline value (1 MUg L-1) in potable water. We demonstrate the potential applicability of the developed method in fast and low-cost water toxicity estimation. PMID- 29479588 TI - Understanding the ionic conductivity maximum in doped ceria: trapping and blocking. AB - Materials with high oxygen ion conductivity and low electronic conductivity are required for electrolytes in solid oxide fuel cells (SOFC) and high-temperature electrolysis (SOEC). A potential candidate for the electrolytes, which separate oxidation and reduction processes, is rare-earth doped ceria. The prediction of the ionic conductivity of the electrolytes and a better understanding of the underlying atomistic mechanisms provide an important contribution to the future of sustainable and efficient energy conversion and storage. The central aim of this paper is the detailed investigation of the relationship between defect interactions at the microscopic level and the macroscopic oxygen ion conductivity in the bulk of doped ceria. By combining ab initio density functional theory (DFT) with Kinetic Monte Carlo (KMC) simulations, the oxygen ion conductivity is predicted as a function of the doping concentration. Migration barriers are analyzed for energy contributions, which are caused by the interactions of dopants and vacancies with the migrating oxygen vacancy. We clearly distinguish between energy contributions that are either uniform for forward and backward jumps or favor one migration direction over the reverse direction. If the presence of a dopant changes the migration energy identically for forward and backward jumps, the resulting energy contribution is referred to as blocking. If the change in migration energy due to doping is different for forward and backward jumps of a specific ionic configuration, the resulting energy contributions are referred to as trapping. The influence of both effects on the ionic conductivity is analyzed: blocking determines the dopant fraction where the ionic conductivity exhibits the maximum. Trapping limits the maximum ionic conductivity value. In this way, a deeper understanding of the underlying mechanisms determining the influence of dopants on the ionic conductivity is obtained and the ionic conductivity is predicted more accurately. The detailed results and insights obtained here for doped ceria can be generalized and applied to other ion conductors that are important for SOFCs and SOECs as well as solid state batteries. PMID- 29479589 TI - Copper-catalyzed three-component cyclization of amidines, styrenes, and fluoroalkyl halides for the synthesis of modular fluoroalkylated pyrimidines. AB - An efficient copper-catalyzed three-component cyclization for the construction of highly functionalized pyrimidine derivatives from readily available amidines, styrenes and fluoroalkyl halides is developed. This protocol distinguishes itself by the formation of three new C-C/C-N bonds and a new six-membered ring through a radical addition/oxidation/cyclization sequence in a one-pot manner. PMID- 29479590 TI - Chemical disorder driven reentrant spin cluster glass state formation and associated magnetocaloric properties of Nd2Ni0.94Si2.94. AB - In this work, we report the synthesis of a new ternary intermetallic compound, Nd2Ni0.94Si2.94, that forms in single phase only in a defect crystal structure. The compound exhibits an antiferromagnetic transition below 7.2 K (TN) followed by a spin cluster freezing behaviour below 2.85 K (Tf), which makes the compound a reentrant spin cluster glass system. The detailed studies of dc and ac magnetization, heat capacity, non-equilibrium dynamical behaviour, viz., aging effect, temperature and field dependent magnetic relaxation and magnetic memory effect establish the compound to be a cluster-glass material below freezing temperature. The interplay between competing exchange coupling (c/a ? 1.04 => JNN ? JNNN) and chemical disorder driven variation in the electronic environment among the Nd ions has been argued to be responsible for such a metastable state formation. A considerable value of MCE parameters (-DeltaS ~ 11.4 J kg-1 K-1, RCP ~ 160 J kg-1 and DeltaTad ~ 5.2 K for a field change of 70 kOe) is obtained for this magnetically frustrated glassy compound. PMID- 29479591 TI - One-step synthesis of 2D-layered carbon wrapped transition metal nitrides from transition metal carbides (MXenes) for supercapacitors with ultrahigh cycling stability. AB - A novel one-step method to synthesize 2D carbon wrapped TiN (C@TiN) was proposed via using 2D metal carbides (MXenes) as precursors. This study provides a novel approach to synthesize carbon wrapped metal nitrides. PMID- 29479592 TI - Improved fluorescence imaging and synergistic anticancer phototherapy of hydrosoluble gold nanoclusters assisted by a novel two-level mesoporous canal structured silica nanocarrier. AB - A novel integrated system composed of hydrosoluble gold nanoclusters (AuNCs), two level mesoporous canal silica, gelatin and folic acid was for the first time designed and synthesized, which could conquer poor stability of AuNCs and shows aggregation-enhanced fluorescence imaging, cancer cell-specific targeting, and synergistic photothermal/photodynamic therapies for the goal of personalized nanotheranostics. PMID- 29479594 TI - Chirality switching of the self-assembled CuPc domains induced by electric field. AB - Chiral switching of the self-assembled domains of CuPc molecules on the Cd(0001) surface has been investigated by means of a low temperature scanning tunneling microscopy (STM). With the coverage increasing, the CuPc molecules show the structural evolutions from an initial gas-like state to a network phase, a square phase, and finally to a compact phase at full monolayer. In the network and square phases, the achiral CuPc molecules reveal both the point chirality and chiral domains. In particular, the chirality of network domain can be switched from one enantiomer to another driven by the electric filed from a STM tip, which can also lead to the lattice rotation of network phase. These results demonstrate that (i) there is strong interaction between the CuPc molecules and STM tip; (ii) the adsorbed CuPc molecules carry considerable net charge or polarizability due to the charge transfer; (iii) the network phase has a low barrier for the interconversion between right- and left-handed domains. Our findings are significant for the understanding and control of the domain's chirality in the self-assembled structures. PMID- 29479593 TI - Effect of surface oxygen vacancy sites on ethanol synthesis from acetic acid hydrogenation on a defective In2O3(110) surface. AB - Developing a new type of low-cost and high-efficiency non-noble metal catalyst is beneficial for industrially massive synthesis of alcohols from carboxylic acids which can be obtained from renewable biomass. In this work, the effect of active oxygen vacancies on ethanol synthesis from acetic acid hydrogenation over defective In2O3(110) surfaces has been studied using periodic density functional theory (DFT) calculations. The relative stabilities of six surface oxygen vacancies from Ov1 to Ov6 on the In2O3(110) surface were compared. D1 and D4 surfaces with respective Ov1 and Ov4 oxygen vacancies were chosen to map out the reaction paths from acetic acid to ethanol. A reaction cycle mechanism between the perfect and defective states of the In2O3 surface was found to catalyze the formation of ethanol from acetic acid hydrogenation. By H2 reduction the oxygen vacancies on the In2O3 surface play key roles in promoting CH3COO* hydrogenation and C-O bond breaking in acetic acid hydrogenation. The acetic acid, in turn, benefits the creation of oxygen vacancies, while the C-O bond breaking of acetic acid refills the oxygen vacancy and, thereby, sustains the catalytic cycle. The In2O3 based catalysts were shown to be advantageous over traditional noble metal catalysts in this paper by theoretical analysis. PMID- 29479595 TI - High-throughput evaluation of organic contaminant removal efficiency in a wastewater treatment plant using direct injection UHPLC-Orbitrap-MS/MS. AB - The removal efficiency (RE) of organic contaminants in wastewater treatment plants (WWTPs) is a major determinant of the environmental impact of these contaminants. However, RE data are available for only a few chemicals due to the time and cost required for conventional target analysis. In the present study, we applied non-target screening analysis to evaluate the RE of polar contaminants, by analyzing influent and effluent samples from a Swedish WWTP with direct injection UHPLC-Orbitrap-MS/MS. Matrix effects were evaluated by spiking the samples with isotope-labeled standards of 40 polar contaminants. For 85% of the compounds, the matrix effects in the influent and effluent were not significantly different. Approximately 10 000 compounds were detected in the wastewater, of which 319 were identified by using the online database mzCloud. Level 1 identification confidence was achieved for 31 compounds for which we had reference standards, and level 2 was achieved for the remainder. RE was calculated from the ratio of the peak areas in the influent and the effluent from the non-target analysis. Good agreement was found with RE determined from the target analysis of the target compounds. The method generated reliable estimates of RE for large numbers of contaminants with comparatively low effort and is foreseen to be particularly useful in applications where information on a large number of chemicals is needed. PMID- 29479596 TI - Mechanical hysteresis in actin networks. AB - Understanding the response of complex materials to external force is central to fields ranging from materials science to biology. Here, we describe a novel type of mechanical adaptation in cross-linked networks of F-actin, a ubiquitous protein found in eukaryotic cells. We show that shear stress changes the network's nonlinear mechanical response even long after that stress is removed. The duration, magnitude and direction of forcing history all change this mechanical response. While the mechanical hysteresis is long-lived, it can be simply erased by force application in the opposite direction. We further show that the observed mechanical adaptation is consistent with stress-dependent changes in the nematic order of the constituent filaments. Thus, this mechanical hysteresis arises from the changes in non-linear response that originates from stress-induced changes to filament orientation. This demonstrates that F-actin networks can exhibit analog read-write mechanical hysteretic properties, which can be used for adaptation to mechanical stimuli. PMID- 29479597 TI - The effect of solvation and temperature on the adsorption of small organic molecules on calcite. AB - We performed density functional theory calculations to investigate the effect of solvation and temperature on the adsorption of small organic molecules on calcite. The Conductor like Screening Model for Real Solvents (COSMO-RS) solvation model was used to describe a multicomponent mixture consisting of both hydrophobic and hydrophilic phases. The results demonstrate that the combination of solvation and temperature significantly influences adsorption, with the effect of temperature dominating over the effect of solvation. At 25 degrees C, carboxylic acids and methanol are stable on calcite with free energy of adsorption <0 in the hydrophobic phase. None of the molecules considered in this study remain on the surface in the hydrophilic phase. PMID- 29479598 TI - The reaction mechanism and selectivity of acetylene hydrogenation over Ni-Ga intermetallic compound catalysts: a density functional theory study. AB - Intermetallic compounds (IMCs) have shown excellent catalytic performance toward the selective hydrogenation of acetylene, but the theoretical understanding on this reaction over Ni-based IMCs is rather limited. In this work, the adsorptions of the C2 species, Bader charge, projected density of states (PDOS) and the reaction pathways were calculated by the density functional theory (DFT) method to investigate the mechanism and selectivity for the acetylene hydrogenation on the (111) surface of NinGa (n = 1, 3) IMCs, with a comparative study on the pristine Ni(111) surface. The results indicate that the adsorption energy of acetylene increased along with the Ni/Ga ratio, therefore a feasible acetylene adsorption on the Ga-rich surface guaranteed a low effective barrier, leading to the best activity for the NiGa(111) surface among three surfaces. Bader charge analysis shows that electrons transferred from Ga atoms to Ni atoms and further delivered to C2 species, decreasing the adsorption capacity of C2 species on NiGa(111) in comparison with those on Ni(111) and Ni3Ga(111). The reaction pathway of acetylene hydrogenation to ethylene via vinyl or even over hydrogenation to ethane via ethyl is more favorable than the pathway involving the ethylidene intermediate on all surfaces. Moreover, the ethylene selectivity has a positive correlation with the gallium content by comparing the desorption barrier with the hydrogenation barrier of ethylene, thus the NiGa(111) surface also exhibits the best selectivity. Therefore, the NiGa(111) surface demonstrates to be an excellent reaction facet for the semihydrogenation of acetylene, which agreed with the experimental findings, and would provide helpful instructions for designing and preparing highly-selective and noble-substitute catalysts of alkyne semihydrogenation. PMID- 29479599 TI - From a square core to square opening: structural diversity and magnetic properties of the oxo-bridged [CrIIINbV] complexes. AB - Three heterometallic oxo-bridged compounds, [Cr2(phen)4(MU-O)4Nb2(C2O4)4].2H2O (1; phen = 1,10-phenanthroline), [Cr2(terpy)2(H2O)2(MU-O)4Nb2(C2O4)4].4H2O (2; terpy = 2,2';6',2''-terpyridine) and [Cr(terpy)(C2O4)(H2O)][Cr2(terpy)2(C2O4)2(MU O)2Nb(C2O4)2].3H2O (3), have been synthesized using a building block approach and characterized by IR spectroscopy, single-crystal and powder X-ray diffraction, magnetization measurements, and DFT calculations. The molecular structures of 1 and 2, crystallizing in P42212 and P21/n space groups, respectively, contain a square-shaped {Cr(MU-O)4Nb} unit, while that of complex salt 3 (P1[combining macron] space group) consists of a mononuclear cation containing CrIII and trinuclear anions in which two CrIII ions are bridged by a -O-NbV-O- fragment. Besides hydrogen-bonding patterns resulting in a 1D- or 3D-supramolecular arrangement in 1-3, an unusual intermolecular contact has been noticed between parallel oxalate moieties occurring due to the electrostatic attraction of electron-rich carbonyl oxygen and severely electron-depleted carbon atoms in the crystal packing of 2. The antiferromagnetic coupling observed in all three compounds, determined from magnetization measurements (J = -13.51(2), -8.41(1) and -7.44(4) cm-1 for 1, 2 and 3, respectively) and confirmed by DFT calculations, originates from two CrIII ions with spin 3/2 interacting through diamagnetic -O-NbV-O- bridge(s). PMID- 29479600 TI - Photocatalytic selectivity switch to C-C scission: alpha-methyl ejection of tert butanol on TiO2(110). AB - The thermal and photochemical mechanistic pathways for tertiary alcohols on the rutile TiO2(110)-surface are studied with the example of tert-butanol. While the thermal reaction is known to yield isobutene, the photochemical ejection of a methyl radical is observed at 100 K. The C-C scission, which is accompanied by the formation of acetone, is the only photochemical reaction pathway at this temperature and can be attributed to the reaction of photoholes that are created upon UV-light illumination at the surface of the n-type semiconductor. At 293 K the selectivity of the reaction changes, as isobutene is additionally formed photochemically. A comparison of the kinetics of the different reactions reveals further insights. Together with the quantitative evaluation of the reaction products at low temperatures and the comparison of the reaction pathways at different temperatures it is demonstrated how thermal effects can influence the selectivity of the reactions in photocatalysis. PMID- 29479601 TI - The effect of SiO2 additives on solid hydroxide ion-conducting polymer electrolytes: a Raman microscopy study. AB - The effect of SiO2 additives on the conductivity and longevity of an alkaline tetraethylammonium hydroxide (TEAOH)-poly(acrylamide) (PAM) polymer electrolyte was investigated. Electrochemical impedance spectroscopy (EIS) and Raman microscopy studies were performed for TEAOH-PAM with micro-sized (mSiO2) or nano sized (nSiO2) additives under highly hydrated and under ambient conditions. At a high relative humidity (RH) of 75%, nSiO2 significantly increased the ionic conductivity of OH-, achieving 25 mS cm-1, while mSiO2 had little influence (10 mS cm-1). Further investigation at lower RH (45%) revealed that dehydration of TEAOH led to crystallization and lower conductivity of the polymer electrolytes. The degree and rate of crystallization in the different systems varied greatly: mSiO2 accelerated the process while nSiO2 delayed it. Using characteristic signatures obtained from Raman microscopy, a correlation between the ionic conductivity and the structural differences among these systems has been established and an explanation for the impact of the SiO2 additives has been proposed. PMID- 29479602 TI - A first-principles study of stability of surface confined mixed metal oxides with corundum structure (Fe2O3, Cr2O3, V2O3). AB - Surface-confined mixed metal oxides can have different chemical properties compared to their host metal oxide support. For this reason, mixed transition metal oxides can offer tunable redox properties. Herein, we use density functional theory to predict the stability of the (0001) surface termination for mixed metal oxides consisting of Fe2O3, Cr2O3 and V2O3. We show that the pure oxide surface stability can predict the surface segregation preference of the surface-confined mixed metal oxides. We focus on substitution of Fe in the V2O3(0001) surface, for which we observe that Fe substitution increases the reducibility of the resulting mixed metal oxide surface. Our results suggest Fe is only stable on the surface under very high temperature and/or low-pressure conditions. Using thermodynamic relationships, we predict the transition points for these surface-confined mixed metal oxides at which exchange between surface/subsurface and subsurface/surface metal atoms occur due to changes in the oxygen chemical potential. PMID- 29479603 TI - Selected anthraquinones as potential free radical scavengers and P-glycoprotein inhibitors. AB - Disruption of homeostasis can increase the amount of free radicals formed during metabolic processes. This phenomenon known as oxidative stress can have numerous negative outcomes. The role of dietary antioxidants is to help the prevention of oxidative stress. We investigated free radical scavenging capacity of six structurally similar anthraquinones (alizarin, purpurin, chrysophanol, emodin, aloe-emodin and 1,3,8-trihydroxyanthraquinone) for inactivating a set of ten hydroxy and peroxy free radicals. The antioxidant capacity of anthraquinones was estimated by considering Gibbs free energy of three studied reaction mechanisms: hydrogen atom transfer (HAT), single-electron transfer followed by proton transfer (SET-PT) and sequential proton loss electron transfer (SPLET). The geometry of all participants in chemical reactions was optimized using the M06 2X/6-311++G(d,p) level of theory. Benzene, pentyl ethanoate, dimethyl sulfoxide and water were used to investigate the impact of solvent polarity on the thermodynamic feasibility of antiradical reactions. It was found that HAT and SPLET mechanisms are operative and competitive, while the SET-PT mechanism is not thermodynamically plausible. Among the studied anthraquinones, AL and PU showed the highest scavenging capacity. Their reactivity toward free radicals decreases as follows:OH > (CH3)3C-O ~ OCH3 > CCl3-O-O > PhO > OOH ~ CH2[double bond, length as m-dash]CH-O-O ~ CH3-O-O ~ CH2[double bond, length as m-dash]CH-CH2-O-O ? O2-. Inhibition activity of anions of the selected six anthraquinones toward P glycoproteins was estimated using docking analysis. The obtained results suggest that all the investigated compounds are potential inhibitors of P-glycoproteins under physiological conditions, indicating them as potential protectors against patient resistance toward various anticancer drugs. PMID- 29479604 TI - Narrowing the diversification of supramolecular assemblies by preorganization. AB - We designed and synthesized three phosphorylated peptides as precursors of the same peptide Nap-YYY. We found that different precursors led to different materials with almost identical chemical compositions at the final stages. Only Nap-YpYY could form very uniform nanofibers in a stable supramolecular hydrogel by enzyme-instructed self-assembly (EISA) at the physiological temperature (37 degrees C). In contrast, de-phosphorylation of the other two precursors (Nap-pYYY and Nap-YYpY) resulted in diverse nanostructures in metastable hydrogels with precipitates. The formation of uniform nanomaterials in the stable hydrogels was due to the preorganization property of the precursor Nap-YpYY, which facilitated rapid folding and accelerated the kinetics of hydrogelation of the resulting peptide Nap-YYY generated by the EISA process. Our study demonstrated the importance of the precursor for the self-assembly of nanomaterials and provided a useful strategy to manipulate them. PMID- 29479605 TI - The role of topology in organic molecules: origin and comparison of the radical character in linear and cyclic oligoacenes and related oligomers. AB - We discuss the nature of electron-correlation effects in carbon nanorings and nanobelts using an analysis tool known as fractional occupation number weighted electron density (rhoFOD) and the RAS-SF method, revealing for the first time significant differences in static correlation effects depending on how the rings (i.e. chemical units) are fused and/or connected until closing the loop. We choose to study in detail linear and cyclic oligoacene molecules of increasing size, and relate the emerging differences with the difficulties for the synthesis of the latter due to their radicaloid character. We finally explore how minor structural modifications of the cyclic forms can alter these results, showing the potential use of these systems as molecular templates for the growth of well shaped carbon nanotubes as well as the usefulness of theoretical tools for molecular design. PMID- 29479606 TI - Phosphaalkene-substituted organo-group 15 compounds: synthesis and characterisation of (NHC)P-EtBu2 (E = P, As, Sb and Bi). AB - Herein, we present the synthesis and characterisation of new group 15 element compounds with low valent phosphorus atoms as substituents. This new series of compounds includes the heavier group 15 elements and represents the rare group of compounds with a direct P-E bond (E = P, As, Sb and Bi). PMID- 29479607 TI - Chemical signaling at the eukaryotic/prokaryotic interface. PMID- 29479608 TI - Chirality in metal-based anticancer agents. AB - Chiral natural biological molecules, such as nucleic acids and proteins, guide the research of chiral compounds. Chiral metal-based drugs are currently an interesting and rapidly growing field in anticancer research. This perspective focuses on chiral metal compounds with application in cancer chemotherapy. The different chiral metal-based anticancer agents and the extent to which the chiral resolution affects their biological properties are discussed. This perspective will aid the design of new potent and efficient chiral metal-based anticancer drugs that exploit their unique properties combined with their potential selectivity toward targeted chiral biomolecules. PMID- 29479609 TI - pH-Gated photoresponsive shuttling in a water-soluble pseudorotaxane. AB - A fluorescent bistable pseudorotaxane was devised and shown to display pH-gated photoresponsive ring shuttling. At pH > 7.5 shuttling does not take place after light stimulation while at pH ~ 5 the macrocycle is quantitatively translocated. PMID- 29479610 TI - The Taiji and Eight Trigrams chemistry philosophy of chiral iridium(iii) complexes with triplex stereogenic centers. AB - Four novel chiral iridium(iii) complexes with triplex stereogenic centers were synthesized by introducing chiral carbon atoms into cyclometalated and ancillary ligands, and separated into eight isomers, which coincide with the old Chinese philosophy Eight Trigrams. The electron circular dichroism and circularly polarized luminescence spectra of four pairs of isomers show perfect mirror images with a dissymmetry factor (glum factor) of around 0.003. PMID- 29479611 TI - Lateral flow assay with pressure meter readout for rapid point-of-care detection of disease-associated protein. AB - Paper-based assays such as lateral flow assays are good candidates for portable diagnostics owing to their user-friendly format and low cost. In terms of analytical detection, lateral flow assays usually require dedicated instruments to obtain quantitative results. Here we demonstrate a lateral flow assay with handheld pressure meter readout for the rapid detection of disease-related protein with high sensitivity and selectivity. Based on the pressure change produced by the catalytic reaction of Pt nanoparticles related to the concentration of the target, a quantitative reaction platform was established. During the lateral flow assay, the Pt nanoparticles are aggregated in the test line to form a gray band by biomolecular recognition and finally convert the recognition signal into highly sensitive pressure readout for quantitative analysis. Without sophisticated instrumentation and complicated operations, the whole detection process can be completed within 20 minutes. The limit of detection for myoglobin (2.9 ng mL-1 in diluted serum samples) meets the requirements of clinical monitoring. With the advantages of low cost, ease of operation, high sensitivity and selectivity, the method represents a versatile platform for point-of-care testing of disease biomarkers. PMID- 29479612 TI - Au26: a case of fluxionality/co-existence. AB - The Au26 cluster is one of the widely studied gold clusters in the size range of n = 21-30. It has been proposed in a more recent combined experimental and theoretical study that the neutral Au26 cluster is fluxional. The fluxionality of a cluster is relevant to its catalytic applications. In this context, to explore the extent of fluxionality, Born Oppenheimer Molecular Dynamical (BOMD) simulations are carried out on experimentally and theoretically proposed fluxional Au26 conformations (three compact or core-shell structures and a high symmetry cage structure). The simulations reveal that the high energy golden tube outperforms the ground state structure (compact C2v conformation) as well as the other two low-symmetry compact conformations in terms of thermal stability. The enhancement in the thermal stability is explained on the basis of structural integrity imposed by the open skeleton of shortest bond distances within Au26 Tube. In addition to this, the homogeneous distribution of charges and the strong s-d hybridization exhibited by FMOs are seen to play a pivotal role in increasing the stability of Au26-Tube. The present investigation also reveals that the characteristic fluxionality proposed to exist in the Au26 system is noted only above 400 K and it is missing at room temperature. The simulations also bring forth the question of how relevant a ground state conformation is at working temperatures. PMID- 29479613 TI - A palladium complex immobilized onto a magnetic GO-MnFe2O4 surface as an effective and recyclable catalyst for the reduction of p-nitrophenol. AB - A magnetically separable palladium complex on a GO-MnFe2O4 surface has been synthesized by covalent immobilization of a palladium complex on the magnetic GO MnFe2O4 surface functionalized with 3-aminopropyltriethoxysilane (APTES). In general, magnetic, iron based materials (MnFe2O4) are effective in many catalytic reactions and are advantageous compared with other metal oxides due to their magnetic recyclability. The catalytic activities of these nanohybrids have been studied in p-nitrophenol (p-Nip) reduction. Fourier transform infrared (FT-IR) spectroscopy, thermogravimetric analysis (TGA), inductively coupled plasma atomic emission spectrometry (ICP-AES), X-ray diffraction (XRD), energy dispersive X-ray analysis (EDAX) and transmission electron microscopy (TEM) were used to characterize the catalyst. The successful incorporation of the palladium complex onto GO-MnFe2O4 has been confirmed by FT-IR spectroscopy, thermogravimetric analysis and ICP-AES. The intact structure of GO-MnFe2O4 was verified by X-ray diffraction (XRD), energy dispersive X-ray analysis (EDAX) and TEM. The strong reduction of p-nitrophenol was shown by the palladium complex on GO-MnFe2O4. This magnetic heterogeneous catalyst was well recoverable with no significant loss of activity and selectivity after five successive runs. PMID- 29479614 TI - Development of small particle speciation for nuclear forensics by soft X-ray scanning transmission spectromicroscopy. AB - Synchrotron radiation spectromicroscopy provides a combination of submicron spatial resolution and chemical sensitivity that is well-suited to analysis of heterogeneous nuclear materials. The chemical and physical characteristics determined by scanning transmission X-ray microscopy (STXM) are complementary to information obtained from standard radiochemical analysis methods. In addition, microscopic quantities of radioactive material can be characterized rapidly by STXM with minimal sample handling and intrusion, especially in the case of particulate materials. The STXM can accommodate a diverse range of samples including wet materials, complex mixtures, and small quantities of material contained in a larger matrix. In these cases, the inventory of species present in a sample is likely to carry information on its process history; STXM has the demonstrated capability to identify contaminants and sample matrices. Operating in the soft X-ray regime provides particular sensitivity to the chemical state of specimens containing low-Z materials, via the K-edges of light elements. Here, recent developments in forensics-themed spectromicroscopy, sample preparation, and data acquisition methods at the Molecular Environmental Science Beamline 11.0.2 of the Advanced Light Source are described. Results from several initial studies are presented, demonstrating the capability to identify the distribution of the species present in heterogeneous uranium-bearing materials. Future opportunities for STXM forensic studies and potential methodology development are discussed. PMID- 29479615 TI - A new triazine-based covalent organic polymer for efficient photodegradation of both acidic and basic dyes under visible light. AB - A new triazine-based covalent organic polymer (named COP-NT), which showed high catalytic activities for the degradation of acidic and basic dyes, is synthesized. Its structure characteristics were fully investigated, which featured large specific surface area, homogeneous porosity, strong visible light absorption, excellent thermal stability and semiconductor performance. The as prepared COP-NT exhibits good chemical stability both in acidic and alkaline aqueous solutions, which could be used as an efficient photocatalyst for the degradation of methyl orange (MO), rhodamine B (RhB) and methylene blue (MB). The Ea values for the degradation of MO, RhB or MB are 9.40 kJ mol-1, 30.94 kJ mol-1 or 17.54 kJ mol-1, respectively. Furthermore, COP-NT showed excellent reusability in degrading all the above dyes without obvious performance decay. PMID- 29479616 TI - Stable emulsions of droplets in a solid edible organogel matrix. AB - Sitosterol and oryzanol self-assemble to form very firm gels in a range of organic solvents. However, due to the formation of sitosterol hydrate crystals, these gels are unstable in the presence of water, prohibiting the dispersal of water droplets throughout the gel matrix. We demonstrate that by using glycerol as the polar phase rather than water, droplets may be dispersed throughout the oil phase without disrupting the self-assembly of the gel. As increasing volumes of water are added to the glycerol, the G' values decrease. This can be correlated to both a drop in water activity, and also the stability of the fibrils in the presence of glycerol compared to water, as elucidated by molecular dynamics simulations. We explore how changing the total volume of polar droplets, and changing the water content of these droplets alters the strength of 15% w/w sterol gels. We find that gels exhibit G' values of ~1 * 107 Pa even with ~30% w/w glycerol dispersed throughout the matrix. At higher glycerol loadings, complex multiple emulsion morphologies can form. PMID- 29479617 TI - Highly efficient Fe(iii) reduction and solar-energy accumulation over a BiVO4 photocatalyst. AB - The amount of adsorbed Fe(iii) on BiVO4 particles, which is controlled by the pH and temperature of the reaction solution, strongly affects the photocatalytic performance of BiVO4 for Fe(iii) reduction. Quantum and solar-energy-conversion efficiencies of 38% and 0.65%, respectively, were achieved. PMID- 29479618 TI - Design of bifunctional chiral phenanthroline ligand with Lewis basic site for palladium-catalyzed asymmetric allylic substitution. AB - Conceptually new bifunctional chiral ligands were developed. The axially chiral N,N-bidentate phenanthroline ligand (S)-1 was found to be effective for Pd catalyzed asymmetric allylic substitution of allyl acetate and dialkyl malonate. The intramolecular Lewis basic group from the hydroxybinaphthyl structure of (S) 1 played a pivotal role in the high reactivity and enantioselectivity. PMID- 29479619 TI - Iodide-derived nanostructured silver promotes selective and efficient carbon dioxide conversion into carbon monoxide. AB - It is of great importance to design and develop highly active and selective electrocatalysts for the CO2 reduction reaction (CO2RR). In this communication, we report an iodide-derived nanostructured silver catalyst (ID-Ag) as an excellent CO2RR catalyst that is able to electrochemically reduce CO2 to CO with approximately 94.5% selectivity at the potential of -0.7 V in CO2-saturated 0.5 M KHCO3. This suggests that the highly electrochemical active surface area and adsorbed I- anions onto the surfaces of the electrode contribute to the enhanced activity and selectivity of the nanostructured Ag electrocatalyst toward CO2 reduction. PMID- 29479620 TI - Novel inorganic tin phosphate gel: multifunctional material. AB - Here, we report a remarkable 15 A nanolayered tin phosphate, Sn(HPO4)2.3H2O (SnP H+ or SnP), and its clay-like gel, which are multifunctional and are prepared using earth-abundant Sn and P chemicals by a facile, environmentally benign and potentially cost-effective process. This new energy material is discovered here as the best proton conductor among all the known layered phosphates with a very high proton conductivity of over 1 * 10-2 S cm-1 at 100 degrees C for potential use in PEM fuel cells. But it is also a very good capacitor material with fast Li storage kinetics (charging time of 13 s). PMID- 29479621 TI - Incorporation of an intact dimeric Zr12 oxo cluster from a molecular precursor in a new zirconium metal-organic framework. AB - Two zirconium-organic frameworks were synthesized by exchanging the acetate ligands in [Zr12O8(OH)8(CH3COO)24] with polydentate linkers. Partial substitution of acetate groups by a phosphine based linker yielded a new porous framework with this unique dimeric Zr12 cluster unit as molecular building block. More exhaustive substitution of acetate resulted in cleavage of the Zr12 unit and formation of UiO-67. PMID- 29479622 TI - Peptide and protein nanoparticle conjugates: versatile platforms for biomedical applications. AB - Peptide- and protein-nanoparticle conjugates have emerged as powerful tools for biomedical applications, enabling the treatment, diagnosis, and prevention of disease. In this review, we focus on the key roles played by peptides and proteins in improving, controlling, and defining the performance of nanotechnologies. Within this framework, we provide a comprehensive overview of the key sequences and structures utilised to provide biological and physical stability to nano-constructs, direct particles to their target and influence their cellular and tissue distribution, induce and control biological responses, and form polypeptide self-assembled nanoparticles. In doing so, we highlight the great advances made by the field, as well as the challenges still faced in achieving the clinical translation of peptide- and protein-functionalised nano drug delivery vehicles, imaging species, and active therapeutics. PMID- 29479623 TI - The chelate-to-bridging shift of phosphane dipalladacycles: convenient synthesis of double A-frame tetranuclear complexes. AB - Palladacycles of the type [Pd2(Ph2PCH2PPh2-P,P)2(C,N:C,N)] (C,N:C,N = bis(N-2,3,4 trimethoxybenzylidene)-4,4'-sulfonyldianiline or -4,4'-oxydianiline) can undergo a spontaneous slow chelate-to-bridging diphosphane coordination shift in solution. Following this strategy a tailor-made synthetic procedure was devised that culminates in isolation of double A-frame tetranuclear palladium complexes. PMID- 29479625 TI - Highly-organized stacked multilayers via layer-by-layer assembly of lipid-like surfactants and polyelectrolytes. Stratified supramolecular structures for (bio)electrochemical nanoarchitectonics. AB - Supramolecular self-assembly is of paramount importance for the development of novel functional materials with molecular-level feature control. In particular, the interest in creating well-defined stratified multilayers through simple methods using readily available building blocks is motivated by a multitude of research activities in the field of "nanoarchitectonics" as well as evolving technological applications. Herein, we report on the facile preparation and application of highly organized stacked multilayers via layer-by-layer assembly of lipid-like surfactants and polyelectrolytes. Polyelectrolyte multilayers with high degree of stratification of the internal structure were constructed through consecutive assembly of polyallylamine and dodecyl phosphate, a lipid-like surfactant that act as a structure-directing agent. We show that multilayers form well-defined lamellar hydrophilic/hydrophobic domains oriented parallel to the substrate. More important, X-ray reflectivity characterization conclusively revealed the presence of Bragg peaks up to fourth order, evidencing the highly stratified structure of the multilayer. Additionally, hydrophobic lamellar domains were used as hosts for ferrocene in order to create an electrochemically active film displaying spatially-addressed redox units. Stacked multilayers were then assembled integrating redox-tagged polyallylamine and glucose oxidase into the stratified hydrophilic domains. Bioelectrocatalysis and "redox wiring" in the presence of glucose was demonstrated to occur inside the stratified multilayer. PMID- 29479626 TI - Soft chemistry of ion-exchangeable layered metal oxides. AB - Soft chemical reactions such as ion-exchange and acid-base reactions have been extensively investigated to synthesize novel metastable layered inorganic solids, to exfoliate them into individual nanosheets, and to re-assemble them as thin films and nanocomposite materials. These reactions proceed at relatively low temperature and enable the synthesis of a rich variety of structures by stepwise reactions. In recent years, the toolbox of soft chemical reactions has been utilized to rationally design and tailor the properties of functional layered transition metal oxides. Layer-by-layer assembly and intercalation chemistry have provided insight into covalent interactions that stabilize oxide-supported nanoparticle catalysts. In addition, topochemical reactions have been utilized to tune the compositions of layered perovskite oxides in order to break inversion symmetry, resulting in piezoelectric and ferroelectric properties. This review focuses on the use of soft chemical approaches to design functional layered transition metal oxides with tunable properties. Soft chemical reactions enable the design of functional materials for diverse applications that include artificial photosynthesis, catalysis, energy storage, fuel cells, optical sensors, ferroics, and high-k dielectrics. PMID- 29479627 TI - Access to 2-substituted-2H-indazoles via a copper-catalyzed regioselective cross coupling reaction. AB - A CuCl catalyzed C-N cross-coupling reaction using commercially available 1H indazoles with diaryliodonium salts is described. The methodology features ample structural versatility, affording 2-substituted-2H-indazole in good yields and complete N(2)-regiocontrol. Furthermore, the utility of the reaction was demonstrated in the synthesis of a known estrogen receptor beta agonist. Mechanistic studies using density functional theory calculations suggested that the complete regioselectivity can be attributed to the only weak base TfO- in our system which could not deprotonate indazoles, and the catalyst oxidation process would be the rate-determining step. PMID- 29479624 TI - The Curtius rearrangement: mechanistic insight and recent applications in natural product syntheses. AB - The Curtius rearrangement is a versatile reaction in which a carboxylic acid can be converted to an isocyanate through an acyl azide intermediate under mild conditions. The resulting stable isocyanate can then be readily transformed into a variety of amines and amine derivatives including urethanes and ureas. There have been wide-ranging applications of the Curtius rearrangement in the synthesis of natural products and their derivatives. Also, this reaction has been extensively utilized in the synthesis and application of a variety of biomolecules. In this review, we present mechanistic studies, chemical methodologies and reagents for the synthesis of isocyanates from carboxylic acids, the conversion of isocyanates to amines and amine derivatives, and their applications in the synthesis of bioactive natural products and their congeners. PMID- 29479628 TI - The effects of osmolytes and crowding on the pressure-induced dissociation and inactivation of dimeric LADH. AB - Investigating the correlation between structure and activity of oligomeric enzymes at high pressure is essential for understanding intermolecular interactions and reactivity of proteins in cellulo of organisms thriving at extreme environmental conditions as well as for biotechnological applications, such as high-pressure enzymology. In a combined experimental effort employing small-angle X-ray scattering, FT-IR and fluorescence spectroscopy as well as stopped-flow enzyme kinetics in concert with high-pressure techniques, we reveal the pressure-induced conformational changes of the dimeric enzyme horse liver alcohol dehydrogenase (LADH) on the quaternary, secondary and tertiary structural level. Moreover, the effects of cosolutes and crowding agents, mimicking intracellular conditions, have been addressed. Our results show that beyond an increase of enzymatic activity at low pressures, loss of enzyme activity occurs around 600-800 bar, i.e. in a pressure regime where small conformational changes take place in the coenzyme's binding pocket, only. Whereas higher-order oligomers dissociate at low pressures, subunit dissociation of dimeric LADH takes place, depending on the solution conditions, between 2000 and 4000 bar, only. Oligomerization and subunit dissociation are modulated by cosolvents such as urea or trimethylamine-N-oxide as well as by the crowding agent polyethylene glycol, based on their tendency to bind to the protein's interface or act via their excluded volume effect, respectively. PMID- 29479629 TI - Yb3+-sensitized upconversion and downshifting luminescence in Nd3+ ions through energy migration. AB - A core-shell-shell nanostructure composed of NaGdF4:Yb/Tm@NaGdF4:Nd@NaYF4 is developed to realize Yb3+-sensitized upconversion and downshifting luminescence in Nd3+ ions. The unusual photon conversion property stems from a gadolinium sublattice mediated Yb3+-> Tm3+-> Gd3+-> Nd3+ energy transfer pathway. The energy transfer processes are investigated by varying the dopant concentration and distribution, in conjunction with time decay measurements. PMID- 29479630 TI - Mechanism and origins of the directing group-controlled endo- versus exo selectivity of iridium-catalysed intramolecular hydroalkenylation of 1,1 disubstituted alkenes. AB - Density functional theory calculations were performed to investigate the iridium catalysed intramolecular hydroalkenylation of 1,1-disubstituted alkenes. The detailed reaction mechanism is established, and the important role of directing groups in determining the experimentally observed endo- versus exo-selectivity is well rationalized by our calculations. PMID- 29479631 TI - Clinical aspects of tacrolimus use in paediatric renal transplant recipients. AB - The calcineurin inhibitor tacrolimus, cornerstone of most immunosuppressive regimens, is a drug with a narrow therapeutic window: underexposure can lead to allograft rejection and overexposure can result in an increased incidence of infections, toxicity and malignancies. Tacrolimus is metabolised in the liver and intestine by the cytochrome P450 3A (CYP3A) isoforms CYP3A4 and CYP3A5. This review focusses on the clinical aspects of tacrolimus pharmacodynamics, such as efficacy and toxicity. Factors affecting tacrolimus pharmacokinetics, including pharmacogenetics and the rationale for routine CYP3A5*1/*3 genotyping in prospective paediatric renal transplant recipients, are also reviewed. Therapeutic drug monitoring, including pre-dose concentrations and pharmacokinetic profiles with the available "reference values", are discussed. Factors contributing to high intra-patient variability in tacrolimus exposure and its impact on clinical outcome are also reviewed. Lastly, suggestions for future research and clinical perspectives are discussed. PMID- 29479632 TI - Eco-evolutionary processes affecting plant-herbivore interactions during early community succession. AB - The quality and outcome of organismal interactions are not only a function of genotypic composition of the interacting species, but also the surrounding environment. Both the strength and direction of natural selection on interacting populations vary with the community context, which itself is changed by these interactions. Here, we test for the role of interacting evolutionary and ecological processes in plant-herbivore interactions during early community succession in the tall goldenrod, Solidago altissima. We use surveys in a large scale field experiment with repeated plots representing 6 years of early oldfield succession and reciprocal transplant common garden experiments to test for the relative importance of rapid evolution (genetic) and environmental changes (soil quality) in affecting mean plant resistance and growth phenotypes during community succession. While plant growth varied strongly with soil quality over the first 5 years of agricultural abandonment, plant secondary metabolism, and herbivore resistance varied minimally with the soil environment. Instead, mean composition and abundance of plant secondary compound bouquets differed between S. altissima plants from populations collected in communities in the first ("early") and sixth ("intermediate") years of oldfield succession, which was reflected in the feeding preference of the specialist herbivore, Trirhabda virgata, for early succession lines. Moreover, this preference was most pronounced on poorer quality, early succession soils. Overall, our data demonstrate that plant quality varies for insect herbivores during the course of early succession and this change is a combination of altered genotypic composition of the population and phenotypic plasticity in different soil environments. PMID- 29479634 TI - Coordination of plantar flexor muscles during bipedal and unipedal stances in young and elderly adults. AB - To investigate the effects of aging on coordination of plantar flexor muscles during bipedal and unipedal stances, we examined a relationship between the center of pressure sway and electromyographic activity of these muscles, and also the common neural input, using a coherence analysis. Healthy young and elderly adults were asked to perform bipedal and unipedal standing. The electromyograms were recorded unilaterally from the medial and lateral gastrocnemius (MG and LG) and soleus (SL) muscles, and the common input was analyzed for MG-LG, MG-SL, and LG-SL pairs in two frequency bands: a delta band, that is associated with force variability, and a beta band, that could reflect the corticospinal drive. Main results indicated that the MG and SL muscles worked for lateral sway, while the LG muscle worked for medial sway during the unipedal stance. The delta-band coherence for the MG-SL pair and the beta-band coherences for all the pairs were larger during the unipedal than bipedal stance for both groups. The delta-band coherence for the MG-SL pair was larger for the elderly than young adults during the unipedal stance. In addition, the beta-band coherence for the MG-SL pair was larger than the other pairs during the unipedal stance for the elderly. These findings suggest that the oscillatory activity between the MG and SL muscles is strongly involved in the control of unipedal stance, and aging would increase the cortical drive to these muscles to deal with the postural sway that could be affected by forces generated cooperatively by them. PMID- 29479633 TI - Influence of genetic and non-genetic factors on acenocoumarol maintenance dose requirement in a Tunisian population. AB - PURPOSE: We aimed to study potential variables involved in interindividual variability to acenocoumarol (AC) response in order to establish a pharmacogenetic algorithm (PA) that includes clinical and genetic factors to predict adequate AC dose to stabilize anticoagulation in a cohort of Tunisian patients. METHODS: Genotyping of the CYP2C9, VKORC1, CYP4F2, and CALU polymorphisms was conducted on 246 patients using PCR-RFLP technique. AC normalized maintenance dose (NMD): ((mean maintenance dose/international normalized ratio (INR)) equilibrium) was calculated. The statistical study was carried out with SPSS V20. RESULTS: A significant correlation was found between age, BMI, and daily AC dose (r = - 0.397; p < 0.001 and r = 0.215; p = 0.001, respectively). The carriers of mutated alleles CYP2C9*2 or CYP2C9*3 or VKORC1 haplotypes (H1 and H7) were associated with AC hyper-sensibility. After adjustment to potential covariates, these patients presented supra-therapeutic INR during treatment period and needed low AC dose (ORs* = 0.28 [0.06-0.60], p = 0.004; ORs* = 0.12 [0.04-0.05], p < 0.001; ORs* = 0.45 [0.24-0.84], p = 0.01; and ORs* = 0.28 [0.06-0.98], p = 0.049, respectively). However, carriers of VKORC1 haplotypes (H3 and H12) or mutated alleles CYP4F2 (rs2108622) or CALU (rs1043550) tend to resist to treatment, hence long period of therapy initiation, and must be treated with high AC dose (ORs* = 2.67 [81.12-5.91], p = 0.013; ORs* = 8.76 [1.07 76.26], p = 0.019; ORs* = 3.12 [1.01-9.63], p = 0.047; and ORs* = 3.96 [1.41 11.09], p = 0.009, respectively). A final multivariate regression model explained 48.1% of the global interindividual variability in AC dose requirement. CONCLUSION: The PA demonstrated that VKORC1 and CYP2C9 polymorphisms contribution was more important than clinical factors. Applying the PA would allow dose adjustment to treat patients in a personalized manner. PMID- 29479636 TI - Effect of diosmin on apoptotic signaling molecules in N-nitrosodiethylamine induced hepatocellular carcinoma in experimental rats. AB - The aim of the present study was to evaluate the antioxidant and chemopreventive efficiency of diosmin against N-nitrosodiethylamine (NDEA)-induced hepatocarcinogenesis in adult male rats. Rats were classified into four groups as follows: Group I: Control, Group II: NDEA-induced hepatocellular carcinogenic rats, Group III: Cancer-bearing animals treated with diosmin (200 mg/kg/body weight/day) orally for 28 days, Group IV: Control animals treated with diosmin (200 mg/kg/body weight/day) alone for 28 days. The model of NDEA-induced HCC rats elicited significant increases in alpha-fetoprotein (AFP), lipid peroxidation (LPO) and increase in anti-apoptotic proteins (Bcl-2, Bcl-xL and Mcl-1) with a concomitant significant decline in liver antioxidant enzymes, pro-apoptotic (Bax and Bad) and caspase-3 &-9 proteins. The oral administration of diosmin as a protective agent normalized the altered levels of AFP, LPO, antioxidant enzymes, pro- and anti-apoptotic proteins as well as caspase-3 and -9 proteins. Transmission electron microscopical studies also revealed that treatment of diosmin has a perspective anti-cancer activity by rearranging hepatic cell structure and its integrity. Results of this study suggest that diosmin may be one of a pharmacological and therapeutic representative against hepatocellular carcinoma. PMID- 29479635 TI - Bacteremia associated with pressure ulcers: a prospective cohort study. AB - The objective of this study is to evaluate the clinical and microbiological characteristics of bacteremia associated with pressure ulcers (BAPU) and factors associated with mortality. This study was a prospective observational cohort study of patients with BAPU at a teaching hospital between January 1984 and December 2015. Fifty-six episodes were included. The incidence of BAPU decreased from 2.78 cases per 10,000 hospital discharges in the period from 1984 to 1999 to 1.05 cases per 10,000 hospital discharges in the period from 2000 to 2015 (p < 0.001). In 20 cases (35.7%), the bacteremia was hospital-acquired, since it occurred more than 48 h after the hospital admission. The most frequent microorganisms isolated in blood culture were Staphylococcus aureus, Proteus spp., and Bacteroides spp. The bacteremia was polymicrobial in 14 cases (25.0%). Overall mortality was observed in 23 episodes (41.1%). The risk factors independently associated with mortality were hospital-acquired bacteremia (odds ratio [OR] 5.51, 95% confidence interval [95%CI] 1.24-24.40), polymicrobial bacteremia (OR 6.88, 95%CI 1.22-38.89), and serum albumin <23 g/L (OR 8.00, 95%CI 1.73-37.01). BAPU is an uncommon complication of pressure ulcers and is mainly caused by S. aureus, Proteus spp., and Bacteroides spp. In our hospital, the incidence of BAPU has declined in recent years, coinciding with the implementation of a multidisciplinary team aimed at preventing and treating chronic ulcers. Mortality rate is high, and hospital-acquired bacteremia, polymicrobial bacteremia, and serum albumin < 23 g/L are associated with increased mortality. PMID- 29479637 TI - The Role of Urodynamics in Post-Prostatectomy Incontinence. AB - PURPOSE OF REVIEW: Radical prostatectomy (RP) is the standard surgical treatment for localized prostate cancer. One of the side effects after RP impacting quality of life is urinary incontinence. Because of the impact in quality of life, more patients are seeking treatment for post-prostatectomy incontinence. Urodynamics are an important tool to help understand how prostate surgery changes bladder and urethral function. We reviewed the current literature in order to determine the role of urodynamics in post-prostatectomy incontinence. RECENT FINDINGS: Studies have been done to demonstrate the anatomical and functional changes in incontinent men after radical prostatectomy compared to continent men, as well as to evaluate the use of urodynamics in the work-up for post-prostatectomy incontinence prior to treatment. However, there is not a consensus about the indications of urodynamics in this population and new studies have questioned the real role of urodynamics in this setting. Because of the impact in quality of life, more patients are seeking treatment for post-prostatectomy incontinence. Urodynamics have been used to have a better understanding of the anatomical and functional changes in incontinent men after radical prostatectomy; however, the role of urodynamic testing to assess these patients and offer treatment is still to be determined. PMID- 29479639 TI - Correction to: Synthetic biology, genome mining, and combinatorial biosynthesis of NRPS-derived antibiotics: a perspective. AB - The original article can be found online at . PMID- 29479640 TI - Endoscopic Management of Urethral Stricture: Review and Practice Algorithm for Management of Male Urethral Stricture Disease. AB - PURPOSE OF REVIEW: Male urethral stricture disease is characterized by the formation of scar tissue within the urethra resulting in lower urinary tract symptoms, infection, and potentially kidney dysfunction. There is significant variability in clinical practice for the treatment of urethral stricture. We sought to summarize the known data on endoscopic management of urethral stricture disease as part of this larger edition on urethral stricture management. RECENT FINDINGS: Older studies quoted high rates of success with endoscopic management of urethral stricture, including repeated DVIU. There is now evidence to support a limited role of endoscopic intervention in the management of urethral stricture, and especially strong evidence that repeated endoscopic procedures are not effective. There is poor evidence to support the long-term efficacy of endoscopic urethral stricture management. Furthermore, novel advances in adjunctive therapies have not yet demonstrated durable patency. We discuss the limited role of endoscopic management and suggest an algorithm for its use in stricture management. PMID- 29479638 TI - Critical Care Management of Stress-Induced Hyperglycemia. AB - PURPOSE OF REVIEW: We discuss key studies that have set the scene for the debate on the efficacy and safety of tight glycemic control in critically ill patients, highlighting important differences among them, and describe the ensuing search towards strategies for safer glucose control. RECENT FINDINGS: Differences in level of glycemic control, glucose measurement and insulin administration, expertise, and nutritional management may explain the divergent outcomes of the landmark studies on tight glycemic control in critical illness. Regarding strategies towards safer glucose control, several computerized algorithms have shown promise, but lack validation in adequately powered outcome studies. Real time continuous glucose monitoring and closed loop blood glucose control systems are not up to the task yet due to technical challenges, though recent advances are promising. Alternatives for insulin have only been investigated in small feasibility studies. Severe hyperglycemia in critically ill patients generally is not tolerated anymore, but the optimal blood glucose target may depend on the specific patient and logistic context. PMID- 29479641 TI - Correlation between the pronucleus size and the potential for human single pronucleus zygotes to develop into blastocysts : 1PN zygotes with large pronuclei can expect an embryo development to the blastocyst stage that is similar to the development of 2PN zygotes. AB - PURPOSE: In this study, we examined the correlation between pronucleus size and the potential for human single pronucleus (1PN) zygotes to develop into blastocysts after IVF and ICSI. METHODS: This study included 112 patients who underwent a total of 112 cycles of IVF/ICSI. To evaluate embryo development, 1PN zygotes were compared with 2PN zygotes in the same IVF/ICSI cycle (control cycles) using time-lapse live embryo imaging. To assess the potential for blastocyst formation, cutoff values for pronuclear area and diameter were established through receiver operating characteristic curve analysis, after which 1PN zygotes were classified based on those cutoff values. RESULTS: Among 1PN zygotes cultured to day 5/6, the rate of embryo development was significantly lower than from 2PN zygotes. However, the rates of blastocyst formation and good quality blastocysts from 1PN zygotes with large pronuclear areas (>= 710 MUm2) or diameters (>= 31 MUm) were significantly higher than from 1PN zygotes with smaller pronuclear areas (<= 509, 510-609, and 610-709 MUm2) or diameters (<= 24, 25-27,and 28-30 MUm) (P < 0.01). Moreover, the results for 1PN zygotes with large pronuclei were similar to those for 2PN zygotes. CONCLUSIONS: The developmental potential of 1PN zygotes with large pronuclear areas (>= 710 MUm2) or diameters (31 MUm) appears to be similar to that of 2PN zygotes, and measurement of pronuclear area or diameter in 1PN zygotes is a simple, potentially useful, clinical method. PMID- 29479642 TI - Identification of Sex Pheromones and Sex Pheromone Mimics for Two North American Click Beetle Species (Coleoptera: Elateridae) in the Genus Cardiophorus Esch. AB - To date, all known or suspected pheromones of click beetles (Coleoptera: Elateridae) have been identified solely from species native to Europe and Asia; reports of identifications from North American species dating from the 1970s have since proven to be incorrect. While conducting bioassays of pheromones of a longhorned beetle (Coleoptera: Cerambycidae), we serendipitously discovered that males of Cardiophorus tenebrosus L. and Cardiophorus edwardsi Horn were specifically attracted to the cerambycid pheromone fuscumol acetate, (E)-6,10 dimethylundeca-5,9-dien-2-yl acetate, suggesting that this compound might also be a sex pheromone for the two Cardiophorus species. Further field bioassays and electrophysiological assays with the enantiomers of fuscumol acetate determined that males were specifically attracted by the (R)-enantiomer. However, subsequent analyses of extracts of volatiles from female C. tenebrosus and C. edwardsi showed that the females actually produced a different compound, which was identified as (3R,6E)-3,7,11-trimethyl-6,10-dodecadienoic acid methyl ester (methyl (3R,6E)-2,3-dihydrofarnesoate). In field trials, both the racemate and the (R)-enantiomer of the pheromone attracted similar numbers of male beetles, suggesting that the (S)-enantiomer was not interfering with responses to the insect-produced (R)-enantiomer. This report constitutes the first conclusive identification of sex pheromones for any North American click beetle species. Possible reasons for the strong and specific attraction of males to fuscumol acetate, which is markedly different in structure to the actual pheromone, are discussed. PMID- 29479643 TI - Multivariate Analysis of Multiple Datasets: a Practical Guide for Chemical Ecology. AB - Chemical ecology has strong links with metabolomics, the large-scale study of all metabolites detectable in a biological sample. Consequently, chemical ecologists are often challenged by the statistical analyses of such large datasets. This holds especially true when the purpose is to integrate multiple datasets to obtain a holistic view and a better understanding of a biological system under study. The present article provides a comprehensive resource to analyze such complex datasets using multivariate methods. It starts from the necessary pre treatment of data including data transformations and distance calculations, to the application of both gold standard and novel multivariate methods for the integration of different omics data. We illustrate the process of analysis along with detailed results interpretations for six issues representative of the different types of biological questions encountered by chemical ecologists. We provide the necessary knowledge and tools with reproducible R codes and chemical ecological datasets to practice and teach multivariate methods. PMID- 29479644 TI - Survival of breast cancer patients in rural Ethiopia. AB - PURPOSE: To describe the histopathological characteristics and survival of female breast cancer (BC) patients in a rural setting with limited access to adjuvant treatment. METHODS: A prospective study of 107 histologically confirmed BC patients treated with surgery from 2010 to 2016 from rural parts of western Ethiopia. Referral pathology was performed, and active follow-up was conducted. Adjusted cox regression analysis (hazard ratio [HR]) was performed. RESULTS: The median age at diagnosis was 45 (16-83) years; 57% of the patients presented with cT3/4 tumors, 71% with clinically positive lymph nodes, 21% with HER2 overexpression (Dako3+) and 68% with grade 3 tumors. Estrogen and/or progesterone receptor expressions were present in 66% and triple-negative disease in 25%. The estimated 1- and 2-year overall survival probability rates were 78 and 53%, respectively. The 2-year survival for patients with clinically positive lymph nodes was 44% compared to 73% for patients with lymph node-negative disease (HR 2.44; 95% confidence interval [95% CI] 1.19-5.02). The corresponding 2-year survival for patients with cT4 tumors was 25% versus 68% for patients with cT1-2 tumors (cT1-3 vs. cT4 HR 3.86; 95% CI 1.82-13.63). The 2-year survival for patients with hormone receptor-negative disease was 40% compared to 59% for patients with hormone receptor-positive disease (HR 1.92; 95% CI 1.06-3.47). CONCLUSION: The majority of breast cancer patients treated with surgery in rural parts of western Ethiopia are diagnosed at advanced stage and have hormone receptor-positive disease. Nearly half of the patients die within 2 years. These findings underscore the need for provision of adjuvant hormonal therapy and for the establishment of pathology service including hormone receptor testing. PMID- 29479645 TI - Association of sitting time and breaks in sitting with muscle mass, strength, function, and inflammation in community-dwelling older adults. AB - : The mechanisms through which excessive sitting time impacts health are important to understand. This study found that each hour of sitting per day was not associated with physical function, although associations with poor body composition were observed. Reducing sitting time for improved weight management in older adults needs further exploration. INTRODUCTION: To examine the association of sitting time and breaks in sitting time with muscle mass, strength, function, and inflammation in older Australians. METHODS: Data from the thigh-worn activPAL3TM monitor (7-day continuous wear) was used to derive time spent sitting (hours) and total number of sit-stand transitions per day. Body composition (dual energy X-ray absorptiometry), lower-body muscle strength, function (timed up-and-go [TUG], 4-m gait speed, four square step test, 30-second sit-to-stand), and serum inflammatory markers (interleukin-[IL-6], IL-8, IL-10, tumor necrosis factor-alpha [TNF-alpha], and adiponectin) were measured. Multiple regression analyses, adjusted for age, sex, ethnicity, education, employment status, marital status, number of prescription medications, smoking status, vitamin D, and stepping time, were used to assess the associations. RESULTS: Data from 123 community-dwelling older adults (aged 65-84 years, 63% female) were used. Total daily sitting time was associated with lower percentage lean mass (beta [95%CI], - 1.70% [- 2.30, - 1.10]) and higher total body fat mass (2.92 kg [1.94, 3.30]). More frequent breaks in sitting time were associated with a 45% reduced risk of having pre-sarcopenia (OR = 0.55; 95% CI 0.34, 0.91; model 1), defined as appendicular lean mass divided by BMI. No significant associations were observed for sitting time or breaks in sitting with measures of muscle strength, function, or inflammation. CONCLUSION: In older community-dwelling adults, greater sitting time was associated with a lower percentage lean mass, while more frequent breaks in sitting time were associated with lower odds of having pre-sarcopenia. This suggests that reducing sedentary time and introducing frequent breaks in sedentary time may be beneficial for improving body composition in healthy older adults. PMID- 29479647 TI - MRI Brain Images Classification: A Multi-Level Threshold Based Region Optimization Technique. AB - Medical image processing is the most challenging and emerging field nowadays. Magnetic Resonance Images (MRI) act as the source for the development of classification system. The extraction, identification and segmentation of infected region from Magnetic Resonance (MR) brain image is significant concern but a dreary and time-consuming task performed by radiologists or clinical experts, and the final classification accuracy depends on their experience only. To overcome these limitations, it is necessary to use computer-aided techniques. To improve the efficiency of classification accuracy and reduce the recognition complexity involves in the medical image segmentation process, we have proposed Threshold Based Region Optimization (TBRO) based brain tumor segmentation. The experimental results of proposed technique have been evaluated and validated for classification performance on magnetic resonance brain images, based on accuracy, sensitivity, and specificity. The experimental results achieved 96.57% accuracy, 94.6% specificity, and 97.76% sensitivity, shows the improvement in classifying normal and abnormal tissues among given images. Detection, extraction and classification of tumor from MRI scan images of the brain is done by using MATLAB software. PMID- 29479646 TI - Prior fragility fracture and risk of incident ischaemic cardiovascular events: results from UK Biobank. AB - : In the large UK Biobank population-based cohort, we found that amongst men, but not women, prior fragility fracture was associated with increased risk of admission with ischaemic heart disease. INTRODUCTION: We aimed to investigate the relationship between prior fracture and risk of incident ischaemic cardiovascular events in a UK population-based cohort. METHODS: UK Biobank is a large prospective cohort comprising 502,637 men and women aged 40-69 years, with detailed baseline assessment. History of fracture was self-reported, and details of hospital admissions for ischaemic heart disease (IHD) (ICD-10:I20-I25) were obtained through linkage to UK Hospital Episode Statistics. Cox proportional hazards models were used to investigate the prospective relationships between prior fracture and hospital admission for men and women, controlling for age, BMI, smoking, alcohol, educational level, physical activity, systolic blood pressure, calcium and vitamin D use, ankle spacing-width, heel BUA and HRT use (women). RESULTS: Amongst men, a fragility fracture (hip, spine, wrist or arm fracture resulting from a simple fall) within the previous 5 years was associated with a 35% increased risk of IHD admission (fully adjusted HR 1.35; 95%CI 1.00, 1.82; p = 0.047), with the relationship predominantly driven by wrist fractures. Associations with hospitalisation for angina in men were similar in age-adjusted models [HR1.54; 95%CI: 1.03, 2.30), p = 0.037], but did not remain statistical significant after full adjustment [HR 1.64; 95%CI: 0.88, 3.07); p = 0.121]. HRs for admission with angina were lower in women, and neither age- nor fully adjusted relationships attained statistical significance. CONCLUSIONS: Prior fragility fracture is an independent risk factor for incident ischaemic cardiovascular events in men. Further work may clarify whether this association is causal or represents shared risk factors, but these findings are likely to be of value in risk assessment of both osteoporosis and cardiovascular disease. PMID- 29479648 TI - Mercury bioremediation by mercury resistance transposon-mediated in situ molecular breeding. AB - Mercury-resistant (HgR) bacteria occur in various bacterial species from a wide variety of environmental sources. Resistance is conferred by a set of operon genes termed the mer operon. Many HgR bacteria have been isolated from diverse environments and clinical samples, and it is recognized that mer operons are often localized on transposons. Previous research reports have suggested that HgR transposons participate in the horizontal gene transfer of mer operons among bacteria. This was confirmed by a study that found that mer operons were distributed worldwide in Bacilli with dissemination of TnMERI1-like transposons. In this mini review, possible strategies for transposon-mediated in situ molecular breeding (ISMoB) of HgR bacteria in their natural habitat are discussed. In ISMoB, the target microorganisms for breeding are indigenous bacteria that are not HgR but that are dominant and robust in their respective environments. Additionally, we propose a new concept of bioremediation technology for environmental mercury pollution by applying transposon-mediated ISMoB for environmental mercury pollution control. PMID- 29479649 TI - Pelvic Organ Prolapse and Pregnancy in the Female Bladder Exstrophy Patient. AB - PURPOSE OF REVIEW: Classic bladder exstrophy (BE) remains one of the most demanding reconstructive challenges encountered in urology. In female BE patients, the long-term sequela of both primary and revision genitoplasty, as well as intrinsic pelvic floor deficits, predispose adult women to significant issues with sexual function, pelvic organ prolapse (POP), and complexities with reproductive health. RECENT FINDINGS: Contemporary data suggest 30-50% of women with BE develop prolapse at a mean age of 16 years. Most women will require revision genitoplasty for successful sexual function, although in some series over 40% report dyspareunia. Current management for pregnancy includes elective cesarean section with involvement of high-risk obstetrics and urologic surgery. This review encapsulates contemporary concepts of etiology, prevalence, and management of POP and pregnancy in the adult female BE patient. PMID- 29479650 TI - Refractory Urethral Stricture Management: Indications for Alternative Grafts and Flaps. AB - PURPOSE OF REVIEW: Urethral strictures that are refractory to initial management present unique challenges to the reconstructive surgeon. Treatment trends have shifted as new tissue resources are becoming available. There is renewed interest in old methods as skill and technique have improved. We describe the scope of the surgical armamentarium available to develop creative approaches and successful outcomes. RECENT FINDINGS: We discuss techniques to maximize the availability of oral mucosa, harvest and use of rectal mucosa, and developments in tissue engineering. Evolving methods to assess success of repair are also described. Urethral reconstruction for refractory urethral strictures requires proficiency with multiple methods as these strictures often require combining techniques for successful treatment. PMID- 29479651 TI - Fate of estrogens in a pilot-scale step-feed anoxic/oxic wastewater treatment system controlling by nitrogen and phosphorus removal. AB - The control measures for estrogens in the aquatic environment are topics of growing concern. It is a meaningful issue to finding optimal process parameters for efficient removal of estrogens with the purpose of efficient total nitrogen (TN) or total phosphorus (TP) removal in sewage treatment plants. The present paper is concerned with the relationships between the estrogen removal and TN or TP removal in a pilot-scale three-stage anoxic/oxic (A/O) system treating real municipal wastewater. The total removal efficiency for estrone (E1) and 17beta estradiol (E2) and their sulfate and glucuronide conjugates were on average 87% in the pilot-scale system. The concentrations of the sulfate and glucuronide conjugates of estrogens (E1 and E2) in the system were much lower than the estrogens, which might be caused by the rapid degradation of conjugates in the pilot-scale system. The average removal efficiencies of E1 and E2 and their sulfate and glucuronide conjugates were significantly lower under high TP removal conditions than those under high TN removal conditions that suggested that the ammonia oxidation promotes estrogen degradation. When the system achieved efficient TN removal, the concentrations of both E1 and E2 were generally lower in the aerobic zones than those in the anoxic zones. Instead, when the system achieved efficient TP removal conditions, the estrogen concentrations were higher in the aerobic zones than in the anoxic zones. However, it was thought that the variation of the concentrations of the estrogen conjugates had weak influence on concentrations of the free estrogens. The increase of the free estrogens in the aerobic zones could be attributed to the release of the estrogens adsorbed on the sludge. The variation of estrogens in a three-stage A/O system can be properly estimated and measured by a binary linear regression model with the variables of TP and TON (NO2--N and NO3--N), which is probably the important information for the improvement and optimization of wastewater treatment processes to obtain higher removal efficiency for estrogens. PMID- 29479653 TI - Normative Data for Thyroid Stimulating Hormone for Screening of Congenital Hypothyroidism. AB - OBJECTIVE: To generate normative data for thyroid stimulating hormone (TSH) levels in heel prick samples collected from newborns from 24 h to 7 d of age. METHODS: Five regional laboratories were designated as the testing laboratories. Dried blood spots (DBS) from babies (> or = 34 wk of gestation) were collected by heel prick at least after 24 h and within seven days after birth. TSH estimation was done using time resolved fluoroimmunoassay. Values above 20mIU/L were labelled as presumptive positive. Hour interval specific normative data was categorized at 6 h intervals. Another category placed was division into 24-72 h category, 73-96 h and 99-168 h. Percentile charts were calculated across these specified intervals. RESULTS: Samples analysed were 104,006 collected cumulatively from the 5 centers. Of the total samples analysed for TSH, 92.8% had values less than 5 mIU/l. When TSH values were interpreted with respect to time, a steady decrease with time was observed. Of the babies' samples, 48,839 were collected between 24 and 48 h, 23,983 between 49 to 72 h and 30,883 were collected after 72 h. The mean TSH concentration demonstrated a steady decline from 24 h to 168 h. It is apparent that 10 mIU/l is the 97.5th percentile value even when corrected for gender, birth weight and age at sampling. Thus 10 mIU/l seems to be the right cutoff beyond which a second sample should be sought. CONCLUSIONS: This is the largest series reported with a broader population mix with representations of both urban (including slums) as well as a rural population. As this study excluded preterm babies, the utility of cut offs generated is not applicable to this subset and also to critically sick neonates. However, this study gives a true representation of the normative values for majority of the newborns born at term with weight appropriate for the gestation. PMID- 29479655 TI - General Psychological Implications of the Human Capacity for Grief. AB - Much theorizing in psychology and related disciplines begins with a given model of the mind that is then applied in research projects to study concrete phenomena. Sometimes psychological research can be theory-driven in quite an explicit way, approaching the logic of the hypothetico-deductive method. Others reject this and prefer to work inductively, and, in the extreme case of positivism, perhaps try to avoid theorizing altogether. In this article I shall suggest another way to think of the relationship between psychological theories and psychological phenomena. My suggestion is not simply to replace the hypothetico-deductive model with an inductive one, but to argue that the most direct route to theories of the human mind that grasp its complexity is to begin with the Kantian question of transcendental philosophy: X exists - how is X possible? In the context of this article, I apply this questioning to the phenomenon of grief: Grief exists - what general psychological theory of the mind do we need in order to account for its possibility? I attempt to extract three general psychological points from the existence of grief, viz. (1) the deep relationality of the self, (2) the limitations of evolutionary accounts, and (3) the normativity of psychological phenomena. I shall argue that these are general psychological lessons to be learned from grief, although they could also be arrived at by considering several other significant psychological phenomena. PMID- 29479654 TI - Pemphigus group: overview, epidemiology, mortality, and comorbidities. AB - Pemphigus forms a group of rare autoimmune bullous diseases that affect the skin and mucous membranes. This group has a chronic course leading to high morbidity and mortality. It is characterized by the production of pathogenic autoantibodies directed against different proteins of the desmosome, leading histologically to intraepidermal cleavage, and clinically to vesicles and erosions on the epithelium of the mucous membranes and/or the skin. The diagnosis of the subtype of pemphigus is based on clinical features, the level of histologic cleavage, and the identification of the antigens recognized by circulating autoantibodies by immunoserological analyses. The epidemiological features of pemphigus vary considerably in different regions of the world. Observational studies examining comorbidities and associations among patients with pemphigus are scarce and sometimes inconclusive. The prognosis, mortality, and clinical outcomes in pemphigus have undergone dramatic change throughout the years. This review provides a brief overview about the different subtypes of pemphigus: pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, pemphigus herpetiformis, and IgA pemphigus. In addition, it summarizes the most recent understanding of the epidemiology, mortality data, and comorbidities of this group of organ specific autoimmune diseases. PMID- 29479656 TI - Updates on Women's Health Issues in Patients with Inflammatory Bowel Disease. AB - PURPOSE OF REVIEW: Inflammatory bowel disease affects approximately 800,000 women in the USA with the peak incidence between ages 15 to 40. Thus for many females, IBD can impact nearly every stage of their life from menarche to pregnancy, menopause, and beyond. This paper will review the most recent updates on the topics of sexual health, cervical cancer screening, menstruation, fertility, contraception, and menopause. RECENT FINDINGS: Menarche can be delayed in females especially those who are underweight, malnourished, or with active inflammatory bowel disease. Cyclical GI symptoms during a menstrual cycle are very common in women with IBD and should not be confused with flares. Overall fertility is similar to the general population unless females with IBD have had significant abdominal surgery but reassuringly this infertility appears to be restored with the use of in vitro fertilization. Discussion regarding family planning is imperative in women with IBD with a strong recommendation to consider long-acting highly effective contraceptives such as intrauterine devices or implants. Cervical cancer screening should be tailored in women on immunosuppressive medications and all women under 26 years of age should be advised to receive the human papilloma virus vaccination. As gastroenterologists will have longitudinal relationships with their female IBD patients, they must be knowledgeable about sex-specific issues during each stage of life from puberty to after menopause to optimize their patient's care. PMID- 29479657 TI - Quantitative evaluation of different far lateral approaches to the cranio vertebral junction using the microscope and the endoscope: a cadaveric study using a tumor model. AB - BACKGROUND: Several far lateral approaches have been proposed to deal with cranio vertebral junction (CVJ) tumors including the basic, transcondylar, and supracondylar far lateral approaches (B-FLA, T-FLA, and S-FLA). However, the indications on when to use one versus the other are not well systematized yet. Our purpose is to evaluate in an experimental cadaveric setting which approach is best suited to remove tumors of different sizes. METHODS: We implanted at the CVJ, using a transoral approach, tumor models of different sizes (five 1-cm3 and five 3-cm3 tumors) in ten embalmed cadaveric heads. The artificial tumors were exposed via the three approaches using endoscopic-assisted microneurosurgical technique and neuronavigation. The skull base area exposed and the maneuverability linked to each approach were evaluated using neuronavigation. RESULTS: In 1-cm3 tumors, the T-FLA and the S-FLA exposed a significantly larger skull base area than the B-FLA both using the microscope and the endoscope (P < 0.05); the T-FLA executed with the microscope provided wider vertical and horizontal maneuverability than the B-FLA (P = 0.030 and 0.017, respectively); the S-FLA executed with the endoscope provided wider vertical maneuverability than the T-FLA (P = 0.031). The S-FLA executed using the microscope and the endoscope provided wider vertical maneuverability than the B-FLA both in 1 and 3 cm3 tumors (P < 0.05). CONCLUSIONS: In 1-cm3 tumors, the S-FLA and the T-FLA expose a wider skull base area than the B-FLA. In larger tumors, the exposure is similar for all three approaches. Use of the endoscope in an assistive mode may further increase the surgical exposure and maneuverability. PMID- 29479658 TI - No correlation between radiological and clinical outcome 1 year following cervical arthrodesis. AB - AIM: To correlate clinical and radiological outcome following one- and two-level anterior cervical discectomy and fusion (ACDF) with stand-alone polyetheretherketone (PEEK) cages filled with demineralized bone matrix (DBM). METHODS: We performed a retrospective review of a consecutive patient cohort with degenerative disc disease that underwent ACDF with stand-alone PEEK cages filled with demineralized bone matrix (DBM) between 2010 and 2013 with a minimum follow up of 12 months. Changes in the operated segments were measured and compared to radiographs directly after surgery. Clinical outcome was evaluated by a physical examination, pain by visual analog scale (VAS) for arm and neck. Health-related quality of life was measured using the EuroQOL questionnaire (EQ-5D). RESULTS: Of 282 consecutive cases, follow-up data were obtained from 194 (69%) cases. The median age at presentation was 54 years and 91 patients were male (46%). Ninety eight and 96 patients had one- and two-level surgeries, respectively. Mean VAS pain was reduced from 5.2 +/- 3.6 to 2.6 +/- 2.4 (p < 0.001) and from 5.8 +/- 3.3 to 2.1 +/- 2.7 (p < 0.001) in the myelopathy and radiculopathy group, respectively. Fusion was achieved in 79 and 82% of segments in one- and two-level surgeries, respectively. Cervical alignment was better in 10 and 1%, similar in 68 and 76%, worse in 23 and 23% in one- and two-level surgeries, respectively. Subsidence was observed in 44 and 34% of segments in one- and two-level surgeries, respectively. Follow-up operations due to symptomatic adjacent disc disease or implant failure were needed in 13 (7%) and 15 (8%) of cases, respectively. Subsidence, adjacent disc disease, and cervical alignment all had no influence on the clinical outcome. CONCLUSIONS: The clinical outcome after ACDF with PEEK cages filled with demineralized bone matrix is highly satisfactory. Radiological signs of non-fusion, subsidence, and cervical alignment have no influence on clinical outcome. PMID- 29479659 TI - In vivo estimation of passive biomechanical properties of human myocardium. AB - Identification of in vivo passive biomechanical properties of healthy human myocardium from regular clinical data is essential for subject-specific modelling of left ventricle (LV). In this work, myocardium was defined by Holzapfel-Ogden constitutive law. Therefore, the objectives of the study were (a) to estimate the ranges of the constitutive parameters for healthy human myocardium using non invasive routine clinical data, and (b) to investigate the effect of geometry, LV end-diastolic pressure (EDP) and fibre orientations on estimated values. In order to avoid invasive measurements and additional scans, LV cavity volume, measured from routine MRI, and empirical pressure-normalised-volume relation (Klotz-curve) were used as clinical data. Finite element modelling, response surface method and genetic algorithm were used to inversely estimate the constitutive parameters. Due to the ill-posed nature of the inverse optimisation problem, the myocardial properties was extracted by identifying the ranges of the parameters, instead of finding unique values. Additional sensitivity studies were carried out to identify the effect of LV EDP, fibre orientation and geometry on estimated parameters. Although uniqueness of the solution cannot be achieved, the normal ranges of the parameters produced similar mechanical responses within the physiological ranges. These information could be used in future computational studies for designing heart failure treatments. Graphical abstract. PMID- 29479660 TI - Evaluation of high resolution thermal imaging to determine the effect of vertebral fractures on associated skin surface temperature in children with osteogenesis imperfecta. AB - Vertebral fractures are common in children with osteogenesis imperfecta (OI). Current imaging methods for fracture detection (X-ray and DXA) use ionising radiation. This pilot study explored whether the alteration in blood flow in vertebral fractures results in skin temperature changes that may be detected using high resolution thermal imaging (HRTI) and thus assist diagnosis and monitoring of fractures in OI patients. Eleven participants aged 5-18 years with OI and known vertebral fractures were enrolled. Small metal discs were placed on the skin surface alongside the vertebrae before participants had DXA and X-ray scans and thermal imaging of their backs. Visibility of the discs on the DXA and X-ray scans and thermal images allowed the temperatures of the skin surface above vertebrae without (healthy) and with fractures to be compared to their respective adjacent skin surface regions (region of reference, ROR) by calculating the temperature percentage change (TPC). The TPC between the skin temperature over the fractured thoracic vertebrae (n = 11) and the ROR was significant (1.44%, p = 0.002, 95% confidence). TPC between the skin temperature over healthy thoracic vertebrae and ROR was not significant (0.97%, p = 0.15, 95% confidence). HRTI may provide a novel tool for assisting in detection of vertebral fractures in OI. Graphical abstract * Patients (aged 5-18) with osteogenesis imperfecta and known vertebral fractures. * Thermal imaging was performed alongside routine imaging (DXA scan and spinal X-ray). * The temperature above each vertebra was compared with its adjacent skin region to assist with diagnosis of the fracture. PMID- 29479661 TI - The nutritive value of cassava starch extraction residue for growing ducks. AB - The cassava root meal (CRM) has been utilized as a cheap energy alternative to replace maize in poultry diets. Recently, the CRM in turn has an increasing demand for starch extraction industry, which renders large amounts of residues. This study evaluated the nutrient composition, amino acid profile, and feeding value of cassava starch extraction residue meal (CReM) for growing ducks. A total of 960, 11-day-old, ducklings were housed in 24 floor pens and allocated randomly into four dietary treatments: (i) 0CReM (control), (ii) 50 g CReM/kg, (iii) 100 g CReM/kg, and (iv) 150 g CReM/kg. The analyses (/kg) of CReM showed high gross energy (3306.88 kcal), ME (2109.54 kcal), and starch (514.0 g), with poor crude protein (20.9 g) and moderate crude fiber (140.0 g) and ash (60.0 g) contents. The total amino acid (AA) content amounted to 19.9 g/kg of CReM DM, in which the methionine, lysine, cystine, and isoleucine were present in low levels. The dietary inclusion of CReM up to 150 g/kg, between 11 and 42 days of age, had no significant effects (P > 0.05) on duck growth parameters, mortality, dressed weight, internal organs, or abdominal fat. Besides, the tested CReM levels did not show any significant effect on the blood proteins or liver enzymes. The results, therefore, revealed that the CReM contains a considerable amount of energy and could be incorporated successfully up to 150 g/kg in the diets of growing ducks. PMID- 29479662 TI - Echocardiographic assessment of right ventricle free wall strain for prediction of right coronary artery proximal lesion in patients with inferior myocardial infarction. AB - In this study, our objective was to evaluate right ventricular functions with speckle-tracking and conventional echocardiographic methods in patients with acute inferior myocardial infarction and to investigate the correlation between the echocardiographic parameters and the prediction of the proximal RCA lesions. 77 patients were included in this study. Patients with a RCA occluded proximal to the right ventricular branch were assigned to Group 1 and patients with an RCA occlusion distal to the right ventricle branch were assigned to Group 2. All echocardiographic examinations were carried out within 24 h after PTCA, which was performed for the treatment of inferior myocardial infarction. RV TAPSE, RV TDI Sm, FAC, RV-FW strain, RV-FW SRE', RV-FW SRA' and RV E/Em which were statistically significant in univariate analysis were evaluated with the help of the multivariate logistic regression analysis. In the multivariate logistic regression test; RV-FW strain (OR 0.751, 95% CI 0.592-0.954, p = 0.019) and RV E/Em (OR 0.442, 95% CI 0.252-0.776, p = 0.004) were determined as the independent predictive parameters for proximal RCA occlusion. In the ROC analysis, RV-FW strain > - 14.75% predicted the proximal RCA occlusion with 83% sensitivity and 61% specificity (AUC = 0.81, p < 0.001) and RV E/Em > 6.25 with 68% sensitivity and 80% specificity (AUC = 0.79, p < 0.001). In this study, we demonstrated that decreased RV FW strain and increased RV E/Em were predictive parameters for the presence of the proximal RCA in patients with acute inferior MI. PMID- 29479664 TI - Spontaneous tumour lysis syndrome in a primary adrenal lymphoma. PMID- 29479663 TI - Influence of different seasons during late gestation on Holstein cows' colostrum and postnatal adaptive capability of their calves. AB - Season may affect calves' thermal comfort and behavior, but the data related to the overall influence of seasonal variations on dams' colostrum and postnatal adaptive capability of calves are limited. The aim of this study was to measure the effects of a 49-day-long low air temperature (LAT) season (5.20 +/- 0.46 degrees C mean air temperature) and a 53-day-long high air temperature (HAT) season (27.40 +/- 0.39 degrees C mean air temperature) on dams' colostrum quality and physiological, biochemical, hormonal, and oxidative stress parameters of their calves during the first 7 days of life. The dams' colostrum was sampled at 2, 14, and 26 h after calving, before feeding of their calves. Calves' blood samples were taken before the first colostrum intake and on days 1, 2, 3, and 7 of life. Calves' physiological parameters were measured on days 0 and 7. HAT season significantly reduced the quality of dams' colostrum. The ingestion of the low-quality colostrum, combined with the thermal discomfort during HAT season, probably provoked impaired physiological, biochemical, hormonal, and oxidative stress parameters in samples taken from the post-colostral calves. Additionally, intravenous glucose tolerance test was performed on day 7, which suggested an enhanced insulin response in HAT season calves. This study highlights the importance of adequate supporting strategies for the care of the late gestation cows and postnatal calves during the HAT season. PMID- 29479665 TI - Scandinavian SSAI clinical practice guideline on choice of inotropic agent for patients with acute circulatory failure. AB - BACKGROUND: Adult critically ill patients often suffer from acute circulatory failure and those with low cardiac output may be treated with inotropic agents. The aim of this Scandinavian Society of Anaesthesiology and Intensive Care Medicine guideline was to present patient-important treatment recommendations on this topic. METHODS: This guideline was developed according to GRADE. We assessed the following subpopulations of patients with shock: (1) shock in general, (2) septic shock, (3) cardiogenic shock, (4) hypovolemic shock, (5) shock after cardiac surgery, and (6) other types of shock, including vasodilatory shock. We assessed patient-important outcome measures, including mortality and serious adverse reactions. RESULTS: For all patients, we suggest against the routine use of any inotropic agent, including dobutamine, as compared to placebo/no treatment (very low quality of evidence). For patients with shock in general, and in those with septic and other types of shock, we suggest using dobutamine rather than levosimendan or epinephrine (very low quality of evidence). For patients with cardiogenic shock and in those with shock after cardiac surgery, we suggest using dobutamine rather than milrinone (very low quality of evidence). For the other clinical questions, we refrained from giving any recommendations or suggestions. CONCLUSIONS: We suggest against the routine use of any inotropic agent in adult patients with shock. If used, we suggest using dobutamine rather than other inotropic agents for the majority of patients, however, the quality of evidence was very low, implying high uncertainty on the balance between the benefits and harms of inotropic agents. PMID- 29479667 TI - One world is not enough: the structured phenomenology of lifestyle migrants in East Asia. AB - The paper is based on original empirical research into the lifestyle migration of European migrants, primarily British, to Thailand and Malaysia, and of Hong Kong Chinese migrants to Mainland China. We combine strong structuration theory (SST) with Heideggerian phenomenology to develop a distinctive approach to the interplay between social structures and the lived experience of migrants. The approach enables a rich engagement with the subjectivities of migrants, an engagement that is powerfully enhanced by close attention to how these inner lives are deeply interwoven with relevant structural contexts. The approach is presented as one that could be fruitfully adopted to explore parallel issues within all types of migration. As is intrinsic to lifestyle migration, commitment to a better quality of life is central to the East Asian migrants, but they seek an uncomplicated, physically enhanced texture of life, framed more by a phenomenology of prosaic well-being than of self-realization or transcendence. In spite of possessing economic and status privileges due to their relatively elite position within global structures the reality for a good number of the lifestyle migrants falls short of their prior expectations. They are subject to particular kinds of socio-structural marginaliszation as a consequence of the character of their migration, and they find themselves relatively isolated and facing a distinct range of challenges. A comparison with research into various groups of migrants to the USA brings into relief the specificities of the socio-structural positioning of the lifestyle migrants of the study. Those East Asian migrants who express the greatest sense of ease and contentment seem to be those who have responded creatively to the specific challenges of their socio-structural situation. Often, this appears to have been achieved through understated but active involvements with their new settings and through sustaining focused transnational connections and relationships. PMID- 29479666 TI - Clinical characteristics and management of patients with rosacea in a tertiary dermatology center in Singapore from 2009 to 2013. AB - INTRODUCTION: Rosacea is a common chronic facial skin disease. A multiethnic society such as Singapore provides an opportunity to evaluate the demographic characteristics and their impact on clinical outcome in rosacea. AIMS: The aim of this study was to evaluate characteristics and outcome of rosacea in a multiracial population in Singapore. METHODS: Records of all rosacea patients between January 2009 and December 2013 were retrospectively retrieved from the electronic medical records (EMR). Descriptive analysis was performed to understand the characteristics of patients with rosacea. Multivariate logistic regression was used to evaluate the associations between the various variables and types of rosacea as well as the clinical outcome. RESULTS: A total of 1340 patients were identified. The mean age at presentation was 42.8 years with a female predominance (65%). Most of the patients had erythematotelangiectatic rosacea (ETR) (56.3%) followed by papulopustular rosacea (PPR) (37%). With multinomial logistic regression, controlling for age, gender, and known triggers, Indians and Caucasians were more likely to have PPR compared to ETR (OR: 3.4, P = 0.01 and OR: 2.1, P = 0.01 respectively). Patients who had phymatous rosacea are also more likely to be older males (OR: 3.82 95% CI 1.64-8.92, P = 0.002). CONCLUSION: The epidemiology and outcome of rosacea among local patients were studied. Rosacea is more common among certain racial groups such as Chinese, Caucasian, and other races. The clinical subtypes also seem to be related to races of certain skin colors and might be related to varied natural intrinsic responses to the sun among different racial groups. PMID- 29479668 TI - A critical appraisal of the evidence for the role of splenectomy in adults and children with ITP. AB - In primary chronic immune thrombocytopenia, long-term response to splenectomy, with 60% of patients enjoying a treatment-free life, is higher when compared with rituximab and similar to that with continuous thrombopoietin-receptor agonists (TPO-RA) administration. Splenectomy should continue to be offered to patients failing initial treatments in the absence of increased surgery-related risks. The higher lifelong safety concerns with splenectomy (increased risk of infection, shared in part with rituximab, and of thrombosis, in common with TPO-RA) and a mortality <1-2%, justify postponing surgery to the chronic phase, when spontaneous remissions are rarer. Patients failing initial treatment with corticosteroids/intravenous immunoglobulin may use TPO-RA (or rituximab in selected cases) as a bridge to surgery if they prefer to reconsider splenectomy later on, in case of no response, adverse effects or if sustained response after stopping TPO-RA is not attained. Special considerations apply in children aged <=5 years, with splenectomy playing a marginal role. The recent approval of TPO RA in children may represent a major advancement. PMID- 29479669 TI - Exposure to selective serotonin reuptake inhibitors in utero and early elementary school outcomes. AB - OBJECTIVE: Data on special education in offspring exposed to selective serotonin reuptake inhibitors (SSRIs) in utero are lacking. We examined associations of in utero SSRI exposure with special education needs and delayed elementary school start. METHODS: A population-based case-cohort study using Danish nationwide birth and prescription registry data from 2005 to 2008. Follow-up ends during 2011-2015 to capture special education needs during and delayed entry to the first elementary school year. Cases were in utero SSRI-exposed offspring. Cohort controls were SSRI-unexposed offspring of mothers previously on SSRIs. We reported odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for relevant potential confounders. RESULTS: Of 117 475 first-incident non-multiple pregnancy births, 3314 were SSRI-exposed, and 3536 were unexposed. Among SSRI exposed offspring, 3.2% (n = 98) had special school needs vs. 2.4% (n = 77) in unexposed offspring, P-value=0.048. Correspondingly, 12.3% (n = 383) among SSRI exposed children had delayed school entry vs. 9.4% (n = 308) in unexposed offspring, P-value < 0.001. Adjusted OR for the association with special school needs was 1.12 (95% CI 0.82-1.55; P-value = 0.48) and 1.38 (95% CI 0.90-2.13; P value = 0.14) for exposure in all three trimesters. The corresponding adjusted ORs for delayed school entry were 1.17 (95% CI 0.99-1.38; P-value = 0.073) and 1.40 (95% CI 1.11-1.76; P-value = 0.004). CONCLUSION: In utero SSRI exposure in all three trimesters was associated with delayed elementary school start but not special education needs. PMID- 29479670 TI - The neutrophil-lymphocyte ratio is prognostic in patients with early stage aggressive peripheral T cell lymphoma. PMID- 29479671 TI - Increased lymphocyte cell size with blastoid morphology associated with splenic rupture following cessation of ibrutinib. PMID- 29479672 TI - The report of two cases with multiple sulfatase deficiency resulting from a rare similar gene mutation. PMID- 29479673 TI - The patient's perspective on breast radiotherapy: Initial fears and expectations versus reality. AB - BACKGROUND: Although the efficacy and toxicity of breast radiotherapy (RT) has been studied extensively, to the authors' knowledge little is known regarding the patient's perspective on the modern breast RT experience. To better inform future patients and providers, the authors explored patient perceptions of their RT experience. METHODS: Consecutive patients who were free of disease recurrence and who had been treated between 2012 and 2016 were surveyed regarding their original fears, how short-term and long-term toxicities compared with initial expectations, and how pretreatment beliefs concerning RT compared with the actual experience. RESULTS: A total of 502 patients were surveyed, with a response rate of 65% (327 patients). The median patient age and posttreatment follow-up was 59 years and 31 months, respectively. Approximately 83% of patients (269 patients) underwent breast conservation therapy. Although approximately 68% of patients (221 patients) endorsed that they initially had little to no knowledge regarding RT, approximately 47% (152 patients) reported that they had heard frightening stories. Approximately 2% of patients (6 patients) agreed that the negative stories they previously heard about RT were actually true. Approximately 92% of patients treated with breast conservation (247 patients) and 81% of patients who underwent mastectomy (47 patients) agreed with the statement "If future patients knew the real truth about RT, they would be less scared about treatment." Approximately 83% (272 patients) and 84% (274 patients), respectively, of all patients reported the overall severity of short-term and long-term side effects to be better than or as expected. CONCLUSIONS: Breast RT is associated with misconceptions and fears. Patients' experiences with modern breast RT appear to be superior to expectations, and the majority of patients in the current study agreed that their initial negative impressions were unfounded. Cancer 2018;124:1673-81. (c) 2018 American Cancer Society. PMID- 29479674 TI - Ecological versatility and the assembly of multiple competitors: cautionary notes for assembly inferences. AB - The role of niche differences and competition is invoked when one finds coexisting species to be more dissimilar in trait composition than expected at random in community assembly studies. This approach has been questioned as competition has been hypothesized to either lead to communities assembled by similar or dissimilar species, depending on whether species similarity reflects fitness or niche differences, respectively. A current problem is that the arguments used to draw relationships between competition and species similarity are based on pairwise theoretical examples, while in nature competition can occurs among a constellation of species with different levels of versatility in resources used. By versatility we mean the documented ability of some species to escape competition for commonly used resources by changing for marginal and unused resources. Thus, a versatile species will have the ability to decrease niche overlap with all other species when facing strong competitors. When these species are embedded in multiple interactions the role of pairwise niche and fitness differences could be reduced due to indirect effects and thus competition would not be detectable. Here we developed a coexistence theory where competition occurs simultaneously among multiple species with different levels of versatility and then used it in a simulation to unravel patterns of species similarity during community assembly. We found that simulated communities can be assembled by species with more, less or equal similarity compared to a null model when using a mean distance based metric (SES.MPD). However, contrasting these varied results, we consistently found species overdispersion using a nearest neighbor-based metric (SES.MNTD), even when species differences reflected more directly their competitive abilities than their niche differences. Strong tendency to overdispersion emerged when high ecological versatility promoted large niche differences and enabled coexistence. This is because versatility to use marginal resources compensates possible fitness differences among species. Our findings provide mounting evidence of the important role of minimum niche differences and versatility in resource consumption for species embedded in multiple direct and indirect interactions. PMID- 29479675 TI - Toward evidence-based severity assessment in rat models with repeated seizures: I. Electrical kindling. AB - OBJECTIVE: Rodent epilepsy models can significantly contribute to our understanding of pathophysiological mechanisms and to validation of biomarker and target candidates. Evidence-based severity assessment is a presupposition for the ethical evaluation of animal experimentation allowances as well as for the development of efficacious refinement concepts. METHODS: Aiming to improve our understanding of the impact of experimental procedures and repeated seizures, we have completed a comprehensive behavioral and biochemical analysis assessing various parameters that can inform about the influence of an electrical kindling paradigm on well-being in rats. Thereby, we have focused on the immediate effects of phases with focal and generalized seizures with behavioral testing during kindling acquisition. RESULTS: Electrode implantation exerted mild effects on anxiety-associated behavior and reduced serum corticosterone at 3 weeks, but not 7 weeks, following surgery. Analysis in kindled rats excluded any relevant impact of focal seizures on behavioral and biochemical parameters. Assessment in rats with generalized seizures revealed an impact on nest complexity scores, nest soiling, and selected parameters in paradigms evaluating anxiety-associated behavior. Moreover, serum corticosterone levels, but neither hair corticosterone nor fecal corticosterone metabolite concentrations were lowered as a consequence of repeated generalized seizures. The assessment of various other behavioral and biochemical parameters did not reveal any other relevant effects of generalized seizures. Cross-correlation analysis suggested that assessment of nest building and maintenance can provide information comparable to that from more elaborate behavioral assays. This finding provides first evidence that nest scoring might serve as a simple and valid approach to evaluate rat well-being during routine assessment schemes. SIGNIFICANCE: The findings argue against a persistent level of pronounced distress and suggest a classification of the kindling paradigm as a model with moderate severity based on a longer-lasting mild impact on animal behavioral patterns. This suggestion provides a basis for a prospective and retrospective case-by-case severity assessment. PMID- 29479676 TI - Experiences of living with fetal alcohol spectrum disorders: a systematic review and synthesis of qualitative data. AB - AIM: To identify and assess available evidence from qualitative studies exploring experiences of individuals living with fetal alcohol spectrum disorders (FASD) or those living with a child with FASD, as well as experiences of interventions aimed at supporting individuals with FASD and their families. METHOD: A systematic literature search was conducted in six electronic databases: PubMed, Embase, Cochrane Library, CINAHL, PsycINFO, and Scopus. Included studies were analysed using manifest content analysis. Methodological limitations and confidence in the evidence were assessed using a modified version of the Critical Appraisal Skills Programme and the Grading of Recommendations, Assessment, Development and Evaluation-Confidence in the Evidence from Reviews of Qualitative Research approach respectively. RESULTS: Findings from 18 studies show that individuals with FASD experience a variation of disabilities, ranging from somatic problems, high pain tolerance, destructive behaviour, hyperactivity, and aggressiveness, to social problems with friendship, school attendance, and maintenance of steady employment. Most studies reported parents' experiences with FASD; parenting was viewed as a lifelong engagement and that the whole family is isolated and burdened because of FASD. People with FASD feel that their difficulties affect their daily life in a limiting way and make them feel different from others. INTERPRETATION: From the perspective of primarily parents, individuals with FASD and their parents face many different difficulties, for which they need societal support. WHAT THIS PAPER ADDS: Individuals with fetal alcohol spectrum disorders (FASD) feel their difficulties make them different from others. Parents think of their parenting as a lifelong engagement. There is a shortage of studies investigating experiences of children with FASD. There is a shortage of studies investigating experiences of interventions given to individuals with FASD. PMID- 29479677 TI - Temporary spontaneous regression of feline non-Hodgkin's lymphoma. AB - CASE REPORT: A 6-year-old neutered male British Shorthair cat presented with two rapidly growing subcutaneous masses, one over each thoracic wall. High-grade, non Hodgkin's lymphoma was confirmed following histopathology, immunohistochemistry and PCR analysis for antigen receptor re-arrangements. Following biopsy there was rapid regression of the remaining neoplastic tissue with no medical treatment. The cat relapsed 3 months later, with poor response to therapy, and was euthanased. CONCLUSION: Spontaneous regression (SR) of cancer is a rare occurrence and is uncommonly reported in veterinary species. To the author's knowledge this is the first reported case of SR of non-FeLV-related feline, high grade non-Hodgkin's lymphoma. PMID- 29479678 TI - The potential for occupational exposure of veterinarians to ketamine resulting in positive drug tests. PMID- 29479679 TI - Spillover of avian haemosporidian parasites (Haemosporidia: Plasmodium) and death of captive psittacine species. AB - CASE REPORT: During February 2014, a yellow-tailed black cockatoo (Calyptorhynchus funereus) and glossy black cockatoo (C. lathami) housed in aviaries on a property in Wamuran, Queensland, were submitted for postmortem. Histopathology and molecular diagnostics demonstrated the presence of Plasmodium sp. infection. The Plasmodium isolate identified has previously only been reported as infecting a healthy wild rufous fantail (Rhipidura rufifrons) in Australia. CONCLUSION: To the authors' knowledge, these are the first reported cases of Plasmodium in Calyptorhynchus. We hypothesised that the maintenance of these two cockatoo species in ground level aviaries in a low-altitude geographic zone resulted in exposure of birds to mosquito vectors of endemic avian Plasmodium. Black cockatoos roost and forage in the mid to high canopy of forests in the wild, outside the likely spatiotemporal distribution of relevant haemosporidian vectors. It is therefore likely that these birds had immunological naivety and susceptibility to infection with Plasmodium circulating in wild passerines. PMID- 29479680 TI - Laparoscopic ovariectomy in eastern grey kangaroos (Macropus giganteus) and red kangaroos (Macropus rufus). AB - OBJECTIVE: To develop a technique for permanent sterilisation of female eastern grey kangaroos (Macropus giganteus) and red kangaroos (M. rufus) as part of a large-scale macropod management program on an enclosed 1545-ha site in western Sydney. METHODS: Free-ranging female kangaroos (n = 1409: 1285 eastern grey kangaroos, 124 red kangaroos) were anaesthetised via remote anaesthetic drug delivery of tiletamine/zolazepam, medetomidine and acepromazine prior to inhalational anaesthesia using isoflurane-oxygen. A laparoscopic ovariectomy technique was developed using standard laparoscopic equipment to effect permanent sterilisation of the kangaroos. The technique described was also adapted for use on immature animals weighing as little as 1 kg. No direct post-surgical care was provided once the animals had recovered from the anaesthetic. RESULTS: The procedure was simple to perform and had a very high success rate, with an overall project mortality rate of 2.13% (n = 30). Seven kangaroos (0.05% of all operated kangaroos) were euthanased as a direct result of the surgical procedure. Surgical complications were rare but included inadvertent gastrointestinal tract puncture with the trocar, intraoperative haemorrhage and subcutaneous emphysema leading to pouch eversion following surgery. CONCLUSION: The procedure described is a rapid and effective method of permanent fertility control in macropods and carries a low mortality rate. PMID- 29479682 TI - Abattoir surveillance of Sarcocystis spp., Cysticercosis ovis and Echinococcus granulosus in Tasmanian slaughter sheep, 2007-2013. AB - OBJECTIVE: To estimate the prevalence of macroscopic Sarcocystis spp., Cysticercus ovis and Echinococcus granulosus recorded at routine postmortem inspection of Tasmanian slaughter sheep during 2007 to 2013. METHODS: A retrospective analysis of routine postmortem meat inspection data maintained on 352,325 Tasmanian adult slaughter sheep inspected across nine abattoirs in Tasmania, Victoria and South Australia as part of the National Sheep Health Monitoring Project (NSHMP). RESULTS: During the period 1 September 2007 to 30 June 2013, the estimated prevalence of macroscopic Sarcocystis spp. was 14.3%, C. ovis was 3.2% and E. granulosus was 0.01%. Mean Sarcocystis spp. line prevalence ranged from 0% to 33.5%. Significant between-abattoir differences in the level of sarcosporidiosis (P < 0.001) and C. ovis were found (P < 0.001). Overall, very low levels of hydatidosis were recorded throughout the surveillance period. Predicted within-line prevalence of macroscopic sarcocysts in animals coming from a known/recorded local government area (LGA) (P < 0.001) was lower than that of lines where the LGA was unknown or not recorded. A higher prevalence of sarcocystosis was recorded in lines of sheep aged >= 2 years compared with those < 2 years (P < 0.001). CONCLUSION: Reasons for the significant between-abattoir differences in recorded levels of ovine sarcosporidiosis and cysticercosis remain unknown, but may represent sampling bias, with subsets of slaughter sheep going to abattoirs with different tiers or access to markets. Further investigation into apparent differences, including epidemiological studies of properties with high lesion prevalence, comparing meat inspector diagnostic sensitivity, assessing the effect of line speed and tiers and market access in different abattoirs, may be useful. PMID- 29479684 TI - Effect of pre-milking teat disinfection on clinical mastitis incidence in a dairy herd in Northern Queensland, Australia. AB - OBJECTIVE: To determine if a pre-milking teat disinfection protocol would reduce the incidence of clinical mastitis by greater than 50%. METHODS: Two pre-milking routines were compared in a natural exposure trial. Cows from a single dairy herd were randomly assigned to control (n = 246) and experimental (pre-milking teat disinfection [PMTD]; n = 244) groups. For cows in the control group, the pre milking routine involved minimal teat-washing, except for cows with wet teat contamination. For cows in the PMTD group, the pre-milking routine involved washing of all teats, dipping with a commercial 0.1% available iodine solution, allowing a minimum of 30 s contact time and then drying of the teats using disposable paper towel. Clinical cases encountered during the trial were recorded and pathogens were isolated from milk samples using standard laboratory methods. RESULTS: The effect of PMTD was determined using multivariable binary logistic regression. Multiparous animals in the PMTD group had higher odds of experiencing clinical mastitis overall and of experiencing clinical mastitis caused by environmental pathogens (odds ratio (OR) 1.97 and 4.11, 95% confidence interval (CI) 1.15-3.38 and 1.49-11.3, respectively). In primiparous animals, pre-milking teat disinfection did not reduce the odds of clinical mastitis by greater than 50% (OR 1.31, 95%CI 0.52-3.29). CONCLUSION: In this herd, PMTD increased the odds of clinical mastitis. The effectiveness of PMTD to prevent clinical mastitis in pasture-based systems is likely to vary greatly between herds. We therefore recommend against the wholesale use of this practice on Australian farms. PMID- 29479686 TI - Internal fixation of proximal fractures of the 2nd and 4th metacarpal and metatarsal bones using bioabsorbable screws. AB - OBJECTIVE: Fractures involving the proximal one-third of the splint bone are relatively rare and are challenging to treat. A variety of management techniques have been reported in the literature. The aim of this retrospective case series was to describe the clinical presentation and evaluate the efficacy of bioabsorbable polylactic acid screws in internal fixation of proximal fractures of the 2nd and 4th metacarpal and metatarsal bones in horses. METHODS: The medical records, diagnostic images and outcome of all horses diagnosed with a proximal fracture of the splint bones and treated with partial resection and internal fixation of the proximal stump using bioabsorbable polylactic acid screws between 2014 and 2015 were reviewed. RESULTS: Eight horses met the inclusion criteria. The results showed that there were no complications encountered during screw placement or postoperatively. Six horses returned to full work 3 months after the operation and two horses remained mildly lame. On follow-up radiographs 12 months postoperatively (n = 2) the screws were not completely absorbed. The screws resulted in a cone-shaped radiolucency, which was progressively replaced from the outer margins by bone sclerosis. CONCLUSION: The use of bioabsorbable screws for fixation of proximal fractures of the splint bone appears to be a safe and feasible technique and may offer several advantages over the use of traditional metallic implants. PMID- 29479687 TI - Altered density, composition and microanatomical distribution of infiltrating immune cells in cutaneous squamous cell carcinoma of organ transplant recipients. AB - BACKGROUND: The inflammatory tumour microenvironment is crucial for effective tumour control, and long-term immunosuppression has been identified as a major risk factor for skin carcinogenesis. In solid organ transplant recipients (OTRs) undergoing long-term pharmacological immunosuppression, an increased incidence of cutaneous squamous cell carcinoma (SCC) and more aggressive tumour growth compared with immunocompetent patients has been reported. OBJECTIVES: To determine the density and phenotype of immune cells infiltrating SCC and surrounding skin in OTRs, and to characterize the microanatomical distribution patterns in comparison with immunocompetent patients. METHODS: We analysed immune cell infiltrates within SCC and at defined regions of interest (ROIs) of tumour surrounding skin in formalin-fixed paraffin-embedded tissue of 20 renal transplant patients and 18 carefully matched immunocompetent patients by high resolution semiautomated microscopy on complete tissue sections stained for CD4, CD8, CD20 and CD68. RESULTS: The overall immune cell density of SCC arising in OTRs was significantly reduced compared with immunocompetent patients. Particularly CD4+ infiltrates at the directly invasive margin and tumour vicinity, intratumoral CD8+ T-cell densities and the overall density of CD20+ tumour-infiltrating B cells were significantly reduced in the tissue of OTRs. CONCLUSIONS: Immune cell infiltrates within SCC and at defined ROIs of tumour surrounding skin in OTRs differ markedly in their composition and microanatomical distribution compared with tumours arising in immunocompetent patients. Our findings substantially broaden the understanding of how long-term systemic immunosuppression modulates the local inflammatory microenvironment in the skin and at the site of invasive SCC. PMID- 29479689 TI - Comparative genetic isolation patterns for multiple headwater fishes in three geographic regions. AB - Headwater-resident fishes may be prone to a high rate of isolation and a pronounced hierarchical genetic structure due to a combination of niche preference and dendritic effects of river networks. Genetic isolation patterns were compared using microsatellites in six headwater fishes, Fundulus olivaceus, Semotilus atromaculatus, Erimyzon claviformis, Etheostoma artesiae, Etheostoma whipplei and Etheostoma parvipinne, in three geographic regions that included drainages of small, medium and large sizes in the southern United States. All species showed hierarchical nesting of genetic populations and there were clear and mostly consistent differences between species and regions that were identified through summary statistics derived from two independent analyses. For species comparisons, a high isolation grouping (increased number of isolated genetic clusters or sites within regions) and a low-isolation grouping (decreased number of clusters or sites) were identified. Species group placement was related to niche breadth along the river continuum and presumed abundance and variability of preferred microhabitats, with increased headwater specialization among species being associated with placement in the high-isolation grouping. There was a weakly significant positive effect of drainage size on the number of isolated clusters or sites across all species. Regional patterns were shared in two species, with the region containing the smallest drainages having lower rates of isolation in both datasets. This study shows the effects of regional and species characteristics on genetic isolation for headwater species, which are especially prone to isolation due to spatial, dendritic effects of river networks. PMID- 29479688 TI - Clinical profile of dermatological emergencies and intensive care unit admissions in a tertiary care center - an Indian perspective. AB - BACKGROUND: Although dermatology is largely considered as an outpatient specialty, dermatological conditions comprise 5-8% of cases presenting to the emergency department. The need for a dermatological intensive care unit is widely acknowledged due to the increasing incidence of acute skin failure. Very few studies have been done to characterize the common conditions seen in the emergency department and intensive care units. We undertook this study to analyze the spectrum of dermatological conditions presenting to the emergency department and the clinical profile of patients admitted to the intensive care unit. METHODS: A prospective study was conducted for 9 months. Patients requiring primary dermatological consultation in the emergency department and patients admitted in the dermatology intensive care unit were examined, and their clinical variables were statistically analyzed. RESULTS: A total of 248 cases were seen in the emergency department, out of which 72 (29.1%) cases were admitted and 176 (70.9%) were treated in the emergency department on an outpatient basis. The most common condition seen in non-admitted patients was acute urticaria (28.9%). The most common cause for admission in patients presenting to the emergency department was erythroderma (23.6%). Sixty-two patients were admitted to the intensive care unit, the most common diagnosis being erythroderma (40.3%). CONCLUSIONS: This prospective study aimed to provide an insight into the types of cases evaluated in the emergency department by dermatologists in a large tertiary care hospital in coastal Karnataka in South India. PMID- 29479690 TI - Out of the pot and into the fire: Explaining the vulnerability of an endangered small headwater stream fish to black-bass Micropterus spp. invasion. AB - Introduced predatory fishes have had consistently severe consequences for native fishes in stream environments around the world, although the drivers of these effects are often unclear. In the Swartkops River headwaters in South Africa, native Eastern Cape redfin Pseudobarbus afer were always absent from sites occupied by non-native black basses Micropterus salmoides and Micropterus dolomieu, but generally co-occurred with the native predators Anguilla marmorata and Anguilla mossambica. A natural experiment provided by flood-mediated recolonization of black-bass occupied sites by P. afer demonstrated depletion in black-bass invaded sites. Field behavioural observations of P. afer indicated that they foraged among benthic cover during the day, but suspended in open water at night. As the nocturnal A. marmorata and A. mossambica foraged actively within structural cover at night and M. dolomieu and M. salmoides are diurnal or crepuscular predators, P .afer is thus optimized to avoid predation by native anguillid predators and not the functionally unique predatory black basses. The integration of distributional, temporal population dynamics and behavioural data suggests that the severe effects of Micropterus spp. are probably a consequence of prey naivete and behaviour evolved to evade native predators. PMID- 29479691 TI - Prospective study of blood metabolites associated with colorectal cancer risk. AB - Few prospective studies, and none in Asians, have systematically evaluated the relationship between blood metabolites and colorectal cancer risk. We conducted a nested case-control study to search for risk-associated metabolite biomarkers for colorectal cancer in an Asian population using blood samples collected prior to cancer diagnosis. Conditional logistic regression was performed to assess associations of metabolites with cancer risk. In this study, we included 250 incident cases with colorectal cancer and individually matched controls nested within two prospective Shanghai cohorts. We found 35 metabolites associated with risk of colorectal cancer after adjusting for multiple comparisons. Among them, 12 metabolites were glycerophospholipids including nine associated with reduced risk of colorectal cancer and three with increased risk [odds ratios per standard deviation increase of transformed metabolites: 0.31-1.98; p values: 0.002-1.25 * 10-10 ]. The other 23 metabolites associated with colorectal cancer risk included nine lipids other than glycerophospholipid, seven aromatic compounds, five organic acids and four other organic compounds. After mutual adjustment, nine metabolites remained statistically significant for colorectal cancer. Together, these independently associated metabolites can separate cancer cases from controls with an area under the curve of 0.76 for colorectal cancer. We have identified that dysregulation of glycerophospholipids may contribute to risk of colorectal cancer. PMID- 29479692 TI - Ontogeny of turbiditaxis in hatchery-reared Japanese anchovy Engraulis japonicus. AB - The ontogenetic change in turbiditaxis (i.e. attraction to turbid waters) was examined in the larvae and juveniles of Japanese anchovy Engraulis japonicus by testing three levels of turbidity (0, 20 and 100 ppm of kaolin). Larvae of 12, 20 and 30 mm standard length (LS ) exhibited turbiditaxis to both 20 and 100 ppm of kaolin, whereas 6 mm LS larvae and 45 mm LS juveniles did not exhibit any turbiditaxis. Turbiditaxis might explain the ontogenetic habitat shift from coastal to offshore waters reported for this species. PMID- 29479693 TI - Revisiting concepts of thermal physiology: Predicting responses of mammals to climate change. AB - The accuracy of predictive models (also known as mechanistic or causal models) of animal responses to climate change depends on properly incorporating the principles of heat transfer and thermoregulation into those models. Regrettably, proper incorporation of these principles is not always evident. We have revisited the relevant principles of thermal physiology and analysed how they have been applied in predictive models of large mammals, which are particularly vulnerable, to climate change. We considered dry heat exchange, evaporative heat transfer, the thermoneutral zone and homeothermy, and we examined the roles of size and shape in the thermal physiology of large mammals. We report on the following misconceptions in influential predictive models: underestimation of the role of radiant heat transfer, misassignment of the role and misunderstanding of the sustainability of evaporative cooling, misinterpretation of the thermoneutral zone as a zone of thermal tolerance or as a zone of sustainable energetics, confusion of upper critical temperature and critical thermal maximum, overestimation of the metabolic energy cost of evaporative cooling, failure to appreciate that the current advantages of size and shape will become disadvantageous as climate change advances, misassumptions about skin temperature and, lastly, misconceptions about the relationship between body core temperature and its variability with body mass in large mammals. Not all misconceptions invalidate the models, but we believe that preventing inappropriate assumptions from propagating will improve model accuracy, especially as models progress beyond their current typically static format to include genetic and epigenetic adaptation that can result in phenotypic plasticity. PMID- 29479694 TI - Effect of fish length and nutritional condition on the fecundity of distressed Atlantic cod Gadus morhua from the Baltic Sea. AB - The disappearance of larger individuals and the decrease in individual body condition suffered by Atlantic cod Gadus morhua in the eastern Baltic during the past two decades can be expected to affect the stock reproductive output. To investigate this, female G. morhua were collected during the spawning and pre spawning period in 2015-2016. The current individual potential fecundity (FP ) of eastern Baltic G. morhua was estimated and analysed in relation to total length (LT ) and indices of nutritional status such as body condition (K) and hepato somatic index (IH ) using generalized linear models. In addition, the current prevalence of atresia and its potential relation to K were investigated. Moreover, a calibration curve to estimate FP from oocyte diameter, based on the autodiametric oocyte counting method, was established for the first time for eastern Baltic G. morhua and can be used for future fecundity studies on this stock. The results showed that FP was mainly positively related to fish length, but K and IH also contributed significantly to the variation in FP . The model predicted that fish with K = 1.2 have a FP 51% higher than fish of the same LT with K = 0.8. The prevalence of fecundity regulation by atresia was 5.8%, but it was found only in fish in the pre-spawning maturity stage and with low K. Temporal changes in biological features such as the length composition and individual body condition of eastern Baltic G. morhua, should be accounted for when estimating stock reproductive potential. PMID- 29479695 TI - Presenting Cost and Efficiency Measures That Support Consumers to Make High-Value Health Care Choices. AB - OBJECTIVE: To identify approaches to presenting cost and resource use measures that support consumers in selecting high-value hospitals. DATA SOURCES: Survey data were collected from U.S. employees of Analog Devices (n = 420). STUDY DESIGN: In two online experiments, participants viewed comparative data on four hospitals. In one experiment, participants were randomized to view one of five versions of the same comparative cost data, and in the other experiment they viewed different versions of the same readmissions data. Bivariate and multivariate analyses examined whether presentation approach was related to selecting the high-value hospital. PRINCIPAL FINDINGS: Consumers were approximately 16 percentage points more likely to select a high-value hospital when cost data were presented using actual dollar amounts or using the word "affordable" to describe low-cost hospitals, compared to when the Hospital Compare spending ratio was used. Consumers were 33 points more likely to select the highest performing hospital when readmission performance was shown using word icons rather than percentages. CONCLUSIONS: Presenting cost and resource use measures effectively to consumers is challenging. This study suggests using actual dollar amounts for cost, but presenting performance on readmissions using evaluative symbols. PMID- 29479696 TI - Cleaning interactions by gobies on a tropical eastern Pacific coral reef. AB - The present study describes the cleaning interactions among species of cleaner gobies Tigrigobius spp. and Elacatinus puncticulatus (family Gobiidae) and the client fish species they clean in a coral reef of Gorgona Island, Colombia. In 419 cleaning events, we observed 27 species acting as clients of Tigrigobius spp., whereas only nine were clients of E. puncticulatus. Paranthias colonus and Cephalopholis panamensis were the species most commonly cleaned by Tigrigobius spp., while Ophioblennius steindachneri and Stegastes acalpulcoensis were the clients most commonly cleaned by E. puncticulatus. The abundance (but not the body size) of clients was an important variable predicting the cleaning frequency observed for clients of Tigrigobius spp., but this was not the case for clients of E. puncticulatus. Additionally, Tigrigobius spp. preferred cleaning planktivores, sessile invertebrate feeders and territorial herbivores (Ivlev's index >0.15), whereas E. puncticulatus did not exhibit any preference. We observed two major peaks of cleaning activity for Tigrigobius spp., one in the early morning and another one in the late afternoon. These results suggest that Tigrigobius spp. is a specialized cleaner goby, whereas E. puncticulatus is a facultative cleaner that cleans sporadically. PMID- 29479697 TI - Cervicovaginal microbiota composition correlates with the acquisition of high risk human papillomavirus types. AB - High-risk (hr) human papillomavirus (HPV) infection is closely associated with the clinical conditions of both squamous intraepithelial lesions (SILs) and cervical carcinoma. However, it remains unclear what factors determine the type of hrHPV infection. Here, we have comprehensively investigated the bacterial composition of the cervicovaginal microbiota of 280 women infected with one type of hrHPV (HPV 16, 52 or 58) by the pyrosequencing of barcoded 16S rRNA genes. Differential microbiota composition was observed among various SIL groups and within the subgroups of each group. This result showed that it is not the microbiota diversity or the common microbiota, but rather agents that are specific to each SIL that might have a positive influence on the acquisition of hrHPV types, independent of abundance. Specifically, a composition of Oribacterium, Lachnobacterium and Thermus in the cervicovaginal microbiota is more likely to be associated with HPV 16, while a composition of Motilibacter in the cervicovaginal microbiota is more likely to be associated with HPV 52, and a composition of Litorilinea and Paludibaculum with a concomitant paucity of L. iners in the cervicovaginal microbiota is more likely to be associated with HPV 58. Furthermore, functional predictions regarding infectious diseases and cancer related genes disclosed significant differences (p < 0.01) among the different (sub)groups. Our study provides an elucidation of the relationship between the composition of the cervicovaginal microbiota and the type of hrHPV acquired. PMID- 29479698 TI - Contemporary factors influencing genetic diversity in the Alaska humpback whitefish Coregonus clupeaformis complex. AB - Thirteen microsatellite loci were used to address three hypotheses regarding genetic diversity in the humpback whitefish Coregonus clupeaformis complex in Alaska. The test results provided further insight into the factors influencing C. clupeaformis complex population structure and level of genetic variation. First, the microsatellite data did not provide evidence of two spatially distinct Beringian and Eurasian refugial groups as revealed in previous phylogeographic analyses of mitochondrial DNA variation. Rather, the population structure inferred from the microsatellite variation appears to reveal the influence of factors on a more recent time scale, including gene flow among the refugial groups and isolation of some anadromous and freshwater resident populations. Second, anadromous C. clupeaformis complex collections exhibited higher intra population genetic diversity than freshwater resident collections. This outcome is consistent with previous meta analyses suggesting that freshwater resident populations probably have smaller historical effective population sizes and less conspecific gene flow because the habitat tends to be smaller and supports fewer and smaller populations. Finally, the analysis of contemporary immigration rates was consistent with, but did not provide statistical support for, the hypothesis that gene flow among anadromous C. clupeaformis complex populations along coastal Alaska is influenced by the Alaska Coastal Current. Further studies are needed to evaluate gene flow among coastal Alaska C. clupeaformis complex populations. PMID- 29479699 TI - Brainstem catecholaminergic neurones and breathing control during postnatal development in male and female rats. AB - KEY POINTS: The brainstem catecholaminergic (CA) modulation on ventilation changes with development. We determined the role of the brainstem CA system in ventilatory control under normocapnic and hypercapnic conditions during different phases of development [postnatal day (P)7-8, P14-15 and P20-21] in male and female Wistar rats. Brainstem CA neurones produce a tonic inhibitory drive that affects breathing frequency in P7-8 rats and provide an inhibitory drive during hypercapnic conditions in both males and females at P7-8 and P14-15. In pre pubertal rats, brainstem CA neurones become excitatory for the CO2 ventilatory response in males but remain inhibitory in females. Diseases such as sudden infant death syndrome, congenital central hypoventilation syndrome and Rett syndrome have been associated with abnormalities in the functioning of CA neurones; therefore, the results of the present study contribute to a better understanding of this system. ABSTRACT: The respiratory network undergoes significant development during the postnatal phase, including the maturation of the catecholaminergic (CA) system. However, postnatal development of this network and its effect on the control of pulmonary ventilation ( PMID- 29479700 TI - Health-Related Quality of Life among Chronic Opioid Users, Nonchronic Opioid Users, and Nonopioid Users with Chronic Noncancer Pain. AB - OBJECTIVE: Evaluate the association between opioid therapy and health-related quality of life (HRQoL) in participants with chronic, noncancer pain (CNCP). DATA SOURCES: Medical Expenditure Panel Survey Longitudinal, Medical Conditions, and Prescription Files. STUDY DESIGN: Using a retrospective cohort study design, the Mental Health Component (MCS12) and Physical Health Component (PCS12) scores of the Short Form-12 Version 2 were assessed to measure mental and physical HRQoL. DATA COLLECTION: Chronic, noncancer pain participants were classified as chronic, nonchronic, and nonopioid users. One-to-one propensity score matching was employed to match chronic opioid users to nonchronic opioid users plus nonchronic opioid users and chronic opioid users to nonopioid users. PRINCIPAL FINDINGS: A total of 5,876 participants were identified. After matching, PCS12 was not significantly different between nonchronic versus nonopioid users (LSM Diff = 0.98, 95% CI: -2.07, 0.10), chronic versus nonopioid users (LSM Diff = -2.24, 95% CI: -4.58, 0.10), or chronic versus nonchronic opioid users (LSM Diff = -2.23, 95% CI: -4.53, 0.05). Similarly, MCS12 was not significantly different between nonchronic versus nonopioid users (LSM Diff = 0.76, 95% CI: -0.46, 1.98), chronic versus nonopioid users (LSM Diff = 1.08, 95% CI: -1.26, 3.42), or chronic versus nonchronic opioid users (LSM Diff = -0.57, 95% CI: -2.90, 1.77). CONCLUSIONS: Clinicians should evaluate opioid use in participants with CNCP as opioid use is not correlated with better HRQoL. PMID- 29479701 TI - Survival of patients with hepatobiliary tract and duodenal cancer sites in Germany and the United States in the early 21st century. AB - Hepatobiliary tract cancers (HBTCs) are a heterogeneous group of cancers with high mortality. Because most of these cancers, with the exception of hepatocellular carcinoma (HCC), are rare, few data are available concerning the population level survival expectations of patients with HBTC. Here, we describe survival of patients with HBTC in Germany with comparison to survival in the US. Therefore, data were extracted from 12 databases in Germany and the Surveillance, Epidemiology and End Results (SEER13) database in the US. Period analysis and modeled period analysis were used to calculate 5-year relative survival estimates for patients with HBTC diagnosed from 1997 to 2013. HCC was the most common HBTC in each database, accounting for over 1/3 of HBTC in Germany and about half of cases in the US. Overall age adjusted 5-year relative survival for HBTC in 2006 2013 was 19.1% in Germany and 20.6% in the US. Five-year relative survival increased by 3.8% units in Germany and 4.5% units in the US between 2002-2005 and 2010-2013. Five-year relative survival for individual types of HBTC ranged from 9.8% in Germany and 2.9% in the US for not otherwise specified biliary tract cancers to 44.4% and 50.1%, respectively, in Germany and the US for duodenal cancers. In conclusion, survival for HBTC remains poor in both Germany and the US, although a small increase in survival in the past decade was observed. Further work to find better treatment options for HBTC is needed to improve survival. PMID- 29479702 TI - Manipulation of the energetic state of Atlantic salmon Salmo salar juveniles and the effect on migration speed. AB - Atlantic salmon Salmo salar smolts were produced with similar energetic states as wild S. salar and the effect of low energetic state on smolt migration was tested. The total energetic state of the fish (body lipids and proteins) in the spring was correlated with Fulton's condition factor (K). Fish at a low energetic state swam slower but migrated further than fish at a higher energetic state when tested in two experimental streams. During a period of starvation throughout the winter and spring, fish conserved their body-lipid reserves at 1.5% by using more protein as an energy source and the metabolic shift occurred between 3.5 and 1.5% body lipids. An energetic state of approximately 3.5 kJ g-1 (K ~ 0.65) appeared to be the critical limit for survival. PMID- 29479703 TI - O- product transfusion, inventory management, and utilization during shortage: the OPTIMUS study. AB - BACKGROUND: Despite conservation strategies, shortages of O- red blood cells (RBCs) occur. The goal of this study was to determine how utilization of O- RBCs can be reduced using age- and location-based O+ substitution for routine transfusions in O- patients during O- shortages. STUDY DESIGN AND METHODS: Recipient age and ABO and D group were obtained for allogeneic RBC transfusions during the 2016 calendar year from 31 participating centers. ABO and D group of each RBC unit was compared to that of the recipient to determine the number of O- RBC units transfused to all patients, the number of RBC units transfused to O- patients, and the number of O- RBC units transfused to O- patients. O- RBC transfusions to O- patients were further analyzed by patient age and location. RESULTS: The fraction of all transfused RBCs that were O- at the participating centers ranged from 3.0% to 13.9%. The percentage of O- RBCs transfused to O- patients ranged from 36.6% to 93.7%. Hospitals differed in the frequency of issuing O- RBCs for O- patient transfusions (55.9%-100%). Relative to current issuing practice, overall use of O- RBCs could have been reduced by 44.5% if O+ units had been given to all O- patients at least 50 years old, 9.9% for all O- patients at least 80 years old, or 8.7% for all O- critical care patients at least 50 years old. CONCLUSION: During O- shortages, O+ switching rules based on the recipient's age and hospital location can be applied for routine transfusions to ensure the availability of O- RBC units for O- females of childbearing age. PMID- 29479704 TI - Mapping face categorization in the human ventral occipitotemporal cortex with direct neural intracranial recordings. AB - The neural basis of face categorization has been widely investigated with functional magnetic resonance imaging (fMRI), identifying a set of face-selective local regions in the ventral occipitotemporal cortex (VOTC). However, indirect recording of neural activity with fMRI is associated with large fluctuations of signal across regions, often underestimating face-selective responses in the anterior VOTC. While direct recording of neural activity with subdural grids of electrodes (electrocorticography, ECoG) or depth electrodes (stereotactic electroencephalography, SEEG) offers a unique opportunity to fill this gap in knowledge, these studies rather reveal widely distributed face-selective responses. Moreover, intracranial recordings are complicated by interindividual variability in neuroanatomy, ambiguity in definition, and quantification of responses of interest, as well as limited access to sulci with ECoG. Here, we propose to combine SEEG in large samples of individuals with fast periodic visual stimulation to objectively define, quantify, and characterize face categorization across the whole VOTC. This approach reconciles the wide distribution of neural face categorization responses with their (right) hemispheric and regional specialization, and reveals several face-selective regions in anterior VOTC sulci. We outline the challenges of this research program to understand the neural basis of face categorization and high-level visual recognition in general. PMID- 29479705 TI - Optimization of mucilage extraction from chia seeds (Salvia hispanica L.) using response surface methodology. AB - BACKGROUND: Chia mucilage has potential application as a functional ingredient; advances on maximizing its extraction yield could represent a significant technological and economic impact for the food industry. Thus, first, the effect of mechanical agitation time (1-3 h) on the exudation of chia mucilage was analyzed. Then, response surface methodology was used to determine the optimal combination of the independent variables temperature (15-85 degrees C) and seed: water ratio (1: 12-1: 40.8 w/v) for the 2 h exudation that give maximum chia mucilage yield. Experiments were designed according to central composite rotatable design. RESULTS: A second-order polynomial model predicted the variation in extraction mucilage yield with the variables temperature and seed: water ratio. The optimal operating conditions were found to be temperature 85 degrees C and a seed: water ratio of 1: 31 (w/v), reaching an experimental extraction yield of 116 +/- 0.21 g kg-1 (dry basis). The mucilage obtained exhibited good functional properties, mainly in terms of water-holding capacity, emulsifying activity, and emulsion stability. CONCLUSION: The results obtained show that temperature, seed: water ratio, and exudation time are important variables of the process that affect the extraction yield and the quality of the chia mucilage, determined according to its physicochemical and functional properties. (c) 2018 Society of Chemical Industry. PMID- 29479706 TI - Dissipation behaviour and dietary risk assessment of boscalid, triflumizole and its metabolite (FM-6-1) in open-field cucumber based on QuEChERS using HPLC-MS/MS technique. AB - BACKGROUND: To resist plant diseases, boscalid and triflumizole have been applied to cucumbers frequently. However, the residue and dietary risk assessment of these fungicides in cucumber should be given attention for food safety. RESULTS: An effective and highly sensitive method based on the liquid chromatography tandem mass spectrometry technique for simultaneous multidetermination of boscalid, triflumizole and its metabolite (FM-6-1) in a cucumber ecosystem was established and validated. Field experiments were conducted in three different locations, where boscalid and triflumizole (35% suspension concentration) were applied at 253 g of active ingredient (a.i.) per hectare (the recommended high dosage) and 379.5 g a.i. ha-1 (1.5 times the recommended high dosage) in each location. The limits of quantification and the limits of detection of the proposed method ranged from 0.01 to 0.05 mg kg-1 and 3.9 * 10-5 to 7.5 * 10-4 mg L-1 respectively. The mean recoveries and relative standard deviations of these compounds were 80-105% and 1.0-6.1% respectively. The dissipation dynamics of compounds followed pseudo-first-order kinetic models remarkably, with a half value period of 2.3-40.8 days. The residues of boscalid and triflumizole in cucumber at harvest were below 0.66 mg kg-1 and 0.07 mg kg-1 respectively. The results of the dietary risk assessments have shown a low dietary risk of compounds in cucumber with hazard ratios <1 and hazard index <1. CONCLUSION: These results from the experiments are the most important for putting a guide on reasonable usage of these fungicides under the open-field conditions in China. (c) 2018 Society of Chemical Industry. PMID- 29479707 TI - Occupational stress, coping strategies, and psychological-related outcomes of nurses working in psychiatric hospitals. AB - AIMS: Psychiatric nurses experience a wide range of stressful events, evolving from the care of violent, aggressive patients, recurrent relapse, and poor prognosis of mental disorders. The aim of the study was to assess workplace stress, coping strategies, and levels of depression among psychiatric nurses. METHODS: A descriptive correlation design was conducted on psychiatric nurses working in mental health settings Port-Said, Egypt. Data were collected from 70 nurses at a mental health hospital. RESULTS: The results revealed that psychiatric nurses had moderate levels of work-related stress and depression, and exhibiting different coping strategies. Stress and depression are prevalent among psychiatric nurses. CONCLUSIONS: Implementing programs aimed at teaching them how to deal with stress at work and improving their coping strategies and problem solving skills are recommended. PMID- 29479708 TI - Hemostatic profile and safety of pooled cryoprecipitate up to 120 hours after thawing. AB - BACKGROUND: AABB standards state that cryoprecipitate should be transfused within 4 to 6 hours after thawing. We evaluated coagulation factor levels and sterility of thawed pooled cryoprecipitate to assess whether shelf life can be safely extended. STUDY DESIGN AND METHODS: Donor cryoprecipitate pools (n = 20, 10 group A, 10 group O) were held at ambient temperature and sampled at 0, 4, 8, 24, 48, 72, 96, and 120 hours post-thawing for fibrinogen, Factor (F)VIII, and von Willebrand factor (vWF) levels. Samples were tested at 0 and 120 hours for sterility (BacT/Alert system). Sixty additional cryoprecipitate pools were evaluated after 72 hours. Longitudinal differences in component levels were determined by linear fixed-effects regression. RESULTS: Group O cryoprecipitate had significantly lower FVIII (p = 0.002) and vWF activity (p = 0.006) compared to group A at 0 hours, but were not statistically different in fibrinogen levels (p = 0.33). Fibrinogen levels were stable over 5 days: 501 +/- 81 mg/unit (mean +/- standard deviation) at 0 hours to 506 +/- 102 mg/unit at 120 hours (p = 0.73). Similarly, there was no decline in vWF activity: 200 +/- 53 IU/unit at 0 hours to 209 +/- 57 IU/unit at 120 hours (p = 0.084). The FVIII activity significantly declined on average by 9.6 IU (95% confidence interval, 5.5-13.8) between 0 hours (111 +/- 33 IU/unit) and 120 hours post-thaw (101 +/- 33) (p < 0.001). No organisms were detected when cryoprecipitate pools were cultured at 0 hours, but at 120 hours Staphylococcus epidermidis was identified from one pool, potentially a contaminant introduced during repeated sampling. No cultures were positive among the 60 additional cryoprecipitate pools assessed at 72 hours. CONCLUSION: Extended cryoprecipitate storage at ambient temperature did not affect fibrinogen levels over 120 hours. Sterility of products held at ambient temperature for an extended period of time could be assessed by secondary culture. PMID- 29479710 TI - Strigolactone-nitric oxide interplay in plants: The story has just begun. AB - Both strigolactones (SLs) and nitric oxide (NO) are regulatory signals with diverse roles during plant development and stress responses. This review aims to discuss the so far available data regarding SLs-NO interplay in plant systems. The majority of the few articles dealing with SL-NO interplay focuses on the root system and it seems that NO can be an upstream negative regulator of SL biosynthesis or an upstream positive regulator of SL signaling depending on the nutrient supply. From the so far published results it is clear that NO modifies the activity of target proteins involved in SL biosynthesis or signaling which may be a physiologically relevant interaction. Therefore, in silico analysis of NO-dependent posttranslational modifications in SL-related proteins was performed using computational prediction tools and putative NO-target proteins were specified. The picture is presumably more complicated, since also SL is able to modify NO levels. As a confirmation, author detected NO levels in different organs of max1-1 and max2-1 Arabidopsis and compared to the wild-type these mutants showed enhanced NO levels in their root tips indicating the negative effect of endogenous SLs on NO metabolism. Exogenous SL analogue-triggered NO production seems to contradict the results of the genetic study, which is an inconsistency should be taken into consideration in the future. In the coming years, the link between SL and NO signaling in further physiological processes should be examined and the possibilities of NO-dependent posttranslational modifications of SL biosynthetic and signaling proteins should be looked more closely. PMID- 29479709 TI - Facial dermatitis caused by undeclared methylisothiazolinone in a gel mask: is the preservation of raw materials in cosmetics a cause of concern? PMID- 29479711 TI - A novel role for cathepsin K in periosteal osteoclast precursors during fracture repair. AB - Osteoporosis management is currently centered around bisphosphonates, which inhibit osteoclast (OC) bone resorption but do not affect bone formation. This reduces fracture risk, but fails to restore healthy bone remodeling. Studies in animal models showed that cathepsin K (CatK) inhibition by genetic deletion or chemical inhibitors maintained bone formation while abrogating resorption during bone remodeling and stimulated periosteal bone modeling. Recently, periosteal mononuclear tartrate-resistant acid phosphatase-positive (TRAP+ ) osteoclast precursors (OCPs) were shown to augment angiogenesis-coupled osteogenesis. CatK gene deletion increased osteoblast differentiation via enhanced OCP and OC secretion of platelet-derived growth factor (PDGF)-BB and sphingosine 1 phosphate. The effects of periosteum-derived OCPs on bone remodeling are unknown, particularly with regard to fracture repair. We hypothesized that periosteal OCPs derived from CatK-null (Ctsk-/- ) mice may enhance periosteal bone formation during fracture repair. We found fewer periosteal OCPs in Ctsk-/- mice under homeostatic conditions; however, after fracture, this population increased in number relative to that seen in wild-type (WT) mice. Enhanced TRAP staining and greater expression of PDGF-BB were observed in fractured Ctsk-/- femurs relative to WT femurs. This early pattern of augmented PDGF-BB expression in Ctsk-/- mice may contribute to improved fracture healing by enhancing callus mineralization in Ctsk-/- mice. PMID- 29479712 TI - Technical Note: Quantitative accuracy evaluation for spectral images from a detector-based spectral CT scanner using an iodine phantom. AB - PURPOSE: The purpose of this study was to evaluate the quantitative accuracy of spectral images from a detector-based spectral CT scanner using a phantom with iodine-loaded inserts. METHODS: A 40-cm long-body phantom with seven iodine inserts (2-20 mg/ml of iodine) was used in the study. The inserts could be placed at 5.5 or 10.5 cm from the phantom axis. The phantom was scanned five times for each insert configuration using 120 kVp tube voltage. A set of iodine, virtual noncontrast, effective atomic number, and virtual monoenergetic spectral CT images were generated and measurements were made for all the iodine rods. Measured values were compared with reference values calculated from the chemical composition information provided by the phantom manufacturer. Radiation dose from the spectral CT was compared to a conventional CT using a CTDI (32 cm) phantom. RESULTS: Good agreement between measurements and reference values was achieved for all types of spectral images. The differences ranged from -0.46 to 0.1 mg/ml for iodine concentration, -9.95 to 6.41 HU for virtual noncontrast images, 0.12 to 0.35 for effective Z images, and -17.7 to 55.7 HU for virtual monoenergetic images. For a similar CTDIvol, image noise from the conventional CT was 10% lower than the spectral CT. CONCLUSIONS: The detector-based spectral CT can achieve accurate spectral measurements on iodine concentration, virtual non-contrast images, effective atomic numbers, and virtual monoenergetic images. PMID- 29479713 TI - Molecular basis of weak D expression in the Indian population and report of a novel, predominant variant RHD allele. AB - BACKGROUND: The Rh blood group system is the most polymorphic system and is implicated in hemolytic transfusion reaction and hemolytic disease of the fetus and newborn. Molecular genetics of the RH genes have been extensively studied in Caucasians, Africans, and East Asians and the variant alleles giving rise to weak and partial D phenotypes have been reported. However, limited genetic studies have been carried out in the large Indian population, even though the variability of Rh expression has been documented. STUDY DESIGN AND METHODS: In this study we sought to characterize the molecular bases of weak D expression in Indians. RHD gene in samples presenting with a weak D phenotype by serologic analyses (n = 223) was genotyped by conventional molecular approaches. RESULTS: In addition to referenced and novel single-nucleotide variations, a novel approximately 12-kb duplication event, including Exon 3, was identified predominantly in variant D samples (130/223, 58.3%) and characterized at the nucleotide sequence level. Functional analyses suggested that this genetic variation quantitatively affects the expression of the normal transcript and then subsequently the expression of the normal RhD protein. CONCLUSION: We describe a major novel, variant RHD allele in Indians that can be easily identified routinely by implementing a simple genotyping assay. Although we may consider this variation as a weak partial D variant, further studies and observations are needed to confirm the same. These findings may contribute to improve significantly Rh blood group diagnostics in more than one billion Indians. PMID- 29479714 TI - Conversion of carlactone to carlactonoic acid is a conserved function of MAX1 homologs in strigolactone biosynthesis. AB - Strigolactones (SLs) are a class of plant hormones which regulate shoot branching and function as host recognition signals for symbionts and parasites in the rhizosphere. However, steps in SL biosynthesis after carlactone (CL) formation remain elusive. This study elucidated the common and diverse functions of MAX1 homologs which catalyze CL oxidation. We have reported previously that ArabidopsisMAX1 converts CL to carlactonoic acid (CLA), whereas a rice MAX1 homolog has been shown to catalyze the conversion of CL to 4-deoxyorobanchol (4DO). To determine which reaction is conserved in the plant kingdom, we investigated the enzymatic function of MAX1 homologs in Arabidopsis, rice, maize, tomato, poplar and Selaginella moellendorffii. The conversion of CL to CLA was found to be a common reaction catalyzed by MAX1 homologs, and MAX1s can be classified into three types: A1-type, converting CL to CLA; A2-type, converting CL to 4DO via CLA; and A3-type, converting CL to CLA and 4DO to orobanchol. CLA was detected in root exudates from poplar and Selaginella, but not ubiquitously in other plants examined in this study, suggesting its role as a species-specific signal in the rhizosphere. This study provides new insights into the roles of MAX1 in endogenous and rhizosphere signaling. PMID- 29479715 TI - Elevated and super-elevated CO2 differ in their interactive effects with nitrogen availability on fruit yield and quality of cucumber. AB - BACKGROUND: Elevated carbon dioxide (CO2 ) and nitrogen (N) availability can interactively promote cucumber yield, but how the yield increase is realized remains unclear, whilst the interactive effects on fruit quality are unknown. In this study, cucumber plants (Cucumis sativus L. cv. Jinmei No. 3) were grown in a paddy soil under three CO2 concentrations - 400 (ambient CO2 ), 800 (elevated CO2 , eCO2 ) and 1200 umol mol-1 (super-elevated CO2 ) - and two N applications - 0.06 (low N) and 0.24 g N kg-1 soil (high N). RESULTS: Compared with ambient CO2 , eCO2 increased yield by 106% in high N but the increase in total biomass was only 33%. This can result from greater carbon translocation to fruits from other organs, indicated by the increased biomass allocation from stems and leaves, particularly source leaves, to fruits and the decreased concentrations of fructose and glucose in source leaves. Super-elevated CO2 reduced the carbon allocation to fruits thus yield increase (71%). Additionally, eCO2 also increased the concentrations of fructose and glucose in fruits, maintained the concentrations of dietary fiber, phosphorus, potassium, calcium, magnesium, sulfur, manganese, copper, molybdenum and sodium, whilst it decreased the concentrations of nitrate, protein, iron, and zinc in high N. Compared with eCO2 , super-elevated CO2 can still improve the fruit quality to some extent in low N availability. CONCLUSIONS: Elevated CO2 promotes cucumber yield largely by carbon allocation from source leaves to fruits in high N availability. Besides a dilution effect, carbon allocation to fruits, carbohydrate transformation, and nutrient uptake and assimilation can affect the fruit quality. (c) 2018 Society of Chemical Industry. PMID- 29479716 TI - Probiotics as a tool for disease mitigation in wildlife: insights from food production and medicine. AB - The use of beneficial microbes to improve host attributes, referred to as probiotic therapy, has been increasingly applied to industries, including aquaculture, agriculture, and human medicine, and is emerging in the field of wildlife medicine. However, there is a general lack of shared knowledge regarding successful practices as well as ecological processes that underlie host-microbe interactions. Presently, probiotics are being developed specifically for preventing and treating particular infectious diseases as an alternative to antibiotic treatments and chemotherapy. We review research on probiotics developed for mitigation of infectious disease in the aforementioned industries to gain insight into how probiotics may be effective in reducing wildlife disease risk. We examine the trends of successful in vivo probiotic applications for disease systems and identify common objectives to reduce intestinal pathogens and sexually transmitted and respiratory diseases, inhibit skin pathogens, and serve as environmental prophylaxis to reduce pathogen loads in the environment. We conclude by highlighting the frontier of wildlife probiotics research and identifying knowledge gaps where research is needed. PMID- 29479717 TI - X-ray-induced acoustic computed tomography for 3D breast imaging: A simulation study. AB - PURPOSE: The objective of this study is to demonstrate the feasibility of x-ray induced acoustic computed tomography (XACT) for early breast un-palpable microcalcification (MUCa) detection in three dimensions (3D). The proposed technique provides the true 3D imaging for breast volume which overcomes the disadvantage of the tissue superposition in mammography. METHODS: A 3D breast digital phantom was rendered from two-dimensional (2D) breast CT slices. Three different tissue types, including the skin, adipose tissue, and glandular tissue, were labeled in the 3D breast phantom. MUCas were manually embedded in different locations inside the breast phantom. For each tissue type, the initial pressure rise caused by the x-ray-induced acoustic (XA) effect was calculated according to its themoacoustic properties. The XA wave's propagation from the point of generation and its detection by ultrasound detector array were simulated by Matlab K-Wave toolbox. The 3D breast XACT volume with MUCa was acquired without tissue superposition, and the system was characterized by MUCas placed at different locations. RESULTS: The simulation results illustrated that the proposed breast XACT system has the ability to show the MUCa cluster in 3D without any tissue superposition. Meanwhile, MUCa as small as 100 MUm in size can be detected with high imaging contrast, high signal to noise ratio (SNR), and high contrast to noise ratio (CNR). The dose required by the proposed XACT configuration was calculated to be 0.4 mGy for a 4.5 cm-thick compressed breast. This is one-tenth of the dose level of a typical two-view mammography for a breast with the same compression thickness. CONCLUSIONS: The initial exploration for the feasibility of 3D breast XACT has been conducted in this study. The system feasibility and characterization were illustrated through a 3D breast phantom and simulation works. The 3D breast XACT with the proposed system configuration has great potential to be applied as a low-dose screening and diagnostic technique for early un-palpable lesion in the breast. PMID- 29479718 TI - Cryoprecipitate transfusions in the neonatal intensive care unit: a performance improvement study to decrease donor exposure. AB - BACKGROUND: The objective of this study was to determine if a change in cryoprecipitate transfusion policy impacts donor exposure and fibrinogen level in a neonatal intensive care unit (NICU) population. STUDY DESIGN AND METHODS: The cryoprecipitate policy was changed from transfusing 10ml/kg to a maximum of 1 unit per transfusion in January 2013. Data were obtained via retrospective chart review of all infants receiving cryoprecipitate transfusions from January 2008 to February 2015 in the NICU at Christiana Hospital. RESULTS: A total of 103 neonates received a total of 144 cryoprecipitate transfusions. Before the policy change, term babies were more likely to be exposed to more than one donor compared to preterm babies (75% vs. 6%, p < 0.01). After the policy change, no babies were exposed to greater than one donor per transfusion and there were similar increases in posttransfusion fibrinogen level as before the policy change. CONCLUSION: Limiting cryoprecipitate transfusions to 1 unit per transfusion decreased donor exposure in infants without negatively impacting posttransfusion fibrinogen levels. This is especially evident in term neonates. PMID- 29479719 TI - Responding to the needs of the population suffering from severe mental disorders by a multifaceted territorial approach: Reorganization of the French mental health system. AB - Organizing the management of severe mental disorders at the national level is a major challenge given the complexity of the disorders and the diversity of responses needed to address all the needs. A founding principle for the creation or development of measures consists in structuring care programs around functional and personal recovery, and not only clinical recovery. The fact that the French psychiatric field is currently being modernized by its missions being redefined within territorial mental health projects gives the opportunity to generalize these principles. This article illustrates how the creation of a hierarchical organization of psychosocial rehabilitation can (a) give more coherence to the part of the French mental health system, (b) improve the quality of care, and (c) promote social inclusion and recovery of people with severe mental disorders. PMID- 29479720 TI - OsSPL regulates meiotic fate acquisition in rice. AB - In angiosperms, the key step in sexual reproduction is successful acquisition of meiotic fate. However, the molecular mechanism determining meiotic fate remains largely unknown. Here, we report that OsSPOROCYTELESS (OsSPL) is critical for meiotic entry in rice (Oryza sativa). We performed a large-scale genetic screen of rice sterile mutants aimed to identify genes regulating meiotic entry and identified OsSPL using map-based cloning. We showed that meiosis-specific callose deposition, chromatin organization, and centromere-specific histone H3 loading were altered in the cells corresponding to pollen mother cells in Osspl anthers. Global transcriptome analysis showed that the enriched differentially expressed genes in Osspl were mainly related to redox status, meiotic process, and parietal cell development. OsSPL might form homodimers and interact with TEOSINTE BRANCHED1/CYCLOIDEA/PCF (TCP) transcription factor OsTCP5 via the SPL dimerization and TCP interaction domain. OsSPL also interacts with TPL (TOPLESS) corepressors, OsTPL2 and OsTPL3, via the EAR motif. Our results suggest that the OsSPL-mediated signaling pathway plays a crucial role in rice meiotic entry, which appears to be a conserved regulatory mechanism for meiotic fate acquisition in angiosperms. PMID- 29479721 TI - Co-production in community mental health services: blurred boundaries or a game of pretend? AB - The concept of co-production suggests a collaborative production of public welfare services, across boundaries of participant categories, for example professionals, service users, peer-workers and volunteers. While co-production has been embraced in most European countries, the way in which it is translated into everyday practice remains understudied. Drawing on ethnographic data from Danish community mental health services, we attempt to fill this gap by critically investigating how participants interact in an organisational set-up with blurred boundaries between participant categories. In particular, we clarify under what circumstances the blurred boundaries emerge as believable. Theoretically, we combine Lamont and Molnar's (2002) distinction between symbolic boundaries and social boundaries with Goffman's (1974) microanalysis of "principles of convincingness". The article presents three findings: (1) co production is employed as a symbolic resource for blurring social boundaries; (2) the believability of blurred boundaries is worked up through participants' access to resources of validation, knowledge and authority; and (3) incongruence between symbolic and social boundaries institutionalises practices where participants merely act 'as if' boundaries are blurred. Clarification of the principles of convincingness contributes to a general discussion of how co-production frames the everyday negotiation of symbolic and social boundaries in public welfare services. PMID- 29479722 TI - Evolution of pyrrolizidine alkaloid biosynthesis in Apocynaceae: revisiting the defence de-escalation hypothesis. AB - Plants produce specialized metabolites for their defence. However, specialist herbivores adapt to these compounds and use them for their own benefit. Plants attacked predominantly by specialists may be under selection to reduce or eliminate production of co-opted chemicals: the defence de-escalation hypothesis. We studied the evolution of pyrrolizidine alkaloids (PAs) in Apocynaceae, larval host plants for PA-adapted butterflies (Danainae, milkweed and clearwing butterflies), to test if the evolutionary pattern is consistent with de escalation. We used the first PA biosynthesis specific enzyme (homospermidine synthase, HSS) as tool for reconstructing PA evolution. We found hss orthologues in diverse Apocynaceae species, not all of them known to produce PAs. The phylogenetic analysis showed a monophyletic origin of the putative hss sequences early in the evolution of one Apocynaceae lineage (the APSA clade). We found an hss pseudogene in Asclepias syriaca, a species known to produce cardiac glycosides but no PAs, and four losses of an HSS amino acid motif. APSA clade species are significantly more likely to be Danainae larval host plants than expected if all Apocynaceae species were equally likely to be exploited. Our findings are consistent with PA de-escalation as an adaptive response to specialist attack. PMID- 29479723 TI - Jk3 alloantibodies during pregnancy-blood bank management and hemolytic disease of the fetus and newborn risk. AB - BACKGROUND: The Kidd-null phenotype, Jk(a-b-), occurs in individuals who do not express the JK glycoprotein. Jk(a-b-) individuals can make an antibody against the Jk3 antigen, a high-incidence antigen present in more than 99.9% of most populations. This presents many challenges to the blood bank including identification of the antibody, masking of other antibodies, and how to provide transfusion support given the rarity of Jk3-negative blood products. Kidd antibodies may cause acute and delayed hemolytic reactions as well as hemolytic disease of the fetus and newborn (HDFN). In this article, we present a series of four practical cases of pregnant women with the anti-Jk3 alloantibody that demonstrate a range of clinical presentations of Kidd-related HDFN. STUDY DESIGN AND METHODS: We retrospectively reviewed the clinical and blood bank records for four patients and their newborns encountered at institutions in Tennessee, Missouri, Hawaii, and Guam with an anti-Jk3 identified during pregnancy. RESULTS: Two cases showed no significant evidence for HDFN, while two cases were of mild to-moderate severity requiring early delivery due to elevated middle cerebral artery (MCA) flow velocities but requiring only phototherapy for hyperbilirubinemia. No intrauterine or neonatal transfusions were necessary. Anti Jk3 alloantibody titers ranged from 2 to 128. CONCLUSION: Clinical manifestations of anti-Jk3 HDFN are generally mild to moderate. Anti-Jk3 titers were not found to correlate directly with HDFN severity. We suggest a titer of 16 to 32 as a cutoff for implementing enhanced monitoring of fetal MCA flow velocities, as such titers may be indicative of elevated HDFN risk. PMID- 29479724 TI - Maize Urb2 protein is required for kernel development and vegetative growth by affecting pre-ribosomal RNA processing. AB - Ribosome biogenesis is a fundamental process in eukaryotic cells. Although Urb2 protein has been implicated in ribosome biogenesis in yeast, the Urb2 domain is loosely conserved between plants and yeast, and the function of Urb2 protein in plants remains unknown. Here, we isolated a maize mutant, designated as urb2, with defects in kernel development and vegetative growth. Positional cloning and transgenic analysis revealed that urb2 encodes an Urb2 domain-containing protein. Compared with the wild-type (WT), the urb2 mutant showed decreased ratios of 60S/40S and 80S/40S and increased ratios of polyribosomes. The pre-rRNA intermediates of 35/33S rRNA, P-A3 and 18S-A3 were significantly accumulated in the urb2 mutant. Transcriptome profiling of the urb2 mutant indicated that ZmUrb2 affects the expression of a number of ribosome-related genes. We further demonstrated that natural variations in ZmUrb2 are significantly associated with maize kernel length. The overall results indicate that, by affecting pre-rRNA processing, the Urb2 protein is required for ribosome biogenesis in maize. PMID- 29479725 TI - Preschoolers' knowledge about language-specific properties of writing. AB - According to the differentiation hypothesis, young children's attempts to write show characteristics common to all writing systems, such as linearity. Characteristics that are specific to the writing system of the child's culture emerge only later. We tested this hypothesis by presenting adults who knew both Chinese and English with written productions of Chinese and United States 2- to 5 year-olds and asking them to judge the nationality of the writer. Adults performed significantly above the level expected by chance even with the productions of 2- and 3-year-olds, suggesting that knowledge of language-specific characteristics emerges earlier than previously thought. Children appeared to show more language-specific characteristics in their names than in other writings, for adults performed better with children's names than with other items. Statement of contribution What is already known on this subject? Children's early attempts to write may show general properties of writing, such as linearity. Knowledge of language-specific features is thought to develop later. What does this study adds? Adults judged whether a writer was an United States or a Chinese child. Adults performed above the level of chance even with the productions of 2- and 3-year-olds. Children begin to learn about language specific features earlier than previously thought. PMID- 29479726 TI - A long-term follow-up study of the Hand Eczema Trial (HET): a randomized clinical trial of a secondary preventive programme introduced to Danish healthcare workers. AB - BACKGROUND: Preventive skin care programmes have shown beneficial effects on the prevalence and severity of hand eczema, but most trials only report short-term outcomes. One such trial was the randomized Hand Eczema Trial (HET, 2009) investigating the effects of a secondary prevention programme in healthcare workers. Positive results have been reported at 5-month follow-up. OBJECTIVES: To examine the long-term (42-47 months) effects of the HET. METHODS: The present study was a follow-up questionnaire study on the effect of the intervention. Outcomes were the presence and severity of hand eczema, health-related quality of life (HR-QoL), skin protective behaviour, and knowledge of skin protection. A supplementary outcome was general improvement/worsening of hand eczema. RESULTS: Comparison of the outcomes at follow-up showed no marked differences between the two groups. General improvement was reported by 70% in the intervention group and by 54% in the control group (p = 0.25). A small, statistically significant improvement was found regarding HR-QoL in the intervention group only (p = 0.015). CONCLUSIONS: The impact of an intervention that is effective after 5 months is attenuated over time, with no long-term effect on the outcomes examined. We suggest that skin care education should be repeated at regular intervals. PMID- 29479727 TI - Efficacy and safety of topical application of 15% and 10% potassium hydroxide for the treatment of Molluscum contagiosum. AB - BACKGROUND/OBJECTIVES: Molluscum contagiosum is the most common skin infection in children. One topical treatment used for Molluscum contagiosum is potassium hydroxide. The objective of this study was to compare the efficacy of potassium hydroxide topical treatment at different concentrations with that of placebo in terms of complete clearing of Molluscum contagiosum lesions and to assess the safety and tolerance of potassium hydroxide topical treatment. METHODS: This was a double-blind randomized clinical trial of three treatments (potassium hydroxide 10%, potassium hydroxide 15%, placebo) applied once daily up to complete clearing of lesions (maximum duration 60 days) in 53 children aged 2-6 years in primary health care pediatric offices in Catalonia, Spain. RESULTS: In the intention-to treat analysis, potassium hydroxide 10% (58.8%, P = .03) and potassium hydroxide 15% (64.3%, P = .02) had efficacy superior to that of placebo (18.8%). The number of Molluscum contagiosum lesions was significantly reduced with potassium hydroxide 10% and 15%. The main efficacy outcome was achieved in 58.8% of children in the potassium hydroxide 10% group (P = .03 vs placebo) and in 64.3% of children in the potassium hydroxide 15% group (P = .02 vs placebo). Potassium hydroxide 10% and 15% were not significantly different in efficacy from each other. Potassium hydroxide 10% and placebo were better tolerated than potassium hydroxide 15%. No adverse events were reported during the study period. CONCLUSIONS: Potassium hydroxide 10% and 15% demonstrated high rates of efficacy in clearing Molluscum contagiosum lesions, with potassium hydroxide 10% being better tolerated. PMID- 29479729 TI - Retronychia a little-known cause of paronychia: A report of two cases in adolescent patients. AB - Retronychia is a clinical condition resulting from embedding of the nail plate into the proximal nail fold. We report two adolescent girls, 14 and 16 years of age, with a history of chronic proximal paronychia of the great toe, one of them developing osteomyelitis. After failure of treatment with several systemic antibiotics, nail avulsion was performed, leading us to the diagnosis of retronychia and with rapid and complete resolution of symptoms in both cases. Delay in diagnosis of retronychia can lead to local complications and prolonged discomfort. PMID- 29479730 TI - Phacomatosis pigmentovascularis type 2b (phacomatosis cesioflammea) with double superior vena cava, abdominal varicosities, and natal tooth: Novel associations. AB - Phacomatosis pigmentovascularis is characterized by coexistent extensive cutaneous vascular (capillary) and pigmentary anomalies. We describe a 2-month old infant presenting with classic features of phacomatosis pigmentovascularis 2b (phacomatosis cesioflammea). He was also found to have hitherto unreported associations in the form of extensive venous anomalies presenting as striking abdominal wall varicosities and persistent left superior vena cava and natal tooth. PMID- 29479728 TI - An expert consensus for the management of chronic hepatitis B in Asian Americans. AB - BACKGROUND: Hepatitis B virus (HBV) infection is common with major clinical consequences. In Asian Americans, the HBsAg carrier rate ranges from 2% to 16% which approximates the rates from their countries of origin. Similarly, HBV is the most important cause of cirrhosis, hepatocellular carcinoma (HCC) and liver related deaths in HBsAg positive Asians worldwide. AIM: To generate recommendations for the management of Asian Americans infected with HBV. METHODS: These guidelines are based on relevant data derived from medical reports on HBV from Asian countries as well as from studies in the HBsAg positive Asian Americans. The guidelines herein differ from other recommendations in the treatment of both HBeAg positive and negative chronic hepatitis B (CHB), in the approach to HCC surveillance, and in the management of HBV in pregnant women. RESULTS: Asian American patients, HBeAg positive or negative, with HBV DNA levels >2000 IU/mL (>104 copies/mL) and ALT values above normal are candidates for anti viral therapy. HBeAg negative patients with HBV DNA >2000 IU/mL and normal ALT levels but who have either serum albumin <3.5 g/dL or platelet count <130 000 mm3 , basal core promoter (BCP) mutations, or who have first-degree relatives with HCC should be offered treatment. Patients with cirrhosis and detectable HBV DNA must receive life-long anti-viral therapy. Indications for treatment include pregnant women with high viraemia, coinfected patients, and those requiring immunosuppressive therapy. In HBsAg positive patients with risk factors, life long surveillance for HCC with alpha-fetoprotein (AFP) testing and abdominal ultrasound examination at 6-month intervals is required. In CHB patients receiving HCC treatments, repeat imaging with contrast CT scan or MRI at 3-month intervals is strongly recommended. These guidelines have been assigned to a Class (reflecting benefit vs. risk) and a Level (assessing strength or certainty) of evidence. CONCLUSIONS: Application of the recommendations made based on a review of the relevant literature and the opinion of a panel of Asian American physicians with expertise in HBV treatment will inform physicians and improve patient outcomes. PMID- 29479731 TI - Severe central sleep apnoea associated with nalmefene: a case report. AB - Nalmefene, an opioid antagonist, has recently been approved for the treatment of alcohol dependence. We describe here the first case of a 52-year-old woman who developed a severe central sleep apnoea (CSA) 5 months after initiation of nalmefene. Scoring of ventilation during sleep recording revealed an apnoea hypopnoea index of 67/h with 98.7% of central events and an apnoea index of 65/h. Nalmefene was withdrawn and a new polysomnography was performed which concluded that CSA has disappeared. Pathophysiology is still unclear but could involve the kappa-opioid receptors. Physicians should be aware that CSA might affect patients treated with nalmefene. Further investigations are required to determine the pathophysiology, frequency, and treatment of CSA associated with nalmefene and other therapy for alcohol disorders. PMID- 29479732 TI - Immune activation by nucleic acids: A role in pregnancy complications. AB - Cell-free self-DNA or RNA may induce an immune response by activating specific sensing receptors. During pregnancy, placental nucleic acids present in the maternal circulation further activate these receptors due to the presence of unmethylated CpG islands. A higher concentration of cell-free foetal DNA is associated with pregnancy complications and a higher risk for foetal rejection. Cell-free foetal DNA originates from placental trophoblasts. It appears in different forms: free, bound to histones in nucleosomes, in neutrophil extracellular traps (NETs) and in extracellular vesicles (EVs). In several pregnancy complications, cell-free foetal DNA triggers the production of proinflammatory cytokines, and this production results in a cellular and humoral immune response. This review discusses preeclampsia, systemic lupus erythematosus, foetal growth restriction, gestational diabetes, rheumatoid arthritis and obesity in pregnancy from an immunological point of view and closely examines the different pathways that result in maternal inflammation. Understanding the role of cell-free nucleic acids, as well as the biogenesis of NETs and EVs, will help us to specify their functions or targets, which seem to be important in pregnancy complications. It is still not clear whether higher concentrations of cell-free nucleic acids in the maternal circulation are the cause or consequence of various complications. Therefore, further clinical studies and, even more importantly, animal experiments that focus on the involved immunological pathways are needed. PMID- 29479733 TI - Studies on the resting behaviour and host choice of Anopheles gambiae and An. arabiensis from Muleba, Tanzania. AB - The relative efficacy of a mechanical (Prokopack) collection method vs. manual aspiration in the collection of resting mosquitoes was evaluated in northern Tanzania before and after an intervention using indoor residual spraying and longlasting insecticide-treated nets. In smoke-free houses mosquitoes were collected from the roof and walls, but in smoky houses mosquitoes were found predominantly on the walls. Anopheles gambiae (Diptera: Culicidae) constituted 97.7% of the 312 An. gambiae complex specimens identified before but only 19.3% of the 183 identified after the intervention. A single sampling with the Prokopack collected a third of the available insects. Anopheles gambiae completed its gonotrophic development indoors, whereas Anopheles arabiensis did so outdoors. In both species gonotrophic development took 2 days. Most unfed resting An. arabiensis collected outdoors were virgins, whereas the majority of engorged insects were parous (with well-contracted sacs). Daily survival was estimated to be 80.0%. Only 9.4% of the engorged An. arabiensis collected outdoors and 47.1% of those collected indoors had fed on humans. Using the Prokopack sampler is more efficient than manual methods for the collection of resting mosquitoes. Malaria transmission may have been affected by a change in vector composition resulting from a change in feeding, rather than reduced survival. Monitoring the proportions of members of the An. gambiae complex may provide signals of an impending breakdown in control. PMID- 29479735 TI - Onycholemmal carcinoma: A case report with its molecular profiling. PMID- 29479734 TI - Tumor mechanosensing and its therapeutic potential. AB - Cancer mechanics have lately emerged as a distinct tumor feature that promotes tumor development, invasion, and metastasis. Tumor mechanosensing involves a mechanical interplay between cancer cells, extracellular matrix, and cells of the surrounding stroma. Mechanoreceptors sense alterations of the extracellular mechanical cues and activate signaling molecules, which mediate oncogenic transcription in favor of cancer initiation, survival, growth, and metastasis. Furthermore, alterations of the matrix rigidity and activation of mechano-induced transcriptional regulators has been strongly associated with resistance to anti cancer agents. In this context, new mechanosensitive molecules arise as potential therapeutic targets. Therefore, tumor mechanosignaling represents a promising field that can potentially offer new combination regimens to overcome drug resistance, but also suggest novel targeting strategies. PMID- 29479736 TI - Gradient waveform pre-emphasis based on the gradient system transfer function. AB - PURPOSE: The gradient system transfer function (GSTF) has been used to describe the distorted k-space trajectory for image reconstruction. The purpose of this work was to use the GSTF to determine the pre-emphasis for an undistorted gradient output and intended k-space trajectory. METHODS: The GSTF of the MR system was determined using only standard MR hardware without special equipment such as field probes or a field camera. The GSTF was used for trajectory prediction in image reconstruction and for a gradient waveform pre-emphasis. As test sequences, a gradient-echo sequence with phase-encoding gradient modulation and a gradient-echo sequence with a spiral read-out trajectory were implemented and subsequently applied on a structural phantom and in vivo head measurements. RESULTS: Image artifacts were successfully suppressed by applying the GSTF-based pre-emphasis. Equivalent results are achieved with images acquired using GSTF based post-correction of the trajectory as a part of image reconstruction. In contrast, the pre-emphasis approach allows reconstruction using the initially intended trajectory. CONCLUSION: The artifact suppression shown for two sequences demonstrates that the GSTF can serve for a novel pre-emphasis. A pre-emphasis based on the GSTF information can be applied to any arbitrary sequence type. PMID- 29479737 TI - Single-scan z-shim method for reducing susceptibility artifacts in gradient echo myelin water imaging. AB - PURPOSE: Myelin water imaging (MWI) reportedly corresponds closely to the myelin content in the brain. An MWI technique based on multi-echo gradient echo (mGRE) has recently been proposed as an alternative to the conventional spin-echo-based MWI. However, the mGRE signal is vulnerable to macroscopic field inhomogeneity, which makes MWI unreliable. In the present study, a z-shim-based single-scan correction method is proposed to overcome this limitation. METHODS: Z-shim gradients in the slice-selection direction were added to an mGRE sequence after an echo time of 12 ms. A 3-pool model corresponding to the proposed sequence was suggested for fitting the acquired signal. The method was evaluated through a comparison with methods without a correction and with post-processing only from non-z-shimmed data. To do this, numerical simulations and in vivo experiments were conducted. RESULTS: The simulation and in vivo experiment results indicated that post-processing alone was not sufficient to offset the macroscopic field inhomogeneity, particularly in inferior regions of the brain. On the other hand, the proposed method compensated the field inhomogeneity in most brain areas. The estimated in vivo myelin water fraction values were in good agreement with literature values obtained by previously proposed field inhomogeneity correction method. CONCLUSION: The proposed method showed reliable myelin water fraction in most regions of the brain in vivo, including those with severe field inhomogeneity. PMID- 29479738 TI - Accelerating 3D-T1rho mapping of cartilage using compressed sensing with different sparse and low rank models. AB - PURPOSE: To evaluate the feasibility of using compressed sensing (CS) to accelerate 3D-T1rho mapping of cartilage and to reduce total scan times without degrading the estimation of T1rho relaxation times. METHODS: Fully sampled 3D T1rho datasets were retrospectively undersampled by factors 2-10. CS reconstruction using 12 different sparsifying transforms were compared, including finite differences, temporal and spatial wavelets, learned transforms using principal component analysis (PCA) and K-means singular value decomposition (K SVD), explicit exponential models, low rank and low rank plus sparse models. Spatial filtering prior to T1rho parameter estimation was also tested. Synthetic phantom (n = 6) and in vivo human knee cartilage datasets (n = 7) were included. RESULTS: Most CS methods performed satisfactorily for an acceleration factor (AF) of 2, with relative T1rho error lower than 4.5%. Some sparsifying transforms, such as spatiotemporal finite difference (STFD), exponential dictionaries (EXP) and low rank combined with spatial finite difference (L+S SFD) significantly improved this performance, reaching average relative T1rho error below 6.5% on T1rho relaxation times with AF up to 10, when spatial filtering was used before T1rho fitting, at the expense of smoothing the T1rho maps. The STFD achieved 5.1% error at AF = 10 with spatial filtering prior to T1rho fitting. CONCLUSION: Accelerating 3D-T1rho mapping of cartilage with CS is feasible up to AF of 10 when using STFD, EXP or L+S SFD regularizers. These three best CS methods performed satisfactorily on synthetic phantom and in vivo knee cartilage for AFs up to 10, with T1rho error of 6.5%. PMID- 29479739 TI - Denosumab-related osteonecrosis of the jaw following non-surgical periodontal therapy: A case report. AB - INTRODUCTION: Osteonecrosis of the jaw associated with bisphosphonates is currently called medication-related osteonecrosis of the jaw (MRONJ), given that in addition to bisphosphonates, jaw osteonecrosis has been related to the administration of other antiresorptive and antiangiogenic drugs, such as denosumab, sunitinib, bevacizumab and ipilimumab. CASE PRESENTATION: A 77-year old patient with osteoporosis treated with subcutaneous injections of denosumab at an interval of 6 months is presented. The patient developed MRONJ after receiving a non-surgical periodontal therapy. Although the MRONJ was initially classified as a stage I lesion in this patient, cone beam computed tomography images confirmed the presence of a significant osteolytic lesion. Treatment consisted of the administration of chlorhexidine mouthwash and systemic doxycycline, exodontia of the involved teeth, sequestrectomy and complete surgical debridement of the necrotic bone. CONCLUSION: To our knowledge, this is the first case reported in the literature of MRONJ following non-surgical periodontal therapy in a patient with osteoporosis treated with denosumab. The risk of MRONJ development after a periodontal procedure and how to prevent this complication are still unknown. PMID- 29479740 TI - Nipple adenoma in a 2-year-old boy. AB - Nipple adenoma is an uncommon proliferative process of the breast and predominantly occurs in women aged 40-50. Its incidence is extremely low in men, and it has not been reported in a boy. Although nipple adenoma is rare and benign, being familiar with it is important because it clinically resembles Paget disease and histologically adenocarcinoma. We report a case of nipple adenoma in a boy. PMID- 29479741 TI - Future questions in insect chitin biology: A microreview. AB - This microreview stems from the Second Symposium on Insect Molecular Toxicology and Chitin Metabolism held at Shanxi University in Taiyuan, China (June 27 to 30, 2017) at the institute for Applied Biology headed by Professor Enbo Ma and Professor Jianzhen Zhang. PMID- 29479743 TI - Catalpol provides a protective effect on fibrillary Abeta1-42 -induced barrier disruption in an in vitro model of the blood-brain barrier. AB - Excessive amyloid beta (Abeta) deposition in brain is mainly responsible for cell damage and blood-brain barrier (BBB) disruption in Alzheimer's disease (AD). Catalpol, an iridoid glucoside extracted from the root of Rehmannia glutinosa Libosch, has neuroprotective effect against AD. It is unclear whether catalpol has a protective effect on Abeta-induced BBB leakage. We employed an immortalized endothelial cell line (bEnd.3) and astrocytes co-culture to mimic a BBB model in vitro and investigated the effect of catalpol on BBB. We found that treatment with catalpol decreased BBB hyperpermeability induced by fibrillar Abeta1-42 . Data from western blotting showed that catalpol prevented fibrillar Abeta1-42 induced bEnd.3 cell apoptosis through mitochondria-dependent and death receptor pathways; decreased the levels of matrix metalloproteinases (MMPs), MMP-2, MMP-9, and the receptor for advanced glycation end products; and increased the levels of tight junction proteins (ZO-1, occludin, and claudin-5), low-density lipoprotein receptor-related protein 1, and P-glycoprotein in fibrillar Abeta1-42 -treated bEnd.3 cells. Moreover, catalpol also enhanced soluble Abeta efflux across the fibrillar Abeta1-42 -treated bEnd.3 cells BBB monolayer model. Altogether, our results suggest that catalpol alleviate fibrillar Abeta1-42 -induced BBB disruption, enhance soluble Abeta clearance, and offer a feasible therapeutic application in AD treatment. PMID- 29479742 TI - Chemical characterisation of Piper amalago (Piperaceae) essential oil by comprehensive two-dimensional gas chromatography coupled with rapid-scanning quadrupole mass spectrometry (GC*GC/qMS) and their antilithiasic activity and acute toxicity. AB - INTRODUCTION: Piper amalago has a distribution from Mexico to Brazil; their aerial parts have been used in folk medicine to treat diuretic and kidney diseases. OBJECTIVE: The purpose of this study was to obtain a deeper understanding of the chemical composition of essential oils (EOs) extracted from both the leaves and stems of P. amalago, compare them, and evaluate their antilithiasic activity and acute toxicity. METHODOLOGY: Extraction was performed by hydrodistillation, whereas chemical characterisation by two-dimensional gas chromatography coupled with rapid-scanning quadrupole mass spectrometry (GC*GC/qMS). The antilithiasic activity was evaluated by the effect of the EOs on calcium oxalate crystallisation in vitro. The turbidity index and the number of crystals formed were determined and used as an estimative of the activity. In the acute toxicity assay, the effects of a single oral dose of the EOs in Wistar rats were determined. General behaviour, adverse effects, and mortality were determined. RESULTS: A total of 322 compounds were identified in the EOs. The sesquiterpenes displayed the highest contribution in leaves EOs among which included bicyclogermacrene and delta-cadinene. Sesquiterpenes and oxygenated sesquiterpenes displayed the highest contribution in EOs from stems, among which included bicyclogermacrene and alpha-cadinol. The EOs demonstrated an excellent action on the crystals growth inhibition, and the oral dose tested did not induce significant changes in the parameters for acute toxicity. CONCLUSION: The oils have a high chemical complexity, and there are differences between their compositions, which could explain the observed differences in antilithiasic activity. The findings support the use of this plant in folk medicine to treat kidney diseases. PMID- 29479744 TI - Nanocarbon-Based Materials for Flexible All-Solid-State Supercapacitors. AB - Because of the rapid development of flexible electronics, it is important to develop high-performance flexible energy-storage devices, such as supercapacitors and metal-ion batteries. Compared with metal-ion batteries, supercapacitors exhibit higher power density, longer cycling life, and excellent safety, and they can be easily fabricated into all-solid-state devices by using polymer gel electrolytes. All-solid-state supercapacitors (ASSSCs) have the advantages of being lightweight and flexible, thus showing great potential to be used as power sources for flexible portable electronics. Because of their high specific surface area and excellent electrical and mechanical properties, nanocarbon materials (such as carbon nanotubes, graphene, carbon nanofibers, and so on) have been widely used as efficient electrode materials for flexible ASSSCs, and great achievements have been obtained. Here, the recent advances in flexible ASSSCs are summarized, from design strategies to fabrication techniques for nanocarbon electrodes and devices. Current challenges and future perspectives are also discussed. PMID- 29479745 TI - Effects of pregnancy on skin properties: A biomechanical approach. AB - BACKGROUND: A woman's skin is dramatically affected by pregnancy. Its biomechanical properties are critical for resisting highly stressed areas. The aim of this work was to evaluate the impact of pregnancy on the mechanical properties of skin, as well as to evaluate the imprint that pregnancy leaves on the skin after delivery. MATERIALS AND METHODS: Suction tests using a cutometer were performed on 15 non-pregnant women and 26 pregnant women at 8 months of pregnancy and 4 months after delivery. Areas of abdomen and thighs were studied. RESULTS: Significant differences between the non-pregnant and 8-month pregnant groups were observed. Our data demonstrate that skin becomes less elastic and less deformable on the abdomen during pregnancy. On the thighs, a loss of elasticity and firmness was also observed. At 4 months after delivery, the skin did not return to its initial state. CONCLUSION: This study showed that the mechanical properties of skin changed drastically during pregnancy compared to the non-pregnant condition and that these properties remain altered 4 months after delivery. In addition to alterations in abdominal skin during pregnancy, we also observed mechanical changes on the thighs, which are less subject to stretching. PMID- 29479746 TI - Dinuclear Lanthanide(III)-m-ODO2A-dimer Macrocyclic Complexes: Solution Speciation, DFT Calculations, Luminescence Properties, and Promoted Nitrophenyl Phosphate Hydrolysis Rates. AB - Potentiometric speciation studies, mass spectrometry, and DFT calculations helped to predict the various structural possibilities of the dinuclear trivalent lanthanide ion (LnIII , Ln=La, Eu, Tb, Yb, Y) complexes of a novel macrocyclic ligand, m-ODO2A-dimer (H4 L), to correlate with their luminescence properties and the promoted BNPP and HPNP phosphodiester bond hydrolysis reaction rates. The stability constants of the dinuclear Ln2 (m-ODO2A-dimer) complexes and various hydrolytic species confirmed by mass spectrometry were determined. DFT calculations revealed that the Y2 LH-1 and the Y2 LH-2 species tended to form structures with the respective closed- and open-form conformations. Luminescence lifetime data for the heterodimetallic TbEuL system confirmed the fluorescence resonance energy transfer from the TbIII to EuIII ion. The internuclear distance RTbEu values were estimated to be in the range of 9.4-11.3 A (pH 6.7-10.6), which were comparable to those of the DFT calculated open-form conformations. Multiple linear regression analysis of the kobs data was performed using the equation: kobs,corr. =kobs -kobs,OH =kLn2LHM->1 [Ln2 LH-1 ]+kLn2LH-2 [Ln2 LH-2 ] for the observed Ln2 L-promoted BNPP/HPNP hydrolysis reactions in solution pH from 7 to 10.5 (Ln=Eu, Yb). The results showed that the second-order rate constants for the Eu2 LH-2 and Yb2 LH-2 species were about 50-400 times more reactive than the structural analogous Zn2 (m-12 N3 O-dimer) system. PMID- 29479747 TI - 2D GeP: An Unexploited Low-Symmetry Semiconductor with Strong In-Plane Anisotropy. AB - Germanium phosphide (GeP), a new member of the Group IV-Group V compounds, is introduced into the fast growing 2D family with experimental and theoretical demonstration of strong anisotropic physical properties. The indirect band gap of GeP can be drastically tuned from 1.68 eV for monolayer to 0.51 eV for bulk, with highly anisotropic dispersions of band structures. Thin GeP shows strong anisotropy of phonon vibrations. Moreover, photodetectors based on GeP flakes show highly anisotropic behavior with anisotropic factors of 1.52 and 1.83 for conductance and photoresponsivity, respectively. This work lays the foundation and ignites future research interests in Group IV-Group V compound 2D materials. PMID- 29479748 TI - Ascorbic acid-A black hole of urine chemistry screening. AB - BACKGROUND: Study was performed in order: (i) to assess the comparability of glucose, bilirubin, hemoglobin, leukocyte esterase, and protein; (ii) to assess accuracy of glucose, bilirubin, hemoglobin, leukocyte esterase, and protein; and (iii) to evaluate interference of ascorbic acid on the glucose, bilirubin, hemoglobin, and nitrite determination using 2 different dipsticks: iChem Velocity, Iris Diagnostics and Combur-10M, Roche Diagnostics. METHODS: Random urine specimens were included in the study. Comparability, accuracy, and ascorbic acid interference testing were performed. RESULTS: Obtained results have shown almost perfect agreement for all parameters between 2 dipsticks in samples with negative ascorbic acid. Agreement in samples with positive ascorbic acid was not acceptable for bilirubin, protein, nitrite, and hemoglobin. Accuracy was not acceptable for hemoglobin and leukocyte esterase on both dipsticks. Ascorbic acid interference examination has shown that intensity of interference differs between dipsticks. Ascorbic acid interferes with glucose, hemoglobin, nitrite, and bilirubin at different concentrations causing false-negative results. CONCLUSION: Obtained results indicate that it is necessary to determine diagnostic accuracy of used dipstick in order to define purpose of urinalysis. It is very important to choose dipstick with ascorbic acid indicator and to examine ascorbic acid impact on dipstick analytes independently of manufacturer claims. PMID- 29479749 TI - The contribution of feedback loops between miRNAs, cytokines and growth factors to the pathogenesis of psoriasis. AB - The present review describes in detail the existent data regarding feedback loops between miRNAs and cytokines or growth factors in the psoriatic inflammation. We have chosen to describe the roles of miR-31, miR-21, miR-146a, miR-155, miR-197 and miR-99a in this process. This choice derives from the fact that among around 250 miRNAs being altered in the psoriatic lesion, the comprehensive functional role was described only in those detailed above. In addition, considering the molecular targets and the pathways, which may possibly be regulated by those miRNAs, it seems that they may be chosen as preferred targets for the therapy of psoriasis. PMID- 29479750 TI - Substituents Have a Large Effect on Photochemical Generation of Benzyl Cations and DNA Cross-Linking. AB - Photoactivated DNA interstrand cross-linking agents have a wide range of biological applications. Recently, several aryl boronates have been reported to induce DNA interstrand cross-link (ICL) formation via carbocations upon photoirradiation. Herein, we synthesized a series of new bifunctional phenyl compounds to test the generality of such a mechanism, and to understand how the chemical structure influences carbocation formation and the DNA cross-linking process. These compounds efficiently form DNA ICLs via generated benzyl cations upon 350 nm irradiation. The DNA cross-linking efficiency and the pathway for carbocation generation depend on both the aromatic substituents and the leaving groups. Bromine as a leaving group facilitates the DNA cross-linking process in comparison with trimethyl ammonium salt. Both electron-donating and -withdrawing substituents induce bathochromic shifts, which favor photoinduced DNA ICL formation. For the bromides, the benzyl cation intermediates were generated through oxidation of the corresponding benzyl radicals. However, for the ammonia salts, the benzyl cations were formed through two pathways: either through oxidation of the benzyl radicals or by direct heterolysis of the C-N bond. Photoinduced C-N homolysis to form benzyl radicals occurred with compounds having donating substituents, whereas direct heterolysis of the C-N bond occurred with those bearing withdrawing substituents. The adducts formed between 1 a and four natural nucleosides were characterized, indicating that the alkylation sites for the photogenerated benzyl cations are dG, dA, and dC. PMID- 29479751 TI - AHS Members' Choice Award for the Best Headache Article. PMID- 29479752 TI - Plagiarism, Self-Plagiarism, and Text Recycling. PMID- 29479753 TI - Intrapartum ultrasound examination of fetal shoulder following head delivery. PMID- 29479755 TI - Fetoscopic laryngo-tracheoscopy: a novel diagnostic modality to avoid unnecessary ex-utero intrapartum treatment (EXIT) in cases with suspected fetal airway compromise. AB - Ex-utero intra-partum treatment (EXIT) is an effective intra-partum fetal procedure that was developed to reduce mortality and morbidity at the time of delivery, which involves neonatal tracheal intubation while fetal oxygenation is maintained by the uteroplacental circulation in a partial fetal delivery under maternal general anesthesia. We describe the use of a novel antepartum fetoscopic laryngo-tracheoscopic procedure prior the delivery to avoid complications associated with an unnecessary EXIT procedure in a case where the fetus had a large neck mass (hemangioma) compressing the trachea. PMID- 29479754 TI - Correlation between testicular mast cell count and spermatogenic epithelium in non-obstructive azoospermia. AB - Although there is emerging evidence that mast cells are involved in infertility, their exact role has not been elucidated clearly. Here we carried out a retrospective case-control study to find out whether there is a correlation between mast cell (MC) count and proliferation (Ki67 index) of the spermatogenic epithelium as well as of the Sertoli cells (vimentin-positive) in non-obstructive azoospermia (NOA). We assessed MCs, Ki67 and vimentin expression in Sertoli cells in testicular biopsies of germ cell aplasia (GCA, n = 14) and maturation arrest (MA, n = 14) vs. normal spermatogenesis (n = 14) cases. There was a significant decrease in the spermatogonial Ki67 index (1.25 +/- 0.91, 4.21 +/- 1.81 vs. 39.57 +/- 3.92) and Johnsen score (2.48 +/- 0.65, 4.89 +/- 1.05 vs. 9.75 +/- 0.30) as well as a significant increase (P < 0.001) in MC count (29.00 +/- 4.11, 7.57 +/- 1.95 vs. 3.00 +/- 1.30) in seminiferous tubules of infertile cases with GCA and MA vs. controls. On the other hand, the percentage of vimentin-expressing Sertoli cells was significantly decreased (P < 0.001) in biopsies of cases with MA (35.50 +/- 15.62) compared to those of cases with GCA and controls (72.64 +/- 10.67 and 98.57 +/- 1.45 respectively). Additionally, a significant negative correlation was detected between MC count and Ki67 index as well as Johnsen score in the MA group which became more significant in the GCA group. The significant increase in MC count in the GCA group and to a lesser extent in the MA group indicates their possible role in NOA particularly at the spermatogonial proliferation level and this is supported by the significant negative correlation with the Ki67 index. PMID- 29479756 TI - Synthesis of Engineered Zeolitic Materials: From Classical Zeolites to Hierarchical Core-Shell Materials. AB - The term "engineered zeolitic materials" refers to a class of materials with a rationally designed pore system and active-sites distribution. They are primarily made of crystalline microporous zeolites as the main building blocks, which can be accompanied by other secondary components to form composite materials. These materials are of potential importance in many industrial fields like catalysis or selective adsorption. Herein, critical aspects related to the synthesis and modification of such materials are discussed. The first section provides a short introduction on classical zeolite structures and properties, and their conventional synthesis methods. Then, the motivating rationale behind the growing demand for structural alteration of these zeolitic materials is discussed, with an emphasis on the ongoing struggles regarding mass-transfer issues. The state-of the-art techniques that are currently available for overcoming these hurdles are reviewed. Following this, the focus is set on core-shell composites as one of the promising pathways toward the creation of a new generation of highly versatile and efficient engineered zeolitic substances. The synthesis approaches developed thus far to make zeolitic core-shell materials and their analogues, yolk-shell, and hollow materials, are also examined and summarized. Finally, the last section concisely reviews the performance of novel core-shell, yolk-shell, and hollow zeolitic materials for some important industrial applications. PMID- 29479757 TI - A simple solid-phase extraction method for the analysis of red cell phospholipids by liquid chromatography- tandem mass spectrometry. AB - BACKGROUND: There has been increasing interest in the analysis of phospholipids in red blood cells as potential long-term biomarkers of different disease states. Here, we describe a simple method for the analysis of two phospholipids: 1 Palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanol (PE 16:0/18:1) and 1-Palmitoyl-2 linoleoyl-sn-glycero-3-phosphoethanol (PE 16:/0/18:2) in erythrocytes by liquid chromatography-tandem mass spectrometry (LC-MS/MS). METHODS: Whole blood samples were removed free of plasma and washed in isotonic saline. Red cells were lysed with ultrapure water. Lysate samples were processed using a hybrid solid-phase extraction (SPE) phospholipid cartridge (1 mL, 30 mg). Both PE 16:0/18:1 and PE 16:0/18:2 and their deuterated internal standards were separated on an ACE C4 (150 mm * 2.1 mm, 2.7 MUm particle size) by gradient elution at a flow rate of 0.5 mL per minute using mobile phases consisting of 0.01 mol/L ammonium acetate in: water (A), methanol (B), and isopropanol (C). The phospholipid species were quantified by the following transitions: PE 16:0/18:1: 701.5->281.3 and PE 16:0/18:2: 699.5->279.3. RESULTS: Both PE species displayed linearity ranging from 10 to 500 MUg/L. The coefficient of variation (CV%) of PE 16:0/18:1 concerning intraday and interday precision was between 1.9%-2.6% and 3.0%-4.3%, respectively. For PE 16:0/18:2, this was between 1.8%-3.4% and 3.7%-4.1%, respectively. Both phospholipid species had accuracy (PE 16:0/18:1: 91%-98% and PE 16:0/18:2: 94%-103%) and extraction recovery (PE 16:0/18:1: 95%-106% and PE 16:0/18:2: 92%-102%) exceeding 90% over the analytical range. The limit of detection was 5 MUg/L. CONCLUSION: Here we propose a simple SPE LC-MS/MS method for analyzing phospholipids in erythrocytes, which can be easily adopted. PMID- 29479758 TI - Commentary on 'Revisiting the 'paradigm shift' in opioid use: Developments and implications 10 years later'. PMID- 29479761 TI - Circadian cortisol dynamics across reproductive stages and in relation to breastfeeding in the Philippines. AB - OBJECTIVE: An increase in cortisol during human pregnancy helps coordinate the onset of parturition, and can have long-term effects on offspring biology. Maternal cortisol can also be transferred to offspring via breast milk during lactation. However, little is known about how diurnal cortisol profiles vary by trimester of pregnancy or during the postpartum period. Here, we describe diurnal cortisol profiles among a large cross-sectional sample of healthy Filipino young adult women varying in reproductive status and, during the postpartum period, in whether or not they are breastfeeding. METHODS: Salivary cortisol, anthropometric, and questionnaire data were obtained from participants in a birth cohort in metropolitan Cebu, Philippines (N = 741; age 20.8-22.4 years). Cortisol was assessed at waking, thirty minutes after waking (cortisol awakening response, CAR), and before bed. RESULTS: Compared with nulliparous women, morning cortisol was roughly 50% higher among women in late gestation, while evening cortisol was roughly 4-fold higher and the CAR was lower. Postpartum waking and evening cortisol were lower among currently breastfeeding women compared to nulliparous women, but were comparable in the absence of breastfeeding. The CAR was significantly lower among postpartum women compared to nulliparous women irrespective of breastfeeding status. CONCLUSIONS: These findings are consistent with known alterations in hypothalamic-pituitary-adrenal axis function during reproduction, and in particular point to marked and progressive elevation in maternal cortisol during the course of gestation. Cortisol appears to return to nulliparous levels after parturition, with levels suppressed below nulliparous levels during lactation. PMID- 29479760 TI - What nurses and midwives want: Findings from the national survey on workplace climate and well-being. AB - AIM: A discussion of the findings from a nationwide study of workplace and well being issues of Australian nurses and midwives. BACKGROUND: Current discourse only provides a fragmented understanding of a multifaceted nature of working conditions and well-being, necessitating a more holistic investigation to identify critical workplace issues within these professions. DESIGN: Discussion paper. DATA SOURCES: A national survey conducted in July 2016 involving Australian Nursing and Midwifery Federation members. The literature supporting this paper focuses on the nursing and midwifery workforce and studies on attraction and retention issues. IMPLICATIONS FOR NURSING AND MIDWIFERY: Workplace policies and practices in place in health care organizations that are within the control of management are key factors in the negative issues associated with the profession from the survey. Proactive and targeted interventions particularly aimed at salient issues of work intensification, declining engagement, and effective voice mechanisms are needed to address these crucial issues if the attrition of individuals from nursing and midwifery occupations is going to be ameliorated. CONCLUSION: To alleviate workforce issues pushing nurses and midwives to the tipping point of exiting the professions, health care organizations need to take a proactive stance in addressing issues under the control of management. PMID- 29479762 TI - Influence of pH and phosphate concentration on the phosphate binding capacity of five contemporary binders. An in vitro study. AB - AIM: Hyperphosphataemia is associated with increased mortality and morbidity in end stage renal disease. Despite phosphate binder therapy, a large proportion of patients do not reach the treatment target. In five contemporary binders we explored the influence of pH and phosphate concentration on phosphate binding. This interaction could be of relevance in clinical practice. METHODS: Phosphate binding was quantified in vitro in 25 mL of purified water containing phosphate concentrations of 10, 15 and 20 mM and baseline pH values of 3.0 or 6.0, with a binder over 6 h. Lanthanum carbonate, calcium acetate/magnesium carbonate, sevelamer carbonate, calcium carbonate and sucroferric oxyhydroxide, 67 mg of each, were used. The experiments were performed in duplicate. The primary outcome was the difference in the amount of bound phosphate for each binder after 6 h in solutions at two different pH values. Secondary outcomes were the influence of phosphate concentration on phosphate binding, next to binding patterns and phosphate binder saturation. RESULTS AND CONCLUSION: In this specific in vitro setting, lanthanum carbonate, sevelamer carbonate, calcium carbonate and sucroferric oxyhydroxide bound more phosphate in the solution with baseline pH of 3.0. Differences however were small except for lanthanum carbonate. Calcium acetate/magnesium carbonate was most effective in a solution with baseline pH of 6.0. All phosphate binders bound more phosphate in solutions with higher concentrations of phosphate. Sevelamer carbonate, calcium acetate/magnesium carbonate and sucroferric oxyhydroxide bound most phosphate in the first hour and reached maximum binding capacity in less than 6 h. PMID- 29479759 TI - Mild diabetes: long-term effects on gastric motility evaluated in rats. AB - Moderate hyperglycaemic levels seem to be related to abnormal gastric motility in diabetes mellitus. However, experimental models designed to evaluate the relationship between motility and diabetes over time are not yet well established. Our objective was to investigate the long-term effects of mild diabetes on gastric motility in rats. Newborn male rats received streptozotocin (mild diabetes groups - MD) or vehicle (control groups - C), and both groups were evaluated after 3 (C3 and MD3) and 6 months (C6 and MD6) postinduction. Mild diabetic animals (MD3 and MD6) showed moderately elevated blood glucose and decreased insulin levels compared with control (C3 and C6). Insulin secretion was enhanced in MD6 compared with MD3, most likely due to partial beta-cell regeneration indicated by HOMA-beta. In HOMA-IR, it was noticed that MD6 animals had impaired insulin response compared with MD3. Gastric emptying was faster, amplitude of contraction was stronger in MD6 compared with MD3, and in both groups, the differences were significant when compared with control animals. A significant abnormal rhythmic index was calculated for the mild diabetic groups, despite unchanged mean frequency of contraction. In conclusion, despite increased insulin levels over time, constant levels of moderate hyperglycaemia are also related to abnormal gastric motility and impairment of gastric function. PMID- 29479763 TI - Diagnostic accuracy of a clinical carotid plaque MR protocol using a neurovascular coil compared to a surface coil protocol. AB - BACKGROUND: Carotid plaque imaging with MRI is becoming more commonplace, but practical challenges exist in performing plaque imaging with surface coils. PURPOSE: To compare the diagnostic performance of a carotid plaque MRI protocol using a standard neurovascular coil (Neurovascular Coil Protocol) to a higher resolution carotid plaque MRI using carotid surface coils (Surface Coil Protocol) in characterizing carotid plaque. STUDY TYPE: Prospective study comparing two MR techniques in plaque characterization. POPULATION: Thirty-eight consecutive carotid artery disease patients. FIELD STRENGTH/SEQUENCE: Patients underwent 3T MRI using 1) a Neurovascular Coil Protocol including the following sequences: 3D FSE T1 pre/postcontrast and precontrast 3D IR-FSPGR, and 2) a Surface Coil Protocol using standard multicontrast MRI sequences. ASSESSMENT: Plaque characteristics analyzed by two independent neuroradiologists included intraplaque hemorrhage (IPH), lipid-rich necrotic-core (LRNC), and thin/ruptured fibrous cap (TRFC). STATISTICAL TESTS: Diagnostic performance of the Neurovascular Coil Protocol was compared to the Surface Coil Protocol reference standard using receiver-operating curves. RESULTS: For IPH, sensitivity, specificity, and area under the curve (AUC) of the Neurovascular Coil Protocol were 91.1% (95% confidence interval [CI] = 78.8-97.5%), 87.0% (95% CI = 66.4 97.2%), and 0.92, respectively. For LRNC without IPH sensitivity, specificity, and AUC were 73.3% (95% CI = 44.9-92.2%), 85.7% (95% CI = 67.3-96.0%), and 0.84, respectively. For TRFC, sensitivity, specificity, and AUC were 35.3% (95% CI = 14.2-61.7%), 97.6% (95% CI = 87.4-99.9%), and 0.66 respectively. Interobserver agreement for IPH, LRNC, and TRFC using the Neurovascular Coil Protocol were k = 0.87 (95% CI = 0.75-0.99), k = 0.54 (95% CI = 0.29-0.80), and k = 0.41 (95% CI = 0.08-0.74), respectively. DATA CONCLUSION: Our Neurovascular Coil Protocol has high sensitivity, specificity, and accuracy in identifying IPH and LRNC but is limited in assessment of TRFC. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1264-1272. PMID- 29479764 TI - How much can synthetic cannabinoid damage the heart? A case of cardiogenic shock following resistant ventricular fibrillation after synthetic cannabinoid use. AB - New substances are constantly being added to the content of synthetic cannabinoids (SCs). SCs can affect the cardiovascular system and cause hypotension and bradycardia, myocardial infarction, atrial fibrillation, prolonged QTc, and Mobitz type II atrioventricular block. However, no cases associated with ventricular fibrillation (VF) have been reported to date. We report a case of a 26-year-old male patient admitted to the emergency department due to altered consciousness after SC use and requiring prolonged cardiopulmonary resuscitation due to resistant VF and cardiogenic shock. PMID- 29479765 TI - A case series of lacosamide as adjunctive therapy in refractory sleep-related hypermotor epilepsy (previously nocturnal frontal lobe epilepsy). AB - The aim of this study was to evaluate the efficacy and tolerability of open-label lacosamide in patients with refractory sleep-related hypermotor epilepsy. The study was a case review of eight patients with refractory sleep-related hypermotor epilepsy treated with lacosamide. Seizure diaries compared the mean baseline seizure frequency with the most recent 3 months of follow-up. Five (62.5%) patients were responders, defined as >=50% reduction in seizure frequency, over a mean duration of exposure of 21.5 months. The mean maintenance dose of lacosamide was 400 mg/day. No-one reported worsening of seizures. Lacosamide was well tolerated with initial fatigue being the main side-effect. Lacosamide is a potentially efficacious adjunctive therapy in patients with refractory sleep-related hypermotor epilepsy. A double-blind placebo-controlled study would determine its efficacy. PMID- 29479766 TI - How do patients with cancer pain view community pharmacy services? An interview study. AB - Pain experienced by many patients with advanced cancer is often not well controlled and community pharmacists are potentially well placed to provide support. The study objective was to explore the views and experiences of patients with advanced cancer about community pharmacies, their services and attitudes towards having a community pharmacist pain medicines consultation. Purposive sampling of GP clinical information systems was used to recruit patients with advanced cancer, living in the community and receiving opioid analgesics in one area of England, UK between January 2015 and July 2016. Thirteen patients had a semi-structured interview which was audio-recorded and transcribed verbatim. Data were analysed deductively and inductively using Framework analysis and incorporating new themes as they emerged. The framework comprised Pain management, Experiences and expectations, Access to care and Communication. All patients reported using one regular community pharmacy citing convenience, service and staff friendliness as influential factors. The idea of a community pharmacy medicines consultation was acceptable to most patients. The idea of telephone consultations was positively received but electronic media such as Skype was not feasible or acceptable for most. Patients perceived a hierarchy of health professionals with specialist palliative care nurses at the top (due to their combined knowledge of their condition and medicines) followed by GPs then pharmacists. Patients receiving specialist palliative care described pain that was better controlled than those who were not. They thought medicines consultations with a pharmacist could be useful for patients before referral for palliative care. There is a need for pain medicines support for patients with advanced cancer, and unmet need appears greater for those not under the care of specialist services. Medicines consultations, in principle, are acceptable to patients both in person and by telephone, and the latter was perceived to be of particular benefit to patients less able to leave the house. PMID- 29479767 TI - Treating complicated grief and posttraumatic stress in homicidally bereaved individuals: A randomized controlled trial. AB - Homicidally bereaved individuals may experience symptoms of Complicated Grief (CG) and Posttraumatic Stress Disorder (PTSD). This Randomized Controlled Trial examined the effectiveness of an 8-session treatment encompassing Cognitive Behavioural Therapy (CBT) and Eye Movement Desensitization and Reprocessing (EMDR) to reduce self-rated CG and PTSD symptoms in 85 Dutch adult homicidally bereaved men and women. We compared changes in symptoms of CG (assessed using the Inventory of Complicated Grief) and PTSD (assessed using the Impact of Event Scale) between an intervention group and a waitlist control group. The treatment was effective in reducing CG and PTSD symptoms, from pretreatment to posttreatment. It can be concluded that EMDR and CBT seem promising treatments for homicidally bereaved individuals for both men and women, and regardless of the time since the loss. Further research is needed to examine whether a combined treatment of EMDR and CBT together is of added value in situations where grief and trauma are intertwined over offering only one of the two treatment modalities. PMID- 29479768 TI - Evening use of caffeine moderates the relationship between caffeine consumption and subjective sleep quality in students. AB - Caffeine is often used to reduce sleepiness; however, research suggests that it can also cause poor sleep quality. The timing of caffeine use, amongst other factors, is likely to be important for the effects it has on sleep quality. In addition, individual differences exist in the effect of caffeine on sleep quality. This cross-sectional study investigated the influence of the timing of caffeine consumption on and a possible moderating role of chronotype in the relationship between caffeine consumption and sleep quality in 880 students (74.9% female, mean age 21.3 years, SD = 3.1). Respondents filled in online questionnaires about chronotype (the Morningness-Eveningness Questionnaire), sleep quality (the Pittsburgh Sleep Quality Index) and caffeine consumption. Mean caffeine consumption was 624 mg per week, and 80.2% of the sample drank caffeine after 18:00 hours. Regression analyses demonstrated that higher total caffeine consumption was only related to poorer sleep quality for people who did not drink caffeine in the evening (beta = 0.209, p = .006). We did not find a relationship between caffeine and sleep quality in people who drank caffeine in the evening (beta = -0.053, p = .160). Furthermore, we found no evidence for a moderating role of chronotype in the relationship between caffeine consumption and sleep quality. We concluded that a self-regulating mechanism is likely to play a role, suggesting that students who know that caffeine negatively affects their sleep quality do not drink it in the evening. Caffeine sensitivity and the speed of caffeine metabolism may be confounding variables in our study. PMID- 29479769 TI - Gender Bias in the Management of Patients Still Exists. PMID- 29479770 TI - Applying nitrogen fertilizer increased anthocyanin in vegetative shoots but not in grain of purple rice genotypes. AB - BACKGROUND: Anthocyanin is a major antioxidant compound in purple rice, with properties that can protect against oxidative damage in some human diseases. This study was undertaken to determine if nitrogen (N) fertilizer can enhance anthocyanin and antioxidant levels in four purple Thai rice genotypes. RESULTS: The anthocyanin concentration and antioxidant capacity were increased in the shoots of N120 plants compared with plants without N. The leaves had higher anthocyanin concentration and antioxidant capacity than the stem+leaf sheath. Maximum shoot anthocyanin concentrations occurred at tillering and then declined by 87-94% at maturity. Antioxidant capacity was high at tillering and panicle initiation and declined by 26% in leaves and by 98% in the stem+leaf sheath at maturity. Unlike in the vegetative shoot, grain anthocyanin was not affected by the addition of N fertilizer. The response of grain antioxidant capacity to N fertilizer was affected by genotype, increasing in KPY by 45% but decreasing in K19959 by 30% in N120 plants. CONCLUSION: Applying N fertilizer could be a promising way to improve the antioxidative properties in vegetative parts for use in rice-grass juice, cosmetics and other products, especially the young leaves, which contained high values of anthocyanin as well as antioxidant capacity. However, further field studies should be undertaken to optimize N utilization for anthocyanin and antioxidant capacity in purple rice genotypes. (c) 2018 Society of Chemical Industry. PMID- 29479771 TI - Capacity to report on mortality attributable to chronic hepatitis B and C infections by Member States: An exercise to monitor progress towards viral hepatitis elimination. AB - Viral hepatitis is globally leading causes of death, and 96% of these are due to hepatitis B and C (HBV/HCV) late outcomes. The first Global Health Sector Strategy (GHSS) aims to reduce by 65% the mortality associated with HBV/HCV, and an indicator (C10) is proposed to monitor progress. Data on viral hepatitis and liver-related mortality are required, and different methods of estimation can be used, depending on availability and quality of sources. We aimed to understand the current situation and practicality of calculating C10, accessing available sources to estimate initial figure for Europe. We listed and compiled regional and national data sources reporting deaths from HCC, cirrhosis and chronic liver disease (CLD) and available estimates of attributable fraction. We critically appraised quality of data, highlighting gaps in current data and estimated mortality attributable to HBV and HCV, for 31 EU/EEA countries from 2010 to 2015. Mortality data are available for 30/31 countries. Quality varies but 60% of national sources report with specificity as required by WHO indicator. Attributable fraction is only available through the literature search. We estimated C10 for 87.6% country-years. Deaths attributable to HBV/HCV for this period and region were 292 600, while HCV deaths were three times higher. Incomplete data for 2015 prevented calculation of time trends. Regional sources are outdated for monitoring C10, but national sources are capable of reporting mortality data. Sources for attributable fraction are sparse, outdated and much needed. We recommend improvement of death registration allowing measuring this indicator. Studies measuring attributable fraction on national and subnational levels are crucial. PMID- 29479772 TI - Adaptation or recovery after health shocks? Evidence using subjective and objective health measures. AB - In this paper, we analyse the effect of an onset of a health shock on subjective survival probability and compare it with objective survival probability and self reported health measures. In particular, we are interested in whether expectations of people respond to health shocks and whether these follow the evolution of objective life expectations and self-reported health measures over time. Using longitudinal data from the Health and Retirement Study, we estimate fixed effects models of adaptation for the objective and subjective survival probabilities and for some self-reported health measures. The results show that after cancer diagnosis, conditional on surviving, both the objective and subjective longevity and self-reported health measures drift back to the before diagnosis trajectories. For stroke and heart attack, in spite of their persistent negative effect on survival, subjective life expectations and self-reported health measures seem to indicate only a transient effect of the health shock. The differences between the objective and subjective measures are in line with the concept of adaptation. We discuss the policy implications of our results. PMID- 29479773 TI - Mutual support groups for family caregivers of people with amyotrophic lateral sclerosis in Italy: A pilot study. AB - Family caregivers of people with amyotrophic lateral sclerosis (ALS) live stressful lives in which they spend most of their time caring for their loved ones and managing difficult situations, thereby reducing the time spent in taking care of themselves. This situation may last several years. Previous literature has widely highlighted that this situation reduces caregivers' quality of life and increases their psychological distress and risk of health problems, but there is a lack of studies that focus on psychological interventions for these situations. This qualitative study examined a pilot experience of two mutual support groups for family caregivers of people with ALS. The aim was to identify caregivers' needs, the prominent aspects of their experience, and to understand whether and how this intervention strategy might help them. Six partners (four men and two women) and six adult children (five women and one man) participated in the groups, which were conducted in northern Italy. After the support groups finished, participants underwent semi-structured interviews. The authors conducted a content analysis of the transcripts of the interviews and the 20 group sessions. The thematic areas identified were "caregiving," "being the son/daughter of a person with ALS," "being the partner of a person with ALS," "group experience" and "group evaluation." The caregiving experience was profoundly different depending on whether the caregiver was a son/daughter or a partner of a patient with ALS. Moreover, comparison with peers and mutual support helped participants to better cope with ALS and its consequences, to improve their care for their relatives and to overcome typical caregiver isolation. These results suggest the usefulness of involving communities in caregiver support in order to create new networks and activate personal and social resources for well being. PMID- 29479774 TI - Hematopoietic Stem Cell Transplantation in Late-Onset Krabbe Disease: No Evidence of Worsening Demyelination and Axonal Loss 4 Years Post-allograft. AB - BACKGROUND AND PURPOSE: Late-onset adult Krabbe disease is a very rare demyelinating leukodystrophy, affecting less than 1 in a million people. Hematopoietic stem cell transplantation (HSCT) strategies can stop the accumulation of toxic metabolites that damage myelin-producing cells. We used quantitative advanced imaging metrics to longitudinally assess the impact of HSCT on brain abnormalities in adult-onset Krabbe disease. METHODS: A 42-year-old female with late-onset Krabbe disease and an age/sex-matched healthy control underwent annual 3T MRI (baseline was immediately prior to HSCT for the Krabbe subject). Imaging included conventional scans, myelin water imaging, diffusion tensor imaging, and magnetic resonance spectroscopy. RESULTS: Brain abnormalities far beyond those visible on conventional imaging were detected, suggesting a global pathological process occurs in Krabbe disease with adult-onset etiology, with myelin being more affected than axons, and evidence of wide-spread gliosis. After HSCT, our patient showed clinical stability in all measures, as well as improvement in gait, dysarthria, and pseudobulbar affect at 7.5 years post transplant. No MRI evidence of worsening demyelination and axonal loss was observed up to 4 years post-allograft. CONCLUSIONS: Clinical evidence and stability of advanced MR measures related to myelin and axons supports HSCT as an effective treatment strategy for stopping progression associated with late-onset Krabbe disease. PMID- 29479775 TI - A case of shiitake mushroom dermatitis. PMID- 29479776 TI - Anaplastic variant of diffuse large B-cell lymphoma with hallmark cell appearance: Two cases highlighting a broad diversity in the diagnostics. AB - The anaplastic variant of diffuse large B-cell lymphoma (A-DLBCL) is morphologically defined but remains an enigmatic disease in its clinicopathologic distinctiveness. Here, we report two cases involving Japanese women aged 59 years, both with A-DLBCL with the hallmark cell appearance and both indistinguishable from common and giant cell-rich patterns, respectively, of anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma. Case 1 was immunohistochemically positive for CD20, CD79a and OCT-2 but not for the other pan-B-cell markers, CD30 and ALK. Case 2 showed CD20 and CD30 positivity for 50% and 20% of tumor cells in addition to strong expression of p53 and MYC. Both were positive for fascin without Epstein-Barr virus association. Our cases provide additional support for the earlier reports that A-DLBCL exhibits clinicopathologic features distinct from ordinal diffuse large B-cell lymphoma (DLBCL), and documented its broader morphologic diversity than previously recognized. They also shed light on the unique feature of absent expression of pan-B-cell markers except for CD20 and CD79a, suggesting that A-DLBCL may biologically mimic a gray zone or intermediate lymphoma between DLBCL and classic Hodgkin lymphoma. PMID- 29479777 TI - Patient satisfaction with prescribed medicines in community health services in China: A cross-sectional survey 6 years after the implementation of the national essential medicines policy. AB - The National essential medicines policy (NEMP) is promoted by the World Health Organization for affordable medicines that can meet the basic needs of communities. Patient acceptance is essential for achieving the policy goals of the NEMP. This study aimed to assess patient satisfaction with prescribed medicines in community health services under the NEMP context in China. A stratified random sampling strategy was adopted to select 1,037 participants in 40 community health centres from four provinces in China. Patient satisfaction was rated on a five-point Likert scale (from 1 = "very dissatisfied" to 5 = "very satisfied") covering four domains: availability, affordability, effectiveness and safety. The results showed that the participants expressed a moderate degree of satisfaction, with a rating in the range of 66-82 out of a total of 100. Older people, those covered by insurance and those with a lower level of education tended to have higher ratings. While eastern (wealthy) residents were more likely to be concerned with "effectiveness," western (poor) residents were more likely to be concerned with "affordability." Awareness of the NEMP was negatively associated with patient satisfaction after control for other factors. PMID- 29479778 TI - Australian general practitioner attitudes to residential aged care facility visiting. AB - Demographic trends suggest that the sustainability of the general practitioner (GP) Residential Aged Care Facility (RACF) workforce, worldwide and in Australia, is under threat, compromising the ongoing care of chronically ill RACF residents. It is therefore important to ascertain current GP attitudes towards this work, to better understand and hypothesise means of reversing this trend. To this end, during 2014 the views of 26 GPs and GP Registrars working in rural and regional New South Wales, Australia, were captured during focus group discussions and one on-one interviews. Analysis of the qualitative date revealed that GP attitudes towards RACF visiting fell into five key themes: pleasure, duty, remuneration and logistics, hesitation, and frustration. The data also revealed that the overriding emotion GPs felt about RACF visitation was frustration with the avoidable delays and inefficiencies associated with the work. Despite the pleasure GPs derived from their work in RACFs and their sense of obligation to be involved, their hesitation and frustration was compounded by the work's perceived poor remuneration. This research suggests that the barriers to GP participation in RACF visiting were managerial rather than attitudinal, and that a strategic focus upon improving administrative and logistical support is needed. PMID- 29479779 TI - Blocking amino acid transporter OsAAP3 improves grain yield by promoting outgrowth buds and increasing tiller number in rice. AB - Amino acid transporters (AATs) play indispensable roles in nutrient allocation during plant development. In this study, we demonstrated that inhibiting expression of the rice amino acid transporter OsAAP3 increased grain yield due to a formation of larger numbers of tillers as a result of increased bud outgrowth. Elevated expression of OsAAP3 in transgenic plants resulted in significantly higher amino acid concentrations of Lys, Arg, His, Asp, Ala, Gln, Gly, Thr and Tyr, and inhibited bud outgrowth and rice tillering. However, RNAi of OsAAP3 decreased significantly Arg, Lys, Asp and Thr concentrations to a small extent, and thus promoted bud outgrowth, increased significantly tiller numbers and effective panicle numbers per plant, and further enhanced significantly grain yield and nitrogen use efficiency (NUE). The promoter sequences of OsAAP3 showed some divergence between Japonica and Indica rice, and expression of the gene was higher in Japonica, which produced fewer tillers than Indica. We generated knockout lines of OsAAP3 on Japonica ZH11 and KY131 using CRISPR technology and found that grain yield could be increased significantly. These results suggest that manipulation of OsAAP3 expression could be used to increase grain yield in rice. PMID- 29479780 TI - Engineering rice with lower grain arsenic. AB - Arsenic (As) is a poisonous element that causes severe skin lesions and cancer in humans. Rice (Oryza sativa L.) is a major dietary source of As in humans who consume this cereal as a staple food. We hypothesized that increasing As vacuolar sequestration would inhibit its translocation into the grain and reduce the amount of As entering the food chain. We developed transgenic rice plants expressing two different vacuolar As sequestration genes, ScYCF1 and OsABCC1, under the control of the RCc3 promoter in the root cortical and internode phloem cells, along with a bacterial gamma-glutamylcysteine synthetase driven by the maize UBI promoter. The transgenic rice plants exhibited reduced root-to-shoot and internode-to-grain As translocation, resulting in a 70% reduction in As accumulation in the brown rice without jeopardizing agronomic traits. This technology could be used to reduce As intake, particularly in populations of South East Asia suffering from As toxicity and thereby improve human health. PMID- 29479781 TI - Efficient Synthesis of Light-Triggered Circular Antisense Oligonucleotides Targeting Cellular Protein Expression. AB - Light-activated ("caged") antisense oligonucleotides are powerful molecules for regulating gene expression at submicron spatial resolution through the focal modulation of endogenous cellular processes. Cyclized caged oligos are particularly promising structures because of their inherent stability and similarity to naturally occurring circular DNA and RNA molecules. Here, we introduce an efficient route for cyclizing an antisense oligodeoxynucleotide incorporating a photocleavable linker. Oligo cyclization was achieved for several sequences in nearly quantitative yields through intramolecular copper(I) catalyzed azide-alkyne cycloaddition (CuAAC). Caging stability and light activation were characterized by FRET efficiency, denaturing gel assay, and melting temperature measurements. Finally, a cyclized caged oligo was designed to target gfap, and it gave a tenfold reduction in glial fibrillary acidic protein upon photoactivation in astrocytes. PMID- 29479783 TI - Utilization of a Fluorescent Dye Molecule as a Proton and Electron Reservoir. AB - Fluorescent dyes have been widely utilized as chemical sensors and in photodynamic therapy, but exploitation of their redox-active nature in chemical reactions has remained mostly unexplored. This report describes the isolation of a 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY)-based radical. The redox active nature of the BODIPY compound can be utilized in combination with a guanidine center, the basicity of which can be manipulated by greater than 14 pKa units, to promote the conversion of protons and electrons into H-atoms for transfer to substrate molecules. PMID- 29479782 TI - Alkenylation of C(sp3 )-H Bonds by Zincation/Copper-Catalyzed Cross-Coupling with Iodonium Salts. AB - alpha-Vinylation of phosphonates, phosphine oxides, sulfones, sulfonamides, and sulfoxides has been achieved by selective C-H zincation and copper-catalyzed C(sp3 )-C(sp2 ) cross-coupling reaction using vinylphenyliodonium salts. The vinylation transformation proceeds in high efficiency and stereospecificity under mild reaction conditions. This zincative cross-coupling reaction represents a general alkenylation strategy, which is also applicable for alpha-alkenylation of esters, amides, and nitriles in the synthesis of beta,gamma-unsaturated carbonyl compounds. PMID- 29479784 TI - Palladium-Catalyzed Decarbonylative Trifluoromethylation of Acid Fluorides. AB - While acid fluorides can readily be made from widely available or biomass feedstock-derived carboxylic acids, their use as functional groups in metal catalyzed cross-coupling reactions is rare. This report presents the first demonstration of Pd-catalyzed decarbonylative functionalization of acid fluorides to yield trifluoromethyl arenes (ArCF3 ). The strategy relies on a Pd/Xantphos catalytic system and the supply of fluoride for transmetalation through intramolecular redistribution to the the Pd center. This strategy eliminated the need for exogenous and detrimental fluoride additives and allows Xantphos to be used in catalytic trifluoromethylations for the first time. Our experimental and computational mechanistic data support a sequence in which transmetalation by R3 SiCF3 occurs prior to decarbonylation. PMID- 29479786 TI - In vivo optical coherence tomography imaging in a case of mucous membrane pemphigoid and a negative Nikolsky's sign. AB - There is currently a growing interest in new diagnostic tools of the oral cavity and mucosa which are non-invasive, repeatable and reliable. A diagnosis of a suspected, autoimmune pathology was made regarding a 57-year-old patient with desquamative gingivitis. However, a negative Nikolsky's sign did not seem to indicate a diagnosis of mucous membrane pemphigoid neither was there any indication as to the optimum location for an incisional biopsy. As an imaging method, the use of optical coherence tomography (OCT) has enabled the obtaining of tomographic (cross-sectional) scans of tissue. Such images are acquired prior to and after verifying Nikolsky's sign, thereby enabling the clinician to identify the presence (or not) of subepithelial bullae. Thereafter, an assessment of changes in the subepithelium (the split) can be performed, even in the absence of a suitable clinical picture, such as, for example, a negative Nikolsky's sign. Histological analysis and the use of indirect immunofluorescence have facilitated a diagnosis of mucous membrane pemphigoid, an autoimmune pathology, which can be confirmed with the appearance of subepithelial bullae. OCT was found to be a valid, non-invasive, auxiliary diagnostic device, capable of revealing in vivo and real-time bullae, which were hitherto clinically undetectable. PMID- 29479785 TI - Training staff to promote self-management in people with intellectual disabilities. AB - BACKGROUND: People with intellectual disabilities have increasing difficulties managing their daily affairs. This study examined the effectiveness of a staff training, which teaches staff to promote self-management in people with intellectual disabilities. METHOD: Effectiveness was assessed with questionnaires addressing clients' (n = 26) independence and self-reliance, support needs and challenging behaviour, using a pre-posttest control group design. Additionally, focus groups were conducted with trained staff members 6 months after the training. RESULTS: In the long term, the intervention group showed a significant increase in independence and self-reliance, in contrast to the comparison group. No effect was found on support needs and challenging behaviour. Trained staff members reported limited benefits of the training, but had noticed changes in their attitude and method of working afterwards. CONCLUSIONS: Further self management research is required to investigate how independence and self-reliance can be promoted more effectively in this population. Future trainings should carefully consider their content, format, and implementation. PMID- 29479788 TI - The Large Second-Harmonic Generation of LiCs2 PO4 is caused by the Metal-Cation Centered Groups. AB - We evaluated the individual atom contributions to the second harmonic generation (SHG) coefficients of LiCs2 PO4 (LCPO) by introducing the partial response functionals on the basis of first principles calculations. The SHG response of LCPO is dominated by the metal-cation-centered groups CsO6 and LiO4 , not by the nonmetal-cation-centered groups PO4 expected from the existing models and theories. The SHG coefficients of LCPO are determined mainly by the occupied orbitals O 2p and Cs 5p as well as by the unoccupied orbitals Cs 5d and Li 2p. For the SHG response of a material, the polarizable atomic orbitals of the occupied and the unoccupied states are both important. PMID- 29479787 TI - Cardiometabolic risks and omega-3 index in recent-onset bipolar I disorder. AB - OBJECTIVES: The aims of the present study were to characterize cardiometabolic risk factors in a cohort of bipolar disorder patients with limited exposure to psychotropic medications, and to evaluate their associations with mood symptoms and omega-3 polyunsaturated fatty acid (PUFA) blood levels. METHODS: Cardiometabolic risk assessments were compared in individuals with bipolar I disorder experiencing a first manic or mixed episode or an early depressive episode (n=117) and healthy subjects (n=56). Patients were medication free at assessment and had no or limited exposure to mood-stabilizer or antipsychotic medications prior to the current admission. Associations among cardiometabolic parameters and Clinical Global Impression-Severity scale (CGI-S), manic (Young Mania Rating Scale [YMRS]), and depressive (Hamilton Depression Rating Scale [HDRS]) symptom ratings were evaluated within the bipolar group. RESULTS: Following adjustment for demographic variables (i.e., age, gender, and parental education), significantly higher fasting triglyceride levels were observed in the bipolar group compared to the healthy group (121.7 mg/dL vs 87.0 mg/dL; P<.01). There were no clear trends for other metabolic indicators, including blood pressure, body mass index, and fasting glucose. Nineteen percent of the bipolar group and 6% of the healthy group met the criteria for metabolic syndrome (P=.23). The omega-3 index was lower in the bipolar group (3.4% vs 3.9%; P<.01). Within the bipolar group, no associations were found between the cardiometabolic parameters and CGI-S, YMRS, and HDRS symptom ratings. CONCLUSIONS: Recent-onset medication-free bipolar disorder is associated with higher triglyceride levels. These findings are suggestive of early metabolic dysregulation prior to long-term psychotropic medication exposure. Lower omega-3 PUFA levels in individuals with bipolar I disorder represent a potential therapeutic target for additional investigation. PMID- 29479789 TI - Synthetic biology approach for plant protection using dsRNA. AB - Pathogens induce severe damages on cultivated plants and represent a serious threat to global food security. Emerging strategies for crop protection involve the external treatment of plants with double-stranded (ds)RNA to trigger RNA interference. However, applying this technology in greenhouses and fields depends on dsRNA quality, stability and efficient large-scale production. Using components of the bacteriophage phi6, we engineered a stable and accurate in vivo dsRNA production system in Pseudomonas syringae bacteria. Unlike other in vitro or in vivo dsRNA production systems that rely on DNA transcription and postsynthetic alignment of single-stranded RNA molecules, the phi6 system is based on the replication of dsRNA by an RNA-dependent RNA polymerase, thus allowing production of high-quality, long dsRNA molecules. The phi6 replication complex was reprogrammed to multiply dsRNA sequences homologous to tobacco mosaic virus (TMV) by replacing the coding regions within two of the three phi6 genome segments with TMV sequences and introduction of these constructs into P. syringae together with the third phi6 segment, which encodes the components of the phi6 replication complex. The stable production of TMV dsRNA was achieved by combining all the three phi6 genome segments and by maintaining the natural dsRNA sizes and sequence elements required for efficient replication and packaging of the segments. The produced TMV-derived dsRNAs inhibited TMV propagation when applied to infected Nicotiana benthamiana plants. The established dsRNA production system enables the broad application of dsRNA molecules as an efficient, highly flexible, nontransgenic and environmentally friendly approach for protecting crops against viruses and other pathogens. PMID- 29479791 TI - Identification of recombinant strains in HCV genotype 1 and 3: Is it needed? PMID- 29479790 TI - Managers' views of skilled support. AB - BACKGROUND: Quality of life of people with intellectual and developmental disabilities has been found to primarily depend on whether staff are providing facilitative and enabling support that helps to compensate for severity of disability. Managers have a key role in facilitating staff to provide such support. METHOD: Qualitative interviews were conducted with 35 managers of supported accommodation services to explore service aims and the nature of, and challenges in providing, skilled support. Key themes were identified using a Thematic Networks Analysis. RESULTS: Service aims were rarely formalised, were related to the individuals supported and not to the organisation. Managers found it difficult to define skilled support, other than by reference to individuals. Practice leadership roles were challenged as a result of austerity measures. CONCLUSIONS: Front-line managers need more information and training in skilled support, with stronger leadership from senior management to provide the motivation and resources needed. PMID- 29479792 TI - A Ligand System for the Flexible Functionalization of Quantum Dots via Click Chemistry. AB - We present a novel ligand, 5-norbornene-2-nonanoic acid, which can be directly added during established quantum dot (QD) syntheses in organic solvents to generate "clickable" QDs at a few hundred nmol scale. This ligand has a carboxyl group at one terminus to bind to the surface of QDs and a norbornene group at the opposite end that enables straightforward phase transfer of QDs into aqueous solutions via efficient norbornene/tetrazine click chemistry. Our ligand system removes the traditional ligand-exchange step and can produce water-soluble QDs with a high quantum yield and a small hydrodynamic diameter of approximately 12 nm at an order of magnitude higher scale than previous methods. We demonstrate the effectiveness of our approach by incubating azido-functionalized CdSe/CdS QDs with 4T1 cancer cells that are metabolically labeled with a dibenzocyclooctyne bearing unnatural sugar. The QDs exhibit high targeting efficiency and minimal nonspecific binding. PMID- 29479793 TI - Alternative splicing of OsLG3b controls grain length and yield in japonica rice. AB - Grain size, one of the important components determining grain yield in rice, is controlled by the multiple quantitative trait loci (QTLs). Intensive artificial selection for grain size during domestication is evidenced in modern cultivars compared to their wild relatives. Here, we report the molecular cloning and characterization of OsLG3b, a QTL for grain length in tropical japonica rice that encodes MADS-box transcription factor 1 (OsMADS1). Six SNPs in the OsLG3b region led to alternative splicing, which were associated with grain length in an association analysis of candidate region. Quantitative PCR analysis indicated that OsLG3b expression was higher during the panicle and seed development stages. Analysis of haplotypes and introgression regions revealed that the long-grain allele of OsLG3b might have arisen after domestication of tropical japonica and spread to subspecies indica or temperate japonica by natural crossing and artificial selection. OsLG3b is therefore a target of human selection for adaptation to tropical regions during domestication and/or improvement of rice. Phylogenetic analysis and pedigree records showed that OsLG3b had been employed by breeders, but the gene still has much breeding potential for increasing grain length in indica. These findings will not only aid efforts to elucidate the molecular basis of grain development and domestication, but also facilitate the genetic improvement of rice yield. PMID- 29479794 TI - Automated diagnosis of colon cancer using hyperspectral sensing. AB - BACKGROUND: Surgical management of colorectal cancer relies on accurate identification of tumor and possible metastatic disease. Hyperspectral (HS) sensing is a passive, non-ionizing diagnostic method that has been considered for multiple tumor types. The ability to use HS for identification of tumor specimens during surgical resection of colorectal cancers was explored. METHODS: Patients with colorectal cancer who underwent operative resection were enrolled. HS measurements were performed both intra- and extra-luminally. Spectral results were correlated with pathologic evaluation. RESULTS: Fifteen patient specimens were analyzed. For patients with confirmed colorectal cancer, extraluminal spectra analysis yielded 61.68% sensitivity with 90% specificity. For intraluminal specimens, sensitivity increased to 91.97% with 90% specificity. CONCLUSIONS: Hyperspectral sensing can reliably detect tumors in resected colon specimens. This research offers promising results for a diagnostic technology that is non-ionizing and does not require the use of contrast agents to achieve accurate colorectal cancer detection. PMID- 29479795 TI - The biology of extracellular microvesicles. AB - The study of extracellular vesicles (EVs) is a rapidly evolving field, owing in large part to recent advances in the realization of their significant contributions to normal physiology and disease. Once discredited as cell debris, these membrane vesicles have now emerged as mediators of intercellular communication by interaction with target cells, drug and gene delivery, and as potentially versatile platforms of clinical biomarkers as a result of their distinctive protein, nucleic acid and lipid cargoes. While there are multiple classes of EVs released from almost all cell types, here we focus primarily on the biogenesis, fate and functional cargoes of microvesicles (MVs). MVs regulate many important cellular processes including facilitating cell invasion, cell growth, evasion of immune response, stimulating angiogenesis, drug resistance and many others. PMID- 29479796 TI - Authors' reply re: Clinical interventions to reduce stillbirths in sub-Saharan Africa: a mathematical model to estimate the potential reduction of stillbirths associated with specific obstetric conditions. PMID- 29479797 TI - Re: Clinical interventions to reduce stillbirths in sub-Saharan Africa: a mathematical model to estimate the potential reduction of stillbirths associated with specific obstetric conditions: Nuchal cord and stillbirths: true or false myth? PMID- 29479798 TI - Hydrophilicity Regulates the Stealth Properties of Polyphosphoester-Coated Nanocarriers. AB - Increasing the plasma half-life is an important goal in the development of drug carriers, and can be effectively achieved through the attachment of polymers, in particular poly(ethylene glycol) (PEG). While the increased plasma half-life has been suggested to be a result of decreased overall protein adsorption on the hydrophilic surface in combination with the adsorption of specific proteins, the molecular reasons for the success of PEG and other hydrophilic polymers are still widely unknown. We prepared polyphosphoester-coated nanocarriers with defined hydrophilicity to control the stealth properties of the polymer shell. We found that the log P value of the copolymer controls the composition of the protein corona and the cell interaction. Upon a significant change in hydrophilicity, the overall amount of blood proteins adsorbed on the nanocarrier remained unchanged, while the protein composition varied. This result underlines the importance of the protein type for the protein corona and cellular uptake. PMID- 29479799 TI - Targeted Gastrointestinal Delivery of Nutraceuticals with Polysaccharide-Based Coatings. AB - Oral delivery is one of the facile methods for the administration of active ingredients (AIs) like nutraceuticals and drugs. However, its intrinsic disadvantages include poor absorption and bioavailability, degradation of the AI during transit through the gastrointestinal tract (GIT), and a lack of action specificity. Hence, a delivery system for targeted gastrointestinal delivery of AI using polysaccharide-based polymers, that are generally recognized as safe and approved for use as a direct food additive, is proposed. In this regard, mucoadhesive chitosan nanoparticles that could adhere to the mucosa of the GIT are fabricated and encapsulated with AI. These particles are subsequently coated with polysaccharides that have different enzymatic susceptibilities, to allow for specific degradation in the small or large intestines. It is observed that the polysaccharide coating efficiently retarded the nonspecific release of the encapsulated agent until it is exposed to its intended environment of release. The cytotoxicity and uptake of chitosan nanoparticles is further evaluated on Caco2 cells. In conclusion, these polysaccharide-coated nanoparticles can potentially be targeted to different organs in the GIT and to be taken up by the enterocytes for improved oral bioavailability. PMID- 29479801 TI - Electric Power Generation through the Direct Interaction of Pristine Graphene Oxide with Water Molecules. AB - Converting ubiquitous environmental energy into electric power holds tremendous social and financial interests. Traditional energy harvesters and converters are limited by the specific materials and complex configuration of devices. Herein, it is presented that electric power can be directly produced from pristine graphene oxide (GO) without any pretreatment or additives once encountering the water vapor, which will generate an open-circuit-voltage of up to 0.4-0.7 V and a short-circuit-current-density of 2-25 uA cm-2 on a single piece of GO film. This phenomenon results from the directional movement of charged hydrogen ions through the GO film. The present work demonstrates and provides an extremely simple method for electric energy generation, which offers more applications of graphene based materials in green energy converting field. PMID- 29479800 TI - An oligosaccharyltransferase from Leishmania major increases the N-glycan occupancy on recombinant glycoproteins produced in Nicotiana benthamiana. AB - N-glycosylation is critical for recombinant glycoprotein production as it influences the heterogeneity of products and affects their biological function. In most eukaryotes, the oligosaccharyltransferase is the central-protein complex facilitating the N-glycosylation of proteins in the lumen of the endoplasmic reticulum (ER). Not all potential N-glycosylation sites are recognized in vivo and the site occupancy can vary in different expression systems, resulting in underglycosylation of recombinant glycoproteins. To overcome this limitation in plants, we expressed LmSTT3D, a single-subunit oligosaccharyltransferase from the protozoan Leishmania major transiently in Nicotiana benthamiana, a well established production platform for recombinant proteins. A fluorescent protein tagged LmSTT3D variant was predominately found in the ER and co-located with plant oligosaccharyltransferase subunits. Co-expression of LmSTT3D with immunoglobulins and other recombinant human glycoproteins resulted in a substantially increased N-glycosylation site occupancy on all N-glycosylation sites except those that were already more than 90% occupied. Our results show that the heterologous expression of LmSTT3D is a versatile tool to increase N glycosylation efficiency in plants. PMID- 29479802 TI - 3D Printed Surgical Simulation Models as educational tool by maxillofacial surgeons. AB - INTRODUCTION: The aim of this study was to evaluate whether inexpensive 3D models can be suitable to train surgical skills to dental students or oral and maxillofacial surgery residents. Furthermore, we wanted to know which of the most common filament materials, acrylonitrile butadiene styrene (ABS) or polylactic acid (PLA), can better simulate human bone according to surgeons' subjective perceptions. MATERIALS AND METHODS: Upper and lower jaw models were produced with common 3D desktop printers, ABS and PLA filament and silicon rubber for soft tissue simulation. Those models were given to 10 blinded, experienced maxillofacial surgeons to perform sinus lift and wisdom teeth extraction. Evaluation was made using a questionnaire. RESULTS: Because of slightly different density and filament prices, each silicon-covered model costs between 1.40-1.60 USD (ABS) and 1.80-2.00 USD (PLA) based on 2017 material costs. Ten experienced raters took part in the study. All raters deemed the models suitable for surgical education. No significant differences between ABS and PLA were found, with both having distinct advantages. CONCLUSION: The study demonstrated that 3D printing with inexpensive printing filaments is a promising method for training oral and maxillofacial surgery residents or dental students in selected surgical procedures. With a simple and cost-efficient manufacturing process, models of actual patient cases can be produced on a small scale, simulating many kinds of surgical procedures. PMID- 29479803 TI - A 0.2 V Micro-Electromechanical Switch Enabled by a Phase Transition. AB - Micro-electromechanical (MEM) switches, with advantages such as quasi-zero leakage current, emerge as attractive candidates for overcoming the physical limits of complementary metal-oxide semiconductor (CMOS) devices. To practically integrate MEM switches into CMOS circuits, two major challenges must be addressed: sub 1 V operating voltage to match the voltage levels in current circuit systems and being able to deliver at least millions of operating cycles. However, existing sub 1 V mechanical switches are mostly subject to significant body bias and/or limited lifetimes, thus failing to meet both limitations simultaneously. Here 0.2 V MEM switching devices with ?106 safe operating cycles in ambient air are reported, which achieve the lowest operating voltage in mechanical switches without body bias reported to date. The ultralow operating voltage is mainly enabled by the abrupt phase transition of nanolayered vanadium dioxide (VO2 ) slightly above room temperature. The phase-transition MEM switches open possibilities for sub 1 V hybrid integrated devices/circuits/systems, as well as ultralow power consumption sensors for Internet of Things applications. PMID- 29479804 TI - COMP report: CPQR technical quality control guidelines for radiation treatment centers. AB - The Canadian Organization of Medical Physicists (COMP), in close partnership with the Canadian Partnership for Quality Radiotherapy (CPQR) has developed a series of Technical Quality Control (TQC) guidelines for radiation treatment equipment. These guidelines outline the performance objectives that equipment should meet in order to ensure an acceptable level of radiation treatment quality. The TQC guidelines have been rigorously reviewed and field tested in a variety of Canadian radiation treatment facilities. The development process enables rapid review and update to keep the guidelines current with changes in technology. This announcement provides an introduction to the guidelines, describing their scope and how they should be interpreted. Details of recommended tests can be found in separate, equipment specific TQC guidelines published in the JACMP (COMP Reports), or the website of the Canadian Partnership for Quality Radiotherapy (www.cpqr.ca). PMID- 29479806 TI - In vivo evaluation of beta-CS/n-HA with different physical properties as a new bone graft material. AB - BACKGROUND: Natural polymer composite materials are becoming increasingly important as scaffolds for bone tissue engineering. Composite materials based on combinations of biodegradable polymers and bioactive ceramics, including CTS and Hap. PURPOSE: beta-Chitosan/n-HA composite with different percentages was prepared. Some of the physical and mechanical properties were examined by using (scanning electron microscope and transmission electron microscope). Histological evaluation of in vivo implantation of beta-Chitosan/n-HA composite as bone graft material was done. MATERIAL AND METHODS: beta-type chitosan was obtained through a modified procedure from squid pens (Loligo vulgaris). It was used in combination with different proportions of nano-hydroxyapatite (n-HA), to develop new series of beta-CS/n-HA nanocomposites. Sample were obtained in a powder form with the ratio of 30 CH to 70% nHA. The product was implanted in the femoral condyle of the animals (adult rabbits). RESULTS: Compact strength was 13.05 MPa for the weight ratio of 30/70. Histological examinations showed that the implant not only biological compatible but also its presence promotes and accelerate bone growth. CONCLUSIONS: The composite beta-CS/HPa (30/70) as biodegradable bone substitute that not only enhance bone generation but also accelerate the formation of Haversian system. We used the composite in a powder form and examined its suitability as artificial bone graft; yet the mechanical properties have shown that 30/70 ratio of beta-CS/HPa offer suitable mechanical strength to be employed as a solid-shaped implants. PMID- 29479805 TI - Three New Indole Diketopiperazine Alkaloids from Aspergillus ochraceus. AB - Asperochramides A - D (1 - 4), a new natural product and three new indole diketopiperazine alkaloids, along with seven known analogs (5 - 11), were isolated from the ethyl acetate extract of Aspergillus ochraceus. Their structures were elucidated by extensive spectroscopic analyses, ECD calculation, and single-crystal X-ray diffraction analysis. Compounds 3 and 4 represent a rare group of indole diketopiperazine alkaloid with a 3-hydroxyl-2-indolone moiety. The in vitro anti-inflammatory effects of compounds 1 and 3 - 11 were investigated by using LPS-stimulated murine macrophage RAW 264.7 cells. Compounds 1, 8, 10, and 11 showed potential anti-inflammatory activities. PMID- 29479807 TI - The effect of 7,8,4'-trihydroxyflavone on tyrosinase activity and conformation: Spectroscopy and docking studies. AB - Tyrosinase is a ubiquitous enzyme that plays an essential role in the production of melanin. Effective inhibitors of tyrosinase have extensive applications in the medical, cosmetic and food industries. In this study, a combination of enzyme kinetics, ultraviolet (UV)-visible absorption, fluorescence spectroscopic techniques and a computational simulation method was used to characterize the inhibitory mechanism of 7,8,4'-trihydroxyflavone on tyrosinase. 7,8,4' Trihydroxyflavone was found to strongly inhibit the oxidation of l-DOPA by tyrosinase with an IC50 value of 10.31 +/- 0.41 MUM. The inhibitory mechanism was determined to be reversible and non-competitive with a Ki of 9.50 +/- 0.40 MUM. The UV absorption spectra showed that 7,8,4'-trihydroxyflavone could chelate with copper ions and form a complex with tyrosinase. The intrinsic fluorescence of tyrosinase was quenched by 7,8,4'-trihydroxyflavone through a static quenching mechanism. 7,8,4'-Trihydroxyflavone was found to occupy a single binding site with a binding constant of 7.50 +/- 1.20 * 104 M-1 at 298 K. The conformation of tyrosinase changed, and the microenvironment became more hydrophilic after 7,8,4' trihydroxyflavone binding. Thermodynamics parameters indicated that the binding was a spontaneous process and involved hydrogen bonds and van der Waals forces. The binding distance was evaluated to be 4.54 +/- 0.05 nm. Docking simulation analysis further authenticated that 7,8,4'-trihydroxyflavone could form hydrogen bonds with the residues His244 and Met280 within the tyrosinase active site. Our results will contribute to further understanding of the inhibitory mechanisms of 7,8,4'-trihydroxyflavone against tyrosinase and will facilitate future screening for tyrosinase inhibitors. PMID- 29479808 TI - 2-Alkyl-3-methoxypyrazines are potent attractants of florivorous scarabs (Melolonthidae, Cyclocephalini) associated with economically exploitable Neotropical palms (Arecaceae). AB - BACKGROUND: 2-Alkyl-3-methoxypyrazines (MPs) are naturally occurring aromatic compounds involved in insect chemical communication as both pheromones and allelochemicals. Although rarely characterized in floral scents, they have been identified as major constituents in headspace samples from palm inflorescences and evidence pointed towards their function as attractive cues for scent-oriented pollinators, as well as florivores. In this study, we investigated the occurrence of MPs in economically exploitable palms belonging to Acrocomia and Attalea through headspace floral scent analysis and assessed their role in the selective attraction of flower-feeding cyclocephaline scarabs (Melolonthidae, Cyclocephalini) in field bioassays conducted in Brazil and Colombia. RESULTS: Three different MPs were identified among floral headspace samples of Acrocomia aculeata, Acr. intumescens, Attalea butyracea and Att. insignis: 2-isopropyl-3 methoxypyrazine (IPMP), 2-isobutyl-3-methoxypyrazine (IBMP) and 2-(sec-butyl)-3 methoxypyrazine (SBMP). Their combined estimated total scent emissions per inflorescence ranged from 246 MUg h-1 to 6.2 mg h-1 . Scented traps, individually baited with either IPMP or SBMP, resulted in species-selective and high yield captures of Cyclocephala amazona and C. distincta, known florivores associated with over 20 different species of Neotropical palms. CONCLUSIONS: The identification of MPs as potent kairomones could prove instrumental in integrated pest management plans for these insects in emerging oil-yielding crops in South America, including those of the wine palm (Att. butyracea) and macaw palms (Acrocomia spp.). (c) 2018 Society of Chemical Industry. PMID- 29479809 TI - Authors' reply re: Subsequent reproductive outcome among women with peripartum cardiomyopathy: a nationwide study. PMID- 29479810 TI - A Monolithic Force-Sensitive 3D Microgripper Fabricated on the Tip of an Optical Fiber Using 2-Photon Polymerization. AB - Microscale robotic devices have myriad potential applications including drug delivery, biosensing, cell manipulation, and microsurgery. In this work, a tethered, 3D, compliant grasper with an integrated force sensor is presented, the entirety of which is fabricated on the tip of an optical fiber in a single-step process using 2-photon polymerization. This gripper can prove useful for the interrogation of biological microstructures such as alveoli, villi, or even individual cells. The position of the passively actuated grasper is controlled via micromanipulation of the optical fiber, and the microrobotic device measures approximately 100 um in length and breadth. The force estimation is achieved using optical interferometry: high-dimensional spectral readings are used to train artificial neural networks to predict the axial force exerted on/by the gripper. The design, characterization, and testing of the grasper are described and its real-time force-sensing capability with an accuracy below 2.7% of the maximum calibrated force is demonstrated. PMID- 29479811 TI - Bioresponsive Microneedles with a Sheath Structure for H2 O2 and pH Cascade Triggered Insulin Delivery. AB - Self-regulating glucose-responsive insulin delivery systems have great potential to improve clinical outcomes and quality of life among patients with diabetes. Herein, an H2 O2 -labile and positively charged amphiphilic diblock copolymer is synthesized, which is subsequently used to form nano-sized complex micelles (NCs) with insulin and glucose oxidase of pH-tunable negative charges. Both NCs are loaded into the crosslinked core of a microneedle array patch for transcutaneous delivery. The microneedle core is additionally coated with a thin sheath structure embedding H2 O2 -scavenging enzyme to mitigate the injury of H2 O2 toward normal tissues. The resulting microneedle patch can release insulin with rapid responsiveness under hyperglycemic conditions owing to an oxidative and acidic environment because of glucose oxidation, and can therefore effectively regulate blood glucose levels within a normal range on a chemically induced type 1 diabetic mouse model with enhanced biocompatibility. PMID- 29479812 TI - Rare LPL gene missense mutation in an infant with hypertriglyceridemia. AB - BACKGROUND: Severe hypertriglyceridemia usually results from a combination of genetic and environmental factors and is most often attributable to mutations in the lipoprotein lipase (LPL) gene. OBJECTIVES: The aim of this study was to identify rare mutations in the LPL gene causing severe hypertriglyceridemia. METHODS: A Chinese infant who presented classical features of severe hypertriglyceridemia recruited for DNA sequencing of the LPL gene. The pathogenicity grade of the variants was defined based on the prediction of pathogenicity using in silico prediction tools. Review some studies to understand the molecular mechanisms underlying the severe hypertriglyceridemia. RESULTS: We identified a rare mutation in the LPL gene causing severe hypertriglyceridemia: a nucleotide substitution (c.836T>G) resulting in a leucine to arginine substitution at position 279 of the protein (p.Leu279Arg).The pathogenicity of the variant was predicted by in silico analysis using PolyPhen2 and SIFT prediction programs, which indicated that mutation p.Leu279Arg is probably harmful. We have also reviewed published studies concerning the molecular mechanisms underlying severe hypertriglyceridemia. A missense mutation in the 6 exon of the LPL gene is reportedly associated with LPL deficiency. CONCLUSIONS: We have here identified a rare pathogenic mutation in the LPL gene in a Chinese infant with severe hypertriglyceridemia. PMID- 29479813 TI - Sudden infant death and sleep practices in the Black community. AB - PURPOSE: A Black infant dies every 13 hours in the state of Indiana. The overall infant mortality rate in 2013 was 7.2 deaths per 1000 live births, but for Black infants, the rate was 15.3 deaths per 1000 live births. For over 20 years, placing an infant to sleep on his back has decreased the death rate from sudden unexpected infant death (SUID) and sudden infant death syndrome (SIDS), but many Black families continue to advocate bed sharing, prone sleeping, and inappropriate bedding/sleep surfaces, predisposing an infant to a significantly higher risk for SUID/SIDS. Therefore, the purpose of this study is to understand why Black women are less likely than White women to follow safe sleep recommendations for their infants. DESIGN: A rigorous search of the literature was performed by searching the Web of Science, OVID, CINAHL, PsychINFO, and PubMed using the search terms: infant or child, death, loss, SIDS, SUID, qualitative, African American, Black, culture, safe sleep, experiences, and United States. A total of 217 articles were obtained. After review of inclusion and exclusion criteria and critical appraisal, only seven articles remained for the research study. METHODS: The meta-synthesis of these seven original qualitative studies was performed using the Qualitative Assessment and Review Instrument from the Joanna Briggs Institute to assist with data management. Data were extracted and representative quotations were categorized. Categories were arranged into like themes. Themes were then synthesized with meta-aggregation. RESULTS: A total of 17 subthemes were identified and were formulated into three primary themes: convenience, safety, and culture. The final synthesized theme was that Black mothers are motivated by their beliefs. PRACTICE IMPLICATIONS: Black mothers tend to believe that SUIDS/SIDS is a random occurrence and is not preventable, so they see a little reason to make their infant sleep in a cold, hard crib, when they could sleep in a warm, comfortable bed with them. Nurses should work with Black mothers to understand their cultural beliefs while educating them about safe sleep practices. PMID- 29479814 TI - Unravelling the Elusive Antiferromagnetic Order in Wurtzite and Zinc Blende CoO Polymorph Nanoparticles. AB - Although cubic rock salt-CoO has been extensively studied, the magnetic properties of the main nanoscale CoO polymorphs (hexagonal wurtzite and cubic zinc blende structures) are rather poorly understood. Here, a detailed magnetic and neutron diffraction study on zinc blende and wurtzite CoO nanoparticles is presented. The zinc blende-CoO phase is antiferromagnetic with a 3rd type structure in a face-centered cubic lattice and a Neel temperature of TN (zinc blende) ~225 K. Wurtzite-CoO also presents an antiferromagnetic order, TN (wurtzite) ~109 K, although much more complex, with a 2nd type order along the c axis but an incommensurate order along the y-axis. Importantly, the overall magnetic properties are overwhelmed by the uncompensated spins, which confer the system a ferromagnetic-like behavior even at room temperature. PMID- 29479815 TI - Fatty Acid/Phospholipid Blended Membranes: A Potential Intermediate State in Protocellular Evolution. AB - Prior to the evolution of membrane proteins, intrinsic membrane stability and permeability to polar solutes are essential features of a primitive cell membrane. These features are difficult to achieve simultaneously in model protocells made of either pure fatty acid or phospholipid membranes, raising the intriguing question of how the transition from fatty acid to phospholipid membranes might have occurred while continuously supporting encapsulated reactions required for genomic replication. Here, the properties of a blended membrane system composed of both oleic acid (OA), a monoacyl fatty acid, and 1 palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), a diacyl phospholipid are described. This hybrid vesicle system exhibits high stability to divalent cations (Mg2+ ), while simultaneously maintaining its permeability to small charged molecules such as nucleotides and divalent ions such as Mg2+ . This combination of features facilitates key reactions expected to occur during a transition from primitive to modern cells, including nonenzymatic RNA replication, and is also compatible with highly evolved functions such as the ribosomal translation of a protein. The observations support the hypothesis that the early transition from fatty acid to phospholipid membranes could be accomplished through intermediate states in which membranes are composed of amphiphile mixtures, and do not require protein transporters. PMID- 29479816 TI - PARP inhibitor olaparib sensitizes cholangiocarcinoma cells to radiation. AB - Cholangiocarcinoma (CCA) is a highly malignant tumor with resistance to radiotherapy alone. Olaparib, a highly potent poly(ADP-ribose) polymerase (PARP) inhibitor, has been shown to sensitize many types of tumor to radiotherapy. However, the effect of olaparib, either as monotherapy or as combination therapy with radiotherapy, on CCA is not known, and our study aimed to explore this. To assess radiosensitization in three CCA cell lines (QBC939, HuH28 and TFK-1), viability and clonogenic assays were conducted. The absorbed radiation doses were 0 Gy, 2 Gy, 4 Gy, and 6 Gy; olaparib concentrations were 0 nmol/L, 1 nmol/L, 10 nmol/L, 100 nmol/L, 1000 nmol/L, 2500 nmol/L, 5000 nmol/L and 10 000 nmol/L. The mechanism of olaparib radiosensitization was explored by Western blotting. Immunofluorescence staining and flow cytometry were conducted to explore DNA damage and apoptosis. The radiosensitivity of CCA cells was enhanced by olaparib, which alone had little effect on the CCA cell lines without BRCA mutations. The degree of radiosensitization increased with increasing doses of olaparib by viability and clonogenic assays in vitro. Olaparib was able to enhance the effect of radiation by inhibiting PARP1, inducing DNA lesions and apoptosis. These findings emphasize the role of olaparib in the radiosensitization of CCA cells. PMID- 29479817 TI - Mechanisms of glyphosate resistance and response to alternative herbicide-based management in populations of the three Conyza species introduced in southern Spain. AB - BACKGROUND: In perennial crops, the most common method of weed control is to spray herbicides, and glyphosate has long been the first choice of farmers. Three species of the genus Conyza are among the most problematic weeds for farmers, exhibiting resistance to glyphosate. The objectives of this study were to evaluate resistance levels and mechanisms, and to test chemical control alternatives in putative resistant (R) populations of Conyza bonariensis, Conyza canadensis and Conyza sumatrensis. RESULTS: Plants from the three R populations of Conyza spp. survived high doses of glyphosate compared with plants from susceptible (S) populations. The rate of movement of 14 C glyphosate out of treated leaves in plants from S populations was higher than in plants from R populations. Only plants from the R population of C. sumatrensis contained the known target site 5-enolpyruvylshikimate-3-phosphate synthase mutation Pro106 Thr. Field responses to the different alternative herbicide treatments tested indicated injury and high effectiveness in most cases. CONCLUSIONS: The results indicate that non-target site resistant (NTSR) mechanisms explain resistance in C. bonariensis and C. canadensis, whereas both NTSR and target site resistant (TSR) mechanisms contribute to resistance in C. sumatrensis. The results obtained in the field trials suggest that the resistance problem can be solved through integrated weed management. (c) 2018 Society of Chemical Industry. PMID- 29479818 TI - Complementary role of MRI and positron emission tomography in diagnosing cerebral abscess in a patient with metastatic paraganglioma. AB - Technological advances have increased the ability of imaging to provide an accurate preoperative diagnosis of an intracranial mass. We present the case of a patient with metastatic paraganglioma, who presented with headache and depressed conscious state. We had chronic tachycardia and low-grade fevers due to increased catecholamine secretion, which limited his clinical assessment. The combination of novel positron emission tomography tracers and advanced magnetic resonance imaging techniques was able to provide a confident preoperative diagnosis of a pyogenic intracranial abscess, which was not suspected clinically. This allowed appropriate therapy to be instituted until the patient's clinical state improved sufficiently for neurosurgery to be performed. PMID- 29479819 TI - Prognostic factors in breast phyllodes tumors: a nomogram based on a retrospective cohort study of 404 patients. AB - The aim of this study was to explore the independent prognostic factors related to postoperative recurrence-free survival (RFS) in patients with breast phyllodes tumors (PTBs). A retrospective analysis was conducted in Fudan University Shanghai Cancer Center. According to histological type, patients with benign PTBs were classified as a low-risk group, while borderline and malignant PTBs were classified as a high-risk group. The Cox regression model was adopted to identify factors affecting postoperative RFS in the two groups, and a nomogram was generated to predict recurrence-free survival at 1, 3, and 5 years. Among the 404 patients, 168 (41.6%) patients had benign PTB, 184 (45.5%) had borderline PTB, and 52 (12.9%) had malignant PTB. Fifty-five patients experienced postoperative local recurrence, including six benign cases, 26 borderline cases, and 22 malignant cases; the three histological types of PTB had local recurrence rates of 3.6%, 14.1%, and 42.3%, respectively. Stromal cell atypia was an independent prognostic factor for RFS in the low-risk group, while the surgical approach and tumor border were independent prognostic factors for RFS in the high-risk group, and patients receiving simple excision with an infiltrative tumor border had a higher recurrence rate. A nomogram developed based on clinicopathologic features and surgical approaches could predict recurrence-free survival at 1, 3, and 5 years. For high-risk patients, this predictive nomogram based on tumor border, tumor residue, mitotic activity, degree of stromal cell hyperplasia, and atypia can be applied for patient counseling and clinical management. The efficacy of adjuvant radiotherapy remains uncertain. PMID- 29479820 TI - Erythrocyte-Derived Nanoparticles as a Theranostic Agent for Near-Infrared Fluorescence Imaging and Thrombolysis of Blood Clots. AB - Ischemic stroke occurs when a blood clot obstructs or narrows the arteries that supply blood to the brain. Currently, tissue plasminogen activator (tPA), a thrombolytic agent, is the only United States Food and Drug Administration (FDA) approved pharmacologic treatment for ischemic stroke. Despite its effective usage, the major limitation of tPA that stems from its short half-life in plasma (~5 min) is the potential for increased risk of hemorrhagic complications. To circumvent these limitations, herein, the first proof-of-principle demonstration of a theranostic nanoconstruct system derived from erythrocytes doped with the FDA-approved near-infrared (NIR) imaging agent, indocyanine green, and surface functionalized with tPA is reported. Using a clot model, the dual functionality of these nanoconstructs in NIR fluorescence imaging and clot lysis is demonstrated. These biomimetic theranostic nanoconstructs may ultimately be effective in imaging and treatment of blood clots involved in ischemic stroke. PMID- 29479821 TI - Patient-specific calibration of cone-beam computed tomography data sets for radiotherapy dose calculations and treatment plan assessment. AB - PURPOSE: In this work, we propose a new method of calibrating cone beam computed tomography (CBCT) data sets for radiotherapy dose calculation and plan assessment. The motivation for this patient-specific calibration (PSC) method is to develop an efficient, robust, and accurate CBCT calibration process that is less susceptible to deformable image registration (DIR) errors. METHODS: Instead of mapping the CT numbers voxel-by-voxel with traditional DIR calibration methods, the PSC methods generates correlation plots between deformably registered planning CT and CBCT voxel values, for each image slice. A linear calibration curve specific to each slice is then obtained by least-squares fitting, and applied to the CBCT slice's voxel values. This allows each CBCT slice to be corrected using DIR without altering the patient geometry through regional DIR errors. A retrospective study was performed on 15 head-and-neck cancer patients, each having routine CBCTs and a middle-of-treatment re-planning CT (reCT). The original treatment plan was re-calculated on the patient's reCT image set (serving as the gold standard) as well as the image sets produced by voxel-to-voxel DIR, density-overriding, and the new PSC calibration methods. Dose accuracy of each calibration method was compared to the reference reCT data set using common dose-volume metrics and 3D gamma analysis. A phantom study was also performed to assess the accuracy of the DIR and PSC CBCT calibration methods compared with planning CT. RESULTS: Compared with the gold standard using reCT, the average dose metric differences were <= 1.1% for all three methods (PSC: 0.3%; DIR: -0.7%; density-override: -1.1%). The average gamma pass rates with thresholds 3%, 3 mm were also similar among the three techniques (PSC: 95.0%; DIR: 96.1%; density-override: 94.4%). CONCLUSIONS: An automated patient-specific calibration method was developed which yielded strong dosimetric agreement with the results obtained using a re-planning CT for head-and-neck patients. PMID- 29479822 TI - Evaluating a preventive biological control agent applied on grapevines against Botrytis cinerea and its influence on winemaking. AB - BACKGROUND: This research was aimed to study the influence on grape and wine quality and on the fermentation processes of the application of a preventive biological treatment against Botrytis cinerea in Tempranillo Rioja grapevines. For this purpose, a biofungicide containing Bacillus subtilis QST713 was applied twice to the vineyard. RESULTS: Results were compared with non-treated samples from the same vineyard and with samples treated with a chemical fungicide composed of fenhexamid. Data showed that general grape quality and spontaneous alcoholic fermentation performance were not influenced by either fungicide application. The chemical fungicide had a considerable influence on the clonal diversity of Saccharomyces cerevisiae species, which led to the alcoholic fermentation. Furthermore, it caused longer malolactic fermentation than with the biological fungicide and in the control. The biofungicide made malolactic fermentation 1 day shorter because the establishment of the commercial lactic acid bacteria used as a starter culture was total. After malolactic fermentation, the wines did not show significant differences in general oenological parameters. CONCLUSION: Preventive biofungicide treatment against B. cinerea did not negatively influence the quality of grapes and wines and the fermentation processes. Therefore, biological control of B. cinerea with B. subtilis applied on grapevines could be advisable in oenological terms. (c) 2018 Society of Chemical Industry. PMID- 29479823 TI - MRI-based measurements of whole-brain global cerebral blood flow: Comparison and validation at 1.5T and 3T. AB - BACKGROUND: Whole-brain global cerebral blood flow (CBF) determined by MRI techniques, calculated using total CBF (TCBF) from phase-contrast MRI (PC-MRI), and brain parenchyma volume (BPV) from T1 -weighted image, have become increasingly popular in many applications. PURPOSE/HYPOTHESIS: To determine if MRI-based measurements of whole-brain global CBF data obtained across different field strengths could be merged, TCBF and BPV data acquired at 1.5T and 3T were compared. STUDY TYPE: Prospective study. POPULATION: Seventeen healthy subjects (eight females, aged 21-29 years old). FIELD STRENGTH/SEQUENCE: Fast spoiled gradient echo (FSPGR) and PC-MRI at both 1.5T and 3T. ASSESSMENT: TCBF and BPV data acquired at 1.5T and 3T were compared. STATISTICAL TESTS: The relationships of TCBF and whole-brain global CBF between two field strengths were examined by using the Pearson correlation coefficient analysis and intraclass correlation coefficient (ICC). RESULTS: Regression analysis revealed a strong correlation between TCBF at two field strengths (R2 = 0.78, P < 0.001), and the ICC was 0.85, suggesting measurements of TCBF at 1.5T were comparable and correlated with those at 3T. There was a significant difference in BPV between field strengths, where the white matter estimate was significantly larger at 1.5T when compared with that at 3T (P < 0.001). When TCBF was further normalized to the brain parenchyma mass to obtain whole-brain global CBF, it only showed a moderate correlation between measurements at the two field strengths (R2 = 0.46, P = 0.003) and lower ICC of 0.66, reflecting the slightly higher interstrength variability in the whole-brain global CBF measurements. DATA CONCLUSION: TCBF measurements could be performed equally well with comparable results at both field strengths, but specific attention should be given when TCBF is further normalized to BPV to obtain whole-brain global CBF. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:1273-1280. PMID- 29479824 TI - Full-length genome sequence analysis of an avian leukosis virus subgroup J (ALV J) as contaminant in live poultry vaccine: The commercial live vaccines might be a potential route for ALV-J transmission. AB - One avian leukosis virus subgroup J (ALV-J) strain was isolated from 67 commercial live poultry vaccines produced by various manufacturers during 2013 2016 in China. The complete genomes of the isolate were sequenced and it was found that the genes gag and pol of the strain were relatively conservative, while the gp85 gene of the strain GX14YYA1 had the highest similarities with a field strain GX14ZS14, which was isolated from the chickens of a farm that had once used the same vaccine as the one found to be contaminated with the GX14YYA1. This is the first report of ALV-J contaminant in live poultry vaccine in China. Our finding demonstrates that vaccination of the commercial live vaccines might be a potential new route for ALV-J transmission in chickens and highlights the need for more extensive monitoring of the commercial live vaccines in China. PMID- 29479825 TI - Preferential modulation of the lateral habenula activity by serotonin-2A rather than -2C receptors: Electrophysiological and neuroanatomical evidence. AB - AIMS: Serotonergic (5-HT) modulation of the lateral habenula (LHb) activity is central in normal and pathologic conditions such as mood disorders. Among the multiple 5-HT receptors (5-HTRs) involved, the 5-HT2C R seems to play a pivotal role. Yet, the role of 5-HT2A Rs in the control of the LHb neuronal activity is completely unknown. METHODS: Single-cell extracellular recording of the LHb neurons was used in rats to study the effect of the general activation and blockade of the 5-HT2C R and 5-HT2A R with Ro 60-0175 and SB242084, TCB-2 and MDL11939, respectively. The expression of both receptors in the LHb was confirmed using immunohistochemistry. RESULTS: Cumulative doses (5-640 MUg/kg, iv) of Ro 60 0175 and TCB-2 affected the activity of 34% and 63% of the LHb recorded neurons, respectively. LHb neurons were either inhibited at low doses or excited at higher doses of the 5-HT2A/C R agonists. SB242084 or MDL11939 (both at 200 MUg/kg, iv) did not modify neuronal firing when injected alone, but reverted the bidirectional effects of Ro 60-0175 or TCB-2, respectively. 5-HT2C Rs and 5-HT2A Rs are expressed in less than the 20% of the LHb neurons, and they neither colocalize nor make heterodimers. Strikingly, only 5-HT2A Rs are expressed by the majority of LHb astrocyte cells. CONCLUSIONS: Peripheral administration of 5-HT2A R agonist promotes a heterogeneous pattern of neuronal responses in the LHb, and these effects are more prominent than those induced by the 5-HT2C R activation. PMID- 29479827 TI - Baclofen: its effectiveness in reducing harmful drinking, craving, and negative mood. A meta-analysis. AB - BACKGROUND AND AIMS: There are a limited number of pharmacotherapies licensed for alcohol use disorders (AUDs). Baclofen is a gamma-aminobutyric acid B (GABA-B) agonist which is used increasingly as an off-label treatment. A meta-analysis of randomized controlled trials (RCTs) was conducted to determine the efficacy of baclofen in reducing drinking behaviour, craving, depression and anxiety compared with placebo. METHODS: Random-effects meta-analyses were computed on outcome data from 12 RCTs comparing baclofen with placebo. Included RCTs provided data on at least one of the primary outcome measures (drinking-related: heavy drinking days, abstinent days, abstinence rates) or secondary outcome measures (craving, anxiety, depression). RESULTS: Baclofen had a significant effect on abstinence rates when using intention-to-treat analysis [total n baclofen = 307, total n control = 283: odds ratio (OR) = 2.67, 95% confidence interval (CI) = 1.03, 6.93; Z = 2.01, P = 0.04, I2 = 76%, number needed to treat = 8]. No other significant effects of treatment efficacy [e.g. heavy drinking days: standardized mean differences (SMD) = -0.26, 95% CI = -0.68, 0.15; Z = 1.24, P = 0.21, I2 = 95%] or mechanism of action (e.g. craving: SMD = -0.13, 95% CI = -0.36, 0.09; Z = 1.18, P = 0.24, I2 = 87%) were observed. There was substantial heterogeneity in effect sizes across each analysis. CONCLUSIONS: As a treatment for alcohol use disorders, baclofen is associated with higher rates of abstinence than placebo. However, there is no superior effect of baclofen on increasing number of abstinent days, or decreasing heavy drinking, craving, anxiety or depression. These results suggest that the current increasing use of baclofen as a treatment for alcohol use disorders is premature. PMID- 29479828 TI - Hemodialysis monitoring using mid- and near-infrared spectroscopy with partial least squares regression. AB - Blood constituents such as urea, glucose, lactate, phosphate and creatinine are of high relevance in monitoring the process of detoxification in ambulant dialysis treatment. In the present work, 2 different vibrational spectroscopic techniques are used to determine those molecules quantitatively in artificial dialysate solutions. The goal of the study is to compare the performance of near infrared (NIR) and mid-infrared (MIR) spectroscopy in hyphenation with partial least squares regression (PLSR) directly by using the same sample set. The results show that MIR spectroscopy is better suited to analyze the analytes of interest. Multilevel multifactor design is used to cover the relevant concentration variations during dialysis. MIR spectroscopy coupled to a multi reflection attenuated total reflection (ATR) cell enables reliable prediction of all target analytes. In contrast, the NIR spectroscopic method does not give access to all 5 components but only to urea and glucose. For both methods, coefficients of determination greater or equal to 0.86 can be achieved in the test-set validation process for urea and glucose. Lactate, phosphate and creatinine perform well in the MIR with R2 >= 0.95 using test-set validation. PMID- 29479826 TI - The prognostic value of CYP2C subfamily genes in hepatocellular carcinoma. AB - Cytochrome P2C (CYP2C) subfamily members (CYP2C8, CYP2C9, CYP2C18, and CYP2C19) are known to participate in clinical drug metabolism. However, the association between CYP2C subfamily members and hepatocellular carcinoma (HCC) remains unclear. This study investigated the prognostic value of CYP2C subfamily gene expression levels with HCC prognosis. Data of 360 HCC patients in The Cancer Genome Atlas database and 231 in the Gene Expression Omnibus database were analyzed. Kaplan-Meier analysis and a Cox regression model were used to ascertain overall survival and recurrence-free survival, and to calculate median survival time using hazard ratios (HR) and 95% confidence intervals (CI). In TCGA database, low expression of CYP2C8, CYP2C9, and CYP2C19 in tumor tissue was associated with a short median survival time (all crude P = 0.001, adjusted P = 0.004, P = 0.047, and P = 0.020, respectively). In TCGA database, joint effects analysis of the combinations of CYP2C8 and CYP2C9, CYP2C8 and CYP2C19, and CYP2C9 and CYP2C19 revealed that high expression of two genes (group 4; group IV, group d) was associated with a reduced risk of death as compared to low expression (group 1, group I, and group a) (adjusted P = 0.005, P = 0.013, and P = 0.016, respectively). In TCGA database, joint effects analysis of CYP2C8, CYP2C9, and CYP2C19 showed that the risk of death from HCC was lower for groups C and D than for group A (adjusted P = 0.012 and P = 0.008, respectively). CYP2C8, CYP2C9, and CYP2C19 gene expression levels are potential prognostic markers of HCC following hepatectomy. PMID- 29479829 TI - Positive Emotion Infusions: Can Savoring Increase Help-Seeking Intentions among People with Depression? AB - BACKGROUND: The current research effort used two experimental studies to assess whether a savoring-based, positive emotion infusion (PEI) could increase help seeking intentions among individuals with elevated depressive symptomatology and whether this relationship would be mediated by positive emotion, arousal, and perceptions of personal control. METHODS: In Study 1, participants with elevated depressive symptomatology, recruited from Amazon's Mechanical Turk (N = 135), were randomly assigned to complete a 6-minute savoring or control writing task followed by a help-seeking intentions scale. Study 2 participants (N = 136) were randomly assigned to the same tasks, but a scale assessing positive emotion, arousal, and personal control was added. RESULTS: Study 1 indicated a direct effect; those who savored reported greater help-seeking intentions compared to control participants. Study 2 revealed an indirect effect of savoring on help seeking intentions through greater positive emotion but not through greater arousal or perceptions of personal control. CONCLUSION: Together, these results offer additional support for continued research on PEIs, and specifically, savoring-based PEIs. Although the experimental manipulations may be limited in regard to their ecological validity, for those seeking to create interventions, these studies offer a novel and efficacious approach for motivating individuals with elevated depressive symptomatology to seek help. PMID- 29479830 TI - Short fiber-reinforced composite restorations: A review of the current literature. AB - A newly-recommended method for restoring large cavities is the biomimetic approach of using short fiber-reinforced composite (SFRC) as dentine-replacing material. The aim of the current review was to present an overview of SFRC and to give the clinician a detailed understanding of this new material and treatment strategy based on available-literature review. A thorough literature search was done up to December 2017. The range of relevant publications was surveyed using PubMed and Google Scholar. From the search results, articles related to our search terms were only considered. The search terms used were "short fiber reinforced composite", "everX posterior", and "fiber-reinforced composite restorations". Of the assessed articles selected (N = 70), most were laboratory based research with various test specimen designs prepared according to the ISO standard or with extracted teeth; only four articles were clinical reports. A common finding was that by combining the SFRC as a bulk base with conventional composite, the load-bearing capacity and failure mode of the material combination were improved, as compared to plain conventional composite restoration. In the reviewed studies, the biomimetic restoration technique of using SFRC showed promising characteristics, and therefore, might be recommended as an alternative treatment option for large cavities. PMID- 29479831 TI - A Hybrid Model for a Hybrid Science. AB - This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies. PMID- 29479832 TI - Osteoporosis in chronic liver disease. AB - Osteoporosis is a frequent complication in patients with chronic liver disease, especially in end-stages and in chronic cholestasis, in addition to non-alcoholic fatty liver disease, haemochromatosis and alcoholism. Mechanisms underlying osteoporosis are poorly understood, but osteoporosis mainly results from low bone formation. In this setting, sclerostin, a key regulator of the Wnt/beta-catenin signalling pathway which regulates bone formation, in addition to the effects of the retained substances of cholestasis such as bilirubin and bile acids on osteoblastic cells, may influence the decreased bone formation in chronic cholestasis. Similarly, the damaging effects of iron and alcohol on osteoblastic cells may partially explain bone disease in haemochromatosis and alcoholism. A role for proinflammatory cytokines has been proposed in different conditions. Increased bone resorption may occur in cholestatic women with advanced disease. Low vitamin D, poor nutrition and hypogonadism, may be contributing factors to the full picture of bone disorders in chronic liver disease. PMID- 29479833 TI - Clinical outcomes of radio-hyperthermo-chemotherapy for soft tissue sarcoma compared to a soft tissue sarcoma registry in Japan: a retrospective matched-pair cohort study. AB - Regional hyperthermia is considered to enhance the antitumor effects of chemotherapy and radiotherapy. In this study, we confirmed the efficacy of concomitant radiotherapy, hyperthermia, and chemotherapy (RHC) for neoadjuvant treatment of malignant soft tissue sarcoma (STS). From 1994 to 2013, we performed RHC in 150 patients. This study was limited to 60 patients using the following exclusion criteria: salvage for recurrence or unplanned excision, trunk location, metastasis at initiation, non-STS, and no definitive surgery. As a control group, we collected data from 11,031 patients in the Bone and Soft Tissue Tumor Registry in Japan (BSTT). We performed multivariate logistic regression analysis, and propensity scores were created for comparisons between groups. The primary outcome of this study was to compare oncologic outcomes (5-year local control rate [LC] and overall survival rate [OS]). In the RHC group, two local recurrences (3.3%) occurred, and no patients underwent amputation. Margins of definitive surgery were not identical between groups [wide margins (60.0% vs. 85.3%), marginal margins (28.3% vs. 10.5%), and intralesional margins (7.4% vs. 4.2%), RHC and BSTT groups, respectively, P < 0.001]. After adjustment, the difference in OS was not significant between groups (HR = 1.26, P = 0.532); however, a statistically significant difference in LC was observed (HR = 4.82, P = 0.037). RHC resulted in a high LC at 5 years compared to the BSTT group, and amputation was averted in the RHC group, despite the wider margins in the BSTT group. This indicates that less invasive surgery might be achieved with effective neoadjuvant therapy. PMID- 29479835 TI - Racial/ethnic disparities in de novo metastases sites and survival outcomes for patients with primary breast, colorectal, and prostate cancer. AB - Racial disparities in cancer mortality still exist despite improvements in treatment strategies leading to improved survival for many cancer types. In this study, we described race/ethnic differences in patterns of de novo metastasis and evaluated the association between site of de novo metastasis and breast, prostate, and colorectal cancer mortality. Data were obtained from the Surveillance Epidemiology and Ends Results (SEER) database from 2010 to 2013 and included 520,147 patients ages >=40 years with primary diagnosis of breast, colorectal, or prostate cancer. Site and frequency of de novo metastases to four sites (bone, brain, liver, and lung) were compared by race/ethnicity using descriptive statistics, and survival differences examined using extended Cox regression models in SAS 9.4. Overall, non-Hispanic (NH) Blacks (11%) were more likely to present with de novo metastasis compared with NH-Whites (9%) or Hispanics (10%). Among patients with breast cancer, NH-Blacks were more likely to have metastasis to the bone, (OR: 1.25, 95% CI: 1.15-1.37), brain (OR: 2.26, 95% CI: 1.57-3.25), or liver (OR: 1.62, 95% CI: 1.35-1.93), while Hispanics were less likely to have metastasis to the liver (OR: 0.76, 95% CI: 0.60-0.97) compared with NH-Whites. Among patients with prostate cancer, NH-Blacks (1.39, 95% CI: 1.31-1.48) and Hispanics (1.39, 95% CI: 1.29-1.49) were more likely to have metastasis to the bone. Metastasis to any of the four sites evaluated increased overall mortality by threefold (for breast cancer and metastasis to bone) to 17 fold (for prostate cancer and metastasis to liver). Racial disparities in mortality remained after adjusting for metastasis site in all cancer types evaluated. De novo metastasis is a major contributor to cancer mortality in USA with racial differences in the site, frequency, and associated survival. PMID- 29479834 TI - Validating the pivotal role of the immune system in low-dose radiation-induced tumor inhibition in Lewis lung cancer-bearing mice. AB - Although low-dose radiation (LDR) possesses the two distinct functions of inducing hormesis and adaptive responses, which result in immune enhancement and tumor inhibition, its clinical applications have not yet been elucidated. The major obstacle that hinders the application of LDR in the clinical setting is that the mechanisms underlying induction of tumor inhibition are unclear, and the risks associated with LDR are still unknown. Thus, to overcome this obstacle and elucidate the mechanisms mediating the antitumor effects of LDR, in this study, we established an in vivo lung cancer model to investigate the participation of the immune system in LDR-induced tumor inhibition and validated the pivotal role of the immune system by impairing immunity with high-dose radiation (HDR) of 1 Gy. Additionally, the LDR-induced adaptive response of the immune system was also observed by sequential HDR treatment in this mouse model. We found that LDR activated T cells and natural killer cells and increased the cytotoxicity of splenocytes and the infiltration of T cells in the tumor tissues. In contrast, when immune function was impaired by HDR pretreatment, LDR could not induce tumor inhibition. However, when LDR was administered before HDR, the immunity could be protected from impairment, and tumor growth could be inhibited to some extent, indicating the induction of the immune adaptive response by LDR. Therefore, we demonstrated that immune enhancement played a key role in LDR-induced tumor inhibition. These findings emphasized the importance of the immune response in tumor radiotherapy and may help promote the application of LDR as a novel approach in clinical practice. PMID- 29479837 TI - Comparison of the Reactivities and Selectivities of Group 9 [Cp*MIII ] Catalysts in C-H Functionalization Reactions. AB - Pentamethylcyclopentadienyl (Cp*)-based Group 9 metal (Co, Rh, or Ir) catalysts have emerged as powerful tools for C-H functionalization reactions. Whilst a diverse range of organic transformations have been developed by using [Cp*MIII ] catalysts, they have often exhibited orthogonal reactivities and varied selectivities that depended on the choice of the central metal atom. An understanding of the physicochemical properties of the metals, as well as of their reaction mechanisms, has led to significant expansion of the synthetic scope of C-H functionalization reactions. This Focus Review summarizes and discusses the comparative catalytic reactivities and selectivities of the [Cp*MIII ] catalysts, with an emphasis on metal-dependent pathway-switching by considering the mechanistic rationale. PMID- 29479836 TI - Perfluoroaryl Bicyclic Cell-Penetrating Peptides for Delivery of Antisense Oligonucleotides. AB - Exon-skipping antisense oligonucleotides are effective treatments for genetic diseases, yet exon-skipping activity requires that these macromolecules reach the nucleus. While cell-penetrating peptides can improve delivery, proteolytic instability often limits efficacy. It is hypothesized that the bicyclization of arginine-rich peptides would improve their stability and their ability to deliver oligonucleotides into the nucleus. Two methods were introduced for the synthesis of arginine-rich bicyclic peptides using cysteine perfluoroarylation chemistry. Then, the bicyclic peptides were covalently linked to a phosphorodiamidate morpholino oligonucleotide (PMO) and assayed for exon skipping activity. The perfluoroaryl cyclic and bicyclic peptides improved PMO activity roughly 14-fold over the unconjugated PMO. The bicyclic peptides exhibited increased proteolytic stability relative to the monocycle, demonstrating that perfluoroaryl bicyclic peptides are potent and stable delivery agents. PMID- 29479838 TI - Estimating the effect of a rare time-dependent treatment on the recurrent event rate. AB - In many observational studies, the objective is to estimate the effect of treatment or state-change on the recurrent event rate. If treatment is assigned after the start of follow-up, traditional methods (eg, adjustment for baseline only covariates or fully conditional adjustment for time-dependent covariates) may give biased results. We propose a two-stage modeling approach using the method of sequential stratification to accurately estimate the effect of a time dependent treatment on the recurrent event rate. At the first stage, we estimate the pretreatment recurrent event trajectory using a proportional rates model censored at the time of treatment. Prognostic scores are estimated from the linear predictor of this model and used to match treated patients to as yet untreated controls based on prognostic score at the time of treatment for the index patient. The final model is stratified on matched sets and compares the posttreatment recurrent event rate to the recurrent event rate of the matched controls. We demonstrate through simulation that bias due to dependent censoring is negligible, provided the treatment frequency is low, and we investigate a threshold at which correction for dependent censoring is needed. The method is applied to liver transplant (LT), where we estimate the effect of development of post-LT End Stage Renal Disease (ESRD) on rate of days hospitalized. PMID- 29479839 TI - Sarcopenia as a comorbidity-independent predictor of survival following radical cystectomy for bladder cancer. AB - BACKGROUND: A multicentre study was conducted to investigate the impact of sarcopenia as an independent predictor of oncological outcome after radical cystectomy for bladder cancer. METHODS: In total, 500 patients with available digital computed tomography scans of the abdomen obtained within 90 days before surgery were identified. The lumbar skeletal muscle index was measured using pre operative computed tomography. Cancer-specific survival (CSS) and overall survival (OS) were estimated using Kaplan-Meier curves. Predictors of CSS and OS were analysed by univariable and multivariable Cox regression models. RESULTS: Based on skeletal muscle index, 189 patients (37.8%) were classified as sarcopenic. Patients with sarcopenia were older compared with their counterparts (P = 0.002), but both groups were comparable regarding to gender, comorbidity, tumor, node, metastasis (TNM) stage, and type of urinary diversion (all P > 0.05). In total, 234 (46.8%) patients died, and of these, 145 (29.0%) died because of urothelial carcinoma of the bladder. Sarcopenic patients had significantly worse 5 year OS (38.3% vs. 50.5%; P = 0.002) and 5 year CSS (49.5% vs. 62.3%; P = 0.016) rates compared with patients without sarcopenia. Moreover, sarcopenia was associated independently with both increased all-cause mortality (hazard ratio, 1.43; 95% confidence interval 1.09-1.87; P = 0.01) and increased cancer-specific mortality (hazard ratio, 1.42; 95% confidence interval, 1.00 2.02; P = 0.048). Our results are limited by the lack of prospective frailty assessment. CONCLUSIONS: Sarcopenia has been shown to be an independent predictor for OS and CSS in a large multicentre study with patients undergoing radical cystectomy for bladder cancer. PMID- 29479840 TI - Replication and discovery of musculoskeletal QTLs in LG/J and SM/J advanced intercross lines. AB - The genetics underlying variation in health-related musculoskeletal phenotypes can be investigated in a mouse model. Quantitative trait loci (QTLs) affecting musculoskeletal traits in the LG/J and SM/J strain lineage remain to be refined and corroborated. The aim of this study was to map muscle and bone traits in males (n = 506) of the 50th filial generation of advanced intercross lines (LG/SM AIL) derived from the two strains. Genetic contribution to variation in all musculoskeletal traits was confirmed; the SNP heritability of muscle mass ranged between 0.46 and 0.56; and the SNP heritability of tibia length was 0.40. We used two analytical software, GEMMA and QTLRel, to map the underlying QTLs. GEMMA required substantially less computation and recovered all the QTLs identified by QTLRel. Seven significant QTLs were identified for muscle weight (Chr 1, 7, 11, 12, 13, 15, and 16), and two for tibia length, (Chr 1 and 13). Each QTL explained 4-5% of phenotypic variation. One muscle and both bone loci replicated previous findings; the remaining six were novel. Positional candidates for the replicated QTLs were prioritized based on in silico analyses and gene expression in muscle tissue. In summary, we replicated existing QTLs and identified novel QTLs affecting muscle weight, and replicated bone length QTLs in LG/SM AIL males. Heritability estimates substantially exceed the cumulative effect of the QTLs, hence a richer genetic architecture contributing to muscle and bone variability could be uncovered with a larger sample size. PMID- 29479842 TI - Sclerosing mucoepidermoid carcinoma with eosinophilia: Cytologic characterization of a rare distinct entity in the thyroid. AB - Sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE) is an extremely rare thyroid carcinoma with limited cytologic descriptions in the literature. Here, we present a 52-year-old woman with a 3.9 cm thyroid nodule. Fine-needle aspiration smears consisted of a highly cellular specimen with tumor cells in isolated patterns and solid squamoid nests. Tumor cells had round to oval nuclei, prominent nucleoli, smooth nuclear contours, and moderate amounts of dense cytoplasm. In addition to the polymorphous population of lymphocytes, the background contained a striking abundance of eosinophils. The subsequent right thyroidectomy showed histologic features diagnostic for SMECE. PMID- 29479843 TI - Being present: oncologists' role in promoting advanced cancer patients' illness understanding. AB - Realistic illness understanding is essential to an advanced cancer patient's ability to make informed medical decisions at the end of life. This study sought to determine whether advanced cancer patients better understood the late stage of their cancer if an oncologist, compared to other members of the care team, was present to discuss their scan results. Data were derived from a multi institutional, longitudinal cohort study of patients recruited between 2010 and 2015. Patients (n = 209) with late-stage cancers (metastatic cancers that progressed after at least one chemotherapy regimen) were interviewed before and after clinic visits in which scan results were discussed. Patients reported pre- and postvisit if their cancer was at a late stage. Postvisit, patients reported if they discussed scan results with an oncologist or another oncology provider (i.e., oncology fellow, oncology resident, nurse practitioner, nurse, physician's assistant, or other). Logistic regression analysis was used to determine if the presence of an oncologist during scan results discussions differentially predicted the patients' likelihood of postvisit late-stage illness understanding (LSIU). Propensity weighting was used to correct for sociodemographic imbalances between groups, and previsit LSIU and the presence of multiple providers were controlled for in the logistic regression analyses. After propensity-weighted adjustment and controlling for previsit LSIU and the presence of multiple providers, patients were 2.6 times more likely (AOR = 2.6; 95% CI = 1.2, 6.0; P = 0.021) to report that their disease was late stage if an oncologist was present for the scan results discussion compared to if an oncologist was absent. The presence of an oncologist during scan results discussions was associated with a higher likelihood of patients acknowledging being in a late stage of their disease. These results suggest that oncologist involvement in scan results discussions is associated with advanced cancer patients having better prognostic understanding. PMID- 29479841 TI - Glioblastoma-activated pericytes support tumor growth via immunosuppression. AB - Glioblastoma multiforme is the most common and aggressive primary brain tumor, with an extremely poor prognosis. The lack of detailed knowledge about the cellular and molecular mechanisms involved in glioblastoma development restricts the design of efficient therapies. A recent study using state-of-art technologies explores the role of pericytes in the glioblastoma microenvironment. Glioblastoma activated pericytes develop an immunosuppressive phenotype, reducing T-cell activation through the induction of an anti-inflammatory response. Strikingly, pericytes support glioblastoma growth in vitro and in vivo. Here, we describe succinctly the results and implications of the findings reported in pericytes' and glioblastomas' biology. The emerging knowledge from this study will be essential for the treatment of brain tumors. PMID- 29479844 TI - Is HPV vaccination of pregnant women really safe? PMID- 29479845 TI - Determinants of malignant pleural mesothelioma survival and burden of disease in France: a national cohort analysis. AB - This study was undertaken to determine the healthcare burden of malignant pleural mesothelioma (MPM) in France and to analyze its associations with socioeconomic deprivation, population density, and management outcomes. A national hospital database was used to extract incident MPM patients in years 2011 and 2012. Cox models were used to analyze 1- and 2-year survival according to sex, age, co morbidities, management, population-density index, and social deprivation index. The analysis included 1,890 patients (76% men; age: 73.6 +/- 10.0 years; 84% with significant co-morbidities; 57% living in urban zones; 53% in highly underprivileged areas). Only 1% underwent curative surgical procedure; 65% received at least one chemotherapy cycle, 72% of them with at least one pemetrexed and/or bevacizumab administration. One- and 2-year survival rates were 64% and 48%, respectively. Median survival was 14.9 (95% CI: 13.7-15.7) months. The mean cost per patient was 27,624 +/- 17,263 euros (31% representing pemetrexed and bevacizumab costs). Multivariate analyses retained men, age >70 years, chronic renal failure, chronic respiratory failure, and never receiving pemetrexed as factors of poor prognosis. After adjusting the analysis to age, sex, and co-morbidities, living in rural/semi-rural area was associated with better 2-year survival (HR: 0.83 [95% CI: 0.73-0.94]; P < 0.01); social deprivation index was not significantly associated with survival. With approximately 1,000 new cases per year in France, MPMs represents a significant national health care burden. Co-morbidities, sex, age, and living place appear to be significant factors of prognosis. PMID- 29479847 TI - A novel HLA-DQB1*03 variant, HLA-DQB1*03:23:03, identified in a Chinese individual. AB - HLA-DQB1*03:23:03 has two nucleotide change from HLA-DQB1*03:03:02:01 at position 254 and 260. PMID- 29479846 TI - The Yokohama system for reporting directly sampled endometrial cytology: The quest to develop a standardized terminology. AB - BACKGROUND: The main purpose of directly sampled endometrial cytology is to detect invasive endometrial malignancies. With this principle in mind, The Yokohama System (TYS) Working Group, composed of cytopathologists, surgical pathologists, and gynecologic oncologists met at the 2016 International Congress of Cytology, Yokohama, with the aim to publish a standardized reporting system inclusive of specific diagnostic categories and cytomorphologic criteria for uniform and reliable diagnosis of endometrial malignancies on directly sampled endometrial samples. METHODS: The diagnostic cytopathologic criteria previously published in the literature by the Japanese and Greek working group on endometrial cytology (Yanoh et al. [2012] Acta Cytol. 56:233; Margari et al. [2016] Diagn Cytopathol. 44:888-901) were critically reviewed with the aim of correlating the diagnostic classes to well defined risk categories for endometrial carcinoma (EC). Moreover, two classes of "atypical" endometrial cells were correlated respectively to a low- and high risk group. Some methodological suggestions for the application of ancillary special technologies to liquid based samples were also given. RESULTS: The TYS group conceived a new Bethesda-style classification for directly sampled endometrial cytology which correlates the cytologic diagnostic classes with definite risk categories. The cytomorphologic findings have been correlated to the molecular pathology of EC, also through the application of ancillary special techniques to liquid-based samples. CONCLUSIONS: The success of TYS will depend on the acceptance of TYS by all the relevant pathology and gynecologic oncology communities who, by their joint efforts, will adopt, critically evaluate, and optimize this method with the only aim of further improving the impact of endometrial cytology on patients' care. PMID- 29479848 TI - The inflammation - cancer connection. AB - This Special Issue comprises ten reviews that highlight the connection between inflammation and cancer; from immune-cancer cell crosstalk to the current targets in cancer immunotherapy. We hope you find these reviews interesting and informative and we thank the authors for these excellent contributions. PMID- 29479850 TI - Radiation exposure to sonographers from nuclear medicine patients: A review. AB - Following nuclear medicine scans a patient can be a source of radiation exposure to the hospital staff, including sonographers. Sonographers are not routinely monitored for occupational radiation exposure as they do not commonly interact with radioactive patients or other sources of ionizing radiation. This review aims to find evidence relating to the risk and amount of radiation the sonographer is exposed to from nuclear medicine patients. It is established in the literature that the radiation exposure to the sonographer following diagnostic nuclear medicine studies is low and consequently the risk is not significant. Nevertheless, it is paramount that basic radiation safety principles are followed to ensure any exposure to ionizing radiation is kept as low as reasonably achievable. Practical recommendations are given to assist the sonographer in radiation protection. Nuclear medicine therapy procedures may place the sonographer at higher risk and as such consultation with a Radiation Safety Officer or Medical Physicist as to the extent of exposure is recommended. PMID- 29479852 TI - The impact of a short-term high-fat diet on mitochondrial respiration, reactive oxygen species production, and dynamics in oxidative and glycolytic skeletal muscles of young rats. AB - Multiple aspects of mitochondrial function and dynamics remain poorly studied in the skeletal muscle of pediatric models in response to a short-term high-fat diet (HFD). This study investigated the impact of a short-term HFD on mitochondrial function and dynamics in the oxidative soleus (SOL) and glycolytic extensor digitorum longus (EDL) muscles in young rats. Young male Wistar rats were submitted to either HFD or normal chow (NCD) diets for 14 days. Permeabilized myofibers from SOL and EDL were prepared to assess mitochondrial respiration and reactive oxygen species (ROS) production. The expression and content of protein involved in mitochondrial metabolism and dynamics (fusion/fission) were also quantified. While no effects of HFD was observed on mitochondrial respiration when classical complex I and II substrates were used, both SOL and EDL of rats submitted to a HFD displayed higher basal and ADP-stimulated respiration rates when Malate + Palmitoyl-L-carnitine were used as substrates. HFD did not alter ROS production and markers of mitochondrial content. The expression of CPT1b was significantly increased in SOL and EDL of HFD rats. Although the expression of UCP3 was increased in SOL and EDL muscles from HFD rats, mitochondrial coupling efficiency was not altered. In SOL of HFD rats, the transcript levels of Mfn2 and Fis1 were significantly upregulated. The expression and content of proteins regulating mitochondrial dynamics was not modulated by HFD in the EDL. Finally, DRP1 protein content was increased by over fourfold in the SOL of HFD rats. Taken altogether, our findings show that exposing young animals to short-term HFD results in an increased capacity of skeletal muscle mitochondria to oxidize fatty acids, without altering ROS production, coupling efficiency, and mitochondrial content. Our results also highlight that the impact of HFD on mitochondrial dynamics appears to be muscle specific. PMID- 29479853 TI - Zinc Oxide Nanoparticles and Voltage-Gated Human Kv 11.1 Potassium Channels Interact through a Novel Mechanism. AB - Membrane-nanoparticle interactions are important in determining the effects of manufactured nanomaterials on cell physiology and pathology. Here, silica, titanium, zinc, and magnesium oxide nanoparticles are screened against human hERG (Kv 11.1) voltage-gated potassium channels under a whole-cell voltage clamp. 10 ug mL-1 ZnO uniquely increases the amplitude of the steady-state current, decreases the rate of hERG current inactivation during steady-state depolarization, accelerates channel deactivation during resurgent tail currents, and shows no significant alteration of current activation rate or voltage dependence. In contrast, ZnCl2 causes increased current suppression with increasing concentration and fails to replicate the nanoparticle effect on decreasing inactivation. The results show a novel class of nanoparticle biomembrane interaction involving channel gating rather than channel block, and have implications for the use of nanoparticles in biomedicine, drug delivery applications, and nanotoxicology. PMID- 29479851 TI - A hierarchical prognostic model for risk stratification in patients with early breast cancer according to 18 F-fludeoxyglucose uptake and clinicopathological parameters. AB - This study was to investigate a hierarchical prognostic model using clinicopathological factors and 18 F-fludeoxyglucose (FDG) uptake on positron emission tomography/computed tomography (PET/CT) for recurrence-free survival (RFS) in patients with early breast cancer who underwent surgery without neoadjuvant chemotherapy. A total of 524 patients with early breast cancer were included. The Cox proportional hazards model was used with clinicopathological variables and maximum standardized uptake value (SUVmax) on PET/CT. After classification and regression tree (CART) modeling, RFS curves were estimated using the Kaplan-Meier method and differences in each risk layer were assessed using the log-rank test. During a median follow-up of 46.2 months, 31 (5.9%) patients experienced recurrence. The CART model identified four risk layers: group 1 (SUVmax <=6.75 and tumor size <=2.0 cm); group 2 (SUVmax <=6.75 and Luminal A [LumA] or TN tumor >2.0 cm); group 3 (SUVmax <=6.75 and Luminal B [LumB] or human epidermal growth factor receptor 2 [HER2]-enriched] tumor >2.0 cm); group 4 (SUVmax >6.75). Five-year RFS was as follows: 95.9% (group 1), 98% (group 2), 82.8% (group 3), and 85.4% (group 4). Group 3 or group 4 showed worse prognosis than group 1 or group 2 (group 1 vs. group 3: P = 0.040; group 1 vs. group 4: P < 0.001; group 2 vs. group 3: P = 0.016; group 2 vs. group 4: P < 0.001). High SUVmax (>6.75) in primary breast cancer was an independent factor for poor RFS. In patients with low SUVmax, LumB or HER2-enriched tumor >2 cm was also prognostic for poor RFS, similar to high SUVmax. PMID- 29479855 TI - Experimental fusion of different versions of the total laboratory automation system and improvement of laboratory turnaround time. AB - BACKGROUND: Use of total laboratory automation (TLA) system has expanded to microbiology and hemostasis and upgraded to second and third generations. We herein report the first successful upgrades and fusion of different versions of the TLA system, thus improving laboratory turnaround time (TAT). METHODS: A 21 day schedule was planned from the time of pre-meeting to installation and clinical sample application. We analyzed the monthly TAT in each menu, distribution of the "out of range for acceptable TAT" samples, and "prolonged time out of acceptable TAT," before and after the upgrade and fusion. RESULTS: We installed and customized hardware, middleware, and software. The one-way CliniLog 2.0 version track, 50.0-m long, was changed to a 23.2-m long one-way 2.0 version and an 18.7-m long two-way 4.0 version. The monthly TAT in the outpatient samples, before and after upgrading the TLA system, were uniformly satisfactory in the chemistry and viral marker menus. However, in the tumor marker menu, the target TAT (98.0% of samples <=60 minutes) was not satisfied during the familiarization period. There was no significant difference in the proportion of "out of acceptable TAT" samples, before and after the TLA system upgrades (7.40/00 and 8.50/00). However, the mean "prolonged time out of acceptable TAT" in the chemistry samples was significantly shortened to 17.4 (+/-24.0) minutes after the fusion, from 34.5 (+/-43.4) minutes. CONCLUSIONS: Despite experimental challenges, a fusion of the TLA system shortened the "prolonged time out of acceptable TAT," indicating a distribution change in overall TAT. PMID- 29479854 TI - Socioeconomic and demographic inequalities in stage at diagnosis and survival among colorectal cancer patients: evidence from a Swiss population-based study. AB - Socioeconomic inequalities in cancer stage at diagnosis and survival are important public health issues. This study investigates the association between socioeconomic position (SEP) and colorectal cancer (CRC) stage at diagnosis and survival in Switzerland, a European country with highest level of medical facilities and life expectancy. We used population-based CRC data from seven Swiss cantonal cancer registries 2001-2008 (N = 10,088) linked to the Swiss National Cohort (SNC). Follow-up information was available until the end of 2013. SEP was estimated based on education. The association between cancer stage and SEP was assessed using logistic regression models including cancer localization (colon/rectum), sex, age, civil status, urbanity of residence, language region, and nationality (Swiss/non-Swiss). Survival was analyzed using competing risk regressions reporting subhazard ratios (SHRs) for the risk of dying due to CRC. We observed a social gradient for later stage CRC with adjusted odds ratios (ORs) of 1.11 (95% CI: 0.97-1.19) and 1.28 (95% CI: 1.08-1.50) for middle and low SEP compared to high SEP. Further, single compared to married people had elevated odds of being diagnosed at later stages. Survival was lower in patients with CRC with low SEP in the unadjusted model (SHR: 1.18, 95% CI: 1.07-1.30). After adjustment for stage at diagnosis and further sociodemographic characteristics, significant survival inequalities by SEP disappeared but remained for non-Swiss compared to Swiss citizens and for patients living in nonurban areas compared to their urban counterparts. Swiss public health strategies should facilitate equal access to CRC screening and optimal CRC care for all social groups and in all regions of Switzerland. PMID- 29479856 TI - Liposome Crosslinked Polyacrylamide/DNA Hydrogel: a Smart Controlled-Release System for Small Molecular Payloads. AB - A novel stimuli-responsive hydrogel system with liposomes serving as both noncovalent crosslinkers and functional small molecules carriers for controlled release is developed. Liposomes can crosslink polyacrylamide copolymers functionalized with cholesterol-modified DNA motifs to yield a DNA hydrogel system, due to the hydrophobic interaction between cholesteryl groups and the lipid bilayer of liposomes. Functional information encoded DNA motifs on the polymer backbones endow the hydrogel with programmable smart responsive properties. In a model system, the hydrogel exhibits stimuli-responsive gel-to sol transformation triggered by the opening of DNA motifs upon the presence of a restriction endonuclease enzyme, EcoR I, or temperature change, realizing the controlled-release of liposomes which are highly efficient carriers of active small molecules payloads. Two active molecules, 1,1-dioctadecyl-3,3,3,3 tetramethylindodicarbocyanine perchlorate (DiIC18(5)) and calcein, are chosen as the hydrophobic and hydrophilic model payloads, respectively, to address the feasibility of the releasing strategy. Moreover, the hydrogel exhibits injectable property as well as self-recovery behaviors. PMID- 29479857 TI - Establishment and validation of a two-step screening scheme for improved performance of serological screening of nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC), which is closely associated with Epstein-Barr virus (EBV), is one of the most prevalent cancers in southeast China. Most NPC patients are diagnosed at late stage due to inconspicuous symptoms at the early stage, and the prognosis of these patients is poor. The early diagnosis rate of NPC could be significantly increased by serological screening, but the positive predictive value (PPV) is relatively low. A simple two-step serological screening scheme was established to improve the PPV of the screening strategy and was validated by a prospective cohort. Serum antibodies specific for EBNA1, Zta, Thymidine Kinase (TK), EAD, EAR, and VCA were detected by enzyme-linked immunosorbent assay. The combination of EBNA1/IgA and VCA/IgA was used in the first step of screening, and anti-early antigens (EAs) were used in the second step of screening. EAD/IgA was the most prominent marker in the second step of screening, and other anti-EAs were complementary to EAD/IgA. As validated by a prospective cohort including 4200 participants, using the combination of EAD/IgA and TK/IgA in the second step decreased the number of high-risk participants from 128 to 27, and increased the PPV from 4.69% to 18.52%, with only one very early stage case missed. The two-step screening scheme provides a standardized approach for NPC screening with an improved PPV and may be used in future field studies. With this two-step serological screening method, more people benefit from the screening program without increasing the need for fiberoptic endoscopy. PMID- 29479859 TI - The emergence of new psychoactive substance (NPS) benzodiazepines: A review. PMID- 29479858 TI - The poor outcome of second primary oral squamous cell carcinoma is attributed to Bmi1 upregulation. AB - Radiotherapy for nasopharyngeal carcinoma has been reported to cause second primary oral squamous cell carcinoma (s-OSCC). The prognosis and pathologic characteristic of s-OSCC are largely unknown. Bmi1 was associated with the repair of radiation-induced DNA damage, suggesting its possible involvement in the pathologic process of s-OSCC. Herein, we compared the prognosis between s-OSCC and primary OSCC (p-OSCC) and explored the involvement of Bmi1 in s-OSCC development. In this retrospective study, s-OSCC and p-OSCC patients were matched by propensity scores. Their outcomes were compared by univariate and multivariate analyses. The expression of Bmi1 in s-OSCC and p-OSCC was detected by immunohistochemistry (IHC). Radiation-induced Bmi1 alteration in early-stage was explored in a rat model and HaCaT cells. After matching, 116 pairs of patients with highly balanced characteristics were included. In univariate analysis, the overall survival (OS), disease-specific survival (DSS), and local recurrence-free survival (LRFS) were poorer in s-OSCC than in p-OSCC (P < 0.05), while their regional metastasis-free survival (RMFS) was parallel (P = 0.112). Multivariate analysis further revealed that radiotherapy history was an independent risk factor for OS, DSS, and LRFS (P < 0.05). IHC results showed that the positive rate of Bmi1 was higher in s-OSCC (P = 0.0027). In a rat model of radiotherapy induced mucositis, Bmi1 upregulation was observed 8 days after irradiation. Consistently, Bmi1 was upregulated in HaCaT cells 1 h after irradiation, and its upregulation was in accord with X-ray exposure duration. In conclusion, the prognosis of s-OSCC is poorer as compared to p-OSCC, which may be attributed to Bmi1 upregulation. PMID- 29479860 TI - Living with family: perceptions of health and subjective well-being of adults with an intellectual disability. AB - BACKGROUND: Little is known about the role of living circumstances to the perception of subjective well-being (SWB) and health of adults with intellectual disability (ID). The aim of the present study was to examine whether living circumstances impact differently on the perception of health and SWB and whether potential differences persist after accounting for other variables (e.g. level of support needs and reporting method). METHODS: Secondary data analysis was undertaken of a large national survey of adults with an ID in England, aged 16 years and over. Participants were identified as living with family (N = 1528) or living out of home (N = 874). RESULTS: The results of t-test and chi-square revealed that levels of health and SWB were perceived as being higher for people living with family than those living in out-of-home settings. Multiple linear regression analyses fitted to explore factors associated with these reported differences revealed that, when controlling for other variables, living with family was highly associated with reports of better SWB. Multiple logistic regression revealed that whilst the health status of people living with families were perceived as better, this was only true when their support needs were low. Poorest health outcomes were found for people with highest support needs who lived with family. CONCLUSIONS: On the whole, the health and well-being of adults living with family were perceived more positively than those living out of home. However, potential health disparities exist for those with high support needs who live with family. Further longitudinal research is needed to explore causes and potential solution to these inequalities. PMID- 29479861 TI - Where have all the children gone? High HIV prevalence in infants attending nutrition and inpatient entry points. AB - INTRODUCTION: Despite notable progress towards PMTCT, only 50% of HIV-exposed infants in sub-Saharan Africa were tested within the first 2 months of life and only 30% of HIV-infected infants are on antiretroviral treatment. This study assessed HIV prevalence in infants and children receiving care at various service entry points in primary healthcare facilities in Uganda. METHODS: A total of 3600 infants up to 24 months of age were systematically enrolled and tested at four regional hospitals across Uganda. Six hundred infants were included and tested from six facility entry points: PMTCT, immunization, inpatient, nutrition, outpatient and community outreach services. FINDINGS: The traditional EID entry point, PMTCT, had a prevalence of 3.8%, representing 19.6% of the total HIV positive infants identified in the study. Fifty percent of the 117 identified HIV positive infants were found in the nutrition wards, which had a prevalence of 9.8% (p < 0.001 compared to PMTCT). Inpatient wards had a prevalence of 3.5% and yielded 17.9% of the HIV-positive infants identified. Infants tested at immunization wards and through outreach services identified 0.8% and 1.7% of the HIV-positive infants respectively, and had a prevalence of less than 0.3%. CONCLUSIONS: Expanding routine early infant diagnosis screening beyond the traditional PMTCT setting to nutrition and inpatient entry points will increase the identification of HIV-infected infants. Careful reflection for appropriate testing strategies, such as maternal re-testing to identify new HIV infections and HIV-exposed infants in need of follow-up testing and care, at immunization and outreach services should be considered given the expectedly low prevalence rates. These findings may help HIV care programmes significantly expand testing to improve access to early infant diagnosis and paediatric treatment. PMID- 29479862 TI - Positive association of plasma leptin with sleep quality in obese type 2 diabetes patients. AB - AIMS/INTRODUCTION: Poor sleep quality is associated with obesity and diabetes. The adipocyte-derived hormone, leptin, was recently shown to underlie the link between abnormal sleep and obesity. We aimed to investigate the association between leptin and sleep quality in type 2 diabetes patients. MATERIALS AND METHODS: In the present cross-sectional study, we studied 182 type 2 diabetes patients, among whom 113 were diagnosed with obesity (body mass index >=25 kg/m2 ). Fasting plasma leptin levels were measured, and sleep architecture was assessed using single-channel electroencephalography. RESULTS: Using unadjusted analyses, the obese type 2 diabetes patients, but not their non-obese counterparts, showed a positive correlation between plasma leptin levels and a parameter for deep sleep assessed by delta power during the first sleep cycle. Multivariate analysis showed that plasma leptin levels were positively associated with delta power, but not with the total sleep time, after adjusting for potential confounders including age, body mass index and the apnea-hypopnea index, in the obesity group. However, neither delta power nor total sleep time was associated with leptin in the non-obesity group. CONCLUSIONS: Plasma leptin levels are independently associated with sleep quality in obese, but not in non obese, type 2 diabetes patients. The present study indicates a favorable relationship between leptin and sleep quality in obese type 2 diabetes patients. PMID- 29479864 TI - Error in Description of Enzyme Range Calculations in Footnote of Table 3 in the Article by Rider et al (Arthritis Rheumatol, May 2017). PMID- 29479865 TI - Error in Percent Increased SRI-6 Response Rate in Subgroup of Atacicept-Treated Patients Versus Placebo in the Article by Merrill et al (Arthritis Rheumatol, February 2018). PMID- 29479863 TI - Long noncoding RNA MALAT1 knockdown reverses chemoresistance to temozolomide via promoting microRNA-101 in glioblastoma. AB - Glioblastoma (GBM) is the most common and lethal tumor of the central nervous system with highly infiltrative and resistant to chemotherapy. Temozolomide (TMZ) is widely used as the first-line treatment for the therapy of GBM. However, a considerable percentage inherent or acquired resistance in GBM accounts for many treatment failures of the TMZ chemotherapy. Therefore, a deeper understanding of the molecular characteristics underlying TMZ resistance and the identification of novel therapeutic target is urgent. Here, we show that MALAT1 was significantly upregulated in TMZ-resistant GBM cells. On the other hand, MALAT1 knockdown reduces TMZ resistance of GBM cells both in vitro and in vivo by inhibiting cell proliferation and promoting apoptosis. We also show that miR-101 overexpression reduced TMZ resistance of GBM cells and played an antagonistic role compared with MALAT1. Importantly, we demonstrate that MALAT1 promoted the chemoresistance through suppressing miR-101 signaling pathway via directly binding it in GBM cells. In conclusion, our study indicates that knockdown of MALAT1 reverses chemoresistance to TMZ via promoting miR-101 regulatory network in GBM and thus offers a novel prognostic marker and potential target for GBM TMZ-based chemotherapy. PMID- 29479866 TI - February 2018 at a glance: heart and brain interaction, prognostic variables, and acute heart failure and post-discharge outcomes. PMID- 29479869 TI - Development of a Strategy Based on the Surface Plasmon Resonance Technology for Platelet Compatibility Testing. AB - BACKGROUND: This study was aimed to establish a novel strategy based on the surface plasmon resonance (SPR) technology for platelet compatibility testing. METHODS: A novel surface matrix was prepared based on poly (OEGMA-co-HEMA) via surface-initiated polymerization as a biosensor surface platform. Type O universal platelets and donor platelets were immobilized on these novel matrices via amine-coupling reaction and worked as a capturing ligand for binding the platelet antibody. Antibodies binding to platelets were monitored in real time by injecting the samples into a microfluidic channel. Clinical serum samples (n = 186) with multiple platelet transfusions were assayed for platelet antibodies using the SPR technology and monoclonal antibody-immobilized platelet antigen (MAIPA) assay. RESULTS: The novel biosensor surface achieved nonfouling background and high immobilization capacity and showed good repeatability and stability after regeneration. The limit of detection of the SPR biosensor for platelet antibody was estimated to be 50 ng/mL. The sensitivity and specificity were 92% and 98.7%. It could detect the platelet antibody directly in serum samples, and the results were similar to MAIPA assay. CONCLUSIONS: A novel strategy to facilitate the sensitive and reliable detection of platelet compatibility for developing an SPR-based biosensor was established in this study. The SPR-based biosensor combined with novel surface chemistry is a promising method for platelet compatibility testing. PMID- 29479870 TI - Comparison of the Temperature Influence on the Activity of Currently Available Procalcitonin Reagents. AB - BACKGROUND: Procalcitonin (PCT) is a stable biomarker for bacterial infections; however, limited data is available on new trivalent reagents. We evaluated temperature influence on the activity of PCT reagents. METHODS: Using both conventional and trivalent reagents, we measured PCT levels of 30 clinical samples, stored residuum at refrigerator (4 degrees C) and room temperature (24 degrees C), and reexamined it after 24 hours. We defined a reduction rate as a percentage of PCT level at 24 hours compared to that after defrost and evaluated a ratio of reduction rate in 4 degrees C to that in 24 degrees C. RESULTS: The reduction rate at room temperature decreased significantly compared to that in the refrigerated condition for all the reagents examined (p < 0.001). In addition, the ratio of reduction rate between the conventional and trivalent reagents showed a significant difference (p < 0.001). CONCLUSIONS: The serum PCT levels significantly decrease at room temperature, particularly when using newer trivalent reagents. PMID- 29479868 TI - Adult nodular lymphocyte-predominant Hodgkin lymphoma: treatment modality utilization and survival. AB - Early-stage nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is associated with a favorable prognosis. Our aim was to evaluate the patterns of care of radiotherapy utilization in this disease and to define the relationship between treatment modality and survival. The National Cancer Database was queried for patients with stages I-II NLPHL diagnosed from 2004 to 2012. Patients were compared based on primary therapy into four categories: radiotherapy, chemotherapy, both, or neither. Covariate-adjusted and propensity score-weighted (PS) Cox proportional hazards models were used, adjusting for potential factors confounding survival. After exclusions, 1420 patients were evaluated, 571 (40%) received radiotherapy alone, 318 (22%) received chemotherapy alone, 351 (25%) received both, and 180 (13%) received neither. Younger patient age (P = 0.001), female gender (P = 0.019), and chemotherapy use (P < 0.001) were associated with decreased radiotherapy utilization. On PS, radiation alone (HR = 0.298, P < 0.001) and chemoradiotherapy (HR = 0.258, P < 0.001) were associated with improved survival compared to no upfront therapy, but the use of chemotherapy alone did not statistically differ compared to no initial therapy (HR = 0.784, P = 0.078). In this large database analysis, over one-third of patients with early stage NLPHL did not receive radiotherapy as a component of initial therapy. The omission of upfront radiotherapy was associated with inferior survival. PMID- 29479867 TI - Retention and mortality on antiretroviral therapy in sub-Saharan Africa: collaborative analyses of HIV treatment programmes. AB - INTRODUCTION: By 2020, 90% of all people diagnosed with HIV should receive long term combination antiretroviral therapy (ART). In sub-Saharan Africa, this target is threatened by loss to follow-up in ART programmes. The proportion of people retained on ART long-term cannot be easily determined, because individuals classified as lost to follow-up, may have self-transferred to another HIV treatment programme, or may have died. We describe retention on ART in sub Saharan Africa, first based on observed data as recorded in the clinic databases, and second adjusted for undocumented deaths and self-transfers. METHODS: We analysed data from HIV-infected adults and children initiating ART between 2009 and 2014 at a sub-Saharan African HIV treatment programme participating in the International epidemiology Databases to Evaluate AIDS (IeDEA). We used the Kaplan Meier method to calculate the cumulative incidence of retention on ART and the Aalen-Johansen method to calculate the cumulative incidences of death, loss to follow-up, and stopping ART. We used inverse probability weighting to adjust clinic data for undocumented mortality and self-transfer, based on estimates from a recent systematic review and meta-analysis. RESULTS: We included 505,634 patients: 12,848 (2.5%) from Central Africa, 109,233 (21.6%) from East Africa, 347,343 (68.7%) from Southern Africa and 36,210 (7.2%) from West Africa. In crude analyses of observed clinic data, 52.1% of patients were retained on ART, 41.8% were lost to follow-up and 6.0% had died 5 years after ART initiation. After accounting for undocumented deaths and self-transfers, we estimated that 66.6% of patients were retained on ART, 18.8% had stopped ART and 14.7% had died at 5 years. CONCLUSIONS: Improving long-term retention on ART will be crucial to attaining the 90% on ART target. Naive analyses of HIV cohort studies, which do not account for undocumented mortality and self-transfer of patients, may severely underestimate both mortality and retention on ART. PMID- 29479871 TI - The Relationship between Trypsin/Calcitonin Gene Related Peptide (CGRP) in Serum and Acute Pancreatitis (AP). AB - BACKGROUND: Activation of trypsin from proteolytic cleavage of trypsinogen in the pancreas can lead to acute pancreatitis. Calcitonin gene related peptide (CGRP) from both peripheral and central neurons is involved in a variety of physiological/pathophysiological processes, especially sensory (nociceptive) and efferent (effector) functions. To better understand the change of trypsin/CGRP in acute pancreatitis, the study investigated the serum level of trypsin/CGRP in patients with acute pancreatitis. METHODS: The study investigated 140 patients with acute pancreatitis, including 72 cases of biliary acute pancreatitis, 60 cases of hyperlipidemic acute pancreatitis, and 8 cases of idiopathic acute pancreatitis. Sixty volunteers acted as the normal control group. The levels of trypsin and CGRP in serum were analyzed. RESULTS: The serum levels of trypsin and CGRP in males with acute pancreatitis were higher than in females, but there was no statistical difference (p > 0.05). However, the serum levels of trypsin and CGRP in different types of acute pancreatitis were significantly higher than controls (p < 0.001), and the level of trypsin and CGRP in serum of patients with inflammation effusion was significantly higher than patients without inflammation effusion (p < 0.001). In addition, the serum levels of trypsin and CGRP in patients with I-II, III, IVA and IVB acute pancreatitis were higher than controls (p < 0.001). CONCLUSIONS: According to the results, we concluded that the trypsin and CGRP in serum can act as a new detection index of acute pancreatitis occurring. The serum levels of trypsin and CGRP in patients with acute pancreatitis is able to determine whether inflammation effusion happens. PMID- 29479872 TI - Associations of Vitamin D Levels and Vitamin D Receptor Genotypes with Patient Reported Outcome/Disease Activity in Patients with Rheumatoid Arthritis. AB - BACKGROUND: The aim of this study is to evaluate the prevalence of vitamin-D insufficiency and vitamin-D receptor (VDR) polymorphisms in rheumatoid arthritis (RA) patients and its association with disease activity and patient reported outcomes (PROs). METHODS: Eighty-two individuals were included in a cross sectional study (41 RA patients, 41 controls). Prior to assessment, each patient completed a PRO questionnaire. Serum vitamin-D levels and genotyping for VDR were assessed. Vitamin-D deficient patients received vitamin-D supplementation. Re assessment of disease activity (DAS28) was performed after 9-months. RESULTS: Low vitamin-D levels were more frequent in RA patients (p < 0.01). A negative, but insignificant, association with DAS-28 score was identified; whereas, there was a significant negative association with the PROs (p < 0.01). Vitamin-D supplementation was associated with significant improvement in the patients' scores for pain, fatigue, global assessment, physical disability, and quality of life. In contrast to the control group, the frequency of the recessive TaqI and FokI genotypes was higher in RA patients. CONCLUSIONS: In RA patients, serum vitamin-D level was significantly and inversely associated with both PROs and disease activity. The TaqI and FokI fragment length polymorphisms of VDR significantly contributed to the risk of RA. Having a significant positive impact on patient reported outcomes, vitamin-D supplementation may have a role in RA management. PMID- 29479873 TI - Fibulin-5 is Down-Regulated in Colorectal Cancer and Correlated with Clinicopathologic Characteristics. AB - BACKGROUND: Fibulin-5 has recently been considered as a potential tumor suppressor in human cancers. Several studies have shown that it is down-regulated in a variety of tumor types and inhibits tumor growth and metastasis. In this study, the expression of fibulin-5 in colorectal cancer (CRC) and its clinical significance were assessed. METHODS: Fibulin-5 expression was detected in 31 samples of surgically resected CRC and paired noncancerous tissues using western blot, qRT-PCR, and immunoblotting. RESULTS: In this study, the expression levels of fibulin-5 protein and mRNA were down-regulated in CRC tissues as compared with those in paired noncancerous tissues. Low expression of fibulin-5 was significantly correlated with poor prognostic features including lymph node metastasis and advanced tumor-node-metastasis (TNM) tumor stage. CONCLUSIONS: Fibulin-5 is down-regulated in CRC and the reduced expression of fibulin-5 was correlated with malignant clinicopathological characteristics. PMID- 29479874 TI - Association between EZH2 Genetic Variants and Hepatocellular Carcinoma in a Chinese Han Population. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Studies have shown that EZH2, as the member of the Polycomb groups (PcGs) family, plays an important biological role in the occurrence and development of HCC. The association between the genetic variants of EZH2 and HCC is not yet fully established. METHODS: In this study, we used 175 patients with HCC and 209 healthy volunteers' blood samples of Chinese Han population to further analyze the relationship between EZH2 variants and HCC susceptibility. RESULTS: The results showed significant differences in distribution of alleles rs2302427 and rs3757441 between patients and the controls (p < 0.05). The three SNPs of EZH2 investigated show significant association with the elevated risk of HCC (p < 0.05) in addition to the overdominant model of rs3757441 and recessive model of rs41277434 (p > 0.05). The haplotype analysis of the three EZH2 SNPs revealed that the CCA and GTA haplotypes were associated with a higher risk of HCC (p < 0.05). CONCLUSIONS: The results of these experiments indicated that the presence of EZH2 variants was significantly associated with HCC, and these variants could be useful genetic markers for predicting susceptibility to HCC in a Chinese Han population. PMID- 29479875 TI - Clinical Utility of Ordered Pathology Blood Smear Reviews - an Overused Resource? AB - BACKGROUND: Blood smear reviews by pathologists (BSR) are ordered frequently at our institution, take time to evaluate, and result in a written report. Minimal research has been done regarding the amount of novel data reported and its clinical utility. METHODS: Detailed chart review was performed on BSR orders from January 1, 2015 to March 31, 2015 to assess reasons for smear review, if results were mentioned in the chart, if laboratory-driven reviews were already performed, and if novel, clinically influential data was reported. The trends in ordering was also evaluated. RESULTS: A total of 277 reviews were performed and were most commonly ordered to evaluate the presence of malignancy (43%), hemolysis (18%), and anemia (16%). For 130 of the 277 specimens, laboratory-driven smear review was already performed. The BSR smear review findings were not mentioned in the patient chart in 52% of cases. The report provided novel data in 187 cases (68%) which mainly were minor findings such as low levels of red blood cell abnormalities. The novel data appeared to influence clinical decision making in only 3 cases (1%). CONCLUSIONS: Although novel data are often reported, only rarely does it appear to be clinically significant and the information frequently overlaps with information already provided by laboratory-initiated smear reviews. Discussion with, and education of, clinical staff may increase appropriate utilization. PMID- 29479876 TI - Role of the Fibrinogen Degradation Products and D-Dimer in the Differential Diagnosis of Pulmonary Tuberculosis and Community-Acquired Pneumonia. AB - BACKGROUND: Differential diagnosis between pulmonary tuberculosis (TB) and community acquired pneumonia (CAP) is often difficult. Pulmonary TB could induce a systemic hypercoagulable state. The present study aims to investigate whether fibrinogen degradation products (FDP) and D-dimer play a diagnostic role for pulmonary TB. METHODS: We retrospectively analyzed the clinical and laboratory characteristics of 192 patients with activated pulmonary TB and 110 patients with CAP. The serum levels of FDP and D-dimer were detected and the diagnostic ability was evaluated. RESULTS: The serum levels of FDP and D-dimer were significantly higher in patients with pulmonary TB compared to CAP (both p < 0.05). ROC curve analyses showed that the diagnostic value of FDP in pulmonary TB was noticeably higher than that of D-dimer (p = 0.0197). Combined detection of FDP and D-dimer may slightly improve the sensitivity of diagnosis for pulmonary TB from CAP. However, the AUC showed no significant differences from FDP alone (p = 0.416). CONCLUSIONS: The serum level of FDP and D-dimer are useful laboratory markers that can be used to distinguish patients with pulmonary TB from patients with CAP. PMID- 29479877 TI - Real Time and Label-Free Research on the Detection of Pituitary Adenylate Cyclase Activating Polypeptide Based on Surface Plasmon Resonance Technique. AB - BACKGROUND: The self-developed portable surface plasmon resonance (SPR) biosensor was used in the quantitative detection and kinetic study of pituitary adenylate cyclase-activating polypeptide (PACAP), as the existing detection methods were complicated, with a long detection period, high-cost instrument, and sample needing to be labeled. METHODS: After preparing SPR biochip, the direct detection proceeded in an immune reaction detection between the PACAP samples with concentrations of 0.5 mg/L, 1 mg/L, 2 mg/L, 5 mg/L, 8 mg/L, 10 mg/L, and PACAP type 1 receptor (PAC1R). The standard curve of PACAP direct detection was established. According to the 1:1 Langumair model, the immune responses dynamic characteristic parameters of PAC1R with PACAP-38, and their reconstructive PN37R, PK38W were calculated, respectively. RESULTS: The direct detection limit of PACAP could be 0.5 mg/L. The absolute deviation and relative deviation of the detected value and the true value are both low. The magnitude orders of kinetic parameters of immune response between PAC1R and PACAP-38, PK38W, PN37R are basically the same. However, the specific values of the binding rate constant and dissociation rate constant of PK38W and PN37R are slightly larger than that of PACAP-38. CONCLUSIONS: The experimental results show that the SPR biochip detection system can be used for the effective quantitative detection of PACAP and can be used for kinetic study. The developed device could provide a labelfree, simple, quick, and low-cost method for the concentration detection of PACAP in the samples and the immune response study between PACAP and its receptors. It could promote PACAP to play an important role in the pharmaceutical industry, clinical treatment, and other industries. PMID- 29479878 TI - Point-of-Care Testing: General Aspects. AB - Point-of-Care Testing (POCT) has been highlighted in the health care sector in recent decades. On the other hand, due to its low demand, POCT is at a disadvantage compared to conventional equipment, since its cost is inversely proportional to the volume of use. In addition, for the implementation of POCT to succeed, it is essential to rely on the work of a multidisciplinary team. The awareness of health professionals of the importance of each step is perhaps the critical success factor. The trend towards the continuous advancement of the use of POCT and the great potential of its contributions reinforce the need to implement quality management tools, including performance indicators, to ensure their results. This review presents some advantages and disadvantages concerning POCT and the real need to use it. A worldwide call for the availability of easy to-use health technologies that are increasingly closer to the final user is one of the main reasons for this focus. PMID- 29479879 TI - A Significant Difference in the Blood Carnitine Values Obtained by the Enzymatic Cycling and Tandem Mass Spectrometry Methods. AB - BACKGROUND: There are no reports in the literature of blood samples obtained from the same individual being subjected to analysis at the same time using the enzymatic cycling (EC) method along with electrospray tandem mass spectrometry (ESI/MS/MS) before and after carnitine treatment. METHODS: Blood samples from 29 patients (median age: 73 years old, age range: 41 - 89 years) receiving regular hemodialysis for chronic renal failure before and after carnitine treatment for 3 months were measured by the EC method, and using a dried blood spot (DBS) and ESI/MS/MS. RESULTS: Before the carnitine treatment, the rate of increase or decrease in the free and acyl-carnitine levels of the DBS using the ESI/MS/MS method to those measured by the EC methods was a median of -28.6% (-36.0 to 14.1%) and -20.8% (-30.0 to 1.5%), respectively. After carnitine treatment, the rate of increase or decrease in the free and acyl-carnitine levels of the DBS with the ESI/MS/MS method compared to the EC method was a median of 52.0% (28.4 to 66.7%) and -31.9% (-47.2 to -21.1%), respectively. CONCLUSIONS: There were significant differences in the blood carnitine values using the ESI/MS/MS and EC methods. Caution should be exercised when evaluating DBS values measured by the ESI/MS/MS method. PMID- 29479880 TI - Lesch-Nyhan Syndrome in a Chinese Family with Mutation in the Hypoxanthine Guanine Phosphoribosyltransferase Gene. AB - BACKGROUND: Lesch-Nyhan syndrome (LNS) is a congenital X-linked recessive neurogenetic disorder caused by mutations in the hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene. The main clinical manifestation includes hyperuricemia, juvenile-onset gouty arthritis, and neurological developmental disorders. Studies have reported more than 400 HPRT gene mutation sites, but the incidence of LNS in the Chinese population is extremely low. METHODS: Here we report a 16-year-old male patient who suffered neurological dysfunction at an early age and gouty arthritis in his youth. RESULTS: No activity of the HPRT enzyme was detected in the erythrocytes. Furthermore, we found a mutation on exon 3 of the HPRT gene in the patient and his mother (exon 3: c.143G>A), which resulted in arginine to histidine (p.R48H) substitution in the encoded protein. The same mutation was reported in several European families, but was found for the first time in a Chinese family. CONCLUSIONS: Clinicians in China have poor experience in diagnosing LNS cases due to the low incidence in China. Therefore, LNS screening for infants or adolescents with hyperuricemia, gouty arthritis, and neurological dysfunction should be performed. PMID- 29479881 TI - The Relationship Between Serum Thiol Levels and Thiol/Disulfide Homeostasis with Head Trauma in Children. AB - BACKGROUND: Oxidative stress may induce brain injury. Thiols are one of the most important antioxidant agents, and thiol/disulphide (SH/SS) homeo stasis is a novel oxidative stress marker. The goal of the study was to investigate the relationship of thiol levels and SH/SS homeostasis with head trauma in pediatric patients. METHODS: This prospective study was conducted in 85 consecutive pediatric patients aged < 18 years with isolated head trauma and 58 age- and gender-matched healthy controls in the Emergency Department (ED). RESULTS: The mean age was 4.40 +/- 3.03 years for the patient group and 4.75 +/- 1.81 years for the controls (p > 0.05). There were no significant differences in biochemical parameters including serum albumin, urea, alanine aminotransferase, total bilirubin, uric acid, high-sensitivity C-reactive protein (hs-CRP), and white blood cells (WBC) in the patient and control groups (for each, p > 0.05). The thiol (SH) level was significantly higher in the patient group than in the controls (388.83 +/- 51.949 vs. 369.04 +/- 37.62 MUmol/L; p = 0.009). The total thiol (TT) level was somewhat higher in the patient group, but the difference was not significant (416.11 +/- 47.29 vs. 405.08 +/- 35.27 MUmol/L; p = 0.113). The disulphide (SS) level was lower in the patient group (p < 0.001). The SS/SH and SS/TT ratios were significantly lower in the patient group, while the SH/ TT ratio was significantly higher (p < 0.001). CONCLUSIONS: Analysis of serum thiol levels and SH/SS homeostasis might be useful in order to determine the head trauma in pediatric patients. PMID- 29479882 TI - Cadmium and Lead in Women Who Miscarried. AB - BACKGROUND: Cadmium (Cd) and lead (Pb) are toxic elements which, when ingested excessively in food and drinking water, accumulate in selected organs and pass through the placenta barrier to the foetus, showing teratogenic effects. The aim of the study was to determine the concentration of Cd and Pb in blood and placental tissue in women who miscarried. METHODS: The study group consisted of 83 women who miscarried. The control group included 35 women in the first trimester of pregnancy and after childbirth. The experimental materials consisted of whole blood and fragments of placental tissue. The concentrations of Cd and Pb were determined using atomic absorption spectrometry (AAS) with electrothermal atomization in a graphite furnace and by Inductively Coupled Plasma Mass Spectrometry (ICP-MS) in standard mode. RESULTS: The average concentration of Cd (2.730 +/- 2.07 ug/L) and Pb (35.54 +/- 11.0 ug/L) in the blood of women with miscarriage was higher in comparison to the level of these toxic metals in the blood of women from the control group (Cd 1.035 +/- 0.59 ug/L; Pb 27.11 +/- 4.6 ug/L). The average Cd (214.4 +/- 514 ug/L) and Pb (199.6 +/- 348 ug/L) content in the placenta of women with miscarriage was higher in comparison to the amount of these elements in the placenta of women from the control group (Cd 127.4 +/- 85 ng/L; Pb 26.35 +/- 7.9 ng/L). Tobacco smoking significantly affected cadmium blood levels and the placental tissue content in women who miscarried. CONCLUSIONS: Elevated Cd and Pb concentrations in the blood and placenta of pregnant women may be connected with the occurrence of miscarriage; therefore, the levels of these heavy metals should be monitored in women who plan pregnancy. It seems that determining the level of molar ratio between toxic metal and antioxidant elements can be analyzed as a marker for selection for control examinations as a valuable complement to existing diagnostic procedures in prevention, especially in early pregnancy. Additional diagnostic methods should be established as new tools in perinatal care in order to enable early diagnosis of pregnancy pathology and, especially, to prevent miscarriage. PMID- 29479883 TI - Use of the Polymerase Chain Reaction as a Complementary Method for the Detection of Central Nervous System Involvement in Children and Adolescents with Acute Lymphoblastic Leukemia. AB - BACKGROUND: Cytological analysis of the cerebrospinal fluid (CSF) remains the most widely used method for diagnosing central nervous system (CNS) involvement in acute lymphoblastic leukemia (ALL). This study aimed at evaluating the use of polymerase chain reaction (PCR), in comparison to other methods, for the assessment of the presence of blast cells in the CSF at the time of diagnosis of ALL. METHODS: This was a prospective, single-centre, study enrolling all patients up to the age of 18 years who were admitted to a university hospital between November 2011 and November 2014 with a diagnosis of ALL and from whom it was possible to draw a sufficient amount of CSF for analysis by conventional cytology (CT), immunophenotyping (IMP), and PCR. RESULTS: A total of 46 CSF samples from 44 ALL pediatric patients were included. CT was performed in all samples, IMP in 44, and PCR in 34. Thirteen (28.2%) samples showed positive results: two by CT, four by IMP, four by PCR, and three by both IMP and PCR. CONCLUSIONS: The results of this study showed that PCR should be considered a complementary method for the evaluation of the CSF in ALL patients at diagnosis. PMID- 29479884 TI - Extramedullary Blast Crisis in a Patient with T315I BCR-ABL Mutated Chronic Myeloid Leukemia. AB - BACKGROUND: Extramedullary blast crisis (EBC) of T315I BCR-ABL mutated chronic myelogenous leukemia (CML) is extremely rare. METHODS: We report an unusual case characterized by fever, right shoulder swelling, pleural effusion, and multiple bone destruction as the first signs of EBC of T315I BCR-ABL mutated CML. RESULTS: The patient did not respond to chemotherapy consisting of anthracyclines, cytarabine and etoposide. His condition improved after the treatment with ponatinib combined with allogenic stem cell transplantation (alloHCT), but soon worsened after ponatinib withdrawal. He got slight relief after he continued ponatinib. CONCLUSIONS: Ponatinib is an important treatment to control EBC even after allo-HCT. PMID- 29479885 TI - Comparison of Immunoassay and Liquid Chromatography-Tandem Mass Spectrometry Methods in the Measurement of Serum Androstenedione Levels. AB - BACKGROUND: Recent reports have described inherent problems with androgen immunoassays compared with mass spectrometry analyses. In this study, a new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed according to CLSI rules. The developed method was compared with two immunoassay methods, the enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA). METHODS: After liquid-liquid extraction, a Shimadzu Prominence LC unit coupled to an ABSCIEX API 3200 mass spectrometer with atmospheric pressure chemical ionization was used to quantify serum androstenedione levels. Serum androstenedione results taken from tandem mass spectrometry were compared with the immunoassays. RESULTS: The androstenedione assay was linear up to 50 ng/mL. Lower limit of quantitation and lower limit of detection were 0.195 ng/mL and 0.097 ng/mL, respectively. This method was not affected by matrix effect and other steroid hormone interferences. In this study, the obtained recovery was 69 99%, carryover value was determined as 0.026 ng/mL. According to the results of an interference study, androstenedione bias % did not exceed the limit of allowable bias % and 88.7% recovery was acquired for androstenedione. In the LC MS/MS and ELISA comparison study, the slope value was found as 18.412, intercept 22.87, and r2 value as 0.1033. In the LC-MS/MS and RIA comparison study, slope value was found as 1.085, intercept 0.4541, and r2 value as 0.3712. In the RIA and ELISA comparison study, slope value was found as 9.57, intercept -15.5, and r2 value as 0.19. CONCLUSIONS: The LC-MS/MS provides agreement with the results of radioimmunoassay but not with ELISA. This method offers better selectivity compared to immunoassay systems. PMID- 29479886 TI - Application of Bone Turnover Markers PICP and beta-CTx in the Diagnosis and Treatment of Breast Cancer with Bone Metastases. AB - BACKGROUND: This study is to investigate the application of the bone turnover markers type I procollagen carboxyterminal propeptide (PICP) and beta-isomerized forms of type I collagen breakdown products (beta-CTx) in the diagnosis and treatment of breast cancer with bone metastases. METHODS: A total of 162 breast cancer patients were included in this study. There were 70 cases with bone metastasis (BM group) and 92 cases without bone metastasis (non-bone metastasis, NBM group). The levels of the bone turnover markers PICP and beta-CTx were measured using Electro-Chemiluminescence Immunoassay to compare the difference between BM and NBM group, before and after treatments in the NBM group, and to analyse the relationship with therapeutic effects. RESULTS: The BM group had higher PICP and beta-CTx levels than the NBM group and also higher in the non luminal type group than the luminal type group, the differences were all statistically significant. However, no statistically significant differences were found among the pN0, pN1, pN2, and pN3 subgroups of the NBM group. Among the 70 cases of BM patient after 3 months of treatment, there were 48 cases that showed clinical benefits, with significantly reduced PICP and beta-CTx levels (p = 0.02, p = 0.00, respectively), but 22 cases showed disease progression with elevated PICP and beta-CTx levels (p = 0.01, p = 0.04, respectively). CONCLUSIONS: The bone turnover markers PICP and beta-CTx have crucial value in the diagnosis and treatment efficacy evaluation for women of breast cancer with bone metastases. PMID- 29479887 TI - Niemann-Pick Disease, Type C1 Gene Expression in PBMCs is Associated with Interleukin 10 Serum Concentration: a Case-Control Study. AB - BACKGROUND: Recent studies showed that atherosclerosis is a lysosomal storage disease (LSD) and Niemann-Pick disease type C1 (NPC1) is the most important protein of the lysosomal membrane that is involved in the removal of FC from lysosomes. Whereas several in vitro and in vivo studies have described the crosstalk between lysosomal cholesterol accumulation and increased inflammation, there is no study addressing the correlation between NPC1 gene expression and an anti-inflammatory cytokine, interleukin 10 (IL-10) serum concentration in atherosclerotic patients. METHODS: IL-10 and 25-hydroxyvitamin D serum concentrations were quantified by enzyme-linked immunosorbent assay (ELISA) in atherosclerotic patients (n = 40) and a control group (n = 40). NPC1 gene expression analysis was performed by quantitative real-time PCR, and correlation between the two parameters was assessed. RESULTS: Mean IL-10 serum concentration and peripheral blood mononuclear cells' (PBMCs) gene expression of NPC1, adjusted for drug consumption, age, and BMI, was not significantly different between the patient and control groups (p = 0.6 and 0.67 respectively). However, NPC1 gene expression showed positive significant correlation with IL-10 serum concentration (p = 0.04, r = 0.29). We also observed lower serum concentration of IL-10 in the subjects with lower 25-hydroxyvitamin D serum concentration (p = 0.034). CONCLUSIONS: Our findings supported the previous observations showing the contribution of lysosomal lipid homeostasis of PBMCs to inflammation and pathogenesis of atherosclerosis. PMID- 29479888 TI - Decreased Serum Level of miR-155 is Associated with Obesity and its Related Metabolic Traits. AB - BACKGROUND: Type 2 diabetes is the most common metabolic disease, affecting many of the adult population all around the world. In recent years much attention has been paid to the role of circulating miRNAs as novel biomarkers for various diseases. The aim of this study was to investigate the expression level of miR 155 in serum samples of diabetic and healthy subjects. METHODS: 42 healthy and 45 type 2 diabetic subjects participated in the study. Serum miR-155 level of the subjects was measured using real-time PCR. The levels of IL-6 and TNF-alpha were quantified using ELISA. RESULTS: There was no significant difference in the level of miR-155 between the diabetic and non-diabetic groups. The level of miR-155 in non-diabetic obese group was significantly lower than the non-diabetic lean subjects. Correlation analyses in non-diabetic group revealed a significant negative correlation between the amount of miR155 and body mass index and cholesterol levels after the elimination of the confounding factors. In diabetic group, a negative correlation was found between miR-155 and insulin, HOMA-IR, and waist circumference levels. Furthermore, no significant relationship between miR 155 and inflammatory cytokines (TNF-alpha and IL-6) was observed in both diabetic and healthy groups. CONCLUSIONS: A reduced level of miR-155 might associate with obesity and its related metabolic traits such as hyperinsulinemia and dyslipidemia. PMID- 29479889 TI - Reference Intervals of Cytokeratin-19 Fragment (CYFRA 21-1) in Healthy Adults in China. AB - BACKGROUND: The reference intervals for serum cytokeratin-19 fragment (CYFRA 21 1) have not been established in Chinese population. This study aimed to measure serum CYFRA 21-1 levels in healthy Chinese subjects. METHODS: This cross sectional, four-center study in two Chinese provinces enrolled participants (aged 18 - 85 years) with normal liver/kidney function and normal results for routine blood tests/urinalysis. Serum CYFRA 211 level was measured by ARCHITECT immunoassay (Abbott Diagnostics). RESULTS: The study included 3,366 participants. The median (interquartile range) value for serum CYFRA 21-1 level was 1.38 (1.00 1.89) ng/mL and tended to increase with age. The upper limit of the 97.5th percentile was 3.55 ng/mL and tended to increase with age. Serum CYFRA 21-1 median level varied between the four centers from 1.22 (0.89, 1.71) to 1.55 (1.12, 2.18) ng/mL, while the 97.5th percentile varied from 3.24 to 4.09 ng/mL. CYFRA 21-1 level correlated weakly with age and creatinine level. CONCLUSIONS: These new data can help to establish the 'normal range' of serum CYFRA 21-1 in people in China. PMID- 29479890 TI - CircRNAs as Potential Biomarkers in Gastrointestinal Tract Tumors: Opportunities and Challenges. AB - Most digestive system tumors have poor prognoses due to the lack of specific biomarkers. Circular RNAs (circRNAs) regulate the expression of genes and play essential roles in digestive system tumorigenesis. Here we review circRNA functions in gastrointestinal tract tumors. CircRNAs are promising biomarkers for clinical applications for gastrointestinal tract tumors. PMID- 29479891 TI - The Clinical Implications of Thrombelastography in the Diagnosis of Acute Cerebral Infarction. AB - BACKGROUND: Thrombelastography (TEG) is an analyzer reflecting the dynamic changes of blood coagulation. It has been used as a diagnosis index in many diseases. The aim of this study was to evaluate the relationship between TEG and acute cerebral infarction. METHODS: Eighty patients with acute cerebral infarction and 80 healthy controls were enrolled. Each patient's TEG results and routine coagulation indices were recorded. All analyses were conducted with SPSS16.0 software. RESULTS: Patients with acute cerebral infarction showed lower TEG R and K levels but higher TEG MA levels. There was a significantly negative correlation between TEG R and fibrinogen in the patient group. In addition, receiver operator characteristic curve analysis showed that TEG MA (cutoff value 63.9 mm) was a predictor of acute cerebral infarction (AUC value = 0.741, sensitivity 61%, specificity 81%). CONCLUSIONS: TEG results have important clinical implications in the early diagnosis of acute cerebral infarction. PMID- 29479892 TI - Anticoagulant Choices Affect the Mean Platelet Volume Measurement by Impedance. AB - BACKGROUND: Mean platelet volume (MPV) is a parameter that evaluates the platelet size. Clinical applications of MPV are limited because of its poor standardization in routine laboratories. This study analyzed the effect of anticoagulants on MPV measurements by impedance technology. METHODS: Blood from 36 healthy volunteers was collected in vacuum tubes filled with K2EDTA and sodium citrate, analyzed immediately (basal) and at 1, 2, and 3 hours after venipuncture. RESULTS: Comparisons between the anticoagulants demonstrated a significant difference (p < 0.05) after 1 hour of exposure with K2EDTA, causing a time-dependent increase on MPV measured. No significant changes in MPV were observed with sodium citrate with 3 hours of exposure (p > 0.05). CONCLUSIONS: The use of sodium citrate is highly indicated for assessment of MPV when the measurement time after blood collection is estimated to be more than 1 hour. PMID- 29479893 TI - Analysis of miRNA-221 Expression Level in Tumors and Marginal Biopsies from Patients with Breast Cancer (Cross-Sectional Observational Study). AB - BACKGROUND: miRNA-221 and miRNA-222 are two homologous microRNAs, the high expression levels of which have been commonly demonstrated in the most current human cancer types as well as breast cancer. The purpose of this research was to determine the clinical value of measuring the expression level of hsa-miR-221-3p in breast cancer tissues and evaluate its biological and prognostic importance in breast cancer (BC). METHODS: A total of 40 tumor samples and matched tumor-free margin specimens were obtained during surgery from patients with BC. After total RNA extraction and cDNA synthesis, the relative expression level of hsa-miR221-3p in tumor and marginal tissues was examined by quantitative real-time PCR. Moreover, the association between hsa-miR-221-3p expression and clinicopathological features of patients was detected. RESULTS: The relative expression level of hsa-miR-221-3p in BC tissues was significantly higher than that in adjacent noncancerous breast biopsies (p <= 0.0001). Also, there was no significant association between hsa-miR-221-3p expression with clinicopathological characteristics (p > 0.05). The receiver operating characteristic (ROC) curve analyses also represented an optimum cutoff point of < 4.34 to show that hsa-miR-221-3p is an effective molecular biomarker for BC diagnosis. CONCLUSIONS: This study illustrated that analysis of hsa-miR-221-3p relative gene expression may be applied as a biomarker for screening BC patients and could be a substantial tool in diagnosis and prognosis. Also, that could be advantageous in decreasing surgical mistakes in tumor elimination through the surgery and enhancing all over the progression of surgery with reformed tumor clearance. PMID- 29479894 TI - Diagnostic Value of MicroRNA-18a for Gastric Cancer: a Meta-Analysis. AB - BACKGROUND: Emerging data demonstrated that circulating microRNA-18a (miR-18a) expression level was significantly different between gastric carcinoma individuals and healthy groups, implying that miR-18a may be a potential biomarker for gastric cancer. Nevertheless, the reports remain inconsistent. This meta-analysis was performed to evaluate the diagnostic value of miR-18a in gastric tumor detection. METHODS: All the relevant papers were searched and collected until July 2017 in PubMed, Cochrane Library, Wiley Online Library, Chinese National Knowledge Infrastructure (CNKI), Technology of Chongqing (VIP), and Wanfang Database. Data was extracted from eligible studies. Diagnostic performance of miR-18a for gastric cancer were evaluated using STATA (version 12.0) and MetaDisc (version 1.4) statistical software. RESULTS: Three studies were included in this meta-analysis with a total of 235 gastric cancer patients and 136 controls enrolled. The pooled sensitivity and specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) of circulating miR-18a to discriminate GC patients were 0.76 (95% confidence interval CI: 0.70, 0.81), 0.73 (95% CI: 0.65, 0.80), 2.76 (95% CI: 2.08, 3.65), 0.32 (95% CI: 0.19, 0.55), and 9.12 (95% CI: 4.36, 19.09), respectively. The area under the summary receiver operator characteristic (SROC) curve was 0.82. CONCLUSIONS: miR-18a could be a promising noninvasive biomarker in gastric carcinoma diagnosis. Further prospective studies should be conducted to highlight the theoretical strengths before its use in clinic. PMID- 29479895 TI - A Cryopellet Containing Silica Can Activate Intrinsic Blood Coagulation in Rotational Thromboelastometry. AB - BACKGROUND: The use of colloidal silica contained in different cryopellet formulations is examined as a contact activator of blood in an intrinsic coagulation test. In particular the necessary amount of silica per cryopellet was determined, as well as the interfering effects of cryopellet components on coagulation. METHODS: Cryopellets were prepared using an established technique and were tested by rotational thromboelastometry using recalcified whole blood. The clotting time (CT) and maximum clot firmness (MCF) were determined from the dynamic coagulation profiles. RESULTS: Levels of silica of 25 - 75 ug per cryopellet weight of 1.25 mg reduced CT to below 200 seconds and gave good MCF. Trehalose had no effects of coagulation, whereas mannitol reduced CT by a third. The incorporation of silica in the liquid feed used for cryopelletization did not inhibit uniformity of droplet and hence cryopellet weight. The activating activity of the silica [CT and MCF] was the same as that of a classic intrinsic assay using ellagic acid. CONCLUSIONS: A silica-containing cryopellet can be prepared and works as well as ellagic acid as an activator in intrinsic rotational thromboelastometry. A cryopellet avoids dilution of the whole blood sample and hence also of coagulation-relevant blood components that can alter the coagulation result. PMID- 29479896 TI - Evaluation of Serum alpha-Fetoprotein Levels During Different Infection Phases of CHB Patients. AB - BACKGROUND: Chronic hepatitis B patients carry a high risk of developing hepatocellular carcinoma (HCC). alpha-Fetoprotein (AFP) is one of the most commonly used and reliable biomarkers for HCC. However, the AFP level during different phases of CHB is not well understood. We aimed to identify the AFP levels during the different infection phases of CHB patient and explore which phase is at high risk of developing HCC. METHODS: Three hundred and fifty-five CHB patients were divided into four groups: a. immune tolerant HBeAgpositive phase (IT); b. immune reactive HBeAg-positive phase (IR), c. inactive carrier state (IC), d. HBeAg-negative activation phase (ENA). The risk of development of HCC in different group is assessed by the serum AFP levels. An electrochemiluminescence assay was used to analyze serum AFP levels. RESULTS: Mean AFP levels were different in each phase of CHB (p < 0.001): IT (9.6 ng/mL), IR (33.7 ng/mL), IC (3.2 ng/mL), and ENA (71.6 ng/mL). The ENA phase had the highest AFP level and IC phase has the lowest. There was no correlation between serum AFP level and HBV viral load. A significant correlation between serum ALT levels and HBV viral load was observed (r = 0.272, p < 0.01). CONCLUSIONS: These findings suggest that high levels of AFP during HBeAg-negative activation phase (ENA) may be associated with a high risk of developing of HCC. Furthermore, higher burden of HBV viral load is associated with more severe liver damage. PMID- 29479897 TI - The rs2839698 Single Nucleotide Polymorphism of lncRNA H19 is Associated with Post-Operative Prognosis in T3 Gastric Adenocarcinoma. AB - BACKGROUND: It has been widely demonstrated that long non-coding RNA H19 (lncRNA H19) plays an important role in the progression of various human cancers. However, the associations of common genetic variations with recurrence and survival in gastric adenocarcinoma in this lncRNA remain largely unknown. METHODS: The rs2839698 single nucleotide polymorphism (SNP) of H19 was genotyped in tissue samples from 441 patients with T3 gastric adenocarcinoma who had surgical operations between 2004 to 2009, and the relationships between the different genotypes and recurrence and survival after surgery alone (n = 156) or surgery plus chemotherapy (n = 285) were assessed using 3 different statistical methods. RESULTS: Based on the final day of investigation (November 2014), the GA genotype was significantly associated with recurrence and survival in patients treated with surgery alone, but not in patients treated with surgery plus chemotherapy. In patients treated with surgery alone, individuals with the GA genotype had significantly lower risks of recurrence and death [adjusted hazard ratio (HR) 0.57, 95% CI 0.37 - 0.88; adjusted HR: 0.58, 95% CI 0.38 - 0.88] than the GG genotype (p = 0.010 and p = 0.010), respectively. More importantly, patients treated with surgery alone who carried the GA genotype achieved significantly longer median disease-free survival time and overall survival than carriers of the GG genotype (45 vs. 26 months, p = 0.010; 44 vs. 23 months, p = 0.013). CONCLUSIONS: The rs2839698 SNP of H19 may have potential as a novel prognostic factor for survival in T3 gastric adenocarcinoma after surgery alone; these finding have special relevance to patients who are not suitable for postoperative chemotherapy. PMID- 29479899 TI - Polymorphisms in Pediatric Idiopathic Nephrotic Syndrome. PMID- 29479898 TI - Glycoprofiling of Early Gastric Cancer Using Lectin Microarray Technology. AB - BACKGROUND: Recently, studies have reported that protein glycosylation plays an important role in the occurrence and development of cancer. Gastric cancer is a common cancer with high morbidity and mortality owing to most gastric cancers are discovered only at an advanced stage. Here, we aim to discover novel specific serum glycanbased biomarkers for gastric cancer. METHODS: A lectin microarray with 50 kinds of tumor-associated lectin was used to detect the glycan profiles of serum samples between early gastric cancer and healthy controls. Then lectin blot was performed to validate the differences. RESULTS: The result of the lectin microarray showed that the signal intensities of 13 lectins showed significant differences between the healthy controls and early gastric cancer. Compared to the healthy, the normalized fluorescent intensities of the lectins PWA, LEL, and STL were significantly increased, and it implied that their specifically recognized GlcNAc showed an especially elevated expression in early gastric cancer. Moreover, the binding affinity of the lectins EEL, RCA-II, RCA-I, VAL, DSA, PHA-L, UEA, and CAL were higher in the early gastric cancer than in healthy controls. These glycan structures containing GalNAc, terminal Galbeta 1-4 GlcNAc, Tri/tetraantennary N-glycan, beta-1, 6GlcNAc branching structure, alpha-linked fucose residues, and Tn antigen were elevated in gastric cancer. While the two lectins CFL GNL reduced their binding ability. In addition, their specifically recognized N-acetyl-D-galactosamine structure and (alpha-1,3) mannose residues were decreased in early gastric cancer. Furthermore, lectin blot results of LEL, STL, PHA-L, RCA-I were consistent with the results of the lectin microarray. CONCLUSIONS: The findings of our study clarify the specific alterations for glycosylation during the pathogenesis of gastric cancer. The specific high expression of GlcNAc structure may act as a potential early diagnostic marker for gastric cancer. PMID- 29479900 TI - Ganglion Cyst of the Knee: A Retrospective Review of a Consecutive Case Series. AB - The aim of this study was to describe relevant medical history, clinical symptoms and outcomes in 12 patients having undergone surgical treatment of intra articular ganglion cysts of the knee at our Department from January 2010 to June 2016. Patient demographics, medical history, knee manifestations, management and outcome were evaluated. The mean patient age was 26.4 (range, 16-46) years. Th ere were seven female and five male patients. Duration of symptoms prior to the operation varied from 2 months to 3 years (mean, 17.1 months). All patients had preoperative magnetic resonance imaging work-up of the knee. Pain was the most common clinical presentation. All patients were surgically treated arthroscopically, and an additional open approach was used in only one of the patients. There were no complications during surgery and the postoperative period was uneventful in all patients. The mean follow up period was 43.5 (range, 9-83) months and no recurrence was observed. All patients remained symptom-free with full range of motion at final follow up. Despite a wide range of intra-articular ganglion cyst presentations and symptoms, our cohort demonstrated an excellent remission rate and functional prognosis following surgical treatment of the ganglion cysts of the knee. PMID- 29479901 TI - Human Papillomavirus as a Potential Risk Factor for Oral Premalignant Lesions. AB - Oral premalignant lesions (OPLs) and numerous alterations of oral mucosa remain unsolved due to their complex etiopathogenesis. Human papillomaviruses (HPVs), in particular, have been reported as the possible risk factors or cofactors. The aim of the study was to determine the association of different HPV types with oral premalignant lesions, and the potential role of smoking and alcohol use. Eighty patients (mean age +/- SD, 52.45+/-5.56) of both genders, 19 (23.75%) male and 61 (76.25%) female, were enrolled in the study. Study group included 40 patients diagnosed with OPLs (leukoplakia, erythroplakia, actinic keratosis and lichen planus), while control group included another 40 patients with healthy oral mucosa. Genotyping of the HPV types was performed by qualitative real-time HPV typing polymerase chain reaction test. HPV DNA was detected in 30% (12/40) of study group patients and 2.5% (1/40) of control group patients. The results revealed the presence of HPV16 in 15% (6/40), HPV56 in 10% (4/40), and HPV18 in 5% (2/40) of study group cases, and HPV31 in 1 (2.5%) control group patient. Th e association of oral HPV positivity and smoking/alcohol use in the study group was not statistically significant (p<0.05). In conclusion, high-risk HPV types are associated with oral premalignant disorders. However, it remains unknown whether HPV acts as an innocent bystander or it has a role in initiating development of premalignant lesions. Smoking and alcohol use were not associated with the existing oral HPV infection. PMID- 29479902 TI - Sensitivity of Diagnostic Tests for Dry Eye in Patients with Blepharospasm. AB - The aim of the study was to evaluate diagnostic tests for keratoconjunctivitis sicca (Schirmer test, tear break-up time (TBUT) test, and corneal staining with fluorescein and lissamine green dye) in patients with blepharospasm. This prospective study included 60 female patients older than 40 with blepharospasm, divided into two groups according to clinical symptoms. For fluorescein test, the surface under the ROC curve was 1.0 with standard error (SE) 0 and 95% confidence interval (95% CI) 0.940-1.0; for Schirmer test, the surface under the ROC curve was 0.817 with SE 0.0555 and 95% CI 0.696-0.905; for lissamine green test, the surface under the ROC curve was 0.813 with SE 0.056 and 95% CI 0.691-0.902; and for TBUT test, the surface under the ROC curve was 0.772 with SE 0.061 and 95% CI 0.645-0.870. According to the results of ROC curve, which determines the sensitivity and specificity of normal values, comparison of diagnostic tests for keratoconjunctivitis sicca used in this study showed that fluorescein test had the best sensitivity and specificity. Schirmer test should be avoided in patients with blepharospasm because its results are influenced by frequent blinking and are not appropriate for study interpretation. Despite the pathologic values of TBUT test (numerically), this test is still acceptable for patients with blepharospasm because its interval takes more time than the interval between two blinks. PMID- 29479903 TI - Analysis of Ganglion Cell Complex and Retinal Nerve Fiber Layer Thickness in Glaucoma Diagnosis. AB - The aim was to compare retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) thicknesses in patients with primary open angle glaucoma (POAG), ocular hypertension (OH) and healthy subjects, and to investigate the role of GCC parameters in glaucoma diagnosis. Eighty-one patients were divided into four groups according to Hodapp-Parrish-Anderson classification: 26 OH, 22 early POAG, 10 moderate to advanced POAG, and 23 healthy subjects. All patients underwent RNFL and GCC thickness measurement using SOCT Copernicus HR. All RNFL and GCC parameters were significantly lower in POAG than in OH and healthy subjects, especially Average RNFL, RNFL Superior and Inferior, GCC Average, and GGC Inferior. Of all RNFL parameters, the highest area under the receiver operating characteristic curve (AUC) was recorded for Average RNFL, 0.906. GCC Average, and GCC Superior and Inferior had the overall highest AUCs (0.957, 0.955 and 0.946, respectively) with 100% specificity. The RNFL Average and Inferior and GCC Average, Superior and Inferior were identified as the main predictors for development of glaucoma (p=0.015 and p=0.014 vs. p=0.002, p=0.002 and p=0.003, respectively). In conclusion, GCC parameters showed a slightly better glaucoma discriminating ability and were found to be better predictors for development of glaucoma as compared with RNFL. PMID- 29479905 TI - Public Awareness, Understanding and Attitudes Towards Epilepsy in Montenegro. AB - Stigma remains a distressing consequence of epilepsy worldwide. We assessed stigma markers among citizens of Montenegro. Randomly selected adults aged 18 to 65 were interviewed using a 10-item questionnaire, which had been used in similar settings. Descriptive statistics, chi2-test and Fisher exact test were used in order to identify factors associated with negative attitudes. After exclusions and refusals, the questionnaire was administered to 1000 people, 91% of whom had heard about epilepsy. Less than half knew someone with epilepsy and 31.5% had witnessed a seizure. One-fifth would object if their child played with a person who had epilepsy and three-quarters would object if their child married a person with epilepsy. Forty percent believed people with epilepsy should be employed in the same way as everybody else. Fewer than 8% of respondents thought epilepsy was a form of insanity. Over 80% favored brain disease as a cause of epilepsy and 95% chose convulsions to be a major feature of an epileptic attack. General awareness of epilepsy in Montenegro is similar to that in other countries. Understanding epilepsy is relatively good but the results suggest that there still are negative attitudes towards people with epilepsy. PMID- 29479904 TI - Standard Lumbar Discectomy Versus Microdiscectomy - Differences in Clinical Outcome and Reoperation Rate. AB - Microdiscectomy (MD) is accepted nowadays as the operative method of choice for lumbar disc herniation, but it is not rare for neurosurgeons to opt for standard discectomy (SD), which does not entail the use of operating microscope. In our study, differences in disc herniation recurrence and clinical outcome of surgical treatment of lumbar disc herniation with and without the use of operating microscope were assessed. Our study included 167 patients undergoing lumbar disc surgery during a three-year period (SD, n=111 and MD, n=56). Clinical outcome assessments were recorded by patients via questionnaire forms filled out by patients at three time points. Operation duration, length of hospital stay and revision surgeries were also recorded. According to study results, after one-year follow up there was no statistically significant difference between the SD and MD groups in functional outcome. However, we recorded a statistically significant difference in leg pain reduction in favor of the MD group. According to the frequency of reoperations with the mean follow up period of 33.4 months, there was a statistically significant difference in favor of the MD group (SD 6.3% vs. MD 3.2%). There appears to be no particular advantage of either technique in terms of functional outcome since both result in good overall outcome. However, we choose MD over SD because it includes significantly lower recurrent disc herniation rate and higher reduction of leg pain. PMID- 29479906 TI - Retinal Nerve Fiber Layer Thickness in Glaucoma Patients Treated with Multiple Intravitreal Anti-Vegf (Bevacizumab) Injections. AB - Over the past decade, intravitreal injections of anti-VEGF agents have been widely used and intensively developed as a treatment option for many ophthalmological indications. Due to its availability and low cost, the most frequently used anti-VEGF agent is bevacizumab. This type of therapy is often indicated in patients with exudative age-related macular degeneration (ARMD) and diabetic macular edema (DME). If, in addition to these two conditions, patients have a diagnosis of primary open angle glaucoma (POAG), they also present with optic nerve head (ONH) retinal nerve fiber layer (RNFL) thinning. The aim of this prospective study was to establish whether administering bevacizumab to patients with POAG leads to additional reduction of RNFL thickness. The study included 60 patients divided into two groups. First group comprised the eyes of patients with exudative ARMD and POAG, whereas second group comprised the eyes of patients with DME and POAG, all treated with bevacizumab. Control group comprised the fellow eye of each involved patient, which was not treated with bevacizumab. In a period of one year, all patients underwent optical coherence tomography (OCT) measurements of ONH RNFL thickness. The results of all patients were compared between the two study groups and then with control group results. Study results showed a decrease of RNFL in both groups of patients. Comparison of these two groups of patients after one year revealed a statistically more significant decrease in RNFL thickness in the second group (DME + POAG). PMID- 29479907 TI - Measurable and Unmeasurable Features of Ultrasound Lymph Node Images in Detection of Malignant Infiltration. AB - The aim of the study was to assess diagnostic value and utility of selected morphological features in predicting lymph node (LN) malignancy using B-mode, Doppler ultrasonography and multivariate settings in a tertiary radiological referral center. The study included 123 patients having undergone ultrasound guided fine-needle aspiration and cytologic analysis (FNAC) of cervical, axillary and inguinal LNs. Each LN was characterized by long/L and short/T-axis, shape, margins, echogenicity, cortical thickness, vascularization, and examiner's subjective impression. Within the limitations of FNAC, altered shape and vascularization had relatively high specificity and positive predictive value (>80%), whereas subjective impression had high sensitivity and negative predictive value (100%) for malignancy. The cut-off levels for different features of LN by ROC analysis were as follows: long-axis 23 mm, short-axis 11 mm, L/T ratio 2.19, and maximal cortical thickness 5.1 mm. On multivariate analysis (adaptive regression splines, n=108), the addition of long-axis, L/T ratio, age and sex considerably improved diagnostic accuracy (88%), sensitivity (margins + vascularization) and specificity (subjective impression) of the diagnostic model. The combination of morphological and demographic features could improve diagnostic accuracy, usually with a trade-off between the sensitivity and specificity of the predictive model. The performance may depend on the level of expertise and institutional settings. PMID- 29479908 TI - Acoustic Reflex and House-Brackmann Rating Scale as Prognostic Indicators of Peripheral Facial Palsy in Neuroborreliosis. AB - Lyme borreliosis is a vector-borne infectious disease characterized by three disease stages. In the areas endemic for borreliosis, every acute facial palsy indicates serologic testing and implies specific approach to the disease. Th e aim of the study was to identify and confirm the value of acoustic refl ex and House-Brackman (HB) grading scale as prognostic indicators of facial palsy in neuroborreliosis. Th e study included 176 patients with acute facial palsy divided into three groups based on serologic testing: borreliosis, Bell's palsy, and facial palsy caused by herpes simplex virus type 1 (HSV-1). Study patients underwent baseline audiometry with tympanometry and acoustic reflex, whereas current state of facial palsy was assessed by the HB scale. Subsequently, the same tests were obtained on three occasions, i.e. in week 3, 6 and 12 of presentation. Th e patients diagnosed with borreliosis, Bell's palsy and HSV-1 differed according to the time to acoustic refl ex recovery, which took longest time in patients with borreliosis. Th ese patients had the highest percentage of suprastapedial lesions at all time points and recovery was achieved later as compared with the other two diagnoses. Th e mean score on the HB scale declined with time, also at a slower rate in borreliosis patients. Th e prognosis of acoustic refl ex and facial palsy recovery according to HB scale was not associated with the length of elapsed time. The results obtained in the present study strongly confirmed the role of acoustic reflex and HB grading scale as prognostic indicators of facial palsy in neuroborreliosis. PMID- 29479909 TI - Problems in Critical Care Nurse-Patient Communication: Examples of Poland and Turkey. AB - The aim of this study was to determine the problems related to nurse-patient communication in the intensive care unit (ICU), with a focus on differences between Poland and Turkey. A descriptive survey design was used. The study was conducted in Surgical ICU, Lwowska Hospital in Poland and ICU, Training and Research Hospital in Turkey. Fifty critical care nurses in Poland and 52 critical care nurses in Turkey were included in the study. Patient data were collected using a questionnaire that was prepared by the researchers. In this study, 46% and 42.3% of the nurses reported they had communication problems with patients in Poland and Turkey, respectively. It was also found that the nurses in Poland mostly used therapeutic touch for non-verbal communication (80%), whereas the nurses in Turkey used facial expression (90.4%). Critical care nurses in both countries experienced similar difficulties in patient communication. It is recommended that the patient to nurse ratio in ICUs be planned according to the intensive care standards. PMID- 29479910 TI - Postoperative Pain Management after Carpal Tunnel Syndrome Surgical Treatment: Comparing Practice with Guidelines. AB - The management of postoperative pain after carpal tunnel syndrome surgical treatment at a tertiary hospital was analyzed and compared with the guidelines for perioperative pain management. This retrospective study included 579 patients operated on for carpal tunnel syndrome at the Split University Hospital Center in Split, Croatia. The following key data were collected from patient medical records: age, gender, type and dosage of premedication, type and dosage of anesthesia, type and dosage of postoperative analgesia per each postoperative day. The procedures related to perioperative pain were analyzed and compared with the current guidelines for perioperative acute pain management. Study results showed that 99.6% of patients with carpal tunnel syndrome were operated under local anesthesia, of which 2.9% also received sedation. Analgesics were prescribed to 45% of patients after surgery, and according to patient charts, 39% of patients actually received postoperative analgesic(s). Generally, postoperative pain was treated on the fi rst postoperative day, mostly with nonsteroidal anti-inflammatory drugs. Only two patients received weak opioids for postoperative pain. Many recommendations from the guidelines for perioperative acute pain management were not followed. In conclusion, the guidelines should be followed and appropriate interventions used to improve postoperative pain management. PMID- 29479911 TI - The Value of Injury Severity Score and Abbreviated Injury Scale in the Management of Traumatic Injuries of Parenchymal Abdominal Organs. AB - The aim of this study was to investigate the influence of etiology, types of injury, levels of consciousness and the Injury Severity Score (ISS) and Abbreviated Injury Scale (AIS) values on the selection of treatment modality and survival in patients with injuries of parenchymal abdominal organs. Case records of 224 patients treated for traumatic injury of parenchymal abdominal organs from January 2003 until December 2015 were reviewed. Th e values of ISS and AIS of injury severity were calculated and compared to the values obtained according to the etiology, state of consciousness and survival. Of the 224 patients, 172 (76.8%) were treated by surgical approach and 52 (23.2%) were treated conservatively. Th e mean patient age was 40.1?}18.3 years. Th ere were 97 (43.3%) polytrauma cases. Of the 224 injured patients, 143 (63.8%) were treated with transfusions of blood products. Two hundred and six (92%) patients survived. Th e mean AIS and ISS values were significantly lower in patients that survived (AIS=3; ISS=28) than in those that died (AIS=5; ISS=34) (p< 0.001). There was a statistically significant difference in AIS and ISS values between conscious (AIS=2.7; ISS=25.9) and unconscious (AIS=3.2; ISS=33) patients (p< 0.001). Of the 224 patients that did not survive, 18 (8%) were hemodynamically unstable. Survival depended on hemodynamic stability at admission; the ISS and AIS values were associated with the injuries and state of consciousness at admission. Hemodynamic stability, state of consciousness, and ISS and AIS values were the quality predictors of survival after abdominal traumatic injury. PMID- 29479912 TI - Undergraduate Students' Knowledge on Temporomandibular Disorders in Croatia. AB - The aim of this study was to evaluate Croatian undergraduate students' knowledge based on what they learned in the recent course, as well as the students' own judgment and opinions about geriatric dentistry education concerning temporomandibular disorders (TMDs) of the elderly. The study was carried out by means of a questionnaire administered in the last study year to students of the School of Dental Medicine, University of Zagreb and students of the Department of Dental Medicine at the School of Medicine, University of Rijeka. Th e questionnaire included questions about relevant specific knowledge on TMD, and statements related to their own opinion about geriatric dentistry education received during the study. Regarding students' knowledge related to TMDs, students from Rijeka gave more positive answers (p=0.012). Students from Rijeka gave more positive answers regarding physical therapy for treatment of TMD (p=0.004) and disc displacement and osteoarthritis as the most common disorders of the temporomandibular joint (p=0.031). Students from Zagreb were more unsatisfi ed with the skills in the field of geriatric dentistry (disagreed 57.45%) than students from Rijeka (45.83% had neutral standpoint and 37.50% agreed) (p=0.005). The level of the participants' knowledge pointed to the need of improving undergraduate dental teaching about the specific geriatric education, including knowledge about TMD. PMID- 29479913 TI - Family Financial Situation, Parental Marital Status and Self-Harm amongst Adolescents in Croatia. AB - The aim of this study was to determine the level of self-harm behaviors among adolescents in the general population (students of secondary schools in Zagreb, Croatia), as well as to determine if the level of self-harm behaviors differed according to financial circumstances of the family and marital status of the parents. The study was conducted in 701 adolescents (male and female, age range 14 to 19 years). A specially designed questionnaire that included family and demographic data was used to determine the family financial circumstances. The Scale of Auto-Destructiveness measuring instrument was used to assess the level self-harm. Study results revealed that 87.3% of adolescents indicated average levels of self-harm, whereas above-average and high above-average self-harm was indicated in 12.7% of the adolescents. Results also showed that single-parent families significantly differentiated the level of self-harm among adolescents of both genders, whereas financial deprivation (perception of financial stress) partially differentiated these levels. Practical implications of this study emphasize the importance of social support to parents of adolescents grown up in single-parent and/or financially challenged families. PMID- 29479914 TI - Transgenerational Transmission of Violence among Parents of Preschool Children in Croatia. AB - The aim of this study was to determine whether there is a transgenerational transmission of violence within the family on a sample of parents of preschool children in Croatia, and to identify the factors that increase the likelihood of child abuse. The Child Abuse Questionnaire was self-administered to the sample of 118 parents of preschool children (91 mothers and 27 fathers) during February 2013. There were 7.7% of mothers and 3.8% of fathers who answered that they slapped their child, while 15.4% of the fathers answered that they even hit their child with a fist. We found the subjects who were psychologically and/or physically abused in childhood by their parents to have a higher probability of following the exact model of violence on their children. So, children suffer physical violence in larger families from parents who, in turn, suffered physical violence in childhood from their fathers, controlled for all other factors in the model. Children suffer psychological violence from parents who experienced psychological violence from their own parents during childhood, controlled for all other factors in the model. We also found the higher number of family members in a household to be a risk factor for abuse. The study has confirmed that additional interventions are necessary to break the model of transmitting violence from generation to generation. PMID- 29479915 TI - The First Hospital-Based Registry of Patients with Multiple Sclerosis in Croatia. AB - The first hospital-based registry of patients with multiple sclerosis (MS) was established at the University Department of Neurology, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia, in 2014. The aim of the registry was to continuously provide data on the number of hospital-managed MS patients, patterns of disease progression, predictors of disability progression, changes in lifespan and long-term outcomes. Relevant medical data included age and gender of MS patients, family history of MS, data on previous immunization, disease course, Expanded Disability Status Scale (EDSS) score, cerebral magnetic resonance imaging (MRI) lesion load quantification, and cerebrospinal fluid analysis. Lifestyle habits in MS patients including smoking and alcohol consumption were also analyzed. All data were obtained from primary medical records between January 1, 2014 and January 1, 2015, and entered into the database. Data were evaluated retrospectively according to age and gender differences. Results showed that the majority of patients enrolled in the registry had the remitting relapsing course of disease, with low EDSS score indicating no disability or minimal disability. Cerebrospinal fluid analysis showed that oligoclonal bands were present in the majority of MS patients, with affected blood-brain-barrier permeability. According to the remitting relapsing course of the disease, cerebral MRI quantitative analysis demonstrated a significant lesion load in the majority of patients. When stratified by lifestyle habits, smokers and alcohol consumers were more prevalent among male patients. Our hospital-based registry might be considered as a prototype for the national MS registry and should be improved for reliable statistical analysis. PMID- 29479916 TI - Epidemiology of Adult Fractures in Eastern Croatia by Cause of Injury, Fracture Location and Type of Treatment. AB - This retrospective study investigated the impact of age on fracture occurrence through the comparison of two patient groups, 17-64 and 64+ age groups. Study data covered all fractures treated at a large hospital in eastern Croatia. A total of 15,519 patients with fractures were treated at the trauma department (inpatient and outpatient), with a total of 17,257 fractures presented, 71% managed as outpatients and 29% as inpatients. A total of 11,046 outpatients were treated for 12,187 fractures and a total of 4473 inpatients were treated for 5070 fractures. The group of 17-64-year old males had 5787 fractures, accounting for 34% of all fractures presented. The group of 17-64-year old females had 4094 fractures, accounting for 24% of total fractures. The group of 65+ year-old males had 2659 fractures, accounting for 15% of all fractures presented and the group of 65+ year-old females presented with 4717 fractures, accounting for 27% of all fractures presented. The 'fall in level' was the predominant cause of injury in all patients. The characteristics of osteoporotic bone fractures were evident in the population of 65+ females and to a lesser degree in 65+ males. The 17-64 age group, both males and females, had more fractures considered as high-energy fractures. PMID- 29479917 TI - Neurosyphilis in Anglo-American Composers and Jazz Musicians. AB - Syphilis is a sexually transmitted, systemic disease caused by the spirochete bacterium Treponema pallidum. The most common mechanism of transmission is sexual intercourse. Although there are several hypotheses, the exact origin of the disease remains unknown. Newly published evidence suggests that the hypothesis supporting the theory of the American origin of the disease is the valid one. Among 1500 analyzed pathographies of composers and musicians, data on ten Anglo American composers and jazz musicians having suffered from neurosyphilis (tertiary stage of the disease) were extracted for this report. In this group of Anglo-American composers and musicians, most of them died from progressive paralysis while still in the creative phase of life. Additionally, diagnoses of eleven other famous neurosyphilitic composers, as well as basic biographic data on ten less known composers that died from neurosyphilis-progressive paralysis are also briefly mentioned. In conclusion, neurosyphilis can cause serious neurological damage, as well as permanent disability or death, preventing further work and skill improvement. PMID- 29479918 TI - Hepatic Osteodystrophy: A Global (Re)View of the Problem. AB - Hepatic osteodystrophy is a common and frequently untreated complication, manifested as osteoporosis or osteopenia, encountered in the evolution of chronic liver diseases. This article provides a narrative review of hepatic osteodystrophy. The aim is to revise the prevalence, pathophysiology, diagnosis and management of hepatic osteodystrophy. We searched medical literature via PubMed, Google Scholar, Wiley, Science Direct, and Springer Link using respective keywords to obtain data on low bone mineral density connected to chronic liver diseases. Many studies have reported an increased prevalence of osteoporosis/osteopenia in patients with chronic liver diseases. The pathogenesis is multifactorial, involving genetic factors, vitamin deficiencies, proinflammatory cytokines, hypogonadism, hyperbilirubinemia, antiviral therapy, corticosteroid drugs, and lifestyle factors. The management of patients should include individualized assessment for fracture risk factors and bone mineral density. Vitamin D and calcium supplementation should be recommended in all patients with chronic liver diseases and osteoporosis. Bisphosphonates are the most efficient drugs used in the treatment of hepatic osteodystrophy. In the future, it is necessary to define better the management and specific treatment of hepatic osteodystrophy for prevention of fragility fractures and to improve the patient quality of life. PMID- 29479919 TI - Cardiopulmonary Interactions with Consecutive Pulmonary Abnormalities in Patients with Chronic Heart Failure. AB - Chronic heart failure places heavy burden on patients, their families and on health care resources, accounting for high numbers of hospital admissions. Despite huge improvements in the treatment of many heart disorders, the clinical syndrome of chronic heart failure as a final pathway of heart pathology is an exception, in that its prevalence is rising, and only small prolongations in survival are occurring. It is associated with high morbidity and poor prognosis, and a survival rate worse than that for some malignant tumors. The reasons for the increasing overall prevalence of chronic heart failure in developed countries lie in prolonged survival owing to modern pharmacological or invasive treatment, better secondary prevention, and aging of the population. Chronic pulmonary disease is common in patients with chronic heart failure. Through sharing some risk factors and overlapping pathophysiological processes, they present diagnostic and therapeutic challenge. The aim of this article is to review various mechanisms responsible for the symptoms of chronic heart failure with consecutive pulmonary interaction and abnormalities in lung function. PMID- 29479920 TI - Treatment of Periprosthetic Femoral Fractures after Total Hip Arthroplasty Vancouver Type B. AB - The rate of periprosthetic femoral fractures following total hip replacement has been growing steadily in the last 20 years and ranges from 0.1% to 2.1%. These fractures are mostly related to older patients with the presence of chronic diseases and frequently poor bone quality. The treatment is surgically very complex and demanding, followed by a series of complications. The evaluation in this retrospective study included 23 patients who were medically treated from January 2004 to December 2015 with the mean follow-up of 14.5 (range, 9-25) months. There were 17 patients with cement total hip arthroplasty (THA) and 6 with cementless THA. During treatment of fractures, different techniques were implemented including the use of wire cerclage, dynamic compression plates (DCP), a locking compression plate (LCP) system, and long revision stem. For the purpose of distinguishing fractures, we used the Vancouver classification by Duncan and Masri. For clinical evaluation, we used the modified Merle d'Aubigne score system and monitored complications during treatment. The aim is to show treatment results of the type B periprosthetic femoral fractures by using different operative treatment techniques. According to the Vancouver classification within type B, 10 (43.47%) patients had type B1 fractures, another 10 (43.47%) patients had type B2 fractures, and three (13.04%) patients had type B3 fractures. According to gender distribution, there were eight (34.8%) male and 15 (65.2%) female patients, mean age 59.5 (range, 47-86) years. Twelve (52.2%) and 11 (47.8%) patients had left- and right-sided fractures, respectively. The mean length of hospital stay was 16 (range, 9-26) days. According to the Merle d'Aubigne score system, 10 patients with type B1 fractures had the mean score of 11.5 points, which is poor result. Poor result was also recorded in patients with type B2 fractures, with the mean score of 10.6 points. The three patients with type B3 fractures had the mean score of 12 points, which is considered fair score. In conclusion, Vancouver classification has been widely accepted and using the protocols makes decision making during treatment much easier. During treatment of this type of fracture, we used various implants, wire cerclage, DCP and LCP, as well as long stem revision. In certain cases, we applied surgical techniques, implants that are not recommended by the Vancouver protocol by which we treated periprosthetic femoral fractures; in these case, we recorded nonunion bone, malunion and breaking of implants, which resulted in poor treatment outcome. PMID- 29479921 TI - Hydrocolloid Dressing Application in the Treatment of Chronic Wounds and Relation to Quality of Life. AB - The aim was to analyze relationship between the application of hydrocolloid dressings in the treatment of chronic wounds and relation to the patient quality of life. The study included 33 vascular outpatients. The authors constructed a questionnaire for assessing the level of daily functional impairment and the quality of life. Participants assessed the level of pain, level of decreased independence in daily activities, level of sleep disturbance, difficulties with keeping hygiene, and level of odor caused by a chronic wound. Significant differences were found in all aspects of chronic wound interference with the quality of life after the application of hydrocolloid dressings: level of pain (t (23)=4.14), independence in everyday activity (t (23)=5.01), interference with sleep (t (23)=3.89), hygiene (t (23)=3.00) and an unpleasant odor (t (23)=3.66) (p<0.01 all). According to the physician's assessment, the treatment of chronic wound with hydrocolloid dressing significantly improved patient condition in 84.8% of cases. The application of hydrocolloid dressings led to reduction. PMID- 29479922 TI - Bilateral Vertebral Artery Dissection - Multiple Artery Affection or Early Recurrence? AB - In a certain percentage of patients with craniocervical artery dissection, dissections affect multiple arteries. Some investigators consider that the dissections diagnosed as multiple might have occurred sequentially within a short time frame. We describe an oligosymptomatic patient with bilateral progressive vertebral artery dissection. Careful history taking added new data on transient left arm weakens two months earlier, as a possibility of the earlier disease onset. PMID- 29479923 TI - Effects of Pressure-Controlleda Volume-Controlled Ventilation on Hemodynamic and Respiratory Parameters in Patients During Laparoscopic Cholecystectomy. AB - Many papers have been published investigating the effects of intraoperative mechanical ventilation on the incidence of intra- and postoperative respiratory complications. The potential advantages of protective pressure over volume controlled ventilation mode during laparoscopic surgery have yet to be proven. This study included 60 patients aged between 18 and 70 with ASA score 1-3, body mass index (BMI) <=35 kg/m2, and without prior history of chronic respiratory diseases, who were scheduled for laparoscopic cholecystectomy under general anesthesia. Patients were assigned randomly to protective pressure or volume controlled mechanical ventilation mode. The initial results showed no significant differences in respiratory and hemodynamic parameters between the groups. Comparison of patients with BMI >=25 showed significantly lower peak inspiratory pressure (Ppeak) at 15 (18.52 vs. 21.83 cm H2O, p=0.022), 30 (18.73 vs. 21.83 cm H2O, p=0.009) and 45 (18.94 vs. 22.667 cm H2O, p=0.010) minutes after tracheal intubation in the pressure-controlled ventilation (PCV) group. Other measured parameters were of similar characteristics. It is concluded that PCV and volume controlled ventilation were equally effective in maintaining adequate ventilation, oxygenation and hemodynamic stability in the groups of patients observed. However, comparison of obese patients revealed some advantages of PCV which, given the present pace of change, should be additionally investigated. PMID- 29479924 TI - Chorea Caused by Unruptured Arteriovenous Malformation: Case Report and Review of Literature. AB - Chorea is a movement disorder that can be caused by a large range of degenerative, vascular, metabolic and toxic disorders in basal ganglia. Arteriovenous malformations are rare vascular malformations the clinical presentation of which depends on the malformation characteristics and localization. They are most commonly presented with intracranial hemorrhage, while focal neurological deficit is the rarest presentation. A case is reported of a 64-year-old female patient presented with hemichorea. Magnetic resonance imaging and digital subtraction angiography revealed the presence of arteriovenous malformation in the right temporal lobe. PMID- 29479925 TI - The Use of Inferior Vena Cava Filters before Surgery in Women with Ovarian Cancer with the Initial Symptom of Deep Venous Thrombosis: Case Report and Review of Literature. AB - Venous thromboembolism is a frequent complication of gynecologic cancer, and may be the first symptom of occult malignant disease. Although anticoagulation therapy remains the standard of care in patients presenting with acute venous thromboembolism, inferior vena cava filters are an important alternative when anticoagulants are contraindicated or ineffective. We report a case of a 69-year old woman who presented with left leg swelling secondary to deep venous thrombosis before the diagnosis of ovarian cancer. The aim of this study is to review the respective literature and report our experience with inferior vena cava filter placement to prevent pulmonary embolism in gynecologic cancer patients. PMID- 29479926 TI - Fecal microbiota profile in atopic asthmatic adult patients. AB - Summary: Background. Studies proposed a link between gut microbiota and airway tract. Objective. Study the diversity and density of gut microbiota in healthy and asthmatic patients. Method. Semi-quantitative stool cultures were performed from fecal samples collected from 80 adult asthmatic patients and 40 healthy individuals. Data on gender, age, dietetic history, clinical examination and investigations as skin prick test and pulmonary function testing were also collected. Results.Lactobacilli were found to be higher among patient group than control group. E. coli density was statistically higher in patient than control group. No significant difference was detected between male and female patients or controls. Lactobacilli were statistically more prevalent in stool culture of male cases than that of male controls. No difference was found between female cases and controls. There was no relationship between type of microbial growth and disease related parameters including age, duration of illness, number of allergens and pulmonary function test in cases. Conclusion. Atopic asthma is significantly associated with gut microbiota Lactobacilli and E. coli. It is important to determine the organism involved, to focus on microbiome-driven disease and therapies. PMID- 29479927 TI - Galactose-alpha-1,3-galactose allergy: a rare syndrome and an atypical presentation. AB - Summary: Allergies to red meat associated with galactose-alpha-1,3-galactose, commonly known as alpha-gal, are rare and have only recently been described. At this time, the literature reports only one case documented in Portugal. In this study, we report the case of a 76-year-old male with an immediate reaction following the ingestion of red meat. Rigorous diagnostic exams, including prick test, prick-to-prick tests, serum specific IgE and SDS-PAGE IgE-immunoblotting, were performed. The alpha-gal epitope IgE re-turned a value of 35.3 kUA/L, leading the authors to believe that this is an atypical case of alpha-gal allergy. PMID- 29479928 TI - Latex sensitization in patients with myelomeningocele: contribution of microarray technique. AB - Summary: Background. Microarray technique employing molecular allergens is pointed out as a new method to evaluate allergic patients. Objective. To evaluate if microarray technique (ImmunoCAP-ISAC(r); I-ISAC(r)) is similar to fluorescence enzyme immunoassay (FEIA; ImmunoCAP(r)) in the diagnosis of latex allergy (specific IgE to latex plus symptoms) and latex sensitization (only antibody) in pediatric (9-mo to 14-yrs) patients with myelomeningocele undergone to surgical repair. Methods. Patients underwent skin prick testing (SPT) to latex and food (prick to prick), and dosage of serum specific IgE to latex and recombinant latex allergens (rHev b 1, rHev b 3, rHev b 5, rHev b 6.01, rHev b 6.02, rHev b 8, rHev b 9, and rHev b 11) by ImmunoCAP(r) and I-ISAC(r). Results. The comparison between the two methods showed high level of concordance considering positive and negative results. A statistically significant correlation for rHev b 3 and rHev b 6.01 for the allergic patients, and for rHev b5 and rHev b6.01 for those sensitized to latex, was observed. I-ISAC(r) is limited to 5 recombinant latex allergens (rHev b 1, 3, 5, 6.01 and 8). Despite the presence of antibodies against pollens, LTP and profilins (I-ISAC(r)) in some patients, none of them reported symptoms related with intake of fruits and/or vegetables. Conclusion. Both methods are effective in assisting the diagnosis of latex allergy, but differ in the assessment of sensitized pediatric patients with myelomeningocele. The assessment of latex sensitized patients is more complete using the 8 recombinant latex fractions available for ImmunoCAP(r), instead of I-ISAC(r). PMID- 29479929 TI - Storage molecules from tree nuts, seeds and legumes: relationships and amino acid identity among homologue molecules. AB - Summary: The families of seed storage proteins, together with profilins, oil bodies-associated oleosins, and pathogenesis-related (PR) proteins like PR-10 (Bet v 1-like), PR-12 (defensins) and PR-14 (non-specific lipid transfer protein), are the main causes of IgE sensitization to tree nuts, legumes and seeds. All these allergens, with the exclusion of profilins and of PR-10, are heat-stable and possibly responsible for fatal or almost fatal adverse reactions to such foods. In this short review, we will discuss the relationship and amino acid identities among some of the seed storage homologue molecules identified to date from tree nuts, seeds and legumes. PMID- 29479930 TI - Delirium and agitation in traumatic brain injury patients: an update on pathological hypotheses and treatment options. AB - Traumatic brain injury (TBI) is a global public health epidemic. It represents the principal cause of death and disability in individuals aged under 35 in the USA. In the subacute phase, severe TBI patients who recover consciousness go through a state of agitation and delirium. However, there is only limited research exploring the characteristics of post-traumatic delirium (PTD) although it is likely to be more frequent than in general Intensive Care Unit (ICU) patients. Evidence suggest the incidence of delirium in non-TBI ICU patients is up to 86%. The exact pathophysiological mechanisms underlying the development and progression of delirium in critically ill patients is still unclear. Many hypotheses have been proposed to play a role: neuroinflammation, neurotransmitter imbalance, structural and functional brain damage. TBI patients are at high risk of post-traumatic cognitive impairment, and up to two thirds of patients who survive TBI develop agitation and delirium which is associated with increased disability and long term cognitive impairment. Recommendation for the treatment of PTD in patients admitted to ICU are not clearly identified. Despite the high prevalence of PTD, the condition often goes misrecognized and attributed primarily to the injury itself. There is increasing evidence that certain drugs such as antipsychotics can reduce the incidence and severity of delirium, whereas other drugs such as dexmedetomidine and remifentanil are associated with decreased risk of developing delirium in general ICU patients. However, there is a lack of high quality studies exploring treatment strategies for PTD in the acute setting. PMID- 29479931 TI - Dexmedetomidine as an adjunct for caudal anesthesia and analgesia in children. AB - INTRODUCTION: The aim of this review was to evaluate the current evidence regarding the use of dexmedetomidine as an adjuvant to local anesthetic agents (LAA) for caudal blockade anesthesia and analgesia in children. EVIDENCE ACQUISITION: A literature search was performed of the Medline, Embase, and CINAHL databases using the keywords "dexmedetomidine" and "caudal". We included all studies that used caudal dexmedetomidine as an adjuvant to a LAA in children, excluding case reports, reviews, expert opinions, and animal studies. EVIDENCE SYNTHESIS: Twenty-one publications met the inclusion criteria and included 1590 children. Fourteen compared the efficacy of adding dexmedetomidine to a LAA alone and seven compared dexmedetomidine to other adjuvants in combination with a LAA. The duration of postoperative analgesia was significantly longer in patients receiving a caudal epidural block with a LAA plus dexmedetomidine when compared to a LAA alone. Only one study demonstrated improved analgesia with a dose of dexmedetomidine >=1 ug/kg. Dexmedetomidine provided longer postoperative analgesia than fentanyl and morphine, while the quality of postoperative analgesia was similar to dexamethasone or clonidine. Although higher sedation scores were associated with caudal dexmedetomidine in the majority of the trials, postoperative behavior scores were improved in these children. There were no reports of respiratory depression. Significant hemodynamic effects were uncommon, and occurred most commonly in patients receiving a higher dose of caudal dexmedetomidine (2 ug.kg-1). CONCLUSIONS: There is sufficient evidence to recommend the addition of caudal dexmedetomidine to the LAA in patients undergoing lower extremity and infra-umbilical surgical procedures. PMID- 29479933 TI - Bariatric surgery made light: the Dutch way. PMID- 29479932 TI - Serratus-intercostal interfascial plane block: alternative analgesia for open nephrectomy? PMID- 29479934 TI - Is the management of Rh-Rh incompatibility with noninvasive fetal Rh genotyping for targeted prophylaxis cost-effective in the Turkish population? AB - Background/aim: The aim of this study was to assess unnecessary immunization rates and compare the cost-effectiveness of targeted prophylaxis with fetal Rh genotyping with that of traditional management of Rh-Rh incompatibility in a virtual economic model. Materials and methods: This retrospective data analysis was conducted at two tertiary centers between 2011 and 2015. The data of 1135 pregnant women were analyzed. The main outcome measure was to determine the unnecessary immunization rate among the whole Rh-Rh incompatibility group. The second outcome measure was to compare the cost-effectiveness of universal immunization with that of targeted prophylaxis with fetal Rh genotyping in a virtual economic model.Results: Average cost per patient was found as $259.20 with universal prophylaxis and the total cost was $177,344, whereas if targeted prophylaxis had been applied to these patients the total cost would have been $263,392 and cost per patient would have been $385. Universal prophylaxis was more cost-effective than targeted prophylaxis in terms of both total cost and cost per patient (P < 0.0001).Conclusion: Unless the cost of noninvasive fetal Rh genotyping is reduced, a universal approach of anti-D immune globulin prophylaxis is more cost-effective than noninvasive determination of fetal Rh genotyping with targeted prophylaxis. PMID- 29479935 TI - The effect of obstructive sleep apnea syndrome on the central auditory system AB - Background/aim: Obstructive sleep apnea syndrome (OSAS) is a disease characterized by repeated hypoxia attacks during sleep. The effect of hypoxia on the central nervous system is a well-known entity. In this study we aimed to investigate the effect of OSAS on the central auditory system. Materials and methods: Twenty-one OSAS patients diagnosed by polysomnography (PSG) and 10 control subjects were included in the study. After a thorough otorhinolaryngology examination, all subjects underwent pure tone audiometry (250 to 8000 Hz frequency). The subjects with normal otoscopic examination and hearing threshold were included in the study. All participants underwent speech discrimination analyses and auditory time processing and sequencing tests, i.e. frequency pattern test (FPT) and duration pattern test (DPT). Results: Although hearing was normal in the OSAS patients, significant loss was observed in the speech discrimination rates compared to the control group (P < 0.05). Significant disruption was also detected in the FPT and SPT in the OSAS patients (P < 0.05). Conclusion: Repeated hypoxic episodes in OSAS resulted in statistically significant impairments in the central auditory pathways, even if the hearing threshold was within normal limits. PMID- 29479936 TI - An analysis of the relationship between autoantibodies and clinical findings in patients with systemic sclerosis AB - Background/aim: We aimed to investigate the prevalence of anti-RNA polymerase (RNAP) III and other autoantibodies in a group of Turkish patients with systemic sclerosis (SSc) and their relation with clinical features. Materials and methods: The prevalence of anti-RNAP III and other autoantibodies was analyzed in 93 patients with SSc and control groups including 86 patients with systemic lupus erythematosus (SLE) and 65 healthy subjects, respectively. Their relationship with diseases findings was assessed in a cross-sectional manner. Results: Prevalences of anti-RNAP III were 2/93 (2.2%) in SSc, 1/86 (1.2%) in SLE, and 1/65 (1.5%) in the healthy group and there was no difference among groups (P > 0.999). Anti-Sm was significantly more common in SLE patients (P < 0.001), whereas antitopoisomerase I and anticentromere protein B were significantly more common in SSc patients (P < 0.001). There was a significant association between antitopoisomerase I positivity and interstitial lung disease (P < 0.001), and interestingly there was also a significant association between anti-SS-A 52 positivity and the presence of digital ulcers in patients with SSc. Conclusion: Our data show that anti-RNAP III in SSc patients was low in frequency in a Turkish population. PMID- 29479938 TI - Omalizumab in chronic spontaneous and inducible urticaria: a 9 year retrospective study in Portugal. AB - Summary: Objective. Describe the safety and long-term use of omalizumab in chronic urticaria (CU), both spontaneous (CSU) and inducible (CIndU). Methods. Retrospective chart-review (2006-15) of CU patients treated with omalizumab for >= 6 months. Statistical analyses: descriptive statistics, Mann-Whitney, generalized linear models. Results. 23 patients with CSU (3 men), 3 with CIndU (2 men). Generalized linear models showed UAS reduction per omalizumab administration of 16% in CIndU and CSU and UAS7, of 15% in CIndU, and 20% in CSU. DLQI score at baseline had a median of 19 (CIndU and CSU) and after omalizumab a median of 0 (in both). Seven CSU patients stopped omalizumab and remain asymptomatic. No side-effects were observed. Conclusion. Omalizumab is safe and efficacious in CU. Stopping omalizumab can be tried, as some patients achieve remission. PMID- 29479937 TI - Role of nasal challenge and local eosinophilia in indirect exposure to cat in allergic rhinitis patients. AB - Summary: Introduction. Sensitization to cat allergens is common worldwide. Currently, there is a trend towards costly and often unavailable diagnostic analysis. Objectives. The aim is to assess the reliability of skin prick test (SPT) and serum specific IgE (ssIgE) to cat sensitization, by performing nasal challenge test (NCT) in a community with low cat ownership but common presence of stray cats. Patients and methods. Forty-one pa-tients with perennial allergic rhinitis (AR) who were mono or polysensitized (including cat) were included. We had 31 cat non-owners and 10 present cat owners. SPT (> 5 mm / diameter), ssIgE (>= 0.70 IU/ml), nasal smear for eosinophil (Eo) and NCT were compared between groups. Outcomes included nasal challenge score, nasal Eo positivity, peak inspiratory and expiratory flow (PIF and PEF) 2 and 8 hours after the NCT, and were compared to baseline. Results. Baseline SPT wheal size and ssIgE level were similar in both groups. NCT positivity was more frequent in cat owners. The strongest nasal reaction was on the top concentration in both groups. Nasal Eo positivity in cat owners was higher before and 2 hours after NCT, but similar to non-owners at last measurement. NCT positive cat non-owners had bigger SPT wheal size than NCT negative non-owners, but smaller than NCT positive cat owners. In contrast to PEF, a significant fall in PIF was noticed in both groups. Mono and polysensitised patients showed similar NCT positivity. Conclusion. Stray cats may pose a relevant risk of developing perennial AR. Regardless of cat ownership status, SPT and ssIgE should be the first diagnostic tool. Nasal Eo and NCT seem to be good diagnostic tools in cat non-owners if diagnosis is elusive. PMID- 29479939 TI - Advantages of b-mode ultrasound combined with strain elastography in differentiation of idiopathic granulomatous mastitis from malignant breast lesions AB - Background/aim: To evaluate the diagnostic performance of strain elastography (SE) combined with B-mode ultrasound in distinguishing between idiopathic granulomatous mastitis (IGM) and malignant breast lesions. Materials and methods: Seventy-seven malignant breast lesions and 36 IGM were assessed using B-mode ultrasound and SE. Ultrasonographic findings for all the breast lesions were classified based on the 2013 American College of Radiology Breast Imaging Reporting and Data System (BI-RADS-US), and the SE findings were evaluated based on the strain ratio and a five-point scale. The diagnostic performances of B-mode ultrasonography, SE, and the combination of both methods were compared. Results: Significant differences in strain ratio and elastography scores were found between IGM and malignant breast lesions. When the lesions were assessed with B mode ultrasound alone, in order to distinguish between IGM and malignant breast lesions, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 94.8%, 66.7%, 85.9%, 85.7%, and 85.8%, respectively. However, when assessed with a combination of B-mode ultrasonography and SE, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 96.1%, 100%, 100%, 92.3%, and 97.3%, respectively. Conclusion: The combination of SE and B-mode ultrasound has better diagnostic performance in the differentiation of IGM and malignant breast lesions than B-mode ultrasonography alone. PMID- 29479940 TI - CPR-related thoracic injuries: comparison of CPR guidelines between 2010 and 2015 AB - Background/aim: This study aimed to evaluate traumatic thorax complications in post-CPR patients and to investigate whether or not there has been a decrease in these complications since the adoption of current chest compression recommendations. Materials and methods: Post-CPR patients with return of spontaneous circulation (ROSC) were admitted between January 2014 and January 2016 were analyzed retrospectively. Patients admitted to the ED in 2014 were resuscitated according to 2010 AHA CPR guidelines, while those admitted to the ED in 2015 were resuscitated according to current ERC CPR guidelines. Results: The study population comprised 48 male and 35 female patients. Of the 2010 AHA guideline patients, 39.21% experienced pulmonary contusion, while 54.83% of 2015 ERC guideline patients had pulmonary contusion. It was found that 11.76% of 2010 AHA guideline patients and 3.22% of 2015 ERC guideline patients had pneumothorax, while 9.8% of 2010 AHA guideline patients and 12.9% of 2015 ERC guideline patients experienced hemothorax. Incidence rates of lung contusion, pneumothorax, and hemothorax were higher in patients with rib fractures. Conclusion: In this study, traumatic thoracic complications were investigated in patients with ROSC after CPR. The incidence of CRP-related injuries did not decrease on application of the new 2015 ERC CPR guideline recommendations. The most common injury in this study was rib fracture, followed by sternal fracture, lung contusion, hemothorax, and pneumothorax. Statistically, rib fracture had a positive relationship with lung contusion, hemothorax, and pneumothorax. PMID- 29479941 TI - Current views of complications associated with neonatal ventilation: a review. AB - Infants born prematurely require external respiratory support device like ventilation for the purpose of life saving. However, these ventilation machines have complications that sometimes unfortunately result in morbidity. New ventilation techniques have been developed to prevent morbidity, but have yet to be fully evaluated. The present review article would discuss current aspects of this life saving gear especially for pediatric patients in clinical setting. Besides basic ventilation apparatus, advancements in the filed like Proportional assist ventilation , Volume Targeted Ventilation would be discussed. PMID- 29479942 TI - Recent perspectives of pediatric beta-thalassaemias. AB - beta-thalassaemia is a potentially lethal hereditary anaemia, caused by reduced or absent expression of HBB polypeptide chains of adult haemoglobin (HbA: alpha2beta2). Current curative treatments options are limited to few patients, while alternative, chronic palliative therapy consisting of frequent transfusions coupled with iron chelation therapy, are costly. The above treatments also affect quality of life of patients. A search was conducted in the electronic databases like medline, pubmed, etc. for screening studies reporting various aspects including gene therapy, prevention strategies, blood, transfusion and chelation therapy for the management of beta-thalassaemia. Increased levels of fetal haemoglobin (HbF: alpha2gamma2) were shown to lessen the severity of beta thalassaemia, highlighting the therapeutic potential of a gene-therapy-mediated increase in HBG1 and HBG2 (HBG) expression. The primary outcome of most of the above studies was the efficient management of beta-thalassaemia, without any major complication. So, the present review is focused on the recent perspectives in the management of beta-thalassaemia including combinatorial gene therapy for beta-thalassaemia. PMID- 29479943 TI - Current perspectives in robot-assisted surgery. AB - From classical surgery to robot-assisted surgery (RAS), there has been a long way allowed by the improvements achieved in minimally invasive surgery (MIS). The last three decades have witnessed a prodigious development of MIS, and especially in the field of laparoscopic pediatric surgery but there are several limitations in the use of conventional laparoscopic surgery and RAS was developed to relieve these drawbacks. This new technology enables today the performance of a wide variety of procedures in children with a minimally invasive approach. As for all new technologies, an objective evaluation is essential with the need to respond to several questions: is the technology feasible?, is the technology safe?, is the technology efficient?, does it bring about benefits compared with current technology?, what are the procedures derived from most benefits of robotic assistance?, how to assume the transition from open surgery to minimally invasive access for RAS? In the first part of this article, some details are provided about technical concerns. Then, the implementation process with its organization, pitfalls, successes, and issues from human resources and financial standpoints is described. The learning curve is also analyzed, and a special focus on small children weighing less than 15 kg is developed. Finally, the concept of evaluation of this emerging technology is evocated and financial concerns are developed. PMID- 29479944 TI - New multimedia advances in surgical information. AB - When discussing new trends in pediatric surgery, the tendency is to focus on novel surgical technology and techniques. However, it is equally important to examine how the practicing surgeon stays abreast in an ever-changing field. This article serves as a brief guide to the future of surgical education for the attending surgeon. Broadly, advances in surgical education consist of new methods of filtration and delivery of knowledge. PMID- 29479945 TI - Antenatal management of congenital diaphragmatic hernia today and tomorrow. AB - Congenital diaphragmatic hernia is rare birth defect, which can be easily corrected after birth. The main problem is that herniation of viscera during fetal life impairs lung development, leading to a 30% mortality and significant morbidity. In isolated cases the outcome can be accurately predicted prenatally by medical imaging. Cases with a poor prognosis can be treated before birth; clinically this is by fetoscopic endoluminal tracheal occlusion. Obstruction of the airways triggers lung growth. This procedure is currently being evaluated in a global clinical trial for left sided cases; right sided cases with poor prognosis are offered the procedure clinically. The search for more potent and less invasive therapies continues. Prenatal transplacental sildenafil administration will in due course be tried clinically, with the aim to reduce the occurrence of persistent pulmonary hypertension, either alone or in combination with fetal surgery. Other medical approaches are in an earlier translational phase. PMID- 29479946 TI - New therapies for vascular anomalies of the gastrointestinal tract. AB - Vascular anomalies are a morphologically and biologically diverse group of vascular channel abnormalities that are often congenital but may evolve or change over time in the developing child. Classification is based on a combination of physical and biological properties and clinical behavior that differentiate primarily between tumors and malformations and includes a few provisionally unclassified lesions. Anomalies of the gastrointestinal (GI) tract may present clinically with GI bleeding, abdominal pain, high-output cardiac failure, and malabsorption. This review focuses on new therapies for the treatment of GI bleeding. Important new pharmacological therapies include treatment of hemangioma with non-selective and selective beta-antagonist agents, propranolol and atenolol, and treatment of blue rubber bleb nevus syndrome and cutaneo-visceral angiomatosis with thrombocytopenia (also known as multifocal lymphangioendotheliomatosis with thrombocytopenia) with sirolimus, an inhibitor of the mammalian target of rapamycin. Therapeutic endoscopy may offer an effective alternative to bowel resection for colonic varices and other focal vascular anomalies of the GI tract that fail to respond to pharmacological therapy. PMID- 29479947 TI - Is the extent of surgical resection important in patient outcome in benign and borderline phyllodes tumors of the breast? AB - Background/aim: Phyllodes tumors (PTs) of the breast are rare, and their diagnosis and treatment remain controversial. This retrospective study aims to examine the clinical outcome of benign and borderline PTs, according to the surgical margins. Materials and methods: We examined the medical records of 122 patients in our clinic, who had histologically confirmed benign and borderline PTs between 1994 and 2017. Results: The mean age of the patients was 40.6 years (range 18.0-81.0, +/-12.1 standard deviation [SD]) and the mean tumor size was 25.8 mm (range 9-65, +/-10.3 SD). All patients underwent a breast-conserving procedure and the median follow-up was 51 months. Tumor margins were positive (tumor touching the ink) in 43 patients (35%). Only 16 patients (13%) had margins >=10 mm. The margins were between 2 and 10 mm in most patients (40%) and <=1 mm in 12% of the patients. Conclusion: Although no re-excision was performed to obtain grossly clear margins, local recurrence was not observed in any patients. Therefore, revision surgery for close or positive surgical margins for benign and borderline PTs should not be performed as a rule. As most tumors recur within 2 years of diagnosis, we propose a close clinical and imaging follow-up during this period. PMID- 29479950 TI - Efficacy of adhesive strips to reduce postoperative periorbital edema and ecchymosis following rhinoplasty AB - Background/aim: Periorbital edema and ecchymosis may develop following rhinoplasty. The aim of this study was to assess the efficacy of adhesive strip application on the upper and lower eyelids to reduce postoperative edema and ecchymosis following rhinoplasty. Materials and methods: The eyelids of one side were randomly selected, and an adhesive strip of standard size and number was applied at the end of the operation. The strips were removed at postoperative day 3; photos of the eyes were taken at days 3 and 7. Edema and ecchymosis were graded on a scale from 1 to 4. The ecchymosis areas on the lower and upper eyelids were measured and compared in square centimeters. Results: The mean ecchymosis area of the lower eyelid on the side of the adhesive strip and on the side without the strip was 1.63 cm2 and 3.32 cm2 in the early period, respectively. It was 1.15 cm2 on the upper eyelid on the side of the adhesive strip, and 1.87 cm2 on the side without the strip. It was 0.224 cm2 on the side of the adhesive strip, and 0.498 cm2 on the side without the adhesive strip in the late period. Conclusion: Applying adhesive strips reduces periorbital edema and ecchymosis. PMID- 29479949 TI - Hybrid SPECT/CT Imaging in the Management of DifferentiatedThyroid Carcinoma AB - Differentiated thyroid cancer (DTC) has a good prognosis overall; however, lifelong follow-up is required formany cases. Radioiodine planar imaging with iodine-123 (I-123) or radioiodine-131 (I-131) remains the standard inthe follow up after initial surgery and ablation of residual thyroid tissue using I-131 therapy. Radioiodine imagingis also used in risk-stratifying and for staging of thyroid cancer, and in long-term follow-up. Unfortunately, the lackof anatomical detail on planar gamma camera imaging and superimposition of areas presenting with increased radioiodineuptake can make accurate diagnosis and localization of radioiodine-avid metastatic disease challenging, leading to falsepositive results and potentially to over-treatment of patients. Hybrid SPECT/CT allows precise anatomical localizationand superior characterization of foci of increased tracer uptake when compared to planar imaging. This, in turn, allows thedifferentiation of pathological and physiological uptake, increasing the accuracy of image interpretation and ultimatelyimproving the accuracy of DTC staging and subsequent patient management. In this review, we look at the unique andemerging role that SPECT/CT plays in the management of DTC, illustrated by examples from our own clinical practice. PMID- 29479952 TI - Correlation between epicardial adipose tissue thickness and the degree of coronary artery atherosclerosis AB - Background/aim: The purpose of the current study was to evaluate the thickness of the epicardial adipose tissue and its association with the degree of coronary artery disease in a group of autopsied cases. Materials and methods: A number of 79 cases were included in the study. Five preestablished incisions of the epicardial adipose tissue (EAT) were made on each of the hearts. These five points were next to/on the path of the major coronary vessels. The degree of coronary atherosclerosis was evaluated during the autopsy. Results: The results revealed the greatest thickness of the EAT on the incision made on the anterior and posterior wall of the right ventricle. EAT was thicker in cases presenting atherosclerosis degree I or II in two of the coronary arteries, the left circumflex artery and left main artery; on the left anterior descending artery, higher EAT thickness associated with fourth degree atherosclerosis. Conclusion: Epicardial adipose tissue thickness was greater at the incision points situated on the right side of the heart. Greater EAT thickness was associated significantly with early atherosclerosis development in three of the coronary arteries (LCx, LMA, LADA). PMID- 29479948 TI - Errors in Mammography Cannot be Solved Through Technology Alone AB - Mammography has been the frontline screening tool for breast cancer for decades. However, high error rates in theform of false negatives (FNs) and false positives (FPs) have persisted despite technological improvements. Radiologistsstill miss between 10% and 30% of cancers while 80% of woman recalled for additional views have normal outcomes,with 40% of biopsied lesions being benign. Research show that the majority of cancers missed is actually visible andlooked at, but either go unnoticed or are deemed to be benign. Causal agents for these errors include human relatedcharacteristics resulting in contributory search, perception and decision-making behaviours. Technical, patient andlesion factors are also important relating to positioning, compression, patient size, breast density and presence ofbreast implants as well as the nature and subtype of the cancer itself, where features such as architectural distortionand triple-negative cancers remain challenging to detect on screening. A better understanding of these causal agentsas well as the adoption of technological and educational interventions, which audits reader performance and provideimmediate perceptual feedback, should help. This paper reviews the current status of our knowledge around error ratesin mammography and explores the factors impacting it. It also presents potential solutions for maximizing diagnosticefficacy thus benefiting the millions of women who undergo this procedure each year. PMID- 29479953 TI - HIV infection and poor renal outcomes following noncardiac surgery AB - Background/aim: The relevance of HIV infection in perioperative renal risk stratification remains unclear. This research sought to investigate the impact of HIV infection, as well as other established preoperative risk factors for poor perioperative renal outcome (PPRO), in a population of 565,225 adult noncardiac surgery patients whose data were obtained from the 2009-2011 California State Inpatient Database. Materials and methods: HIV status, established preoperative risk factors, and the study outcome (PPRO) were determined with the Clinical Classification Software codes recorded for each patient. Data were analyzed using univariate (Mann-Whitney U test, chi-square, and Fisher's exact test) and multivariate (binary logistic regression) statistical methods. Results: The established preoperative risk factors were independently associated with PPRO. HIV infection was not an independent risk factor for PPRO in this study (odds ratio: 1.573, 95% confidence interval: 0.998-2.480; P = 0.051). Patients with HIV infection tended to have a higher burden of certain established preoperative risk factors for PPRO than patients without HIV infection. Conclusion: HIV-infected patients should be thoroughly screened for established preoperative risk factors and carefully managed during the perioperative period to reduce their risk of PPRO. PMID- 29479951 TI - The Complementary Role of Imaging and Tumor Biomarkersin Gynecological Cancers: An Update of the Literature AB - Gynecological tumors, including endometrial, cervical and ovarian cancer, have increased in incidence overtime. The widespread introduction of screening programs and advances in diagnostic imaging methods has lead to aprogressive increase in gynecological cancer detection. Accurate diagnosis and proper monitoring of disease remainthe primary target for a successful treatment. In the last years, knowledge about cancer biomarkers has considerablyincreased providing great opportunities for improving cancer detection and treatment. In addition, in the last few yearsthere has been an important development of imaging techniques. Nowadays, a multimodal approach including theevaluation of serum tumor biomarkers combined with imaging techniques, seems to be the best strategy for assessingtumor presence, spread, recurrence, and/or the response to treatment in female cancer patients In this review we providean overview of the application of biomarkers combined with novel imaging methods and highlight their roles in femalecancer diagnosis and follow-up. PMID- 29479954 TI - Cervical Cancer Prevalence, Incidence and Mortality in Lowand Middle Income Countries: A Systematic Review AB - Introduction: Cervical cancer rates vary across the world, being highest in Eastern Africa (including Zimbabwe) andlowest in Western Asia. It is the second most common type of cancer in women in the South East Asia region and amajor cause of cancer deaths among women of low and middle income countries (LMICs) like Nepal. This reviewis an attempt to make a comprehensive report of prevalence, incidence and mortality of cervical cancer in LMICs.Methods: The review was conducted applying a computerized search with the Medical Subject Heading (MeSH) majortopics "Cervical Cancer", "Cervical neoplasm" "Epidemiology", ("prevalence" OR "incidence" OR "mortality") and"HPV" OR "Human papillomavirus" as MeSH subheading. The search limits were: language ("English"), LMICs,dates (articles published from "1st January 2000 to 31st December 2015"), and species ("Humans"). The search wassupplemented by cross-referencing. Publications that met the inclusion criteria were included in the synthesis. Results:Among the 20 studies reviewed; seven were from Africa, seven from Asia, three from South America, and one eachfrom North America, Europe and Oceania. The review found the highest reported age standardized incidence rate as17.9/100,000/year in Zimbabwe in 2000 and the lowest as 0.11/100,000/year in China in 2006. One study of Nigeriarevealed a cervical cancer prevalence of 5.0 per 1,000 in 2012 in the 25 64 year age group. Further, the highest reportedage standardized mortality rate was 16/100,000/year in India in 2015 and the lowest 1.8/100,000/year in Colombia in2013. In addition, coitarche, tobacco smoking, number of sexual partners and family history of cervical cancer werereported as significant risk factors. Conclusion: The study provides a review of reported prevalence, incidence andmortality of cervical cancer in LMICs from 1st January 2000 to 31st December 2015. The scarcity of informationreveals a substantial need for further studies on cervical cancer prevalence, incidence and mortality with associatedrisk factors in LMICs. PMID- 29479955 TI - Relationship between PK2 and number of Kupffer cells during the progression of liver fibrosis in patients with HBV AB - Background/aim: This study aimed to investigate the potential regulatory role of prokineticin 2 (PK2) in modulation of the number and function of Kupffer cells (KCs) during the progression of liver fibrosis in patients with hepatitis B virus (HBV). Materials and methods: We obtained liver tissue sections from 200 patients with HBV undergoing surgical resection in our hospital between January 2013 and July 2016. Of these 200 tissue sections, 150 were fibrosis tissues and 50 were hepatocellular carcinoma tissues. Immunohistochemical evaluations were performed to assess the expression levels of CD68 and PK2 in the sections. The clinical parameters of these 200 patients were also analyzed. Results: As a potential cytokine, PK2 was commonly expressed in KCs. In addition, a close correlation between PK2 and the number of KCs during the progression of liver fibrosis in patients with HBV was found in this study. Conclusion: PK2 is expressed in KCs and participates in the progression of liver fibrosis after HBV infection. As a potential cytokine, PK2 modulates the number of KCs during fibrosis. Thus, PK2 most likely adjusts the number of M1 cells to modulate the role of KCs in the progression of liver fibrosis after HBV infection. PMID- 29479956 TI - Comparison of standard agglutination tests, enzyme immunoassay, and Coombs gel test used in laboratory diagnosis of human brucellosis AB - Background/aim: It was aimed to evaluate the results of Rose Bengal (RB), ELISA total tests (IgM and IgG), and the Brucella Coombs gel test (BCGT), which are used as screening tests, with the combined results of a tube agglutination test (standard Wright test: SWT) and a tube agglutination test with antihuman globulin (AHG TAT). Materials and methods: Samples from 97 patients prediagnosed with brucellosis (age >=18 years) were screened with RB, ELISA, and BCGT. SWT < 160 samples and RB-negative but ELISA- or BCGT-positive samples were tested by AHG TAT. SWT >= 160 or AHG TAT >= 160 was taken as reference. Results: Thirty-two of 56 RB-positive samples and one RB-negative but ELISA- and BCGT-positive sample were found to be >=160 with SWT or AHG TAT. Sensitivity, specificity, accuracy, and agreement (kappa) values according to SWT >= 160 or AHG TAT >= 160 positivity were as follows, respectively: RB 96.9%, 62.5%, 74.2%, and 0.509; ELISA total 100%, 60.9%, 74.2%, and 0.515; BCGT test 97%, 70.3%, 79.4%, and 0.594. Conclusion: Sensitivities of the screening tests are similar, but positivities should be confirmed by more specific tests. Positive samples from screening tests should be tested with AHG if the SWT value is <160. PMID- 29479957 TI - Neuroendocrine tumors detected in appendectomy specimens: ten-year single-center experience AB - Background/aim: The aim of this study was to investigate neuroendocrine tumors (NETs) detected in appendectomy specimens and the incidence and clinicopathologic characteristics of these tumors in our center. Materials and methods: A total of 13,863 patients were evaluated retrospectively. All underwent appendectomy operation in the Kayseri Training and Research Hospital and had a histopathological examination at the Pathology Clinic between January 2007 and March 2017. Age, sex, preoperative clinical findings, operation procedure, and histopathological examination results of the cases reported to be NET are presented. Results: NET was detected in 29 cases (0.2%) in the histopathological examination of 13,863 appendectomy specimens. Of these, 26 were classical carcinoid tumors and 3 were goblet cell carcinoid tumors (GCCTs). For the NET cases, the mean age was 37 years and the male to female ratio was 1.07. Only 68.9% of the patients underwent an appendectomy, and 31% of the patients underwent a secondary right hemicolectomy. Recurrences were not detected in any of the cases. In the present study, coincidence was determined in all of the cases with NET in the appendix. Conclusion: Contrary to many studies, both NETs of the appendix and GCCT cases were slightly higher among males and advanced age groups in this study. The long-term life expectancy in cases of classical carcinoid tumors of the appendix is quite good. PMID- 29479959 TI - Validity and reliability of the Turkish version of the DSM-5 Generalized Anxiety Disorder Severity Scale for children aged 11-17 years AB - Background/aim: This study aimed to assess the validity and reliability of the Turkish version of the DSM-5 Generalized Anxiety Disorder Severity Scale - Child Form. Materials and methods: The study sample consisted of 32 patients treated in a child psychiatry unit and diagnosed with generalized anxiety disorder and 98 healthy volunteers who were attending middle or high school during the study period. For the assessment, the Screen for Child Anxiety and Related Emotional Disorders (SCARED) was also used along with the DSM-5 Generalized Anxiety Disorder Severity Scale - Child Form. Results: Regarding reliability analyses, the Cronbach alpha internal consistency coefficient was calculated as 0.932. The test-retest correlation coefficient was calculated as r = 0.707. As for construct validity, one factor that could explain 62.6% of the variance was obtained and this was consistent with the original construct of the scale. As for concurrent validity, the scale showed a high correlation with SCARED. Conclusion: It was concluded that Turkish version of the DSM-5 Generalized Anxiety Disorder Severity Scale - Child Form could be utilized as a valid and reliable tool both in clinical practice and for research purposes. PMID- 29479960 TI - Carfilzomib experience in relapsed/refractory multiple myeloma: a single-center experience AB - Background/aim: Carfilzomib (CFZ) is a new-generation proteasome inhibitor with significant activity in relapsed or refractory multiple myeloma (R/R-MM). We have retrospectively evaluated R/R-MM patients who were treated with CFZ plus dexamethasone. Materials and methods: Twenty-one R/R-MM patients who were treated with CFZ plus dexamethasone between October 2013 and January 2016 were screened. The patients were followed until March 2016 after CFZ treatment. Results: Ten (47.6%) of the patients were female and 11 (52.4%) of them were male. The median age was 62 (47-76) years. The median number of prior treatment lines was 3 (2-7). The median number of administered cycles of treatment for CFZ was 4 (1-10). The median overall response rate was 26.3%. The most common hematological adverse events were anemia and thrombocytopenia (38%). The most common nonhematological adverse event was fatigue (71.4%). One patient died because of a cerebrovascular event and 1 patient died because of pneumonia during the treatment period. The median duration of response rate and time to next therapy were 8 (7-9) and 3 (2 16) months, respectively. The median overall survival was 8 (0.5-33) months. Conclusion: Despite the small number of patients, our results suggest that CFZ provides acceptable responses in heavily pretreated R/R-MM patients. PMID- 29479958 TI - Prognostic Value of RUNX1 Mutations in AML: A Meta-Analysis AB - The RUNX1 (AML1) gene is a relatively infrequent mutational target in cases of acute myeloid leukemia (AML).Previous work indicated that RUNX1 mutations can have pathological and prognostic implications. To evaluateprognostic value, we conducted a meta-analysis of 4 previous published works with data for survival according toRUNX1 mutation status. Pooled hazard ratios for overall survival and disease-free survival were 1.55 (95% confidenceinterval (CI) = 1.11-2.15; p-value = 0.01) and 1.76 (95% CI = 1.24-2.52; p-value = 0.002), respectively, for casespositive for RUNX1 mutations. This evidence supports clinical implications of RUNX1 mutations in the developmentand progression of AML cases and points to the possibility of a distinct category within the newer WHO classification.Though it must be kept in mind that the present work was based on data extracted from observational studies, thefindings suggest that the RUNX1 status can contribute to risk-stratification and decision-making in management of AML. PMID- 29479961 TI - Appraisal of the "pediatric ARDS: consensus recommendations from the pediatric acute lung injury consensus conference" with the AGREE II instrument AB - Background/aim: The "Pediatric Acute Lung Injury Consensus Conference" (PALICC) was convened in order to develop a taxonomy to define pediatric acute respiratory distress syndrome (ARDS). The Appraisal of Guidelines for Research and Evaluation (AGREE) assesses the quality of guidelines. The aim of this study is to evaluate the new pediatric ARDS guideline using the AGREE II instrument. To the best of our knowledge, this is the first assessment of the new pediatric ARDS clinical practice guideline in the English literature. Materials and methods: Four appraisers assessed the new pediatric ARDS guideline with the AGREE II instrument. At the end of the evaluation each appraiser rated the overall quality of the guidelines. Results: Results of the assessment were editorial independence 100%, clarity of presentation 94%, scope and purpose 89%, stakeholder involvement 78%, rigor of development 78%, and applicability 78%. Conclusion: The new pediatric ARDS guideline received good scores especially with respect to editorial independence and clarity of presentation. Our overall AGREE II review of the PALICC guideline indicates that it has been created using high quality methodology and should be recommended for use and implementation as currently published. PMID- 29479963 TI - Soft spot: the important zone at the standard posterior portal of shoulder arthroscopy AB - Background/aim: The localization of the standard posterior portal of shoulder arthroscopy and landmarks mentioned in the literature are unclear. The purpose of this prospective cadaveric study was to determine the localization of the standard posterior portal and its distance to the neural structures. Materials and methods: One fresh frozen and 10 formalin-fixed adult cadaveric shoulders were dissected. In the beach chair position, a 5-mm trocar was placed anteroposteriorly from the superior edge of the subscapularis muscle, superior to the tip of the coracoid process and tangent to the glenoid. The relevant distances of the posterior exit point were measured. Results: In all specimens, the exit point was a triangular fibrous area, between the posterior and lateral parts of the deltoid. Medial and inferior distances of the trocar to the posterolateral tip of the acromion were 1.88 +/- 0.53 cm and 1.35 +/- 0.34 cm and distances to the axillary and suprascapular nerves were 4.54 +/- 1.08 cm and 2.54 +/- 0.85 cm, respectively. Conclusion: The most important finding of this study was the superficial localization of the soft spot between the posterior and lateral parts of deltoid. PMID- 29479962 TI - Cd20 Expression and Effects on Outcome of Relapsed/Refractory Diffuse Large B Cell Lymphoma after Treatmentwith Rituximab AB - Introduction: Down regulation of CD20 expression has been reported in diffuse large B cell lymphoma (DLBCL)).Therefore, it is important to determine whether chemotherapy with rituximab induces CD20 down regulation and effectssurvival. Objectives: To determine the incidence of down regulation of CD20 expression in relapsed DLBCL aftertreatment with rituximab and to compare outcomes and assess pattern of relapse between CD20 negative and CD20positive cases. Methodology: We retrospectively reviewed patients with relapsed DLBCL who received rituximab inthe first line setting at Aga Khan University Hospital between January 2007 and December 2014. Data were recordedon predesigned questionnaires, with variables including demographics, details regarding date of diagnosis and relapse,histology, staging, international prognostic index, treatment and outcomes at initial diagnosis and at relapse. The Chisquare test was applied to determine statistical significance between categorical variables. Survival curves were generatedby the Kaplan-Meier method. Results: A total of 54 patients with relapsed DLBCL were included in our study, 38 (70%) males and 16(30%) females. Some 23 (43%) patients were at stage IV at the time of diagnosis and 34 (63%) had Bsymptoms. The most frequent R-IPI at diagnosis was II in 24 (44%) patients. Only 6 (11%) did not show CD20 expressionon re-biopsy for relapsed/refractory disease, 2 with CD20 negative DLBCL responding to second line chemotherapy.A complete response after salvage chemotherapy was noted in 16 (29.6%) cases with relapsed/refractory DLBCL.Seven (13%) patients underwent an autologous bone marrow transplant as consolidation after second line treatment.Median overall survival was 18 months in CD20 positive vs. 13 months in CD20 negative patients. Conclusion: Thisstudy demonstrated that a small percentage of patients treated with rituximab lose their CD20 expression at the timeof relapse. However, it is unclear whether this is associated with an inferior outcome. PMID- 29479964 TI - Bedside measurement of the optic nerve sheath diameter with ultrasound in cerebrovascular disorders AB - Background/aim: We aimed to show the role of determination of optic nerve sheath diameter (ONSD) by bedside ultrasonography in an emergency department in the diagnosis of cerebrovascular disorders and its correlation with the clinical picture. Materials and methods: This prospective cross-sectional study included 55 patients with cerebrovascular disorders and 53 controls. Age, sex, ONSD, comorbid disease status, and multidetector computed tomography results of all subjects and application periods and National Institutes of Health Stroke Scale (NIHSS) scores of the patient group were evaluated. Results: The ONSD of the patient and control groups was determined as a median of 5.7 mm and 3.6 mm, respectively. The ONSD of the patient group was determined to be significantly higher than that of the control group (P < 0.05). A positive relationship was determined between NIHSS scores and ONSD values (P < 0.05). The specificity and sensitivity values were determined as 98.1% and 81.8%, respectively, for a cutoff value of 5 mm and as 100% and 72.7%, respectively, for a cutoff value of 6 mm. Conclusion: This study showed that bedside measurement of ONSD is an easy, cheap, and noninvasive method that can be used to support the diagnosis and evaluation of patients with acute stroke. PMID- 29479966 TI - Evaluation of urinary incontinence and quality of life in married women aged between 20 and 49 years (Sakarya, Turkey) AB - Background/aim: This study aimed to determine the prevalence of urinary incontinence and to evaluate the relationship between urinary incontinence and quality of life in married women. Materials and methods: This is a cross sectional study conducted among married women aged 20-49 years living in the vicinity of the Cokekler Community Clinic (Family Health Center) in Sakarya, Turkey, from 1 November 2011 to 15 April 2012. The study group consisted of 1161 women. Results: The frequency of urinary incontinence was 71.5% (n = 830). Out of a total of 830 patients with symptoms of urinary incontinence, mixed was the most frequently determined type (60.4%), followed by urge (33.9%) and then stress urinary incontinence (5.8%). The mean scores obtained by women with urinary incontinence from the general health perceptions and social functioning domains of the SF-36 survey were lower (P < 0.05 for each domain). Conclusion: Urinary incontinence was found to be a common problem among women, and it affects quality of life adversely. Recurrent urinary tract infection and advancing age were the key risk factors in the development of urinary incontinence. PMID- 29479965 TI - Molecular Study of Parvovirus B19 Infection in Children withAcute Myeloid Leukemia AB - Background: Parvovirus B19 is a common viral infection in children. Nearby evidences are present about itsassociation with acute leukemia, especially acute lymphoblast leukemia. Nevertheless, scanty reports have discussedany role in acute myeloid leukemia (AML). Purpose: To evaluate the frequency of virological markers of B19 infectionincluding its DNA along with specific immunoglobulins G (IgG) and M (IgM) among children with newly diagnosedAML. Besides, describing the clinical importance of Parvovirus B19 infection in those patients. Patients and methods:A case-control retrospective study was conducted on 48 children recently diagnosed with AML before and duringchemotherapy induction and 60 healthy control. Specific serum IgM and IgG levels were determined by enzyme linkedimmunosorbant assay (ELISA) and DNA detection by polymerase chain reaction (PCR). Results: Parvovirus DNA wasdetected in 20 patients with AML. IgM was found in sera of four patients and one case had positive DNA and IgG (5%).Patients with recent parvovirus B19 infection had a significantly reduced hemoglobin levels, RBCs counts, plateletcounts, neutrophil counts and absolute lymphocytosis (p=0.01, p=0.0001, p=0.01, p=0.02, p=0.0003, respectively).There were no clinical findings with statistically significant association to recent infection. Half of the patients withAML had positive PCR and/or IgM for parvovirus B19. Among children with AML under chemotherapy, there werereduced hemoglobin levels (P=0.03), reduced platelet counts (P=0.0001) and absolute neutropenia (mean+/-SD, 1.200+/-1.00) in those with parvovirus B19 infection. More than half of patients with parvovirus B19 (72.2%) had positive PCRand/or IgM and 36.4% of them had positive IgG. Conclusion: This study highlights that parvovirus B19 is commonin children with AML either at diagnosis or under chemotherapy. There are no clinical manifestations that can be usedas markers for its presence, but hematological laboratory findings can provide evidence for infection in the presenceof anemia and neutropenia. Detection of parvovirus B19 by combined molecular and serological markers is requiredin such patients for accurate diagnosis. PMID- 29479967 TI - Diagnostic utility of the sonographic median to ulnar nerve cross-sectional area ratio in carpal tunnel syndrome AB - Background/aim: The aim of this study was to assess the diagnostic utility of the ultrasonographic ratio of median nerve cross-sectional area (m-CSA) to ulnar nerve cross-sectional area (u-CSA), the m-CSA/u-CSA ratio, in carpal tunnel syndrome (CTS). Materials and methods: Fifty patients with positive symptoms and electromyography results of CTS and 50 healthy matched control subjects were evaluated. Ultrasonographic m-CSA and u-CSA measurements of each participant were made at the level of the pisiform bone and the m-CSA/u-CSA ratio was calculated. Results: Using the m-CSA cut-off value of 11.95 mm2 showed a sensitivity of 80% and a specificity of 80% while using a cut-off value 2.95 for the ratio of m CSA/u-CSA showed a sensitivity of 86% and a specificity of 72% in the diagnosis of CTS. Conclusion: The ratio of m-CSA/u-CSA at the level of the pisiform bone was not detected to be superior to m-CSA in the diagnosis of CTS. PMID- 29479968 TI - Prognostic value of interferon-gamma, interleukin-6, and tumor necrosis factor alpha in the radiation response of patients diagnosed with locally advanced non small-cell lung cancer and glioblastoma multiforme AB - Background/aim: This study aimed to investigate the effect of chemoradiotherapy (CRT) on interferon-gamma (IFN-gamma), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha), which are critical markers of the clinical radiation response of patients with locally advanced non-small-cell lung cancer (NSCLC) and glioblastoma multiforme (GBM). Materials and methods: Thirty patients who were treated with CRT and 20 healthy controls were prospectively evaluated. Circulating levels of cytokines were measured by enzyme-linked immunosorbent assay procedure. Post-CRT and pre-CRT levels were compared. Results: Post-CRT, TNF-alpha and IFN-gamma levels were significantly lower than pre-CRT levels in the NSCLC and GBM groups, respectively. The statistical analysis did not show any significant difference between the post- and pre-CRT IL-6 levels. However, the pre-CRT IL-6 levels in the GBM group and post-CRT IL-6 levels in the NSCLC group were significantly higher than those of the control group. Conclusion: CRT affected TNF-alpha levels in NSCLC and IFN-gamma levels in GBM, with the levels of both decreasing significantly. The IL-6 levels of the post-CRT NSCLC group were higher than those of the post-CRT GBM group. Irradiation-induced IL-6 may be responsible for tumor regrowth. Therefore, treatment with IL-6 inhibitors could be a potential therapeutic strategy for sensitizing NSCLC to irradiation in the clinic. PMID- 29479969 TI - Detection of Cytochrome P450 Polymorphisms in BreastCancer Patients May Impact on Tamoxifen Therapy AB - Background: Breast cancer is the most common cancer among women worldwide. Tamoxifen (TAM), a selectiveestrogen receptor modulator, is widely used in its treatment. TAM is metabolized by cytochrome P450 (CYP450) enzymes,including CYP2D6, CYP3A5 and CYP2C19, whose genetic variations may have clinicopathological importance.However, reports on the association of various P450 polymorphisms with certain cancers are contradictory. Methods:We here investigated whether the prevalence of the four most common polymorphism in the CYP2D6*4 (G1934A),CYP2D6*10 (C188T), CYP3A5*3 and CYP2C19*2 alleles has any link with breast cancer using genomic DNA andpolymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis. Results: Prevalences ofCYP2D6*4, CYP2D6*10 and CYP2C19*2 genotypes were differed significantly (P = 0.01 and P = 0.004) betweenbreast cancer patients and controls. The CYP3A5*3 genotype did not demonstrate statistically significant variation.Conclusion: Polymorphisms in CYP2 appear to be associated with breast cancer risk. Our data taken together withother reports indicates that drug resistance gene polymorphisms might be indicators of response to tamoxifen therapyin breast cancer cases. PMID- 29479970 TI - Cross-cultural adaptation, reliability, and validity of the Turkish version of the Cancer Fatigue Scale in patients with breast cancer AB - Background/aim: The Cancer Fatigue Scale (CFS) was developed to evaluate the severity of fatigue in patients with breast cancer. The aim of this study is to translate and culturally adapt a Turkish version and investigate the validity and reliability of the CFS in Turkish patients with fatigue symptoms. Materials and methods: Eighty participants completed the Turkish version of the CFS for breast cancer and the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire "Core 30" (EORTC QLQ-C30). Test-retest reliability was evaluated by repeating the CFS with a 7-day interval. Results: The CFS demonstrated high test-retest reliability (ICC = 0.95) and good internal consistency (Cronbach's alpha = 0.74) for all domains. The Kaiser-Meyer-Olkin measure of sampling adequacy was found to be 0.819, which is considered to be satisfactory (>0.5). Correlations between domains of CFS physical and EORTC physical (r: 0.77), CFS cognitive and EORTC cognitive (r: 0.70), and CFS physical and EORTC fatigue (r: 0.80) were found to be significant. Conclusion: The Turkish version of the CFS is a reliable and valid instrument to assess physical, effective, and cognitive dimensions of fatigue. The CFS may be used to evaluate the severity of fatigue in Turkish-speaking breast cancer patients. PMID- 29479971 TI - Retinopathy of prematurity in extremely premature infants: multiple births versus single births AB - Background/aim: This study aimed to compare the incidence of any stage of retinopathy of prematurity (ROP) and type 1 ROP between extremely preterm multiple- and single-birth infants. Materials and methods: In this retrospective study, we included extremely preterm infants who were <=27 weeks of gestational age at birth. The screened infants were divided into two groups: single and multiple births. The incidence of any stage of ROP and type 1 ROP was compared between the groups. Results: This study included 301 infants; 225 were in the single-birth group and 76 were in multiple-birth group. The incidences of any stage of ROP and type 1 ROP among all infants were 70.7% (213 of 301) and 16.6% (50 of 301), respectively. Regression analysis showed that lower birth weight (OR = 0.99, P = 0.004) and longer length of stay in hospital (OR = 1.02, P = 0.002) were significantly correlated with any stage of ROP. Compared to single-birth infants, the risk of any stage of ROP and type 1 ROP did not statistically increase for multiple-birth infants (P > 0.05). Conclusion: This study showed that multiple birth had no significant correlation with ROP development in extremely preterm infants. PMID- 29479972 TI - Observational study of dermatological manifestations in patients admitted to a tertiary poison center in Iran AB - Background/aim: Acute unintentional and deliberate poisoning by medications and chemicals is a frequent emergency, especially in Iran. This study aimed to evaluate the frequency and character of skin findings occurring in patients with acute intentional and aunintentional poisoning. Materials and methods: This prospective observational study was performed at the Loghman Hakim Hospital Poison Center over a period of 6 months from April 2016 to September 2016. Data including patient demographics, cause of poisoning, and level of consciousness were collected. Pediatric patients (under the age of 13) and patients who died in the first hours of admission were excluded from the study. Results: The most common cause of toxicity-related admission in our patients was methadone overdose. The most common skin finding in these patients was xerosis. According to our results, there was an association between tramadol poisoning and self induced lesions. Shin hyperpigmentation was found to be significantly more frequent in patients with lead poisoning. Conclusion: Further study is recommended to shed light on the possible association of drug poisoning and skin lesions. PMID- 29479973 TI - Mean Platelet Volume and Platelet Distribution Width AreAssociated with Gallbladder Cancer AB - Gallbladder cancer (GBC) represents the most common biliary tract malignancy. Activated platelets play an essentialrole in cancer development and progression. Mean platelet volume (MPV) and platelet distribution width (PDW) arecommonly used indexes of activated platelets in clinical practice. The aim of the current study was to investigate theassociation of MPV and PDW with GBC. 104 GBC patients and 109 normal control subjects were entered in thisstudy between January 2015 and December 2015. We collected all participants' clinical and laboratory characteristicsat initial diagnosis. The odds ratios (ORs) for GBC were calculated using multivariate logistic regression analysis afteradjusting for confounding variables across MPV and PDW quartiles. MPV levels were markedly lower and PDW levelswere remarkably higher in GBC patients than control subjects. A significant correlation between PDW and lymph nodemetastasis was detected. In addition, after adjusting for other risk factors, the ORs (95% CIs) for GBC in each MPVquartile were 5.117 (1.939-13.506), 2.444 (0.917-6.516), 3.718 (1.381 10.007), and 1.000, respectively. The ORs (95%CIs) for GBC in each PDW quartile were 1.000, 2.063 (0.825-5.162), 3.070 (1.108-8.507), and 12.108 (4.243 34.553),respectively. In conclusion, decreased MPV and elevated PDW were independently associated with GBC. Our findingssuggest that MPV and PDW are available parameters for early detection of GBC. PMID- 29479974 TI - Effects of nefopam with fentanyl in intravenous patient-controlled analgesia after arthroscopic orthopedic surgery: a prospective double-blind randomized trial AB - Background/aim: We performed this prospective randomized double-blind study to compare the effects of nefopam versus ketorolac in intravenous fentanyl-based patient-controlled analgesia (PCA) after shoulder arthroscopic orthopedic surgery. Materials and methods: Ninety-two patients were randomly divided into two groups to receive intravenous PCA. Patients were assigned to either the nefopam group (nefopam 120 mg and fentanyl 20 ug/kg) or the ketorolac group (ketorolac 2 mg/kg and fentanyl 20 ug/kg). Pain was assessed on a visual analogue scale (VAS) and a numeric rating scale (NRS). Additionally, patient satisfaction, adverse events, and vital signs were monitored. Results: There were no significant differences in VAS score (P = 0.48) or NRS score (P = 0.15) between the two groups. Similarly, patient satisfaction did not differ between the two groups [8.5(0.8) vs. 8.2(1.0), P = 0.14]. There were no statistically significant differences in the incidence of nausea (P = 0.72), vomiting (P = 0.46), urinary retention (P = 0.82), sweating (P = 0.49), or dizziness (P = 0.45) between the two groups. Likewise, there were no differences in heart rate [78.2(7.7) vs. 75.2(6.5), P = 0.18] or SpO2 [98.4(1.8) vs. 98.5(1.9), P = 0.83]. Conclusion: Nefopam is an appropriate alternative for co-administration with fentanyl-based PCA in patients who have difficulty using nonsteroidal antiinflammatory drugs. PMID- 29479975 TI - Translocation breakpoints of chromosome 3 in male carriers: a report of twelve cases and a review of the literature AB - Background/aim: This study aimed to explore the breakpoints in chromosome 3 translocation and the clinical features present in male carriers to enable informed genetic counseling of these patients. Materials and methods: A total of 5235 men who were infertile or receiving counseling for infertility were recruited. Cytogenetic analyses were performed using G-banding. A search for translocations on chromosome 3 involved in male infertility was performed using PubMed, Google Scholar, and CNKI. The relationships of translocation breakpoints with male infertility and recurrent pregnancy loss were also analyzed. Results: Among the 82 patients with balanced reciprocal translocations among 5235 male patients, 12 patients were carriers of chromosome 3 translocation: two presented with pregestational infertility, while 10 presented with gestational infertility. The breakpoint at 3p13 was related to pregestational infertility, whereas those at 3p23, 3q10, 3q12, 3q21, 3q25, and 3q29 were related to gestational infertility. By an analysis combining data from the literature, 63 carriers of chromosome 3 translocation were reviewed and all breakpoints at chromosome 3 were correlated with gestational infertility. Conclusion: All breakpoints at chromosome 3 were correlated with gestational infertility. The breakpoints at 3q12 and 3q29 were the most common. Carriers of chromosome 3 translocation should thus be counseled on the need for other chromosomal breakpoints and preimplantation genetic diagnosis or prenatal testing. PMID- 29479976 TI - Characteristics of Women Diagnosed with Invasive CervicalCancer in Ghana AB - Objective: To describe the characteristics of women diagnosed with invasive cervical cancer from 2010 to 2013in two large hospitals in Ghana. Method: Medical records and other hospital data on women diagnosed with invasivecervical cancer were collected from the Komfo Anokye and Korle-Bu Teaching Hospitals. Data were recorded ontoa standardized data collection sheet and analyzed using summary statistics. Results: For of the 1,725 women withinvasive cervical cancer who were included in the study, parity was high (5 and more births). The most commondiagnostic investigation undertaken was a cervical biopsy, performed for 95.5% of cases. Few women had an imagingtest performed as part of the diagnostic process (3.3%). Some had comorbid conditions at diagnosis (29.3%). Only 61%of women attended at least one follow-up appointment after diagnosis of their cancer. Conclusion: Our study suggeststhat more work is needed to improve patient education and access to diagnostic and treatment facilities to reduce theincidence and mortality of cervical cancer in Ghana. Additionally, improvement in data quality is needed to providemore complete data for cancer control in Ghana. PMID- 29479977 TI - Neutrophil-to-lymphocyte ratio and microvascular complications in subjects with type 2 diabetes: Pakistan's perspective AB - Background/aim: The aim of this study is to find the association between diabetic microvascular complications and the neutrophil-to-lymphocyte ratio (NLR) in subjects with type 2 diabetes. Materials and methods: This was a retrospective study based on hospital data records from January 2005 to May 2016 at the Baqai Institute of Diabetology and Endocrinology. The eligibility criteria included subjects with type 2 diabetes with their latest complete blood count while subjects with conditions such as chronic inflammation, cancer, heart failure, and end-stage renal disease were not eligible for inclusion. Subjects were divided into two groups: one with any microvascular complications and the other with no microvascular complications. Body mass index, anthropometric measurements, and blood pressure were measured. Results: Out of 5620 type 2 diabetic subjects, 3202 (57%) were male and (2418) 43% were female. Among these, 3374 diabetic subjects had one or more microvascular complications and 2246 had no microvascular complications. The NLR was found to be 1.14 times higher in diabetic subjects with at least one microvascular complication as compared to diabetic subjects without any complications (4.34 +/- 3.32 vs. 3.36 +/- 2.67; P < 0.0001). Factors likely associated with microvascular complications were high levels of NLR, HbA1c, serum creatinine, and systolic blood pressure and longer duration of diabetes. Conclusion: According to the results, the NLR is an efficient, cheaper, and readily available marker of inflammation and it is known as an important predictor for the existence of microvascular complications in subjects with type 2 diabetes. PMID- 29479978 TI - Biofilm formation in uropathogenic Escherichia coli: association with adhesion factor genes AB - Background/aim: Biofilm formation is a major determinant factor in the development of urinary tract infections (UTIs) by uropathogenic Escherichia coli (UPEC). Several adhesion factors are involved in attachment of bacterial cells to the urinary tract and biofilm development. Materials and methods: The possible relationship between different adhesion factor genes (AFGs) and biofilm formation among UPEC isolates was investigated. Prevalence of different AFGs including fimA, fimH, papAH, papC, papEF, sfa-S, foc/G, and bmaE and their association to biofilm formation were investigated. Phenotypic expression of type 1 and P fimbriae was also investigated. Results: Our results showed that 84% of UPEC were moderate to strong biofilm producers. Prevalence of the type 1 and P fimbriae associated genes (fimA, fimH, papEF, papC) as well as the F1C fimbriae gene (foc/G) did not show a difference among different biofilm-producing groups, while higher prevalence of papAH, bmaE (M fimbriae), and sfaS (S-fimbriae) was observed for the strains producing moderate to strong biofilms. Phenotypic expression of type 1 fimbriae was associated with biofilm formation, while no association was observed for P fimbriae. Conclusion: Different AFGs (especially M and S fimbria) and their expression levels affect the biofilm formation ability of UPEC. PMID- 29479980 TI - Effects of cinnamic acid on complications of diabetes AB - Background/aim: Diabetes mellitus (DM) is a major health problem worldwide. Cinnamic acid (CA) and its derivatives are synthesized in plants and increasing attention has been given to them in recent years due to the high number of beneficial health properties attributed to their consumption. The aim of this study was to investigate the effects of CA on streptozotocin-induced diabetes in Wistar albino rats. Materials and methods: DNA damage was evaluated in the blood, liver, and kidney cells of rats by the alkaline comet assay. Oxidative stress parameters such as catalase, superoxide dismutase, glutathione reductase, glutathione-S-transferase, and glutathione peroxidase activities and 8-hydroxy-2 deoxyguanosine, total glutathione, and malondialdehyde levels; biochemical parameters including insulin, total bilirubin, and BCA protein levels; hepatic enzyme levels such as alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase; and lipid profile parameters including high-density lipoprotein, low-density lipoprotein, total cholesterol, and triglyceride levels were also evaluated. Results: DM caused genotoxic damage and alterations in lipid profiles, oxidative stress parameters, and hepatic enzymes levels. CA treatment ameliorated these effects. Conclusion: It seems that CA might have a role in the prevention of the complications of diabetes. PMID- 29479979 TI - Symptom Severity, Anxiety, Depression, Self- Efficacy andQuality of Life in Patients with Cancer AB - Background: Despite advances in cancer disease prevention, diagnosis, and treatment patients with cancer sufferfrom a variety of sometimes severe physical and psychological symptoms regardless of the stage of the disease. The aimis to determine the relationship of antecedent factors and mediating variables to the quality of life (QOL) of patients withcancer. Materials and Methods: The study included 341 patients with cancer and symptoms. Data collection used theCancer Symptom Scale, State-Trait Anxiety Inventory, Centers for Epidemiologic Study Depression, Cancer BehaviorInventory, Multidimensional Quality of Life Index, and a Demographic Form. Results: A multiple regression equationcontaining all the variables explained 68% of the variance in QOL. Overall four variables accounted for the majorityof the total variance: anxiety, depression, self-efficacy, and symptom severity. Three of these variables were mediatingvariables. Of the antecedent factors symptom severity had a significant indirect effect on QOL through the mediatingvariables. Symptom severity also had direct effect on QOL. Conclusion: Data indicate that anxiety, depression, andself-efficacy play major roles in determining the perception of QOL of cancer patients. These mediating variableseither buffered or enhanced the impact of the antecedent factors of symptom severity on QOL. Nursing interventionsshould focus on enhancing self efficacy. Nurses can use health promoting programs to assist patients who are physicallyimpaired. Further research should be aimed at identifying other influential variables, with the ultimate goal of developinginterventions to aid patients in their efforts to maintain their QOL while living with cancer. PMID- 29479981 TI - In vivo attenuation of angiogenesis in hepatocellular carcinoma by Nigella sativa AB - Background/aim: Angiogenesis is imperative in malignant tumor growth. Hepatocellular carcinoma is a typical hypervascular tumor that relies on angiogenesis. The aim of this study is to investigate the in vivo molecular mechanism underlying the antitumor properties of Nigella sativa ethanolic extract (NSEE) through its antiangiogenic effect against diethyl nitrosamine (DENA) induced hepatocarcinogenesis. Materials and methods: Male Wistar rats were divided into 4 groups: normal, NSEE, DENA, and NSEE-DENA groups. Final body weight, hepatosomatic indices, serum AFP, serum vascular endothelial growth factor (VEGF) levels, and liver tissue hepatocyte growth factor beta (HGFbeta) protein expression were estimated. Liver sections were stained for histological examination. AFP levels with the histological variations were chosen to confirm cancer development. Results: DENA significantly increased liver weight, hepatosomatic indices, serum AFP and VEGF levels, and liver HGFbeta protein expression and significantly decreased final body weight. These effects were significantly reversed by NSEE. Furthermore, the histopathological changes that appeared in rat livers due to DENA were reduced by NSEE without harmful effects when taken alone. Conclusion: The results of the present investigation provide evidence that the in vivo antiangiogenic effect of NSEE through downregulation of serum VEGF and liver HGFbeta protein could be implicated in its antitumor activity. Its consumption has health benefits that favor liver cancer management. These findings might prove useful and helpful for the progression of therapies for hepatocarcinogenesis treatment. PMID- 29479982 TI - Protective effect of erdosteine on erythrocyte deformability in a rat model of lower limb ischemia/reperfusion injury AB - Background/aim: The protective effect of erdosteine on local and distant organ injury due to ischemia/reperfusion has been well documented but its effect on erythrocyte deformability needs further investigation. Our aim was to investigate the effect of erdosteine on erythrocyte deformability in the infrarenal aorta of rats undergoing ischemia/reperfusion. Materials and methods: Our study was conducted with 18 Wistar albino rats. Rats were divided into 3 groups: a randomized control group (group 'control', n = 6), an ischemia/reperfusion group without erdosteine (group 'ischemia/reperfusion', n = 6), and an ischemia/reperfusion group with erdosteine at 150 mg kg-1, intraperitoneally (group 'ischemia/reperfusion - erdosteine', n = 6). Packs of erythrocytes were prepared from heparinized blood samples and deformability measurements were conducted. Results: Comparisons of the control and ischemia/reperfusion - erdosteine groups revealed similar results (P = 0.051). The values of the ischemia/reperfusion group were significantly higher than those of the control and ischemia/reperfusion - erdosteine groups (P < 0.0001 and P = 0.024, respectively). Relative resistance, a marker of erythrocyte deformability, was increased significantly by ischemia/reperfusion compared to the control and ischemia/reperfusion - erdosteine groups (P < 0.05). Conclusion: We detected unfavorable effects of ischemia/reperfusion on erythrocyte deformability, which may lead to disturbance in blood flow and hence tissue perfusion in the infrarenal rat aorta. We also found that erdosteine had beneficial effects by reversing undesirable effects of ischemia/reperfusion. However, these promising results should be further supported by more detailed studies with larger volumes. PMID- 29479984 TI - The role of apoptosis and the effect of epidermal growth factor on proapoptotic BNIP 3 in an experimental rat priapism model AB - Background/aim: This study aimed to investigate the effects of apoptosis-inducing Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP 3) and antiapoptotic epidermal growth factor (EGF) on the pathophysiology of experimental low-flow priapism. Materials and methods: Twenty-four adult Sprague-Dawley rats were divided into four equal groups. Group I was the control group. Ischemic priapism was induced for 4 h in Group II rats. In Group III, intraperitoneal EGF at 10 ug/kg was given for 7 days before induction of ischemic priapism for 4 h. In Group IV, intraperitoneal EGF at 20 ug/kg was given for 7 days before induction of ischemic priapism for 4 h. The western blot method was used to determine BNIP 3 expression levels and the TUNEL method was used to determine the apoptotic cells in the cavernosal tissue samples. Results: Although BNIP 3 expression levels were significantly higher in all three study groups compared to the controls, BNIP 3 was significantly higher in EGF-administered groups when compared to Group II (P < 0.05). The TUNEL score of group II was significantly higher than those of the other groups. Conclusion: Decreased apoptosis in cavernosal tissues obtained by antagonizing the apoptotic effect of BNIP 3 with EGF may facilitate the development of new conservative treatment methods via those pathways. PMID- 29479985 TI - Investigation of the relationship between oxidative stress and SCUBE1 levels in high fat diet-induced obese rats AB - Background/aim: This study aimed to investigate signal peptide-Cub-EGF domain containing protein 1 (SCUBE1) levels and oxidative stress (OS) in a high fat diet (HFD)-induced obese rat model. Materials and methods: Fourteen rats were randomly divided into two groups. Group 1, the control group, was given a standard diet (10% calories of fat) and Group 2, the obese group, was given a HFD (60% calories of fat), both for 70 days. Rats were then sacrificed and serum samples were collected. Serum glucose and triglyceride concentrations were determined using an autoanalyzer. Serum SCUBE1, adiponectin, and plasminogen activator inhibitor-1 levels were determined using an enzyme-linked immunosorbent assay. Serum malondialdehyde levels and superoxide dismutase and glutathione peroxidase enzyme activities were determined using colorimetric methods. Results: Final body weight was higher in the obese group (P = 0.007). Serum malondialdehyde concentrations were also higher in the obese group (P = 0.021). Serum glutathione peroxidase activities were higher in the control group (P = 0.028). Serum SCUBE1 levels were also higher in the control group (P = 0.038). Conclusion: There may be no connection between the measured OS parameters and SCUBE1. Differences in SCUBE1 levels may therefore be evaluated independently from OS in obesity. PMID- 29479983 TI - CHEK2 Germ Line Mutations are Lacking among Familialand Sporadic Breast Cancer Patients in Rwanda AB - Worldwide, breast cancer is the most frequent neoplasm and the second leading cause of cancer death amongfemales. It dominates in both developed and developing countries and represents a major public health problem. Theetiology is multifactorial and involves exogenous agents as well as endogenous factors. Although they account for onlya small fraction of the breast cancer burden, mutations in the BRCA1 and BRCA2 genes are known to confer a highrisk predisposition. Mutations in moderate/low-penetrance genes may also contribute to breast cancer risk. Previousstudies have shown that mutations in the CHEK2 gene are involved in breast cancer susceptibility due to its impacton DNA repair processes and replication checkpoints. This study was conducted to evaluate the frequencies of threegermline mutations in CHEK2 gene (c.1100delC, R145W and I157T) in breast cancers in Rwanda. Using direct DNAsequencing, we analyzed 41 breast cancer patients and 42 normal breast controls but could not detect any positives.CHEK2 mutations may be a rare event in Rwandan population and may only play a minor if an role in breast cancerpredisposition among familial and sporadic cases. PMID- 29479986 TI - Genetic Polymorphism of the Glutathione S-transferasePi 1 (GSTP1) and Susceptibility to Cervical Cancer in HumanPapilloma Virus Infected Northeastern Thai Women AB - Objective: We aimed to investigate any association between a genetic polymorphism of the detoxification GSTP1gene and risk of cervical cancer in northeastern Thailand. Materials and Methods: Genotyping of GSTP1 was performedfor 198 squamous cell cervical cancer (SCCA) patients and 198 age-matched healthy controls with the PCR-RFLPmethod. Results: The respective frequencies of the G allele were 0.33 and 0.26 in the controls and cases, the differencebeing significant (OR = 0.69 [95% CI: 0.50-0.95, p=0.0192]). Among women infected with high-risk types of HPV, beinga heterozygous carrier was associated with a reduced risk of cervical cancer (adjusted OR = 0.32 [95% CI: 0.12-0.91,p=0.031]). Similarly, a decreased risk was observed in heterozygous women with a non-smoking partner (adjusted OR= 0.27 [95% CI: 0.09-0.83, p=0.023]). Conclusions: GSTP1 polymorphism could influence susceptibility to cervicalcancer among northeast Thai women; either as a independent factor or in combination with high-risk HPV infection.Dual-testing of HPV and the GSTP1 might prove an effective screening tool for cervical cancer. PMID- 29479987 TI - Ellagic Acid Holds Promise Against Hepatocellular Carcinomain an Experimental Model: Mechanisms of Action AB - This research work was initiated to explore the efficacy of ellagic acid in mitigation of hepatocarcinogenesis inrats. Rats were distributed into 4 groups; negative control, hepatocellular carcinoma (HCC), doxorubicin and ellagicacid. Serum alpha-fetoprotein (AFP), glypican-3 (GPC-3), signal transducer and activator of transcription 3 (STAT3)and suppressors of cytokine signaling 3 (SOCS3) levels were assayed by ELISA. Immunohistochemical examinationof hepatic VEGF expression was also conducted, along with histological procedures for examination of liver tissuesections. Significant elevation in serum AFP, GPC-3 and STAT3 levels with a significant drop in SOCS3 were observedin the HCC group. In contrast, the treated groups showed significant decline in serum AFP, GPC-3 and STAT3 levelsand significant increase in SOCS3. Additionally, the HCC group declared mild positive immunoreaction for VEGF inhepatocytes while treatment with doxorubicin or ellagic acid was associated with a negative immunoreaction for VEGF.These results were supported by histological examination of liver tissue. The obtained findings suggested that ellagicacid may have beneficial chemopreventive role against hepatocarcinogenesis through its apoptotic, antiangiogenic andantiproliferative activities. PMID- 29479988 TI - Perceived Risk of Developing Cancer in a Suburban Communityin Malaysia AB - Objective: To determine the perceived risk of developing cancer in a suburban community in Malaysia. Methods:A cross sectional study using a simple random sampling was conducted among residents aged 18 years old and above(n=520) who had never been diagnosed with cancer, in selected households in a suburban area of Pahang state inMalaysia. The study instruments were a validated questionnaire on risk perception, an automatic blood pressure monitor,a weighing scale and a measuring tape. Data were analyzed using IBM SPSS Statistics for Windows, Version 20.0 andthe p value was taken at p <0.05 as significant. Result: This study revealed that only 5.0 percent individuals perceivedthey were at risk cancer, whilst the perceived severity was 41.3 percent. Multivariable analysis showed a significantassociation only for a family history of cancer (adjusted OR of 4.80; 95% CI = 1.45-15.82) (p=0.010) among thispopulation. Conclusion: The perceived risk of developing cancer in the selected suburban community of Pahang state inMalaysia is low as compared to that for other non-communicable diseases in this country, whilst the perceived severitywas higher than for other diseases. Thus, considering the importance of correct perceptions for behavioral changes,more health education and promotion is needed to make the community better aware of the actual threat of cancer. PMID- 29479990 TI - Expression of Laminin in Oral Squamous Cell Carcinomas AB - Background and objectives: Laminin is a significant basement membrane (BM) glycoprotein, the expression ofwhich reflects BM integrity more precisely than do other ECM proteins. The present study aimed to evaluate lamininexpression in oral squamous cell carcinomas OSCC and to determine any associations with clinico pathologicalparameters (surgical margin status, lymph node involvement, survival and recurrence). Methods: Laminin expression wasevaluated in 31 cases of biopsy proven OSCC by immunohistochemical staining and its association with prognosticatorsand the Brynes grading system was determined by appropriate statistical analysis. Results: We observed a significantincrease in linear staining pattern (p<0.001) at the tumour-host interface in well-differentiated OSCC cases, in contrastto poorly differentiated lesions which exhibited intense cytoplasmic expression within tumour cells. Higher cytoplasmiclaminin expression was seen in 33.3% of cases with involved surgical margins and 69.2% of cases with lymph nodemetastasis (along with weak/absent staining of laminin around the tumour-host interface - Basement membrane aroundtumour islands). Similarly, in 60% of the cases who died and in 81.8% of cases with tumour recurrence, moderatelyintense cytoplasmic laminin expression was seen within tumour cells. On comparing variables of the Brynes gradingsystem, significant cytoplasmic expression of laminin was linked with mild inflammation (p<0.0016) and increasedmitotic activity (p<0.008). Conclusion: Based on these observations, immunohistochemical expression of lamininmight be useful to evaluate histological differentiation and aggressiveness of OSCCs. PMID- 29479989 TI - Clinical Significance of Gli-1 And Caveolin-1 Expression in theHuman Small Cell Lung Cancer AB - Background: Lung cancer is the leading causes of cancer-related deaths around the world. Abnormal activation of thehedgehog (Hh) signaling pathway has been found to be involved in the occurrence, invasion, and metastasis of cancers.Autophagy also plays a significant role in the growth and metastasis of cancers. However, the correlation between theHh signaling pathway and autophagy in small cell lung cancer (SCLC) is still poorly understood. This study aimed toinvestigate the significance of Hh signaling pathway and autophagy in SCLC. Materials and Methods: The expressionof the Hh-induced transcriptional factor, glioma associated oncogene-1 (Gli-1) and the autophagy-related moleculecaveolin-1 (Cav 1) and their clinical significance was performed to detect and assay by immunohistochemistry in tissuemicroarray including 70 patients with SCLC. Results: In our study, 47 (67.1%) patients had positive Gli-1 expression,49 (70.0%) patients had positive Cav-1 expression, and 44 (62.9%) patients had negative fibroblastic Cav-1 expression.In SCLC, Gli-1 expression increased markedly, and was closely associated with decreased fibroblastic Cav-1 expression.Furthermore, we also found that Gli-1 expression was closely associated with increased Cav-1 expression. Conclusions:Our findings suggested that abnormal activation of the Hh signaling pathway is closely related to autophagy in SCLC.We envision that novel targets may come with the further investigation of Gli-1 and Cav-1 in carcinogenesis of SCLC. PMID- 29479991 TI - Association between Dietary Inflammatory Index and ProstateCancer in Shiraz Province of Iran AB - Background: Dietary components like food items and nutrients have been implicated to play a role in modulatinginflammation and the development of prostate cancer. Studies examining this association have not been extensivelyexplored in Middle Eastern Countries. Material and Methods: We examined the association between the dietaryinflammatory index (DIITM) and prostate cancer in the Shiraz province of Iran. A total of 60 incident cases and 60controls attending the same hospital as the cases were recruited. The energy adjusted DII (E-DIITM) was computedbased on dietary intake assessed using a validated food frequency questionnaire (FFQ). Logistic regression was usedto estimate odds ratios. Results: Men with higher E DII (>0.96) were at higher risk of prostate cancer (OR = 2.55;95% CI =1.04-6.23) compared to men with E-DII <=0.96. Conclusion: These data suggest a pro inflammatory diet, asindicated by increasing DII score, may be a risk factor for prostate cancer in Iranian men. PMID- 29479992 TI - Impact of Day 14 Bone Marrow Biopsy on Re-InductionDecisions and Prediction of a Complete Response in AcuteMyeloid Leukemia Cases AB - Background: With acute myeloid leukemia (AML), there are limited data about the accuracy of day 14 bonemarrow (BM) biopsies for predicting complete remission as compared to day 28 BM biopsy results. We here aimedto estimate the correlation between, and the diagnostic accuracy of, both approaches. Materials and Methods: Wereviewed 84 patients with AML treated with standard induction chemotherapy to evaluate the remission rate andtreatment decisions based on day 14 BM biopsy from 2000-2012. Results: Sixty five patients (77%) demonstratedremission (CR) with less than 5% blasts on their day 14 BM. Thirteen patients (16%) had residual disease (RD), and6 (7%) were classified as indeterminate response (IR) i.e., blasts 5-20%. Two patients with RD on day 14 underwentre-induction. Out of the 17 remaining cases with RD+IR, 14 (all 6 with IR and 8 out of 11 with residual disease withno re-induction) demonstrated a morphologic complete remission (CR) on day 28 BM. The percentages for completeremissions on days 28 and 14 were significantly different [94% versus 79.3%, respectively; p=0.004, (OR= 0.143, 95%CI: 0.032-0.63)]. Day 14 BM had 82% sensitivity in predicting CR on Day 28; however, it had insufficient specificity(60%) in predicting failure of CR. Conclusions: Induction treatment response assessment based on day 14 BM doesnot accurately predict the response rate on day 28 and the use of day 14 BM as a sole marker of response to therapymight expose patients to unnecessary interventions. PMID- 29479993 TI - Beliefs Underlying Messages of Anti-Cancer-ScreeningWebsites in Japan: A Qualitative Analysis AB - Background: Cancer screening rates are lower in Japan than in Western countries. Meanwhile, anti-cancer-screeningactivists take to the internet to spread their messages that cancer screening has little or no efficacy, poses substantialhealth risks such as side effects from radiation exposure, and that people should forgo cancer screening. We applied aqualitative approach to explore the beliefs underlying the messages of anti-cancer-screening websites, by focusing onperceived value the beliefs provided to those who held them. Methods: We conducted online searches using GoogleJapan and Yahoo! Japan, targeting websites we classified as "pro," "anti," or "neutral" depending on their claims.We applied a dual analytic approach- inductive thematic analysis and deductive interpretative analysis- to the textualdata of the anti websites. Results: Of the 88 websites analyzed, five themes that correspond to beliefs were identified:destruction of common knowledge, denial of standard cancer control, education about right cancer control, educationabout hidden truths, and sense of superiority that only I know the truth. Authors of anti websites ascribed two values("safety of people" and "self-esteem") to their beliefs. Conclusion: The beliefs of authors of anti-cancer-screeningwebsites were supposed to be strong. It would be better to target in cancer screening promotion not outright screeningrefusers but screening hesitant people who are more amenable to changing their attitudes toward screening. The possiblemeans to persuade them were discussed. PMID- 29479994 TI - Characteristics of goalkeepers' injuries: retrospective, self-reported study among adolescence football players. AB - BACKGROUND: Characteristic types of actions and training/matches loads of football goalkeepers show that goalkeeper's performance differs from other football's formations. Such situation may predispose to the occurrence of other kinds of injuries in this position. The aim of this study was to analyse epidemiology of injuries in young football goalkeepers. METHODS: 48 football goalkeepers (aged:15.2+/-1.9 years) were filled the questionnaire aimed at collecting information about all injuries sustained within 12 months before the data collection. The anthropometric data, football experience and information regarding the injury types and occurrence were analysed. The injury rate proportion for acute and overuse injuries and values of injuries including the burden of the match game and training were evaluated. The level of significance was set at p<0.05. RESULTS: 33(68.8%) questionnaires were given back. 24(72.7%) goalkeepers reported the history of football related injury within a year before the survey. 52 injuries were reported. Significantly higher number of acute (76.9%) vs. overuse (23.1%) injuries was described (p=0.0012). Acute injuries involved fractures/subluxations of the fingers and thigh muscle strain/tears. The group of overuse injuries was dominated by trauma of the knee and pelvic girdle muscles. Majority of injuries occurred during training (88,5% of all injuries), and there was significant higher number of injuries sustained on artificial vs. natural grass for all, acute and overuse types of injuries (p<0,0001). CONCLUSIONS: Young football goalkeepers suffer mostly acute injuries (within the fingers of hands and muscles of thighs). It might be associated with specific characteristic of performance related to goalkeeper's position. PMID- 29479995 TI - Effect of acute intradialytic aerobic and resistance exercise on one-day blood pressure in patients undergoing hemodialysis: a pilot study. AB - BACKGROUND: Hypertension and intradialytic hypotension are independent risk factors for mortality in hemodialysis patients. We hypothesized that intradialytic exercise would increase blood pressure (BP) during dialysis and decrease it during the postdialytic period. The present study aimed to investigate the effect of acute intradialytic exercise on BP both during dialysis and for 20 hours post-dialysis, and to detect any differences in effects of aerobic exercise (AE), resistance exercise (RE), and usual care (UC-the control condition). METHODS: Eleven patients undergoing maintenance hemodialysis performed two complete sets of AE or RE, with a 1-hour rest between the sets. The patients performed AE, RE and UC over three consecutive weeks at 7 day intervals. Intradialytic BP was measured using an oscillometric BP monitor (n=11), and ambulatory BP was measured for 20 hours after each dialysis session using an ambulatory BP monitor (n=8). RESULTS: The mean BP of the patients in the AE and RE interventions increased during exercise (p<0.05), with the exception of the first set of AE. However, only RE increased BP significantly compared with UC (p<0.05). Following dialysis, daytime ambulatory BP was significantly lower after AE and RE than after UC (p<0.05). CONCLUSIONS: Acute intradialytic exercise interventions are effective in increasing BP during dialysis and decreasing daytime ambulatory BP after dialysis. Longer observation periods and larger sample sizes will be needed to confirm our findings. Also further studies should be performed on patients prone to intradialytic hypotension. PMID- 29479996 TI - Chronic wound slough revisited: why its removal aids healing PMID- 29479998 TI - Foreword: management strategies for removing slough. PMID- 29479997 TI - Correlation of Expression Levels of Copper Transporter 1 andThymidylate Synthase with Treatment Outcomes in Patientswith Advanced Non-small Cell Lung Cancer Treated withS-1/Carboplatin Doublet Chemotherapy AB - Background: Copper transporter 1 (CTR1) is a critical determinant of the uptake and cytotoxic effect of the platinumdrugs carboplatin and cisplatin. Thymidylate synthase (TS) is an enzyme involved in DNA synthesis and is associatedwith resistance of tumor cells to 5-fluorouracil. We investigated the correlation between CTR1 and TS expression levelsand treatment outcomes in patients with advanced non-small-cell lung cancer (NSCLC) treated with S-1/carboplatindoublet chemotherapy. Methods: Twenty-nine patients were enrolled in this study. Tumor expression of CTR1 andTS was measured immunohistochemically and analyzed for correlation with tumor response, progression-free survival(PFS), and overall survival (OS). Results: Tumor response was significantly better in patients with CTR1High tumorsthan in patients with CTR1Low tumors (64% vs. 18%, P = 0.02). Patients with TSLow tumors had a significantly longer OS(median 21.2 vs. 8.5 months, P = 0.02), but not PFS, than patients with TSHigh tumors. When CTR1 and TS co-expressionwas analyzed, patients with either CTR1High or TSLow tumors showed a significantly better tumor response (50% vs. 0%,P = 0.01), longer PFS (median 4.2 vs. 2.1 months, P = 0.03), and longer OS (median 21.2 vs. 8.5 months, P = 0.01) thanpatients with both CTR1Low and TSHigh tumors. Conclusions: Our study suggests that combined CTR1/TS expressionstatus has the potential to be an important predictor of good treatment outcomes in patients with advanced NSCLCtreated with S-1/carboplatin doublet chemotherapy. PMID- 29479999 TI - UrgoClean: the evidence base AB - This chapter describes a dressing, UrgoClean, which can rapidly and effectively reduce wound slough and absorb excess exudate. There is strong evidence to support this, including a randomized controlled trial. PMID- 29480001 TI - Deshisced surgical wound. PMID- 29480000 TI - Promoter Methylation of BRCA1, DAPK1 and RASSF1A isAssociated with Increased Mortality among Indian Womenwith Breast Cancer AB - Background: Promoter methylation has been observed for several genes in association with cancer development andprogression. Hypermethylation mediated silencing of tumor suppressor genes (TSGs) may contribute to breast cancerpathogenesis. The present study was conducted to investigate the promoter methylation status of BRCA1, DAPK1 andRASSF1A genes in Indian women with breast cancer. Materials and Methods: Promoter methylation was evaluatedin DNA extracted from mononuclear cells (MNCs) in peripheral blood samples of 60 histopathologically confirmednewly diagnosed, untreated cases of breast cancer as well as 60 age and sex matched healthy controls using MS-PCR.Association of promoter methylation with breast cancer-specific mortality was analyzed with Cox proportional hazardsmodels. Kaplan-Meier survival analysis was performed for overall survival of the breast cancer patients. Results: Weobserved a significant increase of BRCA1, DAPK1 and RASSF1A promoter methylation levels by 51.7% (P <0.001),55.0% (P <0.001) and 46.6% (P <0.001), respectively, when compared to healthy controls. A strong correlation wasnoted between hypermethylation of the tumor suppressor genes BRCA1 (P= 0.009), DAPK1 (P= 0.008) and RASSF1A(P= 0.02)) with early and advanced stages of breast cancer patients. We also found that breast cancer-specific mortalitywas significantly associated with promoter methylation of BRCA1 [HR and 95% CI: 3.25 (1.448-7.317)] and DAPK1[HR and 95% CI: 2.32 (1.05-5.11)], whereas limited significant link was evident with RASSF1A [HR and 95% CI: 1.54(0.697-3.413]. Conclusion: Our results suggest that promoter methylation of BRCA1, DAPK1 and RASSF1A genesmay be associated with disease progression and poor overall survival of Indian women with breast cancer. PMID- 29480002 TI - Pressure damage on the elbow. PMID- 29480003 TI - Mixed aetiology leg ulcers with obdurate slough. PMID- 29480005 TI - Total Synthesis of (-)-Peniphenone A. AB - The asymmetric total synthesis of the polyketide benzannulated spiroketal natural product, (-)-peniphenone A, is reported. The key reaction in the synthesis involved sp3-sp2 Negishi cross-coupling between a chiral organozinc species and an aryl bromide to construct the challenging alpha-chiral beta-aryl carbonyl motif present in the natural product. Access to the spiroketal possessing the correct stereochemistry was facilitated by an unusual thermodynamic resolution at C10. The synthesis was achieved in 14 steps (longest linear sequence) from commercially available 2,4-dihydroxybenzaldehyde in 6% overall yield. Investigations into a parallel approach required extension of Krische's enantioselective hydrogen-mediated C-C coupling to alpha-substituted alcohols and oxetane ring-opening with an aryllithium for assembly of the polyketide domain. These studies provide a useful foundation for further work toward the natural product family, members of which demonstrate significant activity against M. tuberculosis and offer continuing inspiration for the development of efficient new chemical methods. PMID- 29480004 TI - Photothermal Activation of Metal-Organic Frameworks Using a UV-Vis Light Source. AB - Metal-organic frameworks (MOFs) usually require meticulous removal of the solvent molecules to unlock their potential porosity. Herein, we report a novel one-step method for activating MOFs based on the photothermal effect induced by directly irradiating them with a UV-vis lamp. The localized light-to-heat conversion produced in the MOF crystals upon irradiation enables a very fast solvent removal, thereby significantly reducing the activation time to as low as 30 min and suppressing the need for time-consuming solvent-exchange procedures and vacuum conditions. This approach is successful for a broad range of MOFs, including HKUST-1, UiO-66-NH2, ZIF-67, CPO-27-M (M = Zn, Ni, and Mg), Fe-MIL-101 NH2, and IRMOF-3, all of which exhibit absorption bands in the light emission range. In addition, we anticipate that this photothermal activation can also be used to activate covalent organic frameworks (COFs). PMID- 29480006 TI - Metal-Free S-Arylation of Cysteine Using Arenediazonium Salts. AB - A mild chemoselective method for S-arylation of cysteine has been developed in an open-flask procedure under metal-free conditions using arenediazonium salts in methanol. PMID- 29480007 TI - Extending Proteome Coverage by Combining MS/MS Methods and a Modified Bioinformatics Platform Adapted for Database Searching of Positive and Negative Polarity 193 nm Ultraviolet Photodissociation Mass Spectra. AB - To extend proteome coverage obtained from bottom-up mass spectrometry approaches, three complementary ion activation methods, higher energy collision dissociation (HCD), ultraviolet photodissociation (UVPD), and negative mode UVPD (NUVPD), are used to interrogate the tryptic peptides in a human hepatocyte lysate using a high performance Orbitrap mass spectrometer. The utility of combining results from multiple activation techniques (HCD+UVPD+NUVPD) is analyzed for total depth and breadth of proteome coverage. This study also benchmarks a new version of the Byonic algorithm, which has been customized for database searches of UVPD and NUVPD data. Searches utilizing the customized algorithm resulted in over 50% more peptide identifications for UVPD and NUVPD tryptic peptide data sets compared to other search algorithms. Inclusion of UVPD and NUVPD spectra resulted in over 600 additional protein identifications relative to HCD alone. PMID- 29480008 TI - Effect of Nonionic Surfactant Additive in PEDOT:PSS on PFO Emission Layer in Organic-Inorganic Hybrid Light-Emitting Diode. AB - Poly(9,9-dioctylfluorene) (PFO) has attracted significant interests owing to its versatility in electronic devices. However, changes in its optical properties caused by its various phases and the formation of oxidation defects limit the application of PFO in light-emitting diodes (LEDs). We investigated the effects of the addition of Triton X-100 (hereinafter shortened as TX) in poly(3,4 ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) to induce interlayer diffusion between PEDOT:PSS and PFO to enhance the stability of the PFO phase and suppress its oxidation. Photoluminescence (PL) measurement on PFO/TX-mixed PEDOT:PSS layers revealed that, upon increasing the concentration of TX in the PEDOT:PSS layer, the beta phase of PFO could be suppressed in favor of the glassy phase and the wide PL emission centered at 535 nm caused by ketone defects formed by oxidation was decreased considerably. LEDs were then fabricated using PFO as an emission layer, TX-mixed PEDOT:PSS as hole-transport layer, and zinc oxide (ZnO) nanorods as electron-transport layer. As the TX concentration reached 3 wt %, the devices exhibited dramatic increases in current densities, which were attributed to the enhanced hole injection due to TX addition, along with a shift in the dominant emission wavelength from a green electroluminescence (EL) emission centered at 518 nm to a blue EL emission centered at 448 nm. The addition of TX in PEDOT:PSS induced a better hole injection in the PFO layer, and through interlayer diffusion, stabilized the glassy phase of PFO and limited the formation of oxidation defects. PMID- 29480009 TI - Fabrication of Flexible, Fully Organic, Degradable Energy Storage Devices Using Silk Proteins. AB - Flexible and thin-film devices are of great interest in epidermal and implantable bioelectronics. The integration of energy storage and delivery devices such as supercapacitors (SCs) with properties such as flexibility, miniaturization, biocompatibility, and degradability are sought for such systems. Reducing e-waste and using sustainable materials and processes are additional desirable qualities. Herein, a silk protein-based biocompatible and degradable thin-film microSC (MUSC) is reported. A protein carrier with the conducting polymer poly(3,4 ethylenedioxythiophene) polystyrene sulfonate and reduced graphene oxide dopant is used as a photopatternable biocomposite ink. Active electrodes are fabricated using photolithography under benign conditions, using only water as the solvent. These electrodes are printed on flexible protein sheets to form degradable, organic devices with a benign agarose-NaCl gel electrolyte. High capacitance, power density, cycling stability over 500 cycles, and the ability to power a light-emitting diode are shown. The device is flexible, can sustain cyclic mechanical stresses over 450 cycles, and retain capacitive properties over several days in liquid. Significantly, the MUSCs are cytocompatible and completely degraded over the period of ~1 month. By precise control of the device configuration, these silk protein-based, all-polymer organic devices can be designed to be tunably transient and provide viable alternatives for powering flexible and implantable bioelectronics. PMID- 29480010 TI - Periodic Porous Alloyed Au-Ag Nanosphere Arrays and Their Highly Sensitive SERS Performance with Good Reproducibility and High Density of Hotspots. AB - Periodic porous alloyed Au-Ag nanosphere (NS) arrays with different periodic lengths and tunable composition ratios were prepared on Si substrates on a large scale (~cm2) using stepwise metal deposition-annealing and subsequent chemical corrosion from a monolayer of colloidal polystyrene (PS) microspheres as the initial template. The porous alloyed Au-Ag NSs possessed a high porosity and bicontinuous morphology composed of hierarchically interconnected ligaments, which were obtained from an optimized dealloying process in nitric acid. Interestingly, when the dealloying time was prolonged, the average size of the porous alloyed NSs slightly decreased, and the width of the ligaments gradually increased. The periodic length of the array could be facilely changed by controlling the initial particle size of the PS template. Moreover, the porous alloyed Au-Ag NS arrays were explored as a platform for the surface-enhanced Raman scattering (SERS) detection of 4-aminothiophenol (4-ATP) and exhibited excellent reproducibility and high sensitivity because of the periodic structure of the arrays and the abundance of inherent "hotspots". After optimization experiments, a low concentration of 10-10 M 4-ATP could be detected on these porous Au-Ag NS array substrates. Such highly reproducible SERS activity is meaningful for improving the practical application of portable Raman detection equipment. PMID- 29480011 TI - Synthesis, Photophysical, and Electrochemical Properties of Pyrenes Substituted with Donors or Acceptors at the 4- or 4,9-Positions. AB - We report herein an efficient and direct functionalization of the 4,9-positions of pyrene by Ir-catalyzed borylation. Three pinacol boronates (-Bpin), including 4-(Bpin)-2,7-di( tert-butyl)pyrene (5), 4,9- bis(Bpin)-2,7-di( tert-butyl)pyrene (6), and 4,10- bis(Bpin)-2,7-di( tert-butyl)pyrene (7), were synthesized. The structures of 6 and 7 have been confirmed by single-crystal X-ray diffraction. To demonstrate the utility of these compounds, donor (NPh2)-substituted compounds 4 diphenylamino-2,7-di( tert-butyl)pyrene (1) and 4,9- bis(diphenylamino)-2,7-di( tert-butyl)pyrene (2) have been synthesized on a gram scale. Acceptor (BMes2) substituted compounds 4,9- bis(BMes2)pyrene (3) and 4,9- bis(BMes2)-1,2,3,6,7,8 hexahydropyrene (4) were synthesized for comparison. The photophysical and electrochemical properties of compounds 1-4 have been studied both experimentally and theoretically. The S0 -> S1 transitions of the 4- or 4,9-disubstituted pyrenes, 1-3, are allowed, with moderate fluorescence quantum yields and radiative decay rates. The photophysical and electrochemical properties of 1-3 were compared with the 2,6-naphthalenylene-cored compound 4 as well as the previously reported 2,7- and 1,6- pyrenylene-cored compounds. PMID- 29480012 TI - Free-Energy-Based Protein Design: Re-Engineering Cellular Retinoic Acid Binding Protein II Assisted by the Moveable-Type Approach. AB - How to fine-tune the binding free energy of a small-molecule to a receptor site by altering the amino acid residue composition is a key question in protein engineering. Indeed, the ultimate solution to this problem, to chemical accuracy (+/-1 kcal/mol), will result in profound and wide-ranging applications in protein design. Numerous tools have been developed to address this question using knowledge-based models to more computationally intensive molecular dynamics simulations-based free energy calculations, but while some success has been achieved there remains room for improvement in terms of overall accuracy and in the speed of the methodology. Here we report a fast, knowledge-based movable-type (MT)-based approach to estimate the absolute and relative free energy of binding as influenced by mutations in a small-molecule binding site in a protein. We retrospectively validate our approach using mutagenesis data for retinoic acid binding to the Cellular Retinoic Acid Binding Protein II (CRABPII) system and then make prospective predictions that are borne out experimentally. The overall performance of our approach is supported by its success in identifying mutants that show high or even sub-nano-molar binding affinities of retinoic acid to the CRABPII system. PMID- 29480013 TI - Improving patient care after a suicide attempt. AB - OBJECTIVES: Improving the care that patients receive after a suicide attempt will reduce the risk of a subsequent suicide attempt. We described how care for these patients can be improved and identified the available guidelines. METHODS: We reviewed the literature on crisis and aftercare, psychosocial assessment, risk assessment, brief contact interventions, and brief interventions. RESULTS: People who have made a suicide attempt are at increased risk of suicide, and the period immediately after discharge from hospital is particularly risky. Patients require an empathic response at their first point of contact, comprehensive psychosocial assessment, effective discharge planning, rapid and assertive follow-up, and coordinated care in the subsequent months. CONCLUSIONS: Empathic and effective care that begins in the emergency department and extends through to community care is imperative. Enough is known about the risks of inadequate care and the key ingredients of effective care to proceed with changes to Australia's healthcare response to a suicide attempt. PMID- 29480014 TI - A new graduate medical school curriculum in Psychiatry and Addiction Medicine: reflections on a decade of development. AB - OBJECTIVES: The aim of this study is to reflect upon the rationale, design and development of the Psychiatry and Addiction Medicine curriculum at the Australian National University Medical School, Canberra, Australian Capital Territory, Australia. CONCLUSIONS: We conclude that the development of the fourth-year curriculum of a four-year graduate medical degree was a complex evolutionary process. PMID- 29480015 TI - Background and design of the ACCA-EAPCI registry on ST-segment elevation myocardial infarction of the European Society of Cardiology. AB - Treatment of patients with acute ST-segment elevation myocardial infarction has improved over past decades, with reperfusion therapy being the cornerstone in the acute phase. Based on the results of large randomised trials the current ST segment elevation myocardial infarction guidelines of the European Society of Cardiology (ESC) recommend acute treatments and secondary prevention therapies. However, there are large variations between ESC countries in the treatment of patients presenting with ST-segment elevation myocardial infarction. Therefore the ESC has initiated a prospective registry to evaluate the current treatments and outcomes of these patients with a special focus on adherence to the ESC guidelines and on differences between countries and regions. This paper describes the methodology and design of the ST-segment elevation myocardial infarction registry conducted in collaboration of the Acute Cardiac Care Association and the European Association of Percutaneous Coronary Intervention. PMID- 29480016 TI - A direct comparison of decision rules for early discharge of suspected acute coronary syndromes in the era of high sensitivity troponin. AB - BACKGROUND: We tested the hypothesis that a single high sensitivity troponin at limits of detection (LOD HSTnT) (<5 ng/l) combined with a presentation non ischaemic electrocardiogram is superior to low-risk Global Registry of Acute Coronary Events (GRACE) (<75), Thrombolysis in Myocardial Infarction (TIMI) (<=1) and History, ECG, Age, Risk factors and Troponin (HEART) score (<=3) as an aid to early, safe discharge for suspected acute coronary syndrome. METHODS: In a prospective cohort study, risk scores were computed in consecutive patients with suspected acute coronary syndrome presenting to the Emergency Room of a large English hospital. Adjudication of myocardial infarction, as per third universal definition, involved a two-physician, blinded, independent review of all biomarker positive chest pain re-presentations to any national hospital. The primary and secondary outcome was a composite of type 1 myocardial infarction, unplanned coronary revascularisation and all cause death (MACE) at six weeks and one year. RESULTS: Of 3054 consecutive presentations with chest pain 1642 had suspected acute coronary syndrome (52% male, median age 59 years, 14% diabetic, 20% previous myocardial infarction). Median time from chest pain to presentation was 9.7 h. Re-presentations occurred in eight hospitals with 100% follow-up achieved. Two hundred and eleven (12.9%) and 279 (17%) were adjudicated to suffer MACE at six weeks and one year respectively. Only HEART <=3 (negative predictive value MACE 99.4%, sensitivity 97.6%, %discharge 53.4) and LOD HSTnT strategy (negative predictive value MACE 99.8%, sensitivity 99.5%, %discharge 36.9) achieved pre-specified negative predictive value of >99% for MACE at six weeks. For type 1 myocardial infarction alone the negative predictive values at six weeks and one year were identical, for both HEART <=3 and LOD HSTnT at 99.8% and 99.5% respectively. CONCLUSION: HEART <=3 or LOD HSTnT strategy rules out short and medium term myocardial infarction with >=99.5% certainty, and short-term MACE with >99% certainty, allowing for early discharge of 53.4% and 36.9% respectively of suspected acute coronary syndrome. Adoption of either strategy has the potential to greatly reduce Emergency Room pressures and minimise follow-up investigations. Very early presenters (<3 h), due to limited numbers, are excluded from these conclusions. PMID- 29480018 TI - Antifungal activity against Botrytis cinerea of labdane-type diterpenoids isolated from the resinous exudate of Haplopappus velutinus Remy (Asteraceae). AB - Two labdane diterpenoids were isolated, from the resinous exudate of Haplopappus velutinus Remy (Asteraceae); the main compound was identified as 7,13-(E) labdadien-15,18-dioic-acid-18-methyl ester (1) and the minor compound identified as 7-labden-15,18-dioic-acid-18-methyl ester (2). Their structures were obtained using FTIR, MS, HRMS and NMR data: 1D NMR (1H, 13C and DEPT-135), 2D homonuclear NMR (COSY and NOESY) and heteronuclear NMR (HSQC and HMBC). The trans stereochemistry of the decalin moiety of compounds 1 and 2 was established through NOESY experiments of the reduction product of 1; 7-labden-15,18-diol (1a). Diterpenoids 1 and 1a are described for the first time and showed antifungal activity, inhibiting approximately 40% mycelial growth of Botrytis cinerea. PMID- 29480017 TI - Staff awareness of the application of Mental Health and Guardianship Legislation in the care of hospitalised older persons. AB - OBJECTIVE: The study aimed to survey hospital staff knowledge of the application of the Mental Health Act 2007 (NSW) (MHA) and the Guardianship Act 1987 (NSW) (GA) in the care and treatment of older persons in a teaching hospital in Sydney. Method Over a two-month period in 2017, a survey questionnaire was distributed to staff involved in older persons' care across the hospital. RESULTS: The majority of the hospital staff demonstrated basic theoretical knowledge of both the GA (76%) and of the MHA (84.5%). Fewer (64.5%) appeared to understand the practical application of the MHA in the hypothetical clinical situations. An even lower proportion of staff appeared to understand the application of the GA either to obtain consent for medical treatment or to appoint a guardian through the Guardianship Division of the NSW Civil and Administrative Tribunal (NCAT). CONCLUSION: Although clinical staff of the hospital displayed fair knowledge and awareness about the application of the MHA and the GA to inpatient care of older adults, further education is necessary, particularly about the application of the GA. The authors suggest similar findings may occur at other New South Wales hospitals, which may raise concern and need for education. PMID- 29480020 TI - Protective effects of quercetin treatment in a pristane-induced mouse model of lupus nephritis. AB - INTRODUCTION: Lupus nephritis (LN) is one of the most severe complications of systemic lupus erythematosus. As murine models of LN are valuable tools to better understand its pathophysiology and to search for new effective treatments, we investigated the effects of the bioflavonoid quercetin on pristane-induced LN mice through histomorphological analyses. METHODS: Immunofluorescence and biochemical assays were used to evaluate the expression of markers of inflammation (interleukin-6, IL-6; tumour necrosis factor-alpha, TNF-alpha), oxidative stress (catalase, CAT; superoxide dismutase 1, SOD1; thiobarbituric acid reactive substances, TBARS), apoptosis (Bax), and fibrosis (transforming growth factor-beta1, TGF-beta1). Glomerular and tubular ultrastructure was analysed, and tissue messenger RNA of podocin, podoplanin and alpha3beta1 integrin were quantified using the real-time polymerase chain reaction. RESULTS: Pristane-induced LN mice showed severe kidney injury, characterized by increased proteinuria, glomerular mesangial expansion and inflammation, high expression of the pro-fibrotic, apoptotic and prooxidant markers and reduction of antioxidants. In the kidney ultrastructure, foot process (FP) effacement, apoptotic mesangial cells and abnormal mitochondria with disrupted cristae were observed, along with suppressed tissue mRNA of podocin, podoplanin and alpha3beta1-integrin. Treatment with quercetin in the pristane-induced LN mice model was nephroprotective, decreasing proteinuria levels and significantly lowering tissue expression of IL 6, TNF-alpha, TGF-beta1, Bax and TBARS. Simultaneously, quercetin significantly increased CAT and SOD1 expressions in these mice. In addition, it was observed improvement of the kidney ultrastructure, and tissue mRNA of podocin, but not podoplanin and alpha3beta1-integrin, was restored to the levels found in the control mice. CONCLUSION: In conclusion, these findings provide experimental evidence of the renoprotective effects of quercetin in the pristane-induced LN mice model. We suggest that quercetin effectively ameliorates the kidney damage caused by pristane, a bioflavonoid to be further evaluated as a new therapeutic strategy in this disease. PMID- 29480022 TI - A Phenomenological Study of the Office Environments of Clinical Social Workers. AB - OBJECTIVE: The purpose of this study was to explore the meaning and uses of the office space among licensed clinical social workers in private practice. BACKGROUND: Previous research suggests the importance of the office space in clinical practice in regard to therapeutic alliance, client behavior, and the well-being of the therapist. However, therapist offices contain much variation in design. This study looked further into specifically how the therapy room is important through the perspective of the licensed clinical social workers in order to identify common themes. METHODS: Seven licensed clinical social workers in private psychotherapy practice were interviewed in their offices. Phenomenological research methods were used to explore and analyze their experiences. RESULTS: While the offices contained many physical differences, the intentions behind the designs were similar. Three themes emerged regarding how participants used and designed their spaces. First, participants used their offices to provide care for clients and themselves. Second, participants used their spaces to communicate therapeutic messages and to reveal and/or conceal aspects of themselves. Third, participants also used their space in direct practice. CONCLUSION: This phenomenological study provided insight into the importance and use of the psychotherapy office space. These findings may be helpful for therapists designing or redesigning their own practice spaces. PMID- 29480019 TI - Diagnostic validity of CT to assess degenerative temporomandibular joint disease: a systematic review. AB - OBJECTIVES: The aim of this systematic review was to answer the focus question: "In subjects with degenerative joint disease (DJD) of the temporomandibular joint (TMJ), what is the diagnostic validity of CT or cone-beam CT (CBCT) compared with clinical protocols"? METHODS: DJD should be assessed through clinical diagnosis according to RDC/TMD or DC/TMD. Search strategies were specifically developed to the following electronic databases: Cochrane, Latin American And Caribbean Health Sciences (LILACS), PubMed (including Medline), Scopus and Web of Science. Furthermore, partial grey literature search through Google Scholar, OpenGrey and ProQuest was performed. The risk of bias was evaluated using the second version of Quality Assessment Tool for Diagnostic Accuracy Studies (QUADAS-2). RESULTS: The databases search revealed 454 records. After applying the eligibility criteria, four studies were included in this review. All studies were methodologically acceptable, although none of the them fulfilled all criteria of risk of bias according to QUADAS-2. Despite there were some high values for sensitivity and specificity, they were not homogeneous between studies. Regarding specificity outcomes, there were three studies with poor values and only one considered as excellent. CONCLUSIONS: CBCT could be a good image to evaluate DJD progression over time, but should not be used as a screening tool in healthy individuals. PMID- 29480023 TI - 'A matter for conjecture': leucotomy in Western Australia, 1947-70. AB - Very little has been published on the rise and fall of psychosurgery in Australia. In the mid-twentieth century, Western Australia was the largest but most sparsely-populated of the six Australian States, and its local psychiatry practice was, as one commentator put it, 'backward'. Nonetheless, electroconvulsive therapy was introduced in 1945, and leucotomy in 1947. This paper will explore the introduction of leucotomy to Western Australia in the context of wider national and international trends in psychiatry, and posit some reasons for its decline and abandonment in the 1970s. It will present a narrative reconstruction of the local introduction and practice of leucotomy, using retrieved, reconstructed and previously unpublished data. PMID- 29480025 TI - Intradialytic exercise training modalities on physical functioning and health related quality of life in patients undergoing maintenance hemodialysis: systematic review and meta-analysis. AB - OBJECTIVE: To determine the effects of different intradialytic exercise training modalities on physical functioning and health-related quality of life of maintenance hemodialysis patients. METHODS: We searched MEDLINE, Cochrane Trials Register and CINAHL for controlled trials that evaluated the effects of intradialytic exercise training for maintenance hemodialysis patients and published from the earliest available date to December 2017. Weighted mean difference and 95% confidence interval (CI) were calculated, and heterogeneity was assessed using the I2 test. RESULTS: Fifty-six studies met the study criteria, comprising a total of 2586 patients. Compared with no exercise, combined aerobic and resistance exercise resulted in significant improvement in peak VO2 weighted mean difference (5.1 mL kg-1 min-1; 95% CI: 3.4, 6.8 mL kg-1 min-1), depression symptoms (-7.32; 95% CI -9.31, -5.33) and both physical function (10.67 points; 95% CI 1.08, 20.25 points) and vitality (10.01 points; 95% CI 4.30, 15.72 points) domains of health-related quality of life. Resistance exercise alone was significantly associated with improvement in the 6-minute walk test distance (30.2 m; 95% CI 24.6, 35.9 m), knee extensor strength (0.6 N; 95% CI 0.1, 1.0 N) and Physical Component Score of health-related quality of life (9.53 points; 95% CI -3.09, 22.15 points) when compared with control group. Aerobic exercise alone was not significantly associated with aerobic capacity and quality of life improvement. CONCLUSION: The results provide support to interventions that combine intradialytic aerobic and resistance exercises to improve physical functioning and quality of life in end-stage renal disease patients undergoing hemodialysis. PMID- 29480024 TI - Dose Escalation of Vitamin D3 Yields Similar Cryosurgical Outcome to Single Dose Exposure in a Prostate Cancer Model. AB - Vitamin D3 (VD3) is an effective adjunctive agent, enhancing the destructive effects of freezing in prostate cancer cryoablation studies. We investigated whether dose escalation of VD3 over several weeks, to model the increase in physiological VD3 levels if an oral supplement were prescribed, would be as or more effective than a single treatment 1 to 2 days prior to freezing. PC-3 cells in log phase growth to model aggressive, highly metabolically active prostate cancer were exposed to a gradually increasing dose of VD3 to a final dose of 80 nM over a 4-week period, maintained for 2 weeks at 80 nM, and then exposed to mild sublethal freezing temperatures. Results demonstrate that both acute 24-hour exposure to 80 nM VD3 and dose escalation resulted in enhanced cell death following freezing at -15 degrees C or colder, with no significant differences between the 2 exposure regimes. Apoptotic analysis within the initial 24-hour period postfreeze revealed that VD3 treatment induced both caspase 8- and 9 mediated cell death, most notably in caspase 8 at 8-hour postfreeze. These results indicate that both the intrinsic and extrinsic apoptotic pathways are involved in VD3 sensitization prior to freezing. Additionally, both acute and gradual dose escalation regimes of VD3 exposure increase prostate cancer cell sensitivity to mild freezing. Importantly, this study expands upon previous reports and suggests that the combination of VD3 and freezing may offer an effective treatment for both slow growth and highly aggressive prostate cancers. PMID- 29480028 TI - Risks associated with lamotrigine prescription: a review and personal observations. AB - OBJECTIVES:: To detail some serious lamotrigine side effects and their management, and raise awareness about the possible lack of quality control of some brands of lamotrigine. METHODS:: A literature review is provided and some personal observations added. RESULTS:: While most psychiatrists are aware of the risks of Stevens-Johnson syndrome (SJS), awareness of two other serious side effects - toxic epidermal necrosis (TEN) and drug-related eosinophilia and systemic symptoms (DRESS) - is seemingly lower. Awareness that failure to respond to lamotrigine and that the prevalence of serious side effects may reflect poor quality control of some preparations is also less well recognized. CONCLUSIONS:: While lamotrigine may be retrialled at a lower dose escalation rate following some skin reactions, it should not be recommenced following a SJS, TEN or DRESS reaction. Prescribers should be aware of quality control concerns about some available brands of lamotrigine. PMID- 29480026 TI - In Search of a Gold Standard Patient-Reported Outcome Measure for Use in Chemotherapy- Induced Peripheral Neuropathy Clinical Trials. AB - PURPOSE: To test a reduced version-CIPN15-of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy scale (QLQ-CIPN20) to establish a possible gold-standard patient-reported outcome measure for chemotherapy-induced peripheral neuropathy (CIPN). METHODS: Using a prospective, longitudinal, case control design, patients (n = 121) receiving neurotoxic chemotherapy completed the CIPN15 at baseline and 12 weeks and underwent objective neurological assessment using the 5-item Total Neuropathy Score-Clinical (TNSc). Healthy controls (n = 30) completed the CIPN15 once. Structural validity was evaluated using factor analysis. Because a stable factor structure was not found, a sum score was used to evaluate measures of the CIPN15's psychometric properties reliability, validity, sensitivity, and responsiveness-as follows: internal consistency via Cronbach's alpha and item-item correlations; test-retest reliability via correlation between 2 CIPN15 scores from each patient; concurrent validity via correlation between CIPN15 and 5-item TNSc scores; contrasting group validity via comparison of CIPN15 scores from patients and healthy controls; sensitivity via descriptive statistics (means, standard deviation, ranges); and responsiveness via Cohen's d effect size. RESULTS: Most patients received single agent oxaliplatin (33.7%), paclitaxel (21.2%), or more than 1 neurotoxic drug concurrently (29.8%). Factor analysis revealed no stable factor structure. Cronbach's alpha for the CIPN15 sum score was 0.91 (confidence interval [CI] = 0.89-0.93). Test-retest reliability was demonstrated based on strong correlations between the 2 scores obtained at the 12-week time point ( r = 0.86; CI = 0.80 0.90). The CIPN15 and 5-item TNSc items reflecting symptoms (not signs) were moderately correlated ( r range 0.57-0.72): concurrent validity. Statistically significant differences were found between patient and healthy control CIPN15 mean scores ( P < .0001): contrasting group validity. All items encompassed the full score range but the CIPN15 linearly converted sum score did not: sensitivity. The CIPN15 was responsive based on a Cohen's d of 0.52 (CI = 0.25 0.79). CONCLUSION: The sum-scored CIPN15 is reliable, valid, sensitive, and responsive when used to assess taxane- and platinum-induced CIPN. PMID- 29480027 TI - Transcriptomic and epigenetic analysis of breast cancer stem cells. AB - AIM: Cancer stem cells (CSCs) drive triple-negative breast cancer recurrence via their properties of self-renewal, invasiveness and radio/chemotherapy resistance. This study examined how CSCs might sustain these properties. MATERIALS & METHODS: Transcriptomes, DNA methylomes and histone modifications were compared between CSCs and non CSCs. RESULTS: Transcriptome analysis revealed several pathways that were activated in CSCs, whereas cell cycle regulation pathways were inhibited. Cell development and signaling genes were differentially methylated, with histone methylation analysis suggesting distinct H3K4me2 and H3K27me3 enrichment profiles. An integrated analysis revealed several tumor suppressor genes downregulated in CSCs. CONCLUSION: Differential activation of various signaling pathways and genes contributes to the tumor-promoting properties of CSCs. Therapeutic targets identified in the analysis may contribute to improving treatment options for patients. PMID- 29480029 TI - Private Rooms, Semi-Open Areas, or Open Areas for Chemotherapy Care: Perspectives of Cancer Patients, Families, and Nursing Staff. AB - OBJECTIVE: This research aims to better understand the needs and preferences of cancer outpatients, their families, and nursing staff with regard to private rooms, semi-open areas, or open areas for ambulatory cancer care. BACKGROUND: Environments for cancer chemotherapy care are outpatient settings, and recommendations based on findings regarding inpatient settings may not be appropriate. Users of chemotherapy treatment environments include cancer patients, their families, and nursing staff. METHOD: A questionnaire survey was conducted in an academic cancer center in Louisiana. The participants included 171 cancer patients, 145 family members, and 16 nursing staff members. Both quantitative and qualitative methods were used to analyze the data. Participants' environmental preferences were compared using analysis of variance. Reasons for preferences were analyzed through key word and content analysis. RESULTS: Semi open areas were preferred by the staff, whereas the three types of treatment environments were equally popular among both patients and families (preferred by 29%/28%/27% of the participants). Female patients and patients receiving longer periods of treatment per occurrence were more likely to prefer private rooms ( p < .05). Three common reasons for preferences were needs for privacy, social interaction, and patient-nurse access. Additional reasons for patient and family preferences included needs for sleep, openness, and access to nature. A shared environment of chemotherapy care was suggested to be appropriate for four to seven patients to occupy. CONCLUSION: Multiple types of treatment environments should be provided in chemotherapy care to incorporate varied user needs. Privacy, social interaction, patient-nurse access, and access to nature should be considered during the design of environments for cancer chemotherapy. PMID- 29480030 TI - Physicochemical determinants of pH in pectoralis major of three strains of laying hens housed in conventional and furnished cages. AB - 1. Post-mortem decline in muscle pH has traditionally been attributed to glycogenolysis-induced lactate accumulation. However, muscle pH ([H+]) is controlled by complex physicochemical relationships encapsulated in the Stewart model of acid-base chemistry and is determined by three system-independent variables - strong ion difference ([SID]), total concentration of weak acids ([Atot]) and partial pressure of CO2 (PCO2). 2. This study investigated these system-independent variables in post-mortem pectoralis major muscles of Shaver White, Lohmann Lite and Lohmann Brown laying hens housed in conventional cages (CC) or furnished cages (FC) and evaluated the model by comparing calculated [H+] with previously measured [H+] values. 3. The model accounted for 99.7% of the variation in muscle [H+]. Differences in [SID] accounted for most or all of the variations in [H+] between strains. Greater PCO2 in FC was counteracted by greater sequestration of strong base cations. The results demonstrate the accuracy and utility of the Stewart model for investigating determinants of meat [H+]. 4. The housing differences identified in this study suggested that hens housed in FC have improved muscle function and overall health due to the increased opportunity for movement. These findings support past studies showing improved animal welfare for hens housed in FC compared to CC. Therefore, the Stewart model has been identified as an accurate method to assess changes in the muscle at a cellular level that affect meat quality that also detect differences in the welfare status of the research subjects. PMID- 29480031 TI - Different Sickness Responses in Adult and Aged Rats Following Lipopolysaccharide Administration. AB - OBJECTIVE: Immune challenges result in sickness responses such as decreased activity, fever, and spatial learning deficits. While these responses occur simultaneously, they are not usually evaluated concurrently or for an extended time. The purpose of this study was to examine how an immune challenge affected activity and temperature responses in animals tested concurrently in the Morris water maze (MWM) over 5 days and how aging interacts with such responses. METHOD: An accepted model of aging, adult ( n = 10; 5-6 months) and aged ( n = 7; 22 months) male Brown-Norway rats were implanted with a telemetry device (Mini Mitter, Oakmont, PA) to continuously monitor temperature and activity following an immune challenge. These animals were injected with either 250 MUg/kg lipopolysaccharide (LPS) or 0.9% sodium chloride and then assessed in the MWM for 5 days. RESULTS: Temperature responses varied by age. Initial temperatures decreased in both experimental groups followed by an increase (fever) in the adult group, while the temperatures of the aged animals remained decreased. Although both age groups were sedentary at baseline, activity decreased after LPS only in the adult group. CONCLUSION: An LPS immune challenge resulted in age dependent temperature and activity changes. There was an absence of fever and no effect on activity in aged LPS-treated animals. These results may suggest the need to assess a broader spectrum of sickness responses when monitoring elderly individuals for infection and not rely on the presence of fever. Activity may not be a sensitive indicator of sickness in some aging models. PMID- 29480032 TI - Current and future treatment options for community-associated MRSA infection. AB - INTRODUCTION: Community-associated MRSA (CA-MRSA) represents a global epidemic which beautifully encapsulates the fascinating ability of bacterial organisms to adapt quickly on an evolutionary basis to the extreme selective pressure of antibiotic exposure. In stark contrast to Healthcare-associated MRSA (HA-MRSA), it has become apparent that CA-MRSA is less straight forward of a challenge in terms of controlling its transmission, and has forced clinicians to adjust empiric management of clinical syndromes such as skin and soft tissue infection (SSTI) as well as pneumonia. Areas covered: This review details the history and epidemiology of CA-MRSA, while covering both current and future treatment options that are and may be available to clinicians. The authors reviewed both historic and more recent literature on this ever-evolving topic. Expert opinion: While development of new anti-MRSA agents should be encouraged, the importance of antimicrobial stewardship in the battle to stay ahead of the curve with regards to the ongoing control of the MRSA epidemic should be emphasised. PMID- 29480033 TI - Dermatological indications for the use of isotretinoin beyond acne. AB - While the use of isotretinoin has revolutionized the treatment of acne vulgaris, isotretinoin is increasingly recognized as a useful therapeutic option for many other cutaneous conditions. We review the evidence underlying the use of isotretinoin for a variety of dermatological indications including hidradenitis suppurativa, sebaceous gland pathology, rosacea, scarring alopecia, cosmetic dermatology, and non-melanoma skin cancer prophylaxis amongst other uses, and thus consider alternative uses within dermatology practice. The studies found benefit of isotretinoin, however most trials lacked statistical power and in many cases the use was limited to case series. Isotretinoin, if used within the correct cohort with appropriate pretreatment counseling regarding side-effects, is a well-tolerated medication with potential as either an adjunctive treatment or a second-line agent in those recalcitrant cases unresponsive to first-line therapy. PMID- 29480034 TI - Emerging alternatives to tyrosine kinase inhibitors for treating chronic myeloid leukemia. AB - INTRODUCTION: BCR-ABL-directed tyrosine kinase inhibitors (TKIs) have revolutionised therapy for chronic myeloid leukemia. However, despite the availability and efficacy of this class of agents, lifelong treatment is still required in a significant proportion of patients Areas covered: We give an overview of the currently available BCR-ABL-directed TKIs and other conventional therapies for CML. We proceed to review the current market and some of the scientific rationale for new drug development before outlining a number of novel therapies, considered broadly as immunotherapies and targeted agents. Published English-language literature was reviewed regarding currently available TKIs; clinical trials repositories were reviewed to identify novel agents recently investigated or under active study. Expert opinion: We recommend discussion with patients and enrolment on an appropriate clinical trial where feasible. In situations where no trials are available, or if patients decline enrolment, we recommend use of an appropriate BCR-ABL directed TKI, selected on the basis of an evaluation of patient risk factors and side effect profile. Allogeneic stem cell transplant continues to have a role though this is generally limited to cases with advanced phases of disease or in cases with resistance-conferring mutations. PMID- 29480036 TI - Emerging drugs for the treatment of Myelofibrosis. AB - INTRODUCTION: Myelofibrosis (MF) is a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN). It can be sub-categorized into primary myelofibrosis, post polycythemia vera myelofibrosis and post essential thrombocythemia myelofibrosis. MF is a life-threatening hematologic malignancy characterized by dysregulation of the Janus associated kinase (JAK)/signal transducer and activator of transcription (STAT) signaling network and a heightened inflammatory state. Areas covered: We cover the pathogenesis, clinical features, new prognostic models, current treatment of MF and discuss agents in development. We also cover market review and health care costs associated with some of these therapies. Expert opinion: There are many ongoing clinical trials evaluating novel therapeutic approaches, including selective JAK inhibitors, histone deacetylase/DNA methyltransferase inhibitors, PI3K-inhibitors, Hedgehog/mammalian target of rapamycin (MTOR) inhibitors, anti-fibrotic agents, immunomodulators, monoclonal antibodies and immune checkpoint inhibitors. Ruxolitinib, a potent oral JAK1/JAK2 inhibitor remains the only Food and Drug Administration (FDA)-approved medicinal therapy for the treatment of MF. Unmet needs include alleviation of limiting thrombocytopenia and anemia, halting disease progression to acute leukemia, and extending survival. The development of biomarker driven clinical trials of mechanism based novel therapeutics will usher in a new era of advances in the treatment of this chronic and progressive myeloid malignancy. PMID- 29480035 TI - Oral vitamin D3 supplementation for chronic plaque psoriasis: a randomized, double-blind, placebo-controlled trial. AB - PURPOSE: The management of psoriasis remains a challenge for dermatologist and patient. This study aimed to determine whether vitamin D3 supplementation improves psoriasis compared to placebo. MATERIALS AND METHODS: In a randomized, doubled-blind, placebo-controlled trial, 101 participants >=18 years with psoriasis were grouped by severity and allocated to 100,000 International Units (IU) vitamin D3/month for 12 months (200,000 IU at baseline; n = 67) or an identical placebo (n = 34). Psoriasis Area and Severity Index (PASI) and serum 25(OH)D concentrations were assessed at 3-monthly intervals. The primary outcome was the difference in PASI between groups over time. The relationship between 25(OH)D and PASI across the sample was also considered in a post hoc analysis. RESULTS: PASI did not differ between groups at any time (group F(1, 104) = 0.48, p = .49; group*time F(4, 384) = 0.26, p = .90). However, 25(OH)D increased in both groups, rendering these findings inconclusive. A significant inverse relationship existed between PASI and 25(OH)D, with elevation of 25(OH)D by up to 125 nmol/L associated with mild decreases in PASI (estimated range of decrease 0 2.6; p = .002). CONCLUSIONS: A direct benefit of vitamin D3 supplementation for psoriasis could not be determined. However, these findings suggest a relationship between 25(OH)D and psoriasis severity, at least in some subgroups. Australian New Zealand Clinical Trials Registry #12611000648921. PMID- 29480037 TI - Pharmacological management of diabetes in severe mental illness: a comprehensive clinical review of efficacy, safety and tolerability. AB - INTRODUCTION: The increased prevalence of Type 2 diabetes mellitus (T2DM) in severe mental illness (SMI) contributes to increased cardiovascular morbidity and reduced life expectancy for people with SMI. Areas covered: In the present clinical review, we summarize the efficacy, safety and tolerability of selected diabetic pharmacotherapy options in SMI and discuss the quality and strength of evidence. Expert commentary: General principles for treating T2DM in SMI involve identifying treatments which promote weight loss and which have low or no risk of hypoglycemia. Patient engagement in decision making about treatment choices is an important factor to ensure adherence and successful use of the chosen therapy. The first line therapeutic option for T2DM in SMI for which there is most evidence is metformin. Based on general population data, second line treatment options in combination with metformin to achieve glycated haemoglobin treatment goals include GLP-1R agonists, DPP-4 inhibitors, sulphonylureas, SGLT2 inhibitors, pioglitazone and insulin, with most evidence for the use of GLP-1R agonists in SMI. Alongside efficacy and tolerability, treatment for T2DM in SMI should be considered on a patient-tailored basis. PMID- 29480038 TI - NADPH metabolism: a survey of its theoretical characteristics and manipulation strategies in amino acid biosynthesis. AB - Reduced nicotinamide adenine nucleotide phosphate (NADPH), which is one of the key cofactors in the metabolic network, plays an important role in the biochemical reactions, and physiological function of amino acid-producing strains. The manipulation of NADPH availability and form is an efficient and easy method of redirecting the carbon flux to the amino acid biosynthesis in industrial strains. In this review, we survey the metabolic mode of NADPH. Furthermore, we summarize the research developments in the understanding of the relationship between NADPH metabolism and amino acid biosynthesis. Detailed strategies to manipulate NADPH availability are addressed based on this knowledge. Finally, the uses of NADPH manipulation strategies to enhance the metabolic function of amino acid-producing strains are discussed. PMID- 29480039 TI - Intracochlear drug delivery systems: a novel approach whose time has come. PMID- 29480040 TI - The case for introducing pre-registered confirmatory pharmacological pre-clinical studies. AB - When evaluating the design of pre-clinical studies in the field of traumatic brain injury, we found substantial differences compared to phase III clinical trials, which in part may explain the difficulties in translating promising experimental drugs into approved treatments. By using network analysis, we also found cases where a large proportion of the studies evaluating a pre-clinical treatment was performed by inter-related researchers, which is potentially problematic. Subjecting all pre-clinical trials to the rigor of a phase III clinical trial is, however, likely not practically achievable. Instead, we repeat the call for a distinction to be made between exploratory and confirmatory pre clinical studies. PMID- 29480041 TI - Hallucinations in Alzheimer's disease: failure to suppress irrelevant memories. AB - INTRODUCTION: Research with patients with schizophrenia suggests that inhibitory dysfunction leads to the emergence of redundant or irrelevant information from long-term memory into awareness, and that this process may be involved in generating hallucinations. We investigated whether inhibitory dysfunction in Alzheimer's disease (AD) leads to hallucinations. METHOD: AD participants and healthy matched controls were assessed with a hallucinations scale and a directed forgetting task. On the directed forgetting task, they were asked to retain a list of 10 words (i.e., List 1). Thereafter, half of the participants were asked to forget this list whereas the other half were asked to retain the list in memory. After the List 1 presentation, all participants were asked to retain another list of 10 words and, successively, were asked to remember all of the words from both lists, regardless of the previous forget or remember instruction. RESULTS: Relative to healthy matched controls, AD participants showed difficulties in suppressing the words from List 1. AD participants also showed more hallucinatory experiences than healthy matched controls. Interestingly, a significant correlation was observed between the score on the hallucinations measure and difficulties in suppressing List 1 in AD participants. DISCUSSION: Hallucinations in AD may, at least in part, be related to difficulties in suppressing memory representations, such that unwanted or repetitive thoughts intrude into consciousness. PMID- 29480042 TI - Memorcise and Alzheimer's disease. AB - Alzheimer's disease (AD) is a debilitating disease influencing a multitude of outcomes, including memory function. Recent work suggests that memory may be influenced by exercise ('memorcise'), even among those with AD. The present narrative review details (1) the underlying mechanisms of AD; (2) whether exercise has a protective effect in preventing AD; (3) the mechanisms through which exercise may help to prevent AD; (4) the mechanisms through which exercise may help attenuate the progression of AD severity among those with existing AD; (5) the effects and mechanisms through which exercise is associated with memory among those with existing AD; and (6) exercise recommendations for those with existing AD. Such an understanding will aid clinicians in their ability to use exercise as a potential behavioral strategy to help prevent and treat AD. PMID- 29480043 TI - Prospective memory, level of disability, and return to work in severe mental illness. AB - OBJECTIVE: Prospective memory (the ability to remember to do things) has clear implications for everyday functioning, including employment, in people with severe mental illnesses (SMI). This study aimed to evaluate prospective memory performance and its relationship to real-world functional variables in an employment-seeking sample of people with SMI (Clinical Trial registration number NCT00895258). METHOD: 153 individuals with DSM-IV diagnosis of depression (n = 58), bipolar disorder (n = 37), or schizophrenia (n = 58) who were receiving outpatient psychiatric care at a university clinic enrolled in a trial of supported employment and completed a baseline assessment. Prospective memory was measured with the Memory for Intentions Test (MIST); real-world functional status included work history variables, clinical history variables, baseline functional capacity (UCSD Performance-based Skills Assessment-Brief), and work outcomes (weeks worked and wages earned during two years of supported employment). RESULTS: Participants with schizophrenia performed worse on the MIST than did those with affective disorders. Independent of diagnosis, education, and estimated intellectual functioning, prospective memory significantly predicted variance in measures of disability and illness burden (disability benefits, hospitalization history, current functional capacity), and work outcomes over two years of supported employment (weeks worked). CONCLUSIONS: Worse prospective memory appears to be associated with greater illness burden and functional disability in SMI. Mental health clinicians and employment specialists may counsel clients to use compensatory prospective memory strategies to improve work performance and decrease functional disability associated with SMI. PMID- 29480044 TI - [Objective evaluation of orthodontic treatment need with Dental Aesthetic Index]. AB - INTRODUCTION AND AIM: To evaluate the frequency and severity of the malocclusions and treatment need in a group of adult patients in Targu-Mures, dividing them up according to age and gender. METHOD: Sixty-four, randomly selected patients were divided up according to age and gender. Ten occlusal traits related to dentofacial anomalies according to missing teeth, spacing, crowding and occlusion were used to evaluate the malocclusions on each of their study cast. The Dental Aesthetic Index (DAI) regression equation was used to obtain the DAI score that defines severity. RESULTS: The average DAI score was 38 with a range of 18-79, showing that the majority of patients needed mandatory orthodontic treatment. No statistically significant difference was found between gender, age groups and need for treatment. CONCLUSION: More than two-fifths of the examined patients have a mandatory need for orthodontic treatment if the DAI scores are the main screening tool. Orv Hetil. 2018; 159(9): 352-356. PMID- 29480045 TI - [Pre-travel advice and patient education of Hungarian travellers]. AB - INTRODUCTION: According to international surveys, over half of the travellers face some kind of health issue when travelling. The overwhelming majority of travel-related illnesses can be prevented with pre-travel medical consultations, but the syllabus and content of the consultation have to match the travel habits and culture of the given society. AIM: This publication explores the specificities and travel habits of Hungarian travellers. METHOD: One hundred participants of a travel exhibition completed a survey about their international travel. As the survey was not representative, the data could only be processed through simple statistical methods. However, since the exhibition was presumably attended by those wishing to travel, the conclusions drawn from the results are worth publishing, since no similar survey in Hungary has been published before. RESULTS: Based on the suitable classification of age groups in travel medicine, 11% of the participants were adolescents / young adults (aged 15-24), 81% adults (25-59) and 8% elderly (60-74). Twenty-eight percent of the participants travel multiple times a year, 40% yearly and 32% of them less frequently; 16% of the adults, 8% of the adolescents and 4% of the elderly age group travel multiple times a year. CONCLUSIONS: The travel destinations of Hungarian travellers have remained practically unchanged since a study was conducted 13 years ago: the vast majority (95%) travelled within Europe, 2% to the United States, and 11% of them elsewhere. Since Hungarians do not travel to endemic areas, only 5% consulted their general practitioners (GPs) prior to travelling, and 29% did when they had to be vaccinated. Forty-two percent of those wishing to travel never consult their GPs, even though 29% of them are aware of some chronic illness. Instead, 51% gather their health information from the internet and only 6% from their doctors. By the contradiction between the poor health status of the majority of Hungarian travellers and the negligence of seeking pre-travel advice, our survey clearly points out the importance of the propagation of doctor's advice before trips, even if the travellers visit exclusively non-endemic countries like the European Union. Orv Hetil. 2018; 159(9): 357-362. PMID- 29480047 TI - [Low-intensity, evidence-based cognitive-behavioural therapy of a patient with Crohn's disease]. AB - Inflammatory bowel disease (Crohn's disease and colitis ulcerosa) is a chronic, long-term condition that causes chronic inflammation in the digestive tract, and shows an increasing incidence and prevalence worldwide. Changes in disease activity over time affect psychological distress which increases the risk of exacerbations. Beside somatic symptoms (such as abdominal pain, diarrhoea and weight loss), psychiatric comorbidity (in particular major depression, anxiety, social phobia) is common in patients with Crohn's disease. This case study illustrates the management and stabilization of a 21-year-old adult male patient with active Crohn's disease and with severe psychiatric comorbidity. The patient was diagnosed with avoidant personality disorder and dysruptive mood dysregulation disorder based on the results of psychodiagnostics (SCID-II structured clinical interview, MMPI personality inventory and disease-specific clinical questionnaires such as Beck Depression Inventory, Beck Hopelessness Scale, Social Cognition Questionnaire, Anger Expression Scale, Cognitive Emotion Regulation Questionnaire, Rosenberg Self-Esteem Scale). The main aim of psychotherapy is to increase the adherence to pharmacotherapy, to promote psychosocial functioning, to improve well-being and to enhance adaptive coping strategies. Low-intensity cognitive-behavioural psychotherapy was used which included psychoeducation, motivational interview, behavioural activation, patient diary, cognitive restructuring, problem-solving training, and family consulting. Twenty-five sessions were held weekly in outpatient form and 3 sessions of crisis intervention after the surgery at the hospital. The efficacy of the treatment was measured by self-reported questionnaires at baseline and at two follow-up sessions which corroborated a very significant decrease in the severity of depression, hopelessness, while emotional regulation and self-esteem became more adaptive. The remission of the above-mentioned psychiatric symptoms resulted in the improvement of the pharmacotherapy adherence and the quality of life. Low intensity psychosocial interventions are proven to be an effective way of delivering evidence-based psychotherapy. Orv Hetil. 2018; 159(9): 363-369. PMID- 29480046 TI - [Review of the relation between gut microbiome, metabolic disease and hypertension]. AB - Gut flora has personal characteristics for each individual, similar to the fingerprints, consisting of a special mixture of bacterial species living in the intestines, now referred to as the gut microbiome. There is a strong correlation between the loss of microbial diversity and the functional bowel disorders, obesity, type 2 diabetes and cardiovascular disease as well as many autoimmune disorders. With genetic testing of stool diversity of the gut microbiome and exact analysis of the species and phylogenetic classification of the gut flora, the changes of diversity can be identified and the overgrowth of some bacteria can be revealed. In cases with pre- and manifest hypertension, an overgrowth of species from the phylum Firmicutes has been reported along with the relative decline of the phylum Bacteroidetes as opposed with cases of normotension. At the same time, the physiological balance among bacterial families was lost. According to the first studies, there is a correlation between hypertension and the lost balance of the gut microflora, both in animal experiments and in the human clinical setting. This evidence also suggests that targeted dietary alteration of the gut microbiome can be a new innovative approach in the treatment of hypertension. Orv Hetil. 2018; 159(9): 346-351. PMID- 29480048 TI - [Echocardiographic assessment of the left atrial appendage - transoesophageal, transthoracic and intracardiac approaches]. AB - Left atrial appendage is a cardiac chamber in variable shapes and sizes. Its condition is associated with atrial arrhytmias and the presence of a thrombus. Due to its difficult visualisation, the present review aimed to demonstrate the role of different echocardiographic methods in its assessment. Orv Hetil. 2018; 159(9): 335-345. PMID- 29480050 TI - Pharmacokinetics and brain penetration study of chlorogenic acid in rats. AB - 1. The present study is designed to investigate the brain distribution and plasma pharmacokinetics profiles of chlorogenic acid (CGA) after intranasal administration in Charles-Foster rats to evaluate whether the CGA molecules are transported directly via the nose-to-brain path. 2. The CGA is administered intravenously (IV) and intranasally (IN) at the dose of 10 mg/kg. Further, its concentration in the plasma, cerebrospinal fluid (CSF) and the whole brain is analyzed by HPLC-UV method. 3. The study observes that CGA is rapidly absorbed in plasma with tmax of 1 min similar to IV route after IN administration. The peak plasma concentration and AUC0-24 are higher by 3.5 and 4.0 times respectively in IV administration, compared to IN delivery that represents the significant less systemic exposure of CGA in IN route. 4. However, the concentration of CGA in the brain is 4, 6.5, 5.3, 5.2 and 4.5 times higher at 30, 60, 120, 240 and 360 min, respectively in IN administration compared to IV administration. The exposure of CGA in the brain after IN administration (AUCbrain, IN) was significantly greater (4 times) as compared to the exposure of CGA in the brain (AUCbrain, IV) after IV administration reflecting significant brain uptake of CGA through nasal route. Therefore, IN delivery of CGA can be a promising approach for the treatment of stroke and neurodegenerative disorders. PMID- 29480051 TI - Use of antipsychotics and benzodiazepines in connection to minimising coercion and mechanical restraint in a general psychiatric ward. AB - BACKGROUND: Decrease in coercive measures can lead to increased exposure to antipsychotics and benzodiazepines. This is not desirable as these drugs are associated with harmful side effects and reduced life expectancy. AIM: To quantify and compare the use of antipsychotic and anxiolytic medications in connection with the implementation of a programme to reduce coercion and restraint. METHODS: Observational study in a general psychiatric ward comparing psychopharmacological treatment after implementation of non-pharmacological interventions to reduce coercion and mechanical restraint with a historical reference cohort from the same ward. RESULTS: Data from 101 admissions after implementation of interventions were compared with data from 85 admissions in a historical reference cohort. Mean defined daily doses of antipsychotics, benzodiazepines or the total amount of both showed no difference before and after implementation of the programme. Standardised regression coefficients (beta) from a mixed effects linear regression model, adjusted for age, gender, length of admission, involuntary admission and history of substance abuse showed that neither total dose of antipsychotics (adjusted beta: .05, 95% confidence interval (CI): -0.20 to 0.31), total dose of benzodiazepines (adjusted beta: -.13, 95%CI: .42 to 0.16) nor total amount of both drugs (adjusted beta: .00, 95%CI: -.26 to 0.21) increased after implementation. CONCLUSION: Decrease in coercive measures from 2013 to 2016 has not lead to significant increases in the use of antipsychotic medication or benzodiazepines. The interventions are useful in establishing restraint-free wards, and careful monitoring of the psychopharmacological treatment is important for patient safety. PMID- 29480060 TI - 'A more perfect arrangement of plants': the botanical model in psychiatric nosology, 1676 to the present day. AB - Psychiatric classification remains a complex endeavour; since the Enlightenment, nosologists have made use of various models and metaphors to describe their systems. Here we present the most common model, botanical taxonomy, and trace its history from the nosologies of Sydenham, Sauvages and Linnaeus; to evolutionary models; to the later contributions of Hughlings-Jackson, Kraepelin and Jaspers. Over time, there has been a shift from explicit attempts to pattern disease classification on botanical systems, to a more metaphorical use. We find that changes in the understanding of plants and plant relationships parallel changes in the conceptualization of mental illness. Not only have scientific discoveries influenced the use of metaphor, but the language of metaphor has also both illuminated and constrained psychiatric nosology. PMID- 29480062 TI - Suicide Risk Factors Among Older Adults: Exploring Thwarted Belongingness and Perceived Burdensomeness in Relation to Personality and Self-Esteem. AB - The objective of this study was to explore the role of personality and self esteem in later life within two established risk factors for suicidal ideation (SI)-Thwarted Belongingness (TB) and Perceived Burdensomeness (PB). The data about personality (i.e., Five Factor Model [FFM] and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition Personality Disorders [PD]), self esteem, TB, PB, and SI were collected from 102 community-dwelling older adults and analyzed using bivariate and multivariate techniques. All FFM domains and most PD traits were significantly correlated with SI, TB, and PB. Furthermore, FFM and PD traits explained a significant and meaningful amount of variance of SI, TB, and PB. Self-esteem demonstrated strong negative relationships with SI, TB, and PB. Personality features and self-esteem are important associated features for SI, TB, and PB. Clinicians should consider this information when assessing and evaluating for suicidal risk among older adults. The findings also highlight the need to consider personality traits in developing prevention strategies. PMID- 29480061 TI - NEDD4 promotes cell growth and motility in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. In China, the situation is even worse as cancer incidence and mortality continue to increase rapidly. Although tremendous progress has been made toward HCC treatments, the benefits for liver cancer patients are still limited. Therefore, it is necessary to identify and develop novel therapeutic methods. Neuronally expressed developmentally downregulated 4 (NEDD4), an E3 ubiquitin ligase, plays a critical role in the development and progression of various types of human cancers. In our study, NEDD4 acts as an oncoprotein in both QGY7703 and SMMC7721 liver cancer cell lines. We found that depletion of NEDD4 by siRNA transfection led to inhibition of cell growth, invasion and migration, and promotion of apoptosis. In contrast, overexpression of NEDD4 via plasmid transfection resulted in facilitated cell proliferation, invasion and migration, and decreased apoptosis. Importantly, we observed that tumor suppressor LATS1, also a core component of Hippo pathway, was negatively regulated by NEDD4 in liver cancer cells. Our findings suggested that NEDD4 may be involved in the HCC progression via regulating LATS1 associated signaling pathway. Therefore, targeting NEDD4-LATS1 signaling could be a potential therapeutic option for HCC treatment. PMID- 29480063 TI - The structure and emerging trends of construction safety management research: a bibliometric review. AB - Recently, construction safety management (CSM) practices and systems have become important topics for stakeholders to take care of human resources. However, few studies have attempted to map the global research on CSM. A comprehensive bibliometric review was conducted in this study based on multiple methods. In total, 1172 CSM-related papers from the Web of Science Core Collection database were examined. The analyses focused on publication year, country-institute, publication source, author and research topics. The results indicated that the USA, China, Australia and the UK took leading positions in CSM research. Two branches of journals were identified, namely the branch of engineering science and that of safety science and social science. Additionally, seven themes together with 28 specific topics were detected to allow researchers to track the main structure and temporal evolution of CSM research. Finally, the main research trends and potential research directions were discussed to guide the future research. PMID- 29480064 TI - Validation of claims-based algorithms for pulmonary arterial hypertension. AB - Administrative claims studies do not adequately distinguish pulmonary arterial hypertension (PAH) from other forms of pulmonary hypertension (PH). Our aim is to develop and validate a set of algorithms using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes and electronic medical records (EMR), to identify patients with PAH. From January 2012 to August 2015, the EMRs of patients with ICD-9-CM codes for PH with an outpatient visit at the University of Texas Medical Branch were reviewed. Patients were divided into PAH or non-PAH groups according to EMR encounter diagnosis. Patient demographics, echocardiography, right heart catheterization (RHC) results, and PAH-specific therapies were assessed. RHC measurements were reviewed to categorize cases as hemodynamically determined PAH or not PAH. Weighted sensitivity, specificity, and positive and negative predictive values were calculated for the developed algorithms. A logistic regression analysis was conducted to determine how well the algorithms performed. External validation was performed at the University of Virginia Health System. The cohort for the development algorithms consisted of 683 patients with PH, PAH group (n = 191) and non-PAH group (n = 492). A hemodynamic diagnosis of PAH determined by RHC was recorded in the PAH (26%) and non-PAH (3%) groups. The positive predictive value for the algorithm that included ICD-9-CM and PAH-specific medications was 66.9% and sensitivity was 28.2% with a c-statistic of 0.66. The positive predictive value for the EMR-based algorithm that included ICD-9-CM, EMR encounter diagnosis, echocardiography, RHC, and PAH-specific medication was 69.4% and a c-statistic of 0.87. A validation cohort of 177 patients with PH examined from August 2015 to August 2016 using EMR based algorithms yielded a similar positive predictive value of 62.5%. In conclusion, claims-based algorithms that included ICD-9-CM codes, EMR encounter diagnosis, echocardiography, RHC, and PAH-specific medications better-identified patients with PAH than ICD-9-CM codes alone. PMID- 29480065 TI - Potential hypoglycemic effect of acetophenones from the root bark of Cynanchum wilfordii. AB - Three new acetophenones, named cynwilforones A-C (1-3), together with cynandione A (4) were isolated from the root bark of Cynanchum wilfordii (Maxim.) Hemsl. Their structures were deduced based on spectroscopic analysis and chemical methods. Compounds 1 and 4 exhibited potential hypoglycemic effects through inhibition of hepatic gluconeogenesis by down-regulating the expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. This is the first report that acetophenones from the root bark of C. wilfordii possesses potential hypoglycemic activity in vitro. PMID- 29480068 TI - 1998, celebrating oceans in Lisbon Expo'98: World exhibitions and science communication. PMID- 29480066 TI - Novel imaging approaches for small animal models of lung disease (2017 Grover Conference series). AB - Imaging in small animal models of lung disease is challenging, as existing technologies are limited either by resolution or by the terminal nature of the imaging approach. Here, we describe the current state of small animal lung imaging, the technological advances of laboratory-sourced phase contrast X-ray imaging, and the application of this novel technology and its attendant image analysis techniques to the in vivo imaging of the large airways and pulmonary vasculature in murine models of lung health and disease. PMID- 29480067 TI - Reappraisal of the reliability of Doppler echocardiographic estimations for mean pulmonary artery pressure in patients with pulmonary hypertension: a study from a tertiary centre comparing four formulae. AB - Different Doppler echocardiography (DE) models have been proposed for estimation of mean pulmonary arterial pressures (PAMP) from tricuspid regurgitation (TR) jet velocity. We aimed to compare four TR-derived DE models in predicting the PAMP measured by right heart catheterization (RHC) in different groups of precapillary pulmonary hypertension (PH). A total of 287 patients with hemodynamically pre capillary PH were enrolled (mean age = 51 +/- 17.4 years, 59.9% female). All patients underwent DE before RHC (< 3 h) and four formulae (F) were used for TR derived PAMP estimation (PAMP-DE). These were as follows: F1 = Chemla (0.61 * systolic pulmonary artery pressure [PASP] + 2); F2 = Friedberg (0.69 * PASP - 0.22), F3 = Aduen (0.70 * PASP); and F4 = Bech-Hanssen (0.65 * PASP - 1.2). The PASP and PAMP (mmHg) measured by RHC were 89.1 +/- 30.4 and 55.8 +/- 20.8, respectively. In the overall PH group, DE estimates for PASP (r = 0.59, P = 0.001) and PAMP (r = 0.56, P = 0.001 for all) showed significant correlations with corresponding RHC measures. Concordance was noted between Chemla and Bech Hanssen, and Aduen and Bech-Hanssen. The Bland-Altman plot showed that Chemla and Bech-Hanssen overestimated and Friedberg and Aduen underestimated PAMP-RHC measures. Paired-t test showed significant systematic biases for Aduen and Bech Hanssen while Passing-Bablok non-parametric analysis revealed significant systematic biases all four PAMP-DE estimates. There was poor agreement between PAMP-RHC measures and PAMP-DE deciles (Kappa values were 0.112, 0.097, 0.095, and 0.121, respectively). This study showed a poor agreement between PAMP-DE estimates by four TR-derived formulae and PAMP-RHC in patients with PH, regardless of the etiology. However, these results can not be fully extrapolated to a normal population and did not address the reliability of DE estimates for PH screening procedures. PMID- 29480069 TI - Myosin light chain kinase ( MYLK) coding polymorphisms modulate human lung endothelial cell barrier responses via altered tyrosine phosphorylation, spatial localization, and lamellipodial protrusions. AB - Sphingosine 1-phosphate (S1P) is a potent bioactive endogenous lipid that signals a rearrangement of the actin cytoskeleton via the regulation of non-muscle myosin light chain kinase isoform (nmMLCK). S1P induces critical nmMLCK Y464 and Y471 phosphorylation resulting in translocation of nmMLCK to the periphery where spatially-directed increases in myosin light chain (MLC) phosphorylation and tension result in lamellipodia protrusion, increased cell-cell adhesion, and enhanced vascular barrier integrity. MYLK, the gene encoding nmMLCK, is a known candidate gene in lung inflammatory diseases, with coding genetic variants (Pro21His, Ser147Pro, Val261Ala) that confer risk for inflammatory lung injury and influence disease severity. The functional mechanisms by which these MYLK coding single nucleotide polymorphisms (SNPs) affect biologic processes to increase disease risk and severity remain elusive. In the current study, we utilized quantifiable cell immunofluorescence assays to determine the influence of MYLK coding SNPs on S1P-mediated nmMLCK phosphorylation and translocation to the human lung endothelial cell (EC) periphery . These disease-associated MYLK variants result in reduced levels of S1P-induced Y464 phosphorylation, a key site for nmMLCK enzymatic regulation and activation. Reduced Y464 phosphorylation resulted in attenuated nmMLCK protein translocation to the cell periphery. We further conducted EC kymographic assays which confirmed that lamellipodial protrusion in response to S1P challenge was retarded by expression of a MYLK transgene harboring the three MYLK coding SNPs. These data suggest that ARDS/severe asthma-associated MYLK SNPs functionally influence vascular barrier regulatory cytoskeletal responses via direct alterations in the levels of nmMLCK tyrosine phosphorylation, spatial localization, and lamellipodial protrusions. PMID- 29480070 TI - Endoscopic lung volume reduction coil treatment in patients with very low FEV1: an observational study. AB - BACKGROUND: Endoscopic lung volume reduction coil (LVRC) treatment is a therapeutic option for selected patients with advanced emphysema. The effects and the safety of endoscopic lung volume reduction in patients with very low forced expired volume in one second (FEV1) remain to be determined. This study was conducted to assess the effects and the safety of LVRC treatment in patients with very low FEV1. METHODS: The study was performed as a retrospective observational study in the Department of Respiratory Medicine at the University Medical Center Hamburg-Eppendorf on patients with very low FEV1, defined as an FEV1 ? 20% of predicted at baseline in whom LVRC treatment was performed between 1 April 2012 and 28 February 2017. RESULTS: LVRC treatment was performed in 33 patients with very low FEV1. Of these, 45.5% were female and 54.5% were male. At baseline, mean FEV1 was 0.46 +/- 0.12 liters (15 +/- 3% of predicted), mean forced vital capacity (FVC) was 1.61 +/- 0.62 liters (42 +/- 13% of predicted), mean residual volume (RV) was 6.03 +/- 0.81 liters (275 +/- 51% of predicted) and 6-minute walk distance was 229 +/- 102 m. Bilateral LVRC treatment was completed in 21 of these patients (63.6%). Bilateral LVRC treatment led to significant improvements in functional parameters with an increase in mean FEV1 from 0.44 +/- 0.11 liters to 0.54 +/- 0.12 liters ( p = 0.001), equivalent to a relative improvement of 24.5 +/- 26.9%, an increase in mean FVC from 1.49 +/- 0.54 liters to 1.84 +/- 0.49 liters ( p = 0.001), a decrease in mean RV from 6.27 +/- 0.83 liters to 5.83 +/- 1.09 liters ( p = 0.004) and an improvement in 6-minute walk distance from 218 +/ 91 m to 266 +/- 96 m ( p = 0.01). There were no cases of respiratory failure requiring mechanical ventilation and no deaths. CONCLUSIONS: LVRC treatment was effective and safe in patients with very low FEV1. PMID- 29480071 TI - Use of endo-bronchial end-tidal CO2 test for location of the pleural air leakage in patients with intractable pneumothorax. AB - BACKGROUND: Location of the affected bronchus of pleural air leaks is the most important step of trans-bronchoscopic bronchial occlusion for the treatment of intractable pneumothorax. The balloon occlusion test is the most commonly used technique, but has failed in some cases. The aim of the present study was: (1) to determine if endo-bronchial end-tidal CO2 (EtCO2) measurement can identify the affected bronchus that is the source of a persistent pleural air leak; and (2) to establish a methodology for endo-bronchial EtCO2 testing in locating affected bronchus in intractable pneumothorax. METHODS: A total of 28 patients with intractable pneumothorax underwent bronchoscopy with (1) the balloon occlusion test for the identification of the affected bronchus; and (2) endo-bronchial EtCO2 measurement (EtCO2 test) at the orifices of the bronchus of the affected lung. The effectiveness of these two methods of affected bronchus identification were compared. The threshold EtCO2 (T-EtCO2) was determined. RESULTS: The positive rates of locating the affected bronchus by the endo-bronchial EtCO2 test, balloon occlusion test, and combination of the two techniques were 60.7% (17/28), 64.3% (18/28) and 96.4% (27/28), respectively. The average differences in EtCO2 between the affected bronchus and the main carina, main bronchus, and non-affected bronchus were (in mmHg) 4.41 +/- 1.99 (95% confidence interval: 3.5, 5.3), 4.73 +/- 2.10 (3.80, 5.66 ) and 5.57 +/- 2.53 (4.45, 6.69), respectively. CONCLUSIONS: (1) The endo-bronchial EtCO2 test is complementary to the balloon occlusion test of the leading bronchus. (2) A threshold (T-EtCO2) value of >5 mmHg is optimal for this technique. PMID- 29480072 TI - Whole-exome sequencing improves genetic testing accuracy in pulmonary artery hypertension. AB - Sanger sequencing, the traditional "gold standard" for mutation detection, has been wildly used in genetic testing of pulmonary artery hypertension (PAH). However, with the advent of whole-exome sequencing (WES), few studies have compared the accuracy of WES and Sanger sequencing in routine genetic testing of PAH. PAH individuals were enrolled from Fu Wai Hospital and Shanghai Pulmonary Hospital. WES was used to analyze DNA samples from 120 PAH patients whose bone morphogenetic protein receptor type 2 (BMPR2) mutation statuses had been previously studied using Sanger sequencing. The Sanger sequencing and WES agreement was 98.3% (118/120) with near-perfect agreement (kappa coefficient = 0.848). There was no significant difference between the two methods on the McNemar-Bowker test ( P > 0.05). Twenty-one BMPR2 mutation carriers and 99 non carriers were detected by Sanger sequencing. Among the 21 BMPR2 carriers detected by Sanger sequencing, one variant (c.1040 T > A) was not found by WES. Among the 99 BMPR2 non-carriers, WES detected an extra mutation carrier (c.76 + 1 G > C) missed by Sanger sequencing. Both false-positive and false-negative results were highly conserved and were re-analyzed by Sanger sequencing. WES improved the accuracy of Sanger sequencing and detected 1% (1/99) false-positive and 4.8% (1/21) false-negative results of Sanger sequencing. No false-positive and false negative results of WES were identified in our analysis. WES is non-inferior to Sanger sequencing and may play a more important role in genetic testing of PAH patients in the future. PMID- 29480073 TI - The process of adjustment over time following stroke: A longitudinal qualitative study. AB - Understanding how people adjust following stroke is essential to optimise recovery and ensure services are responsive to people's needs. This study aimed to explore people's experiences over the first three years post-stroke and identify what helped or hindered recovery. As part of a longitudinal, qualitative descriptive study, 55 people and 27 significant others purposefully selected from a population-based stroke incidence study were interviewed 6, 12, 24 and 36 months post-stroke. Interviews were audio taped and transcribed verbatim. Participants described an ongoing process of shock, disruption, and fear, making sense of what happened, needing to fit in with what's offered, finding what works for them and evolving a new normal, whilst managing the ups and downs of life. This process needed to be re-negotiated over time, as people experienced changes in their recovery, comorbidities and/or wider circumstances. The adjustment process continued over the three years post-stroke, even for those who perceived that they were recovering well. Rehabilitation services need to support patients to make sense of their stroke, navigate the health system, address individual concerns and priorities and to know what, when and how much to challenge themselves. Rehabilitation plans need to be revised as circumstances change to facilitate adjustment following a stroke. PMID- 29480074 TI - Abrupt treatments of hysteria during World War I, 1914-18. AB - Case reports of the abrupt recovery of hysterical disorders during World War I (1914-18), though undoubtedly subject to publication bias, raise both aetiological and treatment issues regarding pseudo-neurological conversion symptoms. Published clinical anecdotes report circumstantial, psychotherapeutic, hypnotic, persuasive (and coercive) methods seemingly inducing recovery, and also responses to fright and alterations of consciousness. The ethics of modern medical practice would not allow many of these techniques, which were reported to be effective, even in the chronic cases. PMID- 29480076 TI - The cost of cardiovascular-disease-related death in patients with type 2 diabetes mellitus. AB - OBJECTIVES: To assess the magnitude of difference in all-cause healthcare resource utilization (HCRU) and costs between patients with type 2 diabetes mellitus (T2DM) who died from a cardiovascular disease (CVD)-related cause in the year preceding death vs. those who did not die during this same period. METHODS: A large US administrative claims database was used to identify patients with T2DM who died of a CVD-related cause from July 2012 to April 2015. These patients were matched 1:1 to patients with T2DM who did not die, using direct matching methods. HCRU and costs were assessed in each of the four quarters (Q4: 12-10 months; Q3: 9-7 months; Q2: 6-4 months; and Q1: 3-0 months) prior to death and compared between patient cohorts using paired t-tests and McNemar's tests. RESULTS: A final matched cohort of 7648 patients who died and 7648 patients who did not die were identified. A significantly higher proportion of patients who died utilized inpatient services vs. those who did not die (Q4: 12.6% vs. 4.6%, p < .001; Q3: 14.6% vs. 4.6%, p < .001; Q2: 17.6% vs. 5.5%, p < .001; and Q1: 65.0% vs. 10.1%, p < .001). In addition, patients who died incurred significantly higher all-cause costs (Q4: $8882 vs. $3970, p < .001; Q3: $10,462 vs. $3661, p < .001; Q2: $12,564 vs. $4169, p < .001; and Q1: $36,076 vs. $6319, p < .001). CONCLUSIONS: T2DM patients with a CVD-related death had significantly greater HCRU and costs in the year including and preceding death compared to those who did not die. PMID- 29480075 TI - Dietary Factors Associated with Pancreatic Cancer Risk inMinia, Egypt: Principal Component Analysis AB - Background: Pancreatic cancer (PC) is a serious and rapidly progressing malignancy. Identifying risk factorsincluding dietary elements is important to develop preventive strategies. This study focused on possible links betweendiet and PC. Methods: We conducted a case-control study including all PC patients diagnosed at Minia Cancer Centerand controls from general population from June 2014 to December 2015. Dietary data were collected directly throughpersonal interviews. Principal component analysis (PCA) was performed to identify dietary groups. The data wereanalyzed using crude odds ratios (ORs) and multivariable logistic regression with adjusted ORs and 95% confidenceintervals (CIs). Results: A total of 75 cases and 149 controls were included in the study. PCA identified six dietarygroups, labeled as cereals and grains, vegetables, proteins, dairy products, fruits, and sugars. Bivariate analysis showedthat consumption of vegetables, fruits, sugars, and total energy intake were associated with change in PC risk. Inmultivariable-adjusted models comparing highest versus lowest levels of intake, we observed significant lower oddsof PC in association with vegetable intake (OR 0.24; 95% CI, 0.07-0.85, P=0.012) and a higher likelihood with thetotal energy intake (OR 9.88; 95% CI, 2.56-38.09, P<0.0001). There was also a suggested link between high fruitconsumption and reduced odds of PC. Conclusions: The study supports the association between dietary factors and theodds of PC development in Egypt. It was found that higher energy intake is associated with an increase in likelihoodof PC, while increased vegetable consumption is associated with a lower odds ratio. PMID- 29480078 TI - Safety profile of silver sulfadiazine-bFGF-loaded hydrogel for partial thickness burn wounds. AB - In the present investigation, the safety of novel combinational silver sulfadiazine-bFGF-loaded hydrogel was assured by performing acute skin irritation, sensitization, acute dermal toxicity, and eye irritation in compliance with the Organization for Economic Co-operation and Development guidelines. In the skin irritation study, placebo, test, and positive control (0.8% w/v aqueous solution of formaldehyde) were applied on New Zealand rabbits and monitored for abnormal skin responses including erythema and edema. The placebo and test formulation did not induce any adverse reactions and were classified as nonirritating materials. In the skin sensitization test, guinea pigs were sensitized by positive control (0.1% w/v 1-chloro-2,4-dinitrobenzene in 10% of propylene glycol as a standard skin sensitizing agent), placebo, and test formulations. Weak sensitization was observed in the placebo and test formulation treated groups. Additionally, acute dermal toxicity test was performed in Wistar rats, where no signs of toxicity were observed in biochemical, hematological, and histopathological studies. Moreover, the acute eye irritation test was carried out in rabbits and no abnormal clinical signs were evident in the cornea or iris. As a whole, these findings suggest that the hydrogel formulation does not cause any skin irritation, skin sensitizationand dermal toxic effects, and eye irritation following dermal and ocular applications, respectively. Therefore, all the findings obtained from this preclinical study indicated that this hydrogel formulation is nontoxic and safe for use in animal models. PMID- 29480079 TI - (3R)-5,6,7-trihydroxy-3-isopropyl-3-methylisochroman-1-one ameliorates retinal degeneration in Pde6brd10 mice. AB - As a severe photoreceptor-degenerative disease, retinitis pigmentosa (RP) is currently incurable and eventually leads to partial or complete blindness. (3R) 5,6,7-trihydroxy-3-isopropyl-3-methylisochroman-1-one (TIM) is a novel antioxidant isolated from the plant of Alpinia katsumadai Hayata, with protective effects on photoreceptor cells against lipoteichoic acid-induced damage through inhibiting oxidative stress. The present study was to further demonstrate whether TIM could ameliorate retinal degeneration of Pde6brd10 (rd10) mice, a mouse model of RP. rd10 mice were treated with TIM by intraperitoneal injection daily from postnatal Day 10 (P10) to P26. Retinal function was tested by electroretinography. Histology was evaluated by toluidine blue staining and TUNEL assay. Oxidative stress markers were measured by ELISA. Immunohistochemistry, real-time PCR, and western blotting were applied to explore the protective mechanism. Results showed TIM significantly improved the retinal function and decreased photoreceptor cell apoptosis in rd10 mice through reducing oxidative stress. For the first time, this study demonstrated the protective effects of TIM against retinal degeneration in rd10 mice, providing scientific rationale to use TIM treating the RP. PMID- 29480077 TI - Reversible Electroporation-Mediated Liposomal Doxorubicin Delivery to Tumors Can Be Monitored With 89Zr-Labeled Reporter Nanoparticles. AB - Reversible electroporation (RE) can facilitate nanoparticle delivery to tumors through direct transfection and from changes in vascular permeability. We investigated a radiolabeled liposomal nanoparticle (89Zr-NRep) for monitoring RE mediated liposomal doxorubicin (DOX) delivery in mouse tumors. Intravenously delivered 89Zr-NRep allowed positron emission tomography imaging of electroporation-mediated nanoparticle uptake. The relative order of 89Zr-NRep injection and electroporation did not result in significantly different overall tumor uptake, suggesting direct transfection and vascular permeability can independently mediate deposition of 89Zr-NRep in tumors. 89Zr-NRep and DOX uptake correlated well in both electroporated and control tumors at all experimental time points. Electroporation accelerated 89Zr-NRep and DOX deposition into tumors and increased DOX dosing. Reversible electroporation-related vascular effects seem to play an important role in nanoparticle delivery to tumors and drug uptake can be quantified with 89Zr-NRep. PMID- 29480081 TI - Stability of biogenic metal(loid) nanomaterials related to the colloidal stabilization theory of chemical nanostructures. AB - In the last 15 years, the exploitation of biological systems (i.e. plants, bacteria, mycelial fungi, yeasts, and algae) to produce metal(loid) (Me)-based nanomaterials has been evaluated as eco-friendly and a cost-effective alternative to the chemical synthesis processes. Although the biological mechanisms of biogenic Me-nanomaterial (Bio-Me-nanomaterials) production are not yet completely elucidated, a key advantage of such bio-nanostructures over those chemically synthesized is related to their natural thermodynamic stability, with several studies ascribed to the presence of an organic layer surrounding these Bio-Me nanostructures. Different macromolecules (e.g. proteins, peptides, lipids, DNA, and polysaccharides) or secondary metabolites (e.g. flavonoids, terpenoids, glycosides, organic acids, and alkaloids) naturally produced by organisms have been indicated as main contributors to the stabilization of Bio-Me nanostructures. Nevertheless, the chemical-physical mechanisms behind the ability of these molecules in providing stability to Bio-Me-nanomaterials are unknown. In this context, transposing the stabilization theory of chemically synthesized Me nanomaterials (Ch-Me-nanomaterials) to biogenic materials can be used towards a better comprehension of macromolecules and secondary metabolites role as stabilizing agents of Bio-Me-nanomaterials. According to this theory, nanomaterials are generally featured by high thermodynamic instability in suspension, due to their high surface area and surface energy. This feature leads to the necessity to stabilize chemical nanostructures, even during or directly after their synthesis, through the development of (i) electrostatic, (ii) steric, or (iii) electrosteric interactions occurring between molecules and nanomaterials in suspension. Based on these three mechanisms, this review is focused on parallels between the stabilization of biogenic or chemical nanomaterials, suggesting which chemical-physical mechanisms may be involved in the natural stability of Bio-Me-nanomaterials. As a result, macromolecules such as DNA, polyphosphates and proteins may electrostatically interact with Bio-Me nanomaterials in suspension through their charged moieties, showing the same properties of counterions in Ch-Me-nanostructure suspensions. Since several biomolecules (e.g. neutral lipids, nonionic biosurfactants, polysaccharides, and secondary metabolites) produced by metal(loid)-grown organisms can develop similar steric hindrance as compared to nonionic amphiphilic surfactants and block co-polymers generally used to sterically stabilize Ch-Me-nanomaterials. These biomolecules, most likely, are involved in the development of steric stabilization, because of their bulky structures. Finally, charged lipids and polysaccharides, ionic biosurfactants or proteins with amphiphilic properties can exert a dual effect (i.e. electrostatic and steric repulsion interactions) in the contest of Bio-Me-nanomaterials, leading to the high degree of stability observed. PMID- 29480080 TI - The relationship between BDNF Val66Met polymorphism and functional mobility in chronic stroke survivors. AB - Background A single nucleotide polymorphism, Val66Met, in the Brain Derived Neurotrophic Factor (BDNF) gene has been studied for its role in recovery following stroke. Despite this work, the role of BDNF genotype on long-term recovery is unclear. Additionally, no study has examined its impact on functional mobility. As a result, the purpose of this study was to examine the relationship between BDNF genotype and functional mobility in chronic stroke survivors by first accounting for factors related to the Val66Met polymorphism and post-stroke recovery. Methods Participants 6 months post-stroke completed the Fugl-Meyer Lower Extremity Assessment (FMLE), Yesavage Geriatric Depression Scale (YGDS), 10 meter walk test (SSWS), and BDNF genotype testing. A regression model was used to determine if including genotype (Val or Met) and the genotype's interactions with age, gender, and depression increased the model's fit in predicting functional mobility, as measured by SSWS, after accounting for physical impairment (FMLE) and personal information (age, gender, and YGDS). Results Sixty-three subjects, twenty-two percent of whom had at least one Met allele, were included. Impairment and personal information significantly predicted SSWS (R2 = 0.268, p < 0.001 and DeltaR2 = 0.158, p = 0.002, respectively). The addition of genotype and genotype's interactions did not significantly increase the variance accounted for in SSWS (DeltaR2 = 0.012, p = 0.27, and DeltaR2 = 0.006, p = 0.723, respectively). Conclusions Our results suggest that the Val66Met polymorphism does not predict long-term, functional mobility following stroke. This difference may be due to differences in model variables or a reduced impact of the polymorphism as recovery progresses. PMID- 29480082 TI - A bittersweet relationship: What does it mean to be the caregiver of a patient with bipolar disorder? AB - BACKGROUND: As with most of the chronic illnesses, the changes and consequences brought on by bipolar disorder (BD) are not exclusive to the patient and often spread to those around them, especially for direct caregivers of these patients. It is known that there is a significant emotional and physical toll among persons who coexist daily with those who suffer from this disorder. OBJECTIVE: Aware of the importance of the role played by informal caregivers (especially the family) in the stability and evolution of patients with bipolar disorder, this study seeks to explore the perception that family members responsible for bipolar persons have of themselves as caregivers of these patients. METHOD: This is a qualitative study using a phenomenological design, for which the technique of focused or semi-structured interviews was employed. Ten caregivers of people with diagnosis of BD agreed to participate. RESULTS: Within the family, it is a single individual who has the role of caregiver. Experiences and meanings that are generated into the nucleus of the patient-caregiver relationship are full of ambivalence and involve many aspects worthy of analysing, such as the development of identities, the feminization of patient care, the process of therapeutic decision-making and the evolution of the disease. CONCLUSIONS: It is necessary to integrate evaluation and attention for patients' caregivers, recognizing them as individuals and elucidating their constructed meanings and the dynamics established in their relationship with patients. In this way, there would be a more integrative clinical approach of the patient-caregiver relationship, considering not only the necessary pharmacological treatments but also accompanying both patient and family, along the path they travel as they experience BD. PMID- 29480084 TI - Nursing Home Deficiency Citations for Abuse. AB - Deficiency citations for resident abuse from U.S. nursing homes from 2000 to 2007 are examined. Deficiency citations are given to nursing homes that are in violation of Medicare/Medicaid regulations and four specific deficiency citations (representing, abuse; neglect by staff; criminal screening investigating and reporting; and, abuse prevention and policy development and implementation) were examined. The data came from the Online Survey, Certification, and Reporting (OSCAR) system data ( N = 173,219) and the analyses used generalized estimating equations. Abuse deficiency citation rates were relatively stable (from 2000 to 2007), with approximately 20% of facilities per year receiving any one of these citations. For the factors of interest, few significant findings were identified for staffing levels; whereas, a high number of deficiency citations related to quality of care, high number of the most severe deficiency citations, high Medicaid reimbursement rates, and the Medicaid occupancy/reimbursement rate interaction were significantly associated with a greater likelihood of receiving a deficiency citation for abuse. PMID- 29480083 TI - Diagnostic value of urine soluble triggering receptor expressed on myeloid cells (sTREM-1) for late-onset neonatal sepsis in infected preterm neonates. AB - Objective Sepsis is a complex clinical condition caused by a dysregulated immune response to an infection resulting in a fatal outcome. This study aimed to investigate the value of urine soluble triggering receptor expressed on myeloid cells (sTREM-1) for diagnosing culture-proven sepsis in preterm infants. Methods Preterm neonates were evaluated for late-onset sepsis (LOS). Laboratory investigations were performed. Urine sTREM-1 samples and blood cultures were synchronously collected. Using blood culture results, preterm neonates were divided into the culture-proven group and suspected sepsis group. Results A total of preterm 62 infants were included in the study; 31 had culture-proven sepsis and 31 were suspected as having sepsis. There were no significant differences in gestational age, sex, birth weight, and delivery mode between the groups. Neonates in the culture-proven group had significantly higher urine sTREM-1 levels than did those in the suspected sepsis group. Using a cut-off point for a urine sTREM-1 level of 78.5 pg/mL, the sensitivity was 0.90, specificity was 0.78, positive predictive value was 0.68, and negative predictive value was 0.94. Conclusions The present study highlights the role of urine sTREM-1 levels in LOS. Urine sTREM-1 may be a reliable and sensitive marker in detecting sepsis in preterm infants. PMID- 29480085 TI - The Evolution of Nursing Home Report Cards. AB - Nursing home report cards can be potentially key tools for disseminating information to consumers. However, few accounts of state-based nursing home report cards are available. In the research presented here, the scale, scope, utility, and changes over time in these nursing home report cards are described. This article finds that the number of report cards has increased from 24 in 2003 to 29 in 2009. The quality information presented varies considerably; however, deficiency citations are still the most frequently reported quality indicators. The utility of report cards varies considerably. The authors present their opinions of features that seem most conducive for consumer use of these report cards. PMID- 29480086 TI - Aging and Mobility in Rural and Small Urban Areas: A Survey of North Dakota. AB - To investigate issues of aging and mobility in rural and small urban areas, this study analyzes the results from a survey AARP conducted of its North Dakota members. Specific objectives are to estimate the impact of age and other demographic and geographic characteristics on various measures of mobility, including ability to drive, use of public transportation, trip frequency for both discretionary and nondiscretionary travel, unmet travel demand, barriers to using public transportation, and satisfaction with available transportation options. Although most surveyed still drive, results show decreased mobility with increases in age and for people with disabilities due to decreases in driving and an increased likelihood of lack of transportation limiting the number of trips taken. People with disabilities were also significantly more likely to experience problems with public transportation. Women were found to be less likely to drive and more likely to use public transportation. PMID- 29480087 TI - Physical exercise in the treatment of alcohol use disorder (AUD) patients affects their drinking habits: A randomized controlled trial. AB - AIM: The aim of this study is to compare the effect of exercise training on physical capacity and alcohol consumption in alcohol use disorder (AUD) patients. METHODS: One hundred and five AUD patients were randomly assigned to treatment as usual combined with running and brisk walking for 30-45 min twice a week, either in small supervised groups (GR) or individually (IND), or to a control group with no running (C). Assessments were made after 6 and 12 months of training. RESULTS: Training volume was estimated as 36 min per training bout at an intensity of 78% of HRmax with no differences between GR and IND ( p>.05). A highly significant reduction in training frequency was seen in both training groups after the first month ( p<.0001). Only IND increased VO2max, by 5.7% ( p<.05), while no differences were seen between GR, IND and C. Alcohol intake decreased from 219 to 41 units per 30 days as the average for the entire sample with no significant difference of drinking outcomes between groups ( p<.0001). CONCLUSIONS: We saw an effect on drinking habits after running in both groups. However, no additional effect was seen when compared with the control group. A drop in the training frequency during the intervention might have resulted in an insignificant training stimulus. PMID- 29480088 TI - Resource utilization and charges of patients with and without diagnosed venous thromboembolism during primary hospitalization and after elective inpatient surgery: a retrospective study. AB - AIMS: To assess incremental charges of patients experiencing venous thromboembolisms (VTE) across various types of elective inpatient surgical procedures with administration of general anesthesia in the US. METHODS: The authors performed a retrospective study utilizing data from a nationwide hospital operational records database from July 2014 through June 2015 to compare a group of inpatients experiencing a VTE event post-operatively to a propensity score matched group of inpatients who did not experience a VTE. Patients included in the analysis had a hospital admission for an elective inpatient surgical procedure with the use of general anesthesia. Procedures of the heart, brain, lungs, and obstetrical procedures were excluded, as these procedures often require a scheduled ICU stay post-operatively. Outcomes examined included VTE events during hospitalization, length of stay, unscheduled ICU transfers, number of days spent in the ICU if transferred, 3- and 30-day re-admissions, and total hospital charges incurred. RESULTS: The study included 17,727 patients undergoing elective inpatient surgical procedures. Of these, 36 patients who experienced a VTE event were matched to 108 patients who did not. VTE events occurred in 0.2% of the study population, with most events occurring for patients undergoing total knee replacement. VTE patients had a mean total hospital charge of $60,814 vs $48,325 for non-VTE patients, resulting in a mean incremental charge of $11,979 (p < .05). Compared to non-VTE patients, VTE patients had longer length of stay (5.9 days vs 3.7 days, p < .001), experienced a higher rate of 3-day re admissions (3 vs 0 patients) and 30-day re-admissions (7 vs 2 patients). CONCLUSIONS: Patients undergoing elective inpatient surgical procedures with general anesthesia who had a VTE event during their primary hospitalization had a significantly longer length of stay and significantly higher total hospital charges than comparable patients without a VTE event. PMID- 29480089 TI - Right ventricular function mirrors clinical improvement with use of prostacyclin analogues in pediatric pulmonary hypertension. AB - Pulmonary hypertension (PH) causes significant morbidity and mortality in children due to right ventricular (RV) failure. We sought to determine the effect of prostacyclin analogues on RV function assessed by echocardiography in children with PH. We conducted a retrospective cohort study of children with PH treated with a prostacyclin analogue (epoprostenol or treprostinil) between January 2001 and August 2015 at our center. Data were collected before initiation of treatment (baseline) and at 1-3 and 6-12 months after. Protocolized echocardiogram measurements including tricuspid annular plane systolic excursion (TAPSE) and RV global longitudinal strain were made with blinding to clinical information. Forty nine individuals (65% female), aged 0-29 years at the time of prostacyclin initiation were included. Disease types included pulmonary arterial hypertension (idiopathic [35%], heritable [2%], and congenital heart disease-associated [18%]), developmental lung disease (43%), and chronic thromboembolic PH (2%). Participants received intravenous (IV) epoprostenol (14%) and IV/subcutaneous (SQ) (67%) or inhaled (18%) treprostinil. Over the study period, prostacyclin analogues were associated with improvement in TAPSE ( P = 0.007), RV strain ( P < 0.001), and qualitative RV function ( P = 0.037) by echocardiogram, and BNP ( P < 0.001), functional class ( P = 0.047) and 6-min walk distance ( P = 0.001). TAPSE and strain improved at early follow up ( P = 0.05 and P = 0.002, respectively) despite minimal RV pressure change. In children with PH, prostacyclin analogues are associated with an early and sustained improvement in RV function measured as TAPSE and strain as well as clinical markers of PH severity. RV strain may be a sensitive marker of RV function in this population. PMID- 29480091 TI - Comparative analysis of expansin gene codon usage patterns among eight plant species. AB - Expansins are essential components of plant cell wall and play an important role in plant growth, development, and stress resistance via loosening function. To understand the codon usage pattern of expansin genes, we gained the sequence data of expansin genes from eight plant species. Statistics analysis showed obvious codon characteristics between monocot and dicot plants. Comparably, expansin genes in monocot plants had really higher GC content, more high-frequency codons, and more optimal codons than that in dicot plants. Several monocot plants performed somehow as dicot plants in a few characters. Codon information of expansin genes might contribute to the understanding of the relationship and evolution clues between monocot and dicot plants. It further gained insight into the improvement of the gene expression and roles. PMID- 29480090 TI - Racial differences in patients referred for right heart catheterization and risk of pulmonary hypertension. AB - African Americans (AA) have a higher incidence of pulmonary hypertension (PH) risk factors. Few studies have examined the racial differences in the prevalence and etiology of PH and direct comparison of invasive hemodynamics between AAs and Caucasians has rarely been reported. In this study, we examined whether racial differences exist in patients referred for right heart catheterization (RHC) and hypothesized that AA race is an independent risk factor for PH and is associated with increased adjusted mortality. We extracted data for AA and Caucasian patients who underwent RHC at Vanderbilt between 1998 and 2014. Clinical information was obtained from Vanderbilt's Synthetic Derivative, a de-identified mirror of our Electronic Medical Record. A total of 4576 patients were analyzed, including 586 (13%) AAs and 3990 (87%) Caucasians. AAs were younger than Caucasians by an average of eight years, but had more prevalent heart failure, features of metabolic syndrome, and higher creatinine. AAs also had higher mean pulmonary artery pressure and pulmonary vascular resistance. After adjusting for relevant co-morbidities, the AA race is associated with 41% increased risk of PH (odds ratio [OR] = 1.41, 95% confidence interval [CI] = 1.12-1.79). Among patients with PH, AA race is associated with 24% increased adjusted mortality (hazard ratio [HR] = 1.24, 95% CI = 1.09-1.45). AAs were younger but had more prevalent cardiometabolic and renal disease and worse pulmonary hemodynamics. The AA race is an independent risk factor for PH. Among patients with PH, the AA race is associated with increased adjusted mortality. Future studies should focus on delineating whether genetic or environmental factors contribute to PH risk in AAs. PMID- 29480093 TI - Effects of asymmetric loading on lateral spinal curvature in young adults with scoliosis: A preliminary study. AB - BACKGROUND: Usual guidelines recommend symmetric load carriage over asymmetric load carriage. Whether this recommendation is valid for subjects with asymmetric body alignment, such as those with scoliosis, remains unclear. Scoliosis is both a subject-dependent and time-variant condition. Interventions are generally employed to prevent the abnormal spinal curvature from progressing. OBJECTIVES: To investigate the effects of an asymmetric load carriage on lateral spinal deformity in participant with scoliosis. STUDY DESIGN: Repeated measure and single-case experimental designs Methods: Photogrammetry was employed to measure the scoliotic curvature changes in thoracic and lumbar regions without a load (0%) and with a single-strap cross-chest bag loaded at 2.5%, 5%, 7.5%, 10% and 12.5% of body weight. Statistical tests and programming models were adopted to determine the loading conditions (placement and weight of the bag) with optimal and minimal corrections of the affected and unaffected scoliotic spinal regions, respectively. RESULTS: Significant short-term postural correction of scoliosis was achieved through applying an asymmetric load on the ipsilateral shoulder relative to the apex location of the major scoliotic curve. CONCLUSION: A subject specific optimal loading configuration was determined using a programming model. The results suggest that the application of a properly controlled asymmetric load carriage might be possible for reducing scoliotic spinal curvature. Further study of the long-term effects of subject-specific optimal asymmetric load carriage on scoliotic spinal curvatures is warranted. Clinical relevance Short-term reduction of scoliotic spinal curvatures under asymmetric load carriage was demonstrated. Thoracic curvatures could be reduced when asymmetric loading was applied on the ipsilateral shoulder relative to the scoliotic apex. Multiobjective programming was applied to determine the optimal weight of asymmetric load for participant with scoliosis. PMID- 29480094 TI - The impact a surgeon has on primary amputee prosthetic rehabilitation: A survey of residual lower limb quality. AB - BACKGROUND: Substantial improvements have been perceived in surgical results following major lower limb amputation, but there remains observed variation in amputation quality for patients referred for prosthetic rehabilitation from different hospitals. OBJECTIVES: To assess various elements that influence residual limb quality and evaluate their impact on progress through initial prosthetic rehabilitation and mobility outcome after rehabilitation. STUDY DESIGN: Clinical survey. METHODS: A revised 10-item residual limb scoring system was used to survey a succession of 95 primary amputees with transtibial and transfemoral amputations (100 residual limbs) presenting for rehabilitation. RESULTS: The majority of residual limbs scored highly, supporting the perception of generally good amputation quality. There were significant differences in average residual limb scores between some hospitals. The overall scores showed weak or minimal correlation to progress through rehabilitation and mobility outcome but residual limbs scoring higher in seven of the items of the score showed significant advantages in key aspects of progress or mobility at discharge. CONCLUSION: There is need for continued collaboration between surgeons and rehabilitation centres to ensure consistent high standards. The revised residual limb score used in this survey needs further refinement for future use. Clinical relevance Residual limb quality is an important component influencing prosthetic rehabilitation. This survey of residual limbs at one Rehabilitation Centre suggests encouragingly good surgical results but highlights differences between hospitals. A particular issue is the need for effective collaboration between surgeons and prosthetic rehabilitation professionals to optimise residual limb preparation. PMID- 29480095 TI - Infected abscess on the neck. PMID- 29480092 TI - The clinical characteristics and long-term prognosis of pulmonary arterial hypertension associated with hereditary hemorrhagic telangiectasia. AB - Pulmonary arterial hypertension (PAH) is a severe complication of hereditary hemorrhagic telangiectasia (HHT); however, little is known about its clinical characteristics and prognosis. Nine newly diagnosed HHT-PAH patients were prospectively recruited between October 2007 and January 2016 and were followed up every half-year. Eighteen idiopathic pulmonary arterial hypertension (IPAH) patients, matched with HHT-PAH patients on mean pulmonary arterial pressure, pulmonary capillary wedge pressure, pulmonary vascular resistance, cardiac index, and World Health Organization (WHO) functional class (FC), were recruited. The clinical characteristics of HHT-PAH patients were described and the prognosis of these two cohorts were compared. Of HHT-PAH patients, 55.56% were WHO FC III. Kaplan-Meier survival analysis showed one- and three-year survival rates of HHT PAH patients were 77.8% and 53.3% respectively, which were worse than matched IPAH patients (log rank: P = 0.047). HHT-PAH patients had higher red cell distribution width (14.88 +/- 2.93% versus 13.19 +/- 0.83%, P = 0.031), larger right ventricular anteroposterior diameter (34.67 +/- 6.67 mm versus 28.56 +/- 6.35 mm, P = 0.029), and lower mean corpuscular hemoglobin concentration (317.38 +/- 17.71 g/L versus 335.72 +/- 14.68 g/L, P = 0.011) than matched IPAH patients. Multivariate Cox proportional hazards regression analyses showed baseline total bilirubin independently predicted the mortality of HHT-PAH after adjusting by age, cardiac index, mixed venous oxygen saturation, or serum uric acid. HHT-PAH patients may have a worse prognosis than matched IPAH patients. Baseline total bilirubin may be a promising predictor for the long-term prognosis in HHT-PAH patients. PMID- 29480096 TI - A case of ruptured sinus of Valsalva aneurysm and reversible flow-induced pulmonary hypertension. AB - Pulmonary hypertension (PH) in adults with congenital heart disease (CHD) and significant systemic-to-pulmonary shunting is a significant cause of morbidity and mortality. Its pathophysiology is incompletely understood, but involves a flow-induced pulmonary arteriopathy characterized by endothelial cell dysfunction and vascular remodeling that alters pulmonary arterial vasoreactivity. There is a paucity of literature linking PH with left-to-right shunting due to ruptured sinus of Valsalva aneurysms (SOVA). We present a unique case of reversible, flow associated PH due to a ruptured congenital right SOVA fistulizing into the right atrium (RA), with emphasis on non-invasive and invasive assessment of pulmonary hemodynamics before and after surgical intervention. PMID- 29480097 TI - Acute intracystic haemorrhage in postoperative peritoneal cyst. PMID- 29480098 TI - Kyphoscoliosis and pregnancy. AB - Ten pregnancies in eight women with kyphoscoliosis were managed in the Princess Margaret Hospital, Hong Kong, between 1976 and 1984. Five patients were delivered by caesarean section, including four classical sections for malpresentation. Pre operative and postoperative chest physiotherapy was given to all patients. I here were no maternal deaths. Two patients had chest infections but none had cardiopulmonary failure. One baby died of respiratory distress syndrome. The role of active chest physiotherapy is emphasised. PMID- 29480099 TI - Compression of the femoral nerve due to endometriosis of the inguinal region. PMID- 29480100 TI - Absence of an ovary and uterine tube-further evidence for the 'torsion' theory. PMID- 29480101 TI - Mid-trimester levels of placental protein 5 are not predictive of preterm labour. AB - In earlier studies elevated maternal levels of placental protein 5 in the middle trimester were shown to be predictive of preterm labour. In a prospective study on 893 randomly selected pregnant women we were unable to confirm this association despite our own previous positive findings. PMID- 29480102 TI - Asherman's syndrome successfully treated by insertion of a Multiload copper 250 device. PMID- 29480103 TI - Successful pregnancy following suppression of anticardiolipin antibody and lupus anticoagulant with azathioprine in systemic lupus erythematosus. PMID- 29480104 TI - Unilateral salpingitis due to Enterobius vermicularis. PMID- 29480105 TI - Phosphatidylglycerol and neonatal mortality and morbidity. AB - In spite of major improvements in neonatal intensive care, mortality and morbidity remain a problem for the very preterm baby. In a study of 168 babies born before 36 weeks the presence of phosphatidylglycerol (PG) as a marker of fetal lung maturity in amniotic fluid or pharyngeal aspirate was associated with a lower requirement for ventilatory support and a reduced incidence of intraventricular haemorrhage and patent ductus arteriosus. It is suggested that the value of the antenatal assessment of fetal lung maturity should Perhaps be reviewed since babies in whom PG is absent appear to be at a high risk of sustaining considerable morbidity. PMID- 29480106 TI - An unusual presentation of a renal adenocarcinoma. PMID- 29480107 TI - Serum levels of ritodrine used for the management of spontaneous preterm labour. AB - Ritodrine 0.05 mg/min gave a mean scrum level of 3.6ng/ml and 0.55mg/min gave a mean level of 204 ng/ml, when infused intravenously into women in spontaneous preterm labour. Oral administration of ritodrine, 5 mg 3 hourly, gave a mean serum level of 0.3ng/ml; 10 mg 2 hourly gave 1.3ng/ml. The drug crosses the placenta and umbilical vein cord serum levels were higher than maternal levels when it was continued until delivery. Ritodrine was detected in such a baby 24 hours after birth. PMID- 29480109 TI - Intrapartum fetal monitoring-is the scalp electrode necessary? PMID- 29480108 TI - Vulval myoblastoma mimicking squamous carcinoma in a young girl. PMID- 29480110 TI - Mullerian adenosarcoma of the uterine corpus in a 14 year old girl. PMID- 29480111 TI - Obstetric management of the very low birth Weight baby in a district maternity hospital. AB - A retrospective survey of very low birth weight babies delivered in a large non teaching hospital in 1977 and in 1983 was carried out in order to determine how obstetric complications and management were associated with perinatal mortality. The prognosis for these infants had improved markedly by 1983. This was associated with better diagnosis of intra-uterine growth retardation, an increased incidence of elective delivery. Particularly where abnormalities of pregnancy existed in addition to very low birth weight, the liberal use of caesarean section, and better paediatric care of the baby with severe respiratory distress syndrome. PMID- 29480112 TI - Removal of an intra-uterine contraceptive device per rectum. PMID- 29480114 TI - Indications for caesarean section: experience in a district general hospital. AB - Out of 661 deliveries in a district general hospital in 3 Months, 100 (15.1 per cent) were by caesarean section. Of these, 35 sections were performed for delay in the first stage, 16 for breech presentation, 9 for fetal distress and 12 were repeat operations. The study suggests that fewer inductions in the presence of an unfavourable cervix and fewer sections for breech presentation might reduce the caesarean section rate. PMID- 29480115 TI - Malignant hyperpyrexia-relevance for obstetricians. PMID- 29480116 TI - Antenatal visits. A comparative study between integrated and shared antenatal care. AB - A comparison was made of the number of antenatal visits made by 96 women receiving integrated antenatal care in an experimental community clinic with 100 women receiving traditional shared care from two control practices. Most women from the experimental group were cared for within the traditional framework of visits whether or not they had experienced problems or complications in their pregnancies. Women from the control group made higher total numbers of visits per pregnancy and also more visits to the hospital source of care. Most women from both groups were satisfied with the number of visits they made although some women from the experimental group thought that they made too few visits in early pregnancy and some women from the control group thought that they made too many visits to the hospital source of care. A policy for keeping the number of hospital visits to three, where appropriate, should enable specialist obstetricians to spend more time with 'high risk' patients. PMID- 29480117 TI - Transfer of hydralazine across the placenta and into breast milk. AB - Eleven pregnancies were studied in which i.v. hydralazine was given within 24 hours of delivery. Hydralazine (with its active metabolites, the hydrazones) was measured in maternal, cord and neonatal blood and in breast milk by high performance liquid chromatography (HPLC). Cord venous hydralazine concentrations Were approximately equal to maternal venous concentrations. Hydralazine was detectable in breast milk and concentrations were about half those in maternal blood taken simultaneously. Concentrations of hydralazine Were 557 nmol/l and 293nmol/l in the serum of two babies after breast feeding. Boiling expressed breast milk destroyed hydralazine. One other infant, with coarctation of the aorta, required 6 mg/kg/day of hydralazine to lower his blood pressure and his plasma concentration exceeded 8000 nmol/l. We conclude that the transfer of hydralazine across the placenta and into "reast milk is unlikely to subject neonates to pharmacological effects. PMID- 29480118 TI - Transcervical aspiration technique for chorion villus biopsy in the first trimester of pregnancy and chromosomal analysis. AB - The: clinical usefulness of chorion villus sampling is dependent on the rate of obtaining an adequate sample and the overall risk to the fetus. The present study was undertaken to assess essential requirements for successful sampling technique with minimum immediate complications in relation to gestational age and placental site. PMID- 29480119 TI - Obstetric injuries of the lower ureter. AB - Ureteric injuries arc now rare in obstetric practice, even with unilateral and two with bilateral injuries are described, all the result of obstructed labour and difficult surgical intervention late in labour. One of the seven unilateral cases healed spontaneously while the remainder needed surgical repair. Of the two bilateral Cllses, one died of endotoxic shock following nephrostomy and the other patient underwent immediate Compression of both ureteric constrictions. PMID- 29480120 TI - Scalp hair, facial skin and pregnancy. PMID- 29480121 TI - Antenatal management of massive subchorial thrombohaematoma detected by ultrasound. PMID- 29480122 TI - A narrow escape for the second of mono-amniotic twins. PMID- 29480123 TI - The conservative management of abdominal pregnancy. PMID- 29480124 TI - Local analgesia for surgical cure of prolapse in elderly or unfit women. AB - Surgical correction of genital prolapse under local analgesia in elderly or unlit women is described. One hundred patients undergoing such surgery between 1972 and 1984 were reviewed. Eighty-five per cent were more than 60 years of age. Over 50 per cent had Fothergill repairs. Ninety-six per cent were assessed as having a good result. The incidence of postoperative complications was 20 per cent and there was no mortality. From our experience the technique seems to be a safe and worthwhile procedure. PMID- 29480125 TI - Toxic shock syndrome. PMID- 29480126 TI - Multiple peritoneal cysts associated with a ruptured follicular cyst. PMID- 29480127 TI - Recurrent carcinoma of the vulva: relationship with operative blood transfusion. AB - Previous studies of colorectal and breast cancer have indicated better survival in patients not transfused at operation. Retrospective analysis of patients having radical vulvectomy as a curative procedure in the years 1974 to 1984 showed that those transfused had a recurrence rate of 25 per cent while those not transfused had a rate of 10 per cent. Other factors known to be important in the recurrence of this disease were examined and found to be similar for both groups. PMID- 29480128 TI - Correspondence. PMID- 29480129 TI - A longitudinal study of computerized cognitive training in stroke patients - effects on cognitive function and white matter. AB - Background Computerized cognitive training is suggested to enhance attention and working memory functioning following stroke, but effects on brain and behavior are not sufficiently studied and longitudinal studies assessing brain and behavior relationships are scarce. Objective The study objectives were to investigate relations between neuropsychological performance post-stroke and white matter microstructure measures derived from diffusion tensor imaging (DTI), including changes after 6 weeks of working memory training. Methods In this experimental training study, 26 stroke patients underwent DTI and neuropsychological tests at 3 time points - before and after a passive phase of 6 weeks, and again after 6 weeks of working memory training (Cogmed QM). Fractional anisotropy (FA) was extracted from stroke-free brain areas to assess the white matter microstructure. Twenty-two participants completed the majority of training (>=18/25 sessions) and were entered into longitudinal analyses. Results Significant correlations between FA and baseline cognitive functions were observed (r = 0.58, p = 0.004), however, no evidence was found of generally improved cognitive functions following training or of changes in white matter microstructure. Conclusions While white matter microstructure related to baseline cognitive function in stroke patients, the study revealed no effect on cognitive functions or microstructural changes in white matter in relation to computerized working memory training. PMID- 29480131 TI - Narrative Influences on "Desire to Act in My Community" in Digital Storytelling Workshops for Latina Teens. AB - Digital storytelling workshops are increasingly being used to capture lived experiences and develop/disseminate health promotion messages for vulnerable and marginalized populations. Thirty female Latina teens of varied sexual/parity status produced digital stories of significant life experiences in a group context and then viewed and evaluated them using the Narrative Quality Assessment Tool. This tool was used to examine participants' experience of emotional engagement and identification with each story as well as a single-item indicator of desire to "do something in my community" related to the story. Emotional engagement was moderately strong; identification scores were neutral relative to the stories. Emotional engagement was strongly, significantly related to "desire to act in my community," while identification was not related. Emotional engagement should be considered an important factor to incorporate in the production of digital stories for purposes of developing interest in social action beyond the digital storytelling workshop. PMID- 29480136 TI - Is there a commonality of occlusion for dental, TMD and obstructive sleep apnea patients? Thoughts on a snowy day. PMID- 29480137 TI - The effect of Ehlers-Danlos syndromes on TMJ function and craniofacial pain. PMID- 29480138 TI - Shear-wave elastography - virtual touch tissue quantification of fetal placentas with a single umbilical artery. AB - OBJECTIVE: In this study, we aimed to evaluate the elasticities of fetal placentas with a single umbilical artery using the Virtual Touch Tissue Quantification (VTTQ) technique. MATERIALS AND METHODS: Pregnant women with fetuses with a single umbilical artery (SUA) and pregnant women with fetuses having three vessel cord (3VC) at 18-22 weeks of gestation were enrolled in the research. The placentas were evaluated and divided into three equal parts as the inner 1/3 of the placenta (fetal edge), the outer 1/3 of the placenta (maternal edge) and the central 1/3 of the placenta (central part). Shear-wave velocity (SWV) measurements were used in the elastographic evaluation of placentas by VTTQ. RESULTS: Forty pregnant women were included in the study (n = 20 SUA, n = 20 three vessel cord pregnant women). The placental Acoustic Radiation Force Impulse (VTTQ) of the placenta regarding SWV measurement values of the fetal edge of the placenta in the fetuses with SUA and the control group were 0.876 and 0.957 m/sec, respectively. A significant statistical difference was found between the groups regarding the measurement of the stiffness of fetal placenta (p = 0.021). There was no significant difference between the measured stiffness values of the central or outer region of the placentas. CONCLUSIONS: In this study, we found lower SWV scores for the fetal edge of the placenta with SUA. This finding may reflect tissue elasticity level, and we hope that the use of the VTTQ technique may contribute to predicting the pregnancy-related morbidities of fetuses with SUA in the future. PMID- 29480134 TI - Inflammation and autoimmunity in pulmonary hypertension: is there a role for endothelial adhesion molecules? (2017 Grover Conference Series). AB - While pulmonary hypertension (PH) has traditionally not been considered as a disease that is directly linked to or, potentially, even caused by inflammation, a rapidly growing body of evidence has demonstrated the accumulation of a variety of inflammatory and immune cells in PH lungs, in and around the wall of remodeled pulmonary resistance vessels and in the vicinity of plexiform lesions, respectively. Concomitantly, abundant production and release of various inflammatory mediators has been documented in both PH patients and experimental models of PH. While these findings unequivocally demonstrate an inflammatory component in PH, they have fueled an intense and presently ongoing debate as to the nature of this inflammatory aspect: is it a mere bystander of or response to the actual disease process, or is it a pathomechanistic contributor or potentially even a trigger of endothelial injury, smooth muscle hypertrophy and hyperplasia, and the resulting lung vascular remodeling? In this review, we will discuss the present evidence for an inflammatory component in PH disease with a specific focus on the potential role of the endothelium in this scenario and highlight future avenues of experimental investigation which may lead to novel therapeutic interventions. PMID- 29480139 TI - A cost-effectiveness analysis of denosumab for the prevention of skeletal-related events in patients with multiple myeloma in the United States of America. AB - OBJECTIVE: A large, pivotal, phase 3 trial in patients with newly diagnosed multiple myeloma (MM) demonstrated that denosumab, compared with zoledronic acid, was non-inferior for the prevention of skeletal-related events (SREs), extended the observed median progression-free survival (PFS) by 10.7 months, and showed significantly less renal toxicity. The cost-effectiveness of denosumab vs zoledronic acid in MM in the US was assessed from societal and payer perspectives. METHODS: The XGEVA Global Economic Model was developed by integrating data from the phase 3 trial comparing the efficacy of denosumab with zoledronic acid for the prevention of SREs in MM. SRE rates were adjusted to reflect the real-world incidence. The model included utility decrements for SREs, administration, serious adverse events (SAEs), and disease progression. Drug, administration, SRE management, SAEs, and anti-MM treatment costs were based on data from published studies. For the societal perspective, the model additionally included SRE-related direct non-medical costs and indirect costs. The net monetary benefit (NMB) was calculated using a willingness-to-pay threshold of US$150,000. One-way deterministic and probabilistic sensitivity analyses were conducted. RESULTS: From a societal perspective, compared with zoledronic acid, the use of denosumab resulted in an incremental cost of US$26,329 and an incremental quality-adjusted life-year (QALY) of 0.2439, translating into a cost per QALY gained of US$107,939 and a NMB of US$10,259 in favor of denosumab. Results were sensitive to SRE rates and PFS parameters. LIMITATIONS: Costs were estimated from multiple sources, which varied by tumor type, patient population, country, and other parameters. PFS and overall survival were extrapolated beyond the follow-up of the primary analysis using fitted parametric curves. CONCLUSION: Denosumab's efficacy in delaying or preventing SREs, potential to improve PFS, and lack of renal toxicity make it a cost-effective option for the prevention of SREs in MM compared with zoledronic acid. PMID- 29480143 TI - The vocabulary of shape: principal shapes for probing perception and neural response. AB - Humans perceive shape rapidly and effortlessly but have great difficulties describing what they perceive. This suggests that the representation of shape in the brain is abstract and very unlike that used in conscious thought. Here we explore the proposal that this representation is matched to the statistical properties of objects in the environment. From an ensemble of several hundred laser-scanned three-dimensional (3D) human heads we extract the principal components which provide a compact basis for head shape. We show that, with good accuracy, a given head can be represented by linear combinations of a few dozen primary shapes just as colours can be synthesized by combining the three principal colours. We suggest new perceptual adaptation experiments for testing the brain's shape representation system. The principal head shapes can also be used to probe response properties of 'face-cells' in the inferior temporal cortex. PMID- 29480140 TI - Impact of histologic chorioamnionitis on pulmonary hypertension and respiratory outcomes in preterm infants. AB - We aimed to evaluate the association between the presence of histologic chorioamnionitis (HC) and development of pulmonary hypertension (PH) during neonatal intensive care unit (NICU) stay. Data of preterm infants born at 32 weeks of gestation or less were reviewed. The development of PH and other respiratory outcomes were compared according to the presence of HC. Potential risk factors associated with the development of PH during NICU stay were used for multivariable logistic regression analysis. A total of 188 infants were enrolled: 72 in the HC group and 116 in the no HC group. The HC group infants were born at a significantly shorter gestational age and lower birthweight, with a greater proportion presenting preterm premature rupture of membrane (pPROM) > 18 h before delivery. More infants in the HC group developed pneumothorax ( P = 0.008), and moderate and severe bronchopulmonary dysplasia (BPD; P = 0.001 and P = 0.006, respectively). PH in the HC group was significantly more frequent compared to the no HC group (25.0% versus 8.6%, P = 0.002). Based on a multivariable logistic regression analysis, birthweight ( P = 0.009, odds ratio [OR] = 0.997, 95% confidence interval [CI] = 0.995-0.999), the presence of HC ( P = 0.047, OR = 2.799, 95% CI = 1.014-7.731), and duration of invasive mechanical ventilation (MV) > 14 days ( P = 0.015, OR = 8.036, 95% CI = 1.051-43.030) were significant factors. The presence of HC and prolonged invasive MV in infants with lower birthweight possibly synergistically act against preterm pulmonary outcomes and leads to the development of PH. Verification of this result and further investigation to establish effective strategies to prevent or ameliorate these adverse outcomes are needed. PMID- 29480142 TI - Mutual information maximization: models of cortical self-organization. AB - Unsupervised learning procedures based on Hebbian principles have been successful at modelling low-level feature extraction, but are insufficient for learning to recognize higher- order features and complex objects. In this paper we explore a class of unsupervised learning algorithms called Imax (Becker and Hinton 1992 Nature 355 161-3) that are derived from information-theoretic principles. The Imax algorithms are based on the idea of maximizing the mutual information between the outputs of different network modules, and are capable of extracting higher-order features from data. They are therefore well suited to modelling intermediate-to-high-level perceptual processing stages. We substantiate this claim with some novel results for two signal classification problems, as well as by reviewing some previously published results and several related approaches. Finally, Imax is evaluated with respect to computational costs and biological plausibility. PMID- 29480144 TI - Review Articles 1990-1995. PMID- 29480145 TI - Pattern retrieval in threshold-linear associative nets. AB - Networks of threshold-linear neurons have previously been introduced and analysed as distributed associative memory systems. Here, results from simulations of pattern retrieval in a large-scale, sparsely connected network are presented. The storage capacity lies near a = 0.8 and 1.2 for binary and ternary patterns respectively, in reasonable accordance with theoretical estimates. The system is capable of retrieving states strongly correlated with one of the stored patterns even when the initial state is a highly degraded version of one of these patterns. This pattern completion ability holds for an extensive number of memory patterns, up to alpha ~ alphac/2, thereby increasing the credibility of the model as an effective associative memory. PMID- 29480146 TI - Analytical estimates of limited sampling biases in different information measures. AB - Measuring the information carried by neuronal activity is made difficult, particularly when recording from mammalian cells, by the limited amount of data usually available, which results in a systematic error. While empirical ad hoc procedures have been used to correct for such error, we have recently proposed a direct procedure consisting of the analytical calculation of the average error, its estimation (up to subleading terms) from the data, and its subtraction from raw information measures to yield unbiased measures. We calculate here the leading correction terms for both the average transmitted information and the conditional information and, since usually one must first regularize the data, we specify the expressions appropriate to different regularizations. Computer simulations indicate a broad range of validity of the analytical results, suggest the effectiveness of regularizing by simple binning and illustrate the advantage of this over the previously used 'bootstrap' procedure. PMID- 29480147 TI - Coding of time-varying signals in spike trains of linear and half-wave rectifying neurons. AB - The encoding of time-varying stimuli in linear and half-wave rectifying neurons is studied. The information carried in single spike trains is assessed by reconstructing part of the stimulus using mean square estimation methods. For the class of models considered here, the mean square error in the reconstructions and estimates of the rate of information transmission are computed analytically. The optimal encoding of stimuli having statistical properties of natural images predicts a change in the temporal filtering characteristics with mean firing rate. This change relates to those observed experimentally at the early stages of visual processing. The transmission of information by model neurons is shown to be fundamentally limited to a maximum of 1.13 bit/spike and it is conjectured that nonlinear processing is necessary to explain higher rates which have been observed experimentally in certain preparations. In spite of the fact that single neurons might not transmit information efficiently, a substantial part of a time varying stimulus can be recovered from single spike trains. In particular, our results demonstrate that a small number of 'noisy' neurons can carry precise temporal information in their spike trains. PMID- 29480148 TI - Illusory surface perception and visual organization. AB - Illusory contours occur in a wide variety of circumstances in nature. A striking man- made example is the Kanizsa triangle. A common factor in all such figures is the perception of a surface occluding part of a background, i.e. illusory contours are always accompanied by illusory surfaces. The detection of occlusion cues suggest various different local surface configurations, leading to a large combinatorial set of global surface configurations, each one constituting an image organization. We address the problems of why and how the image organizations that yield illusory contours arise. Our approach is to: (i) detect occlusions; (ii) assign surface-states at these locations that reflect the presence of a particular surface configuration; (iii) apply a Bayesian model to diffuse this local surface information; (iv) define an entropy measure for each image organization to select the best one(s) as the one(s) giving the lowest entropy values. We note that: (a) the illusory contours arise from the surface boundaries, and hence we do not propagate/extend intensity edges directly; (b) the overlapping surfaces provide an explanation for amodal completions. The model reproduces various qualitative and quantitative aspects of illusory contour perception and has been supported by a series of experiments. PMID- 29480149 TI - Learning dynamics of simple perceptrons with non-extensive cost functions. AB - A Tsallis-statistics-based generalization of the gradient descent dynamics (using non- extensive cost functions), recently introduced by one of us, is proposed as a learning rule in a simple perceptron. The resulting Langevin equations are solved numerically for different values of an index q (q = 1 and q ? 1 respectively correspond to the extensive and non-extensive cases) and for different cost functions. The results are compared with the learning curve (mean error versus time) obtained from a learning experiment carried out with human beings, showing an excellent agreement for values of q slightly above unity. This fact illustrates the possible importance of including some degree of non-locality (non-extensivity) in computational learning procedures, whenever one wants to mimic human behaviour. PMID- 29480150 TI - Unsupervised learning in general connectionist systems. AB - There is a common framework in which different connectionist systems may be treated in a unified way. The general system in which they may all be mapped is a network which, in addition to the connection strengths, has an adaptive node parameter controlling the output intensity. In this paper we generalize two neural network learning schemes to networks with node parameters. In generalized Hebbian learning we find improvements to the convergence rate for small eigenvalues in principal component analysis. For competitive learning the use of node parameters also seems useful in that, by emphasizing or de-emphasizing the dominance of winning neurons, either improved robustness or discrimination is obtained. PMID- 29480151 TI - Potential biomarkers and targets in reversibility of pulmonary arterial hypertension secondary to congenital heart disease: an explorative study. AB - Whether pulmonary arterial hypertension (PAH) is reversible in congenital heart disease (CHD) is important for the operability of CHD. However, little is known about that. Our research was aimed at exploring novel biomarkers and targets in the reversibility of CHD-PAH. CHD-PAH patients diagnosed with right heart catheterization (RHC) were enrolled (n = 14). Lung biopsy was performed during the repair surgery. After one year follow-up, mean pulmonary arterial pressures (mPAP) were evaluated by RHC to determine the diagnosis of reversible (mPAP < 25 mmHg, n = 10) and irreversible (mPAP >= 25 mmHg, n = 4) PAH. Harvested normal lung tissues (n = 6) were included as the control group. Pulmonary arteriole lesions were identified by pathological grading in tissue staining. iTRAQ labelled mass-spectrometry analysis followed by immunohistochemistry and western blot was used to explore the most meaningful differential proteins. For enrolled patients, the histopathological grading of pulmonary vascular lesions in reversible CHD-PAH patients was all at grades 0-II while grades III-IV were shown only in irreversible CHD-PAH patients. Proteomic analysis identified 85 upregulated and 75 downregulated proteins, including cytoskeletal proteins and collagen chains, mainly involved in cell adhesion, extracellular matrix, cytoskeleton, immune response, and complement pathways. Among them, caveolin-1, filamin A expression, and cathepsin D combined with macrophagocytes counts were significantly increased; glutathione S-transferase mu1 (GSTM1) expression was significantly decreased in the irreversible CHD-PAH group (all P < 0.05). Caveolin-1, filamin A, and cathepsin D expression showed a positive relation and GSTM1 showed a negative relation with pathological grading. Upregulated caveolin 1, filamin A, and cathepsin D combined with increased macrophagocytes and downregulated GSTM1 may be potential biomarkers and targets in the irreversibility CHD-PAH, and which may be useful in evaluating the operability and understanding the irreversibility of CHD-PAH. Expression of these pathological biomarkers combined with pathological changes in lung biopsy may have great value in predicting the irreversibility of PAH. PMID- 29480153 TI - EXPRESS: PHSANZ ASM 2017 - Abstracts. PMID- 29480152 TI - Endothelial dysfunction in pulmonary arterial hypertension: loss of cilia length regulation upon cytokine stimulation. AB - Pulmonary arterial hypertension (PAH) is a syndrome characterized by progressive lung vascular remodelling, endothelial cell (EC) dysfunction, and excessive inflammation. The primary cilium is a sensory antenna that integrates signalling and fine tunes EC responses to various stimuli. Yet, cilia function in the context of deregulated immunity in PAH remains obscure. We hypothesized that cilia function is impaired in ECs from patients with PAH due to their inflammatory status and tested whether cilia length changes in response to cytokines. Primary human pulmonary and mouse embryonic EC were exposed to pro- (TNFalpha, IL1beta, and IFNgamma) and/or anti-inflammatory (IL-10) cytokines and cilia length was quantified. Chronic treatment with all tested inflammatory cytokines led to a significant elongation of cilia in both control human and mouse EC (by ~1 um, P < 0.001). This structural response was PKA/PKC dependent. Intriguingly, withdrawal of the inflammatory stimulus did not reduce cilia length. IL-10, on the other hand, blocked and reversed the pro-inflammatory cytokine-induced cilia elongation in healthy ECs, but did not influence basal length. Conversely, primary cilia of ECs from PAH patients were significantly longer under basal conditions compared to controls (1.86 +/- 0.02 vs. 2.43 +/- 0.08 um, P = 0.002). These cilia did not elongate further upon pro-inflammatory stimulation and anti-inflammatory treatment did not impact cilia length. The missing length modulation was specific to cytokine stimulation, as application of fluid shear stress led to increased cilia length in the PAH endothelium. We identified loss of cilia length regulation upon cytokine stimulation as part of the endothelial dysfunction in PAH. PMID- 29480155 TI - A student-initiated objective structured clinical examination as a sustainable cost-effective learning experience. AB - BACKGROUND: The objective structured clinical examination (OSCE) has gained widespread use as a form of performance assessment. However, opportunities for students to participate in practice OSCEs are limited by the financial, faculty and administrative investments required. OBJECTIVES: To determine the feasibility and acceptability of a student-run mock OSCE (MOSCE) as a learning experience for medical students of all 4 years. DESIGN: We conducted a five-station MOSCE for third-year students. This involved fourth-year students as examiners and first /second-year students as standardized patients (SPs). Each examiner scored examinees using a checklist and global rating scale while providing written and verbal feedback. MOSCE stations and checklists were designed by students and reviewed by a faculty supervisor. Following the MOSCE, participants completed surveys which elucidated their perceptions on the roles they took during the MOSCE. RESULTS: Fifty examinees participated in the MOSCE. Of these, 42 (84%) consented to participate in the study and submitted completed questionnaires. Twenty-four examiners participated in the OSCE and consented to participate in the study, with 22 (92%) submitting completed questionnaires. Fifty-three of 60 SPs (88%) agreed to take part in this study, and 51 (85%) completed questionnaires. The internal consistency of the five-station OSCE was calculated as a Cronbach's alpha of 0.443. Students commented positively on having the opportunity to network and engage in mentorship activities and reinforce clinical concepts. CONCLUSIONS: Examinees, examiners, and SPs all perceived the MOSCE to be a beneficial learning experience. We found the MOSCE to be a feasible and acceptable means of providing additional OSCE practice to students prior to higher-stakes evaluations. PMID- 29480154 TI - Stem cell therapy targeting the right ventricle in pulmonary arterial hypertension: is it a potential avenue of therapy? AB - Pulmonary arterial hypertension (PAH) is an incurable disease characterized by an increase in pulmonary arterial pressure due to pathological changes to the pulmonary vascular bed. As a result, the right ventricle (RV) is subject to an increased afterload and undergoes multiple changes, including a decrease in capillary density. All of these dysfunctions lead to RV failure. A number of studies have shown that RV function is one of the main prognostic factors for PAH patients. Many stem cell therapies targeting the left ventricle are currently undergoing development. The promising results observed in animal models have led to clinical trials that have shown an improvement of cardiac function. In contrast to left heart disease, stem cell therapy applied to the RV has remained poorly studied, even though it too may provide a therapeutic benefit. In this review, we discuss stem cell therapy as a treatment for RV failure in PAH. We provide an overview of the results of preclinical and clinical studies for RV cell therapies. Although a large number of studies have targeted the pulmonary circulation rather than the RV directly, there are nonetheless encouraging results in the literature that indicate that cell therapies may have a direct beneficial effect on RV function. This cell therapy strategy may therefore hold great promise and warrants further studies in PAH patients. PMID- 29480156 TI - Is caregiver refusal of analgesics a barrier to pediatric emergency pain management? A cross-sectional study in two Canadian centres. AB - CLINICIAN'S CAPSULEWhat is known about the topic?Children's pain in the emergency department (ED) continues to be under-recognized and sub-optimally managed.What did this study ask?We sought to evaluate the frequency of caregiver/child acceptance of analgesia offered in the ED.What did this study find?Of the 743 children who presented to the ED with a painful condition, 408 (54.9%) were offered analgesia. If offered in the ED, analgesia was accepted by 91% (373/408) of the caregivers/children.Why does this study matter to clinicians?This study suggests that caregiver/child refusal of analgesia is a not a major barrier to optimal pain management and highlights the importance of ED personnel in encouraging adequate analgesia. PMID- 29480157 TI - The Impact of Alcohol Use on Drop-out and Psychological Treatment Outcomes in Improving Access to Psychological Therapies Services: an Audit. AB - BACKGROUND: The impact of alcohol use disorders (AUD) on psychological treatments for depression or anxiety in primary care psychological treatment services is unknown. AIMS: To establish levels of alcohol misuse in an Improving Access to Psychological Therapies (IAPT) service, examine the impact of higher risk drinking on IAPT treatment outcomes and drop-out, and to inform good practice in working with alcohol misuse in IAPT services. METHOD: 3643 patients completed a brief questionnaire on alcohol use pre-treatment in addition to measures of depression, anxiety and functioning. Symptom and functioning measures were re administered at all treatment sessions. RESULTS: Severity of alcohol misuse was not associated with treatment outcomes, although those scoring eight or more on the AUDIT-C were more likely to drop out from treatment. CONCLUSIONS: IAPT services may be well placed to offer psychological therapies to patients with common mental disorders and comorbid AUD. Patients with AUD can have equivalent treatment outcomes to those without AUD, but some higher risk drinkers may find accessing IAPT treatment more difficult as they are more likely to drop out. Alcohol misuse on its own should not be used as an exclusion criterion from IAPT services. Recommendations are given as to how clinicians can: adjust their assessments to consider the appropriateness of IAPT treatment for patients that misuse alcohol, consider the potential impact of alcohol misuse on treatment, and improve engagement in treatment for higher risk drinkers. PMID- 29480159 TI - An improved optimization algorithm of the three-compartment model with spillover and partial volume corrections for dynamic FDG PET images of small animal hearts in vivo. AB - The three-compartment model with spillover (SP) and partial volume (PV) corrections has been widely used for noninvasive kinetic parameter studies of dynamic 2-[18F] fluoro-2deoxy-D-glucose (FDG) positron emission tomography images of small animal hearts in vivo. However, the approach still suffers from estimation uncertainty or slow convergence caused by the commonly used optimization algorithms. The aim of this study was to develop an improved optimization algorithm with better estimation performance. Femoral artery blood samples, image-derived input functions from heart ventricles and myocardial time activity curves (TACs) were derived from data on 16 C57BL/6 mice obtained from the UCLA Mouse Quantitation Program. Parametric equations of the average myocardium and the blood pool TACs with SP and PV corrections in a three compartment tracer kinetic model were formulated. A hybrid method integrating artificial immune-system and interior-reflective Newton methods were developed to solve the equations. Two penalty functions and one late time-point tail vein blood sample were used to constrain the objective function. The estimation accuracy of the method was validated by comparing results with experimental values using the errors in the areas under curves (AUCs) of the model corrected input function (MCIF) and the 18F-FDG influx constant K i . Moreover, the elapsed time was used to measure the convergence speed. The overall AUC error of MCIF for the 16 mice averaged -1.4 +/- 8.2%, with correlation coefficients of 0.9706. Similar results can be seen in the overall K i error percentage, which was 0.4 +/- 5.8% with a correlation coefficient of 0.9912. The t-test P value for both showed no significant difference. The mean and standard deviation of the MCIF AUC and K i percentage errors have lower values compared to the previously published methods. The computation time of the hybrid method is also several times lower than using just a stochastic algorithm. The proposed method significantly improved the model estimation performance in terms of the accuracy of the MCIF and K i , as well as the convergence speed. PMID- 29480158 TI - Utilization of a hybrid finite-element based registration method to quantify heterogeneous tumor response for adaptive treatment for lung cancer patients. AB - Tumor response to radiation treatment (RT) can be evaluated from changes in metabolic activity between two positron emission tomography (PET) images. Activity changes at individual voxels in pre-treatment PET images (PET1), however, cannot be derived until their associated PET-CT (CT1) images are appropriately registered to during-treatment PET-CT (CT2) images. This study aimed to investigate the feasibility of using deformable image registration (DIR) techniques to quantify radiation-induced metabolic changes on PET images. Five patients with non-small-cell lung cancer (NSCLC) treated with adaptive radiotherapy were considered. PET-CTs were acquired two weeks before RT and 18 fractions after the start of RT. DIR was performed from CT1 to CT2 using B-Spline and diffeomorphic Demons algorithms. The resultant displacements in the tumor region were then corrected using a hybrid finite element method (FEM). Bitmap masks generated from gross tumor volumes (GTVs) in PET1 were deformed using the four different displacement vector fields (DVFs). The conservation of total lesion glycolysis (TLG) in GTVs was used as a criterion to evaluate the quality of these registrations. The deformed masks were united to form a large mask which was then partitioned into multiple layers from center to border. The averages of SUV changes over all the layers were 1.0 +/- 1.3, 1.0 +/- 1.2, 0.8 +/- 1.3, 1.1 +/- 1.5 for the B-Spline, B-Spline + FEM, Demons and Demons + FEM algorithms, respectively. TLG changes before and after mapping using B-Spline, Demons, hybrid-B-Spline, and hybrid-Demons registrations were 20.2%, 28.3%, 8.7%, and 2.2% on average, respectively. Compared to image intensity-based DIR algorithms, the hybrid FEM modeling technique is better in preserving TLG and could be useful for evaluation of tumor response for patients with regressing tumors. PMID- 29480160 TI - Diamond lattice Heisenberg antiferromagnet. AB - We investigate ground-state and high-temperature properties of the nearest neighbour Heisenberg antiferromagnet on the three-dimensional diamond lattice, using series expansion methods. The ground-state energy and magnetization, as well as the magnon spectrum, are calculated and found to be in good agreement with first-order spin-wave theory, with a quantum renormalization factor of about 1.13. High-temperature series are derived for the free energy, and physical and staggered susceptibilities for spin S = 1/2, 1 and 3/2, and analysed to obtain the corresponding Curie and Neel temperatures. PMID- 29480161 TI - Topologically protected edge states for out-of-plane and in-plane bulk elastic waves. AB - Topological phononic insulators (TPnIs) show promise for application in the manipulation of acoustic waves for the design of low-loss transmission and perfectly integrated communication devices. Since solid phononic crystals exist as a transverse polarization mode and a mixed longitudinal-transverse polarization mode, the realization of topological edge states for both out-of plane and in-plane bulk elastic waves is desirable to enhance the controllability of the edge waves in solid systems. In this paper, a two-dimensional (2D) solid/solid hexagonal-latticed phononic system that simultaneously supports the topologically protected edge states for out-of-plane and in-plane bulk elastic waves is investigated. Firstly, two pairs of two-fold Dirac cones, respectively corresponding to the out-of-plane and in-plane waves, are obtained at the same frequency by tuning the crystal parameters. Then, a strategy of zone folding is invoked to form double Dirac cones. By shrinking and expanding the steel scatterer, the lattice symmetry is broken, and band inversions induced, giving rise to an intriguing topological phase transition. Finally, the topologically protected edge states for both out-of-plane and in-plane bulk elastic waves, which can be simultaneously located at the frequency range from 1.223 to 1.251 MHz, are numerically observed. Robust pseudospin-dependent elastic edge wave propagation along arbitrary paths is further demonstrated. Our results will significantly broaden its practical application in the engineering field. PMID- 29480162 TI - Bonding in phase change materials: concepts and misconceptions. AB - Bonding concepts originating in chemistry are surveyed from a condensed matter perspective, beginning around 1850 with 'valence' and the word 'bond' itself. The analysis of chemical data in the 19th century resulted in astonishing progress in understanding the connectivity and stereochemistry of molecules, almost without input from physicists until the development of quantum mechanics in 1925 and afterwards. The valence bond method popularized by Pauling and the molecular orbital methods of Hund, Mulliken, Bloch, and Huckel play major roles in the subsequent development, as does the central part played by the kinetic energy in covalent bonding (Ruedenberg and others). 'Metallic' (free electron) and related approaches, including pseudopotential and density functional theories, have been remarkably successful in understanding structures and bonding in molecules and solids. We discuss these concepts in the context of phase change materials, which involve the rapid and reversible transition between amorphous and crystalline states, and note the confusion that some have caused, in particular 'resonance' and 'resonant bonding'. PMID- 29480163 TI - Preparing cuprous oxide nanomaterials by electrochemical method for non-enzymatic glucose biosensor. AB - Cuprous oxide (Cu2O) nanostructure has been synthesized using an electrochemical method with a two-electrode system. Cu foils were used as electrodes and NH2(OH) was utilized as the reducing agent. The effects of pH and applied voltages on the morphology of the product were investigated. The morphology and optical properties of Cu2O particles were characterized using scanning electron microscopy, x-ray diffraction, and diffuse reflectance spectra. The synthesized Cu2O nanostructures that formed in the vicinity of the anode at 2 V and pH = 11 showed high uniform distribution, small size, and good electrochemical sensing. These Cu2O nanoparticles were coated on an Indium tin oxide substrate and applied to detect non-enzyme glucose as excellent biosensors. The non-enzyme glucose biosensors exhibited good performance with high response, good selectivity, wide linear detection range, and a low detection limit at 0.4 MUM. Synthesized Cu2O nanostructures are potential materials for a non-enzyme glucose biosensor. PMID- 29480164 TI - Optimizing the electromechanical response in morphotropic BiFeO3. PMID- 29480165 TI - CVD-graphene for low equivalent series resistance in rGO/CVD-graphene/Ni-based supercapacitors. AB - Reduced equivalent series resistance (ESR) is necessary, particularly at a high current density, for high performance supercapacitors, and the interface resistance between the current collector and electrode material is one of the main components of ESR. In this report, we have optimized chemical vapor deposition-grown graphene (CVD-G) on a current collector (Ni-foil) using reduced graphene oxide as an active electrode material to fabricate an electric double layer capacitor with reduced ESR. The CVD-G was grown at different cooling rates 20 degrees C min-1, 40 degrees C min-1 and 100 degrees C min-1-to determine the optimum conditions. The lowest ESR, 0.38 Omega, was obtained for a cell with a 100 degrees C min-1 cooling rate, while the sample without a CVD-G interlayer exhibited 0.80 Omega. The CVD-G interlayer-based supercapacitors exhibited fast CD characteristics with high scan rates up to 10 Vs-1 due to low ESR. The specific capacitances deposited with CVD-G were in the range of 145.6 F g-1-213.8 F g-1 at a voltage scan rate of 0.05 V s-1. A quasi-rectangular behavior was observed in the cyclic voltammetry curves, even at very high scan rates of 50 and 100 V s-1, for the cell with optimized CVD-G at higher cooling rates, i.e. 100 degrees C min-1. PMID- 29480166 TI - Methodology to reduce 6D patient positional shifts into a 3D linear shift and its verification in frameless stereotactic radiotherapy. AB - The aim of this article is to derive and verify a mathematical formulation for the reduction of the six-dimensional (6D) positional inaccuracies of patients (lateral, longitudinal, vertical, pitch, roll and yaw) to three-dimensional (3D) linear shifts. The formulation was mathematically and experimentally tested and verified for 169 stereotactic radiotherapy patients. The mathematical verification involves the comparison of any (one) of the calculated rotational coordinates with the corresponding value from the 6D shifts obtained by cone beam computed tomography (CBCT). The experimental verification involves three sets of measurements using an ArcCHECK phantom, when (i) the phantom was not moved (neutral position: 0MES), (ii) the position of the phantom shifted by 6D shifts obtained from CBCT (6DMES) from neutral position and (iii) the phantom shifted from its neutral position by 3D shifts reduced from 6D shifts (3DMES). Dose volume histogram and statistical comparisons were made between [Formula: see text] and [Formula: see text]. The mathematical verification was performed by a comparison of the calculated and measured yaw (gamma degrees ) rotation values, which gave a straight line, Y = 1X with a goodness of fit as R 2 = 0.9982. The verification, based on measurements, gave a planning target volume receiving 100% of the dose (V100%) as 99.1 +/- 1.9%, 96.3 +/- 1.8%, 74.3 +/- 1.9% and 72.6 +/- 2.8% for the calculated treatment planning system values TPSCAL, 0MES, 3DMES and 6DMES, respectively. The statistical significance (p-values: paired sample t-test) of V100% were found to be 0.03 for the paired sample [Formula: see text] and 0.01 for [Formula: see text]. In this paper, a mathematical method to reduce 6D shifts to 3D shifts is presented. The mathematical method is verified by using well-matched values between the measured and calculated gamma degrees . Measurements done on the ArcCHECK phantom also proved that the proposed methodology is correct. The post-correction of the table position condition introduces a minimal spatial dose delivery error in the frameless stereotactic system, using a 6D motion enabled robotic couch. This formulation enables the reduction of 6D positional inaccuracies to 3D linear shifts, and hence allows the treatment of patients with frameless stereotactic radiosurgery by using only a 3D linear motion enabled couch. PMID- 29480167 TI - Electrically tunable polarizer based on graphene-loaded plasmonic cross antenna. AB - The unique gate-voltage dependent optical properties of graphene make it a promising electrically-tunable plasmonic material. In this work, we proposed in situ control of the polarization of nanoantennas by combining plasmonic structures with an electrostatically tunable graphene monolayer. The tunable polarizer is designed based on an asymmetric cross nanoantenna comprising two orthogonal metallic dipoles sharing the same feed gap. Graphene monolayer is deposited on a Si/SiO2 substrate, and inserted beneath the nanoantenna. Our modelling demonstrates that as the chemical potential is incremented up to 1 eV by electrostatic doping, resonant wavelength for the longer graphene-loaded dipole is blue shifted for 500 nm (~10% of the resonance) in the mid-infrared range, whereas the shorter dipole experiences much smaller influences due to the unique wavelength-dependent optical properties of graphene. In this way, the relative field amplitude and phase between the two dipole nanoantennas are electrically adjusted, and the polarization state of the reflected wave can be electrically tuned from the circular into near-linear states with the axial ratio changing over 8 dB. Our study thus confirms the strong light-graphene interaction with metallic nanostructures, and illuminates promises for high-speed electrically controllable optoelectronic devices. PMID- 29480168 TI - Non-perturbative methodologies for low-dimensional strongly-correlated systems: From non-Abelian bosonization to truncated spectrum methods. AB - We review two important non-perturbative approaches for extracting the physics of low-dimensional strongly correlated quantum systems. Firstly, we start by providing a comprehensive review of non-Abelian bosonization. This includes an introduction to the basic elements of conformal field theory as applied to systems with a current algebra, and we orient the reader by presenting a number of applications of non-Abelian bosonization to models with large symmetries. We then tie this technique into recent advances in the ability of cold atomic systems to realize complex symmetries. Secondly, we discuss truncated spectrum methods for the numerical study of systems in one and two dimensions. For one dimensional systems we provide the reader with considerable insight into the methodology by reviewing canonical applications of the technique to the Ising model (and its variants) and the sine-Gordon model. Following this we review recent work on the development of renormalization groups, both numerical and analytical, that alleviate the effects of truncating the spectrum. Using these technologies, we consider a number of applications to one-dimensional systems: properties of carbon nanotubes, quenches in the Lieb-Liniger model, 1 + 1D quantum chromodynamics, as well as Landau-Ginzburg theories. In the final part we move our attention to consider truncated spectrum methods applied to two dimensional systems. This involves combining truncated spectrum methods with matrix product state algorithms. We describe applications of this method to two dimensional systems of free fermions and the quantum Ising model, including their non-equilibrium dynamics. PMID- 29480169 TI - Carbon monoxide sensing properties of B-, Al- and Ga-doped Si nanowires. AB - Silicon nanowires (SiNWs) are considered as potential chemical sensors due to their large surface-to-volume ratio and their possible integration into arrays for nanotechnological applications. Detection of harmful gases like CO has been experimentally demonstrated, however, the influence of doping on the sensing capacity of SiNWs has not yet been reported. For this work, we theoretically studied the surface adsorption of a CO molecule on hydrogen-passivated SiNWs grown along the [111] crystallographic direction and compared it with the adsorption of other molecules such as NO, and O2. Three nanowire diameters and three dopant elements (B, Al and Ga) were considered, and calculations were done within the density functional theory framework. The results indicate that CO molecules are more strongly adsorbed on the doped SiNW than on the pristine SiNW. The following trend was observed for the CO adsorption energies: E A[B-doped] > E A[Al-doped] > E A[Ga-doped] > E A[undoped], for all diameters. The electronic charge transfers between the SiNWs and the adsorbed CO were estimated by using a Voronoi population analysis. The CO adsorbed onto the undoped SiNWs has an electron-acceptor character, while the CO adsorbed onto the B-, Al-, and Ga-doped SiNWs exhibits an electron-donor character. Comparing these results with the ones obtained for the NO and O2 adsorption, the larger CO adsorption energy on B-doped SiNWs indicates their good selectivity towards CO. These results suggest that SiNW-based sensors of toxic gases could represent a clear and advantageous application of nanotechnology in the improvement of human quality of life. PMID- 29480170 TI - Reduced Gray Matter Volume of the Thalamus and Hippocampal Region in Elderly Healthy Adults with no Impact of APOE E4: A Longitudinal Voxel-Based Morphometry Study. AB - BACKGROUND: Many cross-sectional voxel-based morphometry (VBM) investigations have shown significant inverse correlations between chronological age and gray matter (GM) volume in several brain regions in healthy humans. However, few VBM studies have documented GM decrements in the healthy elderly with repeated MRI measurements obtained in the same subjects. Also, the extent to which the APOE E4 allele influences longitudinal findings of GM reduction in the healthy elderly is unclear. OBJECTIVE: Verify whether regional GM changes are associated with significant decrements in cognitive performance taking in account the presence of the APOE E4 allele. METHODS: Using structural MRI datasets acquired in 55 cognitively intact elderly subjects at two time-points separated by approximately three years, we searched for voxels showing significant GM reductions taking into account differences in APOE genotype. RESULTS: We found global GM reductions as well as regional GM decrements in the right thalamus and left parahippocampal gyrus (p < 0.05, family-wise error corrected for multiple comparisons over the whole brain). These findings were not affected by APOE E4. CONCLUSIONS: Irrespective of APOE E4, longitudinal VBM analyses show that the hippocampal region and thalamus are critical sites where GM shrinkage is greater than the degree of global volume reduction in healthy elderly subjects. PMID- 29480171 TI - Executive Dysfunction Detected with the Frontal Assessment Battery in Alzheimer's Disease Versus Vascular Dementia. AB - Alzheimer's disease (AD) and vascular dementia (VaD) lead to progressive decline in executive function. We estimated the prevalence of executive dysfunction in AD and VaD patients, investigating cognitive, functional, and clinical correlates and also using a multidimensional approach based on a standardized comprehensive geriatric assessment (CGA). We included 215 patients (115 AD patients and 100 VaD patients) consecutively evaluated with a complete cognitive and affective assessment, a CGA, and the Frontal Assessment Battery (FAB) with six subtests investigating conceptualization, mental flexibility, motor programming, sensitivity to interference, inhibitory control, and environmental autonomy. The prevalence of dysexecutive syndrome screened with a FAB score <12 points was high in both AD (97 patients) and VaD (77 patients) (84.3% versus 77.0%, p = 0.171). AD patients were significantly younger, with higher grade of cognitive impairment and less severe comorbidity and polypharmacy than VaD patients. AD patients showed a significantly higher impairment in FAB total score and five FAB subtests (conceptualization, motor programming, sensitivity to interference, inhibitory control, and environmental autonomy) than VaD patients. These findings were largely confirmed in a sub-analysis conducted subdividing the sample in mild and moderate-to-severe demented patients and suggesting that in moderate-to-severe AD there was higher impairment in FAB total score and four FAB subtests (conceptualization, sensitivity to interference, inhibitory control, and environmental autonomy). Executive dysfunction could be greater in AD patients with moderate-to-severe dementia compared to VaD patients, although our groups were also not matched for age, comorbidity or polypharmacy, which could also exert an effect. PMID- 29480172 TI - GDF11 Rejuvenates Cerebrovascular Structure and Function in an Animal Model of Alzheimer's Disease. AB - Cerebral amyloid angiopathy (CAA) is present in up to 90% of patients with Alzheimer's disease (AD), and may interact with classical neuropathology to exacerbate cognitive decline. Since growth differentiation factor 11 (GDF11) can activate vascular remodeling, we tested its effects on cognitive function and neuroinflammatory changes of AD model mice. We intravenously administered GDF11 or vehicle daily to 12-month-old transgenic mice overexpressing the amyloid-beta protein precursor (AbetaPP)/PS1). Cognitive function was monitored using the Morris water maze, and after conclusion of the treatment, we assessed the morphology and presence of inflammatory markers in the cerebral vasculature. Subchronic treatment of adult AbetaPP/PS1 mice with GDF11 rescued cognitive function and ameliorated cerebrovascular function. In particular, the de novo genesis of small blood vessels and the expression of vascular-related proteins were significantly higher than in the vehicle-treated AbetaPP/PS1 mice, whereas the expressions of the inflammatory markers Iba-1 and GFAP significantly decreased in proportion to the lower ratio of two forms of amyloid-beta (Abeta40/42). Daily intravenous treatment with GDF11-injection can rejuvenate respects of cognition and cerebrovascular changes in AD mice. PMID- 29480173 TI - Interactions between Atrial Fibrillation, Cardiovascular Risk Factors, and ApoE Genotype in Promoting Cognitive Decline in Patients with Alzheimer's Disease: A Prospective Cohort Study. AB - BACKGROUND: An association between non-valvular atrial fibrillation (NVAF) and cognitive impairment has been hypothesized. OBJECTIVE: We sought to evaluate whether and how permanent NVAF (pNVAF) is associated with progression of cognitive impairment in patients with Alzheimer's disease (AD) in the presence of vascular or genetic risk factors. METHODS: 310 consecutive patients affected by mild-moderate AD were included and followed for a 24-month period. At the end of the follow-up, based on the results of the neuropsychological evaluation patients were classified as stable or deteriorated to severe AD. Clinical history, therapy, time in therapeutic range for anticoagulation, Framingham cardiovascular risk profile (FCRP), CHA2DS2-VASc score, Mini-Mental State Examination (MMSE), ApoE genotype, brain CT-scan, carotid ultrasound, and ECG were collected. Binary logistic and path analysis were adopted to assess relationships between pNVAF, ApoE, and cognitive outcome. RESULTS: Despite anticoagulant therapy, pNVAF was associated with lower entry MMSE, higher mean intima-media thickness (mIMT) and higher FCRP. Among patients carrying ApoE E4 allele and affected by pNVAF, the lowest MMSE (14.90+/-7.62) and the highest mIMT (1.16+/-0.17 mm) and FCRP (26.24+/-3.96) values were detected. In this group, the risk of cognitive deterioration reached the highest probability. pNVAF was associated with an increased cognitive deterioration in subjects with high FCRP, CHA2DS2-VASc, or mIMT. CONCLUSIONS: pNVAF seems to identify AD patients with a significant atherosclerotic burden and reduced cognitive performances. The interaction between pNVAF and ApoE E4 genotype, especially with aggregated risk factors and an advanced stage of vascular damage is associated with higher risk of fast cognitive deterioration. PMID- 29480174 TI - Decreased Prefrontal Activation during Matrix Reasoning in Predementia Progranulin Mutation Carriers. AB - We tested the potential of task-based functional neuroimaging as a biomarker of emerging prefrontal brain changes in progranulin (GRN) mutations carriers. Five GRN mutation carriers free of frontotemporal dementia (FTD) and 11 non-carriers from families with FTD-GRN underwent functional MRI while solving matrix reasoning problems. Mutation carriers displayed slower responses for more difficult problems and lower lateral prefrontal activation across all problems. Overall task-evoked posterior ventrolateral prefrontal activation predicted mutation status with 100% sensitivity and 91% specificity. Volumetric differences did not account for activation differences. Prefrontal activation may have utility as a biomarker in GRN mutation. PMID- 29480175 TI - Visit-To-Visit Blood Pressure Variability and the Risk of Dementia in Older People. AB - BACKGROUND: High visit-to-visit variability (VVV) in blood pressure (BP) is associated with cerebrovascular lesions on neuroimaging. OBJECTIVE: Our primary objective was to investigate whether VVV is associated with incident all-cause dementia. As a secondary objective, we studied the association of VVV with cognitive decline and cardiovascular disease (CVD). METHODS: We included community-dwelling people (age 70-78 year) from the 'Prevention of Dementia by Intensive Vascular Care' (preDIVA) trial with three to five 2-yearly BP measurements during 6-8 years follow-up. VVV was defined using coefficient of variation (CV; SD/mean*100). Cognitive decline was assessed using the Mini-Mental State Examination (MMSE). Incident CVD was defined as myocardial infarction or stroke. We used a Cox proportional hazard regression and mixed-effects model adjusted for sociodemographic factors and cardiovascular risk factors. RESULTS: In 2,305 participants (aged 74.2+/-2.5), mean systolic BP over all available visits was 150.1 mmHg (SD 13.6), yielding a CV of 9.0. After 6.4 years (SD 0.8) follow-up, 110 (4.8%) participants developed dementia and 140 (6.1%) CVD. Higher VVV was not associated with increased risk of dementia (hazard ratio [HR] 1.00 per point CV increase; 95% confidence interval [CI] 0.96-1.05), although the highest quartile of VVV was associated with stronger decline in MMSE (beta -0.09, 95% CI -0.17 to -0.01). Higher VVV was associated with incident CVD (HR 1.07; 95% CI 1.04-1.11). CONCLUSION: In our study among older people, high VVV is not associated with incident all-cause dementia. It is associated with decline in MMSE and incident CVD. PMID- 29480176 TI - Longitudinal Changes in Serum Glucose Levels are Associated with Metabolic Changes in Alzheimer's Disease Related Brain Regions. AB - BACKGROUND: The association between longitudinal changes in serum glucose level and longitudinal changes in [18F] Fluorodeoxyglucose-PET (FDG PET) measurements of Alzheimer's disease (AD) risk are unknown. OBJECTIVE: To investigate whether variation in serum glucose levels across time are associated with changes in FDG PET measurements of cerebral metabolic rate for glucose (rCMRgl) in brain regions preferentially affected by Alzheimer's disease (AD). METHODS: Participants are a subset of a prospective cohort study investigating FDG PET, apolipoprotein E (APOE) E4, and risk for AD which includes data from baseline, interim, and follow up visits over 4.4+/-1.0-years. An automated brain-mapping algorithm was utilized to characterize and compare associations between longitudinal changes in serum glucose levels and longitudinal changes in rCMRgl. RESULTS: This study included 80 adults aged 61.5+/-5 years, including 38 carriers and 42 non-carriers of the APOE E4 allele. Longitudinal increases in serum glucose levels were associated with longitudinal CMRgl decline in the vicinity of parietotemporal, precuneus/posterior cingulate, and prefrontal brain regions preferentially affected by AD (p < 0.05, corrected for multiple comparisons). Findings remained significant when controlled for APOE E4 status and baseline and advancing age. CONCLUSIONS: Additional studies are needed to clarify and confirm the relationship between longitudinal changes in peripheral glucose and FDG PET measurements of AD risk. Future findings will set the stage on the use of FDG PET in the evaluation of possible interventions that target risk factors for the development of AD. PMID- 29480177 TI - Homocysteine and Cerebral Atrophy: The Epidemiology of Dementia in Singapore Study. AB - BACKGROUND: Plasma homocysteine levels are increasingly studied as a potential risk factor for dementia. Elevated homocysteine levels have been linked with gray and white matter volume reduction among individuals with mild cognitive impairment and Alzheimer's disease. However, the effects of homocysteine on brain changes in preclinical stages of dementia remain unexplored. OBJECTIVE: To examine the association of elevated homocysteine levels with markers of neurodegeneration, i.e., white and gray matter volume in an elderly population. METHODS: The study included 768 participants (mean age: 69.6+/-6.5 years, 51.3% women) from the Epidemiology of Dementia In Singapore study. Participants underwent a brain MRI scan and blood tests. Serum homocysteine was measured using competitive immunoassay. Cortical thickness and subcortical structural volume were quantified using FreeSurfer whereas white matter volume was quantified using a previous validated method. RESULTS: Higher homocysteine levels were significantly associated with decreased global white matter volume [mean difference (beta) in volume (ml) per micromole per liter (MUmol/l) increase in homocysteine levels: - 0.555, 95% Confidence Interval (CI): - 0.873; - 0.237], decreased parietal cortical thickness [beta in thickness (MUm) per MUmol/l increase in homocysteine levels:- 1.429, 95% CI: - 2.781; - 0.077], and smaller volumes of the thalamus [beta: - 0.017, 95% CI: - 0.026; - 0.008], brainstem [beta: - 0.037, 95% CI: - 0.058; - 0.016], and accumbens [beta: - 0.004, 95% CI: 0.006; - 0.002]. CONCLUSION: Higher homocysteine levels were associated with cerebral atrophy. Further studies are required to assess whether lowering plasma homocysteine levels may prevent neurodegenerative changes or delay progression of clinical symptoms before the development of dementia. PMID- 29480178 TI - Age-Related Changes in the Spatial Frequency Threshold of Male and Female 3xTg-AD Mice Using OptoMotry. AB - Visual impairments and retinal abnormalities occur in patients with Alzheimer's disease (AD) and in mouse models of AD. It is important to know the visual ability of mouse models of AD to ensure that age-related cognitive deficits are not confounded by visual impairments. Using OptoMotry, the spatial frequency thresholds of male and female 3xTg-AD mice did not differ from their B6129SF2 wildtype controls between 1-18 months of age, but females had higher spatial frequency thresholds than males. However, the differences were quite small, and the visual ability of all mice was comparable to that of C57BL/6 mice. PMID- 29480180 TI - The Role of Verb Fluency in the Detection of Early Cognitive Impairment in Alzheimer's Disease. AB - BACKGROUND: Verb fluency (VF) is the less commonly used fluency test, despite several studies suggesting its potential as a neuropsychological assessment tool. OBJECTIVE: To investigate the presence of VF deficits in mild cognitive impairment (MCI) and mild Alzheimer's disease (AD) dementia; to assess the usefulness of VF in the detection of cognitively healthy (CH) people who will convert to MCI, and from MCI to dementia; and to establish the VF cut-offs useful in the cognitive assessment of Spanish population. METHODS: 568 CH, 885 MCI, and 367 mild AD dementia individuals were administered the VF test and a complete neuropsychological battery. Longitudinal analyses were performed in 231 CH and 667 MCI subjects to search for VF predictors of diagnosis conversion. RESULTS: A worsening on VF performance from CH, MCI to AD dementia groups was found. Lower performances on VF were significantly related to conversion from CH to MCI/MCI to dementia. When the effect of time to conversion was analyzed, a significant effect of VF was found on the faster conversion from CH to MCI, but not from MCI to dementia. Moreover, VF cut-off scores and sensitivity/specificity values were calculated for 6 conditions (3 age ranges by 2 educational levels). CONCLUSION: The VF test may be a useful tool for the differential diagnosis of cognitive failure in the elderly. Since VF deficits seem to take place in early stages of the disease, it is a suitable neuropsychological tool for the detection not only of CH people who will convert to MCI, but also from MCI to dementia. PMID- 29480179 TI - Perspectives on Communicating Biomarker-Based Assessments of Alzheimer's Disease to Cognitively Healthy Individuals. AB - In clinical trials which target pathophysiological mechanisms associated with Alzheimer's disease, research participants who are recruited based on biomarker test results should be informed about their increased risk of developing Alzheimer's dementia. This paper presents the results of a qualitative focus group study of attitudes and concerns toward learning information about biomarker based risk status among healthy research participants in the United Kingdom and Spain and people with dementia and their supporters/caregivers from countries represented in the European Working Group of People with Dementia of Alzheimer Europe. The study identified expectations related to learning risk status and preferences related to the content, quality, and follow-up of the disclosure process. The latter emphasize distinctions between risk and diagnoses, the importance of clear information about risk, and suggestions for risk reduction, as well as expectations for follow up and support. The implications of these preferences for practice are discussed. Providing details of research participants' experience and views may serve as a guide for the development of processes for the responsible disclosure of Alzheimer's disease biomarkers. PMID- 29480184 TI - Ozone Atmospheric Pollution and Alzheimer's Disease: From Epidemiological Facts to Molecular Mechanisms. AB - Atmospheric pollution is a well-known environmental hazard, especially in developing countries where millions of people are exposed to airborne pollutant levels above safety standards. Accordingly, several epidemiological and animal studies confirmed its role in respiratory and cardiovascular pathologies and identified a strong link between ambient air pollution exposure and adverse health outcomes such as hospitalization and mortality. More recently, the potential deleterious effect of air pollution inhalation on the central nervous system was also investigated and mounting evidence supports a link between air pollution exposure and neurodegenerative pathologies, especially Alzheimer's disease (AD). The focus of this review is to highlight the possible link between ozone air pollution exposure and AD incidence. This review's approach will go from observational and epidemiological facts to the proposal of molecular mechanisms. First, epidemiological and postmortem human study data concerning residents of ozone-severely polluted megacities will be presented and discussed. Then, the more particular role of ozone air pollution in AD pathology will be described and evidenced by toxicological studies in rat or mouse with ozone pollution exposure only. The experimental paradigms used to reproduce in rodent the human exposure to ozone air pollution will be described. Finally, current insights into the molecular mechanisms through which ozone inhalation can affect the brain and play a role in AD development or progression will be recapitulated. PMID- 29480181 TI - Assessment of the Genetic Architecture of Alzheimer's Disease Risk in Rate of Memory Decline. AB - Many genetic studies for Alzheimer's disease (AD) have been focused on the identification of common genetic variants associated with AD risk and not on other aspects of the disease, such as age at onset or rate of dementia progression. There are multiple approaches to untangling the genetic architecture of these phenotypes. We hypothesized that the genetic architecture of rate of progression is different than the risk for developing AD dementia. To test this hypothesis, we used longitudinal clinical data from ADNI and the Knight-ADRC at Washington University, and we calculated PRS (polygenic risk score) based on the IGAP study to compare the genetic architecture of AD risk and dementia progression. Dementia progression was measured by the change of Clinical Dementia Rating Sum of Boxes (CDR)-SB per year. Out of the 21 loci for AD risk, no association with the rate of dementia progression was found. The PRS rate was significantly associated with the rate of dementia progression (beta= 0.146, p = 0.03). In the case of rare variants, TREM2 (beta= 0.309, p = 0.02) was also associated with the rate of dementia progression. TREM2 variant carriers showed a 23% faster rate of dementia compared with non-variant carriers. In conclusion, our results indicate that the recently identified common and rare variants for AD susceptibility have a limited impact on the rate of dementia progression in AD patients. PMID- 29480183 TI - Low Prevalence of Cancer in Patients with Frontotemporal Lobar Degeneration. AB - Several studies have reported reduced risk of cancer in patients with Alzheimer's disease (AD) or Parkinson's disease. The relationship between cancer and frontotemporal lobar degeneration (FTLD) has not been previously reported. Here, our aim was to evaluate the occurrence of cancer in Finnish FTLD patients with a high proportion of C9ORF72 repeat expansion carriers in comparison to age- and sex-matched group of AD patients and control subjects classified as not cognitively impaired (NCI). The prevalence of cancer was 9.7% in FTLD, 18.7% in AD, and 17.4% in NCI (FTLD versus AD p = 0.012, FTLD versus NCI p = 0.029) groups. No differences were observed between C9ORF72 repeat expansion carriers and non-carriers inside the FTLD group. To our knowledge, this is the first study showing significantly lower prevalence of cancer in FTLD patients compared to patients with AD or NCI subjects. Our data suggest an inverse association between neurodegeneration and cancer and that FTLD-specific mechanisms may underlie the especially strong inverse association observed in this study. PMID- 29480182 TI - Simultaneous Aerobic Exercise and Memory Training Program in Older Adults with Subjective Memory Impairments. AB - BACKGROUND: Several modifiable lifestyle factors have been shown to have potential beneficial effects in slowing cognitive decline. Two such factors that may affect cognitive performance and slow the progression of memory loss into dementia in older adults are cognitive training and physical activity. There are currently no effective treatments for dementia; therefore, preventative strategies to delay or prevent the onset of dementia are of critical importance. OBJECTIVE: The aim of this study was to determine the relative effectiveness of simultaneous performance of memory training and aerobic exercise to a sequential performance intervention on memory functioning in older adults. METHODS: 55 older adults (aged 60- 75) with subjective memory impairments (non-demented and non MCI) completed the intervention that consisted of 90-minute small group classes held twice weekly. Participants were randomized to either 4-weeks of supervised strategy-based memory training done simultaneously while stationary cycling (SIM) or sequentially after the stationary cycling (SEQ). Standardized neurocognitive measures of memory, executive functioning, speed of processing, attention, and cognitive flexibility were assessed at baseline and post-intervention. RESULTS: The SIM group, but not the SEQ group, had a significant improvement on composite memory following the intervention (t(51) = 2.7, p = 0.01, effect size (ES) = 0.42) and transfer to non-trained reasoning abilities (t(51) = 6.0, ES = 0.49) and complex attention (t(51) = 3.1, p = 0.003, ES = 0.70). Conversely, the SEQ group, but not the SIM, showed significant improvement in executive functioning (t(51) = 5.0, p = 0.0001, ES = 0.96). CONCLUSION: These findings indicate that a 4-week simultaneous memory training and aerobic exercise program is sufficient to improve memory, attention, and reasoning abilities in older adults. PMID- 29480185 TI - Designing an Internet-Based Multidomain Intervention for the Prevention of Cardiovascular Disease and Cognitive Impairment in Older Adults: The HATICE Trial. AB - BACKGROUND: Many dementia and cardiovascular disease (CVD) cases in older adults are attributable to modifiable vascular and lifestyle-related risk factors, providing opportunities for prevention. In the Healthy Aging Through Internet Counselling in the Elderly (HATICE) randomized controlled trial, an internet based multidomain intervention is being tested to improve the cardiovascular risk (CVR) profile of older adults. OBJECTIVE: To design a multidomain intervention to improve CVR, based on the guidelines for CVR management, and administered through a coach-supported, interactive, platform to over 2500 community-dwellers aged 65+ in three European countries. METHODS: A comparative analysis of national and European guidelines for primary and secondary CVD prevention was performed. Results were used to define the content of the intervention. RESULTS: The intervention design focused on promoting awareness and self-management of hypertension, dyslipidemia, diabetes mellitus, and overweight, and supporting smoking cessation, physical activity, and healthy diet. Overall, available guidelines lacked specific recommendations for CVR management in older adults. The comparative analysis of the guidelines showed general consistency for lifestyle-related recommendations. Key differences, identified mostly in methods used to assess the overall CVR, did not hamper the intervention design. Minor country-specific adaptations were implemented to maximize the intervention feasibility in each country. CONCLUSION: Despite differences in CVR management within the countries considered, it was possible to design and implement the HATICE multidomain intervention. The study can help define preventative strategies for dementia and CVD that are applicable internationally. PMID- 29480186 TI - Meta-Analysis of Personality Traits in Alzheimer's Disease: A Comparison with Healthy Subjects. AB - BACKGROUND: The role of specific personality traits as factor risks of Alzheimer's disease (AD) has been consistently found, whereas personality traits specifically related to AD (after the diagnosis) have not been outlined yet. OBJECTIVE: A meta-analysis of published studies was performed to determine whether AD patients have a distinctive personality trait profile compared to healthy subjects (HC), similar to or different from a premorbid personality profile consistently reported in previous studies. METHODS: A systematic literature search was performed using PsycInfo (PROQUEST), PubMed, and Scopus. The meta-analysis pooled results from primary studies using Hedges' g unbiased approach. RESULTS: The meta-analysis included 10 primary studies and revealed that, when the personality was evaluated by informant-rated measures, AD patients had significantly higher levels of Neuroticism, lower levels of Openness, Agreeableness, Conscientiousness, and Extraversion than HCs. When the personality was evaluated by self-rated measures, the results obtained from informants were confirmed for Neuroticism, Openness, and Extraversion but not for Agreeableness and Conscientiousness where AD patients and HCs achieved similar scores. CONCLUSIONS: The meta-analysis revealed that high Neuroticism and low Openness and Extraversion are distinctive personality traits significantly associated with a diagnosis of AD when evaluated both self-rated and informant-rated measures. This personality trait profile is similar to premorbid one, which contributes to development of AD over time. Therefore, our findings indirectly support the idea of specific premorbid personality traits as harbingers of AD. PMID- 29480188 TI - Human Gut Microbiota in Health and Alzheimer's Disease. AB - Gut microbiota plays a crucial role in human health and disease. The alterations in the composition of gut microbiota may cause the onset of certain human pathologies. One of these is Alzheimer's disease (AD). High-fat diets, administration of antibiotics, lack of probiotics and/or prebiotics in diet increase the risk of AD. On the other hand, modulation of the composition of gut microbiota may decrease the risk of AD and be able to slow down the progression of AD. PMID- 29480187 TI - Longitudinal Modeling of Functional Decline Associated with Pathologic Alzheimer's Disease in Older Persons without Cognitive Impairment. AB - BACKGROUND: Therapeutic research on Alzheimer's disease (AD) has moved to intercepting the disease at the preclinical phase. Most drugs in late development have focused on the amyloid hypothesis. OBJECTIVE: To understand the magnitude of amyloid-related functional decline and to identify the functional domains sensitive to decline in a preclinical AD population. METHODS: Data were from the Religious Orders Study and the Rush Memory and Aging Project. Cognitive decline was measured by a modified version of the Alzheimer's Disease Cooperative Study Preclinical Alzheimer Cognitive Composite. The trajectories of functional decline, as measured by the instrumental and basic activities of daily living, were longitudinally modeled in 484 participants without cognitive impairment at baseline and having both a final clinical and a postmortem neuropathology assessment of AD. RESULTS: Individuals with different final clinical diagnoses had different trajectories of cognitive and functional decline. Individuals with AD dementia, minor cognitive impairment, and no cognitive impairment had the most, intermediate, and least declines. While individuals with pathologic AD had significantly more cognitive decline over time than those without, the magnitude of difference in functional decline between these two groups was small. Functional domains such as handling finance and handling medications were more sensitive to decline. CONCLUSION: Demonstrating the functional benefit of an amyloid-targeting drug represents a significant challenge as elderly people experience functional decline due to a wide range of reasons with limited manifestation attributable to AD neuropathology. More sensitive functional scales focusing on the functional domains sensitive to decline in preclinical AD are needed. PMID- 29480190 TI - The First Historically Reported Italian Family with FTD/ALS Teaches a Lesson on C9orf72 RE: Clinical Heterogeneity and Oligogenic Inheritance. AB - BACKGROUND: In 1969, Dazzi and Finizio reported the second observation of frontotemporal dementia (FTD) - amyotrophic lateral sclerosis (ALS) association in a large Italian kindred affected by an autosomal dominant form of ALS with high penetrance, frequent bulbar onset, and frequent cognitive decline. OBJECTIVE: To expand the original characterization of this family and report the link with the C9orf72 repeat expansion (RE). METHODS: We followed or reviewed the medical records of thirteen patients belonging to the original family and performed genetic analyses in four individuals. RESULTS: Eight patients presented with ALS, four with FTD, and one with schizophrenia. The C9orf72 RE was found in three patients but not in the healthy survivor. Additionally, we found a novel possible pathogenic variant in the ITM2B gene in one patient with a complex phenotype, associating movement disorders, psychiatric and cognitive features, deafness, and optic atrophy. The neuropathological examination of this patient did not show the classical features of ITM2B mutation related dementias suggesting that the putative pathogenic mechanism does not involve cellular mislocalization of the protein or the formation of amyloid plaques. CONCLUSION: We showed that the original Italian pedigree described with FTD/ALS carries the C9orf72 RE. Moreover, the finding of an additional mutation in another dementia causing gene in a patient with a more complex phenotype suggests a possible role of genetic modifiers in the disease. Together with other reports showing the coexistence of mutations in multiple ALS/FTD causative genes in the same family, our study supports an oligogenic etiology of ALS/FTD. PMID- 29480191 TI - Alzheimer's Disease: Recent Concepts on the Relation of Mitochondrial Disturbances, Excitotoxicity, Neuroinflammation, and Kynurenines. AB - The pathomechanism of Alzheimer's disease (AD) certainly involves mitochondrial disturbances, glutamate excitotoxicity, and neuroinflammation. The three main aspects of mitochondrial dysfunction in AD, i.e., the defects in dynamics, altered bioenergetics, and the deficient transport, act synergistically. In addition, glutamatergic neurotransmission is affected in several ways. The balance between synaptic and extrasynaptic glutamatergic transmission is shifted toward the extrasynaptic site contributing to glutamate excitotoxicity, a phenomenon augmented by increased glutamate release and decreased glutamate uptake. Neuroinflammation in AD is predominantly linked to central players of the innate immune system, with central nervous system (CNS)-resident microglia, astroglia, and perivascular macrophages having been implicated at the cellular level. Several abnormalities have been described regarding the activation of certain steps of the kynurenine (KYN) pathway of tryptophan metabolism in AD. First of all, the activation of indolamine 2,3-dioxygenase, the first and rate limiting step of the pathway, is well-demonstrated. 3-Hydroxy-L-KYN and its metabolite, 3-hydroxy-anthranilic acid have pro-oxidant, antioxidant, and potent immunomodulatory features, giving relevance to their alterations in AD. Another metabolite, quinolinic acid, has been demonstrated to be neurotoxic, promoting glutamate excitotoxicity, reactive oxygen species production, lipid peroxidation, and microglial neuroinflammation, and its abundant presence in AD pathologies has been demonstrated. Finally, the neuroprotective metabolite, kynurenic acid, has been associated with antagonistic effects at glutamate receptors, free radical scavenging, and immunomodulation, giving rise to potential therapeutic implications. This review presents the multiple connections of KYN pathway related alterations to three main domains of AD pathomechanism, such as mitochondrial dysfunction, excitotoxicity, and neuroinflammation, implicating possible therapeutic options. PMID- 29480192 TI - Neuropsychiatric and Cognitive Subtypes among Community-Dwelling Older Persons and the Association with DSM-5 Mild Neurocognitive Disorder: Latent Class Analysis. AB - BACKGROUND: Neuropsychiatric symptoms (NPS) have been shown to increase the risk of neurocognitive disorders (NCD), leading to the recently-published criteria of mild behavioral impairment (MBI) to identify pre-dementia using NPS alone. However, MBI drew concerns about over-diagnosing subclinical psychiatric disorders. OBJECTIVE: We hypothesized that the specificity of NPS in predicting NCD may be improved by considering NPS together with various domains of cognitive deficits. We tested this hypothesis by identifying subtypes based on the combination of NPS and cognitive deficits among community-dwelling older persons, and evaluating how the identified subtypes were associated with mild NCD. METHODS: Our participants were from a community-based cohort study. They completed assessments such as Geriatric Depression Scale (GDS), Geriatric Anxiety Inventory (GAI), and Montreal Cognitive Assessment (MoCA). Those with possible cognitive impairment underwent further evaluations for mild NCD. Latent class analysis was conducted using GDS, GAI, and MoCA domains. Logistic regression was performed to investigate the association between the latent-classes and mild NCD. RESULTS: We included 825 participants, and identified four distinct subtypes: Subtype 1 (no NPS or cognitive deficits), Subtype 2 (NPS alone), Subtype 3 (cognitive deficits alone), and Subtype 4 (both NPS and cognitive deficits). Subtype 1 and 2 had low risk of prevalent mild NCD (OR 0.92- 1.00), while Subtype 3 conferred a moderate risk (OR 4.47- 4.85) and Subtype 4 had the highest risk (OR 7.95- 8.63). CONCLUSION: We demonstrated the benefits of combining NPS and cognitive deficits to predict those at highest risk of prevalent mild NCD. Our findings highlighted the relevance of subclinical psychiatric symptoms in predicting NCD, and indirectly supported the need for longer durations of NPS to improve its specificity. PMID- 29480189 TI - A Network of Genetic Effects on Non-Demented Cognitive Aging: Alzheimer's Genetic Risk (CLU + CR1 + PICALM) Intensifies Cognitive Aging Genetic Risk (COMT + BDNF) Selectively for APOEE4 Carriers. AB - BACKGROUND: Trajectories of complex neurocognitive phenotypes in preclinical aging may be produced differentially through selective and interactive combinations of genetic risk. OBJECTIVE: We organize three possible combinations into a "network" of genetic risk indices derived from polymorphisms associated with normal and impaired cognitive aging, as well as Alzheimer's disease (AD). Specifically, we assemble and examine three genetic clusters relevant to non demented cognitive trajectories: 1) Apolipoprotein E (APOE), 2) a Cognitive Aging Genetic Risk Score (CA-GRS; Catechol-O-methyltransferase + Brain-derived neurotrophic factor), and 3) an AD-Genetic Risk Score (AD-GRS; Clusterin + Complement receptor 1 + Phosphatidylinositol-binding clathrin assembly protein). METHOD: We use an accelerated longitudinal design (n = 634; age range = 55-95 years) to test whether AD-GRS (low versus high) moderates the effect of increasing CA-GRS risk on executive function (EF) performance and change as stratified by APOE status (E4+ versus E4-). RESULTS: APOEE4 carriers with high AD GRS had poorer EF performance at the centering age (75 years) and steeper 9-year decline with increasing CA-GRS but this association was not present in APOEE4 carriers with low AD-GRS. CONCLUSIONS: APOEE4 carriers with high AD-GRS are at elevated risk of cognitive decline when they also possess higher CA-GRS risk. Genetic risk from both common cognitive aging and AD-related indices may interact in intensification networks to differentially predict (1) level and trajectories of EF decline and (2) potential selective vulnerability for transitions into impairment and dementia. PMID- 29480193 TI - Pramlintide: The Effects of a Single Drug Injection on Blood Phosphatidylcholine Profile for Alzheimer's Disease. AB - Studies suggest that a single injection of pramlintide, an amylin analog, induces changes in Alzheimer's disease (AD) biomarkers in the blood of AD mouse models and AD patients. The aim of this study was to examine whether a pramlintide challenge combined with a phosphatidylcholine (PC) profile diagnoses of AD and mild cognitive impairment (MCI) better than PC alone. Non-diabetic subjects with cognitive status were administered a single subcutaneous injection of 60 mcg of pramlintide under fasting condition. A total of 71 PCs, amyloid-beta peptide (Abeta), and total tau (t-tau) in plasma at different time points were measured and treated as individual variables. A single injection of pramlintide altered the levels of 7 PCs in the blood, while a pramlintide injection plus food modulated the levels of 10 PCs in the blood (p < 0.05). The levels of 2 PCs in MCI and 12 PCs in AD in the pramlintide challenge were significantly lower than the ones in controls. We found that while some PCs were associated with only Abeta levels, other PCs were associated with both Abeta and t-tau levels. A receiver operating characteristic analysis of the PCs was combined with the Abeta and t-tau data to produce an area under the curve predictive value of 0.9799 between MCI subjects and controls, 0.9794 between AD subjects and controls, and 0.9490 between AD and MCI subjects. A combination of AD biomarkers and a group of PCs post a pramlintide challenge may provide a valuable diagnostic and prognostic test for AD and MCI. PMID- 29480194 TI - Development of a High-Sensitivity Method for the Measurement of Human Nasal Abeta42, Tau, and Phosphorylated Tau. AB - Cost-effective and feasible methods for early diagnosis of Alzheimer's disease (AD) are needed. We present two methods to measure AD-related biomarkers simultaneously from one nasal smear for the purpose of diagnosing AD. Japanese men and women aged 63-85 years old were recruited in 2015-2016 for this case control study. A total of 25 AD cases and 25 controls (22 men and 28 women) participated in this research. Nasal smears were collected from the common nasal meatus, inferior concha, middle nasal meatus, and olfactory cleft, and the proteins in the samples were analyzed by two methods, which we named PGD (Pre treatment with guanidine- n-Dodecyl-beta-D-maltoside solution) method 1 (PGD-I) and 2 (PGD-II). The PGD-I method measured total tau and amyloid-beta (Abeta)42, but no differences in median levels of total tau and Abeta42 between AD cases and controls were found in any of the nasal locations. The PGD-II method measured Abeta42, total tau, and phosphorylated tau, but levels of Abeta40 in all nasal locations of both groups were near zero. Median levels of phosphorylated tau to total tau (p-tau/t-tau) ratios in the middle nasal meatus and in the olfactory cleft were significantly higher in AD cases than in controls, and could significantly predict AD. To assess diagnostic reliability, areas under the ROC curve were 0.74 (95% CL = 0.52-0.95, p = 0.030) for the middle nasal meatus and 0.72 (95% CL = 0.52-0.92, p = 0.029) for the olfactory cleft. Thus, PGD-I and PGD II can detect AD-related biomarkers in nasal smears and PGD-II may be a useful tool for diagnosing AD. PMID- 29480195 TI - Albuminuria and Microalbuminuria as Predictors of Cognitive Performance in a General Population: An 11-Year Follow-Up Study. AB - Microalbuminuria, defined as urine albumin-to-creatinine ratio (UACR)>3.0 mg/mmol and <= 30 mg/mmol, is an early marker of endothelial damage of the renal glomeruli. Recent research suggests an association among microalbuminuria, albuminuria (UACR > 3.0 mg/mmol), and cognitive impairment. Previous studies on microalbuminuria, albuminuria, and cognition in the middle-aged have not provided repeated cognitive testing at different time-points. We hypothesized that albuminuria (micro- plus macroalbuminuria) and microalbuminuria would predict cognitive decline independently of previously reported risk factors for cognitive decline, including cardiovascular risk factors. In addition, we hypothesized that UACR levels even below the cut-off for microalbuminuria might be associated with cognitive functioning. These hypotheses were tested in the Finnish nationwide, population-based Health 2000 Survey (n = 5,921, mean age 52.6, 55.0% women), and its follow-up, Health 2011 (n = 3,687, mean age at baseline 49.3, 55.6% women). Linear regression analysis was used to determine the associations between measures of albuminuria and cognitive performance. Cognitive functions were assessed with verbal fluency, word-list learning, word-list delayed recall (at baseline and at follow-up), and with simple and visual choice reaction time tests (at baseline only). Here, we show that micro- plus macroalbuminuria associated with poorer word-list learning and a slower reaction time at baseline, with poorer word-list learning at follow-up, and with a steeper decline in word-list learning during 11 years after multivariate adjustments. Also, higher continuous UACR consistently associated with poorer verbal fluency at levels below microalbuminuria. These results suggest that UACR might have value in evaluating the risk for cognitive decline. PMID- 29480196 TI - Roles of Mitochondrial 17beta-Hydroxysteroid Dehydrogenase Type 10 in Alzheimer's Disease. AB - 17beta-Hydroxysteroid dehydrogenase type 10 is a multifunctional, homotetrameric, mitochondrial protein encoded by the HSD17B10 gene at Xp 11.2. This protein, 17beta-HSD10, is overexpressed in brain cells of Alzheimer's disease (AD) patients. It was reported to be involved in AD pathogenesis as the endoplasmic reticulum-associated amyloid-beta binding protein (ERAB) and as amyloid-beta binding alcohol dehydrogenase (ABAD). However, the exaggerated catalytic efficiencies for ERAB/ABAD in these reports necessitated the re-characterization of the catalytic functions of this brain enzyme. In addition to isoleucine metabolism, 17beta-HSD10 is also responsible for the mitochondrial metabolism of neurosteroids such as 5alpha-androstane-3alpha,17beta-diol and 17beta-estradiol. These neurosteroids are inactivated by the oxidation catalyzed by 17beta-HSD10. Since neurosteroid homeostasis is presumably essential for cognitive function, analysis of the impact of 17beta-HSD10 and its inhibitor, amyloid-beta peptide (Abeta), on the metabolism of neuroactive steroids offers a new approach to AD pathogenesis. PMID- 29480197 TI - Biallelic Loss of Function of SORL1 in an Early Onset Alzheimer's Disease Patient. AB - Heterozygous SORL1 protein truncating variants (PTV) are a strong risk factor for early-onset Alzheimer's disease (EOAD). In case control studies performed at the genome-wide level, PTV definition is usually straightforward. Regarding splice site variants, only those affecting canonical sites are typically included. Some other variants, not annotated as PTV, could, however, affect splicing and hence result in a loss of SORL1 function. We took advantage of the whole exome sequencing data from the 9/484 patients with a previously reported SORL1 PTV in the French EOAD series and searched for a second variant which may affect splicing and eventually result in more than 50% loss of function overall. We found that one patient, known to carry a variant predicted to disrupt the canonical 5' splice site of exon 8, also carried a second novel intronic variant predicted to affect SORL1 splicing of exon 29. Segregation analysis showed that the second variant was located in trans from the known PTV. We performed ex vivo minigene splicing assays and showed that both variants led to the generation of transcripts containing a premature stop codon. This is therefore the first evidence of a human carrying biallelic SORL1 PTV. This patient had a family history of dementia in both maternal and paternal lineages with later ages of onset than the proband himself. However, his 55 years age at onset was in the same ranges as previously published SORL1 heterozygous PTV carriers. This suggests that biallelic loss of SORL1 function is an extremely rare event that was not associated with a dramatically earlier age at onset than heterozygous SORL1 loss-of-function variant carriers, in this single patient. PMID- 29480198 TI - Impact of a Virtual Dementia Experience on Medical and Pharmacy Students' Knowledge and Attitudes Toward People with Dementia: A Controlled Study. AB - BACKGROUND: Clinical practice guidelines for dementia highlight the importance of providing patient-centered care. This can be achieved by improving health professionals' attitudes and knowledge toward people with dementia. OBJECTIVE: Quantitatively evaluate the impact of a virtual dementia experience on medical and pharmacy students' knowledge and attitudes toward people with dementia. METHODS: A non-randomized controlled study from September-October 2016. The intervention group received a 1.5-hour multisensory, virtual simulation of light, sound, color, and visual content to experience the cognitive and perceptual difficulties faced by people with dementia. Controls participated in the standard curriculum only. All students were invited to complete the 20-item Dementia Attitudes Scale (DAS) pre- and post-intervention. RESULTS: A total of 278 students (n = 64 medical, n = 214 pharmacy) were analyzed (n = 80 intervention, n = 198 control). The majority of students were female (n = 184, 66.2%), with an average age of 22.5 years. The intervention improved the DAS total score and subdomains of comfort and knowledge (p < 0.001). CONCLUSION: The intervention had a positive impact on medical and pharmacy students' knowledge and attitudes toward people with dementia. PMID- 29480199 TI - Alterations in the Plasma Levels of Specific Choline Phospholipids in Alzheimer's Disease Mimic Accelerated Aging. AB - Alzheimer's disease (AD) is the most common neurodegenerative disease and of continuously rising prevalence. The identification of easy-to-measure biomarkers capable to assist in the prediction and early diagnosis of AD is currently a main research goal. Lipid metabolites in peripheral blood of human patients have recently gained major attention in this respect. Here, we analyzed plasma of 174 participants (not demented at baseline; mean age: 75.70+/-0.44 years) of the Vienna Transdanube Aging (VITA) study, a longitudinal, population-based birth cohort study, at baseline and after 90 months or at diagnosis of probable AD. We determined the levels of specific choline phospholipids, some of which have been suggested as potential biomarkers for the prediction of AD. Our results show that during normal aging the levels of lysophosphatidylcholine, choline plasmalogen, and lyso-platelet activating factor increase significantly. Notably, we observed similar but more pronounced changes in the group that developed probable AD. Thus, our results imply that, in terms of choline-containing plasma phospholipids, the conversion to AD mimics an accelerated aging process. We conclude that age, even in the comparatively short time frame between 75 and 82.5 years, is a crucial factor in the quest for plasma lipid biomarkers for AD that must be carefully considered in future studies and trials. PMID- 29480201 TI - Generation of a New Tau Knockout (tauDeltaex1) Line Using CRISPR/Cas9 Genome Editing in Mice. AB - Alzheimer's disease and other dementias present with tau pathology. Several mouse lines with knockout of the tau-encoding Mapt gene have been reported, yet findings often differed between lines and sites. Here, we report a new tau knockout strain (tauDeltaex1), generated by CRISPR/Cas9-mediated genome editing of intron -1/exon 1 of Mapt in C57Bl/6J mice. TauDeltaex1 mice had no overt phenotype, but, in line with previous models, they showed a significantly reduced susceptibility to excitotoxic seizures, with normal memory formation in young mice. This new in vivo resource will be made freely available to the research community. PMID- 29480200 TI - Homocysteine and Dementia: An International Consensus Statement. AB - Identification of modifiable risk factors provides a crucial approach to the prevention of dementia. Nutritional or nutrient-dependent risk factors are especially important because dietary modifications or use of dietary supplements may lower the risk factor level. One such risk factor is a raised concentration of the biomarker plasma total homocysteine, which reflects the functional status of three B vitamins (folate, vitamins B12, B6). A group of experts reviewed literature evidence from the last 20 years. We here present a Consensus Statement, based on the Bradford Hill criteria, and conclude that elevated plasma total homocysteine is a modifiable risk factor for development of cognitive decline, dementia, and Alzheimer's disease in older persons. In a variety of clinical studies, the relative risk of dementia in elderly people for moderately raised homocysteine (within the normal range) ranges from 1.15 to 2.5, and the Population Attributable risk ranges from 4.3 to 31%. Intervention trials in elderly with cognitive impairment show that homocysteine-lowering treatment with B vitamins markedly slows the rate of whole and regional brain atrophy and also slows cognitive decline. The findings are consistent with moderately raised plasma total homocysteine (>11 MUmol/L), which is common in the elderly, being one of the causes of age-related cognitive decline and dementia. Thus, the public health significance of raised tHcy in the elderly should not be underestimated, since it is easy, inexpensive, and safe to treat with B vitamins. Further trials are needed to see whether B vitamin treatment will slow, or prevent, conversion to dementia in people at risk of cognitive decline or dementia. PMID- 29480202 TI - Real World Recruiting of Older Subjects with Mild Cognitive Impairment for Exercise Trials: Community Readiness is Pivotal. AB - Prevention trials in subjects with mild cognitive impairment (MCI), especially lifestyle interventions, can be difficult to carry out, particularly the recruitment and retention of subjects. We experienced these challenges in our multi-site one-year exercise trial in MCI, NeuroExercise. Trial recruitment rates differed significantly across sites; the non-medical sport university site, providing free access to a range of group exercise in a sports environment, proved far more successful than memory clinics linked to hospitals. This suggests that non-medical settings and a non-medical research community facilitating physical activities may be important factors in recruitment of subjects with MCI for large prevention trials. PMID- 29480203 TI - Cognitively Healthy Individuals Want to Know Their Risk for Alzheimer's Disease: What Should We Do? AB - Richard Milne and colleagues (2018) present the results of a study to discover what cognitively unimpaired research participants hope to gain by learning Alzheimer's disease (AD) biomarker results and the associated risk for AD dementia. Their results are useful to develop procedures to safely disclose AD biomarker results in prevention trials. They also foreshadow the ethical and pragmatic challenges of using AD biomarkers in routine clinical practice. What is currently known is largely from studies of cognitively unimpaired or mildly impaired individuals who learned they had genetic markers of AD. Little is known about learning biomarker results. Milne and colleagues found that participants expect they will routinely learn risk reduction strategies and have access to follow up care. Can we meet these expectations? Mixed evidence supports effective therapies for delaying symptoms of AD and virtually nonexistent evidence guides prevention of AD. Healthcare resources, including follow-up, are designed to manage patients who have clinical symptoms-not the potentially large numbers of unimpaired individuals. To meet these needs, researchers who disclose AD biomarker results to cognitively unimpaired research participants may have an obligation to develop effective interventions and provide follow up care. PMID- 29480204 TI - Early Neurodegeneration in R6/2 Mice Carrying the Huntington's Disease Mutation with a Super-Expanded CAG Repeat, Despite Normal Lifespan. AB - The threshold of CAG repeat expansion in the HTT gene that causes HD is 36 CAG repeats, although 'superlong' expansions are found in individual neurons in postmortem brains. Previously, we showed that, compared to mice with <250 CAG repeats, onset of disease in R6/2 mice carrying superlong (>440) CAG repeat expansions was delayed, and disease progression was slower. Inclusion pathology also differed from 250 CAG repeat mice, being dominated by a novel kind of extranuclear neuronal inclusion (nENNI) that resembles a class of aggregate seen in patients with the adult onset form of HD. Here, we characterised neuropathology in R6/2 mice with >400 CAG repeats using light and electron microscopy. nENNIs were found with increased frequency and wider distribution with age. Some nENNIs appear to 'mature' as the disease develops, developing a multi-layered cored structure. Mice with superlong CAG repeats do not develop clinical signs until they are around 30-40 weeks of age, and they attain a normal life span (>2 years). Nevertheless, they show brain atrophy and unequivocal neuron loss from the striatum and cortex by 22 weeks of age, an age at which similar pathology is seen in 250 CAG repeat mice. Since this time-point is 'end stage' for a 250 CAG mouse, but very far (at least 18 months) from end stage for a > 440 CAG repeat mouse, our data confirm that the appearance of clinical signs, the formation of inclusions, and neurodegeneration are processes that progress independently. A better understanding of the relationship between CAG repeat length, neurodegenerative pathways, and clinical behavioural signs is essential, if we are to find strategies to delay or reverse the course of this disease. PMID- 29480205 TI - Inhibition of TRPC1-Dependent Store-Operated Calcium Entry Improves Synaptic Stability and Motor Performance in a Mouse Model of Huntington's Disease. AB - BACKGROUND: Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. We previously discovered that mutant Huntingtin sensitizes type 1 inositol 1,4,5-trisphosphate receptor (InsP3R1) to InsP3. This causes calcium leakage from the endoplasmic reticulum (ER) and a compensatory increase in neuronal store-operated calcium (nSOC) entry. We previously demonstrated that supranormal nSOC leads to synaptic loss in striatal medium spiny neurons (MSNs) in YAC128 HD mice. OBJECTIVE: We sought to identify calcium channels supporting supranormal nSOC in HD MSNs and to validate these channels as potential therapeutic targets for HD. METHODS: Cortico striatal cultures were established from wild type and YAC128 HD mice and the density of MSN spines was quantified. The expression of candidate nSOC components was suppressed by RNAi knockdown and by CRISPR/Cas9 knockout. TRPC1 knockout mice were crossed with YAC128 HD mice for evaluation of motor performance in a beamwalk assay. RESULTS: RNAi-mediated knockdown of TRPC1, TRPC6, Orai1, or Orai2, but not other TRPC isoforms or Orai3, rescued the density of YAC128 MSN spines. Knockdown of stromal interaction molecule 1 (STIM1), an ER calcium sensor and nSOC activator, also rescued YAC128 MSN spines. Knockdown of the same targets suppressed supranormal nSOC in YAC128 MSN spines. These channel subunits co immunoprecipitated with STIM1 and STIM2 in synaptosomal lysates from mouse striata. Crossing YAC128 mice with TRPC1 knockout mice improved motor performance and rescued MSN spines in vitro and in vivo, indicating that inhibition of TRPC1 may serve as a neuroprotective strategy for HD treatment. CONCLUSIONS: TRPC1 channels constitute a potential therapeutic target for treatment of HD. PMID- 29480207 TI - Age at Death and Causes of Death in Patients with Huntington Disease in Norway in 1986-2015. AB - BACKGROUND: The literature offers discrepant findings regarding age at death in individuals with Huntington disease (HD). OBJECTIVE: To study the age at death and causes of death in males and females with a diagnosis of HD in Norway. METHODS: Registry study of deaths in 1986-2015 using data from two national registries: the Norwegian Cause of Death Registry (NCDR) and the registry of the Centre for Rare Disorders (CRD), Oslo University Hospital. RESULTS: Mean age at death for individuals with HD was found to be 63.9 years (NCDR) and 61.7 years (CRD), compared to a mean of 76.9 years in the general population (NCDR). There were no significant gender differences for age at death in individuals with HD. The significant increase in age at death within the general population from 1986 to 2015 was not observed in individuals with HD. In 73.5% of individuals with HD, the underlying cause of death was HD, followed by cardiovascular diseases, cancer and respiratory diseases. The most common immediate cause of death was respiratory diseases (44.2%). Suicide was a more common cause of death in the population with HD (2.3%) compared to the general population (1.3%). CONCLUSION: The age at death of individuals with HD was stable over a period of 30 years and 13.3 years lower than in the general population. Longer life expectancy for females from the general population was not found in females with HD. Suicide was more common among individuals with HD compared to the general population. PMID- 29480208 TI - A Genetic Study of Psychosis in Huntington's Disease: Evidence for the Involvement of Glutamate Signaling Pathways. AB - BACKGROUND: Psychotic symptoms of delusions and hallucinations occur in about 5% of persons with Huntington's disease (HD). The mechanisms underlying these occurrences are unknown, but the same symptoms also occur in schizophrenia, and thus genetic risk factors for schizophrenia may be relevant to the development of psychosis in HD. OBJECTIVE: To investigate the possible role of genes associated with schizophrenia in the occurrence of psychotic symptoms in HD. METHODS: DNA from subjects with HD and psychosis (HD+P; n = 47), subjects with HD and no psychosis (HD-P; n = 126), and controls (CTLs; n = 207) was genotyped using the Infinium PsychArray-24 v1.1 BeadChip. The allele frequencies of single-nucleotide polymorphisms (SNPs) that were previously associated with schizophrenia and related psychiatric disorders were compared between these groups. RESULTS: Of the 30 candidate genes tested, 10 showed an association with psychosis in HD. The majority of these genes, including CTNNA2, DRD2, ERBB4, GRID2, GRIK4, GRM1, NRG1, PCNT, RELN, and SLC1A2, demonstrate network interactions related to glutamate signaling. CONCLUSIONS: This study suggests genetic associations between several previously identified candidate genes for schizophrenia and the occurrence of psychotic symptoms in HD. These data support the potential role of genes related to glutamate signaling in HD psychosis. PMID- 29480206 TI - Pridopidine: Overview of Pharmacology and Rationale for its Use in Huntington's Disease. AB - Despite advances in understanding the pathophysiology of Huntington's disease (HD), there are currently no effective pharmacological agents available to treat core symptoms or to stop or prevent the progression of this hereditary neurodegenerative disorder. Pridopidine, a novel small molecule compound, has demonstrated potential for both symptomatic treatment and disease modifying effects in HD. While pridopidine failed to achieve its primary efficacy outcomes (Modified motor score) in two trials (MermaiHD and HART) there were consistent effects on secondary outcomes (TMS). In the most recent study (PrideHD) pridiopidine did not differ from placebo on TMS, possibly due to a large enduring placebo effect.This review describes the process, based on in vivo systems response profiling, by which pridopidine was discovered and discusses its pharmacological profile, aiming to provide a model for the system-level effects, and a rationale for the use of pridopidine in patients affected by HD. Considering the effects on brain neurochemistry, gene expression and behaviour in vivo, pridopidine displays a unique effect profile. A hallmark feature in the behavioural pharmacology of pridopidine is its state-dependent inhibition or activation of dopamine-dependent psychomotor functions. Such effects are paralleled by strengthening of synaptic connectivity in cortico-striatal pathways suggesting pridopidine has potential to modify phenotypic expression as well as progression of HD. The preclinical pharmacological profile is discussed with respect to the clinical results for pridopidine, and proposals are made for further investigation, including preclinical and clinical studies addressing disease progression and effects at different stages of HD. PMID- 29480210 TI - Huntington's Disease Clinical Trials Corner: February 2018 AB - In the second edition of the Huntington's Disease Clinical Trials Corner we list all currently registered and ongoing clinical trials, summarise the top-line results of the recently-announced IONIS-HTTRX trial (NCT02519036), expand on Wave Life Sciences' PRECISION-HD1 (NCT03225833) and PRECISION-HD2 (NCT03225846), and cover one recently finished trial: the FIRST-HD deutetrabenazine trial (NCT01795859). PMID- 29480209 TI - HttQ111/+ Huntington's Disease Knock-in Mice Exhibit Brain Region-Specific Morphological Changes and Synaptic Dysfunction. AB - BACKGROUND: Successful disease-modifying therapy for Huntington's disease (HD) will require therapeutic intervention early in the pathogenic process. Achieving this goal requires identifying phenotypes that are proximal to the HTT CAG repeat expansion. OBJECTIVE: To use Htt CAG knock-in mice, precise genetic replicas of the HTT mutation in patients, as models to study proximal disease events. METHODS: Using cohorts of B6J.HttQ111/+ mice from 2 to 18 months of age, we analyzed pathological markers, including immunohistochemistry, brain regional volumes and cortical thickness, CAG instability, electron microscopy of striatal synapses, and acute slice electrophysiology to record glutamatergic transmission at striatal synapses. We also incorporated a diet perturbation paradigm for some of these analyses. RESULTS: B6J.HttQ111/+ mice did not exhibit significant neurodegeneration or gliosis but revealed decreased striatal DARPP-32 as well as subtle but regional-specific changes in brain volumes and cortical thickness that parallel those in HD patients. Ultrastructural analyses of the striatum showed reduced synapse density, increased postsynaptic density thickness and increased synaptic cleft width. Acute slice electrophysiology showed alterations in spontaneous AMPA receptor-mediated postsynaptic currents, evoked NMDA receptor mediated excitatory postsynaptic currents, and elevated extrasynaptic NMDA currents. Diet influenced cortical thickness, but did not impact somatic CAG expansion, nor did it show any significant interaction with genotype on immunohistochemical, brain volume or cortical thickness measures. CONCLUSIONS: These data show that a single HttQ111 allele is sufficient to elicit brain region specific morphological changes and early neuronal dysfunction, highlighting an insidious disease process already apparent in the first few months of life. PMID- 29480212 TI - What is the Fracture Risk in Patients at a Multidisciplinary Neuromuscular Clinic? AB - Many neuromuscular diseases (NMD) result in muscle weakness, immobility and greater fracture risk. The objective of this study is to determine the fracture risk of adult patients at a multidisciplinary NMD clinic. Fracture risk was calculated using the Fracture Risk Assessment Tool, the presence of osteoporosis was quantified using bone densitometry and contributing co-morbidities were screened through serum markers. Of the 36 patients studied, 47% were found to be of moderate and high fracture risk. Two thirds of these patients had not been previously screened or treated for osteoporosis. These findings suggest that NMD patients warrant routine screening for osteoporosis and early treatment to reduce fragility fracture. PMID- 29480213 TI - NINDS Common Data Elements for Congenital Muscular Dystrophy Clinical Research: A National Institute for Neurological Disorders and Stroke Project. AB - BACKGROUND: A Congenital Muscular Dystrophy (CMD) Working Group (WG) consisting of international experts reviewed common data elements (CDEs) previously developed for other neuromuscular diseases (NMDs) and made recommendations for all types of studies on CMD. OBJECTIVES: To develop a comprehensive set of CDEs, data definitions, case report forms and guidelines for use in CMD clinical research to facilitate interoperability of data collection, as part of the CDE project at the National Institute of Neurological Disorders and Stroke (NINDS). METHODS: One working group composed of ten experts reviewed existing NINDS CDEs and outcome measures, evaluated the need for new elements, and provided recommendations for CMD clinical research. The recommendations were compiled, internally reviewed by the CMD working group, and posted online for external public comment. The CMD working group and the NIH CDE team reviewed the final version before release. RESULTS: The NINDS CMD CDEs and supporting documents are publicly available on the NINDS CDE website (https://www.commondataelements.ninds.nih.gov/CMD.aspx#tab=Data_Standards). Content areas include demographics, social status, health history, physical examination, diagnostic tests, and guidelines for a variety of specific outcomes and endpoints. The CMD CDE WG selected these documents from existing versions that were generated by other disease area working groups. Some documents were tailored to maximize their suitability for the CMD field. CONCLUSIONS: Widespread use of CDEs can facilitate CMD clinical research and trial design, data sharing and retrospective analyses. The CDEs that are most relevant to CMD research are like those generated for other NMDs, and CDE documents tailored to CMD are now available to the public. The existence of a single source for these documents facilitates their use in research studies and offers a clear mechanism for the discussion and update of the information as knowledge is gained. PMID- 29480214 TI - Muscle Cells Fix Breaches by Orchestrating a Membrane Repair Ballet. AB - Skeletal muscle undergoes many micro-membrane lesions at physiological state. Based on their sizes and magnitude these lesions are repaired via different complexes on a specific spatio-temporal manner. One of the major repair complex is a dysferlin-dependent mechanism. Accordingly, mutations in the DYSF gene encoding dysferlin results in the development of several muscle pathologies called dysferlinopathies, where abnormalities of the membrane repair process have been characterized in patients and animal models. Recent efforts have been deployed to decipher the function of dysferlin, they shed light on its direct implication in sarcolemma resealing after injuries. These discoveries served as a strong ground to design therapeutic approaches for dysferlin-deficient patients. This review detailed the different partners and function of dysferlin and positions the sarcolemma repair in normal and pathological conditions. PMID- 29480215 TI - Mutation Spectrum of GNE Myopathy in the Indian Sub-Continent. AB - BACKGROUND: GNE myopathy is an adult onset recessive genetic disorder that affects distal muscles sparing the quadriceps. GNE gene mutations have been identified in GNE myopathy patients all over the world. Homozygosity is a common feature in GNE myopathy patients worldwide. OBJECTIVES: The major objective of this study was to investigate the mutation spectrum of GNE myopathy in India in relation to the population diversity in the country. MATERIALS AND METHODS: We have collated GNE mutation data of Indian GNE myopathy patients from published literature and from recently identified patients. We also used data of people of Indian subcontinent from 1000 genomes database, South Asian Genome database and Strand Life Science database to determine frequency of GNE mutations in the general population. RESULTS: A total of 67 GNE myopathy patients were studied, of whom 21% were homozygous for GNE variants, while the rest were compound heterozygous. Thirty-five different mutations in the GNE gene were recorded, of which 5 have not been reported earlier. The most frequent mutation was p.Val727Met (65%) found mainly in the heterozygous form. Another mutation, p.Ile618Thr was also common (16%) but was found mainly in patients from Rajasthan, while p.Val727Met was more widely distributed. The latter was also seen at a high frequency in general population of Indian subcontinent in all the databases. It was also present in Thailand but was absent in general population elsewhere in the world. CONCLUSION: p.Val727Met is likely to be a founder mutation of Indian subcontinent. PMID- 29480218 TI - Expanded Diagnostic and Therapeutic Options for Cardiac Disease in Duchenne Muscular Dystrophy. PMID- 29480217 TI - Update on Standard Operating Procedures in Preclinical Research for DMD and SMA Report of TREAT-NMD Alliance Workshop, Schiphol Airport, 26 April 2015, The Netherlands. AB - A workshop took place in 2015 to follow up TREAT-NMD activities dedicated to improving quality in the preclinical phase of drug development for neuromuscular diseases. In particular, this workshop adressed necessary future steps regarding common standard experimental protocols and the issue of improving the translatability of preclinical efficacy studies. PMID- 29480216 TI - Anti-HMGCR Myopathy. AB - Anti-HMGCR myopathy was first recognized and characterized in patients with a history of statin exposure and immune-mediated necrotizing myopathy. After the discovery of anti-HMGCR autoantibodies, several international groups identified and characterized more patients, expanding the phenotypic spectrum of this disease to include pediatric patients and young adults without statin exposure and those with a chronic myopathy resembling limb-girdle muscular dystrophy. We provide a summary of clinical findings, pathologic features, muscle imaging, and immunogenetic risk factors of the disease. We also discuss the current treatment strategies and approaches to monitoring the therapeutic response. Lastly, we briefly summarize the current understanding of the pathophysiology of the disease and postulate a model for autoimmunity initiation and propagation in this disease. PMID- 29480219 TI - Actigraphy Detects Greater Intra-Individual Variability During Gait in Non Manifesting LRRK2 Mutation Carriers. AB - BACKGROUND: With recent advances in the search for disease-modifying therapies for Parkinson's disease (PD) the importance of identifying prodromal markers becomes greater. Non-manifesting LRRK2 mutation carriers (NMC) are at risk for developing PD, and provide a population in which to identify possible markers. OBJECTIVE: The aim of this study was to test the hypothesis that NMC have differences in daily activity, fragmentation of sleep, arm swing asymmetry, and movement variability during walking, detectable by actigraphy, as compared to matched control subjects. METHODS: Eleven NMC, fourteen PD patients (4 LRRK2-PD, 10 idiopathic PD (iPD)), and twenty-nine controls wore wristbands containing an accelerometer for seven days, and performed a daily walking task. Outcome measures included daily activity, fragmentation of activity, fragmentation of sleep, arm swing asymmetry during walking, and intra-individual variability. RESULTS: Compared to healthy controls, both NMC and LRRK2/iPD showed higher intra individual variability in activity during walking compared to healthy controls. Individuals with LRRK2-PD/iPD, but not NMC, tend to have lower activity levels, more arm swing asymmetry and less increase of arm swing with transition from slow to faster walking speed compared to healthy controls. CONCLUSION: Higher intra individual variability of gait-associated movements might be a useful biomarker of prodromal PD. These results encourage replication in a larger sample and longitudinal analysis is warranted. PMID- 29480220 TI - Levodopa Effect and Motor Function in Late Stage Parkinson's Disease. AB - BACKGROUND: It is unclear to which degree Levodopa (L-dopa) remains effective also in the late stage of Parkinson's disease (PD) and to which degree motor fluctuations and dyskinesias remain a problem. OBJECTIVE: To assess responsiveness of motor symptomatology to L-dopa in a group of patients with late stage PD. Moreover, to investigate the extent to which motor fluctuations and dyskinesias occur. METHODS: Thirty PD patients in Hoehn and Yahr (HY) stages IV and V in "on" were included. L-dopa responsiveness was assessed with a standardized L-dopa test in the defined "off" and defined "on" states. Motor function was assessed by the Unified PD Rating Scale (UPDRS) III and timed tests. Motor fluctuations and dyskinesias were assessed by the UPDRS IV. The participants were further monitored for 10 days with a mobile movement-analyses system, the Parkinson's Kinetigraph (PKG). The median (q1-q3) L-dopa equivalent daily dose (LEDD) was 799 (536-973) mg. RESULTS: The UPDRS III score improved with >=15% in 15 (50%) and with >=30% in six (20%) participants during the L-dopa test. The median (q1-q3) UPDRS III score in "off" was 46 (37-53) and in "on" 36 (28-46). Twenty-one (70%) of the participants reported either predictable or unpredictable "off" fluctuations (items 36-37). The prevalence of dyskinesias (item 32, duration of dyskinesias >=1) was 47%. The PKG indicated that dyskinesias primarily were mild and that a majority had a pronounced "off" symptomatology, spending a large proportion of the day either asleep or very inactive. CONCLUSIONS: Half of a group of patients with late stage PD had an L dopa response of >=15% on the UPDRS III. According to the UPDRS IV, a majority of the patients had motor fluctuations and about half had dyskinesias, although the PKG results suggested that these were not very severe. PMID- 29480221 TI - Progressive Changes in the Retinal Structure of Patients with Parkinson's Disease. AB - BACKGROUND: Many optical coherence tomography (OCT) studies have reported alterations in the retinal nerve fiber layer (RNFL) in Parkinson's disease (PD) and other neurodegenerative diseases. However, whether retinal alterations are a biomarker for PD is still controversial. OBJECTIVE: To investigate potential correlations between PD and morphological changes in retina using OCT and to determine its usefulness as a biomarker of disease progression in PD. METHODS: We performed a cross-sectional study on patients with PD (N = 37) and age-matched controls (N = 42), followed by a longitudinal study of the PD patients (N = 22) over approximately 2.5 years. RESULTS: The average retinal nerve fiber layer (RNFL) thickness (p < 0.001), total macular thickness (p = 0.001), and macular volume (p = 0.001) were decreased in PD patients compared to controls and had further decreased at the follow-up visit (p < 0.05 for all). The average RNFL thickness and the total thickness of macular were negatively correlated with age in PD patients at baseline. Linear regression analysis revealed that age (p = 0.002, p = 0.003, respectively) and LEDD (p = 0.011, p = 0.013, respectively) were correlated to total thickness and volume of macular in 22 PD patients in the follow-up study. However, no correlation was found between RNFL and other parameters. CONCLUSIONS: PD progression is associated with pronounced retinal structure changes, which can be quantified by OCT. Patterns of RNFL and macular damage detected by the noninvasive technology of OCT can be a useful biomarker for evaluating the progression of PD. PMID- 29480223 TI - Phenotypic Characteristics in GBA-Associated Parkinson's Disease: A Study in a Greek Population. AB - We compared phenotypic characteristics in 35 Greek patients with Parkinson's disease (PD), carriers of GBA1 mutations (GBA-PD), with 35 Genetically Unidentified PD patients (GU-PD). We found a previously reported higher prevalence of cognitive impairment and a little appreciated more frequent bilateral onset of the disease in GBA-PD vs GU-PD. As far as the exposure to environmental factors, linked to PD, is concerned, our study hints to the possibility that pesticide exposure may be more common in GBA-PD patients, and possibly act synergistically with the mutation carrier status to trigger the disease. PMID- 29480222 TI - Physical Activity in Early Parkinson Disease. AB - BACKGROUND: Physical activity and exercise improve outcomes in Parkinson disease (PD), however little is known about activity levels in early PD patients. OBJECTIVE AND METHODS: We examined self-reported activity scores and examined associations with clinical characteristics in 383 PD subjects and 175 healthy controls from the Parkinson Progression Markers Initiative (PPMI). RESULTS: Activity scores were 8% lower for PD subjects than HC (162.6+/-86.2 vs 175.0+/ 78.5, p = 0.10). Higher scores were associated with younger age and male sex. Only 47% of PD subjects and 44% of HC reported activity consistent with standard recommendations for adults. CONCLUSIONS: Our findings highlight the need to encourage exercise even in early PD. PMID- 29480224 TI - Monoaminergic Markers Across the Cognitive Spectrum of Lewy Body Disease. AB - BACKGROUND: Lewy body disorders, including Parkinson's disease (PD), Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB), are characterized by profound central and peripheral monoaminergic dysfunction. OBJECTIVE: To investigate whether these alterations depend on dementia status, we measured cerebrospinal fluid (CSF) and serum monoamine and metabolite levels across subgroups of the cognitive spectrum, and evaluated their marker potential afterwards. METHODS: In total, 153 subjects were included, of which 43 healthy controls (HC), 28 PD patients with normal cognition (PD-NC), 26 patients with PD and mild cognitive impairment (PD-MCI), 18 PDD patients, and 38 DLB patients. The levels of monoamines and metabolites in paired CSF and serum samples were analyzed applying reversed-phase high-performance liquid chromatography with electrochemical detection. RESULTS: Firstly, when comparing subgroups, CSF 3 methoxy-4-hydroxyphenylglycol (MHPG) levels were found lowest in HC and PD-NC groups and significantly higher in PDD/DLB patients. In addition, CSF 5 hydroxyindoleacetic acid (5-HIAA) levels differed significantly between HC and PD MCI/PDD, and DLB patients (P<=0.001), but not between HC and PD-NC patients. Secondly, when performing logistic regression, it was shown that particularly CSF/serum MHPG levels and the serum MHPG to noradrenaline (NA) ratio effectively differentiated between HC and (non-)pooled PD subgroups (AUC = 0.914-0.956), and PDD and DLB patients (AUC = 0.822), respectively. Furthermore, CSF 5-HIAA was the most discriminative parameter to differentiate between PD-NC and PD-MCI (AUC = 0.808), and, PD-NC and PDD subgroups (AUC = 0.916). CONCLUSIONS: Our data revealed that especially alterations of the noradrenergic neurotransmitter system could distinguish between Lewy body disorder subtypes, pinpointing CSF/serum MHPG and NA as potential stage markers across the cognitive spectrum. PMID- 29480227 TI - Effectiveness of a Goal-Based Intensive Rehabilitation in Parkinsonian Patients in Advanced Stages of Disease. AB - BACKGROUND: Parkinsonian patients in advanced stages of disease suffer from many motor and non-motor symptoms, whose responsiveness to dopamine replacement therapy and deep brain stimulation is poor. It is necessary to find complementary strategies in order to improve the clinical conditions of patients in advanced Parkinson's disease (PD) stages. OBJECTIVE: We aimed to understand whether an inpatient, motor-cognitive, multidisciplinary, aerobic, intensive and goal-based rehabilitation treatment (MIRT), specifically designed for PD, is effective for patients in advanced stages of disease. METHODS: 638 Parkinsonian patients, hospitalized to undergo a 4-week MIRT, were retrospectively identified. According to the Hoehn & Yahr (H&Y) scale, 496 were in H&Y stage 3 and 142 in H&Y stage 4 5. Outcome measures included: Unified Parkinson's Disease Rating Scale (UPDRS), Berg Balance Scale (BBS), Timed Up and Go Test (TUG), Six Minute Walk Test (6MWT), and Parkinson's Disease Disability Scale (PDDS). RESULTS: At baseline all measures, except UPDRS IV, significantly worsened passing from H&Y stage 3 to H&Y stage 4-5 (p<=0.002 all). After rehabilitation all outcome measures significantly improved in both groups of patients (p < 0.0001 all). Comparing the amount of improvement in the two groups, significant differences were observed only for the changes in BBS and TUG (both p < 0.0001 after adjustment), with a better improvement in the H&Y stage 4-5 group. CONCLUSIONS: A multidisciplinary, motor cognitive, intensive and goal-based rehabilitation treatment, such as MIRT, could be an effective complementary treatment in PD patients in advanced stages of disease. PMID- 29480226 TI - LRRK2 p.Ile1371Val Mutation in a Case with Neuropathologically Confirmed Multi System Atrophy. AB - BACKGROUND: Mutations in the leucine rich repeat kinase 2 (LRRK2) gene are among the most common genetic causes of Lewy body Parkinson's disease (PD). However, LRRK2 mutations can also lead to a variety of pathological phenotypes other than typical PD, including relatively pure nigrostriatal cell loss without alpha synuclein-positive Lewy bodies or Lewy neurites, progressive supranuclear palsy (PSP), and multiple system atrophy (MSA). The mechanisms behind this remarkable pleomorphic pathology are currently unclear. OBJECTIVE: To genetically and pathologically characterize a case with a LRRK2, p.Ile1371Val rare variant and pathologically proven MSA. METHODS: From the brain donation program at the Parkinson's Institute and Clinical Center, we selected 26 brains with family history and a with clinicopathological diagnosis of PD (n = 20), MSA (n = 4), or PSP (n = 2). We performed neuropathological evaluation, including alpha-synuclein and tau immunohistochemistry and sequenced 188 genes that have been reported as causative for or associated with neurodegenerative diseases. RESULTS: We identified a known LRRK2, p.Ile1371Val genetic variant in a case with clinically diagnosed and pathologically proven MSA. Neuropathology revealed that the olivopontocerebellar system was more affected than the striatonigral system. CONCLUSIONS: Our data suggest that genetic variants in the LRRK2 gene can present clinically and neuropathologically as MSA. One other LRRK2 genetic variant (LRRK2, p.Ile2020Thr) has been reported with a neuropathological diagnosis of MSA. Interestingly, the LRRK2 variant (LRRK2, p.Ile1371Val) identified here has been reported previously in a postmortem case with Lewy body PD.Future studies are critical to discover the mechanisms leading to different neurodegenerative trajectories both in neuronal and glial cell populations. PMID- 29480225 TI - What is Functional Mobility Applied to Parkinson's Disease? AB - Although yet poorly defined and often misused, the concept of functional mobility has been used in research studies as a more global and ecological outcome of patients' health status. Functional mobility is a person's physiological ability to move independently and safely in a variety of environments in order to accomplish functional activities or tasks and to participate in the activities of daily living, at home, work and in the community. Parkinson's disease (PD) has a direct impact on patients' motor control and on mobility in general. Even with optimal medical management, the progression of PD is associated with mounting impairments at different levels of body function, causing marked limitations in a wide variety of activities, as well as a severe disability and loss of autonomy. Despite this, for everyday functioning PD patients need to have a good functional mobility that allow them to get around effortlessly in a reasonable amount of time to access to the same environments as others. This paper reviewed the concept of functional mobility applied to PD. This was done through an International Classification of Functioning and Disability (ICF) perspective. Recommendations to address the known factors that contribute to a poor functional mobility were outlined while suggestions for clinical practice and research were made. PMID- 29480228 TI - Urinary Dysfunctions and Post-Void Residual Urine in Typical and Atypical Parkinson Diseases. AB - BACKGROUND: Urinary dysfunction is relatively common, however, is often underestimated and diagnosed by subjective questionnaires in patients with Parkinsonism. OBJECTIVE: To determine the correlation between subjective urinary dysfunction and post-void residual urine volume in patients with Parkinson's disease (PD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), and to assess the relationship between clinical characteristics and subjective or objective urinary dysfunction. METHODS: A total of 196 patients with de novo Parkinsonism without urological and gynecological disorders were included. For all subjects, data were collected on sonographic post-void residual urine volume and urinary symptoms. All patients were also assessed on motor symptom severity, cognitive and affective measurements, other nonmotor symptoms, 39-item Parkinson's Disease Questionnaire, and renal functions. RESULTS: Seventeen out of 196 parkinsonian patients showed abnormal post-void residual urine volumes, with >=100 ml. The MSA group showed significantly higher post-void residual urine volume compared to the PD and PSP groups. Symptoms of the sense of incomplete emptying, weak urine stream, and nocturia were strongly correlated with post-void residual urine volume. Post-void residual urine volume was positively related to autonomic symptoms, other non-motor symptoms, patient activities of daily living, and negatively related to renal function. CONCLUSION: Increased post-void residual urine volumes were observed in small portion of early drug-naive Parkinsonian patients, especially in MSA. Post-void residual urine volume was significantly related to subjective urinary and other autonomic dysfunctions. Voiding dysfunction is associated with not only end organ damage, but also other nonmotor dysfunctions and patient activities of daily living. PMID- 29480229 TI - Modeling Parkinson's Disease in C. elegans. AB - Parkinson's disease (PD) is an adult onset neurodegenerative disease that is characterized by selective degeneration of neurons primarily in the substantia nigra. At present, the pathogenesis of PD is incompletely understood and there are no neuroprotective treatments available. Accurate animal models of PD provide the opportunity to elucidate disease mechanisms and identify therapeutic targets. This review focuses on C. elegans models of PD, including both genetic and toxicant models. This microscopic worm offers several advantages for the study of PD including ease of genetic manipulation, ability to complete experiments rapidly, low cost, and ability to perform large scale screens for disease modifiers. A number of C. elegans models of PD have been generated including transgenic worms that express alpha-synuclein or LRRK2, and worms with deletions in PRKN/pdr-1, PINK1/pink-1, DJ-1/djr-1.1/djr-1.2 and ATP13A2/catp-6. These worms have been shown to exhibit multiple phenotypic deficits including the loss of dopamine neurons, disruption of dopamine-dependent behaviors, increased sensitivity to stress, age-dependent aggregation, and deficits in movement. As a result, these phenotypes can be used as outcome measures to gain insight into disease pathogenesis and to identify disease modifiers. In this way, C. elegans can be used as an experimental tool to elucidate mechanisms involved in PD and to find novel therapeutic targets that can subsequently be validated in other models. PMID- 29480232 TI - Automated and effective content-based image retrieval for digital mammography. AB - Nowadays, huge number of mammograms has been generated in hospitals for the diagnosis of breast cancer. Content-based image retrieval (CBIR) can contribute more reliable diagnosis by classifying the query mammograms and retrieving similar mammograms already annotated by diagnostic descriptions and treatment results. Since labels, artifacts, and pectoral muscles present in mammograms can bias the retrieval procedures, automated detection and exclusion of these image noise patterns and/or non-breast regions is an essential pre-processing step. In this study, an efficient and automated CBIR system of mammograms was developed and tested. First, the pre-processing steps including automatic labelling artifact suppression, automatic pectoral muscle removal, and image enhancement using the adaptive median filter were applied. Next, pre-processed images were segmented using the co-occurrence thresholds based seeded region growing algorithm. Furthermore, a set of image features including shape, histogram based statistical, Gabor, wavelet, and Gray Level Co-occurrence Matrix (GLCM) features, was computed from the segmented region. In order to select the optimal features, a minimum redundancy maximum relevance (mRMR) feature selection method was then applied. Finally, similar images were retrieved using Euclidean distance similarity measure. The comparative experiments conducted with reference to benchmark mammographic images analysis society (MIAS) database confirmed the effectiveness of the proposed work concerning average precision of 72% and 61.30% for normal & abnormal classes of mammograms, respectively. PMID- 29480230 TI - Cardiovascular Risk Factor Burden in Veterans and Non-Veterans with Parkinson Disease. AB - BACKGROUND: Medical comorbidities, including cardiovascular risk factors such as hypertension and diabetes, influence disease progression in Parkinson disease (PD) and may be variably present in different clinical populations. OBJECTIVE/METHODS: We conducted a retrospective nested case-control study of 29 Veterans with PD and 29 non-Veteran PD controls. The groups were matched for age, gender, and disease duration. Both groups underwent clinical and imaging testing as part of their participation in a larger cross-sectional PD observational study at our research center. Veterans were recruited primarily from movement disorders neurology clinics at the Ann Arbor Veterans Affairs (VA) Health System. Non Veterans were recruited primarily from analogous clinics at the University of Michigan Health System. We explored differences in cardiovascular risks factor burden between the groups. RESULTS: Veterans with PD showed higher scores on the simplified Framingham 10-year general cardiovascular disease risk calculator (FR score; 27.3% (11.5) vs. 20.7% (6.8); t = -2.66, p = 0.011) and fewer years of self-reported education (14.5 (2.5) vs. 16.7 (2.6); t = 3.33, p = 0.002). After adjusting for age, disease duration, education, and the use of antihypertensive medications, Veterans showed higher FR scores (t = 2.95, p = 0.005) and a higher intra-subject ratio of FR score to age-and-gender normalized FR score (t = 2.49, p = 0.016), representing an elevated component of modifiable cardiovascular risk factor burden. CONCLUSION: Cardiovascular comorbidities are common in Veterans with PD and may be more severe than in non-Veteran PD populations. These findings merit replication in other representative cohorts. Veterans may be a preferred population for clinical trials evaluating cardiovascular risk factor management on PD progression. PMID- 29480233 TI - 3D reconstruction images of cone beam computed tomography applied to maxillofacial fractures: A case study and mini review. AB - Maxillofacial injuries can be complex and are clinically important due to their functional and cosmetic significance. Maltreated and missed fractures might cause deformity of the face; thus, accurate evaluation of the fracture provided by X ray images is critical. In this study, we explore the application of cone-beam computed tomography (CBCT) for diagnosis of severe maxillofacial traumas. A patient with a complex fracture that affects the maxilla, mandible, wall of the maxillary sinus, zygoma, zygomatic arch and nasal bone was diagnosed using 3D reconstruction of CBCT images. This diagnostic approach provides detailed information obtained by static images and a systematic model with unique advantages for the following pre-surgical evaluation, surgical treatment and prognostic assessment of complex maxillofacial fractures. PMID- 29480231 TI - Alpha-Synuclein Glycation and the Action of Anti-Diabetic Agents in Parkinson's Disease. AB - Parkinson's disease (PD) is a neurodegenerative disorder with complex etiology and variable pathology. While a subset of cases is associated with single-gene mutations, the majority originates from a combination of factors we do not fully understand. Thus, understanding the underlying causes of PD is indispensable for the development of novel therapeutics. Glycation, the non-enzymatic reaction between reactive dicarbonyls and amino groups, gives rise to a variety of different reaction products known as advanced glycation end products (AGEs). AGEs accumulate over a proteins life-time, and increased levels of glycation reaction products play a role in diabetic complications. It is now also becoming evident that PD patients also display perturbed sugar metabolism and protein glycation, including that of alpha-synuclein, a key player in PD. Here, we hypothesize that anti-diabetic drugs targeting the levels of glycation precursors, or promoting the clearance of glycated proteins may also prove beneficial for PD patients. PMID- 29480234 TI - Computed tomography angiography with 3D reconstruction in diagnosis of hydronephrosis cause by aberrant renal vessel: A case report and mini review. AB - BACKGROUND: Congenital hydronephrosis is often caused by aberrant renal vessel and it is difficult to be diagnosed and treated at the early stage due to lack of the significant symptoms. Although current medical diagnosis tools are widely used, the aberrant renal vessel cannot be displayed very well in the images. OBJECTIVE: To investigate whether applying computed tomography (CT) angiography with 3D reconstruction can improve efficacy in diagnose of this congenital hydronephrosis. MATERIALS AND METHODS: A male patient of 18 years old was diagnosed as hydronephrosis of left kidney. A CT angiography with 3D reconstruction was evaluated in diagnosis of the prenatal hydronephrosis compared to ultrasound (US) and intravenous urogram (IVU). RESULTS: US and IVU images were able to display the dilation of left pelvic and the dilated calyces, and the thinner of renal parenchyma on the left kidney (Grade II-IV), but failed to detect the causing of hydro-nephrosis. CT angiography with 3D reconstruction provided accurate images of the dilated renal pelvic, upper segment of the ureter, and an aberrant vessel bundle overcrossing at the left renal pelvic ureter junction as well. The aberrant vessel could be revealed during surgery. CONCLUSIONS: A CT angiography with 3D reconstruction provides a more accurate diagnostic approach for the congenital hydronephrosis caused by aberrant renal vessel. Thus, it can offer surgeons very important information in the pre-surgery planning. PMID- 29480235 TI - 3D cone beam computed tomography reconstruction images in diagnosis of ameloblastomas of lower jaw: A case report and mini review. AB - Cone beam computed tomography (CBCT) has obvious advantages over regular radiography in diagnosis of complex diseases. Objective of this study is to report a case of a mandibular jaw ameloblastoma recurring cyst, which represents a benign tumor of odontogenic epithelium, using CBCT imaging technology. CBCT examination of the patient suffering with recurrent lower jaw cyst (relapsing four years after surgery) showed a decrease in irregular bone density and appearance of a honeycomb pattern (3.5 cm*2.5 cm*1.8 cm) in the right lower jaw. This suggests that the lesion is more likely to be an ameloblastoma. Preoperative tissue biopsy and pathological examination of surgical sample confirmed the diagnosis. Surgical resection of the diseased tissue and autogenous bone grafting in the mandible was performed. Postoperative CBCT examination showed that the bone defect healed well, without recurrence of the tumor 22 months postoperatively. In conclusion, the rotated 3D CBCT images clearly displays the exact size, location, borders and internal changes of the tumor in the jaw cyst itself and the adjacent tissues. Thus, the dental CBCT allows clinicians to better evaluate lesions, leading to better treatment outcomes. PMID- 29480236 TI - A case report of Rosai-Dorfman disease with kidney involvement. AB - Rosai-Dorfman disease (RDD) is a rare histiocytic disorder of unclear etiology, which commonly presented with the enlargement of lymph nodes of the neck and the head. Here, we report an unusual case of 77-year-old male patient presenting with left kidney lesion with several small enlarged lymph nodes around the abdominal aorta. The diagnosis of left kidney cancer was suspected and the patient underwent left laparoscopic exploration and lymph node biopsy. Only saponification of the renal surrounding fat and enlargement of the left renal pedicle and 5 abdominal aortic lymph nodes were found; no kidney cancer was found. Surrenalectomy and lymphadenectomy dissection were then performed and the left kidney was retained. Intraoperative frozen and postoperative pathology indicates Rosai-Dorfman disease. RDD with kidney involvement is uncommon, and its x-ray imaging appearances are atypical, and often resemble kidney cancer leading to kidney loss. A systematic literature review was also performed to investigate the x-ray imaging and treatment features of this disease. PMID- 29480237 TI - 3D computed tomography angiography as a novel post-processing approach in diagnosis of pediatric malignant bone tumors. AB - OBJECTIVE: This study aimed to investigate the application of 3D computed tomography (CT) angiography with a novel post-processing technique in diagnosis of malignant bone tumors in children. METHODS: Twenty-seven pediatric patients (15 males and 12 females; average age: 10+/-3.4 years old, with a range from 2 months to 14 years old) with suspected bone tumors were evaluated histopathologically using 3D CT angiography and a multislice scanner. CT angiography image data were analyzed with a novel post-processing technique that included separating, fusing opacifying false-coloring, and volume rendering. RESULTS: Among 27 cases, 20 (74%) osteosarcoma, 6 (22%) Ewing's sarcoma, and 1 (4%) non-Hodgkin lymohoma were diagnosed by histological examination of surgical specimens. The tumor features, including size, location, invasion into the adjacent tissue as well as distant metastases, were clearly visualized with the regular volume rendering method and rotational and stereoscopical videos. The post-processing technique provided the reconstructed structure images without any overlap or shelter independently and collectively. Special colors represented different tissue structures, aiding in identification of various anatomical structures and pre-surgical planning. CONCLUSIONS: Compared to traditional 3-D CT methods, 3-D CT angiography with rotational and stereoscopical videos provides more detailed information of bone tumor lesions. It offers a superior and effective imaging technique in pediatric patients with malignant bone tumors. PMID- 29480238 TI - Diagnosis of lymphoepithelial carcinoma in parotid gland with three dimensional computed tomography angiography reconstruction: A case report. AB - Lymphoepithelial carcinoma (LEC) is an uncommon malignant neoplasm. Due to the complicated anatomical structure of the human head, standard imaging modalities including ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI) scan remain limited in detection of salivary tumors. We used three dimensional computed tomography angiography (3D-CT angiography) for the assessment and pre-operative surgical planning of facial fractures of a case with LEC. The study results demonstrated that 3D-CT angiography provided an insightful approach to preoperative evaluation in the treatment of salivary tumors. PMID- 29480239 TI - Three-dimensional computed tomography reconstructive diagnosis of snakebite induced cerebral infarction. AB - Despite common injury caused by snakebite, snakebite-induced ischemic stroke is rare. We reported on a patient who incurred a large cerebral infarction after being bitten by a Deinagkistrodon acutus, one of the most poisonous snakes in the southwestern of China. Applying 3D computed tomography (CT) of head combined with cerebral angiography examinations showed a large cerebral infarction, hernia in the right brain, developmental abnormalities of the right middle cerebral artery and cerebral artery of right brain. In conclusion, head CT imaging combined with cerebral angiography provides an efficient approach in diagnosis of stroke caused by snakebites. PMID- 29480240 TI - Special issue on multimedia presentation assisted clinical diagnosis, prognosis and treatment (II). PMID- 29480241 TI - Universal screening versus universal precautions in ophthalmic surgery. PMID- 29480242 TI - Good quality pays rich dividends. PMID- 29480243 TI - Possible retinoblastoma? PMID- 29480244 TI - Cornea and anterior eye assessment with placido-disc keratoscopy, slit scanning evaluation topography and scheimpflug imaging tomography. AB - Current corneal assessment technologies make the process of corneal evaluation extremely fast and simple and several devices and technologies allow to explore and to manage patients. The purpose of this special issue is to present and also to update in the evaluation of cornea and ocular surface and this second part, reviews a description of the corneal topography and tomography techniques, providing updated information of the clinical recommendations of these techniques in eye care practice. Placido-based topographers started an exciting anterior corneal surface analysis that allows the development of current corneal tomographers that provide a full three-dimensional reconstruction of the cornea including elevation, curvature, and pachymetry data of anterior and posterior corneal surfaces. Although, there is not an accepted reference standard technology for corneal topography description and it is not possible to determine which device produces the most accurate topographic measurements, placido-based topographers are a valuable technology to be used in primary eye care and corneal tomograhers expanding the possibilities to explore cornea and anterior eye facilitating diagnosis and follow-up in several situations, raising patient follow-up, and improving the knowledge regarding to the corneal anatomy. Main disadvantages of placido-based topographers include the absence of information about the posterior corneal surface and limited corneal surface coverage without data from the para-central and/or peripheral corneal surface. However, corneal tomographers show repeatable anterior and posterior corneal surfaces measurements, providing full corneal thickness data improving cornea, and anterior surface assessment. However, differences between devices suggest that they are not interchangeable in clinical practice. PMID- 29480245 TI - Anterior segment optical coherence tomography for evaluation of cornea and ocular surface. AB - Current corneal assessment technologies make the process of corneal evaluation extremely fast and simple. Several devices and technologies allow to explore and manage patients better. Optical coherence tomography (OCT) technology has evolved over the years, and hence a detailed evaluation of anterior segment (AS) structures such as cornea, conjunctiva, tear meniscus, anterior chamber, iris, and crystalline lens has been possible in a noncontact and safe procedure. The purpose of this special issue is to present and update in the evaluation of cornea and ocular surface, and this paper reviews a description of the AS-OCT, presenting the technology and common clinical uses of OCT in the management of diseases involving cornea and ocular surface to provide an updated information of the clinical recommendations of this technique in eye care practice. PMID- 29480247 TI - Ultrasound biomicroscopy image patterns in normal upper eyelid and congenital ptosis in the Indian population. AB - Purpose: To study the features of upper eyelid in healthy individual and different types of congenital ptosis in the Indian population using ultrasound biomicroscopy (UBM). Methods: This was a prospective observational study at a tertiary care center. Eyelid structure of healthy individuals with no eyelid abnormalities (n = 19); simple congenital ptosis (n = 33) cases; Marcus Gunn jaw winking ptosis (MGJWP, n = 7) cases, and blepharophimosis-ptosis-epicanthus inversus syndrome (BPES, n = 20) cases were studied on a vertical UBM scan using 50-MHz probe. Lid-thickness, tarsal-thickness, orbicularis oculi and levator Muller-orbital septum-conjunctival (LMSC) complex were measured in primary gaze. Comparison was made between four groups and results were statistically analyzed using ANOVA test. In normal individuals, LMSC measurements were repeated in down gaze imaging. Results: Skin with subcutaneous tissue, LMSC complex and pre aponeurotic fat-pad appeared echodense while orbicularis oculi and tarsus appeared echolucent. In primary gaze, mean thickness (+/- standard deviation) of the eyelid, tarsus, orbicularis oculi and LMSC, respectively, were: 1.612 +/- 0.205, 0.907 +/- 0.098, 0.336 +/- 0.083, and 0.785 +/- 0.135 mm in normal individual. LMSC showed 46.64% increase in thickness on down-gaze. The mean eyelid thickness and LMSC were thicker in MGJWP and BPES as compared to normal. In different types of congenital ptosis cases, various patterns of UBM imaging were observed. Conclusion: UBM allows noninvasive imaging of eyelid structures with good anatomical correspondence in normal eyelids and study the structural alterations of eyelids in different types of congenital ptosis. UBM can be used to highlight the anatomical difference in normal eyelids that may help modify the surgery for better cosmetic outcomes. Furthermore, it has the potential to be used in preoperative evaluation and operative planning in certain types of acquired ptosis, which needs to be evaluated. PMID- 29480246 TI - Dynamic corneal deformation response and integrated corneal tomography. AB - Measuring corneal biomechanical properties is still challenging. There are several clinical applications for biomechanical measurements, including the detection of mild or early forms of ectatic corneal diseases. This article reviews clinical applications for biomechanical measurements provided by the Corvis ST dynamic non contact tonometer. PMID- 29480248 TI - Quality indicators for eye bank. AB - Purpose: The aim of this study is to identify quality indicators of the eye bank and validate their effectivity. Methods: Adverse reaction rate, discard rate, protocol deviation rate, and compliance rate were defined as Quality Indicators of the eye bank. These were identified based on definition of quality that captures two dimensions - "result quality" and "process quality." The indicators were measured and tracked as part of quality assurance (QA) program of the eye bank. Regular audits were performed to validate alignment of standard operating procedures (SOP) with regulatory and surgeon acceptance standards and alignment of activities performed in the eye bank with the SOP. Prospective study of the indicators was performed by comparing their observed values over the period 2011 2016. Results: Adverse reaction rate decreased more than 8-fold (from 0.61% to 0.07%), discard rate decreased and stabilized at 30%, protocol deviation rate decreased from 1.05% to 0.08%, and compliance rate reported by annual quality audits improved from 59% to 96% at the same time. In effect, adverse reaction rate, discard rate, and protocol deviation rate were leading indicators, and compliance rate was the trailing indicator. Conclusion: These indicators fulfill an important gap in available literature on QA in eye banking. There are two ways in which these findings can be meaningful. First, eye banks which are new to quality measurement can adopt these indicators. Second, eye banks which are already deeply engaged in quality improvement can test these indicators in their eye bank, thereby incorporating them widely and improving them over time. PMID- 29480250 TI - Universal screening: To do or not to do. PMID- 29480249 TI - Seroprevalence, risk associations, and cost analysis of screening for viral infections among patients of cataract surgery. AB - Purpose: The purpose of this study was to estimate the prevalence of blood-borne viral infections (triple H: HBV-hepatitis B virus, HCV-hepatitis C virus, and HIV human immunodeficiency virus) among cataract patients, sought possible risk associations and discuss feasibility of universal preoperative screening. Methods: This prospective, cross-sectional study enrolled consecutive patients of senile cataract. They were screened by immunoassay-based rapid diagnostic card tests for blood-borne viral infections. Positive cases were confirmed with confirmatory ELISA tests. Seropositive patients were enquired about the exposure to possible risk associations for acquiring these infections. Cost of card test per patient was calculated. Results: The prevalence of seropositivity for triple H viral infections (HBV, HCV, and HIV) among patients of senile cataract was 5.9% (95% confidence interval [CI]: 5.3-6.6), and HCV was most common viral infection. The dental extraction was most common (54%; 95% CI:48-60) possible risk association. The total cost of primary screening per patient for triple H infections(HBV, HCV, and HIV) was $0.93. Conclusion: The prevalence of blood borne viral infection among cataract patients is high in this area. Awareness of the prevalence of blood-borne viral infections in service area, along with knowledge of rate of accidental exposure and risk of transmission would help to understand cost-effectiveness of universal preoperative screening before cataract surgery. PMID- 29480251 TI - Comparison of anterior segment measurements using Sirius Topographer(r) and Nidek Axial Length-Scan(r) with assessing repeatability in patients with cataracts. AB - Purpose: The purpose of this study is to evaluate anterior segment measurements obtained using CSO Sirius Topographer(r) (CSO, Firenze, Italy) and Nidek Axial Length (AL)-Scan(r) (Nidek CO., Gamagori, Japan). Methods: A total of 43 eyes of 43 patients were included in this prospective study. The central corneal thickness (CCT), anterior chamber depth (ACD), white-to-white distance (WTW), flat keratometry (K1), steep keratometry (K2), and mean keratometry (K) values were randomly measured three times with each device by the same examiner. The intraclass correlation coefficient of repeatability was analyzed. The compatibility of both devices was evaluated using the 95% limits of the agreement proposed by Bland and Altman. Results: Examiner achieved high repeatability for all parameters on each device except the WTW measured by Sirius. All measurements except WTW and K1 taken with the Sirius were higher than that taken with the Nidek AL-Scan(r). The difference in CCT, ACD, and WTW values was statistically significant. Conclusion: High repeatability of the measurements was achieved on both devices. Although Km, K1, and K2 measurements of the Sirius and the AL Scan(r) showed good agreement, WTW, CCT, and ACD measurements significantly differed between two devices. Thus, anterior segment measurements except for Km, K1, and K2 cannot be used interchangeably between Sirius and Nidek AL-Scan(r) devices. PMID- 29480252 TI - Visual outcomes of patients bilaterally implanted with the extended range of vision intraocular lens: A prospective study. AB - Purpose: The aim of this study was to analyze the objective and subjective visual outcomes of patients bilaterally implanted with the extended range of vision intraocular lens (EROV IOL), the Tecnis Symfony. Methods: This was a prospective interventional case series conducted at a tertiary eye care hospital in South India. The study included patients with bilateral implantation of EROV IOLs. The uncorrected and corrected visual acuity for distance, intermediate, and near vision was recorded at 6 weeks and 6 months' postoperative visit. A subjective questionnaire was administered to assess spectacle independence, photic phenomenon, and overall satisfaction. All data were recorded using Microsoft Excel worksheet. The analyses were performed using SPSS for windows software. Results: Our study included fifty patients with bilateral implantation of EROV IOLs. The mean age was 59.84 +/- 11.68 years. The mean uncorrected binocular distance, intermediate, and near visual acuity (in standard decimal equivalent) was 0.89,0.99 and 0.99 respectively, at 6 months' postoperative visit. Ninety-six percent of the patients did not require spectacles for distance and 98% of the patients were free from spectacles for intermediate and near vision. 94% of our patients perceived no or minimal photic phenomena such as glare and halos. The mean subjective patient satisfaction score (out of 10) for distance, intermediate, and near was 9, 10, and 9, respectively. Conclusion: The EROV IOLs demonstrated high levels of spectacle independence for distance, intermediate, and near vision. The incidence of photic phenomena observed was minimal with a high level of patient satisfaction. PMID- 29480253 TI - Comparative evaluation of rotational stability and visual outcome of toric intraocular lenses with and without a capsular tension ring. AB - Purpose: To evaluate the rotational stability of toric intraocular lens (IOL) when co-implanted with a capsular tension ring (CTR) as compared to that of a toric IOL without a CTR. Methods: This was a prospective randomized clinical trial performed in a tertiary care centre in India. Fifty adult human eyes with visually significant cataract and regular corneal astigmatism >=1.5D divided into two groups of 25 eyes each, A and B by simple randomization. Eyes with corneal pathology, lens subluxation, and a specular endothelial cell count <2000/mm2 were excluded from the study. The eyes in both the groups underwent standard phacoemulsification and were implanted with a toric IOL. In Group A, a CTR was put in the bag before IOL implantation. The groups were called for follow-up on day 1, 1 week, 1 month, and 3 months, postoperatively. The axis of the toric IOL on each visit was measured by slit lamp imaging in retroillumination and analyzed digitally. Results: Mean rotation of toric IOL at 3 months postoperatively was 1.85 +/- 1.72 degrees in Group A and 4.02 +/- 2.04 degrees in Group B. The difference was statistically significant (P = 0.003). Conclusion: Coimplantation of a CTR is a safe and effective technique for ensuring better rotational stability of toric IOLs. PMID- 29480254 TI - The impact of primary open-angle glaucoma: Quality of life in Indian patients. AB - Purpose: Glaucoma significantly affects the quality of life (QoL) of a patient. Despite the huge number of glaucoma patients in India, not many, QoL studies have been carried out. The purpose of the present study was to evaluate the QoL in Indian patients with varying severity of glaucoma. Methods: This was a hospital based, cross-sectional, analytical study of 180 patients. The QoL was assessed using orally administered QoL instruments comprising of two glaucoma-specific instruments; Glaucoma Quality of Life-15 (GQL-15) and Viswanathan 10 instrument, and 1 vision-specific instrument; National Eye Institute Visual Function Questionnaire-25 (NEIVFQ25). Results: Using NEIVFQ25, the difference between mean QoL scores among cases (88.34 +/- 4.53) and controls (95.32 +/- 5.76) was statistically significant. In GQL-15, there was a statistically significant difference between mean scores of cases (22.58 +/- 5.23) and controls (16.52 +/- 1.24). The difference in mean scores with Viswanathan 10 instrument in cases (7.92 +/- 0.54) and controls (9.475 +/- 0.505) was also statistically significant. QoL scores also showed moderate correlation with mean deviation, pattern standard deviation, and vertical cup-disc ratio. Conclusion: In our study, all the three instruments showed decrease in QoL in glaucoma patients compared to controls. With the increase in severity of glaucoma, corresponding decrease in QoL was observed. It is important for ophthalmologists to understand about the QoL in glaucoma patients so as to have a more holistic approach to patients and for effective delivery of treatment. PMID- 29480255 TI - Pneumatic retinopexy outcomes as primary or secondary surgical option for treating rhegmatogenous retinal detachment. AB - Purpose: To report the outcomes of pneumatic retinopexy (PR) performed as a primary surgical procedure for rhegmatogenous retinal detachment (RRD) or as a secondary procedure for recurrent RRD. Methods: We retrospectively analyzed case records of 54 patients (54 eyes) who underwent PR for RRD by injecting 0.3 ml of perfluoropropane (C3F8) in the vitreous cavity and cryopexy to break in the same sitting, followed by positioning. Results: A total 54 eyes of 54 patients aged between 17 and 84 years (mean - 51.3, median - 53 years) were included in the study. Except five eyes, all had breaks in the superior quadrants. The RRD ranged from 1 quadrant to 4 quadrants. Twenty-eight eyes (51.8%) were phakic and 26 (48.1%) were pseudophakic. The follow-up ranged from 6 to 144 months. In 25 eyes (46.2%), PR was the primary intervention and was successful in 15 (60%) eyes with a significant visual improvement (P = 0.023). Twenty-nine eyes (52.7%) with failed scleral buckle or failed pars plana vitrectomy underwent PR with a success rate of 65.5% and significant visual improvement (P = 0.0017). Progression of proliferative vitreoretinopathy changes (40%) was the most common cause of failure. The success rate was higher in phakic eyes, eyes with attached macula, superior breaks, superior RRD, and RRD limited to 3 quadrants or less. Conclusion: PR remains a minimally invasive procedure which can be used primarily or as a salvage procedure in failed surgery with moderately good success rate and minimal complications. One-step procedure reduces patient visits and ensures adequate treatment of the break. PMID- 29480256 TI - Pneumatic retinopexy: A cost-effective alternative. PMID- 29480257 TI - Choroidal thickness in patients with fibromyalgia and correlation with disease severity. AB - Purpose: To evaluate and compare choroidal thickness in patients with fibromyalgia (FM) and healthy controls. Methods: In this prospective, cross sectional study, forty eyes of 40 patients with FM and 40 eyes of 40 age- and sex matched healthy subjects were enrolled. FM was diagnosed according to the American College of Rheumatology criteria. The choroidal thickness measurements of the subjects were obtained using spectral-domain optical coherence tomography (RTVue-100, Optovue). Widespread pain index (WPI), symptom severity scale (SSS), and fibromyalgia impact questionnaire (FIQ) scores were recorded. The choroidal thickness measurements of the groups were compared, and correlations among the WPI, SSS, and FIQ scores and these measurements were calculated. Results: Choroidal thicknesses at 1500 MUm nasally were 198.5 +/- 46.7 MUm and 306.3 +/- 85.4 MUm; at 1000 MUm nasally were 211.7 +/- 50.2 MUm and 310.05 +/- 87.26 MUm; at 500 MUm nasally were 216 +/- 55.05 MUm and 311.5 +/- 83.4 MUm; at subfoveal region were 230.9 +/- 58.4 MUm and 332.4 +/- 91.3 MUm; at 500 MUm temporally 227.5 +/- 58.1 MUm and 318.15 +/- 92.3 MUm; at 1000 MUm temporally 224.5 +/- 57.07 MUm and 315.1 +/- 84.2 MUm; at 1500 MUm temporally 212.5 +/- 56.08 MUm and 312.9 +/- 87.8 MUm in the FM and control groups, respectively (P < 0.001). Choroidal thicknesses were thinner at all measurement location, except temporal 1000 and 1500 in patients with FIQ score >=50 than in FIQ score <50. Conclusion: The results of this study demonstrated that choroidal thickness decreases in patients with FM and correlated with disease activity. This choroidal changes might be related with the alterations in autonomic nervous system functioning. Further studies are needed to evaluate the etiopathologic relationship between choroidal thickness and FM. PMID- 29480258 TI - Spectral domain optical coherence tomography evaluation of macular changes in Eales disease. AB - Purpose: The purpose of the study was to describe macular changes in treatment naive eyes with Eales disease using spectral domain optical coherence tomography (SD-OCT). Methods: A cross-sectional study was done on 79 eyes of 66 patients with Eales disease. Best-corrected visual acuity (BCVA), slit-lamp biomicroscopy (SLB), indirect ophthalmoscopy, fundus fluorescein angiography (FFA), and quantitative (central macular thickness [CMT]) and qualitative analysis on SD-OCT were performed. Results: Forty-six (58.2%) eyes had macular involvement as assessed with SD-OCT, while in 33 (41.8%) eyes, macula was not affected. Macular edema was the most common feature when macula was affected followed by epiretinal membrane. Mean CMT was higher (315.3 +/- 102.3 MUm) in eyes with macular involvement than those without it (243.8 +/- 19.3 MUm). Eyes with active vasculitis involving larger vessels and neovascularization had greater chance of macular involvement. SLB and FFA alone missed 28.3% and 50% eyes with macular abnormalities on SD-OCT, respectively. Conclusion: While the clinical description of Eales disease points mainly to a peripheral location, macular involvement can be commonly picked up when SD-OCT is used. Macular involvement when present is associated with a poorer BCVA. PMID- 29480259 TI - Macular changes in retinal vasculitis. PMID- 29480261 TI - Retinal pigment epithelium rip following single intravitreal ziv-aflibercept injection. PMID- 29480260 TI - Endoscope-assisted harvest of autogenous fascia lata in frontalis suspension surgery: A minimally invasive approach revisited. AB - Purpose: To report endoscope-assisted fascia lata harvest (EAFH) as a minimally invasive technique for correction of severe blepharoptosis. Methods: This was a retrospective case series between January 2013 and April 2017. Medical records of all consecutive patients who underwent frontalis suspension by EAFH in the study period were reviewed and outcome was analyzed. Results: Fourteen patients (10 males) were included in the study. Mean age of the group was 18.14 + 17.03 years (range 4-65 years) and 11 patients had simple congenital blepharoptosis. Blepharophimosis syndrome was seen in 3 patients. Eleven patients had bilateral blepharoptosis. The mean preoperative and postoperative MRD1 was -1.60 +/- 0.87 mm and +2.12 +/- 1.37 mm respectively. Mean lengths of the incision and fascial harvest were 2.25 +/- 0.43 cm and 13.0 +/- 2.35 cm (range 10-17 cm) respectively. The median follow-up of patients was 4.57 + 4.03 months (range 1-15 months). Complications included a wound dehiscence in two patients and these were resutured. The donor sites healed well in all patients leaving a small thigh scar and none needed scar revision. Conclusion: EAFH is a promising minimally-invasive technique performed with a small incision and achieved adequate length of fascial harvest. PMID- 29480262 TI - Multimodal imaging in a case of retinocytoma. PMID- 29480263 TI - Photophobia accompanied by painful plantar punctate hyperkeratotic patches: Tyrosinemia type 2. PMID- 29480264 TI - Acorea: A rare congenital anomaly. PMID- 29480265 TI - Isolated neurofibroma of the eyelid mimicking recurrent chalazion. AB - Neurofibroma is a peripheral nerve sheath tumor which is seen in neurofibromatosis type 1 and is characterized by various ophthalmic manifestations. Solitary neurofibroma of the eyelid is rare. We report a case of a 53-year-old female patient who presented with a painless swelling in the left upper lid of 4 years' duration. She had undergone surgery for the same lesion twice. The lesion was excised and histopathological examination revealed a solitary neurofibroma. She did not have any other features of generalized neurofibromatosis. PMID- 29480266 TI - Encephalocele presenting as lower lid swelling: A rare case report. AB - Encephalocele is a rare congenital abnormality characterized by abnormal protrusion of brain and meninges through an opening in the skull. We report an 8 year-old girl who presented with a swelling in the right lower lid for the last 6 years. In her infancy, she had undergone surgery for a very small swelling located in the right nasolacrimal area. On further clinicoradiological evaluation, anterior encephalocele was diagnosed. This case highlights the uncommon site of anterior encephalocele; misdiagnosis and mismanagement of which could result in dreaded complications such as meningitis and cerebrospinal fluid leaking fistula formation. PMID- 29480267 TI - An unusual case of corneal lipoma. AB - A 24-year-old male presented with a painless yellowish lesion on the nasal part of his cornea that extended to the paracentral area. Without a confirmed clinical diagnosis, the patient was advised surgical removal of the lesion. The lesion showed a smooth, elevated anterior surface without any signs of inflammation. On making a small incision over the lesion, we found yellowish material being extruded from the lesion. Cytological evaluation of the material revealed clear vacuolated cells suggestive of lipocytes, based on which we diagnosed it a rare case of corneal lipoma. PMID- 29480269 TI - Commentary: One size does not fit all. PMID- 29480268 TI - Small lens for a big eye: Successful management of anterior megalophthalmos. AB - We report a case of anterior megalophthalmos and complicated cataract, with apparently smaller lens in both eyes. The right eye had spontaneous retinal detachment. The child underwent cataract surgery in both the eyes with retinal detachment surgery in the right eye. Due to small size of the lenticular bag, a downsized customized intraocular lens (IOL) was implanted. Postoperatively, the IOL was well centered with ambulatory vision till 3 years of follow-up. This case describes this rare disorder and its association with apparently small-sized lens and discusses the course of its management, highlighting the visual rehabilitation with customization of IOLs. PMID- 29480270 TI - Successful management of bee sting induced Aspergillus fumigatus endophthalmitis and scleritis. AB - Ocular bee stings are known to cause corneal melts, corneal infiltrates, cataracts, and secondary glaucoma. Our patient presented with scleritis, corneal infiltrates, and endophthalmitis after a ocular bee sting. Topical treatment led to resolution of anterior segment inflammation, but the scleritis and vitreous inflammation worsened. Vitrectomy with intravitreal antibiotics was done and scrapings from the scleral abscess showed growth of Aspergillus fumigatus on culture. Repeat vitrectomy with silicone oil was needed for retinal detachment. Oral and intravitreal antifungals led to resolution of inflammation with attached retina. This is the first reported case of bee sting-induced fungal endophthalmitis with scleritis. PMID- 29480271 TI - To laser or not? AB - A 64-year-old male patient presented to the clinic with diminished vision in his right eye for the past 2 years. Examination revealed a best-corrected visual acuity (BCVA) of counting fingers at 1 m with a scarred choroidal neovascular membrane (CNVM) in the right eye while the left eye had a BCVA of 20/20 with a small peripapillary subretinal hemorrhage along with angioid streaks in both eyes. Multimodal imaging revealed the presence of a CNVM in the left eye which was treated with focal thermal laser. Regression was noted on optical coherence tomography angiography at 1 month post-laser, but at 3-month follow-up, exacerbation of the CNVM was observed. Subsequently, four intravitreal ziv aflibercept injections were given, and scarring of CNVM was noted on OCT. Thermal laser in the background of angioid streaks has worsened the breaks in the Bruch's membrane leading to worsening of the CNVM. PMID- 29480272 TI - Bilateral central retinal artery occlusion as presenting manifestation of human immunodeficiency virus infection. AB - A 30-year-old male with bilateral acute visual loss presented with retinal edema in the posterior pole and peripapillary region with extensive retinal hemorrhages. Fluorescein angiography revealed delayed arterial filling in the right eye and absent arterial filling in the left eye, suggesting bilateral central retinal artery occlusion. Systemic evaluation revealed a history of chronic low-grade fever and generalized lymphadenopathy. HIV (ELISA) was positive, and other systemic comorbidities were ruled out. Cervical lymph node biopsy stained positive for acid-fast bacilli, with large areas of necrosis, palisaded by epithelioid cell granulomas, macrophages, and multinucleated giant cells, suggesting lymph node tuberculosis. Despite antiretroviral and antitubercular therapy, he developed optic atrophy at 4 weeks. PMID- 29480273 TI - Transient reversal of macular ischemia with intravitreal steroid implant injection in a case of radiation maculopathy. AB - Diabetic retinopathy (DR) is a well-known risk factor in the development of radiation maculopathy (RM). Steroids have been shown to improve the vision and reduce the macular thickness in patients with RM. This observational case report highlights altered course of DR after a course of radiotherapy for orbital lymphoma, after a single dose of intravitreal dexamethasone implant showed a dramatic revascularization of the ischemic macula, with a significant reduction in the size of ischemic area. This appears to be the first case in literature corroborating the favorable effect on steroids on retinal vasculature, seen angiographically. PMID- 29480274 TI - Concurrent management of myopic choroidal neovascularization and rhegmatogenous retinal detachment with intravitreal antivascular endothelial growth factor during primary retinal detachment repair. AB - We report concurrent management of rhegmatogenous retinal detachment and myopic choroidal neovascularization in the left eye of a 24-year-old female who presented with sudden dimness of vision due to retinal detachment and choroidal neovascularization. Intravitreal antivascular endothelial growth factor was injected during primary vitrectomy for retinal detachment. At final follow-up, the retina was attached with scarring of choroidal neovascularization. Ours is the first report of the use of intravitreal antivascular endothelial growth factor during vitrectomy for retinal detachment. PMID- 29480276 TI - Preloaded injectable intraocular lenses: The way forward. PMID- 29480275 TI - Subretinal tissue plasminogen-assisted vitrectomy for posttraumatic full thickness macular hole with submacular hemorrhage. AB - A young male presented with diminution of vision left eye, attributable to full thickness macular hole, and submacular hemorrhage, following closed globe injury 2 weeks ago. The patient was managed successfully with 25-gauge vitrectomy, subretinal injection of tissue plasminogen activator and aspiration of liquefied blood through the macular hole, internal limiting membrane peeling, short-acting gas tamponade, and prone positioning. This resulted in good visual improvement, type 1 macular hole closure, and restoration of foveal architecture. The outcome and rationale of treatment in this unique scenario is discussed. PMID- 29480277 TI - Calibrated Bowman's lacrimal probe. PMID- 29480278 TI - Pediatric ophthalmology training in India. PMID- 29480279 TI - Response to: Pediatric ophthalmology training in India. PMID- 29480280 TI - Comment on: Surgical treatment of superior oblique palsy: Predictors of outcome. PMID- 29480281 TI - Response to: Surgical treatment of superior oblique palsy: Predictors of outcome. PMID- 29480282 TI - Comment on: Variation in the vitreoretinal configuration of Stage 4 retinopathy of prematurity in photocoagulated and treatment-naive eyes undergoing vitrectomy. PMID- 29480283 TI - Response to: Variation in the vitreoretinal configuration of Stage 4 retinopathy of prematurity in photocoagulated and treatment naive eyes undergoing vitrectomy. PMID- 29480284 TI - Erratum: Optical coherence tomography: A guide to interpretation of common macular diseases. AB - [This corrects the article DOI: 10.4103/ijo.IJO_902_17]. PMID- 29480286 TI - Infectious disease: gammadelta T cells stop malarial comeback. PMID- 29480285 TI - Curcumin Attenuates Pulmonary Inflammation in Lipopolysaccharide Induced Acute Lung Injury in Neonatal Rat Model by Activating Peroxisome Proliferator-Activated Receptor gamma (PPARgamma) Pathway. AB - BACKGROUND This study aimed to investigate the therapeutic effect of curcumin in lipopolysaccharide (LPS) induced neonatal acute lung injury (ALI) and the possibly associated molecular mechanisms. MATERIAL AND METHODS ALI neonatal animal model was established by using LPS. Curcumin and/or peroxisome proliferator-activated receptor gamma (PPARgamma) inhibitor BADGE (bisphenol A diglycidyl ether) were administrated to animals. Lung edema was evaluated by PaO2 and lung wet/dry weight ratio (W/D) measurements. EMSA was used to determine the PPARgamma activity. Levels of high-mobility group box 1 (HMGB1), secretory receptor for advanced glycation end products (RAGE), tumor necrosis factor alpha (TNFalpha), interleukin 6 (IL6), and transforming growth factor b1 (TGFbeta1) in bronchoalveolar lavage fluid (BALF) were examined by ELISA. Western blotting was used to evaluate the expression levels of HMGB1, RAGE, heme oxygenase 1 (HO1), TNFalpha, IL6, and TGFbeta1 in lung tissue. RESULTS Curcumin administration significantly improved lung function by increasing PaO2 and decreasing W/D in neonatal ALI rats. Curcumin treatment upregulated the PPARgamma activity and expression level of HO1 which were suppressed in lung tissue of neonatal ALI rats. Elevated levels of HMGB1, RAGE, TNFalpha, IL6, and TGFbeta1 in both lung tissue and BALF from neonatal ALI rats were decreased dramatically by curcumin treatment. PPARgamma inhibitor BADGE administration impaired curcumin's alleviation on lung edema, inhibitory effects on inflammatory cytokine expression and recovery of PPARg/HO1 signaling activation. CONCLUSIONS Curcumin alleviated lung edema in LPS-induced ALI by inhibiting inflammation which was induced by PPARgamma/HO1 regulated-HMGB1/RAGE pro-inflammatory pathway. PMID- 29480287 TI - Foreign antigen-independent memory-phenotype CD4+ T cells: a new player in innate immunity? PMID- 29480290 TI - Collective thermal transport in pure and alloy semiconductors. AB - Conventional models for predicting thermal conductivity of alloys usually assume a pure kinetic regime as alloy scattering dominates normal processes. However, some discrepancies between these models and experiments at very small alloy concentrations have been reported. In this work, we use the full first principles kinetic collective model (KCM) to calculate the thermal conductivity of Si1-xGex and InxGa1-xAs alloys. The calculated thermal conductivities match well with the experimental data for all alloy concentrations. The model shows that the collective contribution must be taken into account at very low impurity concentrations. For higher concentrations, the collective contribution is suppressed, but normal collisions have the effect of significantly reducing the kinetic contribution. The study thus shows the importance of the proper inclusion of normal processes even for alloys for accurate modeling of thermal transport. Furthermore, the phonon spectral distribution of the thermal conductivity is studied in the framework of KCM, providing insights to interpret the superdiffusive regime introduced in the truncated Levy flight framework. PMID- 29480289 TI - Unimolecular reaction energies for polycyclic aromatic hydrocarbon ions. AB - Imaging photoelectron photoion coincidence spectroscopy was employed to explore the unimolecular dissociation of the ionized polycyclic aromatic hydrocarbons (PAHs) acenaphthylene, fluorene, cyclopenta[d,e,f]phenanthrene, pyrene, perylene, fluoranthene, dibenzo[a,e]pyrene, dibenzo[a,l]pyrene, coronene and corannulene. The primary reaction is always hydrogen atom loss, with the smaller species also exhibiting loss of C2H2 to varying extents. Combined with previous work on smaller PAH ions, trends in the reaction energies (E0) for loss of H from sp2-C and sp3-C centres, along with hydrocarbon molecule loss were found as a function of the number of carbon atoms in the ionized PAHs ranging in size from naphthalene to coronene. In the case of molecules which possessed at least one sp3-C centre, the activation energy for the loss of an H atom from this site was 2.34 eV, with the exception of cyclopenta[d,e,f]phenanthrene (CPP) ions, for which the E0 was 3.44 +/- 0.86 eV due to steric constraints. The hydrogen loss from PAH cations and from their H-loss fragments exhibits two trends, depending on the number of unpaired electrons. For the loss of the first hydrogen atom, the energy is consistently ca. 4.40 eV, while the threshold to lose the second hydrogen atom is much lower at ca. 3.16 eV. The only exception was for the dibenzo[a,l]pyrene cation, which has a unique structure due to steric constraints, resulting in a low H loss reaction energy of 2.85 eV. If C2H2 is lost directly from the precursor cation, the energy required for this dissociation is 4.16 eV. No other fragmentation channels were observed over a large enough sample set for trends to be extrapolated, though data on CH3 and C4H2 loss obtained in previous studies is included for completeness. The dissociation reactions were also studied by collision induced dissociation after ionization by atmospheric pressure chemical ionization. When modeled with a simple temperature-based theory for the post-collision internal energy distribution, there was reasonable agreement between the two sets of data. PMID- 29480288 TI - Foreign antigen-independent memory-phenotype CD4+ T cells: a new player in innate immunity? PMID- 29480291 TI - Nanoscale mechanism of the stabilization of nanoporous gold by alloyed platinum. AB - Nanoporous gold (NPG) is usually made by electrochemical dealloying of Ag from binary AgAu alloys. The resulting nanoscale ligaments are not very stable, and tend to coarsen with time by surface self-diffusion, especially in electrolyte, which may lead to inferior electrocatalytic properties. Addition of a small amount of Pt to the precursor alloy is known to refine and stabilize the nanoporous product (NPG-Pt). However, the mechanisms by which Pt serves to refine the microstructure remain poorly understood. The present study aims to expand our knowledge of the role of Pt by examining NPG-Pt at atomic resolution with Atom Probe Tomography (APT), as well as by aberration-corrected Transmission Electron Microscopy. Atomic level observation of Pt enrichment on ligament surfaces sheds light on the underlying mechanisms that give rise to Pt's refining effect. Owing to improved Ag retention with higher Pt content, NPG-Pt1 (made by dealloying Ag77Au22Pt1) was shown to have the highest surface area-to-volume ratio, compared to NPG-Pt3 (made by dealloying Ag77Au20Pt3). Quantitative estimates reveal up to 5-fold enrichment of Pt at nanoligament surfaces, compared to the precursor content, in NPG-Pt. The interface between the dealloyed layer and the substrate was captured by APT, for the first time. The findings of this investigation add insight into the functionality of NPG-Pt and its prospective catalytic performance. PMID- 29480294 TI - Boronic acid functionalized g-C3N4 nanosheets for ultrasensitive and selective sensing of glycoprotein in the physiological environment. AB - As important biomarkers, glycoprotein sensing is frequently facilitated by boronic acid binding with its cis-diols. However, boronic acid based sensors suffer from drawbacks of alkali restriction and/or sensitivity limitation. Herein, we report boronic acid decorated g-C3N4 nanosheets (B-g-CN) with a Wulff type boronic acid feature, which selectively bind glycoprotein under physiological conditions. Meanwhile, the binding causes significant enhancement of the B-g-CN nanosheet fluorescence, providing the basis for glycoprotein sensing. With IgG as a model, a detection limit (LOD) of 2.2 nM (3sigma/s, n = 11) was obtained within a linear range of 6.7-67 nM. The LOD was further improved to 52 pM subject to enrichment of the nanosheets, which well enables IgG assay in human urine samples. Moreover, it was successful in imaging endogenous and exogenous glycoproteins in living cells. PMID- 29480296 TI - An intrinsic energy conversion mechanism via telescopic extension and retraction of concentric carbon nanotubes. AB - The conversion of other forms of energy into mechanical work through the geometrical extension and retraction of nanomaterials has a wide variety of potential applications, including for mimicking biomotors. Here, using molecular dynamics simulations, we demonstrate that there exists an intrinsic energy conversion mechanism between thermal energy and mechanical work in the telescopic motions of double-walled carbon nanotubes (DWCNTs). A DWCNT can inherently convert heat into mechanical work in its telescopic extension process, while convert mechanical energy into heat in its telescopic retraction process. These two processes are nearly thermodynamically reversible. The underlying mechanism for this energy conversion is that the configurational entropy changes with the telescopic overlapping length of concentric individual tubes. We also find that the entropy effect enlarges with the decreasing intertube space of DWCNTs. As a result, the spontaneous telescopic motion of a condensed DWCNT can be switched to extrusion by increasing the system temperature above a critical value. These findings are important for fundamentally understanding the mechanical behavior of concentric nanotubes, and may have general implications in the application of DWCNTs as linear motors in nanodevices. PMID- 29480297 TI - Lattice induced crystallization of nanodroplets: the role of finite-size effects and substrate properties in controlling polymorphism. AB - Targeting specific technological applications requires the control of nanoparticle properties, especially the crystalline polymorph. Freezing a nanodroplet deposited on a solid substrate leads to the formation of crystalline structures. We study the inherent mechanisms underlying this general phenomenon by means of molecular dynamics simulations. Our work shows that different crystal structures can be selected by finely tuning the solid substrate lattice parameter. Indeed, while for our system, face-centered cubic is usually the most preponderant structure, the growth of two distinct polymorphs, hexagonal centered packing and body-centered cubic, was also observed even when the solid substrate was face-centered cubic. Finally, we also demonstrated that the growth of hexagonal centered packing is conditioned by the appearance of large enough body centered cubic clusters thus suggesting the presence of a cross-nucleation pathway. Our results provide insights into the impact of nanoscale effects and solid substrate properties towards the growth of polymorphic nanomaterials. PMID- 29480295 TI - Unexpected insights into antibacterial activity of zinc oxide nanoparticles against methicillin resistant Staphylococcus aureus (MRSA). AB - Zinc oxide nanoparticles (ZnO-NPs) are attractive as broad-spectrum antibiotics, however, their further engineering as antimicrobial agents and clinical translation is impeded by controversial data about their mechanism of activity. It is commonly reported that ZnO-NP's antimicrobial activity is associated with the production of reactive oxygen species (ROS). Here we disprove this concept by comparing the antibacterial potency of ZnO-NPs and their capacity to generate ROS with hydrogen peroxide (H2O2). Then, using gene transcription microarray analysis, we provide evidence for a novel toxicity mechanism. Exposure to ZnO-NPs resulted in over three-log reduction in colonies of methicillin resistant S. aureus with minimal increase in ROS or lipid peroxidation. The amount of ROS required for the same amount of killing by H2O2 was much greater than that generated by ZnO-NPs. In contrast to H2O2, ZnO-NP mediated killing was not mitigated by the antioxidant, N-acetylcysteine. ZnO-NPs caused significant up regulation of pyrimidine biosynthesis and carbohydrate degradation. Simultaneously, amino acid synthesis in S. aureus was significantly down regulated indicating a complex mechanism of antimicrobial action involving multiple metabolic pathways. The results of this study point to the importance of specific experimental controls in the interpretation of antimicrobial mechanistic studies and the need for targeted molecular mechanism studies. Continued investigation on the antibacterial mechanisms of biomimetic ZnO-NPs is essential for future clinical translation. PMID- 29480299 TI - Facile and scalable carbon- and binder-free electrode materials for ultra-stable and highly improved Li-O2 batteries. AB - A carbon- and binder-free Ti@Ru material is synthesized through a facile and controllable strategy. A Ti@Ru based Li-O2 battery can effectively avoid the subsidiary reactions, and can be reversibly and continuously cycled for more than 500 cycles with an efficiency ca. 100%, exhibiting an ultra-cycling stability. PMID- 29480298 TI - Circular reuse of bio-resources: the role of Pleurotus spp. in the development of functional foods. AB - The basidiomycetes fungi belonging to the genus Pleurotus could make an important contribution to sustainable functional food design because they possess an elevated protein content with a valuable essential amino acid scoring pattern, a unique dietary fibre profile, mainly comprised of branched beta-glucan, high levels of some vitamins of the B group, vitamin D, Fe, Zn, Cu, Se and some bioactive mycochemicals, while the Na and fat contents are low. Moreover, Pleurotus spp. can grow efficiently on various clean by-products of food processing, such as wheat straw, wheat stalk and spent beer grain, thus representing a sustainable food source. This review illustrates the compositional variability of Pleurotus spp. grown on various by-products, in order to clarify its potential ability to address the needs of populations with endemic nutritional deficiencies as well as those populations at risk or affected by some chronic diseases. The perspectives for Pleurotus applications in functional foods decisively depend on consumers' acceptability. Hence, the sensory properties of Pleurotus spp. are also clarified herein. Lastly, the three main strategies of functional food development using Pleurotus spp. are summarized, namely its use as a fortifying agent, high-cost protein replacer and prebiotic ingredient. PMID- 29480300 TI - Enhancing the thermoelectric performance of gamma-graphyne nanoribbons by introducing edge disorder. AB - Structure disorder especially edge disorder is unavoidable during the fabrication of nanomaterials. In this paper, using the non-equilibrium Green's function method, we investigate the influence of edge disorder on the thermoelectric performance of gamma(gamma)-graphyne nanoribbons (GYNRs). Our results show that the high Seebeck coefficient in pristine gamma-GYNR could still be preserved although edge disorder is introduced into the structure. Meanwhile, in these edge disordered nanoribbons the suppression of thermal conductance including electronic and phononic contributions outweighs the reduction of electronic conductance. These two positive effects combine together, and finally boost the thermoelectric conversion efficiency of gamma-GYNRs. The thermoelectric figure of merit ZT in the edge-disordered gamma-GYNRs (the length and width are about 55.68 and 1.41 nm) could approach 2.5 at room temperature, and can even reach as high as 4.0 at 700 K, which is comparable to the efficiency of conventional energy conversion methods. The findings in this paper indicate that the edge-disordered gamma-GYNRs are a promising candidate for efficient thermoelectric energy conversion and thermal management of nanodevices. PMID- 29480301 TI - Ultraviolet sensing using a TiO2 nanotube integrated high resolution planar microwave resonator device. AB - This paper presents a unique integrated UV light sensing concept and introduces a device with a detection limit of 1.96 nW cm-2. The combination of a high quality factor, a microwave planar resonator (Q ~ 50 000) with a semiconducting nanomaterial enables a revolutionary potential paradigm for photodetection of low light intensities and small form factors. The presenting device employs a high resolution microwave microstrip resonator as the signal transducer to convert the variant dielectric properties (permittivity and conductivity) of the nanotube membrane into electrical signals such as the resonant frequency, quality factor and resonant amplitude. The microwave resonator has an active feedback loop to improve the initial quality factor of the resonator from 200 to 50 000 and leads to boosting of the sensing resolution by orders of magnitude. Anatase TiO2 nanotubes are assembled on the surface of the microwave resonator. Upon exposure to UV light, electron-hole pair generation, trapping and recombination in the nanotubes are exploited as a unique signature to quantify the UV light intensity. The change of dielectric properties of the nanotube membrane is monitored using the underlying active microwave resonator. The proposed concept enables the detection and monitoring of UV light at high resolution, with very small exposure power and integrated form factors. PMID- 29480302 TI - Palladium-catalyzed site-selective arylation of aliphatic ketones enabled by a transient ligand. AB - Transition metal-catalyzed direct C-H bond functionalization enabled by transient ligands has become an attractive topic. Here we report a palladium-catalyzed site selective arylation of beta-C(sp3)-H bonds in aliphatic ketones with beta-alanine as the transient ligand. PMID- 29480303 TI - Subphthalocyanine-radiaannulene scaffold - a multi-electron acceptor and strong chromophore. AB - Two subphthalocyanine (SubPc) units and a perethynylated, alkyne-expanded radiaannulene (RA) were fused together by a four-fold Sonogashira reaction to give a compound exhibiting: (i) four reversible one-electron reductions, the first signalling good acceptor strength of the RA core itself, while the following three are a consequence of the entire scaffold, and (ii) intense light absorption that spans a remarkably broad region. PMID- 29480304 TI - Achieving foaming control smartly: pre-solubilized flavor oil serves as an in situ homogeneous defoamer. AB - In the wide application of aqueous foam, creating abundant foam and processing appropriate foaming control are both essential, depending upon the actual situation; the latter process is not only harder to achieve, but also more complicated to comprehensively understand on the molecular level. In this paper, a type of natural flavor oil, carvone, was solubilized in a micelle solution of sodium dodecyl sulfate (SDS) to study the effect on the foaming properties. The foamability and foam stability of the swollen micelle solutions were experimentally characterized, and the molecular behavior of the surfactant and oil molecules before, during and after the foaming process were investigated. It was found that the solubilized carvone co-adsorbed with SDS at the gas/water interface and caused a prominent effect on the foam film stability in several approaches, thereby making the flavor oil a possible foam controller that would not inhibit foam formation, but could eliminate foam efficiently once foam was undesired. Interestingly, it was found that the release of flavor in the foaming process was promoted. Detailed discussion of the interfacial behavior of carvone and the effect on the foaming properties of surfactants in different stages of foam may provide a theoretical foundation for exploring green and smart approaches in achieving foaming control. PMID- 29480305 TI - The UV-visible action-absorption spectrum of all-trans and 11-cis protonated Schiff base retinal in the gas phase. AB - The UV-visible absorption of retinal in its protonated Schiff-base form is studied in the gas phase. In particular, transitions to highly-excited electronic states, Sn, in the all-trans and 11-cis forms are considered, and several new states are discovered. Their positions and strengths are compared to state of the art quantum calculations. The location of these states are particularly important when new fs pump-probe experiments are designed to investigate the fast excited state dynamics of retinal chromophores. PMID- 29480306 TI - Does the photo-Fenton reaction work for microalgae control? A case study with Desmodesmus subspicatus. AB - Increased concentrations of nutrients in water bodies caused by effluent discharge, fertilizers and other inputs can lead to artificial eutrophication, increasing the primary productivity, bringing well-known and serious consequences to the environment (such as excessive macrophyte and microalgae growth). Most strategies for phytoplankton control in aquatic ecosystems result in metal accumulation or toxic by-product formation after chlorination. Concerning this matter, the photo-Fenton process (usually applied in wastewater treatment and degradation of a variety of contaminants) has been studied for water and effluent disinfection. However, its application in microalgae inactivation has not been reported until now. Therefore, this work aimed to evaluate the process effectiveness in inactivating microalgae, using Desmodesmus subspicatus as a model. Photo-Fenton experiments were carried out at the lab scale, at 105 cells per mL with 20 mg L-1 of H2O2 and 5 mg L-1 of Fe2+ (complexed with oxalic acid). The cell concentration and Growth Inhibition Test (GIT) were used to evaluate the process efficiency and Scanning Electron Microscopy (SEM) to analyze any alterations in the cell morphology. After performing the photo-Fenton reaction, the individual contribution of the reactants and radiation was investigated. The cell concentration was not significantly reduced during the photo-Fenton reaction, but SEM images indicated possible morphology alterations and the GIT showed the loss of cell viability after 30 minutes of exposure. Effects on the cell growth were also observed when exposed only to hydrogen peroxide. PMID- 29480307 TI - Retention of selenium by calcium aluminate hydrate (AFm) phases under strongly reducing radioactive waste repository conditions. AB - Safety assessment studies of future nuclear waste repositories carried out in many countries predict selenium-79 to be a critical radionuclide due to its presence as anion in three relevant oxidation states (vi, iv, -ii) resulting in weak retardation by most common rock minerals. This assumption, however, ignores its potential uptake by AFm phases, positively charged anion exchangers, which are present in significant quantities in the cementitious materials used in artificial barriers. Here we report for the first time wet chemistry and spectroscopic data on the interaction of the most relevant selenium anion species under the expected strongly reducing conditions, i.e. HSe-, with two AFm phases commonly found in cement, monocarbonate (AFm-MC) and hemicarbonate (AFm-HC). Batch sorption experiments showed that HSe- is retained much more strongly by AFm HC (solid-liquid distribution ratio, Rd, of 100 +/- 50 L kg-1) than by AFm-MC (Rd = 4 +/- 2 L kg-1) at the equilibrium pH (~12). X-ray absorption fine-structure (XAFS) spectroscopy revealed that the larger d-spacing in AFm-HC (d-spacing = 8.2 A) provides easy access for HSe- to the AFm interlayer space for sorption, whereas the smaller d-spacing of AFm-MC (d-spacing = 7.55 A) hinders interlayer access and limits HSe- sorption mostly to the outer planar surfaces and edges of the latter AFm phase. XAFS spectra further demonstrated that Se(-ii) prevalently sorbed in the interlayers of AFm-HC, is better protected from oxidation than Se( ii) prevalently sorbed onto the outer surfaces of AFm-MC. The quantitative sorption data along with the molecular-scale process understanding obtained from this study provide crucial insight into the Se retention by the cementitious near field of a radioactive waste repository under reducing conditions. PMID- 29480309 TI - Few-layer NiPS3 nanosheets as bifunctional materials for Li-ion storage and oxygen evolution reaction. AB - The construction of two-dimensional (2D) ultrathin nanosheets is considered as a promising strategy for enhancing electrochemical performance, owing to their large surface area and fast electron transport. In this study, ultrathin few layer NiPS3 nanosheets are obtained and systematically investigated by high-yield liquid phase exfoliation from their bulk layered crystals, and are exploited as anodes for lithium ion batteries (LIBs) and electrocatalysts for oxygen evolution reaction (OER). When evaluated as an anode for LIBs, NiPS3 nanosheets show excellent electrochemical properties in terms of stable cycling performance and rate capabilities. A stable reversible capacity of 796.2 mA h g-1 is delivered after the 150th cycle at a current density of 100 mA g-1. As for the OER, the exfoliated few-layer NiPS3 nanosheets have demonstrated excellent electrocatalytic performance, such as a low overpotential of 301 mV at a current density of 10 mA cm-2, a small Tafel slope of 43 mV dec-1, and an outstanding long-term durability. This work is expected to make a contribution to develop next generation high-performance electrochemically active materials for catalysts and batteries. PMID- 29480308 TI - Co-administration of genistein with doxorubicin-loaded polypeptide nanoparticles weakens the metastasis of malignant prostate cancer by amplifying oxidative damage. AB - Prostate cancer is a typical malignant disease with a high incidence and a poor prognosis. Doxorubicin hydrochloride (DOX.HCl) is one of the most effective agents in the treatment of prostate cancer, but severe side effects and metastasis after its treatment impose restrictions on its application. Herein, a combination of genistein (GEN) and doxorubicin-loaded polypeptide nanoparticles (DOX-NPs) is constructed for the treatment of prostate cancer. The DOX-NPs can reduce the side effects caused by free DOX.HCl and produce a relatively low level of intracellular reactive oxygen species (ROS)-induced oxidative damage, while GEN, an inhibitor of the oxidative DNA repair enzyme apurinic/apyrimidinic endonuclease1 (APE1), can further amplify the ROS-induced oxidative damage by downregulating the intracellular expression of APE1 and reducing oxidative DNA repair in the prostate cancer cells. Because high levels of ROS-induced oxidative damage can prevent the distant metastasis of tumor cells, the distant metastasis of malignant prostate cancer cells is significantly inhibited by the combination of genistein and DOX-NPs with amplified oxidative damage. PMID- 29480310 TI - Site-specific hydroxyalkylation of chromones via alcohol mediated Minisci-type radical conjugate addition. AB - A metal-free site-specific C2-hydroxyalkylation of chromones through the Minisci type reaction using simple alcohols was developed. This transformation proceeds via radical sp3 C-H activation and subsequent conjugate addition, generating a series of C2-hydroxyalkylated chromanones in moderate to good yields. Besides, ethers were also compatible in this Minisci reaction, leading to corresponding C2 ether-substituted chromanones. PMID- 29480311 TI - Detection of microalgae superoxide dismutase (SOD) using a GNRs-based resonance light scattering system. AB - A novel and label-free, gold nanorods (GNRs)-based resonance light scattering system assay has been developed for the detection of microalgae superoxide dismutase (SOD). The method relies on the fact that interactions between microalgae SOD and GNRs can emit strong fluorescence signals. The prepared GNRs were well dispersed in the solution and intracellular SOD was extracted from Microcystis aeruginosa; the SOD was then absorbed on the surface of the GNRs. The results demonstrated that the intensity of the fluorescence signals increased at 595 nm with an increase in the SOD concentration, the optimum pH value was concluded to be 7.8, the optimum concentration of inorganic salt Na+ ions was 0.2 mol L-1, and the reaction system was stable for 50 min. This method offers the advantages of higher sensitivity and selectivity in microalgae protein detection and exhibits great potential for biological diagnosis. PMID- 29480312 TI - A controllable etching supramolecular hydrogel based on metal ions. AB - We report an interesting gel-etching system in which a gel can be etched with corresponding etching rates and color changes when different types of etching molecules are added to the gel. This gel system may have wide potential application in molecular recognition, pre-packaged, as well as other functional materials. PMID- 29480313 TI - Probing different spin states in xylyl radicals and ions. AB - Resonant one-color two-photon ionization spectroscopy and mass-selected threshold photoelectron spectroscopy were applied to study the electronic doublet states of the three xylyl (methyl-benzyl) radicals above 3.9 eV as well as the singlet and triplet states of the cations up to 10.5 eV. The experiments are complemented by quantum chemical calculations and Franck-Condon simulations to characterize the transitions and to identify the origin bands, allowing a precise determination of singlet-triplet splittings in the cations. Torsional motions of the methyl group notably affect the D0 -> D3 transition of m-xylyl. All other investigated transitions either lead to electronic states with very low rotational barriers or suffer from spectral broadening in excess of methyl torsional energy levels. The methyl internal rotational potential is faithfully reproduced with the most basic ab initio methods, yet hyperconjugation could not be identified as a significant force shaping them. Time-dependent density functional theory describes the excited electronic states better than wave function theory approaches, notably EOM-CCSD. PMID- 29480314 TI - Platinum(iv) azido complexes undergo copper-free click reactions with alkynes. AB - We report our investigations into the first examples of copper-free 1,3-dipolar cycloaddition (click) reactions of electrophiles with a PtIV azido complex. The Pt-IV azido complex trans, trans, trans-[PtIV(py)2(N3)2(OH)2] (1) was reactive towards dimethyl acetylenedicarboxylate (DMAD) (2), diethyl acetylenedicarboxylate DEACD (3), N-[(1R,8S,9s)-bicyclo[6.1.0]non-4-yn-9 ylmethyloxycarbonyl]-1,8-diamino-3,6-dioxaoctane (BCN) (11) and dibenzocyclooctyne-amine (DBCO) (12) resulting in formation of the corresponding mono (a) and bis-substituted (b) complexes. Complexes of 2 undergo further reactions between the Pt centre and the carbonyl group to form 2a' and 2b'. This is not seen for the products of the corresponding PtII azido complex trans [Pt(py)2(N3)2] with acetylene 2. Novel complexes 2a', 2b', 11a and 11b have been characterised by multinuclear NMR, IR and UV-vis spectroscopy and ESI-MS. These reactions represent new synthetic routes to novel Pt(iv) complexes. PMID- 29480315 TI - Directing the mechanism of CO2 reduction by a Mn catalyst through surface immobilization. AB - Immobilization of a Mn polypyridyl CO2 reduction electrocatalyst on nanocrystalline TiO2 electrodes yields an active heterogeneous system and also significantly triggers a change in voltammetric and catalytic behaviour, relative to in solution. A combination of spectroelectrochemical techniques are presented here to elucidate the mechanism of the immobilized catalyst in situ. PMID- 29480316 TI - Effect of adding oat bran to instant oatmeal on glycaemic response in humans - a study to establish the minimum effective dose of oat beta-glucan. AB - Reducing the glycaemic response to carbohydrate-containing foods may have desirable physiological effects for many people. Here, we aimed to determine the minimum amount of oat beta-glucan from oat-bran which, when added to instant oatmeal, would reduce the glycaemic response by 20% compared to a beta-glucan free cereal. Therefore, the glycaemic responses elicited by one serving (27 g) instant-oatmeal plus 247 g 2% milk (IO, 28 g available-carbohydrate, 1.2 g beta glucan) or IO plus 0.2, 0.4, 0.8 or 1.6 g oat beta-glucan (OBG) from oat-bran, or an available-carbohydrate matched portion of cream of rice (CR) plus milk were measured over 2 h in n = 40 subjects using a randomized, cross-over design. The primary endpoint was incremental area under the curve (iAUC). The secondary endpoint was glucose peak-rise. The results showed that grams OBG consumed were significantly correlated with mean iAUC (p = 0.009) and with mean glucose peak rise (p = 0.002). Each gram of OBG reduced iAUC by 7% and peak-rise by 15%. Thus, to achieve a >=20% reduction in iAUC relative to CR, 1.6 g OBG had to be added to IO (74 +/- 7 vs. 93 +/- 6 mmol min L-1, p < 0.05), but, to achieve a 20% reduction in peak-rise, only 0.4 g OBG was required (2.00 +/- 0.1 vs. 2.40 +/- 0.1 mmol, p < 0.05). We conclude that adding OBG to IO flattened postprandial glycaemic responses in a dose-dependent fashion; 1.6 g OBG was required to reduce iAUC by >=20% versus CR, but a 20% reduction in peak-rise required only 0.4 g. The greater effect of OGB on peak-rise than iAUC presumably reflects the way viscous dietary fibres modulate glucose absorption kinetics. PMID- 29480318 TI - [Outpatient palliative medicine : Attitudes in the care of palliative emergencies. Prospective questionnaire-based investigation]. AB - BACKGROUND: The right to adequate outpatient palliative care has existed for several years in Germany. In recent years outpatient palliative care has developed very positively. Nevertheless, in emergency situations paramedics and emergency physicians were often included in the care of palliative care of patients. The aim of our study was to investigate the cooperation between outpatient palliative care teams and the emergency medical services. Another aim was to identify structural realities and based on these to discuss the possibilities in the optimization of outpatient palliative medical emergency situations. METHODS: A standardized self-designed questionnaire was distributed to specialized outpatient palliative care teams (SPCS) in Germany. For this purpose, closed and open questions (mixed methods) were used. The evaluation was carried out according to the questionnaire categories in quantitative and qualitative forms. The questionnaire was subdivided into general information and specific questions. RESULTS: The survey response rate was 79% from a total of 81 SPCS in 2011. The following standards in palliative emergency care were recommended: (1) early integration of outpatient palliative care services and basic outpatient palliative care systems, (2) end-of-life discussions, (3) defined emergency medical documents, emergency drug boxes, do not attempt resuscitation orders and (4) emergency medical training (physicians and paramedics). CONCLUSION: Outpatient palliative care in Germany has developed very positively during the last years; however, there are still deficits in terms of optimal patient care, one of which refers to the treatment of palliative care emergencies. In this context, optimization in the cooperation between outpatient palliative care services and emergency medical services should be discussed. PMID- 29480319 TI - [Abortive course of malignant hyperthermia following preclinical induction of general anesthesia using succinylcholine]. AB - In a 59-year-old woman with a perforating eyeball injury to the right eye, the emergency physician induced a preclinical general anesthesia with propofol, fentanyl and the depolarizing muscle relaxant succinylcholine. Anesthesia was maintained using propofol and remifentanil infusion throughout the preoperative period and the subsequent surgical procedure. Postoperatively, isolated rhabdomyolysis with an increase in serum creatine kinase to >20,000 U/l was observed. The diagnosis of malignant hyperthermia (MH) susceptibility could be confirmed in the patient 4 months after the acute event by the in vitro contracture test and detection of the MH causative mutation p.Val4849Ile in exon 101 of the ryanodine receptor gene. Due to the variable expression, for a long time MH often remained unrecognized. Warning symptoms, such as unspecific tachycardia or masseter spasm following succinylcholine injection, should alert emergency physicians to include MH susceptibility in the differential diagnostics. With an estimated genetic MH prevalence of 1:2000-3000, individuals with known or so far unrecognized MH disposition are likely to be among patients treated in the preclinical setting. If a person develops MH symptoms after exposure to triggering agents, immediate hospital admission is essential in order to initiate guideline-conform treatment without further delay because preclinically the life-saving causal measures are not possible due to the lack of supply of dantrolene. PMID- 29480320 TI - Neutrophil-to-lymphocyte ratio as a feasible prognostic marker for pyogenic liver abscess in the emergency department. AB - PURPOSE: The neutrophil-to-lymphocyte ratio (NLR) is an effective predictor of mortality in patients with for various conditions. To date, there are no previous studies on NLR as a prognostic marker for pyogenic liver abscess (PLA), especially on admission to the emergency department (ED). METHODS: From January 2013 to December 2015, 102 patients diagnosed with PLA in the ED were included. Clinico-radiological and laboratory results, including NLR, were evaluated as variables. NLR was calculated as absolute neutrophil count/absolute lymphocyte count. To evaluate the prognosis of PLA, data on hospital mortality, intensive care unit (ICU) admission, and development of septic shock were obtained. Multivariate logistic regression analyses and receiver-operating characteristic (ROC) curve analysis were performed. RESULTS: Among 102 patients, 10 (9.8%) died, 14 (13.7%) were admitted to the ICU, and 15 (14.7%) developed septic shock during hospitalization. Multivariate logistic regression analysis revealed NLR as an independent factor in predicting death [odds ratio (OR), 1.4; p = 0.020], ICU admission (OR, 1.4; p = 0.021), and development of septic shock (OR, 1.6; p = 0.041). NLR showed an excellent predictive performance for death (areas under the ROC curves [AUC], 0.941; cut-off value, 19.7; p < 0.001), ICU admission (AUC, 0.946; cut-off value, 16.9; p < 0.001), and development of septic shock (AUC, 0.927; cut-off value, 16.9; p < 0.001). CONCLUSION: NLR was positively associated with poor prognosis of PLA; elevated NLR could predictor of high risk of death, ICU admission, and development of septic shock. Emergency physicians should consider NLR for the prognosis of PLA and early aggressive treatment, especially in patients with NLR > 16.9. PMID- 29480321 TI - Evaluating the need to reform the organisation of care for major trauma patients in Belgium: an analysis of administrative databases. AB - PURPOSE: In light of the international evolutions to establish inclusive trauma systems and to concentrate the care for the most severely injured in major trauma centres, we evaluated the degree of dispersion of trauma care in Belgium. METHODS: We used descriptive statistics to illustrate the dispersion of major trauma care in Belgium based on two independent administrative databases: the registry of Mobile Intensive Care Units (2009-2015) and the Belgian Hospital Discharge Dataset (2009-2014). RESULTS: Patients with a severe trauma (n = 3856 in 2015) were transported towards 145 different hospital sites (on a total of 198 hospital sites) resulting in a median of 17 cases per hospital site (min = 1; P25 = 4; P75 = 30; max = 165). A minority of major trauma patients is after admission transferred to another hospital (8%) with a median of 10 days after admission to the hospital (IQR 3.5-24). CONCLUSIONS: The dispersion of care for major trauma patients in Belgium is so high that a reorganisation of care for severe injured patients in major trauma centres concentrating professional expertise and specialised equipment is recommended to guarantee a high quality of care in a qualitative and sustainable way. PMID- 29480322 TI - [Differential indication for psychotherapy in psychosis : Are there evidence based criteria?] AB - The major objective of this paper is to discuss the available evidence on the question as to which patients benefit most from psychotherapy in psychotic disorders and the question of which kind of psychotherapy. From a methodological perspective, this task can be seen as the question of moderators of treatment success. To answer this question, the status of efficacy research on psychotherapeutic interventions in schizophrenia is summarized in a first step. Secondly, studies comparing different active psychotherapeutic approaches are discussed. There are no studies available on routine psychotherapeutic care. However, there appears to be a rationale for recommending a combination of cognitive behavioural therapy (CBT) and family therapy. If patients prefer other approaches or if the treatment model does not suit the patient, other approaches should be offered. There is evidence for CBT that insight into psychosis, female gender, a higher level of education, and age >21 are indicators of a better course in CBT. Overall, the options for differential indications are highly limited and considerably more research is required. PMID- 29480323 TI - Distinct Osmoadaptation Strategies in the Strict Halophilic and Halotolerant Bacteria Isolated from Lunsu Salt Water Body of North West Himalayas. AB - Two strict halophilic bacterial strains, Halobacillus trueperi SS1, and Halobacillus trueperi SS3, and three halotolerant bacterial strains, Shewanella algae SS2, Halomonas venusta SS5, and Marinomonas sp. SS8 of Lunsu salt water body, Himachal Pradesh, India, were selected to study the mechanism of salt tolerance and the role of osmolytes therein. A combination of flame photometry, chromatographic and colorimetric assays was used to study the mechanism of salt tolerance in the selected strict halophilic and halotolerant bacterial strains. The strict halophiles and, one of the halotolerants, Marinomonas sp. SS8 were found to utilize both "salt-in strategy" and "accumulation of compatible solutes strategy" for osmoregulation in hypersaline conditions. On the contrary, the remaining two halotolerants used "accumulation of compatible solutes strategy" under saline stress and not the "salt-in strategy". The present study suggests towards distinct mechanisms of salt tolerance in the two classes, wherein strict halophiles accumulate compatible solutes as well as adopt salt-in strategy, while the halotolerant bacteria accumulate a range of compatible solutes, except Marinomonas sp. SS8, which utilizes both the strategies to combat salt stress. PMID- 29480324 TI - Role of (-)-epigallocatechin gallate in the pharmacokinetic interaction between nadolol and green tea in healthy volunteers. AB - PURPOSE: The aim of the present study is to investigate a possible role of a single dose of (-)-epigallocatechin gallate (EGCG), the major catechin in green tea, for the pharmacokinetic interaction between green tea and nadolol in humans. METHODS: In a randomized three-phase crossover study, 13 healthy volunteers received single doses of 30 mg nadolol orally with water (control), or an aqueous solution of EGCG-concentrated green tea extract (GTE) at low or high dose. Plasma concentrations and urinary excretion of nadolol were determined up to 48 h. In addition, blood pressure and pulse rate were monitored. In vitro transport kinetic experiments were performed using human embryonic kidney 293 cells stably expressing organic anion transporting polypeptide (OATP)1A2 to evaluate the inhibitory effect of EGCG on OATP1A2-mediated substrate transport. RESULTS: Single coadministration of low and high dose GTE significantly reduced the plasma concentrations of nadolol. The geometric mean ratios with 90% CI for area under the plasma concentration-time curves from 0 to infinity of nadolol were 0.72 (0.56-0.87) for the low and 0.60 (0.51-0.69) for the high dose. There were no significant differences in Tmax, elimination half-life, and renal clearance between GTE and water phases. No significant changes were observed for blood pressure and pulse rate between phases. EGCG competitively inhibited OATP1A2 mediated uptake of sulphobromophthalein and nadolol with Ki values of 21.6 and 19.4 MUM, respectively. CONCLUSIONS: EGCG is suggested to be a key contributor to the interaction of green tea with nadolol. Moreover, even a single coadministration of green tea may significantly affect nadolol pharmacokinetics. PMID- 29480325 TI - Poor health and refraining from seeking healthcare are associated with comprehensive health literacy among refugees: a Swedish cross-sectional study. AB - OBJECTIVES: The objectives of the study were to explore the distributions of comprehensive health literacy (CHL), general health, psychological well-being, and having refrained from seeking healthcare among refugees in Sweden. Further objectives were to examine associations between CHL and the above-mentioned factors. METHODS: A cross-sectional study was conducted among 513 refugees speaking Arabic, Dari, and Somali. Participants in the civic orientation course in Sweden responded to a questionnaire. CHL was measured using the HLS-EU-Q16 questionnaire. Uni- and multivariate logistic regression was used to investigate potential associations. RESULTS: The majority of the respondents had limited CHL, and about four of ten had reported poor health and/or having refrained from seeking healthcare. Limited CHL was associated with having reported poor health and having refrained from seeking healthcare. CONCLUSIONS: A considerable proportion of the refugees in Sweden have limited CHL, and report less than good health and impaired well-being, or that they have refrained from seeking healthcare. Furthermore, CHL is associated with the above-mentioned factors. Efforts are needed to promote refugees' CHL, optimal health-seeking behavior, and health. PMID- 29480327 TI - Biophysical Approaches to Protein Folding and Disease, a satellite meeting to the IUPAB-EBSA congress. PMID- 29480326 TI - Does community deprivation determine longevity after the age of 75? A cross national analysis. AB - OBJECTIVES: Analyze the association between socioeconomic deprivation and old-age survival in Europe, and investigate whether it varies by country and gender. METHODS: Our study incorporated five countries (Portugal, Spain, France, Italy, and England). A 10-year survival rate expressing the proportion of population aged 75-84 years who reached 85-94 years old was calculated at area-level for 2001-11. To estimate associations, we used Bayesian spatial models and a transnational measure of deprivation. Attributable/prevention fractions were calculated. RESULTS: Overall, there was a significant association between deprivation and survival in both genders. In England that association was stronger, following a dose-response relation. Although lesser in magnitude, significant associations were observed in Spain and Italy, whereas in France and Portugal these were even weaker. The elimination of socioeconomic differences between areas would increase survival by 7.1%, and even a small reduction in socioeconomic differences would lead to a 1.6% increase. CONCLUSIONS: Socioeconomic deprivation was associated with survival among older adults at ecological-level, although with varying magnitude across countries. Reasons for such cross-country differences should be sought. Our results emphasize the importance of reducing socioeconomic differences between areas. PMID- 29480328 TI - Ultra-early response assessment in lymphoma treatment: [18F]FDG PET/MR captures changes in glucose metabolism and cell density within the first 72 hours of treatment. AB - PURPOSE: To determine whether, in patients with Hodgkin lymphoma (HL) or non Hodgkin lymphoma (NHL), [18F]FDG PET/MR can capture treatment effects within the first week after treatment initiation, and whether changes in glucose metabolism and cell density occur simultaneously. METHODS: Patients with histologically proven HL or NHL were included in this prospective IRB-approved study. Patients underwent [18F]FDG PET/MR before, and then 48-72 h after (follow-up 1, FU-1) and 1 week after (FU-2) initiation of the first cycle of their respective standard chemotherapy (for HL) or immunochemotherapy (for NHL). Standardized [18F]FDG uptake values (SUVmax, SUVmean) and apparent diffusion coefficients (ADCmin, ADCmean) based on diffusion-weighted MRI, and metabolic and morphological tumour volumes (MTV, VOL) were assessed at each time-point. Multilevel analyses with an unstructured covariance matrix, and pair-wise post-hoc tests were used to test for significant changes in SUVs, ADCs, MTVs and VOLs between the three time points. RESULTS: A total of 58 patients (11 with HL and 47 with NHL) with 166 lesions were analysed. Lesion-based mean rates of change in SUVmax, SUVmean, ADCmin, ADCmean, MTV and VOL between baseline and FU-1 were -46.8%, -33.3%, +20.3%, +14%, -46% and -12.8%, respectively, and between baseline and FU-2 were 65.1%, -49%, +50.7%, +32.4%, -61.1% and -24.2%, respectively. These changes were statistically significant (P < 0.01) except for the change in VOL between baseline and FU-1 (P = 0.079). CONCLUSION: In lymphoma patients, [18F]FDG PET/MR can capture treatment-induced changes in glucose metabolism and cell density as early as 48-72 h after treatment initiation. PMID- 29480330 TI - Correction to: Heterogeneous functional expression of the sustained inward Na+ current in guinea pig sinoatrial node cells. AB - Dr. Wei-Guang Ding's given name and family name were inadvertently interchanged initially. The correct names are as shown above. PMID- 29480329 TI - Getting in shape and swimming: the role of cortical forces and membrane heterogeneity in eukaryotic cells. AB - Recent research has shown that motile cells can adapt their mode of propulsion to the mechanical properties of the environment in which they find themselves crawling in some environments while swimming in others. The latter can involve movement by blebbing or other cyclic shape changes, and both highly-simplified and more realistic models of these modes have been studied previously. Herein we study swimming that is driven by membrane tension gradients that arise from flows in the actin cortex underlying the membrane, and does not involve imposed cyclic shape changes. Such gradients can lead to a number of different characteristic cell shapes, and our first objective is to understand how different distributions of membrane tension influence the shape of cells in an inviscid quiescent fluid. We then analyze the effects of spatial variation in other membrane properties, and how they interact with tension gradients to determine the shape. We also study the effect of fluid-cell interactions and show how tension leads to cell movement, how the balance between tension gradients and a variable bending modulus determine the shape and direction of movement, and how the efficiency of movement depends on the properties of the fluid and the distribution of tension and bending modulus in the membrane. PMID- 29480331 TI - Relaxant effect of ghrelin on guinea pig isolated tracheal smooth muscle: role of epithelial NO and PGE2. AB - This study aimed at investigating the potential ghrelin relaxing effect on guinea pig isolated tracheal smooth muscle (TSM). Using an in vitro experimental approach, the physiological role of the airway epithelium on smooth muscle relaxation has been investigated by analyzing the dose-response curves for carbachol- or histamine-induced contractions on epithelium intact versus denuded tracheal tissue. The relaxant effect of ghrelin (5-200 MUmol/L) then investigated on carbachol-contracted, non-sensitized, and ovalbumin (OVA)-sensitized guinea pig TSM with an intact or denuded epithelium. The isolated TSMs from identical guinea pigs were incubated in Krebs solution aerated with 95% O2 and 5% CO2 through an automated tissue organ bath system (n = 6 for each group). The ghrelin relaxation mechanism was assessed by adding L-NAME, indomethacin, and YIL-781 for GHS-R1 into the tissue chamber. The spasmogens carbachol and histamine have shown a significantly higher contracting effect on epithelium-denuded than in epithelium-intact TSM confirmed by the significantly higher mean pEC50 of both agonists on the epithelium-denuded trachea (p < 0.05). Ghrelin has shown a concentration-dependent relaxing effect on carbachol-contracted TSM (r = 0.96, p = 0.00). The effect was more evident in the intact non-sensitized than in epithelium-denuded or OVA-sensitized groups (p < 0.05). Preincubation with nitric oxide (NO) and prostaglandin E2 (PGE2) inhibitors has significantly reduced the ghrelin-induced relaxation on epithelium-intact TSM suggesting an epithelium dependant mechanism. However, GHS-R1a antagonist has also succeeded to reduce ghrelin relaxant effect, which needs further clarification. Ghrelin proved to have a potential TSM relaxant effect possibly through epithelium-dependant mechanisms involving NO and PGE2. PMID- 29480333 TI - Characterization of structural and functional role of selenocysteine in selenoprotein H and its impact on DNA binding. AB - Selenoproteins are a group of proteins which contain selenocysteine (Sec or U) in their primary structure. Selenoproteins play a critical role in antioxidant defense, hormone metabolism, immune responses and muscle development. The selenoprotein H (SELENOH) is essential in the regulation of gene expression in response to redox status and antioxidant defense. It has Sec residue located in conserved CXXU motif similar to other selenoproteins. However, exact biological function of Sec residue in SELENOH is not known in detail. Therefore, it is essential to understand the structural and functional role of Sec in SELENOH. In the present study, homology modelling and MD simulation were performed to understand the role of Sec residue in SELENOH. The modelled 3D structure of wild SELENOH along with two mutants (Mut-U44C and Mut-41CS-SC44) was subjected to MD simulation. Based on simulation results, we demonstrate that wild-SELENOH structure is dynamically stabilized by network of intramolecular hydrogen bonding and internal residue contacts facilitated by Sec residue. In contrast, notable differences have been observed in residue contacts and stability in other two mutant structures. Additionally, docking studies revealed that 3PRGRKRK9 motif of wild-SELENOH interacts with HSE and STRE of DNA molecule as observed experimentally. Similar to earlier reports, our sequence analysis study pinpoints conserved 3PRGRKRK9 motif present in SELENOH perform dual role as AT-hook motif and NLS. Overall, the obtained results clearly illustrate Sec residue plays an important role to restore functionally active conformation of SELENOH. The present study broadened our current understanding regarding the role of selenocysteine in protein structure and function. PMID- 29480332 TI - Handling gene and protein names in the age of bioinformatics: the special challenge of secreted multimodular bacterial enzymes such as the cbhA/cbh9A gene of Clostridium thermocellum. AB - An increasing number of researchers working in biology, biochemistry, biotechnology, bioengineering, bioinformatics and other related fields of science are using biological molecules. As the scientific background of the members of different scientific communities is more diverse than ever before, the number of scientists not familiar with the rules for non-ambiguous designation of genetic elements is increasing. However, with biological molecules gaining importance through biotechnology, their functional and unambiguous designation is vital. Unfortunately, naming genes and proteins is not an easy task. In addition, the traditional concepts of bioinformatics are challenged with the appearance of proteins comprising different modules with a respective function in each module. This article highlights basic rules and novel solutions in designation recently used within the community of bacterial geneticists, and we discuss the present day handling of gene and protein designations. As an example we will utilize a recent mischaracterization of gene nomenclature. We make suggestions for better handling of names in future literature as well as in databases and annotation projects. Our methodology emphasizes the hydrolytic function of multi-modular genes and extracellular proteins from bacteria. PMID- 29480334 TI - Demethylation of methionine and keratin damage in human hair. AB - Growing human head hair contains a history of keratin and provides a unique model for studies of protein damage. Here, we examined mechanism of homocysteine (Hcy) accumulation and keratin damage in human hair. We found that the content of Hcy keratin increased along the hair fiber, with levels 5-10-fold higher levels in older sections at the hair's tip than in younger sections at hair's base. The accumulation of Hcy led to a complete loss of keratin solubility in sodium dodecyl sulfate. The increase in Hcy-keratin was accompanied by a decrease in methionine-keratin. Levels of Hcy-keratin were correlated with hair copper and iron in older hair. These relationships were recapitulated in model experiments in vitro, in which Hcy generation from Met exhibited a similar dependence on copper or iron. Taken together, these findings suggest that Hcy-keratin accumulation is due to copper/iron-catalyzed demethylation of methionine residues and contributes to keratin damage in human hair. PMID- 29480335 TI - Epithelial hyperplasia is responsible for the compensatory enlargement of remaining thyroid lobe after thyroidectomy. PMID- 29480336 TI - Brachial flow-mediated dilation predicts glycemia worsening in normoglycemic young subjects. PMID- 29480337 TI - Recent advances in microbial production of mannitol: utilization of low-cost substrates, strain development and regulation strategies. AB - Mannitol has been widely used in fine chemicals, pharmaceutical industries, as well as functional foods due to its excellent characteristics, such as antioxidant protecting, regulation of osmotic pressure and non-metabolizable feature. Mannitol can be naturally produced by microorganisms. Compared with chemical manufacturing, microbial production of mannitol provides high yield and convenience in products separation; however the fermentative process has not been widely adopted yet. A major obstacle to microbial production of mannitol under industrial-scale lies in the low economical efficiency, owing to the high cost of fermentation medium, leakage of fructose, low mannitol productivity. In this review, recent advances in improving the economical efficiency of microbial production of mannitol were reviewed, including utilization of low-cost substrates, strain development for high mannitol yield and process regulation strategies for high productivity. PMID- 29480338 TI - Rapidly progressive cognitive impairment caused by intracranial dural arteriovenous fistulas (DAVFs): a case report. AB - Intracranial dural arteriovenous fistulas (DAVFs), constituting approximately 10 to15% of intracranial vascular malformations, are anomalous direct connections between dural arteries and venous sinuses, meningeal veins, or cortical veins; the arterial feeders are various, usually fed by branches of internal carotid, external carotid, or vertebral artery (Santillan et al. CNN 115(3):241-251, 2013; Holoekamp et al. JN 124(6):1752-65, 2016; Terada T et al. JN 80(5):884-9, 1994). Spectrums of clinical presentations are widespread, arranging from pulsatile tinnitus to intracranial hemorrhage. Such DAVFs with rapidly progressive dementia as primary presentation, which has been reported in several literature, are still extremely scarce (Santillan et al. CNN 115(3):241-251, 2013; Holoekamp et al JN 124(6):1752-65, 2016). Up to 2015, similar reports are less than 20 cases (Holoekamp et al. JN 124(6):1752-65, 2016). Herein, we report a patient who was misdiagnosed with encephalitis, presented thalamic dementia, and was ultimately diagnosed of DAVFs. PMID- 29480339 TI - Primary Care Provider Practices and Perceptions Regarding HPV Vaccination and Anal Cancer Screening at a Boston Community Health Center. AB - Human papillomavirus (HPV) vaccination and anal cancer screening are valuable, yet underutilized, tools in prevention of HPV-related cancers among sexual and gender minority (SGM) populations. The aim of this study was to characterize primary care providers' (PCPs) practices and perceptions pertaining to HPV vaccination and anal cancer screening. A survey assessing self-reported practice characteristics related to HPV vaccination and anal cancer screening, as well as perceived barriers to vaccination and anal cancer screening at the patient-, provider-, and system-level was distributed to PCPs at a Federally-Qualified Health Center that specializes in care for SGM populations in the greater Boston area. A total of 33 PCPs completed the survey. All PCPs strongly recommended HPV vaccination to their patients by emphasizing that the vaccine is extremely important or very important. Most PCPs told their patients that the HPV vaccine prevents cervical cancer (96.9%), anal cancer (96.9%), oropharyngeal cancer (72.7%), penile cancer (57.5%), and genital warts (63.6%). There is substantial variability among providers regarding recommendations for anal cancer screening and follow-up. Most PCPs perceived that patient-level factors such as poverty, mental illness, and substance use disorders were barriers to HPV vaccination and anal cancer screening. Systems-level barriers such as lack of clinical time with each patient and lack of staffing were also described as barriers to vaccination and screening. Patient-, provider- and systems-level improvements are important to increase HPV vaccination and anal cancer screening rates. PMID- 29480341 TI - Intracanalicular vestibular schwannomas presenting with facial nerve paralysis. AB - BACKGROUND: To describe the surgical management and postoperative course of two patients presenting with facial nerve (FN) paralysis as one of the presenting symptoms of small intracanalicular vestibular schwannomas (VS). METHODS: Among 153 patients operated for VS since September 2010 to August 2017, two adult female patients presented with rapidly progressive hearing decrease, vestibular symptoms, and FN paralysis (House-Brackmann grades III and IV, respectively). In both cases, c.e. T1-weighted magnetic resonance imaging revealed an enhancing tumor within the internal auditory canal without lateral extension beyond the fundus. RESULTS: Retrosigmoid approach and excision of tumor showed that the origin of tumor was from the superior vestibular nerve, extrinsic to FN. Gross total tumor resection was obtained, with FN preservation. In the first case, a millimetric fragment of capsule was left because of tight adhesion on FN itself. Histopathology confirmed schwannoma. After surgery, both patients improved FN motor function. CONCLUSIONS: Although very rarely, VS may start clinically with FN palsy, mimicking FN schwannomas and other less common pathologies. This presentation is exceptional in patients with small intracanalicular VS. Early surgical resection is the only reliable treatment for decompression of nerve, avoiding a complete and not-reversible damage, with possible postoperative FN function improvement or complete recovery. PMID- 29480340 TI - Repeated stimulation by LPS promotes the senescence of DPSCs via TLR4/MyD88-NF kappaB-p53/p21 signaling. AB - Dental pulp stem cells (DPSCs), one type of mesenchymal stem cells, are considered to be a type of tool cells for regenerative medicine and tissue engineering. Our previous studies found that the stimulation with lipopolysaccharide (LPS) might introduce senescence of DPSCs, and this senescence would have a positive correlation with the concentration of LPS. The beta galactosidase (SA-beta-gal) staining was used to evaluate the senescence of DPSCs and immunofluorescence to show the morphology of DPSCs. Our findings suggested that the activity of SA-beta-gal has increased after repeated stimulation with LPS and the morphology of DPSCs has changed with the stimulation with LPS. We also found that LPS bound to the Toll-like receptor 4 (TLR4)/myeloid differentiation factor (MyD) 88 signaling pathway. Protein and mRNA expression of TLR4, MyD88 were enhanced in DPSCs with LPS stimulation, resulting in the activation of nuclear factor-kappaB (NF-kappaB) signaling, which exhibited the expression of p65 improved in the nucleus while the decreasing of IkappaB-alpha. Simultaneously, the expression of p53 and p21, the downstream proteins of the NF kappaB signaling, has increased. In summary, DPSCs tend to undergo senescence after repeated stimulation in an inflammatory microenvironment. Ultimately, these findings may lead to a new direction for cell-based therapy in oral diseases and other regenerative medicines. PMID- 29480343 TI - Correction to: Global dietary calcium intake among adults: a systematic review. AB - The original Electronic Supplementary Material file 3 contained an erroneous reference for Mali. A link to the corrected file is provided here. PMID- 29480342 TI - Heparin-bonded stent graft treatment for major visceral arterial injury after upper abdominal surgery. AB - PURPOSE: To analyse technical success, complications, and short- and intermediate term outcomes after heparin-bonded stent graft implantation for the treatment of major abdominal vessel injury after upper abdominal surgery. METHODS: This retrospective, IRB-approved analysis included 29 consecutive patients (female: n = 6, male: n = 23, mean age 65.9 +/- 11.2 years). All patients underwent angiography and attempted heparin-bonded stent-graft implantation because of a major visceral arterial injury after upper abdominal surgery. Electronic clinical records, angiographic reports and imaging datasets were reviewed to assess technical success and complications. Telephone interviews were performed to obtain follow-up information and to estimate short- (> 30 days) and intermediate term (> 90 days) outcomes. RESULTS: Successful stent graft placement was achieved in 82.8% (24/29). Peri-interventional complications were observed in 20.7% (6/29) and delayed, angiography-associated complications were observed in 34.5% (10/29) of the patients. Symptomatic re-bleeding occurred in 24.1% (7/29). Short-term survival (> 30 days) was 72.4% (21/29). Intermediate survival (> 90 days) was 37.9% (11/29). CONCLUSION: Treatment of major vascular injuries with heparin bonded stent grafts is feasible with a high technical success rate. However, survival depends on the underlying surgical condition, making interdisciplinary patient management mandatory. KEY POINTS: * Stent graft implantation is challenging, but has a high technical success rate. * Complications are frequent but surgical conversion is rarely necessary. * Survival depends on the underlying surgical condition causing the vascular injury. * Interdisciplinary management is crucial for the survival of these patients. PMID- 29480344 TI - Correction to: Stimulation of intestinal calcium absorption by orally administrated vitamin D3 compounds: a prospective open-label randomized trial in osteoporosis. AB - There were two errors in this article. 1. In the section "Ethical considerations", the registration number of the study was incorrectly given as UMIN000024492. The correct number is UMIN0000 20267. 2. The Acknowledgments paragraph was incomplete. PMID- 29480345 TI - Atrial fibrillation and its pernicious role in heart failure with preserved ejection fraction: a new frontier in interventional electrophysiology. PMID- 29480346 TI - U-shaped association between serum free triiodothyronine and recurrence of atrial fibrillation after catheter ablation. AB - PURPOSE: Thyroid dysfunction affects the outcomes of atrial fibrillation (AF) catheter ablation. However, it remains unclear if the variations in thyroid function, especially in the triiodothyronine levels, are associated with AF recurrence in euthyroid subjects. This study investigated the associations of thyroid hormone levels with arrhythmia recurrence after AF catheter ablation in euthyroid patients. METHODS: A total of 1115 consecutive AF patients who underwent catheter ablation were prospectively enrolled and had their thyroid function measured prior to the procedure. The serum free triiodothyronine (FT3), free tetraiodothyronine (FT4), and thyroid-stimulating hormone (TSH) levels were assessed as predictors of recurrence and were adjusted for potential confounders. The subjects were divided into five quintile groups according to the FT3, FT4, and TSH levels, respectively. RESULTS: After a median follow-up of 723 days (interquartile range, 180-1070), 47.2% of patients experienced recurrence. After multivariate adjustment, subject in the lowest and highest FT3 quintiles showed increased risk of recurrence (hazard ratio [HR] 1.60, 95% confidence interval [CI] 1.26-2.03, P < 0.01, and HR 1.47, 95% CI 1.16-1.87, P < 0.01, respectively), compared to the median quintile of FT3 levels. Regarding the FT4 level, the highest quintile group showed a higher risk of recurrence (HR 1.27, 95% CI 1.01 1.60, P = 0.04). The TSH levels were not associated with AF recurrence. CONCLUSIONS: Both high and low FT3 levels were associated with AF recurrence after catheter ablation. High-normal FT4 levels were also related to AF recurrence; however, no association was found between normal TSH levels and AF recurrence. PMID- 29480347 TI - Purinergic signaling as potential target of thiamethoxam-induced neurotoxicity using silver catfish (Rhamdia quelen) as experimental model. AB - Thiamethoxam is a broad-spectrum pesticide widely used in agricultural practice throughout the world. Worryingly, this pesticide is considered a potential contaminant on the surface and underground water, being a significant risk to aquatic ecosystems and humans. In this sense, we decided to evaluate the activity of enzymes belonging to purinergic system, which is linked with regulation of extracellular nucleotides and nucleosides, as adenosine triphosphate (ATP) and adenosine (Ado) molecules involved in the regulation of immune and inflammatory responses. Such as the neurotoxic effects of thiamethoxam remain poorly understood, the aim of this study was to evaluate whether purinergic signaling may be considered a potential target of thiamethoxam-induced neurotoxicity in silver catfish (Rhamdia quelen). Brain ectonucleoside triphosphate diphosphohydrolase (ATP as substrate) and 5'-nucleotidases activities were inhibited at 3.75 ug L-1 after 24 h of exposure and at 1.125 and 3.75 ug L-1 after 96 h of exposure compared with the control group. On the other hand, brain adenosine deaminase activity was stimulated at 3.75 ug L-1 after 24 h of exposure and at 1.125 and 3.75 ug L-1 after 96 h of exposure compared with the control group. Brain ATP levels increased at 3.75 ug L-1 after 24 h of exposure and at 1.125 and 3.75 ug L-1 after 96 h of exposure compared with the control group, while the Ado levels decreased. The enzymatic activity of the purinergic signaling did not return to control levels after a 48-h recovery period, revealing the potential neurotoxic effects of thiamethoxam. In summary, the brain purinergic signaling may be considered a potential target for thiamethoxam induced neurotoxicity in silver catfish. PMID- 29480348 TI - Impact of bacillus Calmette-Guerin therapy of upper urinary tract carcinoma in situ: comparison of oncological outcomes with radical nephroureterectomy. AB - The clinical benefits of bacillus Calmette-Guerin (BCG) therapy for the management of upper urinary tract carcinoma in situ (CIS) remain unclear. We aimed to compare the efficacy and safety of BCG therapy for upper urinary tract CIS with those of radical nephroureterectomy (RNU). Of 490 patients with upper urinary tract carcinoma, we retrospectively reviewed the post-treatment course of 58 patients with upper urinary tract CIS who underwent either RNU (RNU group) or BCG therapy (BCG group). Efficacy and safety were compared between the RNU and BCG groups. Inverse probability treatment-weighted (IPTW)-adjusted multivariate Cox regression analysis was performed to identify the influence of BCG therapy on prognosis. The RNU and BCG groups included 20 and 38 patients, respectively. No significant difference was found in patients' background, including age, sex, and performance status, between the groups. The reason underlying the selection of BCG therapy was bilateral CIS of the upper urinary tract (50%), solitary kidney (26%), unwillingness to undergo RNU (13%), and ineligibility for surgery (11%). The cytology became negative in 30 (79%) out of 38 patients after a 6-week course of BCG therapy, and 17 (57%) out of 30 patients remained negative. BCG-related adverse events (AEs) were observed in 92% of patients. The most common AE was cystitis (76%), followed by fever (50%). No significant differences were found in the progression-free, cancer-specific, and overall survivals between the RNU and BCG groups. IPTW-adjusted multivariate analysis revealed that BCG therapy did not worsen the prognosis of these patients. The limitations of our study were its retrospective design and small sample size. In conclusion, BCG therapy for upper urinary tract CIS might be a useful alternative for patient ineligible for RNU under careful observation for AEs. PMID- 29480350 TI - 3L, 5L, What the L? A NICE Conundrum. PMID- 29480349 TI - Fill in the Gaps of Secondary Mitral Regurgitation: a Continuum Challenge From Pathophysiology to Prognosis. AB - PURPOSE OF REVIEW: Mitral regurgitation (MR) is one of the most frequent valvular heart diseases encountered in clinical practice. In contrast to primary MR, less is still known about the pathophysiology, diagnosis, and prognosis of secondary MR. The purpose of this report is to provide a review, upon the last knowledge reported in the literature, on the role and management of secondary MR in clinical practice. RECENT FINDINGS: Recent data highlight secondary MR not as a single pathological entity but as a wide spectrum of interconnected conditions which portend poor outcome. Although the role of secondary MR on clinical outcome is debated, recent available data suggest an independent association of MR with prognosis. Nevertheless, available treatment did not show a clear benefit after MR correction. Further studies are needed to better categorize and assess secondary MR beyond schematic classification. A management approach should be tailored upon each clinical context of presentation. PMID- 29480351 TI - Leaf Composition of American Bur-Reed (Sparganium americanum Nutt.) to Determine Pesticide Mitigation Capability. AB - American bur-reed (Sparganium americanum Nutt.), a common aquatic plant in the middle and eastern United States and Canada, is often located in water-retaining drainage areas. The purpose of this study was to determine the leaf composition of S. americanum, paying attention to the cuticular waxes and the epidermis, and its ability to sorb pesticides. S. americanum leaves (n = 100) were collected in both early (June) and late (August) summer. Transverse sections of S. americanum were stained and studied with brightfield and fluorescence microscopy to estimate the structural and chemical nature of the leaf tissues cross sections. Mean total lipid content in early summer leaf samples (1.47 +/- 0.83 mg mL-1) was significantly greater (alpha 0.05) than late summer leaves (0.15 +/- 0.36 mg mL 1). In vitro analysis of epidermal peel permeability exposed to atrazine and malathion determined little to no sorption by the plant. Therefore, the structure of S. americanum leaves suggest this species does not have the capacity of sorbing these pesticides from runoff water. PMID- 29480352 TI - Metabolomics Profile in ABAT Deficiency Pre- and Post-treatment. AB - Metabolomic profiling is an emerging technology in the clinical setting with immediate diagnostic potential for the population of patients with Inborn Errors of Metabolism. We present the metabolomics profile of two ABAT deficiency patients both pre- and posttreatment with flumazenil. ABAT deficiency, also known as GABA-transaminase deficiency, is caused by recessive mutations in the gene ABAT and leads to encephalopathy of variable severity with hypersomnolence, hypotonia, hypomyelination, and seizures. Through metabolomics screening of multiple patient tissues, we identify 2-pyrrolidinone as a biomarker for GABA that is informative in plasma, urine, and CSF. These data will enable noninvasive diagnostic testing for the population of patients with disorders of GABA metabolism. PMID- 29480353 TI - Multiplex immunoassay measurement of amyloid-beta42 to amyloid-beta40 ratio in plasma discriminates between dementia due to Alzheimer's disease and dementia not due to Alzheimer's disease. AB - The cerebrospinal fluid (CSF) biomarkers amyloid-beta42 (Abeta42), total Tau, and phospho-181-Tau represent important diagnostic tools to support the clinical diagnosis of Alzheimer's disease (AD). Acquiring CSF by lumbar puncture is considered a moderately invasive procedure, while blood sampling is minimally invasive with calculable risks and can be performed by trained non-medical staff. Thus, the identification of reliable and robust blood biomarkers of AD-related neuropathology would be significantly advantageous in daily practice and would allow more patients to be screened. In this study, we performed a multiplex amyloid-beta assay to simultaneously measure Abeta40 and Abeta42. We analyzed how well Abeta40, Abeta42, and the Abeta42 to Abeta40 ratio (Abeta42/40) could differentiate between patients suffering from dementia either due or not due to AD. In addition, we studied different factors affecting Abeta levels in plasma. Plasma Abeta42/40 level was significantly lower in patients with dementia due to AD than in those with dementia due to other causes. Abeta42/40 correlated weakly between plasma and CSF, but did not differ between amyloid-PET positive or negative patients. Furthermore, we found that kidney function influences Abeta40 and Abeta42 plasma levels, but not Abeta42/40 level. Liver function, age, and sex do not affect Abeta levels in plasma. PMID- 29480354 TI - Effects of saccade training on express saccade proportions, saccade latencies, and peak velocities: an investigation of nasal/temporal differences. AB - Express saccades have very short latencies and are often considered a special population of saccadic eye movements. Recent evidence suggests that express saccade generation in humans increases with training, and that this training is independent of the actual saccade vector being trained. We assessed the time course of these training-induced increases in express saccade generation and how they differ between the nasal and temporal hemifields, and second whether they transfer from the trained to the untrained eye. We also measured the effects of training on saccade latencies more generally, and upon peak velocities. The training effect transferred between the nasal and temporal hemifields and between the trained and untrained eyes. More surprisingly, we found an asymmetric effect of training on express saccade proportions: Before training, express saccade proportions were higher for saccades made into the nasal hemifield but with training this reversed. This training-induced asymmetry was also observed in overall saccade latencies, showing how training can unmask nasal/temporal asymmetries in saccade latencies. Finally, we report for the first time that saccadic peak velocities increased with training, independently of changes in amplitude. PMID- 29480356 TI - Non-immunologic allograft loss in pediatric kidney transplant recipients. AB - Non-immunologic risk factors are a major obstacle to realizing long-term improvements in kidney allograft survival. A standardized approach to assess donor quality has recently been introduced with the new kidney allocation system in the USA. Delayed graft function and surgical complications are important risk factors for both short- and long-term graft loss. Disease recurrence in the allograft remains a major cause of graft loss in those who fail to respond to therapy. Complications of over immunosuppression including opportunistic infections and malignancy continue to limit graft survival. Alternative immunosuppression strategies are under investigation to limit calcineurin inhibitor toxicity. Finally, recent studies have confirmed long-standing observations of the significant negative impact of a high-risk age window in late adolescence and young adulthood on long-term allograft survival. PMID- 29480355 TI - A "matched" sensory reference can guide goal-directed movements of the affected hand in central post-stroke sensory ataxia. AB - Patients with central post-stroke sensory ataxia (CPSA) suffer from not only somatosensory dysfunction but also the ataxic movement disorder of the affected limb. These sensory and motor impairments possibly interfere each other, but such interference is still unclear. We evaluated smoothness of grasp movements in CPSA patients using a kinematic analysis, and verified the effect of somatosensory reference from the intact hand on grasp movements. Eight CPSA patients were enrolled. We recorded their reach-and-pinch movements of both affected and intact hands toward the tip of the 3-cm-diameter vertical bar, using a three-dimensional measurement system. When executing these movements of one hand, the patients simultaneously pinched the same diameter bar as the goal tip (matched-reference condition: Matched-Ref) or the 5-cm-diameter thicker bar (mismatched-reference condition: Mismatched-Ref) by the other hand. The normalized jerk index (i.e., movement smoothness) of the affected hand was disturbed compared with the intact hand. The kinematic data of the finger opening and closing phases were also disturbed. These disturbances were partially improved with Matched-Ref but not Mismatched-Ref of the intact hand. We successfully evaluated the features of CPSA, indicating that the somatosensory reference method could be useful for rehabilitation in sensory ataxia. PMID- 29480357 TI - Maintenance of Remission with Etanercept-DMARD Combination Therapy Compared with DMARDs Alone in African and Middle Eastern Patients with Active Rheumatoid Arthritis. AB - INTRODUCTION: To compare etanercept (ETN) and placebo (PBO) for maintaining low disease activity (LDA) achieved with ETN in patients with rheumatoid arthritis (RA) from Africa and the Middle East. METHODS: In this subset analysis of the Treat-to-Target trial (ClinicalTrials.gov identifier NCT01981473), 53 adult patients with moderate-to-severe RA nonresponsive to methotrexate were treated with 50 mg ETN/week for 24 weeks (Period 1). Patients achieving LDA were randomized to continue ETN treatment or switched to PBO for an additional 28 weeks (Period 2). The proportion of patients maintaining LDA or remission in each arm at the end of Period 2 was determined. Additional efficacy and patient reported outcomes (PROs) were also evaluated. RESULTS: During Period 1, 51 patients achieved LDA according to the disease activity score-28 joints erythrocyte sedimentation rate (DAS28-ESR LDA) and 30 achieved remission. At week 52, nine of 22 and eight of 29 in the ETN and PBO groups, respectively, remained in DAS28-ESR LDA without experiencing a flare. Additionally, six of 14 and five of 16 in the ETN and PBO groups, respectively, remained in remission. Among patients experiencing a flare during Period 2, 13 of 22 and 21 of 29 received ETN or PBO, respectively. The median time to flare was 193 and 87 days in the ETN and PBO groups, respectively. At week 52, consistently more patients in the ETN group than in the PBO group achieved predetermined efficacy and PRO endpoints. CONCLUSIONS: These data suggest continuing ETN maintenance therapy is beneficial to patients after they have achieved their treatment target. However, this subset analysis is limited by the small patient population and must be interpreted with caution. FUNDING: Pfizer. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT0198147. PMID- 29480358 TI - Living with Juvenile Idiopathic Arthritis: Parent and Physician Perspectives. AB - This article, co-authored by a parent of a child with juvenile idiopathic arthritis (JIA) and his pediatric rheumatologist, discusses the parent's experience of having a child with JIA from diagnosis through living day-to-day with the disease. PMID- 29480359 TI - Scaling of work and power in a locomotor muscle of a frog. AB - Muscle work and power are important determinants of movement performance in animals. How these muscle properties scale determines, in part, the scaling of performance during movements, such as jump height or distance. Muscle-mass specific work is predicted to remain constant across a range of scales, assuming geometric similarity, while muscle-mass-specific power is expected to decrease with increasing scale. We tested these predictions by examining muscle morphology and contractile properties of plantaris muscles from frogs ranging in mass from 1.28 to 20.60 g. Scaling of muscle work and power was examined using both linear regression on log10-transformed data (LR) and non-linear regressions on untransformed data (NLR). Results depended on the method of regression not because of large changes in scaling slopes, but because of changing levels of statistical significance using corrections for multiple tests, demonstrating the importance of careful consideration of statistical methods when analyzing patterns of scaling. In LR, muscle-mass-specific work decreased with increasing scale, but an accompanying positive allometry of muscle mass predicts constant movement performance at all scales. These relationships were non-significant in NLR, though scaling with geometric similarity also predicts constant jump performance across scales, because of proportional increases in available muscle energy and body mass. Both intrinsic shortening velocity and muscle-mass-specific power were positively allometric in both types of analysis. Nonetheless, scale accounts for little variation in contractile properties overall over the range examined, indicating that other sources of intraspecific variation may be more important in determining muscle performance and its effects on movement. PMID- 29480360 TI - Cochlear implantation in the elderly: outcomes, long-term evolution, and predictive factors. AB - OBJECTIVE: Our goal in this study is to find out the outcomes of cochlear implantation in elderly (> 60 years) and check if this improvement is similar to that of their younger counterparts in short- and long-term evolution. In addition, we have attempted to ascertain the predictive factors that might affect the verbal comprehension results of older patients. STUDY DESIGN: Retrospective cohort study. METHODS: Ninety-four patients older than 40 years, divided into two groups. 40-60 years n = 55 and > 60 years n = 39. A pure-tone audiometry, a disyllabic word test, and the test of phonetically balanced sentences of Navarra were made in silence to each patient. These measurements were made pre implantation and 1, 5, and 10 year post-implantation. Peri- and postoperative complications were registered. The hypothetic predictive factors of post implanted performance were evaluated in the elderly. RESULTS: Our study shows no significant difference between young and old adult's outcomes in short- and long term evolutions, nor in the complication rate. Furthermore, we proved the significant influence of the side of implantation, use of hearing aids, and duration of hearing loss in the short- and long-term results in the elderly. CONCLUSION: This study shows that cochlear implantation in the elderly is as safe, useful, and worthwhile as in young adults. Age has a low influence in cochlear implant outcomes; however, we have found the significant influence of the side of implantation, the use of hearing aids, and the duration of hearing loss in the short- and long-term results. PMID- 29480361 TI - Effect of long-term oral appliance therapy on obstruction pattern in patients with obstructive sleep apnea. AB - PURPOSE: Oral appliance therapy is an alternative treatment modality for obstructive sleep apnea (OSA). However, there have been no studies to determine whether changes in the obstructive pattern occur following long-term use of oral devices. Therefore, we examined whether the obstructive pattern changes in patients with OSA who undergo long-term oral appliance therapy using drug-induced sleep endoscopy (DISE). METHODS: We investigated 156 consecutive patients diagnosed with OSA. Seventy-nine of these patients were found to be eligible for inclusion in this study. All enrolled patients underwent two DISE examinations: before and after oral appliance use. We compared the DISE findings for each patient in terms of degree and configuration of airway obstruction at the levels of the velum, oropharynx, tongue base, and epiglottis. RESULTS: We found that dental problems, as assessed using the average values of overjet and overbite, were significantly decreased after 2 years of oral appliance use. Comparisons of the DISE findings revealed that there was significant widening of the upper airway structures following long-term oral appliance therapy, especially in the velum (P = 0.022) and epiglottis (P = 0.001). However, changes in the configuration of upper airway obstruction were not observed in any of the structures of the upper airway. CONCLUSIONS: We found evidence possibly indicating decreased obstruction at the levels of the velum and epiglottis after long-term use of oral appliances. We suggest further cohort studies to confirm these findings. PMID- 29480364 TI - Combination of S-1 and gefitinib increases the sensitivity to radiotherapy in lung cancer cells. AB - OBJECTIVE: To investigate the potential radiosensitization of S-1 and gefitinib in human non-small cell lung cancer (NSCLC) in vitro and in vivo. METHODS: The impact of radiation, 5-fluorouracil (5-Fu), and gefitinib on the proliferation and apoptosis of human NSCLC A549, H1299, H1975, and HCC827 cells was examined by MTT and flow cytometry. The effect of radiation, 5-Fu, and gefitinib on the clonogenicity of H1975 and HCC827 cells was determined by colony formation assay. The effect of radiation, 5-fluorouracil (5-Fu), and gefitinib on the EGFR, AKT, and ERK1/2 activation in H1975 cells was determined by Western blot. The therapeutic efficacy of radiation, S-1, and gefitinib in the growth of implanted H1975 tumors and the AKT activation in the tumors were examined in vivo and immunohistochemistry, respectively. RESULTS: Combination of radiation, 5-Fu, and gefitinib significantly inhibited the proliferation of H1975 cells and triggered their apoptosis, but not other NSCLC cells tested. The combination therapy significantly mitigated the clonogenicity and attenuated the activation of EGFR and AKT signaling in H1975 cells. Furthermore, combination of S-1, gefitinib, and radiation significantly inhibited the growth of implanted H1975 tumors in mice and remarkably reduced the AKT phosphorylation in the tumors. CONCLUSIONS: Our data indicated that combination of S-1 and gefitinib significantly increased radiosensitivity of H1975 cells. The triple combination therapies may benefit patients with the EGFR T790M mutant NSCLC. PMID- 29480362 TI - Functional and cosmetic donor site morbidity of the radial forearm-free flap: comparison of two different coverage techniques. AB - BACKGROUND: The use of the radial forearm-free flap is a well-established and reliable reconstruction method in head and neck surgery. Usually, the defect of the donor site is covered with full or split-thickness skin grafts. Since 09/2013, a direct closure of the radial forearm donor site has been performed at the ENT University Hospital Leipzig to avoid secondary donor site morbidity. However, few data are available in the literature on long-term cosmetic and functional results compared to the established indirect donor site defect coverage. METHODS: This study investigated patients with radial forearm-free flap harvest from 01/2012 until 03/2015. A total of n = 39 patients were included, with n = 18 being operated by indirect (group 1) and n = 21 by direct closure technique (group 2). For the validation of surgical revisions and wound healing disorders, we carried out clinical investigations as well as interviews. The "POSAS Observer and Patient Scale" was used for assessing the cosmetic outcome and the "Michigan Hand Outcome Questionnaire (MHQ)" for functional criteria. RESULTS: Group 2 showed an increased rate of wound healing problems, however it was not statistically different compared to group 1. Revision surgery was necessary in both groups only each in one case. Using the POSAS, there were no significant differences between both groups in the observer scale for the items vascularity, pigmentation, thickness, relief, pliability, surface area and even for pain, scar itching, color, stiffness, thickness and relief in the patient scale. The functional results (MHOQ) also showed no significantly inferior results for group 2. CONCLUSIONS: The direct closure procedure is quick, simple and can be performed without secondary donor site morbidity. For wound healing, cosmetic and function of the forearm and hand, no inferior results can be measured for the direct procedure compared to the indirect coverage technique. PMID- 29480363 TI - Ultrasound plus low-level laser therapy for knee osteoarthritis rehabilitation: a randomized, placebo-controlled trial. AB - This study evaluated the synergistic effects of ultrasound (US) and low-level laser therapy (LLLT) with or without therapeutic exercises (TE) in women with knee osteoarthritis. Forty-two Caucasian women with knee osteoarthritis were allocated into three groups: (1) the placebo group who did not perform TE, but the prototype without emitting light or ultrasonic waves was applied, (2) the US + LLLT group in which only the prototype was applied and (3) the TE + US + LLLT group that performed TE before the prototype was applied. However, 35 women completed the full clinical trial. Pressure pain thresholds (PPT) using an algometer and functional performance during the sit-to-stand test were carried out. The average PPT levels increased for US + LLLT (41 +/- 9 to 54 +/- 15 N, p < 0.01) and TE + US + LLLT (32 +/- 8 to 45 +/- 9 N, p < 0.01) groups. The number of sit-to-stands was significantly higher for all groups. However, the change between pre-treatment and post-treatment (delta value) was greater for the US + LLLT (4 +/- 1) and TE + US + LLLT groups (5 +/- 1) than for the placebo group (2 +/- 1) with a significant intergroup difference (p < 0.05). This study showed reduced pain and increased physical functionality after 3 months of US + LLLT with and without TE. PMID- 29480365 TI - [West Africa Ebola outbreak - immediate and hands-on formation: the pre deployment training program for frontline aid workers of the German Red Cross, other aid organizations, and the German Armed Forces, Wuerzburg, Germany 2014/15]. AB - BACKGROUND: In September 2014, the German government mandated the German Red Cross (GRC) and the German Armed Forces to support the international efforts to stop the epidemic of Ebola virus disease (EVD) in West-Africa. The GRC requested specific training from the Medical Mission Institute Wuerzburg (MI). OBJECTIVES: We describe and discuss the development, strategy, results, and evaluation of the program to formulate conclusions and recommendations for similar emergencies. METHODS: On 26 September 2014, it was agreed to establish a two-day training program to prepare Ebola aid workers for the treatment of EVD patients and infection protection in Ebola treatment centers (ETC) in the epidemic area. Course evaluation was based on protocoled discussions with participants and standardized questionnaires. RESULTS: The training started on 6 October 2014. By 24 February 2015, 214 trainees participated in 14 courses. Of 96 GRC staff deployed to West Africa, 90 (94%) participated in the training. Course content included containment strategy in filovirus outbreaks and practical exercises for standardized procedures in personal protective equipment (PPE). The average trainer-trainee ratio in PPE exercises was 1:3. "Excellent" or "good" ratings were received on 93% of the evaluations. CONCLUSION: Rapid implementation was possible by teaching a harmonized, and field-approved concept for infection protection and treatment. Realistic simulated scenarios and field-experienced trainers allowed transfer of knowledge as well as reassurance. Additional recommendations are further conversion of the training into a permanent program and, in the case of a crisis, interlocking of training with operational planning to allow rapid escalation and adaptation. Also, the concepts for training and interventions should be harmonized and developed further for additional challenges like airborne transmission and application of intensive-care medicine. PMID- 29480366 TI - Inflammatory cytokine TNF-alpha promotes corneal endothelium apoptosis via upregulating TIPE2 transcription during corneal graft rejection. AB - PURPOSE: Endothelial dysfunction accounts for 50% of total corneal transplantation failures, suggesting that corneal endothelial damage is the leading cause of graft failure. Tumor necrosis factor-alpha (TNF-alpha) is known to contribute to the negative regulation of corneal transplantation, but how it does so remains unclear. Here, we report a regulatory loop involving TNF-alpha, TNF-alpha-induced protein 8 like 2 (TNFAIP8L2 or TIPE2), and apoptosis during corneal graft rejection. METHODS: We established mice models of penetrating keratoplasty to verify whether the quantification of TNF-alpha in allogeneic corneas is enhanced through ELISA assay and immunofluorescence staining. In cornea tissues, we obtained corneal endothelium and measured apoptosis of the removed cells. Meanwhile, quantitative real-time PCR and Western blotting were used to detect the mRNA and protein expression of TIPE2. In human corneal endothelial cells, we verified the conclusions through some experiments. By specifically knocking down TIPE2, we detected the importance of TIPE2 in TNF alpha-triggered apoptosis. RESULTS: In mice models, TNF-alpha was higher in the cornea and aqueous humor in allograft group and TNF-alpha elevation increased the apoptosis of the corneal endothelium. In addition, high levels of TIPE2 were found in allograft rejection models following TNF-alpha elevation. In human corneal endothelial cells (HCECs), TNF-alpha clearly augments TIPE2 expression and promotes cell apoptosis through upregulating TIPE2 transcription. Knocking down markedly decreased cell apoptosis. CONCLUSIONS: Our study identifies the molecular mechanisms underlying the interplay of TNF-alpha, TIPE2, and apoptosis during allograft rejection, and it suggests that both TNF-alpha and TIPE2 might be potential targets for the successfully grafted corneal endothelium. PMID- 29480367 TI - Subretinal fibrosis is associated with fundus pulverulentus in pseudoxanthoma elasticum. AB - BACKGROUND: Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive disorder caused by mutations in the ABCC6 gene, resulting in various retinal lesions, among other systemic manifestations. Visual loss may occur in PXE, most commonly caused by choroidal neovascularization and macular atrophy, but little is known about the consequences of fundus pulverulentus (FP) in PXE. The aim of this study was to evaluate ophthalmic outcomes in patients with FP associated with PXE in a large series of PXE patients. METHODS: In a retrospective observational study, ophthalmic outcomes were compared between two groups of age-matched patients with genetically and pathologically confirmed PXE: one group with FP versus one without FP. All included patients underwent thorough clinical examination. Further investigation (optical coherence tomography (OCT), Cirrhus, Zeiss Germany, and/or fluorescein/indocyanin green angiography) was performed in cases of suspected choroidal neovascularization (CNV). RESULTS: The study included 13 PXE patients with FP (group 1: 8 men and 5 women, aged 45-65 years) and 47 age matched PXE patients without FP (group 2: 19 men and 28 women). Mean patient follow-up was 63 months (range 0-132 months). Subretinal fibrosis (SRF) was more frequently associated with FP (9/26 eyes, 34.6%), compared to absence of FP (4/94, 4.2%) (p = 0.0001). Independently of SRF, FP can evolve into deep macular atrophy and/or CNV with dramatic consequences for central vision. CONCLUSIONS: Fundus pulverulentus may occur in PXE and is most commonly associated with subretinal fibrosis in the posterior pole and visual loss by macular atrophy even in the absence of CNV. PMID- 29480368 TI - The Global Epidemic of the Metabolic Syndrome. AB - Metabolic syndrome, variously known also as syndrome X, insulin resistance, etc., is defined by WHO as a pathologic condition characterized by abdominal obesity, insulin resistance, hypertension, and hyperlipidemia. Though there is some variation in the definition by other health care organization, the differences are minor. With the successful conquest of communicable infectious diseases in most of the world, this new non-communicable disease (NCD) has become the major health hazard of modern world. Though it started in the Western world, with the spread of the Western lifestyle across the globe, it has become now a truly global problem. The prevalence of the metabolic syndrome is often more in the urban population of some developing countries than in its Western counterparts. The two basic forces spreading this malady are the increase in consumption of high calorie-low fiber fast food and the decrease in physical activity due to mechanized transportations and sedentary form of leisure time activities. The syndrome feeds into the spread of the diseases like type 2 diabetes, coronary diseases, stroke, and other disabilities. The total cost of the malady including the cost of health care and loss of potential economic activity is in trillions. The present trend is not sustainable unless a magic cure is found (unlikely) or concerted global/governmental/societal efforts are made to change the lifestyle that is promoting it. There are certainly some elements in the causation of the metabolic syndrome that cannot be changed but many are amenable for corrections and curtailments. For example, better urban planning to encourage active lifestyle, subsidizing consumption of whole grains and possible taxing high calorie snacks, restricting media advertisement of unhealthy food, etc. Revitalizing old fashion healthier lifestyle, promoting old-fashioned foods using healthy herbs rather than oil and sugar, and educating people about choosing healthy/wholesome food over junks are among the steps that can be considered. PMID- 29480369 TI - Traumatic cervical spine injuries in a patient with pycnodysostosis. AB - Pycnodysostosis is a rare hereditary disease, characterized by systemic bone sclerosis. Susceptibility to long bone fractures is characteristic, whereas vertebral fractures are extremely rare. We report a case of a 21-year-old man with a past history of pycnodysostosis and spontaneous leg fractures who was admitted in hospital for a neck pain after a banal fall. Radiological examination revealed C1-C2-C3 posterior arch fractures with a C3-C4 left articular fracture dislocation. A surgical stabilization was decided but refused by the patient. To the best of our knowledge, this is the first publication that reports pycnodysostosis with cervical spine traumatic staged injuries. PMID- 29480370 TI - New Developments in Hypertensive Encephalopathy. AB - PURPOSE OF REVIEW: This review summarizes the latest science on hypertensive encephalopathy and posterior reversible encephalopathy syndrome (PRES). We review the epidemiology and pathophysiology of these overlapping syndromes and discuss best practices for diagnosis and management. RECENT FINDINGS: Diagnosis of hypertensive encephalopathy largely relies on exclusion of other neurological emergencies. We review the extensive causes of PRES and its imaging characteristics. Management strategies have not changed substantially in the past decade, though newer calcium channel blockers simplify the approach to blood pressure reduction. While this alone may be sufficient for treatment of hypertensive encephalopathy in most cases, management of PRES also depends on modification of other precipitating factors. Hypertensive encephalopathy and PRES are overlapping disorders for which intensive blood pressure lowering is critical. Further research is indicated to both in diagnosis and additional management strategies for these critical conditions. PMID- 29480371 TI - Antirotaviral potential of lactoferrin from different origin: effect of thermal and high pressure treatments. AB - Rotaviral gastroenteritis causes a high rate of infant mortality and severe healthcare implications worldwide. Several studies have pointed out that human milk and dairy fractions, such as whey and buttermilk, possess antirotaviral activity. This activity has been mainly associated with glycoproteins, among them lactoferrin (LF). Thermal treatments are necessary to provide microbiological safety and extend the shelf life of milk products, though they may diminish their biological value. High hydrostatic pressure (HHP) treatment is a non-thermal method that causes lower degradation of food components than other treatments. Thus, the main objective of this study was to prove the antirotaviral activity of LFs from different origin and to evaluate the effect of several thermal and HHP treatments on that activity. LF exerted a high antirotaviral activity, regardless of its origin. Native LFs from bovine, ovine, swine and camel milk, and the human recombinant forms, at 1 mg/mL, showed neutralizing values in the range 87.5 98.6%, while human LF neutralized 58.2%. Iron saturation of bovine LF did not modify its antirotaviral activity. Results revealed interspecies differences in LFs heat susceptibility. Thus, pasteurization at 63 degrees C for 30 min led to a decrease of 60.1, 44.5, 87.1, 3.8 and 8% of neutralizing activity for human, bovine, swine, ovine and camel LFs, respectively. Pasteurization at 75 degrees C for 20 s was less harmful to the activity of LFs, with losses ranging from 0 to 13.8%. HHP treatment at 600 MPa for 15 min did not cause any significant decrease in the neutralizing activity of LFs. PMID- 29480372 TI - Anatomy of the right colic vein and pancreaticoduodenal branches: a surgical landmark for laparoscopic complete mesocolic excision of the right colon. AB - PURPOSE: Knowledge of mesenteric venous anatomy is important to safely perform laparoscopic complete mesocolic excision (CME) of the right colon. Despite their previously reported diversity, consistent features of the right colonic and pancreatic veins can be discerned. The objective of this study was to evaluate anatomical consistency of the right colic vein (RCV) and the pancreaticoduodenal vein associated with the colic vein (PDV-C). METHODS: This study included 125 consecutive patients undergoing contrast-enhanced multidetector-row CT of the abdomen. Images of 100 of these cases were retrospectively reviewed for the positioning of the colonic, gastric and pancreatic veins associated with the superior mesenteric vein (SMV). RCV were classified as three types: Type-I, running on the ventral aspect of the pancreatic head and draining into the right lateral wall of the SMV; Type-II, running apart from the pancreatic head and directly draining into the SMV; and Type-III, draining into the tributaries of the SMV. RESULTS: The RCV was identified in 88% of cases, in which the frequencies of Type-I, -II and -III anatomies were 84.1, 9.1, and 6.8%, respectively. All of the Type-I RCVs formed a common trunk with other veins, including the gastroepiploic vein (93.2%) and the superior RCV (59.5%). The PDV-C joined the RCV in 63.5% of the Type-I cases. CONCLUSIONS: Anatomical consistency of the RCV together with the PDV-C is present in the majority of cases. Our findings support the view that the appearance of the veins is a useful landmark for laparoscopic CME of the right colon. PMID- 29480374 TI - Full-thickness flame burns. PMID- 29480373 TI - Molecular docking, molecular modeling, and molecular dynamics studies of azaisoflavone as dual COX-2 inhibitors and TP receptor antagonists. AB - Designed multi-target ligand (DML) is an emerging strategy for the development of new drugs and involves the engagement of multiple targets with the same moiety. In the context of NSAIDs it has been suggested that targeting the thromboxane prostanoid (TP) receptor along with cyclooxygenase-2 (COX-2) may help to overcome cardiovascular (CVS) complications associated with COXIBs. In the present work, azaisoflavones were studied for their COX-2 and TP receptor binding activities using structure based drug design (SBDD) techniques. Flavonoids were selected as a starting point based on their known COX-2 inhibitory and TP receptor antagonist activity. Iterative design and docking studies resulted in the evolution of a new class scaffold replacing the benzopyran-4-one ring of flavonoids with quinolin-4 one. The docking and binding parameters of these new compounds are found to be promising in comparison to those of selective COX-2 inhibitors, such as SC-558 and celecoxib. Owing to the lack of structural information, a model for the TP receptor was generated using a threading base alignment method with loop optimization performed using an ab initio method. The model generated was validated against known antagonists for TP receptor using docking/MMGBSA. Finally, the molecules that were designed for selective COX-2 inhibition were docked into the active site of the TP receptor. Iterative structural modifications and docking on these molecules generated a series which displays optimum docking scores and binding interaction for both targets. Molecular dynamics studies on a known TP receptor antagonist and a designed molecule show that both molecules remain in contact with protein throughout the simulation and interact in similar binding modes. Graphical abstract ?. PMID- 29480375 TI - Place recognition from distant landmarks: human performance and maximum likelihood model. AB - We present a simple behavioral experiment on human place recognition from a configuration of four visual landmarks. Participants were asked to navigate several paths, all involving a turn at one specific point, and while doing so incidentally learned the position of that turning point. In the test phase, they were asked to return to the turning point in a reduced environment leaving only the four landmarks visible. Results are compared to two versions of a maximum likelihood model of place recognition using either view-based or depth-based cues for place recognition. Only the depth-based model is in good qualitative agreement with the data. In particular, it reproduces landmark configuration dependent effects of systematic bias and statistical error distribution as well as effects of approach direction. The model is based on a place code (depth and bearing of the landmarks at target location) and an egocentric working memory of surrounding space including current landmark position in a local, map-like representation. We argue that these elements are crucial for human place recognition. PMID- 29480377 TI - Phenotypic manifestations of the m.8969G>A variant. PMID- 29480378 TI - Reply to 'Letter to Editor by Finsterer J and Zarrouk-Mahjoub S: Phenotypic manifestations of the m.8969G>A variant'. PMID- 29480376 TI - Neuroendocrine neoplasms - still a challenge despite major advances in clinical care with the development of specialized guidelines. PMID- 29480380 TI - Engineering a thermostable highly active glucose 6-phosphate dehydrogenase and its application to hydrogen production in vitro. AB - Glucose 6-phosphate dehydrogenase (G6PDH) is one of the most important dehydrogenases responsible for generating reduced NADPH for anabolism and is also the rate-limiting enzyme in the Entner-Doudoroff pathway. For in vitro biocatalysis, G6PDH must possess both high activity and good thermostability due to requirements of efficient use and low expense of biocatalyst. Here, we used directed evolution to improve thermostability of the highly active G6PDH from Zymomonas mobilis. Four generations of random mutagenesis and Petri-dish-based double-layer screening evolved the thermolabile wild-type enzyme to the thermostable mutant Mut 4-1, which showed a more than 124-fold increase in half life time (t1/2) at 60 degrees C, a 3.4 degrees C increase in melting temperature (T m ), and a 5 degrees C increase in optimal temperature (Topt), without compromising the specific activity. In addition, the thermostable mutant was conducted to generate hydrogen from maltodextrin via in vitro synthetic biosystems (ivSB), gaining a more than 8-fold improvement of productivity rate with 76% of theoretical yield at 60 degrees C. Thus, the engineered G6PDH has been shown to effectively regenerate NADPH at high temperatures and will be applicable for NAD(P)H regeneration in numerous in vitro biocatalysis applications. PMID- 29480379 TI - Diagnostic and prognostic relevance of salivary microRNA-21, -125a, -31 and -200a levels in patients with oral lichen planus - a short report. AB - BACKGROUND: Oral lichen planus (OLP), a relatively common chronic inflammatory disease of the oral mucosa, is considered to be a premalignant disorder of the oral cavity. Previously, several biomarkers have been tested for their diagnostic potential. Here, we aimed to investigate the diagnostic potential of four miRNAs, miR-21, -125a, -31 and -200a, known to be involved in oral squamous cell carcinoma (OSCC) development, in the saliva of OLP patients as also their putative relation to OSCC development in these patients. MATERIALS AND METHODS: Saliva samples from 30 patients with OLP were collected, 15 of whom were diagnosed with dysplasia upon histopathologic examination. In addition, 15 saliva samples from patients with OSCC and 15 saliva samples from healthy donors were collected. After RNA extraction, the respective miRNA levels were assessed by quantitative RT-PCR. RESULTS: We found that the miR-21 levels were significantly increased in saliva samples derived from patients with OLP, dysplastic OLP and OSCC, compared to those from healthy controls (p = 0.012, p = 0.0017 and p < 0.0001, respectively). Conversely, significant decreases in miR-125a levels were found in the OLP, dysplastic OLP and OSCC samples, compared to those from healthy controls (p < 0.0014, p < 0.0001 and p < 0.0001, respectively). In addition, significant increases in miR-31 levels were found in samples derived from dysplastic OLP and OSCC patients, but not in those from nondysplastic OLP patients, compared to those in healthy controls (p = 0.01 and p = 0.004, respectively). Finally, we found that the miR-200a levels were significantly decreased only in samples derived from OSCC patients (p < 0.0001). CONCLUSIONS: From our data we conclude that increased miR-21 levels in conjunction with decreased miR-125a levels in saliva of OLP patients may be indicative for a poor prognosis. Conversely, we conclude that lack of significant alterations in miR-31 and miR-200a levels in saliva of OLP patients may be indicative for absence of malignant transformation. PMID- 29480381 TI - Factors Associated with Changes in Community Ability and Recovery After Psychiatric Rehabilitation: A Retrospective Study. AB - One of the key goals of psychiatric rehabilitation is to return individuals with mental illnesses back into the community via restoration of the necessary skills. This retrospective study seeks to evaluate the factors associated with improvement in community functioning after a period of outpatient rehabilitation. 223 individuals enrolled into three broad rehabilitation groups-clinical, vocational and creative therapies/individual sessions-were included in this study. The Multnomah Community Ability Scale (MCAS) and Milestones of Recovery Scale (MORS) were used to evaluate each individual before and after the rehabilitation programme. Across all three groups, there were significant improvements in MCAS scores and MORS ratings. In multivariate models, clinical rehabilitation group was superior to creative therapies/individual sessions in predicting MORS change. The study also revealed a close relationship between recovery gains and improvement in community ability. PMID- 29480383 TI - Two flavonol glycosides from Liparis bootanensis. AB - Two new flavonol glycosides, bootanenside I and II (1 and 2), along with ten known compounds (3-12), were isolated from whole plant of Liparis bootanensis Griff. Their structures were elucidated on the basis of extensive spectroscopic analyses, including high-resolution electrospray-ionization mass spectrometry (HR ESIMS) and one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR). The cytotoxicity of the compounds was investigated against HCT116 human cancer cell line, revealing that none of them possessed considerable cytotoxic activity. Bioassays of the new metabolites showed that compounds 1 and 2 displayed moderate in vitro antiinflammatory activity by inhibiting expression of inducible nitric oxide synthase (iNOS) protein in lipopolysaccharide (LPS) stimulated RAW264.7 macrophage cells. PMID- 29480382 TI - Prothrombotic factors do not increase the risk of recurrent ischemic events after cryptogenic stroke at young age: the FUTURE study. AB - BACKGROUND: The role of hypercoagulable states and preceding infections in the etiology of young stroke and their role in developing recurrent ischemic events remains unclear. Our aim is to determine the prevalence of these conditions in patients with cryptogenic stroke at young age and to assess the long-term risk of recurrent ischemic events in patients with and without a hypercoagulable state or a recent pre-stroke infection with Borrelia or Syphilis. PATIENTS AND METHODS: We prospectively included patients with a first-ever transient ischemic attack or ischemic stroke, aged 18-50, admitted to our hospital between 1995 and 2010. A retrospective analysis was conducted of prothrombotic factors and preceding infections. Outcome was recurrent ischemic events. RESULTS: Prevalence of prothrombotic factors did not significantly differ between patients with a cryptogenic stroke and with an identified cause (24/120 (20.0%) and 32/174 (18.4%) respectively). In patients with a cryptogenic stroke the long-term risk [mean follow-up of 8.9 years (SD 4.6)] of any recurrent ischemic event or recurrent cerebral ischemia did not significantly differ between patients with and without a hypercoagulable state or a recent infection. In patients with a cryptogenic stroke 15-years cumulative risk of any recurrent ischemic event was 24 and 23% in patients with and without any prothrombotic factor respectively. CONCLUSIONS: The prevalence of prothrombotic factors and preceding infections did not significantly differ between stroke patients with a cryptogenic versus an identified cause of stroke and neither is significantly associated with an increased risk of recurrent ischemic events after cryptogenic stroke. PMID- 29480384 TI - Journal of Clinical Monitoring and Computing 2017 end of year summary: respiration. AB - This paper reviews 32 papers or commentaries published in Journal of Clinical Monitoring and Computing in 2016, within the field of respiration. Papers were published covering airway management, ventilation and respiratory rate monitoring, lung mechanics and gas exchange monitoring, in vitro monitoring of lung mechanics, CO2 monitoring, and respiratory and metabolic monitoring techniques. PMID- 29480386 TI - Hypertrophic osteoarthropathy: estrogens, prostaglandinE2, prostaglandin A2, and the inflammatory reflex. AB - It has been claimed that hyperestrogenism occurs in hypertrophic osteoarthropathy (HOA), but not in simple clubbing. However, one of our patients had simple clubbing and hyperestrogenism. We therefore measured estrogens, androgens, sex hormone-binding globulin (SHBG), and gonadotropins in five patients with HOA and in 18 patients with simple clubbing. Of the patients with HOA, 80% had a high urinary estriol concentration. In their serum, 80% had high estrone, 0% high estradiol, and 40% high SHBG. Of the patients with simple clubbing, 89% had a high urinary estriol concentration. In their serum, 76% had high estrone, 6% high estradiol, and 31% high SHBG. In all patients, urinary estriol concentration correlated positively with the degree of clubbing. Serum concentration of androstenedione, testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) was mostly normal, but androstenedione concentration correlated positively with the degree of clubbing. Spider angiomas were present in 74%, palmar erythema in 39%, and gynecomastia in 9%. Urinary creatinine concentration was low in 48% and correlated positively with the degree of clubbing. We reject the claim that hyperestrogenism occurs in HOA, but not in simple clubbing. Hyperestrogenism occurs both in HOA and in simple clubbing. Our results also support earlier reports that clubbing and HOA are associated with spider angiomas, palmar erythema, gynecomastia, adrenal cortical hyperfunction, muscle atrophy, and water retention. These results led to a new hypothesis on the pathogenesis of HOA, involving estrogens, prostaglandin E2, prostaglandin A2, and the inflammatory reflex. PMID- 29480385 TI - Quantitative measures of EEG for prediction of outcome in cardiac arrest subjects treated with hypothermia: a literature review. AB - Cardiac arrest (CA) is the leading cause of death and disability in the United States. Early and accurate prediction of CA outcome can help clinicians and families to make a better-informed decision for the patient's healthcare. Studies have shown that electroencephalography (EEG) may assist in early prognosis of CA outcome. However, visual EEG interpretation is subjective, labor-intensive, and requires interpretation by a medical expert, i.e., neurophysiologists. These limiting factors may hinder the applicability of such testing as the prognostic method in clinical settings. Automatic EEG pattern recognition using quantitative measures can make the EEG analysis more objective and less time consuming. It also allows to detect and display hidden patterns that may be useful for the prognosis over longer time periods of monitoring. Given these potential benefits, there have been an increasing interest over the last few years in the development and employment of EEG quantitative measures to predict CA outcome. This paper extensively reviews the definition and efficacy of various measures that have been employed for the prediction of outcome in CA subjects undergoing hypothermia (a neuroprotection method that has become a standard of care to improve the functional recovery of CA patients after resuscitation). The review details the State-of-the-Art and provides some perspectives on what seems to be promising for the early and accurate prognostication of CA outcome using the quantitative measures of EEG. PMID- 29480387 TI - Correction to: Development and application of lateral flow test strip technology for detection of infectious agents and chemical contaminants: a review. AB - The authors would like to call the reader's attention to the fact that unfortunately in the original article Steptococcus suis was introduced as gram negative bacteria. Steptococcus suis is gram positive. The authors apologize for the mistake. PMID- 29480388 TI - Rapid two-dimensional ALSOFAST-HSQC experiment for metabolomics and fluxomics studies: application to a 13C-enriched cancer cell model treated with gold nanoparticles. AB - Isotope labeling enables the use of 13C-based metabolomics techniques with strongly improved resolution for a better identification of relevant metabolites and tracing of metabolic fluxes in cell and animal models, as required in fluxomics studies. However, even at high NMR-active isotope abundance, the acquisition of one-dimensional 13C and classical two-dimensional 1H,13C-HSQC experiments remains time consuming. With the aim to provide a shorter, more efficient alternative, herein we explored the ALSOFAST-HSQC experiment with its rapid acquisition scheme for the analysis of 13C-labeled metabolites in complex biological mixtures. As an initial step, the parameters of the pulse sequence were optimized to take into account the specific characteristics of the complex samples. We then applied the fast two-dimensional experiment to study the effect of different kinds of antioxidant gold nanoparticles on a HeLa cancer cell model grown on 13C glucose-enriched medium. As a result, 1H,13C-2D correlations could be obtained in a couple of seconds to few minutes, allowing a simple and reliable identification of various 13C-enriched metabolites and the determination of specific variations between the different sample groups. Thus, it was possible to monitor glucose metabolism in the cell model and study the antioxidant effect of the coated gold nanoparticles in detail. Finally, with an experiment time of only half an hour, highly resolved 1H,13C-HSQC spectra using the ALSOFAST-HSQC pulse sequence were acquired, revealing the isotope-position-patterns of the corresponding 13C-nuclei from carbon multiplets. Graphical abstract Fast NMR applied to metabolomics and fluxomics studies with gold nanoparticles. PMID- 29480389 TI - Tuning of gold nanoclusters sensing applications with bovine serum albumin and bromelain for detection of Hg2+ ion and lambda-cyhalothrin via fluorescence turn off and on mechanisms. AB - Herein, fluorescent gold nanoclusters (Au NCs) were obtained by one-pot synthetic method using bovine serum albumin (BSA) and bromelain as templates. As synthesized fluorescent Au NCs were stable and showed bright red fluorescence under UV lamp at 365 nm. The fluorescent Au NCs exhibit the emission intensity at 648 nm when excited at 498 nm. Various techniques were used such as spectroscopy (UV-visible, fluorescence, and Fourier-transform infrared), high-resolution transmission electron microscopy, and dynamic light scattering for the characterization of fluorescent Au NCs. The values of I0/I at 648 nm are proportional to the concentrations of Hg2+ ion in the range from 0.00075 to 5.0 MUM and of lambda-cyhalothrin in the range from 0.01 to 10 MUM with detection limits of 0.0003 and 0.0075 MUM for Hg2+ ion and lambda-cyhalothrin, respectively. The practical application of the probe was successfully demonstrated by analyzing Hg2+ ion and lambda-cyhalothrin in water samples. In addition, Au NCs used as probes for imaging of Simplicillium fungal cells. These results indicated that the as-synthesized Au NCs have proven to be promising fluorescent material for the sensing of Hg2+ ion and lambda-cyhalothrin in environmental and for imaging of microorganism cells in biomedical applications. PMID- 29480390 TI - Heart failure and the discrepancy between trials of intensive blood pressure management: an analysis of individual patient data. AB - BACKGROUND: ACCORD and SPRINT are the best randomized controlled trial data evaluating the effects of blood pressure targets below 140 mmHg. These trials had contradictory results regarding the benefits of intensive antihypertensive therapy. We investigate if this discordance was driven by SPRINT's inclusion of Heart Failure in its primary outcome, as this is a parameter not included in ACCORD's original primary outcome. This analysis helps to resolve a significant area of contention. METHODS: Individual patient data from 4733 participants in ACCORD were analyzed from time of randomization. All participants were diabetic and at increased cardiovascular risk. Participants were assigned to their original intervention, a standard blood pressure target of less than 140 mmHg or an intensive target of less than 120 mmHg. Primary composite outcome was defined as in SPRINT: a composite of first occurrence of myocardial infarction, stroke, heart failure, death from cardiovascular causes, and other acute coronary syndromes. RESULTS: Primary outcome was not significantly different between standard and intensive groups [HR: 0.89; 95% CI: (0.76-1.03); p = 0.108]. The primary composite outcome occurred in 370 participants in the standard group (15.6%) and 324 participants in the intensive group (13.7%), with an event rate of 3.38% per year for the standard group and 3.01% per year for the intensive group. CONCLUSIONS: Differing results between ACCORD and SPRINT are not attributable to ACCORD's exclusion of Heart Failure from its original primary outcome measurement. No significant differences in primary outcome were observed between intensive and standard blood pressure groups in the ACCORD patients under the SPRINT primary outcome definition. Caution should be taken in extrapolating the intensive blood pressure control benefits of SPRINT to the diabetic population. PMID- 29480391 TI - The serotonergic system in L-DOPA-induced dyskinesia: pre-clinical evidence and clinical perspective. AB - During the last decade, the serotonergic system has emerged as a key player in the appearance of L-DOPA-induced dyskinesia in animal models of Parkinson's disease. Clinical investigations, based on imaging and postmortem analyses, suggest that the serotonin neurons are also involved in the etiology of this complication of long-term L-DOPA treatment in parkinsonian patients. These findings have stimulated efforts to develop new therapies using drugs targeting the malfunctioning serotonin neurons. In this review, we summarize the experimental and clinical data obtained so far and discuss the prospects for further development of this therapeutic strategy. PMID- 29480392 TI - Early life exposure of zebrafish (Danio rerio) to synthetic pyrethroids and their metabolites: a comparison of phenotypic and behavioral indicators and gene expression involved in the HPT axis and innate immune system. AB - Ecotoxicological studies have revealed the association between synthetic pyrethroid (SP) exposure and aquatic toxicity in fish; however, research on the toxic effects of SP metabolites is still limited. In this study, the toxicity of two SPs (permethrin (PM) and beta-cypermethrin (beta-CP)) and their three metabolites (3-phenoxybenzoic alcohol (PBCOH), 3-phenoxybenzaldehyde (PBCHO), and 3-phenoxybenzoic acid (PBCOOH)) towards zebrafish embryos and larvae was evaluated. Both SPs and their metabolites exhibited significant developmental toxicities, caused abnormal vascular development, and changed locomotor activities in larvae. The alteration of gene expression involved in the thyroid system and the innate immune system indicated that SPs and their three metabolites have the potency to induce thyroid disruption and trigger an immune response. The results from the present study suggest that SP metabolites could induce multiple toxic responses similar to parent compounds, and their toxicity should be considered for improving the understanding of environmental risks of SPs. PMID- 29480393 TI - Latitudinal distribution of OCPs in the open ocean atmosphere between the Argentinian coast and Antarctic Peninsula. AB - Long-range atmospheric transport is one of the most important ways in which persistent organic pollutants can be transported from their source to remote and pristine regions. Here, we report the results of the first Argentinian measurements of organochlorine pesticides in the Antarctic region. During a 9665 km track onboard OV ARA Puerto Deseado, within the framework of Argentinian Antarctic Expeditions, air samples were taken using high-volume samplers and analyzed using GC-MUECD. HCB, HCHs, and endosulfans were the major organic pollutants found, and a north-south gradient in their concentrations was evident by comparing data from the Argentinian offshore zone to the South Scotia Sea. PMID- 29480394 TI - Decrease in the annual emissions of CH4 and N2O following the initial land management change from rice to vegetable production. AB - In recent years, rice paddies have been increasingly converted to vegetable production resulting from economic benefits and changes in demand of diets, potentially altering soil greenhouse gas (GHG) balance. Here, we implemented a parallel field experiment to simultaneously quantify the differences in emissions of CH4 and N2O among rice paddy (RP) and conventional vegetable field (CV) and greenhouse vegetable field (GV), both of which have been recently converted from rice paddy in subtropical China over a full year. The results revealed that CH4 emission was reduced dramatically by nearly 100% following the initial land management change from rice to vegetable production, with annual emissions of 720.9, 0.9, and 0.2 kg CH4-C ha-1 for RP, CV, and GV, respectively. This conversion however substantially increased N2O emissions, resulting in the transition from a minor sink of N2O in RP (-0.1 kg N ha-1 yr-1) to considerable N2O sources in CV (31.8 kg N ha-1 yr-1) and GV (52.2 kg N ha-1 yr-1). Furthermore, annual N2O emission from GV significantly exceeded that from CV due to lower soil pH and higher soil temperature facilitating N2O production in GV relative to CV. Land management change significantly decreased the annual total emissions of CH4 and N2O from CV and GV by 19-51% as compared to RP, attributing to the reduced CH4 emissions outweighing the increased N2O emissions in CV and GV. These results indicate that expansion of vegetable production at the expense of rice paddies for higher economic benefits also helps mitigate the total emissions of CH4 and N2O. PMID- 29480396 TI - Optimizing the vermicomposting of organic wastes amended with inorganic materials for production of nutrient-rich organic fertilizers: a review. AB - Vermicomposting is a bio-oxidative process that involves the action of mainly epigeic earthworm species and different micro-organisms to accelerate the biodegradation and stabilization of organic materials. There has been a growing realization that the process of vermicomposting can be used to greatly improve the fertilizer value of different organic materials, thus, creating an opportunity for their enhanced use as organic fertilizers in agriculture. The link between earthworms and micro-organisms creates a window of opportunity to optimize the vermi-degradation process for effective waste biodegradation, stabilization, and nutrient mineralization. In this review, we look at up-to-date research work that has been done on vermicomposting with the intention of highlighting research gaps on how further research can optimize vermi degradation. Though several researchers have studied the vermicomposting process, critical parameters that drive this earthworm-microbe-driven process which are C/N and C/P ratios; substrate biodegradation fraction, earthworm species, and stocking density have yet to be adequately optimized. This review highlights that optimizing the vermicomposting process of composts amended with nutrient-rich inorganic materials such as fly ash and rock phosphate and inoculated with microbial inoculants can enable the development of commercially acceptable organic fertilizers, thus, improving their utilization in agriculture. PMID- 29480395 TI - Insights into the redox components of dissolved organic matters during stabilization process. AB - The changes of dissolved organic matter (DOM) components during stabilization process play significant effects on its redox properties but are little reported. Composting is a stabilization process of DOM, during which both the components and electron transfer capacities (ETCs) of DOM change. The redox components within compost-derived DOM during the stabilization process are investigated in this study. The results show that compost-derived DOM contained protein-like, fulvic-like, and humic-like components. The protein-like component decreases during composting, whereas the fulvic- and humic-like components increase during the process. The electron-donating capacity (EDC), electron-accepting capacity (EAC), and ETC of compost-derived DOM all increase during composting but their correlations with the components presented significant difference. The humic-like components were the main functional component responsible for both EDC and ETC, whereas the protein- and fluvic-like components show negative effects with the EAC, EDC, and ETC, suggesting that the components within DOM have specific redox properties during the stabilization process. These findings are very meaningful for better understanding the geochemical behaviors of DOM in the environment. PMID- 29480397 TI - Sediment evidence of industrial leakage-induced asynchronous changes in polycyclic aromatic hydrocarbons and trace metals from a sub-trophic lake, southwest China. AB - It has been well established that regional patterns of atmosphere-borne polycyclic aromatic hydrocarbons (PAHs) and trace metals were predominantly associated with the trajectory of socio-economic development; however, they could be potentially modulated by anthropogenic fingerprint of local sources such as industrial spill. Here, we established historical pollution data of both PAHs and trace metals from a well-dated sediment core from Yangzong Lake of Southwest China, which experienced a severe tailing leakage accident derived from a zinc concentrate smelting plant in 2007, aiming to evaluate the heterogeneity in their temporal trajectories and their sources of contamination in the context of regional deposition patterns. Sedimentary records show that the concentrations and fluxes of both PAHs and trace metals remained a consistently low level before the 1950s. An increasing trend and the synchronous changes of both PAHs and trace metals during ~ 1950-2002 were well consistent with the temporal pattern of socio economic development in western China, with coal combustion and smelting industries as the main sources of contamination in this region. However, arsenic (As) and PAHs exhibited a concurrent spike for the period of ~ 2007-2013, contrasting strongly to the regional pattern of these contaminants. The modern concentrations of As revealed a 5- to 14-fold increase over the pre-1950 level, with the contemporary concentrations of PAHs rising by ~ 10-14 times. The sediment records reveal that local fingerprints of smelting activities in the catchment of Yangzong Lake have overridden the temporary pattern of regional atmosphere-borne As and PAHs over the last decade. This highlights the important role of local pollution sources in modulating or even overriding the regional pattern of anthropogenic contamination in highly impacted systems. PMID- 29480398 TI - The optimization of microalgal culturing in liquid digestate after struvite precipitation using gray relational analysis. AB - Liquid digestate (LD) is highly turbid and contains ammonium (NH4+-N), which negatively influences microalgal growth. Therefore, a method of reducing LD turbidity and NH4+-N content is proposed, using struvite precipitation. To obtain struvite precipitation supernatant with an ideal UV transmittance, NH4+-N concentration, and N/P ratio for microalgal growth, the effects of pH and the molar ratio of NH4+/Mg2+/PO43- were studied. Results show that the optimal NH4+/Mg2+/PO43- molar ratio was 1:1.5:1.5, with a pH value of 8.5, following NaOH addition. Gray relational analysis (GRA) was applied to obtain a relative gray scale for the evaluation of multiple outputs. Results show that Chlorella regularis FACHB-1068 was the optimal microalgae species to support growth in the struvite precipitation supernatant. Using struvite precipitation and treatment with cultured C. regularis FACHB-1068 for 7 days, the removal efficiencies of NH4+-N, PO43--P, and COD in LD were 96.52, 99.33, and 35.30%, respectively. PMID- 29480399 TI - The effect of resistant dextrin as a prebiotic on metabolic parameters and androgen level in women with polycystic ovarian syndrome: a randomized, triple blind, controlled, clinical trial. AB - INTRODUCTION: Polycystic ovary syndrome (PCOS) is one of the most common abnormalities in women of reproductive age that can lead to a variety of metabolic and reproductive disorders. Studies reveal that a healthy diet is the most effective way for treating the risk factors associated with metabolic disorders and place greater emphasis on the consumption of prebiotic foods. The present study aims to determine the effect of resistant Dextrin on metabolic parameters, including lipid profile, fasting blood glucose (FBS) and high sensitivity C-reactive protein (hsCRP), and androgen levels, including serum levels of dehydroepiandrosterone sulfate (DHEA-S) and free testosterone, as the primary outcomes, and manifestations of PCOS including menstrual cycle irregularity and hirsutism, as the secondary outcomes. METHODS: This randomized, controlled, triple-blind, clinical trial was conducted on 62 women aged 18-45 in Tabriz, Iran, in 2016-2017. The participants were divided into a prebiotic group and a placebo group using block randomization. The prebiotic group consumed 20 g of resistant dextrin dissolved in a glass of water and the placebo group 20 g of maltodextrin also dissolved in a glass of water on a daily basis for 3 months. To measure the serum lipid profile, FBS, hsCRP, DHEA-S and free testosterone before and 3 months after the intervention, 5-ml blood samples were collected from the participants and analyzed using the ELISA method. The Ferriman-Gallwey scale for assessing hirsutism and a checklist for assessing menstrual cycle characteristics were completed before and 3 months after the intervention. A general linear model was used to analyze the data. RESULTS: No statistically significant differences were observed between the two groups in terms of sociodemographic characteristics and baseline values. 3 months after the intervention, based on the ANCOVA and after adjusting for the baseline values, the mean serum levels of LDL-C (adjusted mean difference = - 29.79; 95% CI = - 43.37 to - 16.21; P < 0.001), triglyceride (AMD = - 38.50; 95% CI = - 59.73 to - 17.28; P = 0.001), total cholesterol (AMD = - 29.98; 95% CI = - 40.14 to - 19.82; P < 0.001), FBS (AMD = - 11.24; 95% CI = - 15.43 to - 7.06; P < 0.001), hsCRP (AMD = - 1.75; 95% CI = - 2.92 to - 0.57; P = 0.004), DHEA-S (AMD = - 0.7; 95% CI = - 1.34 to - 0.13; P = 0.017) and free testosterone (AMD = - 0.32; 95% CI = - 0.56 to - 0.08; P = 0.010) revealed a statistically significant decrease in the intervention group compared to the placebo group, while the mean serum HDL-C showed a statistically significant increase in this group compared to the placebo group (AMD = 5.82; 95% CI = 2.27 9.37; P = 0.002). 3 months after the intervention, there was a significant difference between the two groups in terms of menstrual cycle intervals and hirsutism (P < 0.001). CONCLUSION: Resistant dextrin consumption can regulate metabolic parameters and androgen levels and manifestations including hirsutism and menstrual cycle irregularity in women with PCOS. PMID- 29480400 TI - Rib destruction with Staphylococcus contiguous abscess after septic pulmonary embolism and tricuspid endocarditis. PMID- 29480401 TI - Large Scale Cultivation of Microalgae: Open and Closed Systems. AB - There are two main approaches for cultivating microalgae on a large scale: open or closed cultivation. The main difference between open and closed systems is related to how they operate (e.g., cooling and gas exchange), vulnerability for outside influence (e.g., rainwater and introduction of unwanted species), and costs for building and operating the system. In this chapter we introduce the main cultivation technologies and discuss their main advantages and disadvantages when cultivating microalgae. PMID- 29480402 TI - Assessing Autophagy in the Leydig Cells. AB - Autophagy is an important intracellular degradation system which is implicated in many physiological and pathological processes. During autophagy, cytosolic constituents such as organelles and macromolecules are engulfed by autophagosome, and then they fuse with lysosomes for degradation and recycle of the engulfed components within the autolysosome to maintain cellular homeostasis. In male testis, the Leydig cells provide the major source of testosterone production. Autophagy is extremely active in Leydig cells and is involved in the steroid production. However, the precise role of autophagy in Leydig cells is still largely unknown. Thus, a comprehensive measurement of autophagic activity with different methods would shed light on our knowledge about the functional role of autophagy in regulating male reproductive physiology. In this chapter, we describe the morphological, cellular, and biochemical methods to monitor autophagy in Leydig cells. PMID- 29480404 TI - Molecular identification of fungal isolates and hatching success of green turtle (Chelonia mydas) nests. AB - The aim of this study is to investigate the fungal diversity of green turtle nests and to examine phylogenetic relationships among these isolates. During the nesting season, samples of intra-nest sand and failed eggs were collected from 25% of the surviving nests in Sugozu Beaches, which are amongst the most important nesting beaches for endangered green turtles in the Mediterranean. Twenty-three fungi were identified by molecular techniques. Fungal isolates belonged to genera Aspergillus, Emericella, Rhizopus, Actinomucor and Apophysomyces with two undescribed species. Aspergillus variecolor, Aspergillus quadrilinieatus, Aspergillus tubingensis, Rhizopus oryzae, Actinomucor elegans and Apophysomyces variabilis were firstly detected in all sea turtle nests within this study. Our results demonstrate that 36.4% of the nests had fungal contamination. Also hatching success of the nests contaminated by fungi were significantly lower than the uncontaminated nests (P = 0.029). Also, this may represent a threat to marine turtles and a risk for the health of conservation workers. This study is the first molecular phylogenetic study associated with sea turtle nests in the eastern Mediterranean coast and contributes to the wider body of literature on fungal invasion of sea turtle nests with firstly isolated species. These findings are important for improving potential conservation measures for the nest sites. PMID- 29480403 TI - Hypothalamic Ion Channels in Hypertension. AB - Hypertension is a prevalent and major health problem, involving a complex integration of different organ systems, including the central nervous system (CNS). The CNS and the hypothalamus in particular are intricately involved in the pathogenesis of hypertension. In fact, evidence supports altered hypothalamic neuronal activity as a major factor contributing to increased sympathetic drive and increased blood pressure. Several mechanisms have been proposed to contribute to hypothalamic-driven sympathetic activity, including altered ion channel function. Ion channels are critical regulators of neuronal excitability and synaptic function in the brain and, thus, important for blood pressure homeostasis regulation. These include sodium channels, voltage-gated calcium channels, and potassium channels being some of them already identified in hypothalamic neurons. This brief review summarizes the hypothalamic ion channels that may be involved in hypertension, highlighting recent findings that suggest that hypothalamic ion channel modulation can affect the central control of blood pressure and, therefore, suggesting future development of interventional strategies designed to treat hypertension. PMID- 29480406 TI - Correction to: In vivo performance of a novel silk fibroin scaffold for partial meniscal replacement in a sheep model. AB - The author would like to correct the errors in the publication of the original article. The corrected details are given below for your reading. PMID- 29480405 TI - miR-484/MAP2/c-Myc-positive regulatory loop in glioma promotes tumor-initiating properties through ERK1/2 signaling. AB - Glioma is the most common intracranial malignant tumor. Cancer stem cells (CSCs) are resistant to chemotherapy and radiotherapy, and are closely related to cancer metastasis and recurrence. In this study, we aimed to explore the effect of miR 484 on glioma stemness and the underlying mechanism involved. miR-484 enhanced glioma tumor-initiating properties in vitro and in vivo. Moreover, miR-484 was shown to directly target MAP2, resulting in activation of ERK1/2 signaling and promotion of stemness in glioma. The ERK1/2 signaling facilitated the formation of a miR-484/MAP2/c-Myc positive feedback loop in glioma. High miR-484 expression predicted a poor prognosis for glioma patients, and high MAP2 expression predicted a good prognosis for glioma patients. Low miR-484 expression and high MAP2 expression was associated with the best prognosis in glioma. Our study suggests that miR-484 and MAP2 can be utilized as predictors for the clinical diagnosis and prognosis of glioma, and miR-484 and MAP2 are potential targets for the treatment of glioma. PMID- 29480408 TI - Correction to: Current concept in upright spinal MRI. AB - Unfortunately, the legend of Fig. 5 was incorrectly published in original publication. The corrected legend is given below. PMID- 29480409 TI - The Global Spine Care Initiative: a summary of the global burden of low back and neck pain studies. AB - PURPOSE: This article summarizes relevant findings related to low back and neck pain from the Global Burden of Disease (GBD) reports for the purpose of informing the Global Spine Care Initiative. METHODS: We reviewed and summarized back and neck pain burden data from two studies that were published in Lancet in 2016, namely: "Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015" and "Global, regional, and national disability-adjusted life years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015." RESULTS: In 2015, low back and neck pain were ranked the fourth leading cause of disability-adjusted life years (DALYs) globally just after ischemic heart disease, cerebrovascular disease, and lower respiratory infection {low back and neck pain DALYs [thousands]: 94 941.5 [95% uncertainty interval (UI) 67 745.5-128 118.6]}. In 2015, over half a billion people worldwide had low back pain and more than a third of a billion had neck pain of more than 3 months duration. Low back and neck pain are the leading causes of years lived with disability in most countries and age groups. CONCLUSION: Low back and neck pain prevalence and disability have increased markedly over the past 25 years and will likely increase further with population aging. Spinal disorders should be prioritized for research funding given the huge and growing global burden. These slides can be retrieved under Electronic Supplementary Material. PMID- 29480412 TI - Incubation and interactivity in insight problem solving. AB - Insight is commonly viewed as originating from the restructuring of a mental representation. Distributed cognition frameworks such as the Systemic Thinking Model (SysTM, Vallee-Tourangeau and Vallee-Tourangeau, Cognition beyond the brain: interactivity and human thinking, pp 133-154, 2017), however, assumes that information processing can be transformed when it is distributed across mental and material resources. The experiments reported here investigated whether interactivity enhanced incubation effects with the cheap necklace problem. Participants attempted to solve the problem in a low-interactivity condition with pen and paper or in a high-interactivity condition with a set of metal chains. Performance was substantially better in a task environment that fostered a higher degree of interactivity at Time 1. There was evidence of an incubation effect as participants significantly improved in performance after a 2-week gap, particularly in the high-interactivity condition. Experiment 2 showed that the context within which people can enact their thinking following incubation is key to improve problem-solving performance. When the problem presentation changed after a 2-week gap (low interactivity to high interactivity or high interactivity to low interactivity), performance only improved for those who worked on a highly interactive task at Time 2. Taken together, these findings underscore the importance of adopting a systemic perspective when investigating incubation effects in problem solving. PMID- 29480413 TI - The effects of acrobatic exercise on brain plasticity: a systematic review of animal studies. AB - Acrobatic exercise is considered a complex motor activity and may promote motor learning and neuroplasticity. The objective of this systematic review was to verify possible plastic brain changes induced by acrobatic exercise in non lesioned rat and mouse through the analysis of experimental studies. Manual and electronic searches were conducted in MEDLINE, EMBASE and ISI Web of Science databases, without restriction to language or publication date. Synaptogenesis and neurogenesis were selected as the primary outcomes. To evaluate the risk of bias of individual studies, we used the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) RoB tool. We found 1780 studies, from which 18 fulfilled the inclusion criteria in this review. Seventeen studies evaluated the cerebellum, six the motor cortex, five the striatum and two evaluated the hippocampus. The results showed that acrobatic exercise promotes plastic changes in brain areas of rats, and such changes are dependent of training frequency and duration. However, studies were heterogeneous regarding the proteins analyzed and the training protocols, which made it difficult to compare and determine ideal acrobatic exercise parameters for neuroplasticity. Concerning the methodological quality of studies, most of them presented high risk of bias with absence of relevant study design information. New research with detailing training protocols and analysis might contribute to clarify the role of acrobatic exercise in neuroplasticity and how it could be used in translational research. PMID- 29480414 TI - Metabolic cross-talk between skeletal muscle and adipose tissue in high-intensity interval training vs. moderate-intensity continuous training by regulation of PGC 1alpha. AB - PURPOSE: An imbalance in the production of adipokines and myokines impairs the energy expenditure, increases adipocyte and develops metabolic pathologies. Physical exercise is able to regulate the secretion of myokines and adipokines. The present study considers the metabolic cross talk between skeletal muscle and adipose tissue in high-intensity interval training vs. moderate-intensity continuous training by regulation of PGC-1alpha. METHODS: A sample of 32 male Wistar rats (8 weeks old with mean weight 250 +/- 55 g) were divided into four groups randomly: control of base (CO), control of 8 weeks (CO8w), moderate intensity continuous training (MICT), and high-intensity interval training (HIIT). The rats were fed with standard chow diet. The CO group was killed at the start of the study and the CO8w group was kept alive for the same time as the experimental groups, but did not participate in any exercise. MICT and HIIT groups for 8 weeks were placed under the moderate-intensity continuous training (15-60 min, with speed of 15-30 m/min) and high-intensity interval training (8-4 intense period for 1 min, with speed of 28-55 m/min, with 3-7 slow-intensity period for 1 min, with a speed of 12-30 m/min) for 8 weeks, respectively. To measure the levels of serum irisin, nesfatin, and resistin the ELISA method was used and real-time PCR method was used to evaluate the relative expression of soleus PGC-1alpha gene mRNA. RESULTS: The levels of irisin and nesfatin significantly increased in the HIIT compared with control groups (p = 0.001). Resistin values in both training groups showed a significant decrease compared to the control groups (p = 0.005). The level of PGC-1alpha gene expression in both HIIT and MICT groups was significantly increased in comparison with the control groups (p = 0.001). DISCUSSION: The results showed that HIIT and MICT increase the transcription of the PGC-1alpha gene and possibly the increased expression of this gene after HIIT and MICT plays a central role in the secretion of skeletal muscle myokines and adipokines of adipose tissue. LEVEL OF EVIDENCE: No Level of evidence: Animal study. PMID- 29480410 TI - Peripheral Mechanisms Contributing to Osteoarthritis Pain. AB - PURPOSE OF REVIEW: Osteoarthritis (OA) is the most common form of arthritis and a major source of pain and disability worldwide. OA-associated pain is usually refractory to classically used analgesics, and disease-modifying therapies are still lacking. Therefore, a better understanding of mechanisms and mediators contributing to the generation and maintenance of OA pain is critical for the development of efficient and safe pain-relieving therapies. RECENT FINDINGS: Both peripheral and central mechanisms contribute to OA pain. Clinical evidence suggests that a strong peripheral nociceptive drive from the affected joint maintains pain and central sensitization associated with OA. Mediators present in the OA joint, including nerve growth factor, chemokines, cytokines, and inflammatory cells can contribute to sensitization. Furthermore, structural alterations in joint innervation and nerve damage occur in the course of OA. Several interrelated pathological processes, including joint damage, structural reorganization of joint afferents, low-grade inflammation, neuroplasticity, and nerve damage all contribute to the pain observed in OA. It can be anticipated that elucidating exactly how these mechanisms are operational in the course of progressive OA may lead to the identification of novel targets for intervention. PMID- 29480411 TI - Vasopressin, Central Autonomic Control and Blood Pressure Regulation. AB - PURPOSE OF REVIEW: We present recent advances in understanding of the role of vasopressin as a neurotransmitter in autonomic nervous system control of the circulation, emphasizing hypothalamic mechanisms in the paraventricular nucleus (PVN) involved in controlling sympathetic outflow toward the cardiovascular system. RECENT FINDINGS: Suggest that somato-dendritically released vasopressin modulates the activity of magnocellular neurons in the PVN and SON, their discharge pattern and systemic release. Advances have been made in uncovering autocrine and paracrine mechanisms controlling presympathetic neuron activity, involving intranuclear receptors, co-released neuroactive substances and glia. It is now obvious that intranuclear release of vasopressin and the co-release of neuroactive substances in the PVN, as well as the level of expression of vasopressin receptors, modulate sympathetic outflow to the cardiovascular system and determine vulnerability to stress. Further research involving patho physiological models is needed to validate these targets and foster the development of more efficient treatment. PMID- 29480415 TI - Accelerated Step-Up Infliximab Use Is Associated with Sustained Primary Response in Pediatric Crohn's Disease. AB - BACKGROUND: Earlier introduction of infliximab (IFX) in Crohn's disease (CD) may be associated with a sustained remission. METHODS AND AIMS: Children on scheduled IFX therapy for predominant luminal CD after successful induction (drop in PCDAI by >= 15) and a minimum of 2-year IFX follow-up were included. We compared outcomes of children treated with early (within 3 months from diagnosis) versus later IFX (after failing conventional therapy >= 3 months) and identify clinical predictors of sustained primary response (SPR) in our cohort. SPR was defined as CS-free clinical remission without requiring IFX dose escalation and/or surgical excision and/or switch to second anti-TNFs due to LOR or allergic reaction. RESULTS: Sixty-four children received IFX therapy for CD during the study period. Forty-three children on scheduled IFX therapy for luminal CD met the inclusion criteria. During the median follow-up of 3.05 years (IQR 2.6-3.5 years), SPR was observed in 17/43 (40%). SPR was associated with shorter time from diagnosis to the initiation of IFX (5.4 vs. 18.7 months, p = 0.006). Binary logistic regression using multiple variables also confirmed that only early use of IFX is associated with SPR. CONCLUSION: Early step-up use of IFX in children with CD with inadequate clinical response to conventional therapies leads to sustained primary response over 2 years. PMID- 29480416 TI - Procalcitonin as a Decision-Supporting Marker of Urgent Biliary Decompression in Acute Cholangitis. AB - BACKGROUND AND AIM: This study aimed to evaluate the association of serum procalcitonin (PCT) at hospital presentation with disease severity and clinical deterioration to septic shock in acute cholangitis. METHODS: This study included consecutive patients with a diagnosis of acute cholangitis who presented to the emergency department and underwent biliary drainage. PCT and blood culture tests were conducted at the time of initial presentation. Patients were categorized into three groups based on disease severity. White blood cell count, levels of C reactive protein and PCT were compared regarding the following: cholangitis severity, blood culture positivity, and clinical deterioration to septic shock. RESULTS: A total of 204 consecutive patients were enrolled, with grade I severity in 39 (19.1%), grade II in 139 (68.1%), and grade III in 26 (12.7%). The numbers of patients with blood culture positivity and clinical deterioration were 6 (15.4%) and 1 (2.6%) in grade I, 45 (32.4%) and 4 (2.9%) in grade II, and 14 (53.8%) and 1 (5.6%) in grade III cholangitis, respectively. Only PCT was significantly associated with blood culture positivity (3.25 vs 0.62 ng/mL; P = 0.001) and clinical deterioration (9.11 vs 0.89 ng/mL; P = 0.040). The cutoff value of PCT for clinical deterioration to septic shock among patients with grade I and II was 3.77 ng/mL (sensitivity of 80.0% and specificity of 74.0%). CONCLUSION: PCT could be a promising marker of clinical deterioration to septic shock in acute cholangitis. Therefore, PCT might be used as a decision-supporting biomarker for urgent biliary decompression. PMID- 29480417 TI - Mortality from Spontaneous Bacterial Peritonitis Among Hospitalized Patients in the USA. AB - BACKGROUND AND AIM: Spontaneous bacterial peritonitis (SBP) is a serious complication of cirrhosis and is associated with significant morbidity and mortality. In this study, we examined the clinical characteristics and risk factors associated with mortality in hospitalized patients presenting with SBP. METHODS: The Nationwide Inpatient Sample was queried for all hospitalizations involving SBP from 2006 to 2014 using the International Classification of Disease 9-CM Code. Logistic regression was performed to evaluate the association between SBP mortality and factors such as age, gender, race/ethnicity, and concomitant medical conditions at presentation (e.g., variceal hemorrhage, hepatic encephalopathy, acute renal failure, coagulopathy, and other infections including pneumonia). The lengths of stay (LOS) and total charges were also examined. RESULTS: From 2006 to 2014, there were 88,167 SBP hospitalizations with 29,963 deaths (17.6% in-hospital mortality). The mean age of patients who died in the hospital was higher (58.2 years vs. 55.8, p < 0.01) than those who survived the admission. Acute alcoholic hepatitis was noted among a higher proportion of patients who died (7.0 vs. 5.9%, p < 0.01), who were also likely to have more medical comorbidities. In multivariable analysis, older age, female gender, hepatic encephalopathy, coagulopathy, variceal hemorrhage, sepsis, pneumonia, and acute kidney injury were associated with increased in-hospital mortality. This group also had longer LOS (11.6 days vs. 9.1, p < 0.01) and higher total charges ($138,273 vs. $73,533, p < 0.01). CONCLUSION: SBP is associated with significant in-hospital mortality, especially in patients with concurrent risk factors. SBP remains a significant burden to the healthcare system. PMID- 29480419 TI - A young child with fever and unexplained acute kidney injury: Questions. PMID- 29480418 TI - Cellulosimicrobium arenosum sp. nov., Isolated from Marine Sediment Sand. AB - A Gram-stain-positive, non-spore-forming, yellow pigmented, non-motile, aerobic, short rod-shaped bacterial strain, designated CAU 1455T, was isolated from marine sediment sand. Strain CAU 1455T grew optimally at 30 degrees C and at pH 7.5 in the presence of 1% (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain CAU 1455T was affiliated to the genus Cellulosimicrobium and was most closely related to Cellulosimicrobium terreum DS 61T (similarity 97.9%). The strain possessed MK-9 (H4) as the predominant menaquinone and anteiso-C15:0 as the major cellular fatty acids. Peptidoglycan type was A4a (L-Lys-D-Glu2). The DNA G+C content was 74.3 mol% and the level of DNA-DNA relatedness between CAU 1455T and C. terreum DS-61T was 27.8%. Based on phenotypic, chemotaxonomic, and genetic data, strain CAU 1455T represents a novel species of the genus Cellulosimicrobium, for which the name Cellulosimicrobium arenosum sp. nov. is proposed. The type strain is CAU 1455T (= KCTC 49039T = NBRC 113062T). PMID- 29480420 TI - A young child with fever and unexplained acute kidney injury: Answers. PMID- 29480421 TI - Exit site and tunnel infections in children on chronic peritoneal dialysis: findings from the Standardizing Care to Improve Outcomes in Pediatric End Stage Renal Disease (SCOPE) Collaborative. AB - BACKGROUND: The Standardizing Care to Improve Outcomes in Pediatric End Stage Renal Disease (SCOPE) Collaborative is a quality improvement initiative to reduce dialysis-associated infections. The frequency of peritoneal dialysis (PD) catheter exit site infection (ESI) and variables influencing its development and end result are unclear. We sought to determine ESI rates, to elucidate the epidemiology, risk factors, and outcomes for ESI, and to assess for association between provider compliance with care bundles and ESI risk. METHODS: We reviewed demographic, dialysis and ESI data, and care bundle adherence and outcomes for SCOPE enrollees from October 2011 to September 2014. ESI involved only the exit site, only the subcutaneous catheter tunnel, or both. RESULTS: A total of 857 catheter insertions occurred in 734 children over 10,110 cumulative months of PD provided to these children. During this period 207 ESIs arose in 124 children or 0.25 ESIs per dialysis year. Median time to ESI was 392 days, with 69% of ESIs involving exit site only, 23% involving the tunnel only, and 8% involving both sites. Peritonitis developed in 6%. ESI incidence was associated with age (p = 0.003), being the lowest in children aged < 2 years and highest in those aged 6 12 years, and with no documented review of site care or an exit site score of > 0 at prior month's visit (p < 0.001). Gender, race, end stage renal disease etiology, exit site orientation, catheter cuff number or mobilization, and presence of G-tube, stoma, or vesicostomy were unassociated with ESI incidence. Of the ESIs reported, 71% resolved with treatment, 24% required hospitalization, and 9% required catheter removal, generally secondary to tunnel infection. CONCLUSIONS: Exit site infections occur at an annualized rate of 0.25, typically well into the dialysis course. Younger patient age and documented review of site care are associated with lower ESI rates. Although most ESIs resolve, hospitalization is frequent, and tunnel involvement/catheter loss complicate outcomes. PMID- 29480422 TI - Comparative study of fractional CO2 laser and fractional CO2 laser-assisted drug delivery of topical steroid and topical vitamin C in macular amyloidosis. AB - Macular amyloidosis (MA) represents a common variant of primary localized cutaneous amyloidosis. It has a characteristic female predominance; none of the treatment modalities described is either curative or uniformly effective in patients with macular amyloidosis. To determine the effect of fractional CO2 laser in macular amyloidosis in comparison to fractional CO2 laser-assisted drug delivery of topical steroids and topical vitamin C, the study includes 10 female patients with cutaneous macular amyloidosis aged between 20 and 62 years. Patients were treated with four sessions of fractional CO2 laser with 4 weeks interval. Laser treatments were performed using fractional CO2 laser with the following parameters (power 18 W, spacing 800 MUm, dwell time 600 MUs, stacking 3). The lesion is divided into three areas: area 1, treated by fractional laser only; area 2, treated by fractional laser followed by topical corticosteroid application under occlusion for 24 h; and area 3, treated by fractional laser followed by topical vitamin C serum application under occlusion for 24 h. All lesions were examined clinically and histologically before the therapy and 1 month after the end of the therapy to evaluate the degree of improvement. All treated areas show significant decrease in pigmentation score after treatment, significant drop in rippling (P value < 0.016), and improvement of lichenification; as regards the histological improvement, there was a significant decrease of the amyloid amount after treatment. As regards the amyloid amount, results show significant decrease in the amount of amyloid in all of the three treated areas. Area 2 reported the highest decrease in the amyloid amount followed by areas 1 and 3. One patient (10%) was highly satisfied by the treatment, 6 (60%) reported moderate degree of satisfaction, while only 3 (30%) reported mild satisfaction. Minimal complication occurred in the form of post inflammatory hyperpigmentation in 1 patient. None of the patients suffered pain, ulceration, or infection. Fractional CO2 alone can be used to improve the texture of macular amyloidosis. If used to assist the delivery of topical steroids and topical vitamin C, improvement can be highly increased. PMID- 29480423 TI - Non-structural protein 1 from avian influenza virus H9N2 is an efficient RNA silencing suppressor with characteristics that differ from those of Tomato bushy stunt virus p19. AB - Non-structural protein 1 (NS1) of influenza A virus is a multifunctional dimeric protein that contains a conserved N-terminal RNA binding domain. Studies have shown that NS1 suppresses RNA silencing and the NS1 proteins encoded by different influenza A virus strains exhibit differential RNA silencing suppression activities. In this study, we showed that the NS1 protein from avian influenza virus (AIV) H9N2 suppressed systemic RNA silencing induced by sense RNA or dsRNA. It resulted in more severe Potato virus X symptom, but could not reverse established systemic green fluorescent protein silencing in Nicotiana benthamiana. In addition, its systemic silencing suppression activity was much weaker than that of p19. The local silencing suppression activity of AIV H9N2 NS1 was most powerful at 7 dpi and was even stronger than that of p19. And the inhibition ability to RNA silencing of NS1 is stronger than that of p19 in human cells. Collectively, these results indicate that AIV H9N2 NS1 is an effective RNA silencing suppressor that likely targets downstream step(s) of dsRNA formation at an early stage in RNA silencing. Although NS1 and p19 both bind siRNA, their suppression mechanisms seem to differ because of differences in their suppression activities at various times post-infiltration and because p19 can reverse established systemic RNA silencing, but NS1 cannot. PMID- 29480425 TI - Different approaches for Endo-SPONGE(r) insertion to treat rectal anastomotic leaks. PMID- 29480424 TI - Genome-wide genetic variation and comparison of fruit-associated traits between kumquat (Citrus japonica) and Clementine mandarin (Citrus clementina). AB - KEY MESSAGE: The comprehensive genetic variation of two citrus species were analyzed at genome and transcriptome level. A total of 1090 differentially expressed genes were found during fruit development by RNA-sequencing. Fruit size (fruit equatorial diameter) and weight (fresh weight) are the two most important components determining yield and consumer acceptability for many horticultural crops. However, little is known about the genetic control of these traits. Here, we performed whole-genome resequencing to reveal the comprehensive genetic variation of the fruit development between kumquat (Citrus japonica) and Clementine mandarin (Citrus clementina). In total, 5,865,235 single-nucleotide polymorphisms (SNPs) and 414,447 insertions/deletions (InDels) were identified in the two citrus species. Based on integrative analysis of genome and transcriptome of fruit, 640,801 SNPs and 20,733 InDels were identified. The features, genomic distribution, functional effect, and other characteristics of these genetic variations were explored. RNA-sequencing identified 1090 differentially expressed genes (DEGs) during fruit development of kumquat and Clementine mandarin. Gene Ontology revealed that these genes were involved in various molecular functional and biological processes. In addition, the genetic variation of 939 DEGs and 74 multiple fruit development pathway genes from previous reports were also identified. A global survey identified 24,237 specific alternative splicing events in the two citrus species and showed that intron retention is the most prevalent pattern of alternative splicing. These genome variation data provide a foundation for further exploration of citrus diversity and gene-phenotype relationships and for future research on molecular breeding to improve kumquat, Clementine mandarin and related species. PMID- 29480427 TI - Comment on "A constricted midurethral sling needs loosening within 48-72 hours". PMID- 29480426 TI - Hunting for cultivable Micromonospora strains in soils of the Atacama Desert. AB - Innovative procedures were used to selectively isolate small numbers of Micromonospora strains from extreme hyper-arid and high altitude Atacama Desert soils. Micromonosporae were recognised on isolation plates by their ability to produce filamentous microcolonies that were strongly attached to the agar. Most of the isolates formed characteristic orange colonies that lacked aerial hyphae and turned black on spore formation, whereas those from the high altitude soil were dry, blue-green and covered by white aerial hyphae. The isolates were assigned to seven multi- and eleven single-membered groups based on BOX-PCR profiles. Representatives of the groups were assigned to either multi-membered clades that also contained marker strains or formed distinct phyletic lines in the Micromonospora 16S rRNA gene tree; many of the isolates were considered to be putatively novel species of Micromonospora. Most of the isolates from the high altitude soils showed activity against wild type strains of Bacillus subtilis and Pseudomonas fluorescens while those from the rhizosphere of Parastrephia quadrangulares and from the Lomas Bayas hyper-arid soil showed resistance to UV radiation. PMID- 29480428 TI - A constricted midurethral sling needs loosening within 48-72 hours. PMID- 29480430 TI - Could the correct side of mediolateral episiotomy be determined according to anal sphincter EMG? AB - INTRODUCTION AND HYPOTHESIS: Mediolateral episiotomy is one of the most frequent surgical interventions performed in obstetrics. There is conflicting evidence as to whether mediolateral episiotomy reduces the risk of obstetric anal sphincter injuries (OASI). Recent studies suggest that functional asymmetry of pelvic floor innervation exists in healthy women and is strongly associated with postpartum incontinence when the trauma occurs on the dominant side of innervation. Mediolateral episiotomy is the most common cause of perineal trauma during delivery, and the surgical incision is usually performed on the mediolateral right side. Surface electromyography (EMG) has been recently applied in obstetrics for detecting electrical activity of the external anal sphincter (EAS). METHODS: Two hundred and forty-five pregnant nulliparous women at their second and third trimester of pregnancy were recruited, and EMG signals were detected using a multichannel cylindric anal probe. Measurements were repeated and compared 6-8 weeks after delivery on a subgroup of 167 women who were divided in two groups according to EMG amplitude asymmetry before delivery and two subgroups according to type of delivery: (1A) asymmetric left, episiotomy right; (1B) asymmetric left, other types of deliveries; (2A) asymmetric right, episiotomy right; (2B) asymmetric right, other type of deliveries. RESULTS: The reduction of EMG amplitude after right episiotomy was larger in women with right asymmetric sphincter compared with women with left asymmetry and women with other types of delivery. CONCLUSIONS: Prenatal EMG may be used to predict the impact of right-sided mediolateral episiotomy on EAS and perhaps also function following delivery. PMID- 29480429 TI - Manchester-Fothergill procedure versus vaginal hysterectomy with uterosacral ligament suspension: an activity-based costing analysis. AB - INTRODUCTION AND HYPOTHESIS: Pelvic organ prolapse (POP) is a common diagnosis that imposes high and ever-growing costs to the healthcare economy. Numerous surgical techniques for the treatment of POP exist, but there is no consensus about which is the ideal technique for treating apical prolapse. The aim of this study was to estimate hospital costs for the most frequently performed operation, vaginal hysterectomy with uterosacral ligament suspension (VH) and the uterus preserving Manchester-Fothergill procedure (MP), when including costs of postoperative activities. METHODS: The study was based on a historical matched cohort including 590 patients (295 pairs) who underwent VH or MP during 2010-2014 owing to apical prolapse. The patients were matched according to age and preoperative prolapse stage and followed for a minimum of 20 months. Data were collected from four national registries and electronic medical records. Unit costs were obtained from relevant departments, hospital administration, calculated, or estimated by experts. The hospital perspective was applied for costing the resource use. RESULTS: Total costs for the first 20 months after operation were 3,514 ? per VH patient versus 2,318 ? per MP patient. The cost difference between the techniques was 898 ? (95% confidence interval [CI]: 818 982) per patient when analyzing the primary operation only and 1,196 ? (CI: 927 1,465) when including subsequent activities within 20 months (p < 0.0001). CONCLUSIONS: The MP is substantially less expensive than the commonly used VH from a 20-month time perspective. Healthcare costs can be reduced by one third if MP is preferred over VH in the treatment of apical prolapse. PMID- 29480431 TI - Responses of aquatic macrophytes to anthropogenic pressures: comparison between macrophyte metrics and indices. AB - Macrophyte responses to anthropogenic pressures in two rivers of Central Spain were assessed to check if simple metrics can exhibit a greater discriminatory and explanatory power than complex indices at small spatial scales. Field surveys were undertaken during the summer of 2014 (Duraton River) and the spring of 2015 (Tajuna River). Aquatic macrophytes were sampled using a sampling square (45 * 45 cm). In the middle Duraton River, macrophytes responded positively to the presence of a hydropower dam and a small weir, with Myriophyllum spicatum and Potamogeton pectinatus being relatively favored. Index of Macrophytes (IM) was better than Macroscopic Aquatic Vegetation Index (MAVI) and Fluvial Macrophyte Index (FMI) in detecting these responses, showing positive and significant correlations with total coverage, species richness, and species diversity. In the upper Tajuna River, macrophytes responded both negatively and positively to the occurrence of a trout farm effluent and a small weir, with Leptodictyum riparium and Veronica anagallis-aquatica being relatively favored. Although IM, MAVI, and FMI detected both negative and positive responses, correlations of IM with total coverage, species richness, and species diversity were higher. Species evenness was not sensitive enough to detect either positive or negative responses of aquatic macrophytes along the study areas. Overall, traditional and simple metrics (species composition, total coverage, species richness, species diversity) exhibited a greater discriminatory and explanatory power than more recent and complex indices (IM, MAVI, FMI) when assessing responses of aquatic macrophytes to anthropogenic pressures at impacted specific sites. PMID- 29480432 TI - Frontline Therapy of CLL: Evolving Treatment Paradigm. AB - PURPOSE OF REVIEW: Chronic lymphocytic leukemia (CLL) has multiple current frontline therapy options, including chemoimmunotherapy (CIT) and most recently, ibrutinib. Here, we review the most recent updates in the frontline treatment of CLL, including updates in CIT, updates in targeted therapies, and ongoing clinical trials. RECENT FINDINGS: Ibrutinib was FDA-approved for the upfront treatment of CLL in 2016 after being studied in older patients and those with 17p deletions or TP53 mutations. The introduction of ibrutinib has dramatically changed the treatment paradigm of CLL. Recent updates in CIT include that immunoglobulin heavy chain variable (IGHV) gene mutation status is strongly predictive of response to CIT. Regarding targeted therapy, next-generation BTK and PI3K inhibitors are currently being studied in the upfront treatment of CLL, which may have less toxicity than their first-generation counterparts. Other novel targeted therapies are being studied in the frontline setting, most notably venetoclax including in combinations, with hopes to achieve chemotherapy-free, time-limited treatment options. Multiple key ongoing phase 3 clinical trials will be answering these important clinical questions. PMID- 29480434 TI - The Primary Care Behavioral Health (PCBH) Model: An Overview and Operational Definition. AB - The Primary Care Behavioral Health (PCBH) model is a prominent approach to the integration of behavioral health services into primary care settings. Implementation of the PCBH model has grown over the past two decades, yet research and training efforts have been slowed by inconsistent terminology and lack of a concise, operationalized definition of the model and its key components. This article provides the first concise operationalized definition of the PCBH model, developed from examination of multiple published resources and consultation with nationally recognized PCBH model experts. The definition frames the model as a team-based approach to managing biopsychosocial issues that present in primary care, with the over-arching goal of improving primary care in general. The article provides a description of the key components and strategies used in the model, the rationale for those strategies, a brief comparison of this model to other integration approaches, a focused summary of PCBH model outcomes, and an overview of common challenges to implementing the model. PMID- 29480433 TI - Role of protein kinase N2 (PKN2) in cigarette smoke-mediated oncogenic transformation of oral cells. AB - Smoking is the leading cause of preventable death worldwide. Though cigarette smoke is an established cause of head and neck cancer (including oral cancer), molecular alterations associated with chronic cigarette smoke exposure are poorly studied. To understand the signaling alterations induced by chronic exposure to cigarette smoke, we developed a cell line model by exposing normal oral keratinocytes to cigarette smoke for a period of 12 months. Chronic exposure to cigarette smoke resulted in increased cellular proliferation and invasive ability of oral keratinocytes. Proteomic and phosphoproteomic analyses showed dysregulation of several proteins involved in cellular movement and cytoskeletal reorganization in smoke exposed cells. We observed overexpression and hyperphosphorylation of protein kinase N2 (PKN2) in smoke exposed cells as well as in a panel of head and neck cancer cell lines established from smokers. Silencing of PKN2 resulted in decreased colony formation, invasion and migration in both smoke exposed cells and head and neck cancer cell lines. Our results indicate that PKN2 plays an important role in oncogenic transformation of oral keratinocytes in response to cigarette smoke. The current study provides evidence that PKN2 can act as a potential therapeutic target in head and neck squamous cell carcinoma, especially in patients with a history of smoking. PMID- 29480435 TI - Alleviation of Side Effects and Distress in Breast Cancer Patients by Cognitive Behavioral Interventions: A Systematic Review and Meta-analysis. AB - Cognitive and behavioral interventions (CBI) have been used for breast cancer patients with various stages of the disease or undergoing different treatments. However, no quantitative review has summarized their efficacy on the side effects of treatment, distress, and quality of life in the acute treatment setting after diagnosis. This meta-analysis synthesizes data from 19 randomized clinical trials in order to: (a) provide an estimation of overall effect of CBI in breast cancer patients during treatment for breast cancer, i.e., neo-adjuvant and adjuvant treatment; (b) provide average effect sizes on side effects of treatment, distress, and quality of life; and (c) test possible moderators of effect size. The results show that CBI yielded a small effect size overall, specifically on general side effects of treatment, nausea, vomiting, distress, and quality of life. Individual and behavioral interventions seem to elicit better results on distress and on general side effects of treatment, respectively. While more studies are needed with regard to specific side effects (i.e., fatigue, pain, and sleep disturbance), the overall results clearly support the use of CBI in breast cancer patients during treatment. PMID- 29480436 TI - Decreased suicide rates in recent antidepressant clinical trials. AB - RATIONALE: The last systematic analysis of suicidality in antidepressant clinical trials submitted for approval by the US Food and Drug Administration was in 2000. Given the attention to suicide and antidepressants in the early 2000s, the authors aimed to evaluate if there have been any changes in suicide rates in antidepressant clinical trials following 2000. OBJECTIVE AND METHODS: The Integrated Safety Summary data from approval packets for 14 investigational antidepressant programs (1991-2013, 40,857 patients, 10,890.5 exposure years) were used to calculate suicides and suicide attempts per 100,000 patient exposure years (standardized rates) for antidepressant and placebo treatment groups separately. Suicides/suicide attempt rates, mean age, and percent female were compared between 1991 and 1998 (pre-2000) and 2002-2013 (post-2000). Drug-placebo differences in suicide/suicide attempt rates were explored. RESULTS: Among antidepressant-treated patients, the standardized suicide rate decreased significantly from pre- to post-2000 (643.6 to 25.8, p < 0.0001) as did the standardized suicide attempt rate (3975.7 to 645.4, p < 0.0001). For placebo treated patients, the decrease was not significant for suicide rate (471.1 to 174.2, p = 0.66) but was significant for suicide attempt rate (from 3538.3 to 522.6, p < 0.001). Regression analysis showed a similar pattern with suicide/suicide attempt rates decreasing over time. None of the drug-placebo comparisons in suicide or suicide attempt rates were statistically significant. There was no change in percent female or mean age of patients in trials pre- and post-2000. CONCLUSIONS: Deaths by suicide and suicide attempts have decreased significantly in antidepressant clinical trials following 2000 compared to the decade before 2000. Basic demographic features of the patients have remained consistent and medication treatment effects on suicidality were not apparent. These findings may reflect enhanced screening procedures and effective exclusion of suicidal patients in clinical trials for depression. PMID- 29480438 TI - Alterations in volumes and MRI features of amygdala in Chinese autistic preschoolers associated with social and behavioral deficits. AB - To examine the amygdala volume in 2-5-year-old preschool children with autism and explore the relationship between amygdala volumes based on MRI findings and clinical features. A total of 39 cases with clinically diagnosed autism were collected. The oblique coronal T1 weighted image (T1WI) sequence was used to measure the volume of amygdala and the MRI signals were measured and analyzed. The data were compared to that of 24 age-matched healthy children and correlated to the clinical manifestations. The autism and the control groups were subject to brain scanning in 1 week after Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) review. The 39 cases, diagnosed with autism, were associated with social and behavioral deficits through clinical observation, physical and neurological examination, and assessments according to DSM IV, and the range of ABC scores in the autism group was 47-124, with an average score of 84.7 +/- 24.1. Abnormal MRI signals were found in 19/78 (24.4%) amygdala in the autism group, the amygdala lesions showed punctuate or flaky low signal, slightly low signal, low to iso-signal, slightly high signal, or iso to high-signal intensity on T1 weighted three-dimendional fast low angle shot(T1FL3D) images. The right amygdala volume average was 1.088 +/- 0.38 cm3, while that of the left amygdala was 1.04 +/- 0.41 cm3, without any statistically significant difference (t = 0.533, p = 0.596) in the autism group. Among the 24 cases in the control group, the right amygdala volume average was 0.754 +/- 0.194 cm3, while that of the left amygdala was 0.666 +/- 0.252 cm3; the autism group had a significantly larger right and left amygdala volumes as compared to the age-matched typically developing group with a significant positive correlation between age and right amygdala volume (r = 0.406, p = 0.01). The preschool children with autism had significantly larger bilateral amygdala volumes as compared to age-matched typically developing children, the amygdala lesions may show abnormal signal. A relationship between age and right amygdala volume in the preschool children with autism was established. PMID- 29480437 TI - Alcohol devaluation has dissociable effects on distinct components of alcohol behaviour. AB - RATIONALE: Substance-related behaviour is often viewed as an appetitive behaviour, motivated by the reinforcing effects of the drug. However, there are various indices of substance motivation (e.g. attentional bias, behavioural economic demand, craving) and it is unclear how these are related or whether they play an important role in all types of substance-related behaviour. OBJECTIVES: (1) To determine the effect of alcohol devaluation on several indices of alcohol motivation and goal-directed and cue-elicited alcohol behaviour. (2) To investigate which components of motivation mediate any effect of devaluation on behaviour. METHODS: Sixty-two social drinkers gave baseline measures of alcohol craving, behavioural economic demand and choice for alcohol vs. soft drink. Participants tasted alcohol which was either unadulterated (control) or adulterated with a bitter solution (devaluation) before craving and demand were measured again. Alcohol choice was assessed in several phases: extinction (evaluating goal-directed behaviour), in the presence of drink cues (Pavlovian-to instrumental transfer (PIT, cue-elicited behaviour)), and reacquisition. Attentional bias (AB) was measured by tracking eye movements towards the drink cues during novel PIT trials where both cues were presented. Finally, consumption was evaluated in a taste test. RESULTS: Alcohol devaluation reduced alcohol related demand, AB, alcohol choice in all phases, and consumption. Alcohol cues presented during PIT increased alcohol choice above baseline irrespective of devaluation. AB and demand for alcohol fully mediated the effect of devaluation on alcohol choice during extinction, AB fully mediated the effect on cue-elicited (specific PIT) alcohol choice and alcohol consumption. CONCLUSIONS: Alcohol behaviour in social drinkers is largely sensitive to devaluation, i.e. governed by current motivational value of the drug (suggesting goal-directed behaviour). However, a dissociable form of stimulus control can also drive alcohol-seeking independently of drug value (specific PIT). Mediation analyses suggests that AB may play a paradoxical role in both forms of alcohol seeking and consumption. PMID- 29480439 TI - Assessing motor, visual and language function using a single 5-minute fMRI paradigm: three birds with one stone. AB - Clinical functional Magnetic Resonance Imaging (fMRI) requires inferences on localization of major brain functions at the individual subject level. We hypothesized that a single "triple use" task would satisfy sensitivity and reliability requirements for successfully assessing the motor, visual and language domain in this context. This was tested here by the application in a group of healthy adults, assessing sensitivity and reliability at the individual subject level, separately for each domain.Our "triple use" task consisted of 2 conditions (condition 1, assessing motor and visual domain, and condition 2, assessing the language domain), serving mutually as active/control. We included 20 healthy adult subjects. Random effect analyses showed activation in primary motor, visual and language regions, as expected. Less expected regions were activated both for the motor and visual domains. Further, reliability of primary activation patterns was very high across individual subjects, with activation seen in 70-100% of subjects in primary motor, visual, and left-lateralized language regions.These findings suggest the "triple use" task to be reliable at the individual subject's level to assess motor, visual and language domains in the clinical fMRI context. Benefits of such an approach include shortening of acquisition time, simplicity of the task for each domain, and using a visual stimulus. Following establishment of reliability in adults, the task may also be a valuable addition in the pediatric clinical fMRI context, where each of these factors is of high relevance. PMID- 29480440 TI - Physical activity after commitment lotteries: examining long-term results in a cluster randomized trial. AB - To overcome self-control difficulties, people can commit to their health goals by voluntarily accepting deadlines with consequences. In a commitment lottery, the winners are drawn from all participants, but can only claim their prize if they also attained their gym-attendance goals. In a 52-week, three-arm trial across six company gyms, we tested if commitment lotteries with behavioral economic underpinnings would promote physical activity among overweight adults. In previous work, we presented an effective 26-week intervention. In the present paper we analyzed maintenance of goal attainment at 52-week follow-up and the development of weight over time. We compared weight and goal attainment (gym attendance >= 2 per week) between three arms that-in the intervention period- consisted of (I) weekly short-term lotteries for 13 weeks; (II) the same short term lotteries in combination with an additional long-term lottery after 26 weeks; and (III) a control arm without lottery-deadlines. After a successful 26 week intervention, goal attainment declined between weeks 27 and 52 in the long term lottery arm, but remained higher than in the control group. Goal attainment did not differ between the short-term lottery arm and control arm. Weight declined slightly in all arms in the first 13 weeks of the trial and remained stable from there on. Commitment lotteries can support regular gym attendance up to 52 weeks, but more research is needed to achieve higher levels of maintenance and weight loss. PMID- 29480441 TI - A1AR-mediated renal protection against ischemia/reperfusion injury is dependent on HSP27 induction. AB - PURPOSE: A1 adenosine receptor (AR) activation has been demonstrated to attenuate renal ischemia/reperfusion injury (IRI), but the exact mechanism of this protection remains to be well elucidated. METHODS: Male C57BL/6 mice were used in the present study. Expression of heat shock protein (HSP) 27 and HSF-1 were detected using western blot analysis. An RNA interference with adenovirus vector using short hairpin RNA targeting HSP27 was developed. Together with renal IRI model, indicators of renal function, acute tubular necrosis, inflammation and apoptosis were measured in kidneys after 24-h reperfusion. RESULTS: We found activation of A1AR stimulated induction of HSP27 and its major transcriptional factor HSF-1. It was observed that renal inhibition of HSP27 abolished the renoprotective effects afforded by A1AR activation indicated by worse renal function, severer acute tubular necrosis and pro-inflammatory reaction. In addition, HSP27 induction by A1AR activation protects the kidney from IRI via suppressing cell apoptosis, proved by decreased caspase-3 activation and DNA fragmentation, which was also removed by inhibition of HSP27. CONCLUSIONS: Activation of A1AR produces renoprotective effects via HSP27 induction. It suggests that preconditional HSP27 activation might have a great potential for the treatment of renal IRI. PMID- 29480442 TI - Epidemiological characteristics of and risk factors for patients with postoperative acute kidney injury: a multicenter prospective study in 30 Chinese intensive care units. AB - BACKGROUND: Although there were studies to investigate the risk factors for acute kidney injury (AKI) after surgery, most of them focused on one specific type of surgeries. The risk factors for postoperative AKI in patients undergoing all surgeries in intensive care units (ICU) have not been reported. METHODS: Data from 1731 patients undergoing surgery in 30 ICUs of 28 tertiary hospitals in Beijing from March to August 2012 were prospectively collected. AKI was defined and staged by the KDIGO criteria. Multivariate logistic regression analysis was performed to assess independent risk factors for postoperative AKI. RESULTS: Postoperative AKI occurred in 44.8% of patients (stage 1 54.8%; stage 2 21.9%, stage 3 23.3%). Cardiovascular surgery was identified as an independent factor for postoperative AKI as well as emergency surgery [odds ratio (OR) 1.403], nephrotoxic drugs (OR 1.303), APACHE II score (OR 1.055), SOFA score (OR 1.115), duration for positive fluid balance (OR 1.165), use of diuretics (OR 2.293), sepsis (OR 1.501), and CKD (OR 4.517). AKI stage 3 versus stages 1-2 was associated with higher mortality in ICU, hospital, and 28-day follow-up after cardiovascular, abdominal, limb, and chest surgeries, while this was not observed after neurosurgery or other surgeries. CONCLUSION: Risk factors for AKI in ICU patients after different types of surgery were identified. This might be the first step to reduce the high incidence of AKI after surgery. The presence of AKI in ICU patients was associated with higher mortality after most types of surgery, but not after neurosurgery. TRIAL REGISTRATION: ChiCTR-ONC-11001875. PMID- 29480443 TI - Coercion, dissatisfaction, and social stigma: an ethnographic study of compensated living kidney donation in Iran. AB - This article updates the qualitative research on Iran reported in the 2012 article by Tong et al. "The experiences of commercial kidney donors: thematic synthesis of qualitative research" (Tong et al. in Transpl Int 25:1138-1149, 2012). The basic approach used in the Tong et al. article is applied to a more recent and more comprehensive study of Iranian living organ donors, providing a clearer picture of what compensated organ donation is like in Iran since the national government began regulating compensated donation. Iran is the only country in the world where kidney selling is legal, regulated, and subsidized by the national government. This article focuses on three themes: (1) coercion and other pressures to donate, (2) donor satisfaction with their donation experience, and (3) whether donors fear social stigma. We found no evidence of coercion, but 68% of the paid living organ donors interviewed felt pressure to donate due to extreme poverty or other family pressures. Even though 27% of the living kidney donors interviewed said they were satisfied with their donation experience, 74% had complaints about the donation process or its results, including some of the donors who said they were satisfied. In addition, 84% of donors indicated they feared experiencing social stigma because of their kidney donation. PMID- 29480445 TI - Clinical Applications of Induced Pluripotent Stem Cells - Stato Attuale. AB - In an adult human body, somatic stem cells are present in small amounts in almost all organs with the function of general maintenance and prevention of premature aging. But, these stem cells are not pluripotent and are unable to regenerate large cellular loss caused by infarctions or fractures especially in cells with limited replicative ability such as neurons and cardiomyocytes. These limitations gave rise to the idea of inducing pluripotency to adult somatic cells and thereby restoring their regeneration, replication and plasticity. Though many trials and research were focused on inducing pluripotency, a solid breakthrough was achieved by Yamanaka in 2006. Yamanaka's research identified 4 genes (OCT-4, SOX-2, KLF-4 and c-MYC) as the key requisite for inducing pluripotency in any somatic cells (iPSCs). Our study, reviews the major methods used for inducing pluripotency, differentiation into specific cell types and their application in both cell regeneration and disease modelling. We have also highlighted the current status of iPSCs in clinical applications by analysing the registered clinical trials. We believe that this review will assist the researchers to decide the parameters such as induction method and focus their efforts towards clinical application of iPSCs. PMID- 29480444 TI - Exercise behavior and physical fitness in patients with advanced lung cancer. AB - PURPOSE: The aim of this work was to evaluate exercise behavior and physical fitness of advanced lung cancer patients shortly after primary diagnosis. METHODS: Between November 2013 and December 2016, advanced lung cancer patients (n = 227, mean age 62.2 years) were enrolled shortly after diagnosis and 211 patients were tested for endurance capacity (six-minute walk test) and strength performance (maximum voluntary isometric contraction of upper and lower extremities). Current and previous exercise and walking behavior were assessed using a self-reported questionnaire regarding type, frequency, intensity, and duration. Paired Student's t tests were used to compare physical fitness to reference data. The relation of potential determinants with physical fitness was assessed using linear regression analysis. RESULTS: Exercise behavior was superior in the year before diagnosis compared to the time of study enrollment. Patients reduced frequency, intensity, and duration of sports/exercise after their lung cancer diagnosis. We observed significantly lower endurance capacity (p < .01) and strength performance in lower extremities (p < .01) in male and female patients compared to age and sex-matched reference data. We found significant correlations of previous exercise and walking behavior with physical fitness shortly after diagnosis in patients with advanced lung cancer. CONCLUSION: Patients with advanced lung cancer showed impaired physical fitness regarding endurance and strength capacity. The strong decline in participation of sports/exercise shortly after diagnosis supports early implementation of physical exercise during anti-cancer treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT02055508. PMID- 29480446 TI - Stem Cell Therapy: Repurposing Cell-Based Regenerative Medicine Beyond Cell Replacement. AB - Stem cells exhibit simple and naive cellular features, yet their exact purpose for regenerative medicine continues to elude even the most elegantly designed research paradigms from developmental biology to clinical therapeutics. Based on their capacity to divide indefinitely and their dynamic differentiation into any type of tissue, the advent of transplantable stem cells has offered a potential treatment for aging-related and injury-mediated diseases. Recent laboratory evidence has demonstrated that transplanted human neural stem cells facilitate endogenous reparative mechanisms by initiating multiple regenerative processes in the brain neurogenic areas. Within these highly proliferative niches reside a myriad of potent regenerative molecules, including anti-inflammatory cytokines, proteomes, and neurotrophic factors, altogether representing a biochemical cocktail vital for restoring brain function in the aging and diseased brain. Here, we advance the concept of therapeutically repurposing stem cells not towards cell replacement per se, but rather exploiting the cells' intrinsic properties to serve as the host brain regenerative catalysts. PMID- 29480447 TI - Cell-free DNA in breast cancer: a long way to go. PMID- 29480448 TI - What to look for in cell-free DNA from breast cancer patients. PMID- 29480449 TI - Assessment of the predictive role of pretreatment Ki-67 and Ki-67 changes in breast cancer patients receiving neoadjuvant chemotherapy according to the molecular classification: a retrospective study of 1010 patients. AB - PURPOSE: To assess the predictive role of pretreatment ki67 and Ki67 changes in breast cancer (BC) patients treated with neoadjuvant chemotherapy (NAC) in various molecular subtypes. METHODS: 1010 BC patients who had undergone anthracycline and taxane-based NAC from January 2012 to July 2017 were retrospectively analyzed. Clinical and pathological parameters of the patients were retrieved and the predictive factors for NAC response were evaluated. RESULTS: 705 patients showed clinical response (cRes), and 131 patients acquired pathologic complete response (pCR). Patients with higher pretreatment Ki67 (>= 14%), tumor size >= 4 cm, and positive clinical nodal had better clinical therapy response, while patients with negative ER and PR, higher pretreatment Ki67 (>= 14%), and tumor size < 4 cm were more probable to attain pCR. The pretreatment Ki67 could be used as a predictor of NAC only in luminal subtypes, and 25.5% were identified as an ideal cut-off point to differentiate the cRes from non-cRes cases. Although a decrease in Ki67 had been found in almost all molecular subtypes after NAC, no statistically significant differences were found in the decrease of Ki67 were validated between the cRes and non-cRes group in HER2-rich and triple-negative subtypes (P = 0.488 and P = 0.111, respectively). CONCLUSIONS: The best cut-off for pretreatment Ki67 in predicting the connection with the tumor size lessening was 25.5% in luminal subtype. Aggressive adjuvant systemic treatments should be considered for patients with HER2-rich and triple negative subtype who exhibit tumor shrinkage in NAC but still have high levels of Ki67. PMID- 29480450 TI - [Ewing sarcomas and Ewing-like sarcomas : New aspects]. AB - Sarcomas of the Ewing family of tumors are aggressive neoplasms occurring in bone and soft tissue of mostly children and young adults. Classical Ewing sarcomas are pathognomonically characterized by fusions between a gene of the RNA-binding TET family (EWSR1 or FUS) with a gene of the ETS-transcription family (FLI1, ERG, ETV1, ETV4 or FEV). Less frequent cases designated as Ewing-like sarcomas show different genetic rearrangements between EWSR1 and non-ETS genes (NFATC2, POU5F1, SMARCA5, PATZ, ZSG, SP3). Moreover, new molecular alterations biologically unrelated to Ewing sarcomas have recently been described in the category of undifferentiated round cell sarcomas including CIC-DUX4 fusions or BCOR alterations, each carrying unique gene expression signatures. In contrast to classical Ewing sarcomas, the morphologic spectrum of these tumor entities is much broader and includes round cell areas as well as spindled and myxoid components. The immunohistochemical profile with inconsistent CD99 positivity makes diagnosis more difficult and requires the use of a broad spectrum of antibodies and elaborate molecular work-up. Further studies for future therapeutic decision making in these newly described round cell sarcomas as well as for molecular subclassification of undifferentiated round cell sarcomas are ongoing. PMID- 29480451 TI - When carapace governs size: variation among age classes and individuals in a free ranging ectotherm with delayed maturity. AB - Juvenile growth strongly impacts life-history traits during adulthood. Yet, in juveniles with delayed maturity, elusiveness has hindered age-specific studies of growth, precluding any detailed research on its consequences later in life. Different complex growth patterns have been extracted from captive animals, suggesting species-specific trajectories occur in free-ranging animals. How pronounced are growth and body size variation (VBS) throughout a long-lived ectotherm's life? Is VBS constant among age classes prior to maturity, or do compensatory and/or cumulative effects driven by long-lived-animal-specific strategies create distinct VBS cohorts, to ensure survival? To tackle the issue, we modelled growth data from continuous and dense annual capture-mark-recapture sampling (5096 body measurements of 1134 free-ranging individuals) of both immature and mature, long-lived Hermann's tortoises. We analysed population, cohort, and individual-based growth and VBS. Growth ring inferred ages were cross validated with annual recaptures in 289 juveniles. Analyses unravelled an S shaped growth curve and identified three age cohorts across which VBS increases in a step-wise manner. Neonate-specific constraints and compensatory effects seem to control VBS until 4 years of age, possibly promoting survival with size. Subsequently, a hardened carapace takes over and cumulative effects fuelled by faster growth progressively increase VBS. Whereas ungulates are in a hurry to attain adult size before growth ceases (minimizing VBS), indeterminately growing tortoises can shape individual asymptotic sizes even after growth decelerates. Tortoise size is clearly shaped by age-specific ecological constraints; interestingly, it is likely the carapace that conducts the strategy, rather than maturity per se. PMID- 29480452 TI - Inducible phenotypic plasticity in plants regulates aquatic ecosystem functioning. AB - Differences among individuals within species affect community and ecosystem processes in many systems, and may rival the importance of differences between species. Intraspecific variation consists of both plastic and genetic components that are regulated by different processes and operate on different time scales. Therefore, probing which mechanisms can affect traits sufficiently strongly to affect ecosystem processes is fundamental to understanding the consequences of individual variation. We find that a dominant deciduous tree of Pacific Northwest riparian ecosystems, red alder, exhibits strong and synergistic responses to nutrient resources and herbivory stress. These induced responses, which include shifting nutrient and plant secondary metabolite composition, have cascading effects on aquatic ecosystem function. Defense responses suppress leaf litter decomposition in small streams, thus altering the rate of energy capture for one of the most abundant terrestrial carbon sources entering aquatic systems. We find that alder responses to herbivory stress largely depend on availability of soil nutrients, with modification of the highly cytotoxic diarylheptanoid group of secondary metabolites being favored in nutrient-poor environments and modification of the typically dose-dependent ellagitannins being favored in nutrient-rich environments. Importantly, these findings identify traits for herbivore resistance in alder trees and demonstrate that plastic responses occurring within a species and over short time scales substantially alter a key function of an adjacent ecosystem. Furthermore, demonstrating plasticity among alder secondary metabolites lends insight into this system, in which decomposer communities are known to adjust to the secondary chemistry of local alder trees to facilitate rapid decomposition of locally derived leaf litter. PMID- 29480453 TI - Reply to Braillon et al.: Nalmefene Phase IV Study: A Seeding Flying in the Face of Evidence? PMID- 29480454 TI - Ponatinib for Treating Chronic Myeloid Leukaemia: An Evidence Review Group Perspective of a NICE Single Technology Appraisal. AB - As part of its single technology appraisal process, the National Institute for Health and Care Excellence (NICE) invited the company that manufactures ponatinib (Inclusig(r); Incyte Corporation) to submit evidence for the clinical and cost effectiveness for previously treated chronic myeloid leukaemia (CML) and Philadelphia-chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL). This paper focusses on the three phases of CML: the chronic phase (CP), the accelerated phase (AP) and the blast crisis phase (BP). The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). This article presents the critical review of the company's submission by the ERG and the outcome of the NICE guidance. Clinical evidence for ponatinib was derived from a phase II, industry-sponsored, single-arm, open-label, multicentre, non comparative study. Despite the limited evidence and potential for biases, this study demonstrated that ponatinib was likely to be an effective treatment (in terms of major cytogenetic response and major haematological response) with an acceptable safety profile for patients with CML. Given the absence of any head-to head studies comparing ponatinib with other relevant comparators, the company undertook a matching-adjusted indirect comparison (MAIC) of ponatinib with bosutinib. The approach was only used for patients with CP-CML because comprehensive data were not available for the AP- or BP-CML groups to allow the matching technique to be used. Despite the uncertainty about the MAIC approach, ponatinib was considered likely to offer advantages over bosutinib in the third line setting, particularly for complete cytogenetic response. The company developed two health economic models to assess the cost effectiveness of ponatinib for the treatment of patients in CP-CML or in advanced CML (AP- or BP CML, which were modelled separately). The company did not adequately explore the uncertainty in the survivor functions. As a result, the ERG believed the uncertainty in the decision problem was underestimated. Exploratory analyses undertaken by the ERG produced the following results for ponatinib. In CP-CML, from L18,246 to L27,667 per quality-adjusted life-year (QALY) gained compared with best supportive care (BSC), from L19,680 to L37,381 per QALY gained compared with bosutinib and from L18,279 per QALY gained to dominated compared with allogeneic stem cell transplant (allo-SCT). In AP-CML, the cost per QALY gained for ponatinib ranged from L7123 to L17,625 compared with BSC, and from dominating to L61,896 per QALY gained compared with allo-SCT. In BP-CML, the cost effectiveness of ponatinib ranged from L5033 per QALY gained to dominated compared with allo-SCT, although it was likely to be at the more favourable end of this range, and dominant in all scenarios compared with BSC. The NICE appraisal committee concluded that ponatinib is a cost-effective use of NHS resources in the considered population, subject to the company providing the agreed discount in the Patient Access Scheme. PMID- 29480455 TI - Ixekizumab for Treating Moderate-to-Severe Plaque Psoriasis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal. AB - The National Institute for Health and Care Excellence invited Eli Lilly and Company Ltd, the company manufacturing ixekizumab (tradename Taltz(r)), to submit evidence for the clinical and cost effectiveness of ixekizumab. Ixekizumab was compared with tumour necrosis factor-alpha inhibitors (etanercept, infliximab, adalimumab), ustekinumab, secukinumab, best supportive care and, if non biological treatment or phototherapy is suitable, also compared with systemic non biological therapies and phototherapy with ultraviolet B radiation for adults with moderate-to-severe plaque psoriasis. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Center, was commissioned as the independent Evidence Review Group. This article presents a summary of the company submission, the Evidence Review Group report and the development of the National Institute for Health and Care Excellence guidance for the use of this drug in England and Wales by the Appraisal Committee. The Evidence Review Group produced a critical review of the clinical and cost effectiveness of ixekizumab based on the company submission. The company submission presented three randomised controlled trials identified in a systematic review. All randomised controlled trials were phase III, multicentre placebo-controlled trials including 3866 participants with moderate-to-severe psoriasis. Two trials also included an active comparator (etanercept). All randomised controlled trials showed statistically significant increases in two primary outcomes, static Physician Global Assessment (0,1) and improvement of 75% from baseline in the Psoriasis Area and Severity Index. Ixekizumab was generally well tolerated in the randomised controlled trials, with similar discontinuation rates because of adverse events as placebo or etanercept. The most frequent adverse events of special interest were infections and injection-site reactions. The company submission also included a network meta-analysis of relevant comparators. The Evidence Review Group highlighted some issues regarding the systematic review process and an issue with the generalisability of the findings in that the trials failed to include patients with moderate psoriasis according to a widely used definition. This issue was considered by the Appraisal Committee and the population was deemed generalisable to patients in England and Wales. Based on the network meta-analysis, the Appraisal Committee concluded that ixekizumab was more clinically effective than adalimumab and ustekinumab, and agreed it was likely that ixekizumab was similarly effective compared with secukinumab and infliximab while tolerability was similar to other biological treatments approved for treating psoriasis. The Evidence Review Group's critical assessment of the company's economic evaluation highlighted a number of concerns, including (1) the use of relative outcomes such as Psoriasis Area and Severity Index response to model the cost effectiveness; (2) the exclusion of the consequences of adverse events; (3) the assumption of no utility gain in the induction phase; (4) equal annual discontinuation rates for all treatments; (5) the selection of treatment sequences for consideration in the analyses and; (6) the transparency of the Visual Basic for Applications code used to develop the model. Although some of these issues were adjusted in the Evidence Review Group base case, the Evidence Review Group could not estimate the impact of all of these issues, and thus acknowledges that there are still uncertainties concerning the cost-effectiveness evidence. In the Evidence Review Group base-case incremental analysis, the treatment sequence incorporating ixekizumab in the second line has an incremental cost-effectiveness ratio of L25,532 per quality-adjusted life-year gained vs. the etanercept sequence. Ixekizumab in the first-line sequence has an incremental cost-effectiveness ratio of L39,129 per quality-adjusted life-year gained compared with the treatment sequence incorporating ixekizumab in the second line. Consistent with its conclusion regarding clinical effectiveness, the Appraisal Committee concluded that the cost effectiveness of ixekizumab for treating moderate-to-severe plaque psoriasis was similar to that of other biological treatments, already recommended in previous National Institute for Health and Care Excellence guidance. The committee concluded that the incremental cost effectiveness ratio was within the range that could be considered a cost effective use of National Health Service resources. PMID- 29480456 TI - Becker's myotonia: novel mutations and clinical variability in patients born to consanguineous parents. AB - Myotonia congenita is an inherited muscle disease present from childhood that is characterized by impaired muscle relaxation after contraction resulting in muscle stiffness; moreover, skeletal striated muscle groups may be involved. Myotonia congenita occurs due to chloride (Cl) channel mutations that reduce the stabilizing Cl conductance, and it is caused by mutations in the CLCN1 gene. This paper describes four patients from two different healthy consanguineous Turkish families with muscle stiffness and easy fatigability. A genetic investigation was performed. Mutation analyses showed a homozygous p.Tyr150* (c.450C > A) mutation in patients 1, 2 and 3 and a homozygous p.Leu159Cysfs*11 (c.475delC) mutation in patient 4 in the CLCN1 gene. These mutations have never been reported before and in silico analyses showed that the mutations were disease causing. They may be predicted to cause nonsense-mediated mRNA decay. Our data expand the spectrum of CLCN1 mutations and provide insights for genotype-phenotype correlations of myotonia congenita. PMID- 29480457 TI - Correction to: SOX10-positive cells emerge in the rat pituitary gland during late embryogenesis and start to express S100beta. AB - The published online version contains mistake in Table 1, Table 2, and some data in Materials and Methods. PMID- 29480458 TI - Induction of human umbilical cord mesenchymal stem cells into tissue-forming cells in a murine model: implications for pelvic floor reconstruction. AB - HUMSCs were isolated, differentiated and characterized in vitro. Both HUMSCs and smooth muscle cells differentiated from HUMSCs were used to fabricate tissue engineered fascia equivalents. Forty-eight mature female Sprague Dawley rats were randomly assigned to four groups: group A (GynemeshTMPS, n = 12), group B (GynemeshTMPS + HUMSCs; n = 12), group C (GynemeshTMPS + smooth muscle cells differentiated from HUMSCs; n = 12) and group D (GynemeshTMPS + HUMSCs + smooth muscle cells differentiated from HUMSCs; n = 12). The posterior vaginal wall was incised from the introitus and the mesh was then implanted. Three implants of each type were tested at 1, 4, 8 and 12 weeks. Fibrotic remodeling, inflammation, vascularization and tissue regeneration were histologically assessed. The levels of type I and type III collagen were determined. There was no difference in fibrotic remodeling between cell-seeded and unseeded meshes at any time (p > 0.05). At 12 weeks, there did not appear to be fewer inflammatory cells around the filament bundles in the mesh with cells compared with the mesh alone (P > 0.05). Group D showed a trend toward better vascularization at 12 weeks compared with group A (P < 0.05). Twelve weeks after implantation, a thin layer of new tissue growth covered the unseeded scaffold and a thicker layer covered the cell seeded scaffold (P < 0.05). No significant difference in the ratio of collagen type I/III could be detected among the different groups after 12 weeks (P > 0.05). HUMSCs with differentiated smooth muscle cells might have a potential role in fascia tissue engineering to repair POP in the future. PMID- 29480459 TI - The concept of alpha-synuclein as a prion-like protein: ten years after. AB - Parkinson's disease is characterized by the loss of nigrostriatal dopaminergic signaling and the presence of alpha-synuclein aggregates (also called Lewy bodies and neurites) throughout the brain. In 2003, Braak and colleagues created a staging system for Parkinson's disease describing the connection between the alpha-synuclein pathology and disease severity. Later, they suggested that the pathology might initially be triggered by exogenous insults targeting the gut and olfactory system. In 2008, we and other groups documented Lewy pathology in grafted neurons in people with Parkinson's disease who had been transplanted over a decade prior to autopsy. We proposed that the Lewy pathology in the grafted neurons was the result of permissive templating or prion-like spread of alpha synuclein pathology from neurons in the host to those in the grafts. During the following ten years, several studies described the transmission of alpha synuclein pathology between neurons, both in cell culture and in experimental animals. Recent research has also begun to identify underlying molecular mechanisms. Collectively, these experimental studies tentatively support the idea that the progression from one Braak stage to the next is the consequence of prion like propagation of Lewy pathology. However, definitive proof that intercellular propagation of alpha-synuclein pathology occurs in Parkinson's disease cases has proven difficult to secure. In this review, we highlight several open questions that currently prevent us from concluding with certainty that prion-like transfer of alpha-synuclein contributes to the progression of Parkinson's disease. PMID- 29480462 TI - Role of p62 in the regulation of cell death induction. AB - p62 is a multifunctional adaptor protein implicated in various cellular processes. It has been found to regulate selective autophagy, cell survival, cell death, oxidative stress, DNA repair and inflammation, and to play a role in a number of diseases, such as tumourigenesis, Paget's disease of bone, neurodegenerative disease, diabetes, and obesity. Cell death induction is an important cellular process. The dysregulation of cell death induction is involved in the pathogenesis of various diseases, such as cancer, neurodegeneration diseases, and diabetes. In this review, we discuss the functional role of p62 in inducing cell death in response to multiple stimuli, and we summarize the potential signaling pathways that contribute to this regulation. Given the important role of p62 in regulating cell death, p62 is considered to be a reasonable target for managing cell death dysregulation-related pathogenic conditions. A better understanding of the role of p62 and its related mechanisms in regulating cell death is necessary for the more precise utilization of p62 as a target for treating relevant diseases. PMID- 29480460 TI - Integrative Physiological Aspects of Brain RAS in Hypertension. AB - PURPOSE OF REVIEW: The renin-angiotensin system (RAS) plays an important role in modulating cardiovascular function and fluid homeostasis. While the systemic actions of the RAS are widely accepted, the role of the RAS in the brain, its regulation of cardiovascular function, and sympathetic outflow remain controversial. In this report, we discuss the current understanding of central RAS on blood pressure (BP) regulation, in light of recent literature and new experimental techniques. RECENT FINDINGS: Studies using neuronal or glial-specifc mouse models have allowed for greater understanding into the site-specific expression and role centrally expressed RAS proteins have on BP regulation. While all components of the RAS have been identified in cardiovascular regulatory regions of the brain, their actions may be site specific. In a number of animal models of hypertension, reduction in Ang II-mediated signaling, or upregulation of the central ACE2/Ang 1-7 pathway, has been shown to reduce BP, via a reduction in sympathetic signaling and increase parasympathetic tone, respectively. Emerging evidence also suggests that, in part, the female protective phenotype against hypertension may be due to inceased ACE2 activity within cardiovascular regulatory regions of the brain, potentially mediated by estrogen. Increasing evidence suggests the importance of a central renin-angiotensin pathway, although its localization and the mechanisms involved in its expression and regulation still need to be clarified and more precisely defined. All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines). PMID- 29480461 TI - Fitness to fly in the paediatric population, how to assess and advice. AB - : The number of children on commercial aircrafts is rising steeply and poses a need for their treating physicians to be aware of the physiologic effects and risks of air travel. The most important risk factors while flying are a decrease in partial oxygen pressure, expansion of trapped air volume, low cabin humidity, immobility, recirculation of air and limited options for medical emergencies. Because on-board medical emergencies mostly concern exacerbations of chronic disease, the medical history, stability of current disease and previous flight experience should be assessed before flight. If necessary, hypoxia altitude simulation testing can be performed to simulate the effects of in-flight hypoxia. Although the literature on paediatric safety of air travel is sparse, recommendations for many different situations can be given. CONCLUSION: We present an overview of the most up to date recommendations to ensure the safety of children during flight. What is Known: * Around 65% of on-board medical emergencies are complications of underlying disease. * In children, the three most common emergencies during flight concern respiratory, neurological and infectious disease. What is New: * Although studies are scarce, some advices to ensure safe air travel can be given for most underlying medical conditions in children, based on physiology, studies in adults and expert opinions. * In former preterm infants without chronic lung disease, hypoxia altitude simulation testing to rule out in-flight desaturation is not recommended. PMID- 29480463 TI - Use of alpha2delta Ligands for Restless Legs Syndrome/Willis Ekbom Disease. AB - Restless legs syndrome is a common neurological condition affecting a substantial portion of the population. It can be an idiopathic disorder, or one that is secondary to another cause. Given that the underlying pathophysiology of restless legs syndrome is not well understood, several drug classes have been studied for symptom control. While dopamine agonists have long been the mainstay of first line treatment for restless legs syndrome, recently, the alpha2delta ligands have been increasingly used. These agents have proven both efficacious and safe in a number of clinical trials. Additionally, compared with the dopamine agonists, they have been associated with less augmentation, a phenomenon whereby symptoms emerge earlier in the day, become more severe, and may spread to areas of the body previously unaffected. Newer clinical guidelines for restless legs syndrome are increasingly recommending the alpha2delta ligands as a logical first-choice medication for patients needing drug therapy for symptom control. PMID- 29480464 TI - Evidence of oligogenic sex determination in the apple snail Pomacea canaliculata. AB - A small number of genes may interact to determine sex, but few such examples have been demonstrated in animals, especially through comprehensive mating experiments. The highly invasive apple snail Pomacea canaliculata is gonochoristic and shows a large variation in brood sex ratio, and the involvement of multiple genes has been suggested for this phenomenon. We conducted mating experiments to determine whether their sex determination involves a few or many genes (i.e., oligogenic or polygenic sex determination, respectively). Full-sib females or males that were born from the same parents were mated to an adult of the opposite sex, and the brood sex ratios of the parents and their offspring were investigated. Analysis of a total of 4288 offspring showed that the sex ratios of offspring from the full-sib females were variable but clustered into only a few values. Similar patterns were observed for the full-sib males, although the effect was less clear because fewer offspring were used (n = 747). Notably, the offspring sex ratios of all full-sib females in some families were nearly 0.5 (proportion of males) with little variation. These results indicate that the number of genotypes of the full-sibs, and hence genes involved in sex determination, is small in this snail. Such oligogenic systems may be a major sex determining system among animals, especially those with variable sex ratios. PMID- 29480465 TI - Production and Crystallization of Full-Length Human AMP-Activated Protein Kinase (alpha1beta1gamma1). AB - Determination of the crystal structure of AMP-activated protein kinase (AMPK) is fundamental to understanding its biological function and role in a number of diseases related to energy metabolism including type 2 diabetes, obesity, and cancer. We describe methods for the expression and purification of a human full length active AMPK complex that is suitable for biochemical and structural analyses, followed by methods for its crystallization in complex with small molecule activators. Quality control of the purified protein by functional and biophysical analysis was an essential part of the process enabling the achievement of crystals of the full-length protein capable of being used for high resolution structure determination by X-ray diffraction. X-ray structures have been determined of both phosphorylated and non-phosphorylated forms of full length human AMPK alpha1beta1gamma1. PMID- 29480466 TI - Visualizing AMPK Drug Binding Sites Through Crystallization of Full-Length Phosphorylated alpha2beta1gamma1 Heterotrimer. AB - Here, we describe the crystallization protocol for AMPK, including protein production and purification. AMPK can be readily crystallized in the presence of PEG to give diffracting crystals to a resolution of between 2.5 and 3.5 A using synchrotron radiation. This method allows for visualization of drugs or small molecules that bind to the ADaM site, CBS sites, ATP binding site, and the newly identified C2 binding sites in the gamma-subunit via co-crystallization with phosphorylated AMPK (pT172) alpha2beta1gamma1 isoform or alpha2/1beta1gamma1 chimera. Drugs with binding affinities above 500 nM fail to co-crystallize with AMPK using these parameters. PMID- 29480467 TI - Biophysical Interactions of Direct AMPK Activators. AB - Protein-ligand interactions can be evaluated by a number of different biophysical methods. Here we describe some of the experimental methods that we have used to generate AMPK protein reagents and characterize its interactions with direct synthetic activators. Recombinant heterotrimeric AMPK complexes were generated using standard molecular biology methods by expression either in insect cells via infection with three different viruses or more routinely in Escherichia coli with a tricistronic expression vector. Hydrogen/deuterium exchange (HDX) coupled with mass spectrometry was used to probe protein conformational changes and potential binding sites of activators on AMPK. X-ray crystallographic studies were carried out on crystals of AMPK with bound ligands to reveal detailed molecular interactions formed by AMPK activators at near-atomic resolution. In order to gain insights into the mechanism of enzyme activation and to probe the effects of AMPK activators on kinetic parameters such as Michaelis-Menten constant (K m ) or maximal reaction velocity (V max), we performed classical enzyme kinetic studies using radioactive 33P-ATP-based filter assay. Equilibrium dissociation constants (K D ) and on and off rates of ligand binding were obtained by application of surface plasmon resonance (SPR) technique. PMID- 29480468 TI - Biochemical Measurement of Glycogen: Method to Investigate the AMPK-Glycogen Relationship. AB - Glycogen is a main carbohydrate energy storage primarily found in fungi and animals. It is a glucose polymer that comprises alpha(1-4) glycosidic linkages attaching UDP-glucose molecules linearly and alpha(1-6) linkages branching glucose chains every 8-10 molecules to the main backbone chain. Glycogen synthase, branching enzyme, and glycogen phosphorylase are key enzymes involved in glycogen synthesis and degradation. These enzymes are tightly regulated by upstream kinases and phosphatases that respond to hormonal cues in order to coordinate storage and degradation and meet the cellular and organismal metabolic needs. The 5'AMP-activated protein kinase (AMPK) is one of the main regulators of glycogen metabolism. Despite extensive research, the role of AMPK in glycogen synthesis and degradation remains controversial. Specifically, the level and duration of AMPK activity highly influence the outcome on glycogen reserves. Here, we describe a rapid and robust protocol to efficiently measure the levels of glycogen in vitro. We use the commercially available glycogen determination kit to hydrolyze glycogen into glucose, which is oxidized to form D-gluconic acid and hydrogen peroxide that react with the OxiRed/Amplex Red probe generating a product that could be detected either in a colorimetric or fluorimetric plate format. This method is quantitative and could be used to address the role of AMPK in glycogen metabolism in cells and tissues. Summary This chapter provides a quick and reliable biochemical quantitative method to measure glycogen in cells and tissues. Briefly, this method is based on the degradation of glycogen to glucose, which is then specifically oxidized to generate a product that reacts with the OxiRed probe with maximum absorbance at 570 nm. This method is very accurate and highly sensitive. In the notes of this chapter, we shed the light on important actions that should be followed to get reliable results. We also state advantages and disadvantages of this method in comparison to other glycogen measurement techniques. PMID- 29480469 TI - Cell-Free Assays to Measure Effects of Regulatory Ligands on AMPK. AB - AMP-activated protein kinase (AMPK) is an energy sensor that is activated by increases in the cellular AMP/ATP and ADP/ATP ratios by three mechanisms: (1) allosteric activation, (2) promotion of phosphorylation at Thr172 on the alpha subunit by upstream kinases, and (3) inhibition of dephosphorylation of Thr172 by protein phosphatases. All of these effects are triggered by the binding of AMP or ADP at one or more of three sites on the gamma subunit, where they displace ATP. AMPK is also activated by ligands that bind in the ADaM site, which is located between the alpha and beta subunits. In this chapter we describe cell-free assays that can be used to study these varied activation mechanisms. PMID- 29480470 TI - Applications of NMR and ITC for the Study of the Kinetics of Carbohydrate Binding by AMPK beta-Subunit Carbohydrate-Binding Modules. AB - Understanding the kinetics of proteins interacting with their ligands is important for characterizing molecular mechanism. However, it can be difficult to determine the extent and nature of these interactions for weakly formed protein ligand complexes that have lifetimes of micro- to milliseconds. Nuclear magnetic resonance (NMR) spectroscopy is a powerful solution-based method for the atomic level analysis of molecular interactions on a wide range of timescales, including micro- to milliseconds. Recently the combination of thermodynamic experiments using isothermal titration calorimetry (ITC) with kinetic measurements using ZZ exchange and CPMG relaxation dispersion NMR spectroscopy have been used to determine the kinetics of weakly interacting protein systems. This chapter describes the application of ITC and NMR to understand the differences in the kinetics of carbohydrate binding by the beta1- and beta2-carbohydrate-binding modules of AMP-activated protein kinase. PMID- 29480471 TI - Bioinformatics Approach to Identify Novel AMPK Targets. AB - In silico analysis of Big Data is a useful tool to identify putative kinase targets as well as nodes of signaling cascades that are difficult to discover by traditional single molecule experimentation. System approaches that use a multi tiered investigational methodology have been instrumental in advancing our understanding of cellular mechanisms that result in phenotypic changes. Here, we present a bioinformatics approach to identify AMP-activated protein kinase (AMPK) target proteins on a proteome-wide scale and an in vitro method for preliminary validation of these targets. This approach offers an initial screening for the identification of AMPK targets that can be further validated using mutagenesis and molecular biology techniques. PMID- 29480472 TI - Studying AMPK in an Evolutionary Context. AB - The AMPK protein kinase forms the heart of a complex network controlling the metabolic activities in a eukaryotic cell. Unraveling the steps by which this pathway evolved from its primordial roots in the last eukaryotic common ancestor to its present status in contemporary species has the potential to shed light on the evolution of eukaryotes. A homolog search for the proteins interacting in this pathway is considerably straightforward. However, interpreting the results, when reconstructing the evolutionary history of the pathway over larger evolutionary distances, bears a number of pitfalls. With this in mind, we present a protocol to trace a metabolic pathway across contemporary species and backward in evolutionary time. Alongside the individual analysis steps, we provide guidelines for data interpretation generalizing beyond the analysis of AMPK. PMID- 29480474 TI - Transient Expression of AMPK Heterotrimer Complexes in Mammalian Cells. AB - Regulation of AMP-activated protein kinase (AMPK) signalling is complex and involves contributions from adenine nucleotides, co-/posttranslational modifications, and isoform composition of the AMPK heterotrimer. It is becoming apparent that AMPK activation/inhibition by synthetic drugs involves similar levels of complexity. Major advances in our understanding of these mechanisms have been gained from recombinant expression systems that provide sufficient quantities of highly purified material for structure/function studies. Here, we provide a detailed protocol for transient expression of affinity-tagged AMPK complexes in mammalian cells. We have found this system to be optimal as a source of enzyme possessing regulatory modifications found in vivo. PMID- 29480473 TI - AMPK Protein Interaction Analyses by Yeast Two-Hybrid. AB - Mammalian AMP-activated protein kinase (AMPK) is a Ser/Thr protein kinase that acts as a crucial energy sensor in the cell. Since AMPK plays a key role in a multitude of different pathways in the cell, major efforts have been concentrated to elucidate its signaling network, mainly by the identification of AMPK downstream targets. In this chapter we describe a yeast two-hybrid method for the direct evaluation of the interaction between an AMPK subunit and putative substrates. PMID- 29480475 TI - Knockdown of Human AMPK Using the CRISPR/Cas9 Genome-Editing System. AB - AMP-activated protein kinase (AMPK) is a critical energy sensor, regulating signaling networks involved in pathology including metabolic diseases and cancer. This increasingly recognized role of AMPK has prompted tremendous research efforts to develop new pharmacological AMPK activators. To precisely study the role of AMPK, and the specificity and activity of AMPK activators in cellular models, genetic AMPK inactivating tools are required. We report here methods for genetic inactivation of AMPK alpha1/alpha2 catalytic subunits in human cell lines by the CRISPR/Cas9 technology, a recent breakthrough technique for genome editing. PMID- 29480476 TI - Compound C/Dorsomorphin: Its Use and Misuse as an AMPK Inhibitor. AB - The evolutionary conserved energy sensor AMPK plays crucial roles in many biological processes-both during normal development and pathology. Loss-of function genetic studies in mice as well as in lower organisms underscore its importance in embryonic development, stress physiology in the adult, and in key metabolic disorders including cardiovascular disease, diabetes, cancer, and metabolic syndrome. In contrast to several other kinases important in human health and medicine where specific/selective inhibitors are available, no AMPK specific inhibitors are available. The only reagent called dorsomorphin or compound C that is occasionally used as an AMPK inhibitor unfortunately inhibits several other kinases much more potently than AMPK and is therefore highly non specific. In this chapter, we discuss the pros and cons of using this reagent to study AMPK functions. PMID- 29480477 TI - Identifying the Heterotrimeric Complex Stoichiometry of AMPK in Skeletal Muscle by Immunoprecipitation. AB - The 5'-AMP-activated protein kinase is a complicated enzyme consisting of three different subunits, each of which is expressed as two or three isoforms. This gives the possibility of 12 different heterotrimeric complexes, which could have diverse functions within the cell. To map out which of these complexes are present and to what extent in skeletal muscle, we have used the immunoprecipitation technique and analyzed both the precipitates and the remaining supernatants for coprecipitation of complex partners. We have fine tuned this method to give the best results on lysates from the skeletal muscle, liver, and heart muscle from mouse to man. PMID- 29480478 TI - Kinase Activity Determination of Specific AMPK Complexes/Heterotrimers in the Skeletal Muscle. AB - Measuring the kinase activity of the 5'-AMP-activated protein kinase (AMPK) is an essential part of understanding the regulation of this metabolic master switch. The AMPK heterotrimer can exist in 12 different constellations with potentially diverse activation patterns. It is therefore important to be able to measure heterotrimer-specific activity to discriminate between these patterns. In this chapter we describe how to measure the AMPK activity of specific heterotrimeric complexes by consecutive immunoprecipitations and how the assay can be performed in a medium throughput fashion using 96-well plates. PMID- 29480479 TI - Determination of Adenine Nucleotide Concentrations in Cells and Tissues by High Performance Liquid Chromatography. AB - The serine/threonine AMP-activated protein kinase (AMPK) is a central player in the regulation of energy homeostasis, and its activity is tightly controlled, among other mechanisms, by subtle changes in cellular adenine nucleotide levels. In this chapter, we describe a step-by-step protocol for rapid, highly sensitive, reproducible, and simultaneous determination of ATP, ADP, and AMP concentrations in cell or tissue samples by reversed-phase high-performance liquid chromatography (HPLC). PMID- 29480480 TI - Intact Cell Assays to Monitor AMPK and Determine the Contribution of the AMP Binding or ADaM Sites to Activation. AB - AMP-activated protein kinase (AMPK) is extremely sensitive to cellular stress, so that nonphysiological activation of the kinase can readily occur during harvesting of cells or tissues. In this chapter we describe methods to harvest cells and tissues, and for kinase assays, that preserve the physiological activation status of AMPK as far as possible. Note that similar care with methods of cell or tissue harvesting is required when AMPK function is monitored by Western blotting, rather than by kinase assays. We also describe methods to determine whether compounds that activate AMPK in intact cells do so indirectly by interfering with cellular ATP synthesis or directly by binding to AMPK and, if the latter, whether this occurs by binding at the AMP-binding sites on the gamma subunit or at the ADaM site located between the alpha and beta subunits. PMID- 29480481 TI - Cellular Application of Genetically Encoded Sensors and Impeders of AMPK. AB - Unraveling the spatiotemporal dynamics of 5'-AMP-activated protein kinase (AMPK) signaling is necessary to bridge the gap between nutrient signaling and downstream function. Three genetically encoded Forster Resonance Energy Transfer (FRET)-based AMPK biosensors are available yielding insight into how AMPK-derived signal propagates throughout a cell in response to particular inputs. These findings, together with accumulating evidence obtained from biochemical techniques, promise to give a holistic understanding of the AMPK signaling. In this protocol, we describe the procedures and materials required for imaging intracellular AMPK activity in an organelle-specific manner, with a focus on ABKAR, a FRET-based biosensor. In addition, we introduce a novel AMPK inhibitor peptide that allows us to inhibit AMPK activity at specific subcellular compartments. PMID- 29480482 TI - Assessing Mitochondrial Bioenergetics by Respirometry in Cells or Isolated Organelles. AB - Mitochondrial oxidative phosphorylation is central for generating ATP and maintaining energy homeostasis in most eukaryotic cells. The ex vivo measurement of mitochondrial oxygen consumption rates in intact cells or isolated organelles is a valuable approach to assess mitochondrial bioenergetics in various experimental conditions. In this chapter, we describe several step-by-step protocols for measuring mitochondrial respiration in intact cells, permeabilized cells (in situ mitochondria), and isolated organelles using both Clark-type polarographic oxygen electrode devices and the newly developed oxygen-sensing fluorophore-based Seahorse technology. PMID- 29480483 TI - Study of AMPK-Regulated Metabolic Fluxes in Neurons Using the Seahorse XFe Analyzer. AB - AMP-activated protein kinase (AMPK) is the intracellular master energy sensor and metabolic regulator. AMPK is involved in cell energy homeostasis through the regulation of glycolytic flux and mitochondrial biogenesis. Interestingly, metabolic dysfunctions and AMPK deregulations are observed in many neurodegenerative diseases, including Alzheimer's. While these deregulations could play a key role in the development of these diseases, the study of metabolic fluxes has remained quite challenging and time-consuming. In this chapter, we describe the Seahorse XFe respirometry assay as a fundamental experimental tool to investigate the role of AMPK in controlling and modulating cell metabolic fluxes in living and intact differentiated primary neurons. The Seahorse XFe respirometry assay allows the real-time monitoring of glycolytic flux and mitochondrial respiration from different kind of cells, tissues, and isolated mitochondria. Here, we specify a protocol optimized for primary neuronal cells using several energy substrates such as glucose, pyruvate, lactate, glutamine, and ketone bodies. Nevertheless, this protocol can easily be adapted to monitor metabolic fluxes from other types of cells, tissues, or isolated mitochondria by taking into account the notes proposed for each key step of this assay. PMID- 29480484 TI - Investigating the Role of AMPK in Inflammation. AB - In addition to the well-characterized role of AMPK in the regulation of nutrient metabolism, it is increasingly clear that AMPK activation has multiple actions on inflammatory signalling. Here we describe methods to identify effects of AMPK activity on pro-inflammatory signalling, specifically (1) the nuclear localization of the key inflammatory mediators nuclear factor-kappaB (NFkappaB) and phosphorylated c-Jun N-terminal kinase (JNK), (2) preparation of conditioned medium to analyze the secretion of cytokines/chemokines, and (3) the pro inflammatory adhesion of leukocytes to cultured cells. PMID- 29480485 TI - Studying the Role of AMPK in Cardiac Hypertrophy and Protein Synthesis. AB - Pathological cardiac hypertrophy, which is a compensatory mechanism established to maintain cardiac function in response to neurohormonal or mechanical stresses, becomes maladaptive with time and frequently leads to heart failure. AMP activated protein kinase (AMPK) has been extensively described in the literature to act as a break in cardiac hypertrophy development. Its anti-hypertrophic action mostly correlates with the inhibition of several important players of cardiac hypertrophy including protein synthesis and pro-hypertrophic gene expression pathways involving the transcription factor nuclear factor of activated T cells (NFAT) and the mitogen-activated protein kinases ERK1/2. In this chapter, we describe methodologies designed to evaluate cardiomyocyte hypertrophy and its major molecular mechanisms in response to AMPK activation. Two different compounds, AICAr and the biguanide phenformin, were used to promote AMPK activation. PMID- 29480486 TI - Assessment of AMPK-Stimulated Cellular Long-Chain Fatty Acid and Glucose Uptake. AB - Here we describe an assay for simultaneous measurement of cellular uptake rates of long-chain fatty acids (LCFA) and glucose that can be applied to cells in suspension. The uptake assay includes the use of radiolabeled substrates at such concentrations and incubation periods that exact information is provided about unidirectional uptakes rates. Cellular uptake of both substrates is under regulation of AMPK. The underlying mechanism includes the translocation of LCFA and glucose transporters from intracellular membrane compartments to the cell surface, leading to an increase in substrate uptake. In this chapter, we explain the principles of the uptake assay before detailing the exact procedure. We also provide information of the specific LCFA and glucose transporters subject to AMPK mediated subcellular translocation. Finally, we discuss the application of AMPK inhibitors and activators in combination with cellular substrate uptake assays. PMID- 29480487 TI - Measurement of AMPK-Induced Inhibition of Lipid Synthesis Flux in Cultured Cells. AB - AMP-activated protein kinase (AMPK) is a master regulator of multiple cellular metabolic pathways, including lipid metabolism. Some of the well-known substrates of AMPK are acetyl-CoA carboxylase (ACC) and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, regulatory enzymes of fatty acid and cholesterol synthesis, respectively. The discovery that both of them are inactivated by AMPK suggested the therapeutic potential of AMPK activation in the treatment of metabolic diseases associated with lipid disorders, such as nonalcoholic fatty liver disease (NAFLD). Here we describe a method to measure lipid synthesis flux in intact cells from the saponifiable (including fatty acids) and non saponifiable (including sterols) fractions of lipid extracts. PMID- 29480488 TI - Studying the Role of AMPK in Autophagy. AB - AMPK is an energy-sensing kinase and is required for the induction and progression of the autophagy process. In this chapter, we describe experimental approaches to study the steady state and flux of autophagy in response to AMPK activation. For this purpose, we provide detailed protocols for the measurement of general as well as AMPK-specific autophagy markers by immunoblot and immunofluorescence analysis. PMID- 29480489 TI - Determining AMPK Activation via the Lysosomal v-ATPase-Ragulator-AXIN/LKB1 Axis. AB - Recent studies have revealed how AMPK is activated inside the cell and animal tissues: in response to low glucose, AXIN tethers LKB1, by virtue of their constitutive association, to AMPK located on the surface of late endosome/lysosome. Importantly, the lysosomal v-ATPase (vacuolar ATPase) Ragulator complex, when primed by glucose starvation or concanamycin A, facilitates AXIN/LKB1 to interact with AMPK. Here, we describe the experimental procedures of the assays for detecting the translocation of AXIN/LKB1 or the assembly of the AXIN-based AMPK-activating complexes on the late endosome/lysosome. The methods in this chapter will be useful for determining whether various metabolic stresses or pharmacological stimuli activate AMPK via the v-ATPase-Ragulator-AXIN/LKB1 axis, which also concomitantly inactivates mTORC1. Detailed protocols for determining the levels of adenylates are also described. PMID- 29480490 TI - Manipulation and Measurement of AMPK Activity in Pancreatic Islets. AB - The role of the energy sensor AMPK-activated protein kinase (AMPK) in the insulin secreting beta-cell remains unclear and a subject of intense research. With this chapter, we aim to provide a detailed description of the methods that our group routinely applies to the study of AMPK function in mouse and human pancreatic islets. Thus, we provide detailed protocols to isolate and/or culture mouse and human islets, to modulate and measure AMPK activity in isolated islets, and to evaluate its impact on islet function. PMID- 29480491 TI - Analyzing AMPK Function in the Hypothalamus. AB - Hypothalamic AMPK plays a key role in the control of energy homeostasis by regulating energy intake and energy expenditure, particularly modulating brown adipose tissue (BAT) thermogenesis. The function of AMPK can be assayed by analyzing its phosphorylated protein levels in tissues, since AMPK is activated when it is phosphorylated at Thr-172. Here, we describe a method to obtain hypothalamic (nuclei-specific) protein extracts and the suitable conditions to assay AMPK phosphorylation by Western blotting. PMID- 29480492 TI - Using Ex Vivo Kidney Slices to Study AMPK Effects on Kidney Proteins. AB - The ex vivo kidney slice technique has been used extensively in the fields of kidney physiology and cell biology. Our group and others have used this method to study epithelial traffic of transport proteins in situ in kidney tissue. In this methodology chapter, we summarize our adaptation of this classic protocol for the study of the effect of AMPK in the modulation of transport protein regulation, especially in kidney epithelial cells. Briefly, slices were obtained by sectioning freshly harvested rodent (rat or mouse) kidneys using a Stadie-Riggs tissue slicer. The harvested kidney and the kidney slices are kept in a physiological buffer equilibrated with 5% CO2 at body temperature (37 degrees C) in the presence of different AMPK activating agents vs. vehicle control followed by rapid freezing or fixation of the slices to prevent non-specific AMPK activation. Thus, homogenates of these frozen slices can be used to study AMPK activation status in the tissue as well as the downstream effects of AMPK on kidney proteins via biochemical techniques, such as immunoblotting and immunoprecipitation. Alternatively, the fixed slices can be used to evaluate AMPK mediated subcellular traffic changes of epithelial transport proteins via immunolabeling followed by confocal microscopy. The resulting micrographs can then be used for systematic quantification of AMPK-induced changes in subcellular localization of transport proteins. PMID- 29480493 TI - A Flow Cytometry-Based Protocol to Measure Lymphocyte Viability Upon Metabolic Stress. AB - Distinct lymphocyte subpopulations display discrete metabolic profiles and are differently affected by metabolic resource variations, making the analysis of lymphocyte survival in a complex tissue in response to metabolic stress highly challenging. Here we describe a flow cytometry-based method allowing simultaneous cell identification and viable cell counting in mixed lymphocyte populations without extensive cell subset purification procedures. The example provided herein illustrates the role of AMPK in T lymphocyte survival in response to the mitochondrial poison oligomycin. PMID- 29480494 TI - Methods to Evaluate AMPK Regulation of Macrophage Cholesterol Homeostasis. AB - Macrophages are a driving force in the development and progression of atherosclerosis, a chronic condition that can lead to cardiovascular disease. In this chapter we describe methods that monitor macrophage cholesterol homeostasis such as cholesterol synthesis, uptake, and efflux, all with the use of AMPK activators and potential genetic models that could help shed light on the role of this metabolic regulator in atherosclerosis and other chronic diseases. PMID- 29480495 TI - Modulation of Vascular Function by AMPK: Assessment of NO Bioavailability and Surrogates of Oxidative Stress. AB - The endothelium plays a pivotal role in the development of vascular disease. Decreased bioavailability of nitric oxide, a condition known as "endothelial dysfunction," is considered an early step in this process before atherosclerotic changes of the vessel wall occur. Endothelium-derived nitric oxide (*NO) may be rapidly scavenged by superoxide anions; therefore, the equilibrium between *NO production on one hand and its inactivation by oxidative stress on the other hand is of particular interest. Metabolic enzyme systems such as AMP-activated protein kinase (AMPK) may affect the cellular production of *NO or reactive oxygen species (ROS), while AMPK activity itself can also be modulated by ROS. Therefore, the analysis of *NO as well as ROS levels is essential to understand how metabolism regulating enzymes like AMPK may modulate vascular disease. PMID- 29480496 TI - Measurement of Reactive Oxygen Species (ROS) and Mitochondrial ROS in AMPK Knockout Mice Blood Vessels. AB - Reactive oxygen species (ROS) are a group of unstable and highly reactive molecules or free radicals typically generated as by-products of cellular processes involving molecular oxygen. In vascular cells, the excessive ROS generation results in the initiation and progression of cardiovascular diseases (CVD). Therefore, a dynamic, robust, and accurate ROS detection method in the blood vessels is essential for pathophysiological research studies of the cardiovascular system.In this chapter, we describe a fluorescence dye-based detection method for assaying superoxide and mitochondrial superoxide in mouse aorta using dihydroethidium (DHE) and MitoSOX. The protocol includes preparation of frozen aortic tissue sections, monitoring DHE oxidation-derived fluorescence by fluorescence microscopy, and high-performance liquid chromatograph-based analysis of MitoSOX and its oxidation products. For studying the role of AMP activated protein kinase (AMPK) in the redox regulation, we employed AMPKalpha2 knockout mice and observed increased superoxide and mitochondrial superoxide levels in the aorta of AMPK knockout mice relative to the wild-type group. This novel ROS detection method will be valuable for investigating the roles of cellular and/or mitochondrial ROS in the pathogenesis of CVDs. PMID- 29480497 TI - Studying the Role of AMPK in Angiogenesis. AB - The role of AMPK in angiogenesis can be studied using in vitro and in vivo assays. The endothelial spheroid assay is a robust three-dimensional in vitro test, which allows investigation of tubular morphogenesis by integrating cell cell as well as cell-matrix interactions. The Matrigel plug assay validates the process of angiogenesis in vivo and allows studies in genetically modified mice. Here, we give a detailed description of both assays and their application in AMPK research. PMID- 29480498 TI - Analysis of Muscle Stem Cell Fate Through Modulation of AMPK Activity. AB - In this chapter, we describe the methods to isolate and culture muscle stem cells (MuSCs) from murine skeletal muscle in order to decipher the intrinsic effect of AMP-activated kinase activity on MuSC fate. Culture of MuSCs is a powerful model to recapitulate every step of stem cell behavior observed in vivo: activation, proliferation, differentiation, fusion and also self-renewal. We provide the detailed procedures to isolate pure MuSCs by a flow cytometry-based method using the selection of a combination of specific markers and to characterize MuSC fate (quiescence, activation, and differentiation) in response to AMPK activity modulation by assessing of the expression of stem cell (e.g., Pax7) and myogenic marker (e.g., MyoD). PMID- 29480500 TI - Analysis of Transgenerational Phenotypes Following Acute Starvation in AMPK Deficient C. elegans. AB - Environmental variation experienced early in life can result in long-term reproductive consequences. We have recently identified an important role for AMPK in the prevention of transgenerational defects following starvation of L1 stage larvae in C. elegans. Here we describe a means of analyzing these transgenerational defects following a single exposure to energy stress during early larval development. We also provide methods to quantify the histone modifications that are affected by this stress, along with the resulting reproductive defects that arise in later generations. PMID- 29480499 TI - Evaluating the Role of Host AMPK in Leishmania Burden. AB - The study of host AMP-activated protein kinase (AMPK) activation during Leishmania infection imposes distinct types of techniques to measure protein expression and activation, as well as to quantify, at transcription and translational levels, its downstream targets. The investigation of host AMPK protein modulation during Leishmania infection should primarily be assessed during in vitro infections using as a host murine bone marrow-derived macrophages (BMMos). The infection outcome is assessed measuring the percentage of infected cells in the context of BMMos. To evaluate AMPK activity during infection, the expression of AMPK phosphorylated at Thr172 as well as the transcription and translational levels of its downstream targets are evaluated by quantitative PCR and immunoblotting. The modulation of AMPK activity in vivo is determined specifically in sorted splenic macrophages harboring Leishmania parasites recovered from infected mice using fluorescent-labeled parasites in the infectious inocolum. The modulation of AMPK activity was assessed by AMPK activators and inhibitors and also using AMPK, SIRT1, or LKB1 KO mice models. The infection outcome in BMMos and in vivo was further determined using these two different approaches. To finally understand the metabolic impact of AMPK during infection, in vitro metabolic assays in infected BMMos were measured in the bioenergetic profile using an extracellular flux analyzer. PMID- 29480501 TI - Human gamma2-AMPK Mutations. AB - In humans, dominant mutations in the gene encoding the regulatory gamma2-subunit of AMP-activated protein kinase (PRKAG2) result in a highly penetrant phenotype dominated by cardiac features: left ventricular hypertrophy, ventricular pre excitation, atrial tachyarrhythmia, cardiac conduction disease, and myocardial glycogen storage. The discovery of a link between the cell's fundamental energy sensor, AMPK, and inherited cardiac disease catalyzed intense interest into the biological role of AMPK in the heart. In this chapter, we provide an introduction to the spectrum of human disease resulting from pathogenic variants in PRKAG2, outlining its discovery, clinical genetics, and current perspectives on its pathogenesis and highlighting mechanistic insights derived through the evaluation of disease models. We also present a clinical perspective on the major components of the cardiomyopathy associated with mutations in PRKAG2, together with less commonly described extracardiac features, its prognosis, and principles of management. PMID- 29480503 TI - Cost-Effectiveness of a Behavioral Psychosocial Treatment Integrated Across Home and School for Pediatric ADHD-Inattentive Type. AB - We conducted a cost-effectiveness analysis (CEA) of two behavioral psychosocial interventions for children with ADHD-inattentive type: Child Life and Attention Skills (CLAS) program and parent-focused treatment (PFT) compared to community based treatment as usual (TAU). The CEA evaluated cost per ADHD case resolved measured by parent and teacher reports of ADHD inattentive symptoms. Total cost per patient for CLAS, PFT, and TAU were $1559, $710, and $0. CLAS, the costliest treatment, was more effective than PFT and TAU. The incremental cost effectiveness ratios (ICER) per disordered case resolved are: $3997 for CLAS versus TAU, $3227 for PFT versus TAU, and $4994 for CLAS versus PFT. PFT is the more cost-effective option based on initial CEA. However, CLAS may be comparably cost-effective by streamlining the model, which resulted in an ICER of $29 compared to PFT. Notably, cost for CLAS is substantially below the annual cost for unresolved ADHD. PMID- 29480502 TI - Dental treatment and caries prevention preceding treatment under general anaesthesia in healthy children and adolescents: a retrospective cohort study. AB - AIM: This was to examine healthy children and adolescents treated under general anaesthesia (GA) and a matched control group not receiving GA to compare treatment and preventive care received prior to GA treatment. METHODS: This retrospective cohort study included 71 healthy subjects and 213 age- and gender matched control subjects. The treatment group had been consecutively referred from the Public Dental Health Service (PDS) in Stockholm to the Department of Paediatric Dentistry, Eastman Institute, Stockholm during 2006-2007. Data was extracted from the patient records at the PDS, including variables such as number of dental visits, treatment/prophylaxis prior to GA, number of missed and cancelled appointments, and number of decayed teeth. RESULTS: On average, the treatment group had significantly more decayed teeth (p < 0.001) than the control group. Furthermore, the treatment group had significantly more restorations (p < 0.01), had visited the dentist significantly more often (p < 0.001), and had undergone significantly more behaviour management treatment and preventive treatment (p < 0.001). In the treatment group 65% of the children and adolescents, had received no behaviour management treatment and 48%, no preventive treatment. CONCLUSIONS: In the Stockholm PDS, over half of the children and adolescents referred by general dentists to paediatric specialists had no behaviour management treatment and nearly half, no preventive treatment, despite receiving significantly more operative treatment compared with matched controls. General dentists should target high caries-risk patients for additional behaviour management and preventive care to reduce the need for treatment under GA. PMID- 29480505 TI - Salvage therapy outcomes for atypical meningioma. AB - Atypical menginomas demonstrate increased clinical aggressiveness characterized by recurrence and diminished survival. The optimal management of atypical meningioma in the recurrent setting is especially not well defined. To characterize outcomes following salvage treatment of recurrent atypical meningioma and to identify risk factors for further recurrence. Retrospective chart review was performed on 65 patients who underwent salvage treatment of atypical meningioma at a single institution. Data were analyzed using the Kaplan Meier method and Cox proportional hazards modeling. Sixty-five patients with recurrent atypical meningioma and median imaging follow-up of 4.0 years (range 1.9-6.6 years) underwent 62 surgeries and 114 radiation treatments (RT) for salvage therapy. Salvage modality was surgery (21%), surgery/RT (25%), or RT alone (54%), associated with 2 year local freedom from recurrence (LFFR) of 36, 59, and 73%, respectively (P = 0.01). Twenty percent of patients experienced CTCAE grade >= 3 toxicity with salvage therapy. Thirty-nine percent of patients experienced >= 3 recurrences. The median disease-free survival intervals after first and second salvage treatments were 2.9 and 1.3 years, respectively. On univariate Cox analysis, prior subtotal resection, prior RT, tumor diameter > 2.5 cm, and multifocal local recurrence were associated with recurrence after salvage therapy. On multivariate logistic regression, only multifocal local recurrence was associated with further recurrence. Recurrent atypical meningioma is clinically and pathologically more aggressive than primary atypical meningioma, and the likelihood of durable local control with salvage therapy is lower. Future efforts should identify patients at risk of recurrence, and aggressive upfront treatment should be employed. PMID- 29480506 TI - Patient-Provider Communication: Experiences of Low-Wage-Earning Breast Cancer Survivors in Managing Cancer and Work. AB - In 2017, there will be more than 250,000 new diagnoses of invasive breast cancer; most cases will occur in working-age women. The goal of this qualitative study was to explore low-wage-earning breast cancer survivors' experiences communicating with their oncology team about cancer and employment issues. Twenty four low-wage-earning breast cancer survivors in the USA were interviewed in 2012 using a structured interview protocol. Sociodemographic data, cancer history, and patient-provider communication experiences regarding the management of cancer and work were collected. Interviews were analyzed using grounded theory strategy of constant comparative analysis. Low-wage-earning breast cancer survivors' experiences communicating with their oncology team about employment and cancer focused on three dimensions of patient-provider communication: extent, quality, and content. Over 70% of respondents reported no communication or only routine communication with their providers regarding work; three quarters of women reported poor or standard communication quality, and content of work-related communication covered scheduling issues, work absences, continuing to work during treatment, and financial concerns. Communication between oncology care teams and low-wage-earning cancer patients is critical to the successful management of treatment and work responsibilities given the vulnerable employment situation of these women. There is a need for education of oncology team members about how cancer and its treatment can impact employment for all workers, but especially for low-wage workers, thereby allowing the care team to address these issues proactively and help patients successfully manage both cancer treatment and work responsibilities. PMID- 29480507 TI - Pain Experience is Somatotopically Organized and Overlaps with Pain Anticipation in the Human Cerebellum. AB - Many fMRI studies have shown activity in the cerebellum after peripheral nociceptive stimulation. We investigated whether the areas in the cerebellum that were activated after nociceptive thumb stimulation were separate from those after nociceptive toe stimulation. In an additional experiment, we investigated the same for the anticipation of a nociceptive stimulation on the thumb or toe. For his purpose, we used fMRI after an electrical stimulation of the thumb and toe in 19 adult healthy volunteers. Following nociceptive stimulation, different areas were activated by stimulation on the thumb (lobule VI ipsilaterally and Crus II mainly contralaterally) and toe (lobules VIII-IX and IV-V bilaterally and lobule VI contralaterally), i.e., were somatotopically organized. Cerebellar areas innervated non-somatotopically by both toe and thumb stimulation were the posterior vermis and Crus I, bilaterally. In the anticipation experiment, similar results were found. However, here, the somatotopically activated areas were relatively small for thumb and negligible for toe stimulation, while the largest area was innervated non-somatotopically and consisted mainly of Crus I and lobule VI bilaterally. These findings indicate that nociceptive stimulation and anticipation of nociceptive stimulation are at least partly processed by the same areas in the cerebellum. This was confirmed by an additional conjunction analysis. Based on our findings, we hypothesize that input that is organized in a somatotopical manner reflects direct input from the spinal cord, while non somatotopically activated parts of the cerebellum receive their information indirectly through cortical and subcortical connections, possibly involved in processing contextual emotional states, like the expectation of pain. PMID- 29480508 TI - Understanding the roles of negative immune regulator TIPE2 in different diseases and tumourigenesis. AB - Tumour necrosis factor (TNF)-alpha-induced protein 8-like 2 (TIPE2 or TNFAIP8L2) is a novel identified negative regulator of both innate and adaptive immunity, which participates in immune homeostasis. TIPE2 is expressed in both immune tissues and non-immune tissues. It is significantly down-regulated in patients with infectious and autoimmune diseases, and the depletion of TIPE2 causes severe inflammatory disease. In recent years, accumulating evidence has shown that TIPE2 serves as an ideal biomarker and as a tumour suppressor in several tumour types. In this review, we summarized the roles and corresponding mechanisms of TIPE2 in immune regulation and different diseases, especially in tumourigenesis. PMID- 29480509 TI - [Motor imagery: a systematic review of its effectiveness in the rehabilitation of the upper limb following a stroke]. AB - INTRODUCTION: Motor imagery or mental practice of movement is a relatively new intervention that is being used on an increasingly more frequently basis in the treatment of stroke patients. It consists in the person evoking a movement or gesture in order to learn or improve its execution. Neuroimaging studies have shown that imagining movements activates neuronal patterns that are similar to those produced when they are actually performed. PATIENTS AND METHODS: A systematic review was conducted between January and June 2017 in the Web of Science, PubMed, CINHAL, PEDro and Scopus databases to select clinical trials carried out with stroke patients in whom this technique was used as rehabilitation. Thirteen randomised clinical trials were included. The characteristics of the studies and the measures of results were summarised and the evidence of their outcomes was described. RESULTS: Most of the studies found significant differences in terms of improved motor rehabilitation of the upper limb among the subjects in the experimental groups. Only one of the studies failed to show any evidence of its effectiveness in isolation. None of them made any reference to its effectiveness in improving sensory alterations. CONCLUSIONS: Motor imagery, combined with conventional therapy (physiotherapy or occupational therapy), seems to have positive effects on the motor rehabilitation of the upper limb following a stroke. Further research is needed to improve the heterogeneity of the interventions and to evaluate their effectiveness in the long term. PMID- 29480510 TI - [Functional hemispherectomy: long-term follow-up in a series of five patients]. AB - INTRODUCTION: Functional hemispherectomy consists in palliative epilepsy surgical procedure usually performed in patients with pharmaco-resistant epilepsy and hemispheric syndromes. It is based on the neural disconnection of the affected hemisphere with preservation of the vascular supply. AIM: To analyze long-term prognosis and safety of the hemispherectomies performed in our institution. PATIENTS AND METHODS: Retrospective analysis collecting the following variables: age, gender, age of epilepsy onset, type of seizures, etiology, age of epilepsy surgery, prognosis and potential surgical complications. All patients had a minimum of five years of follow up. RESULTS: Five patients (60% females) underwent hemispherotomy between 1999 and 2010. Age of epilepsy onset was 36 months and time of evolution until surgery was 7 years. The most frequent type of seizures were simple motor seizures with secondary generalization (n = 5). Three patients remained seizure free persistently after surgery and another patient had a more than 90% improvement. Time of follow up was 13 years. One patient suffered a bacterial meningitis without sequelae. Six years after surgery a patient suffered hydrocephalous requiring ventriculoperitoneal shunt. CONCLUSIONS: Functional hemispherectomy constitutes an effective method to treat patients with pharmaco-resistant epilepsy, extensive unihemispheric pathology and seizures limited to that hemisphere. Late complications may occur thus long-term follow-up is needed. PMID- 29480511 TI - [Occipital condyle syndrome as the first symptom of a metastatic hepatocellular carcinoma. Two case reports]. AB - INTRODUCTION: Occipital condyle syndrome consists of the presence of unilateral occipital headache exacerbated by moving the head and is accompanied by paralysis of the ipsilateral hypoglossal nerve. One of its causes is infiltration of the base of the skull by bone metastases, especially those affecting the hypoglossal nerve due to infiltration as it passes through the osseous canal. CASE REPORTS: We report two clinical cases of occipital condyle syndrome secondary to metastatic hepatocarcinoma. The first is that of a 52-year-old male with liver cirrhosis secondary to liver pathology caused by hepatitis C virus with occipital condyle syndrome as the presenting symptom in disseminated hepatocarcinoma. The second case is that of a 56-year-old male after recurrence of hepatocarcinoma following a liver transplant, despite not fulfilling the Milan criteria. CONCLUSION: Occipital condyle syndrome is an alarm symptom and requires a thorough study by means of imaging tests, since it may be the first symptom of an undetected hepatocarcinoma. PMID- 29480512 TI - [Side effects of methylphenidate in children and the young]. AB - INTRODUCTION: The use of psychostimulants has been present in common medical practice since the 20th century and has undergone an exponential growth in terms of the number of prescriptions. AIM: To review the current state of knowledge about the side effects of psychostimulants in the child and teen populations. DEVELOPMENT: A review was performed by searching in different databases and included clinical analyses, observational prospective studies and systematic reviews. A minimum increase in blood pressure and heart rate are observed, but some studies highlight an underestimation of the long-term risk. As regards appetite and growth, almost all the current literature points to a slowing of the rate of growth, which is regained on interrupting treatment. One important factor, as is the parallel evolution of bone age, has not been evaluated in most of the studies carried out to date. No significant worsening of sleep was noted in patients treated with psychostimulants with respect to those who are not being treated. With regard to the central nervous system, there does not seem to be any evidence of an increased risk of the appearance or exacerbation of tics following introduction of the treatment. Affect and emotion are areas that have been barely explored. CONCLUSIONS: It is important to have more evidence on the safety of these drugs. It is therefore essential to have access to studies that cover a period of time consistent with the duration of these treatments. PMID- 29480514 TI - [Familial brain abscesses secondary to hereditary familial telangiectasia]. PMID- 29480513 TI - [Myths and evidence on the use of botulinum toxin: neuropharmacology and dystonia]. AB - INTRODUCTION: Botulinum toxin type A (BTA) is a bacterial endotoxin, whose therapeutic use has had a dramatic impact on different neurological disorders, such as dystonia and spasticity. AIM: To analyze and summarize different questions about the use of BTA in our clinical practice. DEVELOPMENT: A group of experts in neurology developed a list of topics related with the use of BTA. Two groups were considered: neuropharmacology and dystonia. A literature search at PubMed, mainly for English language articles published up to June 2016 was performed. The manuscript was structured as a questionnaire that includes those questions that, according to the panel opinion, could generate more controversy or doubt. The initial draft was reviewed by the expert panel members to allow modifications, and after subsequent revisions for achieving the highest degree of consensus, the final text was then validated. Different questions about diverse aspects of neuropharmacology, such as mechanism of action, bioequivalence of the different preparations, immunogenicity, etc. were included. Regarding dystonia, the document included questions about methods of evaluation, cervical dystonia, blepharospasm, etc. CONCLUSION: This review does not pretend to be a guide, but rather a tool for continuous training of residents and specialists in neurology, about different specific areas of the management of BTA. PMID- 29480515 TI - Predictive risk factors for recurrent atrial fibrillation after modified endoscopic ablation: A 2-year follow-up. AB - BACKGROUND: Our previous study reported a modified endoscopic procedure for nonvalvular atrial fibrillation (AF) that requires only 3 ports in the left chest wall. HYPOTHESIS: Certain preoperative variables might be predictive risk factors for AF recurrence among patients who underwent this procedure. METHODS: From October 2010 to April 2014, 114 patients with either paroxysmal AF (PAF) or nonparoxysmal AF (non-PAF) underwent the procedure and completed postoperative cardiac-rhythm measurement via electrocardiography and Holter monitoring. Univariate and multivariate analyses of the possible AF-related risk factors were conducted. RESULTS: During 2-year follow-up, 99 of 114 patients (86.8%) were free from atrial tachyarrhythmia. Results from univariate analyses showed that AF duration, left atrial diameter (LAD), left atrial minimum volume, left atrial empty fraction, left atrial expansion index, and left atrial active empty fraction (LAAEF) were significantly associated with postoperative AF recurrence. Results from multivariate analyses showed that AF duration (odds ratio [OR]: 1.194, 95% CI: 1.063-1.340, P = 0.003), LAD (OR: 1.101, 95% CI: 1.005-1.205, P = 0.039), and LAAEF (OR: 0.490, 95% CI: 0.277-0.865, P = 0.014) were independent risk factors. There was no difference in AF recurrence between patients with PAF and non-PAF (P = 0.250). CONCLUSIONS: Our 2-year follow-up study suggested that low LAAEF, long AF duration, and large LAD might be potential predictive risk factors for AF recurrence. Patients with PAF and non-PAF had a similar AF recurrence rate after modified endoscopic ablation. PMID- 29480516 TI - One-minute wellness: a no-cost mental health outreach initiative. PMID- 29480517 TI - Evaluation of the Stiffness of Tissues Surrounding Thyroid Nodules with Shear Wave Elastography. AB - OBJECTIVES: This study evaluated the stiffness of tissue surrounding thyroid nodules using shear wave elastography (SWE). METHODS: A total of 128 thyroid nodules in 108 patients were examined with conventional ultrasound imaging and SWE. The maximum Young modulus value was measured to evaluate the stiffness of the thyroid nodules (E) and the 2-mm perinodular region (Eshell ). The number of thyroid fibrocytes was evaluated by Masson trichrome staining and image processing software. The arrangement of the fibrous structure was also classified. RESULTS: The mean age +/- SD of the 108 patients was 33.12 +/- 13.34 years (range, 18-80 years). Thirty-nine thyroid nodules were classified as benign and 89 as malignant. Eshell was significantly higher for malignant nodules (95.0 +/- 21.9 kPa) compared with benign nodules (48.1 +/- 17.0 kPa; P < .001). Eshell yielded an area under the receiver operator characteristic curve value of 0.951, which was used for the diagnosis of nodules. There was a high positive correlation between E and Eshell in the malignant group (R = 0.722; P < .001) and a moderate positive correlation in the benign group (R = 0.601; P < .001). Percentages of fibrocytes correlated highly with Eshell in all samples as well as in malignant samples (R = 0.867 and R = 0.729, respectively; P < .001). The degree of disorder of the tissue surrounding thyroid nodules was positively correlated with Eshell (R = 0.833). CONCLUSIONS: Perinodular stiffness has potential to improve diagnosis of thyroid nodules. PMID- 29480518 TI - Early Transient Prenatal Ultrasound Features of Choanal Atresia. AB - We present a case series of early second-trimester prenatal ultrasound (US) features in 4 fetuses with a confirmed diagnosis of choanal atresia. The clinical characteristics and outcomes evaluated included prenatal US findings, genetic analyses, postmortem autopsies (2 cases), and computed tomographic findings. A transient large nasal cavity was detected by US in all 4 fetuses. This finding disappeared a few weeks later. Three cases were unilateral choanal atresia, and 1 was bilateral. Transient enlargement of the nasal cavity in early pregnancy appears to be a US sign of choanal atresia. PMID- 29480519 TI - Supporting faculty writing at an academic health sciences centre. PMID- 29480520 TI - Cytotoxic activity of halogenated sesquiterpenes from Laurencia dendroidea. AB - Red algae of the genus Laurencia J. V. Lamouroux are found in tropical and subtropical regions throughout the world and are an extremely rich source of active secondary metabolites with diverse structural features. In the present study, 6 sesquiterpenes (obtusol, (-)-elatol, dendoidiol, debrome-elatol, triquinane, and obtusane) isolated from Laurencia dendroidea were investigated for their cytotoxicity, using 4 cancer cell lines (U937, Jurkat, B16F10, and Colo 205). Among all sesquiterpenes tested, obtusol and (-)-elatol showed a promising activity in the treatment of Colo-205 strain, with IC50 of 1.2 +/- 1.4 and 2.5 +/ 1.3 MUg/ml, respectively. In addition, fluorescence microscopy results indicated that, at 100 MUg/ml, obtusol induced apoptosis at 79% and (-)-elatol at 95%. Activation of Caspases 2, 4, 6, and 8 showed to be involved in (-)-elatol activity and only Caspase 6 in obtusol activity. These data demonstrated the effective apoptosis-inducing activity of the sesquiterpene (-)-elatol and obtusol in the treatment of Colo-205 strain. Therefore, more studies should be done so that the sesquiterpenes (-)-elatol and obtusol might become promising chemotherapy. PMID- 29480521 TI - Soft tissue changes following extraction vs. nonextraction orthodontic fixed appliance treatment: a systematic review and meta-analysis. AB - The aim of this systematic review was to assess the effect of systematic extraction protocols during orthodontic fixed appliance treatment on the soft tissue profile of human patients. Nine databases were searched until December 2016 for controlled clinical studies including premolar extraction or nonextraction treatment. After elimination of duplicate studies, data extraction, and risk-of-bias assessment according to the Cochrane guidelines, random-effects meta-analyses of mean differences (MD) or standardized mean differences (SMD) and their 95% CIs were performed, followed by subgroup, meta-regression, and sensitivity analyses. Extraction treatment was associated with increased lower lip retraction (24 studies; 1,456 patients; MD = 1.96 mm), upper lip retraction (21 studies; 1,149 patients; MD = 1.26 mm), nasolabial angle (21 studies; 1,089 patients; MD = 4.21 degrees ), soft-tissue profile convexity (six studies; 408 patients; MD = 1.24 degrees ), and profile pleasantness (three studies; 249 patients; SMD = 0.41). Patient age, extraction protocol, and amount of upper incisor retraction during treatment were significantly associated with the observed extraction effects, while the quality of evidence was very low in all cases due to risk of bias, baseline confounding, inconsistency, and imprecision. Although tooth extractions seem to affect patient profile, existing studies are heterogenous and no consistent predictions of profile response can be made. PMID- 29480522 TI - Safety and efficacy of biological therapies in patients with psoriasis with alcoholic cirrhosis: a French retrospective study of 23 cases. PMID- 29480523 TI - Turmeric (Curcuma longa) and its major constituent (curcumin) as nontoxic and safe substances: Review. AB - Curcumin is the major constituent of turmeric (Curcuma longa). Turmeric has been widely used as a spice in foods and for therapeutic applications such as anti inflammatory, antihyperlipidemic, and antimicrobial activities. Turmeric and curcumin are nonmutagenic and nongenotoxic. Oral use of turmeric and curcumin did not have reproductive toxicity in animals at certain doses. Studies on human did not show toxic effects, and curcumin was safe at the dose of 6 g/day orally for 4 7 weeks. However, some adverse effects such as gastrointestinal upsets may occur. Moreover, oral bioavailable formulations of curcumin were safe for human at the dose of 500 mg two times in a day for 30 days, but there are still few trials and more studies are needed specially on nanoformulations and it should be discussed in a separate article. In addition, curcumin is known as a generally recognized as safe substance. This review discusses the safety and toxicity of turmeric and curcumin in medicine. Turmeric and curcumin are nontoxic for human especially in oral administration. Turmeric and curcumin are also safe in animals. They are nonmutagenic and are safe in pregnancy in animals but more studies in human are needed. PMID- 29480524 TI - Transgenic mouse lines expressing the 3xFLAG-dCas9 protein for enChIP analysis. AB - We developed the engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP) technology to isolate specific genomic regions while retaining their molecular interactions. In enChIP, the locus of interest is tagged with an engineered DNA-binding molecule, such as a modified form of the clustered regularly interspaced short palindromic repeats (CRISPR) system containing a guide RNA (gRNA) and a catalytically inactive form of Cas9 (dCas9). The locus is then affinity-purified to enable identification of associated molecules. In this study, we generated transgenic mice expressing 3xFLAG-tagged Streptococcus pyogenes dCas9 (3xFLAG-dCas9) and retrovirally transduced gRNA into primary CD4+ T cells from these mice for enChIP. Using this approach, we achieved high yields of enChIP at the targeted genomic region. Our novel transgenic mouse lines provide a valuable tool for enChIP analysis in primary mouse cells. PMID- 29480525 TI - High-Throughput Kinetic Analysis for Target-Directed Covalent Ligand Discovery. AB - Cysteine-reactive small molecules are used as chemical probes of biological systems and as medicines. Identifying high-quality covalent ligands requires comprehensive kinetic analysis to distinguish selective binders from pan-reactive compounds. Quantitative irreversible tethering (qIT), a general method for screening cysteine-reactive small molecules based upon the maximization of kinetic selectivity, is described. This method was applied prospectively to discover covalent fragments that target the clinically important cell cycle regulator Cdk2. Crystal structures of the inhibitor complexes validate the approach and guide further optimization. The power of this technique is highlighted by the identification of a Cdk2-selective allosteric (type IV) kinase inhibitor whose novel mode-of-action could be exploited therapeutically. PMID- 29480526 TI - Lysophosphatidic acid-induced increase in adult hippocampal neurogenesis facilitates the forgetting of cocaine-contextual memory. AB - Erasing memories of cocaine-stimuli associations might have important clinical implications for addiction therapy. Stimulating hippocampal plasticity by enhancing adult hippocampal neurogenesis (AHN) is a promising strategy because the addition of new neurons may not only facilitate new learning but also modify previous connections and weaken retrograde memories. To investigate whether increasing AHN prompted the forgetting of previous contextual cocaine associations, mice trained in a cocaine-induced conditioned place preference (CPP) paradigm were administered chronic intracerebroventricular infusions of lysophosphatidic acid (LPA, an endogenous lysophospholipid with pro-neurogenic actions), ki16425 (an LPA1/3 receptor antagonist) or a vehicle solution, and they were tested 23 days later for CPP retention and extinction. The results of immunohistochemical experiments showed that the LPA-treated mice exhibited reduced long-term CPP retention and an approximately twofold increase in the number of adult-born hippocampal cells that differentiated into mature neurons. Importantly, mediation analyses confirmed a causal role of AHN in reducing CPP maintenance. In contrast, the ki16425-treated mice displayed aberrant responses, with initially decreased CPP retention that progressively increased across the extinction sessions, leading to no effect on AHN. The pharmacological treatments did not affect locomotion or general exploratory or anxiety-like responses. In a second experiment, normal and LPA1 -receptor-deficient mice were acutely infused with LPA, which revealed that LPA1 -mediated signaling was required for LPA induced proliferative actions. These results suggest that the LPA/LPA1 pathway acts as a potent in vivo modulator of AHN and highlight the potential usefulness of pro-AHN strategies to treat aberrant cognition in those addicted to cocaine. PMID- 29480527 TI - Does parental mental health moderate the effect of a telephone and internet assisted remote parent training for disruptive 4-year-old children? AB - This study explores the moderators affecting the success of an Internet-based and telephone assisted remote parent training intervention and compares them to an educational control group. We prospectively identified 464 parents who reported at a health check that their 4-year-old children showed elevated levels of externalizing behavior. The moderators explored included parental attention deficit and hyperactivity disorder (ADHD) and parental distress. The dependent variables were child externalization scores and self-reported parenting skills. The measures were completed at baseline, six and 12-months follow-up. The 232 families randomized to active treatment received 11 Internet-based training sessions with weekly phone calls from a coach. The other 232 families had access to a website that provided general positive parenting advice and one 45-minute phone-call from a coach. Using hierarchical linear models, we explored if the parental ADHD or parental distress modified the treatment effects on child externalizing behavior or parenting skills. The results showed that none of the independent variables moderated intervention effects on child externalizing behavior or parenting skills. The lack of significant moderator effects could have been due to the treatment's personalization, the format's flexibility and adaptability to when and how the parents wanted to complete the sessions or the relatively low levels of ADHD and parental distress among the participants. PMID- 29480528 TI - Meta-analysis of risk of developing malignancy in congenital choledochal malformation. AB - BACKGROUND: Choledochal malformations comprise various congenital cystic dilatations of the extrahepatic and/or intrahepatic biliary tree. Choledochal malformation is generally considered a premalignant condition, but reliable data on the risk of malignancy and optimal surgical treatment are lacking. The objective of this systematic review was to assess the prevalence of malignancy in patients with choledochal malformation and to differentiate between subtypes. In addition, the risk of malignancy following cystic drainage versus complete cyst excision was assessed. METHODS: A systematic review of PubMed and Embase databases was performed in accordance with the PRISMA statement. A meta-analysis of the risk of malignancy following cystic drainage versus complete cyst excision was undertaken in line with MOOSE guidelines. Prevalence of malignancy was defined as the rate of biliary cancer before resection, and malignant transformation as new-onset biliary cancer after surgery. RESULTS: Eighteen observational studies were included, reporting a total of 2904 patients with a median age of 36 years. Of these, 312 in total developed a malignancy (10.7 per cent); the prevalence of malignancy was 7.3 per cent and the rate of malignant transformation was 3.4 per cent. Patients with types I and IV choledochal malformation had an increased risk of malignancy (P = 0.016). Patients who underwent cystic drainage had an increased risk of developing biliary malignancy compared with those who had complete cyst excision, with an odds ratio of 3.97 (95 per cent c.i. 2.40 to 6.55). CONCLUSION: The risk of developing malignancy among patients with choledochal malformation was almost 11 per cent. The malignancy risk following cystic drainage surgery was four times higher than that after complete cyst excision. Complete surgical resection is recommended in patients with choledochal malformation. PMID- 29480529 TI - Peptide-Guided Assembly of Repeat Protein Fragments. AB - Herein, we present the peptide-guided assembly of complementary fragments of designed armadillo repeat proteins (dArmRPs) to create proteins that bind peptides not only with high affinity but also with good selectivity. We recently demonstrated that complementary N- and C-terminal fragments of dArmRPs form high affinity complexes that resemble the structure of the full-length protein, and that these complexes bind their target peptides. We now demonstrate that dArmRPs can be split such that the fragments assemble only in the presence of a templating peptide, and that fragment mixtures enrich the combination with the highest affinity for this peptide. The enriched fragment combination discriminates single amino acid variations in the target peptide with high specificity. Our results suggest novel opportunities for the generation of new peptide binders by selection from dArmRP fragment mixtures. PMID- 29480530 TI - Prevalence of Persistent Median Arteries in the Pediatric Population on Ultrasonography. AB - OBJECTIVES: To use real-time ultrasonography to estimate the prevalence of persistent median arteries in a cohort of pediatric orthopedic patients. METHODS: With Institutional Review Board approval, patients between the ages of 3 months and 19 years were recruited for this cross-sectional study. Variables of interest included demographics, underlying diagnoses, and the presence of a Doppler confirmed median artery. Ultrasonographic examinations were performed on both upper extremities by a single investigator. Patient- and limb-level analyses were performed. A multivariable generalized logistic regression analysis was used to test the association between the prevalence of limb-specific persistent median arteries and age. A generalized estimating equation was used to adjust for the inclusion of multiple limbs from the same patient. RESULTS: A total of 135 patients (270 limbs) were evaluated. The patient-specific prevalence rate (persistent median arteries present in 1 or both limbs) was 26.7%. Among these patients (n = 36), a persistent median artery was present bilaterally in 55.6% (n = 20). The limb-specific prevalence rate (proportion of limbs with a persistent median artery) was 20.7%. After adjusting for race, for every 1-year increase in age, the odds of a persistent median artery decreased by 4.4%. After adjusting for age, African Americans were significantly more likely to present with a persistent median artery (odds ratio, 3.78; 95% confidence interval, 1.25-11.48). CONCLUSIONS: Ultrasonography can effectively visualize anatomic variants, such as persistent median arteries, in the pediatric population. The prevalence of persistent median arteries was higher than anticipated, especially among African American patients. PMID- 29480531 TI - Ethnicity, income, and disaster preparedness in Deep South Texas, United States. AB - This paper examines the influence of a series of demographic and socioeconomic factors on preparedness outcomes for a sample of residents of the Rio Grande Valley in the southernmost part of Texas, United States. Data were collected as part of the regional Pulse of the Valley Study, a general social survey of south Texas residents conducted by the Center for Survey Research at the University of Texas-Rio Grande Valley. The purpose of this investigation is to understand better the effects of ethnicity and income on preparedness within a region of the US that suffers from widespread poverty and limited infrastructure and is prone to flooding and hurricanes. Taken together, the results suggest that while age, disaster experience, and income are associated with preparedness, the relationship between preparedness and ethnicity remains complex. Furthermore, policymakers should consider initiatives that address the socioeconomic and other issues that shape preparedness for a disaster. PMID- 29480532 TI - Furazolidone treatment for Helicobacter Pylori infection: A systematic review and meta-analysis. AB - Antibiotic resistance is a major cause of Helicobacter pylori (H. pylori) treatment failures. Because the resistance rate of H. pylori to furazolidone is low, we aimed to assess the efficacy and safety of furazolidone. We searched the PubMed, Web of Science, Cochrane Library, and Embase databases and included randomized controlled trials (RCT) that either compared furazolidone to other antibiotics or changed the administered dose of furazolidone. A total of 18 articles were included in the meta-analysis. According to the intention-to-treat (ITT) analysis, the total eradication rates of furazolidone-containing therapy were superior to those of other antibiotic-containing therapies (relative risk [RR] 1.07, 95% confidence interval [CI] 1.01-1.14) (13 RCTs). Specifically, the eradication rates of furazolidone-containing therapy were better than those for metronidazole-containing therapy (RR 1.10, 95% CI: 1.01-1.21 for ITT). The eradication rate of furazolidone-containing bismuth-containing quadruple therapy was 92.9% (95% CI: 90.7%-95.1%) (PP). In addition, a higher daily dose of furazolidone increased the eradication rate (RR 1.17, 95% CI: 1.05-1.31). And the incidence of some adverse effects, such as fever and anorexia, was higher in the furazolidone group than in the control group, the overall incidences of total side effects and severe side effects showed no significant differences between the groups. Furazolidone-containing treatments could achieve satisfactory eradication rates and did not increase the incidence of total or severe adverse effects, but the incidence of milder side effects, such as fever and anorexia, should be considered when prescribing furazolidone-containing treatments to patients. PMID- 29480533 TI - Bi-exponential 23 Na T2 * component analysis in the human brain. AB - The purpose of this study was to measure the sodium transverse relaxation time T2 * in the healthy human brain. Five healthy subjects were scanned with 18 echo times (TEs) as short as 0.17 ms. T2 * values were fitted on a voxel-by-voxel basis using a bi-exponential model. Data were also analysed using a continuous distribution fit with a region of interest-based inverse Laplace transform. Average T2 * values were 3.4 +/- 0.2 ms and 23.5 +/- 1.8 ms in white matter (WM) for the short and long components, respectively, and 3.9 +/- 0.5 ms and 26.3 +/- 2.6 ms in grey matter (GM) for the short and long components, respectively, using the bi-exponential model. Continuous distribution fits yielded results of 3.1 +/- 0.3 ms and 18.8 +/- 3.2 ms in WM for the short and long components, respectively, and 2.9 +/- 0.4 ms and 17.2 +/- 2 ms in GM for the short and long components, respectively. 23 Na T2 * values of the brain for the short and long components for various anatomical locations using ultra-short TEs are presented for the first time. PMID- 29480534 TI - Novel Synthesis of Anhydrous and Hydroxylated CuF2 Nanoparticles and Their Potential for Lithium Ion Batteries. AB - Anhydrous nanoscopic CuF2 is synthesized from alkoxides Cu(OR)2 (R=Me, tBu) by their reaction either in pure liquid HF at -70 degrees C, or under solvothermal conditions at 150 degrees C using excess HF and THF as solvent. Depending on the synthesis method, nanoparticles of sizes between 10 and 100 nm are obtained. The compound is highly hygroscopic and forms different hydrolysis products under moist air, namely CuF2 ?2 H2 O, Cu2 (OH)F3 , and Cu(OH)F, of which only the latter is stable at room temperature. CuF2 exhibits an electrochemical plateau at a potential of ~2.7 V when cycled versus Li in half cell Li-ion batteries, which is attributed to a non-reversible conversion mechanism. The cell capacity in the first cycle depends on the particle size, being 468 mAh g-1 for ~8 nm crystallite diameter, and 353 mAh g-1 for ~12 nm crystallite diameter, referred to CuF2 . However, such a high capacity cannot be sustained for several cycles and the capacity rapidly fades out. The cell voltage decreases to ~2.0 V for CuF2 ?2 H2 O, Cu2 (OH)F3 , and Cu(OH)F. As all the compounds studied in this work show irreversible conversion reactions, it can be concluded that copper-based fluorides are unsuitable for Li-ion battery applications. PMID- 29480535 TI - Potential impact of effects on reproductive attributes induced by herbicides on a plant community. AB - Current herbicide risk assessment guidelines for nontarget terrestrial plants require testing effects on young, vulnerable life stages (i.e., seedling emergence [and subsequent growth] and vegetative vigor [growth and dry wt]) but not directly on the reproduction of plants. However, the European Food Safety Authority (EFSA) has proposed that effects on reproduction might be considered when evaluating the potential effects on plants. We adapted the plant community model for grassland (IBC-grass) to give insight into the current debate on the sensitivity of reproductive versus vegetative endpoints in ecological risk assessment. In an extensive sensitivity analysis of this model, we compared plant attributes potentially affected by herbicides and the consequences for long-term plant population dynamics and plant diversity. This evaluation was implemented by reducing reproductive as well as vegetative endpoints by certain percentages (e.g., 10-90%) as a theoretical assumption. Plant mortality and seed sterility (i.e., inability of seeds to germinate) were the most sensitive attributes. Our results indicated that effects on seed production at off-field exposure rates must be very strong to have an impact on the risk assessment. Otherwise, effects on seed production are compensated for by the soil seed bank. The present study highlights the usefulness of community level modeling studies to support regulators in their decisions on the appropriate risk assessment endpoints and provides confidence in their assessments. Environ Toxicol Chem 2018;37:1707-1722. (c) 2018 SETAC. PMID- 29480536 TI - Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes with severe systemic symptoms: Pathology and biochemistry. PMID- 29480537 TI - Shear Wave and Strain Elastographic Features of the Brachial Plexus in Healthy Adults: Reliability of the Findings-a Pilot Study. AB - OBJECTIVES: To determine the sonoelastographic findings for the normal brachial plexus via shear wave elastography (SWE) and strain elastography (SE) and the reliability of the measurements. METHODS: Thirty-nine healthy adult volunteers were included in the study. The brachial plexus was evaluated with SWE and SE at the interscalene region by 2 observers separately, and the observers were unaware of each other's outcomes. The elastic modulus (kilopascals), shear wave velocity (SWV, meters per second), and strain ratio were obtained. Elasticity patterns on SE were assessed as hard, intermediate, and soft. An intraclass correlation coefficient analysis was performed for determining the reliability of sonoelastographic findings. The correlation of sonoelastographic features with age and sex was investigated. RESULTS: The volunteers included 13 men and 26 women. The mean age of the participants +/- SD was 36.2 +/- 7.8 (range, 25-56) years. The mean elasticity modulus values of the brachial plexus for observers 1 and 2 were 17.03 (95% confidence interval [CI], 15.03, 19.03) and 13.83 (95% CI, 12.23, 15.43) kPa, respectively; the SWVs were 2.24 (95% CI, 2.12, 2.36) and 2.04 (95% CI, 1.93, 2.15) m/s; and the strain ratios were 1.20 (95% CI, 1.18, 1.25) 1.38 (95% CI, 1.22, 1.54). The elasticity pattern was mostly intermediate stiffness for both observers (n = 72 [92.3%]; n = 75 [96.1%]). The intraclass correlation coefficient was poor to moderate and statistically significant for the elastic modulus, SWV, and elasticity pattern (P < .05 for all parameters). The sonoelastographic characteristics of the brachial plexus had no correlation with age or sex. CONCLUSIONS: The reliability and reproducibility of sonoelastography of the brachial plexus are low, and the appropriateness of this technique in this manner is controversial. PMID- 29480538 TI - Marked pleural effusion after i.v. immunoglobulin therapy for Kawasaki disease. PMID- 29480539 TI - Ultrasonographic confirmation of tracheal intubation for congenital chylothorax. PMID- 29480540 TI - Hopes for the research agenda about hope. PMID- 29480541 TI - Elevated lipoprotein(a) and familial hypercholesterolemia in the coronary care unit: Between Scylla and Charybdis. AB - BACKGROUND: Elevated lipoprotein(a) (Lp[a]) and familial hypercholesterolemia (FH) are inherited lipid disorders. Their frequencies, coexistence, and associations with premature coronary artery disease (CAD) in patients admitted to the coronary care unit (CCU) remain to be defined. HYPOTHESIS: Elevated Lp(a) and FH are commonly encountered among CCU patients and independently associated with increased premature CAD risk. METHODS: Plasma Lp(a) concentrations were measured in consecutive patients admitted to the CCU with an acute coronary syndrome (ACS) or prior history of CAD for 6.5 months. Elevated Lp(a) was defined as concentrations >=0.5 g/L. Patients with LDL-C >= 5 mmol/L exhibited phenotypic FH. Premature CAD was diagnosed in those age < 60 years, and the relationship between this and elevated Lp(a) and FH was determined by logistic regression. RESULTS: 316 patients were screened; 163 (51.6%) had premature CAD. Overall, elevated Lp(a) and FH were identified in 27.0% and 11.6% of patients, respectively. Both disorders were detected in 4.4% of individuals. Elevated Lp(a) (32.0% vs 22.2%; P = 0.019) and FH phenotype (15.5% vs 8.0%; P = 0.052) were more common with premature vs nonpremature CAD. Elevated Lp(a) alone conferred a 1.9 fold, FH alone a 3.2-fold, and the combination a 5.3-fold increased risk of premature CAD (P = 0.005). CONCLUSIONS: Elevated Lp(a) and phenotypic FH were commonly encountered and more frequent with premature CAD. The combination of both disorders is especially associated with increased CAD risk. Patients admitted to the CCU with ACS or previously documented CAD should be routinely screened for elevated Lp(a) and FH. PMID- 29480542 TI - Comparison of in vitro biocompatibility of silicone and polymethyl methacrylate during the curing phase of polymerization. AB - Adverse events have been reported with acrylic bone cements. However, current test standards for acrylic materials fail to characterize the potentially harmful monomers released during the curing stage. In clinical applications, materials are implanted into the human body during this phase. Silicone may be a safer alternative to acrylic cements. Silicone is used in medical applications for its biocompatibility and stability characteristics. Previously, no study has been completed which compares silicone to acrylic cements. In this study, both materials were injected into the cell medium during the curing process which more accurately reflects clinical use of material. Initially, cell cultures followed ASTM standard F813-07 which fails to capture the effects of monomer released during curing. Subsequently, a modified cell culture method was employed which evaluated cytotoxicity while the materials cured. The objective of this study was to capture toxicity data during curing phase. Thus, the test method employed measured and excluded the impact of the exothermic reaction temperature of polymethyl methacrylate (PMMA) on cell growth. The concentration of PMMA monomer was measured at 1 and 24 h after injecting PMMA into culture plates in a manner consistent with established cell growth methodologies. Our results indicate current in vitro cytotoxicity assays recommended by ASTM standards are unable to reveal the real cytotoxic effect caused by methyl methacrylate monomers during polymerization. Our modified experiment can more accurately illustrate the true nature of the toxicity of materials and improve assay results. In these tests, silicone based elastomeric polymers showed excellent cytocompatibility. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2693 2699, 2018. PMID- 29480543 TI - A three-component system incorporating Ppd-D1, copy number variation at Ppd-B1, and numerous small-effect quantitative trait loci facilitates adaptation of heading time in winter wheat cultivars of worldwide origin. AB - The broad adaptability of heading time has contributed to the global success of wheat in a diverse array of climatic conditions. Here, we investigated the genetic architecture underlying heading time in a large panel of 1,110 winter wheat cultivars of worldwide origin. Genome-wide association mapping, in combination with the analysis of major phenology loci, revealed a three-component system that facilitates the adaptation of heading time in winter wheat. The photoperiod sensitivity locus Ppd-D1 was found to account for almost half of the genotypic variance in this panel and can advance or delay heading by many days. In addition, copy number variation at Ppd-B1 was the second most important source of variation in heading, explaining 8.3% of the genotypic variance. Results from association mapping and genomic prediction indicated that the remaining variation is attributed to numerous small-effect quantitative trait loci that facilitate fine-tuning of heading to the local climatic conditions. Collectively, our results underpin the importance of the two Ppd-1 loci for the adaptation of heading time in winter wheat and illustrate how the three components have been exploited for wheat breeding globally. PMID- 29480544 TI - Transcriptional and temporal response of Populus stems to gravi-stimulation. AB - Plants modify development in response to external stimuli, to produce new growth that is appropriate for environmental conditions. For example, gravi-stimulation of leaning branches in angiosperm trees results in modifications of wood development, to produce tension wood that pulls leaning stems upright. Here, we use gravi-stimulation and tension wood response to dissect the temporal changes in gene expression underlying wood formation in Populus stems. Using time-series analysis of seven time points over a 14-d experiment, we identified 8,919 genes that were differentially expressed between tension wood (upper) and opposite wood (lower) sides of leaning stems. Clustering of differentially expressed genes showed four major transcriptional responses, including gene clusters whose transcript levels were associated with two types of tissue-specific impulse responses that peaked at about 24-48 h, and gene clusters with sustained changes in transcript levels that persisted until the end of the 14-d experiment. Functional enrichment analysis of those clusters suggests they reflect temporal changes in pathways associated with hormone regulation, protein localization, cell wall biosynthesis and epigenetic processes. Time-series analysis of gene expression is an underutilized approach for dissecting complex developmental responses in plants, and can reveal gene clusters and mechanisms influencing development. PMID- 29480545 TI - The periplasmic disordered domain of RodZ promotes its self-interaction in Escherichia coli. AB - Rod shape of bacterial cells such as Escherichia coli is mainly regulated by a supramolecular complex called elongasome including MreB actin. Deletion of the mreB gene in rod-shaped bacterium E. coli results in round-shaped cells. RodZ was isolated as a determinant of rod shape in E. coli, Caulobacter crescentus and Bacillus subtilis and it has been shown to be an interaction partner and a regulator of assembly of MreB through its cytoplasmic domain. As opposed to functions of the N-terminal cytoplasmic domain of RodZ, functions of the C terminal periplasmic domain including a disordered region are still unclear. To understand it, we adopted an in vivo photo-cross-linking assay to analyze interaction partners to identify proteins which interact with RodZ via its periplasmic domain, finding that the RodZ self-interacts in the periplasmic disordered domain. Self-interaction of RodZ was affected by MreB actin. Deletion of this region resulted in aberrant cell shape. Our results suggest that MreB binding to the cytoplasmic domain of RodZ causes structural changes in the disordered periplasmic domain of RodZ. We also found that the disordered domain of RodZ contributes to fine-tune rod shape in E. coli. PMID- 29480546 TI - Hydrological and biogeochemical controls governing the speciation and accumulation of selenium in a wetland influenced by mine drainage. AB - Controls governing the speciation and accumulation of Se in a 3.7-ha marsh influenced by mine drainage were assessed through examination of water balance, water quality, sediment, and plant tissue components. Over the 8-mo study period (April through November, 2009), mean monthly flows ranged from 1600 to 2300 m3 d 1 (hydraulic retention time of 1-3 d). Total Se concentrations in the marsh outflow were lower than the inflow by 0.4 to 6.2 MUg L-1 (mean difference = 3.3 MUg L-1 ), illustrating Se removal. The Se accumulation pathways are illustrated by elevated concentrations of Se in sediments (3-35 mg kg-1 dry wt) as well as in below-ground (2-41 mg kg-1 dry wt; mean = 10 mg kg-1 dry wt) and above-ground (0.8-6.3 mg kg-1 dry wt; mean = 2 mg kg-1 dry wt) emergent plant tissues. Redox stratification in the shallow water column had a marked effect on Se speciation and behavior, illustrating bottom water removal of dissolved selenate in suboxic horizons and increased mobility of dissolved organo-Se. Mass balance data yielded inflow and outflow loading rates for Se of 27 and 23 g d-1 , respectively (net accumulation rate of 4 g d-1 or 0.11 mg m2 d-1 ). The rate of accumulation as calculated from the mass balance agrees with independently measured rates of Se accumulation in sediments for the site (3.6-8.1 g d-1 or 0.10-0.22 mg m-2 d-1 ). Environ Toxicol Chem 2018;37:1824-1838. (c) 2018 SETAC. PMID- 29480547 TI - Age and gender may be the key points in hyperglycemic patients with Helicobacter pylori infection combined colorectal adenoma. PMID- 29480549 TI - Combined effects of interspecies interaction, temperature, and zinc on Daphnia longispina population dynamics. AB - Under natural conditions, organisms can experience a variety of abiotic (e.g., temperature, pH) and biotic (e.g., species interactions) factors, which can interact with toxicant effects. By ignoring species interactions conventional ecotoxicological studies (i.e., single-species tests) oversimplify the actual field situation. We investigated whether temperature and interspecific competition affected the effects of zinc (Zn) on a Daphnia longispina population. The D. longispina populations were exposed in a full factorial design to 3 different Zn treatments (background, 29, and 110 MUg Zn/L), 2 different temperature regimes (cold, 17-18 degrees C; warm, 21-22 degrees C), and 2 interspecific competition levels (no interspecific Brachionus competition = no Brachionus calyciflorus added; interspecific Brachionus competition = B. calyciflorus added). Interspecific Brachionus competition and temperature by itself had a limited effect on the Daphnia abundance but significantly interacted with the highest Zn concentration. Without Brachionus competition the D. longispina juvenile and adult abundances under warm conditions were up to 5.5 and 21 times lower, respectively, in the high Zn treatment in comparison with the Zn control, whereas under cold conditions no significant Zn effect was observed. However, with Brachionus competition the highest Zn treatment was on average 2.2 times less toxic to the D. longispina juvenile abundance at higher temperatures. Under cold conditions the highest Zn treatment affected the juvenile abundance sooner and up to 9 times more negatively when simultaneously faced with Brachionus competition. It is possible that the competition for food reduced the amount of energy that could be used by D. longispina for reproduction, and the metabolic costs increased as a result of Zn stress. The present study clearly illustrated the influence of temperature and competition on the effects of a chemical stressor. Thus, not considering such factors in ecological risk assessment may underestimate or overestimate risks in aquatic ecosystems when extrapolating data from standard single-species tests to the field. Environ Toxicol Chem 2018;37:1668-1678. (c) 2018 SETAC. PMID- 29480548 TI - Not just things: the roles of objects at the end of life. AB - While the study of objects in care contexts is an emerging research field, it is largely overlooked in end of life (EoL) care. In this study, we empirically and inductively explore the roles of objects at the EoL from the perspective of bereaved family members. Open individual interviews were conducted with 25 family members recruited from palliative in-patient and homecare units, as well as residential care facilities. After verbatim transcription, the interviews were analysed thematically. Based on these interviews, we conceptualise the roles of objects as relating to temporality, transformations of the everyday, and care. Through analysis we offer two main insights, the first relating to interdependency between objects and people, and the second to the recognition of objects as simultaneously flexible and stable in this interdependent relationship. The capacity and challenge of objects as part of EoL care lies in their ability to encompass various viewpoints and relationships simultaneously. This might provide valuable insights for staff caring for dying persons and their families. We propose that staff's ability to navigate objects in care practices could be meaningful in supporting the relationships between individuals in EoL situations. PMID- 29480550 TI - Violence committed by intimate partners of physicians, nurses and nursing assistants. AB - AIM: To estimate the prevalence of intimate partner abuse in physicians, nurses and nursing assistants and risk factors in the Spanish Health Service. BACKGROUND: In Spain, the national public health service is the most likely point of primary care access for victims of intimate partner violence. However, health professionals are also victims of violence by their intimate partner. Little research has been undertaken exploring the prevalence and risk factors of this abuse in health professionals. METHODS: A cross-sectional multicenter study in professionals of both sexes who were working in the Spanish Public Health Service was performed. The health professionals completed an online survey of intimate violence abuse: for women, the screening of abuse against women by an intimate partner, and for men, the domestic violence screening tool in a family setting. A descriptive and comparative analysis was performed. RESULTS: The sample consisted of 1071 professionals: 49.9% were physicians, 46.9% were nurses and 3.3% were nursing assistants. Of the participants, 26.6% had experienced some form of abuse, and 73.3% of the abused professionals had not spoken of their experience of abuse with anyone else. CONCLUSION: Men experienced a lower incidence of intimate partner violence than women. In fact, 34% of the female participants were in an abusive relationship, which is a higher percentage than that observed in studies of the general Spanish female population (11.7%). It appears that being female and a nurse are risk factors for abuse. IMPLICATIONS FOR NURSING AND HEALTH POLICY: These data suggest the urgent implementation of action plans for the provision of support for the victims and for interventions aimed at reducing the problem. Better training and awareness-raising programmes that improve the detection of intimate partner violence and the care of its victims are also necessary. PMID- 29480551 TI - Low-dose sirolimus in two cousins with autoimmune lymphoproliferative syndrome associated infection. PMID- 29480552 TI - Inflammatory myofibroblastic tumors-A retrospective analysis of the Cooperative Weichteilsarkom Studiengruppe. AB - BACKGROUND: Inflammatory myofibroblastic tumors (IMTs) are a rare subgroup of soft tissue tumors. The outcome of patients with IMT has been reported as favorable when the tumor is completely resected. If surgical resection is not possible, systemic therapy has to be considered. However, the best systemic treatment and response rates are currently unclear. METHODS: Thirty-eight patients under the age of 21, who were registered between 2000 and 2014 with a primary diagnosis of IMT, were analyzed. RESULTS: IMT was typically localized intra-abdominally or in the pelvis. In 20 patients, the tumor was resected without further therapy; 17 patients were in complete remission at last evaluation and two patients were in partial remission. Eighteen patients received systemic therapy, 15 of whom had macroscopically incomplete resection. Systemic therapy most commonly consisted of regimens with dactinomycin, ifosfamide or cyclophosphamide, and vincristine, with or without doxorubicin, and it seemed to reduce tumor extension in individual cases. Five-year event-free survival was 74 +/- 14% and 5-year overall survival was 91 +/- 10% for all patients. The patients who died due to the disease were those with incomplete resection (n = 3). CONCLUSIONS: Surgery without further systemic therapy was a feasible and acceptable therapeutic option for every second patient with IMT. Standard chemotherapy for pediatric soft tissue sarcoma produced favorable results in individual cases and was able to shrink the tumor enough to enable resection. Superior efficacy of new targeted therapies such as anaplastic lymphoma kinase inhibitors compared to standard chemotherapy has to be proven in the future. PMID- 29480553 TI - Performance of an in situ activated carbon treatment to reduce PCB availability in an active harbor. AB - In situ amendment of surface sediment with activated carbon is a promising technique for reducing the availability of hydrophobic organic compounds in surface sediment. The present study evaluated the performance of a logistically challenging activated carbon placement in a high-energy hydrodynamic environment adjacent to and beneath a pier in an active military harbor. Measurements conducted preamendment and 10, 21, and 33 months (mo) postamendment using in situ exposures of benthic invertebrates and passive samplers indicated that the targeted 4% (by weight) addition of activated carbon (particle diameter <=74 um) in the uppermost 10 cm of surface sediment reduced polychlorinated biphenyl availability by an average (+/- standard deviation) of 81 +/- 11% in the first 10 mo after amendment. The final monitoring event (33 mo after amendment) indicated an approximate 90 +/- 6% reduction in availability, reflecting a slight increase in performance and showing the stability of the amendment. Benthic invertebrate census and sediment profile imagery did not indicate significant differences in benthic community ecological metrics among the preamendment and 3 postamendment monitoring events, supporting existing scientific literature that this approximate activated carbon dosage level does not significantly impair native benthic invertebrate communities. Recommendations for optimizing typical site specific assessments of activated carbon performance are also discussed and include quantifying reductions in availability and confirming placement of activated carbon. Environ Toxicol Chem 2018;37:1767-1777. Published 2018 Wiley Periodicals, Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America. PMID- 29480554 TI - Cardiac implantable electrical devices in women. AB - Clinical trials have demonstrated the benefits of cardiac implantable electrical devices, which include pacemakers, implantable cardioverter-defibrillators (ICDs), and cardiac resynchronization therapy (CRT), with respect to key clinical outcomes and survival. Women more often require permanent pacing for sick sinus syndrome, whereas atrioventricular block is more common in men. Women appear to have a higher incidence of complications with pacemaker implantation, as well as with ICD and CRT implantation. The indications for ICDs and CRT do not have any distinctions based on sex, and outcomes are comparable in men and women. In fact, women often seem to have better outcomes with CRT compared with men. Despite the demonstrated benefits of these devices, ICDs and CRT are underutilized in women. In this review, we explore sex differences in utilization, outcomes, and complications with pacemakers, ICDs, and CRT. PMID- 29480556 TI - Prominent Eustachian valve in a preterm infant causing cyanosis. PMID- 29480557 TI - How does the curvature of the upper beak bone reflect the overlying rhinotheca morphology? AB - The beak has independently been evolved accompanied by the edentulism in many tetrapod linages, including extant Testudinata and Aves, and its form and function have been greatly diversified. The beak is formed by beak bones and the overlying keratinous cover, although their profiles are different from each other. Therefore, it is difficult to reliably reconstruct the entire profile of the beak in extinct taxa, whose keratinous tissues are rarely preserved. For elucidation of the morphological relationship between beak bone and overlying keratinous cover, we compared the curvature distribution of the culminal profiles of the upper beak bone and the overlying keratinous cover (rhinotheca) with each other using CT-scan, in 66 extant testudinatan and avian specimens (Aves: 33 genera, 24 families; Testudinata: 12 genera seven families). In both, rhinotheca and beak bone, the curvature of the profile was nearly constant rostral to a certain point, which was defined as the transition point, and the transition points of the rhinotheca and beak bone were close to each other. The profiles of the rhinotheca and beak bone rostral to their transition point were different in curvature and length. However, the ratio between the curvatures of rhinotheca and the beak bone strongly correlated with the arc angle of the rostral culminal profiles of the beak bone. The upper beak profile in extinct taxa is expected to be reconstructed more reliably using the abovementioned relationship between the beak bone and the rhinotheca. PMID- 29480555 TI - Welfare-to-work interventions and their effects on the mental and physical health of lone parents and their children. AB - BACKGROUND: Lone parents in high-income countries have high rates of poverty (including in-work poverty) and poor health. Employment requirements for these parents are increasingly common. 'Welfare-to-work' (WtW) interventions involving financial sanctions and incentives, training, childcare subsidies and lifetime limits on benefit receipt have been used to support or mandate employment among lone parents. These and other interventions that affect employment and income may also affect people's health, and it is important to understand the available evidence on these effects in lone parents. OBJECTIVES: To assess the effects of WtW interventions on mental and physical health in lone parents and their children living in high-income countries. The secondary objective is to assess the effects of welfare-to-work interventions on employment and income. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Ovid, Embase Ovid, PsycINFO EBSCO, ERIC EBSCO, SocINDEX EBSCO, CINAHL EBSCO, Econlit EBSCO, Web of Science ISI, Applied Social Sciences Index and Abstracts (ASSIA) via Proquest, International Bibliography of the Social Sciences (IBSS) via ProQuest, Social Services Abstracts via Proquest, Sociological Abstracts via Proquest, Campbell Library, NHS Economic Evaluation Database (NHS EED) (CRD York), Turning Research into Practice (TRIP), OpenGrey and Planex. We also searched bibliographies of included publications and relevant reviews, in addition to many relevant websites. We identified many included publications by handsearching. We performed the searches in 2011, 2013 and April 2016. SELECTION CRITERIA: Randomised controlled trials (RCTs) of mandatory or voluntary WtW interventions for lone parents in high-income countries, reporting impacts on parental mental health, parental physical health, child mental health or child physical health. DATA COLLECTION AND ANALYSIS: One review author extracted data using a standardised extraction form, and another checked them. Two authors independently assessed risk of bias and the quality of the evidence. We contacted study authors to obtain measures of variance and conducted meta analyses where possible. We synthesised data at three time points: 18 to 24 months (T1), 25 to 48 months (T2) and 49 to 72 months (T3). MAIN RESULTS: Twelve studies involving 27,482 participants met the inclusion criteria. Interventions were either mandatory or voluntary and included up to 10 discrete components in varying combinations. All but one study took place in North America. Although we searched for parental health outcomes, the vast majority of the sample in all included studies were female. Therefore, we describe adult health outcomes as 'maternal' throughout the results section. We downgraded the quality of all evidence at least one level because outcome assessors were not blinded. Follow-up ranged from 18 months to six years. The effects of welfare-to-work interventions on health were generally positive but of a magnitude unlikely to have any tangible effects.At T1 there was moderate-quality evidence of a very small negative impact on maternal mental health (standardised mean difference (SMD) 0.07, 95% Confidence Interval (CI) 0.00 to 0.14; N = 3352; studies = 2)); at T2, moderate-quality evidence of no effect (SMD 0.00, 95% CI 0.05 to 0.05; N = 7091; studies = 3); and at T3, low-quality evidence of a very small positive effect (SMD -0.07, 95% CI -0.15 to 0.00; N = 8873; studies = 4). There was evidence of very small positive effects on maternal physical health at T1 (risk ratio (RR) 0.85, 95% CI 0.54 to 1.36; N = 311; 1 study, low quality) and T2 (RR 1.06, 95% CI 0.95 to 1.18; N = 2551; 2 studies, moderate quality), and of a very small negative effect at T3 (RR 0.97, 95% CI 0.91 to 1.04; N = 1854; 1 study, low quality).At T1, there was moderate-quality evidence of a very small negative impact on child mental health (SMD 0.01, 95% CI -0.06 to 0.09; N = 2762; studies = 1); at T2, of a very small positive effect (SMD -0.04, 95% CI -0.08 to 0.01; N = 7560; studies = 5), and at T3, there was low-quality evidence of a very small positive effect (SMD -0.05, 95% CI -0.16 to 0.05; N = 3643; studies = 3). Moderate-quality evidence for effects on child physical health showed a very small negative effect at T1 (SMD -0.05, 95% CI -0.12 to 0.03; N = 2762; studies = 1), a very small positive effect at T2 (SMD 0.07, 95% CI 0.01 to 0.12; N = 7195; studies = 3), and a very small positive effect at T3 (SMD 0.01, 95% CI -0.04 to 0.06; N = 8083; studies = 5). There was some evidence of larger negative effects on health, but this was of low or very low quality.There were small positive effects on employment and income at 18 to 48 months (moderate-quality evidence), but these were largely absent at 49 to 72 months (very low to moderate-quality evidence), often due to control group members moving into work independently. Since the majority of the studies were conducted in North America before the year 2000, generalisabilty may be limited. However, all study sites were similar in that they were high-income countries with developed social welfare systems. AUTHORS' CONCLUSIONS: The effects of WtW on health are largely of a magnitude that is unlikely to have tangible impacts. Since income and employment are hypothesised to mediate effects on health, it is possible that these negligible health impacts result from the small effects on economic outcomes. Even where employment and income were higher for the lone parents in WtW, poverty was still high for the majority of the lone parents in many of the studies. Perhaps because of this, depression also remained very high for lone parents whether they were in WtW or not. There is a lack of robust evidence on the health effects of WtW for lone parents outside North America. PMID- 29480558 TI - Functional characterisation of bioactive peptide derived from terrestrial snail Cryptozona bistrialis and its wound-healing property in normal and diabetic induced Wistar albino rats. AB - A peptide might be an exciting biomaterial or template for the development of novel wound-healing agents. In this report, it was isolated from the terrestrial snail Cryptozona bistrialis by enzymatic digestion and was evaluated for its in vitro wound-healing activity in NIH/3T3 mouse fibroblasts cell line and in vivo wound-healing activity in normal and diabetic-induced Wistar albino rats. The C. bistrialis protein was digested by the papain enzyme, and 21.79 kDa peptide (Cb peptide) was purified by reversed-phase high-performance liquid chromatography and identified by MALDI (matrix-assisted laser desorption/ionization)-TOF analysis. The isolated Cb-peptide was characterised by various analytical methods. The peptide demonstrated a capacity to prevent the development of pathogenic bacterial and fungal cultures and proved that it promotes significant wound-healing activity in the wound scratch assay method by rapid cell migration and closure of wound. Isolated Cb-peptide was lyophilised and formulated to ointment and analysed for in vivo wound-healing activity in normal and diabetic (alloxan monohydrate)-induced Wistar albino rats. Cb-peptide ointment-treated groups showed a greater degree of wound healing and early and complete period of epithelialisation in normal and diabetic-induced Wistar albino rats. Cb-peptide ointment-treated groups showed significant excision and incision wound-healing activity. A conclusion was reached that the peptide isolated from C. bistrialis showed greater wound-healing activity compared with vehicle control and standard control. PMID- 29480560 TI - Using improvisation to promote teaching- and thinking-in-action. PMID- 29480559 TI - Synergy of Catechol-Functionalized Zinc Oxide Nanorods and Porphyrins in Layer-by Layer Assemblies. AB - Catechol-functionalized, positively charged ZnO nanorods (NRs) and anionic porphyrins were integrated into layer-by-layer (LbL) assemblies. In general, this study focuses on the impact that different porphyrins, varying in size and number of negative charges, exert on the LbL architecture in terms of morphology and spectroscopy. In particular, through a combination of analytical methods, including UV/Vis spectroscopy, SEM, and profilometry, valuable insights into LbL assembly formation were gathered. A key feature was the surface coverage in the resulting films. Denser films and surface coverages were realized when highly negatively charged and sterically demanding porphyrins were employed. As a complement to basic characterization, the LbL assembled films were used to fabricate proof-of-concept solar cells. PMID- 29480561 TI - A Retrospective Evaluation of Echocardiograms to Establish Normative Inferior Vena Cava and Aortic Measurements for Children Younger Than 6 Years. AB - OBJECTIVES: The ability to plot the inferior vena cava (IVC) size on a normal curve for pediatric patients may prove beneficial. First, in patients with normal cardiac anatomy who present in shock, assessing IVC size may be valuable for evaluating the degree of dehydration. Second, in children with heart disease, understanding how a child's IVC size compares to normal could be particularly beneficial for patients with right heart disease. We sought to create normal curves for the IVC and aorta in children younger than 6 years. METHODS: Data were gathered from 347 echocardiograms of healthy children younger than 6 years in a retrospective study at a quaternary care children's hospital. From the subcostal long- and short-axis images, maximum diameters in the transverse and longitudinal views were obtained for both the IVC and the aorta. RESULTS: Both IVC and aortic dimensions increased in a linear fashion and had excellent correlations with the body surface area, body mass, and height (IVC, r = 0.78-0.81; P < .0001; aorta, r = 0.82-0.86; P < .0001). CONCLUSIONS: In children younger than 6 years, the IVC and aorta increase linearly as the children grow. Such normal curves will be beneficial for assessing a pediatric patient's hydration status or right heart function in patients with congenital heart disease. PMID- 29480562 TI - Evaluation of bone marrow stem cell response to PLA scaffolds manufactured by 3D printing and coated with polydopamine and type I collagen. AB - The majority of synthetic polymers used in 3 D printing are not designed to promote specific cellular interactions and hence possess limited bioactivity. Most of the strategies proposed to overcome this limitation demand multiple and expensive processing steps. This study aimed to evaluate the surface modification of 3D-printed poly(lactic acid) (PLA) scaffolds with polydopamine (PDA) coating as an alternative strategy to enhance their bioactivity and to facilitate the immobilization of type I collagen (COL I) onto the implant surface. Physical and chemical properties of PLA scaffolds coated with PDA, COL I or both were evaluated. The response of porcine bone marrow stem cells (MSCs) to the coatings was also investigated. The PDA layer improved COL immobilization onto the surface of the PLA scaffolds by 92%. The combination of PDA and COL functionalizations provided the best conditions for early-stage (<7 days) cell response. In addition, the PDA plus COL surface facilitated the robust deposition of extracellular matrix in the first 14 days of cell culture. Although the behavior of the MSCs appeared to be similar for both uncoated PLA and PDA plus COL-coated scaffolds by day 21, cells seeded onto PDA plus COL scaffolds produced substantially higher amounts of alkaline phosphatase. These results indicate that the osteoinductivity of 3D-printed PLA scaffolds can be enhanced by PDA and type I collagen coatings. This surface modification of polymeric scaffolds represents a promising strategy for bone tissue engineering. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2018. PMID- 29480564 TI - Erratum. PMID- 29480565 TI - Addressing the burden of hospital-related venous thromboembolism: the role of extended anticoagulant prophylaxis. PMID- 29480563 TI - Movement variability: A perspective on success in sports, health, and life. PMID- 29480566 TI - High prevalence of Helicobacter pylori clarithromycin resistance mutations among Seattle patients measured by droplet digital PCR. AB - BACKGROUND: Treatment of Helicobacter pylori infection is often empiric; however, current guidelines for management of Helicobacter pylori infection advise against the use of standard triple therapy (clarithromycin, amoxicillin, and proton-pump inhibitor) when clarithromycin resistance exceeds 20%. We developed and tested a new culture-free assay to detect clarithromycin resistance-conferring mutations to determine the prevalence of H. pylori clarithromycin resistance in patients from the United States Pacific Northwest. MATERIALS AND METHODS: Droplet digital PCR (ddPCR) was used to detect the H. pylori 23S rRNA gene, and resistance conferring mutations, in archived, formalin-fixed, paraffin-embedded (FFPE) gastric tissue and to retrospectively determine the prevalence of clarithromycin resistant H. pylori among 110 patients at an academic medical center in the Northwest United States between 2012 and 2014. RESULTS: Of 102 patients with the H. pylori 23S rRNA gene detected by the ddPCR assay, 45 (44%) had clarithromycin resistance mutations. Thirty-three of the 45 patients with clarithromycin resistance mutations had a mix of wild-type and resistance alleles. Prevalence of clarithromycin resistance mutations differed among racial groups and was highest among Asians, with mutations detected in 14 (67%) of the 21 patient samples. CONCLUSIONS: The prevalence of clarithromycin resistance detected in this region exceeds 20%, indicating that standard triple therapy should not be the first-line antibiotic treatment for H. pylori infection. Culture-free assays for detecting clarithromycin resistance mutations can be performed on archived tissue samples and will aid in informing tailored treatment for effective H. pylori eradication. PMID- 29480567 TI - Intra- and Inter-rater Reliability of Navigated Ultrasound in the Assessment of Pelvic Tilt in Symptom-Free Young Adults. AB - OBJECTIVES: Pelvic tilt is the angle between the anterior pelvic plane and the coronal plane. It affects cup positioning in total hip arthroplasty. The primary objective of this study was to test the intra- and inter-rater reliability of a navigated smart device-based ultrasound system for pelvic tilt assessment. The secondary objective was to test the inter-rater variability of the measurements on a hip phantom. METHODS: A repeated-measures design was used. Two raters measured the pelvic tilt of 12 symptom-free young adults in upright and supine positions. Additionally, pelvic tilt was measured on a hip phantom. Each rater performed 3 measurements in each body position on the participants and 12 measurements on the hip phantom. Intra- and inter-rater reliability were calculated with the use of intraclass correlation coefficients. The variability in measurements on the hip phantom was assessed by a Bland-Altman analysis of agreement. RESULTS: Intraclass correlation coefficient 95% confidence intervals for intra-rater reliability ranged from good to excellent and moderate to excellent for the supine and upright positions respectively. Intraclass correlation coefficient 95% confidence intervals for inter-rater reliability ranged from poor to excellent for both positions. Hip phantom measurements showed no significant average bias (P > .05) and no significant proportional bias (P > .05). The 95% inter-rater limits of agreement were +/-1.3 degrees and +/-1.7 degrees for the supine and upright positions, respectively. CONCLUSIONS: The intra-rater reliability values achieved were suitable. Intraclass correlation coefficient values for inter-rater reliability remained below an acceptable level. Possible reasons and overcoming strategies were presented. The 95% limits of agreement were good, at less than +/-2 degrees . PMID- 29480568 TI - Niclosamide, an oral antihelmintic drug, exhibits antimetastatic activity in hepatocellular carcinoma cells through downregulating twist-mediated CD10 expression. AB - Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world, especially, in eastern Asia, and its prognosis is poor once metastasis occurs. Niclosamide, a US Food and Drug Administration-approved antihelmintic drug, was shown to inhibit the growth of various cancers including HCC, but the effect of niclosamide on cell motility and the underlying mechanism have not yet been completely defined. The present study demonstrated that niclosamide, at 0-40 nM, concentration-dependently inhibited wound closure and the migratory/invasive capacities of human Huh7 and SK-Hep-1 HCC cells without exhibiting cytotoxicity. A protease array analysis showed that CD10 was dramatically downregulated in Huh7 cells after niclosamide treatment. Western blot and flow cytometric assays further demonstrated that CD10 expression was concentration-dependently downregulated in Huh7 and SK-Hep-1 cells after niclosamide treatment. Mechanistic investigations found that niclosamide suppressed Twist-mediated CD10 transactivation. Moreover, knockdown of CD10 expression by CD10 small interfering RNA in HCC cells suppressed cell migratory/invasive abilities and overexpression of CD10 relieved the migration inhibition induced by niclosamide. Taken together, our results indicated that niclosamide could be a potential agent for inhibiting metastasis of HCC, and CD10 is an important target of niclosamide for suppressing the motility of HCC cells. PMID- 29480570 TI - Evaluating the durability of UHMWPE biomaterials used for articulating surfaces of joint arthroplasty using delamination tests. AB - Ultra-high molecular weight polyethylene (UHMWPE) is the most popular material used for the articulating surface of joint replacements. Delamination is a common fatigue-related failure mode in UHMWPE components; however, the relationship between delamination resistance and fatigue crack growth has not been reported. Here, the delamination resistance of contemporary UHMWPE materials, including highly cross-linked UHMWPE (HXLPE), vitamin E blended UHMWPE (VEPE), and vitamin E blended HXLPE (VEXLPE), was measured to verify a previously proposed accelerated test method using a U-shaped sliding motion; the results were compared with those of fatigue crack growth tests. The oxidative stability of each material was estimated using Fourier transform infrared analysis. UHMWPE sterilized by gamma irradiation in an inert atmosphere and annealed HXLPE had lower delamination resistance than virgin UHMWPE after artificial aging. This was consistent with previous findings from retrieval studies, and in vitro knee simulator and ball-on-flat unidirectional reciprocation wear studies. In contrast, remelted HXLPE, VEPE, and VEXLPE showed excellent delamination resistance after artificial aging. The results of the delamination tests were not consistent with those of fatigue crack growth tests, indicating the complex delamination mechanism and importance of evaluating these factors separately. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2018. PMID- 29480569 TI - Neuroanatomical profiles of bilingual children. AB - The goal of the present study was to examine differences in cortical thickness, cortical surface area, and subcortical volume between bilingual children who are highly proficient in two languages (i.e., English and Spanish) and bilingual children who are mainly proficient in one of the languages (i.e., Spanish). All children (N = 49) learned Spanish as a native language (L1) at home and English as a second language (L2) at school. Proficiency of both languages was assessed using the standardized Woodcock Language Proficiency Battery. Five-minute high resolution anatomical scans were acquired with a 3-Tesla scanner. The degree of discrepancy between L1 and L2 proficiency was used to classify the children into two groups: children with balanced proficiency and children with unbalanced proficiency. The groups were comparable on language history, parental education, and other variables except English proficiency. Values of cortical thickness and surface area of the transverse STG, IFG-pars opercularis, and MFG, as well as subcortical volume of the caudate and putamen, were extracted from FreeSurfer. Results showed that children with balanced bilingualism had thinner cortices of the left STG, left IFG, left MFG and a larger bilateral putamen, whereas unbalanced bilinguals showed thicker cortices of the same regions and a smaller putamen. Additionally, unbalanced bilinguals with stronger foreign accents in the L2 showed reduced surface areas of the MFG and STS bilaterally. The results suggest that balanced/unbalanced bilingualism is reflected in different neuroanatomical characteristics that arise from biological and/or environmental factors. PMID- 29480571 TI - Obstetric Sonography: Why Are We Still Terrifying Pregnant Women? PMID- 29480572 TI - 5-Hydroxyferulic acid methyl ester isolated from wasabi leaves inhibits 3T3-L1 adipocyte differentiation. AB - To investigate the compounds present in wasabi leaves (Wasabia japonica Matsumura) that inhibit the adipocyte differentiation, activity-guided fractionation was performed on these leaves. 5-Hydroxyferulic acid methyl ester (1: 5-HFA ester), one of the phenylpropanoids, was isolated from wasabi leaves as a compound that inhibits the adipocyte differentiation. Compound 1 suppressed the intracellular lipid accumulation of 3T3-L1 cells without significant cytotoxicity. Gene expression analysis revealed that 1 suppressed the mRNA expression of 2 master regulators of adipocyte differentiation, PPARgamma and C/EBPalpha. Furthermore, 1 downregulated the expression of adipogenesis-related genes, GLUT4, LPL, SREBP-1c, ACC, and FAS. Protein expression analysis revealed that 1 suppressed PPARgamma protein expression. Moreover, to investigate the relationship between the structure and activity of inhibiting the adipocyte differentiation, we synthesized 12 kinds of phenylpropanoid analog. Comparison of the activity among 1 and its analogs suggested that the compound containing the substructure that possess a common functional group at the ortho position such as a catechol group exhibits the activity of inhibiting the adipocyte differentiation. Taken together, our findings suggest that 1 from wasabi leaves inhibits adipocyte differentiation via the downregulation of PPARgamma. PMID- 29480573 TI - Persistence of depressive symptoms and gait speed recovery in older adults after hip fracture. AB - OBJECTIVE: Depression after hip fracture in older adults is associated with worse physical performance; however, depressive symptoms are dynamic, fluctuating during the recovery period. The study aim was to determine how the persistence of depressive symptoms over time cumulatively affects the recovery of physical performance. METHODS: Marginal structural models estimated the cumulative effect of persistence of depressive symptoms on gait speed during hip fracture recovery among older adults (n = 284) enrolled in the Baltimore Hip Studies 7th cohort. Depressive symptoms at baseline and at 2-month and 6-month postadmission for hip fracture were evaluated by using the Center for Epidemiological Studies Depression Scale, and persistence of symptoms was assessed as a time-averaged severity lagged to standardized 3 m gait speed at 2, 6, and 12 months. RESULTS: A 1-unit increase in time-averaged Center for Epidemiological Studies Depression score was associated with a mean difference in gait speed of -0.0076 standard deviations (95% confidence interval [CI]: -0.0184, 0.0032; P = .166). The association was largest in magnitude from baseline to 6 months: -0.0144 standard deviations (95% CI: -0.0303, 0.0015; P = 0.076). Associations for the other time intervals were smaller: -0.0028 standard deviations (95% CI: -0.0138, 0.0083; P = .621) at 2 months and -0.0121 standard deviations (95% CI: -0.0324, 0.0082; P = .238) at 12 months. CONCLUSION: Although not statistically significant, the magnitude of the numerical estimates suggests that expressing more depressive symptoms during the first 6 months after hip fracture has a meaningful impact on functional recovery. PMID- 29480574 TI - Recurrence of Ewing sarcoma: Is detection by imaging follow-up protocol associated with survival advantage? AB - BACKGROUND: The Cooperative Ewing Sarcoma Study and the Late Effects Surveillance System of the Society for Paediatric Oncology and Haematology recommend a structured follow-up imaging protocol (FUIP) for patients with Ewing sarcoma (EwS) with decreasing frequency of imaging over the first 5 years. The present study aims to assess the effectiveness of the FUIP for EwS patients regarding survival after relapse. PATIENTS AND METHODS: A retrospective multicenter analysis on 160 eligible patients with EwS recurrence was performed. Potential survival differences following recurrence diagnosis between patients with protocol-detected and symptomatic relapse were investigated using the Kaplan Meier method. Additional subgroup analyses were performed on the relapse type. Overall survival (OS) was calculated from diagnosis of relapse to last follow-up or death. RESULTS: In the multicenter analysis, recurrence was detected by FUIP in 77 of 160 patients (48%) and due to symptoms in 83 patients (52%). Regarding the entire study population, OS was significantly superior in patients with protocol-detected relapse compared to patients with symptomatic relapse (median, 2.4 vs. 1.2 years; P < 0.001). In the subgroup analyses, patients whose lung recurrences were detected by the FUIP experienced longer survival after recurrence than those whose recurrences were detected symptomatically (P = 0.023). In the 83 symptomatic patients, pain was the most prevalent symptom of relapse (72%). CONCLUSION: FUIP may benefit survival in EwS relapse, especially in lung recurrence. Pain was the leading symptom of relapse. PMID- 29480575 TI - Not all smokers appear to seek nicotine for the same reasons: implications for preclinical research in nicotine dependence. AB - Tobacco use leads to 6 million deaths every year due to severe long-lasting diseases. The main component of tobacco, nicotine, is recognized as one of the most addictive drugs, making smoking cessation difficult, even when 70 percent of smokers wish to do so. Clinical and preclinical studies have demonstrated consistently that nicotine seeking is a complex behavior involving various psychopharmacological mechanisms. Evidence supports that the population of smokers is heterogeneous, particularly as regards the breadth of motives that determine the urge to smoke. Here, we review converging psychological, genetic and neurobiological data from clinical and preclinical studies supporting that the mechanisms controlling nicotine seeking may vary from individual to individual. It appears timely that basic neuroscience integrates this heterogeneity to refine our understanding of the neurobiology of nicotine seeking, as tremendous progress has been made in modeling the various psychopharmacological mechanisms driving nicotine seeking in rodents. For a better understanding of the mechanisms that drive nicotine seeking, we emphasize the need for individual-based research strategies in which nicotine seeking, and eventually treatment efficacy, are determined while taking into account individual variations in the mechanisms of nicotine seeking. PMID- 29480576 TI - A novel approach to teaching electrocardiogram interpretation: learning by drawing. PMID- 29480577 TI - Injuries to the Collateral Ligaments of the Metacarpophalangeal and Interphalangeal Joints: Sonographic Appearance. AB - Injuries to the collateral ligaments of the metacarpophalangeal (MCP) and interphalangeal (IP) joints are commonly encountered in both athletes and nonathletes. They require prompt evaluation to ensure proper management and prevent loss of joint motion and permanent disability. Imaging is often required to confirm the diagnosis and assess injury severity. This review article aims to provide physicians with guidelines for sonographic assessment of the collateral ligaments of the MCP and IP and related injuries. Sonographic features of ligament injuries ranging from sprains and partial-thickness tears to full thickness tears are described. Specific lesions of the ulnar collateral ligament of the thumb MCP joint, such as gamekeeper's thumb, skier's thumb, and Stener lesions, are also included. In conclusion, sonography is effective in evaluating the collateral ligaments of the MCP and IP joints and related injuries and represents a valuable tool for diagnosis. PMID- 29480578 TI - Houttuynia cordata extract increased systemic exposure and liver concentrations of metformin through OCTs and MATEs in rats. AB - The synergistic activity of Houttuynia cordata ethanol extract (HCT) and metformin combination in diabetic rats has been previously reported, but the fundamental causes remain unsolved. Organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs) transport metformin to the liver and kidneys. Therefore, pharmacological activity and systemic exposure of metformin in HCT-metformin combination were determined from pharmacokinetic change and glucose-lowering activity using in vitro HEK-293 cells expressing human OCTs or human MATEs and in vivo rats. HCT inhibited human OCT2 and human MATE1-mediated metformin transports in vitro. In in vivo rats, treatment with HCT and metformin for 28 days in rats (28MH rats) reduced the rat Oct2-mediated renal excretion of metformin and thereby the increased systemic exposure of metformin compared with only metformin-treated rats for 28 days (28M rats). In 28MH rats, rat Oct1-mediated metformin uptake into the liver was enhanced, leading to an improved glucose-lowering effect without hypoglycaemia compared with 28M rats. There was no impairment of renal function in HCT and metformin treatments. These results suggest that HCT-metformin combination therapy is applicable in terms of efficacy and safety. PMID- 29480579 TI - Acute myocardial infarction due to vegetation in a 13-year-old girl. PMID- 29480580 TI - Assessment of Right Atrium Function in Patients With Systemic Lupus Erythematosus With Different Pulmonary Artery Systolic Pressures by 2-Dimensional Speckle Tracking Echocardiography. AB - OBJECTIVES: To assess right atrium (RA) function of patients with systemic lupus erythematosus (SLE) and pulmonary artery hypertension (PAH) by 2-dimensional speckle-tracking echocardiography. METHODS: Thirty matched healthy adults were selected as group A. Then, 102 patients with SLE were divided into 3 groups according to the severity of PAH. Group B included 37 patients without PAH (pulmonary artery [PA] systolic pressure <= 30 mm Hg); group C included 34 patients with PAH (PA systolic pressure of 30-50 mm Hg); and group D included 31 patients with PAH (PA systolic pressure >= 50 mm Hg). Parameters evaluated included RA maximum volume, minimum volume, preatrial contraction volume, passive ejection fraction (EF), and active EF. The global peak longitudinal systolic strain rate and early and late diastolic strain rates of the RA were obtained by 2-dimensional speckle-tracking echocardiography. RESULTS: No significant differences were found in all parameters between groups B and A (P > .05). The RA maximum volume, minimum volume, preatrial contraction volume, active EF, and late diastolic strain rate in groups C and D were significantly increased compared with those in groups A and B, and the parameters in group D were significantly higher than those in group C (P < .05). Although the RA passive EF, early diastolic strain rate, and systolic strain rate in groups C and D were significantly decreased compared with those in groups A and B, those in group D were significantly lower than those in group C (P < .05). CONCLUSIONS: Two dimensional speckle-tracking echocardiography could effectively assess RA function in patients with SLE who have different severities of PAH. PMID- 29480581 TI - Localization of the cannabinoid type-1 receptor in subcellular astrocyte compartments of mutant mouse hippocampus. AB - Astroglial type-1 cannabinoid (CB1 ) receptors are involved in synaptic transmission, plasticity and behavior by interfering with the so-called tripartite synapse formed by pre- and post-synaptic neuronal elements and surrounding astrocyte processes. However, little is known concerning the subcellular distribution of astroglial CB1 receptors. In particular, brain CB1 receptors are mostly localized at cells' plasmalemma, but recent evidence indicates their functional presence in mitochondrial membranes. Whether CB1 receptors are present in astroglial mitochondria has remained unknown. To investigate this issue, we included conditional knock-out mice lacking astroglial CB1 receptor expression specifically in glial fibrillary acidic protein (GFAP) containing astrocytes (GFAP-CB1 -KO mice) and also generated genetic rescue mice to re-express CB1 receptors exclusively in astrocytes (GFAP-CB1 -RS). To better identify astroglial structures by immunoelectron microscopy, global CB1 knock-out (CB1 -KO) mice and wild-type (CB1 -WT) littermates were intra-hippocampally injected with an adeno-associated virus expressing humanized renilla green fluorescent protein (hrGFP) under the control of human GFAP promoter to generate GFAPhrGFP-CB1 -KO and -WT mice, respectively. Furthermore, double immunogold (for CB1 ) and immunoperoxidase (for GFAP or hrGFP) revealed that CB1 receptors are present in astroglial mitochondria from different hippocampal regions of CB1 -WT, GFAP-CB1 -RS and GFAPhrGFP-CB1 -WT mice. Only non-specific gold particles were detected in mouse hippocampi lacking CB1 receptors. Altogether, we demonstrated the existence of a precise molecular architecture of the CB1 receptor in astrocytes that will have to be taken into account in evaluating the functional activity of cannabinergic signaling at the tripartite synapse. PMID- 29480582 TI - NT-proBNP is associated with mortality and adverse cardiac events in patients with atrial fibrillation presenting to the emergency department. AB - BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia in the emergency department. The CHA2 DS2 -VASc score helps to predict thromboembolic risk; however, the rate of other adverse cardiac events is more difficult to predict. HYPOTHESIS: The biomarker N-terminal pro-brain natriuretic peptide (NT proBNP) has prognostic value in patients presenting to the emergency department with AF. METHODS: During a 1.5-year period, a prospective study was performed in consecutive patients presenting to the emergency department with AF on the presenting electrocardiogram. At baseline, NT-proBNP was measured. The primary endpoints were all-cause death and major adverse cardiac events (MACE: all-cause mortality, myocardial infarction, or revascularization). RESULTS: A total of 355 patients were included (mean age, 71 years; 55% male). The median duration of follow-up was 2 years. After adjustment for baseline variables, the logNT-proBNP was independently correlated with death (hazard ratio [HR]: 1.54, 95% confidence interval [CI]: 1.18-1.99) and MACE (HR: 1.27, 95% CI: 1.03-1.58). After adjustment for baseline variables, a high NT-proBNP value (>500 pmol/L) was independently correlated with death (HR: 2.26, 95% CI: 1.19-4.28), and for MACE a trend was seen (HR: 1.67, 95% CI: 0.96-2.91) compared with a low value (<250 pmol/L). CONCLUSIONS: In patients presenting to the emergency department with AF, higher NT-proBNP values are independently associated with an increased mortality and MACE. Therefore, this biomarker may be a useful prognostic marker in the management and treatment of these patients. PMID- 29480583 TI - Stress augments the rewarding memory of cocaine via the activation of brainstem reward circuitry. AB - Effects of stress on the reward system are well established in the literature. Although previous studies have revealed that stress can reinstate extinguished addictive behaviors related to cocaine, the effects of stress on the rewarding memory of cocaine are not fully understood. Here, we provide evidence that stress potentiates the expression of rewarding memory of cocaine via the activation of brainstem-reward circuitry using a cocaine-induced conditioned place preference (CPP) paradigm combined with restraint stress in rats. The rats exposed to 30 minute restraint stress immediately before posttest exhibited significantly larger CPP scores compared with non-stressed rats. Intra-laterodorsal tegmental nucleus (LDT) microinjection of a beta or alpha2 adrenoceptor antagonist attenuated the stress-induced enhancement of cocaine CPP. Consistent with this observation, intra-LDT microinjection of a beta or alpha2 adrenoceptor agonist before posttest increased cocaine CPP. Additionally, intra-ventral tegmental area (VTA) microinjection of antagonists for the muscarinic acetylcholine, nicotinic acetylcholine or glutamate receptors attenuated the stress-induced enhancement of cocaine CPP. Finally, intra-medial prefrontal cortex (mPFC) microinjection of a D1 receptor antagonist also reduced the stress-induced enhancement of cocaine CPP. These findings suggest a mechanism wherein the LDT is activated by noradrenergic input from the locus coeruleus, leading to the activation of VTA dopamine neurons via both cholinergic and glutamatergic transmission and the subsequent excitation of the mPFC to enhance the memory of cocaine-induced reward value. PMID- 29480584 TI - Vasospastic angina and asymptomatic moyamoya disease in a 14-year-old girl. PMID- 29480585 TI - Nerve wrapping with biomaterials during radical prostatectomy to improve potency recovery. PMID- 29480586 TI - To drain or not to drain after robot-assisted radical prostatectomy? That is the question. PMID- 29480587 TI - Is overall survival not influenced by partial vs radical nephrectomy? PMID- 29480588 TI - Prostate cancer biochemical recurrence after salvage radiotherapy: first look into risk stratification and prognosis. PMID- 29480589 TI - How do we attract and retain women in cardiology? AB - The recruitment and advancement of women in cardiology is an important priority for the cardiology community. Despite improvements in sex disparities over the last 2 decades, women remain a small minority in cardiology. Recent studies have revealed key obstacles facing female cardiologists including radiation exposure, family responsibilities, unequal financial compensations, and lack of career advancement. To attract and retain more women into the field of cardiology, the cardiology community, including professional society leaders, division chiefs, and program directors, must all work to overcome these barriers. PMID- 29480590 TI - Taking cardiology clinical trials to the next level: A call to action. AB - Physicians previously perceived heart disease to be a man's disease; yet, since 1984, more women have died of ischemic heart disease. Because women who develop obstructive coronary heart disease and heart failure tend to do so 10 years later than men, cardiology clinical trials that use arbitrary age cutoffs or exclusion criteria based on comorbidities and polypharmacy often limit the pool of potential participants to a greater extent for women. Issues related to trial design and insufficient accounting for female-predominant disease patterns have contributed to low rates of enrollment of women in certain domains of cardiology research. Accordingly, women do not benefit from as rich an evidence base for cardiology as men. Here, we review major sex differences in heart disease and discuss areas of cardiology research in which women have been underrepresented. Considering the widespread sex differences in cardiovascular structure and function, it is important to include balanced numbers of women and men in cardiovascular clinical trials. Beyond inclusion, sex-specific reporting is also essential. Moreover, with ongoing developments of clinical-trial methodology, it is imperative to seek innovative ways to learn as much as possible about how interventions behave in women and men. Adaptive trials are specifically identified as promising opportunities to consider sex-based analyses at interim stages, allowing sex-specific flexibility as these trials unfold. Finally, we emphasize the importance of factoring sex as a biological variable into the design, analysis, and reporting of preclinical research, because this research critically informs the design and execution of clinical trials. PMID- 29480591 TI - Atherosclerotic vascular disease in the autoimmune rheumatologic woman. AB - Autoimmune rheumatologic conditions have increased cardiovascular morbidity and mortality compared to the general population. Many of these diseases occur more commonly in women, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis, and Sjogren's. Most of the literature that has identified the link between autoimmune diseases and atherosclerotic cardiovascular disease (ASCVD) has been regarding patients with RA and SLE. The reason for the increased ASCVD is related to both traditional risk factors for atherosclerosis and nontraditional risk factors such as the burden of inflammation. Presently, our ability to adequately determinecardiovascular risk in the autoimmune patient is subpar, as scoring systems fail to take into account the role of inflammation. No present guidelines exist that take into account the increased burden of cardiovascular disease in this complex patient cohort. PMID- 29480593 TI - Ameloblastoma-Clinical, radiological, and therapeutic findings. AB - Ameloblastoma are the most common odontogenic tumor. As they usually do not form metastasis, they are considered as benign tumors with a locally invasive growth pattern and destruction of the jaws and the surrounding tissue (Oral Diseases, 23, 2017, 199). This article focuses on clinical, radiological, and therapeutic findings, which may influence diagnosis and treatment of ameloblastoma in the future. PMID- 29480592 TI - Breast cancer patients have increased risk of developing mTOR inhibitor associated stomatitis. AB - A total of 115 patients who used everolimus were evaluated. The mean age was 57 (+/-13.3) years old, and 87 patients were women (75.6%). mTOR inhibitor associated stomatitis (mIAS) was observed in 36 patients (31.3%). The lesions ranged from 0.5 cm to 1.5 cm, and the tongue was the main site affected. In addition, 21 patients (58.3%) required a dose reduction of everolimus due to mIAS. Patients who had breast cancer presented 2.29-fold higher risk for developing mIAS when compared to patients with kidney or neuroendocrine tumors. This study emphasizes the high prevalence of mIAS in patients using everolimus, in particular, in patients with breast cancer. PMID- 29480594 TI - Oral epithelial MUC1 and oral health. AB - OBJECTIVES: To provide information about MUC1, epithelial membrane-bound mucin, in terms of its role in oral health. DESIGN: The expression and functional roles of MUC1 in the oral mucosa and salivary glands were reviewed. Information on the modulation of oral mucosal epithelial MUC1 expression compared with that of endometrial epithelial MUC1 expression was also reviewed. In addition, the possible associations between oral mucosal epithelial MUC1 and oral diseases were explored. RESULTS: MUC1 is expressed in the oral mucosa and major and minor salivary glands. Protection of oral mucosal surfaces is believed to be the main function of oral mucosal epithelial MUC1. Its role in the salivary glands is thought to facilitate salivary flow through the ductal system. Information on the role of MUC1 in signal transduction and modulation of immune function in the oral cavity is sparse. However, the possible roles of MUC1 in dry mouth conditions, burning mouth syndrome, dental caries, and oral candidiasis have been suggested. CONCLUSIONS: Despite limited information, it is clear that oral epithelial MUC1 plays an important role in oral health. Further research evaluating the physiological and pathological roles of MUC1 in the oral cavity is warranted. PMID- 29480595 TI - Methods and risk of bias in molecular marker prognosis studies in oral squamous cell carcinoma. AB - BACKGROUND: We investigated methods and risk of bias, focusing on research design, aim, prognostic factors, outcome, and statistical analysis in molecular marker prognosis studies of oral squamous cell carcinoma. MATERIAL AND METHODS: We used a database search strategy to indentify relevant articles published in English in 2016. We developed a data extraction form to assess and extract information on methods of molecular marker prognosis studies in oral squamous cell carcinoma, based on methodological recommendations for prognosis studies. We used the Quality in Prognosis Studies tool to assess the risk of bias in six domains. RESULTS: Thirty-six papers were retrieved for full text review: 35 were replication prognosis factor studies and one was a model development based only on molecular markers to stratify patient's risk. Retrospective cohort was the design used in most studies (91%). Despite recommendations against dichotomizing continuous prognostic variables, this was observed in the majority of cases. A substantial number of studies (60%) conducted survival analysis, COX regression, and Kaplan-Meier. Prognostic variables included in the multivariate model were often preselected based on the results of univariable analysis. Risk of bias was assessed high for confounding, statistical analysis and reporting domains in 46% and 49% of studies, respectively. CONCLUSIONS: The prognosis studies analyzed here can be considered phase II explanatory studies. The next step is to construct and validate models, which can be applied for use in the clinical practice, to guide patient management or build explanatory models that can help better understand the causative role in the disease process of these markers. PMID- 29480596 TI - Medication-related osteonecrosis of the jaw: Surgical or non-surgical treatment? AB - Medication-related osteonecrosis of the jaw (MRONJ) is a severe side effect of antiresorptive (bisphosphonates and denosumab) and anti-angiogenic therapy used in the management of oncologic and, less frequently, osteoporotic patients. While there is good international agreement on the diagnostic and staging criteria of MRONJ and the cessation of antiresorptive/anti-angiogenic treatments, the gold standard of treatment is still controversial, in particular between non-surgical and surgical approaches. The former usually includes antiseptic mouth rinse, cyclic antibiotic therapy, low-level laser therapy and periodic dental checks; the latter consists of surgical necrotic bone removal. The purpose of this retrospective study was to describe the therapeutic approaches and outcomes of 131 lesions from 106 MRONJ patients treated at the Policlinic of Bari. Non surgical treatments were chosen for 24 lesions that occurred in 21 patients who, due to comorbidities and/or the impossibility of stopping oncologic therapies, could not undergo surgical treatment. As to the outcome, all the surgically treated lesions (107) showed complete healing, with the exception of 13.5% of the lesions, all of which were stage III, which did not completely heal but showed reduction to stage I. The 24 non-surgically treated lesions never completely healed and, rather, generally remained stable. Only two cases exhibited a reduction in staging. Based on our observations, MRONJ occurring both in neoplastic and non-neoplastic patients benefits more from a surgical treatment approach, whenever deemed possible, as non-surgical treatments do not seem to allow complete healing of the lesions. PMID- 29480598 TI - Mobile oral heath technologies based on saliva. AB - In this review we have highlighted a few innovative microfluidic analytical technologies with mobile phone image processing tools for various bio-chemical tests performed using salivary biomarkers. Saliva-based assays for mobile monitoring with a smartphone sensor provide an excellent analytical technique which can be simple to perform. We describe several examples from the literature, utilizing different modalities of analysis, applied to several different applications of mobile health monitoring: cortisol monitoring, infectious disease testing, and drugs of abuse. PMID- 29480597 TI - Microbiopsy a first-level diagnostic test to rule out oral dysplasia or carcinoma in general dental practice. AB - OBJECTIVES: Diagnostic delay in oral oncology could be improved if general dentists had a reliable and easy-to-use first-level diagnostic test to rule out the presence of oral dysplasia or carcinoma. Microbiopsy has been proved to have high sensitivity and high negative predictive value in a clinical setting characterized by high prevalence of disease. Moreover, it has been proved to be easily performed by general dentists. This study aimed to determine the negative predictive value of microbiopsy in routine dental practice: a clinical setting characterized by low prevalence of disease. METHODS: Within the frame of a previous study, general dentists from the Metropolitan Area of Turin performed microbiopsy for each oral mucosal lesion detected during their practice. The clinical outcome of 129 lesions negative at microbiopsy was checked by a query performed through the database of the Piedmont Cancer Registry, covering the population of the Metropolitan Area of Turin, with particular reference to cancer involving the mouth (ICD-10:C03-06). This allowed us to define "true negative" cases and to calculate the negative predictive value of microbiopsy. RESULTS: In a mean follow-up of 7.5 years (range 7-9 years), with a dropout rate of 7.7%, no case of tumour involving the mouth was observed, thus revealing a negative predictive value approaching 100%. CONCLUSIONS: Microbiopsy represents an easy-to use and reliable first-level test able to aid general dentists to select patients requiring an oral medicine assessment in a short time and definitely to avoid diagnostic delay in oncologically relevant oral mucosal lesions. PMID- 29480600 TI - The Mammoth Professor. PMID- 29480599 TI - Co-inhibitory immune checkpoints in head and neck squamous cell carcinoma. AB - The upregulation of co-inhibitory immune checkpoints hampers the immune response toward tumor cells and facilitates the tumor cells ability to evade immunosurveillance. Specific inhibitory immune checkpoint delivers inhibitory signals to T cells using multiple mechanisms. More in-depth understanding of the co-inhibitory immune checkpoints could be exploited for head and neck squamous cell carcinoma (HNSCC) treatment. In this review, we summarize the expression and the mechanism of partial co-inhibitory immune checkpoint signals and discuss targeting co-inhibitory immune checkpoints as an immunotherapeutic target for cancer therapy. This review may provide a better understanding of the co inhibitory immune checkpoints and could promote applications of immunotherapy. PMID- 29480601 TI - Lyophilized bone marrow cell extract functionally restores irradiation-injured salivary glands. AB - OBJECTIVE: Bone marrow cell extract (BMCE) was previously reported to restore salivary gland hypofunction caused by irradiation injury. Proteins were shown to be the main active factors in BMCE. However, BMCE therapy requires multiple injections and protein denaturation is a concern during BMCE storage. This study aimed to preserve, by lyophilization (freeze-drying), the bioactive factors in BMCE. METHODS: We developed a method to freeze-dry BMCE and then to analyze its ingredients and functions in vivo. Freeze-dried (FD) BMCE, freshly prepared BMCE (positive control), or saline (vehicle control) was injected into the tail vein of mice that had received irradiation to damage their salivary glands. RESULTS: Results demonstrated that the presence of angiogenesis-related factors and cytokines in FD-BMCE remained comparable to those found in fresh BMCE. Both fresh and FD-BMCE restored comparably saliva secretion, increased cell proliferation, upregulated regenerative/repair genes, protected salivary acinar cells, parasympathetic nerves, and blood vessels from irradiation-damaged salivary glands. CONCLUSION: Lyophilization of BMCE maintained its bioactivity and therapeutic effect on irradiation-injured salivary glands. The advantages of freeze-drying BMCE are its storage and transport at ambient temperature. PMID- 29480602 TI - Betel quid chewing among adult male immigrants from the Indian subcontinent to Italy. AB - OBJECTIVE: Betel quid chewing (BQC) is an important oral cancer risk factor widespread in the Indian subcontinent. This usage also is common among migrants from this region. As the number of immigrants from South-East Asia is dramatically increasing in Italy, this survey was aimed at investigating BQC prevalence among immigrants from the Indian subcontinent. SUBJECTS AND METHODS: First-generation adult male immigrants coming from Pakistan, India, Sri Lanka, and Bangladesh, living in Rome, were consecutively selected. They were interviewed using a validated questionnaire. Descriptive statistics were performed, and factors associated to regular BQC were investigated through regression analysis. RESULTS: A total of 211 subjects (mean age, 33.8 years) living in Rome for 11 years, on average, participated in the study. BQC prevalence was 37.9% with few differences between Pakistani, Sri Lankans, and Indians. Prevalence among Bangladeshi was 7.3%. 69% of the consumers chewed BQ at least twice daily, 90% chewed BQ with tobacco; 30.3% subjects were smokers and chewers. Chewing parents, smoking, health illiteracy were associated with BQC. Most chewers believed that BQ helps to relieve stress. CONCLUSIONS: The number of oral cancers in Italy is expected to increase because of BQC dissemination. Therefore, specific awareness campaigns directed to residents of South-East Asian origin are needed. PMID- 29480603 TI - Myofibroblasts in oral potentially malignant disorders: Is it related to malignant transformation? AB - In oral cancer, acquisition of alpha-smooth muscle actin (alpha-SMA)-positive fibroblasts, known as myofibroblasts or carcinoma-associated fibroblasts (CAF), is an important event for progression and metastasis. However, the contribution of myofibroblasts in oral potentially malignant disorders (OPMD) remains controversial. This systematic review provides evidence that immunodetection of myofibroblasts may identify oral submucous fibrosis (OSMF) with high risk of malignant transformation, but does not represent an auxiliary tool to predict the malignant potential of leukoplakia and erythroplakia, the most common OPMD. PMID- 29480604 TI - The future of oral medicine. AB - Oral Medicine has been a specialty at the cross-roads of medicine and dentistry, not entirely recognized as a specialty by organized dentistry (at least in the US), and not embraced by medicine. This study makes a case for its place as a specialty of Medicine. PMID- 29480605 TI - Direct oral anticoagulants: A retrospective study of bleeding, behavior, and documentation. AB - OBJECTIVE: To examine the effects of direct oral anticoagulants (DOACs) on bleeding complications following dental surgeries. SUBJECTS AND METHODS: This 6 year retrospective study collected data from records of patients undergoing oral surgical procedures within a university setting. An electronic health record database was searched using current procedural terminology codes for oral surgical procedures. Information regarding patient, procedural factors, and postoperative complications were extracted. Data were analyzed by Fisher's exact test. RESULTS: Of patients who had a procedural code associated with oral surgery, only 0.11% (12/11,320) took a DOAC. Twelve patients (10 males, age ranging from 44 to 90 years) underwent 17 surgeries by nine different practitioners involving 98 extractions, 14 alveoloplasties, two tuberosity reductions, and two tori removals. In nine cases, the DOAC was discontinued a mean of 52.5 hrs prior to surgery (range 12-120 hrs). Bleeding complications were not reported for patients whose drug was discontinued or continued. Documentation of drug continuation/discontinuation was poor. CONCLUSIONS: Bleeding was not observed with direct oral anticoagulation use in this oral surgery cohort. Drug discontinuation/continuation was not a factor in bleeding outcomes, and direct oral anticoagulation interruption was variable and poorly documented. PMID- 29480606 TI - Oral leukoplakia remains a challenging condition. AB - Crispian Scully had many interests in the realm of oral diseases. But oral leukoplakia was one that piqued his curiosity when he was still an academic neophyte and remained a topic which he studied throughout his enormously productive career. It is easy to understand why. While the clinical manifestations of oral leukoplakia are common, we still do not fully understand why one version of the condition is benign, while another, similar in appearance, progresses to a malignancy. The diagnosis of oral leukoplakia is based on expert clinical and histopathological examamination. Management and treatment of leukoplakia remain challenging especially for large lesions and the proliferative subtype. This review aims to provide a general overview on leukoplakia, explore current challenges in its diagnosis and management and discuss the opportunities to better understand the condition. PMID- 29480607 TI - Oral lichen planus: Challenge and management. PMID- 29480608 TI - Significance of cytoplasmic cyclin D1 expression in oral oncogenesis. AB - OBJECTIVES: To examine cytoplasmic cyclin D1 expression levels in oral carcinogenesis and evaluate their possible oncogenic significance and their clinicopathological and prognostic implications. MATERIALS AND METHODS: Immunohistochemical analysis of 69 oral squamous cell carcinomas (OSCCs) was performed, revealing 23 with cytoplasmic cyclin D1 expression. We analyzed the association of the percentage of cyclin D1-positive cells and the intensity of expression with TNM classification, tumor stage, differentiation degree, cell morphology, and Ki-67 expression. RESULTS: Cytoplasmic cyclin D1 expression was associated with advanced tumor stage, poor differentiation, elevated Ki-67 expression, and the presence of invasive cell morphology, indicators of a poor prognosis. An association was observed between nuclear and cytoplasmic expressions of cyclin D1. CONCLUSIONS: Cytoplasmic expression of cyclin D1 appears to possess functions related to increased cell migration and invasion in OSCC. PMID- 29480609 TI - Relationship between dental occlusion and functional dependence in elderly Caucasians. AB - OBJECTIVE: To determine whether a relationship exists between the number of functional masticatory units (FMUs) and the level of functional dependence of elderly. SUBJECTS AND METHODS: The study group comprised 502 elderly Caucasians living in nursing homes in north-west Spain and Portugal. The number of FMUs was counted on direct visual inspection. The degree of dependence was assessed using the Barthel index. The results were validated in a group of 156 elderly. Statistical analysis of the results was performed using a generalised linear model (GLM), a logistic GLM, a ROC-GLM curve and a confusion matrix. RESULTS: The number of FMUs significantly affected the Barthel index score (explained deviance = 27.5%). The number of FMUs was significantly associated with a lower probability of dependence, both for women (explained deviance = 31%) and for men (explained deviance = 33%). The model based on FMUs showed a good discriminatory capacity for dependence (AUC = 0.84 in women and 0.82 in men). The predictive capacity of the dependence model based on FMUs was very high (sensitivity = 0.9 in women and 0.8 in men). CONCLUSIONS: In institutionalised elderly Caucasians, the number of FMUs is significantly associated with the Barthel index score and could be a predictive factor for dependence. PMID- 29480610 TI - Oral lichenoid lesions of the upper lip and gingiva: What we know so far. AB - The clinical presentation of oral lichen planus and oral lichenoid lesions is diverse. A special category of patients presents with lichenoid lesions affecting only the mucosa of their upper lip and the anterior upper gingiva. This is a concise review summarizing the specific characteristics of these patients. PMID- 29480612 TI - Narrow Band Imaging-guided resection of oral cavity cancer decreases local recurrence and increases survival. AB - PURPOSE: Overall local recurrence of oral squamous cell carcinoma (OSCC) is estimated at 20%. Incomplete primary tumour excision contributes to localised postsurgical recurrence of OSCC. The purpose of this study was to report on patient outcomes following resection of OSCC using Narrow Band Imaging (NBI). MATERIALS AND METHODS: Patients with OSCC requiring resection were visualised under conventional white light (WL) then NBI using an Olympus NBI ENF-VQ nasendoscope with CLV-180 light source and processor (Olympus Medical Systems, Tokyo, Japan). OSCC tissue was resected to the NBI-defined surgical margins, and patients followed for a minimum of 5 years postsurgery to assess local recurrence rate (LRR) and disease-free survival (DFS). RESULTS: Of the 20 patients recruited for this study, one patient (5%) declined follow-up. At the latest follow-up period (up to 7 years postsurgery), 14 of 19 patients (73.68%) were alive with no recurrence. Two patients (10.53%) had died from metastatic disease with no local recurrence, one patient (5.26%) had died from disease with local recurrence, and two patients (10.53%) had died disease-free from other causes. In total, 16 of 19 patients (84.21%) who were followed for a minimum of 5 years were still alive and had not developed local recurrence. Only one patient developed local recurrence. Five-year DFS was 84.21% and LRR was 5.26%. CONCLUSION: Resection to NBI-defined margins improves survival rates and decreases recurrence rates of OSCC compared to traditional methods and should be adopted as the new gold standard for determining mucosal surgical margins for treatment of oral cavity cancer. These promising results have set the scene for a multicentred randomised controlled trial comparing NBI to WL currently underway. PMID- 29480611 TI - Radioactive iodine: An unappreciated threat to salivary gland function. AB - Thyroid cancer is an endocrine malignancy whose prevalence is increasing in the United States. Nearly 57,000 new cases of thyroid cancer are estimated to be diagnosed in 2017. The standard of care for differentiated thyroid cancer is thyroidectomy followed by ablation of thyroid remnants with high-dose radioactive iodine (131 I). Apart from thyroid glands, 131 I accumulates in cells of salivary glands and compromises its function. Xerostomia is, therefore, a frequent and often persistent complaint of patients. Despite adoption of standard preventive measures, parenchymal damage and chronic salivary dysfunction are observed in a substantial number of patients. Saliva is important for oral homeostasis, and its reduction increases the risk of oral morbidity. As differentiated thyroid cancer patients have an excellent survival rate, preservation of salivary gland function carries added significance. A focus on treatments that preserve or restore long term salivary flow can significantly improve the quality of life of thyroid cancer survivors. PMID- 29480613 TI - Oral cancer awareness in Spain: A pilot study. AB - OBJECTIVES: To investigate the level of oral cancer knowledge and awareness in a Spanish general population. SUBJECTS AND METHODS: A cross-sectional study using an anonymous questionnaire applied in the community to randomly selected laypersons. Sample size for the general population was determined by quota sampling, resulting in 1,041 individuals. RESULTS: A total of 1,707 pedestrians were approached (response: 61%). When the participants were asked about what cancers had they heard about (up to ten), oral cancer was mentioned in first place by 2% of the sample and by 22% in any order. When specifically asked about oral cancer, the percentage of interviewees who were familiar with it raised to 72%. Participants were also asked about the main signs or symptoms of oral cancer, and the most frequently (22%) mentioned as the first warning sign was a non-healing ulcer. Tobacco smoking generally was recognised as the most important (57%) risk factor for oral cancer. CONCLUSIONS: This pilot study revealed a low awareness of oral cancer, and a poor knowledge of its signs and symptoms and risk factors. PMID- 29480614 TI - Learning from clinical phenotypes: Low-dose biophotonics therapies in oral diseases. AB - This narrative review on the use of biophotonics therapies for management of oral diseases is written as a tribute to Prof. Crispian Scully. His seminal contributions to the field are highlighted by the detailed, comprehensive description of clinical presentations of oral diseases. This has enabled a more thorough, fundamental understanding of many of these pathologies by research from his group as well as inspired mechanistic investigations in many groups globally. In the same vein, a major emphasis of this narrative review is to focus on the evidence from human case reports rather than in vitro or in vivo animal studies that showcases the growing and broad impact of biophotonics therapies. The similarities and differences between two distinct forms of low-dose biophotonics treatments namely photodynamic therapy and photobiomodulation therapy are discussed. As evident in this review, a majority of these reports provide promising evidence for their clinical efficacy. However, a lack of adequate technical details, precise biological rationale, and limited outcome measures limits the current utility of these treatments. Future investigations should attempt to address these shortcomings and develop better designed, rigorous, controlled studies to fully harness the tremendous potential of low-dose biophotonics therapies. PMID- 29480615 TI - Role of tissue-specific steroid metabolism in oral disease: Is there any clinical implication? AB - The discovery of an oral glucocorticoid system has provided novel conceptual frameworks for understanding the effects of endogenous and exogenous corticosteroids in the oral cavity. For example, liquorice derivatives have long been used in the treatment of oral inflammatory conditions and it is now known that a chief constituent of liquorice root, glycyrrhetinic acid, inhibits 11beta hydroxysteroid dehydrogenase (11beta-HSD) type 2 thus increasing local cortisol levels. Hence, targeting the local interconversion between inactive cortisone and active cortisol by 11beta-HSD inhibitors/activators offers potentially advantageous strategies for the treatment of oral inflammatory and autoimmune conditions. The recent characterisation of a cancer-associated glucocorticoid system has further extended the implications of cortisol metabolism in oral disease. New evidence now questions the use of synthetic corticosteroids in patients with cancer and, possibly, in oral potentially malignant disorders. For example, cortisol production by cancer cells has been shown to inhibit tumour specific CD8+ T cells, to promote migration and invasion and to induce chemoresistance in vitro. This viewpoint briefly summarises the recent evidence for a role of the local steroid metabolism in oral oncology and immunology and its potential clinical implications. PMID- 29480616 TI - Oral erythroplakia-What is it? AB - Oral erythroplakia is a rare type of lesion, and little is known about the origin of the lesion. It has traditionally been described as the red counterpart of oral leukoplakia, which implies that it is a red lesion that cannot be characterized clinically or pathologically as any other definable lesion. A definition by exclusion is less satisfactory than a positive description to define a lesion, and as erythroplakia probably is related to lichenoid lesions, a new approach to perceive the lesion is proposed based on the clinical features of a fiery red, sharply demarcated lesion situated at a slightly lower level than the surrounding mucosa. Such a definition would probably help clinicians distinguish erythroplakia from other red lesions of the oral mucosa. Although the course of such lesions varies, a significant proportion will develop malignancy, which is why they should be followed at short intervals. PMID- 29480617 TI - Autophagy in the dentin-pulp complex against inflammation. AB - The dentin-pulp complex is a highly specialized tissue for protecting the dental pulp. Odontoblasts are long-lived, hard-tissue-forming cells in the dentin-pulp complex and critically involved in inflammatory responses against invading pathogens. Autophagy is a highly conserved homeostasis mechanism of living cells under various stress conditions. Growing evidence in the literature addresses the role of autophagy in odontoblast differentiation and aging. This review summarizes the current knowledge about autophagy for the dentin-pulp complex in resisting inflammation. PMID- 29480618 TI - Tissue eosinophilia in oral intraepithelial neoplasia as a probable indicator of invasion. AB - OBJECTIVE: To investigate the presence of eosinophils in oral intraepithelial neoplasia (OIN) and oral squamous cell carcinoma (OSCC) lesions and its relation to invasion. SUBJECTS AND METHODS: Ninety-nine oral biopsies were selected and subdivided into the following: OIN-1(16 cases), OIN-2 (18 cases), OIN-3 (17 cases), microinvasive OSCC (10 cases), non-metastatic OSCC (22 cases) and metastatic OSCC (16 cases). The tissue eosinophilia was evaluated histologically in slices stained with haematoxylin and eosin. RESULTS: Eosinophil distribution was associated with diagnosis severity (p < .01). A significant difference was found between OIN-3 or microinvasive OSCC and non-metastatic or metastatic OSCC. Stromal invasion threshold was 7 eos/10 high power field (hpf) (96.1% specificity and 62.5% sensitivity). Eosinophils were absent in OIN-1; in OIN-2, two cases were positive. In OIN-3, five cases showed tissue eosinophilia, four of which had >=3 eos/hpf or >=7 eos/10 hpf. Three cases were suspected of invasion; two had a previous history of OSCC with elevated eosinophil infiltrate. In microinvasive OSCC, the four positive cases presented >=3 eos/hpf and >=7 eos/10 hpf. Although not significantly different, non-metastatic invasive OSCC had a higher number of cases (68.2%) with >=22 eos/10 hpf contrasting with 50% in metastatic OSCC. CONCLUSION: Our results suggest that eosinophils can be considered an indicator of invasion in OIN, helping in cases of difficult diagnosis. PMID- 29480619 TI - Oral manifestation of systemic diseases-a perspective from an oral pathology diagnostic service. PMID- 29480620 TI - Honoring a champion of Oral Medicine: Professor Crispian Scully. PMID- 29480621 TI - The medically compromised patient: Are dental implants a feasible option? AB - In healthy subjects, dental implants have evolved to be a common therapy to solve problems related to stability and retention of dentures as well as to replace failing teeth. Although dental implants are applied in medically compromised patients, it is often not well known whether this therapy is also feasible in these patients, whether the risk of implant failure and developing peri implantitis is increased, and what specific preventive measures, if any, have to be taken when applying dental implants in these patients. Generally speaking, as was the conclusion by the leading review of Diz, Scully, and Sanz on placement of dental implants in medically compromised patients (J Dent, 41, 2013, 195), in a few disorders implant survival may be lower, and the risk of a compromised peri implant health and its related complications be greater, but the degree of systemic disease control outweighs the nature of the disorder rather than the risk accompanying dental implant treatment. So, as dental implant treatment is accompanied by significant functional benefits and improved oral health-related quality of life, dental implant therapy is a feasible treatment in almost any medically compromised patient when the required preventive measures are taken and follow-up care is at a high level. PMID- 29480622 TI - Primordial odontogenic tumor: Subepithelial expression of Syndecan-1 and Ki-67 suggests origin during early odontogenesis. AB - Primordial odontogenic tumor (POT) is composed of variably cellular myxoid connective tissue, surrounded by cuboidal to columnar odontogenic epithelium resembling the inner epithelium of the enamel organ, which often invaginates into the underlying connective tissue. The tumor is delimited at least partially by a thin fibrous capsule. It derives from the early stages of tooth development. Syndecan-1 is a heparan sulfate proteoglycan that has a physiological role in several cellular functions, including maintenance of the epithelial architecture, cell-to-cell adhesion and interaction of cells with extracellular matrix, and with diverse growth factors, stimulating cell proliferation. Ki-67 is considered the gold standard as a cell proliferation marker. The aim of this study was to examine the expression of Syndecan-1 and Ki-67 proliferation index in POT and normal tooth germs to better understand the biological behavior of this tumor. Results showed that Syndecan-1 was more intensely expressed in subepithelial mesenchymal areas of POT, in a pattern that resembles the early stages of tooth development. The cell proliferation index (4.1%) suggests that POT is a slow growing tumor. Syndecan-1 expression in tooth germs in late cap and early bell stages was similar to POT, showing immunopositivity in subepithelial mesenchymal condensed areas. The immunohistochemical findings showed a pattern in which the population of subepithelial mesenchymal cells exhibited greater proliferative activity than the central portion of the dental papilla. PMID- 29480623 TI - Role of myofibroblasts in normal and pathological periodontal wound healing. AB - Myofibroblasts represent specific subpopulations of cells with important roles in tissue remodeling in both health and disease. They are not usually found in resting healthy tissues. However, they increase in number during the proliferative phase of wound healing. In these conditions, myofibroblasts secrete and organize different molecular components of the extracellular matrix that with time will reconstitute and hopefully regenerate the damaged tissue. Importantly, these cell populations must be eliminated after wound healing has been completed. However, deficiencies in their differentiation or the persistence of this cell population has been associated with the development of delayed wound healing and fibrosis, respectively. In the present review, we analyze the involvement of myofibroblasts in periodontal wound healing and their potential contribution to tissue homeostasis and disease. PMID- 29480624 TI - Oral mucous membrane pemphigoid: A clinical study of 100 low-risk cases. AB - OBJECTIVE: To analyze the severity of the oral lesions in low-risk oral mucous membrane pemphigoid (OMMP) measured according to the size of the bullous areas and the number of simultaneously affected oral locations. MATERIAL AND METHODS: A total of 100 cases of low-risk OMMP were studied. The symptoms and location of OMMP in the oral cavity were analyzed. The bullous areas were measured, establishing three grades according to the greatest bullous lesion size (grade 1: < 3 cm in size; grade 2: 3-6 cm; and grade 3: > 6 cm). RESULTS: The mean age of the patients was 66.07 +/- 13.55 years, with a clear predominance of females (84%). Desquamative gingivitis was the most common presentation (97%). A single oral location was found in 67% of the cases, two in 18% and three in 15%. The most common presentation corresponded to grade 1 (the greatest bullous lesion size < 3 cm; 51.6% of the cases). CONCLUSIONS: Most cases of low-risk OMMP are restricted to a single site in the oral cavity, the gingiva being the most common location-the predominant grade corresponding to the greatest bullous lesion size < 3 cm. PMID- 29480625 TI - Management of dental patients taking direct oral anticoagulants: Dabigatran. AB - Direct oral anticoagulants (DOACs) are increasingly used as alternatives to warfarin because of the superior pharmacokinetic properties. Clinical guidelines on the influences of DOACs for dental procedures have emerged, but all of necessity based on low-quality available evidence. Herein, we share our experience with a case series, and propose a protocol regarding the management of dental patients taking DOACs. PMID- 29480626 TI - Oral stomatitis and mTOR inhibitors: A review of current evidence in 20,915 patients. AB - BACKGROUND: Traditional treatment of malignancies with chemotherapeutic agents is often affected by the damage inflicted on non-cancerous cells. Toxicities of the oral cavity, such as mucositis and stomatitis, are some of the most significant and unavoidable toxicities associated with anti-cancer therapies. For such reason, in the last decades, newer targeted agents have been developed aiming to decrease the rates of side effects on healthy cells. Unfortunately, targeted anti cancer therapies also showed significant rate of toxicity on healthy tissues. mTOR inhibitors showed some adverse events, such as hyperglycemia, hyperlipidemia, hypophosphatemia, hematologic toxicities, and mucocutaneous eruption, but the most important are still stomatitis and skin rash, often reported as dose-limiting side effects. PATIENTS AND METHODS: A search of the literature was performed by authors on the PubMed online database using the following key words: "sirolimus" OR "everolimus" OR "temsirolimus" OR "deforolimus" OR "ridaforolimus" combined with the Boolean operator AND with the terms: "stomatitis" OR "mucositis" OR "oral pain." Titles and abstracts of 382 potentially relevant studies were screened; of these, 114 studies were excluded because they did not report the inclusion criteria. In the second round, 268 studies were read full-text, but only 135 reported the inclusion criteria and were included for data extraction. Of the included studies, 95 referred to everolimus use, 16 to ridaforolimus, and 26 to temsirolimus (two studies referred to both everolimus and temsirolimus). RESULTS: The incidence rate of stomatitis according to the agent used was 25.07% (3,959/15,787) for everolimus, 27.02% (724/2,679) for temsirolimus, and 54.76% (598/1,092) for ridaforolimus. All the three agents analyzed showed high rates of low-grade stomatitis (G1-G2), while the onset of severe stomatitis (G3-G4) was rare. CONCLUSIONS: Analysis of the reports with patients treated with everolimus, temsirolimus, and ridaforolimus showed a clear prevalence of stomatitis grade 1 or 2. These data differ from that of patients treated with conventional chemotherapy in which mucositis is predominantly of grade 3 or 4. PMID- 29480627 TI - EPS8 signaling as a therapeutic target in oral cancer. PMID- 29480628 TI - Chikungunya fever: General and oral healthcare implications. AB - Chikungunya virus (CHIKV) was first isolated in humans in 1952, following an epidemic in Tanzania. The origin of the name means "to bend forward or become contorted," in reference to the posture adopted by patients due to the joint pain that occurs during the infection. Epidemiology data suggest that by the end of 2015, about 1.6 million people had been infected with CHIKV. The acute period of the disease is characterized by high fever, myalgia, joint pain, and severe and disabling polyarthritis, sometimes accompanied by headache, backache, and maculopapular rash, predominantly on the thorax. Around half of the patients will progress to the subacute and chronic phases, that is manifested by persistent polyarthritis/polyarthralgia, accompanied by morning stiffness and fatigue, which could remain for years. Oral features may include gingivitis possibly as a consequence of arthralgia of the hands leading to limited oral health measures as well as burning sensation and oral mucosal ulceration. Treatment in the acute phase includes acetaminophen, and weak opioids (tramadol or codeine) should be used in cases of severe or refractory pain. For patients who have progressed to the subacute stage and who have not had notable benefit from common analgesics or opioids, NSAIDs, or adjunctive pain medications (anticonvulsants or antidepressants) may be of benefit. In patients with moderate-to-severe musculoskeletal pain or in those who cannot be given or tolerate NSIADs or opiates, prednisolone should be prescribed. PMID- 29480629 TI - Immunomodulatory effect of vitamin K2: Implications for bone health. AB - OBJECTIVE: In women with postmenopausal osteoporosis, vitamin K2 appears to decrease the incidence of hip, vertebral, and non-vertebral fractures. Women with postmenopausal osteoporosis have more circulating activated T cells compared with healthy postmenopausal and premenopausal women, but the effects of vitamin K2 on T cells have not been studied. In this study, we have looked at T-cell suppression by vitamin K2. MATERIALS AND METHODS: Peripheral blood mononuclear cells (PBMCs) from three healthy donors were used. The PBMCs were stimulated with the mitogens phytohemagglutinin and concanavalin A, and T-cell proliferation was analyzed using flow cytometry based on carboxyfluorescein succinimidyl ester (CSFE) dye dilution. RESULTS: Vitamin K2 (60 and 100 MUM) inhibited T-cell proliferation. Vitamin K1 at the same concentrations did not inhibit T-cell proliferation. CONCLUSION: Vitamin K2 has immunomodulatory activities. PMID- 29480631 TI - The importance of studying oral and craniofacial manifestations of Mendelian phenotypes. PMID- 29480632 TI - Ellagic acid inhibits HIV-1 infection in vitro: Potential role as a novel microbicide. AB - OBJECTIVE: To investigate the in vitro effects of ellagic acid on HIV-1 replication. METHODS: Anti-HIV-1 activity of ellagic acid was determined in vitro using X4-tropic HIV-1NPO3 and R5-tropic pBaL Env-recombinant virus. Anti-HIV 1NPO3 activity of ellagic acid was investigated at a multiplicity of infection (MOI) of 0.01. Anti-HIV-1 integrase and protease activities of ellagic acid were tested using in vitro integration and proteolytic cleavage assays. RESULTS: Ellagic acid, added either before or after HIV-1NPO3 exposure, suppressed replication of the virus in C8166 cells up to 34%. Ellagic acid showed an anti integrase IC50 of 8.7 MUM. No cytotoxicity of ellagic acid at concentrations ranging from 12.5 to 100 MUM was observed. CONCLUSION: We conclude that ellagic acid can inhibit HIV-1 infection without cytotoxicity. Thus, it may be a new effective agent that has potential to be developed as a novel microbicide against HIV-1. PMID- 29480633 TI - The distinctive jaw and alveolar bone regeneration. AB - The skeletal system is structurally and functionally unique. It can be referred to as connective tissue that lost its ability to resist mineralization as mineralization in any other connective tissues is heterotopic. In addition to providing support for muscular attachments, the skeletal system protects nerves and harbors the hematopoietic and mesenchymal stem cells within the bone marrow compartment. However, there are distinct phenotypic and functional differences between the orofacial skeleton compared to axial and appendicular skeleton. How different is the jaw bone from other non-craniofacial bones? Interestingly, developmental, biological, and clinical outcomes point to distinctive features that make the jaw bone unique. PMID- 29480630 TI - Clastic cells are absent around the root surface in pulp-exposed periapical periodontitis lesions in mice. AB - INTRODUCTION: Clastic cells, originating from the monocyte-macrophage lineage, resorb mineralized tissues. In periapical periodontitis, alveolar bone around the tooth apex becomes resorbed; however, the roots of the teeth are often left intact by yet unknown mechanisms. Here, we examined the status of clastic cells in a periapical periodontitis model in mice. METHODS: Periapical periodontitis was induced by performing pulp exposure on the maxillary first molar. The contralateral maxillary first molar was used as a control. The maxillae were harvested, fixed, and subjected to MUCT scanning and three-dimensional volumetric analysis. TRAP staining was performed, and osteoclasts were quantified. Immunohistochemical staining was performed for RANKL, OPG, and F4/80, a marker for macrophages. RESULTS: At the apex of the tooth, pulp exposure resulted in periapical radiolucency with mineralized tissues at the surrounding bone surfaces but not on the root surfaces. Histologically, clastic cells were present on the bone surfaces but absent around the root surfaces. Expression of F4/80 and RANKL was not found at close proximity to the root surfaces, but OPG was globally expressed. CONCLUSION: The absence of clastic cells around the root surface of pulp-exposed teeth, in part, is associated with the lack of macrophages and RANKL expression. PMID- 29480634 TI - Human papillomavirus load in benign HPV-associated oral lesions from HIV/AIDS individuals. AB - BACKGROUND: Although HPV emerged as a crucial carcinogenic and prognostic biomarker in head and neck cancer, and considering the increase in HPV-associated oral lesions (HPV-OLs) in HIV individuals, molecular information about HPV-OLs is scarce; thus, our aim was to determine viral loads in HPV-OLs from HIV/AIDS individuals. METHODS: HIV/AIDS subjects with HPV-OL were included in this cross sectional study. Following informed consent, biopsies were obtained. HPV detection and typing were carried out by PCR and sequencing (MY09/11, GP5+/6+). HPV-13 and HPV-32 loads were determined by a high-resolution melting assay. For statistical analysis, X2 , Fisher's exact, and Mann-Whitney U tests were applied, using SPSS software (v.23). RESULTS: Twenty-nine HIV subjects (median age 38 years, 93% males) were included. Most were AIDS individuals (72.4%) under HAART (89.7%). Twenty-two (75.9%) participants had more than one HPV-OL (four with florid presentations), mostly multifocal epithelial hyperplasia (62%), being HPV 13 (26%) and HPV-32 (31%) the most frequent types. HPV load was higher in individuals with multiple HPV-OLs than in solitary lesions (4.9 vs. 3.2 Log10 copies/ml, p = .090) and in HPV-32+ than in HPV-13+ (8.3 vs. 6.4 Log10 copies/ml, p = .014). CONCLUSIONS: Multiple HPV-OLs showed high HPV loads, possibly indicating transcriptional activity of the virus; however, in the HIV setting, the individual and local immunological response could be the key process. PMID- 29480635 TI - Comparative analysis of the 2016 ACR-EULAR and the 2002 AECG classification criteria for Sjogren's syndrome: Findings from the NIH cohort. AB - INTRODUCTION: The introduction of new classification criteria for Sjogren's syndrome, known as the 2016 American College of Rheumatology/European League against Rheumatism Classification Criteria (ACR-EULAR), created a need for the evaluation of its performance in an external cohort. The purpose of this study was to compare the performance of the 2016 ACR-EULAR classification set with the widely used American-European Consensus Group Classification criteria (AECG) in the cohort at the National Institutes of Health, USA, and to compare the performance of the sets in classifying both primary and secondary Sjogren's syndrome (pSS and sSS). METHODS: The study cohort at the NIH (N = 1,303) was enrolled for clinical suspicion of SS. Participants were classified as SS, pSS, and sSS according to both classification sets. Performance of 2016 ACR-EULAR and AECG sets was compared holding each as gold standard to the other. Statistical analysis of test diagnostics and agreement between the two sets were undertaken. RESULTS: By the AECG set, 701 were classified as having SS (627 pSS, 74 sSS) and 714 were classified with SS (647 pSS, 67 sSS) by the 2016 ACR-EULAR set. Sensitivity and specificity of the two sets were comparable in classifying SS, pSS, and sSS. There was high agreement between the two sets for classifying SS (kappa = 0.79), pSS (kappa = 0.81), and sSS (kappa = 0.87). The specificity of the 2016 ACR-EULAR set was significantly higher for classifying sSS than pSS, while the sensitivity was similar for the two disease groups. However, this pattern was also exhibited by the AECG set. CONCLUSION: There was high agreement between the two classification sets with comparable performance diagnostics. There was no evidence of superior performance value by the new 2016 ACR-EULAR set over the AECG set, and the two sets were found to be equivalent. Findings from our cohort indicate that 2016 ACR-EULAR classification could be extended to classification of sSS. PMID- 29480636 TI - An evidence-based oral health promotion programme: Lessons from Leicester. AB - OBJECTIVES: To provide an overview and draw lessons from the establishment of a local oral health promotion programme for preschool children in Leicester, England (2013-2017). The article provides information on the strategic approach taken in Leicester, one of the most ethnically diverse cities in England, and also one of the most deprived. Over a third of children aged 3 years, and half of those aged 5 years, have experience of obvious dental decay. METHODS: A description of the evolution and development of the programme is provided along with commentary by the authors. This includes the origins, design and evaluation of the programme. RESULTS: Progress so far has been promising. There has been a statistically significant 8% decrease in the proportion of 5-year-old children in Leicester with dental decay from 2011/2012 to 2014/2015. This will need to be sustained and further developed to deliver the 10% reduction required within the strategy. CONCLUSIONS: The successful implementation of a local oral health improvement programme in Leicester has required leadership to coordinate a multiagency partnership approach to embedding effective concepts and realising opportunities collaboratively. However, longer term sustainability remains a concern. PMID- 29480637 TI - Issues with the surgical treatment of antiresorptive agent-related osteonecrosis of the jaws. AB - Antiresorptive agent-related osteonecrosis of the jaw is a rare but significant complication in patients using antiresorptive agents such as bisphosphonates and denosumab. Although the disease is well recognized, and many studies have been performed on the management of this condition, the treatment of severe osteonecrosis is still a challenge. Most recent studies have shown an advantage of surgical treatment over conservative treatment for stage 2/3 patients, but there is no consensus on the appropriate surgical procedures for antiresorptive agent-related osteonecrosis of the jaw. Furthermore, patients with severe systemic conditions may not be appropriate for extensive surgical treatment, and the treatment protocol for such patients has not been established. In this review, issues regarding the current surgical treatment for antiresorptive agent related osteonecrosis of the jaws are discussed, with an emphasis on the clinical aspects. PMID- 29480638 TI - Shorter specialist time intervals are associated with advanced stage on symptomatic oral cancer. AB - OBJECTIVES: As longer times from the first symptom to diagnosis and treatment of oral cancers have been linked to poorer outcomes, this study investigates the contribution of the specialist to this time (STI). SUBJECTS AND METHODS: A series of 228 oral/oropharyngeal squamous cell carcinoma patients were retrospectively studied to determine the STI and its related factors. RESULTS: Patients were mostly males (n = 170; 74.5%), (50.7% stages I-II), mean age = 61.4 +/- 12.5 years. The STI median was 6 days (X+/-SD:6.8 +/- 5.6 days). Time first symptom to diagnosis was 64 days (X+/-SD:91.0 +/- 84.6 days). Univariate regression unveiled a significant association between STI and TNM stage, which was confirmed by multivariate regression. CONCLUSIONS: Specialist time interval is a short time interval in oral cancer diagnosis, imposing a limited time burden in the context of the whole interval until diagnosis. However, there seems to be room for improvement and a possible target for future interventions to shorten STI particularly for patients at early stages after their disease has been disclosed. PMID- 29480639 TI - Response of epithelial cells infected by Treponema denticola. AB - OBJECTIVE: In the gingival crevice, the interaction between epithelial cells and periodontopathic bacteria is important for the development of periodontitis. Treponema denticola is a major pathogen of chronic periodontitis and possesses several virulence factors, such as major surface protein (Msp) and prolyl phenylalanine-specific protease (dentilisin). Here, we investigated the behaviours of epithelial cells infected with T. denticola by measuring the expression of interleukin (IL)-1beta, IL-6, beta defensin 2 (BD-2) and heat-shock protein 70 (HSP70). METHODS: Epithelial cells were infected with T. denticola wild-type strain, Msp-deficient mutant or dentilisin-deficient mutant, and the expression levels of the above targets were analysed by polymerase chain reaction. RESULTS: Infection with T. denticola wild-type strain and mutants induced the production of IL-6 and HSP70. The level of BD-2 induced by T. denticola wild-type strain at 24 hr was significantly higher than that of the dentilisin-deficient mutant. The level of IL-1beta mRNA in the wild-type strain and dentilisin-deficient mutant was slightly lower than that in the uninfected control. CONCLUSION: These results suggest that the levels of BD-2 were affected by Msp and dentilisin. This effect may contribute to the disruption of the response of epithelial cells to eradicate T. denticola. PMID- 29480640 TI - Cone beam computerized tomography sialography-An emerging novel diagnostic tool for Sjogren's syndrome. PMID- 29480641 TI - Human- and mouse-derived neurons can be simultaneously obtained by co-cultures of human oral mucosal stem cells and mouse neural stem cells. AB - OBJECTIVE: To observe simultaneous differentiation and analyse possible interactions between co-cultured human oral mucosal stem cells (hOMSC) and mouse neural stem cells (mNSC). MATERIALS AND METHODS: hOMSC and mNSC were co-cultured in mouse and in human medium, and their immunocytochemical characterization to detect survival rate and differentiation pattern was performed. Co-cultures in different media were compared to hOMSC in human medium and mNSC in mouse medium as controls. RESULTS: Co-culture of hOMSC and mNSC in medium for human cells led to normal differentiation pattern of human cells, while mNSC were directed towards astrocytes. When the same cells were cultivated in the mouse medium, both cell types succeeded to form neurons, although mNSC showed a tendency to overgrow hOMSC. hOMSC alone in the human-specific medium differentiated towards ectodermal (Oct4, Map2) and mesodermal (Osterix) cell populations. mNSC in the mouse specific medium differentiated towards Map2-, beta3-tubulin- and NeuN-positive neurons. CONCLUSIONS: hOMSC and mNSC can form co-cultures. Different media considerably affected the differentiation pattern of co-cultures, whereas one cell population itself modestly influenced differentiation of the other cell type. The in vitro differentiation pattern of hOMSC in the mouse neural tissue environment suggested that hOMSC could be beneficial in the brain tissue affected by ischaemia. PMID- 29480642 TI - Preface. PMID- 29480643 TI - Role of Matrix Gla protein in midface development: Recent advances. AB - Craniofacial development is a delicate process that involves complex interactions among cells of multiple developmental origins, their migration, proliferation, and differentiation. Tissue morphogenesis of the craniofacial skeleton depends on genetic and environmental factors, and on specific signaling pathways, which are still not well understood. Developmental defects of the midface caused by the absence, delays, or premature fusion of nasal and maxillary prominences vary in severity; leading to clefts, hypoplasias, and midline expansion. In the current review, we focus on the importance of the chondrocranium in craniofacial growth and how its impaired development leads to midface hypoplasia. More importantly, we reported how Matrix Gla protein (MGP), a potent inhibitor of extracellular matrix mineralization, facilitates midface development by preventing ectopic calcification of the nasal septum. In fact, MGP may act as a common link in multiple developmental pathologies all showing midface hypoplasia caused by abnormal cartilage calcification. This brief review discusses the gap in knowledge in the field, raises pertinent questions, which remain unanswered, and sheds light on the future research directions. PMID- 29480644 TI - The oral mucosa: A barrier site participating in tissue-specific and systemic immunity. AB - In the oral cavity, the immune system is constantly exposed to unique tissue specific signals, including a rich community of commensal microbes and their metabolites, continuous tissue damage from mastication, and antigens from food and airborne particles. How this unique combination of signals participates in the training of specialized immunity at this site is not well understood, yet imbalance of local responses is linked to tissue-specific disease susceptibilities with the prototypic disease being periodontitis. However, the oral mucosa is also well recognized as a site where systemic inflammatory and autoimmune diseases often manifest, indicating that systemic immune deregulation is reflected in the function of the oral immune system. This commentary will discuss both aspects of compartmentalized and systemic immunity at the oral mucosa. PMID- 29480645 TI - Knowledge about oral leukoplakia for use at different levels of expertise, including patients. AB - OBJECTIVE: The purpose of this contribution is to discuss how the subject of oral leukoplakia might be communicated among the various healthcare workers and also among patients. MATERIAL AND METHODS: The discussion is based on the available literature and on many decades of clinical and histopathological experience of the author. RESULTS: The literature does not contain guidelines on what level of expertise can be expected from the various dental and medical healthcare workers in the field of oral leukoplakia, nor on how to communicate this disorder with patients. Based on personal experience, a number of suggestions have been proposed to overcome this shortcoming. CONCLUSION: Knowledge about oral leukoplakia varies among the various healthcare workers, depending on their level of expertise. Communication on this subject with patients should be in easy to understand wording, avoiding professional terminology as much as possible. PMID- 29480646 TI - The monoamine stabilizer (-)-OSU6162 prevents the alcohol deprivation effect and improves motor impulsive behavior in rats. AB - Alcohol craving, in combination with impaired impulse control, often leads to relapse. The dopamine system mediates the rewarding properties of alcohol but is also involved in regulating impulsive behavior. The monoamine stabilizer (-) OSU6162 (OSU6162) has the ability to stabilize dopamine activity depending on the prevailing dopaminergic tone and may therefore normalize the dopaminergic transmission regulating both alcohol use disorder and impulsivity. We have recently showed that OSU6162 attenuates voluntary alcohol consumption, operant alcohol self-administration, alcohol withdrawal symptoms and cue-induced reinstatement of alcohol seeking in rats. Here, we evaluated OSU6162's effects on motor impulsivity in Wistar rats that had voluntarily consumed alcohol or water for 10 weeks. The five-choice serial reaction time task was used to measure motor impulsivity, and a prolonged waiting period (changed from 5 to 7 seconds) was applied to induce premature responses. OSU6162-testing was conducted twice a week (Tuesdays and Fridays), every other week with regular baseline training sessions in between. We also tested OSU6162's effects on the alcohol deprivation effect in long-term alcohol drinking Wistar rats. The results showed that OSU6162 (30 mg/kg) pre-treatment significantly improved motor impulsivity in the five-choice serial reaction time task in both alcohol and alcohol-naive rats. Moreover, OSU6162 (30 mg/kg) pre-treatment prevented the alcohol deprivation effect, i.e. relapse-like drinking behavior after a forced period of abstinence in long-term drinking rats. In conclusion, our results provide further support for OSU6162 as a novel treatment for alcohol use disorder. The results further indicate that improvement of motor impulse control might be one mechanism behind OSU6162's ability to attenuate alcohol-mediated behaviors. PMID- 29480647 TI - Food protein-induced enterocolitis syndrome in a 6-year-old girl after ingestion of short-neck clam and squid. PMID- 29480648 TI - Prednisolone for pulmonary hemorrhage after Fontan procedure. PMID- 29480649 TI - Facile Synthesis of A 3D Flower-Like Mesoporous Ni@C Composite Material for High Energy Aqueous Asymmetric Supercapacitors. AB - A 3D flower-like mesoporous Ni@C composite material has been synthesized by using a facile and economical one-pot hydrothermal method. This unique 3D flower-like Ni@C composite, which exhibited a high surface area (522.4 m2 g-1 ), consisted of highly dispersed Ni nanoparticles on mesoporous carbon flakes. The effect of calcination temperature on the electrochemical performance of the Ni@C composite was systematically investigated. The optimized material (Ni@C 700) displayed high specific capacity (1306 F g-1 at 2 A g-1 ) and excellent cycling performance (96.7 % retention after 5000 cycles). Furthermore, an asymmetric supercapacitor (ASC) that contained Ni@C 700 as cathode and mesoporous carbon (MC) as anode demonstrated high energy density (60.4 W h kg-1 at a power density of 750 W kg-1 ). PMID- 29480650 TI - 2:2 Complexes from Diphenylpyridiniums and Cucurbit[8]uril: Encapsulation Promoted Dimerization of Electrostatically Repulsing Pyridiniums. AB - Rigid linear compounds G1 and G2, which contained two 4-phenylpyridinium (PhPy+ ) units, have been prepared to investigate their binding with cucurbit[8]uril (CB[8]). X-ray crystallographic structures revealed that in the solid state both compounds were included by CB[8], through antiparallel stacking, to form 2:2 quaternary complexes (G1)2 @(CB[8])2 and (G2)2 @(CB[8])2 . For the former complex, CB[8] entrapped G1 by holding two heterodimers of its Py+ and benzyl units, which were at opposite ends of the backbone. In contrast, for the first time, the second complex disclosed parallel stacking of two cationic Py+ units of G2 in the cavity of CB[8] in the solid state, despite the generation of important electrostatic repulsion. Isothermal titrations in water afforded high apparent association constants of 4.36*106 and 6.43*106 m-1 for 1:1 complexes G1@CB[8] and G2@CB[8], respectively, and 1 H NMR spectroscopy experiments in D2 O confirmed a similar stacking pattern to that observed in the solid state. A previous study and crystal structures of the 2:1 complexes formed between three new controls, G3-5, and CB[8] did not display such unusual stacking of the cationic Py+ unit; this may be attributed to the multivalency of the two CB[8] encapsulation interactions. PMID- 29480651 TI - Journal Club Challenge: enhancing student participation through gamification. PMID- 29480652 TI - Astragaloside IV inhibits TGF-beta1-induced epithelial-mesenchymal transition through inhibition of the PI3K/Akt/NF-kappaB pathway in gastric cancer cells. AB - Astragaloside IV (AS-IV) has been reported to possess anti-metastasis activity in cancer cells. However, it is unknown whether AS-IV could inhibit epithelial mesenchymal transition (EMT), a cellular de-differentiation program that promotes metastasis, in cancer cells. The aim of this study was to study the effect and mechanism of AS-IV on EMT in gastric cancer (GC) cells. The results showed that AS-IV significantly inhibited cell viability, invasion, and migration of GC cells. The E-cadherin to N-cadherin switch and expression of Vimentin and metastasis-related genes were induced by transforming growth factor beta1 (TGF beta1), whereas AS-IV reversed the induction. In addition, AS-IV inhibited TGF beta1-induced activation of PI3K/Akt/NF-kappaB. Inhibition of the PI3K/Akt/NF kappaB pathway reversed TGF-beta1-induced EMT. In conclusion, AS-IV inhibited TGF beta1-induced EMT through inhibition of the PI3K/Akt/NF-kappaB pathway in GC cells. AS-IV might be an effective candidate for the treatment for GC. PMID- 29480653 TI - Access to Enantioenriched Organosilanes from Enals and beta-Silyl Enones: Carbene Organocatalysis. AB - Herein, an efficient route to enantioenriched organosilanes, containing two consecutive stereogenic centers, from enals and beta-silyl enones under carbene organocatalysis is described. Under mild reaction conditions, this transition metal-free strategy exhibits a broad substrate scope, and excellent diastereo- and enantioselectivity. PMID- 29480654 TI - Long-Term Follow-Up of Lateral Canthal Resuspension. AB - PURPOSE: To evaluate the long-term results of lateral canthal resuspension over time. DESIGN: A cohort study of adults (n = 25, 45 eyelids) undergoing lateral canthal resuspension. METHODS: Marginal reflex distance 2 (MRD2), inferior scleral show, lateral canthal height, lateral canthal angle, horizontal palpebral aperture, and lateral scleral triangle area were measured preoperatively and at postoperative week 1, month 3, and the final follow-up visit. RESULTS: Minimum follow-up time was 6 months (mean, 15.1 months). At the final follow-up visit, MRD2 decreased by 0.41 +/- 0.14 mm, inferior scleral show decreased by 0.27 +/- 0.05 mm, and lateral canthal height increased by 0.81 +/- 0.15 mm. The overall function of time was found to be significant for change in MRD2 (P < 0.01). In multiple comparisons, all time point values were significantly different from one another (Bonferroni corrected, P < 0.05), except for 3 months and the final position, which were not. Similarly, the overall effect of time on lateral canthus position was also significant (P < 0.01). All time points were significantly different from one another (Bonferroni corrected, P < 0.05). The overall effect of time on inferior scleral show was also significant (P < 0.01). Differences were significant from preoperative to final postoperative position, although the other time points were not significant (Bonferroni corrected, P < 0.05). No complications were noted. CONCLUSIONS: Minimally invasive lateral canthal resuspension provides durable, albeit modest, improvements in MRD2, inferior scleral show, and lateral canthal height without significantly changing lateral canthal angle, horizontal palpebral aperture, or lateral scleral triangle area. PMID- 29480656 TI - Developing an integrated resource to promote oral health in nursing homes. AB - Public health is the responsibility of every nurse and nursing practice should adopt a life course approach to the promotion of health and well-being. This approach requires a renewed focus on health promotion interventions aimed at older people, including those resident in nursing homes. The oral health status of older people in nursing homes has been reported as suboptimal, predisposing them to poorer health-related quality of life. Interventions focusing on knowledge and behaviours related to oral health management for nurses, other caregivers and older people have the potential to improve the provision of oral care. This article discusses a project undertaken by a team of preregistration nursing students to plan and develop an integrated oral health promotion resource for older people in nursing homes. Healthy Smile, Healthy Me comprises a poster called five steps for oral hygiene and an oral health box. Initial feedback from a pilot of the resource in a nursing home is encouraging and research is planned to explore the feasibility, acceptability and efficacy of the resource. PMID- 29480655 TI - Sleep Duration in Infants Was Not Associated With Myopia at 3 Years. AB - PURPOSE: To investigate the association of sleep duration and quality at 12 months and myopia at 3 years. DESIGN: Cohort study. METHODS: The Growing Up in Singapore Towards Healthy Outcomes (GUSTO) birth cohort recruited pregnant women at 2 major public maternity hospitals (n = 1236). We included 376 children of Chinese, Malay, and Indian ethnicity who had completed caregiver questionnaires on the child's sleep at 12 months of age [Brief Infant Sleep Questionnaire (BISQ)] and also completed cycloplegic autorefraction and eye axial length (AL) measurement at 3 years of age. Data on total sleep duration and number of night wakings were collected by BISQ. Univariable and multivariable regression models adjusting for potential confounders (age, sex, ethnicity, parental myopia, maternal education level, outdoor time, near work, and height) were used. RESULTS: Thirteen (3.5%) participants were myopic and mean spherical equivalent (SE) was 0.89 diopters (D) (SD 0.88) at 3 years. Total sleep duration and number of night wakings at 12 months were not associated with SE at 3 years (P > 0.05). The total sleep duration (P = 0.07) and number of night wakings (P = 0.49) were not associated with AL in the multivariate model. Total sleep duration in tertile 2 was not associated with AL (P = 0.11) compared with tertile 1. Only total sleep duration in tertile 3 was associated with longer AL (P = 0.006), but there was no association with SE. CONCLUSIONS: Sleep duration and quality at 12 months of age were not associated with refractive error at 3 years. PMID- 29480657 TI - Practical strategies to help develop dementia-friendly hospital wards. AB - Hospital stays can have significant negative effects for people with dementia. This article explores methods of improving dementia care in general hospital wards. Taking its starting point as the importance of person-centred care, it explores ways of improving the ward environment, meaningful activities, personal history work, involving carers, and identifying and treating delirium. Practical strategies are suggested in each of these areas. The article acknowledges that implementing change can be challenging in NHS settings where wards are understaffed, and time is precious. However, it encourages all nurses working in these settings to recognise the importance of person-centred care for people with dementia and to make even small changes that can have a significant effect. PMID- 29480658 TI - Recognition and clinical management of sepsis in frail older people. AB - Sepsis is a common condition caused by the body's immune and coagulation systems being 'switched on' by the presence of infection, either through bacteria or viruses in the blood. If untreated, sepsis can be life-threatening and is a leading cause of death in hospital patients worldwide. However, awareness of sepsis is low. This article provides an overview of the important role played by nurses in acute hospital settings in the early identification and treatment of suspected sepsis in frail older patients, and in escalating the care and management of deteriorating patients. It also explores recommendations in the 2016 National Institute for Health and Care Excellence guideline on sepsis recognition, diagnosis and early management. PMID- 29480659 TI - Complex venous leg ulcer. PMID- 29480660 TI - Complex rheumatoid venous leg ulcer. PMID- 29480661 TI - An exuding, painful postoperative wound. PMID- 29480662 TI - Reperfusion injury in the lower limb. PMID- 29480663 TI - Efficacy of UrgoClean: a 3-year audit. PMID- 29480664 TI - Vaping Topography and Reasons of Use among Adults in Klang Valley, Malaysia AB - Background: Consistency and accuracy of results in assessing health risks due to vaping or e-cigarette use are difficultto achieve without established consumption data. The present report covers baseline data on vaping topography andreasons for use among local users in Klang Valley, Malaysia. Methods: An 80-item survey regarding socio-demographiccharacteristics, smoking topography and reasons for e cigarette use was employed to assess e-cigarette users recruitedfrom several public universities and private organisations. The survey questionnaire was self administered. Data wereanalysed using statistical software. Results: Eighty-six current e-cigarette users participated with more than half (51.2%)of them aged >= 25 years old. Significant proportions of the sample were single (51.2%), had a tertiary education level(63.5%) and a household income of less than USD1000 per month (65.2%). Median duration of e-cigarette use wasless than a year; users drew approximately 50 puffs per day and refilled twice a day. The majority (74%) used e-liquidscontaining nicotine with a concentration of 6 MUg/mL. Daily users spent USD18-23 per month. Reasons for using thee-cigarette included enjoyment of the products (85.9%), perception of lower toxicity than tobacco (87%), and the factthat it was a cheaper smoking alternative (61%). Conclusion: The data on e cigarette smoking topography obtainedin this study are novel. The reasons of usage were mainly users' enjoyment of e-cigarettes, preparation for quittingsmoking, perception of low toxicity and a healthier smoking substitute and cheapness in the long run. The resultsestablish basic knowledge for the local vaping topography and reference material for future e-cigarette-related research. PMID- 29480666 TI - An Altered Ratio of CD4+ And CD8+ T Lymphocytes in Cervical Cancer Tissues and Peripheral Blood - A Prognostic Clue? AB - Background : Several studies have provided evidence of CD4+ and CD8+ lymphocyte infiltration in variousmalignancies with probable implications for prognosis. Cervical cancer accounts for a major part of the cancer burdenin the developing world. Study of genetically and ethnically diverse Indian cervical cancer patients is necessary to assesseffects on lymphocytic infiltration of tumour tissue. Methods : This observational study was conducted over a periodof 12 months with selected cervical cancer patients meeting inclusion criteria. Samples of cervical cancer tissue andperipheral blood were obtained and tumour infiltration with CD4+ and CD8+ lymphocytes was noted. Cell numberswere quantified by flow-cytometry and proportions compared between tumour and peripheral blood samples. Results:Tumour infiltration was noted with both CD4+ (13.93+/-10.95) and CD8+ (19.5+/-12.05) lymphocyte subtypes. However,compared to peripheral blood, CD4+ cells were significantly less predominant in tumour tissue (p, 0.0013). There was astatistically significant (p, 0.0004) reversal of the ratio of CD4+ and CD8+ in the tumour tissue (0.68+/-0.39) comparedto peripheral blood (1.5+/-0.66) with maximal alteration in higher stage disease. Conclusion : The study revealed that Tlymphocyte infiltration of cervical cancer tissue occurs but the ratio of CD4+ to CD8+ subtypes is sifnificantly lowerthan in peripheral blood, especially with in advanced stages of disease. The clinical implications of such a reversal ofCD4+ and CD8+ ratios is unknown, but might have prognostic significance. PMID- 29480667 TI - Maturity Level of the Stigma Concept Associated with Cancer Diagnosis in the Nursing Literature AB - Objective: This study aimed to evaluate the maturity level of stigma as a concept in nursing and its relationshipto care provided for patients with cancer. Methods: The four principles of Morse and his colleagues were used toevaluate the maturity level of the stigma concept: epistemological, logical, pragmaticl, and linguistic. Analysis wasconducted with the literature published between 2006 and 2016. Results: The findings of this study suggest that theconcept of stigma in nursing is immature, defined inconsistently, and measured with different instruments. How stigmais defined can influence nurses in their assessment of patients with cancer and identification of their needs. Conclusion:Although extensive studies have been conducted in the field of mental illness, it is only recently that the effect of stigmaon treatment of cancer patients has attracted attention. Thus, substantial work yet needs to be done to understand thebreadth and scope of stigma impacting on individuals with cancer. PMID- 29480665 TI - AKAP4, SPAG9 and NY-ESO-1 in Iranian Colorectal Cancer Patients as Probable Diagnostic and Prognostic Biomarkers AB - Background and objectives: Colorectal cancer (CRC) is the most common gastrointestinal cancer and the secondleading cause of cancer death in women in the world. Cancer-Testis Antigens (CTAs) are a group of tumor-associatedproteins which typically are expressed in normal reproductive cells of men, but their expression in normal somatic cellsis silenced. CTAs, due to their limited expression pattern, are considered as promising targets for cancer diagnosis andimmuno-therapy. Methods: Expression of AKAP4, SPAG9 and CTAG1B genes from the CTAs family was studiedin both tumor and normal tissues of 62 Iranian CRC patients by RT-PCR with the aim of finding biomarkers for earlydetection and anticipated progression. Statistical analysis was performed SPSS software V22.0 to assess the significanceof any associations. Results: Elevated expression of SPAG9 and AKAP4 genes was observed in approximately 66%and 44% of tumours, respectively, as compared to adjacent non-cancerous tissues. While a significant association wasfound between AKAP4 gene expression and metastasis (P-value: 0.045), expression of the CTAG1B (NY-ESO-1) genewas not observed in our cases. Conclusion: AKAP4 and SPAG9 genes may find use as diagnostic biomarkers for CRCand AKAP4 may play an important role in progression to metastasis. PMID- 29480668 TI - Current status of endovascular catheter robotics. AB - In this review, we will detail the evolution of endovascular therapy as the basis for the development of catheter-based robotics. In parallel, we will outline the evolution of robotics in the surgical space and how the convergence of technology and the entrepreneurs who push this evolution have led to the development of endovascular robots. The current state-of-the-art and future directions and potential are summarized for the reader. Information in this review has been drawn primarily from our personal clinical and preclinical experience in use of catheter robotics, coupled with some ground-breaking work reported from a few other major centers who have embraced the technology's capabilities and opportunities. Several case studies demonstrating the unique capabilities of a precisely controlled catheter are presented. Most of the preclinical work was performed in the advanced imaging and navigation laboratory. In this unique facility, the interface of advanced imaging techniques and robotic guidance is being explored. Although this procedure employs a very high-tech approach to navigation inside the endovascular space, we have conveyed the kind of opportunities that this technology affords to integrate 3D imaging and 3D control. Further, we present the opportunity of semi-autonomous motion of these devices to a target. For the interventionist, enhanced precision can be achieved in a nearly radiation-free environment. PMID- 29480669 TI - Don't just sit there, move more! PMID- 29480670 TI - Ask the doctor: What is a "full metal jacket"? PMID- 29480671 TI - Ask the doctor: Beta blocker blues? PMID- 29480672 TI - Should you stop anti-clotting drugs before a procedure? PMID- 29480673 TI - Novel drug delivery approaches in treating pulmonary fibrosis. PMID- 29480674 TI - Overweight vs overfat: Is your scale lying to you? PMID- 29480675 TI - Midlife heart health shows a link with future risk of dementia. PMID- 29480676 TI - Plant-based diets that protect your heart. PMID- 29480678 TI - Virtual Reality: Coming to a hospital near you. VR may take connected health to a whole new level. PMID- 29480679 TI - Ask What You Can Do for Your Country: A Career as a Scientist in the Federal Government. PMID- 29480680 TI - Modular cervical plate system for adjacent segment disease. AB - BACKGROUND: Adjacent-level disease after anterior cervical discectomy and fusion (ACDF) occurs in a significant proportion of patients and frequently requires revision operation. Methods using traditional plates typically require removal of the plate with anecdotally increased operative-time and morbidity. We review our experience in treating symptomatic adjacent-segment disease using both traditional plate removal and modular- plate system which allows for add-on plate components rather than removal of the entire plate. METHODS: Authors compared 64 patients with revision surgery using modular-plate system for adjacent- segment disease compared to 2-cohorts: (1) patients with traditional plate-removal and (2) patients with no prior plate. Clinical data included demographics, original surgery, presentation, current surgery, use of modular system, need for preoperative computed-topography, operative-time, blood loss, hospital stay, complications, length of dysphagia, neck disability index and time-until-fusion. RESULTS: Modular cervical plate system was utilized to prevent exposure and removal of the entire plate. The terminal portion of the plate was exposed and the distal module was removed. Following the discectomy/arthrodesis, a module plate extension was added onto the previous plate for extension of the prior instrumentation. Preoperative planning computed-topography was required in 26% of plate-removal and 17% of modular-plate cases. Revision surgery with no prior plate had reduced operative-time (77.0+/-18.1 min) when compared with plate removal (103.8+/-46.2 min; p<0.01). Blood-loss was lower for modular-plate system (38.3+/-20.4 mL) and no prior plate (38.4+/-12.6 mL) versus plate removal (78.2+/ 65.9 mL, p<0.01). Hospital stay was similar for all groups. No complications were experienced with modular-plate revision but plate removal and revision after no prior plate carried 7.7% and 10.5% complication rates, respectively. There was a trend towards lower dysphagia and neck disability index with modular-plate revision. CONCLUSIONS: Use of modular cervical plate system allows for extension of a plate and reduces morbidity when treating adjacent-segment disease. PMID- 29480681 TI - Analysis of the learning curve of the surgical procedure for the treatment of thoracic disc herniation using anterolateral trans-thoracic approach with the aid of Image-Guided System (IGS). AB - BACKGROUND: In surgery, the learning process represents one of the critical topics in the development of a young surgeon, where there is often no standardized learning program. The learning curve is defined by plotting proficiency as a function of time, or the number of repetitions. In this study, we have analyzed the learning process for a rare and surgically demanding pathology such as thoracic disc herniations (TDHs) treated with an antero-lateral trans-thoracic approach. METHODS: We analyzed a consecutive series of patients admitted with a diagnosis of TDHs. All of the patients underwent surgery using a standard antero-lateral trans-thoracic approach, assisted by Navigation System based on intraoperative 3D imaging performed with O-ArmTM system. RESULTS: 21 patients underwent surgery from January 2012 to June 2017. The time analysis shows a progressive reduction in time from the first to the last case with continued improvement in operating time but progressively less dramatic, this is explicable considering the classic learning curve model. Predictably, a slow learning curve was charted that is typical for a technically demanding procedure associated with a rare incidence of pathology. CONCLUSIONS: A learning curve is an easy and efficient way to gauge the growth of a surgeon. After 21 cases we obtained an intermediate profile of learning curve between steep and shallow. Despite there being different alternatives for speeding up the learning process, it is not always possible to standardize and reflect them in a learning process. Today, the use of technology is often considered in this but does not always affect the process itself. PMID- 29480682 TI - Intracranial aneurysms of the posterior circulation associated with a fenestration: a systematic review. AB - INTRODUCTION: A fenestration is an anatomical variation that most commonly involves vessels of the posterior circulation, which can predispose the formation of aneurysms and represents a further technical challenge for treatment. There are no large series and the incidence of complications is unknown. This paper is a systematic review on this topic. EVIDENCE ACQUISITION: The relevant English literature was reviewed and the data was extracted for each patient and collected in a pool. Demographics, localization of fenestration, morphology and aneurysm topography, admission and follow-up clinical status, treatments, complications and occlusion rate were recorded. EVIDENCE SYNTHESIS: We analyzed 62 articles published between 1992 and 2016 including 120/133 patients/aneurysms. The most commonly involved segment was the vertebro-basilar junction (82.5%), followed by the basilar trunk (10%). About 96.6% of reported aneurysms were saccular and 80.3% were ruptured. The preferred treatment was endovascular (86.67%) and a surgical clipping was reported in just over 13% of patients. A complete/almost complete occlusion was obtained in about 80% of cases, with a global rate of complications of 12.5%. A serious clinical condition at onset has been independently associated with poor outcome at multivariate analysis (P<.001). CONCLUSIONS: This systematic review has shown that endovascular occlusion is the treatment of choice for posterior circulation aneurysms associated with fenestrations, being highly effective, with an occlusion rate of about 80%, unchanged at follow-up. Although he presence of a fenestration can make more complex the aneurysm occlusion, and the occurrence of complications is not negligible, it is not considered a limiting condition for treatment. PMID- 29480683 TI - Relationship between pineal cyst size and aqueductal CSF flow measured by phase contrast MRI. AB - BACKGROUND: Most patients with pineal cysts referred for neurosurgical consultation have no specific symptoms or objective findings except for pineal cyst size to help in management decisions. Our purpose was to assess the relationship between pineal cyst size and aqueductal CSF flow using PC-MRI. METHODS: Eleven adult patients with pineal cysts (> 1-cm in size) referred for neurosurgical consultations were included. Cyst volume was calculated using 3D T1 images. PC-MRI in axial plane with velocity encoding of 5 cm/sec was used to quantitatively assess CSF flow through the cerebral aqueduct to determine the aqueductal stroke volume, which was then correlated to cyst size using Pearson's correlation. Pineal cysts were grouped by size into small (6/11) and large (5/11) using the median value to compare aqueductal stroke volume using Mann-Whitney test. RESULTS: Patients were 39 +/- 13 years (mean +/- SD) of age, and 10/11 (91%) were female. There was significant negative correlation between cyst volume and aqueductal stroke volume (r=0.74; p=0.009). Volume of small cysts (4954+/ 2157 mm3) was significantly different compared to large cysts (13752+/-3738 mm3; p= 0.008). The aqueductal stroke volume of patients harboring large cysts 33+/-8 MUL/cardiac cycle was significantly lower than that of patients with small cysts 96+/-29 MUL/cardiac cycle (p=0.008). CONCLUSIONS: Aqueductal CSF flow appears to decrease with increasing pineal cyst size. Our preliminary results provide first evidence that even in the absence of objective neurological findings or hydrocephalus; larger pineal cysts already display decreased CSF flow through the cerebral aqueduct. PMID- 29480677 TI - Antibiotic selection in the treatment of acute invasive infections by Pseudomonas aeruginosa: Guidelines by the Spanish Society of Chemotherapy. AB - Pseudomonas aeruginosa is characterized by a notable intrinsic resistance to antibiotics, mainly mediated by the expression of inducible chromosomic beta lactamases and the production of constitutive or inducible efflux pumps. Apart from this intrinsic resistance, P. aeruginosa possess an extraordinary ability to develop resistance to nearly all available antimicrobials through selection of mutations. The progressive increase in resistance rates in P. aeruginosa has led to the emergence of strains which, based on their degree of resistance to common antibiotics, have been defined as multidrug resistant, extended-resistant and panresistant strains. These strains are increasingly disseminated worldwide, progressively complicating the treatment of P. aeruginosa infections. In this scenario, the objective of the present guidelines was to review and update published evidence for the treatment of patients with acute, invasive and severe infections caused by P. aeruginosa. To this end, mechanisms of intrinsic resistance, factors favoring development of resistance during antibiotic exposure, prevalence of resistance in Spain, classical and recently appeared new antibiotics active against P. aeruginosa, pharmacodynamic principles predicting efficacy, clinical experience with monotherapy and combination therapy, and principles for antibiotic treatment were reviewed to elaborate recommendations by the panel of experts for empirical and directed treatment of P. aeruginosa invasive infections. PMID- 29480684 TI - Artificial neural networks can be effectively used to model changes of intracranial pressure (ICP) during spinal surgery using different non invasive ICP surrogate estimators. AB - BACKGROUND: Artificial Intelligence (AI) techniques play a major role in anesthesiology, even though their importance is often overlooked. In the extant literature, AI approaches, such as Artificial Neural Networks (ANNs), have been underutilized, mainly being used to model patient's consciousness state, to predict the precise amount of anesthetic gases, the level of analgesia, or the need of anesthesiological blocks, among others. In the field of neurosurgery, ANNs have been effectively applied to the diagnosis and prognosis of cerebral tumors, seizures, low back pain, and also to the monitoring of intracranial pressure (ICP). METHODS: A MultiLayer Perceptron (MLP), which is a feedforward ANN, with hyperbolic tangent as activation function in the input/hidden layers, softmax as activation function in the output layer, and cross-entropy as error function, was used to model the impact of prone versus supine position and the use of positive end expiratory pressure (PEEP) on ICP in a sample of 30 patients undergoing spinal surgery. Different non invasive surrogate estimations of ICP have been used and compared: namely, mean optic nerve sheath diameter (ONSD), non invasive estimated cerebral perfusion pressure (NCPP), pulsatility index (PI), ICP derived from PI (ICP-PI), and flow velocity diastolic formula (FVDICP). RESULTS: ONSD proved to be a more robust surrogate estimation of ICP, with a predictive power of 75%, whilst the power of NCPP, ICP-PI, PI, and FVDICP were 60.5%, 54.8%, 53.1%, and 47.7%, respectively. CONCLUSIONS: Our MLP analysis confirmed our findings previously obtained with regression, correlation, multivariate Receiving Operator Curve (multi-ROC) analyses. ANNs can be successfully used to predict the effects of prone versus supine position and PEEP on ICP in patients undergoing spinal surgery using different non invasive surrogate estimators of ICP. PMID- 29480685 TI - Efficacy of diffusion tensor imaging in the peri-operative evaluation of corticospinal tracts and gait improvement in normal pressure hydrocephalus. PMID- 29480686 TI - Recurrent meningitis after cysto-sphenoidostomy surgery for craniopharyngioma healed with removal of the implanted catheter. PMID- 29480687 TI - Non-obstructive hydrocephalus in a giant hemorrhagic prolactinoma. PMID- 29480688 TI - Conservative treatment for bilateral subdural hematomas: do patch and hold on. PMID- 29480690 TI - Does the endoscopic approach for lumbar disc prolapse decrease the risk of surgical site infection? PMID- 29480689 TI - UAIS Unruptured Aneurysms Italian Study (Dedicated to Massimo Collice). AB - BACKGROUND: Unruptured intracranial aneurysms (UIAs) are increasingly identified and are an important health-care burden; in the past they were commonly treated by surgical clipping, but nowadays endovascular coil embolization is increasingly employed as an alternative. METHODS: The Unruptured Aneurysms Italian Study (UAIS) is a multicentric cooperative prospective study aimed to delineate the "State of the Art" of UIAs treatment in Italy. 51 Italian Neurosurgical and Neuroradiological Units, representatives of all 20 Italian regions are involved in the Study. RESULTS: UAIS started on June 2003 and ended on July 2007. 1138 patients were collected by that date, but 181 were ruled-out due to severe violation of the protocol; 957 had complete data and could be statistically evaluated. CONCLUSIONS: UAIS demonstrates that the treatment of UAs, as performed in Italy as a Nation, is effective in improving long-term outcome vs natural history, particularly in aneurysms larger than 7 mm. PMID- 29480691 TI - Spinal hydatid cysts: a long life disease? PMID- 29480692 TI - The role of embolization before surgery for Spetzler-Ponce Class B and C brain AVMs: a prospective cohort series. AB - BACKGROUND: There is uncertainty of the benefit of preoperative embolization for Spetzler-Ponce Class (SPC) B and C arteriovenous malformations of the brain (bAVM). We examined whether or not preoperative embolization reduces the risk of permanent neurological deficits in SPC B and C bAVM surgery. METHODS: A prospective bAVM database (between1989 and 2015) was analyzed by regression for factors associated with a new permanent neurological deficit arising as a consequence of surgery or preoperative embolization with a modified Rankin Scale (mRS) score >1 at 12 months after surgery (adverse outcome). RESULTS: From a cohort of 785 patients with bAVM, 277 patients with SPC B or C bAVM were planned for treatment by surgery with (N.=67) or without (N.=210) preoperative embolization. There were significant differences (embolization versus no embolization) in: permanent neurological deficits leading to a mRS>1 (45% versus 20%, P<0.01); permanent neurological deficits leading to a mRS>2 (22% versus 8.1%, P=0.04); perioperative transfusion of 2.5 liters of blood or more (31% versus 16%, P<0.01); and, delayed postoperative hemorrhage (19% versus 8.1%, P=0.01). Regression analysis identified the following factors to be associated with increased likelihood of an adverse outcome: infratentorial location (odds ratio 0.441, P=0.045); SPC C bAVM (OR=0.501, P=0.034); earlier rank order of surgery (OR=0.994, P<0.01); and, preoperative embolization (OR=0.313, P<0.01). CONCLUSIONS: The use of preoperative embolization does not reduce adverse outcomes in SPC B and C bAVM. The role of embolization in the preoperative management of complex bAVM by surgery deserves further study. PMID- 29480693 TI - Cryptococcal-related meningoencephalitis in a patient with sarcoidosis and CD4 lymphocytopenia: thorough immunological characterization of lymphocyte homeostasis. AB - Cryptococcal meningoencephalitis is the most common infective complication observed in patients with CD4 lymphocytopenia, including sarcoidosis. T-cell immunity is well characterized in HIV-related infections and data regarding immunity in cryptococcosis animal models is now available; on the contrary, little is known about the immune status in non-HIV-related infections. We report on reduced production of new T cells observed in a patient with sarcoidosis, CD4 lymphocytopenia, and cryptococcal-related meningoencephalitis. Although T cells presented with an intact proliferative capacity, they were oligoclonally expanded showing an effector memory phenotype. However, the deleterious activity of effector memory cells could have been controlled by the expansion of the regulatory T cell subset with the highest suppressive capability. This information provide a better understanding of the immune response to cryptococcus occurring in non-HIV-associated cases, the predisposition to infection, and the role of different cell subtypes in controlling the disease in humans. PMID- 29480694 TI - The limits of transsellar/transtuberculum surgery for craniopharyngioma. AB - The proximity of craniopharyngiomas to vital neurovascular structures and their high recurrence rates make them one of the most challenging brain tumors to treat. Although surgery remains the first line of therapy and offers the best chance of radical resection and oncological cure, the high recurrence tendency of craniopharyngiomas, even after apparent total removal, often makes adjuvant treatment essential. The endoscopic endonasal approach (EEA) has been recently introduced as a treatment option for both pediatric and adult craniopharyngiomas, rapidly gaining wide acceptance over the traditional transcranial approaches. Although the primary role of EEA over traditional transcranial approaches has been slowly accepted in the literature, little has been written about the limitations and potential contraindications of this approach in the treatment of craniopharyngiomas. This article presents the advantages and highlights the limitations of endoscopic transsellar/transtuberculum surgery for craniopharyngiomas. In every case, surgery should be tailored to individuals based on their age and comorbidities, presenting symptoms, tumor characteristics, prior treatment and treatment tolerance, as well as the surgeon's preference based on personal experience and comfort. PMID- 29480695 TI - Modern classification and outcome predictors of surgery in patients with brain arteriovenous malformations. AB - Brain arteriovenous malformations (bAVM) are challenging lesions. Part of this challenge stems from the infinite diversity of these lesions regarding shape, location, anatomy, and physiology. This diversity has called on a variety of treatment modalities for these lesions, of which microsurgical resection prevails as the mainstay of treatment. As such, outcome prediction and managing strategy mainly rely on unraveling the nature of these complex tangles and ways each lesion responds to various therapeutic modalities. This strategy needs the ability to decipher each lesion through accurate and efficient categorization. Therefore, classification schemes are essential parts of treatment planning and outcome prediction. This article summarizes different surgical classification schemes and outcome predictors proposed for bAVMs. PMID- 29480696 TI - 2016 Guyton Physiology Educator of the Year Award. PMID- 29480697 TI - Innovative image sharing: Security, workflow, and interoperability innovations are key for successful image archiving and sharing. PMID- 29480699 TI - High School Students and Science Teachers Explore Physiology at EB. PMID- 29480698 TI - Michigan Physiological Society Third Annual Meeting Report (2015-2016). PMID- 29480700 TI - New Overtime Rules to Affect Postdoctoral Working Conditions. PMID- 29480701 TI - Enterprise imaging: The next big step toward interoperability. PMID- 29480702 TI - Deploying the next generation of standards: Interoperability takes center stage as providers, suppliers address vital need for data sharing among clinical heath IT systems. PMID- 29480703 TI - Better serve your populations: Cast a wide net for data to get comprehensive population health insights. PMID- 29480704 TI - Communication breakdown: Four tips to help data scientists and business leaders speak the same language. PMID- 29480705 TI - Making wearables meaningful: Factor IoT and wearable data into your analytics platform. PMID- 29480706 TI - Driving hospital efficiency: Data analytics is the key to insightful asset management. PMID- 29480707 TI - Physiology Is Alive and Well. Just Ask an Undergraduate Student. PMID- 29480708 TI - Dealing with the aftermath of a breach--a checklist. PMID- 29480709 TI - Professional Service: Why It Matters. PMID- 29480710 TI - Fast and Versatile Multiscale Patterning by Combining Template-Stripping with Nanotransfer Printing. AB - Metal nanostructures are widely used in plasmonic and electronic applications due to their inherent properties. Often, the fabrication of such nanostructures is limited to small areas, as the processing is costly, low-throughput, and comprises harsh fabrication conditions. Here, we introduce a template-stripping based nanotransfer printing method to overcome these limitations. This versatile technique enables the transfer of arbitrary thin film metal structures onto a variety of substrates, including glass, Kapton, silicon, and PDMS. Structures can range from tens of nanometers to hundreds of micrometers over a wafer scale area. The process is organic solvent-free, multilayer compatible, and only takes minutes to perform. The stability of the transferred gold structures on glass exceeds by far those fabricated by e-beam evaporation. Therefore, an adhesion layer is no longer needed, enabling a faster and cheaper fabrication as well as the production of superior nanostructures. Structures can be transferred onto curved substrates, and the technique is compatible with roll-to-roll fabrication; thus, the process is suitable for flexible and stretchable electronics. PMID- 29480711 TI - Highly Efficient Catalytic Cyclic Carbonate Formation by Pyridyl Salicylimines. AB - Cyclic carbonates as industrial commodities offer a viable nonredox carbon dioxide fixation, and suitable heterogeneous catalysts are vital for their widespread implementation. Here, we report a highly efficient heterogeneous catalyst for CO2 addition to epoxides based on a newly identified active catalytic pocket consisting of pyridine, imine, and phenol moieties. The polymeric, metal-free catalyst derived from this active site converts less reactive styrene oxide under atmospheric pressure in quantitative yield and selectivity to the corresponding carbonate. The catalyst does not need additives, solvents, metals, or co-catalysts, can be reused at least 10 cycles without the loss of activity, and scaled up easily to a kilogram scale. Density functional theory calculations reveal that the nucleophilicity of pyridine base gets stronger due to the conjugated imines and H-bonding from phenol accelerates the reaction forward by stabilizing the intermediate. PMID- 29480712 TI - Direct Observation of CH/CH van der Waals Interactions in Proteins by NMR. AB - van der Waals interactions are important to protein stability and function. These interactions are usually identified empirically based on protein 3D structures. In this work, we performed a solution nuclear magnetic resonance (NMR) spectroscopy study of van der Waals interactions by detecting the through-space vdw JCC-coupling between protein aliphatic side chain groups. Specifically, vdw JCC-coupling values up to ~0.5 Hz were obtained between the methyl and nearby aliphatic groups in protein GB3, providing direct experimental evidence for the van der Waals interactions. Quantum mechanical calculations suggest that the J coupling is correlated with the exchange-repulsion term of van der Waals interaction. NMR detection of vdw JCC-coupling offers a new tool to characterize such interactions in proteins. PMID- 29480713 TI - Exceptional Lithium Storage in a Co(OH)2 Anode: Hydride Formation. AB - Current lithium ion battery technology is tied in with conventional reaction mechanisms such as insertion, conversion, and alloying reactions even though most future applications like EVs demand much higher energy densities than current ones. Exploring the exceptional reaction mechanism and related electrode materials can be critical for pushing current battery technology to a next level. Here, we introduce an exceptional reaction with a Co(OH)2 material which exhibits an initial charge capacity of 1112 mAh g-1, about twice its theoretical value based on known conventional conversion reaction, and retains its first cycle capacity after 30 cycles. The combined results of synchrotron X-ray diffraction and X-ray absorption spectroscopy indicate that nanosized Co metal particles and LiOH are generated by conversion reaction at high voltages, and Co xH y, Li2O, and LiH are subsequently formed by hydride reaction between Co metal, LiOH, and other lithium species at low voltages, resulting in a anomalously high capacity beyond the theoretical capacity of Co(OH)2. This is further corroborated by AIMD simulations, localized STEM, and XPS. These findings will provide not only further understanding of exceptional lithium storage of recent nanostructured materials but also valuable guidance to develop advanced electrode materials with high energy density for next-generation batteries. PMID- 29480714 TI - Wheel-like Ln18 Cluster Organic Frameworks for Magnetic Refrigeration and Conversion of CO2. AB - Two isostructural 2D MOFs ([Ln7(CDA)6(HCOO)3(MU3-OH)6(H2O)8] n, abbreviated as 1 Gd and 2-Dy) were successfully synthesized under solvothermal conditions. The self-assembly of lanthanide(III) nitrate and 1,1'-cyclopropane-dicarboxylic acid (H2CDA) resulted in wheel-like Ln18 cluster second building units (SBU), which are further linked to six neighboring wheels to generate a 2D ordered honeycomb array. Both 1-Gd and 2-Dy exhibit high thermal stability and decompose above 330 degrees C. Moreover, they have good solvent stability in ten common solvents and pH stability with pH values from 1 to 13. Magnetic studies reveal that 1-Gd exhibits weak antiferromagnetic coupling between adjacent Gd3+ ions and has a large magnetocaloric effect of 47.30 J kg-1 K-1 (Delta H = 7.0 T at 2 K), while 2 Dy shows ferromagnetic interaction between adjacent Dy3+ ions. Interestingly, 1 Gd and 2-Dy can catalyze the cycloaddition of CO2 to epoxides under mild conditions and can be reused at least five rounds with negligible loss of catalytic performance. PMID- 29480715 TI - Scalable Nanostructured Carbon Electrode Arrays for Enhanced Dopamine Detection. AB - Dopamine is a neurotransmitter that modulates arousal and motivation in humans and animals. It plays a central role in the brain "reward" system. Its dysregulation is involved in several debilitating disorders such as addiction, depression, Parkinson's disease, and schizophrenia. Dopamine neurotransmission and its reuptake in extracellular space takes place with millisecond temporal and nanometer spatial resolution. Novel nanoscale electrodes are needed with superior sensitivity and improved spatial resolution to gain an improved understanding of dopamine dysregulation. We report on a scalable fabrication of dopamine neurochemical probes of a nanostructured glassy carbon that is smaller than any existing dopamine sensor and arrays of more than 6000 nanorod probes. We also report on the electrochemical dopamine sensing of the glassy carbon nanorod electrode. Compared with a carbon fiber, the nanostructured glassy carbon nanorods provide about 2* higher sensitivity per unit area for dopamine sensing and more than 5* higher signal per unit area at low concentration of dopamine, with comparable LOD and time response. These glassy carbon nanorods were fabricated by pyrolysis of a lithographically defined polymeric nanostructure with an industry standard semiconductor fabrication infrastructure. The scalable fabrication strategy offers the potential to integrate these nanoscale carbon rods with an integrated circuit control system and with other complementary metal oxide semiconductor (CMOS) compatible sensors. PMID- 29480717 TI - Genetic Code Expansion of the Silkworm Bombyx mori to Functionalize Silk Fiber. AB - The genetic code in bacteria and animal cells has been expanded to incorporate novel amino acids into proteins. Recent efforts have enabled genetic code expansion in nematodes, flies, and mice, whereas such engineering is rare with industrially useful animals. In the present study, we engineered the silkworm Bombyx mori to synthesize silk fiber functionalized with azidophenylalanine. For this purpose, we developed a bacterial system to screen for B. mori phenylalanyl tRNA synthetases with altered amino-acid specificity. We created four transgenic B. mori lines expressing the selected synthetase variants in silk glands, and found that two of them supported the efficient in vivo incorporation of azidophenylalanine into silk fiber. The obtained silk was bio-orthogonally reactive with fluorescent molecules. The results showed that genetic code expansion in an industrial animal can be facilitated by prior bacterial selection, to accelerate the development of silk fiber with novel properties. PMID- 29480716 TI - Probing Denatured State Conformational Bias in a Three-Helix Bundle, UBA(2), Using a Cytochrome c Fusion Protein. AB - Previous work with the four-helix-bundle protein cytochrome c' from Rhodopseudomonas palustris using histidine-heme loop formation methods revealed fold-specific deviations from random coil behavior in its denatured state ensemble. To examine the generality of this finding, we extend this work to a three-helix-bundle polypeptide, the second ubiquitin-associated domain, UBA(2), of the human DNA excision repair protein. We use yeast iso-1-cytochrome c as a scaffold, fusing the UBA(2) domain at the N-terminus of iso-1-cytochrome c. We have engineered histidine into highly solvent accessible positions of UBA(2), creating six single histidine variants. Guanidine hydrochloride denaturation studies show that the UBA(2)-cytochrome c fusion protein unfolds in a three-state process with iso-1-cytochrome c unfolding first. Furthermore, engineered histidine residues in UBA(2) strongly destabilize the iso-1-cytochrome c domain. Equilibrium and kinetic histidine-heme loop formation measurements in the denatured state at 4 and 6 M guanidine hydrochloride show that loop stability decreases as the size of the histidine-heme loop increases, in accord with the Jacobson-Stockmayer equation. However, we observe that the His27-heme loop is both more stable than expected from the Jacobson-Stockmayer relationship and breaks more slowly than expected. These results show that the sequence near His27, which is in the reverse turn between helices 2 and 3 of UBA(2), is prone to persistent interactions in the denatured state. Therefore, consistent with our results for cytochrome c', this reverse turn sequence may help to establish the topology of this fold by biasing the conformational distribution of the denatured state. PMID- 29480718 TI - Direct Determination of Atomic Structure and Magnetic Coupling of Magnetite Twin Boundaries. AB - Clarifying how the atomic structure of interfaces/boundaries in materials affects the magnetic coupling nature across them is of significant academic value and will facilitate the development of state-of-the-art magnetic devices. Here, by combining atomic-resolution transmission electron microscopy, atomistic spin polarized first-principles calculations, and differential phase contrast imaging, we conduct a systematic investigation of the atomic and electronic structures of individual Fe3O4 twin boundaries (TBs) and determine their concomitant magnetic couplings. We demonstrate that the magnetic coupling across the Fe3O4 TBs can be either antiferromagnetic or ferromagnetic, which directly depends on the TB atomic core structures and resultant electronic structures within a few atomic layers. Revealing the one-to-one correspondence between local atomic structures and magnetic properties of individual grain boundaries will shed light on in depth understanding of many interesting magnetic behaviors of widely used polycrystalline magnetic materials, which will surely promote the development of advanced magnetic materials and devices. PMID- 29480719 TI - Adenovirus Replication Cycle Disruption from Exposure to Polychromatic Ultraviolet Irradiation. AB - Polychromatic ultraviolet (UV) light with bandwidth of 20 nm and peak emission centered at 224, 254, or 280 nm (UV224, UV254, and UV280, respectively) were used to inactivate human adenovirus type 2 (HAdV-2). Quantitative polymerase chain reaction (qPCR) and reverse transcriptase qPCR assays were used to elucidate the step in the HAdV-2 replication cycle that was disrupted after UV exposure. UV treatment at any of the wavelengths analyzed did not inhibit association of HAdV 2 to the host cells even after exposure to a fluence (UV dose) that would produce a virus inactivation efficiency, measured by plaque assay, greater than 99.99%. In contrast, UV irradiation at all three peak emissions disrupted early E1A gene transcription and viral DNA replication, but different mechanisms appeared to be dominating such disruptions. UV224 seemed to have little effect on the integrity of the viral genome but produced a structural transformation of the viral capsid that may inhibit the delivery of viral genome into the host cell nucleus. On the other hand, UV254 and UV280 did not affect the integrity of the viral capsid, but the mutations they produced on the viral genome might cause the inhibition of the early gene transcription and DNA replication after the viral genome successfully translocated into the host cell nucleus. PMID- 29480721 TI - Enantioselective Synthesis of Nelfinavir via Asymmetric Bromocyclization of Bisallylic Amide. AB - We describe a concise enantioselective synthesis of the HIV-protease inhibitor nelfinavir (1) via a new route in which the key step is construction of the central optically active 1,2-amino alcohol framework via asymmetric bromocyclization of bisallylic amide with N-bromosuccinimide in the presence of a catalytic amount of ( S)-BINAP or ( S)-BINAP monoxide. The remaining alkene and bromo functionalities were used to install the requisite thioether and chiral perhydroisoquinoline units, respectively. PMID- 29480720 TI - A Pressure Test to Make 10 Molecules in 90 Days: External Evaluation of Methods to Engineer Biology. AB - Centralized facilities for genetic engineering, or "biofoundries", offer the potential to design organisms to address emerging needs in medicine, agriculture, industry, and defense. The field has seen rapid advances in technology, but it is difficult to gauge current capabilities or identify gaps across projects. To this end, our foundry was assessed via a timed "pressure test", in which 3 months were given to build organisms to produce 10 molecules unknown to us in advance. By applying a diversity of new approaches, we produced the desired molecule or a closely related one for six out of 10 targets during the performance period and made advances toward production of the others as well. Specifically, we increased the titers of 1-hexadecanol, pyrrolnitrin, and pacidamycin D, found novel routes to the enediyne warhead underlying powerful antimicrobials, established a cell free system for monoterpene production, produced an intermediate toward vincristine biosynthesis, and encoded 7802 individually retrievable pathways to 540 bisindoles in a DNA pool. Pathways to tetrahydrofuran and barbamide were designed and constructed, but toxicity or analytical tools inhibited further progress. In sum, we constructed 1.2 Mb DNA, built 215 strains spanning five species ( Saccharomyces cerevisiae, Escherichia coli, Streptomyces albidoflavus, Streptomyces coelicolor, and Streptomyces albovinaceus), established two cell free systems, and performed 690 assays developed in-house for the molecules. PMID- 29480723 TI - van der Waals interaction of HNCO and H2: Potential Energy Surface and Rotational Energy Transfer. AB - Isocyanic acid (HNCO) is the most stable of all its isomers; it has been observed repeatedly in many different conditions of the Interstellar Media, and its chemistry is poorly known. To quantitatively estimate the abundance of HNCO with respect to other organic molecules, we compute its rotational quenching rates colliding with H2, the most common gas in the gaseous Interstellar Media. We compute ab initio the van der Waals interaction HNCO-H2, in the rigid molecules approximation, with a CCSD(T)-F12a method. On the fitted ab initio surface, inelastic scattering cross sections and rates are calculated for a temperature range of 7-200 K, with the coupled-states quantum time-independent formalism. The critical densities are high enough to yield rotational temperatures of HNCO differing significantly from the kinetic temperature of H2, especially so for the shorter wavelengths observed at the ALMA interferometer. It is found that the quenching rates for collisions with ortho- or para-H2 differ greatly, opening the possibility of far from equilibrium populations of some rotational levels of HNCO. PMID- 29480722 TI - Physical Properties of Biomolecules at the Nanomaterial Interface. AB - The unique size and material dependent properties of nanoparticles have made them highly attractive for biological and medical applications. However, combining nanoparticles with biomolecules and biological environments has faced many challenges. These interface issues often involve protein denaturation, steric hindrance, and orientational issues for the biomolecule, which can impair function and decrease overall performance of the nanoparticle-biomolecule conjugate. Historically, our understanding of the physical and chemical properties of nanoparticle-biomolecule conjugates as appropriate tools and experimental techniques had to be determined. We discuss here selected examples investigating the fundamental physical properties of the interface between nanoparticles and DNA and proteins and protein coronas and how they have provided insight into the properties of the biomolecule when it is interfaced to a nanoparticle. PMID- 29480724 TI - Designing Realizable and Scalable Techniques for Practical Lithium Sulfur Batteries: A Perspective. AB - To progress from the coin lithium sulfur (Li-S) cell to practical applications, it would be necessary to investigate industrially scalable methods to produce high-quality and large quantities of Li-S configurations. In this Perspective, we focused on the feasibility of scalable production of high-quality and large quantities of cathode composite, the construction of highly safe and highly stable electrolyte, and durable lithium metal anode. The results presented here suggest that the construction of highly secondary microstructures from nanoparticles is the key solution to achieve scalable cathode composite. Developing unconventional electrolyte solvent is a meaningful approach to develop high safety Li-S batteries. The high performance and high stability of lithium metal anode will enlighten the practical application of Li-S batteries. This Perspective presents outlooks for the key scalable techniques of realizable Li-S cell in the near future and provides promising strategies to accomplish long cycle-life, high-energy-density Li-S batteries. PMID- 29480725 TI - Layer-by-Layer Assembled Microgels Can Combine Conflicting Properties: Switchable Stiffness and Wettability without Affecting Permeability. AB - Responsive interfacial architectures of practical interest commonly require the combination of conflicting properties in terms of their demand upon material structure. Switchable stiffness, wettability, and permeability, key features for tissue engineering applications, are in fact known to be exclusively interdependent. Here, we present a nanoarchitectonic approach that decouples these divergent properties by the use of thermoresponsive microgels as building blocks for the construction of three-dimensional arrays of interconnected pores. Layer-by-layer assembled poly( N-isopropylacrylamide- co-methacrylic acid) microgel films were found to exhibit an increase in hydrophobicity, stiffness, and adhesion properties upon switching the temperature from below to above the lower critical solution temperature, whereas the permeability of redox probes through the film remained unchanged. Our findings indicate that the switch in hydrophilicity and nanomechanical properties undergone by the microgels does not compromise the porosity of the film, thus allowing the free diffusion of redox probes through the polymer-free volume of the submicrometer pores. This novel approach for decoupling conflicting properties provides a strategic route for creating tailorable scaffolds with unforeseen functionalities. PMID- 29480726 TI - Pore Shape Defines Paths of Metastatic Cell Migration. AB - Invasion of dense tissues by cancer cells involves the interplay between the penetration resistance offered by interstitial pores and the deformability of cells. Metastatic cancer cells find optimal paths of minimal resistance through an adaptive path-finding process, which leads to successful dissemination. The physical limit of nuclear deformation is related to the minimal cross section of pores that can be successfully penetrated. However, this single biophysical parameter does not fully describe the architectural complexity of tissues featuring pores of variable area and shape. Here, employing laser nanolithography, we fabricate pore microenvironment models with well-controlled pore shapes, through which human breast cells (MCF10A) and their metastatic offspring (MCF10CA1a.cl1) could pervade. In these experimental settings, we demonstrate that the actual pore shape, and not only the cross section, is a major and independent determinant of cancer penetration efficiency. In complex architectures containing pores demanding large deformations from invading cells, tall and narrow rectangular openings facilitate cancer migration. In addition, we highlight the characteristic traits of the explorative behavior enabling metastatic cells to identify and select such pore shapes in a complex multishape pore environment, pinpointing paths of least resistance to invasion. PMID- 29480727 TI - Synthetic Access to the Mandelalide Family of Macrolides: Development of an Anion Relay Chemistry Strategy. AB - The mandelalides comprise a family of structurally complex marine macrolides that display significant cytotoxicity against several human cancer cell lines. Presented here is a full account on the development of an Anion Relay Chemistry (ARC) strategy for the total synthesis of (-)-mandelalides A and L, the two most potent members of the mandelalide family. The design and implementation of a three-component type II ARC/cross-coupling protocol and a four-component type I ARC union permits rapid access respectively to the key tetrahydrofuran and tetrahydropyran structural motifs of these natural products. Other highlights of the synthesis include an osmium-catalyzed oxidative cyclization of an allylic 1,3 diol, a mild Yamaguchi esterification to unite the northern and southern hemispheres, and a late-stage Heck macrocyclization. Synthetic mandelalides A and L displayed potent cytotoxicity against human HeLa cervical cancer cells (EC50, 1.3 and 3.1 nM, respectively). This synthetic approach also provides access to several highly potent non-natural mandelalide analogs, including a biotin-tagged mandelalide probe for future biological investigation. PMID- 29480728 TI - Comparative Ascaroside Profiling of Caenorhabditis Exometabolomes Reveals Species Specific (omega) and (omega - 2)-Hydroxylation Downstream of Peroxisomal beta Oxidation. AB - Chemical communication in nematodes such as the model organism Caenorhabditis elegans is modulated by a variety of glycosides based on the dideoxysugar l ascarylose. Comparative ascaroside profiling of nematode exometabolome extracts using a GC-EIMS screen reveals that several basic components including ascr#1 (asc-C7), ascr#2 (asc-C6-MK), ascr#3 (asc-DeltaC9), ascr#5 (asc-omegaC3), and ascr#10 (asc-C9) are highly conserved among the Caenorhabditis. Three novel side chain hydroxylated ascaroside derivatives were exclusively detected in the distantly related C. nigoni and C. afra. Molecular structures of these species specific putative signaling molecules were elucidated by NMR spectroscopy and confirmed by total synthesis and chemical correlations. Biological activities were evaluated using attraction assays. The identification of (omega)- and (omega - 2)-hydroxyacyl ascarosides demonstrates how GC-EIMS-based ascaroside profiling facilitates the detection of novel ascaroside components and exemplifies how species-specific hydroxylation of ascaroside aglycones downstream of peroxisomal beta-oxidation increases the structural diversity of this highly conserved class of nematode signaling molecules. PMID- 29480729 TI - Development of Health Research Structures Over the Last 25 Years: Main Achievements and Challenges. AB - BACKGROUND: In 1990, one of the most important strategies of supporting and managing reproductive research focused on development of research structures. This targeted vision, at the first step, mainly followed through creating research units. The present paper aims to explore the policies and strategies of medical research centers (MRCs)development, and its achievements and challenges over the last 25 years. METHODS: Based on expected outcomes of better directions of research activities aligned with the priorities and policies of research, the Deputy of Research and Technology of Ministry of Health and Medical Education (MOHME), initiated the set up and development of research units. RESULTS: During the last 24 years, the number of MRCs has increased from 1 in 1992 to 736 in 2016. The progressive trends of expansion of the research centers are affected by a complex set of influencing factors. At first steps of program, the process of establishment and development of research structures followed slow trends in few unstructured primary centers. From 2008 to 2012, a rapid investment in development of research structures in biomedicine fields led to numerous complex challenges in supervision and management of MRCs (MRCs). CONCLUSION: Participatory approach in research centers management, benefiting from all available capacities of research stakeholders, could be considered as a practical strategy for better management of limitations and achieving targeted goals. PMID- 29480730 TI - Medical Science and Research in Iran. AB - BACKGROUND: During the last 3 decades, Iran has experienced a rapid population growth and at the same time the health of Iranian people has improved greatly. This achievement was mainly due to training and availability of health manpower, well organized public health network and medical science and research improvement. In this article, we aimed to report the relevant data about the medical science and research situation in Iran and compare them with other countries. METHODS: In this study, after reviewing science development and research indicators in medical sciences with participation of key stakeholders, we selected 3 main hybrid indexes consisting of "Research and Development (R&D) expenditures," "Personnel in Science and Technology sector" and "knowledge generation" for evaluation of medical science and research situation. Data was extracted from reliable databases. RESULTS: Over the past decade, Iran has achieved significant success in medical sciences and for the first time in 2015 based on Scopus index, Iran ranked first in the number of published scientific papers and number of citations in the region and among all Islamic countries. Also, 2% of the world's publications belong to Iran. Regarding innovation, the number of Iranian patents submitted to the United States Patent and Trademark Office (USPTO) was 3 and 43 in 2008 and 2013, respectively. In these years, the number of personnel in science and technology sectors including post graduate students, researchers and academic members in universities of medical sciences (UMSs) have increased. The female students in medical sciences field account for about twothirds of all students. Also, women comprise about one-third of faculty members. Since 5 years ago, Iran has had growth in science and technology parks. These achievements were attained in spite of the fact that research spending in Iran was still very low (0.5% of gross domestic product [GDP]) due to economic hardships and sanctions. CONCLUSION: Medical science and research development has been at least partially due to health technological development, training and availability of health manpower and improvement of overall health status in Iran compared to other Islamic countries. PMID- 29480731 TI - Research Ranking of Iranian Universities of Medical Sciences Based on International Indicators: An Experience From I.R. of Iran. AB - BACKGROUND: In recent years, international ranking systems have been used by diverse users for various purposes. In most of these rankings, different aspects of performance of universities and research institutes, especially scientific performance, have been evaluated and ranked. In this article, we aimed to report the results of research ranking of Iranian universities of medical sciences (UMSs) based on some international indicators in 2015. METHODS: In this study, after reviewing the research indicators of the majority of international ranking systems, with the participation of key stakeholders, we selected eight research indicators, namely research output, high-quality publications, leadership, total citations, citations per paper in 2015, papers per faculty member and h-index. The main sources for data gathering were Scopus, PubMed, and ISI, Web of Science. Data were extracted and normalized for Iranian governmental UMSs for 2015. RESULTS: A total of 18023 articles were indexed in 2015 in Scopus with affiliations of UMSs affiliation. Almost 17% of all articles were published in top journals and 15% were published with international collaborations. The maximum h-index (h-index = 110) belonged to Tehran University of Medical Sciences. The average paper per faculty member was 1.14 (Max = 2.5, Min = 0.13). The mean citation per published articles in Scopus was 0.33. CONCLUSION: Research ranking of Iranian UMSs can create favorable competition among them towards knowledge production. PMID- 29480732 TI - How to Assess Quality of Research in Iran, From Input to Impact? Introduction of Peer-Based Research Evaluation Model in Iran. AB - BACKGROUND: Research evaluation is a systematic and objective process to measure relevance, efficiency and effectiveness of research activities, and peer review is one of the most important tools for assessing quality of research. The aim of this study was introducing research evaluation indicators based on peer reviewing. METHODS: This study was implemented in 4 stages. A list of objective oriented evaluation indicators were designed in 4 axes, including; governance and leadership, structure, knowledge production and research impact. RESULTS: The top 10% medical sciences research centers (RCs) were evaluated based on peer review. Adequate equipment and laboratory instruments, high quality research publication and national or international cooperation were the main strengths in medical sciences RCs and the most important weaknesses included failure to adhere to strategic plans, parallel actions in similar fields, problems in manpower recruitment, knowledge translation & exchange (KTE) in service providers and policy makers' levels. CONCLUSION: Peer review evaluation can improve the quality of research. PMID- 29480733 TI - The Role of Medical Research Centers in Health Research System Promotion in I.R. of Iran: 2001-2014. AB - BACKGROUND: Research centers, defined as organized research units having research as their primary mission, are positioned as an organizational solution to tighten the knowledge to do gap in health research system (HRS). Therefore, this study aims to explore the roles of medical research centers (MRCs) in promoting HRS. METHODS: In this cross-sectional study, we reviewed the evaluation results of research performance of MRCs from 2001 to 2014. Data of evaluation indicators (in knowledge production and capacity building domains) were gathered and finally compared for these years. RESULTS: In the mentioned period, the number of medical research centers has grown by more than 11 folds. In the domain of knowledge production, the total number of published articles and published articles in ISI, Web of Science per researcher rose from 0.5 and 0.05 to about 3.5 and 1.2, respectively. The number of indexed articles in scientific international databases has increased more than 66 times and the total number of citations of MRCs' articles has increased to more than 80000. In the domain of capacity building, the trend of workshops and held congresses is ascending. CONCLUSION: MRCs are well empowered in knowledge production in national HRS. PMID- 29480735 TI - Diseases and Health Outcomes Registry Systems in I.R. Iran: Successful Initiative to Improve Public Health Programs, Quality of Care, and Biomedical Research. AB - Registration systems for diseases and other health outcomes provide important resource for biomedical research, as well as tools for public health surveillance and improvement of quality of care. The Ministry of Health and Medical Education (MOHME) of Iran launched a national program to establish registration systems for different diseases and health outcomes. Based on the national program, we organized several workshops and training programs and disseminated the concepts and knowledge of the registration systems. Following a call for proposals, we received 100 applications and after thorough evaluation and corrections by the principal investigators, we approved and granted about 80 registries for three years. Having strong steering committee, committed executive and scientific group, establishing national and international collaboration, stating clear objectives, applying feasible software, and considering stable financing were key components for a successful registry and were considered in the evaluation processes. We paid particulate attention to non-communicable diseases, which constitute an emerging public health problem. We prioritized establishment of regional population-based cancer registries (PBCRs) in 10 provinces in collaboration with the International Agency for Research on Cancer. This initiative was successful and registry programs became popular among researchers and research centers and created several national and international collaborations in different areas to answer important public health and clinical questions. In this paper, we report the details of the program and list of registries that were granted in the first round. PMID- 29480734 TI - The PERSIAN Cohort: Providing the Evidence Needed for Healthcare Reform. AB - In the past, communicable diseases caused the highest mortality in Iran. Improvements in socioeconomic status and living standards including access to safe drinking water, along with the inception of Health Houses in the 1980s, have changed disease patterns, decreasing the spread of and deaths from infectious and communicable diseases. The incidence and prevalence of non-communicable diseases (NCD), however, have now increased in Iran, accounting for nearly 80% of deaths and disabilities. Without interventions, NCD are predicted to impose a substantial human and economic burden in the next 2 decades. However, Iran's health system is not equipped with the necessary policies to combat this growth and must refocus and reform. Therefore, in the year 2013, the Ministry of Health and Medical Education funded a well-designed nationwide cohort study-Prospective Epidemiological Research Studies in IrAN (PERSIAN)-in order to assess the burden of NCD and investigate the risk factors associated with them in the different ethnicities and geographical areas of Iran. The PERSIAN Cohort, which aims to include 200000 participants, has 4 components: Adult (main), Birth, Youth and Elderly, which are being carried out in 22 different regions of Iran. Having an enormous dataset along with a biobank of blood, urine, hair and nail samples, the PERSIAN Cohort will serve as an important infrastructure for future implementation research and will provide the evidence needed for new healthcare policies in order to better control, manage and prevent NCD. PMID- 29480736 TI - Are Isolated and Complex Fiber Supplements Good Choices for Weight Management? A Systematic Review. AB - BACKGROUND: Previous trials have reported beneficial effects of isolated and complex fiber supplements in obesity treatment. However, recommending fiber supplements in obese subjects remains controversial. To the best of our knowledge, no systematic review has updated the data on the effects of fiber supplements on obesity since 2010 and the need exists for a systematic review on this topic. Accordingly, a systematic review was undertaken to summarize the efficacy of different types of fiber supplements as a complementary treatment for weight management. METHODS: We searched PubMed, Scopus, Cochrane Library and Google Scholar between January 2010 to August 2016 with no language restriction. Considering the inclusion/exclusion criteria and quality assessment score, finally 17 clinical trials met the eligibility criteria and were included. RESULTS: The present study indicated that the efficacy of various fiber supplements on losing weight is variable. Several mechanisms related to physicochemical properties of fibers such as solubility, fermentability and viscosity rates can be involved in their anti-obesity effects. Dextrin, Mannan (gum Arabic) and pectin-rich fiber (lupin kernel) with no dietary interventions indicated a reduction in body weight and energy intake, while from clinical point of view, their effects were not considerable. CONCLUSION: Overall, findings indicated that the efficacy of fiber supplements on obesity management is dependent on their contents and physicochemical properties. It seems that fiber supplements with no weight-loss interventions did not have considerable antiobesity effects. However, due to limited studies on each type of fiber, findings should be declared by caution. Additional research is needed on comparison of different fiber supplements in similar conditions to clarify the best type and dosage of fiber supplement as a complementary therapy in obesity management. PMID- 29480737 TI - Obstructive Tracheal Pseudomembrane. AB - Obstructive tracheal pseudomembrane is a rare complication of endotracheal intubation, which could cause fatal airway obstruction following extubation. Hereby, we reported a patient who had only undergone a short course of intubation for a laparoscopic cholecystectomy and developed progressive respiratory distress after extubation. PMID- 29480738 TI - Photoclinic. PMID- 29480739 TI - Homeopathy, Ritual and Magic. PMID- 29480740 TI - aBayesQR: A Bayesian Method for Reconstruction of Viral Populations Characterized by Low Diversity. AB - RNA viruses replicate with high mutation rates, creating closely related viral populations. The heterogeneous virus populations, referred to as viral quasispecies, rapidly adapt to environmental changes thus adversely affecting efficiency of antiviral drugs and vaccines. Therefore, studying the underlying genetic heterogeneity of viral populations plays a significant role in the development of effective therapeutic treatments. Recent high-throughput sequencing technologies have provided invaluable opportunity for uncovering the structure of quasispecies populations. However, accurate reconstruction of viral quasispecies remains difficult due to limited read lengths and presence of sequencing errors. The problem is particularly challenging when the strains in a population are highly similar, that is, the sequences are characterized by low mutual genetic distances, and further exacerbated if some of those strains are relatively rare; this is the setting where state-of-the-art methods struggle. In this article, we present a novel viral quasispecies reconstruction algorithm, aBayesQR, that uses a maximum-likelihood framework to infer individual sequences in a mixture from high-throughput sequencing data. The search for the most likely quasispecies is conducted on long contigs that our method constructs from the set of short reads via agglomerative hierarchical clustering; operating on contigs rather than short reads enables identification of close strains in a population and provides computational tractability of the Bayesian method. Results on both simulated and real HIV-1 data demonstrate that the proposed algorithm generally outperforms state-of-the-art methods; aBayesQR particularly stands out when reconstructing a set of closely related viral strains (e.g., quasispecies characterized by low diversity). PMID- 29480741 TI - Performance and Return to Sport After Thumb Ulnar Collateral Ligament Surgery in National Football League Players. AB - BACKGROUND: Acute ruptures of the ulnar collateral ligament (UCL) of the thumb are common injuries in sports. Surgical repair of complete tears has yielded excellent results in elite athletes. METHODS: National Football League (NFL) players who underwent thumb UCL surgery and matched controls were identified. Demographic and performance data were collected. Performance scores were calculated using a standardized scoring system. Return to sport (RTS) in the NFL was defined as playing in at least 1 NFL game after thumb UCL surgery. Comparisons between case and control groups and preoperative and postoperative time points were made using paired-samples Student t tests. RESULTS: Twenty-three players were identified (mean age: 28.8 +/- 3.4 years and mean experience in the NFL: 5.9 +/- 3.4 years). Twenty-two players (95.7%) were able to return to sport in the NFL at an average of 132.2 +/- 126.1 days. The overall 1-year NFL career survival rate of players undergoing thumb UCL surgery was 87.0%. There was not a statistically significant decrease in games per season and career length for any position following surgery. No positions had a significant difference in postoperative performance when compared with preoperative performance, and there was no significant performance difference postoperatively when compared with matched controls. CONCLUSIONS: There is a high rate of RTS in the NFL following thumb UCL surgery. Players who underwent thumb UCL surgery played in a similar number of games per season and had similar career lengths in the NFL as controls. No position group had any significant postoperative performance score differences when compared with postindex matched controls. PMID- 29480742 TI - Surveillance, Auditing, and Feedback Can Reduce Surgical Site Infection Dramatically: Toward Zero Surgical Site Infection. AB - BACKGROUND: We evaluated the Surveillance of Surgical Site Infection (SSI), Auditing, and Feedback (SAF) effect on the rate of compliance with an SSI care bundle and measured its effectiveness in reducing the SSI rate. METHOD: A prospective cohort study from January 2014 to December 2016 was classified into three phases: pre-SAF, early-SAF, and late-SAF. Pre-operative baseline characteristics of 24,677 patients who underwent orthopedic, cardiovascular thoracic surgery (CTVS) or urologic operations were recorded. Univariable analyses of the SSI rates in the pre-SAF and post-SAF phases were performed. Percentage compliance and non-compliance with each care component were calculated. Correlation between reduction in the SSI rate and increase in compliance with the pre-operative, peri-operative, and post-operative care-bundle components was performed using the Spearman test. RESULTS: There was a significant decrease in the SSI rate in orthopedic procedures that involved surgical implantation and in mitral valve/aortic valve (MVR/AVR) cardiac operations, with a relative risk (RR) ratio of 0.19 (95% confidence interval [CI] 0.12-0.31) and 0.08 (95% CI 0.03-0.22), respectively. The SSI rate was inversely correlated with the rate of compliance with pre-operative (r = -0.738; p = 0.037), peri-operative (r = - 0.802; p = 0.017), and post-operative (r = -0.762; p = 0.028) care bundles. CONCLUSION: Implementation of the Surveillance of SSI, Auditing, and Feedback bundle had a profound beneficial effect on the SSI rate, thereby reducing healthcare costs and improving patient quality of life. PMID- 29480743 TI - Clinical pharmacists in primary care: a safe solution to the workforce crisis? PMID- 29480744 TI - Foreword. PMID- 29480745 TI - An approach to assessing evidence that can inform clinical decision-making. AB - Following the Cochrane meta-analyses findings, doubts are being expressed about efficacy of silver dressings. However, the need for topical antimicrobials has not diminished, and the evidence for non-silver agents is no better than that for silver. This article describes an alternative system to Cochrane for analysing the evidence base, and suggests a practical approach to making a case for silver to procurement managers. PMID- 29480746 TI - Why use topical antiseptics? AB - Not all wounds heal in a timely fashion at an expected rate. In many cases, this delay in healing occurs because an infection is present. In some cases, the infection manifests as a wound biofilm, with the wound developing a subtle form of inflammation. In such instances, topical treatment with antiseptics is warranted. This article describes when they need to be used. PMID- 29480747 TI - An overview of the evidence on the efficacy of silver dressings. AB - While there is a plethora of clinical and anecdotal evidence on the efficacy of silver dressings, there is no rigorous RCT data to support this. This has led procurement managers to defer the inclusion of silver dressings on wound formularies, despite its clinical popularity. This article gives an overview of the evidence on topical antimicrobials, in order to determine whether there is a case for such a stance. PMID- 29480749 TI - Clinical Judgment Versus a Risk Index at the West Haven VA Center of Excellence in Primary Care Education. PMID- 29480748 TI - Precise Control of Target Temperature Using N6-Cyclohexyladenosine and Real-Time Control of Surface Temperature. AB - Targeted temperature management is standard of care for cardiac arrest and is in clinical trials for stroke. N6-cyclohexyladenosine (CHA), an A1 adenosine receptor (A1AR) agonist, inhibits thermogenesis and induces onset of hibernation in hibernating species. Despite promising thermolytic efficacy of CHA, prior work has failed to achieve and maintain a prescribed target core body temperature (Tb) between 32 degrees C and 34 degrees C for 24 hours. We instrumented Sprague Dawley rats (n = 19) with indwelling arterial and venous cannulae and a transmitter for monitoring Tb and ECG, then administered CHA via continuous IV infusion or intraperitoneal (IP) injection. In the first experiment (n = 11), we modulated ambient temperature and increased the dose of CHA in an attempt to manage Tb. In the second experiment (n = 8), we administered CHA (0.25 mg/[kg.h]) via continuous IV infusion and modulated cage surface temperature to control Tb. We rewarmed animals by increasing surface temperature at 1 degrees C h-1 and discontinued CHA after Tb reached 36.5 degrees C. Tb, brain temperature (Tbrain), heart rate, blood gas, and electrolytes were also monitored. Results show that titrating dose to adjust for individual variation in response to CHA led to tolerance and failed to manage a prescribed Tb. Starting with a dose (0.25 mg/[kg.h]) and modulating surface temperature to prevent overcooling proved to be an effective means to achieve and maintain Tb between 32 degrees C and 34 degrees C for 24 hours. Increasing surface temperature to 37 degrees C during CHA administration brought Tb back to normothermic levels. All animals treated in this way rewarmed without incident. During the initiation of cooling, we observed bradycardia within 30 minutes of the start of IV infusion, transient hyperglycemia, and a mild hypercapnia; the latter normalized via metabolic compensation. In conclusion, we describe an intravenous delivery protocol for CHA at 0.25 mg/(kg.h) that, when coupled with conductive cooling, achieves and maintains a prescribed and consistent target Tb between 32 degrees C and 34 degrees C for 24 hours. PMID- 29480750 TI - Protective Role of Myelocytic Nitric Oxide Synthases against Hypoxic Pulmonary Hypertension in Mice. AB - RATIONALE: Nitric oxide (NO), synthesized by NOSs (NO synthases), plays a role in the development of pulmonary hypertension (PH). However, the role of NO/NOSs in bone marrow (BM) cells in PH remains elusive. OBJECTIVES: To determine the role of NOSs in BM cells in PH. METHODS: Experiments were performed on 36 patients with idiopathic pulmonary fibrosis and on wild-type (WT), nNOS (neuronal NOS)-/-, iNOS (inducible NOS)-/-, eNOS (endothelial NOS)-/-, and n/i/eNOSs-/- mice. MEASUREMENTS AND MAIN RESULTS: In the patients, there was a significant correlation between higher pulmonary artery systolic pressure and lower nitrite plus nitrate levels in the BAL fluid. In the mice, hypoxia-induced PH deteriorated significantly in the n/i/eNOSs-/- genotype and, to a lesser extent, in the eNOS-/- genotype as compared with the WT genotype. In the n/i/eNOSs-/- genotype exposed to hypoxia, the number of circulating BM-derived vascular smooth muscle progenitor cells was significantly larger, and transplantation of green fluorescent protein-transgenic BM cells revealed the contribution of BM cells to pulmonary vascular remodeling. Importantly, n/i/eNOSs-/--BM transplantation significantly aggravated hypoxia-induced PH in the WT genotype, and WT-BM transplantation significantly ameliorated hypoxia-induced PH in the n/i/eNOSs-/- genotype. A total of 69 and 49 mRNAs related to immunity and inflammation, respectively, were significantly upregulated in the lungs of WT genotype mice transplanted with n/i/eNOSs-/--BM compared with those with WT-BM, suggesting the involvement of immune and inflammatory mechanisms in the exacerbation of hypoxia induced PH caused by n/i/eNOSs-/--BM transplantation. CONCLUSIONS: These results demonstrate that myelocytic n/i/eNOSs play an important protective role in the pathogenesis of PH. PMID- 29480751 TI - Cancer Patients Dying in the Intensive Care Units and Access to Palliative Care. AB - BACKGROUND: In France, cancer has become the leading cause of death. Intensive care units (ICU) focus on survival, which may not be an appropriate setting to provide palliative care (PC) as needed by cancer patients and families. OBJECTIVE: To describe the cancer patients who died in the ICU in 2010 in a French academic medical center. DESIGN: Retrospective study Measurements: We reviewed medical records of all cancer patients who died in the ICU in 2010. The information collected from electronic medical records included patient sociodemographics and clinical characteristics, PC service referral, and the date of first contact with PC. RESULTS: Among the 536 cancer patients who died in 2010, 42 (8%) died in the ICU. The cancers were hematological (21%), gastrointestinal (21%) and head and neck (21%). One patient had a PC referral versus 45% in the total population (p < 0.001) and the referral was the same day as the death. Eight (19%) patients had chemotherapy during their last month of life and 2 during the ICU hospitalization. Seventy-four per cent of patient admissions to the ICU related directly to malignancy. The mean time between diagnosis of cancer and death was 2.3 years (standard deviation, 4.4). CONCLUSIONS: Our work highlights the need for early PC in the illness trajectory of cancer patients to prevent the transfer of dying patients to the ICU. More studies are needed to understand the decision making leading to such transfers. PMID- 29480752 TI - Implementation of a Guided, Digital Cognitive Behavioral Program for Anxiety in Primary Care: Preliminary Findings of Engagement and Effectiveness. AB - BACKGROUND: Implementation of digital behavioral health programs in primary care (PC) can improve access to care for patients in need. INTRODUCTION: This study provides preliminary data on user engagement and anxiety symptom change among patients referred by their PC provider to a guided, mobile cognitive behavioral program, Lantern. MATERIALS AND METHODS: Adults aged 20-65 years with at least mild anxiety (GAD-7 >= 5) during routine clinical screening in two PC practices were offered Lantern. The primary outcome was self-reported anxiety collected at baseline and 2 months. Linear mixed effects modeling was used to examine anxiety symptom reduction from baseline to 2 months. Post hoc analyses evaluated how number of units completed, number of techniques practiced, and days of usage impacted symptom change. RESULTS: Sixty-three participants signed up for Lantern and had both baseline and 2- month GAD-7. A mixed effects model adjusted for age, gender, medical complexity score, and physical health found a significant effect of time on GAD-7 (beta = -2.08, standard error = 0.77, t(62) = -2.71, p = 0.009). Post hoc analyses indicated that mean number of units, techniques, and usage days did not significantly impact GAD-7 change over 2 months. However, there was significantly greater improvement in anxiety in participants who completed at least three techniques. DISCUSSION: Results benchmark to previous studies that have found statistically significant symptom change among participants after 4-9 weeks of face-to-face or Internet-based cognitive behavioral therapy (CBT). CONCLUSIONS: This study suggests that use of Lantern is associated with anxiety reduction and provides proof-of-concept for the dissemination and implementation of guided, CBT-based mobile behavioral health interventions in PC settings. PMID- 29480753 TI - Usage Patterns of a Mobile Palliative Care Application. AB - BACKGROUND: Fast Facts Mobile (FFM) was created to be a convenient way for clinicians to access the Fast Facts and Concepts database of palliative care articles on a smartphone or tablet device. We analyzed usage patterns of FFM through an integrated analytics platform on the mobile versions of the FFM application. OBJECTIVE: The primary objective of this study was to evaluate the usage data from FFM as a way to better understand user behavior for FFM as a palliative care educational tool. DESIGN: This is an exploratory, retrospective analysis of de-identified analytics data collected through the iOS and Android versions of FFM captured from November 2015 to November 2016. MEASUREMENTS: FFM App download statistics from November 1, 2015, to November 1, 2016, were accessed from the Apple and Google development websites. Further FFM session data were obtained from the analytics platform built into FFM. RESULTS: FFM was downloaded 9409 times over the year with 201,383 articles accessed. The most searched-for terms in FFM include the following: nausea, methadone, and delirium. We compared frequent users of FFM to infrequent users of FFM and found that 13% of all users comprise 66% of all activity in the application. CONCLUSIONS: Demand for useful and scalable tools for both primary palliative care and specialty palliative care will likely continue to grow. Understanding the usage patterns for FFM has the potential to inform the development of future versions of Fast Facts. Further studies of mobile palliative care educational tools will be needed to further define the impact of these educational tools. PMID- 29480754 TI - Spectral Radiance of Protoporphyrin IX Fluorescence and Its Histopathological Implications in 5-Aminolevulinic Acid-Guided Surgery for Glioblastoma. AB - OBJECTIVE: This study is intended to objectively clarify the relationship between the fluorescence intensity emitted by protoporphyrin IX (PpIX), which is a metabolite of 5-aminolevulinic acid (ALA), and histological findings during glioblastoma surgery. BACKGROUND: ALA is widely used for the intraoperative detection of tumors. There are several reports about the fluorescence of PpIX and the histological findings of tumors, but judgments about the fluorescence intensity depend largely on the subjective sense of each surgeon. METHODS: We quantified the PpIX fluorescence intensity emitted from tissue specimens using a spectroradiometer and evaluated the relationship between a spectral radiance of 635 nm and the histopathological features of surgical specimens of glioblastoma. Surgical samples from glioblastoma patients consist of a strongly fluorescent area (SFA) or vaguely fluorescent area (VFA). Hematoxylin and eosin staining, immunohistochemical Ki-67, and CD31 staining were performed to evaluate the cell density, MIB-1 index, and vascularity, respectively. The fluorescence intensities of each sample were compared with each histopathological parameter. RESULTS: Cell density, MIB-1 index, and total vascular area were significantly correlated with PpIX fluorescence radiance. 87.5% of SFA were judged to be tumor bulk consisting mostly of tumor cells and 12.5% peritumoral invaded brain. In the VFA, 100% of specimens were judged to be peritumoral invaded brain. CONCLUSIONS: ALA-induced PpIX fluorescence has quantitatively correlated well with histopathological malignant features both in SFA and VFA. These findings suggest that not only SFA but also VFA should be removed to the highest extent that does not cause neurological symptoms. PMID- 29480755 TI - Maternal Mortality Improvement Model with Broad Population Health Application. PMID- 29480756 TI - A Pilot Study to Evaluate Compliance with Guidelines for Preprocedural Reconsideration of Code Status Limitations. AB - BACKGROUND: Periprocedural providers are encountering more patients with code status limitations (CSLs) regarding their preferences for resuscitation and life sustaining treatment who choose to undergo palliative procedures. Surgical and anesthesia guidelines for preprocedural reconsideration of CSLs have been available for several years, but it is not known whether they are being followed in practice. OBJECTIVE: We assessed compliance with existing guidelines for patients undergoing venting gastrostomy tube (VGT) for malignant bowel obstruction (MBO), serving as an example of a palliative procedure received by patients near the end of life. DESIGN: Code status was determined at admission and throughout the hospitalization by chart review. Documentation of code status discussions (CSDs) was identified from provider notes and compared with existing guidelines. SETTING/SUBJECTS: An institutional database retrospectively identified patients who underwent VGT placement for MBO at two academic hospitals (2014-2015). MEASUREMENTS: We identified 53 patients who underwent VGT placement for MBO. Interventional radiologists performed 88% of these procedures. Other periprocedural providers involved in these cases included surgeons, gastroenterologists, anesthesiologists, and sedation nurses. RESULTS: CSLs were documented before the procedure in only 43% of cases, and a documented CSD with a periprocedural provider was identified in only 22% of CSL cases. Of all VGT placements performed in patients with CSLs before the procedure, only 13% were compliant with the guidelines of preprocedural reconsideration of CSLs. CONCLUSIONS: Increased compliance with guidelines published by the American Society of Anesthesiologists, the American College of Surgeons, and the Association of Perioperative Registered Nurses is necessary to ensure goal concordant care of patients with CSLs who undergo a procedure. Efforts should be made to incorporate these guidelines into the training of all periprocedural providers. PMID- 29480757 TI - PDGFR-beta modulates vascular smooth muscle cell phenotype via IRF-9/SIRT-1/NF kappaB pathway in subarachnoid hemorrhage rats. AB - Platelet-derived growth factor receptor-beta (PDGFR-beta) has been reported to promote phenotypic transformation of vascular smooth muscle cells (VSMCs). The purpose of this study was to investigate the role of the PDGFR-beta/IRF9/SIRT 1/NF-kappaB pathway in VSMC phenotypic transformation after subarachnoid hemorrhage (SAH). SAH was induced using the endovascular perforation model in Sprague-Dawley rats. PDGFR-beta small interfering RNA (siRNA) and IRF9 siRNA were injected intracerebroventricularly 48 h before SAH. SIRT1 activator (resveratrol) and inhibitor (EX527) were administered intraperitoneally 1 h after SAH induction. Twenty-four hours after SAH, the VSMC contractile phenotype marker alpha-smooth muscle actin (alpha-SMA) decreased, whereas the VSMC synthetic phenotype marker embryonic smooth muscle myosin heavy chain (Smemb) increased. Both PDGFR-beta siRNA and IRF9 siRNA attenuated the induction of nuclear factor kappaB (NF-kappaB) and enhanced the expression of alpha-SMA. The SIRT1 activator (resveratrol) preserved VSMC contractile phenotype, significantly alleviated neurological dysfunction, and reduced brain edema. However, these beneficial effects of PDGFR-beta siRNA, IRF9 siRNA and resveratrol were abolished by the SIRT1 inhibitor (EX527). This study shows that PDGFR-beta/IRF9/SIRT-1/NF-kappaB signaling played a role in the VSMC phenotypic transformation after SAH. Inhibition of this signaling cascade preserved the contractile phenotype of VSMCs, thereby improving neurological outcomes following SAH. PMID- 29480758 TI - Sports Injuries at the Rio de Janeiro 2016 Summer Olympics: Use of Diagnostic Imaging Services. AB - Purpose To describe the occurrence of imaging-depicted sports-related stress injuries, fractures, and muscle and tendon disorders during the 2016 Summer Olympic Games in Rio de Janeiro, Brazil. Materials and Methods Data on radiologic examinations were collected and retrospectively analyzed centrally by two board certified musculoskeletal radiologists (with a third musculoskeletal radiologist acting as an adjudicator in case of discrepancies). Descriptive data on all imaging examinations by using radiography, ultrasonography (US), and magnetic resonance (MR) imaging were collected and analyzed according to imaging modality, country of origin of the athletes, type of sport, and type and location of injury. Results There were 1101 injuries that occurred in 11 274 (9.8%) athletes. A total of 1015 radiologic examinations were performed, including 304 (30.0%) radiographic, 104 (10.2%) US, and 607 (59.8%) MR examinations. Excluding 10 athletes categorized as refugees, athletes from Africa had the highest utilization rate (14.8%, 148 of 1001). Athletes from Europe underwent the most examinations with 103 radiographic, 39 US, and 254 MR examinations. Gymnastics (artistic) had the highest percentage of athletes who underwent imaging (15.5%, 30 of 194). Athletics (track and field) had the most examinations (293, including 53 radiographic, 50 US, and 190 MR examinations). Conclusion The overall occurrence of imaging used to help diagnose sports-related injuries at the Rio de Janeiro 2016 Summer Olympics was 6.4% of athletes. In these cases, MR imaging comprised 60% of imaging utilization. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 29480759 TI - Evaluation of Antibacterial Efficiency of Different Root Canal Disinfection Techniques in Primary Teeth. AB - BACKGROUND: A successful primary root canal treatment depends on effective shaping and cleaning the root canal system and finally filling it with a hermetic sealer. Clinically, roots of primary teeth are difficult to shape and the irrigation/disinfection protocol has great importance on prognosis. OBJECTIVE: The present study evaluated the antibacterial efficiency of Endosafe (Orangedental GmbH & Co. KG), photo-activated disinfection (PAD; Orangedental GmbH & Co. KG), diode laser (Epic 10; Biolase, Inc.), ozone (O3, Ozonytron; Biozonix, Munchen, Germany), and sodium hypochloride applications in primary root canals that were infected with Enterococcus faecalis after standard mechanical instrumentation. METHODS: The study was conducted on roots of 100 human primary molar teeth, which were extracted due to excessive caries. The roots were divided in 5 groups with 15 roots in each root disinfection protocol. In addition, 15 samples and 10 samples served as positive and negative controls, respectively. The Shapiro-Wilk test, the Kruskal-Wallis test and then by post hoc group comparisons with the Bonferroni-adjusted Mann-Whitney U test (unpaired observations) was used. RESULTS: Sodium hypochlorite (NaOCl) exhibited the highest antibacterial effect (0 colony-forming units per mL). Diode laser irradiation was statistically more effective than the ozone, PAD, and Endosafe groups (p < 0.001). Endosafe, PAD, and ozone groups showed similar antibacterial effect (p > 0.05). Although not statistically significant, the Endosafe was more effective in reducing the bacterial count when compared with ozone and PAD. CONCLUSIONS: The five tested irrigation systems were shown to be effective in disinfection of the E. faecalis-contaminated primary root canals and best results were obtained with 2.5% NaOCl and diode laser. PMID- 29480760 TI - Malignant Mesothelioma and Its Non-Asbestos Causes. AB - CONTEXT: - Although many mesotheliomas are related to asbestos exposure, not all are, and there is increasing information on other causes of mesothelioma. OBJECTIVE: - To provide a review of non-asbestos causes for malignant mesothelioma. DATA SOURCES: - Review of relevant published literature via PubMed and other search engines. CONCLUSIONS: - Currently, most pleural mesotheliomas (70% to 90%) in men in Europe and North America are attributable to asbestos exposure; for peritoneal mesothelioma the proportion is lower. In North America few mesotheliomas in women at any site are attributable to asbestos exposure, but in Europe the proportion is higher and varies considerably by locale. In certain geographic locations other types of mineral fibers (erionite, fluoro-edenite, and probably balangeroite) can induce mesothelioma. Therapeutic radiation for other malignancies is a well-established cause of mesothelioma, with relative risks as high as 30. Carbon nanotubes can also induce mesotheliomas in animals but there are no human epidemiologic data that shed light on this issue. Chronic pleural inflammation may be a cause of mesothelioma but the data are scanty. Although SV40 can induce mesotheliomas in animals, in humans the epidemiologic data are against a causative role. A small number of mesotheliomas (probably in the order of 1%) are caused by germline mutations/deletions of BRCA1-associated protein-1 ( BAP1) in kindreds that also develop a variety of other cancers. All of these alternative etiologies account for a small proportion of tumors, and most mesotheliomas not clearly attributable to asbestos exposure are spontaneous (idiopathic). PMID- 29480761 TI - Eighth Edition Staging of Thoracic Malignancies: Implications for the Reporting Pathologist. AB - Context The Staging and Prognostic Factors Committee of the International Association for the Study of Lung Cancer, in conjunction with the International Mesothelioma Interest Group, the International Thymic Malignancy Interest Group, and the Worldwide Esophageal Cancer Collaboration, developed proposals for the 8th edition of their respective tumor, node, metastasis (TNM) staging classification systems. Objective To review these changes and discuss issues for the reporting pathologist. Data Sources Proposals were based on international databases of lung (N = 94 708), with an external validation using the US National Cancer Database; mesothelioma (N = 3519); thymic epithelial tumors (10 808); and epithelial cancers of the esophagus and esophagogastric junction (N = 22 654). Conclusions These proposals have been mostly accepted by the Union for International Cancer Control and the American Joint Committee on Cancer and incorporated into their respective staging manuals (2017). The Union for International Cancer Control recommended implementation beginning in January 2017; however, the American Joint Committee on Cancer has deferred deployment of the eighth TNM until January 1, 2018, to ensure appropriate infrastructure for data collection. This manuscript summarizes the updated staging of thoracic malignancies, specifically highlighting changes from the 7th edition that are relevant to pathologic staging. Histopathologists should become familiar with, and start to incorporate, the 8th edition staging in their daily reporting of thoracic cancers henceforth. PMID- 29480763 TI - An Exploration of Shift Work, Fatigue, and Gender Among Police Officers: The BCOPS Study. AB - The present study examined the association between shift work and fatigue among male ( n = 230) and female ( n = 78) police officers. A 15-year work history database was used to define dominant shifts as day, afternoon, or night. A 10 item questionnaire created from the Standard Shiftwork Index (SSI) assessed fatigue. Gender-stratified analyses of variance and covariance and Poisson regression were used to compare means and prevalence of individual items across shifts. No significant differences in total fatigue scores were observed across shifts. However, the prevalence of the fatigue item "feelings of tiredness" was 89% higher among male officers working the afternoon shift compared with officers working the day shift (prevalence ratio [PR] = 1.89, 95% confidence interval [CI] = [1.12, 3.23], p = .020), after adjustment for covariates. Women reported a lower prevalence of tiredness than men on the afternoon shift. Organizations with afternoon shift workers should consider reducing fatigue at work through education and other methods. PMID- 29480762 TI - Indeterminate Adnexal Cysts at US: Prevalence and Characteristics of Ovarian Cancer. AB - Purpose To assess the prevalence of indeterminate adnexal cysts in women presenting to academic medical centers for pelvic ultrasonography (US), determine the incidence of malignancy, and identify cyst and patient characteristics that are predictive of malignancy. Materials and Methods A multicenter study of US detected adnexal cysts with appropriate follow-up (surgical pathologic examination, imaging and/or clinical examination) was conducted from January 2008 to June 2012. Indeterminate cysts were classified as category 1 (typical benign appearing cysts >5 cm) or category 2 (cysts with avascular solid components) on the basis of a combination of definitions in the existing literature. The incidence of neoplasms and malignant tumors was calculated. Patient and cyst characteristics associated with neoplasm and malignant tumors were evaluated with the chi2 test or Fisher exact test for categorical variables and the t test for continuous variables. A backward stepwise logistic regression model was performed for two outcomes: (a) the presence of any neoplasm (benign or malignant) and (b) the presence of a malignant tumor. Results There were 1637 women with an adnexal cyst at US; 391 (mean age = 41.8 years +/- 13.5.1; range = 17-91 years) had an indeterminate adnexal cyst at US. The prevalence of indeterminate adnexal cysts was 23.9% (391 of 1637; 95% confidence interval [CI]: 0.22, 0.26). Three hundred three indeterminate cysts in 280 women (mean age = 42.9 years +/- 14.1; range = 17-88 years) had adequate follow-up. The incidence of ovarian neoplasms (benign and malignant) was 24.8% (75 of 303 cysts; 95% CI: 0.20, 0.30), and the incidence of malignant tumors was 3.6% (11 of 303 cysts; 95% CI: 0.02, 0.06). The proportion of ovarian neoplasms differed between category 1 and category 2 cysts (17.5% [25 of 143 cysts; 95% CI: 0.12, 0.25] vs 31.3% [50 of 160 cysts; 95% CI: 0.24, 0.39], respectively; P = .001). The proportion of malignant tumors differed between categories 1 and 2 cysts (0% [0 of 143 cysts] vs 6.9% [11 of 160 cysts; 95% CI: 0.03, 0.12]; P < .001). The presence of an avascular nodular component was a significant predictor of malignancy at stepwise logistic regression analysis (odds ratio = 2.83; P <= .0001; 95% CI: 1.69, 4.70). Conclusion The presence of an avascular nodular component was the most significant predictor of the presence of malignancy in indeterminate adnexal cysts. The risk of malignancy is higher with category 2 cysts than with category 1 cysts. (c) RSNA, 2018. PMID- 29480764 TI - Safety Gear Decontamination Practices Among Florida Firefighters: Analysis of a Text-Based Survey Methodology. AB - Despite the National Fire Protection Association (NFPA) 1851 Personal Protective Equipment Care and Maintenance guidelines, little is known about the routine cleaning of firefighter bunker gear. In collaboration with a large Florida firefighter union, a mobile phone text survey was administered, which included eight questions in an item logic format. In total, 250 firefighters participated in the survey of which 65% reported cleaning their bunker gear in the past 12 months. Approximately 32% ( n = 52) indicated that they had above average confidence in gear cleaning procedures. Arriving at a fire incident response was a significant predictor of gear cleaning in the 12 months preceding survey administration. Using mobile phone-based texting for periodic queries on adherence to NFPA cleaning guidelines and safety message distribution may assist firefighters to increase decontamination procedure frequency. PMID- 29480765 TI - Vitamin D deficiency and segregation status in prisoners. AB - Purpose The purpose of this paper is to investigate if any exposure to segregation minimal association in a single male prison population had any association with an increased risk of vitamin D deficiency. Design/methodology/approach A retrospective case study was undertaken with all inmates who had a 25-hyrdoxy-vitamin D test taken during the study period deemed eligible. Hand searching of the medical records by an independent party identified eligible participants whose data were recorded for analysis. Findings In total, 124 prisoners were deemed eligible for inclusion; 67 were vitamin D sufficient and 57 were vitamin D deficient by Australian standards. Time in segregation minimal association was shown not to be significant, however, smoking (OR 2.93, 95% CI 1.27-6.81, p=0.012) and having Asian ethnicity (OR 4.16, 95% CI 1.56-11.10, p=0.004) independently significantly increased the risk of vitamin D deficiency. Research limitations/implications This research is limited by its study design, small sample size and single location. Originality/value This paper presents the first published research into vitamin D levels in a prison population in Australia, and provides a basis for a larger prospective cohort study. PMID- 29480766 TI - Hazardous alcohol consumption in non-aboriginal male inmates in New South Wales. AB - Purpose The purpose of this paper is to examine correlates and predictors of hazardous drinking behaviour, that may be considered evidence of generalised strain, in a sample of incarcerated non-Aboriginal males in New South Wales, Australia. Design/methodology/approach Data were collected from 283 non Aboriginal male inmates as part of a larger epidemiological survey of inmates in NSW undertaken in 2015 by the Justice Health and Forensic Mental Health Network. Data relating to a range of social factors were selected with reference to relevant literature and assessed with regards their predictive value for scores from the Alcohol Use Disorders Identification Test (AUDIT). To facilitate regression analysis, variables were logically organised into historical factors or adult factors. Findings Almost all participants reported some history of alcohol consumption. Hazardous drinking was common among participants. While parental alcohol problems and adult drug use were the only correlates of AUDIT scores, parental misuse of alcohol was shown to be an important predictor of AUDIT scores in regression analysis. The role of parent gender was inconclusive. Previous incarceration as an adult, employment status, and drug use as an adult also predicted AUDIT scores. Originality/value Alcohol abuse is common among inmates and the use of alcohol is implicated in the commission of many offences. A better understanding of its genesis may inspire novel approaches to treatment, leading to improved health outcomes for inmates. PMID- 29480767 TI - Child incarceration and long-term adult health outcomes: a longitudinal study. AB - Purpose Although incarceration may have life-long negative health effects, little is known about associations between child incarceration and subsequent adult health outcomes. The paper aims to discuss this issue. Design/methodology/approach The authors analyzed data from 14,689 adult participants in the National Longitudinal Study of Adolescent to Adult Health (Add Health) to compare adult health outcomes among those first incarcerated between 7 and 13 years of age (child incarceration); first incarcerated at>or=14 years of age; and never incarcerated. Findings Compared to the other two groups, those with a history of child incarceration were disproportionately black or Hispanic, male, and from lower socio-economic strata. Additionally, individuals incarcerated as children had worse adult health outcomes, including general health, functional limitations (climbing stairs), depressive symptoms, and suicidality, than those first incarcerated at older ages or never incarcerated. Research limitations/implications Despite the limitations of the secondary database analysis, these findings suggest that incarcerated children are an especially medically vulnerable population. Practical implications Programs and policies that address these medically vulnerable children's health needs through comprehensive health and social services in place of, during, and/or after incarceration are needed. Social implications Meeting these unmet health and social service needs offers an important opportunity to achieve necessary health care and justice reform for children. Originality/value No prior studies have examined the longitudinal relationship between child incarceration and adult health outcomes. PMID- 29480768 TI - After a childhood with a parent in prison - relationships and well-being as a child and young adult. AB - Purpose The purpose of this paper is to explore whether young adults who had a parent in prison while growing up in Sweden are disadvantaged in terms of parental support, school well-being and functioning, and socioemotional and/or behavioral problems, compared to young adults whose parents were not in prison when they were a child. Design/methodology/approach Retrospective self-report information about parental imprisonment and childhood and adulthood welfare was collected from 2,500 Swedish young adults as part of the RESUME project. Of these, 52 who had had a parent in prison during their childhood were compared to the young adults who had not had a parent in prison, by measuring differences concerning their family relations, school well-being, and well-being as adults, and the risk of some events occurring later in life. Findings Having had a parent in prison was significantly related to feeling less loved during childhood, and having less contact and support from both parents during adulthood, in comparison with other young adults. In school they experienced lower well-being and were more often placed in special education than other children. They were at greater risk of not attending higher education, of planning or attempting suicide, and of being hospitalized for mental health problems than the rest of the young adults. Research limitations/implications Taking into consideration the complexity of childhood conditions and the limitations of retrospective data, prison, and social-services, professionals should pay special attention to the fact that a child has a parent in prison. Originality/value This is a unique study of young adults' experiences of a childhood with parent in prison. PMID- 29480769 TI - Social determinants of health among Canadian inmates. AB - Purpose International studies indicate that offenders have higher rates of infectious diseases, chronic diseases, and physical disorders relative to the general population. Although social determinants of health have been found to affect the mental health of a population, less information is available regarding the impact of social determinants on physical health, especially among offenders. The purpose of this paper is to examine the relationship between social determinants and the physical health status of federal Canadian offenders. Design/methodology/approach The study included all men admitted to federal institutions between 1 April 2012 and 30 September 2012 ( n=2,273) who consented to the intake health assessment. Logistic regression analyses were used to explore whether age group, Aboriginal ancestry, and each of the individual social determinants significantly predicted a variety of health conditions. Findings The majority of men reported having a physical health condition and had experienced social determinants associated with adverse health outcomes, especially men of Aboriginal ancestry. Two social determinants factors in particular were consistently related to the health of offenders, a history of childhood abuse, and the use of social assistance. Research limitations/implications The study is limited to the use of self-report data. Additionally, the measures of social determinants of health were indicators taken from assessments that provided only rough estimates of the constructs rather than from established measures. Originality/value A better understanding of how these factors affect offenders can inform strategies to address correctional health issues and reduce the impact of chronic conditions through targeted correctional education and intervention programmes. PMID- 29480770 TI - Reform of Italian forensic mental health care. Challenges and opportunities following Law 81/2014. PMID- 29480771 TI - An examination of consensual sex in a men's jail. AB - Purpose The purpose of this paper is to use secondary data from qualitative interviews that examined the sexual behaviors, HIV attitudes, and condom use of 17 gay, bisexual, and transgender women housed in a protective custody unit in the Los Angeles County Jail (Harawa et al., 2010), to develop a better understanding of the consensual sexual behaviors of male prisoners. Design/methodology/approach Study eligibility included: report anal or oral sex with another male in the prior six months; speak and understand English; and incarcerated in the unit for at least two weeks. Data analysis consisted of an inductive, qualitative approach. Findings Findings illuminate participants' experiences concerning how the correctional facility shaped their sexual choices and behaviors, and the HIV-risk reduction strategies they employed. Originality/value This study contributes to the prison-sex literature, and is timely, given current federal and local HIV/AIDS priorities. Recommendations that address male prisoners' sexual and health needs and risks are posed. PMID- 29480773 TI - Resumes en Francais. PMID- 29480772 TI - Growth and Decline in Language and Phonological Memory Over Two Years Among Adolescents With Down Syndrome. AB - Forty-two adolescents with Down syndrome (DS) ages 10 to 21 years completed a battery of language and phonological memory measures twice, 2 years apart. Individual differences were highly stable across two years. Receptive vocabulary scores improved, there was no change in receptive or expressive grammar scores, and nonword repetition scores declined. Digit memory and expressive vocabulary scores improved among younger adolescents, but generally held steady among older adolescents. These patterns may reveal key points in development at which interventions may be best applied. Further research is needed to understand specific processes in tasks that appear to be slowing or declining during adolescence. They may be important for understanding early aging and dementia in DS. PMID- 29480775 TI - Child Maltreatment Among Children With Intellectual Disability in the Canadian Incidence Study. AB - This study aims to compare, among a representative sample of substantiated child maltreatment cases, the characteristics of those with intellectual disability (ID) from those without ID. Using the 2008 Canadian Incidence Study of Reported Child Abuse and Neglect, 5,797 cases of substantiated maltreatment that involved children aged between 0 and 14 years were analyzed. One in 10 children (11.3%) was identified with ID. Results revealed functional problems to be higher among children with ID and their parents. Moreover, children with ID experienced more severe maltreatment, and were more often referred to ongoing child protection services. These findings suggest that maltreated children with ID are facing additional challenges that must be accounted for in service planning and delivery. PMID- 29480774 TI - The Emergence of Effortful Control in Young Boys With Fragile X Syndrome. AB - Effortful control, or the ability to suppress a dominant response to perform a subdominant response, is an early-emerging temperament trait that is linked with positive social-emotional development. Fragile X syndrome (FXS) is a single-gene disorder characterized by hallmark regulatory impairments, suggesting diminished effortful control. This study compared the development of effortful control in preschool boys with FXS ( n = 97) and typical development ( n = 32). Unlike their typical peers, the boys with FXS did not exhibit growth in effortful control over time, which could not be accounted for by adaptive impairments, FMR1 molecular measures, or autism symptoms. These results contribute to our understanding of the childhood phenotype of FXS that may be linked to the poor social-emotional outcomes seen in this group. PMID- 29480776 TI - Individual and Contextual Correlates of Frequently Involved Special Olympics Athletes. AB - It is important to understand factors associated with sport participation for youth with intellectual and developmental disabilities (IDD). With a sample of 414 Special Olympics (SO) athletes, this study examined how frequently involved athletes differ from other youth who are less involved in SO. Results showed that frequently involved athletes are older, have more sport-specific parental support, stronger athlete-coach relationships, and more positive SO experiences than other athletes. These factors were predictive of SO involvement, even after controlling for athlete characteristics, including behavior problems and adaptive behavior. Athletes with IDD have the potential to be highly involved in sports when external supports (i.e., coaches and parents) are strong. PMID- 29480777 TI - Physical Activity Research in Intellectual Disability: A Scoping Review Using the Behavioral Epidemiological Framework. AB - Through a scoping review, the current state of physical activity research in people with intellectual disability was examined. A search of publications between 2000 and 2014 retrieved 362 articles that met inclusion criteria. Eligible studies were coded according to the Behavioral Epidemiological Framework. Of the articles identified, 48% examined associations between physical activity and health outcomes, 9% developed or tested methodology to measure physical activity, 34% examined factors that influence physical activity, 8% evaluated interventions to change physical activity, and 1% examined the dissemination of physical activity/health promotion programming. The categories with lower proportions of studies represent the need for greater population specific research in physical activity measurement, interventional designs, and translational programs. PMID- 29480778 TI - Using Structural Analysis to Inform Peer Support Arrangements for High School Students With Severe Disabilities. AB - We examined the effects of peer support arrangements as an alternative to exclusive direct support from paraprofessionals for three high school students with severe disabilities in general education classrooms. We also explored the use of structural analysis as a data-based approach for further refining the interventions to enhance their impact in particular classrooms. Peer support arrangements were associated with substantial increases in social outcomes; academic engagement maintained or improved modestly for all participants. Moreover, structural analyses yielded findings used to adapt peer support arrangements to address students' individual needs. Although the effects of structural analysis-based adaptations resulted in increases in social responses for only one participant, levels of social interactions maintained, and improvements in academic engagement occurred for two participants. PMID- 29480779 TI - Resumenes al Espanol. PMID- 29480781 TI - Race in Supervision: Let's Talk About It. AB - Addressing race and racial trauma within psychotherapy supervision is increasingly important in psychiatry training. A therapist's ability to discuss race and racial trauma in psychotherapy supervision increases the likelihood that these topics will be explored as they arise in the therapeutic setting. The authors discuss the contextual and sociocultural dynamics that contributed to their own avoidance of race and racial trauma within the supervisory relationship. The authors examine the features that eventually led to a robust discussion of race and culture within the supervisory setting and identify salient themes that occurred during three phases of the conversation about race: pre-dialogue, the conversation, and after the conversation. These themes include building an alliance, supercompetence, avoidance, shared vulnerability, "if I speak on this, I own it," closeness versus distance, and speaking up. This article reviews the key literature in the field of psychiatry and psychology that has shaped how we understand race and racial trauma and concludes with guidelines for supervisors on how to facilitate talking about race in supervision. PMID- 29480782 TI - Preliminary Data about the Validation of a Self-Report for the Assessment of Interpersonal Guilt: The Interpersonal Guilt Rating Scales-15s (IGRS-15s). AB - The aim of this article is to present validation data about a self-report rating scale for the assessment of interpersonal guilt according to Control-Mastery Theory (CMT; Silbershatz, 2005; Weiss, 1993; Weiss, Sampson, & The Mount Zion Psychotherapy Research Group, 1986), the Interpersonal Guilt Rating Scale-15s (IGRS-15s). In order to perform the validation of this tool in an Italian sample we have collected a sample of 645 nonclinical subjects. They had to complete the IGRS-15s, the Scale for the Measurement of the Impending Punishment (SMIP; Caprara et al., 1990), the Interpersonal Guilt Questionnaire-67 (IGQ-67; O'Connor et al., 1997), the Psychological General Well-Being Index (PGWBI; Dupuy, 1984), and the Affective Neuroscience Personality Scales (ANPS; Davis, Panksepp, & Normansell, 2003), together with an ad-hoc questionnaire for collecting demographic data, the Socio-Demographical Schedule. We have performed a confirmatory factor analysis to verify if the four-factor solution based on CMT and replicated in previous research (Gazzillo et al., 2017) was confirmed. Then, we checked the retest reliability of IGRS-15s after four weeks in a random subsample of 54 subjects. In order to assess its concurrent and discriminant validity, we calculated the correlations between IGRS-15s assessment and SMIP and IGQ-67. Finally, to test its construct validity, we assessed the relationships between the IGRS-15s and the affective systems using the ANPS and the wellbeing assessed with the PGWBI. The data collected support the retest reliability and the concurrent and discriminant validity of the measure, and we have collected preliminary data about its construct validity. Examples of the possible clinical and research applications of this tool are discussed. PMID- 29480784 TI - Resilience, Trauma, and Coping. AB - The study and use of resilience is of the utmost importance to psychodynamic psychiatry. It is deeply ingrained in ideas about well-being and the treatment and care of patients. However, its neurobiology is incompletely understood, its terminology and relation to trauma and coping not well defined, and its efficacy underutilized in clinical practice. This article reviews the scientific literature on resilience, especially as it relates to trauma and coping. It also attempts to point the way for its greater application in psychiatry and mental health by utilizing resilience in more informed and individualized approaches. PMID- 29480783 TI - Psychodynamic Psychiatry in the 21st Century: Constructing a Comprehensive Science of Experience. AB - Psychodynamic psychiatry is not limited to psychotherapy practice. It is defined by systematic attention to the "common factors" underlying both psychotherapy and psychopharmacology outcomes, which include the patient's subjective systems of meaning and the complex flow of the patient-provider relationship in addition to the patient's "objective" psychopathology. It allows for a non-reductionist milieu where the meaning of the illness and the full complexity of the treatment process can be explored in order to achieve a qualitative and lasting change in the patient's psychopathology. The author proposes an integrated psychobiological model of psychiatric care where attention to the patient's subjective experience and the unique flow of the patient-provider relationship stand on an equal footing with the patient's objective behavioral and symptomatic presentation. This model provides a common foundation for diverse psychopharmacological and psychotherapeutic interventions to enable a paradigm shift from symptom- or syndrome-focused approach to individualized, process-oriented philosophy of care. Psychodynamically informed treatment provision helps to unify psychiatric practice by integrating objective, subjective, and intersubjective science in order to construct a systematic science of experience. PMID- 29480785 TI - Psychoanalysis Today-A Pseudoscience? A Critique of the Arbitrary Nature of Psychoanalytic Theories and Practice. AB - The article centers on psychoanalysts' indifferent attitude to the mutually exclusivity of theoretical conceptualizations and the ensuing technical rules for treatment. In the author's view this indifference is due to psychoanalysts being business people for whom the exchange value of their service is essentially of greater interest than its utility value, which latter is only of interest as a means of realizing the former. The author argues that, as a consequence of the disparate coexisting conceptualizations being treated as equally valid, psychoanalysis becomes a science without truth, that is, a pseudoscience, and demonstrates that all attempts to appropriate the epithet ornans "scientific" to psychoanalysis by linking its concepts to findings in areas beyond its conceptual field have failed. Finally, he offers a proposal of how the situation might be altered. PMID- 29480786 TI - The Role of Psychoeducation in Psychodynamic Psychotherapy. AB - Psychoanalysts have generally avoided discussion of psychoeducational interventions in the context of psychodynamic psychotherapy, despite education being a component of many psychoanalytic techniques. This wariness stems from Freud's early concerns about interventions that could be deemed "suggestion," and a misunderstanding of various aspects of neutrality, including viewing psychoeducational comments as over-gratifying or siding with the ego. Although potential pitfalls exist, the authors review clinical evidence and research that indicate the value of psychoeducational approaches for engaging patients in psychodynamic psychotherapy, considering alternative treatments, providing a psychodynamic formulation, and enhancing the therapeutic alliance. In this context there has been increasing inclusion of psychoeducational interventions in clinical descriptions and manuals of psychodynamic psychotherapy. Various aspects of psychoeducation are described, including education about the patient's problems, how the treatment works, how the mind works, relevant information from other areas of psychology and neuroscience, and how the world works. A case example is provided that further demonstrates the value of psychoeducation in the clinical setting. PMID- 29480787 TI - Redefining Identity after Trauma or Loss. AB - Individuals who experience trauma or loss perceive a seriously altered world. Survivors must revise their mental models of identity and adapt to new circumstances. When emotional disturbances lead to a person seeking treatment, useful therapy techniques include efforts at developing new self-concepts. A particular defense that can interfere with self-growth is dissociative shifting in a binary of self-states. Therapists can share observations of this obstacle and help patients form a balanced, nuanced, and coherent self-organization. PMID- 29480789 TI - Dynamic of alveolar physiology. PMID- 29480790 TI - Reply to Carter and Green: HSP90: an unappreciated mediator of cutaneous vascular adaptation? PMID- 29480788 TI - Commentaries on Viewpoint: Resistance training and exercise tolerance during high intensity exercise: moving beyond just running economy and muscle strength. PMID- 29480791 TI - Reply to Drs. Monjezi and Jamaati: Dynamic alveolar mechanics are more than a soap bubble on a capillary tube. PMID- 29480792 TI - HSP90: an unappreciated mediator of cutaneous vascular adaptation? PMID- 29480793 TI - The Efficacy of Puromycin and Adriamycin for Induction of Glomerular Failure in Larval Zebrafish Validated by an Assay of Glomerular Permeability Dynamics. AB - Defects in the glomerular filtration barrier (GFB) play a major role in the onset of human renal diseases. Highly ramified glomerular cells named podocytes are a critical component of the GFB. Injury to podocytes results in abnormal excretion of plasma proteins, which can lead to chronic kidney disease. The conserved paired nephron of larval zebrafish is an excellent model for assessing glomerular function and injury. The efficacy of two known podocyte toxins was tested to refine models of acute podocyte injury in larval zebrafish. The validated compound was then used to test a novel assay of the dynamics of abnormal protein excretion. Injected adriamycin was found to be unsuitable for induction of glomerular injury due to off-target cardiovascular toxicity. In contrast, puromycin treatment resulted in a loss of discriminative filtration, measured by excretion of 70 kDa dextran, and podocyte effacement confirmed by electron microscopy. The dynamics of dextran excretion during puromycin injury modeled the onset of glomerular damage within 24 hours postinjection. These data validate puromycin for induction of acute podocyte injury in zebrafish larvae and describe a semihigh-throughput assay for quantifying the dynamics of abnormal protein excretion. PMID- 29480795 TI - Comparison of two commercial quantitative PCR assays for EBV DNA detection and their correlation with the first WHO International Standard for EBV. AB - PURPOSE: There are few data on the performance of automated Epstein-Barr virus (EBV) PCR assays. This study compared EBV quantification for the kPCR PLX EBV DNA (kPCR; Siemens, France) and the EBV R-gene (R-gene; Argene, Biomerieux, France) assays and their correlation with the World Health Organization (WHO) standard. METHODOLOGY: WHO International Standard for EBV (WHO standard) dilution panels in different matrices were submitted to nucleic acid extraction with Versant kPCR Molecular Systems SP followed by the kPCR assay, or to nucleic acid extraction with the MagNA Pure LC System or NucliSENS easyMag followed by the R-gene assay. Seventy-four clinical specimens were tested in both assays. Bland-Altman analysis and linear regression analysis were performed. RESULTS: The correlation between the WHO standard diluted in different matrices and the R-gene and kPCR assays was good (R2 >0.96 and R2 >0.92, respectively). A matrix effect was observed. The correlation of quantitative results between both assays yielded a coefficient of determination R2 higher than 0.74. The quantification differences were within one log10 of the averaged results for 34 of the 38 specimens (89 %). Calibration to the WHO standard did not increase the comparability of quantitative results. CONCLUSIONS: The quantitative results of both assays showed reasonable correlation with each other and a good correlation with the WHO standard. PMID- 29480794 TI - Vitellibacter todarodis sp. nov., isolated from intestinal tract of a squid (Todarodes pacificus). AB - A Gram-stain-negative, non-motile, aerobic and rod-shaped or ovoid bacterial strain, designated MYP2-2T, was isolated from the intestinal tract of a squid (Todarodes pacificus) collected from the East Sea, South Korea, and subjected to a polyphasic taxonomic study. Strain MYP2-2T grew optimally at 30-35 degrees C and in the presence of 2.0 % (w/v) NaCl. A neighbour-joining phylogenetic tree based on 16S rRNA gene sequences revealed that strain MYP2-2T belonged to the genus Vitellibacter. Strain MYP2-2T exhibited 16S rRNA gene sequence similarities of 95.4-96.6 % to the type strains of Vitellibacter species and of less than 94.5 % to the type strains of other recognized species examined. Strain MYP2-2T contained menaquinone MK-6 as the predominant respiratory quinone and iso-C15 : 0 and iso-C17 : 0 3-OH as the major fatty acids. The major polar lipids detected in strain MYP2-2T were phosphatidylethanolamine and one unidentified lipid. The DNA G+C content of strain MYP2-2T was 41.6 mol%. Differential phenotypic properties, together with its phylogenetic distinctiveness, revealed that strain MYP2-2T is separated from recognized species of the genus Vitellibacter. On the basis of the data presented, strain MYP2-2T is considered to represent a novel species of the genus Vitellibacter, for which the name Vitellibacter todarodis sp. nov. is proposed. The type strain is MYP2-2T (=KCTC 62141T=NBRC 113025T). PMID- 29480796 TI - The molecular mechanism of contrast-induced nephropathy (CIN) and its link to in vitro studies on iodinated contrast media (CM). AB - Iodinated contrast media (iodinated CM) have increased ability to absorb x-rays and to visualize structures that normally are impossible to observe in a radiological examination. The use of iodinated CM may destory renal function, commonly known as contrast-induced nephropathy (CIN), which can result in acute renal failure (ARF). This review article mainly focuses on the following areas: (1) classifications of iodinated CM: ionic or non-ionic, high-osmolarity contrast media (HOCM), low-osmolarity contrast media (LOCM) and iso-osmolarity contrast media (IOCM); (2) an introduction to the physical and chemical properties of the non-ionic iodinated CM; (3) the management of anaphylactic reaction by iodinated CM; (4) a suggested single injection of adult doses and maximum dose for non ionic iodinated CM; (5) the molecular mechanism of contrast-induced nephropathy (CIN); (6) In vitro studies on iodinated CM. Based on above information, this review article provide an insight for understanding the drug safety of iodinated CM. PMID- 29480797 TI - Prevalence of integrons 1, 2, 3 associated with antibiotic resistance in Pseudomonas aeruginosa isolates from Northwest of Iran. AB - BACKGROUND: The presence of Class 1, 2 and 3 integrons in clinical isolates of Pseudomonas aeruginosa with multi-drug resistance phenotype has rendered the organism as a new concern. OBJECTIVE: This study aimed to investigate the prevalence of Class 1, 2 and 3 integrons in multi-drug resistant clinical isolates of Pseudomonas aeruginosa collected from hospitals in the city of Tabriz Materials and Methods: A total of 200 P. aeruginosa non-duplicated clinical isolates were collected from inpatients and outpatients in different wards of hospitals from May to November 2016. The bacteria were identified by conventional microbiological methods. Antibiotic susceptibility test was performed by disk diffusion method and the presence of integrons was analyzed by polymerase chain reaction (PCR). RESULTS: Colistin was the most effective antibiotic, while 98% of the isolates were resistant to cefotaxime. Fifty-three percent of the isolates were recorded as multi-drug resistant (MDR) phenotype; however, 27.5% of the isolates were resistant to more than 8 antibiotics. In this study, 55 (27.5%), 51 (25.5%), and 30 (15%) clinical isolates of P. aeruginosa were positive for Class 1, 2 and 3 integrons, respectively. aac(6)II in Class I integrons and dfrA1 in ClassII and aacA7 in Class II integrons were the most prevalent genes. Resistance to aminoglycosides were the most common genes harbored by integrons. CONCLUSION: The results of this study showed that the prevalence of Class 1, 2 and 3 in integron genes in most P. aeruginosa strains islated from different parts and equipment used in the hospital. The role of these transferable genetic agents has been proven in the creation of resistance. Therefore, it is essential to use management practices to optimize the use of antibiotics, preferably based on the results of antibiogram and trace coding genes for antibiotic resistance. PMID- 29480798 TI - The relationship between body mass index (BMI) and quality of life in Iranian primary school students in Tehran, Iran. AB - BACKGROUND: This study aimed to investigate the relationship between Body Mass Index (BMI) and quality of life in primary school students in Tehran. METHOD: In this cross-sectional study 829 primary school children and their parents participated. Healthrelated quality of life (HROOL) was evaluated with the Persian version of Pediatric Quality of Life Inventory (PedsQLTM4.0) questionnaire. According to objective measures of height and weight, children BMI computed, and adapted for age and gender. For data analysis we used Pearson correlation test, Independentsample t-test and ANOVA using SPSS version 18. RESULTS: Mean of children self-reported HRQOL total score was 82.05 +/- 12.04 and mean of parent proxyreported HRQOL total score was 81.66 +/- 12.81. Based on HRQOL subscale scores, social functioning was the highest subscale score of HRQOL (84.67 +/- 15.07) and the emotional subscale score was the lowest (77.79 +/- 17.26). Lower HRQOL scores were significantly correlated with Higher BMI and normal weight children had significantly higher HRQOL total score than obese children (P < 0.05). The difference between normal weight and overweight children in HRQOL total scores were not significant. Same results were obtained from parent proxy-reports and a good harmony between children self-report and parent proxy-report of HRQOL was perceived. CONCLUSION: This study showed that HRQOL of obese children were at the lower level in comparison to normal weight and overweight children. At further interventional studies these outcomes can be very important for improving quality of life in obese children. PMID- 29480799 TI - RSF-1 overexpression determines cancer progression and drug resistance in cervical cancer. AB - BACKGROUND: Remodeling spacing factor 1 (RSF-1/HBXAP) has been linked to a variety of cancer types, however, its roles and the therapeutic potential are not clear in cervical cancer. METHODS: RSF-1 expression in cancer tissues was analyzed by immunohistochemical staining followed by statistical analysis with SPSS. Anti-RSF-1 studies were performed by treating cells with specific siRNA or a dominant mutant form (RSF-D4). RESULTS: RSF-1 expression correlates with cancer progression that strongly-positive staining can be found in 67.7% carcinomas and 66.7% CIN lesions, but none in normal tissues. Such overexpression also associated with increased tumor size, poor differentiation, higher nodal metastasis and advanced clinical stages. Kaplan- Meier analysis confirmed that cancer patients with high RSF-1 levels exhibited a significantly shorter survival time than those with low RSF-1 levels. Downregulation of RSF-1 by siRNA silencing or RSF-D4 reduced cell growth and increased drug sensitivity toward paclitaxel treatment in HeLa cells. CONCLUSIONS: RSF-1 participates in the tumor progression of cervical cancer and could be considered as an early prognostic marker for cancer development and clinical outcome. Therapies based on anti-RSF-1 activity may be beneficial for patients with RSF-1 overexpression in their tumors. PMID- 29480801 TI - Late onset of biliopleural fistula following percutaneous transhepatic biliary drainage: a case report. AB - Biliopleural fistula (BF) and formation of biliopleural effusion is a rare complication following percutaneous transhepatic biliary drainage (PTBD). It occurs when the pleura is traversed by the catheter before entering the bile duct. Biliopleural fistula should be suspected when right side pleural effusion develops following the PTBD procedure. The diagnosis of biliopleural fistula is made when greenish pleural fluid with high concentration of bilirubin is aspirated. Here we present a case where a patient develops a biliopleural fistula following PTBD due to obstructive jaundice caused by neuroendocrine tumor of pancreas. Biliopleural fistula was disclosed after a scheduled catheter replacement procedure. Treatments of biliopleural fistula include thoracentesis with drainage tube installation into pleural space. In addition, a drainage tube was installed through percutaneous transhepatic gallbladder drainage (PTGBD) to reduce the bile induced pressure. Surgical repair of fistula was performed after the conservative treatment was unsuccessful. The patient expired 5 days after surgery due to respiratory failure. PMID- 29480800 TI - Association between oral corticosteroid use and pyogenic liver abscesses in a case-control study. AB - BACKGROUND AND AIM: There are no epidemiological studies focusing on the association between oral corticosteroid use and pyogenic liver abscesses. The aim of the study was to assess whether oral corticosteroid use is associated with increased odds of pyogenic liver abscesses in adults in Taiwan. METHODS: This retrospective population-based case-control study was conducted to analyze the database of the Taiwan National Health Insurance Program from 2000 to 2013. Subjects aged 20 to 84 years with their first episode of pyogenic liver abscesses were assigned as the cases (n = 881). Randomly selected subjects without pyogenic liver abscesses aged 20 to 84 years were selected as the controls (n = 3207). A multivariable logistic regression model was used to assess the odds ratio and 95% confidence interval for the correlation of oral corticosteroid use with pyogenic liver abscesses. RESULTS: After regulating for confounders, the adjusted odds ratio of pyogenic liver abscesses was 1.40 for subjects currently using oral corticosteroids (95% confidence interval 1.14, 1.70), compared with subjects who never used them. Upon further analysis, the adjusted odds ratio of pyogenic liver abscesses was 1.03 for subjects with current use of oral corticosteroids when increasing dosage for every one mg (95% CI 1.01, 1.06). CONCLUSION: Although the findings are not unexpected, they are important because they suggest that current use of oral corticosteroids is significantly associated with increased odds of developing pyogenic liver abscesses in adults in Taiwan, with a dose-dependent effect. PMID- 29480802 TI - Serine is the major residue for ADP-ribosylation upon DNA damage. AB - Poly(ADP-ribose) polymerases (PARPs) are a family of enzymes that synthesise ADP ribosylation (ADPr), a reversible modification of proteins that regulates many different cellular processes. Several mammalian PARPs are known to regulate the DNA damage response, but it is not clear which amino acids in proteins are the primary ADPr targets. Previously, we reported that ARH3 reverses the newly discovered type of ADPr (ADPr on serine residues; Ser-ADPr) and developed tools to analyse this modification (Fontana et al., 2017). Here, we show that Ser-ADPr represents the major fraction of ADPr synthesised after DNA damage in mammalian cells and that globally Ser-ADPr is dependent on HPF1, PARP1 and ARH3. In the absence of HPF1, glutamate/aspartate becomes the main target residues for ADPr. Furthermore, we describe a method for site-specific validation of serine ADP ribosylated substrates in cells. Our study establishes serine as the primary form of ADPr in DNA damage signalling. PMID- 29480803 TI - A neural circuit for gamma-band coherence across the retinotopic map in mouse visual cortex. AB - Cortical gamma oscillations have been implicated in a variety of cognitive, behavioral, and circuit-level phenomena. However, the circuit mechanisms of gamma band generation and synchronization across cortical space remain uncertain. Using optogenetic patterned illumination in acute brain slices of mouse visual cortex, we define a circuit composed of layer 2/3 (L2/3) pyramidal cells and somatostatin (SOM) interneurons that phase-locks ensembles across the retinotopic map. The network oscillations generated here emerge from non-periodic stimuli, and are stimulus size-dependent, coherent across cortical space, narrow band (30 Hz), and depend on SOM neuron but not parvalbumin (PV) neuron activity; similar to visually induced gamma oscillations observed in vivo. Gamma oscillations generated in separate cortical locations exhibited high coherence as far apart as 850 MUm, and lateral gamma entrainment depended on SOM neuron activity. These data identify a circuit that is sufficient to mediate long-range gamma-band coherence in the primary visual cortex. PMID- 29480804 TI - Fidaxomicin jams Mycobacterium tuberculosis RNA polymerase motions needed for initiation via RbpA contacts. AB - Fidaxomicin (Fdx) is an antimicrobial RNA polymerase (RNAP) inhibitor highly effective against Mycobacterium tuberculosis RNAP in vitro, but clinical use of Fdx is limited to treating Clostridium difficile intestinal infections due to poor absorption. To identify the structural determinants of Fdx binding to RNAP, we determined the 3.4 A cryo-electron microscopy structure of a complete M. tuberculosis RNAP holoenzyme in complex with Fdx. We find that the actinobacteria general transcription factor RbpA contacts fidaxomycin, explaining its strong effect on M. tuberculosis. Additional structures define conformational states of M. tuberculosis RNAP between the free apo-holoenzyme and the promoter-engaged open complex ready for transcription. The results establish that Fdx acts like a doorstop to jam the enzyme in an open state, preventing the motions necessary to secure promoter DNA in the active site. Our results provide a structural platform to guide development of anti-tuberculosis antimicrobials based on the Fdx binding pocket. PMID- 29480806 TI - Topological nature of the node-arc semimetal PtSn4 probed by de Haas-van Alphen quantum oscillations. AB - Dirac node arc semimetal state is a new topological quantum state which is proposed to exist in PtSn4 (Wu et al 2016 Dirac node arcs in PtSn4 Nat. Phys. 12 667-71). We present a systematic de Haas-van Alphen quantum oscillation study on this compound. Two intriguing oscillation branches, i.e. F 1 and F 2, are detected in the fast Fourier transformation spectra, both of which are characterized to possess tiny effective mass and ultrahigh quantum mobility. And the F 2 branch exhibits an angle-dependent nontrivial Berry phase. The features are consistent with the existence of the node arc semimetal state and shed new light on its complicated Fermi surfaces and topological nature. PMID- 29480805 TI - Identification of PNG kinase substrates uncovers interactions with the translational repressor TRAL in the oocyte-to-embryo transition. AB - The Drosophila Pan Gu (PNG) kinase complex regulates hundreds of maternal mRNAs that become translationally repressed or activated as the oocyte transitions to an embryo. In a previous paper (Hara et al., 2017), we demonstrated PNG activity is under tight developmental control and restricted to this transition. Here, examination of PNG specificity showed it to be a Thr-kinase yet lacking a clear phosphorylation site consensus sequence. An unbiased biochemical screen for PNG substrates identified the conserved translational repressor Trailer Hitch (TRAL). Phosphomimetic mutation of the PNG phospho-sites in TRAL reduced its ability to inhibit translation in vitro. In vivo, mutation of tral dominantly suppressed png mutants and restored Cyclin B protein levels. The repressor Pumilio (PUM) has the same relationship with PNG, and we also show that PUM is a PNG substrate. Furthermore, PNG can phosphorylate BICC and ME31B, repressors that bind TRAL in cytoplasmic RNPs. Therefore, PNG likely promotes translation at the oocyte-to embryo transition by phosphorylating and inactivating translational repressors. PMID- 29480807 TI - Investigation of Upconversion, downshifting and quantum -cutting behavior of Eu3+, Yb3+, Bi3+ co-doped LaNbO4 phosphor as a spectral conversion material. AB - This work presents the spectral conversion characteristics [upconversion (UC), downshifting (DS) and quantum-cutting (QC) optical processes] of Eu3+, Yb3+ and Bi3+ co-doped LaNbO4 (LBO) phosphor samples synthesized by solid state reaction technique. The crystal structure and the pure phase formation have been confirmed by x-ray diffraction (XRD) measurements. The surface morphology and particle size are studied by scanning electron microscopy (SEM). The rarely observed intense red UC emission from Eu3+ ion has been successfully obtained in Eu3+/Yb3+ co doped LaNbO4 phosphor (on excitation with 980 nm) by optimizing the concentrations of Eu3+ and Yb3+ ions. The downshifting (DS) behavior has been studied by photoluminescence (PL) measurements on excitation with 265 nm wavelength from a Xe lamp source. A broad blue emission in the region 300-550 nm with its maximum ~415 nm due to charge transfer band (CTB) of the host and large number of sharp peaks due to f-f transitions of Eu3+ ion have been observed. The energy transfer has been observed from (NbO4)3- to Eu3+ ion and the fluorescence emission has been optimized by varying the concentration of Eu3+ ion. An intense red emission has also been observed corresponding to 5D0 -> 7F2 transition of Eu3+ ion at 611 nm in LBO: 0.09Eu3+ phosphor on excitation with 394 nm. The luminescence properties of Eu3+ ion are enhanced further through the sensitization effect of Bi3+ ion. The near infra-red (NIR) quantum cutting (QC) behavior due to Yb3+ ion has been monitored on excitation with 265 as well as 394 nm. The NIR QC is observed due to 2F5/2 -> 2F7/2 transition of Yb3+ ion via co operative energy transfer (CET) process from (NbO4)3- as well as Eu3+ ions to Yb3+ ion. This multimodal behavior (UC, DS and QC) makes this a promising phosphor material for multi-purpose spectral converter. PMID- 29480808 TI - In vivo optoacoustic temperature imaging for image-guided cryotherapy of prostate cancer. AB - The objective of this study is to demonstrate in vivo the feasibility of optoacoustic temperature imaging during cryotherapy of prostate cancer. We developed a preclinical prototype optoacoustic temperature imager that included pulsed optical excitation at a wavelength of 805 nm, a modified clinical transrectal ultrasound probe, a parallel data acquisition system, image processing and visualization software. Cryotherapy of a canine prostate was performed in vivo using a commercial clinical system, Cryocare(r) CS, with an integrated ultrasound imaging. The universal temperature-dependent optoacoustic response of blood was employed to convert reconstructed optoacoustic images to temperature maps. Optoacoustic imaging of temperature during prostate cryotherapy was performed in the longitudinal view over a region of 30 mm (long) * 10 mm (deep) that covered the rectum, the Denonvilliers fascia, and the posterior portion of the treated gland. The transrectal optoacoustic images showed high contrast vascularized regions, which were used for quantitative estimation of local temperature profiles. The constructed temperature maps and their temporal dynamics were consistent with the arrangement of the cryoprobe and readouts of the thermal needle sensors. The temporal profiles of the readouts from the thermal needle sensors and the temporal profile estimated from the normalized optoacoustic intensity of the selected vascularized region showed significant resemblance, except for the initial overshoot, that may be explained as a result of the physiological thermoregulatory compensation. The temperature was mapped with errors not exceeding +/-2 degrees C (standard deviation) consistent with the clinical requirements for monitoring cryotherapy of the prostate. In vivo results showed that the optoacoustic temperature imaging is a promising non invasive technique for real-time imaging of tissue temperature during cryotherapy of prostate cancer, which can be combined with transrectal ultrasound-the current standard for guiding clinical cryotherapy procedure. PMID- 29480809 TI - Ideal versus real: simulated annealing of experimentally derived and geometric platinum nanoparticles. AB - Platinum nanoparticles find significant use as catalysts in industrial applications such as fuel cells. Research into their design has focussed heavily on nanoparticle size and shape as they greatly influence activity. Using high throughput, high precision electron microscopy, the structures of commercially available Pt catalysts have been determined, and we have used classical and quantum atomistic simulations to examine and compare them with geometric cuboctahedral and truncated octahedral structures. A simulated annealing procedure was used both to explore the potential energy surface at different temperatures, and also to assess the effect on catalytic activity that annealing would have on nanoparticles with different geometries and sizes. The differences in response to annealing between the real and geometric nanoparticles are discussed in terms of thermal stability, coordination number and the proportion of optimal binding sites on the surface of the nanoparticles. We find that annealing both experimental and geometric nanoparticles results in structures that appear similar in shape and predicted activity, using oxygen adsorption as a measure. Annealing is predicted to increase the catalytic activity in all cases except the truncated octahedra, where it has the opposite effect. As our simulations have been performed with a classical force field, we also assess its suitability to describe the potential energy of such nanoparticles by comparing with large scale density functional theory calculations. PMID- 29480810 TI - Effect of carbon fiber addition on the electromagnetic shielding properties of carbon fiber/polyacrylamide/wood based fiberboards. AB - Carbon fiber (CF) reinforced polyacrylamide/wood fiber composite boards are fabricated by mechanical grind-assisted hot-pressing, and are used for electromagnetic interference (EMI) shielding. CF with an average diameter of 150 nm is distributed on wood fiber, which is then encased by polyacrylamide. The CF/polyacrylamide/wood fiber (CPW) composite exhibits an optimal EMI shielding effectiveness (SE) of 41.03 dB compared to that of polyacrylamide/wood fiber composite (0.41 dB), which meets the requirements of commercial merchandise. Meanwhile, the CPW composite also shows high mechanical strength. The maximum modulus of rupture (MOR) and modulus of elasticity (MOE) of CPW composites are 39.52 MPa and 5823.15 MPa, respectively. The MOR and MOE of CPW composites increased by 38% and 96%, respectively, compared to that of polyacrylamide/wood fiber composite (28.64 and 2967.35 MPa). PMID- 29480811 TI - A simple parametric model observer for quality assurance in computer tomography. AB - Model observers are mathematical classifiers that are used for the quality assessment of imaging systems such as computer tomography. The quality of the imaging system is quantified by means of the performance of a selected model observer. For binary classification tasks, the performance of the model observer is defined by the area under its ROC curve (AUC). Typically, the AUC is estimated by applying the model observer to a large set of training and test data. However, the recording of these large data sets is not always practical for routine quality assurance. In this paper we propose as an alternative a parametric model observer that is based on a simple phantom, and we provide a Bayesian estimation of its AUC. It is shown that a limited number of repeatedly recorded images (10 15) is already sufficient to obtain results suitable for the quality assessment of an imaging system. A MATLAB(r) function is provided for the calculation of the results. The performance of the proposed model observer is compared to that of the established channelized Hotelling observer and the nonprewhitening matched filter for simulated images as well as for images obtained from a low-contrast phantom on an x-ray tomography scanner. The results suggest that the proposed parametric model observer, along with its Bayesian treatment, can provide an efficient, practical alternative for the quality assessment of CT imaging systems. PMID- 29480812 TI - Thermoswitchable catalysis controlled by reversible dispersion/aggregation change of nanoreactors in the presence of alpha-CD polymers. AB - The present work was aimed at preparing a thermosensitive nanoreactor system which could adjust its dispersion/aggregation status according to external temperature change to achieve the switchable catalysis. The mesoporous silica nanoparticle (MSNP) was selected as the framework material of the nanoreactor, and Ag nanoparticles were encapsulated in the mesoporous silica by an in situ reaction. Dodecyl groups were introduced onto MSNP surface, which could transform reversibly between complexation and disassociation with alpha-cyclodextrin (CD) cavity upon temperature change. It was found that the nanoreactors aggregated and the catalysis was effectively switched 'off' in the presence of CD polymers at low temperature (20 degrees C). However, when the temperature increased to 50 degrees C, the nanoreactors redispersed and catalysis successfully switched 'on'. PMID- 29480813 TI - Quality assessment of MEG-to-MRI coregistrations. AB - For high precision in source reconstruction of magnetoencephalography (MEG) or electroencephalography data, high accuracy of the coregistration of sources and sensors is mandatory. Usually, the source space is derived from magnetic resonance imaging (MRI). In most cases, however, no quality assessment is reported for sensor-to-MRI coregistrations. If any, typically root mean squares (RMS) of point residuals are provided. It has been shown, however, that RMS of residuals do not correlate with coregistration errors. We suggest using target registration error (TRE) as criterion for the quality of sensor-to-MRI coregistrations. TRE measures the effect of uncertainty in coregistrations at all points of interest. In total, 5544 data sets with sensor-to-head and 128 head-to MRI coregistrations, from a single MEG laboratory, were analyzed. An adaptive Metropolis algorithm was used to estimate the optimal coregistration and to sample the coregistration parameters (rotation and translation). We found an average TRE between 1.3 and 2.3 mm at the head surface. Further, we observed a mean absolute difference in coregistration parameters between the Metropolis and iterative closest point algorithm of [Formula: see text] and [Formula: see text] m. A paired sample t-test indicated a significant improvement in goal function minimization by using the Metropolis algorithm. The sampled parameters allowed computation of TRE on the entire grid of the MRI volume. Hence, we recommend the Metropolis algorithm for head-to-MRI coregistrations. PMID- 29480814 TI - Estimation of patient-specific imaging dose for real-time tumour monitoring in lung patients during respiratory-gated radiotherapy. AB - PURPOSE: To quantify the patient-specific imaging dose for real-time tumour monitoring in the lung during respiratory-gated stereotactic body radiotherapy (SBRT) in clinical cases using SyncTraX. METHODS AND MATERIALS: Ten patients who underwent respiratory-gated SBRT with SyncTraX were enrolled in this study. The imaging procedure for real-time tumour monitoring using SyncTraX was simulated using Monte Carlo. We evaluated the dosimetric effect of a real-time tumour monitoring in a critical organ at risk (OAR) and the planning target volume (PTV) over the course of treatment. The relationship between skin dose and gating efficiency was also investigated. RESULTS: For all patients, the mean D50 to the PTV, ipsilateral lung, liver, heart, spinal cord and skin was 118.3 (21.5-175.9), 31.9 (9.5-75.4), 15.4 (1.1-31.6), 10.1 (1.3-18.1), 25.0 (1.6-101.8), and 3.6 (0.9 7.1) mGy, respectively. The mean D2 was 352.0 (26.5-935.8), 146.4 (27.3-226.7), 90.7 (3.6-255.0), 42.2 (4.8-82.7), 88.0 (15.4-248.5), and 273.5 (98.3-611.6) mGy, respectively. The D2 of the skin dose was found to increase as the gating efficiency decreased. CONCLUSIONS: The additional dose to the PTV was at most 1.9% of the prescribed dose over the course of treatment for real-time tumour monitoring. For OARs, we could confirm the high dose region, which may not be susceptible to radiation toxicity. However, to reduce the skin dose from SyncTraX, it is necessary to increase the gating efficiency. PMID- 29480815 TI - Measurement of the intensity ratio of Auger and conversion electrons for the electron capture decay of 125I. AB - Auger electrons emitted after nuclear decay have potential application in targeted cancer therapy. For this purpose it is important to know the Auger electron yield per nuclear decay. In this work we describe a measurement of the ratio of the number of conversion electrons (emitted as part of the nuclear decay process) to the number of Auger electrons (emitted as part of the atomic relaxation process after the nuclear decay) for the case of 125I. Results are compared with Monte-Carlo type simulations of the relaxation cascade using the BrIccEmis code. Our results indicate that for 125I the calculations based on rates from the Evaluated Atomic Data Library underestimate the K Auger yields by 20%. PMID- 29480816 TI - Evolutionary history of metastatic breast cancer reveals minimal seeding from axillary lymph nodes. AB - Metastatic breast cancers are still incurable. Characterizing the evolutionary landscape of these cancers, including the role of metastatic axillary lymph nodes (ALNs) in seeding distant organ metastasis, can provide a rational basis for effective treatments. Here, we have described the genomic analyses of the primary tumors and metastatic lesions from 99 samples obtained from 20 patients with breast cancer. Our evolutionary analyses revealed diverse spreading and seeding patterns that govern tumor progression. Although linear evolution to successive metastatic sites was common, parallel evolution from the primary tumor to multiple distant sites was also evident. Metastatic spreading was frequently coupled with polyclonal seeding, in which multiple metastatic subclones originated from the primary tumor and/or other distant metastases. Synchronous ALN metastasis, a well-established prognosticator of breast cancer, was not involved in seeding the distant metastasis, suggesting a hematogenous route for cancer dissemination. Clonal evolution coincided frequently with emerging driver alterations and evolving mutational processes, notably an increase in apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like-associated (APOBEC-associated) mutagenesis. Our data provide genomic evidence for a role of ALN metastasis in seeding distant organ metastasis and elucidate the evolving mutational landscape during cancer progression. PMID- 29480817 TI - Cancer vaccine formulation dictates synergy with CTLA-4 and PD-L1 checkpoint blockade therapy. AB - Anticancer vaccination is a promising approach to increase the efficacy of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed death ligand 1 (PD-L1) checkpoint blockade therapies. However, the landmark FDA registration trial for anti-CTLA-4 therapy (ipilimumab) revealed a complete lack of benefit of adding vaccination with gp100 peptide formulated in incomplete Freund's adjuvant (IFA). Here, using a mouse model of melanoma, we found that gp100 vaccination induced gp100-specific effector T cells (Teffs), which dominantly forced trafficking of anti-CTLA-4-induced, non-gp100-specific Teffs away from the tumor, reducing tumor control. The inflamed vaccination site subsequently also sequestered and destroyed anti-CTLA-4-induced Teffs with specificities for tumor antigens other than gp100, reducing the antitumor efficacy of anti-CTLA-4 therapy. Mechanistically, Teffs at the vaccination site recruited inflammatory monocytes, which in turn attracted additional Teffs in a vicious cycle mediated by IFN-gamma, CXCR3, ICAM-1, and CCL2, dependent on IFA formulation. In contrast, nonpersistent vaccine formulations based on dendritic cells, viral vectors, or water-soluble peptides potently synergized with checkpoint blockade of both CTLA 4 and PD-L1 and induced complete tumor regression, including in settings of primary resistance to dual checkpoint blockade. We conclude that cancer vaccine formulation can dominantly determine synergy, or lack thereof, with CTLA-4 and PD L1 checkpoint blockade therapy for cancer. PMID- 29480818 TI - Pharmacological targeting of MYC-regulated IRE1/XBP1 pathway suppresses MYC driven breast cancer. AB - The unfolded protein response (UPR) is a cellular homeostatic mechanism that is activated in many human cancers and plays pivotal roles in tumor progression and therapy resistance. However, the molecular mechanisms for UPR activation and regulation in cancer cells remain elusive. Here, we show that oncogenic MYC regulates the inositol-requiring enzyme 1 (IRE1)/X-box binding protein 1 (XBP1) branch of the UPR in breast cancer via multiple mechanisms. We found that MYC directly controls IRE1 transcription by binding to its promoter and enhancer. Furthermore, MYC forms a transcriptional complex with XBP1, a target of IRE1, and enhances its transcriptional activity. Importantly, we demonstrate that XBP1 is a synthetic lethal partner of MYC. Silencing of XBP1 selectively blocked the growth of MYC-hyperactivated cells. Pharmacological inhibition of IRE1 RNase activity with small molecule inhibitor 8866 selectively restrained the MYC-overexpressing tumor growth in vivo in a cohort of preclinical patient-derived xenograft models and genetically engineered mouse models. Strikingly, 8866 substantially enhanced the efficacy of docetaxel chemotherapy, resulting in rapid regression of MYC overexpressing tumors. Collectively, these data establish the synthetic lethal interaction of the IRE1/XBP1 pathway with MYC hyperactivation and provide a potential therapy for MYC-driven human breast cancers. PMID- 29480819 TI - Integrated RNA and DNA sequencing reveals early drivers of metastatic breast cancer. AB - Breast cancer metastasis remains a clinical challenge, even within a single patient across multiple sites of the disease. Genome-wide comparisons of both the DNA and gene expression of primary tumors and metastases in multiple patients could help elucidate the underlying mechanisms that cause breast cancer metastasis. To address this issue, we performed DNA exome and RNA sequencing of matched primary tumors and multiple metastases from 16 patients, totaling 83 distinct specimens. We identified tumor-specific drivers by integrating known protein-protein network information with RNA expression and somatic DNA alterations and found that genetic drivers were predominantly established in the primary tumor and maintained through metastatic spreading. In addition, our analyses revealed that most genetic drivers were DNA copy number changes, the TP53 mutation was a recurrent founding mutation regardless of subtype, and that multiclonal seeding of metastases was frequent and occurred in multiple subtypes. Genetic drivers unique to metastasis were identified as somatic mutations in the estrogen and androgen receptor genes. These results highlight the complexity of metastatic spreading, be it monoclonal or multiclonal, and suggest that most metastatic drivers are established in the primary tumor, despite the substantial heterogeneity seen in the metastases. PMID- 29480820 TI - Translational repression of HIF2alpha expression in mice with Chuvash polycythemia reverses polycythemia. AB - Chuvash polycythemia is an inherited disease caused by a homozygous germline VHLR200W mutation, which leads to impaired degradation of HIF2alpha, elevated levels of serum erythropoietin, and erythrocytosis/polycythemia. This phenotype is recapitulated by a mouse model bearing a homozygous VhlR200W mutation. We previously showed that iron-regulatory protein 1-knockout (Irp1-knockout) mice developed erythrocytosis/polycythemia through translational derepression of Hif2alpha, suggesting that IRP1 could be a therapeutic target to treat Chuvash polycythemia. Here, we fed VhlR200W mice supplemented with Tempol, a small, stable nitroxide molecule and observed that Tempol decreased erythropoietin production, corrected splenomegaly, normalized hematocrit levels, and increased the lifespans of these mice. We attribute the reversal of erythrocytosis/polycythemia to translational repression of Hif2alpha expression by Tempol-mediated increases in the IRE-binding activity of Irp1, as reversal of polycythemia was abrogated in VhlR200W mice in which Irp1 was genetically ablated. Thus, a new approach to the treatment of patients with Chuvash polycythemia may include dietary supplementation of Tempol, which decreased Hif2alpha expression and markedly reduced life-threatening erythrocytosis/polycythemia in the VhlR200W mice. PMID- 29480821 TI - Delayed suprachoroidal hemorrhage after cataract surgery: A case report and brief review of literature. AB - RATIONALE: To report a case of 44-year-old man with delayed suprachoroidal hemorrhage (DSCH) 2 days after cataract surgery. PATIENT CONCERNS: The patient developed sudden onset of ocular pain and reduction of visual acuity on his left eye 2 days after receiving conventional cataract operation. DIAGNOSES: The ocular conditions were accessed by best-corrected visual acuity, intraocular pressure, slit lamp examination, fundus photography, and B-scan ultrasound. Fundus color photograph revealed a raised choroidal mass and extensive subretinal hemorrhage. B-scan ultrasound also confirmed features of choroidal hemorrhage. Thus, he was diagnosed as DSCH. INTERVENTIONS: He received conservative treatments for 1 month. OUTCOMES: The involved eye recovered well. LESSONS: DSCH is a rare but dreaded complication occurring in intraocular operations. Conservative managements or surgeries may be beneficial for the recovery of visual acuity. PMID- 29480822 TI - Thyrotrophic status in patients with pituitary stalk interruption syndrome. AB - Pituitary stalk interruption syndrome (PSIS) is associated with simultaneous or subsequent pituitary hormone deficiencies (PHDs). Although the clinical features of multiple PHDs are well known, the status of the thyrotrophic axis in PSIS has not been thoroughly investigated.The clinical data of 89 PSIS patients and 34 Sheehan syndrome (SS) patients were retrospectively analyzed.The prevalence of central hypothyroidism in the PSIS patients and the SS patients was 79.8% and 70.6%, respectively. The thyroid-stimulating hormone (TSH) levels in the PSIS patients were significantly higher in comparison with the SS patients (5.13 +/- 3.40 vs 1.67 +/- 1.20 mU/L, P < .05). TSH elevation (8.79 +/- 3.17 mU/L) was noticed in 29 of 71 (40.85%) hypothyroid PSIS patients but not in the 24 hypothyroid SS patients. The TSH levels in the hypothyroid PSIS patients were significantly higher in comparison with the euthyroid PSIS patients (5.42 +/- 3.67 vs 3.66 +/- 1.50 mU/L). Thyroid hormone replacement significantly reduced the TSH levels in the PSIS patients with elevated TSH levels from 7.24 +/- 0.98 to 1.67 +/- 1.51 mU/L (P < .05). The logistic regression analysis suggested that TSH level was not significantly associated with pituitary stalk status and height of the anterior pituitary gland.PSIS is a newly recognized cause of central hypothyroidism. The proportion and amplitude of TSH elevations are higher in PSIS than in other causes of central hypothyroidism. PMID- 29480823 TI - Advanced gastrointestinal stromal tumor patients benefit from palliative surgery after tyrosine kinase inhibitors therapy. AB - The role of palliative surgery is controversial in advanced gastrointestinal stromal tumors (GIST) after tyrosine kinase inhibitors (TKIs) therapy.We evaluated safety and clinical outcomes in a single institution series of advanced GIST patients from January 2002 to December 2008.One hundred and fifty-six patients had been recruited, including 87 patients underwent surgical resection and 69 patients kept on TKIs treatment. Four patients had major surgical complications. Median follow-up was 38.3 months, the overall survival (OS) and progression-free survival (PFS) of the patients in surgical group were longer than the nonsurgical group, PFS: 46.1 versus 33.8 months (P < .01), OS: 54.8 versus 40.4 months. In the subgroup analysis for the patients received surgery, the median PFS for patients with progression disease, stable disease, and partial response was 33.3, 51.5, and 83.0 months, respectively (P < .01). Median OS was 68.0 months in those with only liver or peritoneal metastases, and 45.3 months in those with both metastases. Median PFS of patients underwent R0/R1 resection was 73.6 months compared with 35.8 months in R2 resection patients (P < .01).Patients with advanced GISTs have prolonged OS after debulking procedures. Surgery for patients who have responsive disease after TKIs treatment should be considered. PMID- 29480824 TI - Left minimally invasive esophagectomy in a patient with synchronous esophageal and lung cancers: Case report. AB - RATIONALE: Minimally invasive esophagectomy (MIE) have been increasingly used and are regarded as suitable alternatives to open esophagectomy. However, few previous reports described minimally invasive esophagectomy using a left-sided approach. PATIENT CONCERNS AND DIAGNOSES: A 71-year-old man was admitted to our hospital because of progressive dysphagia. Synchronous double primary thoracic esophageal and left lung cancers were considered before the operation. INTERVENTIONS AND OUTCOMES: A lobectomy and MIE, via a left video-assisted thoracoscopic approach, was performed. Preparation of a gastric conduit and an intra-abdominal lymphadenectomy were completed by laparoscopy and a cervical anastomosis was made. In addition, a cervical mediastinoscopy was performed to dissect the lymph nodes along the bilateral recurrent laryngeal nerves. No postoperative complications were observed. The patient achieved a favorable short term outcome. LESSONS: This is the first report of a patient with synchronous esophageal and left lung cancers treated with minimally invasive resection via left thoracoscopy, laparoscopy, and cervical mediastinoscopy. Our results showed that the left MIE approach in combination with cervical mediastinoscopy is potentially most appropriate for some esophageal cancer patients, when the right MIE approach is not applicable in certain conditions. PMID- 29480825 TI - The allocentric neglect due to injury of the inferior fronto-occipital fasciculus in a stroke patient: A case report. AB - RATIONALE: We report on a patient who developed allocentric neglect due to injury of the inferior fronto-occipital fasciculus (IFOF) following intracranial hemorrhage, diagnosed using diffusion tensor tractography (DTT). PATIENT CONCERNS: Her cognition seemed normal (A 17-year-old, right-handed female patient). However, in spite of a normal visual field, her perception was missing on the left side, and she had no awareness of her deficit. She was unable to perceive the left side in each of 2 objects, regardless of position of the 2 objects, and failed at detail exploration of the left side of 1 object. In addition, the line bisection test, the most representative neglect test, did not reveal any abnormality. DIAGNOSES: She was diagnosed with an intracerebral hemorrhage (right thalamus), intraventricular hemorrhage, and subarachnoid hemorrhage due to arteriovenous malformation in the right thalamus. INTERVENTIONS: Seven weeks after onset, she began rehabilitation. Consequently, the apple cancellation test to discriminate between allocentric and egocentric neglect was performed, with the result of severe allocentric neglect. OUTCOMES: The right superior longitudinal fasciculus and inferior longitudinal fasciculus were well-reconstructed without definite injury compared with those of the left side. However, the right IFOF was discontinued in the anterior portion around the frontal lobe. LESSONS: Allocentric neglect due to injury of IFOF was demonstrated in a stroke patient using DTT. It appears that DTT would be helpful in demonstrating the neglect type and pathway in patients with neglect. PMID- 29480826 TI - Postoperative clinicopathological factors affecting cervical adenocarcinoma: Stages I-IIB. AB - Currently, cervical adenocarcinoma (ADC) receives the same standard treatment as squamous cell carcinoma, but this treatment regimen is not wholly suited for ADC. The present study was conducted to assess the prognostic role of postoperative clinicopathological factors in patients with stage I-IIB cervical ADC.The study examined 312 patients with stage I-IIB cervical ADC who underwent radical hysterectomy, including pelvic lymphadenectomy, at our institutions between October 2006 and September 2014. Overall survival (OS) and relapse-free survival (RFS) was analyzed by the Kaplan-Meier method. Sites of recurrence were classified as local and distant locations.The 5-year OS and RFS rates were 88.2% and 83.8%, respectively. The 5-year OS rates for patients with International Federation of Gynecology and Obstetrics (FIGO) stage IA, IB, IIA, and IIB were 100.0%, 90.7%, 82.8%, and 55.6%, respectively. The Cox model identified number of positive pelvic nodes and age at surgery as independent prognostic factors for survival, and number of positive pelvic nodes and postoperative tumor diameter (>=4 cm) as independent prognostic factors for relapse. Cancer recurrence developed in 35 women. The top three recurrence sites were pelvis, vaginal stump, and lung.A more aggressive therapeutic strategy different from current practice in cervical cancer is urgently required for cervical ADC. As a new prognostic factor, postoperative tumor diameter should receive special attention in ADC treatment. PMID- 29480828 TI - Association of BRCA1/2 mutations with ovarian cancer prognosis: An updated meta analysis. AB - OBJECTIVE: A meta-analysis was performed to determine if BRCA1/2 mutations are associated with improved overall survival (OS) and progression-free survival (PFS) in patients with ovarian cancer. RESEARCH DESIGN AND METHODS: Studies of patients with primary or recurrent ovarian cancer that examined the relationship between BRCA1/2 mutation status and outcomes were included. MAIN OUTCOME MEASURES: The primary outcomes were OS and PFS of patients with and without BRCA1 and BRCA2 mutations. The secondary outcome was treatment response: complete response, partial response, and overall response. RESULTS: Overall analysis revealed BRCA1/2 mutations were associated with improved OS [hazard ratio (HR) = 0.75; 95% confidence interval (CI): 0.64, 0.88; P < .001] and PFS (HR = 0.80; 95% CI: 0.64, 0.99; P = .039). BRCA1 mutations were significantly associated with improved OS (HR = 0.75) but not PFS, and BRCA2 mutations alone were not associated with either improved OS or PFS. The presence of BCRA1/2 mutations was associated with a better overall response rate, higher complete response rate, and lower partial response rate; however, BRCA1 or BRCA2 alone was not associated with overall response rate. CONCLUSIONS: BRCA1 mutations appear to be associated with improved OS in patients with ovarian cancer. However, the effect of BRCA1 mutations on PFS and BRCA2 mutations alone on OS and PFS is less clear. PMID- 29480827 TI - Congenital left atrial appendage aneurysm: A rare case report and literature review. AB - RATIONALE: Left atrial appendage aneurysms (LAAA) are rare. Patients with LAAA are often diagnosed incidentally or after cardiac tachyarrhythmia or systemic thromboembolism happen. Early diagnosis and surgical resection is of utmost importance to prevent hazardous adverse events. PATIENT CONCERNS: We present a case of 46-year-old man with congenital LAAA. The individual in this manuscript has given written informed consent to publish these case details. DIAGNOSES: Imaging studies, such as echocardiography, cardiovascular computed tomography (CT) and magnetic resonance imaging (MRI), demonstrated the large cavity arising from the left atrial appendage. The diagnosis of LAAA was confirmed. INTERVENTIONS: The patient underwent an aneurysmectomy without any complications. OUTCOMES: TTE confirmed the disappearance of the LAAA from the left parasternal short-axis view of the aortic root postoperatively. The patient remained asymptomatic without any adverse events at his 3-month follow-up visits. LESSONS: The associated high risk of life-threatening complications and the relative ease of surgical removal suggest that prompt evaluation should be considered in patients with lesions adjacent to the left heart border. PMID- 29480829 TI - Subcutaneous metastasis of a pulmonary carcinoid tumor: A case report. AB - RATIONALE: Carcinoid tumors are derived from neuroendocrine cells and are most frequently found in the gastrointestinal tract and bronchopulmonary system. They are generally characterized by an indolent clinical course but may in some instances spread to regional lymph nodes or to distant sites. Subcutaneous metastases of carcinoid tumors are extremely rare; there are only few cases reported in the literature and the site of the primary tumor was mainly the gastrointestinal tract. Also, the diagnosis of this type of lesions many years after the surgical resection of the pulmonary carcinoid (PC) could be a challenge for clinicians. PATIENT CONCERNS: A nonsmoker woman diagnosed with a atypical carcinoid stage IA2 maintained follow-up at our institution. Seven years later she incidentally detected a subcutaneous nodular lesion in the lumbar region. DIAGNOSES: A positron emission tomography-computed tomography (PET/CT) was performed and showed pathological uptake of the refered lesion. An excisional biopsy was performed and with the support of immunohistochemistry the diagnosis of a subcutaneous metastasis from a pulmonary atypical carcinoid was made. INTERVENTIONS: The patient initiated chemotherapy with carboplatin plus etoposide and complied 4 cycles of treatment. OUTCOMES: She maintained tight follow-up at our center and for 12 months there were no signs of relapse. LESSONS: This extremely rare case highlights the difficulties in the differential diagnosis and the importance of diagnostic tests as PET/CT and immunohistochemistry in the establishment of a diagnosis. Physicians should be aware of signs of skin metastasis from lung malignancies even if the prognosis is good or many years have passed since the surgical resection. PMID- 29480830 TI - A novel approach for medical research on lymphomas: A study validation of claims based algorithms to identify incident cases. AB - The use of claims database to study lymphomas in real-life conditions is a crucial issue in the future. In this way, it is essential to develop validated algorithms for the identification of lymphomas in these databases. The aim of this study was to assess the validity of diagnosis codes in the French health insurance database to identify incident cases of lymphomas according to results of a regional cancer registry, as the gold standard.Between 2010 and 2013, incident lymphomas were identified in hospital data through 2 algorithms of selection. The results of the identification process and characteristics of incident lymphomas cases were compared with data from the Tarn Cancer Registry. Each algorithm's performance was assessed by estimating sensitivity, predictive positive value, specificity (SPE), and negative predictive value.During the period, the registry recorded 476 incident cases of lymphomas, of which 52 were Hodgkin lymphomas and 424 non-Hodgkin lymphomas. For corresponding area and period, algorithm 1 provides a number of incident cases close to the Registry, whereas algorithm 2 overestimated the number of incident cases by approximately 30%. Both algorithms were highly specific (SPE = 99.9%) but moderately sensitive. The comparative analysis illustrates that similar distribution and characteristics are observed in both sources.Given these findings, the use of claims database can be consider as a pertinent and powerful tool to conduct medico-economic or pharmacoepidemiological studies in lymphomas. PMID- 29480831 TI - Adherence and virologic outcomes among treatment-naive veteran patients with human immunodeficiency virus type 1 infection. AB - Many studies have estimated the association between the adherence to antiretroviral therapies and human immunodeficiency virus (HIV) patients' virologic/immunologic outcomes. However, evidence is lacking on the causal effect of adherence on the outcomes. The goal of this study is to understand whether near perfect adherence is necessary to achieve optimal virologic outcome and also to investigate the effect of initial adherence to antiretroviral therapies on initial viral suppression by different regimens. A cohort study was conducted on HIV veterans initiating antiretroviral therapies in 1999 to 2015. The primary outcome was the first viral suppression occurred within 30 to 60 days since the index date. Multiple imputation was used to impute the missing value of virologic outcomes. The inverse probability of treatment weighting (IPTW) method was applied to estimate the viral suppression rate at each specific adherence category for each regimen category. Marginal structural models with IPTW were used to estimate the risk of viral suppression in lower-adherence categories in comparison to near-perfect adherence level >=95%. Data showed that lower adherence caused lower viral suppression rate, with the association differentiated by the regimen. Patients on integrase strand transfer had the highest viral suppression rate, with patients on protease inhibitors having the lowest rate. Regardless of regimens, the viral suppression rate among patients at initial adherence of 75 to <95% was not statistically different from patients at adherence of >=95%; however, the differences might be clinically significant. PMID- 29480832 TI - Association of maternal diabetes with autism spectrum disorders in offspring: A systemic review and meta-analysis. AB - Studies on the association of maternal diabetes with autism spectrum disorders (ASDs) in offspring provide inconsistent findings; therefore an updated and comprehensive literature review and meta-analysis is necessary to perform in order to evaluate the available evidences.After searching databases systematically, we established the inclusion criteria and selected the eligible studies. In both overall and stratified analyses, the estimated effects were synthesized dependent on the presence or absence of heterogeneity.Twelve articles involving 16 studies were included and synthesized, demonstrating a significant association of maternal diabetes with ASDs among children (relative risk [RR] = 1.48). However, high heterogeneity was observed (I = 56.3%) and publication bias was identified. In terms of the analyses on reliable evidences from case-control studies, heterogeneity and publication bias disappeared, and the risk of ASDs was increased by 62% among diabetic mothers compared with non-diabetic mothers.Maternal diabetes, especially gestational diabetes mellitus, is associated with ASDs in offspring based on a limited number of convincing case control studies. More large-scale population-based prospective studies are still needed to draw firm conclusions. PMID- 29480833 TI - Measuring the reasons that discourage medical students from working in rural areas: Development and validation of a new instrument. AB - The sharply uneven distribution of human resources for health care across urban and rural areas has been a long-standing concern globally. The present study aims to develop and validate an instrument measuring the factors deterring final year students of Bachelor of Medicine and Bachelor of Surgery (MBBS) in 3 northern states of India, from working in rural areas.The medical student's de-motivation to work in rural India (MSDRI) scale was developed using extensive literature review followed by Delphi technique. The psychometric properties of the questionnaire were assessed in terms of content validity, construct validity, data quality and reliability. Exploratory factor analysis (EFA) followed by confirmatory factor analysis (CFA) was performed to identify the primary deterrents.Thirty-three items were generated from literature search followed by Delphi exercise. After assessing psychometric properties, the final instrument included 29 items whereas the EFA and CFA highlighted 5 main factors, namely lack of professional challenge, social segregation, socio-cultural gap, hostile professional environment, and lack of financial incentives as underpinning students' demotivation towards working in rural areas.The MSDRI instrument is the first valid and reliable measure for identifying deterring factors for MBBS students to work in rural areas of India. The use of it may be very helpful for policymakers as well as healthcare organizations in formulating effective measures to encourage medical students to work in rural areas, which suffer from a chronic shortage of medical personnel. PMID- 29480834 TI - Percutaneous treatment for silicosis-induced pulmonary artery stenosis: A case report and review of the literature. AB - BACKGROUND: Exposure to crystalline silica results in silicosis with initiation and progression of pulmonary fibrosis. The impaired lung parenchyma leads to pulmonary arterial hypertension and increased pressure in the right ventricle of the heart. Usually, the silicosis may be followed by enlargement of hilar lymphnodes, but silicosis-induced pulmonary artery stenosis with severe pulmonary hypertension is rare. Percutaneous pulmonary artery stenting and balloon angioplasty were performed to relieve stenosis and pulmonary hypertension. METHODS: We report the case of a 52-year-old man who was admitted for persistent dyspnea for 2 years and progressive dyspnea for half a month. He had been a stonemason for 20 years. The computer tomography pulmonary angiography scan images showed partially fibrotic lungs with a disseminated nodular pattern and enlarged bilateral hilar and mediastinal lymphnodes. The echocardiogram and right heart catheterization confirmed the diagnosis of severe pulmonary arterial hypertension. RESULTS: Pulmonary angiograms showed severe stenosis of the proximal upper right and lower left pulmonary artery. Moderate stenosis occured in a branch of the lower right pulmonary artery and a branch of the upper left pulmonary artery. A total of 2 stents and 4 balloons were used to relieve lesions. The final angiograms showed a significantly increased pulmonary artery caliber. The clinical symptom and 6-minute walk distance of the patient were much improved. CONCLUSION: To our knowledge, this is the first reported case of percutaneous treatment for silicosis-induced pulmonary artery stenosis and pulmonary hypertension. The clinical symptom, 6-minute walking test, and vessel caliber at areas of stenosis improved significantly following stent implantation and balloon dilatation. However, the patient was followed up for a short period and long-term outcomes have not yet been sufficiently evaluated. PMID- 29480835 TI - Membrane translocation of Bruton kinase in multiple myeloma cells is associated with osteoclastogenic phenotype in bone metastatic lesions. AB - Using bone biopsy samples, we examined whether osteolytic cytokine profile is changed in situ in bone samples of metastatic multiple myeloma, and whether this creates an environment of lysis within the bone to which it has spread. This also produces the clinical features of increased circulating plasma calcium, and deleterious effects on the kidney.Using multiple myeloma biopsy and cell extracts from bone metastatic lesions, Bruton kinase, a tyrosine kinase, was demonstrated to be translocated to the membrane. Several transcription factors were upregulated included activin A, inflammatory transcription activator like such as nuclear factor kappa B, and specific bone lytic factor such as receptor activator of nuclear factor kappa-B ligand that is known to drive osteoclastogenesis as opposed to a osteogenic environment. The transcript for Bruton kinase was also elevated in its expression.Cytokines that support osteolytic activity such as a proliferation-inducing ligand, RANTES (regulated on activation, normal T cell expressed and secreted), interleukin-8, and activin A were upregulated. Tartrate resistant acid phosphatase (TRAP)-positive osteoclastic enzymatic activity was significantly elevated in the bone microenvironment in metastatic multiple myeloma. Several tyrosine kinase inhibitors, including inhibitors for Bruton kinase such as ibrutinib have been developed. The results of the present study provide evidence that multiple myeloma possess signal transduction mechanisms to support a bone lytic environment.The results provide a preliminary molecular basis to design specific inhibitors for management of bone metastasis of multiple myeloma. PMID- 29480836 TI - Analysis of correlation between regional implant density and the correction rate in treatment of Lenke 1A and 1B adolescent idiopathic scoliosis with pedicle screws. AB - A retrospective study.The optimal implant density in patients with Lenke type 1 adolescent idiopathic scoliosis (AIS) is undefined, and there is no study reporting the correlation between the partitional implant density and the correction outcome.To determine whether the implant density in structural and nonstructural regions would affect the coronal correction outcome of Lenke 1A and 1B AIS.Preoperative general data and postoperative follow-up data of Lenke 1A and 1B AIS patients who received posterior fusion with the pedicle screw system were analyzed. Correlations between the implant density in structural and nonstructural regions and the correction rate of coronal Cobb angle, as well as between the correction rate and loss of the coronal correction angle during a 2 year follow-up period were analyzed. According to the implant density, the patients were classified into 2 groups: structural region group (including A1 and A2), and nonstructural region group (including B1 and B2). Differences in related parameters between the 2 groups were compared statistically.Except for the mean implant density, there was no statistical difference in the other parameters between group A1 and A2. In group B1 and B2, the correction rate of the main thoracic (MT) curve was 63.0% and 71.6% (P = .022), and the loss of the correction angle was 2.1 degrees and 4.2 degrees , respectively (P < .01), showing a statistical difference in the correction rate and postoperative angle loss of the MT curve between group B1 and B2.The correction rate of the MT curve at the coronal plane and postoperative loss of the correction angle were not related to the implant density in structural regions but may be related to the implant density in nonstructural regions in the treatment of Lenke type 1A and 1B AIS with pedicle screw instrumentation. PMID- 29480837 TI - Assessment of diagnostic and therapeutic vitrectomy for vitreous opacity associated with uveitis with various etiologies. AB - Vitreous opacity (VO) is a common feature of intermediate uveitis, posterior uveitis, and panuveitis. Fundus observation is critical for determining the etiology of uveitis, however, is often interfered with VO. In these clinical settings, vitrectomy contributes to a correct diagnosis and guides alternative management strategies. The purpose of this study was to evaluate the diagnostic yield and surgical outcome of vitrectomy in uveitic patients with VO and compare the visual outcome between infectious and noninfectious uveitis. Forty-five eyes with uveitis-associated VO underwent diagnostic and therapeutic vitrectomy, and etiological diagnosis of uveitis was confirmed in 34 of 45 eyes (75.6%). The diagnoses were infectious uveitis in 13 eyes (28.9%), noninfectious uveitis in 21 eyes (46.7%), and unidentified uveitis in 11 eyes (24.4%). Visual acuity (VA) improvement rates at 6 months after surgery were 69.2%, 76.2%, and 90.9% in the infectious, noninfectious, and unidentified uveitis groups, with no significant difference among 3 groups. Significant decrease in inflammation score after vitrectomy was observed only in the infectious uveitis group. This study demonstrated that diagnostic vitrectomy for inflammatory eyes with VO of unknown etiology was effective in infectious and noninfectious uveitis, and the therapeutic effect of VA improvement was observed in both types of uveitis. PMID- 29480838 TI - Predicting poor adherence to antiretroviral therapy among treatment-naive veterans infected with human immunodeficiency virus. AB - Previous studies suggested that human immunodeficiency virus (HIV) infected patients at risk of poor adherence were not distinguishable only based on the baseline characteristics. This study is to identify patient characteristics that would be consistently associated with poor adherence across regimens and to understand the associations between initial and long-term adherence. HIV treatment-naive patients initiated on protease inhibitors, nonnucleoside reverse transcriptase inhibitors, or integrase strand transfer inhibitors were identified from the Veteran Health Administration system. Initial adherence measured as initial coverage ratio (ICR) and long-term adherence measured as thereafter 1 year proportion days covered (PDC) of base agent and complete regimen were estimated for each patient. The patients most likely to exhibit poor adherence were African-American, with lower socioeconomic status, and healthier. The initial coverage ratio of base agent and complete regimen were highly correlated, but the correlations between ICR and thereafter 1-year PDC were low. However, including initial adherence as a predictor in predictive model would substantially increase predictive accuracy of future adherence. PMID- 29480839 TI - Hepatic rupture: A case report of a severe complication of percutaneous catheter drainage. AB - RATIONALE: Currently, percutaneous catheter drainage (PCD) is regarded as the first-line treatment modality of pyogenic liver abscess. Severe complications associated with PCD were uncommon. Hepatic rupture is an uncommon but life threatening liver trauma with high mortality. Its management is challenging because a delay in the diagnosis may lead to fatal hemorrhagic shock. To our knowledge, PCD-associated hepatic rupture has never been reported. PATIENT CONCERNS: We report herein a rare case of PCD-associated hepatic rupture. Its clinical courses and our therapeutic approaches are presented. Moreover, the clinical significance, underlying causes, and current views on severe liver trauma management will be discussed briefly. DIAGNOSES: A diabetic patient suffering from fever and malaise was diagnosed with a pyogenic liver abscess. PCD was performed because intravenous antibiotics were ineffective. The patient developed a liver rupture following PCD, with clinical and imaging confirmation but without further progression. INTERVENTIONS: Surgical repair and vascular intervention were both inappropriate. As a result, medical treatments with supportive care were adopted and were found to be effective. OUTCOMES: The patient's condition improved gradually, with stabilized imaging and laboratory performance. He recovered uneventfully during follow-ups. LESSONS: Hepatic rupture should be listed as an extremely rare but severe complication of PCD. Immediate suspicion and effective intervention may avoid an unfavorable consequence. PMID- 29480841 TI - Evaluation of the anatomic and hemodynamic abnormalities in tricuspid atresia before and after surgery using computational fluid dynamics. AB - Analysis of hemodynamics inside tricuspid atresia (TA) chamber is essential to the understanding of TA for optimal treatment. In this study, we introduced a combined computational fluid dynamics (CFD) to simulate blood flow in the left ventricle (LV) to study the diastolic flow changes in TA.Real-time 3-dimentional echocardiography loops (ECHO) were acquired in normal control group, in TA patients before surgery (pre-op group) and after surgery (post-op group). ECHO loops were reconstructed and simulated by CFD, the geometric, volumetric changes, and vortices in the LV were studies and compare among 3 groups.Compared with the control group, pre-op TA patients demonstrated significant LV remodeling, manifesting with smaller LV length, larger diameter, width and spherical index, as well as lager volumes; post-op TA group showed revisions in values of both geometric and volumetric measurements. CDF also demonstrated the abnormality of vortices in the pre-op TA patients and the alteration of existence and measurements of vortex in postoperation group.Echo-based CFD modeling can show the abnormality of TA in both LV geometric, volumetric measurements and intracardiac vortices; and CFD is capable to demonstrate the alterations of LV after Fontan and Glenn surgical procedure. PMID- 29480840 TI - Clinical management of a unique case of PNET of the uterus during pregnancy, and review of the literature. AB - RATIONALE: PNETs (primitive neuroectodermal tumors) are a family of highly malignant neoplasms characterized by small round cells of neuroepithelial origin. They usually involve bone and soft tissues, and have a higher incidence in childhood. PATIENT CONCERNS: In this case report, we describe the obstetric and oncological outcome of a huge mass diagnosed as a leiomyoma in a 39-year-old pregnant woman who complained of low back pain, dysuria, and urinary frequency at 22 weeks of gestation. DIAGNOSES: During the 25th week of pregnancy, the patient was referred to our hospital at night with severe anemia and suspected hemoperitoneum. She underwent an emergency caesarean section, delivering a female fetus weighing 400 g, with an Apgar score of 7 at 1 minute and 9 at 5 minutes. INTERVENTION: During surgery, we found a huge uterine sarcoma-like metastatic tumor, invading the pelvic peritoneum and parametria bilaterally; the adnexae seemed disease-free. We performed a type B radical hysterectomy, bilateral salpingo-oophorectomy, pelvic peritonectomy, omentectomy, appendectomy, and excision of a bulky lymph node. Seven days after delivery, staging computed tomography (CT) scan demonstrated a large lombo-aortic lymph node compressing the left renal vein and we completed debulking with a second surgery, including diaphragmatic peritonectomy and excision of a huge lymph node by lombo-aortic lymphadenectomy, requiring partial reconstruction of an infiltrated renal vein. OUTCOME: Ten days after the second surgery, echo-color Doppler showed a regular microcirculation in the left kidney. The patient was discharged after 10 days, and the baby after 1 month, both in good health.Histological examination revealed a uterine body cPNET (central primitive neuroectodermal tumor) orienting the clinical management toward chemotherapy with cisplatin and etoposide. LESSONS: PNETs are aggressive neoplasms, usually diagnosed at an advanced stage. Due to their low incidence, universally accepted guidelines are still unavailable. Radical surgery leaving no macroscopic residual disease is mandatory in advanced stages. A good fertility-sparing procedure can be performed only in young women at early stages of disease, when the wish for childbearing is not yet fulfilled. PMID- 29480842 TI - Prognostic significance of retention index of bone marrow on dual-phase 18F fluorodeoxyglucose positron emission tomography/computed tomography in patients with diffuse large B-cell lymphoma. AB - The purpose of this study was to determine the prognostic significance of F-18 fluorodeoxyglucose (FDG) uptake on a dual-phase positron emission tomography/computed tomography (PET/CT), focusing on the increment in maximal standardized uptake value (SUVinc) of tumor and bone marrow (BM) between initial and delayed phase images and retention index (RI) of tumor and BM, in patients with diffuse large B-cell lymphoma (DLBCL).From September 2009 to January 2013, 70 patients (37 males and 33 females, aged 60.6 +/- 17.5 years) with DLBCL who had undergone dual-phase FDG PET/CT scans for pretreatment staging were enrolled. The patients subsequently received combination chemotherapy with rituximab. The dual-phase SUV, including SUVinc of tumor (SUVinc-t), RI of tumor (RI-t), SUVinc of BM, and RI of BM were measured. The clinical observation period was from September 2009 to December 2014. Both univariate and multivariate analyses were then used to assess the prognostic significance of SUVinc, RI, international prognostic index (IPI), gender, age, clinical stage, and laboratory tests.The median follow-up time was 35.5 months. The 3-year overall survival (OS) for patients with low/high SUVinc-t (cut-off 2.0) and for patients with low/high RI-t (cut-off 20) were 87.5%/ 62.1% (P = .08) and 83.3%/ 62.7% (P = .14), respectively. The 3-year OS for patients with SUVinc-i < 0.35 and for those with SUVinc-i >= 0.35 were 73.2% and 53.3%, respectively (P = .10). The 3-year OS for patients with RI-i < 45 and for those with RI-i >= 45 were 72.7% and 37.5%, respectively (P = .02). Subsequently, the Cox multivariate forward proportional hazards model revealed that a higher RI-i (hazard ratio: 4.49; 95% confidence interval: 1.64-12.32; P = .0035) and IPI were independent prognostic factors affecting OS.For patients with DLBCL, an elevated RI-i (>=45) was a predictor for shorter OS, independent of IPI score. It added to the value of pretreatment dual phase FDG PET/CT scans. PMID- 29480843 TI - Efficacy of early rehabilitation therapy on movement ability of hemiplegic lower extremity in patients with acute cerebrovascular accident. AB - This study aims to investigate the efficacy of early rehabilitation therapy on the movement ability of hemiplegic lower extremity in patients with acute cerebrovascular accident (CVA).A total of 86 patients who suffered from acute CVA were selected and divided into 2 groups, according to random number tables: control group, and research group. Patients in the control group received routine primary therapy, while patients in the research group received rehabilitation based on the basic therapy. The recovery of hemiplegic limb movement ability and the improvement of daily living ability before and after treatment were evaluated using the simplified Fugl-Meyer assessment (FMA), neurologic deficit scale (NDS), and Barthel index (BI). After treatment, the clinical efficacy and satisfaction degree for treatment were compared.The FMA, NDS, and BI of patients in these 2 groups were distinctly ameliorated after treatment (P <.05). After treatment, the ameliorated degrees of FMA, NDS, and BI in the research group were obviously superior to those in the control group, and the differences were statistically significant (P <.05). The total efficacy and satisfaction degree in the research group were evidently higher than those in the control group after early rehabilitation therapy, and the differences were statistically significant (P <.05).Early rehabilitation therapy can significantly ameliorate the movement ability of hemiplegic lower extremity in patients with acute CVA. Its therapeutic effect is remarkable. Hence, it is worthy of popularizing in clinical practice. PMID- 29480844 TI - Solitary duodenum metastasis from breast cancer with 8 years' latency: A case report. AB - RATIONALE: Advanced breast cancer frequently metastasizes to the lungs, liver, and bones. Metastatic involvement of the duodenal bulb is extremely rare and difficult to detect by endoscopy. PATIENT CONCERNS: A 51-year-old menopausal woman presented with abdominal fullness and obstructive symptoms, and was diagnosed with adenocarcinoma in the duodenal bulb. The patient had undergone modified radical mastectomy of the left breast for infiltrating ductal carcinoma (IDC) 8 years previously. DIAGNOSIS: Metastatic infiltration of the duodenal bulb originating from IDC was proven histologically and immunohistochemically. INTERVENTIONS: She received chemotherapy with docetaxel and capecitabine followed by hormone maintenance therapy with letrozole after operation. OUTCOMES: After treatment, the patient recovered well. She is currently being followed up. LESSONS: Patients with known breast cancer history with the IDC histological type and presenting with nonspecific abdominal symptoms or signs, such as abdominal fullness, nausea, and vomiting, should undergo endoscopy with histopathological examination in order to detect possible gastrointestinal metastasis of the primary breast tumor. This report intends to alert people to heed this type of breast cancer metastasis and not treat it as a primary gastrointestinal tumor. PMID- 29480845 TI - Association of rs2279744 and rs117039649 promoter polymorphism with the risk of gynecological cancer: A meta-analysis of case-control studies. AB - BACKGROUND: Increasing evidence has suggested that rs2279744 is associated with rs117039649 polymorphism, which can increase the risk of gynecological cancers, including cervical, ovarian, breast, and endometrial cancer. The results are inconsistent so that we performed a meta-analysis of current literature to clarify the impacts of these polymorphisms on gynecological cancer. METHODS: Eligible articles were identified through an exhaustive search of relevant databases including PubMed, Embase, Web of science, Springer Link, Chinese National Knowledge Infrastructure (CNKI), and Weipu database for the period up to July 2016. Data about the association between single nucleotide polymorphisms (SNPs) and cancer risk were refined from the selected articles as well as other information about cases and controls, and all of them were extracted by 2 independent researchers and pooled odds ratio with 95% confidence interval was calculated. RESULTS: This analysis included 24 articles, 27 case-control studies of rs2279744 polymorphism and 3 case-control studies of rs117039649 polymorphism. Significant association with the risk of gynecological cancer was observed for both SNPs. Subgroup analysis by ethnicity and cancer type (cervical, ovarian, breast, and endometrial) also showed a positive relationship between rs2279744 polymorphism and gynecological cancer risk in Caucasian; and there was also a notable association between rs2279744 polymorphism and cervical cancer. CONCLUSIONS: We found that rs2279744 (SNP309) and rs117039649 (SNP285) were both associated with the risk of gynecological cancers. Subgroup analysis showed that rs2279744 (SNP309) was associated with the risk of gynecological cancers in Caucasian and Asian according to the ethnicity and cancer type, especially for endometrial cancer. PMID- 29480846 TI - Supratentorial intracerebral cerebellar liponeurocytoma: A case report and literature review. AB - RATIONALE: Cerebellar liponeurocytoma is a rare tumor of the central nervous system (CNS) characterized by low proliferation but high likelihood of recurrence. Because of its rarity and the paucity of systematic follow-up, the biological behaviors and clinical features of this tumor are still poorly understood. We herein reported a case of cerebellar liponeurocytoma originating in the cerebral hemisphere. PATIENT CONCERNS: A 11-year-old male with intermittent headache, nausea, and vomiting. The first computed tomography revealed a large mass in the right cerebral hemisphere. He was transferred to our institution for neurosurgical treatment. DIAGNOSIS: Magnetic resonance imaging showed a large cystic-solid mass in the right frontal lobe with obvious contrast enhancement. Histopathological examinations showed sheets of isomorphic small neoplastic cells with clear cytoplasm and focal lipomatous differentiation. On immunohistochemistry, tumor cells were positive for synaptophysin, microtubule associated protein 2, and neuronal nuclei antigen. INTERVENTIONS: The patient was performed a right fronto-parietal craniotomy, and gross total resection of the tumor was achieved without adjuvant therapy. OUTCOMES: No clinical or neuroradiological evidence of recurrence or residual of the tumor was found 6 years and 2 months after initial surgery. LESSONS: Cerebellar liponeurocytoma developing in supratentorial cerebral hemisphere was first reported in the present study. The radiological and histopathological features may be useful in differentiating this rare tumor from other tumors at similar locations. A change in the nomenclature of cerebellar liponeurocytomas should be considered in future World Health Organization (WHO) classifications. PMID- 29480847 TI - Paternal exposure to medical-related radiation associated with low birthweight infants: A large population-based, retrospective cohort study in rural China. AB - Low birthweight (LBW) is closely associated with fetal and perinatal mortality and morbidity. We identified the risk factors of LBW and geographical differences in LBW incidence in 30 Chinese provinces in the present study.This study was a population-based, retrospective cohort study performed in 30 Chinese provinces. We used data from the free National Pre-pregnancy Checkups Project, which is a countrywide population-based retrospective cohort study. To identify regional differences in LBW incidence, we used the Qinling-Huaihe climate line to divide China into northern and southern sections and the Heihe-Tengchong economic line to divide it into eastern and western sections. Multivariate unconditional logistic regression analysis with SAS 9.4 was used for data analysis. P < .05 was considered statistically significant.LBW incidence was 4.54% in rural China. Southern China had a significantly higher incidence (4.65%) than northern China (4.28%). Our main risk factor for LBW is paternal exposure to radiation (odds ratio = 1.537), which has never been studied before.This study identifies multiple risk factors of couples giving birth to LBW babies including paternal risk factors. PMID- 29480849 TI - Patient safety culture perceptions in the college of dentistry. AB - A positive safety culture is essential to patient safety because it improves quality of care. The aim of this study was to assess staff and student perceptions of the patient safety culture in the clinics of the College of Dentistry at King Saud University in Saudi Arabia.A cross-sectional study was conducted in the College of Dentistry at King Saud University in Saudi Arabia. It included 4th and 5th year students, interns, general practitioners, and dental assistants. The data were collected by using paper-based questionnaire of modified version of the Agency for Healthcare Research and Quality Hospital Survey on Patient Safety Culture. Data were entered into SPSS Version 20. Score on a particular safety culture dimension was calculated.The overall response rate was 72.8% (390/536). Team work dimension had the highest average percent positive dimension score (72.3%) while staffing had the lowest score (10%). Dental assistant had high agreement in Teamwork dimension (87.8%); Supervisor/Manager Expectations and Actions Promoting Patient Safety dimension (66.9%); Organizational Learning-Continuous Improvement dimension (79.1%); Management Support for Patient Safety dimension (84.5%); Feedback and Communication About Error dimension (58.3%); Frequency of Events Reported dimension (54.0%); Teamwork Across Units dimension (73.2%). Most of areas perceived that there is no event reported (76.1-85.3%) in the past 12 months.Overall patient safety grade is more than moderate in the clinic. Teamwork within Units and Organizational Learning Continuous Improvement dimension had the highest score while staffing had the lowest score. Dental assistants perceived positive score in most dimensions while students perceived slight negative score in most dimensions. PMID- 29480848 TI - Exenatide once weekly for smoking cessation: study protocol for a randomized clinical trial. AB - BACKGROUND: Cigarette smoking is the greatest preventable cause of morbidity and premature mortality in the United States. Approved pharmacological treatments for smoking cessation are marginally effective, underscoring the need for improved pharmacotherapies. A novel approach might use glucagon-like peptide-1 (GLP-1) agonists, which reduce alcohol and drug use in preclinical studies. GLP-1 is produced in the intestinal L-cells and in the hindbrain. The peptide maintains glucose homeostasis and reduces food intake. Several GLP-1 agonists are used clinically to treat type 2 diabetes and obesity, but none have been tested in humans to reduce smoking. AIMS: We will examine whether extended-release exenatide reduces smoking, craving, and withdrawal symptoms, as well as cue induced craving for cigarettes. METHODS: We will enroll prediabetic and/or overweight treatment seeking smokers (n = 90) into a double-blind, placebo controlled, randomized clinical trial. Participants will be randomized in a 1:1 ratio to receive exenatide or placebo. All participants will receive transdermal nicotine replacement therapy (NRT) and behavioral counseling. Abstinence from smoking (verified via expired CO level of <=5 ppm), craving (Questionnaire of Smoking Urges score), and withdrawal symptoms (Wisconsin Scale of Withdrawal Symptoms score) will be assessed weekly during 6 weeks of treatment and at 1 and 4 weeks posttreatment. Cue-induced craving for cigarettes will be assessed at baseline and at 3 weeks of treatment following virtual reality exposure. EXPECTED OUTCOMES: We hypothesize that exenatide will increase the number of participants able to achieve complete smoking abstinence above that achieved via standard NRT and that exenatide will reduce craving and withdrawal symptoms, as well as cue induced craving for cigarettes. PMID- 29480851 TI - Validation of the Peripheral Ultrasound-guided Vascular Access Rating Scale. AB - Evidence-based standards in proficiency are needed for ultrasound-guided peripheral intravenous access. In this study, we explored the validity of the Peripheral Ultrasound-Guided Vascular Access (P-UGVA) Rating Scale.We recruited 3 groups of physicians (5 novices, 5 intermediates, and 5 experts) of increasing proficiency in peripheral ultrasound-guided intravenous access. All participants performed 3 peripheral ultrasound-guided intravenous accesses on three different patients. Performance was video-recorded by 3 cameras and the ultrasound image. Synchronized and anonymized split-screen film clips were rated using the P-UGVA rating scale by 2 assessors, which also assessed overall performance on a 1-5 Likert-scale. Evidence of validity was explored using the contemporary validity framework by Messick (content, response process, internal structure, relations to other variables, and consequences).Content and response process was ensured in the development of the rating scale and validity study. Internal consistency of the P-UGVA rating scale was excellent and sufficient high for certification purposes (Cronbach's alpha = 0.91). Proficiency groups were successfully discriminated by the UPGIVA rating scale (P = .029, one-way ANOVA), and the P UGVA rating scale scores also correlated strongly with the overall performance evaluations (rho = 0.87, P < .001, Pearson correlation). We calculated a pass/fail score of 29, which lead to a theoretical false positive rate of 26.5% and false negative rate of 8.5%.We present validity evidence for the P-UGVA rating scale and an evidence-based standard in proficiency for ultrasound-guided peripheral intravenous access. PMID- 29480850 TI - Functional analysis of cell-free RNA using mid-trimester amniotic fluid supernatant in pregnancy with the fetal growth restriction. AB - The prediction and monitoring of fetal growth restriction (FGR) fetuses has become with the use of ultrasound. However, these tools lack the fundamental evidence for the growth of fetus with FGR excluding pathogenic factors.Amniotic fluid samples were obtained from pregnant women for fetal karyotyping and genetic diagnosis at 16 to 19 weeks of gestation. For this study, 15 FGR and 9 control samples were selected, and cell-free fetal RNA was isolated from each supernatant of the amniotic fluid for microarray analysis.In this study, 411 genes were differentially expressed between the FGR and control group. Of these genes, 316 genes were up-regulated, while 95 genes were down-regulated. In terms of gene ontology, the up-regulated genes were highly related to metabolic process as well as protein synthesis, while the down-regulated genes were related to receptor activity and biological adhesion. In terms of tissue-specific expression, the up regulated genes were involved in various organs while down-regulated genes were involved only in the brain. In terms of organ-specific expression, many genes were enriched for B-cell lymphoma, pancreas, eye, placenta, epithelium, skin, and muscle. In the functional significance of gene, low-density lipoprotein receptor related protein 10 (LRP10) was significantly increased (6-fold) and insulin-like growth factor (IGF-2) was dramatically increased (17-fold) in the FGR cases.The results show that the important brain-related genes are predominantly down regulated in the intrauterine growth restriction fetuses during the second trimester of pregnancy. This study also suggested possible genes related to fetal development such as B-cell lymphoma, LRP10, and IGF-2. To monitor the fetal development, further study may be needed to elucidate the role of the genes identified. PMID- 29480852 TI - Combined analysis of endometrial thickness and pattern in predicting clinical outcomes of frozen embryo transfer cycles with morphological good-quality blastocyst: A retrospective cohort study. AB - To evaluate the combined effect of endometrial thickness and pattern on clinical outcomes in females following in vitro fertilization/intracytoplasmic sperm injection and frozen-thawed embryo transfer (IVF/ICSI-FET).FET cycles using at least 1 morphological good-quality blastocyst conducted between 2012 and 2013 at a university-based reproductive center were reviewed retrospectively. Endometrial ultrasonographic characteristics were recorded on the day of progesterone supplementation in FET cycles. In the combined analysis, endometrial thickness groups (group 1: equal or < 8 mm; group 2: >8 mm) were subdivided into 2 endometrial patterns (pattern A: triple-line; pattern B: no-triple line). Clinical pregnancy rate, spontaneous abortion rate, and live birth rate in different groups were analyzed.A total of 1512 cycles were reviewed. The results showed that significant differences in endometrial thickness and pattern were observed between the pregnant group (n = 1009) and no pregnant group (n = 503) (P < .05), while no significant differences were found between the live birth group (n = 844) and no live birth group (n = 668). Combined analysis revealed those with endometrial thickness > 8 mm and triple-line endometrial pattern had significant higher clinical pregnancy rates, while spontaneous abortion rates and live birth rates showed no significant differences among these subgroups.This study suggested neither individual nor combined analysis of endometrial thickness and pattern had predicting effects on live birth following IVF treatments, and embryo quality might be the one that really has effects. PMID- 29480853 TI - Effects of remote ischemic preconditioning on contrast induced nephropathy after percutaneous coronary intervention in patients with acute coronary syndrome. AB - OBJECTIVE: The aim of this study was to explore the clinical effects of remote ischemic preconditioning (RIPC) on contrast-induced nephropathy after percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS). PATIENTS AND METHODS: The study was a single-center, prospective, randomized, controlled study. A total of 161 patients with ACS and the rate of estimate glomerular filtration (eGFR) 15 to 70 mL/min/1.73 m2 undergoing PCI were randomly assigned to RIPC group (induced by 4 times of 5-minute inflations of a blood pressure cuff to 200 mmHg around the upper arm, followed by 5-min intervals of reperfusion at 1 hour before PCI therapy) or control group (an uninflated cuff around the arm). Successful completion of the PCI eventually included 107 cases of patients, including 50 cases in the RIPC group and 57 cases in the control group. The level of serum creatinine (Scr), CystatinC (CysC), blood neutrophil gelatinase-associated lipocalin (NGAL), eGFR were measured in all patients at 6 AM before the day of PCI, and 4-hour NGAL, 24-hour CysC, 72-hour Scr, and eGFR after PCI in the 2 groups. The incidence of major adverse events in the kidney (including the incidence of CIN, the need for dialysis, or renal replacement therapy after using contrast agent) and the composite endpoint of cardiovascular events were recorded at 6 months after PCI. RESULTS: There were no statistically significant differences in baseline indicators between the 2 groups. Scr, CysC, and blood NGAL levels and the incidence of CIN in patients with RIPC group were significantly lower than those form the control group after PCI (P < .05), but there were no significant differences between the average value of eGFR and occurrence of Major cardiovascular events in the postoperative 6 months (P > .05). CONCLUSIONS: RIPC can reduce PCI-related CIN and protect renal function in patients with ACS. The benefits of these patients by RIPC may be related to the reduction of the NGAL and CysC. PMID- 29480854 TI - Hypercalcemic pancreatitis a rare presentation of sarcoidosis: A case report. AB - RATIONALE: The usual presentation of sarcoidosis is hilar adenopathy, pulmonary reticular opacities, skin, joint, or eye lesions. Pancreatic involvement is unusual and hypercalcemic pancreatitis as initial manifestation is very rare. PATIENT CONCERNS: We present a case that presented with 1-day history of vomiting, diffuse abdominal pain, and altered mental status. DIAGNOSES: Initial investigations showed highly elevated calcium levels, acute pancreatitis, and kidney failure. Possible causes entertained were malignancy, hyperparathyroidism, hypervitaminosis D, and granulomatous diseases. Full work-up including a hilar lymph node biopsy revealed noncaseating granuloma. After excluding other diseases capable of producing a similar picture, a diagnosis of sarcoidosis was made. INTERVENTIONS AND OUTCOMES: The patient was started on aggressive intravenous fluid hydration and intravenous calcitonin, after which her altered mental status resolved and both kidney function and hypercalcemia improved. The patient was discharged on oral prednisone and serum calcium level normalized with progressive improvement of kidney function at follow-up. LESSONS: The current case highlights the need for a high index of suspicion for this condition in patients who present with acute pancreatitis, as steroids are the treatment of choice. Thus, prompt recognition of this entity is of therapeutic significance. PMID- 29480855 TI - Does pedicle screw density matter in Lenke type 5 adolescent idiopathic scoliosis? AB - The aim of this study is to compare the effects of high versus low implant density on correction in Lenke type 5 adolescent idiopathic scoliosis (AIS) patients. A retrospective study of 59 Lenke type 5 AIS patients treated at a single institution were divided into to 2 groups according to implant density. Implant density, preoperative, early postoperative, and last follow-up thoracolumbar/lumbar (TL/L) curves were measured. Thirty-one constructs were high and 28 constructs were low density. The groups were similar in terms of age, sex, Cobb angle, and follow-up time. Mean implant density in low density group and high density group was 75.4% and 96.6%, respectively. High versus low-density comparison showed that there is no significant difference with regard to curve correction in early postoperative and last follow-up periods. The results show that pedicle screw density being low or high, does not affect curve correction rates in the short and long term in our patients. PMID- 29480856 TI - Association analysis between thrombospondin-2 gene polymorphisms and intervertebral disc degeneration in a Chinese Han population. AB - The aim of this study is to determine the contribution of 2 single nucleotide polymorphisms (SNPs) in thrombospondin 2 (THBS2) gene to the development of intervertebral disc degeneration (IDD) in a Chinese Han population.We studied 138 patients with radiographically proven IDD and 136 healthy volunteers with no history of back problems. Magnetic resonance images (MRIs) were obtained for all the patients and controls. Image evaluation for IDD was performed to evaluate the severity of IDD. All patients and controls were genotyped for rs6422747 and rs6422748. Associations between genotypes and development of IDD were analyzed.We found that 2 SNPs in the intron region of THBS2 gene (rs6422747 and rs6422748) were associated with susceptibility of IDD. However, they were not related with severity of IDD, including the total number of degenerative disc and level of IDD. G allele in both SNPs was associated with a higher risk of IDD.The 2 SNPs (rs6422747 and rs6422748) in the THBS2 gene were associated with susceptibility of IDD but not severity of IDD in a Chinese Han population. Our results indicated that THBS2 gene polymorphisms might be the risk factors for IDD. More studies with larger sample size need to be perfected to make sure the functions of THBS2 gene polymorphisms in IDD development. PMID- 29480857 TI - Electrophysiological examination and high frequency ultrasonography for diagnosis of radial nerve torsion and compression. AB - This study aims to evaluate the value of electrophysiological examination and high frequency ultrasonography in the differential diagnosis of radial nerve torsion and radial nerve compression.Patients with radial nerve torsion (n = 14) and radial nerve compression (n = 14) were enrolled. The results of neurophysiological and high frequency ultrasonography were compared.Electrophysiological examination and high-frequency ultrasonography had a high diagnostic rate for both diseases with consistent results. Of the 28 patients, 23 were positive for electrophysiological examination, showing decreased amplitude and decreased conduction velocity of radial nerve; however, electrophysiological examination cannot distinguish torsion from compression. A total of 27 cases showed positive in ultrasound examinations among all 28 cases. On ultrasound images, the nerve was thinned at torsion site whereas thickened at the distal ends of torsion. The diameter and cross-sectional area of torsion or compression determined the nerve damage, and ultrasound could locate the nerve injury site and measure the length of the nerve.Electrophysiological examination and high-frequency ultrasonography can diagnose radial neuropathy, with electrophysiological examination reflecting the neurological function, and high frequency ultrasound differentiating nerve torsion from compression. PMID- 29480858 TI - Internal jugular vein aneurysm: A case report. AB - INTRODUCTION: Aneurysm is a localized dilatation of an artery of at least 1.5 times the normal diameter that occurs when part of an artery wall weakens or is injured, allowing it to widen abnormally. In practice, an arterial aneurysm is more common in comparison to a venous aneurysm. Because of the rare incidence of venous aneurysms, treatment guidelines are not clearly established and thus treatment strategies vary. This is a case of a 57-year-old Saudi woman, with no significant medical history, who presented to Prince Sultan Military Hospital complaining of swelling in the right side of the neck that started 3 years ago. The patient reported that the swelling enlarged with coughing and straining, but there was no pain, change in skin color, dysphagia, change in voice, neurological defect, shortness of breath, history of any trauma to the neck, surgical intervention, or any lump. The condition can be diagnosed via ultrasonography, computed tomography, or magnetic resonance imaging. CONCLUSION: Despite the lack of guidelines, intervention was necessary because the patient was anxious regarding the increase in the size of the swelling, which she felt had a negative psychosocial impact. Moreover, because the sizable venous aneurysm harbored a mural thrombus that increased the risk of embolization and pulmonary embolism, surgery was offered.Indication for surgery includes pain, swelling, and cosmetic concerns. Conservative management of the condition is described in the literature. PMID- 29480859 TI - Sequential occurrence of diffuse large B-cell lymphoma and carcinoma in the nasopharynx: A case report. AB - BACKGROUND: The sequential occurrence of the 2 malignancies development of nasopharyngeal carcinoma (NPC) and lymphoma is extremely rare and their coexistence raises the question of a common etiologic factor. CLINICAL FINDINGS/CLINICAL CONCERNS: A 71-year-old previously healthy man presented with diffuse large B-cell lymphoma (BCL) followed by NPC almost 2 years later with Epstein-Barr virus (EBV) positive. DIAGNOSIS: Endoscopic examination characterized a fixed, hard and nontender mass in the nasopharynx and biopsies were done. INTERVENTION: A patient successfully underwent chemotherapy for lymphoma and chemoradiation for carcinoma sequentially. OUTCOMES: He was followed up every 3 months for 1 year with endoscopic and radiological examinations. The nasopharynx mass was completely resolved after chemoradiation therapy. CONCLUSION: The presentation with diffuse large B-cell lymphoma (BCL) and NPC in this patient was perhaps caused by dual EBV infection or a different oncogenic mechanism. PMID- 29480861 TI - Evaluation of a central venous catheter tip placement for superior vena cava subclavian central venous catheterization using a premeasured length: A retrospective study. AB - Subclavian central venous catheterization is a common procedure for which misplacement of the central venous catheter (CVC) is a frequent complication that can potentially be fatal. The carina is located in the mid-zone of the superior vena cava (SVC) and is considered a reliable landmark for CVC placement in chest radiographs. The C-length, defined as the distance from the edge of the right transverse process of the first thoracic spine to the carina, can be measured in posteroanterior chest radiographs using a picture archiving and communication system. To evaluate the placement of the tip of the CVC in subclavian central venous catheterizations using the C-length, we reviewed the medical records and chest radiographs of 122 adult patients in whom CVC catheterization was performed (from January 2012 to December 2014) via the right subclavian vein using the C length. The tips of all subclavian CVCs were placed in the SVC using the C length. No subclavian CVC entered the right atrium. Tip placement was not affected by demographic characteristics such as age, sex, height, weight, and body mass index. The evidence indicates that the C-length on chest radiographs can be used to determine the available insertion length and place the right subclavian CVC tip into the SVC. PMID- 29480860 TI - The radiosensitive effect of apatinib for hepatocellular carcinoma patient with big paraspinal metastasis: A case report. AB - RATIONALE: Hepatocellular carcinoma (HCC) is a highly invasive cancer associated with great mortality rates. The prognosis of advanced HCC is very poor. PATIENT CONCERNS: Here, we report a HCC patient with a big paraspinal metastasis with 10 cm in diameter who failed the treatment of sorafenib. DIAGNOSES: Sorafenib refractory HCC with big paraspinal metastasis. INTERVENTIONS: The concurrent treatment of apatinib with stereotactic body radiotherapy (SBRT). OUTCOMES: The paraspinal metastasis with 10 cm in diameter showed nearly complete response. LESSONS: We think that the apatinib may be a good choice for HCC and it may function as a radiosensitizer of HCC. However, it warrants further investigation in the future prospective clinical studies. PMID- 29480862 TI - Refractory chyle leakage after laparoscopic cholecystectomy for gallstone disease: A case report and literature review. AB - RATIONALE: Gallstone disease is commonly worldwide and safely treated by laparoscopic cholecystectomy. Chylous ascites is a rare but serious complication of many abdominal operations. PATIENT CONCERNS: We present a rare case of refractory chyle leakage post-LC for acute cholecystitis that is successfully treated in a 40-year-old man, and review current literature on the prevalence, diagnosis, and management of this complication. DIAGNOSES: Refractory chyle leakage post-LC, a rare but serious complication after laparoscopic cholecystectomy. INTERVENTIONS: Conservative treatment was given initially; however, the outcome was frustrating. Surgical intervention was given without further delay. OUTCOMES: After the reoperation, conservative treatment was still maintained. After nearly 8 months of treatment, the patient recovered and then was discharged. LESSONS: This case represents a previously unreported complication of refractory and high flow chyle leakage after laparoscopic cholecystectomy, which did not improve alter conservative management with dietary changes and other measures. So we suggest that surgical intervention should be given for refractory cases without further delay. It can not only shorten the disease progression, but also alleviate the sufferings of the patient. PMID- 29480863 TI - Tongue diagnosis indices for upper gastrointestinal disorders: Protocol for a cross-sectional, case-controlled observational study. AB - BACKGROUND: Upper gastrointestinal disorders are common in clinical practice, for example, gastritis, peptic ulcer disease, and gastroesophageal reflux disease. Panendoscopy or upper gastrointestinal endoscopy is viewed as the primary tool for examining the upper gastrointestinal mucosa, and permitting biopsy and endoscopic therapy. Although panendoscopy is considered to be a safe procedure with minimal complications, there are still some adverse effects, and patients are often anxious about undergoing invasive procedures. Traditional Chinese medicine tongue diagnosis plays an important role in differentiation of symptoms because the tongue reflects the physiological and pathological condition of the body. The automatic tongue diagnosis system (ATDS), which noninvasively captures tongue images, can provide objective and reliable diagnostic information. METHODS: This protocol is a cross-sectional, case-controlled observational study investigating the usefulness of the ATDS in clinical practice by examining its efficacy as a diagnostic tool for upper gastrointestinal disorders. Volunteers over 20 years old with and without upper gastrointestinal symptoms will be enrolled. Tongue images will be captured and the patients divided into 4 groups according to their panendoscopy reports, including a gastritis group, peptic ulcer disease group, gastroesophageal reflux disease group, and healthy group. Nine primary tongue features will be extracted and analyzed, including tongue shape, tongue color, tooth mark, tongue fissure, fur color, fur thickness, saliva, ecchymosis, and red dots. OBJECTIVES: The aim of this protocol is to apply a noninvasive ATDS to evaluate tongue manifestations of patients with upper gastrointestinal disorders and examine its efficacy as a diagnostic tool. PMID- 29480864 TI - Retrograde gastroesophageal intussusception after peroral endoscopic myotomy in a patient with achalasia cardia: A case report. AB - RATIONALE: Retrograde gastroesophageal intussusception (RGEI) is a relatively rare gastrointestinal (GI) disorder in which a portion of the stomach wall invaginates into the esophagus. More recently, peroral endoscopic myotomy (POEM) has emerged as an endoscopic alternative to surgical myotomy for achalasia, and, to the best of our knowledge, our case is the first RGEI after POEM to be reported. PATIENT CONCERNS: A 22-year-old male was presented with a history of vomiting, intractable retching and hematemesis for 3 days. He had a history of achalasia and underwent POEM 3 years ago caused by symptoms of severe dysphagia to solid and liquid. DIAGNOSES: Initially, the patient was diagnosed with a blood filled esophagus, and the mid esophagus was occluded with a ball-like mass, however, the final diagnosis of RGEI was made by thoracotomy. INTERVENTIONS: A therapeutic strategy of conservative treatment and left transthoracic surgery were applied. OUTCOMES: The surgery and post operative course were uneventful, and he remained asymptomatic 1 year after operation. LESSONS: POEM is a reliable and minimally invasive endoscopic method for esophageal achalasia. Early recognition and severity of RGEI are essential to decrease the unwanted complications. Upper GI series, esophagogastroduodenoscopy and computed tomography scan are helpful for diagnostic purposes of RGEI. Conservative treatment, endoscopic intervention, and surgery are the mainstay of treatments for RGEI. PMID- 29480867 TI - Use of Univent tube for intermittent lung isolation during thoracoscopic mediastinal tracheal resection and reconstruction: A case report: Erratum. PMID- 29480865 TI - Therapeutic effect of chidamide on relapsed refractory angioimmunoblastic T-cell lymphoma: A case report and literature review. AB - INTRODUCTION: Angioimmunoblastic T-cell lymphoma (AITL) is a kind of rare peripheral T cell lymphoma, which usually has acute onset at old age. MATERIALS AND METHODS: Here we report a case of relapsed refractory AITL, which has achieved obvious curative effect after treatment with chidamide. RESULTS: Initially, the patient received 7 courses of treatment with recombinant human endostatin (endostar)+CHOP. The patient achieved complete remission, but suffered from recurrence later. After changing chemotherapy regimens, the outcome was still not satisfactory, and the patient developed systemic skin infiltration and rashes. After 2 courses of chemotherapy with chidamide (30 mg) twice a week + intravenous injections with cyclophosphamide (0.1 g) twice every other day + thalidomide (50 mg) every night, the patient began with the oral intake of chidamide, and the therapeutic effect was satisfactory, with diminishing systemic rashes and shrunken lymph nodes. DISCUSSION AND CONCLUSIONS: Chidamide has good therapeutic effect in the treatment of AITL, which provides a novel therapeutic strategy for relapsed refractory AITL. However, more cases are still needed to further validate its efficacy. PMID- 29480868 TI - Mesalazine as a cause of fetal anemia and hydrops fetalis: A case report: Erratum. PMID- 29480866 TI - Prevalence and mortality of chronic kidney disease in lymphoma patients: A large retrospective cohort study. AB - In patients with lymphoma, an important issue that has been recognized is renal involvement, including glomerulonephritis, acute kidney injury, and lymphoma infiltrating the kidney. However, the prevalence and mortality of chronic kidney disease (CKD) have not been fully understood in lymphoma patients. This study aimed to evaluate the prevalence of CKD and its impact on mortality in those patients.This was a retrospective cohort study of 429 consecutive lymphoma patients who were admitted or regularly visited our hospital from January 2013 to October 2016. CKD was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m and/or proteinuria >= 1+ that was sustained for at least 3 months. The prevalence of CKD at enrollment was evaluated according to the modified CKD classification by Kidney Disease: Improving Global Outcomes (KDIGO) (eGFR and proteinuria category). Dipstick proteinuria was classified into 3 grades: A1 for and +/-; A2 for 1+ or 2+; and A3 for >=3+. The eGFR (mL/min/1.73 m) was classified into 6 stages: G1 for >=90, G2 for 60 to 89, G3a for 45 to 59, G3b for 30 to 44, G4 for 15 to 29, and G5 for <15. The cumulative mortality rate was estimated using the Kaplan-Meier method, with stratification into 2 groups based on the presence or absence of CKD. Furthermore, a multivariate Cox proportional hazards regression model was used to calculate the hazard ratio (HR) and its 95% confidence interval (CI) for all-cause mortality, after adjustments for age, sex, pathologic type, clinical stage of lymphoma, presence or absence of diabetes mellitus, hypertension, and cardiovascular disease.The mean follow-up period was 3.06 +/- 0.96 years, and the prevalence of CKD at study enrollment was 34.5%. The cumulative mortality rate was 20.7%, and was significantly higher in the CKD group than in the group without CKD (36.4% vs 18.0%, P = .02). Multivariate analysis found mortality to be significantly associated with CKD (HR 1.58; 95% CI, 1.01-2.46), and this association was the most robust with very high-risk CKD (HR 6.94; 95% CI, 2.50-17.33).The prevalence of CKD in lymphoma patients was high. CKD should be considered an independent risk factor for mortality among patients with lymphoma. PMID- 29480869 TI - A case report of phosphaturic mesenchymal tumor-induced osteomalacia: Erratum. PMID- 29480870 TI - The clinical effect of rehabilitation following arthroscopic rotator cuff repair: A meta-analysis of early versus delayed passive motion. AB - BACKGROUND: The argument on the recommended rehabilitation protocol following arthroscopic rotator cuff repair remains to be resolved. So this meta-analysis was presented to evaluate the differences of clinical effects between the 2 distinct rehabilitation protocols after arthroscopic rotator cuff repair. METHODS: The PubMed, Cochrane Library, Web of Science, and EMBASE were systematically searched. Only randomized controlled trials (RCTs) published up to July 25, 2017, comparing early passive motion (EPM) versus delayed passive motion (DPM) rehabilitation protocols following arthroscopic rotator cuff repair were identified. The primary outcomes included range of motion and healing rate, while the secondary outcomes were Constant score, American Shoulder and Elbow Society (ASES) score, and Simple Shoulder Test (SST) score. The exclusion criteria contained biochemical trials, reviews, case reports, retrospective studies, without mention about passive motion exercise, no assessment of outcomes mentioned above, and no comparison of EPM and DPM rehabilitation protocols. RESULTS: Eight RCTs with 671 patients were enrolled in this study. The EPM resulted in improved shoulder forward flexion at short term, mid-term, and long term follow-ups. The EPM group was superior to the DPM group in terms of external rotation (ER) at short-term and mid-term follow-ups. However, the DPM performed better long-term ASES score. These 2 protocols were equivalent in terms of ER at long term, ASES score at mid-term, SST score, Constant score, and healing rate. After excluding 2 RCTs that examined only small- and medium-sized tears, the pooled results of healing rate decreased from 82.4% to 76.6% in the EPM and 86.9% to 85.9% in the DPM. CONCLUSION: The meta-analysis suggests that the EPM protocol results in superior ROM recovery after arthroscopic rotator cuff repair but may adversely affect the shoulder function, which should be supported by further research. The healing rate at long-term follow-up is not clearly affected by the type of rehabilitation, but the EPM protocol might result in lower rates of tendon healing in the shoulder with large-sized tendon tears. PMID- 29480871 TI - Association of vitamin D receptor BsmI rs1544410 and ApaI rs7975232 polymorphisms with susceptibility to adolescent idiopathic scoliosis: A systematic review and meta-analysis. AB - BACKGROUND: AIS is the most common spinal deformity disease, yet its etiology remains uncertain. Significant associations have been found between AIS risk and vitamin D receptor (VDR) gene polymorphisms; however, some of these results are controversial. The aim of this study was to determine whether VDR BsmI rs1544410 and ApaI rs7975232 polymorphisms are correlated with AIS. METHODS: Databases, including PubMed, EMBASE, Web of Science, the Cochrane Library, the Chinese Biomedical Literature Database, and the Wanfang Database, were systematically searched, and eligible case-control studies that explored the association of VDR (BsmI and ApaI) and the susceptibility to AIS were selected. The pooled odds ratio (OR) with 95% confidence interval (95% CI) was calculated to assess the associations, and subgroup meta-analyses were performed according to the ethnicity of the study population. RESULTS: A total of 5 studies with 717 cases and 554 controls fulfilled the inclusion criteria after assessment by 2 reviewers. Generally, significant correlations were found between the BsmI polymorphism and AIS risk in overall populations and in Asian populations (overall population: B vs b: OR = 2.12, 95% CI = 1.21-3.75, P = .009; BB vs bb: OR = 3.38, 95% CI = 1.08-10.57, P = .036; Bb vs bb: OR = 2.50, 95% CI = 1.29 4.82, P = .006; BB/Bb vs bb: OR = 2.71, 95% CI = 1.31-5.63, P = .007; Asian population: B vs b: OR = 2.42, 95% CI = 1.27-4.61, P = .007; BB vs bb: OR = 4.09, 95% CI = 1.03-16.22, P = .045; Bb vs bb: OR = 2.94, 95% CI = 1.42-6.10, P = .004; BB/Bb vs bb: OR = 3.23, 95% CI = 1.42-7.35, P = .005). There was no significant association observed in Caucasian populations (all P > .05). With regard to the ApaI polymorphism, we found that it significantly decreased the risk of AIS (Aa vs AA: OR = 0.43, 95% CI = 0.24-0.77, P = .004; Aa/aa vs AA: OR = 0.52, 95% CI = 0.30-0.91, P = .023); however, we could not draw a definitive conclusion for Caucasian populations, as no studies have been conducted in this group to determine the role of the VDR ApaI polymorphism in AIS etiology and development. CONCLUSION: VDR BsmI was significantly associated with AIS susceptibility in the overall and Asian populations, while the VDR ApaI polymorphism only played a key role in AIS etiology and development in Asian populations. PMID- 29480872 TI - Generate the scale-free brain music from BOLD signals. AB - Many methods have been developed to translate a human electroencephalogram (EEG) into music. In addition to EEG, functional magnetic resonance imaging (fMRI) is another method used to study the brain and can reflect physiological processes. In 2012, we established a method to use simultaneously recorded fMRI and EEG signals to produce EEG-fMRI music, which represents a step toward scale-free brain music. In this study, we used a neural mass model, the Jansen-Rit model, to simulate activity in several cortical brain regions. The interactions between different brain regions were represented by the average normalized diffusion tensor imaging (DTI) structural connectivity with a coupling coefficient that modulated the coupling strength. Seventy-eight brain regions were adopted from the Automated Anatomical Labeling (AAL) template. Furthermore, we used the Balloon-Windkessel hemodynamic model to transform neural activity into a blood oxygen-level dependent (BOLD) signal. Because the fMRI BOLD signal changes slowly, we used a sampling rate of 250 Hz to produce the temporal series for music generation. Then, the BOLD music was generated for each region using these simulated BOLD signals. Because the BOLD signal is scale free, these music pieces were also scale free, which is similar to classic music. Here, to simulate the case of an epileptic patient, we changed the parameter that determined the amplitude of the excitatory postsynaptic potential (EPSP) in the neural mass model. Finally, we obtained BOLD music for healthy and epileptic patients. The differences in levels of arousal between the 2 pieces of music may provide a potential tool for discriminating the different populations if the differences can be confirmed by more real data. PMID- 29480873 TI - Low incidence of adjacent segment disease after posterior lumbar interbody fusion with minimum disc distraction: A preliminary report. AB - STUDY DESIGN: A retrospective review of prospectively collected data. OBJECTIVE: To investigate the incidence of radiographic and symptomatic adjacent segment disease (ASD) and identify possible risk factors for ASD after posterior lumbar interbody fusion (PLIF) with minimum disc distraction by selecting low-height interbody cages. SUMMARY OF BACKGROUND DATA: Excessive disc space distraction is reportedly 1 of the risk factors for ASD after PLIF; however, the incidence and other risk factors of ASD after PLIF with minimum disc distraction remain unclear. METHODS: Forty-one consecutive patients who underwent PLIF at L4-L5 and were postoperatively followed up for a minimum of 2 years were included. The height and shape (box or bullet shape) of interbody cages was determined according to the disc height and morphology of the intervertebral space assessed on preoperative computed tomography scans to avoid excessive distraction. The incidence of radiographic and symptomatic ASD was evaluated and all demographic and radiographic parameters were compared between patients with and without ASD. Multivariate logistic regression analysis was performed to identify risk factors for ASD among the variables with P < .20 in univariate analysis. RESULTS: The overall incidence of ASD was 12.2% (5/41 patients): radiographic ASD, 7.3% (3 patients); symptomatic ASD, 4.9% (2 patients). Multivariate analysis revealed preoperative retrolisthesis of L3 on extension as the sole risk factor for ASD after PLIF with minimum disc distraction (odds ratio, 2.13; 95% confidence interval, 1.00-4.05; P = .049). CONCLUSIONS: The incidence of ASD in this study was lower than that of ASD in our previous study about PLIF with distraction of disc space (12.2% vs. 31.8%). Minimum disc distraction by selection of low-height interbody cages is a simple and effective method to prevent ASD at the surgeons' discretion, although preexisting retrolisthesis at the adjacent upper segment should be taken into consideration. PMID- 29480875 TI - Evidence supports blind screening for internal malignancy in dermatomyositis: Data from 2 large US dermatology cohorts. AB - The association between dermatomyositis and internal malignancy is well established, but there is little consensus about the methods of cancer screening that should be utilized.We wished to analyze the prevalence and yield of selected cancer screening modalities in patients with dermatomyositis.We performed a retrospective analysis of 2 large US dermatomyositis cohorts comprising 400 patients.We measured the frequency of selected screening tests used to search for malignancy. Patients with a biopsy-confirmed malignancy were identified. Prespecified clinical and laboratory factors were tested for association with malignancy. For each malignancy we identified the screening test(s) that led to diagnosis and classified these tests as either blind (not guided by suspicious sign/symptom) or triggered (by a suspicious sign or symptom).Forty-eight patients (12.0% of total cohort) with 53 cancers were identified with dermatomyositis associated malignancy. Twenty-one of these 53 cancers (40%) were diagnosed within 1 year of dermatomyositis symptom onset. In multivariate analysis, older age (P = .0005) was the only significant risk factor for internal malignancy. There was no significant difference in cancer incidence between classic and clinically amyopathic patients. Twenty-seven patients (6.8% of the total cohort) harbored an undiagnosed malignancy at the time of dermatomyositis diagnosis. The majority (59%) of these cancers were asymptomatic and computed tomography (CT) scans were the most common studies to reveal a cancer.This is the largest US cohort studied to examine malignancy prevalence and screening practices in dermatomyositis patients. Our results demonstrate that, while undiagnosed malignancy is present in <10% of US patients at the time of dermatomyositis onset, it is often not associated with a suspicious sign or symptom. Our data suggest that effective malignancy screening of dermatomyositis patients often requires evaluation beyond a history, physical examination, and "age-appropriate" cancer screening-these data may help to inform future guidelines for malignancy screening in this population. PMID- 29480874 TI - EVIDENT 3 Study: A randomized, controlled clinical trial to reduce inactivity and caloric intake in sedentary and overweight or obese people using a smartphone application: Study protocol. AB - INTRODUCTION: Mobile technology, when included within multicomponent interventions, could contribute to more effective weight loss. The objective of this project is to assess the impact of adding the use of the EVIDENT 3 application, designed to promote healthy living habits, to traditional modification strategies employed for weight loss. Other targeted behaviors (walking, caloric-intake, sitting time) and outcomes (quality of life, inflammatory markers, measurements of arterial aging) will also be evaluated. METHODS: Randomized, multicentre clinical trial with 2 parallel groups. The study will be conducted in the primary care setting and will include 700 subjects 20 to 65 years, with a body mass index (27.5-40 kg/m), who are clinically classified as sedentary. The primary outcome will be weight loss. Secondary outcomes will include change in walking (steps/d), sitting time (min/wk), caloric intake (kcal/d), quality of life, arterial aging (augmentation index), and pro inflammatory marker levels. Outcomes will be measured at baseline, after 3 months, and after 1 year. Participants will be randomly assigned to either the intervention group (IG) or the control group (CG). Both groups will receive the traditional primary care lifestyle counseling prior to randomization. The subjects in the IG will be lent a smartphone and a smartband for a 3-month period, corresponding to the length of the intervention. The EVIDENT 3 application integrates the information collected by the smartband on physical activity and the self-reported information by participants on daily food intake. Using this information, the application generates recommendations and personalized goals for weight loss. DISCUSSION: There is a great diversity in the applications used obtaining different results on lifestyle improvement and weight loss. The populations studied are not homogeneous and generate different results. The results of this study will help our understanding of the efficacy of new technologies, combined with traditional counseling, towards reducing obesity and enabling healthier lifestyles. ETHICS AND DISSEMINATION: The study was approved by the Clinical Research Ethics Committee of the Health Area of Salamanca ("CREC of Health Area of Salamanca") on April 2016. A SPIRIT checklist is available for this protocol. The trial was registered in ClinicalTrials.gov provided by the US National Library of Medicine-number NCT03175614. PMID- 29480876 TI - Patients' demographics of a convenient clinic located in a large railway station in metropolitan Tokyo area. AB - Hidden barriers to visit a medical facility especially for young busy workers have been neglected in the aging society. The aim of this cross-sectional study is to analyze demographics of patients who had visited the first known convenient clinic located inside a railway station, which is adjusted to the lifestyle of working generations.We analyzed de-identified data of patients who had visited the department of internal medicine of a clinic, which is located inside a railway station building and offers primary care with after-hours accessibility in Tokyo, between August 2013 and June 2016. Data were collected on patients' sex, age, time of visit, waiting time, presence or absence of an appointment, diagnosis, and patients' addresses using the electronic health and billing records.Overall, 28,001 patients visited 87,126 times. Number of visits increased in winter season compared with the other seasons. Sixty-one percent were women and the median age of all patients was 38 years (range, 0-102). The number of visits on Mondays was the highest in a week and the most frequent visiting time was between 6 and 7 p.m. The number of visits of working generations (from 15 to 65 years old) and men increased after 6 p.m. and on weekends. The 3 most common diagnoses were upper respiratory tract infection (22,457), allergic rhinitis (20,916), and hypertension (4869). The number of individuals who were referred to other medical institutions was 1022 (1.2%). The median waiting time was 748 seconds (range, 2-5344). The number of visits from within 2-, 5-, and 10-mile radius from our clinic was 41,696 (50.6%), 63,190 (76.7%), and 75,015 (91.1%), respectively, and patients' addresses were mainly located along the railway network.The locational and temporal convenience of our clinic has attracted the unmet medical demands especially for young workers who have difficulty in visiting conventional medical institutions. PMID- 29480877 TI - Hepatoblastoma with pure fetal epithelial differentiation in a 10-year-old boy: A rare case report and review of the literature. AB - RATIONALE: Hepatoblastoma is a rare malignant embryonal tumor that only accounts for approximately 1% of all pediatric cancers and mostly develops in children younger than 5 years old. Moreover, the occurrence of hepatoblastoma in adults is extremely rare. PATIENT CONCERNS: Herein, we present a rare case of hepatoblastoma with pure epithelial differentiation in a 10-year-old boy.Pathological examination was performed. The tumor was 15 cm * 15 cm in size with clear margins. The cut surface was multiple nodular and grey-yellow. Histologically, the small cuboidal tumor cells were arranged in trabeculae with 2 3 cell layers. The tumor cells had eosinophilic or clear cytoplasm, formed dark and light areas, and were positive for alpha-fetoprotein, CK, CK8/18, CD10, hepatocyte, and GPC3. CD34 staining revealed that the sinusoids were lined by endothelial cells in the tumor tissues. The Ki67 index was approximately 20%. DIAGNOSES: Based on these findings, the case was diagnosed as hepatoblastoma with pure fetal epithelial differentiation. INTERVENTIONS: The tumor was completely removed. OUTCOMES: No recurrence was found 3 months after the operation. LESSONS: Hepatoblastoma with pure epithelial differentiation can also occur in older children. Children rarely notice and report any physical abnormality, and this may be among the primary reasons for the late diagnosis of the tumor. Annual heath checks may be beneficial in the detection of these rare tumors and improvement of patient outcomes. PMID- 29480878 TI - Marginal zone lymphoma of palatine tonsil with prominent plasmacytic differentiation: A CARE-compliant article and review of literature. AB - RATIONALE: The palatine tonsil is an important component of Waldeyer's ring and a site commonly involved by lymphoma. Interestingly, although it is a site of mucosa-associated lymphoid tissue (MALT), primary MALT lymphoma of the palatine tonsil is rare, especially with prominent plasmacytic differentiation. PATIENT CONCERNS: A 59-year-old woman presented to the hospital with a 1-month history of odynophagia. The patient had no fever or pruritus during this period and she declared no family history of hematolymphoid malignancy. DIAGNOSIS: Histopathological examination demonstrated effacement of tonsil architecture; normal follicles were replaced by plasmacytoid tumor cells and small lymphocytes. The tumor cells expanded the marginal zone and infiltrated interfollicular regions, as well as scattered residual follicles. Immunostaining showed tumor cells positive for cluster of differentiation (CD)20, CD79a, paired box-5, Mum 1, and B cell lymphoma (Bcl)-2, and negative for CD5, CD 23, cyclin D1, Bcl-6, and CD10. Staining for kappa and lambda showed prominent light chain restriction. The tumor was classified as tonsil MALT lymphoma with prominent plasmacytic differentiation. INTERVENTIONS: After the patient was diagnosed with MALT lymphoma with prominent plasmacytic differentiation, she underwent complete surgical resection and radiotherapy. OUTCOMES: There was no recurrence evident at 6-months follow-up. LESSONS: Primary tonsil MALT lymphoma with prominent plasmacytic differentiation is very rare and difficult to distinguish from other B-cell lymphomas with plasmacytoid morphology, such as follicular lymphoma, lymphoplasmacytic lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma. Accurate diagnosis of this entity is important in guiding therapy so as to avoid overtreatment. PMID- 29480879 TI - Candida pneumonia with severe clinical course, recovery with antifungal therapy and unusual pathologic findings: A case report. AB - BACKGROUND: Candida is frequently isolated from the respiratory tract and usually reflects airway colonization. True Candida pneumonia is rare. Our aim is to document a case of Candida pneumonia confirmed by cultures, molecular techniques, and surgical lung biopsy, and to highlight a previously unreported pathologic manifestation of this infection. CASE SUMMARY: A 59-year-old man with a history of chronic obstructive pulmonary disease (COPD) presented with dry cough, low grade fever, and progressive dyspnea. He was eventually diagnosed with sarcoidosis based on bilateral lung infiltrates and granulomas in a transbronchial biopsy. His condition worsened after immunosuppression, prompting surgical lung biopsy, which revealed suppurative granulomas containing Candida albicans, confirmed by cultures and polymerase chain reaction. Despite multiple episodes of respiratory failure and a prolonged course in intensive care, he recovered fully after antifungal therapy and is currently alive with COPD-related dyspnea 3 years after his initial presentation. CONCLUSION: Candida can rarely cause clinically significant pneumonia in adults, and should be considered in the differential diagnosis of suppurative granulomas in the lung. PMID- 29480880 TI - Computed tomography findings of primary pulmonary meningioma: A case report. AB - RATIONALE: Primary pulmonary meningiomas are extremely rare, and only a few cases have been reported in the medical literature. Imaging findings of primary pulmonary meningiomas have been reported even more rarely. PATIENT CONCERNS: We present the case of a 54-year-old male patient with cough and sputum lasting for 20 years. This was a case of primary pulmonary meningioma with initial suspicion of a chest wall intercostal neurinoma. DIAGNOSES: A lung lesion was detected on chest computed tomography (CT) imaging 4 years ago. This case appeared as a solitary well-defined round nodule close to the left chest wall, with heterogeneous enhancement on CT, which inaccurately led to the suspicion of a chest wall intercostal neurinoma. INTERVENTIONS: A thoracoscopic wedge resection was performed. OUTCOMES: The postoperative histological diagnosis was primary pulmonary meningioma. After 2 years of follow-up, the patient is still alive without evidence of metastasis or recurrence. LESSONS: Increased awareness of the CT characteristics of this rare tumor may broaden the radiologist's knowledge base. PMID- 29480881 TI - Cheiro-Oral syndrome caused by thalamus hemorrhage: A case report. AB - RATIONALE: Cheiro-Oral syndrome (COS) is a pure sensory deficit confined to the perioral area and ipsilateral distal fingers or hand. Owing to relatively minor clinical findings and various presentations in different cases, the insidious and severe illness it implies may be overlooked at acute settings. PATIENT CONCERNS: A 70-year-old man with history of hypertension and type II diabetes mellitus under regular medication control came to our emergency department with chief complaint of sudden onset of right perioral region and right upper limb numbness. General physical and neurological examinations were normal except for subtle hypoesthesia to light touch, and pinprick in the right corner of mouth and right forearm to distal fingers. DIAGNOSES: Routine blood analysis was all in normal range including white blood cell count, hemocrit platelet, renal and liver function, and electrolytes such as sodium and potassium. Noncontrast brain computed tomography showed abnormal high-attenuation collection in the left thalamus. INTERVENTION: Follow-up computed tomography showed absorption of the hemorrhage after strict control of his blood pressure. OUTCOMES: The patient was discharged 7 days later from our hospital with stable condition. LESSONS: We demonstrated type I COS associated with thalamic hemorrhage to highlight the neurological implication of COS. It is crucial for emergency clinicians to recognize the symptoms and promptly order a neuroimaging study to exclude large infarction/hemorrhage, which would deeply affect the disposition and following treatment of the patient. PMID- 29480882 TI - Delayed diagnosis of xanthogranulomatous pyelonephritis in a quadriplegic patient with uncontrolled cutaneous fistula: A case report. AB - RATIONALE: Xanthogranulomatous pyelonephritis (XGP) is a chronic destructive granulomatous inflammation that is characterized by urinary tract obstruction and invasion of the renal parenchyma. Although rare, XGP can lead to fatal complications, including perinephric inflammation, psoas abscess, and cutaneous fistula. PATIENT CONCERNS: A quadriplegic patient initially presented to the hospital with a chronic open wound and cutaneous fistula. DIAGNOSES: Abdominal computed tomography revealed a renal obstructing stone and enlarged right kidney with a perinephric fluid collection that communicated with the cutaneous fistula. INTERVENTIONS: The patient underwent a right nephrectomy at the department of urology. OUTCOMES: Two months after surgery, the patient was clinically well with no discharging fistula. LESSONS: The XGP accompanied by complications requires an immediate evaluation and early diagnosis. In this case, the diagnosis was delayed because the state of quadriplegia rendered no symptoms of XGP. PMID- 29480883 TI - Do Injured Adolescent Athletes and Their Parents Agree on the Athletes' Level of Psychologic and Physical Functioning? AB - BACKGROUND: Although a parent's perception of his or her child's physical and emotional functioning may influence the course of the child's medical care, including access to care and decisions regarding treatment options, no studies have investigated whether the perceptions of a parent are concordant with that of an adolescent diagnosed with a sports-related orthopaedic injury. Identifying and understanding the potential discordance in coping and emotional distress within the athlete adolescent-parent dyads are important, because this discordance may have negative effects on adolescents' well-being. QUESTIONS/PURPOSES: The purposes of this study were (1) to compare adolescent and parent proxy ratings of psychologic symptoms (depression and anxiety), coping skills (catastrophic thinking about pain and pain self-efficacy), and upper extremity physical function and mobility in a population of adolescent-parent dyads in which the adolescent had a sport-related injury; and (2) to compare scores of adolescents and parent proxies with normative scores when such are available. METHODS: We enrolled 54 dyads (eg, pairs) of adolescent patients (mean age 16 years; SD = 1.6) presenting to a sports medicine practice with sports-related injuries as well as their accompanying parent(s). We used Patient-reported Outcomes Measurement Information System questionnaires to measure adolescents' depression, anxiety, upper extremity physical function, and mobility. We used the Pain Catastrophizing Scale short form to assess adolescents' catastrophic thinking about pain and the Pain Self-efficacy Scale short form to measure adolescents' pain self-efficacy. The accompanying parent, 69% mothers (37 of 54) and 31% fathers (17 of 54), completed parent proxy versions of each questionnaire. RESULTS: Parents reported that their children had worse scores (47 +/- 9) on depression than what the children themselves reported (43 +/- 9; mean difference 4.0; 95% confidence interval [CI], -7.0 to 0.91; p = 0.011; medium effect size 0.47). Also, parents reported that their children engaged in catastrophic thinking about pain to a lesser degree (8 +/- 5) than what the children themselves reported (13 +/- 4; mean difference 4.5; 95% CI, 2.7-6.4; p < 0.001; large effect size 1.2). Because scores on depression and catastrophic thinking were comparable to the general population, and minimal clinically important difference scores are not available for these measures, it is unclear whether the relatively small observed differences between parents' and adolescents' ratings are clinically meaningful. Parents and children were concordant on their reports of the child's upper extremity physical function (patient perception 47 +/- 10, parent proxy 47 +/- 8, mean difference -0.43, p = 0.70), mobility (patient perception 43 +/- 9, parent proxy 44 +/- 9, mean difference -0.59, p = 0.64), anxiety (patient perception 43 +/- 10, parent proxy 46 +/- 8, mean difference 2.1, p = 0.21), and pain self-efficacy (patient perception 16 +/- 5, parent proxy 15 +/- 5, mean difference 0.70, p = 0.35). CONCLUSIONS: Parents rated their children as more depressed and engaging in less catastrophic thinking about pain than the adolescents rated themselves. Although these differences are statistically significant, they are of a small magnitude making it unclear as to how clinically important they are in practice. We recommend that providers keep in mind that parents may overestimate depressive symptoms and underestimate the catastrophic thinking about pain in their children, probe for these potential differences, and consider how they might impact medical care. LEVEL OF EVIDENCE: Level I, prognostic study. PMID- 29480884 TI - What Is the State of Quality Measurement in Spine Surgery? AB - BACKGROUND: Value-based healthcare models rely on quality measures to evaluate the efficacy of healthcare delivery and to identify areas for improvement. Quality measure research in other areas of health care has generally shown that there is a limited number of available quality measures and that those that exist disproportionately focus on processes as opposed to outcomes. The purpose of this study was to assess the current state of quality measures and candidate quality measures in spine surgery. QUESTIONS/PURPOSES: (1) How many quality measures and candidate quality measures are currently available? (2) According to Donabedian domains and National Quality Strategy (NQS) priorities, what aspects or domains of care do the present quality measures and candidate quality measures represent? METHODS: We systematically reviewed the National Quality Forum, the Agency for Healthcare Research and Quality, and the Physician Quality Reporting System for quality measures relevant to spine surgery. A systematic search for candidate quality measures was also performed using MEDLINE/PubMed and Embase as well as publications from the American Academy of Orthopaedic Surgeons, Congress of Neurological Surgeons, and the North American Spine Society. Clinical practice guidelines were included as candidate quality measures if their development was in accordance with Institute of Medicine criteria for the development of clinical practice guidelines, they were based on consistent clinical evidence including at least one Level I study, and they carried the strongest possible recommendation by the developing body. Quality measures and candidate quality measures were then pooled for analysis and categorized by clinical focus, NQS priority, and Donabedian domain. Our initial search yielded a total of 3940 articles, clinical practice guidelines, and quality measures, 74 of which met criteria for inclusion in this study. RESULTS: Of the 74 measures studied, 29 (39%) were quality measures and 45 (61%) were candidate quality measures. Fifty of 74 (68%) were specific to the care of the spine, and 24 of 74 (32%) were related to the general care of spine patients. The majority of the spine-specific measures were process measures (45 [90%]) and focused on the NQS priority of "Effective Clinical Care" (44 [88%]). The majority of the general care measures were also process measures (14 [58%]), the highest portion of which focused on the NQS priority of "Patient Safety" (10 [42%]). CONCLUSIONS: Given the large number of pathologies treated by spine surgeons, the limited number of available quality measures and candidate quality measures in spine surgery is inadequate to support the transition to a value-based care model. Additionally, current measures disproportionately focus on certain aspects or domains of care, which may hinder the ability to appropriately judge an episode of care, extract usable data, and improve quality. Physicians can steward the creation of meaningful quality measures by participating in clinical practice guideline development, assisting with the creation and submission of formal quality measures, and conducting the high quality research on which effective guidelines and quality measures depend. PMID- 29480885 TI - What Is the Relationship of Fear Avoidance to Physical Function and Pain Intensity in Injured Athletes? AB - BACKGROUND: Fear avoidance can play a prominent role in maladaptive responses to an injury. In injured athletes, such pain-related fear or fear avoidance behavior may have a substantial influence on the recovery process. Specifically, it may explain why some are able to reach their preinjury abilities, whereas others are unable to return to sport. QUESTIONS/PURPOSES: (1) Is fear avoidance in athletes associated with decreased physical function after injury? (2) To what degree is fear avoidance associated with athletes' pain intensity? METHODS: In a cross sectional study, we recruited injured athletes-defined as patients with sports related injury, weekly engagement in sport activities, participation in competitive events as part of a team or club, self-identification as an athlete, and a desire to return to sport after recovery-from an orthopaedic sports medicine center at a major urban university hospital. Of 130 approached patients, 102 (84% men; mean +/- SD age 25 +/- 8.5 years) met the inclusion criteria. Participants completed a demographic questionnaire, the Athlete Fear Avoidance Questionnaire, which assesses injury-related fear and avoidance behavior specifically in an athletic population, the Pain Catastrophizing Scale, the Hospital Anxiety and Depression Scale, and two Patient-Reported Outcomes Measurement Information System measures: Physical Function Computerized Adaptive Testing (CAT) and Pain Intensity CAT. RESULTS: After controlling for age, injury region (upper versus lower extremity), catastrophic thinking, and emotional distress, we found that an increase in athletes' fear avoidance was associated with a decrease in physical function (b = -0.32; p = 0.002). The model explained 30% of the variation in physical function with 7.3% explained uniquely by fear avoidance. After controlling for initial appointment/followup, surgery for the current condition, multiple pain conditions, history of prior sport-related injury/surgery, pain medication prescription, catastrophic thinking, and emotional distress, athletes' fear avoidance was not associated with pain (b = 0.14; p = 0.249). The model explained 40% of the variation in pain intensity and pain catastrophizing (b = 0.30; p = 0.001) uniquely explained 7.1% of this variation. CONCLUSIONS: In injured athletes, fear avoidance is independently associated with decreased physical function, whereas pain catastrophizing is associated with high pain intensity. Both level of an athlete's fear avoidance and catastrophic thinking about pain should be accounted for in clinical interventions aimed at helping athletes improve recovery and return to sport. LEVEL OF EVIDENCE: Level II, prognostic study. PMID- 29480886 TI - Does a Brief Mindfulness Exercise Improve Outcomes in Upper Extremity Patients? A Randomized Controlled Trial. AB - BACKGROUND: Mindfulness-based interventions are useful in reducing psychologic distress and pain intensity in patients with chronic pain. However, most mindfulness-based interventions are resource-intensive, lengthy, and not feasible for busy orthopaedic surgical practices. QUESTIONS/PURPOSES: The purpose of this study was to determine if a 60-second personalized mindfulness-based video exercise is (1) associated with improved pain intensity, emotional distress, and state anxiety compared with an attention placebo control (a time-matched educational pamphlet about pain and stress); and (2) feasible and acceptable for patients with upper extremity injury in an orthopaedic practice. METHODS: This was a single-center, single-blind randomized controlled trial of the mindfulness based video exercise (60 seconds duration, free online) versus an attention placebo control (an educational pamphlet about pain and stress presented to patients to read over 60 seconds). One hundred forty-nine patients presenting for a new or followup appointment at the office of one of two orthopaedic hand and upper extremity outpatient surgical practices at an urban academic hospital were invited to participate between September 2016 and December 2016. Of 149 patients screened, 125 patients were randomized and completed a demographic questionnaire, the Numeric Rating Scale to assess pain intensity, the State Anxiety subscale of the State Trait Anxiety Inventory to assess state anxiety, and Emotion Thermometers to assess anxiety, anger, and depression before and after the interventions. Postintervention, patients also completed the Client Satisfaction Questionnaire Scale-3 to assess the acceptability. A mean score of 21 or higher is considered acceptable. Feasibility was determined based on number of patients approached who refused participation. The intervention was defined as feasible if refusal rate was lower than 25%. Analysis of covariance was used to test comparative improved pain intensity on the NRS, psychologic distress on the Emotion Thermometers, and state anxiety on the State Anxiety Subscale of the State Trait Anxiety Index after controlling for respective baseline scores. A 1 point minimal clinically important difference (MCID) was used on the NRS for pain intensity. RESULTS: Adjusted for the baseline means, compared with patients who received the attention placebo control, patients who participated in the mindfulness-based video exercise demonstrated improved pain intensity (mindfulness-based video exercise: 3.03 +/- 0.12; control: 3.49 +/- 0.12; mean difference: 0.46 [0.12-0.80]; p = 0.008); state anxiety (mindfulness-based video exercise: 32.35 +/- 0.59; control: 35.29 +/- 0.59; mean difference: 2.94 [1.29 4.59]; p = 0.001); anxiety symptoms (mindfulness-based video exercise: 1.49 +/- 0.19; control: 2.10 +/- 0.19; mean difference: 0.61 [0.08-1.14]; p = 0.024); depression (mindfulness-based video exercise: 1.03 +/- 0.10; control: 1.47 +/- 0.11; mean difference: 0.44 [0.15-0.73]; p = 0.004); and anger (mindfulness-based video exercise: 0.76 +/- 0.12; control: 1.36 +/- 0.12; mean difference: 0.60 [0.26-0.94]; p = 0.001). However, the observed differences in pain intensity were below 1 point on the NRS, which is the MCID established in patients with chronic pain. No MCID is available for the other measures. The mindfulness-based video exercise was feasible based on a dropout rate of 0%, and acceptability reached the medium range with similar scores in both groups (mindfulness-based video exercise: 20.70 +/- 5.48; control: 20.52 +/- 6.42). CONCLUSIONS: A 60-second mindfulness-based video exercise is feasible to implement and acceptable to patients in busy orthopaedic practices. This video exercise is also effective in improving momentary pain, anxiety, depression, and anger in this population, but it is unclear whether these improved pain and distress levels are meaningful to patients who present with low levels of pain and psychologic distress. Future studies should seek to discern whether the improved pain and distress levels we observed are clinically important or whether the intervention delivers larger effects in subgroups of patients experiencing greater pain intensity and if the improved pain and distress levels are durable. Such studies might also assess cost-effectiveness, because this mindfulness-based tool takes little time and few resources to use, and the effects and durability of multiple sessions of a mindfulness-based video exercise. LEVEL OF EVIDENCE: Level II, therapeutic study. PMID- 29480887 TI - Hand Posturing Is a Nonverbal Indicator of Catastrophic Thinking for Finger, Hand, or Wrist Injury. AB - BACKGROUND: Prior research documents that greater psychologic distress (anxiety/depression) and less effective coping strategies (catastrophic thinking, kinesophobia) are associated with greater pain intensity and greater limitations. Recognition and acknowledgment of verbal and nonverbal indicators of psychologic factors might raise opportunities for improved psychologic health. There is evidence that specific patient words and phrases indicate greater catastrophic thinking. This study tested proposed nonverbal indicators (such as flexion of the wrist during attempted finger flexion or extension of uninjured fingers as the stiff and painful finger is flexed) for their association with catastrophic thinking. QUESTIONS/PURPOSES: (1) Do patients with specific protective hand postures during physical examination have greater pain interference (limitation of activity in response to nociception), limitations, symptoms of depression, catastrophic thinking (protectiveness, preparation for the worst), and kinesophobia (fear of movement)? (2) Do greater numbers of protective hand postures correlate with worse scores on these measures? METHODS: Between October 2014 and September 2016, 156 adult patients with stiff or painful fingers within 2 months after sustaining a finger, hand, or wrist injury were invited to participate in this study. Six patients chose not to participate as a result of time constraints and one patient was excluded as a result of inconsistent scoring of a possible hand posture, leaving 149 patients for analysis. We asked all patients to complete a set of questionnaires and a sociodemographic survey. We used Patient Reported Outcomes Measurement Information System (PROMIS) Depression, Upper Extremity Physical Function, and Pain Interference computer adaptive test (CAT) questionnaires. We used the Abbreviated Pain Catastrophizing Scale (PCS-4) to measure catastrophic thinking in response to nociception. Finally, we used the Tampa Scale of Kinesophobia (TSK) to assess fear of movement. The occurrence of protective hand postures during the physical examination was noted by both the physician and researcher. For uncertainty or disagreement, a video of the physical examination was recorded and a group decision was made. RESULTS: Patients with one or more protective hand postures did not score higher on the PROMIS Pain Interference CAT (hand posture: 59 [56 64]; no posture: 59 [54-63]; difference of medians: 0; p = 0.273), Physical Function CAT (32 +/- 8 versus 34 +/- 8; mean difference: 2 [confidence interval {CI}, -0.5 to 5]; p = 0.107), nor the Depression CAT (48 [41-55] versus 48 [42 53]; difference of medians: 0; p = 0.662). However, having at least one hand posture was associated with a higher degree of catastrophic thinking (PCS scores: 13 [6-26] versus 10 [3-16]; difference of medians: 3; p = 0.0104) and a higher level of kinesophobia (TSK: 40 +/- 6 versus 38 +/- 6; mean difference: -2 [CI, -4 to -1]; p = 0.0420). Greater catastrophic thinking was associated with a greater number of protective hand postures on average (rho: 0.20, p = 0.0138). CONCLUSIONS: Protective hand postures and (based on prior research) specific words and phrases are associated with catastrophic thinking and kinesophobia, less effective coping strategies that hinder recovery. Surgeons can learn to recognize these signs and begin to treat catastrophic thinking and kinesophobia starting with compassion, empathy, and patience and be prepared to add formal support (such as cognitive-behavioral therapy) to help facilitate recovery. LEVEL OF EVIDENCE: Level III, diagnostic study. PMID- 29480888 TI - Resident Participation is Not Associated With Worse Outcomes After TKA. AB - BACKGROUND: Approximately one-half of all US surgical procedures, and one-third of orthopaedic procedures, are performed at teaching hospitals. However, the effect of resident participation and their level of training on patient care for TKA postoperative physical function, operative time, length of stay, and facility discharge are unclear. QUESTIONS/PURPOSES: (1) Are resident participation, postgraduate year (PGY) training level, and number of residents associated with absolute postoperative Patient-Reported Outcomes Measurement Information System (PROMIS(r)-10) global physical function score (PCS), and achieving minimum clinically important difference (MCID) PCS improvement, after TKA? (2) Are resident participation, PGY, and number of residents associated with increased TKA operative time? (3) Are resident participation, PGY, and number of residents associated with increased length of stay after TKA? (4) Are resident participation, PGY, and number of residents associated with higher odds of patients being discharged to another inpatient facility, rather than to their home (facility discharge)? METHODS: We performed a retrospective study using a longitudinally maintained institutional registry of TKAs that included 1626 patients at a single tertiary academic institution from April 2011 through July 2016. All patients who underwent primary, elective unilateral TKA were included with no exclusions. All patients were included in the operative time, length of stay, and facility discharge models. The PCS model required postoperative PCS score (n = 1417; 87%; mean, 46.4; SD, 8.5) and the MCID PCS model required pre- and postoperative PCS (n = 1333; 82%; 55% achieved MCID). Resident participation was defined as named residents being present in the operating room and documented in the operative notes, and resident PGY level was determined by the date of TKA and its duration since the resident entered the program and using the standard resident academic calendar (July - June). Multivariable regression was used to assess PCS scores, operative time, length of stay, and facility discharge in patients whose surgery was performed with and without intraoperative resident participation, accounting for PGY training level and number of residents. We defined the MCID PCS score improvement as 5 points on a 100-point scale. Adjusting variables included surgeon, academic year, age, sex, race-ethnicity, Charlson Comorbidity Index, preoperative PCS, and patient-reported mental function, BMI, tobacco use, alcohol use, and postoperative PCS time for the PCS models. We had postoperative PCS for 1417 (87%) surgeries. RESULTS: Compared with attending-only TKAs (5% of procedures), no postgraduate year or number of residents was associated with either postoperative PCS or MCID PCS improvement (PCS: PGY-1 = -0.98, 95% CI, -6.14 to 4.17, p = 0.708; PGY-2 = -0.26, 95% CI, 2.01to 1.49, p = 0.768; PGY-3 = -0.32, 95% CI, -2.16 to 1.51, p = 0.730; PGY-4 = 0.28, 95% CI, -1.99 to 1.43, p = 0.746; PGY-5 = -0.47, 95% CI, -2.13 to 1.18, p = 0.575; two residents = 0.28, 95% CI, -1.05 to 1.62, p = 0.677) (MCID PCS: PGY-1 = odds ratio [OR], 0.30, 95% CI, 0.07-1.30, p = 0.108; PGY-2 = OR, 0.86, 95% CI, 0.46-1.62, p = 0.641; PGY-3 = OR, 0.97, 95% CI, 0.49-1.89, p = 0.921; PGY-4 = OR, 0.73, 95% CI, 0.39-1.36, p = 0.325; PGY-5 = OR, 0.71, 95% CI, 0.39-1.29, p = 0.259; two residents = OR, 1.23, 95% CI, 0.80-1.89, p = 0.337). Longer operative times were associated with all PGY levels except for PGY-5 (attending surgeon only [reference] = 85.60 minutes, SD, 14.5 minutes; PGY-1 = 100. 13 minutes, SD, 21.22 minutes, +8.44 minutes, p = 0.015; PGY-2 = 103.40 minutes, SD, 23.01 minutes, +11.63 minutes, p < 0.001; PGY-3 = 97.82 minutes, SD, 18.24 minutes, +9.68 minutes, p < 0.001; PGY-4 = 96.39 minutes, SD, 18.94 minutes, +4.19 minutes, p = 0.011; PGY-5 = 88.91 minutes, SD, 19.81 minutes, -0.29 minutes, p = 0.853) or the presence of multiple residents (+4.39 minutes, p = 0.024). There were no associations with length of stay (PGY-1 = +0.04 days, 95% CI, -0.63 to 0.71 days, p = 0.912; PGY-2 = -0.08 days, 95% CI, -0.48 to 0.33 days, p = 0.711; PGY-3 = -0.29 days, 95% CI, -0.66 to 0.09 days, p = 0.131; PGY-4 = -0.30 days, 95% CI, -0.69 to 0.08 days, p = 0.120; PGY-5 = -0.28 days, 95% CI, -0.66 to 0.10 days, p = 0.145; two residents = -0.12 days, 95% CI, -0.29 to 0.06 days, p = 0.196) or facility discharge (PGY-1 = OR, 1.03, 95% CI, 0.26-4.08, p = 0.970; PGY 2 = OR, 0.61, 95% CI, 0.31-1.20, p = 0.154; PGY-3 = OR, 0.98, 95% CI, 0.48-2.02, p = 0.964; PGY-4 = OR, 0.83, 95% CI, 0.43-1.57, p = 0.599; PGY-5 = OR, 0.7, 95% CI, 0.41-1.40, p = 0.372; two residents = OR, 0.93, 95% CI, 0.56-1.54, p = 0.766) for any PGY or number of residents. CONCLUSIONS: Our findings should help assure patients, residents, physicians, insurers, and hospital administrators that resident participation, after adjusting for numerous patient and clinical factors, does not have any association with key medical and financial metrics, including postoperative PCS, MCID PCS, length of stay, and facility discharge. Future research in this field should focus on whether residents affect knee specific patient-reported outcomes such as the Knee Injury and Osteoarthritis Score and additional orthopaedic procedures, and determine how resident medical education can be further enhanced without compromising patient care and safety.Level of Evidence Level III, therapeutic study. PMID- 29480889 TI - Cardiovascular and Cerebrovascular Events Are Associated With Nontraumatic Osteonecrosis of the Femoral Head. AB - BACKGROUND: Endothelial dysfunction has been identified as an etiologic factor for osteonecrosis of the femoral head (ONFH) and major adverse cardiovascular and cerebrovascular events (defined as major cardiovascular disease [CVD] and cerebrovascular accident [CVA]). However, the incidence of major adverse cardiovascular and cerebrovascular events in patients with nontraumatic ONFH and any association between the two diagnoses remain unclear. QUESTIONS/PURPOSES: We compared a large cohort of patients with nontraumatic ONFH and a matched control group without this diagnosis and (1) examined the frequency and hazard ratio (HR) of major adverse cardiovascular and cerebrovascular events in both groups adjusted for age, sex, socioeconomic status, and associated comorbidities (which we defined as the adjusted HR), (2) determined whether any association of ONFH and major adverse cardiovascular and cerebrovascular events was stable after adjusting for confounding variables, and (3) compared the occurrence of major adverse cardiovascular and cerebrovascular events with time in both groups. METHODS: A population-based cohort with a 14-year dataset period (1997-2010) from the Taiwan National Health Insurance Research Database was used for this retrospective study. The database includes a greater than 99.5% Asian population randomly selected from more than 23 million citizens and foreigners residing in Taiwan for longer than 6 months. A total of 1562 patients with nontraumatic ONFH were identified from a population of one million patients in the database after excluding initially concomitant diagnoses of major CVD and CVA. The comparison group (n = 15,620) without ONFH was analyzed in a one-to-10 ratio by matching the study cohort based on age, sex, income, and urbanization. RESULTS: The patients with ONFH had a higher frequency of major adverse cardiovascular and cerebrovascular events than their counterparts without ONFH (19% versus 14%; p < 0.001). The patients with ONFH had 1.34- and 1.27-fold adjusted HRs for occurrence of major CVD and CVA as compared with the normal population (95% CI, 1.11-1.61, p = 0.002, and 95% CI, 1.09-1.47, p = 0.002, respectively). Sensitivity analysis showed a consistent association between ONFH and major adverse cardiovascular and cerebrovascular events after controlling for potentially relevant confounding variables such as hypertension and diabetes. After adjusting for potential confounders including surgery and medications, ONFH remained independently associated with major CVD (adjusted HR, 1.51, 95% CI 1.09 2.03, p = 0.026) and CVA (adjusted HR, 2.44, 95% CI 1.69-3.51, p < 0.001), apart from age older than 65 years and traditional atherosclerotic risk factors. The cumulative incidence of major adverse cardiovascular and cerebrovascular events also was higher in the ONFH group than the non-ONFH group (30.3% vs 23.1% at the end of followup, p < 0.001). CONCLUSIONS: Patients with ONFH have a strong association with major adverse cardiovascular and cerebrovascular events as compared with the normal population, suggesting a potential common pathway involving endothelial dysfunction. In view of this association in the relatively young population with ONFH, it is important to closely monitor these patients, treat relevant comorbidities early, and investigate preventative measures for these major adverse events. LEVEL OF EVIDENCE: Level III, prognostic study. PMID- 29480890 TI - Is Total Femur Replacement a Reliable Treatment Option for Patients With Metastatic Carcinoma of the Femur? AB - BACKGROUND: The majority of metastatic bone lesions to the femoral bone can be treated without surgery or with minimally invasive intramedullary nailing. In rare patients with extensive metastatic disease to the femur, total femur replacement may be the only surgical alternative to amputation; however, little is known about this approach. QUESTIONS/PURPOSES: In a highly selected small group of patients with metastatic carcinoma of the femur, we asked: (1) What was the patient survivorship after this treatment? (2) What was the implant survivorship free from all-cause revision and amputation, and what complications were associated with this treatment? (3) What functional outcomes were achieved by patients after total femur replacement for this indication? METHODS: Eleven patients (three men, eight women) with a mean age of 64 years (range, 41-78 years) received total femur replacements between 1986 and 2016; none were lost to followup. The most common primary disease was breast cancer. In general, during this period, our indications for this procedure were extensive metastatic disease precluding internal fixation or isolated proximal or distal femur replacement, and an anticipated lifespan exceeding 6 months. Our contraindication for this procedure during this time was expected lifespan less than 6 months. Patient survival was assessed by Kaplan-Meier analysis; implant survival free from revision surgery and amputation were assessed by competing risk analysis. Function was determined preoperatively and 6 to 12 weeks postoperatively with the Musculoskeletal Tumor Society (MSTS) score normalized to a 100-point scale, with higher scores representing better function from a longitudinally maintained institutional database. RESULTS: Eleven patients died at a median of 5 months (range, 1-31 months) after surgery. One-year revision-free and limb survival were 82% (95% CI, 51%-98%) and 91% (95% CI, 61%-99%), respectively. Reasons for reoperation were hip dislocation, infection and local recurrence in one patient each. The latter two complications resulted in amputation in two patients. The median MSTS score was 32 (range, 13-57). CONCLUSIONS: Despite attempts to select patients who might have anticipated greater life expectancy, eight of 11 patients died by 6 months after surgery, and an additional two patients had undergone an amputation at 8 and at 17 months postoperatively. Most patients undergoing total femur replacement in this series did not recover from the procedure by the time they died, despite our best attempts to perform the procedure in patients whom we thought would live at least 6 months. Based on this, we believe that most patients with extensive metastatic disease to the femur should be offered palliative care, rather than major reconstruction. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 29480891 TI - High Revision Rate for Large-head Metal-on-metal THA at a Mean of 7.1 Years: A Registry Study. AB - BACKGROUND: Large-diameter head metal-on-metal (MoM) THA has largely been abandoned as a result of higher than anticipated revision rates. However, the majority of these implants are still in situ. Although earlier reports from the Finnish Arthroplasty Register noted similar short-term survivorship between large diameter head MoM THA and conventional cemented THA, longer term survivorship of this population is unclear. Although reported revision rates for this implant group have been high, the majority of these implants have not been revised and followup is important to improve long-term management. QUESTIONS/PURPOSES: The purposes of this study were (1) to compare the 10-year competing risk survivorship of large-diameter head MoM THA with the survivorship of conventional THA in the Finnish Arthroplasty Register; (2) to report the large-diameter head MoM THA survival at the manufacturer/brand level; and (3) to identify the most common reasons for revision of large-diameter head MoM THA in the Finnish Arthroplasty Register. METHODS: The six most commonly used large-diameter head (>= 38 mm) MoM THA devices in Finland between years 2004 and 2013 were selected (n = 10,959 implants). The completeness of the Finnish Registry is > 95% in primary THA and patients are censored from the date of death or at the point of emigration; followup continued until the end of 2015. The conventional THA control group consisted of the two most frequently used devices (Vision/Bimetric and ABG II/ABG II) with metal-on-polyethylene or ceramic-on-ceramic bearing surfaces implanted between 2002 and 2013 (n = 5177). The study group was formed by selecting all pairs of large-diameter head MoM and reference THA protheses within the same age group ( < 49, 50-54, 55-59, 60-64, 65-69, 70-74, and 75+ years), sex, diagnosis (osteoarthritis, other), and hospital yearly operation count (< 100 operations yearly, >= 100 operations yearly); 5166 matched pairs were identified. Revision for any reason was considered as the failure endpoint of followup. Implant survival (the proportion not revised) was calculated from corresponding cumulative incidence function adjusted for patient death as a competing event for revision. Large-diameter head MoM implant group revision hazard ratios with 95% confidence intervals were estimated with age group, sex, diagnosis, and hospital yearly operation count as confounding factors in a Cox regression model. RESULTS: Ten-year survivorship free from all-cause revision was lower for THAs that used a large-diameter femoral head than it was for the control group of conventional THA (83% [95% confidence interval {CI}, 82%-84%] versus 92% [95% CI, 91%-93%]). At the implant level, every large-diameter head MoM THA had a higher risk for revision compared with the conventional THA control group from the fourth postoperative year onward. The highest survival of MoM THA was 88% (95% CI, 86%-90%) for the ReCap/Bimetric and the lowest survival was 46% (95% CI, 41%-51%) for the recalled ASR with either the Summit(r) or Corail(r) stem. The most common revision reason in the MoM THA group was adverse reaction to metal debris, whereas dislocation was predominant in the conventional THA control group. CONCLUSIONS: The revision rate for all large-diameter head MoM THAs in this timeframe in the Finnish Arthroplasty Register is unacceptably high and in our view supports the decision to abandon their use. In agreement with the directives of other national organizations, we recommend regular followup of all patients with large-diameter head MoM THA. Based on our results, strict guidelines for followup should be maintained over the lifetime of the implant to assess patient symptoms and recommend revision when indicated. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29480892 TI - Can Patient Selection Explain the Obesity Paradox in Orthopaedic Hip Surgery? An Analysis of the ACS-NSQIP Registry. AB - BACKGROUND: The "obesity paradox" is a phenomenon described in prior research in which patients who are obese have been shown to have lower postoperative mortality and morbidity compared with normal-weight individuals. The paradox is that clinical experience suggests that obesity is a risk factor for difficult wound healing and adverse cardiovascular outcomes. We suspect that the obesity paradox may reflect selection bias in which only the healthiest patients who are obese are offered surgery, whereas nonobese surgical patients are comprised of both healthy and unhealthy individuals. We questioned whether the obesity paradox (decreased mortality for patients who are obese) would be present in nonurgent hip surgery in which patients can be carefully selected for surgery but absent in urgent hip surgery where patient selection is minimized. QUESTIONS/PURPOSES: (1) What is the association between obesity and postoperative mortality in urgent and nonurgent hip surgery? (2) How is obesity associated with individual postoperative complications in urgent and nonurgent hip surgery? (3) How is underweight status associated with postoperative mortality and complications in urgent and nonurgent hip surgery? METHODS: We used 2011 to 2014 data from the American College of Surgeons National Surgical Quality Improvement Project (ACS NSQIP) to identify all adults who underwent nonurgent hip surgery (n = 63,148) and urgent hip surgery (n = 29,047). We used logistic regression models, controlling for covariants including age, sex, anesthesia risk, and comorbidities, to examine the relationship between body mass _index (BMI) category (classified as underweight < 18.5 kg/m, normal 18.5-24.9 kg/m, overweight 25-29.9 kg/m, obese 30-39.9 kg/m, and morbidly obese > 40 kg/m) and adverse outcomes including 30-day mortality and surgical complications including wound complications and cardiovascular events. RESULTS: For patients undergoing nonurgent hip surgery, regression models demonstrate that patients who are morbidly obese were less likely to die within 30 days after surgery (odds ratio [OR], 0.12; 95% confidence interval [CI], 0.01-0.57; p = 0.038) compared with patients with normal BMI, consistent with the obesity paradox. For patients undergoing urgent hip surgery, patients who are morbidly obese had similar odds of death within 30 days compared with patients with normal BMI (OR, 1.18; 95% CI, 0.76-1.76; p = 0.54). Patients who are morbidly obese had higher odds of wound complications in both nonurgent (OR, 4.93; 95% CI, 3.68-6.65; p < 0.001) and urgent cohorts (OR, 4.85; 95% CI, 3.27-7.01; p < 0.001) compared with normal weight patients. Underweight patients were more likely to die within 30 days in both nonurgent (OR, 3.79; 95% CI, 1.10-9.97; p = 0.015) and urgent cohorts (OR, 1.47; 95% CI, 1.23-1.75; p < 0.001) compared with normal-weight patients. CONCLUSIONS: Patients who are morbidly obese appear to have a reduced risk of death in 30 days after nonurgent hip surgery, but not for urgent hip surgery. Our results suggest that the obesity paradox may be an artifact of selection bias introduced by careful selection of the healthiest patients who are obese for elective hip surgery. Surgeons should continue to consider obesity a risk factor for postoperative mortality and complications such as wound infections for both urgent and nonurgent surgery. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29480893 TI - CORR Insights(r): Preoperative Pain Sensitization Is Associated With Postoperative Pillar Pain After Open Carpal Tunnel Release. PMID- 29480894 TI - Restorative effects of human neural stem cell grafts on the primate spinal cord. AB - We grafted human spinal cord-derived neural progenitor cells (NPCs) into sites of cervical spinal cord injury in rhesus monkeys (Macaca mulatta). Under three-drug immunosuppression, grafts survived at least 9 months postinjury and expressed both neuronal and glial markers. Monkey axons regenerated into grafts and formed synapses. Hundreds of thousands of human axons extended out from grafts through monkey white matter and synapsed in distal gray matter. Grafts gradually matured over 9 months and improved forelimb function beginning several months after grafting. These findings in a 'preclinical trial' support translation of NPC graft therapy to humans with the objective of reconstituting both a neuronal and glial milieu in the site of spinal cord injury. PMID- 29480895 TI - Genital inflammation undermines the effectiveness of tenofovir gel in preventing HIV acquisition in women. AB - Several clinical trials have demonstrated that antiretroviral (ARV) drugs taken as pre-exposure prophylaxis (PrEP) can prevent HIV infection, with the magnitude of protection ranging from -49 to 86% (refs. ). Although these divergent outcomes are thought to be due primarily to differences in product adherence, biological factors likely contribute. Despite selective recruitment of higher-risk participants for prevention trials, HIV risk is heterogeneous even within higher risk groups. To determine whether this heterogeneity could influence patient outcomes following PrEP, we undertook a post hoc prospective analysis of results from the CAPRISA 004 trial for 1% tenofovir gel (n = 774 patients), one of the first trials to demonstrate protection against HIV infection. Concentrations of nine proinflammatory cytokines were measured in cervicovaginal lavages at >2,000 visits, and a graduated cytokine score was used to define genital inflammation. In women without genital inflammation, tenofovir was 57% protective against HIV (95% confidence interval (CI): 7-80%) but was 3% protective (95% CI: -104-54%) if genital inflammation was present. Among women who highly adhered to the gel, tenofovir protection was 75% (95% CI: 25-92%) in women without inflammation compared to -10% (95% CI: -184-57%) in women with inflammation. Immunological predictors of HIV risk may modify the effectiveness of tools for HIV prevention; reducing genital inflammation in women may augment HIV prevention efforts. PMID- 29480896 TI - From patients with arthralgia, pre-RA and recently diagnosed RA: what is the current status of understanding RA pathogenesis? AB - It is believed that therapy for rheumatoid arthritis (RA) is the most effective and beneficial within a short time frame around RA diagnosis. This insight has caused a shift from research in patients with established RA to patients at risk of developing RA and recently diagnosed patients. It is important for improvement of RA therapy to understand when and what changes occur in patients developing RA. This is true for both seropositive and seronegative patients. Activation of the immune system as presented by autoantibodies, increased cytokine and chemokine production, and alterations within several immune cells occur during RA development. In this review we describe RA pathogenesis with a focus on knowledge obtained from patients with arthralgia, pre-RA and recently diagnosed RA. Connections are proposed between altered immune cells, cytokines and chemokines, and events like synovial hyperplasia, pain and bone damage. PMID- 29480899 TI - Erratum: Differences in hospital length of stay between neonates exposed to buprenorphine versus methadone in utero. AB - [This corrects the article DOI: 10.1093/pch/pxx086.056.][This corrects the article DOI: 10.1093/pch/pxx086.056.]. PMID- 29480898 TI - 'Counselling and management for anticipated extremely preterm birth': Informing CPS statements through national consultation. AB - Opinions abound regarding how to best approach anticipated extremely preterm birth. No unified approach presently exists in Canada. In the process of updating the Canadian Paediatric Society statement on 'Counselling and management for anticipated extremely preterm birth', there was recognition of the need for a novel methodology in its development and a primary focus on enhancing the involvement of parents in the generation of a care plan for their infant. The development process involved a national consultation with health care providers and parents from across the country, with much of the feedback provided through the use of validated guideline appraisal tools. Future Canadian Paediatric Society statements may benefit from applying components of this new development process during their creation. Dedication to shared decision making and best practices in communication highlighted the importance of parental involvement in the decision-making process, particularly given the cultural and social diversity in Canada. PMID- 29480900 TI - Zika virus: What does a physician caring for children in Canada need to know? AB - Zika virus (ZIKV) was recently recognized to be teratogenic. The diagnosis of congenital ZIKV syndrome should be considered in children with unexplained microcephaly, intracranial calcifications, ventriculomegaly or major structural central nervous system abnormalities. Management is evolving but suggestions are provided for children with findings compatible with congenital infection and for those born to women with potential exposure during pregnancy. PMID- 29480897 TI - Reversible conduction block in peripheral nerve using electrical waveforms. AB - Introduction: Electrical nerve block uses electrical waveforms to block action potential propagation. Materials & Methods: Two key features that distinguish electrical nerve block from other nonelectrical means of nerve block: block occurs instantly, typically within 1 s; and block is fully and rapidly reversible (within seconds). Results: Approaches for achieving electrical nerve block are reviewed, including kilohertz frequency alternating current and charge-balanced polarizing current. We conclude with a discussion of the future directions of electrical nerve block. Conclusion: Electrical nerve block is an emerging technique that has many significant advantages over other methods of nerve block. This field is still in its infancy, but a significant expansion in the clinical application of this technique is expected in the coming years. PMID- 29480901 TI - Erratum: Screening for disruptive behaviour problems in preschool children in primary health care settings. AB - [This corrects the article DOI: 10.1093/pch/pxx128.][This corrects the article DOI: 10.1093/pch/pxx128.]. PMID- 29480902 TI - Cannabis and Canada's children and youth. AB - Cannabis is the most common illicit drug used worldwide and it is used frequently by Canadian teenagers. Cannabis use during adolescence can cause functional and structural changes to the developing brain, leading to damage. Marijuana use in this age group is strongly linked to: cannabis dependence and other substance use disorders; the initiation and maintenance of tobacco smoking; an increased presence of mental illness, including depression, anxiety and psychosis; impaired neurological development and cognitive decline; and diminished school performance and lifetime achievement. Rates of acute medical care and hospitalization for younger children who have ingested cannabis unintentionally are increasing. Ongoing debate concerning cannabis regulation in Canada makes paying close attention to the evidence for its health effects and ensuring that appropriate safeguards are in place, vital public health priorities. PMID- 29480904 TI - Erratum: Spinal cord inflammation in children with small vessel primary cns vasculitis. AB - [This corrects the article DOI: 10.1093/pch/pxx086.079.][This corrects the article DOI: 10.1093/pch/pxx086.079.]. PMID- 29480903 TI - Calibration of thresholds for functional engagement of vagal A, B and C fiber groups in vivo. AB - : Vagal nerve stimulation is widely used therapeutically but the fiber groups activated are often unknown. Aim: To establish a simple protocol to define stimulus thresholds for vagal A, B and C fibers. Methods: The intact left or right cervical vagus was stimulated with 0.1 ms pulses in spontaneously breathing anesthetized rats. Heart and respiratory rate responses to vagal stimulation were recorded. The vagus was subsequently cut distally, and mass action potentials to the same stimuli were recorded. Results: Stimulating at either 50 Hz for 2 s or 2 Hz for 10 s at experimentally determined strengths revealed A, B and C fiber thresholds that were related to respiratory and heart rate changes. Conclusion: Our simple protocol discriminates vagal A, B and C fiber thresholds in vivo. PMID- 29480905 TI - Management of term infants at increased risk for early-onset bacterial sepsis. AB - Early-onset neonatal bacterial sepsis (EOS) is sepsis occurring within the first 7 days of life. This statement provides updated recommendations for the care of term (>=37 weeks' gestational age) newborns at risk of EOS, during the first 24 hours of life. Maternal Group B streptococcus (GBS) colonization in the current pregnancy, GBS bacteriuria, a previous infant with invasive GBS disease, prolonged rupture of membranes (>=18 hours) and maternal fever (temperature >=38 degrees C) are the factors most commonly associated with EOS. These risk factors are additive; the presence of more than one factor increases the likelihood of EOS. At present, there is no laboratory test, including white blood cell indices, that has sufficient sensitivity to allow clinicians to safely rule out EOS. All unwell infants with clinical signs suggesting sepsis must be treated empirically with antibiotics, once cultures have been taken. The management of well appearing, at-risk term infants depends on the number of risk factors (including maternal GBS colonization) and whether maternal intrapartum antibiotic prophylaxis for GBS was used. In some cases, management should be individualized. Careful assessment and observation of these at-risk infants are a fundamental component of appropriate care. PMID- 29480907 TI - Reactant or reagent? Oxidation of H2 at electronically distinct nickel-thiolate sites [Ni2(MU-SR)2]+ and [Ni-SR]. AB - The chemical bond between a Lewis-acidic metal and a Bronsted/Lewis-basic sulphur donor provides M-S structures with functional properties that are relevant for a variety of processes such as the heterolytic cleavage of H2. Direct comparison of reactivity properties between molecular M-S structures can be difficult owing to divergent electronic properties of stabilizing ligand scaffolds. This work reports on a mechanistic study of stoichiometric H2 oxidation at electronically distinct [Ni2(MU-SR)2]+ and [Ni-SR]+ structures that derive from the same 1,4 terphenyldithiophenol ligand. In this context, the effect of metal containing side-products such as [HNi(PMe3)4]+ on overall H2 oxidation reactivity displayed by Ni-S structures has been investigated quantitatively in addition to external parameters such as solvent and H2 pressure. PMID- 29480908 TI - A sulfur vacancy rich CdS based composite photocatalyst with g-C3N4 as a matrix derived from a Cd-S cluster assembled supramolecular network for H2 production and VOC removal. AB - By calcination, a sulfur vacancy rich CdS based composite photocatalyst with graphitic carbon nitride (g-C3N4) as a matrix has been synthesized successfully from a tetranuclear Cd-S cluster assembled supramolecular network. In this photocatalyst (CdS@g-C3N4), CdS nanoparticles with a size of about 5 to 8 nm disperse homogenously in the g-C3N4 matrix. During calcination, some coordinated nitrogen atoms dope in the lattice of CdS and replace sulfur atoms, which generates a large number of sulfur vacancies. Under visible light irradiation, CdS@g-C3N4 exhibits excellent H2 production activity with a rate achieving as high as 19.88 mmol g-1 h-1 in the absence of a Pt cocatalyst. Its H2 production ability remains stable for 30 h, which does not decay. Besides H2 production, CdS@g-C3N4 also shows excellent photocatalytic activity for Volatile Organic Compound (VOC) degradation. For a photocatalyst, chemical content plays an important role in its performance. Here, the influence of sulfur vacancies on H2 production and VOC degradation is discussed in detail. We expect that the sulfur vacancy rich CdS@g-C3N4 can act as an efficient material for H2 production and indoor air purification. PMID- 29480906 TI - Bionic intrafascicular interfaces for recording and stimulating peripheral nerve fibers. AB - The network of peripheral nerves presents extraordinary potential for modulating and/or monitoring the functioning of internal organs or the brain. The degree to which these pathways can be used to influence or observe neural activity patterns will depend greatly on the quality and specificity of the bionic interface. The anatomical organization, which consists of multiple nerve fibers clustered into fascicles within a nerve bundle, presents opportunities and challenges that may necessitate insertion of electrodes into individual fascicles to achieve the specificity that may be required for many clinical applications. This manuscript reviews the current state-of-the-art in bionic intrafascicular interfaces, presents specific concerns for stimulation and recording, describes key implementation considerations and discusses challenges for future designs of bionic intrafascicular interfaces. PMID- 29480910 TI - Assessing AMBER force fields for protein folding in an implicit solvent. AB - Molecular dynamics (MD) simulation implemented with a state-of-the-art protein force field and implicit solvent model is an attractive approach to investigate protein folding, one of the most perplexing problems in molecular biology. But how well can force fields developed independently of implicit solvent models work together in reproducing diverse protein native structures and measuring the corresponding folding thermodynamics is not always clear. In this work, we performed enhanced sampling MD simulations to assess the ability of six AMBER force fields (FF99SBildn, FF99SBnmr, FF12SB, FF14ipq, FF14SB, and FF14SBonlysc) as coupled with a recently improved pair-wise GB-Neck2 model in modeling the folding of two helical and two beta-sheet peptides. Whilst most of the tested force fields can yield roughly similar features for equilibrium conformational ensembles and detailed folding free-energy profiles for short alpha-helical TC10b in an implicit solvent, the measured counterparts are significantly discrepant in the cases of larger or beta-structured peptides (HP35, 1E0Q, and GTT). Additionally, the calculated folding/unfolding thermodynamic quantities can only partially match the experimental data. Although a combination of the force fields and GB-Neck2 implicit model able to describe all aspects of the folding transitions towards the native structures of all the considered peptides was not identified, we found that FF14SBonlysc coupled with the GB-Neck2 model seems to be a reasonably balanced combination to predict peptide folding preferences. PMID- 29480909 TI - Criegee intermediates and their impacts on the troposphere. AB - Criegee intermediates (CIs), carbonyl oxides formed in ozonolysis of alkenes, play key roles in the troposphere. The decomposition of CIs can be a significant source of OH to the tropospheric oxidation cycle especially during nighttime and winter months. A variety of model-measurement studies have estimated surface level stabilized Criegee intermediate (sCI) concentrations on the order of 1 * 104 cm-3 to 1 * 105 cm-3, which makes a non-negligible contribution to the oxidising capacity in the terrestrial boundary layer. The reactions of sCI with the water monomer and the water dimer have been found to be the most important bimolecular reactions to the tropospheric sCI loss rate, at least for the smallest carbonyl oxides; the products from these reactions (e.g. hydroxymethyl hydroperoxide, HMHP) are also of importance to the atmospheric oxidation cycle. The sCI can oxidise SO2 to form SO3, which can go on to form a significant amount of H2SO4 which is a key atmospheric nucleation species and therefore vital to the formation of clouds. The sCI can also react with carboxylic acids, carbonyl compounds, alcohols, peroxy radicals and hydroperoxides, and the products of these reactions are likely to be highly oxygenated species, with low vapour pressures, that can lead to nucleation and SOA formation over terrestrial regions. PMID- 29480911 TI - A Focus on Research at the First School of Osteopathic Medicine. PMID- 29480912 TI - The Safety of Osteopathic Manipulative Treatment (OMT). PMID- 29480913 TI - Addressing the Opioid Crisis Through the Teachings of A.T. Still. PMID- 29480914 TI - Characterizing Adverse Events Reported Immediately After Osteopathic Manipulative Treatment. AB - Context: Although adverse events in various types of manual therapy have been previously investigated, little is known about the incidence and types of adverse events that occur after osteopathic manipulative treatment (OMT). Objective: To estimate the incidence and characterize the types of adverse events that patients report after OMT and prior to leaving the office to increase the likelihood of identifying adverse events caused by OMT. Methods: As part of a prospective study evaluating the use and effectiveness of OMT, patients assessed how they felt immediately after OMT compared with before OMT using a 5-point ordinal rating scale (much better, better, about the same, worse, much worse). For patients who indicated they felt their condition had changed, a follow-up, open-ended question asked them to describe how it had changed. Patients who felt worse or much worse were considered to have experienced an adverse event. Two reviewers independently coded the types of adverse events based on the descriptions provided by the patients. Generalized logistic regression models were used to calculate incidence rates and 95% CIs for the types of adverse events. These models were also used to calculate the ORs and 95% CIs for associations of adverse events with demographic characteristics and with individual OMT techniques after accounting for demographic characteristics. Results: Immediately after OMT, 884 patients provided data at 1847 office visits (663 [76%] women; 794 [92%] identified as white; mean [SD] age, 51.8 [15.8] years). Patients reported they felt worse or much worse immediately after OMT at 45 office visits; the incidence rate for adverse events was 2.5% (95% CI, 1.3%-4.7%). Pain/discomfort was the most commonly identified type of adverse event (16 [0.9%]; 95% CI, 0.5%-1.6%). Insufficient information was provided to determine the type of adverse event at 20 office visits. Women reported adverse events more frequently than men (OR, 13.9; 95% CI, 1.7-115.6; P=.01). Conclusion: The incidence of adverse events immediately after OMT, most commonly pain/discomfort, was lower than previous reports from other manual medicine disciplines. Larger studies are needed to determine the incidence of serious adverse events and to assess adverse events that occur in the days following OMT. PMID- 29480915 TI - Influence of Transverse Process Landmark Localization on Palpation Accuracy of Lumbar Spine Models. AB - Context: Accurate determination of transverse process displacement in the horizontal plane requires accurate transverse process landmark localization followed by accurate discrimination of asymmetry by the examiner's palpating digits. Objective: To determine whether the accurate localization of transverse process landmarks influences overall accuracy of asymmetry determination in third year osteopathic medical students evaluating covered lumbar spine models. Methods: A class of third-year osteopathic medical students was split into 2 groups and asked to determine whether the right transverse processes of covered lumbar spine models were anterior or posterior relative to the left transverse process. The marked model group (group A) was provided covered models with black dots on the fabric covers over the transverse process landmarks, while the covered models given to the students in the unmarked model group (group B) had no markings. Both groups were asked to assess asymmetry differences from L1 to L5 on 2 models. Landmarks were randomized for asymmetry (ranging from 2 mm to 6 mm) and direction (anterior or posterior on the right side). The number of correct responses was modeled as a binomial random variable in a generalized linear model to compare the effects of marked vs unmarked models on accuracy of palpation. The predicted probability of correctly determining the direction of the asymmetry and 95% CIs were calculated. Results: The probability of correctly identifying the direction of asymmetry was 0.89 (95% CI, 0.87-0.91) for group A and 0.74 (95% CI, 0.71-0.78) for group B, a 15 percentage point difference (OR, 1.2; 95% CI, 1.1 1.3; P<.001). Assuming accurate perception of digit asymmetry and accurate localization of landmarks are independent and correct answers are given only if both events occur, then students were more likely to accurately perceive digit asymmetry (0.89) than accurately localize landmarks (0.83=0.74/0.89). Overall, more students accurately identified the direction of asymmetry when the right transverse process was anterior (0.87; 95% CI, 0.84-0.90) than when it was posterior (0.81; 95% CI, 0.77-0.84) (OR, 1.6; 95% CI, 1.2-2.1; P=.001). Conclusions: Student palpation accuracy was better when transverse process landmark localization was provided on the lumbar spine models than when it was not. Students were more likely to accurately perceive digit asymmetry than accurately localize the landmarks. Improving palpation accuracy requires developing educational methods to improve both accurate landmark localization and accurate digit asymmetry perception. PMID- 29480916 TI - Ultrasonographic Evaluation of the Effect of Osteopathic Manipulative Treatment on Sacral Base Asymmetry. AB - Context: Patients with low back pain (LBP) may receive osteopathic manipulative treatment (OMT) to resolve or manage their pain. The indication for OMT for patients with LBP is the presence of somatic dysfunction, diagnosed using palpatory examination. Because palpatory findings commonly have poor interexaminer reliability, the current study used ultrasonography (US) to establish pre-OMT and post-OMT musculoskeletal measurements of relative asymmetry between pelvic and sacral bony landmarks. Objective: To document objective musculoskeletal changes that occur in response to OMT using US and to compare palpatory assessment of landmark asymmetry with US assessment. Methods: Sixty men and women aged 20 to 55 years with at least 1 episode of LBP in the past 2 weeks were assigned to a seated control, walking control, or OMT group (20 participants per group). Participants received an initial, bilateral US measurement of the skin to posterior superior iliac spine (SPSIS), skin to sacral base position (SBP), and sacral sulcus depth (SSD). Participants in seated control and OMT groups received a palpatory assessment of SBP and SSD prior to initial US assessment. After assessment, the seated control group sat in a waiting room for 30 minutes, the walking control group walked for 5 minutes, and the OMT group received OMT to address sacral base asymmetry using predominantly direct techniques for a maximum of 20 minutes. Participants then received a second US assessment of the same structures. Results: Body mass index (BMI) was correlated with SPSIS (r=0.5, P=.001) and SBP (r=0.6, P<.001). More participants in seated control (75%) and OMT (65%) groups had an increase in asymmetry from first to second US assessment for SPSIS compared with participants in the walking control group (35%, P=.05). No significant differences were found between groups for absolute asymmetry or total change in asymmetry (all P>.10). The kappa was -0.1 (95% CI, -0.2 to 0.03) for SBP and -0.01 (95% CI, -0.1 to 0.1) for SSD. Conclusion: Musculoskeletal changes in SPSIS and SBP measurements related to OMT could not be readily identified using US. The SPSIS and SBP measurements were dependent on BMI, which may have affected the accuracy of US to detect small changes in asymmetry. Qualitative palpatory assessments did not correlate with US measurements. Further study is needed to identify US measurements that demonstrate change with OMT. (ClinicalTrials.gov number NCT02820701). PMID- 29480917 TI - Tool for Predicting Medical Student Burnout From Sustained Stress Levels: Factor Analysis of the Medical Education Hassles Scale-R. AB - Context: Acute stress during medical school affects the health of students and is associated with burnout. The Medical Education Hassles Scale-R (MEHS-R) is designed to measure acute stress among medical students. Researchers using the MEHS-R primarily report overall hassles scores, which are unable to discriminate between different categories of hassles encountered. Objective: The present study examined the factor structure of the MEHS-R to identify subscales that would be useful to categorize hassles for research and assessment purposes. Design: Longitudinal, observational study. Setting: Two osteopathic medical schools. Participants: Five hundred six first-year medical students. Main Outcome Measure: The MEHS-R was administered at orientation and 9 to 10 times throughout the first year, classified into examination, vacation, and routine medical school activity periods. Students rated the 101 items on a 4-point scale (0=none to 3=a great deal) to indicate how much of a hassle each item had been during the previous week. Demographic subgroups were males, females, married students, single students, whites, and ethnic minorities. Results: Exploratory factor analysis was conducted on data collected at the first school during orientation. Seven subscales were identified: Academic and Time Pressures, Financial, Social, External Influences, Day-to-Day Functioning, Relationships With Immediate Family, and Health. Cronbach alpha were >=0.75. Stability of these subscales was examined using confirmatory factor analysis. Both of the fit indices used indicated the 7 subscale model for the MEHS-R adequately fit the data obtained during examination and routine medical school activity periods, one fit index indicated adequate fit for the vacation period, and neither indicated adequate fit for the data from the second school. Of the 7 subscales, 5 had a strong correspondence with categories identified by the scale developers. Fit indices also indicated the 7-subscale model was adequately generalizable to the demographic subgroups with the exception of the ethnic minorities subgroup. Conclusions: Exploratory factor analysis performed on the MEHS-R supported formation of subscales similar to categories identified during MEHS-R development. Results of the current study supported the use of the MEHS-R for the investigation of acute stress in medical students. In future research, targeted wellness interventions for medical students may be developed based on student responses to this instrument. PMID- 29480918 TI - Role of Magnesium in Vitamin D Activation and Function. AB - Nutrients usually act in a coordinated manner in the body. Intestinal absorption and subsequent metabolism of a particular nutrient, to a certain extent, is dependent on the availability of other nutrients. Magnesium and vitamin D are 2 essential nutrients that are necessary for the physiologic functions of various organs. Magnesium assists in the activation of vitamin D, which helps regulate calcium and phosphate homeostasis to influence the growth and maintenance of bones. All of the enzymes that metabolize vitamin D seem to require magnesium, which acts as a cofactor in the enzymatic reactions in the liver and kidneys. Deficiency in either of these nutrients is reported to be associated with various disorders, such as skeletal deformities, cardiovascular diseases, and metabolic syndrome. It is therefore essential to ensure that the recommended amount of magnesium is consumed to obtain the optimal benefits of vitamin D. PMID- 29480919 TI - Increasing Self-Awareness of Medical Students Through the Use of Ultrasonography. AB - Context: Self-awareness is vital for the health and development of medical students, but few reported modalities successfully increase medical student self awareness. Objective: To assess the effect of ultrasonography on medical student self-awareness and health status. Methods: In 2016, first- and second-year osteopathic medical students completed a 9-item survey, created specifically for the current study, which included questions about the use of ultrasonography, health status, and self-awareness after completing at least 1 ultrasonography course. Differences between student responses by class were analyzed using chi2 analysis for items assessing experience with ultrasonography and t tests for items assessing self-awareness. Results: Of the 329 students surveyed, 192 (58.4%) reported using ultrasonography to explore or monitor their own health or body. Forty-nine students (14.9%) found out something about their health that they did not know before their exposure to ultrasonography. Significant differences were found in the use of ultrasonography between first-year and second-year students; more second-year students reported using ultrasonography outside of laboratory hours (P<.05) and discovering incidental findings (P<.05). The largest portions of students reported average health status for exercise (106 of 325 [32.6%]), stress management (174 of 324 [53.7%]), and sleep (137 of 326 [42.0%]). The largest portions of students reported very good health status for tobacco use (282 of 322 [87.6%]), alcohol use (138 of 323 [42.7%]), and healthy relationships (118 of 326 [36.2%]). Statistically significant differences existed in responses between first- and second-year students regarding exercise (P=.007) and alcohol use (P=.001). The majority of students agreed or strongly agreed (182 of 326 [55.8%]) that access to ultrasonography equipment and ultrasonography training during the first and second years of medical school increased their self awareness. Conclusions: The results suggest that the incorporation of ultrasonography into medical education could potentially increase medical student health status and self-awareness. PMID- 29480921 TI - Strangulated Paraesophageal Hiatal Hernia. PMID- 29480920 TI - Physician-Mentored Patient Rounds to Observe and Assess Entrustable Professional Activities 1 and 2 in Preclinical Medical Students. AB - Context: Thirteen entrustable professional activities (EPAs) for entering residency were created to aid medical educators as they prepare preclinical students for their residency and to assess student readiness for residency. The A.T. Still University Kirksville College of Osteopathic Medicine (ATSU-KCOM) developed a program called physician-mentored patient rounds (PMPR), which focuses on EPA 1 and EPA 2. Objective: To determine whether PMPRs could be used to assess expected behaviors of EPA 1 (gather a history and perform a physical examination) and EPA 2 (prioritize a differential diagnosis after a clinical encounter). Methods: The PMPR sessions at ATSU-KCOM take place over several weeks (30-minute sessions per week), during which students gather a patient's history (sessions 1 and 2), observe a physical examination by the physician mentor (session 2), analyze diagnostic test results (session 3), and formulate a treatment plan (session 4). The PMPRs in this study used a real patient with confirmed chronic obstructive pulmonary disease (COPD). This study did not include the session-4 treatment plan. Between sessions, students completed an assignment to further demonstrate their behaviors as expected in the EPAs. Student responses were analyzed and summarized for physician feedback in the subsequent PMPR session. Students' diagnostic accuracy was measured at the conclusion of each session. Results: A total of 516 students were included in the study. The PMPR weekly attendance was high (453-475). Although history gathering in the large-group setting was disorderly, diagnostic accuracy over the 3-session period improved. After history taking, 411 students (86.5%) included COPD in the differential diagnosis. A smaller number, 235 students (49.5%), listed COPD as the most likely diagnosis. After the physical examination, 439 included COPD in the differential diagnosis, and 385 listed COPD as the most likely diagnosis. After analysis of diagnostic test results, 468 students listed COPD as the most likely diagnosis. Conclusion: Physician-mentored patient rounds seem to be an effective means to assess preclinical students' expected behaviors as described in EPA 1 and EPA 2. PMID- 29480922 TI - Nontraumatic First Rib Fracture and Empyema Presenting as Shoulder Pain. AB - Fracture of the first rib is rare because of the anatomic protection provided by surrounding structures. Osseous fatigue caused by repetitive motion and antagonistic muscular contraction is postulated to contribute to nontraumatic first rib fracture, which is most often described in adolescent athletes in sports that involve repetitive overhead motion of the arm. In this report, we describe a 49-year-old man with an occupation involving repetitive overhead motion at the shoulder who was found to have a nontraumatic first rib fracture. The condition resolved with treatment. PMID- 29480923 TI - OMT for Patients With Sacral Somatic Dysfunction. PMID- 29480924 TI - Intrahepatic Cholestasis of Pregnancy: A Review of Diagnosis and Management. AB - Importance: Intrahepatic cholestasis of pregnancy (ICP) complicates approximately 0.2% to 2% of pregnancies and can lead to increased fetal risks in pregnancy. Objective: This review aims to increase the knowledge of women's health care providers regarding the diagnosis, management, and fetal risks associated with ICP. Results: The diagnosis of ICP is based on symptoms of pruritus that typically include the palms and soles, as well as elevated bile acid levels. Other liver function tests such as alanine aminotransferase and aspartate aminotransferase are also frequently elevated, and other causes of liver dysfunction should be ruled out. Fetal risks of ICP include increased risk of preterm birth, meconium-stained amniotic fluid, respiratory distress syndrome, or stillbirth. There is evidence that as bile acid levels increase, so does the risk of adverse neonatal outcomes. Ursodeoxycholic acid treatment has been shown to improve maternal pruritus symptoms, as well as biochemical tests, but no treatment has been shown to definitively improve fetal outcomes. Conclusions and Relevance: Providers should be aware of the signs and symptoms of ICP and provide accurate diagnosis and management of affected women. Women with a diagnosis of ICP should be treated with ursodeoxycholic acid to improve maternal symptoms. Given the increased risk of stillbirth in the setting of ICP, delivery may be considered at 37 weeks' gestation. PMID- 29480926 TI - Evaluation and Management of Maternal Congenital Heart Disease: A Review. AB - Objective: Congenital heart defects represent the most common major congenital anomalies. The objective of this review was to define the most common forms of congenital heart disease (CHD) in pregnancy, outline preconception counseling, discuss the associated morbidity and mortality of each lesion, and review current recommendations for management of CHD in pregnancy. Evidence Acquisition: A MEDLINE search of "congenital heart disease in pregnancy" and specific conditions in pregnancy including "ventricular septal defect," "atrial septal defect," "left outflow obstruction," "right outflow obstruction," "tetralogy of Fallot," and "transposition of the great vessels" was performed. Results: The evidence included in the review contains 18 retrospective studies, 8 meta-analyses or systematic reviews or expert opinions, 5 case reports including surgical case reports, 2 prospective studies, and 2 clinical texts. Conclusions: Given advances in surgical and medical management, women with a history of congenital cardiac defects are more frequently reaching childbearing age and requiring obstetric care. Many women with CHD can have successful pregnancies, although there are a few conditions that confer significant maternal risk, and pregnancy may even be contraindicated. Appropriate care for women with CHD requires a knowledge of cardiac physiology in pregnancy, the common lesions of CHD, and coordinated care from cardiology and maternal-fetal medicine specialists. PMID- 29480925 TI - Pelvic Packing for Intractable Obstetric Hemorrhage After Emergency Peripartum Hysterectomy: A Review. AB - Importance: Postpartum hemorrhage (PPH) is the leading cause of maternal mortality worldwide. Even after emergency peripartum hysterectomy (EPH), bleeding may occur in the setting of acquired coagulopathy. This type of bleeding resistant to clipping, ligating, or suturing could be successfully controlled with a pelvic packing. Objective: This review provides an overview of the different pelvic packing techniques used after the failure of an EPH to control severe PPH. It aims to highlight the outcome of patients after packing, the morbidity and complications of packing, the timing and indications of packing, and finally the optimal duration of packing. Evidence Acquisition: Literature relating to pelvic packing after EPH in a PPH setting was reviewed. Results: Packing techniques can be divided into 2 types: pads or roller gauze and balloon pack. The overall success rate was as high as 78.8% with a mortality rate of 12.5%. No major morbidity related to the pelvic packing was documented. The optimal duration of packing is in the range of 36 to 72 hours. Conclusions: Pelvic packing should be part of the armamentarium available to the obstetrician whenever intractable pelvic hemorrhage is encountered. It is quite simple and quick to perform and requires no special medical materials, the rate of complications is very low, and the success rate is high. Relevance: The pelvic packing should be particularly useful in developing countries where more advanced technologies such as selective arterial embolization are not always available. In developed countries, the pelvic packing may be a valuable temporary measure pending transport to a tertiary care facility. PMID- 29480927 TI - Technical Note: Scintillation well counters and particle counting digital autoradiography devices can be used to detect activities associated with genomic profiling adequacy of biopsy specimens obtained after a low activity 18 F-FDG injection. AB - PURPOSE: Genomic profiling of biopsied tissue is the basis for precision cancer therapy. However, biopsied materials may not contain sufficient amounts of tumor deoxyribonucleonic acid needed for the analysis. We propose a method to determine the adequacy of specimens for performing genomic profiling by quantifying their metabolic activity. METHODS: We estimated the average density of tumor cells in biopsy specimens needed to successfully perform genomic analysis following the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) protocol from the minimum amount of deoxyribonucleonic acid needed and the volume of tissue typically used for analysis. The average 18 F-FDG uptake per cell was assessed by incubating HT-29 adenocarcinoma tumor cells in 18 F-FDG containing solution and then measuring their activity with a scintillation well counter. Consequently, we evaluated the response of two devices around the minimum expected activities which would indicate genomic profiling adequacy of biopsy specimens obtained under 18 F-FDG PET/CT guidance. Surrogate samples obtained using 18G core needle biopsies of gels containing either 18 F-FDG-loaded cells in the expected concentrations or the corresponding activity were measured using autoradiography and a scintillation well counter. Autoradiography was performed using a CCD-based device with real-time image display as well as with digital autoradiography imaging plates following a 30-min off-line protocol for specimen activity determination against previously established calibration. RESULTS: Cell incubation experiments and estimates obtained from quantitative autoradiography of biopsy specimens (QABS) indicate that specimens acquired under 18 F-FDG PET/CT guidance that contained the minimum amount of cells needed for genomic profiling would have an average activity concentration in the range of about 3 to about 9 kBq/mL. When exposed to specimens with similar activity concentration, both a CCD-based autoradiography device and a scintillation well counter produced signals with sufficient signal-to-background ratio for specimen genomic adequacy identification in less than 10 min, which is short enough to allow procedure guidance. CONCLUSION: Scintillation well counter measurements and CCD-based autoradiography have adequate sensitivity to detect the tumor burden needed for genomic profiling during 18 F-FDG PET/CT-guided 18G core needle biopsies of liver adenocarcinoma metastases. PMID- 29480929 TI - Sex, plasticity, and biologically significant variation in one Glomeromycotina species. PMID- 29480928 TI - Interleaved 3D-CNNs for joint segmentation of small-volume structures in head and neck CT images. AB - PURPOSE: Accurate 3D image segmentation is a crucial step in radiation therapy planning of head and neck tumors. These segmentation results are currently obtained by manual outlining of tissues, which is a tedious and time-consuming procedure. Automatic segmentation provides an alternative solution, which, however, is often difficult for small tissues (i.e., chiasm and optic nerves in head and neck CT images) because of their small volumes and highly diverse appearance/shape information. In this work, we propose to interleave multiple 3D Convolutional Neural Networks (3D-CNNs) to attain automatic segmentation of small tissues in head and neck CT images. METHOD: A 3D-CNN was designed to segment each structure of interest. To make full use of the image appearance information, multiscale patches are extracted to describe the center voxel under consideration and then input to the CNN architecture. Next, as neighboring tissues are often highly related in the physiological and anatomical perspectives, we interleave the CNNs designated for the individual tissues. In this way, the tentative segmentation result of a specific tissue can contribute to refine the segmentations of other neighboring tissues. Finally, as more CNNs are interleaved and cascaded, a complex network of CNNs can be derived, such that all tissues can be jointly segmented and iteratively refined. RESULT: Our method was validated on a set of 48 CT images, obtained from the Medical Image Computing and Computer Assisted Intervention (MICCAI) Challenge 2015. The Dice coefficient (DC) and the 95% Hausdorff Distance (95HD) are computed to measure the accuracy of the segmentation results. The proposed method achieves higher segmentation accuracy (with the average DC: 0.58 +/- 0.17 for optic chiasm, and 0.71 +/- 0.08 for optic nerve; 95HD: 2.81 +/- 1.56 mm for optic chiasm, and 2.23 +/- 0.90 mm for optic nerve) than the MICCAI challenge winner (with the average DC: 0.38 for optic chiasm, and 0.68 for optic nerve; 95HD: 3.48 for optic chiasm, and 2.48 for optic nerve). CONCLUSION: An accurate and automatic segmentation method has been proposed for small tissues in head and neck CT images, which is important for the planning of radiotherapy. PMID- 29480930 TI - Effect of oral premedication on the anaesthetic efficacy of inferior alveolar nerve block in patients with irreversible pulpitis - A systematic review and network meta-analysis of randomized controlled trials. AB - This systematic review (SR; PROSPERO database: CRD42017075160) and network meta analysis (NMA) identified the most effective oral premedication for anaesthetic success of inferior alveolar nerve blocks (IANB) in cases of irreversible pulpitis. Medline and Ebscohost databases were searched up until 10/2017. Randomized controlled trials (RCT) studying the effect of oral premedication, alone or in combination, on the success of IANB for cases of irreversible pulpitis, compared to placebo or other oral premedications, were included. Quality of the included studies was appraised by the revised Cochrane risk of bias tool for randomized trials. Pairwise analysis, NMA and quality of evidence assessment using GRADE criteria were performed. Nineteen studies (n = 1654 participants) were included. NMA demonstrated that compared to placebo, dexamethasone was most effective in increasing anaesthetic success (RR, 2.92 [95% CI 1.74,4.91]; SUCRA = 0.96), followed by NSAIDs (RR, 1.92 [95% CI 1.63,2.27], SUCRA = 0.738) and Tramadol (RR, 2.03 [95% CI 1.18,3.49], SUCRA = 0.737). Premedication with acetaminophen added to NSAIDs demonstrated similar efficacy as NSAIDs alone (RR, 1.06 [95% CI 0.79,1.43]). Sensitivity analyses proved the superiority of dexamethasone or NSAIDs over any other premedications. Subgroup analyses of specific dosages in comparison with placebo demonstrated that dexamethasone 0.5 mg was most effective, followed by ketorolac 10 mg, piroxicam 20 mg, ibuprofen 400 mg + acetaminophen 500 mg and Tramadol 50 mg. Ibuprofen 400 mg, 600 mg and 800 mg had a significantly improved IANB success, while Ibuprofen 300 mg had no effect. Oral premedication with dexamethasone, NSAIDs or Tramadol significantly increased anaesthetic success. More trials are needed to evaluate the premedication effects of dexamethasone or Tramadol for improved anaesthetic success of IANB when treating irreversible pulpitis. PMID- 29480932 TI - Effectiveness and clinical implications of the use of topical antibiotics in regenerative endodontic procedures: a review. AB - Regenerative endodontic procedures (REPs) are biologically based procedures planned to replace damaged tissues, including dentinee and root structures, as well as cells of the pulp-dentine complex. Effective sterilization of the root canal is essential in REPs, and antibiotics have been widely used to disinfect root canals. The aim of this paper was to review the scientific literature on (i) Effectiveness of antibiotics used in REPs against bacteria implicated in endodontic disease; (ii) Scientific evidence supporting the use of topical antibiotics in REPs; (iii) Clinical implications of the use of antibiotics in REPs and the possible side effects; (iv) Effect of antibiotics on dental pulp stem cells; and (v) Ongoing research on the use of antibiotics in REPs. Antibiotics used in REPs are effective against bacteria implicated in endodontic infections. Triple antibiotic pastes with minocycline attain complete disinfection of immature teeth with necrotic pulps, without affecting SCAP. Experimental studies carried out in dogs support the use of antibiotics in REPs. Clinical studies report high success rates of RET using antibiotics as intracanal dressings. However, tooth discolouration is an important side effect of the use of TAP. An antibiotic paste containing only metronidazole and ciprofloxacin could be a good alternative to the use of TAP. The use of antibiotic-containing scaffolds or clindamycin-modified triple antibiotic (metronidazole, ciprofloxacin and clindamycin) polymer could be a biologically safe antimicrobial drug delivery system in REPs. PMID- 29480931 TI - Fully automatic segmentation and objective assessment of atrial scars for long standing persistent atrial fibrillation patients using late gadolinium-enhanced MRI. AB - PURPOSE: Atrial fibrillation (AF) is the most common heart rhythm disorder and causes considerable morbidity and mortality, resulting in a large public health burden that is increasing as the population ages. It is associated with atrial fibrosis, the amount and distribution of which can be used to stratify patients and to guide subsequent electrophysiology ablation treatment. Atrial fibrosis may be assessed noninvasively using late gadolinium-enhanced (LGE) magnetic resonance imaging (MRI) where scar tissue is visualized as a region of signal enhancement. However, manual segmentation of the heart chambers and of the atrial scar tissue is time consuming and subject to interoperator variability, particularly as image quality in AF is often poor. In this study, we propose a novel fully automatic pipeline to achieve accurate and objective segmentation of the heart (from MRI Roadmap data) and of scar tissue within the heart (from LGE MRI data) acquired in patients with AF. METHODS: Our fully automatic pipeline uniquely combines: (a) a multiatlas-based whole heart segmentation (MA-WHS) to determine the cardiac anatomy from an MRI Roadmap acquisition which is then mapped to LGE MRI, and (b) a super-pixel and supervised learning based approach to delineate the distribution and extent of atrial scarring in LGE MRI. We compared the accuracy of the automatic analysis to manual ground truth segmentations in 37 patients with persistent long-standing AF. RESULTS: Both our MA-WHS and atrial scarring segmentations showed accurate delineations of cardiac anatomy (mean Dice = 89%) and atrial scarring (mean Dice = 79%), respectively, compared to the established ground truth from manual segmentation. In addition, compared to the ground truth, we obtained 88% segmentation accuracy, with 90% sensitivity and 79% specificity. Receiver operating characteristic analysis achieved an average area under the curve of 0.91. CONCLUSION: Compared with previously studied methods with manual interventions, our innovative pipeline demonstrated comparable results, but was computed fully automatically. The proposed segmentation methods allow LGE MRI to be used as an objective assessment tool for localization, visualization, and quantitation of atrial scarring and to guide ablation treatment. PMID- 29480933 TI - Technical Note: A planning technique to lower normal tissue toxicity in lung SBRT plans based on two likely dependent RTOG metrics. AB - PURPOSE: Intermediate- and low-dose falloff in stereotactic body radiotherapy (SBRT) of lung tumor is known to relate to normal tissue toxicity. The purpose is twofold to analyze the relation between RTOG parameters (namely, R50%, D2cm) in lung SBRT plans and to explore planning methods that correlate with higher than acceptable dose to normal tissue. METHODS: RTOG recommended target dose coverage, conformity index, homogeneity index, R50%, and D2cm were evaluated retrospectively in 105 lung tumor SBRT plans. Deviations in R50% and D2cm were correlated with parameters including prescription dose, tumor location, number of beams or arcs, beam configuration (coplanar or noncoplanar), type of treatment plan (3D-CRT, IMRT or volumetric arc therapy), and shortest distance to the chest wall. RESULT: All plans met the target coverage, conformity index, homogeneity index, and critical organ dose tolerance objectives. Dose falloff product (DFP) of R50% and D2cm has a small variance and small dependence on PTV. Low correlation between DFP and PTV suggests that R50% and D2cm are not independent. Coplanar beam placement was found to be prevalent among plans with large deviations in R50%, D2cm. CONCLUSION: This study questions the independence of the two RTOG recommended metrics, R50% and D2cm in lung SBRT plans, and suggests that noncoplanar beams may provide better normal tissue sparing by reducing the intermediate dose falloff. PMID- 29480934 TI - A Systematic Review and Quantitative Meta-Analysis of Oxytocin's Effects on Feeding. AB - PURPOSE: Oxytocin's anorexigenic effects have been widely documented and accepted; however, no paper has yet used the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines to compile previous findings in a single systematic review and quantitative meta-analysis. The current paper aimed to identify published and unpublished studies examining the effects of oxytocin on energy intake in animals and humans, and the factors that moderate this effect. METHODS: Web of Science, Pub Med, and Ovid were searched for published and unpublished studies reporting the effects of oxytocin on energy intake in wild-type animals and in humans, when administered in the absence of other active drugs or surgery. RESULTS: 2049 articles were identified through the original systematic literature search, from which 54 articles were identified as relevant for inclusion in this review. An additional 3 relevant articles were identified in a later update of the literature search. Overall, a single-dose of oxytocin was found to reduce feeding in animals. Despite several individual studies which found that this effect persists to the end of the third week of chronic administration in rodent models, overall, this anorexigenic effect did not hold in the meta-analyses testing the effects of chronic administration. There was no overall effect of oxytocin on energy intake in humans, although a trend was identified for oxytocin to reduce consumption of solid foods. CONCLUSIONS: Oxytocin reduces energy intake when administered as a single dose. Oxytocin can inhibit feeding over two- to three-week periods in rodent models. These effects typically do not persist beyond the third week of treatment. The anorexigenic effect of oxytocin is moderated by pregnant status, dose, method of administration, and diet composition. This article is protected by copyright. All rights reserved. PMID- 29480935 TI - Diphenylcyclopropenone for alopecia areata: a U.K. survey. PMID- 29480937 TI - Long-term culture of undifferentiated spermatogonia isolated from immature and adult bovine testes. AB - Undifferentiated spermatogonia eventually differentiate in the testis to produce haploid sperm. Within this cell population, there is a small number of spermatogonial stem cells (SSCs). SSCs are rare cells in the testis, and their cellular characteristics are poorly understood. Establishment of undifferentiated cell line would provide an indispensable tool for studying their biological nature and spermiogenesis/spermatogenesis in vitro. However, there have been few reports on the long-term culture of undifferentiated spermatogonia in species other than rodents. Here, we report the derivation and long-term in vitro culture of undifferentiated spermatogonia cell lines from immature and adult bovine testes. Cell lines from immature testes were maintained in serum-free culture conditions in the presence of glial-cell-line-derived neurotropic factor (GDNF) and bovine leukemia inhibitory factor (bLIF). These cell lines have embryonic stem (ES)-like cell morphology, express pluripotent-stem-cell-specific and germ cell-specific markers at the protein and mRNA levels, and contributed to the inner cell mass (ICM) of embryos in the blastocyst stage. Meanwhile, cell lines established from adult testes were maintained in low-serum media in the presence of 6-bromoindirubin-3'-oxime (BIO). These cell lines have characteristics resembling those of previously reported male mouse germ cell lines as confirmed by their botryoidally aggregated morphology, as well as the expression of germ cell-specific markers and pluripotent stem cell markers. These findings could be useful for the development of long-term culture of undifferentiated spermatogonia, which could aid in conservation of species and improvement of livestock production through genome editing technology. PMID- 29480938 TI - The dawn of a new ice age: social egg freezing. AB - Given the age-related decline in ovarian reserve and oocyte quality, it is unsurprising the global trend of deferring motherhood has resulted in increased levels of involuntary childlessness. The development of oocyte vitrification, with pregnancy and livebirth rates now comparable to using fresh oocytes, has provided an opportunity to cryopreserve oocytes electively for future use, empowering women with the capacity to delay their childbearing years. While it enhances reproductive autonomy, age-related obstetric complications, economic implications and the risk of unsuccessful future treatment make this a controversial therapeutic option. However, some women have no reasonable alternative, such as single women approaching their late thirties, in whom egg freezing, although not a guarantee against involuntary childlessness, offers hope by extending the window of opportunity to find a partner. Given the upward trend in women electively cryopreserving their eggs, it would appear that a new ice age, from a fertility perspective, is upon us. PMID- 29480936 TI - TrkB-mediated activation of the phosphatidylinositol-3-kinase/Akt cascade reduces the damage inflicted by oxygen-glucose deprivation in area CA3 of the rat hippocampus. AB - The selective vulnerability of hippocampal area CA1 to ischemia-induced injury is a well-known phenomenon. However, the cellular mechanisms that confer resistance to area CA3 against ischemic damage remain elusive. Here, we show that oxygen glucose deprivation-reperfusion (OGD-RP), an in vitro model that mimic the pathological conditions of the ischemic stroke, increases the phosphorylation level of tropomyosin receptor kinase B (TrkB) in area CA3. Slices preincubated with brain-derived neurotrophic factor (BDNF) or 7,8-dihydroxyflavone (7,8-DHF) exhibited reduced depression of the electrical activity triggered by OGD-RP. Consistently, blockade of TrkB suppressed the resistance of area CA3 to OGD-RP. The protective effect of TrkB activation was limited to area CA3, as OGD-RP caused permanent suppression of CA1 responses. At the cellular level, TrkB activation leads to phosphorylation of the accessory proteins SHC and Gab as well as the serine/threonine kinase Akt, members of the phosphoinositide 3-kinase/Akt (PI-3-K/Akt) pathway, a cascade involved in cell survival. Hence, acute slices pretreated with the Akt antagonist MK2206 in combination with BDNF lost the capability to resist the damage inflicted with OGD-RP. Consistently, with these results, CA3 pyramidal cells exhibited reduced propidium iodide uptake and caspase-3 activity in slices pretreated with BDNF and exposed to OGD-RP. We propose that PI-3-K/Akt downstream activation mediated by TrkB represents an endogenous mechanism responsible for the resistance of area CA3 to ischemic damage. PMID- 29480939 TI - Efficacy of daclatasvir plus asunaprevir in patients with hepatitis C virus infection undergoing and not undergoing hemodialysis. AB - AIM: To evaluate the virologic responses and clinical course of daclatasvir plus asunaprevir treatment in non-hemodialysis (non-HD) and hemodialysis (HD) patients infected with genotype 1 hepatitis C virus (HCV). METHODS: A total of 1113 non-HD patients and 67 HD patients were assessed. To evaluate pretreatment factors contributing to sustained virological response at 12 weeks (SVR12), univariate and multivariate analyses were carried out. To adjust for differences in patient background, propensity score matching was undertaken. RESULTS: The overall SVR12 rates were 91.6% in non-HD patients and 95.5% in HD patients. Compared with non HD patients, HD patients were younger, were more likely to be male, were less likely to have received interferon-based pretreatment, had a lower viral load, and had lower levels of alanine transaminase, hemoglobin, and alpha-fetoprotein. Multivariate analysis revealed that viral load, alpha-fetoprotein, L31 substitution negative, and Y93 substitution negative were independent predictive factors for SVR12 in non-HD patients. The proportion of patients with undetectable HCV-RNA during the initial 4 weeks was significantly higher in HD patients than in non-HD patients. The SVR12 rate was clearly higher in HD patients than in non-HD patients, although the difference was not statistically significant. After propensity score matching to adjust for viral load, alpha fetoprotein, L31 substitution, and Y93 substitution, these trends disappeared. CONCLUSIONS: For treatment of HCV genotype 1 infection, daclatasvir plus asunaprevir is useful not only in non-HD patients but also in HD patients. Viral load, alpha-fetoprotein levels, L31 substitution, and Y93 substitution influence treatment course and outcome. PMID- 29480941 TI - Metal-Free Geminal Difunctionalization of Diazocarbonyl Compounds: A One-Pot Multicomponent Strategy for the Construction of alpha,beta-Diamino Carbonyl Derivatives. AB - An unprecedented three-component domino oxidative coupling of diazocompounds for the efficient synthesis of alpha-azido-beta-amino esters with non-activated dimethylamino compounds and simple TMSN3 was achieved. The main features of this method include metal-free catalysis, satisfactory functional group tolerance, general applicability in complex molecule architectures, and excellent diastereoselectivity in the presence of chiral auxiliaries. In addition, several related control experiments have been conducted to investigate the reaction mechanism. PMID- 29480940 TI - ERAP1/ERAP2 and RUNX3 polymorphisms are not associated with ankylosing spondylitis susceptibility in Chinese Han. AB - Previous studies show that endoplasmic reticulum-associated aminopeptidase (ERAP1/ERAP2) and runt-related transcription factor 3 (RUNX3) gene polymorphisms are associated with AS (ankylosing spondylitis) in European Caucasians. However, contradictory results were reported in different Asian populations. The purpose of this study was to determine whether eleven candidate single nucleotide polymorphisms (SNPs) in ERAP1/ERAP2 and six in RUNX3 genes confer susceptibility to AS with or without acute anterior uveitis (AAU) [AS+ AAU+ or AS+ AAU- ] in Chinese Han. Therefore, a case-control association study was performed in 882 AS+ AAU- , 884 AS+ AAU+ and 1727 healthy controls. Genotyping was performed using the iPLEXGold genotyping assay. A meta-analysis was performed to assess the association of polymorphisms of ERAP1 with AS susceptibility in Asian populations. No association was found between SNPs of ERAP1/ERAP2/RUNX3 and susceptibility of AS with or without AAU. A case-control study between patients with human leucocyte antigen HLA-B27-positive and healthy controls also failed to demonstrate an association of the tested SNP with AS with or without AAU. Moreover, a meta-analysis showed that there was no association of rs30187, rs27037, rs27980, rs27434 and rs27582 in ERAP1 with AS in Chinese Han. Taken together, 17 SNPs in ERAP1/ERAP2 and RUNX3 genes did not confer disease susceptibility to AS in Chinese Han. PMID- 29480942 TI - Excitatory extrinsic afferents to striatal interneurons and interactions with striatal microcircuitry. AB - The striatum constitutes the main input structure of the basal ganglia and receives two major excitatory glutamatergic inputs, from the cortex and the thalamus. Excitatory cortico- and thalamostriatal connections innervate the principal neurons of the striatum, the spiny projection neurons (SPNs), which constitute the main cellular input as well as the only output of the striatum. In addition, corticostriatal and thalamostriatal inputs also innervate striatal interneurons. Some of these inputs have been very well studied, for example the thalamic innervation of cholinergic interneurons and the cortical innervation of striatal fast-spiking interneurons, but inputs to most other GABAergic interneurons remain largely unstudied, due in part to the relatively recent identification and characterization of many of these interneurons. In this review, we will discuss and reconcile some older as well as more recent data on the extrinsic excitatory inputs to striatal interneurons. We propose that the traditional feed-forward inhibitory model of the cortical input to the fast spiking interneuron then inhibiting the SPN, often assumed to be the prototype of the main functional organization of striatal interneurons, is incomplete. We provide evidence that the extrinsic innervation of striatal interneurons is not uniform but shows great cell-type specificity. In addition, we will review data showing that striatal interneurons are themselves interconnected in a highly cell type-specific manner. These data suggest that the impact of the extrinsic inputs on striatal activity critically depends on synaptic interactions within interneuronal circuitry. PMID- 29480943 TI - Pregnancy after heart transplantation: a well-thought-out decision? The Quebec provincial experience - a multi-centre cohort study. AB - Despite reports of successful pregnancies in heart transplant (HTx) recipients, many centers recommend their patients against maternity. We reviewed our provincial experience of pregnancy in HTx recipients by performing charts review of all known gestations following HTx in the province of Quebec (Canada), stratified between planned and unplanned pregnancies. Long-term survival was compared to HTx recipient women of childbearing age who did not become pregnant. Eighteen pregnancies, 56% unplanned, occurred in eight patients, 10.1 (2.6-27.0) years after HTx. Immunosuppression was CNI-based, with a mean dose increase of 48.3% (tacrolimus) and 26.5% (cyclosporine), without rejection. Cardiometabolic complications were high compared to the general Canadian population, including preeclampsia (15.4% vs. 5.5%), hypertension (38.5% vs. 4.6%), and diabetes (15.4% vs. 5.6%). Mean gestational age was 35.1 (23.4-39.6) weeks (72.2% live births; 53.8% prematurity). Mean birthweight was 2418 (660-3612) g. Serum creatinine increased during pregnancy, becoming significant after delivery (P = 0.0239), and returning to preconception level in all but three patients within a year. After 4.6 (1.2-17.2) years of follow-up, two rejection episodes occurred in one patient. Long-term mortality was similar to overall HTx women (Kaplan-Meier; P = 0.8071). Pregnancy in HTx carries high cardiometabolic complications and decreased kidney function, but is feasible with acceptable outcomes and no impact on mother's survival. PMID- 29480944 TI - Sildenafil citrate on experimental periodontitis in rats: Microtomographic and histological analyses. AB - OBJECTIVE: To investigate the effect of sildenafil citrate on the prevention and progression of experimental periodontitis (EP) in rats. MATERIALS AND METHODS: Thirty-six male Wistar rats were randomly assigned into two groups: Group 1 (preventive) and Group 2 (progression). In Group 1, the animals received daily doses of sildenafil (10 mg/kg) or vehicle for 30 days, and EP was induced on the 15th day. In Group 2, the EP was induced on the first day, and the animals received daily doses of sildenafil (10 mg/kg) or vehicle from the 15th day. For EP, ligatures were placed around the right first mandibular molars. Microtomographic, histomorphometric and histological analyses were carried out to evaluate the alveolar bone loss and inflammatory degree. For statistical analyses, t test and the Mann-Whitney test were used, considering a level of significance of 95%. RESULTS: In Group 2, the animals treated with sildenafil showed a significantly lower bone resorption (p = .05). Similarly, the subgroup treated with sildenafil displayed a significantly lesser degree of inflammation (p = .01). No significant differences were observed between the subgroups of the Group 1. CONCLUSIONS: Sildenafil decreased the inflammatory process, as well as the alveolar bone loss when used to modulate the progression of experimental periodontitis. PMID- 29480945 TI - Critically ill neonates displayed stable vital parameters and reduced metabolic acidosis during neonatal emergency airborne transport in Sweden. AB - AIM: This study evaluated the medical quality of acute airborne transports carried out by a neonatal emergency transport service in a Swedish healthcare region from 2012 to 2015. METHODS: The transport charts and patient records of all infants transported to the regional centre were reviewed for transport indications and vital parameters and outcomes. RESULTS: We identified 187 acute airborne transports and the main indications for referral were therapeutic hypothermia after perinatal asphyxia, extremely preterm birth and respiratory failure. There were 37 deaths, but none of these occurred during transport and none of the deaths that occurred within 24 hours after transport were found to be related to the transport per se. No differences were found in vital parameters or ventilator settings before and after transport, except for an improvement in blood pH (7.22 +/- 0.13 versus 7.27 +/- 0.13, mean +/- SD, p < 0.01), due to a decrease in base deficit (-8.0 +/- 6.8 versus -5.4 +/- 6.3 mmol, p < 0.001), while the partial pressure of carbon dioxide remained unchanged. CONCLUSION: During air transport, critically ill neonates displayed stable vital parameters and reduced metabolic acidosis. No transport-related mortality was found, but the high number of extremely preterm infants transported indicates the potential for improving in-utero transport. PMID- 29480946 TI - LIM homeobox transcription factor Isl1 is required for melatonin synthesis in the pig pineal gland. AB - Melatonin is a key hormone that regulates circadian rhythms, metabolism, and reproduction. However, the mechanisms of melatonin synthesis and secretion have not been fully defined. The purpose of this study was to investigate the functions of the LIM homeobox transcription factor Isl1 in regulating melatonin synthesis and secretion in porcine pineal gland. We found that Isl1 is highly expressed in the melatonin-producing cells in the porcine pineal gland. Further functional studies demonstrate that Isl1 knockdown in cultured primary porcine pinealocytes results in the decline of melatonin and arylalkylamine N acetyltransferase (AANAT) mRNA levels by 29.2% and 72.2%, respectively, whereas Isl1 overexpression raised by 1.3-fold and 2.7-fold. In addition, the enhancing effect of norepinephrine (NE) on melatonin synthesis was abolished by Isl1 knockdown. The in vivo intracerebroventricular NE injections upregulate Isl1 mRNA and protein levels by about threefold and 4.5-fold in the porcine pineal gland. We then examined the changes in Isl1 expression in the pineal gland and global melatonin levels throughout the day. The results show that Isl1 protein level at 24:00 is 2.5-fold higher than that at 12:00, which is parallel to melatonin levels. We further found that Isl1 increases the activity of AANAT promoter, and the effect of NE on Isl1 expression was blocked by an ERK inhibitor. Collectively, the results presented here demonstrate that Isl1 positively modulates melatonin synthesis by targeting AANAT, via the ERK signaling pathway of NE. These suggest that Isl1 plays important roles in maintaining the daily circadian rhythm. PMID- 29480947 TI - Geant4-DNA track-structure simulations for gold nanoparticles: The importance of electron discrete models in nanometer volumes. AB - PURPOSE: Gold nanoparticles (GNPs) are known to enhance the absorbed dose in their vicinity following photon-based irradiation. To investigate the therapeutic effectiveness of GNPs, previous Monte Carlo simulation studies have explored GNP dose enhancement using mostly condensed-history models. However, in general, such models are suitable for macroscopic volumes and for electron energies above a few hundred electron volts. We have recently developed, for the Geant4-DNA extension of the Geant4 Monte Carlo simulation toolkit, discrete physics models for electron transport in gold which include the description of the full atomic de excitation cascade. These models allow event-by-event simulation of electron tracks in gold down to 10 eV. The present work describes how such specialized physics models impact simulation-based studies on GNP-radioenhancement in a context of x-ray radiotherapy. METHODS: The new discrete physics models are compared to the Geant4 Penelope and Livermore condensed-history models, which are being widely used for simulation-based NP radioenhancement studies. An ad hoc Geant4 simulation application has been developed to calculate the absorbed dose in liquid water around a GNP and its radioenhancement, caused by secondary particles emitted from the GNP itself, when irradiated with a monoenergetic electron beam. The effect of the new physics models is also quantified in the calculation of secondary particle spectra, when originating in the GNP and when exiting from it. RESULTS: The new physics models show similar backscattering coefficients with the existing Geant4 Livermore and Penelope models in large volumes for 100 keV incident electrons. However, in submicron sized volumes, only the discrete models describe the high backscattering that should still be present around GNPs at these length scales. Sizeable differences (mostly above a factor of 2) are also found in the radial distribution of absorbed dose and secondary particles between the new and the existing Geant4 models. The degree to which these differences are due to intrinsic limitations of the condensed-history models or to differences in the underling scattering cross sections requires further investigation. CONCLUSIONS: Improved physics models for gold are necessary to better model the impact of GNPs in radiotherapy via Monte Carlo simulations. We implemented discrete electron transport models for gold in Geant4 that is applicable down to 10 eV including the modeling of the full de-excitation cascade. It is demonstrated that the new model has a significant positive impact on particle transport simulations in gold volumes with submicron dimensions compared to the existing Livermore and Penelope condensed-history models of Geant4. PMID- 29480948 TI - Melatonin activates FIS1, DYN1, and DYN2 Plasmodium falciparum related-genes for mitochondria fission: Mitoemerald-GFP as a tool to visualize mitochondria structure. AB - Malaria causes millions of deaths worldwide and is considered a huge burden to underdeveloped countries. The number of cases with resistance to all antimalarials is continuously increasing, making the identification of novel drugs a very urgent necessity. A potentially very interesting target for novel therapeutic intervention is the parasite mitochondrion. In this work, we studied in Plasmodium falciparum 3 genes coding for proteins homologues of the mammalian FIS1 (Mitochondrial Fission Protein 1) and DRP1 (Dynamin Related Protein 1) involved in mitochondrial fission. We studied the expression of P. falciparum genes that show ample sequence and structural homologies with the mammalian counterparts, namely FIS1, DYN1, and DYN2. The encoded proteins are characterized by a distinct pattern of expression throughout the erythrocytic cycle of P. falciparum, and their mRNAs are modulated by treating the parasite with the host hormone melatonin. We have previously reported that the knockout of the Plasmodium gene that codes for protein kinase 7 is essential for melatonin sensing. We here show that PfPk7 knockout results in major alterations of mitochondrial fission genes expression when compared to wild-type parasites, and no change in fission proteins expression upon treatment with the host hormone. Finally, we have compared the morphological characteristics (using MitoTracker Red CMX Ros) and oxygen consumption properties of P. falciparum mitochondria in wild-type parasites and PfPk7 Knockout strains. A novel GFP construct targeted to the mitochondrial matrix to wild-type parasites was also developed to visualize P. falciparum mitochondria. We here show that, the functional characteristics of P. falciparum are profoundly altered in cells lacking protein kinase 7, suggesting that this enzyme plays a major role in the control of mitochondrial morphogenesis and maturation during the intra-erythrocyte cell cycle progression. PMID- 29480949 TI - Role of melatonin receptor 1A and pituitary homeobox-1 coexpression in protecting tubular epithelial cells in membranous nephropathy. AB - Membranous nephropathy (MN), a type of glomerular nephritis, is one of the most common causes of nephrotic syndrome in adults. Although it is known that melatonin plays a protective role in MN, the role of melatonin receptors in the pathophysiology of MN is unclear. Using an experimental MN model and clinical MN specimens, we studied melatonin receptor expression and found that melatonin receptor 1A (MTNR1A) expression was significantly downregulated in renal tubular epithelial cells. Molecular studies showed that the transcription factor pituitary homeobox-1 (PITX1) promoted MTNR1A expression via direct binding to its promoter. Treatment of a human tubular cell line with albumin to induce injury resulted in the stable reduction in MTNR1A and PITX1 expression. PITX1 levels were significantly downregulated in tubular epithelial cells from mice MN kidneys and MN renal specimens. Knockdown of MTNR1A, PITX1, or cyclic adenosine monophosphate-responsive element-binding protein (CREB) decreased E-cadherin (CDH1) expression, but upregulated Per2 and alpha-smooth muscle actin (alphaSMA) expression. Blockade of the MTNR1A receptor with luzindole in MN mice further impaired renal function; this was accompanied by CDH1 downregulation and Per2 and alphaSMA upregulation. Together, our results suggest that in injured tissue, decreased PITX1 expression at the MTNR1A promoter regions leads to decreased levels of MTNR1A in renal tubular epithelial cells, which increases the future risk of MN. PMID- 29480950 TI - Reparative bone-like tissue formation in the tooth of a systemic sclerosis patient. AB - AIM: To report a case of reparative bone-like tissue formation in the tooth of a patient with systemic sclerosis. SUMMARY: A 58-year-old Japanese female patient with systemic sclerosis was referred because of tooth fracture. Cone beam computerized tomography (CBCT) revealed multiple root resorption and the unclear transition from alveolar bone to root profile. A sample from a fractured tooth was analysed histologically. Haematoxylin and eosin-stained sections revealed the irregular replacement of pulp and dentine by bone-like tissue. Calcinosis was noted in various parts of the body and a histological analysis identified it as dystrophic calcification on sclerosed fibrous connective tissue. Bite force and the occlusal area were markedly weaker than the means for female of the same age. KEY LEARNING POINTS: CBCT may be more useful than dental radiography for diagnosing multiple root resorption in systemic sclerosis patients. When systemic sclerosis patients have calcinosis, their root status must be examined carefully. When root resorption is present in systemic sclerosis patients, reparative bone like tissue formation in teeth needs to be taken into account prior to the initiation of dental treatment. PMID- 29480951 TI - Cyclic fatigue resistance of new reciprocating glide path files in 45- and 60 degree curved canals. AB - AIM: To compare the cyclic fatigue resistance of R-PILOT and WaveOne Gold Glider files in curved artificial canals. METHODOLOGY: A total of 60 new R-PILOT and WaveOne Gold Glider files were tested in artificial canals with 45 degrees and 60 degrees angles of curvature. Fifteen new files of each brand were tested in both canals. Cyclic fatigue resistance was determined by recording the time to file fracture in the artificial canals. The length of each fractured fragment was also recorded. An independent sample t-test was used to analyse the data. RESULTS: In the canal with a 45 degrees angle of curvature, no significant differences were observed between the R-PILOT and WaveOne Gold Glider files (P > 0.05). In the canal with a 60 degrees angle of curvature, WaveOne Gold Glider files had greater cyclic fatigue resistance than R-PILOT files (P < 0.05). There was no difference between the files in terms of the lengths of fractured fragments in canals with 45 degrees and 60 degrees angles of curvature (P > 0.05). CONCLUSIONS: WaveOne Gold Glider files exhibited greater cyclic fatigue resistance than R-PILOT files in artificial canals with a 60 degrees angle of curvature. PMID- 29480952 TI - Neoadjuvant hyperfractionated chemoradiation and liver transplantation for unresectable perihilar cholangiocarcinoma in Canada. AB - BACKGROUND AND OBJECTIVES: Neoadjuvant chemoradiation and liver transplantation may be offered for unresectable perihilar cholangiocarcinoma (pCCA). This study aimed to determine the dropout rate and survival of patients who entered a national tri-modality protocol. METHOD: Patients enrolled Jan 2009-Aug 2015 were included. Enrolment criteria: <=65 years, brush biopsy-proven unresectable pCCA <3.5 cm diameter. Conformal radiotherapy was given concurrently with Capecitabine. Following surgical staging, patients received maintenance Cisplatin and Gemcitabine until transplant or progression. Time to event analyses were performed from start of neoadjuvant therapy. RESULTS: Of 43 patients screened, 18 started treatment; median age 53.9 (26.7-62.8) years, tumour diameter 2.7 (2.0 3.4) cm. 11/18 dropped out due to metastatic disease identified during chemoradiation (n = 2), surgical staging (n = 6), or maintenance chemotherapy (n = 3). Six patients underwent transplantation. Median follow up was 17.6 (4.9 57.7) months and overall survival 16.4 months. One and two year survival was 70.6% and 35.3%, respectively. One and 2 year post transplant survival was 83.3% and 55.6%. Median progression free survival was 11.5 months. CONCLUSION: Neoadjuvant chemoradiation and liver transplantation for unresectable early stage pCCA is feasible, although with high rates of dropout and disease progression. Further research is required to determine factors to help select patients for treatment. PMID- 29480953 TI - Program of the Twenty-Sixth Annual Meeting of the American Society of Primatologists. PMID- 29480954 TI - Synaptic function and plasticity in identified inhibitory inputs onto VTA dopamine neurons. AB - Ventral tegmental area (VTA) dopaminergic neurons are key components of the reward pathway, and their activity is powerfully controlled by a diverse array of inhibitory GABAergic inputs. Two major sources of GABAergic nerve terminals within the VTA are local VTA interneurons and neurons in the rostromedial tegmental nucleus (RMTg). Here, using optogenetics, we compared synaptic properties of GABAergic synapses on VTA dopamine neurons using selective activation of afferents that originate from these two cell populations. We found little evidence of co-release of glutamate from either input, but RMTg originating synaptic currents were reduced by strychnine, suggesting co-release of glycine and GABA. VTA-originating synapses displayed a lower initial release probability, and at higher frequency stimulation, short-term depression was more marked in VTA- but not RMTg-originating synapses. We previously reported that nitric oxide (NO)-induced potentiation of GABAergic synapses on VTA dopaminergic cells is lost after exposure to drugs of abuse or acute stress; in these experiments, multiple GABAergic afferents were simultaneously activated by electrical stimulation. Here we found that optogenetically-activated VTA originating synapses on presumptive dopamine neurons also exhibited NO-induced potentiation, whereas RMTg-originating synapses did not. Despite providing a robust inhibitory input to the VTA, RMTg GABAergic synapses are most likely not those previously shown by our work to be persistently altered by addictive drugs and stress. Our work emphasises the idea that dopamine neuron excitability is controlled by diverse inhibitory inputs expected to exert varying degrees of inhibition and to participate differently in a range of behaviours. PMID- 29480955 TI - Monitoring olfactory function in chronic rhinosinusitis and the effect of disease duration on outcome. AB - BACKGROUND: Our primary aim in this study was to determine which of the "Sniffin' Sticks" subtest components (threshold, discrimination, or identification) best reflect overall change in olfactory function during treatment for chronic rhinosinusitis (CRS). Our secondary aim was to determine whether duration of CRS affects olfactory outcomes after treatment. METHODS: A retrospective cohort study was performed. Sniffin' Sticks test scores from patients medically treated for CRS at our center from 1999 to 2016 were analyzed. Only patients with 2 test scores available were included. RESULTS: Results from 408 patients were included (mean age, 56 years; male:female ratio, 217:191). There was a statistically significant improvement in threshold (T), discrimination (D), and identification (I) scores as well as the composite "TDI" score between the two testing sessions. Controlling for age, there was a significantly greater improvement in composite TDI score in patients with CRS of <=24 months duration. As expected, we found statistically significant correlations between change in overall composite TDI score and change in threshhold, discrimination, and identification, between sessions. Of the individual subcomponents, change in discrimination correlated best with change in composite TDI score (r = 0.82, p < 0.0001). This relationship was maintained irrespective of duration of CRS. CONCLUSIONS: In patients with CRS, odor discrimination appears to best reflect overall changes in olfactory function, as determined using the composite TDI score. Furthermore, olfactory outcomes are better when treatment is started sooner. PMID- 29480956 TI - Simultaneous operative use of both hands during laryngeal rigid endoscopic surgery. PMID- 29480957 TI - Germination profiling of lentil genotypes subjected to salinity stress. AB - Salinity is one of the most severe environmental stresses, negatively affecting productivity of salt-sensitive crop species. Given that germination is the most critical phase in the plant life cycle, the present study aimed to determine seed germination potential and associated traits under salt stress conditions as a simple approach to identify salt-tolerant lentil genotypes. The genetic material consisted of six lentil genotypes whose adaptation to various agroclimatic conditions is not well elucidated. Salinity stress was applied by addition of NaCl at three different levels of stress, while non-stressed plants were included as controls. Evaluation of tolerance was performed on the basis of germination percentage, seed water absorbance, root and shoot length, seedling water content, seedling vigour index and number of seedlings with an abnormal phenotype. Overall, our findings revealed that salinity stress substantially affects all traits associated with germination and early seedling growth, with the effect of salinity being dependent on the level of stress applied. It is noteworthy, however, that genotypes responded differently to the varying salinity levels. In this context, Samos proved the most salt-tolerant genotype, indicating its possible use for cultivation under stress conditions. In conclusion, the determination of seed germination and early growth potential may be exploited as an efficient strategy to reveal genetic variation in lentil germplasm of unknown tolerance to salinity stress. This approach allows selection of desirable genotypes at early growth stages, thus enabling more efficient application of various breeding methods to achieve stress-tolerant lentil genotypes. PMID- 29480958 TI - Controllable Assembly of Enzymes for Multiplexed Lab-on-a-Chip Bioassays with a Tunable Detection Range. AB - Multiplexed analysis of molecules with different concentrations requires assays with a tunable detection range. A strategy is outlined that uses click chemistry to assemble horseradish peroxidase in a controlled fashion to generate enzyme assemblies as probes for multiplexed bioassays. This controllable assembly of enzymes on detection antibodies allows for lab-on-a-chip immunoassays with a tunable detection range from pg mL-1 to MUg mL-1 . Simultaneous, multiplexed bioassays of clinically relevant inflammatory biomarkers in serum are demonstrated in one lab-on-a-chip format, with a limit of detection of 0.47 pg mL 1 for interleukin-6, 2.6 pg mL-1 for procalcitonin, and 40 ng mL-1 for C-reactive protein. This controlled assembly technique provides a multiplexed platform for simultaneous and quantitative analyses of both low-abundance and high-abundance biomarkers with a broad detection range, which holds great promise as a point-of care platform for biomedical diagnostics. PMID- 29480959 TI - Higher Dairy Food Intake Is Associated With Higher Spine Quantitative Computed Tomography (QCT) Bone Measures in the Framingham Study for Men But Not Women. AB - Previous studies found that dairy foods were associated with higher areal bone mineral density (BMD). However, data on bone geometry or compartment-specific bone density is lacking. In this cross-sectional study, the association of milk, yogurt, cheese, cream, milk+yogurt, and milk+yogurt+cheese intakes with quantitative computed tomography (QCT) measures of bone were examined, and we determined if associations were modified by serum vitamin D (25-OH D, tertiles) or age (<50 versus >=50 years). Participants were 1522 men and 1104 women (aged 32 to 81 years, mean 50 years [men]; 55 years [women]) from the Framingham Heart Study with measures of dairy food intake (servings/wk) from a food-frequency questionnaire, volumetric BMD (vBMD, integral and trabecular, g/cm3 ), cross sectional area (CSA, cm2 ), and estimated vertebral compressive strength (VCS, N) and 25-OH D (radioimmunoassay). Sex-specific multivariable linear regression was used to calculate the association of dairy food intake (energy adjusted) with each QCT measure, adjusting for covariates. Mean milk intake +/-SD was 6 +/- 7 servings/week in both men and women. In men, higher intake of milk, milk+yogurt, and milk+yogurt+cheese was associated with higher integral (p = 0.001 to 0.006) and trabecular vBMD (p = 0.006 to 0.057) and VCS (p = 0.001 to 0.010). Further, a higher cheese intake was related with higher CSA (p = 0.049). In women, no significant results were observed for the dairy foods, except for a positive association of cream intake with CSA (p = 0.016). The associations appeared to be stronger in older men. Across 25-OH D tertiles, dairy was positively associated with bone health. In summary, men with higher intakes of milk, milk+yogurt, and milk+yogurt+cheese had higher trabecular and integral vBMD and VCS but not CSA. Dairy intake seems to be most beneficial for older men, and dairy continued to have positive associations among all 25-OH D levels. (c) 2018 American Society for Bone and Mineral Research. PMID- 29480961 TI - Transpalpebral approach for frontal sinus diseases: A camouflaged technique. PMID- 29480960 TI - Management of Patients With High Baseline Hip Fracture Risk by FRAX Reduces Hip Fractures-A Post Hoc Analysis of the SCOOP Study. AB - The Screening for Osteoporosis in Older Women for the Prevention of Fracture (SCOOP) study was a community-based screening intervention in women aged 70 to 85 years in the United Kingdom. In the screening arm, licensed osteoporosis treatments were recommended in women identified to be at high risk of hip fracture using the FRAX risk assessment tool (including bone mineral density measurement). In the control arm, standard care was provided. Screening led to a 28% reduction in hip fractures over 5 years. In this planned post hoc analysis, we wished to examine for interactions between screening effectiveness on fracture outcome (any, osteoporotic, and hip fractures) on the one hand and baseline FRAX 10-year probability of hip fracture on the other. All analyses were conducted on an intention-to-treat basis, based on the group to which women were randomized, irrespective of whether screening was completed. Of 12,483 eligible participants, 6233 women were randomized to screening, with treatment recommended in 898 (14.4%). No evidence of an effect or interaction was observed for the outcomes of any fracture or osteoporotic fracture. In the screening arm, 54 fewer hip fractures were observed than in the control arm (164 versus 218, 2.6% versus 3.5%), and commensurate with treatment being targeted to those at highest hip fracture risk, the effect on hip fracture increased with baseline FRAX hip fracture probability (p = 0.021 for interaction); for example, at the 10th percentile of baseline FRAX hip probability (2.6%), there was no evidence that hip fractures were reduced (hazard ratio [HR] = 0.93; 95% confidence interval [CI] 0.71 to 1.23), but at the 90th percentile (16.6%), there was a 33% reduction (HR = 0.67; 95% CI 0.53 to 0.84). Prior fracture and parental history of hip fracture positively influenced screening effectiveness on hip fracture risk. We conclude that women at high risk of hip fracture based on FRAX probability are responsive to appropriate osteoporosis management. (c) 2018 American Society for Bone and Mineral Research. PMID- 29480962 TI - Magnetic Mesoporous Silica Nanoparticles Cloaked by Red Blood Cell Membranes: Applications in Cancer Therapy. AB - Targeted drug delivery is an emerging technological strategy that enables nanoparticle systems to be responsive for tumor therapy. Magnetic mesoporous silica nanoparticles (MMSNs) were cloaked with red blood cell membrane (RBC). This integrates long circulation, photosensitizer delivery, and magnetic targeting for cancer therapy. In vivo experiments demonstrate that RBC@MMSNs can avoid immune clearance and achieve magnetic field (MF)-induced high accumulation in a tumor. When light irradiation is applied, singlet oxygen rapidly generates from hypocrellin B (HB)-loaded RBC@MMSN and leads to the necrosis of tumor tissue. Such a RBC-cloaked magnetic nanocarrier effectively integrates immunological adjuvant, photosensitizer delivery, MF-assisted targeting photodynamic therapy, which provides an innovative strategy for cancer therapy. PMID- 29480963 TI - Treatment of Refractory Idiopathic Supraorbital Neuralgia Using Percutaneous Pulsed Radiofrequency. AB - BACKGROUND AND AIMS: No ideal therapeutic method currently exists for refractory idiopathic supraorbital neuralgia patients who do not respond to conservative therapy, including medications and nerve blocks. Pulsed radiofrequency is a neuromodulation technique that does not produce sequelae of nerve damage after treatment. However, the efficacy of percutaneous pulsed radiofrequency for the treatment of refractory idiopathic supraorbital neuralgia is still not clear. The purpose of our study was to evaluate the efficacy and safety of pulsed radiofrequency treatment of the supraorbital nerve for refractory supraorbital neuralgia patients. METHODS: We prospectively investigated the long-term effects of ultrasound-guided percutaneous pulsed radiofrequency in the treatment of 22 refractory idiopathic supraorbital neuralgia patients. A reduction in the verbal pain numeric rating scale score of more than 50% was used as the standard of effectiveness. The effectiveness rates at different time points within 2 years were calculated. RESULTS: After a single pulsed radiofrequency treatment, the effectiveness rate at 1 and 3 months was 77%, and the rates at 6 months, 1 year, and 2 years were 73%, 64%, and 50%, respectively. Except for a small portion of patients (23%) who experienced mild upper eyelid ecchymosis that gradually disappeared after approximately 2 weeks, no obvious complications were observed. CONCLUSIONS: In conclusion, the results of our study demonstrate that for patients with refractory idiopathic supraorbital neuralgia, percutaneous pulsed radiofrequency may be an effective and safe treatment choice. PMID- 29480964 TI - Toxicity of dissolved and precipitated forms of barium to a freshwater alga (Chlorella sp. 12) and water flea (Ceriodaphnia dubia). AB - Barium is present at elevated concentrations in oil and gas produced waters, and there is no international water quality guideline value to assess the potential risk of adverse effects to aquatic biota. Sulfate concentration largely controls the solubility of barium in aquatic systems, with insoluble barium sulfate (barite) assumed to be less bioavailable and less toxic than dissolved barium. We exposed aquatic biota to dissolved barium only and to a mixture of dissolved and precipitated barium. The chronic dissolved barium 48-h growth rate inhibition effect concentrations, (EC10 and EC50) for the tropical freshwater alga Chlorella sp. 12 were 40 mg/L (27-54 mg/L 95% confidence limits [CL]), and 240 mg/L (200 280 mg/L 95% CL), respectively. The acute EC10 and EC50 values for 48-h immobilization of the water flea (Ceriodaphnia dubia) by dissolved barium were 14 mg/L (13-15 mg/L 95% CL) and 17 mg/L (16-18 mg/L 95% CL), respectively. Chlorella sp. 12 was significantly more sensitive to precipitated barium than to dissolved barium, whereas the opposite seemed likely for C. dubia. Ceriodaphnia dubia was predicted to be chronically sensitive to dissolved barium at concentrations measured in produced waters and receiving waters, based on a predicted chronic EC10 of 1.7 mg/L derived from the acute EC50/10. Further chronic toxicity data that account for barium toxicity in dissolved and precipitated forms are required to derive a barium guideline for freshwater biota. Environ Toxicol Chem 2018;37:1632-1642. (c) 2018 SETAC. PMID- 29480965 TI - Ultrasound-Guided Intercostal Nerve Block Following Esophagectomy for Acute Postoperative Pain Relief in the Postanesthesia Care Unit. AB - OBJECTIVE: To explore the feasibility, effectiveness, and safety of ultrasound guided intercostal nerve block (ICNB) for immediate relief of moderate and severe pain following esophagectomy in a postanesthesia care unit (PACU). METHODS: Eighty-one patients who complained of moderate to severe pain on arrival to the PACU after an Ivor Lewis esophagectomy were randomly assigned to 2 groups: a sufentanil treatment group (Group A, n = 41) and an intercostal nerve block treatment group (Group B, n = 40). The visual analog scale (VAS) pain scores at rest and on cough at 1, 2, 4, 12, 24, and 48 hours after treatment were monitored. The heart rate, blood pressure, and pulse oxygen saturation (SpO2 ) 2 hours after treatment and the patients' length of stay in the PACU after treatment were recorded. Patient-controlled intravenous analgesia consumption and the incidence of nausea, vomiting, and other adverse reactions were also recorded. RESULTS: Ultrasound-guided ICNB was performed successfully in all patients in Group B without puncture-related complications. The VAS pain scores at rest and on cough at 1, 2, and 4 hours after treatment in Group B were significantly lower than those in Group A (P < 0.05). The consumption of sufentanil and the incidence of nausea and vomiting were significantly decreased in Group B compared with those in Group A. CONCLUSION: Ultrasound-guided ICNB could provide effective and safe pain relief for patients who suffer from moderate to severe pain (VAS score >= 5) after esophagectomy in the PACU. PMID- 29480966 TI - Editorial for the March 2018 Focus Issue 'Omics in Transplantation'. PMID- 29480968 TI - The alpha2 isoform Na,K-ATPase modulates contraction of rat mesenteric small artery via cSrc-dependent Ca2+ sensitization. AB - AIMS: The Na,K-ATPase is involved in a large number of regulatory activities including cSrc-dependent signalling. Upon inhibition of the Na,K-ATPase with ouabain, cSrc activation is shown to occur in many cell types. This study tests the hypothesis that acute potentiation of agonist-induced contraction by ouabain is mediated through Na,K-ATPase-cSrc signalling-dependent sensitization of vascular smooth muscle cells to Ca2+ . METHODS: Agonist-induced rat mesenteric small artery contraction was examined in vitro under isometric conditions and in vivo in anaesthetized rats. Arterial wall tension and [Ca2+ ]i in vascular smooth muscle cells were measured simultaneously. Changes in cSrc and myosin phosphatase targeting protein 1 (MYPT1) phosphorylation were analysed by Western blot. Protein expression was examined with immunohistochemistry. The alpha1 and alpha2 isoforms of the Na,K-ATPase were transiently downregulated by siRNA transfection in vivo. RESULTS: Ten micromolar ouabain, but not digoxin, potentiated contraction to noradrenaline. This effect was not endothelium-dependent. Ouabain sensitized smooth muscle cells to Ca2+ , and this was associated with increased phosphorylation of cSrc and MYPT1. Inhibition of tyrosine kinase by genistein, PP2 or pNaKtide abolished the potentiating effect of ouabain on arterial contraction and Ca2+ sensitization. Downregulation of the Na,K-ATPase alpha2 isoform made arterial contraction insensitive to ouabain and tyrosine kinase inhibition. CONCLUSION: Data suggest that micromolar ouabain potentiates agonist induced contraction of rat mesenteric small artery via Na,K-ATPase-dependent cSrc activation, which increases Ca2+ sensitization of vascular smooth muscle cells by MYPT1 phosphorylation. This mechanism may be critical for acute control of vascular tone. PMID- 29480969 TI - Transcriptional control of O6 -methylguanine DNA methyltransferase expression and temozolomide resistance in glioblastoma. AB - O6 -methylguanine DNA methyltransferase (MGMT) promoter methylation is a predictive biomarker for benefit from alkylating chemotherapy, specifically temozolomide (TMZ), in glioblastoma, the most common malignant intrinsic brain tumor. Glioma-initiating cells (GIC) with stem-like properties have been associated with resistance to therapy and progression. We assessed the levels of MGMT mRNA and MGMT protein by real-time PCR and immunoblot and evaluated the impact of MGMT on TMZ sensitivity in clonogenicity assays in GIC sphere cultures (S) or differentiated adherent monolayer cultures (M). Nuclear factor kappa B (NF kappaB) signaling was assessed by reporter assay and immunoblot. Compared to M cells, S cells expressed higher levels of MGMT. Differentiation of GIC induced by S-to-M transition resulted in a gradual loss of MGMT expression and increased TMZ sensitivity. This transcriptional regulation of MGMT was restricted to cell lines without MGMT promoter methylation and was not coupled to any specific neurobasal (NB) stem cell medium supplement or loss of cell adhesion. Expression levels of p50/p65 subunits of NF-kappaB, a transcriptional regulator of MGMT, were increased in S cells. Inhibition of NF-kappaB by the small molecule inhibitor, BAY 11-7082, or siRNA-mediated gene silencing, reduced MGMT levels. In summary, alkylator resistance of S cells is mainly promoted by over-expression of MGMT which results from increased activity of the NF-kappaB pathway in this cell culture model of glioma stem-like cells. Read the Editorial Highlight for this article on page 688. PMID- 29480970 TI - Correction. PMID- 29480972 TI - Correction. PMID- 29480971 TI - Hepatology Highlights. PMID- 29480973 TI - Hepatitis C treatment in kidney transplant recipients: the need for sustained vigilance after sustained viral response. PMID- 29480974 TI - Deletion of Uncoupling Protein-2 reduces renal mitochondrial leak respiration, intrarenal hypoxia and proteinuria in a mouse model of type 1 diabetes. AB - AIM: Uncoupling protein-2 (UCP-2) can induce mitochondrial uncoupling in the diabetic kidney. Although mitochondrial uncoupling reduces oxidative stress originating from the mitochondria and can be regarded as a protective mechanism, the increased oxygen consumption occurring secondarily to increased mitochondria uncoupling, that is leak respiration, may contribute to kidney tissue hypoxia. Using UCP-2-/- mice, we tested the hypothesis that UCP-2-mediated leak respiration is important for the development of diabetes-induced intrarenal hypoxia and proteinuria. METHODS: Kidney function, in vivo oxygen metabolism, urinary protein leakage and mitochondrial function were determined in wild-type and UCP-2-/- mice during normoglycaemia and 2 weeks after diabetes induction. RESULTS: Diabetic wild-type mice displayed mitochondrial leak respiration, pronounced intrarenal hypoxia, proteinuria and increased urinary KIM-1 excretion. However, diabetic UCP-2-/- mice did not develop increased mitochondrial leak respiration and presented with normal intrarenal oxygen levels, urinary protein and KIM-1 excretion. CONCLUSION: Although functioning as an antioxidant system, mitochondria uncoupling is always in co-occurrence with increased oxygen consumption, that is leak respiration; a potentially detrimental side effect as it can result in kidney tissue hypoxia; an acknowledged unifying pathway to nephropathy. Indeed, this study demonstrates a novel mechanism in which UCP-2 mediated mitochondrial leak respiration is necessary for the development of diabetes-induced intrarenal tissue hypoxia and proteinuria. PMID- 29480975 TI - Insurance access in adults with congenital heart disease in the Affordable Care Act era. AB - BACKGROUND: Adults with congenital heart disease (ACHD) have traditionally been viewed as an underinsured population. Whether this is true in the Affordable Care Act era is unknown. We determined insurance patterns in ACHD patients compared to the non-ACHD cardiology population in a contemporary cohort. METHODS: All cardiology outpatient visits between July 2016 and February 2017 to a large referral center in the United States were reviewed. The primary payer was categorized as health maintenance organization (HMO), preferred provider organization (PPO), Medicare, Medicaid, self-pay, or other. Diagnosis and lesion severity of ACHD were extracted from ICD-10 diagnostic codes and assigned according to the 2008 American College of Cardiology/American Heart Association ACHD guidelines. Age-matching was used to account for baseline age differences between ACHD and non-ACHD patients. RESULTS: E ACHD and 17 154 non-ACHD patients were identified. Without age-matching, ACHD patients were significantly younger than non-ACHD patients (mean age 38.5 vs 63.8 years). After age-matching (N = 805 in each group), mean age was 39.5 years in both groups. ACHD patients had less HMO (29.1% vs 34.7%, P = .012) and Medicaid (12.4% vs 17.3%, P = .006) coverage, but more PPO (34.4% vs 27.5%, P = .003) and Medicare (23.2% vs 18.1%, P = .005) coverage compared to non-ACHD patients. No differences were found in private insurance, public insurance, or self-pay. Lesion complexity had no effect on insurance in ACHD patients. Eligibility of parental plan coverage did not affect use of private insurance. ACHD patients in states with Medicaid expansion had higher rates of Medicaid (15.6% vs 10.6%, P = .045) but lower rates of HMO coverage (24.5% vs 31.7%, P = .036) and self-pay (0% vs 3.3%, P < .001). ACHD status, age, income, and residence in Medicaid expansion states were independent determinants of insurance types. CONCLUSIONS: In the Affordable Care Act era, ACHD patients are a well-insured population. Governmental policy has substantial effects on individual-level choice and access to insurance. PMID- 29480976 TI - Discovery of Pantoea stewartii ssp. stewartii genes important for survival in corn xylem through a Tn-Seq analysis. AB - The bacterium Pantoea stewartii ssp. stewartii causes Stewart's wilt disease in corn. Pantoea stewartii is transmitted to plants via corn flea beetles, where it first colonizes the apoplast causing water-soaked lesions, and then migrates to the xylem and forms a biofilm that blocks water transport. Bacterial quorum sensing ensures that the exopolysaccharide production necessary for biofilm formation occurs only at high cell density. A genomic-level transposon sequencing (Tn-Seq) analysis was performed to identify additional bacterial genes essential for survival in planta and to provide insights into the plant-microbe interactions occurring during wilt disease. A mariner transposon library of approximately 40 000 mutants was constructed and used to inoculate corn seedlings through a xylem infection model. Cultures of the library grown in Luria-Bertani (LB) broth served as the in vitro pre-inoculation control. Tn-Seq analysis showed that the number of transposon mutations was reduced by more than 10-fold for 486 genes in planta compared with the library that grew in LB, suggesting that they are important for xylem survival. Interestingly, a small set of genes had a higher abundance of mutants in planta versus in vitro conditions, indicating enhanced strain fitness with loss of these genes inside the host. In planta competition assays retested the trends of the Tn-Seq data for several genes, including two outer membrane proteins, Lon protease and two quorum sensing associated transcription factors, RcsA and LrhA. Virulence assays were performed to check for correlation between growth/colonization and pathogenicity. This study demonstrates the capacity of a Tn-Seq approach to advance our understanding of P. stewartii-corn interactions. PMID- 29480977 TI - Unique Intradural Inflammatory Mass Containing Precipitated Morphine: Confirmatory Analysis by LESA-MS and MALDI-MS. AB - Opioids are often used for analgesia via continuous intrathecal delivery by implantable devices. A higher concentration and daily dose of opioid have been postulated as risk factors for intrathecal granuloma formation. We present a 42 year-old female patient with chronic abdominal pain from refractory pancreatitis, with an intrathecal drug delivery device implanted 21 years prior, delivering continuous intrathecal morphine. After many years without concerning physical signs or complaints, with gradual increases in daily morphine dose, she presented with rapidly progressive neurologic deficits, including lower extremity, bladder, and bowel symptoms. These symptoms were determined to be secondary to mass effect and local inflammation related to an intrathecal catheter tip granuloma, detected on magnetic resonance imaging of the spine. The mass was urgently resected. On histopathologic examination, this granuloma was found to be unique, in that in addition to the expected inflammatory components, it appeared to contain precipitated nonpolarizable crystals. These were identified as precipitated morphine using liquid extraction surface analysis-tandem mass spectrometry (LESA MS/MS) and matrix-assisted laser desorption ionization-Fourier transform ion cyclotron resonance-mass spectrometry imaging (MALDI-FTICR-MSI). In addition to the unique finding of precipitated morphine crystals, the long-term follow-up of both morphine concentration and daily dose increases provides insight into the formation of intrathecal granulomas. PMID- 29480978 TI - Simplifying environmental mixtures-An aquatic exposure-based approach via land use scenarios. PMID- 29480980 TI - Letter to Lois Heller PMID- 29480979 TI - Cellular endogenous NAD(P)H fluorescence as a label-free method for the identification of erythrocytes and reticulocytes. AB - Reticulocytes and erythrocytes are the ultimate differentiated stages of erythropoiesis. In addition to being anucleate cells, they are characterized by the clearance of their mitochondrial pool or lack thereof. Given that for most research-oriented flow cytometry experiments erythrocytes and reticulocytes are often undesirable cell types, their identification and exclusion from analyses can be essential. Here, we describe a flow cytometric method based on cellular NAD(P)H-related autofluorescence, whose localization is mainly associated with mitochondria. By increasing the sensitivity of the specific NAD(P)H-fluorescence detector, we discovered a population with weak levels of NAD(P)H fluorescence signals whose immunophenotypical and physiological characterization in mouse bone marrow led to its identification as both erythrocytes and reticulocytes. Our method showed comparable sensitivity and specificity to the detection of red blood cells based on the absorption of light by oxyhemoglobin. This NAD(P)H-based approach consistently identified over 95% of the total pool of erythrocytes and reticulocytes in bone marrow samples and revealed robust as over 93% of these two erythropoietic subsets were identified in melanoma tumor samples with the same method. The measurement of cellular endogenous NAD(P)H fluorescence, therefore, offers a reliable and straightforward alternative to identify erythrocytes and reticulocytes without additional immunostaining or the need to modify the cytometer's optical configuration. (c) 2018 International Society for Advancement of Cytometry. PMID- 29480981 TI - The Times They Are A-Changin'. PMID- 29480982 TI - Report from the Bodil Schmidt-Nielsen Honorary Symposium. PMID- 29480984 TI - On Mentorship, Perseverance, and Generosity. PMID- 29480983 TI - Predicting the Survival of Gastric Cancer Patients UsingArtificial and Bayesian Neural Networks AB - Introduction and purpose: In recent years the use of neural networks without any premises for investigationof prognosis in analyzing survival data has increased. Artificial neural networks (ANN) use small processors witha continuous network to solve problems inspired by the human brain. Bayesian neural networks (BNN) constitute aneural-based approach to modeling and non-linearization of complex issues using special algorithms and statisticalmethods. Gastric cancer incidence is the first and third ranking for men and women in Iran, respectively. The aim of thepresent study was to assess the value of an artificial neural network and a Bayesian neural network for modeling andpredicting of probability of gastric cancer patient death. Materials and Methods: In this study, we used informationon 339 patients aged from 20 to 90 years old with positive gastric cancer, referred to Afzalipoor and Shahid BahonarHospitals in Kerman City from 2001 to 2015. The three layers perceptron neural network (ANN) and the Bayesianneural network (BNN) were used for predicting the probability of mortality using the available data. To investigatedifferences between the models, sensitivity, specificity, accuracy and the area under receiver operating characteristiccurves (AUROCs) were generated. Results: In this study, the sensitivity and specificity of the artificial neural networkand Bayesian neural network models were 0.882, 0.903 and 0.954, 0.909, respectively. Prediction accuracy and thearea under curve ROC for the two models were 0.891, 0.944 and 0.935, 0.961. The age at diagnosis of gastric cancerwas most important for predicting survival, followed by tumor grade, morphology, gender, smoking history, opiumconsumption, receiving chemotherapy, presence of metastasis, tumor stage, receiving radiotherapy, and being residentin a village. Conclusion: The findings of the present study indicated that the Bayesian neural network is preferable toan artificial neural network for predicting survival of gastric cancer patients in Iran. PMID- 29480985 TI - What They Neglected to Tell You About Classroom Practice in Graduate School. PMID- 29480986 TI - Advocacy is Essential PMID- 29480988 TI - Letter to Patangi K. Rangachari PMID- 29480989 TI - Letter to Peter Lauf. PMID- 29480990 TI - Letter to Lois J. Heller. PMID- 29480987 TI - Comparative Study of Serum Lipid Profiles in Nepalese CancerPatients Attending a Tertiary Care Hospital AB - Significant efforts have been made to study cancer at the biochemical and cellular level and identify factorsassociated with progression. The aim of this hospital based randomized comparative study at the Nepalese ArmyInstitute of Health science hospital was to assess factors in 52 people diagnosed with different types of cancer and 56normal control persons. Fasting blood samples were analyzed for serum total cholesterol (TC), high density lipoprotein(HDL), triglycerides (TG) and low density lipoprotein (LDL). We found that biochemical parameter TC, TG, VLDL(very low density lipoprotein), LDL and HDL were significantly different in the cancer patients and healthy controls.Levels of TC, TG, LDL, HDL and VLDL were higher in the age group below 50 and that of TG was found to be higherin women than men. Our results indicate that TC, TG and HDL are increased, while LDL and VLDL are lowered incancer patients. Our study provides clues to risk factors associated with life style, eating habits, and exercise regimens.Monitoring of these parameters with aging is recommended. PMID- 29480991 TI - Survival Time and Prognostic Factors for Breast Cancer amongWomen in North-East Peninsular Malaysia AB - Background: Breast cancer is the most common malignant disease and the leading cause of cancer death amongwomen globally. This study aimed to determine the median survival time and prognostic factors for breast cancerpatients in a North East State of Malaysia. Methods: This retrospective cohort study was conducted from January tillApril 2017 using secondary data obtained from the state's cancer registry. All 549 cases of breast cancer diagnosedfrom 1st January 2007 until 31st December 2011 were selected and retrospectively followed-up until 31st December2016. Sociodemographic and clinical information was collected to determine prognostic factors. Results: The average(SD) age at diagnosis was 50.4 (11.2) years, the majority of patients having Malay ethnicity (85.8%) and a histology ofductal carcinoma (81.5%). Median survival times for those presenting at stages III and IV were 50.8 (95% CI: 25.34,76.19) and 6.9 (95% CI: 3.21, 10.61) months, respectively. Ethnicity (Adj. HR for Malay vs non-Malay ethnicity=2.52;95% CI: 1.54, 4.13; p<0.001), stage at presentation (Adj. HR for Stage III vs Stage I=2.31; 95% CI: 1.57, 3.39; p<0.001and Adj. HR for Stage IV vs Stage I=6.20; 95% CI: 4.45, 8.65; p<0.001), and history of surgical treatment (Adj. HRfor patients with no surgical intervention=1.95; 95% CI: 1.52, 2.52; p<0.001) were observed to be the statisticallysignificant prognostic factors associated with death caused by breast cancer. Conclusion: The median survival timeamong breast cancer patients in North-East State of Malaysia was short as compared to other studies. Primary andsecondary prevention aimed at early diagnosis and surgical management of breast cancer, particularly among the Malayethnic group, could improve treatment outcome. PMID- 29480992 TI - Melanoma Screening Day in Krasnoyarsk Krai of the RussianFederation: Results from 2015-2016 AB - Objective: The Melanoma Screening Day Campaign started in the Russian Federation in 2006. In the present study,we analyzed the 2015-2016 survey questionnaire data acquired from screened individuals in the city of Krasnoyarsk ineastern Siberia, which has a population of one million, in order to understand the level of awareness regarding melanoma/skin cancer prevention and early diagnosis. Methods: Individuals were enrolled in the screening campaign by massmedia advertising. Free whole-body examinations were provided by the doctors, and the standardized questionnaireforms (n=444) were completed to obtain relevant demographic, epidemiological, and clinical data. Descriptive andunivariate analyses were conducted to elucidate the main characteristics of the screened population. Percentage frequencywas used to characterize the population. Result: A substantial proportion of the screened individuals were female(80%). The most common reasons for participating in the screening were a high number of moles, or a change in theappearance of the moles. Internet recourses were the main channel for obtaining the information about the MelanomaDay Screening Campaign. 5% of screened individuals had a family history of melanoma/skin cancer. The mean age ofthe participants was 36.63+/-16.31 years. The percentage of screened individuals who took part in this program increasedin 2016 (18%) versus 2015 (8%). In total, 5 individuals with suspected melanoma/skin cancer were identified duringthe two-year Campaign, all of whom were referred to the regional oncology center. Conclusion: The analysis of datafrom the Melanoma Screening Day Campaign in Krasnoyarsk Krai revealed the necessity to use the media to attractolder subjects with potential melanoma/skin cancer risk to undergo screening. Individuals with suspected malignanciesshould be monitored up until the time when a final diagnosis is determined. Moreover, such events are an appropriateway to inform and educate the public about cutaneous cancer prevention. PMID- 29480993 TI - Does Endometriosis Hinder Successful Ovarian DebulkingSurgery? AB - Background: Endometriosis has a significant effect on many aspects of women's lives, also increasing the risk ofovarian cancer. Although endometriosis is considered as a benign condition, it sometimes behaves like cancer. Methods:All medical records of epithelial ovarian cancer patients during January 2011 to December 2016 were reviewed.Recurrent cases were excluded. Data collected included age at diagnosis, parity, marital status, familial history of cancer,menopausal status, weight, height, smoking histroy, contraception, CA 125 level, result of surgery and pathologicalreport. Results: One hundred and seventy two medical records of patients with epithelial ovarian cancer (EOC) wereincluded. Average age at diagnosis was 52.3 years. Epithelial ovarian cancer coexisting with endometriosis (EAOC)was found in nearly one-fifth of cases. Nullipara and smoking were associated with 2.3 and 8.3 fold higher risk ofEAOC development (aOR 2.349, 95%CI 1.012-5.451; aOR 8.26, 95%CI 1.234-55.278; respectively). Age, familialhistory of cancer and coexistence with endometriosis were factors related to surgical outcome. More of EAOC grouphad optimal surgery compared to the non-EAOC group (61.3% and 41.8%) with statistical significance. Conclusion:Younger age, familial history of cancer and coexistence of endometriosis were factors related to optimal surgery.Success of optimal surgery is greater in EAOC than in non-EAOC patients. Coexistence of endometriosis does nothinder successful ovarian cancer debulking surgery. PMID- 29480994 TI - Impact of Cyclin D1 and Heterogeneous NuclearRibonucleoprotein-K (HnRNP-K) on Urinary BladderCarcinogenesis AB - Objective: This study aimed to investigate the expression of cyclin D1 and hnRNP K in relation to the pathologicalfindings in bladder cancer including the type, grade, muscle invasion and bilharzial association. Methods: We studiedthe immunoexpression; as regard the percentage, intensity and score of both cyclin D1 and hnRNP-K in different bladderlesions including 10 cases of cystitis; 10 cases of carcinoma insitu (CIS), 20 cases of Squamous cell carcinoma (SCC)and 66 cases of urothelial carcinoma (UC). Results: High expression of cyclin D1 was found in UC compared to othergroups (p<0.001) and in UC with low grade, non-muscle invasive and papillary tumors compared to their counterparts(p<0.05, <0.01 and <0.05 respectively), however, bilharzial association does not affect cyclin D1 expression. HigherhnRNP-K expression was found in SCC compared to other groups (p <0.001) and in UC with high grade, muscle invasiveand non-papillary tumors compared to their counterparts (p<0.001each). Bilharzial-associated UC showed higherexpression of hnRNP-K percent (p<0.05) compared to non-bilharzial cases. Conclusion: This study elucidated a possiblecontribution of cyclin D1 and hnRNP-K expression in the initiation and progression of urinary bladder carcinoma,so, both of them can be used in predicting progression of urinary bladder carcinoma and to differentiate between UCand SCC in high grade tumors. The possible role of both markers in immunotherapy deserves supplementary studies. PMID- 29480995 TI - Physical and Emotional Experiences of Chemotherapy: aQualitative Study among Women with Breast Cancer inSouthern Thailand AB - Background: Chemotherapy treatment can increase survival rates among women with breast cancer elsewhere.However, it also has negative impact on women's general appearance, body image and psychological functioning.This study aimed to describe the experiences of chemotherapy treatment among Thai women with breast cancerin rural communities, sounthern Thailand. Methods: Qualitative approach was employed to gain insights aboutthe experiences of the women. In-depth interviewing and drawing methods were conducted with 20 Thai womenwho had been diagnosed with breast cancer. Thematic method was used to analyse the data. Results: Three themesemerged from the findings: I feel so weak: Lack of physical energy; experiencing physical and emotional burdens andmanaging health and life. Women were traumatized by effects of chemotherapy and suffered severe physical side effects.Most received inadequate professional support from health care providers and had to rely on their own judgment anduse local resources to deal with the effects of their treatment and to improve their health and well-being. Conclusions:Chemotherapy brought about traumatic experiences to Thai women with breast cancer. Continual support is needed forthe women to reduce the difficulties they might encounter. Support groups should be established for these women whenreceiving and completing chemotherapy treatment. Our finding suggested that social support programs that meet theirneed are salient means that could reduce the sufferings of these women. Nurses and other health care professionals inthe local community should play their important role to establish such group and make it accessible for all. PMID- 29480996 TI - Expression of Inhibitor of Apoptosis Gene Family Members inBladder Cancer Tissues and the 5637 Tumor Cell Line AB - Background: Apoptosis is suppressed in cancer tissues and tumor cell lines because anti-apoptosis genes are overexpressed.The inhibitor of apoptosis proteins (IAP) gene family contributes to control of apoptosis. The expressionprofile of eight genes of the IAP family in biopsies from patients with a history of bladder cancer and normal bladdertissues, as well as a bladder tumor cell line (5637), was assessed in the present study. Methods: Cancer tissue sampleswere obtained at surgery and the 5637 tumor cell line was cultured in RPMI1640 medium. Beyond tumor marginswere selected as normal tissue. Expressional profile of interested genes was obtained by using specific primers and thereal time PCR method. Results: The results showed that expression of seven of the studied genes was up-regulated incancer tissues and the cell line whereas BIRC4 (XIAP) was down-regulated in both. Conclusions: The results showedthat these genes were expressed to a greater extent in cancer tissue and cancer cells than in normal tissues. The datasuggested that over-expression of anti-apoptotic genes such as IAP family members, can trigger cells to escape fromapoptosis. PMID- 29480997 TI - Exploring Effective Contextual Factors for Regular CervicalCancer Screening in Iranian Women: A Qualitative Study AB - Background: Adherence to regular screening programs for cervical cancer in Iranian women is not common.The aim of this study was to explore contextual factors influencing behavior and compliance with guidelines.Methods: This qualitative content analysis study was conducted in 2016-2017 in Hamadan city, Iran. Semi-structuredin-depth interviews were conducted with 31 participants who were selected purposefully on referring to health centers.Twenty-three were women with various experiences of cervical cancer screening and 8 were health care providers(4 midwives, 1 gynecologist, 1 general practitioner and 1 family health expert). Guba and Lincoln criteria were usedfor tustworthiness. MAXQDA10 software was employed for data analysis. Results: Four themes were extracted fromthe data: an opportunity maker system, opportunities to become acquainted, concerns for healthy living, and perceptionof cancer. Conclusion: The results showed sensitivity of health care providers and their appropriate performancein relation to regular screening behavior of women is very important. Women's perception of cancer and its curabilityis another factor with a major effect on screening behavior. Opportunities for people to become acquainted with thePap smear in a variety of ways and concern for healthy living and the need to have a healthy life to ensure qualityof life were also found to be important. PMID- 29480999 TI - Snapshot: Patient Engagement: How to encourage active participation. PMID- 29480998 TI - Chromosome Abnormalities and Absolute Telomere Lengthsof Leukocytes from Silk Weavers with Emphasis on PotentialGenotoxicity and Mutagenicity of Silk Dyes AB - Objectives: This study is aimed to assess the possible genotoxicity and mutagenicity of silk dyes on silk weavers.Methods: Peripheral blood leukocytes were obtained from 24 silk weavers and 24 age- and sex-matched controls innortheastern Thailand. After mitogen stimulation in culture, chromosome abnormalities were examined using Giemsabanding and the absolute telomere length (aTL) was measured with SYBR green qRT-PCR. To confirm genotoxic andmutagenic effects of silk dyes, leukocytes from one each of healthy male and female volunteers were cultured withvarious concentrations of 3 dark red silk dyes under the presence of mitogen. Chromosome abnormalities and thetelomere length were determined as above. Results: The proportion of normal metaphase in the silk weaving workerswas significantly lower than that in controls. The frequency of chromosome aberrations was higher in the silk weaversthan in control group. Polyploidy was detected only in the silk weavers. The aTL was significantly shorter in the silkweavers than in control group (p < 0.05). When leukocytes from normal volunteers were stimulated with mitogen underthe presence of various concentrations of 3 silk dyes, suppressed the mitotic index (MI) and normal metaphase, whereasthe proportion of prophase and the incomplete chromosome forming increased significantly. All dyes induced polyploidy.Dye #CA5 induced structural changes in male leukocytes, whereas #30 induced the changes in female leukocytes.The #CA5 increased aTL of normal leukocytes in a dose-dependent manner. Conclusions: All dyes, especially #CA5,have high genotoxicity and mutagenicity to induce chromosome aberrations and telomeric instability. Taken all thoseresults together, regular health checking of silk weavers who have been exposed to those dyes is critically necessaryto prevent various chemical-induced carcinogenesis. PMID- 29481000 TI - Mending the payer-provider relationship: Collaboration is critical to value-based healthcare. PMID- 29481002 TI - On the problems of chatting with angels. PMID- 29481003 TI - Walker Percy, burnout and the physician's pilgrimage. PMID- 29481005 TI - A dash of values. PMID- 29481004 TI - The key on the lock: Cardiac catheterization. PMID- 29481006 TI - Hands. PMID- 29481007 TI - Lord Byron's lameness. PMID- 29481008 TI - Joint Families and Cancer Diagnosis in Rural India AB - Background: Each year, there are over a million new cases of cancer in India, which causes many untimely deathsand increases the economic burden to households. By focusing on preventative measures and finding socioeconomicand behavioral contributors to cancer, steps can be taken to help alleviate this burden. This study aims to find the effectliving in a joint family can have on being diagnosed with cancer in rural India. Methods: The study estimates theeffect living in a joint family, along with other demographic information, has on being diagnosed with cancer usinga logit estimation model. The data for the study was collected from a survey was conducted on the households of theHandiganur village (N=251) comprising of several demographic, social, and medical questions. Results: The studyfound that living in a joint family lowers the odds of having cancer. The results indicate that living in a joint familyreduces the probability of being diagnosed by 7.23 percentage points and is significant at a 5% level. Furthermore,among the other tested variables, eating habit is negatively significant at 5% level, suggesting that if a person eats 3 to4 times a day his or her likelihood of suffering from cancer will be lowered by 6.55 percentage points. Access to publicwells and drinking alcohol both increase the likelihood of being diagnosed with cancer by 7.90 (p<0.1) percentagepoints and 11.90 (p<0.05) percentage points respectively. Conclusions: The negative effect of joint family could bedue to two possible reasons. The first is that there is in fact a biological reason. The second reason for this result couldbe a false negative, as it could be because people in joint families are not getting the necessary check-ups required todiagnose cancer. PMID- 29481009 TI - Star-crossed: Love, death, and adolescence in two films. PMID- 29481010 TI - "Time matters in caring for patients: Twenty minutes isn't enough." PMID- 29481011 TI - Matrine Induction of ROS Mediated Apoptosis in Human ALL B-lymphocytes Via Mitochondrial Targeting AB - Background: Acute lymphoblastic leukemia (ALL) is one of the most common malignancies among children,characterized by mass production of leukemic blasts. Chemotherapy is the first step in routine treatment, althoughit may evoke considerable side effects. Matrine, an alkaloid extracted from a Chinese herb, Sophora alopecuroidesflavescens Ait, may be protective. Several investigations have indicated pro-apoptotic and anti-proliferative effects ina diverse range of cancer cells. Methods: Matrine's anti-cancer effects and associated mechanisms were assessed inhuman ALL B-lymphocytes, focusing on parameters of inflammatory change and apoptosis. Results: Treatment ofALL B-lymphocytes with matrine augmented ROS generation, and caused mitochondrial swelling and a decline inmitochondrial membrane potential. Significant up-regulation of the pro apoptotic protein Bax and down-regulation ofthe anti-apoptotic Bcl-2 were also noted. Conclusion: Our results suggest that matrine may be a potential anticanceragent. However, additional studies are needed to clarify involved mechanisms. PMID- 29481012 TI - "Bosch and Bruegel: Disability in sixteenth-century art". PMID- 29481013 TI - Informative Gene Selection for Cancer Classification with Microarray Data Using a Metaheuristic Framework AB - Objective: Cancer diagnosis is one of the most vital emerging clinical applications of microarray data. Due tothe high dimensionality, gene selection is an important step for improving expression data classification performance.There is therefore a need for effective methods to select informative genes for prediction and diagnosis of cancer.The main objective of this research was to derive a heuristic approach to select highly informative genes. Methods:A metaheuristic approach with a Genetic Algorithm with Levy Flight (GA-LV) was applied for classification of cancergenes in microarrays. The experimental results were analyzed with five major cancer gene expression benchmark datasets.Result: GA-LV proved superior to GA and statistical approaches, with 100% accuracy for the dataset for Leukemia,Lung and Lymphoma. For Prostate and Colon datasets the GA-LV was 99.5% and 99.2% accurate, respectively.Conclusion: The experimental results show that the proposed approach is suitable for effective gene selection with allbenchmark datasets, removing irrelevant and redundant genes to improve classification accuracy. PMID- 29481014 TI - Reply: Discussion on Terminal weaning or immediate extubation for withdrawing mechanical ventilation in critically ill patients (the ARREVE observational study). PMID- 29481015 TI - Information and cognitive overload: How much is too much? PMID- 29481016 TI - Managing mission tensions in academic health centers. PMID- 29481017 TI - Antimigration Activity of an Ethylacetate Fraction of Zanthoxylum acanthopodium DC. Fruits in 4T1 Breast CancerCells AB - Objective: This study was carried out to investigate the antimigration activity of Zanthoxylum acanthopodium DC.in the 4T1 breast cancer cell line. Methods: Zanthoxylum acanthopodium DC. fruit powder was extracted by macerationmethod with n-hexane and ethylacetate solvents. Cytotoxicity and proliferation were assessed using the MTT methodand the cell cycle by flow cytometry. In addition, wound healing assays were conducted by a microscopic method,and expression of COX-2 and VEGFR-2 were determined using qRT-PCR. Results: The IC50 of the ethylacetatefraction (EAF) was 48.1 +/- 1.06 MUg/mL. The EAE at a concentration 10 MUg/mL with viable cells was 62.3 +/- 0.28%after 72 h incubation, with accumulation in the G2-M phase, inhibition of cell migration in the wound healing assay,and decrease in expression of COX-2 (0.62 +/- 0.01) and VEGFR-2 (0.39 +/- 0.003). Conclusion: The results reveal thatan ethylacetate fraction of Zanthoxylum acanthopodium DC. fruits provides effective antimigration effects. Furtherstudies are now planned to assess the potential of the ethylacetate fraction to inhibit angiogenesis in breast cancer anddetermine underlying mechanisms. PMID- 29481020 TI - The 20th General Hospital: The reach of formalized medicine during World War II. PMID- 29481021 TI - History of present illness. PMID- 29481022 TI - The slavery hypertension hypothesis. PMID- 29481023 TI - Speaking for a world at war. PMID- 29481024 TI - Prognostic Significance of Serum Vitamin D Levels in Egyptian Females with Breast Cancer AB - Objective: To determine the frequency and prognostic significance of vitamin D deficiency in Egyptian womenwith breast cancer (BC). Methods: This prospective study included 50 women with primary invasive, non-metastaticBC. The serum level of 25-hydroxy vitamin D [25(OH)D was measured by ELISA at diagnosis, before any cancertreatment. Vitamin D deficiency was defined as 25(OH) D<20 ng/mL. Patients were followed up for a median of 30months (range: 18-48). Results: The median level of 25(OH)D was 29.0 ng/mL (range: 10.0-55.0 ng/mL). Fifteenpatients (30%) had vitamin D deficiency, which was positively associated with larger tumor size (p < 0.001), highergrade (p = 0.014), advanced stage (p = 0.001), lymph node positivity (p = 0.012), and HER2/neureceptor expression(p = 0.002). It was also linked with worse overall survival (OS) and disease free survival (DFS) (p = 0.026, andp = 0.004, respectively). On multivariate analysis, DFS was independently affected by vitamin D deficiency withan HR of 2.8 (95% CI: 1.6-7.0, p = 0.022) and advanced stage, i.e. stage II had worse survival compared to stage I withan HR of 4.8 (95%CI: 1.1-21.7, p = 0.042). Conclusion: Vitamin D deficiency had a negative effect on overall anddisease-free survival in our breast cancer cases, being related to tumor size, stage, grade, nodal status and HER2/neureceptor expression. PMID- 29481026 TI - Real and unreal: The two worlds at room. PMID- 29481025 TI - Shakespearean syphilis. An aggressive disease in evolution. PMID- 29481027 TI - On showing up. PMID- 29481029 TI - The uses of medical oaths in the twenty-first century. PMID- 29481028 TI - Factors Associated with Colorectal Cancer Among Jordanians: a Case- Control Study AB - Objective: In recent years, the incidence of colorectal cancer (CRC) in Jordan has been on the rise. We aimed todetermine associations with lifestyle factors, demographic and clinical variables. Methods: This case-control studyincluded 102 patients diagnosed with CRC and 198 age and gender matched healthy subjects as controls. Cases werepurposefully sampled; however, the control group were selected by simple random sampling of a cross-section of thepopulation in Northern Jordan. Participating cases and controls completed an anonymous questionnaire inquiring abouttheir demographic characteristics, lifestyle factors, and clinical variables. Data about the medical history and diagnosisof participating cases were obtained from the cases themselves and confirmed by reviewing their medical records.Results: In the cross tabulation analysis, the Chi square test showed that diabetes and hypertension were significantlyassociated with CRC (P <0.05). Additionally, regression modeling revealed that age >= 45 years (OR=10.93), positivefamily history for CRC (OR=5.53), physical inactivity (OR=7.4), cigarette smoking (OR=3.71), and having other typesof cancer (OR=13.61) were all associated with increased risk of CRC. Conclusions: Physical inactivity and cigarettesmoking are among the top modifiable risk factors for CRC among Jordanians. Moreover, diabetes and hypertensionwere found to be statistically significant risk factors in univariate, but not multivariate analysis. More effective strategiesfor elevating awareness and prevention are required at both national and international levels. Improving screeningstrategies is needed for early detection of CRC in Jordan. PMID- 29481030 TI - "Time matters in caring for patients". PMID- 29481033 TI - Nickel Cobalt Sulfide Double-Shelled Hollow Nanospheres as Superior Bifunctional Electrocatalysts for Photovoltaics and Alkaline Hydrogen Evolution. AB - Transition metal chalcogenides with hollow nanostructures have been considered as promising substitutes as precious metal electrocatalysts for energy conversion and storage. We synthesized NiCo2S4 double-shelled ball-in-ball hollow spheres (BHSs) via a simple solvothermal route and applied them in both dye-sensitized solar cells (DSSCs) and hydrogen evolution reactions (HERs) at the same time, which were clean and sustainable ways to convert energy. Benefiting from their remarkable structure features and advantageous chemical compositions, NiCo2S4 BHSs composed of tiny crystals possessed large surface area, well-defined interior voids, and high catalytic activity. The DSSC with NiCo2S4 BHSs under 100 mW cm-2 irradiation possessed a power conversion efficiency of 9.49% (Pt, 8.30%). Besides, NiCo2S4 BHSs as a HER catalyst also possessed a small onset overpotential (27.9 mV) and a low overpotential (89.7 mV at 10 mA cm-2) under alkaline conditions. Therefore, this work offers a sensible strategy to synthesize bifunctional electrocatalysts for DSSCs and HERs. PMID- 29481034 TI - Enhancing the Photovoltage of Ni/ n-Si Photoanode for Water Oxidation through a Rapid Thermal Process. AB - The Ni in the Ni/ n-Si photoanode can not only protect Si from corrosion, but also catalyze the water oxidation reaction. However, the high density of interface states at the Ni/ n-Si interface could pin the Fermi level of silicon, which will lower the Schottky barrier height of the Ni/ n-Si. As a result, a low photovoltage and consequent high onset potential of Ni/ n-Si photoanode for water oxidation were generated. In this study, the interfacial states of the Ni/ n-Si photoanodes were efficiently diminished through a rapid thermal process (RTP). Calculated from the Mott-Schottky plots, the Schottky barrier height of Ni/ n-Si was increased from 0.58 to 0.78 eV after RTP. Under the illumination of 100 mW cm 2 of the Xe lamp, the onset potential of the Ni/ n-Si photoanode for water oxidation was negatively shifted for 150 mV after RTP. Besides, the RTP-treated Ni/ n-Si photoanode exhibited a high stability during the PEC water oxidation of 8 h in 1 M KOH solution. PMID- 29481036 TI - White Light-Emitting Multistimuli-Responsive Hydrogels with Lanthanides and Carbon Dots. AB - Polymers that confer changes in optical properties in response to chemical or mechanical cues offer diverse sensing applications, particularly if this stimuli response is accessible in humid or aqueous environments. In this study, luminescent hydrogels were fabricated using a facile aqueous process by incorporating lanthanide ions and carbon dots (CD) into a network of polyacrylamide and poly(acrylic acid). White luminescence was obtained by tuning the balance of blue-light-emitting CD to green- and red-light-emitting lanthanide ions. Exploiting the combined specific sensitivities of the different emitters, the luminescent hydrogel showed chromic responsiveness to multiple stimuli, including pH, organic vapors, transition-metal ions, and temperature. The white light-emitting hydrogel was also stretchable with a fracture strain of 400%. We envision this photoluminescent hydrogel to be a versatile and multifunctional material for chemical and environmental sensing. PMID- 29481035 TI - Sulfur-Doped Black Phosphorus Field-Effect Transistors with Enhanced Stability. AB - Black phosphorus (BP) has drawn great attention owing to its tunable band gap depending on thickness, high mobility, and large Ion/ Ioff ratio, which makes BP attractive for using in future two-dimensional electronic and optoelectronic devices. However, its instability under ambient conditions poses challenge to the research and limits its practical applications. In this work, we present a feasible approach to suppress the degradation of BP by sulfur (S) doping. The fabricated S-doped BP few-layer field-effect transistors (FETs) show more stable transistor performance under ambient conditions. After exposing to air for 21 days, the charge-carrier mobility of a representative S-doped BP FETs device decreases from 607 to 470 cm2 V-1 s-1 (remained as high as 77.4%) under ambient conditions and a large Ion/ Ioff ratio of ~103 is still retained. The atomic force microscopy analysis, including surface morphology, thickness, and roughness, also indicates the lower degradation rate of S-doped BP compared to BP. First-principles calculations show that the dopant S atom energetically prefers to chemisorb on the BP surface in a dangling form and the enhanced stability of S-doped BP can be ascribed to the downshift of the conduction band minimum of BP below the redox potential of O2/O2-. Our work suggests that S doping is an effective way to enhance the stability of black phosphorus. PMID- 29481037 TI - In Situ Generated Dual-Template Method for Fe/N/S Co-Doped Hierarchically Porous Honeycomb Carbon for High-Performance Oxygen Reduction. AB - Heteroatoms doping is able to produce catalytic sites in carbon materials for oxygen reduction reaction (ORR); while hierarchically porous structure is necessary for efficient exposure and accessibility of the usually limited catalytic sites in such activated carbon catalysts. This work reports an in situ generated dual-template method to synthesize the Fe/N/S co-doped hierarchically porous carbon (FeNS/HPC), with NaCl crystallites formed during the precursor lyophilization process as the primary template to generate ~500 nm macropores with ultrathin graphene-like carbon-layer walls, and Fe3O4 nanoparticles formed during the high-temperature carbonization process as the secondary template to produce mesopores on the walls of macropores. As well as the coexistence of graphitic-N, pyridinic-N, and thiophene-S which are beneficial to ORR, the as prepared FeNS/HPC possesses a highly graphitized and interconnected hierarchical porous structure, giving a specific surface area as high as 938 m2 g-1. As a consequence, it exhibits excellent four-electron oxygen reduction performance in both alkaline and acid electrolytes. The in situ generation and facile solution removal make the present template method a promising way for scale-up preparation of active porous carbon materials for various applications. PMID- 29481038 TI - Hierarchical Microplates as Drug Depots with Controlled Geometry, Rigidity, and Therapeutic Efficacy. AB - A variety of microparticles have been proposed for the sustained and localized delivery of drugs with the objective of increasing therapeutic indexes by circumventing filtering organs and biological barriers. Yet, the geometrical, mechanical, and therapeutic properties of such microparticles cannot be simultaneously and independently tailored during the fabrication process to optimize their performance. In this work, a top-down approach is employed to realize micron-sized polymeric particles, called microplates (MUPLs), for the sustained release of therapeutic agents. MUPLs are square hydrogel particles, with an edge length of 20 MUm and a height of 5 MUm, made out of poly(lactic- co glycolic acid) (PLGA). During the synthesis process, the MUPL Young's modulus can be varied from 0.6 to 5 MPa by changing the PLGA amounts from 1 to 7.5 mg, without affecting the MUPL geometry while matching the properties of the surrounding tissue. Within the porous MUPL matrix, different classes of therapeutic payloads can be incorporated including molecular agents, such as anti inflammatory dexamethasone (DEX), and nanoparticles containing imaging and therapeutic molecules themselves, thus originating a truly hierarchical platform. As a proof of principle, MUPLs are loaded with free DEX and 200 nm spherical polymeric nanoparticles, carrying DEX molecules (DEX-SPNs). Electron and fluorescent confocal microscopy analyses document the uniform distribution and stability of molecular and nanoagents within the MUPL matrix. This multiscale, hierarchical microparticle releases DEX for at least 10 days. The inclusion of DEX-SPNs serves to minimize the initial burst release and modulate the diffusion of DEX molecules out of the MUPL matrix. The biopharmacological and therapeutic properties together with the fine tuning of geometry and mechanical stiffness make MUPLs a unique polymeric depot for the potential treatment of cancer, cardiovascular, and chronic, inflammatory diseases. PMID- 29481039 TI - Cyclical Annealing Technique To Enhance Reliability of Amorphous Metal Oxide Thin Film Transistors. AB - This study introduces a cyclical annealing technique that enhances the reliability of amorphous indium-gallium-zinc-oxide (a-IGZO) via-type structure thin film transistors (TFTs). By utilizing this treatment, negative gate-bias illumination stress (NBIS)-induced instabilities can be effectively alleviated. The cyclical annealing provides several cooling steps, which are exothermic processes that can form stronger ionic bonds. An additional advantage is that the total annealing time is much shorter than when using conventional long-term annealing. With the use of cyclical annealing, the reliability of the a-IGZO can be effectively optimized, and the shorter process time can increase fabrication efficiency. PMID- 29481040 TI - Tuning Interfacial Magnetic Ordering via Polarization Control in Ferroelectric SrTiO3/PbTiO3 Heterostructure. AB - The electromagnetic properties at the interface of heterostructure are sensitive to the interfacial crystal structure and external field. For example, the two dimensional magnetic states at the interface of LaAlO3/SrTiO3 are discovered and can further be controlled by electric field. Here, we study two types of heterostructures, TiO2/PbTiO3 and SrTiO3/PbTiO3, using first-principle electronic structure calculations. We find that the ferroelectric polarization discontinuity at the interface leads to partially occupied Ti 3d states and the magnetic moments. The magnitude of the magnetic moments and the ground-state magnetic coupling are sensitive to the polarization intensity of PbTiO3. As the ferroelectric polarization of PbTiO3 increases, the two heterostructures show different magnetic ordering that strongly depends on the electron occupation of the Ti t2g orbitals. For the TiO2/PbTiO3 interface, the magnetic moments are mostly contributed by degenerated d yz/d xz orbitals of interfacial Ti atoms and the neighboring interfacial Ti atoms form ferromagnetic coupling. For SrTiO3/PbTiO3 interface, the interfacial magnetic moments are mainly contributed by occupied d xy orbital because of the increased polarization intensity, and as the electron occupation increases, there exists a transition of the magnetic coupling between neighboring Ti atoms from ferromagnetism to antiferromagnetism via the superexchange interaction. Our study suggests that manipulating the polarization intensity is one effective way to control interfacial magnetic ordering in the perovskite oxide heterostructures. PMID- 29481041 TI - Biogenesis of Asparagine-Linked Glycoproteins Across Domains of Life-Similarities and Differences. PMID- 29481042 TI - Comparison of Cell Permeability of Cyclic Peptoids and Linear Peptoids. AB - Cyclic peptoids are emerging as an attractive class of peptidomimetics. Compared to their linear counterparts, cyclic peptoids should have increased conformational rigidity and preorganized structures, enabling them to bind more tightly to target proteins without major entropy penalty. Because cyclic peptoids lack the amide protons in their backbones like linear peptoids, it is perceived that cyclic peptoids are seemingly cell permeable as much as linear peptoids. However, no systematic investigation for cell permeability of cyclic peptoids has been reported yet. Here, we, for the first time, demonstrate that cyclic peptoids are far more cell permeable than linear counterparts irrespective of their size and side chains. This study highlights that cyclic peptoids, along with combinatorial library and high-throughput screening technologies, will serve as a rich source of protein binding molecules, particularly targeting intracellular proteins, given their excellent cell permeability in addition to their conformational rigidity and proteolytic stability. PMID- 29481044 TI - Reversibly Switchable, pH-Dependent Peptide Ligand Binding via 3,5-Diiodotyrosine Substitutions. AB - Cell type-specific targeting ligands utilized in drug delivery applications typically recognize receptors that are overexpressed on the cells of interest. Nonetheless, these receptors may also be expressed, to varying extents, on off target cells, contributing to unintended side effects. For the selectivity profile of targeting ligands in cancer therapy to be improved, stimuli-responsive masking of these ligands with acid-, redox-, or enzyme-cleavable molecules has been reported, whereby the targeting ligands are exposed in specific environments, e.g., acidic tumor hypoxia. One possible drawback of these systems lies in their one-time, permanent trigger, which enables the "demasked" ligands to bind off-target cells if released back into the systemic circulation. A promising strategy to address the aforementioned problem is to design ligands that show selective binding based on ionization state, which may be microenvironment-dependent. In this study, we report a systematic strategy to engineer low pH-selective targeting peptides using an M2 macrophage-targeting peptide (M2pep) as an example. 3,5-Diiodotyrosine mutagenesis into native tyrosine residues of M2pep confers pH-dependent binding behavior specific to acidic environment (pH 6) when the amino acid is protonated into the native tyrosine-like state. At physiological pH of 7.4, the hydroxyl group of 3,5 diiodotyrosine on the peptide is deprotonated leading to interruption of the peptide native binding property. Our engineered pH-responsive M2pep (Ac-Y-I-I) binds target M2 macrophages more selectively at pH 6 than at pH 7.4. In addition, 3,5-diiodotyrosine substitutions also improve serum stability of the peptide. Finally, we demonstrate pH-dependent reversibility in target binding via a postbinding peptide elution study. The strategy presented here should be applicable for engineering pH-dependent functionality of other targeting peptides with potential applications in physiology-dependent in vivo targeting applications (e.g., targeting hypoxic tumor/inflammation) or in in vitro receptor identification. PMID- 29481043 TI - Structural and Functional Studies of a Pyran Synthase Domain from a trans Acyltransferase Assembly Line. AB - trans-Acyltransferase assembly lines possess enzymatic domains often not observed in their better characterized cis-acyltransferase counterparts. Within this repertoire of largely unexplored biosynthetic machinery is a class of enzymes called the pyran synthases that catalyze the formation of five- and six-membered cyclic ethers from diverse polyketide chains. The 1.55 A resolution crystal structure of a pyran synthase domain excised from the ninth module of the sorangicin assembly line highlights the similarity of this enzyme to the ubiquitous dehydratase domain and provides insight into the mechanism of ring formation. Functional assays of point mutants reveal the central importance of the active site histidine that is shared with the dehydratases as well as the supporting role of a neighboring semiconserved asparagine. PMID- 29481045 TI - Combined Chemical Synthesis and Tailored Enzymatic Elongation Provide Fully Synthetic and Conjugation-Ready Neisseria meningitidis Serogroup X Vaccine Antigens. AB - Studies on the polymerization mode of Neisseria meningitidis serogroup X capsular polymerase CsxA recently identified a truncated construct that can be immobilized and used for length controlled on-column production of oligosaccharides. Here, we combined the use of a synthetic acceptor bearing an appendix for carrier protein conjugation and the on-column process to a novel chemo-enzymatic strategy. After protein coupling of the size optimized oligosaccharide produced by the one-pot elongation procedure, we obtained a more homogeneous glycoconjugate compared to the one previously described starting from the natural polysaccharide. Mice immunized with the conjugated fully synthetic oligomer elicited functional antibodies comparable to controls immunized with the current benchmark MenX glycoconjugates prepared from the natural capsule polymer or from fragments of it enzymatically elongated. This pathogen-free technology allows the fast total in vitro construction of predefined bacterial polysaccharide fragments. Compared to conventional synthetic protocols, the procedure is more expeditious and drastically reduces the number of purification steps to achieve the oligomers. Furthermore, the presence of a linker for conjugation in the synthetic acceptor minimizes manipulations on the enzymatically produced glycan prior to protein conjugation. This approach enriches the methods for fast construction of complex bacterial carbohydrates. PMID- 29481046 TI - Exploration of Ultralight Nanofiber Aerogels as Particle Filters: Capacity and Efficiency. AB - Ultralight nanofiber aerogels (NFAs) or nanofiber sponges are a truly three dimensional derivative of the intrinsically flat electrospun nanofiber mats or membranes (NFMs). Here we investigated the potential of such materials for particle or aerosol filtration because particle filtration is a major application of NFMs. Ultralight NFAs were synthesized from electrospun nanofibers using a solid-templating technique. These materials had a tunable hierarchical cellular open-pore structure. We observed high filtration efficiencies of up to 99.999% at the most penetrating particle size. By tailoring the porosity of the NFAs through the processing parameters, we were able to adjust the number of permeated particles by a factor of 1000 and the pressure drop by a factor of 9. These NFAs acted as a deep-bed filter, and they were capable of handling high dust loadings without any indication of performance loss or an increase in the pressure drop. When the face velocity was increased from 0.75 to 6 cm s-1, the filtration efficiency remained high within a factor of 1.1-10. Both characteristics were in contrast to the behavior of two commercial NFM particle filters, which showed significant increases in the pressure drop with the filtration time as well as a susceptibility against high face velocities by a factor of 105. PMID- 29481047 TI - Hole Transport in Exfoliated Monolayer MoS2. AB - Ideal monolayers of common semiconducting transition-metal dichalcogenides (TMDCs) such as MoS2, WS2, MoSe2, and WSe2 possess many similar electronic properties. As it is the case for all semiconductors, however, the physical response of these systems is strongly determined by defects in a way specific to each individual compound. Here we investigate the ability of exfoliated monolayers of these TMDCs to support high-quality, well-balanced ambipolar conduction, which has been demonstrated for WS2, MoSe2, and WSe2, but not for MoS2. Using ionic-liquid gated transistors, we show that, contrary to WS2, MoSe2, and WSe2, hole transport in exfoliated MoS2 monolayers is systematically anomalous, exhibiting a maximum in conductivity at negative gate voltage ( V G) followed by a suppression of up to 100 times upon further increasing V G. To understand the origin of this difference, we have performed a series of experiments including the comparison of hole transport in MoS2 monolayers and thicker multilayers, in exfoliated and CVD-grown monolayers, as well as gate dependent optical measurements (Raman and photoluminescence) and scanning tunneling imaging and spectroscopy. In agreement with existing ab initio calculations, the results of all these experiments are consistently explained in terms of defects associated with chalcogen vacancies that only in MoS2 monolayers, but not in thicker MoS2 multilayers nor in monolayers of the other common semiconducting TMDCs, create in-gap states near the top of the valence band that act as strong hole traps. Our results demonstrate the importance of studying systematically how defects determine the properties of 2D semiconducting materials and of developing methods to control them. PMID- 29481048 TI - Perfluoropolyether-Impregnated Mesoporous Alumina Composites Overcome the Dewetting-Tribological Properties Trade-Off. AB - Conventional omniphobic surfaces suffer from wear-sensitivity due to soft apolar coatings or substrates and protruding surface features that are eroded even for mild abrasion treatments, leading to the loss of dewetting properties after wear. Evidently, there was a trade-off between dewetting and tribological properties. Here, we show the establishment of self-healing slippery properties post severe abrasion by utilizing perfluoropolyether-impregnated mesoporous Al2O3 (MPA) composites. The hard polar alumina matrix provides the optimal tribological properties, and the liquid lubricant in the porous network contributes to both tribological and self-healing dewetting properties. These composites sustained normal pressures up to 350 MPa during reciprocating sliding contacts. The severely abraded surfaces are capable of self-replenishing in ambient environment, driven by capillarity and surface diffusion processes, and regained their slippery properties toward water and hexadecane after 15 h of self-healing. Eventually, a dewetting-tribology diagram has been introduced to show different regimes, namely-optimal slippery properties, optimal tribological properties, and a mixed regime). We found out that the microstructural expression [Formula: see text] is a robust guiding tool to predict the regime of interest. This dewetting tribological diagram may be marked as an inception to designing abrasion resistant slippery liquid impregnated composites for overcoming the dewetting tribological properties trade-off. Such surfaces may potentially find applications in paint industries and as anti-icing surfaces. PMID- 29481049 TI - Programming Nanoparticles in Multiscale: Optically Modulated Assembly and Phase Switching of Silicon Nanoparticle Array. AB - Manipulating and tuning nanoparticles by means of optical field interactions is of key interest for nanoscience and applications in electronics and photonics. We report scalable, direct, and optically modulated writing of nanoparticle patterns (size, number, and location) of high precision using a pulsed nanosecond laser. The complex nanoparticle arrangement is modulated by the laser pulse energy and polarization with the particle size ranging from 60 to 330 nm. Furthermore, we report fast cooling-rate induced phase switching of crystalline Si nanoparticles to the amorphous state. Such phase switching has usually been observed in compound phase change materials like GeSbTe. The ensuing modification of atomic structure leads to dielectric constant switching. Based on these effects, a multiscale laser-assisted method of fabricating Mie resonator arrays is proposed. The number of Mie resonators, as well as the resonance peaks and dielectric constants of selected resonators, can be programmed. The programmable light matter interaction serves as a mechanism to fabricate optical metasurfaces, structural color, and multidimensional optical storage devices. PMID- 29481050 TI - A Bioactive Trypanosoma cruzi Bromodomain Inhibitor from Chemically Engineered Extracts. AB - A set of chemically engineered extracts enriched in compounds including N-N and N O fragments in their structures was prepared. Bromodomain binding screening and bioguided fractionation led to the identification of one oxime hit that interacts with TcBDF3 with affinity in the submicromolar range and that shows interesting antiparasitic properties against the different life cycle stages of T. cruzi. PMID- 29481051 TI - Bactericidal Effects of Silver Nanoparticles on Lactobacilli and the Underlying Mechanism. AB - While the antibacterial properties of silver nanoparticles (AgNPs) have been demonstrated across a spectrum of bacterial pathogens, the effects of AgNPs on the beneficial bacteria are less clear. To address this issue, we compared the antibacterial activity of AgNPs against two beneficial lactobacilli ( Lactobacillus delbrueckii subsp. bulgaricus and Lactobacillus casei) and two common opportunistic pathogens ( Escherichia coli and Staphylococcus aureus). Our results demonstrate that those lactobacilli are highly susceptible to AgNPs, while the opportunistic pathogens are not. Acidic environment caused by the lactobacilli is associated with the bactericidal effects of AgNPs. Our mechanistic study suggests that the acidic growth environment of lactobacilli promotes AgNP dissolution and hydroxyl radical (*OH) overproduction. Furthermore, increases in silver ions (Ag+) and *OH deplete the glutathione pool inside the cell, which is associated with the increase in cellular reactive oxygen species (ROS). High levels of ROS may further induce DNA damage and lead to cell death. When E. coli and S. aureus are placed in a similar acidic environment, they also become more susceptible to AgNPs. This study provides a mechanistic description of a pH-Ag+-*OH bactericidal pathway and will contribute to the responsible development of products containing AgNPs. PMID- 29481052 TI - 4-Diphenylaminocarbazole: Switching Substituent Position for Voltage Reduction and Efficiency Enhancement of OLEDs. AB - Simple but exceptionally efficient 4-diphenylaminocarbazole host material, 4 DPACz, is presented and compared with its positional isomer, 1-DPACz. The shift of diphenylamino substituent from the 1-position to 4-position of carbazole resulted in an increase in the HOMO energy level as well as an increase in triplet energy level. Having a high triplet energy level (2.76 eV) and well matched HOMO energy level (-5.61 eV), 4-DPACz showed reduced driving voltage and higher efficiencies for solution-processed green PhOLEDs compated to PVK as well as 1-DPACz. Maximum luminous, power, and external quantum efficiencies reaching to 47.9 cd A-1, 25.2 lm W-1, and 14.3%, respectively, were achieved with a device configuration of [ITO/PEDOT:PSS/4-DPACz:Ir(mppy)3/TPBi/CsF/Al]. Additional enhancement of efficiencies of 4-DPACz was verified when incorporating another dopant, Ir(Si-bppy)2(acac), resulting in 59.1 cd A-1, 29.5 lm W-1, and 15.8%. Furthermore, reduced efficiency roll-off was clearly observed for 4-DPACz compared with PVK. Such improved device characteristics of 4-DPACz were attributed to its high hole mobility and charge balance inside the emitting layer therof. The excellent results using such a simple-structured 4-DPACz could promote various applications of this 4-DPACz unit as a building block structure for further possible oligomeric, dendritic, and polymeric materials. PMID- 29481053 TI - Characterization of Mega-Dalton-Sized Nanoparticles by Superconducting Tunnel Junction Cryodetection Mass Spectrometry. AB - The characterization of nanomaterials is critical to understand the size/structure-dependent properties of these particles. In this report, a form of heavy ion mass spectrometry, namely, superconducting tunnel junction (STJ) cryodetection mass spectrometry (MS) is used to characterize quantum dot semiconductor nanocrystals and gold nanoparticles. The nanoparticles studied ranged in mass from 200 kDa to >1.5 MDa and included lead sulfide quantum dots, various cadmium selenide and/or telluride-based core-shell quantum dots coated with different ligands, and gold nanoparticles. Nanoparticles were ionized by both matrix-assisted laser desorption ionization (MALDI) and laser desorption ionization (LDI), shot with an aimed ion gun into a flight tube, mass separated by time-of-flight (TOF), and detected by an energy-sensitive STJ cryodetector. STJ cryodetection MS can be used to analyze intact heterogeneous nanoparticles, allowing determination of average particle mass, dispersity, and ligand loading. Some nanoparticles, however, do undergo fragmentation during the MALDI or LDI-TOF mass analyses. The measurement of the energy deposited into the detector was found to be different for different types of particles. Metastable fragments from these nanoparticles were observed at lower energies. The lower energies deposited for metastable fragments can provide insight into the stability and surface compositions of these materials. Cadmium selenide core-shell quantum dots (655 nm emission) conjugated to biomacromolecules, such as cholera toxin B and human serum transferrin, were also analyzed. When compared to unconjugated particles by mass, it was determined that ~96 cholera toxin B and ~14 transferrin proteins were attached to the surface of these nanoparticles. PMID- 29481054 TI - Streptonigrin Inhibits SENP1 and Reduces the Protein Level of Hypoxia-Inducible Factor 1alpha (HIF1alpha) in Cells. AB - Streptonigrin (CAS no. 3930-19-6) is a natural product shown to have antitumor activities in clinical trials conducted in the 1960s-1970s. However, its use in clinical studies eventually faded, and the molecular mechanisms of streptonigrin antitumor effects remain poorly defined. Despite its lack of current clinical use, efforts on its total synthesis have continued. Here, we show that streptonigrin binds and inhibits the SUMO-specific protease SENP1. NMR studies identified that streptonigrin binds to SENP1 on the surface where SUMO binds and disrupts SENP1-SUMO1 interaction. Site-directed mutations in combination with NMR chemical shift perturbation suggest key roles of aromatic pi stacking interactions in binding streptonigrin. Treatment of cells with streptonigrin resulted in increased global SUMOylation levels and reduced level of hypoxia inducible factor alpha (HIF1alpha). These findings inform both the design of SENP1 targeting strategy and the modification of streptonigrin to improve its efficacy for possible future clinical use. PMID- 29481056 TI - [6,6]-Phenyl-C61-Butyric Acid Methyl Ester/Cerium Oxide Bilayer Structure as Efficient and Stable Electron Transport Layer for Inverted Perovskite Solar Cells. AB - Stability issues and high material cost constitute the biggest obstacles of a perovskite solar cell (PVSC), hampering its sustainable development. Herein, we demonstrate that, after suitable surface modification, the low-cost cerium oxide (CeO x) nanocrystals can be well dispersed in both polar and nonpolar solvents and easily processed into high-quality electron transport layers (ETLs). The inverted PVSC with the configuration of "NiMgLiO/MAPbI3/[6,6]-phenyl-C61-butyric acid methyl ester (PCBM)/CeO x" has achieved a high efficiency up to 18.7%. Especially, the corresponding devices without encapsulation can almost keep their initial PCEs in 30% humidity-controlled air in the dark for 30 days and also show no sign of degradation after continuous light soaking and maximum power point tracking for 200 h in a N2 atmosphere. These results have been proved to be associated with the dual functions achieved by the PCBM/CeO x bilayer ETLs in both efficient electron extraction and good chemical shielding. Furthermore, an all inorganic interfacial layer based PVSC with the configuration of "NiMgLiO/MAPbI3/CeO x" has also achieved a promising efficiency of 16.7%, reflecting the potential to fabricate efficient PVSCs with extremely low cost. PMID- 29481055 TI - Top-Down Proteomics Enables Comparative Analysis of Brain Proteoforms Between Mouse Strains. AB - Over the past decade, advances in mass spectrometry-based proteomics have accelerated brain proteome research aimed at studying the expression, dynamic modification, interaction and function of proteins in the nervous system that are associated with physiological and behavioral processes. With the latest hardware and software improvements in top-down mass spectrometry, the technology has expanded from mere protein profiling to high-throughput identification and quantification of intact proteoforms. Murine systems are broadly used as models to study human diseases. Neuroscientists specifically study the mouse brain from inbred strains to help understand how strain-specific genotype and phenotype affect development, functioning, and disease progression. This work describes the first application of label-free quantitative top-down proteomics to the analysis of the mouse brain proteome. Operating in discovery mode, we determined physiochemical differences in brain tissue from four healthy inbred strains, C57BL/6J, DBA/2J, FVB/NJ, and BALB/cByJ, after probing their intact proteome in the 3.5-30 kDa mass range. We also disseminate these findings using a new tool for top-down proteomics, TDViewer and cataloged them in a newly established Mouse Brain Proteoform Atlas. The analysis of brain tissues from the four strains identified 131 gene products leading to the full characterization of 343 of the 593 proteoforms identified. Within the results, singly and doubly phosphorylated ARPP-21 proteoforms, known to inhibit calmodulin, were differentially expressed across the four strains. Gene ontology (GO) analysis for detected differentially expressed proteoforms also helps to illuminate the similarities and dissimilarities in phenotypes among these inbred strains. PMID- 29481057 TI - Improving the Interpretation of Small Molecule Diffusion Coefficients. AB - Diffusion-ordered NMR spectroscopy (DOSY) is increasingly widely used for the analysis of mixtures by NMR spectroscopy, dispersing the signals of different species according to their diffusion coefficients. DOSY is used primarily to distinguish between the signals of different species, with the interpretation of the diffusion coefficients observed usually being purely qualitative, for example to deduce whether one species is bigger or smaller than another. In principle, the actual values of diffusion coefficient obtained carry important information about the sizes of different species and on interactions between species, but the relationship between diffusion coefficient and molecular mass is in general a very complex one. Here a recently proposed analytical relationship between diffusion coefficient and molecular mass for the restricted case of small organic molecules is tested against a wide range of data from the scientific literature and generalized to cover a range of solvents and temperatures. PMID- 29481058 TI - Dynamic Nuclear Polarization Opens New Perspectives for NMR Spectroscopy in Analytical Chemistry. AB - Dynamic nuclear polarization (DNP) can boost sensitivity in nuclear magnetic resonance (NMR) experiments by several orders of magnitude. This Feature illustrates how the coupling of DNP with both liquid- and solid-state NMR spectroscopy has the potential to considerably extend the range of applications of NMR in analytical chemistry. PMID- 29481059 TI - Structural Phase Transformation in Strained Monolayer MoWSe2 Alloy. AB - Two-dimensional (2D) materials exhibit different mechanical properties from their bulk counterparts owing to their monolayer atomic thickness. Here, we have examined the mechanical behavior of 2D molybdenum tungsten diselenide (MoWSe2) precipitation alloy grown using chemical vapor deposition and composed of numerous nanoscopic MoSe2 and WSe2 regions. Applying a bending strain blue shifted the MoSe2 and WSe2 A1g Raman modes with the stress concentrated near the precipitate interfaces predominantly affecting the WSe2 modes. In situ local Raman measurements suggested that the crack propagated primarily thorough MoSe2 rich regions in the monolayer alloy. Molecular dynamics (MD) simulations were performed to study crack propagation in an MoSe2 monolayer containing nanoscopic WSe2 regions akin to the experiment. Raman spectra calculated from MD trajectories of crack propagation confirmed the emergence of intermediate peaks in the strained monolayer alloy, mirroring experimental results. The simulations revealed that the stress buildup around the crack tip caused an irreversible structural transformation from the 2H to 1T phase both in the MoSe2 matrix and WSe2 patches. This was corroborated by high-angle annular dark-field images. Crack branching and subsequent healing of a crack branch were also observed in WSe2, indicating the increased toughness and crack propagation resistance of the alloyed 2D MoWSe2 over the unalloyed counterparts. PMID- 29481061 TI - Distinctive Stress-Stiffening Responses of Regenerated Silk Fibroin Protein Polymers under Nanoscale Gap Geometries: Effect of Shear on Silk Fibroin-Based Materials. AB - Interfacial dynamics, assembly processes, and changes in nanostructures and mechanical properties of Bombyx mori silk fibroin (SF) proteins under varying degrees of nanoconfinement without and with lateral shear are investigated. When only compressive confinement forces were applied, SF proteins adsorbed on the surfaces experienced conformational changes following the Alexander-de Gennes theory of polymer brushes. By contrast, when SF proteins were exposed to a simultaneous nanoconfinement and shear, remarkable changes in interaction forces were observed, displaying the second order phase transitions, which are attributed to the formation of SF micelles and globular superstructural aggregates via hierarchical assembly processes. The resultant nanostructured SF aggregates show several folds greater elastic moduli than those of SF films prepared by drop-casting and compression-only and even degummed SF fibers. Such a striking improvement in mechanical strength is ascribed to a directional organization of beta-sheet nanocrystals, effectively driven by nanoconfinement and shear stress-induced stiffing and ordering mechanisms. PMID- 29481060 TI - Composite Nature of Layered Hybrid Perovskites: Assessment on Quantum and Dielectric Confinements and Band Alignment. AB - Layered hybrid organic-inorganic perovskites (HOPs) have re-emerged as potential technological solutions for next-generation photovoltaic and optoelectronic applications. Their two-dimensional (2D) nature confers them a significant flexibility and results in the appearance of quantum and dielectric confinements. Such confinements are at the origin of their fascinating properties, and understanding them from a fundamental level is of paramount importance for optimization. Here, we provide an in-depth investigation of band alignments of 2D HOP allowing access to carriers' confinement potentials. 2D HOPs are conceptualized as composite materials in which pseudoinorganic and -organic components are defined. In this way, computational modeling of band alignments becomes affordable using first-principles methods. First, we show that the composite approach is suitable to study the position-dependent dielectric profiles and enables clear differentiation of the respective contributions of inorganic and organic components. Then we apply the composite approach to a variety of 2D HOPs, assessing the impact on the confinement potentials of well and barrier thickness, of the nature of the inorganic well, and of structural transitions. Using the deduced potentials, we further discuss the limitations of the effective mass approximation, scrutinizing the electronic properties of this family of composite materials. Our simulations demonstrate type-I dominant band alignment in 2D HOPs. Finally, we outline design principles on band alignment toward achieving specific optoelectronic properties. Thus, we present alternative theoretical methods to inspect the properties of 2D hybrid perovskites and expect that the composite approach will be applicable to other classes of layered materials. PMID- 29481062 TI - Improved Isotopic Profiling by Pure Shift Heteronuclear 2D J-Resolved NMR Spectroscopy. AB - Quantitative information on the carbon isotope content of metabolites is essential for flux analysis. Whereas this information is in principle present in proton NMR spectra through both direct and long-range heteronuclear coupling constants, spectral overlap and homonuclear coupling constants both hinder its extraction. We demonstrate here how pure shift 2D J-resolved NMR spectroscopy can simultaneously remove the homonuclear couplings and separate the chemical shift information from the heteronuclear coupling patterns. We demonstrate the power of this method on cell lysates from different bacterial cultures and investigate in detail the branched chain amino acid biosynthesis. PMID- 29481063 TI - Redox Recycling Amplification Using an Interdigitated Microelectrode Array for Ionic Liquid-Based Oxygen Sensors. AB - A new design for a membrane-free gas sensor modified with a thin layer of ionic liquid is described. The new approach uses miniaturized interdigitated microelectrodes for detecting gases having reversible electrochemistry, for example, dioxygen. Analyte molecules are reduced on the first working electrode, creating an intermediate species (e.g., superoxide, O2*-, from dioxygen) that can be reoxidized back to the original molecule at the second working electrode. The loop of redox reactions enhances the measured current, leading to high sensitivity (3.29 +/- 0.06 nA cm-2 ppm-1) and low detection limit (LOD = 174 ppm). The gas sensor design was demonstrated to monitor typical concentrations of oxygen with good accuracy and precision. The enhancement in the current is characteristic only of gas molecules with reversible electrochemistry, which indicates that the proposed gas sensor can analyze these molecules with greater sensitivity over those with irreversible electrochemistry. PMID- 29481064 TI - Titrations without the Additions: The Efficient Determination of p Ka Values Using NMR Imaging Techniques. AB - It can be very informative to acquire NMR spectra of a sample as a function of the solution pH. Examples can be found in the design of host-guest complexes or in the determination of the p Ka values of organic molecules. In the conventional procedure, a series of spectra must be recorded and the pH of the sample adjusted manually between successive NMR measurements. As an alternative to this laborious procedure, we demonstrate how controlled pH gradients may be established in 5 mm NMR tubes and analyzed using standard NMR equipment in a "single shot" experiment. Using 1H NMR imaging techniques and a set of NMR pH indicator compounds, we are able to measure the pH of a sample as a function of position along a pH gradient. We are thus able to obtain the necessary set of 1H NMR spectra as a function of pH from a single sample in a single NMR experiment. As proof of concept, we demonstrate how the technique may be employed for the determination of the p Ka values of small organic molecules. We are able to measure p Ka values from 1 to 11 to within 0.1 units of their literature values. The method is robust to variations in the setting of the pH gradients and can be readily implemented through an automated sample changer. PMID- 29481065 TI - Direct and Indirect Interlayer Excitons in a van der Waals Heterostructure of hBN/WS2/MoS2/hBN. AB - A van der Waals (vdW) heterostructure composed of multivalley systems can show excitonic optical responses from interlayer excitons that originate from several valleys in the electronic structure. In this work, we studied photoluminescence (PL) from a vdW heterostructure, WS2/MoS2, deposited on hexagonal boron nitride (hBN) flakes. PL spectra from the fabricated heterostructures observed at room temperature show PL peaks at 1.3-1.7 eV, which are absent in the PL spectra of WS2 or MoS2 monolayers alone. The low-energy PL peaks we observed can be decomposed into three distinct peaks. Through detailed PL measurements and theoretical analysis, including PL imaging, time-resolved PL measurements, and calculation of dielectric function epsilon(omega) by solving the Bethe-Salpeter equation with G0 W0, we concluded that the three PL peaks originate from direct K K interlayer excitons, indirect Q-Gamma interlayer excitons, and indirect K-Gamma interlayer excitons. PMID- 29481066 TI - Lanthanide-Based Coordination Polymers with a 4,5-Dichlorophthalate Ligand Exhibiting Highly Tunable Luminescence: Toward Luminescent Bar Codes. AB - Reactions in water of 4,5-dichlorophthalate (dcpa2-) with the heaviest lanthanide ions lead to a family of compounds with the general chemical formula [Ln2(dcpa)3(H2O)5.3H2O]infinity, where Ln = Tb-Lu, Y. The synthesis, crystal structure, thermal behavior, and luminescent properties of this series of homonuclear compounds are described. Additionally, this family can be extended to isostructural heteronuclear compounds that can contain some light lanthanide ions and therefore present some original photophysical properties. These compounds show potential interest as multiemissive materials (visible and infrared light between 450 and 1600 nm) and could find application as luminescent bar codes. PMID- 29481067 TI - Changes of the Specific Infectivity of Tracer Phages during Transport in Porous Media. AB - Phages (i.e., viruses infecting bacteria) are considered to be good indicators and tracers for fecal pollution, hydraulic flow, or colloidal transport in the subsurface. They are typically quantified as total virus particles (VLP) or plaque forming units (PFU) of infectious phages. As transport may lead to phage deactivation, VLP quantification can overestimate the number of infectious phages. In contrast, PFU counts may underestimate the transport of total virus particles. Using PFU and tunable resistive pulse sensing-based counting for active and total phages, respectively, we quantified the effect of transport through laboratory percolation columns on the specific infectivity (SI). The SI is defined by the ratio of total VLP to PFU and is a measure for the minimum particle numbers needed to create a single infection. Transport of three marine tracer phages and the coli-phage (T4) was described by colloidal filtration theory. We found that apparent collision efficiencies of active and total phages differed. Depending on the phage properties (e.g., morphology or hydrophobicity), passage through a porous medium led to either an increasing or decreasing SI of effluent phages. Our data suggest that both phage mass recovery and the SI should be considered in quantitative phage tracer experiments. PMID- 29481068 TI - Switching of Macromolecular Ligand Display by Thermoresponsive Polymers Mediates Endocytosis of Multiconjugate Nanoparticles. AB - Ligand-mediated targeting and internalization of plasma membrane receptors is central to cellular function. These types of receptors have accordingly been investigated as targets to facilitate entry of diagnostic and therapeutic constructs into cells. However, there remains a need to characterize how receptor targeting agents on nanoparticles interact at surface receptors and whether it is possible to control these interactions via exogenous stimuli. Here, we describe the switchable display of the iron-transporting protein, transferrin (Tf), at the surface of thermoresponsive polymer-coated gold nanoparticles and show that internalization of the coated nanoparticles into target cells changes across temperature ranges over which transferrin is expected to be sterically "hidden" by an extended polymer chain and then "revealed" by polymer chain collapse. The switching process is dependent on the numbers of transferrin molecules and thermoresponsive polymer chains attached and whether the assay temperature is above or below the transition temperatures of the responsive polymers at the nanoparticle surfaces. Significantly, however, the control of internalization is critically reliant on overall nanoparticle colloidal stability while the thermoresponsive component of the surface undergoes conformational change. The data show that the cell entry function of complex and large biomolecule ligands can be modulated by polymer-induced accessibility change but that a simple "hide and reveal" mechanism for ligand display following polymer chain collapse is insufficient to account for nanoparticle uptake and subsequent intracellular trafficking. PMID- 29481069 TI - Synthesis and Applications of Unquaternized C-Bound Boron Enolates. AB - A general and facile method to prepare unquaternized C-bound boron enolates by a ligand-controlled O-to-C isomerization is reported. Using this protocol, C-bound pinacolboron enolates have been isolated in pure form for the first time, and have been fully characterized by NMR spectroscopy and X-ray crystallography. In contrast to the general perception, such C-boron enolates are stable without coordinative saturation at the boron. Moreover, C-boron enolates present reactivities that are distinct from the O-boron enolates, and their applications in C-O and C-C bond formations are demonstrated. PMID- 29481070 TI - Theoretical Insights into Monometallofullerene Th@C76: Strong Covalent Interaction between Thorium and the Carbon Cage. AB - Th@C76 has been studied by density functional theory combined with statistical mechanics calculations. The results reveal that Th@ T d(19151)-C76 satisfying the isolated pentagon rule possesses the lowest energy. Nevertheless, considering the enthalpy-entropy interplay, Th@ C1(17418)-C76 with one pair of adjacent pentagons is thermodynamically favorable at elevated temperatures, which is reported for the first time. The bonding critical points in both isomers were analyzed to disclose covalent interactions between the inner Th and cages. In addition, the Wiberg bond orders of M-C bonding in different endohedral metallofullerenes (EMFs) were investigated to prove stronger covalent interactions of Th-C in Th based EMFs. PMID- 29481073 TI - Distinct Mechanical and Self-Healing Properties in Two Polydimethylsiloxane Coordination Polymers with Fine-Tuned Bond Strength. AB - Coordination bonds are effective for constructing highly efficient self-healing materials as their strength is highly tunable. To design self-healing polymers with better performance, it is important to get a profound understanding of the structure-property relationships. However, this is challenging for self-healing polymers based on coordination bonds, because many parameters, such as bond energy, bond dynamics, and coordination number will have an essential effect on the mechanical and self-healing properties of the polymer. In this work, we synthesized two poly(dimethylsiloxane) (PDMS) polymers cross-linked by different Zn(II)-diiminopyridine coordination complexes (denoted as PDMS-NNN-Zn, PDMS-MeNNN Zn respectively). The two cross-linking Zn(II)-diiminopyridine complexes are similar in coordination modes, but differ in coordination dynamics. As manifested by ITC, rheology, and tensile experiments, we confirm that the coordination bond in PDMS-MeNNN-Zn polymer films is weaker but more dynamic. Consequently, the PDMS MeNNN-Zn polymer has poorer mechanical strength but higher stretchability and better self-healing properties. The inflicted cracks on PDMS-MeNNN-Zn polymer films can be completely healed after healing at room temperature for only 30 min with healing efficiencies higher than 90%. Such fast self-healing properties have never been achieved in self-healing polymers based on coordination bonds. Our results also demonstrate the important impact of the thermodynamic stability and kinetic lability of coordination complexes on the mechanical and self-healing properties of polymers. Such a comprehensive understanding is helpful for further design of novel synthetic polymers, which can achieve an optimal balance between the mechanical strength and self-healing performance. PMID- 29481072 TI - Ligand-Enabled gamma-C(sp3)-H Activation of Ketones. AB - We report the first example of Pd(II)-catalyzed gamma-C(sp3)-H activation of ketones directed by a practical 2,2-dimethyl aminooxyacetic acid auxiliary. 2 Pyridone ligands are identified to enable C(sp3)-H activation for the first time. A rare six-membered palladacycle intermediate is isolated and characterized to elucidate the reaction mechanism. Both (hetero)arylation and vinylation of gamma C(sp3)-H bonds are demonstrated. Sequential beta- and gamma-C(sp3)-H (hetero)arylation of muscone showcases the utility of this method for late-stage diversification. A convenient Mn(II)-catalyzed auxiliary removal is also developed to further underscore the practicality of this transformation. PMID- 29481071 TI - Active Probes for Imaging Membrane Dynamics of Live Cells with High Spatial and Temporal Resolution over Extended Time Scales and Areas. AB - Despite the advancement of molecular imaging techniques, there is an unmet need for probes for direct imaging of membrane dynamics of live cells. Here we report a novel type of active (or enzyme responsive) probes to directly image membrane dynamics of live cells with high spatial and temporal resolution over extended time scales and areas. Because lipid rafts enrich cholesterols and GPI-anchored enzymes (e.g., ectophosphatases), we design probes that consist of an enzymatic trigger, a fluorophore, and a cholesterol that are affinitive to the cell membrane. Being water-soluble and as the substrate of ectophosphatase, these cell compatible probes preferentially and rapidly assemble in plasma membrane, exhibit strong fluorescence, work at micromolar concentrations, and easily achieve high resolution monitoring of nanoscale heterogeneity in membranes of live cells, the release of exosomes, and the membrane dynamics of live cells. This work provides a facile means to link membrane dynamics and heterogeneity to cellular processes for understanding the interactions between membranes and proteins. PMID- 29481074 TI - Stereodirecting Effect of C5-Carboxylate Substituents on the Glycosylation Stereochemistry of 3-Deoxy-d- manno-oct-2-ulosonic Acid (Kdo) Thioglycoside Donors: Stereoselective Synthesis of alpha- and beta-Kdo Glycosides. AB - The stereodirecting effect of C5-ester functions on the glycosylation stereoselectivity of 3-deoxy-d- manno-oct-2-ulosonic acid (Kdo) ethyl thioglycoside donors is presented. The coupling of 5- O-arylcarbonyl or acetyl protected Kdo thioglycosides with acceptors proceeds in an alpha-selective and high-yielding manner, leading to formation of alpha-linked Kdo glycosides products. On the other hand, the glycosylation stereoselectivity of the 5- O-2 quinolinecarbonyl (Quin) or 4-nitropicoloyl substituted Kdo thioglycoside donors is switchable: (1) The glycosylation of the 5- O-Quin carrying Kdo donors with primary glycosyl acceptors shows complete beta-stereoselectivity, furnishing the corresponding beta-glycosides in good-to-excellent yield. (2) The stereochemical outcome of the secondary acceptors with these Kdo donors is determined mainly by the stereoelectronic nature of the acceptor. Only or predominant alpha anomeric products are obtained when the Kdo donors couple with the disarmed or highly crowded secondary carbohydrate acceptors, while the selectivity may switch to predominant beta in the glycosylation of the 5- O-4-nitropicoloyl carrying donor with more reactive secondary alcohols. The synthetic use of the newly developed Kdo donors 1c and 7b has been demonstrated by facile preparation of a structurally unique trisaccharide motif 19 which possesses both alpha- and beta Kdo glycosidic bonds. PMID- 29481075 TI - Molecular-Simulation-Driven Fragment Screening for the Discovery of New CXCL12 Inhibitors. AB - Fragment-based drug discovery (FBDD) has become a mainstream approach in drug design because it allows the reduction of the chemical space and screening libraries while identifying fragments with high protein-ligand efficiency interactions that can later be grown into drug-like leads. In this work, we leverage high-throughput molecular dynamics (MD) simulations to screen a library of 129 fragments for a total of 5.85 ms against the CXCL12 monomer, a chemokine involved in inflammation and diseases such as cancer. Our in silico binding assay was able to recover binding poses, affinities, and kinetics for the selected library and was able to predict 8 mM-affinity fragments with ligand efficiencies higher than 0.3. All of the fragment hits present a similar chemical structure, with a hydrophobic core and a positively charged group, and bind to either sY7 or H1S68 pockets, where they share pharmacophoric properties with experimentally resolved natural binders. This work presents a large-scale screening assay using an exclusive combination of thousands of short MD adaptive simulations analyzed with a Markov state model (MSM) framework. PMID- 29481076 TI - Synthesis of Triazole Derivatives of Levoglucosenone As Promising Anticancer Agents: Effective Exploration of the Chemical Space through retro-aza Michael//aza-Michael Isomerizations. AB - The design and synthesis of biomass-derived triazoles and the in vitro evaluation as potential anticancer agents are described. The discovery of base-catalyzed retro-aza-Michael//aza-Michael isomerizations allowed the exploration of the chemical space by affording novel types of triazoles, difficult to obtain otherwise. Following this strategy, 2,4-disubstituted 1,2,3-triazoles could be efficiently obtained from the corresponding 1,4-disubstituted analogues. PMID- 29481077 TI - Correction to GW Vertex Corrected Calculations for Molecular Systems. PMID- 29481078 TI - Surface Composition of Free Mixed NaCl/Na2SO4 Nanoscale Aerosols Probed by X-ray Photoelectron Spectroscopy. AB - The local chemical surface composition of unsupported mixed solid NaCl/Na2SO4 aerosols ( d ~ 70 nm) is studied by X-ray photoelectron spectroscopy. The solid aerosols are generated by drying aqueous droplets containing mixtures of the two salts in different mole fractions. The mole fraction of these salts is found to deviate at the solid aerosol surface significantly from the initial droplet composition. The minority species in the droplets are found to be enhanced at the surface of the solid mixed aerosols. This surface enhancement is rationalized in terms of the nucleation/crystallization process, where the salts evidently do not cocrystallize, rather than each salt forms pure crystal moieties. Characteristic variations of the surface ion concentration as a function of the mole fraction of the salts in the initial droplet are observed in the nanometer size regime. This is unlike core-shell architectures previously found in mixed micron salt aerosols, indicating that aerosol models derived from micron-sized aerosols are evidently not fully reliable to describe the surface composition of nanosized aerosols. Furthermore, surface enhancement of the minority component in mixed NaCl/Na2SO4 aerosols is also different from previous results on surface segregation of mixed NaCl/NaBr aerosols, where one of the anionic species is surface segregated for all mole fractions, which was explained in terms of the ability of the involved salts to cocrystallize and forming solid solutions. The present results rather indicate that mixed NaCl/Na2SO4 aerosols do not cocrystallize. Electron microscopy of deposited mixed salt aerosols reveals mostly a cubic structure of pure NaCl aerosols, whereas mixed salt aerosols are found to show a grainy structure composed of multiple small crystals which supports the present findings obtained from photoelectron spectroscopy. PMID- 29481080 TI - Photodissociation Dynamics of Nitrous Oxide near 145 nm: The O(1S0) and O(3P J=2,1,0) Product Channels. AB - We report the study of photodissociation dynamics of nitrous oxide in the vacuum ultraviolet region, using the time-sliced velocity map ion imaging technique. Ion images of the O(1S0) and O(3P J=2,1,0) products were measured at nine photolysis wavelengths from 142.55 to 148.79 nm. The product channels O(1S0) + N2(X1Sigmag+) and O(3P J=2,1,0) + N2(A3Sigmau+) have been observed. For these dissociation channels, the total kinetic energy releases of the dissociated products were acquired. With vibrational structures of the N2 coproducts partially resolved in the experimental images, the branching ratios of different vibrational states of the N2 coproducts were determined, and the vibrational state specific anisotropy parameters (beta values) were derived. Analysis shows that the O(1S0) + N2(X1Sigmag+) channel is primarily formed via nonadiabatic couplings between the C (1Pi) state and the higher-lying D (1Sigma+) state of the N2O. A moderate rotational excitation and high vibrational excitation of N2(X1Sigmag+) products have been observed through this pathway. On the other hand, for the O(3P J=2,1,0) + N2(A3Sigmau+) channels, where a slightly higher rotational excitation of N2 coproducts have been observed, the possible pathway would be via nonadiabatic couplings from the C (1Pi) state to the lower-lying A(1Sigma-)state. PMID- 29481081 TI - Hydrophobic Collapse Initiates the Poly( N-isopropylacrylamide) Volume Phase Transition Reaction Coordinate. AB - The best-known examples of smart, responsive hydrogels derive from poly( N isopropylacrylamide) (PNIPAM) cross-linked polymer networks. These hydrogels undergo volume phase transitions (VPTs) triggered by temperature, chemical, and/or environmental changes. PNIPAM hydrogels can undergo more than 50-fold volume changes within ~1 MUs intervals. Studies have tried to elucidate the molecular mechanism of these extraordinarily large responses. Nevertheless, the molecular reaction coordinates that drive the VPT remain unclear. Using visible nonresonance Raman temperature-jump spectroscopy, we determined the molecular ordering of this VPT. The PNIPAM hydrophobic isopropyl and methylene groups dehydrate with time constants of 109 +/- 64 and 104 +/- 44 ns, initiating the volume collapse of PNIPAM. The subsequent dehydration of the PNIPAM amide groups is significantly slower, as our group previously discovered (360 +/- 85 ns). This determination of the ordering of the molecular reaction coordinate of the PNIPAM VPT enables the development of the next generation of super-responsive materials. PMID- 29481079 TI - In Vitro and in Vivo Evaluation of 11C-Labeled Azetidinecarboxylates for Imaging Monoacylglycerol Lipase by PET Imaging Studies. AB - Monoacylglycerol lipase (MAGL) is the principle enzyme for metabolizing endogenous cannabinoid ligand 2-arachidonoyglycerol (2-AG). Blockade of MAGL increases 2-AG levels, resulting in subsequent activation of the endocannabinoid system, and has emerged as a novel therapeutic strategy to treat drug addiction, inflammation, and neurodegenerative diseases. Herein we report a new series of MAGL inhibitors, which were radiolabeled by site-specific labeling technologies, including 11C-carbonylation and spirocyclic iodonium ylide (SCIDY) radiofluorination. The lead compound [11C]10 (MAGL-0519) demonstrated high specific binding and selectivity in vitro and in vivo. We also observed unexpected washout kinetics with these irreversible radiotracers, in which in vivo evidence for turnover of the covalent residue was unveiled between MAGL and azetidine carboxylates. This work may lead to new directions for drug discovery and PET tracer development based on azetidine carboxylate inhibitor scaffold. PMID- 29481082 TI - Exploring the Binding of Barbital to a Synthetic Macrocyclic Receptor. A Charge Density Study. AB - Experimental charge density distribution studies, complemented by quantum mechanical theoretical calculations, of a host-guest system composed of a macrocycle (1) and barbital (2) in a 1:1 ratio (3) have been carried out via high resolution single-crystal X-ray diffraction. The data were modeled using the conventional multipole model of electron density according to the Hansen-Coppens formalism. The asymmetric unit of macrocycle 1 contained an intraannular ethanol molecule and an extraannular acetonitrile molecule, and the asymmetric unit of 3 also contained an intraannular ethanol molecule. Visual comparison of the conformations of the macrocyclic ring shows the rotation by 180 degrees of an amide bond attributed to competitive hydrogen bonding. It was found that the intraannular and extraannular molecules inside were orientated to maximize the number of hydrogen bonds present, with the presence of barbital in 3 resulting in the greatest stabilization. Hydrogen bonds ranging in strength from 4 to 70 kJ mol-1 were the main stabilizing force. Further analysis of the electrostatic potential among 1, 2, and 3 showed significant charge redistribution when cocrystallization occurred, which was further confirmed by a comparison of atomic charges. The findings presented herein introduce the possibility of high resolution X-ray crystallography playing a more prominent role in the drug design process. PMID- 29481083 TI - Origin of Stereocontrol in Photoredox Organocatalysis of Asymmetric alpha Functionalizations of Aldehydes. AB - The merger of the common photoredox catalyst Ru(bpy)3Cl2 with an imidazolidinone organocatalyst by MacMillan et al. has enabled a series of highly enantioselective alpha-functionalizations of aldehydes, a landmark discovery in photoredox organocatalysis. Herein, we present the theoretical investigation into the origin of enantioselectivity in asymmetric radical additions to the MacMillan imidazolidinone enamines, the key stereocontrolling step in photoredox organocatalysis of asymmetric alpha-functionalizations of aldehydes. The calculations reveal a hidden but crucial role of E-cis enamine in enantiocontrol. The enantioselectivity in the radical additions is mainly determined by steric effects. A model based on the pseudo C2-symmetric arrangement of the methyl and tert-butyl moieties on the catalyst is proposed. This rationalizes the stereoselective outcome of these reactions and provides a good model to understand MacMillan's imidazolidinone/photoredox dual catalysis. The insights obtained from this study should be valuable in future efforts toward the design and development of new enantioselective catalytic radical reactions. PMID- 29481084 TI - Thermal Rate Coefficients and Kinetic Isotope Effects for the Reaction OH + CH4 > H2O + CH3 on an ab Initio-Based Potential Energy Surface. AB - Thermal rate coefficients for the title reaction and its various isotopologues are computed using a tunneling-corrected transition-state theory on a global potential energy surface recently developed by fitting a large number of high level ab initio points. The calculated rate coefficients are found to agree well with the measured ones in a wide temperature range, validating the accuracy of the potential energy surface. Strong non-Arrhenius effects are found at low temperatures. In addition, the calculations reproduced the primary and secondary kinetic isotope effects. These results confirm the strong influence of tunneling to this heavy-light-heavy hydrogen abstraction reaction. PMID- 29481085 TI - Structural Heterogeneity in Polynucleotide-Facilitated Assembly of Phenothiazine Dyes. AB - The assembly of stacked dyes on DNA is of interest for electron transfer, light harvesting, sensing, and catalysis applications. A combination of UV/vis absorption, linear dichroism (LD), and circular dichroism (CD) was applied to characterize thoroughly the aggregation with DNA of the phenothiazine dyes methylene blue, azure B, and thionine. Aggregates of each dye with [poly(dG dC)]2, [poly(dA-dT)]2, and calf thymus DNA were explored at high dye:DNA binding ratios, where excess dye groove-binds after all intercalation sites are filled. The organization of the aggregates (dimers, trimers, and multimers) with polydeoxynucleotides displays a structural diversity that depends on DNA sequence, extent of methylation of dye exocyclic amine groups, and ionic strength. The dyes typically form right-handed H-aggregates having negative LD, consistent with stepped stacking along the minor groove. However, aggregates in some dye:DNA aggregates show left-handed chirality or positive LD, indicating unusual modes of aggregation such as formation of adventitious dimers between intercalated and minor groove bound dye. In terms of sequence-dependence, methylene blue shows more extensive aggregation with [poly(dA-dT)]2, while thionine aggregates more with [poly(dG-dC)]2. Azure B has distinctive behavior that is unlike either other dyes. Thus, although these phenothiazine dyes possess a common tricyclic framework, the organization of their polynucleotide facilitated aggregates depends sensitively on the extent of methylation of the exocyclic amines. PMID- 29481087 TI - Spin Proximity Effects in Graphene/Topological Insulator Heterostructures. AB - Enhancing the spin-orbit interaction in graphene, via proximity effects with topological insulators, could create a novel 2D system that combines nontrivial spin textures with high electron mobility. To engineer practical spintronics applications with such graphene/topological insulator (Gr/TI) heterostructures, an understanding of the hybrid spin-dependent properties is essential. However, to date, despite the large number of experimental studies on Gr/TI heterostructures reporting a great variety of remarkable (spin) transport phenomena, little is known about the true nature of the spin texture of the interface states as well as their role on the measured properties. Here, we use ab initio simulations and tight-binding models to determine the precise spin texture of electronic states in graphene interfaced with a Bi2Se3 topological insulator. Our calculations predict the emergence of a giant spin lifetime anisotropy in the graphene layer, which should be a measurable hallmark of spin transport in Gr/TI heterostructures and suggest novel types of spin devices. PMID- 29481086 TI - Tumor-Induced Myeloid Cells Are Reduced by Gemcitabine-Loaded PAMAM Dendrimers Decorated with Anti-Flt1 Antibody. AB - While reshaping their microenvironment, tumors are also capable of influencing systemic processes including myeloid cell production. Therefore, the tumor induced myeloid cells, such as myeloid-derived suppressor cells (MDSCs), which are characterized with pro-cancer properties, became another target in order to increase the success of the therapy. This study evaluated the capacity of a novel dendrimeric drug delivery platform to eliminate tumor-induced myeloid cells. As described in a previous study by our research group, the anti-Flt1 antibody conjugated polyethylene glycol (PEG)-cored poly(amidoamine) (PAMAM) dendrimers improved the efficacy of gemcitabine against pancreatic cancer. Here, the biodistribution studies showed that these dendrimeric structures accumulated in the compartments that became rich in myeloid cells in the pancreatic tumor bearing mice. When gemcitabine was loaded into the dendrimer complexes, the number of myeloid cells was significantly reduced while the percentage distribution of granulocytic and monocytic myeloid cells was not always significantly altered. The CD11b+Ly6G-Ly6C+ monocytes were more severely affected by the treatments than CD11b+Ly6G+Ly6C+ granulocytes. Immune infiltration levels in the tumor tissue were also altered. Myeloid cells in the spleen and F4/80+ macrophages of the liver were protected. The compartments, such as the liver and the bone marrow, which are known to have high vascular endothelial growth factor (VEGF)-Flt1 pathway activity, were particularly targeted by gemcitabine when delivered through anti-Flt1 antibody-conjugated PAMAM dendrimers. In conclusion, chemotherapeutic agents complexed with dendrimers not only improve anticancer efficacy, but they also assist in the elimination of the tumor-induced myeloid cells. PMID- 29481088 TI - Computational Modeling of Antiviral Drug Diffusion from Poly(lactic- co-glycolic acid) Fibers and Multicompartment Pharmacokinetics for Application to the Female Reproductive Tract. AB - The need for more versatile technologies to deliver antiviral agents to the female reproductive tract (FRT) has spurred the development of on-demand and sustained-release platforms. Electrospun fibers (EFs), in particular, have recently been applied to FRT delivery, resulting in an alternative dosage form with the potential to provide protection and therapeutic effect against a variety of infection types. However, a multitude of fabrication parameters, as well as the resulting complexities of solvent-drug, drug-polymer, and solvent-polymer interactions, are known to significantly impact the loading and release of incorporated agents. Numerous processing parameters, in addition to their combined interactions, can hinder the iterative development of fiber formulations to achieve optimal release for particular durations, doses, and polymer-drug types. The experimental effort to design and develop EFs could benefit from mathematical analysis and computational simulation that predictively evaluate combinations of parameters to meet product design needs. Here, existing modeling efforts are leveraged to develop a simulation platform that correlates and predicts the delivery of relevant small molecule antivirals from EFs that have been recently applied to target sexually transmitted infections (STIs). A pair of mathematical models is coupled to simulate the release of two structurally similar small molecule antiretroviral reverse transcriptase inhibitors, Tenofovir (TFV) and Tenofovir disoproxil fumarate (TDF), from poly(lactic- co-glycolic acid) (PLGA) EFs, and to evaluate how changes in the system parameters affect the distribution of encapsulated agent in a three-compartment model of the vaginal epithelium. The results indicate that factors such as fiber diameter, mesh thickness, antiviral diffusivity, and fiber geometry can be simulated to create an accurate model that distinguishes the different release patterns of TFV and TDF from EFs, and that enables detailed evaluation of the associated pharmacokinetics. This simulation platform offers a basis with which to further study EF parameters and their effect on antiviral release and pharmacokinetics in the FRT. PMID- 29481089 TI - Electrons, Excitons, and Phonons in Two-Dimensional Hybrid Perovskites: Connecting Structural, Optical, and Electronic Properties. AB - Two-dimensional (2D) hybrid perovskites are stoichiometric compounds consisting of alternating inorganic metal-halide sheets and organoammonium cationic layers. This materials class is widely tailorable in composition, structure, and dimensionality and is providing an intriguing playground for the solid-state chemistry and physics communities to uncover structure-property relationships. In this Perspective, we describe semiconducting 2D perovskites containing lead and tin halide inorganic frameworks. In these 2D perovskites, charges are typically confined to the inorganic framework because of strong quantum and dielectric confinement effects, and exciton binding energies are many times greater than kT at room temperature. We describe the role of the heavy atoms in the inorganic framework; the geometry and chemistry of organic cations; and the "softness" of the organic-inorganic lattice on the electronic structure and dynamics of electrons, excitons, and phonons that govern the physical properties of these materials. PMID- 29481090 TI - Gold-Catalyzed Formal [4 + 2] Cycloaddition of 5-(Ethynylamino)pent-2-yn-1-yl Esters to 1,2,3,5-Tetrahydrobenzo[ g]quinolines. AB - A synthetic method to prepare 1,2,3,5-tetrahydrobenzo[ g]quinolines efficiently that relies on gold(I)-catalyzed cycloisomerization of 5-(ethynylamino)pent-2-yn 1-yl esters at room temperature under atmospheric conditions is described. The proposed reaction mechanism presents a unique instance of an in situ formed allenic ester and gold keteniminium species to undergo a formal [4 + 2] cycloaddition pathway. PMID- 29481091 TI - Dynamics and Interactions of a 29 kDa Human Enzyme Studied by Solid-State NMR. AB - Solid-state NMR has been employed for characterization of a broad range of biomacromolecules and supramolecular assemblies. However, because of limitations in sensitivity and resolution, the size of the individual monomeric units has rarely exceeded 15 kDa. As such, enzymes, which are often more complex and comprise long peptide chains, have not been easily accessible, even though manifold desirable information could potentially be provided by solid-state NMR studies. Here, we demonstrate that more than 1200 backbone and side-chain chemical shifts can be reliably assessed from minimal sample quantities for a 29 kDa human enzyme of the carbonic anhydrase family, giving access to its backbone dynamics and intermolecular interactions with a small-molecule inhibitor. The possibility of comprehensive assessment of enzymes in this molecular-weight regime without molecular-tumbling-derived limitations enables the study of residue-specific properties important for their mode of action as well as for pharmacological interference in this and many other enzymes. PMID- 29481092 TI - Solvent-Controlled Pd(II)-Catalyzed Aerobic Chemoselective Intermolecular 1,2 Aminooxygenation and 1,2-Oxyamination of Conjugated Dienes for the Synthesis of Functionalized 1,4-Benzoxazines. AB - Pd(II)-catalyzed intermolecular 1,2-aminooxygenation and 1,2-oxyamination of conjugated dienes have been developed. The chemoselective preparation of a variety of 2-functionalized and 3-functionalized 1,4-benzoxazine derivatives was accomplished via the adjustment of a coordinating solvent. Oxygen was successfully used in this oxidative difunctionalization of alkenes. Good yields and selectivities were obtained for most products. A product bearing a spiro structure was also obtained from a 2,3-disubstituted-1,3-diene. PMID- 29481094 TI - Layering and Ordering in Electrochemical Double Layers. AB - Electrochemical double layers (EDL) form at electrified interfaces. Whereas the Gouy-Chapman model describes moderately charged EDL, the formation of Stern layers was predicted for highly charged EDL. Our results provide structural evidence for a Stern layer of cations at potentials close to hydrogen evolution in alkali fluoride and chloride electrolytes. Layering was observed by X-ray crystal truncation rods and atomic-scale recoil responses of Pt(111) surface layers. Ordering in the layer was confirmed by glancing-incidence in-plane diffraction measurements. PMID- 29481093 TI - Effect of an Auxiliary Plate on Passive Heat Dissipation of Carbon Nanotube-Based Materials. AB - Carbon nanotubes (CNTs) and other related CNT-based materials with a high thermal conductivity can be used as promising heat dissipation materials. Meanwhile, the miniaturization and high functionality of portable electronics, such as laptops and mobile phones, are achieved at the cost of overheating the high power-density components. The heat removal for hot spots occurring in a relatively narrow space requires simple and effective cooling methods. Here, an auxiliary passive cooling approach by the aid of a flat plate (aluminum-magnesium alloy) is investigated to accommodate heat dissipation in a narrow space. The cooling efficiency can be raised to 43.5%. The cooling performance of several CNT-based samples is compared under such circumstances. Heat dissipation analyses show that, when there is a nearby plate for cooling assistance, the heat radiation is weakened and natural convection is largely improved. Thus, improving heat radiation by increasing emissivity without reducing natural convection can effectively enhance the cooling performance. Moreover, the decoration of an auxiliary cooling plate with sprayed CNTs can further improve the cooling performance of the entire setup. PMID- 29481095 TI - Electrochemical Monitoring of the Reversible Folding of Surface-Immobilized DNA i Motifs. AB - Two cytosine (C) rich DNA sequences folding in i-motif upon protonation of C at low pH have been immobilized at gold electrodes to study the impact of the electrode|electrolyte interface on the stability of the noncanonical DNA secondary structure. The effects of the molecular composition and environment on the melting and folding of the structures immobilized at the gold surface have been compared to the properties of the DNA strands in solution. The DNA folding into i-motif upon protonation, both at the surface and in solution, results in a significant variation of the charge density which is monitored electrochemically through the electrostatic interactions between the DNA strand and the electroactive hexaammineruthenium(III). This method is shown to be sufficiently sensitive to distinguish hemiprotonated folded state and single strand unfolded state of i-motif. The pH of melting has been determined for both sequences in the bulk and at the gold|electrolyte interface. The results evidence a stabilizing effect of the interface on i-motif structure, whereby the pH of melting is higher for the sequences immobilized at the surface. The reversibility and precision of the electrochemical model described here allows a clear and simple characterization of DNA structures and does not require any labeling of the sequence. PMID- 29481096 TI - Visible-Light-Mediated Synthesis of Ketones by the Oxidative Alkylation of Styrenes. AB - The oxidative coupling of photogenerated alkyl radicals with readily available styrenes is disclosed. This visible-light-mediated method allows rapid access to a wide range of alpha-alkyl-acetophenones in good yields and with high functional group tolerance. In addition, the developed protocol features room temperature conditions, low photocatalyst loadings, and the use of dimethyl sulfoxide as nontoxic and mild terminal oxidant. PMID- 29481097 TI - A Next Generation Synthesis of BACE1 Inhibitor Verubecestat (MK-8931). AB - The development of a commercial manufacturing route to verubecestat (MK-8931) is described, highlights of which include the application of a continuous processing step to outcompete fast proton transfer in a Mannich-type ketimine addition, a copper-catalyzed amidation reaction, and an optimized guanidinylation procedure to form the key iminothiadiazine dioxide core. PMID- 29481098 TI - Thermodynamic Driving Force in the Spontaneous Formation of Inorganic Nanoparticle Solutions. AB - Nanoparticles are the bridge between the molecular and the macroscopic worlds. The growing number of commercial applications for nanoparticles spans from consumer products to new frontiers of medicine and next-generation optoelectronic technology. They are most commonly deployed in the form of a colloid, or "ink", which are formulated with solvents, surfactants, and electrolytes to kinetically prevent the solid particulate phase from reaching the thermodynamically favored state of separate solid and liquid phases. In this work, we theoretically determine the thermodynamic requirements for forming a single-phase solution of spherical particles and engineer a model system to experimentally demonstrate the spontaneous formation of solutions composed of only solvent and bare inorganic nanoparticles. We show molecular interactions at the nanoparticle interface are the driving force in high-concentration nanoparticle solutions. The work establishes a regime where inorganic nanoparticles behave as molecular solutes as opposed to kinetically stable colloids, which has far-reaching implications for the future design and deployment of nanomaterial technologies. PMID- 29481100 TI - Volitional and automatic control of the hand when reaching to grasp objects. AB - When picking up an object, we tend to grasp at contact points that allow a stable grip. Recent studies have demonstrated that appropriate grasp points can be selected during an ongoing movement in response to unexpected perturbations of the target object. In this study, we tested whether such online grip adjustments are automatic responses or can be controlled volitionally. Subjects performed virtual grasping movements toward target 2D shapes that sometimes changed shape or orientation during movement. Unlike in previous studies, the conditions and task requirements discouraged any online adjustments toward the perturbed shapes. In Experiment 1, target shapes were perturbed briefly (200 ms) during movement before reverting to the original shape, and subjects were instructed to ignore the transient perturbations. Despite subjects' intentions, we observed online adjustments of grip orientation that were toward the expected grip axis of the briefly presented shape. In Experiment 2, we added a stop-signal to the grasping task, with target perturbation as the stop cue. We again observed unnecessary online adjustments toward the grip axis of the perturbed shape, with similar latency. Furthermore, the grip adjustments continued after the forward motion of the hand had stopped, indicating that the automatic response to the perturbed target shape co-occurred with the volitional response to the perturbation onset. Our results provide evidence that automatic control mechanisms are used to guide the fingers to appropriate grasp points and suggest that these mechanisms are distinct from those involved with volitional control. (PsycINFO Database Record PMID- 29481099 TI - Comorbidity and continuity of depression and conduct problems from elementary school to adolescence. AB - Despite nonoverlapping criterion sets, conduct disorder and depression co-occur at much higher rates than expected by chance. Contemporary model-based approaches to explaining heterotypic comorbidity use factor analysis and its variants to evaluate interrelations among symptoms in large population-based and twin samples. These analyses invariably yield broadband internalizing and externalizing factors, which load on a higher-order general liability factor findings that are robust across age and informant. Although model-based approaches elucidate structural aspects of comorbidity, they are variable centered, and usually cross-sectional. Most therefore do not assess developmental continuity of comorbidity, or whether noncomorbid individuals are prospectively vulnerable to heterotypic comorbidity. We use an accelerated longitudinal design to evaluate growth in parent-reported conduct problems (CPs) and depression among children, ages 8-15 years, who were recruited at study entry into depressed only (n = 27), CPs only (n = 28), comorbid (n = 81), and control (n = 70) groups based on levels of symptoms. Consistent with normative developmental trends across this age range, steep growth in depression was exhibited by all groups, including those who reported only CPs at study entry. In contrast, growth in CPs was restricted to those who reported high symptoms at intake (with or without comorbid depression), compared with low and stable among depressed only and control participants. To our knowledge, this is the first study to demonstrate, using carefully ascertained "pure" versus comorbid groups who were followed naturalistically, that comorbid depression is likely to develop among those with pure CPs, but comorbid CPs are not likely to develop among those with pure depression. (PsycINFO Database Record PMID- 29481102 TI - Fiction reading has a small positive impact on social cognition: A meta-analysis. AB - Scholars from both the social sciences and the humanities have credited fiction reading with a range of positive real-world social effects. Research in psychology has suggested that readers may make good citizens because fiction reading is associated with better social cognition. But does fiction reading causally improve social cognition? Here, we meta-analyze extant published and unpublished experimental data to address this question. Multilevel random-effects meta-analysis of 53 effect sizes from 14 studies demonstrated that it does: compared to nonfiction reading and no reading, fiction reading leads to a small, statistically significant improvement in social-cognitive performance (g = .15 .16). This effect is robust across sensitivity analyses and does not appear to be the result of publication bias. We recommend that in future work, researchers use more robust reading manipulations, assess whether the effects transfer to improved real-world social functioning, and investigate mechanisms. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29481101 TI - Age and sex differences in behavioral flexibility, sensitivity to reward value, and risky decision-making. AB - Compared with adults, adolescent behavior is often characterized by reduced behavioral flexibility, increased sensitivity to reward, and increased likelihood to take risks. These traits, which have been hypothesized to confer heightened vulnerability to psychopathologies such as substance use disorders (SUDs), have been the focus of studies in laboratory animal models that seek to understand their neural underpinnings. However, rodent studies to date have typically used only males and have adopted standard methodological practices (e.g., weight loss inducing food restriction) that are likely to have a disparate impact on adolescents compared with adults. Here, we used adolescent and adult Sprague Dawley rats of both sexes to study instrumental behavior tasks that assess behavioral flexibility (strategy shifting and reversal learning; Experiment 1), sensitivity to reward value (outcome devaluation; Experiment 2), and risky decision making (probability discounting; Experiment 3). In Experiment 1, we found that adolescents were faster to acquire reversal learning than adults but there were no differences in strategy shifting. In Experiments 2 and 3, adolescents and adults were equally sensitive to changes in reward value and exhibited similar reductions in preference for a large reward when reinforcement probability was decreased. However, adolescents responded more efficiently and earned reinforcers at a higher rate than their same-sex, adult counterparts. Together, these findings provide only limited support for the existence of an "adolescent-typical" phenotype in Sprague-Dawley rats and instead suggest that age differences in the expression of these behaviors may depend on conditions such as pubertal status and motivational state. (PsycINFO Database Record PMID- 29481103 TI - Does evaluative conditioning depend on awareness? Evidence from a continuous flash suppression paradigm. AB - The role of awareness in evaluative learning has been thoroughly investigated with a variety of theoretical and methodological approaches. We investigated evaluative conditioning (EC) without awareness with an approach that conceptually provides optimal conditions for unaware learning - the Continuous Flash Suppression paradigm (CFS). In CFS, a stimulus presented to one eye can be rendered invisible for a prolonged duration by presenting a high-contrast dynamic pattern to the other eye. The suppressed stimulus is nevertheless processed. First, Experiment 1 established EC effects in a pseudo-CFS setup without suppression. Experiment 2 then employed CFS to suppress conditioned stimuli (CSs) from awareness while the unconditioned stimuli (USs) were visible. While Experiment 1 and 2 used a between-participants manipulation of CS suppression, Experiments 3 and 4 both manipulated suppression within participants. We observed EC effects when CSs were not suppressed, but found no EC effects when the CS was suppressed from awareness. We relate our finding to previous research and discuss theoretical implications for EC. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29481104 TI - Individual differences in semantic processing: Insights from the Calgary semantic decision project. AB - Most previous studies of semantic processing have examined group-level data. We investigated the possibility that there might be individual differences in semantic decision performance even among the standard undergraduate population and that such differences might provide insights into semantic processing. We analyzed the Calgary Semantic Decision Project dataset, which includes concrete/abstract semantic decision responses to thousands of words and also a vocabulary measure for each of 312 participants. Results of our analyses showed that semantic decision responses had good reliability, and that the speed of those responses was related to individual differences as assessed by vocabulary scores and also by diffusion model parameters. That is, semantic decisions were faster for participants with higher vocabulary scores and for participants with steeper drift rates. Further, in their semantic decision responses high vocabulary participants showed more sensitivity to some lexical/semantic predictors and less sensitivity to others. For responses to both concrete and abstract words, high vocabulary participants were more sensitive to word concreteness and less sensitive to word frequency and age of acquisition. For concrete words, high vocabulary participants were also more sensitive to semantic neighborhood similarity. The results suggest that high vocabulary participants are able to more readily access semantic information and are better able to emphasize task-relevant dimensions. In sum, the results are consistent with a dynamic, multidimensional account of semantic processing. (PsycINFO Database Record PMID- 29481106 TI - Can psychology walk the walk of open science? AB - An "open science movement" is gaining traction across many disciplines within the research enterprise but is also precipitating consternation among those who worry that too much disruption may be hampering professional productivity. Despite this disruption, proponents of open data collaboration have argued that some of the biggest problems of the 21st century need to be solved with the help of many people and that data sharing will be the necessary engine to make that happen. In the United States, a national strategic plan for data sharing encouraged the federally funded scientific agencies to (a) publish open data for community use in discoverable, machine-readable, and useful ways; (b) work with public and civil society organizations to set priorities for data to be shared; (c) support innovation and feedback on open data solutions; and (d) continue efforts to release and enhance high-priority data sets funded by taxpayer dollars. One of the more visible open data projects in the psychological sciences is the presidentially announced "Brain Research Through Advancing Innovative Neurotechnologies" (BRAIN) initiative. Lessons learned from initiatives such as these are instructive both from the perspective of open science within psychology and from the perspective of understanding the psychology of open science. Recommendations for creating better pathways to "walk the walk" in open science include (a) nurturing innovation and agile learning, (b) thinking outside the paradigm, (c) creating simplicity from complexity, and (d) participating in continuous learning evidence platforms. (PsycINFO Database Record PMID- 29481107 TI - Ethical aspects of data sharing and research participant protections. AB - Open access is fast becoming the norm across science. Sharing research data broadly has the potential to accelerate scientific progress, optimize the value of data, and promote scientific integrity. However, data sharing also poses new practical and ethical challenges to the conduct of research with human participants. This article provides an overview of how open access to research data has impacted the core principles of research ethics-respect for persons, beneficence, and justice-and, in turn, how a reinterpretation of these principles translates to procedures for the protection of the rights and wellbeing of human research participants. (PsycINFO Database Record PMID- 29481105 TI - Data sharing in psychology. AB - Routine data sharing, defined here as the publication of the primary data and any supporting materials required to interpret the data acquired as part of a research study, is still in its infancy in psychology, as in many domains. Nevertheless, with increased scrutiny on reproducibility and more funder mandates requiring sharing of data, the issues surrounding data sharing are moving beyond whether data sharing is a benefit or a bane to science, to what data should be shared and how. Here, we present an overview of these issues, specifically focusing on the sharing of so-called "long tail" data, that is, data generated by individual laboratories as part of largely hypothesis-driven research. We draw on experiences in other domains to discuss attitudes toward data sharing, cost benefits, best practices and infrastructure. We argue that the publishing of data sets is an integral component of 21st-century scholarship. Moreover, although not all issues around how and what to share have been resolved, a consensus on principles and best practices for effective data sharing and the infrastructure for sharing many types of data are largely in place. (PsycINFO Database Record PMID- 29481108 TI - Responsible practices for data sharing. AB - Research transparency, reproducibility, and data sharing uphold core principles of science at a time when the integrity of scientific research is being questioned. This article discusses how research data in psychology can be made accessible for reproducibility and reanalysis by describing practical ways to overcome barriers to data sharing. We examine key issues surrounding the sharing of data such as who owns research data, how to protect the confidentiality of the research participant, how to give appropriate credit to the data creator, how to deal with metadata and codebooks, how to address provenance, and other specifics such as versioning and file formats. The protection of research subjects is a fundamental obligation, and we explain frameworks and procedures designed to protect against the harms that may result from disclosure of confidential information. We also advocate greater recognition for data creators and the authors of program code used in the management and analysis of data. We argue that research data and program code are important scientific contributions that should be cited in the same way as publications. (PsycINFO Database Record PMID- 29481109 TI - Professional practice guidelines for occupationally mandated psychological evaluations. AB - Psychological evaluations are relied on by employers, professional licensing boards, and civil service commissions to make hiring and employment decisions affecting individuals, organizations, and the public. To promote best practices, these professional practice guidelines were developed for use by psychologists who perform clinical evaluations of individuals for occupational purposes, regardless of whether the evaluation is intended to obtain employment, to achieve licensure/certification, or to maintain either. These guidelines were created by the Committee on Professional Practice and Standards (COPPS) to educate and inform the practice of psychologists who conduct occupationally mandated psychological evaluations (OMPEs), as well as to stimulate debate and research in this important area. (PsycINFO Database Record PMID- 29481110 TI - Morton Deutsch (1920-2017). AB - Presents an obituary for Morton Deutsch, who died March 13, 2017, at 97 years old. Deutsch believed in the power of ideas to rectify serious social problems, and in the role of science to refine our understanding of those ideas. Ranked among the 100 most eminent psychologists of the 20th century, he was a distinguished theorist and pioneer in the study of cooperation, conflict resolution and social justice, as well as a remarkably warm, wise and respectful mentor. Deutsch held numerous leadership positions, including faculty positions at Teachers College, Columbia University and New York University and various presidencies, and accumulated dozens of awards, including eight lifetime achievement awards and the creation of four awards in his name. He also trained as a psychoanalyst and had a private practice for many years. In 1986, he founded the International Center for Cooperation and Conflict Resolution at Columbia, where he continued to work and welcome students well into his 90s. (PsycINFO Database Record PMID- 29481111 TI - Fred Edward Fiedler (1922-2017). AB - Presents an obituary for Fred Edward Fiedler, who died June 8, 2017. Fiedler made four truly significant contributions to the field of psychology. First, he changed the way psychologists think about successful leadership. His book A Theory of Leadership Effectiveness (1967) provided the foundation for much of his later work. Second, at both the University of Illinois and the University of Washington, Fiedler had his own research building and facility. Third, he had an outstanding reputation. He was known around the world for his writing, lectures, and consulting work. He published over 100 journal articles and had numerous books and chapters in edited volumes. Finally, Fiedler left a huge personal legacy. He was always there to support his students. He provided financial support, advice, and technical assistance. He wrote letters of recommendation and made calls on their behalf. Generations of psychologists trace their academic lineage to him. (PsycINFO Database Record PMID- 29481112 TI - John Chynoweth Burnham (1929-2017). AB - Presents an obituary for John Chynoweth Burhham, who died May 12, 2017. An acknowledged "historian's historian," Burnham's critically acclaimed books and articles dealt prominently with American psychoanalysis, as well as other varied topics including accident proneness, health care in America, bad habits, and the question of "how superstition won and science lost." In his first major book, the 1967 Psychoanalysis and American Medicine, 1894-1918. Burnham approached his controversial subject not from the standpoint of practitioner or partisan, but rather that of an impartial historian placing psychoanalysis within the larger context of American culture and history. Throughout his long career, he continued to emphasize the cultural importance of psychoanalysis in America, most recently by spearheading a "New Freud Studies" movement, intended partly as an antidote to the emotionally overheated "Freud Wars" of the late 1900s. Burnham was named a fellow of APA and winner of the Career Achievement Award by the Society for the History of Psychology in 2009. (PsycINFO Database Record PMID- 29481113 TI - Barbara Henker (1935-2017). AB - Presents an obituary for Barbara Henker, who died January 24, 2017, at the age of 81. Henker was professor emerita and a pioneering female faculty member in the Psychology Department at the University of California, Los Angeles (UCLA). Arriving in 1965, she served on the faculty in the clinical and developmental psychology areas at UCLA as the first woman faculty member hired by the department. Henker also worked in the areas of health-related behaviors, attributional styles, cognitive-behavioral interventions, and early use of electronic diaries to monitor the behavior and emotions of youth and parents. A beloved teacher and mentor, she developed the psychological assessment practicum for graduate students at UCLA and taught the course for many years. Its blend of theory, critical analysis, and practical application was lauded by students, many of whom said it was the best course they had ever taken. (PsycINFO Database Record PMID- 29481114 TI - Jaak Panksepp (1943-2017). AB - Presents an obituary for Jaak Panksepp, who died April 18, 2017. Panksepp reshaped the landscape of psychology by highlighting emotions and coincident feelings in basic and clinical research. Most of his career was spent convincing others that the key to understanding human mental illness was the understanding of primal emotional operating systems in conserved neural circuitry. His framework was carefully laid out in his book Affective Neuroscience: The Foundation of Human and Animal Emotions (1998). His controversial writings vigorously pushed for the acceptance of nonhuman animal feelings as primary states that link to motivated action and emotional expression. His agenda included developing animal models of mental illness with objective measures of emotion and removing the focus on higher level cognition. Panksepp completed the brunt of his research on the emotional operating systems while a professor at Bowling Green State University (BGSU) from 1972 to 1998. After retiring emeritus from Bowling Green, he was the Bailey Endowed Chair of Animal Well-Being Science at Washington State University until his passing. (PsycINFO Database Record PMID- 29481115 TI - "Perceived age discrimination across age in Europe: From an ageing society to a society for all ages": Correction to Bratt et al. (2018). AB - Reports an error in "Perceived age discrimination across age in Europe: From an ageing society to a society for all ages" by Christopher Bratt, Dominic Abrams, Hannah J. Swift, Christin-Melanie Vauclair and Sibila Marques (Developmental Psychology, 2018[Jan], Vol 54[1], 167-180). In the article, the copyright license has been changed to the Creative Commons CC-BY Attribution License. The online version of this article has been corrected. (The following abstract of the original article appeared in record 2017-47508-001.) Ageism is recognized as a significant obstacle to older people's well-being, but age discrimination against younger people has attracted less attention. We investigate levels of perceived age discrimination across early to late adulthood, using data from the European Social Survey (ESS), collected in 29 countries (N = 56,272). We test for approximate measurement invariance across countries. We use local structural equation modeling as well as moderated nonlinear factor analysis to test for measurement invariance across age as a continuous variable. Using models that account for the moderate degree of noninvariance, we find that younger people report experiencing the highest levels of age discrimination. We also find that national context substantially affects levels of ageism experienced among older respondents. The evidence highlights that more research is needed to address ageism in youth and across the life span, not just old adulthood. It also highlights the need to consider factors that differently contribute to forms of ageism experienced by people at different life stages and ages. (PsycINFO Database Record PMID- 29481116 TI - Trends of Mental Health Status in Iranian Population Aged 15 and above between 1999 and 2015. AB - INTRODUCTION: The main objective of this study was to compare the results of mental health surveys on adult populations of all provinces in Iran, between 1999 and 2015. METHODS: This study was an overview of two cross-sectional, descriptive studies that were performed in 1999 and 2015. The study population of these two studies consisted of urban and rural residents of all provinces in Iran. Samples were recruited by systematic random cluster sampling. In both studies, the General Health Questionnaire (GHQ-28) was used to assess mental health status of respondents. Trained psychologists completed questionnaires, and data were analyzed using SPSS software-18. RESULTS: The results showed that in the survey of 1999, 21% of participants suffered from mental disorders (25.9% of females and 14.9% of males). In the survey of 2015, 23.4% of samples were suspected of having mental disorders (27.6% of females and 19.3% of males). The prevalence of mental disorders increased from 1999 to 2014 by about 1.12 fold (1.06 fold in females and 1.3 fold in males). In the survey of 1999, rural residents were more at risk of mental disorders, while in the survey of 2015, urban residents were more prone to mental disorders. In both studies, the risk of suspicion for mental disorders increased with increasing age, and was higher in people aged 65 and above, as well as widowed, divorced and illiterate individuals. CONCLUSION: The results of this study showed an increase in suspected cases of mental disorders in Iran from 1999 to 2015. Therefore, it is vital for policymakers and health officials to take action in order to improve and maintain mental health status of the people who are at risk in the country. PMID- 29481117 TI - A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of Alborz, Iran. AB - INTRODUCTION: The main objective of this study was to determine the mental health status of population aged 15 and over in the province of Alborz in the year 2015. METHODS: The statistical population of this cross-sectional field survey consisted of residents of urban and rural areas of Alborz province in Iran. An estimated sample size of 1200 people was chosen using systematic random cluster sampling. Access was provided by the contribution of Geographical Post Office of Karaj, Mohammad Abad, and Nazar Abad cities. The General Health Questionnaire-28 (GHQ-28) was used as the screening tool for mental disorders. The analysis of data in the current study was carried out using SPSS-18 software. RESULTS: Using GHQ traditional scoring method, the results showed that 19% of individuals (23.8% of females and 14.1% males) were suspected for mental disorders. The prevalence of suspected cases of mental disorders was 21.3% in urban and 13.8% in rural areas. It also showed that somatization and anxiety symptoms were more prevalent than social dysfunction and depression symptoms, and were more common in women than men. The results of this research also showed that the prevalence of suspected cases of mental disorders increased with aging. Such disorders were more common in females, age groups of 65 and above, people living in urban areas, divorced and widowed, illiterate and unemployed individuals compared with other groups. CONCLUSION: The results of this study showed that about one fifth of people in the province are suspected for mental disorders. Therefore, it is mandatory for the provincial public health authorities to take the needed steps to ensure that necessary requirements encompassing prevention and promotion of mental health are implemented. PMID- 29481118 TI - A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of Ardebil, Iran. AB - INTRODUCTION: The main objective of this study was to determine the mental health status of population aged 15 and over in the province of Ardebil in 2015. METHODS: The statistical population of this cross-sectional field survey consisted of residents of urban and rural areas of Ardebil province in Iran. An estimated sample size of 1200 people were chosen using systematic random cluster sampling. Access was provided by the contribution of Geographical Post Office of Ardebil, Pars abad and Germi cities. The General Health Questionnaire-28 (GHQ-28) was used as the screening tool for mental disorders. Data analysis in the current study was carried out using the SPSS-18 software. RESULTS: Using GHQ traditional scoring method, the results showed that 21.4% of individuals (26.3% of females and 16.5% of males) were suspected of mental disorders. The prevalence of suspected cases of mental disorders was 20.8% in urban and 22.8% in rural areas. The results also showed that somatization and anxiety symptoms were more prevalent than social dysfunction and depression symptoms, and were more common in women than men. The results of this research also showed that the prevalence of suspected cases of mental disorders increased with aging. Such disorders were more common in females, age group of 65 and above, people living in rural areas, divorced and widowed, illiterate and unemployed individuals compared with other groups. CONCLUSION: The results of this study showed that about one fifth of people in the province were suspected of mental disorders. Therefore, it is mandatory for the provincial public health authorities to take the needed steps to ensure that necessary requirements encompassing prevention and promotion of mental health are implemented. PMID- 29481119 TI - A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of Bushehr, Iran. AB - INTRODUCTION: This research aims to determine the mental health status of population aged 15 and over in the province of Bushehr in 2015. METHODS: The statistical population of this cross-sectional field survey consisted of residents of urban and rural areas of Bushehr province in Iran. Through systematic random cluster sampling, 1200 individuals were selected from the residents of urban and rural areas of Bushehr, Deilam and Borazjan. The 28-item version of the General Health Questionnaire was applied as the screening tool. Data were analyzed using SPSS, version 18.0 for windows. RESULTS: The results of this study showed that using the traditional scoring method, 23.4% of the subjects (29% of females and 14.7% of males) were suspected of mental disorders. The prevalence of suspected psychiatric disorders in rural areas (24.5%) was more than the prevalence of these disorders in urban areas (22.8%). The prevalence of suspected anxiety and the somatization of symptoms was higher than the prevalence of social dysfunction and depression, and the prevalence of these components was higher in women than men. The findings of this study also showed that the prevalence of suspected cases of mental disorders increased significantly with age. The prevalence of suspected cases of these disorders was higher among females, the age group of 65 and older, people living in rural areas, divorced and widowed, students and primary and secondary education than other groups. CONCLUSION: The results of this study show that more than one fourth of the sample were suspected of mental disorders, and the prevalence of these disorders has increased from 21.3% in 1999 to 23.4% in 2015. Therefore, it seems necessary for the provincial public health authorities to take the needed steps for providing requirements encompassing prevention and promotion of mental health in this area. PMID- 29481120 TI - A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of Chaharmahal and Bakhtiari, Iran. AB - INTRODUCTION: This research aims to determine the mental health status of population aged 15 and over in the province of Chaharmahal and Bakhtiari in 2015. METHODS: The statistical population of this cross-sectional field survey consisted of residents of urban and rural areas of Chaharmahal and Bakhtiari in Iran. An estimated sample size of 1200 people was chosen using systematic random cluster sampling. The access was provided by the contribution of Geographical Post Office of Shahre Kord, Farsan and Farrokhshar cities. The General Health Questionnaire-28 (GHQ-28) was used as the screening tool for mental disorders. The analysis of data in the current study was carried out using the SPSS-18 software. RESULTS: Using GHQ traditional scoring method, the results showed that 24.9% of the subjects were at risk of mental disorders (26.8% of females and 23% of males). Urban areas (27.1%) were more at risk of mental disorders compared with rural residents (19.1%). Anxiety and somatization symptoms were more frequent than depression and social dysfunction among respondents. The obtained data revealed that the prevalence of mental disorders increased with age. The results also indicated that mental disorders were more common in certain subgroups, in particular females, people aged 65 years and above, the divorced and widowed, illiterate and unemployed adults. CONCLUSION: Our findings suggest that one fourth of the participants are at risk of developing mental disorders. Although the prevalence of these disorders has decreased from 39.1% to 24.9% between 1999 and 2015, it is still of great importance to further promote mental health policies and advocate psychological welfare of those suffering from mental disorders along with their re-empowerment. PMID- 29481121 TI - A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of East Azarbaijan, Iran. AB - INTRODUCTION: The main objective of this study was to determine the mental health status of population aged 15 and over in the province of East Azarbaijan in 2015. METHODS: The statistical population of this cross-sectional field survey consisted of residents of urban and rural areas of East Azarbaijan in Iran. An estimated sample size of 1200 people was chosen using systematic random cluster sampling. The access was provided by the contribution of Geographical Post Office of Tabriz, Sarab and Marand cities. The General Health Questionnaire-28 (GHQ-28) was used as the screening tool for mental disorders. The analysis of data in the current study was carried out using the SPSS-18 software. RESULTS: Using GHQ traditional scoring method, the results showed that 24.9% of the studied population (29.9% of the women and 20.1% of the men) were considered as likely cases. The prevalence rate of mental disorders was 23.1% for rural and 25.7% for urban areas. Prevalence rates of somatization and anxiety were higher than social dysfunction and depression and women revealed higher prevalence for these disorders compared with men. It was also shown that the prevalence rate significantly increased with age and was higher in women, people aged 65 and above, urban residents, widowed or divorced, illiterate, unemployed and housewives people. CONCLUSION: The results of this study showed that about a quarter of the people in the province were suspected to have mental disorders. Comparing the results of the current survey with those of the study conducted in 1999 suggests that the prevalence of mental disorders is on the decrease in this province (from 25.2% in 1999 to 24.9% in 2015). Therefore, it seems vital that the officials take action in order to improve and maintain mental health status of the people who are at risk. PMID- 29481122 TI - A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of Fars, Iran. AB - INTRODUCTION: The main objective of this study was to determine the mental health status of population aged 15 and over in the province of Fars in 2015. METHODS: The statistical population of this cross-sectional field survey consisted of residents of urban and rural areas of Fars in Iran. Through systematic random cluster sampling, 1200 individuals were selected from the residents of urban and rural areas of Shiraz, Jahrom and Kazeroun. The 28-item version of the General Health Questionnaire was applied as the screening tool. The data were analyzed using SPSS, version 18.0 for windows. RESULTS: This study showed that using the traditional scoring method, 22.5% of the subjects (26.9% of females and 18% of males) were suspected of having mental disorders. The prevalence of suspected psychiatric disorders in urban areas (24.3%) was more than the prevalence of these disorders in rural areas (18.6%). The prevalence of suspected anxiety and the somatization of symptoms was higher than the prevalence of social dysfunction and depression, and the prevalence of these components was higher in women than men. The findings of this study also showed that the prevalence of suspected mental disorders increased significantly with age. The prevalence of suspected cases of these disorders was higher among women, the age group of 65 and older, people living in urban areas, divorced and widowed, illiterate, and retired compared to other groups. CONCLUSION: The results of this study show that more than a fourth of the sample were suspected of mental disorders, and the prevalence of these disorders has decreased from 22.9% in 1999 to 22.5% in 2015. Therefore, it seems necessary for the provincial public health authorities to take the needed steps for providing requirements encompassing prevention and promotion of mental health in this area. PMID- 29481123 TI - A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of Gilan, Iran. AB - INTRODUCTION: The main objective of this study was to determine the mental health status of population aged 15 and over in the province of Gilan in 2015. METHODS: The statistical population of this cross-sectional field survey consisted of residents of urban and rural areas of Fars in Iran. An estimated sample size of 1200 people was chosen using systematic random cluster sampling. The access was provided by the contribution of Geographical Post Office of Rasht, Fouman, and Hashtpar cities. The General Health Questionnaire-28 (GHQ-28) was used as the screening tool for mental disorders. The analysis of data in the current study was carried out using the SPSS-18 software. RESULTS: Using GHQ traditional scoring method, the results showed that 18% of the studied population (19.3% of the females and 16.6% of the males) were considered as likely cases. The prevalence rate of mental disorders was 18.7% for urban and 17.7% for rural areas. Prevalence rates of somatization and anxiety were higher than social dysfunction and depression and women revealed higher prevalence for these disorders compared with men. It was also shown that the prevalence rate significantly increased with age and was higher in women, people aged 65 and above, urban residents, widowed or divorced, illiterate, and unemployed people. CONCLUSION: The results of this study showed that about a fifth of the people in the province are suspected to have mental disorders. Comparing the results of the current survey with those of the study conducted in 1999 suggests that the prevalence of mental disorders is on the decrease in this province (from 25.2% in 1999 to 18% in 2015). Therefore, it seems vital that the officials take action in order to improve and maintain mental health status of the people who are at risk. PMID- 29481124 TI - A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of Golestan, Iran. AB - INTRODUCTION: This research aims to determine the mental health status of population aged 15 and over in the province of Golestan in 2015. METHODS: The statistical population of this cross-sectional field survey consisted of residents of urban and rural areas of Golestan province in Iran. An estimated sample size of 1200 people was chosen using systematic random cluster sampling. The access was provided by the contribution of Geographical Post Office of Gorgan, Gonbad-e-Qabus, and Aqqala cities. The General Health Questionnaire-28 (GHQ-28) was used as the screening tool for mental disorders. The analysis of data in the current study was carried out using the SPSS-18 computer software. RESULTS: Using GHQ traditional scoring method, the results showed that 12.8% of the subjects showed to be at risk of mental disorders (13.3% of females and 12.3% of males). Urban areas (13%) were more at risk of mental disorders compared with rural residents (12.3%). Anxiety and somatization symptoms were more frequent than depression and social dysfunction among respondents. The obtained data revealed that the prevalence of mental disorders increased with age. The results also indicated that mental disorders were more common in certain subgroups, in particular women, those aged 65 years and above, the divorced and widowed, illiterate and retired adults. CONCLUSION: Our findings suggest that one eighth of the participants were at risk of developing mental disorders. Although the prevalence of these disorders has decreased from 39.1% to 12.8% between 1999 and 2015, it is still of great importance to further promote mental health policies and advocate psychological welfare of those suffering from mental disorders along with their re-empowerment. PMID- 29481125 TI - A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of Hamadan, Iran. AB - INTRODUCTION: This research aims to determine the mental health status of population aged 15 and over in the province of Hamadan in 2015. METHODS: This cross-sectional survey was performed among 1,200 individuals aged 15 years and older, living in urban and rural areas of the three cities of Hamedan, Asadabad, and Malayer. Individuals were enrolled in the study by clustered and systematic randomization. The General Health Questionnaire-28 (GHQ-28), was used for screening for common mental disorders. Those scoring above the cut-off point of the GHQ-28 were considered to be suffering from at least one mental disorder. Data was analyzed using the SPSS-18 software. RESULTS: This study showed that using the traditional scoring method, 30.7% of the subjects (31.4% of females and 29.9% of males) were suspected of having mental disorders. The prevalence of suspected psychiatric disorders in urban areas (32.8%) was higher than the prevalence of these disorders in rural areas (25.3%). The prevalence of suspected anxiety and the somatization of symptoms was higher than the prevalence of social dysfunction and depression, and the prevalence of these components was higher in women than men. The findings of this study also showed that the prevalence of suspected mental disorders increased significantly with age. The prevalence of suspected cases of these disorders among women, the age group of 65 and older, people living in urban areas, divorced and widowed, primary and secondary, and unemployed people was higher than other groups. CONCLUSION: The results of this study show that about one third of the sample are suspected of mental disorders, and the prevalence of these disorders has decreased from 34.7% in 1999 to 30.7% in 2015. Therefore, it is mandatory for the provincial public health authorities to take the needed steps to ensure that necessary requirements encompassing prevention and promotion of mental health are implemented. PMID- 29481126 TI - A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of Hormozgan, Iran. AB - INTRODUCTION: This research aims to determine the mental health status of population aged 15 and over in the province of Hormozgan in 2015. METHODS: This cross-sectional field study was conducted on the residents of both urban and rural areas of the Hormozgan province. Through systematic random cluster sampling, 1200 individuals were selected from the residents of urban and rural areas of Bandar Abbas, Bandar Lengeh and Minab. The 28-item version of the General Health Questionnaire was applied as the tool of screening. The data were analyzed using SPSS, version 18.0 for windows. RESULTS: This study indicates that using the traditional scoring method, 28.2% of study population are highly suspicious for psychiatric disorders (35.4% of females and 21.1% of males). The prevalence of probable psychiatric disorders in urban areas (28.9%) was higher than rural areas (26.5%). The prevalence of probable somatization and anxiety was higher than the prevalence of social dysfunction and depression, and also the prevalence of these disorders was higher in women. The findings of this study show that the prevalence of probable psychiatric disorders has a direct relationship with increasing age and the prevalence of such disorders is higher in women, urban residents, individuals aged more than 65 years, divorced and widowed individuals, illiterate, housewives and unemployed people. CONCLUSION: The results of this study show that 28.2% of study population (more than a fourth) are suspicious for psychiatric disorders, and the prevalence of these disorders increased from 22.9% in 1999 to 28.2% in 2015. So, health authorities in this province have to do their best for provision, maintenance and improvement of mental health. PMID- 29481127 TI - A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of Ilam, Iran. AB - INTRODUCTION: This research aims to determine the mental health status of population aged 15 and over in the province of Ilam in 2015. METHODS: The statistical population of this cross-sectional field survey consisted of residents of urban and rural areas of Ilam in Iran. An estimated sample size of 1200 people was chosen using systematic random cluster sampling. The access was provided by the contribution of Geographical Post Office of Ilam, Dehloran and Eyvan cities. The General Health Questionnaire-28 (GHQ-28) was used as the screening tool for mental disorders. The analysis of data in the current study was carried out using the SPSS-18 software. RESULTS: Using GHQ traditional scoring method, the results showed that 32.4% of individuals (37% of females, and 28.1% of males) were likely to have a mental disorder. The prevalence of suspected cases of mental disorders was 33% in urban and 31% in rural areas. The prevalence of mental disorders was higher in females, people living in urban areas, those aged 65 years and above, divorced or widowed, illiterate, and the retired compared to other groups. In addition, the prevalence increased with age. The prevalence of anxiety and somatization symptoms was higher than social dysfunction and depression. Moreover, the prevalence of these symptoms was higher in females than males. CONCLUSION: Almost one third of the samples were likely to have a mental disorder. Therefore, the provincial authorities and health providers should take essential steps for providing and maintaining mental health services to promote community mental health. PMID- 29481128 TI - A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of Isfahan, Iran. AB - INTRODUCTION: This research aims to determine the mental health status of population aged 15 and over in the province of Isfahan in 2015. METHODS: The statistical population of this cross-sectional field survey consisted of residents of urban and rural areas of Isfahan in Iran. Through systematic random cluster sampling, 1200 individuals were selected from the residents of urban and rural areas of Isfahan, Kashan and Shahin shahr. The 28-item version of the General Health Questionnaire was applied as the screening tool. The data were analyzed using SPSS, version 18.0 for windows. RESULTS: This study showed that using the traditional scoring method, 30.6% of the subjects (38.5% of females and 22.5% of males) were suspected of having mental disorders. The prevalence of suspected psychiatric disorders in urban areas (32.1%) was higher than the prevalence of these disorders in rural areas (27%). The prevalence of suspected anxiety and the somatization of symptoms was higher than the prevalence of social dysfunction and depression, and the prevalence of these components in women was higher than men. The findings of this study also showed that the prevalence of suspected mental disorders increased significantly with age. The prevalence of suspected cases of these disorders among women, the age group of 65 and older, people living in urban areas, divorced and widowed, illiterate, and housewives was higher than other groups. CONCLUSION: The results of this study show that more than one third of the sample are suspected of mental disorders, and the prevalence of these disorders has increased from 21.3% in 1999 to 30.6% in 2015; therefore, it is up to the authorities and health managers of the province to take the basic steps to supply, maintain, and preserve the mental health of those in need and promote the mental health of the community. PMID- 29481129 TI - A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of Kerman, Iran. AB - INTRODUCTION: This research aims to determine the mental health status of population aged 15 and over in the province of Kerman in 2015. METHODS: The statistical population of this cross-sectional field survey consisted of residents of urban and rural areas of Kerman in Iran. An estimated sample size of 1200 people was chosen using systematic random cluster sampling. The access was provided by the contribution of Geographical Post Office of Kerman, Jiroft and Bam cities. The General Health Questionnaire-28 (GHQ-28) was used as the screening tool for mental disorders. The analysis of data in the current study was carried out using the SPSS-18 software. RESULTS: Using GHQ traditional scoring method, the results showed that 18.8% of the subjects showed to be at risk of mental disorders (22.9% of females and 14.8% of males). Urban areas (20.2%) were more at risk of mental disorders compared with rural residents (16%). Anxiety and somatization symptoms were more frequent than depression and social dysfunction among respondents. The obtained data revealed that the prevalence of mental disorders increased with age. The results also indicated that mental disorders were more common in certain subgroups; in particular women, those aged 65 years and above, the divorced and widowed, illiterate and unemployed adults. CONCLUSION: The results of this study showed that one fifth of the samples were suspected of psychiatric disorders and the prevalence of these disorders has decreased from 22.9% in 1999 to 18.8% in 2015; so, it is on the authorities and health managers of the province to maintain the essential elements for continuity of mental health services to people with mental disorders. PMID- 29481130 TI - A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of Kermanshah, Iran. AB - INTRODUCTION: This research aims to determine the mental health status of population aged 15 and over in the province of Kermanshah in 2015. METHODS: The statistical population of this cross-sectional field survey consisted of residents of urban and rural areas of Kermanshah in Iran. An estimated sample size of 1200 people was chosen in three clusters: Kermanshah, Islamabad-e-Gharb, and Sonqor by using the systematic random sampling method. The General Health Questionnaire-28 (GHQ-28) was used as the screening tool for evaluation of status for mental disorders. The traditional method for scoring of GHQ-28 was used in this study. Data analysis was carried out using the SPSS-18 software. RESULTS: Response rate for the study was 97.83%. The results showed that 26.2% of individuals (29.4% of females and 23% of males) were suspected to suffer from mental disorder, in total. The prevalence of being suspected of mental disorders was 28.9% in urban and 19.7% in the rural areas. Somatization and anxiety symptoms were more prevalent than social dysfunction and depression symptoms and were more common in women than men. The results of this research also showed that the prevalence of being suspected of mental disorders increased with aging. Suspicion for these disorders was more common in females, those aged >=65, people living in urban areas, divorced and widowed, illiterate, housewives and unemployed individuals compared with the other groups. CONCLUSION: This study showed that more than a quarter of the people in Kermanshah province were suspected to have mental disorders. These findings mandate further attention in the province health policy and program planning for prevention and promotion of mental health. PMID- 29481131 TI - A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of Khouzestan, Iran. AB - INTRODUCTION: This research aims to determine the mental health status of population aged 15 and over in the province of Khouzestan in 2015. METHODS: The statistical population of this cross-sectional field survey consisted of residents of urban and rural areas of Khouzestan in Iran. An estimated sample size of 1200 people was chosen using systematic random cluster sampling. The access was provided by the contribution of Geographical Post Office of Ahvaz, Imam khomeini Bandar, and Shooshtar cities. The General Health Questionnaire-28 (GHQ-28) was used as the screening tool for mental disorders. Data analysis in the current study was carried out using the SPSS-18 software. RESULTS: Using GHQ traditional scoring method, 21.8% of the subjects were shown to be at risk of mental disorders (26.2% of females and 23% of males). Urban areas (27.1%) were more at risk of mental disorders compared with rural residents (16.8%). The prevalence of suspected cases of mental disorders in urban areas (25.4%) was higher than rural areas (13.4 %). Anxiety and somatization symptoms were more frequent than depression and social dysfunction among respondents. The obtained data revealed that the prevalence of mental disorders increased with age. Such disorders were more common in females, age group of 65 and above, people living in rural areas, divorced and widowed, illiterate, housewives and unemployed individuals compared with the other groups. CONCLUSION: The results of this study showed that about a fourth of the people in the province were suspected to have mental disorders and the prevalence of these disorders has increased from 21.3% in 1999 to 21.8% in 2015. Therefore, it is mandatory for the provincial public health authorities to take the needed steps to ensure that necessary requirements encompassing prevention and promotion of mental health are implemented. PMID- 29481132 TI - A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of Kohghilouyeh and Bouyerahmad, Iran. AB - INTRODUCTION: This research aims to determine the mental health status of population aged 15 and over in the province of Kohghilouyeh and Bouyerahmad in 2015. METHODS: The statistical population of this cross-sectional field survey consisted of residents of urban and rural areas of Kohghilouyeh and Bouyerahmad in Iran. An estimated sample size of 1200 people was chosen using systematic random cluster sampling. The access was provided by the contribution of Geographical Post Office of Yasuj, Dogonbadan, and Dehdasht cities. The General Health Questionnaire-28 (GHQ-28) was used as a screening tool for mental disorders. Data analysis in the current study was carried out using the SPSS-18 software. RESULTS: Using GHQ traditional scoring method, the results showed that 16.9% of the subjects showed to be at risk of mental disorders (20.1% of females and 13.4% of males). Urban areas (18.3%) were more at risk of mental disorders compared with rural residents (13.9%). Anxiety and somatization symptoms were more frequent than depression and social dysfunction among respondents. The obtained data revealed that the prevalence of mental disorders increased with age. The results also indicated that mental disorders were more common in certain subgroups; in particular women, those aged 65 years and above, the divorced and widowed, illiterate and retired adults. CONCLUSION: Our findings suggest that one sixth of the participants are at risk of developing mental disorders. Although the prevalence of these disorders has decreased from 26.2% to 16.9% between 1999 and 2015, it is still of great importance to further promote mental health policies and advocate psychological welfare of those suffering from mental disorders along with their re-empowerment. PMID- 29481133 TI - A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of Kordestan, Iran. AB - INTRODUCTION: This research aims to determine the mental health status of population aged 15 and over in the province of Kordestan in 2015. METHODS: The statistical population of this cross-sectional field survey consisted of residents of urban and rural areas of Kordestan in Iran. An estimated sample size of 1200 people was chosen using systematic random cluster sampling. The access was provided by the contribution of Geographical Post Office of Sanandaj, Divandareh and Bijar cities. The General Health Questionnaire-28 (GHQ-28) was used as a screening tool for mental disorders. Data analysis in the current study was carried out using the SPSS-18 software. RESULTS: With the traditional scoring method used, 30.4% of the participants (38.1% of women and 22.9% of men) were suspected of having mental disorders. The suspected prevalence of mental disorder was higher in urban (32.5%) than rural areas (25.3%). The suspected prevalence of somatic symptoms and anxiety was greater than the suspected prevalence of social dysfunction and depression, and these disorders were more prevalent in women than men. The findings also showed that the suspected prevalence of mental disorder increased with age. The suspected prevalence of these disorders was higher in women, urban residents, the over 65 age group, the divorced and widowed subjects, the illiterate, the retired and the housewives compared to the other groups. CONCLUSION: The present findings showed that almost a third of the samples were suspected of mental disorder, and the prevalence of these disorders had increased from 21.8% in 1999 to 30% in 2015. The health authorities of the province should therefore take the necessary measures to protect and treat people with mental disorders and promote mental health in the community. PMID- 29481134 TI - A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of Lorestan, Iran. AB - INTRODUCTION: This research aims to determine the mental health status of population aged 15 and over in the province of Lorestan in 2015. METHODS: The statistical population of this cross-sectional field survey consisted of residents of urban and rural areas of Lorestan in Iran. An estimated sample size of 1200 people was chosen using the systematic random sampling and the cluster method. Access provided by the contribution of Geographical Post Office of Khorramabad, Aligoodarz, and Kuhdasht cities. The General Health Questionnaire-28 (GHQ-28) was used as a screening tool for mental disorders. Data analysis in the current study was carried out using the SPSS-18 software. RESULTS: This study showed that using the traditional scoring method, 36.3% of the subjects (40.8% of females and 31.8% of males) were suspected of mental disorders. The prevalence of suspected psychiatric disorders in rural areas (38.1%) was higher than the prevalence of these disorders in urban areas (35.7%). The prevalence of suspected anxiety and the somatization of symptoms was higher than the prevalence of social dysfunction and depression, and the prevalence of these components was higher in women than men. The findings of this study also showed that the prevalence of suspected mental disorders increased significantly with age. The prevalence of suspected cases of these disorders among women, the age group of 65 and older, people living in urban areas, divorced and widowed, illiterate, and housewives people was higher than the other groups. CONCLUSION: The results of this study show that more than one third of the sample were suspected of mental disorders, and the prevalence of these disorders has increased from 19.7% in 1999 to 36.3% in 2015. Therefore, it is mandatory for the provincial public health authorities to take the needed steps to ensure that necessary requirements encompassing prevention and promotion of mental health are implemented. PMID- 29481135 TI - A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of Markazi, Iran. AB - INTRODUCTION: This research aims to determine the mental health status of population aged 15 and over in the province of Markazi in 2015. METHODS: The statistical population of this cross-sectional field survey consisted of residents of urban and rural areas of Markazi in Iran. An estimated sample size of 1200 people was chosen using systematic random cluster sampling. The access was provided by the contribution of Geographical Post Office of Arak, Delijan, and Saveh cities. The General Health Questionnaire-28 (GHQ-28) was used as a screening tool for mental disorders. Data analysis in the current study was carried out using the SPSS-18 computer software. RESULTS: This study showed that using the traditional scoring method, 25.1% of the subjects (31% of females and 18.9% of males) were suspected of having mental disorders. The prevalence of suspected psychiatric disorders in urban areas (25.2%) was higher than the prevalence of these disorders in rural areas (24.8%). The prevalence of suspected anxiety and the somatization of symptoms was higher than the prevalence of social dysfunction and depression, and the prevalence of these components was higher in women than men. The findings of this study also showed that the prevalence of suspected mental disorders increased significantly with age. The prevalence of suspected cases of these disorders among women, the age group of 65 and older, people living in urban areas, divorced and widowed, illiterate, and housewives people was higher than other groups. CONCLUSION: The results of this study show that more than one fourth of the sample were suspected of mental disorders, and the prevalence of these disorders has increased from 18.6% in 1999 to 25.1% in 2015. Therefore, it is mandatory for the provincial public health authorities to take the needed steps to ensure that necessary requirements encompassing prevention and promotion of mental health are implemented. PMID- 29481136 TI - A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of Mazandaran, Iran. AB - INTRODUCTION: This research aims to determine the mental health status of population aged 15 and over in the province of Mazandaran in 2015. METHODS: The statistical population of this cross-sectional field survey consisted of residents of urban and rural areas of Mazandaran in Iran. The access was provided by the contribution of Geographical Post Office of Sari, Babol, and Tonekabon cities. The General Health Questionnaire-28 (GHQ-28) was used as the screening tool for mental disorders. Data analysis in the current study was carried out using the SPSS-18 software. RESULTS: Using GHQ traditional scoring method, the results showed that 17% of the studied population (21% of females and 13% of males) were considered as likely cases. The prevalence rate of mental disorders was 19.8% for urban and 15.8% for urban areas. Prevalence of somatization and anxiety was higher than social dysfunction and depression and women revealed higher prevalence for these disorders compared to men. It was also shown that the prevalence rate significantly increased with age and was higher in women, people aged 45-64 years, urban residents, widowed or divorced, illiterate, and unemployed people. CONCLUSION: The results of this study showed that about a sixth of the people in the province are suspected to have mental disorders. Comparing the results of the current survey with those of the study conducted in 1999 suggests that the prevalence of mental disorders has increased in this province (from 12.3% in 1999 to 17% in 2015). Therefore, it seems vital for the officials to take action in order to improve and maintain mental health status of the people who are at risk. PMID- 29481137 TI - A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of North Khorasan, Iran. AB - INTRODUCTION: This research aims to determine the mental health status of population aged 15 and over in the province of North Khorasan in 2015. METHODS: The statistical population of this cross-sectional field survey consisted of residents of urban and rural areas of North Khorasan in Iran. Through systematic random cluster sampling, 1200 individuals were selected from the residents of urban and rural areas of of Bojnourd, Sfaraien and Shirvan. The 28-item version of the General Health Questionnaire was applied as the screening tool. The data were analyzed using SPSS, version 18.0 for windows. RESULTS: This study showed that using the traditional scoring method, 22.2% of the subjects (28% of females and 16.4% of males) were suspected of mental disorders. The prevalence of suspected psychiatric disorders in urban areas (23.9%) was higher than the prevalence of these disorders in rural areas (18.3%). The prevalence of suspected anxiety and the somatization of symptoms was higher than the prevalence of social dysfunction and depression, and the prevalence of these components was higher in women than men. The findings of this study also showed that the prevalence of suspected mental disorders increased significantly with age. The prevalence of suspected cases of these disorders was higher among women, the age group of 65 and older, people living in urban areas, divorced and widowed, illiterate, and retired people compared to the other groups. CONCLUSION: The results of this study show that more than one fifth of the sample were suspected of mental disorders. Therefore, health authorities and administrators need to take the principle measures to ensure and maintain the mental health of individuals as well as the evaluation and treatment of patients with mental disorders. PMID- 29481138 TI - A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of Qazvin, Iran. AB - INTRODUCTION: This research aims to determine the mental health status of population aged 15 and over in the province of Qazvin in 2015. METHODS: The statistical population of this cross-sectional field survey consisted of residents of urban and rural areas of Qazvin in Iran. An estimated sample size of 1200 people was chosen using systematic random cluster sampling. The access was provided by the contribution of Geographical Post Office of Qazvin, Alvand, Mohammadieh and Abhar cities. The General Health Questionnaire-28 (GHQ-28) was used as the screening tool for mental disorders. Data analysis in the current study was carried out using the SPSS-18 software. RESULTS: Using GHQ traditional scoring method, 25.8% of the subjects were shown to be at risk of mental disorders (29.5% of females and 22.1% of males). Urban areas (27%) were more at risk of mental disorders compared with rural residents (23.3%). Anxiety and somatization symptoms were more frequent than depression and social dysfunction among respondents. The obtained data revealed that the prevalence of mental disorders increased with age. These disorders were more common in females, age group of 65 and above, people living in rural areas, divorced and widowed, illiterate and unemployed individuals compared with the other groups. CONCLUSION: The results of this study showed that about a fourth of the people in the province were suspected to have mental disorders. Therefore, it is mandatory for the provincial public health authorities to take the needed steps to ensure that necessary requirements encompassing prevention and promotion of mental health are implemented. PMID- 29481139 TI - A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of Qom, Iran. AB - INTRODUCTION: This research aims to determine the mental health status of population aged 15 and over in the province of Qom in 2015. METHODS: The statistical population of this cross-sectional field survey consisted of residents of urban and rural areas of Qom in Iran. An estimated sample size of 600 people was chosen using systematic random cluster sampling. The access was provided by the contribution of Geographical Post Office of Qom city. The General Health Questionnaire-28 (GHQ-28) was used as the screening tool for mental disorders. Data analysis in the current study was carried out using the SPSS-18 computer software. RESULTS: Using GHQ traditional scoring method, 16.2% of the subjects were shown to be at risk of mental disorders (19.7% of females and 12.6% of males). Urban areas (17%) were more at risk of mental disorders compared with rural residents (6.5%). Anxiety and somatization symptoms were more frequent than depression and social dysfunction among respondents. The obtained data revealed that the prevalence of mental disorders increased with age. Such disorders were more common in females, age group of 65 and above, people living in rural areas, divorced and widowed, illiterate, retired and unemployed individuals compared with the other groups. CONCLUSION: The results of this study showed that a sixth of the people in the province were suspected to have mental disorders. Therefore, it is mandatory for the provincial public health authorities to take the needed steps to ensure that necessary requirements encompassing prevention and promotion of mental health are implemented. . PMID- 29481140 TI - A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of Razavi Khorasan, Iran. AB - INTRODUCTION: This research aims to determine the mental health status of population aged 15 and over in the province of Razavi Khorasan in 2015. METHODS: The statistical population of this cross-sectional field survey consisted of residents of urban and rural areas of Razavi Khorasan in Iran. An estimated sample size of 1200 people was chosen using systematic random cluster sampling. The access was provided by the contribution of Geographical Post Office of Mashhad, Torbate Jam and Sabzavar cities. The General Health Questionnaire-28 (GHQ-28) was used as the screening tool for mental disorders. Data analysis in the current study was carried out using the SPSS-18 software. RESULTS: Using GHQ traditional scoring method, the results showed that 23.7% of individuals (26.9% of females and 20.6% of males) were suspected of mental disorders. The prevalence of suspected cases of mental disorders was 23.6% in urban and 23.8% in rural areas. It was also shown that somatization and anxiety symptoms were more prevalent than social dysfunction and depression symptoms, and were more common in women than men. The results of this research also showed that the prevalence of suspected cases of mental disorders increased with aging. Such disorders were more common in females, people living in rural areas, divorced and widowed, illiterate, housewives and retired individuals compared with the other groups. CONCLUSION: The results of this study showed that about a fourth of the people in the province were suspected to have mental disorders and the prevalence rate of mental disorders increased from 7.7% in 1999 to 23.7% in 2015. Therefore, it is mandatory for the provincial public health authorities to take the needed steps to ensure that necessary requirements encompassing prevention and promotion of mental health are implemented. PMID- 29481141 TI - A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of Semnan, Iran. AB - INTRODUCTION: This research aims to determine the mental health status of population aged 15 and over in the province of Semnan in 2015. METHOD: The statistical population of this cross-sectional field survey consisted of residents of urban and rural areas of Semnan province in Iran. Through systematic random cluster sampling, 1200 individuals were selected from the residents of urban and rural areas of Semnan, Garmsar and Shahroud. The 28-item version of the General Health Questionnaire was applied as the screening tool. The data were analyzed using SPSS, version 18.0 for windows. RESULTS: This study showed that using the traditional scoring method, 14.5% of the subjects (15.8% of females and 13.1% of males) were suspected of having mental disorders. The prevalence of suspected psychiatric disorders in urban areas (15.5%) was higher than the prevalence of these disorders in rural areas (12.1%). The prevalence of suspected anxiety and the somatization of symptoms was higher than the prevalence of social dysfunction and depression, and the prevalence of these components was higher in women than in men. The findings of this study also showed that the prevalence of suspected mental disorders increased significantly with age. The prevalence of suspected cases of these disorders was higher among women, the age group of 65 and older, people living in urban areas, divorced and widowed, illiterate, and unemployed people than the other groups. CONCLUSION: The results of this study showed that about a sixth of the people in the province were suspected to have mental disorders. Therefore, it is mandatory for the provincial public health authorities to take the needed steps to ensure that necessary requirements encompassing prevention and promotion of mental health are implemented. PMID- 29481142 TI - A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of Sistan and Bluchestan, Iran. AB - INTRODUCTION: This research aims to determine the mental health status of population aged 15 and over in the province of Sistan and Baluchestan in 2015. METHOD: The statistical population of this cross-sectional field survey consisted of residents of urban and rural areas of Sistan and Baluchestan province in Iran. An estimated sample size of 1200 people was chosen using systematic random cluster sampling. The access was provided by the contribution of Geographical Post Office of Zahedan, Zabol, and Saravan cities. The General Health Questionnaire-28 (GHQ-28) was used as the screening tool for mental disorders. Data analysis in the current study was carried out using the SPSS-18 software. RESULTS: Using GHQ traditional scoring method, the results showed that 15.1% of individuals (17.2% of females and 13% of males) were suspected of mental disorders. The prevalence of suspected cases of mental disorders was 19% in urban and 13.5% in rural areas. It also showed that somatization and anxiety symptoms were more prevalent than social dysfunction and depression symptoms, and were more common in women than men. The results of this research also showed that the prevalence of suspected cases of mental disorders increased with aging. Such disorders were more common in females, age group of 65 and above, people living in urban areas, divorced and widowed, illiterate and retired individuals compared with the other groups. CONCLUSION: The results of this study showed that about a sixth of the people in the province were suspected to have mental disorders. Therefore, it is mandatory for the provincial public health authorities to take the needed steps to ensure that necessary requirements encompassing prevention and promotion of mental health are implemented. PMID- 29481143 TI - A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of South Khorasan, Iran. AB - INTRODUCTION: This research aims to determine the mental health status of population aged 15 and over in the province of South Khorasan in 2015. METHODS: The statistical population of this cross-sectional field survey consisted of residents of urban and rural areas of South Khorasan in Iran. Through systematic random cluster sampling, 1200 individuals were selected from the residents of urban and rural areas of Birjand, Ghayen and Ferdows cities. The 28-item version of the General Health Questionnaire was applied as the screening tool. The data were analyzed using SPSS, version 18.0 for windows. RESULTS: Based on GHQ traditional scoring method, this study showed that 17.1% of the respondents (20% of women and 14.1% of men) were suspected of having mental disorders. The prevalence of suspected individuals for mental disorders was higher in urban areas (18.2%) than rural areas (14.5%). It was also shown that the prevalence of anxiety and somatization symptoms was higher than social dysfunction and depression symptoms, and women revealed higher prevalence for these disorders compared with men. The findings of this study also indicated that the prevalence of suspected cases for mental disorders increased with age. The prevalence of suspected cases of these disorders was higher in women aged 65 and over, divorced, widowed, uneducated and the retired compared to the other groups. CONCLUSION: The results of this study show that one sixth of the sample population were suspected of mental disorders; therefore, health authorities and administrators need to take the principled measures to ensure and maintain the mental health of individuals as well as the evaluation and treatment of patients with mental disorders. PMID- 29481144 TI - A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of Tehran, Iran. AB - INTRODUCTION: This research aims to determine the mental health status of population aged 15 and over in the province of Tehran in 2015. METHOD: This cross sectional survey was performed on 1,200 individuals aged fifteen years and older, living in urban, and rural areas of the three main districts of Tehran, Shahriar, and Nasimshahr of Tehran Province. Individuals were enrolled in the study by clustered and systematic randomization. The General Health Questionnaire-28 (GHQ 28) was used for screening for common mental disorders. Those scoring above the cut-off point of the GHQ-28 were considered to be suffering from at least one mental disorder. All data was analyzed using the SPSS-18 software. RESULTS: According to our data, 30.2% of the subjects (34.2% of females and 26.4% of males) were suspected of having mental disorders. The prevalence of suspected psychiatric disorders in urban areas (35.1%) was higher than the prevalence of these disorders in rural areas (18.2%). Scoring above the cut-off point of the GHQ-28 also had a positive correlation with age, especially among those aged 65 years old and above. Somatization and also symptoms of anxiety were more prevalent than social dysfunction and depressive symptoms, and also more prevalent among females compared to males. Being suspected of a mental disorder was also more prevalent among those who had been divorced, widowed, unemployed, and having post-graduate university education. CONCLUSION: The results of this study show that about one third of our sample population were suspected of suffering from a mental disorder. The prevalence of common mental disorders has increased from 21.2% in 1999 to 31.7% in 2015. Therefore, it is strongly recommended that public health authorities put more effort to ensure necessary requirements encompassing prevention and promotion of mental health of the Iranian population residing in Tehran province. PMID- 29481145 TI - A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of West Azarbaijan, Iran. AB - INTRODUCTION: This research aims to determine the mental health status of population aged 15 and over in the province of West Azarbaijan in 2015. METHOD: This cross-sectional field study was conducted on the residents of both urban and rural areas of the West Azarbaijan province. Through systematic random cluster sampling, 1200 individuals were selected from the residents of urban and rural areas of Urumia, Salmas and Mahabad. The 28-item version of the General Health Questionnaire was applied as the screening tool. The data were analyzed using SPSS, version 18.0 for windows. RESULTS: Using GHQ traditional scoring method, the results showed that 24% of individuals (29.1% of females and 18.7% of males) were suspected of mental disorders. The prevalence rate of mental disorders was 19.8% for rural and 25.8% for urban areas. Prevalence of somatization and anxiety was higher than social dysfunction and depression and women revealed higher prevalence for these disorders compared with men. It was also shown that the prevalence rate significantly increased with age and was higher in women, people aged 65 and above, urban residents, widowed or divorced, illiterate, housewives, unemployed and retired people. CONCLUSION: The results of this study showed that about a quarter of the people in the province were suspected to have mental disorders. Comparing the results of the current survey with those of the study conducted in 1999 suggests that the prevalence of mental disorders is on the increase in this province (from 13.5% in 1999 to 24% in 2015). Therefore, it seems vital that the officials take action in order to improve and maintain mental health status of the people who are at risk. PMID- 29481146 TI - A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of Yazd, Iran. AB - INTRODUCTION: This research aims to determine the mental health status of population aged 15 and over in the province of Yazd in 2015. METHOD: This cross sectional field study was conducted on the residents of both urban and rural areas of the Yazd province. Through systematic random cluster sampling, 1200 individuals were selected from the residents of urban and rural areas of Yazd, Ardekan and Meybod. The 28-item version of the General Health Questionnaire was applied as the screening tool. The data were analyzed using SPSS, version 18.0 for windows. RESULTS: This study indicates that through traditional scoring method, 26.7% of study population were highly suspicious for psychiatric disorders (32.1% of females and 21.4% of males). The prevalence of probable psychiatric disorders in urban areas (28.7%) was higher than the prevalence in rural areas (21.3%). The prevalence of probable somatization and anxiety was higher than the prevalence of social dysfunction and depression, and also the prevalence of these disorders was higher in women. The findings of this study show that the prevalence of probable psychiatric disorders has a direct relationship with increasing age and the prevalence of such disorders is higher in women, urban residents, individuals aged more than 65, divorced and widowed individuals, illiterate and unemployed people. CONCLUSION: The results of this study show that more than one quarter of study population were suspicious for psychiatric disorders and the prevalence of these disorders increased from 11.8% to 26.7% since 1999. So, health authorities in this province have to do their best for provision, maintenance and improvement of mental health. PMID- 29481147 TI - A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of Zanjan, Iran. AB - INTRODUCTION: This research aims to determine the mental health status of population aged 15 and over in the province of Zanjan in 2015. METHOD: This cross sectional field study was conducted on the residents of both urban and rural areas of the Zanjan province. Through systematic random cluster sampling, 1200 individuals were selected from the residents of urban and rural areas of of Zanjan, Abhar and Qeydar. The 28-item version of the General Health Questionnaire was applied as the screening tool. The data were analyzed using SPSS, version 18.0 for windows. RESULTS: This study showed that using the traditional scoring method, 28.5% of the subjects (32.9% of females and 24.2% of males) were suspected of having mental disorders. The prevalence of suspected psychiatric disorders in urban areas (30%) was higher than the prevalence of these disorders in rural areas (24.8%). The prevalence of suspected anxiety and the somatization of symptoms was higher than the prevalence of social dysfunction and depression, and the prevalence of these components was higher in women than men. The findings of this study also showed that the prevalence of suspected mental disorders increased significantly with age. The prevalence of suspected cases of these disorders was higher among women, the age group of 65 and older, people living in urban areas, divorced and widowed, illiterate, and retired individuals compared to the other groups. CONCLUSION: The results of this study show that more than one quarter of the sample (28.5%) were suspected of mental disorders, and the prevalence of these disorders has increased from 21.3% in 1999 to 28.5% in 2015. Therefore, it is up to the authorities and health managers of the province to take the basic steps to supply, maintain, and preserve the mental health of those in need and promote the mental health of the community. PMID- 29481148 TI - Quantum Spin Liquids in Frustrated Spin-1 Diamond Antiferromagnets. AB - Motivated by the recent synthesis of the spin-1 A-site spinel NiRh_{2}O_{4}, we investigate the classical to quantum crossover of a frustrated J_{1}-J_{2} Heisenberg model on the diamond lattice upon varying the spin length S. Applying a recently developed pseudospin functional renormalization group approach for arbitrary spin-S magnets, we find that systems with S>=3/2 reside in the classical regime, where the low-temperature physics is dominated by the formation of coplanar spirals and a thermal (order-by-disorder) transition. For smaller local moments S=1 or S=1/2, we find that the system evades a thermal ordering transition and forms a quantum spiral spin liquid where the fluctuations are restricted to characteristic momentum-space surfaces. For the tetragonal phase of NiRh_{2}O_{4}, a modified J_{1}-J_{2}^{-}-J_{2}^{?} exchange model is found to favor a conventionally ordered Neel state (for arbitrary spin S), even in the presence of a strong local single-ion spin anisotropy, and it requires additional sources of frustration to explain the experimentally observed absence of a thermal ordering transition. PMID- 29481149 TI - Polaron Polaritons in the Integer and Fractional Quantum Hall Regimes. AB - Elementary quasiparticles in a two-dimensional electron system can be described as exciton polarons since electron-exciton interactions ensures dressing of excitons by Fermi-sea electron-hole pair excitations. A relevant open question is the modification of this description when the electrons occupy flat bands and electron-electron interactions become prominent. Here, we perform cavity spectroscopy of a two-dimensional electron system in the strong coupling regime, where polariton resonances carry signatures of strongly correlated quantum Hall phases. By measuring the evolution of the polariton splitting under an external magnetic field, we demonstrate the modification of polaron dressing that we associate with filling factor dependent electron-exciton interactions. PMID- 29481150 TI - Stimulated Raman Scattering Imposes Fundamental Limits to the Duration and Bandwidth of Temporal Cavity Solitons. AB - Temporal cavity solitons (CS) are optical pulses that can persist in passive resonators, and they play a key role in the generation of coherent microresonator frequency combs. In resonators made of amorphous materials, such as fused silica, they can exhibit a spectral redshift due to stimulated Raman scattering. Here we show that this Raman-induced self-frequency-shift imposes a fundamental limit on the duration and bandwidth of temporal CSs. Specifically, we theoretically predict that stimulated Raman scattering introduces a previously unidentified Hopf bifurcation that leads to destabilization of CSs at large pump-cavity detunings, limiting the range of detunings over which they can exist. We have confirmed our theoretical predictions by performing extensive experiments in synchronously driven fiber ring resonators, obtaining results in excellent agreement with numerical simulations. Our results could have significant implications for the future design of Kerr frequency comb systems based on amorphous microresonators. PMID- 29481151 TI - Erratum: Computation of the Correlated Metal-Insulator Transition in Vanadium Dioxide from First Principles [Phys. Rev. Lett. 114, 176401 (2015)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.114.176401. PMID- 29481152 TI - Emulating Many-Body Localization with a Superconducting Quantum Processor. AB - The law of statistical physics dictates that generic closed quantum many-body systems initialized in nonequilibrium will thermalize under their own dynamics. However, the emergence of many-body localization (MBL) owing to the interplay between interaction and disorder, which is in stark contrast to Anderson localization, which only addresses noninteracting particles in the presence of disorder, greatly challenges this concept, because it prevents the systems from evolving to the ergodic thermalized state. One critical evidence of MBL is the long-time logarithmic growth of entanglement entropy, and a direct observation of it is still elusive due to the experimental challenges in multiqubit single-shot measurement and quantum state tomography. Here we present an experiment fully emulating the MBL dynamics with a 10-qubit superconducting quantum processor, which represents a spin-1/2 XY model featuring programmable disorder and long range spin-spin interactions. We provide essential signatures of MBL, such as the imbalance due to the initial nonequilibrium, the violation of eigenstate thermalization hypothesis, and, more importantly, the direct evidence of the long time logarithmic growth of entanglement entropy. Our results lay solid foundations for precisely simulating the intriguing physics of quantum many-body systems on the platform of large-scale multiqubit superconducting quantum processors. PMID- 29481153 TI - Organic Glasses with Tunable Liquid-Crystalline Order. AB - Liquid crystals (LCs) are known to undergo rapid ordering transitions with virtually no hysteresis. We report a remarkable counterexample, itraconazole, where the nematic to smectic transition is avoided at a cooling rate exceeding 20 K/s. The smectic order trapped in a glass is the order reached by the equilibrium liquid before the kinetic arrest of the end-over-end molecular rotation. This is attributed to the fact that smectic ordering requires orientational ordering and suggests a general condition for preparing organic glasses with tunable LC order for electronic applications. PMID- 29481154 TI - Emergence of Clusters: Halos, Efimov States, and Experimental Signals. AB - We investigate the emergence of halos and Efimov states in nuclei by use of a newly designed model that combines self-consistent mean-field and three-body descriptions. Recent interest in neutron heavy calcium isotopes makes ^{72}Ca (^{70}Ca+n+n) an ideal realistic candidate on the neutron dripline, and we use it as a representative example that illustrates our broadly applicable conclusions. By smooth variation of the interactions we simulate the crossover from well-bound systems to structures beyond the threshold of binding, and find that halo configurations emerge from the mean-field structure for three-body binding energy less than ~100 keV. Strong evidence is provided that Efimov states cannot exist in nuclei. The structure that bears the most resemblance to an Efimov state is a giant halo extending beyond the neutron-core scattering length. We show that the observable large-distance decay properties of the wave function can differ substantially from the bulk part at short distances, and that this evolution can be traced with our combination of few- and many-body formalisms. This connection is vital for interpretation of measurements such as those where an initial state is populated in a reaction or by a beta decay. PMID- 29481155 TI - Laws of Resistance in Transitional Pipe Flows. AB - As everyone knows who has opened a kitchen faucet, pipe flow is laminar at low flow velocities and turbulent at high flow velocities. At intermediate velocities, there is a transition wherein plugs of laminar flow alternate along the pipe with "flashes" of a type of fluctuating, nonlaminar flow that remains poorly understood. In the 19th century, Osborne Reynolds sought to connect these states of flow with quantitative "laws of resistance," whereby the fluid friction is determined as a function of the Reynolds number. While he succeeded for laminar and turbulent flows, the laws for transitional flows eluded him and remain unknown to this day. By properly distinguishing between laminar plugs and flashes in the transitional regime, we show experimentally and numerically that the law of resistance for laminar plugs corresponds to the laminar law and the law of resistance for flashes is identical to that of turbulence. PMID- 29481156 TI - Testing General Relativity with the Reflection Spectrum of the Supermassive Black Hole in 1H0707-495. AB - Recently, we have extended the x-ray reflection model relxill to test the spacetime metric in the strong gravitational field of astrophysical black holes. In the present Letter, we employ this extended model to analyze XMM-Newton, NuSTAR, and Swift data of the supermassive black hole in 1H0707-495 and test deviations from a Kerr metric parametrized by the Johannsen deformation parameter alpha_{13}. Our results are consistent with the hypothesis that the spacetime metric around the black hole in 1H0707-495 is described by the Kerr solution. PMID- 29481157 TI - Spacecraft Observations of Oblique Electron Beams Breaking the Frozen-In Law During Asymmetric Reconnection. AB - Fully kinetic simulations of asymmetric magnetic reconnection reveal the presence of magnetic-field-aligned beams of electrons flowing toward the topological magnetic x line. Within the ~6d_{e} electron-diffusion region, the beams become oblique to the local magnetic field, providing a unique signature of the electron diffusion region where the electron frozen-in law is broken. The numerical predictions are confirmed by in situ Magnetospheric Multiscale spacecraft observations during asymmetric reconnection at Earth's dayside magnetopause. PMID- 29481158 TI - Duality Games and Operational Duality Relations. AB - We give operational meaning to wave-particle duality in terms of discrimination games. Duality arises as a constraint on the probability of winning these games. The games are played with the aid of an n-port interferometer, and involve 3 parties, Alice and Bob, who cooperate, and the House, who supervises the game. In one game called ways they attempt to determine the path of a particle in the interferometer. In another, called phases, they attempt to determine which set of known phases have been applied to the different paths. The House determines which game is to be played by flipping a coin. We find a tight wave-particle duality relation that allows us to relate the probabilities of winning these games, and use it to find an upper bound on the probability of winning the combined game. This procedure allows us to express wave-particle duality in terms of discrimination probabilities. PMID- 29481159 TI - Mapping Thermal Expansion Coefficients in Freestanding 2D Materials at the Nanometer Scale. AB - Two-dimensional materials, including graphene, transition metal dichalcogenides and their heterostructures, exhibit great potential for a variety of applications, such as transistors, spintronics, and photovoltaics. While the miniaturization offers remarkable improvements in electrical performance, heat dissipation and thermal mismatch can be a problem in designing electronic devices based on two-dimensional materials. Quantifying the thermal expansion coefficient of 2D materials requires temperature measurements at nanometer scale. Here, we introduce a novel nanometer-scale thermometry approach to measure temperature and quantify the thermal expansion coefficients in 2D materials based on scanning transmission electron microscopy combined with electron energy-loss spectroscopy to determine the energy shift of the plasmon resonance peak of 2D materials as a function of sample temperature. By combining these measurements with first principles modeling, the thermal expansion coefficients (TECs) of single-layer and freestanding graphene and bulk, as well as monolayer MoS_{2}, MoSe_{2}, WS_{2}, or WSe_{2}, are directly determined and mapped. PMID- 29481160 TI - Multiloop Functional Renormalization Group That Sums Up All Parquet Diagrams. AB - We present a multiloop flow equation for the four-point vertex in the functional renormalization group (FRG) framework. The multiloop flow consists of successive one-loop calculations and sums up all parquet diagrams to arbitrary order. This provides substantial improvement of FRG computations for the four-point vertex and, consequently, the self-energy. Using the x-ray-edge singularity as an example, we show that solving the multiloop FRG flow is equivalent to solving the (first-order) parquet equations and illustrate this with numerical results. PMID- 29481161 TI - Tailoring Laser-Generated Plasmas for Efficient Nuclear Excitation by Electron Capture. AB - The optimal parameters for nuclear excitation by electron capture in plasma environments generated by the interaction of ultrastrong optical lasers with solid matter are investigated theoretically. As a case study we consider a 4.85 keV nuclear transition starting from the long-lived ^{93m}Mo isomer that can lead to the release of the stored 2.4 MeV excitation energy. We find that due to the complex plasma dynamics, the nuclear excitation rate and the actual number of excited nuclei do not reach their maximum at the same laser parameters. The nuclear excitation achievable with a high-power optical laser is up to twelve and up to six orders of magnitude larger than the values predicted for direct resonant and secondary plasma-mediated excitation at the x-ray free electron laser, respectively. Our results show that the experimental observation of the nuclear excitation of ^{93m}Mo and the subsequent release of stored energy should be possible at laser facilities available today. PMID- 29481162 TI - Inertial Effects on Flow and Transport in Heterogeneous Porous Media. AB - We investigate the effects of high fluid velocities on flow and tracer transport in heterogeneous porous media. We simulate fluid flow and advective transport through two-dimensional pore-scale matrices with varying structural complexity. As the Reynolds number increases, the flow regime transitions from linear to nonlinear; this behavior is controlled by the medium structure, where higher complexity amplifies inertial effects. The result is, nonintuitively, increased homogenization of the flow field, which leads in the context of conservative chemical transport to less anomalous behavior. We quantify the transport patterns via a continuous time random walk, using the spatial distribution of the kinetic energy within the fluid as a characteristic measure. PMID- 29481163 TI - Comparing Optical Oscillators across the Air to Milliradians in Phase and 10^{ 17} in Frequency. AB - We demonstrate carrier-phase optical two-way time-frequency transfer (carrier phase OTWTFT) through the two-way exchange of frequency comb pulses. Carrier phase OTWTFT achieves frequency comparisons with a residual instability of 1.2*10^{-17} at 1 s across a turbulent 4-km free space link, surpassing previous OTWTFT by 10-20 times and enabling future high-precision optical clock networks. Furthermore, by exploiting the carrier phase, this approach is able to continuously track changes in the relative optical phase of distant optical oscillators to 9 mrad (7 as) at 1 s averaging, effectively extending optical phase coherence over a broad spatial network for applications such as correlated spectroscopy between distant atomic clocks. PMID- 29481164 TI - Realization of the Axion Insulator State in Quantum Anomalous Hall Sandwich Heterostructures. AB - The "magnetoelectric effect" arises from the coupling between magnetic and electric properties in materials. The Z_{2} invariant of topological insulators (TIs) leads to a quantized version of this phenomenon, known as the topological magnetoelectric (TME) effect. This effect can be realized in a new topological phase called an "axion insulator" whose surface states are all gapped but the interior still obeys time reversal symmetry. We demonstrate such a phase using electrical transport measurements in a quantum anomalous Hall (QAH) sandwich heterostructure, in which two compositionally different magnetic TI layers are separated by an undoped TI layer. Magnetic force microscopy images of the same sample reveal sequential magnetization reversals of the top and bottom layers at different coercive fields, a consequence of the weak interlayer exchange coupling due to the spacer. When the magnetization is antiparallel, both the Hall resistance and Hall conductance show zero plateaus, accompanied by a large longitudinal resistance and vanishing longitudinal conductance, indicating the realization of an axion insulator state. Our findings thus show evidence for a phase of matter distinct from the established QAH state and provide a promising platform for the realization of the TME effect. PMID- 29481165 TI - Bistability of Cavity Magnon Polaritons. AB - We report the first observation of the magnon-polariton bistability in a cavity magnonics system consisting of cavity photons strongly interacting with the magnons in a small yttrium iron garnet (YIG) sphere. The bistable behaviors emerged as sharp frequency switchings of the cavity magnon polaritons (CMPs) and related to the transition between states with large and small numbers of polaritons. In our experiment, we align, respectively, the [100] and [110] crystallographic axes of the YIG sphere parallel to the static magnetic field and find very different bistable behaviors (e.g., clockwise and counter-clockwise hysteresis loops) in these two cases. The experimental results are well fitted and explained as being due to the Kerr nonlinearity with either a positive or negative coefficient. Moreover, when the magnetic field is tuned away from the anticrossing point of CMPs, we observe simultaneous bistability of both magnons and cavity photons by applying a drive field on the lower branch. PMID- 29481166 TI - Strong Electron-Phonon and Band Structure Effects in the Optical Properties of High Pressure Metallic Hydrogen. AB - The recent claim of having produced metallic hydrogen in the laboratory relies on measurements of optical spectra. Here, we present first-principles calculations of the reflectivity of hydrogen between 400 and 600 GPa in the I4_{1}/amd crystal structure, the one predicted at these pressures, based on both time-dependent density functional and Eliashberg theories, thus, covering the optical properties from the infrared to the ultraviolet regimes. Our results show that atomic hydrogen displays an interband plasmon at around 6 eV that abruptly suppresses the reflectivity, while the large superconducting gap energy yields a sharp decrease of the reflectivity in the infrared region approximately at 120 meV. The experimentally estimated electronic scattering rates in the 0.7-3 eV range are in agreement with our theoretical estimations, which show that the huge electron phonon interaction of the system dominates the electronic scattering in this energy range. The remarkable features in the optical spectra predicted here encourage extending the optical measurements to the infrared and ultraviolet regions as our results suggest optical measurements can potentially identify high pressure phases of hydrogen. PMID- 29481167 TI - Scattering from Artificial Piezoelectriclike Meta-Atoms and Molecules. AB - Inspired by natural piezoelectricity, we introduce hybrid-wave electromechanical meta-atoms and metamolecules that consist of coupled electrical and mechanical oscillators with similar resonance frequencies. We explore the linearized electromechanical scattering process and demonstrate that by exploiting the hybrid-wave interaction one may enable functionalities that are forbidden otherwise. For example, we study a dimer metamolecule that is highly directional for electromagnetic waves, although it is electrically deep subwavelength. This unique behavior is a consequence of the fact that, while the metamolecule is electrically small, it is acoustically large. This idea opens vistas for a plethora of exciting dynamics and phenomena in electromagnetics and acoustics, with implications for miniaturized sensors, superresolution imaging, compact nonreciprocal antennas, and more. PMID- 29481168 TI - Ultrafast Electric Field Pulse Control of Giant Temperature Change in Ferroelectrics. AB - There is a surge of interest in developing environmentally friendly solid-state based cooling technology. Here, we point out that a fast cooling rate (~10^{11} K/s) can be achieved by driving solid crystals to a high-temperature phase with a properly designed electric field pulse. Specifically, we predict that an ultrafast electric field pulse can cause a giant temperature decrease up to 32 K in PbTiO_{3} occurring on few picosecond time scales. We explain the underlying physics of this giant electric field pulse-induced temperature change with the concept of internal energy redistribution: the electric field does work on a ferroelectric crystal and redistributes its internal energy, and the way the kinetic energy is redistributed determines the temperature change and strongly depends on the electric field temporal profile. This concept is supported by our all-atom molecular dynamics simulations of PbTiO_{3} and BaTiO_{3}. Moreover, this internal energy redistribution concept can also be applied to understand electrocaloric effect. We further propose new strategies for inducing giant cooling effect with ultrafast electric field pulse. This Letter offers a general framework to understand electric-field-induced temperature change and highlights the opportunities of electric field engineering for controlled design of fast and efficient cooling technology. PMID- 29481169 TI - Collapsed Dark Matter Structures. AB - The distributions of dark matter and baryons in the Universe are known to be very different: The dark matter resides in extended halos, while a significant fraction of the baryons have radiated away much of their initial energy and fallen deep into the potential wells. This difference in morphology leads to the widely held conclusion that dark matter cannot cool and collapse on any scale. We revisit this assumption and show that a simple model where dark matter is charged under a "dark electromagnetism" can allow dark matter to form gravitationally collapsed objects with characteristic mass scales much smaller than that of a Milky-Way-type galaxy. Though the majority of the dark matter in spiral galaxies would remain in the halo, such a model opens the possibility that galaxies and their associated dark matter play host to a significant number of collapsed substructures. The observational signatures of such structures are not well explored but potentially interesting. PMID- 29481170 TI - Origins and Scaling of Hot-Electron Preheat in Ignition-Scale Direct-Drive Inertial Confinement Fusion Experiments. AB - Planar laser-plasma interaction (LPI) experiments at the National Ignition Facility (NIF) have allowed access for the first time to regimes of electron density scale length (~500 to 700 MUm), electron temperature (~3 to 5 keV), and laser intensity (6 to 16*10^{14} W/cm^{2}) that are relevant to direct-drive inertial confinement fusion ignition. Unlike in shorter-scale-length plasmas on OMEGA, scattered-light data on the NIF show that the near-quarter-critical LPI physics is dominated by stimulated Raman scattering (SRS) rather than by two plasmon decay (TPD). This difference in regime is explained based on absolute SRS and TPD threshold considerations. SRS sidescatter tangential to density contours and other SRS mechanisms are observed. The fraction of laser energy converted to hot electrons is ~0.7% to 2.9%, consistent with observed levels of SRS. The intensity threshold for hot-electron production is assessed, and the use of a Si ablator slightly increases this threshold from ~4*10^{14} to ~6*10^{14} W/cm^{2}. These results have significant implications for mitigation of LPI hot electron preheat in direct-drive ignition designs. PMID- 29481171 TI - Near-Band-Edge Optical Responses of CH_{3}NH_{3}PbCl_{3} Single Crystals: Photon Recycling of Excitonic Luminescence. AB - The determination of the band gap and exciton energies of lead halide perovskites is very important from the viewpoint of fundamental physics and photonic device applications. By using photoluminescence excitation (PLE) spectra, we reveal the optical properties of CH_{3}NH_{3}PbCl_{3} single crystals in the near-band-edge energy regime. The one-photon PLE spectrum exhibits the 1s exciton peak at 3.11 eV. On the contrary, the two-photon PLE spectrum exhibits no peak structure. This indicates photon recycling of excitonic luminescence. By analyzing the spatial distribution of the excitons and photon recycling, we obtain 3.15 eV for the band gap energy and 41 meV for the exciton binding energy. PMID- 29481172 TI - Error-Transparent Quantum Gates for Small Logical Qubit Architectures. AB - One of the largest obstacles to building a quantum computer is gate error, where the physical evolution of the state of a qubit or group of qubits during a gate operation does not match the intended unitary transformation. Gate error stems from a combination of control errors and random single qubit errors from interaction with the environment. While great strides have been made in mitigating control errors, intrinsic qubit error remains a serious problem that limits gate fidelity in modern qubit architectures. Simultaneously, recent developments of small error-corrected logical qubit devices promise significant increases in logical state lifetime, but translating those improvements into increases in gate fidelity is a complex challenge. In this Letter, we construct protocols for gates on and between small logical qubit devices which inherit the parent device's tolerance to single qubit errors which occur at any time before or during the gate. We consider two such devices, a passive implementation of the three-qubit bit flip code, and the author's own [E. Kapit, Phys. Rev. Lett. 116, 150501 (2016)PRLTAO0031-900710.1103/PhysRevLett.116.150501] very small logical qubit (VSLQ) design, and propose error-tolerant gate sets for both. The effective logical gate error rate in these models displays superlinear error reduction with linear increases in single qubit lifetime, proving that passive error correction is capable of increasing gate fidelity. Using a standard phenomenological noise model for superconducting qubits, we demonstrate a realistic, universal one- and two-qubit gate set for the VSLQ, with error rates an order of magnitude lower than those for same-duration operations on single qubits or pairs of qubits. These developments further suggest that incorporating small logical qubits into a measurement based code could substantially improve code performance. PMID- 29481173 TI - Direct Characterization of Ultrafast Energy-Time Entangled Photon Pairs. AB - Energy-time entangled photons are critical in many quantum optical phenomena and have emerged as important elements in quantum information protocols. Entanglement in this degree of freedom often manifests itself on ultrafast time scales, making it very difficult to detect, whether one employs direct or interferometric techniques, as photon-counting detectors have insufficient time resolution. Here, we implement ultrafast photon counters based on nonlinear interactions and strong femtosecond laser pulses to probe energy-time entanglement in this important regime. Using this technique and single-photon spectrometers, we characterize all the spectral and temporal correlations of two entangled photons with femtosecond resolution. This enables the witnessing of energy-time entanglement using uncertainty relations and the direct observation of nonlocal dispersion cancellation on ultrafast time scales. These techniques are essential to understand and control the energy-time degree of freedom of light for ultrafast quantum optics. PMID- 29481174 TI - Unfair and Anomalous Evolutionary Dynamics from Fluctuating Payoffs. AB - Evolution occurs in populations of reproducing individuals. Reproduction depends on the payoff a strategy receives. The payoff depends on the environment that may change over time, on intrinsic uncertainties, and on other sources of randomness. These temporal variations in the payoffs can affect which traits evolve. Understanding evolutionary game dynamics that are affected by varying payoffs remains difficult. Here we study the impact of arbitrary amplitudes and covariances of temporally varying payoffs on the dynamics. The evolutionary dynamics may be "unfair," meaning that, on average, two coexisting strategies may persistently receive different payoffs. This mechanism can induce an anomalous coexistence of cooperators and defectors in the prisoner's dilemma, and an unexpected selection reversal in the hawk-dove game. PMID- 29481175 TI - Autobalanced Ramsey Spectroscopy. AB - We devise a perturbation-immune version of Ramsey's method of separated oscillatory fields. Spectroscopy of an atomic clock transition without compromising the clock's accuracy is accomplished by actively balancing the spectroscopic responses from phase-congruent Ramsey probe cycles of unequal durations. Our simple and universal approach eliminates a wide variety of interrogation-induced line shifts often encountered in high precision spectroscopy, among them, in particular, light shifts, phase chirps, and transient Zeeman shifts. We experimentally demonstrate autobalanced Ramsey spectroscopy on the light shift prone ^{171}Yb^{+} electric octupole optical clock transition and show that interrogation defects are not turned into clock errors. This opens up frequency accuracy perspectives below the 10^{-18} level for the Yb^{+} system and for other types of optical clocks. PMID- 29481176 TI - All-Optical Control of the Silicon-Vacancy Spin in Diamond at Millikelvin Temperatures. AB - The silicon-vacancy center in diamond offers attractive opportunities in quantum photonics due to its favorable optical properties and optically addressable electronic spin. Here, we combine both to achieve all-optical coherent control of its spin states. We utilize this method to explore spin dephasing effects in an impurity-rich sample beyond the limit of phonon-induced decoherence: Employing Ramsey and Hahn-echo techniques at temperatures down to 40 mK we identify resonant coupling to a substitutional nitrogen spin bath as limiting decoherence source for the electron spin. PMID- 29481177 TI - Topology and Edge Modes in Quantum Critical Chains. AB - We show that topology can protect exponentially localized, zero energy edge modes at critical points between one-dimensional symmetry-protected topological phases. This is possible even without gapped degrees of freedom in the bulk-in contrast to recent work on edge modes in gapless chains. We present an intuitive picture for the existence of these edge modes in the case of noninteracting spinless fermions with time-reversal symmetry (BDI class of the tenfold way). The stability of this phenomenon relies on a topological invariant defined in terms of a complex function, counting its zeros and poles inside the unit circle. This invariant can prevent two models described by the same conformal field theory (CFT) from being smoothly connected. A full classification of critical phases in the noninteracting BDI class is obtained: Each phase is labeled by the central charge of the CFT, c?1/2N, and the topological invariant, omega?Z. Moreover, c is determined by the difference in the number of edge modes between the phases neighboring the transition. Numerical simulations show that the topological edge modes of critical chains can be stable in the presence of interactions and disorder. PMID- 29481178 TI - Gate-Controlled Transmission of Quantum Hall Edge States in Bilayer Graphene. AB - The edge states of the quantum Hall and fractional quantum Hall effect of a two dimensional electron gas carry key information of the bulk excitations. Here we demonstrate gate-controlled transmission of edge states in bilayer graphene through a potential barrier with tunable height. The backscattering rate is continuously varied from 0 to close to 1, with fractional quantized values corresponding to the sequential complete backscattering of individual modes. Our experiments demonstrate the feasibility to controllably manipulate edge states in bilayer graphene, thus opening the door to more complex experiments. PMID- 29481179 TI - Renyi Entropies from Random Quenches in Atomic Hubbard and Spin Models. AB - We present a scheme for measuring Renyi entropies in generic atomic Hubbard and spin models using single copies of a quantum state and for partitions in arbitrary spatial dimensions. Our approach is based on the generation of random unitaries from random quenches, implemented using engineered time-dependent disorder potentials, and standard projective measurements, as realized by quantum gas microscopes. By analyzing the properties of the generated unitaries and the role of statistical errors, with respect to the size of the partition, we show that the protocol can be realized in existing quantum simulators and used to measure, for instance, area law scaling of entanglement in two-dimensional spin models or the entanglement growth in many-body localized systems. PMID- 29481180 TI - Quantum Linear System Algorithm for Dense Matrices. AB - Solving linear systems of equations is a frequently encountered problem in machine learning and optimization. Given a matrix A and a vector b the task is to find the vector x such that Ax=b. We describe a quantum algorithm that achieves a sparsity-independent runtime scaling of O(kappa^{2}sqrt[n]polylog(n)/epsilon) for an n*n dimensional A with bounded spectral norm, where kappa denotes the condition number of A, and epsilon is the desired precision parameter. This amounts to a polynomial improvement over known quantum linear system algorithms when applied to dense matrices, and poses a new state of the art for solving dense linear systems on a quantum computer. Furthermore, an exponential improvement is achievable if the rank of A is polylogarithmic in the matrix dimension. Our algorithm is built upon a singular value estimation subroutine, which makes use of a memory architecture that allows for efficient preparation of quantum states that correspond to the rows of A and the vector of Euclidean norms of the rows of A. PMID- 29481181 TI - Light-Nuclei Spectra from Chiral Dynamics. AB - In recent years local chiral interactions have been derived and implemented in quantum Monte Carlo methods in order to test to what extent the chiral effective field theory framework impacts our knowledge of few- and many-body systems. In this Letter, we present Green's function Monte Carlo calculations of light nuclei based on the family of local two-body interactions presented by our group in a previous paper in conjunction with chiral three-body interactions fitted to bound and scattering-state observables in the three-nucleon sector. These interactions include Delta intermediate states in their two-pion-exchange components. We obtain predictions for the energy levels and level ordering of nuclei in the mass range A=4-12, accurate to <=2% of the binding energy, in very satisfactory agreement with experimental data. PMID- 29481182 TI - Bose Polarons at Finite Temperature and Strong Coupling. AB - A mobile impurity coupled to a weakly interacting Bose gas, a Bose polaron, displays several interesting effects. While a single attractive quasiparticle is known to exist at zero temperature, we show here that the spectrum splits into two quasiparticles at finite temperatures for sufficiently strong impurity-boson interaction. The ground state quasiparticle has minimum energy at T_{c}, the critical temperature for Bose-Einstein condensation, and it becomes overdamped when T?T_{c}. The quasiparticle with higher energy instead exists only below T_{c}, since it is a strong mixture of the impurity with thermally excited collective Bogoliubov modes. This phenomenology is not restricted to ultracold gases, but should occur whenever a mobile impurity is coupled to a medium featuring a gapless bosonic mode with a large population for finite temperature. PMID- 29481183 TI - Temporal Simultons in Optical Parametric Oscillators. AB - We report the first demonstration of a regime of operation in optical parametric oscillators (OPOs), in which the formation of temporal simultons produces stable femtosecond half-harmonic pulses. Simultons are simultaneous bright-dark solitons of a signal field at frequency omega and the pump field at 2omega, which form in a quadratic nonlinear medium. The formation of simultons in an OPO is due to the interplay of nonlinear pulse acceleration with the timing mismatch between the pump repetition period and the cold-cavity round-trip time and is evidenced by sech^{2} spectra with broad instantaneous bandwidths when the resonator is detuned to a slightly longer round-trip time than the pump repetition period. We provide a theoretical description of an OPO operating in a regime dominated by these dynamics, observe the distinct features of simulton formation in an experiment, and verify our results with numerical simulations. These results represent a new regime of operation in nonlinear resonators, which can lead to efficient and scalable sources of few-cycle frequency combs at arbitrary wavelengths. PMID- 29481184 TI - Electron and Nucleon Localization Functions of Oganesson: Approaching the Thomas Fermi Limit. AB - Fermion localization functions are used to discuss electronic and nucleonic shell structure effects in the superheavy element oganesson, the heaviest element discovered to date. Spin-orbit splitting in the 7p electronic shell becomes so large (~10 eV) that Og is expected to show uniform-gas-like behavior in the valence region with a rather large dipole polarizability compared to the lighter rare gas elements. The nucleon localization in Og is also predicted to undergo a transition to the Thomas-Fermi gas behavior in the valence region. This effect, particularly strong for neutrons, is due to the high density of single-particle orbitals. PMID- 29481185 TI - Vibrational Energy Redistribution in a Gas-Surface Encounter: State-to-State Scattering of CH_{4} from Ni(111). AB - The fate of vibrational energy in the collision of methane (CH_{4}) in its antisymmetric C-H stretch vibration (nu_{3}) with a Ni(111) surface has been studied in a state-to-state scattering experiment. Laser excitation in the incident molecular beam prepared the J=1 rotational state of nu_{3}, and a bolometer in combination with selective laser excitation detected the scattered methane. The rovibrationally resolved scattering distributions reveal very efficient vibrational energy redistribution from nu_{3} to the symmetric C-H stretch vibration (nu_{1}). The branching ratio nu_{1}/nu_{3} is near 0.4 and insensitive to changes in incident kinetic energy in the range from 100 to 370 meV. State-resolved angular distributions and measurements of the residual Doppler linewidths prove that the scattering is direct. The observed vibrationally inelastic scattering provides direct experimental evidence for surface-induced vibrational energy redistribution. PMID- 29481186 TI - Role of Reversible Phase Transformation for Strong Piezoelectric Performance at the Morphotropic Phase Boundary. AB - A functional material with coexisting energetically equivalent phases often exhibits extraordinary properties such as piezoelectricity, ferromagnetism, and ferroelasticity, which is simultaneously accompanied by field-driven reversible phase transformation. The study on the interplay between such phase transformation and the performance is of great importance. Here, we have experimentally revealed the important role of field-driven reversible phase transformation in achieving enhanced electromechanical properties using in situ high-energy synchrotron x-ray diffraction combined with 2D geometry scattering technology, which can establish a comprehensive picture of piezoelectric-related microstructural evolution. High-throughput experiments on various Pb/Bi-based perovskite piezoelectric systems suggest that reversible phase transformation can be triggered by an electric field at the morphotropic phase boundary and the piezoelectric performance is highly related to the tendency of electric-field driven phase transformation. A strong tendency of phase transformation driven by an electric field generates peak piezoelectric response. Further, phase-field modeling reveals that the polarization alignment and the piezoelectric response can be much enhanced by the electric-field-driven phase transformation. The proposed mechanism will be helpful to design and optimize the new piezoelectrics, ferromagnetics, or other related functional materials. PMID- 29481187 TI - Compressible Magnetohydrodynamic Turbulence in the Earth's Magnetosheath: Estimation of the Energy Cascade Rate Using in situ Spacecraft Data. AB - The first estimation of the energy cascade rate |epsilon_{C}| of magnetosheath turbulence is obtained using the Cluster and THEMIS spacecraft data and an exact law of compressible isothermal magnetohydrodynamics turbulence. The mean value of |epsilon_{C}| is found to be close to 10^{-13} J m^{-3} s^{-1}, at least 2 orders of magnitude larger than its value in the solar wind (~10^{-16} J m^{-3} s^{-1} in the fast wind). Two types of turbulence are evidenced and shown to be dominated either by incompressible Alfvenic or compressible magnetosoniclike fluctuations. Density fluctuations are shown to amplify the cascade rate and its spatial anisotropy in comparison with incompressible Alfvenic turbulence. Furthermore, for compressible magnetosonic fluctuations, large cascade rates are found to lie mostly near the linear kinetic instability of the mirror mode. New empirical power-laws relating |epsilon_{C}| to the turbulent Mach number and to the internal energy are evidenced. These new findings have potential applications in distant astrophysical plasmas that are not accessible to in situ measurements. PMID- 29481188 TI - Soft yet Sharp Interfaces in a Vertex Model of Confluent Tissue. AB - How can dense biological tissue maintain sharp boundaries between coexisting cell populations? We explore this question within a simple vertex model for cells, focusing on the role of topology and tissue surface tension. We show that the ability of cells to independently regulate adhesivity and tension, together with neighbor-based interaction rules, lets them support strikingly unusual interfaces. In particular, we show that mechanical- and fluctuation-based measurements of the effective surface tension of a cellular aggregate yield different results, leading to mechanically soft interfaces that are nevertheless extremely sharp. PMID- 29481190 TI - Generic Long-Range Interactions Between Passive Bodies in an Active Fluid. AB - A single nonspherical body placed in an active fluid generates currents via breaking of time-reversal symmetry. We show that, when two or more passive bodies are placed in an active fluid, these currents lead to long-range interactions. Using a multipole expansion, we characterize their leading-order behaviors in terms of single-body properties and show that they decay as a power law with the distance between the bodies, are anisotropic, and do not obey an action-reaction principle. The interactions lead to rich dynamics of the bodies, illustrated by the spontaneous synchronized rotation of pinned nonchiral bodies and the formation of traveling bound pairs. The occurrence of these phenomena depends on tunable properties of the bodies, thus opening new possibilities for self assembly mediated by active fluids. PMID- 29481191 TI - Dual-Sided Adsorption: Devil's Staircase of Coverage Fractions. AB - By adsorbing the same species onto both sides of a suspended, atomically thin membrane, it is possible to couple two distinct surface adsorption systems. This new system, with reflection symmetry about the membrane, is described by a phase diagram with two axes, both representing the chemical potential of the same element, but in distinct half-spaces. For the case of potassium adsorption onto a graphene membrane, the result is a devil's staircase of fractions for the proportion of adsorbates adhered to one side. Fractions with simpler denominators are favored across wider regions of chemical potential, a pattern reminiscent of other fractional systems across a wide range of physics. Since the system can support multiple devil's staircases each at a distinct overall adsorbate areal density, points along the boundary between adjacent staircases can come arbitrarily close to violating the Gibbs phase rule. This dual-sided adsorbate geometry provides a means to explore surface science for pairs of weakly coupled surfaces. PMID- 29481192 TI - Drop Encapsulated in Bubble: A New Encapsulation Structure. AB - A new fluid encapsulation structure, which is characterized by a bubble encapsulating a drop, is reported. It is stably generated from the breakup of a liquid column inside a bubble, which is achieved via the injection of Taylor flow into liquid. A model is constructed to explain the liquid column breakup mechanism. A dimensionless control guidance, which enables the possibility to create different-scale capsules, is provided. The encapsulation stability in external flows is verified, and a method to trigger the release of the encapsulated drop is provided, which supports potential applications with great advantages such as fluid transport. PMID- 29481193 TI - Distillation with Sublogarithmic Overhead. AB - It has been conjectured that, for any distillation protocol for magic states for the T gate, the number of noisy input magic states required per output magic state at output error rate epsilon is Omega[log(1/epsilon)]. We show that this conjecture is false. We find a family of quantum error correcting codes of parameters ??[under i=w+1][over m](m/i),?[under i=0][over w](m/i),?[under i=w+1][over r+1](r+1/i)? for any integers m>2r, r>w>=0, by puncturing quantum Reed-Muller codes. When m>nur, our code admits a transversal logical gate at the nuth level of Clifford hierarchy. In a distillation protocol for magic states at the level nu=3 (T gate), the ratio of input to output magic states is O(log^{gamma}(1/epsilon)), where gamma=log(n/k)/log(d)<0.678 for some m, r, w. The smallest code in our family for which gamma<1 is on ~2^{58} qubits. PMID- 29481189 TI - Quasifree (p, 2p) Reactions on Oxygen Isotopes: Observation of Isospin Independence of the Reduced Single-Particle Strength. AB - Quasifree one-proton knockout reactions have been employed in inverse kinematics for a systematic study of the structure of stable and exotic oxygen isotopes at the R^{3}B/LAND setup with incident beam energies in the range of 300-450 MeV/u. The oxygen isotopic chain offers a large variation of separation energies that allows for a quantitative understanding of single-particle strength with changing isospin asymmetry. Quasifree knockout reactions provide a complementary approach to intermediate-energy one-nucleon removal reactions. Inclusive cross sections for quasifree knockout reactions of the type ^{A}O(p,2p)^{A-1}N have been determined and compared to calculations based on the eikonal reaction theory. The reduction factors for the single-particle strength with respect to the independent-particle model were obtained and compared to state-of-the-art ab initio predictions. The results do not show any significant dependence on proton neutron asymmetry. PMID- 29481194 TI - Generalized Hardy's Paradox. AB - Here, we present the most general framework for n-particle Hardy's paradoxes, which include Hardy's original one and Cereceda's extension as special cases. Remarkably, for any n>=3, we demonstrate that there always exist generalized paradoxes (with the success probability as high as 1/2^{n-1}) that are stronger than the previous ones in showing the conflict of quantum mechanics with local realism. An experimental proposal to observe the stronger paradox is also presented for the case of three qubits. Furthermore, from these paradoxes we can construct the most general Hardy's inequalities, which enable us to detect Bell's nonlocality for more quantum states. PMID- 29481195 TI - Electron Wave Propagation near a Potential Ridge. AB - Few-electron atoms possess unstable equilibrium configurations whose many electron potential surface shows ridges. The diffraction of an electron wave from a potential ridge is shown to deform the potential surface and to create a fictitious force. That force manifests itself as temporary electron-electron attraction. This analysis is based on nonadiabatically modified plane waves in short wavelength approximation. PMID- 29481196 TI - Magnetooptics of Exciton Rydberg States in a Monolayer Semiconductor. AB - We report 65 T magnetoabsorption spectroscopy of exciton Rydberg states in the archetypal monolayer semiconductor WSe_{2}. The strongly field-dependent and distinct energy shifts of the 2s, 3s, and 4s excited neutral excitons permits their unambiguous identification and allows for quantitative comparison with leading theoretical models. Both the sizes (via low-field diamagnetic shifts) and the energies of the ns exciton states agree remarkably well with detailed numerical simulations using the nonhydrogenic screened Keldysh potential for 2D semiconductors. Moreover, at the highest magnetic fields, the nearly linear diamagnetic shifts of the weakly bound 3s and 4s excitons provide a direct experimental measure of the exciton's reduced mass m_{r}=0.20+/-0.01m_{0}. PMID- 29481197 TI - Stochastic Model of Vesicular Sorting in Cellular Organelles. AB - The proper sorting of membrane components by regulated exchange between cellular organelles is crucial to intracellular organization. This process relies on the budding and fusion of transport vesicles, and should be strongly influenced by stochastic fluctuations, considering the relatively small size of many organelles. We identify the perfect sorting of two membrane components initially mixed in a single compartment as a first passage process, and we show that the mean sorting time exhibits two distinct regimes as a function of the ratio of vesicle fusion to budding rates. Low ratio values lead to fast sorting but result in a broad size distribution of sorted compartments dominated by small entities. High ratio values result in two well-defined sorted compartments but sorting is exponentially slow. Our results suggest an optimal balance between vesicle budding and fusion for the rapid and efficient sorting of membrane components and highlight the importance of stochastic effects for the steady-state organization of intracellular compartments. PMID- 29481198 TI - Nonequilibrium Precondensation of Classical Waves in Two Dimensions Propagating through Atomic Vapors. AB - The nonlinear Schrodinger equation, used to describe the dynamics of quantum fluids, is known to be valid not only for massive particles but also for the propagation of light in a nonlinear medium, predicting condensation of classical waves. Here we report on the initial evolution of random waves with Gaussian statistics using atomic vapors as an efficient two dimensional nonlinear medium. Experimental and theoretical analysis of near field images reveal a phenomenon of nonequilibrium precondensation, characterized by a fast relaxation towards a precondensate fraction of up to 75%. Such precondensation is in contrast to complete thermalization to the Rayleigh-Jeans equilibrium distribution, requiring prohibitive long interaction lengths. PMID- 29481199 TI - Quasi-Phase-Matched Supercontinuum Generation in Photonic Waveguides. AB - Supercontinuum generation (SCG) in integrated photonic waveguides is a versatile source of broadband light, and the generated spectrum is largely determined by the phase-matching conditions. Here we show that quasi-phase-matching via periodic modulations of the waveguide structure provides a useful mechanism to control the evolution of ultrafast pulses during supercontinuum generation. We experimentally demonstrate a quasi-phase-matched supercontinuum to the TE_{20} and TE_{00} waveguide modes, which enhances the intensity of the SCG in specific spectral regions by as much as 20 dB. We utilize higher-order quasi-phase matching (up to the 16th order) to enhance the intensity in numerous locations across the spectrum. Quasi-phase-matching adds a unique dimension to the design space for SCG waveguides, allowing the spectrum to be engineered for specific applications. PMID- 29481200 TI - Convex Optimization over Classes of Multiparticle Entanglement. AB - A well-known strategy to characterize multiparticle entanglement utilizes the notion of stochastic local operations and classical communication (SLOCC), but characterizing the resulting entanglement classes is difficult. Given a multiparticle quantum state, we first show that Gilbert's algorithm can be adapted to prove separability or membership in a certain entanglement class. We then present two algorithms for convex optimization over SLOCC classes. The first algorithm uses a simple gradient approach, while the other one employs the accelerated projected-gradient method. For demonstration, the algorithms are applied to the likelihood-ratio test using experimental data on bound entanglement of a noisy four-photon Smolin state [Phys. Rev. Lett. 105, 130501 (2010)PRLTAO0031-900710.1103/PhysRevLett.105.130501]. PMID- 29481201 TI - All-Optical Stern-Gerlach Effect. AB - We introduce a novel formalism in which the paraxial coupled wave equations of the nonlinear optical sum-frequency generation process are shown to be equivalent to the Pauli equation describing the dynamics of a spin-1/2 particle in a spatially varying magnetic field. This interpretation gives rise to a new classical state of paraxial light, described by a mutual beam comprising of two frequencies. As a straightforward application, we propose the existence of an all optical Stern-Gerlach effect, where an idler beam is deflected by a gradient in the nonlinear coupling, into two mutual beams of the idler and signal waves (equivalent to oppositely oriented spinors), propagating in two discrete directions. The Stern-Gerlach deflection angle and the intensity pattern in the far field are then obtained analytically, in terms of the parameters of the original optical system, laying the grounds for future experimental realizations. PMID- 29481202 TI - Nucleation in Sheared Granular Matter. AB - We present an experiment on crystallization of packings of macroscopic granular spheres. This system is often considered to be a model for thermally driven atomic or colloidal systems. Cyclically shearing a packing of frictional spheres, we observe a first order phase transition from a disordered to an ordered state. The ordered state consists of crystallites of mixed fcc and hcp symmetry that coexist with the amorphous bulk. The transition, initiated by homogeneous nucleation, overcomes a barrier at 64.5% volume fraction. Nucleation consists predominantly of the dissolving of small nuclei and the growth of nuclei that have reached a critical size of about ten spheres. PMID- 29481203 TI - Nonmonotonic Classical Magnetoconductivity of a Two-Dimensional Electron Gas in a Disordered Array of Obstacles. AB - Magnetotransport measurements in combination with molecular dynamics simulations on two-dimensional disordered Lorentz gases in the classical regime are reported. In quantitative agreement between experiment and simulation, the magnetoconductivity displays a pronounced peak as a function of the perpendicular magnetic field B which cannot be explained by existing kinetic theories. This peak is linked to the onset of a directed motion of the electrons along the contour of the disordered obstacle matrix when the cyclotron radius becomes smaller than the size of the obstacles. This directed motion leads to transient superdiffusive motion and strong scaling corrections in the vicinity of the insulator-to-conductor transitions of the Lorentz gas. PMID- 29481204 TI - Acoustic Streaming and Its Suppression in Inhomogeneous Fluids. AB - We present a theoretical and experimental study of boundary-driven acoustic streaming in an inhomogeneous fluid with variations in density and compressibility. In a homogeneous fluid this streaming results from dissipation in the boundary layers (Rayleigh streaming). We show that in an inhomogeneous fluid, an additional nondissipative force density acts on the fluid to stabilize particular inhomogeneity configurations, which markedly alters and even suppresses the streaming flows. Our theoretical and numerical analysis of the phenomenon is supported by ultrasound experiments performed with inhomogeneous aqueous iodixanol solutions in a glass-silicon microchip. PMID- 29481205 TI - Ultrahigh Error Threshold for Surface Codes with Biased Noise. AB - We show that a simple modification of the surface code can exhibit an enormous gain in the error correction threshold for a noise model in which Pauli Z errors occur more frequently than X or Y errors. Such biased noise, where dephasing dominates, is ubiquitous in many quantum architectures. In the limit of pure dephasing noise we find a threshold of 43.7(1)% using a tensor network decoder proposed by Bravyi, Suchara, and Vargo. The threshold remains surprisingly large in the regime of realistic noise bias ratios, for example 28.2(2)% at a bias of 10. The performance is, in fact, at or near the hashing bound for all values of the bias. The modified surface code still uses only weight-4 stabilizers on a square lattice, but merely requires measuring products of Y instead of Z around the faces, as this doubles the number of useful syndrome bits associated with the dominant Z errors. Our results demonstrate that large efficiency gains can be found by appropriately tailoring codes and decoders to realistic noise models, even under the locality constraints of topological codes. PMID- 29481206 TI - Hyper- and hybrid nonlocality. AB - The controlled generation and identification of quantum correlations, usually encoded in either qubits or continuous degrees of freedom, builds the foundation of quantum information science. Recently, more sophisticated approaches, involving a combination of two distinct degrees of freedom, have been proposed to improve on the traditional strategies. Hyperentanglement describes simultaneous entanglement in more than one distinct degree of freedom, whereas hybrid entanglement refers to entanglement shared between a discrete and a continuous degree of freedom. In this work we propose a scheme that allows us to combine the two approaches, and to extend them to the strongest form of quantum correlations. Specifically, we show how two identical, initially separated particles can be manipulated to produce Bell nonlocality among their spins, among their momenta, as well as across their spins and momenta. We discuss possible experimental realizations with atomic and photonic systems. PMID- 29481208 TI - Unconventional Superconductivity in Luttinger Semimetals: Theory of Complex Tensor Order and the Emergence of the Uniaxial Nematic State. AB - We investigate unconventional superconductivity in three-dimensional electronic systems with the chemical potential close to a quadratic band touching point in the band dispersion. Short-range interactions can lead to d-wave superconductivity, described by a complex tensor order parameter. We elucidate the general structure of the corresponding Ginzburg-Landau free energy and apply these concepts to the case of an isotropic band touching point. For a vanishing chemical potential, the ground state of the system is given by the superconductor analogue of the uniaxial nematic state, which features line nodes in the excitation spectrum of quasiparticles. In contrast to the theory of real tensor order in liquid crystals, however, the ground state is selected here by the sextic terms in the free energy. At a finite chemical potential, the nematic state has an additional instability at weak coupling and low temperatures. In particular, the one-loop coefficients in the free energy indicate that at weak coupling genuinely complex orders, which break time-reversal symmetry, are energetically favored. We relate our analysis to recent measurements in the half Heusler compound YPtBi and discuss the role of cubic crystal symmetry. PMID- 29481207 TI - Clocking Femtosecond Collisional Dynamics via Resonant X-Ray Spectroscopy. AB - Electron-ion collisional dynamics is of fundamental importance in determining plasma transport properties, nonequilibrium plasma evolution, and electron damage in diffraction imaging applications using bright x-ray free-electron lasers (FELs). Here we describe the first experimental measurements of ultrafast electron impact collisional ionization dynamics using resonant core-hole spectroscopy in a solid-density magnesium plasma, created and diagnosed with the Linac Coherent Light Source x-ray FEL. By resonantly pumping the 1s->2p transition in highly charged ions within an optically thin plasma, we have measured how off-resonance charge states are populated via collisional processes on femtosecond time scales. We present a collisional cross section model that matches our results and demonstrates how the cross sections are enhanced by dense plasma effects including continuum lowering. Nonlocal thermodynamic equilibrium collisional radiative simulations show excellent agreement with the experimental results and provide new insight on collisional ionization and three-body recombination processes in the dense-plasma regime. PMID- 29481209 TI - Nanorheology of Entangled Polymer Melts. AB - We use molecular simulations to probe the local viscoelasticity of an entangled polymer melt by tracking the motion of embedded nonsticky nanoparticles (NPs). As in conventional microrheology, the generalized Stokes-Einstein relation is employed to extract an effective stress relaxation function G_{GSE}(t) from the mean square displacement of NPs. G_{GSE}(t) for different NP diameters d are compared with the stress relaxation function G(t) of a pure polymer melt. The deviation of G_{GSE}(t) from G(t) reflects the incomplete coupling between NPs and the dynamic modes of the melt. For linear polymers, a plateau in G_{GSE}(t) emerges as d exceeds the entanglement mesh size a and approaches the entanglement plateau in G(t) for a pure melt with increasing d. For ring polymers, as d increases towards the spanning size R of ring polymers, G_{GSE}(t) approaches G(t) of the ring melt with no entanglement plateau. PMID- 29481210 TI - Knowledge-Concealing Evidencing of Knowledge About a Quantum State. AB - Bob has a black box that emits a single pure state qudit which is, from his perspective, uniformly distributed. Alice wishes to give Bob evidence that she has knowledge about the emitted state while giving him little or no information about it. We show that zero-knowledge evidencing of such knowledge is impossible in quantum relativistic protocols, extending a previous result of Horodecki, Horodecki, and Horodecki. We also show that no such protocol can be both sound and complete. We present a new quantum relativistic protocol which we conjecture to be close to optimal in security against Alice and which reveals little knowledge to Bob, for large dimension d. We analyze its security against general attacks by Bob and restricted attacks by Alice. PMID- 29481211 TI - Multispeed Prethermalization in Quantum Spin Models with Power-Law Decaying Interactions. AB - The relaxation of uniform quantum systems with finite-range interactions after a quench is generically driven by the ballistic propagation of long-lived quasiparticle excitations triggered by a sufficiently small quench. Here we investigate the case of long-range (1/r^{alpha}) interactions for a d-dimensional lattice spin model with uniaxial symmetry, and show that, in the regime d12 GeV/c^{2}. PMID- 29481244 TI - Low-Field Nuclear Polarization Using Nitrogen Vacancy Centers in Diamonds. AB - It was recently demonstrated that bulk nuclear polarization can be obtained using nitrogen vacancy (NV) color centers in diamonds, even at ambient conditions. This is based on the optical polarization of the NV electron spin, and using several polarization transfer methods. One such method is the nuclear orientation via electron spin locking (NOVEL) sequence, where a spin-locked sequence is applied on the NV spin, with a microwave power equal to the nuclear precession frequency. This was performed at relatively high fields, to allow for both polarization transfer and noise decoupling. As a result, this scheme requires accurate magnetic field alignment in order preserve the NV properties. Such a requirement may be undesired or impractical in many practical scenarios. Here we present a new sequence, termed the refocused NOVEL, which can be used for polarization transfer (and detection) even at low fields. Numerical simulations are performed, taking into account both the spin Hamiltonian and spin decoherence, and we show that, under realistic parameters, it can outperform the NOVEL sequence. PMID- 29481246 TI - Machine Learning Topological Invariants with Neural Networks. AB - In this Letter we supervisedly train neural networks to distinguish different topological phases in the context of topological band insulators. After training with Hamiltonians of one-dimensional insulators with chiral symmetry, the neural network can predict their topological winding numbers with nearly 100% accuracy, even for Hamiltonians with larger winding numbers that are not included in the training data. These results show a remarkable success that the neural network can capture the global and nonlinear topological features of quantum phases from local inputs. By opening up the neural network, we confirm that the network does learn the discrete version of the winding number formula. We also make a couple of remarks regarding the role of the symmetry and the opposite effect of regularization techniques when applying machine learning to physical systems. PMID- 29481247 TI - Steady State Entanglement beyond Thermal Limits. AB - Classical engines turn thermal resources into work, which is maximized for reversible operations. The quantum realm has expanded the range of useful operations beyond energy conversion, and incoherent resources beyond thermal reservoirs. This is the case of entanglement generation in a driven-dissipative protocol, which we hereby analyze as a continuous quantum machine. We show that for such machines the more irreversible the process, the larger the concurrence. Maximal concurrence and entropy production are reached for the hot reservoir being at negative effective temperature, beating the limits set by classic thermal operations on an equivalent system. PMID- 29481249 TI - Nonequilibrium Quantum Phase Transition in a Hybrid Atom-Optomechanical System. AB - We consider a hybrid quantum many-body system formed by a vibrational mode of a nanomembrane, which interacts optomechanically with light in a cavity, and an ultracold atom gas in the optical lattice of the out-coupled light. The adiabatic elimination of the light field yields an effective Hamiltonian which reveals a competition between the force localizing the atoms and the membrane displacement. At a critical atom-membrane interaction, we find a nonequilibrium quantum phase transition from a localized symmetric state of the atom cloud to a shifted symmetry-broken state, the energy of the lowest collective excitation vanishes, and a strong atom-membrane entanglement arises. The effect occurs when the atoms and the membrane are nonresonantly coupled. PMID- 29481248 TI - Strongly Interaction-Enhanced Valley Magnetic Response in Monolayer WSe_{2}. AB - We measure the doping dependence of the valley Zeeman splitting of the fundamental optical transitions in monolayer WSe_{2} under an out-of-plane magnetic field by optical reflection contrast and photoluminescence spectroscopy. A nonlinear valley Zeeman effect, correlated with an over fourfold enhancement in the g factor, is observed. The effect occurs when the Fermi level crosses the spin-split upper conduction band, corresponding to a change of the spin-valley degeneracy from two to four. The enhancement increases and shows no sign of saturation as the sample temperature decreases. Our result demonstrates the importance of the Coulomb interactions in the valley magnetic response of two dimensional transition metal dichalcogenide semiconductors. PMID- 29481250 TI - Turbulence-Free Double-slit Interferometer. AB - Optical turbulence can be detrimental for optical observations. For instance, atmospheric turbulence may reduce the visibility or completely blur out the interference produced by an interferometer in open air. However, a simple two photon interference theory based on Einstein's granularity picture of light makes a turbulence-free interferometer possible; i.e., any refraction index, length, or phase variations along the optical paths of the interferometer do not have any effect on its interference. Applying this mechanism, the reported experiment demonstrates a two-photon double-slit interference that is insensitive to atmospheric turbulence. The turbulence-free mechanism and especially the turbulence-free interferometer would be helpful in optical observations that require high sensitivity and stability such as for gravitational-wave detection. PMID- 29481253 TI - Phase-Sensitive Evidence for the Sign-Reversal s_{+/-} Symmetry of the Order Parameter in an Iron-Pnictide Superconductor Using Nb/Ba_{1-x}Na_{x}Fe_{2}As_{2} Josephson Junctions. AB - Josephson current provides a phase-sensitive tool for probing the pairing symmetry. Here we present an experimental study of high-quality Josephson junctions between a conventional s-wave superconductor Nb and a multiband iron pnictide Ba_{1-x}Na_{x}Fe_{2}As_{2}. Junctions exhibit a large enough critical current density to preclude the d-wave symmetry of the order parameter in the pnictide. However, the I_{c}R_{n} product is very small ?3MUV, which is not consistent with the sign-preserving s_{++} symmetry either. We argue that the small I_{c}R_{n} value, along with its unusual temperature dependence, provides evidence for the sign-reversal s_{+/-} symmetry of the order parameter in Ba_{1 x}Na_{x}Fe_{2}As_{2}. We conclude that it is the phase sensitivity of our junctions that leads to an almost complete (below a subpercent) cancellation of supercurrents from sign-reversal bands in the pnictide. PMID- 29481254 TI - Symmetry Breaking in Photonic Crystals: On-Demand Dispersion from Flatband to Dirac Cones. AB - We demonstrate that symmetry breaking opens a new degree of freedom to tailor energy-momentum dispersion in photonic crystals. Using a general theoretical framework in two illustrative practical structures, we show that breaking symmetry enables an on-demand tuning of the local density of states of the same photonic band from zero (Dirac cone dispersion) to infinity (flatband dispersion), as well as any constant density over an adjustable spectral range. As a proof of concept, we demonstrate experimentally the transformation of the very same photonic band from a conventional quadratic shape to a Dirac dispersion, a flatband dispersion, and a multivalley one. This transition is achieved by finely tuning the vertical symmetry breaking of the photonic structures. Our results provide an unprecedented degree of freedom for optical dispersion engineering in planar integrated photonic devices. PMID- 29481256 TI - Contact Theory for Spin-Orbit-Coupled Fermi Gases. AB - We develop the contact theory for spin-orbit-coupled Fermi gases. By using a perturbation method, we derive analytically the universal two-body behavior at short distance, which does not depend on the short-range details of interatomic potentials. We find that two new scattering parameters need to be introduced because of spin-orbit coupling, besides the traditional s- and p-wave scattering length (volume) and effective ranges. This is a general and unique feature for spin-orbit-coupled systems. Consequently, two new adiabatic energy relations with respect to the new scattering parameters are obtained, in which a new contact is involved because of spin-orbit coupling. In addition, we derive the asymptotic behavior of the large-momentum distribution, and find that the subleading tail is corrected by the new contact. This work paves the way for exploring the profound properties of spin-orbit-coupled many-body systems, according to two-body solutions. PMID- 29481257 TI - Multipolar Polarizabilities and Hyperpolarizabilities in the Sr Optical Lattice Clock. AB - We address the problem of the lattice Stark shifts in the Sr clock caused by the multipolar M1 and E2 atom-field interactions and by the term nonlinear in lattice intensity and determined by the hyperpolarizability. We develop an approach to calculate hyperpolarizabilities for atoms and ions based on a solution of the inhomogeneous equation which allows us to effectively and accurately carry out complete summations over intermediate states. We apply our method to the calculation of the hyperpolarizabilities for the clock states in Sr. We also carry out an accurate calculation of the multipolar polarizabilities for these states at the magic frequency. Understanding these Stark shifts in optical lattice clocks is crucial for further improvement of the clock accuracy. PMID- 29481255 TI - Dawning of the N=32 Shell Closure Seen through Precision Mass Measurements of Neutron-Rich Titanium Isotopes. AB - A precision mass investigation of the neutron-rich titanium isotopes ^{51-55}Ti was performed at TRIUMF's Ion Trap for Atomic and Nuclear science (TITAN). The range of the measurements covers the N=32 shell closure, and the overall uncertainties of the ^{52-55}Ti mass values were significantly reduced. Our results conclusively establish the existence of the weak shell effect at N=32, narrowing down the abrupt onset of this shell closure. Our data were compared with state-of-the-art ab initio shell model calculations which, despite very successfully describing where the N=32 shell gap is strong, overpredict its strength and extent in titanium and heavier isotones. These measurements also represent the first scientific results of TITAN using the newly commissioned multiple-reflection time-of-flight mass spectrometer, substantiated by independent measurements from TITAN's Penning trap mass spectrometer. PMID- 29481258 TI - Epidemic Threshold in Continuous-Time Evolving Networks. AB - Current understanding of the critical outbreak condition on temporal networks relies on approximations (time scale separation, discretization) that may bias the results. We propose a theoretical framework to compute the epidemic threshold in continuous time through the infection propagator approach. We introduce the weak commutation condition allowing the interpretation of annealed networks, activity-driven networks, and time scale separation into one formalism. Our work provides a coherent connection between discrete and continuous time representations applicable to realistic scenarios. PMID- 29481259 TI - Precision Measurement of the beta Asymmetry in Spin-Polarized ^{37}K Decay. AB - Using Triumf's neutral atom trap, Trinat, for nuclear beta decay, we have measured the beta asymmetry with respect to the initial nuclear spin in ^{37}K to be A_{beta}=-0.5707(13)_{syst}(13)_{stat}(5)_{pol}, a 0.3% measurement. This is the best relative accuracy of any beta-asymmetry measurement in a nucleus or the neutron, and is in agreement with the standard model prediction -0.5706(7). We compare constraints on physics beyond the standard model with other beta-decay measurements, and improve the value of V_{ud} measured in this mirror nucleus by a factor of 4. PMID- 29481260 TI - Measurement of Spectral Functions of Ultracold Atoms in Disordered Potentials. AB - We report on the measurement of the spectral functions of noninteracting ultracold atoms in a three-dimensional disordered potential resulting from an optical speckle field. Varying the disorder strength by 2 orders of magnitude, we observe the crossover from the "quantum" perturbative regime of low disorder to the "classical" regime at higher disorder strength, and find an excellent agreement with numerical simulations. The method relies on the use of state dependent disorder and the controlled transfer of atoms to create well-defined energy states. This opens new avenues for experimental investigations of three dimensional Anderson localization. PMID- 29481261 TI - Symmetry-Breaking Assisted Landau-Zener Transitions in Rydberg Atoms. AB - We report the observation of a controlled Landau-Zener transition (LZT) in Rydberg atoms by breaking the symmetry of the underlying Hamiltonian. For a nonhydrogenic Rydberg atom inside a changing electric (F) field, a LZT occurs between the avoided crossing energy levels of neighboring Rydberg states only for a sufficiently high changing rate. If a transverse magnetic (B) field is applied as we implement, the atomic level symmetry is broken, which causes the Stark manifolds denoted by a different |m| (m is the magnetic quantum number) to interact with each other. The mixed state levels end up pushing the adiabatically repelled target states closer and additionally they serve as stepping stones for the sequential LZTs between the neighboring sublevels. Such a feature significantly decreases the changing rate required for an efficient LZT inside a pure electric field. We report experimental observations that support the above scenario. It opens a versatile approach for engineering a controlled LZT in more general systems. PMID- 29481262 TI - Effects of Heterogeneous Social Interactions on Flocking Dynamics. AB - Social relationships characterize the interactions that occur within social species and may have an important impact on collective animal motion. Here, we consider a variation of the standard Vicsek model for collective motion in which interactions are mediated by an empirically motivated scale-free topology that represents a heterogeneous pattern of social contacts. We observe that the degree of order of the model is strongly affected by network heterogeneity: more heterogeneous networks show a more resilient ordered state, while less heterogeneity leads to a more fragile ordered state that can be destroyed by sufficient external noise. Our results challenge the previously accepted equivalence between the static Vicsek model and the equilibrium XY model on the network of connections, and point towards a possible equivalence with models exhibiting a different symmetry. PMID- 29481251 TI - Measurements of Multiparticle Correlations in d+Au Collisions at 200, 62.4, 39, and 19.6 GeV and p+Au Collisions at 200 GeV and Implications for Collective Behavior. AB - Recently, multiparticle-correlation measurements of relativistic p/d/^{3}He+Au, p+Pb, and even p+p collisions show surprising collective signatures. Here, we present beam-energy-scan measurements of two-, four-, and six-particle angular correlations in d+Au collisions at sqrt[s_{NN}]=200, 62.4, 39, and 19.6 GeV. We also present measurements of two- and four-particle angular correlations in p+Au collisions at sqrt[s_{NN}]=200 GeV. We find the four-particle cumulant to be real valued for d+Au collisions at all four energies. We also find that the four particle cumulant in p+Au has the opposite sign as that in d+Au. Further, we find that the six-particle cumulant agrees with the four-particle cumulant in d+Au collisions at 200 GeV, indicating that nonflow effects are subdominant. These observations provide strong evidence that the correlations originate from the initial geometric configuration, which is then translated into the momentum distribution for all particles, commonly referred to as collectivity. PMID- 29481263 TI - Band Dependent Interlayer f-Electron Hybridization in CeRhIn_{5}. AB - A key issue in heavy fermion research is how subtle changes in the hybridization between the 4f (5f) and conduction electrons can result in fundamentally different ground states. CeRhIn_{5} stands out as a particularly notable example: when replacing Rh with either Co or Ir, antiferromagnetism gives way to superconductivity. In this photoemission study of CeRhIn_{5}, we demonstrate that the use of resonant angle-resolved photoemission spectroscopy with polarized light allows us to extract detailed information on the 4f crystal field states and details on the 4f and conduction electron hybridization, which together determine the ground state. We directly observe weakly dispersive Kondo resonances of f electrons and identify two of the three Ce 4f_{5/2}^{1} crystal electric-field levels and band-dependent hybridization, which signals that the hybridization occurs primarily between the Ce 4f states in the CeIn_{3} layer and two more three-dimensional bands composed of the Rh 4d and In 5p orbitals in the RhIn_{2} layer. Our results allow us to connect the properties observed at elevated temperatures with the unusual low-temperature properties of this enigmatic heavy fermion compound. PMID- 29481264 TI - Incomplete Detection of Nonclassical Phase-Space Distributions. AB - We implement the direct sampling of negative phase-space functions via unbalanced homodyne measurement using click-counting detectors. The negativities significantly certify nonclassical light in the high-loss regime using a small number of detectors which cannot resolve individual photons. We apply our method to heralded single-photon states and experimentally demonstrate the most significant certification of nonclassicality for only two detection bins. By contrast, the frequently applied Wigner function fails to directly indicate such quantum characteristics for the quantum efficiencies present in our setup without applying additional reconstruction algorithms. Therefore, we realize a robust and reliable approach to characterize nonclassical light in phase space under realistic conditions. PMID- 29481265 TI - Conformal Dimensions via Large Charge Expansion. AB - We construct an efficient Monte Carlo algorithm that overcomes the severe signal to-noise ratio problems and helps us to accurately compute the conformal dimensions of large-Q fields at the Wilson-Fisher fixed point in the O(2) universality class. Using it, we verify a recent proposal that conformal dimensions of strongly coupled conformal field theories with a global U(1) charge can be obtained via a series expansion in the inverse charge 1/Q. We find that the conformal dimensions of the lowest operator with a fixed charge Q are almost entirely determined by the first few terms in the series. PMID- 29481266 TI - X-Ray Lines from Dark Matter Annihilation at the keV Scale. AB - In 2014, several groups reported hints for a yet unidentified line in astrophysical x-ray signals from galaxies and galaxy clusters at an energy of 3.5 keV. While it is not unlikely that this line is simply a reflection of imperfectly modeled atomic transitions, it has renewed the community's interest in models of keV-scale dark matter, whose decay would lead to such a line. The alternative possibility of dark matter annihilation into monochromatic photons is far less explored, a lapse that we strive to amend in this Letter. More precisely, we introduce a novel model of fermionic dark matter chi with O(keV) mass, annihilating to a scalar state phi which in turn decays to photons, for instance via loops of heavy vectorlike fermions. The resulting photon spectrum is box shaped, but if chi and phi are nearly degenerate in mass, it can also resemble a narrow line. We discuss dark matter production via two different mechanisms-misalignment and freeze-in-which both turn out to be viable in vast regions of parameter space. We constrain the model using astrophysical x-ray data, and we demonstrate that, thanks to the velocity dependence of the annihilation cross section, it has the potential to reconcile the various observations of the 3.5 keV line. We finally argue that the model can easily avoid structure formation constraints on keV-scale dark matter. PMID- 29481267 TI - Stellar Equilibrium in Semiclassical Gravity. AB - The phenomenon of quantum vacuum polarization in the presence of a gravitational field is well understood and is expected to have a physical reality, but studies of its backreaction on the dynamics of spacetime are practically nonexistent outside of the specific context of homogeneous cosmologies. Building on previous results of quantum field theory in curved spacetimes, in this Letter we first derive the semiclassical equations of stellar equilibrium in the s-wave Polyakov approximation. It is highlighted that incorporating the polarization of the quantum vacuum leads to a generalization of the classical Tolman-Oppenheimer Volkoff equation. Despite the complexity of the resulting field equations, it is possible to find exact solutions. Aside from being the first known exact solutions that describe relativistic stars including the nonperturbative backreaction of semiclassical effects, these are identified as a nontrivial combination of the black star and gravastar proposals. PMID- 29481268 TI - Generalized Grover's Algorithm for Multiple Phase Inversion States. AB - Grover's algorithm is a quantum search algorithm that proceeds by repeated applications of the Grover operator and the Oracle until the state evolves to one of the target states. In the standard version of the algorithm, the Grover operator inverts the sign on only one state. Here we provide an exact solution to the problem of performing Grover's search where the Grover operator inverts the sign on N states. We show the underlying structure in terms of the eigenspectrum of the generalized Hamiltonian, and derive an appropriate initial state to perform the Grover evolution. This allows us to use the quantum phase estimation algorithm to solve the search problem in this generalized case, completely bypassing the Grover algorithm altogether. We obtain a time complexity of this case of sqrt[D/M^{alpha}], where D is the search space dimension, M is the number of target states, and alpha~1, which is close to the optimal scaling. PMID- 29481270 TI - What is the Right Theory for Anderson Localization of Light? An Experimental Test. AB - Anderson localization of light is traditionally described in analogy to electrons in a random potential. Within this description, the random potential depends on the wavelength of the incident light. For transverse Anderson localization, this leads to the prediction that the distribution of localization lengths-and, hence, its average-strongly depends on the wavelength. In an alternative description, in terms of a spatially fluctuating electric modulus, this is not the case. Here, we report on an experimentum crucis in order to investigate the validity of the two conflicting theories using optical samples exhibiting transverse Anderson localization. We do not find any dependence of the observed average localization radii on the light wavelength. We conclude that the modulus-type description is the correct one and not the potential-type one. We corroborate this by showing that in the derivation of the traditional potential-type theory, a term in the wave equation has been tacitly neglected. In our new modulus-type theory, the wave equation is exact. We check the consistency of the new theory with our data using the nonlinear sigma model. We comment on the consequences for the general case of three-dimensional disorder. PMID- 29481269 TI - Beyond the Required LISA Free-Fall Performance: New LISA Pathfinder Results down to 20 MUHz. AB - In the months since the publication of the first results, the noise performance of LISA Pathfinder has improved because of reduced Brownian noise due to the continued decrease in pressure around the test masses, from a better correction of noninertial effects, and from a better calibration of the electrostatic force actuation. In addition, the availability of numerous long noise measurement runs, during which no perturbation is purposely applied to the test masses, has allowed the measurement of noise with good statistics down to 20 MUHz. The Letter presents the measured differential acceleration noise figure, which is at (1.74+/ 0.05) fm s^{-2}/sqrt[Hz] above 2 mHz and (6+/-1)*10 fm s^{-2}/sqrt[Hz] at 20 MUHz, and discusses the physical sources for the measured noise. This performance provides an experimental benchmark demonstrating the ability to realize the low frequency science potential of the LISA mission, recently selected by the European Space Agency. PMID- 29481271 TI - Mapping the Damping Dynamics of Mega-Ampere Electron Pulses Inside a Solid. AB - We report the lifetime of intense-laser (2*10^{19} W/cm^{2}) generated relativistic electron pulses in solids by measuring the time evolution of their Cherenkov emission. Using a picosecond resolution optical Kerr gating technique, we demonstrate that the electrons remain relativistic as long as 50 picoseconds more than 1000 times longer than the incident light pulse. Numerical simulations of the propagation of relativistic electrons and the emitted Cherenkov radiation with Monte Carlo geant4 package reproduce the striking experimental findings. PMID- 29481272 TI - Dynamical Disentangling and Cooling of Atoms in Bilayer Optical Lattices. AB - We show how experimentally available bilayer lattice systems can be used to prepare quantum many-body states with exceptionally low entropy in one layer, by dynamically disentangling the two layers. This disentangling operation moves one layer-subsystem A-into a regime where excitations in A develop a single-particle gap. As a result, this operation maps directly to cooling for subsystem A, with entropy being shuttled to the other layer. For both bosonic and fermionic atoms, we study the corresponding dynamics showing that disentangling can be realized cleanly in ongoing experiments. The corresponding entanglement entropies are directly measurable with quantum gas microscopes, and, as a tool for producing lower-entropy states, this technique opens a range of applications beginning with simplifying production of magnetically ordered states of bosons and fermions. PMID- 29481273 TI - Ward Identity and Scattering Amplitudes for Nonlinear Sigma Models. AB - We present a Ward identity for nonlinear sigma models using generalized nonlinear shift symmetries, without introducing current algebra or coset space. The Ward identity constrains correlation functions of the sigma model such that the Adler's zero is guaranteed for S-matrix elements, and gives rise to a subleading single soft theorem that is valid at the quantum level and to all orders in the Goldstone decay constant. For tree amplitudes, the Ward identity leads to a novel Berends-Giele recursion relation as well as an explicit form of the subleading single soft factor. Furthermore, interactions of the cubic biadjoint scalar theory associated with the single soft limit, which was previously discovered using the Cachazo-He-Yuan representation of tree amplitudes, can be seen to emerge from matrix elements of conserved currents corresponding to the generalized shift symmetry. PMID- 29481274 TI - Quantized Self-Assembly of Discotic Rings in a Liquid Crystal Confined in Nanopores. AB - Disklike molecules with aromatic cores spontaneously stack up in linear columns with high, one-dimensional charge carrier mobilities along the columnar axes, making them prominent model systems for functional, self-organized matter. We show by high-resolution optical birefringence and synchrotron-based x-ray diffraction that confining a thermotropic discotic liquid crystal in cylindrical nanopores induces a quantized formation of annular layers consisting of concentric circular bent columns, unknown in the bulk state. Starting from the walls this ring self-assembly propagates layer by layer towards the pore center in the supercooled domain of the bulk isotropic-columnar transition and thus allows one to switch on and off reversibly single, nanosized rings through small temperature variations. By establishing a Gibbs free energy phase diagram we trace the phase transition quantization to the discreteness of the layers' excess bend deformation energies in comparison to the thermal energy, even for this near room-temperature system. Monte Carlo simulations yielding spatially resolved nematic order parameters, density maps, and bond-orientational order parameters corroborate the universality and robustness of the confinement-induced columnar ring formation as well as its quantized nature. PMID- 29481275 TI - Fibonacci Topological Superconductor. AB - We introduce a model of interacting Majorana fermions that describes a superconducting phase with a topological order characterized by the Fibonacci topological field theory. Our theory, which is based on a SO(7)_{1}/(G_{2})_{1} coset factorization, leads to a solvable one-dimensional model that is extended to two dimensions using a network construction. In addition to providing a description of the Fibonacci phase without parafermions, our theory predicts a closely related "anti-Fibonacci" phase, whose topological order is characterized by the tricritical Ising model. We show that Majorana fermions can split into a pair of Fibonacci anyons, and propose an interferometer that generalizes the Z_{2} Majorana interferometer and directly probes the Fibonacci non-Abelian statistics. PMID- 29481276 TI - Selective Solvent-Induced Stabilization of Polar Oxide Surfaces in an Electrochemical Environment. AB - The impact of an electrochemical environment on the thermodynamic stability of polar oxide surfaces is investigated for the example of ZnO(0001) surfaces immersed in water using density functional theory calculations. We show that solvation effects are highly selective: They have little effect on surfaces showing a metallic character, but largely stabilize semiconducting structures, particularly those that have a high electrostatic penalty in vacuum. The high selectivity is shown to have direct consequences for the surface phase diagram and explains, e.g., why certain surface structures could be observed only in an electrochemical environment. PMID- 29481277 TI - Curvature-Guided Motility of Microalgae in Geometric Confinement. AB - Microorganisms, such as bacteria and microalgae, often live in habitats consisting of a liquid phase and a plethora of interfaces. The precise ways in which these motile microbes behave in their confined environment remain unclear. Using experiments and Brownian dynamics simulations, we study the motility of a single Chlamydomonas microalga in an isolated microhabitat with controlled geometric properties. We demonstrate how the geometry of the habitat controls the cell's navigation in confinement. The probability of finding the cell swimming near the boundary increases with the wall curvature, as seen for both circular and elliptical chambers. The theory, utilizing an asymmetric dumbbell model of the cell and steric wall interactions, captures this curvature-guided navigation quantitatively with no free parameters. PMID- 29481278 TI - Multiplet of Skyrmion States on a Curvilinear Defect: Reconfigurable Skyrmion Lattices. AB - Typically, the chiral magnetic Skyrmion is a single-state excitation. Here we propose a system, where multiplet of Skyrmion states appears and one of these states can be the ground one. We show that the presence of a localized curvilinear defect drastically changes the magnetic properties of a thin perpendicularly magnetized ferromagnetic film. For a large enough defect amplitude a discrete set of equilibrium magnetization states appears forming a ladder of energy levels. Each equilibrium state has either a zero or a unit topological charge; i.e., topologically trivial and Skyrmion multiplets generally appear. Transitions between the levels with the same topological charge are allowed and can be utilized to encode and switch a bit of information. There is a wide range of geometrical and material parameters, where the Skyrmion level has the lowest energy. Thus, periodically arranged curvilinear defects can result in a Skyrmion lattice as the ground state. PMID- 29481279 TI - Tightening Quantum Speed Limits for Almost All States. AB - Conventional quantum speed limits perform poorly for mixed quantum states: They are generally not tight and often significantly underestimate the fastest possible evolution speed. To remedy this, for unitary driving, we derive two quantum speed limits that outperform the traditional bounds for almost all quantum states. Moreover, our bounds are significantly simpler to compute as well as experimentally more accessible. Our bounds have a clear geometric interpretation; they arise from the evaluation of the angle between generalized Bloch vectors. PMID- 29481280 TI - Microscopic Engine Powered by Critical Demixing. AB - We experimentally demonstrate a microscopic engine powered by the local reversible demixing of a critical mixture. We show that, when an absorbing microsphere is optically trapped by a focused laser beam in a subcritical mixture, it is set into rotation around the optical axis of the beam because of the emergence of diffusiophoretic propulsion. This behavior can be controlled by adjusting the optical power, the temperature, and the criticality of the mixture. PMID- 29481282 TI - Strong Cosserat Elasticity in a Transversely Isotropic Polymer Lattice. AB - Large size effects are experimentally measured in lattices of triangular unit cells: about a factor of 36 in torsion rigidity and 29 in bending rigidity. This nonclassical phenomenon is consistent with Cosserat elasticity, which allows for the rotation of points and distributed moments in addition to the translation of points and force stress of classical elasticity. The Cosserat characteristic length for torsion is l_{t}=9.4 mm; for bending, it is l_{b}=8.8 mm; these values are comparable to the cell size. Nonclassical effects are much stronger than in stretch-dominated lattices with uniform straight ribs. The lattice structure provides a path to the attainment of arbitrarily large effects. PMID- 29481281 TI - Coherent Bichromatic Force Deflection of Molecules. AB - We demonstrate the effect of the coherent optical bichromatic force on a molecule, the polar free radical strontium monohydroxide (SrOH). A dual-frequency retroreflected laser beam addressing the X[over ~]^{2}Sigma^{+}<->A[over ~]^{2}Pi_{1/2} electronic transition coherently imparts momentum onto a cryogenic beam of SrOH. This directional photon exchange creates a bichromatic force that transversely deflects the molecules. By adjusting the relative phase between the forward and counterpropagating laser beams we reverse the direction of the applied force. A momentum transfer of 70hk is achieved with minimal loss of molecules to dark states. Modeling of the bichromatic force is performed via direct numerical solution of the time-dependent density matrix and is compared with experimental observations. Our results open the door to further coherent manipulation of molecular motion, including the efficient optical deceleration of diatomic and polyatomic molecules with complex level structures. PMID- 29481283 TI - Polymer Semiflexibility Induces Nonuniversal Phase Transitions in Diblock Copolymers. AB - The order-disorder phase transition and the associated phase diagrams of semiflexible diblock copolymers are investigated using the wormlike chain model, incorporating concentration fluctuations. The free energy up to quartic order in concentration fluctuations is developed with chain-rigidity-dependent coefficients, evaluated using our exact results for the wormlike chain model, and a one-loop renormalization treatment is used to account for fluctuation effects. The chain length N and the monomer aspect ratio alpha directly control the strength of immiscibility (defined by the Flory-Huggins parameter chi) at the order-disorder transition and the resulting microstructures at different chemical compositions f_{A}. When monomers are infinitely thin (i.e., large aspect ratio alpha), the finite chain length N lowers the chiN at the phase transition. However, fluctuation effects become important when chains have a finite radius, and a decrease in the chain length N elevates the chiN at the phase transition. Phase diagrams of diblock copolymers over a wide range of N and alpha are calculated based on our fluctuation theory. We find that both finite N and alpha enhance the stability of the lamellar phase above the order-disorder transition. Our results demonstrate that polymer semiflexibility plays a dramatic role in the phase behavior, even for large chain lengths (e.g., N~100). PMID- 29481284 TI - Ultrashort Nucleic Acid Duplexes Exhibit Long Wormlike Chain Behavior with Force Dependent Edge Effects. AB - Despite their importance in biology and use in nanotechnology, the elastic behavior of nucleic acids on "ultrashort" (<15 nt) length scales remains poorly understood. Here, we use optical tweezers combined with fluorescence imaging to observe directly the hybridization of oligonucleotides (7-12 nt) to a complementary strand under tension and to measure the difference in end-to-end extension between the single-stranded and duplex states. Data are consistent with long-polymer models at low forces (<8 pN) but smaller than predicted at higher forces (>8 pN), the result of the sequence-dependent duplex edge effects. PMID- 29481285 TI - Chiral Modes at Exceptional Points in Exciton-Polariton Quantum Fluids. AB - We demonstrate the generation of chiral modes-vortex flows with fixed handedness in exciton-polariton quantum fluids. The chiral modes arise in the vicinity of exceptional points (non-Hermitian spectral degeneracies) in an optically induced resonator for exciton polaritons. In particular, a vortex is generated by driving two dipole modes of the non-Hermitian ring resonator into degeneracy. Transition through the exceptional point in the space of the system's parameters is enabled by precise manipulation of real and imaginary parts of the closed-wall potential forming the resonator. As the system is driven to the vicinity of the exceptional point, we observe the formation of a vortex state with a fixed orbital angular momentum (topological charge). This method can be extended to generate higher order orbital angular momentum states through coalescence of multiple non Hermitian spectral degeneracies. Our Letter demonstrates the possibility of exploiting nontrivial and counterintuitive properties of waves near exceptional points in macroscopic quantum systems. PMID- 29481286 TI - Correlation-Driven Lifshitz Transition at the Emergence of the Pseudogap Phase in the Two-Dimensional Hubbard Model. AB - We study the relationship between the pseudogap and Fermi-surface topology in the two-dimensional Hubbard model by means of the cellular dynamical mean-field theory. We find two possible mean-field metallic solutions on a broad range of interactions, doping, and frustration: a conventional renormalized metal and an unconventional pseudogap metal. At half filling, the conventional metal is more stable and displays an interaction-driven Mott metal-insulator transition. However, for large interactions and small doping, a region that is relevant for cuprates, the pseudogap phase becomes the ground state. By increasing doping, we show that a first-order transition from the pseudogap to the conventional metal is tied to a change of the Fermi surface from hole- to electronlike, unveiling a correlation-driven mechanism for a Lifshitz transition. This explains the puzzling link between the pseudogap phase and Fermi surface topology that has been pointed out in recent experiments. PMID- 29481288 TI - Replication Study Confirms the Association of the Common rs1800629 Variant of the TNFalpha Gene with Postmenopausal Osteoporosis Susceptibility in the Han Chinese Population. AB - BACKGROUND: Previous studies have suggested that tumor necrosis factor alpha (TNF alpha), encoded by the TNFalpha gene, can increase osteoclast formation, and that specific alleles of the TNFalpha gene are associated with postmenopausal osteoporosis susceptibility in some populations; however, the exact molecular mechanism remains unknown. AIMS: To investigate the potential association of nineteen polymorphisms of the TNFalpha gene with postmenopausal osteoporosis and bone mineral density (BMD) traits in a sample of 1288 postmenopausal women from the Han Chinese population. METHODS: A total of 437 postmenopausal osteoporosis patients and 851 unrelated age-matched healthy women were recruited to the study. Single marker and haplotype based analyses were conducted to evaluate the association of nineteen single nucleotide polymorphisms (SNPs) in both patient and control groups. RESULTS: The SNP rs1800629 was identified as being highly significantly associated with postmenopausal osteoporosis after accounting for age and body mass index (p = 0.000087). In addition, the GG genotype of this SNP was associated with significantly lower measures of femoral neck BMD and lumbar spine BMD. Moreover, haplotype based analyses suggested significant association signals between the haplotype block, including rs1800629 with postmenopausal osteoporosis (p < 0.001). CONCLUSION: We have shown that a TNFalpha gene polymorphism, rs1800629, is highly significantly associated with postmenopausal osteoporosis and BMD in the female Han Chinese population. Additional sequencing based studies are needed to investigate the genetic architecture of this genomic region and its relationship with osteoporosis-related phenotypes. PMID- 29481287 TI - Euthanasia- and Lavage-mediated Effects on Bronchoalveolar Measures of Lung Injury and Inflammation. AB - Accurate and reproducible assessments of experimental lung injury and inflammation are critical for basic and translational research. In particular, investigators use various methods for BAL and euthanasia; however, the impact of these methods on assessments of injury and inflammation is unknown. To define potential effects, we compared methods of lavage and euthanasia in uninjured mice and after a mild lung injury model (ozone). C57BL/6J male mice (8-10 weeks old) underwent BAL after euthanasia with ketamine/xylazine, carbon dioxide (CO2), or isoflurane. BAL methods included 800 MUl of isotonic solution instilled and withdrawn three times, and one or three passive fills and drainage to 20 cm H2O. Parallel experiments were performed 24 hours after 3 hours of ozone (O3) exposure at 2 ppm. BAL total cell counts/differentials and total protein/albumin were determined. Lung histology was evaluated for lung inflammation or injury. BAL cells were cultured and stimulated with PBS, PMA, or LPS for 4 hours and supernatants were evaluated for cytokine content. In uninjured mice, we observed differences due to the lavage and euthanasia methods used. The lavage method increased total cells and total protein/albumin in uninjured and O3-exposed mice, with the 800-MUl instillation having the highest values. Isoflurane increased total BAL cells, whereas CO2 euthanasia increased the total protein/albumin levels in uninjured mice. These effects limited our ability to detect differences in BAL injury measures after O3 exposure. In conclusion, the method used for lavage and euthanasia affects measures of lung inflammation/injury and should be considered a variable in model assessments. PMID- 29481289 TI - Impact of T2R38 Receptor Polymorphisms on Pseudomonas aeruginosa Infection in Cystic Fibrosis. PMID- 29481291 TI - Children's Control/Display Stereotypes. AB - Objective The aim of this study was to determine control/display stereotypes for children of a range of ages and development of these stereotypes with age. Background Little is known about control/display stereotypes for children of different ages and the way in which these stereotypes develop with age. This study is part of a program to determine the need to design differentially for these age groups. Method We tested four groups of children with various tasks (age groups 5 to 7, 8 to 10, 11 to 13, 14 to 16), with about 30 in each group. Examples of common tasks were opening a bottle, turning on taps, and allocating numbers to keypads. More complex tasks involved rotating a control to move a display in a requested direction. Results Tasks with which different age groups were familiar showed no effect of age group. Different control/display arrangements generally showed an increase in stereotype strength with age, with dependence on the form of the control/display arrangement. Two-dimensional arrangements, with the control on the same plane as the display, had higher stereotype strength than three-dimensional arrangements for all age groups, suggesting an effect of familiarity with controls and displays with increasing age. Conclusion Children's control/display stereotypes do not differ greatly from those of adults, and hence, design for children older than 5 years of age, for control/display stereotypes, can be the same as that for adult populations. Application When designing devices for children, the relationship between controls and displays can be as for adult populations, for which there are considerable experimental data. PMID- 29481292 TI - PFstats: A Network-Based Open Tool for Protein Family Analysis. AB - PFstats is a software developed for the extraction of useful information from protein multiple sequence alignments. By analyzing positional conservation and residue coevolution networks, the software allows the identification of structurally and functionally important residue groups and the discovery of probable functional subclasses. Furthermore, it contains tools for the identification of the possible biological significance of these findings. PFstats contains methods for maximizing the significance of alignments through filtering and weighting, residue conservation and coevolution analysis, automatic UniprotKb queries for residue-position annotation and many possible data visualization methods. PMID- 29481290 TI - Chronic E-Cigarette Exposure Alters the Human Bronchial Epithelial Proteome. AB - RATIONALE: E-cigarettes vaporize propylene glycol/vegetable glycerin (PG/VG), nicotine, and flavorings. However, the long-term health effects of exposing lungs to vaped e-liquids are unknown. OBJECTIVES: To determine the effects of chronic vaping on pulmonary epithelia. METHODS: We performed research bronchoscopies on healthy nonsmokers, cigarette smokers, and e-cigarette users (vapers) and obtained bronchial brush biopsies and lavage samples from these subjects for proteomic investigation. We further employed in vitro and murine exposure models to support our human findings. MEASUREMENTS AND MAIN RESULTS: Visual inspection by bronchoscopy revealed that vaper airways appeared friable and erythematous. Epithelial cells from biopsy samples revealed approximately 300 proteins that were differentially expressed in smoker and vaper airways, with only 78 proteins being commonly altered in both groups and 113 uniquely altered in vapers. For example, CYP1B1 (cytochrome P450 family 1 subfamily B member 1), MUC5AC (mucin 5 AC), and MUC4 levels were increased in vapers. Aerosolized PG/VG alone significantly increased MUC5AC protein in human airway epithelial cultures and in murine nasal epithelia in vivo. We also found that e-liquids rapidly entered cells and that PG/VG reduced membrane fluidity and impaired protein diffusion. CONCLUSIONS: We conclude that chronic vaping exerts marked biological effects on the lung and that these effects may in part be mediated by the PG/VG base. These changes are likely not harmless and may have clinical implications for the development of chronic lung disease. Further studies will be required to determine the full extent of vaping on the lung. PMID- 29481293 TI - Craniomaxillofacial Disorders and Solutions in Humans and Animals. AB - Cross-disciplinary collaborations have initiated translational studies in an effort to harness naturally occurring diseases in companion animals to accelerate the development of new treatment modalities, drugs, and device inventions. These synergistic collaborations can identify clinically relevant models that offer the opportunity to conduct rigorous translational investigations. However, the relationship between craniomaxillofacial diseases in companion animals and humans has been widely overlooked. We report here an innovative and visionary 2-d symposium that was organized to gather professionals working on craniomaxillofacial disorders and solutions in humans and/or animals from multiple disciplines, including veterinary physicians, basic scientists, biomedical engineers, physicians, and dentists. The symposium provided a platform for junior and senior investigators and basic science and clinical researchers to network, collaborate, and develop a new clinical and translational framework for accelerated therapy development. PMID- 29481294 TI - MMP20 Overexpression Disrupts Molar Ameloblast Polarity and Migration. AB - Ameloblasts responsible for enamel formation express matrix metalloproteinase 20 (MMP20), an enzyme that cleaves enamel matrix proteins, including amelogenin (AMELX) and ameloblastin (AMBN). Previously, we showed that continuously erupting incisors from transgenic mice overexpressing active MMP20 had a massive cell infiltrate present within their enamel space, leading to enamel mineralization defects. However, effects of MMP20 overexpression on mouse molars were not analyzed, although these teeth more accurately represent human odontogenesis. Therefore, MMP20-overexpressing mice ( Mmp20+/+Tg+) were assessed by multiscale analyses, combining several approaches from high-resolution micro-computed tomography to enamel organ immunoblots. During the secretory stage at postnatal day 6 (P6), Mmp20+/+Tg+ mice had a discontinuous ameloblast layer and, unlike incisors, molar P12 maturation stage ameloblasts abnormally migrated away from the enamel layer into the stratum intermedium/stellate reticulum. TOPflash assays performed in vitro demonstrated that MMP20 expression promoted beta-catenin nuclear localization and that MMP20 expression promoted invasion through Matrigel coated filters. However, for both assays, significant differences were eliminated in the presence of the beta-catenin inhibitor ICG-001. This suggests that MMP20 activity promotes cell migration via the Wnt pathway. In vivo, the unique molar migration of amelogenin-expressing ameloblasts was associated with abnormal deposition of ectopic calcified nodules surrounding the adherent enamel layer. Enamel content was assessed just prior to eruption at P15. Compared to wild-type, Mmp20+/+Tg+ molars exhibited significant reductions in enamel thickness (70%), volume (60%), and mineral density (40%), and MMP20 overexpression resulted in premature cleavage of AMBN, which likely contributed to the severe defects in enamel mineralization. In addition, Mmp20+/+Tg+ mouse molar enamel organs had increased levels of inactive p-cofilin, a protein that regulates cell polarity. These data demonstrate that increased MMP20 activity in molars causes premature degradation of ameloblastin and inactivation of cofilin, which may contribute to pathological Wnt-mediated cell migration away from the enamel layer. PMID- 29481295 TI - Medication Safety in Oncology Care: Mapping Checking Procedures From Prescription to Administration of Chemotherapy. AB - PURPOSE: To increase medication safety in oncology, checking procedures are increasingly applied by nurses, physicians, and pharmacists. However, little is known about the number, types, and consistency of implemented checks. The aim of the study was to assess the number and types of different checking procedures that are performed along the lifecycle of a chemotherapy prescription across three hospitals, different care settings, administration routes, and professional groups. METHODS: A scheme to evaluate checking procedures and a mapping approach to illustrate the checks along the phases of the medication process were developed. Checking procedures were assessed on the basis of analysis of internal guidelines and interviews with nurses and physicians who work on wards and in ambulatory infusion units of three hospitals. RESULTS: There were considerable differences in number and type of checking procedures among administration routes, professional groups, wards and ambulatory infusion units, and hospitals. During the prescribing phase, the lowest number of checks was performed. In internal guidelines, checking procedures were documented poorly, though the pharmacy process was an exception. CONCLUSION: In contrast to the pharmacists, nurse and physician clinician checking procedures are less standardized within and across hospitals. The results point to different checking habits for the professional groups; for example, physicians would rather perform plausibility reviews than checks. Our evaluation scheme to categorize checks and the visualized mapping approach was feasible and understandable for practitioners. PMID- 29481296 TI - Top 50 Most-Cited Journal of Clinical Oncology Articles From 2014. PMID- 29481297 TI - Acceptability of an Adapted HIV Prevention Intervention for Native American Adolescents. AB - Relatively few HIV evidence-based interventions (EBIs) among Native Americans have been developed, adapted, evaluated, and/or published in the scientific literature. An adolescent HIV EBI was adapted in three phases: (1) securing input from a Native American Advisory Board; (2) modifying the EBI to be more consistent with Native American culture; and (3) conducing a pilot with 14 Native American adolescents to examine acceptability and cultural congruence between the adapted intervention and the youth's culture based on Likert-scale ratings and a focus group. The adaptations included diverse Native American social and cultural stories that assisted with responsible decision-making skills. The adolescents consistently rated each intervention session as highly acceptable. A difference in knowledge from pre-survey (M = 13.93, SD = 3.08) to post-survey (M = 17.14, SD = 2.25) was statistically significant; t(13) = 4.166, p < .0005. The adapted curriculum did appear culturally responsive based on the pilot test results. PMID- 29481298 TI - Perceptions of HIV Self-Testing Among Men Who Have Sex With Men in the United States: A Qualitative Analysis. AB - HIV testing is the gateway into both prevention and treatment services. It is important to understand how men who have sex with men (MSM) perceive HIV self tests. We conducted focus groups and individual interviews to collect feedback on two HIV self-tests, and on a dried blood spot (DBS) specimen collection kit. Perceptions and attitudes around HIV self-testing (HIVST), and willingness to distribute HIV self-tests to others were assessed. MSM reported HIVST to be complementary to facility-based testing, and liked this approach because it offers privacy and convenience, does not require counseling, and could lead to linkage to care. However, they also had concerns around the accuracy of HIV self tests, their cost, and receiving a positive test result without immediate access to follow-up services. Despite these issues, they perceived HIVST as a positive addition to their HIV prevention toolbox. PMID- 29481299 TI - Data Visualization Promotes Sound Public Health Practice: The AIDSvu Example. AB - The ability to depict surveillance and other complex health-related data in a visual manner promotes sound public health practice by supporting the three core functions of public health: assessment, policy development, and assurance. Further, such efforts potentiate the use of surveillance data beyond traditional public health audiences and venues, thus fostering a "culture of health." This practice report provides several recent examples of how data from AIDSVu-an interactive map of the U.S. showing the impact of HIV at national, state, and local levels-has been used to: fine tune the assessment of HIV-related disparities at a community level, educate and empower communities about HIV and its consequences, and better target HIV interventions to reach underserved, vulnerable populations. PMID- 29481300 TI - Willingness to Take PrEP for HIV Prevention: The Combined Effects of Race/Ethnicity and Provider Trust. AB - Blacks and Hispanics/Latinos are disproportionately burdened by HIV compared to non-Hispanic Whites, as evidenced by higher HIV incidence, prevalence, and deaths attributable to AIDS. Increasing the use of novel prevention techniques such as Truvada for pre-exposure prophylaxis (PrEP) could greatly help in reducing these disparities by lowering HIV incidence among these higher risk groups. Trust in providers, which may differ by race and ethnicity, may influence willingness to take PrEP. This study explores the moderating effect of race/ethnicity on trust in one's primary care provider (PCP) on PrEP willingness. This study found a significant association between PCP trust and PrEP willingness, with those with greater trust having 3.24 times the adjusted odds of being willing to try PrEP. Results regarding the effects of race and ethnicity on these outcomes, however, were inconclusive. Results indicate the importance of fostering trust between PrEP-prescribing PCPs and their patients. PMID- 29481301 TI - Gender Differences in Sexual and Reproductive Health Protective and Risk Factors of Batswana Adolescents: Implications for Parent and Adolescent Interventions. AB - Adolescents in sub-Saharan Africa and in Botswana in particular continue to bear the brunt of the HIV epidemic. This analysis assessed gender differences among theory-based sexual and reproductive health protective and risk factors in a cross-sectional sample of 228 Batswana adolescents. Incongruence between preferred and actual sources of sexual information and several important gender differences in parent-adolescent relationships, psychosocial influences, and adolescent sexual behaviors were identified. Parents were the fourth most common source of information about sex; yet, over three-quarters of adolescents preferred to have parents teach them about sex. Boys reported more positive relationships with their parents and girls reported more positive attitudes toward transactional sex. Both boys and girls reported similarly low levels of parental monitoring, parental communication, and parental responsiveness, all of which are important protective factors. These findings suggest interventions should address these gender differences and consider offering parallel interventions for adolescents and their parents in Botswana. PMID- 29481302 TI - A PrEP Information and Self-Screening Tool for Women. AB - Although HIV pre-exposure prophylaxis (PrEP) is effective for women, studies show limited uptake among women to date. Barriers to women's PrEP uptake include their limited knowledge about PrEP and low perceived HIV risk. To address these barriers, we developed and pretested a printed palm card containing HIV prevention/PrEP information that addressed HIV prevention motivation with self assessment questions about HIV risk. We conducted expert interviews (N = 8), focus groups with health, education, and social service providers (N = 13), and interviews with community women (N = 30) in New York City to assess attention to and acceptability of the card, comprehension of the information, and potential impact on prevention motivation. The card format and content were found to be acceptable and potentially motivational for preventive behaviors, as well as particularly relevant for women. Results of testing for language use, comprehension, and attention guided the final version of the card content. PMID- 29481303 TI - Condomless Anal Intercourse by Partner Type Among Chinese Men Who Have Sex With Men in Tianjin. AB - HIV prevalence and incidence is high among men who have sex with men (MSM) in China, underscoring the need to support and optimize HIV risk reduction strategies for this population. We sought to estimate the prevalence of condomless anal sex among MSM living in Tianjin, China. We recruited 595 HIV negative MSM living in Tianjin to participate in a HIV study between 2013 and 2014. Data were collected after a voluntary counseling and testing session through a face-to-face survey. We used multivariable logistic regressions to examine the association between sociodemographic characteristics and HIV risk correlates and MSM's likelihood of engaging in condomless anal intercourse with main and casual partners in the prior 6 months. Results are presented. HIV risk reduction efforts should be developed to be sensitive and responsive to the unique experiences of Chinese MSM. We discuss opportunities for future work, including the development HIV risk reduction interventions. PMID- 29481304 TI - Identification of an Immortalized Human Airway Epithelial Cell Line with Dyskinetic Cilia. AB - Primary ciliary dyskinesia is an inherited, currently incurable condition. In the respiratory system, primary ciliary dyskinesia causes impaired functioning of the mucociliary escalator, leading to nasal congestion, cough, and recurrent otitis media, and commonly progresses to cause more serious and permanent damage, including hearing deficits, chronic sinusitis, and bronchiectasis. New treatment options for the condition are thus necessary. In characterizing an immortalized human bronchial epithelial cell line (BCi-NS1.1) grown at an air-liquid interface to permit differentiation, we have identified that these cells have dyskinetic motile cilia. The cells had a normal male karyotype, and phenotypic markers of epithelial cell differentiation emerged, as previously shown. Ciliary beat frequency (CBF) as assessed by high-speed videomicroscopy was lower than normal (4.4 Hz). Although changes in CBF induced by known modulators were as expected, the cilia displayed a dyskinetic, circular beat pattern characteristic of central microtubular agenesis with outer doublet transposition. This ultrastructural defect was confirmed by electron microscopy. We propose that the BCi-NS1.1 cell line is a useful model system for examination of modulators of CBF and more specifically could be used to screen for novel drugs with the ability to enhance CBF and perhaps repair a dyskinetic ciliary beat pattern. PMID- 29481305 TI - Improving nuclear envelope dynamics by EBV BFRF1 facilitates intranuclear component clearance through autophagy. AB - Although a vesicular nucleocytoplasmic transport system is believed to exist in eukaryotic cells, the features of this pathway are mostly unknown. Here, we report that the BFRF1 protein of the Epstein-Barr virus improves vesicular transport of nuclear envelope (NE) to facilitate the translocation and clearance of nuclear components. BFRF1 expression induces vesicles that selectively transport nuclear components to the cytoplasm. With the use of aggregation-prone proteins as tools, we found that aggregated nuclear proteins are dispersed when these BFRF1-induced vesicles are formed. BFRF1-containing vesicles engulf the NE associated aggregates, exit through from the NE, and putatively fuse with autophagic vacuoles. Chemical treatment and genetic ablation of autophagy-related factors indicate that autophagosome formation and autophagy-linked FYVE protein mediated autophagic proteolysis are involved in this selective clearance of nuclear proteins. Remarkably, vesicular transport, elicited by BFRF1, also attenuated nuclear aggregates accumulated in neuroblastoma cells. Accordingly, induction of NE-derived vesicles by BFRF1 facilitates nuclear protein translocation and clearance, suggesting that autophagy-coupled transport of nucleus-derived vesicles can be elicited for nuclear component catabolism in mammalian cells.-Liu, G.-T., Kung, H.-N., Chen, C.-K., Huang, C., Wang, Y.-L., Yu, C.-P., Lee, C.-P. Improving nuclear envelope dynamics by EBV BFRF1 facilitates intranuclear component clearance through autophagy. PMID- 29481306 TI - Platelet-derived microparticles promote endothelial cell proliferation in hypertension via miR-142-3p. AB - Endothelial cells (ECs) are located at the interface between flowing blood and the vessel wall, and abnormal EC proliferation induced by pathologic environments plays an important role in vascular remodeling in hypertensive conditions. Exchanges of information between blood components and ECs are important for EC function. Hence, the present study sought to determine how platelets induce EC dysfunction under hypertensive conditions. EC proliferation was increased in renal hypertensive rats established by abdominal aortic coarctation compared with control rats and that elevated thrombin in plasma promoted platelet activation, which may induce the release of platelet-derived microparticles (PMPs). MicroRNA (MiR) array and qPCR revealed a higher level of miR-142-3p in platelets and PMPs. In vitro, PMPs delivered miR-142-3p into ECs and enhanced their proliferation via Bcl-2-associated transcription factor (BCLAF)1 and its downstream genes. These results indicate that PMPs deliver miR-142-3p from activated platelets into ECs and that miR-142-3p may play important roles in EC dysfunction in hypertensive conditions and may be a novel therapeutic target for maintaining EC homeostasis in hypertension.-Bao, H., Chen, Y.-X., Huang, K., Zhuang, F., Bao, M., Han, Y., Chen, X.-H., Shi, Q., Yao, Q.-P., Qi, Y.-X. Platelet-derived microparticles promote endothelial cell proliferation in hypertension via miR-142-3p. PMID- 29481307 TI - Histone demethylase JMJD3 regulates fibroblast-like synoviocyte-mediated proliferation and joint destruction in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is an immune-mediated disease with the characteristics of progressive joint destruction, deformity, and disability. Epigenetic changes have been implicated in the development of some autoimmune disorders, resulting in an alteration of gene transcription. Here, we investigated how Jumonji C family of histone demethylases (JMJD3) regulated the proliferation and activation of fibroblast-like synoviocytes (FLSs), which are involved in RA joint destruction and pathologic process. The JMJD3 expression and proliferation markers in RA-FLS were higher than those in healthy-FLS and were upregulated in platelet-derived growth factor (PDGF)-induced FLS. Elevated JMJD3 promoted the proliferation and migration of FLS. Treatment with JMJD3 small interfering RNA or inhibitor glycogen synthase kinase (GSK) J4 led to decreased proliferation and migration of FLS. Interestingly, induction of proliferating cell nuclear antigen (PCNA), a major player of the cell-cycle regulation, was correlated with trimethylated lysine 27 in histone H3 loss around the gene promoters. The knockdown of JMJD3 abolished PCNA expression in PDGF-induced FLS and further inhibited cell proliferation and migration, suggesting that JMJD3/PCNA played a crucial role in aspects of FLS proliferation and migration. In vivo, the ability of GSK J4 to hinder collagen-induced arthritis (CIA) in DBA/1 mice was evaluated. We found that GSK J4 markedly attenuated the severity of arthritis in CIA mice. The therapeutic effects were associated with ameliorated joint swelling and reduced bone erosion and destruction. This study revealed how JMJD3 integrated with epigenetic processes to regulate RA-FLS proliferation and invasion. These data suggested that JMJD3 might contribute to rheumatoid synovial hyperplasia and have the potential as a novel therapeutic target for RA.-Jia, W., Wu, W., Yang, D., Xiao, C., Su, Z., Huang, Z., Li, Z., Qin, M., Huang, M., Liu, S., Long, F., Mao, J., Liu, X., Zhu, Y. Z. Histone demethylase JMJD3 regulates fibroblast-like synoviocyte-mediated proliferation and joint destruction in rheumatoid arthritis. PMID- 29481309 TI - TNF-alpha-mediated ER stress causes elimination of Mycobacterium fortuitum reservoirs by macrophage apoptosis. AB - Mycobacterium fortuitum (MF), a rapidly growing nontuberculosis mycobacterium, is recognized as an important human pathogen. We investigated whether the endoplasmic reticulum (ER) stress response is associated with the apoptosis of MF infected macrophages. The expression of ER molecular chaperones was significantly induced by MF infection. We found that MF-induced reactive oxygen species (ROS) generation plays a critical role in the induction of ER stress-mediated apoptosis. Excess TNF-alpha in the ER led to ER stress-mediated apoptosis during MF infection. The intracellular survival of MF was significantly increased by TNF alpha knockdown compared with the control. This is the first report of MF-induced TNF-alpha as a cause of ER stress in macrophages. Furthermore, we found that TLR2 mediated ER stress response contributed to the elimination of intracellular MF in vivo. These results suggest that TNF-alpha-mediated ER stress during MF infection contributes to the suppression of intracellular survival of MF in macrophages. Our findings provide new insight into the importance of ER stress in mycobacterial infection.-Oh, S.-M., Lim, Y.-J., Choi, J.-A., Lee, J., Cho, S.-N., Go, D., Kim, S.-H., Song, C.-H. TNF-alpha-mediated ER stress causes elimination of Mycobacterium fortuitum reservoirs by macrophage apoptosis. PMID- 29481308 TI - Inhibition of fibroblast growth factor 23 (FGF23) signaling rescues renal anemia. AB - Severe anemia and iron deficiency are common complications in chronic kidney disease. The cause of renal anemia is multifactorial and includes decreased erythropoietin (Epo) production, iron deficiency, and inflammation, and it is currently treated with injections of synthetic Epo. However, the use of recombinant Epo has several adverse effects. We previously reported that high fibroblast growth factor 23 (FGF23) levels in mice are associated with decreased red blood cell production, whereas genetic inactivation of Fgf23 results in expansion of the erythroid lineage. The present study is the first to show that high FGF23 levels in a mouse model of renal failure contribute to renal anemia, and inhibiting FGF23 signaling stimulates erythropoiesis and abolishes anemia and iron deficiency. Moreover, we show that inhibition of FGF23 signaling significantly decreases erythroid cell apoptosis and influences the commitment of hematopoietic stem cells toward the erythroid linage. Furthermore, we show that blocking FGF23 signaling attenuates inflammation, resulting in increased serum iron and ferritin levels. Our data clearly demonstrate that elevated FGF23 is a causative factor in the development of renal anemia and iron deficiency, and importantly, blocking FGF23 signaling represents a novel approach to stimulate erythropoiesis and possibly improve survival for millions of chronic kidney disease patients worldwide.-Agoro, R., Montagna, A., Goetz, R., Aligbe, O., Singh, G., Coe, L. M., Mohammadi, M., Rivella, S., Sitara, D. Inhibition of fibroblast growth factor 23 (FGF23) signaling rescues renal anemia. PMID- 29481310 TI - Therapeutic modulation of the bile acid pool by Cyp8b1 knockdown protects against nonalcoholic fatty liver disease in mice. AB - Bile acids (BAs) are surfactant molecules that regulate the intestinal absorption of lipids. Thus, the modulation of BAs represents a potential therapy for nonalcoholic fatty liver disease (NAFLD), which is characterized by hepatic accumulation of fat and is a major cause of liver disease worldwide. Cyp8b1 is a critical modulator of the hydrophobicity index of the BA pool. As a therapeutic proof of concept, we aimed to determine the impact of Cyp8b1 inhibition in vivo on BA pool composition and as protection against NAFLD. Inhibition of Cyp8b1 expression in mice led to a remodeling of the BA pool, which altered its signaling properties and decreased intestinal fat absorption. In a model of cholesterol-induced NAFLD, Cyp8b1 knockdown significantly decreased steatosis and hepatic lipid content, which has been associated with an increase in fecal lipid and BA excretion. Moreover, inhibition of Cyp8b1 not only decreased hepatic lipid accumulation, but also resulted in the clearance of previously accumulated hepatic cholesterol, which led to a regression in hepatic steatosis. Taken together, our data demonstrate that Cyp8b1 inhibition is a viable therapeutic target of crucial interest for metabolic diseases, such as NAFLD.-Chevre, R., Trigueros-Motos, L., Castano, D., Chua, T., Corliano, M., Patankar, J. V., Sng, L., Sim, L., Juin, T. L., Carissimo, G., Ng, L. F. P., Yi, C. N. J., Eliathamby, C. C., Groen, A. K., Hayden, M. R., Singaraja, R. R. Therapeutic modulation of the bile acid pool by Cyp8b1 knockdown protects against nonalcoholic fatty liver disease in mice. PMID- 29481311 TI - Phytochemical Profile, Toxicity, and Pharmacological Potential of Peels from Four Species of Tropical Fruits. AB - Tropical fruit peels are generally discarded as waste, yet they contain bioactive substances that could have various uses; in addition, their pharmacological potential remains unexplored. This study aims to characterize the phytochemical profile, toxicity, and pharmacological potential of methanol extracts obtained from the peels of the following tropical fruit species: Annona squamosa L. (purple sugar apple), Annona reticulata L. (custard apple), Chrysophyllum cainito L. (green star apple), and Melicoccus bijugatus Jacq. (mamoncillo). Methanol peel extracts were obtained by maceration. All extracts contained flavonoids, anthraquinones, and triterpenoids as determined by colorimetric methods. A. squamosa and C. cainito exhibited the highest content of total phenols as assayed by the Folin-Ciocalteu method. M. bijugatus showed the highest content of total sugars (fructose, glucose, and sucrose) as determined by high-performance liquid chromatography. A. squamosa and C. cainito presented the highest antioxidant capacities (according to 2,2'-diphenyl-1-picrylhydrazyl, 2,2'-azinobis(3 ethylbenzothiazoline-6-sulfonic acid, and cupric reducing antioxidant capacity assays), displayed moderate toxicity against HCT-116 cells, and increased the vinblastine susceptibility of MCF-7/Vin+. A. squamosa and M. bijugatus extracts demonstrated modulation of acetylcholinesterase activity, whereas those of A. reticulata showed anti-inflammatory activity by inhibiting protein denaturation. These results confirm that tropical fruit peels can be valuable sources of bioactive compounds, and our findings provide new information about their pharmacologic potential so that they can be used as raw material for the development of new drugs aimed at treating a variety of ailments. PMID- 29481252 TI - Search for Dark Photons Produced in 13 TeV pp Collisions. AB - Searches are performed for both promptlike and long-lived dark photons, A^{'}, produced in proton-proton collisions at a center-of-mass energy of 13 TeV, using A^{'}->MU^{+}MU^{-} decays and a data sample corresponding to an integrated luminosity of 1.6 fb^{-1} collected with the LHCb detector. The promptlike A^{'} search covers the mass range from near the dimuon threshold up to 70 GeV, while the long-lived A^{'} search is restricted to the low-mass region 21418 years of age, hospitalized with neurological injuries, at high risk for PU development (Norton scale <14 points; Waterlow scale >15 points), and with at least 1 Stage 2 to Stage 4 PU were eligible to participate in the study. Persons with necrotic wounds, osteomyelitis, electronic or metal implants in the PU area, PUs in need of surgical intervention, acute wound inflammation, diabetes (HBA1c >7%), diabetic neuropathy, cancer, and/or allergies to standard wound treatments were excluded. Patients were randomly assigned to 1 of 3 groups: anodal (AG), cathodal (CG), or placebo (PG) ES. All groups received individualized PU prevention and standard wound care. In the PG, sham ES was applied; the AG and CG were treated with anodal and cathodal HVMPC, respectively (154 MUs 100 Hz; 360 uC/second; 1.08 C/day), 50 minutes per day, 5 days per week, for a maximum of 8 weeks. PSBF was measured using laser Doppler flowmetry at baseline, week 2, and week 4, and wound surface area measurements were obtained and analyzed using a digitizer connected to a personal computer. Data analysis utilized the maximum-likelihood chi-squared test, the analysis of variance Kruskal-Wallis test, the Kruskal-Wallis post-hoc test, and Spearman's rank order correlation. Nonlinear approximation based on exponential function was used to calculate treatment time needed to reduce the wound area by 50%. In all tests, the level of significance was set at P <=.05. Of the 61 participating patients, 20 were in the AG (mean age 53.2 +/- 13.82 years), 21 in the CG (mean age 55.67 +/- 17.83 years), and 20 in the PG (mean age 52.5 +/ 13.18 years). PUs (baseline size range 1.01 cm2 to 59.57 cm2; duration 4 to 48 weeks) were most frequently located in the sacral region (73.77%) and classified as Stage 3 (62.29%). PSBF at week 2 was significantly higher in the AG and CG than in the PG (P <.05). Week 4 differences were not statistically significant. Wound percentage area reduction calculated at week 8 for the AG (64.10% +/- 29.22%) and CG (74.06% +/- 23.23%) were significantly different from PG ulcers (41.42% +/- 27.88%; P = .0391 and P = .0024, respectively). In both ES groups, PSBF at week 4 and percent wound surface area reductions between weeks 4 and 8 were positively correlated, but only the AG correlation was statistically significant (P = .049). In this study, both ES modalities improved blood flow and wound area reduction rate. Studies examining optimal ES treatment times for healing to occur, the effect of comorbidities and baseline wound variables on ES outcomes, and the nature of the relationship between blood flow and healing are necessary. PMID- 29481325 TI - Factors Affecting Wound Healing in Individuals With Pressure Ulcers: A Retrospective Study. AB - Owing to the number and severity of concomitant factors, pressure ulcers remain a significant problem. A retrospective study of data from adult patients with a pressure ulcer was conducted to identify factors that may affect their healing. Data from patients who were hospitalized between January 1, 2011, and December 31, 2015, in a private Turkish university hospital who had a Stage 2, Stage 3, Stage 4, or unstageable pressure ulcer that was assessed using the Bates-Jensen Wound Assessment Tool (BWAT) were abstracted. The following variables were examined: demographic characteristics (gender, age, hospital unit, duration of hospitalization), health status and disease data (vital signs, mobility, nutrition, diagnosis, chronic diseases, medication), laboratory values (albumin, hemoglobin, blood glucose), and pressure ulcer characteristics (stage, location, healing status, duration) and pressure ulcer risk status as determined by patient Braden Scale score. Seventy-eight (78) patient records were identified. Patient mean age was 70.8 +/- 13.47 years, and length of hospitalization was on average 32.52 +/- 27.2 days. Most ulcers (62; 79.5%) were Stage 2 and located in the sacral area (59; 75.6%). Thirty-four (34) patients (43.6%) were discharged and 44 (56.4%) died. At the time of discharge or death, 65.4% of the ulcers had not healed. Patients whose wounds were healed were significantly more likely to have higher hemoglobin and mean arterial pressure, better mobility, received oral nutrition, and discharged from the hospital than patients whose ulcers did not heal. The results suggest that these variables, including Braden Scale and BWAT scores, might be considered when developing a treatment plan of care. Additional studies examining risk factors for nonhealing pressure ulcers, including studies with large samples to facilitate multivariate analyses, are needed. PMID- 29481326 TI - A Retrospective Analysis to Evaluate Seasonal Pressure Injury Incidence Differences Among Hip Fracture Patients in a Tertiary Hospital in East China. AB - Patients with a hip fracture are at high risk for pressure injury. A retrospective review of the electronic medical records of consecutive patients with a hip fracture treated in 2016 in a single tertiary hospital in east China were examined to investigate whether time of year affected the incidence of hospital-acquired pressure injury. Data collected included demographic characteristics (patient name, hospital number, age, gender, and body mass index); possible risk factors for pressure injury, such as presence of diabetes mellitus, admission hemoglobin, admission albumin, length of surgery, and the lowest and/or last Braden Scale score before pressure injury developed; and pressure injury information, which included time of occurrence (days after surgery), location (sacrum and coccyx, ischial tuberosity, or heel), stage, and treatment outcome. Pressure injury incidence was calculated with 95% confidence intervals (CIs) in each month and season (spring, summer, autumn, and winter). Odds ratios (ORs) and 95% CIs were calculated as estimates of risk. Multivariate logistic regression was used for risk factors. Of the 235 patients with a hip fracture included in the study, 95 (40.4%) were male, 140 (59.6%) were female, and mean age was 70.4 +/- 10.5 (range 48-81) years. Thirty-one (31) patients (13.2%, 95% CI 9.1%-18.2%) developed 37 pressure injuries, 30 of which (81.1%) were Stage 1. The incidence of pressure injury was lowest in November (5.0%; 95% CI: 0.0%-24.9%) and highest in June (22.7%; 95% CI: 7.8%-45.4%). Average Braden Scale scores (14.2 +/- 3.2) were lower in June than in November (16.6 +/- 3.5), owing to differences in the Braden Scale skin moisture subscale. Seasonally, the incidence of pressure ulcers was 20.8% (95% CI: 12.2%-32.0%) in the summer compared to 7.5% (2.5%-16.6%) in autumn (crude OR 3.3; 95% CI:1.0-12.1; P = .025). Multivariate logistic regression analysis showed the Braden Scale score was the only independent risk factor (P <.05) for pressure injury incidence. Adjusting for the Braden score, the OR of summer season was 1.537 (95% CI: 0.964 2.872). The findings suggest that humidity and temperature levels, which are very high in the summer in China, may affect pressure injury incidence and that the Braden Scale score - especially the skin-moisture level subscore - is a valid predictor of pressure injury risk in this population. While more research is needed, additional pressure injury prevention strategies should be provided for patients hospitalized with a hip fracture in the summer months. PMID- 29481327 TI - Reconstruction of a Sacral Pressure Ulcer With an Inferior Gluteal Artery Perforator Flap After Failed Reconstruction Using Bilateral V-Y Advancement Flaps. AB - Many types of flaps are available if surgical reconstruction of a pressure ulcer is indicated, including a gluteus maximus flap, V-Y advancement flap, and superior gluteal artery perforator flap. Regional flap failure can complicate treatment, requiring additional flap surgery. An 80-year old woman with a 2-year history of being unconscious following a cerebrovascular accident presented with a Stage 4 sacral pressure ulcer of 2 months' duration with eschar and abscess formation. Because the wound measured 15 * 10 cm2, bilateral V-Y advancement flaps were used for surgical closure. However, 1 week later, ischemic change of the wound edges and wound dehiscence were observed. The wound was subsequently closed with an artery perforator (IGAP) flap, an approach that took into consideration religious preference of keeping the body intact. The patient was discharged with a healed wound 6 weeks postoperatively; long-term postoperative surveillance was hindered by the patient's distance from the care facility (she lived on an outlying island). This is the first case report to describe IGAP flap application in a patient with a sacral pressure ulcer after failed reconstruction using bilateral V-Y advancement flaps. PMID- 29481323 TI - NRF2 regulates core and stabilizing circadian clock loops, coupling redox and timekeeping in Mus musculus. AB - Diurnal oscillation of intracellular redox potential is known to couple metabolism with the circadian clock, yet the responsible mechanisms are not well understood. We show here that chemical activation of NRF2 modifies circadian gene expression and rhythmicity, with phenotypes similar to genetic NRF2 activation. Loss of Nrf2 function in mouse fibroblasts, hepatocytes and liver also altered circadian rhythms, suggesting that NRF2 stoichiometry and/or timing of expression are important to timekeeping in some cells. Consistent with this concept, activation of NRF2 at a circadian time corresponding to the peak generation of endogenous oxidative signals resulted in NRF2-dependent reinforcement of circadian amplitude. In hepatocytes, activated NRF2 bound specific enhancer regions of the core clock repressor gene Cry2, increased Cry2 expression and repressed CLOCK/BMAL1-regulated E-box transcription. Together these data indicate that NRF2 and clock comprise an interlocking loop that integrates cellular redox signals into tissue-specific circadian timekeeping. PMID- 29481328 TI - Laparoscopy-assisted Chimeric Peritoneal-deep Inferior Epigastric Perforator Flap for Reconstruction of Hand and Foot. AB - : Management of hand and foot defects with exposed tendons is a big challenge for plastic surgeons. Thin vascularized tissue offers an ideal surface for tendon excursion. OBJECTIVE: This study examines the reconstructive benefits of a laparoscopy-assisted chimeric peritoneal-deep inferior epigastric artery perforator (DIEP) flap in the treatment of hand and foot injury defects. MATERIALS AND METHODS: A retrospective review was performed on 8 patients (6 men, 2 women) that received hand or foot reconstruction with laparoscopy-assisted chimeric peritoneal-DIEP flap. Soft tissue defects of the hand or foot ranged from 16 cm x 10 cm to 22 cm x 14 cm. The peritoneum supplied by the peritoneal branches of the deep inferior epigastric artery was retrieved by laparoscopy to cover exposed extensor tendons, while the DIEP flap consisted of the cutaneous component part of this chimeric flap. RESULTS: The flaps survived in 7 of 8 patients. Partial necrosis of the chimeric flap was observed in 1 patient due to venous thrombosis. A split-thickness skin graft then was performed to achieve wound closure on that patient. Motor and sensory functions of these 8 patients improved gradually within the first-year follow-up. CONCLUSIONS: The laparoscopy assisted chimeric peritoneal-DIEP flap is useful for reconstructing defects of the hand and foot with exposed tendons. PMID- 29481329 TI - Topical Nystatin Treatment for Candida Infection Following Wound Reconstruction. AB - INTRODUCTION: Wound infection is an important cause of nonhealing wounds and graft rejection. OBJECTIVE: A series of 5 patients (4 females, 1 male; median age, 50; age range, 1.5-83 years) with nosocomial Candida infection of burns and chronic wounds that were reconstructed with split-thickness skin grafts is presented. MATERIALS AND METHODS: This case series was carried out between February 2011 and June 2014. Based on tissue cultures, wounds were treated with 100 000 units/mL of nystatin and 25 mg in 500 cc normal saline of mafenide acetate, which resulted in regression of wound infection symptoms and improvement of skin graft take. CONCLUSIONS: The authors propose this simple, nontoxic, and economic topical treatment for wounds and skin grafts with positive Candida cultures. PMID- 29481330 TI - Total Contact Cast Use in Patients With Peripheral Arterial Disease: A Case Series and Systematic Review. AB - INTRODUCTION: As the majority of diabetic foot ulcerations (DFUs) occur on the plantar foot, excessive pressure is a major contributing factor to delayed healing. The gold standard for offloading is the total contact cast (TCC); yet, TCC use is contraindicated in patients with ischemia. Lower extremity ischemia typically presents in the more severe end stages of peripheral arterial disease (PAD). As PAD exists on a severity spectrum from mild to severe, designation of a clear cutoff where TCC use is an absolute contraindication would assist those who treat DFUs on a daily basis. OBJECTIVE: The aim of this study is to determine if a potential cutoff value for PAD where TCC use would be an absolute contraindication could be ascertained from a retrospective case series and a systematic literature review of patients with PAD in which treatment included TCC use. MATERIALS AND METHODS: A retrospective cases series and systematic review of patients with mild to moderate PAD treated with a TCC was performed. All reports of TCC use in patients with PAD and a neuropathic ulceration that included results of noninvasive vascular studies were included. RESULTS: Results suggested that TCC use is a viable treatment modality for pressure-related DFUs in patients with an ankle pressure >= 80 mm Hg, a toe pressure >= 74 mm Hg, an ankle-brachial index >= 0.55, or a toe-brachial index >= 0.55. CONCLUSIONS: Vascular evaluation, individual risk/benefit analysis, close follow-up, and patient education are essential components of TCC use in these patients. Repeat vascular evaluation is recommended if the wound fails to progress towards resolution with TCC use. PMID- 29481332 TI - Cost-minimization Analysis of Negative Pressure Wound Therapy in Long-term Care Facilities. AB - OBJECTIVE: This study aims to conduct a cost-minimization analysis comparing wound treatment costs between single-use negative pressure wound therapy (sNPWT) and traditional negative pressure wound therapy (tNPWT). MATERIALS AND METHODS: Assuming comparable outcomes, cost data obtained from the ECRI Institute were compared between the 2 NPWT options using data extracted from an electronic wound management program between August 2010 and March 2016. RESULTS: Use of sNPWT versus tNPWT resulted in daily and total treatment duration cost savings of $55 and $1586, respectively. CONCLUSIONS: Long-term care facilities can potentially accrue significant cost savings by using sNPWT instead of tNPWT on a majority of eligible wounds. PMID- 29481333 TI - Pyoderma Gangrenosum of the Scalp: A Rare Clinical Variant. AB - Pyoderma gangrenosum (PG) is a rare, neutrophil-predominant dermatosis that usually presents as a papule or pustule and progresses into a painful ulcer. Clinical and histopathological features are nonspecific, making PG a challenging condition to diagnose. Lesions may occur anywhere on the body; however, the lower extremity is the most common location. Solitary lesions in atypical locations such as the scalp are uncommon, making this clinical variant especially difficult to recognize and diagnose. Although the clinical features and subsequent management of scalp PG might be different from other anatomic sites, the typical presentation and treatment of scalp PG is still unclear. The authors present a recent case of a 34-year-old woman with scalp PG and summarize 16 other cases documented in the literature. This case report and literature review illustrate several similarities and differences between scalp PG and classic PG: (1) scalp PG occurs in a wider age demographic of patients; (2) as with classic PG, inflammatory bowel disease and pregnancy are associated conditions, but head injury and preexisting inflammatory skin conditions of the scalp may be additional predisposing factors for scalp PG; and (3) as with classic PG, scalp PG generally responds well to corticosteroids and immunosuppressive therapy. Scarring occurs in all conditions, though disfigurement and psychosomatic effects may be disproportionately higher in scalp PG. PMID- 29481334 TI - Martorell Hypertensive Ischemic Ulcer Successfully Treated With Punch Skin Grafting. AB - Martorell hypertensive ischemic ulcer can be a real clinical and therapeutic challenge. Controversy exists regarding both the underlying triggers of the disease and the type of treatment that should be established. Early skin grafting has been suggested as an effective treatment to enhance pain reduction and wound healing in these patients. The authors present the case of a 68-year-old woman with well-controlled hypertension and diabetes who developed extremely painful, rapidly progressing bilateral ulcers on the distal aspect of her legs. Without previous surgical debridement, the lesions were covered with punch grafts. Pain and necrotic progression were immediately controlled and complete epithelialization was achieved in 7 weeks. PMID- 29481335 TI - Efficacy of a Nanofabricated Electrospun Wound Matrix in Treating Full-thickness Cutaneous Wounds in a Porcine Model. AB - OBJECTIVE: This study aims to evaluate the comparative performance of a resorbable nanofiber wound matrix (Restrata Wound Matrix; Acera Surgical Inc, St Louis, MO) and a bilayered collagen xenograft (Integra Bilayer Matrix Wound Dressing; Integra, Plainsboro, NJ) in healing critical full-thickness cutaneous wounds in a preclinical porcine model. MATERIALS AND METHODS: Full-thickness cutaneous wounds were created in Yucatan miniature swine and treated with either the nanofiber wound matrix or xenograft. Wound area was measured and inflammation and healing were assessed until euthanasia at day 15 or 30, at which time tissue samples were harvested for histopathology. RESULTS: Wounds treated with the nanofiber wound matrix demonstrated significantly faster wound areal reduction, less inflammation, greater neovascularization, more collagen maturation, and superior quality of healing compared with wounds treated with the xenograft. CONCLUSIONS: The nanofiber wound matrix is an effective wound healing material that may offer a unique alternative in the treatment of challenging refractory wounds. PMID- 29481336 TI - Reply to Comment on 'Nanoscale mapping of optical band gaps using monochromated electron energy loss spectroscopy' by Zhan, Granerod, Venkatachalapathy, Johansen, Jensen, Kuznetsov and Prytz in Nanotechnology 28 (2017) 105703. AB - We respond to the comment by Thomas Walther and reaffirm the findings of our original article. PMID- 29481337 TI - Metformin for lung cancer prevention and improved survival: a novel approach. AB - Diabetes mellitus has been associated with increased risk for the development of many types of cancer. Metformin, an oral medication and first-line treatment for type 2 diabetes mellitus, has been suggested to reduce cancer risk and mortality in various types of cancer. This study focuses on assessing metformin association with lung cancer as reported in the literature. Recent studies and reviews investigating metformin effects on lung cancer incidence and patient survival are critically and systematically discussed. PMID- 29481339 TI - MEETING REPORTER. PMID- 29481338 TI - Optimal colonoscopy surveillance interval period for the adenoma patients who had an adequate polypectomy at baseline colonoscopy. AB - The role of surveillance colonoscopy has long been established: it reduces both the incidence and the mortality of colorectal cancer. We aimed to assess the optimal colonoscopy surveillance interval period for the adenoma patients who underwent an adequate polypectomy at baseline colonoscopy to avoid overuse or underuse of colonoscopy. A retrospective study was carried out on the baseline adenoma patients who had had at least two completed colonoscopy examinations during the years 2000-2013 in the Digestive Endoscopy Center of the First Affiliated Hospital of Kunming Medical University. All the patients had a complete polypectomy of adenomas at baseline. Data on the patients' demographics and colorectal findings were extracted from a specially designed colonoscopy database. The end point was the finding of adenoma during the subsequent surveillance colonoscopy; an analysis was carried out to identify recurrence factors and the optimal colonoscopy surveillance interval period. A total of 765 (463 men, 302 women, average age 56.51+/-11.95) eligible patients were included in the study. Three hundred and twelve patients had adenoma and 453 had no adenoma after surveillance colonoscopies (the frequency of repeat colonoscopy is 1-10, average 1.73+/-1.24). The diameter of adenomas found on the follow-up colonoscopy was 0.2-3.0 cm (average 0.54+/-0.30 cm). The number of adenomas was 1 11 (2.21+/-1.53) and the surveillance adenoma interval period was 0.5-13 years (2.64+/-2.36 years). A total of 576 patients had baseline nonadvanced adenomas. Male sex, age older than 50 years, and more than two different intestine segment adenomas were the risk factors for recurrence. The optimal colonoscopy surveillance interval period is 2.85 years (95% confidence interval: 2.53-3.17) according to the recurrence rate of 5% adenomas. One hundred and eighty-nine patients had baseline advanced adenomas. Male sex, diameter of adenomas less than 1.0 cm, and adenomas in the right colon or the whole colon were the risk factors for recurrence. The optimal colonoscopy surveillance interval period is 2.06 years (95% confidence interval: 1.71-2.45) according to the recurrence rate of 5% adenomas. The optimal colonoscopy surveillance interval period is 3 years or so for the adenoma patients who had an adequate polypectomy at baseline colonoscopy. Male sex, age older than 50 years, less than 1.0 cm adenomas diameter and the right colon, or multisegment intestine adenomas were the risk factors for recurrence. This has significance for guiding the follow-up colonoscopy interval time of the patients with intestine adenomas. PMID- 29481340 TI - Impact of Cervical Sagittal Alignment on Axial Neck Pain and Health-related Quality of Life After Cervical Laminoplasty in Patients With Cervical Spondylotic Myelopathy or Ossification of the Posterior Longitudinal Ligament: A Prospective Comparative Study. AB - STUDY DESIGN: This is prospective observational study. OBJECTIVE: To prospectively investigate the correlation among axial neck pain; a newly developed patient-based quality of life outcome measure, the Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ); and cervical sagittal alignment after open-door laminoplasty for cervical myelopathy. SUMMARY OF BACKGROUND DATA: Many studies have focused on postoperative axial neck pain after laminoplasty. However, the correlation among cervical sagittal alignment, neck pain, and JOACMEQ has not been investigated. MATERIALS AND METHODS: In total, 57 consecutive patients treated by open-door laminoplasty for cervical myelopathy were included (mean age, 63.7 y; 15 women and 42 men) and divided into 2 groups according to diagnosis [cervical spondylotic myelopathy (CSM) group: 35 patients, and ossification of the posterior longitudinal ligament (OPLL) group: 22 patients]. JOA score, a subdomain of cervical spine function (CSF) in the JOACMEQ, and the visual analog scale for axial neck pain were assessed preoperatively and 12 months postoperatively. Radiographic cervical sagittal parameters were measured by C2 sagittal vertical axis (C2 SVA), C2-C7 lordosis, C7 sagittal slope (C7 slope), and range of motion. RESULTS: C2 SVA values in both groups shifted slightly anteriorly between preoperative and 12-month postoperative measurements (CSM: +19.7+/-10.9 mm; OPLL: +22.1+/-13.4 mm vs. CSM: +23.2+/-16.1 mm; OPLL: +28.7+/-15.4 mm, respectively). Postoperative axial neck pain in the OPLL group showed strong negative correlations with C2 SVA and C7 slope. Strong negative correlations were found between axial neck pain and CSF in both the preoperative CSM and OPLL groups (CSM: r=-0.45, P=0.01; OPLL: r=-0.61, P<0.01) and between axial neck pain and CSF in the postoperative OPLL group (r= 0.51, P=0.05). CONCLUSIONS: This study demonstrated a significant negative correlation between neck pain and CSF in both the CSM and OPLL groups preoperatively and in the OPLL group postoperatively. Radiographic cervical sagittal alignment did not significantly correlate with preoperative or postoperative axial neck pain. PMID- 29481341 TI - Is Physician Empathy Associated With Differences in Pain and Functional Limitations After a Hand Surgeon Visit? AB - BACKGROUND: In prior work we demonstrated that patient-rated physician empathy was the strongest driver of patient satisfaction after a visit to an orthopaedic hand surgeon. Data from the primary care setting suggest a positive association between physician empathy and clinical outcomes, including symptoms of the common cold. It is possible that an empathic encounter could make immediate and measureable changes in a patient's mindset, symptoms, and functional limitations. QUESTIONS/PURPOSES: (1) Comparing patients who rated their physicians as perfectly empathic with those who did not, is there a difference in pre- to postvisit change in Patient Reported Outcome Measurement Information System (PROMIS) Upper Extremity Function scores? (2) Do patients who gave their physicians perfectly empathic ratings have a greater decrease in pre- to postvisit change in Pain Intensity, PROMIS Pain Interference, and PROMIS Depression scores? METHODS: Between September 2015 and February 2016, based on the clinic patient flow, 134 new patients were asked to participate in this study. Eight patients were in a rush to leave the surgeon's office, which left us with a final cohort of 126 patients. Directly before and directly after the appointment with their physician, patients were asked to complete three PROMIS Computerized Adaptive Tests (CAT; Upper Extremity Function, Pain Interference, and Depression) as well as an ordinal rating of pain intensity. After the visit, participants were asked to rate their physician using the Consultation And Relational Empathy (CARE) measure. Based on prior experience, we dichotomized the CARE score anticipating a substantial skew: 54 patients (43%) rated their physician perfectly empathic. RESULTS: Between patients who rated physicians as perfectly empathic and those who did not, there was no difference in the pre- to postvisit change in PROMIS Upper Extremity Function CAT score (perfect empathy: 0.84 +/- 2.94; less than perfect empathy: -0.23 +/- 3.12; mean difference: 0.23; 95% confidence interval [CI], -0.31 to 0.77; p = 0.054). There was a small decrease in Pain Intensity (perfect empathy: -0.96 +/- 2.08; less than perfect empathy: -0.33 +/- 1.03; mean difference: -0.60; 95% CI, -0.88 to -0.32; p = 0.028). There were no differences in PROMIS Pain Interference score (perfect empathy: -1.33 +/- 2.85; less than perfect empathy: -1.37 +/- 3.12; mean difference: -1.35; 95% CI, -1.88 to -0.83; p = 0.959) or PROMIS Depression scores (perfect empathy: -1.51 +/- 4.02; less than perfect empathy : -1.21 +/- 3.83; mean difference: -1.34; 95% CI, -2.03 to -0.65; p = 0.663). CONCLUSIONS: A single visit with a surgeon rated perfectly empathic is not associated with change in upper extremity-specific limitations or coping mechanisms or a noticeable change in pain scores during the visit, as these differences were below the minimum clinically important difference. Future research should address the influence of empathy on patient-reported outcomes and physician empathy over time in contrast to a single office visit. LEVEL OF EVIDENCE: Level II, prognostic study. PMID- 29481342 TI - Are Psychosocial Factors Associated With Patient-reported Outcome Measures in Patients With Rotator Cuff Tears? A Systematic Review. AB - BACKGROUND: Psychosocial factors are key determinants of health and can influence patient-reported outcomes after rotator cuff tears. However, to our knowledge, a systematic review of published studies has not been conducted to determine the degree of consistency and strength of the relationship between psychosocial factors and patient-reported outcomes in this patient population. QUESTIONS/PURPOSES: (1) Are psychosocial factors associated with patient-reported measures at initial clinical presentation in patients with rotator cuff tears? (2) Are psychosocial factors associated with patient-reported outcomes after treatment in patients with rotator cuff tears? METHODS: A systematic review of cross-sectional and prospective observational studies was performed in MEDLINE/PubMed, EMBASE, CINAHL, PsycINFO, and Web of Science from each database's inception to June 2016. We included studies examining associations between psychosocial factors and patient-reported measures in patients with rotator cuff tears. We excluded studies not reporting on this relationship, involving patients with nonspecific shoulder pain, and written in a language other than English. Two independent reviewers performed the search, extracted information, and assessed methodological quality. Study quality was assessed using the Methodological Items for Non-Randomized Studies (MINORS) criteria. The primary outcomes for the review were associations between each psychosocial factor and patient-reported measures of function or disability, pain, or quality of life. Associations were interpreted based on significance, strength, and direction of the relationship. A total of 10 studies (five cross-sectional and five prospective) in 1410 patients (age range, 46-62 years, 60% [571 of 958] men) were included in the review. Pooling of results for meta-analyses was not possible as a result of study heterogeneity. RESULTS: Weak to moderate cross-sectional associations were found for emotional or mental health with function or disability and pain in multiple studies. Lower emotional or mental health function was associated with greater pain or disability or lower physical function at initial evaluation. Only one psychosocial factor (patient expectation) was weak to moderately associated with patient-reported outcomes after treatment in more than one study. In the two studies that examined expectations, the higher the expectation of benefit, the greater the perceived benefit after surgical intervention. CONCLUSIONS: At the initial evaluation of patients with rotator cuff tear, there was an association between self-reported function and pain and emotional or mental health. However, these factors were not associated with patient-reported outcomes after intervention. This finding could be attributed to the lack of large prospective studies in this area or complex phenotypes within this patient population. Preoperative patient expectation is an important predictor of patient-reported outcomes in patients after rotator cuff surgery and may be a modifiable target for enhancing recovery. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29481343 TI - Unicompartmental Knee Arthroplasty Revision to TKA: Are Tibial Stems and Augments Associated With Improved Survivorship? AB - BACKGROUND: Some surgeons contend that unicompartmental knee arthroplasty (UKA) can easily be revised to a TKA when revision is called for, whereas others believe that this can be complex and technically demanding. There has been little research regarding the efficacy or rationale of using metal augmentation and tibial stem extensions when revising a UKA to a TKA. QUESTION/PURPOSES: (1) Is the use of stem extensions for the tibial component associated with increased survival when revising a UKA to a TKA? (2) Is the addition of modular augments associated with increased survival compared with stem extensions alone? (3) Is TKA design (minimally stabilized versus posterior-stabilized) or (4) tibial fixation (cemented versus cementless) associated with differences in survivorship? METHODS: Data from the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) were used to analyze implant survival after revision of a UKA to a TKA, comparing results in which tibial components were used with and without modular components. The groups analyzed were TKA without a stem extension, those in which a tibial stem extension was used, and those in which a tibial stem extension was used together with an augment. There were 4438 revisions of UKAs to TKAs available for analysis. The mean duration of followup of patients having the TKA revisions was 5 years (SD, 3.5 years). There were 2901 (65%) procedures in which a tibial stem extension was not used, 870 (20%) procedures with a tibial stem extension, and 667 (15%) with a tibial stem extension and metallic augment. Kaplan-Meier estimates of survivorship were calculated and hazard ratios (HRs) from Cox proportional hazard models, adjusting for age and sex, were used to compare the rate of revision among groups. The overall 10-year cumulative percent revision (CPR) for UKA revised to a TKA was 16%. RESULTS: At 10 years, the CPR was increased when a stem extension was not used (19%; 95% confidence interval [CI],16.5-20.7 without a stem extension compared with 13%; 95% CI, 9.2-17.0 with a stem extension; entire period HR, 1.44; 95% CI, 1.10-1.89; p = 0.007). There was no difference in the 10-year CPR when an augment was used together with a stem extension compared with a stem extension alone (HR, 1.26; 95% CI, 0.85-1.86; p = 0.251). When minimally stabilized and posterior-stabilized TKAs were compared, there was no difference in survivorship. Minimally stabilized TKA designs without stem extensions showed higher CPR compared with when stem extensions were used (HR, 1.77; 95% CI, 1.16 2.70; p = 0.007), whereas posterior-stabilized designs without stem extensions showed higher CPR only when compared with when stem extensions and augments were both used (HR, 2.16; 95% CI, 1.24-3.77; p = 0.006). Cementless fixation of the tibial component resulted in a higher CPR than when cement was used (HR, 1.36; 95% CI 1.08-1.71; p = 0.008). CONCLUSIONS: In this registry study, the risk of repeat revision after revision of a UKA to a TKA was lower when a tibial stem extension was used, but no such difference was found with respect to augments. Our study did not account for the degree of bone loss or surgeon preference when considering stems and augments. Further research to establish the degree of bone loss associated with UKA to TKA revision procedures will help clarify these findings. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29481344 TI - Micrometastatic Drug Screening Platform Shows Heterogeneous Response to MAP Chemotherapy in Osteosarcoma Cell Lines. AB - BACKGROUND: Approximately 80% of patients with osteosarcoma harbor subclinical pulmonary micrometastases at diagnosis. Conventional chemotherapy includes methotrexate, doxorubicin, and cisplatin (MAP); however, this regimen and thus overall survival (60%-70%) have remained largely unchanged for 30 years. It therefore is necessary to identify novel therapeutics targeting the metastatic progression of osteosarcoma. QUESTIONS/PURPOSES: This laboratory study explored application of osteosarcoma spheroids (sarcospheres) for drug screening with the following purposes: (1) to characterize sarcosphere size; (2) to establish accurate measurement of sarcosphere growth; (3) to confirm sarcosphere uniformity; and (4) to apply the platform to evaluate MAP chemotherapy. METHODS: Sarcospheres were first characterized to establish accurate measurement of sarcosphere growth and uniform production. The refined platform then was applied to evaluate MAP chemotherapy to validate its use in drug screening. Sarcospheres were generated from highly metastatic human cell lines (143B, MG-63.3, and LM7) by centrifugation to form three-dimensional aggregates modeling micrometastases. Sarcospheres were matured for 24 hours and then incubated with or without drug from Days 0 to 2. Size was assessed by diameter and volume using brightfield microscopy. Growth was measured by volume and resazurin reduction in viable cells. Sarcosphere uniformity was assessed by diameter and resazurin reduction at Day 0 and the Z' factor, a measure of assay suitability for high-throughput screening, was calculated at Day 2. Sarcospheres were treated with individual MAP agents (0 to 1000 MUmol/L) to determine concentrations at which 50% of growth from Days 0 to 2 was inhibited (GIC50). Cell lines resistant to MAP in sarcospheres were treated in monolayer for comparison. RESULTS: Sarcosphere diameter and growth from Days 0 to 2 were quantitatively dependent on the number of cells seeded and the cell line used. Accurate measurement of growth occurred after resazurin incubation for 6 hours, without EDTA-mediated permeabilization, and was correlated with the number of cells seeded and sarcosphere volume for 143B (Spearman's r: 0.98; p < 0.001), MG-63.3 (0.99; p < 0.001), and LM7 (0.98; p < 0.001). Sarcospheres met established criteria for screening applications as mean Z' factors were greater than 0.5 for all cell lines. Response to MAP therapy was cell line-dependent, because MG-63.3 and LM7 sarcospheres exhibited greater than 2000-fold resistance to methotrexate (GIC50 = 88 +/- 36 MUmol/L and 174 +/- 16 MUmol/L, respectively) compared with the 143B cell line (GIC50 = 0.04 +/- 0.01 MUmol/L; p < 0.001 for MG-63.3 and LM7). MG-63.3 monolayers were more sensitive to methotrexate (GIC50 = 0.01 +/- 0.01 MUmol/L; p < 0.001) than MG-63.3 sarcospheres, whereas LM7 monolayers remained chemoresistent (GIC50 not reached). CONCLUSIONS: This study developed and validated a drug screening platform for progression of osteosarcoma micrometastases. It also highlights heterogeneity among osteosarcoma cell lines. These findings appear to reflect known patient-to patient heterogeneity and underscore the importance of evaluating multiple tumor models when testing drugs for the treatment of osteosarcoma. CLINICAL RELEVANCE: The described approach is a promising starting point for drug screening in osteosarcoma because it is tailored to evaluate micrometastatic disease. A reliable and rapid method to identify novel therapeutics is critical to improve stagnant outcomes for patients with osteosarcoma. PMID- 29481345 TI - Morphologic Features of the Contralateral Femur in Patients With Unilateral Slipped Capital Femoral Epiphysis Resembles Mild Slip Deformity: A Matched Cohort Study. AB - BACKGROUND: Hip osteoarthritis has been reported in the contralateral hip in patients who had been treated for unilateral slipped capital femoral epiphysis (SCFE) during adolescence. Although this might be related to the presence of a mild deformity, the morphologic features of the contralateral hip in unilateral SCFE remains poorly characterized. QUESTIONS/PURPOSES: Do measurements of (1) femoral head-neck concavity (alpha angle and femoral head-neck offset), (2) epiphyseal extension into the metaphysis (epiphyseal extension ratio and epiphyseal angle), and (3) posterior tilt of the epiphysis (epiphyseal tilt angle) differ between the contralateral asymptomatic hips of patients treated for unilateral SCFE and hips of an age- and sex-matched control population without a history of hip disease? METHODS: From January 2005 to May 2015, 442 patients underwent surgical treatment for SCFE at our institution. Patients were included in this study if they had a pelvic CT scan and unilateral SCFE defined by pain or a limp in one hip without symptoms or obligatory external rotation with flexion in the contralateral hip and no evidence of SCFE findings on available radiographs. Seventy-two (16%) patients had a pelvic CT scan; however, 32 patients with bilateral involvement and one patient with CT imaging of inadequate quality for multiplanar reformatting were excluded. Thirty-nine control subjects were identified from a preexisting database of patients who underwent pelvic CT between January 2008 and January 2014 for assessment of abdominal pain in the setting of suspected appendicitis. Patients in the contralateral asymptomatic hip group then were matched to control subjects using a modified nearest-neighbor approach based on sex and age. Patients in the contralateral asymptomatic hip group were separated in males and females and control subjects were assigned to an appropriate sex category. Then subjects closest in age were matched with each patient. If more than one subject was available as a match for a given patient, the control subject with the closest BMI was selected. The contralateral asymptomatic hip and matched groups had 19 (49%) male patients and 20 (51%) female patients, with mean ages (+/- SD) of 16 (+/- 3) years and 16 (+/- 3) years, respectively (p = 0.16). Matched subjects had a mean BMI of 25 +/- 4 kg/m and the mean BMI difference among groups was 5 +/- 5 kg/m (p < 0.001). According to the Southwick radiographic criteria nine patients (23%) had a mild slip, 10 (26%) had a moderate slip, and 19 (49%) had severe SCFE. The alpha angle and femoral head-neck offset, epiphyseal extension ratio and epiphyseal angle, and epiphyseal tilt were assessed in the anterior, anterosuperior, and superior femoral planes on radially reformatted CT by one observer not involved in clinical care of the patients. Inter- and intrarater reliability were determined on 10 randomly selected hips assessed by the same observer and another observer and it was found to be excellent for all femoral measurements (intraclass correlation coefficients > 0.85). Paired t-tests were used to compare the contralateral asymptomatic hip of patients with SCFE and control hips. RESULTS: The head-neck junction showed decreased concavity in the contralateral femur of patients with unilateral SCFE compared with control subjects as assessed by slightly higher mean alpha angle in the anterosuperior plane (51 degrees +/- 6 degrees versus 48 degrees +/- 7 degrees ; mean difference, 2 degrees , 95% CI, 0 degrees -5 degrees ; p = 0.04) and slightly higher median alpha angle in the superior plane (45 degrees [range 37 degrees -72 degrees ] versus 42 degrees [range, 36 degrees -50 degrees ], median shift, 4 degrees [range, 2 degrees -5 degrees ], p < 0.001), and slightly lower head-neck offset (anterosuperior: 5 mm +/- 2 mm versus 6 mm +/- 2 mm, mean difference, -1mm [range, -1 mm to 0 mm], p = 0.009; superior: median, 6 mm [range, 1 mm-8 mm] versus 7 mm [range, 5 mm-9 mm]; median shift, -1 mm [range, -1 mm to 0 mm], p < 0.001). There was less epiphyseal extension in the anterosuperior plane as evidenced by lower epiphyseal extension ratio (72% +/- 6% versus 75% +/- 6%; p = 0.005) and higher epiphyseal angle (64 degrees +/- 7 degrees versus 60 degrees +/- 7 degrees ; p = 0.003). The epiphysis was slightly more posteriorly tilted (anterior plane tilt: 8 degrees +/- 6 degrees versus 5 degrees +/- 4 degrees ; p = 0.03) and more vertically oriented (superior plane tilt 11 degrees +/- 5 degrees versus 14 degrees +/- 4 degrees ; p = 0.006) in the contralateral asymptomatic hip of patients with SCFE. CONCLUSIONS: The contralateral femur in patients treated for unilateral SCFE shows decreased concavity of the head-neck junction assessed by a higher alpha angle and reduced head-neck offset compared with age- and sex-matched control subjects. Because we noted lower epiphyseal extension but a more posteriorly tilted epiphysis, the reduced concavity resembles a mild slip deformity rather than an idiopathic cam morphologic feature. CLINICAL RELEVANCE: Although we noted a difference in the morphologic features of the head-neck junction between the two groups, the clinical significance is unclear because most differences were rather small. However, our findings suggest that the uninvolved hip in patients with unilateral SCFE may have a subtle asymptomatic cam morphologic feature that may be identified only with advanced imaging (CT or MRI). Future studies should investigate whether these morphologic changes influence development of contralateral SCFE or symptomatic femoroacetabular impingement in the contralateral hip of patients with unilateral SCFE and establish thresholds for indication of prophylactic fixation to avoid further slip and worsening of the morphologic features of the cam-femoroacetabular impingement. PMID- 29481346 TI - Do Stem Design and Surgical Approach Influence Early Aseptic Loosening in Cementless THA? AB - BACKGROUND: Some studies have revealed an increased risk of early aseptic loosening of cementless stems in THA when inserted through an anterior or anterolateral approach compared with a posterior approach, whereas approach does not appear to be a risk factor in others. Stem design, whether "anatomic" (that is, stems with a curved lateral profile or an obtuse angle at the proximal lateral portion of the stem) or "shoulder" (that is, straight with a proximal shoulder), may also be associated with a differential risk of aseptic loosening in cementless THA depending on the surgical approach used, but if so, this risk is not well characterized. QUESTIONS/PURPOSES: In this national registry study, we investigated the association between surgical approach and early aseptic loosening of (1) cementless femoral stems with a proximal angular shape (shoulder); and (2) anatomically shaped femoral stems. METHODS: The Dutch Arthroplasty Registry is a nationwide population-based register recording data on primary and revision hip arthroplasty. We selected all primary THAs (n = 63,354) with a cementless femoral stem inserted through an anterior, anterolateral, or posterior approach from 2007 to 2013 with a minimal followup of 2 years. Femoral stems were classified as "anatomic," "shoulder," or "other" (that is, not classifiable as anatomic or shoulder). From the 47,372 THAs with an anatomic or shoulder stem (mean followup, 3.5 years; SD, 1.8 years), 340 (0.7%) underwent revision surgery as a result of aseptic loosening of the femoral stem, 1195 (2.5%) were revised for other reasons, and 1558 patients (3.3%) died. We used Cox proportional hazard models to determine hazard ratios for aseptic loosening of anatomic and shoulder stems for the anterolateral and anterior approaches compared with the posterior approach. RESULTS: After controlling for relevant confounding variables such as sex, American Society of Anesthesiologists score, previous surgery, and coating and material of the femoral stem, we found that there was a stem-approach interaction. Separate analysis showed that shoulder stems had a greater likelihood of early aseptic loosening when the anterolateral approach (hazard ratio [HR], 2.28; 95% confidence interval [CI], 1.43-3.63; p < 0.001) or anterior approach (HR, 10.47; 95% CI, 2.55-43.10; p = 0.001) was used compared with the posterior approach. Separate analysis of the anatomic stems yielded no association with approach (anterolateral: HR, 1.07, 95% CI, 0.70-1.63, p = 0.77; anterior: HR, 1.31, 95% CI, 0.91-1.89, p = 0.15). CONCLUSIONS: In THA, cementless femoral stems with a proximal shoulder are associated with early aseptic loosening when inserted through an anterior or anterolateral approach compared with a posterior approach. An anatomically shaped stem may be preferred with these approaches, although further analysis with larger registry volumes should confirm our results, in particular for shouldered stems when implanted through an anterior approach. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29481347 TI - The 2018 Nicholas Andry Award: The Evidence Base for the Treatment of Developmental Dysplasia of the Hip: The Iowa Contribution. AB - This review summarizes evidence developed at the University of Iowa concerning the management and outcomes of developmental dysplasia of the hip beginning with the observations and analyses of Dr Arthur Steindler in the early 1900s. The strong evidence-based practice tradition established by Steindler 100 years ago continues as we critically evaluate our procedures and patient outcomes, only altering approaches when warranted by strong personal and research evidence. Our practice continues to be conservative in that we strive to produce the best environment possible for the hip to develop on its own and operate only when less invasive methods have failed. PMID- 29481348 TI - Is Legg-Calve-Perthes Disease a Local Manifestation of a Systemic Condition? AB - BACKGROUND: Osteochondrosis includes numerous diseases that occur during rapid growth, characterized by disturbances of endochondral ossification. One example, Legg-Calve-Perthes disease, is characterized by disruption of the blood supply to the femoral head epiphysis, and a systemic etiology often has been suggested. If this were the case, secondary osteochondroses at locations other than the hip might be expected to be more common among patients with Legg-Calve-Perthes disease, but to our knowledge, this has not been evaluated in a nationwide sample. QUESTIONS/PURPOSES: (1) Do patients with Legg-Calve-Perthes disease have an increased prevalence of secondary osteochondroses at locations other than the hip? (2) Is the concept of Legg-Calve-Perthes disease a systemic etiology supported by a higher prevalence of the metabolic diseases obesity and hypothyroidism? METHODS: We designed a retrospective population-based cohort study with data derived from the Swedish Patient Registry (SPR). The SPR was established in 1964 and collects information on dates of hospital admission and discharge, registered diagnoses (categorized along the International Classification of Diseases [ICD]), and applied treatments during the entire lifetime of all Swedish citizens with high validity. Analyzing the time span from 1964 to 2011, we identified 3183 patients with an ICD code indicative of Legg Calve-Perthes disease and additionally sampled 10 control individuals per patient with Legg-Calve-Perthes disease, matching for sex, age, and residence, resulting in 31,817 control individuals. The prevalence of secondary osteochondroses, obesity, and hypothyroidism was calculated separately for patients with Legg Calve-Perthes disease and control individuals based on the presence of ICD codes indicative of these conditions. Using logistic regression analysis, we compared the adjusted relative risk of having either of these conditions develop between patients with Legg-Calve-Perthes disease and their matched control subjects. The mean followup was 26.1 years (range, 2.8-65 years). RESULTS: The prevalence of secondary osteochondroses was greater among patients with Legg-Calve-Perthes disease (3.11%) than among control subjects (0.31%), resulting in an increased adjusted risk of an association with such lesions in the patients (relative risk [RR], 10.3; 95% confidence interval [CI], 7.7-13.6; p < 0.001). When stratified by sex, we attained a similarly increased risk ratio for females (RR, 12.5; 95% CI, 6.1-25.8; p < 0.001) as for males (RR, 9.9; 95% CI, 7.3-13.5; p < 0.001). Patients with Legg-Calve-Perthes disease had an increased adjusted risk of an association with obesity (RR, 2.8; 95% CI, 1.9-4.0; p < 0.001) or hypothyroidism (RR, 2.6; 95% CI, 1.7-3.8; p < 0.001) when compared with control subjects. CONCLUSIONS: To our knowledge, this is the first population-based description of a robust association of Legg-Calve-Perthes disease with osteochondroses at locations other than the hip, and we also found increased risk estimates for an association with obesity and hypothyroidism in patients with Legg-Calve-Perthes disease. Our findings strengthen the hypothesis that Legg-Calve-Perthes disease is the local manifestation of a systemic disease, indicative of an underlying common disease pathway that requires further investigation. Physicians should be aware that patients with Legg-Calve-Perthes disease may present with secondary osteochondroses and metabolic comorbidities. LEVEL OF EVIDENCE: Level III, prognostic study. PMID- 29481349 TI - Is NS-EDTA Effective in Clearing Bacteria From Infected Wounds in a Rat Model? AB - BACKGROUND: Irrigation is one of the key procedures in open fracture management to eliminate pathogens and prevent infection. Metal ion deprivation could inhibit bacterial adhesins and weaken adhesion to the host tissue. EDTA in solution can competitively bind to a metal ion and thus might be able to inhibit bacterial adhesins. QUESTIONS/PURPOSES: (1) Is normal saline-EDTA toxic to fibroblasts and endothelial cells? (2) In a contaminated wound rat model, does irrigation with normal saline-EDTA solution decrease the risk of positive bacterial cultures and infection when compared with normal saline and soap solutions? (3) In an infected wound rat model, are fewer surgical debridements and irrigations with normal saline-EDTA solution required to obtain culture-free wounds when compared with normal saline and soap controls? METHODS: Normal saline-EDTA solution refers to 1 mmol/L EDTA dissolved in normal saline (pH adjusted to 7.4). Normal saline and soap solutions acted as controls. The toxicity of these solutions to fibroblasts and endothelial cells was assessed in vitro by Annexin V/propidium iodide staining and flow cytometer counting (a well-established method to quantitatively measure the number of dead cells). We established contaminated and infected wound models (bone-exposed or not) with either Staphylococcus aureus or Escherichia coli in rats to investigate the efficacy of normal saline-EDTA solution (n = 30 for the contaminated model and n = 50 for the infected model). For contaminated wounds, the proportion of positive bacterial cultures and infections was compared after irrigation and debridement among the three groups. For infected wounds, we performed irrigation and debridement every 48 hours until the cultures were negative and compared the number of debridements required to achieve a negative culture with survival analysis. RESULTS: Normal saline-EDTA showed no additional toxicity to fibroblasts and endothelial cells when compared with normal saline (normal saline [97%] versus EDTA [98%] on fibroblasts, p = 0.654; normal saline [97%] versus EDTA [98%] on endothelial cells, p = 0.711). When bone was exposed in the contaminated models, EDTA irrigation resulted in fewer positive bacterial cultures with S aureus (EDTA: 23%, normal saline: 67%, soap: 40%, p = 0.003) and with E coli (EDTA: 27%, normal saline: 57%, soap: 30%, p = 0.032); however, infection risk was only lower with EDTA irrigation (S aureus with EDTA: 10%, normal saline: 33%, soap: 37%, p = 0.039; E coli with EDTA: 3%, normal saline: 27%, soap: 23%, p = 0.038). In the infected wound model, EDTA irrigation resulted in earlier culture-negative wounds (fewer surgical sessions) compared with normal saline and soap solutions (nonbone-exposed wounds infected by S aureus: p = 0.003, infected by E coli: p = 0.001; bone-exposed wounds infected by S aureus: p = 0.012, infected by E coli: p = 0.022). CONCLUSIONS: After in vitro assessment of toxicity and in vivo evaluation of efficacy, we concluded that normal saline EDTA is superior to normal saline and soap solution in our laboratory models. CLINICAL RELEVANCE: The use of normal-saline EDTA as an irrigation solution may reduce the infection rate of wounds. Future studies in large animals and humans might prove our observation in rat models that normal saline-EDTA has an advantage over normal saline as an irrigation solution. PMID- 29481350 TI - Surgeon Personal Protection: An Underappreciated Benefit of Positive-pressure Exhaust Suits. AB - BACKGROUND: Positive-pressure exhaust suits cost more than standard surgical gowns, and recent evidence suggests that they do not decrease infection risk. As a result, some hospitals and surgeons have abandoned positive-pressure exhaust suits in favor of less expensive alternatives. We propose that in addition to their original purpose of decreasing infection rates, positive-pressure exhaust suits may also improve personal protection for the surgeon and assistants, perhaps justifying their added costs. QUESTIONS/PURPOSES: (1) Do positive pressure exhaust suits decrease exposure to particulate matter during TKA? (2) What areas covered by gowning systems are at risk of exposure to particulate matter? METHODS: Three surgical gowning systems were tested: (1) surgical gown, face mask, surgical skull cap, protective eyewear; (2) surgical gown, face mask, surgical protective hood, protective eyewear; and (3) positive-pressure exhaust suit. For each procedure, a cadaver knee was injected intraarticularly and intraosseously with a 5-um fluorescent powder mixed with water (1 g/10 mL). After gowning in the standard sterile fashion, the primary surgeon and two assistants performed two TKAs with each gowning system for a total of six TKAs. After each procedure, three independent observers graded skin exposure of each surgical participant under ultraviolet light using a standardized scale from 0 (no exposure) to 4 (gross exposure). Statistical analysis was performed using Friedman's and Nemenyi tests. The interrater reliability for the independent observers was also calculated. RESULTS: The positive-pressure exhaust suits had less surgeon and assistant exposure compared with other systems (p < 0.001). The median overall exposure grade for each gowning system was 4 for System 1 (range, 3-4), 2.5 for System 2 (range, 2-3), and 0 for System 3 (range, 0-0). In pairwise comparisons between gowning systems, the positive-pressure exhaust suits had less exposure than gowning System 1 (difference of medians: 4, p < 0.001) and gowning System 2 (difference of medians: 2.5, p = 0.038). There was no difference found in exposure between Systems 1 and 2 (difference of medians: 1.5, p = 0.330). When gowning Systems 1 and 2 were removed, particulate matter was found in places that were covered such as the surgeon's beard, lips, inside the nostrils, behind the protective eyewear around the surgeon's eye, and in both eyebrows and eyelashes. CONCLUSIONS: The positive-pressure exhaust suits provided greater personal protection with each procedure than the other two gowning systems. CLINICAL RELEVANCE: With conventional gowns, particulate matter was found in the surgeon's eyelashes, under the face mask around the mouth, and inside the nostrils. Despite recent evidence that certain types of positive-pressure exhaust suits may not decrease infection, there is a clear benefit of surgeon protection from potentially infectious and harmful patient substances. Despite their added costs, hospitals and surgeons should weigh this protective benefit when considering the use of positive-pressure exhaust suits. PMID- 29481352 TI - CORR Insights(r): Perioperative Inpatient Use of Selective Serotonin Reuptake Inhibitors Is Associated With a Reduced Risk of THA and TKA Revision. PMID- 29481351 TI - Value-based Healthcare: A Surgeon Value Scorecard to Improve Value in Total Joint Replacement. PMID- 29481354 TI - CORR Insights(r): Weighing in on Body Mass Index and Infection After Total Joint Arthroplasty: Is There Evidence for a Body Mass Index Threshold? PMID- 29481355 TI - CORR Insights(r): Risk Adjustment Is Necessary in Value-based Outcomes Models for Infected TKA. PMID- 29481353 TI - Letter to the Editor: Editorial: Do Orthopaedic Surgeons Belong on the Sidelines at American Football Games? PMID- 29481356 TI - Reply to the Letter to the Editor: Pearls: The Mobile Segment in Sarcoma Resections. PMID- 29481357 TI - CORR Insights(r): Morphologic Features of the Contralateral Femur in Patients With Unilateral Slipped Capital Femoral Epiphysis Resembles Mild Slip Deformity: A Matched Cohort Study. PMID- 29481358 TI - CORR Insights(r): Are There Age- and Sex-related Differences in Spinal Sagittal Alignment and Balance Among Taiwanese Asymptomatic Adults? PMID- 29481359 TI - Editor's Spotlight/Take 5: Effectiveness of Preoperative Antibiotics in Preventing Surgical Site Infection After Common Soft Tissue Procedures of the Hand. PMID- 29481360 TI - CORR Insights(r): Unicompartmental Knee Arthroplasty Revision to TKA: Are Tibial Stems and Augments Associated With Improved Survivorship? PMID- 29481361 TI - Editorial: Sparse-data Bias-What the Savvy Reader Needs to Know. PMID- 29481362 TI - Letter to the Editor: Obesity Epidemic: Is Its Impact on Total Joint Arthroplasty Underestimated? An Analysis of National Trends. PMID- 29481363 TI - Gendered Innovations in Orthopaedic Science: Burn and Crash. PMID- 29481364 TI - Letter to the Editor: What Influence Does Progression of a Nonhealing Rotator Cuff Tear Have on Shoulder Pain and Function? PMID- 29481365 TI - CORR Insights(r): The 2018 Nicholas Andry Award: The Evidence Base for the Treatment of Developmental Dysplasia of the Hip: The Iowa Contribution. PMID- 29481366 TI - CORR Insights(r): Looking for Holes in Sterile Wrapping: How Accurate Are We? PMID- 29481367 TI - From Bench to Bedside: An Ounce of (Opportunistic) Prevention. PMID- 29481368 TI - Reply to the Letter to the Editor: What Influence Does Progression of a Nonhealing Rotator Cuff Tear Have on Shoulder Pain and Function? PMID- 29481369 TI - The Alliance for Innovation in Maternal Health Care: A Way Forward. AB - The Alliance for Innovation in Maternal Health is a program supported by the Health Services Resource Administration to reduce maternal mortality and severe maternal morbidity in the United States. This program develops bundles of evidence based action steps for birth facilities to adapt. Progress is monitored at the facility, state and national levels to foster data-driven quality improvement efforts. PMID- 29481370 TI - Beta blockers therapy in traumatic brain injury: Is it the time to disclose the brain-cardiac interactions? PMID- 29481371 TI - Spinal Cord Stimulation 50 Years Later: Clinical Outcomes of Spinal Cord Stimulation Based on Randomized Clinical Trials-A Systematic Review. AB - To assess the efficacy of spinal cord stimulation (SCS) for each indication, one must critically assess each specific clinical outcome to identify outcomes that benefit from SCS therapy. To date, a comprehensive review of clinically relevant outcome-specific evidence regarding SCS has not been published. We aimed to assess all randomized controlled trials from the world literature for the purpose of evaluating the clinical outcome-specific efficacy of SCS for the following outcomes: perceived pain relief or change pain score, quality of life, functional status, psychological impact, analgesic medication utilization, patient satisfaction, and health care cost and utilization. Interventions were SCS, without limitation to the type of controls or the type of SCS in the active arms. For each study analyzed, a quality assessment was performed using a validated scale that assesses reporting, external validity, bias, confounding, and power. Each outcome was assessed specific to its indication, and the primary measure of each abovementioned outcome was a summary of the level of evidence. Twenty-one randomized controlled trials were analyzed (7 for trunk and limb pain, inclusive of failed back surgery syndrome; 8 for refractory angina pectoris; 1 for cardiac X syndrome; 3 for critical limb ischemia; 2 for complex regional pain syndrome; and 2 for painful diabetic neuropathy). Evidence assessments for each outcome for each indication were depicted in tabular format. Outcome-specific evidence scores were established for each of the abovementioned indications, providing both physicians and patients with a summary of evidence to assist in choosing the optimal evidence-based intervention. The evidence presented herein has broad applicability as it encompasses a breadth of patient populations, variations of SCS therapy, and comparable controls that, together, reflect comprehensive clinical decision making. PMID- 29481372 TI - Ethical and scientific misconduct: the beginner's experience. PMID- 29481373 TI - Anticholinergic Medications and Cognitive Function in Late Midlife. PMID- 29481374 TI - Can Mathematical Modeling Explain the Measured Magnitude of the Second Gas Effect? AB - BACKGROUND: Recent clinical studies suggest that the magnitude of the second gas effect is considerably greater on arterial blood partial pressures of volatile agents than on end-expired partial pressures, and a significant second gas effect on blood partial pressures of oxygen and volatile agents occurs even at relatively low rates of nitrous oxide uptake. We set out to further investigate the mechanism of this phenomenon with the help of mathematical modeling. METHODS: Log-normal distributions of ventilation and blood flow were generated representing the range of ventilation-perfusion scatter seen in patients during general anesthesia. Mixtures of nominal delivered concentrations of volatile agents (desflurane, isoflurane and diethyl ether) with and without 70% nitrous oxide were mathematically modeled using steady state mass-balance principles, and the magnitude of the second gas effect calculated as an augmentation ratio for the volatile agent, defined as the partial pressure in the presence to that in the absence of nitrous oxide. RESULTS: Increasing the degree of mismatch increased the second gas effect in blood. Simultaneously, the second gas effect decreased in the gas phase. The increase in blood was greatest for the least soluble gas, desflurane, and least for the most soluble gas, diethyl ether, while opposite results applied in the gas phase. CONCLUSIONS: Modeling of ventilation perfusion inhomogeneity confirms that the second gas effect is greater in blood than in expired gas. Gas-based minimum alveolar concentration readings may therefore underestimate the depth of anesthesia during nitrous oxide anesthesia with volatile agents. The effect on minimum alveolar concentration is likely to be most pronounced for the less soluble volatile agents in current use. PMID- 29481375 TI - Etiology of Acute Coronary Syndrome after Noncardiac Surgery. AB - BACKGROUND: The objective of this investigation was to determine the etiology of perioperative acute coronary syndrome with a particular emphasis on thrombosis versus demand ischemia. METHODS: In this retrospective cohort study, adult patients were identified who underwent coronary angiography for acute coronary syndrome within 30 days of noncardiac surgery at a major tertiary hospital between January 2008 and July 2015. Angiograms were independently reviewed by two interventional cardiologists who were blinded to clinical data and outcomes. Acute coronary syndrome was classified as ST-elevation myocardial infarction, non ST-elevation myocardial infarction, or unstable angina; myocardial infarctions were adjudicated as type 1 (plaque rupture), type 2 (demand ischemia), or type 4b (stent thrombosis). RESULTS: Among 215,077 patients screened, 146 patients were identified who developed acute coronary syndrome: 117 were classified as non-ST elevation myocardial infarction (80.1%); 21 (14.4%) were classified as ST elevation myocardial infarction, and 8 (5.5%) were classified as unstable angina. After coronary angiography, most events were adjudicated as demand ischemia (type 2 myocardial infarction, n = 106, 72.6%) compared to acute coronary thrombosis (type 1 myocardial infarction, n = 37, 25.3%) and stent thrombosis (type 4B, n = 3, 2.1%). Absent or only mild, nonobstructive coronary artery disease was found in 39 patients (26.7%). In 14 patients (9.6%), acute coronary syndrome was likely due to stress-induced cardiomyopathy. Aggregate 30-day and 1-yr mortality rates were 7 and 14%, respectively. CONCLUSIONS: The dominant mechanism of perioperative acute coronary syndrome in our cohort was demand ischemia. A subset of patients had no evidence of obstructive coronary artery disease, but findings were consistent with stress-induced cardiomyopathy. PMID- 29481376 TI - Neural Decoding of Robot-Assisted Gait During Rehabilitation After Stroke. AB - OBJECTIVE: Advancements in robot-assisted gait rehabilitation and brain-machine interfaces may enhance stroke physiotherapy by engaging patients while providing information about robot-induced cortical adaptations. We investigate the feasibility of decoding walking from brain activity in stroke survivors during therapy using a powered exoskeleton integrated with an electroencephalography based brain-machine interface. DESIGN: The H2 powered exoskeleton was designed for overground gait training with actuated hip, knee, and ankle joints. It was integrated with active-electrode electroencephalography and evaluated in hemiparetic stroke survivors for 12 sessions per 4 wks. A continuous-time Kalman decoder operating on delta-band electroencephalography was designed to estimate gait kinematics. RESULTS: Five chronic stroke patients completed the study with improvements in walking distance and speed training for 4 wks, correlating with increased offline decoding accuracy. Accuracies of predicted joint angles improved with session and gait speed, suggesting an improved neural representation for gait, and the feasibility to design an electroencephalography based brain-machine interface to monitor brain activity or control a rehabilitative exoskeleton. CONCLUSIONS: The Kalman decoder showed increased accuracies as the longitudinal training intervention progressed in the stroke participants. These results demonstrate the feasibility of studying changes in patterns of neuroelectric cortical activity during poststroke rehabilitation and represent the first step in developing a brain-machine interface for controlling powered exoskeletons. PMID- 29481377 TI - Management of Early Deep Wound Infection After Thoracolumbar Instrumentation: Continuous Irrigation Suction System versus Vacuum-Assisted Closure System. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: The aim of this study was to compare the clinical outcomes of continuous irrigation suction systems (CISS) or vacuum-assisted closure system (VACS) in early deep wound infection (DWI) after thoracolumbar instrumentation. SUMMARY OF BACKGROUND DATA: DWI after thoracolumbar instrumentation is challenging and debridement followed by either CISS or VACS has been proven to be effective. So far, which one of the system has more advantages over the other remains unclear. METHODS: Patients after thoracolumbar instrumentation were evaluated at our spine surgery center from 2005 to 2015. Patients who were diagnosed with early deep DWI after spinal instrumentation and treated by meticulous debridement in the operating room followed by either CISS or VACS were included. Detailed information was obtained from the medical records, including clinical features, results of laboratory examinations, medical therapies, and outcomes. A follow-up was conducted to observe whether recurrent spinal infection or other complications happened. RESULTS: We identified 11 patients in the CISS group and 12 patients in the VACS group. There were no significant differences in terms of age, gender, follow-up duration, symptoms of infection, laboratory examinations, etc. The number of CISS or VACS replacement was 1.3 and 1.6, respectively, before wound healing (P > 0.05). And there were significant differences in terms of hospital stay and extra cost of infection treatment between the two groups. In the follow-up period, we observed sinus tract formation and low back pain in both groups and one patient in the VACS group died of pulmonary infection 4 years after the initial surgery. CONCLUSION: Thorough debridement followed by CISS or VACS are comparable in treating early DWI after thoracolumbar instrumentation. The CISS treatment was statistically significant in comparison to the VACS treatment in terms of hospital stay and cost. LEVEL OF EVIDENCE: 4. PMID- 29481378 TI - Rheumatoid Arthritis Is Associated With an Increased Risk of Postoperative Infection and Revision Surgery in Elderly Patients Undergoing Anterior Cervical Fusion. AB - STUDY DESIGN: Retrospective review. OBJECTIVE: To identify the incidence and analyze the risk of postoperative complications amongst elderly patients with rheumatoid arthritis undergoing anterior cervical fusion. SUMMARY OF BACKGROUND DATA: Previous studies have reported elevated risks of postoperative complications for patients with rheumatoid arthritis undergoing orthopedic procedures. However, little is known about the risk of postoperative complications in rheumatoid arthritis patients after spine surgery. METHODS: A commercially available database was queried for all Medicare patients 65 years of age and older undergoing one- or two-level primary anterior cervical fusion surgeries from 2005 to 2013. Complications, hospitalization costs, and length of stay were queried. Multivariate logistic regression analyses were performed to estimate the odds ratio for each complication adjusted for age, sex, and Charlson Comorbidity Index. RESULTS: A total of 6067 patients with a history of rheumatoid arthritis and 113,187 controls were identified. Significantly higher incidences of major medical complications (7.5% vs. 5.9%, P < 0.001), postoperative infections (2.6% vs. 1.5%, P < 0.001), and revision surgery (1.1% vs. 0.6%, P < 0.001) were observed amongst the rheumatoid arthritis cohort. Significantly greater average cost of hospitalization ($17,622 vs. $12,489, P < 0.001) and average length of stay (3.13 vs. 2.08 days, P < 0.001) were also observed. CONCLUSION: Patients with rheumatoid arthritis undergoing anterior cervical fusion face increased risks of postoperative infection and revision surgery compared to normal controls. This information is valuable for preoperative counseling and risk stratification. LEVEL OF EVIDENCE: 3. PMID- 29481379 TI - Impact of Psychiatric Comorbidities on Short-Term Outcomes Following Intervention for Lumbar Degenerative Disc Disease. AB - STUDY DESIGN: Retrospective, observational cohort study. OBJECTIVE: To investigate the impact of psychiatric diseases on short-term outcomes in patients undergoing fusion surgery for lumbar degenerative disc disease (LDDD). SUMMARY OF BACKGROUND DATA: Limited literature exists on the prevalence and impact of psychiatric comorbidities on outcomes in patients undergoing surgery for LDDD. METHODS: Adult patients (>18 yr) registered in the Nationwide Inpatient Sample database (2002-2011) and undergoing an elective spine fusion for LDDD that met inclusion criteria formed the study population. Defined primary outcome measures were discharge disposition, length of stay, hospitalization cost, and short-term postsurgical complications (neurological, respiratory, cardiac, gastrointestinal, wound complication and infections, venous thromboembolism, and acute renal failure). Multivariable regression techniques were used to explore the association of psychiatric comorbidities on short-term outcomes by adjusting for patient demographics, clinical, and hospital characteristics. RESULTS: Of the 126,044 adult patients undergoing fusion surgery for LDDD (mean age: 54.91 yr, 58% female) approximately 18% had a psychiatric disease. Multivariable regression analysis revealed patients with psychiatric disease undergoing fusion surgery have higher likelihood for unfavorable discharge (odds ratio [OR] 1.41; 95% confidence interval [CI] 1.35-1.47; P < 0.001), length of stay (OR 1.03; 95% CI 1.02-1.04; P < 0001), postsurgery neurologic complications (OR 1.25; 95% CI 1.13 1.37; P < 0.001), venous thromboembolic events (OR 1.38 95% CI 1.26-1.52; P < 0.001), and acute renal failure (OR 1.17; 95% CI 1.01-1.37; P = 0.040). Patients with psychiatric disease were also associated to have higher hospitalization cost (6.3% higher; 95% CI: 5.6%-7.1%; P < 0.001) compared to those without it. CONCLUSION: Our study quantifies the estimates for presence of concomitant psychiatric comorbid conditions on short outcomes in patients undergoing fusions for LDDD. The data provide supporting evidence for adequate preoperative planning and postsurgical care including consultation for mental health for favorable outcomes. LEVEL OF EVIDENCE: 4. PMID- 29481380 TI - Lymphocyte Count at 4 Days Postoperatively: A Reliable Screening Marker for Surgical Site Infection After Posterior Lumbar Decompression Surgery. AB - STUDY DESIGN: Case-control study. OBJECTIVE: To identify laboratory markers for surgical site infection (SSI) in posterior lumbar decompression surgery, which are not affected by operative factors, and to determine the diagnostic cutoffs of these markers. SUMMARY OF BACKGROUND DATA: Numerous laboratory markers are used for the early detection of SSI; however, these markers may be affected by operative factors. METHODS: The study included 182 participants. They were divided into an SSI group (patients who developed deep SSI; n = 8) and a no-SSI group (n = 174). We reviewed data on the C-reactive protein level and total white blood cell count and differential count before posterior lumbar decompression surgery and 1 and 4 days postoperatively. We determined which markers differed significantly between the groups and identified the markers that were not affected by operative factors (operative time, intraoperative blood loss, and number of operative segments) in the no-SSI group. We then determined the diagnostic cutoffs of these unaffected markers using receiver operating characteristic curves. RESULTS: We identified the lymphocyte percentage at 4 days postoperatively (cutoff, <19.4%; sensitivity, 80.0%; specificity, 62.5%; area under the curve, 0.78) and lymphocyte count at 4 days postoperatively (cutoff, <1010/MUL; sensitivity, 93.7%; specificity, 62.5%; area under the curve, 0.78) as reliable markers. CONCLUSION: Lymphocyte percentage and count at 4 days postoperatively are reliable markers for SSI after posterior lumbar decompression surgery. Lymphocyte count at 4 days postoperatively can be considered as a superior marker for screening because it has a high sensitivity and can be measured early. LEVEL OF EVIDENCE: 4. PMID- 29481381 TI - Diffuse Idiopathic Skeletal Hyperostosis Extended to the Lumbar Segment Is a Risk Factor of Reoperation in Patients Treated Surgically for Lumbar Stenosis. AB - STUDY DESIGN: Retrospective longitudinal cohort study. OBJECTIVE: To investigate the association between diffuse idiopathic skeletal hyperostosis (DISH) and reoperation in patients treated surgically for lumbar spinal stenosis (LSS) in long-term results. SUMMARY OF BACKGROUND DATA: Few studies have evaluated DISH as a potential risk factor of poor surgical results for LSS. METHODS: This study included 1063 responders to a postoperative postal survey out of 2363 consecutive patients who underwent surgery for LSS between 2002 and 2010. The survey included questions about reoperations performed at another hospital and the patient reported outcomes. DISH was evaluated by preoperative standing whole-spine radiographs. We investigated DISH as a predictor of reoperation and characteristics of poor outcomes in patients with DISH. We also assessed selection bias by examining the differences between responders and nonresponders to a postal survey. RESULTS: Reoperations were performed in a total of 115 patients (10.8%) within an average of 8.6 years after the initial surgeries. Patients who only had DISH were not associated with reoperation; however, reoperations were performed significantly more often in patients with DISH extended to the lumbar segment (L-DISH) than in patients without (22% and 7.3%, respectively; P < 0.001). Cox analysis showed that L-DISH was one of the significant independent predictors for reoperation (hazard ratio 2.05, P = 0.009). Surgery-free survival was significantly shorter in patients with L-DISH than in those without (P = 0.005). The cause of reoperation did not differ between the patients with and without L-DISH. Several factors, but not L-DISH, were significantly associated with responders to the survey. CONCLUSION: L-DISH was independently associated with reoperation for LSS. The decreased number of lumbar mobile segments due to L-DISH might lead to unfavorable outcomes. Careful follow-up of patients is needed after surgery for LSS with L-DISH. LEVEL OF EVIDENCE: 3. PMID- 29481382 TI - Impact of Frailty and Comorbidities on Surgical Outcomes and Complications in Adult Spinal Disorders. AB - STUDY DESIGN: Retrospective review of surgically treated 481 adult patients with spinal disorders. OBJECTIVE: The aim of this study was to elucidate the effect of frailty and comorbidities on postoperative health-related quality of life (HRQoL) and complication rates. SUMMARY OF BACKGROUND DATA: Elective surgeries for spinal disorders not only improve clinical outcomes but also have high complication rates. METHODS: We retrospectively reviewed the results of consecutive elective spine surgeries for 156 adult spinal deformities (ASDs: 65 +/- 9 years), 152 degenerative spondylolisthesis (DS: 64 +/- 10 years), or 173 lumbar spinal canal stenosis (LSCS: 71 +/- 9 years) with follow-up of at least 2 years. Modified Frailty Index (mFI) and Charlson Comorbidity Index (CCI) were determined from baseline demographics. We compared the prevalence and the influence of mFI and CCI on postoperative outcomes and complication rates. RESULTS: The mFI and CCI were significantly worse in ASD than in others (mFI: ASD 0.09 +/- 0.12, DS 0.06 +/- 0.06, LSCS 0.04 +/- 0.05, P < 0.01. CCI: ASD 2.1 +/- 1.6, DS 1.4 +/- 0.7, LSCS 1.6 +/- 0.9, P < 0.01). Postoperative HRQoL deteriorated as mFI worsened in ASD (nofrail: Oswestry Disability Index [ODI] 26 +/- 11, Scoliosis Research Society Questionnaire [SRS] 3.7 +/- 0.7; prefrail: ODI 32 +/- 12, SRS 3.6 +/- 0.6; frail: ODI 42 +/- 15, SRS 3.2 +/- 0.7). In DS and LSCS, however, SF-36 physical component score and mental component score improved regardless of mFI and CCI. The 2-year major complications rate increased with frailty (36%, 58%, and 81%) in ASD, but not in others. CONCLUSION: ASDs were more frail and had more comorbidities than the other populations. In ASD, postsurgical outcomes and complication rates deteriorated as frailty and CCI increased, whereas surgery produced favorable outcomes and acceptable complication rates in DS and LSCS regardless of frailty and CCI. Careful patient selection and treatment of comorbidities before surgery may decrease complications and improve outcomes for the surgical treatment of ASD. LEVEL OF EVIDENCE: 4. PMID- 29481383 TI - Pylera and sequential therapy for first-line Helicobacter pylori eradication: a culture-based study in real clinical practice. AB - BACKGROUND AND AIMS: Italian guideline suggests 10-day sequential or bismuth based quadruple therapies for first-line Helicobacter pylori treatment. Comparison between these regimens is lacking. We assessed the efficacy of these therapies in clinical practice and evaluated the role of primary bacterial resistance toward clarithromycin and metronidazole. PATIENTS AND METHODS: Consecutive patients with H. pylori infection were enrolled. Bacterial culture with antibiotics susceptibility testing was attempted in all cases. Patients received either a sequential therapy with esomeprazole 40 mg for 10 days plus amoxicillin 1000 mg for the first 5 days followed by clarithromycin 500 mg and tinidazole 500 mg (all twice daily) for the remaining 5 days, or bismuth-based therapy with esomeprazole 20 mg twice daily and Pylera 3 tablets four times daily for 10 days. H. pylori eradication was assessed by using C-urea breath test. RESULTS: A total of 495 patients were enrolled. Following sequential (250 patients) and quadruple (245 patients) therapies, the eradication rate were 92 and 91%, respectively, at intention-to-treat analysis and 96 and 97%, respectively, at per protocol analysis. Overall, the pattern of bacterial resistance did not significantly affect the cure rate, but the presence of clarithromycin and metronidazole dual resistance tended to reduce the success rate of both sequential (84.8 vs. 90.1%; P=0.4) and quadruple (85 vs. 94.1%; P=0.06) therapies. Adverse events occurred more frequently with the quadruple than with sequential therapy (56.9 vs. 25.8%; P<0.001). CONCLUSION: In our country, sequential and bismuth-based quadruple therapy achieved similarly high eradication rates as first-line treatments for H. pylori infection in clinical practice. PMID- 29481384 TI - The safety and efficacy of ledipasvir/sofosbuvir with or without ribavirin in the treatment of orthotopic liver transplant recipients with recurrent hepatitis C: real-world data. AB - BACKGROUND: Recurrent hepatitis C (RHC) in orthotopic liver transplantation (OLT) population is associated with accelerated rates of fibrosis, low efficacy and decreased tolerability with traditional therapies. AIM: The aim of this study was to evaluate the safety and efficacy of ledipasvir/sofosbuvir (LED/SOF) with or without ribavirin (RBV) in OLT patients with RHC. PATIENTS AND METHODS: Patients at least 3 months post-OLT and with documented RHC were treated with LED/SOF with or without RBV for either 12 or 24 weeks. End-of-treatment and sustained virological response 12 weeks after the completion of treatment were documented. Patients were closely monitored for treatment-related adverse effects and the potential need for adjustment in their immunosuppression. RESULTS: Seventy-one patients were included in the study. Median age was 62 years. Median time from OLT was 55 months. Twenty-six (36.6%) patients were treatment-naive and 45 (63.4%) had previously failed interferon-based therapies. The majority of patients (57.7%) had stage F0-F2 fibrosis. Sixty-seven (94.3%) patients completed 12 weeks of LED/SOF with RBV, three patients completed 12 or 24 weeks of LED/SOF without RBV, and one patient completed only 8 weeks of LED/SOF without RBV owing to severe allograft dysfunction. Sustained virological response was near universal in our cohort (98.5%) regardless of genotype, fibrosis stage, and regimen or treatment duration. Most commonly reported side effects were malaise and gastrointestinal upset. No patient required adjustment in immunosuppression and no episodes of rejection were documented during treatment. CONCLUSION: The combination of LED/SOF with RBV for 12 weeks or LED/SOF for 24 weeks is very effective and safe in treating OLT recipients with RHC. PMID- 29481385 TI - Fertility Preservation Toolkit: A Clinician Resource to Assist Clinical Discussion and Decision Making in Pediatric and Adolescent Oncology. AB - PURPOSE: Fertility preservation (FP) discussions in children with cancer presents unique challenges due to ethical considerations, lack of models-of-care, and the triadic nature of discussions. This study evaluated a fertility toolkit for clinicians involved in FP discussions with pediatric, adolescent, and young adult patients and parents. MATERIALS AND METHODS: A survey-based, longitudinal study of clinicians at The Royal Children's Hospital Melbourne involved in FP discussions undertaken at 3 time-points: 2014, alongside an education session for baseline assessment of oncofertility practices (survey 1); after each toolkit use to evaluate case-specific implementation (survey 2); 2016, to evaluate impact on clinical practice (survey 3). RESULTS: Fifty-nine clinicians completed survey 1. Over 66% reported baseline dissatisfaction with the existing FP system; 56.7% were not confident in providing up-to-date information. Only 34.5% "often" or "always" provided verbal information; 14.0% "often" or "always" provided written information. Survey 2 was completed after 11 consultations. All clinicians were satisfied with the discussions and outcomes using the toolkit. Thirty-nine clinicians completed survey 3. Over 70% felt confident providing up-to-date FP knowledge, 67.7% "often" or "always" provided verbal information, and 35.4% "often" or "always" provided written information. CONCLUSIONS: Clinicians desire improvement in FP practice. The toolkit provided significant perceived and actual benefits. PMID- 29481386 TI - Evaluation of Acellular Dermal Matrix Efficacy in Prosthesis-Based Breast Reconstruction. AB - BACKGROUND: Although many studies have examined the safety of acellular dermal matrix in immediate prosthetic breast reconstruction, few studies have evaluated efficacy. This study examined initial tissue expander fill volume as a marker of efficacy, comparing patients after staged prosthetic breast reconstruction assisted with acellular dermal matrix versus breast reconstruction not assisted with acellular dermal matrix. Number of fill visits and time interval to implant exchange were examined as secondary endpoints. METHODS: An institutional review board-approved retrospective chart review was conducted to identify consecutive staged prosthetic reconstruction cases over 12 years. RESULTS: Mean initial tissue expander fill volume was significantly higher in the acellular dermal matrix group compared with the non-acellular dermal matrix group (180.8 +/- 150.0 versus 45.8 +/- 74.4; p = 0.00). Normalizing for final implant size, the acellular dermal matrix group exhibited significantly higher perioperative fill (0.33 +/- 0.24 versus 0.11 +/- 0.16; p = 0.00). A collinear trend was observed between acellular dermal matrix use and direct-to-implant reconstruction procedures during the study period. CONCLUSIONS: These results suggest that acellular dermal matrix use is more efficacious in achieving greater initial fill volume, fewer visits for expansion, and a shorter time interval to implant exchange compared with non-acellular dermal matrix procedures. The authors also describe a collinear relationship between acellular dermal matrix use and transition to direct-to-implant procedures at their institution. This work serves as a framework for future studies evaluating acellular dermal matrix efficacy, and guides innovation of biomaterials to support breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 29481387 TI - Sifting through the Evidence: A Comprehensive Review and Analysis of Neurotization in Breast Reconstruction. AB - BACKGROUND: An untoward outcome following breast reconstruction is diminished or complete loss of sensation. As the reconstructive paradigm continues to evolve, sensory restoration following reconstruction remains a research focus. Despite the multitude of published outcomes, there is marked heterogeneity across studies, thus confounding published outcomes. This study critically appraises the literature to summarize outcomes and establish a framework to guide clinical practice and future research. METHODS: A literature review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines in an effort to perform a meta-analysis. The Ovid MEDLINE, PubMed, Embase, Scopus, Cochrane, and ClinicalTrials.gov online databases were queried to capture all publications between 1990 and 2017 that investigated postreconstruction breast sensation. The primary outcome of interest was breast sensation following both implant-based and autologous reconstruction with or without neurotization. Secondary outcomes of interest included time to sensory testing and patient-reported outcomes. RESULTS: Overall, 503 titles were screened, from which 37 articles were ultimately included for analysis, accounting for 1299 patients. There was major methodologic variability and inconsistent measurable outcomes across studies. It can be deduced that postoperative sensation returns spontaneously and unpredictably, neurotization enhances the magnitude and rapidity of sensory restoration when compared to nonneurotized reconstruction, and a sensate reconstruction improves patient reported outcomes. CONCLUSIONS: Significant study design discrepancies exist, making it difficult to combine data and assess results. To effectively study breast sensation and the impact of neurotization, future investigation will depend on standardizing the way in which breast sensation is measured. PMID- 29481388 TI - Is the Right Research Being Conducted to Advance Knowledge about Breast Reconstruction? An Analysis of the Research Pipeline. AB - BACKGROUND: It has been estimated that up to 85 percent of research is of limited value or wasted, in part because of the wrong research questions being addressed. In this study, the authors identified research gaps for breast reconstruction using guideline recommendations based on low-quality or no evidence. The authors then evaluated whether research was currently being conducted to fill these gaps. METHODS: The authors extracted grade C and D options, which are based on limited evidence, from the American Society of Plastic Surgeon's clinical practice guideline for breast reconstruction. For each option, the authors created Participants, Intervention, Comparator, Outcome questions and search strings using a systematic process. Searches were conducted of ClinicalTrials.gov and the World Health Organization's International Clinical Trials Registry Platform to locate new and ongoing studies. The authors also catalogued studies on breast reconstruction funded by the Plastic Surgery Foundation. RESULTS: Of the 10 research gaps, only six were being addressed by new and ongoing research. Timing of reconstruction (immediate or delayed) and use of acellular dermal matrix were most frequently studied. Preoperative referral of a plastic surgeon before mastectomy, complications associated with preoperative breast size, effects of hormone therapy on postoperative outcomes, and methods for detecting local recurrence after mastectomy were not being addressed by new research. Studies funded by the Plastic Surgery Foundation showed a similar pattern. CONCLUSIONS: Of the areas identified, some have received more attention than others. Gaps remain. The authors' results should spark interest in conducting research on these topics and, by so doing, strengthen the clinical practice guideline recommendations. PMID- 29481389 TI - Where Do We Look? Assessing Gaze Patterns in Breast Reconstructive Surgery with Eye-Tracking Technology. AB - BACKGROUND: Aesthetics plays a large role in determining a successful outcome in plastic and reconstructive surgery. As such, understanding perceptions of favorable aesthetics is crucial for optimizing patient satisfaction. Eye-tracking technology offers an unbiased way of measuring how viewers evaluate breast reconstructions. METHODS: Twenty-nine raters with varied plastic surgery experience were shown 20 images of breast reconstruction at various stages. Breasts were divided into those with nipples and no reconstruction scars, those with nipples and reconstruction scars, and those with reconstruction scars and no nipples. Raters viewed each image for 8 seconds to evaluate aesthetic outcomes. Eye-tracking equipment and software were used to track raters' gaze and analyze the distribution of attention. RESULTS: In breasts with reconstruction scars and no nipples, viewers spent 53.9 percent of the view time examining scars, whereas viewers' attention was divided evenly in breasts with both reconstruction scars and nipples, spending 27.5 percent and 27.7 percent of view time examining the nipples and reconstruction scars, respectively. When examining complete reconstructions, viewers spent more time scanning the entire image before fixating on scars and spent less time on single-site fixation. CONCLUSIONS: Complete reconstructions, which notably include the final nipple-areola complex, appear to play an important role in restoring normal viewing parameters. In essence, completed breast reconstructions with nipple-areola complexes divert attention from extraneous surgical scars and lead viewers to assess the breasts more holistically. Eye-tracking technology provides a powerful link between objective gaze and viewer attention that may potentially be used to predict subjective aesthetic preferences. PMID- 29481390 TI - The Effect of Radiation on Quality of Life throughout the Breast Reconstruction Process: A Prospective, Longitudinal Pilot Study of 200 Patients with Long-Term Follow-Up. AB - BACKGROUND: Despite well-established correlation of postmastectomy radiotherapy and surgical complications in breast reconstruction, its impact on patient reported outcomes is less clear. We sought to determine the effect of postmastectomy radiotherapy on patient reported outcomes throughout the breast reconstruction process. METHODS: Patients undergoing prosthetic and autologous breast reconstruction from November 2010 to June 2013 were prospectively followed with BREAST-Q surveys (preoperatively, after expander placement, and 6 and 12 months after final reconstruction). Paired t test, Wilcoxon rank sum test, and multiple linear regression were used to determine the effect of radiation on patient reported outcomes. RESULTS: Two hundred patients were included in the study, of which 51 (25.5 percent) received postmastectomy radiotherapy. Prosthetic reconstruction was performed in 75 patients (37.5 percent), autologous reconstruction was performed in 118 (59 percent), and pure fat grafting was performed in seven (3.5 percent). At one-year follow-up, the nonirradiated group reported higher BREAST-Q scores when compared with the irradiated group, in Satisfaction with Breasts (p = 0.003), Psychosocial Well-being (p = 0.003), Sexual Well-being (p < 0.001), Physical Well-being of Chest (p = 0.024), and Satisfaction with Outcome (p = 0.03). When accounting for baseline values, Satisfaction with Breasts and Physical Well-being of Chest significantly worsened in irradiated patients undergoing prosthetic reconstruction, an effect not seen with autologous reconstructions. All irradiated patients significantly worsened in Psychosocial Well-being and Sexual Well-being scores. CONCLUSIONS: Postmastectomy radiotherapy is associated with worse patient reported outcomes following breast reconstruction. Autologous reconstruction can mitigate patient dissatisfaction in some domains. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 29481391 TI - Intraoperative Nerve Blocks Fail to Improve Quality of Recovery after Tissue Expander Breast Reconstruction: A Prospective, Double-Blinded, Randomized, Placebo-Controlled Clinical Trial. AB - BACKGROUND: The authors' study represents the first level I evidence to assess whether intraoperative nerve blocks improve the quality of recovery from immediate tissue expander/implant breast reconstruction. METHODS: A prospective, randomized, double-blinded, placebo-controlled clinical trial was conducted in which patients undergoing immediate tissue expander/implant breast reconstruction were randomized to either (1) intraoperative intercostal and pectoral nerve blocks with 0.25% bupivacaine with 1:200,000 epinephrine and 4 mg of dexamethasone or (2) sham nerve blocks with normal saline. The 40-item Quality of Recovery score, pain score, and opioid use in the postoperative period were compared statistically between groups. Power analysis ensured 80 percent power to detect a 10-point (clinically significant) difference in the 40-item Quality of Recovery score. RESULTS: Forty-seven patients were enrolled. Age, body mass index, laterality, mastectomy type, and lymph node dissection were similar between groups. There were no statistical differences in quality of recovery, pain burden as measured by visual analogue scale, opioid consumption, antiemetic use, or length of hospital stay between groups at 24 hours after surgery. Mean global 40-item Quality of Recovery scores were 169 (range, 155 to 182) for the treatment arm and 165 (range, 143 to 179) for the placebo arm (p = 0.36), indicating a high quality of recovery in both groups. CONCLUSION: Although intraoperative nerve blocks can be a safe adjunct to a comprehensive postsurgical recovery regimen, the authors' results indicate no effect on overall quality of recovery from tissue expander/implant breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, I. PMID- 29481392 TI - Thread-Lift Sutures: Still in the Lift? A Systematic Review of the Literature. AB - BACKGROUND: In 2006, Villa et al. published a review article concerning the use of thread-lift sutures and concluded that the technique was still in its infancy but had great potential to become a useful and effective procedure for nonsurgical lifting of sagged facial tissues. As 11 years have passed, the authors now performed again a systematic review to determine the real scientific current state of the art on the use of thread-lift sutures. METHODS: A systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using the PubMed database and using the Medical Subject Headings search term "Rhytidoplasty." "Rhytidoplasty" and the following entry terms were included by this Medical Subject Headings term: "facelift," "facelifts," "face Lift," "Face Lifts," "Lift," "Face," "Lifts," "Platysmotomy," "Platysmotomies," "Rhytidectomy," "Rhytidectomies," "Platysmaplasty," "and "Platysmaplasties." The Medical Subject Headings term "Rhytidoplasty" was combined with the following search terms: "Barbed suture," "Thread lift," "APTOS," "Suture suspension," "Percutaneous," and "Silhouette suture." RefWorks was used to filter duplicates. Three of the authors (H.A.G., B.C., and B.L.) performed the search independently. RESULTS: The initial search with all search terms resulted in 188 articles. After filtering the duplicates and the articles about open procedures, a total of 41 articles remained. Of these, the review articles, case reports, and letters to the editor were subsequently excluded, as were reports dealing with nonbarbed sutures, such as Vicryl and Prolene with Gore-Tex. This resulted in a total of 12 articles, seven additional articles since the five articles reviewed by Villa et al. CONCLUSIONS: The authors' review demonstrated that, within the past decade, little or no substantial evidence has been added to the peer-reviewed literature to support or sustain the promising statement about thread-lift sutures as made by Villa et al. in 2006 in terms of efficacy or safety. All included literature in the authors' review, except two studies, demonstrated at best a very limited durability of the lifting effect. The two positive studies were sponsored by the companies that manufacture the thread-lift sutures. PMID- 29481393 TI - Double Triangular Cartilage Excision Otoplasty. AB - BACKGROUND: Prominent ears have a negative impact on patients' psychosocial well being. There are numerous surgical correction techniques described, but the majority have high complication and recurrence rates. In this article, the authors present a stitchless technique that takes advantage of different approaches to minimize complications and recurrences. METHODS: The authors prospectively studied patients who underwent a bilateral double triangular cartilage excision otoplasty in an outpatient setting. This prominent ear setback technique is based on a specific cartilage excision to mechanically collapse the ear without using any sutures through the cartilage. Postoperatively, surgical complications were classified according to the Clavien-Dindo classification. The patient-reported outcome was analyzed after completion of a questionnaire 6 months after surgery, and another clinical follow-up appointment was arranged 12 months after surgery. RESULTS: Sixty patients (120 ears) with an average age of 24 years were studied, and the overall complication rate was 6 percent. Three ears (2.5 percent) developed superficial cutaneous necrosis at the anterior concha, and one ear (1 percent) required an additional correction for unsatisfactory pinna rotation. Also, 2.5 percent of the patients experienced a grade I complication, and 1 percent of the patients experienced a grade IIIa complication according to the Clavien-Dindo classification. No wound infections, hematomas, or hypertrophic scars were observed, and the patient-reported outcome showed satisfaction with the results. CONCLUSIONS: The authors' findings show that the double triangular cartilage excision otoplasty is a safe procedure with low complication/recurrence rates. This stitchless technique should be included in each surgeon's repertoire as an alternative to previously published surgical techniques. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 29481394 TI - Abdominoplasty Improves Low Back Pain and Urinary Incontinence. AB - BACKGROUND: The authors studied the incidence of low back pain and urinary incontinence in the postpartum population presenting for abdominoplasty, and the extent of improvement following the operation. METHODS: This multicenter prospective study used validated questionnaires: the Oswestry Disability Index for back pain and the International Consultation on Incontinence Questionnaire Urinary Incontinence-Short Form for urinary incontinence. Questionnaires were administered preoperatively and at 6 weeks and 6 months postoperatively. RESULTS: Results cover 214 patients from nine centers. The mean age was 42.1 years, the mean parity was 2.5, and the mean body mass index was 26.3 kg/m. The mean surgical statistics were as follows: weight removed, 1222 g; liposuction volume, 795 ml; and diastasis, 4.5 cm. Eighty-seven percent of the abdominoplasties were either radical, high lateral tension, or high oblique tension. The mean Oswestry Disability Index score preoperatively was 21.6 percent, and 8.8 percent had no back pain. The mean score was 8 percent at 6 weeks and 3.2 percent at 6 months. These results are statistically significant. The mean International Consultation on Incontinence Questionnaire score preoperatively was 6.5; of the patients assessed, 27.5 percent had no incontinence. This score fell to 1.6 at 6 weeks, and the same, 1.6, at 6 months. These results are also statistically significant. Preoperative predictors of back pain were body mass index greater than 25 kg/m and umbilical hernia; predictors of incontinence were age older than 40 years and vaginal deliveries. There were no significant predictors of postoperative back pain or urinary incontinence improvement at 6 months. All methods of abdominoplasty produced similar improvement. CONCLUSION: Abdominoplasty with rectus repair creates a significant improvement in the functional symptoms of low back pain and urinary incontinence. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 29481395 TI - Effects of Botulinum Toxin on Improving Facial Surgical Scars: A Prospective, Split-Scar, Double-Blind, Randomized Controlled Trial. AB - BACKGROUND: Early intervention might improve the quality of surgical scars. Botulinum toxin type A has been shown to improve surgical scars in the past decade. The purpose of this study was to evaluate the effect of botulinum toxin type A on surgical facial scars. METHODS: In this prospective, split-scar, double blind, randomized controlled trial, 16 consecutive patients who underwent facial surgery between June and October of 2015 were enrolled. Botulinum toxin type A was injected randomly into half of each surgical wound closure immediately after surgery. The scars were assessed independently by two plastic surgeons at a 6 month follow-up visit using the Vancouver Scar Scale and the visual analogue scale. The scar width was also measured. RESULTS: Fourteen patients completed the study. The visual analogue scale score and scar width measurements revealed a significant improvement in appearance and narrower scars for the botulinum toxin type A-treated halves of the scars (p = 0.046 and p = 0.001, respectively). The mean Vancouver Scar Scale score was 4.68 for the botulinum toxin type A-injected group and 5.24 for the control group (p = 0.15). In addition, the Vancouver Scar Scale height score was significantly different between the two groups (p = 0.008). CONCLUSION: This study demonstrates that early postsurgical botulinum toxin injections can produce better, narrower, and flatter facial surgical scars. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 29481396 TI - The Infratip Lobule Butterfly Graft: Balancing the Transition from the Tip Lobule to the Alar Lobule. AB - The nasal alae and the soft-tissue triangles are delicate structures, the contours of which are largely dependent on soft tissue and the indirect influence of the lower lateral cartilages. Creating appropriate and continuous contour from the tip lobule to the alar lobule can be challenging. The alar contour graft is one reliable method of achieving predictable contour. However, alar contour grafts of ideal length may be scarce. The butterfly graft is a simple, reliable, and predictable method of providing support in the region of the soft triangle, and spans the region between the tip lobule and alar lobule, thereby balancing the transition between these regions. PMID- 29481397 TI - Discussion: Deferoxamine Preconditioning of Irradiated Tissue Improves Perfusion and Fat Graft Retention. PMID- 29481398 TI - beta-Catenin-Dependent Wnt Signaling: A Pathway in Acute Cutaneous Wounding. AB - BACKGROUND: Acute wound healing is a dynamic process that results in the formation of scar tissue. The mechanisms of this process are not well understood; numerous signaling pathways are thought to play a major role. Here, the authors have identified beta-catenin-dependent Wnt signaling as an early acute-phase reactant in acute wound healing and scar formation. METHODS: The authors created 6-mm full-thickness excisional cutaneous wounds on adult beta-catenin-dependent Wnt signal (BAT-gal) reporter mice. The expression of canonical Wnt after wounding was analyzed using X-gal staining and quantitative real-time polymerase chain reaction. Next, recombinant mouse Wnt3a (rmWnt3a) was injected subcutaneously to the wound edge, daily. The mice were killed at stratified time points, up to 15 days after injury. Histologic analysis, quantitative real-time polymerase chain reaction, and Western blot were performed. RESULTS: Numerous individual Wnt ligands increased in expression after wounding, including Wnt3a, Wnt4, Wnt10a, and Wnt11. A specific pattern of Wnt activity was observed, localized to the hair follicle and epidermis. Mice injected with rmWnt3a exhibited faster wound closure, increased scar size, and greater expression of fibroblast growth factor receptor-2 and type I collagen. CONCLUSIONS: The authors' data suggest that beta-catenin-dependent Wnt signaling expression increases shortly after cutaneous wounding, and exogenous rmWnt3a accelerates reepithelialization, wound matrix maturation, and scar formation. Future experiments will focus on the intersection of Wnt signaling and other known profibrotic cytokines. PMID- 29481399 TI - Endoscopic versus Open In Situ Cubital Tunnel Release: A Systematic Review of the Literature and Meta-Analysis of 655 Patients. AB - BACKGROUND: Cubital tunnel syndrome is the second most common peripheral entrapment syndrome. To date, there is no true consensus on the ideal surgical management. A minimally invasive, endoscopic approach has gained popularity but has not been adequately compared to the more traditional, open approach. METHODS: With compliance with Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines, a systematic review was performed to identify studies published between 1990 and 2016 that compared the efficacy of endoscopic cubital tunnel release to open cubital tunnel release. A meta-analysis was then performed through a random-effects model with inverse variance weighting to calculate I values for heterogeneity analysis. Forest plots were constructed for each analysis group. RESULTS: Five studies involving 655 patients (endoscopic cubital tunnel release, n = 226; open cubital tunnel release, n = 429) were included. Meta-analysis revealed no significant superiority of open release in achieving an "excellent" or "good" Bishop score (OR, 1.27; 95 percent CI, 0.59 to 2.75; p = 0.54) and reduction in visual analogue scale score (mean difference, -0.41; 95 percent CI, -1.49 to 0.67; p = 0.46). However, in the endoscopic release cohort, lower rates of new-onset scar tenderness/elbow pain were found (OR, 0.19; 95 percent CI, 0.07 to 0.53; p = 0.002), but there was a higher incidence of postoperative hematomas (OR, 5.70; 95 percent CI, 1.20 to 27.03; p = 0.03). The reoperation rate in the endoscopic and open release groups was 4.9 and 4.1 percent, respectively (p = 0.90). CONCLUSIONS: The authors demonstrated equivalent overall clinical improvement between endoscopic and open cubital tunnel release in terms of Bishop score and visual analogue scale score reduction. Because of the low power of most studies, further investigations with a larger patient population and longer follow-up are needed to better characterize the role of endoscopic cubital tunnel release. PMID- 29481400 TI - Change in Hand Function and Dexterity with Age after Index Pollicization for Congenital Thumb Hypoplasia. AB - BACKGROUND: Little is known about how performance on strength, range of motion, and dexterity measures changes as children with index finger pollicization mature. The authors reviewed performance in range of motion, strength, and dexterity over a 7-year period and report outcomes over time. METHODS: Data from children treated with index finger pollicization for congenital thumb hypoplasia from 2007 to 2014 were reviewed retrospectively. Children were followed for an average of 3.9 years (range, 1 to 7 years) during the study period. Standardized assessments included range of motion, grip, key pinch and tripod pinch strength, the Box and Block Test, the Nine Hole Peg Test, and the Functional Dexterity Test. Average score by age and average yearly change were calculated for each assessment, and scores were plotted against published age-matched scores of normal children when available. RESULTS: Twenty-three patients with 29 affected thumbs were included. Distal grasp span increased 0.17 inch and Kapandji opposition improved 0.26 point with each year of age; however, proximal web-space size did not increase over time. Grip strength improved an average of 2.69 kg/year, and tripod and key pinch improved 0.58 kg and 0.67 kg with each year of age. Box and Block Test scores improved an average of 4.11 blocks/year. Scores on the Nine Hole Peg Test improved 3.83 seconds/year, and scores on the Functional Dexterity Test improved 0.026 peg/second each year. CONCLUSIONS: Children with pollicized thumbs improve in dexterity and strength with growth. Web-space size did not change with age; therefore, the thumb should be carefully positioned at the time of surgery. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 29481402 TI - Discussion: State-of-the-Art Techniques in Treating Peripheral Nerve Injury. PMID- 29481403 TI - Evaluating Trends in Headache and Revision Surgery following Cranial Vault Remodeling for Craniosynostosis. AB - BACKGROUND: The recommended treatment for craniosynostosis, is cranial vault expansion to prevent increased intracranial pressure and optimize developmental outcomes. Some patients complain about postoperative headaches and occasionally require revision to treat increased intracranial pressure. This study examines whether specific factors are associated with an increased risk of postoperative headaches or intracranial hypertension. METHODS: This retrospective cohort included patients with craniosynostosis from 1995 and 2010. Primary outcomes included headaches and delayed intracranial hypertension. Logistic regression was used to evaluate the associations with clinical characteristics. RESULTS: The cohort included 383 patients, of whom 127 (33 percent) complained of headaches. The positive predictive value of a headache indicating intracranial hypertension was only 9.4 percent among all patients and 6.7 percent among patients with nonsyndromic craniosynostosis. Headaches occurring in the morning, more than once per week, and associated with nausea, vomiting, or decreased activity level were most likely to be associated with delayed intracranial hypertension. Only 21 patients (6 percent) required revision surgery, and these patients were more likely to have syndromic craniosynostosis (OR, 5.6; 95 percent CI, 2.1 to 14.9), Chiari malformation (OR, 5.8; 95 percent CI, 1.7 to 19.5), or secondary craniosynostosis (additional sutures fused on the 2-year postoperative CT scan) (OR, 5.4; 95 percent CI, 2.2 to 13.5). CONCLUSIONS: Headaches are common after cranial vault remodeling but are not very predictive of who will need revision surgery for intracranial hypertension. Patients with specific headache characteristics, syndromic craniosynostosis, secondary synostosis, and Chiari malformations have the highest risk of developing delayed intracranial hypertension. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 29481401 TI - A Systematic Review and Meta-Analysis on the Strength and Consistency of the Associations between Dupuytren Disease and Diabetes Mellitus, Liver Disease, and Epilepsy. AB - BACKGROUND: The role of diabetes mellitus, liver disease, and epilepsy as risk factors for Dupuytren disease remains unclear. In this systematic review and meta analysis, the strength and consistency of these associations were examined. METHODS: The MEDLINE, EMBASE, and Web of Science databases were searched for articles reporting an association between Dupuytren disease and diabetes mellitus, liver disease, and epilepsy published before September 26, 2016. The frequencies of Dupuytren disease and diabetes mellitus, liver disease, and epilepsy were extracted, as was information on potential confounders. Generalized linear mixed models were applied to estimate pooled odds ratios, adjusted for confounders. Heterogeneity between studies was quantified using an intraclass correlation coefficient and was accounted for by a random effect for study. RESULTS: One thousand two hundred sixty unique studies were identified, of which 32 were used in the meta-analyses. An association between Dupuytren disease and diabetes mellitus was observed (OR, 3.06; 95 percent CI, 2.69 to 3.48, adjusted for age), which was stronger for type 1 diabetes mellitus than for type 2 diabetes mellitus but was not statistically significant (p = 0.24). An association between Dupuytren disease and liver disease was observed (OR, 2.92; 95 percent CI, 2.08 to 4.12, adjusted for sex). Dupuytren disease and epilepsy were associated, yielding an OR of 2.80 (95 percent CI, 2.49 to 3.15). Heterogeneity between studies was moderate to low. CONCLUSIONS: These findings demonstrate an association between Dupuytren disease and diabetes mellitus, liver disease, and epilepsy. Prospective, longitudinal studies are needed to elucidate the pathways causing these associations. PMID- 29481404 TI - Quantifying Normal Craniofacial Form and Baseline Craniofacial Asymmetry in the Pediatric Population. AB - BACKGROUND: Restoring craniofacial symmetry is an important objective in the treatment of many craniofacial conditions. Normal form has been measured using anthropometry, cephalometry, and photography, yet all of these modalities have drawbacks. In this study, the authors define normal pediatric craniofacial form and craniofacial asymmetry using stereophotogrammetric images, which capture a densely sampled set of points on the form. METHODS: After institutional review board approval, normal, healthy children (n = 533) with no known craniofacial abnormalities were recruited at well-child visits to undergo full head stereophotogrammetric imaging. The children's ages ranged from 0 to 18 years. A symmetric three-dimensional template was registered and scaled to each individual scan using 25 manually placed landmarks. The template was deformed to each subject's three-dimensional scan using a thin-plate spline algorithm and closest point matching. Age-based normal facial models were derived. Mean facial asymmetry and statistical characteristics of the population were calculated. RESULTS: The mean head asymmetry across all pediatric subjects was 1.5 +/- 0.5 mm (range, 0.46 to 4.78 mm), and the mean facial asymmetry was 1.2 +/- 0.6 mm (range, 0.4 to 5.4 mm). There were no significant differences in the mean head or facial asymmetry with age, sex, or race. CONCLUSIONS: Understanding the "normal" form and baseline distribution of asymmetry is an important anthropomorphic foundation. The authors present a method to quantify normal craniofacial form and baseline asymmetry in a large pediatric sample. The authors found that the normal pediatric craniofacial form is asymmetric, and does not change in magnitude with age, sex, or race. PMID- 29481406 TI - Reliability of Color Doppler Ultrasound Imaging for the Assessment of Anterolateral Thigh Flap Perforators: A Prospective Study of 30 Perforators. AB - : Despite numerous advantages, the anterolateral thigh perforator flap suffers from the variable position and nature of its perforators. The aim of the authors' study was to assess the reliability of preoperative color Doppler ultrasound imaging for the exploration of perforator location and course of anterolateral thigh perforator flaps. A prospective cohort study involving patients for whom head and neck reconstruction was planned with thin anterolateral thigh perforator flaps was conducted. Each patient underwent a color Doppler ultrasound exploration of the thighs, in the operating room, immediately before surgery. The sonographer was the surgeon who raised the flaps. Perforators were sought according to surgical needs, and the same location protocol was followed for all of the cases, using an orthonormal coordinate system to report the passages of the perforators through the vastus lateralis aponeurosis. Between January of 2016 and January of 2017, 22 thin anterolateral thigh perforator flaps were successfully harvested. Thirty perforators were located and used. The median distance between the preoperative color Doppler ultrasound planning and the final location of the perforators was 5 mm, statistically smaller than a 10-mm threshold (p = 0.002). Color Doppler ultrasound effectively predicted the nature of the perforators in 90 percent of the cases. The median duration for perforator color Doppler ultrasound location was 3 minutes, statistically shorter than 10 minutes (p = 0.0001). Preoperative color Doppler ultrasound seems to be reliable, accurate, and compatible with a quick routine assessment during patient setup for the elevation of thin anterolateral thigh perforator flaps. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, II. PMID- 29481405 TI - The Role of Bipartition Distraction in the Treatment of Apert Syndrome. AB - Apert syndrome is characterized by hypertelorism, a negative canthal axis, and central midfacial hypoplasia, resulting in a biconcave face. Bipartition distraction partially corrects these facial anomalies. This study investigates limitations of bipartition distraction using linear, angular, and geometric morphometric analysis. Preoperative and postoperative three-dimensional computed tomographic craniofacial constructs of 10 patients with Apert syndrome (aged 12 to 21 years) were annotated with 98 landmarks. Twelve age-, sex, and ethnicity matched normal skulls provided control data. Principal component analysis was used to analyze shape characteristics within and between the groups and describe the changes occurring with surgery. Results were displayed graphically using difference color maps. Conventional point-based measurements documented midfacial width, height, and asymmetry. Apert three-dimensional constructs exhibited reduced upper midfacial height and greater extrinsic symmetric variation relative to controls. Facial bipartition partially corrected excessive midfacial width and interorbital distance but did not adequately correct deficient upper midfacial height. Excessive orbital diameter was unaltered by surgery. There was no demonstrable effect on intrinsic or extrinsic midfacial asymmetry. Principal component analysis demonstrated improved midfacial projection and correction of central biconcavity. Bipartition distraction corrects midfacial retrusion, exorbitism, and hypertelorism. It does not treat midfacial height disproportion or correct orbital shape. It leaves the face too wide at the zygomatic level and does not correct facial asymmetry. Although bipartition distraction is an improvement on the unmodified monobloc advancement, further refinements are needed to fully correct Apert dysmorphology. PMID- 29481407 TI - Gender-Affirming Surgery in Persons with Gender Dysphoria. AB - The landscape of gender dysphoria has changed dramatically in recent years secondary to increased societal acceptance, legislative changes, and medical providers' increased awareness of the associated psychosocial burden associated with the diagnosis. National and global advocacy efforts, in conjunction with expanded third-party insurance coverage, have resulted in new health care opportunities for patients suffering from gender dysphoria. Delivering quality, streamlined health care to these patients requires a complex multidisciplinary approach, involving multiple medical and mental health disciplines, including plastic surgeons. To accommodate the expanding demand for gender-affirmation surgery, academic medical centers specializing in these procedures are gradually emerging. Advancing surgical techniques in the setting of rising patient demand encourage plastic surgeons to increasingly provide high-quality health care to this diverse patient population in an effort to optimize psychosocial functioning and minimize the burden of gender dysphoria. Although the current literature is replete with the evolving surgical and technical approaches to gender-affirming surgery, there remain critical gaps in the plastic surgery literature describing the delivery of comprehensive care to these patients. To address these gaps, the authors establish a framework that plastic surgeons can use to guide their management of patients with gender dysphoria to optimize surgical and psychosocial outcomes. First, the authors describe a timeline of events that have shaped present-day transgender medicine and characterize the current role of the plastic surgeon in the management of gender dysphoria. Subsequently, the authors discuss psychosocial and ethical considerations surrounding gender dysphoria. Finally, the authors discuss the future scope of transgender medicine. PMID- 29481408 TI - Discussion: Long-Term Patient-Reported Outcomes following Free Flap Lower Extremity Reconstruction for Traumatic Injuries. PMID- 29481409 TI - Two-Point Discrimination Predicts Pain Relief after Lower Limb Nerve Decompression for Painful Diabetic Peripheral Neuropathy. AB - BACKGROUND: Peripheral nerve decompression surgery has been reported to be effective for pain reduction in patients with painful diabetic peripheral neuropathy. The aim of this study was to characterize which patients may have more pain relief benefits in the lower limbs after nerve decompression surgery. METHODS: A retrospective study was conducted. Pain levels were measured with the Numerical Rating Scale. Treatment effects were classified by either substantial relief (at least 50 percent reduction in Numerical Rating Scale score compared with preoperative Numerical Rating Scale score) or nonsubstantial relief (<50 percent reduction or worse in Numerical Rating Scale score) at 12 months based on established criteria. Sex, age, body mass index, duration of diabetes mellitus, duration of diabetic peripheral neuropathy pain, preoperative Numerical Rating Scale score, and two-point discrimination were evaluated using univariate and logistic regression analysis. RESULTS: The mean preoperative Numerical Rating Scale score (8.65 +/- 1.29) decreased significantly 6 days (3.56 +/- 2.22; p < 0.01), 6 months (3.03 +/- 2.11; p < 0.01), and 12 months (3.44 +/- 2.36; p < 0.01) after surgery; 64.7 percent of patients had substantial pain relief at 12 months. According to univariate and logistic regression analysis, better two point discrimination was associated with substantial pain relief (OR, 3.700; p = 0.046, logistic regression analysis). CONCLUSIONS: Nerve decompression surgery was able to alleviate pain in patients with painful diabetic peripheral neuropathy. Two-point discrimination may be a predictive factor for the prognosis of painful diabetic peripheral neuropathy after nerve decompression surgery. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 29481410 TI - Detection of Perforators for Free Flap Planning Using Smartphone Thermal Imaging: A Concordance Study with Computed Tomographic Angiography in 120 Perforators. AB - : Design and preoperative planning of microsurgical flaps are fundamental steps for successful surgery. Currently, computed tomographic angiography is considered the gold standard, and new technologies such as thermography could complement its usefulness. The aim of this study was to determine the concordance between thermographic images obtained with a smartphone thermal camera and computed tomographic angiography for detecting perforators using the anterolateral thigh flap area as a model. A concordance study of diagnostic tests was performed in patients who underwent limb reconstruction in 2016. Perforators identified in thigh computed tomographic angiographic images and hotspots on thermographic images obtained by means of the FLIR ONE smartphone camera were compared based on the distance from the anterior superior iliac spine. The authors studied 20 patients, including 38 anterolateral thigh flap territories in total, and identified 117 perforators by computed tomographic angiography and 120 hotspots by thermography. The average mean distance from the anterior superior iliac spine using these methods was 193.14 mm, and the mean difference in distance was 2.37 mm, with both measurements being obtained within a radius of 20 mm, with a concordance kappa index of 0.975 (p < 0.001). Thermographic imaging presented a sensitivity of 100 percent and a specificity of 98 percent in detecting perforators. Thermographic images obtained with a smartphone thermal camera have a high concordance with the method considered the gold standard for perforator detection. In addition, its sensitivity and specificity are comparable to those of computed tomographic angiography, which makes it a very useful method for mapping perforators in free flap planning. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, II. PMID- 29481411 TI - Targeting Reflux-Free Veins with a Vein Visualizer to Identify the Ideal Recipient Vein Preoperatively for Optimal Lymphaticovenous Anastomosis in Treating Lymphedema. AB - : Lymphaticovenous anastomosis is one of the main surgical treatments nowadays for alleviating lymphedema. A successful lymphaticovenous anastomosis relies on being able to identify "functional" lymphatic collecting vessels that are still capable of transporting lymph, and a nearby vein that is, ideally, reflux-free. This is a retrospective study. A total of 28 lymphedema patients were enrolled from October of 2016 to March of 2017 in Kaohsiung Chang Gung Hospital, Kaohsiung, Taiwan. A noninvasive vein visualizer was used to preselect reflux free veins for lymphaticovenous anastomosis from five female patients. As a control, the total number of veins used for lymphaticovenous anastomoses without the use of a vein visualizer from 23 consecutive lymphedema patients was also recorded and compared. In the experimental group, a total of 12 of 13 veins (92 percent sensitivity) preselected by using the VeinViewer were confirmed to be reflux-free intraoperatively during lymphaticovenous anastomosis. In the control group, 21 of 56 veins (37.5 percent sensitivity) showed no venous reflux. Statistical analysis with the chi-square test showed a value of p < 0.001 (number needed to treat = 2.706). The odds of identifying reflux-free veins can be increased significantly with the use of a vein visualizer. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, II. PMID- 29481412 TI - Nipple-Areola Complex Reconstruction. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Understand how to determine nipple-areola complex positioning on the reconstructed breast. 2. Understand the multitude of local flap and distant graft options for nipple-areola complex reconstruction. 3. Draw at least three fundamental nipple-areola complex reconstruction patterns. 4. Understand the forces that are responsible for flattening of the reconstructed papule. 5. Understand the current techniques used in secondary nipple-areola complex reconstructions. SUMMARY: Nipple-areola complex reconstruction and tattooing represent the final two stages of breast reconstruction. Nipple-areola complex reconstruction is typically accomplished with the use of local flaps, local flaps with augmentation grafts, or a combination thereof. Regardless of the technique used, however, all nipple-areola complex reconstructions lose a degree of projection over time. Options for secondary reconstruction include the use of local tissue flaps alone or in combination with acellular biological matrices. PMID- 29481413 TI - Alternative Metrics of Scholarly Output: The Relationship among Altmetric Score, Mendeley Reader Score, Citations, and Downloads in Plastic and Reconstructive Surgery. AB - BACKGROUND: The impact of scholarly output is typically measured by the number of citations and, more recently, downloads. Newer metrics have been developed to reflect digital dissemination of knowledge such as the Altmetric and Mendeley reader scores. This article examines the relationship among citations, download rates, Altmetric scores, and Mendeley reader scores in Plastic and Reconstructive Surgery. METHODS: The authors accessed the 55 most-cited articles published in Plastic and Reconstructive Surgery from 2014 to 2015. Altmetric scores, download rates, field-weighted citations, and Mendeley reader number were extracted. Correlation matrices were used to identify methodologies positively correlating between scores. The top-ranked articles were then collectively evaluated for central subject themes and unifying scoring methodologies. RESULTS: The highest Altmetric score obtained was 159, the greatest number of citations was 52, and the greatest number of downloads was 41. There was no apparent correlation between Altmetric scores and Scopus citations (p = 0.58) or article subject themes (p = 0.63). Citation was positively associated with download rates (r = 0.31, p = 0.021) and Mendeley reader number (r = 0.46, p = 0.001). Mendeley reader number demonstrated high precision in identifying top-ranked citation articles (p = 0.044) despite its lack of direct association with Altmetric score (p = 0.83). CONCLUSIONS: With the growing public desire for evidence-based publications, our study quantifies the unique nature of Altmetric score while discouraging its use in isolation. Download rates are a more rapid measure of publication impact compared with citation number. Mendeley readership is also promising as an alternative index. PMID- 29481414 TI - Discussion: Alternative Metrics of Scholarly Output: The Relationship among Altmetric Score, Mendeley Reader Score, Citations, and Downloads in Plastic and Reconstructive Surgery. PMID- 29481415 TI - Consensus of Leaders in Plastic Surgery: Identifying Procedural Competencies for Canadian Plastic Surgery Residency Training Using a Modified Delphi Technique. AB - BACKGROUND: Transitioning to competency-based surgical training will require consensus regarding the scope of plastic surgery and expectations of operative ability for graduating residents. Identifying surgical procedures experts deemed most important in preparing graduates for independent practice (i.e., "core" procedures), and those that are less important or deemed more appropriate for fellowship training (i.e., "noncore" procedures), will focus instructional and assessment efforts. METHODS: Canadian plastic surgery program directors, the Canadian Society of Plastic Surgeons Executive Committee, and peer-nominated experts participated in an online, multiround, modified Delphi consensus exercise. Over three rounds, panelists were asked to sort 288 procedural competencies into five predetermined categories within core and noncore procedures, reflecting increasing expectations of ability. Eighty percent agreement was chosen to indicate consensus. RESULTS: Two hundred eighty-eight procedures spanning 13 domains were identified. Invitations were sent to 49 experts; 37 responded (75.5 percent), and 31 participated (83.8 percent of respondents). Procedures reaching 80 percent consensus increased from 101 (35 percent) during round 1, to 159 (55 percent) in round 2, and to 199 (69 percent) in round 3. The domain "burns" had the highest rate of agreement, whereas "lower extremity" had the lowest agreement. Final consensus categories included 154 core, essential; 23 core, nonessential; three noncore, experience; and 19 noncore, fellowship. CONCLUSIONS: This study provides clarity regarding which procedures plastic surgery experts deem most important for preparing graduates for independent practice. The list represents a snapshot of expert opinion regarding the current training environment. As our specialty grows and changes, this information will need to be periodically revisited. PMID- 29481416 TI - Discussion: Consensus of Leaders in Plastic Surgery: Identifying Procedural Competencies for Canadian Plastic Surgery Residency Training Using a Modified Delphi Technique. PMID- 29481417 TI - So, You Want to Be a Success? Aspire, Inspire, and Perspire-A Lot! PMID- 29481418 TI - Five-Year Follow-Up of Midface Distraction in Growing Children with Syndromic Craniosynostosis: Correction. PMID- 29481419 TI - Microbial Evaluation in Capsular Contracture of Breast Implants: Correction. PMID- 29481420 TI - Reply: The Six-Step Lower Blepharoplasty: Using Fractionated Fat to Enhance Blending of the Lid-Cheek Junction. PMID- 29481421 TI - Reply: Predictors of Autologous Free Fat Graft Retention in the Management of Craniofacial Contour Deformities. PMID- 29481422 TI - Anal and Cervical High-Risk Human Papillomavirus Genotyping in Women With and Without Genital Neoplasia. AB - OBJECTIVE: The aim of the study was to compare the prevalence, genotypes, and rates of concomitant anal and cervical high-risk human papillomavirus (HR-HPV) in women with and without a history of HPV-related genital neoplasia. MATERIALS AND METHODS: This was a prospective cohort study conducted from December 2012 to February 2014. Women with a history of neoplasia were considered the high-risk group. Women without a history of neoplasia were considered the low-risk group. Cervical and anal cytology and HPV genotyping were performed. All women with abnormal anal cytology were referred for anoscopy. RESULTS: One hundred eighty four women met inclusion criteria. High-risk HPV was detected in the anal canal of 17.4% of the high-risk group and 1.5% of the low-risk group (p = .003). High risk HPV was detected in the cervix of 30.5% of the high-risk group and 7.6% of the low-risk group (p < .001). Concomitant anal and cervical high-risk HPV was detected in 4.4% of the high-risk group and was not detected in the low-risk group (p = .2). Among women with anal intraepithelial neoplasia 2 or greater (n = 5), 60% had HR-HPV detected in the anal canal while none had HR-HPV detected in the cervix. CONCLUSIONS: Women with a history of genital neoplasia are more likely to be positive for anal and cervical HR-HPV compared with women without a history of genital neoplasia. Although there was no significant difference in rates of concomitant HR-HPV between low- and high-risk groups, HR-HPV can be found concomitantly in the anus and the cervix and may be associated with anal intraepithelial neoplasia or carcinoma. PMID- 29481423 TI - Diabetes and Blood Glucose Disorders Under Anti-PD1. AB - Acute type 1 diabetes (AD1) is a rare but definitive immune-related adverse event associated with anti-PD1. Most of the reported cases are close to what has been described as "fulminant type 1 diabetes." We sought to determine whether anti-PD1 could impair glycoregulation and whether occurrence of AD1 could be anticipated by prior glycemic changes. Fasting glycemia collected before, under, and after treatment in melanoma patients treated with anti-PD1 over a period of 36 months were retrospectively analyzed. Glycemic trend analyses were performed using linear regression analysis. In total, 1470 glucose values were monitored in 163 patients treated for a mean duration of 5.96 months. Three patients developed an AD1 (1, 84%). Two other cases were observed in the same period in a still-blinded trial of anti-PD1 versus ipilimumab. All cases of AD1 occurred in patients with a normal pretreatment glycemia, and there was no detectable drift of glycemia before ketoacidosis onset. In 4 of 5 cases of AD1, the HLA subgroups were DRB01* 03 or 04, known to increase type 1 diabetes risk in the general population. In the 28 patients with preexisting type 2 diabetes, there was a slight trend for glycemia increase with anti-PD1 infusions (0.05 mmol/L/infusion P=0.004). In the 132 patients with normal pretreatment glycemia, there was a slight trend for a decrease of glycemia with anti-PD1 infusions (-0.012/mmol/L/infusion P=0.026). These data suggest that the monitoring of glycemia under anti-PD1 cannot help to anticipate AD1, and there is no general tendency to glycemic disorder. HLA genotyping before treatment may help to focus surveillance in patients with the HLA DRB1*03/04 group. PMID- 29481424 TI - Dissociation between morphine-induced spinal gliosis and analgesic tolerance by ultra-low-dose alpha2-adrenergic and cannabinoid CB1-receptor antagonists. AB - Long-term use of opioid analgesics is limited by tolerance development and undesirable adverse effects. Paradoxically, spinal administration of ultra-low dose (ULD) G-protein-coupled receptor antagonists attenuates analgesic tolerance. Here, we determined whether systemic ULD alpha2-adrenergic receptor (AR) antagonists attenuate the development of morphine tolerance, whether these effects extend to the cannabinoid (CB1) receptor system, and if behavioral effects are reflected in changes in opioid-induced spinal gliosis. Male rats were treated daily with morphine (5 mg/kg) alone or in combination with ULD alpha2-AR (atipamezole or efaroxan; 17 ng/kg) or CB1 (rimonabant; 5 ng/kg) antagonists; control groups received ULD injections only. Thermal tail flick latencies were assessed across 7 days, before and 30 min after the injection. On day 8, spinal cords were isolated, and changes in spinal gliosis were assessed through fluorescent immunohistochemistry. Both ULD alpha2-AR antagonists attenuated morphine tolerance, whereas the ULD CB1 antagonist did not. In contrast, both ULD atipamezole and ULD rimonabant attenuated morphine-induced microglial reactivity and astrogliosis in deep and superficial spinal dorsal horn. So, although paradoxical effects of ULD antagonists are common to several G-protein-coupled receptor systems, these may not involve similar mechanisms. Spinal glia alone may not be the main mechanism through which tolerance is modulated. PMID- 29481425 TI - Prognostic Value of Secretoneurin in Patients With Severe Sepsis and Septic Shock: Data From the Albumin Italian Outcome Sepsis Study. AB - OBJECTIVES: Secretoneurin directly influences cardiomyocyte calcium handling, and circulating secretoneurin levels seem to improve risk prediction in patients with myocardial dysfunction by integrating information on systemic stress, myocardial function, and renal function. Accordingly, in this study, we hypothesized that secretoneurin would improve risk prediction in patients with sepsis and especially in patients with septic shock as these patients are more hemodynamically unstable. DESIGN: Multicenter, interventional randomized clinical trial. SETTING: Multicenter, pragmatic, open-label, randomized, prospective clinical trial testing fluid administration with either 20% human albumin and crystalloids or crystalloid solutions alone in patients with severe sepsis or septic shock (The Albumin Italian Outcome Sepsis). PATIENTS OR SUBJECTS: In total, 540 patients with septic shock and 418 patients with severe sepsis. INTERVENTIONS: Either 20% human albumin and crystalloids or crystalloid solutions alone. MEASUREMENTS AND MAIN RESULTS: We measured secretoneurin on days 1, 2, and 7 after randomization and compared the prognostic value of secretoneurin for ICU and 90-day mortality with established risk indices and cardiac biomarkers in septic shock and severe sepsis. High secretoneurin levels on day 1 were associated with age and serum concentrations of lactate, bilirubin, creatinine, and N-terminal pro-B-type natriuretic peptide. Adjusting for established risk factors and cardiovascular biomarkers, secretoneurin levels on day 1 were associated with ICU (odds ratio, 2.27 [95% CI, 1.05-4.93]; p = 0.04) and 90-day mortality (2.04 [1.02-4.10]; p = 0.04) in patients with septic shock, but not severe sepsis without shock. Secretoneurin levels on day 2 were also associated with ICU (3.11 [1.34-7.20]; p = 0.008) and 90-day mortality (2.69 [1.26-5.78]; p = 0.01) in multivariate regression analyses and improved reclassification in patients with septic shock, as assessed by the net reclassification index. Randomized albumin administration did not influence the associations between secretoneurin and outcomes. CONCLUSIONS: Secretoneurin provides early and potent prognostic information in septic patients with cardiovascular instability. PMID- 29481426 TI - Development and Initial Evaluation of a Novel, Ultraportable, Virtual Reality Bronchoscopy Simulator: The Computer Airway Simulation System. AB - BACKGROUND: Virtual reality (VR) simulation is an effective and safe method of teaching bronchoscopic skills. Few VR bronchoscopy simulators exist; all are expensive. The present study aimed to describe the design, development, and evaluation of a new, affordable, VR bronchoscopy simulator. METHODS: Anesthesiologists and engineers collaborated to design and develop the Computer Airway Simulation System (CASS), an iPad-based, high-fidelity, VR bronchoscopy simulator. We describe hardware and software development, as well as the technical and teaching features of the CASS. Twenty-two senior anesthesiologists evaluated various aspects of the simulator (using a 5-point Likert scale) to assess its face validity. RESULTS: Anesthesiologists performed a simulated bronchoscopy (mouth to carina) with a median (range) procedural time of 66 seconds (30-96). The simulator's ease of use was rated 4.3 +/- 0.8 and the bronchoscope proxy's handling 4.0 +/- 0.7. Criticisms included that excessive system reactivity created handling difficulties. Anatomical accuracy, 3 dimensional bronchial segmentation, and mucosal texture were judged to be very realistic. The simulator's usefulness for teaching and its educational value were highly rated (4.9 +/- 0.3 and 4.8 +/- 0.4, respectively). CONCLUSIONS: We describe the design, development, and initial evaluation of the CASS-a new, ultraportable, affordable, VR bronchoscopy simulator. The simulator's face validity was supported by excellent assessments from senior anesthesiologists with regard to anatomical realism, quality of graphics, and handling performance, even though some future refinements are required. All the practitioners agreed on the significant educational potential of the CASS. PMID- 29481427 TI - Neuraxial Anesthesia During Cesarean Delivery for Placenta Previa With Suspected Morbidly Adherent Placenta: A Retrospective Analysis. AB - BACKGROUND: General anesthesia (GA) is often selected for cesarean deliveries (CD) with placenta previa and suspected morbidly adherent placenta (MAP) due to increased risk of hemorrhage and hysterectomy. We reviewed maternal outcomes and risk factors for conversion to GA in a cohort of patients undergoing CD and hysterectomy under neuraxial anesthesia (NA). METHODS: We performed a single center, retrospective cohort study of parturients undergoing nonemergent CD for placenta previa with suspected MAP from 1997 to 2015. Patients were classified according to whether they received GA, NA, or intraoperative conversion from NA to GA. The primary outcome measure was postoperative acuity, defined as the need for intensive care unit admission, arterial embolization, reoperation, or ongoing transfusion with >=3 units packed red blood cells. We additionally identified variables positively associated with intraoperative conversion from NA to GA during hysterectomy. Confounding was controlled with logistic regression models. RESULTS: Of 129 patients undergoing nonemergent CD for placenta previa with suspected MAP, 122 (95%) received NA as the primary anesthetic. NA was selected in the majority of patients with a body mass index >=40 kg/m (9 of 10, 90%), a history of >=3 prior CDs (18 of 20, 90%), suspected placenta increta or percreta (29 of 35, 83%), and Mallampati classification >=3 (19 of 21, 90%). Of 72 patients with NA at the time of delivery who required hysterectomy, 15 (21%) required conversion to GA intraoperatively. Converted patients had a higher rate of major packed red blood cell transfusion (60% vs 25%; P = .01), with similar rates of massive transfusion (9% vs 7%; P = 1.0). Converted patients also had a higher incidence of postoperative acuity (47% vs 4%; P < .0001), including 5 intensive care unit admissions for airway management after large-volume resuscitation. After adjusting for multiple confounders, the only independent predictors of conversion among hysterectomy patients were longer surgical duration (adjusted odds ratio 1.54, 95% CI, 1.01-2.42) and a history of >=3 prior CDs (adjusted odds ratio, 6.45; 95% CI, 1.12-45.03). CONCLUSIONS: NA was applied to and successfully used in the majority of patients with suspected MAP. Our findings support selective conversion to GA during hysterectomy in these patients, focusing on those with the highest levels of surgical complexity. PMID- 29481428 TI - Point-of-Care Fibrinogen Testing in Pregnancy. AB - Agreement between estimated fibrinogen concentration via thromboelastography and traditional assays is not established in the parturient. We therefore recruited 56 parturients and performed Clauss and functional fibrinogen level (FLEV) tests. Mean difference of measurements was 36.8 mg/dL (95% CI, 21.8-51.9) with a standard deviation of 52.8 mg/dL. Calculated limits of agreement were 140.2 mg/dL (95% CI, 166.3-114.6) and -66.6 mg/dL (95% CI, -40.8 to -92.5), within the maximum allowable difference of 165 mg/dL. We therefore conclude that while most measurements fell within the limits of agreement, more work is needed to clearly define the role of this test in the obstetric population. PMID- 29481429 TI - Pupillary Dilation Reflex Measurement: Ideal Time-Pre- or Postsurgery? PMID- 29481430 TI - Analgesic Effects of Oxycodone Relative to Those of Sufentanil, in the Presence of Midazolam, During Endoscopic Injection Sclerotherapy for Patients With Cirrhosis and Esophageal Varices. AB - BACKGROUND: We evaluated the efficacy and gastroenterologist/patient satisfaction of midazolam combined with oxycodone, relative to that of midazolam combined with sufentanil, for anesthesia during endoscopic injection sclerotherapy (EIS) in patients with cirrhosis and esophageal varices. METHODS: Patients with cirrhosis (20-69 years of age), body mass index, 18-25 kg/m, American Society of Anesthesiology patient classification physical status I-II who underwent elective EIS were randomly assigned to 1 of 2 groups. In this prospective, double-blinded, randomized controlled trial, 1 group received midazolam and oxycodone (n = 64), and the other group received midazolam and sufentanil (n = 63). Primary and secondary outcome measures were compared between groups. The primary outcome measure was the incidence of hypoxia. Secondary outcome measures included perioperative limb movement, need for rescue analgesics, need for additional sedative propofol, specified adverse reactions (postoperative myoclonus, nausea, vomiting, dizziness, and drowsiness), gastroenterologist satisfaction, and patient satisfaction with postoperative analgesia. RESULTS: Patients in the midazolam-oxycodone group had 32% fewer episodes of hypoxia than did those in the midazolam-sufentanil group (95% confidence interval [CI], -45% to -18%; P < .001), 36.73% fewer perioperative limb movements (95% CI, -51.73% to -21.73%; P < .001), 19.12% fewer required rescue analgesics (95% CI, -30.85% to -7.40%; P = .002), and less propofol requirement in the perioperative period (before EIS, 17.83%; 95% CI, -33.82% to -1.85%; P = .003; throughout EIS, -36.73%; 95% CI, 51.73% to -21.73%; P < .001). The incidence rates for adverse reactions were similar between groups. Both the gastroenterologist and patients reported higher degrees of satisfaction with oxycodone than with sufentanil. CONCLUSIONS: Oxycodone in combination with midazolam may provide an anesthetic technique that results in fewer episodes of hypoxia and other adverse conditions during EIS. PMID- 29481431 TI - Inflammation Triggered by the Use of Blood Products. PMID- 29481432 TI - In Response. PMID- 29481433 TI - Does A Low 6-Minute Walk Distance Predict Elevated Postoperative Troponin? AB - Our study of 100 major vascular and renal transplant patients evaluated the 6 minute walk test (6MWT) as an indicator of perioperative myocardial injury, using troponin as a marker. Using logistic regression and the area under the receiving operator characteristic curve, we compared the 6MWT to the Revised Cardiac Risk Index and metabolic equivalents. Only the 6MWT was associated with elevated postoperative troponins (95% CI, 0.98-0.99). However, the 6MWT area under the receiving operator characteristic curve (0.71 [95% CI, 0.57-0.85]) was not different from the Revised Cardiac Risk Index (P = .23) or metabolic equivalents (P = .14). The 6MWT may have a role in cardiac risk stratification in the perioperative setting. PMID- 29481434 TI - The Migration of Caudally Threaded Thoracic Epidural Catheters in Neonates and Infants. AB - BACKGROUND: The migration of pediatric thoracic epidural catheters via a thoracic insertion site has been described. We assessed the migration of caudally threaded thoracic epidural catheters in neonates and infants at our institution. METHODS: The anesthesia records and diagnostic imaging studies of neonates and infants who had caudal epidural catheters placed during a 26-month period at our hospital were analyzed. Imaging studies were reviewed for changes in epidural catheter tip position. RESULTS: Eighty-five patients 1-325 days of age (median, 51 days; interquartile range, 39-78 days) and weights of 2.5-9.5 kg (median, 5 kg; interquartile range, 4.3-5.8 kg) met the study criteria. Fifty-four (64%) of the patients (95% CI, 52%-73%) experienced catheter migration of 1 or more vertebral levels (range, 3 levels caudad [outward] to 3 levels cephalad [inward]), and 23 (27%) of the patients (95% CI, 18%-38%) experienced catheter migration to the T4 level or higher. Migration of 2 or more vertebral levels occurred only in children who weighed <6 kg and were under 73 days of age. CONCLUSIONS: Epidural catheter migration occurs commonly in neonates and infants. Postoperative imaging is crucial to confirm catheter tip location after epidural catheter placement, as failure to assess catheter migration might result in suboptimal analgesia or other undesirable outcomes. PMID- 29481435 TI - Beyond the "E" in OSCE. PMID- 29481436 TI - Correlation Coefficients: Appropriate Use and Interpretation. AB - Correlation in the broadest sense is a measure of an association between variables. In correlated data, the change in the magnitude of 1 variable is associated with a change in the magnitude of another variable, either in the same (positive correlation) or in the opposite (negative correlation) direction. Most often, the term correlation is used in the context of a linear relationship between 2 continuous variables and expressed as Pearson product-moment correlation. The Pearson correlation coefficient is typically used for jointly normally distributed data (data that follow a bivariate normal distribution). For nonnormally distributed continuous data, for ordinal data, or for data with relevant outliers, a Spearman rank correlation can be used as a measure of a monotonic association. Both correlation coefficients are scaled such that they range from -1 to +1, where 0 indicates that there is no linear or monotonic association, and the relationship gets stronger and ultimately approaches a straight line (Pearson correlation) or a constantly increasing or decreasing curve (Spearman correlation) as the coefficient approaches an absolute value of 1. Hypothesis tests and confidence intervals can be used to address the statistical significance of the results and to estimate the strength of the relationship in the population from which the data were sampled. The aim of this tutorial is to guide researchers and clinicians in the appropriate use and interpretation of correlation coefficients. PMID- 29481437 TI - Treatment Patterns and Clinical Outcomes in Neonates Diagnosed With Respiratory Distress Syndrome in a Low-Income Country: A Report From Bangladesh. AB - Respiratory distress syndrome remains a leading cause of neonatal mortality worldwide. This retrospective study describes practice patterns for respiratory distress syndrome in a resource-limited setting and seeks to identify both risk factors for mortality and beneficial treatment modalities. Health, demographic, and treatment data were collected. Potential associations were analyzed using univariable and multivariable logistic regression. Of 104 children included for analysis, 38 died. Although most children were initially treated with noninvasive respiratory support, 59 progressed to invasive ventilation. Requirement for invasive ventilation was associated with death. A clear trend toward improved survival in mechanically ventilated patients was seen with surfactant administration. PMID- 29481439 TI - Opioid Omission Is Not Opioid Sparing. Response to "Surgery-Induced Opioid Dependence: Adding Fuel to the Fire?" PMID- 29481438 TI - Research Needs Assessment for Children With Obstructive Sleep Apnea Undergoing Diagnostic or Surgical Procedures. AB - Recent concerns have been raised about the quality and safety of adenotonsillectomy, a common surgery performed to treat obstructive sleep apnea (OSA) in children. OSA is a risk factor for opioid-related perioperative respiratory complications including those associated with anoxic brain injury or death. Our objective was to identify controversial issues related to the care of children with OSA. A standardized Delphi consensus technique involving an interdisciplinary group of 24 pediatric OSA experts identified 3 key issues: "postoperative disposition, preoperative screening, and pain management." These topics are prime candidates for future systematic reviews and will guide Society of Anesthesia and Sleep Medicine-related research endeavors. PMID- 29481441 TI - Relationships Between Early Nutrition and Blood Glucose Concentrations in Very Preterm Infants. AB - OBJECTIVES: The aim of the study was to determine whether changes to early nutrition are associated with levels of glycemia in very preterm infants. METHODS: A retrospective, observational study of infants <1500 g or <30 weeks' gestation admitted to Neonatal Intensive Care, National Women's Hospital, New Zealand, before (Old Protocol) and after (New Protocol) a change in nutritional protocol. Nutritional intakes were calculated and averaged by day for postnatal days 1 to 7 (week 1) and 1 to 28 (month 1). Relationships between glycemia measures, macronutrient intakes, and achievement of 10% enteral feeds (>=10% total intake) were explored using logistic regression. RESULTS: Old Protocol (n = 190) and New Protocol (n = 267) groups had similar baseline characteristics. In week 1, New Protocol infants received more protein, less fat, and carbohydrate, had lower mean blood glucose concentrations (BGCs) (mean +/- SD 4.9 +/- 1.2 vs 5.6 +/- 1.4 mmoll/L, P < 0.0001), less hyperglycemia (BGC > 8.5 mmol/L, 71 [27%] vs 80 [42%], P = 0.0005), but similar hypoglycemia (BGC < 2.6). In month 1, New Protocol infants also had less hyperglycemia (105 [39%] vs 96 [51%], P = 0.02) and lower mean BGC (5.0 +/- 1.1 vs 5.5 +/- 1.1 mmol/L, P < 0.0001), but insulin usage was similar. After adjustment for birth weight z score and gestational age, hyperglycemia was significantly associated with week 1 intakes (g . kg . day) of protein (odds ratio [95% confidence intervals] 0.47 [0.23-0.79], P = 0.004), fat (0.54 [0.40-0.74], P < 0.0001), and carbohydrate (1.25 [1.09-1.44], P < 0.0001). These relationships were similar for month 1. Each additional day to achieve 10% enteral feeds was associated with increased odds of hypoglycemia (1.09 [1.00 1.18], P = 0.04) and hyperglycemia (1.16 [1.06-1.28], P = 0.002). CONCLUSIONS: In very preterm infants, macronutrient balance and small, early enteral feeds may assist glycemic control. PMID- 29481440 TI - Blepharophimosis-ptosis-epicanthus inversus syndrome caused by a 54-kb microdeletion in a FOXL2 cis-regulatory element. PMID- 29481442 TI - Early Treatment Response Predicts Outcome in Paediatric Ulcerative Colitis. AB - The disease course of children with ulcerative colitis (UC) varies substantially. Published data on predictors of disease outcomes in children remains scarce. We validate clinical predictors of outcomes in 93 children with UC in a single centre (age range: 2-18 years, minimum follow-up: 18 months). We stratified children into 3 groups according to their disease course, i.e. 1 = mild (38/93, 40.9%), 2 = moderate (38/93, 40.9%), 3 = severe (17, 18.2%). Comparison of clinical and biochemical parameters was performed between groups using Chi square, Mann-Whitney and log-rank tests. Predictors of a severe disease course included pancolitis (P 0.01), low albumin (P 0.005), low haemoglobin at diagnosis (P 0.04), PUCAI at 3 months and non-response to steroids at 3 months (P 0.0001). In our cohort, failure to achieve remission at 3 months implied an 80% likelihood to require biologics or major surgery within 18 months. A specific 3 month review point is recommended to guide future management. PMID- 29481444 TI - Regional Cerebral Oxygen Saturation Changes After Decompressive Craniectomy for Malignant Cerebral Venous Thrombosis: A Prospective Cohort Study. AB - BACKGROUND: Decompressive craniectomy (DC) is a life-saving intervention for malignant cerebral venous thrombosis (CVT). Earlier studies have shown increase in cerebral oxygenation after DC in traumatic brain injury but similar studies are lacking in CVT. We hypothesized that regional cerebral (tissue) oxygen saturation (rSO2) on the side of CVT is lower than the contralateral side and improves after DC. MATERIALS AND METHODS: In this prospective cohort study, rSO2 was monitored using near-infrared spectroscopy technique, before and after DC on both cerebral hemispheres. Data regarding factors likely to affect rSO2 such as systolic blood pressure, partial pressure of oxygen and carbon dioxide in blood (PaO2 and PaCO2), and hemoglobin were simultaneously collected. The primary outcome measure was pre-post change in rSO2 on the ipsilateral cerebral hemisphere. The secondary outcomes were in-hospital mortality and duration of postoperative hospital stay. RESULTS: Seventeen patients underwent DC during the 6-month study period. Their mean age was 39.2+/-12.4 years. The pre-post DC change in rSO2 on the hemisphere with CVT was significant (mean difference=3.6%; 95% confidence interval, 1.5-5.7; P=0.002). One patient died in the hospital. There was no difference in the duration of postoperative hospital stay (10 d [range, 6 to 21 d] vs. 14 d [range, 1 to 30 d], P=0.92) between patients with preoperative ipsilateral rSO2 <60% and >60%. There was no correlation between PaO2, PaCO2, systolic blood pressure, and hemoglobin with rSO2. CONCLUSIONS: Patients with malignant CVT had a lower rSO2 on ipsilateral side of the lesion, which improved significantly after DC. Preoperative rSO2 was not correlated with the duration of hospital stay. PMID- 29481445 TI - Serum Methylarginines and Hearing Loss in a Population-based Cohort of Older Adults. AB - OBJECTIVE: Age-related hearing loss is associated with endothelial dysfunction and increased cardiovascular risk, suggesting a vascular etiology. Methylarginines are endogenous nitric oxide synthase inhibitors that cause endothelial dysfunction and increase cardiovascular disease risk. This study is the first to examine the hypothesis that higher serum concentrations of methylarginines are associated with greater hearing loss prevalence. STUDY DESIGN/PATIENTS: Cross-sectional audiometric data on hearing levels, and serum methylarginines were collected from a population-based sample of 630 older community-dwelling adults. RESULTS: Linear regression analysis showed a statistically significant association between higher serum concentrations of asymmetric dimethylarginine (ADMA) and L-arginine and greater degrees of hearing loss for males, particularly over 75 years. Higher body mass index and previous history of stroke were also associated with hearing loss. For females, ADMA concentration was not associated with hearing loss, but higher serum L-arginine concentrations were associated with reduced hearing loss prevalence in older females. Antihypertensive medication use was also associated with reduced hearing loss prevalence. LDL cholesterol and previous myocardial infarction were associated with greater hearing loss. CONCLUSION: This study showed a significant association between serum concentrations of ADMA and hearing loss for males, consistent with the association between endothelial dysfunction and hearing loss. The opposite effect of L-arginine on hearing loss in males versus females might reflect a different role of this precursor toward nitric oxide versus methylated arginines synthesis. These findings are potentially clinically significant if the association between ADMA and hearing loss is causal, as serum methylarginine levels are modifiable through pharmacotherapeutic/lifestyle interventions. PMID- 29481443 TI - Micronutrient Status and Nutritional Intake in 0- to 2-Year-old Children Consuming a Cows' Milk Exclusion Diet. AB - OBJECTIVES: To study micronutrient status and nutritional intake from complementary feeding in children on a cows' milk exclusion (CME) diet. METHODS: Fifty-seven children with cows' milk allergy, younger than 2 years, were included in a cross-sectional study. Blood was analyzed for micronutrient status. Complementary feeding was defined as all solids and liquids except of breast milk, and assessed by 3-day food diary. The results were analyzed according to 3 feeding patterns: mainly breast-fed (mBF), partially breast-fed, and no breast milk group (nBM). RESULTS: The children had a median age of 9 months and micronutrient status was within normal range for total homocysteine (p-tHcy), s B12, s-folate, b-Hb, s-ferritin, s-zinc, and s-25(OH)D. There were no significant differences between feedings groups, except for B12-biomarkers. The mBF had higher p-tHcy (P < 0.000) and lower s-B12 (P = 0.002) compared nBM. Vitamin B12 deficiency (p-tHcy >6.5 MUmol/L combined with s-B12 <250 pmol/L) was found in 12% of participants, most frequently among the mBF (36%) and none in nBM group (P = 0.009). Vitamin B12 intake from complementary feeding was negatively correlated with p-tHcy (r = -0.479, P = 0.001) and positively with s-B12 (r = 0.410, P = 0.003). Iron deficiency anemia was found in 5%. Iron intake correlated positively with b-Hb (r = 0.324, P = 0.02). Zinc deficiency was found in 7% and low 25(OH)D in 9%. Vitamin D intake was positively correlated with the use of supplements (r = 0.456, P = 0.001). CONCLUSION: The risk of B12 deficiency was high in mBF infants on CME diet, and complementary feeding was associated with better B12 status. Iron, zinc, and vitamin D deficiencies were present in all feeding groups. Complementary feeding should be introduced at 4 to 6 months of age. Vitamin D supplement is recommended to ensure adequate intake. PMID- 29481446 TI - Relationship Between Change of Direction, Speed, and Power in Male and Female National Olympic Team Handball Athletes. AB - Pereira, LA, Nimphius, S, Kobal, R, Kitamura, K, Turisco, LAL, Orsi, RC, Cal Abad, CC, and Loturco, I. Relationship between change of direction, speed, and power in male and female National Olympic Team handball athletes. J Strength Cond Res 32(10): 2987-2994, 2018-The aims of this study were to (a) assess the relationship between selected speed- and power-related abilities (determined by 20-m sprint, unloaded countermovement jump [CMJ] and squat jump [SJ], and loaded jump squat [JS]) and performance in 2 distinct change of direction (COD) protocols (Zigzag test and T-test) and (b) determine the magnitude of difference between female and male Brazilian National Olympic Team handball athletes. Fifteen male and 23 female elite handball athletes volunteered to perform the following assessments: SJ and CMJ; Zigzag test and T-test; 20-m sprint with 5-, 10-, and 20-m splits; and mean propulsive power in JS. Pearson's product-moment correlation (p <= 0.05) was performed to determine the relationship between the COD tests (Zigzag test and T-test) and speed-power measures (sprint, SJ, CMJ, and JS). The differences between male and female performances were determined using the magnitude-based inference. Moderate to very large significant correlations were observed between both COD tests and the speed-power abilities. Furthermore, male athletes demonstrated likely to almost certainly higher performances than female athletes in all assessed variables. The results of the current study suggest that different speed-power qualities are strongly correlated to the performance obtained in various COD assessments (r values varying from 0.38 to 0.84 and from 0.34 to 0.84 for correlations between speed and power tests with Zigzag test and T-test, respectively). However, the level of these associations can vary greatly, according to the mechanical demands of each respective COD task. Although COD tests may be difficult to implement during competitive seasons, because of the strong correlations presented herein, the regular use of vertical jump tests with these athletes seems to be an effective and applied alternative. Furthermore, it might be inferred that the proper development of loaded and unloaded jump abilities has potential for improving the physical qualities related to COD performance in handball athletes. PMID- 29481447 TI - Photobiomodulation Therapy on Physiological and Performance Parameters During Running Tests: Dose-Response Effects. AB - Dellagrana, RA, Rossato, M, Sakugawa, RL, Baroni, BM, and Diefenthaeler, F. Photobiomodulation therapy on physiological and performance parameters during running tests: Dose-response effects. J Strength Cond Res 32(10): 2807-2815, 2018 This study was aimed at verifying effects of photobiomodulation therapy (PBMT) with different energy doses (15, 30, and 60 J per site) on physiological and performance parameters during running tests. Fifteen male recreational runners participated in a crossover, randomized, double-blind, and placebo-controlled trial. They performed testing protocol in 5 sessions with different treatments: control, placebo, and PBMT with 15, 30, or 60 J per site (14 sites in each lower limb). Physiological and performance variables were assessed during submaximal (at 8 and 9 km.h) and maximal running tests. Photobiomodulation therapy with 30 J significantly improved running economy (RE) at 8 and 9 km.h (3.01%, p=0.008 and 3.03%, p=0.009, respectively), rate of perceived exertion (RPE) at 8 km/h21 (7.86%, p=0.033), velocity at V[Combining Dot Above]O2max (3.07%, p= 0.029), peak of velocity (PV) (1.49%, p=0.035), and total time to exhaustion (TTE) (3.41%, p=0.036) compared with placebo. Photobiomodulation therapy with 15 J improved running economy at 9 km/h21 (2.98%, p=0.025), rate of perceived exertion at 8 km/h21 (4.80%, p=0.010), PV (1.33%, p=0.008), total time to exhaustion (3.06%, p=0.008), and total distance (4.01%, p=0.011) compared with the placebo; whereas PBMT with 60 J only increased RE at 9 km/h21 (3.87%, p=0.024) compared with placebo. All PBMT doses positively affected physiological and/or performance parameters; however, magnitude-based inference reported that PBMT applied with 30 J led to more beneficial effects than 15 and 60 J. PMID- 29481448 TI - Reduced Electromyographic Fatigue Threshold after Performing a Cognitive Fatiguing Task. AB - Cognitive fatigue tasks performed prior to exercise may reduce exercise capacity. The electromyographic fatigue threshold (EMGFT) is the highest exercise intensity that can be maintained without significant increase in the EMG amplitude versus time relationship. To date, no studies have examined the effect of cognitive fatigue on the estimation of the EMGFT. The purpose of this study, therefore, was to determine whether or not cognitive fatigue prior to performing exercise reduces the estimated EMGFT. Eight healthy college-aged men were recruited from a university student population and visited the laboratory on multiple occasions. In a randomized order, subjects performed either the cognitive fatigue task (AX Continuous Performance Test; AX-CPT) for 60 min on one visit (experimental condition) or watched a video on trains for 60 min on the other visit (control condition). After each condition, subjects performed the incremental single-leg knee-extensor ergometry test while the EMG amplitude was recorded from the rectus femoris muscle and heart rate was monitored throughout. Thereafter, the EMGFT was calculated for each participant for each visit and compared using paired samples t-test. For exercise outcomes, there were no significant mean differences for maximal power output between the two conditions (control: 51 +/- 5 vs. fatigue: 50 +/- 3 W), but a significant decrease in EMGFT between the two conditions (control: 31 +/- 3 vs. fatigue: 24 +/- 2 W; p = 0.013). Moreover, maximal heart rate was significantly different between the two conditions (control: 151 +/- 5 vs. fatigue: 132 +/- 6; p = 0.027). These results suggest that performing the cognitive fatiguing task reduces the EMGFT with a corresponding reduction in maximal heart rate response. PMID- 29481449 TI - Knowledge, Attitudes, and Beliefs of Youth Sports Coaches Regarding Sport Volume Recommendations and Sport Specialization. AB - Overuse injuries in youth athletes are becoming increasingly common which may be a result of the prevalence of year-round specialized sport participation. Previous research has identified sport volume recommendations related to months per year, hours per week, and simultaneous participation in multiple sports leagues. Coaches are a primary influence on a youth athlete's decision to specialize in a single sport. Therefore, identifying coaches' baseline beliefs and perceptions is important for developing strategies to educate coaches about safe sport participation. A total of 253 youth sport coaches (207 males) completed an anonymous online questionnaire regarding knowledge of sport volume recommendations and attitudes and beliefs regarding sport specialization. Eligible participants were required to serve as a head or assistant coach of a youth sport team in the past 12 months whose members were between the ages of 12 and 18. Most coaches were unaware of recommendations regarding the maximum number of months per year (79.4%), hours per week in one sport (79.3%), or number of simultaneous leagues for an athlete to participate in to reduce injury (77.6%). Fewer than half (43.2%) of all coaches were "very" or "extremely" concerned about the risk of injury in youth sports. A majority (60.1%) believed that sport specialization was either "quite a bit" or "a great deal" of a problem. Two thirds (67.2%) responded that year-round participation in a single sport was either "very" or "extremely" likely to increase an athlete's risk of injury. Although the responses to this survey were predominantly from coaches from one state, our results suggest that coaches are unaware of sport volume recommendations but are concerned about specialization. Future efforts are needed to communicate these recommendations to coaches in order to reduce the risk of overuse injury in youth sports. PMID- 29481450 TI - Using Perceptual and Neuromuscular Responses to Estimate Mechanical Changes During Continuous Sets in the Bench Press. AB - The present study analyzed the effectiveness of the OMNI-RES (0-10) and the electromyographic signal for monitoring changes in the movement velocity during a set to muscular failure performed with different relative loads in the bench press exercise (BP). Ten males (30.8 +/- 5.7 years) were evaluated on eight separate days with 48 hours of rest between sessions. After determining the 1RM value, participants performed seven sets to failure with the following relative loads ranges: 30<40%; 40<50%, 50<60%, 60%<70%, 70<80%, 80<90% and >90%. The mean accelerative velocity (MAV), the Rating of Perceived Exertion (RPE) and the normalized root mean square (N-RMS) signal from the anterior deltoids were measured for every repetition of each set. The RPE expressed after the first repetition and when the maximum value of MAV was achieved over the sets was lower (p <0.001, d >0.80) than the RPE associated with a 10% drop in MAV and at failure. Furthermore, the initial RPE was useful to distinguish different loading zones between the light relative loads (30<40% vs. 40<50% vs. 50<60%) and from these three zones to the higher relative load ranges (60 to >90%). Similar, but less clear, differences were observed for the N-RMS. In conclusion, apart from differentiating between relative loads, the RPE and in some cases N-RMS can both reflect changes associated with the initial, maximal, 10% drop in movement velocity and muscular failure during a continuous set in the BP. PMID- 29481451 TI - Dynamic Balance Evaluation: Reliability and Validity of a Computerized Wobble Board. AB - Computerized Wobble Boards (WB) are inexpensive, transportable and user-friendly devices to objectively quantify the dynamic balance performances out of laboratory settings, although it has not been established if they are reliable and valid tools. Therefore, the purpose of this study was to determine the reliability and validity of a computerized WB. Thirty-nine (18 female, 21 male) young adults (age: 23.3+/-2.1years; body mass: 65.9+/-1.8kg; height: 168.2+/ 8.8cm; leg length: 78.8+/-5.7cm; BMI: 23.2+/-2.1kg.m) participated in the study. Subjects were assessed during three separate sessions on different days with a 48h rest in between. A total number of two WB single limb tests and one Y Balance Test (YBT) were performed. The WB performance was registered using the proprietary software and represented by the time spent in the target zone, which represented the 0 degrees tilt angle measured by the tri-axial accelerometer in the WB. YBT normalized reach distances were recorded for the anterior, posteromedial and posterolateral directions. Intraclass correlation coefficient, 95% confidence interval, standard error of measurement, minimal detectable change and Bland-Altman plots were used to evaluate intrasession and intersession reliability, while Pearson product moment correlation was used to determine concurrent validity. Reliability ranged from fair to excellent, showing acceptable levels of error and low minimal detectable change. However, all correlation coefficients between WB and YBT outcomes were poor. Despite the two methods addressing different aspects of balance performance, WB seems to validly serve its purpose and showed good reliability. Therefore, computerized WBs have the potential to become essential devices for dynamic balance assessment. PMID- 29481452 TI - Effect of Caffeine Supplementation on Quadriceps Performance After Eccentric Exercise. AB - Green, MS, Martin, TD, and Corona, BT. Effect of caffeine supplementation on quadriceps performance after eccentric exercise. J Strength Cond Res 32(10): 2863 2871, 2018-Caffeine use is common among athletes seeking to capitalize on its potential ergogenic effects. Limited research has examined caffeine's effects when used after activities that resulted in exercise-induced muscle damage (EIMD). This study examined the effect of caffeine supplementation on uninjured and injured muscle. Eight men and women (N = 16) who were physically active individuals participated in this study (age: 24.3 +/- 4.3 years; height: 173.0 +/ 7.0 cm, mass: 75.2 +/- 11.5 kg; body fat: 18.2 +/- 15.9%). One leg was assessed under uninjured and injured (100 eccentric quadriceps contractions) conditions after caffeine supplementation (6 mg.kg), with the other leg assessed under both conditions after placebo supplementation. Compared with the placebo, caffeine increased peak isokinetic torque by 6.8 +/- 2.3 and 9.4 +/- 2.5% in uninjured and injured muscle, respectively, but had no effect on maximal voluntary isometric torque or fatigue index in uninjured or injured muscle, with treatments exhibiting similar (p > 0.05) alterations in isometric torque (-11.9 +/- 2.2%), fatigue index (-13.9 +/- 3.4%), and soreness (+44.0 +/- 4.7) after eccentric contractions. The results of this study suggest that caffeine possesses a similar ergogenic effect on isokinetic torque in both uninjured and injured states, but no effect on the production of isometric torque, perception of soreness, or degree of relative fatigue. Athletes should consider the potential caffeine supplementation possesses during recovery from activities that resulted in EIMD. PMID- 29481453 TI - Self-Selected Rest Interval Improves Vertical Jump Post-Activation Potentiation. AB - This study compared the effects of self-selected rest interval and fixed rest interval strategies on post-activation potentiation (PAP) in countermovement jump (CMJ) performance. Twelve strength-trained male's (age: 25.4 +/- 3.6 years; body mass: 78.8 +/- 10.5 kg; height: 175 +/- 7.0 cm; half-squat 1RM: 188.7 +/- 33.4 kg) performed three experimental conditions: 1) fixed rest interval (FRI: CMJ test; 4-min rest interval; 5RM back squat; 4-min rest interval; CMJ test), 2) self-selected rest interval (SSRI: CMJ test; 4-min rest interval; 5RM back squat; SSRI; CMJ test), and 3) control (C: CMJ test; 8-min rest interval; CMJ test). In SSRI, participants were instructed to rest until they felt fully recovered and able to exercise at maximal intensity based on the perceived readiness scale (PR). Significant changes in pre-post CMJ performance were observed in the SSRI condition (38.2 +/- 4.6 cm vs 40.5 +/- 4.4 cm; p = 0.08; CI: 0.72 to 3.82 cm; ES = 0.93). There were significant differences in post CMJ performance when SSRI was compared to FRI (40.5 +/- 4.4 cm vs 37.7 +/- 5.1 cm; p = 0.02; CI 0.43 to 5.08; ES = 1.13) and C (40.5 +/- 4.4 cm vs. 37.4 +/- 5.7 cm; p = 0.01; CI: 0.66 to 5.61; ES = 1.35). The average rest interval length for the SSRI condition was 5:57 +/- 2:44 min:sec (CI: 4:24 to 7:30). Our results suggest the use of SSRI was an efficient and practical strategy to elicit PAP on CMJ height in strength trained individuals. PMID- 29481454 TI - The Effects of Myofascial Trigger Point Release on the Power and Force Production in the Lower Limb Kinetic Chain. AB - The purpose of this study was to firstly investigate the effects of treating latent myofascial trigger points (MTrPs) in the lower limb kinetic chain with respect to performance during sporting actions, as opposed to the traditional goal of pain management with active MTrPs. The second aim was to investigate the effects of dry needling (DN) on performance parameters over time to establish treatment timeframe guidelines prior to performance. Forty male athletes were assigned to four groups; rectus femoris DN (group 1), medial gastrocnemius DN (group 2), rectus femoris and medial gastrocnemius DN (group 3) and no DN (group 4). Subjects completed 6 sessions; familiarisation, baseline, immediately after DN, 48, 72 and 96 hours post intervention. Subjects performed squat jumps at 5 incremental loads and were recorded using the My Jump app (iOS) for jump height, power output, optimal force and optimal velocity. A between-within subject's ANOVA was used for statistical analysis. Results showed a significant increase in jump height in group 2 (gastrocnemius muscle only) from immediately post to 48 hours post intervention (p = 0.01), however, no other statistical significance was observed. From 48 hours onward, a trend for improved performance was observed, with jump height, power and velocity showing trivial increases. This study found improved jump performance from immediately post to 48 hours post DN of the gastrocnemius muscle only. This study suggests a likely immediate decrease in jump performance following DN, with levels increasing above baseline between 48 hours and 96 hours, which may have clinical significance. PMID- 29481455 TI - Tracking of time-dependent changes in muscle hardness after a full marathon. AB - We sought to identify changes in individual muscle hardness after a full marathon and to track time-dependent changes using ultrasound strain elastography (SE). Twenty-one collegiate marathon runners were recruited. Muscle hardness (i.e., strain ratio, SR) was measured using SE for the rectus femoris (RF), vastus lateralis (VL), biceps femoris long head (BF), tibialis anterior (TA), gastrocnemius medial head (GM), and soleus (SOL) muscles at the following time points: pre (PRE), immediately post (POST), day-1 (D1), day-3 (D3), and day-8 (D8), after a full marathon. We found that the SR decreased after the full marathon (i.e., the muscle became harder), and that the lowest SR across all measured muscles was observed on D1. Although there was no difference in the magnitude of change in SR between the muscles of the thigh, that of the MG and SOL were significantly larger than that of the TA. Muscle hardness in the VL, BF, and SOL recovered at D8 (i.e., non-significant difference from PRE), whereas recovery of RF and GM hardness at D8 was not observed. Thus, the degree of change in muscle hardness does not occur uniformly within the lower extremity muscles. In particular, changes in muscle hardness of the TA after a full marathon is small compared with other muscles and time-dependent changes in each muscle varies during recovery. The features of muscle hardness identified in this study will be useful for coaches when mentoring runners on proper forms and for training advisers and therapists who seek to address deficiencies in running. PMID- 29481456 TI - Tweeting for Nutrition: Feasibility and Efficacy Outcomes of a 6-Week Social Media-Based Nutrition Education Intervention for Student-Athletes. AB - The main objective of this study was to determine the feasibility and efficacy of a social media-based nutrition intervention using Twitter on nutrition knowledge, dietary practices, body mass index, self-efficacy, and social support among student-athletes. Participants included 50 male and female NCAA Division I student-athletes between the ages of 18-24 years old. Data were collected in October 2014. The study design employed a six-week, social media intervention using Twitter(c), to increase nutrition knowledge, self-efficacy, social support and dietary adherence to the Dietary Guidelines for Americans recommendations. Descriptive statistics were calculated for all study variables and pre-post differences were assessed using paired t-tests. The results indicate a 6-week nutrition intervention delivered solely through social media resulted in increased nutrition knowledge (t=-2.23; p=0.035), reduced fat intake (t=- 1.57; p=0.13) and decreased BMI (t=2.32; p=0.027) in student athletes. In conclusion, social-media based nutrition education may provide university-based strength and conditioning coaches and other sports practitioners with a tool for widespread and timely access to students in order to facilitate healthy dietary behaviors. PMID- 29481457 TI - Effect of a hamstring flexibility program performed concurrently during an elite canoeist competition season. AB - The aim of this study was to determine de acute effect of an 8-weeks specific hamstring flexibility training on junior canoeist during the competition season. Sixteen canoeists participated, divided into 3 groups: 5 in Experimental Group 1 (EG1), 5 in Experimental Group 2 (EG2) and 6 in a Control Group (CG). The EG1 underwent a supervised program consisted by Simple Static Stretching, Dynamic Static Stretching and P.N.F. while the EG2 performed a program without P.N.F. and no supervision. Two measurements were performed to analyze the effect on the knee joint ROM and trunk flexion; neuromuscular and contractile properties in Biceps Femoris (BF) and Semitendinosus (ST) muscles; maximum power and average speed in lower limbs. A mixed-design factorial analysis of variance (p <0.05) was performed and the effect size was calculated. The results show significant improvements (p <0.05) in both legs for knee joint ROM and trunk flexion in EG1 (8.9% and 25.5%; 5.7% and 20.9% in right and left leg respectively) and EG2 (6.7% and 22%; 3.9% and 24.4%), only EG1 improved muscular stiffness in BF (27.4% left leg) and ST (20.5% and 24.3%), and lateral symmetry in BF (49%) without decreasing average speed in lower limbs. All improvements have a large effect size. In conclusion, it is suggested that a supervised hamstring flexibility program performed concurrently during a canoeist competition season can produce an increase in the knee joint ROM and trunk flexion, without negative repercussions in contractile and neuromuscular capacities, maximum power and average velocity in lower limbs. PMID- 29481458 TI - Self-selected vs. Fixed Repetition Duration: Effects on Number of Repetitions and Muscle Activation in Resistance-Trained Men. AB - Nobrega, SR, Barroso, R, Ugrinowitsch, C, da Costa, JLF, Alvarez, IF, Barcelos, C, and Libardi, CA. Self-selected vs. fixed repetition duration: effects on number of repetitions and muscle activation in resistance-trained men. J Strength Cond Res 32(9): 2419-2424, 2018-The aim of this study was to compare the effects of self-selected and fixed repetition duration (RD) on resistance exercise (RE) volume, muscle activation, and time under tension (TUT) per repetition and per session. Twelve resistance-trained men participated in the study. A randomized cross-over design was used and each participant performed 2 high-intensity RE protocols in a balanced order: (a) 3 sets of RE with self-selected RD (SELF); and (b) 3 sets of RE with fixed RD (2-second concentric and 2-second eccentric [FIX]). Muscle activation was assessed through surface electromyography (EMG) of the vastus lateralis and vastus medialis throughout RE sessions. Overall, RE volume was significantly greater for SELF (p = 0.01), whereas TUT per repetition was significantly greater for FIX (p = 0.0001). No significant differences between protocols were detected for TUT per session. Between-protocol comparisons revealed significantly greater EMG amplitude for SELF compared with FIX at S1 (p = 0.01), S2 (p = 0.03), and S3 (p = 0.03). Both SELF and FIX protocols produced significant increases in EMG amplitude from 25 to 100% (p < 0.001) of set completion. Between-protocol comparisons revealed significantly greater EMG amplitude for SELF compared with FIX at 75% (p = 0.03) and 100% (p = 0.01). In conclusion, self-selected RD resulted in greater volume and muscle activation compared with fixed RD in an RE session. PMID- 29481459 TI - Write On. PMID- 29481460 TI - Prelicensure Employment and Student Nurse Self-Efficacy. AB - There is a lack of literature regarding how prelicensure employment affects self efficacy in nursing practice. The purpose of this study was to examine the relationship among prelicensure employment and self-efficacy in nursing practice of senior student nurses. Healthcare experience was identified as the best predictor of positive self-efficacy in managing an assignment of three and four patients. Findings of this study provide insight for providing orientation for newly licensed nurses regarding their readiness to practice. PMID- 29481462 TI - Simulation as an Assessment Strategy to Assist With Unit Placement for New Graduate Nurses. AB - Orienting new graduates through simulation, which incorporated critical thinking performance at the bedside, improved their readiness to respond to critical situations and eased transition to the appropriately assigned unit. Graduate nurses' critical thinking processes at the bedside were observed and scored according to how quickly correct diagnoses were made and interventions identified. A scorecard was developed based on defined criteria. PMID- 29481461 TI - Transition From Clinical to Educator Roles in Nursing: An Integrative Review. AB - This review identified barriers to and facilitators of nurses' transition from clinical positions into nursing professional development and other nurse educator roles. The author conducted literature searches using multiple databases. Twenty one articles met search criteria, representing a variety of practice settings. The findings, both barriers and facilitators, were remarkably consistent across practice settings. Four practice recommendations were drawn from the literature to promote nurses' successful transition to nursing professional development roles. PMID- 29481463 TI - Clinical Transition Framework: Integrating Coaching Plans, Sampling, and Accountability in Clinical Practice Development. AB - The clinical transition framework (CTF) is a competency-based practice development system used by nursing professional development practitioners to support nurses' initial orientation or transition to a new specialty. The CTF is applicable for both new graduate and proficient nurses. The current framework and tools evolved from 18 years of performance improvement and research projects engaged in both acute and community care environments in urban and rural settings. This article shares core CTF concepts, a description of coaching plans, and a professional accountability statement as experienced within the framework. PMID- 29481464 TI - Longitudinal Study Transformed Onboarding Nurse Graduates. AB - The outcomes of a longitudinal research study on a nurse residency program indicated improvement in the onboarding experience for new graduate nurses. Practice changes and implications for nursing professional development practitioners resulting from the study include the number and orientation of preceptors, program length standardization, and improvement of emergency clinical response education. Additional research studies were implemented to further explore issues novice nurses and their proficient registered nurse colleagues experience throughout the organization. PMID- 29481465 TI - Preparing Nursing Professional Development Practitioners in Their Leadership Role: Management and Leadership Skills. PMID- 29481466 TI - A Model to Support Newly Licensed Nurses. PMID- 29481467 TI - Mindfulness Training for the Modern Day Workforce. PMID- 29481468 TI - Precepting and the Art of Storytelling. PMID- 29481469 TI - Looking Back at 2017: Caring in Action. PMID- 29481470 TI - Orienting the New Graduate Nurse to Floating: Ideas to Ease the Transition. PMID- 29481472 TI - Prelicensure Employment and Student Nurse Self-Efficacy. PMID- 29481471 TI - Can You Escape? Creating an Escape Room to Facilitate Active Learning. AB - Nursing professional development practitioners have the responsibility to find creative and innovative ways to teach and provide learners with the education needed to practice safely in the hospital setting. This article describes an interactive game-based learning experience as a way to engage and empower both nurse residents and experienced nurses. PMID- 29481473 TI - Fortuitous administration of denosumab in breast carcinoma with osteoclastic giant cells. AB - Breast carcinoma with osteoclastic giant cells (OGCs) is a rare entity characterized by an admixture of giant cells and malignant epithelial cells within an inflammatory and vascular stroma. Denosumab is a monoclonal antibody that targets the pathway for osteoclast formation and activation, indicated for the prevention of skeletal-related events in patients with bone metastases, as well as for the treatment of giant cell tumor of bone. We report a patient who presented with aggressive bone recurrence of breast cancer 12 years after her original diagnosis, showing a transformed histology that included multinucleated OGCs, and that was refractory to traditional therapy. Misdiagnosed with a tumor to-tumor metastasis of breast cancer to a giant cell tumor of bone, she was treated with denosumab for her presumed primary bone disease and had a remarkable clinical and radiological response. To the best of our knowledge, this is the first report of breast cancer with OGCs occurring initially in a metastasis while absent in the original tumor and the first description of its successful treatment with denosumab. This case sheds light on the development of giant cells in the tumor microenvironment and suggests the potential use of denosumab in the management of cancers with giant cell elements. PMID- 29481474 TI - Clinicopathological features and prediction values of HDAC1, HDAC2, HDAC3, and HDAC11 in classical Hodgkin lymphoma. AB - Histone deacetylases (HDACs) are involved in multiple physical and pathological processes in classical Hodgkin lymphoma (cHL). The prognostic value of HDACs in cHL patients has not been discussed. The aim of the current study is to investigate the HDAC1, HDAC2, HDAC3, and HDAC11 expressions, and to evaluate the correlation of HDAC1, HDAC2, HDAC3, and HDAC11 expressions with the survival rate in cHL patients. We retrospectively analyzed clinicopathological data of 28 patients who were diagnosed with cHL between August 2002 and March 2010. Immunohistochemistry was used to detect the expression of HDAC1, HDAC2, HDAC3, and HDAC11 in these patients. The results showed that HDAC1, HDAC3, and HDAC11 were expressed at a higher level in Hodgkin Reed-Sternberg cells, whereas HDAC2 was expressed at a lower level in Hodgkin Reed-Sternberg cells. The expression of HDAC2 had a relationship with pathological type (P=0.012). There was also a correlation between the expression of HDAC11 and the erythrocyte sedimentation rate (P=0.054). Other clinicopathological parameters had no significant correlation with the expression of HDAC1, HDAC2, HDAC3, and HDAC11 in terms of survival (P>0.05). The 10-year total survival rate by Cox multivariate analysis, after taking into account all clinical and pathologic factors, showed that bulky disease retained significance (P=0.028). Higher expression of HDAC1 predicted shorter progression-free survival and overall survival (OS) in cHL patients (P<0.05, in both cases), and higher expression of HDAC11 might be correlated with lower OS (P=0.05). The study showed that the expressions of HDAC2 and HDAC11 have a particular relationship with the pathologic subtype. Increased expression of HDAC1 was correlated negatively with progression-free survival and OS, and increased expression of HDAC11 had a borderline relationship with the OS rate in patients with cHL. PMID- 29481475 TI - The Role of Triple-Antibiotic Saline Irrigation in Breast Implant Surgery. AB - Implant-based breast reconstruction accounts for more than 70% of all breast reconstructions, and breast augmentation is the most commonly performed cosmetic operation annually. The clinically significant impact of infection and capsular contracture after breast implant surgery has brought clinicians to create infection reduction protocols for both oncologic and cosmetic operations alike. The use of triple-antibiotic saline irrigation has become a recommended intraoperative maneuver within these protocols to minimize surgical site infections, but the constituents of the irrigation, its individual efficacy, and the acceptability of including povidone-iodine within irrigation recipes have been debated. This review will investigate the microbiological data behind the selection of the constituents of triple-antibiotic saline. In vitro testing of the effectiveness of topical antibiotics used in saline irrigation against microorganisms responsible for breast implant infection is reviewed. Clinical data are presented describing the impact of triple-antibiotic saline on implant infection and capsular contracture after cosmetic and reconstructive surgery. PMID- 29481476 TI - Suture and Splint Compared With K-Wire Fixation for Open Zone 1 Extensor Tendon Injuries. AB - Extensor tendon injuries are classified as per the zone of injury. Zone 1 injuries disrupt the lateral bands with resultant inability to extend the distal interphalangeal joint. Open Zone 1 injuries have many well-described treatment options. To date, none of these have been compared directly. Our aim was to compare the benefit of additional Kirschner-wire fixation with suture repair and splinting of open Zone 1 extensor tendon injuries. We performed a retrospective cohort analysis comparing 2 different surgical procedures, "Suture and Splint" versus "Suture, Splint, and Kirschner wire." The 2 outcomes measured were final range of movement and lag. We had a total of 50 patients. There was no difference in range of motion and the mean length of splint time between the 2 groups. There was increased incidence of lag associated with Kirschner-wire group. PMID- 29481477 TI - Reducing Prominent Mandibular Angle Osteotomy Complications: 10-Year Retrospective Review. AB - BACKGROUND: Several methods are available for mandibular reduction, and each method is characterized by unique limitations and complications. However, only a few studies have systematically analyzed these complications. This study aimed to investigate the effects of the outcome of performing curved mandibular angle ostectomy and outer cortex grinding in 1-stage operation and to examine the causes of different types and characteristics of complications. METHODS: The subjects consisted of 528 patients who were subjected to curved mandibular angle ostectomy and outer cortex grinding in 1-stage operation through an intraoral approach. Surgical complications and related factors were recorded, and the rates of complication according to surgeons were simultaneously evaluated. RESULTS: The esthetic appearance of all of the patients was significantly improved, and they were satisfied with the results of the operation. The complication rate was 5.87%. No serious complications, such as subcondylar fracture, massive bleeding, permanent facial nerve, or asymmetry, occurred. Some complications, including 4 cases of hematoma, 4 cases of severe swelling, 2 cases of infection, and 1 case of sagging face, were detected. The absolute complication rate among faculty members ranged from 3.5% to 11.1%. CONCLUSIONS: Our protocol is an effective method for mandibular angle osteotomy with very few complications. The rate of complications can be effectively reduced, and some serious complications can be avoided because protective measures are improved. PMID- 29481478 TI - Surgical Management of Large Periorbital Cutaneous Defects: Aesthetic Considerations and Technique Refinements. AB - PURPOSE: The aim of this study was to repair large periorbital cutaneous defects by an innovative technique called PEPSI (periorbital elevation and positioning with secret incisions) technique with functional and aesthetic outcomes. METHODS: In this retrospective study, unilateral periorbital cutaneous defects in 15 patients were repaired by the PEPSI technique. The ages of patients ranged from 3 to 46 years (average, 19 years). The outcome evaluations included scars (Vancouver Scar Scale and visual analog scale score), function and aesthetic appearance of eyelids, and patient satisfaction. The repair size was measured by the maximum advancement distance of skin flap during operation. RESULTS: All patients achieved an effective repair with a mean follow-up of 18.3 months. Except one with a small (approximately 0.3 cm) necrosis, all patients healed with no complication. The mean Vancouver Scar Scale and visual analog scale scores were 2.1 +/- 1.7 and 8.5 +/- 1.2, respectively. Ideal cosmetic and functional outcomes were achieved in 14 patients (93.3%). All patients achieved complete satisfaction except 1 patient with partial satisfaction. The mean maximum advancement distance of skin flap was 20.2 mm (range, 8-50 mm). CONCLUSIONS: This study demonstrated that the PEPSI technique is an effective method to repair large periorbital cutaneous defects with acceptable functional and aesthetic outcomes. PMID- 29481479 TI - A 3-Dimensional Biomimetic Platform to Interrogate the Safety of Autologous Fat Transfer in the Setting of Breast Cancer. AB - INTRODUCTION: Obesity is a known risk factor for the development and prognosis of breast cancer. Adipocytes have been identified as a source of exogenous lipids in other cancer types and may similarly provide energy to fuel malignant survival and growth in breast cancer. This relationship is of particular relevance to plastic surgery, because many reconstructions after oncologic mastectomy achieve optimal aesthetics and durability using adjunctive autologous fat transfer (AFT). Despite the increasing ubiquity and promise of AFT, many unanswered questions remain, including safety in the setting of breast cancer. Clinical studies to examine this question are underway, but an in vitro system is critical to elucidate the complex interplay between the cells that normally reside at the surgical recipient site. To study these interactions and characterize possible lipid transfer between adipocytes to breast cancer cells, we designed a 3 dimensional in vitro model using primary patient-derived tissues. METHODS: Breast adipose tissue was acquired from patients undergoing breast reduction surgery. The tissue was enzymatically digested and sorted to retrieve adipocytes and adipose stromal cells. Polydimethylsiloxane wells were filled with type I collagen-encapsulated adipocytes labeled with the fluorescent lipid dye boron dipyrromethene, as well as unlabeled adipose stromal cells. A monolayer of red fluorescently labeled MDA-MB-231 and MDA-MB-468 breast cancer cells was seeded on the surface of the construct. Lipid transfer at the interface between adipocytes and breast cancer cells was analyzed. RESULTS: Confocal microscopy revealed a dense culture of native adipocytes containing fluorescent lipid droplets in the 3 dimensional collagen culture platform. RFP-positive breast cancer cells were found in close proximity to lipid-laden adipocytes. Lipid transfer from adipocytes to breast cancer cells was observed by the presence of boron dipyrromethene-positive lipid droplets within RFP-labeled breast cancer cells. CONCLUSION: We have established a 3-dimensional model to study complex breast cancer-adipose tissue interactions. Direct transfer of fluorescently labeled lipids from adipocytes to breast cancer cells may indicate aberrant metabolism to fuel malignant growth and adaptive survival. Our novel platform can untangle the complex interplay within the breast cancer tumor microenvironment for high throughput analysis and better elucidate the safety of AFT in postoncologic mastectomy. PMID- 29481480 TI - In Search of a Murine Model of Radiation-Induced Periprosthetic Capsular Fibrosis. AB - INTRODUCTION: Capsular contracture after breast reconstruction is a morbid complication, occurring in 30.0% to 47.5% of patients undergoing postoperative radiotherapy. Although it is well known that radiation increases rate of capsular contracture, there are few well-established animal models that faithfully replicate standard-of-care clinical practice, that is, prosthesis placement at the time of mastectomy followed by delayed radiotherapy. To better recapitulate current clinical practice, we developed a murine model in which the implant sites were irradiated 10 days postoperatively, rather than at time of surgery. METHODS: Hemispherical implants were created from polydimethylsiloxane and implanted bilaterally in the subcutaneous dorsa of 20 C57Bl/6 mice. Mice were randomized to 5 treatment groups, differing in irradiation dose: 0 to 40 Gy. Ten days postoperatively, irradiation was performed using 250-kVp x-rays (XRAD225Cx, Precision X-ray, North Branford, Conn). In 1 mouse per group, dosimeters were placed subcutaneously to measure the delivered absorbed dose. Thirty-one days postoperatively, the mice were sacrificed and examined grossly, and periprosthetic tissues were removed for histologic analysis of periprosthetic capsule thickness and cellular deposition. RESULTS: Total radiation dose was calculated by the treatment planning software and confirmed by the in vivo dosimeters. Physical examination of the irradiated region demonstrated evidence of local radiation delivery, including circular patterns of hair blanching and thinning directly over the implants. Furthermore, histologic analysis of the irradiated epidermis demonstrated dose-dependent radiation changes including keratin whorls and patches of uneven epidermal thickness. There was no statistically significant difference in capsule thickness among the groups. Mice in the 30 and 40 Gy groups endured complications including shortness of breath, coagulopathy, and death, signs of systemic radiation poisoning. CONCLUSIONS: There was no evidence of increased periprosthetic capsule thickness with localized irradiation, irrespective of dose up to 20 Gy. These results differ from those previously published, which demonstrated increased capsule thickness with 10 Gy irradiation. Given the evidence of local radiation delivery, we believe that the lack of increase in capsule thickness observed in our experiment is a real phenomenon and demonstrate the difficulty in creating an easily reproducible rodent model that mimics the effects of postmastectomy implant-based reconstruction and irradiation. PMID- 29481481 TI - Antigen-Mediated, Macrophage-Stimulated, Accelerated Wound Healing Using alpha Gal Nanoparticles. AB - BACKGROUND: Macrophages are known to be crucial to timely and efficacious wound healing. They have been shown to modulate inflammation and the migration and proliferation of regenerative cells, promoting tissue deposition and wound closure. This study explored the use of the natural antigen Galalpha1-3Galbeta1 4GlcNAc-R (alpha-gal), present in lower mammals yet absent in Old World primates and humans, to induce a transiently enhanced macrophage response and thereby direct accelerated wound closure and healing in a standard murine model. METHODS: alpha1,3galactosyltransferase knockout mice were stimulated to produce anti-Gal antibodies at levels comparable with humans. alpha-Gal-containing micelle nanoparticles were generated and applied to full-thickness splinted wounds on the mice. At 1, 2, 3, 6, and 9 days postoperatively, mice were killed, and wounds were analyzed histologically for macrophage invasion, epithelialization, vascularization, and granulation tissue deposition. Flow cytometry of wound tissue was performed to quantify relative levels of proinflammatory M1 to anti inflammatory M2 macrophage subtypes. RESULTS: Treatment of splinted full thickness murine wounds with alpha-gal-containing nanoparticles led to accelerated wound healing and closure as demonstrated by accelerated rates of keratinization, vascular growth, and wound tissue deposition. Furthermore, treated wounds demonstrated early and enhanced macrophage invasion, as well as a lower M1-M2 ratio. CONCLUSION: Application of alpha-gal-containing nanoparticles to wounds stimulated a transiently increased inflammatory response, accelerating the rate of wound healing. Use of alpha-gal may be a simple and effective way to stimulate the wound healing response in both normal and pathologic wound beds. PMID- 29481483 TI - Outcomes of 270 Consecutive Deep Inferior Epigastric Perforator Flaps for Breast Reconstruction. AB - BACKGROUND: The deep inferior epigastric perforator (DIEP) flap has gradually become the superior choice for autologous breast reconstruction because it reduces donor site morbidity, abdominal wall complications, and postoperative recovery time when compared with other flap types. METHODS: The purposes of this study are to report on the experience and clinical outcomes of consecutive DIEP flap breast reconstructions performed by a single surgeon at a cancer center between April 2011 and May 2016 and to characterize the trends among these flaps. RESULTS: Two hundred seventy DIEP flaps from 202 consecutive patients were assessed. Patient ages ranged from 31 to 73 years, with a mean (SD) of 52.81 (9.89) years. Ischemia time ranged from 17 to 211 minutes (mean [SD], 51.51 [23.02] minutes), and procedure length (including mastectomy time) was between 224 and 950 minutes (mean [SD], 548.13 [154.77] minutes). Venous coupler size was between 2 and 4 mm (mean [SD], 2.69 [0.33] mm), and 1 to 3 perforating vessels were maintained per flap (mean [SD], 1.71 [0.68] perforators). Total reexploration rate was 3.3% (n = 9), and the total complete flap loss rate was 1.1% (n = 3). CONCLUSIONS: In our experience, the DIEP flap is a safe, consistent, and reliable option for breast reconstruction. PMID- 29481482 TI - Evaluation of Contralateral and Bilateral Prophylactic Mastectomy and Reconstruction Outcomes: Comparing Alloplastic and Autologous Reconstruction. AB - BACKGROUND: Over the last decade, there has been a 12% increase in prophylactic mastectomy (PM) per year. The aim of the study was to analyze complication rates and associated risk factors in patients undergoing PM and reconstruction. METHODS: We reviewed patients undergoing PM (contralateral and bilateral) from 2010 to 2015 at a single academic institution. Data on patient characteristics and postoperative outcomes were obtained. Postoperative complications were categorized into minor and major groups. We compared complication rates between autologous and alloplastic reconstruction. Patient characteristics were assessed using univariable and multivariable models. RESULTS: Reconstruction after PM was performed on 390 breasts over the study period: 214 underwent autologous and 176 underwent alloplastic reconstruction. When comparing autologous and alloplastic reconstruction, significant differences were seen between the number of immediate breast reconstructions (96.3% vs 48.9%, P < 0.001, respectively) and 2-stage reconstructions (0.5% vs 44.9%, P < 0.001, respectively). The overall complication rate was 15.9%: 14.6% were minor complications, and 6.9% were major. Autologous reconstruction compared with alloplastic reconstruction had a lower incidence of minor complications (11.2% vs 18.8%, P = 0.036), breast infection (1.9% vs 13.1%, P < 0.001), and breast seroma (2.3% vs 7.4%, P = 0.018), respectively. Risk factors for complications included age (>=65), obesity, American Society of Anesthesiology class (>=3), smoking, hypertension, anxiety, tissue expander (with acellular dermal matrix), and implant-only reconstructions. CONCLUSION: In our study, autologous reconstruction appeared to have a better complication profile than alloplastic reconstruction. Clinicians may potentially use this information to guide preoperative counseling of women considering PM and reconstruction. PMID- 29481484 TI - Single-Institution Experience With Component Separation for Ventral Hernia Repair: A Retrospective Review. AB - PURPOSE: In this study, we reviewed our institution's experience using component separation for repair of ventral hernias. METHODS: This was a retrospective review of all component separations for ventral hernia between July 2009 and December 2015. Recorded data included body mass index (BMI), preoperative albumin, smoking history, comorbidities, additional procedures, length of surgery, hospitalization, recurrence, and postoperative complications. RESULTS: One hundred ninety-six component separations were performed in the study period. The average patient age was 56 years, and 65.3% of patients were female. The average BMI was 32.6 kg/m; preoperative albumin was 3.59; 18.4% were current smokers; 28.1% were diabetic; and 14.3% had heart disease. Postoperative complications developed in 16.8% of patients. Recurrence developed in 8.7% of patients. Patients who developed a postoperative complication had a higher BMI (P = 0.025) and lower albumin (P = 0.047) compared with patients who did not develop complications. Current smokers were more likely to develop complications (P = 0.008). More than one third of patients had additional procedures at the time of the ventral hernia repair. The addition of a plastic surgery procedure was not associated with an increased risk of developing a complication (P = 0.25). Patients who developed complications had a significantly longer hospital course (P < 0.001) but no difference in total operative time (P = 0.975). Increased number of comorbidities did not statistically correlate with an increased complication rate (P = 0.65) or length of hospital stay (P = 0.43). CONCLUSIONS: We identified risk factors that increase the likelihood of postoperative complications and length of hospital stay. In addition, this study suggests that more comorbidities and additional procedures at the time of the hernia repair may not have as large of impact on complication risk as previously thought. PMID- 29481485 TI - Total HIV-1 DNA Dynamics and Influencing Factors in Long-Term ART-Treated Japanese Adults: A Retrospective Longitudinal Analysis. AB - BACKGROUND: Understanding HIV persistence in treated patients is an important milestone toward drug-free control. We aimed at analyzing total HIV DNA dynamics and influencing factors in Japanese patients who received more than a decade of suppressive antiretroviral treatment (ART). METHODS: A retrospective study including clinical records and 840 peripheral blood mononuclear cells samples (mean 14 samples/patient) for 59 patients (92% male) was performed. Subjects were divided into 2 groups: with and without hematological comorbidity (mainly hemophilia) plus hepatitis C virus coinfection. Total HIV DNA was measured in peripheral blood mononuclear cells by quantitative polymerase chain reaction. The dynamics, regression over time, and influence of antiretrovirals by group were estimated using a novel regression model (R software v 3.2.3). RESULTS: Total HIV DNA decreased on ART initiation, and subsequently, its dynamics varied between groups with previously undescribed fluctuations. If calculated by on-treatment, the mean total HIV DNA levels were similar. The comorbidity group had unstable levels showing different regression over time (P = 0.088/0.094 in year 1/after year 8 of ART) and significantly different treatment responses as shown by antiretroviral group switching estimates. Furthermore, curing hepatitis C virus in hemophiliacs did not significantly alter total HIV DNA levels or regression. CONCLUSIONS: Our data identified some effects of the long-term treatment on total HIV DNA levels and highlighted the partial influence of comorbidities and coinfections. Total HIV DNA monitoring contributed to therapy response estimates and HIV reservoir quantification. The results suggest that HIV DNA monitoring during ART might be useful as a persistence marker in both HIV-monoinfected patients and those with comorbidities and coinfections. PMID- 29481486 TI - Brief Report: Efficacy and Safety of Switching to Coformulated Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide (E/C/F/TAF) in Virologically Suppressed Women. AB - BACKGROUND: The integrase inhibitor regimen [elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (TDF)] demonstrated superior efficacy when compared with a protease inhibitor regimen [ritonavir-boosted atazanavir (ATV + RTV) and FTC/TDF] in 575 treatment-naive women at week 48. We investigated the efficacy, safety, and tolerability of switching to a TAF-based, single-tablet regimen containing elvitegravir, cobicistat, FTC, and tenofovir alafenamide (E/C/F/TAF) versus remaining on ATV + RTV plus FTC/TDF. METHODS: After completing the initial randomized, blinded phase, virologically suppressed (HIV-1 RNA <50 copies/mL) women on ATV + RTV plus FTC/TDF were rerandomized (3:1) to receive open-label E/C/F/TAF versus remaining on their current regimen. The primary end point was proportion of participants with plasma HIV-1 RNA <50 copies per milliliter at week 48 (U.S. FDA snapshot algorithm), with a prespecified noninferiority margin of 12%. Safety [adverse events (AEs)] and tolerability were also assessed. RESULTS: Of 575 women originally randomized and treated in the blinded phase, 159 were rerandomized to switch to E/C/F/TAF and 53 to remain on ATV + RTV plus FTC/TDF. At week 48, virologic suppression was maintained in 150 (94%) of women on E/C/F/TAF and 46 (87%) on ATV + RTV plus FTC/TDF [difference 7.5% (95% confidence interval -1.2% to 19.4%)], demonstrating noninferiority of E/C/F/TAF to ATV + RTV and FTC/TDF. Incidence of AEs was similar between groups; study drug-related AEs were more common with E/C/F/TAF (11% versus 4%). CONCLUSIONS: Switching to E/C/F/TAF was noninferior to continuing ATV + RTV plus FTC/TDF in maintaining virologic suppression and was well tolerated at 48 weeks. PMID- 29481487 TI - Positive or Not, That Is the Question: HIV Testing for Individuals on Pre exposure Prophylaxis. PMID- 29481488 TI - Neprilysin in the Cerebrospinal Fluid and Serum of Patients Infected With HIV1 Subtypes C and B. AB - OBJECTIVE: Neprilysin (NEP) is the dominant Abeta peptide-degrading enzyme in the brain. HIV-1 subtype B transactivator of transcription protein is known to interfere with NEP function, but whether this is true of HIV-1C transactivator of transcription, which has a defective chemokine motif, is not known. This study aimed to analyze the impact of HIV subtype on NEP-mediated cleavage of Abeta by comparing cerebrospinal fluid (CSF) and serum levels of NEP between HIV+ (27 patients with HIV-1B and 26 with HIV-1C), healthy HIV- controls (n = 13), and patients with Alzheimer disease (n = 24). METHODS: NEP and Abeta oligomers 38, 40, 42 levels were measured in CSF and serum by immunoassays. Ratios between NEP and Abeta-38, 40, 42, and total were calculated in CSF and serum. Comparisons between HIV(+) and HIV(-) were adjusted by linear regression for sex and age; HIV subtype comparisons were adjusted for nadir CD4 and plasma viral load suppression. RESULTS: Levels of NEP and ratios in CSF were comparable for HIV-1C and B subtypes. The ratio of serum NEP/Abeta-40 was lower for HIV1-C than HIV1-B (P = 0.032). The CSF/serum index of NEP/Abeta-40, NEP/Abeta-42, and NEP/Abeta total were lower for HIV1-B than HIV1-C (P = 0.008, 0.005, and 0.017, respectively), corroborating the findings for serum. CSF NEP was comparable for HIV+, HIV-, and AD. CONCLUSION: There was impact of HIV subtype on NEP. The ratio of NEP/Abeta-40 on serum was lower on HIV1-C than HIV1-B. These results are consistent with the results of CSF Abeta-42 levels decreased in HIV1-C compared with HIV1-B, suggesting higher amyloid beta deposit on HIV1-C than HIV1-B. PMID- 29481489 TI - Post-mortem analysis of suicide victims shows ABCB1 haplotype 1236T-2677T-3435T as a candidate predisposing factor behind adverse drug reactions in females. AB - BACKGROUND: Genetic variation in efflux transporter, permeability glycoprotein (P gp), has recently been associated with completed violent suicides and also violent suicide attempts. As depression is known to be a risk factor for suicide and many antidepressants are P-gp substrates, it has been speculated that inadequate antidepressant treatment response or adverse side effects could be involved. OBJECTIVES: The aim of this study was to investigate whether there is an association between the P-gp coding ABCB1 gene and completed suicides in citalopram users. Also, the effect of sex and suicide method used (violent vs. non-violent) was evaluated. MATERIALS AND METHODS: All cases included in the study population, 349 completed suicide victims and 284 controls, were shown to be positive for antidepressant citalopram in a post-mortem toxicological drug screen. ABCB1 1236C>T, 2677G>T/A and 3435C>T polymorphisms were determined by TaqMan genotyping assays. Haplotypes were constructed from genotype data using the PHASE software. The association between the manner of death and the ABCB1 haplotype was tested with logistic regression analysis. RESULTS: No statistically significant differences were observed in the ABCB1 allele or genotype frequencies between the suicide and control groups. However, the ABCB1 1236T-2677T-3435T haplotype was associated with completed suicides of female citalopram users (odds ratio: 2.23; 95% confidence interval: 1.22-4.07; P=0.009). After stratification by the method used for suicide, the association emerged in fatal intoxications (odds ratio: 2.51; 95% confidence interval: 1.29-4.87; P=0.007). In other groups, no statistically significant associations were observed. CONCLUSION: Our results suggest that female citalopram users with ABCB1 1236T-2677T-3435T are more vulnerable to adverse effects of the drugs as this haplotype was enriched in non violent suicides of female citalopram users. Even though the biological mechanism behind this observation is unknown, the results provide another example of the importance of sex-based segregation in pharmacogenetics studies. PMID- 29481490 TI - An Interview With Dr. Dennis Tarnow: The Propensity for Probing Around Dental Implants. PMID- 29481491 TI - Assessing Postoperative Reduction After Acetabular Fracture Surgery: A Standardized Digital Computed Tomography-Based Method. AB - Quality of reduction after acetabular fracture surgery is an important predictor of clinical outcome. Computed tomography (CT) is likely superior to plain pelvic radiography for assessment of postoperative reduction, but interobserver reliability may be limited in the absence of a widely adopted technique. We describe a standardized digital CT-based method for measuring residual (gap and step) displacement on CT after acetabular fracture surgery. In a selection of patients, we determined the interobserver reliability for measuring displacement and grading the quality of reduction on postoperative pelvic radiography and CT, with and without the use of this novel technique. PMID- 29481492 TI - Early evolution of BRAFV600 status in the blood of melanoma patients correlates with clinical outcome and identifies patients refractory to therapy. AB - Serial analysis of BRAF mutations in circulating-free DNA (cfDNA) could be of prognostic value in melanoma patients. We collected blood samples from 63 advanced BRAFV600E/K melanoma patients and determined BRAFV600E/K status in cfDNA using a quantitative 5'-nuclease PCR-based assay. Levels of BRAF mutation in pre cfDNAs were associated significantly with tumour burden, progression-free survival and overall survival. Changes in BRAF status in cfDNA after initiation of treatment (early-cfDNA) had a significant correlation with outcome. In patients with persistent BRAF mutations (n=12), progression-free survival and overall survival were 3.5 months [95% confidence interval (CI): 1.6-4.6] and 5.3 months (95% CI: 3.4-8.1) compared with 16.6 months (95% CI: 8.2-22.3) and 21.9 months (95% CI: 10.2-NR) in patients with BRAF negativization (n=16), and 15.1 months (95% CI: 2.3-NR) and NR (95% CI: 5.1-NR) in patients who maintained their initial negative status (n=12) (P<0.0001). The median duration of response in patients with radiological response, but persistence of BRAFV600 in early-cfDNA (n=5) was 4 months. Our study indicates that serial BRAF testing in the blood of advanced melanoma identifies patients refractory to therapy. PMID- 29481494 TI - Simplified Access for Reduction and Fixation of a Frontal Bone Fracture. AB - The frontal bone fractures occur very often in service units in oral and maxillofacial surgery. Bicoronal access is the most common for the surgical treatment of frontal bone fractures. However, patients are surprised when they receive notice that such invasive access will be made. This approach allows adequate visualization of the fracture site, but may be associated with complications, which can be avoided by the use of less invasive techniques. We describe an alternative approach that aims to minimize the complications of a coronal incision. PMID- 29481493 TI - Contour Restoration of Over-Resected Mandibular Angle and Lower Border by Reduction Mandibuloplasty Using Three-Dimensional Planning and Computer-Aided Design and Manufacturing Custom-Made Titanium Implants. AB - OBJECTIVE: The purpose of this clinical report was to introduce a new methodology for contour restoration of the over-resected mandible by reduction mandibuloplasty using 3-dimensional (3D) planning and computer-assisted design and manufacturing (CAD-CAM) custom-made titanium implants. PATIENT AND METHOD: A 20-year-old male patient had undergone reduction of the zygoma and mandibular angle and lower border for esthetic reason 1 year ago at a private clinic. However, he was not satisfied with surgical outcome and wanted to restore his original facial volume and contour. To assess the volume and dimension of resected bone, 3D-computed tomography (3D-CT) data at the original stage was superimposed with postsurgical CT. For restoration of the malar prominence, porous polyethylene malar implants with extensions into the lateral malar region (Medpor) were placed and fixed with microscrews. Custom-made titanium implants were fabricated for contour restoration of the mandibular angle and lower border using CAD-CAM technology (iDDA, Daegu, South Korea). Two-piece design per each titanium implant was adopted for easy placement and avoidance of tissue damage during placement. Thin buccal extension was incorporated for placement of screw holes. Location, direction, and length of bicortical screws were planned to avoid damage of the inferior alveolar nerve. RESULT: With the help of 3D planning and CAD-CAM technology, rigid fixation of the custom-made titanium implants into the mandibular angle and lower border successfully restored the contour of over resected mandible to the original state. CONCLUSION: When over-resection by reduction mandibuloplasty becomes an issue, this method may be an effective treatment option for contour restoration of over-resected mandibular angle and lower border. PMID- 29481495 TI - Virtual Surgical Planning for Correction of Delayed Presentation Scaphocephaly Using a Modified Melbourne Technique. AB - BACKGROUND: Late treatment of scaphocephaly presents challenges including need for more complex surgery to achieve desired head shape. Virtual surgical planning for total vault reconstruction may mitigate some of these challenges, but has not been studied in this unique and complex clinical setting. METHODS: A retrospective chart review was conducted for patients with scaphocephaly who presented to our institution between 2000 and 2014. Patients presenting aged 12 months or older who underwent virtual surgical planning-assisted cranial vault reconstruction were included. Patient demographic, intraoperative data, and postoperative outcomes were recorded. Pre- and postoperative anthropometric measurements were obtained to document the fronto-occipital (FO) and biparietal (BP) distance and calculate cephalic index (CI). Virtual surgical planning predicted, and actual postoperative anthropometric measurements were compared. RESULTS: Five patients were identified who fulfilled inclusion criteria. The mean age was 50.6 months. One patient demonstrated signs of elevated intracranial pressure preoperatively. Postoperatively, all but one needed no revisional surgery (Whitaker score of 1). No patient demonstrated postoperative evidence of bony defects, bossing, or suture restenosis. The mean preoperative, simulated, and actual postoperative FO length was 190.3, 182, and 184.3 mm, respectively. The mean preoperative, simulated, and actual postoperative BP length was 129, 130.7, and 131 mm, respectively. The mean preoperative, simulated, and actual postoperative CI was 66, 72, and 71.3, respectively. CONCLUSIONS: Based on our early experience, virtual surgical planning using a modified Melbourne technique for total vault remodeling achieves good results in the management of late presenting scaphocephaly. PMID- 29481496 TI - Short-Blunt Injury in Child Resulting From Pet Bite. AB - The frequency of accidents due to dog bite in children is high, and in the most cases, the child already knows the aggressor dog. Patient, 3 years, female, melanoderm, victim of pet dog attack on the right side of the face region. After the physical examination, conscious sedation was performed with the supplementation of oxygen by pediatrics and the suture by oral and maxillofacial surgeon, under local anesthesia with adrenergic vasoconstrictor, with internal points in the muscles using vicryl 4-0 and in the skin with 5-0 nylon; the lesser number of stitches were performed in the lower region of the wound, allowing spontaneous drainage spaces. The immediate wounds closure of dog bites on the face is safe, even in cases after several hours of the injury. PMID- 29481497 TI - Single-Piece Titanium Plate Cranioplasty Reconstruction of Complex Defects. AB - BACKGROUND: Different methods have been described for the reconstruction of cranial defects and orbital defects. The complex contouring between the orbital roof and frontal bone creates significant design challenges for prefabricated cranio-orbital reconstructions. In describing the first reported patient of combined skull and orbital roof reconstruction with a single-piece titanium plate cranioplasty, the authors present a new method of combined complex cranio-orbital reconstruction. METHODS: A 63-year-old lady presented with a large, right-sided frontal en-plaque meningioma involving the right orbit and sphenoid wing. Complete resection would require reconstruction of both the skull and the orbital roof. Surgical preplanning involved marking resection margins on a three dimensional (3D) printed acrylonitrile-butadiene-styrene model. This margin was used to virtually resect the tumor and generate a repaired surface. A titanium plate was then fabricated using hydrostatic pressing into a 3D-printed mold and the orbital roof portion (a reentrant surface) was hand-finished. Lateral canthus and temporalis muscle suspension holes were prefabricated into the cranioplasty plate. RESULTS: The patient underwent hemicraniectomy and tumor resection guided by a custom-made 3D-printed cutting guide. The surgical defect was reconstructed with the prefabricated titanium plate achieving a good functional and cosmetic result. CONCLUSION: Single-piece titanium plate cranioplasty is an effective novel reconstruction method for complex cranio-orbital defects. PMID- 29481498 TI - Postpartum Depression in Mothers of Infants With Cleft Lip and/or Palate. AB - This study describes postpartum depression rates and risk factors for mothers with infants with cleft lip and/or palate as postpartum depression has been associated with a range of negative maternal and child outcomes. A retrospective chart review from August 2009 to May 2015 included medical diagnoses, demographics, receipt of prenatal diagnosis, and the Edinburgh Postnatal Depression Scale (EPDS). Mothers (N = 206) had infants (59.2% male; mean age in weeks 5.1 +/- 6.9) with isolated cleft lip (18%), cleft palate (22.8%), or cleft lip and palate (59.2%). Mothers ranged from 16 to 45 years old (mean age 29 +/- 6.2) and half had received a prenatal diagnosis. Patients mostly had public insurance (57.8%) and represented diverse ethnicities. Based on the EPDS, 11.7% of mothers met the depression cutoff of 10 or higher. The majority endorsed self blame (68.9%), difficulty coping (59.2%), and feeling anxious (57.3%). Mothers of infants with cleft lip or cleft lip and palate who did not receive a prenatal diagnosis had higher total EPDS scores, anxiety, and incidence of feeling scared. Higher EPDS scores were predicted by not having a prenatal diagnosis and by older maternal age. Mothers of infants with a cleft had similar rates of postpartum depression as the general population; however, those who were older and who did not receive a prenatal diagnosis endorsed more symptoms. Prenatal diagnosis may contribute to positive maternal postpartum adjustment. Providers should incorporate screening for risk factors into their evaluation and treatment planning. PMID- 29481499 TI - Respiratory Obstruction Due to Richards Type 4 Fracture. AB - Facial fractures can be potentially fatal in polytraumatized patients due to retropositioning tissues to upper airway obstruction. In the first aids, this situation can be reversed using a tracheostomy procedure to break out the airways. However, fractures leading to airway obstruction are rare and according to Richards Classification can be classified into 5 types. The purpose of this article is to report a clinical patient with a bilateral condylar and mandibular symphysis fractures that resulted in airway obstruction and severe mandibular rear projection. PMID- 29481500 TI - Anatomical and Radiological Investigation of Dry Bone Adult Mandibles Having Impacted Third Molar Teeth. AB - OBJECTIVE: To investigate the incidence of the impacted mandibular third molars in dry bones adult mandibles. METHODS: The 198 dry bones adult mandibles gathered from the bone collections in Laboratory of the Anatomy Department of Dokuz Eylul University School of Medicine were macroscopically examined for the presence of impacted mandibular third molars. The genders of the adult bones were unknown. The adult mandibles having impacted third molars were photographed with Canon 400B (55 mm objective). The mandibles having impacted third molars were also radiographically examined with orthopantomography (a dental radiographic technique, kV 60, mA 2.0) in radiology unit of Faculty of Dentistry, Ege University. The impacted teeth were grouped according to their position and degree of impaction. RESULTS: The each of 2 of 198 adult mandibles (2/198; 1.01%) was having an impacted 3rd molar teeth. These 2 molar teeth were belonged to class 1, B and partially buried, vertically oriented. The first impacted 3rd molar teeth was located on the left side of the one mandible and the second one on the right side of the other mandible. CONCLUSION: The present study provides information about impacted mandibular 3rd molar in dry bones. PMID- 29481501 TI - Review of "Sensitizing Surgeons to Their Outcome Has No Measurable Short-term Benefit" by Cauchy F, Farges O, Vibert E, Boleslawski E, Pruvot FR, Regimbeau JM, Mabrut JY, Scatton O, Adham M, Laurent C, Gregoire E, Delpero JR, Bachellier P, Soubrane O in Ann Surg 266: 884-889, 2017. PMID- 29481502 TI - Retracted or Withdrawn Publications in Journals Relating to Plastic Surgery. AB - The aim of this study was to determine how many papers have been retracted or withdrawn, and for what reason, in journals relating to plastic surgery.PubMed and SCOPUS were used, with the search terms (retracted OR withdrawn) AND (article OR publication OR paper) AND {(plastic surgery) OR (cosmetic surgery) OR (maxillofacial surgery) OR (craniofacial surgery)}. The papers were analyzed and classified according to the reason for retraction or withdrawal, journal name, publication year, and author. In the PubMed and SCOPUS, 227 and 114 titles were found, respectively, from which 34 duplicate titles were removed. An additional 261 titles which did not include "retracted" or "withdrawn" were removed, leaving 46 papers and 6 mined papers were added. The 52 full texts (42 "retracted" and 10 "withdrawn") were analyzed.The most frequent reason for retraction or withdrawal was duplication (17, 32.7%) followed by the author's request (9, 17.3%), plagiarism (7, 13.5%), and lack of permission (5, 9.6%). Retraction was most common in Plast Reconstr Surg (6, 12%) followed by Aesthetic Plast Surg (4, 7.9%), Ann Plast Surg (2, 3.9%), J Plast Reconstr Aesthet Surg (2, 3.9%), and Surg Res (2, 3.9%). Most authors retracted a paper just once; however, 6 authors retracted a paper twice or more. The first retraction was found in 1991, and the number of retractions showed a tendency to increase over time. However, the duplication rate did not change over time (R = 0.178, P = 0.117).Journal reviewers, as well as production editors, should check for duplication, plagiarism, or permission-related problems. PMID- 29481503 TI - Early Tarsorrhaphy in Conjunctival Chemosis After Orbit Bone Reconstruction. AB - OBJECTIVE: Chemosis is a common occurrence after orbital reconstruction surgery by the transconjunctival approach. The authors propose an early tarsorrhaphy approach for treating severe conjunctival chemosis following orbital fracture repair. METHODS: All severe conjunctival chemosis patients following orbital fracture repair were divided into 2 groups: tarsorrhaphy performed immediately when the eyelids could not close completely due to prominent conjunctival edema (early tarsorrhaphy, n = 10); and tarsorrhaphy performed 3 days after the appearance of severe chemosis (delayed tarsorrhaphy, n = 10). Once the conjunctiva subsided, the sutures were immediately removed. The duration of conjunctival edema was recorded. RESULTS: The average time to resolution of severe chemosis was significantly shorter in the early versus delayed tarsorrhaphy group (3.5 +/- 0.5 versus 7.2 +/- 1.73 days, P < 0.05). No recurrence of conjunctival edema occurred in any patient 4 months postoperatively. CONCLUSIONS: Early temporary tarsorrhaphy is a fast and effective method for the treatment of conjunctival chemosis following orbital fracture surgery. The sooner eyelid suturing is performed, the faster conjunctival chemosis will subside. PMID- 29481505 TI - Active Intracystic Negative Pressure Could Induce Osteogenesis. AB - Based on previous findings, the author introduces the term "sugosteogenesis," a biological phenomenon that occurs by using the Evocyst, a device that exerts active intracystic negative pressure. The term "sugosteogenesis" comes from the Latin word "sugo-," meaning "suck," and Greek words "osteo-," meaning "bone," and genesis, "origin." PMID- 29481504 TI - Autologous Bone Marrow Concentrates and Concentrated Growth Factors Accelerate Bone Regeneration After Enucleation of Mandibular Pathologic Lesions. AB - Stem cell therapy is a revolutionary new way to stimulate mesenchymal tissue regeneration. The platelets concentrate products started with platelet-rich plasma (PRP), followed by platelet-rich fibrin (PRF), whereas concentrated growth factors (CGF) are the latest generation of the platelets concentrate products which were found in 2011. The aim of the present study was to evaluate the potential of combining autologous bone marrow concentrates and CGF for treatment of bone defects resulting from enucleation of mandibular pathologic lesions. Twenty patients (13 males and 7 females) with mandibular benign unilateral lesions were included, and divided into 2 groups. Group I consisted of 10 patients who underwent enucleation of the lesions followed by grafting of the bony defects with autologous bone marrow concentrates and CGF. Group II consisted of 10 patients who underwent enucleation of the lesions without grafting (control). Radiographic examinations were done immediately postoperative, then at 1, 3, 6, and 12 months, to evaluate the reduction in size and changes in bone density at the bony defects. Results indicated a significant increase in bone density with respect to the baseline levels in both groups (P < 0.05). The increase in bone density was significantly higher in group I compared with group II at the 6- and 12-month follow-up examinations (P < 0.05). The percent of reduction in the defects' size was significantly higher in group I compared with group II after 12 months (P = 0.00001). In conclusion, the clinical application of autologous bone marrow concentrates with CGF is a cost effective and safe biotechnology, which accelerates bone regeneration and improves the density of regenerated bone. PMID- 29481506 TI - Autologous Free Fat Grafting for Management of the Facial Contour Asymmetry. AB - BACKGROUND: The purposes of this study were to report autologous free fat grafting as the workhorse procedure to augment the facial soft-tissue envelope and restore facial contour symmetry of patients with asymmetric facial malformations; to detail the SOBRAPAR Hospital algorithm for soft-tissue reconstruction of patients with facial contour asymmetry; and to assess facial symmetry after fat grafting. METHODS: A retrospective analysis of consecutive patients (n = 178) who underwent fat grafting to restore the facial contour symmetry according to the SOBRAPAR Hospital algorithm between 2009 and 2016 was conducted. Computerized photogrammetric quantitative and qualitative facial symmetry analyses were performed. RESULTS: There were significant (all P < 0.05) postoperative quantitative facial symmetry enhancement and an overall qualitative facial symmetry enhancement, with a mean fat graft procedures per patient of 1.6 +/- 0.7, ranging of 1 to 3. CONCLUSION: A significant improvement of facial contour symmetry was obtained in a subset of patients using fat grafting according to the SOBRAPAR Hospital algorithm. PMID- 29481507 TI - Clinical Efficacy Evaluation for Treating Trigeminal Neuralgia Using a Personalized Digital Guide Plate-Assisted Temperature-Controlled Radiofrequency. AB - The aim of this study was to explore the application and efficacy of personalized digital guiding plate-aided radiofrequency in treating trigeminal neuralgia (TN). A total of 117 cases (93 patients) of TN from January 2015 to December 2016 were divided into the study group (n = 53) and the traditional group (n = 64). Patients in the study group were treated by the radiofrequency through a personalized digital guiding plate, whereas those in the traditional group were treated by the traditional method. We found that no significant difference between these 2 groups in age, sex, and divisions affected (V2, V3). However, the values for operation time, recurrence rate, and patient's satisfaction in the plate assisted group were significantly improved compared with those in the traditional group. Therefore, the personalized digital guiding plate-assisted radiofrequency has higher application value than traditional method. PMID- 29481508 TI - Suitability of Wrist External Fixator for Treatment of Mandibular Fracture. AB - The mandibular fracture is one of the most commonly fractures of the facial bones. In high-energy traumas, a comminuted mandible fracture may occur. The closed reduction with external fixator is an interesting alternative for these types of fractures. The aim of this article is to report the case of a patient with comminuted fracture in the right mandibular body, whose surgical treatment was the noninvasive reduction of fracture and stabilization using a Colles' wrist external fixator. After 1 year of follow-up, the patient is without complaints, with satisfactory dental occlusion, adequate contour, and mandibular alignment. External fixation with wrist orthopedic fixators adapted to the mandible provides many advantages owing to its versatility and simplicity of use. Therefore, this method should be remembered as a valid and affordable option for the treatment of complex lesions when indicated correctly. PMID- 29481510 TI - Removal of the Residual Roots Displaced Into the Maxillary Sinus via Endoscopy. AB - Minimally invasive endoscopic surgery has been developed for various indications in the craniomaxillofacial area. The case report presented in this article is focused on the possibility of removing the residual roots displaced into the maxillary sinus by means of an endoscopic technique. When planning endoscopic surgery to access the residual roots displaced in the maxillary sinus, we performed 2 different approaches into the maxillary sinus, a transnasal approach through the middle or inferior turbinate and transoral approach via the anterior maxillary sinus wall. The endoscopic surgical approach described is reliable and minimally invasive for removing the residual roots displaced into the maxillary sinus. Therefore, we concluded that the application of this clinical procedure is worth promoting. PMID- 29481509 TI - Outcome of Conventional Adipose Tissue Grafting for Contour Deformities of Face and Role of Ex Vivo Expanded Adipose Tissue-Derived Stem Cells in Treatment of Such Deformities. AB - OBJECTIVES: To evaluate the outcomes of conventional fat grafting for facial contour deformities and to describe clinical outcome of a patient with contour deformity of face treated with ex vivo expanded adipose tissue-derived mesenchymal stem cells (ASCs) enriched fat graft. PLACE AND DURATION OF STUDY: The Department of Plastic Surgery and Tissue Engineering and Regenerative Medicine Laboratory, King Edward Medical University/Mayo Hospital, Lahore, from September 2015 to September 2017. METHODS: Patients with contour deformities of face requiring soft tissue augmentation were included. Fat was harvested, processed, and injected following a standard protocol. Both subjective and objective assessments were performed and complications were also noted. RESULTS: Twenty-five patients underwent 51 fat-grafting sessions over a period of 24 months. Eighteen (72%) patients underwent multiple fat-grafting sessions. Mean (standard deviation) soft tissue thickness after 72 hours and 6 months of first fat graft session was 18.62 (7.2) and 12.88 (6.21) mm, respectively, which corresponds to 30.77 (13)% reduction of transplanted fat. Physician and patient assessment scores were 3.42 (0.92) and 4 (1.04), respectively. Few minor complications were observed. In the patient undergoing ex vivo expanded ASCs enriched fat graft, there was minimal decrease in soft tissue thickness of treated area (44 mm vs 42 mm) 6 months postoperatively and patient was highly satisfied with the outcome after the single session. CONCLUSION: Conventional fat grafting is safe for correction of facial contour deformities. However, procedure needs to be repeated multiple times to produce satisfactory results. Beneficial effects of ex vivo expanded ASCs enriched fat grafting have a potential to alter the current treatment paradigm of fat grafting for soft tissue reconstruction. PMID- 29481511 TI - Spring-Assisted Surgery in the Treatment of Complex Craniosynostosis. AB - Multisutural nonsyndromic craniosynostosis is a rare group of malformations, whose frequency has been reported between 3% and 7% of all craniosynostosis. The clinical diagnosis can be difficult and computed tomography is usually required. Surgical treatment is challenging and staged procedures are performed in up to 80% of patients. The aim of the present study was to determine the reoperation rate and to evaluate the surgical outcomes by measuring intracranial volume (ICV) preoperatively and at follow-up, and comparing it to a control group. Perioperative variables and reoperation rate were recorded. Fifty-one patients presented with a complex pattern of synostosis without a recognizable syndrome (5% of cases of total patients evaluated). Fifteen patients have been treated with spring-assisted surgery, either alone or in combination with a foreheadplasty. The mean follow-up was 6.2 years. The mean preoperative ICV of the patients was smaller, but not significantly, than in the normal population (P = 0.13). Postoperatively, the mean ICV was similar to that of the control group at 1 year (P = 0.92), while at 3 years it was appreciably smaller, although not significantly different (P = 0.06). Five patients (33%) went through a secondary skull expansion for either raised intracranial pressure or cosmetic reasons. Spring-assisted surgery seems to temporarily expand ICV in children with complex synostosis and lower the reoperation rate, thus reducing the need for a second procedure. A longer follow-up would be necessary to further investigate the effects of springs over time. PMID- 29481512 TI - Surgical Treatment Outcomes of Vocal Process Granuloma After Endotracheal Intubation. AB - INTRODUCTION: The objective of this study was to review the clinical characteristics and surgical treatment outcomes of the vocal process granuloma after the endotracheal intubation. METHODS: A retrospective chart review was performed at Chonnam National University Hwasun Hospital from January 2008 to December 2015. RESULTS: Twenty-one vocal process granulomas after endotracheal intubation were diagnosed in 13 patients. The most common symptom was hoarseness. Among 13 patients, bilateral vocal process granulomas were in 8 patients. For the remaining 5 patients, their unilateral vocal process granulomas were all left sided. All the cases of vocal process granulomas after the endotracheal intubation were treated by laryngoscope microsurgery under general anesthesia. Recurrence of vocal process granulomas was identified in 1 lesion. CONCLUSION: This study suggests that surgery for vocal process granuloma after endotracheal intubation is a good treatment option for a rapid resolution of lesions and the associated symptoms, along with having low recurrence rates. PMID- 29481513 TI - The Relationship Between Cephalogram Analysis and Oxygen Desaturation Index During Sleep in Patients Submitted for Mandibular Setback Surgery. AB - OBJECTIVES: The aim of this study was to examine the relationship between morphologic factors of mandibular protrusion patients and clinical indices of obstructive sleep apnea (OSA). METHODS: Fifty-two Japanese patients divided into 2 groups: 1 jaw surgery group (30 patients) and 2 jaw surgery group (22 patients). Morphologic changes were studied using cephalograms taken before surgery and 1 year after surgery. Functional changes studied using impulse oscillometry and pulse oximetry during sleep, both of which are clinically useful measures in assessing OSA, taken before surgery and 1 year after surgery. RESULT: Lower face cage area significantly decreased in 1 jaw group than in 2 jaw group patients. Positive significant correlation was found between changes in 3% oxygen desaturation index (ODI) and changes of tongue area and vertical position of the hyoid bone in 1 jaw surgery group. Multiple regression analysis indicates that tongue area and airway area were independently significant predictors of 3% ODI in 1 jaw group patients. CONCLUSION: In 2 jaw surgery, maxillary surgery compensated for the effect of mandibular setback surgery. Mandibular setback surgery to mandibular protrusion patients was performed within the range of adequate movement distance, but precautions for risk of postoperative obstructive sleep apnea syndrome should be considered. PMID- 29481514 TI - Perceptions of Healthy-Looking and Sexy-Looking Brow Thickness. AB - This study aims to determine which brow thickness levels were considered ideal, healthy-looking, young-looking, and sexy-looking by Koreans.The 163 women and 38 men who visited a brow bar were asked to view illustrations of 4 brow thickness levels defined in terms of the percentage of the eye width at the lateral canthus: very thin (VTn-1/6) (16% of eye width), thin (Tn-1/5) (20%), medium (Med 1/4) (25%), and thick (Tk-1/3) (33%) and to choose which they thought were ideal, young-looking, healthy-looking, and sexy-looking.Med-1/4 (61.2%) was the brow thickness most often considered to be ideal, followed by Tk-1/3 (17.4%) and Tn 1/5 (15.9%). VTn-1/6 was the least preferred (5.5%). Med-1/4 was the most preferred ideal thickness among both sexes. Tk-1/3 (40.8%) was the thickness most often considered to be young-looking, followed by Med-1/4 (35.3%) and Tn-1/5 (18.4%). VTn-1/6 was the least preferred (5.5%). Tk-1/3 was the most preferred young-looking thickness among both sexes. Tk-1/3 (48.8%) was the thickness most often considered to be healthy-looking, followed by Med-1/4 (30.8%) and Tn-1/5 (11.9%). VTn-1/6 was the least preferred (8.5%). Tk-1/3 was the most preferred healthy-looking thickness by women (52.2%), whereas Med-1/4 was the most common choice among men (39.5%). Tn-1/5 (40.8%) was the thickness most often considered to be sexy-looking, followed by VTn-1/6 (25.9%) and Med-1/4 (21.4%). Tk-1/3 was the least preferred (11.9%). Tn-1/5 was the most preferred sexy-looking thickness among both sexes.The results may be used as guidelines for patient or customer preferences in facial rejuvenation operations, brow esthetics, or tattooing. PMID- 29481515 TI - Evaluation of Mandibular Lingual Foramina With Cone-Beam Computed Tomography. AB - The aim of this study was to evaluate the characteristics of 3 kinds of mandibular lingual foramina through cone beam computed tomography images to analyze its diameter, frequency, location and its correlation with age in southeast Chinese mainland population. Lingual foramina in 299 patients were grouped into midline lingual foramina (MLF), lateral lingual foramina (LLF), and nutrient foramina (NF) with diameters and frequency measured. Vertical distances from foramina to mandibular inferior border were recorded as Hinf. Data were analyzed using ANOVA, independent sample t tests and Pearson correlation. Results showed that MLF had a frequency of 99.3% at midline symphysis. Average diameter and Hinf of MLF were 0.65 +/- 0.19 and 13.79 +/- 2.15 mm, respectively. Lateral lingual foramina had a frequency of 63.2% with the majority observed in premolar region. Average diameter and Hinf of LLF were 0.62 +/- 0.19 and 6.90 +/- 1.88 mm, respectively. Nutrient foramina had a frequency of 91.3% and was most frequently detected between mandibular incisors. Average diameter and Hinf of NF were 0.57 +/- 0.15 and 28.39 +/- 2.38 mm, respectively. Mean diameter of MLF and NF of each patient correlated with age (r = 0.174 and 0.201, respectively, P < 0.05). No statistical correlation was observed between average diameter of LLF and age (r = 0.114, P > 0.05). Preoperative cone beam computed tomography is a valuable aid in locating lingual foramina, which could be used as an indication to avoid unwanted hemorrhage in implant surgery. PMID- 29481516 TI - Bidirectional Management of a Transnasal Intracranial Chopstick Transecting Optic Nerve. AB - Herein, the authors report a rare patient with a transnasal intracranial penetration injury caused by a chopstick that resulted in optic nerve transection as well as the removal of the chopstick using a bidirectional approach. A 25-year old male presented to our emergency department with right blindness and bilateral epistaxis. Preoperative computed tomographic angiography demonstrated a transnasal stick-like foreign body causing a skull base fracture and suspected vascular injury. Due to the shape of the chopstick and the high risk of massive bleeding, an exclusively endoscopic or open craniotomy approach is not suitable for removal. A bidirectional method, including both an open craniotomy and transnasal endoscopy, was used to remove the chopstick. After the operation, there were no further neurologic deficits or complications during the treatment course and follow-up. The bidirectional approach may provide an alternative method to address a foreign body when the patient is not a candidate for an exclusively endoscopic or open craniotomy approach management. PMID- 29481517 TI - Iatrogenic Conchal Defect Secondary to Auricular Cartilage Graft. AB - BACKGROUND: Cleft lip and palate are the most common craniofacial congenital malformations. Timing of the nasal repair remains somewhat controversial. Some authors perform a combined nasal and lip repair in infancy while others advocate for a staged repair with the nasal component occurring later in childhood. Frequently, secondary repair is needed to address residual nasal deformities in early adulthood. Conchal cartilage has become increasingly popular as a source of cartilage for secondary reconstruction. Donor site morbidities include hematoma formation, scar formation, and wound healing complications. To the best of the authors' knowledge, there is 1 previous report of a full through-and-through conchal defect as a complication of auricular cartilage graft harvesting. The authors report an infrequently described iatrogenic conchal defect due to cartilage harvesting managed with a single-stage reconstruction using bookend flaps. METHODS: A 19-year-old female with a history of unilateral cleft lip and palate repair underwent secondary rhinoplasty using conchal cartilage. A bolster dressing was applied to the conchal harvest site. The patient was unable to attend her postoperative clinic visit and was eventually seen 2 months postoperatively with the bolster still in place. A full-thickness conchal defect was present when the bolster was removed. RESULTS: A pressure dressing such as a bolster is commonly used to prevent hematoma formation after conchal cartilage graft harvesting. This is routinely removed during the initial postoperative visit. Prolonged placement can result in donor site complications such as a full thickness conchal defect. CONCLUSION: A functional and aesthetic reconstruction of a full-thickness iatrogenic conchal defect was achieved with excellent results using a local posterior flap, and 2 anteriorly based bookend flaps for closure. To the best of the authors' knowledge, this report is the first to describe a single-stage reconstruction of an iatrogenic defect in the concha as a complication of conchal cartilage harvesting. PMID- 29481518 TI - Juvenile Nasopharyngeal Angiofibroma With Sphenoid Sinus Invasion and Protrusion: Treatment Approach With Le Fort I Osteotomy. AB - Juvenile nasopharyngeal angiofibroma (JNA) is a rare benign tumor that occurs predominantly in young males. The authors report the case of a 22-year-old male patient who presented with a painless, exophytic tumor mass protruding through the right nostril, with anterior lateral extension associated with severe posterior involvement, erosion of the sphenoid bone to the right of the pterygoid process, and significant epistaxis. The preoperative evaluation, surgical approach, postoperative results, and a review of the literature are presented. The surgical approach with Le Fort I osteotomy was designed to facilitate surgical access to the tumor in the nasal cavity. Before down-fracture of the maxilla, plates were placed for fixation and holes were made to produce reference points for restoration of normal anatomy after tumor removal. Although the literature describes the use of nonsurgical therapies, it is well established that surgical treatment is the best option for patients with JNA. Treatment also requires preoperative embolization to avoid bleeding and ensure safety during tumor resection. Long-term imaging follow-up every 6 to 8 months for at least 3 years after surgery is needed for detection of residual tumor/recurrence. The modified technique used here together with preoperative embolization was essential to successful outcome. PMID- 29481519 TI - Risk Assessment of Isolated Single-Wall Orbit Fractures and Eye Injury. AB - INTRODUCTION: Ideally, all patients with isolated orbit fracture would undergo ophthalmologic evaluation before surgical intervention to rule out concomitant globe injury and possible vision loss. Unfortunately, not all institutions are capable of providing the evaluation before surgery. The authors hypothesize that the anatomic location of a single-wall orbit isolated orbit fracture can help predict the likelihood of ocular injury and thus identify high-risk patients who mandate ophthalmologic evaluation before surgical repair. METHODS: A retrospective chart review was performed at a tertiary academic medical center using the institutional trauma registry for maxillofacial trauma. All subjects with an isolated single-wall orbit fracture were included in this study. Statistical analysis was performed using a Fisher exact test. RESULTS: Two hundred seventy-nine subjects with orbit fractures were identified for inclusion in this study. Forty-one of the 279 (14.7%) subjects had isolated single-wall orbit fractures. Isolated single-wall fractures included orbit floor = 19 of 41 (46.3%), medial wall = 15 of 41 (36.6%), lateral wall = 4 of 41 (9.8%), and orbit roof = 3 of 41 (7.3%). Concomitant ocular injury (13 of 41, 31.8%) was associated with isolated orbit wall fractures as follows: orbit floor = 4 of 19 (21.1%), medial wall = 6 of 15 (40%), lateral wall = 2 of 4 (50%), and orbit roof = 1 of 3 (33.3%). A Fisher exact test demonstrated that there was no statistically significant association between individual isolated wall fractures and ocular injury (P = 0.5000). CONCLUSIONS: Isolated orbit wall fractures are common in maxillofacial trauma and often require surgical repair. Concomitant ocular injury is common (31.8%) with this highest incidence occurring with lateral wall fractures (50%); however, statistical analysis did not demonstrate a significant relationship between the anatomic location of an isolated single-wall fracture and eye injuries. PMID- 29481520 TI - Perforation in Submucous Cleft Palate Due to Methotrexate-Induced Mucositis in a Patient With Rheumatoid Arthritis. AB - Spontaneous palatal perforation can be rarely developed by several causes, such as tumor, trauma, and infection. This article reports a patient with large mid palatal perforation after suffering from severe oral mucositis, which occurred about a month after taking methotrexate (MTX) for rheumatoid arthritis. Through computed tomography and clinical examination, this patient was diagnosed with perforation in unrecognized submucous cleft palate (SMCP) due to drug-induced mucositis. After MTX discontinuation, the oral mucositis was almost healed completely in a month, and the hole was successfully closed by palatoplasty. The author can see that the palatal perforation can occur by oral complication of MTX in SMCP patient. It is an important awareness to dentists as the use of MTX continues to increase for antirheumatic therapy. PMID- 29481521 TI - Proliferation and committed differentiation into dopamine neurons of neural stem cells induced by the active ingredients of radix astragali. AB - Neural stem cells (NSCs) are important cellular sources of transplantation therapies for Parkinson's disease. This study aimed to determine the effects of extracts of radix astragali on the proliferation and differentiation into dopamine (DA) neurons in NSCs. NSCs were dealt with astragaloside IV (ASI), astragalus polysaccharide (APS), and astraisoflavan (ASF), the main active ingredients of radix astragali. First, the results from cell-count kit-8 (CCK-8) assay showed that ASI, ASF, and APS had positive effects on the proliferation of NSCs. Next, we also confirmed the effects of ASI, APS, and ASF on BrdU and nestin by immunocytochemistry. Moreover, results from quantitative RT-PCR showed ASI, APS, and ASF could promote the expressions of tyrosine hydroxylase and dopamine transporter mRNA, which are specifically expressed in DA neurons. Simultaneously, sonic hedgehog (Shh), orphan nuclear hormone 1 (Nurr1), and pituitary homeobox 3 (Ptx3) are considered to motivate the formation of DA neurons. Our result showed ASI, APS, and ASF can also promote the expressions of Shh, Nurr1, and Ptx3 mRNAs. In conclusion, our study verifies that the active ingredients of radix astragali can promote the proliferation of NSCs and induce NSC differentiation toward DA neurons in vitro. These phenomena may occur through upregulation of Shh, Nurr1, and Ptx3 in the process of drug treatment. PMID- 29481522 TI - Three-dimensional multiple object tracking in the pediatric population: the NeuroTracker and its promising role in the management of mild traumatic brain injury. AB - As mild traumatic brain injury (mTBI) affects hundreds of thousands of children and their families each year, investigation of potential mTBI assessments and treatments is an important research target. Three-dimensional multiple object tracking (3D-MOT), where an individual must allocate attention to moving objects within 3D space, is one potentially promising assessment and treatment tool. To date, no research has looked at 3D-MOT in a pediatric mTBI population. Thus, the aim of this study was to examine 3D-MOT learning in children and youth with and without mTBI. Thirty-four participants (mean age=14.69+/-2.46 years), with and without mTBI, underwent six visits of 3D-MOT. A two-way repeated-measures analysis of variance (ANOVA) showed a significant time effect, a nonsignificant group effect, and a nonsignificant group-by-time interaction on absolute speed thresholds. In contrast, significant group and time effects and a significant group-by-time interaction on normalized speed thresholds were found. Individuals with mTBI showed smaller training gains at visit 2 than healthy controls, but the groups did not differ on the remaining visits. Although youth can significantly improve their 3D-MOT performance following mTBI, similar to noninjured individuals, they show slower speed of processing in the first few training sessions. This preliminary work suggests that using a 3D-MOT paradigm to train visual perception after mTBI may be beneficial for both stimulating recovery and informing return to activity decisions. PMID- 29481523 TI - Flavonoids extracted from leaves of Diospyros kaki regulates RhoA activity to rescue synapse loss and reverse memory impairment in APP/PS1 mice. AB - Synapse dysfunction is an early hallmark of Alzheimer's disease (AD), and was considered to be closely related to memory loss. The molecular mechanisms that trigger synapse loss and dysfunction remain poorly understood. Increasing evidence shows a link between Rho GTPases and synapse plasticity. Rho GTPases play a role in controlling synapse function by regulating actin cytoskeleton and dendritic spines. Observations have suggested that phytochemicals, such as flavonoids, alleviate cognition impairment in AD. However, to date, the link between the protective effect of flavonoids on AD and the activity of Rho GTPases remains uninvestigated. In this study, APP/PS1 mice were used as an AD model, and we found that synapse loss occurred in AD mice brain. Flavonoids extracted from leaves of Diospyros kaki (FLDK) were used to investigate whether its protective effects on synapse were related to Rho GTPases activity in AD mice. The Rho GTPases Activation Kit showed that Ras homologous member A (RhoA)-GTP was significantly higher and Ras-related C3 botulinum toxin substrate 1 (Rac1)-GTP was significantly lower in APP/PS1 mice than in normal mice, and RhoA-GTP activity was significantly inhibited by FLDK. We also found that FLDK improved learning and memory function, and antagonized the downregulation expressions of synapse-related proteins such as synaptophysin and drebrin. These findings suggest that FLDK is a potential therapeutic agent for AD, and modulation of Rho GTPases activity might contribute toward its protective effect. PMID- 29481524 TI - Can the integrity of the corticospinal tract predict the long-term motor outcome in poststroke hemiplegic patients? AB - This study aimed to investigate the long-term motor outcome according to early diffusion tensor tractography findings for the affected corticospinal tract (CST) in poststroke hemiplegic patients. A total of 48 supratentorial subacute patients after stroke were enrolled, who had a brain MRI scan within 6 weeks from onset, and no stroke recurrence reported within the 2-year follow-up period. Diffusion tensor images were obtained and CSTs were reconstructed. The participants were classified into three groups: type A, the CST originating from the primary motor cortex was preserved around the lesion area; type B, the CST was similar to type A, except that the fiber originated from the area adjacent to the primary motor cortex; and type C, the CST was interrupted or not shown. Motor functions using Fugl-Meyer Motor Assessment (FMA), the Box and Block Test (BBT), and Functional Ambulation Category, and cognitive function using Mini-Mental Status Examination (MMSE) were measured at baseline and at 2 years from stroke onset. Changes in FMA and BBT were significantly different according to diffusion tensor tractography type at follow-up (P<0.05), but Functional Ambulation Category and Mini-Mental Status Examination were not. In post-hoc analysis, groups A and B showed greater significant improvements on the BBT and on the upper FMA subscale (shoulder/elbow, wrist, and hand) compared with group C (corrected P<0.05), but did not on lower FMA. This study showed the importance of CST integrity for stoke motor recovery. The early integrity of the CST may be useful in predicting long term motor outcomes, specifically with motor recovery of the upper extremity and hand function. PMID- 29481525 TI - Association between glutamate/glutamine and blood oxygen level dependent signal in the left dorsolateral prefrontal region during verbal working memory. AB - Functional MRI (fMRI) has provided much insight into the changes in the neuronal activity on the basis of blood oxygen level dependent (BOLD) phenomenon. The dynamic changes in the metabolites can be detected using functional proton magnetic resonance spectroscopy (H-fMRS). The strategy of combining fMRI and H fMRS would facilitate the understanding of the neurochemical interpretation of the BOLD signal. The dorsolateral prefrontal region is critically involved in the processing of working memory (WM), as demonstrated by the studies involving the neuroimaging, neuropsychological, and electrophysiological experiments. In this study, we tested the association between BOLD signal and changes in brain metabolites in the left dorsolateral prefrontal region using N-back verbal WM task. We used single-voxel task-based H-MRS acquired in the left dorsolateral prefrontal region and fMRI during the performance of N-back verbal WM task to investigate the association between changes in metabolites and BOLD response in 10 healthy participants. The correlation between changes in metabolites and percent signal change was examined by the Pearson correlation. The Pearson correlation analysis revealed a significant positive correlation between the BOLD signal and glutamate/glutamine in the left dorsolateral prefrontal region during the verbal WM. Our finding suggests that glutamate/glutamine cycle plays a critical role in the neuronal activation as reflected by the changes in the BOLD response. PMID- 29481526 TI - Change of information represented by thalamic mediodorsal neurons during the delay period. AB - The thalamic mediodorsal (MD) nucleus plays an important role in transforming visual information into motor information during spatial working-memory performances. To understand the neural mechanism of this transformation process, we examined whether or not the information represented in individual MD neuron's activity changes during a trial of the task. Two monkeys performed two oculomotor delayed-response tasks (an ordinary and a rotatory oculomotor delayed-response task). As MD neurons show directional delay-period activity, we compared the directional selectivity of the same MD neuron between these two tasks and determined whether the activity represented the cue direction or the saccade direction. Among the 26 MD neurons that showed directional delay-period activity, representing information of 27% of neurons gradually altered from the visual domain to the oculomotor domain, while the remaining neurons kept holding either the visual or the oculomotor information throughout the delay period. These results indicate that gradual alteration of information representing in individual MD neurons during the delay period plays an important role in spatial working-memory performance. This alteration could be performed by interactions among MD neurons representing different information during the delay period. PMID- 29481527 TI - Aquaporin-4 facilitator TGN-073 promotes interstitial fluid circulation within the blood-brain barrier: [17O]H2O JJVCPE MRI study. AB - The blood-brain barrier (BBB), which imposes significant water permeability restriction, effectively isolates the brain from the systemic circulation. Seemingly paradoxical, the abundance of aquaporin-4 (AQP-4) on the inside of the BBB strongly indicates the presence of unique water dynamics essential for brain function. On the basis of the highly specific localization of AQP-4, namely, astrocyte end feet at the glia limitans externa and pericapillary Virchow-Robin space, we hypothesized that the AQP-4 system serves as an interstitial fluid circulator, moving interstitial fluid from the glia limitans externa to pericapillary Virchow-Robin space to ensure proper glymphatic flow draining into the cerebrospinal fluid. The hypothesis was tested directly using the AQP-4 facilitator TGN-073 developed in our laboratory, and [O]H2O JJ vicinal coupling proton exchange MRI, a method capable of tracing water molecules delivered into the blood circulation. The results unambiguously showed that facilitation of AQP 4 by TGN-073 increased turnover of interstitial fluid through the system, resulting in a significant reduction in [O]H2O contents of cortex with normal flux into the cerebrospinal fluid. The study further suggested that in addition to providing the necessary water for proper glymphatic flow, the AQP-4 system produces a water gradient within the interstitial space promoting circulation of interstitial fluid within the BBB. PMID- 29481528 TI - The Past Informs the Future: An Overview of the Million Worker Study and the Mallinckrodt Chemical Works Cohort. AB - The purpose of this paper is to present an overview of ongoing work on the Million Worker Study (MWS), highlighting some of the key methods and progress so far as exemplified by the study of workers at the Mallinckrodt Chemical Works (MCW). The MWS began nearly 25 y ago and continues in a stepwise fashion, evaluating one study cohort at a time. It includes workers from U.S. Department of Energy (DOE) Manhattan Project facilities, U.S. Nuclear Regulatory Commission (NRC) regulated nuclear power plants, industrial radiographers, U.S. Department of Defense (DoD) nuclear weapons test participants, and physicians and technologists working with medical radiation. The purpose is to fill the major gap in radiation protection and science: What is the risk when exposure is received gradually over time rather than briefly as for the atomic bomb survivors? Studies published or planned in 2018 include leukemia (and dosimetry) among atomic veterans, leukemia among nuclear power plant workers, mortality among workers at the MCW, and a comprehensive National Council on Radiation Protection and Measurements (NCRP) Report on dosimetry for the MWS. MCW has a singular place in history: the 40 tons (T) of uranium oxide produced at MCW were used by Enrico Fermi on 2 December 1942 to produce the first manmade sustained and controlled nuclear reaction, and the atomic age was born. Seventy-six years later, the authors followed the over 2,500 MCW workers for mortality and reconstructed dose from six sources of exposure: external gamma rays from the radioactive elements in pitchblende; medical x rays from occupationally required chest examinations; intakes of pitchblende (uranium, radium, and silica) measured by urine samples; radon breath analyses and dust surveys overseen by Robley Evans and Merril Eisenbud; occupational exposures received before and after employment at MCW; and cumulative radon concentrations and lung dose from the decay of radium in the work environment. The unique exposure reconstructions allow for multiple evaluations, including estimates of silica dust. The study results are relevant today. For example, NASA is interested that radium, deposited in the brain, releases high-LET alpha particles - the only human analogue, though limited, for high energy, high-Z particles (galactic cosmic rays) traveling through space that might affect astronauts on Mars missions. Don't discount the past; it's the prologue to the future! PMID- 29481529 TI - Dosimetry is Key to Good Epidemiology: Workers at Mallinckrodt Chemical Works had Seven Different Source Exposures. AB - Mallinckrodt Chemical Works was the earliest uranium processing facility in the Manhattan Project, beginning in 1942. Even then, concern existed about possible health effects resulting from exposure to radiation and pitchblende dust. This concern was well founded as the facility processed Belgian Congo pitchblende ore that was up to 60% pure uranium with high U content and up to 100 mg of radium per ton. Workers were exposed to external gamma radiation plus internal radiation from inhalation and ingestion of pitchblende dust (uranium, radium, and silica). Multiple sources of exposure were available for organ dose reconstruction to a degree unique for an epidemiologic study. Personal film badge measures available from 1945 captured external exposures. Additional external exposure included 15,518 occupational medical x-rays and 210 radiation exposure records from other facilities outside of Mallinckrodt employment. Organ dose calculations considered organ-specific coefficients that account for photon energy and job-specific orientation of workers to the radiation source during processing. Intakes of uranium and radium were based on 39,451 uranium urine bioassays and 2,341 breath radon measurements, and International Commission on Radiological Protection (ICRP) Publication 68 biokinetic models were used to estimate organ-specific radiation absorbed dose. Estimates of exposure to airborne radon and its short lived progeny were based on radon measurements in work areas where radium containing materials were handled or stored, together with estimated exposure times in these areas based on job titles. Dose estimates for radon and its short lived progeny were based on models and methods recently recommended in ICRP Publication 137. This comprehensive dosimetric approach follows methods outlined by the National Council on Radiation Protection Scientific Committee 6-9 for the Million Worker Study. Annual doses were calculated for six organs: lung, brain, heart, kidney, colon and red bone marrow. Evaluation and adjustment for individual cumulative measures of pitchblende dust inhalation were made for lung and kidney diseases. PMID- 29481530 TI - Effect of Residential Radon Decay Product Dose Factor Variability on Reporting of Dose. AB - Guidelines for occupational exposure to radiation are based on annual absorbed or effective dose. Guidelines for Rn exposure are currently based on air concentrations of Rn or decay products. Models of bronchial dose from decay product exposure are based on calculations that have five major parameters with parameter variabilities ranging from 20 to 50%. Many countries currently use the ICRP dose conversion convention, which is a ratio of lifetime Rn lung cancer risk to lifetime atomic bomb dose risk. The results of ongoing epidemiology changed both lifetime risk values, and the dose conversion convention has increased by a factor of 2. Therefore, the current dose conversion convention risk ratio is to be replaced by biokinetic dosimetric models. The main effect of variability in the value of Rn dose factors on industry is that the workplace atmosphere must be characterized accurately, and at present, this is not possible. A history of the dose factor models is central to factor development. The values of the dose model parameters are described illustrating the difficulty in calculation of a dose factor with universal applicability. The objective is to show the range of each parameter and the effect of the dose factor used when reporting occupational or residential bronchial dose. PMID- 29481531 TI - Comparison of the Current Center of Site Annual Neshap Dose Modeling at the Savannah River Site with Other Assessment Methods. AB - The U.S. Environmental Protection Agency (EPA) requires the use of the model CAP88 to estimate the total effective dose (TED) to an offsite maximally exposed individual (MEI) for demonstrating compliance with 40 CFR 61, Subpart H: The National Emission Standards for Hazardous Air Pollutants (NESHAP) regulations. For NESHAP compliance at the Savannah River Site (SRS), the EPA, the U.S. Department of Energy (DOE), South Carolina's Department of Health and Environmental Control, and SRS approved a dose assessment method in 1991 that models all radiological emissions as if originating from a generalized center of site (COS) location at two allowable stack heights (0 m and 61 m). However, due to changes in SRS missions, radiological emissions are no longer evenly distributed about the COS. An area-specific simulation of the 2015 SRS radiological airborne emissions was conducted to compare to the current COS method. The results produced a slightly higher dose estimate (2.97 * 10 mSv vs. 2.22 * 10 mSv), marginally changed the overall MEI location, and noted that H Area tritium emissions dominated the dose. Thus, an H-Area dose model was executed as a potential simplification of the area-specific simulation by adopting the COS methodology and modeling all site emissions from a single location in H-Area using six stack heights that reference stacks specific to the tritium production facilities within H-Area. This "H-Area Tritium Stacks" method produced a small increase in TED estimates (3.03 * 10 mSv vs. 2.97 * 10 mSv) when compared to the area-specific simulation. This suggests that the current COS method is still appropriate for demonstrating compliance with NESHAP regulations but that changing to the H-Area Tritium Stacks assessment method may now be a more appropriate representation of operations at SRS. PMID- 29481532 TI - Dose Deposition Profiles in Untreated Brick Material. AB - In nuclear forensics or accident dosimetry, building materials such as bricks can be used to retrospectively determine radiation fields using thermoluminescence and/or optically stimulated luminescence. A major problem with brick material is that significant chemical processing is generally necessary to isolate the quartz from the brick. In this study, a simplified treatment process has been tested in an effort to lessen the processing burden for retrospective dosimetry studies. It was found that by using thermoluminescence responses, the dose deposition profile of a brick sample could be reconstructed without any chemical treatment. This method was tested by estimating the gamma-ray energies of an Am source from the dose deposition in a brick. The results demonstrated the ability to retrospectively measure the source energy with an overall energy resolution of approximately 6 keV. This technique has the potential to greatly expedite dose reconstructions in the wake of nuclear accidents or for any related application where doses of interest are large compared to overall process system noise. PMID- 29481533 TI - Impact of Low-level Ionizing Radiation on Cell Death During Zebrafish Embryonic Development. AB - Ionizing radiation (IR) has been linked to multiple types of cellular responses, but its effects on developing organisms are still poorly understood. The authors investigated whether zebrafish embryos exhibit differential responses relative to IR dose and developmental age at time of exposure. Early-stage zebrafish embryos were exposed to different levels of gamma radiation and then, at varying points after irradiation, assayed for morphological defects and levels of cell death. To quantify in vivo cellular responses to low-dose IR exposure and explore how tissue-specific cell functions affect radiation response, apoptotic cells were counted in three regions: the tail, urogenital papilla, and left eye. The authors found that increased gamma radiation doses correlated with increased levels of apoptosis in the developing tail and eye, whereas cells of the urogenital papilla appeared to undergo apoptosis independently of radiation dose. This suggests that the linear-no-threshold model may not be appropriate in all contexts. Grouping embryos by age at IR exposure revealed that gamma radiation exposure resulted in higher levels of apoptosis in embryos irradiated at 2 d post fertilization (dpf), suggesting a radiosensitive stage of development. Moreover, levels of apoptosis were statistically influenced by days grown after irradiation, with embryos fixed at later stages showing more dramatic apoptotic responses to radiation exposure. This latency to effect suggests potential competition between DNA repair and apoptosis pathways, which may lead to the accumulation of apoptotic cells only after an initial lag period. PMID- 29481534 TI - Importance of Uranium Recovery Facility Product Characteristics for Dose Assessment and Assignment. AB - Two traditional methods are used, often in combination, for assessing the intake and resulting dose from the inhalation of radioactive aerosols. The first calculates the intake based on air sampling programs and assessing and assigning dose using published dose conversion factors. The second approach assigns dose from the results of bioassay programs using measurements of radionuclides in human excreta (ex vivo, sometimes referred to as "in vitro") or via direct measurements of radionuclides in the body (in vivo) in combination with metabolic models. This paper describes standard practices using each of these methods to assess and assign worker dose from inhalation of uranium products produced at natural uranium processing facilities, namely uranium mills and in-situ uranium recovery facilities (ISRs). Chemical speciation is an important consideration, which relates directly to solubility in body fluids and associated metabolic behavior. The concepts are illustrated by specific examples applicable to the products to which workers can be exposed at natural uranium processing facilities. PMID- 29481535 TI - Analysis of 238U, 232TH, 222RN, AND 220RN in Fresh and Canned Marine Fish Samples Using Solid State Nuclear Track Detectors and Resulting Alpha Radiation Doses to Adult Consumers. AB - Consumption of seafoods has increased during the last two decades in many countries. In Morocco, annual fresh marine fish consumption has increased significantly due to the existence of modern fish markets in major cities. To explore the exposure pathway of U, Th, Rn, and Rn radionuclides to the human body of consumers, these radionuclides were measured in various fresh and canned marine fish samples widely consumed by the Moroccan population by using two types of solid state nuclear track detectors (SSNTDs). A census was taken of the fresh and canned marine fish consumed by adult members of the public and building material workers. Committed equivalent doses due to annual intakes of U, Th, Rn, and Rn were determined in the organs of adult members of the urban Moroccan population from the ingestion of fresh and canned marine fish samples. The influence of pollution caused by building material dusts on committed effective doses to workers due to the U, Th, Rn, and Rn radionuclides from the ingestion of canned fish samples was investigated. PMID- 29481536 TI - Murine-specific Internal Dosimetry for Preclinical Investigations of Imaging and Therapeutic Agents. AB - There is a growing need to estimate the absorbed dose to small animals from preclinical investigations involving diagnostic and therapeutic radiopharmaceuticals. This paper introduces a Monte Carlo-based dosimetry platform called RAPID, which is capable of calculating murine-specific three dimensional (3D) dose distributions. A comparison is performed between absorbed doses calculated with RAPID and absorbed doses calculated in a commonly used reference mouse phantom called MOBY. Four test mice containing different xenografts underwent serial PET/CT imaging using a novel diagnostic therapy (theranostic) agent NM404, which can be labeled with I for imaging or I for therapy. Using the PET/CT data, 3D dose distributions from I-NM404 were calculated in the mice using RAPID. Mean organ doses in these four test mice were compared to mean organ doses derived by using two previously published I S-values datasets in MOBY. In addition, mean tumor doses calculated in RAPID were compared to mean organ doses derived from unit density spheres. Large differences were identified between mean organ doses calculated in the test mice using RAPID and those derived in the MOBY phantom. Mean absorbed dose percent errors in organs ranged between 0.3% and 333%. Overall, mass scaling improved agreement between MOBY phantom calculations and RAPID, where percent errors were all less than 26%, with the exception of the lung in which percent errors reached values of 48%. Percent errors in mean tumor doses in the test mice and unit density spheres were less pronounced but still ranged between 8% and 23%. This work demonstrates the limitations of using pre-computed S-values in computational phantoms to predict organ doses in small animals from theranostic procedures. RAPID can generate accurate 3D dose distributions in small animals and in turn offer much greater insight on the ability of a given theranostic agent to image and treat diseases. PMID- 29481537 TI - NIST-Traceable Neutron Dosimetry Is Needed for Air Travel Radiation Safety. PMID- 29481538 TI - Schauer Neglects Neutron Dose in Aviation. PMID- 29481539 TI - Reply to Bramlitt and Shonka. PMID- 29481540 TI - Erratum. PMID- 29481541 TI - Radiation Attenuation and Stability of ClearView Radiation Shielding TM-A Transparent Liquid High Radiation Shield. AB - Radiation exposure is a limiting factor to work in sensitive environments seen in nuclear power and test reactors, medical isotope production facilities, spent fuel handling, etc. The established choice for high radiation shielding is lead (Pb), which is toxic, heavy, and abidance by RoHS. Concrete, leaded (Pb) bricks are used as construction materials in nuclear facilities, vaults, and hot cells for radioisotope production. Existing transparent shielding such as leaded glass provides minimal shielding attenuation in radiotherapy procedures, which in some cases is not sufficient. To make working in radioactive environments more practicable while resolving the lead (Pb) issue, a transparent, lightweight, liquid, and lead-free high radiation shield-ClearView Radiation Shielding-(Radium Incorporated, 463 Dinwiddie Ave, Waynesboro, VA). was developed. This paper presents the motivation for developing ClearView, characterization of certain aspects of its use and performance, and its specific attenuation testing. Gamma attenuation testing was done using a 1.11 * 10 Bq Co source and ANSI/HPS-N 13.11 standard. Transparency with increasing thickness, time stability of liquid state, measurements of physical properties, and performance in freezing temperatures are reported. This paper also presents a comparison of ClearView with existing radiation shields. Excerpts from LaSalle nuclear power plant are included, giving additional validation. Results demonstrated and strengthened the expected performance of ClearView as a radiation shield. Due to the proprietary nature of the work, some information is withheld. PMID- 29481544 TI - Examining the Reproducibility of 6 Published Studies in Public Health Services and Systems Research. AB - OBJECTIVE: Research replication, or repeating a study de novo, is the scientific standard for building evidence and identifying spurious results. While replication is ideal, it is often expensive and time consuming. Reproducibility, or reanalysis of data to verify published findings, is one proposed minimum alternative standard. While a lack of research reproducibility has been identified as a serious and prevalent problem in biomedical research and a few other fields, little work has been done to examine the reproducibility of public health research. We examined reproducibility in 6 studies from the public health services and systems research subfield of public health research. DESIGN: Following the methods described in each of the 6 papers, we computed the descriptive and inferential statistics for each study. We compared our results with the original study results and examined the percentage differences in descriptive statistics and differences in effect size, significance, and precision of inferential statistics. All project work was completed in 2017. RESULTS: We found consistency between original and reproduced results for each paper in at least 1 of the 4 areas examined. However, we also found some inconsistency. We identified incorrect transcription of results and omitting detail about data management and analyses as the primary contributors to the inconsistencies. RECOMMENDATIONS: Increasing reproducibility, or reanalysis of data to verify published results, can improve the quality of science. Researchers, journals, employers, and funders can all play a role in improving the reproducibility of science through several strategies including publishing data and statistical code, using guidelines to write clear and complete methods sections, conducting reproducibility reviews, and incentivizing reproducible science. PMID- 29481545 TI - Beyond Research Ethics: Novel Approaches of 3 Major Public Health Institutions to Provide Ethics Input on Public Health Practice Activities. AB - Public health institutions increasingly realize the importance of creating a culture in their organizations that values ethics. When developing strategies to strengthen ethics, institutions will have to take into account that while public health research projects typically undergo thorough ethics review, activities considered public health practice may not be subjected to similar oversight. This approach, based on a research-practice dichotomy, is increasingly being criticized as it does not adequately identify and manage ethically relevant risks to those affected by nonresearch activities. As a reaction, 3 major public health institutions (the World Health Organization, US Centers for Disease Control and Prevention, and Public Health Ontario) have implemented mechanisms for ethics review of public health practice activities. In this article, we describe and critically discuss the different modalities of the 3 approaches. We argue that although further evaluation is necessary to determine the effectiveness of the different approaches, public health institutions should strive to implement procedures to ensure that public health practice adheres to the highest ethical standards. PMID- 29481546 TI - Media Flight Schedules and Seasonality in Relation to Quitline Call Volume. AB - CONTEXT: Given the high profile, cost, and vulnerability to budget cuts of mass reach health education campaigns, researchers have cited the need for media buying strategies. OBJECTIVE: The objective of the current study is to fill a gap in the literature by comparing the impact of media flight schedule types in relation to tobacco quitline call volume. DESIGN: The retrospective study was designed to determine whether type of media flight schedule (eg, flighting, continuous, pulsing) impacted number of calls to the Maine Tobacco Helpline, while accounting for number of gross rating points (GRPs), seasonality, holidays, and other factors. SETTING: Maine has 3 designated market areas (DMAs): Portland/Auburn, Bangor, and Presque Isle. MAIN OUTCOME MEASURES: Daily call volume was matched with weekly GRPs. METHODS: A negative binomial regression model was created to examine the relationship among media flight schedules, number of GRPs, and call volume. Gross rating points reflect national networks and local cable TV media buys. A second model examined the association between GRP dose levels and call volume. RESULTS: The number of GRPs was a significant predictor of call volume (P < .001). Weekly number of GRPs within a media flight schedule was the most important indicator for potential effectiveness. Weekly low dose GRPs were not effective in increasing calls, indicating a minimum threshold. For every 250 GRPs, 29% (or 73) more calls per week were attributed to the media campaigns (P < .001). Weekly quitline call volume was 21% (or 53 calls) lower during the weeks of Christmas, US Thanksgiving, and US Independence Day. CONCLUSION: Type of media flight schedule should be considered in the context of purchasing sufficient weekly, as well as quarterly, rating points to increase tobacco quitline call volume. In addition, our study is the first to quantify and report on lower tobacco quitline call volume during several US holidays. PMID- 29481547 TI - Changes in Sugary Beverage Consumption and Public Perceptions in Upstate New York After Implementation of a Community Awareness Campaign and Healthier Vending Strategies. AB - OBJECTIVE: We evaluated the impact of a community-based healthy beverage procurement and serving practices program, and educational media campaign, on residents' behaviors and beliefs regarding sugary beverages. DESIGN: Repeated cross-sectional population surveys in 2013 and 2014 were conducted, as well as semistructured interviews with key informants. We employed multivariate differences-in-differences regression analysis, adjusting for demographics and weight status, using the survey data. Key informant interviews were reviewed for common themes. SETTING: Three rural counties in upstate New York with high prevalence of children living in poverty and childhood obesity. PARTICIPANTS: Residents of Broome, Cattaraugus, and Chautauqua, with Chemung as a control, reached through cross-sectional random-digit-dial landline and cellular telephones, and practitioners involved in intervention implementation. INTERVENTION: Community organizations were encouraged through presentations to leadership to adopt healthier vending policies, providing more low- and no-sugar options, and were provided assistance with implementation. In addition, a media campaign supported by presentations to the public aimed to educate residents regarding the health consequences of sugary beverage consumption. OUTCOME MEASURES: The survey measured population demographics and sugary beverage consumption frequency, availability, beliefs about harmfulness, and support for regulation, pre- and postintervention. Key informant interviews elicited perceived program challenges and successes. RESULTS: Compared with temporal trends in the control county, availability of regular soda in the intervention counties decreased (differences-in-differences estimator: beta = -.341, P = .04) and support for regulation increased (differences-in-differences estimator: beta = .162, P = .02). However, there were no differences regarding beliefs about harmfulness or consumption. Practitioners confirmed that the intervention increased awareness but was insufficient to spur action. CONCLUSION: Although public education on the harmfulness of sugary beverages and provision of healthier options in some vending machines successfully impacted soda availability and support for regulation, it did not reduce consumption. This intervention seems promising but should be paired with other community-based interventions for a more comprehensive approach. PMID- 29481548 TI - DNA MemoChip: Long-Term and High Capacity Information Storage and Select Retrieval. AB - Over the course of history, human beings have never stopped seeking effective methods for information storage. From rocks to paper, and through the past several decades of using computer disks, USB sticks, and on to the thin silicon "chips" and "cloud" storage of today, it would seem that we have reached an era of efficiency for managing innumerable and ever-expanding data. Astonishingly, when tracing this technological path, one realizes that our ancient methods of informational storage far outlast paper (10,000 vs. 1,000 years, respectively), let alone the computer-based memory devices that only last, on average, 5 to 25 years. During this time of fast-paced information generation, it becomes increasingly difficult for current storage methods to retain such massive amounts of data, and to maintain appropriate speeds with which to retrieve it, especially when in demand by a large number of users. Others have proposed that DNA-based information storage provides a way forward for information retention as a result of its temporal stability. It is now evident that DNA represents a potentially economical and sustainable mechanism for storing information, as demonstrated by its decoding from a 700,000 year-old horse genome. The fact that the human genome is present in a cell, containing also the varied mitochondrial genome, indicates DNA's great potential for large data storage in a 'smaller' space. PMID- 29481549 TI - Bias, robustness and scalability in single-cell differential expression analysis. AB - Many methods have been used to determine differential gene expression from single cell RNA (scRNA)-seq data. We evaluated 36 approaches using experimental and synthetic data and found considerable differences in the number and characteristics of the genes that are called differentially expressed. Prefiltering of lowly expressed genes has important effects, particularly for some of the methods developed for bulk RNA-seq data analysis. However, we found that bulk RNA-seq analysis methods do not generally perform worse than those developed specifically for scRNA-seq. We also present conquer, a repository of consistently processed, analysis-ready public scRNA-seq data sets that is aimed at simplifying method evaluation and reanalysis of published results. Each data set provides abundance estimates for both genes and transcripts, as well as quality control and exploratory analysis reports. PMID- 29481550 TI - Cell-type specific sequencing of microRNAs from complex animal tissues. AB - MicroRNAs (miRNAs) play an essential role in the post-transcriptional regulation of animal development and physiology. However, in vivo studies aimed at linking miRNA function to the biology of distinct cell types within complex tissues remain challenging, partly because in vivo miRNA-profiling methods lack cellular resolution. We report microRNome by methylation-dependent sequencing (mime-seq), an in vivo enzymatic small-RNA-tagging approach that enables high-throughput sequencing of tissue- and cell-type-specific miRNAs in animals. The method combines cell-type-specific 3'-terminal 2'-O-methylation of animal miRNAs by a genetically encoded, plant-specific methyltransferase (HEN1), with chemoselective small-RNA cloning and high-throughput sequencing. We show that mime-seq uncovers the miRNomes of specific cells within Caenorhabditis elegans and Drosophila at unprecedented specificity and sensitivity, enabling miRNA profiling with single cell resolution in whole animals. Mime-seq overcomes current challenges in cell type-specific small-RNA profiling and provides novel entry points for understanding the function of miRNAs in spatially restricted physiological settings. PMID- 29481551 TI - A hybridization-chain-reaction-based method for amplifying immunosignals. AB - Immunosignal hybridization chain reaction (isHCR) combines antibody-antigen interactions with hybridization chain reaction (HCR) technology, which results in amplification of immunofluorescence signals by up to two to three orders of magnitude with low background. isHCR's highly modular and easily adaptable design enables the technique to be applied broadly, and we further optimized its use in multiplexed imaging and in state-of-the-art tissue expansion and clearing techniques. PMID- 29481552 TI - Human dengue virus serotype 2 neutralizing antibodies target two distinct quaternary epitopes. AB - Dengue virus (DENV) infection causes dengue fever, dengue hemorrhagic fever and dengue shock syndrome. It is estimated that a third of the world's population is at risk for infection, with an estimated 390 million infections annually. Dengue virus serotype 2 (DENV2) causes severe epidemics, and the leading tetravalent dengue vaccine has lower efficacy against DENV2 compared to the other 3 serotypes. In natural DENV2 infections, strongly neutralizing type-specific antibodies provide protection against subsequent DENV2 infection. While the epitopes of some human DENV2 type-specific antibodies have been mapped, it is not known if these are representative of the polyclonal antibody response. Using structure-guided immunogen design and reverse genetics, we generated a panel of recombinant viruses containing amino acid alterations and epitope transplants between different serotypes. Using this panel of recombinant viruses in binding, competition, and neutralization assays, we have finely mapped the epitopes of three human DENV2 type-specific monoclonal antibodies, finding shared and distinct epitope regions. Additionally, we used these recombinant viruses and polyclonal sera to dissect the epitope-specific responses following primary DENV2 natural infection and monovalent vaccination. Our results demonstrate that antibodies raised following DENV2 infection or vaccination circulate as separate populations that neutralize by occupying domain III and domain I quaternary epitopes. The fraction of neutralizing antibodies directed to different epitopes differs between individuals. The identification of these epitopes could potentially be harnessed to evaluate epitope-specific antibody responses as correlates of protective immunity, potentially improving vaccine design. PMID- 29481554 TI - A comment on priors for Bayesian occupancy models. AB - Understanding patterns of species occurrence and the processes underlying these patterns is fundamental to the study of ecology. One of the more commonly used approaches to investigate species occurrence patterns is occupancy modeling, which can account for imperfect detection of a species during surveys. In recent years, there has been a proliferation of Bayesian modeling in ecology, which includes fitting Bayesian occupancy models. The Bayesian framework is appealing to ecologists for many reasons, including the ability to incorporate prior information through the specification of prior distributions on parameters. While ecologists almost exclusively intend to choose priors so that they are "uninformative" or "vague", such priors can easily be unintentionally highly informative. Here we report on how the specification of a "vague" normally distributed (i.e., Gaussian) prior on coefficients in Bayesian occupancy models can unintentionally influence parameter estimation. Using both simulated data and empirical examples, we illustrate how this issue likely compromises inference about species-habitat relationships. While the extent to which these informative priors influence inference depends on the data set, researchers fitting Bayesian occupancy models should conduct sensitivity analyses to ensure intended inference, or employ less commonly used priors that are less informative (e.g., logistic or t prior distributions). We provide suggestions for addressing this issue in occupancy studies, and an online tool for exploring this issue under different contexts. PMID- 29481553 TI - Genetic mechanisms of Coxiella burnetii lipopolysaccharide phase variation. AB - Coxiella burnetii is an intracellular pathogen that causes human Q fever, a disease that normally presents as a severe flu-like illness. Due to high infectivity and disease severity, the pathogen is considered a risk group 3 organism. Full-length lipopolysaccharide (LPS) is required for full virulence and disease by C. burnetii and is the only virulence factor currently defined by infection of an immunocompetent animal. Transition of virulent phase I bacteria with smooth LPS, to avirulent phase II bacteria with rough LPS, occurs during in vitro passage. Semi-rough intermediate forms are also observed. Here, the genetic basis of LPS phase conversion was investigated to obtain a more complete understanding of C. burnetii pathogenesis. Whole genome sequencing of strains producing intermediate and/or phase II LPS identified several common mutations in predicted LPS biosynthesis genes. After passage in broth culture for 30 weeks, phase I strains from different genomic groups exhibited similar phase transition kinetics and elevation of mutations in LPS biosynthesis genes. Targeted mutagenesis and genetic complementation using a new C. burnetii nutritional selection system based on lysine auxotrophy confirmed that six of the mutated genes were necessary for production of phase I LPS. Disruption of two of these genes in a C. burnetii phase I strain resulted in production of phase II LPS, suggesting inhibition of the encoded enzymes could represent a new therapeutic strategy for treatment of Q fever. Additionally, targeted mutagenesis of genes encoding LPS biosynthesis enzymes can now be used to construct new phase II strains from different genomic groups for use in pathogen-host studies at a risk group 2 level. PMID- 29481555 TI - The two glycolytic markers GLUT1 and MCT1 correlate with tumor grade and survival in clear-cell renal cell carcinoma. AB - BACKGROUND: Clear-cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer. Although ccRCC is characterized by common recurrent genetic abnormalities, including inactivation of the von Hippel-Lindau (vhl) tumor suppressor gene resulting in stabilization of hypoxia-inducible factors (HIFs), the tumor aggressiveness and outcome of ccRCC is variable. New biomarkers are thus required to improve ccRCC diagnosis, prognosis and therapeutic options. This work aims to investigate the expression of HIF and proteins involved in metabolism and pH regulation. Their correlation to histoprognostic parameters and survival was analyzed. METHODS: ccRCC of 45 patients were analyzed. HIF-1alpha, HIF-2alpha, HAF, GLUT1, MCT1, MCT4, CAIX and CAXII expression was assessed by immunohistochemistry in a semi-quantitative and qualitative manner. The GLUT1, MCT1, MCT4, CAIX and CAXII mRNA levels were analyzed in an independent cohort of 43 patients. RESULTS: A significant correlation was observed between increased GLUT1, MCT1, CAXII protein expression and a high Fuhrman grade in ccRCC patients. Moreover, while HIF-1alpha, HIF-2alpha and HAF expression was heterogenous within tumors, we observed and confirmed that HIF-2alpha co-localized with HAF. We confirmed, in an independent cohort, that GLUT1, MCT1 and CAXII mRNA levels correlated with the Fuhrman grade. Moreover, we demonstrated that the high mRNA level of both MCT1 and GLUT1 correlated with poor prognosis. CONCLUSIONS: This study demonstrates for the first time a link between the aggressiveness of high- Fuhrman grade ccRCC and metabolic reprogramming. It also confirms the role of HIF 2alpha and HAF in tumor invasiveness. Finally, these results demonstrate that MCT1 and GLUT1 are strong prognostic markers and promising therapeutic targets. PMID- 29481556 TI - Social capital and Internet use in an age-comparative perspective with a focus on later life. AB - Older adults (aged 65+) are still less likely to adopt the Internet when compared to other age groups, although their usage is increasing. To explore the societal effects of Internet usage, scholars have been using social capital as an analytical tool. Social capital pertains to the resources that are potentially available in one's social ties. As the Internet becomes a prominent source of information, communication, and participation in industrialized countries, it is critical to study how it affects social resources from an age-comparative perspective. Research has found a positive association between Internet use and social capital, though limited attention has been paid to older adults. Studies have also found a positive association between social capital and wellbeing, health, sociability, and social support amongst older adults. However, little is known about how Internet usage or lack thereof relates to their social capital. To address this gap, we used a mixed-methods approach to examine the relationship between Internet usage and social capital and whether and how it differs by age. For this, we surveyed a representative sample of 417 adults (18+) living in Lisbon, Portugal, of which 118 are older adults. Social capital was measured through bonding, bridging, and specific resources, and analyzed with Latent Class Modeling and logistic regressions. Internet usage was measured through frequency and type of use. Fourteen follow-up semi-structured interviews helped contextualize the survey data. Our findings show that social capital decreased with age but varied for each type of Internet user. Older adults were less likely to have a high level of social capital; yet within this age group, frequent Internet users had higher levels than other users and non-users. On the one hand, the Internet seems to help maintain, accrue, and even mobilize social capital. On the other hand, it also seems to reinforce social inequality and accumulated advantage (known as the Matthew effect). PMID- 29481557 TI - Transformation of Fonsecaea pedrosoi into sclerotic cells links to the refractoriness of experimental chromoblastomycosis in BALB/c mice via a mechanism involving a chitin-induced impairment of IFN-gamma production. AB - Fonsecaea pedrosoi (F. pedrosoi) is the most common agent of chromoblastomycosis. Transformation of this fungus from its saprophytic phase into pathogenic sclerotic cells in tissue is an essential link to the refractoriness of this infection. Experimental studies in murine models have shown that the absence of CD4+ T cells impairs host defense against F. pedrosoi infection. Clinical research has also suggested that a relatively low level of the Th1 cytokine INF gamma and inefficient T cell proliferation are simultaneously present in patients with severe chromoblastomycosis upon in vitro stimulation with ChromoAg, an antigen prepared from F. pedrosoi. In the present study, we show that in mice intraperitoneally infected with F. pedrosoi-spores, -hyphae or in vitro-induced sclerotic cells respectively, the transformation of this causative agent into sclerotic cells contributes to a compromised Th1 cytokine production in the earlier stage of infection with impaired generation of neutrophil reactive oxygen species (ROS) and pan-inhibition of Th1/Th2/Th17 cytokine production with disseminated infection in the later stage by using a CBA murine Th1/Th2/Th17 cytokine kit. In addition, we have further demonstrated that intraperitoneal administration of recombinant mouse IFN-gamma (rmIFN-gamma) effectively reduces the fungal load in the infected mouse spleen, and dampens the peritoneal dissemination of F. pedrosoi-sclerotic cells. Meanwhile, exogeneous rmIFN-gamma contributes to the formation and maintenance of micro-abscess and restores the decrease in neutrophil ROS generation in the mouse spleen infected with F. pedrosoi-sclerotic cells. Of note, we have once again demonstrated that it is a chitin-like component, but not beta-glucans or mannose moiety, that exclusively accumulates on the outer cell wall of F. pedrosoi-sclerotic cells which were induced in vitro or isolated from the spleens of intraperitoneally infected BALB/c mice. In addition, our results indicate that decreased accumulation of chitin on the surface of live F. pedrosoi-sclerotic cells after chitinase treatment can be self-compensated in a time-dependent manner. Importantly, we have for the first time demonstrated that exclusive accumulation of chitin on the transformed sclerotic cells of F. pedrosoi is involved in an impaired murine Th1 cytokine profile, therefore promoting the refractoriness of experimental murine chromoblastomycosis. PMID- 29481558 TI - Coverage, social mobilization and challenges of mass Zithromax administration campaign in South and South East zones of Tigray, Northern Ethiopia: A cross sectional study. AB - BACKGROUND: The antibiotic treatment of people with trachoma helps to prevent transmission the disease in a community. Currently, Zithromax is the drug recommended for mass drug administration (MDA). MDA should be carried out annually for three to five years in trachoma endemic areas. Coverage survey is essential to track progress towards program goals and to identify communities with poor coverage in order to permit timely and appropriate actions. We assessed mass Zithromax administration coverage, social mobilization and campaign challenges in south and southeast zones of Tigray, Ethiopia. METHOD: We conducted a survey in community in Southern and South East zones of Tigray region from August 15 to August 31, 2016. The survey included nine Woredas. It was supported by qualitative methods. A total of 3741 individuals were enrolled from 933 households using multistage sampling. We used structured questionnaire. In-depth interview and focus group discussion were also applied. Descriptive statistics was performed using SPSS version 20.We thematically analyzed the qualitative data using Atlas 7. RESULT: The overall coverage of Zithromax MDA was 93.3%. It ranges from 90.0% in Seharti Samre to 97.9% in Endamokoni. The coverage was 93.4% for males and 93.1% for females. A higher proportion (98.3%) of children aged 5 to 15 years and 409 (87.8%) under five children took Zithromax. The coverage was 94% in rural and 91.2% in urban. Women development army (43.3%) and health extension workers (32.5%) were the main source of information. Frequent occurrence of drug side effects, rumors, lack of community and leaders' engagement in the campaign, fasting, shortage of human power and short term unavailability of supplies were barriers during the campaign. CONCLUSION: The Zithromax MDA coverage in the study zones was higher than the minimum WHO set criteria of 80%. There was a wide difference in coverage among Woredas and Kebeles. The MDA coverage was lower in urban than rural. Misconceptions and poor mobilization were common challenges. Thus, proper planning, community mobilization and uniform training will need to be done ahead of the campaign in the future. PMID- 29481559 TI - Timing of host feeding drives rhythms in parasite replication. AB - Circadian rhythms enable organisms to synchronise the processes underpinning survival and reproduction to anticipate daily changes in the external environment. Recent work shows that daily (circadian) rhythms also enable parasites to maximise fitness in the context of ecological interactions with their hosts. Because parasite rhythms matter for their fitness, understanding how they are regulated could lead to innovative ways to reduce the severity and spread of diseases. Here, we examine how host circadian rhythms influence rhythms in the asexual replication of malaria parasites. Asexual replication is responsible for the severity of malaria and fuels transmission of the disease, yet, how parasite rhythms are driven remains a mystery. We perturbed feeding rhythms of hosts by 12 hours (i.e. diurnal feeding in nocturnal mice) to desynchronise the host's peripheral oscillators from the central, light-entrained oscillator in the brain and their rhythmic outputs. We demonstrate that the rhythms of rodent malaria parasites in day-fed hosts become inverted relative to the rhythms of parasites in night-fed hosts. Our results reveal that the host's peripheral rhythms (associated with the timing of feeding and metabolism), but not rhythms driven by the central, light-entrained circadian oscillator in the brain, determine the timing (phase) of parasite rhythms. Further investigation reveals that parasite rhythms correlate closely with blood glucose rhythms. In addition, we show that parasite rhythms resynchronise to the altered host feeding rhythms when food availability is shifted, which is not mediated through rhythms in the host immune system. Our observations suggest that parasites actively control their developmental rhythms. Finally, counter to expectation, the severity of disease symptoms expressed by hosts was not affected by desynchronisation of their central and peripheral rhythms. Our study at the intersection of disease ecology and chronobiology opens up a new arena for studying host-parasite-vector coevolution and has broad implications for applied bioscience. PMID- 29481560 TI - Failure of fluconazole in treating cutaneous leishmaniasis caused by Leishmania guyanensis in the Brazilian Amazon: An open, nonrandomized phase 2 trial. AB - BACKGROUND: The treatment of Leishmaniasis caused by Leishmania (Viannia) guyanensis is based on a weak strength of evidence from very few clinical trials and some case series reports. Current treatment guidelines recommend pentamidine isethionate or meglumine antimoniate (Glucantime) as the first-line choices. Both are parenteral drugs with a low therapeutic indexes leading to a high risk of undesired effects. Imidazole derivatives interfere with the production of leishmanial ergosterol, an essential component of their membrane structure. One drug that has been studied in different clinical presentations of Leishmania is fluconazole, a hydrophilic bis-triazole, which is easily absorbed through the oral route with a low toxicity profile and is considered safe for children. This drug is readily available in poor countries with a reasonable cost making it a potential option for treating leishmaniasis. METHODS AND FINDINGS: An adaptive nonrandomized clinical trial with sequential groups with dose escalation of oral fluconazole was designed to treat adult men with localized cutaneous leishmaniasis (LCL) in Manaus, Brazil. Eligible participants were patients with LCL with confirmed Leishmania guyanensis infection. RESULTS: Twenty adult male patients were treated with 450 mg of fluconazole daily for 30 days. One patient (5%) was cured within 30 days of treatment. Of the 19 failures (95%), 13 developed a worsening of ulcers and six evolved lymphatic spreading of the disease. Planned dose escalation was suspended after the disappointing failure rate during the first stage of the trial. CONCLUSION/SIGNIFICANCE: Oral fluconazole, at the dose of 450mg per day, was not efficacious against LCL caused by Leishmania guyanensis in adult men. TRIAL REGISTRATION: Brazilian Clinical Trial Registration (ReBec)-RBR-8w292w; UTN number-1158-2421. PMID- 29481561 TI - Differential tissue growth and cell adhesion alone drive early tooth morphogenesis: An ex vivo and in silico study. AB - From gastrulation to late organogenesis animal development involves many genetic and bio-mechanical interactions between epithelial and mesenchymal tissues. Ectodermal organs, such as hairs, feathers and teeth are well studied examples of organs whose development is based on epithelial-mesenchymal interactions. These develop from a similar primordium through an epithelial folding and its interaction with the mesenchyme. Despite extensive knowledge on the molecular pathways involved, little is known about the role of bio-mechanical processes in the morphogenesis of these organs. We propose a simple computational model for the biomechanics of one such organ, the tooth, and contrast its predictions against cell-tracking experiments, mechanical relaxation experiments and the observed tooth shape changes over developmental time. We found that two biomechanical processes, differential tissue growth and differential cell adhesion, were enough, in the model, for the development of the 3D morphology of the early tooth germ. This was largely determined by the length and direction of growth of the cervical loops, lateral folds of the enamel epithelium. The formation of these cervical loops was found to require accelerated epithelial growth relative to other tissues and their direction of growth depended on specific differential adhesion between the three tooth tissues. These two processes and geometrical constraints in early tooth bud also explained the shape asymmetry between the lateral cervical loops and those forming in the anterior and posterior of the tooth. By performing mechanical perturbations ex vivo and in silico we inferred the distribution and direction of tensile stresses in the mesenchyme that restricted cervical loop lateral growth and forced them to grow downwards. Overall our study suggests detailed quantitative explanations for how bio-mechanical processes lead to specific morphological 3D changes over developmental time. PMID- 29481562 TI - Mathematical modelling of the antibiotic-induced morphological transition of Pseudomonas aeruginosa. AB - Here we formulate a mechanistic mathematical model to describe the growth dynamics of P. aeruginosa in the presence of the beta-lactam antibiotic meropenem. The model is mechanistic in the sense that carrying capacity is taken into account through the dynamics of nutrient availability rather than via logistic growth. In accordance with our experimental results we incorporate a sub population of cells, differing in morphology from the normal bacillary shape of P. aeruginosa bacteria, which we assume have immunity from direct antibiotic action. By fitting this model to experimental data we obtain parameter values that give insight into the growth of a bacterial population that includes different cell morphologies. The analysis of two parameters sets, that produce different long term behaviour, allows us to manipulate the system theoretically in order to explore the advantages of a shape transition that may potentially be a mechanism that allows P. aeruginosa to withstand antibiotic effects. Our results suggest that inhibition of this shape transition may be detrimental to bacterial growth and thus suggest that the transition may be a defensive mechanism implemented by bacterial machinery. In addition to this we provide strong theoretical evidence for the potential therapeutic strategy of using antimicrobial peptides (AMPs) in combination with meropenem. This proposed combination therapy exploits the shape transition as AMPs induce cell lysis by forming pores in the cytoplasmic membrane, which becomes exposed in the spherical cells. PMID- 29481563 TI - Economic burden of cancer in India: Evidence from cross-sectional nationally representative household survey, 2014. AB - With the ongoing demographic and epidemiological transition, cancer is emerging as a major public health concern in India. This paper uses nationally representative household survey to examine the overall prevalence and economic burden of cancer in India. The age-standardized prevalence of cancer is estimated to be 97 per 100,000 persons with greater prevalence in urban areas. The evidence suggests that cancer prevalence is highest among the elderly and also among females in the reproductive age groups. Cancer displays a significant socioeconomic gradient even after adjusting for age-sex specifics and clustering in a multilevel regression framework. We find that out of pocket expenditure on cancer treatment is among the highest for any ailment. The average out of pocket spending on inpatient care in private facilities is about three-times that of public facilities. Furthermore, treatment for about 40 percent of cancer hospitalization cases is financed mainly through borrowings, sale of assets and contributions from friends and relatives. Also, over 60 percent of the households who seek care from the private sector incur out of pocket expenditure in excess of 20 percent of their annual per capita household expenditure. Given the catastrophic implications, this study calls for a disease-based approach towards financing such high-cost ailment. It is suggested that universal cancer care insurance should be envisaged and combined with existing accident and life insurance policies for the poorer sections in India. In concluding, we call for policies to improve cancer survivorship through effective prevention and early detection. In particular, greater public health investments in infrastructure, human resources and quality of care deserve priority attention. PMID- 29481564 TI - Short-term renal outcomes following acute kidney injury among dengue patients: A follow-up analysis from large prospective cohort. AB - BACKGROUND: Despite myriad improvements in the care of dengue patients, acute kidney injury (AKI) remained least appreciated intricacy of dengue infection. Exiting literature does not provide any information on renal outcomes among dengue patients surviving an episode of AKI. METHODS: Dengue patients who developed AKI were followed up for post-discharge period of three months and renal recovery was assessed by using recovery criteria based on different thresholds of serum creatinine (SCr) and estimated glomerular filtration rates (eGFR). RESULTS: Out of the 526 dengue participants, AKI was developed in 72 (13.7%) patients. Renal recovery was assessed among AKI survivors (n = 71). The use of less (+/-50% recovery to baseline) to more (+/-5% recovery to baseline) stringent definitions of renal recovery yielded recovery rates from 88.9% to 2.8% by SCr and 94.4% to 5.6% by eGFR, as renal function biomarkers. At the end of study, eight patients had AKI with AKIN-II (n = 7) and AKIN-III (n = 1). Approximately 50% patients (n = 36/71) with AKI had eGFR primitive to CKD stage 2, while 18.3% (n = 13/71) and 4.2% (n = 3/71) patients had eGFR corresponding to advanced stages of CKD (stage 3 & 4). Factors such as renal insufficiencies at hospital discharge, multiple organ involvements, advance age, female gender and diabetes mellitus were associated with poor renal outcomes. CONCLUSIONS: We conclude that dengue patients with AKI portend unsatisfactory short-term renal outcomes and deserve a careful and longer follow-up, especially under nephrology care. PMID- 29481566 TI - Correction: Association between the 2012 Health and Social Care Act and specialist visits and hospitalisations in England: A controlled interrupted time series analysis. AB - [This corrects the article DOI: 10.1371/journal.pmed.1002427.]. PMID- 29481565 TI - Analysis of age-related changes in psychosine metabolism in the human brain. AB - alpha-Synuclein aggregation has been linked to Gaucher's disease (GD) and Krabbe's disease (KD), lysosomal conditions affecting glycosphingolipid metabolism. alpha-Synuclein pathology has been directly attributed to the dysregulation of glycosphingolipids in both conditions, specifically to increased galactosylsphingosine (psychosine) content in the context of KD. Furthermore, the gene (GALC) coding for the psychosine degrading enzyme galactosylceramidase (GALC), has recently been identified as a risk loci for Parkinson's disease. However, it is unknown if changes in psychosine metabolism and GALC activity in the context of the aging human brain correlate with Parkinson's disease. We investigated psychosine accumulation and GALC activity in the aging brain using fresh frozen post-mortem tissue from Parkinson's (PD, n = 10), Alzheimer's (AD, n = 10), and healthy control patients (n = 9), along with tissue from neuropsychiatric patients (schizophrenia, bipolar disorder and depression, n = 15 each). An expanded mutational analysis of PD (n = 20), AD (n = 10), and healthy controls (n = 30) examined if PD was correlated with carriers for severe GALC mutations. Psychosine content within the cerebral cortex of PD patients was elevated above control patients. Within all patients, psychosine displayed a significant (p<0.05) and robust regional distribution in the brain with higher levels in the white matter and substantia nigra. A mutational analysis revealed an increase in the incidence of severe GALC mutations within the PD patient population compared to the cohorts of Alzheimer's patients and healthy controls tested. In addition to alpha-synuclein pathology identified in the KD brain, control patients identified as GALC mutational carriers or possessing a GALC pathogenic variant had evidence of alpha-synuclein pathology, indicating a possible correlation between alpha-synuclein pathology and dysregulation of psychosine metabolism in the adult brain. Carrier status for GALC mutations and prolonged exposure to increased psychosine could contribute to alpha-synuclein pathology, supporting psychosine metabolism by galactosylceramidase as a risk factor for Parkinson's disease. PMID- 29481567 TI - Evaluation of the Trypanosoma brucei 6-oxopurine salvage pathway as a potential target for drug discovery. AB - Due to toxicity and compliance issues and the emergence of resistance to current medications new drugs for the treatment of Human African Trypanosomiasis are needed. A potential approach to developing novel anti-trypanosomal drugs is by inhibition of the 6-oxopurine salvage pathways which synthesise the nucleoside monophosphates required for DNA/RNA production. This is in view of the fact that trypanosomes lack the machinery for de novo synthesis of the purine ring. To provide validation for this approach as a drug target, we have RNAi silenced the three 6-oxopurine phosphoribosyltransferase (PRTase) isoforms in the infectious stage of Trypanosoma brucei demonstrating that the combined activity of these enzymes is critical for the parasites' viability. Furthermore, we have determined crystal structures of two of these isoforms in complex with several acyclic nucleoside phosphonates (ANPs), a class of compound previously shown to inhibit 6 oxopurine PRTases from several species including Plasmodium falciparum. The most potent of these compounds have Ki values as low as 60 nM, and IC50 values in cell based assays as low as 4 MUM. This data provides a solid platform for further investigations into the use of this pathway as a target for anti-trypanosomal drug discovery. PMID- 29481568 TI - Multiscale modeling of layer formation in epidermis. AB - The mammalian skin epidermis is a stratified epithelium composed of multiple layers of epithelial cells that exist in appropriate sizes and proportions, and with distinct boundaries separating each other. How the epidermis develops from a single layer of committed precursor cells to form a complex multilayered structure of multiple cell types remains elusive. Here, we construct stochastic, three-dimensional, and multiscale models consisting of a lineage of multiple cell types to study the control of epidermal development. Symmetric and asymmetric cell divisions, stochastic cell fate transitions within the lineage, extracellular morphogens, cell-to-cell adhesion forces, and cell signaling are included in model. A GPU algorithm was developed and implemented to accelerate the simulations. These simulations show that a balance between cell proliferation and differentiation during lineage progression is crucial for the development and maintenance of the epidermal tissue. We also find that selective intercellular adhesion is critical to sharpening the boundary between layers and to the formation of a highly ordered structure. The long-range action of a morphogen provides additional feedback regulations, enhancing the robustness of overall layer formation. Our model is built upon previous experimental findings revealing the role of Ovol transcription factors in regulating epidermal development. Direct comparisons of experimental and simulation perturbations show remarkable consistency. Taken together, our results highlight the major determinants of a well-stratified epidermis: balanced proliferation and differentiation, and a combination of both short- (symmetric/asymmetric division and selective cell adhesion) and long-range (morphogen) regulations. These underlying principles have broad implications for other developmental or regenerative processes leading to the formation of multilayered tissue structures, as well as for pathological processes such as epidermal wound healing. PMID- 29481569 TI - Improvement of bread making quality by supplementation with a recombinant xylanase produced by Pichia pastoris. AB - Xylanases (EC 3.2.1.8) are hydrolytic enzymes, which randomly cleave the beta-1,4 linked xylose residues from xylan. The synthetic gene xynBS27 from Streptomyces sp. S27 was successfully cloned and expressed in Pichia pastoris. The full-length gene consists of 729 bp and encodes 243 amino acids including 51 residues of a putative signal peptide. This enzyme was purified in two steps and was shown to have a molecular weight of 20 kDa. The purified r-XynBS27 was active against beechwood xylan and oat spelt xylan as expected for GH 11 family. The optimum pH and temperature values for the enzyme were 6.0 and 75 degrees C, respectively. The Km and Vmax were 12.38 mg/mL and 13.68 MUmol min/mg, respectively. The r XynBS27 showed high xylose tolerance and was inhibited by some metal ions and by SDS. r-XynBS27 was employed as an additive in the bread making process. A decrease in firmness, stiffness and consistency, and improvements in specific volume and reducing sugar content were recorded. PMID- 29481570 TI - Leprosy among schoolchildren in the Amazon region: A cross-sectional study of active search and possible source of infection by contact tracing. AB - BACKGROUND: The high rate of leprosy cases among children under 15 years of age in Brazil indicates ongoing transmission within the community. The identification of the new leprosy cases among contacts can help identify the source of infection and interrupt the transmission chain. This study aims to determine the detection rate of previously undiagnosed cases of leprosy among schoolchildren who are under 15 years of age living in Manaus, Amazonas, Brazil, and their possible source of infection by contact tracing. METHODOLOGY/PRINCIPAL FINDINGS: This was a school-based, cross-sectional study in which the identification of active leprosy cases was conducted in 277 out of 622 randomly selected public schools in Manaus, Amazonas, Brazil. Suspected cases of leprosy were referred to the Alfredo da Matta Foundation, a reference center for leprosy in Manaus. A total of 34,547 schoolchildren were examined, and 40 new leprosy cases were diagnosed. Among new cases, 57.5% were males, and 80.0% demonstrated paucibacillary leprosy. A total of 196 of 206 registered contacts were screened, and 52.5% of the newly diagnosed children's cases had at least one positive household contact. In these contacts, grandparents (52.4%) were the most common co-prevalent cases, while 14.3% were uncles, 9.5% were parents and 9.5% were granduncles. Seven contacts (5.0%), including four siblings of child patients were newly diagnosed. Our data indicate that the prevalence is 11.58 per 10,000, which is 17 times higher than the registered rate. CONCLUSIONS/SIGNIFICANCE: This study suggests that the detection rate of leprosy among schoolchildren may have remained unchanged over the past thirty years. It also indicates that that active case finding is necessary for reaching the World Health Organization's goals of zero detection among children, especially in endemic areas where the prevalence of leprosy is obscure. Moreover, we assert that all children must have their household contacts examined in order to identify the possible source of infection and interrupt the disease's transmission. Novel strategies to reinforce contact tracing associated with large scale strategies of chemo- and immune-prophylaxis should be expanded to prevent the perpetuation of the disease cycle. PMID- 29481572 TI - Scene and human face recognition in the central vision of patients with glaucoma. AB - Primary open-angle glaucoma (POAG) firstly mainly affects peripheral vision. Current behavioral studies support the idea that visual defects of patients with POAG extend into parts of the central visual field classified as normal by static automated perimetry analysis. This is particularly true for visual tasks involving processes of a higher level than mere detection. The purpose of this study was to assess visual abilities of POAG patients in central vision. Patients were assigned to two groups following a visual field examination (Humphrey 24-2 SITA-Standard test). Patients with both peripheral and central defects and patients with peripheral but no central defect, as well as age-matched controls, participated in the experiment. All participants had to perform two visual tasks where low-contrast stimuli were presented in the central 6 degrees of the visual field. A categorization task of scene images and human face images assessed high level visual recognition abilities. In contrast, a detection task using the same stimuli assessed low-level visual function. The difference in performance between detection and categorization revealed the cost of high-level visual processing. Compared to controls, patients with a central visual defect showed a deficit in both detection and categorization of all low-contrast images. This is consistent with the abnormal retinal sensitivity as assessed by perimetry. However, the deficit was greater for categorization than detection. Patients without a central defect showed similar performances to the controls concerning the detection and categorization of faces. However, while the detection of scene images was well maintained, these patients showed a deficit in their categorization. This suggests that the simple loss of peripheral vision could be detrimental to scene recognition, even when the information is displayed in central vision. This study revealed subtle defects in the central visual field of POAG patients that cannot be predicted by static automated perimetry assessment using Humphrey 24-2 SITA Standard test. PMID- 29481571 TI - 17-AAG inhibits vemurafenib-associated MAP kinase activation and is synergistic with cellular immunotherapy in a murine melanoma model. AB - Heat shock protein 90 (HSP90) is a molecular chaperone which stabilizes client proteins with important roles in tumor growth. 17-allylamino-17 demethoxygeldanamycin (17-AAG), an inhibitor of HSP90 ATPase activity, occupies the ATP binding site of HSP90 causing a conformational change which destabilizes client proteins and directs them towards proteosomal degradation. Malignant melanomas have active RAF-MEK-ERK signaling which can occur either through an activating mutation in BRAF (BRAFV600E) or through activation of signal transduction upstream of BRAF. Prior work showed that 17-AAG inhibits cell growth in BRAFV600E and BRAF wildtype (BRAFWT) melanomas, although there were conflicting reports about the dependence of BRAFV600E and BRAFWT upon HSP90 activity for stability. Here, we demonstrate that BRAFWT and CRAF are bound by HSP90 in BRAFWT, NRAS mutant melanoma cells. HSP90 inhibition by 17-AAG inhibits ERK signaling and cell growth by destabilizing CRAF but not BRAFWT in the majority of NRAS mutant melanoma cells. The highly-selective BRAFV600E inhibitor, PLX4032 (vemurafenib), inhibits ERK signaling and cell growth in mutant BRAF melanoma cells, but paradoxically enhances signaling in cells with wild-type BRAF. In our study, we examined whether 17-AAG could inhibit PLX4032-enhanced ERK signaling in BRAFWT melanoma cells. As expected, PLX4032 alone enhanced ERK signaling in the BRAFWT melanoma cell lines Mel-Juso, SK-Mel-2, and SK-Mel-30, and inhibited signaling and cell growth in BRAFV600E A375 cells. However, HSP90 inhibition by 17-AAG inhibited PLX4032-enhanced ERK signaling and inhibited cell growth by destabilizing CRAF. Surprisingly, 17-AAG also stimulated melanin production in SK-Mel-30 cells and enhanced TYRP1 and DCT expression without stimulating TYR production in all three BRAFWT cell lines studied as well as in B16F10 mouse melanoma cells. In vivo, the combination of 17-AAG and cellular immunotherapy directed against Tyrp1 enhanced the inhibition of tumor growth compared to either therapy alone. Our studies support a role for 17-AAG and HSP90 inhibition in enhancing cellular immunotherapy for melanoma. PMID- 29481573 TI - Pyrenoid functions revealed by proteomics in Chlamydomonas reinhardtii. AB - Organelles are intracellular compartments which are themselves compartmentalized. Biogenic and metabolic processes are localized to specialized domains or microcompartments to enhance their efficiency and suppress deleterious side reactions. An example of intra-organellar compartmentalization is the pyrenoid in the chloroplasts of algae and hornworts. This microcompartment enhances the photosynthetic CO2-fixing activity of the Calvin-Benson cycle enzyme Rubisco, suppresses an energetically wasteful oxygenase activity of Rubisco, and mitigates limiting CO2 availability in aquatic environments. Hence, the pyrenoid is functionally analogous to the carboxysomes in cyanobacteria. However, a comprehensive analysis of pyrenoid functions based on its protein composition is lacking. Here we report a proteomic characterization of the pyrenoid in the green alga Chlamydomonas reinhardtii. Pyrenoid-enriched fractions were analyzed by quantitative mass spectrometry. Contaminant proteins were identified by parallel analyses of pyrenoid-deficient mutants. This pyrenoid proteome contains 190 proteins, many of which function in processes that are known or proposed to occur in pyrenoids: e.g. the carbon concentrating mechanism, starch metabolism or RNA metabolism and translation. Using radioisotope pulse labeling experiments, we show that pyrenoid-associated ribosomes could be engaged in the localized synthesis of the large subunit of Rubisco. New pyrenoid functions are supported by proteins in tetrapyrrole and chlorophyll synthesis, carotenoid metabolism or amino acid metabolism. Hence, our results support the long-standing hypothesis that the pyrenoid is a hub for metabolism. The 81 proteins of unknown function reveal candidates for new participants in these processes. Our results provide biochemical evidence of pyrenoid functions and a resource for future research on pyrenoids and their use to enhance agricultural plant productivity. Data are available via ProteomeXchange with identifier PXD004509. PMID- 29481574 TI - Mesenchymal stem cells ameliorate experimental arthritis via expression of interleukin-1 receptor antagonist. AB - Human bone marrow-derived mesenchymal stem cells (MSCs) have been observed to inhibit arthritis in experimental animal models such as collagen-induced arthritis. However, the exact anti-inflammatory mechanisms remain poorly understood. Interleukin-1 receptor antagonist (IL-1Ra) is an anti-inflammatory cytokine produced by immune and stromal cells. We postulated that MSCs could produce IL-1Ra and attenuate experimental arthritis. In this study, 5x106 MSCs were injected into the peritoneal cavity of IL-1Ra knockout (IL-1RaKO) mice. MSCs reduced the severity of the arthritis by histology and decreased pro-inflammatory cytokine levels in IL-1RaKO mice. The ratio of splenic T helper 17 (Th17) cells to regulatory T cells (Treg) was significantly decreased in MSC-injected IL-1RaKO mice. Purified splenic CD4+ T cells from mice in each of the treatment groups were cultured under Th17 polarizing conditions and analyzed by flow cytometry. Less expansion of the Th17 population was observed in the MSC-treated group. Interestingly, MSCs expressed inducible IL-1Ra against inflammatory environmental stimuli. Human recombinant IL-1Ra could suppress Th17 cells differentiation under Th17 polarizing conditions. These results indicate that IL-1Ra expressed by MSCs can inhibit Th17 polarization and decrease the immune response in IL-1RaKO mice. Therefore, MSC-derived IL-1Ra may inhibit inflammation in IL-1RaKO mice via effects on Th17 differentiation. PMID- 29481575 TI - Methods for fine-mapping with chromatin and expression data. AB - Recent studies have identified thousands of regions in the genome associated with chromatin modifications, which may in turn be affecting gene expression. Existing works have used heuristic methods to investigate the relationships between genome, epigenome, and gene expression, but, to our knowledge, none have explicitly modeled the chain of causality whereby genetic variants impact chromatin, which impacts gene expression. In this work we introduce a new hierarchical fine-mapping framework that integrates information across all three levels of data to better identify the causal variant and chromatin mark that are concordantly influencing gene expression. In simulations we show that our method is more accurate than existing approaches at identifying the causal mark influencing expression. We analyze empirical genetic, chromatin, and gene expression data from 65 African-ancestry and 47 European-ancestry individuals and show that many of the paths prioritized by our method are consistent with the proposed causal model and often lie in likely functional regions. PMID- 29481577 TI - Lipids at the crossroad: Shaping biological membranes heterogeneity defines trafficking pathways. AB - Lipids are essential components of biological membranes that present a wide diversity in eukaryotic cells. Recent impressive advances in lipid biochemistry and biophysics have enabled a refocus of our view of lipids as functional units for cellular activity. However, the gap between molecular and cellular processes remains to be bridged. Here, 2 papers meet the burden of proof that choline transporters participate in local lipid composition modifications at the trans Golgi network, an intracellular compartment that serves as the main sorting station in the cell. Localization of choline transporters to this precise compartment could be a way for plant cells to quickly modify the membrane lipid composition and asymmetry during both the allocation of cargos and the recruitment of trafficking machineries into distinct subcellular pathways. PMID- 29481578 TI - Silica exposure increases the risk of stroke but not myocardial infarction-A retrospective cohort study. AB - INTRODUCTION: Work-related exposure to silica is a global health hazard that causes diseases such as silicosis. Some studies have also reported that silica exposure is linked to elevated cardiovascular disease mortality. However, these diagnoses have not been investigated in detail and there have been few studies on morbidity. The aim of this study is to examine morbidity and mortality from different cardiovascular diseases among silica-exposed Swedish foundry workers. METHODS: Historical and contemporary measurements (1968-2006) of respiratory silica exposure were matched to job categories, individual foundries, and 4 time periods (1968-1979, 1980-1989, 1990-1999, 2000-2006) using a mixed model. Morbidity and mortality data for the studied cohorts were matched against the General Population Registry. Statistical analyses were performed with SPSS and STATA, and the data were stratified by age, gender, and year. RESULTS: Mortality from cardiovascular disease (SMR 1.3; 95% CI 1.2-1.4) and stroke (SMR 1.6, 95% CI 1.2-2.1) was significantly elevated among the studied population. The cohort also exhibited significantly elevated morbidity from stroke (SIR 1.34; 95% CI 1.2-1.5) but not myocardial infarction. The mean age at the time of first morbidity from stroke was 64 years, with 36% of the cases occurring before the age of 60. CONCLUSIONS: Swedish foundry workers exposed to respirable silica exhibit elevated morbidity and mortality from stroke, but not from myocardial infarction. Our results also suggest a relationship between silica exposure and morbidity from stroke at a younger age than the general population. PMID- 29481576 TI - Comparative and network-based proteomic analysis of low dose ethanol- and lipopolysaccharide-induced macrophages. AB - Macrophages are specialized phagocytes that play an essential role in inflammation, immunity, and tissue repair. Profiling the global proteomic response of macrophages to microbial molecules such as bacterial lipopolysaccharide is key to understanding fundamental mechanisms of inflammatory disease. Ethanol is a widely abused substance that has complex effects on inflammation. Reports have indicated that ethanol can activate or inhibit the lipopolysaccharide receptor, Toll-like Receptor 4, in different settings, with important consequences for liver and neurologic inflammation, but the underlying mechanisms are poorly understood. To profile the sequential effect of low dose ethanol and lipopolysaccharide on macrophages, a gel-free proteomic technique was applied to RAW 264.7 macrophages. Five hundred four differentially expressed proteins were identified and quantified with high confidence using >= 5 peptide spectral matches. Among these, 319 proteins were shared across all treatment conditions, and 69 proteins were exclusively identified in ethanol-treated or lipopolysaccharide-stimulated cells. The interactive impact of ethanol and lipopolysaccharide on the macrophage proteome was evaluated using bioinformatics tools, enabling identification of differentially responsive proteins, protein interaction networks, disease- and function-based networks, canonical pathways, and upstream regulators. Five candidate protein coding genes (PGM2, ISYNA1, PARP1, and PSAP) were further validated by qRT-PCR that mostly related to glucose metabolism and fatty acid synthesis pathways. Taken together, this study describes for the first time at a systems level the interaction between ethanol and lipopolysaccharide in the proteomic programming of macrophages, and offers new mechanistic insights into the biology that may underlie the impact of ethanol on infectious and inflammatory disease in humans. PMID- 29481579 TI - Loss of Full-Length GATA1 Expression in Megakaryocytes Is a Sensitive and Specific Immunohistochemical Marker for the Diagnosis of Myeloid Proliferative Disorder Related to Down Syndrome. AB - Objectives: Myeloid proliferative disorders associated with Down syndrome (MPD DS), including transient abnormal myelopoiesis and myeloid leukemia associated with Down syndrome (DS), harbor mutations of GATA1, a transcription factor essential for erythroid and megakaryocytic development. These mutations result in a N-terminally truncated GATA1 (GATA1s) and prohibit the production of the full length GATA1 (GATA1f). Here, we demonstrate the utility of immunohistochemical GATA1f reactivity in diagnosing MPD-DS. Methods: Immunohistochemical studies for GATA1f expression were performed on bone marrow biopsy specimens. Results: In all cases of MPD-DS, megakaryocytes lacked GATA1f expression. In contrast, GATA1f expression was detected in megakaryocytes in all specimen types from patients without DS (normal bone marrows, pediatric myelodysplastic syndrome, juvenile myelomonocytic leukemia, adult acute megakaryocytic leukemia [pediatric and adult; without trisomy 2]), as well as normal bone marrows from patients with DS. Conclusions: The lack of GATA1f expression is a sensitive and specific immunohistochemical marker for MPD-DS. PMID- 29481581 TI - Evaluation of a novel cryoballoon swipe ablation system in bench, porcine, and human esophagus models. AB - Current ablation devices for dysplastic Barrett's esophagus are effective but have significant limitations. This pilot study aims to evaluate the safety, feasibility, and dose response of a novel cryoballoon swipe ablation system (CbSAS) in three experimental in vitro and in vivo models. CbSAS is a through-the scope compliant balloon that is simultaneously inflated and cooled by liquid nitrous oxide delivered from a disposable handheld unit. When the cryogen is applied through a special diffuser it covers a 90 degrees section of the circumference of the esophagus for 3 cm length. Doses range from 0.9 to 0.5 mm/second. (1) Bench model: The fixture consisted of an 'esophagus-like' tube lined with agar at 37 degrees C to create an inner diameter of 20 or 30 mm, within which thermocouples were embedded. (2) In vivo porcine esophagus: CbSAS ablations were performed in animals that were euthanized and histological assessments of depth and percentage of esophageal mucosa successfully ablated were done. (3) In vivo, pre-esophagectomy human esophagus. After CbSAS ablations, histological assessments were performed (at 0, 4, and 28 days) to assess the depth and percentage of ablated mucosa. As outcomes, we assessed the safety and tolerability (pain and serious, device-related adverse events); efficacy (depth and uniformity) of ablation; and device performance (ease of deployment and device malfunction). In the bench model, during CbSAS, thermocouples measured minimal temperatures of -40 to -48 degrees C at all doses. In the porcine model, maximal effect on the mucosa was reached with a dose of 0.8 mm/second that extended to superficial submucosa, while 0.5 mm/second extended through the submucosa. All animals tolerated the treatments and, regardless of ablation dose, continued oral intake and gained weight. In the human model, six patients (5 male, 1 female, mean age 68) tolerated the procedure without adverse events. CbSAS was simple to operate, and balloon contact with tissue was easily and uniformly maintained. The maximal effect on the mucosa is achieved with a 0.8 mm/second dose. We concluded that the CbSAS device enables uniform 3 cm long, quarter-circumferential mucosal ablation in a one-step process by using a novel, through-the-scope balloon. The CbSAS delivers predictable ablation with mucosal and limited submucosal necrosis in bench, animal, and human esophagus. Because of its ease of use, this new device merits further clinical study in the treatment of patients with dysplastic Barrett's esophagus. PMID- 29481582 TI - Right ventricular pseudoaneurysm. PMID- 29481580 TI - Diagnosis and Treatment of Neurocysticercosis: 2017 Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH). PMID- 29481583 TI - An efficient approach for the development of genome-specific markers in allohexaploid wheat (Triticum aestivum L.) and its application in the construction of high-density linkage maps of the D genome. AB - In common wheat, the development of genotyping platforms has been hampered by the large size of the genome, its highly repetitive elements and its allohexaploid nature. However, recent advances in sequencing technology provide opportunities to resolve these difficulties. Using next-generation sequencing and gene targeting sequence capture, 12,551 nucleotide polymorphisms were detected in the common wheat varieties 'Hatsumochi' and 'Kitahonami' and were assigned to chromosome arms using International Wheat Genome Sequencing Consortium survey sequences. Because the number of markers for D genome chromosomes in commercially available wheat single nucleotide polymorphism arrays is insufficient, we developed markers using a genome-specific amplicon sequencing strategy. Approximately 80% of the designed primers successfully amplified D genome specific products, suggesting that by concentrating on a specific subgenome, we were able to design successful markers as efficiently as could be done in a diploid species. The newly developed markers were uniformly distributed across the D genome and greatly extended the total coverage. Polymorphisms were surveyed in six varieties, and 31,542 polymorphic sites and 5,986 potential marker sites were detected in the D genome. The marker development and genotyping strategies are cost effective, robust and flexible and may enhance multi-sample studies in the post-genomic era in wheat. PMID- 29481585 TI - PhyloMAd: efficient assessment of phylogenomic model adequacy. AB - Summary: Statistical phylogenetic inference plays an important role in evolutionary biology. The accuracy of phylogenetic methods relies on having suitable models of the evolutionary process. Various tools allow comparisons of candidate phylogenetic models, but assessing the absolute performance of models remains a considerable challenge. We introduce PhyloMAd, a user-friendly application for assessing the adequacy of commonly used models of nucleotide substitution and among-lineage rate variation. Our software implements a fast, likelihood-based method of model assessment that is tractable for analyses of large multi-locus datasets. PhyloMAd provides a means of informing model improvement, or selecting data to enhance the evolutionary signal in phylogenomic analyses. Availability and implementation: PhyloMAd, together with a manual, a tutorial and the source code, are freely available from the GitHub repository github.com/duchene/phylomad. PMID- 29481586 TI - Directed Interaction Between Monkey Premotor and Posterior Parietal Cortex During Motor-Goal Retrieval from Working Memory. AB - Goal-directed behavior requires cognitive control of action, putatively by means of frontal-lobe impact on posterior brain areas. We investigated frontoparietal directed interaction (DI) in monkeys during memory-guided rule-based reaches, to test if DI supports motor-goal selection or working memory (WM) processes. We computed DI between the parietal reach region (PRR) and dorsal premotor cortex (PMd) with a Granger-causality measure of intracortical local field potentials (LFP). LFP mostly in the beta (12-32 Hz) and low-frequency (f<=10Hz) ranges contributed to DI. During movement withholding, beta-band activity in PRR had a Granger-causal effect on PMd independent of WM content. Complementary, low frequency PMd activity had a transient Granger-causing effect on PRR specifically during WM retrieval of spatial motor goals, while no DI was associated with preliminary motor-goal selection. Our results support the idea that premotor and posterior parietal cortices interact functionally to achieve cognitive control during goal-directed behavior, in particular, that frontal-to-parietal interaction occurs during retrieval of motor-goal information from spatial WM. PMID- 29481588 TI - Bioinformatics tools for quantitative and functional metagenome and metatranscriptome data analysis in microbes. PMID- 29481584 TI - Hemochorial placentation: development, function, and adaptations. AB - Placentation is a reproductive adaptation that permits fetal growth and development within the protected confines of the female reproductive tract. Through this important role, the placenta also determines postnatal health and susceptibility to disease. The hemochorial placenta is a prominent feature in primate and rodent development. This manuscript provides an overview of the basics of hemochorial placental development and function, provides perspectives on major discoveries that have shaped placental research, and thoughts on strategies for future investigation. PMID- 29481589 TI - Computational prediction of neoantigens: do we need more data or new approaches? PMID- 29481590 TI - Quality of Life After Breast Enlargement With Implants Versus Augmentation Mastopexy: A Comparative Study. AB - Background: Research regarding quality of life (QoL) among women who have undergone breast aesthetic surgery is expanding. A comparative, anonymous study between the two main breast aesthetic procedures is needed. Objectives: The authors compared patient characteristics and aspects of QoL among women who underwent breast enlargement with implants (BI group) and those who underwent augmentation mastopexy (AM group). Methods: Patients at the Oslo Plastic Surgery Clinic were given a 47-question survey to measure QoL. The survey was anonymous; 61 patients who received breast implants and 37 patients who underwent augmentation mastopexy between 2005 and 2009 responded. Answers were processed by a QuestBack return mail system and sent to the authors. Statistical analyses were performed to evaluate significance between the groups. Results: The response rate was 67% in the BI group and 88% in the AM group. Mean follow-up time was 2.8 years in both groups. Motivation for surgery was primarily cosmetic (65%) and emotional (48%) in the BI group as well as cosmetic (78%) and physical (31%) in the AM group. The effects on psychosocial aspects were significant in the BI group regarding life changes and feeling like a "whole" person (68.9% vs 40.5% and 73.8% vs 40%). BI group also had a significantly higher satisfaction with overall cosmetic result, enlargement, and breast volume (93.4 %, 90.2%, 80% vs 69.4%, 70.2% vs 67% in AM group). Additionally, the BI group was more satisfied with shape, scar, and symmetry (90.1% vs 63.9%, 70.6% vs 40.5%, and 83.6% vs 54.0%, respectively). Conclusions: None of our patient groups were stereotypical and motivation for surgery was primarily cosmetic in both groups. BI patients were significantly more satisfied with the aesthetic outcome and the QoL of many psychosocial aspects. AM patients may have had different expectations than BI patients and a significant dissatisfaction was reported in shape, scarring, symmetry, and the nipple-areola complex. Level of Evidence 3: PMID- 29481587 TI - Functional divergence of duplicate genes several million years after gene duplication in Arabidopsis. AB - Lineage-specific duplicated genes likely contribute to the phenotypic divergence in closely related species. However, neither the frequency of duplication events nor the degree of selection pressures immediately after gene duplication is clear in the speciation process. Here, using Illumina DNA-sequencing reads from Arabidopsis halleri, which has multiple closely related species with high-quality genome assemblies (A. thaliana and A. lyrata), we succeeded in generating orthologous gene groups in Brassicaceae. The duplication frequency of retained genes in the Arabidopsis lineage was ~10 times higher than the duplication frequency inferred by comparative genomics of Arabidopsis, poplar, rice and moss (Physcomitrella patens). The difference of duplication frequencies can be explained by a rapid decay of anciently duplicated genes. To examine the degree of selection pressure on genes duplicated in either the A. halleri-lyrata or the A. halleri lineage, we examined positive and purifying selection in the A. halleri-lyrata and A. halleri lineages throughout the ratios of nonsynonymous to synonymous substitution rates (KA/KS). Duplicate genes tended to have a higher proportion of positive selection compared with non-duplicated genes. Interestingly, we found that functional divergence of duplicated genes was accelerated several million years after gene duplication compared with immediately after gene duplication. PMID- 29481591 TI - Effect of new-onset atrial fibrillation on cause-specific late mortality after coronary artery bypass grafting surgery. AB - OBJECTIVES: Postoperative atrial fibrillation (POAF) is a common complication after coronary artery bypass grafting. Although transient, POAF is linked to increased late mortality. We hypothesized that POAF increases late cerebrovascular (CeV) and composite cerebrovascular/cardiovascular/vascular (CV* = CeV + CV + Other-V) but not non-cardiovascular (Non-CV) mortality. METHODS: We analysed 8807 non-salvage coronary artery bypass grafting patients (1994-2011). Fifteen-year and time-segmented (early, 0-1 year; intermediate, 1-6 years and late, 6-15 years) all-cause and cause-specific mortality were compared for POAF versus No-POAF patients. Corresponding POAF versus No-POAF adjusted hazard ratios [AHRs (95% confidence interval, CI)] were derived using the competing risk Cox regression. RESULTS: POAF occurred in 1992 (23%) patients. Complications other than POAF occurred in 1875 (21%) patients but were more frequent among POAF patients (31% vs 18%; P < 0.001). Overall mean follow-up was 9 +/- 4 years. POAF patients had a higher 15-year unadjusted mortality (53% vs 39%; P < 0.001) and were consequently associated with higher adjusted all-cause [AHR (95% CI) = 1.23 (1.14-1.33)] and composite cardiovascular [CV*: AHR (95% CI) = 1.15 (1.02-1.30)] mortality. The trends towards a higher 15-year CeV [AHR (95% CI) = 1.34 (0.94 1.91)] and Non-CV [AHR (95% CI) = 1.12 (0.99-1.26)] mortality were not significant. Time-segmented analyses showed that (i) POAF increased all-cause mortality early, and this persisted in the intermediate and late periods and (ii) CeV [AHR (95% CI) = 2.14 (1.14-4.04)] and CV* [AHR (95% CI) = 1.31 (1.06-1.62)] mortality rates were increased in the intermediate but not in the early or late periods. Non-CV mortality was similar in POAF and No-POAF for all time intervals. These findings were corroborated in propensity-matched sub-cohorts and in sensitivity analyses in patients free of any other complication. CONCLUSIONS: POAF is associated with worse long-term survival principally driven by increased intermediate-term cerebrovascular and cardiovascular mortality, while Non-CV mortality was similar. PMID- 29481592 TI - Clinical Trials of Blood Pressure Lowering and Antihypertensive Medication: Is Cognitive Measurement State-of-the-Art? AB - Randomized controlled trials of blood pressure (BP) lowering and antihypertensive medication use on cognitive outcomes have often been disappointing, reporting mixed findings and small effect sizes. We evaluate the extent to which cognitive assessment protocols used in these trials approach state-of-the-art. Overall, we find that a primary focus on cognition and the systematic selection of cognitive outcomes across trials take a backseat to other trial goals. Twelve trials investigating change in cognitive functioning were examined and none met criteria for state-of-the-art assessment, including use of at least 4 tests indexing 2 cognitive domains. Four trials investigating incident dementia were also examined. Each trial used state-of-the-art diagnostic criteria to assess dementia, although follow-up periods were relatively short, with only 2 trials lasting for at least 3 years. Weaknesses in each trial may act to obscure or weaken the positive effects of BP lowering on cognitive functioning. Improving trial designs in terms of cognitive outcomes selected and length of follow-up periods employed could lead to more promising findings. We offer logical steps to achieve state-of-the-art assessment protocols, with examples, in hopes of improving future trials. PMID- 29481593 TI - Micafungin antifungal prophylaxis in children undergoing HSCT: can we give higher doses, less frequently? A pharmacokinetic study. AB - Background: Micafungin has a distinct advantage for antifungal prophylaxis in HSCT owing to its better safety profile, specifically in terms of hepatic and renal toxicity. In children, prophylactic micafungin is given as either 1 mg/kg every day or 3 mg/kg every other day. Objectives: We performed a prospective single-centre observational study that investigated the pharmacokinetics (PK) of a single 5 mg/kg dose of micafungin in young children undergoing HSCT, to ascertain the eventual feasibility of twice-weekly prophylactic administration. Methods: Nine children, <=10 years of age undergoing HSCT, were enrolled and received a single intravenous dose of 5 mg/kg micafungin. Blood samples were obtained for PK analysis. Micafungin plasma concentration of >0.2 mg/L was chosen for target attainment (i.e. considered adequate prophylactic concentration). In addition, a population PK model was developed based on current and our previous PK study data. We also evaluated PK model-based simulation of PK profiles and target attainment using Monte Carlo simulation, for several dosing scenarios. Results: Mean clearance was 15.3 mL/h/kg (range 11.0-21.4 mL/h/kg) and the mean elimination half-life was 11.6 h (range 7.8-16.6 h). The mean concentration at 96 h was 0.11 mg/L (range 0.03-0.26 mg/L). Eleven percent (n = 1) of patients achieved target attainment at the end of 96 h. Simulation data showed that 1 mg/kg daily dosing and 3 mg/kg alternate-day dosing strategies achieved at least 99% and 81% target attainment, respectively, whereas a 5 mg/kg with 3 day interval dosing strategy resulted in 64%, 72% and 84% target attainments in patients with body weights of 10, 20 and 30 kg, respectively. Conclusions: Micafungin at 5 mg/kg dosing did not achieve target attainment at the end of 96 h for antifungal prophylaxis in children undergoing HSCT. Simulation data suggest that a dosing strategy of micafungin at 5 mg/kg every 72 h is more likely to achieve target attainment in children with a higher body weight in comparison with children with a lower body weight. A cautious approach is advisable when using a high, but less frequent, dosing strategy in very young children. PMID- 29481594 TI - Polyphosphate metabolic gene expression analyses reveal mechanisms of phosphorus accumulation and release in Microlunatus phosphovorus strain JN459. AB - The ability of Microlunatus phosphovorus to accumulate large amounts of polyphosphate (Poly-P) plays an important role in removing soluble phosphorus from wastewater. Strain JN459, isolated from a sewage system, was previously demonstrated to be Microlunatus phosphovorus. In this study, we analyzed the phosphorus-accumulating and phosphorus-releasing characteristics of strain JN459. Our analyses indicate that strain JN459 accumulates Poly-P under aerobic conditions but releases phosphorus under anaerobic conditions. To determine the mechanisms underlying Poly-P metabolism in strain JN459, we compared transcriptional profiles under aerobic and anaerobic conditions. Significant differences were detected in the expression levels of genes associated with Poly P metabolism between aerobic and anaerobic conditions, including ppk (MLP_47700, MLP_50300 and MLP_05750), ppgk (MLP_05430 and MLP_26610), ppx (MLP_44770), pap (MLP_23310) and ppnk (MLP_17420). The high expression of polyphosphate glucokinase (MLP_05430) and polyphosphate/ATP-dependent NAD kinase (MLP_17420) indicated that both of them might be responsible for utilizing Poly-P as the energy resource for growth under anaerobic conditions. These findings enhance our understanding of phosphate metabolism in a major bacterial species involved in wastewater phosphorus reduction. PMID- 29481595 TI - More on dissidents and dietary sodium. PMID- 29481596 TI - Regulation of the aceI multidrug efflux pump gene in Acinetobacter baumannii. AB - Objectives: To investigate the function of AceR, a putative transcriptional regulator of the chlorhexidine efflux pump gene aceI in Acinetobacter baumannii. Methods: Chlorhexidine susceptibility and chlorhexidine induction of aceI gene expression were determined by MIC and quantitative real-time PCR, respectively, in A. baumannii WT and DeltaaceR mutant strains. Recombinant AceR was prepared as both a full-length protein and as a truncated protein, AceR (86-299), i.e. AceRt, which has the DNA-binding domain deleted. The binding interaction of the purified AceR protein and its putative operator region was investigated by electrophoretic mobility shift assays and DNase I footprinting assays. The binding of AceRt with its putative ligand chlorhexidine was examined using surface plasmon resonance and tryptophan fluorescence quenching assays. Results: MIC determination assays indicated that the DeltaaceI and DeltaaceR mutant strains both showed lower resistance to chlorhexidine than the parental strain. Chlorhexidine-induced expression of aceI was abolished in a DeltaaceR background. Electrophoretic mobility shift assays and DNase I footprinting assays demonstrated chlorhexidine stimulated binding of AceR with two sites upstream of the putative aceI promoter. Surface plasmon resonance and tryptophan fluorescence quenching assays suggested that the purified ligand-binding domain of the AceR protein was able to bind with chlorhexidine with high affinity. Conclusions: This study provides strong evidence that AceR is an activator of aceI gene expression when challenged with chlorhexidine. This study is the first characterization, to our knowledge, of a regulator controlling expression of a PACE family multidrug efflux pump. PMID- 29481598 TI - Cardiac manifestation of polyarteritis nodosa. PMID- 29481597 TI - Deletion of the RabGAP TBC1D1 Leads to Enhanced Insulin Secretion and Fatty Acid Oxidation in Islets From Male Mice. AB - The Rab guanosine triphosphatase-activating protein (RabGAP) TBC1D1 has been shown to be a key regulator of glucose and lipid metabolism in skeletal muscle. Its function in pancreatic islets, however, is not yet fully understood. Here, we aimed to clarify the specific impact of TBC1D1 on insulin secretion and substrate use in pancreatic islets. We analyzed the dynamics of glucose-stimulated insulin secretion (GSIS) and lipid metabolism in isolated islets from Tbc1d1-deficient (D1KO) mice. To further investigate the underlying cellular mechanisms, we conducted pharmacological studies in these islets. In addition, we determined morphology and number of both pancreatic islets and insulin vesicles in beta cells using light and transmission electron microscopy. Isolated pancreatic islets from D1KO mice exhibited substantially increased GSIS compared with wild type (WT) controls. This was attributed to both enhanced first and second phase of insulin secretion, and this enhanced secretion persisted during repetitive glucose stimuli. Studies with sulfonylureas or KCl in isolated islets demonstrated that TBC1D1 exerts its function via a signaling pathway at the level of membrane depolarization. In line, ultrastructural analysis of isolated pancreatic islets revealed both higher insulin-granule density and number of docked granules in beta-cells from D1KO mice compared with WT controls. Like in skeletal muscle, lipid use in isolated islets was enhanced upon D1KO, presumably as a result of a higher mitochondrial fission rate and/or higher mitochondrial activity. Our results clearly demonstrate a dual role of TBC1D1 in controlling substrate metabolism of the pancreatic islet. PMID- 29481599 TI - Incidence, Risk Factors, and Long-term Outcome of Acute Leukemia Patients With Early Candidemia After Allogeneic Stem Cell Transplantation: A Study by the Acute Leukemia and Infectious Diseases Working Parties of European Society for Blood and Marrow Transplantation. AB - Background: This study was performed to assess the incidence of and risk factors for Candida infection in the first 100 days after allogeneic hematopoietic stem cell transplantation (HSCT) and the impact on long-term survival. Methods: We performed an outcome analysis of 28542 acute leukemia patients who underwent HSCT from 2000 to 2012. There were 347 patients with candidemia by day 100 and 28195 without candidemia or any other type of Candida infection. Results: The incidence of candidemia by day 100 was 1.2% and occurred at a median of 22 days after HSCT. Higher 100-day nonrelapse mortality (NRM; hazards ratio [HR], 3.0, P < .0001) and lower 100-day overall survival (OS; HR, 2.5, P < .0001) were observed in patients with candidemia. The case fatality rate by day 100 in patients with candidemia was 22% (76/347). Factors associated with candidemia occurrence were female gender, bone marrow or cord blood stem cell source, T-cell depletion, use of total body irradiation, and acute graft vs host disease. Among the patients alive at day 100, the 5-year NRM and OS after a median follow-up of 5.6 years (95% confidence interval, 5.5 - 5.7) for patients with and without candidemia were 22.5% vs 13.5%, P < .0001 and 45.6% vs. 53.4%, P = .0003, respectively. In multivariate analysis, the occurrence of a candidemia episode by day 100 was an independent risk factor for higher NRM (HR, 1.7, P = .001) and lower OS (HR, 1.4, P = .001). Conclusions: The early occurrence of candidemia after HSCT is still associated with higher NRM and lower short- and-long-term OS. PMID- 29481600 TI - Evaluation of three broth microdilution systems to determine colistin susceptibility of Gram-negative bacilli. AB - Background: The broth microdilution (BMD) method is currently the recommended technique to determine susceptibility to colistin. Objectives: We evaluated the accuracy of three commercialized BMD panels [Sensititre (ThermoFisher Diagnostics), UMIC (Biocentric) and MicroScan (Beckman Coulter)] to determine colistin susceptibility. Methods: A collection of 185 isolates of Gram-negative bacilli (133 colistin resistant and 52 colistin susceptible) was tested. Manual BMD according to EUCAST guidelines was used as the reference method, and EUCAST 2017 breakpoints were used for susceptibility categorization. Results: The UMIC system gave the highest rate of very major errors (11.3%) compared with the Sensititre and MicroScan systems (3% and 0.8%, respectively). A high rate of major errors (26.9%) was found with the MicroScan system due to an overestimation of the MICs for the non-fermenting Gram-negative bacilli, whereas no major errors were found with the Sensititre and UMIC systems. Conclusions: The UMIC system was easy to use, but failed to detect >10% of colistin-resistant isolates. The MicroScan system showed excellent results for enterobacterial isolates, but non susceptible results for non-fermenters should be confirmed by another method and the range of MICs tested was narrow. The Sensititre system was the most reliable marketed BMD panel with a categorical agreement of 97.8%. PMID- 29481601 TI - Ethical Issues in Integrated Health Care: Implications for Social Workers. AB - Integrated health care has come of age. What began modestly in the 1930s has evolved into a mature model of health care that is quickly becoming the standard of care. Social workers are now employed in a wide range of comprehensive integrated health care organizations. Some of these settings were designed as integrated health care delivery systems from their beginning. Others evolved over time, some incorporating behavioral health into existing primary care centers and others incorporating primary care into existing behavioral health agencies. In all of these contexts, social workers are encountering complex, sometimes unprecedented, ethical challenges. This article identifies and discusses ethical issues facing social workers in integrated health care settings, especially related to informed consent, privacy, confidentiality, boundaries, dual relationships, and conflicts of interest. The author includes practical resources that social workers can use to develop state-of-the-art ethics policies and protocols. PMID- 29481602 TI - Recent developments of software and database in microbial genomics and functional genomics. PMID- 29481603 TI - Annals of Work Exposures and Health Performance, 2017. PMID- 29481604 TI - Detection and accurate false discovery rate control of differentially methylated regions from whole genome bisulfite sequencing. AB - With recent advances in sequencing technology, it is now feasible to measure DNA methylation at tens of millions of sites across the entire genome. In most applications, biologists are interested in detecting differentially methylated regions, composed of multiple sites with differing methylation levels among populations. However, current computational approaches for detecting such regions do not provide accurate statistical inference. A major challenge in reporting uncertainty is that a genome-wide scan is involved in detecting these regions, which needs to be accounted for. A further challenge is that sample sizes are limited due to the costs associated with the technology. We have developed a new approach that overcomes these challenges and assesses uncertainty for differentially methylated regions in a rigorous manner. Region-level statistics are obtained by fitting a generalized least squares regression model with a nested autoregressive correlated error structure for the effect of interest on transformed methylation proportions. We develop an inferential approach, based on a pooled null distribution, that can be implemented even when as few as two samples per population are available. Here, we demonstrate the advantages of our method using both experimental data and Monte Carlo simulation. We find that the new method improves the specificity and sensitivity of lists of regions and accurately controls the false discovery rate. PMID- 29481605 TI - Response to: 'More on dissidents and dietary sodium'. PMID- 29481607 TI - Reply to Kinlaw et al. PMID- 29481606 TI - Subset of Cortical Layer 6b Neurons Selectively Innervates Higher Order Thalamic Nuclei in Mice. AB - The thalamus receives input from 3 distinct cortical layers, but input from only 2 of these has been well characterized. We therefore investigated whether the third input, derived from layer 6b, is more similar to the projections from layer 6a or layer 5. We studied the projections of a restricted population of deep layer 6 cells ("layer 6b cells") taking advantage of the transgenic mouse Tg(Drd1a-cre)FK164Gsat/Mmucd (Drd1a-Cre), that selectively expresses Cre recombinase in a subpopulation of layer 6b neurons across the entire cortical mantle. At P8, 18% of layer 6b neurons are labeled with Drd1a-Cre::tdTomato in somatosensory cortex (SS), and some co-express known layer 6b markers. Using Cre dependent viral tracing, we identified topographical projections to higher order thalamic nuclei. VGluT1+ synapses formed by labeled layer 6b projections were found in posterior thalamic nucleus (Po) but not in the (pre)thalamic reticular nucleus (TRN). The lack of TRN collaterals was confirmed with single-cell tracing from SS. Transmission electron microscopy comparison of terminal varicosities from layer 5 and layer 6b axons in Po showed that L6b varicosities are markedly smaller and simpler than the majority from L5. Our results suggest that L6b projections to the thalamus are distinct from both L5 and L6a projections. PMID- 29481609 TI - Surrogacy and the ECtHR: Reflections on Paradiso and Campanelli v Italy. AB - This case note analyses the recent judgment of the European Court of Human Rights in Paradiso and Campanelli v Italy and examines its implications for cross-border surrogacy in Europe. It is argued that this judgment is highly significant, because it sets new standards in terms of the concept of family life under Article 8 of the European Convention on Human Rights. This judgment, it is argued, only appears to bring a halt to the (seemingly) backdoor legitimacy of commercial surrogacy established by the findings of the Second Section and previous judgments of the Court. Finally, this case note critiques the Grand Chamber's findings and examines its likely impact on the problem of cross-border surrogacy. PMID- 29481608 TI - The Role of Mitochondrial DNA Variation in Age-Related Decline in Gait Speed Among Older Men Living With Human Immunodeficiency Virus. AB - Background: Age-related gait speed decline is accelerated in men with human immunodeficiency virus (HIV). Mitochondrial genetic variation is associated with frailty and mortality in the general population and may provide insight into mechanisms of functional decline in people aging with HIV. Methods: Gait speed was assessed semiannually in the Multicenter AIDS Cohort Study. Mitochondrial DNA (mtDNA) haplogroups were extracted from genome-wide genotyping data, classifying men aged >=50 years into 5 groups: mtDNA haplogroup H, J, T, Uk, and other. Differences in gait speed by haplogroups were assessed as rate of gait speed decline per year, probability of slow gait speed (<1.0 m/s), and hazard of slow gait using multivariable linear mixed-effects models, mixed-effects logistic regression models, and the Andersen-Gill model, controlling for hepatitis C virus infection, previous AIDS diagnosis, thymidine analogues exposure, education, body composition, smoking, and peripheral neuropathy. Age was further controlled for in the mixed-effects logistic regression models. Results: A total of 455 HIV positive white men aged >=50 years contributed 3283 person-years of follow-up. Among them, 70% had achieved HIV viral suppression. In fully adjusted models, individuals with haplogroup J had more rapid decline in gait speed (adjusted slopes, 0.018 m/s/year vs 0.011 m/s/year, pinteraction = 0.012) and increased risk of developing slow gait (adjusted odds ratio, 2.97; 95% confidence interval, 1.24-7.08) compared to those with other haplogroups. Conclusions: Among older, HIV-infected men, mtDNA haplogroup J was an independent risk factor for more rapid age-related gait speed decline. PMID- 29481611 TI - TGFbeta signaling hyperactivation-induced tumorigenicity during the derivation of neural progenitors from mouse ESCs. AB - Clinical therapies of pluripotent stem cells (PSCs)-based transplantation have been hindered by frequent development of teratomas or tumors in animal models and clinical patients. Therefore, clarifying the mechanism of carcinogenesis in stem cell therapy is of great importance for reducing the risk of tumorigenicity. Here we differentiate Oct4-GFP mouse embryonic stem cells (mESCs) into neural progenitor cells (NPCs) and find that a minority of Oct4+ cells are continuously sustained at Oct4+ state. These cells can be enriched and proliferated in a standard ESC medium. Interestingly, the differentiation potential of these enriched cells is tightly restricted with much higher tumorigenic activity, which are thus defined as differentiation-resistant ESCs (DR-ESCs). Transcriptomic and epigenomic analyses show that DR-ESCs are characterized by primordial germ cell like gene signatures (Dazl, Rec8, Stra8, Blimp1, etc.) and specific epigenetic patterns distinct from mESCs. Moreover, the DR-ESCs possess germ cell potential to generate Sycp3+ haploid cells and are able to reside in sperm-free spermaduct induced by busulfan. Finally, we find that TGFbeta signaling is overactivated in DR-ESCs, and inhibition of TGFbeta signaling eliminates the tumorigenicity of mESC-derived NPCs by inducing the full differentiation of DR-ESCs. These data demonstrate that these TGFbeta-hyperactivated germ cell-like DR-ESCs are the main contributor for the tumorigenicity of ESCs-derived target cell therapy and that inhibition of TGFbeta signaling in ESC-derived NPC transplantation could drastically reduce the risk of tumor development. PMID- 29481610 TI - Characterization of clinically used oral antiseptics as quadruplex-binding ligands. AB - Approaches to characterize the nucleic acid-binding properties of drugs and druglike small molecules are crucial to understanding the behavior of these compounds in cellular systems. Here, we use a Small Molecule Microarray (SMM) profiling approach to identify the preferential interaction between chlorhexidine, a widely used oral antiseptic, and the G-quadruplex (G4) structure in the KRAS oncogene promoter. The interaction of chlorhexidine and related drugs to the KRAS G4 is evaluated using multiple biophysical methods, including thermal melt, fluorescence titration and surface plasmon resonance (SPR) assays. Chlorhexidine has a specific low micromolar binding interaction with the G4, while related drugs have weaker and/or less specific interactions. Through NMR experiments and docking studies, we propose a plausible binding mode driven by both aromatic stacking and groove binding interactions. Additionally, cancer cell lines harbouring oncogenic mutations in the KRAS gene exhibit increased sensitivity to chlorhexidine. Treatment of breast cancer cells with chlorhexidine decreases KRAS protein levels, while a KRAS gene transiently expressed by a promoter lacking a G4 is not affected. This work confirms that known ligands bind broadly to G4 structures, while other drugs and druglike compounds can have more selective interactions that may be biologically relevant. PMID- 29481612 TI - Accelerated acute severe antibody-mediated graft failure related to a Ross procedure 17 years earlier. AB - A 31-year-old male patient underwent a heart transplantation due to dilated cardiomyopathy. He experienced accelerated acute antibody-mediated rejection despite being negative for human leukocyte antigen antibodies (0% panel-reactive antibodies prior to surgery). Further assessment revealed a common antigen between a homograft implanted 17 years earlier during the Ross procedure and the heart donor. The homograft likely induced specific antibody formation. Interestingly, panel-reactive antibody levels measured 7 years prior to transplantation were 7%. Because of the long time span between the Ross procedure and heart transplantation, no circulating antibodies could be detected in 2015, but reactivation of memory cells might potentially have led to this fulminant rejection episode. For future cases, particular attention should be given to patients with homografts. PMID- 29481613 TI - Thirty-Day Outcomes After Craniotomy for Primary Malignant Brain Tumors: A National Surgical Quality Improvement Program Analysis. AB - BACKGROUND: Despite improved perioperative management, the rate of postoperative morbidity and mortality after brain tumor resection remains considerably high. OBJECTIVE: To assess the rates, causes, timing, and predictors of major complication, extended length of stay (>10 d), reoperation, readmission, and death within 30 d after craniotomy for primary malignant brain tumors. METHODS: Patients were extracted from the National Surgical Quality Improvement Program registry (2005-2015) and analyzed using multivariable logistic regression. RESULTS: A total of 7376 patients were identified, of which 948 (12.9%) experienced a major complication. The most common major complications were reoperation (5.1%), venous thromboembolism (3.5%), and death (2.6%). Furthermore, 15.6% stayed longer than 10 d, and 11.5% were readmitted within 30 d after surgery. The most common reasons for reoperation and readmission were intracranial hemorrhage (18.5%) and wound-related complications (11.9%), respectively. Multivariable analysis identified older age, higher body mass index, higher American Society of Anesthesiologists (ASA) classification, dependent functional status, elevated preoperative white blood cell count (white blood cell count [WBC], >12 000 cells/mm3), and longer operative time as predictors of major complication (all P < .001). Higher ASA classification, dependent functional status, elevated WBC, and ventilator dependence were predictors of extended length of stay (all P < .001). Higher ASA classification and elevated WBC were predictors of reoperation (both P < .001). Higher ASA classification and dependent functional status were predictors of readmission (both P < .001). Older age, higher ASA classification, and dependent functional status were predictors of death (all P < .001). CONCLUSION: This study provides a descriptive analysis and identifies predictors for short-term complications, including death, after craniotomy for primary malignant brain tumors. PMID- 29481614 TI - In Reply: The Wolf Sign. PMID- 29481615 TI - Critique of Cheatle et al.'s Study of Risk of Opioid Use Disorder Due to Prescribing Opioids for Chronic Noncancer Pain. PMID- 29481616 TI - Tobacco use prevalence and smoking cessation pharmacotherapy prescription patterns among hospitalized patients by medical specialty. AB - Introduction: Effective smoking cessation medications are readily available but may be underutilized in hospital settings. In our large, tertiary care hospital, we aimed to: 1) characterize patient tobacco use prevalence across medical specialties, 2) determine smoking cessation pharmacotherapy prescription variation across specialties, and 3) identify opportunities for improvement in practice. Methods: Using electronic health records at Barnes Jewish Hospital (BJH), we gathered demographic data, admitting service, admission route, length of stay, self-reported tobacco use, and smoking cessation prescriptions over a 6 year period, from 2010 to 2016. We then compared tobacco use prevalence and smoking cessation prescriptions across medical specialties using a cross sectional, retrospective design. Results: Past 12 month tobacco use was reported by patients in 27.9% of inpatient admissions; prescriptions for smoking cessation pharmacotherapy were provided during 21.5% of these hospitalizations. The proportion of patients reporting tobacco use was highest in psychiatry (55.3%) and lowest in orthopedic surgery (17.1%). Psychiatric patients who reported tobacco use were most likely to receive pharmacotherapy (71.8% of admissions) and plastic surgery patients were least likely (4.7% of admissions). Compared with Caucasian tobacco users, African American patients who used tobacco products were less likely to receive smoking cessation medications (aOR=0.65; 95% CI=0.62 0.68). Conclusions: Among hospitalized tobacco users, safe and cost-effective pharmacotherapies are under-prescribed. We identified substantial variation in prescribing practices across different medical specialties and demographic groups, suggesting the need for an electronic medical record protocol that facilitates consistent tobacco use cessation pharmacotherapy treatment. Implications: Tobacco use cessation pharmacotherapy is underutilized during hospitalization and prescription rates vary greatly across medical specialties and patient characteristics. Hospitals may benefit from implementing policies and practices that standardize and automate the offer of smoking pharmacotherapy for all hospitalized patients who use tobacco. PMID- 29481617 TI - Turnover of aberrant pre-40S pre-ribosomal particles is initiated by a novel endonucleolytic decay pathway. AB - Ribosome biogenesis requires more than 200 trans-acting factors to achieve the correct production of the two mature ribosomal subunits. Here, we have identified Efg1 as a novel, nucleolar ribosome biogenesis factor in Saccharomyces cerevisiae that is directly linked to the surveillance of pre-40S particles. Depletion of Efg1 impairs early pre-rRNA processing, leading to a strong decrease in 18S rRNA and 40S subunit levels and an accumulation of the aberrant 23S rRNA. Using Efg1 as bait, we revealed a novel degradation pathway of the 23S rRNA. Co immunoprecipitation experiments showed that Efg1 is a component of 90S pre ribosomes, as it is associated with the 35S pre-rRNA and U3 snoRNA, but has stronger affinity for 23S pre-rRNA and its novel degradation intermediate 11S rRNA. 23S is cleaved at a new site, Q1, within the 18S sequence by the endonuclease Utp24, generating 11S and 17S' rRNA. Both of these cleavage products are targeted for degradation by the TRAMP/exosome complexes. Therefore, the Q1 site defines a novel endonucleolytic cleavage site of ribosomal RNA exclusively dedicated to surveillance of pre-ribosomal particles. PMID- 29481618 TI - Impact of diet and bariatric surgery on anti-Mullerian hormone levels. AB - STUDY QUESTION: Do serum levels of anti-Mullerian hormone (AMH) change in women of reproductive age following dietary and surgery-induced weight loss? SUMMARY ANSWER: AMH levels increased after very low-calorie diet (VLCD) before surgery and decreased at 6 and 12 months after Roux-en-Y gastric bypass (RYGB), beyond expected normal age-related decline. WHAT IS KNOWN ALREADY: Obesity has negative effects on fertility and IVF outcomes, and possibly also on AMH levels. AMH correlates to the number of growing follicles and is used to predict the response to IVF treatment. However, AMH might decrease after bariatric surgery. STUDY DESIGN, SIZE, DURATION: A prospective cohort study of 48 women followed first for 8 weeks preoperatively, then operated with RYGB and followed postoperatively for 1 additional year. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women aged 18-35 years with a mean (SD) BMI 40.9 (3.6) kg/m2 were included at baseline (BL). After the VLCD, a RYGB was performed. Body weight and height were measured at BL and 1 year postoperatively. Hormones were analysed at BL, after VLCD on the day before surgery, and at 6 and 12 months postoperatively. MAIN RESULTS AND THE ROLE OF CHANCE: Median AMH levels were 30.0 pmol/L at BL and rose significantly after VLCD (median: 35.0 pmol/L; P = 0.014). Median AMH at 6 and 12 months postoperatively were significantly lower (19.5 and 18.0 pmol/L, respectively; P = 0.001). Free androgen index (FAI) was significantly lower after 12 months, compared to BL (1.2 vs 3.5, P < 0.0005). LIMITATIONS REASONS FOR CAUTION: Ultrasound for PCOS diagnosis was not performed. The change in laboratory methods for AMH analysis during the study might be a limitation. WIDER IMPLICATIONS OF THE FINDINGS: Obese young women might choose bariatric surgery also for fertility reasons, and the observed decrease in FAI is in line with improved fertility. More research is needed to evaluate the clinical effects of the decrease of AMH, and the effect of bariatric surgery prior to IVF treatment. STUDY FUNDING/COMPETING INTEREST(S): Study-specific laboratory analyses were funded by the Swedish Regional Research Fund (ALF). Authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A. PMID- 29481619 TI - Influence of the genetic background on the reproductive phenotype of mice lacking Cysteine-Rich Secretory Protein 1 (CRISP1). AB - Epididymal sperm protein CRISP1 has the ability to both regulate murine CatSper, a key sperm calcium channel, and interact with egg-binding sites during fertilization. In spite of its relevance for sperm function, Crisp1-/-mice are fertile. Considering that phenotypes can be influenced by the genetic background, in the present work mice from the original mixed Crisp1-/- colony (129/SvEv*C57BL/6) were backcrossed onto the C57BL/6 strain for subsequent analysis of their reproductive phenotype. Whereas fertility and fertilization rates of C57BL/6 Crisp1-/- males did not differ from those reported for mice from the mixed background, several sperm functional parameters were clearly affected by the genetic background. Crisp1-/- sperm from the homogeneous background exhibited defects in both the progesterone-induced acrosome reaction and motility not observed in the mixed background, and normal rather than reduced protein tyrosine phosphorylation. Additional studies revealed a significant decrease in sperm hyperactivation as well as in cAMP and protein kinase A (PKA) substrate phosphorylation levels in sperm from both colonies. The finding that exposure of mutant sperm to a cAMP analog and phosphodiesterase inhibitor overcame the sperm functional defects observed in each colony indicated that a common cAMP-PKA signaling defect led to different phenotypes depending on the genetic background. Altogether, our observations indicate that the phenotype of CRISP1 null males is modulated by the genetic context and reveal new roles for the protein in both the functional events and signaling pathways associated to capacitation. PMID- 29481620 TI - Vitamin D status and mortality risk among patients on dialysis: a systematic review and meta-analysis of observational studies. AB - Background: Vitamin D deficiency is highly prevalent in patients on dialysis. Although vitamin D deficiency is closely associated with cardiovascular disease (CVD) and high mortality in the general population, the relationship between serum 25-hydroxyvitamin D [25(OH)D] and all-cause and cardiovascular mortality in dialysis patients is uncertain. We aim to explore the relationship between serum 25(OH)D levels and all-cause and cardiovascular mortality in dialysis patients. Methods: This is a systematic review and meta-analysis of clinical studies among patients receiving maintenance dialysis. We did a systematic literature search in PubMed and Embase to identify studies reporting the relationship between serum 25(OH)D levels and all-cause and cardiovascular mortality in patients on dialysis. The search was last updated on 10 February 2017. Results: The study included 18 moderate to high-quality cohort studies with an overall sample of 14 154 patients on dialysis. The relative risk of all-cause mortality per 10 ng/mL increase in serum 25(OH)D level was 0.78 [95% confidence interval (CI) 0.71 0.86], although there was marked heterogeneity (I2=96%, P < 0.01) that was partly explained by differences in CVD prevalence, baseline parathyroid hormone level and dialysis duration among included studies. The relative risk of cardiovascular mortality per 10 ng/mL increase in serum 25(OH)D level was 0.71 (95% CI 0.63 0.79), with substantial heterogeneity (I2=74%, P=0.004) that was largely explained by differences in study type and serum 25(OH)D measurement method. Conclusions: In the present study, increased serum 25(OH)D level was significantly associated with lower all-cause mortality and lower cardiovascular mortality in dialysis patients. PMID- 29481621 TI - Two Cases Of BCG Osteomyelitis Diagnosed Through PCR/ESI-MS Technology. PMID- 29481622 TI - Hurricanes: Are You Prepared? AB - Severe weather events such as hurricanes have the potential to cause significant disruption of laboratory operations. Comprehensive planning is essential to mitigate the impact of such events. The essential elements of a Hurricane Plan, based on our personal experiences, are detailed in this article. PMID- 29481623 TI - Aeolian dispersal of bacteria in southwest Greenland: their sources, abundance, diversity and physiological states. AB - The Arctic is undergoing dramatic climatic changes that cause profound transformations in its terrestrial ecosystems and consequently in the microbial communities that inhabit them. The assembly of these communities is affected by aeolian deposition. However, the abundance, diversity, sources and activity of airborne microorganisms in the Arctic are poorly understood. We studied bacteria in the atmosphere over southwest Greenland and found that the diversity of bacterial communities correlated positively with air temperature and negatively with relative humidity. The communities consisted of 1.3*103 +/- 1.0*103 cells m 3, which were aerosolized from local terrestrial environments or transported from marine, glaciated and terrestrial surfaces over long distances. On average, airborne bacterial cells displayed a high activity potential, reflected in the high 16S rRNA copy number (590 +/- 300 rRNA cell-1), that correlated positively with water vapor pressure. We observed that bacterial clades differed in their activity potential. For instance, a high activity potential was seen for Rubrobacteridae and Clostridiales, while a low activity potential was observed for Proteobacteria. Of those bacterial families that harbor ice-nucleation active species, which are known to facilitate freezing and may thus be involved in cloud and rain formation, cells with a high activity potential were rare in air, but were enriched in rain. PMID- 29481624 TI - Long-term outcomes using the stentless LivaNova-Sorin Pericarbon FreedomTM valve after aortic valve replacement. AB - OBJECTIVES: Information on the long-term safety, efficacy and durability of third generation stentless aortic valves is lacking. METHODS: In this single-centre, single-surgeon retrospective observational study, between 2003 and 2015, consecutive, non-selected aortic valve replacement (AVR) patients were implanted with the LivaNova-Sorin Pericarbon FreedomTM, a third-generation stentless aortic xenograft. Changes in clinical and echocardiographic parameters were examined, as were mortality, structural valve deterioration and reoperation, according to age at 5, 10 and 14 years. RESULTS: The mean logistic EuroSCORE was 8.5% in 22 AVR patients (mean age 68.3 years; range 15-89 years). Many patients [n = 139 (43%)] underwent a concomitant procedure. Before AVR, 68.0% of patients were in New York Heart Association (NYHA) Class I or II, and at discharge, mean gradient was 10.0 +/- 4.3 mmHg. Follow-up lasted up to 8.9 +/- 2.8 years. At the last follow-up, 95.6% of patients were in New York Heart Association Class I or II, the mean gradient was 8.0 +/- 3.5 mmHg (P < 0.001) and reduction in interventricular septum thickness and improvement of ejection fraction were significant (both P < 0.001). Early 30-day in-hospital mortality was 1.6% overall and 0% in the AVR only population. Overall survival probability was 99.9%, 87.9% and 82.7% at 5, 10 and 14 years. Freedom from structural valve deterioration at 14 years was 67.5%, 88.9% and 68.2% in AVR patients overall, in those aged >70 years and in those aged 60-70 years, respectively. Freedom from reoperation at 14 years was 70.3%, 88.3% and 78.0% in the corresponding groups. CONCLUSIONS: Sorin Pericarbon Freedom is a valuable aortic bioprosthesis with favourable haemodynamics, particularly in smaller annuli, and durability similar to that of stented valves, which make Sorin Pericarbon Freedom a useful option in AVR. PMID- 29481625 TI - Interaction patterns of trauma providers are associated with length of stay. AB - Background: Trauma-related hospitalizations drive a high percentage of health care expenditure and inpatient resource consumption, which is directly related to length of stay (LOS). Robust and reliable interactions among health care employees can reduce LOS. However, there is little known about whether certain patterns of interactions exist and how they relate to LOS and its variability. The objective of this study is to learn interaction patterns and quantify the relationship to LOS within a mature trauma system and long-standing electronic medical record (EMR). Methods: We adapted a spectral co-clustering methodology to infer the interaction patterns of health care employees based on the EMR of 5588 hospitalized adult trauma survivors. The relationship between interaction patterns and LOS was assessed via a negative binomial regression model. We further assessed the influence of potential confounders by age, number of health care encounters to date, number of access action types care providers committed to patient EMRs, month of admission, phenome-wide association study codes, procedure codes, and insurance status. Results: Three types of interaction patterns were discovered. The first pattern exhibited the most collaboration between employees and was associated with the shortest LOS. Compared to this pattern, LOS for the second and third patterns was 0.61 days (P = 0.014) and 0.43 days (P = 0.037) longer, respectively. Although the 3 interaction patterns dealt with different numbers of patients in each admission month, our results suggest that care was provided for similar patients. Discussion: The results of this study indicate there is an association between LOS and the extent to which health care employees interact in the care of an injured patient. The findings further suggest that there is merit in ascertaining the content of these interactions and the factors that induce these differences in interaction patterns within a trauma system. PMID- 29481628 TI - Meeting the Needs of the Health Care Workforce through E-Learning. PMID- 29481626 TI - Developmental Lead Exposure and Prenatal Stress Result in Sex-Specific Reprograming of Adult Stress Physiology and Epigenetic Profiles in Brain. AB - Developmental exposure to lead (Pb) and prenatal stress (PS) both impair cognition, which could derive from their joint targeting of the hypothalamic pituitary-adrenal axis and the brain mesocorticolimbic (MESO) system, including frontal cortex (FC) and hippocampus (HIPP). Glucocorticoids modulate both FC and HIPP function and associated mediation of cognitive and other behavioral functions. This study sought to determine whether developmental Pb +/- PS exposures altered glucocorticoid-related epigenetic profiles in brain MESO regions in offspring of female mice exposed to 0 or 100 ppm Pb acetate drinking water from 2 mos prior to breeding until weaning, with half further exposed to prenatal restraint stress from gestational day 11-18. Overall, changes in females occured in response to Pb exposure. In males, however, Pb-induced neurotoxicity was modulated by PS. Changes in serum corticosterone levels were seen in males, while glucocorticoid receptor changes were seen in both sexes. In contrast, both Pb and PS broadly impacted brain DNA methyltransferases and binding proteins, particularly DNMT1, DNMT3a and methyl-CpG-binding protein 2, with patterns that differed by sex and brain regions. Specifically, in males, effects on FC epigenetic modifiers were primarily influenced by Pb, whereas extensive changes in HIPP were produced by PS. In females, Pb exposure and not PS primarily altered epigenetic modifiers in both FC and HIPP. Collectively, these findings indicate that epigenetic mechanisms may underlie associated neurotoxicity of Pb and of PS, particularly associated cognitive deficits. However, mechanisms by which this may occur will be different in males versus females. PMID- 29481629 TI - Esthesioneuroblastoma: A Patterns-of-Care and Outcomes Analysis of the National Cancer Database. AB - BACKGROUND: The available literature to guide treatment decision making in esthesioneuroblastoma (ENB) is limited. OBJECTIVE: To define treatment patterns and outcomes in ENB according to treatment modality using a large national cancer registry. METHODS: This study is a retrospective cohort analysis of 931 patients with a diagnosis of ENB who were treated with surgery, radiation therapy, and/or chemotherapy in the United States between the years of 2004 and 2012. Log-rank statistics were used to compare overall survival by primary treatment modality. Logistic regression modeling was used to identify predictors of receipt of postoperative radiotherapy (PORT). Cox proportional hazards modeling was used to determine the survival benefit of PORT. Subgroup analyses identified subgroups that derived the greatest benefit of PORT. RESULTS: Primary surgery was the most common treatment modality (90%) and resulted in superior survival compared to radiation (P < .01) or chemotherapy (P < .01). On multivariate analysis, PORT was associated with decreased risk of death (hazard ratio [HR] 0.53, P < .01). PORT showed a survival benefit in Kadish stage C (HR 0.42, P < .01) and D (HR 0.09, P = .01), but not Kadish A (HR 1.17, P = .74) and B (HR 1.37, P = .80). Patients who received chemotherapy derived greater benefit from PORT (HR 0.22, P < .01) compared with those who did not (HR 0.68, P = .13). Predictors of PORT included stage, grade, extent of resection, and chemotherapy use. CONCLUSION: Best outcomes were obtained in patients undergoing primary surgery. The benefit of PORT was driven by patients with stages C and D disease, and by those also receiving chemotherapy. PMID- 29481631 TI - In Reply: The Wolf Sign. PMID- 29481630 TI - Open-label randomised phase III trial of vinflunine versus an alkylating agent in patients with heavily pretreated metastatic breast cancer. AB - Background: There is no standard treatment after progression on second-line chemotherapy for metastatic breast cancer (MBC). We compared vinflunine with physician's choice of alkylating agent (AA) for patients with heavily pretreated MBC. Patients and methods: In this open-label phase III trial, patients with MBC were included if they had received at least two prior chemotherapy regimens for MBC and had received anthracycline, taxane, antimetabolite and vinca alkaloid therapy. Patients were no longer candidates for these chemotherapies because of resistance and/or intolerance. Patients were randomised to either vinflunine 280 mg/m2 intravenously every 3 weeks (q3w) or AA monotherapy q3w. Stratification factors were performance status, number of prior chemotherapy lines for MBC, disease measurability and study site. The primary end point was overall survival (OS). Results: A total of 594 patients were randomised (298 to vinflunine, 296 to AA). There was no difference between treatment arms in OS (hazard ratio 1.04, P = 0.67; median 9.1 months for vinflunine versus 9.3 months for AA), progression free survival (hazard ratio 0.94, P = 0.49; median 2.5 versus 1.9 months, respectively) or overall response rate (6% versus 4%, respectively). However, the disease control rate was significantly higher with vinflunine than AA (44% versus 35%, respectively; P = 0.04). The most common adverse events (any grade) were haematological and gastrointestinal disorders and asthenia in both arms. The most common grade 3/4 adverse events were neutropenia (19% versus 11% with vinflunine versus AA, respectively) and asthenia (10% versus 4%). Conclusions: Vinflunine 280 mg/m2 q3w did not improve OS compared with the physician's choice of AA as third- or later-line therapy for MBC. Vinflunine demonstrated an acceptable safety profile, suggesting that vinflunine 320 mg/m2 merits evaluation. ClinicalTrials.gov: NCT01091168. PMID- 29481632 TI - Evaluation of tools for highly variable gene discovery from single-cell RNA-seq data. AB - Traditional RNA sequencing (RNA-seq) allows the detection of gene expression variations between two or more cell populations through differentially expressed gene (DEG) analysis. However, genes that contribute to cell-to-cell differences are not discoverable with RNA-seq because RNA-seq samples are obtained from a mixture of cells. Single-cell RNA-seq (scRNA-seq) allows the detection of gene expression in each cell. With scRNA-seq, highly variable gene (HVG) discovery allows the detection of genes that contribute strongly to cell-to-cell variation within a homogeneous cell population, such as a population of embryonic stem cells. This analysis is implemented in many software packages. In this study, we compare seven HVG methods from six software packages, including BASiCS, Brennecke, scLVM, scran, scVEGs and Seurat. Our results demonstrate that reproducibility in HVG analysis requires a larger sample size than DEG analysis. Discrepancies between methods and potential issues in these tools are discussed and recommendations are made. PMID- 29481627 TI - European Society of Cardiology, acute cardiovascular care association, SCAD study group: a position paper on spontaneous coronary artery dissection. PMID- 29481633 TI - Fatty acid addition and thermotolerance of Kluyveromyces marxianus. AB - Membrane fatty acid composition has an important role in yeast stress resistance, particularly in temperature tolerance. Most studies investigating temperature and membrane fatty acids use the yeast Saccharomyces cerevisiae without considering other yeasts, such as Kluyveromyces marxianus, which has physiological differences and industrial advantages with respect to S. cerevisiae. One of the primary traits of K. marxianus is its thermotolerance. The effect of fatty acid addition (oleic acid, linoleic acid, linolenic acid and araquidic acid) on the thermotolerance of the K. marxianus strain SLP1 was evaluated. SLP1 yeast exhibited temperature tolerance of up to 50 degrees C; at 55 degrees C, viability was reduced significantly, probably due to an increase in the generation of reactive oxygen chemical species. Externally added fatty acids were incorporated in the yeast membrane, increasing their proportion to approximately 70%, thereby changing membrane fluidity. SLP1 cells supplemented with polyunsaturated fatty acids decreased cell thermotolerance and increased the degree of lipoperoxidation, while arachidic acid addition exhibited a tendency to increase yeast thermotolerance. PMID- 29481634 TI - Prognostic Significance of Modified Residual Disease in Breast and Nodes (mRDBN) Algorithm After Neoadjuvant Chemotherapy for Breast Cancer. AB - Objectives: We hypothesized that prognostic accuracy of the residual disease in breast and lymph nodes (RDBN) method, which is calculated using residual tumor size, nodal involvement, and tumor grade, may be improved by incorporating residual tumor cellularity. Methods: Cases included 614 patients who underwent neoadjuvant therapy for breast cancer. Tumor size was adjusted for residual cellularity of invasive carcinoma and used to calculate modified RDBN (mRDBN) and compared with unmodified gross tumor size (gRDBN). Results: RDBN could be calculated in 428 cases. Relative risks of recurrence and death were significantly higher for RDBN-3 and RDBN-4 compared with RDBN-1. Kaplan-Meier analysis showed significant differences in disease-free survival and overall survival for estrogen receptor (ER)-negative/human epidermal growth factor receptor 2 (HER2)-negative and ER-positive/HER2-negative subgroups (P < .0001). Conclusions: Both mRDBN and gRDBN provide prognostic information, particularly in HER2-negative carcinoma; however, mRDBN showed better stratification of RDBN-3 and RDBN-4 patients. PMID- 29481635 TI - What Is the Best Model for HIV Primary Care? Assessing the Influence of Provider Type on Outcomes of Chronic Comorbidities in HIV Infection. PMID- 29481637 TI - Reply to Spyridou, et al. PMID- 29481638 TI - The first known virus isolates from Antarctic sea ice have complex infection patterns. AB - Viruses are recognized as important actors in ocean ecology and biogeochemical cycles, but many details are not yet understood. We participated in a winter expedition to the Weddell Sea, Antarctica, to isolate viruses and to measure virus-like particle abundance (flow cytometry) in sea ice. We isolated 59 bacterial strains and the first four Antarctic sea-ice viruses known (PANV1, PANV2, OANV1 and OANV2), which grow in bacterial hosts belonging to the typical sea-ice genera Paraglaciecola and Octadecabacter. The viruses were specific for bacteria at the strain level, although OANV1 was able to infect strains from two different classes. Both PANV1 and PANV2 infected 11/15 isolated Paraglaciecola strains that had almost identical 16S rRNA gene sequences, but the plating efficiencies differed among the strains, whereas OANV1 infected 3/7 Octadecabacter and 1/15 Paraglaciecola strains and OANV2 1/7 Octadecabacter strains. All the phages were cold-active and able to infect their original host at 0 degrees C and 4 degrees C, but not at higher temperatures. The results showed that virus-host interactions can be very complex and that the viral community can also be dynamic in the winter-sea ice. PMID- 29481636 TI - Effects of nutritional vitamin D supplementation on markers of bone and mineral metabolism in children with chronic kidney disease. AB - Background: We investigated the effects of nutritional vitamin D supplementation on markers of bone and mineral metabolism, i.e. serum levels of fibroblast growth factor 23 (FGF23), Klotho, bone alkaline phosphatase (BAP) and sclerostin, in two cohorts with chronic kidney disease (CKD). Methods: In all, 80 vitamin D deficient children were selected: 40 with mild to moderate CKD from the ERGO study, a randomized trial of ergocalciferol supplementation [estimated glomerular filtration rate (eGFR) 55 mL/min/1.73 m2], and 40 with advanced CKD from the observational Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study (eGFR 24 mL/min/1.73 m2). In each study, vitamin D supplementation was started in 20 children and 20 matched children not receiving vitamin D served as controls. Measures were taken at baseline and after a median period of 8 months. Age- and gender-related standard deviation scores (SDSs) were calculated. Results: Before vitamin D supplementation, children in the ERGO study had normal FGF23 (median 0.31 SDS) and BAP (-0.10 SDS) but decreased Klotho and sclerostin ( 0.77 and -1.04 SDS, respectively), whereas 4C patients had increased FGF23 (3.87 SDS), BAP (0.78 SDS) and sclerostin (0.76 SDS) but normal Klotho (-0.27 SDS) levels. Vitamin D supplementation further increased FGF23 in 4C but not in ERGO patients. Serum Klotho and sclerostin normalized with vitamin D supplementation in ERGO but remained unchanged in 4C patients. BAP levels were unchanged in all patients. In the total cohort, significant effects of vitamin D supplementation were noted for Klotho at eGFR 40-70 mL/min/1.73 m2. Conclusions: Vitamin D supplementation normalized Klotho and sclerostin in children with mild to moderate CKD but further increased FGF23 in advanced CKD. PMID- 29481639 TI - Distribution, mobility, and anchoring of lignin-related oxidative enzymes in Arabidopsis secondary cell walls. AB - Lignin is an important phenolic biopolymer that provides strength and rigidity to the secondary cell walls of tracheary elements, sclereids, and fibers in vascular plants. Lignin precursors, called monolignols, are synthesized in the cell and exported to the cell wall where they are polymerized into lignin by oxidative enzymes such as laccases and peroxidases. In Arabidopsis thaliana, a peroxidase (PRX64) and laccase (LAC4) are shown to localize differently within cell wall domains in interfascicular fibers: PRX64 localizes to the middle lamella whereas LAC4 localizes throughout the secondary cell wall layers. Similarly, laccases localized to, and are responsible for, the helical depositions of lignin in protoxylem tracheary elements. In addition, we tested the mobility of laccases in the cell wall using fluorescence recovery after photobleaching. mCHERRY-tagged LAC4 was immobile in secondary cell wall domains, but mobile in the primary cell wall when ectopically expressed. A small secreted red fluorescent protein (sec mCHERRY) was engineered as a control and was found to be mobile in both the primary and secondary cell walls. Unlike sec-mCHERRY, the tight anchoring of LAC4 to secondary cell wall domains indicated that it cannot be remobilized once secreted, and this anchoring underlies the spatial control of lignification. PMID- 29481640 TI - Cost-effectiveness Evaluation of the Inclusion of Dry Needling into an Exercise Program for Subacromial Pain Syndrome: Evidence from a Randomized Clinical Trial. AB - Objective: To evaluate the cost-effectiveness of the inclusion of trigger point dry needling (TrP-DN) into an exercise program for the management of subacromial pain syndrome. Methods: Fifty patients with unilateral subacromial pain syndrome were randomized with concealed allocation to exercise alone or exercise plus TrP DN. Both groups were asked to perform an exercise program targeting the rotator cuff musculature twice daily for five weeks. Patients allocated to the exercise plus TrP-DN group also received dry needling during the second and fourth sessions. Societal costs and health-related quality of life (estimated by EuroQol 5D-5L) over a one-year follow-up were used to generate incremental cost per quality-adjusted life-year (QALY) ratios for each intervention. Results: Intention-to-treat analysis was possible for 48 (96%) of the participants. Those in the exercise group made more visits to medical doctors and received a greater number of other treatments (P < 0.001). The major contributor to societal costs (77%) was the absenteeism paid labor in favor of the exercise plus TrP-DN group (P = 0.03). The combination of exercise plus TrP-DN was less costly (mean difference cost/patient = ?517.34, P = 0.003) than exercise alone. Incremental QALYs showed greater benefit for exercise plus TrP-DN (difference = 2.87, 95% confidence interval = 2.85-2.89). Therefore, the inclusion of TrP-DN into an exercise program was more likely to be cost-effective than an exercise program alone, with 99.5% of the iterations falling in the dominant area. Conclusions: The inclusion of TrP-DN into an exercise program was more cost-effective for individuals with subacromial pain syndrome than exercise alone. From a cost benefit perspective, the inclusion of TrP-DN into multimodal management of patients with subacromial pain syndrome should be considered. PMID- 29481641 TI - Association of 24-Hour Blood Pressure With Urinary Sodium Excretion in Healthy Adults. AB - BACKGROUND: While the positive relationship between urinary sodium excretion and blood pressure (BP) is well established for middle-aged to elderly individuals using office BP, data are limited for younger individuals and ambulatory BP measurements. METHODS: Our analysis included 2,899 individuals aged 18 to 90 years from 2 population-based studies (GAPP, Swiss Kidney Project on Genes in Hypertension [SKIPOGH]). Participants with prevalent cardiovascular disease, diabetes, or on BP-lowering treatment were excluded. In SKIPOGH, 24-hour urinary sodium excretion was used as a measure of sodium intake, while in GAPP it was calculated from fasting morning urinary samples using the Kawasaki formula. Multivariable linear regression models were used to assess the relationships of 24-hour urinary salt excretion with office and ambulatory BP measurements. RESULTS: Mean age, ambulatory BP, sodium excretion, and estimated glomerular filtration rate in GAPP and SKIPOGH were 35 and 44 years, 123/78 and 118/77 mm Hg, 4.2 and 3.3 g/d, and 110 and 99 ml/min/1.73 m2, respectively. A weak linear association was observed between 24-hour ambulatory systolic BP and urinary sodium excretion (beta (95% confidence interval [CI]) per 1 g increase in sodium excretion (0.33 % (0.09; 0.57); P = 0.008). No significant relationships were observed for 24-hour ambulatory diastolic BP (beta (95% CI) (0.13 % (-0.15; 0.40) P = 0.37). When repeating the analyses in different age groups, all BP indices appeared to have stronger relationships in the older age groups (>40 years). CONCLUSIONS: In these large cohorts of healthy adults, urinary sodium excretion was only weakly associated with systolic 24-hour ambulatory BP. PMID- 29481643 TI - From phenotype to genotype: towards identifying recurrent genetic aberrations in bicuspid aortic valve disease. PMID- 29481644 TI - Learning curve analysis of transapical NeoChord mitral valve repair. AB - OBJECTIVES: Transapical off-pump mitral valve intervention with neochordae implantation is a novel, minimally invasive procedure for treatment of degenerative mitral valve regurgitation. The aim of this study was to apply control charts (CUSUM curves) to monitor the performance of NeoChord repair during the initial phase of its adoption. METHODS: The first 112 consecutive patients who underwent NeoChord repair at our institution between November 2013 and March 2016 were included in the analysis. Mitral Valve Academic Research Consortium criteria for 1-year patient success was utilized to determine failed procedures. Control charts had predetermined acceptable and unacceptable failure rates of 5% and 15%, respectively. RESULTS: The actual incidence of 1-year patient failure was 11% (12 of 112 cases), with a cluster of failures within the first 20 cases. The CUSUM analysis demonstrated an initial learning curve; however, the upper boundary (alarm line) was never crossed. The reassurance line was first crossed after 40 procedures and performance remained stable after 49 procedures. CONCLUSIONS: NeoChord repair is a safe procedure, and the results are maintained through the 1-year follow-up. A relative high number of implants were required to overcome the learning curve at our institution due to the concurrent development of patient selection criteria and the technical refinement of the procedure. Future studies are needed to assess the evolution of the learning curve after the wide adoption of the procedure across European and North American centres. PMID- 29481642 TI - LncRNA-OIS1 regulates DPP4 activation to modulate senescence induced by RAS. AB - Oncogene-induced senescence (OIS), provoked in response to oncogenic activation, is considered an important tumor suppressor mechanism. Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nt without a protein-coding capacity. Functional studies showed that deregulated lncRNA expression promote tumorigenesis and metastasis and that lncRNAs may exhibit tumor-suppressive and oncogenic function. Here, we first identified lncRNAs that were differentially expressed between senescent and non-senescent human fibroblast cells. Using RNA interference, we performed a loss-function screen targeting the differentially expressed lncRNAs, and identified lncRNA-OIS1 (lncRNA#32, AC008063.3 or ENSG00000233397) as a lncRNA required for OIS. Knockdown of lncRNA-OIS1 triggered bypass of senescence, higher proliferation rate, lower abundance of the cell cycle inhibitor CDKN1A and high expression of cell-cycle-associated genes. Subcellular inspection of lncRNA-OIS1 indicated nuclear and cytosolic localization in both normal culture conditions as well as following oncogene induction. Interestingly, silencing lncRNA-OIS1 diminished the senescent associated induction of a nearby gene (Dipeptidyl Peptidase 4, DPP4) with established role in tumor suppression. Intriguingly, similar to lncRNA-OIS1, silencing DPP4 caused senescence bypass, and ectopic expression of DPP4 in lncRNA OIS1 knockdown cells restored the senescent phenotype. Thus, our data indicate that lncRNA-OIS1 links oncogenic induction and senescence with the activation of the tumor suppressor DPP4. PMID- 29481645 TI - State of the Art Treatment of Spinal Metastatic Disease. AB - Treatment paradigms for patients with spine metastases have evolved significantly over the past decade. Incorporating stereotactic radiosurgery into these paradigms has been particularly transformative, offering precise delivery of tumoricidal radiation doses with sparing of adjacent tissues. Evidence supports the safety and efficacy of radiosurgery as it currently offers durable local tumor control with low complication rates even for tumors previously considered radioresistant to conventional radiation. The role for surgical intervention remains consistent, but a trend has been observed toward less aggressive, often minimally invasive, techniques. Using modern technologies and improved instrumentation, surgical outcomes continue to improve with reduced morbidity. Additionally, targeted agents such as biologics and checkpoint inhibitors have revolutionized cancer care, improving both local control and patient survivals. These advances have brought forth a need for new prognostication tools and a more critical review of long-term outcomes. The complex nature of current treatment schemes necessitates a multidisciplinary approach including surgeons, medical oncologists, radiation oncologists, interventionalists, and pain specialists. This review recapitulates the current state-of-the-art, evidence-based data on the treatment of spinal metastases, integrating these data into a decision framework, NOMS, which integrates the 4 sentinel decision points in metastatic spine tumors: Neurologic, Oncologic, Mechanical stability, and Systemic disease and medical co-morbidities. PMID- 29481646 TI - Rheumatoid factors do not preferentially bind to ACPA-IgG or IgG with altered galactosylation. PMID- 29481648 TI - Bariatric surgery helps to reduce blood pressure - insights from GATEWAY trial. PMID- 29481647 TI - SA1/SA2 cohesion proteins and SIRT1-NAD+ deacetylase modulate telomere homeostasis in cumulus cells and are eligible biomarkers of ovarian aging. AB - STUDY QUESTION: Are cohesins SA1/SA2 and the NAD-dependent deacetylase SIRT1 involved in telomere homeostasis of cumulus cells and thus eligible as biomarkers of follicular physiology and ovarian aging? SUMMARY ANSWER: SA1/SA2 cohesins and SIRT1 are associated with telomere length in cumulus cells and may be eligible biomarkers of follicular physiology and ovarian aging. WHAT IS KNOWN ALREADY: In somatic cells, cohesins SA1/SA2 mediate sister chromatid cohesion at the telomere termini (for SA1) and along chromatid arms (for SA2). The NAD+-dependent protein deacetylase Sirtuin 1 (SIRT1), which preserves DNA integrity from oxidative stress, may also modulate genome stability and telomere length. STUDY DESIGN, SIZE, DURATION: Collectively 280 cumulus/oocyte complex samples were recovered from a total of 50 women undergoing in vitro fertilization. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cumulus cells were separated from the oocyte-cumulus complex. DNA and total mRNA were extracted from cumulus cells and assayed for telomere length and for SA1, SA2 and SIRT1 gene expression profiling. Telomere length was determined by quantitave PCR and analyzed relative to the single copy of the housekeeping gene (albumin) to generate a T/S ratio (Telomere/single copy gene). Gene expression levels of SA1, SA2 and SIRT1 mRNA were assayed by quantitative RT-PCR and confirmed by western blotting and immunofluorescent studies (SIRT1). SA1/SA2 and SIRT1 gene expression levels and telomere length analysis of patients/samples were ranked in relation to their clinical setting parameters (BMI, age) and to the number of oocyte retrieved. MAIN RESULTS AND THE ROLE OF CHANCE: SA1 and SA2 transcripts were both detected in all cumulus cells analyzed and the relative amount showed a clear decreasing trend according to the age of patients. A significant increase in SA1 and SA2 was disclosed in high responder women (>6 oocytes retrieved) compared to poor responders (<4 oocytes) (P < 0.05). Furthermore, statistically significant positive correlations were also recorded between the transcripts levels of the two cohesin molecules (r = 0.89; P < 0.05) and, to a lesser extent, between telomere length and SA1 (r = 0.42; P < 0.001) and SA2 (r = 0.36; P < 0.001) mRNA levels. SIRT1 expression was also significantly increased in high responders (>6 oocytes) compared to poor responders. Significant correlations were found between SIRT1 and SA1 (r = 0.69; P < 0.001), between SIRT1 and SA2 (r = 0.78; P < 0.001), and between SIRT1 and telomere length (r = 0.36; P < 0.001). However, in the older patient group (>38 years), SIRT1 mRNA levels were twice as high as the levels recorded in the younger patient cohort (<34 years). Western blot analysis and immunofluorescent studies confirmed the increments in SIRT1 protein levels in patients over 38 years old. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Cumulus/oocyte complexes were retrieved by patients undergoing ovarian stimulation protocol for IVF. We cannot exclude the possibility that different stimulation protocols affect the correlations highlighted in this study. Future investigations should shed light on cumulus cells molecular profile according to different stimulation protocols. WIDER IMPLICATIONS OF THE FINDINGS: The overall results of our study point to the involvement of cohesins SA1/SA2 and SIRT1 deacetylase in telomere homeostasis in cumulus cells and highlight their possible eligibility as biomarkers of follicular physiology and ovarian aging. STUDY FUNDING/COMPETING INTEREST(S): Merck Serono S.P.A Italy sponsored the study with financial support. There are no competing interests to declare. PMID- 29481649 TI - The Secret of the Kissing Cousins: an ER-mitochondrial tethering protein regulates Ca2+ crosstalk in mammalian neurons. PMID- 29481650 TI - Dr Jyoti Patel, ESC Scientist of Tomorrow, interviews Dr Eva Van Rooij. PMID- 29481651 TI - Pushing the frontiers of cardiovascular biology. PMID- 29481652 TI - Novel Dual-Action Targeted Nanomedicine in Mice With Metastatic Thyroid Cancer and Pancreatic Neuroendocrine Tumors. AB - Background: The advantages of nanomedicines include preferential delivery of the payload directly to tumor tissues. CYT-21625 is the novel, first-in-class gold nanomedicine designed to target tumor vasculature and cancer cells by specifically delivering recombinant human tumor necrosis factor alpha (rhTNF) and a paclitaxel prodrug. Methods: We analyzed TNF receptor expression in publicly available gene expression profiling data and in thyroid tissue samples. Mice with metastatic FTC-133 and 8505C xenografts and the MEN1 conditional knock-out mice were treated weekly with CYT-21625 and gold nanoparticles with rhTNF only (CYT 6091); controls included mice treated with either paclitaxel or saline. In vivo luciferase activity was used to assess the effects on tumor growth. Computed tomography, magnetic resonance imaging, and 18F-Fludeoxyglucose positron emission tomography were used to study tumor selectivity in mice with insulin-secreting pancreatic neuroendocrine tumors (PNETs). All statistical tests were two-sided. Results: Anaplastic thyroid cancer (ATC) expressed statistically significantly higher levels of TNF receptor superfamily 1A and 1B messenger RNA (n = 11) and protein (n = 6) than control samples (n = 45 and 13, respectively). Mice (n = 5-7 per group) with metastatic ATC (P < .009) and FTC-133 xenografts (P = .03 at week 3, but not statistically significant in week 4 owing to reduced sample size from death in non-CYT-21625 groups) treated with CYT-21625 had a statistically significantly lower tumor burden. Treatment with CYT-21625 resulted in loss of CD34 expression in intratumoral vasculature, decreased proliferating cell nuclear antigen, and increased cleaved caspase-3. Intratumoral vascular leakage occurred only in mice with PNET and ATC treated with CYT-6091 and CYT-21625. CYT-6091 and CYT-21625 preferentially deposited in PNETs and statistically significantly decreased serum insulin levels (n = 3 per group, P < .001). There were no toxicities observed in mice treated with CYT-21625. Conclusions: CYT-21625 is effective in mice with PNETs and metastatic human thyroid cancer with no toxicities. Thus, CYT-21625 should be studied in patients with advanced PNETs and thyroid cancer. PMID- 29481653 TI - When Darwin's Special Difficulty Promotes Diversification in Insects. AB - Eusociality, Darwin's special difficulty, has been widely investigated but remains a topic of great debate in organismal biology. Eusocial species challenge existing theories, and the impact of highly integrated societies on diversification dynamics is controversial with opposing assertions and hypotheses in the literature. Here, using phylogenetic approaches in termites-the first group that has evolved eusociality-we assessed the fundamental prediction that eusocial lineages have higher diversification rates than non-eusocial clades. We found multiple lines of evidence that eusociality provided higher diversification as compared to non-eusociality. This is particularly exacerbated for eusocial species with "true" workers as compared to species with "false" workers. Because most species with "true" workers have an entirely prokaryotic microbiota, the latter feature is also related to higher diversification rates, but it should be investigated further, notably in relation to angiosperm diversification. Overall, this study suggests that societies with "true" workers are not only more successful at ecological timescales but also over millions of years, which further implies that both organism- and species-level traits act on species selection. PMID- 29481655 TI - Gout misdiagnosis due to dual-energy computed tomography artefact. PMID- 29481654 TI - Incidence, predictors and clinical outcome of early bleeding events in patients undergoing a left ventricular assist device implant. AB - OBJECTIVES: Bleeding is a common complication following left ventricular assist device (LVAD) implantation. The goal of this study was to investigate the incidence, predictors and clinical outcome of early bleeding events in patients after LVAD implantation. METHODS: A total of 83 patients (age 50 +/- 13 years, 76% men) had an LVAD implanted [77% HeartMate II, 19% HeartMate 3 (Abbott, Chicago, IL, USA)] over a period of 11 years. Patients were included consecutively. An early bleeding event was defined as the need for thoracic surgical re-exploration or transfusion with >4 units of packed red blood cells before discharge. RESULTS: Overall, 39 (47%) patients (age 50 +/- 14 years, 77% men) experienced an early bleeding event [median time 6 days (interquartile range 1-9 days)]. Furthermore, 10 (26%) of these patients had >=2 bleeding events. Twelve of the 14 (92%) patients with venoarterial extracorporeal membrane oxygenation (ECMO) support before LVAD implantation experienced an early bleeding event versus 27 of the 69 (39%) patients without ECMO support (P < 0.001). No difference was found in early bleeding rates between HeartMate II and HeartMate 3. Predictors for early bleeding events were lower pre- and postimplant platelet counts and ECMO support preimplantation. After multivariable adjustment, early bleeding events were associated with ECMO support preimplantation (odds ratio 6.3, 95% confidence interval 1.2-32.4; P = 0.03) and thrombocytopenia (<150 * 109/l) postimplant (odds ratio 5.9, 95% confidence interval 1.9-18.7; P = 0.002). Patients who experienced an early bleeding event had a significantly worse 90-day survival rate compared to patients who did not (79% vs 96%, P = 0.03). CONCLUSIONS: An early bleeding event needing surgical exploration is highly prevalent after LVAD implantation, especially in patients bridged with ECMO and with pre- and postimplant thrombocytopenia. PMID- 29481656 TI - Subclinical Hypothyroidism and Depression: Is There a Link? PMID- 29481657 TI - Applying definitions for multidrug resistance, extensive drug resistance and pandrug resistance to clinically significant livestock and companion animal bacterial pathogens. AB - Standardized definitions for MDR are currently not available in veterinary medicine despite numerous reports indicating that antimicrobial resistance may be increasing among clinically significant bacteria in livestock and companion animals. As such, assessments of MDR presented in veterinary scientific reports are inconsistent. Herein, we apply previously standardized definitions for MDR, XDR and pandrug resistance (PDR) used in human medicine to animal pathogens and veterinary antimicrobial agents in which MDR is defined as an isolate that is not susceptible to at least one agent in at least three antimicrobial classes, XDR is defined as an isolate that is not susceptible to at least one agent in all but one or two available classes and PDR is defined as an isolate that is not susceptible to all agents in all available classes. These definitions may be applied to antimicrobial agents used to treat bovine respiratory disease (BRD) caused by Mannheimia haemolytica, Pasteurella multocida and Histophilus somni and swine respiratory disease (SRD) caused by Actinobacillus pleuropneumoniae, P. multocida and Streptococcus suis, as well as antimicrobial agents used to treat canine skin and soft tissue infections (SSTIs) caused by Staphylococcus and Streptococcus species. Application of these definitions in veterinary medicine should be considered static, whereas the classification of a particular resistance phenotype as MDR, XDR or PDR could change over time as more veterinary specific clinical breakpoints or antimicrobial classes and/or agents become available in the future. PMID- 29481658 TI - Bias-Corrected Estimates of Time-Varying Adverse Drug Event Rates for Patients on Outpatient Parenteral Antimicrobial Therapy. PMID- 29481659 TI - Cytokine Release Syndrome Grade as a Predictive Marker for Infections in Patients With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia Treated With Chimeric Antigen Receptor T Cells. AB - Background: Chimeric antigen receptor (CAR)-modified T cells that target the CD19 antigen present a novel promising therapy for the treatment of relapsed B-cell acute lymphoblastic leukemia (B-ALL). Although cytokine release syndrome (CRS) and neurotoxicity have emerged as predominant noninfectious complications of CD19 CAR T-cell therapy, infections associated with this treatment modality have not been well documented. Methods: We analyzed infectious complications that followed CD19 CAR T-cell therapy in 53 adult patients with relapsed B-ALL enrolled in a phase I clinical trial at Memorial Sloan Kettering Cancer Center (NCT01044069). Results: Overall, 22 patients (42%) experienced 26 infections (17 bacterial, 4 fungal, and 5 viral) within the first 30 days of CAR T-cell infusion. In 10 of 32 (31%) patients in whom complete remission was achieved, 15 infections developed between days 31 and 180; the majority of these late infections were due to respiratory viruses. In general, bacterial, fungal, and viral infections were detected at a median of 18, 23, and 48 days, respectively, after CAR T-cell infusion. CRS grade 3 or higher was independently associated with increased risk of subsequent infection (adjusted hazard ratio [HR], 2.67; P = .05) and in particular with bloodstream infection (adjusted HR, 19.97; P < .001). Three of 53 patients (6%) died of an infection-related cause. Conclusions: Infections in adult patients with relapsed B-ALL are common after CD19 CAR T-cell therapy. Understanding the infectious complications that are temporally coincident with CD19 CAR T-cell therapy is critical for developing effective prophylactic and other supportive care measures to improve clinical outcomes. Clinical Trials Registration: NCT01044069. PMID- 29481661 TI - Early response to therapy predicts 6-month and 1-year disease activity outcomes in psoriatic arthritis patients. AB - Objectives: In PsA management, remission and low disease activity represent preferential treatment targets. We aimed at evaluating the predictive value and clinical use of initial therapeutic response for subsequent achievement of these targets. Methods: Based on data of 216 patients enrolled in a randomized controlled trial of golimumab (GO-REVEAL), we performed diagnostic testing analyses using 3- and 6-month disease activity as tests for treatment outcomes to understand the implications of early response. In regression analyses, we estimated the probabilities for achieving at least LDA. Disease activity was measured by the disease activity index for PsA (DAPSA). Results: Three-month DAPSA levels were excellent tests for disease activity at 6 months (and at 1 year), with areas under the receiver operating characteristic curves of 0.92 (and 0.88, respectively). The estimated probability for 6-month LDA could be quantified as <22% if patients did not reach at least moderate disease activity after 3 months on golimumab. Similar data were seen for early DAPSA response: patients achieving a DAPSA 85% at 3 months had an 84% probability for 6-month LDA or REM. All results were validated in an independent trial cohort of patients treated with infliximab (IMPACT 2). Conclusion: Three months after implementation of therapy in PsA, it is already possible to evaluate the potential for accomplishing therapeutic goals. This substantiates the choice of the 3-month assessment as essential for treatment adaptations. PMID- 29481660 TI - JAK1/JAK2 inhibition by baricitinib in diabetic kidney disease: results from a Phase 2 randomized controlled clinical trial. AB - Background: Inflammation signaled by Janus kinases (JAKs) promotes progression of diabetic kidney disease (DKD). Baricitinib is an oral, reversible, selective inhibitor of JAK1 and JAK2. This study tested the efficacy of baricitinib versus placebo on albuminuria in adults with Type 2 diabetes at high risk for progressive DKD. Methods: In this Phase 2, double-blind, dose-ranging study, participants were randomized 1:1:1:1:1 to receive placebo or baricitinib (0.75 mg daily; 0.75 mg twice daily; 1.5 mg daily; or 4 mg daily), for 24 weeks followed by 4-8 weeks of washout. Results: Participants (N = 129) were 63+/-9.1 (mean+/ standard deviation) years of age, 27.1% (35/129) women and 11.6% (15/129) African American race. Baseline hemoglobin A1c (HbA1c) was 7.3+/-1% and estimated glomerular filtration rate was 45.0+/-12.1 mL/min/1.73 m2 with first morning urine albumin-creatinine ratio (UACR) of 820 (407-1632) (median; interquartile range) mg/g. Baricitinib, 4 mg daily, decreased morning UACR by 41% at Week 24 compared with placebo (ratio to baseline 0.59, 95% confidence interval 0.38-0.93, P = 0.022). UACR was decreased at Weeks 12 and 24 and after 4-8 weeks of washout. Baricitinib 4 mg decreased inflammatory biomarkers over 24 weeks (urine C-X-C motif chemokine 10 and urine C-C motif ligand 2, plasma soluble tumor necrosis factor receptors 1 and 2, intercellular adhesion molecule 1 and serum amyloid A). The only adverse event rate that differed between groups was anemia at 32.0% (8/25) for baricitinib 4 mg daily versus 3.7% (1/27) for placebo. Conclusions: Baricitinib decreased albuminuria in participants with Type 2 diabetes and DKD. Further research is required to determine if baricitinib reduces DKD progression. PMID- 29481662 TI - A Common DIO2 Polymorphism and Alzheimer Disease Dementia in African and European Americans. AB - Context: A common single nucleotide polymorphism in DIO2, Thr92AlaD2, has been associated with a transcriptome typically found in neurodegenerative diseases in postmortem human brain tissue. Objective: To determine whether Thr92AlaD2 is associated with incident Alzheimer disease (AD). Design: Population-based study; human brain tissue microarray. Setting: Community-based cohorts from Chicago and northeastern Illinois and religious clergymen from across the United States constituted the primary population. A representative sample of the U.S. population was used for secondary analyses. Participants: 3054 African Americans (AAs) and 9304 European Americans (EAs). Main Outcome Measure: Incident AD. Results: In the primary population, AAs with Thr92AlaD2 had 1.3 times [95% confidence interval (CI), 1.02 to 1.68; P = 0.048] greater odds of developing AD. AAs from a second population with Thr92AlaD2 showed a trend toward increased odds of dementia (odds ratio, 1.33; 95% CI, 0.99 to 1.78; P = 0.06) and 1.35 times greater odds of developing cognitive impairment not demented (CIND; 95% CI, 1.09 to 1.67; P = 0.006). Meta-analysis showed that AAs with Thr92AlaD2 had 1.3 times increased odds of developing AD/dementia (95% CI, 1.07 to 1.58; P = 0.008). In EAs, no association was found between Thr92AlaD2 and AD, dementia, or CIND. Microarray of AA brain tissue identified transcriptional patterns linked to AD pathogenesis. Conclusions: Thr92AlaD2 was associated with molecular markers known to underlie AD pathogenesis in AAs, translating to an observed phenotype of increased odds of developing AD/dementia in AAs in these populations. Thr92AlaD2 might represent one factor contributing to racial discrepancies in incident AD. PMID- 29481664 TI - Light Touch Contact Improves Pain-Evoked Postural Instability During Quiet Standing. AB - Objective: To investigate if attention to additional sensory information from the fingertip can improve postural stability during pain, which is known to impair balance. Methods: In 16 healthy volunteers, experimental pain was induced by intramuscular injection of hypertonic saline in the right vastus medialis muscle (isotonic saline used as nonpainful control, intramuscular injection in the same location). Pain intensity was assessed on an 11-point numeric rating scale (NRS; 0 representing "no pain" and 10 "maximum pain"). Subjects were asked to stand as still as possible on a force plate for 40 seconds with their eyes closed. Their postural stability was quantified by the area and velocity of center of pressure (CoP) displacement. The CoP was recorded with and without pain during two different conditions: 1) no touch and 2) the subjects were asked to lightly touch a curtain with their right index finger and focus their attention on keeping it as still as possible. Results: Hypertonic injections induced higher NRS scores compared with control injections (P < 0.05). During the hypertonic injection condition, the CoP area and velocity in both directions increased during no touch compared with the light touch condition (P < 0.05). No differences were found during light touch between the hypertonic and isotonic injection conditions. Although experimental knee-related pain impaired postural stability, lightly touching a curtain with the fingertip decreased postural sway during painful conditions. Conclusions: Providing additional sensory information while pain patients are performing balance exercises may improve postural stability and increase the quality of exercise, consequent rehabilitation protocols, and clinical outcomes. PMID- 29481663 TI - Radiographic knee osteoarthritis impacts multiple dimensions of health-related quality of life: data from the Osteoarthritis Initiative. AB - Objectives: To estimate the multi-dimensional health impact of radiographic knee OA and quantify the overall health-related quality of life (HRQoL) burden, using a preference-based health utilities measure. Methods: Data on self-reported HRQoL, measured using the SF-12 multi-dimensional health state instrument, were obtained for 2895 patients with radiographic knee OA (Kellgren-Lawrence grade of at least 2) from the Osteoarthritis Initiative and for a general population sample of 3202 from the National Health Measurement Study. The SF-12 was converted to the six-dimensional SF-6D classification to compute preference-based health utilities. Generalized ordinal regression and multinomial regression were used to estimate the health loss on each SF-6D dimension for Osteoarthritis Initiative participants with radiographic knee OA relative to the general population, adjusted for differences in age, BMI, sex, ethnicity and educational level. Predicted SF-6D profiles were then used to compute the average HRQoL loss attributable to radiographic knee OA. Results: Radiographic knee OA was associated with substantial health losses on all dimensions of the SF-6D except for social functioning. Health losses increased with the radiographic severity of OA in dimensions related to physical health, while there was no relationship between worse radiographic disease and worse self-assessed health in mental and emotional dimensions of health. Overall, radiographic knee OA was associated with a HRQoL detriment of 0.040-0.044 at Kellgren-Lawrence grade 2, increasing to 0.045-0.050 at grade 3 and 0.073-0.081 at grade 4. Conclusion: Radiographic knee OA is significantly associated with worse HRQoL across most dimensions of health. PMID- 29481665 TI - Biopsychosocial Challenges and Needs of Young African American Women with Triple Negative Breast Cancer. AB - Triple-negative breast cancer (TNBC) is a subtype of breast cancer known to have poorer prognoses and lower survival rates compared with other types of breast cancer. In addition, TNBC is overrepresented in premenopausal African American women. Using grounded theory as the qualitative methodological approach, the present article elucidates unique biopsychosocial challenges and needs of young African American women with TNBC. A study group of six women with TNBC and a comparison group of six women with estrogen receptor-positive breast cancer were interviewed longitudinally over three time points throughout the cancer treatment trajectory. Major themes that were unique to the study group of women with TNBC include (a) longer, more aggressive treatment trajectories; (b) more difficult struggles with feminine identity; (c) the presence of fertility and parenting issues; (d) higher burdens of care; (e) barriers to separation and individuation as a maturation milestone; and (f) feeling out of place compared with peers. These themes provide a foundation to inform how social workers care for this underserved group of women. PMID- 29481667 TI - Can bioprosthetic valve thrombosis be promoted by aortic root morphology? An in vitro study. AB - OBJECTIVES: Bioprosthetic valve thrombosis has been considered uncommon, but recent studies have shown that it is more frequent than previously thought. Insufficient washout of the aortic sinus is believed to be a risk factor for bioprosthetic valve thrombosis. The objective of this in vitro experiment was to investigate the impact of aortic root morphology on blood flow in the aortic sinus and to relate these results to in vivo data obtained in patients with a transcatheter aortic valve implant. METHODS: Two compliant aortic root phantoms with different morphologies (symmetrical and patient-specific) were fabricated with silicone. A bioprosthetic aortic valve was inserted in both phantoms. Haemodynamic measurements were performed in a pulsatile flow-loop replicating physiological flow and pressure conditions. The flow in the aortic root was visualized by injecting contrast agent (CA). The distribution of the CA was captured by a high-speed camera, and image post-processing was performed to quantify CA distribution in the aortic sinus. The results were compared with angiographic images after a transcatheter aortic valve implant. RESULTS: Blood flow in the aortic root and the washout of the sinus portion are significantly affected by aortic root morphology. CA arrives at the aortic sinus of the 2 phantoms at 0.09 s and 0.16 s after the valve opens in the symmetrical and the patient-specific phantoms, respectively. Delayed CA arrival was also observed in the patients with a transcatheter aortic valve implant. CONCLUSIONS: Aortic root morphology affects the blood flow in the aortic sinus and may be a factor in bioprosthetic valve thrombosis. Therefore, patient-specific aortic root morphology should be considered when selecting and positioning a prosthesis. PMID- 29481668 TI - CD8+ T cells with characteristic T cell receptor beta motif are detected in blood and expanded in synovial fluid of ankylosing spondylitis patients. AB - Objective: The risk of AS is associated with genomic variants related to antigen presentation and specific cytokine signalling pathways, suggesting the involvement of cellular immunity in disease initiation/progression. The aim of the present study was to explore the repertoire of TCR sequences in healthy donors and AS patients to uncover AS-linked TCR variants. Methods: Using quantitative molecular-barcoded 5'-RACE, we performed deep TCR beta repertoire profiling of peripheral blood (PB) and SF samples for 25 AS patients and 108 healthy donors. AS-linked TCR variants were identified using a new computational approach that relies on a probabilistic model of the VDJ rearrangement process. Results: Using the donor-agnostic probabilistic model, we reveal a TCR beta motif characteristic for PB of AS patients, represented by eight highly homologous amino acid sequence variants. Some of these variants were previously reported in SF and PB of patients with ReA and in PB of AS patients. We demonstrate that identified AS-linked clones have a CD8+ phenotype, present at relatively low frequencies in PB, and are significantly enriched in matched SF samples of AS patients. Conclusion: Our results suggest the involvement of a particular antigen specific subset of CD8+ T cells in AS pathogenesis, confirming and expanding earlier findings. The high similarity of the clonotypes with the ones found in ReA implies common mechanisms for the initiation of the diseases. PMID- 29481666 TI - Identification of seven novel loci associated with amino acid levels using single variant and gene-based tests in 8545 Finnish men from the METSIM study. AB - Comprehensive metabolite profiling captures many highly heritable traits, including amino acid levels, which are potentially sensitive biomarkers for disease pathogenesis. To better understand the contribution of genetic variation to amino acid levels, we performed single variant and gene-based tests of association between nine serum amino acids (alanine, glutamine, glycine, histidine, isoleucine, leucine, phenylalanine, tyrosine, and valine) and 16.6 million genotyped and imputed variants in 8545 non-diabetic Finnish men from the METabolic Syndrome In Men (METSIM) study with replication in Northern Finland Birth Cohort (NFBC1966). We identified five novel loci associated with amino acid levels (P = < 5*10-8): LOC157273/PPP1R3B with glycine (rs9987289, P = 2.3*10-26); ZFHX3 (chr16:73326579, minor allele frequency (MAF) = 0.42%, P = 3.6*10-9), LIPC (rs10468017, P = 1.5*10-8), and WWOX (rs9937914, P = 3.8*10-8) with alanine; and TRIB1 with tyrosine (rs28601761, P = 8*10-9). Gene-based tests identified two novel genes harboring missense variants of MAF <1% that show aggregate association with amino acid levels: PYCR1 with glycine (Pgene = 1.5*10-6) and BCAT2 with valine (Pgene = 7.4*10-7); neither gene was implicated by single variant association tests. These findings are among the first applications of gene-based tests to identify new loci for amino acid levels. In addition to the seven novel gene associations, we identified five independent signals at established amino acid loci, including two rare variant signals at GLDC (rs138640017, MAF=0.95%, Pconditional = 5.8*10-40) with glycine levels and HAL (rs141635447, MAF = 0.46%, Pconditional = 9.4*10-11) with histidine levels. Examination of all single variant association results in our data revealed a strong inverse relationship between effect size and MAF (Ptrend<0.001). These novel signals provide further insight into the molecular mechanisms of amino acid metabolism and potentially, their perturbations in disease. PMID- 29481669 TI - Pathogenic CTC1 mutations cause global genome instabilities under replication stress. AB - Coats plus syndrome is a complex genetic disorder that can be caused by mutations in genes encoding the CTC1-STN1-TEN1 (CST) complex, a conserved single-stranded DNA binding protein complex. Studies have demonstrated that mutations identified in Coats plus patients are defective in telomere maintenance, and concluded that Coats plus may be caused by telomere dysfunction. Recent studies have established that CST also plays an important role in countering replication stress and protecting the stability of genomic fragile sites. However, it is unclear whether instabilities at genomic regions may promote Coats plus development. Here, we characterize eleven reported disease-causing CTC1 missense and small deletion mutations in maintaining genome stability. Our results show that these mutations induce spontaneous chromosome breakage and severe chromosome fragmentation that are further elevated by replication stress, leading to global genome instabilities. These mutations abolish or reduce CST interaction with RAD51, disrupt RAD51 foci formation, and/or diminish binding to GC-rich genomic fragile sites under replication stress. Furthermore, CTC1 mutations limit cell proliferation under unstressed condition and significantly reduce clonal viability under replication stress. Results also suggest that the aa 600-989 region of CTC1 contains a RAD51-interacting domain. Our findings thus provide molecular evidence linking replication-associated genomic defects with CP disease pathology. PMID- 29481670 TI - Impact of late-follicular phase elevated serum progesterone on cumulative live birth rates: is there a deleterious effect on embryo quality? AB - STUDY QUESTION: Is elevated late-follicular phase progesterone (EP) associated with a deleterious impact on embryo quality (EQ) and cumulative live birth rates (LBRs)? SUMMARY ANSWER: EP was associated with a decrease in embryo utilization and cumulative LBRs. WHAT IS KNOWN ALREADY: Ovarian stimulation promotes the production of progesterone (P) which adversely affects IVF pregnancy outcomes. However, evidence regarding a potential association between EP an EQ is lacking. STUDY DESIGN, SIZE, DURATION: A retrospective analysis of all GnRH antagonist down-regulated ICSI cycles followed by a fresh embryo transfer (ET) between 2010 and 2015 was performed. The sample was stratified according to the following P levels on the day of ovulation triggering: <=0.50, 0.51-1.49 and >=1.50 ng/ml. The primary outcomes were embryo utilization rates (number of embryos transferred or cryopreserved) and cumulative LBR, defined as the occurrence of the first live birth after either the fresh or one of the subsequent frozen ET. PARTICIPANTS/MATERIALS, SETTING, METHODS: Overall, 3400 cycles were included in the analysis, using multivariable regression to account for potential confounding. MAIN RESULTS AND THE ROLE OF CHANCE: Female age and the number of oocytes retrieved increased significantly with increasing serum P values. Utilization rates decreased linearly as P increased for Day 3 embryos (72.3, 63.0 and 45.4%, respectively), while for Day 5 embryos only the EP group was associated with a significant decrease (48.8, 47.8 and 38.8%, respectively). EP was also associated with decreased fresh and cumulative LBRs. LIMITATIONS REASONS FOR CAUTION: The main limitations of this study were its retrospective nature and the fact that it was restricted to GnRH antagonist cycles. WIDER IMPLICATIONS OF THE FINDINGS: These results raise the question whether EP may also be associated with a decrease in cumulative pregnancy outcomes by increasing embryo wastage. Further studies may evaluate the potential benefit of additional measures besides the freeze-all strategy to avoid this issue, such as lowering the stimulation dose or applying a step-down protocol. STUDY FUNDING/COMPETING INTEREST(S): None. PMID- 29481673 TI - Macrophage activation syndrome in adults: recent advances in pathophysiology, diagnosis and treatment. AB - Haemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome, which if not promptly treated, can lead rapidly to critical illness and death. HLH is termed macrophage activation syndrome (MAS) when associated with rheumatic disease (where it is best characterized in systemic JIA) and secondary HLH (sHLH) when associated with other triggers including malignancy and infection. MAS/sHLH is rare and coupled with its mimicry of other conditions, is underrecognized. These inherent challenges can lead to diagnostic and management challenges in multiple medical specialties including haematology, infectious diseases, critical care and rheumatology. In this review we highlight the pathogenesis of MAS/sHLH including its underlying triggers, key clinical features and diagnostic challenges, prognostic factors and current treatments in adults. PMID- 29481674 TI - Renal injury progression in autosomal dominant polycystic kidney disease: a look beyond the cysts. AB - Hypertension and progressive decline of renal function are among the common clinical manifestations in autosomal dominant polycystic kidney disease (ADPKD). At present, cyst formation in ADPKD patients is still considered the main pathogenic mechanism for the onset of these manifestations. However, the presence of polycystins in the vessels and the cilia of the endothelial cells and vascular smooth muscle cells, as well as development of hypertension prior to renal function decline and its prognostic role for the latter, indicate that polycystins may have an important role for endothelial damage in several vascular beds. Pathological polycystins induce intracellular calcium abnormalities, which affect various cellular organelles and functions and possibly lead not only to several abnormal biochemical reactions within endothelial cells, but also to an imbalance between oxidant and antioxidant capacity. Among the consequences of this process is accumulation of asymmetric-dimethylarginine, which not only participates in the induction and progression of renal damage, but also interferes with the normal vascular response due to nitric oxide (NO) inhibition. Reduced NO bioavailability would result in the long-run in relative vasoconstriction, impaired renal blood flow and vascular remodelling. This review summarizes the existing data from studies supporting that mechanisms other than cyst formation also contribute to the pathogenesis of hypertension and renal function decline in ADPKD. PMID- 29481671 TI - Mechanistic basis of an epistatic interaction reducing age at onset in hereditary spastic paraplegia. AB - Many genetic neurological disorders exhibit variable expression within affected families, often exemplified by variations in disease age at onset. Epistatic effects (i.e. effects of modifier genes on the disease gene) may underlie this variation, but the mechanistic basis for such epistatic interactions is rarely understood. Here we report a novel epistatic interaction between SPAST and the contiguous gene DPY30, which modifies age at onset in hereditary spastic paraplegia, a genetic axonopathy. We found that patients with hereditary spastic paraplegia caused by genomic deletions of SPAST that extended into DPY30 had a significantly younger age at onset. We show that, like spastin, the protein encoded by SPAST, the DPY30 protein controls endosomal tubule fission, traffic of mannose 6-phosphate receptors from endosomes to the Golgi, and lysosomal ultrastructural morphology. We propose that additive effects on this pathway explain the reduced age at onset of hereditary spastic paraplegia in patients who are haploinsufficient for both genes. PMID- 29481675 TI - Human Amniotic Membrane for the Prevention of Intradural Spinal Cord Adhesions: Retrospective Review of its Novel Use in a Case Series of 14 Patients. AB - BACKGROUND: Tethering after spinal surgery is caused by adhesions that arise from intradural tissue manipulation. Microsurgical detethering is the only treatment for symptomatic patients, but retethering occurs commonly and no treatment is widely available to prevent this complication. OBJECTIVE: To apply human amniotic membrane (HAM) grafts, which are immune-privileged and known to possess antifibrogenic properties, in patients requiring microsurgical detethering. For this first-in-human use, we evaluated the safety and potential efficacy of these grafts for preventing retethering. METHODS: We retrospectively reviewed the medical records of all patients who required detethering surgery and received an HAM graft between 2013 and 2016 at our institution after various previous intradural spinal surgeries. In all 14 cases, intradural lysis of adhesions was achieved, an HAM graft was sewn in place intradurally, and a dural patch was closed in a watertight fashion over the graft. RESULTS: Fourteen patients had received HAM grafts to prevent retethering. All patients had at least 6 mo of follow-up (mean follow-up, 14 mo). Retethering was noted in only 1 patient. Surgical re-exploration showed that the retethering occurred caudal to the edge of the HAM graft, with no tethering underneath the original graft. No complications were attributed specifically to the HAM graft placement. CONCLUSION: This first-in-human series provides evidence that HAM grafts are a safe and potentially efficacious method for preventing retethering after microsurgical intradural lysis of adhesions. These results lay the groundwork for further prospective controlled trials in patients with this difficult-to-treat pathology. PMID- 29481676 TI - Everyday Cyborgs: On Integrated Persons and Integrated Goods. AB - Using the metaphor and actuality of the 'everyday cyborg', this article makes the case that the law is ill-equipped to deal with challenges raised by the linking of the organic, biological person with synthetic, inorganic parts and devices. For instance, should internal medical devices that keep the person alive be viewed as part of the person or mere objects (or something else)? Is damage to neuro-prostheses (eg nervous system integrated limb prostheses) personal injury or damage to property? Who ought to control/own the software in implanted medical devices? And how should the law deal with risks around third-party device access (including that of unauthorised access and hacking)? We argue that satisfactorily answering such questions will likely require a re-analysis of the conceptual and philosophical underpinnings of the law, as well as the law itself. To demonstrate this, we examine the uncharted terrain which everyday cyborgs pose for the law, looking in particular at five areas: (i) medical device regulation, safety, and product liability; (ii) damage to devices and liability; (iii) data and privacy; (iv) security and biohacking; and (v) intellectual property rights. The article highlights how advancing biotechnology continues to reveal, and prompts us to confront, lacunae within the law. Our analysis calls particular attention to law's boundary-work (how the law utilises and incorporates supposed ontological and moral boundaries) and the challenges which everyday cyborgs pose to this. PMID- 29481678 TI - Working-Class Ideas and Experiences of Sexuality in Twentieth-Century Britain: Regionalism as a Category of Analysis. AB - This article will explore region as a category of analysis for understanding gender, sexual cultures, and the expression of same-sex desire. In unpicking the notion of regional difference in both its tangible and intangible forms, it outlines the corresponding impact on how sexual cultures developed and were experienced in twentieth-century Britain. By recognizing that the area in which an individual lived could have as much impact on their sense of self and their sexual experiences as issues of race, gender, and class, a new and fruitful avenue of interpretation is opened up for the history of sexuality and twentieth century British history more broadly. Such a methodology has the potential to add a new dimension to all histories of non-state-sanctioned sexual experience such as illegitimacy, premarital sex, extramarital affairs, and prostitution. In using regional case studies and interrogating ideas of sexual taboo, this article offers a unique interpretation of sexual experience that destabilizes current London-centric narratives and offers a more democratic and nuanced history of sex. PMID- 29481679 TI - 'A Tactical Manoeuvre to Apply Pressure': Race and the Role of Public Inquiries in the 1980 Bristol 'Riot'. AB - When violence erupted on the streets of England in 1981, it undoubtedly shocked the country in its scope and severity. However, such disorder had been foreshadowed when the St Pauls area of Bristol saw anti-police disturbances on 2 April 1980. This article focusses on the responses to this, from the local community and organizations as well as local and national government, which in the historiography has often been relegated to passing mentions prior to detailed discussion of the 1981 events. Utilizing recently released and understudied local records, it argues that appeals for a public inquiry from sections of the local community demonstrates the value awarded to them by this politically marginalized group, and the failings of other democratic forms of registering complaints. Public inquiries have long been a key component of the British constitutional system, allowing a unique public interaction with authorities-but it would take increased violence in Brixton the following year before establishment figures were sufficiently alarmed to grant one. This article argues that obtaining this government-endorsed response and an increased participation in the public discourse should be viewed as an aspect within a broader black civil rights movement, challenging claims that minorities played an underrepresented role in motivating advances. However, there was a clear division of attitudes towards public inquiries, demonstrating the moderate tactics utilized by local organizations and older generations, as opposed to more militant groups and the black youth who took to the streets. PMID- 29481677 TI - N4-cytosine DNA methylation regulates transcription and pathogenesis in Helicobacter pylori. AB - Many bacterial genomes exclusively display an N4-methyl cytosine base (m4C), whose physiological significance is not yet clear. Helicobacter pylori is a carcinogenic bacterium and the leading cause of gastric cancer in humans. Helicobacter pylori strain 26695 harbors a single m4C cytosine methyltransferase, M2.HpyAII which recognizes 5' TCTTC 3' sequence and methylates the first cytosine residue. To understand the role of m4C modification, M2.hpyAII deletion strain was constructed. Deletion strain displayed lower adherence to host AGS cells and reduced potential to induce inflammation and apoptosis. M2.hpyAII gene deletion strain exhibited reduced capacity for natural transformation, which was rescued in the complemented strain carrying an active copy of M2.hpyAII gene in the genome. Genome-wide gene expression and proteomic analysis were carried out to discern the possible reasons behind the altered phenotype of the M2.hpyAII gene deletion strain. Upon the loss of m4C modification a total of 102 genes belonging to virulence, ribosome assembly and cellular components were differentially expressed. The present study adds a functional role for the presence of m4C modification in H. pylori and provides the first evidence that m4C signal acts as a global epigenetic regulator in H. pylori. PMID- 29481680 TI - Landlordism, Rent Regulation and the Labour Party in mid-twentieth century Britain, 1950-64. AB - This article examines the politics of private renting in 1950s and early 1960s Britain, through the radical approach taken by Labour Party towards private landlords. Through setting the radical aims of Labour in a mid-twentieth-century context of decrepit housing, rising rents and sluggish public housing programmes, Labour's rationale in arguing for the 'abolition' of the private landlord is more transparent. This article takes a chronological approach, investigating what actions Labour actors took, at local and national level, and what effect this had on the wider housing market. Part one takes a long view of Labour attitudes to the private rented sector. Part two explores the policy of 'municipalization'-the attempt to place rented homes under local authority control. Part three discusses the post-1962 policy shift to state-sponsored 'improvement' of private rented housing, prior to Labour's victory at the 1964 general election. Three key arguments are made: that Labour's radicalism hastened the collapse of the post war private rented sector; that rental market weaknesses indicated the confused place of renting in the 'tenurial pattern'; and that the proposed 'abolition' of private landlords had a direct effect on slum clearance and the composition of British cities. The conclusion suggests that Labour's pursuit of the private landlord can shed light on the vast urban transformations of the post-war period. It invites greater attention to be paid to the effects that political ideas had on the composition of the twentieth-century British housing market. PMID- 29481681 TI - Liberal Party Politics, the South African War, and the Rhetoric of Imperial Governance. AB - This article examines the imperial rhetoric of the Liberal Party during the South African War of 1899-1902, charting its use and development across five key controversies spanning the course of the conflict. Moving beyond traditional interpretations of the Liberal split as the product of competing visions of Empire and approaches to imperialism, this article argues for the need to recognize also the continuities within the imperial rhetoric of fin-de-siecle British Liberalism. Building on recent studies of political languages, it identifies how Liberal speakers from across the party operated within a rhetorical framework that emphasized three ideals of imperial governance: good government, self-government, and pluralism. In doing so, this article seeks to advance our understanding of the South African War as an episode in British party politics, demonstrating the complexity and nuance of the Liberal Party's response to the conflict. Furthermore, by undertaking an in-depth exploration of the rhetoric of imperial governance, this article highlights the Liberal response to the South African War as a case study for the reinvention and reiteration of both party and imperial languages in early twentieth-century Britain, with the potential to offer new insights into the political and imperial cultures of the period. PMID- 29481682 TI - Reflections on 'British Studies in a Broken World', July 2017. PMID- 29481683 TI - International Institutions and Domestic Reform: Equal Pay and British Membership in the European Economic Community. AB - Despite having been overlooked in the standard histories of the UK and the European Community, gender politics and gender policies played a significant role in Britain's applications for membership in the EEC in the 1960s. Joining the European Community required that Britain comply with Article 119 on equal pay for equal work. A combination of domestic feminist and labour movement activism, the commitment of unions and parties, and the internationalization of formal commitments to women's rights constituted internal and external pressures for the passage of an Equal Pay Act in 1970. The article argues that the formal legislative commitment to gender pay equality, changing public attitudes towards women's employment, and European membership impacted further domestic social policy reform and slowly began to shift government attitudes towards gender equality. PMID- 29481684 TI - On Tour with the Prince: Monarchy, Imperial Politics and Publicity in the Prince of Wales's Dominion Tours 1919-20. AB - The stage managers of ritual and the media transformed the British monarchy in the late-nineteenth and early-twentieth century, consolidating its image as splendid and popular and also as more accessible and quasi-democratic. Historians have emphasized that these processes of modernization largely began in Britain. This article locates the origins of democratized royal ritual in the white dominions, especially after 1918. Canada, Australia and New Zealand were political and cultural laboratories where royal advisors and British and dominion politicians launched experiments in the practice of progressive empire and innovatory styles of informal ceremonial, which had a long-term impact on imperial and later Commonwealth relations. Focusing on the Prince of Wales's early dominion tours, the article argues that though royal diplomacy followed earlier itineraries in efforts to consolidate the racialized British world, it also threw up new and unintended consequences. These registered the rapidly changing international order after the collapse of the European monarchies, together with the demands of the prince's own modernist personality. Faced with republican and socialist opposition in Australia and Canada, the touring prince was drawn into competing forms of nationalism, as dominion politicians and journalists embraced him as representing domestic aspirations for self-government and cultural recognition. It is argued that modern royalty personified by the Prince of Wales problematizes the history of twentieth-century public reputations defined by the culture of celebrity. The British monarchy was forced to confront both the constitutional claims of empire and the politics of dominion nationalism, as well as the pressures of international publicity. PMID- 29481685 TI - Glycerol positive promoters for tailored metabolic engineering of the yeast Saccharomyces cerevisiae. AB - Glycerol offers several advantages as a substrate for biotechnological applications. An important step toward using the popular production host Saccharomyces cerevisiae for glycerol-based bioprocesses has been the fact that in recent studies commonly used S. cerevisiae strains were engineered to grow in synthetic medium containing glycerol as the sole carbon source. For metabolic engineering projects of S. cerevisiae growing on glycerol, characterized promoters are missing. In the current study, we used transcriptome analysis and a yECitrine-based fluorescence reporter assay to select and characterize 25 useful promoters. The promoters of the genes ALD4 and ADH2 showed 4.2-fold and 3-fold higher activities compared to the well-known strong TEF1 promoter. Moreover, the collection contains promoters with graded activities in synthetic glycerol medium and different degrees of glucose repression. To demonstrate the general applicability of the promoter collection, we successfully used a subset of the characterized promoters with graded activities in order to optimize growth on glycerol in an engineered derivative of CEN.PK, in which glycerol catabolism exclusively occurs via a non-native DHA pathway. PMID- 29481686 TI - Estimated glomerular filtration rate for longitudinal follow-up of living kidney donors. AB - Background: Living kidney donor safety requires reliable long-term follow-up of renal function after donation. The current study aimed to define the precision and accuracy of post-donation estimated glomerular filtration rate (eGFR) slopes compared with measured GFR (mGFR) slopes. Methods: In 349 donors (age 51 +/- 10, 54% female), we analysed eGFR according to the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault/body surface area (CG/BSA), creatinine clearance (CrCl) and mGFR (125I-iothalamate) changes from 3 months until 5 years post-donation. Results: Donors had a pre-donation mGFR of 116 +/- 23 mL/min, at 3 months post-donation mGFR was 73 +/- 14 mL/min and at 5 years it was 79 +/- 16 mL/min. Between 3 months and 5 years post-donation, 28% of donors had a declining mGFR (-0.82 +/- 0.79 mL/min/year), 47% were stable and 25% had an increasing mGFR. Overall, eGFR equations showed good slope estimates (bias eGFRCKD-EPI 0.13 +/- 2.16 mL/min/year, eGFRMDRD 0.19 +/- 2.10 mL/min/year, eGFRCG/BSA -0.08 +/- 2.06 mL/min/year, CrCl -0.12 +/- 4.75 mL/min/year), but in donors with a decreasing mGFR the slope was underestimated (bias eGFRCKD-EPI 1.41 +/- 2.03 mL/min/year, eGFRMDRD 1.51 +/- 1.96 mL/min/year, eGFRCG/BSA 1.20 +/- 1.87 mL/min/year). The CrCl had a high imprecision [bias interquartile range -1.51 3.41 mL/min/year]. Conclusions: All eGFR equations underestimated GFR slopes in donors with a declining GFR between 3 months and 5 years post-donation. This study underlines the value of mGFR in the follow-up of donors with risk of progressive GFR loss. PMID- 29481687 TI - Assessment of mechanical dyssynchrony can improve the prognostic value of guideline-based patient selection for cardiac resynchronization therapy. AB - Aim: To determine if incorporation of assessment of mechanical dyssynchrony could improve the prognostic value of patient selection based on current guidelines. Methods and results: Echocardiography was performed in 1060 patients before and 12 +/- 6 months after cardiac resynchronization therapy (CRT) implantation. Mechanical dyssynchrony, defined as the presence of apical rocking or septal flash was visually assessed at the baseline examination. Response was defined as >=15% reduction in left ventricular end-systolic volume at follow-up. Patients were followed for a median of 59 months (interquartile range 37-86 months) for the occurrence of death of any cause. Applying the latest European guidelines retrospectively, 63.4% of the patients had been implanted with a Class I recommendation, 18.2% with Class IIa, 9.4% with Class IIb, and in 9% no clear therapy recommendation was present. Response rates were 65% in Class I, 50% in IIa, 38% in IIb patients, and 40% in patients without a clear guideline-based recommendation. Assessment of mechanical dyssynchrony improved response rates to 77% in Class I, 75% in IIa, 62% in IIb, and 69% in patients without a guideline based recommendation. Non-significant difference in survival among guideline recommendation classes was found (Log-rank P = 0.2). Presence of mechanical dyssynchrony predicted long-term outcome better than guideline Classes I, IIa, IIb (Log-rank P < 0.0001, 0.006, 0.004, respectively) and in patients with no guideline recommendation (P = 0.02). Comparable results were observed using the latest American Guidelines. Conclusion: Our data suggest that current guideline criteria for CRT candidate selection could be improved by incorporating assessment of mechanical asynchrony. PMID- 29481688 TI - Different endophyte communities colonize buds of sprouts compared with mature trees of mountain birch recovered from moth herbivory. AB - Plant meristems were previously thought to be sterile. Today, meristem-associated shoot endophytes are mainly reported as contaminants from plant tissue cultures, the number of observed species being very low. However, the few strains characterized have the capacity for infecting host cells and affecting plant growth and development. Here we studied the communities of endophytic bacteria in the buds of mountain birch (Betula pubescens ssp. czerepanovii (N. I. Orlova) Hamet-Ahti) exposed to winter moth (Operophtera brumata L.) herbivory, to identify differences between sprouts and branches of mature birch trees. Mountain birch of the high subarctic is cyclically exposed to winter moth and produces sprouts to generate new trees as a survival mechanism. The majority (54%) of operational taxonomic units belonged to Xanthomonadaceae and Pseudomonales of Proteobacteria. Most of the observed species were classified as Xanthomonas (28%). Sprout buds had the highest diversity, containing approximately three times more species, and significantly more (43%) Pseudomonas species than the mature trees (14%). Our results demonstrate that endophytic communities of buds are richer than previously thought. We suggest that the meristem-associated endophytes should be studied further for a possible role in sprouting and aiding regeneration of trees. PMID- 29481690 TI - Meningitis due to autochthonous acute infection with hepatitis E virus in a chef: a case report. PMID- 29481691 TI - Patient Selection and Technical Nuances for Microsurgical Clipping of Carotid Ophthalmic Aneurysms: 2-Dimensional Operative Video. PMID- 29481689 TI - Human RAD51 rapidly forms intrinsically dynamic nucleoprotein filaments modulated by nucleotide binding state. AB - Formation of RAD51 filaments on single-stranded DNA is an essential event during homologous recombination, which is required for homology search, strand exchange and protection of replication forks. Formation of nucleoprotein filaments (NF) is required for development and genomic stability, and its failure is associated with developmental abnormalities and tumorigenesis. Here we describe the structure of the human RAD51 NFs and of its Walker box mutants using electron microscopy. Wild-type RAD51 filaments adopt an 'open' conformation when compared to a 'closed' structure formed by mutants, reflecting alterations in helical pitch. The kinetics of formation/disassembly of RAD51 filaments show rapid and high ssDNA coverage via low cooperativity binding of RAD51 units along the DNA. Subsequently, a series of isomerization or dissociation events mediated by nucleotide binding state creates intrinsically dynamic RAD51 NFs. Our findings highlight important a mechanistic divergence among recombinases from different organisms, in line with the diversity of biological mechanisms of HR initiation and quality control. These data reveal unexpected intrinsic dynamic properties of the RAD51 filament during assembly/disassembly, which may be important for the proper control of homologous recombination. PMID- 29481692 TI - Decreasing Revision Surgery in FAMM Flap Reconstruction of the Oral Cavity: Traditional Versus Modified Harvesting Technique. AB - OBJECTIVE: To compare the surgical and functional outcomes between two harvesting techniques for the inferiorly based facial artery musculomucosal (FAMM) flap for oral cavity and oropharynx reconstructions. METHODS: Multicenter retrospective chart review. RESULTS: We reviewed 55 cases of FAMM flap, including 29 traditional cases and 26 performed using the modified harvesting method. The overall rate of surgical re-intervention in the traditional group was 31% (n = 9 of 29) and 15% (n = 4 of 26) in the modified group (P = 0.196). The specific re intervention rate for pedicle sectioning was 27% (n = 8 of 29) in the traditional group versus 0% (n = 0 of 26) in the modified group. The overall rate of complications was 21%. Nine out of 10 dentate patients in the traditional group and four out of five in the modified group needed tooth extraction. There was no difference between the two groups in terms of tracheostomy duration (P = 0.338) and time to first oral intake (P = 0.629). Speech and feeding outcomes were similar among groups (P = 0.922; P = 0.700, respectively). Dental rehabilitation was achieved in 67% and 78% of patients in the traditional and modified groups, respectively. CONCLUSION: The FAMM flap offers a low morbidity approach to reconstruct the oral cavity. The modified approach to harvesting the flap is a safe and effective technique, with similar functional results and equally low morbidity profile as the traditional technique. It has the added advantage of lower rates of secondary surgical interventions. LEVEL OF EVIDENCE: 4. Laryngoscope, 1802-1805, 2018. PMID- 29481693 TI - Improving adherence to Standard Precautions for the control of health care associated infections. AB - BACKGROUND: 'Standard Precautions' refers to a system of actions, such as using personal protective equipment or adhering to safe handling of needles, that healthcare workers take to reduce the spread of germs in healthcare settings such as hospitals and nursing homes. OBJECTIVES: To assess the effectiveness of interventions that target healthcare workers to improve adherence to Standard Precautions in patient care. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, LILACS, two other databases, and two trials registers. We applied no language restrictions. The date of the most recent search was 14 February 2017. SELECTION CRITERIA: We included randomised trials of individuals, cluster randomised trials, non-randomised trials, controlled before-after studies, and interrupted time-series studies that evaluated any intervention to improve adherence to Standard Precautions by any healthcare worker with responsibility for patient care in any hospital, long-term care or community setting, or artificial setting, such as a classroom or a learning laboratory. DATA COLLECTION AND ANALYSIS: Two review authors independently screened search results, extracted data from eligible trials, and assessed risk of bias for each included study, using standard methodological procedures expected by Cochrane. Because of substantial heterogeneity among interventions and outcome measures, meta-analysis was not warranted. We used the GRADE approach to assess certainty of evidence and have presented results narratively in 'Summary of findings' tables. MAIN RESULTS: We included eight studies with a total of 673 participants; three studies were conducted in Asia, two in Europe, two in North America, and one in Australia. Five studies were randomised trials, two were cluster-randomised trials, and one was a non-randomised trial. Three studies compared different educational approaches versus no education, one study compared education with visualisation of respiratory particle dispersion versus education alone, two studies compared education with additional infection control support versus no intervention, one study compared peer evaluation versus no intervention, and one study evaluated use of a checklist and coloured cues. We considered all studies to be at high risk of bias with different risks. All eight studies used different measures to assess healthcare workers' adherence to Standard Precautions. Three studies also assessed healthcare workers' knowledge, and one measured rates of colonisation with methicillin-resistant Staphylococcus aureus (MRSA) among residents and staff of long-term care facilities. Because of heterogeneity in interventions and outcome measures, we did not conduct a meta-analysis.Education may slightly improve both healthcare workers' adherence to Standard Precautions (three studies; four centres) and their level of knowledge (two studies; three centres; low certainty of evidence for both outcomes).Education with visualisation of respiratory particle dispersion probably improves healthcare workers' use of facial protection but probably leads to little or no difference in knowledge (one study; 20 nurses; moderate certainty of evidence for both outcomes).Education with additional infection control support may slightly improve healthcare workers' adherence to Standard Precautions (two studies; 44 long-term care facilities; low certainty of evidence) but probably leads to little or no difference in rates of health care-associated colonisation with MRSA (one study; 32 long-term care facilities; moderate certainty of evidence).Peer evaluation probably improves healthcare workers' adherence to Standard Precautions (one study; one hospital; moderate certainty of evidence).Checklists and coloured cues probably improve healthcare workers' adherence to Standard Precautions (one study; one hospital; moderate certainty of evidence). AUTHORS' CONCLUSIONS: Considerable variation in interventions and in outcome measures used, along with high risk of bias and variability in the certainty of evidence, makes it difficult to draw conclusions about effectiveness of the interventions. This review underlines the need to conduct more robust studies evaluating similar types of interventions and using similar outcome measures. PMID- 29481694 TI - Computed tomography-fusion image guidance for children with thin calvaria undergoing bone-anchored hearing aid placement. PMID- 29481695 TI - Factors associated with benefit of active middle ear implants compared to conventional hearing aids. AB - OBJECTIVE: Identify factors associated with benefit of middle ear implants (MEIs) as compared to conventional hearing aids (HAs). STUDY DESIGN: Independent review of audiological data from a multicenter prospective U.S. Food and Drug Administration (FDA) clinical trial. Preoperative and postoperative earphone, unaided/aided/implanted pure-tone thresholds, and word recognition scores were evaluated. RESULTS: Ninety-one subjects were included in this study. Mean word recognition was better with MEIs than with HAs (81.8% +/- 12.0% vs. 77.6% +/- 14.6%, P = 0.035). Word recognition with MEIs showed a low positive correlation with word recognition measured with earphones (r = 0.25, P = 0.016) and a moderate positive correlation with aided word recognition (r = 0.42, P < 0.001). Earphone word recognition alone was not predictive of MEI benefit over HA benefit (r = 0.09, P = 0.41), unlike differences between scores with earphone and HAs (earphone-aided differences [EAD]) (r = 0.62, P < 0.011). As compared to those with -EADs, subjects with +EADs showed greater improvement in word recognition from unaided to implanted and from HAs to implanted (P < 0.0001). Using the 95% CI for word recognition scores, 16 subjects showed significantly higher scores with the MEI than with HAs. Of those, 14 had +EAD. CONCLUSION: Word recognition benefit derived from conventional HAs and MEIs from this large, multi-center FDA trial provides further evidence of the importance of aided word recognition in clinical decision making, such as determining candidacy for and success with MEIs. LEVEL OF EVIDENCE: 2b. Laryngoscope, 128:2133-2138, 2018. PMID- 29481696 TI - Continuous vagal monitoring value in prevention of vocal cord paralysis following thyroid surgery. AB - OBJECTIVES/HYPOTHESIS: Continuous intraoperative neuromonitoring (CIONM) of the vagus nerve was proposed to obtained frequent repetitive electromyography (EMG) data to recognize early change in intraoperative function of the recurrent laryngeal nerve. We examine our initial experience using this technology. STUDY DESIGN: Retrospective review. METHODS: Data for all patients who underwent neck surgery by a single surgeon at a North American institution over a 5-year period were reviewed. CIONM was used in cases with possible higher risk of traction injury and according to surgeon preference. In these cases, stretch injury was established by warning alarm with threshold of >=50% reduction in amplitude and/or >= 10% increase in latency. Preoperative and postoperative direct laryngoscopy was performed for all patients. RESULTS: A total of 879 endocrine neck surgeries were performed. CIONM was used to monitor 455 recurrent laryngeal nerves (RLNs) in 344 (39.1%) surgeries. An automatic periodic stimulation (APS) alarm detected impending nerve injury in 33 (9.6%) cases by 64.9% +/- 12.7% decrease in amplitude and by 27.3% increase in latency in one case. A total loss of signal (LOS) was detected in 15 (4.36%) cases. The immediate release of causative retraction successfully preserved the nerves in all cases with impending injury; however, there was no improvement in the LOS cases. Other than the cases with LOS, postoperative laryngoscopy showed normal vocal cord function in all cases. CONCLUSIONS: APS technology is safe, feasible, and helpful in approximately 10% of cases in our series, which developed nascent neurapraxia adverse EMG changes associated with intraoperative RLN stretch that could be reversed intraoperatively. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:2429-2432, 2018. PMID- 29481697 TI - Osseointegrated implants for auricular prostheses: An alternative to autologous repair. AB - OBJECTIVES/HYPOTHESIS: This study compares the hospital cost of osseointegrated implants for retention of an auricular prosthesis to autologous ear reconstruction. STUDY DESIGN: Retrospective review. METHODS: This study includes patients who underwent reconstruction for either congenital or acquired ear defects at Duke University Medical Center during 2009 to 2015. RESULTS: A total of nine patients had autologous repair representing nine operative ears, and 16 patients had an osseointegrated implant representing 18 operative ears (two bilateral). The average age for the autologous repair was 11.6 years with 56% male versus 40.7 years with 56% male for the osseointegrated implant patients. For autologous patients, indications for surgery were anotia/microtia in 8/9 (89%) and trauma in 1/9 (11%) versus 6/16 (387.5%) anotia/microtia, 8/16 (50%) cancer, and 2/16 (132.5%) trauma in the osseointegrated implant group. The mean number of surgeries was 3.1 for autologous repairs and 1.0 for osseointegrated repairs (mean difference confidence interval [CI]: -2.4 to -1.8, P < .001). The average cost to the hospital for an osseointegrated repair was $6,491.39 versus $10,047.93 for autologous repairs (CI: $6,496.38 to $-616.68, P = .02) CONCLUSIONS: Osseointegrated implants for retaining an auricular prosthesis has a similar cost to autologous repair of ear defects, but patients underwent an average of two more surgeries with autologous repair. Patients should be able to choose the reconstruction option that best suits their condition and preferences. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:2153-2156, 2018. PMID- 29481698 TI - A clinically relevant IMRT QA workflow: Design and validation. AB - PURPOSE: The purpose of this study was to determine clinically relevant pass/question/fail criteria for gamma analysis of intensity-modulated radiation therapy quality assurance (IMRT QA) plans, identify which plans should be further analyzed with dose-volume histogram (DVH) metrics, and create a workflow for performing that DVH-based analysis. METHODS: A total of 11 plans, 5 prostate and 6 head/neck, were selected to represent known good plans based on their high passing rate using conventional IMRT QA criteria. These were modified by moving the programmed MLC positions to underdose the target or overdose important structures by varying amounts. Commercially available hardware/software was used to measure and analyze all plans (76 total) using 4%/3 mm, 3%/3 mm, 3%/2 mm, and 2%/2 mm gamma criteria. Two receiver operator characteristic (ROC) curves per criterion were created to assess effective passing rates. One ROC curve was to find a higher threshold that determined a clear pass and the second to find a lower threshold to determine a clear failure. Plans between these two thresholds need DVH-based analysis to assess the clinical consequence of the dose difference. The modified plans were analyzed in the planning system and reconstructed in commercially available DVH-based analysis software to access the accuracy and usefulness of the software. RESULTS: Analysis of the ROC curves showed optimal pass and fail thresholds for plan error detection per criterion to achieve clinically relevant sensitivity and specificity. Based on measurement uncertainty and pass/fail ranges, 3%/2 mm gamma criteria with a pass threshold of 95% and a fail threshold of 90% were most optimal. DVH analysis showed good agreement with all reconstructed plans except where the changes to the MLC patterns caused the periphery of the target to be underdosed. For questionable plans, comparing the organ-specific DVHs to the physician-provided planning constraints proved to be an efficient and effective workflow since plans for which the target dose was slightly high or where organs at risk were underdosed could be released for the treatment without consulting the physician for a clinical decision. CONCLUSION: This work indicates the potential for appreciable improvement in error detection for IMRT QA. Using effective pass/fail thresholds to determine plans that need DVH-based analysis minimizes the need for excessive, time-consuming, analysis, and making use of the dosimetric constraints of the plan minimizes the burden on physicians. Overall, DVH-based analysis is a powerful tool that can provide substantial insight over the traditional approach that does not provide structure-specific data. PMID- 29481699 TI - In response to Socioeconomic disparities and comorbidities, not race, affect salivary gland malignancy survival outcomes. PMID- 29481700 TI - Conventional and novel "omics"-based approaches to the study of carbon nanotubes pulmonary toxicity. AB - The widespread application of carbon nanotubes (CNT) on industrial, biomedical, and consumer products can represent an emerging respiratory occupational hazard. Particularly, their similarity with the fiber-like shape of asbestos have raised a strong concern about their carcinogenic potential. Several in vitro and in vivo studies have been supporting this view by pointing to immunotoxic, cytotoxic and genotoxic effects of some CNT that may conduct to pulmonary inflammation, fibrosis, and bronchioloalveolar hyperplasia in rodents. Recently, high throughput molecular methodologies have been applied to obtain more insightful information on CNT toxicity, through the identification of the affected biological and molecular pathways. Toxicogenomic approaches are expected to identify unique gene expression profiles that, besides providing mechanistic information and guiding new research, have also the potential to be used as biomarkers for biomonitoring purposes. In this review, the potential of genomic data analysis is illustrated by gene network and gene ontology enrichment analysis of a set of 41 differentially expressed genes selected from a literature search focused on studies of C57BL/6 mice exposed to the multiwalled CNT Mitsui 7. The majority of the biological processes annotated in the network are regulatory processes and the molecular functions are related to receptor-binding signalling. Accordingly, the network-annotated pathways are cell receptor-induced pathways. A single enriched molecular function and one biological process were identified. The relevance of specific epigenomic effects triggered by CNT exposure, for example, alteration of the miRNA expression profile is also discussed in light of its use as biomarkers in occupational health studies. Environ. Mol. Mutagen. 59:334-362, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29481701 TI - Patterns of concurrent cigarette, alcohol, and e-cigarette use: Off-setting or additive behaviors? AB - OBJECTIVES: To understand nationwide concurrent use of e-cigarettes (Ecig) with alcohol and conventional cigarettes (Ccig), the major risk factors for head and neck cancer. STUDY DESIGN: Cross-sectional analysis of nationally representative survey. METHODS: The National Health Interview Surveys for 2014 and 2015 were analyzed for adult responses to specific questions regarding the daily frequency of alcohol, Ccig, and Ecig use. Statistical relationships between these social habits were determined. RESULTS: A total of 241.1 million adults (raw N = 162,048) were surveyed (mean age 47.1 years, 51.8% female). Of those, 12.1% (29.2 million) and 3.8% (9.08 million) reported being every day Ccig users and some days Ccig users, respectively. A total of 2.3% (5.63 million) and 1.1% (2.76 million) reported being every day Ecig users and some days Ecig users, respectively. In addition, 58.4% of everyday Ecig users reported also being everyday Ccig users (P < 0.001). Furthermore, 25.6% (61.3 million) and 8.3% (20.0 million) of adults reported light drinking (1-3 drinks/week) and moderate/heavy drinking (4-7 drinks/week), respectively. Of the moderate/heavy drinkers, 17.7% were everyday Ccig users, whereas 12.2% of everyday Ccig users were moderate/heavy drinkers (P < 0.001). Among everyday Ecig users, 34.6% and 11.2% were light drinkers and moderate/heavy drinkers, respectively (P < 0.001). Among non-Ccig users, everyday Ecig users were likely to consume higher levels of alcohol given that 36.5% and 8.9% were light drinkers and moderate/heavy drinkers, respectively (P < 0.01). CONCLUSION: We demonstrate a substantial level of Ccig use among moderate/heavy drinkers and Ecig users, as well as a novel independent association between Ecig and moderate/heavy alcohol use. These patterns of concurrent risk factor exposure should be considered when counseling patients who report Ecig use. LEVEL OF EVIDENCE: 2b. Laryngoscope, 1817-1821, 2018. PMID- 29481702 TI - How to Perform an Ethical Risk Analysis (eRA). AB - Ethical analysis is often needed in the preparation of policy decisions on risk. A three-step method is proposed for performing an ethical risk analysis (eRA). In the first step, the people concerned are identified and categorized in terms of the distinct but compatible roles of being risk-exposed, a beneficiary, or a decisionmaker. In the second step, a more detailed classification of roles and role combinations is performed, and ethically problematic role combinations are identified. In the third step, further ethical deliberation takes place, with an emphasis on individual risk-benefit weighing, distributional analysis, rights analysis, and power analysis. Ethical issues pertaining to subsidiary risk roles, such as those of experts and journalists, are also treated in this phase. An eRA should supplement, not replace, a traditional risk analysis that puts emphasis on the probabilities and severities of undesirable events but does not cover ethical issues such as agency, interpersonal relationships, and justice. PMID- 29481703 TI - Quality assurance tool for organ at risk delineation in radiation therapy using a parametric statistical approach. AB - PURPOSE: To develop a quality assurance (QA) tool that identifies inaccurate organ at risk (OAR) delineations. METHODS: The QA tool computed volumetric features from prior OAR delineation data from 73 thoracic patients to construct a reference database. All volumetric features of the OAR delineation are computed in three-dimensional space. Volumetric features of a new OAR are compared with respect to those in the reference database to discern delineation outliers. A multicriteria outlier detection system warns users of specific delineation outliers based on combinations of deviant features. Fifteen independent experimental sets including automatic, propagated, and clinically approved manual delineation sets were used for verification. The verification OARs included manipulations to mimic common errors. Three experts reviewed the experimental sets to identify and classify errors, first without; and then 1 week after with the QA tool. RESULTS: In the cohort of manual delineations with manual manipulations, the QA tool detected 94% of the mimicked errors. Overall, it detected 37% of the minor and 85% of the major errors. The QA tool improved reviewer error detection sensitivity from 61% to 68% for minor errors (P = 0.17), and from 78% to 87% for major errors (P = 0.02). CONCLUSIONS: The QA tool assists users to detect potential delineation errors. QA tool integration into clinical procedures may reduce the frequency of inaccurate OAR delineation, and potentially improve safety and quality of radiation treatment planning. PMID- 29481704 TI - Risk Assessment and Risk Governance of Liquefied Natural Gas Development in Gladstone, Australia. AB - This article is a retrospective analysis of liquefied natural gas development (LNG) in Gladstone, Australia by using the structure of the risk governance framework developed by the International Risk Governance Council (IRGC). Since 2010 the port of Gladstone has undergone extensive expansion to facilitate the increasing coal export as well as the new development of three recently completed LNG facilities. Significant environmental and socio-economic impacts and concerns have occurred as a result of these developments. The overall aim of the article, therefore, is to identify the risk governance deficits that arose and to formulate processes capable of improving similar decision-making problems in the future. The structure of the IRGC framework is followed because it represents a broad analytical approach for considering risk assessment and risk governance in Gladstone in ways that include, but also go beyond, the risk approach of the ISO 31000:2009 standard that was employed at the time. The IRGC risk framework is argued to be a consistent and comprehensive risk governance framework that integrates scientific, economic, social, and cultural aspects and advocates the notion of inclusive risk governance through stakeholder communication and involvement. Key aspects related to risk preassessment, risk appraisal, risk tolerability and acceptability, risk management, and stakeholder communication and involvement are considered. The results indicate that the risk governance deficits include aspects related to (i) the risk matrix methodology, (ii) reflecting uncertainties, (iii) cumulative risks, (iv) the regulatory process, and (v) stakeholder communication and involvement. PMID- 29481705 TI - Utility of the bow and lean test in predicting subtype of benign paroxysmal positional vertigo. AB - OBJECTIVES/HYPOTHESIS: To investigate the role of the bow and lean test (BLT) in the diagnosis of benign paroxysmal positional vertigo (BPPV). STUDY DESIGN: Retrospective case-control study. METHODS: Between March 2015 and June 2017, we enrolled 113 patients with posterior semicircular canal (PSCC) BPPV, 74 patients with lateral semicircular canal (LSCC) canalolithiasis, 53 patients with LSCC cupulolithiasis, and 32 patients with light cupula. We retrospectively assessed bowing nystagmus (BN) and leaning nystagmus (LN). RESULTS: In PSCC BPPV, 75% of the patients showed at least one of BN and LN, and direction of nystagmus provoked by a Dix-Hallpike test on the affected side was consistent with that of LN and opposite to that of BN. In LSCC canalolithiasis, 65% (48 of 74) of the patients showed both BN and LN, which were in the same direction in 38 patients (of 48) and in the opposite direction in 10 patients (of 48). The affected side can be determined according to the results of THE BLT in 74% (55 of 74) of LSCC canalolithiasis patients, and among them, the side determined according to the results of head-roll test was discordant with that according to the BLT in 20 of 55 patients (36%). In LSCC cupulopathy (n = 85), both BN and LN were persistent and observed in all cases, but we could not distinguish LSCC cupulolithiasis from light cupula according to nystagmus direction in the BLT. CONCLUSIONS: Although a BLT yields better lateralization in LSCC canalolithiasis, it may be more useful in predicting the diagnosis and lateralization of PSCC BPPV than LSCC canalolithiasis. LEVEL OF EVIDENCE: 4 Laryngoscope, 2600-2604, 2018. PMID- 29481706 TI - Should children with an enlarged vestibular aqueduct be restricted from playing contact sports? PMID- 29481707 TI - Web Content Management Systems: An Analysis of Forensic Investigatory Challenges. AB - With an increase in the creation and maintenance of personal websites, web content management systems are now frequently utilized. Such systems offer a low cost and simple solution for those seeking to develop an online presence, and subsequently, a platform from which reported defamatory content, abuse, and copyright infringement has been witnessed. This article provides an introductory forensic analysis of the three current most popular web content management systems available, WordPress, Drupal, and Joomla! Test platforms have been created, and their site structures have been examined to provide guidance for forensic practitioners facing investigations of this type. Result's document available metadata for establishing site ownership, user interactions, and stored content following analysis of artifacts including Wordpress's wp_users, and wp_comments tables, Drupal's "watchdog" records, and Joomla!'s _users, and _content tables. Finally, investigatory limitations documenting the difficulties of investigating WCMS usage are noted, and analysis recommendations are offered. PMID- 29481708 TI - 2-Hydroxypyridine-N-oxide (HOPO): Equivocal in the ames assay. AB - 2-Hydroxypyridine-N-oxide (HOPO) is a useful coupling reagent for synthesis of active pharmaceutical ingredients. It has been reported to be weakly mutagenic in the Ames assay (Ding W et al. []: J Chromatogr A 1386:47-52). According to the ICH M7 guidance (2014) regarding control of mutagenic impurities to limit potential carcinogenic risk, mutagens require control in drug substances such that exposure not exceeds the threshold of toxicological concern. Given the weak response observed in the Ames assay and the lack of any obvious structural features that could confer DNA reactivity we were interested to determine if the results were reproducible and investigate the role of potentially confounding experimental parameters. Specifically, Ames tests were conducted to assess the influence of compound purity, solvent choice, dose spacing, toxicity, type of S9 (aroclor vs phenobarbital/beta-napthoflavone), and lot variability on the frequency of HOPO induced revertant colonies. Initial extensive testing using one lot of HOPO produced no evidence of mutagenic potential in the Ames assays. Subsequent studies with four additional lots produced conflicting results, with an ~2.0-fold increase in revertant colonies observed. Given the rigor of the current investigation, lack of reproducibility between lots, and the weak increase in revertants, it is concluded that HOPO is equivocal in the bacterial reverse mutation assay. It is highly unlikely that HOPO poses a mutagenic risk in vivo; therefore, when it is used as a reagent in pharmaceutical synthesis, it should not be regarded as a mutagenic impurity, but rather a normal process related impurity. Environ. Mol. Mutagen. 59:312-321, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29481709 TI - Detecting early warning signals of tree mortality in boreal North America using multiscale satellite data. AB - Increasing tree mortality from global change drivers such as drought and biotic infestations is a widespread phenomenon, including in the boreal zone where climate changes and feedbacks to the Earth system are relatively large. Despite the importance for science and management communities, our ability to forecast tree mortality at landscape to continental scales is limited. However, two independent information streams have the potential to inform and improve mortality forecasts: repeat forest inventories and satellite remote sensing. Time series of tree-level growth patterns indicate that productivity declines and related temporal dynamics often precede mortality years to decades before death. Plot-level productivity, in turn, has been related to satellite-based indices such as the Normalized difference vegetation index (NDVI). Here we link these two data sources to show that early warning signals of mortality are evident in several NDVI-based metrics up to 24 years before death. We focus on two repeat forest inventories and three NDVI products across western boreal North America where productivity and mortality dynamics are influenced by periodic drought. These data sources capture a range of forest conditions and spatial resolution to highlight the sensitivity and limitations of our approach. Overall, results indicate potential to use satellite NDVI for early warning signals of mortality. Relationships are broadly consistent across inventories, species, and spatial resolutions, although the utility of coarse-scale imagery in the heterogeneous aspen parkland was limited. Longer-term NDVI data and annually remeasured sites with high mortality levels generate the strongest signals, although we still found robust relationships at sites remeasured at a typical 5 year frequency. The approach and relationships developed here can be used as a basis for improving forest mortality models and monitoring systems. PMID- 29481710 TI - Unilateral radiotherapy treatment for p16/human papillomavirus-positive squamous cell carcinoma of unknown primary in the head and neck. AB - OBJECTIVES/HYPOTHESIS: The outcomes of unilateral radiotherapy treatment for patients with p16/HPV-positive squamous cell carcinomas of unknown primary (SCCUP) affecting cervical lymph nodes are under-reported. Compared to radiating large volumes of the pharyngeal axis (the more common approach), this is potentially a much less toxic treatment for a good prognosis group. STUDY DESIGN: Retrospective cohort study. METHODS: We identified patients with SCCUP who were treated radically at our center and did not have parotid or isolated level IV or V nodal involvement. Failure-free and overall survivals were calculated using Kaplan-Meier methods. RESULTS: From 2004 to 2012, there were 49 radically treated patients with SCCUP. Fourteen patients had bilateral neck treatment (they had bilateral nodal disease or suspected lesions in the base of tongue, though not proven with biopsy), two had surgery alone, whereas 33 had unilateral radiotherapy (after neck dissection, excisional biopsy, or definitively with concurrent chemotherapy). Of the 33 patients, 21 tested positive to p16/HPV and had median follow-up of 57 months. In this group, no isolated contralateral neck failures or putative primaries emerged. There was 1/21 (4.3%) ipsilateral neck failure, 1/21 (4.3%) concurrent contralateral neck and distant failure, and 1/21 (4.3%) patient with distant failure. The 5-year freedom from failure was 78% (95% confidence interval [CI]: 56%-100%) and overall survival was 90% (95% CI: 79% 100%). CONCLUSIONS: With no emergence of putative primaries and no isolated contralateral neck failures, this single-institution experience in p16/HPV positive SCCUP patients suggests that unilateral radiotherapy may be an underutilized management strategy. LEVELS OF EVIDENCE: 4 Laryngoscope, 128:2076 2083, 2018. PMID- 29481713 TI - Effects of Alkali-Metal Ions and Counter Ions in Sn-Beta-Catalyzed Carbohydrate Conversion. AB - Alkali-metal ions have recently been shown to strongly influence the catalytic behavior of stannosilicates in the conversion of carbohydrates. An effect of having alkali-metal ions present is a pronounced increase in selectivity towards methyl lactate. Mechanistic details of this effect have remained obscure and are herein addressed experimentally through kinetic experiments and isotope tracking. The presence of alkali-metal ions has a differential effect in competing reaction pathways and promotes the rate of carbon-carbon bond breakage of carbohydrate substrates, but decreases the rates of competing dehydration pathways. Further addition of alkali-metal ions inhibits the activity of Sn-Beta in all major reaction pathways. The alkali-metal effects on product distribution and on the rate of product formation are similar, thus pointing to a kinetic reaction control and to irreversible reaction steps in the main pathways. Additionally, an effect of the accompanying basic anions is shown, supposedly facilitating the cation exchange and eliciting a different concentration-dependent effect to that of neutral alkali-metal salts. PMID- 29481712 TI - The impact of adjuvant chemoradiotherapy timing on survival of head and neck cancers. AB - BACKGROUND: Delays in postoperative head and neck (HN) radiotherapy have been associated with decreased overall survival; however, the impact of delays in postoperative HN chemoradiotherapy remains undefined. METHODS: All patients with nonmetastatic HN cancer (oral cavity, oropharynx, larynx, hypopharynx) who underwent curative intent surgery and received adjuvant chemoradiotherapy were identified from the National Cancer Database (2005-2012). Overall treatment time (OTT) was defined as the time from surgery to the end of radiation therapy. Statistical methods included Cox proportional hazards modeling, which adjusted for clinicopathologic, demographic, and socioeconomic factors. Recursive partitioning analysis (RPA) identified the optimal threshold of OTT via conditional inference trees to estimate the greatest differences in overall survival (OS) on the basis of randomly selected training and validation sets. RESULTS: A total of 16,733 patients were included, with a median follow-up of 37 months. Median OS for OTT in a predefined threshold of <= 13 weeks was 10.1 years (95% confidence interval [CI], 9.8 years; not reached) compared with 8.7 years (95% CI, 8.2-9.2 years) in > 13 weeks. On multivariate analysis, OTT of > 13 weeks versus <= 13 weeks independently increased mortality risk (hazard ratio, 1.10; 95% CI, 1.04-1.17; P = < 0.001). RPA identified an optimal OTT threshold of 97 days (interquartile range: 96-98 days). The OTT threshold of 97 days was confirmed in a full Cox regression model estimating the risk of death according to overall treatment time as a continuous variable. CONCLUSION: In this large hospital-based national data, an OTT of greater than approximately 14 weeks most consistently increased the risk of death. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:2326-2332, 2018. PMID- 29481714 TI - Antileishmanial Activity, Cytotoxicity and Mechanism of Action of Clioquinol Against Leishmania infantum and Leishmania amazonensis Species. AB - In this study, a quinoline derivate, clioquinol (5-chloro-7-iodoquinolin-8-ol), was evaluated against Leishmania amazonensis and Leishmania infantum promastigotes and amastigotes. The cytotoxicity in murine macrophages and human red blood cells, as well as the efficacy in treating infected macrophages and the inhibition of infection using pre-treated parasites were also evaluated. Results showed that clioquinol inhibited L. amazonensis and L. infantum promastigotes with effective concentration 50% (EC50 ) values of 2.55 +/- 0.25 and 1.44 +/- 0.35 MUg/mL, respectively, and of 1.88 +/- 0.13 and 0.98 +/- 0.17 MUg/mL against axenic amastigotes, respectively. The cytotoxic EC50 concentrations of clioquinol in murine macrophages and human red blood cells were, respectively, 255 +/- 23 and 489 +/- 20 MUg/mL. With these results, the selectivity index was calculated, showing values of 99.9 and 177.1 against promastigotes, respectively, and of 135.6 and 260.1 against axenic amastigotes, respectively. Significant reductions in the percentage of infected macrophages after treatment using clioquinol were also observed, as well as when parasites were pre-treated with clioquinol and used to infect murine macrophages. The mechanism of action of clioquinol was investigated in L. amazonensis, and results revealed morphological and biochemical alterations in the clioquinol-treated parasites, including reduction in cell volume, loss of mitochondrial membrane potential, increase in the ROS production and rupture of the plasma membrane. The externalization of phosphatidylserine (PS) at the cell surface was evaluated in treated parasites that had been doubly labelled with annexin and propidium iodide (PI). The results showed no significant difference for PS exposure when compared to the untreated control, although a significant increase in the PI/annexin V-labelled cell population was found in the treated parasites. Results suggest that clioquinol induces a discontinuity of the parasite membrane, possibly related to a characteristic event of cell death caused by necrosis. This study demonstrates, for the first time, the antileishmanial activity of clioquinol against two relevant Leishmania species and suggests that the mitochondria of the parasites may be a possible biological target leading to parasite necrosis. Our findings suggest that clioquinol may have a potential application in treatment of leishmaniasis and further studies should be performed in infected mammalian hosts. PMID- 29481715 TI - Association between serum total homocysteine and arterial stiffness in adults: a community-based study. AB - Both increased arterial stiffness and higher total homocysteine (tHcy) are associated with an elevated risk for cardiovascular disease. However, the relationship between tHcy and arterial stiffness is still inconclusive. The authors aimed to test the relationship of tHcy with carotid-femoral pulse wave velocity (cfPWV) and examine the possible effect modifiers in adults. A study was conducted from July to September 2016 in Jiangsu Province, China. A total of 16 644 participants were enrolled in the final analysis. Increased arterial stiffness is defined as a cfPWV >=10 m/s. Overall, there was a positive association between tHcy and cfPWV levels (per 5-MUmol/L tHcy increase: beta = 0.10; 95% confidence interval [CI], 0.08-0.13) and increased arterial stiffness (per 5-MUmol/L tHcy increase: odds ratio, 1.11; 95% CI, 1.07-1.14). Compared with participants with tHcy <10 MUmol/L, the significantly higher cfPWV levels were observed in those with tHcy >=15 MUmol/L (beta = 0.37; 95% CI, 0.28-0.47). Accordingly, a higher prevalence of increased arterial stiffness was found in patients with tHcy10 to <15 MUmol/L (odds ratio, 1.18; 95% CI, 1.05-1.33) and tHcy >=15 MUmol/L (odds ratio, 1.50; 95% CI, 1.32-1.71) as compared with participants with tHcy <10 MUmol/L. Furthermore, the stronger positive association was found in participants who were older (>=60 years, P for interaction = .008), had low body mass index (<25 kg/m2 , P for interaction = .026), high systolic blood pressure levels (>=145 mm Hg [median], P for interaction = .048), or diabetes mellitus (P for interaction = .045). The present study demonstrated that serum tHcy concentrations were positively associated with cfPWV and the prevalence of increased arterial stiffness. These results suggest that the cardiovascular effects of tHcy may partly be mediated through arterial stiffness. PMID- 29481716 TI - Synthesis of (-)-Hebelophyllene E: An Entry to Geminal Dimethyl-Cyclobutanes by [2+2] Cycloaddition of Alkenes and Allenoates. AB - The first synthesis of hebelophyllene E is presented, along with assignment of its previously unknown relative configuration through synthesis of epi-ent hebelophyllene E. Development of a catalytic enantioselective [2+2] cycloaddition of alkenes and allenoates provides access to the required chiral geminal dimethylcyclobutanes. Key to its success is the identification of a novel oxazaborolidine catalyst which promotes the cycloaddition in high enantioselectivities with good functional-group tolerance (9 examples, up to 97:3 e.r.). Thus, a late-stage cycloaddition using a fully functionalized alkene, followed by a diastereoselective reduction allows a concise entry to this class of natural products. PMID- 29481717 TI - Impella removal with access site salvage. AB - Removal of the percutaneous Impella CP assist device while maintaining femoral artery access site is not always possible. This case highlights a technique of Impella removal with access site salvage. PMID- 29481718 TI - Long-term efficacy of drug coated balloons compared with new generation drug eluting stents for the treatment of de novo coronary artery lesions. AB - BACKGROUND: Studies comparing drug coated balloons (DCB) with new generation drug eluting stents (nDES) for the treatment of de novo coronary artery lesions are lacking. METHODS: From 2009 to 2016, DCB or nDES used for treatment of de novo coronary lesions at our institution were included, in total 1,197 DEB and 6,458 nDES. We evaluated target lesions restenosis (TLR) and definite target lesion thrombosis (TLT). Propensity score modeling were utilized to study adjusted associations between treatment and outcomes. RESULTS: Median follow-up was 901days. DCB patients were older, with higher cardiovascular risk profile. Bailout stenting after DCB was performed in 8% of lesions. The cumulative rate of TLR and TLT was 7.0 vs. 4.9% and 0.2 vs. 0.8% for DCB vs. nDES, respectively. Before adjustment, DCB was associated with a higher risk of TLR [hazard ratio (HR) 1.44; 95% confidence interval (CI) 1.07-1.94] and a non-significantly lower risk of TLT (HR 0.30; 95% CI 0.07-1.24), compared to nDES. In the propensity matched population consisted of 1,197 DCB and 1,197 nDES, treatment with DCB was associated with similar risk for TLR (adjusted HR 1.05; 95% CI 0.72-1.53) but significantly lower risk for TLT (adjusted HR 0.18; 95% CI 0.04-0.82) compared to nDES. CONCLUSIONS: Treatment with DCB was associated with a similar risk of TLR and a lower risk of definite TLT compared with nDES. In selected cases, DCB appears as a good alternative to nDES for the treatment of de novo coronary lesions. PMID- 29481719 TI - Dual-Functional Small Molecules for Generating an Efficient Cytochrome P450BM3 Peroxygenase. AB - We report a unique strategy for the development of a H2 O2 -dependent cytochrome P450BM3 system, which catalyzes the monooxygenation of non-native substrates with the assistance of dual-functional small molecules (DFSMs), such as N-(omega imidazolyl fatty acyl)-l-amino acids. The acyl amino acid group of DFSM is responsible for bounding to enzyme as an anchoring group, while the imidazolyl group plays the role of general acid-base catalyst in the activation of H2 O2 . This system affords the best peroxygenase activity for the epoxidation of styrene, sulfoxidation of thioanisole, and hydroxylation of ethylbenzene among those P450-H2 O2 system previously reported. This work provides the first example of the activation of the normally H2 O2 -inert P450s through the introduction of an exogenous small molecule. This approach improves the potential use of P450s in organic synthesis as it avoids the expensive consumption of the reduced nicotinamide cofactor NAD(P)H and its dependent electron transport system. This introduces a promising approach for exploiting enzyme activity and function based on direct chemical intervention in the catalytic process. PMID- 29481720 TI - The SET protein promotes androgen production in testicular Leydig cells. AB - Approximately 40% of middle-aged men exhibit symptoms of late-onset hypogonadism (LOH). However, the mechanism of androgen deficiency is still currently unclear. As shown in our previous studies, the SET protein is expressed in testicular Leydig cells and ovarian granule cells. This study was designed to investigate the effect of the SET protein on androgen production in Leydig cells. The AdCMV/SET and AdH1siRNA/SET adenoviruses were individually transduced into a cultured mouse Leydig cell line (mLTC-1) with or without human chorionic gonadotropin (HCG) stimulation in vitro. The primary mouse Leydig cells were used to confirm the main data from mLTC-1 cells. The SET protein was expressed in the cytoplasm and nucleus of mLTC-1 cells. Testosterone production was significantly increased in mLTC-1 cells overexpressing the SET protein compared with the control group (p < 0.05), whereas testosterone production was significantly decreased in the SET knockdown mLTC-1 cells (p < 0.05). Consistent with the testosterone levels, the expression levels of the steroidogenic acute regulatory (StAR) and cytochrome P450c17alpha-hydroxylase (CYP17a1) mRNAs and proteins synchronously changed according to the expression level of the SET protein. Interestingly, the expression of the SET protein was significantly increased in the mLTC-1 cells stimulated with 0.04 and 0.1 U/mL hCG. In the mLTC-1 cells transfected with AdH1siRNA/SET and concurrently stimulated with 0.1 U/mL hCG, both testosterone production and StAR expression were significantly lower than in the cells without SET knockdown (p < 0.05). In conclusion, the SET protein participates in regulating testosterone production by increasing the expression of StAR and CYP17a1, and it may be a downstream factor of the classic luteinizing hormone (LH)/luteinizing hormone receptor (LHR) signaling pathway. This study improves our understanding of the intracellular mechanism of testicular steroidogenesis and the pathophysiological mechanism of LOH in the aging male. PMID- 29481722 TI - Coronary sinus perforation during reducer implantation. AB - Coronary Sinus Reducer (Neovasc, Inc., Richmond B.C., Canada) has shown to be an effective and safe treatment option for the treatment of refractory angina. Until now, a few number of complications related to its implantation have been reported. Coronary sinus perforation is a rare complication, more often related to cardiac surgery procedures. We report the first case of coronary sinus perforation after a sinus Reducer implantation. PMID- 29481721 TI - Intramuscular Fat Accumulation and Associations With Body Composition, Strength, and Physical Functioning in Patients With Rheumatoid Arthritis. AB - OBJECTIVE: Rheumatoid arthritis (RA) is associated with adverse body composition profiles and low muscle density due to the accumulation of intramuscular fat. Linear regression was used to assess differences between RA patients and controls and to determine associations between muscle density, strength, and physical functioning. METHODS: Patients with RA, ages 18-70 years, and healthy control subjects underwent whole-body dual x-ray absorptiometry and peripheral quantitative computed tomography, in order to quantify the appendicular lean mass index (ALMI) and the fat mass index (FMI), visceral fat area, and muscle density. Dynamometry was used to measure hand grip strength and muscle strength at the knee and lower leg. Disability and physical functioning were measured using the Health Assessment Questionnaire (HAQ) and the Short Physical Performance Battery (SPPB). Linear regression analyses were performed to assess differences related to RA and associations between muscle density, strength, and function. RESULTS: The study group included 103 patients with RA (51 men) and 428 healthy control subjects. Among patients with RA, low muscle density was associated with higher disease activity, C-reactive protein and interleukin-6 levels, greater total and visceral fat area, lower ALMI Z scores, physical inactivity, and long-term use of glucocorticoids (>1 year). Patients with low ALMI Z scores had lower muscle density Z scores compared with reference participants with similarly low ALMI scores. Low muscle density was independently associated with lower muscle strength, higher HAQ scores, and lower SPPB scores, after adjustment for ALMI and FMI Z scores. CONCLUSION: The low muscle density observed in patients with RA was associated with low muscle mass, excess adiposity, poor strength, and greater disability. Interventions to address poor muscle quality could potentially affect important functional outcomes. PMID- 29481724 TI - Incidence, predictors and longer-term impact of troponin elevation following hybrid chronic total occlusion percutaneous coronary intervention. AB - OBJECTIVES: We examined the incidence of periprocedural cardiac enzyme rise (PCER) [troponin T (TnT) or high-sensivity (hs)TnT >5* the upper limit of normal (ULN)] and periprocedural myocardial infarction (PMI), predictors of PCER and impact of PCER on the longer-term major adverse cardiac events (MACE) following hybrid chronic total occlusion (CTO) percutaneous coronary intervention (PCI). BACKGROUND: PCER and PMI after CTO PCI, risk factors for PCER and its impact on longer-term MACE are not fully understood. METHODS: Among 469 CTO PCI cases performed between 01/2010 and 12/2015, next-day TnT or hsTnT was measured in 455 (97%). We examined the incidence of PCER and PMI (with clinical context or TnT >=70* ULN). In 269 successful cases who had TnT measured, longer-term MACE (death, MI or target-vessel revascularisation/re-occlusion) were assessed. RESULTS: Overall, 420 CTOs (92.3%) were treated successfully. PCER was documented in 34%, while PMI in 2.9%. By multivariable analyses, higher J-CTO score (OR = 1.3 per point; P = 0.002), lower creatinine clearance (OR = 1.01 per each cc/min decrease; P < 0.0001) and recent MI (OR = 2.4; P = 0.007) were independent pre PCI risk factors for PCER. Among procedural variables, retrograde approach (OR = 1.9; P = 0.014) and procedure duration (OR = 1.2 per 30 min; P = 0.007) were associated with PCER. At a median follow-up of 396 days following successful CTO PCI, PCER was not associated with higher MACE (9.3% vs. 8.1%; P = 0.60), and was not a predictor of MACE in multivariable analysis. CONCLUSIONS: PCER following hybrid CTO PCI is detected in 1/3 of patients. However, true PMI occurs in 2.9%. PCER does not predict adverse long-term outcomes. PMID- 29481723 TI - Phenome-Wide Association Studies Uncover a Novel Association of Increased Atrial Fibrillation in Male Patients With Systemic Lupus Erythematosus. AB - OBJECTIVE: Phenome-wide association studies (PheWAS) scan across billing codes in the electronic health record (EHR) and re-purpose clinical EHR data for research. In this study, we examined whether PheWAS could function as an EHR-based discovery tool for systemic lupus erythematosus (SLE) and identified novel clinical associations in male versus female patients with SLE. METHODS: We used a de-identified version of the Vanderbilt University Medical Center EHR, which includes more than 2.8 million subjects. We performed EHR-based PheWAS to compare SLE patients with age-, sex-, and race-matched control subjects and to compare male SLE patients with female SLE patients, controlling for multiple testing using a false discovery rate (FDR) P value of 0.05. RESULTS: We identified 1,097 patients with SLE and 5,735 matched control subjects. In a comparison of patients with SLE and matched controls, SLE patients were shown to be more likely to have International Classification of Diseases, Ninth Revision codes related to the SLE disease criteria. In the PheWAS of male versus female SLE patients, with adjustment for age and race, male patients were shown to be more likely to have atrial fibrillation (odds ratio 4.50, false discovery rate P = 3.23 * 10-3 ). Chart review confirmed atrial fibrillation, with the majority of patients developing atrial fibrillation after the SLE diagnosis and having multiple risk factors for atrial fibrillation. After adjustment for age, sex, race, and coronary artery disease, SLE disease status was shown to be significantly associated with atrial fibrillation (P = 0.002). CONCLUSION: Using PheWAS to compare male and female patients with SLE, we identified a novel association of an increased incidence of atrial fibrillation in male patients. SLE disease status was shown to be independently associated with atrial fibrillation, even after adjustment for age, sex, race, and coronary artery disease. These results demonstrate the utility of PheWAS as an EHR-based discovery tool for SLE. PMID- 29481725 TI - Prescribing for Children with Rheumatic Disease: Perceived Treatment Approaches between Pediatric and Adult Rheumatologists. AB - According to the Arthritis Foundation there are more than 300,000 children in the US with juvenile arthritis and there are many more children with musculoskeletal conditions that could benefit from rheumatologic care. Yet there are only about 350 board certified pediatric rheumatologists in this country and 8 states do not have a single board certified practitioner. As a consequence over 75% of children with rheumatic disease are cared for by an adult certified rheumatologist. This article is protected by copyright. All rights reserved. PMID- 29481726 TI - A Highly Active N-Heterocyclic Carbene Manganese(I) Complex for Selective Electrocatalytic CO2 Reduction to CO. AB - We report here the first purely organometallic fac-[MnI (CO)3 (bis-Me NHC)Br] complex with unprecedented activity for the selective electrocatalytic reduction of CO2 to CO, exceeding 100 turnovers with excellent faradaic yields (etaCO ~95 %) in anhydrous CH3 CN. Under the same conditions, a maximum turnover frequency (TOFmax ) of 2100 s-1 was measured by cyclic voltammetry, which clearly exceeds the values reported for other manganese-based catalysts. Moreover, the addition of water leads to the highest TOFmax value (ca. 320 000 s-1 ) ever reported for a manganese-based catalyst. A MnI tetracarbonyl intermediate was detected under catalytic conditions for the first time. PMID- 29481727 TI - Off-label diagnostic and therapeutic utilization of perforated monorail balloon catheters in the catheterization laboratory. PMID- 29481728 TI - Diffuse Idiopathic Skeletal Hyperostosis-On the Wrong Side? PMID- 29481729 TI - Total Synthesis of Tambromycin by Combining Chemocatalytic and Biocatalytic C-H Functionalization. AB - A combination of genomic and metabolomic approaches recently resulted in the identification of a nonribosomal tetrapeptide tambromycin, which possesses promising antiproliferative activity and several unusual structural features, including a densely substituted indole, a methyloxazoline ring, and an unusual pyrrolidine-containing amino acid called tambroline. In this work, we identify a concise synthetic route to access tambromycin, which relies on the strategic use of biocatalytic and chemocatalytic C-H functionalization methods to prepare two key precursors to the natural product in an efficient and scalable manner. The success of our study highlights the benefits of applying the principles of biocatalytic retrosynthesis as well as C-H functionalization logic to the synthesis of complex molecular scaffolds. PMID- 29481730 TI - Semen quality associated with subsequent hospitalizations - Can the effect be explained by socio-economic status and lifestyle factors? AB - Semen quality is suggested to be a universal biomarker for future health. Previous studies have mostly been registry based excluding the possibility to address the importance of lifestyle, fertility status, health and socio-economic status. We aimed to investigate whether the association between semen quality and subsequent risk of hospitalization could be explained by differences in occupation, education, fertility, cryptorchidism, BMI or smoking; 1423 men with first semen sample at Fertility Clinic, Frederiksberg Hospital, Denmark, from 1977 to 2010 responded to a questionnaire in 2012 about current health, lifestyle, educational level and occupation. They were followed in the Danish National Patient Registry to first-time hospitalizations using ICD-8 and ICD-10 classification. Data were analysed by Cox proportional hazard regression models to adjust for the possible confounding factors. We found a significant higher risk of being hospitalized with decreasing sperm concentrations (0-15 mill/mL: HR1.78, 95% CI:1.51-2.09; 16-50 mill/mL: HR 1.37 95% CI: 1.17-1.60; 51-100 mill/mL: HR1.25 95% CI: 1.07-1.45). Same significant association of being hospitalized with decreasing total sperm counts was seen. The dose-response increase in risk in hospitalization with decreasing sperm concentration and total sperm count remained constant after further individual adjustment for occupation, marital status, fertility, cryptorchidism, BMI or smoking. The association between semen quality and subsequent morbidity was not explained by differences in lifestyle, behavioural or fertility status. We were unable to adjust for all possible confounders simultaneously due to limited sample size, and reverse causation is a possible explanation as information about education and lifestyle was obtained after semen analysis and hospitalizations occurred and may have changed as consequence of both. Semen quality may be a universal biomarker for future health not explained by lifestyle and socio-economic status, but this needs to be addressed further in future studies. PMID- 29481731 TI - Transcatheter aortic valve implantation via the superficial femoral artery: An underused access route? AB - Common femoral arterial (CFA) access is the most commonly used access route for transcatheter aortic valve implantation (TAVI). In majority of cases, it is easily accessible percutaneously without requiring surgical cut down. However, in patients with high body mass index (BMI) or central obesity, it can be more than 8-10 cm below the skin making the procedure more technically demanding and satisfactory hemostasis more difficult to achieve. The superficial femoral artery (SFA) lies only a few centimeters distal to the CFA with little compromise on vessel caliber, yet can allow more suitable access in certain patients with a high BMI. We describe three cases in which SFA access was successfully used as the primary delivery route for TAVI. PMID- 29481732 TI - Ultrasonographic Efficacy of Biologic and Targeted Synthetic Disease-Modifying Antirheumatic Drug Therapy in Rheumatoid Arthritis From a Multicenter Rheumatoid Arthritis Ultrasound Prospective Cohort in Japan. AB - OBJECTIVE: To explore the variables associated with initial favorable power Doppler (PD) ultrasound (US) response induced by biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in patients with rheumatoid arthritis (RA). METHODS: We have been prospectively investigating the course of active RA patients using US after the introduction of b/tsDMARDs in the Kyushu region of Japan since June 2013. A total of 150 patients have completed the first 6 months of observation at present and have been evaluated. US was assessed in 22 joints of bilateral hands using gray-scale and PD images on a scale from 0-3. The sum of these scores was used as the indicator of US disease activity. We defined PD remission as attaining a total PD score of 0 at 6 months and investigated the associated variables by multivariate logistic regression analysis. RESULTS: The total PD and gray-scale scores and the clinical composite measures significantly improved at 6 months, whereas these reductions were less in bDMARD switchers as compared with bDMARD-naive patients. Multivariate logistic regression analysis showed that short disease duration, the absence of any previous use of bDMARDs, and low total PD scores at baseline were independent predictors of PD remission at 6 months. CONCLUSION: This present prospective US cohort has for the first time shown the variables that are associated with initial PD response to b/tsDMARDs. PMID- 29481733 TI - Mycotic aneurysm of the hepatic artery in pediatric liver transplantation: A case series and literature review. AB - Mycotic aneurysm of the hepatic artery (HA) is a rare, unpredictable, and potentially lethal complication of liver transplantation (LT). Pediatric LT is not exempt from it but the related literature is rather scanty. We present our experience with post-LT mycotic aneurysm of the HA in pediatric age, describing four cases occurred with a special focus on the possible risk factors for its development and a proposal for the management of high-risk recipients. PMID- 29481734 TI - The neuropeptide orexin A - search for its possible role in regulation of steroidogenesis in adult mice testes. AB - Orexin A, a hypothalamic neuropeptide, regulates food intake and sleep-wake cycle by binding to orexin receptor 1. Besides brain, orexin A and orexin receptor 1 are also present in peripheral organs. In our earlier studies, localization and expression of orexin A and orexin receptor 1 have been shown in adult mouse testis, and further their role in testicular development in neonatal mouse was also demonstrated. In this study, role of orexin A and orexin receptor 1 in the testis of adult mouse by blocking binding of orexin A to orexin receptor 1 using an orexin receptor 1 antagonist, SB-334867, was investigated under in vivo and ex vivo conditions. Mice were given a single bilateral intratesticular injection of the antagonist at doses of 4 and 12 MUg/mouse and were sacrificed 24 h post injection. The antagonist treatment caused degenerative changes in the seminiferous tubules in the testis and also caused alterations in steroidogenesis, with a concomitant decrease in the level of testosterone (T) and an increase in the level of 17beta-estradiol (E2 ) in serum and in testis. Further, expressions of SF1, StAR, P450scc and 17beta-HSD were downregulated, while the expressions of 3beta-HSD and P450arom were upregulated in antagonist treated mice compared with controls. Also, the oxidative stress in the testis was increased in treated mice. In ex vivo study, antagonist treatment to the testis caused a marked decrease in the level of T and an increase in the level of E2 in the media, accompanied by downregulated expression of SF1, StAR, P450scc and 17beta-HSD and an upregulation in the expression of 3beta-HSD and P450arom, indicating a direct role of orexin A in regulation of testicular steroidogenesis. The results of ex vivo study supported the findings of in vivo study. In conclusion, the results suggest potential involvement of orexin A and orexin receptor 1 in regulation of steroidogenesis and spermatogenesis in the testis of adult Parkes mice. PMID- 29481735 TI - Role of Lgals9 Deficiency in Attenuating Nephritis and Arthritis in BALB/c Mice in a Pristane-Induced Lupus Model. AB - OBJECTIVE: In systemic lupus erythematosus (SLE), an autoimmune disease associated with multiple organ involvement, the development of lupus nephritis determines prognosis, and arthritis impairs quality of life. Galectin 9 (Gal-9, Lgals9) is a beta-galactoside-binding lectin that has been used for clinical application in autoimmune diseases, since recombinant Gal-9, as a ligand for T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), induces apoptosis of activated CD4+TIM-3+ Th1 cells. This study was undertaken to investigate whether deficiency of Lgals9 has beneficial or deleterious effects on lupus in a murine model. METHODS: Gal-9+/+ and Gal-9-/- female BALB/c mice were injected with pristane, and the severity of arthritis, proteinuria, and levels of autoantibody production were assessed at several time points immediately following injection. At 7 months after pristane injection, renal pathologic features, the severity of joint inflammation, and formation of lipogranulomas were evaluated. Subsets of inflammatory cells in the spleen and peritoneal lavage were characterized, and expression levels of cytokines from peritoneal macrophages were analyzed. RESULTS: Lgals9 deficiency protected against the development of immune complex glomerulonephritis, arthritis, and peritoneal lipogranuloma formation in BALB/c mice in this murine model of pristane-induced lupus. The populations of T cell subsets and B cells in the spleen and peritoneum were not altered by Lgals9 deficiency in pristane-injected BALB/c mice. Furthermore, Lgals9 deficiency protected against pristane-induced lupus without altering the Toll-like receptor 7-type I interferon pathway. CONCLUSION: Gal-9 is required for the induction and development of lupus nephritis and arthritis in this murine model of SLE. The results of the current investigation provide a potential new strategy in which antagonism of Gal-9 may be beneficial for the treatment of nephritis and arthritis in patients with SLE through targeting of activated macrophages. PMID- 29481736 TI - Inflammation Intensity-Dependent Expression of Osteoinductive Wnt Proteins Is Critical for Ectopic New Bone Formation in Ankylosing Spondylitis. AB - OBJECTIVE: To investigate the molecular mechanism underlying inflammation-related ectopic new bone formation in ankylosing spondylitis (AS). METHODS: Spinal tissues and sera were collected from patients with AS and healthy volunteers and examined for the expression of Wnt proteins. An in vitro cell culture system mimicking the local inflammatory microenvironment of bone-forming sites was established to study the relationship between inflammation and Wnt expression, the regulatory mechanism of inflammation-induced Wnt expression, and the role of Wnt signaling in new bone formation. Modified collagen-induced arthritis (CIA) and proteoglycan-induced spondylitis (PGIS) animal models were used to confirm the key findings in vivo. RESULTS: The levels of osteoinductive Wnt proteins were increased in sera and spinal ligament tissues from patients with AS. Constitutive low-intensity tumor necrosis factor (TNF) stimulation, but not short-term or high intensity TNF stimulation, induced persistent expression of osteoinductive Wnt proteins and subsequent bone formation through NF-kappaB (p65) and JNK/activator protein 1 (c-Jun) signaling pathways. Furthermore, inhibition of either the Wnt/beta-catenin or Wnt/protein kinase Cdelta (PKCdelta) pathway significantly suppressed new bone formation. The increased expression of Wnt proteins was confirmed in both the modified CIA and PGIS models. A kyphotic and ankylosing phenotype of the spine was seen during long-term observation in the modified CIA model. Inhibition of either the Wnt/beta-catenin or Wnt/PKCdelta signaling pathway significantly reduced the incidence and severity of this phenotype. CONCLUSION: Inflammation intensity-dependent expression of osteoinductive Wnt proteins is a key link between inflammation and ectopic new bone formation in AS. Activation of both the canonical Wnt/beta-catenin and noncanonical Wnt/PKCdelta pathways is required for inflammation-induced new bone formation. PMID- 29481738 TI - Coulomb Fission in Multiply-Charged Ammonia Clusters: Accurate Measurements of the Rayleigh Instability Limit from Fragmentation Patterns. AB - A series of experiments have been undertaken on the fragmentation of multiply charged ammonia clusters, (NH3) nz+, where z <= 8 and n <= 850, to establish Rayleigh instability limits, whereby clusters at certain critical sizes become unstable due to Coulomb repulsion between the resident charges. Experimental results on size-selected clusters are found to be in excellent agreement with theoretical predictions of Rayleigh instability limits at all values of the charge. Electrostatic theory has been used to help identify fragmentation patterns on the assumption that the clusters separate into two dielectric spheres, and the predicted Coulomb repulsion energies used to establish pathways and the sizes of cluster fragments. The results show that fragmentation is very asymmetric in terms of both the numbers of molecules involved and the amount of charge each fragment accommodates. For clusters carrying a charge <=+4, the results show that fragmentation proceeds via the loss of small, singly charged clusters. When clusters carry a charge of +5 or more, the experimental observations suggest a marked switch in behavior. Although the laboratory measurements equate to fragmentation via the loss of a large dication cluster, electrostatic theory supports an interpretation that involves the sequential loss of two smaller, singly charged clusters possibly accompanied by the extensive evaporation of neutral molecules. It is suggested that this change in fragmentation pattern is driven by the channelling of Coulomb repulsion energy into intermolecular modes within these larger clusters. Overall, the results appear to support the ion evaporation model that is frequently used to interpret electrospray experiments. PMID- 29481739 TI - Omics Advances in Ecotoxicology. AB - Toxic substances in the environment generate adverse effects at all levels of biological organization from the molecular level to community and ecosystem. Given this complexity, it is not surprising that ecotoxicologists have struggled to address the full consequences of toxic substance release at ecosystem level, due to the limits of observational and experimental tools to reveal the changes in deep structure at different levels of organization. -Omics technologies, consisting of genomics and ecogenomics, have the power to reveal, in unprecedented detail, the cellular processes of an individual or biodiversity of a community in response to environmental change with high sample/observation throughput. This represents a historic opportunity to transform the way we study toxic substances in ecosystems, through direct linkage of ecological effects with the systems biology of organisms. Three recent examples of -omics advance in the assessment of toxic substances are explored here: (1) the use of functional genomics in the discovery of novel molecular mechanisms of toxicity of chemicals in the environment; (2) the development of laboratory pipelines of dose dependent, reduced transcriptomics to support high-throughput chemical testing at the biological pathway level; and (3) the use of eDNA metabarcoding approaches for assessing chemical effects on biological communities in mesocosm experiments and through direct observation in field monitoring. -Omics advances in ecotoxicological studies not only generate new knowledge regarding mechanisms of toxicity and environmental effect, improving the relevance and immediacy of laboratory toxicological assessment, but can provide a wholly new paradigm for ecotoxicology by linking ecological models to mechanism-based, systems biology approaches. PMID- 29481740 TI - GAtor: A First-Principles Genetic Algorithm for Molecular Crystal Structure Prediction. AB - We present the implementation of GAtor, a massively parallel, first-principles genetic algorithm (GA) for molecular crystal structure prediction. GAtor is written in Python and currently interfaces with the FHI-aims code to perform local optimizations and energy evaluations using dispersion-inclusive density functional theory (DFT). GAtor offers a variety of fitness evaluation, selection, crossover, and mutation schemes. Breeding operators designed specifically for molecular crystals provide a balance between exploration and exploitation. Evolutionary niching is implemented in GAtor by using machine learning to cluster the dynamically updated population by structural similarity and then employing a cluster-based fitness function. Evolutionary niching promotes uniform sampling of the potential energy surface by evolving several subpopulations, which helps overcome initial pool biases and selection biases (genetic drift). The various settings offered by GAtor increase the likelihood of locating numerous low-energy minima, including those located in disconnected, hard to reach regions of the potential energy landscape. The best structures generated are re-relaxed and re ranked using a hierarchy of increasingly accurate DFT functionals and dispersion methods. GAtor is applied to a chemically diverse set of four past blind test targets, characterized by different types of intermolecular interactions. The experimentally observed structures and other low-energy structures are found for all four targets. In particular, for Target II, 5-cyano-3-hydroxythiophene, the top ranked putative crystal structure is a Z' = 2 structure with P1 symmetry and a scaffold packing motif, which has not been reported previously. PMID- 29481741 TI - Celecoxib-Induced Self-Assembly of Smart Albumin-Doxorubicin Conjugate for Enhanced Cancer Therapy. AB - Recent years have witnessed the great contributions that drug combination therapy has made for enhanced cancer therapy. However, because of the complicated pharmacokinetics of combined drug formulations, the majority of combination strategies show severe adverse effects at high dosage and poor biodistribution in vivo. To overcome these deficiencies and achieve enhanced cancer therapy, we put forward a method to construct a smart albumin-based nanoplatform, denoted as K237 HSA-DC, for codelivery of cyclooxygenase-2 (COX-2) inhibitor (celecoxib) and chemotherapeutic agent (doxorubicin, DOX). Both in vitro and in vivo studies indicate that K237-HSA-DC exhibits the best therapeutic efficacy on tumor cells compared with all the other formulations. Moreover, K237-HSA-DC shows fewer side effects on normal organs in contrast to other formulations. To understand the reasons behind the improved drug efficacy in depth, we performed a cell metabonomics-based mechanism study and found that celecoxib could enhance the inhibitory effect of DOX on the transport of glucose into cells and then lead to subsequent significant energy metabolism inhibition. Considering the above mentioned advantages of K237-HSA-DC, we believe the smart albumin-based nanoplatform can serve as a promising drug delivery system for enhanced cancer therapy. PMID- 29481742 TI - Dipole-Bound Anions of Intramolecular Complexes. AB - Dipole-bound molecular anions are often envisioned as unperturbed neutral, polar molecules with single excess electrons. We report the observation of intramolecular structural distortions within silatrane molecules due to the formation of their dipole-bound anions. The combination of Rydberg electron transfer-anion photoelectron spectroscopy (RET-PES) and ab initio computational methodologies (CCSD and MP2) was used to study 1-hydro- (HS) and 1-fluoro- (FS) silatranes and their dipole bound anions, HS- and FS-. The vertical detachment energies (VDEs) of HS- and FS- were measured to be 48 and 93 meV, respectively. Ab initio calculations accurately reproduced these VDE values as well as their photoelectron spectral profiles. This work revealed significant shortening (by ~0.1 A) of dative Si <- N bond lengths when HS and FS formed dipole-bound anions, HS- and FS-. Detailed computational (Franck-Condon) analyses explained the absence of vibrational features in the photoelectron spectra of HS- and FS-. PMID- 29481737 TI - Subcutaneous Abatacept in Patients With Polyarticular-Course Juvenile Idiopathic Arthritis: Results From a Phase III Open-Label Study. AB - OBJECTIVE: To investigate the pharmacokinetics, effectiveness, and safety of subcutaneous (SC) abatacept treatment over 24 months in patients with polyarticular-course juvenile idiopathic arthritis (JIA). METHODS: In this phase III, open-label, international, multicenter, single-arm study, patients with polyarticular JIA (cohort 1, ages 6-17 years and cohort 2, ages 2-5 years) in whom treatment with >=1 disease-modifying antirheumatic drug was unsuccessful received weight-tiered SC abatacept weekly: 10 to <25 kg (50 mg), 25 to <50 kg (87.5 mg), >=50 kg (125 mg). Patients who had met the JIA-American College of Rheumatology 30% improvement criteria (achieved a JIA-ACR 30 response) at month 4 were given the option to continue SC abatacept to month 24. The primary end point was the abatacept steady-state serum trough concentration (Cminss ) in cohort 1 at month 4. Other outcome measures included JIA-ACR 30, 50, 70, 90, 100, and inactive disease status, the median Juvenile Arthritis Disease Activity Score in 71 joints using the C-reactive protein level (JADAS-71-CRP) over time, safety, and immunogenicity. RESULTS: The median abatacept Cminss at month 4 (primary end point) and at month 24 was above the target therapeutic exposure (10 MUg/ml) in both cohorts. The percentage of patients who had achieved JIA-ACR 30, 50, 70, 90, or 100 responses or had inactive disease responses at month 4 (intent-to-treat population) was 83.2%, 72.8%, 52.6%, 28.3%, 14.5%, and 30.1%, respectively, in cohort 1 (n = 173) and 89.1%, 84.8%, 73.9%, 58.7%, 41.3%, and 50.0%, respectively, in cohort 2 (n = 46); the responses were maintained to month 24. The median (interquartile range) JADAS-71-CRP improved from baseline to month 4: cohort 1, from 21.0 (13.5, 30.3) to 4.6 (2.1, 9.4); cohort 2, from 18.1 (14.0, 23.1) to 2.1 (0.3, 4.4). Improvements were sustained to month 24, at which time 27 of 173 patients (cohort 1) and 11 of 22 patients (cohort 2) had achieved JADAS 71-CRP remission. No unexpected adverse events were reported; 4 of 172 patients (2.3%) in cohort 1 and 4 of 46 (8.7%) in cohort 2 developed anti-abatacept antibodies, with no clinical effects. CONCLUSION: Weight-stratified SC abatacept yielded target therapeutic exposures across age and weight groups, was well tolerated, and improved polyarticular JIA symptoms over 24 months. PMID- 29481743 TI - T3NS: Three-Legged Tree Tensor Network States. AB - We present a new variational tree tensor network state (TTNS) ansatz, the three legged tree tensor network state (T3NS). Physical tensors are interspersed with branching tensors. Physical tensors have one physical index and at most two virtual indices, as in the matrix product state (MPS) ansatz of the density matrix renormalization group (DMRG). Branching tensors have no physical index, but up to three virtual indices. In this way, advantages of DMRG, in particular a low computational cost and a simple implementation of symmetries, are combined with advantages of TTNS, namely incorporating more entanglement. Our code is capable of simulating quantum chemical Hamiltonians, and we present several proof of-principle calculations on LiF, N2, and the bis(MU-oxo) and MU-eta2:eta2 peroxo isomers of [Cu2O2]2+. PMID- 29481744 TI - Can Density Matrix Embedding Theory with the Complete Activate Space Self Consistent Field Solver Describe Single and Double Bond Breaking in Molecular Systems? AB - Density matrix embedding theory (DMET) [ Phys. Rev. Lett. 2012, 109, 186404] has been demonstrated as an efficient wave-function-based embedding method to treat extended systems. Despite its success in many quantum lattice models, the extension of DMET to real chemical systems has been tested only on selected cases. Herein, we introduce the use of the complete active space self-consistent field (CASSCF) method as a correlated impurity solver for DMET, leading to a method called CAS-DMET. We test its performance in describing the dissociation of H-H single bonds in a H10 ring model system and an N?N double bond in azomethane (CH3-N?N-CH3) and pentyldiazene (CH3(CH2)4-N?NH). We find that the performance of CAS-DMET is comparable to CASSCF with different active space choices when single embedding DMET corresponding to only one embedding problem for the system is used. When multiple embedding problems are used for the system, the CAS-DMET is in good agreement with CASSCF for the geometries around the equilibrium, but not in equal agreement at bond dissociation. PMID- 29481746 TI - Environmental Risks and Challenges Associated with Neonicotinoid Insecticides. AB - Neonicotinoid use has increased rapidly in recent years, with a global shift toward insecticide applications as seed coatings rather than aerial spraying. While the use of seed coatings can lessen the amount of overspray and drift, the near universal and prophylactic use of neonicotinoid seed coatings on major agricultural crops has led to widespread detections in the environment (pollen, soil, water, honey). Pollinators and aquatic insects appear to be especially susceptible to the effects of neonicotinoids with current research suggesting that chronic sublethal effects are more prevalent than acute toxicity. Meanwhile, evidence of clear and consistent yield benefits from the use of neonicotinoids remains elusive for most crops. Future decisions on neonicotinoid use will benefit from weighing crop yield benefits versus environmental impacts to nontarget organisms and considering whether there are more environmentally benign alternatives. PMID- 29481745 TI - Modulating Antibody-Drug Conjugate Payload Metabolism by Conjugation Site and Linker Modification. AB - Previous investigations on antibody-drug conjugate (ADC) stability have focused on drug release by linker-deconjugation due to the relatively stable payloads such as maytansines. Recent development of ADCs has been focused on exploring technologies to produce homogeneous ADCs and new classes of payloads to expand the mechanisms of action of the delivered drugs. Certain new ADC payloads could undergo metabolism in circulation while attached to antibodies and thus affect ADC stability, pharmacokinetics, and efficacy and toxicity profiles. Herein, we investigate payload stability specifically and seek general guidelines to address payload metabolism and therefore increase the overall ADC stability. Investigation was performed on various payloads with different functionalities (e.g., PNU-159682 analog, tubulysin, cryptophycin, and taxoid) using different conjugation sites (HC-A118C, LC-K149C, and HC-A140C) on THIOMAB antibodies. We were able to reduce metabolism and inactivation of a broad range of payloads of THIOMAB antibody-drug conjugates by employing optimal conjugation sites (LC-K149C and HC-A140C). Additionally, further payload stability was achieved by optimizing the linkers. Coupling relatively stable sites with optimized linkers provided optimal stability and reduction of payloads metabolism in circulation in vivo. PMID- 29481747 TI - Mesoporous Hollow Ge Microspheres Prepared via Molten-Salt Metallothermic Reaction for High-Performance Li-Storage Anode. AB - Generally, Ge-based anodes are prepared by metallothermic reduction of GeO2 with Mg at 650 degrees C. Herein, a molten-salt system is developed a low-temperature metallothermic reduction of GeO2 to prepare nanostructured Ge based anode materials. Typically, mesoporous hollow Ge microspheres are prepared by reduction of GeO2 with metallic Mg in molten ZnCl2 (mp 292) at 350 degrees C. Monodispersed Ge particles are synthesized through reduction of GeO2 with Mg in molten AlCl3 (mp 192 degrees C) at 250 degrees C. The meso-porous Ge anode delivers the reversible capacity of 1291 mA h g-1 at 0.2 C after 150 cycles with a retention of 97.3%, 1217 mA h g-1 at 0.8 C after 400 cycles with a retention of 91.9%, and superior rate capability with a capacity of 673 mA h g-1 even at 10 C. Then, the reaction mechanism and full-cell performance of as-prepared Ge anodes are studied systemically. PMID- 29481748 TI - Hydrogel-Embedded Model Photocatalytic System Investigated by Raman and IR Spectroscopy Assisted by Density Functional Theory Calculations and Two Dimensional Correlation Analysis. AB - The presented study reports the synthesis and the vibrational spectroscopic characterization of different matrix-embedded model photocatalysts. The goal of the study is to investigate the interaction of a polymer matrix with photosensitizing dyes and metal complexes for potential future photocatalytic applications. The synthesis focuses on a new rhodamine B derivate and a Pt(II) terpyridine complex, which both contain a polymerizable methacrylate moiety and an acid labile acylhydrazone group. The methacrylate moieties are afterward utilized to synthesize functional model hydrogels mainly consisting of poly(ethylene glycol) methacrylate units. The pH-dependent and temperature dependent behavior of the hydrogels is investigated by means of Raman and IR spectroscopy assisted by density functional theory calculations and two dimensional correlation spectroscopy. The spectroscopic results reveal that the Pt(II) terpyridine complex can be released from the polymer matrix by cleaving the C?N bond in an acid environment. The same behavior could not be observed in the case of the rhodamine B dye although it features a comparable C?N bond. The temperature-dependent study shows that the water evaporation has a significant influence neither on the molecular structure of the hydrogel nor on the model photocatalytic moieties. PMID- 29481749 TI - Influence of Counterions on the Hydration Structure of Lanthanide Ions in Dilute Aqueous Solutions. AB - A synergic approach combining molecular dynamics (MD) simulations and X-ray absorption spectroscopy (XAS) has been used to investigate diluted (0.1 M) aqueous solutions of two lanthanide ions (Ln3+), namely, La3+ and Dy3+, with triflate, nitrate, and bis(trifluoromethylsulfonyl)imide (Tf2N-) as counterions. The different complexing ability of the three anions has been highlighted by the analysis of the MD simulations: Tf2N- does not form inner-sphere complexes, while a small amount of triflate coordinates both the La3+ and Dy3+ cations in their first solvation shell. On the other hand, the nitrate ion is almost absent in the La3+ first coordination sphere, while forming contact ion pairs with Dy3+. Both lanthanide ions are found to preferentially interact with the water molecules, and the total number of oxygen atoms coordinating the Ln3+ cations in their first solvation sphere is the same in all of the solutions, regardless of whether they belong to water molecules or to the counterion. The presence of counterions in the cation first or second shell changes neither the first shell distance nor the symmetry of the hydration complex formed in solution. The MD results have been confirmed by comparison with the Ln K-edge XAS experimental data, and the quantitative analysis of the extended X-ray absorption fine structure (EXAFS) spectra of the three salt solutions has provided a definite proof of the accuracy of the force field employed in the simulations and of the MD structural result. The anion-water and water-water hydrogen bond lifetimes have been analyzed highlighting the slow down effect of the triflate, nitrate, and Tf2N- anions on the hydrogen bond dynamics in the Ln3+ first solvation shell, with the effect being stronger in the Dy3+ solutions, due to the higher charge density of the Dy3+ ion as compared to La3+. PMID- 29481750 TI - Solvent Effects on Electronically Excited States: QM/Continuum Versus QM/Explicit Models. AB - The inclusion of solvent effects in the calculation of excited states is vital to obtain reliable absorption spectra and density of states of solvated chromophores. Here we analyze the performance of three classical approaches to describe aqueous solvent in the calculation of the absorption spectra and density of states of pyridine, tropone, and tropothione. Specifically, we compare the results obtained from quantum mechanics/polarizable continuum model (QM/PCM) versus quantum mechanics/molecular mechanics (QM/MM) in its electrostatic embedding (QM/MMee) and polarizable-embedding (QM/MMpol) fashions, against full QM computations, in which the solvent is described at the same level of theory as the chromophore. We show that QM/PCM provides very accurate results describing the excitation energies of pipi* and npi* transitions, the last ones dominated by strong hydrogen-bonding effects, for the three chromophores. The QM/MMee approach also performs very well for both types of electronic transitions, although the description of the pipi* ones is slightly worse than that obtained from QM/PCM. The QM/MMpol approach performs as well as QM/PCM for describing the energy of pipi* states, but it is not able to provide a satisfactory description of hydrogen-bonding effects on the npi* states of pyridine and tropone. The relative intensity of the absorption bands is better accounted for by the explicit-solvent models than by the continuum-solvent approach. PMID- 29481751 TI - Growth of Compact CH3NH3PbI3 Thin Films Governed by the Crystallization in PbI2 Matrix for Efficient Planar Perovskite Solar Cells. AB - As a convenient preparation technique, a two-step method, which is normally done by spin-coating CH3NH3I onto PbI2 film followed by a thermal annealing, is generally used to prepare solution-processed CH3NH3PbI3 films for planar perovskite solar cells. Here, we prepare the compact CH3NH3PbI3 thin films by the two-step method at a low temperature (<80 degrees C) and investigate the effects of PbI2 crystallization on the structure-property correlation in the CH3NH3PbI3 films. It is found that the importance of the crystallization in PbI2 matrix lies in governing the transition from the (001) plane of trigonal PbI2 to the (002) plane of tetragonal CH3NH3PbI3 in the rapid reaction process for atoms to coordinate into perovskite during spin-coating, which actually determines the morphology and the type of vacancy defects in resulting perovskite; a better crystallized PbI2 film has a much stronger ability to react with CH3NH3I solution and produces larger CH3NH3PbI3 grains with a higher crystallinity. The CH3NH3PbI3/TiO2 planar solar cell derived from a better crystallized PbI2 film exhibits significantly improved performance and stability as the result of the higher crystallinity inside the perovskite film. Moreover, it is demonstrated that the crystalline PbI2 film matrix subjected to the annealing after a slow heating process prior to contacting CH3NH3I solution is more effective for CH3NH3PbI3 formation than that with a direct annealing history. The results in this paper provide a guide for preparing high-quality CH3NH3PbI3 thin films for efficient perovskite solar cells and CH3NH3PbI3 interfacial films over the layers susceptible to temperature. PMID- 29481752 TI - Integration of Enhanced Sampling Methods with Saturation Transfer Difference Experiments to Identify Protein Druggable Pockets. AB - Saturation transfer difference (STD) is an NMR technique conventionally applied in drug discovery to identify ligand moieties relevant for binding to protein cavities. This is important to direct medicinal chemistry efforts in small molecule optimization processes. However, STD does not provide any structural details about the ligand-target complex under investigation. Herein, we report the application of a new integrated approach, which combines enhanced sampling methods with STD experiments, for the characterization of ligand-target complexes that are instrumental for drug design purposes. As an example, we have studied the interaction between StOASS-A, a potential antibacterial target, and an inhibitor previously reported. This approach allowed us to consider the ligand target complex from a dynamic point of view, revealing the presence of an accessory subpocket which can be exploited to design novel StOASS-A inhibitors. As a proof of concept, a small library of derivatives was designed and evaluated in vitro, displaying the expected activity. PMID- 29481753 TI - Reduced Near-Resonant Vibrational Coupling at the Surfaces of Liquid Water and Ice. AB - We study the resonant interaction of the OH stretch vibrations of water molecules at the surfaces of liquid water and ice using heterodyne-detected sum-frequency generation (HD-SFG) spectroscopy. By studying different isotopic mixtures of H2O and D2O, we vary the strength of the interaction, and we monitor the resulting effect on the HD-SFG spectrum of the OH stretch vibrations. We observe that the near-resonant coupling effects are weaker at the surface than in the bulk, for both water and ice, indicating that for both phases of water the OH vibrations are less strongly delocalized at the surface than in the bulk. PMID- 29481754 TI - Ultra-Coarse-Grained Models Allow for an Accurate and Transferable Treatment of Interfacial Systems. AB - Interfacial systems are fundamentally important in many processes. However, constructing coarse-grained (CG) models for such systems is a significant challenge due to their inhomogeneous nature. This problem is made worse due to the generally nontransferable nature of the interactions in CG models across different phases. In this paper, we address these challenges by systematically constructing ultra-coarse-grained (UCG) models for interfaces, in which the CG sites are allowed to have internal states. We find that a multiscale coarse grained (MS-CG) representation of a single CG site model fails to identify the directionality of a molecule and is unable to reproduce the correct phase coexistence for aspherical molecules. In contrast with conventional MS-CG models, the UCG methodology allows chemical and environmental changes to be captured by modulating the interactions between internal states. In this work, we design the internal states to depend on local particle density to distinguish different phases in liquid/vapor or liquid/liquid interfaces. These UCG models are able to capture phase coexistence and recapitulate structures, notably at state points in which the MS-CG method yields poor results. Interestingly, effective pairwise forces and potentials from the UCG models are almost identical to those of the bulk liquids that correspond to each phase, indicating that the UCG approach can provide transferable interactions. This approach is expected to be applicable to other systems that exhibit phase coexistence and also to complex macromolecular systems by modulating interactions based on local density or other order parameters to unravel the complex nature underlying heterogeneous system boundaries. PMID- 29481755 TI - Kinetics Study of Heterogeneous Bromine Release from the Reaction between Gaseous Ozone and Aqueous Bromide Solution. AB - The heterogeneous release of molecular bromine, Br2, from the reaction between gaseous ozone and aqueous bromide ion in seawater ice and sea salt aerosols is considered to be an initial source of reactive bromine species in the troposphere. Recent studies have demonstrated that the uptake of ozone by aqueous bromide solution is promoted by reactions at the gas-liquid interface. The present work investigated the heterogeneous reaction between gaseous ozone and aqueous bromide solution at atmospheric pressure and room temperature using a wetted wall flow reactor combined with a chemical ionization mass spectrometer. The emission rate of Br2 was measured as a function of gaseous ozone concentration, aqueous bromide concentration, and pH. In addition, we conducted a simple kinetics model simulation that included only bulk aqueous-phase reactions and compared the theoretical values with the experimentally determined values. The Br2 emission rates measured experimentally differ from the simulated rates at relatively high bromide concentration, as well as in the pH region of 6-9. These differences might be explained by different Br- concentration and/or deprotonation efficiency near the interface region and those in the bulk solution. PMID- 29481756 TI - Identification of Allergenic Epitopes and Critical Amino Acids of Major Allergens in Chinese Shrimp ( Penaeus chinensis) by Immunoinformatics Coupled with Competitive-Binding Strategy. AB - Chinese shrimp ( Penaeus chinensis) is widely cultured and consumed in Asia but is also a major food allergen locally. Although they may be the foundation for preventing and treating allergies, the allergenic epitopes of the major allergens tropomyosin (TM) and arginine kinase (AK) in Penaeus chinensis have not been identified. Here, we applied Immunoinfo-CB (immunoinformatics coupled with competitive-binding strategy) to address the point. Potential allergenic epitopes of TM and AK were predicted by multiple immunoinformatics tools, followed by validating with inhibitory dot-blot assay, indirect competition ELISA, and mast cell degranulation assay. Furthermore, critical amino acids in allergenic epitopes were also identified by Immunoinfo-CB. Our findings provide new insight into allergenic epitopes and critical amino acids of TM and AK responsible for the anaphylactic response. The Immunoinfo-CB therefore offers promises for characterization of IgE-binding epitopes that might be used as new targets for immunotherapy of food allergy. PMID- 29481757 TI - Layers and Multilayers of Self-Assembled Polymers: Tunable Engineered Extracellular Matrix Coatings for Neural Cell Growth. AB - Growing primary cells and tissue in long-term cultures, such as primary neural cell culture, presents many challenges. A critical component of any environment that supports neural cell growth in vivo is an appropriate 2-D surface or 3-D scaffold, typically in the form of a thin polymer layer that coats an underlying plastic or glass substrate and aims to mimic critical aspects of the extracellular matrix. A fundamental challenge to mimicking a hydrophilic, soft natural cell environment is that materials with these properties are typically fragile and are difficult to adhere to and stabilize on an underlying plastic or glass cell culture substrate. In this review, we highlight the current state of the art and overview recent developments of new artificial extracellular matrix (ECM) surfaces for in vitro neural cell culture. Notably, these materials aim to strike a balance between being hydrophilic and soft while also being thick, stable, robust, and bound well to the underlying surface to provide an effective surface to support long-term cell growth. We focus on improved surface and scaffold coating systems that can mimic the natural physicochemical properties that enhance neuronal survival and growth, applied as soft hydrophilic polymer coatings for both in vitro cell culture and for implantable neural probes and 3-D matrixes that aim to enhance stability and longevity to promote neural biocompatibility in vivo. With respect to future developments, we outline four emerging principles that serve to guide the development of polymer assemblies that function well as artificial ECMs: (a) design inspired by biological systems and (b) the employment of principles of aqueous soft bonding and self-assembly to achieve (c) a high-water-content gel-like coating that is stable over time in a biological environment and possesses (d) a low modulus to more closely mimic soft, compliant real biological tissue. We then highlight two emerging classes of thick material coatings that have successfully captured these guiding principles: layer-by-layer deposited water-soluble polymers (LbL) and silk fibroin (SF) materials. Both materials can be deposited from aqueous solution yet transition to a water-insoluble coating for long-term stability while retaining a softness and water content similar to those of biological materials. These materials hold great promise as next-generation biocompatible coatings for tissue engineers and for chemists and biologists within the biomedical field. PMID- 29481758 TI - Influence of Nonuniform Micron-Scale Strain Distributions on the Electrical Reorientation of Magnetic Microstructures in a Composite Multiferroic Heterostructure. AB - Composite multiferroic systems, consisting of a piezoelectric substrate coupled with a ferromagnetic thin film, are of great interest from a technological point of view because they offer a path toward the development of ultralow power magnetoelectric devices. The key aspect of those systems is the possibility to control magnetization via an electric field, relying on the magneto-elastic coupling at the interface between the piezoelectric and the ferromagnetic components. Accordingly, a direct measurement of both the electrically induced magnetic behavior and of the piezo-strain driving such behavior is crucial for better understanding and further developing these materials systems. In this work, we measure and characterize the micron-scale strain and magnetic response, as a function of an applied electric field, in a composite multiferroic system composed of 1 and 2 MUm squares of Ni fabricated on a prepoled [Pb(Mg1/3Nb2/3)O3]0.69-[PbTiO3]0.31 (PMN-PT) single crystal substrate by X-ray microdiffraction and X-ray photoemission electron microscopy, respectively. These two complementary measurements of the same area on the sample indicate the presence of a nonuniform strain which strongly influences the reorientation of the magnetic state within identical Ni microstructures along the surface of the sample. Micromagnetic simulations confirm these experimental observations. This study emphasizes the critical importance of surface and interface engineering on the micron-scale in composite multiferroic structures and introduces a robust method to characterize future devices on these length scales. PMID- 29481759 TI - Design and Synthesis of Novel Deuterated Ligands Functionally Selective for the gamma-Aminobutyric Acid Type A Receptor (GABAAR) alpha6 Subtype with Improved Metabolic Stability and Enhanced Bioavailability. AB - Recent reports indicate that alpha6beta2/3gamma2 GABAAR selective ligands may be important for the treatment of trigeminal activation-related pain and neuropsychiatric disorders with sensori-motor gating deficits. Based on 3 functionally alpha6beta2/3gamma2 GABAAR selective pyrazoloquinolinones, 42 novel analogs were synthesized, and their in vitro metabolic stability and cytotoxicity as well as their in vivo pharmacokinetics, basic behavioral pharmacology, and effects on locomotion were investigated. Incorporation of deuterium into the methoxy substituents of the ligands increased their duration of action via improved metabolic stability and bioavailability, while their selectivity for the GABAAR alpha6 subtype was retained. 8b was identified as the lead compound with a substantially improved pharmacokinetic profile. The ligands allosterically modulated diazepam insensitive alpha6beta2/3gamma2 GABAARs and were functionally silent at diazepam sensitive alpha1beta2/3gamma2 GABAARs, thus no sedation was detected. In addition, these analogs were not cytotoxic, which render them interesting candidates for treatment of CNS disorders mediated by GABAAR alpha6beta2/3gamma2 subtypes. PMID- 29481760 TI - Immune response in highly active young men to the 2014/2015 seasonal influenza vaccine. AB - During the 2009 H1N1 pandemic, individuals with obesity were disproportionately affected by H1N1 with increased levels of mortality and morbidity. This led to questions regarding the potential impact of lifestyle on the effectiveness of immunization. Currently, the research is limited on influenza vaccination and the associated changes in immune response with body composition and physical activity. The purpose of this pilot study was to investigate the potential role of adiposity and physical activity in the immune response elicited by the 2014/2015 seasonal trivalent influenza vaccine. A prospective cohort study examining the 2014/2015 seasonal trivalent influenza vaccine was conducted by collecting baseline and 4-week postvaccination fasting blood samples from 45 male Albertans between the ages of 18 and 35 years. Percent body fat (%BF) was assessed through dual X-ray absorptiometry imagining and physical activity through self-reported survey scores. While no differences in median %BF were associated with seroconversion rates in participants, the median physical activity score was higher among those that did not seroconvert to the vaccine. Significant differences were found for the A/Texas strain (p < 0.01) and a similar trend of lower magnitude observed for the remaining 2 influenza strains. These results suggest that higher physical activity levels may influence immune response to vaccination and that assessing factors beyond those commonly used can be of value when identifying vaccine response in the population. PMID- 29481761 TI - Transillumination and HDR Imaging for Proximal Caries Detection. AB - The purpose of this study was to develop an in vitro model for the validation of near-infrared transillumination (NIRT) for proximal caries detection, to enhance NIRT with high-dynamic-range imaging (HDRI), and to compare both methods, using micro-computed tomography (uCT) as a reference standard. Both proximal surfaces of 53 healthy or decayed permanent human teeth were examined using the Diagnocam (DC) (KaVo) and NIRT with HDRI (NIRT-HDRI). NIRT was combined with HDRI to improve the diagnostic performance by reducing under- and overexposed image areas. For NIRT-HDRI, an exposure series was captured and merged into a single HDR image. A classification was applied according to lesion depth. All surfaces were assessed twice by 2 trained examiners, and additionally with uCT for validation. The Kappa statistic was used to calculate inter-rater reliability and agreement between DC and NIRT-HDRI. Inter-rater reliability (weighted Kappa, wkappa) showed very good agreement for the DC (0.90) and NIRT-HDRI (0.96). The overall agreement (wkappa) was almost perfect (0.85). In the individual categories (0 to 4), the agreement (simple Kappa) ranged from almost perfect (category 4) to moderate (1 and 2) to substantial (categories 0 and 3). Sensitivity and specificity of sound surfaces, enamel, and dentin caries ranged from 0.57 to 0.99 and were similar for both methods in the different categories. NIRT-HDRI had a higher sensitivity for sound surfaces and enamel caries, as well as a higher specificity for dentin caries. Regarding the obtained images, HDRI allowed for the detection of caries within a greater range of luminance levels, resulting in a more detailed visualization of structures without under- or overexposure. However, HDRI this did not improve the diagnostics significantly. Distinguishing between a processed demineralized enamel and dentin lesions appears to be a problem specific to NIRT and cannot be balanced using HDRI. PMID- 29481762 TI - Automated Closed-System Expansion of Pluripotent Stem Cell Aggregates in a Rocking-Motion Bioreactor. AB - Pluripotent stem cell suspension aggregates have proven to be an efficient and phenotypically stable means for expansion and directed differentiation. Bioreactor systems with automation of perfusion, fluidization, and gas exchange are essential for scaling up pluripotent stem cell cultures. Since stem cell pluripotency and differentiation are affected by both chemical and physical signals, we investigated a low-shear method for the expansion of cells in a rocking-motion bioreactor. The rocking motion drives continual mixing and aeration, and the single-use disposable bioreactors avoid issues around contamination during seeding, medium exchange, passage, and cell harvest. Serial passaging from a 150 mL to a 1 L scale was demonstrated, achieving cell densities of up to 4 million cells/mL. In an average of 13 experiments, pluripotent stem cell aggregates expanded 5.7-fold (with maximal 9.5-fold expansion) and maintained 97% viability over 4 days in a rocking bioreactor culture. In seven experiments with improved culture conditions, the average expansion was 6.8-fold. Maintenance of pluripotency was confirmed by differentiation to all three germ layers and surface marker expression, and the expanded aggregates maintained a stable normal karyotype. The automation associated with the rocking platform bioreactor required no user intervention during the 4-day culture, providing hands-off expansion of pluripotent stem cells. PMID- 29481763 TI - Differences in the motor unit firing rates and amplitudes in relation to recruitment thresholds during submaximal contractions of the first dorsal interosseous between chronically resistance-trained and physically active men. AB - Previous investigations report no changes in motor unit (MU) firing rates during submaximal contractions following resistance training. These investigations did not account for MU recruitment or examine firing rates as a function of recruitment threshold (REC). Therefore, MU recruitment and firing rates in chronically resistance-trained (RT) and physically active controls (CON) were examined. Surface electromyography signals were collected from the first dorsal interosseous during isometric muscle actions at 40% and 70% maximal voluntary contraction (MVC). For each MU, force at REC, mean firing rate (MFR) during the steady force, and MU action potential amplitude (MUAPAMP) were analyzed. For each individual and contraction, the MFRs were linearly regressed against REC, whereas, exponential models were applied to the MFR versus MUAPAMP and MUAPAMP versus REC relationships with the y-intercepts and slopes (linear) and A and B terms (exponential) calculated. For the 40% MVC, the RT had less negative slopes (p = 0.001) and lower y-intercepts (p = 0.006) of the MFR versus REC relationships and lower B terms (p = 0.011) of the MUAPAMP versus REC relationships. There were no differences in either relationship between groups for the 70% MVC. During the 40% MVC, the RT had a smaller range of MFRs and MUAPAMPS in comparison with the CON, likely because of reduced MU recruitment. The RT had lower MFRs and recruitment during the 40% MVC, which may indicate a leftward shift in the force-frequency relationship, and thus require less excitation to the motoneuron pool to match the same relative force. PMID- 29481764 TI - Interdental Cleaning Is Associated with Decreased Oral Disease Prevalence. AB - The purpose of this study was to evaluate the associations between interdental cleaning behavior and the prevalence of caries and periodontal disease and numbers of missing teeth, with data from the National Health and Nutrition Examination Survey (2011 to 2012 and 2013 to 2014). Analysis included the following parameters: interproximal clinical attachment level (iCAL) >=3 mm, interproximal probing depth (iPD) >=4 mm, number of coronal and interproximal caries, number of missing teeth, >=1 surfaces with coronal caries, and periodontal profile classes (PPCs). Chi-square was used for bivariate associations. Associations of interdental cleaning with outcomes were assessed with multiple linear regression and generalized logit regression, adjusting for age, race, sex, diabetes, smoking, education, dental visits, and sugar consumption. Nonusers had a significantly higher percentage of sites with iCAL >=3 mm and iPD >=4 mm as compared with individuals who used interdental cleaning devices ( P < 0.0001). Individuals with a higher frequency of cleaning (4 to 7*/wk) had a significantly lower extent of sites with iCAL >=3 mm as compared with lower-frequency cleaning (1 to 3*/wk; P <= 0.05). Interdental cleaning users showed lower numbers of coronal caries, interproximal coronal caries, and missing teeth as compared with nonusers ( P < 0.0001). Nonusers had 1.73-times (95% confidence interval, 1.53 to 1.94) higher odds for having >=1 surfaces of coronal caries as compared with interdental cleaning users, regardless of the weekly frequency. Individuals were less likely to be in diseased PPCs if they were interdental cleaning users. Low-frequency cleaners (1 to 3*/wk) had significantly greater odds (1.43; 95% confidence interval, 1.08 to 1.88) to have severe disease (PPC-G) versus health (PPC-A) than were high-frequency cleaners (4 to 7*/wk). Interdental cleaning users showed lower levels of periodontal disease and caries and lower numbers of missing teeth. Higher frequency of interdental cleaning was correlated with increased periodontal health. Individuals with severe periodontal disease could show additional oral health benefits by increasing cleaning frequency. The data support the use of interdental cleaning devices as an oral hygiene behavior for promoting health. PMID- 29481765 TI - A randomised controlled trial of a brief intervention for illicit drug use linked to ASSIST screening in a primary healthcare setting: results from the Australian component of the World Health Organization Phase III ASSIST studies. AB - This report presents the findings from the Australian component of the Phase III World Health Organization (WHO) Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) randomised controlled trial investigating the effectiveness of a 5-10-min brief intervention (BI) for illicit drug use delivered in primary healthcare (PHC) settings. Participants (n=171) recruited from a South Australian PHC setting (sexual health clinic) who scored in the 'moderate risk' range on the ASSIST were randomly allocated to an intervention group or wait-list control group at baseline and were followed up 3 months later. The ASSIST was administered to both groups at baseline and follow up as a measure of relative risk. Those in the intervention group received a prescribed 10-step BI at baseline. The majority (n=63) of participants received the BI for amphetamine-type stimulants (ATS) or cannabis (n=17). There was a significant reduction in total illicit substance (P<0.001) and ATS Involvement (P<0.01) for those receiving the ASSIST-linked BI, compared with control participants. There was no significant effect on cannabis involvement. The results of this study demonstrate that the ASSIST-linked BI may be a reasonably easy and effective way of reducing illicit substance use by Australian PHC clients. PMID- 29481766 TI - Knowing and telling: how African-Australians living with chronic hepatitis B understand hepatocellular carcinoma risk and surveillance. AB - African-Australians have a high prevalence of chronic hepatitis B (CHB) and an increased risk of liver cancer (hepatocellular carcinoma, HCC) at a younger age than other affected groups living with CHB. The prevention of HCC-related mortality is possible with timely diagnosis of CHB, regular monitoring including liver cancer surveillance and appropriate treatment with antiviral therapy. Currently, little is known about how African-Australians living with CHB understand their condition, their risk of liver cancer and the need for regular monitoring. There were 19 semi-structured interviews conducted with African Australians who have CHB. The interviews explored the participants' knowledge of CHB, their perceptions of future health risks and experiences and understanding of healthcare. The three major themes identified in the analysis were (i) the risks to physical health including liver cancer, (ii) risks to social and emotional wellbeing from diagnosis and disclosure and (iii) the fear and worry associated with being infectious. The understanding of risk and mitigation of that risk was framed by their understanding of health, ageing, as well as participants' educational background and faith. Our findings show the importance of engagement with the broader social and emotional effects of CHB by clinicians and services, and can assist in developing interventions to increase participation in healthcare, including liver cancer surveillance. PMID- 29481767 TI - Diffuse ST-Segment Elevation in Myocardial Infarction. PMID- 29481768 TI - Cloning and mRNA expression of NPB and its effect on hormone secretion of the reproductive cells in the pig. AB - Neuropeptide B (NPB) is an endogenous ligand for the orphan G protein-coupled receptors NPBWR1 (GPR7) and NPBWR2 (GPR8). Some reports have investigated the role of NPB in the regulation of feeding, energy metabolism and hormone secretion in many species. However, few papers reported the physiological function of NPB in the pig. In this study, we cloned and sequenced the NPB mRNA from a pig, which was found to consist of 123 bases. NPB mRNA expression was detected in central and peripheral tissues by the quantitative fluorescence method. The results showed that NPB mRNA expression was higher in hippocampus, cerebellum, spinal cord, thymus, tonsil, duodenum, cecum, colon, ovary and testis. The distribution of NPB suggested that it may be involved in the regulation of reproductive functions in the pig. Subsequently, the expression and distribution of NPBWR1 and NPBWR2 were found in Leydig cells and ovarian granular cells. We then investigated the direct effect of NPB on pig reproductive cells in vitro. The results showed that different concentrations of NPB (10-12, 10-10, 10-8 and 10-6 M) promoted the secretion of testosterone in Leydig cells in concentration dependent manner. Different doses of NPB could promote the secretion of progesterone in ovarian granulosa cells in dose-dependent manner. Low concentrations of NPB (10-8 and 10-10 M) promoted estradiol secretion, but high concentrations of NPB (10-6 M) inhibited its secretion. All the results suggested that the NPB/NPBWR1 or NPBWR2 system may play a role in modulating the reproductive activity in the pig. PMID- 29481769 TI - Long noncoding RNA NKILA enhances the anti-cancer effects of baicalein in hepatocellular carcinoma via the regulation of NF-kappaB signaling. AB - Hepatocellular carcinoma (HCC) is one of the most common cancer and leading cause of cancer-related death worldwide. Baicalein, a principle flavonoid, has shown attractive anti-cancer effects on HCC. However, the underlying molecular mechanisms and influencing factors contributing to the anti-cancer effects of baicalein on HCC are still largely unknown. Long noncoding RNAs (lncRNAs) have been revealed to be fascinating therapeutic targets for cancers. The roles of NF kappaB Interacting LncRNA (NKILA) are recently explored in several cancers. However, the expressions, clinical significances, roles and action mechanisms of NKILA in the anti-cancer effects of baicalein on HCC are unknown. In this study, we found that NKILA is down-regulated in HCC and reduced expression of NKILA indicts poor survival of HCC patients. Functional assays showed that overexpression of NKILA enhances the roles of baicalein on HCC cell proliferation inhibition, apoptosis induction, and migration inhibition in vitro and tumor growth suppression in vivo. Conversely, knockdown of NKILA suppresses the effects of baicalein. Mechanistically, we found that NKILA inhibits IkappaBalpha phosphorylation, NF-kappaB nuclear translocation, and NF-kappaB activity. NKILA also enhances the inhibitory effects of baicalein on NF-kappaB signaling. Furthermore, the effects of NKILA on baicalein-induced NF-kappaB activity inhibition, cell growth inhibition, apoptosis induction, and migration inhibition are reversed by NF-kappaB nuclear translocation inhibitor JSH-23. Collectively, our data demonstrated that NKILA enhances the anti-cancer effects of baicalein on HCC in vitro and in vivo via the regulation of NF-kappaB signaling, and implied that the combination of NKILA and baicalein would be potential therapeutic strategies for HCC. PMID- 29481770 TI - Amelioration effect of Egyptian sweet orange hesperidin on Ehrlich ascites carcinoma (EAC) bearing mice. AB - There are global increased interests to identify novel agents that can possess anti-tumor effects or maximize the anti-tumor effects of low doses for conventional anti-cancer drugs. The aim of this study was to investigate anti tumor effects and protective role of isolated hesperidin from sweet orange on doxorubicin-induced toxicity in Ehrlich ascites carcinoma (EAC) bearing mice. Tumor cells were injected into Swiss albino mice followed by hesperidin administration either alone or in combination with doxorubicin. Biochemical parameters on serum and hepatic were measured. In addition, the effect of hesperidin on apoptotic genes (Caspase3 and Bax) and anti-apoptotic gene (Bcl2) on tumor cells were evaluated by RT- PCR. The results showed that addition of hesperidin to doxorubicin-induced higher anti-tumor responses than treatment with hesperidin or doxorubicin alone. Hesperidin and doxorubicin in combination prolonged the life span of EAC tumor-bearing mice which was associated with a decrease in the number of viable tumor cells and increases in dead tumor cells number. In addition, co-administration of hesperidin with doxorubicin ameliorated the alteration in serum ALT, AST, ALP, GGT and LDH activities, total protein, albumin, creatinine, urea and total lipids concentrations. Moreover, hesperidin alone and in combination with doxorubicin-treated group decreased hepatic, TBARS level significantly as compared with tumor bearing mice and doxorubicin treated group. In contrast, hesperidin alone and combined with doxorubicin ameliorated total antioxidant capacity, reduced glutathione level, and antioxidant enzymes activities such as GPx and CAT in liver tissues. Moreover, hesperidin induced apoptosis of tumor cells which appeared as DNA fragmentation by down-regulation of Bcl2 as anti-apoptotic gene and stimulation of Caspase3 and Bax genes expression as apoptotic genes. In conclusion, Egyptian citrus peels are a rich source of the antioxidant hesperidin. Moreover, it can ameliorate the cytotoxic effect of doxorubicin while enhancing its anti-tumor effect. PMID- 29481771 TI - Quality of Life and Adaptation in People With Spinal Cord Injury: Response Shift Effects From 1 to 5 Years Postinjury. AB - OBJECTIVE: To investigate response shift effects in spinal cord injury (SCI) over 5 years postinjury. DESIGN: Prospective cohort study observed at 1, 2, and 5 years post-SCI. SETTING: Specialized SCI centers. PARTICIPANTS: Sample included 1125, 760, and 219 participants at 1, 2, and 5 years post-SCI (N = 2104). The study sample was 79% men; 39% were motor/sensory complete (mean age, 44.6+/ 18.3y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Patient-reported outcomes included the Medical Outcomes Study 36-Item Short-Form Health Survey version 2 and the Life Satisfaction-11 Questionnaire. Participant latent variable scores were adjusted for (1) potential attrition bias and (2) propensity scores reflecting risk of worse outcomes. The Oort structural equation modeling approach for detecting and accounting for response shift effects was used to test the hypothesis that people with SCI would undergo response shifts over follow-up. RESULTS: The study data comprised the time after FIM scores, an objective measure of motor and cognitive function, had improved and stabilized. Three latent variables (Physical, Mental, and Symptoms) were modeled over time. The response shift model indicated uniform recalibration and reconceptualization response shift effects over time. When adjusted for these response shift effects, Physical showed small true change improvements at 2- and 5-year follow-up, despite FIM stability. CONCLUSIONS: We detected recalibration and reconceptualization response shift effects in 1- to 5-year follow-up of people with SCI. Despite stable motor and cognitive function, people with SCI are adapting to their condition. This adaptation reflects a progressive disconnection between symptoms and physical or mental health, and a real improvement in the Physical latent variable. PMID- 29481772 TI - Pasteurized Donor Human Milk and Milk Banking Through the Human Milk Banking Association of North America. PMID- 29481773 TI - Providing Anesthesia in the Oral and Maxillofacial Surgery Office: A Look Back, Where We Are Now and a Look Ahead. AB - Throughout its development the practice of oral and maxillofacial surgery has been richly associated with the provision of anesthetic services. Dentists and particularly oral and maxillofacial surgeons have advanced the science associated with anesthesia especially in the outpatient setting. This article will look back on the development of anesthesia as it relates to oral and maxillofacial surgery, discuss the current mode of anesthesia in the oral surgeon's practice and look ahead to what innovations are advancing this field. PMID- 29481774 TI - Enzymatic quantification and length determination of polyphosphate down to a chain length of two. AB - Polyacrylamide gel electrophoresis, being the current method of choice for length determination of inorganic polyphosphate (polyP), requires a sequencing apparatus, relies on commercially not available polyP length standards and yields only a chain length distribution. State of the art polyP quantification involves enzymatic hydrolysis of polyP to orthophosphate with the Saccharomyces cerevisiae exopolyphosphatase 1 (scPpx1p) and subsequent colorimetric orthophosphate detection. Because scPpx1p leaves one pyrophosphate per polyP, short chain polyPs are only partially detected. To overcome this analytical limitation, a method involving both the scPpx1p and the S. cerevisiae inorganic pyrophosphatase (scIpp1p) is proposed. Differential enzymatic hydrolysis of polyP with scPpx1p, and a combination of scIpp1p and scPpx1p allows not only for comprehensive quantification of polyP (excluding cyclic polyP) down to a chain length of two, but also absolute average chain length determination in the range of two to approximately 80. An optimized one-reagent method for rapid (2 min) orthophosphate quantification is part of the assay. Biological phosphorous containing molecules at equimolar phosphorous concentrations regarding polyP do not interfere. The method requires 1.5 MUg polyP and calls only for a plate reader. This is the first enzymatic method for simultaneous average polyP chain length determination as well as comprehensive quantification. PMID- 29481775 TI - Was the calf circumference associated with serum vitamin D level in obesity and non-obesity adults. AB - PURPOSED: This study examined the associations between 25-hydroxyvitamin D [25(OH)D] and common anthropometric parameters. METHODS: The data were derived from the National Health and Nutrition Examination Survey from 2001 through 2004. We divided all subjects into two groups with a cut-off point for body mass index set at 30. The primary outcome was the potential relationship between the anthropometric parameters and 25(OH)D status. RESULTS: A positive association was found between the 25(OH)D levels and calf circumference (CC) in all of the designed models (P < 0.001). The adjusted beta coefficient of the 25(OH)D levels for the CC was 0.542 (95% confidence intervals (CI), 0.376-0.708, P < 0.001) after adjusting for all covariates. An increasing linear tendency for 25(OH)D was present in non-obese participants. Additionally, subjects in the higher tertiles of CC tended to have higher 25(OH)D levels with a significant correlation (P for trend <0.001). CONCLUSION: A positive association between 25(OH)D concentration and CC in non-obese individuals was observed. PMID- 29481777 TI - New Developments in Managing Variceal Bleeding. AB - Liver cirrhosis is the end stage of chronic liver disease, independent of etiology, and is characterized by accumulation of fibrotic tissue and conversion of the normal liver parenchyma into abnormal regenerative nodules. Complications include portal hypertension (PH) with gastroesophageal varices, ascites, hepatorenal syndrome, hepatic encephalopathy, bacteremia, and hypersplenism. The most life-threatening complication of liver cirrhosis is acute variceal bleeding (AVB) which is associated with increased mortality that, despite recent progress in management, is still around 20% at 6 weeks. Combined treatment with vasoactive drugs, prophylactic antibiotics, and endoscopic techniques is the recommended standard of care for patients with acute variceal bleeding. There are many promising new modalities including the combination of coil and glue injection for management of bleeding or non-bleeding gastric varices and hemostatic powder application, that requires minimal expertise, when performed early after admission of a cirrhotic patient with AVB and overt hematemesis acting as a bridge therapy till definitive endoscopic therapy can be performed in hemodynamically stable conditions and without acute bleeding. PMID- 29481776 TI - Metabolomic profiling suggests long chain ceramides and sphingomyelins as a possible diagnostic biomarker of epithelial ovarian cancer. AB - INTRODUCTION: Epithelial ovarian cancer (EOC) is a disease with a poor survival rate mostly due to its discovery in late stages. The aim of this study was to investigate the metabolomic profile of ovarian cancer with the intention of identifying and describing novel biomarkers with diagnostic potential. MATERIAL AND METHODS: Targeted serum metabolomic profiling was performed on 15 patients with ovarian cancer, 21 healthy controls and 21 patients with benign ovarian conditions, using HPLC-TQ/MS. RESULTS: Panel of 49 top performing biomarkers shows separation between EOC and controls with 87% specificity and 87% sensitivity with AUC of 93% (CI 90%-95%). Using only 5 top biomarkers, specificity of 80% and sensitivity of 83% was achieved on extended sample set. Most significant biomarkers belong to sphingolipid classes, especially long chain ceramides and sphingomyelins. Different concentrations of various fatty acid chain lengths ceramides and sphingomyelins are also implying their respective roles in cell proliferation and growth inhibition. CONCLUSION: Long chain ceramides and sphingomyelins may serve as a novel biomarker for epithelial ovarian cancer detection and may also offer insight into the role of sphingolipid metabolism in cell proliferation. PMID- 29481778 TI - Methotrexate Reduces DNA Integrity in Sperm From Men With Inflammatory Bowel Disease. AB - There are few data on the effects of methotrexate on reproductive capacity in men with inflammatory bowel diseases (IBDs). We performed a case-control study to determine the effects of methotrexate on sperm quality and genetic integrity. We compared sperm samples from 7 men with IBD who had been exposed to methotrexate for at least 3 months with sperm samples collected from 1912 age-matched men at fertility centers (controls) where sperm parameters would be expected to be worse than those of the general population. Sperm were evaluated by basic semen analysis and advanced sperm integrity testing. In samples from men with IBD, all basic semen analysis parameters were within normal limits. However, these samples had reduced sperm integrity, based on significant increases in levels of DNA fragmentation and damage from oxidative stress compared with controls. Our findings indicate that methotrexate can reduce DNA integrity in sperm and cause damage via oxidative stress. PMID- 29481779 TI - Dietary Patterns After the Weaning and Lactation Period Are Associated With Celiac Disease Autoimmunity in Children. AB - BACKGROUND & AIMS: There have been many studies of associations between infant feeding practices and development of celiac disease during childhood, but few studies have focused on overall diets of young children after the weaning period. We aimed to examine the association between common dietary patterns in infants and the occurrence of celiac disease autoimmunity during childhood. METHODS: We performed a prospective analysis of data from the Generation R Study that comprised 1997 children born from April 2002 through January 2006 in Rotterdam, the Netherlands. Food consumption around 1 year of age was assessed with a validated food-frequency questionnaire. Dietary data were examined using a priori (based on existing guidelines) and a posteriori (principal component analysis and reduced rank regression) dietary pattern analyses. Five dietary patterns were compared. Celiac disease autoimmunity, determined on the basis of serum concentration of transglutaminase-2 autoantibody (ie, TG2A) below or above 7 U/mL, was evaluated at 6 years. Associations between dietary pattern adherence scores and celiac disease autoimmunity were examined using multivariable logistic regression models. RESULTS: Higher adherence to the a posteriori-derived prudent dietary pattern (high intake of vegetables, vegetable oils, pasta, and grains and low consumption of refined cereals and sweet beverages) at 1 year was significantly associated with lower odds of celiac disease autoimmunity at 6 years (odds ratio, 0.67; 95% confidence interval, 0.53-0.84). No significant associations were found for the 4 remaining dietary patterns. CONCLUSIONS: In a prospective study of dietary patterns of young children in the Netherlands, we associated a dietary pattern characterized by high consumption of vegetables and grains and low consumption of refined cereals and sweet beverages, with lower odds of celiac disease autoimmunity. Early-life dietary patterns might therefore be involved in the development of celiac disease during childhood. PMID- 29481780 TI - Intracholecystic papillary neoplasm of the gallbladder protruding into the common bile duct. PMID- 29481782 TI - Cryopreservation and characterization of canine preantral follicles. AB - The aim of this study was to define the population, morphological and ultrastructural characteristics of bitch preantral follicles (PAFs) and to compare the effects on the morphology of PAF of two cryopreservation techniques - slow freezing (SF) and vitrification (V) - of bitches' ovarian tissue. The average population (number per ovary) of PAFs was 48,541 +/- 18,366, where 94.25% were primordial (45,145 +/- 16,076). The average diameter of the primordial follicles was 27.5 +/- 4.2 MUm. The overall percentage of morphologically normal PAFs was 93.66 +/- 6.81% for the control group, 86.16 +/- 11.05% after SF and 68.14 +/- 12.75% after V. The percentage of normal primordial follicles was 96.69 +/- 4.72% in control, 89.51 +/- 10.39% in SF and 75.32 +/- 9.23% in V. There was no significant difference in the overall percentage of normal PAFs among SF and the control. However, slow frozen follicles presented ultrastructural damage, while vitrified primordial and primary follicles were well preserved. In conclusion, although slow freezing seemed to be a good preserving method, vitrification was more effective than slow freezing in preserving the ultrastructure of primordial and primary follicles of bitches. PMID- 29481781 TI - Ferrochelatase pi-helix: Implications from examining the role of the conserved pi helix glutamates in porphyrin metalation and product release. AB - Protoporphyrin ferrochelatase catalyzes the insertion of Fe2+ into protoporphyrin IX to form heme. To determine whether a conserved, active site pi-helix contributes to the translocation of the metal ion substrate to the ferrochelatase bound porphyrin substrate, the invariant pi-helix glutamates were replaced with amino acids with non-negatively charged side chains, and the kinetic mechanisms of the generated variants were examined. Analysis of yeast wild-type ferrochelatase-, E314Q- and E318Q-catalyzed reactions, under multi- and single turnover conditions, demonstrated that the mutations of the pi-helix glutamates hindered both protoporphyrin metalation and release of the metalated porphyrin, by slowing each step by approximately 30-50%. Protoporphyrin metalation occurred with an apparent pKa of 7.3 +/- 0.1, which was assigned to binding of Fe2+ by deprotonated Glu-314 and Glu-314-assisted Fe2+ insertion into the porphyrin ring. We propose that unwinding of the pi-helix concomitant with the adoption of a protein open conformation positions the deprotonated Glu-314 to bind Fe2+ from the surface of the enzyme. Transition to the closed conformation, with pi-helix winding, brings Glu-314-bound Fe2+ to the active site for incorporation into protoporphyrin. PMID- 29481783 TI - Nonthrombotic Pulmonary Embolism From Inorganic Particulate Matter and Foreign Bodies. AB - Nonthrombotic pulmonary embolism (NTPE) is a complete or partial occlusion of the pulmonary vasculature by various organic and inorganic materials. These materials include organic particulate matter (PM) such as adipocytes, tumor cells, bacteria, fungi, or gas and inorganic PM. Although NTPE due to organic PM has been extensively reported in the medical literature, there are no comprehensive reviews of inorganic material embolizing to the lungs. The purpose of this article is to examine the current literature describing NTPE resulting from inorganic PM and foreign bodies. Cases of NTPE are uncommon and often difficult to diagnose. The diagnosis is challenging due to its varied presentation, clinical features, and unusual radiologic features. In contrast to the "classic" pulmonary thromboembolism, the pathophysiologic effects of embolism by PM are not only mechanical but also a consequence of the nature of the offending material. NTPE caused by these substances can be relatively innocuous, life-threatening, or lead to chronic pulmonary disease, if left undetected. We hope that the heightened sense of awareness of this entity may allow earlier diagnosis and recognition of its complications. PMID- 29481784 TI - Endophilin A1 mediates seizure activity via regulation of AMPARs in a PTZ-kindled epileptic mouse model. AB - Endophilin A1 is a member of the endophilin A family and is primarily expressed in the central nervous system. Endophilin A1 can mediate neuronal excitability by regulating neuronal synaptic plasticity, which indicates that the protein may be involved in epilepsy. However, to date, its role in epilepsy remains unclear. To explore the role of endophilin A1 in epilepsy, we aimed to investigate the expression patterns of endophilin A1 in patients with temporal lobe epilepsy (TLE) and in a pentylenetetrazole (PTZ)-kindled epileptic mouse model and to conduct behavioral and electrophysiological analyses after lentivirus-mediated knockdown of endophilin A1 in the hippocampus of epileptic mice. This study found that the expression of endophilin A1 was significantly up-regulated in the temporal neocortex of TLE patients and in the hippocampus and adjacent temporal cortex of the PTZ-kindled epileptic mouse model. Behavioral analyses indicated that knockdown of endophilin A1 in the mouse hippocampus increased the latency of the first seizure and reduced the frequency and duration of seizure activity. Whole-cell patch-clamp recordings of pyramidal neurons in the hippocampal CA3 area indicated that knockdown of endophilin A1 in the mouse hippocampus resulted in a reduced frequency of action potentials and decreased amplitudes of miniature excitatory postsynaptic currents (mEPSCs) and evoked AMPA-dependent EPSCs. Moreover, western blotting analysis showed that the surface expression of the AMPAR GluR2 subunit was also decreased after endophilin A1 knockdown, and co immunoprecipitation indicated an association between endophilin A1 and AMPAR GluR2 in the mouse hippocampus. Further, when AMPARs were activated by CX546, the antiepileptic function of endophilin A1 knockdown was decreased. Based on these results, endophilin A1 plays a critical role in epilepsy, and its suppression in the mouse hippocampus can restrain neuronal excitability and seizure activity via regulating AMPARs. PMID- 29481785 TI - Cerebral ischemia induces angiogenesis in the peri-infarct regions via Notch1 signaling activation. AB - The Notch1 signaling pathway is considered as one of important regulators of angiogenesis during development, but its role in cerebral ischemia-induced angiogenesis is less well understood. Here, we used human and rodent brains to explore whether Notch1 signaling was involved in the angiogenesis after focal cerebral ischemia. Using immunohistochemistry on surgically resected ischemic stroke brain tissue, we found that the area, volume, and length of the blood vessels in the peri-infarct regions were significantly increased after ischemic stroke in humans, compared with non-ischemic stroke specimens. In addition, the expression of the activated form of Notch1 (Notch intracellular domain; NICD) was increased in endothelial cells of the peri-infarct region. The Notch1 ligand, Jagged1, also increased in abundance in the peri-infarct regions in human. We further confirmed that Notch1 signaling was activated in the peri-infarct regions in a mouse distal middle cerebral artery occlusion (dMCAO) model. Lentivirus mediated Notch1 knockdown reduced ischemia-induced angiogenesis in the peri infarct regions of the brain. Our findings suggest that ischemic stroke in human can also induce angiogenesis in the peri-infarct regions as does in animal models of focal ischemia and that Notch1 signaling plays a critical role in mediating this process, which may provide fundamental knowledge regarding the potential mechanisms underlying angiogenesis after ischemic stroke. PMID- 29481787 TI - A Calcified Amorphous Tumor Originating in the Aortic Valve Cusp. AB - Calcified amorphous tumor (CAT) of the heart is a rare nonneoplastic cardiac tumor. The clinical features of cardiac CATs resemble those of other cardiac tumors that include symptoms related to obstruction or embolization. Cardiac CATs have been found in all chambers of the heart but predominantly present in the left ventricle, mitral annulus, and mitral valve. Here we report an extremely rare case of CAT originating in the aortic valve cusp, which may be related to aortic annular calcification and aortic valve stenosis. We successfully treated this patient with tumor resection and aortic valve replacement. PMID- 29481788 TI - Truncus Superior Artery Ventral to the Apical Vein of the Right Upper Lobe. PMID- 29481786 TI - Fibrocyte migration, differentiation and apoptosis during the corneal wound healing response to injury. AB - The aim of this study was to determine whether bone marrow-derived fibrocytes migrate into the cornea after stromal scar-producing injury and differentiate into alpha-smooth muscle actin (alphaSMA) + myofibroblasts. Chimeric mice expressing green fluorescent protein (GFP) bone marrow cells had fibrosis (haze) generating irregular phototherapeutic keratectomy (PTK). Multiplex immunohistochemistry (IHC) for GFP and fibrocyte markers (CD34, CD45, and vimentin) was used to detect fibrocyte infiltration into the corneal stroma and the development of GFP+ alphaSMA+ myofibroblasts. IHC for activated caspase-3, GFP and CD45 was used to detect fibrocyte and other hematopoietic cells undergoing apoptosis. Moderate haze developed in PTK-treated mouse corneas at 14 days after surgery and worsened, and persisted, at 21 days after surgery. GFP+ CD34+ CD45+ fibrocytes, likely in addition to other CD34+ and/or CD45+ hematopoietic and stem/progenitor cells, infiltrated the cornea and were present in the stroma in high numbers by one day after PTK. The fibrocytes and other bone marrow-derived cells progressively decreased at four days and seven days after surgery. At four days after PTK, 5% of the GFP+ cells expressed activated caspase 3. At 14 days after PTK, more than 50% of GFP+ CD45+ cells were also alphaSMA+ myofibroblasts. At 21 days after PTK, few GFP+ alphaSMA+ cells persisted in the stroma and more than 95% of those remaining expressed activated caspase-3, indicating they were undergoing apoptosis. GFP+ CD45+ SMA+ cells that developed from 4 to 21 days after irregular PTK were likely developed from fibrocytes. After irregular PTK in the strain of C57BL/6-C57/BL/6-Tg(UBC-GFP)30Scha/J chimeric mice, however, more than 95% of fibrocytes and other hematopoietic cells underwent apoptosis prior to the development of mature alphaSMA+ myofibroblasts. Most GFP+ CD45+ alphaSMA+ myofibroblasts that did develop subsequently underwent apoptosis-likely due to epithelial basement membrane regeneration and deprivation of epithelium-derived TGFbeta requisite for myofibroblast survival. PMID- 29481789 TI - The Ross Procedure: How I Teach It. PMID- 29481790 TI - Chronic kidney disease induces inflammation by increasing Toll-like receptor-4, cytokine and cathelicidin expression in neutrophils and monocytes. AB - TLR expression in neutrophils and monocytes is associated with increased cytokine synthesis, resulting in increased inflammation. However, the inflammatory pathway related to TLR and cathelicidin expression in these cells from CKD patients is unclear. To evaluate TLR4, cathelicidin, TNF-alpha, IL-6, IL-10 and MCP-1 expression in neutrophils and monocytes from HD and CKD patients. Blood samples were drawn from 47 CKD and 43 HD patients and 71 age and gender-matched healthy volunteers (CONT). TLR4 was analyzed using flow cytometry. Cathelicidin, TNF alpha, IL-6, IL-10 and MCP-1 were analyzed via ELISA.TLR4 expression in neutrophils was higher in HD patients than in stage 3 and 4 CKD patients. In these cells, we observed a positive correlation between TLR4 and cathelicidin, TNF-alpha, IL-6, IL-10 and MCP-1 levels. In monocytes, TLR4 expression was significantly higher in CKD 3 and 4 groups than in the control and HD groups and positively and negatively correlated with IL-6 and MCP-1 and cathelicidin, respectively. TNF-alpha, IL-6 and MCP-1 serum levels were higher in HD and CKD patients than in control. Cathelicidin and IL-10 levels were only higher in HD patients. IL-6 serum levels were positively correlated with all cytokines, and cathelicidin was negatively correlated with MCP-1 (r = - 0.35; p < 0.01) and positively correlated with IL-10 (r = 0.37; p = 0.001). These results suggest that a uremic environment induces high TLR4, cathelicidin and cytokine expression and may increase inflammation. Thus, future studies should be conducted to evaluate whether TLR4 and cathelicidin should be targets for anti-inflammatory therapeutic strategies. PMID- 29481791 TI - Egr-1 mediated cardiac miR-99 family expression diverges physiological hypertrophy from pathological hypertrophy. AB - : The physiological cardiac hypertrophy is an adaptive condition without myocyte cell death, while pathological hypertrophy is a maladaptive condition associated with myocyte cell death. This study explores the miRNome of alpha-2M-induced physiologically hypertrophied cardiomyocytes and the role of miRNA-99 family during cardiac hypertrophy. Physiological and pathological cardiac hypertrophy was induced in H9c2 cardiomyoblast cell lines using alpha-2M and isoproterenol respectively. Total RNA isolation and small RNA sequencing were executed for physiological hypertrophy model. The differentially expressed miRNAs and its target mRNAs were validated in animal models. Transcription factor binding sites were predicted in the promoter of specific miRNAs and validated by ChIP-PCR. Subsequently, the selected miRNA was functionally characterized by overexpression and silencing. The effects of silencing of upstream regulator and downstream target gene were studied. Analysis of small RNA reads revealed the differential expression of a large set of miRNAs during hypertrophy, of which miR-99 family was highly downregulated upon alpha-2M treatment. However, this miR-99 family expression was upregulated during pathological hypertrophy and confirmed in animal models. ChIP-PCR confirms the binding of Egr-1 transcription factor to the miR-99 promoter. Further, silencing of Egr-1 decreased the expression of miR-99. The overexpression or silencing of miR-99 diverges the physiological hypertrophy to pathological hypertrophy and vice versa by regulating Akt-1 pathway. Silencing of Akt-1 replicates the effect of overexpression of miR-99. CONCLUSION: The results proved Egr-1 mediated regulation of miR-99 family that plays a key role in determining the fate of cardiac hypertrophy by regulating Akt-1 signaling. PMID- 29481792 TI - Fasudil inhibits neutrophil-endothelial cell interactions by regulating the expressions of GRP78 and BMPR2. AB - Regulation of leukocyte-endothelial cell interactions and of vascular permeability plays a critical role in the maintenance of functional pulmonary microvascular barriers. Little is yet known about the effect of the Rho associated protein kinase (ROCK) inhibitor fasudil on leukocyte-endothelial cell interactions or the underlying mechanism. In the present study, as evaluated using co-culture systems of neutrophils and human pulmonary microvascular endothelial cells (HPMECs), fasudil dose-dependently suppressed neutrophil chemotaxis by decreasing the production of chemotactic factors in lipopolysaccharide (LPS)-treated HPMECs. The inhibitory role of fasudil in neutrophil chemotaxis was mediated by down-regulation of the chaperone glucose regulated protein 78 (GRP78), since the inhibition was abolished by 4-phenyl butyric acid (a chemical chaperone mimicking GRP78). In addition, fasudil inhibited LPS-induced neutrophil-endothelial adhesion by reducing the expression of intercellular adhesion molecule (ICAM)-1. By use of lentiviral transfection in HPMECs, bone morphogenic protein receptor 2 (BMPR2) overexpression suppressed the LPS-induced increase of both ICAM-1 expression and neutrophil-endothelial adhesion, whereas knocking down BMPR2 abolished the inhibitory role of fasudil in both ICAM-1 expression and neutrophil-endothelial adhesion. Moreover, fasudil alleviated LPS-induced hyperpermeability of HPMEC monolayers by leading to the recovery of intercellular junctions, thereafter reduced neutrophil transendothelial cell migration. Therefore, fasudil inhibited leukocyte endothelial cell interactions and vascular hyperpermeability through modulation of GRP78 and BMPR2 expression, suggesting a potential role for ROCK as a switch for inhibiting leukocyte-endothelial cell interactions. PMID- 29481793 TI - Patterns of epileptic seizure occurrence. AB - BACKGROUND: The occurrence of epileptic seizures in seemingly random patterns takes a great toll on persons with epilepsy and their families. Seizure prediction may markedly improve epilepsy management and, therefore, the quality of life of persons with epilepsy. METHODS: Literature review. RESULTS: Seizures tend to occur following complex non-random patterns. Circadian oscillators may contribute to the rhythmic patterns of seizure occurrence. Complex mathematical models based on chaos theory try to explain and even predict seizure occurrence. There are several patterns of epileptic seizure occurrence based on seizure location, seizure semiology, and hormonal factors, among others. These patterns are most frequently described for large populations. Inter-individual variability and complex interactions between the rhythmic generators continue to make it more difficult to predict seizures in any individual person. The increasing use of large databases and machine learning techniques may help better define patterns of seizure occurrence in individual patients. Improvements in seizure detection such as wearable seizure detectors- and in seizure prediction -such as machine learning techniques and artificial as well as neuronal networks- promise to provide further progress in the field of epilepsy and are being applied to closed loop systems for the treatment of epilepsy. CONCLUSIONS: Seizures tend to occur following complex and patient-specific patterns despite their apparently random occurrence. A better understanding of these patterns and current technological advances may allow the implementation of closed-loop detection, prediction, and treatment systems in routine clinical practice. PMID- 29481794 TI - Enriched environment promotes post-stroke neurogenesis through NF-kappaB-mediated secretion of IL-17A from astrocytes. AB - Enriched environment (EE) has been shown to promote post-stroke neurogenesis and functional recovery. However, the underlying molecular mechanisms remains poorly understood. Male C57BL/6 mice underwent 60-min middle cerebral artery occlusion (MCAO) followed by reperfusion, after which mice were housed in either standard environment (SE) or EE. We found that post-ischemic EE exhibited reduced protein level of nuclear factor kappaB (NF-kappaB)/p65 in cytoplasm and increased its expression correspondingly in nucleus at 28 days post-ischemia (dpi). However, post-ischemic EE had no effects on terminal deoxynucleotidyl transferase biotin dUTP nick end labeling (TUNEL)-positive cells in ischemic hemisphere at 28dpi. EE mice treated with NF-kB inhibitor Bay11-7082 had decreased subventricular zone (SVZ) neural precursor cells (NPCs) proliferation, neuronal differentiation and subsequent functional recovery after stroke at 28dpi. Bay11-7082 treatment attenuated the promoting effects of post-ischemic EE on interleukin 17A (IL-17A) messenger RNA (mRNA) and protein expression at 28dpi. Furthermore, our in vitro data revealed that in primary astrocyte cultures addition of Bay11-7082 markedly decreased the expression of IL-17A in both the cell lysate and culture supernatant of activated astrocytes. Blockade of IL-17A with neutralizing antibody abrogated the promoting role of EE in NPCs proliferation derived from SVZ, neuronal differentiation and subsequent functional recovery after stroke. Thus, our results reveal a previously uncharacterized property of NF-kappaB/IL 17A signaling pathway in EE-mediated neurogenesis and functional recovery after ischemic stroke. PMID- 29481796 TI - Transcortical descending pathways through granular insular cortex conveying orofacial proprioception. AB - Our motor behavior can be affected by proprioceptive information. However, little is known about which brain circuits contribute to this process. We have recently revealed that the proprioceptive information arising from jaw-closing muscle spindles (JCMSs) is conveyed to the supratrigeminal nucleus (Su5) by neurons in the trigeminal mesencephalic nucleus (Me5), then to the caudo-ventromedial edge of ventral posteromedial thalamic nucleus (VPMcvm), and finally to the dorsal part of granular insular cortex rostroventrally adjacent to the rostralmost part of secondary somatosensory cortex (dGIrvs2). Our next question is which brain areas receive the information from the dGIrvs2 for the jaw-movements. To test this issue, we injected an anterograde tracer, biotinylated dextranamine, into the dGIrvs2, and analyzed the resultant distribution profiles of the labeled axon terminals. Anterogradely labeled axons were distributed in the pontomedullary areas (including the Su5) which are known to receive JCMS proprioceptive inputs conveyed directly by the Me5 neurons and to contain premotoneurons projecting to the jaw-closing motoneurons in the trigeminal motor nucleus (Mo5). They were also found in and around the VPMcvm. In contrast, no labeled axonal terminals were detected on the cell bodies of Me5 neurons and motoneurons in the Mo5. These data suggest that jaw-movements, which are evoked by the classically defined jaw reflex arc originating from the peripheral JCMS proprioceptive information, could also be modulated by the transcortical feedback connections from the dGIrvs2 to the VPMcvm and Su5. PMID- 29481797 TI - Design of tryptophan-containing mutants of the symmetrical Pizza protein for biophysical studies. AB - beta-propeller proteins are highly symmetrical, being composed of a repeated motif with four anti-parallel beta-sheets arranged around a central axis. Recently we designed the first completely symmetrical beta-propeller protein, Pizza6, consisting of six identical tandem repeats. Pizza6 is expected to prove a useful building block for bionanotechnology, and also a tool to investigate the folding and evolution of beta-propeller proteins. Folding studies are made difficult by the high stability and the lack of buried Trp residues to act as monitor fluorophores, so we have designed and characterized several Trp containing Pizza6 derivatives. In total four proteins were designed, of which three could be purified and characterized. Crystal structures confirm these mutant proteins maintain the expected structure, and a clear redshift of Trp fluorescence emission could be observed upon denaturation. Among the derivative proteins, Pizza6-AYW appears to be the most suitable model protein for future folding/unfolding kinetics studies as it has a comparable stability as natural beta-propeller proteins. PMID- 29481798 TI - First description of a novel mitochondrial mutation in the MT-TI gene associated with multiple mitochondrial DNA deletion and depletion in family with severe dilated mitochondrial cardiomyopathy. AB - Mitochondria are essential for early cardiac development and impaired mitochondrial function was described associated with heart diseases such as hypertrophic or dilated mitochondrial cardiomyopathy. In this study, we report a family including two individuals with severe dilated mitochondrial cardiomyopathy. The whole mitochondrial genome screening showed the presence of several variations and a novel homoplasmic mutation m.4318-4322delC in the MT-TI gene shared by the two patients and their mother and leading to a disruption of the tRNAIle secondary structure. In addition, a mitochondrial depletion was present in blood leucocyte of the two affected brother whereas a de novo heteroplasmic multiple deletion in the major arc of mtDNA was present in blood leucocyte and mucosa of only one of them. These deletions in the major arc of the mtDNA resulted to the loss of several protein-encoding genes and also some tRNA genes. The mtDNA deletion and depletion could result to an impairment of the oxidative phosphorylation and energy metabolism in the respiratory chain in the studied patients. Our report is the first description of a family with severe lethal dilated mitochondrial cardiomyopathy and presenting several mtDNA abnormalities including punctual mutation, deletion and depletion. PMID- 29481795 TI - Neurosteroid regulation of GABAA receptors: A role in catamenial epilepsy. AB - The female reproductive hormones progesterone and estrogen regulate network excitability. Fluctuations in the circulating levels of these hormones during the menstrual cycle cause frequent seizures during certain phases of the cycle in women with epilepsy. This seizure exacerbation, called catamenial epilepsy, is a dominant form of drug-refractory epilepsy in women of reproductive age. Progesterone, through its neurosteroid derivative allopregnanolone, increases gamma-aminobutyric acid type-A receptor (GABAR)-mediated inhibition in the brain and keeps seizures under control. Catamenial seizures are believed to be a neurosteroid withdrawal symptom, and it was hypothesized that exogenous administration of progesterone to maintain its levels high during luteal phase will treat catamenial seizures. However, in a multicenter, double-blind, phase III clinical trial, progesterone treatment did not suppress catamenial seizures. The expression of GABARs with reduced neurosteroid sensitivity in epileptic animals may explain the failure of the progesterone clinical trial. The expression of neurosteroid-sensitive delta subunit-containing GABARs is reduced, and the expression of alpha4gamma2 subunit-containing GABARs is upregulated, which alters the inhibition of dentate granule cells in epilepsy. These changes reduce the endogenous neurosteroid control of seizures and contribute to catamenial seizures. PMID- 29481799 TI - Low levels of TSC22 enhance tumorigenesis by inducing cell proliferation in colorectal cancer. AB - Transforming growth factor beta-stimulated clone 22 domain 1 (TSC22) has been identified as a cancer suppressor gene in various kinds of cancers. The purpose of this study was to explore the expression of TSC22 in colorectal cancer (CRC) tissues and cell lines. 24 matched CRC and normal tissue samples by qPCR along with 18 pairs of them by Western blot demonstrated TSC22 level was decreased in CRC compared with normal tissue. The protein expression of TSC22 was examined in 310 CRC specimens. Results showed low expression of TSC22 was significantly correlated with tumor size (P = 0.048) and tumor infiltration (P = 0.016). Kaplan Meier method suggested low expression of TSC22 was inversely associated with OS for 276 samples (P < 0.01). Multivariate Cox regression analysis confirmed TSC22 expression as independent predictors of the OS in CRC patients. Furthermore, we found TSC22 could suppress tumor by inhibiting cell proliferation in CRC cell lines. PMID- 29481800 TI - BACH1 promotes the progression of human colorectal cancer through BACH1/CXCR4 pathway. AB - The present study was to investigate clinical significance, biological functions and underlying mechanisms of BTB Domain and CNC Homolog 1(BACH1) deregulation in human colorectal cancer (CRC). The result showed that BACH1 upregulation was significantly associated with enhanced tumor invasion (P = 0.014) and gender (P = 0.028) of CRC patients. Kaplan-Meier method results showed that the overall survival of CRC patients with high BACH1 mRNA expression was markedly shorter than those with low expression (P = 0.015), and multivariate analyzes results showed that BACH1 was an independent prognostic predictor for CRC patients (P = 0.049). In vitro studies revealed that BACH1 efficiently promoted invasion and migration of CRC cell line. In vitro studies proved that the HCT116 cell stably expressing BACH1 formed significantly larger tumor nodules and remarkably accelerated tumor xenografts growth. In addition, Immunohistochemical scores of CD31 and Vimentin were significantly higher than those of the control group. Finally, correlation analysis indicated that BACH1 expression was positively correlated with C-X-C Motif Chemokine Receptor 4(CXCR4) in tumor tissues and cell lines. Together, BACH1 serves as an oncogene to promote CRC progression and an independent prognostic factor for survival and metastasis. BACH1 may inhibit the progression of CRC through BACH1/CXCR4 pathway. PMID- 29481801 TI - Transplantation of skin mesenchymal stem cells attenuated AngII-induced hypertension and vascular injury. AB - Skin mesenchymal stem cells (S-MSCs) revealed an important immunomodulatory activity to markedly suppress the formation of the atherosclerosis (AS) plaque by modulating macrophages, and also inhibit the development of experimental autoimmune encephalomyelitis (EAE) by regulating T helper 17 (Th17) cell differentiation. Macrophages and Th17 cells play important roles in hypertension. However, it remains unclear whether S-MSCs are capable of improving angiotensin (AngII)-induced hypertension by acting on inflammatory cells. Therefore, we studied a direct effect of S-MSC treatment on an AngII-induced hypertensive mouse model. Twenty-seven C57BL/6 (WT) mice were divided into three groups: Control group (WT-NC), AngII-infused group (WT-AngII), and S-MSC treatment group (WT AngII + S-MSCs). In contrast to WT-AngII group, systolic blood pressure (SBP) and vascular damage were strikingly attenuated after tail-vein injection of S-MSCs. Numbers of Th17 cells in mouse peripheral blood of S-MSC treated group were significantly decreased, and IL-17 mRNA and protein levels were also reduced in the aorta and serum compared with WT-AngII group. Furthermore, macrophages in S MSC treated group were switched to a regulatory profile characterized by a low ability to produce pro-inflammatory cytokine TNF-alpha and a high ability to produce anti-inflammatory cytokines Arg1 and IL-10. Mechanistically, we found that S-MSCs inhibited Th17 cell differentiation and induced M2 polarization. Moreover, we found proliferation and migration of S-MSCs were elevated, and expression of CXCR4, the receptor for Stromal derivated factor -1(SDF-1), was markedly increased in lipopolysaccharide (LPS)- stimulated S-MSCs. Given that SDF 1 expression was increased in the serum and aorta in AngII- induced hypertensive mice, the immunomodulatory effects exerted by S-MSCs involved the CXCR4/SDF-1 signaling. Collectively, our data demonstrated that S-MSCs attenuated AngII induced hypertension by inhibiting Th17 cell differentiation and by modulating macrophage M2 polarization, suggesting that S-MSCs potentially have a role in stem cell based therapy for hypertension. PMID- 29481802 TI - Serum apolipoprotein A2 isoforms in autoimmune pancreatitis. AB - Recently, apolipoprotein A2 (apoA2) isoforms have been reported as candidate serum/plasma biomarkers of pancreatic cancer. However, the distribution of apoA2 isoforms in patients with autoimmune pancreatitis (AIP) has not been investigated yet. In this study, we evaluated the distribution of serum apoA2 isoforms; i.e., homodimer apoA2-ATQ/ATQ, heterodimer apoA2-ATQ/AT, and homodimer apoA2-AT/AT, in AIP patients and healthy volunteers (HV) using enzyme-linked immunosorbent assays, and the clinical characteristics and serum levels of each apoA2 isoform in 32 AIP patients and 38 HV were investigated. The calculated apoA2-ATQ/AT levels of the AIP patients were significantly lower than those of the HV, which agreed with results obtained for patients with pancreatic cancer. Interestingly, most of the AIP patients exhibited high levels of apoA2-ATQ along with low levels of apoA2-AT, indicating that the processing of the C-terminal regions of apoA2 dimer was inhibited in the AIP patients. This specific distribution of serum apoA2 isoforms might provide important information about the disease states of AIP patients and aid the differential diagnosis of AIP versus pancreatic cancer. PMID- 29481803 TI - Tumor-targeting Salmonella typhimurium A1-R is a highly effective general therapeutic for undifferentiated soft tissue sarcoma patient-derived orthotopic xenograft nude-mouse models. AB - Undifferentiated soft tissue sarcoma (USTS) is a recalcitrant and heterogeneous subgroup of soft tissue sarcoma with high risk of metastasis and recurrence. Due to heterogeneity of USTS, there is no reliably effective first-line therapy. We have generated tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R), which previously showed strong efficacy on single patient-derived orthotopic xenograft (PDOX) models of Ewing's sarcoma and follicular dendritic cell sarcoma. In the present study, tumor resected from 4 patients with a biopsy-proven USTS (2 undifferentiated pleomorphic sarcoma [UPS], 1 undifferentiated sarcoma not otherwise specified [NOS] and 1 undifferentiated spindle cell sarcoma [USS]) were grown orthotopically in the biceps femoris muscle of mice to establish PDOX models. One USS model and one UPS model were doxorubicin (DOX) resistant. One UPS and the NOS model were partially sensitive to DOX. DOX is first-line therapy for these diseases. S. typhimurium A1-R arrested tumor growth all 4 models. In addition to arresting tumor growth in each case, S. typhimurium A1-R was significantly more efficacious than DOX in each case, thereby surpassing first line therapy. These results suggest that S. typhimurium A1-R can be a general therapeutic for USTS and possibly sarcoma in general. PMID- 29481804 TI - Cytochrome C oxydase deficiency: SURF1 gene investigation in patients with Leigh syndrome. AB - Leigh syndrome (LS) is a rare progressive neurodegenerative disorder occurring in infancy. The most common clinical signs reported in LS are growth retardation, optic atrophy, ataxia, psychomotor retardation, dystonia, hypotonia, seizures and respiratory disorders. The paper reported a manifestation of 3 Tunisian patients presented with LS syndrome. The aim of this study is the MT[HYPHEN]ATP6 and SURF1 gene screening in Tunisian patients affected with classical Leigh syndrome and the computational investigation of the effect of detected mutations on its structure and functions by clinical and bioinformatics analyses. After clinical investigations, three Tunisian patients were tested for mutations in both MT-ATP6 and SURF1 genes by direct sequencing followed by in silico analyses to predict the effects of sequence variation. The result of mutational analysis revealed the absence of mitochondrial mutations in MT-ATP6 gene and the presence of a known homozygous splice site mutation c.516-517delAG in sibling patients added to the presence of a novel double het mutations in LS patient (c.752-18 A > C/c. c.751 + 16G > A). In silico analyses of theses intronic variations showed that it could alters splicing processes as well as SURF1 protein translation. Leigh syndrome (LS) is a rare progressive neurodegenerative disorder occurring in infancy. The most common clinical signs reported in LS are growth retardation, optic atrophy, ataxia, psychomotor retardation, dystonia, hypotonia, seizures and respiratory disorders. The paper reported a manifestation of 3 Tunisian patients presented with LS syndrome. The aim of this study is MT-ATP6 and SURF1 genes screening in Tunisian patients affected with classical Leigh syndrome and the computational investigation of the effect of detected mutations on its structure and functions. After clinical investigations, three Tunisian patients were tested for mutations in both MT-ATP6 and SURF1 genes by direct sequencing followed by in silico analysis to predict the effects of sequence variation. The result of mutational analysis revealed the absence of mitochondrial mutations in MT-ATP6 gene and the presence of a known homozygous splice site mutation c.516-517delAG in sibling patients added to the presence of a novel double het mutations in LS patient (c.752-18 A>C/ c.751+16G>A). In silico analysis of theses intronic vaiations showed that it could alters splicing processes as well as SURF1 protein translation. PMID- 29481805 TI - Novel stable HBV producing cell line systems for expression and screening antiviral inhibitor of hepatitis B virus in human hepatoma cell line. AB - Chronic hepatitis B virus (HBV) infection is currently a major public health burden. Therefore, there is an urgent need for the development of novel antiviral inhibitors. The stable HBV-producing cell lines of genotype D are widely used to investigate the HBV life cycle and to evaluate antiviral agents. However, stable HBV-producing cell lines of different genotypes do not exist. To construct more convenient and efficient novel cell systems, stable cell lines of genotypes A, B, and C were established using a full-length HBV genome sequence isolated from chronic HBV patients in human hepatoma HepG2 cells. Novel HBV clones were identified and stable HBV-producing cell lines derived from these clones were constructed. HBV replication activities demonstrated time-dependent expression, and the novel cell lines were susceptible to several antiviral inhibitors with no cytotoxicity. Furthermore, infectious viruses were produced from these cell lines. In conclusion, we have established novel stable HBV-producing cell line systems of genotypes A, B, and C. These systems can provide valuable tools for screening antiviral agents and analyzing viral phenotypes in vitro. PMID- 29481806 TI - Interaction of MreB-derived antimicrobial peptides with membranes. AB - Antimicrobial peptides are critical components of defense systems in living forms. The activity is conferred largely by the selective membrane-permeabilizing ability. In our earlier work, we derived potent antimicrobial peptides from the 9 residue long, N-terminal amphipathic helix of E. coli MreB protein. The peptides display broad-spectrum activity, killing not only Gram-positive and Gram-negative bacteria but opportunistic fungus, Candida albicans as well. These results proved that membrane-binding stretches of bacterial proteins could turn out to be self harming when applied from outside. Here, we studied the membrane-binding and membrane-perturbing potential of these peptides. Steady-state tryptophan fluorescence studies with tryptophan extended peptides, WMreB1-9 and its N terminal acetylated analog, Ac-WMreB1-9 show preferential binding to negatively charged liposomes. Both the peptides cause permeabilization of E. coli inner and outer-membranes. Tryptophan-lacking peptides, though permeabilize the outer membrane efficiently, little permeabilization of the inner-membrane is observed. These data attest membrane-destabilization as the mechanism of rapid bacterial killing. This study is expected to motivate the research in identifying microbes' self-sequences to combat them. PMID- 29481807 TI - Gonadal hormones, but not sex, affect the acquisition and maintenance of a Go/No Go odor discrimination task in mice. AB - In mice, olfaction is crucial for identifying social odors (pheromones) that signal the presence of suitable mates. We used a custom-built olfactometer and a thirst-motivated olfactory discrimination Go/No-Go (GNG) task to ask whether discrimination of volatile odors is sexually dimorphic and modulated in mice by adult sex hormones. Males and females gonadectomized prior to training failed to learn even the initial phase of the task, which involved nose poking at a port in one location obtaining water at an adjacent port. Gonadally intact males and females readily learned to seek water when male urine (S+) was present but not when female urine (S-) was present; they also learned the task when non-social odorants (amyl acetate, S+; peppermint, S-) were used. When mice were gonadectomized after training the ability of both sexes to discriminate urinary as well as non-social odors was reduced; however, after receiving testosterone propionate (castrated males) or estradiol benzoate (ovariectomized females), task performance was restored to pre-gonadectomy levels. There were no overall sex differences in performance across gonadal conditions in tests with either set of odors; however, ovariectomized females performed more poorly than castrated males in tests with non-social odors. Our results show that circulating sex hormones enable mice of both sexes to learn a GNG task and that gonadectomy reduces, while hormone replacement restores, their ability to discriminate between odors irrespective of the saliency of the odors used. Thus, gonadal hormones were essential for both learning and maintenance of task performance across sex and odor type. PMID- 29481808 TI - High innate attractiveness to black targets in the blue blowfly, Calliphora vomitoria (L.) (Diptera: Calliphoridae). AB - Calliphora vomitoria is a myiasis-causing fly in many animal species including humans. The control of blowflies is still anchored on the use of chemicals. However, mass trapping and lure-and-kill techniques represent a promising alternative to pesticides. Visual and olfactory cues are the main stimuli routing the fly's landing behavior. Notably, color attractiveness has been barely explored in flies of medical and veterinary importance, with special reference to blowflies. In this study, we investigated the innate color preferences in C. vomitoria adults, testing binary combinations of painted targets under laboratory conditions. The identity of tested species C. vomitoria was confirmed by DNA sequencing (18S and cox1 genes). C. vomitoria flies showed a significant preference for black colored targets in all tested binary color combinations, after 5, 15, 30 and 60 min of exposure. Black targets were significantly preferred over blue, red, yellow and white ones. Spectral characteristics of all tested color combinations were quantified and the innate attraction of blowflies towards black targets was discussed in relation to their behavioral ecology. To the best of our knowledge, this is the first report on innate color preferences in the Calliphora genus. Our findings can be useful to develop new, cheap and reliable monitoring traps as well as "lure and kill" tools to control blowfly pests. PMID- 29481809 TI - Newer therapeutic strategies for soft-tissue sarcomas. AB - Metastatic soft-tissue sarcoma (STS), a devastating disease, has a median overall survival of only 12-18 months. Until recently, therapeutic options were limited and relied primarily on the use of anthracycline-based chemotherapy. Over the past two decades, improvement in the knowledge of the biology of STS has allowed the investigation of new therapeutic strategies including new cytotoxic agents, epigenetic drugs, specific targeted therapies, and immunotherapeutic treatments. PMID- 29481810 TI - Nutraceuticals and osteoarthritis pain. AB - Arthritis is a chronic disease of joints. It is highly prevalent, particularly in the elderly, and is commonly associated with pain that interferes with quality of life. Because of its chronic nature, pharmacological approaches to pain relief and joint repair must be safe for long term use, a quality many current therapies lack. Nutraceuticals refer to compounds or materials that can function as nutrition and exert a potential therapeutic effect, including the relief of pain, such as pain related to arthritis, of which osteoarthritis (OA) is the most common form. Of interest, nutraceuticals have recently been shown to have potential in relieving OA pain in human clinical trials. Emerging evidence indicates nutraceuticals may represent promising alternatives for the relief of OA pain. In this paper, we will overview OA pain and the use of nutraceuticals in OA pain management, focusing on those that have been evaluated by clinical trials. Furthermore, we discuss the biologic and pharmacologic actions underlying the nutraceutical effects on pain relief based on the potential active ingredients identified from traditional nutraceuticals in OA pain management and their potential for drug development. The review concludes by sharing our viewpoints that future studies should prioritize elucidating the mechanisms of action of nutraceuticals in OA and developing nutraceuticals that not only relieve OA pain, but also mitigate OA pathology. PMID- 29481811 TI - Behavioral testing and litter effects in the rabbit. AB - BACKGROUND: Behavioral testing provides an essential approach in further developing our understanding of brain structure and function. The aim of our study was to outline a more expanded approach to cognition- and anxiety-related behavior in the rabbit. METHODS: Twenty-one 70-day old rabbits (13 female, 8 male) were exposed to open field test, dark-light box test and object recognition testing with variations in inter-trial-interval, olfactory recognition and object location testing. Independent T-tests were used to compare data by individual baseline characteristics, i.e. birth weight, weight at testing, sex, litter #, litter size. RESULTS: In the open field test, median time spent in the center was 3.64 s (0.84-41.36) for the 9 rabbits who entered the center; median distance moved in the arena was 874.42 cm (54.20-3444.83). In the dark light box test, 12 rabbits entered the light compartment. In the object recognition task, rabbits spent significantly less time exploring the familiar object compared to the novel (0.40 s [0-2.8] vs. 3.17 s [1.30-32.69]; P = 0.003) when using a 30-min inter trial interval, as well with a 90-min inter-trial interval: 0.87 s [0-7.8] vs. 7.65 s [0-37.6] (P = 0.008). However, recognition was lost when using a 24-h inter-trial interval (time spent exploring the familiar object: 3.33 [0-10.90]; novel object:3.87 [1.15-48.53]; n.s). In the object location task and in olfactory object recognition task, median discrimination indexes were 0.69 (-1 to 1) and 0.37 (-0.38 to 0.78) respectively, higher than level expected by chance (P < 0.001). Litter size >3 during the neonatal period was associated with increased explorative behavior in the dark light box test (P = 0.046) and in the visual object recognition task (P = 0.005), whereas body weight and sex were not. CONCLUSIONS: Settings and outcome measures for multiple behavioral tests, providing reference values and considerations for future developmental studies are reported. Discrimination and memory in the rabbit appear to relate to litter characteristics, although a larger sample size is needed to confirm our findings. PMID- 29481812 TI - Food poisoning associated with ingestion of wild wasp broods in the upstream region of the Lancang river valley, Yunnan province, China. AB - INTRODUCTION: Food poisoning due to wild wasp broods ingestion has long been noted in the upstream region of the Lancang river valley, Yunnan province, China. This study describes the epidemiological and clinical features of the poisoning and possible causes. METHODS: Surveillance data collected between 2008 and 2016 were analyzed to produce demographic data on patients, information on clinical presentations, wasp species identification, and estimations of possible risk factors for symptomatic cases. RESULTS: Eleven poisoning events were associated with the ingestion of wild wasp broods, including 46 exposed persons with 31 symptomatic living cases and 8 deceased cases that were reported in the Yunnan province between 2008 and 2016. Poisoning cases were only detected in the upstream region of the Lancang river valley in the autumn. The severity of the symptoms was correlated with an evident dose-effect relationship regarding the quantity ingested. The mean latent period from wild wasp broods ingestion to the onset of the symptoms was 10 h for symptomatic living cases and 7 h for deceased cases, respectively. Both gastrointestinal and neurological symptoms were commonly observed in the poisoning cases. CONCLUSION: The toxin source may be indirectly caused by the wasp broods due to the prevalence of local poisonous plants, such as Tripterygium wilfordii Hook F, Tripterygium hypoglaucum Hutch and Vaccinium bracteatum Thunb. Educational programs at the start of wasp harvest season in September in the high-risk area should be carried out to reduce the incidence of poisonings. PMID- 29481813 TI - Investigation of Aspergillus flavus in animal virulence. AB - Aspergillus flavus is a common fungal pathogen of plants, animals and humans. Recently, many genes of A. flavus have been reported involving in regulation of pathogenesis in crops, but whether these genes are involved in animal virulence is still unknown. Here, we used a previous easy-to-use infection model for A. flavus based on mouse model by intravenous inoculation of A. flavus conidia. The outcome of infections in mice model showed that A. flavus NRRL3357 and laboratory strain CA14 PTS were both in dose dependent manner and highly reproducible. The progress of disease could be monitored by mice survival and histology analysis. Fungal burden analysis indicated it was gradually decreased within 7 days after infection. Moreover, aspergillosis caused by A. flavus significantly up-regulated gene expression levels of immune response mediators, including INF-gamma, TNF alpha, Dectin-1 and TLR2. Furthermore, the defined deletion A. flavus strains that previously displayed virulence in crop infection were also determined in this mouse model, and the results showed comparable degrees of infection in mice. Our results suggested that intravenous inoculation of conidia could be a suitable model for testing different A. flavus mutants in animal virulence. We hope to use this model to determine distinct A. flavus strains virulence in animals and study novel therapeutic methods to help control fungus diseases in the future. PMID- 29481814 TI - Baicalin is an inhibitor of subgroup J avian leukosis virus infection. AB - Avian leukosis virus subgroup J (ALV-J) can cause great economic losses to the poultry industry worldwide. Baicalin, one of the flavonoids present in S.baicalensis Georgi, has been shown to have antiviral activities. To investigate whether baicalin has antiviral effects on the infection of ALV-J in DF-1 cells, the cells were treated with baicalin at different time points. We found that baicalin could inhibit viral mRNA, protein levels and overall virus infection in a dose- and time-dependent manner using a variety of assays. Baicalin specifically targeted virus internalization and reduced the infectivity of ALV-J particles, but had no effect on the levels of major ALV-J receptor and virus binding to DF-1 cells. Collectively, these results suggest that baicalin might have potential to be developed as a novel antiviral agent for ALV-J infection. PMID- 29481815 TI - The ER-alpha36/EGFR signaling loop promotes growth of hepatocellular carcinoma cells. AB - Hepatocellular carcinoma (HCC) is the common primary liver cancer and the third leading cause of cancer related mortality worldwide. It is generally thought that the estrogen-signaling pathway is not related to the development and progression of human HCC. However, accumulating evidences indicate the existence of a rapid estrogen signaling in HCC cells that is able to promote cell growth. However, the receptor that mediates the rapid estrogen signaling in HCC cells has not been established. Previously, our laboratory identified a variant of ER-alpha, ER alpha36, and found that ER-alpha36 mediates the rapid estrogen signaling such as the activation of the MAPK/ERK signaling in breast carcinoma cells. Our current experiments studied the role of the rapid estrogen signaling mediated by ER alpha36 in growth of HCC HepG2 and PLC/PRF/5 cells that highly express ER-alpha36 and found these cells were strongly responsive to the rapid estrogen signaling. Knockdown of ER-alpha36 expression in these HCC cells using the shRNA method attenuated their responsiveness to estrogen and destabilized EGFR protein. ER alpha36 mediated estrogen-induced phosphorylation of Src and the MAPK/ERK as well as cyclin D1 expression. In addition, there existed an ER-alpha36/EGFR positive regulatory loop in HCC cells that was important for the maintenance and positive regulation of HCC tumorsphere cells. Our results thus indicated that the rapid estrogen receptor is mediated by ER-alpha36 in HCC cells through the EGFR/Src/ERK signaling pathway and suggested that the ER-alpha36/EGFR signaling loop is a potential target to develop novel therapeutic approaches for HCC treatment. PMID- 29481816 TI - A long-term quality-of-care score for predicting the occurrence of macrovascular diseases in patients with type 2 diabetes mellitus. AB - AIMS: The aim of this study was to develop a long-term quality-of-care score to predict the occurrence of macrovascular diseases in patients with type 2 diabetes mellitus, on the basis of the hypothesis that good quality of care can reduce the risk of macrovascular complications. METHODS: Using Taiwan's Longitudinal Cohort of Diabetes Patients Database and the medical records in a medical center, we identified the incident patients diagnosed with type 2 diabetes during 1999-2003 and followed them until 2011. A summary score (from 0 to 8) was calculated according to process indicators (frequencies of HbA1c and lipid profile testing and urine, foot and retinal examinations), intermediate outcome indicators (low density lipoprotein, blood pressure and HbA1c), and the co-morbidity of hypertension. We used Cox regression models to evaluate the association between the score and the incidence of macrovascular complications. RESULTS: Of the 4275 patients enrolled, 1928 developed macrovascular complication events after a mean follow-up period of 8.2 years. Compared to the risk of developing a macrovascular disease event in patients with scores <=1, the risk was 64% lower in those with quality-of-care scores >=5 (adjusted hazard ratio = 0.36; 95% confidence interval: 0.28-0.45). CONCLUSIONS: Good quality of care can reduce the risk of macrovascular diseases in patients with type 2 diabetes. The score developed in this study had a significant association with the risk of macrovascular complications and thus can be applied to guiding the care for these patients. PMID- 29481817 TI - Exercise and physical activity in people with Type 1 diabetes: The importance of behaviour change. PMID- 29481818 TI - Can administrative health utilisation data provide an accurate diabetes prevalence estimate for a geographical region? AB - AIM: To validate the New Zealand Ministry of Health (MoH) Virtual Diabetes Register (VDR) using longitudinal laboratory results and to develop an improved algorithm for estimating diabetes prevalence at a population level. METHODS: The assigned diabetes status of individuals based on the 2014 version of the MoH VDR is compared to the diabetes status based on the laboratory results stored in the Auckland regional laboratory result repository (TestSafe) using the New Zealand diabetes diagnostic criteria. The existing VDR algorithm is refined by reviewing the sensitivity and positive predictive value of the each of the VDR algorithm rules individually and as a combination. RESULTS: The diabetes prevalence estimate based on the original 2014 MoH VDR was 17% higher (n = 108,505) than the corresponding TestSafe prevalence estimate (n = 92,707). Compared to the diabetes prevalence based on TestSafe, the original VDR has a sensitivity of 89%, specificity of 96%, positive predictive value of 76% and negative predictive value of 98%. The modified VDR algorithm has improved the positive predictive value by 6.1% and the specificity by 1.4% with modest reductions in sensitivity of 2.2% and negative predictive value of 0.3%. At an aggregated level the overall diabetes prevalence estimated by the modified VDR is 5.7% higher than the corresponding estimate based on TestSafe. CONCLUSION: The Ministry of Health Virtual Diabetes Register algorithm has been refined to provide a more accurate diabetes prevalence estimate at a population level. The comparison highlights the potential value of a national population long term condition register constructed from both laboratory results and administrative data. PMID- 29481819 TI - Pharmacologic inhibition of the enzymatic effects of tissue transglutaminase reduces cardiac fibrosis and attenuates cardiomyocyte hypertrophy following pressure overload. AB - Tissue transglutaminase (tTG) is a multifunctional protein with a wide range of enzymatic and non-enzymatic functions. We have recently demonstrated that tTG expression is upregulated in the pressure-overloaded myocardium and exerts fibrogenic actions promoting diastolic dysfunction, while preventing chamber dilation. Our current investigation dissects the in vivo and in vitro roles of the enzymatic effects of tTG on fibrotic remodeling in pressure-overloaded myocardium. Using a mouse model of transverse aortic constriction, we demonstrated perivascular and interstitial tTG activation in the remodeling pressure-overloaded heart. tTG inhibition through administration of the selective small molecule tTG inhibitor ERW1041E attenuated left ventricular diastolic dysfunction and reduced cardiomyocyte hypertrophy and interstitial fibrosis in the pressure-overloaded heart, without affecting chamber dimensions and ejection fraction. In vivo, tTG inhibition markedly reduced myocardial collagen mRNA and protein levels and attenuated transcription of fibrosis-associated genes. In contrast, addition of exogenous recombinant tTG to fibroblast-populated collagen pads had no significant effects on collagen transcription, and instead increased synthesis of matrix metalloproteinase (MMP)3 and tissue inhibitor of metalloproteinases (TIMP)1 through transamidase-independent actions. However, enzymatic effects of matrix-bound tTG increased the thickness of pericellular collagen in fibroblast-populated pads. tTG exerts distinct enzymatic and non enzymatic functions in the remodeling pressure-overloaded heart. The enzymatic effects of tTG are fibrogenic and promote diastolic dysfunction, but do not directly modulate the pro-fibrotic transcriptional program of fibroblasts. Targeting transamidase-dependent actions of tTG may be a promising therapeutic strategy in patients with heart failure and fibrosis-associated diastolic dysfunction. PMID- 29481820 TI - Essential tremor quantification based on the combined use of a smartphone and a smartwatch: The NetMD study. AB - BACKGROUND: The use of wearable technology is an emerging field of research in movement disorders. This paper introduces a clinical study to evaluate the feasibility, clinical correlation and reliability of using a system based in smartwatches to quantify tremor in essential tremor (ET) patients and check its acceptance as clinical monitoring tool. NEW METHOD: The system is based on a commercial smartwatch and an Android smartphone. An investigational Android application controls the process of recording raw data from the smartwatch three dimensional gyroscopes. Thirty-four ET patients were consecutively enrolled in the experiments and assessed along one year. Arm tremor was videofilmed and scored using the Fahn-Tolosa-Marin Tremor Rating Scale (FTM-TRS). Tremor intensity was quantified with the root mean square of angular velocity measured in the patients' wrists. RESULTS: Eighty-two assessments with smartwatches were performed. Spearman's correlation coefficients (rho) between clinical tremor (FTM TRS) scores and smartwatch measures for tremor intensity were 0.590 at rest; rho = 0.738 in steady posture; rho = 0.189 in finger-to-nose maneuvers; and rho = 0.652 in pouring water task. Smartwatch reliability was checked by intraclass realiability coefficients: 0.85, 0.95, 0.91, 0.95 respectively. Most of patients showed good acceptance of the system. COMPARISON WITH EXISTING METHOD(S): This commodity hardware contributes to quantify tremor objectively in a consulting room by customized Android smart devices as clinical monitoring tool. CONCLUSIONS: The NetMD system for tremor analysis is feasible, well-correlated with clinical scores, reliable and well-accepted by patients to tremor follow-up. Therefore, it could be an option to objectively quantify tremor in ET patients during their regular follow-up. PMID- 29481821 TI - The efficacy of direct anti-HCV drugs improves early post-liver transplant survival and induces significant changes in waiting list composition. AB - BACKGROUND & AIMS: The efficacy of direct-acting antivirals (DAAs) has dramatically changed the prognosis of patients with chronic hepatitis C. We aimed to evaluate the impact of DAA therapy on the composition of the liver transplant (LT) waiting list and the early post-transplant survival. METHODS: We evaluated all patients admitted to the waiting list for a primary LT between 1st January 2008 and 31st of December 2016 in Catalonia, Spain. Time span was divided into two periods according to the availability of different antiviral therapies: 2008 2013 (interferon-based therapies) and 2014-2016 (DAA). Changes in the indications of LT and the aetiology of liver disease, as well as post-LT patient survival, were evaluated according to the year of inclusion and transplantation, respectively. RESULTS: We included 1,483 patients. Admissions in the waiting list for hepatitis C virus (HCV)-related liver disease decreased significantly, from 47% in 2008-2013 to 35% in 2014-2016 (p <0.001), particularly because of a reduction in patients with decompensated cirrhosis. In contrast, NASH-related inclusions increased from 4% to 7% (p = 0.003). Three-year post-LT patient survival increased significantly in the second period in the whole cohort (82% vs. 91%, p = 0.002), because of better survival in anti-HCV positive patients (76% vs. 91%, p = 0.001), but not in anti-HCV negative patients (88% vs. 91% p = 0.359). Anti-HCV positive serology, the time period of 2008-2013 and higher donor age were independently associated with post-LT mortality in the whole cohort; while time period and donor age were independently associated with post-LT mortality in anti-HCV positive recipients. CONCLUSIONS: The high efficacy of DAAs is associated with significant changes in the composition of the LT waiting list and, more importantly, results in improved post-transplant survival. LAY SUMMARY: The efficacy of the new direct-acting antivirals is associated with a significant improvement in survival of patients undergoing liver transplantation because of hepatitis C virus-related liver disease. In addition, it has decreased the number of patients with hepatitis C that need a liver transplant. PMID- 29481822 TI - Extended logistic growth model for heterogeneous populations. AB - Cell proliferation is the most important cellular-level mechanism responsible for regulating cell population dynamics in living tissues. Modern experimental procedures show that the proliferation rates of individual cells can vary significantly within the same cell line. However, in the mathematical biology literature, cell proliferation is typically modelled using a classical logistic equation which neglects variations in the proliferation rate. In this work, we consider a discrete mathematical model of cell migration and cell proliferation, modulated by volume exclusion (crowding) effects, with variable rates of proliferation across the total population. We refer to this variability as heterogeneity. Constructing the continuum limit of the discrete model leads to a generalisation of the classical logistic growth model. Comparing numerical solutions of the model to averaged data from discrete simulations shows that the new model captures the key features of the discrete process. Applying the extended logistic model to simulate a proliferation assay using rates from recent experimental literature shows that neglecting the role of heterogeneity can, at times, lead to misleading results. PMID- 29481823 TI - Targeted suicide gene transfections reveal promising results in nu/nu mice with aggressive neuroblastoma. AB - Neuroblastoma represents the third most common malign neoplasm occurring in children and the most common in newborn. Although mortality in childhood cancer declined in the last decade, high-risk patients have poor prospects, due to the aggressiveness of the cancer. In the recent past, we underlined the potential of sapofectosid as novel and efficient transfection enhancer, demonstrating non toxic gene delivery, but its value in tumor therapies has yet to be elucidated. A suicide gene, coding for saporin, a ribosome-inactivating protein type I, was incorporated into targeted, peptide-based nanoplexes. The nanoplexes were characterized for their size, zeta potential and appearance by electron microscopy. Gene delivery was observed via confocal imaging. In vitro transfections were conducted to monitor the real-time cell viability. After initial tolerability studies, NMRI nu/nu-mice bearing tumors from Neuro-2A-Luc cells (murine neuroblastoma cells, transduced with a luciferase gene), were treated with targeted nanoplexes (30 MUg saporin-DNA i.v./treatment) and sapofectosid (30 MUg s.c. treatment). The treatment was compared to a vehicle (PBS) control and treatment without sapofectosid in terms of body weight, tumor growth and integrated density of tumor luminescence. The study revealed an anti tumoral effect of the sapofectosid mediated gene therapy in the Neuro-2A-tumor model. The treatments were well tolerated by the animals indicating the applicability of this approach. With these results, we were able to proof the efficacy of a therapy, consisting of targeted suicide gene nanoplexes and sapofectosid, a novel and potent transfection enhancer. This study points out the enormous value for future targeted cancer and gene therapies. PMID- 29481825 TI - Chronic stress induced duration dependent alterations in immune system and their reversibility in rats. AB - The objective was to find out whether severity of stress effects on immunity increases with duration of exposure and recovery depends on duration of exposure. Adult male rats (n = 30) were subjected to restraint (1 h) followed by forced swimming exercise (15 min) after a gap of 4 h daily for 2, 4 and 8 weeks and allowed to recover for 6 weeks after each exposure period. Exposure of rats to stress resulted in duration dependent significant decreases in leukocyte count, phagocytic indices of neutrophils, number of bone marrow stem cells and serum levels of IL-12 and increases in apoptotic index of peripheral blood mononuclear cells and serum levels of IL-10. The alterations in counts of neutrophils, total immunoglobulin content, phagocytic index, apoptotic index of peripheral blood mononuclear cells and serum levels of IL-10 returned to control levels in recovery group rats of 2 and 4 weeks exposure but not in that of 8 weeks exposure. However, alterations in number and apoptotic index of bone marrow stem cells returned to control levels in 2, 4 and 8 weeks stress recovery groups. The results for the first time reveal that increase in duration of exposure results in more severe damage in immune system and that shorter the exposure period, faster the recovery. In addition, in vitro study for the first time showed that corticosterone causes apoptosis of peripheral blood mononuclear cells and bone marrow stem cells in dose dependent manner. Hence death of leukocytes and their stem cells is the major cause of stress induced immune dysfunction. PMID- 29481824 TI - Regulation of immunophenotype modulation of monocytes-macrophages from M1 into M2 by prostate cancer cell-culture supernatant via transcription factor STAT3. AB - BACKGROUND: Transcription factor STAT3 has a prominent innate immunity effect on cancer progression. We determined the regulation of STAT3 in the immunophenotype modulation of macrophages from M1 into M2 induced by the cell-culture supernatant of the Prostate-Cancer line PC3. METHODS: Monocytes-macrophages from healthy donors were cultured in the supernatant of PC3 cells, membrane proteins, and intracytoplasmic and phosphorylated STAT3 were measured using flow cytometry, while cytokines and growth factors were studied using luminescence. Cytotoxicity and nitric oxide were evaluated via colorimetric assays. RESULTS: The supernatant of PC3 prostate-tumor cells effectively induced macrophages toward an M2 profile, and the expression of phosphorylated STAT3 in the monocytes-macrophages notably increased, and mainly related to IL-10. In the group of monocytes-macrophages treated with a STAT3 inhibitor, the macrophages were induced toward an M1 phenotype. CONCLUSIONS: In this study, we showed that the secretion profile of PC3 prostate-cancer cells induces a change in macrophage phenotype from M1 into M2, and that the phenomenon is related to phosphorylation of transcription factor STAT3 and IL-10. PMID- 29481826 TI - Transcriptomic studies in tolerance: Lessons learned and the path forward. AB - Immunosuppression after solid organ transplantation is a delicate balance of the immune response and is a complex phenomenon with many factors involved. Despite advances in the care of patients receiving organ transplants the adverse effects associated with immunosuppressive agents and the risks of long-term immunosuppression present a series of challenges and the need to weigh the risks and benefits of either over or under-immunosuppression. Ideally, if all transplant recipients could develop donor-specific immunological tolerance, it could drastically improve long-term graft survival without the need for immunosuppressive agents. In the absence of this ideal situation, the next best approach would be to develop tools to determine the adequacy of immunosuppression in each patient, in a manner that would individualize or personalize therapy. Despite current genomics-based studies of tolerance biomarkers in transplantation there are currently, no clinically validated tools to safely increase or decrease the level of IS that is beneficial to the patient. However, the successful identification of biomarkers and/or mechanisms of tolerance that have implications on long-term graft survival and outcomes depend on proper integration of study design, experimental protocols, and data-driven hypotheses. The objective of this article is to first, discuss the progress made on genomic biomarkers of immunological tolerance and the future avenues for the development of such biomarkers specifically in kidney transplantation. Secondly, we provide a set of guiding principles and identify the pitfalls, advantages, and drawbacks of studies that generate genomic data aimed at understanding transplant tolerance that is applicable to all solid transplants. PMID- 29481827 TI - Public support for safe consumption sites and syringe services programs to combat the opioid epidemic. AB - We examine Americans' support for two evidence-based harm reduction strategies - safe consumption sites and syringe exchange programs - and their attitudes about individuals who use opioids. We conducted a web-based survey of a nationally representative sample of U.S. adults in July-August 2017 (N = 1004). We measured respondents' support for legalizing safe consumption sites and syringe services programs in their communities and their attitudes toward people who use opioids. We used ordered logistic regression to assess how stigmatizing attitudes toward people who use opioids, political party identification, and demographic characteristics correlated with support for the two harm reduction strategies. Twenty-nine percent of Americans supported legalizing safe consumption sites and 39% supported legalizing syringe services programs. Respondents reported high levels of stigmatizing attitudes toward people who use opioids: 16% of respondents were willing to have a person using opioids marry into their family and 28% were willing to have a person using opioids start working closely with them on a job, and 27% and 10% of respondents rated persons who use opioids as deserving (versus worthless) and strong (versus weak). Stigmatizing attitudes were associated with lower support for legalizing safe consumption sites and syringe services programs. Democrats and Independents were more likely than Republicans to support both strategies. Stigmatizing attitudes toward people who use opioids are a key modifiable barrier to garnering the public support needed to fully implement evidence-based harm reduction strategies to combat the opioid epidemic. Dissemination and evaluation of stigma reduction campaigns are a public health priority. PMID- 29481828 TI - Dissociating absolute and relative reward- and punishment-related electrocortical processing: An event-related potential study. AB - The meaning of reward and punishment signals depends on context. Receiving a small reward where a larger reward could have been obtained can be considered a punishment, while a small loss in the context of avoiding a larger loss can be experienced as a reward. The aim of this study was to investigate the electrophysiological processes associated with absolute and relative reward and punishment signals. Twenty healthy right-handed volunteers performed a decision making task and were instructed to judge which of two neutral objects was the most expensive. The received outcome was presented together with the non-received outcome for the alternative choice. The feedback-related potentials P200, FRN and P300 were recorded in response to absolute (i.e., received) outcome and relative (i.e., received in the context of the alternative) outcome. Absolute rewards yielded higher P200 amplitudes as compared to relative rewards, while the P200 amplitude was largest for relative as compared to absolute punishments. The P300 amplitude showed a main effect of valence with larger amplitudes for more positive relative and absolute outcomes. No effect of absolute or relative outcome was observed for the feedback-related negativity (FRN). Our findings suggest distinct processes associated with context-dependent and context independent processing during feedback processing. PMID- 29481829 TI - Evaluating personality as a moderator of the association between life events stress and cardiovascular reactivity to acute stress. AB - The present study investigated the possible interaction between life events stress and personality in predicting cardiovascular stress responses. Participants (N = 184) completed psychometric measures of life event stress and personality styles and had cardiovascular responses monitored during a standardised stress testing protocol. In adjusted models, the observed blunted association between life event stress and SBP and DBP was moderated by openness; this was more evident at -1SD below the mean openness value. Further, the association between life event stress and TPR vascular resistance was found to be moderated by conscientiousness. In particular, we found conscientiousness at both the mean and 1SD above the mean buffered against the negative impact of life stress on TPR reactivity. The findings are discussed in relation to theory and future directions. PMID- 29481830 TI - Reproducibility and replicability in zebrafish behavioral neuroscience research. AB - Reproducibility and replicability are fundamentally important aspects of the scientific method. From time to time the discussion about whether scientific findings are replicable enough flares up. In fact, some recent publications claim we are witnessing a replication crisis. This is a particularly important problem in laboratory organisms that are relatively new, i.e., for which only limited amount of information is available, and for which only a limited number of methods have been developed. The zebrafish is a relative newcomer in behavioral neuroscience. This review considers four distinct reasons as possibly underlying reproducibility issues in behavioral neuroscience studies using the zebrafish. One, publication bias for positive results. Two, statistical issues that surround the question of how to address type 1 and type 2 errors, and how to make statistical inference. Three, inappropriate control of factors that are known to potentially influence results. And four, methodological issues stemming from insufficient understanding of factors that may influence experimental results. The review will mainly focus on experimental issues and solutions, i.e. the latter two reasons listed above. It is not intended to be comprehensive, and its examples are drawn mainly from the author's own studies and experience with zebrafish. Nevertheless, most issues discussed are not unique to his laboratory, to the zebrafish, or even to behavioral neuroscience. PMID- 29481831 TI - Obstetric competence and compliance with surgical hand antisepsis prior to elective and emergency surgical procedures: a closed-loop audit. PMID- 29481832 TI - World Antibiotic Awareness Week 2017 and its influence on digital information seeking on antibiotic resistance: A Google Trends study. PMID- 29481834 TI - Recurrent wheezing in children following human metapneumovirus infection. PMID- 29481833 TI - Autophagy modulates transforming growth factor beta 1 induced epithelial to mesenchymal transition in non-small cell lung cancer cells. AB - Lung cancer is considered one of the most frequent causes of cancer-related death worldwide and Non-Small Cell Lung Cancer (NSCLC) accounts for 80% of all lung cancer cases. Autophagy is a cellular process responsible for the recycling of damaged organelles and protein aggregates. Transforming growth factor beta-1 (TGFbeta1) is involved in Epithelial to Mesenchymal Transition (EMT) and autophagy induction in different cancer models and plays an important role in the pathogenesis of NSCLC. It is not clear how autophagy can regulate EMT in NSCLC cells. In the present study, we have investigated the regulatory role of autophagy in EMT induction in NSCLC and show that TGFbeta1 can simultaneously induce both autophagy and EMT in the NSCL lines A549 and H1975. Upon chemical inhibition of autophagy using Bafilomycin-A1, the expression of the mesenchymal marker vimentin and N-cadherin was reduced. Immunoblotting and immunocytochemistry (ICC) showed that the mesenchymal marker vimentin was significantly downregulated upon TGFbeta1 treatment in ATG7 knockdown cells when compared to corresponding cells treated with scramble shRNA (negative control), while E-cadherin was unchanged. Furthermore, autophagy inhibition (Bafilomycin A1 and ATG7 knockdown) decreased two important mesenchymal functions, migration and contraction, of NSCLC cells upon TGFbeta1 treatment. This study identified a crucial role of autophagy as a potential positive regulator of TGFbeta1-induced EMT in NSCLC cells and identifies inhibitors of autophagy as promising new drugs in antagonizing the role of EMT inducers, like TGFbeta1, in the clinical progression of NSCLC. PMID- 29481835 TI - Inhaled corticosteroids in infants and toddlers attenuate linear growth. PMID- 29481836 TI - Nonclinical evaluation of immunological safety in Gottingen Minipigs: The CONFIRM initiative. AB - There is a growing need to consider non-rodent species for the immunological safety evaluation of drug candidates. The EU Framework-6 RETHINK Project demonstrated that the Gottingen Minipig is a relevant animal model for regulatory toxicology studies. Extensive knowledge on the immune system of domestic pigs is available and fewer differences from humans have been identified as compared to other species, such as mice or non-human primates. Minipig data are too scarce to allow for claiming full immunological comparability with domestic pigs. Another gap limiting minipig use for immunological safety evaluation is the lack of a qualified and validated database. However, available data lend support to the use of minipigs. The need for a COllaborative Network For Immunological safety Research in Minipigs (the CONFIRM Initiative) was obvious. It is intended to trigger immunological safety research in Gottingen Minipigs, to assist and synergize fundamental, translational and regulatory investigative efforts relevant to the immunological safety evaluation of pharmaceuticals and biologics, and to spread current knowledge and new findings to the scientific and regulatory toxicology community. PMID- 29481837 TI - Allergenic sensitization versus elicitation risk criteria for novel food proteins. AB - The value of criteria used in the weight-of-evidence assessment of allergenic risk of genetically modified (GM) crops has been debated. This debate may originate, in part, from not specifying if the criteria are intended to contribute to the assessment of sensitization risk or elicitation risk. Here, this distinction is explicitly discussed in the context of exposure and hazard. GM crops with structural relationships with known allergens or sourced from an organism known to cause allergy (hazard) are screened for IgE-antibody reactivity using serum from sensitized individuals. If IgE reactivity is observed, the GM crop is not developed. While digestive and heat stability impact exposure and thus the elicitation risk to sensitized individuals, these attributes are not interpretable relative to sensitization risk. For novel food proteins with no identified hazard, heat stability cannot be validly assessed because relevant IgE antibodies are not available. Likewise, the uncertain and sometime non-monotonic dose relationship between oral exposure to allergens and sensitization makes digestive stability a poor predictor of sensitization risk. It is hoped that by explicitly distinguishing between sensitization risk and elicitation risk, some of the debate surrounding the weight-of evidence criteria for predicting the allergenic risk of GM crops can be resolved. PMID- 29481838 TI - mTORC2 Signaling: A Path for Pancreatic beta Cell's Growth and Function. AB - The mechanistic target of rapamycin (mTOR) signaling pathway is an evolutionary conserved pathway that senses signals from nutrients and growth factors to regulate cell growth, metabolism and survival. mTOR acts in two biochemically and functionally distinct complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2), which differ in terms of regulatory mechanisms, substrate specificity and functional outputs. While mTORC1 signaling has been extensively studied in islet/beta-cell biology, recent findings demonstrate a distinct role for mTORC2 in the regulation of pancreatic beta-cell function and mass. mTORC2, a key component of the growth factor receptor signaling, is declined in beta cells under diabetogenic conditions and in pancreatic islets from patients with type 2 diabetes. beta cell selective mTORC2 inactivation leads to glucose intolerance and acceleration of diabetes as a result of reduced beta-cell mass, proliferation and impaired glucose-stimulated insulin secretion. Thereby, many mTORC2 targets, such as AKT, PKC, FOXO1, MST1 and cell cycle regulators, play an important role in beta-cell survival and function. This indicates mTORC2 as important pathway for the maintenance of beta-cell homeostasis, particularly to sustain proper beta-cell compensatory response in the presence of nutrient overload and metabolic demand. This review summarizes recent emerging advances on the contribution of mTORC2 and its associated signaling on the regulation of glucose metabolism and functional beta-cell mass under physiological and pathophysiological conditions in type 2 diabetes. PMID- 29481839 TI - Anammox Organism KSU-1 Expresses a Novel His/DOPA Ligated Cytochrome c. AB - Anammox is a bacterial energy metabolic process that forms N2 gas from nitrite and ammonium ions. The enzymatic mechanisms of anammox have been gradually revealed; however, the electron transport chain in anammox bacteria remains poorly understood. In the present study, we purified and characterized two low molecular-weight c-type cytochromes from an enriched culture of the anammox bacterium strain, KSU-1. Their genes, KSU1_B0428 and KSU1_C0855, were identified in the KSU-1 genome, and their recombinant proteins were characterized. KSU1_B0428 is a typical c-type cytochrome with a His/Met coordinated heme, acting as an electron transfer protein. In contrast, KSU1_C0855 could not be assigned as a known cytochrome and its heme was suggested to have an uncommon axial ligand set. Crystal structural analyses of C0855 clearly showed that its heme iron is coordinated by His15 as a fifth ligand. Moreover, the sixth coordination site is occupied by the aromatic ring of Tyr60, and an unassignable electron density that is inseparable with that of aromatic carbon of Tyr60 was found. The additional electron density was assigned to an O atom by molecular mass analyses. Therefore, Tyr60 would be chemically modified to 3,4-dihydroxyphenylalanine and bound to the Fe atom. We revealed that an anammox bacterium strain KSU-1 expresses a novel cytochrome c having an unprecedented His/3,4-dihydroxyphenylalanine coordinating heme. The expression of the novel c-type cytochrome might be required for the redox reaction of the anammox process. PMID- 29481840 TI - Selenium, selenoprotein P, and Alzheimer's disease: is there a link? AB - The essential trace element, selenium (Se), is crucial to the brain but it may be potentially neurotoxic, depending on dosage and speciation; Se has been discussed for decades in relation to Alzheimer's disease (AD). Selenoprotein P (SELENOP) is a secreted heparin-binding glycoprotein which serves as the main Se transport protein in mammals. In vivo studies showed that this protein might have additional functions such as a contribution to redox regulation. The current review focuses on recent research on the possible role of SELENOP in AD pathology, based on model and human studies. The review also briefly summarizes results of epidemiological studies on Se supplementation in relation to brain diseases, including PREADViSE, EVA, and AIBL. Although mainly positive effects of Se are assessed in this review, possible detrimental effects of Se supplementation or exposure, including potential neurotoxicity, are also mentioned. In relation to AD, various roles of SELENOP are discussed, i.e. as the means of Se delivery to neurons, as an antioxidant, in cytoskeleton assembly, in interaction with redox-active metals (copper, iron, and mercury) and with misfolded proteins (amyloid-beta and hyperphosphorylated tau-protein). PMID- 29481841 TI - Whole-genome analysis of structural variations between Xiang pigs with larger litter sizes and those with smaller litter sizes. AB - To gain a better knowledge of structural variations (SVs) in Xiang pig, we used next-generation sequencing to analyze the Xiang pigs with larger (XL) or smaller litter sizes (XS). Our analysis yielded 28,040 putative SVs in the Xiang pig. These SVs distributed throughout all of chromosomes. Some functional regions including exons and untranslated regions were less varied than introns and intergenic regions. We detected 4637 and 4119 specific SVs, which contained 1697 and 1582 genes in XL and XS group, respectively. These genes were mainly enriched in the well-known pathways involved in development and reproduction processes. Population validation was carried out on 50 SVs candidates using PCR method in 144 Xiang pig crowds. All of 50 SVs were confirmed by PCR method and 14 SVs were associated with the litter size of Xiang pigs. These results may be helpful for the elucidation of growth and reproduction regulation in Xiang pig. PMID- 29481842 TI - A novel gene and pathway-level subtyping analysis scheme to understand biological mechanisms in complex disease: a case study in rheumatoid arthritis. AB - Complex diseases have heterogeneous underlying molecular mechanisms. In order to improve the diagnosis and treatment of disease, it is vital to stratify patients into homogeneous subgroups that share a similar disease etiology. In this study, we performed gene-level subtyping analysis on two independent Rheumatoid Arthritis gene expression cohorts from different ethnic groups to discover the possible disease mechanisms associated with each subtype. Also, a novel pathway level analysis is proposed to increase the subtyping robustness and facilitate biological interpretation. This approach could stratify RA patients into two robust and homogeneous groups with differing activation of central signal transduction pathways and pro-inflammatory cytokines in the pathogenesis of RA. Such a methodology can help understand disease mechanisms at play in different patient sub-populations and also potentially explain why some patients don't respond to anti-TNF treatment. PMID- 29481843 TI - MicroRNA-target gene responses to root knot nematode (Meloidogyne incognita) infection in cotton (Gossypium hirsutum L.). AB - MicroRNAs (miRNAs) are a large class of small regulatory RNA molecules, however no study has been performed to elucidate the role of miRNAs in cotton (Gossypium hirsutum) response to the root knot nematode (RKN, Meloidogyne incognita) infection. We selected 28 miRNAs and 8 miRNA target genes to investigate the miRNA-target gene response to M. incognita infection. Our results show that RKN infection significantly affected the expression of several miRNAs and their targeted genes. After 10 days of RKN infection, expression fold changes on miRNA expressions ranged from down-regulated by 33% to upregulated by 406%; meanwhile the expression levels of miRNA target genes were 45.8% to 231%. Three miRNA target pairs, miR159-MYB, miR319-TCP4 and miR167-ARF8, showed inverse expression patterns between gene targets and their corresponded miRNAs, suggesting miRNA mediated gene regulation in cotton roots in response to RKN infection. PMID- 29481845 TI - Atypical assortative mating based on body size in an explosive-breeding toad from a tropical island of southern China. AB - Mating patterns exhibit considerable intra- and interspecific variation. Sexual selection can lead to the occurrence of random and assortative mating in different populations of the same species. Thus, understanding variation in mating decisions is crucial to understanding variation in the direction of sexual selection. We investigated natural mating patterns in Black-spectacled toads (Duttaphrynus melanostictus), an explosive-breeding species that breeds throughout the year. We captured amplectant pairs (137) and non-amplectant males (212) during breeding seasons from November 2016 to April 2017 in tropical-island population of southern China. Our study found no significant difference in snout vent length (SVL) between amplectant and non-amplectant males. Female and male SVL were positively correlated with each other. Small females were paired more frequently with small males, less frequently with large males, but had no preference for or against medium males. Medium females exhibited no preference. Large females showed no preference for large males, but were paired less frequently with small males. These data suggested that successful amplectant males had body sizes representative of the entire population. Both random and size-assortative mating were present simultaneously in the same population and within the same breeding season. Female choice was important in shaping the mating behavior of Black-spectacled toads, promoting genotype-frequency stabilization and body-size diversity in the population. PMID- 29481844 TI - Non-Glycanated Biglycan and LTBP4: Leveraging the extracellular matrix for Duchenne Muscular Dystrophy therapeutics. AB - The extracellular matrix (ECM) plays key roles in normal and diseased skeletal and cardiac muscle. In healthy muscle the ECM is essential for transmitting contractile force, maintaining myofiber integrity and orchestrating cellular signaling. Duchenne Muscular Dystrophy (DMD) is caused by loss of dystrophin, a cytosolic protein that anchors a transmembrane complex and serves as a vital link between the actin cytoskeleton and the basal lamina. Loss of dystrophin leads to membrane fragility and impaired signaling, resulting in myofiber death and cycles of inflammation and regeneration. Fibrosis is also a cardinal feature of DMD. In this review, we will focus on two cases where understanding the normal function and regulation of ECM in muscle has led to the discovery of candidate therapeutics for DMD. Biglycan is a small leucine rich repeat ECM protein present as two glycoforms in muscle that have dramatically different functions. One widely expressed form is biglycan proteoglycan (PG) that bears two chondroitin sulfate GAG chains (typically chondroitin sulfate) and two N-linked carbohydrates. The second glycoform, referred to as 'NG' (non-glycanated) biglycan, lacks the GAG side chains. NG, but not PG biglycan recruits utrophin, an autosomal paralog of dystrophin, and an NOS-containing signaling complex to the muscle cell membrane. Recombinant NG biglycan can be systemically delivered to dystrophic mice where it upregulates utrophin at the membrane and improves muscle health and function. An optimized version of NG biglycan, 'TVN-102', is under development as a candidate therapeutic for DMD. A second matrix-embedded protein being evaluated for therapeutic potential is latent TGFbeta binding protein 4 (LTBP4). Identified in a genomic screen for modifiers of muscular dystrophy, LTBP4 binds both TGFbeta and myostatin. Genetic studies identified the hinge region of LTBP4 as linked to TGFbeta release and contributing to the "hyper TGFbeta" signaling state that promotes fibrosis in muscular dystrophy. This hinge region can be stabilized by antibodies directed towards this domain. Stabilizing the hinge region of LTBP4 is expected to reduce latent TGFbeta release and thus reduce fibrosis. PMID- 29481846 TI - Hypothalamus and pituitary transcriptome profiling of male and female Hong Kong grouper (Epinephelus akaara). AB - Hong Kong grouper (Epinephelus akaara) is an important commercially cultured marine fish in Asia, and a protogynous hermaphrodite with the "diandry" pattern. In order to explore the gene expression patterns of hypothalamus and pituitary between male and female Hong Kong grouper, we used RNA-seq technology to investigate transcriptomes of both tissues in immature and mature male and female adults. This produced 227,227,148 and 215,858,948 high quality reads from hypothalamus and pituitary, which were jointly assembled into 199,203 unigenes. Among them, 30,786 unigenes were mapped to known genes. Differential expression analysis revealed 275 unigenes that were differentially expressed between immature male and female adults and 561 between mature male and female adults. According to annotation and KEGG information, these differentially expressed genes (DEGs) were involved in development, metabolism, and regulation of transcription. One DEG, amino-terminal enhancer of split (AES), a member of the Groucho/transducin-like enhancer of split family of transcriptional regulators that played important roles in neurogenesis, segmentation, and sex determination, was significantly upregulated in male individuals in both immature and mature adult comparisons, indicating it may be involved in male reproductive function during development. Our report, for the first time, uses RNA-seq technology to investigate transcriptomes of both hypothalamus and pituitary in teleost fish, and provides a basis for further studies of molecular mechanism of sex determination and development in Hong Kong grouper. PMID- 29481847 TI - Ayu C-reactive protein/serum amyloid P agglutinates bacteria and inhibits complement-mediated opsonophagocytosis by monocytes/macrophages. AB - The short-chain pentraxins (PTXs), including C-reactive protein (CRP) and serum amyloid P (SAP), are soluble pattern recognition molecules (PRMs) that exhibit calcium-dependent binding to bacterial surface molecules. They opsonize pathogens or other particles by phagocytic clearance. However, the detailed functions of short-chain PTXs in teleosts remained unclear. In this study, we identified a short-chain PTX gene from ayu, Plecoglossus altivelis, and tentatively named as PaCRP/SAP. Sequence analysis revealed that PaCRP/SAP has typical characteristics of fish CRP/SAP and is mostly closely related to rainbow smelt (Osmerus mordax) SAP. PaCRP/SAP transcripts were detected in all tested tissues, with the highest level in the liver, and its expression significantly upregulated following Vibrio anguillarum infection. The active recombinant mature PaCRP/SAP (rPaCRP/SAPm) agglutinated Gram-negative bacteria (Escherichia coli, V. anguillarum, Aeromonas hydrophila, and Vibrio parahaemolyticus) and Gram-positive bacteria (Staphylococcus aureus and Listeria monocytogenes) in a calcium-dependent manner in vitro, and it correspondingly bound peptidoglycan and lipopolysaccharide in a dose-dependent manner. The binding of rPaCRP/SAPm to E. coli and S. aureus resulted in a clear inhibition of the deposition of ayu complement 3 (PaC3) on the bacteria. Furthermore, rPaCRP/SAPm decreased phagocytosis of rPaCRP/SAPm bound E. coli and S. aureus cells by ayu monocytes/macrophages (MO/MPhi) in a complement-dependent way. However, rPaCRP/SAPm alone had no significant influence on phagocytosis. These results provided the first evidence that PaCRP/SAP might function in ayu immune responses via agglutinating bacteria and inhibiting complement-mediated opsonophagocytosis by MO/MPhi. PMID- 29481848 TI - Antioxidant defense system, immune response and erythron profile modulation in gold fish, Carassius auratus, after acute manganese treatment. AB - The manganese contamination has become a global problem, recently, because it is perceived as a real threat to the human health and the environment. It is well known that overexposure to Mn2+ may have negative physiological effects on fish and other organisms inhabiting heavy metal polluted waters. To the best of our knowledge, studies relating with manganese effects on fish antioxidant enzyme response in the blood, immunocompetence and erythron profile alteration, are scarce. In this study, the acute sub-lethal effects of manganese on blood antioxidant response, immune status and erythron profile were determined by exposing the freshwater model organism, Carassius auratus, to two doses of this metal (3.88 +/- 0.193 mg/L and 7.52 +/- 0.234 mg/L Mn2+) for 96 h. Significant increases in blood antioxidant enzyme activity like superoxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST), were observed in fish exposed to manganese. Furthermore, plasmatic glucose and cortisol levels increased, while total protein decreased significantly. White blood cell differential count revealed a significant increase in monocyte and neutrophil number and a significant decrease of lymphocyte's number in fish exposed to manganese compared with those of control group. That can be considered as a clear evidence of altered immune system. Measured of erythron profile revealed a significant increasing of cellular and nuclear alteration of red blood cells, with karryorhectic, dividing and micronucleated erythrocytes in exposed fish, indicating the cytotoxic and genotoxic effects Mn2+ ions. Our data shown also that manganese could trigger antioxidant response, modulate immune response and induce erythron profile modification leading to eryptosis, compromising the blood oxygen carrying capacity, and overall health status in fish. This may suggest those parameters consider as useful biomarkers for monitoring effects of sub lethal metal exposure on fish. PMID- 29481849 TI - Mechanisms of toxicity and biomarkers of flavoring and flavor enhancing chemicals in emerging tobacco and non-tobacco products. AB - Tobacco products containing flavorings, such as electronic nicotine delivery devices (ENDS) or e-cigarettes, cigars/cigarillos, waterpipes, and heat-not-burn devices (iQOS) are continuously evolving. In addition to increasing the exposure of teenagers and adults to nicotine containing flavoring products and flavoring enhancers, chances of nicotine addiction through chronic use and abuse also increase. These flavorings are believed to be safe for ingestion, but little information is available about their effects on the lungs. In this review, we have discussed the in vitro and in vivo data on toxicity of flavoring chemicals in lung cells. We have further discussed the common flavoring agents, such as diacetyl and menthol, currently available detection methods, and the toxicological mechanisms associated with oxidative stress, inflammation, mucociliary clearance, and DNA damage in cells, mice, and humans. Finally, we present potential biomarkers that could be utilized for future risk assessment. This review provides crucial parameters important for evaluation of risk associated with flavoring agents and flavoring enhancers used in tobacco products and ENDS. Future studies can be designed to address the potential toxicity of inhaled flavorings and their biomarkers in users as well as in chronic exposure studies. PMID- 29481850 TI - Coiled-coil oligomerization controls localization of the plasma membrane REMORINs. AB - REMORINs are nanodomain-organized proteins located in the plasma membrane and involved in cellular responses in plants. The dynamic assembly of the membrane nanodomains represents an essential tool of the versatile membrane barriers to control and modulate cellular functions. Nevertheless, the assembly mechanisms and protein organization strategies of nanodomains are poorly understood and many structural aspects are difficult to visualize. Using an ensemble of biophysical approaches, including solid-state nuclear magnetic resonance, cryo-electron microscopy and in vivo confocal imaging, we provide first insights on the role and the structural mechanisms of REMORIN trimerization. Our results suggest that the formation of REMORIN coiled-coil trimers is essential for membrane recruitment and promotes REMORIN assembly in vitro into long filaments by trimer trimer interactions that might participate in nanoclustering into membrane domains in vivo. PMID- 29481852 TI - The pharmacological properties of Ophiocordyceps xuefengensis revealed by transcriptome analysis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The Yao ethnic group in Xuefeng Mountains area have used Xuefeng cordyceps, the caterpillar-fungus complex of Ophiocordyceps xuefengensis, for treating a variety of diseases for long. Just like some other cordyceps, O. xuefengensis, which is identified as the sister taxon of O. sinensis in 2013, also seems to have broad pharmacological properties, not only enhancing human immunity, anti-bacteria, anti-virus, but also anti-tumor. However, investigation of the medicinal fugal species O. xuefengensis can be found only in few literature records since its pharmacological and therapeutic use is mainly in traditional Yao communities by local healers. AIM OF THE STUDY: The aim of this study is to collect samples of Xuefeng cordyceps and isolate the strain of O. xuefengensis, to determine bioactive components and evaluate the anti-tumor activity, to obtain the gene expression profile of O. xuefengensis and reveal its pharmacological properties by de novo transcriptome analysis. Accordingly, we attempt to provide information and give a comprehensive understanding of this mysterious medicinal fugal species from traditional Yao communities of China. MATERIAL AND METHODS: Bioactive components were determined with HPLC-DAD-Q-TOF-MS technology; in vitro anti-tumor activity against 6 cell lines was evaluated using standard MTT assay; transcriptome analysis was done by de novo sequencing; unique genes were functionally profiled basing on Gene Ontology Database and the targeted genes were examined by blast. RESULTS: Trace cordycepin, an anti-tumor agent, was detected in O. xuefengensis water extract. To some extent, the raw water extract of O. xuefengensis showed in vitro anti tumor activity, against A549, HepG2, MCF-7, PC-3 and Raji cell lines. A total of 94,858 transcripts and 49,001 unique genes were obtained, amongst, 43.4% unique genes were matched with those of O. sinensis. Not all supposed genes related to cordycepin biosynthetic pathways were found by transcriptome analysis. CONCLUSION: According to the gene expression profile, O. xuefengensis is very close to medicinal fungus O. sinensis. Raw water extract of O. xuefengensis, to a certain degree, could inhibit the growth of tumor cells, indicating that this fungus could be a new resource for the exploration of anti-tumor drug. PMID- 29481853 TI - Protective role of alpha-lipoic acid in impairments of social and stereotyped behaviors induced by early postnatal administration of thimerosal in male rat. AB - : Aim Thimerosal, a mercury-containing preservative has been widely used in a number of biological and drug products, including many vaccines, and has been studied as a possible etiological factor for some neurodevelopmental disabilities. Here, the protective effects of Alpha Lipoic Acid (ALA), an organosulfur compound derived from Octanoic Acid, on Thimerosal-induced behavioral abnormalities in rat were examined. METHODS: 108 male Wistar rats were divided into three cohorts and treated as follows: 1) Thimerosal at different doses (30, 300, or 3000 MUg Hg/kg) in four i.m. injections on 7, 9, 11, 15postnatal days. 2) ALA (at doses of 5, 10 and 20 mg/kg), following the same order; 3) single dose of Thimerosal (3000 MUg Hg/kg) plus ALA at different doses (5, 10 or 20 mg/kg), by the previously described method. A saline treated control group and a ALA vehicle control (0.1% NaOH) were also included. At 5 and 8 weeks after birth, rats were evaluated with behavioral tests, to assess locomotor activity, social interactions and stereotyped behaviors, respectively. RESULTS: The data showed that Thimerosal at all doses (30, 300 and 3000 MUg Hg/kg) significantly impacted locomotor activity. Thimerosal at doses of 300 and 3000 but not 30 MUg Hg/kg impaired social and stereotyped behaviors. In contrast, ALA (at doses of 5, 10 and 20 mg/kg) did not alter behaviors by itself, at doses of 20 mg/kg, it reduced social interaction deficits induced by the highest dose of Thimerosal (3000 MUg Hg/kg). Moreover, ALA, at all doses prevented the adverse effects of Thimerosal on stereotyped behaviors. CONCLUSIONS: the results of this preclinical study, consistent with previous studies on mice and rats, reveals that neonatal dose-dependent exposure to Thimerosal mimicking the childhood vaccine schedule can induce abnormal social interactions and stereotyped behaviors similar to those observed in neurodevelopmental disorders such as autism, and, for the first time, revealed that these abnormalities may be ameliorated by ALA. This indicates that ALA may protect against mercurial-induced abnormal behaviors. PMID- 29481851 TI - Activation and desensitization of ionotropic glutamate receptors by selectively triggering pre-existing motions. AB - Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that are key players in synaptic transmission and plasticity. They are composed of four subunits, each containing four functional domains, the quaternary packing and collective structural dynamics of which are important determinants of their molecular mechanism of function. With the explosion of structural studies on different members of the family, including the structures of activated open channels, the mechanisms of action of these central signaling machines are now being elucidated. We review the current state of computational studies on two major members of the family, AMPA and NMDA receptors, with focus on molecular simulations and elastic network model analyses that have provided insights into the coupled movements of extracellular and transmembrane domains. We describe the newly emerging mechanisms of activation, allosteric signaling and desensitization, as mainly a selective triggering of pre-existing soft motions, as deduced from computational models and analyses that leverage structural data on intact AMPA and NMDA receptors in different states. PMID- 29481854 TI - A possible principal function of corticosteroid signaling that is conserved in vertebrate evolution: Lessons from receptor-knockout small fish. AB - Corticosteroid receptors are critical for homeostasis maintenance, but understanding of the principal roles of the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) throughout vertebrates is limited. Lines of constitutive GR-knockout zebrafish and MR-knockout medaka have recently been generated as the first adult-viable corticosteroid receptor-knockout animals, in contrast to the lethality of these receptor knockouts in mice. Here, we describe behavioral and physiological modifications following disruption of corticosteroid receptor function in these animal models. We suggest these data point toward a potentially conserved function of corticosteroid receptors in integrating brain behavior and visual responses in vertebrates. Finally, we discuss how future work in cartilaginous fishes (Chondrichthyes) will further advance understanding of the unity and diversity of corticosteroid receptor function, since distinct orthologs of GR and MR derived from an ancestral corticoid receptor appear in these basal jawed vertebrates. PMID- 29481855 TI - The evolution of methods for urinary steroid metabolomics in clinical investigations particularly in childhood. AB - The metabolites of cortisol, and the intermediates in the pathways from cholesterol to cortisol and the adrenal sex steroids can be analysed in a single separation of steroids by gas chromatography (GC) coupled to MS to give a urinary steroid profile (USP). Steroids individually and in profile are now commonly measured in plasma by liquid chromatography (LC) coupled with MS/MS. The steroid conjugates in urine can be determined after hydrolysis and derivative formation and for the first time without hydrolysis using GC-MS, GC-MS/MS and liquid chromatography with mass spectrometry (LC-MS/MS). The evolution of the technology, practicalities and clinical applications are examined in this review. The patterns and quantities of steroids changes through childhood. Information can be obtained on production rates, from which children with steroid excess and deficiency states can be recognised when presenting with obesity, adrenarche, adrenal suppression, hypertension, adrenal tumours, intersex condition and early puberty, as examples. Genetic defects in steroid production and action can be detected by abnormalities from the GC-MS of steroids in urine. New mechanisms of steroid synthesis and metabolism have been recognised through steroid profiling. GC with tandem mass spectrometry (GC-MS/MS) has been used for the tentative identification of unknown steroids in urine from newborn infants with congenital adrenal hyperplasia. Suggestions are made as to areas for future research and for future applications of steroid profiling. As routine hospital laboratories become more familiar with the problems of chromatographic and MS analysis they can consider steroid profiling in their test repertoire although with LC-MS/MS of urinary steroids this is unlikely to become a routine test because of the availability, cost and purity of the internal standards and the complexity of data interpretation. Steroid profiling with quantitative analysis by mass spectrometry (MS) after chromatography now provides the most versatile of tests of adrenal function in childhood. PMID- 29481856 TI - Preregistration and publication of nonregulated intervention trials are here to stay (letter commenting Wallach et al 2018, 93, 88-93). PMID- 29481857 TI - Sectioned images and 3D models of a cadaver head with reference to dermal filler injection. AB - The purpose of this study was to describe anatomical consideration with reference to dermal filler injection on sectioned images and three dimensional (3D) models using Visible Korean for medical education and clinical training purposes in the field of facial surgery. Serially sectioned images of the head were acquired from a cadaver. Anatomic structures related to dermal filler injection were 3D reconstructed based on sectioned images, and additional structures were built on the basis of the established ones using a semi-automatic method. The anatomical 3D models were assembled and converted to a PDF file (66MB), which can be downloaded and used for free. In the PDF file, noticeable anatomical structures related with dermal filler injection can be identified on the 3D models as well as on the sectioned anatomical images. The 3D models in PDF were optimized and displayed in real time. These state-of-the-art sectioned images, outlined images, and 3D models will aid students and trainees to acquire a better understanding of the anatomy related to dermal filler injection, and will also improve medical understanding of patients and the general public. The 3D models in PDF files also can be used on dermal filler injection simulations. PMID- 29481858 TI - Impact of maternal immune activation on maternal care behavior, offspring emotionality and intergenerational transmission in C3H/He mice. AB - Maternal immune activation (MIA) is a well-established model for the investigation of the deleterious effects of gestational infection on offspring mental health later in life. Hence, MIA represents a critical environmental variable determining brain development and the depending neural and behavioral functions in the progeny. Transgenerational transmission of some of the effects of MIA has been recently reported using the Polyinosinic:polycytidylic acid (Poly (I:C)) MIA model in C57BL/6 (C57) inbred mice. However, little is known about the underlying molecular mechanisms and the possible relevance of the specific genetic make-up of the inbred mouse strain used. Here we set out to characterize the effects of gestational Poly (I:C) treatment in C3H/HeNCrl mice (C3H), focusing on maternal care and offspring depression-like behavior and its intergenerational potential. miRNA expression in the offspring hippocampus in the F1 and F2 generations was examined as possible mechanism contributing to the observed behavioral effects. The impact of MIA on maternal care and its transmission to F1 females was previously observed in C57 mice was also found in C3H mice. Depression-like behavior in the adult offspring in C3H F1 and F2 females differed from reports of the C57 strain in the literature, suggesting a potential modulating role of the genetic background in the Poly(I:C) MIA mouse model. As the pattern of expression of selected candidate miRNAs in the F1 and F2 offspring hippocampus was not conserved between the two generations, it is unlikely to be a direct consequence of altered maternal care, or to be an immediate determinant of offspring emotionality. PMID- 29481859 TI - Effect of vinylpyrrolidone polymers on the solubility and supersaturation of drugs; a study using the Cheqsol method. AB - The development of methods to increase the bioavailability of drugs is of great interest, especially for those which are poorly soluble or permeable. One of the strategies to enhance the solubility (which in turn has the potential of increase bioavailability) of drugs is the use of additives in the formulation process, so that the drug can stay supersaturated in biological fluids for a period of time long enough to allow absorption. The use of polymers as pharmaceutical excipients in order to stabilize the supersaturation of drugs is common practice. In this work, the ability of different polymers of vinylpyrrolidone (K-12, K-17, K-25, K 29/32, K-90) and a copolymer of vinylpyrrolidone and vinylacetate (S-630) have been tested for their impact on the supersaturation of drugs. Sixteen drugs of different chemical nature have been selected, and analyzed using the Cheqsol method. The results of the drug alone, and of physical mixtures with the different polymers at several polymer:drug ratios have been compared in terms of supersaturation extent and duration. It has been observed that acidic compounds displayed enhanced solubility in different ways: sometimes the supersaturated state of the drug is maintained for a long time, due to the precipitation of an amorphous solid, as determined by X-ray diffraction studies; on other occasions supersaturation increases but only for a short time, compared to the drug alone, and then the drug precipitates to a crystalline form. Only a few basic drugs displayed enhanced solubility in the presence of PVP polymers, in contrast to acidic compounds. PMID- 29481860 TI - Reconciliation of pH, conductivity, total organic carbon with carboxylic acids detected by ion chromatography in solution after contact with multilayer films after gamma-irradiation. AB - The impact of gamma-irradiation on polymers in multilayer films was studied by means of the study of the diffusion and release (spontaneous migration of the molecules from the container into the product) of chemical species in aqueous solution. A series of different measurements have been performed: pH, conductivity, total organic carbon (TOC) and ion chromatography (IC). Their evolution according to gamma-irradiation dose was studied. More several rinsings made over several months allowed to quantify well the impact of the irradiation on these polymers. The samples are irradiated at several gamma-doses, up to 270 kGy, and compared with a non-irradiated sample used as reference. It shows that quantity of generated carboxylic acids depends on the film material (PE/EVOH/PE and EVA/EVOH/EVA) and increases with gamma-dose. PMID- 29481861 TI - Androgens and androgen receptor: Above and beyond. PMID- 29481862 TI - Effects of bisphenol A on metabolism and evidences of a mode of action mediated through endocrine disruption. AB - Based on rodent studies after prenatal and/or perinatal or adult exposure, there is now evidence that BPA may increase metabolic disturbances eventually leading to type-2 diabetes development via an ED MoA. In particular, BPA has been shown to alter insulin synthesis and/or release by pancreatic beta-cells, and insulin signaling within insulin-sensitive organs (i.e., liver, muscle, adipose tissues). This resulted in variations in the expression of specific hepatic or adipose tissue markers, which are indicative of a state of insulin resistance. These effects are considered by experts to be hallmarks of adverse hormonal effects, each leading to insulin resistance within the different insulin-sensitive tissues. Although epidemiological studies are inconclusive, these effects are considered relevant for humans, because similarities exist in homeostatic regulation of insulin production and sensitivity between rodents and humans and because evidence was also shown through in vitro experimental data using human cells or tissues. PMID- 29481863 TI - Transthyretin uptake in placental cells is regulated by the high-density lipoprotein receptor, scavenger receptor class B member 1. AB - Transfer of thyroid hormone into cells is critical for normal physiology and transplacental transfer of maternal thyroid hormones is essential for normal fetal growth and development. Free thyroid hormone is known to enter cells through specific cell surface transport proteins, and for many years this uptake of unbound thyroid hormones was assumed to be the only relevant mechanism. Recently, evidence has emerged of alternate pathways for hormone entry into cells that are dependent on hormone binding proteins. In this study we identify the high-density lipoprotein receptor Scavenger Receptor class B member 1 (SR-B1) as important in the uptake and transport of transthyretin-bound thyroid hormone by placental trophoblast cells. High-density lipoprotein increases expression of SR B1 in placental cells but also reduces uptake of transthyretin-thyroid hormone through the SR-B1 transporter. SR-B1 is expressed in many cells and this study suggests that SR-B1 may be universally important in thyroid hormone uptake. Further investigation of SR-B1-TTR interactions may fundamentally change our understanding of hormone biology and have important clinical consequences. PMID- 29481865 TI - The Fusarium oxysporum Avr2-Six5 Effector Pair Alters Plasmodesmatal Exclusion Selectivity to Facilitate Cell-to-Cell Movement of Avr2. AB - Pathogens use effector proteins to manipulate their hosts. During infection of tomato, the fungus Fusarium oxysporum secretes the effectors Avr2 and Six5. Whereas Avr2 suffices to trigger I-2-mediated cell death in heterologous systems, both effectors are required for I-2-mediated disease resistance in tomato. How Six5 participates in triggering resistance is unknown. Using bimolecular fluorescence complementation assays we found that Avr2 and Six5 interact at plasmodesmata. Single-cell transformation revealed that a 2xRFP marker protein and Avr2-GFP only move to neighboring cells in the presence of Six5. Six5 alone does not alter plasmodesmatal transduction as 2xRFP was only translocated in the presence of both effectors. In SIX5-expressing transgenic plants, the distribution of virally expressed Avr2-GFP, and subsequent onset of I-2-mediated cell death, differed from that in wild-type tomato. Taken together, our data show that in the presence of Six5, Avr2 moves from cell to cell, which in susceptible plants contributes to virulence, but in I-2 containing plants induces resistance. PMID- 29481864 TI - DEPDC5 and NPRL3 modulate cell size, filopodial outgrowth, and localization of mTOR in neural progenitor cells and neurons. AB - Mutations in DEPDC5 and NPRL3 subunits of GATOR1, a modulator of mechanistic target of rapamycin (mTOR), are linked to malformations of cortical development (MCD). Brain specimens from these individuals reveal abnormal cortical lamination, altered cell morphology, and hyperphosphorylation of ribosomal S6 protein (PS6), a marker for mTOR activation. While numerous studies have examined GATOR1 subunit function in non-neuronal cell lines, few have directly assessed loss of GATOR1 subunit function in neuronal cell types. We hypothesized that DEPDC5 or NPRL3 shRNA-mediated knockdown (DEPDC5/NPRL3 KD) leads to inappropriate functional activation of mTOR and mTOR-dependent alterations in neuronal morphology. Neuronal size was determined in human specimens harboring DEPDC5 or NPRL3 mutations resected for epilepsy treatment. DEPDC5/NPRL3 KD effects on cell size, filopodial extension, subcellular mTOR complex 1 (mTORC1) localization, and mTORC1 activation during nutrient deprivation were assayed in mouse neuroblastoma cells (N2aC) and mouse subventricular zone derived neural progenitor cells (mNPCs). mTORC1-dependent effects of DEPDC5/NPRL3 KD were determined using the mTOR inhibitor rapamycin. Changes in mTOR subcellular localization and mTORC1 pathway activation following DEPDC5/NPRL3 KD were determined by examining the proximity of mTOR to the lysosomal surface during amino acid starvation. Neurons exhibiting PS6 immunoreactivity (Ser 235/236) in human specimens were 1.5* larger than neurons in post-mortem control samples. DEPDC5/NPRL3 KD caused mTORC1, but not mTORC2, hyperactivation, soma enlargement, and increased filopodia in N2aC and mNPCs compared with wildtype cells. DEPDC5/NPRL3 KD led to inappropriate mTOR localization at the lysosome along with constitutive mTOR activation following amino acid deprivation. DEPDC5/NPRL3 KD effects on morphology and functional mTOR activation were reversed by rapamycin. mTOR-dependent effects of DEPDC5/NPRL3 KD on morphology and subcellular localization of mTOR in neurons suggests that loss of-function in GATOR1 subunits may play a role in MCD formation during fetal brain development. PMID- 29481866 TI - Blount disease. AB - Blount disease is an asymmetrical disorder of proximal tibial growth that produces a three-dimensional deformity. Tibia vara is the main component of the deformity. Blount disease exists as two clinical variants, infantile or early onset, and adolescent or late-onset, defined based on whether the first manifestations develop before or after 10 years of age. The pathophysiological mechanisms are unclear. In the Americas and Caribbean, Blount disease chiefly affects black obese children. Without treatment, the prognosis is often severe, particularly in the infantile form due to the development of medial tibial epiphysiodesis at about 6 to 8 years of age. In other parts of the world, the associations with black ethnicity and obesity are less obvious and the prognosis is often less severe. A consensus exists about the optimal treatment in two situations: before 4 years of age, progressive Blount disease should be corrected, preferably by a simple osteotomy; and once medial tibial epiphysiodesis has developed, both a complementary epiphysiodesis and gradual external fixator correction of the other alignment abnormalities, rotational deformity, and limb length are required. After 4 years of age, the outcome in the individual patient is difficult to predict. Magnetic resonance imaging supplies information on the morphology and vascularisation of the growth regions, thereby helping to guide treatment decisions. In the adolescent form, morbid obesity limits the treatment options. Untreated Blount disease in adults is rarely encountered. A more common occurrence is the presence of residual abnormalities at skeletal maturity in patients treated for Blount disease in childhood. Premature osteoarthritis may develop. In this situation, osteotomy may delay the need for total knee arthroplasty. PMID- 29481867 TI - Circumferential minimally invasive approach for low-grade isthmic spondylolisthesis: A clinical and radiological study of 43 patients. AB - INTRODUCTION: Circumferential fusion for lumbar low-grade isthmic spondylolisthesis (LGIS) provides the best spinal stability and highest fusion rates. The aim of this study is to investigate results of minimal invasive management of LGIS and correlations between Intervertebral Foramen Surface (IFS) and other parameters. METHODS: We retrospectively reviewed cases of 43 patients who underwent a minimally invasive circumferential fusion (Anterior lumbar interbody fusion followed by percutaneous posterior pedicle screw fixation) for LGIS between January 2010 and December 2014 in our institution. Inclusion criteria were one-level (L4-L5 or L5-S1) LGIS with low back and/or radicular pain. Pre- and postoperative radiographic evaluations were performed at 6, 12 and 24months. Measurements (Percentage of anterior displacement, degree of slip angle, height of the intervertebral space and the IFS) were obtained using Surgimap(r). RESULTS: Nineteen patients (44.2%) were males. Mean age was 43 years old (19-72years). The mean follow-up of the series was 18.3months (3-72months). Mean preoperative Visual Analogy Scale (VAS) for low back pain decreased from 70mm to 20mm and from 80mm to 10mm as to radicular pain. Anterior displacement was reduced from 18% to 7% (p<0.01), degree of slippage were increased from 9.8 degrees to 15.2 degrees (p<0.01), intervertebral height was restored from 4.4mm to 8.5mm (p<0.01) and increase of the IFS was calculated 48.8%. CONCLUSION: One stage circumferential fixation for adults' LGIS without decompression, allows restoration of intervertebral height permitting good reduction of the slippage, an increasing of the IFS and liberation of nerve roots. PMID- 29481868 TI - An overview of mosquito vectors of Zika virus. AB - The mosquito-borne arbovirus Zika virus (ZIKV, Flavivirus, Flaviviridae), has caused an outbreak impressive by its magnitude and rapid spread. First detected in Uganda in Africa in 1947, from where it spread to Asia in the 1960s, it emerged in 2007 on the Yap Island in Micronesia and hit most islands in the Pacific region in 2013. Subsequently, ZIKV was detected in the Caribbean, and Central and South America in 2015, and reached North America in 2016. Although ZIKV infections are in general asymptomatic or causing mild self-limiting illness, severe symptoms have been described including neurological disorders and microcephaly in newborns. To face such an alarming health situation, WHO has declared Zika as an emerging global health threat. This review summarizes the literature on the main vectors of ZIKV (sylvatic and urban) across all the five continents with special focus on vector competence studies. PMID- 29481869 TI - A large transcribed enhancer region regulates C. elegans bed-3 and the development of egg laying muscles. AB - Gene expression is regulated by the interaction of the RNA polymerase with various transcription factors at promoter and enhancer elements. Transcriptome analyses found that many non-protein-coding regions are transcribed to produce long non-coding RNAs and enhancer-associated RNAs. Production of these transcripts is associated with activation of nearby protein-coding genes, and at least in some cases, the transcripts themselves mediate this activation. Non coding transcripts are also reported from large enhancers or clusters of enhancers. However, not much is known about the function of large transcribed enhancer regions during organismal development. Here we investigated a transcribed 10.6 kb intergenic region located upstream of the C. elegans bed-3 gene. We found that parts of this region exhibit tissue-specific promoter and enhancer activities. Deletion of the region disrupts egg laying, a phenotype also observed in bed-3 mutants, but with the severity correlating with the size of the deletion. This phenotype is not caused by overall reduction in bed-3 expression. Rather, deletions reduce bed-3 expression specifically in the mesoderm lineage. We found that bed-3 has a previously unknown function in the generation of sex myoblast (SM) cells from the M lineage, and deletions cause loss of SM cells leading to loss of vulval muscles required for egg laying. Furthermore, injection of dsRNA targeting non-coding transcripts from this region disrupted egg laying in the wild type but not in RNAi-defective mutants. Therefore, the region upstream of bed-3 is required for robust expression of bed-3 in a specific tissue, and non-coding transcripts may mediate this interaction. PMID- 29481870 TI - Circulating Plasma Cells at the Time of Collection of Autologous PBSC for Transplant in Multiple Myeloma Patients is a Negative Prognostic Factor Even in the Age of Post-Transplant Maintenance Therapy. AB - Circulating plasma cells (CPCs) have been detected in patients with multiple myeloma (MM) at various stages of disease and associated with worse outcomes. Little data exist regarding the impact of CPCs at the time of autologous peripheral blood stem cell (PBSC) collection on outcomes, and the impact of maintenance therapy after autologous stem cell transplantation (ASCT) on prognosis in patients with CPC-containing collections. All patients with MM who underwent first ASCT at Fred Hutchinson Cancer Research Center from 2012 to 2015 and had evaluation for CPCs at the time of PBSC collection were included in our analysis. Seven-color flow cytometry was used to detect the presence of CPCs. Kaplan-Meier estimates were used to generate overall survival (OS) and progression-free survival (PFS) rates from the time of ASCT. A multivariate analysis, including receipt of maintenance therapy post-ASCT, high-risk cytogenetics, and international staging system (ISS) stage, was included in a Cox proportional hazards regression model for associations with OS and PFS. We identified 227 patients with MM who underwent ASCT; of these, 144 (63.4%) patients had routine assessment of CPCs at the time of PBSC collection. One hundred seventeen (81.3%) patients did not have CPCs and 27 (18.8%) did have CPCs. The presence of CPCs was highly associated with poorer PFS (P = .031 by log rank analysis), but did not affect OS. The median PFS for those patients without CPCs was 39.4 months (95% confidence interval [CI], 31.1 to not reached), while the median PFS for those patients with CPCs was 16.5 months (95% CI, 13.7 to not reached). A subgroup analysis of patients achieving very good partial response (VGPR) or better at time of collection, showed the median PFS for patients without CPCs was 38.3 months (95% CI, 29 to not reached), as compared with those patients with CPCs, where it was only 16.5 months (95% CI, 12 months to not reached; P = .02). There was no statistically significant difference in PFS or OS among those patients achieving partial response at the time of collection. In a Cox proportional hazards model, adjusting for post-ASCT maintenance therapy, high risk cytogenetics, and ISS stage at time of initial diagnosis, there was a 43% higher risk of progression or death among the patients with CPCs (P = .04). The presence of CPCs at the time of autologous PBSC collection is a negative prognostic factor for risk of early relapse or death despite the advent of novel agents and maintenance strategies. The impact of CPCs was most significant among patients achieving a VGPR or better at time of collection. The presence of CPCs denotes a unique group of high-risk MM patients for whom alternative treatment strategies are needed to overcome resistance to current standard therapies. PMID- 29481871 TI - Histone-targeted gene transfer of bone morphogenetic protein-2 enhances mesenchymal stem cell chondrogenic differentiation. AB - : Skeletal tissue regeneration following traumatic injury involves a complex cascade of growth factor signals that direct the differentiation of mesenchymal stem cells (MSCs) within the fracture. The necessity for controlled and localized expression of these factors has highlighted the role gene therapy may play as a promising treatment option for bone repair. However, the design of nanocarrier systems that negotiate efficient intracellular trafficking and nuclear delivery represents a significant challenge. Recent investigations have highlighted the roles histone tail sequences play in directing nuclear delivery and activating DNA transcription. We previously established the ability to recapitulate these natural histone tail activities within non-viral nanocarriers, improving gene transfer and expression by enabling effective navigation to the nucleus via retrograde vesicular trafficking. Herein, we demonstrate that histone-targeting leads to ~4-fold enhancements in osteogenic bone morphogenetic protein-2 (BMP-2) expression by MSCs over 6 days, as compared with standard polymeric transfection reagents. This improved expression augmented chondrogenesis, an essential first step in fracture healing. Importantly, significant enhancements of cartilage specific protein expression were triggered by histone-targeted gene transfer, as compared with the response to treatment with equivalent amounts of recombinant BMP-2 protein. In fact, an ~100-fold increase in recombinant BMP-2 was required to achieve similar levels of chondrogenic gene and protein expression. The enhancements in differentiation achieved using histone-targeting were in part enabled by an increase in transcription factor expression, which functioned to drive MSC chondrogenesis. These novel findings demonstrate the utility of histone targeted gene transfer strategies to enable substantial reductions in BMP-2 dosing for bone regenerative applications. STATEMENT OF SIGNIFICANCE: This contribution addresses significant limitations in non-viral gene transfer for bone regenerative applications by exploiting a novel histone-targeting approach for cell-triggered delivery that induces osteogenic BMP-2 expression coincident with the initiation of bone repair. During repair, proliferating MSCs respond to a complex series of growth factor signals that direct their differentiation along cellular lineages essential to mature bone formation. Although these MSCs are ideal targets for enhanced transfection during cellular mitosis, few non-viral delivery approaches exist to enable maximization of this effect. Accordingly, this contribution seeks to utilize our histone-targeted nanocarrier design strategy to stimulate BMP-2 gene transfer in dividing MSCs. This gene-based approach leads to significantly augmented MSC chondrogenesis, an essential first step in bone tissue repair. PMID- 29481872 TI - aPDT for periodontitis treatment in ovariectomized rats under systemic nicotine. AB - BACKGROUND: This study evaluated the antimicrobial photodynamic therapy (aPDT) as an adjunctive therapy to scaling and root planning (SRP) for the treatment of experimental periodontitis (EP) in ovariectomized rats under systemic nicotine. METHODS: Female ovariectomized rats (n = 180) were divided into two groups: vehicle administration (Veh) and nicotine administration (Nic). Mini-pumps containing either vehicle or nicotine were inserted in the rats 30 days before the induction of EP, which was induced by placing a ligature around the left mandibular first molar. The rats were randomly divided into three treatment subgroups: SRP, SRP plus low-level laser therapy (LLLT), and SRP plus aPDT. aPDT consisted of the application of a phenothiazine photosensitizer followed by LLLT. Ten animals from each group were euthanized at days 7, 15, and 30 after periodontal treatment. The furcation region was evaluated using histological, histometric analyses and immunolabelling for PCNA, TRAP, RANKL, and OPG. RESULTS: Nicotine administration resulted in greater bone loss (BL). aPDT resulted in lower BL compared to SRP. aPDT showed higher quantities of PCNA-positive cells compared to SRP, regardless of the nicotine status. aPDT resulted in less recruitment of osteoclasts and lower RANKL immunolabelling compared to LLLT and SRP. CONCLUSION: aPDT was effective in animals treated with nicotine. PMID- 29481873 TI - Diabetes at the time of rheumatoid arthritis diagnosis is an independent predictor of pejorative outcomes: Data from the early arthritis ESPOIR cohort. PMID- 29481874 TI - Maltese cross interpretation. Comment on: "Acute phospholipid microspherule associated arthritis: Is it rare?" by Coiffier et al., Joint Bone Spine 2017;84;537-40. PMID- 29481875 TI - Cornual Suture at the Time of Laparoscopic Salpingectomy Reduces the Incidence of Interstitial Pregnancy after In Vitro Fertilization. AB - STUDY OBJECTIVE: To investigate the effect of cornual suture at the time of laparoscopic salpingectomy on the incidence of interstitial pregnancy (IP) after in vitro fertilization (IVF). DESIGN: Single-center, retrospective review (Canadian Task Force classification II-2). SETTING: University hospital. PATIENTS: Patients with hydrosalpinx who were treated with salpingectomy before IVF-embryo transfer and managed in our center were included in this study. INTERVENTIONS: A total of 542 patients who underwent laparoscopic salpingectomy from April 2011 to March 2014 comprised group A. A total of 502 patients who underwent cornual suture at the time of laparoscopic salpingectomy from April 2014 to February 2016 comprised group B. MEASUREMENTS AND MAIN RESULTS: The overall IP rate was significantly lower in group B (7/293, 2.39%) than in group A (27/373, 7.24%; p < .05). The intrauterine pregnancy and ongoing pregnancy/live birth rates were significantly higher in group B than in group A (both p < .05). All 34 patients with IP underwent laparoscopic cornuostomy and cornual repair. Seven of 11 patients with combined interstitial and intrauterine pregnancies carried the intrauterine pregnancy to term and delivered via cesarean section, whereas 4 patients underwent inevitable miscarriage. IP rupture occurred in 8 of 34 patients at a mean of 23.43 +/- 2.77 days after embryo transfer. The earliest time of rupture was on day 20 after embryo transfer. CONCLUSION: An optimized salpingectomy technique plays an important role in pretreatment before embryo transfer in patients with hydrosalpinx. Cornual suture at the time of salpingectomy helps reduce the risk of IP. PMID- 29481876 TI - Recent advances in near-infrared light-responsive nanocarriers for cancer therapy. AB - In recent years, research has focused on the development of smart nanocarriers that can respond to specific stimuli. Among the various stimuli-responsive platforms for cancer therapy, near-infrared (NIR) light (700-1000nm)-responsive nanocarriers have gained considerable interest because of their deeper tissue penetration capacity, precisely controlled drug release, and minimal damage towards normal tissues. In this review, we outline various therapeutic applications of NIR-responsive nanocarriers in drug delivery, photothermal therapy (PTT), photodynamic therapy (PDT), and bioimaging. We also highlight recent trends towards NIR-responsive combinatorial therapy and multistimuli responsive nanocarriers for improving therapeutic outcomes. PMID- 29481877 TI - Human disease MiRNA inference by combining target information based on heterogeneous manifolds. AB - The emergence of network medicine has provided great insight into the identification of disease-related molecules, which could help with the development of personalized medicine. However, the state-of-the-art methods could neither simultaneously consider target information and the known miRNA-disease associations nor effectively explore novel gene-disease associations as a by product during the process of inferring disease-related miRNAs. Computational methods incorporating multiple sources of information offer more opportunities to infer disease-related molecules, including miRNAs and genes in heterogeneous networks at a system level. In this study, we developed a novel algorithm, named inference of Disease-related MiRNAs based on Heterogeneous Manifold (DMHM), to accurately and efficiently identify miRNA-disease associations by integrating multi-omics data. Graph-based regularization was utilized to obtain a smooth function on the data manifold, which constitutes the main principle of DMHM. The novelty of this framework lies in the relatedness between diseases and miRNAs, which are measured via heterogeneous manifolds on heterogeneous networks integrating target information. To demonstrate the effectiveness of DMHM, we conducted comprehensive experiments based on HMDD datasets and compared DMHM with six state-of-the-art methods. Experimental results indicated that DMHM significantly outperformed the other six methods under fivefold cross validation and de novo prediction tests. Case studies have further confirmed the practical usefulness of DMHM. PMID- 29481878 TI - Molecular characterization, tissue distribution, localization and mRNA expression of the bucky ball gene in the Dabry's sturgeon (Acipenser dabryanus) during oogenesis. AB - In many organisms, germ cells are specified during embryogenesis by the inheritance of maternally deposited RNAs and proteins termed germ plasm. In vertebrates, the bucky ball (buc) gene plays an essential role in the germ plasm aggregation. In this study, the full-length cDNA of buc homologue in Dabry's sturgeon, Adbuc, was isolated and characterized. Multiple sequence alignments showed that the BUVE domain of Buc was highly conserved in vertebrates, despite exhibiting low identities with each other across the whole protein. By quantitative real-time PCR analysis, we found that Adbuc RNAs were only detected in the gonad with a high level in the ovary and a very low level in the testis. During embryogenesis, these RNAs were highly expressed from the unfertilized eggs to blastula, declined dramatically from the gastrula stage, and hardly found after the neurula stage. Moreover, with the development of ovary, the expression level of Adbuc was increasing. By in situ hybridization, the signal of Adbuc was not found in the oogonia, increased slightly in the stage I oocytes, and extremely strong in the stage II oocytes, suggesting that the signal became much stronger with increasing size of oocytes. Additionally, Adbuc co-localized with the mitochondrial cloud. Thus, we conclude that Dabry's sturgeon buc gene might also function in germplasm formation. PMID- 29481879 TI - Analysis of respiratory movements in a mouse model of late Parkinson's disease submitted to stress. AB - Parkinson's disease (PD) is known to cause tremor and rigidity, but other symptoms such as respiratory and autonomic dysfunctions are a major cause of disability and mortality in patients. In this study, we examined respiratory movements by using cineradiography on a murine model of late/advanced PD. Under surgical anesthesia, C57BL/6J mice received an injection of either 6-OHDA or vehicle solution to the right striatum. Two weeks after surgery, the animals had their respiratory movements recorded by video X-ray without any restraint. During recordings the animals were submitted to a mild acute-stress challenge. Behavioral tests were performed to assess the severity of the 6-OHDA lesion. As a result, behavioral tests confirmed severe motor impairments in 6-OHDA mice as compared to controls. 6-OHDA mice showed a predominantly thoracic respiratory pattern with reduced diaphragmatic excursion, and reduced respiratory frequency after stress. These results suggest that advanced nigrostrial degeneration may cause respiratory alterations with the features of obstructive-type respiratory disorders. PMID- 29481880 TI - A one-step TaqMan real-time qRT-PCR assay for the specific detection and quantitation of the Spanish goat encephalitis virus (SGEV). AB - Louping ill-like virus (LI) has been recently detected in two different locations in the north of Spain and separated by only around 400 km. Using molecular approaches, the viruses causing both outbreaks have been shown to be different to LI virus, but also different to each other. They have been called SSEV (Spanish sheep encephalitis virus) and SGEV (Spanish goat encephalitis virus) taking into account the species from which they were isolated. The aim of this paper was to design a quantitative TaqMan real-time RT-PCR protocol, for the specific diagnostic and quantitation of SGEV. Linearity, efficiency and dynamic range as well as reproducibility and specificity of the method has been tested and established. The method has proved to be valid for the specific detection and viral load quantitation of SGEV genome in virus isolates and tissue samples from infected animals. This assay will be a useful analytical tool in early diagnosis and epidemiological surveys. PMID- 29481881 TI - Use of the Filovirus Animal Non-Clinical Group (FANG) Ebola virus immuno-assay requires fewer study participants to power a study than the Alpha Diagnostic International assay. AB - As part of the scientific community's development of medical countermeasures against Ebola virus disease, optimization of standardized assays for product evaluation is paramount. The recent outbreak heightened awareness to the scarcity of available assays and limited information on performance and reproducibility. To evaluate the immunogenicity of vaccines entering Phase I-III trials and to identify survivors, two enzyme-linked immunosorbent assays, the Filovirus Animal Non-Clinical Group assay and the Alpha Diagnostics International assay, were evaluated for detection of immunoglobulin G against Ebola virus glycoprotein. We found that the Filovirus Animal Nonclinical Group assay produced a wider range of relative antibody concentrations, higher assay precision, larger relative accuracy range, and lower regional background. Additionally, to sufficiently power a vaccine trial, use of the Filovirus Animal Nonclinical Group assay would require one third the number of participants than the Alpha Diagnostics International assay. This reduction in needed study participants will require less money, fewer man hours, and much less time to evaluate vaccine immunogenicity. PMID- 29481882 TI - A novel dual-luciferase assay for anti-HIV drug screening based on the CCR5/CXCR4 promoters. AB - Acquired immunodeficiency syndrome (AIDS) is a serious worldwide disease caused by infection with the human immunodeficiency virus (HIV). C-C chemokine receptor 5 (CCR5) and C-X-C chemokine receptor 4 (CXCR4) are important coreceptors mediating HIV-1 cell entry. Many new anti-HIV drugs are currently in preclinical and clinical trials; however, drug development has proceeded slowly partly because of the lack of a high-throughput system to screen these drugs. Here, we describe the development of a novel dual-luciferase assay using a CCR5/CXCR4 promoter-driven firefly and Renilla luciferase vector (pGL4.10-RLUC-CCR5/CXCR4). Drugs were screened for the ability to regulate CCR5 and CXCR4 promoter activities. The CCR5 and CXCR4 promoters were inserted separately into the recombinant vector and transfected into the acute T lymphocyte leukemia cell line H9. Treatment of stable transfected cells with four traditional Chinese medicine compounds resulted in the dose-dependent inhibition of the CXCR4 and CCR5 promoter activities. The dual-luciferase reporter assay provides a rapid and direct method to screen anti-AIDS/HIV drugs. PMID- 29481884 TI - Local anesthetic effect of docosahexaenoic acid on the nociceptive jaw-opening reflex in rats. AB - Although docosahexaenoic acid (DHA) administration suppresses sodium channels in primary afferent sensory neurons, the acute local effect of DHA on the trigeminal nociceptive reflex remains to be elucidated, in vivo. Therefore, the aim of the present study was to investigate whether local administration of DHA attenuates the nociceptive jaw-opening reflex (JOR) in vivo in the rat. The JOR evoked by electrical stimulation of the tongue was recorded by a digastric muscle electromyogram (dEMG) in pentobarbital-anesthetized rats. The amplitude of the dEMG response was significantly increased in proportion to the electrical stimulation intensity (1-5 x threshold). At 3 x threshold, local administration of DHA (0.1, 10 and 25 mM) dose-dependently inhibited the dEMG response, and lasted 40 min. Maximum inhibition of the dEMG signal amplitude was seen within approximately 10 min. The mean magnitude of inhibition of the dEMG signal amplitude by DHA (25 mM) was almost equal to the local anesthetic, 1% lidocaine (37 mM), a sodium channel blocker. These findings suggest that DHA attenuates the nociceptive JOR via possibly blocking sodium channels, and strongly support the idea that DHA is a potential therapeutic agent and complementary alternative medicine for the prevention of acute trigeminal nociception. PMID- 29481883 TI - Loss of GPRC5B impairs synapse formation of Purkinje cells with cerebellar nuclear neurons and disrupts cerebellar synaptic plasticity and motor learning. AB - GPRC5B is a membrane glycoprotein robustly expressed in mouse cerebellar Purkinje cells (PCs). Its function is unknown. In Gprc5b-/- mice that lack GPRC5B, PCs develop distal axonal swellings in deep cerebellar nuclei (DCN). Numerous misshapen mitochondria, which generated excessive amounts of reactive oxygen species (ROS), accumulated in these distal axonal swellings. In primary cell cultures of Gprc5b-/- PCs, pharmacological reduction of ROS prevented the appearance of such swellings. To examine the physiological role of GPRC5B in PCs, we analyzed cerebellar synaptic transmission and cerebellum-dependent motor learning in Gprc5b-/- mice. Patch-clamp recordings in cerebellum slices in vitro revealed that the induction of long-term depression (LTD) at parallel fiber-PC synapses was normal in adult Gprc5b-/- mice, whereas the induction of long-term potentiation (LTP) at mossy fiber-DCN neuron synapses was attenuated in juvenile Gprc5b-/- mice. In Gprc5b-/- mice, long-term motor learning was impaired in both the rotarod test and the horizontal optokinetic response eye movement (HOKR) test. These observations suggest that GPRC5B plays not only an important role in the development of distal axons of PCs and formation of synapses with DCN neurons, but also in the synaptic plasticity that underlies long-term motor learning. PMID- 29481886 TI - Relationship between traffic-related air pollution particle exposure and asthma exacerbations: Association or causation? PMID- 29481885 TI - TNFR2 mediated TNF-alpha signaling and NF-kappaB activation in hippocampus of 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice. AB - 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) -induced neuroinflammation and its impact in hippocampus remain elusive till date. Our present study includes the time dependent changes of inflammatory molecules in mouse hippocampus during MPTP treatment. MPTP treatment increased level of TNF-alpha, enhanced expression of TNFR2 along with PI3 kinase (PI3K) induced phosphorylation of Akt resulting in persistent nuclear factor-kappaB (NF-kappaB) activation. The expressions gradually increased from Day1 post-MPTP treatment, maximally at Day3 post-treatment. MPTP induced translocation of p65 and p52, two subunits of NF kappaB family, to nucleus where they had been found to dimerize. Therefore, MPTP induced TNF-alpha signaling through TNFR2 mediated pathway and recruited p65-p52 dimer in hippocampal nucleus which is reported to have protective effect on hippocampal neurons indicated by unchanged neuronal count in hippocampus in treated groups with respect to control. Our finding suggests that this unique NF kappaB dimer plays some role in providing inherent protection to hippocampus during MPTP-treatment. PMID- 29481887 TI - Evaporative coolers are not associated with dust mite or mold sensitization in a large pediatric cohort. PMID- 29481888 TI - Cow's milk-associated chronic food protein-induced enterocolitis syndrome exacerbated by extensively hydrolyzed formula. PMID- 29481889 TI - Authors' response. PMID- 29481890 TI - A case of neuropathic pain in monoclonal mast cell activation syndrome. PMID- 29481891 TI - Xolair-induced recurrent anaphylaxis through sensitization to the excipient polysorbate. PMID- 29481892 TI - Concurrent immunoglobulin E-mediated neuromuscular blocking agent allergy in systemic mastocytosis. PMID- 29481893 TI - Response surface methodology as a tool for modeling and optimization of Bacillus subtilis spores inactivation by UV/ nano-Fe0 process for safe water production. AB - One of the most important aspects of environmental issues is the demand for clean and safe water. Meanwhile, disinfection process is one of the most important steps in safe water production. The present study aims at estimating the performance of UV, nano Zero-Valent Iron particles (nZVI, nano-Fe0), and UV treatment with the addition of nZVI (combined process) for Bacillus subtilis spores inactivation. Effects of different factors on inactivation including contact time, initial nZVI concentration, UV irradiance and various aerations conditions were investigated. Response surface methodology, based on a five level, two variable central composite design, was used to optimize target microorganism reduction and the experimental parameters. The results indicated that the disinfection time had the greatest positive impact on disinfection ability among the different selected independent variables. According to the results, it can be concluded that microbial reduction by UV alone was more effective than nZVI while the combined UV/nZVI process demonstrated the maximum log reduction. The optimum reduction of about 4 logs was observed at 491 mg/L of nZVI and 60 min of contact time when spores were exposed to UV radiation under deaerated condition. Therefore, UV/nZVI process can be suggested as a reliable method for Bacillus subtilis spores inactivation. PMID- 29481894 TI - Dietary Se supplementation partially restores the REDOX proteomic map of M. spretus liver exposed to p,p'-DDE. AB - The toxicity of p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE), a contaminant and metabolite derivative of DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane] is partially mediated by reactive oxygen species. Protein cysteine-based regulatory switches and subsequent alterations of the overall hepatic metabolism are triggered by p,p'-DDE through the disruption of the cellular redox status. The consequences are reproductive impairment, metabolic disorders, diabetes, neurotoxicity and cancer. In recent years, the risk of p,p'-DDE exposure has increased worldwide, reflecting the rise of mosquito-borne diseases in tropical countries that produce and export contaminated foods. Selenium (Se) is an essential trace element in animal nutrition with antioxidant properties that protects against the toxicity of some xenobiotics. We analyzed the ability of diet Se-supplementation to prevent damages induced by p,p'-DDE in the liver of M. spretus mice, by using redox proteomics based on the determination of the redox status of protein Cys residues. Se selectively acted on specific target, restoring the redox status and functionality of some membrane proteins involved in mitochondrial functionality, protein transport, cell signaling and protein metabolism. However, the Se-enriched diet did not completely prevent the metabolic shift caused by p,p'-DDE exposure that leads to disturbed lipogenesis, hepatic steatosis and alterations in the synthesis of hormones and other cell signals. PMID- 29481895 TI - Tartary buckwheat protein prevented dyslipidemia in high-fat diet-fed mice associated with gut microbiota changes. AB - As one of low-digestible proteins, tartary buckwheat protein (BWP) revealed a cholesterol-lowering activity. The relationship between the prevention of BWP on dyslipidemia and changes in the numbers of gut microbiota was investigated. The male C57BL/6 mice were separately fed on normal diet, high-fat diet (HFD) with casein, and HFD with BWP extract for 6 weeks. Quantitative PCR assay was applied to quantify the microbiota composition in feces. The levels of plasma total cholesterol (TC) and triglyceride (TG) in the mice fed on HFD with BWP were significantly lower than those on HFD with casein. BWP promoted the growth of Lactobacillus, Bifidobacterium and Enterococcus and inhibited the growth of Escherichia coli in HFD-fed mice. Moreover, Bifidobacterium population was closely related to contents of plasma lipids. Further, BWP significantly decreased the levels of plasma inflammation factors as induced by HFD, including lipopolysaccharide, tumor necrosis factor alpha and interleukin 6. BWP significantly increased the excretion of total bile acids and short-chain fatty acids in feces. In conlusion, BWP benefited cholesterol metabolism, which could be attributed to regulating composition of gut microbiota. PMID- 29481896 TI - Zinc as a therapy in a rat model of autism prenatally induced by valproic acid. AB - Autism is characterized by numerous behavioral impairments, such as in communication, socialization and cognition. Recent studies have suggested that valproic acid (VPA), an anti-epileptic drug with teratogenic activity, is related to autism. In rodents, VPA exposure during pregnancy induces autistic-like effects. Exposure to VPA may alter zinc metabolism resulting in a transient deficiency of zinc. Therefore, we selected zinc as a prenatal treatment to prevent VPA-induced impairments in a rat model of autism. Wistar female rats received either saline solution or VPA (400 mg/kg, i.p) on gestational day (GD) 12.5. To test the zinc supplementation effect, after 1 h of treatment with saline or VPA, a dose of zinc (2 mg/kg, s.c.) was injected. The offspring were tested for abnormal communication behaviors with an ultrasound vocalization task on postnatal day (PND) 11, repetitive behaviors and cognitive ability with a T-maze task on PND 29, and social interaction with a play behavior task on PND 30. Tyrosine hydroxylase protein (TH) expression was evaluated in the striatum. Prenatal VPA decreased ultrasonic vocalization, induced repetitive/restricted behaviors and cognitive inflexibility, impaired socialization, and reduced striatal TH levels compared with control group. Zinc treatment reduced VPA induced autistic-like behaviors. However, we found no evidence of an effect of zinc on the VPA-induced reduction in TH expression. The persistence of low TH expression in the VPA-Zn group suggests that Zn-induced behavioral improvement in autistic rats may not depend on TH activity. PMID- 29481897 TI - Development-related aberrations in Kv1.1 alpha-subunit exert disruptive effects on bioelectrical activities of neurons in a mouse model of fragile X syndrome. AB - Kv1.1, a Shaker homologue potassium channel, plays a critical role in homeostatic regulation of neuronal excitability. Aberrations in the functional properties of Kv1.1 have been implicated in several neurological disorders featured by neuronal hyperexcitability. Fragile X syndrome (FXS), the most common form of inherited mental retardation, is characterized by hyperexcitability in neural network and intrinsic membrane properties. The Kv1.1 channel provides an intriguing mechanistic candidate for FXS. We investigated the development-related expression pattern of the Kv1.1 alpha-subunit by using a Fmr1 knockout (KO) mouse model of FXS. Markedly decreased protein expression of Kv1.1 was found in neonatal and adult stages when compared to age-matched wild-type (WT) mice. Immunohistochemical investigations supported the delayed development-related increases in Kv1.1 expression, especially in CA3 pyramidal neurons. By applying a Kv1.1-specific blocker, dendrotoxin-kappa (DTX-kappa), we isolated the Kv1.1 mediated currents in the CA3 pyramidal neurons. The isolated DTX-kappa-sensitive current of neurons from KO mice exhibited decreased amplitude, lower threshold of activation, and faster recovery from inactivation. The equivalent reduction in potassium current in the WT neurons following application of the appropriate amount of DTX-kappa reproduced the enhanced firing abilities of KO neurons, suggesting the Kv1.1 channel as a critical contributor to the hyperexcitability of KO neurons. The role of Kv1.1 in controlling neuronal discharges was further supported by the parallel developmental trajectories of Kv1.1 expression, current amplitude, and discharge impacts, with a significant correlation between the amplitude of Kv1.1-mediated currents and Kv1.1-blocking-induced firing enhancement. These data suggest that the expression of the Kv1.1 alpha-subunit has a profound pathological relevance to hyperexcitability in FXS, as well as implications for normal development, maintenance, and control of neuronal activities. PMID- 29481898 TI - Evaluation of the rewarding properties of nicotine and caffeine by implementation of a five-choice conditioned place preference task in zebrafish. AB - The rewarding properties of drugs in zebrafish can be studied using the conditioned place preference (CPP) paradigm. Most devices that have been used for CPP consist of two-half tanks with or without a central chamber. Here we evaluated the rewarding effects of nicotine and caffeine using a tank with five arms distributed radially from a central chamber that we have denoted Fish Tank Radial Maze (FTRM). Zebrafish were trained to associate nicotine or caffeine with a coloured arm. In testing sessions to assess CPP induction, between two and five different arms were available to explore. We found that when offering the two arms, one of them associated to the drug mediating conditioning for 14 days, zebrafish showed nicotine-induced CPP but not caffeine-induced CPP. When zebrafish had the option to explore drug-paired arms together with new coloured arms as putative distractors, the nicotine-CPP strength was maintained for at least three days. The presence of novel environments induced caffeine-CPP, which was still positive after three days of testing sessions. Complementary behavioural data supported these findings. Nicotine-CPP was prevented by the histone deacetylase inhibitor phenylbutyrate administered during conditioning; however, there were no effects on caffeine-CPP. The specific acetylation of lysine 9 in histone 3 (H3-K9) was increased in nicotine-conditioned zebrafish brains. This study suggests that novel environmental cues facilitate drug environment associations, and hence, the use of drugs of abuse. PMID- 29481899 TI - Lumen and media-adventitia border detection in IVUS images using texture enhanced deformable model. AB - Lumen and media-adventitia (MA) borders in intravascular ultrasound (IVUS) images are critical for assessing the dimensions of vascular structures and providing plaque information in the diagnosis and navigation of vascular interventions. However, manual delineation of the lumen and MA borders is an intricate and time consuming process. In this paper, a texture-enhanced deformable model (TEDM) is proposed to accurately detect these borders by incorporating texture information with the morphological factors of deformable model. An ensemble support vector machine classifier is used to classify IVUS pixels presented by texture features into different tissue types. The image regionalization maps of different tissue types are further used for texture enhancement modules in the TEDM. The proposed TEDM method has been tested on 1500 images from 15 clinical IVUS datasets by comparing with the manual delineations. Evaluation results demonstrate that our method can accurately detect lumen and MA surfaces with small surface distance errors of 0.17 and 0.19 mm, respectively. Accurate segmentation results provide 2D measurements of MA/lumen areas and 3D vessel visualizations for vascular interventions. PMID- 29481900 TI - Biochemical markers of striatal desensitization in cortical-limbic hyperglutamatergic TS- & OCD-like transgenic mice. AB - Tics and compulsions in comorbid Tourette's syndrome (TS) and obsessive compulsive disorder (OCD) are associated with chronic hyperactivity of parallel cortico/amygdalo-striato-thalamo-cortical (CSTC) loop circuits. Comorbid TS- & OCD-like behaviors have likewise been observed in D1CT-7 mice, in which an artificial neuropotentiating transgene encoding the cAMP-elevating intracellular subunit of cholera toxin (CT) is chronically expressed selectively in somatosensory cortical & amygdalar dopamine (DA) D1 receptor-expressing neurons that activate cortico/amygdalo-striatal glutamate (GLU) output. We've now examined in D1CT-7 mice whether the chronic GLU output from their potentiated cortical/limbic CSTC subcircuit afferents associated with TS- & OCD-like behaviors elicits desensitizing neurochemical changes in the striatum (STR). Microdialysis-capillary electrophoresis and in situ hybridization reveal that the mice's chronic GLU-excited STR exhibits pharmacodynamic changes in three independently GLU-regulated measures of output neuron activation, co-excitation, and desensitization, signifying hyperactive striatal CSTC output and compensatory striatal glial and neuronal desensitization: 1) Striatal GABA, an output neurotransmitter induced by afferent GLU, is increased. 2) Striatal d-serine, a glial excitatory co-transmitter inhibited by afferent GLU, is decreased. 3) Striatal Period1 (Per1), which plays a non-circadian role in the STR as a GLU + DA D1- (cAMP-) dependent repressor thought to feedback-inhibit GLU + DA- triggered ultradian urges and motions, is transcriptionally abolished. These data imply that chronic cortical/limbic GLU excitation of the STR desensitizes its co excitatory d-serine & DA inputs while freezing its GABA output in an active state to mediate chronic tics and compulsions - possibly in part by abolishing striatal Per1-dependent ultradian extinction of urges and motions. PMID- 29481901 TI - A Human Stem Cell-Based System to Study the Role of TP63 Mutations in Ectodermal Dysplasias. PMID- 29481902 TI - Panel Sequencing Shows Recurrent Genetic FAS Alterations in Primary Cutaneous Marginal Zone Lymphoma. AB - Primary cutaneous marginal zone lymphoma (PCMZL) represents an indolent subtype of non-Hodgkin lymphoma that is clinically characterized by slowly growing skin tumors with a very low propensity for systemic dissemination. The underlying genetic basis of PCMZL has not been comprehensively elucidated. To gain deeper insight into the molecular pathogenesis of PCMZL, we performed hybridization based panel sequencing of 38 patients with well-characterized PCMZL. In 32 of the 38 patients, we identified genetic alterations within 39 selected target genes. The most frequently detected alterations (24/38 patients, 63.2%) affected the FAS gene, of which 22 patients harbored alterations, which affect the functionally relevant death domain of the apoptosis-regulating FAS/CD95 protein in a dominant negative manner. In addition, we identified highly recurrent mutations in three other genes, namely SLAMF1, SPEN, and NCOR2. Our molecular data suggest that apoptosis defects provide the molecular basis of the observed clinical features of PCMZL, which commonly presents with only slowly growing skin tumors, reflecting its invariably indolent behavior. From a diagnostic point of view, highly recurrent FAS mutations in PCMZL presumably separate this indolent lymphoma entity from pseudolymphoma, and this adds adjunctive discriminatory features at a molecular level. PMID- 29481904 TI - KLHL16 Degrades Epidermal Keratins. PMID- 29481903 TI - Prevalence of Tanning Addiction and Behavioral Health Conditions among Ethnically and Racially Diverse Adolescents. AB - Evidence indicates that tanning may be addictive and is associated with other behavioral health conditions. Few studies have examined tanning addiction among adolescents. We performed a cross-sectional study to explore the relationship between tanning addiction, substance use, and psychological conditions among a racially and ethnically diverse adolescent population. Tanning addiction was assessed using the modified CAGE measure among 11th grade students in Los Angeles (N = 2,637; response rate 78%). Overall, 7.02% of the sample met tanning addiction criteria. Tanning addiction was significantly associated with past 30 day smoking and marijuana use, problem substance use, depression, panic disorder, obsessive-compulsive disorder, and bipolar disorder in regression models. After controlling for all significant substance use and psychological variables, we found that problem marijuana use and obsessive-compulsive disorder remained significantly associated with tanning addiction (odds ratio = 2.06 [95% confidence interval = 1.03-4.09] and odds ratio = 2.54 [95% confidence interval = 1.73-3.72], respectively.) Tanning addiction was also significantly associated with multiple problem substance use and behavioral health conditions. Our findings indicate an appreciable prevalence of tanning addiction among ethnically and racially diverse adolescents and suggest the importance of addressing tanning addiction in the context of comorbid behavioral conditions to reduce this high risk behavior among diverse youth. PMID- 29481905 TI - A C-type lectin (CL11X1-like) from Nile tilapia (Oreochromis niloticus) is involved in host defense against bacterial infection. AB - Collectins, a subfamily of the C-type lectins, are able to bind non-self glycoconjugates on the surface of microorganisms and inhibit infection by direct neutralization, agglutination and/or opsonization, which play important roles in innate immunity. In this study, a CL11X1-like collectin (OnCL11X1) was identified from Nile tilapia (Oreochromis niloticus) and characterized at expression and agglutination functional levels. The open reading frame of OnCL11X1 is 840 bp of nucleotide sequence encoding polypeptides of 279 amino acids. The deduced amino acid sequence is highly homology to teleost and similar to mammalian CL11X1, containing a canonical collagen-like region, a carbohydrate recognition domain and a neck region. Expression analysis revealed that the OnCL11X1 was highly expressed in the liver, and widely exhibited in other tissues including kidney, intestines and spleen. In addition, the OnCL11X1 expression was significantly up regulated in spleen and anterior kidney following challenges with a Gram-positive bacterial pathogen (Streptococcus agalactiae) and a Gram-negative bacterial pathogen (Aeromonas hydrophila). The up-regulation of OnCL11X1 expression was also demonstrated in hepatocytes and macrophages in vitro stimulation with S. agalactiae and A. hydrophila. Recombinant OnCL11X1 protein was able to agglutinate both S. agalactiae and A. hydrophila in vitro and promote the phagocytosis by macrophages. Taken together, the results of this study indicated that OnCL11X1, possessing apparent agglutination and opsonization ability to bacterial pathogens, might be involved in host defense against bacterial infection in Nile tilapia. PMID- 29481907 TI - Resuscitated cardiac arrest without STEMI-Should we go immediately to the cath lab? PMID- 29481906 TI - Revealing Mytilus galloprovincialis transcriptomic profiles during ontogeny. AB - Mediterranean mussels are a worldwide spread bivalve species with extraordinary biological success. One of the reasons of this success could be the reproduction strategy of bivalves, characterized by the presence of trochophore larvae. Larval development in bivalves has been a topic of raising interest in the scientific community but it deserves much more attention. The principal objective of this work was to study the transcriptomic profile of the ontogeny of Mytilus galloprovincialis analyzing the gene expression in different developmental stages, from oocytes to juveniles. For this purpose, after conducting a 454 sequencing of the transcriptomes of mussel hemocytes, adult tissues and larvae, a new DNA microarray was designed and developed. The studied developmental stages: unfertilized oocytes, veliger, pediveliger, settled larvae and juveniles, showed very different transcriptomic profiles and clustered in groups defining their characteristic gene expression along ontogeny. Our results show that oocytes present a distinct and characteristic transcriptome. After metamorphosis, both settled larvae and juveniles showed a very similar transcriptome, with no enriched GO terms found between these two stages. This suggests: 1.- the progressive loss of RNA of maternal origin through larval development and 2.- the stabilization of the gene expression after settlement. On the other hand during metamorphosis a specific profile of differentially expressed genes was found. These genes were related to processes such as differentiation and biosynthesis. Processes related to the immune response were strongly down regulated. These suggest a development commitment at the expense of other non-essential functions, which are temporary set aside. Immune genes such as antimicrobial peptides suffer a decreased expression during metamorphosis. In fact, we found that the oocytes which express a higher quantity of genes such as myticins are more likely to reach success of the offspring, compared to oocytes poor in such mRNAs, whose progeny died before reaching metamorphosis. PMID- 29481908 TI - A disparity in outcomes of out-of-hospital cardiac arrest by community socioeconomic status: A ten-year observational study. AB - BACKGROUND: The objective of this study was to compare the temporal trends in good neurologic outcome after out-of-hospital cardiac arrest (OHCA) between communities with different socioeconomic status (SES). METHODS: A nationwide, population-based observational study was conducted in adult patients with OHCA of cardiac etiology from 2006 to 2015. Community SES was defined using the Carstairs index categorized into 5 groups, from Q1 (the least deprived) to Q5 (the most deprived). Outcomes included good neurologic outcome, survival to hospital discharge and rate of bystander cardiopulmonary resuscitation (CPR). Using multivariable logistic regression, we examined temporal trends in risk-adjusted outcome rates according to community SES and estimated a difference-in differences model between 2006 and 2015 to compare the changes over time in communities with different SES. RESULTS: A total of 120,365 OHCAs met inclusion criteria. Risk-adjusted rates increased from 2006 to 2015 for bystander CPR (1.2% 23.2%), survival to discharge (3.0%-8.0%), and good neurological outcome (0.9% 5.8%). However, the degree of improvement in each risk-adjusted rate among SES groups were different. The communities with highest SES showed much greater improvement (bystander CPR 1.6%-34.6%; survival to discharge 3.5%-9.9%; and good neurological outcome 1.6%-7.4%) while less improvement in lower SES communities (1.6%-15.5%; 2.3%-6.2%; and 0.5%-4.2%, respectively). For rates of bystander CPR, the adjusted difference-in-differences value was statistically significant in highest SES communities, showing gradient from 11.48% increase in the lowest SES to 22.39% increase in the highest SES. CONCLUSION: In Korea, both survival to hospital discharge and good neurologic outcomes after OHCA have improved during the past decade. However, disparity in outcomes was observed based on community socioeconomic status. Outcome improvements were greatest in communities with higher SES but relatively less in lower SES communities. PMID- 29481909 TI - Beyond induced sedation: BIS for post-arrest monitoring. PMID- 29481910 TI - Hypothermia outcome prediction after extracorporeal life support for hypothermic cardiac arrest patients: The HOPE score. AB - AIMS: Currently, the decision to initiate extracorporeal life support for patients who suffer cardiac arrest due to accidental hypothermia is essentially based on serum potassium level. Our goal was to build a prediction score in order to determine the probability of survival following rewarming of hypothermic arrested patients based on several covariates available at admission. METHODS: We included consecutive hypothermic arrested patients who underwent rewarming with extracorporeal life support. The sample comprised 237 patients identified through the literature from 18 studies, and 49 additional patients obtained from hospital data collection. We considered nine potential predictors of survival: age; sex; core temperature; serum potassium level; mechanism of hypothermia; cardiac rhythm at admission; witnessed cardiac arrest, rewarming method and cardiopulmonary resuscitation duration prior to the initiation of extracorporeal life support. The primary outcome parameter was survival to hospital discharge. RESULTS: Overall, 106 of the 286 included patients survived (37%; 95% CI: 32-43%), most (84%) with a good neurological outcome. The final score included the following variables: age, sex, core temperature at admission, serum potassium level, mechanism of cooling, and cardiopulmonary resuscitation duration. The corresponding area under the receiver operating characteristic curve was 0.895 (95% CI: 0.859-0.931) compared to 0.774 (95% CI: 0.720-0.828) when based on serum potassium level alone. CONCLUSIONS: In this large retrospective study we found that our score was superior to dichotomous triage based on serum potassium level in assessing which hypothermic patients in cardiac arrest would benefit from extracorporeal life support. External validation of our findings is required. PMID- 29481911 TI - RNF185 modulates JWA ubiquitination and promotes gastric cancer metastasis. AB - Gastric cancer (GC) is one of the most common malignant cancers worldwide. Metastasis leads to poor prognoses in GC patients in advanced stages. Our previous studies have demonstrated that JWA functions as a tumour suppressor and that low expression of JWA in GC tissues is significantly correlated with shorter overall survival (OS) as well as with advanced clinicopathologic features in patients. However, the mechanism of dysregulation of JWA in cancers is not clear. In the present study, we found that an E3 ubiquitin ligase, RNF185, directly interacted with JWA and promoted its ubiquitination at the K158 site, resulting in subsequent degradation. Moreover, the protein level of RNF185 was negatively correlated with JWA in tumour tissues from GC patients. High RNF185 expression was significantly correlated with shorter OS. Additionally, increased RNF185 expression facilitated GC cell migration in vitro and promoted GC metastasis in vivo by downregulating JWA expression. However, this effect was reversed by replenishment of JWA. In conclusion, our findings highlight the following: (1) RNF185 promotes GC metastasis by mediating JWA degradation via a ubiquitin proteasome pathway; (2) the K158 site of JWA is essential for its ubiquitination in GC cells. These findings suggest that RNF185 is a novel candidate prognostic marker and potential therapeutic target for GC. PMID- 29481913 TI - Maintenance of a gluten free diet in coeliac disease: The roles of self regulation, habit, psychological resources, motivation, support, and goal priority. AB - INTRODUCTION: A strict lifelong gluten free diet (GFD) is the only treatment for coeliac disease (CD). Theory-based research has focused predominantly on initiation, rational, and motivational processes in predicting adherence. The aim of this study was to evaluate an expanded collection of theoretical constructs specifically relevant to the maintenance of behaviour change, in the understanding and prediction of GFD adherence. METHODS: Respondents with CD (N = 5573) completed measures of GFD adherence, psychological distress, intentions, self-efficacy, and the maintenance-relevant constructs of self-regulation, habit, temptation and intentional and unintentional lapses (cognitive and behavioural consequences of lowered or fluctuating psychological resources and self-control), motivation, social and environmental support, and goal priority, conflict, and facilitation. Correlations and multiple regression were used to determine their influence on adherence, over and above intention and self-efficacy, and how relationships changed in the presence of distress. RESULTS: Better adherence was associated with greater self-regulation, habit, self-efficacy, priority, facilitation, and support; and lower psychological distress, conflict, and fewer self-control lapses (e.g., when busy/stressed). Autonomous and wellbeing-based, but not controlled motivations, were related to adherence. In the presence of distress, the influence of self-regulation and intentional lapses on adherence were increased, while temptation and unintentional lapses were decreased. DISCUSSION: The findings point to the importance of considering intentional, volitional, automatic, and emotional processes in the understanding and prediction of GFD adherence. Behaviour change interventions and psychological support are now needed so that theoretical knowledge can be translated into evidence-based care, including a role for psychologists within the multi disciplinary treatment team. PMID- 29481914 TI - Associations among fear, disgust, and eating pathology in undergraduate men and women. AB - Fear and disgust are distinct emotions that have been independently linked with EDs and may motivate avoidance behaviors that may be relevant targets for ED interventions (e.g., food rejection). Despite similar motivational function, it is possible that one emotion is more strongly associated with ED symptoms, relative to the other. Given that emerging evidence suggests that disgust-based behavior may be more difficult to change than fear-based behaviors, research is needed to evaluate whether each emotion differentially relates to ED symptoms. Therefore, the current study tested the relative importance of fear and disgust in accounting for variance in ED symptoms. Participants included undergraduate men (n = 127) and women (n = 263) from a university in the northeast US. Participants completed self-report measures assessing demographics, disordered eating attitudes and behaviors, and visual analog scales assessing fear and disgust responses to high-calorie food images, low-calorie food images, and non food fear and disgust images. Bivariate correlations revealed significant positive associations among fear, disgust, and EDE-Q global symptom scores. Relative weights analysis results yielded relative importance weights that suggested disgust responding to high calorie food images accounts for the greatest total variance in EDE-Q global symptom scores in men, and fear responding to high calorie food images accounts for the greatest total variance in EDE-Q scores in women. Findings provide initial evidence that investigative and clinical efforts should consider fear and disgust as unique facets of negative affect with different patterns of relative importance to ED symptoms in undergraduate men and women. PMID- 29481915 TI - Cognitive dysfunction and metabolic comorbidities in mood disorders: A repurposing opportunity for glucagon-like peptide 1 receptor agonists? AB - Major depressive disorder and bipolar disorder are highly prevalent and disabling conditions. Cognition is considered a core domain of their psychopathology and a principle mediator of psychosocial impairment, disproportionately accounting for overall illness-associated costs. There are few interventions with replicated evidence of efficacy in treating cognitive deficits in mood disorders. Evidence also indicates that cognitive deficits are associated with obesity and involve significant impairment across multiple domains. Conversely, weight-loss interventions, such as physical exercise and bariatric surgery, have been shown to beneficially affect cognitive function. This convergent phenomenology suggests that currently available agents that target metabolic systems may also be capable of mitigating deficits in cognitive functions, and are, therefore, candidates for repurposing. The incretin glucagon-like peptide-1 (GLP-1) is a hormone secreted by intestinal epithelial cells. GLP-1 receptors (GLP-1R) are widely expressed in the central nervous system. Activation of GLP-1R leads to facilitation of glucose utilization and antiapoptotic effects in various organs. Pre-clinical trials have demonstrated significant neuroprotective effects of GLP-1, including protection from cell death, promotion of neuronal differentiation and proliferation; and facilitation of long-term potentiation. Liraglutide is a GLP-1R agonist that has been approved for the treatment of type 2 diabetes mellitus and obesity. Convergent preclinical and clinical evidence, including a proof-of-concept pilot study from group, has suggested that liraglutide may improve objective measures of cognitive function in adults with mood disorders. The safety and availability of GLP-1R agonists indicate that they are promising candidates for repurposing, and that they may be viable therapeutic options for mood disorders. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.' PMID- 29481912 TI - Suppression of aberrant choroidal neovascularization through activation of the aryl hydrocarbon receptor. AB - The aryl hydrocarbon receptor (AhR) is a ligand activated transcription factor, initially discovered for its role in regulating xenobiotic metabolism. There is extensive evidence supporting a multi-faceted role for AhR, modulating physiological pathways important in cell health and disease. Recently we demonstrated that the AhR plays a role in the pathogenesis of age-related macular degeneration (AMD), the leading cause of vision loss in the elderly. We found that loss of AhR exacerbates choroidal neovascular (CNV) lesion formation in a murine model. Herein we tested the therapeutic impact of AhR activation on CNV lesion formation and factors associated with aberrant neovascularization. We screened a panel of synthetic drugs and endogenous AhR ligands, assessed their ability to activate AhR in choroidal endothelial cells, and inhibit angiogenesis in vitro. Drugs with an anti-angiogenic profile were then administered to a murine model of CNV. Two compounds, leflunomide and flutamide, significantly inhibited CNV formation concurrent with positive modifying effects on angiogenesis, inflammation, extracellular matrix remodeling, and fibrosis. These results validate the role of the AhR pathway in regulating CNV pathogenesis, identify mechanisms of AhR-based therapies in the eye, and argue in favor of developing AhR as a drug target for the treatment of neovascular AMD. PMID- 29481916 TI - Pramipexole and Fingolimod exert neuroprotection in a mouse model of Parkinson's disease by activation of sphingosine kinase 1 and Akt kinase. AB - Parkinson's disease (PD) is one of the most severe neurodegenerative diseases with unknown pathogenesis and currently unsuccessful therapies. Recently, neuroprotection via sphingosine-1-phosphate (S1P)-dependent signalling has become a promising target for the treatment of neurodegenerative disorders. Our previous study demonstrated down-regulation and inhibition of the S1P-synthesizing enzyme sphingosine kinase 1 (SPHK1) in a PD cellular model. Moreover, we have previously identified a neuroprotective effect of fingolimod (FTY720), a first S1P receptor modulator utilized in the clinic. This study focused on the effects of FTY720 and the dopamine D2/D3 receptor agonist pramipexole (PPX) in a PD mouse model, induced by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Administration of FTY720, similar to PPX, abolished an observed loss of tyrosine hydroxylase (TH) immunoreactivity in MPTP-lesioned brain regions. Moreover, significant changes in SPHK1 expression/activity in MPTP-lesioned mouse midbrain were identified. PPX, but not FTY720 treatment, significantly protected against these alterations. Both drugs activate another pro-survival enzyme, Akt kinase, which is a crucial protein downstream of S1PR(s). FTY720 increased BAD protein phosphorylation and in this way may protect mitochondria against the BAD-induced apoptotic signalling pathway. Both FTY720 and PPX enhanced the locomotor activity of PD mice in the rotarod tests. Our data suggest a neuroprotective role for FTY720 related to the S1PR/Akt kinase signalling pathways as a beneficial treatment target in planning new PD therapeutic options. Moreover, our findings have shed new light on a neuroprotective mechanism of PPX action associated with SPHK1 activation, which provides an opportunity for evaluating multi-target (SPHK1/S1P/S1PR) effects in the context of PD. PMID- 29481917 TI - Cost-effectiveness of generic celecoxib in knee osteoarthritis for average-risk patients: a model-based evaluation. AB - OBJECTIVE: The cost-effectiveness of the recently-introduced generic celecoxib in knee OA has not been examined. METHOD: We used the Osteoarthritis Policy (OAPol) Model, a validated computer simulation of knee OA, to evaluate long-term clinical outcomes, costs, and cost-effectiveness of generic celecoxib in persons with knee OA. We examined eight treatment strategies consisting of generic celecoxib, over the-counter (OTC) naproxen, or prescription naproxen, with or without prescription or OTC proton-pump-inhibitors (PPIs) to reduce gastrointestinal (GI) toxicity. In the base case, we assumed that annual cost was $130 for OTC naproxen, $360 for prescription naproxen, and $880 for generic celecoxib. We considered a willingness-to-pay threshold of $100,000 per quality-adjusted life year (QALY) and discounted costs and benefits at 3% annually. In sensitivity analyses we varied celecoxib toxicity, discontinuation, cost, and pain level. RESULTS: In the base case analysis of the high pain cohort (WOMAC 50), celecoxib had an incremental cost-effectiveness ratio (ICER) of $284,630/QALY compared with OTC naproxen. Only under highly favorable cost, toxicity, and discontinuation assumptions (e.g., annual cost below $360, combined with a reduction in the cardiovascular (CV) event rates below baseline values) was celecoxib likely to be cost-effective. Celecoxib might also be cost-effective at an annual cost of $600 if CV toxicity were eliminated completely. In subjects with moderate pain (WOMAC 30), at the base case CV event rate of 0.2%, generic celecoxib was only cost effective at the lowest plausible cost ($190). CONCLUSION: In knee OA patients with no comorbidities, generic celecoxib is not cost-effective at its current price. PMID- 29481919 TI - Ultrasound Guided Compression for Iatrogenic Femoral Artery Pseudo Aneurysms. PMID- 29481918 TI - A Comparison Between Upper Arm and Chest for Optimal Site of Totally Implanted Venous Access Ports in Patients with Female Breast Cancer. AB - BACKGROUND: The objective of the study was to evaluate the safety, technical feasibility, and complications of totally implanted venous access ports (TIVAPs) in the upper arm, for comparison with transjugular chest ports in patients with breast cancer. METHODS: In total, 223 consecutive female breast cancer patients who received a TIVAP in the upper arm or chest between July 2014 and February 2016 were included. All procedures were performed via a sonographic and fluoroscopic-guided approach using the Seldinger technique under local anesthesia. We reviewed the medical records to determine technical success, pain scale, and early (<=30 days) and late (>30 days) complications. RESULTS: In total, 231 devices were implanted in the upper arms (n = 176, 76%) and chests (n = 55, 24%) of the patients. The mean age was 51.6 +/- 10.7 years (range 23-78 years; upper arm, 52.1 +/- 11.0 years; chest, 50.1 +/- 9.7 years, P > 0.05). The mean implantation time for TIVAPs was 181.7 +/- 109.2 days (range, 9-460 days; upper arm 175.2 +/- 102.7 days; chest, 202.4 +/- 126.6 days, P > 0.05), with 41,974 catheter days. The technical success rate was 100%. Fourteen complications (6.1%) occurred in 14 patients (0.33/1,000 catheter days). There was no significant difference in complication-free survival for patients with upper arm TIVAPs and those with transjugular chest TIVAPs. The mean amount of 2% lidocaine, used as local anesthesia, was 3.3 +/- 1.7 mL and 14.5 +/- 4.1 mL for upper arm and chest TIVAPs, respectively. (P < 0.001). CONCLUSIONS: Implantation of TIVAPs in the upper arm is a safe procedure with a low rate of complications. Upper arm TIVAPs can be implanted with less pain compared with transjugular chest TIVAPs. PMID- 29481920 TI - Reversal of Lower-Extremity Intermittent Claudication and Rest Pain by Hydration. AB - BACKGROUND: Medical treatment of disabling intermittent claudication or critical limb-threatening ischemia causing rest pain often fails or has partial response. METHODS: In this pilot study, 36 patients (12 females) affected by disabling intermittent claudication or rest pain of the lower extremities were exposed to a daily 3-L water intake for up to 6 weeks. Cutaneous foot temperature, ankle/brachial index, time and distance of claudication, and pain intensity were recorded before and at the completion of the hydration period. RESULTS: Patients with a mean +/- SE age of 71 +/- 2 years (range, 40-86) had disabling claudication (less than 100 meters) for more than 5 months while 11% reported pain at rest. A 6-week water intake of more than 2,500 mL/24 hr was achieved in 35 of the 36 patients enrolled in the study. Increased water intake was associated with significant improvements in median ankle/brachial index (from 0.60 to 0.76; P < 0.0001) and skin temperature (first dorsal right toe, from 29.95 degrees C to 30.0 degrees C, P < 0.001). Time and distance to report claudication of supervised treadmill exercise improved from 1.25 to 6.25 min (P < 0.0001) and from 100 meters to 535 meters (P < 0.0001), respectively. CONCLUSIONS: This study suggests that hydration attained by daily water consumption of more than 2.5 L has a robust impact on reducing the symptoms of disabling claudication and rest pain caused by peripheral vascular disease. PMID- 29481921 TI - Successful Thoracic Endovascular Aortic Repair using 2- and 3-Dimensional Fusion Imaging without Further Contrast Enhancement. AB - We report a case of successful thoracic endovascular aortic repair using a 3 dimensional computed tomography (3D CT) roadmap for a patient with severe contrast media allergy. As 3D CT image data were previously obtained, we integrated the data with the fluoroscopic image three dimensionally and constructed a 3D CT roadmap. This method is anticipated to be effective in patients who require less contrast enhancement or radiological dose by examining the appropriate imaging protocol for the kinds, shapes, and positions of the benchmarks for fusion. PMID- 29481922 TI - Recurrent Iliofemoral Venous Thrombosis in the Setting of May-Thurner Syndrome as the Presenting Symptom of Behcet's Disease. AB - BACKGROUND: Vascular manifestations including pulmonary artery aneurysms and venous thrombosis are seen in up to 14% of patients with Behcet's disease. We report a patient who had recurrent deep vein thrombosis (DVT) as the presenting symptom of Behcet's Disease. METHODS: A 19-year-old male who presented with acute iliofemoral DVT, confirmed by intravascular ultrasound (IVUS) and venogram. May Thurner syndrome was also observed. Repeated catheter-based pharmacomechanical thrombolysis, thrombectomy, and subsequent iliac vein stenting were performed. The patient was then discharged on rivaroxaban and aspirin. RESULTS: Five months later, the patient experienced left calf pain. In the interim, he had been diagnosed with Behcet's disease by a rheumatologist who was consulted due to oral ulcers and skin lesions and accordingly started on prednisone, colchicine, and azathioprine. At this time, IVUS and venogram revealed thrombotic occlusion of the previously placed stent. Tissue plasminogen activator was infused into the stent, and pharmacomechanical thrombectomy restored flow through the left iliac veins. Follow-up laboratory workup revealed that subtherapeutic azathioprine dosing, and after appropriate adjustment, the patient has been asymptomatic for 12 months. CONCLUSIONS: Acute refractory DVT is a possible presenting symptom of Behcet's disease, which may be complicated by May-Thurner syndrome. Such patients should receive therapeutic immunosuppression in addition to anticoagulation. PMID- 29481923 TI - How Compression Inside a Delivery System can Degrade the Cover of Aortic Endografts. AB - BACKGROUND: The goal of the present study was to identify the potential degradations undergone by textile endoprostheses (EPs) over the crimping process related to the catheter insertion purpose. In particular, we studied how the device design parameters can influence the wrinkling of the textile material, assuming that wrinkling induces stress concentration and may jeopardize the lifetime of the device. MATERIALS AND METHODS: Custom-designed EPs were obtained from various stent designs and textile constructions. Monofilament and multifilament materials were considered for the cover. Stent segment size, distance, and wire diameter were considered as variable for the stent. The EPs of 26-mm diameter were then crimped in a mock transparent 6-mm diameter catheter sheath for 8 and 30 days duration. After releasing the EPs from the sheath, the textile cover was characterized for roughness properties to identify the crease level induced on the surface by crimping. RESULTS: Results brought out that the monofilament material was characterized by a larger number of deeper creases in the zones where the stent was in contact with the cover. Conversely, the multifilament was more folded in the zones between stent segments. Moreover, it appeared that the stent design influenced the creases' topography. The textile seemed to be less prone to heavy wrinkling with stent segments made from larger wire diameter and larger segment size. Regarding the crimping duration, it came out that a longer stay in the sheath tends to promote more significant wrinkling. CONCLUSIONS: In this work, it was shown that wrinkling of the textile cover occurs in the EPs already at crimping level. However, an appropriate design of the EPs should limit the phenomenon and improve the performances of the EPs. PMID- 29481924 TI - Surgical Treatment of Synchronous Type B Acute Aortic Dissection and Abdominal Aortic Aneurysm. AB - BACKGROUND: We report the results of the operative treatment of synchronous type B acute aortic dissection (TBAAD) and infrarenal abdominal aortic aneurysm (AAA). METHODS: It is an observational, descriptive multicenter case series. Inclusion criterion was patients with diagnosis of TBAAD and AAA detected synchronously for the first time at clinical onset of dissection. Follow-up imaging protocol included triple-phase spiral/computed tomography angiography performed at 1, 6, and 12 months after thoracic endovascular aortic repair (TEVAR), and annually thereafter. Major end points were perioperative mortality and long-term survival, freedom from aortic events, and freedom from reintervention. RESULTS: We identified and treated 15 cases. All TBAADs were treated by TEVAR in the acute phase: infrarenal aortic repair was performed with stent graft (SG) in 10 (66.7%) patients, with open repair in 5 (33.3%). Overall, staged repair was used in 11 (73.3%) patients. Mean descending aortic endovascular length coverage was 21 cm +/- 7 (range, 10-35; interquartile range [IQR], 150-265). Overall, early perioperative mortality occurred in 1 (6.7%) patient. Median radiologic follow-up was 48 months (range, 6-120; IQR, 36-67). During the follow-up, TEVAR-related mortality was not observed. Aortic remodeling after TEVAR was obtained in 12 (85.7%) patients; abdominal sac shrinkage after SG was obtained in 8 (80.0%) patients. Freedom from aortic event rate was 79% +/- 10 (95% confidence interval [CI]: 53.1-92.6) at 1 year and 64% +/- 13 (95% CI: 38.1-83.5) at 5 year. Freedom from reintervention rate at 1 and 5 year was 85% +/- 10 (95% CI: 57.8-95.7). CONCLUSIONS: In our experience, the association of TBAAD and AAA was a rare finding. Because of the lack of available evidence to opt for a single intervention or a staged approach, selective approach with TEVAR and endovascular/open conventional treatment of the abdominal aorta yielded satisfactory results at midterm follow-up. PMID- 29481925 TI - Arterial Injury in the Upper Limb Resulting from Dog Bite. AB - Dog bites in the upper limbs have particular significance, because despite the small size of the puncture wounds, penetration is deep, causing serious injuries to deeper structures. There is currently very little data relating to upper extremity dog bite arterial injury. We present the case of a 32-year-old man who sustained a dog bite injury to his right arm, leading to direct puncture and spasm of the brachial artery. He was successfully treated with a jump bypass graft to the right brachial artery, with the use of the reversed ipsilateral cephalic vein as a conduit. We identified 34 cases in the literature reporting upper limb arterial injury secondary to dog bite. Twenty-two cases in the literature detailed axillobrachial artery damage (65%), 24% radial artery, 3% ulnar artery, and 9% combined. Presentation was most commonly with diminished pulses found in at least 45% of the patients. Arterial thrombosis occurred in 29% of cases of single artery injury, transection in 15%, intimal tear in 9% of cases, and undisclosed in 44%. Management most commonly included interposition graft (47%) and primary repair (20%), while 15% did not undergo surgical intervention, 9% underwent ligation, and 3% were treated with thromboembolectomy. Follow-up data for these patients are scarce, with some experiencing residual neurological deficit. This report highlights the importance of prompt recognition and treatment of vascular injury following dog bite to attain an optimal outcome and minimize complications. PMID- 29481926 TI - Anticoagulation Obtained below the Arterial Clamp Using a Single Fixed Bolus of Heparin in Vascular Surgery: A Pilot Study. AB - BACKGROUND: No clear recommendations exist regarding the optimal dosing of unfractionated heparin (UFH) during vascular surgery. Moreover, little is known about the effect of the UFH bolus downstream of the arterial clamp, where stasis and inflammation can possibly alter the anticoagulation obtained. METHODS: The aim of our prospective observational study was to assess anticoagulation below the arterial clamp and its clinical impact on the quality of revascularization. Thirty-six patients American Society of Anaesthesiologists physical status (ASA) grade I-III undergoing open revascularization surgeries were included. A baseline activated coagulation time (ACT) was obtained. Thirty minutes after a single bolus of 5,000 units of UFH, we measured an upstream ACT via a radial arterial catheter and an ACT below the arterial clamp via surgeon sampling. The quality of revascularization was assessed with preoperative and postoperative ankle-brachial and toe-brachial indexes (TBIs). RESULTS: The upstream postheparin ACT was significantly higher than the downstream postheparin ACT, with a mean difference of 24.3 sec (P < 0.0001). In 7 patients, the downstream ACT was lower than the baseline ACT. The upstream and downstream heparin concentrations were similar. There was no relationship between the downstream ACT and either ankle-brachial index improvement (28 patients, P = 0.51) or TBI improvement (27 patients, P = 0.21). CONCLUSIONS: Our study demonstrates a significant difference between the ACT above and below the arterial clamp without any clinical impact of this possibly insufficient anticoagulation. Further investigations are warranted to determine the optimal dose of UFH in vascular surgery. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02477072. PMID- 29481927 TI - Who Should Be Operated When Presenting with a Ruptured Abdominal Aortic Aneurysm? A Monocentric Study in a Tertiary Hospital. AB - BACKGROUND: Mortality with ruptured abdominal aortic aneurysms (rAAAs) is 80% overall, 50% when operated, and 100% when not operated. Distinguishing in emergency patients who should be operated versus being offered palliative treatment is difficult. We sought to identify key factors to consider in this decision-making. METHODS: Between 2001 and 2014, we selected all consecutive patients with rAAA treated by open or endovascular procedures in a tertiary hospital for inclusion in this retrospective, single-center study. Symptomatic aneurysms and isolated ruptured iliac aneurysms were excluded. The primary outcome was in-hospital mortality, and secondary outcomes were institutionalization rate and long-term mortality. Associations between predictive factors and in-hospital mortality were evaluated using univariate logistic regression. The local ethics committee approved this study. RESULTS: The mean age (+/-standard deviation) of the 72 included patients was 73 years (+/ 9.0) and 88% were men. Among the 65 open (90%) and 7 endovascular procedures (10%), overall in-hospital mortality was 21%, 1- and 2-year mortalities were both 26%, and the institutionalization rate was 5%. Mean follow-up was 43 months (Kaplan-Meier estimate). Univariate analysis identified age as associated with a 20% per year increased risk of in-hospital mortality (correlation, P < 0.0001). Female sex was the other main preoperative risk factor correlated with in hospital mortality (P = 0.006). Significant perioperative risk factors were suprarenal clamping (P = 0.038), amount of fresh frozen plasma transfused (P = 0.018), and number of blood transfusions (P < 0.0001). CONCLUSIONS: The most significant preoperative mortality-related factors were age and female sex. Our study also showed that institutionalization and long-term mortality are not factors to consider in the decision-making process. PMID- 29481928 TI - Outcomes and Risk Factors Associated with Prolonged Intubation after EVAR. AB - BACKGROUND: Time to discharge has decreased for aortic surgery since the advent of endovascular aortic aneurysm repair (EVAR), partially due to improved perioperative management. We aimed to investigate outcomes and risk factors associated with prolonged intubation following EVAR. METHODS: The Vascular Study Group of New England (VSGNE) database was queried to select all patients who underwent elective EVAR between January 2003 and December 2014. Patients who were not extubated in the operating room were classified as having prolonged intubation. Patients requiring prolonged intubation were compared with those extubated in the operating room using t-test and chi-square statistics. Kaplan Meier survival analyses estimated all-cause mortality. Independent predictors associated with prolonged intubation, including postoperative pneumonia or respiratory failure, were examined using multivariable logistic regression. RESULTS: A total of 3,979 patients were identified within the elective EVAR VSGNE data set, among whom 5.2% required prolonged intubation. Patients with prolonged intubation were older, more frequently female, non-Hispanic, had larger aneurysms, and had a more frequent diagnoses of diabetes, congestive heart failure, coronary artery disease, ejection fraction < 50%, and chronic obstructive pulmonary disease (all P < 0.05). Respiratory complications occurred in 25.5% of patients with prolonged intubation vs. 1.8% of patients who were extubated in the operating room (P < 0.001). Kaplan-Meier survival estimates suggested patients requiring prolonged intubation after EVAR had significantly lower survivals than those who extubated in the operating room (P < 0.05). On multivariable analysis, independent risk factors associated with prolonged intubation included subjective lack of fitness for open procedure (OR: 4.8, 95% confidence interval [CI]: 3.5-8.7), ejection fraction < 50% (1.8, 1.3-2.8), and ASA class >3 (1.5, 1.1-1.7). CONCLUSIONS: Prolonged intubation following EVAR is associated with increased risk of postoperative respiratory complications, as well as decreased long-term survival. High-risk patients for prolonged intubation, including those deemed subjectively unfit for an open procedure, ejection fraction < 50% and ASA class >3, may not benefit from an elective EVAR. PMID- 29481929 TI - Preexisting Conditions Determine the Occurrence of Unplanned Readmissions after Procedures for Treatment of Peripheral Arterial Disease. AB - BACKGROUND: Readmissions after surgical procedures are increasingly considered a metric to indicate the quality of care received during the index hospitalization. Patients with peripheral arterial disease (PAD) requiring peripheral vascular interventions (PVIs) or lower extremity bypasses (LEBs) often have several serious medical comorbidities. Risk factors associated with readmission after PVI and LEB have previously been identified. The purpose of this study is to compare the readmissions among patients receiving PVI and LEB procedures to identify risk factors associated with high risk of readmission. METHODS: The 2013 Procedure targeted American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database and generalized 2013 general and vascular surgery ACS-NSQIP Program User Files were used for this study. Patient, diagnosis, and procedure characteristics of patients undergoing PVI and LEB were assessed. Odds ratios (ORs) with confidence intervals (CIs) for PVI versus LEB groups within the subgroups of these characteristics were then obtained where significant associations existed between the study groups. RESULTS: A total of 3,742 patients (males: 2,384 [63.7%] and females: 1,358 [36.3%]) underwent surgical procedures for lower extremity PAD during the year 2013. Among these patients, 1,096 (29.3%) were treated with endovascular interventions and 2,646 (70.7%) were treated with surgical bypasses. Patients were divided into 2 groups: PVI (n = 1,096) and LEB (n = 2,646) groups. Each group was further subdivided into 2 groups: readmission and no readmission. The incidence of readmission was as follows: PVI group (n = 147, 13.4%) and LEB (n = 425, 16.1%). The PVI and LEB groups showed a significant association with readmission within the following factors: dialysis dependency (PVI 32.6% vs. LEB 19.1%, OR: 2.06, CI: 1.13-3.75, P < 0.001), emergency operation (PVI 40.4% vs. LEB 18.7%, OR: 2.96, CI: 1.45-6.03, P < 0.001), chronic obstructive pulmonary disease (COPD; PVI 23.7% vs. LEB 14.6%, OR: 1.82, CI: 1.08 3.07, P = 0.001), cardiac arrest (PVI 45.5% vs. LEB 9.5%, OR: 7.92, CI: 1.21 51.9, P = 0.017), and body mass index > 30 (PVI 9.9% vs. LEB 18.4%, OR: 0.49, CI: 0.33-0.73, P = 0.009). CONCLUSIONS: Readmissions after lower extremity endovascular or surgical interventions can be used as a quality metric. Patients with dialysis dependency, COPD, in need of emergent operation, or having cardiac arrest are highly likely to be readmitted if treated with endovascular interventions. Similarly, patients with high body mass index are highly likely to be readmitted if treated with open surgical bypasses. PMID- 29481930 TI - Hybrid Revascularization Combining Iliofemoral Endarterectomy and Iliac Stent Grafting for TransAtlantic Inter-Society Consensus C and D Aortoiliac Occlusive Disease. AB - BACKGROUND: This study examines the outcome of hybrid revascularization combining iliofemoral endarterectomy and iliac artery stenting using covered stents in TransAtlantic Inter-Society Consensus (TASC) C and D aortoiliac occlusive disease (AIOD) involving the common femoral artery (CFA). METHODS: A retrospective review was conducted in patients with TASC C and D AIOD involving the CFA and undergoing hybrid revascularization. Covered stents were used primarily. Demographics, indications for surgery, lesion classification, hospital length of stay (LOS), 30 day morbidity/mortality, hemodynamic and clinical success, and patency were assessed. RESULTS: Thirty-six male patients (41 limbs), mean age 63.9 +/- 6 years, were identified (TASC C = 39%, D = 61%). Indications for surgery were claudication (27%), rest pain (44%), and tissue loss (29%). A simultaneous adjunctive procedure (5 infrainguinal bypass, 3 superficial femoral artery stents) was performed in 22%. Thirty-day outcomes included 1 mortality (2.7%) and 2 reoperation (5.5%), 1 for femoral artery pseudoaneurysm and 1 for bilateral groin seroma. LOS was 4 days (interquartile range 3-6). All patients with available data experienced 30-day clinical and hemodynamic success. Mean follow up was 23 months (range 1-79 months) with a primary patency of 85.4%. Cumulative primary assisted and secondary patency was 92.6%. The femoral patch repair was the most frequent site of reintervention (3/3). Mortality was 34% during the study period, and it was significantly higher in patients with tissue loss (57.1% vs. 14.8%, P = 0.01). CONCLUSIONS: The hybrid approach has low morbidity, mortality, and fast recovery. The use of covered stents/stent grafts provides good mid-term patency. Close follow-up with noninvasive imaging is paramount to avoid repair failure, in particular at the femoral patch repair site. PMID- 29481931 TI - The Presence of Gas in Aneurysm Sac during Early Postoperative Period Is Associated to the Type of Endograft and Perfused Lumen's Size. AB - BACKGROUND: The aim of the present study was to examine the frequency of gas within the aneurysm sac following endovascular aneurysm repair (EVAR) on early postoperative computed tomography (CT) scans, to measure its volume, record the location, and analyze anatomical and procedural risk factors of its presence. METHODS: A retrospective analysis of prospectively collected data of patients undergoing standard, fenestrated, or branched EVAR between January 2013 and December 2015 was undertaken. The presence, position, and size of gas in the postoperative computed tomography angiography (CTA) (within 10 days) was examined, classified as (1) gas near aortic wall; (2) between aortic wall and endograft; and (3) near endograft and further analyzed in terms of anatomical and procedural risk factors associated with its presence. RESULTS: From a total of 241 (85% males, 204/241 and 15% females, 37/241) patients who were treated with EVAR, CTA within 10 days was available in 211 patients with mean age of 73 +/- 8.3 years. Gas was present on postoperative CT scan in 83 of 211 (39%) patients; 59/83 (71%) standard, 19/83 (23%) fenestrated, and 5/83 (6%) branched EVAR. The location of the gas was more frequently near the aortic wall (a) (46/83; 55.4%), with the mean gas volume to be 0.41 mL (range 0.01-2.74). Endoleak type II was diagnosed in 31.2% (66/211) of the cases and was not associated with the presence of gas (20/83; presence vs. 46/128; absence of gas; P = 0.069). The presence of gas was associated with larger preoperative diameter of the aortic perfused lumen (P = 0.013). The type of graft was correlated to the presence of gas on postoperative CTA (more frequent in standard EVAR [odds ratio 8; 95% confidence interval {CI} 2.01-31.25] and fenestrated [odds ratio 5.81; 95% CI 1.41-23.81]). In standard EVAR patients, the presence of gas was more frequently identified in early CTA (<5 days) than in later one (6-10 days) (P = 0.000). During the first month follow-up, no patient demonstrated any signs of infection in clinical and radiological assessment. CONCLUSIONS: The presence of gas in the aneurysm sac after EVAR is a frequent finding on postoperative CTA and not related to infection or endoleak. Type of stent graft and size of the perfused lumen is associated with the presence of gas. PMID- 29481932 TI - Prior Radiological Investigations in 65-Year-Old Men Screened for AAA. AB - BACKGROUND: The National Health Service abdominal aortic aneurysm screening programme (NAAASP) is now fully operational. Those who have previously been formally investigated for abdominal aortic aneurysm (AAA) are excluded; however, many patients undergo radiological investigation of the abdomen for other reasons. Such practices may find incidental AAA which may be eroding the performance of the NAAASP. We investigated the rates of preinvestigation before invitation to screening in our local AAA screening programme. METHODS: Electronic patient records were retrospectively reviewed for all patients called between March 2013 and February 2016 in 1 local AAA screening programme. Their records were interrogated to identify any abdominal imaging within 5 years of their invitation to screening. RESULTS: Two thousand six hundred thirty-eight men were invited for screening; of these, 563 (21.3%) had been "prescreened". Median time between prescreening and screening was 19 months (0-60 months). Ultrasound abdomen was the most prevalent at 248 (44.0%). Two thousand two hundred forty three (85.0%) men attended screening, and 6 (0.27%) were excluded for known AAA. Prevalence of AAA was 1.8% (n = 41). Of these, 15 (36.6%) had prior investigation with 6 (40.0%) having AAA diagnosed. Therefore, 9 (22.0%) had potential missed AAA on "prescreening" (mean diameter 35 mm [30-45], mean time lapse between investigation and screening 21.1 months [1-49]). Incidence of missed aneurysm in the "prescreened" cohort was 1.6% (9/563). CONCLUSIONS: Large numbers of men invited for AAA screening have undergone preinvestigation of their abdominal aorta, with 60% of the present AAA being missed. Reliance on incidental detection of AAA would leave many patients undiagnosed in the community-at risk of future rupture. PMID- 29481933 TI - Aneurysm of the Fibular Vein: A Case Report. AB - BACKGROUND: Aneurysms of the deep veins of the lower limbs are rare and often asymptomatic. Although natural history is unclear, these aneurysms have been associated with deep venous thrombosis and fatal pulmonary embolism events. To our knowledge, this case represents the fifth patient with isolated aneurysm of a calf vein described in the literature and the second one affecting the fibular vein. METHODS: We report the case of a 20-year-old white man with an aneurysm of the fibular vein that we believe is the second case in the literature RESULTS: After evaluation and diagnosis, the aneurysm was resected with full recovery of the patient. CONCLUSIONS: Treatment of this unusual condition seems to be mandatory for major thromboembolic events can be as high as 71% with 2 deaths, according to a review of 24 patients with popliteal vein aneurysms. Unlike proximal veins, where reconstruction is advisable, calf vein aneurysms can be safely managed by simple excision and ligature. In our patient, aneurysm resection eliminated symptoms, and good result was maintained in long follow-up. PMID- 29481935 TI - Two-stage Treatment Using Balloon Pulmonary Angioplasty and Pulmonary Endarterectomy in a Patient with Chronic Thromboembolic Pulmonary Hypertension. AB - We performed a 2-stage procedure combining balloon pulmonary angioplasty and pulmonary endarterectomy for a high-risk chronic thromboembolic pulmonary hypertension patient with high pulmonary vascular resistance. First, balloon pulmonary angioplasty was performed for distal lesions to improve hemodynamics and decrease the surgical risk. Subsequently, pulmonary endarterectomy was performed for proximal lesions, and the hemodynamics and symptoms improved dramatically. Our strategy was therefore found to be useful for treating a high risk chronic thromboembolic pulmonary hypertension patient. PMID- 29481934 TI - Differences in Aortic Diameter Measurements with Intravascular Ultrasound and Computed Tomography After Blunt Traumatic Aortic Injury. AB - BACKGROUND: Intravascular ultrasound (IVUS) has been recommended as an adjunct to thoracic endovascular aortic repair (TEVAR) as computed tomography (CT) in injured patients may inaccurately determine the true aortic diameter. We hypothesize that CT and IVUS offer discordant measurements of aortic diameter in trauma patients and that each modality may result in different graft size estimates for TEVAR. METHODS: Patients treated by TEVAR for blunt aortic injury from June 2011 to 2016 were reviewed. Cases where IVUS was not used and those without complete CT and IVUS images were excluded. Three-dimensional reconstructions were used to derive centerline diameters of the aorta, proximal and distal to the injury. IVUS diameters were taken from the flow lumen, not including the aortic wall itself. Measurements were made by an investigator blinded to the graft implanted. Descriptive statistics were used to compare patients with concordant diameter (group 1) with patients with discordant diameters (group 2). RESULTS: A total of 24 blunt thoracic aortic injuries were repaired with TEVAR during the study period; complete data were available for 16. The mean age of the patients was 43 (+/-18), and 12 of the patients were men. The median time from injury to CT was 2.5 hr (0.9-8.5) and to TEVAR was 18 (3-48) hr. Stent graft diameter for implantation based on CT and IVUS imaging was the same in 5 cases (group 1). In 11 cases, the graft diameter for implantation based on IVUS was differently sized compared with that determined by CT (group 2). Ten diameters were 1 size larger, and 1 diameter was 1 size smaller by IVUS. There were no significant differences in the mean lowest systolic blood pressure (98 vs. 92, P = 0.53), median fluid resuscitation in the first 24 hr (4.9 vs. 5.0 L, P = 0.97), or median 24-hr transfusion requirements (130 vs. 1311 mL, P = 0.11) between the groups 1 and 2, respectively. In group 2, the graft size chosen for surgery correlated more with measurements obtained from the CT than from IVUS (9 vs. 2). CONCLUSIONS: The TEVAR has become the standard therapy for blunt aortic injury, despite a dearth of long-term outcome data. The preoperative CT frequently underestimates aortic diameter compared with intraoperative IVUS. The implications of placing thoracic endografts and whether excessive oversizing results in long-term aortic dilation need to be the focus of long-term studies in these relatively young patients. PMID- 29481936 TI - Sizing Considerations for GORE Excluder in Angulated Aortic Aneurysm Necks. AB - BACKGROUND: Device selection for endovascular treatment of abdominal aortic aneurysms (AAAs) with necks >60 degrees is challenging. We sought to identify whether such anatomy necessitated graft oversizing during (endovascular aneurysm repair [EVAR]), and whether this increased the risk of type 1A endoleaks. METHODS: Prospective analysis of patients undergoing implantation of a C3 Gore Excluder, with aortic anatomy defined as outside Instructions for Use (IFU) due to proximal neck angulation >60 degrees was performed. RESULTS: Of the 1,394 patients enrolled, 127 patients (9.2%) were included, with median follow-up of 236 days. Mean neck angle was 78.0 +/- 13.2%, neck length 2.88 +/- 1.31, and mean graft oversize 23.5 +/- 9.6%. There were 7 type 1A endoleaks (5.5% males, 5.6% females). Neither neck length, angle, nor degree of oversizing were predictors of type IA endoleak. CONCLUSIONS: In conclusion, when selecting endografts for patients with proximal neck angulation over 60 degrees , endovascular interventionalists are not adhering to IFU. However, this was not associated with increased risk of type 1A endoleaks. PMID- 29481937 TI - Possible Mechanism for Common Femoral Artery Occlusion with the Perclose Suture Device. AB - BACKGROUND: Common femoral artery (CFA) occlusion by the Perclose suture device has been rarely reported in the literature. Authors and industry have no proposed mechanism. A review of patients who required operative repair may identify a possible mechanism for CFA occlusion. METHODS: At a single center, 2 patients were identified with CFA occlusion due to posterior CFA wall suturing. Vessel characteristics, angiographic, and intraoperative findings were reviewed. RESULTS: In both patients, the CFA diameter was >5 mm with no evidence of atherosclerotic plaque. Puncture sites by angiogram were near vessel branch points-the inferior epigastric and profunda femoris. Intraoperative findings identified posterior CFA suturing at the origin of a branch vessel as the mechanism for vessel occlusion. CONCLUSIONS: CFA occlusion by the Perclose device is the result of suture firing into the posterior CFA wall, which requires interposition of the vessel between the footplate and suture needles. The proposed mechanism is anchoring of the footplate in the origin of the branch vessel, which allows for capture of the posterior CFA wall. Technical reasons may include high or low puncture near CFA branches, less than 45 degrees angulation of the device in relation to the CFA, and axial rotation of the device, which may allow for footplate anchoring in the branch vessel origin. PMID- 29481938 TI - Disease Progression in the Contralateral Carotid Artery is Still Common After Endarterectomy. AB - BACKGROUND: Disease progression in the contralateral carotid artery (CA) after a carotid endarterectomy (CEA) was common in the past. Current medication regimens for these patients are better and have probably modified this progression. We evaluated the rate of disease progression in the contralateral CA over the last decade. METHODS: A retrospective analysis of 291 consecutive patients undergoing a CEA between 2005 and 2014 was performed. Disease progression in the contralateral CA after CEA was determined by a duplex ultrasound. Statistics were calculated by Kaplan-Meier life-tables and Cox regression. RESULTS: Of the 291 patients, 246 (84.5%) received at baseline antiplatelet and/or anticoagulant agents, and 223 (77%) received statins. These proportions increased over the second half of the study. Disease progression in the contralateral CA was evaluated in 200 patients during a mean follow-up of 3.5 years. Progression-free survival rates from any disease progression at 1 and 5 years were of 89.3% and 68.6%, respectively. Free survival rates from <50% to >50% progression or from 50% to 69% to a higher category at 1 and 5 years were of 89.3% and 75.5%, respectively. Finally progression-free survival rates to a >70% stenosis or occlusion at 1 and 5 years were of 96.8% and 90.1%, respectively. Age (hazard ratio = 1.034, P = 0.048) and dyslipidemia (hazard ratio = 1.93, P = 0.045) were also associated with any disease progression. CONCLUSIONS: Current rates of disease progression in the contralateral CA after CEA are similar to those reported more than 1 decade ago. Further research will be needed to evaluate the impact of current medical regimens at these stages of disease. PMID- 29481939 TI - Durability of Carotid Endarterectomy with Bovine Pericardial Patch. AB - BACKGROUND: Multiple studies have shown that patch angioplasty after carotid endarterectomy (CEA) reduces the risk of stroke and restenosis when compared with primary closure. Biological, synthetic, or vein patches have been traditionally used in CEA. This article reports the early and long-term outcomes of bovine pericardium (BP) for patch angioplasty in CEA. METHODS: A retrospective, consecutive analysis of 874 patients who underwent CEA during the past 17 years at Mayo Clinic, Florida, was performed. BP patch (BPP) was used in 680 patients. Other CEA techniques were used in 194 patients (standard without patch, 78; standard with Dacron, 74; standard with vein patch, 16; and other techniques: bypasses, 26). We defined group 1 as those who underwent BPP angioplasty and group 2 as those who underwent all other techniques. Early and late clinical outcomes and patch-related complications (restenosis, infection, and hematoma) were recorded and analyzed. RESULTS: Median follow-up for the entire series was 39.6 months. There were no statistically significant differences in 30-day mortality and morbidity between the 2 groups, except that BP group has less 30 day stroke (0.1%, 1 of 680) versus other techniques (1.5%, 3 of 194, P = 0.03). Thirty-day postoperative mortality rate was 0.1% (1 of 680) in BPP group and 1.0% (2 of 194) in other technique group (P = 0.13). No statistically significant difference was noted in 30-day postoperative major complications (transient ischemic attack [TIA], wound infection, hematoma requiring surgical evacuation, and nerve injury) between the 2 groups. Ten-year freedom from stroke/TIA were 97.8% in the BP group compared with 98.5% in the other group (P = 0.86). Ten-year freedom from restenosis was also similar between groups (89.0% BP vs. 90.4% others, P = 0.69). Ten-year survival rate was 38.4% in BP group and 45.0% in other technique group, and this was statistically significant on univariate analysis only. CONCLUSIONS: CEA with BP angioplasty has excellent early and late outcomes with minor morbidity and mortality. PMID- 29481940 TI - Why Did I Not Think of This? Water Therapy for PAD! (Invited Commentary). PMID- 29481941 TI - The Role of Interleukins and Inflammatory Markers in the Early Restenosis of Covered Stents in the Femoropopliteal Arterial Segment. AB - BACKGROUND: The objective of this study was to evaluate the relationship between inflammatory markers, such as interleukin (IL)-1beta, IL-6, IL-8, IL-10, tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta), and highly sensitive C-reactive protein, and the development of arterial restenosis 6 months after femoropopliteal percutaneous transluminal angioplasty (PTA) with covered stent implantation. METHODS: We recruited 27 patients of a tertiary hospital in Brazil who were treated with covered stents for atherosclerotic peripheral arterial disease. Serum samples were collected before stent implantation, then 24 hr later, and 6 months after the procedure. RESULTS: At 6-month follow-up, 4 patients (15%) presented restenosis. IL1- beta, IL-6, IL 8, and TNF-alpha levels showed a statistically significant reduction after both 24 hr and 6 months compared with pretreatment levels (P < 0.01). There were increased levels of IL-10 and TGF-beta both 24 hr and 6 months after PTA and stenting compared with pretreatment levels (P < 0.01). None of the cytokines studied were correlated with restenosis. CONCLUSIONS: This study demonstrated a significant increase in anti-inflammatory TGF-beta and IL-10 and a decrease in proinflammatory cytokines IL-1beta, IL-6, IL-8, and TNF-alpha 6 months after the procedure, but no inflammatory marker was independently identified as a risk factor for in-stent restenosis. PMID- 29481942 TI - Use of Local Thermal Load for Patients with Critical Limb Ischemia. PMID- 29481943 TI - Technique to Avoid Hemodialysis Catheter in Patients with Failing Aneurysmal Arteriovenous Fistula by Creating a Concomitant New Arteriovenous Fistula. AB - Autogenous arteriovenous fistula (AVF) is the primary recommended access for hemodialysis. Long-term use will not uncommonly result in AVF aneurysmal degeneration. Aneurysm-associated complications encompass pain, skin ulceration, infection, thrombosis, cannulation difficulties, and life-threatening bleeding. Various methods to repair aneurysmal AVFs have been described. However, there may be circumstances when this is not possible and require insertion of a temporary hemodialysis catheter (HDC) until a new arteriovenous access is created. We describe a case series of creating a new simultaneous AVF while continuing to use the primary failing aneurysmal AVF to avoid placement of an HDC. Once the new AVF becomes operational, the primary aneurysmal AVF can be abandoned. Six patients underwent simultaneous new AVF creation, 4 ipsilateral, and 2 contralateral. None of the patients developed symptomatic steal syndrome or congestive heart failure. Five of 6 patients had successful usage of the new AVF, and subsequently underwent ligation and excision of the aneurysmal AVF, thus avoiding a temporary HDC. Close monitoring for skin compromise and bleeding in the aneurysmal AVF is recommended while the new AVF matures. PMID- 29481945 TI - Interdependence of particle properties and bulk powder behavior of indomethacin in quench-cooled molten two-phase solid dispersions. AB - Solid dispersions (SDs) hold a proven potential in formulating poorly water soluble drugs. The present paper investigates the interfacial phenomena associated with the bulk powder flow, water sorption, wetting and dissolution of the SDs prepared by a modified melt and quench-cooling (QC) method. Poorly water soluble indomethacin (IND) was QC molten with solubilizing graft copolymer (Soluplus(r)) or polyol sugar alcohol (xylitol, XYL). The interfacial interactions of SDs with air/water were found to be reliant on the type (amorphous/crystalline) and amount of the carrier material used. The final SDs were composed of fused agglomerates (SOL) or large jagged particles (XYL) with good wetting and powder flow properties. The initial dissolution of IND was accelerated by both carrier materials studied. The QC molten SDs with amorphous Soluplus(r) significantly improved the dissolution rate of IND at pH 6.8 (79.9 +/ 0.2% at 30 min) compared to that of pure crystalline drug. The substantial improvement in the dissolution rate of IND was in connection with the amorphous state of the drug being stabilized by Soluplus(r) in the QC molten SDs. However, it is evident that a strong H-bond formation between the components in some regions of the QC molten SDs can limit the dissolution of IND. The QC molten two phase SDs with a polyol carrier (XYL) showed rapid and continuous drug release without reaching a plateau. PMID- 29481944 TI - Prior Endovascular Intervention Is Not Detrimental to Pedal Bypasses for Ischemic Wounds. AB - BACKGROUND: Endovascular strategies are often preferred for revascularization of ischemic foot wounds secondary to infrapopliteal disease because of the less invasive technique and faster recovery. Bypass is typically reserved for failures or lesions not amenable to balloon angioplasty. However, the effects of an endovascular-first approach on subsequent bypass grafts are largely unknown. This study evaluates the effects of prior endovascular tibial interventions (PTIs) on successive bypasses to pedal targets. METHODS: Patients who presented with ischemic tissue loss and tibial arterial occlusive disease to University of Pittsburgh Medical Center between 2006 and 2013 and underwent a surgical bypass to pedal arteries were included in this study. A retrospective chart review was conducted to obtain patient demographics, past medical history, extent of disease, prior tibial endovascular interventions, the treatment intervention, subsequent interventions, wound healing status, limb salvage, and patient survival. The primary outcome was primary patency of the pedal bypass graft. RESULTS: From 122 eligible patients, 27 had a PTI, whereas 95 had no prior endovascular tibial intervention (nPTI) in the treatment of ischemic pedal wounds with mean follow-up of 24.5 and 20.5 months, respectively (P = 0.36). The 2 groups were largely similar in terms of demographics, comorbidities, wound size, and degree of ischemia. Runoff scores between the 2 groups were also comparable (5.0 +/- 1.6 for PTI and 4.8 +/- 1.9 for nPTI, P = 0.59). The plantar artery was a more common target vessel in the PTI group, whereas the posterior tibial artery was targeted more often in the nPTI group (P = 0.04). At 12 months, those with a PTI exhibited a shorter primary patency (34.8% vs. 60.2%, P = 0.04). In a multivariate model, PTI was a significant risk factor for primary patency loss (hazard ratio 2.51, P = 0.004). Primary assisted patency and secondary patency were similar between the 2 groups. Wound healing was improved in those patients who had a prior endovascular intervention with 63.8% healed at 1 year compared with only 34.8% of those without intervention (P = 0.01). Amputation-free survival was similar (P = 0.68), as was survival alone (P = 0.50). CONCLUSIONS: Despite a decrease in primary patency, pedal bypass was not otherwise negatively affected by a PTI. Similar primary assisted patency, secondary patency, wound healing, and survival between the 2 patient populations indicate that an endovascular-first approach is a feasible treatment strategy to achieve similar clinical outcomes in the management of ischemic foot wounds. PMID- 29481946 TI - Human serum albumin nanoparticles for ocular delivery of bevacizumab. AB - Bevacizumab-loaded nanoparticles (B-NP) were prepared by a desolvation process followed by freeze-drying, without any chemical, physical or enzymatic cross linkage. Compared with typical HSA nanoparticles cross-linked with glutaraldehyde (B-NP-GLU), B-NP displayed a significantly higher mean size (310 nm vs. 180 nm) and a lower negative zeta potential (-15 mV vs. -36 mV). On the contrary, B-NP displayed a high payload of approximately 13% when measured by a specific ELISA, whereas B-NP-GLU presented a very low bevacizumab loading (0.1 MUg/mg). These results could be related to the inactivation of bevacizumab after reacting with glutaraldehyde. From B-NP, bevacizumab was released following an initial burst effect, proceeded by a continuous release of bevacizumab at a rate of 6 MUg/h. Cytotoxicity studies in ARPE cells were carried out at a single dose up to 72 h and with repeated doses over a 5-day period. Neither bevacizumab nor B-NP altered cell viability even when repeated doses were used. Finally, B-NP were labeled with 99mTc and administered as eye drops in rats. 99mTc-B-NP remained in the eye for at least 4 h while 99mTc-HSA was rapidly drained from the administration point. In summary, HSA nanoparticles may be an appropriate candidate for ocular delivery of bevacizumab. PMID- 29481947 TI - Monitoring of multiple solvent induced form changes during high shear wet granulation and drying processes using online Raman spectroscopy. AB - Form changes during drug product processing can be a risk to the final product quality in terms of chemical stability and bioavailability. In this study, online Raman spectroscopy was used to monitor the form changes in real time during high shear wet granulation of Compound A, a highly soluble drug present at a high drug load in an extended release formulation. The effect of water content, temperature, wet massing time and drying technique on the degree of drug transformation were examined. A designed set of calibration standards were employed to develop quantitative partial least square regression models to predict the concentration of each drug form during both wet granulation and the drying process. Throughout all our experiments we observed complex changes of the drug form during granulation, manifest as conversions between the initial non solvated form of Compound A, the hemi-hydrate form and the "apparent" amorphous form (dissolved drug). The online Raman data demonstrate that the non-solvated form converts to an "apparent" amorphous form (dissolved drug) due to drug dissolution with no appearance of the hemi-hydrate form during water addition stage. The extent of conversion of the non-solvated form was governed by the amount of water added and the rate of conversion was accelerated at higher temperatures. Interestingly, in the wet massing zone, the formation of the hemi hydrate form was observed at a rate equivalent to the rate of depletion of the non-solvated form with no change in the level of the "apparent amorphous" form generated. The level of hemi-hydrate increased with an increase in wet massing time. The drying process had a significant effect on the proportion of each form. During tray drying, changes in drug form continued for hours. In contrast fluid bed drying appeared to lock the final proportions of drug form product attained during granulation, with comparatively small changes observed during drying. In conclusion, it was possible to simultaneously monitor the three forms in real time during wet granulation and drying using online Raman spectroscopy. The results regarding the effect of process parameters on the degree of transformation are critical for designing a robust process that ensures a consistent form in the final drug product. PMID- 29481948 TI - Enhanced dissolution of solid dispersions containing bicalutamide subjected to mechanical stress. AB - The anticancer drug bicalutamide was co-milled with either Macrogol 6000 or Poloxamer 407, and the physicochemical parameters that drive the phase transition of binary systems and influence the dissolution modification of bicalutamide were studied. Milled binary systems with reduced particle size were assessed by scanning electron microscopy and laser diffraction measurements. The results of thermal analysis supported by X-ray diffractometry confirmed the reduction of the crystallinity of bicalutamide co-milled with Macrogol 6000. Infrared spectroscopy was used to determine the molecular structure of the samples and indicated weak interactions between drug and polymer molecules. Two mechanisms were identified and were involved in up to 11-fold enhanced dissolution. The first one was based on improved wettability due to a decreased contact angle in samples containing Macrogol 6000. The second one relied on the solubilization of bicalutamide within nanoaggregates formed by Poloxamer 407 that resulted from its surface activity. This finding was confirmed with fluorescence spectroscopy, dynamic light scattering and cryogenic transmission electron microscopy assays. Given the dissolution rate-limited absorption combined with the reduced bioavailability of bicalutamide as a BCS class II drug, the assessment of the mechanisms driving the increase in drug dissolution is of particular importance in drug development. PMID- 29481949 TI - Evolutionary history of ergot with a new infrageneric classification (Hypocreales: Clavicipitaceae: Claviceps). AB - The ergot, genus Claviceps, comprises approximately 60 species of specialised ovarial grass parasites famous for the production of food toxins and pharmaceutics. Although the ergot has been known for centuries, its evolution have not been resolved yet. Our approach combining multilocus phylogeny, molecular dating and the study of ecological, morphological and metabolic features shows that Claviceps originated in South America in the Palaeocene on a common ancestor of BEP (subfamilies Bambusoideae, Ehrhartoideae, Pooideae) and PACMAD (subfamilies Panicoideae, Aristidoideae, Chloridoideae, Micrairoideae, Arundinoideae, Danthonioideae) grasses. Four clades described here as sections diverged during the Paleocene and Eocene. Since Claviceps are parasitic fungi with a close relationship with their host plants, their evolution is influenced by interactions with the new hosts, either by the spread to a new continent or the radiation of the host plants. Three of the sections possess very narrow host ranges and biogeographical distributions and have relatively low toxicity. On the contrary, the section Claviceps, comprising the rye ergot, C. purpurea, is unique in all aspects. Fungi in this section of North American origin have spread all over the world and infect grasses in all subfamilies as well as sedges, and it is the only section synthesising toxic ergopeptines and secalonic acids. The evolutionary success of the Claviceps section members can be explained by high toxin presence, serving as feeding deterrents and playing a role in their protective mutualism with host plants. Closely related taxa Neoclaviceps monostipa and Cepsiclava phalaridis were combined into the genus Aciculosporium. PMID- 29481950 TI - Methylglyoxal induced glycation and aggregation of human serum albumin: Biochemical and biophysical approach. AB - Serum protein glycation and formation of advanced glycation end products (AGEs) correlates with many diseases viz. diabetes signifying the importance of studying the glycation pattern of serum proteins. In our present study, methylglyoxal was investigated for its effect on the structure of human serum albumin (HSA); exploring the formation of AGEs and aggregates of HSA. The analytical tools employed includes intrinsic and extrinsic fluorescence, UV spectroscopy, far UV circular dichroism, Thioflavin T fluorescence, congo red binding, polyacrylamide gel electrophoresis (PAGE). UV and fluorescence spectroscopy revealed the structural transition of native HSA evident by new peaks and increased absorbance in UV spectra and quenched fluorescence in the presence of MG. Far UV CD spectroscopy revealed MG induced secondary structural alteration evident by reduced alpha-helical content. AGEs formation was confirmed by AGEs specific fluorescence. Increased ThT fluorescence and CR absorbance of 10mM MG incubated HSA suggests that glycated HSA results in the formation of aggregates of HSA. SEM and TEM were reported to have an insight of these aggregates. Molecular docking was also utilized to see site specific interaction of MG-HSA. This study is clinically significant as HSA is a clinically relevant protein which plays a crucial role in many diseases. PMID- 29481951 TI - Soil burial-induced chemical and thermal changes in starch/poly (lactic acid) composites. AB - Soil burial degradation was confirmed to be an efficient waste disposal method for the biodegradable materials with short service life, such as starch/poly (lactic acid) (PLA) composite. The biodegradation behavior about chemical and thermal properties of starch/PLA composite was analyzed by using X-ray photoelectron spectroscopy (XPS), infrared microscopy (IRM), differential scanning calorimetry (DSC), and thermal gravimetric analysis (TGA). XPS and IRM results indicated that the biodegradation of PLA occurred at the ester groups in PLA chains. XPS demonstrated the cleavage of CO linkages between glucose rings in starch. DSC and TGA results showed that the starch/PLA composite degraded faster than the pure PLA. During the soil burial degradation, the glass transition temperature of starch/PLA composite exhibited an obviously decrease while it had a slight variation for PLA. The thermal stability of starch/PLA composite shifted towards to that of PLA when they were subjected to soil burial for the same time. It is established that the starch can accelerate the degradation of PLA-based materials, which will enlarge the markets of biodegradable PLA materials used for short service life products. PMID- 29481952 TI - Engineered chitosan based nanomaterials: Bioactivities, mechanisms and perspectives in plant protection and growth. AB - Excessive use of agrochemicals for enhancing crop production and its protection posed environmental and health concern. Integration of advanced technology is required to realize the concept of precision agriculture by minimizing the input of pesticides and fertilizers per unit while improving the crop productivity. Notably, chitosan based biodegradable nanomaterials (NMs) including nanoparticles, nanogels and nanocomposites have eventually proceeded as a key choice in agriculture due to their inimitable properties like antimicrobial and plant growth promoting activities. The foreseeable role of chitosan based NMs in plants might be in achieving sustainable plant growth through boosting the intrinsic potential of plants. In-spite of the fact that chitosan based NMs abode immense biological activities in plants, these materials have not yet been widely adopted in agriculture due to poor understanding of their bioactivity and modes of action towards pathogenic microbes and in plant protection and growth. To expedite the anticipated claims of chitosan based NMs, it is imperative to line up all the possible bioactivities which denote for sustainable agriculture. Herein, we have highlighted, in-depth, various chitosan based NMs which have been used in plant growth and protection mainly against fungi, bacteria and viruses and have also explained their modes of action. PMID- 29481953 TI - Structural insights on starch hydrolysis by plant beta-amylase and its evolutionary relationship with bacterial enzymes. AB - The conversion of starch to maltose is catalysed in plants by beta-amylase. The enzymatic mechanism has been well-characterized for the soybean and barley enzymes, which utilise a glutamic acid-glutamate pair. In the present study, we present a surprise observation of maltotetraose at the active site, the presence of which elucidates the clear role of Thr344 as a conformational "switch" between substrate binding and product release during hydrolysis. This observation is confirmed by the selection of maltotetraose by the crystallized enzyme although that carbohydrate was present in only trace amounts. The conformation of the residues in the substrate-binding site changed upon substrate binding, leading to the movement of threonine, glutamic acid, and the loop conformation, elucidating a missing link in the existing mechanism. By aligning our substrate-free and maltotetraose-bound structures with other existing structures, the sequence of events from substrate binding to hydrolysis can be visualized. Apart from this, the evolutionary relationship among beta-amylases of bacterial and amyloplastic origin could be established. The presence of a sugar-binding domain in the bacterial enzyme and its absence in the plant counterpart could be attributed to a carbohydrate-rich environment. Interestingly, cladogram analysis indicates the presence of N-terminal additions in some plant beta-amylases. Based on sequence similarity, we postulate that the role of such additions is important for the regulation of enzymatic activity, particularly under stress conditions. PMID- 29481954 TI - Influence of TEMPO-oxidized NFC on the mechanical, barrier properties and nisin release of hydroxypropyl methylcellulose bioactive films. AB - Bioactive films from hydroxypropyl methylcellulose (HPMC), nisin (N), and different percentage (5% to 75%) of TEMPO-oxidized nanofibrillated cellulose (NFC) isolated from rice straw pulp were prepared by solution casting technique and their properties were studied. Scanning electron microscope images (SEM) of films showed homogeneous surface with absence of nanofibers agglomeration. The mechanical and barrier properties were evaluated by measuring their tensile strength, tensile modulus, strain at maximum load, dynamic mechanical thermal properties (DMTA), and water vapor permeability (WVP). In all films, there was an improvement in the mechanical, thermomechanical, and moisture barrier properties as a result of presence of NFC. The molecular structure of the films was studied by Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction patterns (XRD). Presence of NFC in HPMC films affected crystallinity of the later. The prepared HPMC/N, NFC/N, and HPMC/N/NFC films exhibited significant antimicrobial activities against Gram-positive bacteria Staphylococcus aureus with noticeable controlled release of nisin in case of films containing HPMC/NFC. PMID- 29481955 TI - Crosslinking induces high mineralization of apatite minerals on collagen fibers. AB - Type I collagen, as the critical organic component of bone matrix, plays a template role in mineralization. Gamma-ray irradiation is used to prepare collagen with different crosslinking degrees without introducing foreign substances for mineralization. Significant improvement in crosslinking degree of collagen can be inferred by enzymolysis and differential scanning calorimetry analysis. Scanning electron microscopy observation reveals that, as crosslinking degree increases, the pore structure of collagen becomes more compact. Fourier transform infrared spectroscopy analysis shows the intact retention of classical triple-helical structure of collagen after crosslinking and the following mineralization. Atomic force microscopy characterization, calcium and phosphorus assay kit tests and thermogravimetry measurements indicate that the more compact the collagen structure, the more hydroxyapatite can attach on collagen fibers. These findings reveal the high crosslinking degree of collagen is favorable for the improvement of mineralization ability by providing a more stable and compact network structure. Such crosslinked collagen may provide a more potential way for the preparation of bone substitute materials. PMID- 29481956 TI - Synthesis and in vitro study of modified chitosan-polycaprolactam nanocomplex as delivery system. AB - In this work, chitosan/polycaprolactam (PCL-CS) nano-complex was synthesized and their micelles were formed as self-assembled amphiphilic nano-compartments. These micelles were utilize for drug delivery after loading quercetin (QU) as chemotherapeutic agent and delivery potency of this nano-complex was investigated. This nano-complex was also functionalized with folic acid (FA) in order to targeting delivery of nano-carrier to cancer cell lines. This foure dimensional nano-complex was successfully characterized based on UV-vis, FT-IR, DLS, and TGA analytical devices to confirm the synthesis. Drug loading was estimated 21.5% in final nano-carrier. In vitro drug release study was applied to investigation of QU release in PBS that was exhibited high potency of nano complex in controlled drug release. Cell viability of assay was implemented to determination of biocompatibility, bioavailability and therapeutic potency of nano-complexes on different cancer and normal cell lines. Micelles demonstrated safety levels for 24 and 48 h post-treatment incubation and FA receptor mediated uptake of chitosan/polycaprolactam/folic acid/quercetin (PCL-CS-FA-QU) was exhibited excellent efficiency on inhibition of cancer cells. PMID- 29481957 TI - Synthesis and characterization of basil seed mucilage coated Fe3O4 magnetic nanoparticles as a drug carrier for the controlled delivery of cephalexin. AB - A novel drug delivery system, loaded the drug cephalexin on the basil seed mucilage coated magnetic nanoparticles (Fe3O4@BSM-CPX) was prepared and characterized by means of X-ray diffraction (XRD), Furier Transform Infrared (FTIR), Field Emission Scanning Electron Microscope (FESEM), Vibrating Sample Magnetometer (VSM), Transmission Electron Microscopy (TEM), and Anti-bacterial, and Specific Surface (BET). By comparing the size of the uncoated nanoparticles (12nm) and the size of the coated magnetite nanoparticles (6nm), it was found that with the mucilage coating being put on the magnetite nanoparticles, the size of the nanoparticle cores has also decreased. The optimum pH results showed that the higher adsorption capacity occurs when cephalexin is cationic at pH2.5 because the NH3+ group of cephalexin interacts better with negative functional groups of the basil seed mucilage. Disk Diffusion Anti-Bacterial test showed that the loading of CPX on the Fe3O4@BSM nanocarrier, not only does not have any negative effects on the structure and performance of the drug, but also increases the antibacterial properties of CPX. Furthermore, the in vitro release of Fe3O4@BSM-CPX nanocomposites showed an initial burst release in the first 18h, followed by a more gradual and sustained release for 120h. PMID- 29481958 TI - Erratum to "Tear cytokine profile of glaucoma patients treated with preservative free or preserved latanoprost". PMID- 29481959 TI - Inhibition of nuclear translocation of notch intracellular domain (NICD) by diosgenin prevented atherosclerotic disease progression. AB - Notch signaling plays a pivotal role in homeostasis and cardiovascular development. The role of notch signaling in atherosclerosis cannot be complete without analysing the key role of notch in macrophages, which trigger the inflammatory response and subsequent plaque formation in atherosclerosis. Diosgenin showed its anti-atherosclerotic property by the unifying mechanism of suppressing the expression of notch signaling pathway, particularly the nuclear translocation of notch intracellular domain (NICD) in aorta and in differentiated macrophage cells. It is further confirmed by the inhibition of NICD by DAPT (N-[N (3, 5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester), which also restricted the differentiation of macrophage. Hence, inhibition of nuclear translocation of NICD by diosgenin aids in preventing atherosclerosis. PMID- 29481960 TI - Frailty Predicts Failure to Rescue after Thoracoabdominal Operation. AB - BACKGROUND: An association between frailty and mortality exists; we hypothesized this is secondary to failure to rescue (F2R). STUDY DESIGN: Data were obtained from the NSQIP (2005 to 2012) for patients undergoing thoracoabdominal operations. Using the Modified Frailty Index, patients were classified as not (0 points), mildly (1 point), moderately (2 points), and severely (>=3) frail. RESULTS: There were 962,913 patients included; a majority were non-frail (52.2%), followed by mildly frail (33.8%). Complications were noted in 15.3%, major complications in 9.5%, mortality in 1.8%, and F2R in 1.3% of patients. On multivariate analysis, increases in frailty were associated with an increase in the risk of major complications (mildly: risk ratio [RR] 1.51; moderately: RR 2.69; and severely frail: RR 5.63 compared with non-frail; p < 0.0001), and death (mildly frail: RR 1.84; moderately frail: RR 4.44; and severely frail: RR 12.4). On univariate analysis, older patients, males, those undergoing small bowel interventions, gastric operations, or other procedures, and the frail were more likely to experience F2R (p < 0.0001). On multivariate analysis, males (RR 1.07), those undergoing small bowel intervention (RR 1.91), gastric operation (RR 1.83), and other procedures (RR 2.43) compared with hernia repair were more likely to experience F2R. As frailty increases F2R increases (mildly frail: RR 1.48; moderately frail: RR 2.41; and severely frail: RR 4.41) (p < 0.0001). Components of the Modified Frailty Index were analyzed separately; measures of impaired functional status were independently associated with increased F2R (RR 2.91; p < 0.0001), and those measuring comorbid medical conditions were not. CONCLUSIONS: Increases in frailty independently predict risk for F2R. The greatest predictors of F2R in the Modified Frailty Index are those associated with disability and not comorbidities. PMID- 29481961 TI - Up-regulated Th17 cell function is associated with increased peptic ulcer disease in Helicobacter pylori-infection. AB - BACKGROUND: During Helicobacter pylori (H. pylori) infection CD4+ T cells in the gastric lamina propria are hyporesponsive and polarized by Th1/Th17 cell responses controlled by Treg cells. The objective of this study was to determine the number of Th17 cells in gastric mucosa of patients with gastritis and peptic ulcer and determined the relationship between main virulence factor of H. pylori and Th17 cells. METHODS AND MATERIALS: A total of 89 H. pylori-infected gastritis patients, 63 H. pylori-infected peptic ulcer patients and 48 H. pylori-negative non-ulcer dysplasia patients were enrolled in this study. The number of Th17 was determined by immunohistochemistry. IL-8 and IL-17A expressions were determined by real-time polymerase chain reaction (qPCR). Also, the grade of chronic and active inflammation was investigated for involvement according to the density of neutrophils and mononuclear in gastric mucosal crypts, from one to all crypts. RESULTS: The number of Th17 cells and the expression of IL-8 and IL-17A in infected patients were significantly higher than uninfected subjects. The number of Th17 cells and the expression of IL-8 and IL-17A in infected patients with peptic ulcer were significantly higher than patients with gastritis. Additionally, the numbers of Th17 cells as well as the expression of IL-8 and IL 17A were positively correlated with the degree of H. pylori density in infected patients with peptic ulcer, while this correlation was negative in infected patients with gastritis. The numbers of Th17 cells as well as the expression of IL-8 and IL-17A were positively correlated with the degree of chronic inflammation. CONCLUSION: The predominant Th17 cell responses may play a role in the pathogenesis of peptic ulcers disease in infected patients. PMID- 29481962 TI - Our Differences Make Us Stronger. PMID- 29481963 TI - Acute blood pressure elevation: Therapeutic approach. AB - International guidelines have suggested to avoid the term "hypertensive crisis" for the description of an acute and severe increase in blood pressure (BP) and to consider the definition of 'hypertensive emergencies' or 'hypertensive urgencies'. These two clinical presentations are characterized by the presence of high BP values but imply a different diagnostic and therapeutic approach. Hypertension awareness, treatment and control are slightly increased in the last years mostly in the United States and in some European nations. Nevertheless the prevalence of hypertensive emergencies is still high and remains associated to a higher mortality. International Guidelines have also given some recommendations regarding the target BP during treatment and the use of antihypertensive drugs in hypertensive emergencies, although the adherence to these indications is frequently suboptimal. The present paper is aimed to update the currently available data on the treatment of hypertensive emergencies. PMID- 29481964 TI - No association between HPV vaccine and reported post-vaccination symptoms in Japanese young women: Results of the Nagoya study. AB - Nagoya City introduced free HPV vaccination in 2010 and in April 2013 the Ministry of Health, Labour and Welfare included the HPV vaccine in the National Immunization Program. However, in June 2013, the Ministry suspended proactive recommendation of the vaccine after unconfirmed reports of adverse events. To investigate any potential association between the vaccine and reported symptoms, Nagoya City conducted a questionnaire-based survey. Participants were 71,177 female residents of Nagoya City born between April 2, 1994 and April 1, 2001. The anonymous postal questionnaire investigated the onset of 24 symptoms (primary outcome), associated hospital visits, frequency, and influence on school attendance. Totally, 29,846 residents responded. No significant increase in occurrence of any of the 24 reported post-HPV vaccination symptoms was found. The vaccine was associated with increased age-adjusted odds of hospital visits for "abnormal amount of menstrual bleeding" (OR: 1.43, 95% CI: 1.13-1.82), "irregular menstruation" (OR: 1.29, 95% CI: 1.12-1.49), "severe headaches" (OR: 1.19, 95% CI: 1.02-1.39), and chronic, persisting "abnormal amount of menstrual bleeding" (OR 1.41, 95% CI: 1.11-1.79). No symptoms significantly influenced school attendance and no accumulation of symptoms was observed. The results suggest no causal association between the HPV vaccines and reported symptoms. PMID- 29481965 TI - The bispectrum and its relationship to phase-amplitude coupling. AB - Most biological signals are non-Gaussian, reflecting their origins in highly nonlinear physiological systems. A versatile set of techniques for studying non Gaussian signals relies on the spectral representations of higher moments, known as polyspectra, which describe forms of cross-frequency dependence that do not arise in time-invariant Gaussian signals. The most commonly used of these employ the bispectrum. Recently, other measures of cross-frequency dependence have drawn interest in EEG literature, in particular those which address phase-amplitude coupling (PAC). Here we demonstrate a close relationship between the bispectrum and popular measures of PAC, which we relate to smoothings of the signal bispectrum, making them fundamentally bispectral estimators. Viewed this way, however, conventional PAC measures exhibit some unfavorable qualities, including poor bias properties, lack of correct symmetry and artificial constraints on the spectral range and resolution of the estimate. Moreover, information obscured by smoothing in measures of PAC, but preserved in standard bispectral estimators, may be critical for distinguishing nested oscillations from transient signal features and other non-oscillatory causes of "spurious" PAC. We propose guidelines for gauging the nature and origin of cross-frequency coupling with bispectral statistics. Beyond clarifying the relationship between PAC and the bispectrum, the present work lays out a general framework for the interpretation of the bispectrum, which extends to other higher-order spectra. In particular, this framework holds promise for the detailed identification of signal features related to both nested oscillations and transient phenomena. We conclude with a discussion of some broader theoretical implications of this framework and highlight promising directions for future development. PMID- 29481966 TI - Value encoding in the globus pallidus: fMRI reveals an interaction effect between reward and dopamine drive. AB - The external part of the globus pallidus (GPe) is a core nucleus of the basal ganglia (BG) whose activity is disrupted under conditions of low dopamine release, as in Parkinson's disease. Current models assume decreased dopamine release in the dorsal striatum results in deactivation of dorsal GPe, which in turn affects motor expression via a regulatory effect on other nuclei of the BG. However, recent studies in healthy and pathological animal models have reported neural dynamics that do not match with this view of the GPe as a relay in the BG circuit. Thus, the computational role of the GPe in the BG is still to be determined. We previously proposed a neural model that revisits the functions of the nuclei of the BG, and this model predicts that GPe encodes values which are amplified under a condition of low striatal dopaminergic drive. To test this prediction, we used an fMRI paradigm involving a within-subject placebo controlled design, using the dopamine antagonist risperidone, wherein healthy volunteers performed a motor selection and maintenance task under low and high reward conditions. ROI-based fMRI analysis revealed an interaction between reward and dopamine drive manipulations, with increased BOLD activity in GPe in a high compared to low reward condition, and under risperidone compared to placebo. These results confirm the core prediction of our computational model, and provide a new perspective on neural dynamics in the BG and their effects on motor selection and cognitive disorders. PMID- 29481968 TI - High levels of an endothelial dysfunction marker (sVCAM-1) are associated with injurious and recurrent falls and mortality over a 5-year interval in an older population. AB - We investigated the association between elevated plasma concentrations of circulating soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1) and injurious falls and mortality over a 5-year period. We studied the prospective relationship between levels of circulating adhesion molecules and falls in 680 community dwelling participants in the MOBILIZE Boston Study. The mean sVCAM-1 (+/-SD) concentration was 1192 +/- 428 ng/mL. Over 5-years of follow-up, 10.2% of participants died. The baseline sVCAM-1 (+/-SD) concentration was 1434 +/- 511 ng/mL in those who died vs. 1162 +/- 402 ng/mL in those who survived (P < 0.0001). sVCAM-1 level was associated with recurrent falls (P < 0.01); compared to the lowest quintile, the highest quintile of sVCAM-1 was associated with increased risk of injurious falls [multivariable adjusted Incidence Rate Ratio = 1.9, 95% CI (1.2-2.9), P = 0.009]. On survival analysis, the highest sVCAM-1 quintile was associated with the greatest mortality over 5 years (log-rank test, P < 0.0001). The adjusted hazard ratio was 2.4 [95% CI (2.1-2.7), P = 0.002]. High sVCAM-1 blood concentration was strongly associated with recurrent falls, injurious falls, and mortality in older adults. PMID- 29481967 TI - Human neuromuscular aging: Sex differences revealed at the myocellular level. AB - Age-related muscle loss (sarcopenia) is a major clinical problem affecting both men and women - accompanied by muscle weakness, dysfunction, disability, and impaired quality of life. Current definitions of sarcopenia do not fully encompass the age-related changes in skeletal muscle. We therefore examined the influence of aging and sex on elements of skeletal muscle health using a thorough histopathological analysis of myocellular aging and assessments of neuromuscular performance. Two-hundred and twenty-one untrained males and females were separated into four age cohorts [mean age 25 y (n = 47), 37 y (n = 79), 61 y (n = 51), and 72 y (n = 44)]. Total (-12%), leg (-17%), and arm (-21%) lean mass were lower in both 61 y and 72 y than in 25 y or 37 y (P < 0.05). Knee extensor strength (-34%) and power (-43%) were lower (P < 0.05) in the older two groups, and explosive sit-to-stand power was lower by 37 y (P < 0.05). At the histological/myocellular level, type IIx atrophy was noted by 37 y and type IIa atrophy by 61 y (P < 0.05). These effects were driven by females, noted by substantial and progressive type IIa and IIx atrophy across age. Aged female muscle displayed greater within-type myofiber size heterogeneity and marked type I myofiber grouping (~5-fold greater) compared to males. These findings suggest the predominant mechanisms leading to whole muscle atrophy differ between aging males and females: myofiber atrophy in females vs. myofiber loss in males. Future studies will be important to better understand the mechanisms underlying sex differences in myocellular aging and optimize exercise prescriptions and adjunctive treatments to mitigate or reverse age-related changes. PMID- 29481969 TI - Real-World Safety and Efficacy of Fluid-Filled Dual Intragastric Balloon for Weight Loss. AB - BACKGROUND & AIMS: Reshape Duo is a saline-filled dual, integrated intragastric balloon (IGB) approved by the Food and Drug Administration for weight loss in patients with obesity. In a prospective, randomized trial, obese patients who received the balloon had significantly greater percent excess weight loss (%EWL) compared with patients treated with diet and exercise alone. However, there are limited data on the real-world efficacy of the Reshape balloon. METHODS: We performed a retrospective study of data collected from 2 academic centers and 5 private practices in which all patients paid for the IGB and follow-up visits out of pocket. The IGB was removed after 6 months. We collected data (demographic, medical, and laboratory) from 202 adults (mean age 47.8 +/- 10.8 years; 83% female) with a baseline mean body mass index of 36.8 + 8.4 kg/m2 who had IGB insertion for weight loss therapy, along with counselling on lifestyle modifications focused on diet and exercise. Primary outcomes were percent total body weight loss (%TBWL) and %EWL at 1, 3, 6, 9, and 12 months after the procedure. RESULTS: Mean %TBWL at 1, 3, 6, 9 and 12 months was 4.8 +/- 2.4%, 8.8 +/- 4.3%, 11.4 +/- 6.7%, 13.3 +/- 7.8%, and 14.7 +/- 11.8%, respectively. Data were available from 101 patients at 6 months and 12 patients at 12 months; 60.4% of patients achieved more than 10% TBWL and 55.4% had more than 25% EWL. Seventeen patients (8.4%) had esophageal tears during balloon insertion, with no intervention required. Thirteen patients (6.4%) had their IGB removed before the end of the 6-month treatment period. Nausea, vomiting, and abdominal pain were the most common adverse effects, occurring in 149 (73.8%), 99 (49%), and 51 (25.2%) patients. In one patient, the IGB migrated distally leading to small intestinal obstruction requiring surgical removal. CONCLUSION: In a retrospective analysis of real-world patients who received the Reshape Duo IGB, we found it to be a safe and efficacious endoscopic method for producing weight loss, with most patients achieving greater than 10% TBWL at 6 months. PMID- 29481970 TI - Combining Biologics in Inflammatory Bowel Disease and Other Immune Mediated Inflammatory Disorders. AB - Current therapies used in the treatment of inflammatory bowel disease (IBD) are not effective in all patients. Biologic agents result in approximately 40% remission rates at 1 year in selected populations, prompting a growing interest in combining biologic therapy to improve outcomes. There are limited published data regarding the efficacy and safety of combination targeted therapy in IBD specifically, which include only 1 exploratory randomized control trial and 3 case reports or series. This review evaluates the published literature regarding this therapeutic paradigm in IBD and its extensive utilization in the treatment of other immune-mediated inflammatory disorders. The combination of biologic therapies demonstrates variable degrees of efficacy and highlights some safety concerns, depending upon the agents used and the disease state treated. A trial (Clinical Trials.gov Identifier: NCT02764762) combining vedolizumab and adalimumab is currently underway evaluating the effectiveness and safety of this approach in patients with Crohn's disease, which should provide further insight into this treatment concept. While combination biologic therapy is an attractive strategy, the lack of consistent superior efficacy as well as safety concerns militates the need for further trials prior to its general application in IBD. PMID- 29481971 TI - Comparing the performance of different techniques for percutaneous dilatational tracheostomy. PMID- 29481972 TI - Long non-coding RNAs - A crucial part of the vasculature puzzle. AB - With the advent of empowering sequencing techniques over the past two decades, the scientific community has uncovered many underlying secrets of our genome. Non coding transcripts covering a staggering 98% of our genome strongly suggest their involvement in diverse cellular pathways. A special class of non-coding RNAs (ncRNAs) namely long non-coding RNAs (lncRNAs) has garnered tremendous attention considering its implications in multiple developmental and pathophysiological processes. Accumulating evidence has established lncRNAs as robust regulators of pathways ranging from embryonic cell development to ultimate diseased phenotype. Here, in particular, we summarize the lncRNAs actively participating in the development of our vasculature and the ones which function as drivers or modulators of fatal vascular diseases. PMID- 29481973 TI - Detection of floR gene and active efflux mechanism of Escherichia coli in Ningxia, China. AB - Florfenicol is an antibiotic, a fluorinated structural analogue of thiamphenicol and chloramphenicol, approved exclusively for use in Asia for aquaculture since the 1980's. Our study examined the prevalence of florfenicol resistance in bovine mastitis Escherichia coli isolates. A total of 245 E. coli isolates were collected from bovine mastitis in Ningxia Province, China between May 2016 to July 2017 and screened for florfenicol resistance gene, floR gene by PCR analysis. About 7.35% (15/245) of the isolates were positive for floR gene. Minimal inhibitory concentration (MIC) results showed that 9 isolates were susceptible strains and 6 isolates were highly resistant to florfenicol. HPLC (high performance liquid chromatography) results showed that the amounts of florfenicol was significantly improved in the presence of carbonyl cyanide 3 chlorophenylhydrazone (CCCP) as an efflux pump inhibitor. This, therefore, indicates that the employment of florfenicol in conjunction with CCCP in future drug formulations should be considered. PMID- 29481974 TI - Responses of haptoglobin and serum amyloid A in goats inoculated intradermally with C. pseudotuberculosis and mycolic acid extract immunogen. AB - Haptoglobin (Hp) and Serum Amyloid A (SAA) are a group of blood proteins whose concentrations in animals can be influenced by infection, inflammation, surgical trauma or stress. Corynebacterium pseudotuberculosis is the causative agent of caseous lymphadenitis (CLA), and Mycolic acid is a virulent factor extracted from C. pseudotuberculosis. There is a dearth of sufficient evidence on the clinical implication of MAs on the responses of Hp and SAA in goats. Therefore, this study was conducted to evaluate the potential effects of Mycolic acid (MAs) and C. pseudotuberculosis on the responses of Hp and SAA in female goats. A total of 12 healthy female goats was divided into three groups; A, B and C each comprising of 4 goats and managed for a period of three months. Group (A) was inoculated with 2 mL of sterile phosphate buffered saline (as a negative control group) intradermally, while group (B) and (C) were inoculated intradermally with 2 ml each of mycolic acid and 1? * 109 cfu of active C. pseudotuberculosis respectively. The result of the study showed that the Hp concentration in goats inoculated with C. pseudotuberculosis was significantly increased up to 7-fold (1.17 +/- 0.17 ng/L) while MAs showed a 3-fold increased (0.83 +/- 0.01 ng/L) compared with the control. Whereas SAA concentration in C. pseudotuberculosis and MAs groups showed a significant 3-fold (17.85 +/- 0.91 pg/mL) and 2-fold (10.97 +/- 0.71 pg/mL) increased compared with the control. This study concludes that inoculation of C. pseudotuberculosis and MAs have significant effects on Hp and SAA levels, which indicates that MAs could have a role in the pathogenesis of caseous lymphadenitis. PMID- 29481976 TI - Randomized Controlled Trial of Online Acceptance and Commitment Therapy for Fibromyalgia. AB - : In this study, 67 participants (95% female) with fibromyalgia (FM) were randomly assigned to an online acceptance and commitment therapy (online ACT) and treatment as usual (TAU; ACT + TAU) protocol or a TAU control condition. Online ACT + TAU participants were asked to complete 7 modules over an 8-week period. Assessments were completed at pre-treatment, post-treatment, and 3-month follow up periods and included measures of FM impact (primary outcome), depression, pain, sleep, 6-minute walk, sit to stand, pain acceptance (primary process variable), mindfulness, cognitive fusion, valued living, kinesiophobia, and pain catastrophizing. The results indicated that online ACT + TAU participants significantly improved in FM impact, relative to TAU (P <.001), with large between condition effect sizes at post-treatment (1.26) and follow-up (1.59). Increases in pain acceptance significantly mediated these improvements (P = .005). Significant improvements in favor of online ACT + TAU were also found on measures of depression (P = .02), pain (P = .01), and kinesiophobia (P = .001). Although preliminary, this study highlights the potential for online ACT to be an efficacious, accessible, and cost-effective treatment for people with FM and other chronic pain conditions. PERSPECTIVE: Online ACT reduced FM impact relative to a TAU control condition in this randomized controlled trial. Reductions in FM impact were mediated by improvements in pain acceptance. Online ACT appears to be a promising intervention for FM. PMID- 29481978 TI - Novel mutation in a family with WNT1-related osteoporosis. AB - Osteogenesis imperfecta (OI) is an inherited disorder with osteoporosis and recurrent fractures. Children presenting with recurrent fractures and bowing of limbs have severe form of the disorder. Patients carrying homozygous WNT1 mutations have more frequent fractures while heterozygous carriers of the mutation in WNT1 gene are also found to have early onset osteoporosis. We identified a family with novel WNT1 mutation. The index case, a 6 month old child presented with fractures from early infancy. Next generation sequencing (NGS)done for the child didn't show any variations in other OI genes including COL1A1, COL1A2, SERPINH1, CRTAP, LEPRE1, PP1B, 1F1TM5 and BMP1 genes. Sanger sequencing showed 41bp deletion in splice region following exon 1 of WNT1 gene in homozygous state. The mutation was found to be likely pathogenic on bioinformatic analysis. To further characterize the significance of the mutation we studied his mother who is 30 year old with blue sclera and history of backache but no fractures. Her DXA scan of lumber spine showed osteoporosis and she was heterozygous for the mutation. The child's DXA scan showed T-score of -6.4 at lumbar spine level. Father also has history of backache and was carrier for the same deletion variant. The child was given 3 doses of zoledronate and did not have any further fractures. Thus, we conclude that this novel variant identified in the child with OI is likely cause for the disease and possibly zoledronate has a role in prevention of fractures in this case. PMID- 29481980 TI - Biomechanical evaluation of sacroiliac joint fixation with decortication. AB - BACKGROUND CONTEXT: Fusion typically consists of joint preparation, grafting, and rigid fixation. Fusion has been successfully used to treat symptomatic disruptions of the sacroiliac joint (SIJ) and degenerative sacroiliitis using purpose-specific, threaded implants. The biomechanical performance of these systems is important but has not been studied. PURPOSE: The objective of this study was to compare two techniques for placing primary (12.5 mm) and secondary (8.5 mm) implants across the SIJ. STUDY DESIGN: This is a human cadaveric biomechanical study of SIJ fixation. MATERIALS AND METHODS: Pure-moment testing was performed on 14 human SIJs in flexion-extension (FE), lateral bending (LB), and axial rotation (AR) with motion measured across the SIJ. Specimens were tested intact, after destabilization (cutting the pubic symphysis), after decortication and implantation of a primary 12.5-mm implant at S1 plus an 8.5-mm secondary implant at either S1 (S1-S1, n=8) or S2 (S1-S2, n=8), after cyclic loading, and after removal of the secondary implant. Ranges of motion (ROMs) were calculated for each test. Bone density was assessed on computed tomography and correlated with age and ROM. This study was funded by Zyga Technology but was run at an independent biomechanics laboratory. RESULTS: The mean+/-standard deviation intact ROM was 3.0+/-1.6 degrees in FE, 1.5+/-1.0 degrees in LB, and 2.0+/-1.0 degrees in AR. Destabilization significantly increased the ROM by a mean 60% 150%. Implantation, in turn, significantly decreased ROM by 65%-71%, below the intact ROM. Cyclic loading did not impact ROM. Removing the secondary implant increased ROM by 46%-88% (non-significant). There was no difference between S1-S1 and S1-S2 constructs. Bone density was inversely correlated with age (R=0.69) and ROM (R=0.36-0.58). CONCLUSIONS: Fixation with two threaded rods significantly reduces SIJ motion even in the presence of joint preparation and after initial loading. The location of the secondary 8.5-mm implant does not affect construct performance. Low bone density significantly affects fixation and should be considered when planning fusion constructs. Findings should be interpreted in the context of ongoing clinical studies. PMID- 29481977 TI - Pain After Spinal Cord Injury Is Associated With Abnormal Presynaptic Inhibition in the Posterior Nucleus of the Thalamus. AB - : Pain after spinal cord injury (SCI-Pain) is one of the most debilitating sequelae of spinal cord injury, characterized as relentless, excruciating pain that is largely refractory to treatments. Although it is generally agreed that SCI-Pain results from maladaptive plasticity in the pain processing pathway that includes the spinothalamic tract and somatosensory thalamus, the specific mechanisms underlying the development and maintenance of such pain are yet unclear. However, accumulating evidence suggests that SCI-Pain may be causally related to abnormal thalamic disinhibition, leading to hyperactivity in the posterior thalamic nucleus (PO), a higher-order nucleus involved in somatosensory and pain processing. We previously described several presynaptic mechanisms by which activity in PO is regulated, including the regulation of GABAergic as well as glutamatergic release by presynaptic metabotropic gamma-aminobutyric acid (GABAB) receptors. Using acute slices from a mouse model of SCI-Pain, we tested whether such mechanisms are affected by SCI-Pain. We reveal 2 abnormal changes in presynaptic signaling in the SCI-Pain condition. The substantial tonic activation of presynaptic GABAB receptors on GABAergic projections to PO-characteristic of normal animals-was absent in mice with SCI-Pain. Also absent in mice with SCI Pain was the normal presynaptic regulation of glutamatergic projections to the PO by GABAB receptors. The loss of these regulatory presynaptic mechanisms in SCI Pain may be an element of maladaptive plasticity leading to PO hyperexcitability and behavioral pain, and may suggest targets for development of novel treatments. PERSPECTIVE: This report presents synaptic mechanisms that may underlie the development and maintenance of SCI-Pain. Because of the difficulty in treating SCI-Pain, a better understanding of the underlying neurobiological mechanisms is critical, and may allow development of better treatment modalities. PMID- 29481979 TI - Dose-response and efficacy of spinal manipulation for care of cervicogenic headache: a dual-center randomized controlled trial. AB - BACKGROUND CONTEXT: The optimal number of visits for the care of cervicogenic headache (CGH) with spinal manipulative therapy (SMT) is unknown. PURPOSE: The present study aimed to identify the dose-response relationship between visits for SMT and chronic CGH outcomes and to evaluate the efficacy of SMT by comparison with a light-massage control. STUDY DESIGN/SETTING: This is a two-site, open label randomized controlled trial. PATIENT SAMPLE: Participants were 256 adults with chronic CGH. OUTCOME MEASURES: The primary outcome was days with CGH in the previous 4 weeks evaluated at the 12- and 24-week primary end points. Secondary outcomes included CGH days at remaining end points, pain intensity, disability, perceived improvement, medication use, and patient satisfaction. METHODS: Participants were randomized to four dose levels of chiropractic SMT: 0, 6, 12, or 18 sessions. They were treated three times per week for 6 weeks and received a focused light-massage control at sessions when SMT was not assigned. Linear dose effects and comparisons with the no-manipulation control group were evaluated at 6, 12, 24, 39, and 52 weeks. The present study was funded by the National Center for Complementary and Integrative Health (R01AT006330) and is registered at ClinicalTrials.gov (NCT01530321). The authors declare no conflicts of interest. RESULTS: A linear dose-response was observed for all follow-ups, a reduction of approximately 1 CGH day/4 weeks per additional 6 SMT visits (p<.05); a maximal effective dose could not be determined. Cervicogenic headache days/4 weeks were reduced from about 16 to 8 for the highest and most effective dose of 18 SMT visits. Mean differences in CGH days/4 weeks between 18 SMT visits and control were -3.3 (p=.004) and -2.9 (p=.017) at the primary end points, and were similar in magnitude at the remaining end points (p<.05). Differences between other SMT doses and control were smaller in magnitude (p>.05). Cervicogenic headache intensity showed no important improvement nor differed by dose. Other secondary outcomes were generally supportive of the primary outcome. CONCLUSIONS: There was a linear dose-response relationship between SMT visits and days with CGH. For the highest and most effective dose of 18 SMT visits, CGH days were reduced by half and about 3 more days per month than for the light-massage control. PMID- 29481981 TI - Estrogen receptor beta activation stimulates the development of experimental autoimmune thyroiditis through up-regulation of Th17-type responses. AB - Estrogens play important roles in autoimmune thyroiditis, but it remains unknown which estrogen receptor (ER) subtype mediates the stimulatory effects. Herein we treated ovariectomized mice with ERalpha or ERbeta selective agonist followed by thyroglobulin-immunization to induce experimental autoimmune thyroiditis (EAT), and observed the aggravation of EAT after diarylpropionitrile (DPN, ERbeta selective agonist) administration. The mRNA levels of interleukin(IL)-17A, IL-21 and RORgammat and percentages of T helper (Th) 17 cells were up-regulated in the splenocytes of DPN-treated mice. Activated ERbeta was found directly binding to IL-17A and IL-21 gene promoters, and also indirectly promoting IL-21 and RORgammat gene transcription through interaction with NF-kappaB. The expressions of co-stimulatory molecules were increased on antigen-presenting cells (APCs) after DPN administration. It suggests that ERbeta is the predominant ER subtype responsible for EAT development, and its activation may enhance Th17-type responses through genomic pathways and alteration of APCs' activities. PMID- 29481982 TI - IL10 promoter haplotypes may contribute to altered cytokine expression and systemic inflammation in celiac disease. AB - Celiac disease (CD) is an autoimmune/inflammatory condition triggered by dietary gluten intake in genetically predisposed individuals. Though associations with MHC class II HLA-DQ2 or -DQ8 are the primary and necessary genetic predisposition for CD, >97% of genetically predisposed individuals never develop CD. Cytokines were measured in the serum of CD patients and controls. Possible associations with IL10 promoter variants were investigated. Cytokine expression from PBMCs was monitored in response to gluten exposure, or CD3/TCR complex stimulation in the absence or presence of recombinant IL-10. Serum cytokines varied between patients with CD at the time of diagnosis, after dietary elimination of gluten, and healthy controls. Serum IL-17A reflected disease activity. Reduced IL-10 serum levels and altered IL-10 expression by PBMCs coincided with IL10 promoter haplotypes that encode for "low" IL-10 expression (ATA). Increased prevalence of ATA IL10 promoter haplotypes and subsequently reduced IL-10 expression may be an immunological cofactor in individuals genetically predisposed for the development of CD. Resulting cytokine imbalances may be utilized as disease biomarkers in CD. PMID- 29481975 TI - Neuroprotective strategies for retinal disease. AB - Diseases that affect the eye, including photoreceptor degeneration, diabetic retinopathy, and glaucoma, affect 11.8 million people in the US, resulting in vision loss and blindness. Loss of sight affects patient quality of life and puts an economic burden both on individuals and the greater healthcare system. Despite the urgent need for treatments, few effective options currently exist in the clinic. Here, we review research on promising neuroprotective strategies that promote neuronal survival with the potential to protect against vision loss and retinal cell death. Due to the large number of neuroprotective strategies, we restricted our review to approaches that we had direct experience with in the laboratory. We focus on drugs that target survival pathways, including bile acids like UDCA and TUDCA, steroid hormones like progesterone, therapies that target retinal dopamine, and neurotrophic factors. In addition, we review rehabilitative methods that increase endogenous repair mechanisms, including exercise and electrical stimulation therapies. For each approach, we provide background on the neuroprotective strategy, including history of use in other diseases; describe potential mechanisms of action; review the body of research performed in the retina thus far, both in animals and in humans; and discuss considerations when translating each treatment to the clinic and to the retina, including which therapies show the most promise for each retinal disease. Despite the high incidence of retinal diseases and the complexity of mechanisms involved, several promising neuroprotective treatments provide hope to prevent blindness. We discuss attractive candidates here with the goal of furthering retinal research in critical areas to rapidly translate neuroprotective strategies into the clinic. PMID- 29481984 TI - Extending the hosts of Tectiviridae into four additional genera of Gram-positive bacteria and more diverse Bacillus species. AB - Tectiviridae are composed of tailless bacteriophages with an icosahedral capsid and an inner membrane enclosing a double-stranded 15 kb linear DNA genome. Five of the seven previously studied Tectivirus isolates infect bacteria from Bacillus cereus sensu lato group (Betatectivirus), one distantly related member (PRD1) infect Enterobactericeae (Alpatectivirus) and one recently discovered virus infect Gluconobacter cerinus (Gammatectivirus). Here we expand the host spectrum of Betatectivirus elements to four additional genera (Streptococcus, Exiguobacterium, Clostridium and Brevibacillus) and to more distantly related Bacillus species (B. pumilus and B. flexus) by studying the genomes of fourteen novel tectiviral elements. Overall, the genomes show significant conservation in gene synteny and in modules responsible for genome replication and formation of the virion core (including DNA packaging). Notable variation exists in regions encoding host attachment and lysis along with the surrounding area of a site in which mutations are known to alter phage life cycle. PMID- 29481983 TI - NDV entry into dendritic cells through macropinocytosis and suppression of T lymphocyte proliferation. AB - Newcastle disease virus (NDV) causes major economic losses in the poultry industry. Previous studies have shown that NDV utilizes different pathways to infect various cells, including dendritic cells (DCs). Here, we demonstrate that NDV gains entry into DCs mainly via macropinocytosis and clathrin-mediated endocytosis. The detection of cytokines interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin-12 (IL-12), interleukin-4 (IL-4) and interleukin-10 (IL-10) indicates that NDV significantly induces Th1 responses and lowers Th2 responses. Furthermore, NDV entry into DCs resulted in the upregulation of TNF-related apoptosis-inducing ligand (TRAIL) and cleaved caspase 3 proteins, which in turn activated the extrinsic apoptosis pathway and induced DCs apoptosis. Transwell(r) co-culture demonstrated that direct contact between live NDV-stimulated DCs and T cells, rather than heated-inactivated NDV, inhibited CD4+ T cell proliferation. Taken together, these findings provide new insights into the mechanism underlying NDV infections, particularly in relation to antigen presentation cells and suppression of T cell proliferation. PMID- 29481986 TI - Replacement of soybean oil by fish oil increases cytosolic lipases activities in liver and adipose tissue from rats fed a high-carbohydrate diets. AB - Several studies have demonstrated that fish oil consumption improves metabolic syndrome and comorbidities, as insulin resistance, nonalcoholic fatty liver disease, dyslipidaemia and hypertension induced by high-fat diet ingestion. Previously, we demonstrated that administration of a fructose-rich diet to rats induces liver lipid accumulation, accompanied by a decrease in liver cytosolic lipases activities. In this study, the effect of replacement of soybean oil by fish oil in a high-fructose diet (FRUC, 60% fructose) for 8 weeks on lipid metabolism in liver and epididymal adipose tissue from rats was investigated. The interaction between fish oil and FRUC diet increased glucose tolerance and decreased serum levels of triacylglycerol (TAG), VLDL-TAG secretion and lipid droplet volume of hepatocytes. In addition, the fish oil supplementation increased the liver cytosolic lipases activities, independently of the type of carbohydrate ingested. Our results firmly establish the physiological regulation of liver cytosolic lipases to maintain lipid homeostasis in hepatocytes. In epididymal adipose tissue, the replacement of soybean oil by fish oil in FRUC diet did not change the tissue weight and lipoprotein lipase activity; however, there was increased basal and insulin-stimulated de novo lipogenesis and glucose uptake. Increased cytosolic lipases activities were observed, despite the decreased basal and isoproterenol-stimulated glycerol release to the incubation medium. These findings suggest that fish oil increases the glycerokinase activity and glycerol phosphorylation from endogenous TAG hydrolysis. Our findings are the first to show that the fish oil ingestion increases cytosolic lipases activities in liver and adipose tissue from rats treated with high-carbohydrate diets. PMID- 29481985 TI - Systemic antibodies administered by passive immunization prevent generalization of the infection by foot-and-mouth disease virus in cattle after oronasal challenge. AB - The role of passively transferred sera in the protection against aerogenous foot and-mouth disease (FMD) virus infection in cattle was evaluated using vaccine induced immune serum preparations obtained at 7 and 26 days post-vaccination (dpv). We showed that circulating antibodies were sufficient to prevent disease generalization after oronasal infection in animals passively transferred with 26 dpv serum but not with the 7-dpv serum. Conversely, conventional FMD vaccination provided clinical protection at 7 dpv, promoting fast and robust antibody responses upon challenge and even though antibody titers were similar to those found in animals passively immunized with 7-dpv serum. These results demonstrate that presence of antigen-specific antibodies is critical to prevent the dissemination of the virus within the animal. Conventional FMD vaccination additionally promoted the deployment of rapid, high titer and isotype-switched antibody responses at systemic and mucosal levels after infection, thus conferring protection even in the presence of low pre-challenge antibody titers. PMID- 29481987 TI - Lower frequency of the HLA-G UTR-4 haplotype in women with unexplained recurrent miscarriage. AB - HLA-G expressed by trophoblasts at the fetal-maternal interface and its soluble form have immunomodulatory effects. HLA-G expression depends on the combination of DNA polymorphisms. We hypothesized that combinations of specific single nucleotide polymorphisms (SNPs) in the 3'untranslated region (3'UTR) of HLA-G play a role in unexplained recurrent miscarriage. In a case control design, 100 cases with at least three unexplained consecutive miscarriages prior to the 20th week of gestation were included. Cases were at time of the third miscarriage younger than 36 years, and they conceived all their pregnancies from the same partner. The control group included 89 women with an uneventful pregnancy. The association of HLA-G 3'UTR SNPs and specific HLA-G haplotype with recurrent miscarriage was studied with logistic regression. Odds ratios (OR) and 95% confidence intervals (95% CI) were reported. Individual SNPs were not significantly associated with recurrent miscarriage after correction for multiple comparisons. However, the presence of the UTR-4 haplotype, which included +3003C, was significantly lower in women with recurrent miscarriage (OR 0.4, 95% CI 0.2 0.8, p = 0.015). In conclusion, this is the first study to perform a comprehensive analysis of HLA-G SNPs and HLA-G haplotypes in a well-defined group of women with recurrent miscarriage and women with uneventful pregnancy. The UTR 4 haplotype was less frequently observed in women with recurrent miscarriage, suggesting an immunoregulatory role of this haplotype for continuation of the pregnancy without complications. Thus, association of HLA-G with recurrent miscarriage is not related to single polymorphisms in the 3'UTR, but is rather dependent on haplotypes. PMID- 29481988 TI - The association between digit ratio (2D:4D) and the first spermatorrhea among Chinese boys. AB - BACKGROUND: The second-to-fourth digit ratio (2D:4D) is a marker of prenatal hormone exposure, which is negatively correlated with prenatal androgen and positively correlated with prenatal estrogen. The study was to analyze the association between 2D:4D and the first spermatorrhea to indirectly show the possible role of prenatal hormone during puberty development among boys. METHOD: The total of 367 boys aged 8-15 years were enrolled by using the stratified cluster sampling method. The variables of index finger (2D), ring finger (4D), height, weight, waist circumference (WC), skinfold thickness, testosterone and estradiol were measured, and the age at the first spermatorrhea was surveyed. RESULTS: The average age at the first spermatorrhea was 12.15 years. The 2D:4D was not related to first spermatorrhea, circulating testosterone in boys (P > 0.05), however, was positively correlated with circulating estradiol (P < 0.05). The direct association (OR value) between 4D, average of index finger and ring finger (AIR) and first spermatorrhea were 2.79 and 2.29, and the mediating effect (OR value) of which were 1.95 and 2.01 by testosterone, accounting for 41.18% and 46.73% of the total effect, respectively. The 2D, MIDRL, lean body mass (LBM) were indirectly related to first spermatorrhea by testosterone, the mediating effects (OR value) were 2.11, 1.71 and 2.41, respectively. CONCLUSION: The prenatal androgen exposure may be directly and indirectly related to first spermatorrhea. In addition, the high prenatal estrogen exposure may be indirectly associated with first spermatorrhea by testosterone. PMID- 29481989 TI - The efficacy of dexamethasone reducing postoperative pain and emesis after total knee arthroplasty: A systematic review and meta-analysis. AB - BACKGROUND: Total knee arthroplasty (TKA) is gradually emerging as the treatment of choice for end-stage osteoarthritis. In the past, Perioperative dexamethasone treatment is still a controversial subject in total knee arthroplasty. Therefore, we write this systematic review and meta-analysis to evaluate the efficacy of dexamethasone on pain and recovery after Total knee Arthroplasty. MATERIALS AND METHODS: Embase, Pubmed, and Cochrane Library were comprehensively searched. Randomized controlled trials, cohort studies were included in our meta-analysis. Eight studies that compared dexamethasone groups with placebo groups were included in our meta-analysis. The research was reported according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines. Randomized controlled trials were included in our meta-analysis. RESULTS: Our study demonstrated that the dexamethasone group was more effective than the placebo group in term of VAS score at 24 h(P < 0.00001), 48 h(P = 0.0002); Opioid consumption (P < 0.00001); postoperative nausea (P < 0.00001); and Inflammatory factors of CPR at 24 h (P = 0.003). CONCLUSION: Our meta analysis demonstrated that dexamethasone decreased postoperative pain, the incidence of POVN, and total opioid consumption effectively which played a critical role in rapid recovery to TKA. However, we still need large sample size, high quality studies to explore the relationship between complications and dose response to give the final conclusion. PMID- 29481990 TI - 20 years' experience with laparoscopic splenectomy. Single center outcomes of a cohort study of 500 cases. AB - BACKGROUND: Laparoscopic splenectomy (LS) has become the gold standard in elective spleen surgery. Although it is considered relatively safe, treatment results vary depending on a hospital's profile and the experience of the surgeon and center. We would like to present experience of a high-volume referral center with minimally invasive operations of the spleen. MATERIAL AND METHODS: The retrospective cohort study included consecutive patients undergoing laparoscopic splenectomy in tertiary referral surgical center in 1998-2017. The entire study population (500 patients) was grouped into 5 cohorts of 100 consecutively operated patients. The primary endpoints were short-term outcomes of LS and secondary - analysis of indications and operative technique. The study group consisted of 316 women and 184 men, 46 (28-59) years old on average. RESULTS: The most common indications for splenectomy were ITP (53%), lymphoma (21%) and spherocytosis (7%). Ratio of ITP versus other indications decreased significantly over time in favor of more difficult cases (<0.001). Average operative time of 100 (75-132.5) min and blood loss of 50 (20-150) ml were changing during study. Forty two patients required a blood transfusion with no difference among groups (p = 0.765). The use of postoperative drainage diminished from 100% to 7% (p < 0.001). The overall conversion rate (3%) and intraoperative complications (5%) did not differ among groups (p = 0.863 and 0.888). Perioperative morbidity was 8.6% and decreased significantly over time (OR: 0.78, 95%CI: 0.62-0.98). We noted mortality of 0.4% (1 patient in 1st and 1 in 5th group). Median LOS was 4 (1-16) days. A significant change in the operative technique from vessels first to hilar transection was noted. CONCLUSION: Laparoscopic splenectomy seems to be a safe method associated with a low risk of perioperative complications and mortality. A careful reproducible operative technique, along with a well-trained team and standardized modern postoperative care is critical to improving outcomes. PMID- 29481991 TI - The role of two tumor foci for predicting central lymph node metastasis in papillary thyroid carcinoma: A meta-analysis. AB - BACKGROUND AND OBJECTIVE: Two tumor foci are the most common in multifocal papillary thyroid carcinoma, but whether they should be regarded as the indicator of central lymph node metastasis remains unclear. To investigate the role of two tumor foci for predicting central lymph node metastasis, we performed a meta analysis of published studies. METHODS: We performed a systematic literature search of PubMed, Embase and Web of Science prior to September 29, 2017. The relevant articles were examined and the eligible studies were included to assess the metastatic risk of central lymph node in papillary thyroid carcinoma with one, two and more than two (>2) tumor foci. RESULTS: Five eligible studies included 4045 patients in this meta-analysis. Two tumor foci were the most common in multifocal papillary thyroid carcinoma (63.8%, 939/1471). Multifocality group showed a higher risk of central lymph node metastasis compared with unifocality group (odds ratio: 1.58, 95% confidence interval: 1.37-1.81). The risk of central lymph node metastasis was higher in two tumor foci group than unifocality group (odds ratio: 1.38, 95% confidence interval: 1.17-1.62). However, this risk in two tumor foci group was lower than >2 tumor foci group (odds ratio: 0.62, 95% confidence interval: 0.42-0.92). Begg's test revealed no obvious publication bias. CONCLUSION: This meta-analysis suggested that two tumor foci should be regarded as the predictive factor of central lymph node metastasis, but the role of it was less important than three or more than three tumor foci. Understanding the role of two tumor foci for predicting central lymph node metastasis may help clinicians make an optimal decision of treatment and the extent of surgery for multifocal papillary thyroid carcinoma. PMID- 29481992 TI - The clinical application of a silicate-based wound dressing (DermFactor(r)) for wound healing after anal surgery: A randomized study. AB - BACKGROUND: The object of the present study is to evaluate the feasibility of a silicate-based wound dressing (DermFactor(r)) in treating the wound of the patients after anorectal surgery. MATERIALS AND METHODS: The present study included 328 patients who received anal surgery during the period from March 2013 to June 2015. The patients were randomized to 2 groups. The patients (n = 162) in the control group received conventional dressing therapy, while those in the observation group (n = 166) were treated with the combination of conventional dressing therapy and the use of a silicate-based wound dressing (DermFactor(r)). The wound healing outcomes of the two groups were observed and compared with each other by statistical analysis. RESULTS: The average healing cycles in the observation group were 19.04 days for combined hemorrhoid patients, 23.72 days for anal fistula patients and 21.14 days for anal fissure patients, respectively, which were shorter than those in the control group (23.25 days for mixed hemorrhoid patients, 27.76 days for anal fistula patients and 24.32 days for fissure in ano patients, respectively). In addition, the observation group presented a significantly higher effective rate (80.4%) than the control group (70.4%). CONCLUSION: Our data demonstrated that the wound after anorectal surgery could be more effectively treated by using silicate-containing DermFactor(r). PMID- 29481993 TI - Long-term use of valproic acid and the prevalence of cancers in bipolar disorder patients in a Taiwanese population: An association analysis using the National Health Insurance Research Database (NHIRD). AB - BACKGROUND: Epigenetic events play a major role in the carcinogenesis of many cancers. A retrospective cohort study had been performed to evaluate the effects of exposure to the anticonvulsant agent valproic acid (VPA), a histone deacetylase inhibitor, on the risk of developing cancers. METHODS: The study was based on the 1998 through 2009 National Health Insurance Research Database (NHIRD), provided by the Taiwan National Health Research Institute. Patients with a diagnosis of bipolar disorder (ICD-9-CM codes 296.0, 296.1, 296.4-8) from 1998 to 2009 were identified. VPA and lithium were the primary index drugs. Patients treated with anticonvulsants who did not use VPA or lithium were selected as the control group. Competing risk regression analysis were used to estimate hazards ratios (HR) and 95% confidence intervals (95% CI) reflecting the association between use of VPA and cancer incidence. RESULTS: The cancer incidence of bipolar disorder patients treated with VPA was no significant difference than treated with lithium and other anticonvulsants. In subgroup analysis, VPA associated to higher risk of genitourinary cancer in the duration < 1 year group (HR: 3.49; 95%CI: 1.04, 11.67). No significant differences in other cancers incidence in any duration of VPA treatment. LIMITATIONS: The cancer prevalence in selected bipolar disorder patients was still low. The sample size was not enough for some types of cancer. CONCLUSIONS: A role of VPA in cancer prevention was not found in this study. An increased subgroup risk of genitourinary cancer was observed. PMID- 29481994 TI - Correlates of a general psychopathology factor in a clinical sample of childhood sexual abuse survivors. AB - BACKGROUND: Childhood sexual abuse (CSA) increases risk for most psychiatric disorders. There is evidence that the structure of psychopathology can be explained by a number of latent dimensions of psychopathology including a 'General Psychopathology' (P) factor. The objective of the current study was to provide the first assessment as to whether P is identifiable, and what its correlates might be in a clinical sample. METHODS: An adult, clinical sample of Danish CSA survivors (N = 420) was assessed using the Millon Clinical Multiaxial Inventory-III. Confirmatory factory analysis (CFA) was used to assess the latent structure of nine psychiatric disorders, and structural equation modelling (SEM) was used to determine correlates of the best-fitting dimensional model. RESULTS: CFA results favoured a bifactor model including three specific dimensions of psychopathology, "Internalizing", "Externalizing", and "Thought Disorder", and a bi-factor "P". A SEM model that included ten predictors was a good fit to the data and explained 55% of variance in 'P'. The 'P' factor was significantly associated with emotional coping, negative self-worth, traumatic life events, and anxious attachments. LIMITATIONS: Psychiatric disorders were assessed using self report measures, and the sample was predominately female. CONCLUSIONS: Results provide initial evidence of P in a clinical sample and several unique correlates of this factor were identified. PMID- 29481995 TI - Involvement of the reward network is associated with apathy in cerebral small vessel disease. AB - INTRODUCTION: Apathy is a common yet under-recognised feature of cerebral small vessel disease (SVD), but its underlying neurobiological basis is not yet understood. We hypothesized that damage to the reward network is associated with an increase of apathy in patients with SVD. METHODS: In 114 participants with symptomatic SVD, defined as a magnetic resonance imaging confirmed lacunar stroke and confluent white matter hyperintensities, we used diffusion tensor imaging tractography to derive structural brain networks and graph theory to determine network efficiency. We determined which parts of the network correlated with apathy symptoms. We tested whether apathy was selectively associated with involvement of the reward network, compared with two "control networks" (visual and motor). RESULTS: Apathy symptoms negatively correlated with connectivity in network clusters encompassing numerous areas of the brain. Network efficiencies within the reward network correlated negatively with apathy scores; (r = - 0.344, p < 0.001), and remained significantly correlated after co-varying for the two control networks. Of the three networks tested, only variability in the reward network independently explained variance in apathetic symptoms, whereas this was not observed for the motor or visual networks. LIMITATIONS: The analysis refers only to cerebrum and not cerebellum. The apathy measure is derivative of depression measure. DISCUSSION: Our results suggest that reduced neural efficiency, particularly in the reward network, is associated with increased apathy in patients with SVD. Treatments which improve connectivity in this network may improve apathy in SVD, which in turn may improve psychiatric outcome after stroke. PMID- 29481996 TI - Are suicidal thoughts reinforcing? A preliminary real-time monitoring study on the potential affect regulation function of suicidal thinking. AB - BACKGROUND: Theoretical work and clinical observation suggest that many patients experience relief from negative affect after thinking about suicide, which may increase the likelihood of future suicidal thoughts. Accordingly, our objective was to examine whether the occurrence of suicidal thinking was followed by decreased negative affect and increased positive affect. METHODS: Participants were 43 adults who attempted suicide at least once in the past year (78% female, 78% White, M age = 23.28 years, SD age = 4.38 years) who completed 28 days of smartphone-based real-time monitoring, where they were signaled four times/day to report on current affect and whether they were having suicidal thoughts. Participants could initiate a survey whenever they had a suicidal thought. RESULTS: First, we examined changes in affect that occurred when suicidal thinking at the current time (T) but not at T + 1 (approximately 4-8 h later). Negative affect decreased and positive affect increased when participants went from a period when they were experiencing suicidal thoughts to a period where they were not. Second, to assess the time course of changes in affect, we examined changes in affect before and after participant-initiated reports of suicidal thinking. Positive affect increased and sadness decreased. LIMITATIONS: Given its preliminary nature, the study has some limitations including insufficient power to expand beyond a 4-8 h timespan. CONCLUSIONS: Findings provide preliminary evidence that suicidal thinking leads to shifts in affect. These shifts in affect may be reinforcing, helping to explain (in part) why suicidal thinking is so persistent for some patients. PMID- 29481997 TI - Biased neurocognitive self-perception in depressive and in healthy persons. AB - BACKGROUND: Cognitive deficits across several domains and subjective complaints about cognition are prevalent in major depression disorder (MDD). Nevertheless, subjective and objective cognitive functions show no associations. However, research concerning the extent and direction of discrepancy is rare. The present study examined the relationship and discrepancy between subjective and objective cognitive deficits both in patients with MDD and healthy individuals. METHOD: Outpatients with MDD (n = 102) and a healthy control group (n = 88) were assessed with a neuropsychological test battery and completed a questionnaire for the self assessment of cognitive performance (FLei) concerning the domains of attention, memory, and executive functions. RESULTS: There were no associations between subjective and objective cognitive deficits in any domain in both the MDD group and the healthy control group. The groups did not differ regarding the extent of the discrepancy between subjective and objective cognition. However, depressed outpatients' subjective cognitive complaints significantly exceeded their neuropsychological deficits, whereas healthy individuals reported significantly higher subjective cognitive functioning than objectively measured. LIMITATIONS: The cross-sectional study design does not allow for causal conclusions. Due to concerns regarding the suitability of the subjective measure of cognitive deficits used in this study, the findings should be interpreted cautiously. CONCLUSIONS: The current study reveals a discrepancy between subjective and objective cognitive function not only in the MDD group, but also in the control group. Whereas depressed outpatients tend to underestimate their objective cognitive abilities, healthy individuals tend to overestimate them. PMID- 29481998 TI - Risk Stratification of Oral Potentially Malignant Disorders in Fanconi Anemia Patients Using Autofluorescence Imaging and Cytology-On-A Chip Assay. AB - Fanconi anemia (FA) is a hereditary genomic instability disorder with a predisposition to leukemia and oral squamous cell carcinomas (OSCCs). Hematopoietic stem cell transplantation (HSCT) facilitates cure of bone marrow failure and leukemia and thus extends life expectancy in FA patients; however, survival of hematologic malignancies increases the risk of OSCC in these patients. We developed a "cytology-on-a-chip" (COC)-based brush biopsy assay for monitoring patients with oral potentially malignant disorders (OPMDs). Using this COC assay, we measured and correlated the cellular morphometry and Minichromosome Maintenance Complex Component 2 (MCM2) expression levels in brush biopsy samples of FA patients' OPMD with clinical risk indicators such as loss of autofluorescence (LOF), HSCT status, and mutational profiles identified by next generation sequencing. Statistically significant differences were found in several cytology measurements based on high-risk indicators such as LOF-positive and HSCT-positive status, including greater variation in cell area and chromatin distribution, higher MCM2 expression levels, and greater numbers of white blood cells and cells with enlarged nuclei. Higher OPMD risk scores were associated with differences in the frequency of nuclear aberrations and differed based on LOF and HSCT statuses. We identified mutation of FAT1 gene in five and NOTCH-2 and TP53 genes in two cases of FA patients' OPMD. The high-risk OPMD of a non-FA patient harbored FAT1, CASP8, and TP63 mutations. Use of COC assay in combination with visualization of LOF holds promise for the early diagnosis of high-risk OPMD. These minimally invasive diagnostic tools are valuable for long-term surveillance of OSCC in FA patients and avoidance of unwarranted scalpel biopsies. PMID- 29481999 TI - Relationship between the Dynamics of Orientation Tuning and Spatiotemporal Receptive Field Structures of Cat LGN Neurons. AB - Simple cells in the cat primary visual cortex usually have elongated receptive fields (RFs), and their orientation selectivity can be largely predicted by their RFs. As to the relay cells in cats' lateral geniculate nucleus (LGN), they also have weak but significant orientation bias (OB). It is thus of interest to investigate the fine spatiotemporal receptive field (STRF) properties in LGN, compare them with the dynamics of orientation tuning, and examine the dynamic relationship between STRF and orientation sensitivity in LGN. We mapped the STRFs of the LGN neurons in cats with white noise and characterized the dynamics of the orientation tuning by flashing gratings. We found that most of the LGN neurons showed elongated RFs and that the elongation axes were consistent with the preferred orientations. STRFs and the dynamics of orientation tuning were closely correlated temporally: the elongation of RFs and OB emerged, peaked and decayed at the same pace, with unchanged elongation axis of RF and preferred orientation but consistently changing aspect ratio of RF and OB strength across time. Importantly, the above consistency between RF and orientation tuning was not influenced by the ablation of the primary visual cortex. Furthermore, biased orientation tuning emerged 20-30 ms earlier than those in the primary visual cortex. These data demonstrated that similar to the primary visual cortex, the orientation sensitivity was closely reflected by the RF properties in LGN. However, the elongated RF and OB in LGN did not originate from the primary visual cortex feedback. PMID- 29482000 TI - Suppression of HDAC2 in Spinal Cord Alleviates Mechanical Hyperalgesia and Restores KCC2 Expression in a Rat Model of Bone Cancer Pain. AB - Epigenetic modulation participates in the mechanism of multiple types of pathological pain, so targeting the involved regulators may be a promising strategy for pain treatment. Our previous research identified the analgesic effect of the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) on mechanical hyperalgesia in a rat model of bone cancer pain (BCP) via restoration of MU-opioid receptor (MOR) expression. However, the specific types of HDACs contributing to BCP have not been explored. The present study investigated the expression pattern of some common HDACs and found that HDAC2 was up-regulated in a time-dependent manner in the lumbar spinal cord of BCP rats. TSA application suppressed HDAC2 expression in cultured PC12 cells and reversed the augmented HDAC2 in BCP rats. An RNA-interfering strategy confirmed the essential role of HDAC2 in the modulation of mechanical hyperalgesia following tumor cell inoculation, and we further examined its possible downstream targets. Notably, HDAC2 knock-down did not restore MOR expression, but it robustly reversed the down-regulation of potassium-chloride cotransporter 2 (KCC2). The impaired KCC2 expression is a vital mechanism of many types of pathological pain. Therefore, our results demonstrated that HDAC2 in spinal cord contributed to the mechanical hyperalgesia in BCP rats, and this effect may be associated with KCC2 modulation. PMID- 29482001 TI - Hypothermia-Modulating Matrix Elasticity of Injured Brain Promoted Neural Lineage Specification of Mesenchymal Stem Cells. AB - Both chemical and physical microenvironments appear to be important for lineage specification of umbilical cord mesenchymal stem cells (UCMSCs). However, physical factors such as the elastic modulus in traumatic brain injury (TBI) are seldom studied. Intracranial hypertension and cerebral edema after TBI may change the brain's physical microenvironment, which inhibits neural lineage specification of transplanted UCMSCs. The purpose of this study is to investigate the potential regulatory effect of mild hypothermia on the elastic modulus of the injured brain. First, we found that more UCMSCs grown on gels mimicking the elastic modulus of the brain (0.5 kPa) differentiated into neural cells, which were verified with the formation of branched cells and the expression of neural markers. Then, UCMSCs were transplanted into TBI rats, and we observed that mild hypothermia resulted in the differentiation of more neurons and astrocytes from transplanted UCMSCs. To demonstrate that more neural specification of UCMSCs was due to the regulation of the elastic modulus, we monitored intracranial pressure and cerebral edema. The results showed that mild hypothermia significantly reduced intracranial pressure and brain water content, indicating modulation of the elastic modulus by mild hypothermia. An examination with atomic force microscopy (AFM) in a cell injury model in vitro further verified hypothermia regulated elastic modulus. In this study, we found a novel role of mild hypothermia in modulating the elastic modulus of the injured brain, resulting in the promotion of neural lineage specification of UCMSCs, which suggested that the combination of mild hypothermia had more advantages in cell-based therapy after TBI. PMID- 29482002 TI - Sensitive and selective Affimer-functionalised interdigitated electrode-based capacitive biosensor for Her4 protein tumour biomarker detection. AB - A novel Affimer-functionalised interdigitated electrode-based capacitive biosensor platform was developed for detection and estimation of Her4, a protein tumour biomarker, in undiluted serum. An anti-Her4 Affimer with a C-terminal cysteine was used to create the bio-recognition layer via self-assembly on gold interdigitated electrodes for the sensor fabrication. Electrochemical impedance spectroscopy (EIS) in the absence of redox markers was used to evaluate the sensor performance by monitoring the changes in capacitance. The Affimer sensor in buffer and in undiluted serum demonstrated high sensitivity with a broad dynamic range from 1 pM to 100 nM and a limit of detection lower than 1 pM both in buffer and in serum. Furthermore, the Affimer sensor demonstrated excellent specificity with negligible interference from serum proteins, suggesting resilience to non-specific binding. The sensing ability of the present Affimer sensor in spiked undiluted serum suggests its potential for a new range of Affimer-based sensors. The fabricated Affimer sensor can thus be further adapted with other probes having affinities to other biomarkers for a new range of biosensors. PMID- 29482003 TI - Neurosurgery in the Developing World: Specialty Service and Global Health. PMID- 29482004 TI - Lethal Ultra-Early Subarachnoid Hemorrhage Due to Rupture of De Novo Aneurysm 5 Months After Primary Aneurysmatic Subarachnoid Hemorrhage. AB - BACKGROUND: Approximately 1% of all patients surviving rupture of a cerebral aneurysm suffer from a second aneurysmatic subarachnoid hemorrhage later in their lives, 61% of which are caused by rupture of a de novo aneurysm. Latency between bleedings is usually many years, and younger patients tend to achieve better outcomes from a second subarachnoid hemorrhage. CASE DESCRIPTION: We report an unusual case of lethal ultra-early rupture of a de novo aneurysm of the anterior communicating artery only 5 months after the initial subarachnoid hemorrhage and complete coiling in a young, healthy male patient. CONCLUSION: Despite complete aneurysm obliteration, young age, and good recovery, patients may be subjected to secondary subarachnoid hemorrhages from de novo aneurysms after only a few months of the initial bleeding. Early-control magnetic resonance angiography might hence be advisable. PMID- 29482005 TI - Efficacy of Posterior Fossa Decompression with Duraplasty for Patients with Chiari Malformation Type I: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: To quantitatively assess and compare the effectiveness and safety of posterior fossa decompression with duraplasty (PFDD) and posterior fossa decompression (PFD) in treating patients with Chiari malformation type I. METHODS: PubMed, Embase, and Cochrane Library were searched through May 2017. Fourteen cohort studies comprising 3666 patients with Chiari malformation type I were included. Studies were pooled, and the relative risk (RR) and corresponding 95% confidence interval (CI) were calculated. RESULTS: The decrease in syringomyelia was better in patients in the PFDD group than in patients in the PFD group (RR = 1.57, 95% CI = 1.07-2.32, Pheterogeneity = 0.042, I2 = 56.6%). The incidence of cerebrospinal fluid leak (RR = 5.23, 95% CI = 2.61-10.51, Pheterogeneity = 0.830, I2 = 0%) and aseptic meningitis (RR = 4.02, 95% CI = 1.46 11.03, Pheterogeneity = 0.960, I2 = 0%) significantly increased among patients in the PFDD group compared with patients in the PFD group. When stratifying by age, a significantly reduced risk in the reoperation rate was observed in the adult group. However, the clinical improvement and the incidence of wound infection were not significantly different between the 2 groups. CONCLUSIONS: This study confirmed that the decrease in syringomyelia was better for patients treated with PFDD than for patients treated with PFD alone. However, no significant difference was found in the clinical improvement and the reoperation rate between the 2 groups. PMID- 29482006 TI - Early Cranioplasty Benefits Patients with Obvious Bilateral Frontotemporal Bone Window Collapse After Decompressive Craniectomy. AB - OBJECTIVE: Obvious skin flap collapse is often accompanied by reduced neurologic recovery after decompressive craniectomy. This study explored the feasibility of early cranioplasty (EC) in patients with obvious bilateral frontotemporal bone window (BFBW) collapse after decompressive craniectomy. METHODS: Patients with obvious BFBW collapse who underwent EC or traditional cranioplasty (TC) were divided into 3 groups according to their preoperative Glasgow Coma Scale (GCS) scores. The indexes, including postoperative incision healing, salivation symptoms, postoperative infection, and 6-month postoperative follow-up after EC or TC, were compared in each group. RESULTS: Two of 32 patients with GCS scores of 3 to 8 points experienced poor healing of the scalp incision after EC, whereas no TC patients had poor healing. Incision healing significantly differed between these 2 groups (P > 0.05), and long-term prognoses based on GOS scores were the same after a 6-month postoperative follow-up (P > 0.05). In patients with GCS scores of 9 to 12 points, salivation improved by 84.2% and 17.6% in the EC and TC groups, respectively (P < 0.05) after a mean follow-up time of 6 months. Similarly, positive neurologic recovery rates (GOS score 4-5 points) were higher in the EC group (88.9%) than in the TC group (60.0%) (P < 0.05) and did not differ between the EC (79.3%) and TC (80.6%) groups in patients with GCS scores of 13 to 15 points (P > 0.05). However, salivation improved by 86.7% in the EC group but by only 12.5% in the TC group (P < 0.05). CONCLUSION: We therefore recommend EC for patients with obvious BFBW collapse and GCS scores >=9. PMID- 29482007 TI - Endovascular Treatment of Pulsatile Tinnitus by Sigmoid Sinus Aneurysm: Technical Note and Review of the Literature. AB - BACKGROUND: Pulse-synchronous tinnitus is rare, and it almost always points toward a vascular pathology. CASE DESCRIPTION: We encountered a 56-year-old patient presenting with a 3-month history of right-side tinnitus who was found to have a sigmoid sinus aneurysm after initial imaging. The patient was managed successfully with dual endovascular access and stent placement across the aneurysm, with a subsequent complete symptomatic relief. CONCLUSIONS: Description of the endovascular management of sigmoid sinus aneurysm is not infrequent in the literature. This report provides a brief review of the available literature specifically addressing the management strategies. PMID- 29482008 TI - Balloon Bridge: Novel Technique for Reaccessing Carotid Artery Stent. AB - BACKGROUND: Crossing a nascently deployed carotid artery stent (CAS) is required to perform angioplasty and filter recapture. If the traversing balloon or filter recapture catheters are eccentric or tangentially angled to the vertical axis of the CAS, they can ensnare on the ledge of the proximal CAS step-off, potentially causing life-threatening complications secondary to deformation, displacement, or mechanical occlusion of the stent. We report a novel "balloon bridge" technique that facilitates safe entry and passage across the CAS with both a balloon catheter and a large-bore guide catheter (LBGC). METHODS: We used the balloon bridge technique for 2 patients with >90% carotid artery stenosis and steep carotid artery angles of origin who underwent routine CAS, balloon angioplasty, and distal embolic protection. During filter recapture, the balloon was inflated across the junction of the distal LBGC tip and proximal CAS, centering the LBGC within the vessel lumen and CAS. During balloon deflation, the LBGC was sequentially advanced, successfully navigating the LBGC across the proximal stent construct without resistance or complication. RESULTS: The balloon bridge technique was completed without complications. We believe that the mechanism of action is secondary to balloon-facilitated LBGC alignment with the true axis of the stent. CONCLUSIONS: Traversing a CAS with an LBGC or balloon catheter can be tedious and fraught with the potential of neurologic peril should mechanical deformation and occlusion occur. The balloon bridge technique is safe and highly effective for navigating a catheter that is eccentric or tangentially angled to the long axis of a CAS. PMID- 29482009 TI - Quantitative Assessment of Invasion of High-Grade Gliomas Using Diffusion Tensor Magnetic Resonance Imaging. AB - OBJECTIVE: To determine heterogeneity of high-grade glioma (HGG) and its surrounding area and explore quantitative analysis of invasion of HGG using diffusion tensor imaging. METHODS: This study included 14 patients with HGG and preoperative magnetic resonance imaging and diffusion tensor imaging examinations. Three regions of interest were placed. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values of these regions of interest were measured, and specimens from the 3 regions of interest were obtained under navigation guidance. Postoperative examinations of specimens were carried out. Correlations between ADC and FA values and tumor cell density were evaluated. RESULTS: Median survival was 36.7 months. As distance from the tumor increased, the number of tumor cells significantly decreased. Regarding levels of matrix metalloproteinase-9 and Ki-67, only the differences between tumor and distances of 1 cm and 2 cm away from the tumor were statistically significant. For analysis of the relationship between tumor cell density and ADC and FA values, the discriminant formulas were as follows: G1 = -13.678 + 14984.791 (X) + 14443.847 (Y) (tumor cell density >=10%); G2 = -11.649 + 14443.847 (X) + 33.285 (Y) (tumor cell density <10%). CONCLUSIONS: We verified the heterogeneity of HGG and its surrounding area and found that patients with extensive resection may have longer survival. We also found a few formulas using FA and ADC values to predict tumor cell density. PMID- 29482010 TI - Structure-reactivity relationship of naphthenic acids in the photocatalytic degradation process. AB - Bitumen extraction in Canada's oil sands generates oil sands process-affected water (OSPW) as a toxic by-product. Naphthenic acids (NAs) contribute to the water's toxicity, and treatment methods may need to be implemented to enable safe discharge. Heterogeneous photocatalysis is a promising advanced oxidation process (AOP) for OSPW remediation, however, its successful implementation requires understanding of the complicated relationship between structure and reactivity of NAs. This work aimed to study the effect of various structural properties of model compounds on the photocatalytic degradation kinetics via high resolution mass spectrometry (HRMS), including diamondoid structures, heteroatomic species, and degree of unsaturation. The rate of photocatalytic treatment increased significantly with greater structural complexity, namely with carbon number, aromaticity and degree of cyclicity, properties that render particular NAs recalcitrant to biodegradation. It is hypothesized that a superoxide radical mediated pathway explains these observations and offers additional benefits over traditional hydroxyl radical-based AOPs. Detailed structure-reactivity investigations of NAs in photocatalysis have not previously been undertaken, and the results described herein illustrate the potential benefit of combining photocatalysis and biodegradation as a complete OSPW remediation technology. PMID- 29482011 TI - Two-year continuous measurements of carbonaceous aerosols in urban Beijing, China: Temporal variations, characteristics and source analyses. AB - Organic carbon (OC) and elemental carbon (EC) in the PM2.5 of urban Beijing were measured hourly with a semi-continuous thermal-optical analyzer from Jan 1, 2013 to Dec 31, 2014. The annual average OC and EC concentrations in Beijing were 17.0 +/- 12.4 and 3.4 +/- 2.0 MUg/m3 for 2013, and 16.8 +/- 14.5 and 3.5 +/- 2.9 MUg/m3 for 2014. It is obvious that the annual average concentrations of OC and EC in 2014 were not less than those in 2013 while the annual average PM2.5 concentration (89.4 MUg/m3) in 2014 was slightly reduced as compared to that (96.9 MUg/m3) in 2013. Strong seasonality of the OC and EC concentrations were found with high values during the heating seasons and low values during the non heating seasons. The diurnal cycles of OC and EC characterized by higher values at night and in the morning were caused by primary emissions, secondary transformation and stable meteorological condition. Due to increasing photochemical activity, the OC peaks were observed at approximately noon. No clear weekend effects were observed. Interestingly, in the early mornings on weekends in the autumn and winter, the OC and EC concentrations were close to or higher than those on weekdays. Our data also indicate that high OC and EC concentrations were closely associated with their potential source areas which were determined based on the potential source contribution function analysis. High potential source areas were identified and were mainly located in the south of Beijing and the plain of northern China. A much denser source region was recorded in the winter than in the other seasons, indicating that local and regional transport over regional scales are the most important. These results demonstrate that both regional transport from the southern regions and local accumulation could lead to the enhancements of OC and EC and likely contribute to the severe haze pollution in Beijing. PMID- 29482012 TI - Use of the intramuscular route to administer pentamidine isethionate in Leishmania guyanensis cutaneous leishmaniasis increases the risk of treatment failure. AB - BACKGROUND: New world cutaneous leishmaniasis (NWCL) can be found in French Guiana as well as in several other parts of Central and South America. Leishmania guyanensis accounts for nearly 90% of cases in French Guiana and is treated with pentamidine isethionate, given by either intramuscular or intravenous injection. The military population is particularly exposed due to repeated missions in the rainforest. The purpose of the present study was to identify the factors associated with pentamidine isethionate treatment failure in a series of service members with L. guyanensis NWCL acquired in French Guiana. METHOD: All the French service members reported as having acquired leishmaniasis in French Guiana from December 2013 to June 2016 were included. RESULTS: Seventy-three patients infected with L. guyanensis were included in the final analysis. Patients treated with IV pentamidine isethionate had better response rates than those treated with IM pentamidine isethionate (p = 0.002, adjusted odds ratio (AOR) = 0.15, 95% CI [0.04-0.50]). The rate of treatment success was 85.3% (95% CI [68.9-95.0]) for IV pentamidine isethionate and 51.3% (95% CI [34.8-67.6]) for IM pentamidine isethionate. CONCLUSIONS: The use of intramuscular pentamidine isethionate in the treatment of Leishmania guyanensis cutaneous leishmaniasis is associated with more treatment failures than intravenous pentamidine isethionate. PMID- 29482014 TI - The role of 'filth flies' in the spread of antimicrobial resistance. AB - BACKGROUND: 'Filth flies' feed and develop in excrement and decaying matter and can transmit enteric pathogens to humans and animals, leading to colonization and infection. Considering these characteristics, 'filth flies' are potential vectors for the spread of antimicrobial resistance (AMR). This review defines the role of flies in the spread of AMR and identifies knowledge gaps. METHODS: The literature search (original articles, reviews indexed for PubMed) was restricted to the English language. References of identified studies were screened for additional sources. RESULTS: 'Filth flies' are colonized with antimicrobial-resistant bacteria of clinical relevance. This includes extended spectrum beta-lactamase-, carbapenemase-producing and colistin-resistant (mcr-1 positive) bacteria. Resistant bacteria in flies often share the same genotypes with bacteria from humans and animals when their habitat overlap. The risk of transmission is most likely highest for enteric bacteria as they are shed in high concentration in excrements and are easily picked up by flies. 'Filth flies' can 'bio-enhance' the transmission of AMR as bacteria multiply in the digestive tract, mouthparts and regurgitation spots. CONCLUSION: To better understand the medical importance of AMR in flies, quantitative risk assessment models should be refined and fed with additional data (e.g. vectorial capacity, colonization dose). This requires targeted ecological, epidemiological and in vivo experimental studies. PMID- 29482013 TI - Place and practice: Sexual risk behaviour while travelling abroad among Swedish men who have sex with men. AB - BACKGROUND: The proportion of newly diagnosed HIV and STI cases among men who have sex with men (MSM) that were contracted abroad has been increasing in Sweden. The present study explored factors associated with casual unprotected anal intercourse (UAI) and travelling abroad among MSM. METHODS: A cross sectional stratified survey with 2751 MSM was conducted. The frequency of sexual practices among men who had casual UAI abroad (<12 months) with that of men who had casual UAI only in Sweden were compared and factors associated with casual UAI abroad were identified through regression analysis. RESULTS: Factors associated with casual UAI abroad within the previous 12 months were: visit a gay sauna (OR 6.15, 95% CI 3.43-11.06), visit gay cafe/bar/pub (OR 3.24, 95% CI 1.62 6.48), experience of UAI with a foreign visitor (OR 4.80, 95% CI 2.37-9.75), living with HIV (OR 2.73, 95% CI 1.15-6.48), reporting poor overall health (OR 2.24, 95% CI 1.13-4.44), being born outside Sweden (OR 2.21, 95% CI 1.08-4.53), and being vaccinated against hepatitis A, hepatitis B, or both (OR 1.92, 95% CI 1.13-3.27). CONCLUSION: MSM who engage in casual UAI abroad need to increase their understanding of related risks and that risk varies with place and practice. Health care professionals should address the preventive needs of traveling MSM and offer counselling and STI-preventive measures. PMID- 29482015 TI - Neuroanatomical basis of number synaesthesias: A voxel-based morphometry study. AB - In synaesthesia, a specific sensory dimension leads to an involuntary sensation in another sensory dimension not commonly associated with it; for example, synaesthetes may experience a specific colour when listening or thinking of numbers or letters. Large-scale behavioural studies provide a rich description of different synaesthesia phenotypes, and a great amount of research has been oriented to uncovering whether a single or multiple brain mechanisms underlie these various synaesthesia phenotypes. Interestingly, most of the synaesthetic inducers are conceptual stimuli such as numbers, letters, and months. However, the impact of these concepts on the synaesthetic brain remains largely unexplored. Numbers appear as the most typical inducer in two common types of synaesthesia: grapheme-colour and sequence-space. Numbers are symbols that denote quantity information and their processing recruits a specific neural network. Therefore, numbers may play an important role in the brain mechanisms underlying some types of synaesthesia. We used voxel-based morphometry (VBM) to compare grey matter (GM) volume in synaesthetes and controls. Relative to controls, synaesthetes showed increase in GM in the right amygdala and in the left cerebellum. Within the synaestheste group, comparing synaesthetes who reported numbers as the inducer with synaesthetes who reported other stimuli as the inducer revealed increase in GM in the left angular gyrus, which is associated with the verbal aspect of number processing. These results reveal neuroanatomical differences between synaesthetes and controls, and show the impact of the type of inducer in the synaesthetic brain. We discuss these findings in line with current neurobiological models of synaesthesia. PMID- 29482016 TI - Motor sequence learning and intermanual transfer with a phantom limb. AB - Amputees with phantom limb sometimes report vivid experiences of moving their phantom. Is phantom movement only "imaginary", or, instead, it has physiological properties comparable to those pertaining to real movements? To answer this question, we took advantage of the intermanual transfer of sequence learning, occurring when one hand motor skills improve after training with the other hand. Ten healthy controls and two upper-limb amputees (with and without phantom movement) were recruited. They were asked to perform with the right (intact) hand a fingers-thumb opposition sequence either in Naive condition or after an active (Real condition) or a mental (Imagery condition) training with the left (phantom) hand. In healthy controls, the results showed different effects after active training (i.e., faster movement duration (MD) with stable accuracy) and after mental training (i.e., increased accuracy with stable MD). Opposite results between moving-phantom case and static-phantom case were found. In the Real condition, after an "active" training with her phantom hand, the moving-phantom case showed a faster performance of the intact hand. This transfer effect was not different from that found in healthy controls, actually performing the active training with an existing hand (Real condition), but, crucially, it was significantly different from both Imagery and Naive conditions of controls. Contrariwise, in the static phantom case, the performance during the Real condition was significantly different from the Real condition of healthy controls and it was not significantly different from their Imagery and Naive conditions. Importantly, a significant difference was found when the transfer effect in Real condition was compared between the two phantom cases. Taken together, these findings provide the first evidence that a phantom limb can learn motor skills and transfer them to the intact limb. PMID- 29482017 TI - Effects of spatial attention on mental time travel in patients with neglect. AB - Numerous studies agree that time is represented in spatial terms in the brain. Here we investigate how a deficit in orienting attention in space influences the ability to mentally travel in time, that is to recall the past and anticipate the future. Right brain-damaged patients, with (RBD-N+) and without neglect (RBD-N-), and healthy controls (HC) were subjected to a Mental Time Travel (MTT) task. Participants were asked to project themselves in time to past, present or future (i.e., self-projection) and, for each self-projection, to judge whether events were located relatively in the past or the future (i.e., self-reference). The MTT task was performed before and after a manipulation, through prismatic adaptation (PA), inducing a leftward shift of spatial attention. Before PA, RBD-N+ were slower for future than for past events, whereas RBD-N- and HC responded similarly to past and future events. A leftward shift of spatial attention by PA reduced the difference in past/future processing in RBD-N+ and fastened RBD-N- and HC's response to past events. Assuming that time concepts, such as past/future, are coded with a left-to-right order on a mental time line (MTL), a recursive search of future-events can explain neglect patients' performance. Improvement of the spatial deficit following PA reduces the recursive search of future events on the rightmost part of the MTL, facilitating exploration of past events on the leftmost part of the MTL, finally favoring the correct location of past and future events. In addition, the study of the anatomical correlates of the temporal deficit in mental time travel through voxel-based lesion-symptom mapping showed a correlation with a lesion located in the insula and in the thalamus. These findings provide new insights about the inter-relations of space and time, and can pave the way to a procedure to rehabilitate a deficit in these cognitive domains. PMID- 29482018 TI - Aggregation kinetics of microplastics in aquatic environment: Complex roles of electrolytes, pH, and natural organic matter. AB - Microplastics are an emerging contaminants of concern in aquatic environments. The aggregation behaviors of microplastics governing their fate and ecological risks in aquatic environments is in need of evaluation. In this study, the aggregation behavior of polystyrene microspheres (micro-PS) in aquatic environments was systematically investigated over a range of monovalent and divalent electrolytes with and without natural organic matter (i.e., Suwannee River humic acid (HA)), at pH 6.0, respectively. The zeta potentials and hydrodynamic diameters of micro-PS were measured and the subsequent aggregation kinetics and attachment efficiencies (alpha) were calculated. The aggregation kinetics of micro-PS exhibited reaction- and diffusion-limited regimes in the presence of monovalent or divalent electrolytes with distinct critical coagulation concentration (CCC) values, followed the Derjaguin-Landau-Verwey Overbeek (DLVO) theory. The CCC values of micro-PS were14.9, 13.7, 14.8, 2.95 and 3.20 mM for NaCl, NaNO3, KNO3, CaCl2 and BaCl2, respectively. As expected, divalent electrolytes (i.e., CaCl2 and BaCl2) had stronger influence on the aggregation behaviors of micro-PS as compared to monovalent electrolytes (i.e., NaCl, NaNO3 and KNO3). HA enhanced micro-PS stability and shifted the CCC values to higher electrolyte concentrations for all types of electrolytes. The CCC values of micro-PS were lower than reported carbonaceous nanoparticles CCC values. The CCC[Ca2+]/CCC [Na+] ratios in the absence and presence of HA at pH 6.0 were proportional to Z-2.34 and Z-2.30, respectively. These ratios were in accordance with the theoretical Schulze-Hardy rule, which considers that the CCC is proportional to z-6-z-2. These results indicate that the stability of micro-PS in the natural aquatic environment and the possibility of significant aqueous transport of micro-PS. PMID- 29482019 TI - Emission measurement of diesel vehicles in Hong Kong through on-road remote sensing: Performance review and identification of high-emitters. AB - A two-year remote sensing measurement program was carried out in Hong Kong to obtain a large dataset of on-road diesel vehicle emissions. Analysis was performed to evaluate the effect of vehicle manufacture year (1949-2015) and engine size (0.4-20 L) on the emission rates and high-emitters. The results showed that CO emission rates of larger engine size vehicles were higher than those of small vehicles during the study period, while HC and NO were higher before manufacture year 2006 and then became similar levels between manufacture years 2006 and 2015. CO, HC and NO of all vehicles showed an unexpectedly increasing trend during 1998-2004, in particular >=6001 cc vehicles. However, they all decreased steadily in the last decade (2005-2015), except for NO of >=6001 cc vehicles during 2013-2015. The distributions of CO and HC emission rates were highly skewed as the dirtiest 10% vehicles emitted much higher emissions than all the other vehicles. Moreover, this skewness became more significant for larger engine size or newer vehicles. The results indicated that remote sensing technology would be very effective to screen the CO and HC high emitters and thus control the on-road vehicle emissions, but less effective for controlling NO emissions. No clear correlation was observed between the manufacture year and percentage of high-emitters for <=3000 cc vehicles. However, the percentage of high-emitters decreased with newer manufacture year for larger vehicles. In addition, high-emitters of different pollutants were relatively independent, in particular NO emissions, indicating that high-emitter screening criteria should be defined on a CO-or-HC-or-NO basis, rather than a CO-and-HC-and NO basis. PMID- 29482020 TI - Organophosphate esters and phthalate esters in human hair from rural and urban areas, Chongqing, China: Concentrations, composition profiles and sources in comparison to street dust. AB - Human hair and street dust from rural and urban areas in Chongqing were collected to analyze Organophosphate esters (OPEs) and phthalate esters (PAEs). Concentrations of OPEs in urban hair were significantly higher than those in rural hair, whereas PAEs concentrations in rural hair were significantly higher than those in urban hair. Different composition patterns of OPEs were observed in rural and urban hair, where tris (2-chloroisopropyl) phosphate (TCIPP), tris (butyl) phosphate (TNBP) and triphenyl phosphate (TPHP) were the dominating analogues in rural hair, accounting for 62.1% of the OPEs burden, and tris (methylphenyl) phosphate (TMPP) exhibited a high contribution in urban hair, responsible for 51.3% of total OPEs, which differed from the composition profiles in corresponding street dust. Analogous composition patterns of PAEs were found in hair of both areas. Di-(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DNBP), diisobutyl phthalate (DIBP) and diethyl phthalate (DEP) were the most abundant analogues in hair samples, while DEHP was the predominant analogue in dust samples. No clear tendency was obtained between the increasing ages and the concentrations of both compounds. Most OPEs and PAEs congeners showed significantly positive correlation with one another in rural hair. On the contrary, different correlation patterns were observed in urban hair for OPEs and PAEs, indicating multiple or additional sources existed in urban areas. Significant correlations of OPEs and PAEs were found between hair and corresponding street dust samples, but poor correlations of OPEs and PAEs were observed between rural hair and rural indoor dust, suggesting that street dust may be a predominant exogenous source for human exposure to OPEs and PAEs in this area. PMID- 29482021 TI - Fractionation and mobility of thallium in areas impacted by mining-metallurgical activities: Identification of a water-soluble Tl(I) fraction. AB - Mining and metallurgy generate residues that may contain thallium (Tl), a highly toxic metal, for which it is currently not feasible to determine its geochemical speciation through X-ray absorption spectroscopy due to a combination of very low contents and the interference of accompanying high arsenic contents. Therefore, fractionation studies in residues and soils are required to analyze the mobility and bioavailability of this metal, which in turn provide information to infer its speciation. For this purpose, in this work a modification of the BCR procedure was applied to residues and contaminated soils from three mining zones of Mexico and two mining zones of Spain, spanning samples with acidic to alkaline pH values. The Tl extraction procedure consisted of the following fractions: (1) water-extractable, (2) easily exchangeable and associated to carbonates, associated to (3) poorly-crystalline and (4) crystalline Fe and Mn oxyhydroxides, and (5) associated to organic matter and sulfides; and finally a residual fraction as associated to refractory primary and other secondary minerals. The extracted contents were analyzed by Inductively-Coupled Plasma with Mass Spectrometry. Surprisingly, water-soluble, in Tl(I) oxidation state, was detected in most areas, regardless of the pH, a fact that has not been reported before in these environments, and alerts to potential health risks not previously identified. Most of the samples from a metallurgy area showed high levels of Tl in non-residual fractions and a strong correlation was obtained between extracted Mn and Tl in the third fraction, suggesting its association to poorly crystalline manganese oxides. In the majority of samples from purely mining environments, most of the Tl was found in the residual fraction, most probably bound to alumino silicate minerals. The remaining Tl fractions were extracted mainly associated to the reducible mineral fractions, and in one case also in the oxidizable fraction (presumably associated to sulfides). Capsule: Soluble Tl(I) was found in all soil samples contaminated with either mining or metallurgical wastes. Additionally, in those affected by metallurgical wastes a very strong Tl-Mn correlation was found. PMID- 29482022 TI - delta15N and nutrient stoichiometry of water, aquatic organisms and environmental implications in Taihu lake, China. AB - Nitrogen pollution has become a worldwide problem and the source identification is important for the development of pertinent control measures. In this study, isotope end members (rain, nitrogen fertilizer, untreated/treated sewage), and samples (river water discharging to Taihu lake, lake water, aquatic organisms of different trophic levels) were taken during 2010-2015 to examine their delta15N values and nutrient stoichiometry. Results indicated that phytoplankton (primary producers), which directly take up and incorporate N from the lake water, had a similar delta15N value (14.10/00 +/- 3.2) to the end member of treated sewage (14.00/00 +/- 7.5), and the most frequently observed delta15N value in the lake water was 8-120/00, both indicating the dominant impact of the sewage discharge. Relationship analysis between N isotope value of nitrate and nitrate concentration indicated that different N cycling existed between the algae dominated northwest lake (NW) and the macrophyte-dominated southeast lake (SE), which is a result of both impacts of river inputs and denitrification. Our nutrient stoichiometry analysis showed that the lake water had a significantly higher N:P ratio than that of algae (p < 0.05), suggesting that N is available in excess relative to the amount demanded by the algae. The long-term trend of the socio-economic development in the watershed further confirmed that the rapid population increase and urbanization have resulted in a great change in the N loading and source proportion. We suggest that although P control is necessary in terms of eutrophication control, N pollution control is urgent for the water quality and ecological recovery for Taihu lake. PMID- 29482024 TI - Characteristics of atmospheric polychlorinated naphthalenes (PCNs) collected at different sites in northern Taiwan. AB - Ambient air samples were collected simultaneously at three sites in northern Taiwan using high-volume samplers during winter and summer to evaluate the atmospheric PCN characteristics including concentration, distribution, potential sources and gas/particle partitioning. The average concentration (Sigma73 PCNs from di-to octa-CN) observed at industrial site is the highest (172 +/- 111 pg m 3), while PCN levels measured at urban and rural sites are comparable (45.2 +/- 8.20 and 45.9 +/- 24.4 pg m-3, respectively). The PCN concentrations are higher in summer compared with those measured in winter for all three sampling sites. Gas-phase PCNs predominate in ambient air, accounting for 94 +/- 6.0% of total concentration. Homologue distributions of PCNs measured at industrial site are different from two other sites for both gas and particulate phases, suggesting that different sources contribute to PCNs collected at industrial site. Based on the ratios of characteristic PCN congeners and fraction of Sigmacombustion related PCNs/SigmaPCNs, thermal processes are identified as major sources of PCNs at industrial site. PCNs collected at urban and rural sites are mixed sources of thermal emissions and evaporation, however, more influence of thermal sources in winter and more impact of evaporation sources in summer are observed. Results of the logKp-logPL relationship indicate that both adsorption and absorption govern gas/particle partitioning of atmospheric PCNs in northern Taiwan. Furthermore, the relationship between logKp and logKOA reveals that absorption is more important in governing gas/particle partitioning of PCNs in winter compared to summer. PMID- 29482023 TI - Dopaminergic dysregulation and impaired associative learning behavior in zebrafish during chronic dietary exposure to selenium. AB - A growing body of evidence indicates that exposure to selenium (Se) can cause neurotoxicity, and this can occur because of its interference with several neurotransmitter systems in humans and animals. Dopamine is a critical modulator of a variety of brain functions and a prime target for environmental neurotoxicants. However, effects of environmentally relevant concentrations of Se on dopaminergic system and its neurobehavioral effects are still largely unknown. For this purpose, we exposed zebrafish, a model organism, to different concentrations of dietary l-selenomethionine (control, 3.5, 11.1, 27.4, and 63.4 MUg Se/g dry weight) for a period of 60 days. Cognitive performance of fish was evaluated using a plus maze associative learning paradigm. Oxidative stress, as the main driver of Se neurotoxicity, was assessed by measuring the ratio of reduced to oxidized glutathione (GSH:GSSG), lipid peroxidation (LPO) levels, and mRNA expression of several antioxidant enzymes in the zebrafish brain. Dopamine levels in the brain and the expression of genes involved in dopamine synthesis, storage, reuptake, metabolism, and receptor activation were examined. Moreover, transcription of several synaptic plasticity-related immediate-early and late response genes was determined. Overall, fish fed with the two highest concentrations of dietary Se displayed impaired associative learning. Se exposure also induced oxidative stress in the zebrafish brain, as indicated by a reduction in GSH:GSSG ratio, increased LPO levels, and up-regulation of antioxidant genes in fish treated with the two highest concentrations of Se. An increase in brain dopamine levels associated with altered expression of dopaminergic cell markers was evident in different treatment groups. Moreover, Se exposure led to the down regulation of immediate-early and late response genes in fish that exhibiting learning impairment. Taken together, the results of this study imply that the induction of oxidative stress and dysregulation of dopaminergic neurotransmission may underlie Se-induced impairment of associative learning in zebrafish. PMID- 29482025 TI - Lifecycle exposure to perchlorate differentially alters morphology, biochemistry, and transcription as well as sperm motility in Silurana tropicalis frogs. AB - Perchlorate (ClO4-) contamination has been reported in ground and surface waters across North America. However, few studies have examined the effects of prolonged exposure to this thyroid hormone disrupting chemical, particularly at environmentally relevant concentrations in lower vertebrates, such as amphibians. The aim of this study was to examine the effects of a yearlong chronic exposure to ClO4- in adult male and female Western clawed frogs (Silurana tropicalis). Frogs were spawned and raised from fertilized embryo until sexual maturity in potassium perchlorate (KClO4)-treated water at different concentrations (0, 20, 53, and 107 MUg/L). Developmental and reproductive indices - including adult morphology, androgen plasma levels, gonadal thyroid hormone- and sex steroid related transcript levels, and sperm motility - were evaluated in male and female adult frogs. Female growth (e.g., body mass, snout-vent length, and hind limb length) was significantly reduced following chronic exposure to environmentally relevant concentrations of KClO4 resulting in females with morphometric indices similar to those of control males - indicating potential sex-specific sensitivities to KClO4. Changes to reproductive indices (i.e., plasma androgen levels, gonadal thyroid hormone- and sex steroid-related transcript levels, and sperm motility) were also observed in both sexes and suggest that KClO4 exposure may also have indirect secondary effects on the reproductive axes in male and female adult frogs. These effects were observed at concentrations at or below those reported in surface waters contaminated with ClO4- suggesting that this contaminant may have developmental and reproductive effects post-metamorphosis in natural amphibian populations. PMID- 29482026 TI - Determinants of Diuretic Responsiveness and Associated Outcomes During Acute Heart Failure Hospitalization: An Analysis From the NHLBI Heart Failure Network Clinical Trials. AB - BACKGROUND: Poor response to loop diuretic therapy is a marker of risk during heart failure hospitalization. We sought to describe baseline determinants of diuretic response and to further explore the relationship between this response and clinical outcomes. METHODS AND RESULTS: Patient data from the National Heart, Lung, and Blood Institute Heart Failure Network ROSE-AHF and CARRESS-HF clinical trials were analyzed to determine baseline determinants of diuretic response. Diuretic efficiency (DE) was defined as total 72-hour fluid output per total equivalent loop diuretic dose. Data from DOSE-AHF was then used to determine if these predictors of DE correlated with response to a high- versus low-dose diuretic strategy. At 72 hours, the high-DE group had median fluid output of 9071 ml (interquartile range: 7240-11775) with median furosemide dose of 320 mg (220 480) compared with 8030 ml (6300-9915) and 840 mg (600-1215) respectively for the low DE group. Cystatin C was independently associated with DE (odds ratio 0.36 per 1mg/L increase; 95% confidence interval: 0.24-0.56; P < 0.001). Independently from baseline characteristics, reduced fluid output, weight loss and DE were each associated with increased 60 day mortality. Among patients with estimated glomerular filtration rate below the median, those randomized to a high-dose strategy had improved symptoms compared with those randomized to a low-dose strategy. CONCLUSIONS: Elevated baseline cystatin C, as a biomarker of renal dysfunction, is associated with reduced diuretic response during heart failure hospitalization. Higher loop diuretic doses are required for therapeutic decongestion in patients with renal insufficiency. Poor response identifies a high-risk population. PMID- 29482028 TI - The Current Focus of Heart Failure Clinical Trials. AB - BACKGROUND: Heart failure (HF) is a major global health problem. Clinical trials test efficacy, effectiveness, and safety of novel and emerging therapies in HF. We sought to determine the salient features of ongoing interventional clinical trials in HF. METHODS AND RESULTS: We accessed the ClinicalTrials.gov registry of the National Institutes of Health (NIH) and the International Clinical Trials Registry Platform of the World Health Organization on January 1, 2017, and extracted pertinent information on current HF clinical trials for systematic review. Of 794 HF trials that met our inclusion criteria, almost one-half (49.1%) evaluated clinical end points and one-third (32.8%) examined imaging end points as primary outcomes. One-fourth (24.8%) were industry sponsored and one-third (35.6%) were university sponsored. The NIH and other United States federal agencies funded only 14 trials (1.8% of all trials; 10.7% of trials in the US). Among 536 HF trials with specified left ventricular ejection fraction status, 434 (81.0%) focused on HF with reduced ejection fraction (HFrEF) and only 102 (19.0%) trials targeted HF with preserved ejection fraction (HFpEF). CONCLUSIONS: Ongoing HF trials are predominantly sponsored by nongovernmental funding agencies. Although HFpEF occurs as commonly as HFrEF in the community, the number of clinical trials targeting HFpEF is substantially lower compared with HFrEF. PMID- 29482029 TI - A Contemporary Analysis of Heart Transplantation and Bridge-to-Transplant Mechanical Circulatory Support Outcomes in Cardiac Sarcoidosis. AB - BACKGROUND: Patients with end-stage cardiomyopathy due to cardiac sarcoidosis (CS) may be referred for mechanical circulatory support (MCS) and heart transplantation (HT). We describe outcomes of patients with CS undergoing HT, focusing on the use of MCS as a bridge to transplant (BTT). METHODS: Using the United Network for Organ Sharing Scientific Registry of Transplant Recipients, we identified all adult waitlisted patients and isolated HT recipients from 2006 to 2015. These were divided into those with and without CS and further divided into those who did or did not receive MCS as BTT. Outcomes included 1- and 5-year post transplantation freedom from mortality and 5-year freedom from primary graft failure. RESULTS: Over the study period, 31,528 patients were listed for HT, 148 (0.4%) of whom had CS. Among the CS patients, 34 (23%) received MCS as BTT. 18,348 patients (58%) eventually underwent HT, including 67 (0.4%) with CS, 20 (30%) of whom had received BTT MCS. Compared with non-CS diagnoses, CS patients had similar 1-year (91% vs 90%; log rank P = .88) and 5-year (83% vs 77%; log rank P = .46) freedom from mortality. Survival was also similar between CS BTT and non-CS BTT groups at 1 year (89% vs 89%; log-rank P = .92) and 5 years (72% vs 75%; log-rank P = .77). CONCLUSIONS: Survivals after HT were similar between CS and non-CS patients out to 5 years, and were also similar between CS and non CS BTT cohorts. Both HT and BTT MCS should be considered in patients with CS. PMID- 29482027 TI - Diastolic Dysfunction in Individuals With Human Immunodeficiency Virus Infection: Literature Review, Rationale and Design of the Characterizing Heart Function on Antiretroviral Therapy (CHART) Study. AB - Antiretroviral therapy (ART) has been associated with a shift in the epidemiology of human immunodeficiency virus (HIV)-associated cardiomyopathy from a phenotype of primarily left ventricular (LV) systolic dysfunction to LV diastolic dysfunction (DD). Patients with HIV receiving ART have higher rates of DD compared with age-matched control subjects and develop DD at a younger age. However, little is known about the natural history and pathogenesis of DD in virally suppressed HIV-infected patients. Current evidence suggests that immune processes modulate the risk for cardiac involvement in HIV-infected persons. Ongoing inflammation appears to have myocardial effects, and accelerated myocardial fibrosis appears to be a key mediator of HIV-induced DD. The Characterizing Heart Function on Antiretroviral Therapy (CHART) study aims to systematically investigate determinants, mechanisms, and consequences of DD in HIV-infected patients. We will compare ART-treated virally suppressed HIV infected individuals with and without DD and HIV- individuals with DD regarding (1) systemic inflammation, myocardial stress, and subclinical myocardial necrosis as indicated by circulating biomarkers; (2) immune system activation as indicated by cell surface receptors; (3) myocardial fibrosis according to cardiac magnetic resonance examination; (4) markers of fibrosis and remodeling, oxidative stress, and hypercoagulability; (5) left atrial function according to echocardiographic examination; (6) myocardial stress and subclinical necrosis as indicated by circulating biomarkers; (7) proteomic and metabolic profiles; and (8) phenotype signatures derived from clinical, biomarker, and imaging data. PMID- 29482030 TI - The physiological stress response of the Atlantic stingray (Hypanus sabinus) to aerial exposure. AB - Although secondary stress physiology of elasmobranchs is fairly well studied, gaps remain in our understanding of species differences, including stress recovery. We examined the physiological stress response to air exposure in Atlantic stingrays (Hypanus sabinus) using a serial sampling method requiring minimal handling. Many elasmobranch stress studies exclusively quantify glucose, although there is evidence that elasmobranchs are unusually reliant on ketone bodies. Therefore, we also tested the hypothesis that ketone bodies play a significant role in the elasmobranch stress response by examining plasma beta hydroxybutyrate. Plasma osmolality, urea, trimethylamine-N-oxide, and a suite of ions were also measured to characterize departures from homeostasis due to air exposure. H. sabinus were exposed to air for 30 min and serially sampled at 0, 15, and 30 min, as well as 48 h after the stressor to assess the extent of recovery. Blood lactate and acidosis increased significantly during the stressor and returned to basal levels by 48 h. Glucose values were significantly affected, with the highest values observed at 48 h, suggesting that animals were not fully recovered as initially indicated by other metrics. Average plasma beta hydroxybutyrate was unaffected by the stressor. This suggests that ketone bodies may not be a major fuel source used during acute stress, at least in the timeframe examined. PMID- 29482031 TI - The chitosan - Porphyrazine hybrid materials and their photochemical properties. AB - Three magnesium sulfanyl porphyrazines differing in the size of peripheral substituents (3,5-dimethoxybenzylsulfanyl, (3,5 dimethoxybenzyloxy)benzylsulfanyl, 3,5-bis[(3,5-bis[(3,5 dimethoxybenzyloxy)benzyloxy]benzylsulfanyl) were exposed to visible and ultraviolet radiation (UV A + B + C) in order to determine their photochemical properties. The course of photochemical reactions in dimethylformamide solutions and the ability of the systems to generate singlet oxygen were studied by UV-Vis spectroscopy, which additionally gave information on aggregation processes. The porphyrazines were found to be stable upon visible light irradiation conditions, but when exposed to high energy UV radiation, the efficient photodegradation of these macrocycles was observed. Therefore, these three magnesium sulfanyl porphyrazines were incorporated into chitosan matrix. The obtained thin films of chitosan doped with porphyrazines were subjected to polychromatic UV-radiation and studied by spectroscopic methods (UV-Vis, FTIR), scanning electron microscopy (SEM) and atomic force microscopy (AFM). Application of chitosan as a polymer matrix for porphyrazines was found to be successful method that effectively stopped the unwelcome degradation of macrocycles, thus worth considering for their photoprotection. In addition, the surface properties of the hybrid material were determined by contact angle measurements and calculation of surface free energy. Intermolecular interactions between these novel porphyrazines and chitosan were detected. The mechanism of photochemical reactions occurring in studied systems has been discussed. PMID- 29482033 TI - In-treatment cigarette demand among treatment-seeking smokers with depressive symptoms. AB - INTRODUCTION: Despite previous evidence supporting the use of the Cigarette Purchase Task (CPT) as a valid tool for assessing smoking reinforcement, research assessing how environmental changes affect CPT performance is scarce. AIMS: This study addressed for the first time the differential effect of treatment condition [Cognitive Behavioral Treatment (CBT) + Behavioral Activation (BA) versus CBT + BA + Contingency Management (CM)] on cigarette demand among treatment seeking smokers with depressive symptoms. It also sought to assess whether reductions in smoking consumption arranged over the course of an intervention for smoking cessation impact on in-treatment cigarette demand. METHOD: Participants were 92 smokers with depressive symptoms from a randomized clinical trial that received eight weeks of either CBT + BA or CBT + BA + CM. Individuals completed the CPT 8 times; the first during the intake visit and the remaining 7 scheduled once a week in midweek sessions. Cotinine samples were collected in each session. RESULTS: Participants receiving CBT + BA + CM showed higher reduction in cigarette demand across sessions than participants receiving CBT + BA, although this comparison was only significant for the intensity index (p = .004). Cotinine was positively related to cigarette demand (all p values < .001), although this association became less prominent across sessions. In-treatment cotinine decreases were associated with demand reductions (all p values < .001), but this association was not significant for elasticity. CONCLUSIONS: Reductions in nicotine intake arranged over the course of an intervention for smoking cessation impact in-treatment cigarette demand. PMID- 29482032 TI - Carnosine-graphene oxide conjugates decorated with hydroxyapatite as promising nanocarrier for ICG loading with enhanced antibacterial effects in photodynamic therapy against Streptococcus mutans. AB - Antimicrobial photodynamic therapy (aPDT) has been emerged as a noninvasive strategy to remove bacterial contaminants such as S. mutans from the tooth surface. Photosensitizer (PS), like indocyanine green (ICG), plays a key role in this technique which mainly suffers from the poor stability and concentration dependent aggregation. An appropriate nanocarrier (NC) with enhanced antibacterial effects could overcome these limitations and improve the efficiency of ICG as a PS. In this study, various ICG-loaded NCs including graphene oxide (GO), GO-carnosine (Car) and GO-Car/Hydroxyapatite (HAp) were synthesized and characterized by Fourier Transform Infrared Spectroscopy (FT-IR), X-ray Diffraction (XRD), Filed Emission Scanning Electron Microscopy (FE-SEM), Energy Dispersive Spectroscopy (EDS), Zeta Potential and Ultraviolet-Visible spectrometry (UV-Vis). The colony forming unit and crystal violet assays were performed to evaluate the antimicrobial and anti-biofilm properties of PSs against S. mutans. The quantitative real-time PCR approach was also applied to determine the expression ratio of the gtfB gene in S. mutans. The zeta potential analysis and UV-Vis spectrometry indicated successful loading of ICG onto/into NCs. GO-Car/HAp showed highest amount of ICG loading (57.52%) and also highest aqueous stability after one week (94%). UV-Vis spectrometry analyses disclosed a red shift from 780 to 800 nm for the characteristic peak of ICG-loaded NCs. In the lack of aPDT, GO-Car@ICG showed the highest decrease in bacterial survival (86.4%) which indicated that Car could significantly promote the antibacterial effect of GO. GO@ICG, GO-Car@ICG and GO-Car/HAp@ICG mediated aPDT, dramatically declined the count of S. mutans strains to 91.2%, 95.5% and 93.2%, respectively (P < 0.05). The GO@ICG, GO-Car@ICG, GO-Car/HAp@ICG significantly suppressed the S. mutans biofilm formation by 51.4%, 63.8%, and 56.8%, respectively (P < 0.05). The expression of gtfB gene was considerably reduced to 6.0, 9.0 and 7.9-fold after aPDT in the presence of GO@ICG, GO-Car@ICG, GO-Car/HAp@ICG, respectively (P < 0.05). It could be concluded that the multi-functionalized GO as a novel nanocarrier could significantly enhance the ICG loading, stability, and improve its inhibitory effects as a photosensitizer in aPDT against S. mutans. These findings might provide opportunity for efficient treatment of local dental infections. PMID- 29482034 TI - Health-related quality of life in children with Developmental Coordination Disorder: Association between the PedsQL and KIDSCREEN instruments and comparison with their normative samples. AB - BACKGROUND AND AIMS: One of the major concerns for Developmental Coordination Disorder (DCD) are the mental and physical consequences of the condition, especially as they relate to quality of life factors. Here, we examined health related quality of life (HRQOL) in children with DCD, determined the association between two standardized parent reports, and compared HRQOL of our sample with DCD with the normative sample of each assessment for typically developing (TD) children and a sample of children with chronic health conditions. METHODS AND PROCEDURES: Parents of children with reported DCD with ages between 6 and 12 completed the PedsQL and KIDSCREEN instruments through an online survey. The PedsQL measures HRQOL in the Physical, Emotional, Social, Academic, and Psychosocial Functioning domains, while the KIDSCREEN assesses HRQOL in Physical and Psychological Well-Being, Autonomy & Parents, Peers & Social Support, and School Environment. OUTCOMES AND RESULTS: Pearson's correlation analyses showed low to moderate correlations between dimensions of the assessments, with the exception of the KIDSCREEN Autonomy & Parents. T-test analyses showed that the group with DCD showed significantly lower scores than the normative samples on the PedsQL and KIDSCREEN, and the PedsQL scores were significantly lower than those of a sample of children experiencing chronic illness. CONCLUSIONS AND IMPLICATIONS: Scores on both instruments state that DCD likely represents a serious problem for children, and add to the body of evidence supporting the notion that children with DCD have lower overall HRQOL. We urge professionals to address or refer these children to services that can help improve children's quality of life and prevent future health problems. PMID- 29482035 TI - Prediction and persistence of late talking: A study of Italian toddlers at 29 and 34 months. AB - This study analyzed the communicative, linguistic and symbolic skills in Italian Late Talking (LT) toddlers. Thirty-five participants were identified through a language-screening program at 29 months by using the Italian version of MB-CDI W&S Short Form. Cognitive, communicative and linguistic skills were evaluated 5 later, with indirect and direct tools. The MB-CDI WS Short Form revealed, in LT children, weakness in gesture production, decontextualized comprehension, verbal imitation, symbolic play, and phonological accuracy. Our results confirmed lexical size at 29 months is the predictive factor to identify language delay at 34 months. The clinical assessment at 34 months confirmed that 89% of the LT children had a vocabulary size below the 10th percentile on the MB-CDI Complete Form. On a structured task, LT children showed lexical comprehension more preserved than lexical production, and more advanced skills in nouns than in predicates. Weakness in socioconversational abilities emerged. Correlation among maternal education, expressive vocabulary and socio-conversational competence in LT children was evidenced. Strong association among cognitive, communicative and linguistic skills were documented. PMID- 29482036 TI - Health-related quality of life in people with intellectual disability who use long-term antipsychotic drugs for challenging behaviour. AB - BACKGROUND: Many people with intellectual disabilities use long-term antipsychotics for challenging behaviour and experience side-effects from these drugs, which may affect Health-related Quality of Life (HQoL). AIMS: This study aimed to investigate HQoL in people with intellectual disabilities who use long term antipsychotics and to investigate its associations with challenging behaviour and physical symptoms often associated with antipsychotics. MATERIALS AND METHODS: We used baseline data of two studies of long-term used antipsychotics. The RAND-36 and the emotional and physical wellbeing subscales of the Personal Outcome Scale (POS) were used to assess HQoL. Associations with challenging behaviour, measured with the Aberrant Behavior Checklist (ABC) and physical symptoms (extrapyramidal, autonomic, metabolic) with HQoL outcomes were analysed by univariate and multivariate linear regression. RESULTS: The mental subscales of the RAND-36 and emotional wellbeing of the POS were associated with the irritability and lethargy ABC-subscales. Physical wellbeing was negatively associated with parkinsonism urinary problems, dysphagia and temperature dysregulation possibly due to antipsychotics use. CONCLUSION: Both mental and physical wellbeing are related to challenging behaviour and physical symptoms associated with antipsychotics. Therefore HQoL could be a helpful measure when balancing benefits and disadvantages of antipsychotics prescribed for challenging behaviour. PMID- 29482037 TI - Biology and function of adipose tissue macrophages, dendritic cells and B cells. AB - The increasing incidence of obesity and its socio-economical impact is a global health issue due to its associated co-morbidities, namely diabetes and cardiovascular disease [1-5]. Obesity is characterized by an increase in adipose tissue, which promotes the recruitment of immune cells resulting in low-grade inflammation and dysfunctional metabolism. Macrophages are the most abundant immune cells in the adipose tissue of mice and humans. The adipose tissue also contains other myeloid cells (dendritic cells (DC) and neutrophils) and to a lesser extent lymphocyte populations, including T cells, B cells, Natural Killer (NK) and Natural Killer T (NKT) cells. While the majority of studies have linked adipose tissue macrophages (ATM) to the development of low-grade inflammation and co-morbidities associated with obesity, emerging evidence suggests for a role of other immune cells within the adipose tissue that may act in part by supporting macrophage homeostasis. In this review, we summarize the current knowledge of the functions ATMs, DCs and B cells possess during steady-state and obesity. PMID- 29482038 TI - Progression of subclinical atherosclerosis in subjects with rheumatoid arthritis and the metabolic syndrome. AB - BACKGROUND AND AIMS: Rheumatoid arthritis (RA) has been associated with an increased risk of atherosclerosis. We aimed to evaluate the progression of carotid intima media thickness (cIMT) in RA patients subject to a cardiovascular treat-to-target intervention. In addition, the presence of the metabolic syndrome (MetS) on cIMT outcomes was evaluated. METHODS: We performed a cohort analysis of FRANCIS, in which RA patients <=70 years without CVD or diabetes mellitus were randomized for either a treat-to-target intervention or usual care concerning CVD risk factors. MetS was scored at baseline. RESULTS: Three-year data was available in 212 well-controlled RA patients. The treat-to-target intervention resulted in a lower cIMT progression over three years compared to the usual care. However, there was no difference in cIMT at three years between groups. MetS was present in 40.1% of RA patients. Baseline cIMT was significantly higher in RA patients with MetS compared to those without (0.619 (0.112) versus 0.557 (0.104) mm; p < 0.001). After three years, cIMT progression was comparable (0.043 (0.071) versus 0.043 (0.072) mm; p = 0.96). In RA patients with MetS, the presence of plaques increased over three years from 12.9% to 23.5% (p = 0.01). The type of intervention had no effect on cIMT progression in RA patients with MetS. However, in subjects without MetS, treat-to-target resulted in a lower progression. CONCLUSIONS: RA patients with MetS showed an increased CVD risk profile based on both a higher prevalence of CVD risk factors and structural vascular changes. A treat-to-target approach of CVD risk factors reduced cIMT progression only in RA patients without MetS. PMID- 29482040 TI - Cognitive impairments and low BDNF serum levels in first-episode drug-naive patients with schizophrenia. AB - Evidence shows that BDNF may regulate activity-dependent forms of synaptic plasticity underlying learning and memory. Previous studies reported low BDNF levels and cognitive impairment in the early stage of schizophrenia. Our current study aimed to explore the association between serum BDNF and cognitive functions in first-episode drug-naive (FEDN) patients with schizophrenia, which has been under-investigated. We recruited 80 FEDN patients and 80 healthy controls and examined the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and serum BDNF in both groups. Patient psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). BDNF levels were significantly lower in patients compared to controls (p < 0.001). The RBANS total score and nearly all indexes (all p < 0.001) except for visuospatial/constructional index (p > 0.05) were significantly lower in patients than controls. No significant correlation was found between BDNF and any index or total scores of RBANS in either patients or healthy controls (all p > 0.05). However, the PANSS negative subscale score were negatively associated with both the immediate memory and language indexes (both p < 0.005). Our findings suggest that excessive cognitive impairments are present in the early stage of schizophrenia. Low BDNF may contribute to the pathogenesis of schizophrenia, but maybe not to its cognitive impairments. PMID- 29482039 TI - A genetic association study of carotid intima-media thickness (CIMT) and plaque in Mexican Americans and European Americans with rheumatoid arthritis. AB - BACKGROUND AND AIMS: Little is known about specific genetic determinants of carotid-intima-media thickness (CIMT) and carotid plaque in subjects with rheumatoid arthritis (RA). We have used the Metabochip array to fine map and replicate loci that influence variation in these phenotypes in Mexican Americans (MAs) and European Americans (EAs). METHODS: CIMT and plaque were measured using ultrasound from 700 MA and 415 EA patients with RA and we conducted association analyses with the Metabochip single nucleotide polymorphism (SNP) data using PLINK. RESULTS: In MAs, 12 SNPs from 11 chromosomes and 6 SNPs from 6 chromosomes showed suggestive associations (p < 1 * 10-4) with CIMT and plaque, respectively. The strongest association was observed between CIMT and rs17526722 (SLC17A2 gene) (beta +/- SE = -0.84 +/- 0.18, p = 3.80 * 10-6). In EAs, 9 SNPs from 7 chromosomes and 7 SNPs from 7 chromosomes showed suggestive associations with CIMT and plaque, respectively. The top association for CIMT was observed with rs1867148 (PPCDC gene, beta +/- SE = -0.28 +/- 0.06, p = 5.11 * 10-6). We also observed strong association between plaque and two novel loci: rs496916 from COL4A1 gene (OR = 0.51, p = 3.15 * 10-6) in MAs and rs515291 from SLCA13 gene (OR = 0.50, p = 3.09 * 10-5) in EAs. CONCLUSIONS: We identified novel associations between CIMT and variants in SLC17A2 and PPCDC genes, and between plaque and variants from COL4A1 and SLCA13 that may pinpoint new candidate risk loci for subclinical atherosclerosis associated with RA. PMID- 29482041 TI - Rape myth acceptance and rape acknowledgment: The mediating role of sexual refusal assertiveness. AB - Unacknowledged rape, defined as when an individual experiences an event that meets a legal or empirical definition of rape but the individual does not label it as such, is prevalent. Research examining predictors of rape acknowledgment is needed. Sexual assertiveness may be an important variable to consider, as an individual's typical behavior during sexual situations may influence rape acknowledgment. To assess the indirect effect of rape myth acceptance on rape acknowledgment through sexual refusal assertiveness, an online survey of 181 female rape survivors was conducted. The indirect effects of two types of rape myths (He didn't mean to and Rape is a deviant event) were significant and positive. Specifically, acceptance of these two rape myths was negatively related to sexual refusal assertiveness, which was negatively associated with likelihood of rape acknowledgment. The results of this study indicate that sexual refusal assertiveness is associated with lower likelihood of rape acknowledgment among rape survivors. As a result, it appears that, under certain circumstances, women high in rape myth acceptance may be more likely to acknowledge rape when it results in decreased sexual refusal assertiveness. PMID- 29482042 TI - Efficacy of high-frequency repetitive transcranial magnetic stimulation on PANSS factors in schizophrenia with predominant negative symptoms - Results from an exploratory re-analysis. AB - Repetitive transcranial magnetic stimulation (rTMS) applied to the left frontal lobe is discussed to be a promising add-on treatment for negative symptoms in schizophrenia. The Positive and Negative Syndrome Scale (PANSS) has been used as outcome parameter in several previous rTMS trials, but studies focusing on PANSS factor analyses are lacking. For this purpose, we used the available PANSS data of the 'rTMS for the Treatment of Negative Symptoms in Schizophrenia' (RESIS) trial to calculate different literature-based PANSS factors and to re-evaluate the impact of rTMS on negative symptoms in this trial. In an exploratory re analysis of published data from the RESIS study (Wobrock et al. 2015), we tested the impact of rTMS applied to the left dorsolateral prefrontal cortex on two PANSS factors for negative symptoms in psychotic disorders as well as on a PANSS five-factor consensus model intending to show that active rTMS treatment improves PANSS negative symptom subscores. In accordance to the original analysis, all PANSS factors showed an improvement over time in the active and, to a considerable extent, also in the sham rTMS group. However, comparing the data before and directly after the rTMS intervention, the PANSS excitement factor improved in the active rTMS group significantly more than in the sham group, but this finding did not persist if follow-up data were taken into account. These additional analyses extend the previously reported RESIS trial results showing unspecific improvements in the PANSS positive subscale in the active rTMS group. Our PANSS factor-based approach to investigate the impact of prefrontal rTMS on different negative symptom domains confirmed no overall beneficial effect of the active compared to sham rTMS. PMID- 29482043 TI - No major influence of regular tobacco smoking on cerebrospinal fluid monoamine metabolite concentrations in patients with psychotic disorder and healthy individuals. AB - Metabolism of the monoamines dopamine, serotonin and noradrenaline, is altered in the central nervous system of people with schizophrenia, and their major metabolites homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3 methoxy-4-hydroxyphenylglycol (MHPG), respectively, have been intensively studied as indirect measures of these neurotransmitters in cerebrospinal fluid (CSF). Regular tobacco smoking has been shown to alter neurotransmitter metabolism in the brain and studies have found CSF monoamine metabolite concentrations to be substantially lower in smokers. However, few studies investigating these monoamines in CSF have controlled for regular tobacco smoking. We investigated if regular tobacco smoking influences CSF HVA, 5-HIAA and MHPG concentrations in patients treated for psychotic disorders (n = 69) and healthy non-psychotic human volunteers (n = 200). After lumbar puncture CSF samples were analyzed with mass fragmentography. CSF HVA, 5-HIAA and MHPG concentrations did not significantly differ between smokers and non-smokers neither in patients, nor in healthy subjects, whereas back-length predicted HVA and 5-HIAA and antipsychotic medication MHPG concentrations. The results indicate that regular tobacco smoking has no significant effect on monoamine metabolite concentrations in CSF. This suggests that lack of controlling for regular tobacco smoking should not substantially violate the results in studies of the major monoamine metabolites in CSF. PMID- 29482044 TI - Screening for panic-related anxiety in emergency department patients with cardiopulmonary complaints: A comparison of two self-report instruments. AB - The present study examined 1) the accuracy of two self-report measures for detecting panic-related anxiety in emergency department (ED) patients with cardiopulmonary complaints; and 2) whether modified scoring resulted in improved performance. English-speaking adults presenting to the ED of a large public hospital with palpitations, chest pain, dizziness, or difficulty breathing were evaluated for the presence of panic-related anxiety with the Structured Clinical Interview for DSM-IV (SCID) over a one-year period. Patients completed the panic disorder modules of the Patient Health Questionnaire (PHQ-PD) and Psychiatric Diagnostic Screening Questionnaire (PDSQ-PD). Sensitivity, specificity, area under the curve (AUC), and predictive values were compared for various cut-offs and scoring algorithms using SCID diagnosis of panic attacks (in the absence of panic disorder) or panic disorder as the reference standard. In this sample of 200 participants, the majority had a chief complaint of chest pain and 46.5% met SCID criteria for panic-related anxiety. The PDSQ-PD demonstrated only fair operating characteristics for panic attacks (AUC = 0.57) and good operating characteristics for panic disorder (AUC = 0.79). The PHQ-PD achieved adequate operating characteristics (AUC = 0.66) for panic attacks and good operating characteristics for panic disorder (AUC = 0.76) using a modified scoring algorithm or a single screening question (AUC = 0.72). PMID- 29482045 TI - Donor EBV at the time of hematopoietic cell transplantation: Is it time to adopt molecular assays? PMID- 29482047 TI - Clarifying of the potential mechanism of Sinisan formula for treatment of chronic hepatitis by systems pharmacology method. AB - Chronic hepatitis is a general designation class of diseases, which results in different degrees of liver necrosis and inflammatory reaction, followed by liver fibrosis, may eventually develop into cirrhosis. However, the molecular pathogenesis of chronic hepatitis is too complex to elucidate. Herbal medicines, featured with multiple targets and compounds, have long displayed therapeutic effect in treating chronic hepatitis, though their molecular mechanisms of contribution remain indistinct. This research utilized the network pharmacology to confirm the molecular pathogenesis of chronic hepatitis through providing a comprehensive analysis of active chemicals, drug targets and pathways' interaction of Sinisan formula for treating chronic hepatitis. The outcomes showed that 80 active ingredients of Sinisan formula interacting with 91 therapeutic proteins were authenticated. Sinisan formula potentially participates in immune modulation, anti-inflammatory and antiviral activities, even has regulating effects on lipid metabolism. These mechanisms directly or indirectly are involved in curing chronic hepatitis by an interaction way. The network pharmacology based analysis demonstrated that Sinisan has multi-scale curative activity in regulating chronic hepatitis related biological processes, which provides a new potential way for modern medicine in the treatment of chronic diseases. PMID- 29482046 TI - Pharmacological values and therapeutic properties of black tea (Camellia sinensis): A comprehensive overview. AB - Medicinal plants are essential parts of traditional medicine due to their phytochemical constituents having pharmacological values and therapeutic applications. Black tea have thousands of various biological compounds such as flavonoids (Thearubigins (TRs) and theaflavins (TFs) and catechins), amino acids (L.theanine), vitamins (A, C, K), phenolic acids (caffeic acid (CA), gallic acid (GA), chlorogenic acids (CGA) and cauramic acid), lipids, proteins, volatile compounds carbohydrates, beta-carotene and fluoride that illustrated many promising pharmacological effects regarded as growth promoter, cardioprotector, potent cholesterol-lowering effect, antioxidant and antimicrobial, etc inhuman. Although there is an exponential growth in molecular evidence of cholesterol lowering and antioxidant effect in human, there is still a lack of information of the pharmacological effects of black tea. To fill this information gap, therefore, this review article underscores broadening the new insight pertaining to black tea that could be used as safe food additive. This article also illuminates the interesting role of black tea as an herbal medicine that is the future demand to get rid of synthetic health promoters in the human health practice. Moreover, this information would be useful in terms of the low-cost practice of natural medicines with no residual effects, and a natural protection of the human being. In addition, further studies at a molecular level are needed to reveal its mechanism of action particularly for the hypocholesterolemic effect of black tea to overcome the heart-related diseases, fewer side effects and being a natural safeguard of human health. PMID- 29482048 TI - Methylphenidate clinically oral doses improved brain and heart glutathione redox status and evoked renal and cardiac tissue injury in rats. AB - Methylphenidate (MPH) is a first-line stimulant drug to treat attention deficit hyperactivity disorder (ADHD). Overdiagnosis of ADHD and MPH abuse lead to serious concerns about the possible long-term adverse consequences of MPH in healthy children and adolescents. We aimed to evaluate MPH effects in adolescent male Wistar rats (postnatal day 40) using an oral dose scheme (2 daily MPH doses 5 mg/kg in a 5% sucrose solution, 5 h apart, for 7 days) that mimics the therapeutic doses given to human adolescents. Twenty-four hours after the last MPH administration, rats were sacrificed and brain areas [cerebellum, prefrontal cortex (PFC), hippocampus, and striatum], peripheral organs (liver, heart, and kidneys), and blood were collected for biochemical and histological analysis. MPH treatment did not alter rats' body temperature or weight, neither food or water intake throughout the experiment. The ratio of reduced glutathione/oxidized glutathione (GSH/GSSG) significantly increased in the PFC and hippocampus of MPH treated rats, meanwhile protein carbonylation remained unchanged in the brain. In the heart, the GSH/GSSG ratio and GSH levels were significantly increased, with decreased GSSG, while histology revealed significant damage, namely interstitial edema, vascular congestion, and presence of a fibrin-like material in the interstitial space. In the kidneys, MPH treatment resulted in extensive necrotic areas with cellular disorganization and cell infiltration, and immunohistochemistry analysis revealed a marked activation of nuclear factor-KB. This study showed that clinically relevant oral MPH doses improve the GSH redox status in the brain and heart, but evoke heart and kidney tissue damage to adolescent rats. PMID- 29482049 TI - Effect of sodium fluoride on oral biofilm microbiota and enamel demineralization. AB - OBJECTIVE: Fluoride is widely used as an anti-caries agent, e.g. in toothpastes and mouth rinses. However, the nature of the anti-caries action is not entirely clear. Mechanisms suspected to explain the cariostatic effect include inhibitory effects on acid formation by bacteria, inhibition of extracellular polysaccharide (EPS) production, inhibition of enamel demineralization and enhancement of remineralizaton or combination thereof. The aim of this study was to examine with the supragingival Zurich in vitro biofilm model the effect of fluoride in NaF formulation, on the microbiota and on demineralization. METHODS: Biofilms consisting of Actinomyces oris, Candida albicans, Fusobacterium nucleatum, Streptococcus oralis, Veillonella dispar and Streptococcus sobrinus, were grown anaerobically on sintered hydroxyapatite or bovine enamel disks, exposed to 200, 400, and 1400 ppm of NaF, or 0.1% chlorhexidine (positive control). The biofilms were harvested after 64 h and CFUs were assessed for total bacteria. Demineralization of enamel disks was measured by quantitative light-induced fluorescence. RESULTS: NaF did not affect the bacterial numbers. No enamel mineral loss was observed at 1400 and 400 ppm of fluoride, whereas the pH of the surrounding medium was increased to 5.5 and 5.0, respectively, compared to the untreated control (pH 4.5 and mineral loss DeltaF of -32%). At 1400 ppm NaF the biofilm's EPS volume was also significantly reduced. CONCLUSIONS: Administration of NaF completely prevented demineralization without affecting biofilm composition and growth. This protective effect may be attributed to the observed decrease in acid production or EPS volume, or to a shift in the de/remineralization balance. PMID- 29482050 TI - Investigating the psychological resilience, self-confidence and problem-solving skills of midwife candidates. AB - BACKGROUND: The high level of psychological resilience, self-confidence and problem solving skills of midwife candidates play an important role in increasing the quality of health care and in fulfilling their responsibilities towards patients. OBJECTIVES: This study was conducted to investigate the psychological resilience, self-confidence and problem-solving skills of midwife candidates. DESIGN: It is a convenience descriptive quantitative study. SETTINGS: Students who study at Health Sciences Faculty in Turkey's Central Anatolia Region. PARTICIPANTS: Midwife candidates (N = 270). METHODS: In collection of data, the Personal Information Form, Psychological Resilience Scale for Adults (PRSA), Self Confidence Scale (SCS), and Problem Solving Inventory (PSI) were used. RESULTS: There was a negatively moderate-level significant relationship between the Problem Solving Inventory scores and the Psychological Resilience Scale for Adults scores (r = -0.619; p = 0.000), and between Self-Confidence Scale scores (r = -0.524; p = 0.000). There was a positively moderate-level significant relationship between the Psychological Resilience Scale for Adults scores and the Self-Confidence Scale scores (r = 0.583; p = 0.000). There was a statistically significant difference (p < 0.05) between the Problem Solving Inventory and the Psychological Resilience Scale for Adults scores according to getting support in a difficult situation. CONCLUSIONS: As psychological resilience and self confidence levels increase, problem-solving skills increase; additionally, as self-confidence increases, psychological resilience increases too. Psychological resilience, self-confidence, and problem-solving skills of midwife candidates in their first-year of studies are higher than those who are in their fourth year. Self-confidence and psychological resilience of midwife candidates aged between 17 and 21, self-confidence and problem solving skills of residents of city centers, psychological resilience of those who perceive their monthly income as sufficient are high. Psychological resilience and problem-solving skills for midwife candidates who receive social support are also high. The fact that levels of self-confidence, problem-solving skills and psychological resilience of fourth year students are found to be low presents a situation that should be taken into consideration. PMID- 29482051 TI - Computer-delivered indirect screening and brief intervention for drug use in the perinatal period: A randomized trial. AB - BACKGROUND: Under-reporting of drug use in the perinatal period is well documented, and significantly limits the reach of proactive intervention approaches. The Wayne Indirect Drug Use Screener (WIDUS) focuses on correlates of drug use rather than use itself. This trial tested a computer-delivered, brief intervention designed for use with indirect screen-positive cases, seeking to motivate reductions in drug use without presuming its presence. METHODS: Randomized clinical trial with 500 WIDUS-positive postpartum women recruited between August 14, 2012 and November 19, 2014. Participants were randomly assigned to either a time control condition or a single-session, tailored, indirect brief intervention. The primary outcome was days of drug use over the 6 month follow-up period; secondary outcomes included urine and hair analyses results at 3- and 6-month follow-up. All outcomes were measured by blinded evaluators. RESULTS: Of the 500 participants (252 intervention and 248 control), 36.1% of participants acknowledged drug use in the 3 months prior to pregnancy, but 89% tested positive at the 6-month follow-up. Participants rated the intervention as easy to use (4.9/5) and helpful (4.4/5). Analyses revealed no between-group differences in drug use (52% in the intervention group, vs. 53% among controls; OR 1.03). Exploratory analyses also showed that intervention effects were not moderated by baseline severity, WIDUS score, or readiness to change. CONCLUSIONS: The present trial showed no evidence of efficacy for an indirect, single-session, computer-delivered, brief intervention designed as a complement to indirect screening. More direct approaches that still do not presume active drug use may be possible and appropriate. PMID- 29482052 TI - Substance abuse treatment engagement, completion and short-term outcomes in the Western Cape province, South Africa: Findings from the Service Quality Measures Initiative. AB - BACKGROUND: Optimizing the effectiveness of substance use disorder (SUD) treatment is critical in low-and middle-income countries (LMICs) with limited opportunities for SUD treatment. This is the first study to identify targets for interventions to improve the quality of SUD treatment in a LMIC. METHOD: We explored correlates of three indicators of treatment quality (treatment engagement, completion and abstinence at treatment exit) using data from a SUD performance measurement system implemented in the Western Cape Province of South Africa. The sample included data from 1094 adult treatment episodes representing 53% of the treatment episodes in 2016. Using multivariate logistic regression analyses, we modeled socio-demographic, substance use and program correlates of treatment engagement, completion, and abstinence at treatment exit. RESULTS: Overall, 59% of patients completed treatment (48% of patients from outpatient services). Treatment completion was associated with greater likelihood of abstinence at treatment exit. Patients were more likely to complete treatment if they engaged in treatment, were older, and had more severe drug problems (characterized by daily drug use and heroin problems) and attended programs of shorter duration. Residential treatment was associated with greater likelihood of treatment engagement, completion, and abstinence at treatment exit. CONCLUSION: Improving rates of outpatient treatment completion will enhance the effectiveness of South Africa's SUD treatment system. Interventions that promote engagement in treatment, particularly among younger patients; reduce program length through referral to step-down continuing care; and ensure better matching of drug problem to treatment level and type could improve rates of treatment completion. PMID- 29482053 TI - Comparing substance use and mental health outcomes among sexual minority and heterosexual women in probability and non-probability samples. AB - OBJECTIVE: To examine similarities and differences in demographics and key substance use and mental health outcomes in a probability sample of heterosexual women and two samples of sexual minority women (SMW), one recruited using probability and the other using non-probability methods. METHODS: Using data from four waves of the National Alcohol Survey (NAS; n = 315 SMW; 10,523 heterosexual women) and Wave 3 of the Chicago Health and Life Experiences of Women (CHLEW; n = 688 SMW) study, we examined hazardous drinking, drug use, tobacco use, depression, and help-seeking for alcohol or other drug problems. RESULTS: Compared to SMW in the probability sample, SMW in the non-probability sample were older, more likely to be college educated, and more likely to be in a partnered relationship. Compared to heterosexuals, SMW in both the probability and non probability samples had greater odds of past-year hazardous drinking, marijuana use, and other drug use. We found similar results for lifetime help-seeking for alcohol or drug problems, past week depression, and co-occurring hazardous drinking and depression. In comparisons with heterosexual women, the magnitude of difference for drug use was greater for the SMW non-probability sample; for tobacco use, the difference was greater for the SMW probability sample. CONCLUSION: Given the difficulties recruiting probability samples of SMW, researchers will continue to use non-probability samples in the foreseeable future. Thus, understanding how findings may differ between probability and non probability samples is critically important in advancing research on sexual orientation-related health disparities. PMID- 29482054 TI - Sex work, injection drug use, and abscesses: Associations in women, but not men. AB - BACKGROUND: Abscesses commonly occur among people who inject drugs (PWID). However, whether the risks are comparable between males and females, and the impact of sex work on abscess risk is unclear. The goal of this study was to examine the contemporary associations of gender and sex work with the risk of abscesses in PWID. METHODS: Combining data from two cross-sectional studies conducted in the Greater Boston Area with people at risk for HIV and hepatitis C virus (HCV), we used the following inclusion criteria: age 18-45 years and report of illicit or non-prescription drug injection within the 30 days prior to the survey. Information on demographics, injection-mediated risks, and sexual behaviors was collected using Audio Computer-Assisted Self-Interview Software. Multivariable logistic regressions were used to model associations. RESULTS: The study sample included 298 people including 30% were female. Females were more likely than men to report sex work (28% vs. 16%, p = .012) and abscess during their lifetime (55% vs. 37% p = .004). Among the females, engaging in sex work increased by >5-fold the odds of reporting abscesses [Adjusted odds ratio 5.42; 95% CI: 1.27, 23.10]. There was no association between sex work and abscesses among men. DISCUSSION: We found a female-specific association between sex work, injection drug use, and abscesses among PWID. Although the cross-sectional designs precluded causal inferences, longitudinal studies could enhance understanding of gender-associated risks for abscesses and inform the development of harm reduction interventions. PMID- 29482056 TI - Interventional program to reduce both the incidence of anal sphincter tears and rate of Caesarean sections. AB - OBJECTIVE: To estimate the ability of an intensive interventional program to decrease the number of obstetric anal sphincter injuries (OASIS), while simultaneously decreasing the rate of Caesarean sections (CS). STUDY DESIGN: The intervention, which aimed at decreasing the number of OASIS, started with a compulsory tutorial for all the midwives and physicians. At the same time, the clinic initiated a program to decrease the number of CS. We compared the outcomes before and after the intervention by calculating the risk ratios with 95% confidence intervals. The changes in selected outcomes were also tested using the test of relative proportions. The follow-up was extended for 1 year after the intervention. RESULTS: The number of deliveries by CS decreased significantly, as did the number of OASIS in all the subgroups, except for the multi-parous women. The rate of OASIS for instrumental deliveries (mostly by vacuum) decreased significantly (p < 0.003), as compared to pre-interventional period. The number of Grade 4 tears decreased significantly: from 0.4 ruptures per 100 deliveries before the start of the intervention to 0.1 ruptures after the start of the intervention (RR 0.37, 95% CI 0.14-0.98, p = 0.037). However, the OASIS and Grade 4 sphincter injuries increased with forceps delivery. The CS rate decreased from 17.7 to 15.0 per 100 deliveries (RR 0.85, 95% CI 0.78-0.93). The post interventional follow-up period revealed a further decrease in the frequency of OASIS (to 1.28%, p < 0.001) and a stable CS rate (14.2%). CONCLUSION: The intervention significantly decreases the frequency of OASIS, in line with the results obtained for earlier interventions. At the same time, a decrease in CS rate was obtained. PMID- 29482055 TI - Predictors of injecting cessation among a cohort of people who inject drugs in Tijuana, Mexico. AB - INTRODUCTION: Little is known about the cessation of injecting drug use (IDU) among people who inject drugs (PWID) in low and middle-income settings, where access to effective interventions for reducing drug use (e.g., opioid substitution treatment; OST), may be limited. We measured the incidence and identified predictors of IDU cessation among a cohort of PWID in Tijuana, Mexico. METHODS: Data were drawn from 621 participants in Proyecto El Cuete IV, a prospective cohort of PWID recruited in 2011 and interviewed biannually to 2016. A multivariable Extended Cox model was constructed to identify socio-demographic, drug use, risk environment and health-related predictors of IDU cessation (no IDU for >=six months). RESULTS: 141 participants (23%) reported at least one IDU cessation event during follow-up. The crude IDU cessation rate was 7.3 per 100 person-years (95% Confidence Interval [CI]: 6.2-8.7). IDU cessation was negatively associated with injecting at least daily on average and heroin/methamphetamine co-injection in the past six months, and positively associated with testing HIV positive at baseline, being on methadone maintenance therapy in the past six months, and recent arrest. Concern for personal safety was also independently associated with IDU cessation. CONCLUSIONS: The rate of IDU cessation among PWID in Tijuana was low. These findings underscore the importance of expansion of services including OST to help reduce drug use and facilitate IDU cessation for those who wish to do so. In this setting, interventions addressing individual-level economic barriers as well as broader social and structural barriers to harm reduction services are integral. PMID- 29482057 TI - Grape seed proanthocyanidin reverses pulmonary vascular remodeling in monocrotaline-induced pulmonary arterial hypertension by down-regulating HSP70. AB - Heat shock protein 70 (HSP70) is a molecular chaperone which has a low content in cytoplasm under normal physiological conditions. A higher intracytoplasmic HSP70 level can be observed in pulmonary arterial smooth muscle cell (PASMC) in pulmonary arterial hypertension (PAH), and this up-regulation can promote pho IkappaBalpha expression, which is an NF-kappaB signaling pathway inhibitor. NF kappaB signaling pathway up-regulation can promote PASMC proliferation and pulmonary vascular remodeling in PAH, resulting in elevation of pulmonary pressure and the subsequent right heart failure caused by right ventricular hypertrophy. Grape seed proanthocyanidin (GSP) is effective in vascular protection and several tumor treatments, and its effect on PAH treatment remains to be elucidated. In this study, we made observations and contrasts in monocrotaline(MCT) -induced PAH rats, and found decrease in mPAP, PVR and RVHI after GSP administration. Our study also proved GSP's effect on down-regulating the intracytoplasmic HSP70 content both in cellular and animal levels. The results indicate a possible mechanism of GSP reversing pulmonary vascular remodeling by down-regulating HSP70, and this change may influence pho IkappaBalpha expression. Therefore, inhibition of NF-kappaB signaling pathway caused by GSP can lead to inhibition of PASMC proliferation in PAH. PMID- 29482058 TI - Dual function of programmed cell death 10 (PDCD10) in drug resistance. AB - Drug resistance, a major challenge in cancer chemotherapy, is a result of several mechanistic alterations including resistance to apoptosis. Apoptosis is a well controlled cell death mechanism which is regulated by several signaling pathways. Alterations in structure, function, and expression pattern of the proteins involved in the regulation of apoptosis have been linked to drug resistance. Programmed Cell Death 10 (PDCD10) protein is recently associated with the regulation of cell survival and apoptosis. However, the role of PDCD10 in drug resistance has not been clearly established. Here, we aimed to figure out the role of PDCD10 in resistance to anti-cancer agents in different cell lines. We found that PDCD10 expression was cell- and anti-cancer agent-specific; down regulated in doxorubicin- and docetaxel-resistant MCF7 cells while up-regulated in doxorubicin-resistant HeLa cells. Down-regulation of PDCD10 expression by siRNA in parental MCF7 cells increased the resistance while it increased sensitivity in doxorubicin-resistant HeLa cells. Similarly, over-expression of PDCD10 in parental HeLa cells increased the resistance to doxorubicin while it re sensitized doxorubicin-resistant MCF7 cells. Moreover, the alterations in PDCD10 expression led to changes in caspase 3/7 activity and the levels of apoptosis related genes. Our results point out a possible dual role of PDCD10 in drug resistance for the first time in the literature and emphasize PDCD10 as a novel target for reversal of drug resistance in cancer. PMID- 29482060 TI - Inhibition of class IIa histone deacetylase activity by gallic acid, sulforaphane, TMP269, and panobinostat. AB - Histone deacetylase (HDAC) inhibitors are gaining increasing attention as potential therapeutics for cardiovascular diseases as well as cancer. We recently reported that the class II HDAC inhibitor, MC1568, and the phytochemical, gallic acid, lowered high blood pressure in mouse models of hypertension. We hypothesized that class II HDACs may be involved in the regulation of hypertension. The aim of this study was to determine and compare the effects of well-known HDAC inhibitors (TMP269, panobinostat, and MC1568), phytochemicals (gallic acid, sulforaphane, and piceatannol), and anti-hypertensive drugs (losartan, carvedilol, and furosemide) on activities of class IIa HDACs (HDAC4, 5, 7, and 9). The selective class IIa HDAC inhibitor, TMP269, and the pan-HDAC inhibitor, panobinostat, but not MC1568, clearly inhibited class IIa HDAC activities. Among the three phytochemicals, gallic acid showed remarkable inhibition, whereas sulforaphane presented mild inhibition of class IIa HDACs. Piceatannol inhibited only HDAC7 activity. As expected, the anti-hypertensive drugs losartan, carvedilol, and furosemide did not affect the activity of any class IIa HDAC. In addition, we evaluated the inhibitory effect of several compounds on the activity of class l HDACs (HDAC1, 2, 3, and 8) and class IIb HDAC (HDAC6). MC1568 did not affect the activities of HDAC1, HDAC2, and HDAC3, but it reduced the activity of HDAC8 at concentrations of 1 and 10 MUM. Gallic acid weakly inhibited HDAC1 and HDAC6 activities, but strongly inhibited HDAC8 activity with effectiveness comparable to that of trichostatin A. Inhibition of HDAC2 activity by sulforaphane was stronger than that by piceatnnaol. These results indicated that gallic acid is a powerful dietary inhibitor of HDAC8 and class IIa/b HDAC activities. Sulforaphane may also be used as a dietary inhibitor of HDAC2 and class IIa HDAC. Our findings suggest that the class II HDAC inhibitor, MC1568, does not inhibit class IIa HDAC, but inhibits HDAC8. PMID- 29482059 TI - Evaluation of cell toxicity and DNA and protein binding of green synthesized silver nanoparticles. AB - Silver nanoparticles (AgNPs) were prepared by GREEN chemistry relying on the reduction of AgNO3 by phytochemicals present in black tea extract. AgNPs were fully characterized by transmission electron microscopy (TEM), ultraviolet visible spectroscopy ((UV-vis)), X-ray diffraction (XRD) and energy dispersive absorption spectroscopy (EDS). The synthesized AgNPs induced a decrease of the cell viability in a dose-dependent manner with a low IC50 (0.5 +/- 0.1 MUM) for an ovarian carcinoma cell line (A2780) compared to primary human fibroblasts (IC50 5.0 +/- 0.1 MUM). The DNA binding capability of CT (calf thymus) DNA was investigated using electronic absorption and fluorescence spectroscopies, circular dichroism and viscosity titration methods. Additionally, the AgNPs strongly quench the intrinsic fluorescence of BSA, as determined by synchronous fluorescence spectra. PMID- 29482061 TI - Surface modification of nanofibrous matrices via layer-by-layer functionalized silk assembly for mitigating the foreign body reaction. AB - The inherent hydrophobicity and large surface area of electrospun synthetic polymeric scaffolds often cause non-specific protein adsorption, thereby influencing macrophage functions and eventually leading to fibrosis at the tissue scaffold interface. This work reports fabrication of silk fibroin (SF) functionalized electrospun polycaprolactone (PCL) fibers by single-component layer-by-layer assembly and decorate the SF with heparin disaccharide (HD), resulting in the non-covalent binding of interleukin-4 (IL-4) with the capacity to modulate macrophage polarization. A modified SF derivative was obtained by diazonium coupling and then covalently bonded with HD via click chemistry to eventually bind IL-4 efficiently and maintain its bioactivity. In vitro studies showed that IL-4 surface-functionalized nanofibrous scaffolds promoted polarization to M2 macrophages in the short-term. Importantly, in a murine subcutaneous implantation model, we found that promoting transient shifts in macrophage polarization at early stage can significantly inhibit the extent of the late foreign body reactions. Furthermore, the results of a transcriptomic profiling showed that MARK, PI3K, JNK and NF-kappaB signaling pathways played an important role in regulating the macrophage phenotypes in the SF/HD/IL-4 functionalized fibers. Our results suggest that such a strategy offers a new approach for utilizing biological agent surface functionalization to modulate the foreign body reaction to nanofibrous scaffolds. PMID- 29482062 TI - Polymeric nanoparticles encapsulating novel TLR7/8 agonists as immunostimulatory adjuvants for enhanced cancer immunotherapy. AB - Cytotoxic T lymphocytes (CTLs) play a major role in cancer immunotherapy because of their ability to directly kill tumor cells and secrete tumor suppressive cytokines. Anticancer vaccines aim to provoke tumor-specific CTL responses, which require activation of antigen presenting cells (APCs) including dendritic cells (DCs) and macrophages. Therefore, a potent immunostimulatory adjuvant capable of activating APCs is an essential component of anticancer vaccines. In this study, we introduce novel TLR 7/8 bi-specific agonists that significantly enhance cytokine secretion compared to TLR7 mono-selective compounds. Encapsulation of these TLR 7/8 agonists in poly(lactide-co-glycolide) (PLGA) nanoparticles increased the co-stimulatory molecule expression and antigen presentation via MHC I by DCs compared to the soluble agonist. When administered subcutaneously, these nanoparticles migrated to draining lymph node and triggered DC activation and expansion. This lead to expansion of antigen-specific CD8 T cells and enhanced CTL response, which resulted in significant prophylactic and therapeutic efficacy in melanoma, bladder and renal cell carcinoma tumor models. Importantly, our studies demonstrate significant reductions in systemic metastasis with the nanoparticle vaccine. Our results suggest novel TLR 7/8 agonist-encapsulated nanoparticles are potent immunostimulatory adjuvants for cancer immunotherapy. PMID- 29482063 TI - Scales for assessing patient satisfaction with mental health care: A systematic review. AB - BACKGROUND: Patient satisfaction with mental health care has become an important construct in research and routine care. Both as a process measure and as an outcome criterion in its own right, it needs to be assessed with appropriate scales. PURPOSE: To provide a review of scales for assessing patient satisfaction in different settings, their characteristics and the content of care that they cover. METHOD: A systematic search of electronic databases was conducted to identify studies that used a scale to assess patient satisfaction with care in mental health services. Peer reviewed articles were screened by two independent reviewers and included when they met predetermined criteria. Data on the characteristics of scales found in at least two studies were extracted and a qualitative analysis was performed to identify the contents of included scales. RESULTS: Twenty-eight scales were identified. They vary substantially in terms of structure, length, focus and quality. The qualitative analyses identified a total of 19 contents of care that were covered in the scales. The most consistent contents across scales were overall satisfaction, followed by relationship with staff and staff skills. DISCUSSION: A wide range of scales have been used to assess patient satisfaction with mental health care in different settings. Whilst some scales have been frequently used, there is no consensus on a gold standard one. The choice of the most appropriate scale depends on the aim of the assessment, the setting, the content that should be covered, and the time available for the assessment. PMID- 29482064 TI - The health impacts of women's low control in their living environment: A theory based systematic review of observational studies in societies with profound gender discrimination. AB - We conducted a systematic review of observational evidence on the health impacts of women's low control/autonomy in the living environment in societies with profound gender discrimination and gender bias. Thirty observational studies of varying methodological quality were included. Overall, the evidence suggests that women's lower control or autonomy (for example lack of freedom of movement outside the home, lack of authority to access healthcare for sick children) was associated with poorer mental and physical health for women and higher morbidity and mortality for their children, after adjusting for their socioeconomic circumstances. Further studies are needed to disentangle and understand the pathways between low control and health outcomes in contexts of profound gender discrimination. This systematic review has highlighted the general low quality of the evidence base on this research question. It identifies the pressing need for high quality, longitudinal studies in the future. PMID- 29482065 TI - Independence of diabetes and obesity in adults with serious mental illness: Findings from a large urban public hospital. AB - OBJECTIVE: There is limited research on metabolic abnormalities in psychotropic naive patients with serious mental illness (SMI). Our study examined metabolic conditions in a large, ethnically diverse sample of psychotropic-naive and non naive adults with SMI at an urban public hospital. METHODS: In this cross sectional study of 923 subjects, the prevalences of hyperglycemia meeting criteria for type 2 diabetes mellitus (T2DM) based on fasting plasma glucose and obesity defined by BMI and abdominal girth were compared across duration of psychotropic medication exposure. Multiple logistic regression models used hyperglycemia and obesity as dependent variables and age, sex, race/ethnicity, and years on psychotropics as independent variables. RESULTS: Psychotropic-naive patients, including both schizophrenia and non-psychotic subgroups, showed an elevated prevalence of hyperglycemia meeting criteria for T2DM and a decreased prevalence of obesity compared to the general population. Obesity rates significantly increased for those on psychotropic medications more than 5 years, particularly for patients without psychosis (BMI: aOR = 5.23 CI = 1.44-19.07; abdominal girth: aOR = 6.40 CI = 1.98-20.69). Women had a significantly higher obesity rate than men (BMI: aOR = 1.63 CI = 1.17-2.28; abdominal girth: aOR = 3.86 CI = 2.75-5.44). Asians had twice the prevalence of hyperglycemia as whites (aOR = 2.29 CI = 1.43-3.67), despite having significantly less obesity (BMI: aOR = .39 CI = .20-.76; abdominal girth: aOR = .34 CI = .20-.60). Hispanics had a higher rate of obesity by BMI than whites (aOR = 1.91 CI = 1.22-2.99). CONCLUSIONS: This study showed disparities between obesity and T2DM in psychotropic-naive patients with SMI, suggesting separate risk pathways for these two metabolic conditions. PMID- 29482066 TI - Uncontrolled burning of solid waste by households in Mexico is a significant contributor to climate change in the country. AB - Uncontrolled burning of municipal solid waste (MSW) is an important source of air pollution and is wide spread in many developing countries, but only limited data quantify the extent of domestic open burning of household waste. Here, we present some of the first field data to be reported on the uncontrolled domestic burning of waste. A representative community of Mexico (Huejutla de Reyes Municipality) was investigated and household surveys, interviews with waste operators and a waste characterisation analysis were completed to assess the extent of, and factors controlling, the open burning of waste. Waste collection provision to rural communities was very limited and, consequently 92% of households in rural areas reported that they disposed of waste by uncontrolled burning in backyards or unofficial dumps. Overall, 24% of the total MSW generated in the Municipality was disposed by uncontrolled burning. Urban and periurban areas received twice weekly collections and the rate of uncontrolled burning was considerably smaller compared to rural households, corresponding to approximately 2% of total waste generation. Carbon equivalency calculations showed that burning waste in backyards represented approximately 6% of the total and 8.5% of fuel related CO2Eq emissions by the municipality. Moreover, the equivalent carbon dioxide (CO2Eq) from black carbon (BC) emitted by uncontrolled burning in backyards was over fifteen times larger compared to methane (CH4) potentially released from equivalent amounts of combustible biodegradable waste disposal at the official dumpsite. An assessment of local respiratory health data showed the incidence of disease was higher in rural than in urban areas, when the opposite trend is typically observed in the international literature; given the high rate of burning activity found in rural areas we suggest that open burning of waste could be a major reason for the apparent poorer respiratory health status of the rural population and requires further investigation. The results emphasise the importance of including BC from uncontrolled burning of waste in international emission inventories of greenhouse gases and in the assessment of the health status of local communities in developing countries where this practice is prevalent. PMID- 29482067 TI - Influence of geometry on proximal femoral shaft strains: Implications for atypical femoral fracture. AB - INTRODUCTION: Atypical femoral fractures (AFF) are characterized as low-energy fractures of the femoral shaft or subtrochanteric region. Femoral geometry is known to play a role in AFF risk; it is hypothesized that high-risk geometries are associated with elevated femoral shaft strain. However, it is not well known which geometric parameters have the greatest effect on strain, or whether interaction between parameters is significant. The purpose of this study was to thoroughly quantify the relationship between femoral geometry and diaphyseal strain, using patient specific finite element (FE) modelling in concert with parametric mesh morphing. METHODS: Ten FE models were generated from computed tomography (CT) images of cadaveric femora. Heterogeneous material properties were assigned based on average CT intensities at element locations and models were subject to loads and boundary conditions representing the stance phase of gait. Mesh morphing was used to manipulate 8 geometric parameters: neck shaft angle (NSA), neck version angle (NV), neck length (NL), femoral length (FL), lateral bowing angle (L.Bow), anterior bowing angle (A.Bow), shaft diameter (S.Dia), and cortical bone thickness (C.Th). A 2-Level full factorial analysis was used to explore the effect of different combinations of physiologically realistic minimum and maximum values for each parameter. Statistical analysis (Generalized Estimating Equations) was used to assess main effects and first order interactions of each parameter. RESULTS: Six independent parameters and seven interaction terms had statistically significant (p<0.05) effects on peak strain and strained volume. For both measures, the greatest changes were caused by S.Dia, L.Bow, and A.Bow, and/or first order interactions involving two of these variables. CONCLUSIONS: As hypothesized, a large number of geometric measures (six) and first order interactions (seven) are associated with changes in femoral shaft strain. These measures can be evaluated radiographically, which may have important implications for future studies investigating AFF risk in clinical populations. PMID- 29482068 TI - Cortical bone loss due to skeletal unloading in aldehyde dehydrogenase 2 gene knockout mice is associated with decreased PTH receptor expression in osteocytes. AB - Aldehyde dehydrogenase 2 (ALDH2) is the enzyme that degrades and detoxifies the acetaldehyde produced by alcohol metabolism. In our previous study, we found that compared with wild-type mice (WT), climbing exercises did not increase trabecular bone mass in Aldh2 knockout mice (KO). The purpose of this study was to clarify the effect of the Aldh2 gene on cortical bone structure and on the dynamics of skeletal unloading. Eight-week-old male KO and WT were divided into ground control (GC) or tail suspension (TS) groups for one week (i.e., the KOGC, KOTS, WTGC and WTTS groups). We measured the bone mineral density (BMD) of the femur using dual-energy X-ray absorptiometry. We assessed the femoral morphometry using peripheral quantitative computed tomography (pQCT) and evaluated the femoral cortex histomorphometry, and cortical mRNA using quantitative RT-PCR and cortical bone immunohistostaining. No significant differences were found between the femoral BMD of WTGC and that of WTTS, but the BMD in KOTS was significantly lower than that of KOGC. The pQCT results revealed that the cortical BMD of the femoral diaphysis in KOTS was significantly lower than that of KOGC. Furthermore, the cortical bone area and cortical thickness were significantly lower in KOTS than in the other three groups. Cortical histomorphometric analysis revealed that the endosteal and periosteal bone formation parameters were significantly lower in KOTS than in KOGC. Bone formation signals such as parathyroid hormone receptor (PTHR) were significantly decreased in KOTS compared with the levels in KOGC. Cortical bone immunohistostaining revealed a significantly decreased expression of PTHR in the osteocytes of KOTS compared with the expression level in KOGC. Thus, we concluded that when the Aldh2 gene is disrupted, skeletal unloading suppresses bone formation to decrease cortical bone mass, which may be mediated by a decreased expression of PTH receptors in osteocytes. PMID- 29482069 TI - Growth and physiological responses of two phenotypically distinct accessions of centipedegrass (Eremochloa ophiuroides (Munro) Hack.) to salt stress. AB - Salinity is one of the major abiotic environmental stress factors affecting plant growth and development. Centipedegrass (Eremochloa ophiuroides [Munro)] Hack.) is an important warm-season turfgrass species with low turf maintenance requirements, but is sensitive to salinity stress. To explore salt tolerant germplasms in centipedegrass and better understand the growth and physiological responses of centipedegrass to salinity, we conducted anatomic observation and phytochemical quantification, examined growth parameters, and investigated photosynthetic machinery and antioxidant system in two phenotypically distinct centipedegrass accessions under NaCl salt stress. The morphophenotypical difference of the stems in the two accessions mainly depends on whether or not a thickened epidermal horny layer with purple colour was formed, which was caused by anthocyanin accumulation in the tissue. Successive salinity treatment was found to result in an inhibition of leaf growth, a marked decrease in photosynthesis, chlorophyll contents, and the maximal photochemical efficiency of PSII (Fv/Fm). Under the same treatment, purple-stem accession (E092) showed a lower degree of inhibition or decrease than green-stem one (E092-1). With the exception of malondialdehyde level, both proline content and antioxidant enzymes were upregulated to a greater extent in E092 following exposure to salinity condition. Meanwhile, significant enhancements of anthocyanin accumulation and total protein synthesis were detected in E092 after salt treatment, but not in E092-1. These results demonstrated that E092 favor better accumulation of anthocyanins under salinity condition, which contribute to salt tolerance by adjusting physiological functions and osmotic balance, and better maintenance of high turf quality. Hence, genetic phenotype can be utilized as a key indicator in E. ophiuroides breeding for salt-tolerance. PMID- 29482070 TI - Transcription profile analysis of Lycopersicum esculentum leaves, unravels volatile emissions and gene expression under salinity stress. AB - Salinity stress can impede development and plant growth adversely. However, there is very little molecular information on NaCl resistance and volatile emissions in Lycopersicum esculentum. In order to investigate the effects of salt stress on the release of volatile compounds, we quantified and compared transcriptome changes by RNA-Seq analysis and volatile constituents with gas chromatography/mass spectrometry (GC/MS) coupled with solid-phase microextraction (SPME) after exposure to continuous salt stress. Chemical analysis by GC-MS analysis revealed that NaCl stress had changed species and quantity of volatile compounds released. In this research, 21,578 unigenes that represented 44,714 assembled unique transcripts were separated from tomato leaves exposed to NaCl stress based on de novo transcriptome assembly. The total number of differentially expressed genes was 7210 after exposure to NaCl, including 6200 down-regulated and 1208 up-regulated genes. Among these differentially expressed genes (DEGs), there were eighteen differentially expressed genes associated with volatile biosynthesis. Of the unigenes, 3454 were mapped to 131 KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, mainly those are involved in RNA transport, plant-pathogen interactions, and plant hormone signal transduction. qRT-PCR analysis showed that NaCl exposure affected the expression profiles of the biosynthesis genes for eight volatile compounds (IPI, GPS, and TPS, etc.), which corresponded well with the RNA-Seq analysis and GC-MS results. Our results suggest that NaCl stress affects the emission of volatile substances from L. esculentum leaves by regulating the expression of genes that are involved in volatile organic compounds' biosynthesis. PMID- 29482071 TI - Evidence of Subpopulations with Distinct Biological Features Within a Leishmania (Viannia) braziliensis Strain. AB - The present study demonstrates that the Leishmania (Viannia) braziliensis strain MCAN/BR/1998/R619 is composed of multiple subpopulations with measurable distinctions. Single parasites were separated from a culture of promastigotes in stationary phase by cell sorting and then cultivated as subpopulations. Subsequently, these subpopulations were evaluated for features of in vitro growth, infectivity to murine macrophages and proteinase gene expression. The first evidence of distinct characteristics was observed during the in vitro cultivation of isolated subpopulations, as distinct clusters of patterns were formed among the cultures, indicating the existence of quantifiable fluctuations in metrics. Further, when infecting murine macrophages, the subpopulations induced distinct patterns of production of immune response mediators. While some subpopulations mainly induced the production of IL-1beta, IL-6 and TNF-alpha, others induced the production of IL-12p70 and nitric oxide. Finally, amastigotes of these subpopulations had higher expression of proteinase genes than promastigotes. Additionally, cysteine proteinase, serine proteinase, metalloproteinase and aspartic proteinases were differentially expressed in promastigote and amastigote forms. These data suggest the existence of distinct profiles for the L. (V.) braziliensis MCAN/BR/1998/R619 strain and subpopulations that could drive the success of parasite adaptation to the environments that they inhabit. PMID- 29482072 TI - The roles of human MTH1, MTH2 and MTH3 proteins in maintaining genome stability under oxidative stress. AB - The hydrolysis of nucleotides containing 8-oxo-7,8-dihydroguanine (8-oxoG) is important in the maintenance of genome stability. Human cells possess three types of proteins, MTH1 (NUDT1), MTH2 (NUDT15) and MTH3 (NUDT18), which have the potential to hydrolyze deoxyribonucleoside di- and triphosphates containing 8 oxoG to the monophosphate, the form of which is unusable for DNA synthesis. To elucidate the physiological roles of these enzymes, we constructed single knockout (KO) cell lines for each of the MTH1, MTH2 and MTH3 genes and MTH1 and MTH2-double KO cell lines from the human HeLa S3 line using CRISPR/Cas9. With the exception of MTH3-KO, all of the KO cell lines showed similar proliferation rates to the parental line, HeLa S3, indicating that the MTH1 and MTH2 functions are dispensable for cell growth. On the other hand, the MTH3-KO cells showed a significantly slower growth rate, suggesting that MTH3 has a definite role in cell growth in addition to the cleavage of 8-oxoG-containing deoxyribonucleotide. MTH1-KO, MTH2-KO and MTH1- MTH2-KO cells exhibited increased sensitivity to hydrogen peroxide, whereas MTH3-KO did not. MTH1-KO cells showed only a slight increase in mutant frequency in comparison to the parental HeLa S3 line. The overproduction of MTH1 and MTH2 suppressed the mutator phenotype of mutT deficient E. coli cells, whereas the overproduction of MTH3 did not show such a suppressive effect. Our findings suggest that both MTH1 and MTH2 are involved in the maintaining genome stability in human cells against oxidative stress, while MTH3 may play some other role(s). PMID- 29482073 TI - NOTCH1 modulates activity of DNA-PKcs. AB - DNA-dependent protein kinase catalytic subunit (DNA-PKcs) controls one of the most frequently used DNA repair pathways in a cell, the non-homologous end joining (NHEJ) pathway. However, the exact role of DNA-PKcs in NHEJ remains poorly defined. Here we show that NOTCH1 attenuates DNA-PKcs-mediated autophosphorylation, as well as the phosphorylation of its specific substrate XRCC4. Surprisingly, NOTCH1-expressing cells do not display any significant impairment in the DNA damage repair, nor cellular survival, and remain sensitive to small molecule DNA-PKcs inhibitor. Additionally, in vitro DNA-PKcs kinase assay shows that NOTCH1 does not inhibit DNA-PKcs kinase activity, implying that NOTCH1 acts on DNA-PKcs through a different mechanism. Together, our set of results suggests that NOTCH1 is a physiological modulator of DNA-PKcs, and that it can be a useful tool to clarify the mechanisms by which DNA-PKcs governs NHEJ DNA repair. PMID- 29482074 TI - A change in structural integrity of c-Kit mutant D816V causes constitutive signaling. AB - Several signaling pathways, ligands, and genes that regulate proliferative and self-renewal properties of the Hematopoietic Stem Cells (HSCs) have been studied meticulously. One of the signaling pathways that play a crucial role in the process of hematopoiesis is the Stem Cell Factor (SCF) mediated c-Kit pathway. The c-Kit is a Receptor Tyrosine Kinase (RTK), which is expressed in the cells including HSCs. It undergoes dimerization upon binding with its cognate ligand SCF. As a result, phosphorylation of the Juxtamembrane (JM) domain of c-Kit takes place at Tyr568 and Tyr570 residues. These phosphorylated residues become the docking sites for protein tyrosine phosphatases (PTPs) namely SHP-1 and SHP-2, which in turn cause dephosphorylation and negative regulation of the downstream signaling responsible for the cell proliferation. Interestingly, it has been reported that the mutation of c-Kit at D816V makes it independent of SCF stimulation and SHP-1/SHP-2 inhibition, thereby, causing its constitutive activation. The present study was commenced to elucidate the structural behavior of this mutation in the JM and A-loop region of c-Kit using Molecular Dynamics (MD) simulations of the wild-type and mutant c-Kit in unphosphorylated and phosphorylated states. The energy difference computed between the wild type and mutant (D816V) c-Kit, and protein-protein docking and complex analysis revealed the impact of this single residue mutation on the integrity dynamics of c-Kit that makes it independent of SHP-1/SHP-2 negative regulation. PMID- 29482075 TI - Metoprolol induces oxidative damage in common carp (Cyprinus carpio). AB - During the last decade, beta-blockers such as metoprolol (MTP) have been frequently detected in surface water, aquatic systems and municipal water at concentrations of ng/L to MUg/L. Only a small number of studies exist on the toxic effects induced by this group of pharmaceuticals on aquatic organisms. Therefore, the present study aimed to evaluate the oxidative damage induced by MTP in the common carp Cyprinus carpio, using oxidative stress biomarkers. To this end, indicators of cellular oxidation such as hydroperoxide content (HPC), lipid peroxidation (LPX) and protein carbonyl content (PCC) were determined, as well as the activity of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT). Also, concentrations of MTP and its metabolite O-desmethyl metoprolol were determined in water as well as carp gill, liver, kidney, brain and blood, along with the partial uptake pattern of these compounds. Results show that carp takes up MTP and its metabolite in the different organs evaluated, particularly liver and gill. The oxidative stress biomarkers, HPC, LPX, and PCC, as well as SOD and CAT activity all increased significantly at most exposure times in all organs evaluated. Results indicate that MTP and its metabolite induce oxidative stress on the teleost C. carpio and that the presence of these compounds may constitute a risk in water bodies for aquatic species. PMID- 29482076 TI - Effects of atrazine on vitellogenesis, steroid levels and lipid peroxidation, in female red swamp crayfish Procambarus clarkii. AB - Atrazine, a widely use herbicide, has been classified as a potential endocrine disruptor, especially for freshwater species. In this study, we tested the hypothesis that atrazine can affect reproduction in crayfish through dysregulation of vitellogenin expression and hormone synthesis. Adult female crayfish (Procambarus clarkii) were exposed during one month to atrazine at concentrations of either 1 or 5 mg/L. At the end of the exposure, ovaries, hepatopancreas, and hemolymph samples were harvested for analysis of vitellogenin expression and steroid hormone levels. Ovarian tissue was also sampled for both biochemical and histological analyses. Our results show that atrazine-exposed crayfish had a lower expression of vitellogenin in the ovary and hepatopancreas, as well as smaller oocytes, and reduced vitellogenin content in the ovary. Despite these effects, circulating levels of estradiol increased in females exposed to 5 mg/L of atrazine, showing that the inhibiting effect of atrazine on vitellogenin production was not related to a lower secretion of sexual steroids. Instead, some early stimulating effects of estradiol on vitellogenesis could have occurred, particularly in the hepatopancreas. On the other hand, atrazine caused a higher metabolic effort, in terms of lactate production, presumably triggered to provide the energy needed to face the unspecific stress produced by the herbicide. Lipid peroxidation was not affected by atrazine, but glutathione levels were significantly increased. PMID- 29482078 TI - Assessment of intraspecies variability in fungal growth initiation of Aspergillus flavus and aflatoxin B1 production under static and changing temperature levels using different initial conidial inoculum levels. AB - Intraspecies variability in fungal growth and mycotoxin production has important implications for food safety. Using the Bioscreen C we have examined spectrophotometrically intraspecies variability of A. flavus using 10 isolates under different environments, including temperature shifts, in terms of growth and aflatoxin B1 (AFB1) production. Five high and five low AFB1 producers were examined. The study was conducted at 5 isothermal conditions (from 15 to 37 degrees C) and 4 dynamic scenarios (between 15 and 30 degrees C). The experiments were carried out in a semisolid YES medium at 0.92 aw and two inoculum levels, 102 and 103 spores/mL. The Time to Detection (TTD) of growth initiation was determined and modelled as a function of temperature through a polynomial equation and the model was used to predict TTD under temperature upshifts conditions using a novel approach. The results obtained in this study have shown that a model can be developed to describe the effect of temperature upshifts on the TTD for all the studied isolates and inoculum levels. Isolate variability increased as the growth conditions became more stressful and with a lower inoculum level. Inoculum level affected the intraspecies variability but not the repeatability of the experiments. In dynamic conditions, isolate responses depended both on the temperature shift and, predominantly, the final temperature level. AFB1 production was highly variable among the isolates and greatly depended on temperature (optimum temperature at 30-35 degrees C) and inoculum levels, with often higher production with lower inoculum. This suggests that, from an ecological point of view, the potential isolate variability and interaction with dynamic conditions should be taken into account in developing strategies to control growth and predicting mycotoxin risks by mycotoxigenic fungi. PMID- 29482077 TI - Short telomeres - A hallmark of heritable cardiomyopathies. AB - Cardiovascular diseases are the leading cause of death worldwide and the incidence increases with age. Genetic testing has taught us much about the pathogenic pathways that drive heritable cardiomyopathies. Here we discuss an unexpected link between shortened telomeres, a molecular marker of aging, and genetic cardiomyopathy. Positioned at the ends of chromosomes, telomeres are DNA repeats which serve as protective caps that shorten with each cell division in proliferative tissues. Cardiomyocytes are an anomaly, as they are largely non proliferative post-birth and retain relatively stable telomere lengths throughout life in healthy individuals. However, there is mounting evidence that in disease states, cardiomyocyte telomeres significantly shorten. Moreover, this shortening may play an active role in the development of mitochondrial dysfunction central to the etiology of dilated and hypertrophic cardiomyopathies. Elucidation of the mechanisms that underlie the telomere-mitochondrial signaling axis in the heart will provide fresh insights into our understanding of genetic cardiomyopathies, and could lead to the identification of previously uncharacterized modes of therapeutic intervention. PMID- 29482079 TI - On the origin of epileptic High Frequency Oscillations observed on clinical electrodes. AB - OBJECTIVE: In this study we aim to identify the key (patho)physiological mechanisms and biophysical factors which impact the observability and spectral features of High Frequency Oscillations (HFOs). METHODS: In order to accurately replicate HFOs we developed virtual-brain/virtual-electrode simulation environment combining novel neurophysiological models of neuronal populations with biophysical models for the source/sensor relationship. Both (patho)physiological mechanisms (synaptic transmission, depolarizing GABAA effect, hyperexcitability) and physical factors (geometry of extended cortical sources, size and position of electrodes) were taken into account. Simulated HFOs were compared to real HFOs extracted from intracerebral recordings of 2 patients. RESULTS: Our results revealed that HFO pathological activity is being generated by feed-forward activation of cortical interneurons that produce fast depolarizing GABAergic post-synaptic potentials (PSPs) onto pyramidal cells. Out of phase patterns of depolarizing GABAergic PSPs explained the shape, entropy and spatiotemporal features of real human HFOs. CONCLUSIONS: The terminology "high frequency oscillation" (HFO) might be misleading as the fast ripple component (200-600 Hz) is more likely a "high-frequency activity" (HFA), the origin of which is independent from any oscillatory process. SIGNIFICANCE: New insights regarding the origins and observability of HFOs along depth-EEG electrodes were gained in terms of spatial extent and 3D geometry of neuronal sources. PMID- 29482080 TI - A case report of large gastric diverticulum with literature review. AB - INTRODUCTION: A gastric diverticulum is a rare form of diverticular disease due to outpouching of the gastric wall. It is equally presented within both sexes and commonly occurs in fifth and sixth decades of life. Patients mostly asymptomatic but may present with mild gastric symptoms. Surgical treatment is largely dependent on the patient's symptoms, and a laparoscopic approach is usually recommended for surgery. CASE PRESENTATION: A 77-year-old gentleman presented to the outpatient clinic with a one-month history of passing black stools. He was arranged for an oesophagogastroduodenoscopy (OGD) which revealed a gastric body polyp and a diverticulum in the fundus of the stomach. DISCUSSION: Gastric diverticulum is defined as an outpouching of the gastric wall. They are uncommon, with an incidence between 0.01-0.11%. Predisposing factors include: areas of weakness caused by splitting of the longitudinal muscle fibres, an absence of peritoneal membrane and perforating arterioles. The management of patients with gastric diverticulum depend largely on their symptoms. There is no specific treatment required for an asymptomatic diverticulum. CONCLUSION: Gastric diverticula are rare conditions which are largely asymptomatic but may present with varying signs and symptoms and may require surgical intervention. PMID- 29482081 TI - Benign osseous metaplasia of the breast: Case report. AB - INTRODUCTION: Benign Osseous metaplasia of the breast is rare, with only a few cases reported in the literature. Here we present a case of benign osseous metaplasia of the breast presenting as a breast lump. CASE PRESENTATION: 38-year old previously well woman presented with a one-year history of bilateral breast pain and a left-sided breast lump. Ultrasound and mammography suggested calcified fibroadenoma. An ultrasound-guided true cut biopsy revealed fibrous tissue containing foci of adenosis in the presence of a myoepithelial cell layer. Excision biopsy was performed, and histopathological examination showed bone matrix deposition occupying most of the nodule with peripheral hyalinized tissue but no evidence of malignancy. A diagnosis of benign osseous metaplasia of the breast was made, and the patient recovered well without recurrence after lump excision. DISCUSSION: Only a few cases of osseous metaplasia are reported in the literature. Most reported cases are malignant, such as in fibrosarcoma, malignant mesenchymoma, osteoid sarcoma, osteogenic sarcoma, and osteochondrosarcoma.Very few cases of osseous sarcoma are reported in benign lesions such as fibroadenoma, pleomorphic adenoma, benign mesenchymoma, phyllodes tumor, and amyloid tumor of the breast. Joshi et al. first reported a case of benign osseous metaplasia of the breast presenting as breast lump in an HIV-positive patient [18]. We, therefore, consider this case to be the second case report of benign osseous metaplasia of the breast presenting as a breast lump, but the patient had no chronic illness. CONCLUSION: A breast lump can be the first presentation of benign osseous metaplasia. PMID- 29482082 TI - Metastatic gastric adenocarcinoma and synchronous carcinoid tumour mimicking appendicitis: A case report. AB - INTRODUCTION: Silent metastatic gastric adenocarcinoma presenting as appendicitis is very rare. Rare pathologies may be encountered during common operations such as appendicectomy and an awareness of possible alternative pathological entities would be helpful in a surgeon's wealth of knowledge. PRESENTATION OF CASE: A 63 year-old man presented with a three-day history of acute abdominal pain suggestive of appendicitis. Intra-operatively, a macroscopically inflamed and perforated appendix was found. There were however some atypical features, which included multiple inflamed ulcerated lesions throughout the small bowel mesentery and along the terminal ileum. Appendicectomy was performed and biopsies of these lesions were taken. Subsequent histopathology revealed that there were metastatic deposits of poorly differentiated adenocarcinoma in the appendix and mesenteric biopsies, as well as a neuroendocrine (carcinoid) tumour of the appendix. Upper endoscopy confirmed a gastric primary leading to peritoneal dissemination. The patient was scheduled to undergo a course of palliative chemotherapy. DISCUSSION: Metastatic gastric adenocarcinomas with peritoneal dissemination have a very poor prognosis and often the first choice of treatment is chemotherapy as a complete cure through surgery is often not feasible. As for classical carcinoid tumours smaller than 2 cm towards the tip of the appendix with low proliferative index and without angiolymphatic or mesoappendiceal extension, then appendicectomy alone is indicated. Synchronous neoplastic pathologies presenting as appendicitis is largely unknown. CONCLUSION: To our knowledge, this is the first report in the literature of synchronous carcinoid tumour and metastatic gastric cancer co existing within an inflamed appendix. PMID- 29482083 TI - Using relative phase analyses and vector coding to quantify Pelvis-Thorax coordination during lifting-A methodological investigation. AB - Low-back disorder risk can be modulated by pelvis-thorax coordination when lifting. To objectively discriminate between coordination patterns during lifting, the analytical methods used require evaluation. The primary study objective was to determine if continuous relative phase (CRP) and vector coding (VC) analyses can discriminate between lifting techniques that differ based on biomechanical risk criteria. The secondary objective was to determine if normalization/transformation of input segmental angular position and velocity data is required to discriminate between lifting techniques. Sixteen volunteers performed a sagittal lifting task using freestyle (FRE), flexed spine (FLX), and neutral spine (NTL) techniques. CRP and VC analyses were implemented to quantify pelvis-thorax coordination patterns based on time-normalized, phase-normalized, and Hilbert-transformed segmental angular kinematic data. Mean relative phase angles along with thorax-only and in-phase coupling patterns were significantly different between FRE-NTL and FLX-NTL techniques (p < 0.01), but not FRE-FLX (p > 0.44). This finding was consistent across all relative phase normalization/transformation methods. Therefore, CRP and VC analyses successfully discriminated between different lifting techniques, regardless of the relative phase normalization/transformation method used. PMID- 29482084 TI - Electromyographic findings in sporadic inclusion body myositis. AB - INTRODUCTION: Clinically oriented diagnostic criteria can be as specific for diagnosis of sporadic inclusion body myositis (sIBM) as pathological criteria, especially at the time of presentation. EMG may provide an convincing proof that a muscle biopsy should be performed. AIMS: To compare the EMG results in patients with sIBM divided into subgroups based on the newest ENMC criteria for sIBM and to obtain the utility of EMG in the diagnostic process at the time of presentation. METHODS: We retrospectively analysed 16 patients with sIBM for motor unit action potential (MUAP) morphology as well as occurrence and distribution of abnormal spontaneous activity (SA) in muscles. RESULTS: Abnormal SA was recorded in 62.5% of sIBM patients. We found statistically significant differences between subgroups in the incidence of polyphasic MUAPs and high amplitude outliers which were more commonly seen in the "clinico-pathologically defined sIBM". Duration of MUAP in the tibialis anterior was significantly shorter in "probable sIBM". DISCUSSION: "Pseudo-neurogenic" MUAPs, mainly in lower limb muscles, are more commonly seen in "clinico-pathologically defined sIBM" while myopathic MUAPs with prominent abnormal SA are recorded in patients diagnosed with "probable sIBM". Both EMG patterns may be suggestive of sIBM and be an indication for further diagnosis. PMID- 29482085 TI - Neural control of parental behaviors. AB - Parenting is a multicomponent social behavior that is essential for the survival of offspring in many species. Despite extensive characterization of individual brain areas involved in parental care, we do not fully understand how discrete aspects of this behavior are orchestrated at the neural circuit level. Recent progress in identifying genetically specified neuronal populations critical for parenting, and the use of genetic and viral tools for circuit-cracking now allow us to deconstruct the underlying circuitry and, thus, to elucidate how different aspects of parental care are controlled. Here we review the latest advances, outline possible organizational principles of parental circuits and discuss future challenges. PMID- 29482086 TI - Laparoscopic splenectomy for a simultaneous wandering spleen along with an ectopic accessory spleen. Case report and review of the literature. AB - BACKGROUND: Wandering spleen and accessory spleen are uncommon entity occurring during embryonic development. Wandering spleen results in an excessive mobility and migration of the spleen from its normal position in the left hypochondrium while accessory spleen is characterized by ectopic splenic masses or tissue disjointed from the main body of spleen. Due to the nonspecific and multiple symptoms the clinical diagnosis of both conditions is uncertain even with imaging techniques, such as CT and MRI. The coexistence of both diseases (wandering spleen ad accessory spleen) is uncommon. CASE REPORT: A 17-year old European female with a history of minor beta thalassemia and recurrent attacks of abdominal pain. Pre- operative management consisted of routine laboratory tests, ultrasound, CT scan. An ectopic spleen along with an accessory spleen were diagnosed. After a multidisciplinary board a laparoscopic splenectomy was performed. Post-operative recovery was uneventful, and the patient was discharged on the 6th post-operative day with the indication to continue the therapy with low molecular weight heparin (LMWH) for 30 days CONCLUSIONS: This case represents a simultaneous condition of wandering splenomegaly along with an ectopic wandering spleen. The coexistence of these two rare conditions is peculiar such as the age of the patient, as literature reports such diseases to affect children or more commonly people in the range of 20-40 years of age. Laparoscopic treatment for this particular condition is also unusual. PMID- 29482087 TI - The impact of hip implant alignment on muscle and joint loading during dynamic activities. AB - BACKGROUND: Component alignment is an important consideration in total hip arthroplasty. The impact of changes in alignment on muscle forces and joint contact forces during dynamic tasks are not well understood, and have the potential to influence surgical decision making. The objectives of this study were to assess the impact of femoral head/stem and cup component placement on hip muscle and joint contact forces during tasks of daily living and to identify which alignment parameters have the greatest impact on joint loading. METHODS: Using a series of strength-calibrated, subject-specific musculoskeletal models of patients performing gait, sit-to-stand and step down tasks, component alignments were perturbed and joint contact and muscle forces evaluated. FINDINGS: Based on the range of alignments reported clinically, variation in head/stem anteversion retroversion had the largest impact of any degree of freedom throughout all three tasks; average contact forces 413.5 (319.1) N during gait, 262.7 (256.4) N during sit to stand, and 572.7 (228.1) N during the step down task. The sensitivity of contact force to anteversion-retroversion of the head/stem was 31.5 N/ degrees for gait, which was similar in magnitude to anterior-posterior position of the cup (34.6 N/m for gait). Additionally, superior-inferior cup alignment resulted in 16.4 (4.9) degrees of variation in the direction of the hip joint contact force across the three tasks, with the most inferior cup placements moving the force vector towards the cup equator at the point of peak joint contact force. INTERPRETATION: A quantitative understanding of the impact and potential tradeoffs when altering component alignment is valuable in supporting surgical decision making. PMID- 29482088 TI - Asymmetrical time-to-contact error with two moving objects persists across different vertical separations. AB - When human observers estimate the time-to-contact (TTC) of more than one object there is an asymmetric pattern of error consistent with prioritizing the lead object at the expense of the trail object. Here, we examined TTC estimation in a prediction motion task where two objects moved along horizontal trajectories (5 or 7.5 degrees /s) that had different vertical separation, and thus placed specific demands on visuospatial attention. Results showed that participants were able to accurately judge arrival order, irrespective of vertical separation, in all but two conditions where the object trajectories crossed close to the arrival location. Constant error was significantly higher for the object that trailed, as opposed to led, by 250 or 500 ms. Asymmetry in constant error between the lead and trail object was not influenced by vertical separation, and was also evident across a range of arrival times. However, while the lag between the two consecutive TTC estimations was scaled to the actual difference in object arrival times, lag did increase with vertical separation. Taken together, our results confirm that TTC estimation of two moving objects in the prediction motion task suffers from an asymmetrical interference, which is likely related to factors that influence attentional allocation. PMID- 29482089 TI - Positive, negative, or all relative? Evaluative conditioning of ambivalence. AB - In evaluative conditioning (EC), the pairing of a positively or negatively valenced stimulus (US) with a neutral stimulus (CS) leads to a corresponding change in liking of the CS. EC research so far has concentrated on using unambiguously positive or negative USs. However, attitude objects are often ambivalent, i.e., can simultaneously possess positive and negative features. The present research investigated whether ambivalence can be evaluatively conditioned and whether contingency awareness moderates this effect. In two studies, positive, negative, neutral, and ambivalent USs were paired with affectively neutral CSs. Results showed standard EC effects that were moderated by contingency awareness. Most interestingly, EC effects were also obtained for the ambivalent USs, indicating that ambivalence can indeed be conditioned. However, contingency awareness seemed to play a lesser role in ambivalence conditioning. Ambivalence EC effects were obtained on subjective and objective direct measures of ambivalence as well as on a more indirect measure. PMID- 29482090 TI - Investigating evolutionary constraints on the detection of threatening stimuli in preschool children. AB - Numerous objects and animals could be threatening, and thus, children learn to avoid them early. Spiders and syringes are among the most common targets of fears and phobias of the modern word. However, they are of different origins: while the former is evolutionary relevant, the latter is not. We sought to investigate the underlying mechanisms that make the quick detection of such stimuli possible and enable the impulse to avoid them in the future. The respective categories of threatening and non-threatening targets were similar in shape, while low-level visual features were controlled. Our results showed that children found threatening cues faster, irrespective of the evolutionary age of the cues. However, they detected non-threatening evolutionary targets faster than non evolutionary ones. We suggest that the underlying mechanism may be different: general feature detection can account for finding evolutionary threatening cues quickly, while specific features detection is more appropriate for modern threatening stimuli. PMID- 29482091 TI - Animal manure-derived biochars produced via fast pyrolysis for the removal of divalent copper from aqueous media. AB - Here, we report a pyrolyzed guinea fowl manure-derived biochar (GFM-BC) and cattle manure-derived biochar (CTM-BC) and their use as adsorbent for the removal of divalent copper from aqueous media was evaluated. The BCs physical and chemical properties were characterized by Scanning electron microscopy (SEM), Elemental dispersive x-ray analysis (EDX), Fourier transform infrared microscopy (FTIR) and thermo gravimetric analysis (TGA). The results presented that the BCs obtained higher content were quite effective for Cu (II) removal with maximum capacities of 43.60 and 44.50 mg g-1 for GFM-BC and CTM-BC, respectively. From simulation of experimental data with different adsorption isotherms and kinetics models it was found that the adsorption of both BCs was adequately fitted by Freundlich adsorption model and pseudo-second order kinetic model, respectively. Thermodynamic parameters suggested that the adsorption of Cu (II) onto both BCs was feasible, spontaneous and exothermic under evaluated parameters. Thus, the biomass used in this study proved to be effective adsorbents for the removal of Cu (II) from aqueous media. PMID- 29482092 TI - Electrocoagulation with polarity switch for fast oil removal from oil in water emulsions. AB - An electrocoagulation technique using a 3.5 L reactor, with aluminum electrodes in a monopolar arrangement with polarity switch at each 10 s was used to separate oil from synthetic oily water similar in oil concentration to produced water from offshore platforms. Up to 98% of oil removal was achieved after 20 min of processing. Processing time dependence of the oil removal and pH was measured and successfully adjusted to exponential models, indicating a pseudo first order behavior. Statistical analysis was used to prove that electrical conductivity and total solids depend significantly on the concentration of electrolyte (NaCl) in the medium. Oil removal depends mostly on the distance between the electrodes but is proportional to electrolyte concentration when initial pH is 8. Electrocoagulation with polarity switch maximizes the lifetime of the electrodes. The process reduced oil concentration to a value below that stipulated by law, proving it can be an efficient technology to minimize the offshore drilling impact in the environment. PMID- 29482093 TI - Dam operations may improve aquatic habitat and offset negative effects of climate change. AB - Dam operation impacts on stream hydraulics and ecological processes are well documented, but their effect depends on geographical regions and varies spatially and temporally. Many studies have quantified their effects on aquatic ecosystem based mostly on flow hydraulics overlooking stream water temperature and climatic conditions. Here, we used an integrated modeling framework, an ecohydraulics virtual watershed, that links catchment hydrology, hydraulics, stream water temperature and aquatic habitat models to test the hypothesis that reservoir management may help to mitigate some impacts caused by climate change on downstream flows and temperature. To address this hypothesis we applied the model to analyze the impact of reservoir operation (regulated flows) on Bull Trout, a cold water obligate salmonid, habitat, against unregulated flows for dry, average, and wet climatic conditions in the South Fork Boise River (SFBR), Idaho, USA. PMID- 29482094 TI - Removal of norfloxacin in deionized, municipal water and urine using rice (Oryza sativa) and coffee (Coffea arabica) husk wastes as natural adsorbents. AB - The removal of the widely used antibiotic norfloxacin (NOR), the presence of which has been reported in natural water, was evaluated using rice (RH) and coffee (CH) husk wastes as adsorbents. Low particle sizes and natural pH in distilled water favored NOR elimination in both materials. In order to investigate the type of adsorption, the data was adjusted to the Langmuir, Freundlich and Redlich-Peterson isotherms. The best fit for the Langmuir and Redlich-Peterson isotherms suggested a monolayer-type adsorption model. Kinetic models of pseudo first and second order were also evaluated, the latter being the most suitable to represent the NOR adsorption phenomenon. Meanwhile, the intraparticle diffusion model indicated that the adsorption of NOR occurs both at the surface and within the pores of the material. Studies performed on thermodynamic aspects such as activation energy (Ea), enthalpy change (DeltaH) and Gibbs free energy change (DeltaG) suggest that the physisorption of the pollutant takes place through a spontaneous endothermic process. Additionally, PZC determination, Boehm method, chemical composition, thermodynamic analysis, and FTIR spectra before and after the adsorption of the antibiotic suggest that in CH adsorbents this occurred mainly through electrostatic interactions, while in RH hydrogen bonds also contributed significantly. Finally, the efficiency of natural adsorbents for the removal of NOR was evaluated in synthetic matrices of municipal wastewater and urine, and promising results were obtained despite the complexity of these matrices. The results presented in this work show the potential application of RH and CH residues as a low-cost alternative for the removal of NOR even in complex matrices. However, despite the similarities between the materials, CH waste showed better properties for the removal of the tested NOR due to its higher surface area, lower PZC and higher number of acid groups. PMID- 29482095 TI - Pharmaceutical grey water footprint: Accounting, influence of wastewater treatment plants and implications of the reuse. AB - Emerging pollutants, including pharmaceutical compounds, are producing water pollution problems around the world. Some pharmaceutical pollutants, which mainly reach ecosystems within wastewater discharges, are persistent in the water cycle and can also reach the food chain. This work addresses this issue, accounting the grey component of the water footprint (GWFP) for four of the most common pharmaceutical compounds (carbamazepine (CBZ), diclofenac (DCF), ketoprofen (KTP) and naproxen (NPX)). In addition, the GWFC for the main conventional pollutants is also accounted (nitrate, phosphates and organic matter). The case study is the Murcia Region of southeastern Spain, where wastewater treatment plants (WWTPs) purify 99.1% of the wastewater discharges and there is an important direct reuse of the treated wastewater in irrigation. Thus, the influence of WWTPs and reuse on the GWF is analysed. The results reveal that GWFP, only taking into account pharmaceutical pollutants, has a value of 301 m3 inhabitant-1 year-1; considering only conventional pollutants (GWFC), this value increases to 4718 m3 inhabitant-1 year-1. So, the difference between these values is such that in other areas with consumption habits similar to those of the Murcia Region, and without wastewater purification, conventional pollutants may well establish the value of the GWF. On average, the WWTPs reduce the GWFC by 90% and the GWFP by 26%. These different reductions of the pollutant concentrations in the treated effluents show that the GWF is not only due to conventional pollutants, and other contaminants can became critical, such as the pharmaceutical pollutants. The reuse further reduces the value of the GWF for the Murcia Region, by around 43.6%. However, the reuse of treated wastewater is controversial, considering the pharmaceutical contaminants and their possible consequences in the food chain. In these cases, the GWF of pharmaceutical pollutants can be used to provide a first approximation of the dilution that should be applied to the treated wastewater discharges when they are reused for another economic activity that imposes quality restrictions. For the case of agriculture in the Murcia Region, the dilution required is 2 (fresh water) to 1 (treated wastewater), taking into account the pollution thresholds established in this work. PMID- 29482096 TI - Nanoparticle-enabled delivery of surfactants in porous media. AB - The adsorption of surfactants on the reservoir rocks surface is a serious issue in many energy and environment related areas. Learning from the concept of drug delivery in the nano-medicine field, this work proposes and validates the concept of using nanoparticles to deliver a mixture of surfactants into a porous medium. TiO2 nanoparticles (NPs) are used as carriers for a blend of surfactants mixtures including anionic alkyl aryl sulfonic acid (AAS) and nonionic alcohol ethoxylated (EA) at the optimum salinity and composition conditions. The transport of NPs through a core sample of crushed sandstone grains and the adsorption of surfactants are evaluated. By using TiO2 NPs, the adsorption of surfactant molecules can be significantly reduced, i.e. half of the initial adsorption value. The level of surfactant adsorption reduction is related to the NPs transport capability through the porous medium. An application study shows that comparing to surfactant flooding alone, the total oil recovery can be increased by 7.81% of original oil in place (OOIP) by using nanoparticle bonded surfactants. Such work shows the promise of NP as an effective surfactant carrier for sandstone reservoirs, which could have many potential applications in enhanced oil recovery (EOR) and environmental remediation. PMID- 29482097 TI - Characterization of the complexation phenomenon and biological activity in vitro of polyplexes based on Tetronic T901 and DNA. AB - The complexation process and underlying mechanisms that rule the interaction of DNA with the cationic block copolymer Tetronic T901 to form polyplexes and their potential transfection efficiency have been studied under different solution conditions. We noted that T901 favors the formation of self-assembled structures with partially condensed DNA at smaller polymer concentrations than other PluronicTM/TetronicTM-type copolymers previously analysed. The observed polyplexes display sizes from the nano- to the micro- range as derived from DLS, electronic and optical microscopies. Also, copolymer micelles are observed at concentrations below the copolymer critical micellar concentration (cmc) induced by the presence of DNA. The complexation process is dependent on solution conditions, with electrostatic and ionic interactions being more important at acidic pH thanks to the predominant diprotonated form of the block copolymer which is less aggregation-prone, whilst dispersive forces are increasingly enhanced under basic conditions or when rising the solution temperature. Whatever the case, the complexation is mainly governed by entropic contributions, as denoted from ITC data. In vitro transfection experiments after complexing T901 with a pDNA encoding the expression of green fluorescein protein, GFP, show a relative successful fluorescence of transfected HeLa cells, which confirms the uptake, internalization and release of the genetic material within the cells at suitable [N]/[P] ratios with relatively low cytotoxicity. Despite the observed successful outcomes, the obtained transfection efficacies are slightly lower than those obtained with Lipofectamine2000, so further optimization of the polyplex formation conditions is envisaged in future studies. PMID- 29482098 TI - Concentration effect of Quillaja saponin - Co-surfactant mixtures on emulsifying properties. AB - HYPOTHESIS: This study examined the emulsifying properties of mixed surfactant systems of Quillaja saponins and food-grade co-surfactants (Na-caseinate, pea protein, rapeseed lecithin, and egg lecithin). We hypothesized to these mixtures may build mixed adsorption layers and thus enhance emulsion stabilization. EXPERIMENTS: Oil-in-water emulsions (10%, pH 7) were prepared with different concentrations of co-surfactants (0.1-5.0%) alone or mixed with Quillaja saponins (0.05 or 0.5%). Dynamic interfacial tension measurements were performed to characterize the behavior of the surfactants at an oil-water interface. FINDINGS: Low Quillaja saponin concentrations led to either no changes or substantial increases in particle sizes of protein stabilized emulsions, but d43-values decreased in lecithin stabilized emulsions at low lecithin concentrations. The dominating effect of Quillaja saponins at high concentrations led to formation of small droplets (d43<=2 um) in all emulsions, except with 2.5% pea proteins. All co-surfactants showed synergistic or additive effects with respect to interfacial tension reductions upon addition of Quillaja saponins (except for egg lecithin with 0.005% Quillaja saponin addition). The results indicated a competing effect for saponin-protein interfaces, but formation of mixed saponin-lecithin interfaces, thus showing that the emulsion stabilization and interfacial properties can be tuned by specific binary surfactant mixtures. PMID- 29482099 TI - Synthesis of organic-inorganic hybrid compounds and their self-assembled behavior in different solvents. AB - Self-assembly behavior of polyoxometalates (POMs) is influenced by the functional group linked with polyoxometalates structure. We modified the POMs with organic molecule terpyridine to endow POMs the ability to assemble into nanostructure and control the properties of POMs. An amphiphilic organic-inorganic hybrid compound was prepared through combining the 4'-para-phenylcarboxyl-2,2':6',2''-terpyridine (PPCT) with POM to form the (TBA)3POM-PPCT. After cationic exchange, tetrabutylammonium cation (TBA+) can be turned into H+ to produce H3POM-PPCT. H3POM-PPCT showed excellent self-assembly behavior in different solvents. By adjusting the proportion of solvents, different fibers and leaf-like aggregates were obtained, which were determined by SEM and TEM observations. According to the experimental observations, mechanism of the formation of nanostructures was established. The redox properties of POMs can be maintained after the modification with PPCT, which were demonstrated by cyclic voltammetry (CV) measurements. The successful synthesis of these POMs may provide us an opportunity to find more functionalized ramifications of POMs, with self assembled structures controlled in different solvent, but the interesting properties of these novel POMs can also provide motivation and guidance for the further development of novel functionalized POMs. PMID- 29482100 TI - Fabrication of ultrathin MIL-96(Al) films and study of CO2 adsorption/desorption processes using quartz crystal microbalance. AB - This contribution reports the fabrication and characterization of ultrathin films of nanoparticles of the water stable microporous Al tricarboxylate metal organic framework MIL-96(Al). The preparation of MOF dispersions in chloroform has been optimized to obtain dense monolayer films of good quality, without nanoparticle agglomeration, at the air-water interface that can be deposited onto solid substrates of different nature without any previous substrate functionalization. The MOF studied shows great interest for CO2 capture because it presents Al3+ Lewis centers and hydroxyl groups that strongly interact with CO2 molecules. A comparative CO2 adsorption study on drop-cast, Langmuir-Blodgett (LB) and Langmuir-Schaefer (LS) films using a Quartz Crystal Microbalance-based setup (QCM) has revealed that the CO2 uptake depends strongly on the film fabrication procedure and the storage conditions. Noteworthy the CO2 adsorption capacity of LB films is increased by 30% using a simple and green treatment (immersion of the film into water during 12 h just after film preparation). Finally, the stability of LB MOF monolayers upon several CO2 adsorption/desorption cycles has been demonstrated, showing that CO2 can be easily desorbed from the films at 303 K by flowing an inert gas (He). These results show that MOF LB monolayers can be of great interest for the development of MOF-based devices that require the use of very small MOF quantities, especially gas sensors. PMID- 29482101 TI - Interaction of thermal responsive NIPAM nanogels with model lipid monolayers at the air-water interface. AB - Understanding the interaction of nanoparticles (NP) with ceramide lipids is important in developing strategies to overcome the formidable obstacle that is skin. This paper presents studies of interactions between N-isopropylacrylamide nanogels, crosslinked with 30% N,N'-methylenebisacrylamide, and model ceramide lipid monolayers at the air-water interface as a function of temperature. In the case of the mixed ceramide/cholesterol/behenic acid monolayer, the interaction of nanogels with the ceramide was strongly mediated by the fatty acids. This interaction between nanogels and monolayer components is dominated by hydrophobic hydrophobic binding. The data show the important intermediary role of the fatty acid in facilitating transmembrane transport. For a pure ceramide lipid monolayer, the neutron reflectivity (NR), Brewster angle microscopy (BAM) and surface pressure results showed a lipid-nanogel complex formation and the subsequent depletion/solubilisation of the lipids from the interface when the area per molecule for the lipid was increased from 42 to 44 A2. PMID- 29482102 TI - A novel antibody-based approach to detect the functional ERCC1-202 isoform. AB - ERCC1/XPF endonuclease plays an important role in multiple DNA repair pathways and stands as a potential prognostic and predictive biomarker for cisplatin-based chemotherapy. Four distinct ERCC1 isoforms arising from alternative splicing have been described (201, 202, 203 and 204) but only the 202 isoform is functional in DNA excision repair, when interacting with its obligate partner XPF. Currently, there is no tool to assess specifically the expression of ERCC1-202 due to high sequence homology between the four isoforms. Here, we generated monoclonal antibodies directed against the heterodimer of ERCC1 and its obligate interacting partner XPF by genetic immunization. We obtained three monoclonal antibodies (2C11, 7C3 and 10D10) recognizing specifically the heterodimer ERCC1-202/XPF as well as the ERCC1-204/XPF with no affinity to ERCC1 or XPF monomers. By combining one of these three heterodimer-specific antibodies with a commercial anti-ERCC1 antibody (clone 4F9) unable to recognize the 204 isoform in a proximity ligation assay (PLA), we managed to specifically detect the functional ERCC1-202 isoform. This methodological breakthrough can constitute a basis for the development of clinical tests to evaluate ERCC1 functional proficiency. PMID- 29482103 TI - Superhydrophobic surfaces: From nature to biomimetic through VOF simulation. AB - The contact angle, surface structure and chemical compositions of Canna leaves were investigated. According to the surface structure of Canna leaves which observed by Scanning Electron Microscopy(SEM), the CFD (Computational Fluid Dynamics)model was established and the method of volume of fluid (VOF) was used to simulate the process of droplet impacting on the surface and established a smooth surface for comparison to verify that the surface structure was an important factor of the superhydrophobic properties. Based on the study of Canna leaf and VOF simulation of its surface structure, the superhydrophobic samples were processed successfully and showed a good superhydrophobic property with a contact angle of 156 +/- 1 degrees. A high-speed camera (5000 frames per second) was used to assess droplet movement and determine the contact time of the samples. The contact time for the sample was 13.1 ms. The results displayed that the artificial superhydrophobic surface is perfect for the performance of superhydrophobic properties. The VOF simulation method was efficient, accurate and low cost before machining artificial superhydrophobic samples. PMID- 29482104 TI - Kit-dependent discrepancy in D16S539 and general considerations for database matches. AB - Throughout the last decade more companies have been offering multiplex PCR kits for forensic STR typing. As a consequence, it has been demonstrated, that an observed genotype may unexpectedly vary at a single locus when different STR kits have been used. Analysing STR profiles which have to be entered in a national database, unknown or undetected primer binding site mutations, insertions or deletions within the flanking region of STR loci may hinder matches and therefore have far-reaching consequences. The current study is a further example indicating that sequence variations in flanking regions are a common problem within STR typing which should not be underestimated. A deletion of 16 nucleotides close to the primer binding site downstream of the repeat sequence resulted in deviant genotypes at the D16S539 locus according to different STR kits used. PMID- 29482105 TI - Wearer and non-wearer DNA on the collars and cuffs of upper garments of worn clothing. AB - During an investigation, the question of interest might be whether or not a person has worn a given garment. Wearer DNA studies have contributed to our knowledge and understanding of DNA transfer and persistence on items of worn clothing. However, there is currently no extensive dataset on DNA profiling outcomes from a variety of upper garments. Therefore we investigated the DNA profiling outcomes from the collars and/or cuffs of forty-four upper garments of worn clothing and determined the quantity of wearer and non-wearer DNA recovered. Interpretable DNA profiles were more likely to be obtained from collars than cuffs (84% versus 71%). The wearer was detected in all interpretable profiles and a major profile corresponding to the wearer was the most common outcome from both collar and cuff samples (48% and 50%, respectively). There was large variation in the amount of wearer DNA recovered and the average recovered was approximately 20 ng. Usually more wearer DNA was found on collars than cuffs of the same garment and, on average, more non-wearer DNA was found on cuffs than collars. No DNA was recovered from the cuffs of two garments despite these garments being worn for three and four hours, respectively. On one occasion a non-wearer contributed more DNA to a cuff sample than the wearer. We found no correlation between wearing time and the amount of wearer DNA recovered which indicates that other factors (e.g. shedder status and/or the manner of contact between the garment and skin) have a greater influence, than wearing time, on the amount of DNA transferred. However, there was a positive correlation between wearing time and the likelihood of obtaining interpretable profiles. This work has generated data to support the evaluation of DNA evidence from clothing and we provide a case example to demonstrate this. PMID- 29482106 TI - Development and validation of an LC-MS/MS method for quantitative determination of GS87, a novel antineoplastic agent, in mouse plasma. AB - GS87 is a novel, highly specific GSK3 inhibitor, which has shown to induce extensive differentiation of acute myeloid leukemia (AML) cells in early mouse studies and has great potential for therapeutic advancement. This work described the development and validation of an LC-MS/MS method for quantitative determination of GS87 in mouse plasma. In this method, GS87 and T6447952 (a structural analog used as internal standard) were extracted from plasma using hexane as extraction solvent, and separated isocratically on a Waters XTerra(r) MS C8 column (2.1 * 50 mm, 3.5 MUm) using a mobile phase consisting of acetonitrile and 5.00 mM ammonium formate (35:65, v/v) pumped at a flow rate of 0.200 mL min-1. Quantitation of GS87 was done by positive electrospray ionization tandem mass spectrometry operated in multiple-reaction-monitoring (MRM) mode. The method has been validated in accordance with the US Food and drug administration guidelines for bioanalytical method validation. It has linear calibration range of 2.50-250 ng mL-1 with correlation coefficient of >0.999. The intra- and inter- assay accuracy and precision were <= +/-5 and <=6%, respectively. The IS normalized recovery of GS87 was 103-106%. The stability studies showed that GS87 was stable under all tested conditions. The method developed has been successfully applied to the measurement of GS87 concentrations in mouse plasma samples from an animal study, and may be useful for further preclinical investigation of GS87. PMID- 29482107 TI - Service needs of adolescent parents in child welfare: Is an evidence-based, structured, in-home behavioral parent training protocol effective? AB - SafeCare is an evidence-based behavioral parent training intervention that has been successfully implemented in multiple state child welfare systems. A statewide implementation in Oklahoma established the effectiveness of SafeCare with a diverse group of parents, which included adolescent parents under 21 years of age, a particularly at-risk group. The current study examined whether SafeCare is also effective for this subsample of 294 adolescent parents with regard to child welfare recidivism, depression and child abuse potential, and attainment of service goals. Post-treatment adolescent parent ratings of program engagement and satisfaction were also examined. Among the subsample of adolescent parents, the SafeCare intervention did not result in significantly improved outcomes in terms of preventing recidivism or reduction in risk factors associated with child abuse and neglect as compared to child welfare services as usual. Further, no significant differences in program engagement and satisfaction between SafeCare and services as usual were detected. These findings shed light on the potential differences in program effectiveness between adolescent and adult parents, and the need for future research to rigorously evaluate the effectiveness of behavioral parenting programs with adolescent parents. PMID- 29482108 TI - Outcomes of psychotherapeutic and psychoeducative group interventions for children exposed to intimate partner violence. AB - Witnessing violence toward a caregiver during childhood is associated with negative impact on children's health and development, and there is a need for effective interventions for children exposed to intimate partner violence in clinical as well as in community settings. The current effectiveness study investigated symptom reduction after participation in two established group interventions (one community-based psychoeducative intervention; one psychotherapeutic treatment intervention) for children exposed to intimate partner violence and for their non-offending parent. The study included 50 children-24 girls and 26 boys-aged 4-13 years and their mothers. Child and maternal mental health problems and trauma symptoms were assessed pre- and post treatment. The results indicate that although children showed benefits from both interventions, symptom reduction was larger in the psychotherapeutic intervention, and children with initially high levels of trauma symptoms benefited the most. Despite these improvements, a majority of the children's mothers still reported child trauma symptoms at clinical levels post-treatment. Both interventions substantially reduced maternal post-traumatic stress. The results indicate a need for routine follow-up of children's symptoms after interventions. PMID- 29482109 TI - Differences in child sexual abuse cases involving child versus adolescent complainants. AB - While adolescents report the highest rates of sexual abuse victimization, few studies have investigated how child sexual abuse (CSA) cases involving adolescent complainants may differ from cases involving child complainants. The current study draws on 3,430 allegations of CSA in Canada to compare abuse characteristics and judicial outcomes in cases involving adolescent complainants to cases involving child complainants. Adolescent complainants were more likely than child complainants to be abused by a stranger or a person with a community connection to the complainant, while children were more likely than adolescents to be abused by a parent or other relative. Furthermore, compared to child complainants, adolescent complainants were more frequently involved in the most intrusive offenses and their cases were more likely to involve violence. Both groups were most likely to disclose the abuse to a parent, though a greater proportion of children disclosed the abuse to a parent. There were no differences in the delay to disclosure. Accused were equally likely to plead "guilty" and to be convicted in cases involving child and adolescent complainants. However, offenders convicted of the most intrusive offenses received longer probation sentences when the complainant was a child than when the complainant was an adolescent. These findings have implications for ensuring appropriate support and services to adolescent victims of CSA. PMID- 29482110 TI - Challenges in the identification of dead migrants in the Mediterranean: The case study of the Lampedusa shipwreck of October 3rd 2013. AB - Every year thousands of migrants die during the endeavour to reach the Italian coasts, making the Mediterranean the theatre of one of the greatest tragedies of mankind. Over 60% of these victims is buried unidentified: one of the reasons behind this is related to the specific difficulties and lack of strategies concerning AM and PM data collection. The present article describes how Italy is trying to face the problem of migrant identification, thanks to the collaboration between government, the Italian national police and universities. In particular, this is the first pilot study carried out to identify the victims of the second greatest tragedy of its kind off the Italian coast, near Lampedusa, on October 3rd 2013, which caused 366 victims. The present article shows the strategies conceived to collect postmortem and especially antemortem data and to compare them to identify matches, using medicolegal, anthropological, odontological and genetic approaches. Thirty-one victims out of 53 missing sought by relatives were identified (58.5%). The type and the quality of antemortem data available, generally photos and videos, pinpoints the importance of the face and the body for identification when the bodies are well preserved and how DNA analyses may at times present difficulties. In fact, critical points emerged concerning especially the lack of genetic information of the populations to which the victims belonged, the number of genetic markers needed to reach a statistical support for the identification and the need to adopt lineage markers such as mitochondrial DNA and Y-chromosome polymorphisms to identify parental relationships. This pilot study however has proven that families continue to seek their relatives and that it is possible, as well as mandatory, to identify migrant victims in spite of the difficulties in the collection of antemortem and postmortem data. In addition, considering the peculiar scenario, novel strategies for positive identification have to be defined in each field (anthropological, odontological and genetic) as well as in combination. PMID- 29482111 TI - Effect of surface nano/micro-structuring on the early formation of microbial anodes with Geobacter sulfurreducens: Experimental and theoretical approaches. AB - Smooth and nano-rough flat gold electrodes were manufactured with controlled Ra of 0.8 and 4.5nm, respectively. Further nano-rough surfaces (Ra 4.5nm) were patterned with arrays of micro-pillars 500MUm high. All these electrodes were implemented in pure cultures of Geobacter sulfurreducens, under a constant potential of 0.1V/SCE and with a single addition of acetate 10mM to check the early formation of microbial anodes. The flat smooth electrodes produced an average current density of 0.9A.m-2. The flat nano-rough electrodes reached 2.5A.m-2 on average, but with a large experimental deviation of +/-2.0A.m-2. This large deviation was due to the erratic colonization of the surface but, when settled on the surface, the cells displayed current density that was directly correlated to the biofilm coverage ratio. The micro-pillars considerably improved the experimental reproducibility by offering the cells a quieter environment, facilitating biofilm development. Current densities of up to 8.5A.m-2 (per projected surface area) were thus reached, in spite of rate limitation due to the mass transport of the buffering species, as demonstrated by numerical modelling. Nano-roughness combined with micro-structuring increased current density by a factor close to 10 with respect to the smooth flat surface. PMID- 29482112 TI - Role of voltage-gated calcium channels on striatal dopamine release induced by inorganic mercury in freely moving rats. AB - The possible role of voltage-sensitive calcium channels (VSCC) activation on the HgCl2-induced dopamine release was investigated using selective VSCC blockers and the dopamine levels were measured by HPLC from samples obtained by in vivo brain microdialysis. Infusion of HgCl2 in nicardipine (10 or 100 MUM) or flunaricine (10 MUM) pretreated animals had no significant effect on dopamine release induced by HgCl2. Pretreatment with 100 MUM flunaricine, 20 MUM omega-conotoxin MVIIC, or omega-conotoxin GVIA significantly decreased the HgCl2-induced dopamine release over 61%, 88%, and 99%, respectively. HgCl2-induced dopamine release could be produced, at least in part, by activation of VSCC at dopaminergic terminals, especially N- and P/Q-type. PMID- 29482113 TI - iTRAQ-based proteomic analysis identifies proteins involved in limb regeneration of swimming crab Portunus trituberculatus. AB - The swimming crab (Portunus trituberculatus) has a striking capacity for limb regeneration, which has drawn the interest of many researchers. In this study, isobaric tag for relative and absolute quantitation (iTRAQ) approach was utilised to investigate protein abundance changes during limb regeneration in this species. A total of 1830 proteins were identified, of which 181 were significantly differentially expressed, with 94 upregulated and 87 downregulated. Our results highlight the complexity of limb regeneration and its regulation through cooperation of various biological processes including cytoskeletal changes, extracellular matrix (ECM) remodelling and ECM-receptor interactions, protein synthesis, signal recognition and transduction, energy production and conversion, and substance transport and metabolism. Additionally, real-time PCR confirmed that mRNA levels of differentially expressed genes were correlated with protein levels. Our results provide a basis for studying the regulatory mechanisms associated with crab limb regeneration. PMID- 29482114 TI - Proteomic analysis reveals the distinct energy and protein metabolism characteristics involved in myofiber type conversion and resistance of atrophy in the extensor digitorum longus muscle of hibernating Daurian ground squirrels. AB - Previous hibernation studies demonstrated that such a natural model of skeletal muscle disuse causes limited muscle atrophy and a significant fast-to-slow fiber type shift. However, the underlying mechanism as defined in a large-scale analysis remains unclarified. Isobaric tags for relative and absolute quantification (iTRAQ) based quantitative analysis were used to examine proteomic changes in the fast extensor digitorum longus muscles (EDL) of Daurian ground squirrels (Spermophilus dauricus). Although the wet weights and fiber cross sectional area of the EDL muscle showed no significant decrease, the percentage of slow type fiber was 61% greater (P < 0.01) in the hibernation group. Proteomics analysis identified 264 proteins that were significantly changed (ratio < 0.83 or >1.2-fold and P < 0.05) in the hibernation group, of which 23 proteins were categorized into energy production and conversion and translation and 22 proteins were categorized into ribosomal structure and biogenesis. Along with the validation by western blot, MAPKAP kinase 2, ATP5D, ACADSB, calcineurin, CSTB and EIF2S were up-regulated in the hibernation group, whereas PDK4, COX II and EIF3C were down-regulated in the hibernation group. MAPKAP kinase 2 and PDK4 were associated with glycolysis, COX II and ATP5D were associated with oxidative phosphorylation, ACADSB was associated with fatty acid metabolism, calcineurin and CSTB were associated with catabolism, and EIF2S and EIF3C were associated with anabolism. Moreover, the total proteolysis rate of EDL in the hibernation group was significantly inhibited compared with that in the pre-hibernation group. These distinct energy and protein metabolism characteristics may be involved in myofiber type conversion and resistance to atrophy in the EDL of hibernating Daurian ground squirrels. PMID- 29482115 TI - Priming the tuberculosis drug pipeline: new antimycobacterial targets and agents. AB - Claiming close to two million lives each year, tuberculosis is now the leading cause of death from an infectious disease. The rise in number of Mycobacterium tuberculosis (Mtb) strains resistant to existing TB drugs has underscored the urgent need to develop new antimycobacterials with novel mechanisms of action. To meet this need, a drug pipeline has been established that is populated with new and repurposed drugs. Recent advances in identifying molecules with inhibitory activity against Mtb under conditions modelled on those encountered during infection, and in elucidating their mechanisms of action, have primed the pipeline with promising drug/target couples, hit compounds and new targets. In this review, we highlight recent advances and emerging areas of opportunity in this field. PMID- 29482116 TI - Morphological MR features and quantitative ADC evaluation in invasive breast cancer: Correlation with prognostic factors. AB - OBJECTIVE: Assess the correlation between MRI characteristics of invasive breast cancer and tumor prognostic features. MATERIALS AND METHODS: 95 women with invasive breast cancer underwent pre-treatment MR. Morphological findings and quantitative ADC were retrospectively evaluated. RESULTS: Smaller size, round shape, spiculated margins and homogeneous internal enhancement pattern on dynamic MRI were independently associated with established predictors of good prognosis, while larger size and rim enhancement pattern were related to predictors of poor prognosis. A positive correlation was observed between ADC value and clinical stage. CONCLUSIONS: MRI may be a useful tool for breast cancer aggressiveness prediction and for guiding subsequent clinical-therapeutic management. PMID- 29482117 TI - Free-breathing 320-row computed tomographic angiography with low-tube voltage and hybrid iterative reconstruction in infants with complex congenital heart disease. AB - We explored the clinical value of low-tube voltage prospective second-generation ECG-triggered 320-row CT angiography in infants with complex CHD (37 male, 23 female, aged 0-2 years). The diagnostic accuracy of 320-row CT in complex CHD was 99.4% for intracardiac cardiovascular malformations, 99.8% for extracardiac cardiovascular malformations, and 100% for other malformations. The average subjective overall image quality score for cardiac structures was 3.7 +/- 0.5 points. Second-generation 320-row CT angiography with low-tube voltage and prospective ECG-triggered volume target scanning allows accurate diagnosis of cardiovascular anomalies in infants with complex CHD. PMID- 29482118 TI - Extended endoscopic endonasal approach to the ventral skull base lesions. AB - OBJECTIVE: With the use of multiple endoscopic endonasal surgical corridors, extended endoscopic endonasal approaches (EEEAs) are now being used to treat a wide range of ventral skull base lesions. Our aim was to present our experience with EEEAs to the ventral skull base lesions. PATIENTS AND METHODS: The study group consisted of 106 patients (57 men and 49 women) who underwent surgery for skull base lesions using EEEAs from 2010 to 2017. The EEEA was most commonly used for giant pituitary macroadenomas, sinonasal malignancies, cerebrospinal fluid (CSF) leaks, meningiomas, craniopharyngiomas, and fibro-osseous lesions. Four different approaches were used including transtuberculum-transplanum, transethmoidal-transcribriform, transclival, and transmaxillary-transpterygoidal. RESULTS: The overall gross total resection (GTR) rate for these diverse pathologies was 75.0% in 88 patients (excluding the operations performed for non neoplastic pathologies). GTR was achieved in 100%, 77.8%, 75%, 75%, 72.2%, 62.5%, 60% of fibro-osseous lesions, giant/large pitutary adenomas, meningiomas, esthesioneuroblastomas, sinonasal malignancies, craniopharyngiomas, and chordomas, respectively. The overall rate of improvement in visual fields was 86%. The overall rate of CSF leak was 8.4%. Other surgical complications included intracerebral hematoma and tension pneumocephalus. The mortality rate was 0.9%. CONCLUSION: EEEA is a safe, well-tolerated and effective surgical treatment modality in the management of ventral skull base lesions. It should be performed with close interdisciplinary collaboration. Appropriate case selection is mandatory. However, despite improved reconstruction techniques, postoperative CSF leakage still remains a challenge. PMID- 29482119 TI - eTRIKS platform: Conception and operation of a highly scalable cloud-based platform for translational research and applications development. AB - We describe the genesis, design and evolution of a computing platform designed and built to improve the success rate of biomedical translational research. The eTRIKS project platform was developed with the aim of building a platform that can securely host heterogeneous types of data and provide an optimal environment to run tranSMART analytical applications. Many types of data can now be hosted, including multi-OMICS data, preclinical laboratory data and clinical information, including longitudinal data sets. During the last two years, the platform has matured into a robust translational research knowledge management system that is able to host other data mining applications and support the development of new analytical tools. PMID- 29482120 TI - What factors can affect lumbopelvic flexion-extension motion in the sagittal plane?: A literature review. AB - Clinicians use forward bending and backward return in routine clinical examinations for evaluating spine mobility. The magnitude and timing of lumbar spine and pelvic contributions have been described in the literature as lumbopelvic rhythm. There is still limited knowledge about the factors which can determinate lumbar and hip mobility and coordination in the sagittal plane. The aim of this study is to demonstrate those factors contributing to the lumbopelvic rhythm and to explain the differences observed between subjects. The studies included in the review present possible explanations of observed lumbar-pelvic motion and/or coordination. They measure movement of the lumbar spine, the pelvis and/or the hip in the sagittal plane. The search was conducted in August 2017. Two databases (PubMed and Web of Science) were searched. The search identified 126 potentially relevant articles (53 in PubMed, 73 in Web of Science). Initial screening based on titles and abstracts retrieved 35 articles. The second stage of selection involved reading the full texts of articles. Twenty-four papers were selected in this stage. After careful bibliographic study, seven papers were added for this review, resulting in a total of 31. This literature review demonstrates those factors contributing to lumbopelvic motion. Age and gender, hamstring muscle tightness, feet position, muscle fatigue, movement speed and external loading as well phase of motion can affect various aspects of lumbopelvic rhythm. PMID- 29482121 TI - A high-throughput UPC2-MS/MS method for the separation and quantification of C19 and C21 steroids and their C11-oxy steroid metabolites in the classical, alternative, backdoor and 11OHA4 steroid pathways. AB - In the present study an ultra-performance convergence chromatography tandem mass spectrometry (UPC2-MS/MS) analytical method was developed and validated for the determination of 17 C19 and 14 C21 steroids, including C11-oxy C19 and C11-oxy C21 steroids. The limit of detection and limit of quantification ranged from 0.01 to 10 ng/mL and from 0.01 to 20 ng/mL, respectively, and the method shows the recovery, matrix effect and process efficiency of steroids isolated from a serum matrix to be within acceptable limits. Good accuracy, repeatability and reproducibility were also shown and the method provided excellent sensitivity and selectivity as stereoisomers and regioisomers were also resolved and quantified accurately. Clinical conditions such as congenital adrenal hyperplasia, polycystic ovary syndrome in females and disorders of sex development in neonates and in children, amongst others, are characterized by abnormal steroid levels. Steroid profiling is essential to accurately diagnose steroid levels in the above settings as well as in androgen excess or deficiency in adrenal-linked endocrine diseases. Our method, separating C19 and C21 steroids in a single chromatographic step, offers a reduced sample turnover rate in the clinical setting, while providing comprehensive steroid profiles of in vivo steroids in the nmol/L range. This is, to our knowledge, the first method reported to simultaneously separate C19 and C21 steroids, together with their C11-hydroxy and C11-keto metabolites one which may hold promise in the identification of new steroid markers in steroid-linked endocrine diseases, in addition to profiling steroid metabolism and abnormal enzyme activity in patients. PMID- 29482122 TI - Evaluation of a method for measuring the radioprotective metabolite WR-1065 in plasma using chemical derivatization combined with UHPLC-MS/MS. AB - Hypotension is the dose-limiting side effect of the radio-protective drug Amifostine and results from relaxation of the vascular smooth muscle, which is directly mediated by the active metabolite, WR-1065, of Amifostine. The route of administration (currently FDA-approved only for intravenous administration) and the rapid metabolic conversion of Amifostine combine to yield high systemic levels of WR-1065 and facilitate the onset of hypotension. Research efforts aiming to optimize the delivery of WR-1065 to maintain efficacy while reducing its peak, systemic concentration below levels that induce hypotension are underway. To fully characterize the effect of reduced dose levels and alternative routes of administration of Amifostine on systemic WR-1065 concentrations, improved analytical techniques are needed. We have developed and evaluated a highly sensitive method for measuring WR-1065 in rat plasma that employs chemical derivatization, protein precipitation and UPLC-MS/MS analysis. The method exhibits a limit of quantification (LOQ) of 7.4 nM in plasma, which is a significant improvement over conventional approaches that utilize LC electrochemical detection (ECD) (LOQ 150 nM or higher). The method was assessed in a pharmacokinetics study in rats administered Amifostine intravenously and via direct jejunal injection (10 mg/kg each route). The bioavailability of WR-1065 was 61.5% after direct jejunal injection indicating rapid conversion and absorption of the metabolite in the intestinal tract. This demonstrates that an oral formulation of Amifostine designed for site-specific release of the drug in the upper GI tract can deliver systemic absorption/conversion to WR-1065, provided that the formulation protects the therapeutic from gastric decomposition in the stomach. PMID- 29482123 TI - Therapeutic challenges in comorbid obsessive compulsive disorder with substance use. PMID- 29482124 TI - Treatment complexities in psychosis associated with cabergoline treatment in patients having pituitary prolactinomas. PMID- 29482125 TI - Power spectral estimation of high-harmonics in echoes of wall resonances to improve resolution in non-invasive measurements of wall mechanical properties in rubber tube and ex-vivo artery. AB - : The aim of this work is to develop a new type of ultrasonic analysis of the mechanical properties of an arterial wall with improved resolution, and to confirm its feasibility under laboratory conditions. MOTIVATION: it is expected that this would facilitate a non-invasive path for accurate predictive diagnosis that enables an early detection & therapy of vascular pathologies. In particular, the objective is to detect and quantify the small elasticity changes (in Young's modulus E) of arterial walls, which precede pathology. A submicron axial resolution is required for this analysis, as the periodic widening of the wall (under oscillatory arterial pressure) varies between +/-10 and 20 MUm. This high resolution represents less than 1% of the parietal thickness (e.g., << 7 MUm in carotid arteries). The novelty of our proposal is the new technique used to estimate the modulus E of the arterial walls, which achieves the requisite resolution. It calculates the power spectral evolution associated with the temporal dynamics in higher harmonics of the wall internal resonance f0. This was attained via the implementation of an autoregressive parametric algorithm that accurately detects parietal echo-dynamics during a heartbeat. Thus, it was possible to measure the punctual elasticity of the wall, with a higher resolution (> an order of magnitude) compared to conventional approaches. The resolution of a typical ultrasonic image is limited to several hundred microns, and thus, such small changes are undetected. The proposed procedure provides a non-invasive and direct measure of elasticity by doing an estimation of changes in the Nf0 harmonics and wall thickness with a resolution of 0.1%, for first time. The results obtained by using the classic temporal cross-correlation method (TCC) were compared to those obtained with the new procedure. The latter allowed the evaluation of alterations in the elastic properties of arterial walls that are 30 times smaller than those being detectable with TCC; in fact, the depth resolution of the TCC approach is limited to ~20 MUm for typical SNRs. These values were calculated based on echoes obtained using a reference pattern (rubber tube). The application of the proposed procedure was also confirmed via "ex-vivo" measurements in pig carotid segments. PMID- 29482126 TI - Effects of elevated sulfate concentration on the mobility of arsenic in the sediment-water interface. AB - The adsorption/desorption of arsenic (As) at the sediment-water interface in lakes is the key to understanding whether As can enter the ecosystem and participate in material circulation. In this study, the concentrations of As(III), total arsenic [As(T)], sulfide, iron (Fe), and dissolved organic carbon (DOC) in overlying water were observed after the initial sulfate (SO42-) concentrations were increased by four gradients in the presence and absence of microbial systems. The results indicate that increased SO42- concentrations in overlying water triggered As desorption from sediments. Approximately 10% of the desorbed As was desorbed directly as arsenite or arsenate by competitive adsorption sites on the iron salt surface; 21% was due to the reduction of iron (hydr)oxides; and 69% was due to microbial activity, as compared with a system with no microbial activity. The intensity of microbial activity was controlled by the SO42- and DOC concentrations in the overlying water. In anaerobic systems, which had SO42- and DOC concentrations higher than 47 and 7 mg/L, respectively, microbial activity was promoted by SO42- and DOC; As(III) was desorbed under these indoor simulation conditions. When either the SO42- or DOC concentration was lower than its respective threshold of 47 or 7 mg/L, or when either of these indices was below its concentration limit, it was difficult for microorganisms to use SO42- and DOC to enhance their own activities. Therefore, conditions were insufficient for As desorption. The migration of As in lake sediments was dominated by microbial activity, which was co-limited by SO42- and DOC. The concentrations of SO42- and DOC in the overlying water are thus important for the prevention and control of As pollution in lakes. We recommend controlling SO42- and DOC concentrations as a method for controlling As inner-source pollution in lake water. PMID- 29482127 TI - Differentiation of sympatric zebra and quagga mussels in ecotoxicological studies: A comparison of morphometric data, gene expression, and body metal concentrations. AB - The zebra mussel is among the best studied freshwater molluscs in ecotoxicology, but information on the quagga mussel is lacking. Considering its potential spread, we selected a river in France in which zebra and quagga mussels coexisted, and then we used genetic markers to differentiate the two species and compared morphological parameters. cDNA sequencing assays of ten genes already used in zebra mussels were performed on quagga mussels to obtain functional specific primers. Then we analyzed the expression of genes involved in cellular metabolic activities (Cytochrome-c-oxidase - cox, and ATP synthase - atp), detoxification processes (Glutathione-S-Transferase - gst), oxidative stress (Catalase - cat), and digestive functions (Amylase - amy) on the two species. Whereas morphometric analysis underlined similarities in shape between the two species, relative gene expression profiles and metal concentrations evidenced strong differences. Quagga mussels notably presented half as high concentrations in Cd and Pb, two particularly toxic elements, as zebra mussels. These results imply that i) particular attention should be paid to properly distinguish the two species considering their similar external appearance, and ii) zebra mussels cannot be replaced by quagga mussels in ecotoxicological studies without preliminary investigations on biomarker response patterns. To our knowledge, this study is the first to have undertaken such an approach in gene expression analysis in quagga mussels, and more generally to have compared such biomarker responses of zebra and quagga mussels in the field. PMID- 29482128 TI - Disulfide-cross-linked PEG-block-polypeptide nanoparticles with high drug loading content as glutathione-triggered anticancer drug nanocarriers. AB - The development of stimuli-responsive drug carrier systems enabling to deliver high doses of anti-cancer drugs to tumor tissues is still urgently needed. In this study, we report the preparation of reduction-responsive methoxypolyethylene glycol-block-(poly(l-lysine)-co-poly(l-tyrosine)) (mPEG-b-(PLL-co-PLY)) nanoparticles (NPs) exhibiting sizes smaller than 100 nm and high drug loading content (DLC) of doxorubicin (DOX) by selecting the Lys and Tyr residues as the polypeptide building blocks. The disulfide-cross-linked mPEG-b-(PLL-co-PLY) assemblies with sizes can be tuned by varying the polypeptide composition followed by subsequent disulfide-cross-linking. Cytotoxicity assays showed that the Dox-loaded NPs exhibited efficient cell internalization and proliferation inhibition toward cancer cells, whereas the copolymers exhibited low hemolysis to human red blood cells and excellent biocompatibility to both normal and cancer cells. The enhanced internalization and cytotoxicity of DOX-NPs can be possible due to their small size and their reduction-responsive property. Anticancer studies using C57BL/6 mice bearing LLC tumor model showed that the DOX-loaded NPs significantly suppressed tumor growth and prolonged the survival of tumor-bearing mice without obvious body weight loss and damage to major organs. This approach provides a platform for developing stimuli-responsive, polypeptide-based drug delivery systems with high DLC for cancer treatment. PMID- 29482129 TI - Biopolymer assisted synthesis of silica-carbon composite by spray drying. AB - Spray drying had been used to synthesize silica-carbon black nanocomposite micrometric granules with a uniform distribution of the two components. This was achieved by hindering the preferential diffusion of hydrophobic carbon and hydrophilic silica particles in the water droplets during evaporative assembly by introducing gum arabic as a stabilizing agent and network former. Both positive and negatively charged silica nanoparticles were used to check the stability of the sol and its effect on the morphology of the spray dried granules. X-ray and neutron scattering, complemented with electron microscopy, were used to investigate the correlation and distribution of the nanoparticles within the granules. Porous silica granules, having surface area of 157 m2/g, were obtained after removal of carbon black by calcination. An environment-friendly solar absorbing coating had been prepared using as synthesized granules. PMID- 29482130 TI - Design of diversified self-assembly systems based on a natural rosin-based tertiary amine for doxorubicin delivery and excellent emulsification. AB - A novel rosin-based ester tertiary amine (RETA) with three hydrophilic groups and a rigid hydrophobic group was synthesized from rosin by Diels-Alder addition, acylation and esterification reactions. RETA was characterized by infrared spectroscopy (FT-IR) and proton nuclear magnetic resonance spectroscopy (13C NMR). Results from testing surface tension, zeta potential, and transmission electron spectroscopy showed that RETA had unique pH responsiveness. RETA self assembled into worm-like micelles, spherical micelles 130 nm in diameter and big spherical worm-like aggregates with diameter of 2 MUm at pH = 5.76, 8.04 and 9.38, respectively. The critical micelle concentration (CMC) of RETA was 0.42 mmol/L, and the surface tension at CMC (gammacmc) was 38.73 mN/m when pH was 8.04. The RETA had a potential application in delivering doxorubicin hydrochloride (DOX) due to the pH responsiveness. Self-assembly mixed systems of RETA and rosin-based phosphoric acid (DDPD) were designed to improve emulsification. The mixed systems had obvious synergistic effects and unexpected emulsification. The gammacmc and CMC of mixtures were 41.74 mN/m and 0.20 mmol/L, the size of mixture micelles increased up to 300 nm in the optimum molar ratio of RETA/DDPD (7:3) by TEM and cryo-TEM. It was worth noting that the mixture system formed vesicles in the RETA/DDPD molar ratio of 5:5. The stability time of emulsion with RETA and DDPD as emulsifier were only 63 s and 52 s respectively, but the stability time increased to 234 s in the optimum molar ratio. In addition, the formation mechanisms of micelles at different pH and in various mixtures were discussed in detail. What's more, cytotoxicity results showed that the toxicity of RETA was lower significantly than that of lecithin, a food ingredient in egg yolk and soybean. The cell viability was more than 83% in the high concentration of RETA (4000 MUg/ml). PMID- 29482131 TI - Preparation of antimicrobial and hemostatic cotton with modified mesoporous particles for biomedical applications. AB - N-halamine polymers have been successfully attached surfaces of mesoporous materials. The modified mesoporous materials have been applied on the modification of cotton. Soaking in household bleach, the coated cotton shows good antimicrobial efficacy against S. aureus and E. coli O157:H7. The chlorinated samples could completely inactivate 100% S. aureus within 10 min, and 99.99% E. coli O157:H7 within 30 min. The chlorinated sample had better platelet adhesion and red blood cell cohesion than the control sample. The blood clotting index and fluid absorptive property of the samples enhanced after coating with modified mesoporous materials, indicating that the coated sample can prevent wound infection from bacteria and control hemorrhaging simultaneously. The coating of the modified mesoporous materials and N-halamines on cotton has not affect the bioactivity of cotton in the simulated body fluid. The active chlorine of the coated sample decreased 30% after soaking in the whole blood for 1 h. Considering the good antimicrobial efficacy against microorganisms and hemostasis property in blood control of the prepared materials, they have potentials for biomedical applications in wound dressing. PMID- 29482132 TI - Software electron counting for low-dose scanning transmission electron microscopy. AB - The performance of the detector is of key importance for low-dose imaging in transmission electron microscopy, and counting every single electron can be considered as the ultimate goal. In scanning transmission electron microscopy, low-dose imaging can be realized by very fast scanning, however, this also introduces artifacts and a loss of resolution in the scan direction. We have developed a software approach to correct for artifacts introduced by fast scans, making use of a scintillator and photomultiplier response that extends over several pixels. The parameters for this correction can be directly extracted from the raw image. Finally, the images can be converted into electron counts. This approach enables low-dose imaging in the scanning transmission electron microscope via high scan speeds while retaining the image quality of artifact free slower scans. PMID- 29482133 TI - Blunted cortisol stress reactivity in low-income children relates to lower memory function. AB - Lower socioeconomic status (SES) environments are marked by higher stress that is hypothesized to alter cortisol secretion in children, thereby damaging hippocampal volume and memory performance. However, empirical evidence demonstrating these putative links is lacking. We assessed the diurnal cortisol awakening response (CAR) on two mornings and cortisol stress reactivity (CSR) with the Trier Social Stress Test for Children in 102 healthy, socio demographically diverse 6-to-7-year-old children (46% female). Children performed a hippocampal-dependent item-location associative memory task and 60 of these children underwent structural MRI scanning for hippocampal volume. Cortisol values were modeled with latent-change structural equation models to represent overall levels and change. We found lower income is associated with a flatter CAR, blunted reactivity and recovery to acute stress, and smaller hippocampal volume. Furthermore, hyporeactivity in CSR was related to lower memory among lower-income children, whereas there was no reliable association of CSR and memory among higher-income children (an income x cortisol interaction). We found no evidence that smaller hippocampal volume in lower income was associated with poorer memory performance. Notably, hyporeactivity in both CAR and CSR was specific to using income as the SES predictor. The income x cortisol interaction and smaller hippocampal effects, however, were replicated with education and an SES composite score. This suggests that hyporeactivity to acute stress may function as a mediator in SES-cognition associations at the lower end of the SES spectrum, but it does not imply environmental- or genetically-mediated causation. PMID- 29482134 TI - Decreased circulating urokinase plasminogen activator receptor (uPAR) concentration in acute episodes of bipolar disorder; could it be a reflection of axonal injury? AB - INTRODUCTION: In recent years, the role of inflammation in the pathogenesis of Bipolar Disorder (BD) has been studied thoroughly. Urokinase-type plasminogen activator receptor (uPAR) is one of the molecules, whose concentration is of predictive value with regards to an ongoing inflammation and tissue regeneration, and it is hypothesized that it may also be altered in Bipolar Disorder. In this study, it is aimed to compare the levels of serum soluble uPAR during the manic, depressive and euthymic states of cases diagnosed with bipolar disorder, with healthy individuals. MATERIALS AND METHODS: Forty-four BD patients at manic state (BD-m), 35 BD patients at depressive state (BD-d), 42 euthymic patients (BD-e) and 41 healthy controls (HC) who were similar with the diseased subjects regarding age and smoking status included in the study. Serum soluble uPAR levels of patients and healthy controls were measured. RESULTS: The main finding of our study is that serum soluble uPAR levels are lower in patients diagnosed with BD either in depressive (BD-d) or in manic state (BD-m) than in BD patients in euthymic state (BD-e) or in healthy controls (HC). There was no significant difference in serum soluble uPAR concentrations between BD-m and BD-d s or between BD-e and HC with regards to serum soluble uPAR concentrations. CONCLUSIONS: Urokinase-type plasminogen (uPA) is a molecule which is an element of uPAR system and the molecules collectively take role in inflammation, tissue regeneration and axonal regeneration within the Central Nervous System (CNS). It has previously suggested in some studies that there may be a decrease in axonal density or axonal dysfunction in CNS in bipolar individuals. Accordingly, one may say that the low concentrations of soluble uPAR measured in our bipolar patients either at depressive or at manic state is due to the diminished regulatory role of soluble uPAR on axonal regeneration in CNS of BD cases. PMID- 29482135 TI - Single dose testosterone administration modulates emotional reactivity and counterfactual choice in healthy males. AB - Testosterone has been implicated in the regulation of emotional responses and risky decision-making. However, the causal effect of testosterone upon emotional decision-making, especially in non-social settings, is still unclear. The present study investigated the role of testosterone in counterfactual thinking: regret is an intense negative emotion that arises from comparison of an obtained outcome from a decision against a better, non-obtained (i.e. counterfactual) alternative. Healthy male participants (n = 64) received a single-dose of 150 mg testosterone Androgel in a double-blind, placebo-controlled, between-participants design. At 180 min post-administration, participants performed the counterfactual thinking task. We applied a computational model derived from behavioral economic principles to uncover latent decision-making mechanisms that may be invisible in simple choice analyses. Our data showed that testosterone increased the ability to use anticipated regret to guide choice behavior, while reducing choice based on expected value. On affective ratings, testosterone increased sensitivity to both obtained and counterfactual outcomes. These findings provide evidence that testosterone causally modulates emotional decision-making, and highlight the role of testosterone in affective sensitivity. PMID- 29482136 TI - The association between estradiol levels, hormonal contraceptive use, and responsiveness to one-session-treatment for spider phobia in women. AB - Preclinical studies have demonstrated that conditioned fear extinction is impaired in females with low endogenous levels of the sex hormone estradiol, due to menstrual fluctuations or hormonal contraceptive use. As fear extinction is a laboratory model of exposure therapy for anxiety and trauma disorders, here we assessed the hypothesis that treatment outcomes may be diminished when exposure therapy occurs during periods of low estradiol. 90 women with spider phobia (60 cycling and 30 using hormonal contraceptives) underwent a one-session exposure treatment for spider phobia, following which, serum estradiol levels were assessed. A median split in estradiol level was used to divide cycling participants into two groups; lower and higher estradiol. Behavioral avoidance and self-reported fear of spiders were measured pre-treatment, post-treatment, and at a 12 week follow-up assessment. Women using hormonal contraceptives exhibited a significantly slower rate of improvement across treatment, greater behavioral avoidance at post-treatment and follow-up, and fewer self-initiated post-treatment exposure tasks, relative to both groups of cycling women, who did not differ. No group differences in self-reported fear were evident. Correlational analyses revealed that across the whole sample, lower estradiol levels were associated with slower rates of improvement across treatment, and greater self-reported fear and behavioral avoidance at post-treatment, but not follow-up. These results provide the first evidence of an association between endogenous estradiol, hormonal contraceptive use, and exposure therapy outcomes in spider phobic women. Hormonal profile may partly account for variability in responsiveness to psychological treatments for anxiety and trauma disorders in women. PMID- 29482137 TI - Multiple grid arrangement improves ligand docking with unknown binding sites: Application to the inverse docking problem. AB - The identification of comprehensive drug-target interactions is important in drug discovery. Although numerous computational methods have been developed over the years, a gold standard technique has not been established. Computational ligand docking and structure-based drug design allow researchers to predict the binding affinity between a compound and a target protein, and thus, they are often used to virtually screen compound libraries. In addition, docking techniques have also been applied to the virtual screening of target proteins (inverse docking) to predict target proteins of a drug candidate. Nevertheless, a more accurate docking method is currently required. In this study, we proposed a method in which a predicted ligand-binding site is covered by multiple grids, termed multiple grid arrangement. Notably, multiple grid arrangement facilitates the conformational search for a grid-based ligand docking software and can be applied to the state-of-the-art commercial docking software Glide (Schrodinger, LLC). We validated the proposed method by re-docking with the Astex diverse benchmark dataset and blind binding site situations, which improved the correct prediction rate of the top scoring docking pose from 27.1% to 34.1%; however, only a slight improvement in target prediction accuracy was observed with inverse docking scenarios. These findings highlight the limitations and challenges of current scoring functions and the need for more accurate docking methods. The proposed multiple grid arrangement method was implemented in Glide by modifying a cross docking script for Glide, xglide.py. The script of our method is freely available online at http://www.bi.cs.titech.ac.jp/mga_glide/. PMID- 29482138 TI - Characterization of halotolerant, pigmented, plant growth promoting bacteria of groundnut rhizosphere and its in-vitro evaluation of plant-microbe protocooperation to withstand salinity and metal stress. AB - The use of plant associated, indigenous beneficial microbes for sustainable agriculture is getting worldwide acceptance as they successfully colonize at different plant niche under stress conditions to enhance the crop productivity. They also generate several plant growth regulators and protect plants from adversity like presence of salts and metals. In the present study, indigenous, halotolerant, plant growth promoting (PGP) bacterial isolates were isolated from the saline rhizospheric soil of groundnut plants aiming to investigate its in vitro metal remediation capabilities under saline stress condition. Two pigmented bacteria were selected based on their phenotypic, biochemical, physiological and PGP characters and identified as members of family Bacillaceae (Bacillus and Halobacillus) based on 16S rRNA gene sequence similarity. The pigments were extracted, tested for different antioxidant properties and identified by GC-MS and FT-IR spectra. Simultaneously, both strains exhibited a wide range of salinity (NaCl>=25%), metal resistance (Zinc~1700mgkg-1, Aluminium~1800mgkg-1, Lead~1800mgkg-1), pH (6-10), PGP attributes (indole - 1.05-3.15MUgml-1, ammonia - 0.13-19.95mmolml-1, nitrite - 0.07-0.26mmolml-1) and antibiotics sensitivity revealing their wide range of metabolic diversity. In-vitro inoculation of groundnut seedlings with selected isolates under salinity (1% NaCl) and metal (Zn, Al and Pb) stress had a positive impact on different plant physiological parameters (lesser lignification, intact proto xylem and cortical parenchyma) which was correlated with PGP attributes. Microwave plasma atomic emission spectroscopy analysis of seedling samples also detected less amount of metals in plants treated with bacteria indicating, an establishment of plant-microbe protocooperation to withstand salinity and metal stress. This strategy can be implemented to improve crop production in saline metal polluted agriculture fields. PMID- 29482139 TI - VSI: Environmental concentrations, cycling and modeling of technology critical elements. PMID- 29482140 TI - Hollow fibre supported liquid membrane extraction for BTEX metabolites analysis in human teeth as biomarkers. AB - The use of human teeth as biomarkers has been previously applied to characterize environmental exposure mainly to metal contamination. Difficulties arise when the contaminants are volatile or its concentration level is very low. This study presents the development of a methodology based on the transport through hollow fibre membrane liquid-phase microextraction (HF-LPME), followed by HPLC-UV measurement, to determine three different metabolites of BTEX contaminants, mandelic acid (MA), hyppuric acid (HA), and methylhippuric acid (4mHA). The driving force for the liquid membrane has been studied by using both non facilitated (pH gradient 2-12) and facilitated transport (ionic and non-ionic carriers). Enrichment factors of several hundreds were accomplished. Different ionic and non-ionic water insoluble compounds were used as metabolite carriers for the facilitated transport at HF-LPME. Three organic solvents were used to constitute the liquid membrane, dodecane, dihexyl ether and n-decanol. Other parameters affecting the extraction process, such as extraction time, stirring speed, acceptor buffer and salt content were optimised in spiked solutions and selected those that presented the best enrichment factors for all analytes. Final conditions were established for donor solution as 20mL, pH2 of 0.5M NaCl, the OLM (Organic Liquid Membrane) as n-decanol and the acceptor solution as 40MUL of 1M NaOH. The selected extraction time was 20h with stirring speed of 500rpm. Validation of the optimised method included the determination of individual linearity range (MA: 0.002-5.7MUg; HA: 0.01-7.9MUg; 4mHA 0.002-5.3MUg), limits of detection (MA: 1.6ng; HA: 0.2ng; 4mHA 0.2ng), repeatability (RSD 7-10%) and reproducibility (5-8%). The developed method was applied to the analysis of MA, HA and 4mHA in teeth samples of 8 workers exposed to BTEX. PMID- 29482141 TI - DGT technique to assess P mobilization from greenhouse vegetable soils in China: A novel approach. AB - Intensive phosphorus (P) inputs to plastic-covered greenhouse vegetable production (PGVP) in China has led to excessive soil P accumulation increasing the potential for leaching to surface waters. This study examined the mobility and hence the potential risk of P losses through correlations between soil solution P (PSol) and soil extractable P as determined by conventional soil P test methods (STPs) including degree of P saturations (DPSs), and diffusive gradient in thin-films (DGT P) technique. A total of 75 topsoil samples were chosen from five representative Chinese PGVPs covering a wide range of physiochemical soil properties and cultivation history. Total P and Olsen P contents varied from 260 to 4900, and 5 to 740mgkg-1, respectively, while PSol concentrations were between 0.01 and 10.8mgL-1 reflecting the large differences in vegetation history, fertilization schemes, and soil types. Overall, DGT P provided the best correlation with PSol (r2=0.97) demonstrating that DGT P is a versatile measure of P mobility regardless of soil type. Among the DPSs tested, oxalate extractable Al (DPSOx-Al) had the best correlation with PSol (r2=0.87). In the STP versus PSol relationships, STP break-points above which P mobilization increases steeply were 513MUgL-1 and 190mgkg-1 for DGT P or Olsen P, respectively, corresponding to PSol concentration of 0.88mgL-1. However, for PSol concentration of 0.1mgL-1 that initiates eutrophication, the corresponding DGT P and Olsen P values were 27MUgL-1 and 22mgkg-1, respectively. Over 80% of the investigated soils had DGT P and Olsen P above these values, and thus are at risk of P mobilization threatening receiving waters by eutrophication. This paper demonstrates that the DGT extracted P is a powerful measure for soluble P and hence for assessment of P mobility from a broad range of soil types. PMID- 29482142 TI - Scientific support to prescribed underburning in southern Europe: What do we know? AB - Prescribed burning is a technically demanding and usually highly scrutinized and debated practice. Barriers of various natures have constrained the development of prescribed burning in forests (PUB) in southern Europe, with insufficient research and outreach among the contributing factors. This paper synthesizes PUB knowledge in the region and identifies research needs. PUB research in the western Mediterranean basin was fostered by international cooperative projects that studied the ecological and management ramifications of low-intensity burning for fire hazard mitigation. Effects of PUB on soil and vegetation are minor and short-lived and regulated through forest floor moisture content, fire intensity, tree resistance to fire, and ignition patterns. Generic burn prescriptions are available and specific burn windows targeting site-specific burn objectives can be developed with the existing software tools. However, the need to increase the depth and breadth of PUB research is apparent. Current knowledge is based upon pine forests, particularly Pinus pinaster, as past research has overlooked hardwoods; was obtained across a limited number of research teams and study sites; and essentially reflects short-term treatments. Fuel consumption by PUB effectively decreases fire potential, but post-treatment fuel dynamics and effects on wildfire spread and severity warrant further study. Future work should devote more attention to the socioeconomic, biodiversity and carbon storage implications of PUB and should expand to encompass cumulative effects and the whole PUB regime and its variation; long-term experiments and monitored management programs are crucial to this end. PMID- 29482144 TI - Estimating the freshwater-lens reserve in the coastal plain of the middle Rio de la Plata Estuary (Argentina). AB - Drinking-water supply is one of the main issues that populations face in many coastlands. Shallow coastal aquifers are often characterized by the presence of lens-shaped freshwater floating on the saline groundwater plume of marine origin. These groundwater lenses are commonly associated with landforms, such as littoral ridges and dunes and in many cases they represent the main source of water supply in remote coastal areas. At the right side of the middle Rio de la Plata estuary (Argentina) the aquifer system is generally saline. Elongated and thin sandy beach ridge systems emerging from the general flat morphology of the marsh-flood plain are capable of storing precipitations forming freshwater lenses, which to date are the main freshwater supply for inhabitants. The aim of this study is to identify and delimitate the presence of such valuable freshwater reserves in order to provide the first necessary guidelines for the water management plan in this area, which has never been implemented since, to the Authors' knowledge, no specific investigation had been carried out before this study. To achieve this goal, Vertical Electrical Sounding, groundwater electrical conductivity measurements, water balances and groundwater chemical analyses were performed and interpreted together. The whole dataset was processed to define the electro stratigraphic model of the study area and to produce the map of the electrical conductivity of the shallow aquifer. In addition, a three-dimensional model of the fresh water reservoir has been implemented for a better understanding of the relationship between geomorphology and groundwater. Results point out that a total freshwater volume of 78,259,700m3 is stored into a continuous lens and the annual average recharge from precipitation amounts to 6,303,500m3. Although preliminary, this work provides the basic knowledge on the potential fresh groundwater lenses and provides important information for addressing a sustainable use of the freshwater resource. PMID- 29482143 TI - The water footprint of hydraulic fracturing in Sichuan Basin, China. AB - Shale gas is likely to play a major role in China's transition away from coal. In addition to technological and infrastructural constraints, the main challenges to China's sustainable shale gas development are sufficient shale gas production, water availability, and adequate wastewater management. Here we present, for the first time, actual data of shale gas production and its water footprint from the Weiyuan gas field, one of the major gas fields in Sichuan Basin. We show that shale gas production rates during the first 12 months (24 million m3 per well) are similar to gas production rates in U.S. shale basins. The amount of water used for hydraulic fracturing (34,000 m3 per well) and the volume of flowback and produced (FP) water in the first 12 months (19,800 m3 per well) in Sichuan Basin are also similar to the current water footprints of hydraulic fracturing in U.S. basins. We present salinity data of the FP water (5000 to 40,000 mgCl/L) in Sichuan Basin and the treatment operations, which include sedimentation, dilution with fresh water, and recycling of the FP water for hydraulic fracturing. We utilize the water use data, empirical decline rates of shale gas and FP water productions in Sichuan Basin to generate two prediction models for water use for hydraulic fracturing and FP water production upon achieving China's goals to generate 100 billion m3 of shale gas by 2030. The first model utilizes the current water use and FP production data, and the second assumes a yearly 5% intensification of the hydraulic fracturing process. The predicted water use for hydraulic fracturing in 2030 (50-65 million m3 per year), FP water production (50 55 million m3 per year), and fresh water dilution of FP water (25 million m3 per year) constitute a water footprint that is much smaller than current water consumption and wastewater generation for coal mining, but higher than those of conventional gas production in China. Given estimates for water availability in Sichuan Basin, our predictions suggest that water might not be a limiting factor for future large-scale shale gas development in Sichuan Basin. PMID- 29482145 TI - High resolution mapping of soil organic carbon stocks using remote sensing variables in the semi-arid rangelands of eastern Australia. AB - Efficient and effective modelling methods to assess soil organic carbon (SOC) stock are central in understanding the global carbon cycle and informing related land management decisions. However, mapping SOC stocks in semi-arid rangelands is challenging due to the lack of data and poor spatial coverage. The use of remote sensing data to provide an indirect measurement of SOC to inform digital soil mapping has the potential to provide more reliable and cost-effective estimates of SOC compared with field-based, direct measurement. Despite this potential, the role of remote sensing data in improving the knowledge of soil information in semi-arid rangelands has not been fully explored. This study firstly investigated the use of high spatial resolution satellite data (seasonal fractional cover data; SFC) together with elevation, lithology, climatic data and observed soil data to map the spatial distribution of SOC at two soil depths (0-5cm and 0-30cm) in semi-arid rangelands of eastern Australia. Overall, model performance statistics showed that random forest (RF) and boosted regression trees (BRT) models performed better than support vector machine (SVM). The models obtained moderate results with R2 of 0.32 for SOC stock at 0-5cm and 0.44 at 0-30cm, RMSE of 3.51MgCha-1 at 0-5cm and 9.16MgCha-1 at 0-30cm without considering SFC covariates. In contrast, by including SFC, the model accuracy for predicting SOC stock improved by 7.4-12.7% at 0-5cm, and by 2.8-5.9% at 0-30cm, highlighting the importance of including SFC to enhance the performance of the three modelling techniques. Furthermore, our models produced a more accurate and higher resolution digital SOC stock map compared with other available mapping products for the region. The data and high-resolution maps from this study can be used for future soil carbon assessment and monitoring. PMID- 29482146 TI - Tertiary treatment and dual disinfection to improve microbial quality of reclaimed water for potable and non-potable reuse: A case study of facilities in North Carolina. AB - Treated wastewater is increasingly of interest for either nonpotable purposes, such as agriculture and industrial use, or as source water for drinking water supplies; however, this type of advanced treatment for water supply is not always possible for many low resource settings. As an alternative, multiple barriers of physical, chemical and biological treatment with lower cost and simpler operation and maintenance have been proposed as more globally applicable. One such water reclamation system for both non-potable and potable reuse, is that approved by the State of North Carolina "for Type 2" reclaimed water (NCT2RW). NC Type 2 potable reuse systems consist of a sequence of tertiary treatment to produce well oxidized reclaimed water that is then then further treated by two steps of disinfection, typically UV radiation and chlorination. In this case study, the log10 microbial reduction performance of NCT2RW producing water reclamation facilities is evaluated. Based on the results presented here, NCT2RW consistently achieved high (6 for bacteria, 4 for virus and 4 for protozoan parasite surrogates) log10 reductions using the NC proposed treatment methods. Additionally, lower but significant log10 reduction performance was also documented for protozoan parasites and human enteric viruses. PMID- 29482147 TI - Fine resolution map of top- and subsoil carbon sequestration potential in France. AB - Although soils have a high potential to offset CO2 emissions through its conversion into soil organic carbon (SOC) with long turnover time, it is widely accepted that there is an upper limit of soil stable C storage, which is referred to SOC saturation. In this study we estimate SOC saturation in French topsoil (0 30cm) and subsoil (30-50cm), using the Hassink equation and calculate the additional SOC sequestration potential (SOCsp) by the difference between SOC saturation and fine fraction C on an unbiased sampling set of sites covering whole mainland France. We then map with fine resolution the geographical distribution of SOCsp over the French territory using a regression Kriging approach with environmental covariates. Results show that the controlling factors of SOCsp differ from topsoil and subsoil. The main controlling factor of SOCsp in topsoils is land use. Nearly half of forest topsoils are over-saturated with a SOCsp close to 0 (mean and standard error at 0.19+/-0.12) whereas cropland, vineyard and orchard soils are largely unsaturated with degrees of C saturation deficit at 36.45+/-0.68% and 57.10+/-1.64%, respectively. The determinant of C sequestration potential in subsoils is related to parent material. There is a large additional SOCsp in subsoil for all land uses with degrees of C saturation deficit between 48.52+/-4.83% and 68.68+/-0.42%. Overall the SOCsp for French soils appears to be very large (1008Mt C for topsoil and 1360Mt C for subsoil) when compared to previous total SOC stocks estimates of about 3.5Gt in French topsoil. Our results also show that overall, 176Mt C exceed C saturation in French topsoil and might thus be very sensitive to land use change. PMID- 29482148 TI - Life cycle assessment of Mexican polymer and high-durability cotton paper banknotes. AB - This study compares the environmental performance of Mexican banknotes printed on high-durability cotton paper (HD paper) and thermoplastic polymer (polymer) through a life cycle assessment to appraise the environmental impacts from the extraction of raw materials to the final disposal of the banknotes. The functional unit was defined considering the next parameters: 1) lifespan of the banknotes, stablished in 31.5 and 54months for HD paper and polymer, respectively; 2) denomination, selecting $200 pesos banknotes; 3) a 5year time frame and 4) a defined amount of money, in this case stablished as the monthly cash supply of an average Mexican household, equaling $12,708 pesos. Accordingly, 121 pieces for the HD paper and 71 pieces for the polymer banknotes were analyzed. The results favor the banknotes printed on polymer substrate primarily because of the longer lifespan of this type of material; however, there is a considerable environmental impact in the stages of distribution, followed by the extraction of the raw materials (crude oil) during manufacturing. Regarding the HD cotton paper, the major impact corresponds to extraction of the raw materials, followed by the distribution of the banknotes. The inclusion of the automatic teller machines (ATMs) in the life cycle assessment of banknotes shows that the electricity required by these devices became the largest contributor to the environmental impacts. Additionally, the sensitivity analysis that the average lifetime of the banknotes is a determining factor for the environmental impacts associated with the whole life cycle of this product. The life cycle stages that refer to the extraction of the raw materials, combined with the average lifetime of the banknotes and the electricity required during the usage stage, are determining factors in the total environmental impact associated with Mexican banknotes. PMID- 29482149 TI - Abiotic and biotic determinants of coarse woody productivity in temperate mixed forests. AB - Forests play an important role in regulating the global carbon cycle. Yet, how abiotic (i.e. soil nutrients) and biotic (i.e. tree diversity, stand structure and initial biomass) factors simultaneously contribute to aboveground biomass (coarse woody) productivity, and how the relative importance of these factors changes over succession remain poorly studied. Coarse woody productivity (CWP) was estimated as the annual aboveground biomass gain of stems using 10-year census data in old growth and secondary forests (25-ha and 4.8-ha, respectively) in northeast China. Boosted regression tree (BRT) model was used to evaluate the relative contribution of multiple metrics of tree diversity (taxonomic, functional and phylogenetic diversity and trait composition as well as stand structure attributes), stand initial biomass and soil nutrients on productivity in the studied forests. Our results showed that community-weighted mean of leaf phosphorus content, initial stand biomass and soil nutrients were the three most important individual predictors for CWP in secondary forest. Instead, initial stand biomass, rather than diversity and functional trait composition (vegetation quality) was the most parsimonious predictor of CWP in old growth forest. By comparing the results from secondary and old growth forest, the summed relative contribution of trait composition and soil nutrients on productivity decreased as those of diversity indices and initial biomass increased, suggesting the stronger effect of diversity and vegetation quantity over time. Vegetation quantity, rather than diversity and soil nutrients, is the main driver of forest productivity in temperate mixed forest. Our results imply that diversity effect for productivity in natural forests may not be so important as often suggested, at least not during the later stage of forest succession. This finding suggests that as a change of the importance of different divers of productivity, the environmentally driven filtering decreases and competitively driven niche differentiation increases with forest succession. PMID- 29482150 TI - Identifying injection drug use and estimating population size of people who inject drugs using healthcare administrative datasets. AB - BACKGROUND: Large linked healthcare administrative datasets could be used to monitor programs providing prevention and treatment services to people who inject drugs (PWID). However, diagnostic codes in administrative datasets do not differentiate non-injection from injection drug use (IDU). We validated algorithms based on diagnostic codes and prescription records representing IDU in administrative datasets against interview-based IDU data. METHODS: The British Columbia Hepatitis Testers Cohort (BC-HTC) includes ~1.7 million individuals tested for HCV/HIV or reported HBV/HCV/HIV/tuberculosis cases in BC from 1990 to 2015, linked to administrative datasets including physician visit, hospitalization and prescription drug records. IDU, assessed through interviews as part of enhanced surveillance at the time of HIV or HCV/HBV diagnosis from a subset of cases included in the BC-HTC (n = 6559), was used as the gold standard. ICD-9/ICD-10 codes for IDU and injecting-related infections (IRI) were grouped with records of opioid substitution therapy (OST) into multiple IDU algorithms in administrative datasets. We assessed the performance of IDU algorithms through calculation of sensitivity, specificity, positive predictive, and negative predictive values. RESULTS: Sensitivity was highest (90-94%), and specificity was lowest (42-73%) for algorithms based either on IDU or IRI and drug misuse codes. Algorithms requiring both drug misuse and IRI had lower sensitivity (57-60%) and higher specificity (90-92%). An optimal sensitivity and specificity combination was found with two medical visits or a single hospitalization for injectable drugs with (83%/82%) and without OST (78%/83%), respectively. Based on algorithms that included two medical visits, a single hospitalization or OST records, there were 41,358 (1.2% of 11-65 years individuals in BC) recent PWID in BC based on health encounters during 3- year period (2013-2015). CONCLUSION: Algorithms for identifying PWID using diagnostic codes in linked administrative data could be used for tracking the progress of programing aimed at PWID. With population-based datasets, this tool can be used to inform much needed estimates of PWID population size. PMID- 29482151 TI - New acrylamide-substituted quinazoline derivatives with enhanced potency for the treatment of EGFR T790M-mutant non-small-cell lung cancers. AB - A new class of acrylamide-substituted quinazoline derivatives with enhanced inhibitory activity against mutant EGFR T790M enzyme were synthesized. Among them, compound 10b displayed the strongest inhibitory potency to block the phosphorylation of the EGFR T790M enzyme, with an IC50 value of 4.3 nM. Compared with the lead compound gefitinib, compound 10b significantly strengthened the activity against EGFR T790M (194 times higher). Furthermore, compound 10b only exhibited moderate activity against wild type EGFR, with an IC50 of 105.0 nM, suggesting its improved selectivity over the T790M-mutated EGFR. In addition, compound 10b also showed stronger activity against H1975 cells harboring the EGFR T790M mutation than gefitinib. Moreover, compound 10b has low inhibitory activity toward the normal HBE cells (IC50 > 34.04 MUM), indicating its low cell cytotoxicity. Overall, this modification provided a new insight to design covalent binding EGFRT790M inhibitors to prevent NSCLC resistance. PMID- 29482152 TI - Age, socioeconomic patterns and regional variations in grip strength among older adults (50+) in India: Evidence from WHO's Study on Global Ageing and Adult Health (SAGE). AB - BACKGROUND: Muscle strength, measured as grip strength is a potential marker of bodily function and sarcopaenia. Yet, not much is known about its patterns and correlates among older population in India. This study assesses the age and socioeconomic patterns and state variations in grip strength among older adults (50+) in India. METHODS: A cross-sectional and nationally representative data from the first wave of WHO's Study on global Ageing and Adult Health (SAGE) -2007 (n = 6262) was used. Multivariable linear regression analyses were used to understand the regional variations and association of socioeconomic status and general health with grip strength, adjusting for anthropometric and demographic confounders. RESULTS: Socioeconomic status has a significant association with grip strength. Moreover, the association between wealth quintile and grip strength was highly significant. Further, the socioeconomic differences in grip strength narrowed in older ages, especially among men, supporting the convergence of health inequality hypothesis. Notable differences were observed in grip strength across selected states of India. Poor self-rated health was negatively associated with grip strength. Edentulism in men was associated with reduced grip strength. CONCLUSION: This study has contributed to a better understanding of significant social and regional inequalities in grip strength among older population in India. State-specific and subgroup level interventions are important to improve the physical functioning of the growing older population in India. PMID- 29482153 TI - Optical parameters and dispersion behavior of potassium magnesium chloride sulfate single crystals doped with Co+2 ions. AB - Single crystals of potassium magnesium chloride sulfate (KMCS) doped with cobalt ions were grown by slow cooling method. Powder XRD study confirmed the monoclinic structure of the grown crystals. The functional group vibrations were checked through FTIR spectroscopy measurements. In optical studies, the absorbance behavior of the crystals and their optical energy gap were established by Tauc plot. The refractive index, the extinction coefficient and other optical constants were calculated for the grown crystals. The normal dispersion of the refractive index was analyzed according to single oscillator Sellmeier's model. The Urbach's rule was applied to analyze the localized states density in the forbidden gap. PMID- 29482154 TI - Childhood obesity in China: Does grandparents' coresidence matter? AB - Childhood obesity in China has been increasingly cited as a major public health issue in recent decades. The effect of grandparents on grandchildren's weight outcome is under-analyzed. Using data from the China Health and Nutrition Survey, we examine the effect of grandparents' coresidence on childhood weight outcome with a sample of 2-13-year-old children in China. We use instrumental variables to address the potential endogeneity of grandparents' coresidence. We show that the effect of grandparents' coresidence on childhood weight outcome is significantly positive. Grandparents' coresidence affects a grandchild's weight outcome through changes in dietary patterns and physical activity. The effects on dietary patterns exist in urban areas and significantly lower in rural areas. Grandparents' coresidence decreases physical activity more in rural areas than in urban areas. Furthermore, the effects of coresidence on protein intake and physical activities of children above 6 are significantly higher for males than females. A robustness check, including an ordered logit model with a body mass index category and estimation with additional data, validates our findings. PMID- 29482155 TI - Sex selection and health at birth among Indian immigrants. AB - I use birth-certificate data for Spain to document extremely son-biased sex ratios at birth among Indian immigrants (122 boys per 100 girls), especially at higher parities. I also show that the children of Indian immigrants display poor health outcomes during infancy. For instance, almost 10% of boys with Indian parents are born prematurely, compared with 6% of boys with native parents. However, there is no evidence of a gender gap in infant health among the children of Indian immigrants. I provide evidence suggesting that the poor outcomes of Indian children at birth may be attributed to the low endowments of Indian mothers, while the absence of a gender gap may be driven by the fact that the parents who would invest less in girls are less likely to carry the pregnancies of girls to term (more likely to practice sex-selective abortion), combined with the lower cost of prenatal investments in Spain (compared with India). PMID- 29482157 TI - IL-17A promotes the formation of deep vein thrombosis in a mouse model. AB - Deep venous thrombosis (DVT) is a significant problem in the health care industry worldwide. However, the factors and signaling pathways that trigger DVT formation are still largely unknown. In this study, we investigated the role of interleukin 17A (IL-17A) in DVT formation, focusing on the role of platelet aggregation, neutrophil infiltration, and endothelium cell (EC) activation. Notably, IL-17A levels increased in DVT patients as well as in a mouse DVT model. The DVT model mice were injected with recombinant mouse-IL-17A (rIL-17A) or anti-IL-17A monoclonal antibody (mAb) to further evaluate the effects of this cytokine. We found that rIL-17A promotes DVT formation, while IL-17A mAb represses DVT formation. Furthermore, platelet activation, highlighted by CD61 and CD49beta expression, and aggregation were enhanced in platelets of rIL-17A-treated mice. rIL-17A also enhanced neutrophil infiltration by regulating the expression of macrophage inflammatory protein-2 (MIP-2) and the release of neutrophil extracellular traps (NETs). IL-17A mAb treatment inhibited both platelet activation and neutrophil activity. Moreover, rIL-17A appears to promote vein EC activation, while IL-17A mAb deters it. Taken together, these data suggest that IL-17A promotes DVT pathogenesis by enhancing platelet activation and aggregation, neutrophil infiltration, and EC activation and that anti-IL-17A mAb could be used for the treatment of DVT. PMID- 29482156 TI - Berberine inhibits macrophage M1 polarization via AKT1/SOCS1/NF-kappaB signaling pathway to protect against DSS-induced colitis. AB - Berberine has been reported to have protective effects in colitis treatment. However, the detailed mechanisms remain unclear. Herein, we demonstrated that berberine could protect against dextran sulfate sodium (DSS)-induced colitis in mice by regulating macrophage polarization. In the colitis mouse model, berberine ameliorated DSS-induced colon shortening and colon tissue injury. Moreover, berberine-treated mice showed significant reduction in the disease activity index (DAI), pro-inflammatory cytokines expression and macrophages infiltration compared with the DSS-treated mice. Notably, berberine significantly reduced the percentage of M1 macrophages. In vitro analysis also confirmed the inhibitory effects of berberine on macrophages M1 polarization in RAW267.4 cells. Further investigation showed that berberine promoted AKT1 expression in mRNA and protein level. Silence of AKT1 abolished the inhibitory effect of berberine on macrophages M1 polarization. The berberine-induced AKT1 expression promoted suppressers of cytokine signaling (SOCS1) activation, which inhibited nuclear factor-kappa B (NF-kappaB) phosphorylation. In addition, we also found that berberine activated AKT1/SOCS1 signaling pathway but inhibited p65 phosphorylation in macrophages in vivo. Therefore, we concluded that berberine played a regulatory role in macrophages M1 polarization in DSS-induced colitis via AKT1/SOCS1/NF-kappaB signaling pathway. This unexpected property of berberine may provide a potential explanation for its protective effects in colitis treatment. PMID- 29482158 TI - TIM-3 expression identifies a distinctive PD-1+ follicular helper T cell subset, with reduced interleukin 21 production and B cell help function in ovarian cancer patients. AB - Follicular helper T (Tfh) cells are critical regulators of immune responses in several human malignancies. Their characteristics in ovarian cancer (OC) patients remain unclear. In this study, the circulating CD4+CXCR5+ Tfh cells was examined and compared in OC patients and non-cancer (NC) controls. Data showed that the frequency of PD-1+ Tfh cells was significantly higher in OC patients than in NC controls. Compared to PD-1- Tfh cells, PD-1+ Tfh cells presented higher interleukin (IL)-21 and IL-10 secretion and stronger proliferation. The PD-1+ Tfh cells from OC patients presented further increased IL-21 and IL-10 secretion than those from NC controls. When incubated with autologous naive B cells, PD-1+ Tfh cells from both OC patients and NC controls presented elevated capacity at inducing Ig secretion. Interestingly, TIM-3 expression was predominantly found in PD-1+ Tfh cells. Compared to TIM-3- PD-1+ Tfh cells, TIM-3+ PD-1+ Tfh cells presented significantly lower levels of IL-21 secretion and lower proliferation. In addition, TIM-3+ PD-1+ Tfh cells presented marked impairment in inducing IgM, IgG, and IgA secretion from B cells. Importantly, in OC patients, the frequencies of PD-1+ Tfh cells and TIM-3+ PD-1+ Tfh significantly enriched in tumor infiltrating lymphocytes than in peripheral blood. Together, we demonstrated that Tfh cells could be subdivided into distinctive functional subsets based on PD-1 and TIM-3 expressions, and while PD-1 demarcated a potent Tfh subset, TIM-3 seemed to associate with reduced Tfh function. PMID- 29482159 TI - Substance P-regulated leukotriene B4 production promotes acute pancreatitis associated lung injury through neutrophil reverse migration. AB - Leukotriene B4 (LTB4) is a potent chemoattractant and inflammatory mediator involved in multiple inflammatory diseases. Substance P (SP) has been reported to promote production of LTB4 in itch-associated response in vivo and in some immune cells in vitro. Here, we investigated the role of LTB4 in acute pancreatitis (AP), AP-associated acute lung injury (ALI) and the related mechanisms of LTB4 production in AP. In vivo, murine AP model was induced by caerulein and lipopolysaccharide or L-arginine. The levels of LTB4 and its specific receptor BLT1 were markedly upregulated in both AP models. Blockade of BLT1 by LY293111 attenuated the severity of AP, decreased neutrophil reverse transendothelial cell migration (rTEM) into the circulation and alleviated the severity of ALI. In vitro, treatment of pancreatic acinar cells with SP increased LTB4 production. Furthermore, SP treatment increased phosphorylation of protein kinase C (PKC) alpha and mitogen activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK), p-38 MAPK and c-Jun NH2-terminal kinase (JNK). Finally, blockade of neurokinin-1 receptor by CP96345 significantly attenuated the severity of AP and decreased the level of LTB4 when compared to AP group. In summary, these results show that SP regulates the production of LTB4 via PKCalpha/MAPK pathway, which further promotes AP-associated ALI through neutrophil rTEM. PMID- 29482160 TI - Development of a novel carboplatin like cytoplasmic trackable near infrared fluorophore conjugate via strain-promoted azide alkyne cycloaddition. AB - The successful design and pre-clicked synthesis of a non-toxic and cytosol trackable carboplatin-like near infrared fluorophore conjugate via strain promoted azide alkyne cycloaddition (SPAAC) is reported. Reaction of cis-[Pt(2 azidopropane-1,3-diamine)(cbdca)] (cbdca = cyclobutane-1,1-dicarboxylato) and a bicyclo[6.1.0]non-4-yne near-infrared (NIR) azadipyrromethene fluorophore gave the corresponding clicked Pt-Fluorophore conjugate. The X-ray crystal structure of cis-[Pt(2-azidopropane-1,3-diamine)(cbdca)] was determined featuring the azide on the bidentate 1,3-diaminopropane ligand. The Pt-fluorophore conjugate is the first example of a Pt conjugate clicked via strain-promoted azide alkyne cycloaddition (SPAAC) where the reactive azide handle is on the amine carrier ligand. The in vitro cytotoxicity and widefield fluorescence imaging of the Pt Fluorophore conjugate in A2780P and A2780cisR cells are described. PMID- 29482161 TI - Direct imaging of how lanthanides break the normal evolution of plants. AB - After rare earth elements [REE(III)] are anchored outside of the plasma membrane, REE(III) break plant evolution to initiate leaf cell endocytosis, which finally affects plant growth. However, the molecule for anchoring REE(III) in the acidic environment outside of the plasma membrane is not clear, which is crucial for exploring the mechanism of REE(III) breaking plant evolution. Here, lanthanum(III) [La(III)] and terbium(III) [Tb(III)] were respectively served as a representative of REE(III) without and with f electrons, and Arabidopsis was served as a representative of plants, cellular and molecular basis for arabinogalactan proteins (AGP) anchoring REE(III) outside of the plasma membrane was investigated. By using interdisciplinary methods, when REE(III) initiated leaf cell phagocytosis, we observed the increase in the expression of AGP and their migration to the outside of the plasma membrane. In the acidic environment outside of the plasma membrane, Tb(III) formed more stable Lewis acid-base [REE(III)-AGP] complexes with a higher apparent binding constant (1.51 * 10-6) than La(III) (1.24 * 10-6). In REE(III)-AGP complexes, the bond lengths of REE(III)-O were in normal range and H-bonds were strong H-bonds. The formation of REE(III)-AGP complexes sequentially disturbed the secondary and tertiary structure of AGP, which were enhanced with increasing the concentration of REE(III), and Tb(III) caused stronger structural changes than La(III). Hence, AGP could be molecules for anchoring REE(III) outside of the plasma membrane. The results of this study are direct imaging of how lanthanides break the normal evolution of plants, and can serve as an important guidance for investigating mechanism of lanthanides in organisms. PMID- 29482162 TI - Ethanol production from mixtures of sugarcane bagasse and Dioscorea composita extracted residue with high solid loading. AB - Various mixing ratios of alkali pretreated sugarcane bagasse and starch-rich waste Dioscorea composita hemls extracted residue (DER) were evaluated via simultaneous saccharification and fermentation (SSF) with 12% (w/w) solid loading, and the mixture ratio of 1:1 achieved the highest ethanol concentration and yield. When the solid loading was increased from 12% to 32%, the ethanol concentration was increased to 72.04 g/L, whereas the ethanol yield was reduced from 84.40% to 73.71%. With batch feeding and the addition of 0.1% (w/v) Tween 80, the final ethanol concentration and yield of SSF at 34% loading were 82.83 g/L and 77.22%, respectively. Due to the integration with existing starch-based ethanol industry, the co-fermentation is expected to be a competitive alternative form for cellulosic ethanol production. PMID- 29482163 TI - Effect of pretreatments on biogas production from microalgae biomass grown in pig manure treatment plants. AB - Methane production from pretreated and raw mixed microalgae biomass grown in pig manure was evaluated. Acid and basic pretreatments provided the highest volatile solids solubilisation (up to 81%) followed by alkaline-peroxide and ultrasounds (23%). Bead milling and steam explosion remarkably increased the methane production rate, although the highest yield (377 mL CH4/g SV) was achieved by alkali pretreatment. Nevertheless, some pretreatments inhibited biogas production and resulted in lag phases of 7-9 days. Hence, experiments using only the pretreated solid phase were performed, which resulted in a decrease in the lag phase to 2-3 days for the alkali pretreatment and slightly increased biomass biodegradability of few samples. The limiting step during the BMP test (hydrolysis or microbial inhibition) for each pretreatment was elucidated using the goodness of fitting to a first order or a Gompertz model. Finally, the use of digestate as biofertilizer was evaluated applying a biorefinery concept. PMID- 29482164 TI - Mechanism analyses of high specific filtration resistance of gel and roles of gel elasticity related with membrane fouling in a membrane bioreactor. AB - In this study, mechanisms and roles of gel elasticity in extremely high specific filtration resistance (SFR) were investigated. It was found that, as compared with cake layer in a membrane bioreactor (MBR), real gel layer in the MBR and agar gel possessed extremely high SFR. Foulant characterization showed that foulants were easy to bind water, and agar gel possessed a network structure. Mechanisms based on Flory-Huggins and Flory-Rehner models were deduced to describe the high SFR of agar gel. Model simulation showed that sum of SFR induced by the mixing chemical potential and the elastic chemical potential change is close to that of the agar gel, suggesting feasibility of the deduced models. Gel elasticity accounted for about 13% of total SFR of agar gel under conditions in this study. This study satisfactorily explained the extremely high SFR of gel, and addressed roles of gel elasticity in gel SFR. PMID- 29482165 TI - Investigation on the fates of vanadium and nickel during co-gasification of petroleum coke with biomass. AB - This study investigates the volatilization behaviors and mineral transformation of vanadium and nickel during co-gasification of petroleum coke with biomass. Moreover, the evolution of occurrence modes of vanadium and nickel was also determined by the method of sequential chemical extraction. The results show that the volatilities of vanadium and nickel in petroleum coke have a certain level of growth with an increase in the temperature. With the addition of biomass, their volatilities both show an obvious decrease. Organic matter and stable forms are the dominant chemical forms of vanadium and nickel. After gasification, organic bound vanadium and nickel decompose completely and convert into other chemical forms. The crystalline phases of vanadium trioxide, coulsonite, nickel sulfide, and elemental nickel are clearly present in petroleum coke and biomass gasification ashes. When the addition of biomass reaches 60 wt%, the diffraction peaks of orthovanadate are found while that of vanadium trioxide disappear. PMID- 29482166 TI - The composition of accessory enzymes of Penicillium chrysogenum P33 revealed by secretome and synergistic effects with commercial cellulase on lignocellulose hydrolysis. AB - Herein, we report the secretome of Penicillium chrysogenum P33 under induction of lignocellulose for the first time. A total of 356 proteins were identified, including complete cellulases and numerous hemicellulases. Supplementing a commercial cellulase with increasing dosage of P33 enzyme cocktail from 1 to 5 mg/g substrate increased the release of reducing sugars from delignified corn stover by 21.4% to 106.8%. When 50% cellulase was replaced by P33 enzyme cocktail, release of reducing sugars was 78.6% higher than with cellulase alone. Meanwhile, glucan and xylan conversion was increased by 37% and 106%, respectively. P33 enzyme cocktail also enhanced commercial cellulase hydrolysis against four different delignified lignocellulosic biomass. These findings demonstrate that mixing appropriate amount of P33 cocktail with cellulase improves polysaccharide hydrolysis, suggesting P33 enzymes have great potential for industrial applications. PMID- 29482167 TI - Pandoraea sp. B-6 assists the deep eutectic solvent pretreatment of rice straw via promoting lignin depolymerization. AB - Lignin depolymerization is a challenging process in biorefinery due to the recalcitrant and complex structure of lignin. This challenge was herein addressed via elaborating a new strategy of combining the bacterial strain Pandoraea sp. B 6 (hereafter B-6) with a deep eutectic solvent (DES) to pretreat rice straw (RS). In this approach, DES effectively depolymerized lignin yet easily caused sugar loss under severe conditions. B-6 not only overcame the obstacle of lignin droplets, but also significantly improved enzymatic digestibility. After B-6 assisted DES pretreatment, the reducing sugar yield increases by 0.3-1.5 times over DES pretreatment and 0.9-3.1 times over the untreated RS. Furthermore, a "cornhusking" mechanism explaining the improvement of the enzymatic digestibility by B-6 was suggested based on physicochemical characterizations of the untreated and pretreated RS. The findings provided a comprehensive perspective to establish a DES-microbial process for lignocellulose pretreatment. PMID- 29482169 TI - Architecture shapes contractility in actomyosin networks. AB - Myosin-driven contraction of the actin cytoskeleton is at the base of cell and tissue morphogenesis. At the molecular level, myosin motors drive contraction by sliding actin filaments past one another using energy produced by ATP hydrolysis. How this microscopic sliding activity gives rise to cell-scale contractions has been an active research question first in muscle cells, and over the last few decades in non-muscle cells. While many early investigations focused on myosin motor activity, increasingly, the nanoscale architecture of the actin network emerges as a key regulator of contractility. Here we review theoretical and in vitro reconstitution studies that have uncovered some of the key mechanisms by which actin network organization controls contractile tension generation. We then discuss recent findings indicating that similar principles apply in cells. PMID- 29482168 TI - Fasting exacerbates hepatic growth differentiation factor 15 to promote fatty acid beta-oxidation and ketogenesis via activating XBP1 signaling in liver. AB - Liver coordinates a series of metabolic adaptations to maintain systemic energy balance and provide adequate nutrients for critical organs, tissues and cells during starvation. However, the mediator(s) implicated in orchestrating these fasting-induced adaptive responses and the underlying molecular mechanisms are still obscure. Here we show that hepatic growth differentiation factor 15 (GDF15) is regulated by IRE1alpha-XBP1s branch and promotes hepatic fatty acids beta oxidation and ketogenesis upon fasting. GDF15 expression was exacerbated in liver of mice subjected to long-term fasted or ketogenic diet feeding. Abrogation of hepatic Gdf15 dramatically attenuated hepatic beta-oxidation and ketogenesis in fasted mice or mice with STZ-initiated type I diabetes. Further study revealed that XBP1s activated Gdf15 transcription via binding to its promoter. Elevated GDF15 in liver reduced lipid accumulation and impaired NALFD development in obese mice through enhancing fatty acids oxidation in liver. Therefore, our results demonstrate a novel and critical role of hepatic GDF15 activated by IRE1alpha XBP1s branch in regulating adaptive responses of liver upon starvation stress. PMID- 29482170 TI - Lexical olfaction recruits olfactory orbitofrontal cortex in metaphorical and literal contexts. AB - The investigation of specific lexical categories has substantially contributed to advancing our knowledge on how meaning is neurally represented. One sensory domain that has received particularly little attention is olfaction. This study aims to investigate the neural representation of lexical olfaction. In an fMRI experiment, participants read olfactory metaphors, their literal paraphrases, and literal olfactory sentences. Regions of interest were defined by a functional localizer run of odor processing. We observed activation in secondary olfactory areas during metaphorical and literal olfactory processing, thus extending previous findings to the novel source domain of olfaction. Previously reported enhanced activation in emotion-related areas due to metaphoricity could not be replicated. Finally, no primary olfactory cortex was found active during lexical olfaction processing. We suggest that this absence is due to olfactory hedonicity being crucial to understand the meaning of the current olfactory expressions. Consequently, the processing of olfactory hedonicity recruits secondary olfactory areas. PMID- 29482171 TI - Pressure rise in medical cyclotron liquid targets: Transient analysis. AB - Transient behavior of proton-beam bombarded liquid-targets are studied at various initial conditions at the TR13 cyclotron at TRIUMF. Depending on the initial condition, experiments show a range of different responses from steady-state to self-sustained oscillations. To address this, a system of equations based on the conservation of mass and energy is proposed. Coupling between the beam and fluid density and chemical reactions driven by the beam (radiolysis) are identified as the main reasons to describe this behavior. Excellent qualitative agreements are achieved. PMID- 29482172 TI - The importance of meaningful activity in people living with acute myeloid leukemia. AB - PURPOSE: The symptom burden of acute myeloid leukemia (AML) and its treatment can accelerate physical deconditioning and impair mobility and quality of life. In the present study, we explore the subjective experience of functional capacity in people living with AML. METHODS: A secondary qualitative analysis was performed on a subset of interviews (n = 21) obtained from an observational cohort study of people with acute leukemia. Conventional content analysis was employed to identify key themes and concepts. RESULTS: Participants valued their physical function to the extent that it was required to pursue personally meaningful activities and interests. We identified Meaningful Activity as an overarching goal of participants. Three interrelated themes captured the obstacles participants reported facing when attempting to realize this goal: Compromised Body, Threatened Identity, and Shrinking World. Adaptation was common across themes, representing the strategies employed to overcome such challenges. Themes were consistent across participants, despite the variability in disease states at the time of the interview. CONCLUSIONS: Dynamic interactions between physical, psychological, and environmental factors affect the pursuit and achievement of meaningful activity among people living with AML. It may be important to consider personal incentives when designing interventions for physical rehabilitation in this patient population. PMID- 29482173 TI - Widespread use of measurable residual disease in acute myeloid leukemia practice. AB - PURPOSE: Measurable residual disease (MRD) has prognostic importance for patients with acute myeloid leukemia (AML). How leukemia providers incorporate MRD into routine practice remains undefined. PATIENTS AND METHODS: A survey was developed and distributed to a large sample of leukemia physicians. Demographic information was collected along with details concerning MRD practices. A multivariable logistic regression model evaluated provider characteristics predictive of MRD utilization. RESULTS: 268 responses were received (response rate of 41%). 69% of providers reported routine use of MRD in management of AML, most commonly (90%) for its role in guiding therapy; providers who did not use MRD routinely most frequently cited inadequate resources (58%). Providers utilized flow cytometry- more than polymerase chain reaction-based assays with nucleophosmin-1 being the most common target with the latter. We found substantial variability in how MRD affected clinical decision making, particularly in pre- and post-transplant scenarios. CONCLUSIONS: MRD was frequently used in making treatment decisions and in estimating prognosis. However, there was lack of uniformity in these practices. Standardization of assays, adoption of requisite technology, and dissemination of data about the value of MRD use would likely increase usage of MRD in the care of patients with AML. PMID- 29482174 TI - Knockdown of the Wnt receptor Frizzled-1 (FZD1) reduces MDR1/P-glycoprotein expression in multidrug resistant leukemic cells and inhibits leukemic cell proliferation. AB - Multidrug resistance (MDR) is a major obstacle to leukemia treatment. The Frizzled-1 (FZD1) Wnt receptor is involved in MDR in some solid cancers, but has rarely been reported to act in acute myeloid leukemia (AML). We investigated whether the knockdown of FZD1 affects MDR1 expression and P-glycoprotein (P-gp) function in multidrug resistant leukemic cell lines, as well as FZD1 and MDR1/P gp expression in leukemic cells taken from patients with AML (n = 112). FZD1 knockdown significantly reduced MDR1 expression through the Wnt/beta-catenin pathway, disrupted the P-gp efflux function, induced the recovery of sensitivity to chemotherapeutic agents, and hindered cell proliferation in cell lines. FZD1 expression in leukemic cells was significantly higher in patients experiencing relapse (n = 34) than in those with no relapse (n = 44, P = .003). Leukemic cells unable to achieve complete response (CR) showed an increased expression of MDR1 and P-gp, compared to patients who achieved CR. Obtaining CR in patients with higher FZD1 expression at diagnosis is difficult. Moreover, they tend to present instances of relapse, suggesting that AML cells with increased FZD1 expression are resistant to chemotherapy. We conclude that the activated FZD1 observed in leukemic cells likely confers acquired drug resistance, whereas FZD1 silencing may be more effective in reversing MDR. PMID- 29482175 TI - Postnatal care in the context of decreasing length of stay in hospital after birth: The perspectives of community midwives. PMID- 29482177 TI - Evaluation on the effects of 0.1% Peumus boldus leaf and Spiraea ulmaria plant extract combination on bacterial colonization in canine atopic dermatitis: A preliminary randomized, placebo controlled, double-blinded study. AB - Defective skin barrier characterize canine atopic dermatitis (AD). Pyoderma is the most common complication. Herbal compounds have been suggested as alternatives to control bacterial colonization for their effect on natural antimicrobial peptides (AMPs). This study evaluated the effects of 0.1% Peumus boldus leaf and Spiraea ulmaria plant extract combination on clinical signs, bacterial colonization and AMPs secretion in atopic dogs compared to placebo. Twenty privately-owned atopic dogs were randomly divided in 2 groups (treatment: n = 10; placebo: n = 10) and their abdomen was sprayed every 24 h for 4 weeks. Total and inguinal clinical scores (CADESI-03), manual bacterial count, and skin washes for AMPs (cBD3-like and cCath) were performed on days 0, 14 and 28. AMPs were detected using in-house, previously-validated, canine-specific ELISAs. Data were statistically analyzed and a p < 0.05 was considered significant. Clinical scores and AMPs secretion did not differ significantly between the two groups at any time point. A significant reduction of the clinical scores was seen in the placebo group at 14 and 28 days (p < 0.04). On days 14 and 28, a reduction in the bacterial count was seen in the treated group compared with placebo (p < 0.009 and p = 0.04, respectively). Compared to baseline, a reduction in Staphylococcus spp. was seen in the treated group after 14 days of treatment (p < 0.03). These results show the efficacy of this plant extract combination against bacterial colonization, suggesting its potential usefulness in preventing bacterial infection in atopic dogs. The influence of this compound on AMPs secretion or other mechanisms should be further evaluated. PMID- 29482176 TI - Age-related immune response to experimental infection with Eimeria ninakohlyakimovae in goat kids. AB - Both the immune response developed in ruminants against Eimeria spp. and the ability to bear patent infections seems to be dependent on the age of the host. In the present study we have evaluated the influence of the age in the development of protective immune responses against Eimeria ninakohlyakimovae. For this purpose, 3, 4 and 5-week-old goat kids were infected with sporulated oocysts and subjected to a homologous challenge 3 weeks later. Goat kids primary infected at 6, 7 and 8 weeks of age served as challenge controls, and uninfected animals were used as negative controls. The protective immunity was assessed by clinical, haematological, parasitological, immunological and pathological parameters. Altogether, the results demonstrate that goat kids of either 3, 4 or 5 weeks of age are able to develop patent infections and immunoprotective responses against E. ninakohlyakimovae, as all age groups: (i) released significantly less oocysts after challenge, which was associated to milder clinical signs; (ii) displayed a local immune response, with significant increase of numerous cellular populations; and (iii) had increased levels of IgG and IgM, and mainly of local IgA. Nevertheless, detailed analysis of the data showed some differences between the three age groups, related both to the Eimeria infection outcome and the resulting immune response, suggesting that youngest goat kids are not fully immunocompetent. This finding may be of interest for the design of immunoprophylactic approaches and/or prophylactic/methaphylactic treatments against goat coccidiosis. PMID- 29482178 TI - The impact of shape memory test on degradation profile of a bioresorbable polymer. AB - The semicrystalline poly(L-lactide) (PLLA) belongs to the materials with shape memory effect (SME) and as a bioresorbable and biocompatible polymer it have found many applications in medical and pharmaceutical field. Assessment of the SME impact on the polymer degradation profile plays crucial role in applications such as drug release systems or in regenerative medicine. Herein, the results of in vitro degradation studies of PLLA samples after SME full test cycle are presented. The samples were loaded and deformed in two manners: progressive and non-progressive. The performed experiments illustrate also influence of the material mechanical damages, caused e.g. during incorrect implantation of PLLA product, on hydrolytic degradation profile. Apparently, degradation profiles are significantly different for the material which was not subjected to the deformation and the deformed ones. The materials after deformation of 50% (in SME cycle) was characterized by non-reversible morphology changes. The effect was observed in deformed samples during the SME test which were carried out ten times. PMID- 29482179 TI - On the stability efficiency of anchorage self-tapping screws: Ex vivo experiments on miniscrew implants used in orthodontics. AB - BACKGROUND: The clinical success of orthodontic miniscrews is strictly related to primary stability, which depends on bone viscoelastic properties too. In this study, we evaluated the short time mechanical response of native bone to miniscrews, by a laboratory test based on dynamic loading. METHODS: Thirty-six segments of porcine ribs were first scanned by cone-beam computerized tomography to obtain insertion-site cortical thickness, cortical and marrow bone density. Twelve different types of miniscrews were implanted in the bone samples to evaluate the elastic compliance of the implants in response to a point force applied at the screw head normally to the screw axis. The compliance was measured dynamically in a Dynamic Mechanical Analysis apparatus as the Fourier Response Function between the signals of displacement and force. The measurements were repeated in five days successive to the insertion of the miniscrew. FINDINGS: The elastic compliance was positively related to observation timepoints, but it was not related neither to the screw type nor to the value of the insertion torque. INTERPRETATION: Stability behavior is significantly related to the short time response of native bone rather than to the screw design or the insertion torque values. PMID- 29482180 TI - Effects of crystal refining on wear behaviors and mechanical properties of lithium disilicate glass-ceramics. AB - OBJECTIVES: The purpose of this study is to improve wear resistance and mechanical properties of lithium disilicate glass-ceramics by refining their crystal sizes. METHODS: After lithium disilicate glass-ceramics (LD) were melted to form precursory glass blocks, bar (N = 40, n = 10) and plate (N = 32, n = 8) specimens were prepared. According to the differential scanning calorimetry (DSC) of precursory glass, specimens G1-G4 were designed to form lithium disilicate glass-ceramics with different crystal sizes using a two-step thermal treatment. In the meantime, heat-pressed lithium disilicate glass-ceramics (GC-P) and original ingots (GC-O) were used as control groups. Glass-ceramics were characterized using X-ray diffraction (XRD) and were tested using flexural strength test, nanoindentation test and toughness measurements. The plate specimens were dynamically loaded in a chewing simulator with 350 N up to 2.4 * 106 loading cycles. The wear analysis of glass-ceramics was performed using a 3D profilometer after every 300,000 wear cycles. Wear morphologies and microstructures were analyzed by scanning electron microscopy (SEM). One-way analysis of variance (ANOVA) was used to analyze the data. Multiple pairwise comparisons of means were performed by Tukey's post-hoc test. RESULTS: Materials with different crystal sizes (p < 0.05) exhibited different properties. Specifically, G3 with medium-sized crystals presented the highest flexural strength, hardness, elastic modulus and fracture toughness. G1 and G2 with small sized crystals showed lower flexural strength, whereas G4, GC-P, and GC-O with large-sized crystals exhibited lower hardness and elastic modulus. The wear behaviors of all six groups showed running-in wear stage and steady wear stage. G3 showed the best wear resistance while GC-P and GC-O exhibited the highest wear volume loss. CONCLUSIONS: After crystal refining, lithium disilicate glass ceramic with medium-sized crystals showed the highest wear resistance and mechanical properties. PMID- 29482181 TI - Nickel nanoclusters as a novel emitter for molecularly imprinted electrochemiluminescence based sensor toward nanomolar detection of creatinine. AB - In this study nickel nanoclusters (NiNCs), was promised as novel and economic electrochemiluminescence (ECL) emitter for highly sensitive and selective determination of creatinine in the presence of molecularly imprinted polymer (MIP). The uniform magnetic graphene oxide (GO-Fe3O4) MIP film was established on the surface of ITO electrode and Ni NCs-embedded in MIP, showed a strong anodic ECL emission using tri-n-propylamine (TPrA) as coreactant. During the ECL process, TPrA was oxidized, and Ni NCs got the energy to generate excited state Ni NCs* for light emission. When the imprinted cavities were occupied by creatinine, the ECL emission of Ni NCs on the MIP-modified electrode surface was efficiently quenched. Under optimal conditions, the proposed sensor demonstrated ultrasensitive and accurate analytical performance toward creatinine detection with a linear range from 5 nM to 1 mM and detection limit of 0.5 nM (S/N = 3). The biosensor showed good specificity for creatinine determination compared to other compounds that having the chemical structure analogue or close to the template creatinine, when the concentration ratio of interference to creatinine was more than 100 times. Furthermore, the biosensor was successfully applied to determination of creatinine in human serum and urine samples with satisfactory results. So, this assay for creatinine detection possesses high sensitivity, good selectivity, excellent reproducibility and stability. We expect the combination of molecular imprinting system with ECL assay in the presence of Ni NCs as a new type of superior luminophore candidate can be developed for design of ultrasensitive sensors, biosensors and other measuring devices. PMID- 29482182 TI - Meeting the imperative to accelerate environmental bioelectromagnetics research. AB - In this article, the author draws on his experience in the world of geospatial information technology standards to suggest a path toward acceleration of bioelectromagnetics science. Many studies show biological effects of extremely low frequency (ELF) and radiofrequency (RF) radiation despite that fact that the radiation is too weak to cause temperature changes in biological features. Considered together in worst case scenarios, such effects, many of which appear to have long latencies, could have potentially disastrous consequences for the health and safety of humans and wildlife. Other studies show no such effects, and in both cases, often there are significant research quality deficits that make it difficult to draw firm conclusions from the data. The progress of bioelectromagnetics science is retarded by a lack of standard data models and experimental protocols that could improve the overall quality of research and make it easier for researchers to benefit from omics-related bioinformatics resources. "Certainty of safety" of wireless devices used in digital communications and remote sensing (radar) is impossible without dosimetry standards that reflect the effects of non-thermal exposures. Electrical signaling in biological systems, a poorly funded research domain, is as biologically important as chemical signaling, a richly funded research domain, and these two types of signaling are inextricably connected. Entreprenuerial scientists pursuing bioelectronic innovations have begun to attract new funding. With appropriate institutional coordination, this new funding could equally benefit those investigating environmental effects of ELF and RF radiation. The author proposes a concerted effort among both bioelectronics technology stakeholders and environmental bioelectromagnetics science researchers to collaborate in developing institutional arrangements and standard data models that would give the science a stronger bioinformatics platform and give researchers better access to omics data. What is proposed here is essentially a bioelectromagnetics omics initiative. PMID- 29482183 TI - Maternal use of personal care products during pregnancy and risk of testicular germ cell tumors in sons. AB - BACKGROUND: The etiology of testicular germ cell tumors (TGCT) is poorly understood, however, exposure to endocrine disrupting chemicals (EDCs) may be related to increased risk. Personal care products, some of which contain EDCs, are widely used on a daily basis and are known to cross the placenta, be present in breastmilk, and are capable of inducing reproductive tract abnormalities. To determine the association between personal care product use during pregnancy and breastfeeding and TGCT risk, an analysis among mothers of TGCT cases and controls was conducted. METHODS: The US Servicemen's Testicular Tumor Environmental and Endocrine Determinants (STEED) study enrolled TGCT cases and controls and their mothers between 2002 and 2005. The current analysis examined personal care product use during pregnancy among 527 mothers of TGCT cases and 562 mothers of controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression adjusting for identified covariates. RESULTS: Maternal use of face lotion more than one time per week was associated with a significantly increased risk of TGCT (OR: 1.42, 95% CI: 1.08-1.86, p trend: 0.01). None of the other products examined (perfume, hairspray, nail polish, hair dye, permanent wave, body lotion, deodorant, sunscreen) were associated with TGCT risk. CONCLUSIONS: Frequent exposure to face lotion during pregnancy and while breastfeeding may be associated with increased TGCT risk. Further investigation into the endocrine disrupting effects of personal care products is warranted. PMID- 29482184 TI - A new approach to modeling temperature-related mortality: Non-linear autoregressive models with exogenous input. AB - Temperature-mortality relationships are nonlinear, time-lagged, and can vary depending on the time of year and geographic location, all of which limits the applicability of simple regression models in describing these associations. This research demonstrates the utility of an alternative method for modeling such complex relationships that has gained recent traction in other environmental fields: nonlinear autoregressive models with exogenous input (NARX models). All cause mortality data and multiple temperature-based data sets were gathered from 41 different US cities, for the period 1975-2010, and subjected to ensemble NARX modeling. Models generally performed better in larger cities and during the winter season. Across the US, median absolute percentage errors were 10% (ranging from 4% to 15% in various cities), the average improvement in the r-squared over that of a simple persistence model was 17% (6-24%), and the hit rate for modeling spike days in mortality (>80th percentile) was 54% (34-71%). Mortality responded acutely to hot summer days, peaking at 0-2 days of lag before dropping precipitously, and there was an extended mortality response to cold winter days, peaking at 2-4 days of lag and dropping slowly and continuing for multiple weeks. Spring and autumn showed both of the aforementioned temperature-mortality relationships, but generally to a lesser magnitude than what was seen in summer or winter. When compared to distributed lag nonlinear models, NARX model output was nearly identical. These results highlight the applicability of NARX models for use in modeling complex and time-dependent relationships for various applications in epidemiology and environmental sciences. PMID- 29482185 TI - Mercury exposure and health impacts in dental personnel. AB - Based on toxicological, clinical, and epidemiological knowledge, the present paper reviews the status regarding possible deleterious health effects from occupational exposure to metallic mercury (Hg) in dental practice. Symptoms from the central nervous system are among the health problems that most often are attributed to Hg exposure in dentists and dental nurses working with amalgam. Uncharacteristic symptoms of chronic low-level Hg vapor exposure including weakness, fatigue, and anorexia have been observed in numerous studies of dental personnel. It is crucial to protect both human health and the environment against negative effects of Hg. In line with this, the use of dental amalgam in industrial countries is about to be phased out. In Norway and Sweden, the use of the filling material is banned. PMID- 29482186 TI - Dynamic assessment of urban economy-environment-energy system using system dynamics model: A case study in Beijing. AB - Economic development, accompanying with environmental damage and energy depletion, becomes essential nowadays. There is a complicated and comprehensive interaction between economics, environment and energy. Understanding the operating mechanism of Energy-Environment-Economy model (3E) and its key factors is the inherent part in dealing with the issue. In this paper, we combine System Dynamics model and Geographic Information System to analyze the energy environment-economy (3E) system both temporally and spatially, which explicitly explore the interaction of economics, energy, and environment and effects of the key influencing factors. Beijing is selected as a case study to verify our SD-GIS model. Alternative scenarios, e.g., current, technology, energy and environment scenarios are explored and compared. Simulation results shows that, current scenario is not sustainable; technology scenario is applicable to economic growth; environment scenario maintains a balanced path of development for long term stability. Policy-making insights are given based on our results and analysis. PMID- 29482187 TI - Adapting ecological risk valuation for natural resource damage assessment in water pollution. AB - Ecological risk assessment can address requirements of natural resource damage assessment by quantifying the magnitude of possible damages to the ecosystem. This paper investigates an approach to assess water damages from pollution incident on the basis of concentrations of contaminants. The baseline of water pollution is determined with not-to-exceed concentration of contaminants required by water quality standards. The values of damage cost to water quality are estimated through sewage treatment cost. To get a reliable estimate of treatment cost, DEA is employed to classify samples of sewage plants based on their efficiency of sewage treatment. And exponential fitting is adopted to determine the relation between treatment cost and the decrease of COCs. The range of damage costs is determined through the fitting curves respectively based on efficient and inefficient samples. PMID- 29482188 TI - Residential proximity to agricultural fumigant use and respiratory health in 7 year old children. AB - OBJECTIVES: To examine the relationship between residential proximity to agricultural fumigant use and respiratory symptoms and lung function in 7-year old children. METHODS: Participants were 294 children living in the agricultural Salinas Valley, California and enrolled in the Center for the Health Assessment of Mothers and Children Of Salinas (CHAMACOS) study. We obtained information on respiratory symptoms and asthma medication use from maternal questionnaires and children performed spirometry to determine the forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and forced expiratory flow 25-75% (FEF25-75) at 7-years of age. We estimated agricultural fumigant use within 3, 5 and 8 km of residences during pregnancy and from birth to age 7 using California's Pesticide Use Report data. We evaluated the association between prenatal and postnatal residential proximity to agricultural use of methyl bromide, chloropicrin, metam sodium and 1,3-dichloropropene with respiratory symptoms and use of asthma medication with logistic regression models and continuous lung function measurements with linear regression models adjusted for confounders. RESULTS: There were no significant associations between residential proximity to use of fumigants and respiratory symptoms or use of asthma medication. We did not observe any adverse relationships between residential proximity to fumigant use and lung function measurements. Unexpectedly, we observed suggestive evidence of improved FEV1 and FEF25-75 with higher use of methyl bromide and chloropicrin during the prenatal period. For example, for each 10-fold increase in methyl bromide use during the prenatal development period we observed higher FEV1 (beta = 0.06 L/s; 95% CI: 0.00, 0.12) and higher FEF25-75 (beta = 0.15 L/s; 95% CI: 0.03, 0.27). Maternal report of child allergies (runny nose without a cold during the previous year) modified the relationship between FEV1 and prenatal proximity to methyl bromide use (p = .07) and we only observed higher FEV1 among children without allergies (beta = 0.08 L/s; 95% CI: 0.02, 0.14 for a 10-fold increase in methyl bromide use during the prenatal period). CONCLUSIONS: Residential proximity to agricultural fumigant use during pregnancy and childhood did not adversely affect respiratory health in the children through 7 years of age. These findings should be explored in larger studies. PMID- 29482189 TI - Downregulation of the Cl-/HCO3-Exchanger Pendrin in Kidneys of Mice with Cystic Fibrosis: Role in the Pathogenesis of Metabolic Alkalosis. AB - BACKGROUND/AIMS: Patients with cystic fibrosis (CF) are prone to the development of metabolic alkalosis; however, the pathogenesis of this life threatening derangement remains unknown. We hypothesized that altered acid base transport machinery in the kidney collecting duct underlies the mechanism of impaired bicarbonate elimination in the CF kidney. METHODS: Balance studies in metabolic cages were performed in WT and CFTR knockout (CF) mice with the intestinal rescue in response to bicarbonate loading or salt restriction, and the expression levels and cellular distribution of acid base and electrolyte transporters in the proximal tubule, collecting duct and small intestine were examined by western blots, northern blots and/or immunofluorescence labeling. RESULTS: Baseline parameters, including acid-base and systemic vascular volume status were comparable in WT and CF mice, as determined by blood gas, kidney renin expression and urine chloride excretion. Compared with WT animals, CF mice demonstrated a significantly higher serum HCO3- concentration (22.63 in WT vs. 26.83 mEq/l in CF mice; n=4, p=0.013) and serum pH (7.33 in WT vs. 7.42 in CF mice; n=4, p=0.00792) and exhibited impaired kidney HCO3- excretion (urine pH 8.10 in WT vs. 7.35 in CF mice; n=7, p=0.00990) following a 3-day oral bicarbonate load. When subjected to salt restriction, CF mice developed a significantly higher serum HCO3- concentration vs. WT animals (29.26 mEq/L in CF mice vs. 26.72 in WT; n=5, p=0.0291). Immunofluorescence labeling demonstrated a profound reduction in the apical expression of the Cl-/HCO3- exchanger pendrin in cortical collecting duct cells and western and northern blots indicated diminished plasma membrane abundance and mRNA expression of pendrin in CF kidneys. CONCLUSIONS: We propose that patients with cystic fibrosis are prone to the development of metabolic alkalosis secondary to the inactivation of the bicarbonate secreting transporter pendrin, specifically during volume depletion, which is a common occurrence in CF patients. PMID- 29482190 TI - The Long Intergenic Noncoding RNA 00707 Promotes Lung Adenocarcinoma Cell Proliferation and Migration by Regulating Cdc42. AB - BACKGROUND/AIMS: Lung cancer (LC) is a serious disease with high morbidity and mortality. Long noncoding RNAs (lncRNAs) have garnered attention because they participate in diverse human disorders, including cancer. Our study examined the long intergenic noncoding RNA 00707 (LINC00707). The effects of LINC00707 on lung adenocarcinoma (LAD) and molecular mechanisms are unclear. This study is aimed to investigate the role of LINC00707 in the malignant processes of LAD. METHODS: Quantitative reverse transcription PCR (qRT-PCR) was used to examine the expression level of LINC00707 in tissues and cell lines. The association of LINC00707 expression and postoperative prognosis was analyzed by the Kaplan-Meier method and log-rank test. Cell proliferation was evaluated in vitro and in vivo. Transwell assays were performed to examine cell migration. Cell cycle and apoptosis was determined by flow -cytometric and western blot analyses. Microarray analysis was conducted to screen for the downstream target gene Cdc42 of LINC00707, which was identified by qRT-PCR, functional analysis, and rescue experiment. RESULTS: The expression level of LINC00707 was clearly upregulated in LAD tissues compared to that in corresponding normal tissues. Its overexpression was related to advanced TNM stage, larger tumor size, lymphatic metastasis, and poor prognosis. Functional assays revealed that LINC00707 knockdown repressed LAD cell proliferation both in vitro and in vivo. This process may involve the inducing of G1 arrest and apoptosis. Moreover, cell migration was impaired after LINC00707 inhibition. Microarray analysis and rescue assays suggested that Cdc42 is an important target gene involved in the carcinogenesis of LINC00707. CONCLUSIONS: In summary, LINC00707 is a noncoding oncogene that exerts important regulatory functions in LAD, suggesting its potential as a biomarker in the prognosis and treatment of LAD. PMID- 29482191 TI - Post-Transcriptional Control of Angiotensin II Type 1 Receptor Regulates Osteosarcoma Cell Death. AB - BACKGROUND/AIMS: MicroRNAs (miRNAs) play an essential role in the tumorigenesis of osteosarcoma (OS). However, the effects of miR-1248 on chemo-resistant potential of OS have not been studied. Here, we addressed this question. METHODS: The levels of miR-1248 and apoptotic protein angiotensin II type 1 receptor (AGTR1) in OS specimens were examined by RT-qPCR and Western blotting, respectively. The relationship between miR-1248 and AGTR1 was determined by analysis of Spearman's Rank Correlation Coefficients. The patient survival was determined with Kaplan-Meier curves. Bioinformatics analyses were done to predict microRNAs (miRNAs) that target AGTR1. The functional binding of miRNAs to AGTR1 mRNA was examined by a dual luciferase reporter assay. Cell viability was determined by an CCK-8 assay. Apoptosis was determined by a fluorescence-based apoptosis assay. RESULTS: The levels of miR-1248 were significantly elevated while the levels of AGTR1 were significantly decreased in OS specimens than in paired adjacent normal tissue. The levels of miR-1248 were negatively correlated to the levels of AGTR1. Moreover, the patients with high miR-1248 levels had poorer survival than those with low MiR-1248 levels, and the patients with low AGTR1 levels had poorer survival than those with high AGTR1 levels. MiR-1248 inhibited protein translation of AGTR1, through binding to the 3'-UTR of the AGTR1 mRNA. The AGTR1-mediated cell apoptosis was suppressed by overexpressing miR-1248, and was augmented by depleting miR-1248. CONCLUSION: Increased miR-1248 expression in OS may inhibit AGTR1-mediated cancer cell death in chemotherapy. The outcome of chemotherapy may be improved by the suppression of miR-1248 in OS cells. PMID- 29482192 TI - Type I Diabetic Akita Mouse Model is Characterized by Abnormal Cardiac Deformation During Early Stages of Diabetic Cardiomyopathy with Speckle-Tracking Based Strain Imaging. AB - BACKGROUND/AIMS: Diabetes mellitus (DM) has been demonstrated to have a strong association with heart failure. Conventional echocardiographic analysis cannot sensitively monitor cardiac dysfunction in type I diabetic Akita hearts, but the phenotype of heart failure is observed in molecular levels during the early stages. METHODS: Male Akita (Ins2WT/C96Y) mice were monitored with echocardiographic imaging at various ages, and then with conventional echocardiographic analysis and speckle-tracking based strain analyses. RESULTS: With speckle-tracking based strain analyses, diabetic Akita mice showed changes in average global radial strain at the age of 12 weeks, as well as decreased longitudinal strain. These changes occurred in the early stage and remained throughout the progression of diabetic cardiomyopathy in Akita mice. Speckle tracking showed that the detailed and precise changes of cardiac deformation in the progression of diabetic cardiomyopathy in the genetic type I diabetic Akita mice were uncoupled. CONCLUSIONS: We monitored early-stage changes in the heart of diabetic Akita mice. We utilize this technique to elucidate the underlying mechanism for heart failure in Akita genetic type I diabetic mice. It will further advance the assessment of cardiac abnormalities, as well as the discovery of new drug treatments using Akita genetic type I diabetic mice. PMID- 29482193 TI - Two chemically similar stellar overdensities on opposite sides of the plane of the Galactic disk. AB - Our Galaxy is thought to have an active evolutionary history, dominated over the past ten billion years or so by star formation, the accretion of cold gas and, in particular, the merging of clumps of baryonic and dark matter. The stellar halo the faint, roughly spherical component of the Galaxy-reveals rich 'fossil' evidence of these interactions, in the form of stellar streams, substructures and chemically distinct stellar components. The effects of interactions with dwarf galaxies on the content and morphology of the Galactic disk are still being explored. Recent studies have identified kinematically distinct stellar substructures and moving groups of stars in our Galaxy, which may have extragalactic origins. There is also mounting evidence that stellar overdensities (regions with greater-than-average stellar density) at the interface between the outer disk and the halo could have been caused by the interaction of a dwarf galaxy with the disk. Here we report a spectroscopic analysis of 14 stars from two stellar overdensities, each lying about five kiloparsecs above or below the Galactic plane-locations suggestive of an association with the stellar halo. We find that the chemical compositions of these two groups of stars are almost identical, both within and between these overdensities, and closely match the abundance patterns of stars in the Galactic disk. We conclude that these stars came from the disk, and that the overdensities that they are part of were created by tidal interactions of the disk with passing or merging dwarf galaxies. PMID- 29482194 TI - Cognitive Behavioral Therapy Versus Education for Chronic Pain. PMID- 29482195 TI - Appropriately Framing Child Health Care Spending: A Prerequisite for Value Improvement. PMID- 29482196 TI - Unrecognized Cardiovascular Emergencies Among Medicare Patients. AB - Importance: The Institute of Medicine described diagnostic error as the next frontier in patient safety and highlighted a critical need for better measurement tools. Objectives: To estimate the proportions of emergency department (ED) visits attributable to symptoms of imminent ruptured abdominal aortic aneurysm (AAA), acute myocardial infarction (AMI), stroke, aortic dissection, and subarachnoid hemorrhage (SAH) that end in discharge without diagnosis; to evaluate longitudinal trends; and to identify patient characteristics independently associated with missed diagnostic opportunities. Design, Setting, and Participants: This was a retrospective cohort study of all Medicare claims for 2006 to 2014. The setting was hospital EDs in the United States. Participants included all fee-for-service Medicare patients admitted to the hospital during 2007 to 2014 for the conditions of interest. Hospice enrollees and patients with recent skilled nursing facility stays were excluded. Main Outcomes and Measures: The proportion of potential diagnostic opportunities missed in the ED was estimated using the difference between observed and expected ED discharges within 45 days of the index hospital admissions as the numerator, basing expected discharges on ED use by the same patients in earlier months. The denominator was estimated as the number of recognized emergencies (index hospital admissions) plus unrecognized emergencies (excess discharges). Results: There were 1 561 940 patients, including 17 963 hospitalized for ruptured AAA, 304 980 for AMI, 1 181 648 for stroke, 19 675 for aortic dissection, and 37 674 for SAH. The mean (SD) age was 77.9 (10.3) years; 8.9% were younger than 65 years, and 54.1% were female. The proportions of diagnostic opportunities missed in the ED were as follows: ruptured AAA (3.4%; 95% CI, 2.9%-4.0%), AMI (2.3%; 95% CI, 2.1%-2.4%), stroke (4.1%; 95% CI, 4.0%-4.2%), aortic dissection (4.5%; 95% CI, 3.9%-5.1%), and SAH (3.5%; 95% CI, 3.1%-3.9%). Longitudinal trends were either nonsignificant (AMI and aortic dissection) or increasing (ruptured AAA, stroke, and SAH). Patient characteristics associated with unrecognized emergencies included age younger than 65 years, dual eligibility for Medicare and Medicaid coverage, female sex, and each of the following chronic conditions: end-stage renal disease, dementia, depression, diabetes, cerebrovascular disease, hypertension, coronary artery disease, and chronic obstructive pulmonary disease. Conclusions and Relevance: Among Medicare patients, opportunities to diagnose ruptured AAA, AMI, stroke, aortic dissection, and SAH are missed in less than 1 in 20 ED presentations. Further improvement may prove difficult. PMID- 29482197 TI - Overtreatment of Asymptomatic Hypertension-Urgency Is Not an Emergency: A Teachable Moment. PMID- 29482198 TI - Initiating Phototherapy at Subthreshold Levels: The Slippery Slope. PMID- 29482199 TI - The Trade-offs When Focusing on the Mortality Benefit. PMID- 29482200 TI - Structured Review of Dichotic Tests of Binaural Integration: Clinical Performance in Children. AB - Purpose: The aim of the study was to evaluate the evidence of clinical utility for dichotic speech tests of binaural integration used to assess auditory processing in English-speaking children 6-14 years old. Method: Dichotic speech test recordings and pertinent research studies were identified from iterative searches of the Internet and bibliographic databases, as well as communication with colleagues and test publishers. Test documentation and peer-reviewed literature were evaluated for evidence of reliability, accuracy, usefulness, and value. Results: Eleven dichotic tests of binaural integration were identified for children. Evidence of test-retest reliability was found for 5 tests and demonstrated moderate to good correlation between results on repeated administration (r = .59-.92). Evidence of accuracy was identified for 5 tests but was either inconsistent with accurate performance or was not generalizable due to significant limitations in study design. No evidence was found to either support or dispute claims of usefulness or value. Conclusions: A medical diagnostic framework is useful for evaluating dichotic tests. Although dichotic procedures show moderate reliability, the absence of a widely accepted gold standard reference test limits our ability to assess their value. Overall, the data available at the time of this review do not support the routine use of dichotic tests of binaural integration for clinical evaluation of children. PMID- 29482201 TI - Sexting-Prevalence, Age, Sex, and Outcomes. PMID- 29482202 TI - Predictive Factors for Vestibular Loss in Children With Hearing Loss. AB - Purpose: The aim of this study was to determine if there are factors that can predict whether a child with hearing loss will also have vestibular loss. Method: A retrospective chart review was completed on 186 children with hearing loss seen at Boys Town National Research Hospital for vestibular testing from 1999 to 2015 through neurosensory genetics clinic or cochlear implant candidacy. Each child's medical chart was reviewed to obtain the following data: vestibular loss severity (classified as normal, bilateral, or mild to moderate), degree of hearing loss (bilateral pure-tone average [PTA]), imaging abnormalities (classified as "normal" or "abnormal"), parental concerns for gross motor delay (classified as "yes, there is concern" or "no, there is not a concern"), parent report of age when their child sat (months) and walked independently (months), comorbidities (classified as "yes" if there were 1 or more comorbidities or "no" if there were no comorbidities), and score on the Developmental Profile-3. Results: Children were grouped according to vestibular loss severity; 115 children had normal vestibular function, 31 had bilateral vestibular loss, and 40 had mild-to moderate vestibular loss. As severity of vestibular loss increased, children (a) sat and walked later, (b) scored more poorly on the Developmental Profile-3 physical subscale, (c) had more severe hearing loss, (d) had parents who more frequently reported concern for gross motor delay, and (e) were more likely to have other comorbidities. Of these factors, age-to-sit, age-to-walk, PTA, and parental concerns for gross motor developmental delay had the greatest ability to differentiate children with vestibular loss from children with normal vestibular function. For age-to-sit, using a cutoff value of 7.25 months yielded a sensitivity of 62% and a specificity of 81%. For age-to-walk, a cutoff value of 14.5 months yielded a sensitivity of 78% and a specificity of 77%. For PTA for the neurosensory genetics group, a cutoff value of 40 dB yielded a sensitivity of 80% and a specificity of 55%; however, a cutoff value of 66 dB yielded a sensitivity of 33% and an improved specificity of 91%. Conclusions: A referral for vestibular evaluation should be considered for children whose hearing loss is greater than 66 dB and particularly those who sit later than 7.25 months or walk later than 14.5 months or whose parents report concerns for gross motor development. Collectively, these factors appear to be more sensitive for identifying children with bilateral vestibular loss compared with children with mild-to-moderate vestibular loss. Because of the benefit of physical therapy, children identified with vestibular loss should then be referred to physical therapy for further evaluation and treatment. PMID- 29482203 TI - Management of Gait Impairments in Chronic Unilateral Upper Motor Neuron Lesions: A Review. AB - Importance: Gait impairments are common in patients with chronic supratentorial upper motor neuron lesions and are a source of disability. Clinical management aimed at improving the gait pattern in these patients is generally perceived as a challenging task because many possible abnormalities may interact. Moreover, a multitude of treatment options exist, ranging from assistive devices and muscle stretching to pharmacologic and surgical interventions, but evidence is inconclusive for most approaches and clear treatment guidelines are lacking. Observations: Gait deviations in adults with a chronic supratentorial upper motor neuron lesion can approximately be reduced to the following 3 groups of primary deficits: (1) imbalance of muscle strength, length, and activity around the ankle and tarsal joints leading to pes equinovarus or pes equinus; (2) calf muscle weakness; and (3) overactivity of proximal leg muscles. Conclusions and Relevance: A stepwise treatment algorithm emphasizes medical-technical interventions, which are based on evidence when available and otherwise reflect practice-based experience. PMID- 29482204 TI - High Frequency of Systemic Corticosteroid Use for Acute Respiratory Tract Illnesses in Ambulatory Settings. PMID- 29482205 TI - Association of Coprescription of Triptan Antimigraine Drugs and Selective Serotonin Reuptake Inhibitor or Selective Norepinephrine Reuptake Inhibitor Antidepressants With Serotonin Syndrome. AB - Importance: In 2006, the US Food and Drug Administration (FDA) issued an advisory warning on the risk of serotonin syndrome with concomitant use of triptans and selective serotonin reuptake inhibitor (SSRI) or selective norepinephrine reuptake inhibitor (SNRI) antidepressants, but the true risk of serotonin syndrome in these patients remains unknown. Objective: To assess the risk of serotonin syndrome with concomitant use of triptans and SSRI or SNRI antidepressants. Design, Setting, and Participants: This study used electronic health record data from the Partners Research Data Registry (RPDR) to identify patients who had received an International Classification of Diseases, Ninth Revision diagnosis compatible with serotonin syndrome who had been coprescribed triptans and SSRI or SNRI antidepressants in the Greater Boston, Massachusetts, area from January 1, 2001, through December 31, 2014 (14 years). Clinical information was extracted to determine whether the case met formal diagnostic criteria and had coprescription within a calendar year. Both conservative and broad case definitions were used to better characterize the spectrum of risk. Data analysis was performed from November 23, 2016, to July 15, 2017. Main Outcomes and Measures: Incidence of serotonin syndrome. Results: The RPDR search revealed 47 968 (+/-3) unique patients who were prescribed triptans during the 14 year period of the study. A total of 19 017 (+/-3) patients were coprescribed triptans and antidepressants during the study, with a total of 30 928 person years of exposure. Serotonin syndrome was suspected in 17 patients. Only 2 patients were classified as having definite serotonin syndrome (incidence rate, 0.6 cases per 10 000 person-years of exposure; 95% CI, 0.0-1.5). Five patients were classified as having possible serotonin syndrome (incidence rate with these 5 cases added to the 2 definite cases, 2.3 cases per 10 000 person-years of exposure; 95% CI, 0.6-3.9). The proportion of patients with triptan prescriptions who were coprescribed an SSRI or SNRI antidepressant was relatively stable during the study, ranging from 21% to 29%. Conclusions and Relevance: The risk of serotonin syndrome associated with concomitant use of triptans and SSRIs or SNRIs was low. Coprescription of these drugs is common and did not decrease after the 2006 FDA advisory. Our results cast doubt on the validity of the FDA advisory and suggest that it should be reconsidered. PMID- 29482206 TI - Parenting Education. PMID- 29482207 TI - Leaving Against Medical Advice. PMID- 29482209 TI - Errors in Figure 1. PMID- 29482210 TI - Hidden Curricula, Ethics, and Professionalism: Optimizing Clinical Learning Environments in Becoming and Being a Physician: A Position Paper of the American College of Physicians. AB - Much of what is formally taught in medicine is about the knowledge, skills, and behaviors required of a physician, including how to express compassion and respect for patients at the bedside. What is learned, however, includes not only admirable qualities but also behaviors and qualities that are inconsistent with ethics and professionalism. Positive role models may reinforce the character and values the profession seeks to cultivate; negative ones directly contradict classroom lessons and expectations of patients, society, and medical educators. These positive and negative lessons, which are embedded in organizational structure and culture, are the hidden curricula conveyed in medical schools, residency programs, hospitals, and clinics. This position paper from the American College of Physicians focuses on ethics, professionalism, and the hidden curriculum. It provides strategies for revealing what is hidden to foster the development of reflective and resilient lifelong learners who embody professionalism and clinicians who are, and are perceived as, positive role models. Making the hidden visible and the implicit explicit helps to create a culture reflecting medicine's core values. PMID- 29482208 TI - Efficacy of Subthreshold Newborn Phototherapy During the Birth Hospitalization in Preventing Readmission for Phototherapy. AB - Importance: Treatment of jaundiced newborns with subthreshold phototherapy (phototherapy given to newborns with bilirubin levels below those recommended in American Academy of Pediatrics [AAP] guidelines) is common. However, the use of subthreshold phototherapy may have risks and increase costs, and, to date, it has not been systematically studied in newborns. Objectives: To estimate the efficacy of subthreshold phototherapy for newborns with total serum bilirubin (TSB) levels from 0.1 to 3.0 mg/dL below the appropriate AAP phototherapy threshold during the birth hospitalization in preventing readmissions for phototherapy, and to identify predictors of readmission for phototherapy. Design, Setting, and Participants: Retrospective cohort study of 25 895 newborns born at 35 or more weeks' gestation, born in 1 of 16 Kaiser Permanente Northern California hospitals from January 1, 2010, through December 31, 2014, with at least 1 TSB level from 0.1 to 3.0 mg/dL below the appropriate AAP phototherapy threshold and not exceeding the threshold during the birth hospitalization. Data were analyzed from November 1, 2015, to November 28, 2017. Exposure: Subthreshold phototherapy during the birth hospitalization. Main Outcomes and Measures: Readmission for phototherapy. Results: Among 25 895 newborns with qualifying TSB levels from 0.1 to 3.0 mg/dL below the appropriate AAP phototherapy threshold, 4956 (19.1%) received subthreshold phototherapy and 241 of these (4.9%) were readmitted for phototherapy compared with 2690 of 20 939 untreated newborns (12.8%) (unadjusted odds ratio [OR], 0.35; 95% CI, 0.30-0.40). In a logistic regression model, adjustment for confounding variables, including gestational age, race/ethnicity, formula feedings per day, and the difference between the TSB level and the phototherapy threshold, strengthened the association (OR, 0.28; 95% CI, 0.19 0.40). Estimated numbers needed to treat ranged from 60.8 in the lowest quintile of predicted risk to 6.3 in the highest quintile. Newborns who received formula feedings had lower adjusted odds of readmission for phototherapy compared with exclusively breastfed newborns (OR, 0.58; 95% CI, 0.47-0.72 for >0 to <2 formula feedings per day; OR, 0.24; 95% CI, 0.21-0.27 for >=6 formula feedings per day). Subthreshold phototherapy was associated with a 22-hour longer length of stay (95% CI, 16-28 hours). Conclusions and Relevance: Subthreshold phototherapy during the birth hospitalization is effective in preventing readmissions for phototherapy; however, for each readmission prevented, many newborns require phototherapy who would otherwise not need it. PMID- 29482211 TI - Parenting Education-Reply. PMID- 29482212 TI - Proximity to Parental Symptom Onset and Amyloid-beta Burden in Sporadic Alzheimer Disease. AB - Importance: Alzheimer disease (AD) develops during several decades. Presymptomatic individuals might be the best candidates for clinical trials, but their identification is challenging because they have no symptoms. Objective: To assess whether a sporadic parental estimated years to symptom onset calculation could be used to identify information about amyloid-beta (Abeta) levels in asymptomatic individuals with a parental history of AD dementia. Design, Setting, and Participants: This cohort study analyzed Abeta1-42 in cerebrospinal fluid (CSF) specimens from 101 cognitively normal individuals who had a lumbar puncture as part of the Presymptomatic Evaluation of Novel or Experimental Treatments for Alzheimer Disease (PREVENT-AD) cohort from September 1, 2011, through November 30, 2016 (374 participants were enrolled in the cohort during this period). The study estimated each participant's proximity to his/her parent's symptom onset by subtracting the index relative's onset age from his/her current age. The association between proximity to parental symptom onset and Abeta levels was then assessed using apolipoprotein E epsilon4 (APOE4) status and sex as interactive terms. These analyses were performed again in 2 independent cohorts using CSF and Pittsburgh compound B carbon 11-labeled positron emission tomography (PIB-PET) Abeta biomarkers: the Adult Children Study (ACS) and the Wisconsin Registry for Alzheimer Prevention (WRAP) cohorts. Main Outcomes and Measures: The association between proximity to parental symptom onset and Abeta burden in asymptomatic individuals with a parental history of sporadic AD. Results: The present analysis included a subset of 101 PREVENT-AD individuals (mean [SD] age, 61.8 [5.1] years; 30 [29.7%] male), 128 ACS participants (112 participants underwent CSF measurement: mean [SD] age, 63.4 [5.1] years; 31 [27.7%] male; and 107 underwent PIB-PET: mean [SD] age, 64.6 [5.3] years; 27 [25.2%] male), and 135 WRAP participants (85 participants underwent CSF measurement: mean [SD] age, 59.9 [6.0] years; 27 [31.8%] male; and 135 underwent PIB-PET: mean [SD] age, 59.6 [6.1] years; 43 [31.9%] male). In the PREVENT-AD cohort, individuals approaching their parent's onset age had lower CSF Abeta1-42 levels (range, 402-1597; B = 9.09, P = .04). This association was stronger in APOE4 carriers (B = -17.9, P = .03) and women (B = -19.8, P = .02). In the ACS cohort, the main association was replicated using PIB-PET data, and the sex interaction was replicated using CSF and PIB-PET data. In the WRAP cohort, the results were not replicated using cross sectional data, but the main association and the APOE interaction were replicated using PIB-PET longitudinal data. Conclusions and Relevance: These results suggest that proximity to parental symptom onset may help estimate Abeta biomarker changes in women or APOE4 carrier asymptomatic individuals with a parental history of sporadic AD. PMID- 29482214 TI - Association of Standardization of Continuous Renal Replacement Therapy and High Value Care: An Evidence-Based Approach. PMID- 29482213 TI - Literacy-Adapted Cognitive Behavioral Therapy Versus Education for Chronic Pain at Low-Income Clinics: A Randomized Controlled Trial. AB - Background: Chronic pain is common and challenging to treat. Although cognitive behavioral therapy (CBT) is efficacious, its benefit in disadvantaged populations is largely unknown. Objective: To evaluate the efficacy of literacy-adapted and simplified group CBT versus group pain education (EDU) versus usual care. Design: Randomized controlled trial. (ClinicalTrials.gov: NCT01967342). Setting: Community health centers serving low-income patients in Alabama. Patients: Adults (aged 19 to 71 years) with mixed chronic pain. Interventions: CBT and EDU delivered in 10 weekly 90-minute group sessions. Measurements: Self-reported, postintervention pain intensity (primary outcome) and physical function and depression (secondary outcomes). Results: 290 participants were enrolled (70.7% of whom were women, 66.9% minority group members, 72.4% at or below the poverty level, and 35.8% reading below the fifth grade level); 241 (83.1%) participated in posttreatment assessments. Linear mixed models included all randomly assigned participants. Members of the CBT and EDU groups had larger decreases in pain intensity scores between baseline and posttreatment than participants receiving usual care (estimated differences in change scores-CBT: -0.80 [95% CI -1.48 to 0.11]; P = 0.022; EDU: -0.57 [CI, -1.04 to -0.10]; P = 0.018). At 6-month follow up, treatment gains were not maintained in the CBT group but were still present in the EDU group. With regard to physical function, participants in the CBT and EDU interventions had greater posttreatment improvement than those receiving usual care, and this progress was maintained at 6-month follow-up. Changes in depression (secondary outcome) did not differ between either the CBT or EDU group and the usual care group. Limitations: Participants represented a single health care system. Self-selection bias may have been present. Conclusion: Simplified group CBT and EDU interventions delivered at low-income clinics significantly improved pain and physical function compared with usual care. Primary Funding Source: Patient-Centered Outcomes Research Institute. PMID- 29482215 TI - Prevalence of Multiple Forms of Sexting Behavior Among Youth: A Systematic Review and Meta-analysis. AB - Importance: The existing literature on sexting among youth shows that sexting is a predictor of sexual behavior and may be associated with other health outcomes and risky behaviors. However, there remains a lack of consensus on the prevalence of sexting, which is needed to inform future research, intervention, and policy development. Objective: To provide a meta-analytic synthesis of studies examining the prevalence of multiple forms of sexting behavior, analyzed by age, sex, geography, and method of sexting. Data Sources: In an academic setting, electronic searches in MEDLINE, PsycINFO, EMBASE, and Web of Science were conducted for the period January 1990 to June 2016, yielding 1147 nonduplicate records. Study Selection: Studies were included if participants were younger than 18 years and the prevalence of sexting explicit images, videos, or messages was reported. Data Extraction and Synthesis: Literature review and data extraction followed established PRISMA guidelines. Two independent reviewers extracted all relevant data. Random-effects meta-analyses were used to derive the mean prevalence rates. Thirty-nine studies met final inclusion criteria. Main Outcomes and Measures: Meta-analyses of the prevalence of sending, receiving, and forwarding without consent, as well as having one's sext forwarded without consent. Results: Among 39 included studies, there were 110 380 participants; the mean age was 15.16 years (age range, 11.9-17.0 years), and on average 47.2% were male. Studies were available for sending (n = 34), receiving (n = 20), forwarding without consent (n = 5), and having a sext forwarded without consent (n = 4). The mean prevalences for sending and receiving sexts were 14.8% (95% CI, 12.8%-16.8%) and 27.4% (95% CI, 23.1%-31.7%), respectively. Moderator analyses revealed that effect sizes varied as a function of child age (prevalence increased with age), year of data collection (prevalence increased over time), and sexting method (higher prevalence on mobile devices compared with computers). The prevalence of forwarding a sext without consent was 12.0% (95% CI, 8.4%-15.6%), and the prevalence of having a sext forwarded without consent was 8.4% (95% CI, 4.7% 12.0%). Conclusions and Relevance: The prevalence of sexting has increased in recent years and increases as youth age. Further research focusing on nonconsensual sexting is necessary to appropriately target and inform intervention, education, and policy efforts. PMID- 29482217 TI - Time for Value-Based Payment Models to Adopt a Disparities-Sensitive Frame Shift. PMID- 29482219 TI - Teaching and Learning by Example. PMID- 29482218 TI - Effect of a Collaborative Care Intervention vs Usual Care on Health Status of Patients With Chronic Heart Failure: The CASA Randomized Clinical Trial. AB - Importance: Many patients with chronic heart failure experience reduced health status despite receiving conventional therapy. Objective: To determine whether a symptom and psychosocial collaborative care intervention improves heart failure specific health status, depression, and symptom burden in patients with heart failure. Design, Setting, and Participants: A single-blind, 2-arm, multisite randomized clinical trial was conducted at Veterans Affairs, academic, and safety net health systems in Colorado among outpatients with symptomatic heart failure and reduced health status recruited between August 2012 and April 2015. Data from all participants were included regardless of level of participation, using an intent-to-treat approach. Interventions: Patients were randomized 1:1 to receive the Collaborative Care to Alleviate Symptoms and Adjust to Illness (CASA) intervention or usual care. The CASA intervention included collaborative symptom care provided by a nurse and psychosocial care provided by a social worker, both of whom worked with the patients' primary care clinicians and were supervised by a study primary care clinician, cardiologist, and palliative care physician. Main Outcomes and Measures: The primary outcome was patient-reported heart failure specific health status, measured by difference in change scores on the Kansas City Cardiomyopathy Questionnaire (range, 0-100) at 6 months. Secondary outcomes included depression (measured by the 9-item Patient Health Questionnaire), anxiety (measured by the 7-item Generalized Anxiety Disorder Questionnaire), overall symptom distress (measured by the General Symptom Distress Scale), specific symptoms (pain, fatigue, and shortness of breath), number of hospitalizations, and mortality. Results: Of 314 patients randomized (157 to intervention arm and 157 to control arm), there were 67 women and 247 men, mean (SD) age was 65.5 (11.4) years, and 178 (56.7%) had reduced ejection fraction. At 6 months, the mean Kansas City Cardiomyopathy Questionnaire score improved 5.5 points in the intervention arm and 2.9 points in the control arm (difference, 2.6; 95% CI, -1.3 to 6.6; P = .19). Among secondary outcomes, depressive symptoms and fatigue improved at 6 months with CASA (effect size of -0.29 [95% CI, -0.53 to -0.04] for depressive symptoms and -0.30 [95% CI, -0.55 to -0.06] for fatigue; P = .02 for both). There were no significant changes in overall symptom distress, pain, shortness of breath, or number of hospitalizations. Mortality at 12 months was similar in both arms (10 patients died receiving CASA, and 13 patients died receiving usual care; P = .52). Conclusions and Relevance: This multisite randomized clinical trial of the CASA intervention did not demonstrate improved heart failure-specific health status. Secondary outcomes of depression and fatigue, both difficult symptoms to treat in heart failure, improved. Trial Registration: clinicaltrials.gov Identifier: NCT01739686. PMID- 29482216 TI - Association of Serum Retinol-Binding Protein 4 Concentration With Risk for and Prognosis of Amyotrophic Lateral Sclerosis. AB - Importance: Knowledge about the metabolic states of patients with amyotrophic lateral sclerosis (ALS) may provide a therapeutic approach. Objective: To investigate the association between the onset and prognosis of ALS and serum retinol-binding protein 4 (RBP4) concentration as a biomarker for insulin resistance and vitamin A metabolism. Design, Setting, and Participants: Case control design for risk factors of ALS; cohort design for prognostic factors within ALS cases. Between October 1, 2010, and June 30, 2014, a population-based case-control study with randomly selected controls was established based on the ALS Registry Swabia in southern Germany, with a target population of 8.4 million inhabitants. Response rates were 64.8% among the cases and 18.7% among the controls. The dates of analysis were April 2016 to May 2017. Main Outcomes and Measures: Serum samples were measured for RBP4. Information on covariates was assessed by an interview-based standardized questionnaire. Main outcomes and measures were adjusted odds ratios for risk of ALS associated with serum RBP4 concentration, as well as time to death associated with RBP4 concentration at baseline in ALS cases only. Conditional logistic regression was applied to calculate multivariable odds ratios for risk of ALS. Survival models were used in cases only to appraise their prognostic value. Results: Data from 289 patients with ALS (mean [SD] age, 65.7 [10.5] years; 172 [59.5%] male) and 504 controls (mean [SD] age, 66.3 [9.8] years; 299 [59.3%] male) were included in the case control study. Compared with controls, ALS cases were characterized by lower body mass index, less educational attainment, smoking, light occupational work intensity, and self-reported diabetes. The median serum RBP4 concentration was lower in ALS cases than in controls (54.0 vs 59.5 mg/L). In the multivariable model, increasing RBP4 concentration was associated with reduced odds for ALS (top vs bottom quartile odds ratio, 0.36; 95% CI, 0.22-0.59; P for trend <.001), which persisted after further adjustment for renal function and for leptin and adiponectin. Among 279 ALS cases during a median follow-up of 14.5 months, 104 died (mean [SD] age, 68.9 [10.3] years; 56 [53.9%] male). In this ALS cohort, an inverse association was found between serum RBP4 concentration as a continuous measure and survival. Conclusions and Relevance: RBP4 was inversely related to risk for and prognosis of ALS, suggesting that vitamin A metabolism or impaired insulin signaling could be involved. Further research, including a prospective design and other biological markers, is necessary to clarify the role of insulin resistance in the pathogenesis of ALS. PMID- 29482220 TI - Peripheral Neuropathy and the Ceruloplasmin Gene. PMID- 29482221 TI - Medical Students in Puerto Rico After Hurricane Maria. PMID- 29482222 TI - Shining the LAMP on Efforts to Transform Pain Care in America. PMID- 29482224 TI - What Parents Need to Know About Sexting. PMID- 29482226 TI - ? PMID- 29482227 TI - ? PMID- 29482223 TI - Efficacy of Exome-Targeted Capture Sequencing to Detect Mutations in Known Cerebellar Ataxia Genes. AB - Importance: Molecular diagnosis is difficult to achieve in disease groups with a highly heterogeneous genetic background, such as cerebellar ataxia (CA). In many patients, candidate gene sequencing or focused resequencing arrays do not allow investigators to reach a genetic conclusion. Objectives: To assess the efficacy of exome-targeted capture sequencing to detect mutations in genes broadly linked to CA in a large cohort of undiagnosed patients and to investigate their prevalence. Design, Setting, and Participants: Three hundred nineteen index patients with CA and without a history of dominant transmission were included in the this cohort study by the Spastic Paraplegia and Ataxia Network. Centralized storage was in the DNA and cell bank of the Brain and Spine Institute, Salpetriere Hospital, Paris, France. Patients were classified into 6 clinical groups, with the largest being those with spastic ataxia (ie, CA with pyramidal signs [n = 100]). Sequencing was performed from January 1, 2014, through December 31, 2016. Detected variants were classified as very probably or definitely causative, possibly causative, or of unknown significance based on genetic evidence and genotype-phenotype considerations. Main Outcomes and Measures: Identification of variants in genes broadly linked to CA, classified in pathogenicity groups. Results: The 319 included patients had equal sex distribution (160 female [50.2%] and 159 male patients [49.8%]; mean [SD] age at onset, 27.9 [18.6] years). The age at onset was younger than 25 years for 131 of 298 patients (44.0%) with complete clinical information. Consanguinity was present in 101 of 298 (33.9%). Very probable or definite diagnoses were achieved for 72 patients (22.6%), with an additional 19 (6.0%) harboring possibly pathogenic variants. The most frequently mutated genes were SPG7 (n = 14), SACS (n = 8), SETX (n = 7), SYNE1 (n = 6), and CACNA1A (n = 6). The highest diagnostic rate was obtained for patients with an autosomal recessive CA with oculomotor apraxia-like phenotype (6 of 17 [35.3%]) or spastic ataxia (35 of 100 [35.0%]) and patients with onset before 25 years of age (41 of 131 [31.3%]). Peculiar phenotypes were reported for patients carrying KCND3 or ERCC5 variants. Conclusions and Relevance: Exome capture followed by targeted analysis allows the molecular diagnosis in patients with highly heterogeneous mendelian disorders, such as CA, without prior assumption of the inheritance mode or causative gene. Being commonly available without specific design need, this procedure allows testing of a broader range of genes, consequently describing less classic phenotype-genotype correlations, and post hoc reanalysis of data as new genes are implicated in the disease. PMID- 29482229 TI - ? PMID- 29482228 TI - ? PMID- 29482225 TI - Effectiveness of an Intervention Supporting Shared Decision Making for Destination Therapy Left Ventricular Assist Device: The DECIDE-LVAD Randomized Clinical Trial. AB - Importance: Shared decision making helps patients and clinicians elect therapies aligned with patients' values and preferences. This is particularly important for invasive therapies with considerable trade-offs. Objective: To assess the effectiveness of a shared decision support intervention for patients considering destination therapy left ventricular assist device (DT LVAD) placement. Design, Setting, and Participants: From 2015 to 2017, a randomized, stepped-wedge trial was conducted in 6 US LVAD implanting centers including 248 patients being considered for DT LVAD. After randomly varying time in usual care, sites were transitioned to an intervention consisting of clinician education and use of DT LVAD pamphlet and video patient decision aids. Follow up occurred at 1 and 6 months. Main Outcomes and Measures: Decision quality as measured by knowledge and values-choice concordance. Results: In total, 135 patients were enrolled during control and 113 during intervention periods. At enrollment, 59 (23.8%) participants were in intensive care, 60 (24.1%) were older than 70 years, 39 (15.7%) were women, 45 (18.1%) were racial/ethnic minorities, and 62 (25.0%) were college graduates. Patient knowledge (mean test performance) during the decision making period improved from 59.5% to 64.9% in the control group vs 59.1% to 70.0% in the intervention group (adjusted difference of difference, 5.5%; P = .03). Stated values at 1 month (scale 1 = "do everything I can to live longer..." to 10 = "live with whatever time I have left...") were a mean of 2.37 in control and 3.33 in intervention (P = .03). Patient-reported treatment choice at 1 month favored LVAD more in the control group (than in the intervention group (47 [59.5%] vs 95 [91.3%], P < .001). Correlation between stated values and patient reported treatment choice at 1 month was stronger in the intervention group than in the control group (difference in Kendall's tau, 0.28; 95% CI, 0.05-0.45); however, there was no improved correlation between stated values and actual treatment received by 6 months for the intervention compared with the control group (difference in Kendall's tau, 0.01; 95% CI, -0.24 to 0.25). The adjusted rate of LVAD implantation by 6 months was higher for those in the control group (79.9%) than those in the intervention group (53.9%, P = .008), with significant variation by site. There were no differences in decision conflict, decision regret, or preferred control. Conclusions and Relevance: A shared decision-making intervention for DT LVAD modestly improved patient decision quality as measured by patient knowledge and concordance between stated values and patient-reported treatment choice, but did not improve concordance between stated values and actual treatment received. The rate of implantation of LVADs was substantially lower in the intervention compared with the control group. Trial Registration: clinicaltrials.gov Identifier: NCT02344576. PMID- 29482230 TI - ? PMID- 29482231 TI - ? PMID- 29482232 TI - ? PMID- 29482233 TI - ? PMID- 29482234 TI - ? PMID- 29482235 TI - ? PMID- 29482236 TI - ? PMID- 29482238 TI - Video Comment on Raf Bisschops et al. PMID- 29482237 TI - [Fever and Pulmo-Renal Syndrome with Cholecystitis in a Traveller - a Differential Diagnostic Challenge]. AB - ANAMNESIS: In winter, a 37-year old male patient consulted our outpatient clinic complaining about fever, malaise and headache. He had returned from vacation in Thailand 14 days earlier. EXAMINATIONS: Clinical findings, laboratory examinations and apparative diagnostics revealed a pulmo-renal syndrom accompagnied by multi-organ failure. DIAGNOSIS: Finally, we could confirm that our patient suffered from leptospirosis. TREATMENT: The patient received a penicillin-based antibiotic treatment. CLINICAL COURSE: Two days after presentation, the patient had to be transferred to the intensive care unit. Noninvasive respiratory support and hemodialysis helped to stabilize the patient. Finally, the patient could be discharged after four weeks in the hospital. CONCLUSION: Taking into account the seasonal accumulation of flu-like symptoms in winter and the patient's stay in a tropical region, differential-diagnostics were challenging in this case. Leptospirosis often presents as pulmp-renal syndrome. PMID- 29482239 TI - Video Comment on Katsuro Ichimasa et al. PMID- 29482240 TI - Video Comment on Je-Wook Shin et al. PMID- 29482241 TI - Video Comment on Joaquin Rodriguez-Sanchez et al. PMID- 29482242 TI - Video Comment on Roel M. M. Bogie et al. PMID- 29482243 TI - Implementing endoscopy checklists - a step in the right direction? PMID- 29482244 TI - The BASIC Classification: does it shed (blue) light on colorectal polyp differentiation? PMID- 29482245 TI - Diminutive polyps and future colorectal cancer risk perception: how low do we need to go? PMID- 29482246 TI - Cold snare polypectomy of large lesions: One swallow does not a summer make. PMID- 29482247 TI - Gum chewing for bowel preparation. PMID- 29482248 TI - [French comment on article Implementation of a checklist before colonoscopy: a quality improvement initiative]. PMID- 29482249 TI - [French comment on article BASIC (BLI Adenoma Serrated International Classification) classification for colorectal polyp characterization with blue light imaging]. PMID- 29482250 TI - [French comment on article Patients' willingness to defer resection of diminutive polyps: results of a multicenter survey]. PMID- 29482251 TI - [French comment on article Artificial intelligence may help in predicting the need for additional surgery after endoscopic resection of T1 colorectal cancer]. PMID- 29482252 TI - [French comment on article Risk of recurrence after endoscopic resection of early colorectal cancer with positive margins]. PMID- 29482253 TI - Brain Arteriovenous Malformations and Arteriovenous Fistulas. PMID- 29482254 TI - Erratum: Rett Syndrome. PMID- 29482255 TI - Imaging Pediatric Multiple Sclerosis-Challenges and Recent Advances. AB - Pediatric onset multiple sclerosis (POMS) is a rare disease with an incidence of 0.07 to 2.9/100'000 children per year. It follows a relapsing-remitting disease course and is characterized by rapid accrual of inflammatory lesions, high relapse frequency, and early cognitive impairment. Magnetic resonance imaging (MRI) plays a pivotal role in the diagnosis of POMS, and in the exclusion of other disorders mimicking POMS. Furthermore, MRI aids in disease monitoring, and in the evaluation of therapeutic efficacy in both clinical practice and clinical trials. Volumetric MRI studies, diffusion tensor imaging, resting-state, and task based functional MRI provide deeper insight into the impact of POMS on maturing neural networks. This review article aims to highlight the importance of MRI in the care of POMS patients and to provide an overview on the different MRI techniques used in the management of POMS. PMID- 29482256 TI - Effects of Risperidone and Aripiprazole on Serum Levels of Prolactin, Testosterone and Estradiol in Female Patients with Schizophrenia. AB - OBJECTIVE: To evaluate the effects of treatment with risperidone and aripiprazole on serum prolactin, testosterone and estradiol levels in female patients with schizophrenia in China. METHODS: In the retrospective study, Data were collected and included prolactin, testosterone and estradiol levels of 30 female patients with risperidone monotherapy. In the prospective study, Another 30 female schizophrenic patients were randomized to receive risperidone or adjunctive aripiprazole for six weeks. Serum prolactin, testosterone and estradiol levels were measured. RESULTS: Serum prolactin, testosterone and estradiol levels in both studies were significantly decreased after risperidone treatment compared with baseline (P<0.05), and prolactin levels remained at a high level. Serum prolactin levels in the adjunctive aripiprazole group were significantly decreased after treatment compared with baseline in the prospective study (P<0.05). Doses of 5 mg and 10 mg of adjunctive aripiprazole achieved the same efficacy at the end of treatment. CONCLUSIONS: Risperidone treatment decreased serum testosterone and estradiol levels. Adjunctive aripiprazole relieved hyperprolactinemia, but had no effect on testosterone or estradiol levels. Adjunctive aripiprazole at a dose of 5 mg is recommended for clinical use. PMID- 29482257 TI - Histone Deacetylase Inhibitor (Trapoxin A) Enhances Stemness Properties in Adipose Tissue Derived Mesenchymal Stem Cells. AB - BACK GROUND: Adipose tissue derived mesenchymal stem cells (ASCs) have unique potential for regenerative cell therapies. However, during ex-vivo cultivation, they undergo considerable quality loss regarding their phenotypic properties, stemness genes expression and differentiation potential. Recent studies reported that the loss of stemness properties of MSCs is a result of chromatin histone deacetylations through in-vitro cultivation. The present work aimed to study the effect of Trapoxin A (TPX) as a histone deacetylase inhibitor (HDACi) on overall stemness properties of ASCs. METHODS: First, the effects of TPX treatments on ASCs viability and proliferation were evaluated using MTT assay. Second, the desired doses of TPX supporting ASCs proliferation were determined and the lack of their negative effects was confirmed by DAPI staining. In addition, the influence of TPX on cell cycle of ASCs and the mRNA levels of stemness genes were measured by flowcytometry and qPCR, respectively. Finally, the effect of TPX treatment on osteogenic potential of ASCs was studied. RESULTS: The results indicated that short time TPX treatment (nM concentrations) caused stimulation of proliferation and considerable percentage of ASCs entered to S-phase of cell cycle (p<0.05). Moreover, the findings demonstrated significant up-regulation of stemness markers genes (Oct-4, Sox-2, Nanog, TERT, Klf-4, Rex-1) (p<0.05) and enhanced osteogenic differentiation potential of ASC after TPX treatment. CONCLUSION: The addition of low dose of TPX to the expansion medium could possibly enhance the stemness properties and prevent the quality decline of ex vivo cultured ASCs. PMID- 29482258 TI - [Medical Confidentiality in Elite Sports]. AB - A doctor-patient relationship is basically characterised by medical confidentiality, which means that doctors have to remain silent about any information coming to their attention in the respective context. A breach of medical confidentiality constitutes an act of misconduct relevant in terms of criminal and professional law. If a doctor has the permission or obligation to disclose confidential information, a breach of medical confidentiality is not illegitimate. A permission to disclose confidential information is given if a patient releases a doctor from his or her medical confidentiality obligation either explicitly or through coherent action. Doctors who provide concurrent or successive treatment of a patient are also released from their obligation to keep medical confidentiality towards their attending colleagues. Furthermore, doctors are allowed to disclose confidential information if disclosure is of superior interest. Those specific constellations are narrowly defined by law. Moreover, a permission to disclose confidential information can be the result of a legal provision. Obligations of disclosure are limited to cases regulated by law. Medical confidentiality also applies to the treatment of athletes without any restrictions. However, there are particular constellations in elite sports where doctors either have a permission to disclose confidential information or may assume that athletes agree with the transfer of their diagnostic findings to certain third parties. PMID- 29482259 TI - [The Contributions of the East-German Sports Medicine Specialist and Neurologist Bernhard Schwarz (1918-1991) in the Field of Boxing]. AB - This study is the first to provide research on the East-German (GDR) sports physician and neurologist Bernhard Schwarz. It summarises Schwarz's publications from 1953 to 1966 regarding the impact of boxing on health, particularly craniocerebral injury. Also, the study analyses his work in the context of current discussions. It shows that Schwarz, who was a tenured professor and director of the Department of Psychiatry at the University Hospital of Leipzig and the physician of the GDR national boxing team, conducted systematic clinical surveys and pointed to the health impacts of boxing at an early point in time. He believed that risk exposure for athletes could be minimised through intensive and trained supervision by the coach and the physician as well as through changes to the conditions of boxing matches. Schwarz opposed a ban on boxing. Instead, he picked up suggestions concerning the prevention of adverse health impacts and added his own recommendations, which are remarkably similar to current practices aimed at minimising risk. For instance, he advised that ring-side physicians be trained to recognise dangerous conditions. Today, physicians must obtain a license to be allowed to care for a boxer. In addition, Schwarz pursued the concept of integral medicine. He called for a diversified training of boxers and argued that injured athletes should be treated holistically. Being a neurologist, he emphasised the important role of psychotherapy in this context. He identified the key role of rehabilitation, and suggested that rehabilitation is complete only with the patient's successful social and professional reintegration. PMID- 29482260 TI - Beta blockers in patients with end-stage renal disease-Evidence-based recommendations. AB - For patients who require hemodialysis, beta blockers offer a simultaneous opportunity and challenge in the treatment of cardiovascular disease. Beta blockers are well supported by data from nondialysis populations and directly mitigate the sympathetic overactivity that links chronic kidney disease with cardiovascular sequelae. However, the evidence supporting their use in patients receiving hemodialysis is sparse and the heterogeneity of the beta blocker class makes it difficult to prescribe these medications with confidence. Despite these limitations, both trial and observational data exist that can help guide the use of these medications. In this review, we outline the reasons to consider beta blockers for patients receiving hemodialysis, discuss the barriers to their use, and provide specific evidence-based recommendations for beta blocker use in patients with heart failure, hypertension, ischemic heart disease and arrhythmia. PMID- 29482261 TI - Amniotic membrane transplantation for ligneous conjunctivitis in a doberman. AB - An approximately 2-year-old female Doberman Pinscher was referred for the evaluation of bilateral, chronic proliferative conjunctivitis. Ophthalmic examination revealed bilateral thick, opaque pseudomembranes originating from the conjunctivae that prevented visualization of the cornea and interior structures of the eye. Histopathological findings of biopsies of the pseudomembranes were consistent with ligneous conjunctivitis. Serum plasminogen activity levels were within the normal range. Treatment with topical and systemic anti-inflammatory and immunosuppressive drugs did not improve the conjunctival lesions. The pseudomembranes were surgically excised, and the conjunctival surfaces were reconstructed with amniotic membrane. At final re-examination two years postsurgery, there was no evidence of recurrence of the pseudomembranes. To the authors' knowledge, this is the first reported case of the successful treatment of canine ligneous conjunctivitis with amniotic membrane transplantation. PMID- 29482262 TI - Do current quality measures truly reflect the quality of dialysis? AB - The US End Stage Renal Disease (ESRD) Program, which came into existence in 1973, was initially envisioned to provide needed financial coverage for about 50 000 patients through Medicare. Over the past 45 years the evolution of the ESRD program has been quite different, and it now serves over one half million dialysis and transplant patients. The Medicare Improvements for Patients and Providers Act (MIPPA) of 2008 Section 153(c) requires the Centers for Medicare and Medicaid Services (CMS) to develop and implement quality measures for dialysis patients as part of the ESRD Quality Incentive Program (QIP) beginning in payment year (PY) 2012. The annual ESRD Prospective Payment System (PPS) rulemaking process allows CMS to create ESRD QIP rules that specify the measures, scoring methods, and payment reduction ranges applicable to the respective PY. CMS assesses each facility's performance and calculates a score for each measure, according to the method detailed for that PY. Scores for each measure are combined to create the Total Performance Score (TPS) for each facility. If a facility's TPS does not meet or exceed the performance standards established during the earlier comparison period, the facility will incur a payment reduction of up to 2% for the entire PY. The QIP program has evolved over the several years since its inception. There have been deletions and additions of various measures. CMS uses additional measures in its Dialysis Facility Compare (DFC) website which is available to the public and forms the basis of the 5-star rating system for dialysis facilities. The evidence underlying inclusion many of these measures in the QIP and DFC remains an area of debate. In this review, we discuss the evolution of these measures and their appropriateness. We recommend that some of the current QIP and DFC measures should not be used for public reporting and/or payment as unintended consequences may occur. Nonetheless, all the current QIP and DFC measures and others are suitable for internal quality review. PMID- 29482263 TI - Why does the choice of dialysate sodium concentration remain controversial? AB - The choice of the ideal dialysate sodium concentration remains controversial. Most dialysis centers have a standard dialysate concentration. In theory, choosing a dialysate sodium concentration lower than serum sodium should result in an additional loss of sodium by diffusion with a reduction in the prevalence of hypertension and interdialytic weight gains (IDWGs) on one hand, but with potential increased risk of intradialytic hypotension and cramps on the other hand, and the opposite effects may accompany the choice of dialysate sodium concentrations greater than serum concentration. Although most studies have reported a reduction in IDWG with lower dialysate sodium concentrations, the effects on blood pressure control, and adverse intradialytic events have been variable. Different outcomes between studies may be partially explained by patient selection, with differences in dietary sodium intake, urinary sodium losses, and sodium stores in the body. In addition, multicenter trials potentially introduce additional confounders, including differences in local quality control of delivered dialysate sodium concentration and sodium measurements. Although there may be advantages for lower dialysate sodium concentration, observational studies have reported a survival advantage for higher dialysate sodium concentrations for those patients with lower serum sodium concentrations pre-dialysis. As there is no current consensus for a universal dialysate sodium concentration, attention has turned to considering an individualized approach to choosing a dialysate sodium concentration. PMID- 29482266 TI - A second (understandable) error by Aristotle in comparing the location of the human left kidney with that of a cow. PMID- 29482264 TI - Nutritional labelling for healthier food or non-alcoholic drink purchasing and consumption. AB - BACKGROUND: Nutritional labelling is advocated as a means to promote healthier food purchasing and consumption, including lower energy intake. Internationally, many different nutritional labelling schemes have been introduced. There is no consensus on whether such labelling is effective in promoting healthier behaviour. OBJECTIVES: To assess the impact of nutritional labelling for food and non-alcoholic drinks on purchasing and consumption of healthier items. Our secondary objective was to explore possible effect moderators of nutritional labelling on purchasing and consumption. SEARCH METHODS: We searched 13 electronic databases including CENTRAL, MEDLINE and Embase to 26 April 2017. We also handsearched references and citations and sought unpublished studies through websites and trials registries. SELECTION CRITERIA: Eligible studies: were randomised or quasi-randomised controlled trials (RCTs/Q-RCTs), controlled before and-after studies, or interrupted time series (ITS) studies; compared a labelled product (with information on nutrients or energy) with the same product without a nutritional label; assessed objectively measured purchasing or consumption of foods or non-alcoholic drinks in real-world or laboratory settings. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies for inclusion and extracted study data. We applied the Cochrane 'Risk of bias' tool and GRADE to assess the quality of evidence. We pooled studies that evaluated similar interventions and outcomes using a random-effects meta-analysis, and we synthesised data from other studies in a narrative summary. MAIN RESULTS: We included 28 studies, comprising 17 RCTs, 5 Q-RCTs and 6 ITS studies. Most (21/28) took place in the USA, and 19 took place in university settings, 14 of which mainly involved university students or staff. Most (20/28) studies assessed the impact of labelling on menus or menu boards, or nutritional labelling placed on, or adjacent to, a range of foods or drinks from which participants could choose. Eight studies provided participants with only one labelled food or drink option (in which labelling was present on a container or packaging, adjacent to the food or on a display board) and measured the amount consumed. The most frequently assessed labelling type was energy (i.e. calorie) information (12/28).Eleven studies assessed the impact of nutritional labelling on purchasing food or drink options in real-world settings, including purchases from vending machines (one cluster-RCT), grocery stores (one ITS), or restaurants, cafeterias or coffee shops (three RCTs, one Q-RCT and five ITS). Findings on vending machines and grocery stores were not interpretable, and were rated as very low quality. A meta analysis of the three RCTs, all of which assessed energy labelling on menus in restaurants, demonstrated a statistically significant reduction of 47 kcal in energy purchased (MD -46.72 kcal, 95% CI -78.35, -15.10, N = 1877). Assuming an average meal of 600 kcal, energy labelling on menus would reduce energy purchased per meal by 7.8% (95% CI 2.5% to 13.1%). The quality of the evidence for these three studies was rated as low, so our confidence in the effect estimate is limited and may change with further studies. Of the remaining six studies, only two (both ITS studies involving energy labels on menus or menus boards in a coffee shop or cafeteria) were at low risk of bias, and their results support the meta-analysis. The results of the other four studies which were conducted in a restaurant, cafeterias (2 studies) or a coffee shop, were not clearly reported and were at high risk of bias.Seventeen studies assessed the impact of nutritional labels on consumption in artificial settings or scenarios (henceforth referred to as laboratory studies or settings). Of these, eight (all RCTs) assessed the effect of labels on menus or placed on a range of food options. A meta-analysis of these studies did not conclusively demonstrate a reduction in energy consumed during a meal (MD -50 kcal, 95% CI -104.41, 3.88, N = 1705). We rated the quality of the evidence as low, so our confidence in the effect estimate is limited and may change with further studies.Six laboratory studies (four RCTs and two Q-RCTs) assessed the impact of labelling a single food or drink option (such as chocolate, pasta or soft drinks) on energy consumed during a snack or meal. A meta-analysis of these studies did not demonstrate a statistically significant difference in energy (kcal) consumed (SMD 0.05, 95% CI 0.17 to 0.27, N = 732). However, the confidence intervals were wide, suggesting uncertainty in the true effect size. We rated the quality of the evidence as low, so our confidence in the effect estimate is limited and may change with further studies.There was no evidence that nutritional labelling had the unintended harm of increasing energy purchased or consumed. Indirect evidence came from five laboratory studies that involved mislabelling single nutrient content (i.e. placing low energy or low fat labels on high-energy foods) during a snack or meal. A meta-analysis of these studies did not demonstrate a statistically significant increase in energy (kcal) consumed (SMD 0.19, 95% CI -0.14to 0.51, N = 718). The effect was small and the confidence intervals wide, suggesting uncertainty in the true effect size. We rated the quality of the evidence from these studies as very low, providing very little confidence in the effect estimate. AUTHORS' CONCLUSIONS: Findings from a small body of low-quality evidence suggest that nutritional labelling comprising energy information on menus may reduce energy purchased in restaurants. The evidence assessing the impact on consumption of energy information on menus or on a range of food options in laboratory settings suggests a similar effect to that observed for purchasing, although the evidence is less definite and also of low quality.Accordingly, and in the absence of observed harms, we tentatively suggest that nutritional labelling on menus in restaurants could be used as part of a wider set of measures to tackle obesity. Additional high-quality research in real world settings is needed to enable more certain conclusions.Further high-quality research is also needed to address the dearth of evidence from grocery stores and vending machines and to assess potential moderators of the intervention effect, including socioeconomic status. PMID- 29482268 TI - Aphorisms related to nephrological subjects in Rhazes' The Guide Book or The Book of Aphorisms. PMID- 29482267 TI - The use of water for the treatment of kidney disorders. PMID- 29482269 TI - On the contributions of Fernand Widal to the classification of chronic kidney disease. PMID- 29482270 TI - Leon Ambard (1876-1962): his priority in using urea as a tool for assessment of kidney function in healthy subjects and in patients undergoing renal surgery. PMID- 29482272 TI - Nils Alwall. One of precursors of dialysis treatment. PMID- 29482271 TI - Carmelo Giordano (1930-2016): uremia therapy by low protein alimentation and sorbents. PMID- 29482273 TI - Nils Alwall- a personal appreciation. PMID- 29482274 TI - Nils Alwall and his input into development of Polish haemodialysis. PMID- 29482275 TI - Nobel Prize Winners Who Contributed To Transplantation. PMID- 29482276 TI - The History of the European Renal Association - European Dialysis and Transplant Association. PMID- 29482277 TI - History of the Polish Society of Nephrology. PMID- 29482278 TI - The Prehistory of Transplantation: up to the 1950s. PMID- 29482279 TI - The history of renal transplantation in France. PMID- 29482280 TI - History of kidney transplantation in Poland. PMID- 29482281 TI - History of Erythropoietin Stimulating Agents use for the treatment of renal anemia in Poland. PMID- 29482282 TI - PD catheters: evolution towards optimal design. PMID- 29482283 TI - The renal lesions in Bardet-Biedl Syndrome: history before and after the discovery of BBS genes. PMID- 29482284 TI - Treatment of the urinary tract diseases in the 16th-century work Cieplice (Thermal Springs) by Wojciech Oczko (1537-1599). PMID- 29482285 TI - The management of renal stones in Ratio medendi in nosocomio practico (1773) of Anton De Haen (1704-1776). PMID- 29482286 TI - Remedies for kidney ailments in the "Botany Practical" (1838) by Dionysios Pyrros the Thessalian (1774-1853). PMID- 29482287 TI - Works of Napoleon Cybulski (1859-1919) and Wladyslaw Szymonowicz (1869-1939) on Adrenal Function. PMID- 29482288 TI - Filippo Romeo (1908-1981): a pioneer and teacher of nephrology at Messina University. PMID- 29482289 TI - Pioneer women in Pediatric Nephrology in Poland. PMID- 29482290 TI - The contribution to nephrology of Professor Josef Erben (1926-2015). PMID- 29482292 TI - Uromodulin and its two discoverers: Igor Tamm and Frank Lappin Horsfall, Jr. PMID- 29482291 TI - The contribution of Professor Karel Opatrny Jr., MD, DSc. (1954-2006) to nephrology. PMID- 29482293 TI - The historical relevance of urine and the future implications. PMID- 29482294 TI - Urolithiasis from the point of view of the head physician of Ottoman emperors: Ahi Ahmed Celebi. PMID- 29482295 TI - Urine analysis of the 20th century Ottoman royal palace members and their interpretation: samples from 'Prime ministry Ottoman archives. PMID- 29482296 TI - The Rise and Fall of Acute Tubular Necrosis - An exercise in medical semiotics. PMID- 29482298 TI - The application of philosophy and history of medicine in current medical practice. The Nephrotic Syndrome Example. PMID- 29482297 TI - Water immersion model in nephrology: from hydrotherapy to weightlessness. PMID- 29482300 TI - Unicompartmental Knee Arthroplasty. PMID- 29482301 TI - Intentionally Increased Flexion Angle of the Femoral Component in Mobile Bearing Unicompartmental Knee Arthroplasty. AB - Purpose: The purpose of this study was to determine the results of mobile bearing unicompartmental knee arthroplasty (UKA) with an intentionally increased flexion angle of the femoral component in patients requiring high flexion. Materials and Methods: We investigated 45 knees treated by UKA. Clinically, we measured the range of motion (ROM) and the American Knee Society (AKS) score preoperatively and at final follow-up and investigated complications. Radiologically, we measured the flexion angle of the femoral component, the posterior slope angle of the tibial component, the femorotibial angle and mechanical axis of the limb postoperatively. Results: The ROM was increased from 123 degrees preoperatively to 139 degrees at the final follow-up. The AKS knee and function scores increased from 59 and 68, respectively, preoperatively to 94 and 96, respectively, at the final follow-up. The flexion angle of the femoral component was 9.1 degrees , and the posterior slope angle of the tibial component was 8.6 degrees . There was one case of bearing dislocation in the largest femoral flexion angle case. Conclusions: The results might reflect the positive effect of an increased flexion angle of the femoral component up to 10 degrees on ROM in mobile bearing UKA, which would contribute to better quality of life after UKA especially in populations requiring deep knee flexion. PMID- 29482302 TI - Clinical and Radiological Results with Second-Look Arthroscopic Findings after Open Wedge High Tibial Osteotomy without Arthroscopic Procedures for Medial Meniscal Root Tears. AB - Purpose: To identify the structural integrity of the healing site after medial open wedge high tibial osteotomy (MOWHTO) in patients with a posterior root tear of the medial meniscus (PRTMM) and chondral lesion by second-look arthroscopy and to determine the clinical and radiological findings. Materials and Methods: From August 2010 to June 2016, 52 consecutive patients underwent MOWHTO and arthroscopic examination without a chondral resurfacing procedure and meniscal treatment for PRTMM. Twenty-four patients were available for second-look arthroscopic evaluation. The mean follow-up period was 19.5 months (range, 5 to 46 months). Clinical evaluation was based on the Lysholm knee scores and Hospital for Special Surgery (HSS) scores. Results: There were 5 lax healing, 6 scar tissue, 13 failed healing of PRTMM. Definite change of chondral lesion was not observed. The Kellgren-Lawrence grade did not improve according to the follow-up plain radiograph. The mean Lysholm score improved from 34.7 preoperatively to 77.1 at the last follow-up, and the mean HSS score significantly increased from 36.5 to 82.4. Conclusions: This study revealed a low rate of healing potency of PRTMM and chondral lesion after MOWHTO without any attempt for meniscal treatment or chondral resurfacing. The cartilage and healing status of PRTMM was not associated with improved clinical outcomes and radiological findings. PMID- 29482303 TI - Seasonal Influence on Postoperative Complications after Total Knee Arthroplasty. AB - Purpose: This study is aimed at investigating whether inpatient complications and surgical site infections (SSIs) occurred more commonly in patients undergoing total knee arthroplasty (TKA) during the summer season. Materials and Methods: A total of 725 patients who underwent unilateral or bilateral TKA were included in this study. A total of 241 patients (33.2%) underwent TKA between May and August. Our outcomes of interest were the incidence of postoperative complications and length of stay. Results: May-August surgeries were associated with a higher risk of postoperative inpatient complications (p=0.003). May-August surgeries (odds ratio [OR], 2.13; 95% confidence interval [CI], 1.18 to 3.85), postoperative transfusion (OR, 2.46; 95% CI, 1.43 to 4.26), postoperative special care unit stay (OR, 4.68; 95% CI, 1.99 to 11.0) and chronic kidney disease (OR, 3.27; 95% CI, 1.15 to 9.28) were associated with a higher odds of developing inpatient complications. No association was present between summer surgeries and SSIs (p=0.486). Conclusions: The results of this study show that overall complication rates following TKA exhibit a seasonal trend, with a peak during the summer months. These results may have some implication in clinical practice and stricter approaches to hospital guidelines during the summer months. PMID- 29482305 TI - Relationship between Lateral Femoral Bowing and Varus Knee Deformity Based on Two Dimensional Assessment of Side-to-Side Differences. AB - Purpose: The objective was to evaluate the relationship between side-to-side differences of lateral femoral bowing and varus knee deformity based on two dimensional (2D) assessment in unilateral total knee arthroplasty (TKA). Materials and Methods: A total of 143 patients with varus knee osteoarthritis who underwent unilateral TKA were enrolled. We evaluated the side-to-side differences of the frontal lower limb alignment by assessing lateral femoral bowing, anatomical medial distal femoral angle, and anatomical medial proximal tibial angle (aMPTA). Results: The average values of all anatomical indices were significantly different between the operated side and the non-operated side (p<0.05). The side-to-side difference in hip knee ankle (HKA) angle had a statistically significant correlation with that in lateral femoral bowing (intraclass correlation coefficient, 0.259; p=0.002) and that in aMPTA. Linear regression analysis showed 0.199 degrees of side-to-side difference in lateral femoral bowing was associated with 1 degrees of side-to-side difference in bilateral HKA angle. Conclusions: The side-to-side difference in lateral femoral bowing showed a tendency to increase in proportion to varus knee deformity based on 2D assessment in unilateral TKA patients. PMID- 29482304 TI - Using Illness Rating Systems to Predict Discharge Location Following Total Knee Arthroplasty. AB - Purpose: Total knee arthroplasty (TKA) is increasing in frequency and cost. Optimization of discharge location may reduce total expenditure while maximizing patient outcomes. Although preoperative illness rating systems-including the American Society for Anesthesiologists Physical Classification System (ASA), severity of illness scoring system (SOI), and Mallampati rating scale (MP)-are associated with patient morbidity and mortality, their predictive value for discharge location, length of stay (LOS), and total costs remains unclear. Materials and Methods: We conducted a retrospective analysis of 677 TKA patients (550 primary and 127 revision) treated at a single institution. The influence of ASA, SOI, and MP scores on discharge locations, LOS, and total costs was assessed using multivariable regression analyses. Results: None of the systems were significant predictors of discharge location following TKA. SOI scores of major or higher (beta=2.08 days, p<0.001) and minor (beta=-0.25 days, p=0.009) significantly predicted LOS relative to moderate scores. Total costs were also significantly predicted by SOI scores of major or higher (beta=$6,155, p=0.022) and minor (beta=-$1,163, p=0.007). Conclusions: SOI scores may be harnessed as a predictive tool for LOS and total costs following TKA, but other mechanisms are necessary to predict discharge location. PMID- 29482306 TI - Effects of Femoral Lateral Bowing on Coronal Alignment and Component Position after Total Knee Arthroplasty: A Comparison of Conventional and Navigation Assisted Surgery. AB - Purpose: To evaluate the effects of femoral lateral bowing on coronal alignment after total knee arthroplasty (TKA) and examine whether the use of navigation helps obtain better postoperative coronal alignment and component position. Materials and Methods: Radiological results and outlier rates were compared between the conventional TKA group and the navigation-assisted TKA group, and factors associated with postoperative alignment were evaluated. For clinical assessment, patient-reported outcomes were used. Results: A total of 297 knees were retrospectively reviewed. Among the patients with femoral lateral bowing, a significant difference was observed between the conventional TKA group (n=72) and the navigation-assisted TKA group (n=96) in postoperative mechanical femorotibial angle (mFTA, 1.6 degrees vs. 0.8 degrees ; p=0.005) and femoral component alignment angle (89.0 degrees vs 90.0 degrees ; p=0.017). Preoperative mFTA (p<0.001), femoral bowing angle (p<0.001), and mechanical lateral distal femoral angle (p=0.032) had effects on postoperative mFTA in the conventional TKA group. In the navigation-assisted TKA group, only preoperative mFTA (p<0.001) had effects on postoperative mFTA. Conclusions: Despite the individualized determination of the valgus correction angle through preoperative planning, in the cases with severe lateral bowing, the outlier rate was higher in the conventional TKA group than in the navigation-assisted TKA group. However, there was no significant difference in the clinical results between the two groups in the short-term follow-up. PMID- 29482308 TI - Acute Arterial Occlusion Following Primary Total Knee Arthroplasty. AB - Acute arterial occlusion is a rare complication following total knee arthroplasty (TKA). This is a report of a case of acute femoral artery occlusion and its sequelae following TKA in a patient with a history of atrial fibrillation. Arterial circulation of the lower limb could not be restored by thrombectomy treatments, and above-knee amputation had to be carried out. PMID- 29482307 TI - Combined Rotational Alignment Change after Total Knee Arthroplasty in Different Tibial Component Designs: Implications for Optimal Tibial Component Rotational Alignment. AB - Purpose: The rotational alignment of the femoral and tibial components is closely related to the results after total knee arthroplasty (TKA). In this study, we measured the combined rotational alignment change (DeltaCR) after TKA and compared the different influence of symmetric and asymmetric tibial component designs on the combined rotational alignment. Materials and Methods: Eighty-four patients (mean age, 67.9 years) were included. A symmetric tibial component was used in 51 knees (group I), whereas an asymmetric tibial component was used in 50 knees (group II). We measured the angles of four anatomical landmarks by using preoperative and postoperative computed tomography images. The combined rotational alignment and the amount of change were calculated. The correlation between the isolated tibial component rotation (ITR) and DeltaCR was analyzed by using the Spearman correlation coefficient. Results: The mean DeltaCR was -0.1 degrees +/-6.3 degrees in group I and -4.8 degrees +/-5.7 degrees in group II after TKA. Excluding the intercomponent rotation, the change was -1.0 degrees +/ 7.3 degrees and -6.7 degrees +/-6.7 degrees in group I and group II, respectively. A correlation analysis between the ITR and tibial component rotation relative to the tibial tuberosity showed a statistically significant correlation. Conclusions: The combined lower limb rotational alignment was internally rotated in both symmetric and asymmetric tibial component designs after TKA. The asymmetric tibial component was better than the symmetric tibial component in achieving internally rotated combined lower limb rotational alignment. The internal rotation of the symmetric tibial component relative to the tibial tuberosity tip should fall within 20 degrees to correct the externally deformed lower limb. PMID- 29482309 TI - Serial Radiographs Showing Progression of a Patellar Stress Fracture and Beneficial Surgical Technique for a Displaced Patellar Stress Fracture. AB - Stress fractures of the patella occurring in athletes are quite rare and only 23 cases have been introduced in English literatures. Stress fractures of the patella are classified into two types: transverse and longitudinal. They are mostly seen in the distal one-third of the patella on a plain lateral radiograph. We present here a 16-year-old female basketball player with a stress fracture of the patella. Her serial radiographs demonstrated progression of the fracture including a lytic cortex lesion, known as the gray cortex sign for early stage stress fractures, in the distal one-third of the patella on plain lateral radiographs. In addition, we introduce a surgical technique using non-absorbable suture ligatures (No.2 Ethibond) for a displaced transverse stress fracture of the patella when the extensor mechanism is intact. The ligatures are passed through into the patella using suture passers and simply tied down over the top of the patella. In our case, it led to neither hardware-related nor circumferential loop-related irritation postoperatively. PMID- 29482310 TI - Optimal Xeno-free Culture Condition for Clinical Grade Stem Cells from Human Exfoliated Deciduous Teeth. AB - Background and Objectives: Stem cells from human exfoliated deciduous teeth (SHED) are a promising clinical resource for various tissue defects, including lumbar spondylosis, neural compression, and cleft palate. Use of media containing animal-derived serum carries potential risk of infectious diseases and unwanted immunogenicity. To increase the potential utility of SHED for clinical application, SHED was adapted to xeno-free conditions. Methods: Define xeno-free culture media were compared with the conventional serum containing media in the culture of SHED. Cultured SHED in different media were further characterized through proliferative capacities, cellular phenotype, and differentiation potential. Results: Selected xeno-free media were capable of supporting the growth of SHED. MSCGM-CD Bulletkit medium greatly increased the number and proliferate capacity of colony-forming unit-fibroblast than SHED cultured in other media. In addition, the characteristic surface markers expression and multipotent differentiation potential of SHED in the MSCGM-CD Bulletkit medium were comparable to those observed with serum-containing medium. Conclusions: The xeno-free medium described herein has the potential to be further used for the safe expansion and to determine efficient way to produce clinical grade dental stem cells for therapeutic applications. PMID- 29482311 TI - Mesenchymal Stem Cell Therapy for Ischemic Heart Disease: Systematic Review and Meta-analysis. AB - Background and Objectives: Mesenchymal stem cells (MSC) have emerged as breakthrough treatments for myocardial infarction. However, the efficacy of MSC remains unclear. The aim of the study was to evaluate treatment effect of MSC in terms of mechanical, regenerative, and clinical outcomes for patients with myocardial infarction (MI) using meta-analysis. Methods: A systematic search and critical review of MEDLINE, EMBASE, and Cochrane database literature published from inception through December 2017 was performed. The inclusion criteria were randomized controlled trials, studies on patients with myocardial infarction, and studies compared with placebo as a control group. Results: A total of 950 patients from 14 randomized placebo controlled trials were included in the final meta-analysis. MSC treatment showed benefits for mechanical, regenerative, and clinical outcomes. In terms of mechanical outcomes, the LVEF of the MSC treatment group increased by 3.84% (95% CI: 2.32~5.35, I2=43) and the effect was maintained for up to 24 months. Regenerative outcomes were measured by scar mass and WMSI. Scar mass was reduced by -1.13 (95% CI: -1.80 to -0.46, I2=71) and WMSI was reduced by -0.05 (95% CI: -0.07 to -0.03, I2=45) at 6 months after MSC treatment. Mortality rate and incidence of re-hospitalization for HF in MSC group patients trended toward reduced incidence compared to the control group, although this was not statistically significant because of the low event rate. Conclusions: The findings of this meta-analysis indicate that MSCs can be beneficial in improving heart function in the treatment of MI. However, the efficacy of MSCs must be further explored through large randomized controlled trials based on rigorous research design. PMID- 29482313 TI - Exploring the Link between Helicobacter pylori Eradication and Metachronous Gastric Cancer Development. PMID- 29482314 TI - Fecal Immunochemical Test and Fecal Calprotectin Measurement Are Noninvasive Monitoring Tools for Predicting Endoscopic Activity in Patients with Ulcerative Colitis. PMID- 29482315 TI - Diagnosis of Meckel's Diverticulum Using Colon Capsule Endoscopy for Small Bowel Investigation. PMID- 29482316 TI - Study Break: Possible Diagnostic Improvement for Cutaneous Leishmaniasis: Is It Achievable? PMID- 29482317 TI - Acid-Promoter-Free Ethylene Methoxycarbonylation over Ru-Clusters/Ceria: The Catalysis of Interfacial Lewis Acid-Base Pair. AB - The interface of metal-oxide plays pivotal roles in catalytic reactions, but its catalytic function is still not clear. In this study, we report the high activity of nanostructured Ru/ceria (Ru-clusters/ceria) in the ethylene methoxycarbonylation (EMC) reaction in the absence of acid promoter. The catalyst offers 92% yield of MP with TOF of 8666 h-1, which is about 2.5 times of homogeneous Pd catalyst (~3500 h-1). The interfacial Lewis acid-base pair [Ru-O Ce-Vo], which consists of acidic Ce-Vo (oxygen vacancy) site and basic interfacial oxygen of Ru-O-Ce linkage, acts as active site for the dissociation of methanol and the subsequent transfer of hydrogen to the activated ethylene, which is the key step in acid-promoter-free EMC reaction. The combination of 1H MAS NMR, pyridine-IR and DFT calculations reveals the hydrogen species derived from methanol contains Bronsted acidity. The EMC reaction mechanism under acid promoter-free condition over Ru-clusters/ceria catalyst is discussed. PMID- 29482318 TI - Insight into the Crucial Factors for Photochemical Deposition of Cobalt Cocatalysts on g-C3N4 Photocatalysts. AB - Photochemical preparation of inexpensive hydrogen evolution cocatalysts is of great significance and is challenging. Currently, the crucial factors in the photochemical preparation of nonnoble metals are still unknown. In this work, taking Co/g-C3N4 composite photocatalysts as a case, complexing agents and sacrificial agents were found to be the crucial factors for the photochemical deposition process. Cobalt was supported on the electron outlet points of g-C3N4 for 1 h, and the ratio of Co in the Co/g-C3N4 composite photocatalyst can be regulated by changing the irradiation time of the preparation process. The optimized hydrogen evolution rate of Co/g-C3N4 was about 11.48 MUmol h-1, which was 75 times more than pure g-C3N4. The photocatalytic H2 evolution rate was stable after 48 h. The mechanism for the high activity of Co/g-C3N4 composites was explored by surface photovoltage spectra and photoluminescence spectra. Co effectively promoted the separation of the photogenerated electrons and holes of g-C3N4 and improved the H2 production rate. PMID- 29482319 TI - Drug Partitioning in Micellar Media and Its Implications in Rational Drug Design: Insights with Streptomycin. AB - Oral bioavailability of a drug molecule requires its effective delivery to the target site. In general, majority of synthetically developed molecular entities have high hydrophobic nature as well as low bioavailability, therefore the need for suitable delivery vehicles arises. Self-assembled structures such as micelles, niosomes, and liposomes have been used as effective delivery vehicles and studied extensively. However, the information available in literature is mostly qualitative in nature. We have quantitatively investigated the partitioning of antibiotic drug streptomycin into cationic, nonionic, and a mixture of cationic and nonionic surfactant micelles and its interaction with the transport protein serum albumin upon subsequent delivery. A combination of calorimetry and spectroscopy has been used to obtain the thermodynamic signatures associated with partitioning and interaction with the protein and the resulting conformational changes in the latter. The results have been correlated with other class of drugs of different nature to understand the role of molecular features in the partitioning process. These studies are oriented toward understanding the physical chemistry of partitioning of a variety of drug molecules into suitable delivery vehicles and hence establishing structure-property-energetics relationships. Such studies provide general guidelines toward a broader goal of rational drug design. PMID- 29482320 TI - Effects of Trimethylamine- N-oxide (TMAO) on Hydrophobic and Charged Interactions. AB - Effects of trimethylamine- N-oxide (TMAO) on hydrophobic and charge-charge interactions are investigated using molecular dynamics simulations. Recently, these interactions in model peptides and in the Trp-Cage miniprotein have been reported to be strongly affected by TMAO. Neopentane dimers and Na+Cl- are used, here, as models for hydrophobic and charge-charge interactions, respectively. Distance-dependent interactions, i.e., potential of mean force, are computed using an umbrella sampling protocol at different temperatures which allows us to determine enthalpy and entropic energies. We find that the large favorable entropic energy and the unfavorable enthalpy, which are characteristic of hydrophobic interactions, become smaller when TMAO is added to water. These changes account for a negligible effect and a stabilizing effect on the strength of hydrophobic interactions for simulations performed with Kast and Netz models of TMAO, respectively. Effects of TMAO on the enthalpy are mainly due to changes in terms of the potential energy involving solvent-solvent molecules. At the molecular level, TMAO is incorporated in the solvation shell of neopentane which may explain its effect on the enthalpy and entropic energy. Charge-charge interactions become stronger when TMAO is added to water because this osmolyte decreases the enthalpic penalty of bringing Na+ and Cl- close together mainly by affecting ion-solvent interactions. TMAO is attracted to Na+, becoming part of its solvation shell, whereas it is excluded from the vicinity of Cl-. These results are more pronounced for simulation performed with the Netz model which is more hydrophobic and has a larger dipole moment compared to the Kast model of TMAO. PMID- 29482322 TI - Beyond Fluorescent Proteins: Hybrid and Bioluminescent Indicators for Imaging Neural Activities. AB - Optical biosensors have been invaluable tools in neuroscience research, as they provide the ability to directly visualize neural activity in real time, with high specificity, and with exceptional spatial and temporal resolution. Notably, a majority of these sensors are based on fluorescent protein scaffolds, which offer the ability to target specific cell types or even subcellular compartments. However, fluorescent proteins are intrinsically bulky tags, often insensitive to the environment, and always require excitation light illumination. To address these limitations, there has been a proliferation of alternative sensor scaffolds developed in recent years, including hybrid sensors that combine the advantages of synthetic fluorophores and genetically encoded protein tags, as well as bioluminescent probes. While still in their early stage of development as compared with fluorescent protein-based sensors, these novel probes have offered complementary solutions to interrogate various aspects of neuronal communication, including transmitter release, changes in membrane potential, and the production of second messengers. In this Review, we discuss these important new developments with a particular focus on design strategies. PMID- 29482323 TI - Strategies toward Dicarbofunctionalization of Unactivated Olefins by Combined Heck Carbometalation and Cross-Coupling. AB - The use of combined Heck carbometalation and cross-coupling remains one of the most powerful ways for the difunctionalization of unactivated olefins with organometallic reagents and organohalides. This synopsis will provide an overview of this reaction developed in the last three and a half decades. Herein, both the three-component and the two-component cyclization/cross-coupling processes will be reviewed with a focus on strategies utilized to overcome the complications of beta-hydride elimination from Heck C(sp3)-[M] intermediates, which usually functions as a major side reaction. PMID- 29482321 TI - A Comprehensive Analysis of Anion-Quadrupole Interactions in Protein Structures. AB - The edgewise interactions of anions with phenylalanine (Phe) aromatic rings in proteins, known as anion-quadrupole interactions, have been well studied. However, the anion-quadrupole interactions of the tyrosine (Tyr) and tryptophan (Trp) rings have been less well studied, probably because these have been considered weaker than interactions of anions hydrogen bonded to Trp/Tyr side chains. Distinguishing such hydrogen bonding interactions, we comprehensively surveyed the edgewise interactions of certain anions (aspartate, glutamate, and phosphate) with Trp, Tyr, and Phe rings in high-resolution, nonredundant protein single chains and interfaces (protein-protein, DNA/RNA-protein, and membrane protein). Trp/Tyr anion-quadrupole interactions are common, with Trp showing the highest propensity and average interaction energy for this type of interaction. The energy of an anion-quadrupole interaction (-15.0 to 0.0 kcal/mol, based on quantum mechanical calculations) depends not only on the interaction geometry but also on the ring atom. The phosphate anions at DNA/RNA-protein interfaces interact with aromatic residues with energies comparable to that of aspartate/glutamate anion-quadrupole interactions. At DNA-protein interfaces, the frequency of aromatic ring participation in anion-quadrupole interactions is comparable to that of positive charge participation in salt bridges, suggesting an underappreciated role for anion-quadrupole interactions at DNA-protein (or membrane-protein) interfaces. Although less frequent than salt bridges in single chain proteins, we observed highly conserved anion-quadrupole interactions in the structures of remote homologues, and evolutionary covariance-based residue contact score predictions suggest that conserved anion-quadrupole interacting pairs, like salt bridges, contribute to polypeptide folding, stability, and recognition. PMID- 29482324 TI - Energy Landscapes for the Aggregation of Abeta17-42. AB - The aggregation of the Abeta peptide (Abeta1-42) to form fibrils is a key feature of Alzheimer's disease. The mechanism is thought to be a nucleation stage followed by an elongation process. The elongation stage involves the consecutive addition of monomers to one end of the growing fibril. The aggregation process proceeds in a stop-and-go fashion and may involve off-pathway aggregates, complicating experimental and computational studies. Here we present exploration of a well-defined region in the free and potential energy landscapes for the Abeta17-42 pentamer. We find that the ideal aggregation process agrees with the previously reported dock-lock mechanism. We also analyze a large number of additional stable structures located on the multifunnel energy landscape, which constitute kinetic traps. The key contributors to the formation of such traps are misaligned strong interactions, for example the stacking of F19 and F20, as well as entropic contributions. Our results suggest that folding templates for aggregation are a necessity and that aggregation studies could employ such species to obtain a more detailed description of the process. PMID- 29482325 TI - Cloning and Functional Analysis of CncC and Keap1 Genes in Silkworm. AB - CncC/keap1-ARE is an important signaling pathway for detoxification and antioxidation in Diptera and Coleoptera insects. However, such a signaling pathway has not been studied in Bombyx mori. In this study, BmCncC and Bmkeap1 genes were cloned, their amino acid sequences were analyzed, and each functional domain was mapped. Through phylogenetic analysis and sequence comparison among multiple species, we found that the Neh1 motif of CncC was highly conserved and the DLG motif was replaced by the DMG motif in Neh2. Conformational analysis showed that Neh1 of BmCncC forms a hairpin structure to bind DNA. The DGR region of Bmkeap1 contained abundant beta sheets, which was involved in the recognition of Neh2. The transcription and expression analyses showed that both BmCncC and Bmkeap1 were highly expressed in the first instar larvae, and these two genes were expressed at a high level in the reproductive gland, fat body, and head. The transcriptional and expression levels of Akt and BmCncC in the fat body were significantly upregulated, and the expression of Bmkeap1 was downregulated after the phoxim treatment in silkworm. The transcriptional levels of CncC-regulated detoxification enzymes GST, cyp4M5, cyp6AE2, and cyp9G3 were increased by 4.026-, 5.246-, 3.821-, and 9.787-fold, respectively, while the activities of GST and CYP450 were increased by 1.521- and 1.231-fold, respectively, after phoxim treatment. These results indicated that the BmCncC/Bmkeap1 signaling pathway was activated by phoxim, leading to the expression of downstream detoxifying enzymes and detoxification of phoxim in silkworm. PMID- 29482326 TI - Enzymatic Acylation of Anthocyanins Isolated from Alpine Bearberry ( Arctostaphylos alpina) and Lipophilic Properties, Thermostability, and Antioxidant Capacity of the Derivatives. AB - Cyanidin-3- O-galactoside (cy-gal) isolated from alpine bearberry ( Arctostaphylos alpine L.) was enzymatically acylated with saturated fatty acids of different chain lengths with Candida antarctica lipase immobilized on acrylic resin (Novozyme 435). The acylation reaction was optimized by considering the reaction medium, acyl donor, substrate molar ratio, reaction temperature, and reaction time. The highest conversion yield of 73% was obtained by reacting cy gal with lauric acid (molar ratio of 1:10) in tert-butanol at 60 degrees C for 72 h. A novel compound was synthesized, which was identified as cyanidin-3- O-(6" dodecanoyl)galactoside by mass spectrometry and nuclear magnetic resonance. Introducing lauric acid into cy-gal significantly improved both the lipophilicity and thermostability and substantially preserved the ultraviolet-visible absorbance and antioxidant properties. The research provides important insight in expanding the application of natural anthocyanins in the cosmetic and food industries. PMID- 29482327 TI - DNA-Mold Templated Assembly of Conductive Gold Nanowires. AB - We introduce a new concept for the solution-based fabrication of conductive gold nanowires using DNA templates. To this end, we employ DNA nanomolds, inside which electroless gold deposition is initiated by site-specific attached seeds. Using programmable interfaces, individual molds self-assemble into micrometer-long mold superstructures. During subsequent internal gold deposition, the mold walls constrain the metal growth, such that highly homogeneous nanowires with 20-30 nm diameters are obtained. Wire contacting using electron-beam lithography and electrical conductance characterization at temperatures between 4.2 K and room temperature demonstrate that metallic conducting wires were produced, although for part of the wires, the conductance is limited by boundaries between gold grains. Using different mold designs, our synthesis scheme will, in the future, allow the fabrication of complex metal structures with programmable shapes. PMID- 29482328 TI - Subnanometer Resolution and Enhanced Friction Contrast at the Surface of Perylene Diimide PDI8-CN2 Thin Films in Ambient Conditions. AB - We report high-resolution surface morphology and friction force maps of polycrystalline organic thin films derived by deposition of the n-type perylene diimide semiconductor PDI8-CN2. We show that the in-plane molecular arrangement into ordered, cofacial slip-stacked rows results in a largely anisotropic surface structure, with a characteristic sawtooth corrugation of a few Angstroms wavelength and height. Load-controlled experiments reveal different types of friction contrast between the alternating sloped and stepped regions, with transitions from atomic-scale dissipative stick-slip to smooth sliding with ultralow friction within the surface unit cell. Notably, such a rich phenomenology is captured under ambient conditions. We demonstrate that friction contrast is well reproduced by numerical simulations assuming a reduced corrugation of the tip-molecule potential nearby the step edges. We propose that the side alkyl chains pack into a compact low-surface-energy overlayer, and friction modulation reflects periodic heterogeneity of chains bending properties and subsurface anchoring to the perylene cores. PMID- 29482329 TI - Synthesis and Evaluation of Two Novel All -trans-Retinoic Acid Conjugates: Biocompatible and Functional Tools for Retina Research. AB - The vitamin A derivative all- trans-retinoic acid (ATRA) is an important biologically active metabolite that regulates a variety of essential biological processes in particular via gene-regulatory mechanisms. In the retina, ATRA is a light-dependent byproduct of the phototransduction cascade. Here, ATRA is not only needed for proper retinal development, but it also acts as a neuromodulator on horizontal cells, second-order inhibitory neurons in the outer retina, which reveal morphological and physiological changes when the retina is treated with ATRA. There is evidence that gene-regulatory mechanisms may only be partially involved in these neuromodulatory processes and the underlying nontranscriptional mechanisms are still elusive. This is, among other things, due to the lack of appropriately labeled ATRA, which would allow the tracking of ATRA in cells or a given tissue. To overcome this obstacle, we designed, synthesized, and evaluated two conjugates of ATRA, one conjugated with biotin (biotin-ATRA) and one conjugated with diaminoterephthalate fluorophore (DAT-ATRA), as molecular tools for different fields of application. The biocompatibility of both compounds was demonstrated via cell viability assays in cultured N2a-cells. N2a-cells exposed to the compounds showed no significant changes in the viability rate. The functionality of synthesized ATRA-conjugates was verified using retinal tissue derived from adult carp. The binding of ATRA-conjugates to distinct retinal cells was assessed in primary cultures of carp retina. Hereby, horizontal and Muller cells have been identified as specific target cells of the new ATRA compounds. Electron microscopy further confirmed that the new substances are still able to induce synaptic plasticity at horizontal cell dendrites resulting in formation of spine synapses, as it is shown for native ATRA. Taken together, the novel ATRA conjugates represent biocompatible and functional molecular tools, which may further provide the possibility to track ATRA in neuronal cells and study its modulatory effects in different cell systems. PMID- 29482331 TI - Associations Between Secret-Keeping and Quality of Life in Older Adults. AB - This study examined the effects of secrecy on quality of life in a sample consisting of older adults (>50 years; N = 301). Three key components of secrecy were examined with the Tilburg Secrecy Scale-25 (TSS25; possession of a secret, self-concealment, and cognitive preoccupation). The TSS25 distinguishes between the tendency to conceal personal information (self-concealment) and the tendency to worry or ruminate about the secret (cognitive preoccupation), thereby enabling investigation of the effects of secrecy on quality of life in detail. Confirming previous findings in younger samples, we found a positive effect of possession of a secret on quality of life, after controlling for both TSS25's self-concealment and cognitive preoccupation. This suggests that keeping secrets may have a positive association with quality of life in older adults as well, as long as they do not have the tendency to self-conceal and are not cognitively preoccupied with their secret. PMID- 29482330 TI - Observation of endoplasmic reticulum tubules via TOF-SIMS tandem mass spectrometry imaging of transfected cells. AB - Advances in three-dimensional secondary ion mass spectrometry (SIMS) imaging have enabled visualizing the subcellular distributions of various lipid species within individual cells. However, the difficulty of locating organelles using SIMS limits efforts to study their lipid compositions. Here, the authors have assessed whether endoplasmic reticulum (ER)-Tracker Blue White DPX(r), which is a commercially available stain for visualizing the endoplasmic reticulum using fluorescence microscopy, produces distinctive ions that can be used to locate the endoplasmic reticulum using SIMS. Time-of-flight-SIMS tandem mass spectrometry (MS2) imaging was used to identify positively and negatively charged ions produced by the ER-Tracker stain. Then, these ions were used to localize the stain and thus the endoplasmic reticulum, within individual human embryonic kidney cells that contained higher numbers of endoplasmic reticulum-plasma membrane junctions on their surfaces. By performing MS2 imaging of selected ions in parallel with the precursor ion (MS1) imaging, the authors detected a chemical interference native to the cell at the same nominal mass as the pentafluorophenyl fragment from the ER-Tracker stain. Nonetheless, the fluorine secondary ions produced by the ER-Tracker stain provided a distinctive signal that enabled locating the endoplasmic reticulum using SIMS. This simple strategy for visualizing the endoplasmic reticulum in individual cells using SIMS could be combined with existing SIMS methodologies for imaging intracellular lipid distribution and to study the lipid composition within the endoplasmic reticulum. PMID- 29482332 TI - Mindful Self-Care and Secondary Traumatic Stress Mediate a Relationship Between Compassion Satisfaction and Burnout Risk Among Hospice Care Professionals. AB - BACKGROUND: Effective self-care in hospice is anecdotally proclaimed to reduce burnout risk. Yet, the topic has received little empirical attention. PURPOSE: This study developed a model for predicting burnout risk from compassion satisfaction (CS), secondary traumatic stress (STS), and mindful self-care. PARTICIPANTS: Hospice care professionals (n = 324). DESIGN: Cross-sectional self report survey. RESULTS: Mindful self-care was correlated with CS ( r = 0.497, p < .01), Burnout ( r = -0.726, p < .01), and STS ( r = -0.276, p < .01). A multiple regression model indicated that the combined effect of CS, STS, and mindful self care explained 73.7% of the variance in Burnout. Mindful self-care and STS mediated a relationship between CS and Burnout. Each self-care category was statistically significant protective factors against burnout risk ( p < .01). Associations with Burnout in order of strength were self-compassion and purpose (SC; r = -0.673), supportive structure (SS; r = -0.650), mindful self-awareness (MS; r = -0.642), mindful relaxation (MR; r = -0.531), supportive relationships (SR; r = -0.503), and physical care (PC; r = -0.435). However, for STS, only SS ( r = -0.407, p < .01) and MR ( r = -0.285, p < .05) were statistically significant protective factors. CONCLUSION: Hospice care professional had higher self-care, CS, lower STS, and Burnout compared to published norms. Those who engaged in multiple and frequent self-care strategies experienced higher professional quality of life. Implications for hospice providers and suggestions for future research are discussed. PMID- 29482333 TI - Understanding experiences of the self-harm of others: A qualitative exploration of the views of young people with complex mental health needs. AB - As adolescent self-harm is a growing public health concern, more research is needed to identify potential risk factors. Studies have highlighted that exposure to the self-harm of others may be a risk factor associated with engagement in self-harm. However, research investigating young people's experiences of the self harm of others has been limited. This qualitative study aimed to explore young people's experiences of the self-harm of others and interviewed a total of eight young people (five females and three males; aged between 13 and 18 years) resident at one of two adolescent mental health inpatient units in the North of England. The interviews were analysed using Interpretative Phenomenological Analysis and four themes were identified: 'Pre-admission exposure to self-harm', 'Exposure on the inside: An unpleasant environment', 'Helper vs helped' and 'Separation from the attention seekers: competing for authenticity'. Prevention efforts to reduce the social transmission and stigma surrounding self-harm among young people are discussed. PMID- 29482336 TI - Advanced Oxidation Protein Products Aggravate Tubulointerstitial Fibrosis Through Protein Kinase C-Dependent Mitochondrial Injury in Early Diabetic Nephropathy. AB - AIMS: Diabetic nephropathy (DN) is the most common microvascular complications and the principal cause of mortality and morbidity rates in patients with diabetes. The expression of advanced oxidation protein products (AOPPs) has been found in vacuolated renal tubules in DN and correlated with patients' decreased renal function. The accumulation of AOPPs is regarded as an initiating factor in podocyte injuries via the protein kinase C (PKC) signaling, which plays a critical role in triggering oxidative stress and mitochondrial injuries in diseases including DN. Whether AOPPs could induce mitochondrial injuries and fibrosis in renal tubules remains largely unknown. Herein, we tested the hypothesis that the accumulation of AOPPs in diabetes incurs mitochondrial dysfunction and oxidative stress, causing renal tubulointerstitial fibrosis (TIF) via PKC signaling pathway. RESULTS: In vivo, intrarenal AOPPs accumulation correlated with oxidative stress, renal fibrosis, proteinuria, and declined renal function in DN patients and diabetic rats. AOPPs-induced mitochondrial injuries, apoptosis, and TIF were significantly mitigated by PKCeta inhibition in diabetic rats. In vitro, high glucose (HG) stimulated AOPP expression and augmented PKC mediated oxidative stress and fibrosis in HK-2 cells. Furthermore, we provide mechanistic evidence that inhibition of PKCeta isoform alleviated mitochondrial injuries and function, attenuated apoptosis, and renal fibrosis in HG-cultured AOPPs-induced HK-2 cells. Innovation and Conclusion: We propose a novel mechanism that AOPPs-induced mitochondrial dysfunction and oxidative stress cause TIF in DN via activation of the PKCeta isoform. Antioxid. Redox Signal. 00, 000-000. PMID- 29482337 TI - The mother's carnet de sante (health booklet) in Cameroon: a tool for preventing mother-to-child transmission of HIV? AB - In the global effort against HIV and AIDS, prevention of mother-to-child transmission of HIV (PMTCT) in resource-poor countries is an issue of international importance. In Cameroon, a widely disseminated protocol defines the process to be followed by all pregnant women within the public health system before and after screening, whatever the result. The protocol as a representation of professional practices can be discerned in inscriptions made in files, registers and the carnet de sante that we use here as the cornerstone of our analysis. By granting it the status of a 'script' and intermediary object, we hypothesize that its purpose is to link together human and non-human actors around the PMTCT protocol in order to reduce the risk of mother-to-child transmission. However, as we show, representations and forms of interactions that are structured and reconfigured around it paradoxically contribute to the re emergence of the risk of mother-to-child transmission of HIV. PMID- 29482338 TI - Effect of Bacillus subtilis C-3102 on loose stools in healthy volunteers. AB - Ingestion of Bacillus subtilis C-3102 spores (C-3102) has relieved the symptoms of diarrhoea in piglets and changed the composition of gut microbiota in humans. Recently, it was suggested that the composition of the human gut microbiota affects stool consistency. In this study, a double-blind, randomised, placebo controlled trial was conducted to assess the preventive effects of chronic diarrhoea in healthy volunteers with loose stools by ingestion of C-3102. The results showed that oral doses of C-3102 tablets significantly decreased the Bristol Stool Scale score and stool frequency, and also significantly improved abdominal sounds. With regard to gut microbiota, the relative abundance of Lachnospira, Actinomyces and SMB53 were significantly changed. This study shows that C-3102 could be effective for treating loose stools (Trial registration: UMIN000022583, http://tinyurl.com/ya4refqn ). PMID- 29482339 TI - Gut microbiota characterisation in obese patients before and after bariatric surgery. AB - Intestinal microbiota analysis of obese patients after bariatric surgery showed that Proteobacteria decreased after laparoscopic sleeve gastrectomy (SG), while it increased after laparoscopic gastric bypass (LGB). Comparing to normal weight (NW) patients, obese patients that were selected for SG showed an almost equal amount of Firmicutes and Bacteroidetes and the ratio was not affected by the surgery. Obese patients before LGB showed a predominance of Bacteroidetes, whose amount regained a relative abundance similar to NW patients after surgery. Obese patients before LGB showed the predominance of Bacteroides, which decreased after surgery in favour of Prevotella, a bacterium associated with a healthy diet. The bacteria detected at the highest percentages belonged to biofilm forming species. In conclusion, in this study, we found that the characterization of the gut microbial communities and the modality of mucosal colonisation have a central role as markers for the clinical management of obesity and promote the maintenance of good health and the weight loss. PMID- 29482340 TI - Sensory processing, cognitive fatigue, and quality of life in multiple sclerosis: Traitement de l'information sensorielle, fatigue cognitive et qualite de vie des personnes atteintes de sclerose en plaques. AB - BACKGROUND: Quality of life for persons living with multiple sclerosis (MS) is significantly lower than population norms. Fatigue, both physical and cognitive, is one of the most prevalent and debilitating symptoms of MS that decrease quality of life. Cognitive fatigue presents similarly to sensory overresponsiveness, but the connection has not been explored. PURPOSE: This study aims to describe how sensory-processing preferences and cognitive fatigue relate to variances in quality of life for people with MS. METHOD: A cross-sectional design was used with 30 people living with MS to complete the Adolescent/Adult Sensory Profile (AASP), Modified Fatigue Impact Scale, and RAND-36. Spearman's coefficient measured nonparametric correlations between variables. FINDINGS: People with MS who have high scores in low registration, sensory sensitivity, and sensation avoidant quadrants of the AASP also have higher levels of cognitive fatigue and poorer quality of life. Those with high scores in sensory seeking experience greater quality of life and less cognitive fatigue. IMPLICATIONS: The findings shape clinical practice by supporting the assessment of sensory processing alongside fatigue, offering individualized intervention planning to shape fatigue management, and fostering hope and quality of life for persons living with MS. PMID- 29482342 TI - Acceptability and feasibility of a Peer Mentor program to train young Black men who have sex with men to promote HIV and STI home-testing to their social network members. AB - Young Black men who have sex with men (YBMSM) experience persistently high rates of undiagnosed HIV and other sexually transmitted infections (STIs) and testing rates remain sub-optimal. Home-based testing (HBT) has been found to be acceptable among MSM and while awareness about HBT is relatively high, uptake has been low. Peer-based approaches have been shown to be effective in reducing HIV risk behavior, yet have not been used to increase utilization of HBT. The purpose of this study was to assess acceptability and feasibility of a program to train YBMSM as Peer Mentors to use and promote HIV and STI home-based testing and specimen collection to their social network members. Fifteen YBMSM ages 18-30 completed in-depth structured interviews and were asked to talk with their social network members about home-based testing. Participants reported acceptability of the Peer Mentor role and two-thirds had conversations with diverse social network members (e.g., male and female, sex partners, friends, family). Facilitators of peer outreach included the novelty of home-based testing, confidence about accuracy of the tests, and resources for linkage to care. Barriers included concerns about negative responses and disclosure of sexual identity/behavior. Results of this study suggest that YBMSM are willing and able to promote HBT to their social networks. This is a promising approach to increasing dissemination of HBT kits for both HIV and STI testing. PMID- 29482341 TI - Measuring occupational balance and its relationship to perceived stress and health: Mesurer l'equilibre occupationnel et sa relation avec le stress percus et la sante. AB - BACKGROUND: There is an assumption that occupational balance is integrally related to health and well-being. PURPOSE: This study aimed to investigate test retest reliability of the English-translated Occupational Balance Questionnaire (OBQ), its relationship to measures of health (Short Form Health Survey-36 Version 2.0 [SF-36v2]) and stress (Perceived Stress Scale-10; PSS-10), and demographic differences in OBQ scores in Canadian adults. METHOD: Test-retest reliability (2 weeks) was assessed using intraclass correlation (ICC) coefficients. Online surveys from 86 adults were analyzed using descriptive, correlational, and t test statistics. FINDINGS: OBQ test-retest reliability was ICC = 0.74 (95% CI [0.34, 0.90]; p = .003) when excluding an influential case ( n = 20). OBQ correlations with PSS-10 were r = -.72; with SF-36v2 Mental Component Score, r = .65; and with Physical Component Score, r = .31; all p < .001. Age and gender had no impact on OBQ scores. IMPLICATIONS: Findings help elucidate relationships among health, stress, and occupational balance; however, further psychometric testing is warranted before using OBQ for clinical purposes. PMID- 29482343 TI - Enhanced Tobacco Control Initiative at Johns Hopkins Health System: Employee Fairness Perception. AB - Organizations often fail to establish a clear awareness of what employees consider fair when implementing changes to employee benefits in the workplace. In 2016, the Johns Hopkins Health System (JHHS) enhanced their tobacco control efforts. In addition to enhanced smoking cessation benefits, employees were offered an increased reduction in their insurance premiums if they were nonsmokers. To qualify for the reduction, employees participated in testing rather than relying on self-reporting as had been done in the past. The shift to testing prompted a concern by some senior management at JHHS who did not want employees to feel they were not trusted. As the program unfolded at JHHS, the four-component model of procedural justice was applied to provide a framework for reviewing the implementation of the new voluntary tobacco testing at JHHS from a fairness lens. The purpose of this article is to illustrate the application of the four-component procedural model of justice to the tobacco testing process at JHHS. As approximately 75% of employees participated in the program, the experience at JHHS can be instructive to other employers who are looking to implement changes in their workplaces and how to minimize unintended consequences with their employees. PMID- 29482344 TI - Brain susceptibility changes in neurologically asymptomatic pediatric patients with Wilson's disease: evaluation with quantitative susceptibility mapping. AB - Background Wilson's disease (WD) is a copper metabolism disorder that causes hepatolenticular degeneration. It is important to diagnose WD before central nervous system involvement. Purpose To demonstrate the early susceptibility changes associated with the copper accumulation in the brain of neurologically asymptomatic pediatric patients with WD using quantitative susceptibility mapping (QSM). Material and Methods Twelve patients with neurologically asymptomatic WD (mean age = 13.7 +/- 3.3 years) and 14 age-matched controls were prospectively examined using a 1.5-T clinical scanner. Routine magnetic resonance (MR) sequences and a three-dimensional multi-echo spoiled gradient echo (GRE) sequence were used and QSM maps were reproduced. The quantitative susceptibility of corpus striatum, thalamus, substantia nigra, and pons were analyzed with the region of interest analysis on QSM maps. The susceptibility values of two groups were statistically compared using a two-sample t-test. Results Conventional MR images of the patients and control group were similar. However increased magnetic susceptibility in the thalamus, pons and left posterior putamen were observed in the patients compared to the control group ( p < 0.05). Conclusion We observed statistically increased susceptibility values in the brains of neurologically asymptomatic patients with WD although the conventional MR images were normal. This might be compatible with early brain impairment, before neurological symptoms occur. PMID- 29482345 TI - Subcortical nuclei in Alzheimer's disease: a volumetric and diffusion kurtosis imaging study. AB - Background Previous studies revealed that subcortical nuclei were harmed in the process of Alzheimer's disease (AD). Purpose To investigate the volumetric and diffusion kurtosis imaging (DKI) parameter changes of subcortical nuclei in AD and their relationship with cognitive function. Materials and Methods A total of 17 mild AD patients, 15 moderate to severe AD patients, and 16 controls underwent neuropsychological tests and magnetic resonance imaging (MRI) scans. Volume, mean kurtosis (MK), mean diffusivity (MD), and fractional anisotropy (FA) were measured in hippocampus, thalamus, caudate, putamen, pallidum, and amygdala. MRI parameters were compared. Correlation analysis was performed between subcortical nuclei volume, DKI parameters, and MMSE score. Results Significant volume reduction was seen in the left hippocampus in mild AD, and the bilateral hippocampus, thalamus, putamen, left caudate, and right amygdala in moderate to severe AD ( P < 0.05). Increased MD values were observed in the left hippocampus, left amygdala, and right caudate in mild AD, and the bilateral hippocampus and right amygdala in moderate to severe AD ( P < 0.05). Decreased MK values were observed only in the bilateral hippocampus in moderate to severe AD ( P < 0.05). No group significances were found in FA value. MMSE score was positively correlated with the volume of the bilateral hippocampus, thalamus, and putamen, and MK value of the left hippocampus ( P < 0.05). A negative correlation was found with the MD value of the bilateral hippocampus and left amygdala ( P < 0.05). Conclusion Mild AD mainly has microscopic subcortical changes revealed by increased MD value, and moderate to severe AD mainly has macroscopic subcortical changes revealed by volume reduction. MK is more sensitive in severe AD than mild AD. PMID- 29482346 TI - Percutaneous kyphoplasty for the treatment of distal lumbosacral pain caused by osteoporotic thoracolumbar vertebral fracture. AB - Background Kyphoplasty has been demonstrated to be minimally invasive and effective in treating osteoporotic vertebral fracture patients with back pain over the level of the fractured vertebrae. Rare studies have reported on thoracolumbar vertebral fracture patients presenting with distal lumbosacral pain (DLP). Whether kyphoplasty had a favorable therapeutic benefit for these patients remains unclear. Purpose To evaluate the therapeutic efficacy of kyphoplasty in treating osteoporotic thoracolumbar vertebral fracture (OTVF) patients with DLP and assess the clinical significance of focal tenderness to palpation in these patients. Material and Methods Thirty-two OTVF patients who only complained of DLP were treated by kyphoplasty. The vertebral heights, local kyphotic angle, Visual Analogue Scale (VAS), and Oswestry Disability Index (ODI) scores were assessed preoperatively, one day after surgery, and at last follow-up. All patients were evaluated regarding their degree of satisfaction with kyphoplasty. In addition, we compared the therapeutic efficacy of kyphoplasty in patients with and without focal tenderness to palpation. Results All patients successfully underwent kyphoplasty without complications. The vertebral heights, local kyphotic angles, VAS, and ODI scores were all significantly improved after kyphoplasty and maintained at last follow-up in our patients ( P < 0.001). At last follow-up, all patients expressed satisfaction with kyphoplasty. No significant differences in these parameters were detected between patients with and without focal tenderness. Conclusion The possibility of thoracolumbar vertebral fractures in elderly patients complaining of DLP should not be neglected. Kyphoplasty presents a superior benefit in treating OTVF patients with DLP. The absence of focal tenderness does not influence the clinical efficacy in these patients. PMID- 29482348 TI - An Epidemiological Survey of Venous Disease Among General Practitioner Attendees in Different Geographical Regions on the Globe: The Final Results of the Vein Consult Program. AB - This study measured the prevalence of chronic venous disease (CVD, C1-C6), chronic venous insufficiency (C3-C6) in 23 countries. The possible influence of risk factors was assessed. Patient recruitment was carried out by general practitioners. Patient characteristics, prevalence of risk factors, and C classification were recorded. We assessed differences in prevalence and risk factors between Asia (A), Eastern Europe (EE), Latin America (LA), and Western Europe (WE). A total of 99 359 patients were included. The prevalence of CVD (51.9% A, 70.18% EE, 68.11% LA, and 61.65% WE) was significantly ( P < .001) lower in A. Risk factors such as age, obesity, smoking, having regular exercise, use of birth control pills, prolonged standing and sitting, and having a positive family history differ significantly between regions. After model-based probabilities corrected for risk factors, significant differences in the probability of having CVD were only found in the older age-group (>65 years). The lowest prevalence was noted in A. Chronic venous disease is very common and the prevalence varies between different geographical areas. After correcting for risk factors, these differences diminished. PMID- 29482347 TI - Degenerative changes of the thoracic spine do exist in patients with diffuse idiopathic skeletal hyperostosis: a detailed thoracic spine CT analysis. AB - Background Degenerative intervertebral disease (DID) is an exclusion criterion in the Resnick and Niwayama radiographic classification for diffuse idiopathic skeletal hyperostosis (DISH). However, although DID was previously described in DISH, no systematic computed tomography (CT) analysis has been reported so far. Purpose To assess for the presence and prevalence of such changes on CT examinations of the thoracic spine of individuals with DISH. Material and Methods Intervertebral space (D1-L1) on chest CT examinations of DISH patients was retrospectively evaluated for the presence of DID. Parameters evaluated were disc space height, disc protrusion, subchondral cysts/sclerosis, Schmorl nodes, vacuum phenomenon, and posterior elements including costovertebral and facet joints. Parameters were compared with two age- and gender-matched control groups of individuals whose entire spine CT lacked evidence of DISH (Control 1 individuals < 2 flowing osteophytes, Control 2 individuals < 4 and >= 2 flowing osteophytes). Results A total of 158 participants (DISH/Control 1/Control 2 = 54/54/50; 106 men, 52 women; average age = 70.6 years) were evaluated. Average intervertebral disc height was significantly lower in the DISH group compared with both control groups (DISH/Control 1/Control 2 = 4.55/5.13/5.01 mm, P < 0.001). Costovertebral degenerative changes were more prevalent in DISH patients ( P < 0.05) and, except for vacuum phenomenon (more prevalent in controls), other DID changes were as prevalent in DISH as in controls. Conclusion The presence of degenerative intervertebral changes on thoracic CT should not deter from diagnosing DISH. Thus, the radiographic Resnick and Niwayama DISH criteria cannot be directly adapted to CT. PMID- 29482349 TI - Low Levels of High-Density Lipoprotein Cholesterol Are Linked to Impaired Clopidogrel-Mediated Platelet Inhibition. AB - Low high-density lipoprotein cholesterol (HDL-C) levels are an independent predictor of ischemic events in patients with atherosclerotic cardiovascular disease. This may in part be due to decreased clopidogrel-mediated platelet inhibition in patients with low HDL-C. We investigated the association of HDL-C with on-treatment platelet reactivity to adenosine diphosphate (ADP) in 314 patients on dual antiplatelet therapy with clopidogrel and aspirin undergoing angioplasty and stenting. Platelet P-selectin expression was assessed by flow cytometry, and platelet aggregation was determined by the VerifyNow P2Y12 assay and the Impact-R. High-density lipoprotein cholesterol levels were inversely associated with P-selectin expression and the VerifyNow P2Y12 assay (both P <= .01). Moreover, we found a positive correlation of HDL-C with surface coverage by the Impact-R ( P = .003). Patients with low HDL-C (<=35 mg/dL) exhibited a significantly higher P-selectin expression in response to ADP and higher platelet aggregation by the VerifyNow P2Y12 assay and the Impact-R than patients with normal HDL-C (>35 mg/dL; all P < .05). High on-treatment residual platelet reactivity by the VerifyNow P2Y12 assay occurred significantly more frequently in patients with low HDL-C levels than in those with normal HDL-C (47.4% vs 30.1%, P = .01). In conclusion, low HDL-C is linked to impaired clopidogrel-mediated platelet inhibition after angioplasty and stenting. PMID- 29482350 TI - Tumor Protein p53 (TP53) Gene and Left Main Coronary Artery Disease. AB - Patients with left main (LM) coronary artery disease (CAD) are at the highest risk of cardiovascular events. We evaluated possible gene polymorphisms of tumor protein 53 ( TP53, rs1042522, p.Arg72Pro) that can differentiate LM-CAD from patients with more peripheral CAD (MP-CAD) and healthy participants (control group) in 520 individuals (LM-CAD, n = 175; MP-CAD, n = 185; and control group, n = 160). Patients with LM-CAD had the lowest Arg/Arg genotype frequency (36.0%) compared with the MP-CAD (57.3%) and control groups (61.9%), P < .001 for both comparisons. Similarly, the Arg allele was more frequent in the control group than in patients with MP-CAD (78.8% vs 73.2%; P = .007) and LM-CAD (78.8% vs 64.0%; P < .001). The Arg/Pro genotype was more frequent in the LM-CAD group compared with the MP-CAD and control groups (56.0, 31.9, and 33.8, respectively, P < .001 for both comparisons). Furthermore, the frequency of Arg/Arg genotypes was the lowest in the LM-CAD group compared with the MP-CAD and control groups. Knowing that TP53 is an antioncogene protein that acts as a tumor suppressor and regulator of apoptosis, the lowest frequency of Arg/Arg genotype observed in these high-risk patients may indicate lower protection from the atherosclerosis process. Replication studies are needed to evaluate this association. PMID- 29482351 TI - Sarilumab: Review of a Second IL-6 Receptor Antagonist Indicated for the Treatment of Rheumatoid Arthritis. AB - : Major Objectives: To review the efficacy, safety, and economics of sarilumab, an interleukin-6 (IL-6) receptor antagonist, in the treatment of rheumatoid arthritis (RA). DATA SOURCES: PubMed (1966 to January 2018), Clinicaltrials.gov (January 2018), and Scopus (1970 to January 2018) were searched using sarilumab, Kevzara, REGN88, and SAR153191. STUDY SELECTION AND DATA EXTRACTION: Human studies published in peer-reviewed publications in English were the primary sources for efficacy and safety. DATA SYNTHESIS: Data from randomized, double blind, controlled, published clinical studies weeks demonstrated statistically significantly higher American College of Rheumatology (ACR) 20, ACR50, and Disease Activity Score-28 (DAS28) remission response rates and improvements in DAS28 and Health Assessment Questionnaire-Disability Index scores for sarilumab monotherapy versus adalimumab monotherapy (P < 0.05) and for sarilumab versus placebo in patients receiving methotrexate or other conventional synthetic disease-modifying antirheumatic drugs (DMARDs); P < 0.05. The ACR20 and ACR50 response rates were, respectively, 56-72% and 35-46% for sarilumab, 58% and 30% for adalimumab, and 33-34% and 15-18% for placebo. DAS28 remission rates were 20 34% for sarilumab, 7% for adalimumab, and 7-10% for placebo. Sarilumab has a higher risk for neutropenia than tocilizumab, the other IL-6 inhibitor, but a lower risk for dyslipidemia, injection site reactions, and gastrointestinal perforation. The acquisition costs of sarilumab are expected to be similar to those of most other biologic DMARDs. CONCLUSION: Sarilumab is an alternative to biologic DMARDs or targeted synthetic DMARDs in patients with moderate to severely active RA who have not responded adequately to prior conventional synthetic DMARDs or tumor necrosis factor-alpha inhibitors. PMID- 29482352 TI - Dolutegravir Plus Rilpivirine as a Switch Option in cART-Experienced Patients: 96 Week Data. AB - BACKGROUND: Data from clinical studies confirm the efficacy of switching to dolutegravir (DTG) plus rilpivirine (RPV) in selected patients. OBJECTIVE: The primary objective is to report the 96-week virological suppression in our cohort, assessing the durability of this strategy in complicated situations. The secondary objective is to describe the safety and metabolic profile. METHODS: All patients who had switched to DTG plus RPV between October 1, 2014, and September 30, 2015, were analyzed using a retrospective-prospective design, approved by ethics committees. Routine metabolic, immunological, and virological data were regularly sent to the coordinating center. Viral control was classified as HIV-1 RNA >=50 copies/mL, 1 to 49 copies/mL, or undetectable (no virus detected [NVD]). RESULTS: We followed 145 patients for a median of 101 weeks. The median age was 52 years; 31.7% were women, and 9.6% non-Caucasian; 50.3% had failed at least 1 antiretroviral regimen; and 15% had >=50 copies/mL at baseline. The reasons for switching were as follows: simplification (51.7%), toxicity (36.5%), drug-drug interactions (6.9%), persistent low-level viremia (3.0%), nonadherence (2.1%), and viral failure (1.4%). By week 96, seven patients dropped out. At week 96, none had >=50 HIV-1 RNA copies/mL, 138 (95.2%) had <50 copies/mL, and 123 (84.8%) had NVD. The low- to high-density lipoprotein cholesterol (LDL-C/HDL-C) ratio decreased significantly ( P = 0.04). Of the 287 baseline altered laboratory parameters, 32.7% normalized by week 96. Serum glucose and total- and LDL cholesterol normalization were statistically significant. CONCLUSIONS: Switching to DTG plus RPV improved viral suppression and LDL-C/HDL-C ratio. PMID- 29482353 TI - Lesinurad: A Novel Agent for Management of Chronic Gout. AB - OBJECTIVE: To review the pharmacology, efficacy, and safety of lesinurad and determine its role relative to other agents in the management of chronic gout. DATA SOURCES: A PubMed search (1946 to February 2018) using the terms lesinurad and RDEA594 was conducted to identify relevant articles. STUDY SELECTION AND DATA EXTRACTION: In vitro or in vivo evaluations of lesinurad published in the English language were eligible for inclusion. Phase II and III trials were selected for review of efficacy and safety. DATA SYNTHESIS: Five clinical trials were evaluated. In 4 trials in which lesinurad was used in combination with a xanthine oxidase inhibitor (XOI), a greater percentage of patients receiving lesinurad 200 mg (54.0%-63.0%) compared with placebo (23.3%-46.8%) achieved a serum uric acid (sUA) level of <6 mg/dL at 1 to 6 months. In one trial involving lesinurad used as monotherapy, a sUA level of <6 mg/dL was achieved by a significantly greater percentage of patients receiving lesinurad 400 mg (29.9%) compared with placebo (1.9%) at 6 months. When used as combination therapy, the drug had an acceptable safety profile, with upper-respiratory-tract infection, nasopharyngitis, and hypertension occurring most commonly and transient renal-related events detected less frequently. CONCLUSIONS: Lesinurad has a novel mechanism of action and is safe and effective for the treatment of chronic gout. At this time, lesinurad may be considered as an add-on therapy for patients who have an inadequate response to maximum tolerated doses of a XOI. PMID- 29482354 TI - Drug-Induced Restless Legs Syndrome. AB - OBJECTIVE: To review the literature on drug-induced restless legs syndrome (DI RLS). DATA SOURCES: The review included a search for English-language literature from 1966 to December 2017 in the MEDLINE, PubMed, and Ovid databases using the following search terms: restless legs syndrome (RLS), periodic limb movement, adverse effects, and drug-induced. In addition, background articles on the pathophysiology, etiology, and epidemiology of RLS were retrieved. Bibliographies of relevant articles were reviewed for additional citations. STUDY SELECTION AND DATA EXTRACTION: All case reports, case series, and review articles of DI-RLS were identified and analyzed. There were only a small number of controlled clinical trials, and most data were from case reports and case series. RESULTS: Several drugs and drug classes have been implicated in DI-RLS, with antidepressants, antipsychotics, and antiepileptics having the most evidence. In addition, RLS may be linked with a number of disorders or underlying predisposing factors as well. CONCLUSIONS: The prevalence of RLS is variable and ranges from 3% to 19% in the general population. There are many predisposing factors to RLS, but an emerging body of evidence suggests that there is an association between numerous drugs and RLS. PMID- 29482355 TI - The role of palliative care in addressing the health needs of Syrian refugees in Jordan. AB - Refugees are often afflicted with health conditions that require long-term, specialized and continuous care services that are costly and difficult to secure in host countries and camp settings. This study interviewed 21 Syrian refugees in Jordan with life-limiting conditions such as cancer, diabetes, chronic disability and renal failure, and 4 caregivers caring for refugee children with similar conditions. This study found that patients in refugee camps and communities would benefit from receiving palliative care services that are often either unavailable or inaccessible. Training humanitarian teams and primary care providers to implement pain management, offer psychosocial support services and address emotional, spiritual, and psychological conditions could ameliorate many of the problems faced by this vulnerable group. PMID- 29482356 TI - Grape seed proanthocyanidins and metformin combination attenuate hepatic endoplasmic reticulum stress in rats subjected to nutrition excess. AB - CONTEXT: Endoplasmic reticulum (ER) stress in the liver is a pathological outcome of nutrient excess and is suggested to be one of the hits for progressive liver injury. OBJECTIVE: This study investigated whether grape seed proanthocyanidins (GSP) and metformin (MET) alone or in combination can relieve hepatic ER stress induced in rats subjected to calorie excess. MATERIAL AND METHODS: Male albino Wistar rats were given high calorie diet (HCD) for 45 days, while GSP (100 mg/kg body weight) and MET (50 mg/kg body weight) were administered either alone or in combination for last 15 days. RESULTS: GSP, MET or both had reduced the levels of ER stress markers and chaperons, and suppressed the activation of lipogenic and inflammatory mediators in rat liver. DISCUSSION: Though GSP and MET had reduced ER stress and inflammation individually, combination treatment with GSP + MET was more effective. CONCLUSION: We suggest intervention with GSP and MET intake has to be considered for the management of liver disorders. PMID- 29482357 TI - Workplace Mental Health Training in Health Care: Key Ingredients of Implementation. AB - OBJECTIVES: Despite growing awareness of the importance of workplace mental health training and an increasing number of educational resources, there is a gap in knowledge regarding what shapes training effectiveness. The purpose of this study was to compare and describe the active ingredients of 2 workplace mental health education programs for health care workers. METHODS: Within the context of a randomized clinical trial, a multimethod process evaluation was conducted to explore key process elements shaping implementation outcomes: the innovation, service recipients, service providers, and the organizational context. Data collection included descriptive statistics regarding program participation, postprogram interviews with a purposive sample of 18 service recipients, 182 responses to open-ended questions on postgroup and follow-up surveys, and field journal reflections on the process of implementation. Data analysis was informed by an interpretive description approach, using a process evaluation framework to categorize responses from all data sources, followed by within and cross-case comparison of data from both programs. RESULTS: Five key forces shaped the implementation and perceived outcomes of both programs: a contact-based education approach, information tailored to the workplace context, varied stakeholder perspectives, sufficient time to integrate and apply learning, and organizational support. The Beyond Silence program provided more opportunity for contact-based education, health care-specific content, and in-depth discussion of diverse perspectives. CONCLUSIONS: To increase mental health literacy and reduce stigma, workplace training should be based on best practice principles of contact-based education, with contextually relevant examples and support from all levels of the organization. PMID- 29482358 TI - Cannabis Legalization and Psychiatric Disorders: Caveat "Hemp-tor". PMID- 29482359 TI - In Pursuit of "queer-friendly" Healthcare: An Interview Study of How Queer Individuals Select Care Providers. AB - LGBQ+ individuals experience worse health outcomes than do other individuals. Some communication research finds that LGBQ+ individuals report receiving poor care during the mid- to post-health care, but this research assumes that LGBQ+ individuals have already received care. Little research has examined the pre- to early encounter experience of LGBQ+ individuals. This study presents exploratory research into how LGBQ+ individuals seek "queer-friendly" health care during pre- and early encounter experiences. Using an interview methodology, we report the facilitators and barriers to seeking queer-friendly care reported by LGBQ+ individuals. We offer implications for how health care providers and systems can better promote queer-friendly healthcare. PMID- 29482360 TI - Magnetic core mesoporous silica nanoparticles doped with dacarbazine and labelled with 99mTc for early and differential detection of metastatic melanoma by single photon emission computed tomography. AB - Cancer is responsible for more than 12% of all causes of death in the world, with an annual death rate of more than 7 million people. In this scenario melanoma is one of the most aggressive ones with serious limitation in early detection and therapy. In this direction we developed, characterized and tested in vivo a new drug delivery system based on magnetic core-mesoporous silica nanoparticle that has been doped with dacarbazine and labelled with technetium 99 m to be used as nano-imaging agent (nanoradiopharmaceutical) for early and differential diagnosis and melanoma by single photon emission computed tomography. The results demonstrated the ability of the magnetic core-mesoporous silica to be efficiently (>98%) doped with dacarbazine and also efficiently labelled with 99mTc (technetium 99 m) (>99%). The in vivo test, using inducted mice with melanoma, demonstrated the EPR effect of the magnetic core-mesoporous silica nanoparticles doped with dacarbazine and labelled with technetium 99 metastable when injected intratumorally and the possibility to be used as systemic injection too. In both cases, magnetic core-mesoporous silica nanoparticles doped with dacarbazine and labelled with technetium 99 metastable showed to be a reliable and efficient nano imaging agent for melanoma. PMID- 29482361 TI - Effect of reserpine on Pseudomonas aeruginosa quorum sensing mediated virulence factors and biofilm formation. AB - This study aimed to evaluate the effect of reserpine, a plant-derived indole alkaloid, against Pseudomonas aeruginosa PAO1 biofilms. The anti-biofilm activity of reserpine was evaluated by crystal violet staining, MTT assay, confocal laser scanning microscopy and scanning electron microscopy. Reserpine effects were also assessed by qRT-PCR of quorum sensing (QS)-regulated genes and biochemical quantification of the QS-mediated virulence factors pyocyanin, rhamnolipids, proteases and elastases. Reserpine reduced biofilm formation, cell motility, virulence factor production, and QS-controlled gene expression. Additionally, molecular docking analysis for AHL synthase LasI and QS transcriptional regulators LasR/MvfR revealed a plausible molecular mechanisms of reserpine QS inhibition. These findings provide insights into the underlying mode of action of reserpine, which may be useful in the development of new drugs against biofilm related infections. PMID- 29482362 TI - Quadrupole mass filter acceptance in stability island created by double-frequency quadrupole excitation. AB - Increase in quadrupole mass filter resolution at separation in narrow band stability island (X-band) formed by biharmonic resonance excitation of ion oscillation is discussed. X-band and the normal working quadrupole mass filter modes are compared at theoretical resolution of 10,000 and different separation times. Transmission curves, acceptance ellipses parameters, and acceptance characteristics are obtained by numerical simulation. Transmission coefficients are approximately the same in both modes. Dependence of acceptance ellipses parameters on ion inlet phases has a complicated oscillating form in the X-band mode. Acceptance contours calculated for given transition levels have been compared. At low acceptance level, the combined acceptance in the X-band mode was found to be one order of magnitude higher than in the normal mode. PMID- 29482363 TI - Method development for the determination of 1,1-dimethylhydrazine by the high performance liquid chromatography-mass spectrometry technique. AB - Unsymmetrical dimethyl hydrazine is highly toxic, carcinogenic compound, widely used for organic synthesis and drug development. Therefore, due to its high reactivity, direct analysis is problematic. Current study proposes to use derivatization reaction to increase selectivity and sensitivity of high performance liquid chromatography-mass spectrometry method. Different derivatization agents were tested and optimal reaction media was found. Derivatization was performed by using small amounts of reagents to lower the cost of analysis. The full validation of the method was performed and it can be used in a routine control in pharmaceutical analysis. Method sensitivity is 0.15 ppm, and linearity range is 0.15-2.70 ppm. PMID- 29482364 TI - Efficacy and safety of the trastuzumab biosimilar candidate CT-P6. AB - Trastuzumab is an anti-HER2 monoclonal antibody indicated for the treatment of HER2-overexpressing breast and gastric cancers. Despite its clinical efficacy, access to the biological drug can be limited due to its relatively high price, especially in low-income countries. CT-P6 (Herzuma(r)) is a biosimilar candidate of originator or 'reference' trastuzumab, which may offer an alternative, more cost-effective treatment option. This article reviews the unmet needs of patients eligible to receive reference trastuzumab and the potential place of a trastuzumab biosimilar within the market. The review also summarizes the available clinical evidence supporting the biosimilarity of CT-P6 and reference trastuzumab with respect to pharmacokinetics, efficacy, safety and immunogenicity. PMID- 29482365 TI - Sub-acute nickel exposure impairs behavior, alters neuronal microarchitecture, and induces oxidative stress in rats' brain. AB - Nickel (Ni) is a heavy metal with wide industrial uses. Environmental and occupational exposures to Ni are potential risk factors for neurological symptoms in humans. The present study investigated the behavior and histomorphological alterations in brain of rats sub-acutely exposed to nickel chloride (NiCl2) and the possible involvement of oxidative stress. Rats were administered with 5, 10 or 20 mg/kg NiCl2 via intraperitoneal injections for 21 days. Neurobehavioral assessment was performed using the Y-maze and open field test (OFT). Histomorphological analyses of brain tissues, as well as biochemical determination of oxidative stress levels were performed. Results showed that Ni treatments significantly reduced body weight and food intake. Cognitive and motor behaviors on the Y-maze and OFT, respectively, were compromised following Ni treatments. Administration of Ni affected neuronal morphology in the brain and significantly reduced percentage of intact neurons in both hippocampus and striatum. Additionally, markers of oxidative stress levels and nitric oxide (NO) levels were significantly altered following Ni treatments. These data suggest that compromised behavior and brain histomorphology following Ni exposures is associated with increase in oxidative stress. PMID- 29482366 TI - Sodium trimetaphosphate and hexametaphosphate impregnated with silver nanoparticles: characteristics and antimicrobial efficacy. AB - This study aimed to synthesize and characterize materials containing silver nanoparticles (AgNP) with polyphosphates (sodium trimetaphosphate (TMP) or sodium hexametaphosphate (HMP), and evaluate their effect against Candida albicans and Streptococcus mutans. The minimum inhibitory concentration (MIC) was determined, which was followed by the quantification of the biofilm by counting colony forming units (CFUs), the amount of metabolic activity, and the total biomass. The MICs revealed greater effectiveness of composites containing 10% Ag (TMP + Ag10% (T10) and HMP + Ag10% (H10)) against both microorganisms. It was observed that T10 and H10 reduced the formation of biofilms by 56-76% for C. albicans and by 52-94% for S. mutans for total biomass and metabolic activity. These composites promoted significant log reductions in the number of CFUs, between 0.45-1.43 log10 for C. albicans and 2.88-3.71 log10 for S. mutans (p < .001). These composites demonstrated significant antimicrobial activity, especially against S. mutans, and may be considered a potential alternative for new dental materials. PMID- 29482367 TI - The effect of troxerutin on anxiety- and depressive-like behaviours in the offspring of high-fat diet fed dams. AB - This study aimed at investigating the metabolic and behavioural effects of troxerutin treatment in the offspring of high fat diet (HFD) fed dams. Female Wistar rats (n = 40) received normal diet (ND) or HFD for 8 weeks prior to breeding. After mating, pregnant animals were assigned to four subgroups: ND, ND + Tro (troxerutin 150 mg/kg/day), HFD, and HFD + Tro. On the 21st day, male offspring were weaned and fed ND until 12 weeks old. Behavioural tests were performed on postnatal day (PND) 80 and 90. Compared to the controls, the HFD offspring showed more anxiety- and depressive-like behaviours, higher blood glucose, cholesterol, and cortisol levels. On the other hand, chronic troxerutin administration during gestation restored metabolic and behavioural changes to normal. In summary, troxerutin improved anxiety- and depressive-like behaviours, as well as metabolic status in the offspring of the HFD fed dams. More studies are needed to determine the underlying mechanisms. PMID- 29482368 TI - Comparison of Corneal Tomography: Repeatability, Precision, Misalignment, Mean Elevation, and Mean Pachymetry. AB - PURPOSE: To compare corneal tomography and its statistical uncertainty for measurements obtained by three clinically used corneal tomographers: A Scheimpflug camera (Pentacam HR), a swept source optical coherence tomography system (CASIA SS-1000), and Placido ring imaging (TMS-5). MATERIAL AND METHODS: Repeated measurements with all three devices on 34 normal eyes were used to estimate the repeatability, precision, and mean values of corneal elevation and pachymetry within 8 mm diameter. The repeatability (standard deviation) was calculated for each data point of the corneal elevation data-maps of anterior and posterior cornea as well as for the pachymetry data-maps. Uncertainty on the position of the eye at each measurement might contribute to the differences between elevation data-maps. To take this into account, we defined the precision as the standard deviation for the elevation data-maps of anterior and posterior cornea after correction of misalignment-effects (rotation, translation). The mean elevation and pachymetry data-maps were fitted with Zernike polynomials for interdevice-comparison. RESULTS: Pentacam HR offered the best repeatability and precision for the anterior corneal elevation (<3 and <1.6 MUm, respectively). CASIA SS-1000 offered good repeatability and precision with high resolution for posterior corneal elevation, and the best repeatability for pachymetry (<3 MUm). TMS-5 measured anterior elevation with similar repeatability to CASIA SS-1000 (<6 MUm). The data-maps of the three tomographers could not be used interchangeably. The largest differences were observed for pachymetry and posterior corneal elevation data-maps. CONCLUSIONS: Misalignment limited the repeatability of TMS-5 and Pentacam HR, but had little influence on the repeatability of CASIA SS-1000. PMID- 29482369 TI - Mitigating effects of antioxidant properties of Artemisia herba alba aqueous extract on hyperlipidemia and oxidative damage in alloxan-induced diabetic rats. AB - Chronic hyperglycemia and excess reactive oxygen species overproduced in diabetes were associated with oxidative stress, led to continuous injury and functions damage to different organs: eyes, kidneys, neural and cardiovascular system. The present study was undertaken to evaluate the protective effect of Artemisia herba alba (AHA) leaf powder against alloxane-induced oxidative damage in diabetic rats. Rats were randomly divided into four groups: Group I controls received saline solution 9%; Group II was treated with 150 mg alloxane/(kg body weight) administered by intraperitoneal. Rats of Group III have received saline solution and treated with 400 mg AHA/(kg body weight). Animals of Group IV were treated with alloxane and AHA. Alloxane exposure led to increased blood glucose, total cholesterol, triglycerides, malondialdehyde, and a decrease in the antioxidants enzymes activities (catalase, glutathione peroxidase and glutathione-S transferase). Administration of AHA aqueous extract ameliorated these parameters. These results demonstrate that AHA ameliorates hyperglycemia, hyperlipidemia and oxidative damage in alloxan-induced diabetes in rats. PMID- 29482370 TI - Coffee mitigates cyclophosphamide-induced genotoxic damage in Drosophila melanogaster germ cells. AB - In the present study, coffee (CF) was evaluated for its protective effects against genotoxic damage and oxidative stress induced by the chemotherapeutic drug, cyclophosphamide (CPH). The sex-linked recessive lethal (SLRL) test was employed to study the induction of mutations in the larvae as well as in all the successive germ cell stages of treated males. Control and treated third instar larvae were used to monitor the biomarkers of oxidative stress response such as glutathione content (GSH), glutathione-S-transferase (GST), catalase (CAT), superoxide dismutase (SOD) and lipid peroxidation (MDA content). Our results demonstrated that co-administration of CF (2%) with CPH (3 mM) has significantly reduced CPH-induced lethal mutations in the germ cells of larvae and adult flies. The reductions observed in mutation frequencies were: 75% in larvae and 62.4% in the adult. Significant enhancement in antioxidant enzymatic levels: CAT (46.6%) > SOD (43.0%) > GST (42.4%) > GSH (31.6%) and reduction in MDA levels (32.05%) in the pretreated third instar larvae demonstrated the antioxidant activity of CF against CPH-induced oxidative stress. The findings from the present study suggest that the Drosophila model is an ideal one for evaluating the antigenotoxic and antioxidant activity of complex mixtures like CF. PMID- 29482371 TI - Social functioning following pediatric stroke: contribution of neurobehavioral impairment. AB - Pediatric stroke can result in long-term neurobehavioral impairments including cognitive, language, and motor deficits, all of which may disrupt the normal development of social skills. This study aimed to examine specific components of social function at 5-year poststroke at a group and individual level and explore the contribution of neurobehavioral impairment. Thirty-one children with arterial ischemic stroke participated in the study. Assessment included parent-rated questionnaires measuring social adjustment and social participation as well as behavior and fatigue. Children underwent testing of social cognition and neurobehavioral abilities (intellectual function, attention, pragmatic language, motor function, and neurological impairment). Group means for social function were generally within the normal range, with social adjustment poorer than normative expectations. Examination of impairment rates showed a significant proportion of children had impaired function across social domains. Childhood stroke was associated with poorer social adjustment and a range of neurobehavioral outcomes, compared to neonatal stroke. Social function was found to be impacted by fatigue and intellectual function, but not by attention, pragmatic language, behavior, motor function, or neurological impairment. PMID- 29482372 TI - Effects of a Personal Narrative in Messages Designed to Promote Healthy Fish Consumption Among Women of Childbearing Age. AB - Women of childbearing age (WCBA) can attain health benefits of fish consumption while minimizing risks by following state and federal fish consumption guidelines, but many women avoid fish out of concerns about mercury exposure. This study tested the impact of brochures, informed by communication theory and research, to promote healthy fish consumption among licensed female anglers. We conducted a randomized, two-wave longitudinal experiment between May 2014 and September 2015 among 1,135 women ages 18-48 years (at baseline), drawn from a sample of licensed anglers in the Great Lakes region of the United States. We randomly assigned women to one of five groups, to either be sent one of four brochures in spring 2015 using a two (including a short personal narrative or not) by two (using certain or uncertain language) factorial design, or to a no exposure control arm. Participants reported their fish consumption in summer 2014 and summer 2015 via an online diary. Exposure to brochure versions that included a short personal narrative helped move women whose baseline levels of fish consumption were furthest from federal recommendations closer to these guidelines; effects were clearest among women confirmed, by self-report or web tracking, to have seen the brochure. Narratives hold promise as a strategy to communicate effectively about the benefits of healthy fish consumption and risks of overconsumption among WCBA, but widespread dissemination may be necessary to achieve these effects. PMID- 29482373 TI - Thymoquinone and fluoxetine alleviate depression via attenuating oxidative damage and inflammatory markers in type-2 diabetic rats. AB - The study was designed to find out the effect of thymoquinone (TQ) alone and combination of TQ + fluoxetine in depression of type-2 diabetic rats. Glucose level was significantly decreased in TQ alone treated group, whereas no significant change was recorded when TQ was combined with fluoxetine. Administration of TQ alone and combination of TQ and fluoxetine significantly decreased immobility time, increased latency to immobility and increased locomotor activity. Treatment with TQ alone significantly decreased level of TBARS, increased GSH and restored the activities of antioxidant enzymes (GPx, GR & CAT). However, TQ and fluoxetine combination reduced TBARS level, increased GSH content but no change in the antioxidant enzymes activities. Inflammatory markers (IL-1beta, IL-6 & TNF-alpha) levels were significantly reduced after the administration of TQ alone and TQ + fluoxetine. The study suggests that combination of TQ and fluoxetine can be used to control depression in type-2 diabetes mellitus. PMID- 29482375 TI - Antithrombotic Therapy Underutilization in Patients With Atrial Flutter. AB - BACKGROUND: Patients with atrial fibrillation not being adequately treated with oral anticoagulant (OAC) therapy, with therapy underutilization or premature termination, have been commonly reported. However, studies on the utilization pattern of OAC therapy for patients with atrial flutter (AFL) are few. The aim of this study was to investigate the utilization of OAC therapy, and its influencing factors for patients with AFL in South Korea, as well as the types and percentages of anticoagulants used. METHODS: We analyzed Aged Population Sample data compiled by the Health Insurance Review & Assessment Service from 2011 to 2015. We identified patients with AFL having the KCD-6 code I48.1. Patients at high risk of stroke with a congestive heart failure, hypertension, age >=75 years, diabetes mellitus, stroke (or transient ischemic attack), vascular disease, sex score of >=2 and at low risk of bleeding with an anticoagulation and risk factors in atrial fibrillation score of <=4 were included in the study. Oral anticoagulant therapy underutilization was estimated in these patients using anticoagulant underutilization (ACU) scales. Demographic and clinical factors associated with OAC therapy underutilization were investigated using a logistic regression model. RESULTS: The mean ACU value was calculated as 67.4% between 2011 and 2015. Positive risk factors for ACU were identified as follows: female sex, aspirin utilization, and limited anticoagulant options. Negative risk factors included comorbidities, such as congestive heart failure and valvular heart disease, and a history of stroke or transient ischemic attack. CONCLUSIONS: Our study demonstrates that two-third of patients with AFL in South Korea failed to obtain adequate stroke prevention treatment, even in the era of direct OAC availability. This tendency was more profound in women or those on aspirin therapy. PMID- 29482374 TI - A Conversation between Theory, Methods, and Data. AB - The 10 year anniversary of the COGITO Study provides an opportunity to revisit the ideas behind the Cattell data box. Three dimensions of the persons * variables * time data box are discussed in the context of three categories of researchers each wanting to answer their own categorically different question. The example of the well-known speed-accuracy tradeoff is used to illustrate why these are three different categories of statistical question. The 200 persons by 100 variables by 100 occasions of measurement COGITO data cube presents a challenge to integrate theories and methods across the dimensions of the data box. A conceptual model is presented for the speed-accuracy tradeoff example that could account for cross-sectional between persons effects, short-term dynamics, and long-term learning effects. Thus, two fundamental differences between the time axis and the other two axes of the data box include ordering and time scaling. In addition, nonstationarity in human systems is a pervasive problem along the time dimension of the data box. To illustrate, the difference in nonstationarity between dancing and conversation is discussed in the context of the interaction between theory, methods, and data. An information theoretic argument is presented that the theory-methods-data interaction is better understood when viewed as a conversation than as a dance. Entropy changes in the development of a theory-methods-data conversation provide one metric for evaluating scientific progress. PMID- 29482376 TI - Score on Coma Recovery Scale-Revised at admission predicts outcome at discharge in intensive rehabilitation after severe brain injury. AB - OBJECTIVE: To assess the prognostic utility of the Coma Recovery Scale-Revised (CRS-R) in rehabilitation of patients surviving from severe brain injury. METHODS: In this prospective cohort study, all patients consecutively admitted to an Italian Intensive Rehabilitation Unit, with a diagnosis of unresponsive wakefulness syndrome (UWS) or minimally conscious state (MCS) due to acquired brain injury, underwent clinical evaluations using the Italian version of the CRS R. At discharge, patients transitioning from UWS to MCS or emergence from MCS (E MCS) and from MCS to E-MCS were classified as improved responsiveness (IR). Score on the Glasgow Outcome Scale (GOS) at discharge was recorded. RESULTS: In total, 137 (66 UWS, 71 MCS) subjects were enrolled. After a mean hospital stay of 5.3 +/ 2.9 months, 81 (59.1%) patients achieved an IR. In the multivariable analysis, IR was associated with higher CRS-R score at admission (p = 0.002) and younger age at injury (p = 0.010). Moreover, higher GOS scores at discharge were related to younger age at injury (p = 0.018), shorter time post-onset (p = 0.003) and higher CRS-R score at admission (p < 0.001). CONCLUSIONS: Higher CRS-R scores at admission in intensive rehabilitation unit can help differentiate patients with better outcome at discharge, providing information for rehabilitation planning and communication with patients and their caregivers. PMID- 29482377 TI - Green tea supplementation upregulates uncoupling protein 3 expression in severe obese women adipose tissue but does not promote weight loss. AB - This study aims (i) to verify expression of the UCPs, PLIN1, PPARG2, and ADRB3 genes in the abdominal subcutaneous adipose tissue of obese women at baseline and after 8 weeks of supplementation with decaffeinated green tea extract, and (ii) to associate findings with clinical parameters. This is a longitudinal study during which 11 women with obesity grade III were submitted to supplementation with 450 mg of (-)-epigallocatechin gallate (EGCG) (intervention group); the control group consisted of 10 eutrophic women. Anthropometric parameters [weight, height, and body mass index (BMI)], resting metabolic rate (RMR, measured by indirect calorimetry), and gene expression (measured by real-time PCR, RT-qPCR) were determined before and after supplementation. After 8 weeks, clinical parameters and UCP1, PLIN1, PPARG2, and ADRB3 expression remained unaltered in the intervention group (p > .05). Genetic analysis also showed that the UCP3 gene was upregulated (p = .026), but its upregulation did not promote weight loss. PMID- 29482378 TI - Is Treatment Readiness Associated With Substance Use Treatment Engagement? An Exploratory Study. AB - With nearly 8.2% of Americans experiencing substance use disorders (SUDs), a need exists for effective SUD treatment and for strategies to assist treatment participants to complete treatment programs (Chandler, Fletcher, & Volkow, 2009). The purpose of the current research is to contribute to an emerging knowledge base about treatment readiness and its utility for predicting substance use treatment process performance measures. The study examines the relative salience of treatment readiness as a predictor of treatment engagement. Data are derived from adult cases included in the 2012 Global Appraisal of Individual Needs-Intake data set ( n = 5,443). Binary logistic regression was used to identify if treatment readiness predicts substance use treatment engagement. The findings of this study do not provide support for treatment readiness significantly predicting substance use treatment engagement. Further research is needed to better understand treatment engagement. PMID- 29482379 TI - Natural History of Conservatively Managed Ureteral Stones: Analysis of 6600 Patients. AB - INTRODUCTION: Ureteral colic has a lifetime prevalence of 10%-15% and is one of the most common emergency urologic presentations. Current European Association of Urology recommends conservative management for "small" (<6 mm) ureteral stones if active removal is not indicated. It is important to understand the natural history of ureteral stone disease to help counsel patients with regard to their likelihood of stone passage and anticipated time frame with which they could be safely observed. We aimed to conduct a systematic review to better establish the natural history of stone expulsion. METHODOLOGY: Literature search was performed using Cochrane and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines. Outcome measures were patient and stone demographics, expulsion rates, expulsion times, and side effect of the medication. A cumulative analysis, with subgroup analysis, was performed on stone location and size. The results were depicted as percentages and an intention-to-treat basis was used. RESULTS: The literature search identified 70 studies and a total of 6642 patients, with a median age of 46 and range of 18-74 years. Overall, 64% of patients successfully passed their stones spontaneously. About 49% of upper ureteral stones, 58% of midureteral stones, and 68% of distal ureteral stones passed spontaneously. Almost 75% of stones <5 mm and 62% of stones >=5 mm passed spontaneously. The average time to stone expulsion was about 17 days (range 6-29 days). Nearly 5% of participants required rehospitalization due to a deterioration of their condition and only about 1% of patients experienced side effects from analgesia provided. CONCLUSION: We believe this current review is the largest study for the evaluation of natural history of ureteral stones. The evidence suggests that ureteral stones will pass without intervention in 64% of patients, however, this varies from nearly 50%-75% depending on the size and location, in the span of 1-4 weeks. PMID- 29482380 TI - Corrigendum. PMID- 29482381 TI - Bone marrow plasma cell infiltration in light chain amyloidosis: impact on organ involvement and outcome. AB - OBJECTIVES: Prognosis of immunoglobulin light-chain (AL) amyloidosis depends mainly on the presence of cardiac involvement and the disease burden. A higher bone marrow plasma cell (BMPC) burden has been recognized as an adverse prognostic factor. The aim of our study was to analyze the correlation between the BMPC infiltration, clinical features and outcomes in patients with AL amyloidosis. METHODS: The clinical records of 79 patients with AL amyloidosis treated at a single institution. RESULTS: Median BMPC infiltration at diagnosis was 11% and significantly correlated with the serum free light-chain difference (p < .001). Patients with more than 10% BMPCs had more frequent cardiac involvement (86 vs. 63%; p = .015), a trend towards a higher early mortality (27 vs. 11%; p = .08) and a significantly shorter progression-free survival (PFS) (median of 18 vs. 48 months, p = .02) and overall survival (median of 33 months vs. not reached; p = .046). In the multivariate analysis, a BMPC infiltration over 10% retained its adverse prognostic value for PFS (HR = 2.26; 95% CI, 1.048 4.866; p = .038). The use of new drugs seemed to overcome the negative prognostic impact of a higher BMPC infiltration. CONCLUSION: Higher BMPC infiltration in AL amyloidosis might be associated with increased systemic organ damage, particularly cardiac involvement and is rarely related to the development of myeloma features. PMID- 29482382 TI - Guselkumab for the treatment of psoriasis. AB - INTRODUCTION: Psoriasis is a chronic immune mediated disease in which the interplay of T cells and keratinocytes seems to play a key role. In this context, the interleukin (IL)-23/IL-17 axis is currently considered to be crucial in the pathogenesis of psoriasis and the selective inhibition of IL-23 may be viewed as an improvement of treatments blocking both IL-23 and IL-12, since its upstream actions. Areas covered: The authors performed a thorough and updated review on guselkumab, a fully human IgG1lambda monoclonal antibody that blocks the p19 subunit of IL-23, analyzing efficacy and safety data from phase I, II and III trials. Expert opinion: Guselkumab represents a very promising therapy, providing an alternative mechanism of action with high efficacy and safety profiles, sustained total skin clearance, and rapid onset of effect also to psoriasis patients who previously failed or experienced an inadequate response to anti-TNF alpha or anti-IL12/23. Guselkumab will definitively shift therapeutic goals of psoriasis management from PASI 75 to PASI 90 and 100 due to its exciting trials results, also favored by its increased treatment adherence due to its administering regimen (100 mg injection at week 0, 4 and then every 8 weeks). PMID- 29482383 TI - Cytotoxicity and genotoxicity of clothianidin in human lymphocytes with or without metabolic activation system. AB - Clothianidin (CHN) is a broad-spectrum neonicotinoid insecticide. Limited studies have been carried out on the cytotoxic and genotoxic effects of both CHN using different genotoxicity tests in human cells with or without human metabolic activation system (S9 mix). Therefore, the aim of this study is to investigate the cytotoxic and genotoxic effects of CHN and its metabolites on human lymphocyte cultures with or without S9 mix using chromosomal aberration (CA) and micronucleus (MN) tests. The cultures were treated with 25, 50, and 100 ug/ml of CHN in the presence (3 h treatment) and absence (48 h treatment) of S9 mix. Dimethyl sulfoxide (DMSO) was used as a solvent control. CHN showed cytotoxic and genotoxic effects due to significant decreases in mitotic index (MI) and nuclear division index (NDI), and significant increases in the CAs, aberrant cells, and MN formation in the absence of S9 mix when compared with solvent control. However, CHN did not significantly induce cytotoxicity and genotoxicity in the presence of S9 mix. Our results indicated that CHN has cytotoxic, cytostatic, and genotoxic potential on human peripheral blood lymphocyte cultures, but not its metabolites under the experimental conditions. PMID- 29482384 TI - Avelumab: a new standard for treating metastatic Merkel cell carcinoma. AB - INTRODUCTION: Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. Although MCC is chemosensitive, responses to traditional chemotherapeutic agents are not durable. Avelumab, a novel anti-PD-L1 immune checkpoint inhibitor, recently became the first FDA-approved agent for the treatment of metastatic MCC and represents a new option to improve patient survival. Areas covered: This article presents an overview of MCC and summarizes the development of avelumab in the treatment of metastatic MCC. Preclinical studies, phase 1 and phase 2 clinical trials, and the safety profile of avelumab are reviewed. Future perspectives and ongoing studies are also discussed. Expert commentary: Avelumab demonstrated rapid and durable responses and a manageable safety profile in the treatment of metastatic MCC. Patient outcomes are favorable when compared to historical responses to standard chemotherapy. Ongoing clinical trials will continue to characterize avelumab and its optimal use in MCC therapy. PMID- 29482385 TI - Roles of Guilt Cognitions in Trauma-Related Sleep Disturbance in Military Veterans With Posttraumatic Stress Disorder. AB - OBJECTIVE/BACKGROUND: Despite a well-established role of guilt cognitions in the maintenance and treatment of posttraumatic stress disorder (PTSD), relationships of guilt cognitions to nightmares are not well understood. This study investigated the ways in which guilt cognitions, related to traumatic events, influenced the relationship between combat exposure and trauma-related sleep disturbance in military Veterans with PTSD. PARTICIPANTS: We recruited a sample of 50 Veterans with PTSD who completed study measures at a screening session. METHODS: Participants completed self-report measures of exposure to potentially traumatic events, trauma-related guilt (hindsight bias, wrongdoing, and lack of justification) and trauma-related sleep disturbance as measured by a self-report scale and clinician ratings of nightmare severity. RESULTS: Bivariate regression analyses established a relationship of combat exposure to wrongdoing (beta = .31, p = .031), and a relationship of wrongdoing with self-reported trauma-related sleep disturbance (beta = .27, p = .049) and clinician-rated nightmare severity (beta = .36, p = .009). Bootstrapping analysis that included years of education as a covariate found a significant overall indirect effect of combat exposure on clinician-rated nightmare severity exerted through wrongdoing (beta = .10, 95% CI [.004, .246]). CONCLUSIONS: Results suggest the association of combat exposure with trauma-related sleep disturbance is significantly influenced by perceived wrongdoing related to a traumatic event. Targeting cognitions related to wrongdoing and moral injury during a traumatic event in PTSD treatment may help ameliorate trauma-related sleep disturbance. PMID- 29482387 TI - The effects of maternal asthma during pregnancy on child cognitive and behavioral development: A systematic review. AB - OBJECTIVE: Maternal asthma during pregnancy is associated with a higher risk of negative perinatal outcomes. However, little is known about the direct effects of maternal asthma on infant cognitive development. We examined the evidence for an impact of maternal asthma during pregnancy on cognitive and behavioral development of the child. DATA SOURCES: We conducted a MEDLINE, PsychINFO, and manual search of the databases for all available studies until January 9th, 2018. STUDY SELECTIONS: Studies were deemed relevant if they included child cognitive and behavioral development as the outcome, with maternal asthma as the determinant of interest. RESULTS: Ten articles matched selection criteria. Some studies report that maternal asthma is associated with increased risk for autism and intellectual disability in children. However, these effects are small and are often eliminated when controlling for confounding variables. Other studies have found no association. The only prospective study found that well-managed asthma during pregnancy was not associated with negative developmental outcomes in children. CONCLUSIONS: The evidence suggests that the relationship between maternal asthma during pregnancy and poor developmental and behavioral outcomes of children is weak. Children of mothers with well-managed asthma during pregnancy have similar developmental trajectories to those born to healthy mothers. Prospective, longitudinal studies are needed to confirm these conclusions. Optimal asthma management is important in pregnancy as it may have longer term benefits for the health of the offspring. As the rate of asthma increases in the population, the implications of maternal asthma on child development will be of greater importance. PMID- 29482386 TI - Antitumor efficacy of liposome-encapsulated NVP-BEZ 235 in combination with irreversible electroporation. AB - Irreversible electroporation (IRE) is an emerging minimally invasive tumor ablation technique that delivers short pulses of strong electric fields and kills cancer cells by disrupting their cell membranes with the electric pulses. However, clinical studies report that more than 10% of local tumor recurrences occur at the original ablated site. NVP BEZ-235 (BEZ) is a dual PI3K/mTOR inhibitor that has substantial anticancer effects. However, the clinical trials of BEZ was not satisfactory because of its low bioavailability and high toxicity, which stemmed from the use of oral administration of high doses over a long period of time. In this research, we prepared a liposomal formulation of BEZ (L BEZ) for intratumoral injection and studied its antitumor efficacy alone and in combination with IRE. We hypothesized that IRE could release BEZ from the liposomes and that the combination could decrease tumor viability. Our results show that IRE released BEZ from its liposomal encapsulation. The combination of L BEZ and IRE killed more Hep3B tumor cells in vitro than did L-BEZ or IRE alone and also inhibited cancer cell proliferation in nude mice bearing Hep3B xenografts. Combination of chemotherapeutic agent loaded nanoparticles could enhance the antitumor efficacy of IRE. PMID- 29482388 TI - Correction of nasolabial folds wrinkle using intraoral non-ablative Er:YAG laser. AB - BACKGROUND: The accentuated nasolabial folds (NLFs) is the most pronounced sign of aging. Non-ablative erbium:yttrium aluminum garnet laser (ER:YAG), Smooth mode was used for the treatment of mucosal tissue. It was reported that it is effective in facial rejuvenation. AIM: To assess the safety and the effectiveness of intraoral ER:YAG Smooth mode laser in the treatment of NLFs wrinkle. MATERIALS AND METHODS: A total of 20 patients with different grades of NLFs wrinkle treated with 2940 nm Er:YAG laser intraorally. Six sessions were done every 2 weeks. The efficacy was assessed by two blinded dermatologists. Photographs were taken at the baseline, end of treatment and 6 months after the final session to document visible changes in NLFs wrinkle. The assessment was based on Modified Fitzpatrick Wrinkle Scale (MFWS) and by comparing the photographs. Patient's self-assessment and patient's satisfaction were used for assessment of final results and any side effects associated to treatment were observed. RESULTS: There was significant reduction of the NLFs wrinkle. The MFWS was significantly improved 6 months after treatment compared to before treatment (p < 0.001). At the end of the follow-up period, there was improvement in overall appearance of the wrinkles. Patient's self -assessment and satisfaction demonstrated better cosmetic outcomes. CONCLUSION: Intraoral Er:YAG laser is safe, painless, and effective treatment option for NLFs wrinkle. PMID- 29482390 TI - Controlling pertussis: how can we do it? A focus on immunization. AB - INTRODUCTION: Pertussis is a highly contagious disease of the respiratory tract which is caused by the bacterium Bordetella pertussis and is most severe in those <1 year of age. A vaccine against pertussis, introduced in the 1950's, led to a significant decrease in incidence of the disease, but recent increases in outbreaks have been attributed to insufficient vaccine uptake, suboptimal protection conferred by vaccines, and waning immunity after immunization. Areas covered: In this review we discuss the major challenges for controlling pertussis, and what we believe the best strategies are to overcome these challenges, focusing on immunization against pertussis in Europe, but with recommendations that are relevant worldwide. Expert commentary: To provide maximum vaccine coverage we propose a schedule that incorporates immunization of infants, preschoolers, adolescents, adults, and pregnant women. Uptake of vaccines may also vary between populations due to a variety of causes, including hesitancy to vaccinate, so any national strategy to control pertussis should also include sustaining public and healthcare provider confidence in vaccination. Addressing and improving regional variations in surveillance will also help better monitor annual incidence and outbreaks. Looking towards the future, the development of new pertussis vaccines with longer duration of protection would be advantageous. PMID- 29482389 TI - Anticancer evaluation and molecular modeling of multi-targeted kinase inhibitors based pyrido[2,3-d]pyrimidine scaffold. AB - An efficient synthesis of substituted pyrido[2,3-d]pyrimidines was carried out and evaluated for in vitro anticancer activity against five cancer cell lines, namely hepatic cancer (HepG-2), prostate cancer (PC-3), colon cancer (HCT-116), breast cancer (MCF-7), and lung cancer (A-549) cell lines. Regarding HepG-2, PC 3, HCT-116 cancer cell lines, 7-(4-chlorophenyl)-2-(3-methyl-5-oxo-2,3-dihydro-1H pyrazol-1-yl)-5-(p-tolyl)- pyrido[2,3-d]pyrimidin-4(3H)-one (5a) exhibited strong, more potent anticancer (IC50: 0.3, 6.6 and 7 uM) relative to the standard doxorubicin (IC50: 0.6, 6.8 and 12.8 uM), respectively. Kinase inhibitory assessment of 5a showed promising inhibitory activity against three kinases namely PDGFR beta, EGFR, and CDK4/cyclin D1 at two concentrations 50 and 100 uM in single measurements. Further, a molecular docking study for compound 5a was performed to verify the binding mode towards the EGFR and CDK4/cyclin D1 kinases. PMID- 29482391 TI - Systemic inhibition of BMP1-3 decreases progression of CCl4-induced liver fibrosis in rats. AB - Liver fibrosis is a progressive pathological process resulting in an accumulation of excess extracellular matrix proteins. We discovered that bone morphogenetic protein 1-3 (BMP1-3), an isoform of the metalloproteinase Bmp1 gene, circulates in the plasma of healthy volunteers and its neutralization decreases the progression of chronic kidney disease in 5/6 nephrectomized rats. Here, we investigated the potential role of BMP1-3 in a chronic liver disease. Rats with carbon tetrachloride (CCl4)-induced liver fibrosis were treated with monoclonal anti-BMP1-3 antibodies. Treatment with anti-BMP1-3 antibodies dose-dependently lowered the amount of collagen type I, downregulated the expression of Tgfb1, Itgb6, Col1a1, and Acta2 and upregulated the expression of Ctgf, Itgb1, and Dcn. Mehanistically, BMP1-3 inhibition decreased the plasma levels of transforming growth factor beta 1(TGFbeta1) by prevention of its activation and lowered the prodecorin production further suppressing the TGFbeta1 profibrotic effect. Our results suggest that BMP1-3 inhibitors have significant potential for decreasing the progression of fibrosis in liver cirrhosis. PMID- 29482393 TI - Transanal Minimally Invasive Surgery: A Promising Alternative for Certain Advanced Rectal Cancer Patients. PMID- 29482392 TI - Laser immunotherapy for cutaneous squamous cell carcinoma with optimal thermal effects to enhance tumour immunogenicity. AB - BACKGROUND: Laser immunotherapy is a new anti-cancer therapy combining photothermal therapy and immunostimulation. It can eliminate the tumours by damaging tumour cells directly and promoting the release of damage-associated molecular patterns (DAMPs) to enhance tumour immunogenicity. The aim of this study was to investigate the thermal effects of laser immunotherapy and to evaluate the effectiveness and safety of laser immunotherapy for cutaneous squamous cell carcinoma (cSCC). METHODS: The cell viability and the DAMPs productions of heat-treated cSCC A431 cells in different temperatures were investigated. Laser immunotherapy with the optimal thermal effect for DAMPs production was performed on SKH-1 mice bearing ultraviolet-induced cSCC and a patient suffering from a large refractory cSCC. RESULTS: The temperature in the range of 45-50 degrees C killing half of A431 cells had an optimal thermal effect for the productions of DAMPs. The thermal effect could be further enhanced by local application of imiquimod, an immunoadjuvant. Laser immunotherapy eliminated most tumours and improved the survival rate of the ultraviolet-induced cSCC-bearing SKH-1 mice (p < 0.05). The patient with cSCC treated by laser immunotherapy experienced a significant tumour reduction after laser immunotherapy increased the amounts of infiltrating lymphocytes in the tumour. No obviously adverse effect was observed in the mice experiment or in the clinical application. CONCLUSIONS: Our results strongly indicate that laser immunotherapy with optimal thermal effects is an effective and safe treatment modality for cSCC. PMID- 29482395 TI - A manual physical therapy intervention for symptoms of knee osteoarthritis and associated fall risk: A case series of four patients. AB - BACKGROUND AND PURPOSE: Patients with knee osteoarthritis (OA) are at an increased risk of falling. Further, the symptoms associated with knee OA are correlated with fall risk. A manual physical therapy (MPT) approach consisting of mobilizing techniques and reinforcing exercise improves the symptoms and functional limitations associated with knee OA. The purpose of this case series is to evaluate an MPT intervention of mobilization techniques and exercise for knee OA on improving symptoms and quantify the secondary benefit of improving stumble recovery. CASE DESCRIPTION: Four patients with symptomatic knee OA and four matched controls completed a fall risk assessment. Following 4 weeks of intervention, patients were reevaluated. OUTCOMES: Initial Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores indicated notable symptoms and functional limitations in all patients. In addition, all patients displayed elevated fall risk and/or impaired stumble responses. Following 4 weeks of intervention, all patients reported meaningful reductions in all three WOMAC subscales and demonstrated improvements in at least two of the three fall risk measures. DISCUSSION: We identified potential connections between symptom relief in patients with knee OA, stumble response, and ultimately fall risk. The results suggest that MPT intervention designed to improve the signs and symptoms of knee OA may lead to a secondary benefit of improved gait stability and stumble response. PMID- 29482396 TI - Effects of lactational exposure to low-dose BaP on allergic and non-allergic immune responses in mice offspring. AB - Benzo[a]pyrene (BaP) can induce developmental and reproductive toxicity; however, the full scope of its immunotoxic effects remains unknown. This study aimed to assess effects of lactational exposure to low-dose BaP (comparable to human exposure) on potential allergic?non-allergic immune responses in murine offspring. Lactating C3H/HeJ dams were orally dosed with BaP at 0, 0.25, 5.0, or 100 pmol/animal/week) at post-natal days [PND] 1, 8, and 15. Five-weeks-old pups then received intratracheally ovalbumin (OVA) every 2 weeks for 6 weeks. Following the final exposure, mice were processed to permit analyses of bronchoalveolar lavage (BAL) fluid cell profiles as well as levels of lung inflammatory cytokines and chemokines, serum OVA-specific immunoglobulin, and mediastinal lymph node (MLN) cell activation/proliferation. In OVA-sensitized male offspring, lactational low-dose BaP exposure led to enhanced (albeit not significantly) macrophage, neutrophil, and eosinophil infiltration to, and increased T-helper (TH)-2 cytokine production in, the lungs. In females, BaP exposure, regardless of dose, led to slightly enhanced lung levels of macrophages and eosinophils, and of inflammatory molecules. Protein levels of interleukin (IL)-33 in the OVA + BaP (middle dose) group, and interferon (IFN)-gamma in the OVA + BaP (low dose) group, were higher than that of the OVA (no BaP) group. Ex vivo studies showed lactational exposure to BaP partially induced activation of T cells and antigen-presenting cells (APCs) in the MLN cells of both male and female offspring, with or without OVA sensitization. Further, IL-4 and IFNgamma levels in MLN culture supernatants were elevated even without OVA-re-stimulation in OVA + BaP groups. In conclusion, lactational exposure to low-dose BaP appeared to exert slight effects on later allergic and non-allergic immune responses in offspring by facilitating development of modest TH2 responses and activating MLN cells. In addition, lactational exposures to BaP might give rise to gender differences in allergic/non-allergic immune responses of offspring. PMID- 29482394 TI - Synthesis and biological evaluation of N-arylpiperazine derivatives of 4,4 dimethylisoquinoline-1,3(2H,4H)-dione as potential antiplatelet agents. AB - Despite the substantial clinical success of aspirin and clopidogrel in secondary prevention of ischemic stroke, up to 40% of patients remain resistant to the available antiplatelet treatment. Therefore, there is an urgent clinical need to develop novel antiplatelet agents with a novel mechanism of action. Recent studies revealed that potent alpha 2B-adrenergic receptor (alpha 2B-ARs) antagonists could constitute alternative antiplatelet therapy. We have synthesized a series of N-arylpiperazine derivatives of 4,4-dimethylisoquinoline 1,3(2H,4H)-dione as potential alpha 2B receptor antagonists. The most potent compound 3, effectively inhibited the platelet-aggregation induced both by collagen and ADP/adrenaline with IC50 of 26.9 MUM and 20.5 MUM respectively. Our study confirmed that the alpha 2B-AR antagonists remain an interesting target for the development of novel antiplatelet agents with an alternative mechanism of action. PMID- 29482397 TI - A prospective, randomized, double-blinded, split-face pilot study comparing Q switched 1064-nm Nd:YAG versus 532-nm Nd:YAG laser for the treatment of solar lentigines. AB - Treating photoaging with laser technologies has increased in popularity due to their efficacy, minimal downtime, and side effects. New Q-Switched (QS) Nd:YAG lasers' frequency doubled with 532 nm wavelength can both target epidermal chromophores as well as stimulate collagen production. The objective of this study was to compare single-pulsed 1064-nm Nd:YAG with dual-pulsed 532-nm/1064-nm QS laser for reducing solar lentigines. Ten subjects with solar lentigines were enrolled in this prospective, randomized, double-blind, split-face study. Subjects received six laser treatments (half-face dual, half single) at 2-week intervals. Blinded investigator and subject assessments were conducted 1 month posttreatment to evaluate global skin improvement, safety, and patient satisfaction. Blinded investigator assessments showed statistically significant improvement in the dual-treated side. Patient satisfaction was also statistically significantly increased in the dual-treated side. In conclusion, dual laser treatment can result in superior and safe global improvement of photoaging. PMID- 29482398 TI - The role of anxiety sensitivity-physical concerns in terms of quit day withdrawal symptoms and cravings: A pilot test among smokers with asthma. AB - OBJECTIVE: The aim of the current study was to conduct secondary analyses of data collected from a study examining a self-guided quit attempt of smokers with and without asthma in order to examine the unique predictive ability of precessation (i.e., baseline) anxiety sensitivity physical concerns in terms of quit day withdrawal symptoms and cravings among abstinent smokers with asthma. METHODS: Participants were 24 regular cigarette smokers with asthma (50% female, Mage = 37.63 years, SD = 12.20) who participated in a self-guided-quit attempt and were able to maintain abstinence on their quit day. RESULTS: After controlling for the effects of the cognitive and social concerns domains of anxiety sensitivity, anxiety sensitivity-physical concerns significantly predicted greater quit day withdrawal symptoms (20.8% unique variance) and urges to smoke (38.0% unique variance). CONCLUSIONS: These findings suggest that smokers with asthma who fear anxiety-related sensations due to their feared physical consequences are more likely to experience intense withdrawal symptoms and desire to smoke at the beginning of a quit attempt. Clinically, smokers with higher levels of anxiety sensitivity physical concerns may benefit from smoking cessation interventions that specifically target anxiety sensitivity as well as prolonged use of nicotine replacement therapies to target withdrawal symptoms and cravings. PMID- 29482399 TI - Interpreting intracorporeal landscapes: how patients visualize pathophysiology and utilize medical images in their understanding of chronic musculoskeletal illness. AB - Medical science and other sources, such as the media, increasingly inform the general public's understanding of disease. There is often discordance between this understanding and the diagnostic interpretations of health care practitioners (HCPs). In this paper - based on a supra-analysis of qualitative interview data from two studies of joint pain, including osteoarthritis - we investigate how people imagine and make sense of the pathophysiology of their illness, and how these understandings may affect self-management behavior. We then explore how HCPs' use of medical images and models can inform patients' understanding. In conceptualizing their illness to make sense of their experience of the disease, individuals often used visualizations of their inner body; these images may arise from their own lay understanding, or may be based on images provided by HCPs. When HCPs used anatomical models or medical images judiciously, patients' orientation to their illness changed. Including patients in a more collaborative diagnostic event that uses medical images and visual models to support explanations about their condition may help them to achieve a more meaningful understanding of their illness and to manage their condition more effectively. Implications for Rehabilitation Chronic musculoskeletal pain is a leading cause of pain and years lived with disability, and despite its being common, patients and healthcare professionals often have a different understanding of the underlying disease. An individual's understanding of his or her pathophysiology plays an important role in making sense of painful joint conditions and in decision-making about self-management and care. Including patients in a more collaborative diagnostic event using medical images and anatomical models to support explanations about their symptoms may help them to better understand their condition and manage it more effectively. Using visually informed explanations and anatomical models may also help to reassure patients about the safety and effectiveness of core treatments such as physical exercise and thereby help restore or improve patients' activity levels and return to social participation. PMID- 29482401 TI - Alopecia with foreign body granulomas induced by Radiesse injection: A case report. AB - Radiesse is a soft tissue filler which has been widely used for cosmetic enhancement. The safety of Radiesse has been thoroughly investigated via numerous studies. A late-onset complication of Radiesse injection consists of foreign body granulomas, with only three case reports in over 10 years of clinical use. Herein, we describe the case of a patient who experienced alopecia with foreign body granulomas at the injection region one month after receiving a Radiesse injection. To our knowledge, this is the first report in the English literature of alopecia as an adverse event associated with Radiesse injection. The present case reminded physicians to evaluate more cautiously the necessity of injecting filler into hair-bearing area for lifting purpose. This procedure may cause foreign body granulomatous reaction, which may result in hair loss at the injection region. PMID- 29482400 TI - Optimization of rhein-loaded polymeric nanoparticles using a factorial design and evaluation of the cytotoxic and anti-inflammatory effects. AB - The aim of the work was to develop rhein loaded polymeric nanoparticles (R-PNPs). Nanoparticles were prepared by three methods, solvent emulsion-evaporation, double emulsion, and nanoprecipitation, by means of experimental design. Additionally, the effects of the best formulation on in vitro cytotoxicity and inflammation were evaluated. The solvent emulsion-evaporation method presented the highest encapsulation efficiency of the three techniques (38.41%), as well as had a mean diameter of 189.33 nm and a polydispersity index of less than 0.1. Despite efforts to optimize the encapsulation of rhein, the drug release from nanoparticles was close to 50% during the first 5 min, followed by a continuous release within 60 min. It was observed that macrophages exposed to the highest concentration of R-PNPs showed cell viability about 80% and at the lowest nanoparticle concentrations was closed to 100%. IL-1beta in cell culture supernatants was decreased in the presence of R-PNPs and TNFalpha concentrations were lower than the sensitivity of the assay. ROS production was only inhibited with R-PNPs at concentrations of 2.5 and 5 MUM. In conclusion, the solvent emulsion-evaporation was the best method evaluated to obtain nanoparticles with the desired specifications. It was possible to assess R-PNPs with low cytotoxicity and anti-inflammatory properties showed by the inhibition of IL 1beta production and a low decrease in ROS production. PMID- 29482402 TI - Etanercept for the treatment of rheumatoid arthritis. AB - Etanercept was the first specific anticytokine therapy approved for the treatment of rheumatoid arthritis (RA). Its clinical efficacy and safety has been demonstrated by several clinical trials in early as well as established disease. Etanercept, along with other TNF inhibitors, have revolutionized management of RA and dramatically improved disease activity, function, quality of life and mortality for these patients. It is structurally distinct from other TNF inhibitors and thus has desirable profiles for immunogenicity, drug survival and infection rate. With the increasing number of etanercept biosimilars, there will likely be a resurgence of their prescription. This article reviews the pharmacology, efficacy and safety of the etanercept reference product, and its biosimilars, in the context of RA treatment. PMID- 29482403 TI - Consensus on core phenomena and statements describing Basic Body Awareness Therapy within the movement awareness domain in physiotherapy. AB - Physiotherapists are facing complex health challenges in the treatment of persons suffering from long-lasting musculoskeletal disorders and mental health problems. Basic Body Awareness Therapy (BBAT) is a physiotherapy approach within the movement awareness domain developed to bridge physical, mental, and relational health challenges. The purpose of this study was to reach a consensus on core phenomena and statements describing BBAT. A consensus-building process was conducted using the nominal group technique (NGT). Twenty-one BBAT experts from 10 European countries participated in a concentrated weekend workshop of 20 hours. All participants signed informed consent. Participants reached a consensus on 138 core phenomena, clustered in three overarching categories: clinical core, historical roots, and research and evaluation phenomena. Of the 106 clinical core phenomena, the participants agreed on three categories of phenomena: movement quality, movement awareness practice, and movement awareness therapy and pedagogy. Furthermore, the participants reached 100 percent consensus on 16 of 30 statements describing BBAT. This study provides a consensus on core phenomena and statements describing BBAT. The data reveal phenomena implemented when promoting movement quality through movement awareness. Data provide clarity in some aspects of the vocabulary as fundamental theory. Further reearch will be developed. PMID- 29482404 TI - Chemotherapy-Associated Endometrial Atypia: A Potential Diagnostic Pitfall. AB - Cytotoxic chemotherapy, typically as a component of a multimodal approach, is a standard of patient care for numerous malignancies. Chemotherapy-associated cytologic alterations in otherwise normal tissues have been reported at several anatomic sites. We describe in this article distinctive cytologic alterations of the endometrium, including severe severe cytologic atypia, that was attributed to chemotherapy. PMID- 29482405 TI - Ultrasound measurement of abdominal muscles during clinical isometric endurance tests in women with and without low back pain. AB - PURPOSE: The present study investigated group differences between the thickness changes of the transverse abdominis (TrA), internal oblique (IO), and external oblique (EO) muscles, during performance of the isometric supine chest raise and the supine double leg-straight leg raise tests in women with and without low back pain (LBP). METHOD: Twenty women with LBP and 20 women without LBP participated in this case-control study. The thickness of the right TrA, IO, and EO muscles was measured using B-mode ultrasound (US) at rest, immediately at the beginning of performing the tests and when participants in both groups self-reported fatigue. The percentage of change in thickness of the abdominal muscles from rest to the initiation and fatigue stages of both tests was measured. RESULTS: The results indicate a statistically significant difference in the pattern of changes in deep (TrA) and superficial (EO) abdominal muscles thickness at the fatigue stage of the supine double straight-leg raise (SDSLR) test between groups (P < 0.05). There was no significant difference between groups for the abdominal muscles thicknesses change at rest or during stages of the clinical isometric endurance tests (P > 0.05). CONCLUSIONS: An altered activation pattern in the deep (TrA) and superficial (EO) muscles of LBP participants during fatigue stage of the SDSLR test as compared to controls indicates motor control dysfunction in the LBP group. Comparison of the activity of TrA and EO muscles during fatigue stage of SDSLR test can be used to assess alterations in motor control of abdominal muscles. PMID- 29482406 TI - The use of Mechanical Diagnosis and Therapy (MDT) in patients with lower urinary tract symptoms (LUTS): case series. AB - Lower urinary tract symptoms (LUTS) are highly prevalent among men over the age of 40. Even though associations between lumbar spine conditions and LUTS have been documented in the literature, no studies have detailed a specific lumbar assessment and classification process, and the related treatment effects in patients with LUTS. In this case series, we present three male patients with LUTS as primary complaints, who were evaluated and treated with Mechanical Diagnosis and Therapy (MDT) for the lumbar spine. The duration of their symptoms was between 4 months and 7 years. Urogenital pathologies were ruled out for all patients. The Chronic Prostatitis Symptom Index was used as a functional outcome measure. All patients were classified as having lumbar derangements. Treatment of derangements with directional preference exercises resulted in the improvement of their LUTS, with clinically significant improvements (56.0%-77.4%) in functional outcome measures over an average of six sessions. Preliminary indications suggest that these LUTS cases may possibly have had a lumbar spine origin and "mechanical" nature. Therefore, they may be within the scope of MDT assessments and interventions. With careful monitoring of symptoms, MDT may serve as a screening tool and conservative treatment option. PMID- 29482407 TI - Reliability and responsiveness of a goniometric device for measuring the range of motion in the dart-throwing motion plane. AB - BACKGROUND: Dart-throwing motion (DTM) is an important component of wrist function and, consequently, has the potential to become an evaluation tool in rehabilitation. However, no measurement method is currently available to reliably measure range of motion (ROM) of the wrist in the DTM plane. OBJECTIVES: To determine the reliability and responsiveness of a goniometric device to measure wrist ROM in the DTM plane. METHODS: ROM of the wrist in the DTM plane was measured in 70 healthy participants. The intra-class correlation coefficient (ICC) was used to evaluate the relative reliability of measurement, and a Bland Altman analysis conducted to establish its absolute reliability, including the 95% limits of agreement (95% LOA). The standard error of the measurement (SEM) and minimal detectable change at the 95% confidence level (MDC95) were calculated as measures of responsiveness. RESULTS: The intra-rater ICC was 0.87, and an inter-rater ICC of 0.71. There was no evidence of a fixed or proportional bias. For intra- and inter-rater reliability, 95% LOA ranged from -13.83 to 11.12 and from -17.75 to 16.19, respectively. The SEM and MDC95 were 4.5 degrees and 12.4 degrees , respectively, for intra-rater reliability, and 6.0 degrees and 16.6 degrees , respectively, for inter-rater reliability. CONCLUSION: The ROM of the wrist in the DTM plane was measured with fair-to-good reliability and responsiveness and, therefore, has the potential to become an evaluation tool for rehabilitation. PMID- 29482408 TI - To Explore the Validity of Change Scores of the Children's Hand-use Experience Questionnaire (CHEQ) in Children with Unilateral Cerebral Palsy. AB - AIMS: To explore the validity of change scores of the Children's Hand-use Experience Questionnaire (CHEQ). METHODS: Analysis of the CHEQ included 44 children (15 girls) between 6-16 years (median 9.0; IQR 8-11) with unilateral cerebral palsy, with baseline and post- (two-week intensive) intervention assessments using the Goal Attainment Scale (GAS) as external anchor for change. Hypotheses on the magnitude of expected change were formulated and correlation coefficients and effect sizes calculated. Receiver operating curve analysis was performed and the area under the curve (AUC) calculated to investigate the ability of CHEQ to discriminate between improvement and non-improvement according to GAS. RESULTS: All hypotheses about the magnitude of change were confirmed supporting longitudinal validity of CHEQ scales to measure change in the perception of bimanual performance. AUCs for the Grasp efficacy and the Time utilization were slightly below, and for the Feeling bothered slightly above the threshold. The latter one accurately discriminating between children that improved and did not improve according to the GAS. CONCLUSIONS: Evidence was found that CHEQ scales capture change in bimanual performance but with limited accuracy for two out of three scales. The validity of CHEQ change scores needs to be further explored in a wider population. PMID- 29482409 TI - Reliability of two-point discrimination test in carpal tunnel syndrome patients. AB - OBJECTIVES: To evaluate the reliability (intra and inter) of two-point discrimination (2PD) test in carpal tunnel syndrome (CTS) patients. PARTICIPANTS: Eighty-six adults with unilateral right hand CTS. METHODS: Two examiners performed measurements of 2PD sensation (using Dellon discriminator) on the first three fingers on both hands. The first examiner performed three series of measurements at 1-minute intervals. After 7 days, measurements were repeated by the same examiner (intra-rater). For inter-rater reliability, the examination (by second examiner) was also repeated after 7 days. RESULTS: For the first measurement, inter-rater reliability (ICC2,1) at the affected site ranged from 0.96 to 0.97; values at the non-affected site ranged from 0.79 to 0.89. Analysis of the averages of two measurements (ICC2,2) yielded values at the affected site of 0.98; values at the non-affected site ranged from 0.92 to 0.94. The average of two measurements reduces the smallest detectable difference (SDD) value < 1 mm in all cases. Intra-rater reliability was at least good for all tested fingers for the first measurement, but to record SDD < 1 mm it is necessary to use an average of the first two measurements. CONCLUSIONS: The execution of two repeated measurements provides adequate reliability in measurements of 2PD test in CTS patients. For clinical trials, we recommend using at least the average of two measurements of 2PD, which reduce SDD (below 1 mm). This may be particularly important in assessing the effectiveness of therapy. PMID- 29482410 TI - The Impact of Applying Quality Management Practices on Patient Centeredness in Jordanian Public Hospitals: Results of Predictive Modeling. AB - Targeting the patient's needs and preferences has become an important contributor for improving care delivery, enhancing patient satisfaction, and achieving better clinical outcomes. This study aimed to examine the impact of applying quality management practices on patient centeredness within the context of health care accreditation and to explore the differences in the views of various health care workers regarding the attributes affecting patient-centered care. Our study followed a cross-sectional survey design wherein 4 Jordanian public hospitals were investigated several months after accreditation was obtained. Total 829 clinical/nonclinical hospital staff members consented for study participation. This sample was divided into 3 main occupational categories to represent the administrators, nurses, as well as doctors and other health professionals. Using a structural equation modeling, our results indicated that the predictors of patient-centered care for both administrators and those providing clinical care were participation in the accreditation process, leadership commitment to quality improvement, and measurement of quality improvement outcomes. In particular, perceiving the importance of the hospital's engagement in the accreditation process was shown to be relevant to the administrators (gamma = 0.96), nurses (gamma = 0.80), as well as to doctors and other health professionals (gamma = 0.71). However, the administrator staff (gamma = 0.31) was less likely to perceive the influence of measuring the quality improvement outcomes on the delivery of patient-centered care than nurses (gamma = 0.59) as well as doctors and other health care providers (gamma = 0.55). From the nurses' perspectives only, patient centeredness was found to be driven by building an institutional framework that supports quality assurance in hospital settings (gamma = 0.36). In conclusion, accreditation is a leading factor for delivering patient-centered care and should be on a hospital's agenda as a strategy for continuous quality improvement. PMID- 29482411 TI - A Triangulated Qualitative Study of Veteran Decision-Making to Seek Care During Heart Failure Exacerbation: Implications of Dual Health System Use. AB - Among Veterans, heart failure (HF) contributes to frequent emergency department visits and hospitalization. Dual health care system use (dual use) occurs when Veterans Health Administration (VA) enrollees also receive care from non-VA sources. Mounting evidence suggests that dual use decreases efficiency and patient safety. This qualitative study used constructivist grounded theory and content analysis to examine decision making among 25 Veterans with HF, for similarities and differences between all-VA users and dual users. In general, all VA users praised specific VA providers, called services helpful, and expressed positive capacity for managing HF. In addition, several Veterans who described inadvertent one-time non-VA health care utilization in emergent situations more closely mirrored all-VA users. By contrast, committed dual users more often reported unmet needs, nonresponse to VA requests, and faster services in non-VA facilities. However, a primary trigger for dual use was VA telephone referral for escalating symptoms, instead of care coordination or primary/specialty care problem-solving. PMID- 29482412 TI - Whole body vibration improves maximum voluntary isometric contraction of knee extensors in patients with chronic kidney disease: A randomized controlled trial. AB - BACKGROUND: Whole body vibration (WBV) training improves maximum voluntary isometric contraction (MVIC) of knee extensors, postural balance, functional capacity, and quality of life (QOL) in several diseases. The objective was to assess the efficacy of WBV training in patients with chronic kidney disease (CKD) on hemodialysis (HD) in the interdialytic period. METHOD: A randomized, controlled trial study with concealed allocation, intention-to-treat analysis, and triple blinding. Sixteen patients with CKD of both genders aged over 40 years were allocated in two groups, the WBV group or the sham group, training 2 times a week for 12 weeks. The primary outcome was knee extensor muscle strength, and the secondary outcomes were quadriceps thickness, distance walked, balance, and QOL. RESULTS: The WBV group improved MVIC of knee extensors with a difference between groups in improvement of 117.29 N (95% CI, 32.25-202.24) at the end of training. The other outcomes were not different between groups. Practical applications: The WBV program has shown to be effective and may be able to help in prescribing the appropriate training program for CKD. CONCLUSION: WBV training improves MVIC of knee extensors in patients with CKD on HD in the interdialytic period. WBV training could be considered in the management of patients with CKD. PMID- 29482413 TI - Antigravity treadmill training during the early rehabilitation phase following unicompartmental knee arthroplasty: A case series. AB - Patients who have undergone unicompartmental knee arthroplasty (UKA) have been reported to exhibit altered gait 19-25 months post-surgery. The most common gait impairment in this population is inadequate knee flexion and a corresponding decrease in the knee extensor moment during loading response (i.e., quadriceps avoidance). The purpose of this case series was to determine whether incorporation of antigravity treadmill training into a standard physical therapy program can eliminate quadriceps avoidance gait during the early rehabilitation phase following UKA. Four females who underwent UKA were recruited for this study. Participants completed antigravity treadmill training three times per week for 12 weeks in addition to their standard physical therapy program. Instrumented gait analysis was performed at baseline (pre-intervention), week 6 (mid intervention), and week 12 (post-intervention). We found that peak knee flexion and the peak knee extensor moment during the weight acceptance phase of gait increased to normal values following the 12-week intervention period (14.1 +/- 6.5 degrees to 20.6 +/- 1.5 degrees and 0.4 +/- 0.3 to 0.7 +/- 0.2 Nm/kg respectively). The findings of this case series suggest that a standard physical therapy program that incorporates early gait training using an antigravity treadmill may be beneficial in eliminating "quadriceps avoidance" during the early rehabilitation phase following UKA. PMID- 29482414 TI - Effect of individualized physical rehabilitation programs on respiratory function in women with post-mastectomy syndrome. AB - PURPOSE: The purpose of this study was to determine the effectiveness of an individualized physical rehabilitation programs aimed at improving respiratory function in women with post-mastectomy syndrome. METHODS: In a randomized controlled trial 50 women with post-mastectomy syndrome were enrolled in the experimental group (EG, n = 25) or the comparison group (CG, n = 25). The program for the EG included: aqua aerobics (i.e. aqua jogging, aqua building, and aqua stretching); conditional swimming; and recreational aerobics. The program for the CG included: conditional swimming and Pilates exercises. Both intervention groups attended individualized physical rehabilitation programs three times per week for 48 weeks. The primary outcome measure was spirometry of the patients measured before, 6 and 12 months after the intervention. RESULTS: This study demonstrated that most of the respiratory function parameters increased significantly in both groups over the year of exercise training. After the year of training the individualized physical rehabilitation program for the EG was significantly better (p < 0.01) as compared with the CG, except for inspiratory reserve volume and maximal voluntary ventilation, which were not statistically different. CONCLUSIONS: The results of the study suggest that individual programs of physical rehabilitation could be considered effective for the improvement of respiratory function of the patients with post-mastectomy syndrome. The results obtained could serve as a basis for more widespread clinical program development. PMID- 29482415 TI - Ethnic variation in deep lateral orbital anatomy and its implications on decompression surgery. AB - AIM: To describe differences in the deep lateral orbital wall (specifically, trigone) between Chinese, Malay, Indian and Caucasian subjects Methods: Single centre retrospective Computed Tomogram (CT)-based study; 20 subjects of each ethnicity were used from existing databases, matched for gender, average age and laterality. Subjects below 16 years of age were excluded. DICOM image viewing software CARESTREAM Vue PACS (Carestream Health Inc., USA) and OsiriX version 7.5 (Pixmeo., Switzerland) were used to measure deep lateral wall length, thickness and volume, as well as orbital depth and statistical analyses performed using Statistical Package for Social Sciences version 21 (IBM, USA). RESULTS: In each group, there were 12 males (60%) and average age was not significantly different (p = 0.682-0.987). Using Chinese subjects as a reference, in Chinese, Malay, Indian and Caucasian subjects, mean trigone thickness was 13.68, 14.02, 11.60 (p < 0.001) and 13.80 mm, curved total wall length 45.23, 42.29 (p = 0.048), 41.91 (p = 0.020) and 45.00 mm, curved trigone length 23.03, 22.61, 17.19 (p = 0.011) and 18.76 mm (p = 0.030) and trigone volume 3120.97, 3221.01, 1613.66 (p < 0.001), 2498.46 mm3 (p = 0.059) respectively. Similarly, perpendicular orbital depth was 27.54, 24.97, 22.12 (p = 0.001) and 25.93 mm and diagonal orbital depth was 34.19, 33.27, 29.48 (p = 0.01) and 34.63 mm respectively. CONCLUSIONS: Indian and, to a lesser extent, Caucasian subjects have smaller trigones compared to their Chinese and Malay counterparts. Indian subjects also have shallower orbits and due care should be taken during decompression surgery. PMID- 29482417 TI - Microbial co-infection alters macrophage polarization, phagosomal escape, and microbial killing. AB - Macrophages are important innate immune cells that respond to microbial insults. In response to multi-bacterial infection, the macrophage activation state may change upon exposure to nascent mediators, which results in different bacterial killing mechanism(s). In this study, we utilized two respiratory bacterial pathogens, Mycobacterium bovis (Bacillus Calmette Guerin, BCG) and Francisella tularensis live vaccine strain (LVS) with different phagocyte evasion mechanisms, as model microbes to assess the influence of initial bacterial infection on the macrophage response to secondary infection. Non-activated (M0) macrophages or activated M2-polarized cells (J774 cells transfected with the mouse IL-4 gene) were first infected with BCG for 24-48 h, subsequently challenged with LVS, and the results of inhibition of LVS replication in the macrophages was assessed. BCG infection in M0 macrophages activated TLR2-MyD88 and Mincle-CARD9 signaling pathways, stimulating nitric oxide (NO) production and enhanced killing of LVS. BCG infection had little effect on LVS escape from phagosomes into the cytosol in M0 macrophages. In contrast, M2-polarized macrophages exhibited enhanced endosomal acidification, as well as inhibiting LVS replication. Pre-infection with BCG did not induce NO production and thus did not further reduce LVS replication. This study provides a model for studies of the complexity of macrophage activation in response to multi-bacterial infection. PMID- 29482418 TI - Physical therapy for nocturnal lower limb cramping: A case report. AB - BACKGROUND AND PURPOSE: Nocturnal lower limb cramps are sudden, intensely painful, and can decrease sleep, increase anxiety, and reduce quality of life. The purpose of this case report is to describe the effectiveness of an evidence based physical therapy intervention for a person with lower limb cramps. CASE DESCRIPTION: The patient was a 34-year-old female who presented with idiopathic bilateral lower limb foot pain and cramps. INTERVENTION: Rehabilitation addressed muscle strength, joint mobility, soft tissue extensibility, and biomechanical influences during functional movement, for a total of seven sessions over seven weeks. OUTCOMES: The frequency and severity of cramps decreased from three to four times/night, lasting several minutes down to one episode/week, lasting less than a minute. Her Numeric Pain Rating Scale (NPRS) score at worst decreased from 6/10 at the initial examination to 0/10 upon discharge. Lower extremity strength and functional mobility outcomes also exhibited improvement over the course of care. The patient's Lower Extremity Functional Scale (LEFS) score decreased from 87.5% to 80.0%, indicating greater disability, though this did not reach minimal detectable change levels. DISCUSSION: While her cramping and resulting pain improved, perceived participation restrictions persisted. Lack of improvement in the participation measure may have been related to the lack of a structured biopsychosocial approach to the rehabilitation process. PMID- 29482416 TI - Evaluation of analytical similarity between trastuzumab biosimilar CT-P6 and reference product using statistical analyses. AB - The evaluation of analytical similarity has been a challenging issue for the biosimilar industry because the number of lots for reference and biosimilar products available at the time of development are limited, whilst measurable quality attributes of target molecule are numerous, which can lead to potential bias or false negative/positive conclusions regarding biosimilarity. Therefore, appropriate statistical analyses are highly desirable to achieve a high level of confidence in the similarity evaluation. A recent guideline for the risk-based statistical approaches recommended by the US Food and Drug Administration provides useful tools to systematically evaluate analytical similarity of biosimilar products compared with reference products. Here, we evaluated analytical similarity of CT-P6, a biosimilar product of trastuzumab, with the reference products (EU-Herceptin(r) or US-Herceptin(r)) following these statistical approaches. Various quality attributes of trastuzumab were first ranked based on the clinical impact of each attribute and subsequently adjusted to one of three tiers (Tier 1, Tier 2 and Tier 3) considering the characteristics of the assay, the level of attribute present and the feasibility of statistical analysis. Two biological activities with highest potential clinical impact were evaluated by an equivalent test (Tier 1), and other bioactivities and structural/physicochemical properties relevant to the clinical impact were evaluated by a quality range approach (Tier 2). The attributes with low risk ranking or qualitative assay were evaluated by visual comparison (Tier 3). Analytical similarity assessment analyzed by the three tiers clearly demonstrated that CT-P6 exhibits highly similar structural and physicochemical properties, as well as functional activities, compared with the reference products. There were small differences observed in a few quality attributes between CT-P6 and the reference products, but the differences were very minor, and unlikely to impact on clinical outcome. The recently reported equivalent clinical efficacy of CT-P6 with the reference product further supports that CT-P6 is highly similar compared with the reference product in the view of totality-of-evidence. PMID- 29482419 TI - Thermal and mechanical pain sensitization in patients with osteoarthritis of the knee. AB - OBJECTIVE: The aim was to assess sensitization using quantitative sensory testing in mechanical and thermal modes in individuals with and without osteoarthritis (OA) of the knee. Pain thresholds were correlated with functionality, symptoms of depression and intensity of pain. METHODS: Thirty control volunteers and 30 patients with OA of the knee were assessed. Punctate pain thresholds using Von Frey filaments and thermal pain thresholds using a Thermal Sensory Analyzer were evaluated in the periarticular region of the knee and forearm. Using a digital pressure algometer, pressure pain thresholds were assessed in the periarticular region of the knee and on the root exit zone on the lumbar and sacral spine. RESULTS: Punctate, pressure, and thermal pain thresholds differed significantly between participants with and without OA (p < 0.05). Values in those with OA were consistent with pain sensitization. Pressure pain thresholds also showed moderate and negative correlations with data on functionality, symptoms of depression and intensity of pain (-0.36 < r > -0.56), contributing up to 30% of their variability. CONCLUSIONS: Allodynia and hyperalgesia were demonstrated in the OA group, suggesting central sensitization in patients with mild to moderate severity of joint damage. Correlation between mechanical hypersensitivity and psychosocial factors seems to be small, despite of its significance. PMID- 29482420 TI - Acute transient large-angle exotropia caused by traumatic orbital contusion. AB - We report an unusual case of acute large-angle left exotropia associated with blunt orbital trauma in a healthy 8-year-old boy. Examination revealed a large angle left exotropia with limitation in adduction of the left eye. Microhyphema and commotio retinae of the left eye were also present. High-resolution orbital magnetic resonance imaging (MRI) demonstrated perimuscular and intramuscular edema mostly involving the left medial rectus muscle but also involving the left lateral rectus muscle. The extraocular muscle insertions were intact. Complete resolution of the strabismus and adduction limitation occurred within 24 hours of starting systemic steroid therapy. This case highlights the utility of high resolution imaging to assess for injury to the extraocular muscles. If disinsertion, transection, or rupture of the muscle is not present on imaging, resolution may occur with systemic steroid therapy and surgical intervention is not needed. PMID- 29482421 TI - Multifocal Cytokeratin Expression in a Dedifferentiated Solitary Fibrous Tumor With Heterologous Rhabdomyosarcomatous Differentiation: A Challenging Diagnosis! AB - We report the case of a dedifferentiated solitary fibrous tumor with heterologous rhabdomyosarcomatous differentiation in a 74-year-old male presenting with a rapidly growing, large soft tissue tumoral mass in the gluteal muscles of the right hip. Dedifferentiation in solitary fibrous tumor had not been recognized until very recently and is an extremely rare phenomenon in this tumor type. In the present case, the diagnosis of dedifferentiated solitary fibrous tumor was difficult because of the absence of areas of conventional solitary fibrous tumor with a predominantly poorly differentiated, anaplastic tumor component in the incision biopsy composed of heterogeneous areas with small blue round cell (Ewing sarcoma-like), rhabdoid, epithelioid, and pleomorphic morphology. Moreover, the "unforeseen" strong patchy to multifocal positivity for cytokeratin AE1/AE3 and desmin made the diagnosis of a dedifferentiated solitary fibrous tumor even more challenging in this case. The morphology (presence of branching thin-walled, hemangiopericytoma-like blood vessels) and the immunohistochemical profile (including STAT6 and GRIA2 positivity) were very useful to differentiate this very challenging case of a cytokeratin-positive dedifferentiated solitary fibrous tumor with heterologous rhabdomyosarcomatous differentiation from a broad list of differential diagnoses. PMID- 29482423 TI - Genetic diversity and population structure of penis fish (Urechis unicinctus) based on mitochondrial and nuclear gene markers. AB - Urechis unicinctus is distributed only in Bohai Gulf of China and Korean and Japanese coast. The wild populations of this species have sharply declined in China and Japan. We collected 105 samples from six localities of Bohai Gulf and Korea coast, and investigated genetic diversity and population structure with mitochondrial COI, 16S-rRNA and nuclear 28S-rRNA gene fragments. Genetic diversity of U. unicinctus based on COI sequences was still high (Hd: 0.9595, pi: 0.0101), however, 28S-rRNA gene sequences showed low level of genetic diversity (Hd: 0.4084, pi: 0.0007). Based on COI sequences, FST values between populations ranged from -0.00204 to 0.05210, and 99.12% genetic diversity was contributed by different individuals within population. Both phylogenetic trees and median joining network did not show clear geographic cluster, haplotypes from different populations were mixed. Our results indicated low level of genetic divergence among different localities of U. unicinctus, and this species should be treated as a whole population among China, Japan and Korea coast during species conservation. PMID- 29482422 TI - Five-year immunity persistence following immunization with inactivated enterovirus 71 type (EV71) vaccine in healthy children: A further observation. AB - The longevity of antibodies induced by inactivated enterovirus 71 type (EV71) vaccine is not well studied. To estimate the immunity persistence following two dose vaccination of EV71 vaccine, a five-year follow-up study was conducted as an extension of a Phase III clinical trial. In this study, a sub-cohort of volunteers who was eligible for enrollment and randomly administrated either 2 dose EV71 vaccine or placebo in the phase III clinical trial was selected, and then further observed 64 months post the 1st vaccination. 211 Subjects (106 vaccine subjects and 105 placebo subjects) who provided a full series of blood samples (at all the sampling points) were included in the final analyzed population. Seropositive rate (SR) and geometric mean titer (GMT) of the neutralizing antibodies (NAb) was calculated to detect the dynamic profiles of EV71 vaccine-induced immunogenicity. SR at the 5th year remained 94.34% in the vaccine subjects, with a GMT of 141.42. The SR was 71.43% in the placebo subjects, with a GMT of 71.83. Despite natural infection consistently promoted the NAb increase in the placebo subjects, the SR and GMT in vaccine subjects remained significantly higher than that in the placebo subjects at all the sampling points. The inactivated EV71 vaccine-induced immunity had a good persistence, within 5 years following the primary vaccination. PMID- 29482424 TI - Histologic and ultrastructural features in early and advanced phases of Zellweger spectrum disorder (infantile Refsum disease). AB - Zellweger spectrum disorders (ZSD) are rare autosomal recessive inherited metabolic disorders and include severe (Zellweger syndrome) and milder phenotypes [neonatal adrenoleukodystrophy and infantile Refsum disease (IRD)]. ZSD are characterized by impaired peroxisomal functions and lack of peroxisomes detected by electron microscopy (EM). ZSD are caused by mutations in any of the 14 PEX genes. Patients with ZSD commonly demonstrate nonspecific hepatic symptoms within the first year, often without clinical suspicion of ZSD. Thus, recognition of pathologic findings in the liver is critical for the early diagnosis. We herein demonstrate the histologic and ultrastructural features in liver biopsies in the early and advanced phases from a 16-year-old male with IRD. The initial biopsy at 5 months of age showed a lack of peroxisomes by EM, and this finding played a critical role in the early diagnosis. In contrast, the second biopsy at 14 years of age, after long-term diet therapy, demonstrated significant disease progression with near-cirrhotic liver. In addition to lack of peroxisomes, EM revealed abundant trilamellar inclusions within large angulated lysosomes in many of the hepatocytes and Kupffer cells. Mitochondrial abnormalities were identified only in the second biopsy and were mainly identified in damaged cells; thus they were likely nonspecific secondary changes. This is the first report demonstrating histological and ultrastructural features of liver biopsies in the early and advanced phases from a child with ZSD. Trilamellar inclusions are considered to be an ultrastructural hallmark of ZSD, but they may not be apparent in the early phases. PMID- 29482425 TI - Do Schools That Screen for Body Mass Index Have Recommended Safeguards in Place? AB - The Centers for Disease Control and Prevention recommends that schools adopt 10 safeguards before launching a body mass index (BMI) screening program; however, little is known about schools' safeguard adoption. Authors identified questions from the 2014 School Health Policies and Practices Study that aligned with 4 of the 10 safeguards to estimate safeguard prevalence among schools that screened students for BMI (40.7%, N = 223). Among these schools, 3.1% had all four safeguards and 56.5% had none or one. The most prevalent safeguard was having reliable and accurate equipment (54.1%, 95% confidence interval [CI] = [46.1, 62.1]). Providing staff with appropriate expertise and training was the least prevalent; respondents in 26.4% (95% CI [17.1, 35.6]) of schools received recent training on weight status assessment, weight management, and eating disorder identification. School-based BMI screening is common, but adopting multiple recommended safeguards is not. Absent these safeguards, BMI screening programs may fall short of intended outcomes and potentially incur unintended consequences. PMID- 29482426 TI - Bullying Victimization Type and Feeling Unsafe in Middle School. AB - Given their significance to school violence, this study quantifies the association between bullying victimization and perceptions of safety separately for victimization where the type is not specified versus victimization that is physical in nature. Generalized liner mixed modeling was employed with 5,138 sixth- to eighth-grade students in 24 schools who self-reported on their bullying victimization and perceptions of school safety on an anonymous survey in fall 2015. Results indicate a multiplicative interaction exists with regard to the odds of feeling unsafe at school among those who were bullied at all (odds ratio [ OR] = 3.1) compared to those who were bullied physically ( OR = 9.12). For school nurses who work with students with a variety of concerns and health issues, this research indicates that the use of bullying victimization as an outcome, proxy and/or predictor, requires inquiry into the type of bullying experienced to aid in the care and support received. PMID- 29482427 TI - Immunization and technology among newcomers: A needs assessment survey for a vaccine-tracking app. AB - OBJECTIVES: Newcomers experience unique challenges with respect to vaccination. These challenges are compounded by the need to navigate complex vaccination catch up schedules upon arrival in their new home countries. Our group has pioneered the development of CANImmunize, a free, bilingual, pan-Canadian digital application designed to empower individuals to manage their vaccination records. To inform how a vaccine tracking app such as CANImmunize might be tailored to meet the unique needs of newcomers, this study sought to determine commonly spoken languages, technology use, and current methods of vaccine tracking among recent newcomers to Canada. METHODS: Government-assisted refugees attending a health clinic in Ottawa, Canada were invited to complete a 17-question needs assessment survey. The survey captured data on household demographics, spoken languages, country of origin, technology use and methods used to track vaccination history. RESULTS: 50 newcomers completed the needs assessment survey. Arabic was the predominant language spoken by surveyed individuals. Although 92% of participants owned a smartphone, the majority did not actively use digital health applications. 18 (36%) participants reported being vaccinated before arriving in Canada. 27 (54%) participants were parents, 23 of whom reported that their children were vaccinated prior to arrival in Canada. 38 (76%) participants indicated that they would use a vaccine tracking app such as CANImmunize if it were translated into their primary language of communication. CONCLUSIONS: The results of our study indicate that mobile technology may be a useful tool to help newcomer families stay on track with provincial and territorial immunization schedules. PMID- 29482428 TI - Topical lotions utilized in outpatient rehabilitation clinics as a potential source of bacterial contamination. AB - Soft tissue mobilization and massage requiring lotions or creams are commonly used interventions in outpatient rehabilitation clinics. For at least 50 years hand creams used in healthcare settings have been found to be contaminated by bacteria. The purpose of this study was to determine the current state of bacterial contamination of lotions used in clinics and to determine the efficacy of lotion preservatives to kill bacteria. Unopened containers of lotions were studied, along with 81 lotion containers used in 22 outpatient clinics in southeast Tennessee and northwest Georgia. Three sites on each container were sampled using sterile swabs. At a microbiology lab, bacterial growth media was inoculated and incubated. Of the 81 containers sampled, 16 supported bacterial growth (19.8%). Container threads displayed the highest contamination compared with other container locations (p < 0.01). No bacteria were found in unopened lotion containers, although when challenged with live bacterial cultures lotion preservatives did not kill bacteria tested. Enrichment cultures using lotions studied here supported the growth of several bacterial species. These findings suggest the need for standardized protocols to help reduce potential healthcare associated infections due to use of lotions. Improved efficacy of preservatives added to lotions should be a priority. PMID- 29482429 TI - Refinement and reduction through application of a quantitative score system for estimation of TB-induced disease burden using computed tomography. AB - Until validated correlates of protection are identified, animal models remain the only way to test the efficacy of the new vaccines and drugs urgently needed to fight the global epidemic caused by infection with Mycobacterium tuberculosis. Non-human primates (NHP) offer the most relevant models of human tuberculosis (TB) and are central to the development process for new interventions. Efficacy evaluations are dependent on the capability of the test model to discriminate improved outcomes between treated groups after experimental exposure to M. tuberculosis and therefore the ability to measure TB-induced disease burden is central to the process. We have developed a score system that allows us to quantify the disease burden induced in macaques by infection with M. tuberculosis, based on the extent and features of disease visible on computed tomography (CT) images. The CT determined disease burden was then verified against that obtained using an established pathology-based approach. Trials of the system as a tool to measure disease burden have shown the approach capable of revealing differences between treatment groups in order to: (a) characterise outcome of infection and enable model refinement; (b) demonstrate the efficacy of drug treatment regimens by showing differences in outcome between test groups. Initial trials suggest that the imaging-based score system provides a valuable additional tool for the measurement of TB-induced disease burden that offers the opportunity to apply both refinement and reduction within studies. PMID- 29482430 TI - Effect of a novel polyethylene glycol compound on lung lavage in dogs after the inhalation of depleted uranium dust. AB - PURPOSE: The purpose of this study was to assess the effect of a lavage solution containing methoxypolyethylene glycol 4-(3,4-dihydroxyphenethylamino)-4 oxobutanoate (MDO) for whole lung lavage (WLL) in dogs after the inhalation of depleted uranium (DU) dust at a dose of 30 mgUkg-1. MATERIALS AND METHODS: WLL was performed using lavage solutions made of normal saline (saline group) or normal saline plus MDO (MDO group) at 2 days post-DU exposure. Meanwhile, a control group was set up without any treatment. RESULTS: At 10 days post-DU exposure, the saline and MDO groups had a lower DU content in urine and lung compared with the DU group (without lavage), while the MDO group content was significantly lower than that in the saline group. In terms of blood urea nitrogen and creatinine levels, the DU group maintained relatively high levels from day 3 to day 10; the saline group levels were reduced compared with the DU group at day 8 and day 10, while the MDO group levels remained markedly lower than both the DU and saline group levels. Pathological changes in the lungs and kidneys showed that the saline group was improved compared with the DU group, but not as significantly as the MDO group. CONCLUSIONS: In brief, WLL has a remarkable effect in promoting the decorporation of inhaled DU dust in the lungs of dogs. By comparison, a MDO-containing lavage solution has a better lavage effect than normal saline. PMID- 29482432 TI - Metabolic Correlates of Health-Related Quality of Life in Patients With Type 2 Diabetes Mellitus. AB - BACKGROUND: The increasing prevalence of type 2 diabetes mellitus (T2DM) and associated metabolic complications lead to the development of a syndrome known as "metabolic syndrome" (MetS), which is considered as one of the major risk factor not only for the development of cardiovascular diseases but also have a great impact on the quality of life. RESEARCH DESIGN AND METHODS: A descriptive, observational study involving the recruitment of patients with T2DM with and without MetS was carried out in outpatient department of endocrinology. The MetS was defined as per the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) criteria. Patients with T2DM were screened as per the American Diabetes Association (ADA; ie, fasting blood glucose [FBG] >= 126 mg/dL) and who were using oral antidiabetic drugs. Short Form-36 (SF-36) was used to assess the health-related quality of life (HRQoL). RESULTS: Patients were grouped as T2DM with MetS (n = 100) and T2DM without MetS (n = 100). A greater significant decline was observed in physical component summary (PCS) and mental component summary (MCS) in patients with T2DM with MetS as compared to patients without MetS ( P <= .05). Multiple linear regression analysis revealed that in patients with T2DM having MetS, age and waist circumference (WC) are independent predictors for worsening of both PCS and MCS aspects of health-related quality of life (HRQOL). In addition, high triglycerides and raised FBG were found to be correlated with the decline in PCS and MCS, respectively. CONCLUSION: The study demonstrated that patients with T2DM with MetS have overall poor HRQOL as compared to patients with T2DM without MetS. PMID- 29482431 TI - MicroRNA meta-signature of oral cancer: evidence from a meta-analysis. AB - AIM: It was the aim of the study to identify commonly deregulated miRNAs in oral cancer patients by performing a meta-analysis of previously published miRNA expression profiles in cancer and matched normal non-cancerous tissue in such patients. MATERIAL AND METHODS: Meta-analysis included seven independent studies analyzed by a vote-counting method followed by bioinformatic enrichment analysis. RESULTS: Amongst seven independent studies included in the meta-analysis, 20 miRNAs were found to be deregulated in oral cancer when compared with non cancerous tissue. Eleven miRNAs were consistently up-regulated in three or more studies (miR-21-5p, miR-31-5p, miR-135b-5p, miR-31-3p, miR-93-5p, miR-34b-5p, miR 424-5p, miR-18a-5p, miR-455-3p, miR-450a-5p, miR-21-3p), and nine were down regulated (miR-139-5p, miR-30a-3p, miR-376c-3p, miR-885-5p, miR-375, miR-486-5p, miR-411-5p, miR-133a-3p, miR-30a-5p). The meta-signature of identified miRNAs was functionally characterized by KEGG enrichment analysis. Twenty-four KEGG pathways were significantly enriched, and TGF-beta signaling was the most enriched signaling pathway. The highest number of meta-signature miRNAs was involved in the sphingolipid signaling pathway. Natural killer cell-mediated cytotoxicity was the pathway with most genes regulated by identified miRNAs. The rest of the enriched pathways in our miRNA list describe different malignancies and signaling. CONCLUSIONS: The identified miRNA meta-signature might be considered as a potential battery of biomarkers when distinguishing oral cancer tissue from normal, non-cancerous tissue. Further mechanistic studies are warranted in order to confirm and fully elucidate the role of deregulated miRNAs in oral cancer. PMID- 29482433 TI - Safety issues from a Phase 3 clinical trial of a live-attenuated chimeric yellow fever tetravalent dengue vaccine. AB - A tetravalent live-attenuated 3-dose vaccine composed of chimeras of yellow fever 17D and the four dengue viruses (CYD, also called Dengvaxia) completed phase 3 clinical testing in over 35,000 children leading to a recommendation that vaccine be administered to >/ = 9 year-olds residing in highly dengue- endemic countries. When clinical trial results were assessed 2 years after the first dose, vaccine efficacy among seropositives was high, but among seronegatives efficacy was marginal. Breakthrough dengue hospitalizations of vaccinated children occurred continuously over a period of 4-5 years post 3rd dose in an age distribution suggesting these children had been vaccinated when seronegative. This surmise was validated recently when the manufacturer reported that dengue NS1 IgG antibodies were absent in sera from hospitalized vaccinated children, an observation consistent with their having received Dengvaxia when seronegative. Based upon published efficacy data and in compliance with initial published recommendations by the manufacturer and WHO the Philippine government undertook to vaccinate 800,000-plus 9 year-olds starting in April 2016. Eighteen months later, dengue hospitalizations and a deaths were reported among vaccinated children. The benefits of administering Dengvaxia predicted by the manufacturer, WHO and others derive from scoring dengue hospitalizations of vaccinated children as vaccine failures rather than as vaccine enhanced dengue disease. Recommended regimens for administration of Dengvaxia should have been structured to warn of and avoid serious adverse events. PMID- 29482434 TI - An index of fatal toxicity for new psychoactive substances. AB - An index of fatal toxicity for new psychoactive substances has been developed based solely on information provided on death certificates. An updated index of fatal toxicity (Tf), as first described in 2010, was calculated based on the ratio of deaths to prevalence and seizures for the original five substances (amphetamine, cannabis, cocaine/crack, heroin and 3,4 methylenedioxymethylamphetamine)*. These correlated well with the 2010 index. Deaths were then examined for cases both where the substance was and was not found in association with other substances. This ratio (sole to all mentions; S/A) was then calculated for deaths in the period 1993 to 2016. This new measure of fatal toxicity, expressed by S/A, was well-correlated with the index Ln (Tf) of the original reference compounds. The calculation of S/A was then extended to a group of new psychoactive substances where insufficient prevalence or seizure data were available to directly determine a value of Tf by interpolation of a graph of Tf versus S/A. Benzodiazepine analogues had particularly low values of S/A and hence Tf. By contrast, gamma-hydroxybutyrate/gamma-butyrolactone, alpha methyltryptamine, synthetic cannabinoid receptor agonists and benzofurans had a higher fatal toxicity. PMID- 29482435 TI - H4K20me2: Orchestrating the recruitment of DNA repair factors in nucleotide excision repair. AB - The integrity of the genome is maintained by specific DNA repair pathways. The main pathway removing DNA lesions induced by exposure to UV light is nucleotide excision repair (NER). The DNA damage response at chromatin is accompanied by the recruitment of DNA repair factors to the lesion site and the deposition of specific histone marks. The function of these histone marks in NER stays for the most part elusive. We have recently reported that the methyltransferase MMSET catalyzes the dimethylation of histone H4 at lysine 20 (H4K20me2) at the lesion site. The deposition of H4K20me2 at DNA damage sites elicits the recruitment of the NER factor XPA providing evidence for an H4K20me2-dependent DNA repair factor recruitment mechanism during lesion recognition in the global-genomic branch of NER. Here we discuss how H4K20me2 might impact on the chromatin conformation and the DNA damage response. PMID- 29482436 TI - The Top 100 Papers of 25 Years of Macular Imaging Using Optical Coherence Tomography. AB - We analyzed and quantified the 100 most frequently cited papers in macular imaging using optical coherence tomography (OCT). The databases of the Institute for Scientific Information databases utilized for identification of articles in macular imaging using OCT over the last 25 years since the introduction of OCT in ophthalmology. All articles containing "optical coherence tomography" and "retina" without "glaucoma". The publication dates of the 100 most-cited articles ranged from 1991 to 2015, with the greatest number of articles published in the 2000s, while the total number of citations per article was greatest for articles published in the 1990s. Most studies were conducted in the U.S. and represented Level-IV clinical outcome studies indicating that also small case series or cohort studies could gain attention. The top 5 senior authors contributed to 39 of the 100 selected publications and accrued a total of 66.0% of all citations of those articles. PMID- 29482437 TI - Maternal Experiences of Transitioning Their Emerging Adult With Type 1 Diabetes to College. AB - Purpose The purpose of this study was to gain a deeper understanding about mothers' experiences of transitioning their emerging adult with type 1 diabetes mellitus to college. Methods A descriptive, qualitative study was conducted with 9 mothers of high school seniors with type 1 diabetes (T1DM) using semi structured questions via recorded telephone interviews. Results Among the 9 participants, 8 had daughters, and 1 had a son. The thematic analysis resulted in 4 themes: (1) concern for health and safety at college, (2) evolving roles of the parent and emerging adult dyad, (3) communication dynamics, and (4) social support systems. Conclusions Results indicate that mothers of emerging adults with T1DM experience heightened levels of concern during the college transition. These concerns are above and beyond those that are experienced by mothers of emerging adults without T1DM. Findings indicated that increasing levels of support for both parents as well as emerging adults with T1DM during the college transition may serve to decrease maternal stress and enhance the development of preparedness for diabetes self-management. Recommendations for diabetes educators in clinical practice include a family-centered approach focusing on the transition before the late adolescent period, interventions from colleges to promote a smooth transition, and interventions that address concerns of both the emerging adult with T1DM and the parent. Further research is necessary to identify barriers and facilitators to support parent/emerging adult dyads during the college transition period. PMID- 29482438 TI - Impact of human development on safety consciousness in construction. AB - The International Labour Organization (ILO) reports that the risk of fatal occupational injuries in developing countries is almost twice as high as in developed countries, indicating a potential relationship between the fatality rates and the development level. The human development index (HDI), based on life expectancy, knowledge level and purchasing power parity, endorsed by the United Nations Development Programme, is a widely accepted measure of the development level. This study investigates the relationship between the HDI and the fatality rates reported by the ILO. A 23-country data set is used to demonstrate the general trend of the relationship followed by country-specific analyses for Australia, Spain, Hungary and Turkey. The study conducted is limited to fatal occupational injuries in construction, where the accidents are notoriously high. The results demonstrate a statistically significant inverse relationship between the fatality rates and the HDI. PMID- 29482440 TI - Why coffee reduces heart disease risks. PMID- 29482439 TI - Chronic exposure to traffic-related air pollution and cancer incidence among 10,000 patients undergoing percutaneous coronary interventions: A historical prospective study. AB - Background Exposure to traffic-related air pollution (TRAP) is considered to have a carcinogenic effect. The authors previously reported a nonsignificant association between TRAP and cancer risk in a relatively small cohort of myocardial infarction survivors. This study assessed whether TRAP exposure is associated with subsequent cancer in a large cohort of coronary patients. Methods & results Consecutive patients undergoing percutaneous coronary interventions in a major medical centre in central Israel from 2004 to 2014 were followed for cancer through 2015. Residential levels of nitrogen oxides (NOx) - a proxy for TRAP - were estimated based on a high-resolution national land use regression model. Cox proportional hazards models were constructed to study relationships with cancer. Among 12,784 candidate patients, 9816 had available exposure data and no history of cancer (mean age, 68 years; 77% men). During a median (25th 75th percentiles) follow-up of 7.0 (3.9-9.3) years, 773 incident cases of cancer (8%) were diagnosed. In a multivariable-adjusted model, a 10-ppb increase in mean NOx exposure was associated with hazard ratios (HRs) of 1.07 (95% confidence interval [CI] 1.00-1.15) for all-site cancer and 1.16 (95% CI 1.05-1.28) for cancers previously linked to TRAP (lung, breast, prostate, kidney and bladder). A stronger association was observed for breast cancer (HR = 1.43; 95% CI 1.12 1.83). Associations were slightly strengthened after limiting the cohort to patients with more precise exposure assessment. Conclusion Coronary patients exposed to TRAP are at increased risk of several types of cancer, particularly lung, prostate and breast. As these cancers are amenable to prevention strategies, identifying highly exposed patients may provide an opportunity to improve clinical care. PMID- 29482441 TI - CHA2DS2-VASc score and risk of thromboembolism and bleeding in patients with atrial fibrillation and recent cancer. AB - Background Cancer may influence the risk of thromboembolism and bleeding associated with the CHA2DS2-VASc score. We examined the risk of thromboembolism and bleeding associated with the CHA2DS2-VASc score in atrial fibrillation patients with and without recent cancer. Methods and results Using nationwide registers all patients diagnosed with atrial fibrillation from 2000 to 2015 and not on oral anticoagulation or heparin therapy were included and followed for 2 years. Recent cancer was defined by a cancer diagnosis 5 years or fewer earlier. Risks of thromboembolism and bleeding were estimated in cumulative incidence curves and Cox regression models. We included 122,053 patients with incident atrial fibrillation, 12,014 (10%) had recent cancer. The 2-year cumulative incidence of thromboembolism and bleeding in patients with versus without recent cancer was 1.7% (95% confidence interval (CI) 0.5-2.8) and 4.3% (95% CI 2.4-6.2) versus 1.2% (95% CI 0.9-1.5) and 1.7% (95% CI 1.4-2.0) for CHA2DS2-VASc score 0; 3.2% (95%CI 2.2-4.3) and 4.4% (95%CI 3.2-5.6) versus 1.8% (95%CI 1.6-2.1) and 3.0% (95% CI 2.7-3.3) for CHA2DS2-VASc score 1; and 7.1% (95% CI 6.6-7.7) and 6.8% (95% CI 6.3-7.2) versus 10.9% (95% CI 10.7-11.1) and 6.2% (95% CI 6.1-6.4) for CHA2DS2-VASc score 2 or greater. Although the CHA2DS2-VASc score was associated with thromboembolism and bleeding in both patients with and without cancer, the association differed between the groups for thromboembolism (test for interaction, p < 0.001) and bleeding (test for interaction, p < 0.001). Conclusion The association of the CHA2DS2-VASc score and risk of thromboembolism and bleeding differed between atrial fibrillation patients with and without recent cancer. Therefore, the CHA2DS2-VASc score should be used with caution in patients with recent cancer. PMID- 29482442 TI - New reference equation for maximal functional capacity. PMID- 29482443 TI - Serum soluble CD25 as a risk factor of renal impairment in systemic lupus erythematosus - a prospective cohort study. AB - Objective Serum soluble CD25 (sCD25) could be used as a biomarker for disease activity in conditions associated with T-cell activation including various autoimmune diseases. This study aimed to explore the role of sCD25 as an indicator of disease activity and organ involvement in patients with systemic lupus erythematosus (SLE). Methods Serum samples were collected from 107 SLE patients and 92 age-matched healthy controls (HCs). All patients were followed up for 24 weeks, and sCD25 was measured by enzyme-linked immunosorbent assay. Clinical and laboratory data were recorded at baseline and then every two weeks until week 24. The Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI)-2K was adopted for assessing disease activity at all visits. Results Serum sCD25 levels were significantly increased in SLE patients compared to those in HCs ( p < 0.001). More patients in the high-sCD25 group had lupus nephritis, arthritis and vasculitis ( p = 0.010, p = 0.023 and p = 0.042, respectively). SLEDAI-2K, erythrocyte sedimentation rate, C-reactive protein and 24-hour urinary protein excretion were all associated with high levels of sCD25 ( p < 0.001, p = 0.002, p = 0.038 and p = 0.029, respectively). During the 24-week follow-up, more patients in the high-sCD25 group developed renal impairment (48% vs 6.2%, p = 0.005), and higher levels of sCD25 ( p = 0.033) were found at the time of onset of renal disease. Conclusions Serum sCD25 is a hallmark of disease activity and a predictor of renal disease in patients with SLE. PMID- 29482444 TI - The possible protective effect of N-acetyl-L-cysteine and folic acid in combination against aspartame-induced cerebral cortex neurotoxicity in adult male rats: a light and transmission electron microscopic study. AB - The purpose of this study is to investigate structural and ultrastructural alterations in the rat's brain cerebral cortex after aspartame (ASP) treatment and to evaluate the possible ameliorating role of N-acetyl-L-cysteine (NAC) and folic acid (FA). Forty adult rats were divided into four equal groups: Group I, received appropriate vehicle only and served as control. Group II, received oral doses of both NAC (600 mg/kg body weight (b.w.)) and FA (12 mg/kg b.w.) daily for 42 days. Group III, received oral doses of ASP (500 mg/kg b.w.) daily for 42 days. Group IV, received both NAC and FA, concurrently with ASP at the same doses, route and period of administration of the previous groups. Histological examination of the cerebral cortex of ASP-treated rats showed severe degenerative changes, especially in the nerve cells. Some of these cells appeared shrunken, irregular in shape, while the others appeared swollen and were surrounded by pericellular halos. Immunohistochemical and morphometric study of ASP-treated group revealed a weak B-cell lymphoma-2 (Bcl-2) immunoexpression in the cytoplasm of many cells, while intense positive immunoreaction for glial fibrillary acidic protein (GFAP) was observed in the cytoplasm and processes of astrocytes compared to control group with statistically significant difference (p < 0.001). Light microscopic results were confirmed by ultrastructural findings. However, NAC and FA in combination had an obvious protective effect against ASP-induced injury in the rat's cerebral cortex. In conclusion, these results suggested that NAC combined with FA can ameliorate the toxic effect of ASP on the rat's cerebral cortex. PMID- 29482445 TI - Single-Stage Preparation of Human Cartilage Grafts Generated from Bone Marrow Derived CD271+ Mononuclear Cells. AB - Due to the limited self-healing capacity of articular cartilage, innovative, regenerative approaches are of particular interest. The use of two-stage procedures utilizing in vitro-expanded mesenchymal stromal cells (MSCs) from various cell sources requires good manufacturing practice-compliant production, a process with high demands on time, staffing, and financial resources. In contrast, one- stage procedures are directly available, but need a safe enrichment of potent MSCs. CD271 is a surface marker known to marking the majority of native MSCs in bone marrow (BM). In this study, the feasibility of generating a single-stage cartilage graft of enriched CD271+ BM-derived mononuclear cells (MNCs) without in vitro monolayer expansion from eight healthy donors was investigated. Cartilage grafts were generated by magnetic-activated cell sorting and separated cells were directly transferred into collagen type I hydrogels, followed by 3D proliferation and differentiation period of CD271+, CD271-, or unseparated MNCs. CD271+ MNCs showed the highest proliferation rate, cell viability, sulfated glycosaminoglycan deposition, and cartilage marker expression compared to the CD271- or unseparated MNC fractions in 3D culture. Analysis according to the minimal criteria of the International Society for Cellular Therapy highlighted a 66.8-fold enrichment of fibroblast colony-forming units in CD271+ MNCs and the only fulfillment of the MSC marker profile compared to unseparated MNCs. In summary, CD271+ MNCs are capable of generating adequate articular cartilage grafts presenting high cell viability and notable chondrogenic matrix deposition in a CE-marked collagen type I hydrogel, which can obviate the need for an initial monolayer expansion. PMID- 29482446 TI - Technical aspects and limitations of fractional flow reserve measurement. AB - BACKGROUND: The only indication for coronary revascularization is elimination of ischaemia. Invasive hemodynamic methods (fractional flow reserve - FFR and instantaneous wave-free ratio (iFR) are superior to coronary angiography in detection of lesions causing myocardial ischaemia. Current European guidelines for myocardial revascularization recommend using of FFR for detection of functional assessment of lesions severity in category IA and number of these procedures increases. However, routine usage of these methods requires knowledge of technical requirements and limitations. AIM: The aim of the study is to summarise good clinical practice for FFR and iFR measurements with explanation of possible technical challenges, that are necessary for increasing of measurement accuracy. CONCLUSIONS: Authors describe frequent technical mistakes and malpractice during invasive assessment of lesion severity in coronary arteries. PMID- 29482447 TI - Epigenome Interactions with Patterned Neuronal Activity. AB - The temporal coding of action potential activity is fundamental to nervous system function. Here we consider how gene expression in neurons is regulated by specific patterns of action potential firing, with an emphasis on new information on epigenetic regulation of gene expression. Patterned action potential activity activates intracellular signaling networks selectively in accordance with the kinetics of activation and inactivation of second messengers, phosphorylation and dephosphorylation of protein kinases, and cytoplasmic and nuclear calcium dynamics, which differentially activate specific transcription factors. Increasing evidence also implicates activity-dependent regulation of epigenetic mechanisms to alter chromatin architecture. Changes in three-dimensional chromatin structure, including chromatin compaction, looping, double-stranded DNA breaks, histone and DNA modification, are altered by action potential activity to selectively inhibit or promote transcription of specific genes. These mechanisms of activity-dependent regulation of gene expression are important in neural development, plasticity, and in neurological and psychological disorders. PMID- 29482448 TI - Factors associated with repeat diagnosis of syphilis in genitourinary medicine (GUM) clinic attendees in the North East of England, 2002-2014. AB - This study aimed to identify factors associated with repeat syphilis infection in North East England, in order to inform local prevention and control opportunities. We undertook a case-case study comparing individuals diagnosed with single or multiple episodes of syphilis infection within genitourinary medicine (GUM) clinics in NE England (12 clinics serving a population of 2.5 million). Study cases were verified as having had true re-infection by a GUM clinician (using serological and/or clinical parameters) and control cases (3 per case) frequency matched to cases by age and year of presentation. The odds of exposure to sexual behavioural and clinical factors were compared for cases and control cases using stepwise multivariable logistic regression. We included 66 cases and 235 control cases. The majority of cases (62/66) and control cases (165/235) were men who had sex with men (MSM). Data were missing for 0-64% of cases across different variables. Following multivariable analysis HIV seropositivity (OR 23.3, 95% CI 4.32-125.9), failure to attend follow-up (OR 4.63, 95% CI 1.11-19.31), stage of infection and deprivation were associated with re-infection ( p < 0.001). In this study, HIV seropositivity and failure to attend follow-up were associated with re-infection with syphilis. Actions targeted at these groups may help to reduce ongoing transmission. PMID- 29482449 TI - P53 Promotes Retinoid Acid-induced Smooth Muscle Cell Differentiation by Targeting Myocardin. AB - TP53 is a widely studied tumor suppressor gene that controls various cellular functions, including cell differentiation. However, little is known about its functional roles in smooth muscle cells (SMCs) differentiation from embryonic stem cells (ESCs). SMC differentiation is at the heart of our understanding of vascular development, normal blood pressure homeostasis, and the pathogenesis of vascular diseases such as atherosclerosis, hypertension, restenosis, as well as aneurysm. Using retinoid acid (RA)-induced SMC differentiation models, we observed that p53 expression is increased during in vitro differentiation of mouse ESCs into SMCs. Meanwhile, suppression of p53 by shRNA reduced RA-induced SMC differentiation. Mechanistically, we have identified for the first time that Myocardin, a transcription factor that induces muscle cell differentiation and muscle-specific gene expression, is the direct target of p53 by bioinformatic analysis, luciferase reporter assay, and chromatin immunoprecipitation approaches. Moreover, in vivo SMC-selective p53 transgenic overexpression inhibited injury-induced neointimal formation. Taken together, our data demonstrate that p53 and its target gene, Myocardin, play regulatory roles in SMC differentiation. This study may lead to the identification of novel target molecules that may, in turn, lead to novel drug discoveries for the treatment of vascular diseases. PMID- 29482450 TI - Cognitive, behavioral and psychological functioning in children with metopic synostosis: a meta-analysis examining the impact of surgical status. AB - Neurodevelopmental delays are known to occur in children with metopic synostosis, but it is presently unclear whether the cognitive, behavioral and psychological outcomes of children with metopic synostosis differ to those of their healthy peers. This meta-analysis consolidated data from 17 studies (published prior to August 2017) that examined the cognitive, behavioral and psychological outcomes of children (n = 666; aged <=19 yrs) with metopic synostosis. Hedges'g (gw) effect sizes compared the outcomes of samples with metopic synostosis (unoperated, operated) to healthy controls or normative data and, where available, the prevalence of problems/disorders was calculated. Children with unoperated metopic synostosis performed significantly worse than their healthy peers on measures of: general cognition (gw = -.38), motor functioning, (gw = .81), and verbal (gw = -.82) and visuospatial (gw = -.92) abilities. Children with operated metopic synostosis performed significantly worse on measures of motor functioning (gw = -.45), visuospatial skills (gw = -.32), attention (gw = .50), executive functioning (gw = -.36), arithmetic ability (gw = -.37), and behavior (gw = -.34). Cognitive, behavioral, and psychological problems were prevalent, but variable. Overall, the cognitive, behavioral, and psychological outcomes of children with metopic synostosis are generally worse than their healthy peers, regardless of surgical status. However, research is sparse, samples small, controls are rarely recruited, and the severity of metopic synostosis often not stated. Nevertheless, the findings suggest that children with metopic synostosis are likely to experience a variety of negative outcomes and should therefore receive ongoing monitoring and support. PMID- 29482451 TI - Does Self-Esteem Have an Interpersonal Imprint Beyond Self-Reports? A Meta Analysis of Self-Esteem and Objective Interpersonal Indicators. AB - Self-esteem promises to serve as the nexus of social experiences ranging from social acceptance, interpersonal traits, interpersonal behavior, relationship quality, and relationship stability. Yet previous researchers have questioned the utility of self-esteem for understanding relational outcomes. To examine the importance of self-esteem for understanding interpersonal experiences, we conducted systematic meta-analyses on the association between trait self-esteem and five types of interpersonal indicators. To ensure our results were not due to self-esteem biases in perception, we focused our meta-analyses to 196 samples totaling 121,300 participants wherein researchers assessed interpersonal indicators via outsider reports. Results revealed that the association between self-esteem and the majority of objective interpersonal indicators was small to moderate, lowest for specific and distal outcomes, and moderated by social risk. Importantly, a subset of longitudinal studies suggests that self-esteem predicts later interpersonal experience. Our results should encourage researchers to further explore the link between self-esteem and one's interpersonal world. PMID- 29482452 TI - Sleep and stress hormone responses to training and competition in elite female athletes. AB - Stress hormone and sleep differences in a competition versus training setting are yet to be evaluated in elite female team-sport athletes. The aim of the current study was to evaluate salivary cortisol and perceptual stress markers during competition and training and to determine the subsequent effects on sleep indices in elite female athletes. Ten elite female netball athletes (mean +/- SD; age: 23 +/- 6 years) had their sleep monitored on three occasions; following one netball competition match (MATCH), one netball match simulation session (TRAIN), and one rest day (CONTROL). Perceived stress values and salivary cortisol were collected immediately pre- (17:15 pm) and post-session (19:30 pm), and at 22:00 pm. Sleep monitoring was performed using wrist actigraphy assessing total time in bed, total sleep time (TST), efficiency (SE%), latency, sleep onset time and wake time. Cortisol levels were significantly higher (p < .01) immediately post MATCH compared with TRAIN and CONTROL (mean +/- SD; 0.700 +/- 0.165, 0.178 +/- 0.127 and 0.157 +/- 0.178 MUg/dL, respectively) and at 22:00 pm (0.155 +/- 0.062, 0.077 +/- 0.063, and 0.089 +/- 0.083 MUg/dL, respectively). There was a significant reduction in TST (-118 +/- 112 min, p < .01) and SE (-7.7 +/- 8.5%, p < .05) following MATCH vs. TRAIN. Salivary cortisol levels were significantly higher, and sleep quantity and quality were significantly reduced, following competition when compared to training and rest days. PMID- 29482453 TI - The effect of an active steering system on city bus drivers' muscle activity. AB - City bus drivers spend hours driving under time pressure, in congested traffic and in a monotonous sitting position. This leads to unhealthy working conditions, especially in terms of physical and psychological stress. The aim of this study is to investigate whether an active steering system can alleviate the musculoskeletal stress involved in manoeuvring a bus. Twenty bus drivers drove a city bus equipped with the Volvo dynamic steering (VDS) support system in real traffic. Steering effort was evaluated with electromyography and with a questionnaire. Compared to baseline, VDS significantly reduced the required muscle activity by on average 15-25% while turning, and up to 68% in the part of the manoeuvre requiring maximum effort. The bus drivers believed that VDS will help reduce neck and shoulder problems, and they expressed a desire to have VDS installed in their own bus. PMID- 29482454 TI - NP and PA Privileging in Acute Care Settings: Do Scope of Practice Laws Matter? AB - As hospitals' interest in nurse practitioners (NPs) and physician assistants (PAs) grows, their leadership is eager to know how their medical staffing privileging policies for these professionals compare to peer hospitals. This study assesses the extent of variation of these policies in four clinical areas and examines whether the differences are associated with state scope of practice laws for NPs and PAs. We also examine the relationship of NP and PA privileging policies to each other. Our analysis finds no evidence that hospital privileging is associated with state scope of practice, and indeed within-state variation is more significant than cross-state variation. We also find a strong correlation between NP and PA privileging in all four clinical areas. These results suggest the need for additional research to understand the institutional-level variables and human dynamics at the level of medical staffing committees that may explain the dramatic variation in privileging policies and, ultimately, the effects of different privileging levels on costs and quality. PMID- 29482456 TI - Long-Term Hematopoietic Engraftment of Congenic Amniotic Fluid Stem Cells After in Utero Intraperitoneal Transplantation to Immune Competent Mice. AB - Clinical success of in utero transplantation (IUT) using allogeneic hematopoietic stem cells (HSCs) has been limited to fetuses that lack an immune response to allogeneic cells due to severe immunological defects, and where transplanted genetically normal cells have a proliferative or survival advantage. Amniotic fluid (AF) is an autologous source of stem cells with hematopoietic potential that could be used to treat congenital blood disorders. We compared the ability of congenic and allogeneic mouse AF stem cells (AFSC) to engraft the hematopoietic system of time-mated C57BL/6J mice (E13.5). At 4 and 16 weeks of age, multilineage donor engraftment was higher in congenic versus allogeneic animals. In vitro mixed lymphocyte reaction confirmed an immune response in the allogeneic group with higher CD4 and CD8 cell counts and increased proliferation of stimulated lymphocytes. IUT with congenic cells resulted in 100% of donor animals having chimerism of around 8% and successful hematopoietic long-term engraftment in immune-competent mice when compared with IUT with allogeneic cells. AFSCs may be useful for autologous cell/gene therapy approaches in fetuses diagnosed with congenital hematopoietic disorders. PMID- 29482457 TI - Barriers and facilitators to housing access and maintenance in HUD-VASH: Participant and staff perspectives. AB - Though the U.S. Departments of Housing and Urban Development (HUD) and Veterans Affairs (VA) supportive housing (HUD-VASH) program endeavors to address barriers to Veterans accessing and maintaining housing, participants report challenges that lead to program exits. This study aims to understand participants' views on the factors contributing to their exits from HUD-VASH, as well as how program staff may respond to challenges. This mixed methods study includes four sources of data: (1) surveys with Veterans, (2) semi-structured interviews with a subsample of surveyed Veterans, (3) Veterans' administrative data from VA electronic data systems, and (4) focus groups with staff from local public housing authorities and VA case management teams. Veterans reported barriers to housing access (e.g., difficult procedures, lack of communication, lack of affordable and adequate housing stock) and housing maintenance (e.g., program rules, mental health and substance use, access to resources), and staff described strategies devised, at the local level, in response to these issues (e.g., better engagement with property owners, funds for deposits and household goods, increased interagency collaboration through HUD-VASH Boot Camps). Findings can inform communities seeking to eliminate Veteran homelessness through HUD-VASH and other supported housing programs. PMID- 29482459 TI - Unilateral Apraxic Agraphia without Ideomotor Apraxia from a callosal lesion in a patient with Marchiafava-Bignami disease. AB - Apraxic agraphia can be caused by left hemispheric cerebral lesions in the area that contains the spatial representations of the movements required to write, from a lesion in, or connections to, the frontal premotor cortex that converts these spatial representations to motor programs (Exner's area). A right-handed woman with Marchiafava Bignami disease and lesions of the genu and splenium of her corpus callosum had apraxic agraphia without ideomotor apraxia of her left. A disconnection of Exner's area in the left hemisphere from the right hemisphere's premotor and motor areas may have led to her inability to write with her left hand. PMID- 29482460 TI - Pain-related anxiety and opioid misuse in a racially/ethnically diverse young adult sample with moderate/severe pain. AB - Pain problems are of significant public health concern, and with opioid-related problems and death due to overdose at an all-time high, there is significant public health importance to identify risk factors that link instances of pain to opioid misuse among persons with pain whether or not they have been prescribed opioids for pain management. Severe pain and pain-related problems have been associated with increased risk for opioid misuse, and recent research indicates that pain-related anxiety (worry about the negative consequences of pain) may contribute to a more debilitating pain experience. Additionally, pain-related anxiety has previously been linked to substance use motives and dependence for cannabis and tobacco. However, little research has examined pain-related anxiety as a transdiagnostic risk factor for opioid misuse. The current study examined the relationship between pain-related anxiety and self-reported opioid misuse (addiction, prescription denial, family concerns, detox) in a racially/ethnically diverse sample of young adults (N = 256, M age = 22.84) reporting moderate to severe bodily pain over the previous four weeks. Results indicated that pain related anxiety was significantly related to several indicators of opioid misuse as well as an increased number of opioid-related problems. Findings from the current study suggest that targeting pain-related anxiety may be one therapeutic strategy to reduce opioid misuse. PMID- 29482458 TI - Onyx embolization with the Apollo detachable tip microcatheter: A single-center experience. AB - Purpose The Apollo Onyx Delivery Microcatheter (Ev3, Irvine, CA) is a detachable tip microcatheter that was developed to reduce the risk of microcatheter entrapment during ethylene-vinyl alcohol copolymer (Onyx) embolizations. We report our experience with the microcatheter in a variety of neurointerventional procedures. Methods We retrospectively reviewed all Onyx embolizations performed in the head, neck, and spine using the Apollo Onyx Delivery Microcatheter from its introduction at our institution in July 2014 to August 2016. Information regarding patient diagnoses, procedural details, as well as clinical outcomes were obtained from the electronic medical record, procedure reports, and relevant angiographic imaging. Results A total of 58 arterial pedicle Onyx embolizations were performed in 37 patients. There were no cases of microcatheter entrapment, early/inadvertent tip detachment, or vessel injury upon removal of the device. There were two instances (3.5%) of leakage of Onyx from the microcatheter detachment site during embolization, which did not result in adverse sequelae. Clinical outcomes were excellent, with nearly all embolizations achieving the intended goal. In multivariate analysis, length of Onyx reflux along the microcatheter tip and utilization of a higher viscosity agent, Onyx 34, were significantly associated with tip detachment. Conclusion The use of the Apollo Microcatheter is both safe and effective during neurointerventional embolizations using Onyx. Leakage of liquid embolic agent from the detachment site is an infrequent technical complication that may be encountered with the device. PMID- 29482462 TI - In vitro inhibition of food borne mutagens induced mutagenicity by cinnamon (Cinnamomum cassia) bark extract. AB - Cinnamon (Cinnamomum cassia) is an important spice which is widely consumed in the Indian subcontinent as well as in several other parts of the world. In the present study, NMR spectroscopy showed the presence of cinnamaldehyde to be the major component of the bark. The possible mutagenic effects of cinnamon bark ethanolic extract (CEE, 0.01-1 mg/plate) cinnamon oil (CNO, 0.125-1 mg/plate), and its active component cinnamadehyde (CLD, 0.125-1 mg/plate) were evaluated. Antimutagenic activity of CEE, CNO, and CLD was also tested against various food borne mutagens (heterocyclic amines and aflatoxin B1 (AFB1)) and sodium azide (SA) using Ames assay. Similarly, the antimicrobial activity was studied using agar well diffusion assay against various pathogens. CEE was non-mutagenic in any of the five tester strains of Salmonella typhimurium (TA97a, TA98, TA100, TA102, and TA104) in Ames test. CEE exhibited antimutagenic activity against all the mutagens tested in the higher doses. Additionally, CEE, CNO, and CLD were effective against various pathogens such as Staphylococcus aureus, Proteus vulgaris, S. typhimurium, Klebsiella pneumoniae, and Escherichia coli in the agar well diffusion assay. Promising antimutagenic and antimicrobial properties were shown by the cinnamon bark ethanolic extract and cinnamaldehyde, respectively. Therefore, their role in cancer chemoprevention, as well as a natural antimicrobial agent must be exploited and studied in depth in in vivo conditions. PMID- 29482461 TI - Mothers' Experience of Post-Traumatic Growth in Pediatric Kidney Transplantation. AB - Parenting a child with chronic kidney disease has a profound impact on the parental caregivers across social, emotional, and physical functioning. As the survival rates for children with chronic kidney disease increase, the demands on parents caring for these children intensify. The aim of this study was to understand the lived experience of being a mother of a child who has undergone kidney transplantation. Seven mothers caring for children with chronic kidney disease in Ontario, Canada participated in in-depth interviews that were analyzed according to the principles of hermeneutic phenomenology. The present study presents the findings concerning post-traumatic growth: personal strength, new possibilities, enhanced relationships, appreciation of life and spiritual change. Recognizing positive aspects of stressful situations and the potential for growth can impact the practice of social workers and other health-care professionals. Ultimately the assistance that is provided to parent caregivers can be improved with a better understanding of the whole experience. PMID- 29482463 TI - Validation of the ambient TUG chair with light barriers and force sensors in a clinical trial. AB - To initiate appropriate interventions and avoid physical decline, comprehensive measurements are needed to detect functional changes in elderly people at the earliest possible stage. The established Timed Up&Go (TUG) test takes little time and, due to its standardized and easy procedure, can be conducted by elderly people in their own homes without clinical guidance. Therefore, cheap light barriers (LBs) and force sensors (FSs) are well suited ambient sensors that could easily be attached to existing (arm)chairs to measure and report TUG times in order to identify functional decline. We validated the sensitivity of these sensors in a clinical trial with 100 elderlies aged 58-92 years with a mean of 74 (+/-6.78) years by comparing the sensor-based results with standard TUG measurements using a stopwatch. We further evaluated the accuracy enhancement when calibrating the algorithm via a mixed linear model. With calibration, the LBs achieved a root mean square error (RMSE) of 0.83 s, compared to 1.90 s without, and the FSs achieved 0.90 s compared to 2.12 s without. The suitability of measuring accurate TUG times with each of the ambient sensors and of measuring TUG regularly in the homes of elderly people could be confirmed. PMID- 29482464 TI - "Every soul shall taste death." Attitudes and beliefs of Moroccan muslim women living in Antwerp (Belgium) toward dying, death, and the afterlife. AB - This study aims to elicit the beliefs and attitudes of middle-aged and elderly Moroccan Muslim women toward dying, death, and the afterlife; to identify whether differences are observable between middle-aged and elderly participants and to document how the actual attitudes of our participants relate to normative Islamic literature. Interviews were conducted with middle-aged and elderly Moroccan women living in Belgium (n = 30) and with experts in the field (n = 15). This study reveals that the belief in an omnipotent and omniscient God and in an afterlife strongly marks the attitudes of first- and second-generation Muslims in Belgium toward life and death. PMID- 29482465 TI - An 8-week scapular stabilization exercise program in an elite archer with scapular dyskinesis presenting joint noise: A case report with one-year follow up. AB - This case report demonstrates the effects of a scapular stabilization exercise program for managing the clinical symptoms of scapular dyskinesis in an archer presenting joint noise during shoulder movement. A 31-year-old man with a 20-year career in archery who complained of scapular dyskinesis and joint noise during shoulder movement was referred for proper management. The player performed the scapular stabilization exercise program, with an emphasis on strengthening scapular stabilizers and neutralization of scapular position, for 40 min, three times per week for 8 weeks (a total of 24 sessions). Measurements included the extent of scapular deviation, strength of scapular stabilizers, emotional burden related to joint noise, and upper limb disability. These measurements were taken before and after the intervention and during 1-year follow-up. After the 8-week intervention, scapular position improved by a range of 3.75-12.88% and muscle strength improved by a range of 8.69-28.60%. Further, emotional burden and upper limb disability improved by 56.86% and 91.67%, respectively. A 1-year follow-up showed that these improvements had been favorably maintained. These findings indicate that shoulder stabilization exercise may be helpful for alleviating scapular and shoulder problems related to archery performance. PMID- 29482466 TI - Health risk assessment and source study of PAHs from roadside soil dust of a heavy mining area in India. AB - The total concentrations of 13 detected polycyclic aromatic hydrocarbons (PAHs) in different traffic soil samples of Dhanbad heavy mining area, India, were between 8.256 and 12.562 ug/g and were dominated by four ring PAHs (44%). Diagnostic ratio study revealed that fossil fuel burning and vehicular pollution are the most prominent sources of the PAHs in roadside soil even at a heavy coal mining area. The 90th percentiles cancer risks determined by probabilistic health risk assessment (Monte Carlo simulations) for both the age groups (children and adults) were above tolerable limit (>1.00E-06) according to USEPA. The simulated mean cancer risk was 1.854E-05 for children and 1.823E-05 for adults. For different exposure pathways, dermal contact was observed to be the major pathway with an exposure load of 74% for children and 85% for adults. Sensitivity analysis demonstrated relative skin adherence factor for soil (AF) is the most influential parameter of the simulation, followed by exposure duration (ED). PMID- 29482467 TI - The role of oral fluvastatin on postoperative peritoneal adhesion formation in an experimental rat model. AB - BACKGROUND: Postoperative peritoneal adhesions are a momentousness complication after abdominal surgery. Although varied means have been used to prevent and treat adhesions, the effects have not been satisfactory. Fluvastatin, a HMG-CoA reductase inhibitors, exhibits a variety of pharmacological effects. Aim of this study was to evaluate the effect of fluvastatin on postoperative peritoneal adhesion formation. METHODS: Seventy-five male Wistar rats weighting 220-250g were randomly assigned equally to three groups. Group A was given sham operation without treatment, Group B was the model group in which postoperative peritoneal adhesion model was created without medication, and Group C was given oral fluvastatin treatment after postoperative peritoneal adhesion model created. After laparotomy on day 7, macroscopic and pathological assessment were evaluated, IL-1beta and t-PA in plasma were performed to measure, and tissue samples were taken to measure MMP-9 protein. RESULTS: There were significant differences between the groups on adhesion grade (p < .05), IL-1beta content of the plasma and t-PA activity of the adhesions (p < .05). The grading of adhesion demonstrated significant differences between all groups. The levels of the IL 1beta content of plasma, t-PA activity and MMP-9 of adhesion showed pivotal changes in Group B compared with Group A and C, while the difference between Group A and C was not statistically significant. CONCLUSION: Oral fluvastatin application could reduce formation of intra-abdominal adhesion by promoting expression of MMP-9 level, lowering the levels of IL-1beta and increasing the activity of t-PA after abdominal surgery. PMID- 29482469 TI - Facial attractiveness impressions precede trustworthiness inferences: lower detection thresholds and faster decision latencies. AB - Prior research has found a relationship between perceived facial attractiveness and perceived personal trustworthiness. We examined the time course of attractiveness relative to trustworthiness evaluation of emotional and neutral faces. This served to explore whether attractiveness might be used as an easily accessible cue and a quick shortcut for judging trustworthiness. Detection thresholds and judgment latencies as a function of expressive intensity were measured. Significant correlations between attractiveness and trustworthiness consistently held for six emotional expressions at four intensities, and neutral faces. Importantly, perceived attractiveness preceded perceived trustworthiness, with lower detection thresholds and shorter decision latencies. This reveals a time course advantage for attractiveness, and suggests that earlier attractiveness impressions could bias trustworthiness inferences. A heuristic cognitive mechanism is hypothesised to ease processing demands by relying on simple and observable clues (attractiveness) as a substitute for more complex and not easily accessible information (trustworthiness). PMID- 29482468 TI - 'M-TRACK' (mobile phone reminders and electronic tracking tool) cuts the risk of pre-treatment loss to follow-up by 80% among people living with HIV under programme settings: a mixed-methods study from Gujarat, India. AB - BACKGROUND: In 2016, the National AIDS Control Programme (NACP) in Gujarat, India implemented an innovative intervention called 'M-TRACK' (mobile phone reminders once every week for four weeks after diagnosis and electronic patient tracking tool) to reduce pre-treatment loss to follow-up (LFU) among people living with HIV (PLHIV) in Vadodara district while other districts received standard of care. OBJECTIVES: To assess the effectiveness of M-TRACK in reducing pre-treatment LFU (proportion of diagnosed PLHIV not registering for HIV care by four weeks after diagnosis) and to explore the implementation enablers and challenges from health care providers' and PLHIV perspective. METHODS: An explanatory mixed-methods study design was used wherein the quantitative phase (cohort study with two groups: Vadodara district exposed to M-TRACK and Rajkot district as unexposed) was followed by a qualitative phase (descriptive study involving group interview with 16 health care providers, personal interviews with two programme managers and telephonic interviews with 16 PLHIV). Data were collected during October 2016 to February 2017. RESULTS: During the pre-M-TRACK period (July-September 2016), the LFU proportion was similar [13% (25/191) in Vadodara; 15% (21/141) in Rajkot (p = 0.8)]. During the M-TRACK period (October-December 2016), LFU decreased to 4% (9/209) in Vadodara (exposed), whereas it remained similar at 16% (18/113) in Rajkot (unexposed) district (p = 0.02). PLHIV exposed to M-TRACK had an 80% lower risk of LFU (aRR 0.2; 95% CI: 0.1-0.5) compared with standard care, after adjusting for socio-demographics, time and clustering at district level. During interviews, M-TRACK was welcomed by both PLHIV and the counsellors. The latter felt it saved time by obviating the need for home visits and helped in documentation. Inconvenience of using landline phone available at the health facility, lack of budgets for reimbursement of mobile call expenses and internet connectivity problems were the key implementation challenges. CONCLUSION: M-TRACK was highly effective in reducing the gap between diagnosis and treatment. It may be considered for scale-up after addressing the challenges noted. PMID- 29482470 TI - The Importance of Attention to Cultural Factors in the Approach to Dementia Care Services for Older Persons. PMID- 29482471 TI - Vitamin B2 (riboflavin) increases drought tolerance of Agaricus bisporus. AB - Drought is a stressor for many soil-inhabiting organisms. Although plants have been extensively investigated for drought-adaptive mechanisms, little information is available for fungi. Antioxidants are especially relevant, since desiccation is accompanied by an excessive intracellular production of reactive oxygen species. Riboflavin (vitamin B2) is one antioxidant regulating drought tolerance in plants. A similar function may exist in fungi. Here, we examined the respiratory and transcriptional responses of Agaricus bisporus to drought and the impact of riboflavin. Mesocosm experiments with four groups were established: hyphae were treated with or without 50 uM riboflavin under drought or no drought conditions. Drought increased riboflavin content in hyphae about 5 times with, but also without, addition of riboflavin. Without addition of riboflavin, fungal respiration decreased by more than 50% at water potentials of about -20 MPa. With addition of riboflavin, respiration remained about 2-3 times higher. The transcriptional responses to only drought or only riboflavin strongly overlapped and were mainly based on factors regulating transcription and translation. This was even stronger in combined treatments. Riboflavin induced protective mechanisms in drought-stressed hyphae. Most pronounced was the methylglyoxal (cytotoxic by-product of glycolysis) detoxifying of lactoylglutathione lyase. Thus, our data suggest a stress-priming function and a role of riboflavin in drought responses of A. bisporus. PMID- 29482472 TI - A magic-themed upper limb intervention for children with unilateral cerebral palsy: The perspectives of parents. AB - AIM: To explore parent's perspective of their child's participation in a magic themed intervention called Amazing Magic Club (AMC), and to further our understanding of motivated engagement and the impact of themed group-based interventions for children with unilateral cerebral palsy (CP). METHODS: Twenty nine parents of children with unilateral CP completed semi-structured interviews. The child participants (n = 28) attended one of three AMCs; average age of the children was 10y 6mo (SD 2y 2mo). The parent interviews were analysed using thematic analysis. RESULTS: The three themes are: "It's okay to be me", the magic effect and "I can do it". Parents observed their children to belong and learn about their abilities. The importance of the magicians and the performance is described. Parents observed their children to have increased self-belief and a new willingness to attempt difficult tasks. DISCUSSION: AMC appears to capture intrinsic motivation for children with unilateral CP to complete challenging tasks. PMID- 29482473 TI - Systematic review: Investigating the effectiveness of assistive technology to enable internet access for individuals with deafblindness. AB - The purpose of this study is to systematically review published evidence regarding the development, use, and effectiveness of assistive devices and technol ogies that enable internet access for individuals who are deafblind. Eight electronic research databases (CINAHL, Embase, Engineering Village MEDLINE, PsycINFO, PubMed, Cochrane Library, and Web of Science) and three clinical trials registries (ISRCTN Registry, WHO ICTRP, and ClinicalTrials.gov) were searched. Seven articles met the inclusion criteria for this systematic review. The assistive technologies described were in the preliminary stages of development, with only three of the technologies having undergone any testing. The effectiveness of all seven assistive technologies was quantified in this review based on the proposed impacts of internet access on the domains of the World Health Organization's International Classification of Functioning, Disability and Health framework. Internet access technologies for individuals with deafblindness are in the early stages of development and are targeted toward specific functions of the internet. It is imperative that future device development and evaluation seek input from persons who are deafblind. There is also a need to address the gap between academic research, which seeks to develop assistive technology to access the internet and the translation into real-world use of this technology. PMID- 29482474 TI - Potential Role of ADRA2A Genetic Variants in the Etiology of ADHD Comorbid With Tic Disorders. AB - OBJECTIVE: To evaluate the role of the adrenergic receptor alpha-2A gene ( ADRA2A) in the genetic etiology of ADHD comorbid with tic disorders (ADHD+TD). METHOD: Two single nucleotide polymorphisms (SNPs) of ADRA2A were genotyped and analyzed in 936 normal controls and 1,815 ADHD probands, including 1,249 trios. Approximately 16% of the ADHD probands also had a diagnosis of TD. RESULTS: No significant association was found between ADRA2A and ADHD in general. Case control analyses indicated different allelic and genotypic distributions of rs553668 between ADHD+TD and controls in males. Family-based association tests showed that the G allele of rs1800544, the A allele of rs553668, and the GA haplotype consisting of these two SNPs were overtransmitted in the ADHD+TD trios, especially in males. Moreover, the allelic/genotypic distribution and allelic transmission were different between ADHD+TD and ADHD without TD. CONCLUSION: ADRA2A may be associated with ADHD+TD, especially in males. PMID- 29482475 TI - Are Parent- and Teacher-Reported Executive Function Difficulties Associated With Parenting Stress for Children Diagnosed With ADHD? AB - OBJECTIVE: To examine the relationship between parenting stress and parent- and teacher-reported executive function difficulties (EFDs) for childhood ADHD. METHOD: A secondary analysis using linear regression was conducted on parent- and teacher-completed Behavior Rating Inventory of Executive Function and Parenting Stress Indexes for 5- to 12-year-olds ( n = 243) with ADHD. RESULTS: The linear combination of teacher- and parent-reported EFDs accounted for 49% of the variance in child-related parenting stress. Teacher-reported school-based EFDs were relatively inconsequential, having accounted for only 3% of this variance. This stress is best explained by EFDs with emotional control in the school environment and parent-reported EFDs with emotional control, inhibit, monitor, and shift. CONCLUSION: Parent-reported EFDs, and less so school-based EFDs, are related to parenting stress, but only in regard to EFDs likely underpinning behavioral outbursts and those likely underpinning the daily hassles of providing specialized care to children with ADHD. PMID- 29482476 TI - Correlation between mast cell-mediated allergic inflammation and length of perfluorinated compounds. AB - Perfluorinated compounds (PFC) have widely been used in numerous applications including clothing, food packaging, and nonstick coating. With the widespread use of PFC, concerns regarding potential adverse health effects in humans and wildlife have increased. In spite of the known PFC-mediated immunotoxiciy, correlation with PFC and allergic inflammation still requires elucidation. The aim of this study was to examine the effect of four types of PFC (perfluoroheptanoic acid [PFHpA], perfluorononanoic acid [PFNA], perfluorodecanoic acid [PFDA], and perfluoroundecanoic acid [PFUnA]) on mast cell mediated allergic inflammation in the presence of high-affinity immunoglobulin (Ig) E receptor (FcepsilonRI) cross-linking. Among PFC family, long-chain PFDA and PFUnA increased release of histamine and beta-hexosaminidase by up-regulation of intracellular calcium levels in IgE-stimulated mast cells. In addition, PFDA and PFUnA enhanced gene expression of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and IL-8 by activation of nuclear factor-kappaB in IgE-stimulated mast cells. In ovalbumin (OVA)-induced model of systemic anaphylaxis in the presence of hypothermia, PFNA, PFDA, and PFUnA exacerbated allergic symptoms accompanied by elevation in serum histamine, TNF-alpha, IgE, and IgG1. Our data indicate that some PFC aggravated high affinity IgE receptor (FcepsilonRI)-mediated mast cell degranulation and allergic symptoms. Consequently, the results demonstrated that carbon-chain length of PFC may serve as a factor in allergic inflammation. PMID- 29482477 TI - Mothers' Ideal Positive Affect Predicts their Socialization of Children's Positive Affect. AB - Parents generally want their children to be happy, but little is known about particular types of positive affect (PA) that parents want their children to experience. Tsai's (2007) affect valuation theory offers a useful framework to understand how parents' emotional goals may shape the socialization of particular types of PA (e.g., excitement vs. relaxation). Participants were 96 mothers and their 7- to 12-year-old children. Results indicated that mothers endorsed similar levels of ideal PA (IPA) for low-, moderate-, and high-arousal PA for both themselves and for their child, suggesting that mothers desire the same type of PA for their children as they want for themselves. In support of the study's main hypothesis, mothers' IPA for their children predicted specific socialization responses that would encourage that type of PA (e.g., mothers' high-arousal IPA predicted greater encouragement of their child to celebrate, whereas mothers' low arousal IPA predicted encouragement of affection). The findings extend affect valuation theory and emotion socialization research by indicating that parents' emotional goals (i.e., IPA) for their children may contribute to their socialization of children's PA. PMID- 29482478 TI - Novel mutation (R192C) in CYB5R3 gene causing NADH-cytochrome b5 reductase deficiency in eight Indian patients associated with autosomal recessive congenital methemoglobinemia type-I. AB - OBJECTIVE: To investigate the cause of recessive congenital methemoglobinemia (RCM) in Indian families and to identify molecular defect associated with RCM. METHODS: Eight cases of RCM have been addressed to our laboratory in order to investigate the cause of cyanosis associated with genetic disorders. NADH cytochrome b5 reductase (cytb5r) enzyme activities were measured by standard methods, and molecular analysis was performed by polymerase chain reaction (PCR) followed by DNA sequencing. The interpretation of mutation effect and the molecular modeling were performed by using specific software DEEP VIEW SWISS-PDB VIEWER and Pymol molecular graphics program. RESULTS AND DISCUSSION: Eight index cases from four unrelated families were referred for the cause of cyanosis. All patients showed mild to moderate cyanosis without mental retardation or any neurologic abnormalities. The methemoglobin levels were in the range of 11.5 22.41% with 50-70% reduction in CYTB5R activity. Spectroscopic analysis of the hemolysate showed normal peaks suggesting the absence of Hb-M. Molecular characterization showed a novel homozygous mutation p.Arg192Cys in CYB5R3 gene is an evolutionarily conserved position located in exon 7 in all eight index cases. The substitution of Cys is located on the interface of two domains of NADH binding domain and is close proximity to the adenosine moiety would preclude the reciprocal ionic interaction (salt bridge) between Arg192 and Ile97 and may influence binding of the NADH coenzyme is hypothesized to cause disruption of hydrogen bonding and instability. Our study indicated that novel homozygous mutation p.Arg192Cys in CYB5R3 gene present in eight cases and the possibility of high prevalence of heterozygous in Indian population causing Type I RCM. PMID- 29482479 TI - Molecular phylogeny of Neodevriesia, with two new species and several new combinations. AB - To identify Cladosporium-like isolates associated with marine algae, phylogenetic analyses were conducted using a combined data set of the nuc rDNA internal transcribed spacer (ITS) region (ITS1-5.8S-ITS2 = ITS), 28S gene, and partial RNA polymerase II second largest subunit (RPB2). These isolates were confirmed as belonging to Neodevriesia (Neodevriesiaceae), a genus recently segregated from Cladosporium. Two new species, Neodevriesia cladophorae and N. grateloupiae, are described on the basis of morphological and phylogenetic distinctions, and this is the first report of Neodevriesia species from the marine environment. Devriesia fici, D. fraserae, and D. sardiniae are transferred to Neodevriesia based on the phylogenetic affinities and morphological characters of their ex type specimens. PMID- 29482481 TI - Intradermal injections of a hair growth factor formulation for enhancement of human hair regrowth - safety and efficacy evaluation in a first-in-man pilot clinical study. AB - BACKGROUND: Research has shown the efficacy of hair growth factors in hair regrowth. We describe the intradermal injections of a recombinant, bioengineered hair formulation, containing growth factors, into the scalp skin, for enhancement of hair regrowth and evaluate its efficacy. OBJECTIVES: The objective of this study was to assess the efficacy and safety of the hair growth factor formulation in reducing hair loss and enhancing hair growth. MATERIALS AND METHODS: This was an open-label, prospective, single-arm interventional pilot study in which 1000 patients were given intradermal injections of a hair formulation into the scalp skin. The formulation contains vascular endothelial growth factor, basic fibroblast growth factor, insulin-like growth factor, keratinocyte growth factor, thymosin beta4, and copper tripeptide-1 suspended in a sterile injectable vehicle. Intradermal injections of this hair formulation were injected into the scalp once every 3 weeks for a total of eight such sessions. Hair pull test was performed before every session. Videomicroscopic and global images were taken at baseline, fourth session, eighth session, and 2 months after the completion of the eight sessions. Relevant safety assessments through physical examination, questionnaires, and appropriate laboratory examination were conducted throughout the study. RESULTS: Significant reduction in hair fall was seen in 83% of the patients on hair pull test. Videomicroscopic image evaluation showed that most patients had a decrease in the number of vellus hairs, increase in number of terminal hairs, and increase in shaft diameter. Seventy-five percent of the patients believed that the hair injections were aiding the treatment of their hair loss, and it was also beneficial in post-hair transplant patients. At 1 year, a statistically significant increase in total hair count (P = 0.002) continued to be seen. Treatment was well tolerated. CONCLUSIONS: Intradermal injections of this hair formulation may be a promising option for treating male as well as female patterns of hair loss. PMID- 29482482 TI - Factors associated with early career progression in professional Australian Football players. AB - This study examined the association between individual and team characteristics and the probability of being offered a second contract in professional Australian Football. Contract status was obtained from the AFL for players who were drafted in the AFL National Draft between 1999 and 2013 (n = 999). Individual player characteristics were retrieved from the AFL while variables relating to performance were accessed online via Champion Data(r). A binary logistic regression examined the influence of each characteristic on the probability of a professional Australian Football player receiving a second contract. Receiver operating characteristic (ROC) curves and the associated AUC were used to assess the discriminant ability of both a training (n = 938) and test data set (n = 61). The characteristics that influenced the probability of receiving a second contract included first year debut (pr 0.606), draft order (pr - 0.126), draft year (pr 0.059), games played (pr 1.848), team state (pr 0.458), rising star nomination (pr 1.553) and team ladder position (pr -0.043) (chi2 (8) = 198.28, p < 0.001). The ROC curve demonstrated an AUC of 82.4% (training) and 76.0% (test). A combination of individual and team based characteristics are associated with early career progression in professional Australian Football. PMID- 29482480 TI - Struggling with one's own parenting after an upbringing with substance abusing parents. AB - AIM: To add to our knowledge concerning the key elements involved in the individual's experience of growing up with substance abusing parents and the resulting challenges this involved for their own parenthood. METHODS: In-depth interviews were conducted with 19 parents who had participated in a mental health intervention programme. All had experienced substance abusing parents in their family of origin. Qualitative content analysis was used to analyse the data. They also completed a self-report questionnaire assessing their attachment style. RESULT: Participants reported a high incidence of emotional abuse and neglect coupled with inadequate support from the community. Their own parental role was influenced by high parental stress and a majority had an insecure attachment style. CONCLUSIONS: All participants had experienced a very difficult childhood which was reinforced by the fact that they received little support from society. Their childhood experience and the resulting challenges that this created in their own parenting role could negatively influence their own children's ability to form a secure psychosocial development. It is therefore important to develop instruments that can help to identify children who were raised in misuse families in order to accommodate the transgenerational effects of growing up with substance abusing parents. PMID- 29482483 TI - Assessment of Postural Ergonomics and Surgical Performance in Laparoendoscopic Single-Site Surgery Using a Handheld Robotic Device. AB - PURPOSE: New laparoscopic devices are being continuously developed to overcome some of the technical and ergonomic limitations of laparoendoscopic single-site (LESS) surgery. This study aims to assess the surgeon's surgical performance and ergonomics during the use of a handheld, robotic-driven, articulating laparoscopic instrument during LESS surgery. METHODS: Seven right-handed experienced surgeons took part in this study. A set of basic suturing tasks and digestive and urological procedures in a porcine model were performed. Surgeons used both a conventional laparoscopic needle holder and a robotic device. The learning curve, execution time, and precision using the surgical needle were assessed. The surgeon's posture was analyzed using a motion tracking system and a data glove. RESULTS: After the training period, execution time on the intracorporeal suturing was significantly shorter using the conventional needle holder. The precision was higher using the conventional instrument in the horizontal plane, but the number of attempts to position the needle was lower using the robotic device (1.625 +/- 0.250 vs 1.188 +/- 0.375 attempts). The extension of the elbow (134.681 +/- 14.35 degrees vs 120.631 +/- 13.134 degrees ) and the flexion of the shoulder (26.122 +/- 7.411 degrees vs 18.475 +/- 14.166 degrees ) were significantly lower using the robotic instrument. The wrist posture using the robotic device was ergonomically acceptable during both surgical procedures. CONCLUSIONS: Results show a positive learning curve in ergonomics and surgical performance using the robotic instrument during LESS surgery. This instrument improves the surgeon's body posture and the needle positioning errors. The use of the robotic instrument is feasible and safe during LESS partial nephrectomy and sigmoidectomy procedures. PMID- 29482484 TI - The evaluation of radio-sensitivity of mung bean proteins aqueous extract on MCF 7, hela and fibroblast cell line. AB - PURPOSE: Breast cancer is one of the most common malignant tumors in women all over the world. Many of these women resist the common treatments. Therefore, it is important to find new products to increase the efficacy of the treatment process. Legume beans, with their various pharmacological properties, can be regarded as a sensitizer when they are combined with radiation. The present study strove to survey the radio-sensitivity effect of proteins isolated from mung bean aqueous extract on the human breast adenocarcinoma cell line (MCF-7), human cervical cancer cells (Hela) and the human dermal fibroblast cell line. MATERIALS AND METHODS: The mung bean aqueous extract was partially purified by ammonium sulfate. At first, various concentrations of the extracts were used to evaluate the inhibitory activity by MTT cell proliferation assay. RESULTS: The results showed that MCF-7 cells and Hela cells were inhibited by an IC50 value of less than 250 and 411 ug/ml, respectively, but it proved to have a proliferation effect on the fibroblast cells. Then, the cells were incubated with 250 ug/ml extract and exposed to 2, 4, and 6 Gy of X-ray radiation. The percentage of the cell survival was investigated through MTT and the clonogenic assay. Apoptosis was measured using acridine orange/ethidium bromide staining. The results demonstrated that the treated MCF-7 cells and Hela cells had significant radio sensitivity compared with the results of the control group in radiation dose manner in all MTT, clonogenic, and apoptosis assays. In contrast, the treated fibroblast showed a protective effect against radiation. CONCLUSION: The results suggest that mung bean proteins have the capacity to be regarded as a radio sensitizer for breast cancer. Our results also indicated that it could be worth to investigate on mung bean proteins further and they should be tested in animal models for being treated in radiotherapy. PMID- 29482485 TI - An Institution-Wide Algorithm for Treatment of Type II Endoleak Following Endovascular Aneurysm Repair (EVAR). AB - OBJECTIVES: Multiple endovascular techniques have been described for the treatment of persistent type II endoleaks (pT2ELs) causing aneurysm sac growth following endovascular aneurysm repair (EVAR). In the event of a failed endovascular procedure and a pT2EL, a consensus regarding further treatment is lacking, and the literature suggests repeated endovascular attempts are rarely successful. Herein, we propose an algorithm for definitive management of pT2ELs with persistent sac growth following EVAR. METHODS: A retrospective review of 29 patients who underwent treatment of persistent sac growth in the setting of pT2ELs was performed. Intervention methods were determined at the discretion of the operating surgeon. Aneurysmal sac enlargement was defined as a diameter increase > 5 mm, and persistent endoleak was defined as lasting greater than 6 months. RESULTS: From 2000 to 2015, 917 EVAR procedures were performed at our institution. Isolated pT2ELs with sac enlargement were identified in 29 patients. Twenty-five patients underwent direct translumbar sac puncture and coiling and/or Onyx (Onyx, Plymouth, Minnesota) embolization of the culprit vessels. Thirteen (52%) of 25 patients had pT2EL after first endovascular intervention, and 10 (40%) of 25 patients failed 2 endovascular treatments. Of those 10, 7 displayed persistent aneurysmal sac growth and underwent a third embolization procedure. Type II endoleaks persisted in 6 patients; 3 patients were subsequently treated with laparotomy, ligation of lumbar vessels, sac exploration, and sac plication around the endograft. Technical success for this technique was 100%. During a mean follow-up of 38.4 months, no recurrent T2ELs, stent graft migration, and/or disjunction were observed. CONCLUSIONS: We propose a new algorithm for the management of pT2ELs. If 2 endovascular procedures fail to control of the endoleak, repeat endovascular attempts are not recommended. Endovascular failure should be followed by laparotomy with surgical ligation of culprit feeding vessels followed by sac exploration and plication of the sac, and endoaneurysmorrhaphy. PMID- 29482486 TI - Endovascular Management of Ureteroarterial Fistula: Single Institution Experience and Systematic Literature Review. AB - BACKGROUND: Ureteroarterial fistula (UAF) represents an uncommon complication after urological surgery; however, this is a well-documented condition in patients with predisposing risk factors. The aim of the present study is to report and analyze the endovascular management of a series of patients with UAF, treated in authors' hospital, and to report and analyze the same data concerning patients retrieved from a systematic literature review. METHODS: Authors conducted a retrospective analysis of prospectively collected data and a systematic literature review. The research was carried out through PubMed database searching the following keywords: "uretero arterial fistula" and "uretero iliac fistula." It includes only articles reporting the endovascular management. RESULTS: Forty-six articles were included in the present study for a total of 94 patients. Risk factors were as follows: chronic indwelling ureteral stents, pelvic surgery, radiotherapy, iliac artery pseudo-aneurysm, and chemotherapy. All patients had gross hematuria at presentation. Stent graft placement was performed in 89 patients, embolization in 5 patients, and iliac internal artery embolization combined with stent graft placement was performed in 24 patients. Four postprocedural complications were observed (4.2%). During a median follow-up of 8 months, 10 complications related to UAF were observed (10.6%): rebleeding (7 cases) and stent thrombosis (3 cases). Two patients died for causes related to UAF (2.1%): rebleeding (1) and retroperitoneal abscess (1). CONCLUSION: Based on the present data, endovascular treatment is feasible and safe with low postprocedural complications and mortality rate. Considering the increase in surgery and radiotherapy performed, UAF should be always debated in patients with massive hematuria. PMID- 29482488 TI - Expression of concern. PMID- 29482487 TI - Two-Wire Technique With a Gooseneck Snare to Bail Out the Tip Separation of a Crosser Catheter. AB - Tip separation of a Crosser catheter is a serious complication; however, there is limited information on bailout methods. Here, we describe a case of successful retrieval of the separated tip of a Crosser catheter using a 2-wire technique with a gooseneck snare. A 76-year-old woman with a history of hemodialysis and diabetes mellitus who developed ulcers on her right toes was diagnosed as having critical limb ischemia and underwent transfemoral antegrade endovascular treatment of the anterior tibial artery (ATA). A 0.014-inch guidewire was passed through the ATA chronic total occlusion, and then a Crosser catheter was advanced along the wire. During catheter withdrawal, the tip completely detached from the shaft and remained in the ATA. We passed another 0.014-inch guidewire into the distal ATA through the small space beside the tip. A gooseneck snare catheter was advanced to the distal side of the tip along the new wire, and subsequently the 2 wires were entrapped by the snare. The detached tip was finally retrieved with the entire system as a unit and successfully withdrawn into the guiding sheath with no complications. Interventionists should be familiar with the bailout method of this unfavorable complication. Our technique may be widely adapted for various situations involving this complication. PMID- 29482489 TI - Implicit Cognitions as a Behavioral Marker of Suicide Attempts in Adolescents. AB - Using self-harm Implicit Association Tests (IATs), we sought to test whether (1) suicidal adolescents show implicit identification with self-harm and whether (2) IATs are reliable and sensitive to psychiatric change and (3) predict future suicide attempts. We administered 6 self-harm IATs to 71 adolescents from a psychiatric inpatient unit and assessed suicidal behaviors at admission, discharge and 3 months after discharge. Results were in the expected direction for each IAT but not statistically significant. After aggregating trials across IATs, suicide attempters showed increased implicit identification with self-harm, compared with non-suicidal controls. IATs showed good reliability and sensitivity to psychiatric change but did not prospectively predict suicide attempts. Adolescent suicide attempters may have stronger implicit associations with self harm than non-suicidal controls. PMID- 29482490 TI - Editor's Introduction. PMID- 29482491 TI - Hispanic Hospice Patients' Experiences of End-Stage Restlessness. AB - End-stage restlessness, or terminal agitation, is experienced by some patients during their final days and is characterized by physical, emotional, or spiritual distress, agitation or anxiety. End-stage restlessness negatively affects the patient's death experience and can be distressing to the family and care team. Using the 2007 National Home and Hospice Care survey, this study examined factors associated with experiencing end-stage restlessness among non-Hispanic white and Hispanic hospice patients deceased at time of discharge. Results showed that being Hispanic/Latino, experiencing dyspnea, pain, and receiving palliative sedation treatment were risk factors for experiencing end-stage restlessness. The association between pain and restlessness was stronger for Hispanics compared with non-Hispanic whites. The Hispanic population remains underrepresented and little is known about the patient-centered experiences of Hispanic hospice users. Findings indicated that dying Hispanic patients continue to experience pain and other negative symptoms, even when hospice care is in place. Thus, it is important that social workers provide education to interdisciplinary team members about culturally competent practices, and advocate for a patient-centered approach to care. PMID- 29482492 TI - Designing instrumented walker to measure upper-extremity's efforts: A case study. AB - The high prevalence of shoulder pain in using walkers in patients who have spinal cord injury (SCI). Also, the limited options available to economically measure grip forces in walkers, which drove the need to create one. This article describes a method to obtain upper-extremities' forces and moments in a person with SCI by designing an appropriate instrumented walker. First, since the commercial multidirectional loadcells are too expensive, custom loadcells are fabricated. Ultimately, a complete gait analysis by means of VICON motion analysis and using inverse dynamic method has been held to measure upper extremities' efforts. The results for a person with SCI using a two-wheel walker in low and high heights and a basic walker show that there are higher shoulder and elbow flexion-extension moments and also higher shoulder forces in superior inferior direction and higher elbow and wrist forces in anterior-posterior directions. The results are not much different in using two different types of walker. By using the proposed method, upper-extremities' forces and moments were obtained and the results were compared to each other in using two different walkers. PMID- 29482493 TI - The Action Level. PMID- 29482495 TI - The feasibility of using actigraphy to characterize sleep in Rett syndrome. AB - BACKGROUND: Rett syndrome (RTT) is a neurodevelopmental disorder primarily caused by mutations in the MECP2 gene. Sleep problems are reported by the majority of caregivers of individuals with RTT. METHODS: The present study aimed to replicate and extend previous work about the feasibility of measuring sleep with an actigraph device in a sample of girls with clinically diagnosed RTT (N = 13, mean age = 9 years, 5 months). Participants wore an actigraph device day and night for seven consecutive days. Materials also included a parent-completed sleep diary to measure bedtime, duration of nighttime sleep, and daytime sleep, and the Child Sleep Habit's Questionnaire (CSHQ). RESULTS: The means for the sample as measured by actigraphy were 492.3 min (SD = 47.3) of total night sleep (TNS), 76.0% (SD = 6.7) sleep efficiency, 86.0 min (SD = 34.2) of wake after sleep onset, and 46.1 min (50.8) of sleep when parents reported a nap occurring. Parents reported 589.7 min (SD = 53.6) of TNS, 15.9 min (SD = 12.0) of WASO, and 93.6 min (SD = 66.8) of daytime sleep according to sleep diaries, with all parents reporting at least one nap during the week. Relations were found between sleep characteristics and seizure status and CSHQ total scores. No age-related changes were observed for any sleep characteristic, regardless of collection method. Five of nine participants above the cutoff score on the CSHQ indicate the need for further evaluation for a sleep disorder. CONCLUSIONS: Overall, actigraphy was feasible in this community-based sample of girls with RTT. The results replicated some aspects of previous studies of sleep in RTT (e.g., no age-related changes in total nighttime sleep or efficiency). Some participants met the American Academy of Sleep Medicine guidelines for recommended total sleep time, with others showing too much or too little sleep. Each of the three methods for describing sleep presented its own advantages and challenges. Future work should be prospectively designed, validate the use of actigraphy in this population, and include a typically developing comparison sample to improve the precision of our understanding of sleep in RTT. PMID- 29482494 TI - NoLogo: a new statistical model highlights the diversity and suggests new classes of Crm1-dependent nuclear export signals. AB - BACKGROUND: Crm1-dependent Nuclear Export Signals (NESs) are clusters of alternating hydrophobic and non-hydrophobic amino acid residues between 10 to 15 amino acids in length. NESs were largely thought to follow simple consensus patterns, based on which they were categorized into 6-10 classes. However, newly discovered NESs often deviate from the established consensus patterns. Thus, identifying NESs within protein sequences remains a bioinformatics challenge. RESULTS: We describe a probabilistic representation of NESs using a new generative model we call NoLogo that can account for a large diversity of NESs. Using this model to predict NESs, we demonstrate improved performance over PSSM and GLAM2 models, but do not achieve the performance of the state-of-the-art NES predictor LocNES. Our findings illustrate that over 30% of NESs are best described by novel NES classes rather than the 6-10 classes proposed by current/existing models. Finally, many NESs have additional hydrophobic residues either upstream or downstream of the canonical four residues, suggesting possible functionality. CONCLUSION: Applying the NoLogo model highlights the observation that NESs are more diverse than previously appreciated. Our work questions the practice of assigning each NES to one of several predefined NES classes. Finally, our analysis suggests a novel and testable biophysical perspective on interaction between Crm1 receptor and Crm1-dependent NESs. PMID- 29482496 TI - Microvessel prediction in H&E Stained Pathology Images using fully convolutional neural networks. AB - BACKGROUND: Pathological angiogenesis has been identified in many malignancies as a potential prognostic factor and target for therapy. In most cases, angiogenic analysis is based on the measurement of microvessel density (MVD) detected by immunostaining of CD31 or CD34. However, most retrievable public data is generally composed of Hematoxylin and Eosin (H&E)-stained pathology images, for which is difficult to get the corresponding immunohistochemistry images. The role of microvessels in H&E stained images has not been widely studied due to their complexity and heterogeneity. Furthermore, identifying microvessels manually for study is a labor-intensive task for pathologists, with high inter- and intra observer variation. Therefore, it is important to develop automated microvessel detection algorithms in H&E stained pathology images for clinical association analysis. RESULTS: In this paper, we propose a microvessel prediction method using fully convolutional neural networks. The feasibility of our proposed algorithm is demonstrated through experimental results on H&E stained images. Furthermore, the identified microvessel features were significantly associated with the patient clinical outcomes. CONCLUSIONS: This is the first study to develop an algorithm for automated microvessel detection in H&E stained pathology images. PMID- 29482497 TI - Uteroglobin and FLRG concentrations in aqueous humor are associated with age in primary open angle glaucoma patients. AB - BACKGROUND: The pathophysiological changes occurring in the trabecular meshwork in primary open angle glaucoma are poorly understood, but are thought to include increased extracellular matrix deposition, trabecular meshwork cell apoptosis, inflammation, trabecular meshwork calcification and altered protein composition of the aqueous humor. Although many proteins are present in aqueous humor, relatively few have been studied extensively, and their potential roles in primary open angle glaucoma are unknown. METHODS: Analyte concentrations in aqueous humor from 19 primary open angle glaucoma and 18 cataract patients were measured using a multiplex immunoassay. Fisher's exact test was used to assess statistical significance between groups, and correlations of analyte concentrations with age, intraocular pressure, pattern standard deviation, mean deviation, cup-to-disc ratio and disease duration since commencing treatment were tested by Spearman's method. RESULTS: CHI3L1, FLRG, HGF, MIF, P-selectin and Uteroglobin were detected in more than 50% of samples of one or both patient groups, some of which have not previously been quantified in aqueous humor. In the glaucoma but not the cataract group, significant correlations were determined with age for Uteroglobin/SCGB1A1 (rs = 0.805, p < 0.0001) and FLRG (rs = 0.706, p = 0.0007). Furthermore, HGF correlated significantly with disease duration (rs = 0.723, p = 0.0007). There were no differences in analyte concentrations between groups, and no other significant associations with clinical descriptors that passed correction for multiple testing. CONCLUSIONS: The correlations of uteroglobin and FLRG with age in primary open angle glaucoma but not cataract may suggest a heightened requirement for anti-inflammatory (uteroglobin) or anti calcification (FLRG) activity in the ageing glaucomatous trabecular meshwork. PMID- 29482498 TI - High-level cytoplasmic claudin 3 expression is an independent predictor of poor survival in triple-negative breast cancer. AB - BACKGROUND: The subtype of claudin-low breast cancer can be reliably determined only by gene-expression profiling. Attempts have been made to develop immunohistochemical surrogates, which nearly always focus on membranous claudin expression. METHODS: We assessed the immunohistochemical expression of both membranous and cytoplasmic claudins 3, 4 and 7 in a series of 197 non-metastatic breast cancers, enriched with triple-negative breast cancers (TNBCs; 60%). The expression of epithelial-to-mesenchymal transition-regulating transcription factors Sip1, Zeb1 and vimentin had previously been determined in the same material. RESULTS: In multivariate analysis, strong cytoplasmic claudin 3 expression was associated with poor relapse-free survival (RFS), disease-free survival, distant disease-free survival, breast cancer-specific survival and overall survival among TNBC patients (for RFS, RR 5.202, 95% CI 1.210-22.369, p = 0.027, vs. T-class, RR 0.663, 95% CI 0.168-2.623, p = 0.558, and N-class, RR 3.940, 95% CI 0.933-16.631, p = 0.062). Cytoplasmic claudin 3 expression was also associated with strong nuclear Sip1 expression (p = 0.000053), TNBC phenotype (p = 0.012) and within them, non-basal-like phenotype (p = 0.026). Cytoplasmic claudin 7 was associated with dismal RFS (RR 6.328, 95% CI 1.401-28.593, p = 0.016, vs. T-class, RR 0.692, 95% CI 0.242-1.982, p = 0.493, and N-class, RR 2.981, 95% CI 1.1016-8.749, p = 0.047). Low cytoplasmic expression of claudins 3, 4 and 7 together also predicted poor RFS (RR 6.070, 95% CI 1.347-27.363, p = 0.019, vs. T-class, RR 0.677, 95% CI 0.237-1.934, p = 0.467, and N-class, RR 3.167, 95% CI 1.079-9.290, p = 0.036). CONCLUSIONS: Immunohistochemical expression levels of cytoplasmic claudins 3 and 7 appear to be novel prognostic factors in TNBC. PMID- 29482499 TI - Genomic epidemiology and population structure of Neisseria gonorrhoeae from remote highly endemic Western Australian populations. AB - BACKGROUND: Neisseria gonorrhoeae causes gonorrhoea, the second most commonly notified sexually transmitted infection in Australia. One of the highest notification rates of gonorrhoea is found in the remote regions of Western Australia (WA). Unlike isolates from the major Australian population centres, the remote community isolates have low rates of antimicrobial resistance (AMR). Population structure and whole-genome comparison of 59 isolates from the Western Australian N. gonorrhoeae collection were used to investigate relatedness of isolates cultured in the metropolitan and remote areas. Core genome phylogeny, multilocus sequencing typing (MLST), N. gonorrhoeae multi-antigen sequence typing (NG-MAST) and N. gonorrhoeae sequence typing for antimicrobial resistance (NG STAR) in addition to hierarchical clustering of sequences were used to characterize the isolates. RESULTS: Population structure analysis of the 59 isolates together with 72 isolates from an international collection, revealed six population groups suggesting that N. gonorrhoeae is a weakly clonal species. Two distinct population groups, Aus1 and Aus2, represented 63% of WA isolates and were mostly composed of the remote community isolates that carried no chromosomal AMR genotypes. In contrast, the Western Australian metropolitan isolates were frequently multi-drug resistant and belonged to population groups found in the international database, suggesting international transmission of the isolates. CONCLUSIONS: Our study suggests that the population structure of N. gonorrhoeae is distinct between the communities in remote and metropolitan WA. Given the high rate of AMR in metropolitan regions, ongoing surveillance is essential to ensure the enduring efficacy of the empiric gonorrhoea treatment in remote WA. PMID- 29482500 TI - Evaluation of HIV-1 rapid tests and identification of alternative testing algorithms for use in Uganda. AB - INTRODUCTION: The World Health Organization recommends that countries conduct two phase evaluations of HIV rapid tests (RTs) in order to come up with the best algorithms. In this report, we present the first ever such evaluation in Uganda, involving both blood and oral based RTs. The role of weak positive (WP) bands on the accuracy of the individual RT and on the algorithms was also investigated. METHODS: In total 11 blood based and 3 oral transudate kits were evaluated. All together 2746 participants from seven sites, covering the four different regions of Uganda participated. Two enzyme immunoassays (EIAs) run in parallel were used as the gold standard. The performance and cost of the different algorithms was calculated, with a pre-determined price cut-off of either cheaper or within 20% price of the current algorithm of Determine + Statpak + Unigold. In the second phase, the three best algorithms selected in phase I were used at the point of care for purposes of quality control using finger stick whole blood. RESULTS: We identified three algorithms; Determine + SD Bioline + Statpak; Determine + Statpak + SD Bioline, both with the same sensitivity and specificity of 99.2% and 99.1% respectively and Determine + Statpak + Insti, with sensitivity and specificity of 99.1% and 99% respectively as having performed better and met the cost requirements. There were 15 other algorithms that performed better than the current one but rated more than the 20% price. None of the 3 oral mucosal transudate kits were suitable for inclusion in an algorithm because of their low sensitivities. Band intensity affected the performance of individual RTs but not the final algorithms. CONCLUSION: We have come up with three algorithms we recommend for public or Government procurement based on accuracy and cost. In case one algorithm is preferred, we recommend to replace Unigold, the current tie breaker with SD Bioline. We further recommend that all the 18 algorithms that have shown better performance than the current one are made available to the private sector where cost may not be a limiting factor. PMID- 29482501 TI - Development of macular retinoschisis long after the onset of retinal arterial occlusion (RAO): a retrospective study. AB - BACKGROUND: To describe a retrospective study of macular retinoschisis that developed long after the onset of retinal artery occlusion (RAO) using optical coherence tomography (OCT). METHODS: We describe changes in macular findings and visual acuity (VA) of 29 patients (21 males and 8 females, mean age: 66.1 +/- 16.9 years) with RAO (18 branch RAOs [BRAOs] and 11 central RAOs [CRAOs] who visited Osaka Medical College Hospital over an 8-year period based on a medical chart review. RESULTS: The mean VA (logMAR) increased from 1.06 +/- 1.08 (CRAO: 2.04 +/- 0.99; BRAO: 0.37 +/- 0.40) at the first visit to 0.71 +/- 0.87 (CRAO: 1.46 +/- 0.86; BRAO: 0.18 +/- 0.30) at the final visit. Macular OCT revealed swelling or hyper-reflectivity of the inner retina in the early phase of RAO and retinal thinning in the late phase. Among the 29 patients, two patients (a patient with BRAO and a patient with CRAO) developed macular retinoschisis about 1 year after RAO onset. The VA of the patient with BRAO was 20/300 at the first visit, and it improved to 20/25 two days after onset following eye massage and anterior chamber paracentesis. However, his VA worsened, declining from 20/25 to 20/50, and retinoschisis occurred 13 months after RAO onset. The patient with CRAO showed macular changes including small cystoids at the first follow-up visit more than 3 weeks after onset and developed retinoschisis 11 months after the first visit. In addition, two patients with BRAO and one patient with CRAO developed macular changes including small cystoids 3 weeks after onset, with the BRAO complicated by retinal vein occlusion. In the CRAO patient, the cystoid macular edema was resolved 1 month after the first visit. CONCLUSIONS: Macular retinoschisis is unusual, but a possible complication of RAO that can develop long after the onset of the occlusion, potentially resulting in renewed VA deterioration. PMID- 29482502 TI - Prevalence of chronic kidney disease and comorbidities in isolated African descent communities (PREVRENAL): methodological design of a cohort study. AB - BACKGROUND: Chronic kidney disease (CKD) is considered a serious public health problem, both in Brazil and worldwide, with an increasing number of cases observed inrecent years. Especially, CKD has been reported to be highly prevalent in those of African descent. However, Brazil lacks data from early-stage CKD population studies, and the prevalence of CKD is unknown for both the overall and African descent populations. Hence, the present study aimsto estimate the prevalence of early-stage CKD and its associated risk factors in African Brazilians from isolated African-descent communities. Herein, the detailed methodology design of the study is described. METHODS: This population-based, prospective, longitudinal, cohort study (PREVRENAL) is performed in three stages: first, clinical, nutritional, and anthropometric evaluations; measurements of serum and urinary markers; and examinations of comorbiditieswere performed. Second, repeated examinations of individuals with CKD, systemic arterial hypertension, and/or diabetes mellitus; image screening; and cardiac risk assessment were performed. Third, long-term monitoring of all selected individuals will be conducted (ongoing). Using probability sampling, 1539 individuals from 32 communities were selected. CKD was defined asaglomerular filtration rate (GFR) <=60 mL/min/1.73m2 and albuminuria > 30 mg/day. DISCUSSION: This study proposes to identify and monitor individuals with and without reduced GFR and high albuminuria in isolated populations of African descendants in Brazil. As there are currently no specific recommendations for detecting CKD in African descendants, four equations for estimating the GFR based on serum creatinine and cystatin C were used and will be retrospectively compared. The present report describes the characteristics of the target population, selection of individuals, and detection of a population at risk, along with the imaging, clinical, and laboratory methodologies used. The first and second stages have been concluded and the results will be published in the near future. The subsequent (third) stage is the long-term, continuous monitoring of individuals diagnosed with renal abnormalities or with CKD risk factors. The entire study population will be re-evaluated five years after the study initiation. The expectation is to obtain information about CKD evolution among this population, including the progression rate, complication development, and cardiovascular events. PMID- 29482503 TI - Microenvironment dependent gene expression signatures in reprogrammed human colon normal and cancer cell lines. AB - BACKGROUND: Since the first evidence suggesting existence of stem-like cancer cells, the process of cells reprogramming to the stem cell state remains as an attractive tool for cancer stemness research. Current knowledge in the field of cancer stemness, indicates that the microenvironment is a fundamental regulator of cell behavior. With regard to this, we investigated the changes of genome wide gene expression in reprogrammed human colon normal epithelial CRL-1831 and colon carcinoma DLD1 cell lines grown under more physiologically relevant three dimensional (3D) cell culture microenvironment compared to 2D monolayer. METHODS: Whole genome gene expression changes were evaluated in both cell lines cultured under 3D conditions over a 2D monolayer by gene expression microarray analysis. To evaluate the biological significance of gene expression changes, we performed pathway enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Gene network analysis was used to study relationships between differentially expressed genes (DEGs) in functional categories by the GeneMANIA Cytoscape toolkit. RESULTS: In total, we identified 3228 and 2654 differentially expressed genes (DEGs) for colon normal and cancer reprogrammed cell lines, respectively. Furthermore, the expression of 1097 genes was commonly regulated in both cell lines. KEGG enrichment analysis revealed that in total 129 and 101 pathways for iPSC-CRL-1831 and for CSC-DLD1, respectively, were enriched. Next, we grouped these pathways into three functional categories: cancer transformation/metastasis, cell interaction, and stemness. beta-catenin (CTNNB1) was confirmed as a hub gene of all three functional categories. CONCLUSIONS: Our present findings suggest common pathways between reprogrammed human colon normal epithelium (iPSC-CRL-1831) and adenocarcinoma (CSC-DLD1) cells grown under 3D microenvironment. In addition, we demonstrated that pathways important for cancer transformation and tumor metastatic activity are altered both in normal and cancer stem-like cells during the transfer from 2D to 3D culture conditions. Thus, we indicate the potential of cell culture models enriched in normal and cancer stem-like cells for the identification of new therapeutic targets in cancer treatment. PMID- 29482504 TI - Porphyromonas gingivalis ATCC 33277 promotes intercellular adhesion molecule-1 expression in endothelial cells and monocyte-endothelial cell adhesion through macrophage migration inhibitory factor. AB - BACKGROUND: Porphyromonas gingivalis (P. gingivalis), one of the main pathogenic bacteria involved in periodontitis, induces the expression of intercellular adhesion molecule - 1 (ICAM-1) and monocyte-endothelial cell adhesion. This effect plays a pivotal role in atherosclerosis development. Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine and critically affects atherosclerosis pathogenesis. In this study, we tested the involvement of MIF in the P. gingivalis ATCC 33277-enhanced adhesive properties of endothelial cells. RESULTS: Endothelial MIF expression was enhanced by P. gingivalis ATCC 33277 infection. The MIF inhibitor ISO-1 inhibited ICAM-1 production in endothelial cells, and monocyte-endothelial cell adhesion was induced by P. gingivalis ATCC 33277 infection. However, the addition of exogenous human recombinant MIF to P. gingivalis ATCC 33277-infected endothelial cells facilitated monocyte recruitment by promoting ICAM-1 expression in endothelial cells. CONCLUSIONS: These experiments revealed that MIF in endothelial cells participates in the pro atherosclerotic lesion formation caused by P. gingivalis ATCC 33277 infection. Our novel findings identify a more detailed pathological role of P. gingivalis ATCC 33277 in atherosclerosis. PMID- 29482505 TI - Laparotomy in women with severe acute maternal morbidity: secondary analysis of a nationwide cohort study. AB - BACKGROUND: Although pregnancy-related laparotomy is a major intervention, literature is limited to small case-control or single center studies. We aimed to identify national incidence rates for postpartum laparotomy related to severe acute maternal morbidity (SAMM) in a high-income country and test the hypothesis that risk of postpartum laparotomy differs by mode of birth. METHODS: In a population-based cohort study in all 98 hospitals with a maternity unit in the Netherlands, pregnant women with SAMM according to specified disease and management criteria were included from 01/08/2004 to 01/08/2006. We calculated the incidence of postpartum laparotomy after vaginal and cesarean births. Laparotomies were analyzed in relation to mode of birth using all births in the country as reference. Relative risks (RR) were calculated for laparotomy following emergency and planned cesarean section compared to vaginal birth, excluding laparotomies following births before 24 weeks' gestation and hysterectomies performed during cesarean section. RESULTS: The incidence of postpartum laparotomy in women with SAMM in the Netherlands was 6.0 per 10,000 births. Incidence was 30.1 and 1.8 per 10,000 following cesarean and vaginal birth respectively. Compared to vaginal birth, RR of laparotomy after cesarean birth was 16.7 (95% confidence interval [95% CI] 12.2-22.6). RR was 21.8 (95% CI 15.8-30.2) for emergency and 10.5 (95% CI 7.1-15.6) for planned cesarean section. CONCLUSIONS: Risk of laparotomy, although small, was considerably elevated in women who gave birth by cesarean section. This should be considered in counseling and clinical decision making. PMID- 29482506 TI - Effect of the sequence data deluge on the performance of methods for detecting protein functional residues. AB - BACKGROUND: The exponential accumulation of new sequences in public databases is expected to improve the performance of all the approaches for predicting protein structural and functional features. Nevertheless, this was never assessed or quantified for some widely used methodologies, such as those aimed at detecting functional sites and functional subfamilies in protein multiple sequence alignments. Using raw protein sequences as only input, these approaches can detect fully conserved positions, as well as those with a family-dependent conservation pattern. Both types of residues are routinely used as predictors of functional sites and, consequently, understanding how the sequence content of the databases affects them is relevant and timely. RESULTS: In this work we evaluate how the growth and change with time in the content of sequence databases affect five sequence-based approaches for detecting functional sites and subfamilies. We do that by recreating historical versions of the multiple sequence alignments that would have been obtained in the past based on the database contents at different time points, covering a period of 20 years. Applying the methods to these historical alignments allows quantifying the temporal variation in their performance. Our results show that the number of families to which these methods can be applied sharply increases with time, while their ability to detect potentially functional residues remains almost constant. CONCLUSIONS: These results are informative for the methods' developers and final users, and may have implications in the design of new sequencing initiatives. PMID- 29482507 TI - Consequences of continuing renin angiotensin aldosterone system antagonists in the preoperative period: a systematic review and meta-analysis. AB - BACKGROUND: Patients who use angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs) are prone to developing side effects like hypotension and even refractory hypotension during anesthesia use, and whether ACEIs/ARBs should be continued or discontinued in such patients remains debatable. The present systematic review and meta-analysis was conducted to clarify the consequences of continuing or withholding these drugs, especially with regards to the incidence of intraoperative hypotension, in patients who continue to use ACEIs/ARBs on the day of their scheduled surgery. METHODS: Studies with data pertinent to the incidence of intraoperative hypotension during anesthesia use in patients who continued the use of ACEIs/ARBs on the day of their scheduled surgery were considered for inclusion. RESULTS: Thirteen studies reporting on the incidences of intraoperative hypotension between patients who continued receiving ACEIs/ARBs and those who did not on the day of their surgical procedure were included. The pooled effects showed that hypotension during anesthesia was more likely to develop in patients who continued to take ACEIs/ARBs when compared to those who did not (RR = 1.41, 95% CI: 1.21-1.64). However, there were no significant differences between these groups of patients with regards to postoperative complications including ST-T abnormalities, myocardial injury, myocardial infarction, stroke, major adverse cardiac events, acute kidney injury, or death (RR = 1.25, 95% CI: 0.76-2.04). The differences remained similar in subgroup analyses and sensitivity analyses. CONCLUSIONS: No sufficient available evidence to recommend discontinuing ACEIs/ARBs on the day of surgery was found in this literature review and meta-analysis. However, anesthetists should be cautious about the risk for intraoperative hypotension in patients chronically receiving ACEIs/ARBs, and should know how to treat it effectively. PMID- 29482508 TI - Difficult diagnosis and genetic analysis of fibrodysplasia ossificans progressiva: a case report. AB - BACKGROUND: Fibrodysplasia ossificans progressiva (FOP), an ultra-rare and disabling genetic disorder of skeletal malformations and progressive heterotopic ossification, is caused by heterozygous activating mutations in activin A receptor, type I/activin-like kinase 2 (ACVR1/ALK2). The rarity of the disease makes it common to make a misdiagnosis and cause mismanagement. CASE PRESENTATION: We reported a case of a sixteen-year-old male patient who had suffered from pain and swelling in the biopsy site for two months. His physical examination presented serious stiffness and multiple bony masses in the body, with his bilateral halluces characterized by hallux valgus deformity and macrodactyly. Imaging examinations showed widespread heterotopic ossification. All laboratory blood tests were normal except for the one on alkaline phosphatase. A de novo heterozygous mutation (c.617G > A; p.R206H) were found in the ACVR1/ALK2 using gene sequencing. CONCLUSION: Even though FOP is a rare disorder of genetic origin, which is generally misdiagnosed, the genetic analysis could provide definitive confirmation of the disease. Awareness of such an important approach can help clinicians to avoid the commonly practiced misdiagnosis and mismanagement of the rare disease. PMID- 29482510 TI - P66Shc expression in diabetic rat retina. AB - BACKGROUND: P66Shc is partially localised within the mitochondrial fraction. It is primarily related to the generation of mitochondrial reactive oxygen species and apoptosis. Based on previous studies, we hypothesize that in the retina, p66Shc may exist and affect the development of diabetic retinopathy. The purpose of this study was to investigate p66Shc expression in retinal in streptozotocin induced diabetic (SD) rats, which may provide a pathway to study the pathogenesis of diabetic retinopathy. METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) and western blot were used to detect retinal p66Shc mRNA and protein expression in SD rats, respectively. Immunohistochemical staining was applied to detect the location of rat retinal p66Shc expression. TUNEL assay was applied to detect the number of apoptotic cells. RESULTS: P66Shc expression was found in the retina of normal and diabetic rats, and the level of mRNA and protein expression increased with the progression of diabetes mellitus (DM). P66Shc expression was mainly located in the retinal ganglion cell layer and inner nuclear layer. Compared with the normal group, retinal cell tissue apoptosis rate in the D12w group was significantly increased. CONCLUSION: Rat retinal p66Shc expression was mainly in the ganglion cell layer and inner nuclear layer. As the degree of DM progressed, p66Shc expression gradually increased, and the number of apoptotic cells also increased. PMID- 29482509 TI - How well do general practitioners know their elderly patients' social relations and feelings of loneliness? AB - BACKGROUND: Social relationships are important to people and affect their quality of life, morbidity and mortality. The aim of this study was to examine the correlation between elderly patients' descriptions of their social relations and feelings of loneliness, and their general practitioners' assessments of these. METHODS: Cross-sectional study in 12 general practices in the Capital Region of Denmark. During a three-week period each practice asked their patients aged 65 and older to fill out a questionnaire regarding health, social relations and loneliness; the general practitioner (GP) filled out a matching questionnaire regarding their perception of the patient's social relations and loneliness. Data were collected from February to September 2014. RESULTS: Of the 767 eligible patients 476 were included in the study. For 447 patients both GP and patient had answered at least one question on loneliness or social participation. The correlations between patients' and GPs' answers regarding social participation and loneliness were low (0.04-0.26). While GPs were less able to identify lonely patients and patients with low social participation, they were better at identifying not-lonely patients or those with high social participation. It was especially difficult for GPs to identify lonely patients when they were not living alone or if the GP believed the patient had high social participation. CONCLUSION: GPs have difficulty identifying patients who are lonely or have low social participation and this ability is further diminished when the patients do not live alone or if the GP believes them to have high social participation. Given the consequences of loneliness and limited social participation on patients' health and well-being, and GPs' limited ability to identify these patients, GPs' obligations and resources in this area need to be clarified. PMID- 29482511 TI - Increased urinary excretion of kynurenic acid is associated with non-recovery from acute kidney injury in critically ill patients. AB - BACKGROUND: Acute kidney injury (AKI) is often observed in critically ill patients and is associated with high morbidity and mortality. Non-recovery from AKI has a negative impact on the prognosis of affected patients and early risk stratification seems key to improve clinical outcomes. We analyzed metabolites of a conserved key inflammatory pathway (i.e. tryptophan degradation pathway) in serial urine samples of patients with AKI. METHODS: One hundred twelve ICU patients with AKI were included in a prospective observational analysis. After exclusion criteria, 92 patients were eligible for analysis. Serial urine samples were collected and tryptophan levels including key tryptophan metabolites were measured using tandem mass spectrometry. RESULTS: Sixty-seven patients recovered in the first 7 days of AKI (early recovery, ER) whereas n = 25 had late-/non recovery (LNR). Urinary concentrations of tryptophan, kynurenine, 3-OH anthranillic acid, serotonine, and kynurenine/tryptophan were significantly lower in LNR patients. In contrast, creatinine normalized excretion of kynurenic acid (KynA) was substantially increased in LNR patients (7.59 +/- 6.81 vs. 3.19 +/- 3.44 (ER) MUmol/mmol, p < 0.005). High urinary KynA excretion was associated with higher RIFLE class, longer AKI duration, increased need for RRT, and 30-day mortality. Logistic regression revealed KynA as the single most important predictor of renal recovery on days 1 and 2 of AKI. CONCLUSIONS: Increased urinary levels of kynurenic acid, a key inflammatory metabolite of the tryprophan degradation pathway, are associated with adverse renal and clinical outcomes in critically ill patients with AKI. Urinary KynA may serve as an early risk stratificator in respective patients with AKI. PMID- 29482513 TI - Risk of chronic kidney disease in young adults with impaired glucose tolerance/impaired fasting glucose: a retrospective cohort study using electronic primary care records. AB - BACKGROUND: The risk of chronic kidney disease (CKD) is known to be elevated in patients with diabetes mellitus but the risk of young adults aged 18 to 40 years with impaired glucose tolerance/impaired fasting glucose (IGT/IFG) developing CKD is not well characterised. Furthermore, progression of IGT/IFG to diabetes and subsequent CKD development is not well understood. METHODS: A retrospective cohort study was undertaken using The Health Improvement Network (THIN) database, a large dataset of electronic patient records. THIN database is jointly managed by IMS Health Real World Evidence Solution ( http://www.epic-uk.org/index.html ) and In Practice System (InPs). Cases were aged 18 to 40, with a diagnosis of IGT/IFG and registered at a practice contributing to THIN between 2000 and 2015. The study population consisted of 40,092 patients, including 21,454 (53.5%) female and 18,638 (46.5%) male. The median follow-up was approximately 2 years. The outcome was a diagnosis of CKD determined from either clinical coding or laboratory results. For the primary analysis the unadjusted and adjusted relative risk of CKD in IGT/IFG was compared to age, sex and practice matched controls with normoglycaemia. For the secondary analysis we compared the incidence of CKD before to after a diagnosis of type 2 diabetes (T2DM) in the IGT/IFG study cohort. RESULTS: The Incidence Rate Ratio (IRR) for CKD for IGT/IFG compared to normoglycaemia was 4.0 [95% confidence interval (CI), 3.2 to 5.1, P < 0.001]. The adjusted IRR was 2.6 [95% CI, 2.0 to 3.4, P < 0.001]. The unadjusted IRR was 8.8 [95% CI, 7.7 to 10.0, P < 0.001] after IGT/IFG patients had developed T2DM and the adjusted IRR was 6.3 [95% CI, 5.5 to 7.2, P < 0.001]. CONCLUSION: Our results show that young IGT/IFG subjects are also at higher risk of developing CKD. This risk is modulated by the degree of baseline renal function and glucose tolerance, being higher in those developing T2DM. PMID- 29482512 TI - Exploring the arthritogenicity of Streptococcus dysgalactiae subspecies equisimilis. AB - BACKGROUND: During the past decades, Streptococcus dysgalactiae subspecies equisimilis (SDSE) has been increasingly recognized as an important human pathogen. Osteoarticular infections is one of the predominant disease manifestations of SDSE, but the pathogenetic rationale for its arthritogenicity has yet to be unravelled. We aimed to explore if the rising incidence of osteoarticular infections caused by this pathogen in our region emanated from clonal expansion of strains with enhanced tropism for bone and joint tissue components or orthopaedic implants. RESULTS: Twenty-nine SDSE-isolates associated with osteoarticular infections were retrospectively identified. Their genomic content and affinity for fibronectin, collagen and stainless steel were compared to 24 temporally and geographically matched SDSE blood culture isolates obtained from patients without bone or joint infections. Despite a thorough genetic and phenotypic dissection, neither the presence or absence of any single gene, nor the binding abilities of the SDSE isolates, were predictive of clinical entity. SNP analysis revealed a heterogenous population, and a correlation between phylogenetic relationships and disease manifestation was not evident. However, we identified a strong concordance between phenotypic binding abilities and genetic variations in the pilus-region, also denoted as the FCT-region (Fibronectin binding, Collagen binding and T-antigen). This observation could be related to the ample and varied repertoire of putative adhesins residing within this region, including proteins predicted to adhere to fibronectin and collagen, as well as fibrinogen. CONCLUSIONS: SDSE strains associated with osteoarticular infections do not emanate from subpopulation characterized by distinct genetic or phenotypic traits. The genetic architecture of the pilus region was predictive of the adhesive properties of the SDSE-isolates, but its role in tissue tropism needs further investigation. To the best of our knowledge, this is the first comprehensive characterization of the genetic landscape of the SDSE pilus region. PMID- 29482514 TI - Expansion of phenotypic spectrum of MYO15A pathogenic variants to include postlingual onset of progressive partial deafness. AB - BACKGROUND: MYO15A variants, except those in the N-terminal domain, have been shown to be associated with congenital or pre-lingual severe-to-profound hearing loss (DFNB3), which ultimately requires cochlear implantation in early childhood. Recently, such variants have also been shown to possibly cause moderate-to-severe hearing loss. Herein, we also demonstrate that some MYO15A mutant alleles can cause postlingual onset of progressive partial deafness. METHODS: Two multiplex Korean families (SB246 and SB224), manifesting postlingual, progressive, partial deafness in an autosomal recessive fashion, were recruited. Molecular genetics testing was performed in two different pipelines, in a parallel fashion, for the SB246 family: targeted exome sequencing (TES) of 129 known deafness genes from the proband and whole exome sequencing (WES) of all affected subjects. Only the former pipeline was performed for the SB224 family. Rigorous bioinformatics analyses encompassing structural variations were executed to investigate any causative variants. RESULTS: In the SB246 family, two different molecular diagnostic pipelines provided exactly the same candidate variants: c.5504G > A (p.R1835H) in the motor domain and c.10245_10247delCTC (p.S3417del) in the FERM domain of MYO15A. In the SB224 family, c.9790C > T (p.Q3264X) and c.10263C > G (p.I3421M) in the FERM domain were detected as candidate variants. CONCLUSIONS: Some recessive MYO15A variants can cause postlingual onset of progressive partial deafness. The phenotypic spectrum of DFNB3 should be extended to include such partial deafness. The mechanism for a milder phenotype could be due to the milder pathogenic potential from hypomorphic alleles of MYO15A or the presence of modifier genes. This merits further investigation. PMID- 29482515 TI - DecoFungi: a web application for automatic characterisation of dye decolorisation in fungal strains. AB - BACKGROUND: Fungi have diverse biotechnological applications in, among others, agriculture, bioenergy generation, or remediation of polluted soil and water. In this context, culture media based on color change in response to degradation of dyes are particularly relevant; but measuring dye decolorisation of fungal strains mainly relies on a visual and semiquantitative classification of color intensity changes. Such a classification is a subjective, time-consuming and difficult to reproduce process. RESULTS: DecoFungi is the first, at least up to the best of our knowledge, application to automatically characterise dye decolorisation level of fungal strains from images of inoculated plates. In order to deal with this task, DecoFungi employs a deep-learning model, accessible through a user-friendly web interface, with an accuracy of 96.5%. CONCLUSIONS: DecoFungi is an easy to use system for characterising dye decolorisation level of fungal strains from images of inoculated plates. PMID- 29482517 TI - DeepSurv: personalized treatment recommender system using a Cox proportional hazards deep neural network. AB - BACKGROUND: Medical practitioners use survival models to explore and understand the relationships between patients' covariates (e.g. clinical and genetic features) and the effectiveness of various treatment options. Standard survival models like the linear Cox proportional hazards model require extensive feature engineering or prior medical knowledge to model treatment interaction at an individual level. While nonlinear survival methods, such as neural networks and survival forests, can inherently model these high-level interaction terms, they have yet to be shown as effective treatment recommender systems. METHODS: We introduce DeepSurv, a Cox proportional hazards deep neural network and state-of the-art survival method for modeling interactions between a patient's covariates and treatment effectiveness in order to provide personalized treatment recommendations. RESULTS: We perform a number of experiments training DeepSurv on simulated and real survival data. We demonstrate that DeepSurv performs as well as or better than other state-of-the-art survival models and validate that DeepSurv successfully models increasingly complex relationships between a patient's covariates and their risk of failure. We then show how DeepSurv models the relationship between a patient's features and effectiveness of different treatment options to show how DeepSurv can be used to provide individual treatment recommendations. Finally, we train DeepSurv on real clinical studies to demonstrate how it's personalized treatment recommendations would increase the survival time of a set of patients. CONCLUSIONS: The predictive and modeling capabilities of DeepSurv will enable medical researchers to use deep neural networks as a tool in their exploration, understanding, and prediction of the effects of a patient's characteristics on their risk of failure. PMID- 29482518 TI - Identification of novel KMT2D mutations in two Chinese children with Kabuki syndrome: a case report and systematic literature review. AB - BACKGROUND: Kabuki syndrome (KS) is a rare pediatric congenital disorder with multiple congenital anomalies and intellectual disabilities, which is inherited in an autosomal dominant manner. Mutations in KMT2D and KDM6A have been proven to be the primary cause in most cases of KS. CASE PRESENTATION: Here we report two Chinese boys with clinical features of KS referred to our hospital for clinical diagnosis. Next-generation sequencing was performed on MiSeq to analyze the genetic mutations in both patients. In both, two novel de novo mutations in KMT2D gene (c.5235delA, p.(A1746Lfs*39) and c.7048G > A, p.(Q2350*)) were detected, both of which were subsequently confirmed by the two-generation pedigree analysis based on Sanger sequencing. A systematic literature review of previously reported mutational spectrum of KMT2D was also conducted. CONCLUSIONS: Two novel de novo mutations in KMT2D gene were identified and considered to be pathogenic in both of KS patients. Our data adds information to the growing knowledge on the mutational spectrum of KS. PMID- 29482516 TI - Effectiveness of an educational group intervention in primary healthcare for continued exclusive breast-feeding: PROLACT study. AB - BACKGROUND: The World Health Organization leads a global strategy to promote the initiation and maintenance of breast-feeding. Existing literature shows that education and supportive interventions, both for breast-feeding mothers as well as for healthcare professionals, can increase the proportion of women that use exclusive breast-feeding, however, more evidence is needed on the effectiveness of group interventions. METHODS: This study involves a community-based cluster randomised trial conducted at Primary Healthcare Centres in the Community of Madrid (Spain). The project aims to evaluate the effectiveness of an educational group intervention performed by primary healthcare professionals in increasing the proportion of mother-infant pairs using exclusive breastfeeding at six months compared to routine practice. The number of patients required will be 432 (216 in each arm). All mother-infant pairs using exclusive breastfeeding that seek care or information at healthcare centres will be included, as long as the infant is not older than four weeks, and the mother has used exclusive breastfeeding in the last 24 h and who gives consent to participate. The main response variable is mother-infant pairs using exclusive breast-feeding at six months. Main effectiveness will be analysed by comparing the proportion of mother-infant pairs using exclusive breast-feeding at six months between the intervention group and the control group. All statistical tests will be performed with intention-to treat. The estimation will be adjusted using an explanatory logistic regression model. A survival analysis will be used to compare the two groups using the log rank test to assess the effect of the intervention on the duration of breastfeeding. The control of potential confounding variables will be performed through the construction of Cox regression models. DISCUSSION: We must implement strategies with scientific evidence to improve the percentage of exclusive breast feeding at six months in our environment as established by the WHO. Group education is an instrument used by professionals in Primary Care that favours the acquisition of skills and modification of already-acquired behaviour, all making it a potential method of choice to improve rates of exclusive breast-feeding in this period. TRIAL REGISTRATION: The trial was registered with ClinicalTrials.gov under code number NCT01869920 (Date of registration: June 3, 2013). PMID- 29482519 TI - Gap junctions contribute to anchorage-independent clustering of breast cancer cells. AB - BACKGROUND: Cancer cell aggregation is a key process involved in the formation of clusters of circulating tumor cells. We previously reported that cell-cell adhesion proteins, such as E-cadherin, and desmosomal proteins are involved in cell aggregation to form clusters independently of cell migration or matrix adhesion. Here, we investigated the involvement of gap junction intercellular communication (GJIC) during anchorage-independent clustering of MCF7 breast adenocarcinoma cells. METHODS: We used live cell image acquisition and analysis to monitor the kinetics of MCF7 cell clustering in the presence/absence of GJIC pharmacological inhibitors and to screen a LOPAC(r) bioactive compound library. We also used a calcein transfer assay and flow cytometry to evaluate GJIC involvement in cancer cell clustering. RESULTS: We first demonstrated that functional GJIC are established in the early phase of cancer cell aggregation. We then showed that pharmacological inhibition of GJIC using tonabersat and meclofenamate delayed MCF7 cell clustering and reduced calcein transfer. We also found that brefeldin A, an inhibitor of vesicular trafficking, which we identified by screening a small compound library, and latrunculin A, an actin cytoskeleton-disrupting agent, both impaired MCF7 cell clustering and calcein transfer. CONCLUSIONS: Our results demonstrate that GJIC are involved from the earliest stages of anchorage-independent cancer cell aggregation. They also give insights into the regulatory mechanisms that could modulate the formation of clusters of circulating tumor cells. PMID- 29482520 TI - Extraocular muscle repositioning as the last therapeutic option for a patient with a severe course of Graves' Ophthalmopathy: a case report. AB - BACKGROUND: Graves' disease is a common autoimmune inflammatory condition of the thyroid. About one in four of affected patients also develop orbital symptoms like exophthalmos, proptosis and diplopia - called Graves' Ophthalmopathy. Not all patients respond well to the standard therapy of systemic glucocorticoid administration. The inflammatory swelling of the intraorbital muscles can lead to pressure-induced damage of the optic nerve. Orbital decompression surgery is a therapeutic option for these patients with varying success. Other symptoms like the extreme malposition of the ocular globe are poorly addressed by decompression surgery and demand for different therapeutic approaches. CASE PRESENTATION: Presented is the case of a 46-year old patient with an acute exacerbation of Graves' ophthalmopathy. Clinically apparent was a convergent strabismus fixus with severe hypotropia of both eyes. The patient suffered from attacks of heavy retrobulbar pain and eyesight deteriorated dramatically. Since neither systemic glucocorticoid therapy nor orbital decompression surgery had helped to halt the progress of the disease, a decision was made in favour of the surgical release and repositioning of the inferior and medial rectus muscle as a final therapeutic option. Surgery of both eyes was performed consecutively within one week. Detailed descriptions and illustrations of the surgical steps and treatment outcome are provided supplemented by a discussion of the current literature. CONCLUSIONS: Graves' Ophthalmopathy is a variant and therapeutically challenging disease. Exceptional courses of the disease call for therapeutic approaches off the beaten track. Surgical extraocular muscle repositioning, which has not been described before in the context of Graves' Ophthalmopathy, proved to be effective in improving the patient's eyesight and quality of life. Furthermore, we regard the measurement of extraocular muscle volume as a valuable method to monitor the course of Graves' Ophthalmopathy. PMID- 29482521 TI - Distinct fermentation and antibiotic sensitivity profiles exist in salmonellae of canine and human origin. AB - BACKGROUND: Salmonella enterica is a recognised cause of diarrhoea in dogs and humans, yet the potential for transfer of salmonellosis between dogs and their owners is unclear, with reported evidence both for and against Salmonella as a zoonotic pathogen. A collection of 174 S. enterica isolates from clinical infections in humans and dogs were analysed for serotype distribution, carbon source utilisation, chemical and antimicrobial sensitivity profiles. The aim of the study was to understand the degree of conservation in phenotypic characteristics of isolates across host species. RESULTS: Serovar distribution across human and canine isolates demonstrated nine serovars common to both host species, 24 serovars present in only the canine collection and 39 solely represented within the human collection. Significant differences in carbon source utilisation profiles and ampicillin, amoxicillin and chloramphenicol sensitivity profiles were detected in isolates of human and canine origin. Differences between the human and canine Salmonella collections were suggestive of evolutionary separation, with canine isolates better able to utilise several simple sugars than their human counterparts. Generally higher minimum inhibitory concentrations of three broad-spectrum antimicrobials, commonly used in veterinary medicine, were also observed in canine S. enterica isolates. CONCLUSIONS: Differential carbon source utilisation and antimicrobial sensitivity profiles in pathogenic Salmonella isolated from humans and dogs are suggestive of distinct reservoirs of infection for these hosts. Although these findings do not preclude zoonotic or anthroponotic potential in salmonellae, the separation of carbon utilisation and antibiotic profiles with isolate source is indicative that infectious isolates are not part of a common reservoir shared frequently between these host species. PMID- 29482522 TI - Distinct core promoter codes drive transcription initiation at key developmental transitions in a marine chordate. AB - BACKGROUND: Development is largely driven by transitions between transcriptional programs. The initiation of transcription at appropriate sites in the genome is a key component of this and yet few rules governing selection are known. Here, we used cap analysis of gene expression (CAGE) to generate bp-resolution maps of transcription start sites (TSSs) across the genome of Oikopleura dioica, a member of the closest living relatives to vertebrates. RESULTS: Our TSS maps revealed promoter features in common with vertebrates, as well as striking differences, and uncovered key roles for core promoter elements in the regulation of development. During spermatogenesis there is a genome-wide shift in mode of transcription initiation characterized by a novel core promoter element. This element was associated with > 70% of male-specific transcription, including the use of cryptic internal promoters within operons. In many cases this led to the exclusion of trans-splice sites, revealing a novel mechanism for regulating which mRNAs receive the spliced leader. Binding of the cell cycle regulator, E2F1, is enriched at the TSS of maternal genes in endocycling nurse nuclei. In addition, maternal promoters lack the TATA-like element found in zebrafish and have broad, rather than sharp, architectures with ordered nucleosomes. Promoters of ribosomal protein genes lack the highly conserved TCT initiator. We also report an association between DNA methylation on transcribed gene bodies and the TATA-box. CONCLUSIONS: Our results reveal that distinct functional promoter classes and overlapping promoter codes are present in protochordates like in vertebrates, but show extraordinary lineage-specific innovations. Furthermore, we uncover a genome wide, developmental stage-specific shift in the mode of TSS selection. Our results provide a rich resource for the study of promoter structure and evolution in Metazoa. PMID- 29482523 TI - Predictors of cervical cancer screening intention of HIV-positive women in the central region of Ghana. AB - BACKGROUND: Cervical cancer affects women, especially those with HIV-positive status. This study hypothesised that more HIV-positive women with high cues about cervical cancer screening, high perceived susceptibility to cervical cancer, high perceived seriousness of cervical cancer, high perceived benefits of cervical cancer screening, and low perceived barriers about cervical cancer screening have intention to seek cervical cancer screening than HIV-positive women with low cues, low perceived susceptibility, low perceived seriousness, low perceived benefits, and high perceived barriers. METHODS: A descriptive cross-sectional study was conducted with 660 HIV-positive women aged 20 to 65 years using an interviewer administered questionnaire. Data were summarised using frequencies, percentages and binary logistic regression analysis. RESULTS: The findings showed that 82% (n = 540) of the respondents had intention to seek cervical cancer screening. The determinants of cervical cancer screening intention by HIV positive women were cues, perceived seriousness and perceived benefits. Specifically, HIV-positive women with high cues were 3.48 times more likely to have intention to screen than those with low cues (95% CI, 1.43-8.49). Those with high perceived seriousness were 2.02 times more likely to have intention to screen than those with low perceived seriousness (95% CI, 1.24-3.30). Similarly, those with high perceived benefits were 1.7 times more likely to have intention to screen than those with low perceived benefits (95% CI, 1.05-2.71). However, perceived susceptibility (p = 0.063, OR 2.57, [95% CI, 0.95-6.93]) and perceived barriers (p = 0.969, OR = 1.01, [95% CI, 0.54-1.88]) were not statistically significant predictors of intention to seek cervical cancer screening in the sample studied. CONCLUSIONS: Cervical cancer screening interventions for HIV positive women need to have a strong focus on explaining the seriousness of the disease, benefits of screening, and increase cues about screening, as these factors could improve attitude towards cervical cancer screening and promote the health of high risk women. PMID- 29482524 TI - Prevalence of chronic musculoskeletal conditions and associated factors in Brazilian adults - National Health Survey. AB - BACKGROUND: Chronic non-communicable diseases entail high impact on health systems in Brazil and worldwide. Among the most frequent are the musculoskeletal conditions which comprise a group of diseases that influence individuals' physical status, quality of life and functional capacity. Epidemiological studies investigating the scale of such conditions in the adult population are scarce in Brazil. This study estimates the prevalence of chronic musculoskeletal conditions and their association with demographic, socioeconomic, behavioural and clinical factors. METHODS: Cross-sectional study with data from Brazil's 2013 National Health Survey (Pesquisa Nacional de Saude), a nationwide household survey of 60,202 adults. Musculoskeletal conditions were specified by self-reported medical diagnosis of arthritis or rheumatism and self-reported spinal disorders. The variables were examined using a hierarchical model of determination. Prevalences of musculoskeletal conditions were calculated with their respective 95% confidence intervals for Brazil and its five regions. Prevalence ratios (PRs) were obtained by Poisson regression with robust variance. RESULTS: Of the 60,202 individuals evaluated, 21.6% presented musculoskeletal conditions, with higher prevalences for females, older adults, indigenous, those living with a partner, low education, no occupational activity, those living in the South Region of Brazil, in rural areas, daily smokers, sedentary, obese, those who did not drink alcohol, with depressive symptoms or suffering from three or more chronic diseases. Multivariate analysis identified strong associations with advanced age (PR = 3.61; 95% CI 3.27-3.98), depressive symptoms (PR = 1.69; 95% CI 1.57-1.81) and multimorbidity (PR = 1.94; 95% CI 1.77-2.12). CONCLUSIONS: The results show high prevalence of musculoskeletal conditions in Brazil's adult population. Considering the process of aging and steady growth in chronic diseases, this study underlines the need for health policies directed to prevention, treatment and rehabilitation for people affected by chronic musculoskeletal conditions. PMID- 29482526 TI - Development of the Japanese version of an information aid to provide accurate information on prognosis to patients with advanced non-small-cell lung cancer receiving chemotherapy: a pilot study. AB - BACKGROUND: Without explicit prognostic information, patients may overestimate their life expectancy and make poor choices at the end of life. We sought to design the Japanese version of an information aid (IA) to provide accurate information on prognosis to patients with advanced non-small-cell lung cancer (NSCLC) and to assess the effects of the IA on hope, psychosocial status, and perception of curability. METHODS: We developed the Japanese version of an IA, which provided information on survival and cure rates as well as numerical survival estimates for patients with metastatic NSCLC receiving first-line chemotherapy. We then assessed the pre- and post-intervention effects of the IA on hope, anxiety, and perception of curability and treatment benefits. RESULTS: A total of 20 (95%) of 21 patients (65% male; median age, 72 years) completed the IA pilot test. Based on the results, scores on the Distress and Impact Thermometer screening tool for adjustment disorders and major depression tended to decrease (from 4.5 to 2.5; P = 0.204), whereas no significant changes were seen in scores for anxiety on the Japanese version of the Support Team Assessment Schedule or in scores on the Hearth Hope Index (from 41.9 to 41.5; p = 0.204). The majority of the patients (16/20, 80%) had high expectations regarding the curative effects of chemotherapy. CONCLUSION: The Japanese version of the IA appeared to help patients with NSCLC maintain hope, and did not increase their anxiety when they were given explicit prognostic information; however, the IA did not appear to help such patients understand the goal of chemotherapy. Further research is needed to test the findings in a larger sample and measure the outcomes of explicit prognostic information on hope, psychological status, and perception of curability. PMID- 29482525 TI - Internet-based grief therapy for bereaved individuals after loss due to Haematological cancer: study protocol of a randomized controlled trial. AB - BACKGROUND: Approximately 10% of the individuals experiencing the death of a loved one develop prolonged grief disorder (PGD) after bereavement. Family members of haematological cancer patients might be particularly burdened since their loss experience is preceded by a very strenuous time of disease and aggressive treatment. However, support needs of relatives of cancer patients often remain unmet, also after the death of the patient. Therapeutic possibilities are enhanced by providing easily available and accessible Internet based therapies. This study will adapt and evaluate an Internet-based grief therapy for bereaved individuals after the loss of a significant other due to haematological cancer. METHODS: The efficacy of the Internet-based grief therapy is evaluated in a randomized controlled trial with a wait-list control group. Inclusion criteria are bereavement due to hematological cancer and meeting the diagnostic criteria for PGD. Exclusion criteria are severe depression, suicidality, dissociative tendency, psychosis, posttraumatic stress disorder, substance use disorder, and current psychotherapeutic or psychopharmacological treatment. The main outcome is PGD severity. Secondary outcomes are depression, anxiety, somatization, posttraumatic stress, quality of life, sleep quality, and posttraumatic growth. Data is collected pre- and posttreatment. Follow-up assessments will be conducted 3, 6, and 12 months after completion of the intervention. The Internet-based grief therapy is assumed to have at least moderate effects regarding PGD and other bereavement-related mental health outcomes. Predictors and moderators of the treatment outcome and PGD will be determined. DISCUSSION: Individuals bereaved due to haematological cancer are at high risk for psychological distress. Tailored treatment for this particularly burdened target group is missing. Our study results will contribute to a closing of this healthcare gap. TRIAL REGISTRATION: German Clinical Trial Register UTN: U1111-1186-6255 . Registered 1 December 2016. PMID- 29482527 TI - Effects of a work-based critical reflection program for novice nurses. AB - BACKGROUND: Critical reflection is effective in improving students' communication abilities and confidence. The aim of this study was to evaluate the effectiveness of a work-based critical reflection program to enhance novice nurses' clinical critical-thinking abilities, communication competency, and job performance. METHODS: The present study used a quasi-experimental design. From October 2014 to August 2015, we collected data from 44 novice nurses working in an advanced general hospital in S city in Korea. Nurses in the experimental group participated in a critical reflection program for six months. Outcome variables were clinical critical-thinking skills, communication abilities, and job performance. A non-parametric Mann-Whitney U-test and a Wilcoxon rank sum test were selected to evaluate differences in mean ranks and to assess the null hypothesis that the medians were equal across the groups. RESULTS: The results showed that the clinical critical-thinking skills of those in the experimental group improved significantly (p = 0.003). The differences in mean ranks of communication ability between two groups was significantly statistically different (p = 0.028). Job performance improved significantly in both the experimental group and the control group, so there was no statistical difference (p = 0.294). CONCLUSIONS: We therefore suggest that a critical reflection program be considered an essential tool for improving critical thinking and communication abilities among novice nurses who need to adapt to the clinical environment as quickly as possible. Further, we suggest conducting research into critical reflection programs among larger and more diverse samples. PMID- 29482528 TI - Comparison of glycemic control and beta-cell function in new onset T2DM patients with PCOS of metformin and saxagliptin monotherapy or combination treatment. AB - BACKGROUND: Impaired insulin activity in women with polycystic ovary syndrome might differ from that seen in type 2 diabetes mellitus without polycystic ovary syndrome. This study was designed to compare the effects of treatment with metformin, saxagliptin, and their combination in newly diagnosed women with type 2 diabetes mellitus and polycystic ovary syndrome in China. METHODS: A total of 75 newly diagnosed patients from Shanghai, China with type 2 diabetes mellitus and polycystic ovary syndrome were included in this randomized, parallel, open label study. All patients received treatment for 24 weeks with metformin, saxagliptin, or their combination. Patients were allocated to one of three treatment groups by a computer-generated code that facilitated equal patient distribution of 25 patients per group. The primary outcome was a change in glycemic control and beta-cell function. RESULTS: A total of 63 patients completed the study (n = 21, for each group). The reduction in hemoglobin A1c was significant in the combination group, compared to the monotherapy groups (saxagliptin vs. combination treatment vs. metformin: - 1.1 vs. -1.3 vs. -1.1%, P = 0.016), whereas it was comparable between the metformin and saxagliptin groups (P > 0.05). Saxagliptin, metformin, and the combination treatment significantly reduced the homeostasis model assessment- insulin resistance index and increased the deposition index (P < 0.01 for all). However, no significant change was observed in the homeostasis model assessment- beta-cell function among the metformin and combination groups, and no significant changes were observed in the insulinogenic index among all three groups (P > 0.05 for all). In addition, saxagliptin and metformin treatments significantly reduced body mass index and high-sensitivity C-reactive protein levels (P < 0.01 for both). CONCLUSIONS: Saxagliptin and metformin were comparably effective in regulating weight loss, glycemic control, and beta-cell function, improving lipid profiles, and reducing inflammation in newly diagnosed type 2 diabetes mellitus patients with polycystic ovary syndrome. TRIAL REGISTRATION: ChiCTR-IPR-17011120 (retrospectively registered on 2017-04-12). PMID- 29482529 TI - Competing priorities that rival health in adults on probation in Rhode Island: substance use recovery, employment, housing, and food intake. AB - BACKGROUND: Individuals on probation experience economic disadvantage because their criminal records often prohibit gainful employment, which compromises their ability to access the basic components of wellbeing. Unemployment and underemployment have been studied as distinct phenomenon but no research has examined multiple determinants of health in aggregate or explored how these individuals prioritize each of these factors. This study identified and ranked competing priorities in adults on probation and qualitatively explored how these priorities impact health. METHODS: We conducted in-depth interviews in 2016 with 22 adults on probation in Rhode Island to determine priority rankings of basic needs. We used Maslow's hierarchy of needs theory and the literature to guide the priorities we pre-selected for probationers to rank. Within a thematic analysis framework, we used a modified ranking approach to identify the priorities chosen by participants and explored themes related to the top four ranked priorities. RESULTS: We found that probationers ranked substance use recovery, employment, housing, and food intake as the top four priorities. Probationers in recovery reported sobriety as the most important issue, a necessary basis to be able to address other aspects of life. Participants also articulated the interrelatedness of difficulties in securing employment, food, and housing; these represent stressors for themselves and their families, which negatively impact health. Participants ranked healthcare last and many reported underinsurance as an issue to accessing care. CONCLUSIONS: Adults on probation are often faced with limited economic potential and support systems that consistently place them in high-risk environments with increased risk for recidivism. These findings emphasize the need for policies that address the barriers to securing gainful employment and safe housing. Interventions that reflect probationer priorities are necessary to begin to mitigate the health disparities in this population. PMID- 29482530 TI - Deficiency of the BMP Type I receptor ALK3 partly protects mice from anemia of inflammation. AB - BACKGROUND: Inflammatory stimuli induce the hepatic iron regulatory hormone hepcidin, which contributes to anaemia of inflammation (AI). Hepcidin expression is regulated by the bone morphogenetic protein (BMP) and the interleukin-6 (IL-6) signalling pathways. Prior results indicate that the BMP type I receptor ALK3 is mainly involved in the acute inflammatory hepcidin induction four and 72 h after IL-6 administration. In this study, the role of ALK3 in a chronic model of inflammation was investigated. The intact, heat-killed bacterium Brucella abortus (BA) was used to analyse its effect on the development of inflammation and hypoferremia in mice with hepatocyte-specific Alk3-deficiency (Alk3fl/fl; Alb Cre) compared to control (Alk3fl/fl) mice. RESULTS: An iron restricted diet prevented development of the iron overload phenotype in mice with hepatocyte specific Alk3 deficiency. Regular diet leads to iron overload and increased haemoglobin levels in these mice, which protects from the development of AI per se. Fourteen days after BA injection Alk3fl/fl; Alb-Cre mice presented milder anaemia (Hb 16.7 g/dl to 11.6 g/dl) compared to Alk3fl/fl control mice (Hb 14.9 g/dl to 8.6 g/dl). BA injection led to an intact inflammatory response in all groups of mice. In Alk3fl/fl; Alb-Cre mice, SMAD1/5/8 phosphorylation was reduced after BA as well as after infection with Staphylococcus aureus. The reduction of the SMAD1/5/8 signalling pathway due to hepatocyte-specific Alk3 deficiency partly suppressed the induction of STAT3 signalling. CONCLUSION: The results reveal in vivo, that 1) hepatocyte-specific Alk3 deficiency partly protects from AI, 2) the development of hypoferremia is partly dependent on ALK3, and 3) the ALK3/BMP/hepcidin axis may serve as a possible therapeutic target to attenuate AI. PMID- 29482531 TI - A qualitative investigation of healthcare workers' strategies in response to readmissions. AB - BACKGROUND: Readmission of a patient to a hospital is typically associated with significant clinical changes in the patient's condition, but it is unknown how healthcare workers modify their provision of care when considering these changes. The purpose of the present study was to determine how healthcare workers shift their care strategies when treating readmitted patients. METHODS: A typical case sampling study of healthcare workers was conducted using the grounded theory approach. The study setting comprised several patient care units at an academic center and tertiary-care hospital. We purposively sampled 34 healthcare workers (19 women, 15 men) to participate in individual interviews, either face-to-face or by telephone. We asked the participants semi structured questions regarding their thoughts on readmissions and how they altered their process and behavior for readmitted patients. Interviews were audio-recorded and transcribed. We used a qualitative data analyses based on an inductive approach to generate themes about how healthcare workers shift their strategies for readmitted patients. RESULTS: Healthcare workers' shifts in strategy for readmissions were reflected in three major themes: clinical assessment, use and management of information, and communication patterns. Participants reported that they became more conservative in their assessment of the clinical condition of a readmitted patient. The participants also indicated that readmitted patients would be treated in a similar way to normal admission based on care requirements; however, somewhat paradoxically, they also expressed that having access to prior patient information changed the way they treated a readmitted patient. CONCLUSIONS: Although healthcare workers may exhibit a tendency to become more conservative with readmissions, readily available patient information from the previous admission played a large part in guiding their thinking. A more conservative approach with a readmitted patient, on its own, does not necessarily lead to improved documentation or better patient care. PMID- 29482532 TI - Social capital in a regional inter-hospital network among trauma centers (trauma network): results of a qualitative study in Germany. AB - BACKGROUND: As inter-hospital alliances have become increasingly popular in the healthcare sector, it is important to understand the challenges and benefits that the interaction between representatives of different hospitals entail. A prominent example of inter-hospital alliances are certified 'trauma networks', which consist of 5-30 trauma departments in a given region. Trauma networks are designed to improve trauma care by providing a coordinated response to injury, and have developed across the USA and multiple European countries since the 1960s. Their members need to interact regularly, e.g. develop joint protocols for patient transfer, or discuss patient safety. Social capital is a concept focusing on the development and benefits of relations and interactions within a network. The aim of our study was to explore how social capital is generated and used in a regional German trauma network. METHODS: In this qualitative study, we performed semi-standardized face-to-face interviews with 23 senior trauma surgeons (2013 14). They were the official representatives of 23 out of 26 member hospitals of the Trauma Network Eastern Bavaria. The interviews covered the structure and functioning of the network, climate and reciprocity within the network, the development of social identity, and different resources and benefits derived from the network (e.g. facilitation of interactions, advocacy, work satisfaction). Transcripts were coded using thematic content analysis. RESULTS: According to the interviews, the studied trauma network became a group of surgeons with substantial bonding social capital. The surgeons perceived that the network's culture of interaction was flat, and they identified with the network due to a climate of mutual respect. They felt that the inclusive leadership helped establish a norm of reciprocity. Among the interviewed surgeons, the gain of technical information was seen as less important than the exchange of information on political aspects. The perceived resources derived from this social capital were smoother interactions, a higher medical credibility, and joint advocacy securing certain privileges. CONCLUSION: Apart from addressing quality of care, a trauma network may, by way of strengthening social capital among its members, serve as a valuable resource for the participating surgeons. Some member hospitals could exploit the social capital for strategic benefits. PMID- 29482533 TI - Indicators for early assessment of palliative care in lung cancer patients: a population study using linked health data. AB - BACKGROUND: Analysing linked, routinely collected data may be useful to identify characteristics of patients with suspected lung cancer who could benefit from early assessment for palliative care. The aim of this study was to compare characteristics of newly diagnosed lung cancer patients dying within 30 days of diagnosis (short term survivors) with those surviving more than 30 days. To identify indicators for early palliative care assessment we distinguished between characteristics available at diagnosis (age, gender, smoking status, marital status, comorbid disease, admission type, tumour stage and histology) from those available post diagnosis. A second aim was to examine the association between receiving any tumour-directed treatment, place of death and survival time. METHODS: A retrospective observational population based study comparing lung cancer patients who died within 30 days of diagnosis (short term survivors) with those who survived longer using Chi-squared tests and logistic regression. Incident lung cancer (ICD-03:C34) patients diagnosed 2005-2012 inclusive who died before 01-01-2014 (n = 14,228) were identified from the National Cancer Registry of Ireland linked to death certificate data and acute hospital episode data. RESULTS: One in five newly diagnosed lung cancer patients died within 30 days of diagnosis. After adjusting for stage and histology, death within 30 days was higher in patients who were aged 80 years or older (adjusted OR 2.46; 95%CI 2.05 3.96; p < 0.001), patients with emergency admissions at diagnosis (adjusted OR 2.96; 95%CI 2.61-3.37; p < 0.001) and patients with any comorbidities at diagnosis (adjusted OR 1.32 95%CI 1.15-1.52; p < 0.001). Overall, 75% of those who died within 30 days died in hospital compared to 43% of longer term survivors. CONCLUSIONS: We have shown a high proportion of lung cancer patients who die within 30 days of diagnosis are older, have comorbidities and are admitted through the emergency department. These characteristics, available at diagnosis, may be useful prognostic factors to guide decisions on early assessment for palliative care for lung cancer patients. Patients who die shortly after diagnosis are more likely to die in hospital so reporting place of death by survival time may be useful to evaluate interventions to reduce deaths in acute hospitals. PMID- 29482534 TI - The association of Val109Asp polymorphic marker of intelectin 1 gene with abdominal obesity in Kyrgyz population. AB - BACKGROUND: The aim of this study was to quantify the association of Val109Asp polymorphism of intelectin 1 (ITLN1) gene with the abdominal obesity (AO) in Kyrgyz population. METHODS: Patients admitted to annual screening at a local outpatient facility were enrolled or this study. We genotyped 297 nonrelated adults of Kyrgyz ethnicity, of whom 127 were AO patients, including 46 men and 81 women with the mean age 53.2 +/- 7.1 years, and 170 non-obese controls, including 61 men and 109 women with the mean age 52.0 +/- 9.0 years. AO was defined as having waist circumferences >= 102 cm in men and >= 88 cm in women. We used PCR RFLP method to define Val109Asp polymorphism of ITLN1 gene. RESULTS: Asp109Asp, Asp109Val and Val109Val genotypes were found in 48%, 40%, and 12% of AO patients respectively, and in 53%, 43%, and 4% of controls, whereas Val109Val homozygous genotype of ITLN1 gene Val109Asp polymorphic marker was significantly more prevalent in AO patients. In Kyrgyz population, Val109Val genotype of ITLN1 gene increased the risk of AO (odds ratio (OR) 3.12, 95% CI 1.23-7.90). Asp109Asp homozygous genotype, on opposite, was not associated with this condition (OR 0.82, 95% CI 0.53-1.30). Finally, the allelic variants of Val109Asp polymorphism of ITLN1 gene were not associated with AO. CONCLUSION: Significant increase in the frequency of Val109Val genotype of ITLN1 gene in AO patients may be indicative of some potential role of ITLN1 gene in molding genetic predisposition to AO in the Kyrgyz. This requires further elaboration in the future studies. PMID- 29482535 TI - MRI findings of low-grade fibromyxoid sarcoma: a case report and literature review. AB - BACKGROUND: Low-grade fibromyxoid sarcoma (LGFMS) is a distinctive slow growing soft tissue neoplasm, mostly affecting young individuals with no gender difference. It usually arises in deep soft tissue of the lower limbs and trunk, but few cases of LGFMS located in pelvis have been reported. CASE PRESENTATION: We describe the magnetic resonance imaging(MRI) features of LGFMS located in the anterior pelvic wall of a 21-year-old female and correlate them with clinicopathological features. The tumor was completely resected and there is no recidivism during the follow-up one year. CONCLUSIONS: We report on the radiological findings of LGFMS with histological correlation. Awareness of the imaging features may be useful for the diagnosis of LGFMS and helpful to distinguish among mimics. PMID- 29482536 TI - Rules of engagement: perspectives on stakeholder engagement for genomic biobanking research in South Africa. AB - BACKGROUND: Genomic biobanking research is undergoing exponential growth in Africa raising a host of legal, ethical and social issues. Given the scientific complexity associated with genomics, there is a growing recognition globally of the importance of science translation and community engagement (CE) for this type of research, as it creates the potential to build relationships, increase trust, improve consent processes and empower local communities. Despite this level of recognition, there is a lack of empirical evidence of the practise and processes for effective CE in genomic biobanking in Africa. METHODS: To begin to address this vacuum, 17 in-depth face to face interviews were conducted with South African experts in genomic biobanking research and CE to provide insight into the process, benefits and challenges of CE in South Africa. Emerging themes were analysed using a contextualised thematic approach. RESULTS: Several themes emerged concerning the conduct of CE in genomic biobanking research in Africa. Although the literature tends to focus on the local community in CE, respondents in this study described three different layers of stakeholder engagement: community level, peer level and high level. Community level engagement includes potential participants, community advisory boards (CAB) and field workers; peer level engagement includes researchers, biobankers and scientists, while high level engagement includes government officials, funders and policy makers. Although education of each stakeholder layer is important, education of the community layer can be most challenging, due to the complexity of the research and educational levels of stakeholders in this layer. CONCLUSION: CE is time consuming and often requires an interdisciplinary research team approach. However careful planning of the engagement strategy, including an understanding of the differing layers of stakeholder engagement, and the specific educational needs at each layer, can help in the development of a relationship based on trust between the research team and various stakeholder groups. Since the community layer often comprises vulnerable populations in low and middle income countries (LMICs), co development of innovative educational tools on genomic biobanking is essential. CE is clearly a component of a broader process best described as stakeholder engagement. PMID- 29482538 TI - Dialectical behaviour therapy for treating adults and adolescents with emotional and behavioural dysregulation: study protocol of a coordinated implementation in a publicly funded health service. AB - BACKGROUND: In the Republic of Ireland, borderline personality disorder (BPD) is a feature of approximately 11-20% of clinical presentations to outpatient clinics within mental health services. These estimates are similar to other countries including the UK and USA. Dialectical behaviour therapy (DBT) is an intervention with a growing body of evidence that demonstrates its efficacy in treating individuals diagnosed with BPD. While a number of randomised controlled trials (RCTs) have demonstrated the efficacy of DBT, there is limited research which evaluates the effectiveness of this model when applied to real world settings. Funding was secured to co-ordinate DBT training in public community-based mental health services across Ireland. As no other study has evaluated a co-ordinated national implementation of DBT, the current study proposes to investigate the effectiveness of DBT in both adult and child/adolescent community mental health services across Ireland, evaluate the coordinated implementation of DBT at a national level, and complete a comprehensive economic evaluation comparing DBT versus treatment-as-usual. METHODS/ DESIGN: This study takes the form of a quasi experimental design. Individuals attending community mental health services who meet criteria for participation in the DBT programme will be allocated to the intervention group. Individuals who live in areas in Ireland where DBT is not yet available, and individuals who choose not to participate in the intervention, will be invited to participate in a treatment-as-usual comparison group. Self report clinical measures and health service use questionnaires for DBT participants (and parent/guardians as appropriate) will be administered at pre-, mid- and post-intervention, as well as follow-up for participants who complete the intervention. Survey and interview data for DBT therapists will be gathered at three time points: prior to DBT training, 6 months after teams begin delivery of the intervention, and 2 years following training completion. DISCUSSION: It is anticipated that the results of this study will provide evidence for the effectiveness of DBT for patients, and report on recommendations regarding best practice guidelines for implementation of DBT and its economic merit in a publicly funded service. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03180541 ; Registered June 7th 2017 'retrospectively registered'. PMID- 29482537 TI - Ethical issues in pragmatic randomized controlled trials: a review of the recent literature identifies gaps in ethical argumentation. AB - BACKGROUND: Pragmatic randomized controlled trials (RCTs) are designed to evaluate the effectiveness of interventions in real-world clinical conditions. However, these studies raise ethical issues for researchers and regulators. Our objective is to identify a list of key ethical issues in pragmatic RCTs and highlight gaps in the ethics literature. METHODS: We conducted a scoping review of articles addressing ethical aspects of pragmatic RCTs. After applying the search strategy and eligibility criteria, 36 articles were included and reviewed using content analysis. RESULTS: Our review identified four major themes: 1) the research-practice distinction; 2) the need for consent; 3) elements that must be disclosed in the consent process; and 4) appropriate oversight by research ethics committees. 1) Most authors reject the need for a research-practice distinction in pragmatic RCTs. They argue that the distinction rests on the presumptions that research participation offers patients less benefit and greater risk than clinical practice, but neither is true in the case of pragmatic RCTs. 2) Most authors further conclude that pragmatic RCTs may proceed without informed consent or with simplified consent procedures when risks are low and consent is infeasible. 3) Authors who endorse the need for consent assert that information need only be disclosed when research participation poses incremental risks compared to clinical practice. Authors disagree as to whether randomization must be disclosed. 4) Finally, all authors view regulatory oversight as burdensome and a practical impediment to the conduct of pragmatic RCTs, and argue that oversight procedures ought to be streamlined when risks to participants are low. CONCLUSION: The current ethical discussion is framed by the assumption that the function of research oversight is to protect participants from risk. As pragmatic RCTs commonly involve usual care interventions, the risks may be minimal. This leads many to reject the research-practice distinction and question the need for informed consent. But the function of oversight should be understood broadly as protecting the liberty and welfare interest of participants and promoting public trust in research. This understanding, we suggest, will focus discussion on questions about appropriate ethical review for pragmatic RCTs. PMID- 29482539 TI - Anti-tobacco control industry strategies in Turkey. AB - BACKGROUND: Transnational tobacco companies (TTCs) penetrated the Turkish cigarette market due to trade and investment liberalization in the post-1980 period and eventually secured full control. Despite tobacco control policies put in place in reaction to accelerating consumption, TTCs reinforced their market power through a variety of strategies. This paper explores industry strategies that counteract tobacco control policies in Turkey. METHODS: The study employs both qualitative and quantitative analyses to explore industry strategies in Turkey. Besides the content analyses of industry and market reports, descriptive analyses were conducted for the sub-periods of 1999-2015. The analyses focus on the market strategies of product innovation, advertisement-promotion, cost management and pricing. RESULTS: Rising sales of low tar, ultra-low tar, slim, super-slim and flavoured cigarettes indicate that product innovation served to sustain consumption. Besides, the tobacco industry, using its strong distribution channels, the Internet, and CSR projects, were found to have promoted smoking indirectly. The industry also rationalized manufacturing facilities and reduced the cost of tobacco, making Turkey a cigarette-manufacturing base. Tobacco manufacturers, moreover, offered cigarettes in different price segments and adjusted net prices both up and down according to price categories and market conditions. In response to the successful effect of shifts in price margins, the market share of mid-priced cigarettes expanded while those within the economy category maintained the highest market share. As a result of pricing strategies, net sales revenues increased. Aside from official cigarette sales, the upward trends in the registered and unregistered sales of cigarette substitutes indicate that the demand-side tobacco control efforts remain inadequate. CONCLUSIONS: The Turkish case reveals that the resilience of the tobacco industry vis-a-vis mainstream tobacco control efforts necessitates a new policy perspective. Rising market concentration by TTCs and the global nature of industry strategies require that the highly profitable manufacturing and trade of tobacco products should be discouraged on a basis of international collaboration. To reduce and eventually eradicate tobacco consumption, supply-side tobacco control measures are needed along with demand-side policies. PMID- 29482540 TI - Risk factors for malnutrition among preschool children in rural Karnataka: a case control study. AB - BACKGROUND: The prevalence of malnutrition among children in developing countries is very high. As a step towards reducing the prevalence of malnutrition, there is a need to identify the important determinants of malnutrition in the specific population so that preventive and control measures can be implemented. The objective of the study is to determine the risk factors for malnutrition among preschool children in Rural Karnataka, South India. METHODS: A case-control study was carried out among preschool children, aged between three to six years, attending the Anganwadi centers and their mothers' in Udupi district of Karnataka, India. A total of 570 children (190 cases and 380 controls) were selected by multistage cluster sampling technique. A semi-structured risk factors questionnaire was used to identify the risk factors for malnutrition among children. RESULTS: The majority (45.8 and 45.5%) of the children in the study were in the age group of 3.0 to 4.0 years in case and control groups respectively. There was a slight preponderance of illiterate parents among cases in comparison to the controls. Largely, 87.4% of the children belonged to poor socio-economic status in the case groups compared to 82.4% in the control group. After adjusting for the confounders, underweight was significantly associated with socio-economic status of the parents (aOR: 2.05, 95% CI: 1.06, 3.96), birth weight < 2000 g (aOR: 25, 95% CI: 0.10, 0.59), recurrent diarrhoea (aOR: 2.74, 95% CI: 1.56, 4.83), recurrent cold and cough (aOR: 3.88, 95% CI: 1.96, 7.67), worm infestation (aOR: 2.0, 95% CI: 1.19, 3.38) and prelacteal feed given (aOR: 3.64, 95% CI: 2.27, 5.86). CONCLUSION: Parental education, childhood illness, short birth interval, open defecation, type of weaning and complimentary food given to children were some of the significant determinants of underweight that were found in the study. Information, Education and Communication (IEC) campaigns alleviating food habits and taboos and promoting birth spacing is the need of the hour for preventing the occurrence of undernutrition among preschool children. PMID- 29482541 TI - Correction to: Effective nationwide school-based participatory extramural program on adolescent body mass index, health knowledge and behaviors. AB - CORRECTION: Following the publication of the original article [1], it was brought to our attention that author Judith Wylie-Rosett was erroneously included as Judith Wylie. PMID- 29482542 TI - Matters to address prior to introducing new life support technology in Japan: three serious ethical concerns related to the use of left ventricular assist devices as destination therapy and suggested policies to deal with them. AB - BACKGROUND: Destination therapy (DT) is the permanent implantation of a left ventricular assist device (LVAD) in patients with end-stage, severe heart failure who are ineligible for heart transplantation. DT improves both the quality of life and prognosis of patients with end-stage heart failure. However, there are also downsides to DT such as life-threatening complications and the potential for the patient to live beyond their desired length of life following such major complications. Because of deeply ingrained cultural and religious beliefs regarding death and the sanctity of life, Japanese society may not be ready to make changes needed to enable patients to have LVADs deactivated under certain circumstances to avoid needless suffering. MAIN TEXT: Western ethical views that permit LVAD deactivation based mainly on respect for autonomy and dignity have not been accepted thus far in Japan and are unlikely to be accepted, given the current Japanese culture and traditional values. Some healthcare professionals might regard patients as ineligible for DT unless they have prepared advance directives. If this were to happen, the right to prepare an advance directive would instead become an obligation to do so. Furthermore, patient selection for DT poses another ethical issue. Given the predominant sanctity of life principle and lack of cost-consciousness regarding medical expenses, medically appropriate exclusion criteria would be ignored and DT could be applied to various patients, including very old patients, the demented, or even patients in persistent vegetative states, through on-site judgment. CONCLUSION: There is an urgent need for Japan to establish and enact a basic act for patient rights. The act should include: respect for a patient's right to self-determination; the right to refuse unwanted treatment; the right to prepare legally binding advance directives; the right to decline to prepare such directives; and access to nationally insured healthcare. It should enable those concerned with patient care involving DT to seek ethical advice from ethics committees. Furthermore, it should state that healthcare professionals involved in the discontinuation of life support in a proper manner are immune to any legal action and that they have the right to conscientiously object to LVAD deactivation. PMID- 29482543 TI - Effects of nonsurgical periodontal treatment on glycated haemoglobin on type 2 diabetes patients (PARODIA 1 study): a randomized controlled trial in a sub Saharan Africa population. AB - BACKGROUND: There is a burglar association between diabetes and periodontitis. Many studies has shown that periodontitis treatment can help improving glycemic control in diabetes patients but little evidence of non-surgical treatment benefit is available in sub Saharan african diabetes patients. We aimed to assess the effects of non-surgical periodontal treatment (NSPT) of chronic periodontitis on glycaemic control in poorly controlled type 2 diabetes patients (T2D) in a sub Saharan Africa urban setting. METHODS: A total of 34 poorly controlled T2D patients with chronic periodontitis aged 51.4 +/- 8.8 years (mean +/- SD), with known duration of diabetes of 55.5 +/- 42.6 months, and HbA1c of 9.3 +/- 1.3% were randomly assigned to two groups. The treatment group (Group 1, n = 17) received immediate ultrasonic scaling, scaling and root planning along with subgingival 10% povidone iodine irrigation, whereas the control group (Group 2, n = 17) was assigned to receive delayed periodontal treatment 3 months later. Pharmacological treatment was unchanged and all participants received the same standardized education session on diabetes management and dental hygiene. The primary outcome was the 3-month change in HbA1c from baseline. Plaque index (PI), gingival bleeding index (GBI), pocket depth (PD), clinical attachment loss (CAL) were also assessed prior to, at 6 and 12 weeks after enrolment. RESULTS: Two subjects in each group were excluded from the study. Data were analyzed on thirty patients (15 per group). Non-surgical periodontal treatment with education for better dental hygiene (group 1) significantly improved all periodontal parameters whereas education only (group 2) improved only the plaque index among all periodontal parameters. Immediate non-surgical periodontal treatment induced a reduction of HbA1c levels by 3.0 +/- 2.4 points from 9.7 +/- 1.6% at baseline to 6.7 +/- 2.0% 3 months after NSPT, (p ? 0.001) but the change was not significant in group 2, from mean 8.9 +/- 0.9% at baseline vs 8.1 +/- 2.6% after 3 months (p = 0.24). CONCLUSION: Non-surgical periodontal treatment markedly improved glycaemic control with an attributable reduction of 2.2 points of HbA1c in poorly controlled T2D patients in a sub Saharan setting. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02745015 Date of registration: July 17, 2016 'Retrospectively registered'. PMID- 29482544 TI - Reducing time-to-unit among patients referred to an outpatient stroke assessment unit with a novel triage process: a prospective cohort study. AB - BACKGROUND: To evaluate the performance of a novel triage system for Transient Ischemic Attack (TIA) units built upon an existent clinical prediction rule (CPR) to reduce time to unit arrival, relative to the time of symptom onset, for true TIA and minor stroke patients. Differentiating between true and false TIA/minor stroke cases (mimics) is necessary for effective triage as medical intervention for true TIA/minor stroke is time-sensitive and TIA unit spots are a finite resource. METHODS: Prospective cohort study design utilizing patient referral data and TIA unit arrival times from a regional fast-track TIA unit on Vancouver Island, Canada, accepting referrals from emergency departments (ED) and general practice (GP). Historical referral cohort (N = 2942) from May 2013-Oct 2014 was triaged using the ABCD2 score; prospective referral cohort (N = 2929) from Nov 2014-Apr 2016 was triaged using the novel system. A retrospective survival curve analysis, censored at 28 days to unit arrival, was used to compare days to unit arrival from event date between cohort patients matched by low (0-3), moderate (4 5) and high (6-7) ABCD2 scores. RESULTS: Survival curve analysis indicated that using the novel triage system, prospectively referred TIA/minor stroke patients with low and moderate ABCD2 scores arrived at the unit 2 and 1 day earlier than matched historical patients, respectively. CONCLUSIONS: The novel triage process is associated with a reduction in time to unit arrival from symptom onset for referred true TIA/minor stroke patients with low and moderate ABCD2 scores. PMID- 29482545 TI - Association between education and blood lipid levels as income increases over a decade: a cohort study. PMID- 29482546 TI - Child marriage and associated outcomes in northern Ghana: a cross-sectional study. AB - BACKGROUND: Child marriage is a human rights violation disproportionately affecting girls in lower- and middle-income countries and has serious public health implications. In Ghana, one in five girls marry before their 18th birthday and one in 20 girls is married before her 15th birthday. This paper uses a unique dataset from Northern Ghana to examine the association between child marriage and adverse outcomes for women among a uniquely vulnerable population. METHODS: Baseline data from on ongoing impact evaluation of a government-run cash transfer programme was used. The sample consisted of 1349 ever-married women aged 20-29 years from 2497 households in the Northern and Upper East regions of Ghana. We estimated a series of ordinary least squares (OLS) and logistic regression models to examine associations of child marriage with health, fertility, contraception, child mortality, social support, stress and agency outcomes among women, controlling for individual characteristics and household-level factors. RESULTS: Child marriage in this sample was associated with increased odds of poorer health, as measured by difficulties in daily activities (OR = 2.08; CI 1.28-3.38 among women 20-24 years and OR = 1.58; CI 1.19-2.12 among women 20-29 years), increased odds of child mortality among first-born children (OR = 2.03; CI 1.09 3.77 among women 20-24 years) and lower odds of believing that one's life is determined by their own actions (OR = 0.42; CI 0.25-0.72 among women 20-24 years and OR = 0.54; CI 0.39-0.75 among women 20-29 years). Conversely, child marriage was associated with lower levels of reported stress (regression coefficient = - 1.18; CI -1.84--0.51 among women 20-29 years). CONCLUSIONS: Child marriage is common in Northern Ghana and is associated with poor health, increased child mortality, and low agency among women in this sample of extremely poor households. While not much is known about effective measures to combat child marriage in the context of Ghana, programmes that address key drivers of early marriage such as economic insecurity and school enrolment at the secondary level, should be examined with respect to their effectiveness at reducing early marriage. TRIAL REGISTRATION: Registered in the Registry for International Development Impact Evaluations (RIDIE) on 01 July 2015, with number RIDIE-STUDY ID- 55942496d53af . PMID- 29482547 TI - Is there a C-reactive protein value beyond which one should consider infection as the cause of acute heart failure? AB - BACKGROUND: Heart Failure (HF) is a low grade inflammatory condition. High sensitivity C-reactive protein (hsCRP) is an established marker of inflammation. A cut-off value of hsCRP beyond which an infection should be sought has never been studied in HF. We aimed to determine the best hsCRP cut-off for infection prediction in acute HF. METHODS: We analyzed patients included in an acute HF registry - EDIFICA (Estratificacao de Doentes com InsuFIciencia Cardiaca Aguda). Admission hsCRP measurement was available as part of the registry's protocol. Patients with acute coronary syndrome as the cause of acute HF were excluded from the registry. Infection was considered according to the diagnosis registered in the discharge record. A receiver-operating characteristic (ROC) curve was used to determine the best hsCRP cut-off for infection prediction. RESULTS: We studied 615 patients. Mean age was 76 years, 45.2% were male, 60.3% had systolic dysfunction. Median admission hsCRP was 20.3 (9.5-55.5)mg/L; in 41.6% the cause of decompensation was an infection. The area under the ROC curve for admission hsCRP in the prediction of infection was 0.79 (0.76-0.83); the best hsCRP cut-off was 25 mg/L with a sensitivity of 72.7%, specificity 77.2%, positive predictive value 69.4% and negative predictive value 79.9%. Age and elevated hsCRP independently associated with an infection as the precipitant of acute HF. CONCLUSIONS: We suggest 25 mg/L as a cut-off beyond which an infection should be sought underlying acute HF. Almost 80% of the patients with hsCRP< 25 mg/L are not infected and 69.4% of those with higher hsCRP have a concomitant infection. PMID- 29482548 TI - An adaptable chromosome preparation methodology for use in invertebrate research organisms. AB - BACKGROUND: The ability to efficiently visualize and manipulate chromosomes is fundamental to understanding the genome architecture of organisms. Conventional chromosome preparation protocols developed for mammalian cells and those relying on species-specific conditions are not suitable for many invertebrates. Hence, a simple and inexpensive chromosome preparation protocol, adaptable to multiple invertebrate species, is needed. RESULTS: We optimized a chromosome preparation protocol and applied it to several planarian species (phylum Platyhelminthes), the freshwater apple snail Pomacea canaliculata (phylum Mollusca), and the starlet sea anemone Nematostella vectensis (phylum Cnidaria). We demonstrated that both mitotically active adult tissues and embryos can be used as sources of metaphase chromosomes, expanding the potential use of this technique to invertebrates lacking cell lines and/or with limited access to the complete life cycle. Simple hypotonic treatment with deionized water was sufficient for karyotyping; growing cells in culture was not necessary. The obtained karyotypes allowed the identification of differences in ploidy and chromosome architecture among otherwise morphologically indistinguishable organisms, as in the case of a mixed population of planarians collected in the wild. Furthermore, we showed that in all tested organisms representing three different phyla this protocol could be effectively coupled with downstream applications, such as chromosome fluorescent in situ hybridization. CONCLUSIONS: Our simple and inexpensive chromosome preparation protocol can be readily adapted to new invertebrate research organisms to accelerate the discovery of novel genomic patterns across the branches of the tree of life. PMID- 29482549 TI - The effects of type I collagenase on the degelification of chimpanzee (Pan troglodytes) semen plug and sperm quality. AB - BACKGROUND: Semen from the chimpanzee species becomes a colloidal solid after ejaculation. The formation of this copulatory plug is believed to prevent additional spermatozoa of subsequent mating events from accessing the ova. However, this naturally preserved strategy hampers the processes for sperm preparation. In this study, we investigated whether collagenase can be used to degelify the semen plug and accelerate the semen liquefaction process in zoo captive chimpanzee species (Pan troglodytes). RESULTS: We showed that incubation of chimpanzee ejaculates with 0.1% type I collagenase efficiently and significantly (p < 0.05) releases 2.7-fold more spermatozoa from the coagulated ejaculates, and this degelification process did not alter sperm morphology or viability; nor did it stimulate spontaneous capacitation or an acrosome reaction as assessed by tyrosine phosphorylation and peanut agglutinin stains; moreover, based on computer assisted sperm analysis assay, motility-related parameters remained similar to those of untreated spermatozoa. When collagenase effects were evaluated on cryopreserved sperm samples, we observed post collagenase treatment in which 2.5% glycerol, as a cryoprotectant, preserved sperm acrosome integrity better than 7.8%; however, 7.8% glycerol, as a cryoprotectant, maintained sperm motility better than that of 2.5% glycerol. CONCLUSIONS: Our results demonstrated for the first time that type I collagenase can be used to obtain a significantly higher number of spermatozoa from colloid chimpanzee semen ejaculate without affecting the physiological properties of spermatozoa, and these results are critical for the subsequent gamete development. Our results would benefit sperm preparation processes and cryopreservation efficiency per ejaculate, as more unaffected spermatozoa can be released from the semen plug within a shorter period of time. These results would also benefit the genetic diversity of the chimpanzee species, using sperm cells from less dominant individuals, and for achieving better pregnancy success in primates with significantly higher amounts of sperm for artificial insemination. PMID- 29482550 TI - The use of advanced medical technologies at home: a systematic review of the literature. AB - BACKGROUND: The number of medical technologies used in home settings has increased substantially over the last 10-15 years. In order to manage their use and to guarantee quality and safety, data on usage trends and practical experiences are important. This paper presents a literature review on types, trends and experiences with the use of advanced medical technologies at home. METHODS: The study focused on advanced medical technologies that are part of the technical nursing process and 'hands on' processes by nurses, excluding information technology such as domotica. The systematic review of literature was performed by searching the databases MEDLINE, Scopus and Cinahl. We included papers from 2000 to 2015 and selected articles containing empirical material. RESULTS: The review identified 87 relevant articles, 62% was published in the period 2011-2015. Of the included studies, 45% considered devices for respiratory support, 39% devices for dialysis and 29% devices for oxygen therapy. Most research has been conducted on the topic 'user experiences' (36%), mainly regarding patients or informal caregivers. Results show that nurses have a key role in supporting patients and family caregivers in the process of homecare with advanced medical technologies and in providing information for, and as a member of multi-disciplinary teams. However, relatively low numbers of articles were found studying nurses perspective. CONCLUSIONS: Research on medical technologies used at home has increased considerably until 2015. Much is already known on topics, such as user experiences; safety, risks, incidents and complications; and design and technological development. We also identified a lack of research exploring the views of nurses with regard to medical technologies for homecare, such as user experiences of nurses with different technologies, training, instruction and education of nurses and human factors by nurses in risk management and patient safety. PMID- 29482551 TI - Clinical significance of plasma cell-free DNA mutations in PIK3CA, AKT1, and ESR1 gene according to treatment lines in ER-positive breast cancer. AB - The somatic activation of PI3K/AKT pathway mutations, PIK3CA and AKT1, and ESR1 mutations in plasma cell-free DNA (cfDNA) has been studied as a non-invasive procedure to quickly assess and monitor disease progression or therapeutic effect in breast cancer (BC) patients, but the clinical significance of these mutations in late treatment lines (TLs) remains unclear. The subjects of this study were a total of 251 plasma samples from 128 estrogen receptor-positive (ER+) BC patients. Of these plasma samples, 133 were from 73 primary BC (PBC) patients, and 118 plasma samples were from 68 metastatic BC (MBC) patients. We developed droplet digital PCR (ddPCR) assays to verify the clinical significance of PIK3CA, AKT1, and ESR1 mutations in these patients. cfDNA PIK3CA mutations were observed in 15.1% of the PBC patients, while a cfDNA AKT1 mutation was observed in 1.4% of patients, and cfDNA ESR1 mutations were observed in 2.7% of patients. Patients with detectable cfDNA PIK3CA mutations were not associated with clinical outcomes. According to the TL, the prevalence of the PIK3CA and ESR1 mutations in cfDNA were lower in early TLs compared with late TLs. In the early TL group, patients with cfDNA PIK3CA mutations had a shorter time to treatment failure (TTF) than patients without mutations (P = 0.035). However, there was no statistically significant difference between patients with or without cfDNA ESR1 mutations. However, in the late TL group, patients with cfDNA ESR1 mutations had a shorter TTF than patients without mutations (P = 0.048). However, there was no statistically significant difference between patients with or without cfDNA PIK3CA mutations. Since the prevalence of cfDNA AKT1 mutation is low in both PBC and MBC patients, the impact of AKT1 mutations on the prognosis remains unclear. We have demonstrated the difference in the clinical significance of the hotspot PIK3CA, AKT1, and ESR1 mutations in cfDNA for each TL in ER+ BC patients. PMID- 29482552 TI - Short-term effects of ambient fine particulate matter pollution on hospital visits for chronic obstructive pulmonary disease in Beijing, China. AB - BACKGROUND: Little is known about the effect of ambient fine particulate matter (PM2.5) on chronic obstructive pulmonary disease (COPD) in China. The objective of this study was to explore the short-term effects of PM2.5 on outpatient and inpatient visits for COPD in Beijing, China. METHODS: A total of 3,503,313 outpatient visits and 126,982 inpatient visits for COPD between January 1, 2010, and June 30, 2012, were identified from the Beijing Medical Claim Data for Employees. A generalized additive Poisson model was applied to estimate the percentage change with 95% confidence interval (CI) in hospital visits for COPD in relation to an interquartile range (IQR) (90.8 MUg/m3) increase in PM2.5 concentrations. RESULTS: Short-term exposure to PM2.5 was significantly associated with increased use of COPD-related health services. There were clear exposure-response associations of PM2.5 with COPD outpatient and inpatient visits. An IQR increase in the concurrent day PM2.5 concentrations was significantly associated with a 2.38% (95% CI, 2.22%-2.53%) and 6.03% (95% CI, 5.19%-6.87%) increase in daily outpatient visits and inpatient visits, respectively. Elderly people were more sensitive to the adverse effects. The estimated risk was higher during the warm season compared to the cool season. CONCLUSIONS: Short-term exposure to PM2.5 was associated with increased risk of hospital visits for COPD. Our findings contributed to the limited evidence concerning the effects of ambient PM2.5 on COPD morbidity in developing countries. PMID- 29482553 TI - Pattern of all-causes and cause-specific mortality in an area with progressively declining malaria burden in Korogwe district, north-eastern Tanzania. AB - BACKGROUND: Although death records are useful for planning and monitoring health interventions, such information is limited in most developing countries. Verbal autopsy (VA) interviews are alternatively used to determine causes of death in places without or with incomplete hospital records. This study was conducted to determine all causes and cause-specific mortality in Korogwe health and demographic surveillance system (HDSS) undertaken in Korogwe district, northeastern Tanzania. METHODS: The study was conducted from January 2006 to December 2012 in 14 villages under Korogwe HDSS. Vital events such as births, deaths and migrations were routinely updated quarterly. A standard VA questionnaire was administered to parents/close relatives of the deceased to determine cause of death. RESULTS: Overall, 1325 deaths of individuals with median age of 46 years were recorded in a population with 170,471.4 person years observed (PY). Crude mortality rate was 7.8 per 1000 PY (95% CI 7.2-8.4) and the highest rate was observed in infants (77.9 per 1000 PY; 95% CI 67.4-90.0). The overall mortality increased between 2006 and 2007, followed by a slight decline up to 2011, with the highest decrease observed in 2012. Causes of deaths were established in 942 (71.1%) deaths and malaria (198 deaths, 21.0%) was the leading cause of death in all age groups except adults (15-59 years). HIV/AIDS (17.6%, n = 365) was the leading cause of death in individuals aged 15-59 years followed by malaria (13.9%) and tuberculosis. Non-communicable diseases (NCDs) including stroke, hypertension, cancer, and cardiac failure caused majority of deaths in elderly (60 years and above) accounting for 37.1% (n = 348) of all deaths, although malaria was the single leading cause of death in this group (16.6%). CONCLUSION: The study showed a significant decline of deaths in the Korogwe HDSS site and malaria was the main cause of death in all age groups (except adults, aged 15-59 years) while HIV/AIDS and NCDs were the main causes in adults and elderly, respectively. Further surveillance is required to monitor and document changes in cause-specific mortality as malaria transmission continues to decline in this and other parts of Tanzania. PMID- 29482554 TI - Cadence (steps/min) and intensity during ambulation in 6-20 year olds: the CADENCE-kids study. AB - BACKGROUND: Steps/day is widely utilized to estimate the total volume of ambulatory activity, but it does not directly reflect intensity, a central tenet of public health guidelines. Cadence (steps/min) represents an overlooked opportunity to describe the intensity of ambulatory activity. We sought to establish thresholds linking directly observed cadence with objectively measured intensity in 6-20 year olds. METHODS: One hundred twenty participants completed multiple 5-min bouts on a treadmill, from 13.4 m/min (0.80 km/h) to 134.0 m/min (8.04 km/h). The protocol was terminated when participants naturally transitioned to running, or if they chose to not continue. Steps were visually counted and intensity was objectively measured using a portable metabolic system. Youth metabolic equivalents (METy) were calculated for 6-17 year olds, with moderate intensity defined as >=4 and < 6 METy, and vigorous intensity as >=6 METy. Traditional METs were calculated for 18-20 year olds, with moderate intensity defined as >=3 and < 6 METs, and vigorous intensity defined as >=6 METs. Optimal cadence thresholds for moderate and vigorous intensity were identified using segmented random coefficients models and receiver operating characteristic (ROC) curves. RESULT: Participants were on average (+/- SD) aged 13.1 +/- 4.3 years, weighed 55.8 +/- 22.3 kg, and had a BMI z-score of 0.58 +/- 1.21. Moderate intensity thresholds (from regression and ROC analyses) ranged from 128.4 steps/min among 6-8 year olds to 87.3 steps/min among 18-20 year olds. Comparable values for vigorous intensity ranged from 157.7 steps/min among 6-8 year olds to 119.3 steps/min among 18-20 year olds. Considering both regression and ROC approaches, heuristic cadence thresholds (i.e., evidence-based, practical, rounded) ranged from 125 to 90 steps/min for moderate intensity, and 155 to 125 steps/min for vigorous intensity, with higher cadences for younger age groups. Sensitivities and specificities for these heuristic thresholds ranged from 77.8 to 99.0%, indicating fair to excellent classification accuracy. CONCLUSIONS: These heuristic cadence thresholds may be used to prescribe physical activity intensity in public health recommendations. In the research and clinical context, these heuristic cadence thresholds have apparent value for accelerometer-based analytical approaches to determine the intensity of ambulatory activity. PMID- 29482555 TI - Guideline appraisal with AGREE II: online survey of the potential influence of AGREE II items on overall assessment of guideline quality and recommendation for use. AB - BACKGROUND: The AGREE II instrument is the most commonly used guideline appraisal tool. It includes 23 appraisal criteria (items) organized within six domains. AGREE II also includes two overall assessments (overall guideline quality, recommendation for use). Our aim was to investigate how strongly the 23 AGREE II items influence the two overall assessments. METHODS: An online survey of authors of publications on guideline appraisals with AGREE II and guideline users from a German scientific network was conducted between 10th February 2015 and 30th March 2015. Participants were asked to rate the influence of the AGREE II items on a Likert scale (0 = no influence to 5 = very strong influence). The frequencies of responses and their dispersion were presented descriptively. RESULTS: Fifty-eight of the 376 persons contacted (15.4%) participated in the survey and the data of the 51 respondents with prior knowledge of AGREE II were analysed. Items 7-12 of Domain 3 (rigour of development) and both items of Domain 6 (editorial independence) had the strongest influence on the two overall assessments. In addition, Items 15-17 (clarity of presentation) had a strong influence on the recommendation for use. Great variations were shown for the other items. The main limitation of the survey is the low response rate. CONCLUSIONS: In guideline appraisals using AGREE II, items representing rigour of guideline development and editorial independence seem to have the strongest influence on the two overall assessments. In order to ensure a transparent approach to reaching the overall assessments, we suggest the inclusion of a recommendation in the AGREE II user manual on how to consider item and domain scores. For instance, the manual could include an a-priori weighting of those items and domains that should have the strongest influence on the two overall assessments. The relevance of these assessments within AGREE II could thereby be further specified. PMID- 29482556 TI - Evidence and strategies for malaria prevention and control: a historical analysis. AB - Public health strategies for malaria in endemic countries aim to prevent transmission of the disease and control the vector. This historical analysis considers the strategies for vector control developed during the first four decades of the twentieth century. In 1925, policies and technological advances were debated internationally for the first time after the outbreak of malaria in Europe which followed World War I. This dialogue had implications for policies in Europe, Russia and the Middle East, and influenced the broader international control agenda. The analysis draws on the advances made before 1930, and includes the effects of mosquito-proofing of houses; the use of larvicides (Paris Green) and larvivorous fish (Gambusia); the role of large-scale engineering works; and the emergence of biological approaches to malaria. The importance of strong government and civil servant support was outlined. Despite best efforts of public health authorities, it became clear that it was notoriously difficult to interrupt transmission in areas of moderately high transmission. The importance of combining a variety of measures to achieve control became clear and proved successful in Palestine between 1923 and 1925, and improved education, economic circumstances and sustained political commitment emerge as key factors in the longer term control of malaria. The analysis shows that the principles for many of the present public health strategies for malaria have nearly all been defined before 1930, apart from large scale usage of pesticides, which came later at the end of the Second World War. No single intervention provided an effective single answer to preventing transmission, but certainly approaches taken that are locally relevant and applied in combination, are relevant to today's efforts at elimination. PMID- 29482557 TI - Identification of a highly active tannase enzyme from the oral pathogen Fusobacterium nucleatum subsp. polymorphum. AB - BACKGROUND: Tannases are tannin-degrading enzymes that have been described in fungi and bacteria as an adaptative mechanism to overcome the stress conditions associated with the presence of these phenolic compounds. RESULTS: We have identified and expressed in E. coli a tannase from the oral microbiota member Fusobacterium nucleatum subs. polymorphum (TanBFnp). TanBFnp is the first tannase identified in an oral pathogen. Sequence analyses revealed that it is closely related to other bacterial tannases. The enzyme exhibits biochemical properties that make it an interesting target for industrial use. TanBFnp has one of the highest specific activities of all bacterial tannases described to date and shows optimal biochemical properties such as a high thermal stability: the enzyme keeps 100% of its activity after prolonged incubations at different temperatures up to 45 degrees C. TanBFnp also shows a wide temperature range of activity, maintaining above 80% of its maximum activity between 22 and 55 degrees C. The use of a panel of 27 esters of phenolic acids demonstrated activity of TanBFnp only against esters of gallic and protocatechuic acid, including tannic acid, gallocatechin gallate and epigallocatechin gallate. Overall, TanBFnp possesses biochemical properties that make the enzyme potentially useful in biotechnological applications. CONCLUSIONS: We have identified and characterized a metabolic enzyme from the oral pathogen Fusobacterium nucleatum subsp. polymorphum. The biochemical properties of TanBFnp suggest that it has a major role in the breakdown of complex food tannins during oral processing. Our results also provide some clues regarding its possible participation on bacterial survival in the oral cavity. Furthermore, the characteristics of this enzyme make it of potential interest for industrial use. PMID- 29482558 TI - Spasticity assessment based on the Hilbert-Huang transform marginal spectrum entropy and the root mean square of surface electromyography signals: a preliminary study. AB - BACKGROUND: Most of the objective and quantitative methods proposed for spasticity measurement are not suitable for clinical application, and methods for surface electromyography (sEMG) signal processing are mainly limited to the time domain. This study aims to quantify muscle activity in the time-frequency domain, and develop a practical clinical method for the objective and reliable evaluation of the spasticity based on the Hilbert-Huang transform marginal spectrum entropy (HMSEN) and the root mean square (RMS) of sEMG signals. METHODS: Twenty-six stroke patients with elbow flexor spasticity participated in the study. The subjects were tested at sitting position with the upper limb stretched towards the ground. The HMSEN of the sEMG signals obtained from the biceps brachii was employed to facilitate the stretch reflex onset (SRO) detection. Then, the difference between the RMS of a fixed-length sEMG signal obtained after the SRO and the RMS of a baseline sEMG signal, denoted as the RMS difference (RMSD), was employed to evaluate the spasticity level. The relations between Modified Ashworth Scale (MAS) scores and RMSD were investigated by Ordinal Logistic Regression (OLR). Goodness-of-fit of the OLR was obtained with Hosmer-Lemeshow test. RESULTS: The HMSEN based method can precisely detect the SRO, and the RMSD scores and the MAS scores were fairly well related (test: chi2 = 8.8060, p = 0.2669; retest: chi2 = 1.9094, p = 0.9647). The prediction accuracies were 85% (test) and 77% (retest) when using RMSD for predicting MAS scores. In addition, the test-retest reliability was high, with an interclass correlation coefficient of 0.914 and a standard error of measurement of 1.137. Bland-Altman plots also indicated a small bias. CONCLUSIONS: The proposed method is manually operated and easy to use, and the HMSEN based method is robust in detecting SRO in clinical settings. Hence, the method is applicable to clinical practice. The RMSD can assess spasticity in a quantitative way and provide greater resolution of spasticity levels compared to the MAS in clinical settings. These results demonstrate that the proposed method could be clinically more useful for the accurate and reliable assessment of spasticity and may be an alternative clinical measure to the MAS. PMID- 29482560 TI - 3D marker-controlled watershed for kidney segmentation in clinical CT exams. AB - BACKGROUND: Image segmentation is an essential and non trivial task in computer vision and medical image analysis. Computed tomography (CT) is one of the most accessible medical examination techniques to visualize the interior of a patient's body. Among different computer-aided diagnostic systems, the applications dedicated to kidney segmentation represent a relatively small group. In addition, literature solutions are verified on relatively small databases. The goal of this research is to develop a novel algorithm for fully automated kidney segmentation. This approach is designed for large database analysis including both physiological and pathological cases. METHODS: This study presents a 3D marker-controlled watershed transform developed and employed for fully automated CT kidney segmentation. The original and the most complex step in the current proposition is an automatic generation of 3D marker images. The final kidney segmentation step is an analysis of the labelled image obtained from marker controlled watershed transform. It consists of morphological operations and shape analysis. The implementation is conducted in a MATLAB environment, Version 2017a, using i.a. Image Processing Toolbox. 170 clinical CT abdominal studies have been subjected to the analysis. The dataset includes normal as well as various pathological cases (agenesis, renal cysts, tumors, renal cell carcinoma, kidney cirrhosis, partial or radical nephrectomy, hematoma and nephrolithiasis). Manual and semi-automated delineations have been used as a gold standard. Wieclawek Among 67 delineated medical cases, 62 cases are 'Very good', whereas only 5 are 'Good' according to Cohen's Kappa interpretation. The segmentation results show that mean values of Sensitivity, Specificity, Dice, Jaccard, Cohen's Kappa and Accuracy are 90.29, 99.96, 91.68, 85.04, 91.62 and 99.89% respectively. All 170 medical cases (with and without outlines) have been classified by three independent medical experts as 'Very good' in 143-148 cases, as 'Good' in 15-21 cases and as 'Moderate' in 6-8 cases. CONCLUSIONS: An automatic kidney segmentation approach for CT studies to compete with commonly known solutions was developed. The algorithm gives promising results, that were confirmed during validation procedure done on a relatively large database, including 170 CTs with both physiological and pathological cases. PMID- 29482559 TI - Geostatistical modelling of the association between malaria and child growth in Africa. AB - BACKGROUND: Undernutrition among children under 5 years of age continues to be a public health challenge in many low- and middle-income countries and can lead to growth stunting. Infectious diseases may also affect child growth, however their actual impact on the latter can be difficult to quantify. In this paper, we analyse data from 20 Demographic and Health Surveys (DHS) conducted in 13 African countries to investigate the relationship between malaria and stunting. Our objective is to make inference on the association between malaria incidence during the first year of life and height-for-age Z-scores (HAZs). METHODS: We develop a geostatistical model for HAZs as a function of both measured and unmeasured child-specific and spatial risk factors. We visualize stunting risk in each of the 20 analysed surveys by mapping the predictive probability that HAZ is below - 2. Finally, we carry out a meta-analysis by modelling the estimated effects of malaria incidence on HAZ from each DHS as a linear regression on national development indicators from the World Bank. RESULTS: A non-spatial univariate linear regression of HAZ on malaria incidence showed a negative association in 18 out of 20 surveys. However, after adjusting for spatial risk factors and controlling for confounding effects, we found a weaker association between HAZ and malaria, with a mix of positive and negative estimates, of which 3 out of 20 are significantly different from zero at the conventional 5% level. The meta-analysis showed that this variation in the estimated effect of malaria incidence on HAZ is significantly associated with the amount of arable land. CONCLUSION: Confounding effects on the association between malaria and stunting vary both by country and over time. Geostatistical analysis provides a useful framework that allows to account for unmeasured spatial confounders. Establishing whether the association between malaria and stunting is causal would require longitudinal follow-up data on individual children. PMID- 29482561 TI - Development of a functionalized UV-emitting nanocomposite for the treatment of cancer using indirect photodynamic therapy. AB - BACKGROUND: Photodynamic therapy is a promising cancer therapy modality but its application for deep-seated tumor is mainly hindered by the shallow penetration of visible light. X-ray-mediated photodynamic therapy (PDT) has gained a major attention owing to the limitless penetration of X-rays. However, substantial outcomes have still not been achieved due to the low luminescence efficiency of scintillating nanoparticles and weak energy transfer to the photosensitizer. The present work describes the development of Y2.99Pr0.01Al5O12-based (YP) mesoporous silica coated nanoparticles, multifunctionalized with protoporphyrin IX (PpIX) and folic acid (YPMS@PpIX@FA) for potential application in targeted deep PDT. RESULTS: A YP nanophosphor core was synthesized using the sol-gel method to be used as X-ray energy transducer and was then covered with a mesoporous silica layer. The luminescence analysis indicated a good spectral overlap between the PpIX and nanoscintillator at the Soret as well as Q-band region. The comparison of the emission spectra with or without PpIX showed signs of energy transfer, a prerequisite for deep PDT. In vitro studies showed the preferential uptake of the nanocomposite in cancer cells expressing the folate receptorFolr1, validating the targeting efficiency. Direct activation of conjugated PpIX with UVA in vitro induced ROS production causing breast and prostate cancer cell death indicating that the PpIX retained its activity after conjugation to the nanocomposite. The in vivo toxicity analysis showed the good biocompatibility and non-immunogenic response of YPMS@PpIX@FA. CONCLUSION: Our results indicate that YPMS@PpIX@FA nanocomposites are promising candidates for X-ray-mediated PDT of deep-seated tumors. The design of these nanoparticles allows the functionalization with exchangeable targeting ligands thus offering versatility, in order to target various cancer cells, expressing different molecular targets on their surface. PMID- 29482562 TI - Determinants of immunization status among 12- to 23-month-old children in Indonesia (2008-2013): a multilevel analysis. AB - BACKGROUND: Immunization is one of the most cost-effective public health interventions to prevent children from contracting vaccine-preventable diseases. Indonesia launched the Expanded Program for Immunization (EPI) in 1977. However, immunization coverage remains far below the United Nations International Children's Emergency Fund (UNICEF) and World Health Organization (WHO) target of 80%. This study aims to investigate the determinants of complete immunization status among children aged 12-23 months in Indonesia. METHODS: We used three waves of the Indonesian National Socioeconomic Survey (2008, 2011, and 2013) and national village censuses from the same years. Multilevel logistic regression was used to conduct the analysis. RESULTS: The number of immunized children increased from 47.48% in 2008 to 61.83% in 2013. The presence of health professionals, having an older mother, and having more educated mothers were associated with a higher probability of a child's receiving full immunization. Increasing the numbers of hospitals, village health posts, and health workers was positively associated with children receiving full immunization. The MOR (median odds ratio) showed that children's likelihood of receiving complete immunization varied significantly among districts. CONCLUSIONS: Both household- and district-level determinants were found to be associated with childhood immunization status. Policy makers may take these determinants into account to increase immunization coverage in Indonesia. PMID- 29482563 TI - Risk factors associated with exposure to bovine respiratory disease pathogens during the peri-weaning period in dairy bull calves. AB - BACKGROUND: Bovine respiratory disease (BRD) remains among the leading causes of death of cattle internationally. The objective of this study was to identify risk factors associated with exposure to BRD pathogens during the peri-weaning period (day (d)-14 to d 14 relative to weaning at 0) in dairy bull calves using serological responses to these pathogens as surrogate markers of exposure. Clinically normal Holstein-Friesian and Jersey breed bull calves (n = 72) were group housed in 4 pens using a factorial design with calves of different breeds and planes of nutrition in each pen. Intrinsic, management and clinical data were collected during the pre-weaning (d - 56 to d - 14) period. Calves were gradually weaned over 14 days (d - 14 to d 0). Serological analysis for antibodies against key BRD pathogens (BRSV, BPI3V, BHV-1, BHV-4, BCoV, BVDV and H. somni) was undertaken at d - 14 and d 14. Linear regression models (for BVDV, BPI3V, BHV-1, BHV-4, BCoV and H. somni) and a single mixed effect random variable model (for BRSV) were used to identify risk factors for changes in antibody levels to these pathogens. RESULTS: BRSV was the only pathogen which demonstrated clustering by pen. Jersey calves experienced significantly lower changes in BVDV S/P than Holstein-Friesian calves. Animals with a high maximum respiratory score (>=8) recorded significant increases in H. somni S/P during the peri-weaning period when compared to those with respiratory scores of <=3. Haptoglobin levels of between 1.32 and 1.60 mg/ml at d - 14 were significantly associated with decreases in BHV-1 S/N during the peri-weaning period. Higher BVDV S/P ratios at d - 14 were significantly correlated with increased changes in serological responses to BHV-4 over the peri-weaning period. CONCLUSIONS: Haptoglobin may have potential as a predictor of exposure to BHV-1. BRSV would appear to play a more significant role at the 'group' rather than 'individual animal' level. The significant associations between the pre-weaning levels of antibodies to certain BRD pathogens and changes in the levels of antibodies to the various pathogens during the peri-weaning period may reflect a cohort of possibly genetically linked 'better responders' among the study population. PMID- 29482564 TI - Comparing public and private providers: a scoping review of hospital services in Europe. AB - BACKGROUND: What is common to many healthcare systems is a discussion about the optimal balance between public and private provision. This paper provides a scoping review of research comparing the performance of public and private hospitals in Europe. The purpose is to summarize and compare research findings and to generate questions for further studies. METHODS: The review was based on a methodological approach inspired by the British EPPI-Centre's methodology. This review was broader than review methodologies used by Cochrane and Campbell and included a wider range of methodological designs. The literature search was performed using PubMed, EconLit and Web of Science databases. The search was limited to papers published from 2006 to 2016. The initial searches resulted in 480 studies. The final sample was 24 papers. Of those, 17 discussed economic effects, and seven studies addressed quality. RESULTS: Our review of the 17 studies representing more than 5500 hospitals across Europe showed that public hospitals are most frequently reported as having the best economic performance compared to private not-for-profit (PNFP) and private for-profit (PFP) hospitals. PNFP hospitals are second, while PFP hospitals are least frequently reported as superior. However, a sizeable number of studies did not find significant differences. In terms of quality, the results are mixed, and it is not possible to draw clear conclusions about the superiority of an ownership type. A few studies analyzed patient selection. They indicated that public hospitals tend to treat patients who are slightly older and have lower socioeconomic status, riskier lifestyles and higher levels of co-morbidity and complications than patients treated in private hospitals. CONCLUSIONS: The paper points to shortcomings in the available studies and argues that future studies are needed to investigate the relationship between contextual circumstances and performance. A big weakness in many studies addressing economic effects is the failure to control for quality and other operational dimensions, which may have influenced the results. This weakness should also be addressed in future comparative studies. PMID- 29482565 TI - Characterization of the resistance class 1 integrons in Staphylococcus aureus isolates from milk of lactating dairy cattle in Northwestern China. AB - BACKGROUND: Integrons are mobile DNA elements and they have an important role in acquisition and dissemination of antimicrobial resistance genes. However, there are limited data available on integrons of Staphylococcus aureus (S. aureus) from bovine mastitis, especially from Chinese dairy cows. To address this knowledge gap, bovine mastitis-inducing S. aureus isolates were investigated for the presence of integrons as well as characterization of gene cassettes. Integrons were detected using PCR reactions and then further characterized by a restriction fragment-length polymorphism analysis and amplicon sequencing. RESULTS: All 121 S. aureus isolates carried the class 1 integrase gene intI1, with no intI2 and intI3 genes detected. One hundred and three isolates were positive for the presence of 12 resistance genes, either alone or in combination with other gene cassettes. These resistance genes encoded resistance to trimethoprim (dhfrV, dfrA1, dfrA12), aminoglycosides (aadA1, aadA5, aadA4, aadA24, aacA4, aadA2, aadB), chloramphenicol (cmlA6) and quaternary ammonium compound (qacH) and were organized into 11 different gene cassettes arrangements (A-K). The gene cassette arrays dfrA1-aadA1 (D, 44.6%), aadA2 (K, 31.4%), dfrA12-orfX2-aadA2 (G, 27.3%) and aadA1 (A, 25.6%) were most prevalent. Furthermore, 74 isolates contained combinations of 2 to 4 gene cassette arrays. Finally, all of the integron/cassettes-positive isolates were resistant to aminoglycoside antibiotics. CONCLUSIONS: This is the first study on the integrons and gene cassette arrays in S. aureus isolates from milk of mastitic cows from Northwestern China and provide the evidence for class 1 integron as possible antibiotic resistance determinants on dairy farms. PMID- 29482566 TI - Predictive value of neutrophil to lymphocyte ratio and platelet to lymphocyte ratio for acute deep vein thrombosis after total joint arthroplasty: a retrospective study. AB - BACKGROUND: Deep vein thrombosis (DVT) is a common and severe complication of total joint arthroplasty (TJA). Inflammation has been proved to play a role in DVT. The neutrophil to lymphocyte ratio (NLR) and the platelet to lymphocyte ratio (PLR) are biomarkers for systemic inflammation. The aim of the study is to investigate the predictive value of NLR and PLR for acute TJA-induced DVT. METHOD: A total of 773 patients who underwent primary TJA in our hospital were included in this retrospective study. Venography was performed routinely after the surgery to define acute DVT. NLR and PLR before and after operation were calculated according to the blood routine test. Multiple logistic regression analyses and ROC curve analyses were performed to assess the association of NLR and PLR with TJA-induced DVT. RESULTS: One hundred twenty out of 773 patients (15.5%) were diagnosed with DVT by venography. In patients with DVT, preoperative NLR (P = 0.030) and postoperative NLR (P = 0.015) were significantly higher but postoperative PLR (P = 0.002) was significantly lower. Multiple logistic regression analyses indicated that age (OR = 1.05, P < 0.005), gender (OR = 0.47, P = 0.005), BMI (OR = 1.06, P < 0.014), preoperative NLR (OR = 1.11, P < 0.035), postoperative NLR (OR = 1.20, P < 0.001), and PLR (OR = 0.99, P < 0.001) were independently associated with DVT. However, the ROC curve analysis demonstrated the specificity and sensitivity of NLR or PLR in predicting DVT were low. CONCLUSION: Although the present study demonstrated significant association of perioperative NLR or PLR with acute TJA-induced DVT, NLR or PLR cannot predict TJA-induced DVT accurately. PMID- 29482567 TI - Oxidative stress and endothelial function in normal pregnancy versus pre eclampsia, a combined longitudinal and case control study. AB - BACKGROUND: Pre-eclampsia (PE) is related to an impaired endothelial function. Endothelial dysfunction accounts for altered vascular reactivity, activation of the coagulation cascade and loss of vascular integrity. Impaired endothelial function originates from production of inflammatory and cytotoxic factors by the ischemic placenta and results in systemic oxidative stress (OS) and an altered bioavailability of nitric oxide (*NO). The free radical *NO, is an endogenous endothelium-derived relaxing factor influencing endothelial function. In placental circulation, endothelial release of *NO dilates the fetal placental vascular bed, ensuring feto-maternal exchange. The Endopreg study was designed to evaluate in vivo endothelial function and to quantify in vitro OS in normal and pre-eclamptic pregnancies. METHODS/DESIGN: The study is divided into two arms, a prospective longitudinal study and a matched case control study. In the longitudinal study, pregnant patients >=18 years old with a singleton pregnancy will be followed throughout pregnancy and until 6 months post-partum. In the case control study, cases with PE will be compared to matched normotensive pregnant women. Maternal blood concentration of superoxide (O2*) and placental concentration of *NO will be determined using EPR (electron paramagnetic resonance). Endothelial function and arterial stiffness will be evaluated using respectively Peripheral Arterial Tonometry (PAT), Flow-Mediated Dilatation (FMD) and applanation tonometry. Placental expression of eNOS (endothelial NOS) will be determined using immune-histochemical staining. Target recruitment will be 110 patients for the longitudinal study and 90 patients in the case-control study. DISCUSSION: The results of Endopreg will provide longitudinal information on in vivo endothelial function and in vitro OS during normal pregnancy and PE. Adoption of these vascular tests in clinical practice potentially predicts patients at risk to develop cardiovascular events later in life after PE pregnancies. *NO, O2*- and eNOS measurements provide further inside in the pathophysiology of PE. TRIAL REGISTRATION: This trial has been registered on clinicaltrials.gov. ClinicalTrials.gov Identifier: NCT02603913 . Registered October 2015. PMID- 29482569 TI - Generation of GHR-modified pigs as Laron syndrome models via a dual-sgRNAs/Cas9 system and somatic cell nuclear transfer. AB - BACKGROUND: Laron syndrome is an autosomal disease resulting from mutations in the growth hormone receptor (GHR) gene. The only therapeutic treatment for Laron syndrome is recombinant insulin-like growth factor I (IGF-I), which has been shown to have various side effects. The improved Laron syndrome models are important for better understanding the pathogenesis of the disease and developing corresponding therapeutics. Pigs have become attractive biomedical models for human condition due to similarities in anatomy, physiology, and metabolism relative to humans, which could serve as an appropriate model for Laron syndrome. METHODS: To further improve the GHR knockout (GHRKO) efficiency and explore the feasibility of precise DNA deletion at targeted sites, the dual-sgRNAs/Cas9 system was designed to target GHR exon 3 in pig fetal fibroblasts (PFFs). The vectors encoding sgRNAs and Cas9 were co-transfected into PFFs by electroporation and GHRKO cell lines were established by single cell cloning culture. Two biallelic knockout cell lines were selected as the donor cell line for somatic cell nuclear transfer for the generation of GHRKO pigs. The genotype of colonies, cloned fetuses and piglets were identified by T7 endonuclease I (T7ENI) assay and sequencing. The GHR expression in the fibroblasts and piglets was analyzed by confocal microscopy, quantitative polymerase chain reaction (q-PCR), western blotting (WB) and immunohistochemical (IHC) staining. The phenotype of GHRKO pigs was recapitulated through level detection of IGF-I and glucose, and measurement of body weight and body size. GHRKO F1 generation were generated by crossing with wild-type pigs, and their genotype was detected by T7ENI assay and sequencing. GHRKO F2 generation was obtained via self-cross of GHRKO F1 pigs. Their genotypes of GHRKO F2 generation was also detected by Sanger sequencing. RESULTS: In total, 19 of 20 single-cell colonies exhibited biallelic modified GHR (95%), and the efficiency of DNA deletion mediated by dual-sgRNAs/Cas9 was as high as 90% in 40 GHR alleles of 20 single-cell colonies. Two types of GHR allelic single-cell colonies (GHR-47/-1, GHR-47/-46) were selected as donor cells for the generation of GHRKO pigs. The reconstructed embryos were transferred into 15 recipient gilts, resulting in 15 GHRKO newborn piglets and 2 fetuses. The GHRKO pigs exhibited slow growth rates and small body sizes. From birth to 13 months old, the average body weight of wild-type pigs varied from 0.6 to 89.5 kg, but that of GHRKO pigs varied from only 0.9 to 37.0 kg. Biochemically, the knockout pigs exhibited decreased serum levels of IGF-I and glucose. Furthermore, the GHRKO pigs had normal reproduction ability, as eighteen GHRKO F1 piglets were obtained via mating a GHRKO pig with wild-type pigs and five GHRKO F2 piglets were obtained by self-cross of F1 generation, indicating that modified GHR alleles can pass to the next generation via germline transmission. CONCLUSION: The dual sgRNAs/Cas9 is a reliable system for DNA deletion and that GHRKO pigs conform to typical phenotypes of those observed in Laron patients, suggesting that these pigs could serve as an appropriate model for Laron syndrome. PMID- 29482568 TI - Proteomic profile of human spermatozoa in healthy and asthenozoospermic individuals. AB - Asthenozoospermia is considered as a common cause of male infertility and characterized by reduced sperm motility. However, the molecular mechanism that impairs sperm motility remains unknown in most cases. In the present review, we briefly reviewed the proteome of spermatozoa and seminal plasma in asthenozoospermia and considered post-translational modifications in spermatozoa of asthenozoospermia. The reduction of sperm motility in asthenozoospermic patients had been attributed to factors, for instance, energy metabolism dysfunction or structural defects in the sperm-tail protein components and the differential proteins potentially involved in sperm motility such as COX6B, ODF, TUBB2B were described. Comparative proteomic analysis open a window to discover the potential pathogenic mechanisms of asthenozoospermia and the biomarkers with clinical significance. PMID- 29482570 TI - Factors contributing to the decision to perform a cesarean section in Labrador retrievers. AB - BACKGROUND: In the past 10 years, the frequency of unplanned cesarean sections in the Labrador Retriever breeding colony at Guiding Eyes for the Blind stayed around 10% (range 5% to 28%). To reduce the number of cesarean sections, factors influencing the occurrence of a cesarean section need to be known. The goal of this study was to identify factors that contribute to the decision to perform a cesarean section. RESULTS: Of the 688 Labrador Retriever litters whelped between 2003 and 2016, 667 litters had sufficient data and remained in the analysis. The target trait was ordinal with the three levels "normal whelping", "assisted whelping" and "cesarean section". A general ordinal logistic regression approach was used to analyze the data. Model selection with possible predictors resulted in a final model including weight of the dam, the weight of the heaviest puppy of a litter, the number of fetuses malpositioned and the quality of uterine contractions. Weight and size of a litter, parity, maternal inbreeding coefficient, whelping season, dam and sire were dropped from the model because they were not significant. The risk of a cesarean section was influenced by the combination of the weight of the dam and the weight of the heaviest puppy in the litter, as well as by the number of malpositioned fetuses and the quality of the contractions. Larger puppies increased the risk of cesarean section especially when the dam had a lighter weight. For dams weighing 23.6 kg and 32.8 kg the predicted probability of a cesarean section was low, with 0.06 and 0.02, respectively, when the heaviest puppy in a litter was light (0.42 kg), contractions were normal and no fetus was malpositioned. However, the probability of a cesarean section was much higher, ranging from 0.24 to 0.08, when the heaviest puppy in a litter was heavy (0.66 kg). CONCLUSIONS: Means to reduce the cesarean section frequency in this Labrador Retriever breeding colony should include genetic selection for ideal puppy weight. In addition, dams with an adult body weight substantially below average should not be selected as breeders in this colony. PMID- 29482571 TI - Prenatal exposure to TCDD and atopic conditions in the Seveso second generation: a prospective cohort study. AB - BACKGROUND: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a toxic environmental contaminant that can bioaccumulate in humans, cross the placenta, and cause immunological effects in children, including altering their risk of developing allergies. On July 10, 1976, a chemical explosion in Seveso, Italy, exposed nearby residents to a high amount of TCDD. In 1996, the Seveso Women's Health Study (SWHS) was established to study the effects of TCDD on women's health. Using data from the Seveso Second Generation Health Study, we aim to examine the effect of prenatal exposure to TCDD on the risk of atopic conditions in SWHS children born after the explosion. METHODS: Individual-level TCDD was measured in maternal serum collected soon after the accident. In 2014, we initiated the Seveso Second Generation Health Study to follow-up the children of the SWHS cohort who were born after the explosion or who were exposed in utero to TCDD. We enrolled 677 children, and cases of atopic conditions, including eczema, asthma, and hay fever, were identified by self-report during personal interviews with the mothers and children. Log-binomial and Poisson regressions were used to determine the association between prenatal TCDD and atopic conditions. RESULTS: A 10-fold increase in 1976 maternal serum TCDD (log10TCDD) was not significantly associated with asthma (adjusted relative risk (RR) = 0.93; 95% CI: 0.61, 1.40) or hay fever (adjusted RR = 0.99; 95% CI: 0.76, 1.27), but was significantly inversely associated with eczema (adjusted RR = 0.63; 95% CI: 0.40, 0.99). Maternal TCDD estimated at pregnancy was not significantly associated with eczema, asthma, or hay fever. There was no strong evidence of effect modification by child sex. CONCLUSIONS: Our results suggest that maternal serum TCDD near the time of explosion is associated with lower risk of eczema, which supports other evidence pointing to the dysregulated immune effects of TCDD. PMID- 29482572 TI - Wilms' tumor 1-associating protein promotes renal cell carcinoma proliferation by regulating CDK2 mRNA stability. AB - BACKGROUND: Wilms' tumor 1-associating protein (WTAP) plays an important role in physiological processes and the development of tumor such as cell cycle regulation. The regulation of cell cycle is mainly dependent on cyclins and cyclin-dependent protein kinases (CDKs). Recent studies have shown that CDKs are closely related to the tumor diagnosis, progression and response to treatment. However, their specific biological roles and related mechanism in renal cell carcinoma (RCC) remain unknown. METHODS: Quantitative real-time PCR, western blotting and immunohistochemistry were used to detect the expression of WTAP and CDK2. The survival analysis was adopted to explore the association between WTAP expression and the prognosis of RCC. Cells were stably transfected with lentivirus approach and cell proliferation and cell cycle, as well as tumorigenesis in nude mice were performed to assess the effect of WTAP in RCC. RNA immunoprecipitation, Luciferase reporter assay and siRNA were employed to identify the direct binding sites of WTAP with CDK2 transcript. Colony formation assay was conducted to confirm the function of CDK2 in WTAP-induced growth promoting. RESULTS: In RCC cell lines and tissues, WTAP was significantly over expressed. Compared with patients with low expression of WTAP, patients with high expression of WTAP had lower overall survival rate. Additionally, cell function test indicated that cell proliferation abilities in WTAP over-expressed group were enhanced, while WTAP knockdown showed the opposite results. Subcutaneous xenograft tumor model displayed that knockdown of WTAP could impede tumorigenesis in vivo. Mechanism study exhibited that CDK2 expression was positively associated with the expression of WTAP. Moreover, WTAP stabilized CDK2 transcript to enhance CDK2 expression via binding to 3'-UTR of CDK2 transcript. Additionally, specific inhibitors of CDK2 activity and small interfering RNA (siRNA) of CDK2 expression inhibited WTAP-mediated promotion of proliferation. CONCLUSIONS: These findings suggest that WTAP may have an oncogenic role in RCC through physically binding to CDK2 transcript and enhancing its transcript stability which might provide new insights into RCC therapy. PMID- 29482573 TI - Clinicopathological features and EBV infection status of lymphoma in children and adolescents in South China: a retrospective study of 662 cases. AB - BACKGROUND: The clinicopathological features and Epstein-Barr virus (EBV) infection status of lymphoma in children and adolescents in South China is under researched. South China is a well-known high-incidence area of EBV-associated nasopharyngeal carcinoma. METHODS: A cohort of 662 consecutive children and adolescents' lymphomas was retrospectively analyzed and Epstein-Barr virus encoded RNAs (EBERs) in situ hybridization was performed to detect the EBV infection. RESULTS: The majority (501/662, 75.7%) of lymphomas in children and adolescents was Non-Hodgkin lymphoma (NHL). One hundred sixty one cases (24.3%) were Hodgkin lymphoma (HL). Of the NHL, precursor cell lymphoma, mature B-cell lymphoma and peripheral T/NK-cell lymphoma accounted for 32.0%, 41.1% and 26.9% respectively. The five common subtypes were lymphoblastic lymphoma (32.0%), Burkitt lymphoma (BL) (21.0%), anaplastic large-cell lymphoma (ALCL) (14.2%), diffuse large B-cell lymphoma (DLBCL) (13.8%) and extranodal NK/T-cell lymphoma, nasal type (ENKTCL) (6.2%). EBV infection was detected in 58.9% classical Hodgkin lymphomas (CHLs), 21.4% mature B-cell lymphomas and 52.4% peripheral T/NK-cell lymphomas. Moreover, EBV was associated with high grade NHL including ENKTCL (100.0%), BL (30.5%) and DLBCL (17.6%). CONCLUSION: The high proportion of peripheral T/NK-cell lymphomas in children and adolescents in South China are presented in this study and compared to western countries due to the high percentage of ENKTCL. ENKTCL is firmly associated with EBV infection, while more than half of HL, a portion of BL and DLBCL are related to EBV infection. This study conclusively demonstrates that EBV infection is more prevalent in children and adolescents with lymphomas in South China compared to western countries. PMID- 29482574 TI - Potential role of orexin A binding the receptor 1 for orexins in normal and cryptorchid dogs. AB - BACKGROUND: Cryptorchidism is one of the most common birth disorders of the male reproductive system identified in dogs and other mammals. This condition is characterised by the absence of one (unilateral) or both (bilateral) gonads from the scrotum. The peptides orexin A (OxA) and B (OxB) were obtained by post transcriptional proteolytic cleavage of a precursor molecule, called prepro orexin. These substances bind two types of G-coupled receptors called receptor 1 (OX1R) and 2 (OX2R) for orexins. OX1R is specific to OxA while OX2R binds the two peptides with equal affinity. Orexins modulate a great variety of body functions, such as the reproductive mechanism. The purpose of the present research was to study the presence of OxA and its receptor 1 and their possible involvement in the canine testis under healthy and pathological conditions. METHODS: This study was performed using adult male normal dogs and male dogs affected by unilateral cryptorchidism. Tissue samples were collected from testes and were divided into three groups: normal, contralateral and cryptic. The samples were used for immunohistochemistry, Western blot and in vitro tests for testosterone evaluation in normal and pathological conditions. RESULTS: OxA-immunoreactivity (IR) was described in interstitial Leydig cells of the normal gonad, and Leydig, Sertoli cells and gonocytes in the cryptic gonad. In the normal testis, OX1R-IR was described in Leydig cells, in pachytene and second spermatocytes and in immature and mature spermatids throughout the stages of the germ developing cycle of the male gonad. In the cryptic testis OX1R-IR was distributed in Leydig and Sertoli cells. The presence of prepro-orexin and OX1R was demonstrated by Western blot analysis. The incubation of fresh testis slices with OxA caused the stimulation of testosterone synthesis in the normal and cryptic gonad while the steroidogenic OxA-induced effect was cancelled by adding the selective OX1R antagonist SB 408124. CONCLUSIONS: These results led us to hypothesise that OxA binding OX1R might be involved in the modulation of spermatogenesis and steroidogenesis in canine testis in healthy and pathological conditions. PMID- 29482575 TI - i-GONAD: a robust method for in situ germline genome engineering using CRISPR nucleases. AB - We present a robust method called improved-Genome editing via Oviductal Nucleic Acids Delivery (i-GONAD) that delivers CRISPR ribonucleoproteins to E0.7 embryos via in situ electroporation. The method generates mouse models containing single base changes, kilobase-sized deletions, and knock-ins. The efficiency of i-GONAD is comparable to that of traditional microinjection methods, which rely on ex vivo handling of zygotes and require recipient animals for embryo transfer. In contrast, i-GONAD avoids these technically difficult steps, and it can be performed at any laboratory with simple equipment and technical expertise. Further, i-GONAD-treated females retain reproductive function, suggesting future use of the method for germline gene therapy. PMID- 29482576 TI - The viable circulating tumor cells with cancer stem cells feature, where is the way out? AB - With cancer stem cells (CSCs) became the research hotspot, emerging studies attempt to reveal the functions of these special subsets in tumorigenesis. Although various approaches have been used in CSCs researches, only a few could really reflect or simulate the microenvironment in vivo. At present, CSCs theories are still difficult to apply for clinical remedy because CSCs subpopulations are always hard to identify and trace. Thus an ideal approach for clinicians and researchers is urgently needed. Circulating tumor cells (CTCs), as the method of noninvasive-liquid biopsy, could be detected in the peripheral blood (PB) from many tumors and even could be treated as procurators for CSCs deeper researches from patient-derived sample. However, CTCs, as a diagnostic marker, also raise much controversy over theirs clinical value. Mechanisms causing CTCs to shed from the tumor have not been fully characterized, thus it is unclear whether CTCs represent the entire makeup of cancer cells in the tumor or only a subset. The heterogeneity of CTCs also caused different clinical outcomes. To overcome these unsolved problems, recently, CTC researches are not just depend on enumerations, whereas those CTC subsets that could expand in vitro may play a pivotal role in the metastatic cascade. Here, we retrospect the CTC developmental history and discourse upon the enrichment of viable CTCs in functional assays, probe the further avenue at the crossroad. PMID- 29482577 TI - Inhibition of thioredoxin activates mitophagy and overcomes adaptive bortezomib resistance in multiple myeloma. AB - BACKGROUND: Although current chemotherapy using bortezomib (Velcade) against multiple myeloma in adults has achieved significant responses and even remission, a majority of patients will develop acquired resistance to bortezomib. Increased thioredoxin level has been reported to be associated with carcinogenesis; however, the role of thioredoxin in bortezomib drug resistance of myeloma remains unclear. METHODS: We generated several bortezomib-resistant myeloma cell lines by serially passaging with increased concentrations of bortezomib over a period of 1.5 years. Thioredoxin expression was measured by real-time PCR and western blot. RESULTS: The role of thioredoxin in the survival of bortezomib-resistant myeloma cells was determined by specific shRNA knockdown in vitro and in vivo. Thioredoxin inhibitor (PX12) was used to determine the effectiveness of thioredoxin inhibition in the treatment of bortezomib-resistant myeloma cells. The effect of thioredoxin inhibition on mitophagy induction was examined. The correlation of thioredoxin expression with patient overall survival was interrogated. Thioredoxin expression was significantly upregulated in bortezomib resistant myeloma cells and the change correlated with the increase of bortezomib concentration. Thioredoxin gene knockdown using specific shRNA sensitized bortezomib-resistant myeloma cells to bortezomib efficiency in vitro and in vivo. Similarly, pharmacological inhibition with PX12 inhibited the growth of bortezomib-resistant myeloma cells and overcame bortezomib resistance in vitro and in vivo. Furthermore, inhibition of thioredoxin resulted in the activation of mitophagy and blockage of mitophagy prevented the effects of PX12 on bortezomib resistant myeloma cells, indicating that mitophagy is the important molecular mechanism for the induction of cell death in bortezomib-resistant myeloma cells by PX12. Moreover, inhibition of thioredoxin resulted in downregulation of phosphorylated mTOR and ERK1/2. Finally, thioredoxin was overexpressed in primary myeloma cells isolated from bortezomib-resistant myeloma patients and overexpression of thioredoxin correlated with poor overall survival in patients with multiple myeloma. CONCLUSIONS: Our findings demonstrated that increased thioredoxin plays a critical role in bortezomib resistance in multiple myeloma through mitophagy inactivation and increased mTOR and ERK1/2 phosphorylation. Thioredoxin provides a potential target for clinical therapeutics against multiple myeloma, particularly for bortezomib-resistant/refractory myeloma patients. PMID- 29482578 TI - NOD-like receptor X1 functions as a tumor suppressor by inhibiting epithelial mesenchymal transition and inducing aging in hepatocellular carcinoma cells. AB - BACKGROUND: This study was performed to investigate the role of nucleotide binding oligomerization domain (NOD)-like receptor X1 (NLRX1) in regulating hepatocellular carcinoma (HCC) progression. METHODS: Expression levels of NLRX1 in clinical specimens and cell lines were determined by reverse transcription polymerase chain reaction (RT-PCR) and western blot (WB). Transwell assays were conducted to evaluate the effect of NLRX1 on cell invasion, and flow cytometry was used to assess apoptosis. Expression patterns of key molecules in the phosphoinositide 3-kinase (PI3K)-AKT pathways were determined via WB. The effect of NLRX1 on cell senescence was evaluated with beta-galactosidase assays. Kaplan Meier analyses and Cox regression models were used for prognostic evaluation. RESULTS: NLRX1 was downregulated in tumor tissue compared with adjacent normal liver tissue. Low tumor NLRX1 expression was identified as an independent indicator for HCC prognosis (recurrence: hazard ratio [HR] 1.87, 95% confidence interval [CI] 1.26-2.76, overall survival [OS] 2.26, 95% CI 1.44-3.56). NLRX1 over-expression (OE) significantly inhibited invasiveness ability and induced apoptosis in HCC cells. In vivo experiments showed that NLRX1 knock-down (KD) significantly promoted HCC growth. Mechanistically, NLRX1 exhibited a suppressor function by decreasing phosphorylation of AKT and thus downregulating Snail1 expression, which inhibited epithelial-mesenchymal-transition (EMT) in HCC cells. Moreover, NLRX1 OE could induce cell senescence via an AKT-P21-dependent manner. CONCLUSIONS: NLRX1 acted as a tumor suppressor in HCC by inducing apoptosis, promoting senescence, and decreasing invasiveness by repressing PI3K-AKT signaling pathway. Future investigations will focus on restoring expression of NLRX1 to provide new insights into HCC treatment. PMID- 29482579 TI - Vasomotor function in rat arteries after ex vivo and intragastric exposure to food-grade titanium dioxide and vegetable carbon particles. AB - BACKGROUND: Humans are continuously exposed to particles in the gastrointestinal tract. Exposure may occur directly through ingestion of particles via food or indirectly by removal of inhaled material from the airways by the mucociliary clearance system. We examined the effects of food-grade particle exposure on vasomotor function and systemic oxidative stress in an ex vivo study and intragastrically exposed rats. METHODS: In an ex vivo study, aorta rings from naive Sprague-Dawley rats were exposed for 30 min to food-grade TiO2 (E171), benchmark TiO2 (Aeroxide P25), food-grade vegetable carbon (E153) or benchmark carbon black (Printex 90). Subsequently, the vasomotor function was assessed in wire myographs. In an in vivo study, lean Zucker rats were exposed intragastrically once a week for 10 weeks to vehicle, E171 or E153. Doses were comparable to human daily intake. Vasomotor function in the coronary arteries and aorta was assessed using wire myographs. Tetrahydrobiopterin, ascorbate, malondialdehyde and asymmetric dimethylarginine were measured in blood as markers of oxidative stress and vascular function. RESULTS: Direct exposure of E171 to aorta rings ex vivo increased the acetylcholine-induced vasorelaxation and 5 hydroxytryptamine-induced vasocontraction. E153 only increased acetylcholine induced vasorelaxation, and Printex 90 increased the 5-hydroxytryptamine-induced vasocontraction, whereas Aeroxide P25 did not affect the vasomotor function. In vivo exposure showed similar results as ex vivo exposure; increased acetylcholine induced vasorelaxation in coronary artery segments of E153 and E171 exposed rats, whereas E171 exposure altered 5-hydroxytryptamine-induced vasocontraction in distal coronary artery segments. Plasma levels of markers of oxidative stress and vascular function showed no differences between groups. CONCLUSION: Gastrointestinal tract exposure to E171 and E153 was associated with modest albeit statistically significant alterations in the vasocontraction and vasorelaxation responses. Direct particle exposure to aorta rings elicited a similar type of response. The vasomotor responses were not related to biomarkers of systemic oxidative stress. PMID- 29482580 TI - Upregulation of lactate-inducible snail protein suppresses oncogene-mediated senescence through p16INK4a inactivation. AB - BACKGROUND: The preferential use of aerobic glycolysis by tumor cells lead to high accumulation of lactate in tumor microenvironment. Clinical evidence has linked elevated lactate concentration with cancer outcomes. However, the role and molecular mechanisms of lactate in cellular senescence and tumor progression remain elusive. METHODS: The function of Snail in lactate-induced EMT in lung cancer cells was explored by wound healing assay and cell invasion assay. The qRT PCR and dual luciferase reporter assay were performed to investigate how lactate regulates Snail expression. The level of TGF-beta1 in culture supernatant of cells was measured by ELISA for its correlation with extracellular levels of lactate. Ras activity assay and SA-beta-gal activity assay were established to determine the effect of lactate on oncogene-induced senescence in human lung epithelial cells. ChIP assays were conducted to determine the binding of snail to p16INK4a promoter. Two TCGA data sets (TCGA-LUAD and TCGA-LUSC) were used to explore the correlations between SNAI1 and CDKN2A expression. RESULTS: In this study, we showed the invasive and migratory potential of lung cancer cells was significantly enhanced by lactate and was directly linked to snail activity. We also demonstrated that extracellular acidification itself is a direct cause of the increased snail expression and physiologically coupled to LDHA-dependent conversion of pyruvate to lactate. Mechanistically, lactate exerts its central function in induction of snail and EMT by directly remodeling ECM and releasing activated TGF-beta1. We also demonstrated that Snail help premalignant cells to escape the oncogene-induced senescence by directly targeting and inhibiting p16INK4a expression. CONCLUSIONS: Our study extends the understanding of EMT in tumorigenesis by uncovering the role of snail in cellular senescence. This study also reveals lactate may be a potent tumor-promoting factor and provides the basis for the development of lactate-targeted therapy. PMID- 29482581 TI - The chromatin remodeling subunit Baf200 promotes normal hematopoiesis and inhibits leukemogenesis. AB - BACKGROUND: Adenosine triphosphate (ATP)-dependent chromatin remodeling SWI/SNF like BAF and PBAF complexes have been implicated in the regulation of stem cell function and cancers. Several subunits of BAF or PBAF, including BRG1, BAF53a, BAF45a, BAF180, and BAF250a, are known to be involved in hematopoiesis. Baf200, a subunit of PBAF complex, plays a pivotal role in heart morphogenesis and coronary artery angiogenesis. However, little is known on the importance of Baf200 in normal and malignant hematopoiesis. METHODS: Utilizing Tie2-Cre-, Vav-iCre-, and Mx1-Cre-mediated Baf200 gene deletion combined with fetal liver/bone marrow transplantation, we investigated the function of Baf200 in fetal and adult hematopoiesis. In addition, a mouse model of MLL-AF9-driven leukemogenesis was used to study the role of Baf200 in malignant hematopoiesis. We also explored the potential mechanism by using RNA-seq, RT-qPCR, cell cycle, and apoptosis assays. RESULTS: Tie2-Cre-mediated loss of Baf200 causes perinatal death due to defective erythropoiesis and impaired hematopoietic stem cell expansion in the fetal liver. Vav-iCre-mediated loss of Baf200 causes only mild anemia and enhanced extramedullary hematopoiesis. Fetal liver hematopoietic stem cells from Tie2-Cre + , Baf200 f/f or Vav-iCre + , Baf200 f/f embryos and bone marrow hematopoietic stem cells from Vav-iCre + , Baf200 f/f mice exhibited impaired long-term reconstitution potential in vivo. A cell-autonomous requirement of Baf200 for hematopoietic stem cell function was confirmed utilizing the interferon-inducible Mx1-Cre mouse strain. Transcriptomes analysis revealed that expression of several erythropoiesis- and hematopoiesis-associated genes were regulated by Baf200. In addition, loss of Baf200 in a mouse model of MLL-AF9-driven leukemogenesis accelerates the tumor burden and shortens the host survival. CONCLUSION: Our current studies uncover critical roles of Baf200 in both normal and malignant hematopoiesis and provide a potential therapeutic target for suppressing the progression of leukemia without interfering with normal hematopoiesis. PMID- 29482582 TI - CAMKs support development of acute myeloid leukemia. AB - BACKGROUND: We recently identified the human leukocyte immunoglobulin-like receptor B2 (LILRB2) and its mouse ortholog-paired Ig-like receptor (PirB) as receptors for several angiopoietin-like proteins (Angptls). We also demonstrated that PirB is important for the development of acute myeloid leukemia (AML), but exactly how an inhibitory receptor such as PirB can support cancer development is intriguing. RESULTS: Here, we showed that the activation of Ca (2+)/calmodulin dependent protein kinases (CAMKs) is coupled with PirB signaling in AML cells. High expression of CAMKs is associated with a poor overall survival probability in patients with AML. Knockdown of CAMKI or CAMKIV decreased human acute leukemia development in vitro and in vivo. Mouse AML cells that are defective in PirB signaling had decreased activation of CAMKs, and the forced expression of CAMK partially rescued the PirB-defective phenotype in the MLL-AF9 AML mouse model. The inhibition of CAMK kinase activity or deletion of CAMKIV significantly slowed AML development and decreased the AML stem cell activity. We also found that CAMKIV acts through the phosphorylation of one of its well-known target (CREB) in AML cells. CONCLUSION: CAMKs are essential for the growth of human and mouse AML. The inhibition of CAMK signaling may become an effective strategy for treating leukemia. PMID- 29482583 TI - Control angiography for perioperative myocardial Ischemia after coronary surgery: meta-analysis. AB - BACKGROUND: Perioperative myocardial ischemia (PMI) in patients undergoing coronary artery bypass grafting (CABG) is associated with poor outcome. The aim of this study was to pool the available data on the outcome after control angiography and repeat revascularization in patients with perioperative myocardial ischemia (PMI) after coronary artery bypass grafting (CABG). METHODS: A literature review was performed through PubMed, Scopus, ScienceDirect and Google Scholar to identify studies published since 1990 evaluating the outcome of PMI after CABG. RESULTS: Nine studies included 1104 patients with PMI after CABG and 1056 of them underwent control angiography early after CABG. Pooled early mortality after reoperation for PMI without control angiography was 43.6% (95%CI 29.7-57.6%) and 79.8% of them (95%CI 64.4-95.2%) had an acute graft failure detected at reoperation. Among patients who underwent control angiography for PMI, 31.7% had a negative finding at angiography (95%CI 25.6-37.8%) and 62.1% had an acute graft failure (95%CI 56.6-67.6%). Repeat revascularization was performed after early control angiography in 46.3% of patients (95%CI 39.9-52.6%; 54.2% underwent repeat surgical revascularization; 45.8% underwent percutaneous coronary intervention). Pooled early mortality after control angiography with or without repeat revascularization was 8.9% (95%CI 6.7-11.1%). Three studies reported on early mortality rates which did not differ between repeat surgical revascularization and PCI (11.7% vs. 9.2%, respectively; risk ratio 1.45, 95%CI 0.67-3.11). In these three series, early mortality after conservative treatment was 5.9% (95%CI 3.6-8.2%). CONCLUSIONS: Control angiography seems to be a valid life-saving strategy to guide repeat revascularization in hemodynamically stable patients suffering PMI after CABG. PMID- 29482584 TI - Differential cyclooxygenase expression levels and survival associations in type I and type II ovarian tumors. AB - BACKGROUND: High cyclooxygenase (COX)-2 expression in ovarian tumors has been associated with poor prognosis, but the role of COX-1 expression and its relation to survival is less clear. Here, we evaluated COX expression and associations with survival outcomes between type I (clear cell, mucinous, low grade endometrioid and low grade serous) and type II (high grade serous and high grade endometrioid) ovarian tumors. METHODS: We developed and validated a new COX-1 antibody, and conducted immunohistochemical (IHC) staining for COX-1 and COX-2 on a tissue microarray (TMA) of 190 primary ovarian tumors. In addition to standard IHC scoring and H-scores to combine the percentage of positive cells and staining intensity, we also measured COX-1 and COX-2 mRNA expression by QPCR. High expression was defined as greater than or equal to median values. Clinical characteristics and disease outcomes were ascertained from medical records. Associations with disease-free survival (DFS) and overall survival (OS) were quantified by hazard ratios (HRs) and confidence intervals (CIs) from proportional hazards regression. RESULTS: Type I tumors had high COX-2 expression, while type II tumors had high COX-1 expression. In multivariable adjusted regression models, higher COX-1 mRNA expression was associated with shorter DFS (HR: 6.37, 95% CI: 1.84-22.01) and OS (HR: 2.26, 95% CI: 1.04-4.91), while higher H-scores for COX-2 expression were associated with shorter DFS (HR: 1.92, 95% CI: 1.06-3.49). Stratified analysis indicated that COX-2 was significantly associated with DFS among cases with Type II tumors (HR: 1.93, 95% CI: 1.06-3.53). CONCLUSIONS: These findings suggest that ovarian tumor type contributes to differences in COX expression levels and associations with survival. PMID- 29482585 TI - "The Notion of Neutrality in Clinical Ethics Consultation". AB - Clinical ethics consultation (CEC), as an activity that may be provided by clinical ethics committees and consultants, is nowadays a well-established practice in North America. Although it has been increasingly implemented in Europe and elsewhere, no agreement can be found among scholars and practitioners on the appropriate role or approach the consultant should play when ethically problematic cases involving conflicts and uncertainties come up. In particular, there is no consensus on the acceptability of consultants making recommendations, offering moral advice upon request, and expressing personal opinions. We translate these issues into the question of whether the consultant should be neutral when performing an ethics consultation. We argue that the notion of neutrality 1) functions as a hermeneutical key to review the history of CEC as a whole; 2) may be enlightened by a precise assessment of the nature and goals of CEC; 3) refers to the normative dimension of CEC. Here, we distinguish four different meanings of neutrality: a neutral stance toward the parties involved in clinical decision making, toward the arguments offered to frame the discussion, toward the values and norms involved in the case, and toward the outcome of decision making, that is to say the final decision and action that will be implemented. Lastly, we suggest a non-authoritarian way to intend the term "recommendation" in the context of clinical ethics consultation. PMID- 29482586 TI - Assessing the efficacy of a culturally adapted cognitive behavioural internet delivered treatment for depression: protocol for a randomised controlled trial. AB - BACKGROUND: Depression is the principal cause of disability in the world. High prevalence rates of depression in general populations and college students have been found worldwide and in various cultural groups. Low-intensity cognitive behavioural internet-delivered treatment has demonstrated efficacy in high-income countries (HICs). However little is known of their potential for adaptation and efficacy in low and middle-income countries. METHODS: Study (1) involves the cultural adaptation of the Space from Depression cognitive-behaviour internet delivered programme with an asynchronous support for depressive symptoms. This includes initial researcher/clinician adaptation and the integration of cultural assessment feedback of the programme by a panel of experts and users through the theoretically-based Cultural Relevance Questionnaire (CRQ). Study (2) describes the implementation of the culturally adapted intervention using a randomised controlled trial methodology. The efficacy trial will include an active treatment group and a waiting-list control group of participants meeting eligibility criteria (mild to moderate depression symptoms). The active condition will consist of 7 weekly modules of internet-delivered cognitive behavioural therapy (iCBT) Space from Depression, with post-session feedback support. The primary outcome will be the Patient Health Questionnaire (PHQ-9). The study also involves collection of client reported significant events and client satisfaction with the internet-delivered treatment. Data will be collected at baseline and at post treatment (week 7), and at follow-up (week 20/3 months). Analysis will be conducted on the intention-to-treat basis. DISCUSSION: The study seeks to establish a theoretically robust methodology for culturally adapting internet delivered interventions for mental health disorders and to evaluate the efficacy of a culturally adapted internet-delivered treatment for depression in Colombia, with support. The study will be a first contribution to a method for culturally adapting internet-delivered interventions and also a first to examine the efficacy of such an adapted intervention in Latin America. TRIAL REGISTRATION: Clinical trials NCT03062215. Retrospectively registered 14th February 2017. PMID- 29482587 TI - High rate of unplanned pregnancy in the context of integrated family planning and HIV care services in South Africa. AB - BACKGROUND: Integration of family planning services into HIV care was implemented in South Africa as a core strategy aimed at reducing unintended pregnancies among childbearing women living with HIV. However, it is unclear whether this strategy has made any significant impact at the population level. This paper describes the prevalence and correlates of self-reported unplanned pregnancy among HIV-infected parturient women attending three large maternity centres in the Eastern Cape, South Africa. We also compare unplanned pregnancy rates between HIV-infected parturient women already in care (who have benefitted from services' integration) and newly diagnosed parturient women (who have not benefitted from services' integration). METHODS: Drawing from the baseline data of the East London Prospective Cohort Study (ELPCS), data of 594 parturient women living with HIV in the Eastern Cape were included. Chi-square statistics and binary logistics regression were employed to determine the correlates of unplanned pregnancy among the cohort. RESULTS: The prevalence of unplanned pregnancy was 71% (n = 422) with a higher rate among parturient women newly diagnosed during the index pregnancy (87%). Unplanned pregnancy was significantly associated with younger age, single status, HIV diagnosis at booking, high parity and previous abortion. Women who reported unplanned pregnancy were more likely to book late and have lower CD4 counts. After adjusting for confounding variables, having one child and five to seven children (AOR = 2.2; CI = 1.3-3.1), age less than 21 years (AOR = 3.3; CI = 1.1-9.8), late booking after 27 weeks (AOR = 2.7; CI = 1.5-5.0), not married (AOR = 4.3; CI = 2.7-6.8) and HIV diagnosis at booking (AOR = 3.0; CI = 1.6-5.8) were the significant correlates of unplanned pregnancy in the cohort. CONCLUSION: Unplanned pregnancy remains high overall among parturient women living with HIV in the region, however, with significant reduction among those who were exposed to integrated services. The study confirms that integration of HIV care and family planning services is an important strategy to reduce unplanned pregnancy among women living with HIV. The study's findings have significant implications for the elimination of mother-to-child transmission of HIV in South Africa. Innovative interventions are needed to further consolidate and maximise the benefit of the integration of family planning services with HIV care. PMID- 29482588 TI - Antifibrotic and molecular aspects of rifaximin in alcoholic liver disease: study protocol for a randomized controlled trial. AB - BACKGROUND: Alcoholic liver disease is the leading cause of cirrhosis worldwide. Due to an increase in alcohol overuse, alcoholic liver disease has become an increased burden on health care systems. Abstinence from alcohol remains the cornerstone of alcoholic liver disease treatment; however, this approach is hampered by frequent relapse and lack of specific therapy for treating advanced cases of liver disease. In the present study, we hypothesized that gut microbiota drive the development of liver fibrosis and that modulation of gut microbiota with the gut-selective, nonabsorbable antibiotic rifaximin attenuates alcoholic liver fibrosis. METHODS/DESIGN: Our double-blind, placebo-controlled trial will include 136 participants with biopsy-verified alcoholic fibrosis (Ishak liver fibrosis score of 1-4). Participants are randomized 1:1 to receive placebo or 550 mg of rifaximin twice daily for 18 months. A liver biopsy will be performed at the end of the treatment period to evaluate the effect of drug treatment on liver fibrosis. Stool, urine, and saliva specimens will be collected before treatment begins, at 1 month, and at the end of the treatment period. Fecal samples are used for microbiome deep sequencing. Changes in microbiome composition are compared before and after the trial medication period and linked to changes in liver fibrosis. DISCUSSION: This is the first clinical trial to evaluate the effect of gut microbiota on liver fibrosis in humans. If gut microbiota are an important promoter of alcoholic liver disease, current results may open new therapeutic avenues and revolutionize the current understanding of chronic liver diseases. TRIAL REGISTRATION: EudraCT, 2014-001856-51 . Registered on 16 August 2014. PMID- 29482589 TI - Heterologous expression and antitumor activity analysis of syringolin from Pseudomonas syringae pv. syringae B728a. AB - BACKGROUND: Syringolin, synthesized by a mixed non-ribosomal peptide synthetase/polyketide synthetase in Pseudomonas syringae pv. syringae (Pss) B728a, is a novel eukaryotic proteasome inhibitor. Meanwhile, directly modifying large fragments in the PKS/NRPS gene cluster through traditional DNA engineering techniques is very difficult. In this study, we directly cloned the syl gene cluster from Pss B301D-R via Red/ET recombineering to effectively express syringolin in heterologous hosts. RESULTS: A 22 kb genomic fragment containing the sylA-sylE gene cluster was cloned into the pASK vector, and the obtained recombinant plasmid was transferred into Streptomyces coelicolor and Streptomyces lividans for the heterologous expression of syringolin. Transcriptional levels of recombinant syl gene in S. coelicolor M145 and S. lividans TK24 were evaluated via RT-PCR and the production of syringolin compounds was detected via LC-MS analysis. The extracts of the engineered bacteria showed cytotoxic activity to B16, 4T1, Meth-A, and HeLa tumor cells. It is noteworthy that the syringolin displayed anticancer activity against C57BL/6 mice with B16 murine melanoma tumor cells. Together, our results herein demonstrate the potential of syrinolin as effective antitumor agent that can treat various cancers without apparent adverse effects. CONCLUSIONS: This present study is the first to report the heterologous expression of the entire syl gene cluster in Streptomyces strains and the successful expression of syringolin in both S. coelicolor M145 and S. lividans TK24. Syringolin derivatives demonstrated high cytotoxicity in vitro and in vivo. Hence, this paper provided an important foundation for the discovery and production of new antitumor compounds. PMID- 29482590 TI - Proper detailed parameters for S1 sacral alar iliac screw placement in the Chinese population, a 3D imaging study. AB - BACKGROUND: S1-AI technique may be used as a salvage technique in pelvic fixation of complex spinal deformity surgery. However, the proper detailed parameters in the Chinese population has not been analyzed before to instruct S1-AI screws placement and to ensure the safety of clinical application while the trajectory in pelvic changes significantly at each angle. RESULTS: The ideal S1AI screw trajectory could be obtained in 28 of 30 female patient images (93.3%) and in all of the male patient images (100%). The screws that have already been used clinically in S2AI pathways can be applied in S1AI fixations. CONCLUSION: It is feasible to place S1AI screws in 93.3% of female Chinese adult patients and in all male Chinese patients. Preoperative CT reconstruction should be performed to evaluate proper trajectory parameters and to avoid anterior violation. PMID- 29482591 TI - Clinical significance of circulating microRNAs as markers in detecting and predicting congenital heart defects in children. AB - BACKGROUND: Circulating microRNAs (miRNAs) are emerging as novel biomarkers for detecting cardiovascular diseases. In this study, we aimed to investigate the usefulness of miRNAs as biomarkers in diagnosing and predicting children with congenital heart defects (CHD), particularly in the context of multiple subtypes of CHD. METHODS: We recruited 26 families, each having a child with CHD and parents who do not have any cardiovascular disorder. 27 families unaffected by cardiovascular disease were also included as controls. Firstly, we screened 84 circulating miRNAs relating to cardiovascular development in 6 children with atrial septal defects (ASD) and 5 healthy children. We validated the selected miRNAs with differential expression in a larger sample size (n = 27 for controls, n = 26 for cases), and evaluated their signal in different types of septal defects. Finally, we examined the identified miRNAs signatures in the parent population and assessed their diagnostic values for predicting CHD. RESULTS: The three miRNAs hsa-let-7a, hsa-let-7b and hsa-miR-486 were significantly upregulated in children with ASD. A further validation study showed that overexpression of hsa-let-7a and hsa-let-7b was specifically present in ASD children, but not in children with other subtypes of septal defects. A similar expression profile of hsa-let-7a and hsa-let-7b was discovered in mothers of ASD children. Receiver-operating characteristic curve analyses indicated that hsa-let 7a and hsa-let-7b had significant diagnostic values for detecting ASD and in maternal samples predicting the occurrence of ASD in offspring. CONCLUSIONS: Circulating miRNAs are important markers not only for diagnosing CHD, but also for predicting CHD risk in offspring. The distinct miRNA signatures are likely to present in various subtypes of CHD, and the phenotypic heterogeneity of CHD should be considered to develop such miRNA-based assays. PMID- 29482592 TI - PMA: Protein Microarray Analyser, a user-friendly tool for data processing and normalization. AB - OBJECTIVE: Protein microarrays provide a high-throughput platform to measure protein interactions and associated functions, and can aid in the discovery of cancer biomarkers. The resulting protein microarray data can however be subject to systematic bias and noise, thus requiring a robust data processing, normalization and analysis pipeline to ensure high quality and robust results. To date, a comprehensive data processing pipeline is yet to be developed. Furthermore, a lack of analysis consistency is evident amongst different research groups, thereby impeding collaborative data consolidation and comparison. Thus, we sought to develop an accessible data processing tool using methods that are generalizable to the protein microarray field and which can be adapted to individual array layouts with minimal software engineering expertise. RESULTS: We developed an improved version of a previously developed pipeline of protein microarray data processing and implemented it as an open source software tool, with particular focus on widening its use and applicability. The Protein Microarray Analyser software presented here includes the following tools: (1) neighbourhood background correction, (2) net intensity correction, (3) user defined noise threshold, (4) user-defined CV threshold amongst replicates and (5) assay controls, (6) composite 'pin-to-pin' normalization amongst sub-arrays, and (7) 'array-to-array' normalization amongst whole arrays. PMID- 29482594 TI - Tracheal injury detected immediately after median sternotomy by inexperienced surgeons: two case reports. AB - BACKGROUND: Although median sternotomy is standard during cardiac surgery, the procedure is associated with a risk of injury to mediastinal organs. Here, we discuss two cases of tracheal injury following median sternotomy during cardiac surgery. CASE PRESENTATION: Ventilation failure occurred in a 78-year-old Japanese man and a 71-year-old Japanese man after median sternotomy, and tracheal injury was identified. The sites of injury were directly repaired and covered with mediastinal fat tissue, following which ventilation was successful. The burn like deposits observed at the site of tracheal injury and on the removed endotracheal tube support the notion that the injuries in our patients were caused by electrocautery prior to median sternotomy. In one case, short sternotracheal distance may have contributed to tracheal injury during post sternal manipulation. In both cases, the relative inexperience of both surgeons also supports the suspected cause of injury. CONCLUSIONS: Tracheal injury represents a potential complication following median sternotomy, especially when performed by inexperienced surgeons or in cases of short sternotracheal distance. Anesthesiologists should consider this rare yet potentially lethal complication. PMID- 29482595 TI - Lessons learned from the blockade of immune checkpoints in cancer immunotherapy. AB - The advent of immunotherapy, especially checkpoint inhibitor-based immunotherapy, has provided novel and powerful weapons against cancer. Because only a subset of cancer patients exhibit durable responses, further exploration of the mechanisms underlying the resistance to immunotherapy in the bulk of cancer patients is merited. Such efforts may help to identify which patients could benefit from immune checkpoint blockade. Given the existence of a great number of pathways by which cancer can escape immune surveillance, and the complexity of tumor-immune system interaction, development of various combination therapies, including those that combine with conventional therapies, would be necessary. In this review, we summarize the current understanding of the mechanisms by which resistance to checkpoint blockade immunotherapy occurs, and outline how actionable combination strategies may be derived to improve clinical outcomes for patients. PMID- 29482593 TI - Spatial and temporal variation in the abundance of Culicoides biting midges (Diptera: Ceratopogonidae) in nine European countries. AB - BACKGROUND: Biting midges of the genus Culicoides (Diptera: Ceratopogonidae) are vectors of bluetongue virus (BTV), African horse sickness virus and Schmallenberg virus (SBV). Outbreaks of both BTV and SBV have affected large parts of Europe. The spread of these diseases depends largely on vector distribution and abundance. The aim of this analysis was to identify and quantify major spatial patterns and temporal trends in the distribution and seasonal variation of observed Culicoides abundance in nine countries in Europe. METHODS: We gathered existing Culicoides data from Spain, France, Germany, Switzerland, Austria, Denmark, Sweden, Norway and Poland. In total, 31,429 Culicoides trap collections were available from 904 ruminant farms across these countries between 2007 and 2013. RESULTS: The Obsoletus ensemble was distributed widely in Europe and accounted for 83% of all 8,842,998 Culicoides specimens in the dataset, with the highest mean monthly abundance recorded in France, Germany and southern Norway. The Pulicaris ensemble accounted for only 12% of the specimens and had a relatively southerly and easterly spatial distribution compared to the Obsoletus ensemble. Culicoides imicola Kieffer was only found in Spain and the southernmost part of France. There was a clear spatial trend in the accumulated annual abundance from southern to northern Europe, with the Obsoletus ensemble steadily increasing from 4000 per year in southern Europe to 500,000 in Scandinavia. The Pulicaris ensemble showed a very different pattern, with an increase in the accumulated annual abundance from 1600 in Spain, peaking at 41,000 in northern Germany and then decreasing again toward northern latitudes. For the two species ensembles and C. imicola, the season began between January and April, with later start dates and increasingly shorter vector seasons at more northerly latitudes. CONCLUSION: We present the first maps of seasonal Culicoides abundance in large parts of Europe covering a gradient from southern Spain to northern Scandinavia. The identified temporal trends and spatial patterns are useful for planning the allocation of resources for international prevention and surveillance programmes in the European Union. PMID- 29482596 TI - Baden Prevention and Reduction of Incidence of Postoperative Delirium Trial (PRIDe): a phase IV multicenter, randomized, placebo-controlled, double-blind clinical trial of ketamine versus haloperidol for prevention of postoperative delirium. AB - BACKGROUND: Delirium is a neurobehavioural syndrome that frequently develops in the postoperative setting. The incidence of elderly patients who develop delirium during hospital stay ranges from 10-80%. Delirium was first described more than half a century ago in the cardiac surgery population, where it was already discovered as a state that might be accompanied by serious complications such as prolonged ICU and hospital stay, reduced quality of life and increased mortality. Furthermore, the duration of delirium is associated with worse long-term cognitive function in the general ICU population. This long-term experience with delirium suggests a high socioeconomic burden and has been a focus of many studies. Due to the multifactorial origin of delirium, we have several but no incontestable options for prevention and symptomatic treatment. Overall, delirium represents a high burden not only for patient and family members, but also for the medical care team that aims to prevent postoperative delirium to avoid serious consequences associated with it.The purpose of this study is to determine whether postoperative delirium can be prevented by the combination of established preventive agents. In addition, measured levels of pre- and postoperative cortisol, neuron specific enolase (NSE) and S-100beta will be used to investigate dynamics of these parameters in delirious and non-delirious patients after surgery. METHODS/DESIGN: The Baden PRIDe Trial is an investigator-initiated, phase IV, two-centre, randomised, placebo-controlled, double-blind clinical trial for the prevention of delirium with haloperidol, ketamine, and the combination of both vs. placebo in 200 patients scheduled for surgery. We would like to investigate superiority of one of the three treatment arms (i.e., haloperidol, ketamine, combined treatment) to placebo. DISCUSSION: There is limited but promising evidence that haloperidol and ketamine can be used to prevent delirium. Clinical care for patients might improve as the results of this study may lead to better algorithms for the prevention of delirium. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02433041 . Registered on 7 April 2015. Swiss National Clinical Trial Portal, SNCTP000001628. Registered on 9 December 2015. PMID- 29482597 TI - Effects of substance use disorder on treatment process and outcome in a ten session psychiatric treatment for borderline personality disorder. AB - BACKGROUND: Dual diagnosis is common in Borderline Personality Disorder (BPD), one of the most common being Substance Use Disorder (SUD). Previous studies have shown that general psychiatric management (GPM) was effective in reducing borderline symptoms. In the present study, we tested whether the short GPM was as effective in the BPD + SUD as in the BPD group. METHODS: We analysed a group of 99 patients presenting a BPD. 51 of these patients presented a SUD. The BPD group and the BPD + SUD group received a manual-based short variant of the GPM treatment. Previous studies have shown that a 10-session version of GPM was effective in reducing borderline symptoms at the end of the treatment (Psychother Psychosom 83:176-86, 2014). RESULTS: We found no significant difference in the reduction of general symptoms, which diminished in both groups. The specific borderline symptoms were also reduced in both groups, but there was a slightly higher reduction of the borderline symptoms in the SUD group. The therapeutic alliance progressed positively in all groups. Moreover, the alliance increased more over time in the SUD group. CONCLUSION: The short variant of GPM seems to be effective in BPD treatment independently from the presence of SUD. Therefore, this treatment could be an effective entry-level treatment for patients with dual diagnosis as well as patients with BPD only. Further studies are needed to confirm efficacy and long-term outcome. TRIAL REGISTRATION: The trial was registered at ClinicalTrial.gov (identifier NCT01896024 ). PMID- 29482598 TI - Human-induced pluripotent stem cell-derived macrophages and their immunological function in response to tuberculosis infection. AB - BACKGROUND: Induced pluripotent stem cells (iPS) represent an innovative source for the standardized in vitro generation of macrophages (Mphi). Mphi show great promise in disease pathogenesis, particularly tuberculosis. However, there is no information about human iPS-derived (hiPS) macrophages (hiPS-Mphi) in response to tuberculosis infection. METHODS: In the present study, macrophages derived from hiPS were established via embryoid body (EB) formation by using feeder-free culture conditions, and the human monocyte cell line THP-1 (THP-1-Mphi) was used as control. iPS-Mphi were characterized by using morphology, Giemsa staining, nonspecific esterase staining (alpha-NAE), phagocytosis, and surface phenotype. Additionally, after treatment with Bacillus Calmette-Guerin (BCG) for 24 h, cell apoptosis was detected by using an Annexin V-FITC Apoptosis Detection assay. The production of nitric oxide (NO), expression of tumor necrosis factor alpha (TNF alpha), activity of apoptosis-related protein cysteine-3 (Caspase-3) and expression of B-cell lymphoma-2 (Bcl-2) were analyzed. RESULTS: With respect to morphology, surface phenotype, and function, the iPS-Mphi closely resembled their counterparts generated in vitro from a human monocyte cell line. iPS-Mphi exhibited the typically morphological characteristics of macrophages, such as round, oval, fusiform and irregular characteristics. The cells were Giemsa stained-positive, alpha-NAE-positive, and possessed phagocytic ability. iPS-Mphi express high levels of CD14, CD11b, CD40, CD68, and major histocompatibility complex II (MHC-II). Moreover, with regard to the apoptotic rate, the production of NO, expression of TNF-alpha, and activity of Caspase-3 and Bcl-2, iPS-Mphi closely resemble that of their counterparts generated in vitro from human monocyte cell line in response to BCG infection. The rate of apoptosis of BCG treated iPS-Mphi was 37.77 +/- 7.94% compared to that of the untreated group at 4.97 +/- 1.60% (P < 0.01) by using Annexin V-FITC Apoptosis Detection. Additionally, the rate of apoptosis of BCG-treated THP-1-Mphi was 37.1 +/- 2.84% compared to that of the untreated group at 6.19 +/- 1.68% (P < 0.001). The expression of TNF-alpha and the production of NO were significantly increased (P < 0.001), and the activity of Caspase-3 was increased. However, the expression of Bcl-2 was inhibited (P < 0.001). CONCLUSIONS: Our results demonstrate that Mphi derived from hiPS perform the immunological function in response to Bacillus Calmette-Guerin infection by undergoing apoptosis, increasing the production of NO and expression of TNF-alpha. Thus, our study may help to overcome the limitations of research into certain rare diseases due to the lack of adequate supply of disease-specific primary cells. PMID- 29482599 TI - Protocol: mixed-methods study to evaluate implementation, enforcement, and outcomes of U.S. state laws intended to curb high-risk opioid prescribing. AB - BACKGROUND: The U.S. opioid epidemic has been driven by the high volume of opioids prescribed by healthcare providers. U.S. states have recently enacted four types of laws designed to curb high-risk prescribing practices, such as high dose and long-term opioid prescribing, associated with opioid-related mortality: (1) mandatory Prescription Drug Monitoring Program (PDMP) enrollment laws, which require prescribers to enroll in their state's PDMP, an electronic database of patients' controlled substance prescriptions, (2) mandatory PDMP query laws, which require prescribers to query the PDMP prior to prescribing an opioid, (3) opioid prescribing cap laws, which limit the dose and/or duration of opioid prescriptions, and (4) pill mill laws, which strictly regulate pain clinics to prevent nonmedical opioid prescribing. Some pain experts have expressed concern that these laws could negatively affect pain management among patients with chronic non-cancer pain. This paper describes the protocol for a mixed-methods study analyzing the independent effects of these four types of laws on opioid prescribing patterns and chronic non-cancer pain treatment, accounting for variation in implementation and enforcement of laws across states. METHODS: Many states have enacted multiple opioid prescribing laws at or around the same time. To overcome this issue, our study focuses on 18 treatment states that each enacted a single law of interest, and no other potentially confounding laws, over a 4-year period (2 years pre-/post-law). Qualitative interviews with key leaders in each of the 18 treatment states will characterize the timing, scope, and strength of each state law's implementation and enforcement. This information will inform the design and interpretation of synthetic control models analyzing the effects of each of the two types of laws on two sets of outcomes: measures of (1) high-risk opioid prescribing and (2) non-opioid treatments for chronic non cancer pain. DISCUSSION: Study of mandatory PDMP enrollment, mandatory PDMP query, opioid prescribing cap, and pill mill laws is timely given a dynamic policy environment in which numerous states pass, revise, implement, and enforce varied laws to address opioid prescribing each year. Findings will inform enactment, implementation, and enforcement of these laws in additional states. PMID- 29482600 TI - Effects of undernutrition on survival of human immunodeficiency virus positive children on antiretroviral therapy. AB - BACKGROUND: The relationship between undernutrition and HIV is bidirectional, ultimately contributing to quality of life and survival of affected individuals. Ethiopia is a sub-Saharan nation influenced by both undernutrition and HIV. In Ethiopia, although individuals are often dually impacted, the effect of undernutrition on the survival of HIV positive children on anti-retroviral therapy (ART) has not been well investigated. Therefore, this study assessed the effect of undernutrition on survival rates of HIV positive children on ART in Amhara Regional State of Ethiopia. METHODS: An institution-based retrospective cohort study was conducted among 390 HIV positive children on ART from the 1st of January, 2012 to the 28th of February, 2017 in Amhara Regional State Referral Hospitals. A simple random sampling technique was used to select the study participants. Data were extracted by reviewing patients' ART intake and follow-up forms. Data were entered into Epi-Data Version 3.1, and analysis was done using STATA Version 13. The Kaplan-Meier survival curve was used to estimate the cumulative survival time of the sample. Log rank tests were employed to compare the survival time between different categories of explanatory variables. Bivariable and multivariable Cox proportional hazards models were fitted to identify predictors of mortality. RESULTS: Among the 390 records included in the final analysis, 9.7% of the individuals died within the follow-up period. In this study, the overall mortality rate was found to be 4.4 per 100 child-years (95% CI: 3.2, 6.0) while undernourished children had a lower survival time than well nourished children. Low hemoglobin level (AHR: 3.2, 95% CI: 1.4, 7.4), CD4 cell count or percent below the threshold (AHR: 5.2, 95% CI: 1.9, 14.1), severe stunting (AHR: 3.9, 95% CI: 1.7, 9.4), severe wasting (AHR: 3.0, 95% CI: 1.3, 6.9) and advanced disease stage (III and IV) (AHR: 2.6, 95% CI: 1.1, 6.6) were found to be predictors of mortality. CONCLUSION: There was a high rate of mortality. A significant difference was observed in the survival rate of undernourished and well-nourished children. Low hemoglobin level, CD4 count or percent below the threshold, severe wasting, severe stunting, and advanced disease stage were found to be predictors of mortality. PMID- 29482601 TI - Efficacy of high-intensity, low-volume interval training compared to continuous aerobic training on insulin resistance, skeletal muscle structure and function in adults with metabolic syndrome: study protocol for a randomized controlled clinical trial (Intraining-MET). AB - BACKGROUND: Evidence of the efficacy of high-intensity, low-volume interval training (HIIT-low volume) in treating insulin resistance (IR) in patients with metabolic disorders is contradictory. In addition, it is unknown whether this effect is mediated through muscle endocrine function, which in turn depends on muscle mass and fiber type composition. Our aims were to assess the efficacy of HIIT-low volume compared to continuous aerobic exercise (CAE) in treating IR in adults with metabolic syndrome (MS) and to establish whether musclin, apelin, muscle mass and muscle composition are mediators of the effect. METHODS: This is a controlled, randomized, clinical trial using the minimization method, with blinding of those who will evaluate the outcomes and two parallel groups for the purpose of showing superiority. Sixty patients with MS and IR with ages between 40 and 60 years will be included. A clinical evaluation will be carried out, along with laboratory tests to evaluate IR (homeostatic model assessment (HOMA)), muscle endocrine function (serum levels of musclin and apelin), thigh muscle mass (by dual energy x-ray absorptiometry (DXA) and thigh muscle composition (by carnosine measurement with proton magnetic resonance spectroscopy (1H-MRS)), before and after 12 weeks of a treadmill exercise program three times a week. Participants assigned to the intervention (n = 30) will receive HIIT-low volume in 22-min sessions that will include six intervals at a load of 90% of maximum oxygen consumption (VO2 max) for 1 min followed by 2 min at 50% of VO2 max. The control group (n = 30) will receive CAE at an intensity of 60% of VO2 max for 36 min. A theoretical model based on structural equations will be proposed to estimate the total, direct and indirect effects of training on IR and the proportion explained by the mediators. DISCUSSION: Compared with CAE, HIIT-low volume can be effective and efficient at improving physical capacity and decreasing cardiovascular risk factors, such as IR, in patients with metabolic disorders. Studies that evaluate mediating variables of the effect of HIIT-low volume on IR, such as endocrine function and skeletal muscle structure, are necessary to understand the role of skeletal muscle in the pathophysiology of MS and their regulation by exercise. TRIAL REGISTRATION: NCT03087721 . High intensity Interval, Low Volume Training in Metabolic Syndrome (Intraining-MET). Registered on 22 March 2017, retrospectively registered. PMID- 29482602 TI - Correction to: Self-sampling for human papillomavirus testing among rural young women of KwaZulu-Natal, South Africa. AB - Following publication of the original article [1], one of the authors reported that his name had been spelled incorrectly. It should be Galappaththi-Arachchige, not Galapaththi-Arachchige. PMID- 29482603 TI - Genetic risk for Alzheimer's disease is concentrated in specific macrophage and microglial transcriptional networks. AB - BACKGROUND: Genome-wide association studies of Alzheimer's disease (AD) have identified a number of significant risk loci, the majority of which lie in non coding regions of the genome. The lack of causal alleles and considerable polygenicity remains a significant barrier to translation into mechanistic understanding. This includes identifying causal variants and the cell/tissue types in which they operate. A fuller understanding of the cell types and transcriptional networks involved in AD genetic risk mechanisms will provide important insights into pathogenesis. METHODS: We assessed the significance of the overlap between genome-wide significant AD risk variants and sites of open chromatin from data sets representing diverse tissue types. We then focussed on macrophages and microglia to investigate the role of open chromatin sites containing motifs for specific transcription factors. Partitioned heritability using LDscore regression was used to investigate the contribution of specific macrophage and microglia transcription factor motif-containing open chromatin sites to the heritability of AD. RESULTS: AD risk single nucleotide polymorphisms (SNPs) are preferentially located at sites of open chromatin in immune cells, particularly monocytes (z score = 4.43; corrected P = 5.88 * 10- 3). Similar enrichments are observed for macrophages (z score = 4.10; corrected P < 2.40 * 10 3) and microglia (z score = 4.34, corrected P = 0.011). In both macrophages and microglia, AD risk variants are enriched at a subset of open chromatin sites that contain DNA binding motifs for specific transcription factors, e.g. SPI1 and MEF2. Genetic variation at many of these motif-containing sites also mediate a substantial proportion of AD heritability, with SPI1-containing sites capturing the majority of the common variant SNP-chip heritability (microglia enrichment = 16.28, corrected enrichment P = 0.0044). CONCLUSIONS: AD risk alleles plausibly operate in immune cells, including microglia, and are concentrated in specific transcriptional networks. Combined with primary genetic association results, the SPI1 and MEF2 transcriptional networks appear central to AD risk mechanisms. Investigation of transcription factors targeting AD risk SNP associated regulatory elements could provide powerful insights into the molecular processes affected by AD polygenic risk. More broadly, our findings support a model of polygenic disease risk that arises from variants located in specific transcriptional networks. PMID- 29482604 TI - Autoimmune reactivity to malondialdehyde adducts in systemic lupus erythematosus is associated with disease activity and nephritis. AB - BACKGROUND: Immunoglobulin M (IgM) autoreactivity to malondialdehyde (MDA) protein modifications is part of the natural antibody repertoire in health and may have beneficial functions. In contrast, IgG anti-MDA are increased in chronic inflammation and autoimmunity and may instead have pathogenic properties. METHODS: Herein, we investigated serum IgG anti-MDA levels by enzyme-linked immunosorbent assay (ELISA) in 398 systemic lupus erythematosus (SLE) patients in the Swedish Karolinska SLE cohort and compared these to findings in 225 US SLE patients from New York University and Johns Hopkins University. RESULTS: In two independent cohorts, IgG anti-MDA levels correlated positively with disease activity by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI; p < 0.0001, Spearman R = 0.3). Meta-analysis found an odds ratio of 2.7 (confidence interval (CI) 1.9-3.9; p < 0.0001) for high anti-MDA IgG levels with active disease (SLEDAI >= 6). Furthermore, IgG anti-MDA correlated directly with erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), soluble tumor necrosis factor receptors (sTNFR-1, sTNFR-2), and vascular cell adhesion molecule 1 (VCAM-1) measurements, and inversely with complement factors (C1q, C2, C3, C4). Importantly, IgG anti-MDA levels were significantly elevated in SLE patients with active nephritis (p = 0.0005) and correlated with cystatin C estimated glomerular filtration rate and albuminuria. CONCLUSIONS: Elevated IgG anti-MDA in SLE patients was associated with high disease activity, with active lupus nephritis, and with biomarkers of systemic inflammation. This natural antibody reactivity may have potential prognostic utility, and may also actively contribute to pathogenesis. PMID- 29482605 TI - The relationship between under-five child death and maternal mental distress in Gamo Gofa Zone, Southern Ethiopia: a community based comparative cross-sectional study. AB - BACKGROUND: Knowledge of the association between child death and maternal mental distress may help to understand the indirect impact of reduction of under-five mortality on maternal mental wellbeing. This will further have a positive impact on the development of the nation. Depression is associated substantially with reduced quality of life and functional capacity of women. Although studies in the country assessed the magnitude of Common Mental Disorders (CMD) among postpartum mothers, those assessing the association between child death and maternal mental distress are lacking. Therefore, this study examined the association between child death and maternal mental distress. METHODS: We conducted a comparative cross-sectional study in 2014 on a total of 356 mothers who lost their children and 712 mothers with alive children. We measured CMD symptoms using the World Health Organization's (WHO's) self-reporting questionnaire (SRQ-20). A cut-off score of >=6 was taken as an indicator of mental distress. To determine the relationship between child death and maternal mental distress, we conducted weighted conditional logistic regression analysis with mental distress coded as a binary outcome. RESULTS: Mothers who lost children had significantly higher rate of mental distress (adjusted odds ratio (AOR) of 1.84(1.11-3.04) compared to their counterparts. Similarly, mothers with child loss reported a significantly higher rate of suicidal ideation (23.3%) than mothers without child death (16.3%), with p-value of 0.003. The effect of child loss on maternal mental distress was greater during earlier periods (within 6 months of child death) and it decreased through time. However, it was shown to be persistently high at least during the first three years after child death, relative to mothers with alive child. CONCLUSIONS: Significantly higher proportions of women with child loss experienced mental distress including suicidal ideation than those without. Screening for maternal mental health problems by incorporating simple common mental distress assessing tools, like WHO's SRQ into the maternal and child health care programs of health facilities may have significant effect on reducing the impact of maternal mental health problems in the designated communities. PMID- 29482606 TI - enChIP systems using different CRISPR orthologues and epitope tags. AB - OBJECTIVE: Previously, we developed the engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP) technology, which isolates specific genomic regions while preserving their molecular interactions. In enChIP, the locus of interest is tagged with engineered DNA-binding molecules such as the clustered regularly interspaced short palindromic repeats (CRISPR) system, consisting of a catalytically inactive form of Cas9 (dCas9) and guide RNA, followed by affinity purification of the tagged locus to allow identification of associated molecules. In our previous studies, we used a 3xFLAG-tagged CRISPR system from Streptococcus pyogenes (S. pyogenes). In this study, to increase the flexibility of enChIP, we used the CRISPR system from Staphylococcus aureus (S. aureus) along with different epitope tags. RESULTS: We generated a plasmid expressing S. aureus dCas9 (Sa-dCas9) fused to a nuclear localization signal (NLS) and a 3xFLAG-tag (Sa-dCas9-3xFLAG). The yields of enChIP using Sa-dCas9 3xFLAG were comparable to those using S. pyogenes dCas9 fused with an NLS and a 3xFLAG-tag (3xFLAG-Sp-dCas9). We also generated another enChIP system using Sp dCas9 fused with an NLS and a 2xAM-tag (Sp-dCas9-2xAM). We obtained high enChIP yields using this system as well. Our findings indicate that these tools will increase the flexibility of enChIP analysis. PMID- 29482608 TI - Environmental stochasticity and intraspecific competition influence the population dynamics of Culex quinquefasciatus (Diptera: Culicidae). AB - BACKGROUND: Members of the Culex pipiens complex (Cx. pipiens quinquefasciatus in Southern USA) play a critical role in the spillover of urban arboviruses such as West Nile virus or St. Louis encephalitis virus. Field studies have shown strong correlation between the periodicity of rainfall events and larval proliferation. However, mechanistic determinants driving this relationship are poorly understood. We hypothesize that rainfall events decrease strain from intraspecific competition through the associated reduction of immature density and the introduction of detritus. RESULTS: To address our hypothesis, we used laboratory competition experiments to inform a deterministic matrix projection model consisting of an age-structured larval matrix coupled with a stage structured adult mosquito matrix. Rain events were simulated in a competition based metabolic age model and compared to a null model including environmental variability. Variable rain delays in two-event simulations showed optimal proliferation occurring with rain delays between 16 and 21 days when including density-dependent effects. CONCLUSIONS: These results are comparable to the pattern observed in natural populations, indicating that Cx. quinquefasciatus proliferation rates can be modeled mechanistically as a density-dependent system. The empirical understanding of density-dependence as it relates to environmental stochasticity provides a theoretical platform for the study of larval dynamics and the impact of larval control in this medically relevant disease vector. PMID- 29482607 TI - Cardiomyocyte differentiation of mesenchymal stem cells from bone marrow: new regulators and its implications. AB - In the past years, cardiac mortality has decreased, but cardiac diseases are still responsible for millions of deaths every year worldwide. Bone-marrow mesenchymal stem cells (BMSCs) transplantation may be a promising therapeutic strategy because of its capacity to differentiate into cardiac cells. Current research indicates that chemical substances, microRNAs, and cytokines have biological functions that regulate the cardiomyocytes differentiation of BMSCs. In this review, we chiefly summarize the regulatory factors that induce BMSCs to differentiate into cardiomyocytes. PMID- 29482609 TI - MicroRNA-302b negatively regulates IL-1beta production in response to MSU crystals by targeting IRAK4 and EphA2. AB - BACKGROUND: Interleukin-1beta (IL-1beta) is a pivotal proinflammatory cytokine that is strongly associated with the inflammation of gout. However, the underlying mechanism through which the production of IL-1beta is regulated has not been fully elucidated. Our previous work identified that miR-302b had an important immune regulatory role in bacterial lung infections. This study was conducted to evaluate the function of miR-302b on monosodium urate (MSU) crystal induced inflammation and its mechanism. METHODS: The expression pattern and the immune-regulatory role of miR-302b were evaluated both in vitro and in vivo. The functional targets of miR-302b were predicted by bioinformatics, and then validated by genetic approaches. In addition, the clinical feature of miR-302b was analyzed using serum samples of patients with gouty arthritis. RESULTS: The extremely high expression of miR-302b was observed in both macrophages and mouse air membranes treated with MSU. Intriguingly, overexpression of miR-302b regulated NF-kappaB and caspase-1 signaling, leading to significantly attenuate MSU-induced IL-1beta. By genetic analysis, miR-302b exhibited inhibitory function on IRAK4 and EphA2 by binding to their 3'-UTR regions. Corporately silencing IRAK4 and EphA2 largely impaired MSU-induced IL-1beta protein production. Moreover, it was also found that miR-302b and EphA2 suppressed the migration of macrophages. Finally, it was observed that high expression of miR-302b was a general feature in patients with gouty arthritis. CONCLUSIONS: These results suggest that miR-302b can regulate IL-1beta production in MSU-induced inflammation by targeting NF-kappaB and caspase-1 signaling, and may be a potential therapeutic target for gouty arthritis. PMID- 29482610 TI - Characterization and clinical use of inflammatory cerebrospinal fluid protein markers in Alzheimer's disease. AB - BACKGROUND: Neuroinflammation has gained increasing attention as a potential contributing factor in Alzheimer's disease (AD) pathology. A clinical cerebrospinal fluid biomarker capable of monitoring this process during the course of the disease has yet to emerge, chiefly owing to contradictory research findings. In this study, we sought to clarify the utility of inflammatory biomarkers in diagnostic procedures of AD in three steps: (1) to screen for proteins that are robustly detectable in cerebrospinal fluid; (2) based on this analysis, to explore any associations between the analytically robust markers and salient pathological features of AD; and (3) to determine the discriminative power of these markers in the clinical diagnosis of AD. METHODS: From a total of 46 proteins, 15 that were robustly detectable in cerebrospinal fluid were identified. A subsequent analysis of these markers in a cohort of 399 patients (nondemented subjects, patients with mild cognitive impairment [MCI], and patients with AD, supplemented by smaller cohorts of other diseases) was conducted. Fluid biomarker data were related to AD pathology and neuropsychological markers and adjusted for confounders such as age, sex, apolipoprotein E genotype, and biobank storage time. RESULTS: Cerebrospinal fluid levels of C-reactive protein and soluble TREM2 differed between nondemented subjects, patients with MCI, or patients with AD and were associated with amyloid and tau pathology. Several markers were associated with tau pathology only or with other neurodegenerative diseases. Correlations between neuropsychological performance and inflammatory markers were weak, but they were most prominent in AD and for the most challenging cognitive tests. All investigated covariates had significant influence, with varying effects across the markers. Still, none of the markers achieved discriminative power of more than 70% to distinguish between patient groups defined by clinical or neuropathological categories. CONCLUSIONS: Basic analytical considerations proved indispensable for this type of study because only one-third of the tested markers were robustly detectable in cerebrospinal fluid. Detectable inflammatory protein markers were associated in multiple ways with AD pathology. Yet, even significantly associated markers were not powerful enough in terms of effect strength, sensitivity, and specificity, and hence they were not suited for direct use in clinical diagnostic practice. Targets other than those most commonly considered in this field of research might provide results with better clinical applicability. PMID- 29482611 TI - Biomechanical evaluation of cervical disc replacement with a novel prosthesis based on the physiological curvature of endplate. AB - BACKGROUND: Most of the current available cervical disc prostheses present a flat surface instead of an arcuate surface which is most similar to the morphology of cervical endplate. Therefore, we designed a novel prosthesis (Pretic-I, Trauson) based on the physiological curvature of the cervical endplate. Biomechanical evaluation of cervical disc replacement (CDR) with this novel prosthesis was performed and compared with the Prestige LP prosthesis. METHODS: Three motion segments of 18 cadaveric cervical specimens (C2-C7) were evaluated with a 75 N follower load. Overall, the biomechanics of three models, intact specimen, CDR with the novel prosthesis and CDR with the Prestige LP prosthesis, were studied to gain insight into the effective function of the novel prosthesis. The range of motion (ROM) of all three segments and intradiscal pressure (IDP) on adjacent levels were measured and analysed. RESULTS: Compared to the intact condition, the ROM of all three segments showed no significant difference in the replacement group. Moreover, there was also no significant difference in the ROM between the two prostheses. Besides, the IDP on the cranial adjacent level showed no obvious difference between the two prostheses; nevertheless, the IDP on the caudal adjacent level of the novel prosthesis was significantly less than the Prestige LP prosthesis. CONCLUSIONS: In summary, the novel disc prosthesis was effective to maintain the ROM at the target segment and adjacent segments. Besides, CDR with the novel prosthesis could reduce the IDP on the caudal adjacent level to a certain extent, compared with the Prestige LP prosthesis. PMID- 29482612 TI - Prospective clinical study to evaluate an oscillometric blood pressure monitor in pet rabbits. AB - BACKGROUND: Rabbits are particularly sensitive to develop hypotension during sedation or anaesthesia. Values of systolic or mean non-invasive arterial blood pressure below 80 or 60 mmHg respectively are common under anaesthesia despite an ongoing surgery. A reliable method of monitoring arterial blood pressure is extremely important, although invasive technique is not always possible due to the anatomy and dimension of the artery. The aim of this study was to evaluate the agreement between a new oscillometric device for non-invasive arterial blood pressure measurement and the invasive method. Moreover the trending ability of the device, ability to identify changes in the same direction with the invasive methods, was evaluated as well as the sensibility of the device in identifying hypotension arbitrarily defined as invasive arterial blood pressure below 80 or 60 mmHg. RESULTS: Bland-Altman analysis for repeated measurements showed a poor agreement between the two methods; the oscillometric device overestimated the invasive arterial blood pressure, particularly at high arterial pressure values. The same analysis repeated considering oscillometric measurement that match invasive mean pressure lower or equal to 60 mmHg showed a decrease in biases and limits of agreement between methods. The trending ability of the device, evaluated with both the 4-quadrant plot and the polar plot was poor. Concordance rate of mean arterial blood pressure was higher than systolic and diastolic pressure although inferior to 90%. The sensibility of the device in detecting hypotension defined as systolic or mean invasive arterial blood pressure lower than 80 or 60 mmHg was superior for mean oscillometric pressure rather than systolic. A sensitivity of 92% was achieved with an oscillometric measurement for mean pressure below 65 mmHg instead of 60 mmHg. Non-invasive systolic blood pressure is less sensitive as indicator of hypotension regardless of the cutoff limit considered. CONCLUSIONS: Although mean invasive arterial blood pressure is overestimated by the device, the sensitivity of this non-invasive oscillometric monitor in detecting invasive mean pressure below 60 mmHg is acceptable but a cutoff value of 65 mmHg needs to be used. PMID- 29482614 TI - Improving pain treatment with a smartphone app: study protocol for a randomized controlled trial. AB - BACKGROUND: Chronic pain has become a major health problem across the world, especially in older adults. Unfortunately, the effectiveness of medical interventions is modest. Some have argued that assessment strategies should be improved if the impact of medical interventions is to be improved. Ecological momentary assessment using smartphones is now considered the gold standard in monitoring in health settings, including chronic pain. However, to the best of our knowledge, there is no randomized controlled trial to show that telemonitoring using a smartphone app can indeed improve the effectiveness of medical treatments in adults with chronic pain. The goal of this study will be to explore the effects of using a smartphone app for telemonitoring adults with chronic pain. METHODS: The study will be a randomized controlled trial with three groups: treatment as usual (TAU), TAU+app, and TAU+app+alarms. All groups will receive the adequate treatment for their pain, which will be prescribed the first day of study according to clinical guidelines. Assessment in the TAU group will be the usual at the Pain Clinic, that is, a paper-and-pencil evaluation at the onset of treatment (beginning of study) and at follow up (end of study, 30 days later). The other two groups (TAU+app and TAU+app+alarms) will be assessed daily using Pain Monitor, a smartphone app developed by our multidisciplinary team. Telemonitoring will only be made in the TAU+app+alarms group. For this group, physicians at the Pain Clinic may decide to adjust pain treatment in response to alarms. Telemonitoring is not the usual practice at the Pain Clinic and will not occur in the other two groups (TAU and TAU+app), so no changes in treatment are expected in these groups after the first appointment. The total sample size will be 150, with 50 patients in each group. The assessment protocol will be the same in all groups and will include pain intensity and side effects of the medication (primary outcomes), together with several pain-related variables like pain interference, activity level, use of rescue medication, pain catastrophizing, and pain acceptance, among others. DISCUSSION: We believe that the present trial has important clinical implications. We think that telemonitoring using ecological momentary assessment is crucial to improve current interventions for pain. The armamentarium of available treatments for pain is large, so physicians can turn to different treatments or dosages in the presence of an undesired event. The use of the app for telemonitoring can allow for this rapid detection of unwanted events, thus improving patient safety (i.e., withdrawal of treatment causing side effects) and augmenting treatment effectiveness (i.e., changing an ineffective treatment or dosage). In a time when smartphones are a mainstream technology, we should take advantage of them in the promotion of health care. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03247725 . Registered on 25 July 2017. PMID- 29482613 TI - Identification of a novel mechanism of action of bovine IgG antibodies specific for Staphylococcus aureus. AB - Staphylococcus aureus is a major pathogen that causes subclinical mastitis associated with huge economic losses to the dairy industry. A few vaccines for bovine mastitis are available, and they are expected to induce the production of S. aureus-specific antibodies that prevent bacterial adherence to host cells or promote opsonization by phagocytes. However, the efficacy of such vaccines are still under debate; therefore, further research focusing on improving the current vaccines by seeking additional mechanisms of action is required to reduce economic losses due to mastitis in the dairy industry. Here, we generated S. aureus-specific bovine IgG antibodies (anti-S. aureus) that directly inhibited bacterial growth in vitro. Inhibition depended on specificity for anti-S. aureus, not the interaction between Protein A and the fragment crystallizable region of the IgG antibodies or bacterial agglutination. An in vitro culture study using S. aureus strain JE2 and its deletion mutant JE2DeltaSrtA, which lacks the gene encoding sortase A, revealed that the effect of anti-S. aureus was sortase-A independent. Sortase A is involved in the synthesis of cell-wall-associated proteins. Thus, other surface molecules, such as membrane proteins, cell surface polysaccharides, or both, may trigger the inhibition of bacterial growth by anti S. aureus. Together, our findings contribute insights into developing new strategies to further improve the available mastitis vaccine by designing a novel antigen on the surface of S. aureus to induce inhibitory signals that prevent bacterial growth. PMID- 29482615 TI - 'This is the beginning of the new me': process evaluation of a group fitness intervention to promote wellbeing in formerly homeless individuals. AB - BACKGROUND: Homelessness is a persistent social issue with diverse impacts reaching far beyond individuals. Strategies and research concerning homelessness and health have largely focused on the risk factors and weaknesses of individuals. Such preoccupation has meant the potential strengths and resources within individuals, and so-called strength-based approaches have received less attention. Consequently, understanding how to effectively work with and engage this population in such interventions is limited. METHODS: The current study presents a process evaluation of an 8-week group fitness intervention in a supportive housing facility. The purpose of the intervention was to increase tenants' physical activity together with opportunities for social interaction and support to, in turn, improve physical and mental wellbeing, and ultimately help individuals re-engage in their community. The evaluation focused on seven key components: context, recruitment, reach/participation, dose delivered, dose received, satisfaction/feedback and fidelity. Data collection methods included observation, attendance records and participant and staff interviews. RESULTS: Findings indicate the intervention was appropriate, well delivered, and enjoyed by participants who highlighted the importance of the sessions for their mental wellbeing and social inclusion. The intervention being conducted on site, the trainers' ability to build good rapport with participants together with the supportive environment they created were central to successful implementation. CONCLUSION: Group fitness sessions represent a promising intervention to improve wellbeing of this population. However, the need for more personalised care when delivering fitness sessions, due to the complexity of health issues prevalent in this population, was identified. This has implications for already limited resources, including staffing. Strategies to address this are required to ensure the continuity of fitness programs. Impact evaluation to quantify changes/improvements in wellbeing would complement this work and add much to understanding the effects of participation. PMID- 29482616 TI - The cutoff point of clinical chronic obstructive pulmonary disease questionnaire for more symptomatic patients. AB - BACKGROUND: An adequate threshold for the Clinical Chronic Obstructive Pulmonary Disease (COPD) Questionnaire (CCQ) defining more symptomatic COPD patients has not been determined. We aimed to determine the efficacy of the CCQ and the appropriate CCQ threshold for more symptomatic COPD patients. METHODS: COPD patients aged > 40 years who smoked/had smoked >=10 packs/year were prospectively enrolled over 1 year from three South Korean hospitals (n = 126). Correlations between the CCQ and St. George's Respiratory Questionnaire (SGRQ), COPD Assessment Test (CAT), the modified Medical Round Council (mMRC) scale, lung function, and exercise capacity were evaluated. "More symptomatic patients" were those with an SGRQ score >= 25. Area under the receiver operating curve and classification and regression tree analyses were performed to determine the CCQ threshold equivalent to an SGRQ score >= 25. RESULTS: The CCQ significantly correlated with the SGRQ, CAT, and mMRC scale (r = 0.76, 0.69, and 0.53, respectively). A CCQ cutoff of 1.4 predicted an SGRQ score of 25 better than others. A CCQ score of 1.4 was a significant determinant of an SGRQ score >= 25 even after adjusting for potential confounders. CONCLUSIONS: The CCQ was correlated with other symptom indicators, lung function, and exercise capacity. A CCQ cutoff of 1.4 agreed better than CCQ cutoff of 1.0, suggested by guideline, and this cutoff value may identify more symptomatic COPD patients well. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02527486 . Date of registration: December 19, 2014, retrospectively registered. PMID- 29482617 TI - Systematic comparative validation of self-report measures of sedentary time against an objective measure of postural sitting (activPAL). AB - BACKGROUND: Sedentary behaviour is a public health concern that requires surveillance and epidemiological research. For such large scale studies, self report tools are a pragmatic measurement solution. A large number of self-report tools are currently in use, but few have been validated against an objective measure of sedentary time and there is no comparative information between tools to guide choice or to enable comparison between studies. The aim of this study was to provide a systematic comparison, generalisable to all tools, of the validity of self-report measures of sedentary time against a gold standard sedentary time objective monitor. METHODS: Cross sectional data from three cohorts (N = 700) were used in this validation study. Eighteen self-report measures of sedentary time, based on the TAxonomy of Self-report SB Tools (TASST) framework, were compared against an objective measure of postural sitting (activPAL) to provide information, generalizable to all existing tools, on agreement and precision using Bland-Altman statistics, on criterion validity using Pearson correlation, and on data loss. RESULTS: All self-report measures showed poor accuracy compared with the objective measure of sedentary time, with very wide limits of agreement and poor precision (random error > 2.5 h). Most tools under-reported total sedentary time and demonstrated low correlations with objective data. The type of assessment used by the tool, whether direct, proxy, or a composite measure, influenced the measurement characteristics. Proxy measures (TV time) and single item direct measures using a visual analogue scale to assess the proportion of the day spent sitting, showed the best combination of precision and data loss. The recall period (e.g. previous week) had little influence on measurement characteristics. CONCLUSION: Self-report measures of sedentary time result in large bias, poor precision and low correlation with an objective measure of sedentary time. Choice of tool depends on the research context, design and question. Choice can be guided by this systematic comparative validation and, in the case of population surveillance, it recommends to use a visual analog scale and a 7 day recall period. Comparison between studies and improving population estimates of average sedentary time, is possible with the comparative correction factors provided. PMID- 29482618 TI - Readability of written medicine information materials in Arabic language: expert and consumer evaluation. AB - BACKGROUND: Written Medicine Information (WMI) is one of the sources that patients use to obtain information concerning medicine. This paper aims to assess the readability of two types of WMIs in Arabic language based on vocabulary use and sentence structure using a panel of experts and consumers. METHODS: This is a descriptive study. Two different types of materials, including the online text from King Abdullah Bin Abdulaziz Arabic Health Encyclopaedia (KAAHE) and medication leaflets submitted by the manufacturers to the Saudi Food and Drug Authority (SFDA) were evaluated. We selected a group of sentences from each WMI. The readability was assessed by experts (n = 5) and consumers (n = 5). The sentence readability of each measured using a specific criteria and rated as 1 = easy, 2 = intermediate, or 3 = difficult. RESULTS: A total of 4476 sentences (SFDA 2231; KAHEE 2245) extracted from websites or patient information leaflets on 50 medications and evaluated. The majority of the vocabulary and sentence structure was considered easy by both expert (SFDA: 68%; KAAHE: 76%) and consumer (SFDA: 76%; KAAHE: 84%) groups. The sentences with difficult or intermediate vocabulary and sentence structure are derived primarily from the precautions and side effects sections. CONCLUSIONS: The SFDA and KAAHE WMIs are easy to read and understand as judged by our study sample. However; there is room for improvement, especially in sections related to the side effects and precautions. PMID- 29482619 TI - Population-based analysis of ocular Chlamydia trachomatis in trachoma-endemic West African communities identifies genomic markers of disease severity. AB - BACKGROUND: Chlamydia trachomatis (Ct) is the most common infectious cause of blindness and bacterial sexually transmitted infection worldwide. Ct strain specific differences in clinical trachoma suggest that genetic polymorphisms in Ct may contribute to the observed variability in severity of clinical disease. METHODS: Using Ct whole genome sequences obtained directly from conjunctival swabs, we studied Ct genomic diversity and associations between Ct genetic polymorphisms with ocular localization and disease severity in a treatment-naive trachoma-endemic population in Guinea-Bissau, West Africa. RESULTS: All Ct sequences fall within the T2 ocular clade phylogenetically. This is consistent with the presence of the characteristic deletion in trpA resulting in a truncated non-functional protein and the ocular tyrosine repeat regions present in tarP associated with ocular tissue localization. We have identified 21 Ct non synonymous single nucleotide polymorphisms (SNPs) associated with ocular localization, including SNPs within pmpD (odds ratio, OR = 4.07, p* = 0.001) and tarP (OR = 0.34, p* = 0.009). Eight synonymous SNPs associated with disease severity were found in yjfH (rlmB) (OR = 0.13, p* = 0.037), CTA0273 (OR = 0.12, p* = 0.027), trmD (OR = 0.12, p* = 0.032), CTA0744 (OR = 0.12, p* = 0.041), glgA (OR = 0.10, p* = 0.026), alaS (OR = 0.10, p* = 0.032), pmpE (OR = 0.08, p* = 0.001) and the intergenic region CTA0744-CTA0745 (OR = 0.13, p* = 0.043). CONCLUSIONS: This study demonstrates the extent of genomic diversity within a naturally circulating population of ocular Ct and is the first to describe novel genomic associations with disease severity. These findings direct investigation of host-pathogen interactions that may be important in ocular Ct pathogenesis and disease transmission. PMID- 29482620 TI - Experimental infection model for vibriosis in Dover sole (Solea solea) larvae as an aid in studying its pathogenesis and alternative treatments. AB - Severe economic losses due to diseases in marine larviculture may be linked to vibriosis. To better understand the pathogenesis of vibriosis and evaluate new ways to prevent and combat this important disease, there is a great need for reliable and reproducible experimental infection models. The present study aimed at developing a challenge model for vibriosis in Dover sole larvae and testing its applicability to study the effect of the probiotic treatment. For that purpose, larvae were challenged at 10 days post hatching with Vibrio anguillarum WT, V. anguillarum HI610 or V. harveyi WT. Following administration of V. anguillarum WT via immersion at 1 * 107 colony forming units/mL, a larval mortality of 50% was observed at 17 days post-inoculation. In a next step, the probiotic potential of 371 isolates retrieved from Dover sole was assessed by screening for their inhibitory effects against Vibrio spp. and absence of haemolytic activity. One remaining isolate (V. proteolyticus) and V. lentus, known for its protective characteristics in seabass larvae, were further tested in vivo by means of the pinpointed experimental infection model. Neither isolate provided via the water or feed proved to be protective for the Dover sole larvae against challenge with V. anguillarum WT. This developed challenge model constitutes a firm basis to expedite basic and applied research regarding the pathogenesis and treatment of vibriosis as well as for studying the impact of (a)biotic components on larval health. PMID- 29482621 TI - ISL1 overexpression enhances the survival of transplanted human mesenchymal stem cells in a murine myocardial infarction model. AB - BACKGROUND: The LIM-homeobox transcription factor islet-1 (ISL1) has been proposed as a marker for cardiovascular progenitor cells. This study investigated whether forced expression of ISL1 in human mesenchymal stem cells (hMSCs) improves myocardial infarction (MI) treatment outcomes. METHODS: The lentiviral vector containing the human elongation factor 1alpha promoter, which drives the expression of ISL1 (EF1alpha-ISL1), was constructed using the Multisite Gateway System and used to transduce hMSCs. Flow cytometry, immunofluorescence, Western blotting, TUNEL assay, and RNA sequencing were performed to evaluate the function of ISL1-overexpressing hMSCs (ISL1-hMSCs). RESULTS: The in vivo results showed that transplantation of ISL1-hMSCs improved cardiac function in a rat model of MI. Left ventricle ejection fraction and fractional shortening were greater in post-MI hearts after 4 weeks of treatment with ISL1-hMSCs compared with control hMSCs or phosphate-buffered saline. We also found that ISL1 overexpression increased angiogenesis and decreased apoptosis and inflammation. The greater potential of ISL1-hMSCs may be attributable to an increased number of surviving cells after transplantation. Conditioned medium from ISL1-hMSCs decreased the apoptotic effect of H2O2 on the cardiomyocyte cell line H9c2. To clarify the molecular basis of this finding, we employed RNA sequencing to compare the apoptotic-related gene expression profiles of control hMSCs and ISL1-hMSCs. The results showed that insulin-like growth factor binding protein 3 (IGFBP3) was the only gene in ISL1-hMSCs with a RPKM value higher than 100 and that the difference fold-change between ISL1-hMSCs and control hMSCs was greater than 3, suggesting that IGFBP3 might play an important role in the anti-apoptosis effect of ISL1 hMSCs through paracrine effects. Furthermore, the expression of IGFBP3 in the conditioned medium from ISL1-hMSCs was almost fourfold greater than that in conditioned medium from control hMSCs. Moreover, the IGFBP3 neutralization antibody reversed the apoptotic effect of ISL1-hMSCs-CM. CONCLUSIONS: These results suggest that overexpression of ISL1 in hMSCs promotes cell survival in a model of MI and enhances their paracrine function to protect cardiomyocytes, which may be mediated through IGFBP3. ISL1 overexpression in hMSCs may represent a novel strategy for enhancing the effectiveness of stem cell therapy after MI. PMID- 29482622 TI - Structured approaches to promote patient and family engagement in treatment in acute care hospital settings: protocol for a systematic scoping review. AB - BACKGROUND: While effective engagement of patients and families in treatment is increasingly viewed as a priority for many healthcare systems, much remains to be learned about the nature and outcomes of approaches that seek to accomplish this goal in the acute care hospital setting. Wide variability in the implementation of practices designed to promote patient and family engagement in hospitals has been noted. Approaches aimed at promoting patient and family engagement in treatment share the over-arching goal of changing behaviors of patients, families, and healthcare providers and possibly administrators. Behavior change techniques (BCTs) can be a key element of patient and family engagement approaches. This scoping review will contribute to the development of an evidence base detailing that the BCTs have potential to be effective in patient and family engagement interventions. The specific objectives of this review are to (a) identify and classify approaches used in acute care hospitals to engage patient and families in treatment according to the behavior change technique taxonomy; and (b) evaluate and synthesize the outcomes for these approaches for patients and families, healthcare providers, and health administrators/funders. METHODS: This systematic scoping review will allow us to determine the extent, range, and nature of research activity related to initiatives designed to promote patient and family engagement in care. A comprehensive electronic literature search will be conducted in MEDLINE, EMBASE, and CINAHL. Studies will be included if they report on outcomes of a structured or systematic approach to the promotion of adult inpatient and family engagement in treatment in acute care settings. Studies will be selected in a two-stage screening process (title and abstract; full text) and quality will be assessed using the mixed methods assessment tool. Data extraction will include narrative descriptions of the intervention and classification of the behavior change techniques employed. DISCUSSION: This review aims to identify and classify the specific behavior change techniques underpinning patient and family engagement interventions used in acute care hospital settings. By identifying the "active ingredients" in these interventions, our findings will be transferable to a wide range of acute care hospital contexts and populations. PMID- 29482623 TI - Extraction of total RNA from single-oocytes and single-cell mRNA sequencing of swine oocytes. AB - OBJECTIVE: Analyses of single oocytes are essential for a fine dissection of molecular features governing developmental competence. We adapted the phenol chloroform procedure for the purification of total RNA from single oocytes. RESULTS: Key modifications include the use of PhasemakerTM tubes, a second chloroform wash of the aqueous phase, and the precipitation of the RNA with glyclogen in a 200 MUl micro-centrifuge tube. Assessment of the RNA profile from single oocytes showed distinct peaks for 18S and 28S ribosomal subunits. This approach permitted the extraction of small RNAs from single oocytes, which was evident by the presence of 5S and 5.8S rRNAs and tRNAs around 122-123 nucleotides long. The amplification of polyadenylated RNA resulted in detectable DNA products ranging from ~ 500 to ~ 5000 nucleotides. We used the amplified DNA as template for single-cell mRNA-sequencing of five swine oocytes and quantified the expression levels of 9587 genes with complete coverage of transcripts over 10,000 nucleotides in length. The coverage was similar in all oocytes sequenced, demonstrating consistent high RNA quality across samples. We isolated total RNA from single oocytes and demonstrated that the quality was appropriate for single cell mRNA-sequencing. PMID- 29482624 TI - One-step genetic correction of hemoglobin E/beta-thalassemia patient-derived iPSCs by the CRISPR/Cas9 system. AB - BACKGROUND: Thalassemia is the most common genetic disease worldwide; those with severe disease require lifelong blood transfusion and iron chelation therapy. The definitive cure for thalassemia is allogeneic hematopoietic stem cell transplantation, which is limited due to lack of HLA-matched donors and the risk of post-transplant complications. Induced pluripotent stem cell (iPSC) technology offers prospects for autologous cell-based therapy which could avoid the immunological problems. We now report genetic correction of the beta hemoglobin (HBB) gene in iPSCs derived from a patient with a double heterozygote for hemoglobin E and beta-thalassemia (HbE/beta-thalassemia), the most common thalassemia syndrome in Thailand and Southeast Asia. METHODS: We used the CRISPR/Cas9 system to target the hemoglobin E mutation from one allele of the HBB gene by homology-directed repair with a single-stranded DNA oligonucleotide template. DNA sequences of the corrected iPSCs were validated by Sanger sequencing. The corrected clones were differentiated into hematopoietic progenitor and erythroid cells to confirm their multilineage differentiation potential and hemoglobin expression. RESULTS: The hemoglobin E mutation of HbE/beta-thalassemia iPSCs was seamlessly corrected by the CRISPR/Cas9 system. The corrected clones were differentiated into hematopoietic progenitor cells under feeder-free and OP9 coculture systems. These progenitor cells were further expanded in erythroid liquid culture system and developed into erythroid cells that expressed mature HBB gene and HBB protein. CONCLUSIONS: Our study provides a strategy to correct hemoglobin E mutation in one step and these corrected iPSCs can be differentiated into hematopoietic stem cells to be used for autologous transplantation in patients with HbE/beta-thalassemia in the future. PMID- 29482625 TI - Yield of tuberculosis among household contacts of tuberculosis patients in Accra, Ghana. AB - BACKGROUND: The End TB Strategy calls for systematic screening of selected high risk groups including contacts of tuberculosis (TB) cases to facilitate early TB case detection. Contact investigation is not usually routinely practiced in low TB burden countries, such as Ghana, with consequent paucity of data on the yield of TB case detection from such interventions. This study's objective was to document the outcomes and feasibility of implementing contact investigation activities under programmatic conditions in Ghana. METHODS: Retrospective analyses were conducted of abstracted data from the National TB Program, following a contact investigation intervention for TB cases diagnosed in 10 facilities in Accra from June 2010 to December 2014. Various proportions and yield from number of contacts needed to screen (NNS) and number needed to test (NNT) to detect a TB case were assessed. RESULTS: Overall, out of the 8519 listed contacts of 3267 index cases, 8166 (96%) were screened and 614 (7.5%) were identified as presumptive TB. Out of these, 438 (71%) underwent sputum smear microscopy/evaluation and 53 TB cases were diagnosed. Of these, 56.6% were males, and 49% had sputum smear-positive TB, 38% had sputum smear-negative TB, and 7% had extra-pulmonary TB. The NNS and NNT to detect a TB case of all forms were 154 and 8, respectively. The proportion of TB cases with contacts listed and proportion of contacts screened annually were 88-96% and 83-100%, respectively. The proportion of presumptive TB cases tested and proportion of TB cases diagnosed among contacts tested that were 100% and 36%, respectively, in 2010 dropped to 40% and 14%, respectively, by 2014. CONCLUSIONS: The study demonstrates that contact identification and prioritization components of a contact investigation were feasible, but overall yield of TB cases may have been lower due to the declining rate of clinical evaluation of presumptive TB contacts over time. Addressing barriers to accessing appropriate diagnostic tests may enhance yield from contact investigation in Ghana. PMID- 29482627 TI - Baseline autoantibody profile in rheumatoid arthritis is associated with early treatment response but not long-term outcomes. AB - BACKGROUND: The autoantibody profile of seropositive rheumatoid arthritis (RA) is very diverse and consists of various isotypes and antibodies to multiple post translational modifications. It is yet unknown whether this varying breadth of the autoantibody profile is associated with treatment outcomes. Therefore, we investigated whether the composition of the autoantibody profile in RA, as a marker of the underlying immunopathology, influences initial and long-term treatment outcomes. METHODS: In serum from 399 seropositive patients with RA in the IMPROVED study, drawn at baseline and at the moment of drug tapering, we measured IgG, IgM, and IgA isotypes for anti-cyclic citrullinated peptide-2 and anti-carbamylated protein antibodies, IgM and IgA rheumatoid factor, and reactivity against four citrullinated and two acetylated peptides (anti-modified protein antibodies (AMPAs)). We investigated the effect of the breadth of the autoantibody profile on (1) change in disease activity score (DAS)44 between 0 and 4 months, (2) initial drug-free remission (DFR, drug-free DAS44 < 1.6) achieved between 1 and 2 years of follow up, and (3) long-term sustained DFR until last follow up. RESULTS: Patients with a broad autoantibody profile at baseline had a significantly better early treatment response: DeltaDAS 0-4 months of 1-2, 3-4, and 5-6 vs 7-8 isotypes, -1.5 (p < 0.001), -1.7 (p = 0.03), and -1.8 (p = 0.04) vs -2.2. Similar results were observed for AMPA number. However, patients with a broad baseline autoantibody profile achieved less initial DFR. For long-term sustained DFR there was no longer an association with the breadth of the autoantibody response. When assessing autoantibodies at the moment of tapering, similar trends were observed. CONCLUSIONS: A broad baseline autoantibody profile is associated with a better early treatment response. The breadth of the baseline autoantibody profile, reflecting a break in tolerance against several different autoantigens and extensive isotype switching, may indicate a more active humoral autoimmunity, which could make the underlying disease processes initially more suppressible by medication. The lack of association with long-term sustained DFR suggests that the relevance of the baseline autoantibody profile diminishes over time. TRIAL REGISTRATION: ISRCTN11916566 . Registered on 7 November 2006. EudraCT, 2006- 06186-16. Registered on 16 July 2007. PMID- 29482626 TI - Alterations in sperm DNA methylation, non-coding RNA and histone retention associate with DDT-induced epigenetic transgenerational inheritance of disease. AB - BACKGROUND: Environmental toxicants such as DDT have been shown to induce the epigenetic transgenerational inheritance of disease (e.g., obesity) through the germline. The current study was designed to investigate the DDT-induced concurrent alterations of a number of different epigenetic processes including DNA methylation, non-coding RNA (ncRNA) and histone retention in sperm. METHODS: Gestating females were exposed transiently to DDT during fetal gonadal development, and then, the directly exposed F1 generation, the directly exposed germline F2 generation and the transgenerational F3 generation sperm were investigated. RESULTS: DNA methylation and ncRNA were altered in each generation sperm with the direct exposure F1 and F2 generations being predominantly distinct from the F3 generation epimutations. The piRNA and small tRNA were the most predominant classes of ncRNA altered. A highly conserved set of histone retention sites were found in the control lineage generations which was not significantly altered between generations, but a large number of new histone retention sites were found only in the transgenerational generation DDT lineage sperm. CONCLUSIONS: Therefore, all three different epigenetic processes were concurrently altered as DDT induced the epigenetic transgenerational inheritance of sperm epimutations. The direct exposure generations sperm epigenetic alterations were distinct from the transgenerational sperm epimutations. The genomic features and gene associations with the epimutations were investigated to help elucidate the integration of these different epigenetic processes. Observations demonstrate all three epigenetic processes are involved in transgenerational inheritance. The different epigenetic processes appear to be integrated in mediating the epigenetic transgenerational inheritance phenomenon. PMID- 29482628 TI - LRRK2 mediated Rab8a phosphorylation promotes lipid storage. AB - BACKGROUND: Several mutations in leucine rich repeat kinase 2 (LRRK2) gene have been associated with pathogenesis of Parkinson's disease (PD), a neurodegenerative disorder marked by resting tremors, and rigidity, leading to Postural instability. It has been revealed that mutations that lead to an increase of kinase activity of LRRK2 protein are significantly associated with PD pathogenesis. Recent studies have shown that some Rab GTPases, especially Rab8, serve as substrates of LRRK2 and undergo phosphorylation in its switch II domain upon interaction. Current study was performed in order to find out the effects of the phosphorylation of Rab8 and its mutants on lipid metabolism and lipid droplets growth. METHODS: The phosphorylation status of Rab8a was checked by phos tag gel. Point mutant construct were generated to investigate the function of Rab8a. 3T3L1 cells were transfected with indicated plasmids and the lipid droplets were stained with Bodipy. Fluorescent microscopy experiments were performed to examine the sizes of lipid droplets. The interactions between Rab8a and Optineurin were determined by immunoprecipitation and western blot. RESULTS: Our assays demonstrated that Rab8a was phosphorylated by mutated LRRK2 that exhibits high kinase activity. Phosphorylation of Rab8a on amino acid residue T72 promoted the formation of large lipid droplets. T72D mutant of Rab8a had higher activity to promote the formation of large lipid droplets compared with wild type Rab8a, with increase in average diameter of lipid droplets from 2.10 MUm to 2.46 MUm. Moreover, phosphorylation of Rab8a weakened the interaction with its effector Optineurin. CONCLUSIONS: Y1699C mutated LRRK2 was able to phosphorylate Rab8a and phosphorylation of Rab8a on site 72 plays important role in the fusion and enlargement of lipid droplets. Taken together, our study suggests an indirect relationship between enhanced lipid storage capacity and PD pathogenesis. PMID- 29482629 TI - Primary carcinosarcoma of the liver: imaging features and clinical findings in six cases and a review of the literature. AB - BACKGROUND: Carcinosarcoma of the liver is a very rare tumor composed of a mixture of carcinomatous and sarcomatous elements. Less than 25 adequately documented cases have been reported, with inadequate description of imaging features. In order to improve the awareness of this rare tumor, this study aimed to analyze the clinicopathologic and imaging features of six cases of hepatic carcinosarcoma (HCS) confirmed by surgical pathologic evaluation. METHODS: We retrospectively studied the clinicopathologic and imaging features of six cases of HCS (matching the World Health Organization definition) and discussed the differential diagnosis on the basis of imaging findings. The patients, including five men and one woman, were 38 to 69 years of age. Five patients underwent CT scans, one underwent MRI scans. RESULTS: While 3 patients were positive for hepatitis-B surface antigen, 2 had cirrhosis. The largest tumor diameter ranged from 5.0 to 21.0 cm. Satellite nodules, venous thrombi, and organ invasion (gastric wall, gallbladder, and right adrenal gland) were identified. Pathologically, the carcinomatous components corresponded to hepatocellular carcinoma in three cases, cholangiocellular carcinoma in one case, and adenocarcinoma in two cases. The sarcomatous components exhibited complex features, with undifferentiated spindle cells in five cases and a leiomyosarcoma in one. All tumors showed heterogeneous density/intensity with extensive cystic change and necrosis; spot calcification was observed in one case. Capsule was not identified. While four tumors showed heterogeneous hypervascular enhancement, two showed hypovascular enhancement. All patients underwent surgical resection. The follow-up period ranged from 2 to 18 months. Four patients died from recurrence and metastasis. CONCLUSIONS: The clinical and imaging features of HCS are heterogeneous. Due to the heterogenous nature and very low morbidity of HCS, combination of careful analysis of imaging findings and clinical features might be useful for a more accurate diagnosis of HCS. PMID- 29482630 TI - Perceptions of health and illness among the Konso people of southwestern Ethiopia: persistence and change. AB - BACKGROUND: Cross-cultural studies indicate that every culture has its own particular explanations for health and illness and its own healing strategies. The Konso people have always practiced indigenous medicine and have multifaceted accounts or multiple dimensions of illness perceptions and health-care beliefs and practices. This paper describes how perceptions of health and illness are instrumental in health and treatment outcomes among the Konso people in southwestern Ethiopia. Results may provide an understanding of the perceptions of health and illness in relation to the local cosmology, religion, and environment. METHODS: The ethnographic method was employed to generate evidence, complemented by focus group discussions, in-depth interviews, and direct observation. Thematic analysis was employed to categorize and interpret the data. RESULTS: Findings indicate that the Konso people's worldview, particularly as it relates to health, illness, and healing systems, is closely linked to their day-to-day lives. Older people believe illnesses are caused by a range of supernatural forces, including the wrath of God or local gods, oritta (spirit possession), and karayitta (ancestral spirits), and they use culturally prescribed treatment. Young and formally educated members of the community attribute causes of diseases to germitta (germs) and factorta (bacteria) and tend to seek treatment mostly in modern health facilities. CONCLUSION: Perceptions of health and illness as well as of healing are part of Konso people's worldview. Local communities comprehend health problems and solutions within their cultural frame of reference, which has changed over the years. The Konso people associate their health situations with socio-cultural and religious factors. The individual's behavior and interactions with the social, natural, and supernatural powers affect the well-being of the whole group. The individual, the family, the clan leaders, and the deceased are intimately linked to one's culturally based health beliefs and are associated by the Konso with health problems and illnesses. PMID- 29482631 TI - Effects of home delivery on colostrum avoidance practices in North Wollo zone, an urban setting, Ethiopia: a cross sectional study. AB - BACKGROUND: Colostrum is the first liquid that is produced in the first few days after delivery. It is the perfect first food for newborns which is considered as an infant's first immunization. Despite of this fact colostrum is discarded as unclean and bad for the infant's health. This study aimed to investigate the prevalence and the factors associated with colostrum avoidance in Woldia, Kobo and Lalibela town administrations of North Wollo zone. METHODS: A quantitative community based cross sectional study was employed in March 2015 on 810 mothers of children aged less than 24 months. Descriptive statistics, binary and multivariable logistic regression analysis were employed to identify the factors associated with colostrum avoidance. Variables with a p-value < 0.05 in the multivariable model were identified as predictors of colostrum avoidance practices. RESULTS: Colostrum was discarded by 12.0% (95%CI: 10.0-14.0%) of mothers of children aged less than 24 months. In multivariable logistic regression analysis late initiation of breastfeeding [AOR (95% CI) =2.03 (1.18, 3.49)], prelacteal feeding [AOR (95% CI) =3.38 (1.83, 6.24)], mothers not living with their husband [AOR (95% CI) = 2.24 (1.22, 4.12)] and delivering the index child at home [AOR (95% CI) =2.92 (1.521, 5.59)] were independent positive predictors of colostrum avoidance practices. CONCLUSION: The foundation of any nutrition package for the prevention of childhood malnutrition is the promotion of an optimal breastfeeding practices, including colostrum feeding, in the community. Therefore, promoting institutional delivery, early initiation of breastfeeding and creating awareness on the dangers of prelacteal feeding and the advantages of colostrum feeding are recommended interventions to reduce colostrum avoidance practices in the study area. PMID- 29482632 TI - Development and differentiability of three brief interventions for risky alcohol use that include varying doses of motivational interviewing. AB - BACKGROUND: While brief intervention (BI) for risky alcohol use generally yields positive effects among those identified by screening, effect sizes are small and there is unexplained heterogeneity in outcome. The heterogeneity may be related to differences in intervention style and content, including elements of motivational interviewing (MI). To date, it has been difficult to interpret the role of MI in BI and these gaps in knowledge interfere with efforts to train, disseminate and implement BI that retains and maximizes efficacy. This study sought to develop BI protocols with varying doses of MI and test their differentiability. Differentiable BI protocols could allow for future studies that prospectively evaluate the role MI plays in affecting BI outcome. METHODS: We developed three intervention protocols: brief advice, standard BI (NIAAA Clinician's Guide), and MI-enhanced BI and administered them to 45 primary care patients who reported exceeding recommended drinking limits. We then rated the BI sessions for fidelity to the assigned protocol as well as MI consistency based on Motivational Interviewing Treatment Integrity (MITI) scale scores. The differentiability of BI protocols was determined by calculating fidelity to assigned protocols and comparing MITI scores using pairwise, Tukey-adjusted comparisons of least squares mean scores. RESULTS: High rates of fidelity to each protocol were achieved. The three BI protocols were also highly differentiable based on MITI scores. CONCLUSIONS: The three interventions can be used in future trials to prospectively examine the role MI has in determining BI outcome. Trial registration clinicaltrials.gov NCT02978027, retrospectively registered 11/28/16. PMID- 29482633 TI - Development and reliability of a streetscape observation instrument for international use: MAPS-global. AB - BACKGROUND: Relationships between several built environment factors and physical activity and walking behavior are well established, but internationally comparable built environment measures are lacking. The Microscale Audit of Pedestrian Streetscapes (MAPS)-Global is an observational measure of detailed streetscape features relevant to physical activity that was developed for international use. This study examined the inter-observer reliability of the instrument in five countries. METHODS: MAPS-Global was developed by compiling concepts and items from eight environmental measures relevant to walking and bicycling. Inter-rater reliability data were collected in neighborhoods selected to vary on geographic information system (GIS)-derived macro-level walkability in five countries (Australia, Belgium, Brazil, Hong Kong-China, and Spain). MAPS Global assessments (n = 325) were completed in person along a >= 0.25 mile route from a residence toward a non-residential destination, and a commercial block was also rated for each residence (n = 82). Two raters in each country rated each route independently. A tiered scoring system was created that summarized items at multiple levels of aggregation, and positive and negative valence scores were created based on the expected effect on physical activity. The intraclass correlation coefficient (ICC) was computed for scales and selected items using one-way random models. RESULTS: Overall, 86.6% of individual items and single item indicators showed excellent agreement (ICC >= 0.75), and 13.4% showed good agreement (ICC = 0.60-0.74). All subscales and overall summary scores showed excellent agreement. Six of 123 items were too rare to compute the ICC. The median ICC for items and scales was 0.92 with a range of 0.50-1.0. Aesthetics and social characteristics showed lower ICCs than other sub-scales, but reliabilities were still in the excellent range (ICC >= 0.75). CONCLUSION: Evaluation of inter observer reliability of MAPS-Global across five countries indicated all items and scales had "good" or "excellent" reliability. The results demonstrate that trained observers from multiple countries were able to reliably conduct observations of both residential and commercial areas with the new MAPS-Global instrument. Next steps are to evaluate construct validity in relation to physical activity in multiple countries and gain experience with using MAPS-Global for research and practice applications. PMID- 29482634 TI - Individual retrotransposon integrants are differentially controlled by KZFP/KAP1 dependent histone methylation, DNA methylation and TET-mediated hydroxymethylation in naive embryonic stem cells. AB - BACKGROUND: The KZFP/KAP1 (KRAB zinc finger proteins/KRAB-associated protein 1) system plays a central role in repressing transposable elements (TEs) and maintaining parent-of-origin DNA methylation at imprinting control regions (ICRs) during the wave of genome-wide reprogramming that precedes implantation. In naive murine embryonic stem cells (mESCs), the genome is maintained highly hypomethylated by a combination of TET-mediated active demethylation and lack of de novo methylation, yet KAP1 is tethered by sequence-specific KZFPs to ICRs and TEs where it recruits histone and DNA methyltransferases to impose heterochromatin formation and DNA methylation. RESULTS: Here, upon removing either KAP1 or the cognate KZFP, we observed rapid TET2-dependent accumulation of 5hmC at both ICRs and TEs. In the absence of the KZFP/KAP1 complex, ICRs lost heterochromatic histone marks and underwent both active and passive DNA demethylation. For KAP1-bound TEs, 5mC hydroxylation correlated with transcriptional reactivation. Using RNA-seq, we further compared the expression profiles of TEs upon Kap1 removal in wild-type, Dnmt and Tet triple knockout mESCs. While we found that KAP1 represents the main effector of TEs repression in all three settings, we could additionally identify specific groups of TEs further controlled by DNA methylation. Furthermore, we observed that in the absence of TET proteins, activation upon Kap1 depletion was blunted for some TE integrants and increased for others. CONCLUSIONS: Our results indicate that the KZFP/KAP1 complex maintains heterochromatin and DNA methylation at ICRs and TEs in naive embryonic stem cells partly by protecting these loci from TET-mediated demethylation. Our study further unveils an unsuspected level of complexity in the transcriptional control of the endovirome by demonstrating often integrant specific differential influences of histone-based heterochromatin modifications, DNA methylation and 5mC oxidation in regulating TEs expression. PMID- 29482635 TI - Binding determinants in the interplay between porcine aminopeptidase N and enterotoxigenic Escherichia coli F4 fimbriae. AB - The binding of F4+ enterotoxigenic Escherichia coli (ETEC) and the specific receptor on porcine intestinal epithelial cells is the initial step in F4+ ETEC infection. Porcine aminopeptidase N (APN) is a newly discovered receptor for F4 fimbriae that binds directly to FaeG adhesin, which is the major subunit of the F4 fimbriae variants F4ab, F4ac, and F4ad. We used overlapping peptide assays to map the APN-FaeG binding sites, which has facilitated in the identifying the APN binding amino acids that are located in the same region of FaeG variants, thereby limiting the major binding regions of APN to 13 peptides. To determine the core sequence motif, a panel of FaeG peptides with point mutations and FaeG mutants were constructed. Pull-down and binding reactivity assays using piglet intestines determined that the amino acids G159 of F4ab, N209 and L212 of F4ac, and A200 of F4ad were the critical residues for APN binding of FaeG. We further show using ELISA and confocal microscopy assay that amino acids 553-568, and 652-670 of the APN comprise the linear epitope for FaeG binding in all three F4 fimbriae variants. PMID- 29482637 TI - Treatment outcomes of tuberculosis patients under directly observed treatment short-course at Debre Tabor General Hospital, northwest Ethiopia: nine-years retrospective study. AB - BACKGROUND: Data regarding tuberculosis (TB) treatment outcomes, proportion of TB/HIV co-infection and associated factors have been released at different TB treatment facilities in Ethiopia and elsewhere in the world as part of the auditing and surveillance service. However, these data are missing for the TB clinic offering directly observed treatment short-course (DOTs) at Debre Tabor General Hospital (DTGH). METHODS: The authors analysed the records of 985 TB patients registered at the DTGH from September 2008 to December 2016. Data on patients' sex, age, type of TB, and treatment outcomes were extracted from the TB treatment registration logbook. The treatment outcome of patients was categorized according to the National TB and Leprosy Control Program guidelines: cured, treatment completed, treatment failed, died, and not evaluated (transferred out and unknown cases). RESULTS: Around half of the registered patients were males (516, 52.4%). In terms of TB types, 381 (38.7%), 241 (24.5%), and 363 (36.9%) patients had smear-negative pulmonary TB, smear-positive pulmonary TB, and extra pulmonary TB, respectively. Six hundred and seventy-two patients (90.1%) had successful treatment outcomes (cured and treatment completed), while 74 patients (9.9%) had unsuccessful treatment outcomes (death and treatment failure).TB treatment outcome was not associated with age, sex, type and history of TB, or co infection with HIV (P > 0.05). The proportion of TB/HIV co-infection was at 24.2%, and these were found to be significantly associated with the age groups of 25-34, 35-44 and >=65 years:(aOR: 0.44; 95% CI: 0.25-0.8), (aOR: 0.39; 95% CI: 0.20-0.70), (aOR: 4.2; 95% CI: 1.30-12.9), respectively. CONCLUSIONS: The proportion of patients with successful treatment outcomes was above the World Health Organization target set for Millennium Development Goal of 85% and in line with that of the global milestone target set at > 90% for 2025. Relatively higher proportions of transfer-out cases were recorded in the present study. Similarly, the proportion of TB/HIV co-infection cases was much higher than the national average of 8%.Thus, the health facility under study should develop strategies to record the final treatment outcome of transfer-out cases. In addition, strategies to reduce the burden of TB/HIV co-infection should be strengthened. PMID- 29482636 TI - The effects of acceptance and commitment therapy on eating behavior and diet delivered through face-to-face contact and a mobile app: a randomized controlled trial. AB - BACKGROUND: Internal motivation and good psychological capabilities are important factors in successful eating-related behavior change. Thus, we investigated whether general acceptance and commitment therapy (ACT) affects reported eating behavior and diet quality and whether baseline perceived stress moderates the intervention effects. METHODS: Secondary analysis of unblinded randomized controlled trial in three Finnish cities. Working-aged adults with psychological distress and overweight or obesity in three parallel groups: (1) ACT-based Face to-face (n = 70; six group sessions led by a psychologist), (2) ACT-based Mobile (n = 78; one group session and mobile app), and (3) Control (n = 71; only the measurements). At baseline, the participants' (n = 219, 85% females) mean body mass index was 31.3 kg/m2 (SD = 2.9), and mean age was 49.5 years (SD = 7.4). The measurements conducted before the 8-week intervention period (baseline), 10 weeks after the baseline (post-intervention), and 36 weeks after the baseline (follow up) included clinical measurements, questionnaires of eating behavior (IES-1, TFEQ-R18, HTAS, ecSI 2.0, REBS), diet quality (IDQ), alcohol consumption (AUDIT C), perceived stress (PSS), and 48-h dietary recall. Hierarchical linear modeling (Wald test) was used to analyze the differences in changes between groups. RESULTS: Group x time interactions showed that the subcomponent of intuitive eating (IES-1), i.e., Eating for physical rather than emotional reasons, increased in both ACT-based groups (p = .019); the subcomponent of TFEQ-R18, i.e., Uncontrolled eating, decreased in the Face-to-face group (p = .020); the subcomponent of health and taste attitudes (HTAS), i.e., Using food as a reward, decreased in the Mobile group (p = .048); and both subcomponent of eating competence (ecSI 2.0), i.e., Food acceptance (p = .048), and two subcomponents of regulation of eating behavior (REBS), i.e., Integrated and Identified regulation (p = .003, p = .023, respectively), increased in the Face-to-face group. Baseline perceived stress did not moderate effects on these particular features of eating behavior from baseline to follow-up. No statistically significant effects were found for dietary measures. CONCLUSIONS: ACT-based interventions, delivered in group sessions or by mobile app, showed beneficial effects on reported eating behavior. Beneficial effects on eating behavior were, however, not accompanied by parallel changes in diet, which suggests that ACT-based interventions should include nutritional counseling if changes in diet are targeted. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT01738256 ), registered 17 August, 2012. PMID- 29482639 TI - Improving saliva shotgun metagenomics by chemical host DNA depletion. AB - BACKGROUND: Shotgun sequencing of microbial communities provides in-depth knowledge of the microbiome by cataloging bacterial, fungal, and viral gene content within a sample, providing an advantage over amplicon sequencing approaches that assess taxonomy but not function and are taxonomically limited. However, mammalian DNA can dominate host-derived samples, obscuring changes in microbial populations because few DNA sequence reads are from the microbial component. We developed and optimized a novel method for enriching microbial DNA from human oral samples and compared its efficiency and potential taxonomic bias with commercially available kits. RESULTS: Three commercially available host depletion kits were directly compared with size filtration and a novel method involving osmotic lysis and treatment with propidium monoazide (lyPMA) in human saliva samples. We evaluated the percentage of shotgun metagenomic sequencing reads aligning to the human genome, and taxonomic biases of those not aligning, compared to untreated samples. lyPMA was the most efficient method of removing host-derived sequencing reads compared to untreated sample (8.53 +/- 0.10% versus 89.29 +/- 0.03%). Furthermore, lyPMA-treated samples exhibit the lowest taxonomic bias compared to untreated samples. CONCLUSION: Osmotic lysis followed by PMA treatment is a cost-effective, rapid, and robust method for enriching microbial sequence data in shotgun metagenomics from fresh and frozen saliva samples and may be extensible to other host-derived sample types. PMID- 29482638 TI - Investigation of hypoxia networks in ovarian cancer via bioinformatics analysis. AB - BACKGROUND: Ovarian cancer is a leading cause of the death from gynecologic malignancies. Hypoxia is closely related to the malignant growth of cells. However, the molecular mechanism of hypoxia-regulated ovarian cancer cells remains unclear. Thus, this study was conducted to identify the key genes and pathways implicated in the regulation of hypoxia by bioinformatics analysis. METHODS: Using the datasets of GSE53012 downloaded from the Gene Expression Omnibus (GEO), the differentially expressed genes (DEGs) were screened by comparing the RNA expression from cycling hypoxia group, chronic hypoxia group, and control group. Subsequently, cluster analysis was performed followed by the construction of the protein-protein interaction (PPI) network of the overlapping DEGs between the cycling hypoxia and chronic hypoxia using ClusterONE. In addition, gene ontology (GO) functional and pathway enrichment analyses of the DEGs in the most remarkable module were performed using Database for Annotation, Visualization and Integrated Discovery (DAVID) software. Ultimately, the signaling pathways associated with hypoxia were verified by RT-PCR, WB, and MTT assays. RESULTS: A total of 931 overlapping DEGs were identified. Nine hub genes and seven node genes were screened by analyzing the PPI and pathway integration networks, including ESR1, MMP2, ErbB2, MYC, VIM, CYBB, EDN1, SERPINE1, and PDK. Additionally, 11 key pathways closely associated with hypoxia were identified, including focal adhesion, ErbB signaling, and proteoglycans in cancer, among which the ErbB signaling pathway was verified by RT-PCR, WB, and MTT assays. Furthermore, functional enrichment analysis revealed that these genes were mainly involved in the proliferation of ovarian cancer cells, such as regulation of cell proliferation, cell adhesion, positive regulation of cell migration, focal adhesion, and extracellular matrix binding. CONCLUSION: The results show that hypoxia can promote the proliferation of ovarian cancer cells by affecting the invasion and adhesion functions through the dysregulation of ErbB signaling, which may be governed by the HIF-1alpha-TGFA-EGFR-ErbB2-MYC axis. These findings will contribute to the identification of new targets for the diagnosis and treatment of ovarian cancer. PMID- 29482640 TI - Investigation of short-term surgical complications in a low-resource, high-volume dog sterilisation clinic in India. AB - BACKGROUND: Surgical sterilisation is currently the method of choice for controlling free-roaming dog populations. However, there are significant logistical challenges to neutering large numbers of dogs in low-resource clinics. The aim of this study was to investigate the incidence of short-term surgical complications in a low-resource sterilisation clinic which did not routinely administer post-operative antibiotics. The medical records of all sterilisation surgeries performed in 2015 at the Worldwide Veterinary Service International Training Centre in Tamil Nadu, India were reviewed (group A) to assess immediate surgical complications. All animals in this group were monitored for at least 24 h post-surgery but were not released until assessed by a veterinarian as having uncomplicated wound healing. In the second part of this study from August to December 2015, 200 free-roaming dogs undergoing sterilisation surgery, were monitored for a minimum of 4-days post-surgery to further assess postoperative complications (group B). RESULTS: Surgery related complications were seen in 5.4% (95%CI, 4.5-6.5%) of the 1998 group A dogs monitored for at least 24 h, and in 7.0% (3.9-11.5%) of the 200 group B dogs monitored for 4 days. Major complications were classed as those requiring an intervention and resulted in increased morbidity or mortality. Major complications were seen in 2.8% (2.1 3.6%) and 1.5% (3.1-4.3%) of group A and B, respectively. Minor complications requiring little or no intervention were recorded for 2.6% (1.9-3.4%) for group A and 5.5% (2.8-9.6%) for group B. There was no evidence for a difference in complication rates between the two groups in a multivariate regression model. CONCLUSION: This study demonstrated that high volume, low-resource sterilisation of dogs can be performed with a low incidence of surgical complications and low mortality. PMID- 29482642 TI - Prognostic impact of CD4-positive T cell subsets in early breast cancer: a study based on the FinHer trial patient population. AB - BACKGROUND: The clinical importance of tumor-infiltrating cluster of differentiation 4 (CD4) T cells is incompletely understood in early breast cancer. We investigated the clinical significance of CD4, forkhead box P3 (FOXP3), and B cell attracting chemokine leukocyte chemoattractant-ligand (C-X-C motif) 13 (CXCL13) in early breast cancer. METHODS: The study is based on the patient population of the randomized FinHer trial, where 1010 patients with early breast cancer were randomly allocated to adjuvant chemotherapy containing either docetaxel or vinorelbine, and human epidermal growth factor receptor 2 (HER2) positive patients were also allocated to trastuzumab or no trastuzumab. Breast cancer CD4, FOXP3, and CXCL13 contents were evaluated using quantitative real time polymerase chain reaction (qRT-PCR), and their influence on distant disease free survival (DDFS) was examined using univariable and multivariable Cox regression and Kaplan-Meier estimates in the entire cohort and in selected molecular subgroups. Interactions between variables were analyzed using Cox regression. The triple-negative breast cancer (TNBC) subset of the HE10/97 randomized trial was used for confirmation. RESULTS: High CXCL13 was associated with favorable DDFS in univariable analysis, and independently in multivariable analysis (HR 0.44, 95% CI 0.29-0.67, P <= 0.001), most strongly in TNBC (HR 0.39, 95% CI 0.19-0.79, P = 0.009). No significant interaction with chemotherapy or trastuzumab administration was detected. Neither tumor CD4 content nor FOXP3 content was associated with DDFS. The favorable prognostic influence of CXCL13 was confirmed in the HE10/97 trial patient population with TNBC (HR 0.30, 95% CI 0.09-0.93; P = 0.038). CONCLUSIONS: The results provide a high level of evidence that humoral immunity influences the survival outcomes of patients with early breast cancer, in particular of those with TNBC. TRIAL REGISTRATION: The study reports retrospective biomarker analyses in the prospective FinHer trial and the prospective HE10/97 trial. ISRCTN76560285 . Registered on 18 March 2005. ACTRN12611000506998 . Registered on 16 May 2011. PMID- 29482643 TI - Do policy-makers find commissioned rapid reviews useful? AB - BACKGROUND: Rapid reviews are increasingly used by policy agencies to access relevant research in short timeframes. Despite the growing number of programmes, little is known about how rapid reviews are used by health policy agencies. This study examined whether and how rapid reviews commissioned using a knowledge brokering programme were used by Australian policy-makers. METHODS: This study used interview data to examine the use of 139 rapid reviews by health policy agencies that were commissioned between 2006 and 2015. Transcripts were coded to identify how rapid reviews were used, the type of policy processes in which they were used, what evidence of use was provided and what reasons were given when rapid reviews were not used. Fisher's exact test was used to assess variation between types of agencies. RESULTS: Overall, 89% of commissioned rapid reviews were used by the commissioning agencies and 338 separate instances of use were identified, namely, on average, three uses per review. Policy-makers used reviews primarily to determine the details of a policy or programme, identify priorities for future action or investment, negotiate interjurisdictional decisions, evaluate alternative solutions for a policy problem, and communicate information to stakeholders. Some variation in use was observed across agencies. Reasons for non-use were related to changes in organisational structures, resources or key personnel in the commissioning agencies, or changes in the broader political environment. CONCLUSIONS: This study found that almost all rapid reviews had been used by the agencies who commissioned them, primarily in policy and programme development, agenda-setting, and to communicate information to stakeholders. Reviews were used mostly in instrumental and conceptual ways and there was little evidence of symbolic use. Variations in use were identified across agencies. The findings suggest that commissioned rapid reviews are an effective means of providing timely relevant research for use in policy processes and that review findings may be applied in a variety of ways. PMID- 29482641 TI - Transcription factors Tp73, Cebpd, Pax6, and Spi1 rather than DNA methylation regulate chronic transcriptomics changes after experimental traumatic brain injury. AB - Traumatic brain injury (TBI) induces a wide variety of cellular and molecular changes that can continue for days to weeks to months, leading to functional impairments. Currently, there are no pharmacotherapies in clinical use that favorably modify the post-TBI outcome, due in part to limited understanding of the mechanisms of TBI-induced pathologies. Our system biology analysis tested the hypothesis that chronic transcriptomics changes induced by TBI are controlled by altered DNA-methylation in gene promoter areas or by transcription factors. We performed genome-wide methyl binding domain (MBD)-sequencing (seq) and RNA-seq in perilesional, thalamic, and hippocampal tissue sampled at 3 months after TBI induced by lateral fluid percussion in adult male Sprague-Dawley rats. We investigated the regulated molecular networks and mechanisms underlying the chronic regulation, particularly DNA methylation and transcription factors. Finally, we identified compounds that modulate the transcriptomics changes and could be repurposed to improve recovery. Unexpectedly, DNA methylation was not a major regulator of chronic post-TBI transcriptomics changes. On the other hand, the transcription factors Cebpd, Pax6, Spi1, and Tp73 were upregulated at 3 months after TBI (False discovery rate < 0.05), which was validated using digital droplet polymerase chain reaction. Transcription regulatory network analysis revealed that these transcription factors regulate apoptosis, inflammation, and microglia, which are well-known contributors to secondary damage after TBI. Library of Integrated Network-based Cellular Signatures (LINCS) analysis identified 118 pharmacotherapies that regulate the expression of Cebpd, Pax6, Spi1, and Tp73. Of these, the antidepressant and/or antipsychotic compounds trimipramine, rolipramine, fluspirilene, and chlorpromazine, as well as the anti cancer therapies pimasertib, tamoxifen, and vorinostat were strong regulators of the identified transcription factors, suggesting their potential to modulate the regulated transcriptomics networks to improve post-TBI recovery. PMID- 29482644 TI - Identification of a phenoloxidase- and melanin-dependent defence mechanism in Achatina fulica infected with Angiostrongylus vasorum. AB - BACKGROUND: Angiostrongylus vasorum has different freshwater aquatic and terrestrial gastropod molluscs as an intermediate host, e.g. Arion spp. The mollusc Achatina fulica is a danger to public health, given the large diversity of nematodes utilizing it as an intermediate host, such as the parasites of the genus Angiostrongylus, of importance in human and veterinary medicine. Achatina fulica has been shown to have an excellent capacity for maintaining outbreaks and natural infections with A. cantonensis in Asia. Within the mollusc, the nematode parasites activate haemocytes and/or haemolymph factors and in some invertebrates, phenoloxidase (PO), that induces the release of toxic elements and eliminates the parasites. Despite the importance of A. fulica in the life-cycle of nematodes, little is known regarding the defence mechanisms involving PO in molluscs infected with nematodes. Here, the presence of PO and nitric oxide (NO) in the haemolymph and haemocytes of A. fulica infected with first-stage (L1) larvae of Angiostrongylus vasorum was evaluated, together with the presence of melanin in the cephalopod mollusc tissue. RESULTS: An increase in PO at one day post infection (dpi), in comparison with the control using the substrates L tyrosine (F(4,90) = 6.73, P = 0.00006), L-DOPA (F(4,90) = 22.67, P = 0.02) and p phenylenediamine (PPD) (F(4,90) = 27.58, P = 0.0019), was observed. PO increase coincided with the presence of melanin in the cephalopodal tissue. At 8 dpi, PO activity, compared to L-DOPA (F(4,90) = 22.67, P = 0.00002) and PPD (F(4,90) = 27.58, P = 0.079) decreased, while melanin increased. At 13 dpi, PO decreased with PPD (F(4,90) = 27.58, P = 0.000015) and also the amount of melanin observed in histology. At 30 dpi, PO increased along with the substrates L-DOPA and PPD, while melanin decreased. NO levels increased until 8 dpi, and decreased after 13 dpi. CONCLUSIONS: To our knowledge, this is the first study that illustrates PO activity in a helminth-infected A. fulica and provides the first observation of an L-tyrosine dependent PO activity in molluscs infected with A. vasorum. This work suggests that PO pathway may help to control A. vasorum infection in A. fulica. PMID- 29482645 TI - Prevalence of hepatitis E virus infection in wild boars from Spain: a possible seasonal pattern? AB - BACKGROUND: It has been shown that wildlife can serve as natural reservoirs of hepatitis E virus (HEV). The wild boar (Sus scrofa) is probably the main natural reservoir of HEV and could therefore represent an important route of transmission in Europe, especially in regions where game meat is widely consumed. We evaluated the prevalence of HEV infection in wild boar in the south of Spain, with the aim of identifying associated risk factors. A cross-sectional study that included hunted wild boar was carried out during the 2015/2016 hunting season (October 15 to February 15) in Andalusia (southern Spain). The outcome variable was HEV infection, defined as amplification of HEV RNA in serum by RT-PCR. RESULTS: A total of 142 animals, selected from 12 hunting areas, were included and formed the study population. Thirty-three wild boars (23.2%; 95% CI: 16.8%-30.7%) were positive for HEV infection. Prevalence peaked in October and November, then gradually declined until the end of December. After multivariate analysis, only hunting date was independently associated with HEV infection across sex and age. CONCLUSIONS: Our study found a relatively high prevalence of HEV infection in wild boar in the south of Spain, suggesting that prevalence may depend on the season when the animal is hunted. In consequence, the potential risk of zoonotic transmission could fluctuate. PMID- 29482646 TI - Correcting for 16S rRNA gene copy numbers in microbiome surveys remains an unsolved problem. AB - The 16S ribosomal RNA gene is the most widely used marker gene in microbial ecology. Counts of 16S sequence variants, often in PCR amplicons, are used to estimate proportions of bacterial and archaeal taxa in microbial communities. Because different organisms contain different 16S gene copy numbers (GCNs), sequence variant counts are biased towards clades with greater GCNs. Several tools have recently been developed for predicting GCNs using phylogenetic methods and based on sequenced genomes, in order to correct for these biases. However, the accuracy of those predictions has not been independently assessed. Here, we systematically evaluate the predictability of 16S GCNs across bacterial and archaeal clades, based on ~ 6,800 public sequenced genomes and using several phylogenetic methods. Further, we assess the accuracy of GCNs predicted by three recently published tools (PICRUSt, CopyRighter, and PAPRICA) over a wide range of taxa and for 635 microbial communities from varied environments. We find that regardless of the phylogenetic method tested, 16S GCNs could only be accurately predicted for a limited fraction of taxa, namely taxa with closely to moderately related representatives (?15% divergence in the 16S rRNA gene). Consistent with this observation, we find that all considered tools exhibit low predictive accuracy when evaluated against completely sequenced genomes, in some cases explaining less than 10% of the variance. Substantial disagreement was also observed between tools (R2<0.5) for the majority of tested microbial communities. The nearest sequenced taxon index (NSTI) of microbial communities, i.e., the average distance to a sequenced genome, was a strong predictor for the agreement between GCN prediction tools on non-animal-associated samples, but only a moderate predictor for animal-associated samples. We recommend against correcting for 16S GCNs in microbiome surveys by default, unless OTUs are sufficiently closely related to sequenced genomes or unless a need for true OTU proportions warrants the additional noise introduced, so that community profiles remain interpretable and comparable between studies. PMID- 29482647 TI - Purpura induced by laser hair removal: a case report. AB - BACKGROUND: Laser hair removal is an effective and safe method for the permanent reduction of unwanted hair. Common side effects include temporary pain, transient erythema, and perifollicular edema. Purpuric eruption is a rare adverse event. CASE PRESENTATION: To the best of our knowledge, this is the second case report of purpura induced by laser hair removal. Our patient is a 50-year-old woman of Arab origin. Her positive reaction to a laser hair removal provocation test helped in the diagnosis; her condition was managed with an orally administered corticosteroid, leading to complete resolution within 5 days. CONCLUSION: Purpura induced by laser hair removal is a self-limiting and unusual side effect; physicians' awareness of such adverse events can help them to avoid unnecessary investigations and provide guidance for better management. PMID- 29482648 TI - EEPIC - Enhancing Employability through Positive Interventions for improving Career potential: the impact of a high support career guidance intervention on the wellbeing, hopefulness, self-efficacy and employability of the long-term unemployed - a study protocol for a randomised controlled trial. AB - BACKGROUND: Labour market policy (LMP) and its implementation have undergone rapid change internationally in the last three decades with a continued trend towards active LMP. In Ireland however, this shift has been more recent with ongoing reforms since 2012 and a concomitant move toward active labour market 'work-first' policy design (i.e. whereby unemployed people are compulsorily required to work in return for their social welfare benefits). Labour market policies vary from those that require this compulsory approach to those which enable the unemployed to move towards sustainable quality work in the labour market through upskilling (human capital approach). Despite this, however, long term unemployment-a major cause of poverty and social exclusion-remains high, while current employment support approaches aimed at sustainable re-employment are, arguably, unevaluated and under examined. This study examines the effectiveness of a new high support career guidance intervention in terms of its impact on aspects of wellbeing, perceived employability and enhancing career sustainability. METHOD: The study involves a single-centre randomised, controlled, partially blinded trial. A total of 140 long-term unemployed job seekers from a disadvantaged urban area will be randomly assigned to two groups: (1) an intervention group; and (2) a 'service as usual' group. Each group will be followed up immediately post intervention and six months later. The primary outcome is wellbeing at post intervention and at six-month follow-up. The secondary outcome is perceived employability, which includes a number of different facets including self-esteem, hopefulness, resilience and career self efficacy. DISCUSSION: The study aims to assess the changes in, for example, psychological wellbeing, career efficacy and hopefulness, that occur as a result of participation in a high support intervention vs routinely available support. The results will help to inform policy and practice by indicating whether a therapeutic approach to job-seeking support is more effective for long-term unemployed job-seekers than routinely available (and less therapeutic) support. The findings will also be important in understanding what works and for whom with regard to potentially undoing the negative psychological impacts of unemployment, building psychological capital and employability within the individual, and developing career trajectories leading to more sustainable employment. TRIAL REGISTRATION: ISRCTN registry, ISRCTN16801028 . Registered on 9 February 2016. PMID- 29482649 TI - A randomized phase 3 trial comparing paclitaxel plus 5-fluorouracil versus cisplatin plus 5-fluorouracil in Chemoradiotherapy for locally advanced esophageal carcinoma-the ESO-shanghai 1 trial protocol. AB - BACKGROUND: Concurrent chemoradiotherapy is a standard modality for locally advanced esophageal squamous cell carcinoma (ESCC) patients. Cisplatin combined with 5-fluorouracil continuous infusion (PF) remains the standard concurrent chemotherapy regimen. However, radiotherapy concurrent with PF showed a high incidence of severe side effects. Paclitaxel showed a promising radiosensitivity enhancement in the treatment of esophageal carcinoma in both vitro and vivo studies. The ESO-Shanghai 1 trial examines the hypothesis that paclitaxel plus 5 fluorouracil (TF) concurrent with radiotherapy has better overall survival and lower toxicity for patients with local advanced ESCC. METHOD: Four hundred thirty six ESCC patients presenting with stage IIa to IVa will be enrolled in a prospective multicenter randomized phase 3 study. Patients will be randomized to either concurrent chemoradiotherapy with PF (cisplatin 25 mg/m2/d, d1-3, plus 5 fluorouracil 1800 mg/m2, continuous infusion for 72 h) once every 4 weeks for 2 cycles followed by consolidation chemotherapy for 2 cycles or concurrent chemoradiotherapy with weekly TF (5-fluorouracil 300 mg/m2, continuous infusion for 96 h plus paclitaxel 50 mg/m2, d1) for 5 weeks followed by consolidation chemotherapy (5-fluorouracil 1800 mg/m2, continuous infusion for 72 h, plus paclitaxel 175 mg/m2 d1) once every 4 weeks for 2 cycles. The radiotherapy dose is 61.2 Gy delivered in 34 fractions to the primary tumor including lymph nodes. The primary end-point is the 3-yr overall survival analyzed by intention to treat. The secondary endpoints are disease progression-free survival, local progression-free survival, and number and grade of participants with adverse events. DISCUSSION: The aim of this phase 3 study is to determine whether the TF regimen could replace the standard PF regimen for inoperable ESCC patients. An overall survival benefit of 12% at 3 years should be expected in the TF group to achieve this goal. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01591135 . Registered 18 April 2012. PMID- 29482651 TI - Effects of platelet-rich plasma on the activity of human menstrual blood-derived stromal cells in vitro. AB - BACKGROUND: Human menstrual blood-derived stromal cells (MenSCs) are highly proliferative and show multiple differentiation capacity. The convenience and non invasiveness make MenSC a novel cell source for regenerative medicine applications. Platelet-rich plasma (PRP) contains abundant growth factors which are beneficial to wound healing. However, the influence of PRP on MenSCs remains elusive. Here, we evaluated the role of PRP in MenSCs proliferation and assessed the effects of PRP on endometrial receptivity regulation in vitro. METHODS: MenSCs cultured with 10% activated PRP were compared with those cultured with 10% fetal bovine serum (FBS). Differences in cell proliferation, differentiation, and endometrial receptivity-related gene expression were evaluated. RESULTS: Notably, 10% activated PRP significantly promoted MenSCs proliferation and adipogenic/osteogenic differentiation while suppressing apoptosis. Expression of the mesenchymal stem cells (MSCs) marker CD105 and the perivascular markers SUSD2 and CD146 were elevated after PRP treatment. Moreover, short-term PRP stimulation activated the phosphorylation of Akt and signal transducer and activator of transcription 3 (STAT3) pathways, upregulated expression of FoxO1, LIF, and IL1 beta, and downregulated IL-6. CONCLUSIONS: In summary, PRP could promote MenSC proliferation, markedly accelerate cell stemness, and evaluate MenSC functions by enhancing the expression of angiogenesis and endometrial receptivity markers, suggesting its potential use as a promising supplement for MenSCs in endometrial regenerative medicine. Our results provide a theoretical basis for the clinical application of co-transplantation of PRP combined with MenSCs. PMID- 29482650 TI - Intraoperative milrinone versus dobutamine in cardiac surgery patients: a retrospective cohort study on mortality. AB - BACKGROUND: Several choices of inotropic therapy are available and used in relation to cardiac surgery. Comparisons are necessary to select optimal therapy. In Denmark, dobutamine and milrinone are the two inotropic agents most commonly used to treat post-bypass low cardiac output syndrome. This study compares all cause mortality with these drugs. METHODS: In a retrospective observational study we investigated 10,700 consecutive patients undergoing cardiac surgery from 1 April 2006 to 31 December 2013 at Aarhus and Aalborg University Hospitals in the Central and Northern Denmark Region. Prospectively entered data in the Western Danish Heart Registry on intraoperative use of inotropes were used to identify 952 patients treated with milrinone, 418 patients treated with dobutamine, and 82 patients receiving a combination of the two inotropes. All-cause mortality among patients receiving dobutamine was compared to all-cause mortality among milrinone receivers. Multiple logistic regression analyses including preoperative and intraoperative variables along with g-formula analyses were used to model 30-day and 1-year mortality risks. Reported were standardized mortality risk differences between the treatment groups. RESULTS: Among patients receiving intraoperative dobutamine, 18 (4.3%) died within 30 days and 49 (11.7%) within 1 year. Corresponding 30-day and 1-year mortality for milrinone receivers were 81 (8.5%) and 170 (17.9%). Risk of death within 30 days and 1 year was increased for intraoperative milrinone compared to dobutamine with a standardized risk difference of 4.06% (confidence interval (CI) 1.23; 6.89, p = 0.005) and 4.77% (CI 0.39; 9.15, p = 0.033), respectively. Sensitivity analyses including adjustment for milrinone preference, hemodynamic instability prior to cardiopulmonary bypass, and separate analyses on hospital level all confirmed a sign toward increased mortality among milrinone receivers. CONCLUSIONS: Intraoperative use of milrinone in cardiac surgery may be associated with an increase in all-cause mortality compared to use of dobutamine. PMID- 29482652 TI - A new tissue segmentation method to calculate 3D dose in small animal radiation therapy. AB - BACKGROUND: In pre-clinical animal experiments, radiation delivery is usually delivered with kV photon beams, in contrast to the MV beams used in clinical irradiation, because of the small size of the animals. At this medium energy range, however, the contribution of the photoelectric effect to absorbed dose is significant. Accurate dose calculation therefore requires a more detailed tissue definition because both density (rho) and elemental composition (Zeff) affect the dose distribution. Moreover, when applied to cone beam CT (CBCT) acquisitions, the stoichiometric calibration of HU becomes inefficient as it is designed for highly collimated fan beam CT acquisitions. In this study, we propose an automatic tissue segmentation method of CBCT imaging that assigns both density (rho) and elemental composition (Zeff) in small animal dose calculation. METHODS: The method is based on the relationship found between CBCT number and rho*Zeff product computed from known materials. Monte Carlo calculations were performed to evaluate the impact of rhoZeff variation on the absorbed dose in tissues. These results led to the creation of a tissue database composed of artificial tissues interpolated from tissue values published by the ICRU. The rhoZeff method was validated by measuring transmitted doses through tissue substitute cylinders and a mouse with EBT3 film. Measurements were compared to the results of the Monte Carlo calculations. RESULTS: The study of the impact of rhoZeff variation over the range of materials, from rhoZeff = 2 g.cm- 3 (lung) to 27 g.cm- 3 (cortical bone) led to the creation of 125 artificial tissues. For tissue substitute cylinders, the use of rhoZeff method led to maximal and average relative differences between the Monte Carlo results and the EBT3 measurements of 3.6% and 1.6%. Equivalent comparison for the mouse gave maximal and average relative differences of 4.4% and 1.2%, inside the 80% isodose area. Gamma analysis led to a 94.9% success rate in the 10% isodose area with 4% and 0.3 mm criteria in dose and distance. CONCLUSIONS: Our new tissue segmentation method was developed for 40kVp CBCT images. Both density and elemental composition are assigned to each voxel by using a relationship between HU and the product rhoZeff. The method, validated by comparing measurements and calculations, enables more accurate small animal dose distribution calculated on low energy CBCT images. PMID- 29482653 TI - Physical activity for people with young-onset dementia and carers: protocol for a scoping review. AB - BACKGROUND: Physical activity has been cited as a potential symptomatic treatment option for people living with dementia. At present, much of the research concerning physical activity and dementia considers older adults, and there are several review articles summarising the evidence in this area. Less is known about physical activity for younger people with dementia, despite the marked differences in needs and preferences between the two groups. The aim of this scoping review is to systematically explore and critically appraise the current state of the evidence regarding physical activity for people with young-onset dementia and carers. METHODS: Several electronic databases (i.e. MEDLINE, SPORTDiscus, CINAHL, Cochrane Library, PsycINFO, Applied Social Sciences Index & Abstracts (ASSIA) and Scopus), grey literature (i.e. NICE Evidence Search (UK) and targeted international organisations e.g. Alzheimer's Society (UK), Age UK, Young Dementia UK, Alzheimer's Association (USA), Dementia Australia) and trial registries (i.e. UK Clinical Trials Gateway, International Clinical Trials Registry Platform and EU Clinical Trials Register) will be searched for published and unpublished evidence regarding physical activity for people with young-onset dementia and carers. Studies included in the review will be subjected to a narrative synthesis to explore similarities and differences, both within and between studies, to identify patterns and themes and to postulate explanations for research findings (e.g. how and why certain interventions or programmes have worked (or not); factors that might have influenced the findings ). DISCUSSION: This will be the first review to systematically explore and critically appraise the current state of the evidence regarding physical activity for people with young-onset dementia and carers. It is hoped that findings from this review will be used to inform the development of future physical activity interventions, to serve as a basis for consultation with key stakeholders and to identify appropriate outcome measures relevant to people with young-onset dementia and carers. SYSTEMATIC REVIEW REGISTRATION: At present, scoping reviews are not eligible for registration on the international prospective register of systematic reviews (i.e. PROSPERO). PMID- 29482654 TI - Strategies to improve the therapeutic effects of mesenchymal stromal cells in respiratory diseases. AB - Due to their anti-inflammatory, antiapoptotic, antimicrobial, and antifibrotic properties, mesenchymal stromal cells (MSCs) have been considered a promising alternative for treatment of respiratory diseases. Nevertheless, even though MSC administration has been demonstrated to be safe in clinical trials, to date, few studies have shown evidence of MSC efficacy in respiratory diseases. The present review describes strategies to enhance the beneficial effects of MSCs, including preconditioning (under hypoxia, oxidative stress, heat shock, serum deprivation, and exposure to inflammatory biological samples) and genetic manipulation. These strategies can variably promote increases in MSC survival rates, by inducing expression of cytoprotective genes, as well as increase MSC potency by improving secretion of reparative factors. Furthermore, these strategies have been demonstrated to enhance the beneficial effects of MSCs in preclinical lung disease models. However, there is still a long way to go before such strategies can be translated from bench to bedside. PMID- 29482656 TI - Beyond antibody engineering: directed evolution of alternative binding scaffolds and enzymes using yeast surface display. AB - Pioneered exactly 20 years ago, yeast surface display (YSD) continues to take a major role in protein engineering among the high-throughput display methodologies that have been developed to date. The classical yeast display technology relies on tethering an engineered protein to the cell wall by genetic fusion to one subunit of a dimeric yeast-mating agglutination receptor complex. This method enables an efficient genotype-phenotype linkage while exploiting the benefits of a eukaryotic expression machinery. Over the past two decades, a plethora of protein engineering efforts encompassing conventional antibody Fab and scFv fragments have been reported. In this review, we will focus on the versatility of YSD beyond conventional antibody engineering and, instead, place the focus on alternative scaffold proteins and enzymes which have successfully been tailored for purpose with regard to improving binding, activity or specificity. PMID- 29482655 TI - Characterization of cross-tissue genetic-epigenetic effects and their patterns in schizophrenia. AB - BACKGROUND: One of the major challenges in current psychiatric epigenetic studies is the tissue specificity of epigenetic changes since access to brain samples is limited. Peripheral tissues have been studied as surrogates but the knowledge of cross-tissue genetic-epigenetic characteristics remains largely unknown. In this work, we conducted a comprehensive investigation of genetic influence on DNA methylation across brain and peripheral tissues with the aim to characterize cross-tissue genetic-epigenetic effects and their roles in the pathophysiology of psychiatric disorders. METHODS: Genome-wide methylation quantitative trait loci (meQTLs) from brain prefrontal cortex, whole blood, and saliva were identified separately and compared. Focusing on cis-acting effects, we tested the enrichment of cross-tissue meQTLs among cross-tissue expression QTLs and genetic risk loci of various diseases, including major psychiatric disorders. CpGs targeted by cross-tissue meQTLs were also tested for genomic distribution and functional enrichment as well as their contribution to methylation correlation across tissues. Finally, a consensus co-methylation network analysis on the cross-tissue meQTL targeted CpGs was performed on data of the three tissues collected from schizophrenia patients and controls. RESULTS: We found a significant overlap of cis meQTLs (45-73 %) and targeted CpG sites (31-68 %) among tissues. The majority of cross-tissue meQTLs showed consistent signs of cis-acting effects across tissues. They were significantly enriched in genetic risk loci of various diseases, especially schizophrenia, and also enriched in cross-tissue expression QTLs. Compared to CpG sites not targeted by any meQTLs, cross-tissue targeted CpGs were more distributed in CpG island shores and enhancer regions, and more likely had strong correlation with methylation levels across tissues. The targeted CpGs were also annotated to genes enriched in multiple psychiatric disorders and neurodevelopment-related pathways. Finally, we identified one co methylation network shared between brain and blood showing significant schizophrenia association (p = 5.5 * 10-6). CONCLUSIONS: Our results demonstrate prevalent cross-tissue meQTL effects and their contribution to the correlation of CpG methylation across tissues, while at the same time a large portion of meQTLs show tissue-specific characteristics, especially in brain. Significant enrichment of cross-tissue meQTLs in expression QTLs and genetic risk loci of schizophrenia suggests the potential of these cross-tissue meQTLs for studying the genetic effect on schizophrenia. The study provides compelling motivation for a well designed experiment to further validate the use of surrogate tissues in the study of psychiatric disorders. PMID- 29482657 TI - Fatty acid oxidation promotes reprogramming by enhancing oxidative phosphorylation and inhibiting protein kinase C. AB - BACKGROUND: Changes in metabolic pathway preferences are key events in the reprogramming process of somatic cells to induced pluripotent stem cells (iPSCs). The optimization of metabolic conditions can enhance reprogramming; however, the detailed underlying mechanisms are largely unclear. By comparing the gene expression profiles of somatic cells, intermediate-phase cells, and iPSCs, we found that carnitine palmitoyltransferase (Cpt)1b, a rate-limiting enzyme in fatty acid oxidation, was significantly upregulated in the early stage of the reprogramming process. METHODS: Mouse embryonic fibroblasts isolated from transgenic mice carrying doxycycline (Dox)-inducible Yamanaka factor constructs were used for reprogramming. Various fatty acid oxidation-related metabolites were added during the reprogramming process. Colony counting and fluorescence activated cell sorting (FACS) were used to calculate reprogramming efficiency. Fatty acid oxidation-related metabolites were measured by liquid chromatography mass spectrometry. Seahorse was used to measure the level of oxidative phosphorylation. RESULTS: We found that overexpression of cpt1b enhanced reprogramming efficiency. Furthermore, palmitoylcarnitine or acetyl-CoA, the primary and final products of Cpt1-mediated fatty acid oxidation, also promoted reprogramming. In the early reprogramming process, fatty acid oxidation upregulated oxidative phosphorylation and downregulated protein kinase C activity. Inhibition of protein kinase C also promoted reprogramming. CONCLUSION: We demonstrated that fatty acid oxidation promotes reprogramming by enhancing oxidative phosphorylation and inhibiting protein kinase C activity in the early stage of the reprogramming process. This study reveals that fatty acid oxidation is crucial for the reprogramming efficiency. PMID- 29482658 TI - Independent functions of DNMT1 and USP7 at replication foci. AB - BACKGROUND: It has been reported that USP7 (ubiquitin-specific protease 7) prevents ubiquitylation and degradation of DNA methyltransferase 1 (DNMT1) by direct binding of USP7 to the glycine-lysine (GK) repeats that join the N terminal regulatory domain of DNMT1 to the C-terminal methyltransferase domain. The USP7-DNMT1 interaction was reported to be mediated by acetylation of lysine residues within the (GK) repeats. RESULTS: We found that DNMT1 is present at normal levels in mouse and human cells that contain undetectable levels of USP7. Substitution of the (GK) repeats by (GQ) repeats prevents lysine acetylation but does not affect the stability of DNMT1 or the ability of the mutant protein to restore genomic methylation levels when expressed in Dnmt1-null ES cells. Furthermore, both USP7 and PCNA are recruited to sites of DNA replication independently of the presence of DNMT1, and there is no evidence that DNMT1 is degraded in cycling cells after S phase. CONCLUSIONS: Multiple lines of evidence indicate that homeostasis of DNMT1 in somatic cells is controlled primarily at the level of transcription and that interaction of USP7 with the (GK) repeats of DNMT1 is unlikely to play a major role in the stabilization of DNMT1 protein. PMID- 29482660 TI - TRAPPED - an insight into two sisters' struggle to access treatment for a rare genetic disease. AB - Medical student training is largely focused on acquiring knowledge of diseases and their management, which may leave one with a naive perception of what is achievable in practice, particularly in the field of rare diseases. Tumour Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS) is a rare autoinflammatory disorder with a prevalence of one in a million. Its features include recurrent disabling episodes of high-grade fever associated with rash and arthralgia. Its rarity, combined with its somewhat vague and heterogenous clinical presentation, means that patients often suffer with TRAPS for years before they are diagnosed. Although it has a licensed treatment, Interleukin-1 blocker Anakinra, this is not currently funded by the NHS. This report provides an insight into the experiences of two sisters recently diagnosed with TRAPS, and the barriers they face preventing them from accessing the treatment they need, without which they are likely to suffer life-threatening organ failure. I have argued that the commissioning policy model for rare diseases needs reconsideration to improve access to Anakinra on a national level, and have highlighted the significant impact that clinicians can have on an individual level by being advocates for their patients. PMID- 29482659 TI - Yale School of Public Health Symposium on tissue imaging mass spectrometry: illuminating phenotypic heterogeneity and drug disposition at the molecular level. PMID- 29482661 TI - A novel affordable reagent for room temperature storage and transport of fecal samples for metagenomic analyses. AB - BACKGROUND: The number of large-scale studies on the gut microbiota in human cohorts is rapidly increasing. However, the few and expensive options for storage of fecal samples at room temperature have been an obstacle for large-scale metagenomic studies and the development of clinical/commercial personal metagenomic sequencing. RESULTS: In this study, we systematically tested a novel N-octylpyridinium bromide-based fecal sample preservation method and compared it with other currently used storage methods. We found that the N-octylpyridinium bromide-based method enabled preservation of the bacterial composition in fecal samples transported and stored at room temperature for up to at least 14 days. CONCLUSIONS: We describe a novel chemical stabilizer that allows cost-effective transportation and storage at room temperature for several days with preservation of bacterial composition. This method will facilitate sample collection even in remote area and also enable transport via normal commercial transportation routes. PMID- 29482662 TI - Bright light therapy versus physical exercise to prevent co-morbid depression and obesity in adolescents and young adults with attention-deficit / hyperactivity disorder: study protocol for a randomized controlled trial. AB - BACKGROUND: The risk for major depression and obesity is increased in adolescents and adults with attention-deficit / hyperactivity disorder (ADHD) and adolescent ADHD predicts adult depression and obesity. Non-pharmacological interventions to treat and prevent these co-morbidities are urgently needed. Bright light therapy (BLT) improves day-night rhythm and is an emerging therapy for major depression. Exercise intervention (EI) reduces obesity and improves depressive symptoms. To date, no randomized controlled trial (RCT) has been performed to establish feasibility and efficacy of these interventions targeting the prevention of co morbid depression and obesity in ADHD. We hypothesize that the two manualized interventions in combination with mobile health-based monitoring and reinforcement will result in less depressive symptoms and obesity compared to treatment as usual in adolescents and young adults with ADHD. METHODS: This trial is a prospective, pilot phase-IIa, parallel-group RCT with three arms (two add-on treatment groups [BLT, EI] and one treatment as usual [TAU] control group). The primary outcome variable is change in the Inventory of Depressive Symptomatology total score (observer-blinded assessment) between baseline and ten weeks of intervention. This variable is analyzed with a mixed model for repeated measures approach investigating the treatment effect with respect to all three groups. A total of 330 participants with ADHD, aged 14 - < 30 years, will be screened at the four study centers. To establish effect sizes, the sample size was planned at the liberal significance level of alpha = 0.10 (two-sided) and the power of 1 beta = 80% in order to find medium effects. Secondary outcomes measures including change in obesity, ADHD symptoms, general psychopathology, health-related quality of life, neurocognitive function, chronotype, and physical fitness are explored after the end of the intervention and at the 12-week follow-up. DISCUSSION: This is the first pilot RCT on the use of BLT and EI in combination with mobile health based monitoring and reinforcement targeting the prevention of co-morbid depression and obesity in adolescents and young adults with ADHD. If at least medium effects can be established with regard to the prevention of depressive symptoms and obesity, a larger scale confirmatory phase-III trial may be warranted. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00011666. Registered on 9 February 2017. ClinicalTrials.gov, NCT03371810. Registered on 13 December 2017. PMID- 29482663 TI - Impaired lymph node stromal cell function during the earliest phases of rheumatoid arthritis. AB - BACKGROUND: Systemic autoimmunity can be present years before clinical onset of rheumatoid arthritis (RA). Adaptive immunity is initiated in lymphoid tissue where lymph node stromal cells (LNSCs) regulate immune responses through their intimate connection with leucocytes. We postulate that malfunctioning of LNSCs creates a microenvironment in which normal immune responses are not properly controlled, possibly leading to autoimmune disease. In this study we established an experimental model for studying the functional capacities of human LNSCs during RA development. METHODS: Twenty-four patients with RA, 23 individuals positive for autoantibodies but without clinical disease (RA risk group) and 14 seronegative healthy control subjects underwent ultrasound-guided inguinal lymph node (LN) biopsy. Human LNSCs were isolated and expanded in vitro for functional analyses. In analogous co-cultures consisting of LNSCs and peripheral blood mononuclear cells, alphaCD3/alphaCD28-induced T-cell proliferation was measured using carboxyfluorescein diacetate succinimidyl ester dilution. RESULTS: Fibroblast-like cells expanded from the LN biopsy comprised of fibroblastic reticular cells (gp38+CD31-) and double-negative (gp38-CD31-) cells. Cultured LNSCs stably expressed characteristic adhesion molecules and cytokines. Basal expression of C-X-C motif chemokine ligand 12 (CXCL12) was lower in LNSCs from RA risk individuals than in those from healthy control subjects. Key LN chemokines C C motif chemokine ligand (CCL19), CCL21 and CXCL13 were induced in LNSCs upon stimulation with tumour necrosis factor-alpha and lymphotoxin alpha1beta2, but to a lesser extent in LNSCs from patients with RA. The effect of human LNSCs on T cell proliferation was ratio-dependent and altered in RA LNSCs. CONCLUSIONS: Overall, we developed an experimental model to facilitate research on the role of LNSCs during the earliest phases of RA. Using this innovative model, we show, for the first time to our knowledge, that the LN stromal environment is changed during the earliest phases of RA, probably contributing to deregulated immune responses early in disease pathogenesis. PMID- 29482664 TI - Human mesenchymal stem cells in spheroids improve fertility in model animals with damaged endometrium. AB - BACKGROUND: Asherman's syndrome (AS) is one of the gynecological disorders caused by the destruction of the endometrium. For some cases of AS available surgical methods and hormonal therapy are ineffective. Stem cell transplantation may offer a potential alternative for AS cure. METHODS: Human endometrial mesenchymal stem cells (eMSC) organized in spheroids were transplanted in rats with damaged endometrium modeled on AS. Treatment response was defined as pregnancy outcome and litter size. RESULTS: Application of eMSC in spheroids significantly improved the rat fertility with the AS model. eMSC organized in spheroids retain all properties of eMSC in monolayer: growth characteristics, expression of CD markers, and differentiation potential. Synthesis of angiogenic and anti inflammatory factors drastically increased in eMSC assembled into spheroids. CONCLUSIONS: Human endometrial mesenchymal stem cells (eMSC) can be successfully applied for Asherman's syndrome (AS) treatment in the rat model. eMSC organized in spheroids were more therapeutically effective than the cells in monolayer. After transplantation of eMSC in spheroids the pregnancy outcome and litter size in rats with AS was higher than in rats that received autologous rat bone marrow cells. It suggests the therapeutic plausibility of heterologous eMSC in case of failure to use autologous cells. PMID- 29482665 TI - Study on the relationship between expression patterns of cocaine-and amphetamine regulated transcript and hormones secretion in porcine ovarian follicles. AB - BACKGROUND: Cocaine-and amphetamine regulated transcript (CART) is an endogenous neuropeptide, which is widespread in animals, plays a key role in regulation of follicular atresia in cattle and sheep. Among animal ovaries, CART mRNA was firstly found in the cattle ovaries. CART was localized in the antral follicles oocytes, granulosa and cumulus cells by immunohistochemistry and in situ hybridization. Further research found that secretion of E2 was inhibited in granulosa cells with a certain dose of CART, the effect depends on the stage of cell differentiation, suggesting that CART could play a crucial role in regulating follicle atresia. The objective of this study was to characterize the CART expression model and hormones secretion in vivo and vitro in pig follicle granulosa cells, preliminarily studied whether CART have an effect on granulosa cells proliferation and hormones secretion in multiparous animals such as pigs. METHODS: The expression levels of CART mRNA in granulosa cells of different follicles were analyzed using qRT-PCR technology. Immunohistochemistry technology was used to localize CART peptide. Granulosa cells were cultured in medium supplemented with different concentrations of CART and FSH for 168 h using Long term culture system, and observed using a microscope. The concentration of Estradiol (E2) and progesterone (P) in follicular fluids of different test groups were detected by enzyme linked immunosorbent assay (ELISA). RESULTS: Results showed that expression level of CART mRNA was highest in medium follicles, and significantly higher than that in large and small follicles (P < 0.05). Immunohistochemical results showed that CART were expressed both in granulosa cells and theca cells of large follicles, while CART were detected only in theca cells of medium and small follicles. After the granulosa cells were cultured for 168 h, and found that concentrations of E2 increase with concentrations of follicle-stimulating hormone (FSH) increase when the CART concentration was 0 MUM. And the concentration of FSH reached 25 ng/mL, the concentration of E2 is greatest. It shows that the production of E2 needs induction of FSH in granulosa cells of pig ovarian follicles. With the increasing of CART concentrations (0.01, 0.1, 1 MUM), E2 concentration has a declining trend, when the FSH concentrations were 25 and 50 ng/mL in the medium, respectively. CONCLUSIONS: These results suggested that CART plays a role to inhibit granulosa cells proliferation and E2 production, which induced by FSH in porcine ovarian follicular granulosa cells in vitro, but the inhibition effect is not significant. So we hypothesis CART maybe not a main local negative regulatory factor during porcine follicular development, which is different from the single fetal animals. PMID- 29482666 TI - Bus Crashes in Iran. AB - Parvaresh-Masoud M , Asayesh H . Bus crashes in Iran. Prehosp Disaster Med. 2018;33(2):227-227. PMID- 29482667 TI - Phloroglucinol derivatives from Hypericum species trigger mitochondrial dysfunction in Leishmania amazonensis. AB - Bioactive molecules isolated from plants are promising sources for the development of new therapies against leishmaniasis. We investigated the leishmanicidal activity of cariphenone A (1), isouliginosin B (2) and uliginosin B (3) isolated from Hypericum species. Promastigotes and amastigotes of Leishmania amazonensis were incubated with compounds 1-3 at concentrations 1-100 um for 48 h. The anti-promastigote effect of compounds was also tested in combinations. The cytotoxicity against macrophages and human erythrocytes were determined using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) method and hemolysis assay, respectively. The compounds 1-3 showed high leishmanicidal activity against promastigotes, IC50 values of 10.5, 17.5 and 11.3 um, respectively. Synergistic interactions were found to the associations of compounds 1 and 2 [Sigma fractional inhibitory concentration (FIC) = 0.41], and 2 and 3 (SigmaFIC = 0.28) on promastigotes. All Hypericum compounds induced mitochondrial hyperpolarization and reactive oxygen species production in promastigotes. The compounds showed low cytotoxicity toward mammalian cells, high selectivity index and killed intracellular amastigotes probably mediated by oxidative stress. These results indicate that these compounds are promising candidates for the development of drugs against leishmaniasis. PMID- 29482668 TI - IMPORTANCE OF CONTEXTUAL DATA IN PRODUCING HEALTH TECHNOLOGY ASSESSMENT RECOMMENDATIONS: A CASE STUDY. AB - OBJECTIVES: Contextual data and local expertise are important sources of data that cannot be ignored in hospital-based health technology assessment (HTA) processes. Despite a lack of or unconvincing evidence in the scientific literature, technology can be recommended in a given context. We illustrate this using a case study regarding biplane angiography for vascular neurointervention. METHODS: A systematic literature review was conducted, along with an analysis of the context in our setting. The outcomes of interest were radiation doses, clinical complications, procedure times, purchase cost, impact on teaching program, the confidence of clinicians in the technology, quality of care, accessibility, and the volume of activity. A committee comprising managers, clinical experts, physicians, physicists and HTA experts was created to produce a recommendation regarding biplane technology acquisition to replace a monoplane device. RESULTS: The systematic literature review yielded nine eligible articles for analysis. Despite a very low level of evidence in the literature, the biplane system appears to reduce ionizing radiation and medical complications, as well as shorten procedure time. Contextual data indicated that the biplane system could improve operator confidence, which could translate into reduced risk, particularly for complex procedures. In addition, the biplane system can support our institution in its advanced procedures teaching program. CONCLUSIONS: Given the advantages provided by the biplane technology in our setting, the committee has recommended its acquisition. Contextual data were of utmost importance in this recommendation. Moreover, this technology should be implemented alongside a responsibility to collect outcome data to optimize clinical protocol in the doses of ionizing delivered. PMID- 29482669 TI - Shifts in positive and negative psychotic symptoms and anger: effects on violence. AB - BACKGROUND: Changes in positive and negative symptom profiles during acute psychotic episodes may be key drivers in the pathway to violence. Acute episodes are often preceded by fluctuations in affect before psychotic symptoms appear and affective symptoms may play a more important role in the pathway than previously recognised. METHODS: We carried out a prospective cohort study of 409 male and female patients discharged from medium secure services in England and Wales to the community. Measures were taken at baseline (pre-discharge), 6 and 12 months post-discharge using the Positive and Negative Syndrome Scale. Information on violence was obtained using the McArthur Community Violence Instrument and Police National Computer. RESULTS: The larger the shift in positive symptoms the more likely violence occurred in each 6-month period. However, shifts in angry affect were the main driving factor for positive symptom shifts associated with violence. Shifts in negative symptoms co-occurred with positive and conveyed protective effects, but these were overcome by co-occurring shifts in anger. Severe but stable delusions were independently associated with violence. CONCLUSIONS: Intensification of angry affect during acute episodes of psychosis indicates the need for interventions to prevent violence and is a key driver of associated positive symptoms in the pathway to violence. Protective effects against violence exerted by negative symptoms are not clinically observable during symptom shifts because they are overcome by co-occurring anger. PMID- 29482670 TI - Atrial septal defect closure with the new Cardia Ultrasept IITM device with interposed Goretex patch: Mexican experience - has the perforation of Ivalon's membrane been solved? AB - OBJECTIVES: The objective of this study was to demonstrate the safety and feasibility of using the new Cardia Ultrasept IITM device with interposed Goretex patch referring to the perforation of polyvinyl alcohol membrane. BACKGROUND: Great advances have been made in the development of devices for closure of atrial septal defect. The Cardia Ultrasept IITM with interposed Goretex patch is the modified last generation of Cardia devices, having the advantage of a super-low profile within the atria and an integral locking delivery-retrieval mechanism that ensures safe deployment. In addition, with the interposition of the Goretex, it has been possible to abolish perforation of Ivalon's membrane as a complication.Methods and resultsPatients with ostium secundum atrial septal defect with surrounding rims with a minimum length of 5 mm and who underwent atrial septal defect closure with the new Ultrasept IITM with Goretex patch were included from two paediatric cardiac centres. Primary end point was to determine perforation of the Goretex membrane at follow-up; secondary end point included right ventricular diastolic diameter. In total, 30 patients underwent atrial septal defect closure at a median age of 6 (1-29) years. At follow-up for 6 (range, 1-15) months, freedom from perforations was 100%. A continuous decrease in right ventricular diastolic diameter was found with an initial median of 30 (25-49) mm and after catheterisation of 27.5 (18-33) mm, p=0.01, and Z-score of 2.6 (1.7-3.6) versus 1.9 (1-2.9) after procedure, p=0.01. CONCLUSIONS: The new modified generation of the Ultrasept IITM device with interposed Goretex patch is a good alternative to achieve atrial septal defect closure safely and feasibly with no membrane perforation at follow-up. PMID- 29482671 TI - Does thinner right entorhinal cortex underlie genetic liability to cannabis use? AB - BACKGROUND: Although alterations in medial temporal lobe structures have been previously associated with use of cannabis, one of the most widely used illicit drugs, whether such alterations are a cause or effect of cannabis use has been unclear. METHODS: In this cross-sectional observational study involving 404 twins/siblings, we have compared cortical thickness and surface area between groups of gender-matched sibling-pairs (concordant cannabis unexposed, concordant exposed and discordant for cannabis exposure) using permutation tests after controlling for potential confounds. Bi-variate polygenic model was used to assess the genetic and environmental contributions underlying cortical morphological phenotypes and frequency of cannabis use. RESULTS: Cortical thickness of the right entorhinal cortex was significantly lower in the concordant exposed siblings compared to both discordant unexposed and discordant exposed groups [false discovery rate (FDR)-corrected, q < 0.05]. The association between the right entorhinal cortex thickness and frequency of cannabis use is due to the contribution of significant shared additive genetic (rhog = -0.19 +/- 0.08; p = 0.02) factors but not unique environment (rhoe = 0.05 +/- 0.09; p = 0.53). Significantly lower surface area of the right entorhinal cortex in discordant exposed group compared with the discordant unexposed group furnishes preliminary evidence in support of causal effect of cannabis use (FDR-corrected, q < 0.05). However, bi-variate polygenic model-based analysis did not show any significant effect. CONCLUSIONS: Shared genetic liability may underlie the association between cannabis exposure and thinner right entorhinal cortex. Prospective longitudinal studies are necessary to definitively disentangle the cause-effect relationships of cannabis use. PMID- 29482672 TI - The impact of floor type on lameness and hoof health of dairy origin bulls. AB - This study aimed to evaluate the effect of using different floor types to accommodate growing and finishing beef cattle on lameness. In all, 80 dairy origin bulls were blocked according to live weight and breed into 20 groups, and randomly allocated within groups to one of four treatments. The floor types studied were fully slatted flooring throughout the entire experimental period (CS); fully slatted flooring covered with rubber strips throughout the entire experimental period (RS); fully slatted flooring during the growing period and then moved to a solid floor covered with straw bedding during the finishing period (CS-S) and fully slatted flooring during the growing period and then moved to fully slatted flooring covered with rubber strips during the finishing period (CS-RS). The total duration of the study was 204 days. The first 101 days was defined as the growing period, with the remainder of the study defined as the finishing period. During the growing period, there was a tendency for bulls accommodated on CS to have a higher locomotion score compared with those accommodated on RS (P=0.059). However, floor type had no significant effect on locomotion score during the finishing period. There was also no significant effect of floor type on digital dermatitis during both the growing or finishing period. Floor type had no significant effect on swelling at the leg joints at the end of the finishing period. Bulls accommodated on RS had the least probability of bruised soles during both the growing and finishing period (P<0.01). Growing bulls accommodated on CS had significantly greater front heel height net growth compared with those accommodated on RS (P<0.05). However, bulls accommodated on RS had a tendency to have greater front toe net growth compared with those accommodated on CS (P=0.087). Finishing bulls accommodated on CS-RS had the greatest front toe net growth (P<0.001). Heel height net growth was greatest in bulls accommodated on CS-S (P<0.001). Floor type had no significant effect on mean maximum hoof temperature during the growing period. Finishing bulls accommodated on CS-S had a significantly lower mean maximum hoof temperature compared with those accommodated on any other floor type (P<0.001). The study concluded that rubber flooring is a suitable alternative to fully slatted flooring, reducing the prevalence of bruised soles. Despite greater toe net growth in bulls accommodated on rubber flooring, there was no effect of floor type on locomotion score, suggesting that increased toe net growth does not adversely affect walking ability. In addition, although mean maximum hoof temperature was lowest in bulls accommodated on straw bedding, there was no evidence to suggest this is indicative of improved hoof health. PMID- 29482675 TI - What We Can Count On. PMID- 29482676 TI - Oral Health and Its Effect on the Academic Performance of Children and Adolescents. AB - PURPOSE: The purpose of this systematic review was to verify whether child and adolescent oral health affected academic performance. METHODS: A literature search conducted in March 2017 on PubMed, Lilacs, Web of Science, and Scopus databases identified 2,009 papers, six of which were included in the final review. Quality appraisal and risk of bias were evaluated using the quality assessment tool for observational cohort and cross-sectional studies. RESULTS: Two papers were classified as being of good quality, one as fair, and three as poor. In four publications, oral health conditions were measured by taking only dental caries into account, while in two others treatment needs and dental trauma were also considered. Although four papers concluded that children's academic performance and poor oral health were associated, the results were not considered reliable because of the high risk of bias. The two papers classified as being of good quality did not show an association between oral health and academic performance, unless mediated by socioeconomic factors. CONCLUSION: Further well designed studies are required to demonstrate whether children's oral health can have a negative influence on their academic performance. PMID- 29482677 TI - Communication Application for Use During the First Dental Visit for Children and Adolescents with Autism Spectrum Disorders. AB - PURPOSE: The purpose of this study was to develop and evaluate an application (app) facilitating patient-professional communication among individuals with autism spectrum disorder (ASD) and compare it with the Picture Exchange Communication System (PECS). METHODS: Forty nine- to 15-year-olds were randomly divided into two groups: G1 (app; N equals 20) and G2 (PECS; N equals 20). Initially, the visual contact timing of the groups was measured. Pictures of a room, ground, chair, dentist, mouth, low-speed handpiece, and air-water syringe were presented to both groups. Each picture was shown up to three times per appointment to evaluate whether or not the child accepted the procedure. After dental prophylaxis, caries experience was recorded. RESULTS: The prevalence of dental caries was 37.5 percent. Differences in the number of attempts required for each picture to acquire the skill proposed were found between the groups (Mann-Whitney, P<0.05). A significant difference in the median number of attempts (G1 equals 9.5 and G2 equals 15) and appointments (G1 equals three and G2 equals five) was observed (Mann-Whitney, P<0.05). CONCLUSIONS: The app was more effective than the Picture Exchange Communication System for dentist-patient communication, decreasing the number of appointments required for preventive dental care and clinical examinations. PMID- 29482678 TI - Parent's Sense of Coherence and Children's Oral Health-Related Behaviors: Is There an Association? AB - PURPOSE: Parental capacity to face day-to-day stressors has a relevant role in recognizing and mobilizing resources to control children's oral health behaviors. This capacity has been explored by means of the sense of coherence. The purpose of this study was to explore the association between mothers' sense of coherence (SOC) and their preschool children's oral health-related behaviors. METHODS: Mothers and their pre-school children were recruited during immunization programs at community health centers in Edmonton, Canada. Participants answered eight questions on socio-demographics (covariates), parents' SOC (main independent variable), and children's oral health-related practices (outcome variables). Statistical analyses comprised a two-sample t test, chi-square test, and logistic regression. RESULTS: A total of 378 pairs of mothers/ children participated in this study. Children's mean age was 3.92+/-(1.33) years. Mothers' SOC was statistically associated with children's frequency of sugar consumption and frequency and pattern of dental visits. The children of mothers who had higher levels of SOC presented a lower frequency intake of food or drink containing sugar and were more likely to visit the dentist for preventive purposes. CONCLUSIONS: Mothers' sense of coherence had a significant association with children's oral health-related behaviors; a higher SOC of mothers was associated with more positive behaviors among their children. PMID- 29482681 TI - Does Achievement of Hemostasis After Pulp Exposure Provide an Accurate Assessment of Pulp Inflammation? AB - PURPOSE: The purpose of this study was to determine in primary molars with carious exposures whether hemostasis at the exposure site and pulp orifice reflected inflammatory status of the pulp at the canal orifice based on cytokine levels. METHODS: Forty mandibular primary molars with deep caries were included in the study. Teeth were divided into two groups: group A had teeth where hemostasis at the exposure site was achieved within five minutes, and group B had teeth where hemostasis at the exposure site could not be achieved within five minutes. Blood samples were harvested from the exposure sites and canal orifices. Cytokine levels for IL-1beta, IL-2, IL-6, IL-8, IL-10, TNF-alpha, and PGE2 were measured using ELISA for all sample sites. RESULTS: The IL-6 levels at the exposure sites were found to be significantly higher in group A when compared to group B, but there was no statistically significant differences in any of the cytokine levels at the canal orifices between the two groups. CONCLUSIONS: Controlling bleeding at the exposure site or canal orifices does not provide accurate assessment of inflammation at the canal orifice and may be misleading for diagnosing vital pulp treatment in primary teeth with a carious pulp exposure. PMID- 29482680 TI - Importance of Content and Format of Oral Health Instruction to Low-income Mexican Immigrant Parents: A Qualitative Study. AB - PURPOSE: This study's purpose was to explore how content and format of children's oral health instruction in the dental clinic is perceived by parents and might affect parents' knowledge and behaviors. METHODS: Thirty low-income Mexican immigrant parents of children age five years and under were recruited from dental clinics in 2015 to 2016. In-person qualitative interviews in Spanish about their children's and their own experiences of dental care and home oral hygiene practices were conducted, digitally recorded, translated, and transcribed. Data analysis involved iteratively reading text data and developing and refining codes to find common themes. RESULTS: Twenty-five of 30 parents recalled receiving oral hygiene instruction, and 18 recalled receiving nutrition instruction and were included in analyses. The format and effectiveness of instruction varied. More engaging educational approaches were recalled and described in more detail than less engaging educational approaches. As a result of oral hygiene and nutritional instruction, most parents reported changing their oral hygiene home behaviors for their children; half aimed to reduce purchasing sugary foods and drinks. CONCLUSIONS: Most parents recalled receiving oral hygiene and nutrition instruction as part of their child's dental visit and reported incorporating the instruction and recommendations they received into their children's home routine. PMID- 29482682 TI - Comparison of Two Morphine-Benzodiazepine-Hydroxyzine Combinations for the Oral Sedation of Pediatric Dental Patients: A Retrospective Study. AB - PURPOSE: To investigate the effectiveness of oral morphine sulfate regimens in sedating pediatric dental patients and assess whether pre-sedation disposition and willingness to take the sedative were related to the outcome of the sedation. METHODS: The sedation records of 271 pediatric dental patients sedated with oral morphine were reviewed. Children were either sedated with regimen one (morphine plus midazolam plus hydroxyzine) or regimen two (morphine plus diazepam plus hydroxyzine). Data gathered included the patient's pre-sedation disposition, willingness to take the sedative, effectiveness of sedation, and occurrence of any adverse event. Data analysis was conducted using descriptive statistics, Pearson's chi-square, and logistic regression. RESULTS: Regimens one and two had an overall success rate of 80 percent (143 out of 178) and 81 percent (75 out of 93), respectively. A positive correlation was observed between the patient's willingness to take his/her sedative medication and the effectiveness of the sedation using both the Pearson's chi-square (P=.004) and logistic regression (P=.028). Adverse events occurred in six percent (17 out of 271) of the cases. CONCLUSIONS: Overall rate of effective sedation using various oral morphine sulfate regimens was above 80 percent. Minimal adverse events occurred. The patient's willingness to take the sedative was positively associated with the outcome of the sedation regimen. PMID- 29482683 TI - Cost Estimates for Bioactive Cement Pulpotomies and Crowns in Primary Molars. AB - PURPOSE: To explore cost-effective options for pulpotomy, chamber fillings, and crowns in primary molars using bioactive cements. METHODS: Thirty extracted primary molars were divided into five groups, each having two sets of three teeth (one first molar and two second molars). Pulpotomy and restorative options were randomly assigned: Biodentine plus Ketac Molar; NuSmile NeoMTA plus Tempit LC; NeoMTA Plus plus Fuji IX; MTA Angelus plus IRM capsule; MTA Flow plus IRM powder and liquid. After mixing one dose, pulp chambers of the first molar and one second molar were filled with a two-millimeter layer of bioactive cement and filling material (protocol A). The other second molar's chamber was solo filled by a single mixed dose of bioactive cement (protocol B). The cost for each material was calculated independently, regardless of the group to which they belonged. A market assessment for primary molar crowns was performed, and a comparison table was produced. RESULTS: For protocol A, the lowest mean cost per tooth (LMC) was obtained for NeoMTA cements and IRM powder and liquid; for solo bioactive cement pulp chamber filling, protocol (B), LMC was obtained for NeoMTA cements. Zirconia crowns were the costliest. CONCLUSIONS: NeoMTA-type cements were the most cost-effective option for single-tooth pulpotomy. Zirconia crowns had the highest cost per tooth. PMID- 29482684 TI - Dental Management of a Pediatric Patient with Moyamoya Syndrome: A Rare Clinical Entity. AB - Moyamoya disease (MMD) is a rare cerebrovascular disorder involving progressive constriction of the internal carotid artery and its branches. The disease has a particularly aggressive course in very young patients, and early surgical intervention is often necessary to prevent permanent neurological damage. MMD patients have an increased risk of stroke development, which may be provoked by pain or anxiety. Currently, no reports of pediatric patients with MMD exist in the dental literature. The purpose of this paper was to discuss the dental management of a two-year-old with moyamoya disease who presented with early childhood caries and dental fear, offering recommendations for dental providers with emphasis on stroke prevention, collaboration with the medical team, anesthesia considerations for patients with increased stroke risk, and the challenges to maintain the oral health of a patient undergoing complex medical treatment. PMID- 29482685 TI - Diagnosis of Hypofibrinogenemia After Dental Treatment Under General Anesthesia. AB - Congenital hypofibrinogenemia is a rare coagulation disorder characterized by a deficiency in fibrinogen protein, which is critical to the normal coagulation process. This hematological disorder can go undiagnosed until an event leads to prolonged bleeding. The purposes of this report were to describe an incidental diagnosis of congenital hypofibrinogenemia after a dental procedure, discuss the importance of recognizing coagulopathies on the delivery of dental care, examine the multi-disciplinary clinical management of prolonged bleeding after a dental procedure, and evaluate the challenges health care practitioners may encounter when obtaining a thorough medical history. PMID- 29482686 TI - Abdominal Supernumerary Testis Complicated by Yolk Sac Tumor. AB - We describe a case of a 26-year man with complaints of suprapubic pain and burning micturition for two weeks and intermittent hematuria for two months. On physical examination, there was palpable mobile pelvic mass measuring 10x10 cm. Both testes were palpable in the scrotum. CT scan abdomen revealed well-defined, soft tissue mass, about 11x10 cm between rectum and urinary bladder. Mass showed internal necrotic changes and enhancement along the walls. No calcification was seen. Exploratory laparotomy was done. Tumour mass was nodular tissue weighing 194 gm. Diagnosis was confirmed histologically showing yolk sac tumor. Postoperatively, tumour markers were normal. MRI pelvis revealed no residual tumor. PMID- 29482687 TI - Life-Threatening Hypokalemic Quadriplegia in a Postoperative Patient. AB - Acute hypokalemic paralysis is a reversible but potentially lethal clinical condition. We report a case, who developed rapidonset quadriparesis in immediate postoperative period after undergoing right percutaneous nephrolithotomy for bilateral renal stones. On evaluation, she was found to have hypernatremic, hyperchloremic, hypokalemic acidosis. This severe hypokalemia-induced quadriparesis was precipitated by repeated furosemide injections, use of potassium-free fluid as maintenance, intracellular shift due to free water administration in this patient, who had pre-existing distal renal tubular acidosis. PMID- 29482688 TI - Complete Heart Block due to Occlusion of Jailed Septal Perforator after Percutaneous Coronay Intervention of Proximal Left Anterior Descending Artery. AB - A 70-year diabetic and hypertensive lady admitted with acute coronary syndrome (ACS) underwent coronary angiography, which showed severe diffuse disease of proximal left anterior descending (LAD). She underwent percutaneous coronay intervention (PCI) of proximal LAD artery that resulted in occlusion of jailed first septal perforator. She remained stable and asymptomatic and was shifted to Coronary Care Unit (CCU) after successful procedure. Approximately five hours later, patient developed complete heart block (CHB) and became hemodynamically unstable. Temporary pacemaker (TPM) was implanted and relook angiogram was performed, which showed patent stent. Patient remained dependent on TPM. After one week, permanent pacemaker was implanted and patient discharged in stable condition. PMID- 29482689 TI - Treatment of a Rare Vascular Complication of Coronary Stenting in an Octagenarian. AB - The ability of drug-eluting stent (DES) to inhibit intimal proliferation has resulted in a massive increase in their usage over the years. However, it is known that the application of DES can alter the normal cascade of vascular healing, resulting in delayed endothelialisation with risk of vascular complications. Coronary artery aneurysms (CAN) are defined as more than 50% dilatation of the coronary artery compared to the reference vessel diameter with the reported incidence after percutaneous intervention (PCI) being only around 0.35 to 6.0%. Previously, CAN had been reported with the use of bare metal stent secondary to stretch, stent fracture and dissection. However, recently, increasing number of cases have been reported describing CAN after DES implantation. To the best of the authors' knowledge, they present the first case from Pakistan of a left anterior descending coronary artery aneurysm after DES implantation treated successfully with stenting under intravascular ultrasound guidance. PMID- 29482690 TI - Use of TAP Technique in Percutaneous Coronary Intervention, for Stenting Critical Osteal Disease in an Old Patient with Compromised Left Ventricular Function. AB - With recent advancements in techniques and technologies in the field of interventional cardiology, Percutaneous Coronary Intervention (PCI) is preferred over Coronary Artery Bypass Grafting (CABG), provided patient selection is kept in mind, and all the technical facilities are available to ensure successful end results without any immediate or late cardiac complications. However, dealing with Left Main Coronary Artery (LMCA) osteal disease can be challenging. We report a case of T and Protrusion (TAP) technique performed at Hearts International Hospital, Rawalpindi, Pakistan. The patient was old and had compromised Left Ventricular Ejection Fraction (LVEF).The results were excellent with no complications. PMID- 29482691 TI - Swirl Sign - A C T Angiogram Alarm Sign or Congenital Trans-Mesenteric Hernias. AB - Congenital trans-mesenteric hernias (CTMHs) are caused by rent in the mesentry of bowel. The lesions commonly present in pediatric age group. Adult CTMHs usually present with complication of the problem. The diagnosis is often late and is associated with morbidity as well as mortality due to bowel ischemia. There is no specific sign associated with this condition. A case is reported of a patient diagnosed with CTMH on high suspicion by the radiologist based on her finding of abnormal swirling of superior mesenteric artery on CT angiogram. Swirl sign on CT angiogram warrants an early surgical consultation to prevent any morbidity. PMID- 29482693 TI - Kissing Nevus of the Penis. AB - Kissing nevus is a very rare congenital melanocytic nevus. Here, we describe one case of kissing nevus on the penis. A 15-year boy presented with asymptomatic black to dark brown color patches on his penis. Histopathological findings showed that there were nests and cords of nevus cells in upper dermis. No significant cytologic atypia and mitoses were noted. Immunohistochemical stains revealed a partial positive for HMB-45 only in upper dermis and a stronger positivity for S 100 in almost all nevus cells. We diagnosed the lesion as kissing nevus of penis. The patient and his parents refused further treatment, and the patient is being followed in our clinic. PMID- 29482692 TI - Tuberous Sclerosis Complex with Gingival Enlargement in an Adolescent. AB - Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystem genetic disorder. It is characterised by formation of benign hamartomas, neurofibromas, and angiofibromas located in different organs. We describe a case of a 13-year boy who complained of gingival enlargement. Clinical examination showed distinctive dermatological signs like hypopigmented macules, shagreen plaques, miliary fibromas, fibrous plaques and multiple angiofibromas. Oral manifestation included localised gingival enlargement. Gingivectomy was performed and the excised tissue was submitted for histopathological examination. The microscopic examination of gingival tissue revealed multiple bundles of collagen fibres with proliferating fibroblast and multiple proliferating blood vessels in the connective tissue. The clinical and histopathological findings were consistent with gingival angiofibromas of TSC. Gingivectomy allowed the patient to have better function and aesthetics. Periodontal examination in conjunction with dermatological examination is important for early diagnosis of TSC. PMID- 29482694 TI - Pseudohypoaldosteronism Type II: A Young Girl Presented with Hypertension, Hyperkalemia and Metabolic Acidosis. AB - Pseudohypoaldosteronism (PHA) type II is an extremely rare disorder which presents with hypertension, hyperkalemia, and normal anion gap metabolic acidosis. PHA II is also known as familial hyperkalemic hypertension, Gordon syndrome, and chloride shunt syndrome. PHA II is an autosomal dominant disorder and is caused by mutation in WNK1, WNK4, CULLIN3, KLHL3, OSR, SPAK gene. The expression of these proteins is limited to the distal convoluted tube and collecting duct of the kidney. PHA II usually responds to salt restriction and thiazide diuretics. We are reporting here a case of 16-year girl who presented with generalised fatigue and shortness of breath, and blood pressure (BP) of 220/110 mmHg. Laboratory investigation showed hyperkalemia, normal anion gap metabolic acidosis, and hypercalciuria. Workup for secondary causes of hypertension was negative. She responded to thiazide diuretics and her BP is well controlled, and acidosis and hyperkalemia are corrected. PMID- 29482695 TI - Acute Onset of Quadriplegia Secondary to Hypoparathyroidism: Mimicker of AMAN Variant of GBS. AB - Acute onset of quadriplegia is a rare phenomenon seen with hypocalcemia due to hypoparathyroidism. We describe a 33-year gentleman who presented with weakness of all four limbs and areflexia. ECG showed QT abnormality. Nerve conduction study revealed normal sensory and significantly low motor CMAP amplitudes in both the upper and lower extremities. This nerve conduction study can be seen in acute motor neuropathy of various etiologies, among which GBS is the most worrisome. Our patient found to have low calcium and parathyroid hormone level. His symptoms improved after calcium replacement. Occurrence of quadriplegia in hypoparathyroidism, and its improvement after correction of calcium, suggests crucial role of calcium in neuromuscular transmission. One should suspect electrolyte imbalance, like hypocalcemia in patients presenting with nerve conduction features of AMAN variant of GBS. PMID- 29482696 TI - A Gastric Duplication Cyst Initially Mimicking Staghorn Calculus. AB - Gastric duplication cyst is an uncommon anomaly typically found in the greater curvature of the stomach. It is usually diagnosed in children and quite difficult to diagnose in adult because of variable presentation. We present a 76-year woman who was admitted for abdominal pain of few weeks' duration. Her X-ray showed calcification in the region of left kidney, and she was subsequently managed with a presumptive diagnosis of staghorn calculus. Computerized Tomography (CT) scan of her abdomen disclosed calcification in the gastric wall for which an endoscopic ultrasound and biopsy was done. Findings were consistent with the presence of gastric epithelium and a diagnosis of gastric duplication cyst was made. Surgery was the continuation of care. The presence of symptomatic gastric cyst in an elderly patient is very rare. This is the first case in which gastric duplication cyst mimicked staghorn calculus on abdominal X-ray. Consequently, this diagnosis, though rare, should be considered in the differentials of upper abdominal pain. PMID- 29482697 TI - Managing a Large-Size Adrenal Cyst by Hand-Assisted Laparoscopic Surgery in a Young Male. AB - Adrenal cysts are not common and are most often non-functional and asymptomatic. Most of these cysts are found incidentally. These lesions exhibit a broad histomorphologic spectrum and may vary from benign cysts to malignant cystic neoplasms. Our patient was a 21-year male who presented with abdominal discomfort and epigastric pain and was diagnosed with left adrenal cyst on ultrasound, which was later confirmed by CT scan. PMID- 29482698 TI - Occult Pneumothorax: What Do We Need to Do? AB - Occult pneumothorax is a condition in which a patient's clinical examination and chest radiograph are normal; but there is pneumothorax on computed tomography (CT) scan. We here describe two cases of trauma whose initial survey and chest X ray showed normal lung markings bilaterally; but CT scan done subsequently, showed pneumothorax which was managed by chest intubation. There is still an ongoing debate about the management of occult pneumothorax. Simple observation is recommended for an asymptomatic pneumothorax. However, chest intubation is recommended for patients undergoing a surgery or mechanical ventilation due to the fear of converting a close pneumothorax into a tension pneumothorax. PMID- 29482699 TI - Uterine Arteriovenous Malformations after Suction Evacuation of Missed Miscarriage. AB - Uterine arteriovenous malformation (AVM) is an uncommon but life-threating source of bleeding. AVM is an abnormal connection between uterine arteries and veins. Patients typically present with vaginal bleeding following miscarriage (medical/surgical) or cesarean section. The treatment of choice depends on the symptoms, age, desire of fertility, localization and size of the lesion. Uterine artery embolization is the first choice in symptomatic patients of reproductive age group. We report a case of AVM presenting after dilation and evacuation with extensive lesion, which was successfully treated with bilateral uterine artery embolization. PMID- 29482700 TI - Fatal Elizabethkingia MeningosepticaCholangitis Following Biliary Stent Placement. AB - Elizabethkingia (E.) meningosepticais a ubiquitous gram-negative bacillus belonging to the genus Chryseobacteriumand has been reported to cause nosocomial infections in both the immunocompromised and immunocompetent patients. E. meningoseptica can colonize the biliary tree after endoscopic procedures; and cholangitis, caused by this organism, is associated with a favorable prognosis. Here, we report a fatal case of cholangitis secondary to E. meningoseptica that developed following biliary stent placement. This case suggests that E. meningoseptica can be a cause of potentially fatal biliary tract infections in patients who undergo biliary tract endoscopic procedures. Clinicians must not disregard this organism as a contaminant (or colonizer) as a delay in diagnosis and treatment can lead to a fatal outcome, as seen in this case. PMID- 29482701 TI - A Young Boy with Persistent Nodules and Hoarseness: A Rare Presentation of Nodular Secondary Syphilis. AB - Syphilis is a venereal disease caused by treponema pallidum, historically known as "great mimicker" because of its variable presentations. Secondary syphilis usually presents with maculopapular or papulosquamous rash. Rare manifestations include papulonodular, annular and lichenoid lesions. Nodules are usually found in benign tertiary syphilis. We present a case of a young boy who presented with five months' history of nodular skin lesions and hoarseness of voice. Venereal disease research laboratory (VDRL) was initially negative owing to prozone phenomenon. However, histopathology was confirmatory and he responded to benzathine penicillin. We present this case because of rare clinical presentation with persistent nodular lesions, unusual age group, and negative initial VDRL test. PMID- 29482702 TI - Endobronchial Tuberculosis Simulating Carcinoid Tumor. AB - Diagnosing endobronchial tuberculosis (EBTB) can be difficult due to the lack of specific signs and symptoms that differentiate it from other respiratory diseases, such as lung tumors. We hereby report a case of a very rare presentation of tuberculosis (TB) in a patient who presented with a dry cough and significant weight loss for 3 months. Chest X-ray and CT scan of the chest showed partial atelectasis and a segmental collapse of the right upper lobe and tumor like arising from its bronchus along with a large right para-tracheal mediastinal lymphadenopathy, mimicking a metastatic (N2) disease. Fiber-optic bronchoscopy revealed a fleshy, highly vascularized mass occluding the right upper lobe bronchus, and thus the initial diagnosis of carcinoid tumor was made. Mediastinoscopy and biopsy of these mediastinal lymph nodes showed caseating chronic granulomatous inflammation consistent with TB, which changed the diagnosis to EBTB. The patient was treated with first-line anti-tuberculous drugs that led to a full resolution in terms of symptoms, radiological findings and complete disappearance of the endobronchial mass by bronchoscopy. To the best of authors' knowledge, there are no other similar cases in presentation and management in the literature. PMID- 29482703 TI - Epigastric Heteropagus Conjoined Twins. AB - Heteropagus twins are an extremely rare form of asymmetrical conjoined monochorial, monoamniotic twins with an estimated incidence of less than one per one million live births. An often used synonym is parasitic twins. We report a very rare case of epigastric heteropagus twins with a large omphalocoele. The parasite had fully formed pelvis, lower limbs and upper limbs with male genitalia and it was attached to the autosite in the epigastrium. PMID- 29482704 TI - Ellis-Van Creveld Syndrome in a Neonate. AB - Ellis-van Creveld syndrome is a rare form of skeletal and chondroectodermal dysplasia which affects all the three ectodermal, mesodermal, and endodermal derivatives. It has an autosomal recessive inheritance. This is caused by mutations in 1 of 2 genes, EVC 1 or EVC 2. This syndrome has a constellation of characteristic features that include bilateral post-axial polydactyly, mainly involving the upper limbs, hypoplastic nails and teeth, congenital heart defects, and chondroectodermal dysplasia. It is mainly a disorder of Amish population where incidence of this disease is 1/5000 and its incidence in non-Amish population is 7/1000000. Our patient had all the major characteristic features consistent with Ellis-van Creveld syndrome including post-axial polydactyly, teeth and nail abnormalities, congenital heart defect and skeletal dysplasia. Until now, only five cases have been reported from this region of the world, none of them diagnosed in neonatal life and having characteristic common atrium. PMID- 29482705 TI - MELAS: A Complex and Challenging Diagnosis. AB - Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is a rare multisystem disorder and is the most common maternally inherited mitochondrial disease. This condition has a special predilection for the nervous system and muscles. Typical findings on brain imaging include stroke-like areas, calcification of basal ganglia and brain atrophy. This accounts for the disease being, both clinically and radiologically, mistaken for ischemic stroke. The differentiation features from stroke include comparatively young age of the patients, site of the lesions, and relative overlap between the cerebral vasculature territories. In this case report, we discuss a 16-year male with clinical and radiological features highly suggestive of MELAS syndrome. Since this disease is rare and its clinical presentation is complex, it is among the most challenging to diagnose. It is particularly difficult to differentiate between ischemic stroke and MELAS. Magnetic resonance imaging (MRI) with diffusion weighted imaging (DWI), susceptibility weighted imaging (SWI) sequences and MR spectroscopy may aid in establishing the diagnosis. A particularly characteristic feature of MELAS syndrome is that recurrence may occur in locations different than previously noted, which was also seen in our patient. PMID- 29482706 TI - A Rare Case: Rupture of Internal Pudendal and Uterine Artery in a Vaginal Delivery. AB - The management of puerperal hematomas after normal delivery has always been challenging for obstetricians. Vulvar, vulvovaginal, or paravaginal hematomas are common. On the other hand, retroperitoneal hematomas are uncommon and can be life threatening. The diagnosis of vascular injury is rarely made preoperatively as atonic or traumatic postpartum hemorrhage (PPH), uterine rupture and amniotic fluid embolism are more common differential diagnoses. Injury to internal pudendal and uterine vessels is extremely rare in cases of vaginal delivery and, therefore, the literature on this topic is very scarce. We present a rare case of both internal pudendal and uterine artery rupture in a normal vaginal delivery, which led to massive postpartum hemorrhage. The diagnosis was made on Magnetic Resonance imaging (MRI) and arterial embolization was performed. This case stresses on the need for careful post-delivery monitoring for revealed postpartum hemorrhage. Vascular injury is a rare life-threatening cause of obstetric shock, and active; and timely operative intervention can prevent morbidity and mortality. PMID- 29482707 TI - Hydatid Cyst of Skeletal Muscle Presenting as Soft Tissue Tumour. AB - Hydatid disease is helminthic infection caused by tape worm echinococcus granulosis. It commonly involves liver (65-75%) and the lungs (25 to 30%). Involvement of bones and skeletal muscle is very rare, i.e. 3 to 5%. This is the report of a 21-year girl, city resident, presented with mass involving left proximal thigh. The mass was painless and had gradually increased in size over three years. MRI revealed solid cum cystic lesion in vastus medialis muscle. Tru Cut needle biopsy of the lesion revealed necrotic material. Intraoperative findings were of different sized cystic lesions, typical of hydatid cyst. The cysts were removed intact. No recurrence was seen in 11-month follow-up. Hydatid cyst involving skeletal muscle is very rare entity, but should be considered while making differential diagnosis of soft tissue mass. PMID- 29482708 TI - Caroticocavernous Fistula: Successful Reversal by Endovascular Treatment. AB - A 22-year male presented in outpatient department with right sided proptosis and chemosis, after a roadside accident two months back. He was on treatment for orbital cellulitis and taking steroids with antibiotics, both orally and topically. He was also on topical antiglaucoma agents. Detailed examination revealed bruit on auscultation. On magnetic resonance imaging (MRI), dilated superior ophthalmic vein led to diagnosis of caroticocavernous fistula (CCF) and the patient was referred to Neurosurgery Department of Lahore General Hospital (LGH), Lahore, where digital subtraction angiography (DSA) and balloon catheterization by a radiologist in the same sitting, resulted in successful closure of fistula and amelioration of all the signs and symptoms within six weeks. PMID- 29482709 TI - A Rare Presentation of Cyclitis Induced Myopia. AB - Unilateral cyclitis leading to myopia is a rare and clinical relevant entity. In clinical settings, pseudomyopia is generally encountered in the form of accommodative spasm, which is always bilateral. Cyclitis due to inflammation, on the other hand, can cause pseudomyopia unilaterally and it is a very rare presentation. A young male with acute anterior uveitis, presented with acute episode of unilateral myopia. When patient was examined on first visit, there were no cells in anterior chamber; so he was started on cycloplegic eye drops, but his condition didn't improve. Examination on subsequent visit revealed cellular reaction in anterior chamber and narrowing of anterior chamber angles on anterior segment optical coherence tomography (OCT). Treatment for uveitis was started and patient's visual acuity and refractive error improved. Pseudomyopia is a known complication of several drugs and certain medical conditions. The possible mechanism is supraciliary exudation causing relaxation of zonular fibers and increased convexity of the crystalline lens. Myopia in the setting of a mild cellular reaction can easily be missed and has not been reported yet to the best of authors' literature search. PMID- 29482710 TI - Cold Agglutinins in Peripheral Blood with Atypical Cells with an Owl-Eye Appearance in Bone Trephine. AB - Autoimmune hemolytic anemia (AIHA) is a form of hemolytic anemia in which red cells lysis occurs due to presence of an autoantibody. Association of AIHA is well known with lymphoproliferative disorders, especially with non-Hodgkin's lymphoma. However, AIHA in association with Hodgkin's lymphoma is seen occasionally. Of the AIHA associated with Hodgkin's lymphoma, most are of warm type or mixed type. Cold AIHA, as seen in our case, is very rare in Hodgkin's lymphoma. PMID- 29482711 TI - Botulinum Toxin A and Task-Specific Training for Hand Dystonia due to 5 Year Old Stroke. AB - Focal hand dystonia after stroke, a result of maladaptive plasticity, impairs hand function, affects daily activities, and undermines independence. A 59-year male patient, who had developed focal hand dystonia after suffering from ischemic stroke 5 years ago, received training following an injection of Botulinum Toxin A (BoNTA). Task-specific training for a duration of 60 minutes per day for 3 days per week was provided for 12 weeks. Assessments were done by using arm dystonia disability scale, action research arm test, Fugl-Meyer assessment of upper extremity, and stroke-specific quality of life. Substantial improvement was observed in all the parameters, at short-term follow-up. PMID- 29482712 TI - Bipolar Affective Disorder in a Patient of Profound Deafness. AB - Profound deafness is a lifelong impairment, leading to the physical disability as well as poor psychological adjustment. We herein present a mental health disorder rarely seen among the patients of profound deafness. A 16-year deaf and dumb girl, previously treated for depression, presented with unusual laughter, irritability, flight of ideas, decreased sleep, ideas of self importance, and decreased social functioning and educational performance. These problems were understood by the parents via sign language, who interpreted them to the interviewer. Her Young Mania Rating Scale (YMRS) score was 19 and Brief Psychiatric Rating Scale (BPRS) score was 52. She was diagnosed as a case of bipolar affective disorder (BPAD). Marked improvement in the symptoms and social and educational performance was noted after two weeks of the treatment with sodium valproate, resperidone and clonazepam. Treatment options were explained to the patient with risks and benefits, and she was involved in the decision-making. This case report highlights the importance of accurately diagnosing and managing a rare mental health disorder among the physically handicapped people, especially those who cannot communicate effectively and explain their unusual subjective experiences. PMID- 29482713 TI - Primary Renal Epithelioid Angiosarcoma. AB - Primary renal angiosarcoma is a rare tumor. Epithelioid variant of primary renal angiosarcoma is extremely rare and aggressive entity described in literature as a few case reports. It presents as solid looking renal mass as other renal cell carcinomas. Management is not well described due to scarcity of cases and aggressiveness of disease. We hereby report a case of epithelioid renal angiosarcoma in a 62-year female who presented with features of infected perinephric collection. Histopathological and immunohistochemical examinations of the renal specimen revealed lower polar renal tumor with atypical epithelioid cells having eccentric nuclei with coarse chromatin and eosinophilic cytoplasm, which were positive for vascular endothelial (FLI-1, CD 34, CD31 and factor VII) as well as epithelial (CKAE1/AE3) immune markers. Based on the histopathological and immunohistochemical findings, the patient was diagnosed with primary renal epithelioid angiosarcoma. PMID- 29482714 TI - Giant Urethral Calculus without Acute Urinary Retention. AB - A 46-year gentleman presented with a left-sided lumbar region pain without fever or dysuria. He denied episodes of acute urinary retention. There was a hard mass at the distal urethra with normal laboratory blood tests. Computed tomography urogram revealed a concurrent left renal staghorn calculus and large distal urethral stone. The urethral stone was fragmented via endourologic technique successfully. We report a case of a non-obstructing large urethral calculus in a gentleman with concurrent left renal staghorn calculus and discuss the literature review. PMID- 29482715 TI - Expression of C-type lectin receptors and Toll-like receptors in decidua of patients with unexplained recurrent spontaneous abortion. AB - In the present study, the mechanisms underlying the pathogenesis of unexplained recurrent spontaneous abortion (URSA) were explored. The protein and mRNA expression of two C-type lectin-like receptors (CLRs), namely dendritic cell specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) and mannose receptor (MR), and two Toll-like receptors (TLRs), namely TLR2 and TLR4, in the decidua and dendritic cells (DCs) was compared between URSA patients and normal controls. URSA patients had significantly lower protein and mRNA expression of DC-SIGN and significantly higher expression of TLR2 and TLR4 in decidual tissues compared with normal controls. In addition, URSA patients had significantly higher levels of the T helper (Th) 1 cytokines interleukin (IL)-2 and interferon-gamma, and significantly lower levels of the Th2 cytokines IL-10 and transforming growth factor beta1 in decidual tissues compared with the control group. The TLR2 agonist synthetic triacylated lipoprotein (Pam3CSK4) and the TLR4 agonist lipopolysaccharide were used to demonstrate that TLR2 and TLR4 modulate Th1/Th2 cytokine imbalance in DC-T cell cocultures. The results suggest that the balance between CLRs and TLRs was tilted towards a TLR-dominant response in URSA patients, which may disrupt maternal-fetal immune tolerance, resulting in spontaneous abortion. PMID- 29482716 TI - The control of tonic pain by active relief learning. AB - Tonic pain after injury characterises a behavioural state that prioritises recovery. Although generally suppressing cognition and attention, tonic pain needs to allow effective relief learning to reduce the cause of the pain. Here, we describe a central learning circuit that supports learning of relief and concurrently suppresses the level of ongoing pain. We used computational modelling of behavioural, physiological and neuroimaging data in two experiments in which subjects learned to terminate tonic pain in static and dynamic escape learning paradigms. In both studies, we show that active relief-seeking involves a reinforcement learning process manifest by error signals observed in the dorsal putamen. Critically, this system uses an uncertainty ('associability') signal detected in pregenual anterior cingulate cortex that both controls the relief learning rate, and endogenously and parametrically modulates the level of tonic pain. The results define a self-organising learning circuit that reduces ongoing pain when learning about potential relief. PMID- 29482717 TI - A randomised double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV-uninfected adults. AB - Adjunctive dexamethasone reduces mortality from tuberculous meningitis (TBM) but not disability, which is associated with brain infarction. We hypothesised that aspirin prevents TBM-related brain infarction through its anti-thrombotic, anti inflammatory, and pro-resolution properties. We conducted a randomised controlled trial in HIV-uninfected adults with TBM of daily aspirin 81 mg or 1000 mg, or placebo, added to the first 60 days of anti-tuberculosis drugs and dexamethasone (NCT02237365). The primary safety endpoint was gastro-intestinal or cerebral bleeding by 60 days; the primary efficacy endpoint was new brain infarction confirmed by magnetic resonance imaging or death by 60 days. Secondary endpoints included 8-month survival and neuro-disability; the number of grade 3 and 4 and serious adverse events; and cerebrospinal fluid (CSF) inflammatory lipid mediator profiles. 41 participants were randomised to placebo, 39 to aspirin 81 mg/day, and 40 to aspirin 1000 mg/day between October 2014 and May 2016. TBM was proven microbiologically in 92/120 (76.7%) and baseline brain imaging revealed >=1 infarct in 40/114 (35.1%) participants. The primary safety outcome occurred in 5/36 (13.9%) given placebo, and in 8/35 (22.9%) and 8/40 (20.0%) given 81 mg and 1000 mg aspirin, respectively (p=0.59). The primary efficacy outcome occurred in 11/38 (28.9%) given placebo, 8/36 (22.2%) given aspirin 81 mg, and 6/38 (15.8%) given 1000 mg aspirin (p=0.40). Planned subgroup analysis showed a significant interaction between aspirin treatment effect and diagnostic category (Pheterogeneity = 0.01) and suggested a potential reduction in new infarcts and deaths by day 60 in the aspirin treated participants with microbiologically confirmed TBM (11/32 (34.4%) events in placebo vs. 4/27 (14.8%) in aspirin 81 mg vs. 3/28 (10.7%) in aspirin 1000 mg; p=0.06). CSF analysis demonstrated aspirin dose-dependent inhibition of thromboxane A2 and upregulation of pro-resolving CSF protectins. The addition of aspirin to dexamethasone may improve outcomes from TBM and warrants investigation in a large phase 3 trial. PMID- 29482718 TI - Early alterations of social brain networks in young children with autism. AB - Social impairments are a hallmark of Autism Spectrum Disorders (ASD), but empirical evidence for early brain network alterations in response to social stimuli is scant in ASD. We recorded the gaze patterns and brain activity of toddlers with ASD and their typically developing peers while they explored dynamic social scenes. Directed functional connectivity analyses based on electrical source imaging revealed frequency specific network atypicalities in the theta and alpha frequency bands, manifesting as alterations in both the driving and the connections from key nodes of the social brain associated with autism. Analyses of brain-behavioural relationships within the ASD group suggested that compensatory mechanisms from dorsomedial frontal, inferior temporal and insular cortical regions were associated with less atypical gaze patterns and lower clinical impairment. Our results provide strong evidence that directed functional connectivity alterations of social brain networks is a core component of atypical brain development at early stages of ASD. PMID- 29482719 TI - Why plants make puzzle cells, and how their shape emerges. AB - The shape and function of plant cells are often highly interdependent. The puzzle shaped cells that appear in the epidermis of many plants are a striking example of a complex cell shape, however their functional benefit has remained elusive. We propose that these intricate forms provide an effective strategy to reduce mechanical stress in the cell wall of the epidermis. When tissue-level growth is isotropic, we hypothesize that lobes emerge at the cellular level to prevent formation of large isodiametric cells that would bulge under the stress produced by turgor pressure. Data from various plant organs and species support the relationship between lobes and growth isotropy, which we test with mutants where growth direction is perturbed. Using simulation models we show that a mechanism actively regulating cellular stress plausibly reproduces the development of epidermal cell shape. Together, our results suggest that mechanical stress is a key driver of cell-shape morphogenesis. PMID- 29482720 TI - A randomized feasibility trial comparing four antimalarial drug regimens to induce Plasmodium falciparum gametocytemia in the controlled human malaria infection model. AB - Background Malaria elimination strategies require a thorough understanding of parasite transmission from human to mosquito. A clinical model to induce gametocytes to understand their dynamics and evaluate transmission-blocking interventions (TBI) is currently unavailable. Here, we explore the use of the well-established Controlled Human Malaria Infection model (CHMI) to induce gametocyte carriage with different antimalarial drug regimens. Methods In a single centre, open-label randomised trial, healthy malaria-naive participants (aged 18-35 years) were infected with Plasmodium falciparum by bites of infected Anopheles mosquitoes (ClinicalTrials.gov, NCT02836002). Participants were randomly allocated to four different treatment arms (n = 4 per arm) comprising low-dose (LD) piperaquine (PIP) or sulfadoxine-pyrimethamine (SP), followed by a curative regimen upon recrudescence. Male and female gametocyte densities were determined by molecular assays. Findings Mature gametocytes were observed in all participants (16/16, 100%). Gametocytes appeared 8.5-12 days after the first detection of asexual parasites. Peak gametocyte densities and gametocyte burden was highest in the LD-PIP/SP arm, and associated with the preceding asexual parasite biomass (p=0.026). Male gametocytes had a mean estimated circulation time of 2.7 days (95% CI 1.5-3.9) compared to 5.1 days (95% CI 4.1-6.1) for female gametocytes. Exploratory mosquito feeding assays showed successful sporadic mosquito infections. There were no serious adverse events or significant differences in the occurrence and severity of adverse events between study arms (p=0.49 and p=0.28). Conclusions The early appearance of gametocytes indicates gametocyte commitment during the first wave of asexual parasites emerging from the liver. Treatment by LD-PIP followed by a curative SP regimen, results in the highest gametocyte densities and the largest number of gametocyte-positive days. This model can be used to evaluate the effect of drugs and vaccines on gametocyte dynamics, and lays the foundation for fulfilling the critical unmet need to evaluate transmission-blocking interventions against falciparum malaria for downstream selection and clinical development. Funding PATH Malaria Vaccine Initiative (MVI). PMID- 29482721 TI - Vibrator and PI4KIIIalpha govern neuroblast polarity by anchoring non-muscle myosin II. AB - A central feature of most stem cells is the ability to self-renew and undergo differentiation via asymmetric division. However, during asymmetric division the role of phosphatidylinositol (PI) lipids and their regulators is not well established. Here, we show that the sole type I PI transfer protein, Vibrator, controls asymmetric division of Drosophilaneural stem cells (NSCs) by physically anchoring myosin II regulatory light chain, Sqh, to the NSC cortex. Depletion of vib or disruption of its lipid binding and transfer activities disrupts NSC polarity. We propose that Vib stimulates PI4KIIIalpha to promote synthesis of a plasma membrane pool of phosphatidylinositol 4-phosphate [PI(4)P] that, in turn, binds and anchors myosin to the NSC cortex. Remarkably, Sqh also binds to PI(4)P in vitro and both Vib and Sqh mediate plasma membrane localization of PI(4)P in NSCs. Thus, reciprocal regulation between Myosin and PI(4)P likely governs asymmetric division of NSCs. PMID- 29482722 TI - Erratum to: Somatic Mosaicism: Implications for Disease and Transmission Genetics. PMID- 29482723 TI - Editorial overview: Omics. PMID- 29482724 TI - RNA interference of glutamate-gated chloride channel decreases abamectin susceptibility in Bemisia tabaci. AB - The Bemisia tabaci (Gennadius) cryptic species complex comprises very destructive insect pests of agricultural crops worldwide and has been found to be resistant to various insecticides in China. Abamectin is one of the most widely used insecticides for insect pest control and the glutamate-gated chloride channel (GluCl) in insects was presumed to be the main target site of abamectin. In this study, a 1353bp full-length cDNA encoding GluCl (named BtGluCl, GenBank ID: MF673854) was cloned and characterized from B. tabaci. BtGluCl encodes 450 amino acids, which shares 71-81% identity with other insect GluCl isoforms. Spatial and temporal expression revealed BtGluCl was highly expressed in the 4th nymphal instar and adult head, and the least expressed in the 1st nymphal instar and adult leg. Dietary ingestion of dsBtGluCl significantly reduced the mRNA level of BtGluCl in the treated adults by 62.9% and greatly decreased abamectin-induced mortality. Thus, our results could be conducive to further understanding the mechanisms of resistance to abamectin in arthropods. PMID- 29482725 TI - Design, synthesis and biological evaluation of novel N-nitrophenyl derivatives based on the structure of acetohydroxyacid synthase. AB - Acetohydroxyacid synthase (AHAS, EC: 2.2.1.6) is a target for the development of novel herbicides. Two series of N-nitrophenyl derivatives, type-A and type-B, were designed and synthesized based on the active site of the AHAS structure. All the structures of newly prepared compounds were thorough characterized by IR, and 1H NMR spectrums. The IC50 values of all synthesized target compounds against AHAS enzyme and EC50 values for herbicidal activity against Brassica campestris L., Amaranthus mangostanus L. and Sorghum sudanense were determined. The bioactive assay results showed that the type-B compounds exhibited highly improved inhibitory activity against the AHAS enzyme and the tested plants comparing to type-A compounds. The IC50 values of most type-B compounds against the AHAS enzyme were between 25-177MUM. The EC50 values of several type-B compounds against Sorghum sudanense reached 5.0mg/L. The differences in the biological activity between type-A and type-B compounds were attributed to two structural features - the orthogonal bend at the N-nitro amides group and the common plane structure of another phenyl with chain bridge. With the structure of the target compounds and the IC50 values for AHAS enzyme, a statistically significant CoMFA model with high predict abilities (q2=0.606, r2=0.982, N=4, SEE=0.058, F=280.255) was obtained, and its reliability was verified. The model will provide a theoretical basis for the further structural optimization. PMID- 29482726 TI - Effects of nicosulfuron on growth, oxidative damage, and the ascorbate glutathione pathway in paired nearly isogenic lines of waxy maize (Zea mays L.). AB - Nicosulfuron is a postemergence herbicide used for weed control in maize fields (Zea mays L.). We used the pair of nearly isogenic inbred lines, SN509-R (nicosulfuron resistant) and SN509-S (nicosulfuron sensitive), to study the effect of nicosulfuron on growth, oxidative stress, and the ascorbate-glutathione (AA-GSH) cycle in waxy maize seedlings. Nicosulfuron treatment was applied when the fourth leaves were fully developed and the obtained effects were compared to water treatment as control. After nicosulfuron treatment, compared to SN509-R, the death of SN509-S might be associated with increased oxidative stress, since higher O2- and H2O2 accumulations were observed in SN509-S. This in turn might have caused severe damage to lipids and proteins, thus reducing membrane stability. These effects were exacerbated with increasing exposure time. After nicosulfuron treatment, ascorbate peroxidase, monodehydroascorbate reductase, dehydroascorbate reductase, glutathione reductase, and guaiacol peroxidase of SN509-S were significantly lower than those of SN509-R. Compared to SN509-R, dehydroascorbate content, glutathione (GSH) content, and GSH to glutathione disulphide ratios significantly declined with increasing exposure time in SN509 S. Our results suggest that the rapid degradation of nicosulfuron in SN509-R results in only a small and transient increase in reactive oxygen species (ROS). In contrast, in SN509-S, reduced nicosulfuron degradation leads to increase ROS, while at the same time, the AA-GSH pathway is not activated. PMID- 29482727 TI - A new point mutation in beta2-tubulin confers resistance to carbendazim in Fusarium asiaticum. AB - Resistance to benzimidazole fungicides in many phytopathogenic fungi is caused by specific point mutations in the beta-tubulin gene (beta-tubulin). However, the mutated locus and genotype of beta-tubulin differ among phytopathogenic fungi. To validate the point mutation in Fusarium asiaticum beta2-tubulin that confers resistance to carbendazim and to analyze the molecular interaction between carbendazim and F. asiaticum beta2-tubulin. In this study, a new point mutation (GAG->GCG, E198A) at codon 198 of beta2-tubulin in a wild-type F. asiaticum strain was constructed by site-directed mutagenesis followed by a split marker strategy. The site-directed mutants were verified and exhibited a high level of resistance to carbendazim. In the absence of fungicide treatment, the biological characteristics did not differ between the site-directed mutants and the wild type strain. Molecular docking between carbendazim and beta2-tubulin was carried out using the Surflex-Dock program in Sybyl X-2.0 version and the results indicated that the E198A mutation altered the configuration of beta2-tubulin, resulting in the change of the bonding sites and docking scores. We concluded that the point mutation of F. asiaticum beta2-tubulin conferring carbendazim resistance may not always be the bonding site for carbendazim. PMID- 29482728 TI - Activity of a novel succinate dehydrogenase inhibitor fungicide pyraziflumid against Sclerotinia sclerotiorum. AB - Pyraziflumid is a novel member of succinate dehydrogenase inhibitor fungicides (SDHI). In this study, baseline sensitivity of Sclerotinia sclerotiorum (Lib.) de Bary to pyraziflumid was determined using 105 strains collected during 2015 and 2017 from different geographical regions in Jiangsu Province of China, and the average EC50 value was 0.0561 (+/-0.0263)MUg/ml for mycelial growth. There was no cross-resistance between pyraziflumid and the widely used fungicides carbendazim, dimethachlon and the phenylpyrrole fungicide fludioxonil. After pyraziflumid treated, hyphae were contorted with offshoot of top increasing, cell membrane permeability increased markedly, oxalic acid content significantly decreased and mycelial respiration was strongly inhibited. But the number and dry weight of sclerotia did not change significantly. The protective and curative activity test of pyraziflumid suggested that pyraziflumid had great control efficiency against S. sclerotiorum on detached rapeseed leaves, and protective activity was better than curative activity. These results will contribute to us on evaluating the potential of the new SDHI fungicide pyraziflumid for management of diseases caused by S. sclerotiorum and understanding the mode of action of pyraziflumid against S. sclerotiorum. PMID- 29482729 TI - Ovicidal and larvicidal activity and possible mode of action of phenylpropanoids and ketone identified in Syzygium aromaticum bud against Bradysia procera. AB - Bradysia procera is a serious insect pest of Panax ginseng plants. This study was conducted to determine the toxicity and mechanism of action of three phenylpropanoids, three terpenoids, and a ketone from Syzygium aromaticum bud methanol extract and hydrodistillate against third-instar larvae and eggs of B. procera. In a filter-paper mortality bioassay, methyl salicylate (LC50, 5.26MUg/cm2) was the most toxic compound, followed by 2-nonanone, eugenol, and eugenyl acetate (8.77-15.40MUg/cm2). These compounds were significantly less toxic than either thiamethoxam, clothianidin, or cypermethrin. Egg hatching was inhibited by 97, 85, and 40% at 11.7MUg/cm2 of methyl salicylate, 2-nonanone, and eugenol, respectively. The egg-hatching inhibition of these insecticides was between 90 and 94% at 0.09MUg/cm2. These constituents were consistently more toxic in closed versus open containers, indicating that toxicity was achieved mainly through the action of vapor. The mechanism of larvicidal action of methyl salicylate, eugenol, and eugenyl acetate might be primarily due to interference with the octopaminergic system. 2-Heptyl acetate and 2-nonanone might act on both acetylcholinesterase and the octopaminergic receptor. 2-Heptanone might act primarily on acetylcholinesterase. Further studies will warrant possible applications of S. aromaticum bud-derived products as potential larvicides and ovicides for the control of B. procera. PMID- 29482730 TI - Garcinia kola seed biflavonoid fraction (Kolaviron), increases longevity and attenuates rotenone-induced toxicity in Drosophila melanogaster. AB - Rotenone, a naturally occurring and commonly used pesticide, has been established as a model for inducing Parkinson's Disease (PD) in rodents. Kolaviron is a biflavonoid complex from Garcinia kola seeds with anti-oxidative and anti inflammatory properties. Here, we evaluated the ameliorative role of Kolaviron on rotenone-induced toxicity in Drosophila melanogaster. Flies for longevity study were exposed to Kolaviron (100-500mg/kg diet) throughout the lifespan. For biochemical study, Groups A, B and C flies were treated with ethanol (2.0%, control, vehicle), Kolaviron (200mg/kg diet) and rotenone (250MUM) respectively. Flies in Group D were co-treated with both rotenone (250MUM) and Kolaviron (200mg/kg diet) for 7days. Subsequently, selected markers of antioxidant status, inflammatory and neurotoxicity were evaluated in the flies. The results from longevity experiment showed that Kolaviron (200, 100, 300 and 400mg/kg) extended lifespan of flies by 38.2%, 20.6%, 11.8% and 2.9% respectively. Also, Kolaviron attenuated rotenone-induced inhibition of catalase, glutathione-S-transferase and acetylcholinesterase activities and depletion of total thiols content in flies. Moreover, Kolaviron prevented rotenone-induced increases in hydrogen peroxide and nitric oxide (nitrite and nitrate) levels and improved rotenone-induced decrease in locomotor performance of flies (p<0.05). Overall, this study evidenced for the first time, the lifespan extension property of Kolaviron and its chemoprotective role on rotenone-induced toxicity in D. melanogaster via anti-oxidative and anti inflammatory mechanisms. PMID- 29482731 TI - Understanding the fate of human serum albumin upon interaction with edifenphos: Biophysical and biochemical approaches. AB - Edifenphos (EDF), an important organophosphate fungicide used in agriculture, is a great threat to human health and environment. To assess the toxicity of EDF at the level of protein molecule, the effect of EDF on human serum albumin (HSA) was investigated by biophysical and biochemical approaches. EDF-HSA complex is formed as a result of static quenching as revealed by the intrinsic fluorescence analysis. Thermodynamic analysis of the binding data suggests involvement of hydrophobic interactions in EDF-HSA complex formation, which is in line with molecular docking results. Moreover, thermodynamic parameters of binding between EDF and HSA suggest entropy-driven spontaneous interaction, presumably dominated by hydrophobic forces. Further, binding site of EDF seems to have been located within sub-domain IIA of HSA. EDF binding to HSA decreases its alpha helical content as analyzed by CD spectra. Marked micro-environmental changes around tryptophan/tyrosine residues in HSA upon EDF binding were recorded via three dimensional fluorescence spectroscopy. Substantial release of protein carbonyl from HSA as a result of EDF treatment suggested involvement of ROS in EDF induced protein damage. This work is expected to provide some leads toward EDF induced toxicity in humans and would be helpful in reinforcing the check on food safety. PMID- 29482732 TI - A peptide derived from enzymatic digestion of globulins from amaranth shows strong affinity binding to the replication origin of Tomato yellow leaf curl virus reducing viral replication in Nicotiana benthamiana. AB - Tomato yellow leaf curl virus (TYLCV; genus Begomovirus; family Geminiviridae) infects mainly plants of the family Solanaceae, and the infection induces curling and chlorosis of leaves, dwarfing of the whole plant, and reduced fruit production. Alternatives for direct control of TYLCV and other geminiviruses have been reported, for example, the use of esterified whey proteins, peptide aptamer libraries or artificial zinc finger proteins. The two latter alternatives affect directly the replication of TYLCV as well as of other geminiviruses because the replication structures and sequences are highly conserved within this virus family. Because peptides and proteins offer a potential solution for virus replication control, in this study we show the isolation, biochemical characterization and antiviral activity of a peptide derived from globulins of amaranth seeds (Amaranthus hypochondriacus) that binds to the replication origin sequence (OriRep) of TYLCV and affects viral replication with a consequent reduction of disease symptoms in Nicotiana benthamiana. Aromatic peptides obtained from papain digests of extracted globulins and albumins of amaranth were tested by intrinsic fluorescent titration and localized surface resonance plasmon to analyze their binding affinity to OriRep of TYLCV. The peptide AmPep1 (molecular weight 2.076 KDa) showed the highest affinity value (Kd = 1.8 nM) for OriRep. This peptide shares a high amino acid similarity with a part of an amaranth 11S globulin, and the strong affinity of AmPep1 could be explained by the presence of tryptophan and lysine facilitating interaction with the secondary structure of OriRep. In order to evaluate the effect of the peptide on in vitro DNA synthesis, rolling circle amplification (RCA) was performed using as template DNA from plants infected with TYLCV or another begomovirus, pepper huasteco yellow vein virus (PHYVV), and adding AmPep1 peptide at different concentrations. The results showed a decrease in DNA synthesis of both viruses at increasing concentrations of AmPep1. To further confirm the antiviral activity of the peptide in vivo, AmPep1 was infiltrated into leaves of N. benthamiana plants previously infected with TYLCV. Plants treated with AmPep1 showed a significant decrease in virus titer compared with untreated N. benthamiana plants as well as reduced symptom progression due to the effect of AmPep1 curtailing TYLCV replication in the plant. The peptide also showed antiviral activity in plants infected with PHYVV. This is the first report, in which a peptide is directly used for DNA virus control in plants, supplied as exogenous application and without generation of transgenic lines. PMID- 29482733 TI - Exposure of carbendazim induces structural and functional alteration in garlic phytocystatin: An in vitro multi-spectroscopic approach. AB - Carbendazim is a broad spectrum benzimidazole fungicide which is used to ensure plants' protection from pest and pathogens' invasion. The present work describes the impact of carbendazim (CAR) on garlic phytocystatin (GPC) which is a crucial plant regulatory protein. Interaction of carbendazim with GPC has been investigated through various biophysical techniques viz. UV absorption, fluorescence spectroscopy, isothermal titration calorimetry, far-UV circular dichroism and FTIR spectroscopy which showed binding between them with consequent modulatory effects. Functional activity of GPC was monitored by the anti-papain inhibitory assay which suggests that incubation of GPC with the higher concentration of CAR disrupts the inhibitory function of GPC. UV spectroscopy confirmed the formation of GPC-CAR complex. Intrinsic fluorescence suggests binding of CAR to GPC which reflects the changes in microenvironment around tryptophan residues of GPC. Isothermal titration calorimetry suggests that interaction of CAR to GPC is an exothermic reaction. Secondary structure analysis was also performed which confirmed that binding of CAR decreases the alpha helical content of GPC. Collectively, these results demonstrated that GPC exhibited significant structural and functional alteration upon interaction with carbendazim. Since GPC is involved in various regulatory processes, therefore, its structural or functional alteration may lead to disruption of physiological and biological balance within the plant. Hence, our study signifies that exposure of carbendazim to plant exerts physicochemical alteration within the plant. PMID- 29482734 TI - Organochlorine pesticide acetofenate and its hydrolytic metabolite in rabbits: Enantioselective metabolism and cytotoxicity. AB - Acetofenate (AF) is a chiral organochlorine pesticide used for controlling hygiene pests. In this study, the metabolism of AF in rabbits in vivo and in vitro was investigated and the primary chiral metabolite acetofenate-alcohol (AF A) was analyzed. The cytotoxicity of AF and AF-A was also determined. AF in rabbits in vivo was eliminated so rapidly that AF could not be detected within 10min after intravenous administration at 20mg/kg (body weight), and AF-A was quickly formed. In vitro metabolism assay, using plasma and liver microsomes, showed that AF was also quickly metabolized to AF-A and the metabolic process was significantly enantioselective with preferential degradation of (-)-AF and formation of (-)-AF-A. The cytotoxicity of AF and AF-A were investigated by assessing cell proliferation, apoptosis and generation of reactive oxygen species. The results showed that AF and AF-A induce enantioselective cytotoxicity. This study will be helpful for improving knowledge about the metabolism and toxicity of AF on an enantiomeric level and providing evidence to understand the potential environmental risk. PMID- 29482735 TI - Screening and characterization of Xanthomonas oryzae pv. oryzae strains with resistance to pheazine-1-carboxylic acid. AB - Xanthomonas oryzae pv. oryzae (Xoo) causes bacterial leaf blight (BLB) and can be effectively controlled by phenazine-1-carboxylic acid (PCA), an antibiotic secreted by Pseudomonas spp. PCA resistance in Xoo was investigated in this research. Only four PCA-resistant strains were obtained by extensive screening, and the resistance was genetically stable in only one of them (P4). P4 was also resistant to phenazine and 1-hydroxyphezine but not to captan, bismerthiazol, or streptomycin. The following were reduced in P4 relative to the parental wild type: growth, virulence, EPS production, extracellular cellulase production and activity, biofilm formation, and swimming ability. ROS accumulation was reduced, resistance to exogenous H2O2 was increased, and expression of catalase genes and catalase activities were increased in P4, suggesting that PCA resistance in P4 results from a reduction in ROS production and/or an increased ability to metabolize ROS following PCA treatment. Given the low risk of Xoo developing PCA resistance and the reduced virulence and fitness of the resistant strain, PCA can be used in alternation with other common bactericides to control BLB in rice fields. PMID- 29482736 TI - Aphicidal activity of selected Asteraceae essential oils and their effect on enzyme activities of the green peach aphid, Myzus persicae (Sulzer). PMID- 29482738 TI - Medical cannabis: What physicians need to know? PMID- 29482737 TI - Kinetic analysis of oxime-assisted reactivation of human, Guinea pig, and rat acetylcholinesterase inhibited by the organophosphorus pesticide metabolite phorate oxon (PHO). AB - : Phorate is a highly toxic agricultural pesticide currently in use throughout the world. Like many other organophosphorus (OP) pesticides, the primary mechanism of the acute toxicity of phorate is acetylcholinesterase (AChE) inhibition mediated by its bioactivated oxon metabolite. AChE reactivation is a critical aspect in the treatment of acute OP intoxication. Unfortunately, very little is currently known about the capacity of various oximes to rescue phorate oxon (PHO)-inhibited AChE. To help fill this knowledge gap, we evaluated the kinetics of inhibition, reactivation, and aging of PHO using recombinant AChE derived from three species (rat, guinea pig and human) commonly utilized to study the toxicity of OP compounds and five oximes that are currently fielded (or have been deemed extremely promising) as anti-OP therapies by various nations around the globe: 2-PAM Cl, HI-6 DMS, obidoxime Cl2, MMB4-DMS, and HLo7 DMS. The inhibition rate constants (ki) for PHO were calculated for AChE derived from each species and found to be low (i.e., 4.8*103 to 1.4*104M-1min-1) compared to many other OPs. Obidoxime Cl2 was the most effective reactivator tested. The aging rate of PHO-inhibited AChE was very slow (limited aging was observed out to 48h) for all three species. CONCLUSIONS: (1) Obidoxime Cl2 was the most effective reactivator tested. (2) 2-PAM Cl, showed limited effectiveness in reactivating PHO-inhibited AChE, suggesting that it may have limited usefulness in the clinical management of acute PHO intoxication. (3) The therapeutic window for oxime administration following exposure to phorate (or PHO) is not limited by aging. PMID- 29482739 TI - Ethical issues in medical cannabis use. AB - The increasing use of medical cannabis (MC) in the past decade raises several ethical considerations for the clinician. Regulatory issues stem from a gap between MC registration and certification in each country. Professional issues derive from the lack of sufficient knowledge of MC characteristics and the intersection between the physician, the patient and commercial interests. Finally, there are medical and psychological implications which are related to the use of MC regimens. We will discuss these issues in the light of the current era, in which policy has rapidly shifted toward legalization of cannabis, which influences the decisions of both clinicians and patients. PMID- 29482740 TI - Cannabinoids and cancer pain: A new hope or a false dawn? AB - The endocannabinoid system is involved in many areas of physiological function and homeostasis. Cannabinoid receptors are expressed in the peripheral and central nervous system and on immune cells, all areas ideally suited to modulation of pain processing. There are a wealth of preclinical data in a number of acute, chronic, neuropathic and cancer pain models that have demonstrated a potent analgesic potential for cannabinoids, especially in patients with cancer. However, although there are some positive results in pain of cancer patients, the clinical evidence for cannabinoids as analgesics has not been convincing and their use can only be weakly recommended. The efficacy of cannabinoids seems to have been 'lost in translation' which may in part be related to using extracts of herbal cannabis rather than targeted selective full agonists at the cannabinoid CB1 and CB2 receptors. PMID- 29482741 TI - Prospective analysis of safety and efficacy of medical cannabis in large unselected population of patients with cancer. AB - BACKGROUND: Cancer is a major public health problem as the leading cause of death. Palliative treatment aimed to alleviate pain and nausea in patients with advanced disease is a cornerstone of oncology. In 2007, the Israeli Ministry of Health began providing approvals for medical cannabis for the palliation of cancer symptoms. The aim of this study is to characterize the epidemiology of cancer patients receiving medical cannabis treatment and describe the safety and efficacy of this therapy. METHODS: We analyzed the data routinely collected as part of the treatment program of 2970 cancer patients treated with medical cannabis between 2015 and 2017. RESULTS: The average age was 59.5 +/- 16.3 years, 54.6% women and 26.7% of the patients reported previous experience with cannabis. The most frequent types of cancer were: breast (20.7%), lung (13.6%), pancreatic (8.1%) and colorectal (7.9%) with 51.2% being at stage 4. The main symptoms requiring therapy were: sleep problems (78.4%), pain (77.7%, median intensity 8/10), weakness (72.7%), nausea (64.6%) and lack of appetite (48.9%). After six months of follow up, 902 patients (24.9%) died and 682 (18.8%) stopped the treatment. Of the remaining, 1211 (60.6%) responded; 95.9% reported an improvement in their condition, 45 patients (3.7%) reported no change and four patients (0.3%) reported deterioration in their medical condition. CONCLUSIONS: Cannabis as a palliative treatment for cancer patients seems to be well tolerated, effective and safe option to help patients cope with the malignancy related symptoms. PMID- 29482742 TI - Functional limitation and chronic diseases are associated with food insecurity among U.S. adults. AB - PURPOSE: This study examined associations of functional limitation due to any health problems and six chronic diseases (arthritis, diabetes, coronary heart disease, heart attack, hypertension, and stroke) with food security among U.S. adults. METHODS: The 2011 National Health Interview Survey data for 30,010 adults (>=18 years) were used. Adults were categorized into food secure, low food secure, or very low food secure. Multivariable logistic regressions were used to estimate adjusted odds ratio (OR) and 95% confidence interval (CI) for having functional limitation and chronic diseases while adjusting for sociodemographic and lifestyle factors. RESULTS: The prevalence of functional limitation and the chronic diseases were higher in low-food-secure and very low-food-secure than food-secure adults. The adjusted ORs were significant in both low food secure and very low food secure, respectively, for functional limitation (OR: 1.87; 95% CI: 1.63, 2.14), (OR: 2.20; 95% CI: 1.91, 2.52), inflammatory diseases or joint/muscular pain (OR: 1.42; 95% CI: 1.21, 1.68), (OR: 1.74; 95% CI: 1.49, 2.04), diabetes (OR: 1.26; 95% CI: 1.06, 1.51), (OR: 1.23; 95% CI: 1.02, 1.48), and hypertension (OR: 1.18; 95% CI: 1.04, 1.35), (OR: 1.42; 95% CI: 1.22, 1.65) when compared with food-secure adults. CONCLUSIONS: Findings indicate that food insecurity is associated with functional limitation and chronic diseases, whereas directionality is unknown. Besides the traditional food assistance program for food-insecure populations, interventions to prevent or manage chronic diseases may be necessary to help them reduce the risk of the diseases and manage their conditions. PMID- 29482743 TI - The association of fitness and school absenteeism across gender and poverty: a prospective multilevel analysis in New York City middle schools. AB - PURPOSE: One-fifth to one-third of students in high poverty, urban school districts do not attend school regularly (missing >=6 days/year). Fitness is shown to be associated with absenteeism, although this relationship may differ across poverty and gender subgroups. METHODS: Six cohorts of New York City public school students were followed up from grades 5 to 8 during 2006/2007-2012/2013 (n = 349,381). Stratified three-level longitudinal generalized linear mixed models were used to test the association between changes in fitness and 1-year lagged child-specific days absent across gender and poverty. RESULTS: In girls attending schools in high/very high poverty areas, greater improvements in fitness the prior year were associated with greater reductions in absenteeism (P = .034). Relative to the reference group (>20% decrease in fitness composite percentile scores from the prior year), girls with a large increase in fitness (>20%) demonstrated 10.3% fewer days absent (incidence rate ratio [IRR] 95% confidence interval [CI]: 0.834, 0.964), followed by those who had a 10%-20% increase in fitness (9.2%; IRR 95% CI: 0.835, 0.987), no change (5.4%; IRR 95% CI: 0.887, 1.007), and a 10%-20% decrease in fitness (3.8%; IRR 95% CI: 0.885, 1.045). In girls attending schools in low/mid poverty areas, fitness and absenteeism also had an inverse relationship, but no clear trend emerged. In boys, fitness and absenteeism had an inverse relationship but was not significant in either poverty group. CONCLUSIONS: Fitness improvements may be more important to reducing absenteeism in high/very high poverty girls compared with low/mid poverty girls and both high/very high and low/mid poverty boys. Expanding school-based physical activity programs for youth particularly in high poverty neighborhoods may increase student attendance. PMID- 29482744 TI - Why do studies show different associations between intrauterine exposure to maternal smoking and age at menarche? AB - PURPOSE: Studies suggests that intrauterine exposure to maternal smoking both accelerates or delays age at menarche. We hypothesize that these opposing findings relate to different infant and childhood growth patterns across cohorts. METHODS: Using data from an adult follow-up study of the Child Health and Development Studies and the National Collaborative Perinatal Project, we examined, using generalized estimating linear regression models, whether intrauterine exposure to maternal smoking was associated with age at menarche in 1090 daughters before and after accounting for growth in weight. RESULTS: Compared to the nonexposed, intrauterine exposure to maternal smoking was associated with a 4-month acceleration in menarche in the National Collaborative Perinatal Project (beta = -0.35 years; 95% confidence interval [CI]: -0.63, 0.08), but a 6-month delay in menarche in the Child Health and Development Studies (beta = 0.48 years; 95% CI: 0.13, 0.83), despite having a similar reduction in birth weight in both cohorts (~300 g). The results were more consistent across cohorts when we stratified by postnatal growth patterns. For example, in those with rapid weight gain (increasing two growth references from 0 to 4 years), intrauterine exposure to maternal smoking was related to a 7-month acceleration in menarche (beta = -0.56 years; 95% CI: -0.95, -0.17). CONCLUSIONS: These findings suggest that the association of intrauterine exposure to maternal smoking on age at menarche depends on postnatal growth patterns. PMID- 29482745 TI - Erratum to: 'The potential impact of coinfection on antimicrobial chemotherapy and drug resistance'. PMID- 29482746 TI - The Role of Computed Tomography and Magnetic Resonance Imaging in Gynecologic Oncology. AB - This article discusses the role of Computed tomography (CT) and MR imaging in gynecologic malignancies by reviewing epidemiology, histologic subtypes, and staging systems. Imaging findings specific to different gynecologic malignancies on CT and MR imaging are reviewed and the advantages of each imaging modality discussed. Imaging of endometrial, cervical, and ovarian cancer is reviewed in depth, with a brief discussion of rare gynecologic cancers. PMID- 29482747 TI - The Usefulness of Ultrasound Imaging in Gynecologic Oncology. AB - Pelvic ultrasound examination is the primary imaging modality for evaluating a wide range of female pelvic symptomatology, and is often the first imaging test to detect a gynecologic malignancy. Ultrasound imaging is particularly useful for evaluating the thickness and appearance of the endometrium in patients with abnormal bleeding, and in detecting and characterizing ovarian lesions. This article reviews the ultrasound appearance of gynecologic neoplasms grouped by anatomic site of origin, the ultrasound appearance of select benign pelvic pathology not to be misinterpreted as malignancy, as well as available ultrasound imaging-based guidelines for managing potential gynecologic neoplasms. PMID- 29482749 TI - Fludeoxyglucose F 18 PET/CT Assessment of Ovarian Cancer. AB - Ovarian cancer is one of the most common gynecologic cancers and one of the leading causes of cancer death in women. It is often asymptomatic in early stages, and thus most patients are diagnosed when it is of advanced stage. For these reasons, the role of biomarkers and tomographic imaging is crucial. Fludeoxyglucose F 18 PET/CT is a useful imaging modality in different clinical settings of the disease, overcoming some limits of conventional imaging and influencing prognosis and therapeutic approaches. PET/MR imaging is an emerging modality, and its potential role remains to be explored. PMID- 29482748 TI - [18F]-2-Fluoro-2-Deoxy-D-glucose-PET Assessment of Cervical Cancer. AB - This article provides an overview of PET in cervical cancer, primarily with regard to the use of 18F-2-fluoro-2-deoxy-d-glucose-PET/computed tomography. A brief discussion of upcoming technologies, such as PET/MR imaging, is presented. PMID- 29482750 TI - FDG-PET Assessment of Other Gynecologic Cancers. AB - PET and PET/computed tomography play a role in the staging, monitoring of response to therapy, and surveillance for cervical and ovarian cancers. Currently, it is also an integral part of the assessment of patients with endometrial cancer and other gynecologic malignancies, such as vaginal and vulvar cancers and uterine sarcomas. In this article, we discuss in detail and highlight the potential role of PET and PET/computed tomography in evaluating these gynecologic malignancies using illustrative cases with relevant imaging findings. PMID- 29482751 TI - The Role of PET Imaging in Gynecologic Radiation Oncology. AB - The goal of this review is to discuss the current utility of fluorine-18 fluorodeoxyglucose (FDG)-PET for radiation oncologists who treat gynecologic malignancies. FDG-PET/computed tomography (CT) is recommended for baseline assessment in cervical cancer and for staging in vulvar and vaginal cancer. The authors use FDG-PET/CT in definitive radiation treatment planning for cervical, vulvar, and vaginal cancer. PET may be helpful for salvage radiation treatment planning for any recurrent gynecologic malignancy. There are published data to support the use of PET in posttreatment evaluation of cervical and vulvar cancer. PMID- 29482752 TI - Non-18F-2-Fluoro-2-Deoxy-d-Glucose PET/Computed Tomography in Gynecologic Oncology: An Overview of Current Status and Future Potential. AB - The current status and future potential targets of non-18F-2-fluoro-2-deoxy-d glucose (FDG) PET/computed tomography (CT) in 3 major gynecologic malignancies are discussed. Estrogen receptor-based 16alpha-18F-fluoro-17beta-estradiol (18F FES) PET/CT has been investigated in (a) Uterine malignancies (both endometrial and myometrial pathologies) and (b) ovarian carcinoma. For uterine tumors, FDG/FES standardized uptake value and/or uptake ratio showed a positive correlation with malignant transformation (ie, endometrial carcinoma and uterine sarcoma) and higher malignant grades, whereas higher 18F-FES uptake was documented in benign pathologies (ie, endometrial hyperplasia and leiomyoma). For epithelial ovarian carcinomas, 18F-FES PET/CT can predict the response to antiestrogen therapy in platinum-resistant cases. PMID- 29482753 TI - Normal Variants and Pitfalls Encountered in PET Assessment of Gynecologic Malignancies. AB - Combined PET/computed tomography is used for oncological indications. PET/computed tomography benefits from the metabolic information of PET and the anatomic localization of computed tomography. The integrated scanner provides data with accurate registration of anatomy and molecular information. Many physiologic conditions, normal variants, and benign lesions within the pelvis and the body can cause confusion and uncertainty. False-negative results owing to low 18F-fluorodeoxyglucose uptake from the tumor can produce diagnostic challenges and inaccurate conclusions. This article reviews normal variants and potential pitfalls encountered in PET assessment of gynecologic malignancies to provide useful information for the referring and reporting physicians. PMID- 29482755 TI - Emerging Molecular Imaging Techniques in Gynecologic Oncology. AB - Molecular imaging (mainly PET and MR imaging) has played important roles in gynecologic oncology. Emerging MR-based technologies, including DWI, CEST, DCE-MR imaging, MRS, and DNP, as well as FDG-PET and many novel PET radiotracers, will continuously improve practices. In combination with radiomics analysis, a new era of decision making in personalized medicine and precisely guided radiation treatment planning or real-time surgical interventions is being entered into, which will directly impact on patient survival. Prospective trials with well defined endpoints are encouraged to evaluate the multiple facets of these emerging imaging tools in the management of gynecologic malignancies. PMID- 29482756 TI - Imaging in Gynecologic Oncology. PMID- 29482757 TI - Talking heads. PMID- 29482754 TI - Quantitative Assessment of Gynecologic Malignancies. AB - 18F-fluorodeoxyglucose PET/CT as a dual-modality imaging, plays a key role in the diagnosis, staging, response assessment, and disease surveillance. Uptake by tumor cells offers an opportunity to differentiate viable malignant cells from posttreatment effects. 18F-fluorodeoxyglucose PET/CT-based criteria have been developed to evaluate treatment response. Uptake can reflect the biologic aggressiveness of the tumor, predicting the risk of metastasis and recurrence. The standardized uptake value can be measured as maximum, mean, or peak. Volumetric uptake measurements have shown substantial promise in providing accurate tumor assessment. We discuss these quantitative parameters in the assessment of gynecologic malignancies. PMID- 29482758 TI - Digital phenotyping: an overarching framework to capture our extended mental states. PMID- 29482759 TI - Continuing the conversation about AVATAR therapy. PMID- 29482762 TI - Mental health in post-conflict Colombia. PMID- 29482761 TI - Lorna Brookes: helping children of imprisoned parents. PMID- 29482763 TI - Isn't that Columbo? PMID- 29482764 TI - The Lancet Psychiatry Commission on psychological treatments research in tomorrow's science. PMID- 29482765 TI - Safety and tolerability of prescription omega-3 fatty acids: A systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Omega-3 fatty acids [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] are widely recommended for health promotion. Over the last decade, prescription omega-3 fatty acid products (RxOME3FAs) have been approved for medical indications. Nonetheless, there is no comprehensive analysis of safety and tolerability of RxOME3FAs so far. METHODS: A systematic review of randomized controlled trials (RCTs) was carried out based on searches in six electronic databases. The studies involving marketed RxOME3FA products were included, and adverse-effect data were extracted for meta-analysis. Subgroup analysis and meta regression were conducted to explore the sources of potential heterogeneity. RESULTS: Among the 21 included RCTs (total 24,460 participants; 12,750 from RxOME3FA treatment cohort and 11,710 from control cohort), there was no definite evidence of any RxOME3FA-emerging serious adverse event. Compared with the control group, RxOME3FAs were associated with more treatment-related dysgeusia (fishy taste; p = 0.011) and skin abnormalities (eruption, itching, exanthema, or eczema; p < 0.001). Besides, RxOME3FAs had mild adverse effects upon some non lipid laboratory measurements [elevated fasting blood sugar (p = 0.005); elevated alanine transaminase (p = 0.022); elevated blood urea nitrogen (p = 0.047); decreased hemoglobin (p = 0.002); decreased hematocrit (p = 0.009)]. Subgroup analysis revealed that EPA/DHA combination products were associated with more treatment-related gastrointestinal adverse events [eructation (belching; p = 0.010); nausea (p = 0.044)] and low-density lipoprotein cholesterol elevation (p = 0.009; difference in means = 4.106mg/dL). CONCLUSION: RxOME3FAs are generally safe and well tolerated but not free of adverse effects. Post-marketing surveillance and observational studies are still necessary to identify long-term adverse effects and to confirm the safety and tolerability profiles of RxOME3FAs. PMID- 29482766 TI - Distinct effects of dietary ALA, EPA and DHA on rat adipose oxylipins vary by depot location and sex. AB - Dietary EPA and DHA given together alter oxylipins in adipose tissue. To compare the separate effects of individual dietary n-3 PUFA on oxylipins in different adipose depots (gonadal, mesenteric, perirenal, subcutaneous) in males and females, rats were provided diets containing higher levels of alpha-linolenic acid (ALA), EPA or DHA. Each n-3 PUFA enhanced its respective oxylipins the most, while effects on other n-3 oxylipins varied. For example: in perirenal and subcutaneous depots, more DHA oxylipins were higher with dietary ALA than with EPA; dietary EPA uniquely decreased 14-hydroxy-docosahexaenoic acid, in contrast to increasing many other DHA oxylipins. The n-3 PUFAs also reduced oxylipins from n-6 PUFAs in order of effectiveness: DHA > EPA > ALA. Diet by sex interactions in all depots except the perirenal depot resulted in higher oxylipins in males given DHA, and higher oxylipins in females given the other diets. Diet and sex effects on oxylipins did not necessarily reflect effects on either their tissue phospholipid or neutral lipid PUFA precursors. These varying diet and sex effects on oxylipins in the different adipose sites indicate that they may have distinct effects on adipose function. PMID- 29482767 TI - PGE2 downregulates LPS-induced inflammatory responses via the TLR4-NF-kappaB signaling pathway in bovine endometrial epithelial cells. AB - Postpartum bacterial infections of the uterus cause endometritis in dairy cows. Inflammatory responses to bacterial infections in the bovine uterus were generated through pattern recognition receptors (PRRs) that bind to pathogen associated molecules such as lipopolysaccharide (LPS) from Escherichia coli. Among these PRRs, Toll-like receptor 4 (TLR4) is primarily responsible for LPS recognition, which triggers inflammatory responses via mitogen-activated protein kinases (MAPKs) and NF-kappaB signaling activation, resulting in the expression of inflammatory mediators in mammals such as IL-8 and IL-6. Previous studies indicate that PGE2 plays an important role in bacterial endometritis, although details on the mechanism underlying how it regulates LPS-induced inflammatory responses in bovine endometrial epithelial cells (bEECs) remain elusive. In the present study, bEECs were pre-treated with exogenous PGE2 and/or PGF2alpha prior to LPS stimulation. With PGE2 pre-treatment, we observed an augmentation in LPS stimulated PKA, ERK, and IkappaBalpha phosphorylation and cyclooxygenase-2 (COX 2) and anti-inflammatory cytokine IL-6 expression and downregulation of prostaglandin E2 receptor 4 (EP4) and TLR4 in bEECs. These results indicate that LPS-induced inflammatory responses through TLR4 signaling in bEECs could be downregulated by exogenous PGE2 pre-treatment, but not PGF2alpha. PMID- 29482769 TI - Perspectives on the Affordability of Precision Medicine. AB - This commentary highlights the article by Hsiao et al, who explore the recent migration of Current Procedural Terminology codes for reimbursement of genomic tests. PMID- 29482768 TI - Impaired verbal episodic memory in healthy older adults is marked by increased F2 Isoprostanes. AB - Age-associated cognitive decline amongst otherwise healthy older individuals is a multifaceted characteristic of ageing. The role of oxidative stress biomarkers has been increasingly examined in the context of pathological aging conditions that affect cognition. Plasma F2-Isoprostane levels are a reliable index of systemic oxidative stress (specifically lipid peroxidation) and are elevated in dementia patients. Less is known about their role in healthy cognitive ageing. This study evaluated the relationship between F2-Isoprostanes and cognitive functioning in a cohort of 211 healthy elderly adults (60-75 years: Male; 88, Female; 123). Cognitive assessment included the Cognitive Drug Research (CDR) computerised assessment battery, which produces five validated factor scores (corresponding to 'Quality of Episodic Memory', 'Speed of Memory', Quality of Working Memory', Power of Attention' and 'Continuity of Attention'). Participants with higher F2-Isoprostane levels had significantly lower Quality of Episodic Memory scores (suggesting inferior abilities in retaining and retrieving verbal information in episodic memory). This is, to our knowledge, the first report of compromised verbal episodic memory in healthy ageing humans being linked to increased levels of F2-Isoprostanes. These results have relevance for interventions aimed at improving cognitive performance in the healthy elderly. PMID- 29482770 TI - MYD88 Mutations and Sensitivity to Ibrutinib Therapy. AB - This Correspondence relates to the article by Bobee et al (Determination of Molecular Subtypes of Diffuse Large B-Cell Lymphoma Using a Reverse Transcriptase Multiplex Ligation-Dependent Probe Amplification Classifier: A CALYM Study. J Mol Diagn 2017,19:892-904). PMID- 29482771 TI - Authors' Reply. AB - Authors' Reply to the Letter to the Editor by Y. Lynn Wang (MYD88 mutations and sensitivity to ibrutinib therapy). PMID- 29482772 TI - Reappraisal of primary hepatic lymphoma: Is surgical resection underestimated? AB - Primary hepatic lymphoma (PHL) is defined as a lympho-proliferative disorder limited to the liver without any involvement of the spleen, lymph nodes, bone marrow or blood. Diffuse large B-cell lymphoma (DLBCL) is the most common histological type counting more than 60-80% of all PHL. Usually, it occurs in middle-aged men with aspecific symptoms and diagnosis is confirmed by histopathology. In order to expand current knowledge and to investigate an optimal therapeutic strategy, a systematic review of literature was conducted in February 2016. A total of 274 articles were retrieved, and after exclusion, 55 were retained, reporting 147 cases of PHL. Patients were mainly men (64.9%) with a median age at diagnosis of 57 years (range: 17-92) and right hepatic lobe involvement (69.6%). Among the 147 patients, 9% received no therapy while 77% underwent treatment including chemotherapy, surgery and radiotherapy in 64%, 26% and 1% of cases, respectively. Mean follow-up was 22.6 months (range: 0.2-360). Overall mortality was 29.2% with a 90-day mortality of 26%. Risk factors for increased mortality include; bilobar lesions (p = 0.001), right lobe localisation (p = 0.003) and non-surgical approach or the absence of any treatment (p = 0.001). A trend towards favourable outcomes for young patients (mean = 50.4 years) with a large liver lesion was achieved by surgical management of PHL but this did not achieve statistical significance. Statistical analysis indicates that in cases of resectable disease, an aggressive surgical approach in selected patients leads to increase long-term survival. Thus, two hypotheses should be assessed in further randomized studies: 1 degrees ) resectable PHL is a less severe form or 2 degrees ) hepatectomy is an effective treatment for PHL. PMID- 29482773 TI - The SWI/SNF complex subunit genes: Their functions, variations, and links to risk and survival outcomes in human cancers. AB - SWI/SNF is a multiprotein complex essential for regulation of eukaryotic gene expression. In this article, we review the function and characteristics of this complex and its subunits in cancer-related phenotypes. We also present and discuss the publically available survival analysis data for TCGA patient cohorts, revealing novel relationships between the expression levels of the SWI/SNF subunit genes and patient survival times in several cancers. Overall, multiple lines of research point to a wide-spread role for the SWI/SNF complex genes in human cancer susceptibility and patient survival times. Examples include the mutations in ARID1A with cancer-driving effects, associations of tumor SWI/SNF gene expression levels and patient survival times, and two BRM promoter region polymorphisms linked to risk or patient outcomes in multiple human cancers. These findings should motivate comprehensive studies in order to fully dissect these relationships and verify the potential clinical utility of the SWI/SNF genes in controlling cancer. PMID- 29482774 TI - A systematic review of palliative bone radiotherapy based on pain relief and retreatment rates. AB - Palliative radiotherapy has been shown to have effects on Quality of Life during painful bone metastasis. This review aimed to determine equivalence in pain relief (PR) and retreatment rate (RR) using both single and multi-fraction irradiations, based on evaluation of the trial's quality. We performed a systematic review since ICRU 50 Report (1993) to June 2017, then evaluated trials for reproducibility and good methodology criteria. We found five studies that were reproducible in both dose and volume prescription. One study used three dimensional (3D) treatment planning. Equivalence between single and multi fraction schedules was demonstrated for PR after 3 months, but a 2-3 time RR appeared after single-fraction schedules, notably in the first year after treatment (primarily during the first four months). Reserving long course therapy for well-preserved patients would allow for better long-term efficacy with lower RR, while altered patients would suffer less from single-fraction treatments. It appears that life expectancy might not be used as a criterion for this choice. PMID- 29482775 TI - Total body irradiation in allogeneic bone marrow transplantation conditioning regimens: A review. AB - Hematologic malignancies may require, at one point during their treatment, allogeneic bone marrow transplantation. Total body irradiation combined with chemotherapy or radiomimetic used in allogeneic bone marrow transplantation is known to be very toxic. Total body irradiation (TBI) induces immunosuppression to prevent the rejection of donor marrow. TBI is also used to eradicate malignant cells and is in sanctuary organs that are not reached by chemotherapy drugs. TBI has evolved since its introduction in the late fifties, but acute and late toxicities remain. Helical tomotherapy, which is widely used for some solid tumors, is a path for the improvement of outcomes and toxicities in TBI because of its sparing capacities. In this article, we first review the practical aspects of TBI with patient positioning, radiobiological considerations and total dose and fractionation prescriptions. Second, we review the use of intensity modulated radiation therapy in bone marrow transplantation with a focus on helical tomotherapy TBI, helical tomotherapy total marrow irradiation (TMI) and total marrow and lymphoid irradiation (TMLI) and their dosimetric and clinical outcomes. Finally, we review the perspective of dose escalation and the extension to older patients and patients with comorbidity who do not benefit from a standard bone marrow transplantation conditioning regimen. PMID- 29482776 TI - Resistance to EGFR inhibitors in non-small cell lung cancer: Clinical management and future perspectives. AB - In the last few years, the development of targeted therapies for non-small cell lung cancer (NSCLC) expressing oncogenic driver mutations (e.g. EGFR) has changed the clinical management and the survival outcomes of this specific minority of patients. Several phase III trials demonstrated the superiority of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) over chemotherapy in EGFR-mutant NSCLC patients. However, in the vast majority of cases EGFR TKIs lose their clinical activity within 8-12 months. Many genetic aberrations have been described as possible mechanisms of EGFR TKIs acquired resistance and can be clustered in four main sub-groups: 1. Development of secondary EGFR mutations; 2. Activation of parallel signaling pathways; 3. Histological transformation; 4. Activation of downstream signaling pathways. In this review we will describe the molecular alterations underlying each of these EGFR TKIs resistance mechanisms, focusing on the currently available and future therapeutic strategies to overcome these phenomena. PMID- 29482777 TI - Meta-analyses evaluating surrogate endpoints for overall survival in cancer randomized trials: A critical review. AB - BACKGROUND: In cancer randomized controlled trials (RCT), alternative endpoints are increasingly being used in place of overall survival (OS) to reduce sample size, duration and cost of trials. It is necessary to ensure that these endpoints are valid surrogates for OS. Our aim was to identify meta-analyses that evaluated surrogate endpoints for OS and assess the strength of evidence for each meta analysis (MA). MATERIALS AND METHODS: We performed a systematic review to identify MA of cancer RCTs assessing surrogate endpoints for OS. We evaluated the strength of the association between the endpoints based on (i) the German Institute of Quality and Efficiency in Health Care guidelines and (ii) the Biomarker-Surrogate Evaluation Schema. RESULTS: Fifty-three publications reported on 164 MA, with heterogeneous statistical methods Disease-free survival (DFS) and progression-free survival (PFS) showed good surrogacy properties for OS in colorectal, lung and head and neck cancers. DFS was highly correlated to OS in gastric cancer. CONCLUSION(S): The statistical methodology used to evaluate surrogate endpoints requires consistency in order to facilitate the accurate interpretation of the results. Despite the limited number of clinical settings with validated surrogate endpoints for OS, there is evidence of good surrogacy for DFS and PFS in tumor types that account for a large proportion of cancer cases. PMID- 29482778 TI - A systematic review of the influence of radiation-induced lymphopenia on survival outcomes in solid tumors. AB - Lymphopenia is a common accompaniment of multimodal cancer therapy. As the most radiosensitive cells of the hematopoietic system, lymphocytes residing within or circulating through a radiation portal are frequently depleted by radiation therapy. The recognition that radiation-induced reduction of circulating lymphocyte counts and eventual lymphocyte infiltration of tumors have a tangible impact on overall survival outcomes has revived the interest in understanding the causes of treatment-associated lymphopenia and developing strategies to predict, prevent and ameliorate this well-documented phenomenon. In this systematic review, we have performed a comprehensive search of the literature to elucidate the studies that document a correlation between radiation-associated lymphopenia and survival outcomes in solid malignancies. We also summarize potential unifying paradigms that account for radiation-induced lymphopenia across studies and lay the groundwork for attempting to explain and/or counter this phenomenon. PMID- 29482779 TI - Treatment of squamous cell carcinoma of the anal canal: A new strategies with anti-EGFR therapy and immunotherapy. AB - The incidence of squamous cell carcinoma of the anal canal (SCAC) is increasing in both sexes but the standard treatment remains that of 20 years ago. However, interesting data have recently emerged on the use of anti-epidermal growth factor receptor (EGFR) agents and immunotherapy in advanced disease. Thus, new avenues of research are opening up that will hopefully lead to more effective therapeutic strategies. We provide an overview of the latest studies published on this tumor and discuss the possible future therapeutic options for combination therapy, anti EGFR treatment and radiotherapy. PMID- 29482780 TI - Diet and supplements in cancer prevention and treatment: Clinical evidences and future perspectives. AB - In recent years, calorie-restricted dietary regimens and compounds such as vitamins, curcumin, green tea extracts and omega-3 fatty acids have attracted attention for their potential anticancer effects. While definitive conclusions cannot be drawn in this field, many patients adopt complementary antitumor therapies aiming to improve efficacy or reduce toxicity of chemotherapy, with uncertain benefits and the risk of additional toxicities or antagonistic interactions with standard therapies. In this manuscript, we review the different levels of available evidence to suggest or discourage specific dietary changes or supplement use in the context of cancer prevention, reduction of tumor recurrences and survival prolongation in advanced cancers. Preventing or treating obesity, as well as adhering to healthy dietary patterns, should be recommended to both the general population and cancer survivors because they are convincingly associated with reduced risk of primary or second cancers and, in some cases, with reduced cancer recurrences. On the contrary, the role of specific interventions or supplements in patients with advanced malignancies is much more uncertain and actually a highly debated topic. With some exceptions, such as melatonin, the use of most complementary therapies cannot be encouraged, or should be discouraged, because of the lack of sufficient safety and efficacy data. PMID- 29482781 TI - Global comparison of targeted alpha vs targeted beta therapy for cancer: In vitro, in vivo and clinical trials. AB - Targeted therapy for cancer is a rapidly expanding and successful approach to the management of many intractable cancers. However, many immunotherapies fail in the longer term and there continues to be a need for improved targeted cancer cell toxicity, which can be achieved by radiolabelling the targeting vector with a radioisotope. Such constructs are successful in using a gamma ray emitter for imaging. However, traditionally, a beta emitter is used for therapeutic applications. The new approach is to use the short range and highly cytotoxic alpha radiation from alpha emitters to achieve improved efficacy and therapeutic gain. This paper sets out to review all experimental and theoretical comparisons of efficacy and therapeutic gain for alpha and beta emitters labelling the same targeting vector. The overall conclusion is that targeted alpha therapy is superior to targeted beta therapy, such that the use of alpha therapy in clinical settings should be expanded. PMID- 29482782 TI - Regulation of epithelial to mesenchymal transition by BRCA1 in breast cancer. AB - Reports till its discovery has proven multiple facets of Breast Cancer type 1 susceptibility gene (BRCA1) from nucleus to cytoplasm; from DNA repair to drug resistance; from Homologous Recombination (HR) to Ubiquitination; from breast to brain; from cancer to HIV and many of the roles are still unexplored. One of the recent attractions of BRCA1 is its role in regulating breast cancer metastasis though the exact mechanism is poorly understood. In this review, we will discuss the molecular interactions between BRCA1 and the key molecules of Epithelial to Mesenchymal Transition (EMT) associated with metastasis, its associated drug resistance and the possible treatment strategy for BRCA1 mutated breast cancer. PMID- 29482783 TI - Evolution in sentinel lymph node biopsy in breast cancer. AB - Sentinel lymph node biopsy (SLNB) is the standard of care for axillary staging in clinically node-negative (cN0) breast cancer patients without neoadjuvant chemotherapy (NAC). The application of SLNB in patients receiving NAC has also been explored. Evidence supports its use after NAC in pretreatment cN0 patients. Nonetheless, its routine use in all the pretreatment node-positive patients who become cN0 after NAC is unjustified due to the unacceptably high false-negative rate, which can be improved in a subset of patients. Axillary surgery omission in selected patients with a low risk of ALN metastasis has gained more and more research interest because the SLNs are tumor-free in more than 70% of all patients. To avoid drawbacks of conventional mapping methods, novel techniques for SLN detection have been developed and shown to be highly accurate in patients with early breast cancer. This article reviews the progress in SLNB in patients with breast cancer. PMID- 29482784 TI - The stem cell division theory of cancer. AB - All cancer registries constantly show striking differences in cancer incidence by age and among tissues. For example, lung cancer is diagnosed hundreds of times more often at age 70 than at age 20, and lung cancer in nonsmokers occurs thousands of times more frequently than heart cancer in smokers. An analysis of these differences using basic concepts in cell biology indicates that cancer is the end-result of the accumulation of cell divisions in stem cells. In other words, the main determinant of carcinogenesis is the number of cell divisions that the DNA of a stem cell has accumulated in any type of cell from the zygote. Cell division, process by which a cell copies and separates its cellular components to finally split into two cells, is necessary to produce the large number of cells required for living. However, cell division can lead to a variety of cancer-promoting errors, such as mutations and epigenetic mistakes occurring during DNA replication, chromosome aberrations arising during mitosis, errors in the distribution of cell-fate determinants between the daughter cells, and failures to restore physical interactions with other tissue components. Some of these errors are spontaneous, others are promoted by endogenous DNA damage occurring during quiescence, and others are influenced by pathological and environmental factors. The cell divisions required for carcinogenesis are primarily caused by multiple local and systemic physiological signals rather than by errors in the DNA of the cells. As carcinogenesis progresses, the accumulation of DNA errors promotes cell division and eventually triggers cell division under permissive extracellular environments. The accumulation of cell divisions in stem cells drives not only the accumulation of the DNA alterations required for carcinogenesis, but also the formation and growth of the abnormal cell populations that characterize the disease. This model of carcinogenesis provides a new framework for understanding the disease and has important implications for cancer prevention and therapy. PMID- 29482785 TI - Prognostic significance of residual lymph node status after definitive chemoradiotherapy in patients with node-positive cervical cancer. PMID- 29482786 TI - Surgical Management Navicular and Cuboid Fractures. AB - The tarsal navicular is a critical component of the foot's medial longitudinal arch. Injuries to the navicular have significant long-term functional consequences. In addition to stress fractures, acute injuries to the navicular include acute avulsion, tuberosity, and body fractures. Nonoperative treatment is the mainstay for avulsion injuries and nondisplaced body fractures. Open reduction and internal fixation is performed to achieve anatomic reduction in the other situations. Common complications following operative intervention include pain, stiffness, post-traumatic arthritis, avascular necrosis, nonunion, and hindfoot deformity. This article provides an overview for recognition and treatment of common presentations of these injuries as described in the literature. PMID- 29482787 TI - Management of Talar Fractures. AB - Fractures of the talus are significant injuries with associated significant complications where the recovery zenith is less frequently good to excellent, and more commonly fair to satisfactory. These outcomes are a consequence of combinations of the inherent intrinsic and surrounding anatomy, technical and logistic difficulties in adequate fracture access, and the high-energy mechanisms typically associated with these injuries that further traumatize the surrounding tissues. This article reviews and provides current management recommendations for these devastating injuries. PMID- 29482788 TI - Paradigm Shift for the Surgical Management of Calcaneal Fractures? AB - Calcaneal fractures account for up to 75% of all foot fractures and 1% to 2% of all fractures. Approximately 75% of calcaneal fractures are intraarticular, resulting in a prolonged recovery, more pain, and disability. The most common mechanism of injury includes falls from a height and motor vehicle accidents. This article reviews studies that compare nonoperative with operative treatment. The literature continues to support surgical intervention; however, these injuries can still be managed nonoperatively in certain clinical scenarios. This article focuses on the surgical management of intraarticular calcaneal fractures and highlights the sinus tarsi approach. PMID- 29482789 TI - Role for Primary Repair of Deltoid Ligament Complex in Ankle Fractures. AB - Acute deltoid injuries may occur with ankle fractures. They are often left to heal without repair, possibly leading to chronic medial ankle instability. Stress radiographs identify the need for surgical repair of fractures or soft tissue damage. Gravity stress views have benefits over manually stressing the ankle. MRI can explore the extent of medial soft tissue injuries. Arthroscopy can evaluate and potentially treat deltoid injuries. Interposition of the deltoid may preclude adequate fracture reduction. Except with deltoid tear, fractures should be reduced and fixated, then the deltoid assessed. With persistent instability, primary repair may prevent long-term sequelae. PMID- 29482791 TI - Minimally Invasive Plate Osteosynthesis for Distal Tibia Fractures. AB - Surgical treatment of distal tibia fractures can present as a difficult task. Intramedullary nailing (IMN), external fixation, and open reduction internal fixation (ORIF) have displayed various complications ranging from a high rate of knee morbidity with IMN to wound complications and infection with ORIF. Minimally invasive plate osteosynthesis (MIPO) has been used to decrease development of these complications. MIPO respects the soft tissue envelope along with maintaining the biological environment needed for proper osseous healing. Favorable results have been shown with MIPO in regard to function, healing time, and decreased complications. PMID- 29482790 TI - Arthroscopic-Assisted Open Reduction Internal Fixation. AB - The indications for arthroscopy have expanded over the years. Arthroscopic assisted open reduction internal fixation in the setting of acute trauma is gaining popularity with foot and ankle surgeons. It serves to facilitate direct visualization of fracture fragments and allows for precise articular reduction with minimal soft tissue insult. Current evidence reports a high incidence of chondral injury with ankle fractures. Arthroscopy performed at the time of open reduction internal fixation allows for joint inspection and potential treatment of these posttraumatic defects. PMID- 29482792 TI - Primary Arthrodesis in Severely Comminuted Fractures. AB - At present there is controversy regarding the appropriate treatment of severely comminuted fractures of the lower extremity. Even with near-perfect anatomic reduction of severely comminuted fractures, development of posttraumatic arthritis is still present at an increased rate. Primary fusion of comminuted fractures of the foot and ankle creates successful and predictable outcomes, which dismisses the chance of developing posttraumatic arthritis and decreases complications and the need for revisional procedures. PMID- 29482793 TI - Intramedullary Nailing of Fibular Fractures. AB - The reamed intramedullary (IM) technique has many benefits. However, open plating is the most commonly used technique. Previously, IM stabilization was reserved for fibular fractures, which were given lower priority, and generally associated with injuries to the distal tibia or instances in which the soft tissue envelope was unsuitable for an open approach. This article reviews the literature and the level of evidence, and presents case examples and operative technique. PMID- 29482794 TI - Advanced Techniques in the Management of Foot and Ankle Trauma. PMID- 29482795 TI - Advanced Techniques in the Management of Foot and Ankle Trauma. PMID- 29482796 TI - Patterns of Energy Imbalance of the Meridians in Patients with Temporomandibular Dysfunction. AB - Temporomandibular dysfunction (TMD) is a set of changes that affects the muscles of mastication, temporomandibular joint, teeth, and associated periodontal and orofacial structures. According to Traditional Chinese Medicine, the imbalance of energy (Qi) circulating in the acupuncture meridians is always the primary etiologic cause of any physical manifestation. The aim of this study was to describe the patterns of Qi imbalance in patients with TMD by means of an objective measurement. The clinical study was conducted at the Piracicaba Dental School (FOP/Unicamp), in Piracicaba-SP, Brazil. We evaluated 40 adult volunteers with TMD. The Qi measurement was carried out by the researcher using the Ryodoraku method using 24 points representing the 12 acupuncture meridians: LU9 (Taiyuan), PC7 (Daling), HT7 (Shemen), SI5 (Yanggu), TE4 (Yangchi), LI5 (Yangxi), SP3 (Taibai), LR3 (Taichong), KI3 (Taixi), BL64 (Jinggu), GB40 (Qiuxu), and ST42 (Chongyang). The average total Qi of 40 volunteers (21.7 MUA +/- 1.5), was below the normal range (40-60 MUA) and was classified as deficiency of Qi (empty). The coupled meridians that showed the highest Qi imbalance were the kidney (29.4 MUA +/- 2.8) and bladder (13.8 MUA +/- 1). The Qi planes with greatest imbalance were the Shao Yang and Shao Yin. In conclusion, volunteers with TMD presented a pattern of Qi deficiency, and the most prevalent imbalance patterns identified were in the kidney and bladder coupled meridians and in the energetic planes Shao Yin (heart/kidney) and Shao Yang (triple energizer/gall bladder). PMID- 29482797 TI - The Effect of Auricular and Systemic Acupuncture on the Electromyographic Activity of the Trapezius Muscle with Trigger Points-A Pilot Study. AB - The purpose of this study was to analyze and compare intra and intergroup the immediate effect of the auricular and LR8 systemic acupuncture on the electromyographic activity of the trapezius with the trigger points. This is an experimental clinical trial; 40 people were split in 4 distinct groups (n = 10): GI mustard seed application in the auricular acupoint; GII bilateral needle application in the LR8 acupoint; GIII combination of the techniques; GIV/Control Group mustard seed application in an acupoint not linked to the muscle tension. The EMG was used to assess the muscle contraction for 5 seconds during the resting time and during the isometric contraction time. The EMG signal was first collect without the acupuncture intervention; then both techniques were applied for 5 minutes; and the EMG was collected again right after these applications. The Shapiro-Wilk test was used, the t test was paired with the Wilcoxon test to the intragroup comparison; One-way analysis of variance test for intergroup comparison. There was no statistical difference in the intragroup comparison for the groups. The same happened to the intergroup comparison before and after application. Systemic and auricular acupuncture did not promote immediate changes in the EMG activity of the trapezius muscle in individuals with MTrPs. PMID- 29482799 TI - Assessing the Links Between Anthropometrics Data and Akabane Test Results. AB - According to popular belief, metabolic disorders and imbalances are one of the main factors contributing to various human illnesses. Early diagnosis of these disorders is one of the main methods for preventing serious diseases. The goal of this study was to assess the correlations between main physical indicators and the activity of certain acupuncture channels using the thermal Akabane test based on ancient Chinese diagnostic methods. This test measures the pain thresholds' temperature sensitivity when a point source of heat is applied to the "entrance exit" points of each channel. The skin temperature sensitivity in our bodies is a basic reactive system; it is as significant as such important indicators as body temperature and provides a very clear representation of functional and psychophysiological profiles. On the basis of our statistical study, we revealed reliable correspondence between the activity of certain acupuncture channels and main anthropometric and biometric data. PMID- 29482798 TI - Treating Pain in Pregnancy with Acupuncture: Observational Study Results from a Free Clinic in New Zealand. AB - INTRODUCTION: Clinic-based acupuncturists, midwives, and physiotherapists have reported using acupuncture to treat lumbopelvic pain in pregnancy, a common condition that may affect functioning and quality of life. To contribute to the emerging evidence on treatment outcomes, we collected patient-reported pain reduction data from women treated during pregnancy in a no-pay, hospital-based acupuncture service in New Zealand. METHODS: Observational study of patient reported symptom reduction.The main outcome measure was the MYMOP (Measure Your Medical Outcome Profile), a brief, validated self-report instrument. Open-ended questions on treatment experiences and adverse events were included. RESULTS: Of the 81 women on whom we had complete treatment data, the majority (N = 72, 89%) reported clinically meaningful symptom reduction. Patient-reported adverse events were infrequent and mild. DISCUSSION: Patient-reported and treatment-related lumbopelvic pain symptom reduction findings provide further evidence that acupuncture in pregnancy is safe and beneficial in a field setting. We discuss this study's unique contributions in providing guidance for clinicians who practice acupuncture in pregnancy, including midwives, physiotherapists, and physicians. PMID- 29482800 TI - A New Theory for Acupuncture: Promoting Robust Regulation. AB - Robustness, an ability of biological networks to uphold their functionalities in the face of perturbations, is a key characteristic of all living systems. Acupuncture is a procedure in which fine needles are inserted into an individual at discrete points and then manipulated, with the intent of preventing and curing diseases. Acupuncture does not directly eliminate pathogenic factors or pathological tissue; rather, acupuncture enhances the ability of the human body to self-medicate itself by activating complex regulatory systems and by maintaining physiological homeostasis to prevent or treat diseases. From this point of view, the effect of acupuncture on the human body is more likely a kind of regulation to promote robustness. That is to say, acupuncture has the ability to promote robustness. In this article, we review the properties and functions of acupuncture in preventing and treating diseases and in maintaining health by enhancing robustness. PMID- 29482801 TI - Smoking Disturbs the Intrinsic Tendencies of Autonomic Nervous System Reflected in the Bioelectric Potential at 12 Alarm Points: A Pilot Study. AB - OBJECTIVES: The objective of this study was to investigate the effect of smoking on the bioelectrical potential (BEP) at 12 alarm points. METHODS: A crossover study was conducted on 17 normal adult male smokers. The BEP was measured at 12 alarm points both before and after breathing through a filter (control) and smoking. RESULTS: The participants were classified into three subtypes according to the way in which their BEP changed after having breathed through a filter: increasing, decreasing, and irregular types. Compared with breathing through a filter, smoking decreased the BEP in the increasing type, whereas it increased the BEP in the decreasing type. No significant changes were observed in the irregular-type participants. CONCLUSIONS: This study suggests that smoking increases sympathetic activity in smokers with a parasympathetic tendency, whereas it lessens sympathetic activity in smokers with a sympathetic tendency. Smoking does this by eliminating the intrinsic tendency of the autonomic nervous system, and these effects can be observed in the BEP at 12 alarm points. PMID- 29482803 TI - Sexsomnia: a diagnostic challenge, a case report. PMID- 29482802 TI - Effects of electroacupuncture on luteal regression and steroidogenesis in ovarian hyperstimulation syndrome model rat. AB - AIMS: Electroacupuncture (EA) is an effective and safe therapeutic method widely used for treating clinical diseases. Previously, we found that EA could decrease serum hormones and reduce ovarian size in ovarian hyperstimulation syndrome (OHSS) rat model. Nevertheless, the mechanisms that contribute to these improvements remain unclear. MATERIALS AND METHODS: HE staining was used to count the number of corpora lutea (CL) and follicles. Immunohistochemical and ELISA were applied to examine luteal functional and structural regression. Immunoprecipitation was used for analyzing the interaction between NPY (neuropeptide Y) and COX-2; western blotting and qRT-PCR were used to evaluate the expressions of steroidogenic enzymes and PKA/CREB pathway. KEY FINDINGS: EA treatment significantly reduced the ovarian weight and the number of CL, also decreased ovarian and serum levels of PGE2 and COX-2 expression; increased ovarian PGF2alpha levels and PGF2alpha/PGE2 ratio; decreased PCNA expression and distribution; and increased cyclin regulatory inhibitor p27 expression to have further effect on the luteal formation, and promote luteal functional and structural regression. Moreover, expression of COX-2 in ovaries was possessed interactivity increased expression of NPY. Furthermore, EA treatment lowered the serum hormone levels, inhibited PKA/CREB pathway and decreased the expressions of steroidogenic enzymes. Hence, interaction with COX-2, NPY may affect the levels of PGF2alpha and PGE2 as well as impact the proliferation of granulosa cells in ovaries, thus further reducing the luteal formation, and promoting luteal structural and functional regression, as well as the ovarian steroidogenesis following EA treatment. SIGNIFICANCE: EA treatment could be an option for preventing OHSS in ART. PMID- 29482804 TI - Vitamin D and obstructive sleep apnea: a systematic review and meta-analysis. AB - OBJECTIVE/BACKGROUND: Several studies have reported an association between 25 hydroxyvitamin D (25(OH)D) levels and obstructive sleep apnea (OSA) patients. The objective of the current study was to perform a systematic review and meta analysis of these studies and report the findings. PATIENTS/METHODS: Authors searched for studies (through January 1, 2017) reporting 25(OH)D serum levels in OSA patients. The Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) statement was followed. RESULTS: Fourteen studies with 4937 subjects met inclusion criteria. There were 1513 controls and 3424 OSA patients. The 25(OH)D serum levels for controls and mild OSA patients were 28.16 +/- 9.39 ng/mL (95% CI 27.64, 28.68) and 27.41 +/- 9.42 ng/mL (95% CI 26.87, 27.95), respectively. The 25(OH)D serum levels for controls and moderate OSA patients were 28.21 +/- 9.38 ng/mL (95% CI 27.70, 28.72) and 25.48 +/- 10.34 ng/mL (95% CI 24.68, 26.28), respectively. The 25(OH)D serum levels for controls and severe OSA patients were 28.32 +/- 9.65 ng/mL (95% CI 27.80, 28.84) and 21.88 +/- 10.24 ng/mL (95% CI 21.08, 22.68), respectively. Using random effects modeling, the 25(OH)D serum levels were decreased for patients with OSA when compared to control groups (mean differences were -2.7% for mild OSA, -10.1% for moderate OSA and -17.4% for severe OSA). CONCLUSIONS: There was a relative insufficiency in serum 25(OH)D levels among OSA patients compared to control patients, which was incrementally exacerbated with increasing severity of sleep apnea. It was unclear whether a low 25(OH)D was a risk factor for OSA or if OSA was a risk factor for 25(OH)D. It was also possible that the association between 25(OH)D and OSA was due to body mass index (BMI). PMID- 29482805 TI - Comorbidities in a community sample of narcolepsy. AB - STUDY OBJECTIVE: To assess comorbidities in a community-based cohort of narcolepsy. METHODS: A 2000-2014 community-based narcolepsy cohort was identified in Olmsted County, Minnesota. Records were reviewed by a certified sleep specialist for accuracy of diagnosis, and comorbidities were extracted and analyzed. Comorbidities in narcolepsy subjects, both at diagnosis and upon follow up, were compared with those in unaffected and age- and sex-matched cohort using conditional logistic regression. RESULTS: At diagnosis, there was increased association of narcolepsy with anxiety (OR 4.56, 95% CI 1.99-10.44), thyroid disease (3.07, 1.19-7.90), hypertension (2.69, 1.22-5.93), and hyperlipidemia (2.49, 1.05-5.92). At the end of the prolonged observation period of 9.9 years (SD 7.27 years), there was increased association of narcolepsy with peripheral neuropathy (11.21, 1.16-108.11), non-migrainous headache (6.00, 1.73-20.83), glucose intolerance (2.39, 1.05-5.45), and automobile-related trauma (2.43, 1.08 5.45). Persistently increased both at diagnosis and after a prolonged observation period were associations of narcolepsy with obstructive sleep apnea (OSA) (69.25, 9.26-517.99 decreasing to 13.55, 5.08-36.14), chronic low back pain (5.46, 2.46 12.11 to 2.58, 1.39-4.77), depression (4.88, 2.45-9.73 to 3.79, 2.12-6.79), psychiatric disorders in general (4.73, 2.49-9.01 to 3.40, 1.94-5.98), endocrinopathies (4.15, 1.81-9.56 to 2.45, 1.33-4.49), and obesity (2.27, 1.13 4.56 to 2.07, 1.15-3.7). CONCLUSIONS: In this community-based study of narcolepsy comorbidities, both at diagnosis and after prolonged follow-up, persistent comorbidities were revealed, including OSA, chronic low back pain, psychiatric disorders in general, endocrinopathies, and obesity. The comprehensive management of narcolepsy requires monitoring for and managing these important associated health conditions. PMID- 29482806 TI - Mortality and use of psychotropic medication in sleep apnoea patients: a population-wide register-based study. AB - BACKGROUND: This study aimed to evaluate all-cause mortality in relation to the use of benzodiazepines, antidepressants and antipsychotics in obstructive sleep apnoea (OSA) patients and matched controls. METHODS: Patients with a diagnosis of OSA and no pre-index use of psychotropic medication (n = 38,735) were compared with control subjects (n = 75,941) matched by age, gender, marital status and community location. National register data were used to obtain information on diagnoses (the Danish National Patient Registry), mortality (the Central Person Register) and psychotropic medication use (the Danish Register on Medicinal Product Statistics). RESULTS: All-cause mortality was higher in patients with OSA than in control subjects. Mortality hazard ratios were higher for OSA patients and controls who were prescribed serotonergic antidepressant drugs (HR = 1.808, SD = 0.015, p = 0.001 in OSA patients; HR = 2.607, SD = 0.158, p < 0.001 in controls), tricyclic antidepressants (HR = 1.846, SD = 0.166, p < 0.001; HR = 2.087, SD = 0.172, p < 0.001), benzodiazepines (HR = 2.590, SD = 0.040, p < 0.001); (HR = 3.705, SD = 0.085, p < 0.001), benzodiazepine-like drugs (HR = 1.980, SD = 0.087, p < 0.001; HR = 2.227, SD = 0.083, p < 0.001), first generation antipsychotics (HR = 2.894, SD = 0.268, p < 0.001; HR = 1.210, SD = 0.509, NS), and second-generation antipsychotics (HR = 2.069, SD = 0.182, p < 0.001; HR = 1.355, SD = 0.171, NS), compared with those who did not receive the drugs. Interaction analysis suggested that similar or slightly lower mortality was associated with selective serotonin re-uptake inhibitors, benzodiazepines and second-generation antipsychotics in OSA compared with controls when comorbidities were taken into consideration. CONCLUSION: All-cause mortality was higher in OSA patients and especially controls treated with benzodiazepines, antidepressants or antipsychotics than in untreated controls. The findings were not controlled for psychiatric comorbidity and the results may have partly been attributable to confounding by indication. The results raised the possibility that the use of psychotropic medication may have deleterious health consequences, but the risk did not seem to be higher in OSA than in controls. PMID- 29482807 TI - Increased dopaminergic function in the thalamus is associated with excessive daytime sleepiness. AB - OBJECTIVES/BACKGROUND: Excessive daytime sleepiness (EDS) is a common disorder, which can manifest in isolation or in combination with other neurological or psychiatric disorders. We know relatively little about the mechanisms underlying the development of EDS and the clinical management of patients with EDS remains an unmet need. In this study, we hypothesised that thalamic dopaminergic function would be altered in subjects with EDS and we sought to investigate this by assessing [123I]FP-CIT Single Photon Emission Computed Tomography (SPECT) data, which is a molecular imaging marker of dopamine transporter (DAT). PATIENTS/METHODS: We performed a case-control study using people registered as healthy subjects in the Parkinson's Progression Markers Initiative database. We assessed and compared semi-quantified [123I]FP-CIT-SPECT in two groups of 21 healthy subjects with and without EDS, who were matched for age, gender, years of education and Rapid eyemovement (REM) sleep behaviour disorder (RBD) Questionnaire scores. RESULTS: Our findings show increased thalamic DAT binding in people with EDS compared to matched healthy subjects without EDS. Higher thalamic DAT binding also correlated with worse EDS scores. CONCLUSION: Our findings provide evidence that increased dopaminergic function in the thalamus may mediate excessive daytime sleepiness in humans. PMID- 29482808 TI - A not so incidental finding in a 12-year old with sleepiness and headaches. PMID- 29482809 TI - Differences in rapid eye movement (REM) sleep abnormalities between posttraumatic stress disorder (PTSD) and major depressive disorder patients: REM interruption correlated with nightmare complaints in PTSD. AB - OBJECTIVE: The presence of repeated nightmares in posttraumatic stress disorder (PTSD) has been hypothesized as a dysfunction of rapid eye movement (REM) sleep, but there has been remarkably little agreement about the pathophysiology. This presents a deterrent to more effective treatments. REM sleep abnormalities including elevated REM density also have been replicated in major depressive disorder (MDD). The purpose of this study was to clarify the difference of REM sleep abnormalities between the two disorders for understanding the pathophysiology of sleep disturbances in PTSD. METHODS: Polysomnographic measures were compared among 14 PTSD patients (aged 23.7 +/- 5.5 years) and 14 MDD patients (aged 27.9 +/- 10.1 years) under drug-naive or drug-free conditions. We defined REM interruption by summing the intrusive wake times during the REM period and adding the subsequent wake times to the last epoch of REM period. The significant polysomnographic measures were correlated with PTSD symptoms within the PTSD group. RESULTS: REM interruption was significantly increased in the PTSD group compared with the MDD group (12.2 vs 2.1 min, p = 0.001). REM density was also significantly increased in the PTSD group compared with the MDD group (30.5 vs 23.1%, p = 0.019). Within the PTSD group, we found significant correlations between the severity of trauma-related nightmare complaints and the percentage of REM interruption (R = 0.62, p = 0.017), but not REM density. CONCLUSIONS: REM sleep abnormalities are different between PTSD and MDD. Increased REM interruption may be a biological marker correlated with nightmare complaints in PTSD patients. Treatments including pharmacotherapy that reduces REM interruption might ameliorate nightmares in PTSD. PMID- 29482810 TI - Dyspnea or Cheyne-Stokes respiration associated with Ticagrelor? PMID- 29482811 TI - Prevalence of restless legs syndrome in Parkinson's disease: a systematic review and meta-analysis of observational studies. AB - OBJECTIVE: Restless legs syndrome (RLS) and Parkinson's disease (PD) are common neurological disorders that respond to dopaminergic therapy. RLS prevalence among people with PD varies widely (0-38%) in the literature, complicating efforts to understand whether the two diseases might be associated. METHOD: The databases Web of Science, PubMed, Embase, Chinese National Knowledge Infrastructure, Wanfang, and SinoMed were searched for observational and case-control studies of RLS prevalence in PD. Eligible studies were meta-analyzed using Stata 12.0. RESULTS: Pooled RLS prevalence in PD among various patient populations was 14%, and prevalence in Asia (12%) was slightly lower than outside Asia (16%). Prevalence was higher among patients who had previously received PD treatment (15%) than among drug-naive patients (11%). Prevalence of RLS was higher in female PD patients (13%) than in male patients (11%). RLS prevalence was much higher among PD patients than among healthy controls (OR 2.86, 95% CI 2.10-3.90; p < 0.001). CONCLUSION: This meta-analysis may provide the first reliable pooled estimate of RLS prevalence in PD, and strong evidence that RLS risk is higher among PD patients than among healthy individuals. PMID- 29482812 TI - Restless legs syndrome: a rarity in the Nigerian pregnant population? AB - OBJECTIVES: The prevalence of RLS in pregnancy is higher when compared with the general population however it remains unknown among indigenous black Africans. Available data indicate that RLS is uncommon in sub-Saharan Africa. We embarked on this study to determine the prevalence and characteristics of RLS in an antenatal clinic sample of Nigerian pregnant women compared with a primary care sample of non-pregnant women. METHODS: A total of 310 pregnant women and non pregnant women filled out a questionnaire which incorporated the 2014 minimal criteria of the International Restless Legs Syndrome Study Group. Demographic and clinical data, including sleep duration and samples for blood hemoglobin concentration and urinalysis were obtained. RESULTS: The mean ages of the pregnant and non-pregnant women were 24.9 +/- 5.6 years and 23.6 + 5.4 years, respectively (p = 0.003). There was no case of RLS found among pregnant women while five (1.6%) of the non-pregnant women fulfilled the criteria for RLS. Overall, the prevalence report of RLS symptoms was associated with lower mean habitual nocturnal sleep duration (p < 0.05) coffee (p = 0.013) and kola nut (0.023) consumption, report of leg cramps (p < 0.001) and proteinuria (p = 0.047), Report of leg cramps and proteinuria were independently associated with RLS. CONCLUSION: The prevalence of restless legs syndrome is low among women of child-bearing age in the Nigerian population and may be lower in pregnancy. Report of leg cramps and proteinuria are independently associated with RLS. PMID- 29482813 TI - Sex differences in sleep-disordered breathing after stroke: results from the BASIC project. AB - OBJECTIVE/BACKGROUND: Sleep-disordered breathing (SDB), an independent risk factor for stroke, is associated with worse post-stroke outcomes. Differences in the relationship between SDB and stroke may exist for women versus men. In this population-based study, we compared the prevalence of both pre- and post-stroke SDB by sex. We also explored whether menopausal status is related to post-stroke SDB. PATIENTS/METHODS: We performed a cross-sectional study of subjects enrolled in the Brain Attack Surveillance in Corpus Christi (BASIC) project. Each subject (n = 1815) underwent a baseline interview including the Berlin Questionnaire to assess pre-stroke SDB risk and, if relevant, questions regarding menopausal status. Subjects were offered overnight SDB screening with a validated portable respiratory device (n = 832 with complete data). Log Poisson and linear regression models were used to assess the differences in SDB between men and women with adjustment for demographics, stroke risk factors, stroke severity, and other potential confounders. RESULTS: Women were less likely than men to be at high risk for pre-stroke SDB (56.6% versus 61.9%) (prevalence ratio [PR] 0.87 for women; 95% confidence interval [CI], 0.81-0.95). A lower proportion of women than men (50.8% versus 70.2%) had post-stroke SDB by respiratory monitoring (PR 0.71; 95% CI, 0.63-0.80). SDB severity was higher for men than for women (mean difference in respiratory event index [REI] 6.5; 95% CI, 4.3-8.7). No significant association existed between post-stroke SDB and either menopausal status or age at menopause. CONCLUSIONS: After acute ischemic stroke, SDB was more prevalent and more severe in men than in women. PMID- 29482814 TI - Pre-Sleep Arousal Scale (PSAS): psychometric study of a European Portuguese version. AB - OBJECTIVE/BACKGROUND: Pre-sleep arousal constitutes one of the major features of insomnia. As such, it is imperative to have adequate instruments to measure this construct in both clinical and research settings. The Pre-Sleep Arousal Scale (PSAS) is the most well-known measure to evaluate pre-sleep arousal. The current study aimed to examine some of the psychometric properties of a European Portuguese version of the scale. PARTICIPANTS/METHODS: For this purpose, data from 691 undergraduate students from a medical school were analyzed. Internal consistency indices and factor analysis were performed. In addition, the association between the PSAS and its subscales with other measures was also examined. Finally, PSAS scores of self-reported insomniacs were compared with those of self-reported non-insomniacs. RESULTS: The results indicated that the PSAS comprises a cognitive scale and a somatic scale, both with adequate internal consistency indices (alpha = 0.82 and 0.79, respectively). However, a three factor solution also seemed plausible, suggesting that the original somatic arousal subscale might be divided into two subscales. Significant associations between the PSAS total score and its subscales were found with other concurrent measures such as sleep reactivity to stress, arousability and neuroticism. Self defined insomniacs presented higher levels of cognitive and somatic arousal than healthy individuals. CONCLUSIONS: Further investigations of the PSAS are needed to refine its psychometric properties and explore its research and clinical utility in other populations. PMID- 29482815 TI - Long-term prediction of adherence to continuous positive air pressure therapy for the treatment of moderate/severe obstructive sleep apnea syndrome. AB - BACKGROUND: Continuous positive airway pressure (CPAP) therapy is a highly effective treatment for obstructive sleep apnea syndrome (OSAS). However, poor adherence is a limiting factor, and a significant proportion of patients are unable to tolerate CPAP. The aim of this study was to determine predictors of long-term non-compliance with CPAP. METHODS: CPAP treatment was prescribed to all consecutive patients with moderate or severe OSAS (AHI >=15 events/h) (n = 295) who underwent a full-night CPAP titration study at home between February 1, 2002 and December 1, 2016. Adherence was defined as CPAP use for at least 4 h per night and five days per week. Subjects had periodical follow-up visits including clinical and biochemical evaluation and assessment of adherence to CPAP. RESULTS: Median follow-up observation was 74.8 (24.2/110.9) months. The percentage of OSAS patients adhering to CPAP was 41.4% (42.3% in males and 37.0% in females), and prevalence was significantly higher in severe OSAS than in moderate (51.8% vs. 22.1%; p < 0.001; respectively). At multivariate analysis, lower severity of OSAS (HR = 0.66; CI 95 0.46-0.94) p < 0.023), cigarette smoking (HR = 1.72; CI 95 1.13 2.61); p = 0.011), and previous cardiovascular events (HR = 1.95; CI 95 1.03 3.70; p = 0.04) were the only independent predictors of long-term non-adherence to CPAP after controlling for age, gender, and metabolic syndrome. CONCLUSIONS: In our cohort of patients with moderate/severe OSAS who were prescribed CPAP therapy, long-term compliance to treatment was present in less than half of the patients. Adherence was positively associated with OSAS severity and negatively associated with cigarette smoking and previous cardiovascular events at baseline. PMID- 29482816 TI - Impaired cerebrovascular reactivity in obstructive sleep apnea: a case-control study. AB - OBJECTIVE: Obstructive sleep apnea (OSA) is an independent risk factor for stroke. Little is known about the cerebrovascular hemodynamic changes during apnea. Hypercapnia occurs in apneas and hypopneas, and a reduced cerebral vasodilatory response to CO2 could compromise the cerebral blood flow (CBF). Therefore, we aimed to evaluate whether the apnea-hypopnea index (AHI) affected the cerebrovascular response to CO2. METHODS: A total of 11 patients with OSA were compared to 16 controls. We assessed the cerebrovascular responses with arterial spin labeling (ASL) and blood oxygen level-dependent (BOLD) magnetic resonance imaging during hypercapnia or breath-holding tasks. RESULTS: The CBF response to CO2 was impaired with increasing AHI (average CBF: p = 0.018; gray matter: p = 0.038; white matter: p = 0.045), that is, increased OSA severity. When comparing the OSA patients to the control subjects, the OSA patients had a significantly reduced CO2 response of the white matter CBF (p = 0.04). However, the BOLD response to CO2 and the breath-holding task did not show any significant differences between OSA patients and control subjects. CONCLUSION: The cerebrovascular CO2 reactivity, measured by the CBF, was impaired with increasing AHI, that is, OSA severity. These findings may add to the understanding of the increased stroke risk found in OSA patients. PMID- 29482817 TI - Elevated tau and interleukin-6 concentrations in adults with obstructive sleep apnea. AB - Obstructive sleep apnea (OSA) is characterized by apneas and hypopneas that result in hypoxia, cerebral hypoperfusion, endothelial dysfunction, inflammation, and oxidative stress. These pathophysiologic processes likely contribute to neuronal damage. Tau is a protein that stabilizes microtubules and, along with amyloid beta (Abeta), is associated with neurodegenerative processes. We sought to determine if tau and other biomarkers of inflammation were related to OSA severity. Concentrations of tau, Abeta40, Abeta42, c-reactive protein (CRP), TNF alpha, interleukin (IL)-6, and IL-10 were measured in blood and compared between participants with moderate-severe OSA (n = 28), those with mild OSA (n = 22), and healthy controls (n = 24). The cohort included relatively young, primarily male active duty military personnel without a history of traumatic brain injury or neurodegenerative disease. Total biomarker concentrations were determined from plasma samples using an ultra-sensitive detection method, SimoaTM, and CRP was assayed by ELISA. Total tau and IL-6 concentrations were elevated in participants with moderate-severe OSA, with a mean apnea-hypopnea index (AHI) of 26.1/h, compared to those with mild OSA (mean AHI 8.6/h) and healthy controls (mean AHI 2.1/h). Tau concentrations were also significantly correlated with the AHI (r = 0.342, p = 0.004). Our findings show that tau is elevated in the blood of young patients with moderate-severe OSA, suggesting that this degree of sleep disordered breathing is a contributing factor in the development of neurodegenerative disorders. The finding of increased IL-6 further suggests that inflammatory biomarkers are present early in the course of this chronic disease. PMID- 29482818 TI - The association between sleep disturbances of children with anxiety disorders and those of their mothers. AB - OBJECTIVE: Previous research has demonstrated a link between childhood anxiety and sleep problems, but little is known about the link between these difficulties and parental sleep disturbances. The purpose of the current study was to explore the association between anxious children's sleep difficulties and those of their mothers. METHOD: A total of 101 children aged 8-18 years and their mothers participated in this study. The clinical group included 66 children (mean age = 11.45 years, standard deviation = 2.79 years) diagnosed with anxiety disorders, and the control group included 35 age- and sex-matched normal healthy controls. Mothers completed questionnaires assessing their child's anxiety and sleep, as well as their own sleep. Children completed questionnaires assessing anxiety, sleep, depression, and obsessive symptoms. RESULTS: Both children and mothers in the clinical group exhibited more sleep difficulties compared to controls. A regression analysis revealed that pre-sleep arousal negatively predicted children's sleep. Furthermore, children's anxiety level was associated with parental levels of sleep disturbances. This link was fully mediated by the children's sleep disturbances score. CONCLUSION: Mothers of children with anxiety disorders exhibit higher levels of sleep disturbances than controls. These difficulties are linked to children's anxiety and sleep problems. When treating children with anxiety, it is therefore important to assess their overall sleep disturbances, as well as parental sleep difficulties, and when appropriate to add a specific sleep intervention component. PMID- 29482819 TI - The relationship between excessive daytime sleepiness, disability, and mortality, and implications for life expectancy. AB - OBJECTIVE: To assess the relationship between excessive daytime sleepiness (EDS), disability, mortality, and life expectancy (with and without disability) in a cohort of middle-aged American adults. METHODS: The Wisconsin Longitudinal Study, a life-course study on 10,317 high school graduates from Wisconsin, was used to assess the odds ratio (OR) between EDS in 2004 for prevalent and incident disability to 2011 through multiple logistic regression, and to estimate the hazard ratio (HR) of EDS in 2004 for mortality over ten years through a Cox proportional hazard model. We estimated age and sex-specific rates for mortality and disability from US nation-wide survey data in 2004. Combining these data with age-, sex- and EDS-specific mortality rates and disability prevalence estimated from our study, we constructed Sullivan life tables for those with and without EDS. Life expectancy (total, with, and without disability) from age 60 was estimated for those with and without EDS. RESULTS: The study participants were on average 64 years old and 47% were men. Those with EDS were more likely to develop disability than those without (OR 1.40, 95%CI 1.01-1.95). The HR for mortality associated with having EDS was 1.43 (95%CI 1.11-1.85). The results from life table analysis suggest that a sixty-year-old individual with EDS had a four-year decrease in disability-free life years, and no change in years lived with disability. CONCLUSIONS: EDS is associated with higher likelihood of disability, increased risk of mortality, and substantially shorter disability-free life expectancy at age 60. PMID- 29482820 TI - Night-waking and behavior in preschoolers: a developmental trajectory approach. AB - OBJECTIVE: The aim was to study, with a developmental approach, the longitudinal association between night-waking from age 2 to 5-6 years and behavior at age 5-6 years. METHODS: Within the French birth cohort study Etude sur les Determinants pre et post natals du developpement et de la sante de l'ENfant (EDEN), repeated measures of children's night-waking were collected at age 2, 3 and 5-6 through parental questionnaires and were used to model night-waking trajectories. Behavior was assessed with the "Strengths and Difficulties Questionnaire," which provides five subscales measuring a child's conduct problems, emotional symptoms, peer relation problems, antisocial behavior, and hyperactivity/attention problems. The behavioral subscales were dichotomized at the tenth percentile. Multivariable logistic regressions, adjusted for parents' socio-economic factors, parental characteristics, and children's characteristics and sleep habits allowed us to study, in 1143 children, the association between night-waking trajectories from 2 to 5-6 years and behavior at age 5-6 years. RESULTS: The "2 to 5-6 rare night-waking" trajectory represented 78% of the included population (n = 896), and the "2 to 5-6 common night-waking" 22% (n = 247%). Children belonging to the "2 to 5-6 common night-waking trajectory" had, at age 5-6, increased risk of presenting emotional symptoms (odds ratio [OR] = 2.17, 95% CI = 1.27-3.70, p = 0.004), conduct problems (OR = 1.63, 95% CI = 1.00-2.65, p = 0.050), and hyperactivity/attention problems (OR = 1.61, 95% CI = 1.00-2.57, p = 0.049). After adjusting for baseline behavior at age two years, only the association with emotional symptoms remained significant (OR = 2.02, 95% CI = 1.15-3.55, p = 0.015). Results did not differ according to sex. CONCLUSION: Results suggest that the persistence of night-waking difficulties in early years is positively associated with emotional symptoms, hyperactivity/inattention, and conduct problems. PMID- 29482822 TI - Sensory Cortex Is Nonessential in Working Memory Storage. PMID- 29482821 TI - Association of polysomnographic parameters with clinical symptoms severity grading in Robin sequence patients: a cohort nested cross-sectional study. AB - OBJECTIVES: To evaluate the association of polysomnographic parameters with clinical symptom severity in Robin sequence (RS) patients. METHODS: All patients diagnosed as presenting with RS at Hospital de Clinicas de Porto Alegre from October 2012 to June 2016 were enrolled. They were classified as isolated RS, RS plus, and syndromic RS. Polysomnography (PSG) was performed, except for those patients in need of respiratory support. Symptom severity was evaluated as defined by the Cole et al. CLASSIFICATION: Ordinal OR (for the chance of increase in one grade on the clinical severity scale) and R2 (determination coefficient from ordinal logistic regression) were computed from data analysis. RESULTS: A total of 80 participants were enrolled in the study. Fifty-five of these were able to undergo polysomnography. Worsening of the studied PSG parameters was associated with increase in clinical severity grading, as follows: desaturation index (OR 1.27; 95% CI; 1.07-1.51; R2 = 19.8%; p = 0.006); apnea/hypopnea Index (OR 1.13; 95% CI; 1.01-1.26; R2 = 12.5%; p = 0.02); sleep mean oxygen saturation (OR 0.16; 95% CI; 0.05-0.52; R2 = 22.6%; p = 0.002); oxygen saturation nadir (OR 0.73; 95% CI; 0.56-0.96; R2 = 10.0%; p = 0.02); percentage of time with oxygen saturation <90% (OR 9.49; 95% CI; 1.63-55.31, R2 = 37.6%; p = 0.012); and percentage of time presenting with obstruction (OR 2.5; 95% CI; 1.31-4.76; R2 = 25.1%; p = 0.006). CONCLUSIONS: Polysomnography parameters were associated with severity of clinical manifestations in patients with RS. Oxyhemoglobin saturation based parameters had surprisingly significant R2 values. Therefore, those parameters, which have traditionally been undervalued in other clinical settings, should also be assessed in the polysomnographic evaluation of RS patients. PMID- 29482823 TI - Seeing Other Minds in 3D. PMID- 29482824 TI - Erratum to "The contribution of pathways initiated via the Gq?11 G-protein family to atrial fibrillation" [Pharmacol. Res. 105 (2016) 54-61]. PMID- 29482825 TI - Corrigendum to "The contribution of household chemicals to environmental discharges via effluents: Combining chemical and behavioural data" [J. Environ. Manag. 150 (2015) 427-434]. PMID- 29482826 TI - Change in Low Back Movement Patterns After Neurosurgical Intervention for Lumbar Spondylosis. AB - OBJECTIVES: The purpose of this study was to assess the use of computer-aided combined movement examination (CME) to measure change in low back movement after neurosurgical intervention for lumbar spondylosis and to use a CME normal reference range (NRR) to compare and contrast movement patterns identified from lumbar disk disease, disk protrusion, and nerve root compression cases. METHODS: A test-retest, cohort observational study was conducted. Computer-aided CME was used to record lumbar range of motion in 18 patients, along with pain, stiffness, disability, and health self-report questionnaires. A minimal clinically important difference of 30% was used to interpret meaningful change in self-reports. z Scores were used to compare CME. Post hoc observation included subgrouping cases into 3 discrete pathologic conditions-disk disease, disk protrusion, and nerve root compression-to report intergroup differences in CME. RESULTS: Self-report data indicated that 11, 7, and 10 patients improved by >=30% in pain, stiffness, and function, respectively. Three patients experienced clinically significant improvement in health survey. A CME pattern reduced in all directions suggested disk disease. Unilaterally restricted movement in side-flexed or extended directions suggested posterolateral disk protrusion with or without ipsilateral nerve root compression. Bilateral restrictions in extension suggested posterior disk protrusion with or without nerve root compression. In 11 of the 18 cases, CME converged toward the NRR after surgery. CONCLUSION: We described the use of CME to identify atypical lumbar movement relative to an NRR. Data from this short term postoperative study provide preliminary evidence for CME movement patterns suggestive of disk disease, disk protrusion, and nerve root compression. PMID- 29482827 TI - Chiropractic Integrated Care Pathway for Low Back Pain in Veterans: Results of a Delphi Consensus Process. AB - OBJECTIVE: The purpose of this study was to develop an integrated care pathway for doctors of chiropractic, primary care providers, and mental health professionals who manage veterans with low back pain, with or without mental health comorbidity, within Department of Veterans Affairs health care facilities. METHODS: The research method used was a consensus process. A multidisciplinary investigative team reviewed clinical guidelines and Veterans Affairs pain and mental health initiatives to develop seed statements and care algorithms to guide chiropractic management and collaborative care of veterans with low back pain. A 5-member advisory committee approved initial recommendations. Veterans Affairs based panelists (n = 58) evaluated the pathway via e-mail using a modified RAND/UCLA methodology. Consensus was defined as agreement by 80% of panelists. RESULTS: The modified Delphi process was conducted in July to December 2016. Most (93%) seed statements achieved consensus during the first round, with all statements reaching consensus after 2 rounds. The final care pathway addressed the topics of informed consent, clinical evaluation including history and examination, screening for red flags, documentation, diagnostic imaging, patient reported outcomes, adverse event reporting, chiropractic treatment frequency and duration standards, tailored approaches to chiropractic care in veteran populations, and clinical presentation of common mental health conditions. Care algorithms outlined chiropractic case management and interprofessional collaboration and referrals between doctors of chiropractic and primary care and mental health providers. CONCLUSION: This study offers an integrative care pathway that includes chiropractic care for veterans with low back pain. PMID- 29482828 TI - Uniaxial Tensile Properties of Atherosclerotic Carotid Artery After Mobilization of Pushing on Qiao-Gong: A Safety Study Using an Animal Model of Carotid Atherosclerosis. AB - OBJECTIVES: This study aimed to preliminarily explore the effects of the soft tissue mobilization of pushing on Qiao-Gong (MPQ) on biomechanical properties of the carotid artery using an animal model of carotid atherosclerosis (CAS). METHODS: Fifty rabbits were randomly divided into 4 groups: animals with CAS treated with MPQ (CAS-MPQ [n = 15]); animals with CAS treated without MPQ (CAS [n = 15]); normal animals treated with MPQ (normal-MPQ [n = 10]); and a blank control group (n = 10). The MPQ procedure consisted of soft tissue mobilization of the Qiao-Gong acupoint on the front edge of the sternocleidomastoid muscle applied from top to bottom, by flat pushing with the thumb repeatedly for 20 times. Disease in the CAS models was induced by carotid artery balloon injury combined with a high-fat diet for 12 weeks. At the end of modeling, carotid color Doppler ultrasonography examination was performed to confirm which animal models were successfully induced with CAS, excluding model rabbits without typical CAS at the same time. Then, MPQ was applied on rabbits in the CAS-MPQ and the normal MPQ groups for 3 weeks. By contrast, rabbits in the other 2 groups were fed normally without MPQ. Uniaxial failure tests were later performed on carotid arteries in all 4 groups, and at the end of the study, a 2-way factorial analysis of variance of the results was conducted. RESULTS: (1) At the end of modeling, 10 rabbits in the CAS-MPQ group and 9 in the CAS group were included with typical carotid atherosclerotic characteristics. (2) Young's elastic modulus of the rabbit carotid artery increased more significantly in the CAS-MPQ group than the CAS group. (3) Compared with normal rabbit carotid arteries, atherosclerotic carotid arteries had lower levels of ultimate stress and ultimate strain but higher levels of ultimate load. CONCLUSIONS: The uniaxial tensile mechanical properties of the rabbit atherosclerotic carotid artery were impaired after MPQ. PMID- 29482829 TI - Association of Subclinical Neck Pain With Altered Multisensory Integration at Baseline and 4-Week Follow-up Relative to Asymptomatic Controls. AB - OBJECTIVE: The purpose of this study was to test whether people with subclinical neck pain (SCNP) had altered visual, auditory, and multisensory response times, and whether these findings were consistent over time. METHODS: Twenty-five volunteers (12 SCNP and 13 asymptomatic controls) were recruited from a Canadian university student population. A 2-alternative forced-choice discrimination task with multisensory redundancy was used to measure response times to the presentation of visual (color filled circles), auditory (verbalization of the color words, eg, red or blue), and multisensory (simultaneous audiovisual) stimuli at baseline and 4 weeks later. RESULTS: The SCNP group was slower at both visual and multisensory tasks (P = .046, P = .020, respectively), with no change over 4 weeks. Auditory response times improved slightly but significantly after 4 weeks (P = .050) with no group difference. CONCLUSIONS: This is the first study to report that people with SCNP have slower visual and multisensory response times than asymptomatic individuals. These differences persist over 4 weeks, suggesting that the multisensory technique is reliable and that these differences in the SCNP group do not improve on their own in the absence of treatment. PMID- 29482830 TI - Discussion of "Panniculectomy after bariatric surgical weight loss: Analysis of complications and modifiable risk factors". PMID- 29482832 TI - Discussion of "Total intracorporeal anastomosis for right hemicolectomy: Experience from a Canadian center". PMID- 29482831 TI - Sustained culture and surgical outcome improvement. AB - BACKGROUND: A focus on the culture of safety and patient outcomes continues to grow in importance. Several initiatives targeted at individual deficits have been described but few institutions have shown the effect of a global change in culture on patient outcomes. METHODS: Patient care perception was assessed using Safety Attitudes Questionnaire (SAQ) by Pascal Metrics(r). A change in culture was initiated, followed by implementation of initiatives targeting communication and patient safety. ACS-NSQIP data was analyzed to assess outcomes during the period of improved culture. RESULTS: Our institution had poor outcomes as measured by ACS-NSQIP data and several deficiencies in our culture score. Both statistically improved after initiative implementation. A difference in mean culture score across time (p < 0.001 = .031) was seen from 2013 to 2015, while NSQIP odds ratios falling in the 'exemplary' category increased. CONCLUSION: Our results demonstrate an improvement in both culture and outcomes from 2013 to 2015, suggesting a correlation between culture and surgical outcomes. PMID- 29482833 TI - Correction to: 'The Warburg Effect: How Does it Benefit Cancer Cells?': [Trends in Biochemical Sciences, 41 (2016) 211]. PMID- 29482834 TI - Data-driven adaptive fractional order PI control for PMSM servo system with measurement noise and data dropouts. AB - In this paper, data-driven adaptive fractional order proportional integral (AFOPI) control is presented for permanent magnet synchronous motor (PMSM) servo system perturbed by measurement noise and data dropouts. The proposed method directly exploits the closed-loop process data for the AFOPI controller design under unknown noise distribution and data missing probability. Firstly, the proposed method constructs the AFOPI controller tuning problem as a parameter identification problem using the modified lp norm virtual reference feedback tuning (VRFT). Then, iteratively reweighted least squares is integrated into the lp norm VRFT to give a consistent compensation solution for the AFOPI controller. The measurement noise and data dropouts are estimated and eliminated by feedback compensation periodically, so that the AFOPI controller is updated online to accommodate the time-varying operating conditions. Moreover, the convergence and stability are guaranteed by mathematical analysis. Finally, the effectiveness of the proposed method is demonstrated both on simulations and experiments implemented on a practical PMSM servo system. PMID- 29482835 TI - Reliability analysis of a phaser measurement unit using a generalized fuzzy lambda-tau(GFLT) technique. AB - Nowadays power consumption is increasing day-by-day. To fulfill failure free power requirement, planning and implementation of an effective and reliable power management system is essential. Phasor measurement unit(PMU) is one of the key device in wide area measurement and control systems. The reliable performance of PMU assures failure free power supply for any power system. So, the purpose of the present study is to analyse the reliability of a PMU used for controllability and observability of power systems utilizing available uncertain data. In this paper, a generalized fuzzy lambda-tau (GFLT) technique has been proposed for this purpose. In GFLT, system components' uncertain failure and repair rates are fuzzified using fuzzy numbers having different shapes such as triangular, normal, cauchy, sharp gamma and trapezoidal. To select a suitable fuzzy number for quantifying data uncertainty, system experts' opinion have been considered. The GFLT technique applies fault tree, lambda-tau method, fuzzified data using different membership functions, alpha-cut based fuzzy arithmetic operations to compute some important reliability indices. Furthermore, in this study ranking of critical components of the system using RAM-Index and sensitivity analysis have also been performed. The developed technique may be helpful to improve system performance significantly and can be applied to analyse fuzzy reliability of other engineering systems. PMID- 29482836 TI - Myeloid cell heterogeneity in cancer: not a single cell alike. AB - Tumors of various histological origins show abundant infiltration of myeloid cells from early stages of disease progression. These cells have a profound impact on antitumor immunity and influence fundamental processes that underlie malignancy, including neoangiogenesis, sustained cancer cell proliferation, metastasis and therapy resistance. For these reasons, development of therapeutic approaches to deplete or reprogram myeloid cells in cancer is an emerging field of interest. However, knowledge about the heterogeneity of myeloid cells in tumors and their variability between patients and disease stages is still limited. In this review, we summarize the most recent advances in our understanding about how the phenotype of tumor-associated macrophages, monocytes, neutrophils, myeloid-derived suppressor cells and dendritic cells is dictated by their ontogeny, activation status and localization. We also outline major open questions that will only be resolved by applying high-dimensional single-cell technologies and systems biology approaches in the analysis of the tumor microenvironment. PMID- 29482837 TI - Letter to the Editor concerning "Pilon fractures: A new classification system based on CT-scan" by Danilo Leonetti, *, Domenico Tigani (2017). Injury. 2017 Oct;48(10):2311-2317. PMID- 29482838 TI - Radical parametrectomy after 'cut-through' hysterectomy in low-risk early-stage cervical cancer: Time to consider this procedure obsolete. AB - OBJECTIVE: The goal of this study is to identify predictive factors in patients with a diagnosis of early-stage cervical cancer after simple hysterectomy in order to avoid a radical parametrectomy. METHODS: A retrospective review was performed of all patients who underwent radical parametrectomy and bilateral pelvic lymphadenectomy at MD Anderson Cancer Center and at the Instituto de Cancerologia Las Americas in Medellin, Colombia from December 1999 to September 2017. We sought to determine the outcomes in patients diagnosed with low-risk factors (squamous, adenocarcinoma or adenosquamous lesions<2cm in size, and invading<10mm) undergoing radical parametrectomy and pelvic lymphadenectomy. RESULTS: A total of 30 patients were included in the study. The median age was 40.4years (range; 26-60) and median body mass index (BMI) was 26.4kg/m2 (range; 17.7-40.0). A total 22 patients had tumors<1cm and 8 had tumors between 1 and 2cm. A total of 6 (33%) of 18 patients had evidence of lymph-vascular invasion (LVSI). No radical parametrectomy specimen had residual tumor, involvement of the parametrium, vaginal margin positivity, or lymph node metastasis. None of the patients received adjuvant therapy. After a median follow-up of 99months (range; 6-160) only one patient recurred. CONCLUSION: Radical parametrectomy may be avoided in patients with low-risk early-stage cervical cancer detected after a simple hysterectomy. Rates of residual disease (parametrial or vaginal) and the need for adjuvant treatments or recurrences are very low. PMID- 29482840 TI - Characteristics of team briefings in gynecological surgery. AB - Preoperative briefings have been proven beneficial for improving team performance in the operating room. However, there has been minimal research regarding team briefings in specific surgical domains. As part of a larger project to develop a briefing structure for gynecological surgery, the study aimed to better understand the current state of pre-operative team briefings in one department of an academic hospital. Twenty-four team briefings were observed and video recorded. Communication was analyzed and social network metrics were created based on the team member verbal interactions. Introductions occurred in only 25% of the briefings. Network analysis revealed that average team briefings exhibited a hierarchical structure of communication, with the surgeon speaking the most frequently. The average network for resident-led briefings displayed a non hierarchical structure with all team members communicating with the resident. Briefings conducted without a standardized protocol can produce variable communication between the role leading and the team members present. PMID- 29482839 TI - Levonorgestrel-releasing intrauterine system use is associated with a decreased risk of ovarian and endometrial cancer, without increased risk of breast cancer. Results from the NOWAC Study. AB - OBJECTIVE: Women with ovarian cancer have poor survival rates, which have proven difficult to improve; therefore primary prevention is important. The levonorgestrel-releasing intrauterine system (LNG-IUS) prevents endometrial cancer, and recent studies suggested that it may also prevent ovarian cancer, but with a concurrent increased risk of breast cancer. We compared adjusted risks of ovarian, endometrial, and breast cancer in ever users and never users of LNG-IUS. METHODS: Our study cohort consisted of 104,318 women from the Norwegian Women and Cancer Study, 9144 of whom were ever users and 95,174 of whom were never users of LNG-IUS. Exposure information was taken from self-administered questionnaires, and cancer cases were identified through linkage to the Cancer Registry of Norway. Relative risks (RRs) with 95% confidence intervals (CIs) were estimated with Poisson regression using robust error estimates. RESULTS: Median age at inclusion was 52years and mean follow-up time was 12.5 (standard deviation 3.7) years, for a total of 1,305,435 person-years. Among ever users of LNG-IUS there were 18 cases of epithelial ovarian cancer, 15 cases of endometrial cancer, and 297 cases of breast cancer. When ever users were compared to never users of LNG IUS, the multivariable RR of ovarian, endometrial, and breast cancer was 0.53 (95% CI: 0.32, 0.88), 0.22 (0.13, 0.40), and 1.03 (0.91, 1.17), respectively. CONCLUSION: In this population-based prospective cohort study, ever users of LNG IUS had a strongly reduced risk of ovarian and endometrial cancer compared to never users, with no increased risk of breast cancer. PMID- 29482841 TI - In Patients With ST-Segment Elevation Myocardial Infarction, Which Fibrinolytic Agent Is the Safest and Most Effective? PMID- 29482843 TI - The arrival of axilla conserving therapy (ACT). Is this the second revolution in locoregional management of breast cancer care? PMID- 29482844 TI - After neoadjuvant chemoradiation therapy, predicted pulmonary function may be reduced by 10. PMID- 29482842 TI - The Pharmacology of CD38/NADase: An Emerging Target in Cancer and Diseases of Aging. AB - Recent reports indicate that intracellular NAD levels decline in tissues during chronological aging, and that therapies aimed at increasing cellular NAD levels could have beneficial effects in many age-related diseases. The protein CD38 (cluster of differentiation 38) is a multifunctional enzyme that degrades NAD and modulates cellular NAD homeostasis. At the physiological level, CD38 has been implicated in the regulation of metabolism and in the pathogenesis of multiple conditions including aging, obesity, diabetes, heart disease, asthma, and inflammation. Interestingly, many of these functions are mediated by CD38 enzymatic activity. In addition, CD38 has also been identified as a cell-surface marker in hematologic cancers such as multiple myeloma, and a cytotoxic anti-CD38 antibody has been approved by the FDA for use in this disease. Although this is a remarkable development, killing CD38-positive tumor cells with cytotoxic anti CD38 antibodies is only one of the potential pharmacological uses of targeting CD38. The present review discusses the biology of the CD38 enzyme and the current state of development of pharmacological tools aimed at CD38, and explores how these agents may represent a novel approach for treating human conditions including cancer, metabolic disease, and diseases of aging. PMID- 29482845 TI - Exosome signaling: A ubiquitous process in rejection and regeneration? PMID- 29482846 TI - Is it possible that radiotherapy for local control does not matter in patients with esophageal adenocarcinoma? More studies are needed. PMID- 29482847 TI - Imaging and scopes? It's bloody time for another branch in the decision tree. PMID- 29482848 TI - Exuberance meets harsh realities in the bioprosthetic tissue valve era. PMID- 29482849 TI - Meta-analysis is not an exact science: Call for guidance on quantitative synthesis decisions. AB - Meta-analysis is becoming increasingly popular in the field of ecology and environmental management. It increases the effective power of analyses relative to single studies, and allows researchers to investigate effect modifiers and sources of heterogeneity that could not be easily examined within single studies. Many systematic reviewers will set out to conduct a meta-analysis as part of their synthesis, but meta-analysis requires a niche set of skills that are not widely held by the environmental research community. Each step in the process of carrying out a meta-analysis requires decisions that have both scientific and statistical implications. Reviewers are likely to be faced with a plethora of decisions over which effect size to choose, how to calculate variances, and how to build statistical models. Some of these decisions may be simple based on appropriateness of the options. At other times, reviewers must choose between equally valid approaches given the information available to them. This presents a significant problem when reviewers are attempting to conduct a reliable synthesis, such as a systematic review, where subjectivity is minimised and all decisions are documented and justified transparently. We propose three urgent, necessary developments within the evidence synthesis community. Firstly, we call on quantitative synthesis experts to improve guidance on how to prepare data for quantitative synthesis, providing explicit detail to support systematic reviewers. Secondly, we call on journal editors and evidence synthesis coordinating bodies (e.g. CEE) to ensure that quantitative synthesis methods are adequately reported in a transparent and repeatable manner in published systematic reviews. Finally, where faced with two or more broadly equally valid alternative methods or actions, reviewers should conduct multiple analyses, presenting all options, and discussing the implications of the different analytical approaches. We believe it is vital to tackle the possible subjectivity in quantitative synthesis described herein to ensure that the extensive efforts expended in producing systematic reviews and other evidence synthesis products is not wasted because of a lack of rigour or reliability in the final synthesis step. PMID- 29482850 TI - A heterogeneous tRNA granule structure exhibiting rapid, bi-directional neuritic transport. AB - mRNA translation is regulated by diverse mechanisms that converge at the initiation and elongation steps to determine the rate, profile, and localization of proteins synthesized. A consistently relevant feature of these mechanisms is the spatial re-distribution of translation machinery, a process of particular importance in neural cells. This process has, however, been largely overlooked with respect to its potential role in regulating the local concentration of cytoplasmic tRNAs, even as a multitude of data suggest that spatial regulation of the tRNA pool may help explain the remarkably high rates of peptide elongation. Here, we report that Cy3/Cy5-labeled bulk tRNAs transfected into neural cells distribute into granule-like structures - "tRNA granules" - that exhibit dynamic mixing of tRNAs between granules and rapid, bi-directional vectorial movement within neurites. Imaging of endogenous tRNAgly and tRNAlys by fluorescent in situ hybridization revealed a similar granular distribution of tRNAs in somata and neurites; this distribution was highly overlapping with granules imaged by introduction of exogenous Cy5-tRNAthr and Cy3-tRNAval. A subset of tRNA granules located in the cell body, neurite branch points and growth cones displayed fluorescence resonance energy transfer (FRET) between Cy3 and Cy5-labeled tRNAs indicative of translation, and co-localization with elongation machinery. A population of smaller, rapidly trafficked granules in neurites lacked FRET and showed poor colocalization with translation initiation and elongation factors, suggesting that they are a translationally inactive tRNA transport particle. Our data suggest that tRNAs are packaged into granules that are rapidly transported to loci where translation is needed, where they may greatly increase the local concentration of tRNAs in support of efficient elongation. The potential implications of this newly described structure for channeling of elongation, local translation, and diseases associated with altered tRNA levels or function are discussed. PMID- 29482851 TI - Relation of Waist-Hip Ratio to Long-Term Cardiovascular Events in Patients With Coronary Artery Disease. AB - We aimed to assess the association between measures of obesity and outcomes in coronary artery disease (CAD) patients. We included consecutive patients referred to cardiac rehabilitation for previous CAD events, who were classified using body mass index (BMI) groups and gender-specific tertiles of waist-to-hip ratio (WHR). Follow-up was ascertained using a population-based, record linkage system. Major cardiovascular event (MACE) was defined as the composite outcome including acute coronary syndromes, coronary revascularization, ventricular arrhythmias, stroke, or death from any cause. We used Cox proportional hazards models adjusted for potential confounders. The cohort included 1,529 patients (74% men), 63.1 +/- 12.5 years (mean age +/- SD), of whom 40% were obese by BMI. Eighty-eight percent of men and 57% of women were classified as having central obesity by WHR. Median follow-up was 5.7 years and 415 patients had MACE. After adjustment, a high WHR tertile was a significant predictor for MACE in women (hazard ratio [HR] 1.85, 95% confidence interval [CI] 1.16, 2.94, p = 0.01) but not in men (HR 0.92, 95% CI 0.69, 1.22, p = 0.54). This relation in women persisted after further adjustment for BMI (HR 1.75, 95% CI 1.07, 2.87, p = 0.03). Obesity by BMI was not associated with MACE in either men (HR 1.07, 95% CI 0.76, 1.51, p = 0.69) or women (HR 0.98, 95% CI 0.62, 1.56, p = 0.95). In conclusion, WHR is associated with a higher risk of MACE among women with CAD but not in men. There was no obesity paradox when assessing obesity by BMI in patients with CAD when including nonfatal events. PMID- 29482852 TI - Sutureless Versus Conventional Pulmonary Vein Repair: A Magnetic Resonance Pilot Study. AB - BACKGROUND: Two different surgical techniques are used to repair anomalous pulmonary venous connection or pulmonary vein (PV) stenosis: the classic repair (CR) and the sutureless repair (SR). The purpose of this study was to compare the prevalence of PV stenosis between the two surgical approaches. METHODS: Patients were prospectively recruited irrespective of symptoms or previous imaging findings. Cardiac magnetic resonance imaging and echocardiography were performed in a blinded fashion on the same day. RESULTS: Twenty-five patients (13 male) after PV repair completed the study. Twelve patients had undergone CR and 13 SR (in 1 patient as a reoperation after CR). The median age at operation was 2 months (range: 1 day to 5 years) and was similar for both groups; the median age at the time of cardiac magnetic resonance was 9 years (range: 6 to 17 years) and 9 years (range: 6 to 14 years) for the CR and SR, respectively. Four patients had PV stenosis. All 4 patients had had total anomalous pulmonary venous connection, 1 patient had undergone repair with the CR and 2 with a primary SR; 1 patient had first undergone a CR, followed by a SR for stenosis. Echocardiography provided complete visualization of all PVs in only 11 patients (44%). Notable stenosis of at least one PV was missed by echocardiography in 2 patients. CONCLUSIONS: This pilot study indicates that not only CR but also SR may be burdened by a risk of postoperative PV stenosis. Magnetic resonance imaging should be used routinely for the postoperative monitoring for the development of PV obstruction. PMID- 29482853 TI - A huge infected necrotic submucosal leiomyoma in association with advanced uterovaginal prolapse. PMID- 29482854 TI - Direct shedding of endometrioma contents through the follicle rupture: Insight on the pathogenesis of endometriosis. PMID- 29482855 TI - Successful pregnancy outcome in Eisenmenger's syndrome during pregnancy. PMID- 29482856 TI - Corrigendum to "Associations of neurofunctional, morphometric and metabolic abnormalities with clinical symptom severity and recognition deficit in obsessive compulsive disorder" [J. Affect. Disord. 227 (2018) 603-612]. PMID- 29482858 TI - Biomechanical Evaluation of a Transtendinous All-Suture Anchor Technique Versus Interference Screw Technique for Suprapectoral Biceps Tenodesis in a Cadaveric Model. AB - PURPOSE: To compare the biomechanical properties of an transtendinous all-suture anchor technique with the commonly-accepted interference screw technique in a cadaveric model. METHODS: Sixteen fresh-frozen human cadaveric shoulders (mean age, 67.6 +/- 5.8 years) were used and were randomly divided into 2 experimental long head of the biceps brachii (LHB) tenodesis groups (n = 8), namely transtendinous all-suture anchor technique and interference screw technique. The location of tenodesis was in the bicipital groove, 1 cm distal to the proximal border of the bicipital groove. Tensile force parallel to the longitudinal axis of the humerus was applied to each specimen. A preload of 5 N was applied for 2 minutes, followed by cyclic loading for 500 cycles from 5 to 70 N at 1 Hz; then, a load-to-failure test at 1 mm/s was performed. The ultimate failure load, stiffness, cyclic displacement, failure displacement, and failure modes were recorded. RESULTS: The transtendinous all-suture anchor technique provided similar ultimate failure load and stiffness as the interference screw technique. However, the cyclic and failure displacements of the transtendinous all-suture anchor technique were significantly greater than the interference screw technique (P = .009 and .021, respectively). Six specimens in the transtendinous all-suture anchor group failed because of suture anchor pullout, while failure of the other 2 was caused by tendon tear; by contrast, all specimens in the interference screw group failed because of tendon tear. CONCLUSIONS: The transtendinous all-suture anchor technique for LHB tenodesis offered equivalent ultimate failure load and stiffness but had significantly larger cyclic and failure displacement values when compared with the interference screw technique in this cadaveric biomechanical study. CLINICAL RELEVANCE: The transtendinous all-suture anchor technique is an alternative technique for suprapectoral LHB tenodesis; however, care should be taken because only time zero biomechanical data are available. PMID- 29482857 TI - Cognitive function in Japanese women with posttraumatic stress disorder: Association with exercise habits. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) has been associated with cognitive impairments, yet little is documented on the cognitive function of PTSD patients in Asian countries. It is shown that regular exercise can reduce PTSD symptoms, while no study has investigated the association between exercise and cognition in PTSD patients. This study aimed to examine cognitive functions of Japanese women with PTSD, and to explore the association between regular exercise and cognitive functions. METHODS: Forty-two women with DSM-IV PTSD and 66 demographically matched healthy control women participated in this study. Most of the patients developed PTSD after experiencing interpersonal violence. Cognitive functions were assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Regular exercise habit was assessed by a self reported questionnaire. RESULTS: Compared to controls, PTSD patients performed significantly more poorly in all cognitive domains examined, including immediate memory, visuospatial construction, language, attention, delayed memory, as well as the total score of RBANS (all p < 0.001). Compared to PTSD patients without the habit of exercise, those who habitually exercised showed significantly better performance on delayed memory (p = 0.006), which survived after controlling for potentially confounding variables in a multiple regression model. LIMITATIONS: The cross-sectional design and relatively small sample size limited our findings. CONCLUSIONS: PTSD in Japanese women is associated with pervasively impaired cognitive functions, including notable impairments in verbal memory. Such memory deficits might be improved by regular exercise, although further studies are needed to investigate the causal relationship between exercise and cognition in PTSD. PMID- 29482859 TI - Magnetic Resonance Imaging and Functional Outcomes After a Polyurethane Meniscal Scaffold Implantation: Minimum 5-Year Follow-up. AB - PURPOSE: To report the magnetic resonance imaging (MRI) and clinical outcomes at a minimum 5-year follow-up in a series of patients with postmeniscectomy syndrome and treated with a polyurethane scaffold. METHODS: All consecutive patients operated on from September 2008 to February 2011 for either persistent medial or lateral joint line compartmental pain receiving a polyurethane scaffold due to a previous partial meniscus resection with a minimum 5-year follow-up were included. Functional scores (Knee Injury and Osteoarthritis Outcomes Score, International Knee Documentation Committee, Lysholm, and Tegner) were assessed preoperatively and at the last follow-up. The state of the scaffold as well as postoperative scaffold extrusion and the total remaining meniscal volume was also evaluated in MRI. RESULTS: Thirty-two patients were included. The mean follow-up was 70.8 +/- 7.5 months. The functionality of the knees improved in all the scores used (P < .001) except for the Tegner score that stayed steady. Most of meniscal implants showed extrusion of 2.4 mm (95% confidence interval [CI], 1.1 3.7) were smaller and a hyperintensity signal was seen in the MRI. Three scaffolds were resorbed at the last follow-up. The meniscal volume, determined by MRI, was 1.14 cm3 (95% CI, 0.96-1.31) preoperatively and 1.61 cm3 (95% CI, 1.43 1.7) at the last follow-up. No differences were presented. CONCLUSIONS: The use of a polyurethane meniscal scaffold in patients with a symptomatic meniscus deficit had a good functional outcome at 5 years after surgery. However, the implanted scaffolds did not present normal meniscal tissue with MRI, and the implant volume was considerably less than expected. The fact that most of patients included received different concomitant procedures during scaffold implantation introduces a degree of performance bias into the results. LEVEL OF EVIDENCE: Level IV, case series. PMID- 29482860 TI - Performance, Return to Play, and Career Longevity After Ulnar Collateral Ligament Reconstruction in Professional Catchers. AB - PURPOSE: The purpose of our study was to evaluate return to play and postinjury performance of professional catchers who sustained an ulnar collateral ligament (UCL) rupture requiring surgical reconstruction. We looked to evaluate these players to determine the rate of return to play, the level of return to play, and career longevity after surgery as well as how statistical performance is affected by reconstruction. METHODS: Twenty-five professional catchers who underwent UCL reconstruction between 1985 and 2015 were identified and compared with an age-, position-, and competition-matched control group. Priority was placed on level of play, year of injury, age, and years played prior to injury in matching controls. Injury information and demographic data (age at injury, level of play, and career length) were collected from publicly available team websites and press releases. Offensive and defensive performance statistics were collected for 3 years prior to injury and 3 years after return. Return to play, return to level of play, and career after return were also analyzed. RESULTS: The average age at time of UCL injury was 24.4 (standard deviation, 4.5) years old. Return to play for all catchers was 80% (20/25), with only one player not returning to the same previous level of play (95%). Average years in Major League Baseball (MLB) after return was 2.3 years versus 2.6 years in the control group (P = .07), with 4.3 years total (MLB and minors) versus 3.8 years total in the control group (P = .28). There were no changes in offensive or defensive performance before and after injury. CONCLUSIONS: UCL reconstruction in professional catchers can lead to successful outcomes. Catchers can expect a high rate of return to play with high rate of return to previous level of play, similar performance, and no change in career longevity following return from UCL reconstruction. STUDY DESIGN: Level III, case-control series. PMID- 29482861 TI - What Is the Risk Posed to the Lateral Femoral Cutaneous Nerve During the Use of the Anterior Portal of Supine Hip Arthroscopy and the Minimally Invasive Anterior Approach for Total Hip Arthroplasty? AB - PURPOSE: To determine: (1) What is the proximity of the lateral femoral cutaneous nerve (LFCN) to the anterior portal (AP) used in supine hip arthroscopy? (2) What is the proximity of the LCFN to the incision in the minimally invasive anterior approach (MIAA) for total hip arthroplasty? (3) What effect does lateralizing the AP have on the likelihood of nerve injury? (4) What branching patterns are observable in the LFCN? METHODS: Forty-five hemipelves were dissected. The LFCN was identified and its path dissected. The positions of the nerve in relation to the AP and the MIAA incision were measured. RESULTS: The AP intersected with 38% of nerves. In the remainder, the LFCN was located 5.7 +/- 4.5 mm from the portal's edge. In addition, 44% of nerves crossed the incision of the MIAA. Of those that did not, the average minimum distance from the incision was 14.4 +/- 7.0 mm. We found a significant reduction in risk if the AP is moved medially by 5 mm or laterally by 15 mm (P = .0054 and P = .0002). The LFCN showed considerable variation with 4 branching variants. CONCLUSIONS: These results show that the LFCN is at high risk during supine hip arthroscopy and the MIAA, emphasizing the need for meticulous dissection. We suggest that relocation of the AP 5 mm medially or 15 mm laterally will reduce the risk to the LFCN. CLINICAL RELEVANCE: These findings should aid surgeons in minimizing the risk to the LCFN during hip arthroscopy and the minimally invasive anterior approach to the hip. PMID- 29482862 TI - Meniscal Allograft Transplantation: The Effect of Cartilage Status on Survivorship and Clinical Outcome. AB - PURPOSE: To evaluate the survivorship of meniscal allograft transplantations (MATs), their clinical outcomes, and to compare the effect of perioperative cartilage status on survivorship. METHOD: A consecutive series of MATs with a minimum postsurgical time of 4 years were included from a prospectively collected database from 2001 to 2015. Mechanical failure was defined as transplant removal or knee arthroplasty. The effect of peri-operative cartilage status on survivorship was analyzed using a Kaplan-Meier analysis. Also, pre- and postoperative outcome scores were evaluated. The clinical outcome tools used were the Lysholm Knee Scoring Scale, Tegner Activity Level Scale, Oxford Knee Score (OKS) and International Knee Documentation Committee (IKDC) subjective knee form. RESULTS: The mean (+/-SD) postsurgical follow-up (n = 45 MATs, 43 knees) was 8.6 +/- 3.4 years. Among the 45 MATs, 31 had an Outerbridge Cartilage Score (OCS) of 3 to 4. Eight transplants (17.7%) failed at an average of 6.1 +/- 4.4 years postoperatively, and all occurred in patients with an OCS of 3 to 4. Functional outcomes showed significant improvement in the Lysholm by 17.7 points (95% confidence interval [CI], 8.5-26.9, P < .001), OKS by 8 (CI, 0.81-15.11, P = .031), and IKDC scores by 15.6 (CI, 6-25.2, P = .001). However, the Tegner score improvement by 0.6 was not statistically significant (CI, 0.3545-1.6212, P = .2). In a subanalysis, the OCS 3-4 group had a significant improvement in all the clinical outcomes except the Tegner score. In the OCS 0-2 group, the Lysholm and Tegner significantly improved, whereas the improvement in the OKS and IKDC was not significant. CONCLUSIONS: MAT is a viable and effective surgical option for the painful meniscus-deficient knee, with good survivorship and functional outcomes in the medium to long term. Mechanical failure is associated with advanced OCS. Patients with minimal cartilage damage have improved MAT survivorship but both groups benefit clinically. LEVEL OF EVIDENCE: Level IV, case series. PMID- 29482863 TI - Clinical Characteristics and Outcomes Associated With High-Dose Intravenous Thiamine Administration in Patients With Encephalopathy. AB - BACKGROUND: Wernicke encephalopathy is a common neuropsychiatric syndrome due to thiamine deficiency. There is no consensus regarding thiamine dosing when Wernicke encephalopathy is suspected. A longstanding dosing strategy for Wernicke encephalopathy is 100mg daily, yet updated clinical guidelines suggest using high dose intravenous (HDIV) thiamine. OBJECTIVE: To describe thiamine prescribing practices at a large, public academic hospital and investigate clinical characteristics and outcomes associated with HDIV thiamine in patients with encephalopathy who received IV thiamine. METHODS: Electronic medical records of hospitalized patients who received thiamine between 4/4/2014 and 11/1/2015 were reviewed. Chi-square tests, Wilcoxon Rank Sum tests, and logistic regression were used to compare clinical variables in patients with encephalopathy who received HDIV thiamine (>= 200mg twice daily) vs lower doses of IV thiamine. RESULTS: Among the total of 5236 thiamine orders, 29% (n = 1531) were IV; 10% (n = 150) of IV orders met HDIV criteria. In patients with encephalopathy who received IV thiamine (n = 432), HDIV thiamine was administered to 20% (n = 86) and only 2.1% (n = 9) received dosing consistent with Royal College of Physicians guidelines. In bivariable analyses, HDIV thiamine was associated with surgical services (p = 0.001), psychiatric consultation (p < 0.001), and decreased mortality (p = 0.004). In multivariable models, the association between HDIV thiamine and decreased in-hospital mortality did not meet statistical significance (p = 0.061). CONCLUSIONS: In a large, public academic hospital, guideline-concordant thiamine supplementation is rare and HDIV thiamine is infrequently prescribed to patients with encephalopathy. Further studies are needed to confirm the possible benefits of HDIV thiamine for patients with suspected thiamine-deficient encephalopathy. PMID- 29482864 TI - Laser Peripheral Iridotomy in Primary Angle Closure: A Report by the American Academy of Ophthalmology. AB - PURPOSE: To examine the efficacy and complications of laser peripheral iridotomy (LPI) in subjects with primary angle closure (PAC). METHODS: Literature searches in the PubMed and Cochrane databases were last conducted in August 2017 and yielded 300 unique citations. Of these, 36 met the inclusion criteria and were rated according to the strength of evidence; 6 articles were rated level I, 11 articles were rated level II, and 19 articles were rated level III. RESULTS: Reported outcomes were change in angle width, effect on intraocular pressure (IOP) control, disease progression, and complications. Most of the studies (29/36, 81%) included only Asian subjects. Angle width (measured by gonioscopy, ultrasound biomicroscopy, and anterior segment OCT) increased after LPI in all stages of angle closure. Gonioscopically defined persistent angle closure after LPI was reported in 2% to 57% of eyes across the disease spectrum. Baseline factors associated with persistent angle closure included narrower angle and parameters representing nonpupillary block mechanisms of angle closure, such as a thick iris, an anteriorly positioned ciliary body, or a greater lens vault. After LPI, further treatment to control IOP was reported in 0%-8% of PAC suspect (PACS), 42% to 67% of PAC, 21% to 47% of acute PAC (APAC), and 83%-100% of PAC glaucoma (PACG) eyes. Progression to PACG ranged from 0% to 0.3% per year in PACS and 0% to 4% per year in PAC. Complications after LPI included IOP spike (8-17 mmHg increase from baseline in 6%-10%), dysphotopsia (2%-11%), anterior chamber bleeding (30%-41%), and cataract progression (23%-39%). CONCLUSIONS: Laser peripheral iridotomy increases angle width in all stages of primary angle closure and has a good safety profile. Most PACS eyes do not receive further intervention, whereas many PAC and APAC eyes, and most PACG eyes, receive further treatment. Progression to PACG is uncommon in PACS and PAC. There are limited data on the comparative efficacy of LPI versus other treatments for the various stages of angle closure; 1 randomized controlled trial each demonstrated superiority of cataract surgery over LPI in APAC and of clear lens extraction over LPI in PACG or PAC with IOP above 30 mmHg. PMID- 29482865 TI - Editorial. PMID- 29482866 TI - Retraction notice to " Bioaccumulation and physiological responses to lead (Pb) in Chenopodium murale L."[YEESA(2018)83-90]. PMID- 29482867 TI - [Asthma and the microbiome]. AB - INTRODUCTION: It has been demonstrated recently that the respiratory tract, considered for a long time to be sterile in the healthy subject, contains a vast community of bacteria called the respiratory microbiome. This microbiome, like the intestinal microbiome, is in constant interaction with the immune system of the human host. This relationship has allowed us to formulate some new theories on the pathophysiology of asthma. BACKGROUND: The respiratory microbiome of the asthmatic differs quantitatively and qualitatively from that of the healthy subject. Equally there seem to be differences in the microbiome according to the degree of severity of the asthma and the response to treatment with corticosteroids. It has been shown in murine models of allergic asthma that an early disturbance of the microbiome by different perinatal factors could be responsible for disorders of the development of the immune system, leading to the development of asthma in the long term. OUTLOOK: As a disorder of the microbiome might be implicated in the pathophysiology of asthma, the maintenance or restoration of a healthy microbiome is emerging as a possible new strategy in the management of the disease. CONCLUSION: The implication of the microbiome in the pathogenesis of human asthma seems to be more and more likely. This could have possible therapeutic implications, notably the restoration of a healthy microbiome. PMID- 29482868 TI - Characterization and high-quality draft genome sequence of Herbivorax saccincola A7, an anaerobic, alkaliphilic, thermophilic, cellulolytic, and xylanolytic bacterium. AB - An anaerobic, cellulolytic-xylanolytic bacterium, designated strain A7, was isolated from a cellulose-degrading bacterial community inhabiting bovine manure compost on Ishigaki Island, Japan, by enrichment culture using unpretreated corn stover as the sole carbon source. The strain was Gram-positive, non-endospore forming, non-motile, and formed orange colonies on solid medium. Strain A7 was identified as Herbivorax saccincola by DNA-DNA hybridization, and phylogenetic analysis based on 16S rRNA gene sequences showed that it was closely related to H. saccincola GGR1 (= DSM 101079T). H. saccincola A7 (= JCM 31827=DSM 104321) had quite similar phenotypic characteristics to those of strain GGR1. However, the optimum growth of A7 was at alkaline pH (9.0) and 55 degrees C, compared to pH 7.0 at 60 degrees C for GGR1, and the fatty acid profile of A7 contained 1.7 times more C17:0 iso than GGR1. The draft genome sequence revealed that H. saccincola A7 possessed a cellulosome-like extracellular macromolecular complex, which has also been found for Clostridium thermocellum and C. clariflavum. H. saccincola A7 contained more glycoside hydrolases (GHs) belonging to GH families 11 and -2, and more diversity of xylanolytic enzymes, than C. thermocellum and C. clariflavum. H. saccincola A7 could grow on xylan because it encoded essential genes for xylose metabolism, such as a xylose transporter, xylose isomerase, xylulokinase, and ribulose-phosphate 3-epimerase, which are absent from C. thermocellum. These results indicated that H. saccincola A7 has great potential as a microorganism that can effectively degrade lignocellulosic biomass. PMID- 29482869 TI - Determination of Intrafraction Prostate Motion During External Beam Radiation Therapy With a Transperineal 4-Dimensional Ultrasound Real-Time Tracking System. AB - PURPOSE/OBJECTIVE: To determine intrafraction prostate motion during volumetric modulated arc therapy (VMAT) using transperineal ultrasound (US) real-time tracking. METHODS AND MATERIALS: 770 US monitoring sessions in 38 prostate cancer patients' VMAT treatment series were retrospectively evaluated. Intrafraction motion assessment of the prostate was based on continuous position monitoring with a 4-dimensional US system along the 3 directions: left-right (LR), anterior posterior (AP), and inferior-superior (SI). The overall mean values and standard deviations (SD) along with random and systematic errors were calculated. RESULTS: The mean duration of each monitoring session was 254 s. The mean (MU), the systematic error (Sigma), and the random error (sigma) of intrafraction prostate displacement were MU = (0.01, -0.08, 0.15) mm, Sigma = (0.30, 0.34, 0.23) mm, and sigma = (0.59, 0.73, 0.64) mm in the LR, AP and SI directions, respectively. The percentage of treatments for which prostate displacement was <=2 mm was 97.01%, 92.24%, and 95.77% in the LR, AP, and SI directions, respectively. At 60 s, a vector length of prostate displacement >2 mm was present in 0.67% of the data. The percentage increased to 2.42%, 6.14%, and 9.35% at 120 s, 180 s, and 240 s, respectively. CONCLUSIONS: The magnitudes of intrafraction prostate motion along the SI and AP directions were comparable. On average, the smallest motion was in the LR direction and the largest in AP direction. Most of the prostate displacements were within a few millimeters. However, with increasing treatment time (eg, during hypofractionation), larger 3-dimensional prostate displacements up to 18.30 mm could be observed. Shortening treatment time can reduce the impact of intrafraction motion and potentially allows smaller safety margins. PMID- 29482870 TI - Radiation Dose-Volume Effects for Liver SBRT. AB - Stereotactic body radiation therapy (SBRT) has emerged as an effective, noninvasive treatment option for primary liver cancer and metastatic disease occurring in the liver. Although SBRT can be highly effective for establishing local control in hepatic malignancies, a tradeoff exists between tumor control and normal tissue complications. The objective of the present study was to review the normal tissue dose-volume effects for SBRT-induced liver and gastrointestinal toxicities and derive normal tissue complication probability models. PMID- 29482871 TI - Detection of colistin heteroresistance in Acinetobacter baumannii from blood and respiratory isolates. AB - Polymyxins are one of the last-line antibiotics for multidrug-resistant Acinetobacter baumannii. Reports have demonstrated the emergence of colistin heteroresistance in A. baumannii, which can complicate assessment of minimum inhibitory concentrations and promote resistance to colistin. We aimed to determine the presence of colistin heteroresistance in A. baumannii isolates and correlate the results with clinical and microbiological outcomes via a retrospective study of 24 adult patients: 12 blood and 12 invasive respiratory cultures positive for colistin-susceptible A. baumannii between 1 January 2013 and 31 July 2015. Heteroresistance testing was performed by plating a 100-MUL bacterial cell suspension on Mueller-Hinton agar plates containing 0, 1, 2, and 4 MUg/mL colistin, and assessing for growth at 24 and 48 h. Colistin heteroresistance was exhibited in 83% of isolates. Median age was 56 [43-65] years, 10 (42%) patients resided at a facility prior to admission, 5 (21%) had a chronic tracheostomy, 18 (75%) were in the intensive care unit at the time of culture collection, and median infection-related length of stay was 12 [7-15] days. Clinical and microbiological cures were achieved in 75% of patients. Overall infection-related mortality was 21%. Our study demonstrated a high rate of colistin heteroresistance in clinical isolates of colistin-susceptible A. baumannii, although this was not associated with suboptimal clinical outcomes due to the use of aggressive colistin dosing and combination therapy. Further studies are needed to establish the association between in vitro colistin heteroresistance and clinical and microbiological outcomes. PMID- 29482872 TI - Corrigendum to Effects of tectonics and large scale climatic changes on the evolutionary history of Hyalomma ticks Molecular Phylogenetics and Evolution (2017) 114:153-165. PMID- 29482873 TI - Corrigendum to "Multilocus phylogeny and species delimitation within the Natterer's bat species complex in the Western Palearctic" [Molecular Phylogenetics and Evolution 61 (2011) 888-898]. PMID- 29482874 TI - Validity of an Alternate Hand Behind Back Shoulder Range of Motion Measurement in Patients With Shoulder Pain and Movement Dysfunction. AB - OBJECTIVES: The purpose of this study was to determine the criterion-related validity of a novel method of measuring hand behind back (HBB) shoulder range of motion (ROM) for evaluating pain and disability in people with shoulder pain and movement impairment. METHODS: This cross-sectional study design evaluated shoulder ROM, pain, fear-avoidance beliefs, and disability in 60 people (aged 35 70 years, 31 male) with chronic unilateral shoulder dysfunction (mean duration 15.73 weeks). Shoulder HBB ROM was measured with a bubble inclinometer in a manner that did not require the patient to disrobe. Correlations were sought between HBB ROM and other shoulder movements, as well as scores recorded on the Shoulder Pain and Disability Index (SPADI), visual analogue scale for pain, Fear Avoidance Beliefs Questionnaire (FABQ), and duration of symptoms. RESULTS: Restriction of HBB movement was significantly correlated with SPADI total disability score (r = 0.39, P < .01), flexion ROM (r = 0.30, P < .05), abduction ROM (r = 0.39, P < .01), and external rotation ROM (r = 0.60, P < .01). Other variables were not significantly correlated with HBB ROM. Multiple linear regression analysis indicated that the variance in HBB ROM was explained by the SPADI disability subscore (P = .01) but not by visual analogue scale score (P = .05), FABQ score (P = .65), or duration of symptoms (P = .73). The FABQ score was not explained by limitation in HBB ROM and shoulder movements. CONCLUSION: These findings suggest that this novel method of measuring HBB ROM could be used as a functional outcome measure in the evaluation of patients with shoulder disorders. This method could be considered as an additional or alternative where there are challenges in measuring HBB because of restrictions in undressing a patient, such as for cultural reasons. PMID- 29482875 TI - PEGylated multi-walled carbon nanotubes as versatile vector for tumor-specific intracellular triggered release with enhanced anti-cancer efficiency: Optimization of length and PEGylation degree. AB - PEGylated multi-walled carbon nanotubes (PEG-MWCNTs) were optimized as versatile vector for tumor-specific intracellular triggered release of doxorubicin (DOX), based on the effect of their length and PEGylation degree on the cytotoxicity and DOX-loading capacity. The length and surface carboxyl groups of the carboxylated multi-walled carbon nanotubes (CMWCNTs) were easily tailored by adjusting the oxidation time. The longer CMWCNTs or those with high carboxyl group content showed obvious cytotoxicity, while the PEG-MWCNTs <= 300 nm showed better cytocompatibility. The PEG-MWCNTs-3 of about 300 nm was selected as drug delivery vector, possessing a high drug-loading capacity of 0.55 mg/mg. They released DOX rapidly under lower pH media mimicking the tumor microenvironment with cumulative release of 57% within 24 h, while the premature leakage under the simulated physiological condition was only 10%. The WST-1 assays demonstrated the DOX loaded PEG-MWCNTs-3 exhibited the enhanced inhibitory efficiency against HepG2 cells, in comparison with free DOX. PMID- 29482876 TI - Low carotid stump pressure as a predictor for ischemic symptoms and as a marker for compromised cerebral reserve in octogenarians undergoing carotid endarterectomy. AB - BACKGROUND: Carotid artery occlusive disease can cause stroke by embolization, thrombosis, and hypoperfusion. The majority of strokes secondary to cervical carotid atherosclerosis are believed to be of embolic etiology. However, cerebral hypoperfusion could be an important factor in perioperative stroke. We retrospectively reviewed the stump pressure (SP) of carotid endarterectomy (CEA) of patients at Pennsylvania Hospital to identify whether physiologic perfusion differences account for differences in perioperative stroke rates, particularly in octogenarians. METHODS: We conducted a retrospective review of our prospectively maintained database for CEA performed between 1992 and 2015. SP was measured and recorded for 1190 patients. A low SP was defined as systolic pressure <50 mm Hg. Shunts were used only for patients under general anesthesia with SP <50 mm Hg, for awake patients with neurologic changes with carotid clamping, and in some patients with recent stroke. RESULTS: Symptomatic patients were more likely to have SP <50 mm Hg compared with asymptomatic patients (35.6% vs 26.2%; P = .0015). Patients having SP <50 mm Hg had a higher postoperative stroke rate compared with patients with SP >50 mm Hg (2.9% vs 0.9%; P = .0174). Octogenarians were more likely to have a lower SP compared with patients younger than 80 years (35.7% vs 27.7%; P = .0328). Symptomatic patients with low SP were at highest risk for perioperative stroke (6.4% vs 1.2%; P = .001) compared with patients without these factors. CONCLUSIONS: SP is a marker for decreased cerebrovascular reserve and along with symptomatic status identifies those at highest risk for periprocedural stroke with CEA. Whereas patients older than 80 years may benefit from carotid intervention, they are likely to be at somewhat elevated stroke risk because of higher prevalence of low SP, and shunting does not eliminate this risk. PMID- 29482878 TI - Stallion sperm freezing with sucrose extenders: A strategy to avoid permeable cryoprotectants. AB - The aim of this study was to assess different concentrations of sucrose-based extenders combined with bovine serum albumin (BSA) as an alternative to stallion sperm cryopreservation with permeable cryoprotectants. Semen samples (n = 16) were collected from six stallions. Sperm was cooled, filled in 0.5 mL straws and frozen in nitrogen vapor. Post-thaw sperm kinetic parameters, plasma and acrosome membrane integrity were statistically compared among treatments. In Experiment 1, extenders containing 1% of BSA and different concentrations of sucrose (mmol/L, M): 0, 50, 100, 250, 350 and 450 mM were compared. Use of sucrose [100 mM (S2)] resulted in greater values for most of the sperm kinetic parameters assessed (P < 0.001). There were no differences for plasma membrane integrity, except for when sucrose was used at 50 and 250 mM concentrations, and plasma membrane integrity was less (P < 0.05) when these concentrations were used than with the other sucrose concentrations. In Experiment 2, the selected sucrose extender (S2) was compared to an extender containing glycerol as permeable cryoprotectant. Use of the S2 extender resulted in a lesser proportion of sperm with denuded-acrosomes (P < 0.05) in comparison to use of glycerol and values for several kinetic parameters were also greater (P < 0.05) with use of S2. There were no significant differences for the other parameters assessed in this study. In conclusion, stallion sperm can be frozen in the absence of permeable cryoprotectants, using a combination of sucrose 100 mM with BSA-1% as alternative agents. PMID- 29482877 TI - The impact of race on outcomes after carotid endarterectomy in the United States. AB - OBJECTIVE: Black patients undergoing carotid endarterectomy (CEA) in the United States are more often symptomatic at presentation and have more comorbidities compared with white patients. However, the impact of race on outcomes after CEA is largely unknown. METHODS: We identified CEA patients in the Vascular Quality Initiative registry (2012-2017) and compared them by race (black vs white). All other nonwhite races (891 [1.4%]) and Hispanics (2222 [3.4%]) were excluded. We used multilevel logistic regression to account for differences in demographics and comorbidities. We assessed long-term survival using multivariable Cox regression. The primary outcome was perioperative stroke/death, with long-term survival as a secondary outcome. RESULTS: We included 57,622 CEA patients; 2909 (5.0%) were black, of whom 983 (34%) were symptomatic. Of the 54,713 white patients, 16,132 (30%) were symptomatic. Black patients, compared with white patients, had a higher vascular disease burden and were less likely to be operated on in a high-volume hospital or by a high-volume surgeon. In addition, black symptomatic patients, compared with white symptomatic patients, were more often operated on <2 weeks after the index neurologic symptom (47% vs 40%; P < .001). Perioperative stroke/death was comparable between black and white patients (symptomatic, 2.8% vs 2.2% [P = .2]; asymptomatic, 1.6% vs 1.3% [P = .2]), as was unadjusted survival at 3 years (93% vs 93%; P = .7). However, after adjustment, black patients did experience better long-term survival compared with white patients (hazard ratio, 0.8; 95% confidence interval, 0.7-0.9; P = .01). On multilevel logistic regression, race was not associated with perioperative stroke/death (odds ratio, 1.0; 95% confidence interval, 0.8-1.3; P = .98). CONCLUSIONS: Despite the greater prevalence of vascular risk factors in black patients and racial inequalities in surgical treatment, rates of perioperative stroke/death and unadjusted survival were similar between white and black patients. Moreover, black patients experienced better adjusted long-term survival after CEA. PMID- 29482879 TI - Fetal biometry: Relevance in obstetrical practice. AB - Ultrasound imaging in obstetrics and gynecology dates back to 1958 when The Lancet published the first article about the use of ultrasonography for fetal and gynecological assessments. It is now almost inconceivable, 60 years later, to think of effective performance in obstetrics and gynecology without the variety of ultrasound, for example, real time imaging, power and color Doppler, 3D/4D ultrasonography, etc. Such examinations facilitate the assessment of intrauterine fetal growth and development during pregnancy, provide alerts about the risk of pre-eclampsia and preterm birth, help identify anatomic reasons for infertility, diagnose ectopic pregnancies, uterine, ovary and tubal pathology. Ultrasonography is also used for diagnostic and treatment procedures during pregnancy or for the treatment of infertility. This article is an overview of the development of fetal ultrasound, the methodology and interpretation of ultrasound in the assessment of intrauterine fetal growth and fetal biometry standards both worldwide and in Lithuania. PMID- 29482880 TI - Perceived changes in knowledge and confidence of doctors and midwives after the completion of the Standardized Trainings in Obstetrical Emergencies. AB - BACKGROUND AND OBJECTIVES: There are only few training programs in obstetric emergencies currently in use and only some of them were evaluated with an adequate sample of participants. Therefore, we present the evaluation of the novel Standardized Trainings in Obstetrical Emergencies (STrObE), conducted in Lithuania. The aim of this study was to analyze whether participants' self reported knowledge and confidence increased after the trainings, and whether the impact of the trainings was long-lasting. MATERIALS AND METHODS: Data was collected across the majority of hospitals providing secondary and tertiary obstetrical care in Lithuania in 2015. A total of 650 obstetricians-gynecologists and midwives attended the trainings; 388 (response rate 59.7%) of them filled in the initial questionnaire before the trainings, 252 (64.9%) immediately after, 160 (41.2%) 6 weeks after, and 160 (41.2%) 6 months after the trainings, which was the final sample for the analyses. Participants used a Likert-type scale to evaluate their knowledge and confidence about management of urgent obstetrical situations: vacuum-assisted vaginal delivery, shoulder dystocia, postpartum hemorrhage, preeclampsia/eclampsia, early preterm labor, and dystocia. We assessed how participants' self-reported knowledge and confidence changed after the trainings (compared to before the trainings) and how long the effect was retained for. RESULTS: The mean score of self-reported knowledge in obstetrical emergencies increased immediately after the trainings comparing to the scores before the trainings (P<0.001) and it did not differ further between the three time points after the trainings (i.e. immediately, 6 weeks, and 6 months; P>0.05). The same pattern was observed for self-reported confidence scores. The increase in self-reported knowledge and confidence after the trainings was stable. Moreover, the self-reported knowledge and confidence gains were greater for those participants with lower work experience, although benefit was seen across all experience levels. CONCLUSIONS: STrObE improved participants' self reported knowledge and confidence and lasting positive effects were observed for at least 6 months after the initial trainings. Moreover, the trainings were more beneficial for those with lower work experience, although they benefited all the participants. PMID- 29482881 TI - Duration but not intensity influences transcranial direct current stimulation (tDCS) after-effects on cortical excitability. AB - Recent studies have shown heterogeneous results regarding the influence of intensity and duration of motor transcranial direct current stimulation (tDCS) on cortical excitability. In this pilot crossover study including 14 healthy participants, we compared the effects of a single session of anodal-tDCS set with two commonly used durations (20 and 30minutes) and intensities (1 and 2mA) on short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF). Regardless of the current intensity, 20minutes of tDCS increased SICI (3ms inter-stimulus interval ISI) and decreased ICF (7ms ISI); 30minutes of tDCS did not affect cortical excitability. PMID- 29482882 TI - Vasodilators in acute heart failure - evidence based on new studies. AB - Acute heart failure (AHF) contributes largely to the worldwide burden of heart failure (HF) and is associated with high mortality, poor prognosis and high rehospitalization rate. The pharmacologic therapy of AHF includes diuretics and vasodilators, which are a keystone when fluid overload and congestion are present. However, vasodilators are mainly focused on controlling symptoms, and drugs that also improve long-term mortality and morbidity seem to be in high demand. In this review, we summarize the existing evidence on mortality benefits of IV vasodilators in AHF. There is lack of evidence on the mortality benefits of IV vasodilators in AHF, as well as well-designed and large-scale trials for some of them. The existing trials on nitrates have conflicting results and are insufficient to establish definitive conclusions. Other vasodilators, such as enalaprilat, clevidipine, carperitide, and ularitide, have been evaluated only in a few trials assessing mortality. Levosimendan, nesititide and carperitide are approved by some regulatory agencies; however, data regarding mortality are also conflicting and large-scale post-marketing studies would be important. Serelaxin is a recent therapy with a novel mechanism of action and seemed to be promising; although serelaxin was safe and well tolerated in earlier trials, the results of a larger phase III trial failed to meet the primary endpoints of reduction in cardiovascular death at day 180 and reduction of worsening heart failure at day 5. The absence of definitive mortality benefits and high-quality and large-scale data not allow firm conclusions to be drawn about the role of IV vasodilators in AHF. Well-designed studies are needed to clarify the role of these drugs in the long-term outcome of AHF, as well as new therapies entering the clinical investigation. PMID- 29482883 TI - Implementation of an academic half day in a vascular surgery residency program improves trainee and faculty satisfaction with surgical indications conference. AB - BACKGROUND: The Accreditation Council for Graduate Medical Education mandates scheduled didactics for residency programs but allows flexibility in implementation. Work-hour restrictions, patient care duties, and operative schedules create barriers to attendance for surgical trainees. We explored vascular surgery trainees and faculty perceptions on trainees operative preparation and participation, and overall fund of knowledge after implementing an academic half day conference (AHD) schedule. METHODS: The vascular surgery conference at a single academic institution was changed from three 1-hour conferences weekly, to a single protected, 3-hour conference once weekly. Faculty and trainees were surveyed before and 5 months after implementing the new AHD schedule. RESULTS: Overall satisfaction improved after initiating the AHD (4 of 4 trainees, 3 of 4 faculty). All trainees (n = 4) and faculty (n = 4) believed the AHD conference format was worthwhile. Most trainees believed the AHD format improved their Vascular Surgery in Service Training Exam preparation (3 of 4), fund of knowledge (4 of 4), and operative preparation (3 of 4). More trainees than faculty tended to feel that the AHD interfered with operative participation (3 of 4 trainees vs 1 of 4 faculty). Neither group agreed that the conference was optimally scheduled. CONCLUSION: This single-institution, pilot study suggests a positive association in the attitudes of most vascular surgery trainees and faculty regarding preparation for the Vascular Surgery In-Training Exam and overall fund of knowledge after implementing a protected AHD schedule. Further research is needed to understand the impact of the AHD conference on operative experience and training exam scores. PMID- 29482884 TI - Influence of English proficiency on patient-provider communication and shared decision-making. AB - BACKGROUND: The number of patients in the United States (US) who speak a language other than English is increasing. We evaluated the impact of English proficiency on self-reported patient-provider communication and shared decision-making. METHODS: The 2013-2014 Medical Expenditure Panel Survey database was utilized to identify respondents who spoke a language other than English. Patient-provider communication (PPC) and shared decision-making (SDM) scores from 4-12 were categorized as "poor" (4-7), "average" (8-11), and "optimal." The relationship between PPC, SDM, and English proficiency was analyzed. RESULTS: Among 13,880 respondents, most were white (n = 10,281, 75%), age 18-39 (n = 6,677, 48%), male (n = 7,275, 52%), middle income (n = 4,125, 30%), and born outside of the US (n = 9,125, 65%). English proficiency was rated as "very well" (n = 7,221, 52%), "well" (n = 2,378, 17%), "not well" (n = 2,820, 20%), or "not at all" (n = 1,463, 10%). On multivariable analysis, patients who rated their English as "well" (OR 1.73, 95% CI 1.37-2.18) or "not well" (OR 1.53, 95% CI 1.10-2.14) were more likely to report "poor" PPC (both P < .01). Similarly, SDM was more commonly self reported as "poor" among patients who reported English proficiency as "not well" (OR 1.31, 95% CI 1.04-1.65, P = .02). CONCLUSION: Decreased English proficiency was associated with worse self-reported patient-provider communication and shared decision-making. Attention to patients' language needs is critical to patient satisfaction and improved perception of care. PMID- 29482885 TI - Interleukin-6 and interleukin-8 serum levels in prognosis of hormone-dependent breast cancer. AB - BACKGROUND: Increasing amount of evidence points to the importance of immunity in breast cancer. The prognostic value of cytokines and their effect on tumorigenesis remains inconsistent. AIM: To investigate the prognostic significance of IL6 and IL8 and their association with ER and HER2 in estrogen dependent (ER+) breast cancer. MATERIAL AND METHODS: The study included 79 premenopausal women with early and locally advanced ER+ breast cancer. All patients received adjuvant hormonal therapy: tamoxifen alone (56/79) or combination with LHRH agonist goserelin (23/79). IL6 and IL8 serum protein levels were measured by ELISA. Cox proportional hazards regression analysis was implemented for prognostic evaluation of the data categorized based on metastasis outcome. RESULTS: IL6 associated with good (P = 0.001, HR = 0.05) and IL8 with poor disease outcome (P = 0.03, HR = 2.5) in the whole group of patients. Multivariate analyses highlighted IL6 as the independent prognostic factor (P = 0.001, HR = 0.0007). When patients were classified according to ER or HER2 status, IL6 did not have prognostic significance in ERlow and ERhigh subgroups, while IL8 retained prognostic significance only in the ERhigh subgroup (P = 0.04, HR = 2.8). IL6 was significant in both HER2- (P = 0.001, HR = 0.05) and HER2+ subgroups (P = 0.002, HR = 0.04), while IL8 retained its prognostic significance only in the HER2+ subgroup (P = 0.001, HR = 77.8). CONCLUSIONS: This study contributes to the clarification of the prognostic performance of IL6 and IL8 by providing their first prognostic evaluation in the homogenized ER+ breast cancer patient group. IL6 was indicated as a marker of favorable, whereas IL8 was a marker of unfavorable disease outcome. PMID- 29482886 TI - Elevated serum uric acid predicts the development of moderate coronary artery calcification independent of conventional cardiovascular risk factors. AB - BACKGROUND AND AIMS: Hyperuricemia was frequently noted in subjects with a high risk of cardiovascular disease (CVD). This study aimed to elucidate whether serum uric acid (SUA) is associated with development of moderate coronary artery calcification in generally healthy adults. METHODS: A total of 9297 subjects underwent multidetector CT for the evaluation of CAC at least two times during their annual health examinations. Among them, 4461 participants without CVD history and who had no (scores 0) or minimal CAC (scores 1-10) in their first examination were enrolled. The association between SUA as a continuous and categorical variable and development of moderate coronary artery calcification (CAC score > 100) was assessed by Cox regression analysis. Receiver-operating characteristic (ROC) curves were constructed to investigate the diagnostic efficacy of SUA. RESULTS: During a median follow-up of 4.1 years, 131 incident cases of moderate calcification developed. Baseline SUA concentration was significantly higher in subjects with progression to moderate coronary artery calcification (6.6 +/- 1.3 vs. 5.8 +/- 1.3 mg/dL, p < 0.001). SUA as a continuous variable (per 1 mg/dL) and divided into quartiles was positively associated with a higher risk of development of moderate calcification after adjustment for conventional CVD risk factors. The addition of SUA to the conventional CVD risk factors improved the predictive power for development of moderate coronary artery calcification. CONCLUSIONS: SUA was an independent predictor for development of moderate coronary artery calcification in subjects with no or minimal calcification. PMID- 29482887 TI - Urea functionalized surface-bonded sol-gel coating for on-line hyphenation of capillary microextraction with high-performance liquid chromatography. AB - Sol-gel urea functionalized-[bis(hydroxyethyl)amine] terminated polydimethylsiloxane coating was developed for capillary microextraction-high performance liquid chromatographic analysis from aqueous samples. A fused silica capillary is coated from the inside with surface bonded coating material and is created through in-situ sol-gel reaction. The urea-functionalized coating was immobilized to the inner surface of the capillary by the condensation reaction of silanol groups of capillary and sol-solution. The characterization of the coating material was successfully done by using X-ray photoelectron spectroscopy, thermogravimetric analysis, field emission scanning electron microscope, and energy dispersive X-ray spectrometer. To make a setup of online capillary microextraction-high performance liquid chromatography, the urea functionalized capillary was installed in the HPLC manual injection port. The analytes of interest were pre-concentrated in the coated sampling loop, desorbed by the mobile phase, chromatographically separated on C-18 column, and analyzed by UV detector. Sol-gel coated capillaries were used for online extraction and high performance liquid chromatographic analysis of phenols, ketones, aldehydes, and polyaromatic hydrocarbons. This newly developed coating showed excellent extraction for a variety of analytes ranging from highly polar to non-polar in nature. The analysis using sol-gel coating showed excellent overall sensitivity in terms of lower detection limits (S/N = 3) for the analytes (0.10 ng mL-1-14.29 ng mL-1) with acceptable reproducibility that is less than 12.0%RSD (n = 3). Moreover, the capillary to capillary reproducibility of the analysis was also tested by changing the capillary of the same size. This provided excellent%RSD of less than 10.0% (n = 3). PMID- 29482888 TI - Clinicopathological and Ultrasonic Features of Triple-Negative Breast Cancers: A Comparison with Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Breast Cancers. AB - The purpose of this study was to analyze the clinicopathological and ultrasound characteristics of triple-negative breast cancers (TNBCs) and compare these findings with those for hormone receptor-positive (HR-positive)/human epidermal growth factor receptor-2-negative (HER-2-negative) tumors. Seventy-five TNBCs and 135 HR-positive/HER-2-negative breast cancers were reviewed. Data from conventional ultrasound, Doppler vascularity and elastography were included in the analysis. TNBCs had a higher histologic grade and Ki-67 level. On ultrasound, TNBCs often appeared as microlobulated, markedly hypo-echoic masses with an abrupt interface boundary, posterior acoustic enhancement, absence of calcifications and more characteristics of surrounding tissue. Results from multivariate regression analysis revealed that margin, posterior acoustic features and surrounding tissue features of tumors were independent predictive factors in differentiating TNBCs from HR-positive/HER-2-negative tumors. Our results suggest that a thorough evaluation of sonographic findings might be useful in discriminating between TNBCs and HR-positive/HER-2-negative tumors, which may provide accurate evidence for clinical early diagnosis. PMID- 29482889 TI - Measuring the Absolute Concentration of Microparticles in Suspension Using High Frequency B-Mode Ultrasound Imaging. AB - Concentration measurement of particles in suspension is an important procedure performed in biological and clinical laboratories. Existing methods based on instruments such as hemocytometers, Coulter counters and flow cytometers are often laborious, destructive and incapable of in vivo measurements. On the other hand, an ultrasound-based method can be non-destructive and non-invasive and have the potential for in vivo measurement. In this work, a method is presented that estimates absolute particle concentration from high-frequency B-mode ultrasound images of a sample. The method is based on the detection and characterization of the echoes from individual particles to estimate the effective slice thickness of the image. Calibration using a reference sample is not required because the estimation is entirely image based. The particle type differential is also performed by using the backscatter coefficient of each detected echoes. The method is demonstrated by measuring microsphere suspensions as well as human T cell suspensions. The proposed method has a wide range of potential clinical applications including non-invasive measurement of cell concentration in biological fluids such as cerebrospinal fluid. PMID- 29482890 TI - [Endovascular repair of the thoracic aorta]. AB - Degenerative aneurysms of the thoracic aorta are increasing in prevalence. The recognition of the decreased morbidity of this approach compared with open repair was readily apparent, as it avoided left thoracotomy, aortic cross-clamping, and left heart bypass. Repair of isolated descending thoracic aortic aneurysms using stent grafts was introduced in 1995, and in an anatomically suitable subgroup of patients with thoracic aortic aneurysm, repair with endovascular stent graft provides favorable outcomes, with decreased perioperative morbidity and mortality relative to open repair. The cornerstones of successful thoracic endovascular aneurysm repair are appropriate patient selection, thorough preprocedural planning, and cautious procedural execution. Since then, TEVAR is increasingly being used for other aortic pathologies such as complicated type B dissection, traumatic aortic transection, and aneurysmal disease extending into the arch or visceral segment, requiring debranching procedures. PMID- 29482891 TI - Early experimental results of using a novel delivery carrier, hyaluronan phosphatidylethanolamine (HA-PE), which may allow simple bladder instillation of botulinum toxin A as effectively as direct detrusor muscle injection. AB - INTRODUCTION: Botulinum toxin A (BTX-A) is a neurotoxin that inhibits acetylcholine release by cleaving cytosolic synaptosome-associated protein 25 (SNAP-25) and results in bladder relaxation. A BTX-A intravesical injection has been established as an effective option for treating detrusor overactivity. STUDY DESIGN: Sixty female Sprague Dawley rats were equally divided into control and experimental groups. Control Groups 1 to 3 received: BTX-A 10 units + saline instillation; hyaluronan-phosphatidylethanolamine (HA-PE) 0.5 g + saline instillation; and BTX-A 5 Uintra-detrusor injections, respectively. Treatment Groups 4 to 6 received: Alexa(r)594-labeled BTX-A 10 U + HA-PE 0.5 g + saline instillation; BTX-A 5 U + HA-PE 0.2-0.5 g instilled for 60 min; and BTX-A 10 U + HA-PE 0.2-0.5 g instilled for 30 min, respectively. All procedures were performed under isoflurane general anesthesia. The primary outcome of this study was the degree of SNAP-25 staining in control and experimental groups compared to Group 3 (detrusor muscle injection). Urodynamic studies were performed at baseline and at day 14 after 1% acetic acid (AA) instillation, to evaluate the maximum pressure during filling (MP) and inter-contraction intervals (ICI). Group 4 rats were examined for Alexa(r)594 fluorescence to demonstrate physical translocation of BTX-A-HA-PE complex. Standard histology was performed to assess the effect of HA PE on bladder mucosa and detrusor muscle. RESULTS: Group 3 showed the least SNAP 25 staining (7.3 +/- 5.0%) compared with all groups except Group 5A (12.4 +/- 12.27%, P = 1.0). Group 6A, which had high HA-PE dose but a shorter instillation time, showed fairly extensive SNAP-25 staining (22.9 +/- 10%). Confocal microscopy of Group 4 confirmed the presence of Alexa(r)594 fluorescence across the urothelium. Urodynamic parameters were not significantly different at baseline (P = 1.0). After acetic acid instillation, Group 5A showed minimal change in ICI, which was comparable to ICI in Group 3 rats. DISCUSSION: SNAP-25 staining in Group 5A was comparable to Group 3, suggesting that adequate HA-PE and instillation time allows the efficacy of this carrier mechanism to be comparable to standard intra-detrusor injections. All other groups showed significantly higher SNAP-25 staining compared to Group 3. A dose response effect was demonstrated; higher dose of HA-PE (Group 5A vs Group 5B) and longer instillation time (Group 5 vs Group 6) led to lower SNAP-25 staining. CONCLUSION: This novel method of BTX-A delivery to the bladder using a carrier (HA-PE) is promising and requires further investigation. Using a larger animal model, identifying an optimal dose of HA-PE and instillation time, and reproducing the current results are further required to validate this carrier. PMID- 29482892 TI - Pancreatic exocrine insufficiency following acute pancreatitis: Systematic review and study level meta-analysis. AB - OBJECTIVES: This study systematically explores the prevalence of pancreatic exocrine insufficiency (PEI) after acute pancreatitis in different subgroups of etiology (biliary/alcoholic/other), disease severity and follow-up time (<12, 12 36 and > 36 months after index admission). METHODS: PubMed and EMBASE databases were searched, 32 studies were included in this study level meta-analysis. RESULTS: In a total of 1495 patients with acute pancreatitis, tested at a mean of 36 months after index admission, the pooled prevalence of PEI was 27.1% (95% confidence interval [CI]: 20.3%-35.1%). Patients from seven studies (n = 194) underwent direct tests with pooled prevalence of 41.7% [18.5%-69.2%]. Patients from 26 studies (n = 1305) underwent indirect tests with pooled prevalence of 24.4% [18.3%-31.8%]. In subgroup analyses on patients that underwent fecal elastase-1 tests, PEI occurred more often in alcoholic pancreatitis (22.7% [16.6% 30.1%]) than in biliary pancreatitis (10.2% [6.2%-16.4%]) or other etiology (13.4% [7.7%-22.4%]; P = 0.02). Pooled prevalence of PEI after mild and severe pancreatitis was 19.4% [8.6%-38.2%] and 33.4% [22.6%-46.3%] respectively in studies using fecal elaste-1 tests (P = 0.049). Similar results were seen in patients without (18.9% [9.3%-34.6%]) and with necrotizing pancreatitis (32.0% [18.2%-49.8%]; P = 0.053). Over time, the prevalence of PEI decreased in patients who underwent the fecal elastase-1 test and increased in patients who underwent the fecal fat analysis. CONCLUSIONS: After acute pancreatitis, a quarter of all patients develop PEI during follow-up. Alcoholic etiology and severe and necrotizing pancreatitis are associated with higher risk of PEI. The prevalence of PEI may change as time of follow-up increases. PMID- 29482893 TI - Enterovirus D68 and acute flaccid myelitis-evaluating the evidence for causality. AB - Increased circulation of enterovirus D68 in 2014 and 2016 temporally and geographically coincided with increases in cases of acute flaccid myelitis, an uncommon condition of paralysis due to lesions in the anterior horn of the spinal cord. The identification of enterovirus D68 in respiratory specimens from cases of acute flaccid myelitis worldwide further supports an association, yet the absence of direct virus isolation from affected tissues, infrequent detection in cerebrospinal fluid, and the absence, until recently, of an animal model has left the causal nature of the relationship unproven. In this Personal View we evaluate epidemiological and biological evidence linking enterovirus D68 and acute flaccid myelitis. We applied the Bradford Hill criteria to investigate the evidence for a causal relationship and highlight the importance of comprehensive surveillance and research to further characterise the role of enterovirus D68 in acute flaccid myelitis and pursue effective therapies and prevention strategies. PMID- 29482894 TI - Review of immune tolerance induction in hemophilia A. AB - At first sight the bleeding disorder hemophilia A seems to have little in common with immune disorders, but immunology research intersects with other disciplines including hematology. Nowadays, the most important complication in the treatment of hemophilia A is the development of neutralizing antibodies (inhibitors) against exogenous administered factor VIII (FVIII), which occurs in approximately 30% of all patients with severe hemophilia A. This antibody response renders FVIII replacement therapy ineffective, thereby increasing the risk for uncontrollable bleeding and morbidity, decreasing quality of life and increasing healthcare costs. The only proven effective therapy to eradicate these inhibitors is immune-based. Using a protocol called "immune tolerance induction" (ITI), the repeated and frequent administration of FVIII under non-inflammatory conditions downregulates the established antibody response and induces immune tolerance. There has been progress in research clarifying the mechanisms that mediate tolerance induction using ITI, both from patient studies and from research in cell culture and animal-based models. Peripheral tolerance induction to FVIII involves the apoptosis of antigen-specific B-memory cells, anergy induction in antigen-specific effector T-cells (Teff), induction of regulatory T-cells (Treg) and the formation of anti-idiotypic antibodies. In this review hemophilia A will be used as an example to discuss current concepts of tolerance induction as they are applied in patient care. Where possible, we will extrapolate tolerance findings in hemophilia A to related pathways known to affect auto-immune disorders or allergy. PMID- 29482895 TI - Bispecific antibody based therapeutics: Strengths and challenges. AB - Monoclonal antibody-based targeted therapy has greatly improved treatment options for patients. However, long-term efficacy of such antibodies is limited by resistance mechanisms. New insights into the mechanisms by which tumors evade immune control have driven innovative therapeutic strategies to eliminate cancer by re-directing immune cells to tumors. Advances in protein engineering technology have generated multiple bispecific antibody (BsAb) formats capable of targeting multiple antigens as a single agent. Approval of two BsAb and three check point blocking mAbs represent a paradigm shift in the use of antibody constructs. Since BsAbs can directly target immune cells to tumors, drug resistance and severe adverse effects are much reduced. The wave of next generation "bispecific or multispecific antibodies" has advanced multiple candidates into ongoing clinical trials. In this review, we focus on preclinical and clinical studies in hematological malignancies as well as discuss reasons for the limited success of BsAbs against solid tumors. PMID- 29482897 TI - Comparing motor-vehicle crash risk of EU and US vehicles. AB - OBJECTIVE: This study examined the hypotheses that passenger vehicles meeting European Union (EU) safety standards have similar crashworthiness to United States (US) -regulated vehicles in the US driving environment, and vice versa. METHODS: The first step involved identifying appropriate databases of US and EU crashes that include in-depth crash information, such as estimation of crash severity using Delta-V and injury outcome based on medical records. The next step was to harmonize variable definitions and sampling criteria so that the EU data could be combined and compared to the US data using the same or equivalent parameters. Logistic regression models of the risk of a Maximum injury according to the Abbreviated Injury Scale of 3 or greater, or fatality (MAIS3+F) in EU regulated and US-regulated vehicles were constructed. The injury risk predictions of the EU model and the US model were each applied to both the US and EU standard crash populations. Frontal, near-side, and far-side crashes were analyzed together (termed "front/side crashes") and a separate model was developed for rollover crashes. RESULTS: For the front/side model applied to the US standard population, the mean estimated risk for the US-vehicle model is 0.035 (sd = 0.012), and the mean estimated risk for the EU-vehicle model is 0.023 (sd = 0.016). When applied to the EU front/side population, the US model predicted a 0.065 risk (sd = 0.027), and the EU model predicted a 0.052 risk (sd = 0.025). For the rollover model applied to the US standard population, the US model predicted a risk of 0.071 (sd = 0.024), and the EU model predicted 0.128 risk (sd = 0.057). When applied to the EU rollover standard population, the US model predicted a 0.067 risk (sd = 0.024), and the EU model predicted 0.103 risk (sd = 0.040). CONCLUSIONS: The results based on these methods indicate that EU vehicles most likely have a lower risk of MAIS3+F injury in front/side impacts, while US vehicles most likely have a lower risk of MAIS3+F injury in llroovers. These results should be interpreted with an understanding of the uncertainty of the estimates, the study limitations, and our recommendations for further study detailed in the report. PMID- 29482896 TI - Police documentation of drug use in injured drivers: Implications for monitoring and preventing drug-impaired driving. AB - INTRODUCTION: Most countries have laws against driving while impaired by drugs. However, in many countries, including Canada and the United States, police must have individualized suspicion that the driver has recently used an impairing substance before they can gather the evidence required for laying a criminal charge. This report studies police documentation of drug involvement among drivers who had a motor-vehicle crash after using an impairing substance. METHODS: We obtained blood samples and police reports on injured drivers treated in participating British Columbia trauma centres following a crash. Blood was analyzed for alcohol, cannabinoids, other recreational drugs, and impairing medications. Corresponding police reports were examined to determine whether police recorded that the driver's ability was impaired by alcohol, drug or medication, or that one of these substances was a possible contributory factor in the crash. RESULTS: We obtained blood samples and corresponding police reports on 1816 injured drivers. Mean driver age was 44 years, 63.2% were male, and 25.8% were admitted to hospital. Alcohol was detected in 272 drivers (15.0%), THC (tetrahydrocannabinol - the principal psychoactive ingredient in cannabis) in 136 (7.5%), other recreational drugs in 166 (9.1%), and potentially impairing medications in 363 (20.0%). Police reported that the driver's ability was impaired by alcohol or that alcohol was a possible contributory factor in 64.1% of the crashes involving alcohol-positive drivers. Drug impairment or drugs as a possible contributory factor was reported in 5.9% of the crashes involving THC positive drivers, and in 16.9% of the crashes involving drivers who tested positive for other recreational drugs. Medication impairment was reported in only 2.2% of the crashes involving medication-positive drivers. CONCLUSION: Police seldom document drug involvement in drivers who were in a crash after using cannabis, other recreational drugs or potentially impairing medications. This finding raises serious concerns about the ability of the police to effectively enforce current drug-impaired driving laws and public health officials' continued reliance on police crash reports to monitor the prevalence of drug-impaired driving. PMID- 29482898 TI - The Voices of Older African American Women Living with HIV Disease. AB - African American women are disproportionately affected by HIV. We used a phenomenological approach to understand the experiences of living with HIV in a group of older African American women. Approvals were obtained, and a criterion sample of 10 participants who self-identified as African American were recruited. Data were collected using unstructured interviews. The emergence of seven essential themes resulted in a textual interpretative statement that indicated that the meaning of living with HIV disease for this group of older African American women was (a) the dynamic interrelated patterning processes of transcending adversity and becoming as they responded to their emotional ebbs and flows, (b) being always hypervigilant to HIV stigma, and (c) managing the paradoxical process of concealing while revealing aspects of their lives with HIV. The women used knowledge as empowerment and strove to maintain relationality by caring for others while they, themselves, were being cared for. PMID- 29482899 TI - The Afferent Limb of Rapid Response Systems: Continuous Monitoring on General Care Units. AB - The prevention of adverse events continues to be the focus of patient safety work. Although rapid response systems have improved the efferent limb of the patient's rescue, the detection of the patient's deterioration (the afferent limb) has not been solved. This article provides an overview of the complex issues surrounding patient surveillance by addressing the principal considerations of continuous monitoring as they relate to implementation, choice of sensors and physiologic variables, notification, and alarm balancing, as well as future research opportunities. PMID- 29482900 TI - Trigger Criteria: Big Data. AB - Electronic medical records can be used to mine clinical data (big data), providing automated analysis during patient care. This article describes the source and potential impact of big data analysis on risk stratification and early detection of deterioration. It compares use of big data analysis with existing methods of identifying at-risk patients who require rapid response. Aggregate weighted scoring systems combined with big data analysis offer an opportunity to detect clinical changes that precede rapid response team activation. Future studies must determine if this will decrease transfers to intensive care units and cardiac arrests on the floors. PMID- 29482901 TI - Surgical Rescue in Medical Patients: The Role of Acute Care Surgeons as the Surgical Rapid Response Team. AB - Failure to rescue is death occurring after a complication. Rapid response teams developed as a prompt intervention for patients with early clinical deterioration, generally from medical conditions or complications. Patients with surgical complications or surgical pathology require prompt evaluation and management by surgeons to avoid deterioration; this is surgical rescue. Patients in the medical intensive care unit may develop intra-abdominal pathology that requires expeditious operative intervention. Acute care surgeons should serve as the surgical rapid response team to help assess and manage these complex patients. Collaboration between intensivists and surgeons is essential to rescue patients from complications and surgical disease. PMID- 29482902 TI - Crisis Teams for Obstetric Patients. AB - An obstetric-specific crisis team allows institutions to optimize the care response for patients with emergent maternal or fetal needs. Characteristics of optimal obstetric rapid response teams are team member role designations; streamlined communication; prompt access to resources; ongoing education, rehearsal, and training; and continual team quality analysis. The outcomes must be incorporated into team responses and reinforced in training. Team response provides a key resource to reassure staff, physicians, and patients that prompt crisis care is only a single call away. Data show that team activation is common, improves the care process, and has promise to improve outcomes. PMID- 29482903 TI - A Decade of Difficult Airway Response Team: Lessons Learned from a Hospital-Wide Difficult Airway Response Team Program. AB - A decade ago the Difficult Airway Response Team (DART) program was created at The Johns Hopkins Hospital as a multidisciplinary effort to address airway-related adverse events in the nonoperative setting. Root cause analysis of prior events indicated that a major factor in adverse patient outcomes was lack of a systematic approach for responding to difficult airway patients in an emergency. The DART program encompasses operational, safety, and educational initiatives and has responded to approximately 1000 events since its initiation, with no resultant adult airway-related adverse events or morbidity. This article provides lessons learned and recommendations for initiating a DART program. PMID- 29482904 TI - Sepsis Rapid Response Teams. AB - Sepsis rapid response teams are being incorporated into hospitals around the world. Based on the concept of the medical emergency team, the sepsis rapid response team consists of a specifically trained team of health care providers educated in the early recognition, diagnosis, and treatment of patients at risk of having or who have sepsis. Using hospital-wide initiatives consisting of multidisciplinary education, training, and specific resource utilization, such teams have been found to improve patient outcomes. PMID- 29482905 TI - Intensivist Presence at Code Events Is Associated with High Survival and Increased Documentation Rates. AB - To better support the highest function of the Johns Hopkins Hospital adult code and rapid response teams, a team leadership role was created for a faculty intensivist, with the intention to integrate improve processes of care delivery, documentation, and decision-making. This article examines process and outcomes associated with the introduction of this role. It demonstrates that an intensivist has the potential to improve patient care while offsetting costs through improved billing capture. PMID- 29482906 TI - Applied Physiology of Fluid Resuscitation in Critical Illness. AB - Fluids during resuscitation from shock increase mean systemic pressure and venous return. The pressure gradient for venous return must increase. Mean systemic pressure is the amount of vascular space in unstressed and stressed volume, mostly unstressed. Shock states can decrease mean systemic pressure by increasing unstressed volume, decreasing total blood volume, or decreasing the pressure gradient for venous return. Crystalloids across bodily spaces restore normal volume, whereas colloids remain in the intravascular space. Electrolyte content of fluids matters and excess chloride impairs renal blood flow. Albumin seems to be more effective at restoring blood volume in severe sepsis, but not in other conditions. PMID- 29482908 TI - Blood Product Administration in the Critical Care and Perioperative Settings. AB - The critical care and perioperative settings are high consumers of blood products, with multiple units and different products often given to an individual patient. The recommendation of this review is always to consider the risks and benefits for a specific blood product for a specific patient in a specific clinical setting. Optimize patient status by treating anemia and preventing the need for red blood cell transfusion. Consider other options for correction of anemia and coagulation disorders and use an imperative non-overtransfusion policy for all blood products. PMID- 29482907 TI - Does Fluid Type and Amount Affect Kidney Function in Critical Illness? AB - Acute kidney injury (AKI) is common, although commonly used clinical diagnostic markers are imperfect. Intravenous fluid administration remains a cornerstone of therapy worldwide, but there is minimal evidence of efficacy for the use of fluid bolus therapy outside of specific circumstances, and emerging evidence associates fluid accumulation with worse renal outcomes and even increased mortality among critically ill patients. Artificial colloid solutions have been associated with harm, and chloride-rich solutions may adversely affect renal function. Large trials to provide guidance regarding the optimal fluid choices to prevent or ameliorate AKI, and promote renal recovery, are urgently required. PMID- 29482909 TI - Why RRS? Where RRS? PMID- 29482910 TI - Fluid Therapy in the Critically Ill. PMID- 29482911 TI - Modified Yarham and Smith scores for pathogenicity assessment of mtDNA tRNA variants - Response. PMID- 29482912 TI - Erratum to "Guidelines of the French Society of Otorhinolaryngology (SFORL), short version. Extension assessment and principles of resection in cutaneous head and neck tumors" [Eur. Ann. Otorhinolaryngol. Head Neck Dis. 131 (6) (2014) 375 383]. PMID- 29482913 TI - Single onabotulinumtoxinA 200U dose improved clinical symptoms but not urothelial dysfunction in neurogenic detrusor overactivity due to spinal cord injury. AB - OBJECTIVE: To evaluate the changes in urothelial dysfunction protein expressions in bladder after onabotulinumtoxin injection and correlate that with clinical outcomes in spinal cord injury (SCI) patients. METHODS: Twenty-six patients with neurogenic detrusor overactivity (NDO) and urinary incontinence due to suprasacral SCI were treated with onabotulinumtoxinA 200U detrusor injection. Urodynamic studies and bladder biopsies were obtained at baseline, 3, and 6 months after treatment. Biopsy tissues were investigated for E-cadherin, zonula occludens-1 (ZO-1), mast cell activity, and urothelial cell apoptosis, sensory protein expression including purinergic receptor P2X3, endothelial NOS, inducible NOS, beta3-adrenoceptors, and muscarinic receptors M2 and M3. Differences in functional protein expression between controls and SCI patients and between successful and failed treatment groups were analyzed. RESULTS: SCI patients had significantly lower E-cadherin, higher mast cell activity, increased apoptosis, decreased M3 and eNOS expressions than the controls at baseline. Of the 26 patients, 17 (65%) showed improvement in bladder capacity by >50% at 3 months; however, improvement declined by 6 months after treatment. The urothelial expression of E-cadherin and ZO-1 increased at 3 months but had declined at 6 months. The urothelial sensory protein expression did not change significantly after treatment. M3 receptor density was significantly decreased in SCI patients at baseline and patients with treatment success 3 months after injection (p = 0.01). CONCLUSION: A single injection of onabotulinumtoxinA 200U improved clinical symptoms but did not significantly alter urothelial sensory protein expression. The results imply that a single 200U onabotulinumtoxinA dose might not be adequate for urothelial dysfunction in NDO. IRB: TCGH 098-53. PMID- 29482914 TI - [First results of a German second opinion program show high patient satisfaction and large discrepancies between initial therapy recommendations and second opinion]. AB - BACKGROUND AND OBJECTIVES: Although legally anchored, there are no empirical results from German second opinion programs. In this study, various aspects within a population of a second opinion program are examined. METHODS: In this study patients were analyzed who sought a second opinion in the period from August 2011 to December 2016. Differences in patient characteristics, differentiated by agreement of first and second opinion, were analyzed using multivariate logistic regression. Patients' satisfaction and quality of life were examined one, three and six months after obtaining the second opinion. RESULTS: In total, 1,414 patients sought a second opinion. Most frequently, second opinions were sought on knee (38.7 %), back (26.8 %), hip (11.7 %), and shoulder (10.2 %) complaints. Except for the indication (p=0.035), no patient characteristic had influence on the conformation of the second opinion. Approximately two out of three initial recommendations were not confirmed by the specialists. 89 % of the patients were satisfied or very satisfied with the second opinion and the service offered. CONCLUSIONS: The second opinion offers patients the opportunity to seek an additional independent medical opinion and thus provides support for decision making. Further research is needed to examine the reasons for the high discrepancies between the first and second opinions. PMID- 29482915 TI - The effect of encoding duration on implicit and explicit eyewitness memory. AB - The present study investigated the effect of encoding duration on implicit and explicit eyewitness memory. Participants (N = 227) viewed a mock crime (brief, 15 s vs. long, 30-s vs. irrelevant/control) and were then tested with both implicit and explicit memory prompts or with explicit memory prompts only. Brief-encoding participants revealed more critical details implicitly than long-encoding or control participants. Further, the number and percentage of accurate details recalled explicitly were higher for long-encoding than for brief-encoding participants. Implicit testing prior to explicit recall-as compared to completing a filler task-was detrimental to free recall performance. Interestingly, brief encoding participants were significantly more likely to remember critical details implicitly but not explicitly than long-encoding participants. This is the first study to investigate implicit eyewitness memory for a multimodal mock crime. Findings are theoretically consistent with prior research on cognition while expanding upon the extant eyewitness memory and investigative interviewing literature. PMID- 29482916 TI - Attention is a sterile concept; iterative reentry is a fertile substitute. AB - Attention has been defined as a filter, a limited resource, a spotlight, a zoom lens, and even as a glue that binds disconnected visual features into a coherent object. Here, I claim that all of these metaphor-based explanations are circular. As such, they fail to provide adequate accounts of the phenomena they are purported to explain. In contrast, those very phenomena can be explained on the idea that perceptions emerge from iterative exchanges between cortical regions linked by two-way pathways. Processing can occur in one of two modes: feed forward and reentrant. In feed-forward mode, the system is configured optimally for the expected input, and perception occurs on the feed-forward sweep. This form of processing corresponds to what is commonly referred to as "preattentive". If the system cannot be configured appropriately, perceptions emerge from iterative reentrant processing, which is slower, and corresponds to what is commonly referred to as "attentive". PMID- 29482917 TI - Peritraumatic distress predicts depression in traumatically injured patients admitted to a Level I trauma center. PMID- 29482918 TI - Early toxicity and health-related quality of life results of high-dose-rate brachytherapy as monotherapy for low and intermediate-risk prostate cancer. AB - PURPOSE: To determine the acute toxicity and effect on health-related quality of life of a two-fraction regimen of high-dose-rate (HDR) prostate brachytherapy. METHODS AND MATERIALS: Patients with low- or intermediate-risk prostate cancer were treated with HDR brachytherapy as monotherapy in two implants of 13.5 Gy spaced 7-14 days apart. Patients completed International Prostate Symptom Score (IPSS) and Expanded Prostate Index Composite (EPIC) questionnaires at 1, 3, 6, 9, 12, 16, 20, and 24 months after brachytherapy. Proportion of patients in each IPSS category (mild = 0-7, moderate = 8-18, severe = 19+) was evaluated at each of the intervals above. Paired t tests with baseline values were done for IPSS and EPIC scores. RESULTS: Thirty patients were accrued to the study. Median prostate-specific antigen was 8,7 (range 4.1-17.5). T stages were T1c = 65%, T2a = 21%, and T2b = 14%. Twenty-seven percent of patients had a Gleason score of 6 and 73% had a Gleason score of 7. IPSS categories at baseline, 1, 3, 6, 12, and 24 months were mild (81%, 43%, 58%, 62%, 76%, 64%), moderate (19%, 32%, 29%, 30%, 20%, 29%), and severe (0%, 25%, 13%, 7%, 4%, 6%), respectively. There was a significant decrease in EPIC sexual summary scores at 1, 3, 6, and 12 months of 0 points (p < 0.001), 17 points (p = 0.01), 18 points (p = 0.02), and 17 points (p = 0.01), respectively. CONCLUSIONS: This is the first report of this cohort of patients treated with two-fraction HDR monotherapy. This regimen shows rates of toxicity and health-related quality of life that appear acceptable as compared to other treatment modalities. These results are also comparable with other reports with similar treatment regimens. PMID- 29482919 TI - SARS-CoV related Betacoronavirus and diverse Alphacoronavirus members found in western old-world. AB - The emergence of SARS-CoV and MERS-CoV, triggered the discovery of a high diversity of coronaviruses in bats. Studies from Europe have shown that coronaviruses circulate in bats in France but this reflects only a fraction of the whole diversity. In the current study the diversity of coronaviruses circulating in western Europe was extensively explored. Ten alphacoronaviruses in eleven bat species belonging to the Miniopteridae, Vespertilionidae and Rhinolophidae families and, a SARS-CoV-related Betacoronavirus in Rhinolophus ferrumequinum were identified. The diversity and prevalence of bat coronaviruses presently reported from western Europe is much higher than previously described and includes a SARS-CoV sister group. This diversity demonstrates the dynamic evolution and circulation of coronaviruses in this species. That said, the identified coronaviruses were consistently associated with a particular bat species or genus, and these relationships were maintained no matter the geographic location. The observed phylogenetic grouping of coronaviruses from the same species in Europe and Asia, emphasizes the role of host/pathogen coevolution in this group. PMID- 29482920 TI - Otolaryngology-Related Disorders in Underserved Populations, Otolaryngology Training and Workforce Considerations in North America. AB - In North America, underserved and vulnerable populations experience poorer health outcomes despite greater per capita health care expenditures. Biologic, behavioral, and socioeconomic factors lead to more advanced disease presentation that may necessitate disparate treatment. Additionally, vulnerable populations are more likely to obtain care from low-volume providers, and are more likely to receive inappropriate care. Disparities in care are exacerbated by the distribution of the physician workforce and limited participation by physicians in the care of vulnerable populations. Multipronged strategies are needed to ameliorate observed disparities in care. PMID- 29482921 TI - Workforce Considerations, Training, and Diseases of the Asia-Pacific Region. AB - The Asia-Pacific region has 60% of the world's population. There is a huge variability in ethnic groups, geography, diseases, and income. The otolaryngology workforce depends on the number of medical graduates, training programs, scope of practice, and available employment. Training has been influenced by the British, Russian, and US training systems, and by local influences and experience. Otolaryngologic diseases are similar to those seen in the United States but with ethnic and regional differences. There are opportunities for humanitarian service but the most sustainable projects will include repetitive visits with transfer of knowledge. PMID- 29482923 TI - Noninvasive Ventilation as a Temporizing Measure in Critical Fixed Central Airway Obstruction: A Case Report. AB - BACKGROUND: Critical central airway obstruction (CAO) requires emergent airway intervention, but current guidelines lack specific recommendations for airway management in the emergency department (ED) while awaiting rigid bronchoscopy. There are few reports of the use of noninvasive ventilation (NIV) in tracheomalacia, but its use as a temporizing treatment option in fixed, malignant CAO has not, to the best of our knowledge, been reported. CASE REPORT: An 84-year old woman presented to the ED in respiratory distress, too breathless to speak and using her accessory muscles of respiration, with bilateral rhonchi throughout the lung fields. Point-of-care arterial blood gas revealed severe hypercapnia, and NIV was initiated to treat a presumed bronchitis with hypercapnic respiratory failure. Chest radiography revealed a paratracheal mass with tracheal deviation and compression. A diagnosis of critical CAO was made. While arranging for rigid bronchoscopic stenting, the patient was kept on NIV to good effect. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Recommendations for emergent treatment of life-threatening, critical CAO before bronchoscopic intervention are not well established. Furthermore, reports of NIV use in CAO are rare. We suggest that emergency physicians consider NIV as a temporizing measure for critical CAO while awaiting availability of bronchoscopy. PMID- 29482922 TI - Use of Targeted Therapeutics in Epithelial Ovarian Cancer: A Review of Current Literature and Future Directions. AB - PURPOSE: Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer death in the United States. Most patients will ultimately fail platinum based chemotherapy and have the disease recur. Interest is increasing in the use of targeted therapies in the treatment of EOC. This review focuses on the current use of targeted therapeutics in EOC as well as future directions. METHODS: A literature search of Medline and PubMed was conducted (January 2000-October 2017) to identify recent reports of targeted drugs in EOC. FINDINGS: A wide range of targeted therapeutics is currently being used as both monotherapy and in combination in the treatment of EOC. Clinically, the most commonly used classes of drugs currently are antiangiogenics and poly (ADP-ribose) polymerase inhibitors. However, a number of drugs in varying stages in development target a wide range of biochemical pathways. Activity and response rates of these drugs vary greatly. Questions continue about combination drug therapy and appropriate patient selection. IMPLICATIONS: The use of targeted therapeutics in the treatment of EOC, both as monotherapy and in combination, will continue to expand as more mechanisms of tumorigenesis are identified. Multiple clinical trials of a wide range of targeted therapeutics are currently ongoing. Evidence-based selection of drug targets and appropriate patient populations will allow strategic application of targeted therapeutics. PMID- 29482924 TI - Movement disorders associated with Neurocysticercosis. PMID- 29482925 TI - Climbing fiber-Purkinje cell synaptic pathology across essential tremor subtypes. AB - BACKGROUND: Essential tremor (ET) is heterogeneous in nature and cases may be subdivided based on clinical features. ET patients may thus be subdivided by age of onset, family history of tremor, and presence of head tremor. We recently described climbing fiber-Purkinje cell (CF-PC) synaptic abnormalities in ET; however, these CF pathological features have not been studied across different ET subtypes. OBJECTIVES: To explore whether these CF-PC synaptic abnormalities differ across ET subtypes. METHODS: We studied two climbing fiber (CF-PC) synaptic pathologies (CF synaptic density and percentage of CFs in the parallel fiber [PF] territory) in the cerebella of 60 ET cases with a range of clinical presentations and 30 age-matched controls. RESULTS: Compared to controls, ET cases had lower CF synaptic density and a higher percentage of CFs in the PF territory. ET cases with tremor onset <50 years and tremor onset >= 50 years did not differ significantly with respect to CF synaptic density and percentage of CFs in the PF territory. Similar results were found when comparing familial vs. sporadic ET cases, and ET cases with head tremor vs. those without head tremor. Among all ET cases, lower CF synaptic density was associated with lower PC counts and higher torpedo counts. In addition, higher percentage of CFs in the PF territory was associated with lower PC counts and higher torpedo counts. CONCLUSIONS: These findings support the notion that changes in the distribution of CF-PC synapses are broadly part of the neurodegenerative process in the ET cerebellum. PMID- 29482926 TI - The influence of joint rigidity on impact efficiency and ball velocity in football kicking. AB - Executing any skill with efficiency is important for performance. In football kicking, conflicting and non-significant results have existed between reducing ankle plantarflexion during foot-ball contact with impact efficiency, making it unclear as to its importance as a coaching instruction. The aims of this study were to first validate a mechanical kicking machine with a non-rigid ankle, and secondly compare a rigid to a non-rigid ankle during the impact phase of football kicking. Measures of foot-ball contact for ten trials per ankle configuration were calculated from data recorded at 4000 Hz and compared. The non-rigid ankle was characterised by initial dorsiflexion followed by plantarflexion for the remainder of impact, and based on similarities to punt and instep kicking, was considered valid. Impact efficiency (foot-to-ball speed ratio) was greater for the rigid ankle (rigid = 1.16 +/- 0.02; non-rigid = 1.10 +/- 0.01; p < 0.001). The rigid ankle was characterised by significantly greater effective mass and significantly less energy losses. Increasing rigidity allowed a greater portion of mass from the shank to be used during the collision. As the ankle remained in plantarflexion at impact end, stored elastic energy was not converted to ball velocity and was considered lost. Increasing rigidity is beneficial for increasing impact efficiency, and therefore ball velocity. PMID- 29482927 TI - Measurement of lower limb segmental excursion using inertial sensors during single limb stance. AB - Advances in wearable technology have afforded health scientists and clinicians the ability to quantify clinically meaningful kinematic data with performance based outcome measures in a variety of environments. However, no method for assessing segmental excursion of the lower limb during single limb stance (SLS) with wearable technology has been described in the literature nor has its clinical meaning been explored. This study introduces a clinically friendly measure to quantify lower limb segmental excursion during SLS with inertial measurement units (IMUs) which called the region of limb stability (ROLS). The purpose of this study was to determine the concurrent validity of an IMU-based system versus an optical motion capture system and to determine the effects of knee injury on the ROLS value. Excursion areas of five healthy adults were calculated with the IMU-based system and data were compared with an optical motion capture system. There were high correlations (0.82-0.93) and no significant difference (p > 0.05) in the tested parameters between the optical- and IMU-based systems. The IMU-based method was also implemented in five Division I athletes with knee injuries to determine changes in ROLS due to the injury. The ROLS Symmetry Index value offered a higher sensitivity and specificity to assess the presence of knee impairment than the sacral IMU. Quantified lower limb segmental excursion via IMUs can make better and more precise return-to-sport decisions that would decrease the risk of re-injury. PMID- 29482928 TI - Population-specific material properties of the implantation site for transcatheter aortic valve replacement finite element simulations. AB - Patient-specific computational models are an established tool to support device development and test under clinically relevant boundary conditions. Potentially, such models could be used to aid the clinical decision-making process for percutaneous valve selection; however, their adoption in clinical practice is still limited to individual cases. To be fully informative, they should include patient-specific data on both anatomy and mechanics of the implantation site. In this work, fourteen patient-specific computational models for transcatheter aortic valve replacement (TAVR) with balloon-expandable Sapien XT devices were retrospectively developed to tune the material parameters of the implantation site mechanical model for the average TAVR population. Pre-procedural computed tomography (CT) images were post-processed to create the 3D patient-specific anatomy of the implantation site. Balloon valvuloplasty and device deployment were simulated with finite element (FE) analysis. Valve leaflets and aortic root were modelled as linear elastic materials, while calcification as elastoplastic. Material properties were initially selected from literature; then, a statistical analysis was designed to investigate the effect of each implantation site material parameter on the implanted stent diameter and thus identify the combination of material parameters for TAVR patients. These numerical models were validated against clinical data. The comparison between stent diameters measured from post-procedural fluoroscopy images and final computational results showed a mean difference of 2.5 +/- 3.9%. Moreover, the numerical model detected the presence of paravalvular leakage (PVL) in 79% of cases, as assessed by post-TAVR echocardiographic examination. The final aim was to increase accuracy and reliability of such computational tools for prospective clinical applications. PMID- 29482930 TI - Hydrostatic pressure gradient ultrafiltration device: A novel approach for extracellular fluid removal. PMID- 29482929 TI - WASP (Write a Scientific Paper) using Excel -5: Quartiles and standard deviation. AB - The almost inevitable descriptive statistics exercise that is undergone once data collection is complete, prior to inferential statistics, requires the acquisition of basic descriptors which may include standard deviation and quartiles. This paper provides pointers as to how to do this in Microsoft ExcelTM and explains the relationship between the two. PMID- 29482931 TI - Prognostic relevance of appropriate renal function evaluation in pulmonary arterial hypertension. PMID- 29482932 TI - Does recipient work status pre-transplant affect post-heart transplant survival? A United Network for Organ Sharing database review. AB - BACKGROUND: Recipient-related factors, such as education level and type of health insurance, are known to affect heart transplantation outcomes. Pre-operative employment status has shown an association with survival in abdominal organ transplant patients. We sought to evaluate the effect of work status of heart transplant (HTx) recipients at the time of listing and at the time of transplantation on short- and long-term survival. METHODS: We evaluated the United Network for Organ Sharing (UNOS) registry for all adult HTx recipients from 2001 to 2014. Recipients were grouped based on their work status at listing and at heart transplantation. Kaplan-Meier estimates illustrated 30-day, 1-year, 5-year, and 10-year survival comparing working with non-working groups. The Cox proportional hazards regression model was applied to adjust for covariates that could potentially confound the post-transplantation survival analysis. RESULTS: Working at listing for HTx was not significantly associated with 30-day and 1 year survival. However, 5- and 10-year mortality were 14.5% working vs 19.8% not working (p < 0.0001) and 16% working vs 26% not working (p < 0.0001), respectively. Working at HTx appeared to be associated with a survival benefit at every time interval, with a trend toward improved survival at 30 days and 1 year and a significant association at 5 and 10 years. Kaplan-Meier analysis demonstrated a 5% and 10% decrease in 5- and 10-year mortality, respectively, for the working group compared with the group not working at transplantation. The Cox proportional hazards regression model showed that working at listing and working at transplantation were each associated with decreased mortality (hazard ratio [HR] = 0.8, 95% confidence interval [CI] 0.71 to 0.91; and HR = 0.76, 95% CI 0.65 to 0.89, respectively). CONCLUSIONS: This study is the first analysis of UNOS STAR data on recipient work status pre-HTx demonstrating: (1) an improvement in post-transplant survival for working HTx candidates; and (2) an association between working pre-HTx and longer post-HTx survival. Given that work status before HTx may be a modifiable risk factor for better outcomes after HTx, we strongly recommend that UNOS consider these important findings for moving forward this patient-centered research on work status. Working at listing and working at HTx are associated with long-term survival benefits. The association may be reciprocal, where working identifies less ill patients and also improves well being. Consideration should be given to giving additional weight to work status during organ allocation. Work status may also be a modifiable factor associated with better post-HTx outcomes. PMID- 29482933 TI - Deletion of Thioredoxin-interacting protein ameliorates high fat diet-induced non alcoholic steatohepatitis through modulation of Toll-like receptor 2-NLRP3 inflammasome axis: Histological and immunohistochemical study. AB - Endemic prevalence of obesity is associated with alarming increases in non alcoholic steatohepatitis (NASH) with limited available therapeutics. Toll-like receptor2 (TLR2) and Nod-like receptor protein 3 (NLRP3) Inflammasome are implicated in hepatic steatosis, inflammation and fibrosis; the histological landmark stages of NASH. TXNIP, a member of alpha-arrestin family activates NLRP3 in response to various danger stimuli. The aim of current work was to investigate the effect of TXNIP genetic deletion on histological manifestations of high fat diet-induced steatohepatitis and activation of TLR2-NLRP3-inflammasome axis. Wild type mice (WT) and TXNIP knock out (TKO) littermates were randomized to normal diet (WT-ND and TKO-ND) or high fat diet (HFD, 60% fat) (WT-HFD and TKO-HFD). After 8-weeks, liver samples from all groups were evaluated by histological, immunohistochemical and western blot analysis. HFD resulted in significant induction of micro and macrovesicular hepatic steatosis, that was associated with increased inflammatory immune cell infiltration in WT-HFD compared with WT-ND and TKO-ND controls, but not in TKO-HFD group. In parallel, WT-HFD group showed significant fibrosis and alpha-SMA expression; a marker of pro-fibrotic stellate cell activation, in areas surrounding the central vein and portal circulation, versus all other groups. Western blot revealed increased activation of TLR2-NLRP3 inflammasome pathway and downstream IL-1beta and TNFalpha in WT-HFD group, but not in TKO-HFD group. IL-1beta expression coincided within the same areas of steatosis, inflammatory cell infiltration, collagen deposition and alpha-SMA expression in WT-HFD mice, that was significantly reduced in TKO-HFD mice. In conclusion, TXNIP deletion ameliorates the HFD-induced steatosis, inflammatory and fibrotic response via modulation of TLR2-NLRP3 inflammasome axis. Targeting TXNIP-TLR2-NLRP3 pathway may provide potential therapeutic modalities for NASH treatment. PMID- 29482934 TI - Association of Ring Finger Protein 213 Gene P.R4810k Polymorphism with Intracranial Major Artery Stenosis/Occlusion. AB - BACKGROUND: Intracranial major artery stenosis/occlusion (ICASO) is a common cause of ischemic stroke worldwide. A number of studies have assessed the association of the p.R4810K polymorphism in the ring finger protein 213 (RNF213) gene with ICASO, but the results have not been entirely consistent. METHODS: We conducted a case-control study to estimate the association between the p.R4810K polymorphism and the risk of ICASO in a Chinese population. A total of 124 patients and 230 controls were enrolled. Moreover, a meta-analysis was performed to evaluate this association in the East Asian populations. RESULTS: In our case control study, the frequencies of the G/A genotype of p.R4810K were significantly higher in the ICASO patients than in the control group (4.03% versus .43%, P = .021, respectively). Moreover, in the meta-analysis, we assessed 7 case-control studies that included 1239 patients and 1377 controls. The pooled odds ratios (ORs) indicated significant association between the p.R4810K polymorphism and the ICASO risk in the dominant model (OR = 9.37, 95% confidence interval: 4.61-19.02, P = .000), the heterozygote comparison (OR = 8.97, 95% CI: 4.41-18.25, P = .000), and the allele comparison (OR = 9.50, 95% confidence interval: 4.71-19.19, P = .000) in the East Asian populations. Subgroup analysis based on ethnicity revealed that the risks in the Japanese and the Korean populations were higher than that in the Chinese population. CONCLUSIONS: The p.R4810K polymorphism was associated with an increased risk of ICASO in the East Asian populations. Further studies on the function of the RNF213 protein and the clinical features of this subtype of ICASO are needed. PMID- 29482935 TI - Physical Activity in Kidney Transplant Recipients: A Review. AB - Physical activity has known health benefits and is associated with reduced cardiovascular risk in the general population. Relatively few data are available for physical activity in kidney transplant recipients. Compared to the general population, physical activity levels are lower overall in kidney recipients, although somewhat higher compared to the dialysis population. Recipient comorbid condition, psychosocial and socioeconomic factors, and long-term immunosuppression use negatively affect physical activity. Physical inactivity in kidney recipients may be associated with reduced quality of life, as well as increased mortality. Interventions such as exercise training appear to be safe in kidney transplant recipients and are associated with improved quality of life and exercise capacity. Additional studies are required to evaluate long-term effects on cardiovascular risk factors and ultimately cardiovascular disease outcomes and patient survival. Currently available data are characterized by wide variability in the interventions and outcome measures investigated in studies, as well as use of small sample-sized cohorts. These limitations highlight the need for larger studies using objective and standardized measures of physical activity and physical fitness in kidney transplant recipients. PMID- 29482937 TI - Perioperative Management of Cardiovascular Medications. PMID- 29482936 TI - Two-Year Outcomes of Sacral Neuromodulation Versus OnabotulinumtoxinA for Refractory Urgency Urinary Incontinence: A Randomized Trial. AB - BACKGROUND: Urgency urinary incontinence (UUI) is a chronic condition for which sacral neuromodulation (SNM) (InterStim/Medtronic) and onabotulinumtoxinA (BTX) (BotoxA/Allergan) are utilized. These therapies have not been compared over extended time. OBJECTIVE: To compare UUI episodes (UUIE) over 24 mo following SNM or BTX. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, open-label, randomized, extension trial (February 2012-July 2016) at nine US medical centers involving 386 women with >=6 UUIE over 3 d inadequately managed by medications. Participants were clinical responders to treatment: >=50% reduction in UUIEs after SNM placement or 1 mo post BTX. INTERVENTION: SNM (n=194) versus 200 U BTX (n=192). SNM reprogrammings occurred throughout the 24 mo. After 6 mo, two additional BTX injections were allowed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary outcome: change in mean daily UUIE over 24 mo. SECONDARY OUTCOMES: no UUIE, >=75% and >=50% UUIE reduction; Overactive Bladder Questionnaire Short Form; Urinary Distress Inventory short form; Incontinence Impact Questionnaire; Patient Global Impression of Improvement; Overactive Bladder Satisfaction of Treatment Questionnaire; and adverse events (AEs). Primary analysis used a linear mixed model. RESULTS AND LIMITATIONS: Outcome data were available for 260/298 (87%) clinical responders. No difference in decreased mean UUIE was found over 24 mo (-3.88 vs -3.50 episodes/d,95% confidence interval [CI]=-0.14-0.89; p=0.15), with no differences in UUI resolution, >=75% or >=50% UUIE reduction. BTX group maintained higher satisfaction (mean difference=-9.14, 95% CI=-14.38--3.90; p<0.001), treatment endorsement (mean difference=-12.16, 95% CI=-17.7--6.63; p<0.001) through 24 mo. Other secondary measures did not differ. Recurrent urinary tract infections (UTIs) were higher after BTX (24% vs 10%; p<0.01), 6% required intermittent catheterization post second injection. SNM revision and removals occurred in 3% and 9% patients, respectively. CONCLUSIONS: Both treatments offered sustainable UUI improvement, and higher BTX dosing had low clean intermittent catheterization rates, but with UTI risk. SNM revision/removal rates were low due to standardized lead placement with strict treatment response definitions. PATIENT SUMMARY: We compared a large group of US women with severe urgency urinary incontinence (UUI) who received sacral neuromodulation (InterStim) or onabotulinumtoxinA (Botox A) therapy during a 2-yr period. We found that both therapies had similar success in reducing UUI symptoms, and adverse events were low. However, women in the BotoxA group had higher satisfaction and endorsement with their treatment, but with a higher chance of a urinary tract infection. We conclude that both therapies offer sustained reduction in daily incontinence over 2 yr. PMID- 29482938 TI - Heparin Resistance and Intracardiac Thrombosis May Be a Harbinger of Heparin Induced Thrombocytopenia (HIT). PMID- 29482939 TI - Transvenous Lead Extraction: A Clinical Commentary for Anesthesiologists. AB - With increasing use of cardiovascular implantable electronic devices, the need for lead extractions has increased to an annual volume of more than 10,000 extractions worldwide. This article provides a focused clinical commentary on the perioperative management, identification, and treatment of life-threatening complications associated with lead extractions. In addition, a summary of indications, techniques, and lead extraction complications is provided. Although uncommon, lead extractions are associated with a consistent rate of major procedure-related complications and mortality. Major life-threatening complications include vascular laceration, cardiac avulsion, hemothorax, pericardial effusion, and cardiac arrest. Comprehensive preoperative risk assessment and adequate planning and preparedness are crucial to decreasing all procedure-related adverse events. The location of the procedure (electrophysiology suite v hybrid operating room) and the nature of cardiac surgical backup are determined after meticulous risk stratification. In addition to decisions on vascular access, invasive monitoring, and modality of rhythm support, transesophageal echocardiography plays a crucial role in early diagnosis, timely management, and potential prevention of these complications. PMID- 29482940 TI - Anti-inflammatory isoflavones and isoflavanones from the roots of Pongamia pinnata (L.) Pierre. AB - A phytochemical study on the roots of Pongamia pinnata afforded five new isoflavone and isoflavanone derivatives (1-5), including two previously undescribed phenylisoflavones possessing an 1,2-oxetane ring, along with 21 known compounds (6-26) among which compound 18 is the first time to be isolated from nature. The structures of the isolated compounds were determined on the basis of 1D, 2D NMR, and HRESIMS. The absolute configurations of the compounds were assigned via analysis of the specific rotations and circular dichroism (CD) spectra, as well as by comparison of the calculated and experimental electronic circular dichroism (ECD) data. All the isolated compounds were evaluated for their inhibitory effects on NO production in LPS-stimulated BV-2 microglial cells. Twelve compounds exhibited different levels of inhibitory effects against NO production, and compound 1 showed the best activity with an IC50 value at 9.0 MUM. PMID- 29482942 TI - New 4-aryl-1,3,2-oxathiazolylium-5-olates: Chemical synthesis and photochemical stability of a novel series of S-nitrosothiols. AB - S-nitrosothiols (RSNOs) remain one of the most popular classes of NO-donating compounds due to their ability to release nitric oxide (NO) under non-enzymatic means whilst producing an inert disulphide by-product. However, alligning these compounds to the different biological fields of NO research has proved to be problematic due to the inherent instability of such compounds under a variety of conditions including heat, light and the presence of copper ions. 1,3,2 Oxathiazolylium-5-olates (OZOs) represent an interesting subclass of S nitrosothiols that lock the -SNO moiety into a five membered heterocyclic ring in an attempt to improve the compound's overall stability. The synthesis of a novel series of halogen-containing OZOs was comprehensively studied resulting in a seven-step route and overall yields ranging between 21 and 37%. The photochemical stability of these compounds was assessed to determine if S-nitrosothiols locked within these mesoionic ring systems can offer greater stability and thereby release NO in a more controllable fashion than their non-cyclic counterparts. PMID- 29482941 TI - Design, synthesis, and in vitro evaluation of quinolinyl analogues for alpha synuclein aggregation. AB - Here we report the synthesis and in vitro evaluation of 25 new quinolinyl analogues for alpha-synuclein aggregates. Three lead compounds were subsequently labeled with carbon-11 or fluorine-18 to directly assess their potency in a direct radioactive competitive binding assay ng both alpha-synuclein fibrils and tissue homogenates from Alzheimer's disease (AD) cases. The modest binding affinities of these three radioligands toward alpha-synuclein were comparable with results from the Thioflavin T fluorescence assay. However, all three ligand also showed modest binding affinity to the AD homogenates and lack selectivity for alpha-synuclein. The structure-activity relationship data from these 25 analogues will provide useful information for design and synthesis of new compounds for imaging alpha-synuclein aggregation. PMID- 29482943 TI - Synthesis and evaluation of substituted 4-arylimino-3-hydroxybutanoic acids as potential HIV-1 integrase inhibitors. AB - A series of readily accessible 4-arylimino-3-hydroxybutanoic acids have been prepared and evaluated as potential HIV-1 Integrase inhibitors. None of the ligands exhibited significant toxicity against human embryonic kidney (HEK 293) cells, while five of them showed activity against HIV-1 integrase - the most active (6c) with an IC50 value of 3.5 MUM. In silico docking studies indicate the capacity of ligand 6c to interact with several amino acid residues and the two Mg2+ cations in the HIV-1 integrase receptor cavity. PMID- 29482944 TI - Synthesis and biological evaluation of 4,6-diaryl-2-pyrimidinamine derivatives as anti-breast cancer agents. AB - Breast cancer is the most frequently diagnosed cancers and the leading causes of cancer death among females worldwide. Estrogen receptor positive has been identified as the predominant internal reasons, involving in more than 70% breast cancer patients and SERMs which competes with estradiol for the binding to ERalpha in breast tissue are widely used in the treatment of ER+ breast cancer, such as tamoxifen, raloxifene. However, many SERMs may cause negative side effects due to their estrogenic activity in other tissues and approximate 50% of patients with ER-positive tumors either initially do not respond or become resistant to these drugs. Here, a series of designed 4,6-diaryl-2-pyrimidinamine derivatives had been synthesized to treat estrogen receptor positive breast cancer by simultaneously antagonizing ER and inhibiting VEGFR-2. Bioactivity evaluation showed that these compounds could significantly inhibit the proliferation of MCF-7, HUVEC and Ishikawa cells. Further studies identified compound III-3A could antagonize against estrogen action and inhibit the phosphorylation of VEGFR-2 as well as inhibit angiogenesis in vivo. The results indicated designed 4,6-diaryl-2-pyrimidinamine derivatives can be used to further study as anti-breast cancer drugs. PMID- 29482945 TI - Metformin influences drug sensitivity in pancreatic cancer cells. AB - Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, highly metastatic malignancy and accounts for 85% of pancreatic cancers. PDAC patients have poor prognosis with a five-year survival of only 5-10% after diagnosis and treatment. Pancreatic cancer has been associated with type II diabetes as the frequency of recently diagnosed diabetics that develop pancreatic cancer within a 10-year period of initial diagnosis of diabetes in increased in comparison to non diabetic patients. Metformin is a very frequently prescribed drug used to treat type II diabetes. Metformin acts in part by stimulating AMP-kinase (AMPK) and results in the suppression of mTORC1 activity and the induction of autophagy. In the following studies, we have examined the effects of metformin in the presence of various chemotherapeutic drugs, signal transduction inhibitors and natural products on the growth of three different PDAC lines. Metformin, by itself, was not effective at suppressing growth of the pancreatic cancer cell lines at concentration less than 1000 nM, however, in certain PDAC lines, a suboptimal dose of metformin (250 nM) potentiated the effects of various chemotherapeutic drugs used to treat pancreatic cancer (e.g., gemcitabine, cisplatin, 5 fluorouracil) and other cancer types (e.g., doxorubicin, docetaxel). Furthermore, metformin could increase anti-proliferative effects of mTORC1 and PI3K/mTOR inhibitors as well as natural products such as berberine and the anti-malarial drug chloroquine in certain PDAC lines. Thus, metformin can enhance the effects of certain drugs and signal transduction inhibitors which are used to treat pancreatic and various other cancers. PMID- 29482946 TI - [We need patients more obese]. PMID- 29482947 TI - Pharmacogenetics as Personalized Medicine: Association Investigation of SOD2 rs4880, CYP2C19 rs4244285, and FCGR2A rs1801274 Polymorphisms in a Breast Cancer Population in Iraqi Women. AB - BACKGROUND: Breast cancer is the most common cancer in women characterized by a high variable clinical outcome among individuals treated with targeted therapies. PATIENTS AND METHODS: In this study, we performed a population-based approach intersecting high-throughput genotype data from Iraqi populations with publicly available pharmacogenomics information to estimate the frequency of genotypes correlated with responsiveness to breast cancer treatment thus improving the clinical management of this disease in an efficient and cost effective way. A total of 50 patients and 25 healthy controls were enrolled in our study. Genotyping of rs4880, rs4244285, and rs1801274 were examined in association with breast cancer in Iraqi women. RESULTS: We found that individuals carrying the CT genotype of rs4880 manifested an increased risk of breast cancer compared with those carrying the TT genotype (odds ratio [OR], 0.171; 95% confidence interval [CI], 0.053-0.551; P = .002). In the dominant model, we observed that the CT and CC genotype of rs4880 showed an increased risk of breast cancer compared with the TT genotype (OR, 0.248; 95% CI, 0.089-0.690; P = .006). Moreover, subjects with the GA genotype of rs4244285 presented a higher risk of breast cancer than the GG genotype (OR, 0.256; 95% CI, 0.066-0.987; P = .038) and dominant models (OR, 0.025; 95% CI, 0.054-0.775; P = .013). CONCLUSION: The analysis revealed that rs1801274 showed linkage disequilibrium and decreased risk of breast cancer. In conclusion, our study suggests that rs4880 and rs4244285 polymorphisms play an important role in development of breast cancer in an Iraqi population, and no significant association was found between rs1801274 and the risk of breast cancer. PMID- 29482948 TI - No-shows in appointment scheduling - a systematic literature review. AB - No-show appointments significantly impact the functioning of healthcare institutions, and much research has been performed to uncover and analyze the factors that influence no-show behavior. In spite of the growing body of literature on this issue, no synthesis of the state-of-the-art is presently available and no systematic literature review (SLR) exists that encompasses all medical specialties. This paper provides a SLR of no-shows in appointment scheduling in which the characteristics of existing studies are analyzed, results regarding which factors have a higher impact on missed appointment rates are synthetized, and comparisons with previous findings are performed. A total of 727 articles and review papers were retrieved from the Scopus database (which includes MEDLINE), 105 of which were selected for identification and analysis. The results indicate that the average no-show rate is of the order of 23%, being highest in the African continent (43.0%) and lowest in Oceania (13.2%). Our analysis also identified patient characteristics that were more frequently associated with no-show behavior: adults of younger age; lower socioeconomic status; place of residence is distant from the clinic; no private insurance. Furthermore, the most commonly reported significant determinants of no-show were high lead time and prior no-show history. PMID- 29482949 TI - Improving health care service provision by adapting to regional diversity: An efficiency analysis for the case of Germany. AB - The provision of health care in Germany exhibits sizeable geographic variation with a heterogeneous allocation of medical services in rural and urban areas. Furthermore, distinct utilisation patterns and access barriers due to the socio economic environment might cause inefficiencies in the provision of health care services. Accordingly, an improved understanding of factors governing inefficiencies in health care provision is likely to benefit an efficient spatial allocation of health care infrastructure. We analyse how socio-economic factors influence the regional distribution of (in)efficiencies in the provision of health care services by means of a stochastic frontier analysis. Our results highlight that regional deprivation relates to inefficient provision of health care services. As a consequence, policies should also consider socio-economic conditions to improve the allocation of medical services and overall health. PMID- 29482950 TI - Structure-activity relationships for analogs of the tuberculosis drug bedaquiline with the naphthalene unit replaced by bicyclic heterocycles. AB - Replacing the naphthalene C-unit of the anti-tuberculosis drug bedaquiline with a range of bicyclic heterocycles of widely differing lipophilicity gave analogs with a 4.5-fold range in clogP values. The biological results for these compounds indicate on average a lower clogP limit of about 5.0 in this series for retention of potent inhibitory activity (MIC90s) against M.tb in culture. Some of the compounds also showed a significant reduction in inhibition of hERG channel potassium current compared with bedaquiline, but there was no common structural feature that distinguished these. PMID- 29482951 TI - Synthesis of 3-aza[4.4.3]propellanes with high sigma1 receptor affinity. AB - In order to obtain rigid sigma1 receptor ligands with defined orientation of pharmacophoric elements, the azapropellane scaffold was chosen. Schmidt rearrangement of propellan-8-ones 6 and 10 provided 3-azapropellan-4-ones 7 and 11. Benzylation of the secondary lactams 7 and 11 followed by LiAlH4 reduction furnished the azapropellanes 4a and 4c, respectively. A second hydrophobic element was introduced by transformation of the alcohols 4a into carbamates 4b. The sigma1 affinity of the azapropellanes 4 is strongly dependent on the stereochemistry and the substitution pattern in 12-position. anti-configured azapropellanes anti-4a and anti-4b show higher sigma1 affinity than their syn configured counterparts syn-4a and syn-4b. Conversion of the alcohol anti-4a into the carbamate anti-4b led to increased sigma1 affinity, but complete removal of the 12-substituent resulted in the highest sigma1 affinity (Ki(4c) = 17 nM). It can be concluded that the propellane scaffold alone is able to form strong lipophilic interactions and stabilize the ligand-sigma1 receptor complex as does usually the primary hydrophobic region. PMID- 29482952 TI - Site-selective installation of an electrophilic handle on proteins for bioconjugation. AB - Site-selective protein modification strategies can be used to insert non-natural functional groups into protein structures. Herein, we report on the use of the bis-electrophile 3-bromo-2-bromomethyl-1-propene as a reagent to introduce an electrophilic handle at cysteine residues under mild conditions. This method is demonstrated on a variety of proteins containing a solvent-exposed cysteine residue, including an anti-HER2 nanobody. Chemically distinct protein conjugates are then efficiently formed through further reaction of the electrophilic site with various nucleophiles, including thiols and amines. The resulting chemically defined conjugates are highly stable in the presence of glutathione or human plasma and retain both the structure and function of the native protein. PMID- 29482953 TI - Primary central nervous system lymphoma in immunocompetent patients: spectrum of findings and differential characteristics. AB - Primary central nervous system (CNS) lymphomas are uncommon and their management differs significantly from that of other malignant tumors involving the CNS. This article explains how the imaging findings often suggest the diagnosis early. The typical findings in immunocompetent patients consist of a supratentorial intraaxial mass that enhances homogeneously. Other findings to evaluate include multifocality and incomplete ring enhancement. The differential diagnosis of primary CNS lymphomas should consider mainly other malignant tumors of the CNS such as glioblastomas or metastases. Primary CNS lymphomas tend to have less edema and less mass effect; they also tend to spare the adjacent cortex. Necrosis, hemorrhage, and calcification are uncommon in primary CNS lymphomas. Although the findings in morphologic sequences are characteristic, they are not completely specific and atypical types are sometimes encountered. Advanced imaging techniques such as diffusion or especially perfusion provide qualitative and quantitative data that play an important role in differentiating primary CNS lymphomas from other brain tumors. PMID- 29482954 TI - Ventricular Ectopy in the Context of Left Ventricular Systolic Dysfunction: Risk Factors and Outcomes Following Catheter Ablation. AB - BACKGROUND: Ectopy-mediated cardiomyopathy (EMC) is a potentially reversible form of left ventricular systolic dysfunction. Various risk factors for the development of EMC have been proposed in the literature. We aim to assess medium term outcomes of focal ventricular arrhythmia (VA) ablation in the setting of cardiomyopathy (CMP) and to validate published risk factors for EMC. METHODS: Medium term recovery of left ventricular (LV) function and freedom from VA recurrence was assessed and compared between patients undergoing focal VA ablation in the setting of CMP and a control group with normal LV function. Univariate and multivariate analyses for CMP risk factors were performed and compared against prior published risk factors. RESULTS: Of 152 patients who underwent 170 focal VA ablation procedures, 54 (36%) had CMP and the remaining 98 patients had normal LV systolic function. At medium term follow-up, 85% of patients with CMP were free of VA recurrence and median left ventricular ejection fraction (LVEF) had improved from 40 to 52%. Age, male gender, premature ventricular complex (PVC) burden, non- right ventricular outflow tract (RVOT) sites of origin, PVC QRS duration and PVC minimum coupling interval were predictive of CMP on univariate analysis, but only gender persisted on multivariate analysis. CONCLUSIONS: Medium term outcome in patients undergoing focal VA in the setting of CMP are satisfactory with improvement in LV function achievable in most patients. Prior risk factors described in the literature are variable and inconsistent, likely reflecting heterogeneous study populations. PMID- 29482955 TI - A Prospective, Randomized Trial of Splinting After Minicarpal Tunnel Release. AB - PURPOSE: To determine if any significant differences exist in patient-reported or clinical outcomes among 3 different postoperative orthotic regimens: no orthosis, removable orthosis, and plaster nonremovable orthosis-following miniopen carpal tunnel release (CTR) surgery for symptomatic isolated carpal tunnel syndrome. METHODS: A total of 249 patients received a miniopen CTR and were subsequently randomized into 1 of 3 orthotic regimens: 80, no orthosis; 83, removable orthosis; and 86, nonremovable orthosis-to be removed at the first postoperative visit 10 to 14 days later. Patient-reported outcomes included the quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) surveys, Levine-Katz Symptom Severity and Functional Status Scales, and Pain at Rest and in Action using the Numerical Pain Rating Scale. Clinical outcomes included wrist range of motion, grip, and lateral pinch strengths. All outcomes were evaluated bilaterally at 10 to 14 days, 6 weeks, and 3, 6, and 12 months after surgery by evaluators blinded to the assigned regimen. Demographic information was obtained before surgery, and complications were recorded throughout the study. RESULTS: There were no statistically significant differences in any patient-reported or clinical outcomes at any follow-up period except at 6 and 12 months: the lateral pinch strength of the nonremovable orthosis group with CTR in the dominant hand was weaker than both of the other groups. Patient demographic characteristics did not significantly influence the outcomes at any time. Scar tenderness was the most commonly observed complication followed by stiffness. There were 2 cases each of complex regional pain syndrome and superficial wound dehiscence and 1 case of wound infection that resolved with oral antibiotics. CONCLUSIONS: The postoperative orthotic regimen does not change any patient-reported outcome up to at least 12 months following miniopen CTR. Lateral pinch strength was weaker in the nonremovable orthosis group at 6 and 12 months. Our data do not support the use of any postoperative orthosis following routine miniopen CTR. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic I. PMID- 29482956 TI - Barriers to Epineural Scarring: Role in Treatment of Traumatic Nerve Injury and Chronic Compressive Neuropathy. AB - The physiological limitations of neural regeneration make peripheral nerve surgery challenging to both the surgeon and the patient. Presence of nerve gaps and local wound factors may all influence outcome, suggesting that barriers to reduce perineural scarring, minimize fibrosis, and avoid ischemia would be beneficial. To examine the evidence supporting their use, we reviewed the autologous and commercially-available options for barriers against scarring around a nerve. Numerous clinical case series demonstrated the effectiveness and safety of local/rotational flaps and autologous vein wrapping when used in the presence of recurrent compressive neuropathy. Translational research in animal models supports the biocompatibility of commercially available nerve wraps following nerve repair. To date, there are no reports of clinical use of commercially available nerve wraps in acute nerve repair, but a growing number of case series demonstrate their effectiveness and safety in chronic compressive neuropathy. Limited clinical evidence exists to support the efficacy of vein or flap coverage in acute nerve repairs. PMID- 29482957 TI - Squamous Cell Carcinoma of the Nail Unit: Review of the Literature. AB - Squamous cell carcinoma of the nail unit (SCCNU) is often misdiagnosed and improperly treated because it mimics a number of other conditions. This review details current knowledge of anatomy, pathophysiology, clinical presentation, diagnosis, and treatment of SCCNU. A heightened clinical awareness is critical to treating SCCNU and preventing development of advanced disease at which time amputation is needed and metastasis may occur. Physicians should consider SCCNU in each case of a nail abnormality unresponsive to topical treatment. For adequate diagnosis and excision of SCCNU, timely and appropriate specialist referral is necessary. PMID- 29482958 TI - Validity and internal consistency of the Helsinki Serratus Palsy Index for patients with serratus palsy. AB - BACKGROUND: To our knowledge, no validated scales exist as yet for measuring quality of life and functioning level in patients with serratus palsy. This cross sectional survey study examined whether a broadly validated Western Ontario Rotator Cuff Index (WORC) could be partially adapted for patients with serratus palsy. METHODS: The relevancy of WORC, 21 items, along with 4 additional new items, was tested by 95 patients with serratus palsy and a panel of 9 medical experts. Its content validity was measured by a content validity index (CVI), a content validity ratio (CVR), and a modified kappa. The internal consistency of 11 retained items was assessed with the Cronbach alpha. Its construct validity was assessed by exploratory factor analysis. RESULTS: Of the 25 items, 11 were considered relevant (CVI >=0.78) for serratus palsy by the panelists, with overall test CVI (S-CVI) of 0.86. The internal consistency of these 11 items was excellent, with a Cronbach alpha of 0.94. The exploratory factor analysis accompanied by a parallel analysis confirmed the unidimensionality of a new test. All except 2 items of WORC that were considered relevant by the panelists were also marked with scores of >5 by the patients on an 11-point scale of relevancy. CONCLUSIONS: Adapted from the WORC, the new 11-item Helsinki Serratus Palsy Index scale was internally consistent and face and content valid for serratus palsy patients. PMID- 29482959 TI - Risk factors for failing to achieve improvement after anatomic total shoulder arthroplasty for glenohumeral osteoarthritis. AB - BACKGROUND: Although anatomic total shoulder arthroplasty (TSA) successfully improves pain and function, not all patients improve clinically. This study was conducted to determine patient-related factors for failure to achieve improvement after primary TSA for osteoarthritis at 2 years postoperatively. METHODS: This prospective study reviewed an institutional shoulder registry for consecutive patients who underwent primary TSA for osteoarthritis from 2007 to 2013 with baseline and 2-year postoperative American Shoulder and Elbow Surgeons (ASES) Standardized Shoulder Assessment Form scores. A failed outcome was defined as (1) a failure to reach the ASES minimal clinically important difference of 16.1 points or (2) revision surgery within 2 years of the index procedure, or both. Univariate and multivariable analyses of clinical and demographic patient factors were performed using logistic regression. RESULTS: Of 459 arthroplasties that met inclusion criteria, 411 were deemed successful by the aforementioned criteria, and 48 (10.5%) failed to achieve a desirable outcome. Clinical risk factors associated with failure included previous surgery to the shoulder (P = .047), presence of a torn rotator cuff (P = .025), and presence of diabetes (P = .036), after adjusting for age, sex, race, and body mass index. A higher preoperative ASES score at baseline was associated with failure (P < .001). CONCLUSION: Previous shoulder surgery, a rotator cuff tear requiring repair during TSA, presence of diabetes, surgery on the nondominant arm, and a higher baseline ASES score were associated with a higher risk of failing to achieve improvement after anatomic TSA. PMID- 29482960 TI - Approximate dynamic programming approaches for appointment scheduling with patient preferences. AB - During the appointment booking process in out-patient departments, the level of patient satisfaction can be affected by whether or not their preferences can be met, including the choice of physicians and preferred time slot. In addition, because the appointments are sequential, considering future possible requests is also necessary for a successful appointment system. This paper proposes a Markov decision process model for optimizing the scheduling of sequential appointments with patient preferences. In contrast to existing models, the evaluation of a booking decision in this model focuses on the extent to which preferences are satisfied. Characteristics of the model are analysed to develop a system for formulating booking policies. Based on these characteristics, two types of approximate dynamic programming algorithms are developed to avoid the curse of dimensionality. Experimental results suggest directions for further fine-tuning of the model, as well as improving the efficiency of the two proposed algorithms. PMID- 29482961 TI - Personalized prediction of drug efficacy for diabetes treatment via patient-level sequential modeling with neural networks. AB - Patients with type 2 diabetes mellitus are generally under continuous long-term medical treatment based on anti-diabetic drugs to achieve the desired glucose level. Thus, each patient is associated with a sequence of multiple records for prescriptions and their efficacies. Sequential dependencies are embedded in these records as personal factors so that previous records affect the efficacy of the current prescription for each patient. In this study, we present a patient-level sequential modeling approach utilizing the sequential dependencies to render a personalized prediction of the prescription efficacy. The prediction models are implemented using recurrent neural networks that use the sequence of all the previous records as inputs to predict the prescription efficacy at the time the current prescription is provided for each patient. Through this approach, each patient's historical records are effectively incorporated into the prediction. The experimental results of both the regression and classification analyses on real-world data demonstrate improved prediction accuracy, particularly for those patients having multiple previous records. PMID- 29482963 TI - Gut microbiome composition in lean patients with NASH is associated with liver damage independent of caloric intake: A prospective pilot study. AB - BACKGROUND AND AIM: The aim of the study was to compare the gut microbiomes from obese and lean patients with or without NASH to outline phenotypic differences. METHODS AND RESULTS: We performed a cross-sectional pilot study comprising biopsy proven NASH patients grouped according to BMI. Microbiome DNA was extracted from stool samples, and PCR amplification was performed using primers for the V4 region of the 16S rRNA gene. The amplicons were sequenced using the Ion PGM Torrent platform, and data were analyzed using QIIME software. Macronutrient consumption was analyzed by a 7-day food record. Liver fibrosis >= F2 was associated with increased abundance of Lactobacilli (p = 0.0007). NASH patients showed differences in Faecalibacterium, Ruminococcus, Lactobacillus and Bifidobacterium abundance compared with the control group. Lean NASH patients had a 3-fold lower abundance of Faecalibacterium and Ruminococcus (p = 0.004), obese NASH patients were enriched in Lactobacilli (p = 0.002), and overweight NASH patients had reduced Bifidobacterium (p = 0.018). Moreover, lean NASH patients showed a deficiency in Lactobacillus compared with overweight and obese NASH patients. This group also appeared similar to the control group with regard to gut microbiome alpha diversity. Although there were qualitative differences between lean NASH and overweight/obese NASH, they were not statistically significant (p = 0.618). The study limitations included a small sample size, a food questionnaire that collected only qualitative and semi-quantitative data, and variations in group gender composition that may influence differences in FXR signaling, bile acids metabolism and the composition of gut microbiota. CONCLUSION: Our preliminary finding of a different pathogenetic process in lean NASH patients needs to be confirmed by larger studies, including those with patient populations stratified by sex and dietary habits. PMID- 29482962 TI - Diet and primary prevention of stroke: Systematic review and dietary recommendations by the ad hoc Working Group of the Italian Society of Human Nutrition. AB - BACKGROUND AND AIMS: To systematically review the latest evidence on established and emerging nutrition-related risk factors for incidence of and mortality from total, ischemic and haemorrhagic strokes. The present review was conducted in the framework of the work carried out through 2015 and 2016 for the preparation of the Italian Guidelines for the Prevention and Treatment of Stroke, 8th Edition, by ISO-SPREAD (Italian Stroke Organization and the Stroke Prevention and Educational Awareness Diffusion). METHODS AND RESULTS: Systematic review of articles focused on primary prevention of stroke published between January 2013 to May 2016 through an extensive search of the literature using MEDLINE/PUBMED, EMBASE and the Cochrane Library. Articles were ranked according to the SIGN methodology while the GRADE system was used to establish the strength of recommendations. As a result of our literature search, we examined 87 meta analyses overall (mainly of prospective studies), a few isolated more recent prospective studies not included in the meta-analyses, and a smaller number of available randomized controlled trials and case-control studies. Based on the analysis of the above articles, 36 Syntheses of the available evidence and 36 Recommendations were eventually prepared. The present document was developed by organizing the available evidence into three individual areas (nutrients, food groups and dietary patterns) to provide a systematic and user-friendly overview of the available evidence on the relationship between nutrition and primary prevention of stroke. Yet analysis of foods and food patterns allowed translating the information about nutrients in a tool more amenable to use in daily life also in the light of the argument that people eat foods rather than nutrients. CONCLUSIONS: The present literature review and dietary recommendations provide healthcare professionals and all interested readers with a useful overview for the reduction of the risk of total, ischemic and haemorrhagic stroke through dietary modifications. PMID- 29482965 TI - Identifying and Documenting Malnutrition in Inpatient Rehabilitation Facilities. PMID- 29482964 TI - Early Childhood Vegetable, Fruit, and Discretionary Food Intakes Do Not Meet Dietary Guidelines, but Do Show Socioeconomic Differences and Tracking over Time. AB - BACKGROUND: Dietary intakes of young children are likely to be important determinants of their short- and long-term health, yet there are few longitudinal dietary studies of this age group, and no previous assessments of diets before age 2 years compared with national dietary guidelines. OBJECTIVE: This study aimed to compare vegetable, fruit, and discretionary food intakes of children aged 9 months to 5 years to dietary guidelines, and to assess differences in intakes by socioeconomic status and tracking of intakes across early childhood. DESIGN: This study analyzed longitudinal data from the Melbourne Infant Feeding Activity and Nutrition Trial Program early childhood lifestyle intervention trial, and is the first study to compare diets of children younger than age 2 years to national dietary guidelines. PARTICIPANTS/SETTING: Participants were 467 children in Melbourne, Australia, aged 4 months at baseline (study conducted 2008 2015). MAIN OUTCOME MEASURES: Multiple 24-hour recalls with parents were conducted at child ages 9 months, 1.5 years, 3.5 years, and 5 years. STATISTICAL ANALYSES PERFORMED: Intakes of vegetables, fruits, and discretionary foods were compared with Australian Dietary Guidelines. Differences by socioeconomic status and tracking of intakes of each food group were assessed by multivariable linear regression. RESULTS: Few children (<10%) met guidelines for discretionary food intakes at any age. Most children (>=90%) met vegetable and fruit guidelines at 9 months, but thereafter rates of adequate intakes reduced substantially. Children of higher socioeconomic status consumed diets closer to guidelines for most food groups at most ages. Tracking of intakes was apparent across ages, with the strongest and most consistent tracking for discretionary foods. CONCLUSIONS: This study shows that diets of Australian children participating in this lifestyle intervention trial were suboptimal from early life. The evidence of differences by socioeconomic status and tracking from age 9 months, particularly for discretionary foods, highlights the importance of research and action to support appropriate introduction of complementary foods during the first year of life, and of focusing these efforts on disadvantaged groups. PMID- 29482966 TI - Mixtures of tritiated water, zinc and dissolved organic carbon: Assessing interactive bioaccumulation and genotoxic effects in marine mussels, Mytilus galloprovincialis. AB - Release of tritium (3H) in the marine environment is of concern with respect to its potential bioaccumulation and detrimental impact on the biota. Previous studies have investigated the uptake and toxicity of this radionuclide in marine mussels, and the interaction of 3H with dissolved organic ligands and elevated temperature. However, despite the well-established view that toxicity is partly governed by chemical speciation, and that toxic effects of mixture of contaminants are not always additive, there have been no studies linking the prevailing chemistry of exposure waters with observed biological effects and tissue specific accumulation of 3H in combination with other constituents commonly found in natural waters. This study exposed the marine mussel Mytilus galloprovincialis for 14 days to mixtures of 3H (as tritiated water, HTO) and zinc (Zn) at 5 Mbq L-1, and 383, 1913 and 3825 nM Zn, respectively, to investigate (a) 3H and Zn partitioning in soft tissues of mussels, and (b) DNA damage in haemocytes, determined using the single cell gel electrophoresis or the comet assay. Additionally, the extent of association of 3H with dissolved organic carbon (DOC, added as humic acid) over the exposure period was investigated in order to aid the interpretation of biological uptake and effects. Results concluded a clear antagonistic effect of Zn on 3H-induced DNA damage at all Zn concentrations used, likely explained by the importance of Zn in DNA repair enzymes. The interaction of DOC with 3H was variable, with strong 3H-DOC associations observed in the first 3 d of the experiment. The secretion of 3H binding ligands by the mussels is suggested as a possible mechanism for early biological control of 3H toxicity. The results suggest risk assessments for radionuclides in the environment require consideration of potential mixture effects. PMID- 29482967 TI - An incidental image of a patient with chest pain after fall from a tree: Swyer James-MacLeod syndrome? AB - Unilateral hyperlucent lung was firstly described by Swyer and James 1950s. After that, some patients with same disease were detected by Macleod . Then this syndrome was named as Swyer- James-Macleod syndrome (SJMS), and this syndrome includes a smaller or normal sized unilateral hyperlucent lung. The diagnosis of SJMS includes a detailed evaluation and the exclusion of other reasons of unilateral hypertranslucency. In literature, small groups of patients with this syndrome have been described. This paper reports a 45-year-old male presented to our emergency department with chest pain after fall from height 24 h ago. In his computed tomography no rib fracture, pneumothorax and hemothorax. But an abnormal image (5.5 cm hyperlucent area) was seen in his left lung. This report aims to present one of incidentally diagnosed rare case of SJMS. PMID- 29482968 TI - Quality of irradiated and non-irradiated plateletpheresis concentrates stored in platelet additive solution. AB - INTRODUCTION: Platelet additive solutions (PAS) allow to maintain platelet storage properties in platelet concentrates (PCs). The aim of the present study was to evaluate the in-vitro quality of irradiated and non-irradiated PCs, suspended in PAS, over a storage period of 6 days. METHODS: Plateletpheresis donors fulfilling current eligibility criteria underwent plateletpheresis with the MCS+ blood cell separator. The PAS SSP+ was used to store platelets (PLT) for up to 6 days. Aliquots were drawn from the PCs after collection, at day 4, 5 and 6 of storage. A battery of tests was performed to analyse the quality of the PCs: PLT count, mean PLT volume (MPV), PLT activation marker CD 62, swirl, RBC and WBC contamination, pH, citrate, glucose, lactate and lactate dehydrogenase. RESULTS: An average of 2.53 +/- 0.21 * 1011 PLT were collected in a product volume of 231 +/- 5 mL in irradiated and 233 +/- 6 mL in non-irradiated PCs, respectively. RBC- and WBC-contamination were within the allowed ranges. Delta CD62 steadily decreased in irradiated and non-irradiated PCs while the pH was well maintained over storage time. Glucose and lactate levels of irradiated and non-irradiated PCs showed characteristic pattern of PC storage within acceptable ranges. CONCLUSION: Our data demonstrate that parameters of PC quality were well maintained over a storage period of 6 days using PAS. Irradiation had no impact on the quality of PCs. The product quality of irradiated and non-irradiated PCs met national and European guidelines. PMID- 29482969 TI - Simple and complex renal cysts in adults: Classification system for renal cystic masses. AB - Ultrasound and slice imaging are currently the key modalities for diagnosing simple renal cysts. Benign simple renal cysts are defined by a set of strict criteria. Any cystic lesions that do not meet these criteria should be classified as "atypical" or "complex" and considered as suspicious. For over three decades, the Bosniak classification has been the central tool for diagnosing renal cystic masses larger than 1 cm. The Bosniak classification is based upon the results of a well-established pre- and post-contrast computed tomography (CT) protocol. Lesions that are difficult to classify or that remain indeterminate after CT can benefit from a multimodal diagnostic approach combining CT, non-contrast-enhanced and contrast-enhanced ultrasound, and magnetic resonance imaging. PMID- 29482970 TI - Brain-state determines learning improvements after transcranial alternating current stimulation to frontal cortex. AB - BACKGROUND: Theories of executive control propose that communication between medial frontal cortex (MFC) and lateral prefrontal cortex (lPFC) is critical for learning. 6-Hz phase synchronization may be the mechanism by which neural activity between MFC and lPFC is coordinated into a functional network. Recent evidence suggests that switching from eyes closed to open may induce a change in brain-state reflected by enhanced executive control and related functional connectivity. OBJECTIVE/HYPOTHESIS: To examine whether causal manipulation of MFC and lPFC can improve learning according to the brain-state induced by switching from eyes closed to open. METHODS: Within-subjects, sham-controlled, double-blind study of 30 healthy subjects, each receiving 6-Hz in-phase high definition transcranial alternating-current stimulation (HD-tACS) applied to MFC and right lPFC prior to performing a time estimation task. RESULTS: HD-tACS with eyes open improved learning ability relative to sham, whereas HD-tACS with eyes closed had no significant effect on behavior. CONCLUSION: Results suggest a phase-sensitive mechanism in frontal cortex mediates components of learning performance in a state-dependent manner. PMID- 29482971 TI - Enhanced astaxanthin accumulation in Haematococcus pluvialis using high carbon dioxide concentration and light illumination. AB - In this study, an economical two-stage method was proposed for the production of natural astaxanthin from Haematococcus pluvialis without a medium replacement step. In stage 1, H. pluvialis were grown under low light illumination until they reached optimal biomass. In stage 2, cells were switched to astaxanthin induction conditions utilizing the combination of high light illumination and elevated carbon dioxide levels (5 or 15%). The introduction of CO2 altered the C/N balance creating a nutrient deficiency without a change of media. The resulting astaxanthin yield was 2-3 times that of using either stressor alone. This astaxanthin induction method has many advantages over current methods including no medium replacement and a short induction time of less than four days. PMID- 29482972 TI - Editor's Choice - The Impact of Centralisation and Endovascular Aneurysm Repair on Treatment of Ruptured Abdominal Aortic Aneurysms Based on International Registries. AB - OBJECTIVES: Current management of ruptured abdominal aortic aneurysms (RAAA) varies among centres and countries, particularly in the degree of implementation of endovascular aneurysm repair (EVAR) and levels of vascular surgery centralisation. This study assesses these variations and the impact they have on outcomes. MATERIALS AND METHODS: RAAA repairs from vascular surgical registries in 11 countries, 2010-2013, were investigated. Data were analysed overall, per country, per treatment modality (EVAR or open aortic repair [OAR]), centre volume (quintiles IV), and whether centres were predominantly EVAR (>=50% of RAAA performed with EVAR [EVAR(p)]) or predominantly OAR [OAR(p)]. Primary outcome was peri-operative mortality. Data are presented as either mean values or percentages with 95% CI within parentheses, and compared with chi-square tests, as well as with adjusted OR. RESULTS: There were 9273 patients included. Mean age was 74.7 (74.5-74.9) years, and 82.7% of patients were men (81.9-83.6). Mean AAA diameter at rupture was 7.6 cm (7.5-7.6). Of these aneurysms, 10.7% (10.0-11.4) were less than 5.5 cm. EVAR was performed in 23.1% (22.3-24.0). There were 6817 procedures performed in OAR(p) centres and 1217 performed in EVAR(p) centres. Overall peri operative mortality was 28.8% (27.9-29.8). Peri-operative mortality for OAR was 32.1% (31.0-33.2) and for EVAR 17.9% (16.3-19.6), p < .001, and the adjusted OR was 0.38 (0.31-0.47), p < .001. The peri-operative mortality was 23.0% in EVAR(p) centres (20.6-25.4), 29.7% in OAR(p) centres (28.6-30.8), p < .001; adjusted OR = 0.60 (0.46-0.78), p < .001. Peri-operative mortality was lower in the highest volume centres (QI > 22 repairs per year), 23.3% (21.2-25.4) than in QII-V, 30.0% (28.9-31.1), p < .001. Peri-operative mortality after OAR was lower in high volume centres compared with the other centres, 25.3% (23.0-27.6) and 34.0% (32.7 35.4), respectively, p < .001. There was no significant difference in peri operative mortality after EVAR between centres based on volume. CONCLUSIONS: Peri operative mortality is lower in centres with a primary EVAR approach or with high case volume. Most repairs, however, are still performed in low volume centres and in centres with a primary OAR strategy. Reorganisation of acute vascular surgical services may improve outcomes of RAAA repair. PMID- 29482973 TI - HYDration and Bicarbonate to Prevent Acute Renal Injury After Endovascular Aneurysm Repair With Suprarenal Fixation: Pilot/Feasibility Randomised Controlled Study (HYDRA Pilot Trial). AB - OBJECTIVE/BACKGROUND: Up to 25% of patients undergoing elective endovascular aneurysm repair (EVAR) develop acute kidney injury (AKI), which is associated with short and long-term morbidity and mortality. There is no high quality randomised evidence regarding prevention of EVAR related AKI. METHODS: A novel AKI prevention strategy for EVAR was devised, based on best evidence and an expert consensus group. This included a bolus of high dose sodium bicarbonate (NaHCO3) immediately before EVAR (1 mL/kg of 8.4% NaHCO3) and standardised crystalloid based hydration pre- and post-EVAR. A pilot/feasibility randomised controlled trial (RCT) was performed in two centres to assess the safety of the intervention, potential impact on AKI prevention, and feasibility of a national RCT; the primary end point was the proportion of eligible patients recruited into the study. AKI was defined using "Kidney Disease Improving Global Outcomes" and "Acute Kidney Injury Network" criteria based on National Institute for Health and Clinical Excellence AKI recommendations, using serum creatinine and hourly urine output. RESULTS: Fifty-eight patients (84% of those screened; median age 75 years [range 57-89 years], 10% female) were randomised to receive the standardised intravenous hydration with (intervention) or without (control) NaHCO3. Groups were comparable in terms of AKI risk factors; 56 of 58 participants had a device with suprarenal fixation. Overall, 33% of patients in the control arm developed AKI versus 7% in the intervention arm (as treated analysis). None of the patients receiving NaHCO3 developed a serious intervention related adverse event; five patients did not attend their 30 day follow-up. CONCLUSION: Bolus high dose NaHCO3 and hydration is a promising EVAR related AKI prevention method. This trial has confirmed the feasibility of delivering a definitive large RCT to confirm the efficacy of this novel intervention, in preventing EVAR related AKI. PMID- 29482974 TI - Cognitive predictors of illness course at 12 months after first-episode of depression. AB - Major Depressive Disorder (MDD) entails cognitive dysfunction in many cognitive domains, but it is still uncertain whether such deficits are present in the early stages. The purpose of the study is to determine the cognitive performance in first episode depression (FED) exploring the presence of different cognitive profiles, and the role of cognition in FED at baseline and long-term. Ninety subjects (18-50 years) were included, 50 patients with a FED and 40 healthy controls. Participants were assessed with a neuropsychological battery, covering language, attention, verbal memory, processing speed and executive domains. Neuropsychological group comparisons were performed with MANOVAs. A hierarchical cluster analysis was run to identify clusters of patients with similar neuropsychological performance. Two generalized linear models were built to predict baseline HDRS-17 and changes at 12 months. Patients performed significantly worse than healthy controls in language, attention/working memory, verbal memory, processing speed and executive functioning, with moderate to large effect sizes (0.5 - 1). Two clusters were found: cognitively preserved patients (n=37) and cognitively impaired patients (n=13). Large effect sizes of cognitive impairment in FED were observed between the two cognitive clusters (preserved and impaired). Depressive symptoms at baseline were predicted by verbal memory (p=0.003), while 12-month changes were predicted by executive function (p=0.041) and language (p=0.037). Cognitive performance predicted depressive symptoms at baseline and at follow-up, pointing to the usefulness of cognitive assessment even at the commencement of the illness. PMID- 29482975 TI - Development and evaluation of indirect enzyme linked immunosorbent assay for the serological diagnosis of Microsporum canis infection in humans. AB - PURPOSE: The aim of this study was to develop and evaluate the diagnostic potential of indirect enzyme-linked immunosorbent assay (I-ELISA) for the rapid and precise diagnosis of Microsporum canis infection in humans. BASIC PROCEDURES: The present study reports the production, partial purification and SDS-PAGE analysis of M. canis mycelial antigens and production of specific polyclonal antibodies. It also reports the development and optimization of indirect ELISA and evaluation of its potential for the diagnosis of M. canis infection in humans. MAIN FINDINGS: An I-ELISA showed the sensitivity of 94.55% and specificity of 93.33%. Positive and negative predictive values were 96.30% and 90.32% respectively. Receiver operating characteristic (ROC) curve analysis of the data showed higher diagnostic accuracy. The area under the curve (AUC) was 0.925. A significant correlation coefficient of 0.8771 (P<0.0001) was obtained between I-ELISA and fungal culture method. PRINCIPAL CONCLUSIONS: In conclusion, the present study clearly shows the detection of specific antibodies by indirect ELISA using M. canis antigens. The assay is sensitive, specific and easy to perform, could enable rapid and more convenient diagnosis of dermatophytosis in humans. PMID- 29482976 TI - Role of Doppler Diastolic Parameters in Differentiating Physiological Left Ventricular Hypertrophy from Hypertrophic Cardiomyopathy. AB - BACKGROUND: The association between athletic participation and alteration in diastolic function is not well established. The aims of this study were to determine the spectrum of Doppler parameters of left ventricular (LV) diastolic function in a large cohort of healthy athletes and to quantify the overlap between physiologic LV hypertrophy and hypertrophic cardiomyopathy (HCM). METHODS: A retrospective analysis of indices of LV diastolic function was performed in 1,510 healthy athletes (mean age, 22 +/- 5 years; range, 13-33 years; 72% men). The results were compared with those from 58 young patients with HCM. RESULTS: Septal E' < 7 cm/sec and lateral E' < 10 cm/sec were found in five (0.3%) and eight (0.5%) athletes, respectively. Septal E' was >14.6 cm/sec in 170 (11%) and lateral E' was >19.9 cm/sec in 430 (28%) athletes. Athletes aged >25 years showed lower E' velocities compared with younger athletes (mean septal E', 11.8 +/- 6.1 vs 12.9 +/- 5.9 cm/sec [P < .001]; mean lateral E', 17.1 +/- 3.6 vs 19.3 +/- 4.1 cm/sec [P < .001]). Athletes with high indexed LV end-diastolic diameters (>32 mm/m2) exhibited lower septal E' compared with athletes with normal indexed LV end-diastolic diameters (mean septal E', 11.9 +/- 6 vs 12.7 +/- 6 cm/sec; P = .002). Septal E' < 10 cm/sec and lateral E' < 12 cm/sec showed the best accuracy in differentiating between HCM and athlete's heart. CONCLUSIONS: Reduced septal and lateral E' are rarely observed in young elite athletes. Tissue Doppler velocities tend to decrease with increasing age and LV size, and values representative of supernormal diastolic function are found in less than one-third of young athletes. Cutoff thresholds for Doppler parameters of diastolic function should be corrected for multiple demographic and clinical variables to differentiate cardiac adaptation to exercise from HCM in young individuals. PMID- 29482977 TI - Transcatheter Mitral Valve Repair Using the Edge-to-Edge Clip. AB - Percutaneous intervention for mitral valve (MV) disease has been established as an alternative to open surgical MV repair in patients with prohibitive surgical risk. Multiple percutaneous approaches have been described and are in various stages of development. Edge-to-edge leaflet plication with the MitraClip (Abbott, Menlo Park, CA) is currently the only Food and Drug Administration-approved device specifically for primary or degenerative lesions. Use of the edge-to-edge clip for secondary mitral regurgitation is currently under investigation and may result in expanded indications. Echocardiography has significantly increased our understanding of the anatomy of the MV and provided us with the ability to classify and quantify the associated mitral regurgitation. For percutaneous interventions of the MV, transesophageal echocardiography imaging is used for patient screening, intraprocedural guidance, and confirmation of the result. Optimal outcomes require the echocardiographer and the proceduralist to have a thorough understanding of intra-atrial septal and MV anatomy, as well as an appreciation for the key points and potential pitfalls of each of the procedural steps. With increasing experience, more complex valvular pathology can be successfully percutaneously treated. In addition to two-dimensional echocardiography, advances in three-dimensional echocardiography and fusion imaging will continue to support the refinement of current technologies, the expansion of clinical applications, and the development of novel devices. PMID- 29482978 TI - Title TBA: Revising the Abstract Submission Process. AB - Academic conferences are among the most prolific scientific activities, yet the current abstract submission and review process has serious limitations. We propose a revised process that would address these limitations, achieve some of the aims of Open Science, and stimulate discussion throughout the entire lifecycle of the scientific work. PMID- 29482979 TI - One-day diagnosis for hepatobiliary and pancreatic lesions: An innovative patient centered care pathway organization. AB - OBJECTIVE: Reducing the time required for diagnosis is one of the major challenges to improving and accelerating the management of patients. The aim of this work is to describe an organizational innovation in the management of patients with hepatobiliary or pancreatic diseases, and to report the initial results. MATERIALS AND METHODS: A multidisciplinary and multi-professional working group designed and instituted a patient-centered organizational system that optimizes the investigation of liver and pancreatic diseases, in order to achieve diagnosis in one day. From January 2017 to June 2017, all patients referred for consultation for hepatobiliary or pancreatic pathology were included in this new management pathway. Data were collected prospectively in a standardized form. RESULTS: Fifty-six patients with hepatobiliary or pancreatic disease were evaluated in the program during dedicated slots over a total of 20 days. Of these, four patients underwent evaluation in the program twice. The average number of patient slots in the program was three per day (range: 1-5). An additional computed tomography (CT) and/or magnetic resonance imaging (MRI) was required in 23 (41.7%) of the visits. These imaging studies were performed the same day, including nine patients who required both types of imaging (16.7% of cases). "One-day diagnosis" established an accurate diagnosis by the end of the day in 49 patient encounters (81.7%). Overall assessment of this organization was considered excellent by 46 (83%) of patients. CONCLUSION: An organizational innovation has made it possible to effectively diagnose hepatobiliary or pancreatic pathology within one day in the majority of cases, with good patient satisfaction. It is now necessary to evaluate the medico-economic aspect of this organization, and more generally to develop a methodology for multidimensional evaluation of organizational innovations. PMID- 29482980 TI - Esophageal obstruction due to a right-sided Zenker diverticulum. AB - A Zenker's or pharyngoesophageal diverticulum may represent a rare cause of upper digestive obstruction, or more often, cervical dysphagia, regurgitations and cough. It develops most often on the posterior left side of cervical oesophagus in elderly patients, and depending on the severity of clinical symptoms may warrant surgical or endoscopic treatment. For large lesions with a difficult endoscopic access to the diverticular neck, surgery is recommended. In our case, we illustrate a giant right-sided Zenker's diverticulum responsible for complete aphagia in a 78-year-old male patient. Open surgery by right cervical approach, with diverticulopexy and cricopharyngeal myotomy was performed, with an uneventful recovery. This paper presents with preoperative and intraoperative illustrations of high educational value for this, often underdiagnosed, clinical entity. PMID- 29482981 TI - Pediatric Catheter Ablation: Characteristics and Results of a Series in a Tertiary Referral Hospital. AB - INTRODUCTION AND OBJECTIVES: Catheter ablation has become the treatment of choice in an increasing number of arrhythmias in children and adolescents. There is still limited evidence of its use at a national level in Spain. The aim was to describe the characteristics and results of a modern monocentric series form a referral tertiary care centre. METHODS: Retrospective register of invasive procedures between 2004 and 2016 performed in patients under 17 years and recorded clinical characteristic, ablation methodology and acute and chronic results of the procedure. RESULTS: A total of 291 procedures in 224 patients were included. Median age was 12.2 years, 60% male. Overall, 46% patients were referred from other autonomous communities. The most frequent substrates were accessory pathways (AP) (70.2%,>50% septal AP localization) and atrioventricular nodal reentrant tachycardia (AVNRT) (15.8%). Congenital and acquired heart disease was frequent (16.8%). Cryoablation was used in 35.5% of the cases. Overall acute success of the primary procedure was 93.5% (AP 93.8%; AVNRT 100%). Redo procedures after recurrence were performed in 18.9% of all substrates, with a long-term cumulative efficacy of 98.4% (AP 99.3%; AVNRT 100%). One (0.37%) serious complication occurred, a case of complete atrioventricular block. CONCLUSIONS: Our study replicated previous international reports of high success rates with scarce complications in a high complexity series, confirming the safety and efficacy of pediatric catheter ablation in our environment performed at highly experienced referral centers. PMID- 29482982 TI - An Early Post-discharge Intervention Planned to Reduce 30-day Readmissions in old and Frail Heart Failure Patients Remains Beneficial at 1 Year. PMID- 29482984 TI - Adjuvant aromatase inhibition: more options for patients. PMID- 29482985 TI - Loss of p27kip1 expression is associated with poor prognosis in patients with taxane-treated breast cancer. AB - PURPOSE: Decreased expression of p27kip1 and p57kip2 is considered as a prognostic indicator in patients with breast cancer receiving adjuvant chemotherapy. Previous in vitro studies have reported that reduced expression of p27kip1 and p57kip2 is associated with resistance to taxane, which is one of the most effective chemotherapeutic agents. In this study, we investigated the association of low p27kip1 and p57kip2 expression with outcomes in patients with breast cancer. METHODS: We investigated 226 cases of breast cancer from Kangbuk SMC between 2000 and 2005. Levels of p27kip1 and p57kip2 expression were evaluated using immunohistochemical staining of tumor tissue microarray specimens. The relationships between the expression levels of the markers and patients' outcomes were analyzed using the Kaplan-Meier method and Cox proportional hazard model. RESULTS: Low p57kip2 expression was only associated with negative progesterone receptor status (p = 0.034), whereas p27kip1 expression was associated with poor prognosis of patients receiving adjuvant chemotherapy (p = 0.005). More detailed analysis revealed that low p27kip1 expression affects the overall survival rate of patients receiving adjuvant chemotherapy including taxane (p = 0.026), but not that of patients receiving chemotherapy without taxane. CONCLUSIONS: Low p27kip1 expression may be useful to predict overall survival in patients with breast cancer who are treated with taxane. Evaluation of p27kip1 expression may provide further prognostic information beyond traditional prognostic biomarkers and an understanding of the mechanisms that impart resistance against chemotherapy. PMID- 29482986 TI - Hyalinizing clear cell carcinoma of salivary glands: A retrospective study focused on uncommon morphology, immunohistochemistry, and detection of gene fusion using fluorescence in situ hybridization. AB - AIMS: To investigate histological, immunohistochemical, and molecular features, especially uncommon morphology of hyalinizing clear cell carcinoma (HCCC) to expand the morphological spectrum of HCCC. METHODS AND RESULTS: We examined 5 cases of HCCC by histological, immunohistochemical, and molecular analysis. Generally, 5 HCCC cases shared similar characteristics, exhibiting clear to slightly eosinophilic cells arranged in cords, nests, islands, or trabeculae with a hyalinized stroma, while myxoid stroma, perineural invasion, and polygonal cells with high-grade nuclei were observed in 3 cases. Immunohistochemically, 5 cases were entirely immunoreactive for CKpan, whereas 80% HCCC cases were positive for P63, and CK14. None expressed immunoreactivity for S-100, Calponin, or GFAP. The positive rate of Ki-67 staining was about 5% in the classic area of case 3, but 40% in the high-grade area. As for the result of FISH findings, EWSR1 gene break was detected in all 5 HCCC cases. CONCLUSIONS: Our study has expanded the morphological spectrum of HCCC, and proposed the diagnosis of HCCC should be confirmed by fully analyzing histological, immunohistochemical, and molecular features practically. PMID- 29482987 TI - Immunohistochemical evaluation of H3K27 trimethylation in malignant peripheral nerve sheath tumors. AB - The histological definitive diagnosis of malignant peripheral nerve sheath tumor (MPNST) is quite difficult because the morphological features are not specific and no useful immunohistochemical marker has been identified. Loss-of-function mutations in EED or SUZ12, which encode the core subunit of polycomb repressive complex 2 (PRC2), were reported in MPNSTs, and the mutations were shown to cause inactivation of PRC2, leading to loss of trimethylation of histone H3 at lysine 27 (H3K27me3). Immunohistochemistry of H3K27me3 is expected to be a specific marker for MPNSTs. We evaluated immunohistochemical expression of H3K27me3 in MPNSTs with heterologous components and metachronous cases of MPNSTs. Among 145 MPNST samples, 50 (34.5%) showed complete loss of staining, and 45 (31.0%) showed partial loss of staining. Regarding the backgrounds of MPNSTs, 43 patients of neurofibromatosis type 1 (NF-1)-associated MPNST demonstrated 19 (44.2%) complete and 12 (27.9%) partial loss of H3K27me3. Among MPNSTs with heterologous component, almost all of MPNSTs with epithelioid differentiation (8/9 samples, 88.9%) retained H3K27me3, and malignant Triton tumors without epithelioid component lacked H3K27me3 at high rate (91.7%). Five of 20 metachronous MPNST cases showed significantly reduced expression of H3K27me3 between primary and later-occurring tumors, but in some cases increased expression of H3K27me3 in the clinical course (such as complete loss to partial loss) was observed. If the tumors are recurrent or metastatic, H3K27me3 expression should be reduced or at least maintained because loss of H3K27me3 is due to genetic mutation of EED or SUZ12. MPNSTs, especially those associated with NF-1, can occur in heterochronous and multiple patterns, and the identification of increased expression of H3K27me3 during a patient's clinical course can be helpful for determining whether the tumors are heterochronous, multiple or not. As heterochronous and multiple tumors may show lower malignancy compared to recurrent or metastatic tumors, favorable prognosis may be expected when H3K27me3 expression is increased. PMID- 29482988 TI - Effects of miR-200a and FH535 combined with taxol on proliferation and invasion of gastric cancer. AB - Gastric cancer is one of the most common cancers in the world; taxol displayed modest efficacy as first-line chemotherapy for gastric cancer, conversely, it has limitations used alone. beta-catenin is a multifunctional oncogenic protein and the elevation in expression and activity of beta-catenin has been implicated in many cancers. Therefore, we assume that the inhibition of beta-catenin can enhanced the efficacy of taxol. The purpose of this study was to investigate the inhibitory effect of miR-200a mimics, FH535 combined with taxol on proliferation and invasion of human gastric cancer cell lines SGC-7901 and BGC-823. In the current study, we identified that the combination of FH535 and miR-200a with taxol had potent growth-inhibitory and pro-apoptotic effects. Further, similar results were also observed in vivo, intratumoral injection of FH535, taxol and miR-200a mimics which also delayed tumor growth in nude mice harboring subcutaneous SGC-7901 xenografts. Collectively, miR-200a and FH535 can enhance the inhibitory effect of taxol on cell proliferation and moderate the invasion of human gastric cancer. PMID- 29482989 TI - Clinicopathological features of low-grade malignant endolymphatic sac tumors. AB - BACKGROUND: Low-grade malignant endolymphatic sac tumor (ELST) is a rare neoplasm, occurring in the inner ear and invading the temporal bone. This study aims to investigate the clinicopathological features of low-grade malignant ELSTs. METHODS: The clinicopathological data of 21 patients with low-grade malignant ELSTs were collected and analyzed. RESULTS: The patients were aged 16 71 years, with an average age of 40.3 years and a median age of 39 years, and the male to female ratio was 1:1.6. There were 13 cases (61.9%) of ELSTs occurring on the left side, 7 cases (33.3%) on the right side, and 1 case (4.8%) on both sides. Blood types O and B were noted in 71.4% of the patients. Immunohistochemistry showed that CK, EMA and Vim were all positive, and S-100 (71.4%, 10/14), CD56 (75.0%, 9/12), NSE (50.0%, 2/4), and GFAP (11.1%, 1/9) were also positive, while Syn, CgA, TTF-1, TG, CD34, and calcitonin were negative. The Ki-67 index was 4.3% on average. Histologically, cells were arranged in a papillary shape often with branches and abundant fibrous axial vessel. Some cells had an expanded different-sized thyroid-follicle-like structure, with the follicles containing red-stained colloids and scallop-like secretary vacuoles. There were expanded cavities. Some cases were in a glandular arrangement, and a few in a nest-like, gland-cystoid arrangement. Most tumors were coated with a monolayer of cubic epithelium, a few cells were flat or columnar, with translucent cytoplasm and light staining. The nuclei were oval, nucleolus was not obvious, chromatin was delicate, and a few nucleoli were small. The tissue was prone to bleeding, with fresh and old bleeding. Approximately half of the patients had necrotic bones, and in some cases the tumor tissue had destroyed the surrounding bone. The background fibrous tissue showed hyperplasia with hyaline degeneration, some had calcification and formation of sandy-gravel bodies. The clinical manifestations were hearing reduction or loss, followed by tinnitus, and accompanied by varying degrees of cranial nerve injury. No patients died during follow-up. CONCLUSIONS: Low-grade malignant ELSTs occur most frequently on the left side, with a female preponderance. The disease progressed slowly, with no death, and but relapse in two patients in this series. These tumors are often misdiagnosed. PMID- 29482990 TI - Whole-exome sequencing of chondroid hamartoma of lung identified no driver mutations. PMID- 29482983 TI - Adjuvant anastrozole versus exemestane versus letrozole, upfront or after 2 years of tamoxifen, in endocrine-sensitive breast cancer (FATA-GIM3): a randomised, phase 3 trial. AB - BACKGROUND: Uncertainty exists about the optimal schedule of adjuvant treatment of breast cancer with aromatase inhibitors and, to our knowledge, no trial has directly compared the three aromatase inhibitors anastrozole, exemestane, and letrozole. We investigated the schedule and type of aromatase inhibitors to be used as adjuvant treatment for hormone receptor-positive early breast cancer. METHODS: FATA-GIM3 is a multicentre, open-label, randomised, phase 3 trial of six different treatments in postmenopausal women with hormone receptor-positive early breast cancer. Eligible patients had histologically confirmed invasive hormone receptor-positive breast cancer that had been completely removed by surgery, any pathological tumour size, and axillary nodal status. Key exclusion criteria were hormone replacement therapy, recurrent or metastatic disease, previous treatment with tamoxifen, and another malignancy in the previous 10 years. Patients were randomly assigned in an equal ratio to one of six treatment groups: oral anastrozole (1 mg per day), exemestane (25 mg per day), or letrozole (2.5 mg per day) tablets upfront for 5 years (upfront strategy) or oral tamoxifen (20 mg per day) for 2 years followed by oral administration of one of the three aromatase inhibitors for 3 years (switch strategy). Randomisation was done by a computerised minimisation procedure stratified for oestrogen receptor, progesterone receptor, and HER2 status; previous chemotherapy; and pathological nodal status. Neither the patients nor the physicians were masked to treatment allocation. The primary endpoint was disease-free survival. The minimum cutoff to declare superiority of the upfront strategy over the switch strategy was assumed to be a 2% difference in disease-free survival at 5 years. Primary efficacy analyses were done by intention to treat; safety analyses included all patients for whom at least one safety case report form had been completed. Follow-up is ongoing. This trial is registered with the European Clinical Trials Database, number 2006-004018-42, and ClinicalTrials.gov, number NCT00541086. FINDINGS: Between March 9, 2007, and July 31, 2012, 3697 patients were enrolled into the study. After a median follow-up of 60 months (IQR 46-72), 401 disease-free survival events were reported, including 211 (11%) of 1850 patients allocated to the switch strategy and 190 (10%) of 1847 patients allocated to upfront treatment. 5-year disease-free survival was 88.5% (95% CI 86.7-90.0) with the switch strategy and 89.8% (88.2-91.2) with upfront treatment (hazard ratio 0.89, 95% CI 0.73-1.08; p=0.23). 5-year disease-free survival was 90.0% (95% CI 87.9 91.7) with anastrozole (124 events), 88.0% (85.8-89.9) with exemestane (148 events), and 89.4% (87.3 to 91.1) with letrozole (129 events; p=0.24). No unexpected serious adverse reactions or treatment-related deaths occurred. Musculoskeletal side-effects were the most frequent grade 3-4 events, reported in 130 (7%) of 1761 patients who received the switch strategy and 128 (7%) of 1766 patients who received upfront treatment. Grade 1 musculoskeletal events were more frequent with the upfront schedule than with the switch schedule (924 [52%] of 1766 patients vs 745 [42%] of 1761 patients). All other grade 3-4 adverse events occurred in less than 2% of patients in either group. INTERPRETATION: 5 years of treatment with aromatase inhibitors was not superior to 2 years of tamoxifen followed by 3 years of aromatase inhibitors. None of the three aromatase inhibitors was superior to the others in terms of efficacy. Therefore, patient preference, tolerability, and financial constraints should be considered when deciding the optimal treatment approach in this setting. FUNDING: Italian Drug Agency. PMID- 29482991 TI - Diurnal variability of transportation noise exposure and cardiovascular mortality: A nationwide cohort study from Switzerland. AB - BACKGROUND: Most epidemiological noise studies consider 24 h average noise exposure levels. Our aim was to exploratively analyze the impact of noise exposure at different time windows during day and night on cardiovascular mortality. METHODS: We generated Switzerland-wide exposure models for road traffic, railway and aircraft noise for different time windows for the year 2001. Combined noise source equivalent continuous sound levels (Leq) for different time windows at the most exposed facade were assigned to each of the 4.41 million Swiss National Cohort adult participants. Follow-up period was from 2000 to 2008. Hazard ratios (HR) of noise effects on various cardiovascular primary causes of death were computed by Cox regression models adjusted for potential confounders and NO2 levels. RESULTS: For most cardiovascular causes of death we obtained indications for a diurnal pattern. For ischemic heart disease the highest HR was observed for the core night hours from 01 h to 05 h (HR per standard deviation of Leq: 1.025, 95% CI: 1.016-1.034) and lower HR for the daytime 07 h to 19 h (1.018 [1.009-1.028]). Heart failure and daytime Leq yielded the highest HR (1.047 [1.027-1.068]). CONCLUSION: For acute cardiovascular diseases, nocturnal intermittent noise exposure tended to be more relevant than daytime exposure, whereas it was the opposite for chronic conditions such as heart failure most strongly associated with continuous daytime noise. This suggests that for acute diseases sleep is an important mediator for health consequences of transportation noise. PMID- 29482992 TI - Corrigendum to "Comparative genome analysis of Lactobacillus plantarum GB-LP3 provides candidates of survival-related genetic factors" [Infect. Genet. Evol. 9 (2017) 218-226]. PMID- 29482993 TI - SGLT2 inhibitors and renal outcomes in type 2 diabetes with or without renal impairment: A systematic review and meta-analysis. AB - BACKGROUND: Sodium-glucose co-transporter 2 (SGLT2) inhibitors may have renal protective effects in people with impaired kidney function. We assessed the use of SGLT2 inhibitors in people with type 2 diabetes with or without renal impairment [defined as estimated glomerular filtration rate (eGFR) of >=30 and <60ml/min/1.73m2 and/or UACR>300 and <=5000mg/g] by conducting a systematic review and meta-analysis of available studies. METHODS: Randomised controlled trials (RCTs) were identified from MEDLINE, EMABASE, Web of Science, the Cochrane Library, and search of bibliographies to March 2017. No relevant observational study was identified. Summary measures were presented as mean differences and narrative synthesis performed for studies that could not be pooled. RESULTS: 42 articles which included 40 RCTs comprising 29,954 patients were included. In populations with renal impairment, SGLT2 inhibition compared with placebo was consistently associated with an initial decrease in eGFR followed by an increase and return to baseline levels. In pooled analysis of 17 studies in populations without renal impairment, there was no significant change in eGFR comparing SGLT2 inhibitors with placebo (mean difference, 0.51ml/min/1.73m2; 95% CI: -0.69, 1.72; p=403). SGLT2 inhibition relative to placebo was associated with preservation in serum creatinine levels or initial increases followed by return to baseline levels in patients with renal impairment, but levels were preserved in patients without renal impairment. In populations with or without renal impairment, SGLT2 inhibitors (particularly canagliflozin and empagliflozin) compared with placebo were associated with decreased urine albumin, improved albuminiuria, slowed progression to macroalbuminuria, and reduced the risk of worsening renal impairment, the initiation of kidney transplant, and death from renal disease. CONCLUSIONS: Emerging data suggests that with SGLT2 inhibition, renal function seems to be preserved in people with diabetes with or without renal impairment. Furthermore, SGLT2 inhibition prevents further renal function deterioration and death from kidney disease in these patients. PMID- 29482994 TI - The importance of language in mental health care. PMID- 29482995 TI - Impact of airborne zinc pollution on the antimicrobial activity of olive oil and the microbial metabolic profiles of Zn-contaminated soils in an Italian olive orchard. AB - The growing of microbial resistance leads to a great interest about some natural alternatives to synthetic compounds. This study was carried out in two olive orchards (Olea europaea L., cv. Coratina) South Italy (Basilicata region), one located in a polluted area near a fertilizers factory releasing Zn and the other in a control unpolluted site, both managed with similar cultivation techniques. Olive oil samples were studied from both areas during 2014 and 2015. The soil microbiological status of the polluted and unpolluted orchards has been characterized and the antimicrobial effects of olive oils extracted from polluted plants (PP) and control plants (CP) against some phytopathogens have been explored. Results showed that the antibacterial activity of PP oil was significantly higher than CP and this could be due to the high content of some phenolic compounds elicited by air and soil Zn pollution (especially in the layer 0-20 cm). There is no detectable antifungal activity of the studied oils. The metabolic activity (both total and for each carbon substrate group), diversity and evenness of PP soil bacterial communities were significantly different from CP soil, while the effects of soil depth was negligible. The same parameters measured on soil fungal communities are lower in PP soil at 0-20 cm soil depth. The current research clarified the impact of atmospheric Zn pollution on the antimicrobial activity of olive oil and the soil microbial metabolic profiles. The bioactive substances extracted from olive oils growing in Zn-polluted area might be used as antibiotics. PMID- 29482996 TI - Enterobacterial repetitive intergenic consensus (ERIC)-PCR analysis as a reliable evidence for suspected Shigella spp. outbreaks. AB - BACKGROUND: Shigellosis remains a serious public health problem and an important cause of morbidity and mortality worldwide. The aim of this study was to characterize fliC and the genetic relatedness of Shigella spp. isolated during a one-year period from children in a suspected outbreak in Tehran, Iran. METHODS AND RESULTS: Fifty Shigella spp. were isolated from 3779 stool samples of children with diarrhea (prevalence rate: 1.32%). Among the isolates, 92% were characterized as Shigella sonnei, while 6% and 2% were identified as S. flexneri and S. boydii, respectively. S. dysenteriae was not recovered from the patients. All isolates were negative for fliC except for Shigella standard strains. The enterobacterial repetitive intergenic consensus-polymerase chain reaction (ERIC PCR) profiles allowed differentiating the 50 isolates into 5 ERIC types, which were grouped into five clusters (ET1-ET5). Computer-assisted clustering of the strains showed a high degree of similarity among the isolates. CONCLUSION: In conclusion, given the clonal correlation of the Shigella strains isolated in this study and the lack of fliC among them, we propose that probably a single or limited fliC-defected Shigella clone spread and caused the outbreak. PMID- 29482997 TI - Genetic characterization, evaluation of growth and production of biomass of strains from wild edible mushrooms of Lyophyllum of Central Mexico. AB - The present study conducted a genetic characterization and determined growth rate and biomass production in solid and liquid media, using strains obtained from wild edible sporomes of Lyophyllum that grow in high mountains. Vegetative isolation was used to obtain a total of four strains, which were divided into two clades within the section Difformia: Lyophyllum sp. and Lyophyllum aff. shimeji. Growth rate and biomass production were influenced by both the culture media and the strains. In a potato dextrose agar medium, the strains presented a higher growth rate, while in a malt extract-peptone and yeast agar medium, the growth rate was lower, but with a higher biomass production that was equal to that in the malt extract-peptone and yeast liquid medium. PMID- 29482998 TI - Antioxidant response of cowpea co-inoculated with plant growth-promoting bacteria under salt stress. AB - Soil salinity is an important abiotic stress worldwide, and salt-induced oxidative stress can have detrimental effects on the biological nitrogen fixation. We hypothesized that co-inoculation of cowpea plants with Bradyrhizobium and plant growth-promoting bacteria would minimize the deleterious effects of salt stress via the induction of enzymatic and non-enzymatic antioxidative protection. To test our hypothesis, cowpea seeds were inoculated with Bradyrhizobium or co-inoculated with Bradyrhizobium and plant growth promoting bacteria and then submitted to salt stress. Afterward, the cowpea nodules were collected, and the levels of hydrogen peroxide; lipid peroxidation; total, reduced and oxidized forms of ascorbate and glutathione; and superoxide dismutase, catalase and phenol peroxidase activities were evaluated. The sodium and potassium ion concentrations were measured in shoot samples. Cowpea plants did not present significant differences in sodium and potassium levels when grown under non-saline conditions, but sodium content was strongly increased under salt stress conditions. Under non-saline and salt stress conditions, plants co inoculated with Bradyrhizobium and Actinomadura or co-inoculated with Bradyrhizobium and Paenibacillus graminis showed lower hydrogen peroxide content in their nodules, whereas lipid peroxidation was increased by 31% in plants that were subjected to salt stress. Furthermore, cowpea nodules co-inoculated with Bradyrhizobium and plant growth-promoting bacteria and exposed to salt stress displayed significant alterations in the total, reduced and oxidized forms of ascorbate and glutathione. Inoculation with Bradyrhizobium and plant growth promoting bacteria induced increased superoxide dismutase, catalase and phenol peroxidase activities in the nodules of cowpea plants exposed to salt stress. The catalase activity in plants co-inoculated with Bradyrhizobium and Streptomyces was 55% greater than in plants inoculated with Bradyrhizobium alone, and this value was remarkably greater than that in the other treatments. These results reinforce the beneficial effects of plant growth-promoting bacteria on the antioxidant system that detoxifies reactive oxygen species. We concluded that the combination of Bradyrhizobium and plant growth-promoting bacteria induces positive responses for coping with salt-induced oxidative stress in cowpea nodules, mainly in plants co-inoculated with Bradyrhizobium and P. graminis or co inoculated with Bradyrhizobium and Bacillus. PMID- 29482999 TI - Surgeon Scientists Are Disproportionately Affected by Declining NIH Funding Rates. AB - BACKGROUND: Obtaining National Institutes of Health (NIH) funding over the last 10 years has become increasingly difficult due to a decrease in the number of research grants funded and an increase in the number of NIH applications. STUDY DESIGN: National Institutes of Health funding amounts and success rates were compared for all disciplines using data from NIH, Federation of American Societies for Experimental Biology (FASEB), and Blue Ridge Medical Institute. Next, all NIH grants (2006 to 2016) with surgeons as principal investigators were identified using the National Institutes of Health Research Portfolio Online Reporting Tools Expenditures and Results (NIH RePORTER), and a grant impact score was calculated for each grant based on the publication's impact factor per funding amount. Linear regression and one-way ANOVA were used for analysis. RESULTS: The number of NIH grant applications has increased by 18.7% (p = 0.0009), while the numbers of funded grants (p < 0.0001) and R01s (p < 0.0001) across the NIH have decreased by 6.7% and 17.0%, respectively. The mean success rate of funded grants with surgeons as principal investigators (16.4%) has been significantly lower than the mean NIH funding rate (19.2%) (p = 0.011). Despite receiving only 831 R01s during this time period, surgeon scientists were highly productive, with an average grant impact score of 4.9 per $100,000, which increased over the last 10 years (0.15 +/- 0.05/year, p = 0.02). Additionally, the rate of conversion of surgeon scientist-mentored K awards to R01s from 2007 to 2012 was 46%. CONCLUSIONS: Despite declining funding over the last 10 years, surgeon scientists have demonstrated increasing productivity as measured by impactful publications and higher success rates in converting early investigator awards to R01s. PMID- 29483000 TI - Editorial. PMID- 29483001 TI - Prevalence, awareness, treatment, and control of hypertension among Chinese working population: results of a workplace-based study. AB - We investigated the prevalence, awareness, treatment, and control of hypertension and the related risk factors among Chinese working population. From 2012 to 2013, a total of 37,856 employees aged 18-60 years from 61 workplaces were sampled. Standard questionnaire surveys and physical examinations were undertaken. Multilevel logistic regression models were performed to identify the risk factors. Overall, the age-standardized prevalence of hypertension was 23.3% (95% confidence interval [CI]: 22.9%-23.7%). Among the hypertensives, 47.8% (95% CI: 46.8%-48.8%) were aware of their condition, 20.6% (95% CI: 19.8%-21.4%) were in treatment, but only 8.5% (95% CI: 7.9%-9.1%) had controlled hypertension. White collar employees had a lower odds of hypertension compared with the blue-collar (odds ratio: 0.77, 95% CI: 0.71-0.84), whereas the state-owned enterprise employees had a higher odds compared with their private enterprise counterparts (odds ratio: 1.69, 95% CI: 1.07-2.65). Lower awareness and treatment were associated with being younger, higher education, and those from workplace without affiliated hospital. Higher occupation status individuals were more likely to be treated but no sign of better control. There is substantial room for improvement in hypertension diagnosis and treatment among the employees. Effective intervention programs are urgently needed at the workplaces. PMID- 29483002 TI - Front-of-pack Nutri-Score labelling in France: an evidence-based policy. PMID- 29483003 TI - Comparison of facemask and mouthpiece interfaces for multiple breath washout measurements. AB - BACKGROUND: Different interfaces (mouthpiece/nose clip vs. facemask) are used during multiple breath washout (MBW) tests in young children. METHODS: We investigated the effect of interface choice and breathing modalities on MBW outcomes in healthy adults and preschool children. RESULTS: In adults (n = 26) facemask breathing significantly increased LCI, compared to mouthpiece use (mean difference (95% CI) 0.4 (0.2; 0.6)), with results generalizable across sites and different equipment. Exclusively nasal breathing within the facemask increased LCI, as compared to oral breathing. In preschoolers (2-6 years, n = 46), no significant inter-test difference was observed across interfaces for LCI or FRC. Feasibility and breathing stability were significantly greater with facemask (incorporating dead space volume minimization), vs. mouthpiece. This was more pronounced in subjects <4 years of age. CONCLUSION: Both nasal vs. oral breathing and mouthpiece vs. facemask affect LCI measurements in adults. This effect was minimal in preschool children, where switching between interfaces is most likely to occur. PMID- 29483004 TI - Dual lumen balloon catheter - An effective substitute for two single lumen catheters in treatment of vascular targets with challenging anatomy. AB - The aim of this study was to describe our experience in the treatment of various pathological conditions of the cranial and spinal blood vessels and hypervascularized lesions using dual lumen balloon catheters. Twenty-five patients were treated with endovascular techniques: two with vasospasm of cerebral blood vessels caused by subarachnoid hemorrhage, one with a hypervascularized metastasis in the vertebral body, two with spinal dural fistula, four with cerebral dural fistula, three with cerebral arteriovenous malformations, and 13 with aneurysms. The dual lumen balloon catheters were used for remodeling of the coil mesh, injection of various liquid embolic agents, particles and nimodipine, for the prevention of reflux and deployment of coils and stents. The diameter of catheterized blood vessels varied from 0.7 mm to 4 mm. Two complications occurred: perforation of an aneurysm in one case and gluing of the tip of balloon catheter by embolic material in another case. All other interventions were uneventful, and therapeutic goals were achieved in all cases except in the case with gluing of the tip of balloon catheter. The balloons effectively prevented reflux regardless of the type of the embolic material and diameter of blood vessel. The results of our study show that dual lumen balloon catheters allow complex interventions in the narrow cerebral and spinal blood vessels where the safe use of two single lumen catheters is either limited or impossible. PMID- 29483005 TI - Clinical presentation and treatment paradigms of brain arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia. AB - Hereditary hemorrhagic telangiectasia (HHT) is characterized by recurrent spontaneous epistaxis, mucocutaneous telangiectases, and multisystem arteriovenous malformations (AVMs). Brain AVMs typically present at birth and are identified in approximately 10-20% of patients with HHT. A retrospective review was undertaken of all HHT patients with known single or multiple brain AVMs treated at our institution. Thirty-nine patients with brain AVM(s) were diagnosed with HHT. Most patients presented with at least one Curacao criterion. A total of 78 brain AVMs were identified in 39 patients. Two-thirds of patients had solitary brain AVMs, whereas 33% of patients harbored at least two lesions (range: 2-16). Brain AVMs of the supratentorial cerebral hemispheres comprised 83% of all lesions, whereas infratentorial lesions accounted for only 17%. Of the 55 brain AVMs assigned Spetzler-Martin grading, the majority of patients were Grade 1 (73%), and 23% and 4% were Grades 2 and 3, respectively. Patients were treated with surgery alone (51%), embolization alone (6%), embolization followed by surgery (9%), stereotactic radiosurgery (11%), stereotactic radiosurgery followed by surgery (3%), or observation (20%). Of patients who underwent genetic analysis, 62% possessed mutations in ENG (HHT type 1), whereas 38% had mutations in ACVRL1 (HHT type 2). This robust patient cohort of brain AVMs in 39 patients with HHT advances the collective understanding of this disease's varied presentation, diagnostic workup, genetic underpinnings, and available treatment options. PMID- 29483006 TI - Acute progressive paraplegia in heroin-associated myelopathy. AB - As the opioid epidemic continues, understanding manifestations of abuse, including heroin-associated myelopathy remains essential. Here we describe a young man with a past medical history significant for polysubstance abuse who developed acute-onset, rapidly progressive myelopathy after resumption of intravenous heroin use. He had significant spinal cord involvement with findings suggestive of heroin-associated myelopathy. The salient features of this case include diffusion imaging of the spine and spinal angiography supporting a possible vasculopathy as the pathophysiologic mechanism underlying heroin associated myelopathy. Additionally, CSF studies showed the transition from a neutrophilic pleocytosis to a lymphocytic pleocytosis suggesting an inflammatory component. PMID- 29483007 TI - Infant with recurrent ventriculoperitoneal shunt migration to right scrotum. AB - Migration of the distal catheter of a ventriculoperitoneal shunt to the scrotum is a documented but rare event. We present a case in which a 13 month old infant with hydrocephalus had recurrent migration of the peritoneal catheter to the right scrotum associated with a developing hydrocele. The patient underwent two revision operations and the distal catheter was ultimately shortened. He later underwent bilateral inguinal hernia repairs. PMID- 29483008 TI - The utilization of MGMT promoter methylation testing in United States hospitals for glioblastoma and its impact on prognosis. AB - Multiple studies have identified O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status to be an important prognostic factor in glioblastoma (GBM). We used the National Cancer Data Base (NCDB) to analyze completeness of coding for MGMT as well as to compare outcomes of GBM patients treated with adjuvant chemoradiation based on MGMT promoter methylation status (positive, negative, unknown). Patients diagnosed with GBM from 2010 to 2012 who received adjuvant chemoradiation were identified. MGMT promoter methylation status was obtained. The Kaplan-Meier method was used to assess overall survival (OS) by coding status of MGMT promoter methylation (positive, negative, unknown) and Cox regression analysis was used to assess impact of covariables on OS. There were 12,725 patients who met the study criteria, of which 626 (4.9%) were MGMT+, 1,037 (8.1%) were MGMT- and 11.062 (86.9%) were coded as unknown/not coded. Treatment at academic centers was strongly associated with MGMT promoter status testing (OR 2.23, p < 0.001), as well as hospital facility within the Northeast (OR 1.55, p < 0.001). The median and 2-year OS was 20 months and 40.2% for MGMT+ compared to 15 months and 24.1% for MGMT-, respectively (p < 0.001). For those coded as MGMT unknown, median and 2-year OS was 14.6 months and 27.5%, which was significantly worse compared to MGMT+ (p < 0.001) but not compared to MGMT- (p = 0.78). On multivariable analysis, MGMT+ was strongly associated with improved OS (HR 0.74, p < 0.001). Despite convincing evidence that MGMT promoter methylation status has a strong influence on prognosis; it appears to be a highly underutilized test in United States hospitals. PMID- 29483009 TI - Congenital achiasma and see-saw nystagmus in VATER syndrome association with hydrocephalus. PMID- 29483010 TI - Modified CHADS2 and CHA2DS2-VASc scores to predict atrial fibrillation in acute ischemic stroke patients. AB - It is important to identify candidates who warrant extended cardiac monitoring after ischemic stroke. We investigated the predictive performance of the CHADS2 and CHA2DS2-VASc scores for previously unknown atrial fibrillation during in hospital electrocardiographic monitoring. Patients were selected from a prospective trial in China. The clinical prediction of the scores was examined using the C statistic. Multivariate logistic regressions were performed to analyze the relevant risk factors. Among 1315 patients enrolled in study, previously unknown atrial fibrillation was detected in 110 (8.4%). Age, heart failure, NIHSS on admission, creatinine, and triglycerides were independently associated with newly detected atrial fibrillation. For newly detected atrial fibrillation, the C statistic value was 0.55 (OR 1.14, 95% CI: 0.97-1.33) for CHADS2 and 0.62 (OR 1.26, 95% CI: 1.12-1.42) for CHA2DS2-VASc; adding newly identified risk factors to these two scores, the value of C statistic was improved to 0.74 and 0.75, respectively. Age, heart failure, NIHSS on admission, creatinine and triglycerides were independent predictors of previously unknown atrial fibrillation. The CHADS2 and CHA2DS2-VASc scores are useful but not optimal for atrial fibrillation prediction. Addition of newly identified risk factors to these two scores resulted in significant improvement of the predictive performance. PMID- 29483011 TI - Histology of hemangioblastoma treated with stereotactic radiosurgery confirms its effectiveness. AB - Hemangioblastoma is usually amenable to total surgical resection, but indication for surgery can be hampered by its location, multiplicity, or repeated recurrences frequently observed in patients with von Hippel Lindau disease (VHLD). Stereotactic radiosurgery (SRS) has been administered for such cases as an alternative therapeutic option with generally favorable clinical response, but the effect of SRS has not been underscored by histological examination of the treated hemangioblastoma. Here we present histology of VHLD-associated hemangioblastoma tissue resected three months after SRS because of cyst enlargement. It confirmed that hemangioblastoma cells totally disappeared after SRS with a marginal dose of 20 Gy. Furthermore, Electron microscope revealed that endothelial cells of the vascular structure disappeared while maintaining the basement membranes, and leakage of intraluminal contents was observed around the structure. We showed the SRS was effective for hemangioblastoma pathologically at least with the marginal dose of 20 Gy. Leakage of intraluminal contents from the damaged vascular structure losing the endothelial cells is one possible mechanism for the cyst enlargement, and it may be a reason of poor control rate of SRS for the cystic hemangioblastoma. PMID- 29483012 TI - Lactate dehydrogenase as a prognostic marker in neoplastic meningitis. AB - This study aimed to establish the prognostic utility of lactate dehydrogenase (LDH) levels in the cerebrospinal fluid (CSF) of patients with neoplastic meningitis (NM). Patients with a confirmed diagnosis of NM at a cancer referral center were included. Data on demographic and oncological background, clinical symptoms, diagnostic tests, treatment, and survival were analyzed. In total, 119 patients were included, 74% of whom were females. The mean age was 44.2 years at the time of cancer diagnosis and 46.6 years at the time between NM diagnosis. Primary cancers were mostly breast cancer, lung cancer, or hematologic malignancies. The mean Karnofsky performance score (KPS) was 65. Frequent clinical symptoms were visual complaints, headache, cranial neuropathy, focal weakness, and decreased awareness. Diagnosis was made based on clinical symptoms, cytological CSF analysis results, and/or magnetic resonance imaging findings. The median overall survival (OS) was 4 months (95% CI 2.48-5.52). Prognostic variables associated with a better OS were hematopoietic malignancies, KPS >= 70, absence of meningeal signs, receiving any form of treatment, normal CSF glucose levels, and normal CSF LDH levels. After bivariate analysis, high LDH in the CSF remained statistically significant as a poor prognostic indicator. The LDH level is a useful parameter to assess the prognosis of patients with NM. Other factors associated with the prognosis of these patients were tumor type, CSF glucose levels, performance status, and receiving any form of treatment. PMID- 29483013 TI - Endoscopic third ventriculostomy for shunt malfunction in children: A review. AB - Endoscopic third ventriculostomy (ETV) is increasingly used in place of shunt revision for shunt malfunction (secondary ETV). This review provides a comprehensive overview of preoperative, operative and postoperative considerations for patients undergoing a secondary ETV. Preoperatively, patient selection is vital and there is evidence that secondary ETV is more effective than primary ETV in certain hydrocephalic aetiologies. Operative considerations include use of neuronavigation and consideration of surgeon technical experience due to anatomical differences that are likely to accompany chronic shunting, management of existing shunt hardware and the use of temporary external ventricular drains or short/long-term ventricular access devices. Postoperatively, there are varying institutional practices with regards to ICP monitoring and length of follow-up after discharge. Finally, this review examines the slit ventricle syndrome as a special case requiring a different approach. PMID- 29483015 TI - Ultrasonographic assessment of joint pathology in type 2 diabetes and hyperuricemia: The Fremantle Diabetes Study Phase II. AB - AIMS: The prevalence and consequences (articular and extra-articular) of hyperuricemia in type 2 diabetes, especially when asymptomatic (ASH), are incompletely understood. The aim of this study was to use ultrasonography to assess pathology associated with monosodium urate deposition in the joints of well-characterized hyperuricemic patients with type 2 diabetes. METHODS: A subset of 101 participants (mean age 70.4 years, 59.8% males, median diabetes duration 14.6 years) with hyperuricemia (fasting serum uric acid >=0.42 mmol/L) from the community-based observational Fremantle Diabetes Study Phase II were assessed by ultrasound for signs of intra-articular urate deposition and inflammation in 14 joints at increased risk of involvement in patients with gout. RESULTS: Most participants had evidence of crystal deposition comprising aggregates (59.4%), tophi (19.8%) or a double contour sign (27.7%), and 37% had a power Doppler signal indicative of inflammation in at least one joint. There was no difference between the prevalence of these abnormalities in those with ASH (n = 60) versus participants with a history of gout (n = 41; P >= 0.15). There was no association between a history of ischemic heart disease (reported by 17.8% of participants) and either any abnormality on joint ultrasound or inflammatory changes assessed by power Doppler (P >= 0.41). CONCLUSIONS: Joint inflammation and/or urate deposition were present in the majority of community-based patients with type 2 diabetes and hyperuricemia regardless of whether there was a history of gout. Given the potential consequences of chronic inflammation for joint damage and extra-articular complications such as cardiovascular disease, these data have potential clinical implications. PMID- 29483014 TI - Endovascular stent-coiling of a giant basilar artery aneurysm through a previous radial artery bypass. AB - Giant, partially-thrombosed basilar artery (BA) aneurysms are extraordinarily difficult to treat. Due to the high risk of rupture exclusion of these aneurysms from the circulation is imperative. In certain instances, direct clipping is unsuitable, and high-flow bypass and proximal parent vessel clip occlusion is required. We report a case of a recurrent partially-thrombosed giant BA apex aneurysm treated with endovascular stent-coiling through a previous radial artery bypass graft. Following the initial bypass and aneurysm trapping six years prior, the patient was neurologically stable until three months prior to admission when he developed new diplopia and left third nerve palsy. Imaging studies demonstrated interval enlargement of the thrombosed portion of the aneurysm and increased size in the filling portion of the aneurysm. In the present case, the existing radial artery bypass graft between left VA and left PCA permitted successful stent-assisted embolization of the recurrent BA aneurysm. To our knowledge, this is the first published case of endovascular stent-coiling of a BA aneurysm through a radial artery bypass graft. This novel technique can be a useful alternative for endovascular aneurysm treatment in these challenging lesions. PMID- 29483017 TI - Clinical utility of EEG in diagnosing and monitoring epilepsy in adults. AB - Electroencephalography (EEG) remains an essential diagnostic tool for people with epilepsy (PWE). The International Federation of Clinical Neurophysiology produces new guidelines as an educational service for clinicians to address gaps in knowledge in clinical neurophysiology. The current guideline was prepared in response to gaps present in epilepsy-related neurophysiological assessment and is not intended to replace sound clinical judgement in the care of PWE. Furthermore, addressing specific pathophysiological conditions of the brain that produce epilepsy is of primary importance though is beyond the scope of this guideline. Instead, our goal is to summarize the scientific evidence for the utility of EEG when diagnosing and monitoring PWE. PMID- 29483018 TI - Oxfam: sex scandal or governance failure? PMID- 29483019 TI - Canada's vision for global health and gender equality. PMID- 29483016 TI - Coronary artery disease severity modifies associations between glycemic control and both mortality and myocardial infarction. AB - AIMS: This study examined whether the association between hemoglobin A1c (HbA1c) and short-term clinical outcomes is moderated by CAD severity. METHODS: We studied 17,394 US Veterans with type 2 diabetes who underwent elective cardiac catheterization between 2005 and 2013. CAD severity was categorized as obstructive, non-obstructive, or no CAD. Using multivariable Cox proportional hazards regression, we assessed associations between time-varying HbA1c and two year all-cause mortality and non-fatal MI, with an interaction term between HbA1c and CAD severity. RESULTS: 61%, 22%, and 17% of participants had obstructive, non obstructive, and no CAD, respectively. CAD severity modified the relationship between HbA1c and each outcome (interaction p-value 0.0005 for mortality and <0.0001 for MI). Low HbA1c (<42 mmol/mol) was associated with increased mortality, relative to HbA1c of 48-52 mmol/mol, in individuals with obstructive CAD (HR 1.52 [1.17, 1.97]) and non-obstructive CAD (HR 2.61 [1.61, 4.23]), but not in those with no CAD (HR 0.91 [0.46, 1.79]). In contrast, higher HbA1c levels (>=53 mmol/mol) were associated with increased MI risk only in individuals with obstructive CAD. CONCLUSIONS: The associations between HbA1c and mortality and MI were moderated by CAD severity. Measures of cardiovascular disease severity may inform optimal individualized diabetes management. PMID- 29483020 TI - Canada's time to act. PMID- 29483021 TI - Cindy Blackstock: advocate for First Nations children. PMID- 29483022 TI - Canada's efforts to ensure the health and wellbeing of Indigenous peoples. PMID- 29483023 TI - Picturing health: health advocates for Indigenous communities in British Columbia, Canada. PMID- 29483024 TI - Challenges in health equity for Indigenous peoples in Canada. PMID- 29483025 TI - Monique Begin: Canadian health icon. PMID- 29483026 TI - Canada's global health role: supporting equity and global citizenship as a middle power. AB - Canada's history of nation building, combined with its status as a so-called middle power in international affairs, has been translated into an approach to global health that is focused on equity and global citizenship. Canada has often aspired to be a socially progressive force abroad, using alliance building and collective action to exert influence beyond that expected from a country with moderate financial and military resources. Conversely, when Canada has primarily used economic self-interest to define its global role, the country's perceived leadership in global health has diminished. Current Prime Minister Justin Trudeau's Liberal federal government has signalled a return to progressive values, driven by appreciation for diversity, equality, and Canada's responsibility to be a good global citizen. However, poor coordination of efforts, limited funding, and the unaddressed legacy of Canada's colonisation of Indigenous peoples weaken the potential for Canadians to make meaningful contributions to improvement of global health equity. Amid increased nationalism and uncertainty towards multilateral commitments by some major powers in the world, the Canadian federal government has a clear opportunity to convert its commitments to equity and global citizenship into stronger leadership on the global stage. Such leadership will require the translation of aspirational messages about health equity and inclusion into concrete action at home and internationally. PMID- 29483028 TI - Canada and global health: accelerate leadership now. PMID- 29483027 TI - Canada's universal health-care system: achieving its potential. AB - Access to health care based on need rather than ability to pay was the founding principle of the Canadian health-care system. Medicare was born in one province in 1947. It spread across the country through federal cost sharing, and eventually was harmonised through standards in a federal law, the Canada Health Act of 1984. The health-care system is less a true national system than a decentralised collection of provincial and territorial insurance plans covering a narrow basket of services, which are free at the point of care. Administration and service delivery are highly decentralised, although coverage is portable across the country. In the setting of geographical and population diversity, long waits for elective care demand the capacity and commitment to scale up effective and sustainable models of care delivery across the country. Profound health inequities experienced by Indigenous populations and some vulnerable groups also require coordinated action on the social determinants of health if these inequities are to be effectively addressed. Achievement of the high aspirations of Medicare's founders requires a renewal of the tripartite social contract between governments, health-care providers, and the public. Expansion of the publicly funded basket of services and coordinated effort to reduce variation in outcomes will hinge on more engaged roles for the federal government and the physician community than have existed in previous decades. Public engagement in system stewardship will also be crucial to achieve a high-quality system grounded in both evidence and the Canadian values of equity and solidarity. PMID- 29483029 TI - Midwives' attitudes, beliefs and concerns about childhood vaccination: A review of the global literature. AB - Vaccine hesitancy in industrialised countries is an area of concern. Health professionals play a significant role in parental vaccination decisions, however, to date the role of midwives has not been widely explored. This review sought to describe the attitudes and communication practices of midwives in developed countries towards childhood vaccines. Medline, Cinahl, PsychInfo, Embase and the grey literature were searched. Inclusion criteria were qualitative and quantitative studies reporting midwives' beliefs, attitudes and communication practices toward childhood vaccination. The search returned 366 articles, of which 359 were excluded by abstract. Two additional articles were identified from the grey literature and references, resulting in nine studies from five countries included in the review. Across the studies, the majority of midwives supported vaccination, although a spectrum of beliefs and concerns emerged. A minority expressed reservations about the scientific justification for vaccination, which focussed on what is not yet known rather than mistrust of current evidence. Most midwives felt that vaccines were safe; a minority were unsure, or believed they were unsafe. The majority of midwives agreed that childhood vaccines are necessary. Among those who expressed doubt, a commonly held opinion was that vaccine preventable diseases such as measles are relatively benign and didn't warrant vaccination against them. Finally, the midwifery model of care was shown to focus on providing individualised care, with parental choice being placed at a premium. The midwifery model care appears to differ in approach from others, possibly due to a difference in the underpinning philosophies. Research is needed to understand how midwives see vaccination, and why there appears to be a spectrum of views on the subject. This information will inform the development of resources tailored to the midwifery model of care, supporting midwives in advocating for childhood vaccination. PMID- 29483031 TI - New and safe formulation for scorpion immunotherapy: Comparative study between saponin and FCA adjuvants associated to attenuated venom. AB - Envenoming by scorpion is a major health problem in Maghreb regions as well as in several regions of the world. Immunotherapy is the only effective treatment for scorpion stings. The immune sera are obtained from hyper-immunized animals with a formulation of venom associated to Freund's Complete Adjuvant (FCA). This formulation seems to protect against several alterations in immunized animals leading to worsening of their health due to added toxicity of native venom and FCA adjuvant. This study aims to provide a more efficient and non-toxic alternative to this formulation. Two formulations of saponin or FCA associated to irradiated venom of Androctonus australis hector (Aah) were used to compare their safety and their efficiency to better enhance the antibody titers against toxic antigens. Both of these formulations were used in immunization schedule of three months. Blood samples were collected every week, cell count, myeloperoxydase (MPO) and eosinophil peroxidase (EPO) activities and specific antibody titers were evaluated. Four months after the last immunization, rabbits were challenged with increased doses of native Aah venom. Results showed that immunization with saponin formulation induced lower inflammatory cell activation as well as reduced MPO and EPO activities compared to that using FCA. The formulation of irradiated venom with saponin seems also to be more efficient in the activation of lymphocytes resulting in higher titers of specific IgG. The immunoprotective effect evaluation showed that the formulation using saponin seems to protected animals until 3 LD50 of native venom compared to that using FCA which protected only until 2 LD50. These results indicate that saponin formulation with irradiated antigen could be more efficient and safe immunizing preparation for the production of sera against scorpion envenomation. PMID- 29483030 TI - Acceptability of intranasal live attenuated influenza vaccine, influenza knowledge and vaccine intent in The Gambia. AB - BACKGROUND: The burden of influenza is increasingly recognised in Africa. The WHO recommends introducing influenza vaccination to high-risk groups: pregnant women, children <5 years, and the elderly. The Gambia currently has no influenza vaccination policy, but the NASIMMUNE study, a clinical trial of intranasal live attenuated influenza vaccines (LAIV) in young children provided an opportunity to study maternal attitudes towards LAIV for the first time in sub-Saharan Africa. We assess acceptability of LAIV, influenza knowledge and attitudes towards influenza vaccination in Gambian women. Additionally, we investigate predictors of willingness to receive influenza vaccine (intent) in pregnancy or seasonally for children <5. METHODS: A cross-sectional survey was conducted in Gambian women at two urban health facilities. To assess LAIV acceptability, the exposure group (women whose children had received LAIV during the NASIMMUNE study) were compared to a control group (women whose children were not enrolled in the NASIMMUNE study). Demographics and health belief constructs were analysed as predictors of influenza knowledge and vaccine intent. FINDINGS: The exposure group (n = 150) expressed a higher preference for a nasal spray vaccine than an injection compared to the control group (n = 304) (93.3% vs. 34.9%, OR = 26.15, p < 0.0001). Those in the exposure group who preferred the nasal spray found it less distressing, safer or equally safe, and easier or equally easy to give (all p < 0.001) than injections. Influenza knowledge increased with education level (p = 0.006 for higher education vs. none), and varied between sites (p = 0.0005). Vaccine intent was >98%, but no association with influenza knowledge or difference between groups was observed. Various health belief constructs were associated with vaccine intent. CONCLUSION: LAIV acceptability was higher in those with first-hand experience. Influenza vaccine intent was also high. Incorporation of seasonal LAIV into the childhood immunisation schedule in The Gambia would be feasible, particularly if combined with community-based health education. PMID- 29483033 TI - Immunization of pregnant cows with Shiga toxin-2 induces high levels of specific colostral antibodies and lactoferrin able to neutralize E. coli O157:H7 pathogenicity. AB - E. coli O157:H7 is a foodborne pathogen responsible for bloody diarrhea, hemorrhagic colitis and hemolytic uremic syndrome (HUS). The objective of the present work was to evaluate the ability of colostral IgG obtained from Stx2 immunized cows to prevent against E. coli O157:H7 infection and Stx2 cytotoxicity. Hyperimmune colostrum (HC) was obtained from cows intramuscularly immunized with inactivated Stx2 or vehicle for controls. Colostral IgG was purified by affinity chromatography. Specific IgG antibodies against Stx2 and bovine lactoferrin (bLF) levels in HC and the corresponding IgG (HC-IgG/bLF) were determined by ELISA. The protective effects of HC-IgG/bLF against Stx2 cytotoxicity and adhesion of E. coli O157:H7 and its Stx2-negative mutant were analyzed in HCT-8 cells. HC-IgG/bLF prevention against E. coli O157:H7 was studied in human colon and rat colon loops. Protection against a lethal dose of E. coli O157:H7 was evaluated in a weaned mice model. HC-IgG/bLF showed high anti Stx2 titers and high bLF levels that were able to neutralize the cytotoxic effects of Stx2 in vitro and in vivo. Furthermore, HC-IgG/bLF avoided the inhibition of water absorption induced by E. coli O157:H7 in human colon and also the pathogenicity of E. coli O157:H7 and E. coli O157:H7Deltastx2 in rat colon loops. Finally, HC-IgG/bLF prevented in a 100% the lethality caused by E. coli O157:H7 in a weaned mice model. Our study suggests that HC-IgG/bLF have protective effects against E. coli O157:H7 infection. These beneficial effects may be due to specific anti-Stx2 neutralizing antibodies in combination with high bLF levels. These results allow us to consider HC-IgG/bLF as a nutraceutical tool which could be used in combination with balanced supportive diets to prevent HUS. However further studies are required before recommendations can be made for therapeutic and clinical applications. PMID- 29483034 TI - Effectiveness of a Low Fidelity Cast Removal Module in Orthopaedic Surgical Simulation. AB - OBJECTIVE: The purpose of this study is to determine if an educational model during a surgical skills laboratory results in a significant reduction in cast saw blade temperatures generated during cast removal. DESIGN: As part of an orthopedic resident surgical skills laboratory an Institutional Review Board approved study was performed. A total of 17 study subjects applied a short arm cast. Everyone removed 1 short arm cast with temperatures recorded on the saw blade. Following cast removal, an educational session was conducted on proper cast removal and blade cooling techniques. Everyone then removed a second cast. Blade temperatures were recorded. To assess reproducibility, the 5 PGY-1 orthopedic residents removed a short arm cast 3 months later. SETTING: Carolinas Medical Center, Charlotte, NC, tertiary care center PARTICIPANTS: A total of 17 study subjects with minimal casting experience (5 PGY-1 orthopedic residents and 12 senior medical students) applied a short arm cast. RESULTS: Following the educational session there was a significant reduction in mean and mean maximum blade temperatures (p < 0.05). During the second round of cast removal assessment of blade temperatures and specific techniques to cool the blade were observed among all participants. At 3 months' time, the mean and mean maximum blade temperatures remained significantly lower than before the educational session (p < 0.05). CONCLUSIONS: The intervention in this study reduced the maximum blade temperatures to levels below the threshold known to cause burns. This simple, low cost, and easily reproducible model can easily be disseminated across institutions and simulation laboratories. PMID- 29483032 TI - Vaccination coverage among foreign-born and U.S.-born adolescents in the United States: Successes and gaps - National Immunization Survey-Teen, 2012-2014. AB - BACKGROUND: An overall increase has been reported in vaccination rates among adolescents during the past decade. Studies of vaccination coverage have shown disparities when comparing foreign-born and U.S.-born populations among children and adults; however, limited information is available concerning potential disparities in adolescents. METHODS: The National Immunization Survey-Teen is a random-digit-dialed telephone survey of caregivers of adolescents aged 13-17 years, followed by a mail survey to vaccination providers that is used to estimate vaccination coverage among the U.S. population of adolescents. Using the National Immunization Survey-Teen data, we assessed vaccination coverage during 2012-2014 among adolescents for routinely recommended vaccines for this age group (>=1 dose tetanus and diphtheria toxoids and acellular pertussis [Tdap] vaccine, >=1 dose quadrivalent meningococcal conjugate [MenACWY] vaccine, >=3 doses human papillomavirus [HPV] vaccine) and for routine childhood vaccination catch-up doses (>=2 doses measles, mumps, and rubella [MMR] vaccine, >=2 doses varicella vaccine, and >=3 doses hepatitis B [HepB] vaccine). Vaccination coverage prevalence and vaccination prevalence ratios were estimated. RESULTS: Of the 58,090 respondents included, 3.3% were foreign-born adolescents. Significant differences were observed between foreign-born and U.S.-born adolescents for insurance status, income-to-poverty ratio, education, interview language, and household size. Foreign-born adolescents had significantly lower unadjusted vaccination coverage for HepB (89% vs. 93%), and higher coverage for the recommended >=3 doses of HPV vaccine among males, compared with U.S.-born adolescents (22% vs. 14%). Adjustment for demographic and socioeconomic factors accounted for the disparity in HPV but not HepB vaccination coverage. CONCLUSIONS: We report comparable unadjusted vaccination coverage among foreign born and U.S.-born adolescents for Tdap, MenACWY, MMR, >=2 varicella. Although coverage was high for HepB vaccine, it was significantly lower among foreign-born adolescents, compared with U.S.-born adolescents. HPV and >=2-dose varicella vaccination coverage were low among both groups. PMID- 29483035 TI - Burnout is Associated With Emotional Intelligence but not Traditional Job Performance Measurements in Surgical Residents. AB - OBJECTIVE: To evaluate whether burnout was associated with emotional intelligence and job performance in surgical residents. DESIGN: General surgery residents at a single institution were surveyed using the Maslach Burnout Inventory (MBI) and trait EI questionnaire (TEIQ-SF). Burnout was defined as scoring in 2 of the 3 following domains; Emotional Exhaustion (high), Depersonalization (high), and Personal Accomplishment (low). Job performance was evaluated using faculty evaluations of clinical competency-based surgical milestones and standardized test scores including the American Board of Surgery In-Training Exam (ABSITE) and the United States Medical Licensing Examination (USMLE) Step 3. USMLE Step 1 and USMLE Step 2, which were taken prior to residency training, were included to examine possible associations of burnout with USMLE examinations. Statistical comparison was made using Pearson correlation and simple linear regression adjusting for PGY level. SETTING: This study was conducted at the University of Alabama at Birmingham (UAB) general surgery residency program. PARTICIPANTS: All current and incoming general surgery residents at UAB were invited to participate in this study. RESULTS: Forty residents participated in the survey (response rate 77%). Ten residents, evenly distributed from incoming residents to PGY-4, had burnout (25%). Mean global EI was lower in residents with burnout versus those without burnout (3.71 vs 3.9, p = 0.02). Of the 4 facets of EI, mean self-control values were lower in residents with burnout versus those without burnout (3.3 vs 4.06, p < 0.01). Each component of burnout was associated with global EI, with the strongest correlation being with personal accomplishment (r = 0.64; p < 0.01). Residents with burnout did not have significantly different mean scores for USMLE Step 1 (229 vs 237, p = 0.12), Step 2 (248 vs 251, p = 0.56), Step 3 (223 vs 222, p = 0.97), or ABSITE percentile (44.6 vs 58, p = 0.33) compared to residents without burnout. Personal accomplishment was associated with ABSITE percentile scores (r = 0.35; p = 0.049). None of the 16 surgical milestone scores were significantly associated with burnout. CONCLUSIONS: Burnout is present in surgery residents and associated with emotional intelligence. There was no association of burnout with USMLE scores, ABSITE percentile, or surgical milestones. Traditional methods of assessing resident performance may not be capturing burnout and strategies to reduce burnout should consider targeting emotional intelligence. PMID- 29483036 TI - Blood glucose monitoring during aerobic and anaerobic physical exercise using a new artificial pancreas system. AB - AIM: To assess an artificial pancreas system during aerobic (AeE) and anaerobic exercise (AnE). METHODS: A pilot clinical trial on five subjects with type 1 diabetes (4 males) aged 37+/-10.9 years, diabetes diagnosed 21.2+/-12.2 years before, insulin pump users, and with a mean HbA1c level of 7.8+/-0.5%. Every subject did three AeE and three AnE sessions. Blood glucose levels were monitored by the artificial pancreas system during exercise and up to four hours later. Before the start of exercise, 23g of carbohydrates were administered orally. RESULTS: The mean glucose level was 124.0+/-25.1mg/dL in the AeE studies and 152.1+/-34.1mg/dL in the AnE studies. Percent times in the different glucose ranges of 70-180, >180 and <70mg/dL were 89.8+/-18.6% and 75.9+/-27.6%; 7.7+/ 18.4% and 23.2+/-28.0%; and 2.5+/-6.3% and 1.0+/-3.6% during the AeE and AnE sessions, respectively. Only six rescues with carbohydrates (15g) were required during the studies (4 in AeE and 2 in AnE). Total insulin dose during the five hours of the study was 3.1+/-1.0IU in the AeE studies and 3.5+/-1.3IU in the AnE studies. CONCLUSIONS: Blood glucose response to AeE and AnE exercise is different. The evaluated artificial pancreas system appeared to achieve effective and safe blood glucose control during exercise and up to four hours later. However, new control strategies that minimize patient intervention should be designed. PMID- 29483037 TI - Treatment with the SQ house dust mite sublingual immunotherapy tablet may be initiated year-round. PMID- 29483038 TI - Macrophages Remember Cheeseburgers and Promote Inflammation via NLRP3. AB - In a recent study, Christ and colleagues identify a key role for NLRP3/IL-1beta in the induction of innate immune memory in monocytes by the Western diet, promoting atherosclerosis and inflammatory diseases. PMID- 29483039 TI - A New Chapter in Genetic Medicine: RNA Editing and its Role in Disease Pathogenesis. AB - The transfer of genomic information from DNA to mRNA to protein usually occurs with high fidelity, but can also be subverted by a programmed RNA sequence alteration termed 'RNA editing', involving deamination of adenosine to inosine (decoded as guanosine), or of cytosine to uracil. These sequence changes can lead to cellular heterogeneity by generating variable sets of transcripts within otherwise identical cells. Recent studies have demonstrated that editing is most prevalent in cells and tissues with high propensity for plasticity. Within those, RNA editing reproducibly targets transcripts of related function, altering the outcomes of entire pathways at once. In ongoing work, changes in patterns of editing have been correlated with neuronal disease pathogenesis, suggesting that RNA editing harbors diagnostic potential. PMID- 29483040 TI - Pharmacodynamic assessment of diuretic efficacy and braking in a furosemide continuous infusion model. AB - INTRODUCTION: Diuretic failure is a potential life-ending event but is unpredictable and poorly understood. The objectives of this study were to evaluate pharmacodynamic markers of furosemide-induced diuresis and to investigate mechanisms of diuretic braking in dogs receiving constant rate infusion (CRI) of furosemide. ANIMALS: Six healthy male dogs. METHODS: Raw data and stored samples from one arm of a previously published study were further analyzed to mechanistically investigate causes of diuretic braking in these dogs. Urine volume was recorded hourly during a 5-h furosemide CRI. Urine and blood samples were collected hourly to measure serum and urine electrolytes, urine aldosterone, and plasma and urine furosemide. Serum electrolyte fractional excretion was calculated. Urine sodium concentration was indexed to urine potassium (uNa:uK) and urine furosemide (uNa:uFur) concentrations, plasma furosemide concentration was indexed to urine furosemide concentration (pFur:uFur), and urine aldosterone was indexed to urine creatinine (UAldo:C). Temporal change and the relationship to urine volume were evaluated for these measured and calculated variables. RESULTS: Urine volume was significantly correlated with urine electrolyte amounts and with uNa:uK. The ratio of pFur:uFur decreased during the infusion, whereas furosemide excretion was unchanged. CONCLUSIONS: There was a strong relationship between urine volume and absolute urine electrolyte excretion. Urine volume was strongly correlated to uNa:uK, giving it potential as a spot indicator of urine production during diuresis. The decrease in uNa:uK over time during the infusion is consistent with mineralocorticoid modification of urinary electrolyte excretion, supporting renin angiotensin-aldosterone activation as a cause of diuretic braking in this model. PMID- 29483041 TI - A Dosimetric Comparison of Breast Radiotherapy Techniques to Treat Locoregional Lymph Nodes Including the Internal Mammary Chain. AB - AIMS: Radiotherapy target volumes in early breast cancer treatment increasingly include the internal mammary chain (IMC). In order to maximise survival benefits of IMC radiotherapy, doses to the heart and lung should be minimised. This dosimetry study compared the ability of three-dimensional conformal radiotherapy, arc therapy and proton beam therapy (PBT) techniques with and without breath-hold to achieve target volume constraints while minimising dose to organs at risk (OARs). MATERIALS AND METHODS: In 14 patients' datasets, seven IMC radiotherapy techniques were compared: wide tangent (WT) three-dimensional conformal radiotherapy, volumetric-modulated arc therapy (VMAT) and PBT, each in voluntary deep inspiratory breath-hold (vDIBH) and free breathing (FB), and tomotherapy in FB only. Target volume coverage and OAR doses were measured for each technique. These were compared using a one-way ANOVA with all pairwise comparisons tested using Bonferroni's multiple comparisons test, with adjusted P-values <= 0.05 indicating statistical significance. RESULTS: One hundred per cent of WT(vDIBH), 43% of WT(FB), 100% of VMAT(vDIBH), 86% of VMAT(FB), 100% of tomotherapy FB and 100% of PBT plans in vDIBH and FB passed all mandatory constraints. However, coverage of the IMC with 90% of the prescribed dose was significantly better than all other techniques using VMAT(vDIBH), PBT(vDIBH) and PBT(FB) (mean IMC coverage +/- 1 standard deviation = 96.0% +/- 4.3, 99.8% +/- 0.3 and 99.0% +/- 0.2, respectively). The mean heart dose was significantly reduced in vDIBH compared with FB for both the WT (P < 0.0001) and VMAT (P < 0.0001) techniques. There was no advantage in target volume coverage or OAR doses for PBT(vDIBH) compared with PBT(FB). CONCLUSIONS: Simple WT radiotherapy delivered in vDIBH achieves satisfactory coverage of the IMC while meeting heart and lung dose constraints. However, where higher isodose coverage is required, VMAT(vDIBH) is the optimal photon technique. The lowest OAR doses are achieved by PBT, in which the use of vDIBH does not improve dose statistics. PMID- 29483042 TI - Triterpene Messages from the EU-FP7 Project TriForC. AB - TriForC is an innovative EU-funded collaborative project that has established an integrative pipeline for the exploitation of plant triterpenes for commercialization in agriculture and pharmacology. We discuss the main outcomes of TriForC and reflect on its potential long-term impact and on the importance of EU projects for science, industry, and society. PMID- 29483043 TI - Role of WNT/beta-Catenin Pathway as Potential Prognostic and Predictive Factors in Renal Cell Cancer Patients Treated With Everolimus in the Second and Subsequent Lines. AB - BACKGROUND: The aim of the present study was to search for predictive and prognostic factors in patients with metastatic renal cell carcinoma (mRCC) treated with everolimus among the components of the WNT/beta-catenin pathway. PATIENTS AND METHODS: In a prospective, single-arm, phase II study, patients with mRCC received everolimus (10 mg/d) in a 30-day cycle. We performed a prospectively planned evaluation of the potential biomarkers of the WNT/beta catenin pathway. RESULTS: The serum level of soluble E-cadherin (sE-cadherin) in patients with RCC was significantly greater than that in the controls (71.62 +/- 22.28 pg/mL vs. 54.26 +/- 10.317 pg/mL; P = .0069). After 2 cycles of everolimus therapy, we observed a significance increase in sE-cadherin (from 71.81 +/- 21.18 pg/mL to 77.50 +/- 28.212 pg/mL; P = .0151). The Dickkopf-1 protein levels in the study and control groups were not significantly different (P = .2135). The favorable independent predictors for everolimus therapy were normal lactate dehydrogenase level before treatment (hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.28-0.98; P = .0443) and low sE-cadherin level (HR, 0.54; 95% CI, 0.29-0.98; P = .0422). On multivariate analysis, we observed that worse overall survival was seen in patients with a lower regression coefficient of sE-cadherin after 2 cycles of treatment (HR, 2.60; 95% CI, 1.23-5.52; P = .0128), an increased corrected calcium level (HR, 3.09; 95% CI, 1.21-7.88; P = .0180), and an increased lactate dehydrogenase level before treatment (HR, 1.98; 95% CI, 1.02 3.83; P = .0426). CONCLUSION: WNT/beta-catenin component expression in patients with mRCC had no effect on progression-free survival or overall survival. However, we found that the sE-cadherin level might interact with response to everolimus therapy, although confirmation in future studies is needed. PMID- 29483044 TI - Leiomyoma of the Prostate: Case Report and Review of the Literature. AB - Leiomyomas can develop in any organ containing smooth muscles. They most commonly occur in the gastrointestinal and the female genital tracts. Leiomyoma of the prostate is a rare, benign tumor. We report 3 cases of rare prostatic leiomyomas. The paucity of literature describing prostatic leiomyoma increases the chance for misdiagnosis. Fewer than 30 cases in the English literature, with none including magnetic resonance imaging, computed tomography (CT), ultrasound, positron emission tomography-CT, and pathological findings together were found. Over the past decade, there has been a shift in the management of prostatic leiomyomas. Prostatectomy was once considered a standard approach for treatment, but now nonsurgical treatment options such as embolization are preferred. Conservative management including surveillance is an option for asymptomatic patients. PMID- 29483045 TI - Active Surveillance for Prostate Cancer: Are We Failing Latino Patients at a Large Safety Net Hospital? AB - INTRODUCTION: Active surveillance (AS) is one recommended option for low-risk prostate cancer and involves close follow-up and monitoring. Our objective was to determine whether non-clinical trial patients adhere to AS protocols and how many are lost to follow-up (LTFU). PATIENTS AND METHODS: Retrospective chart review was performed for patients with nonmetastatic prostate cancer who initiated AS at Los Angeles County Hospital (LAC) and University of Southern California Norris Comprehensive Cancer Center (Norris) between January 1, 2008, and January 1, 2015. Competing-risks regression analyses examined the difference in LTFU rates of AS patients in the 2 institutions and examined the association between LTFU and patient characteristics. We used California Cancer Registry data to verify if patients LTFU were monitored and/or treated at other LAC medical facilities. RESULTS: We found 116 patients at LAC and 98 at Norris who met the AS criteria for this study. Patients at LAC and Norris had similar tumor characteristics but differed in median income, race, primary language spoken, distance residing from hospital, and socioeconomic status (SES). LTFU was significantly different between the institutions: 57 +/- 7% at LAC and 32 +/- 6% at Norris at 5 years (P < .001). By multivariable analysis, the main determinant of LTFU was SES (P = .045). By 5 years, the chance of an LAC patient remaining on AS was 8 +/- 6% compared to 20 +/- 6% for a Norris patient (P < .001). CONCLUSION: Successful AS implementation relies on patient follow-up. We found that patients on AS from lower SES strata are more often LTFU. Identifying barriers to follow-up and compliance among low SES patients is critical to ensure optimal AS. PMID- 29483046 TI - A national approach to medicines information research: A systematic review. AB - BACKGROUND: The Finnish Medicines Agency Fimea published the first National Medicines Information (MI) strategy in 2012. For the purpose of implementing the MI strategy into practice by the national MI Network, a comprehensive inventory of MI research in Finland was needed. OBJECTIVE: To systematically review literature on MI research conducted in Finland by analyzing and classifying the studies, and identifying the gaps in MI research. METHODS: Medline, Scopus and Medic databases were searched for peer-reviewed MI publications by using key word screening criteria. The search and extraction process followed PRISMA Guidelines and covered the period from January 2000 to June 2016. Included studies were content analyzed according to MI practices identified, trends over time in research methodology and theory. RESULTS: Included publications (n = 126) applied a variety of research methods, most often cross-sectional surveys (n = 51, 40% of all studies), but more than half of the studies were qualitative (n = 68, 54%). Twelve were intervention studies of which 6 were randomized and had a control group. Studies were categorized into: patient counseling in different settings (n = 45); MI sources and needs of medicine users (n = 25); healthcare professionals' (HCPs) competence in patient counseling and pharmacotherapy (n = 25); MI sources and needs of HCPs (n = 23); MI education and literacy (n = 13); and MI policies and strategies (n = 3). Most of the studies were descriptive, and only 6 studies applied a theory. CONCLUSIONS: Regardless of some methodological pitfalls, MI research conducted in Finland since 2000 provides multifaceted understanding of MI practices and their development needs. Research should shift towards larger research lines having a stronger theory base and study designs to deepen the understanding of MI practices and behaviors, and effectiveness of MI in different healthcare settings. Future research should cover also the use of electronic MI sources and services which apply modern information technology to clinical decision making and medication reviews, national MI policy, MI literacy, MI needs of HCPs and consumers. PMID- 29483047 TI - Author's Reply. PMID- 29483048 TI - Radiation Oncology Practice Accreditation: A Story of the Surveyor Experience. PMID- 29483049 TI - Virtual Palpation: The Role of MR Elastography in Quantifying and Spatially Resolving Tissue Stiffness as a Biomarker of Disease. PMID- 29483050 TI - When Given a Lemon-Write a Book. PMID- 29483051 TI - Re: "Management of Incidental Pancreatic Cysts: A White Paper of the ACR Incidental Findings Committee". PMID- 29483052 TI - The Percent Share of All Medicare Payments to Physicians That Is Attributable to Noninvasive Diagnostic Imaging. AB - PURPOSE: To ascertain the proportion of all Medicare payments to physicians under the Medicare Physician Fee Schedule (PFS) that is attributable to noninvasive diagnostic imaging (NDI). MATERIALS AND METHODS: The Medicare Part B Physician/Supplier Procedure Summary Master Files for 2003 to 2015 were the data source. Total approved payments to physicians for all medical services were determined each year. We then selected all procedure codes for NDI and determined aggregate approved payments to physicians for those codes. Also, Medicare's provider specialty codes were used to define payments to four provider categories: radiologists, cardiologists, all other physicians, and independent diagnostic testing facilities together with multispecialty groups (in this category, the specialty of the actual provider cannot be determined). RESULTS: Total Medicare-approved payments for all physician services under the PFS increased progressively from $92.73 billion in 2003 to $132.85 billion in 2015. In 2003, the share of those payments attributable to NDI was 9.5%, increasing to a peak of 10.8% in 2006, but then progressively declining to 6.0% in 2015. All four provider categories saw the same trend pattern-a peak in 2006 but then decline thereafter. By 2015, the shares of total PFS payments to physicians that were attributable to NDI were as follows: radiologists 3.2%, cardiologists 1.2%, all other physicians 1.2%, independent diagnostic testing facilities or multispecialty groups 0.4%. CONCLUSION: The proportion of Medicare PFS spending on physician services that is attributable to NDI has been declining in recent years and is now quite small. PMID- 29483053 TI - Structured Reporting in the Academic Setting: What the Referring Clinician Wants. PMID- 29483054 TI - The Utility of the Modified Yale Preoperative Anxiety Scale for Predicting Success in Pediatric Patients Undergoing MRI Without the Use of Anesthesia. AB - PURPOSE: MRI is a common modality for diagnostic imaging. In children, general anesthesia is often required to complete MRI examinations. Simulation training can reduce the need for anesthesia in some children. Reliable screening tools to select who could benefit from practice MRI sessions are lacking. This study evaluates the use of the modified Yale Preoperative Anxiety Scale (mYPAS) in effectively identifying patients who may benefit from simulation-based training. METHODS: Children aged 5 and older who were originally scheduled for MRI with anesthesia in 2015 to 2016 were prospectively recruited for simulation-based training. The mYPAS assessment was performed by trained certified child life specialists before and after practice MRI sessions. The primary outcome was whether mYPAS could predict completing an MRI examination without anesthesia. RESULTS: Eighty patients (43 boys and 37 girls, age 8.5 +/- 3.0 years) were enrolled in the study. Eleven subjects (14%) required general anesthesia to complete the MRI examination despite participating in the simulation. In the overall cohort, mYPAS scores improved after simulation from 31 +/- 11 to 27 +/- 9 (95% confidence interval of difference, -6, -2; P < .001 by paired t test). Receiver operating characteristic curve analysis found that presimulation mYPAS had good utility for predicting anesthesia requirement for MRI completion (area under the curve = 0.81). A presimulation mYPAS score > 33 predicted need for anesthesia with 82% sensitivity and 78% specificity. CONCLUSIONS: The mYPAS is a quick screening tool to identify pediatric patients who could benefit from simulation training by being able to complete an MRI examination without anesthesia. PMID- 29483055 TI - Coverage of the dorsal surface of a digit based on a pedicled free-style perforator flap concept. AB - BACKGROUND: Reconstruction of the finger and thumb dorsum has been considered difficult because of the need for a thin and flexible flap, and the surrounding tissue is sometimes insufficient for a local flap. The purpose of this report is to describe our concept for finger and thumb dorsum reconstruction with free style perforator flaps and our clinical experience with transfer of various perforator flaps. METHODS: Thirty-two finger dorsum defects in 32 patients were covered with pedicled free-style perforator flaps. The perforator origin was a digital artery perforator in 22 cases and a dorsal metacarpal artery perforator in 10 cases. The flap style was advancement type in 11 cases, rotation in 2, propeller in 14, and adipofascial in 5. RESULTS: The mean size of the digital artery perforator flap was 3.4 cm2 and that of the dorsal metacarpal artery perforator flap was 7.9 cm2. All flaps, except for two propeller flaps with 180 degrees rotation, survived completely. These flaps were of elongated style, and the length-to-width ratios were approximately 3:1 and 3.5:1, respectively. CONCLUSIONS: There are multiple perforators in the finger and thumb dorsum region from the proper digital artery, which are suitable for pedicled free-style perforator flaps. These perforators increase flap flexibility and reliability in clinical applications. PMID- 29483056 TI - Response to "Letter to the editor: Predictors of internal mammary vessel diameter: A computed tomographic angiography-assisted anatomic analysis", Madada Nyakauru, et al. PMID- 29483057 TI - An autochthonous confirmed case of Rickettsia parkeri rickettsiosis in Uruguay. AB - Rickettsia parkeri, a member of the spotted fever group (SFG) rickettsiae, was first confirmed as an etiological agent of human rickettsiosis in 2004. Nearly all cases are characterized by an inoculation eschar, and no fatalities have been reported. In Uruguay, probable human cases of R. parkeri infection (confused initially with R. conorii infection) have been described since 1990 using the clinical name "cutaneous-ganglionar" rickettsiosis. This is the only tick-borne rickettsiosis reported in the country. A single case of R. parkeri rickettsiosis has been confirmed by molecular and serological testing in a Spanish traveler returning from Uruguay. We report the first autochthonous human R. parkeri infection, confirmed by molecular testing in Uruguay. PMID- 29483058 TI - Occurrence of tick-borne haemoparasites in cattle in the Mungwi District, Northern Province, Zambia. AB - Little is known about the occurrence of haemoparasites in cattle in communal grazing areas of Mungwi District of Northern Province, Zambia. Clinical signs and post mortem lesions are pathognomonic of mixed tick-borne infections especially babesiosis, anaplasmosis and East Coast fever. The main objective of this study was to screen selected communal herds of cattle for tick-borne haemoparasites, and identify the tick vectors associated with the high cattle mortalities due to suspected tick-borne diseases in the local breeds of cattle grazing along the banks of the Chambeshi River in Mungwi District, Northern Province, Zambia. A total of 299 cattle blood samples were collected from July to September 2010 from Kapamba (n = 50), Chifulo (n = 102), Chisanga (n = 38), Kowa (n = 95) and Mungwi central (n = 14) in the Mungwi District. A total of 5288 ticks were also collected from the sampled cattle from April to July 2011. DNA was extracted from the cattle blood and the hypervariable region of the parasite small subunit rRNA gene was amplified and subjected to the reverse line blot (RLB) hybridization assay. The results of the RLB assay revealed the presence of tick-borne haemoparasites in 259 (86.6%) cattle blood samples occurring either as single (11.0%) or mixed (75.6%) infections. The most prevalent species present were the benign Theileria mutans (54.5%) and T. velifera (51.5%). Anaplasma marginale (25.7%), Babesia bovis (7.7%) and B. bigemina (3.3%) DNA were also detected in the samples. Only one sample (from Kapamba) tested positive for the presence of T. parva. This was an unexpected finding; also because the tick vector, Rhipicephalus appendiculatus, was identified on animals from Kowa (14.0%), Chisanga (8.5%), Chifulo (6.0%) and Kapamba (1.4%). One sample (from Kapamba) tested positive for the presence of Ehrlichia ruminantium even though Amblyomma variegatum ticks were identified from 52.9% of the sampled animals from all study areas. There was significant positive association between T. mutans and T. velifera (p < 0.001) infections, and between A. marginale and B. bovis (p = 0.005). The presence of R. microplus tick vectors on cattle was significantly associated with B. bovis (odds ratio, OR = 28.4, p < 0.001) and A. marginale (OR = 42.0, p < 0.001) infections, while A. variegatum presence was significantly associated with T. mutans (OR = 213.0, p < 0.001) and T. velifera (OR = 459.0, p < 0.001) infections. Rhipicephalus decoloratus was significantly associated with B. bigemina (OR = 21.6, p = 0.004) and A. marginale (OR = 28.5, p < 0.001). Multivariable analysis showed a significant association between location and tick borne pathogen status for A. marginale (p < 0.001), T. mutans (p = 0.004), T. velifera (p = 0.003) and T. taurotragi (p = 0.005). The results of our study suggest that the cause of cattle mortalities in Mungwi during the winter outbreaks is mainly due to A. marginale, B. bovis and B. bigemina infections. This was confirmed by the clinical manifestation of the disease in the affected cattle and the tick species identified on the animals. The relatively low prevalence of T. parva, B. bigemina, B. bovis and E. ruminantium could indicate the existence of endemic instability with a pool of susceptible cattle and the occurrence of disease outbreaks. PMID- 29483059 TI - SGLT2 inhibitors and GLP-1 receptor agonists: a sound combination. PMID- 29483060 TI - Dulaglutide as add-on therapy to SGLT2 inhibitors in patients with inadequately controlled type 2 diabetes (AWARD-10): a 24-week, randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors improve glycaemic control and reduce bodyweight in patients with type 2 diabetes through different mechanisms. We assessed the safety and efficacy of the addition of the once-weekly GLP-1 receptor agonist dulaglutide to the ongoing treatment regimen in patients whose diabetes is inadequately controlled with SGLT2 inhibitors, with or without metformin. METHODS: AWARD-10 was a phase 3b, double-blind, parallel-arm, placebo controlled, 24-week study done at 40 clinical sites in Austria, Czech Republic, Germany, Hungary, Israel, Mexico, Spain, and the USA. Eligible adult patients (>=18 years) with inadequately controlled type 2 diabetes (HbA1c concentration >=7.0% [53 mmol/mol] and <=9.5% [80 mmol/mol]), a BMI of 45 kg/m2 or less, and taking stable doses (>3 months) of an SGLT2 inhibitor (with or without metformin) were randomly assigned (1:1:1) via an interactive web-response system to subcutaneous injections of either dulaglutide 1.5 mg, dulaglutide 0.75 mg, or placebo once per week for 24 weeks. Patients and investigators were masked to dulaglutide and placebo assignment, and those assessing outcomes were masked to study drug assignment. The primary objective was to test for the superiority of dulaglutide (1.5 mg or 0.75 mg) versus placebo for change in HbA1c concentration from baseline at 24 weeks. All analyses were done in the intention-to-treat population, defined as all randomly assigned patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02597049. FINDINGS: Between Dec 7, 2015, and Feb 3, 2017, 424 patients were randomly assigned to dulaglutide 1.5 mg (n=142), dulaglutide 0.75 mg (n=142), and placebo (n=140). One patient in the dulaglutide 0.75 mg group was excluded from the analysis because they did not receive any dose of the study drug. The reduction in HbA1c concentration at 24 weeks was larger in patients receiving dulaglutide (least squares mean [LSM] for dulaglutide 1.5 mg -1.34% [SE 0.06] or 14.7 mmol/mol [0.6]; dulaglutide 0.75 mg -1.21% [0.06] or -13.2 mmol/mol [0.6]) than in patients receiving placebo (-0.54% [0.06] or -5.9 mmol/mol [0.6]; p<0.0001 for both groups vs placebo). The LSM differences were -0.79% (95% CI 0.97 to -0.61) or -8.6 mmol/mol (-10.6 to -6.7) for dulaglutide 1.5 mg and -0.66% (-0.84 to -0.49) or -7.2 mmol/mol (-9.2 to -5.4) for dulaglutide 0.75 mg (p<0.0001 for both). Serious adverse events were reported for five (4%) patients in the dulaglutide 1.5 mg group, three (2%) patients in the dulaglutide 0.75 mg group, and five (4%) patients in the placebo group. Treatment-emergent adverse events were more common in patients treated with dulaglutide than in patients who received placebo, mainly because of an increased incidence of gastrointestinal adverse events. Nausea (21 [15%] patients in the dulaglutide 1.5 mg group vs seven [5%] in the dulaglutide 0.75 mg group vs five [4%] in the placebo group), diarrhoea (eight [6%] vs 14 [10%] vs four [3%]), and vomiting (five [4%] vs four [3%] vs one [1%]) were more common with dulaglutide than with placebo. One episode of severe hypoglycaemia was reported in the dulaglutide 0.75 mg group. Two (1%) patients receiving dulaglutide 1.5 mg died, but these deaths were not considered to be related to study drug; no deaths occurred in the other groups. INTERPRETATION: Dulaglutide as add-on treatment to SGLT2 inhibitors (with or without metformin) resulted in significant and clinically relevant improvements in glycaemic control, with acceptable tolerability that is consistent with the established safety profile of dulaglutide. FUNDING: Eli Lilly and Company. PMID- 29483061 TI - DDT and Obesity in Humans: Exploring the Evidence in a New Way. PMID- 29483062 TI - Another Potential Risk Factor for ALS: Exposure to Traffic-Related Air Pollutants. PMID- 29483064 TI - Help-Seeking on Facebook Versus More Traditional Sources of Help: Cross-Sectional Survey of Military Veterans. AB - BACKGROUND: The media has devoted significant attention to anecdotes of individuals who post messages on Facebook prior to suicide. However, it is unclear to what extent social media is perceived as a source of help or how it compares to other sources of potential support for mental health problems. OBJECTIVE: This study aimed to evaluate the degree to which military veterans with depression use social media for help-seeking in comparison to other more traditional sources of help. METHODS: Cross-sectional self-report survey of 270 adult military veterans with probable major depression. Help-seeking intentions were measured with a modified General Help-Seeking Questionnaire. Facebook users and nonusers were compared via t tests, Chi-square, and mixed effects regression models. Associations between types of help-seeking were examined using mixed effects models. RESULTS: The majority of participants were users of social media, primarily Facebook (n=162). Mean overall help-seeking intentions were similar between Facebook users and nonusers, even after adjustment for potential confounders. Facebook users were very unlikely to turn to Facebook as a venue for support when experiencing either emotional problems or suicidal thoughts. Compared to help-seeking intentions for Facebook, help-seeking intentions for formal (eg, psychologists), informal (eg, friends), or phone helpline sources of support were significantly higher. Results did not substantially change when examining users of other social media, women, or younger adults. CONCLUSIONS: In its current form, the social media platform Facebook is not seen as a venue to seek help for emotional problems or suicidality among veterans with major depression in the United States. PMID- 29483063 TI - Understanding the Impact of Childhood Sexual Abuse on Men's Risk Behavior: Protocol for a Mixed-Methods Study. AB - BACKGROUND: Childhood sexual abuse (CSA) remains a critical public health issue among black and Latino men who have sex with men (MSM), as it is associated with multiple negative outcomes including substance misuse, poor mental health, revictimization, and high-risk sexual behavior. Most CSA research with MSM relies on quantitative assessment that often precludes consideration of cultural variations in how formative sexual experiences are understood and is based on inconsistent or overly restrictive definitions of abuse, and therefore may fail to detect certain abusive experiences (eg, those involving female perpetrators), which can have harmful health consequences if they remain unrecognized. OBJECTIVE: The objective of this study is to overcome existing limitations in the literature by drawing on perspectives of black and Latino MSM and men who have sex with men and women (MSMW), as well as relevant service providers to better understand the role of, and the need to include, sexual abuse histories (eg, CSA) in treatment and counseling settings, with the long-term goal of improving assessment and health outcomes. METHODS: We will conduct mixed-methods interviews, framed by an intersectionality approach, with 80 black and Latino men (40 MSM and 40 MSMW) in New York City (NYC), exploring appraisals of their formative sexual experiences, including those described as consensual but meeting criteria for CSA. We will also interview 30 local service providers representing substance abuse treatment, mental health care, and HIV prevention and outreach. RESULTS: The study was launched in May 2017. CONCLUSIONS: This formative research will inform testable approaches to assessing and incorporating sexual abuse history into substance abuse treatment and other health and mental health services used by men with such histories. PMID- 29483065 TI - A Web-Based, Social Networking Beginners' Running Intervention for Adults Aged 18 to 50 Years Delivered via a Facebook Group: Randomized Controlled Trial. AB - BACKGROUND: Online social networks continue to grow in popularity, with 1.7 billion users worldwide accessing Facebook each month. The use of social networking sites such as Facebook for the delivery of health behavior programs is relatively new. OBJECTIVE: The primary aim of this study was to determine the effectiveness of a Web-based beginners' running program for adults aged 18 to 50 years, delivered via a Facebook group, in increasing physical activity (PA) and cardiorespiratory fitness. METHODS: A total of 89 adults with a mean age of 35.2 years (SD 10.9) were recruited online and via print media. Participants were randomly allocated to receive the UniSA Run Free program, an 8-week Web-based beginners' running intervention, delivered via a closed Facebook group (n=41) that included daily interactive posts (information with links, motivational quotes, opinion polls, or questions) and details of the running sessions; or to the control group who received a hard copy of the running program (n=48). Assessments were completed online at baseline, 2 months, and 5 months. The primary outcome measures were self-reported weekly moderate to vigorous physical activity (MVPA) and objectively measured cardiorespiratory fitness. Secondary outcomes were social support, exercise attitudes, and self-efficacy. Analyses were undertaken using random effects mixed modeling. Compliance with the running program and engagement with the Facebook group were analyzed descriptively. RESULTS: Both groups significantly increased MVPA across the study period (P=.004); however, this was significantly higher in the Facebook group (P=.04). The Facebook group increased their MVPA from baseline by 140 min/week versus 91 min for the control at 2 months. MVPA remained elevated for the Facebook group (from baseline) by 129 min/week versus a 50 min/week decrease for the control at 5 months. Both groups had significant increases in social support scores at 2 months (P=.02); however, there were no group by time differences (P=.16). There were no significant changes in the other outcomes. A process evaluation revealed relatively high levels of engagement with the Facebook group during the 8-week intervention (eg, mean number of interactions 35 [SD 41]). CONCLUSIONS: An 8-week beginners' running program delivered through Facebook produced sizable and sustained changes in weekly MVPA and received strong engagement and positive feedback from participants. Future research investigating this intervention approach is warranted in other populations and health behaviors. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12616001500448; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=371607&isReview= rue (Archived by WebCite at http://www.webcitation.org/6xSAuz4NW). PMID- 29483067 TI - Supporting Our Valued Adolescents (SOVA), a Social Media Website for Adolescents with Depression and/or Anxiety: Technological Feasibility, Usability, and Acceptability Study. AB - BACKGROUND: Supporting Our Valued Adolescents (SOVA), a social media website for adolescents, was designed to increase mental health literacy and address negative health beliefs toward depression and/or anxiety diagnosis and treatment. This stakeholder-informed site underwent iterative user testing to evolve into its current version with daily blog posts, round-the-clock site moderation, and Web based peer interaction to create an online support community. OBJECTIVE: The aim of this study was to evaluate the technological feasibility (at least 100 users on the site, logging in 12 to 18 times in the first 6 weeks) and acceptability of the SOVA site determined by the System Usability Scale (SUS). METHODS: Adolescents and young adults (aged 14-26 years) with a self-reported history of depressive and/or anxiety symptoms were recruited to access the research website (sova.pitt.edu). Participants were screened out if they reported active suicidality or a prior suicide attempt. Baseline survey measures included demographics, symptomatology using the Patient Health Questionnaire-9 modified for adolescents (PHQ-9A) and Screen for Child Anxiety Related Disorders (SCARED C), and mental health treatment history. The 6-week follow-up measures taken in addition to the symptomatology, included feasibility (total number of log-ins), usability, and acceptability of SOVA using SUS. RESULTS: Most of the 96 participants identified as female (75% [72/96]) and white (67% [64/96]). Most participants (73% [70/96]) reported having taken prior professional psychological help. The average PHQ-9A score was 11.8 (SD 5.5), and for SCARED-C, 85% (80/94) of the participants reported a score consistent with being susceptible to a diagnosed anxiety disorder. There were 46% (41/90) of eligible users who ever logged in. Out of the total users who ever logged in, the mean of total log-ins over the entire study was 4.1 (SD 6.9). Median number of users rated the user friendliness of the site as "good." The average SUS score was 71.2% (SD 18.7), or a "C-grade," which correlated to an acceptable range. The participants reported to have liked the "easy-to-understand format" and "positive, helpful atmosphere," but they also reported a desire for greater social interaction. Iterative recruitment resulted in incremental improvements to the site. CONCLUSIONS: The SOVA site met feasibility goals of recruiting almost 100 users and establishing acceptable usability. Subsequent interventions are planned to increase site engagement and to evaluate efficacy in increasing uptake of primary care recommended depression and/or anxiety treatment. PMID- 29483066 TI - Self-Management and Self-Efficacy in Patients With Acute Spinal Cord Injuries: Protocol for a Longitudinal Cohort Study. AB - BACKGROUND: People with recently acquired spinal cord injury (SCI) experience changes in physical, social and psychological aspects of their lives. In the last decades, attention has grown for aspects of self-management and self-efficacy in SCI research. However, we still do not know what the self-management and self efficacy outcomes of first rehabilitation are and whether utilizing these skills may prevent secondary health conditions (SHCs) and increase participation and psychological adjustment early after SCI. OBJECTIVE: To describe the course and determinants of self-management and self-efficacy during and after first SCI rehabilitation; and to determine theory-based associations between self management and self-efficacy with SHCs, participation and psychological adjustment. METHODS: Multicenter prospective longitudinal cohort study. All people with a newly acquired SCI admitted to one of the 8 specialized SCI rehabilitation centers in the Netherlands will be considered for inclusion in this study. Main assessments will take place during the first and last week of admission and 3, 6 and 12 months after discharge. The target sample is 250 participants. The primary outcomes are self-management (knowledge and execution of self-care) and self-efficacy (confidence in the ability to manage the consequences of SCI and of self-care). Secondary outcome measures are SHCs, participation and psychological adjustment to SCI. RESULTS: The first results with the complete set of data are expected in June 2019. CONCLUSIONS: This protocol describes the SELF-SCI cohort study investigating self-management and self-efficacy of initial inpatient SCI rehabilitation. Second, associations will be investigated with SHCs, participation and psychological adjustment early after onset of SCI, until 1 year after discharge. The results will be used to test theories about motivation to perform health-promoting behaviors and adjustment to SCI. PMID- 29483068 TI - Input of Psychosocial Information During Multidisciplinary Team Meetings at Medical Oncology Departments: Protocol for an Observational Study. AB - BACKGROUND: Multidisciplinary team meetings (MDTMs) have become standard practice in oncology and gained the status of the key decision-making forum for cancer patient management. The current literature provides evidence that MDTMs are achieving their intended objectives but there are also indications to question the positive impact of MDTMs in oncology settings. For cancer management to be patient-centered, it is crucial that medical information as well as psychosocial aspects-such as the patients' living situation, possible family problems, patients' mental state, and patients' perceptions and values or preferences towards treatment or care-are considered and discussed during MDTMs. Previous studies demonstrate that failure to account for patients' psychosocial information has a negative impact on the implementation of the treatment recommendations formulated during MDTMs. Few empirical studies have demonstrated the predominant role of physicians during MDTMs, leading to the phenomenon that medical information is shared almost exclusively at the expense of psychosocial information. However, more in-depth insight on the underlying reasons why MDTMs fail to take into account psychosocial information of cancer patients is needed. OBJECTIVE: This paper presents a research protocol for a cross-sectional observational study that will focus on exploring the barriers to considering psychosocial information during MDTMs at medical oncology departments. METHODS: This protocol encompasses a cross-sectional comparative case study of MDTMs at medical oncology departments in Flanders, Belgium. MDTMs from various oncology subspecialties at inpatient medical oncology departments in multiple hospitals (academic as well as general hospitals) are compared. The observations focus on the "multidisciplinary oncology consultation" (MOC), a formally regulated and financed type of MDTM in Belgian oncology since 2003. Data are collected through nonparticipant observations of MOC-meetings. Observational data are supplemented with semi-structured individual interviews with members of the MOC-meetings. RESULTS: The protocol is part of a larger research project on communication and multidisciplinary collaboration in oncology departments. Results of this study will particularly focus on the input of psychosocial information during MDTMs. CONCLUSIONS: The concept of an MDTM should not merely be a group of care professionals who mostly work independently and occasionally liaise with one another. Interventions aiming to enhance the input of psychosocial information are crucial to ensure that MDTMs can benefit from their diverse membership to achieve their full potential. The findings from this study can be used to design nonclinical and organizational interventions that enhance multidisciplinary decision-making in oncology. PMID- 29483069 TI - Open Availability of Patient Medical Photographs in Google Images Search Results: Cross-Sectional Study of Transgender Research. AB - BACKGROUND: This paper focuses on the collision of three factors: a growing emphasis on sharing research through open access publication, an increasing awareness of big data and its potential uses, and an engaged public interested in the privacy and confidentiality of their personal health information. One conceptual space where this collision is brought into sharp relief is with the open availability of patient medical photographs from peer-reviewed journal articles in the search results of online image databases such as Google Images. OBJECTIVE: The aim of this study was to assess the availability of patient medical photographs from published journal articles in Google Images search results and the factors impacting this availability. METHODS: We conducted a cross-sectional study using data from an evidence map of research with transgender, gender non-binary, and other gender diverse (trans) participants. For the original evidence map, a comprehensive search of 15 academic databases was developed in collaboration with a health sciences librarian. Initial search results produced 25,230 references after duplicates were removed. Eligibility criteria were established to include empirical research of any design that included trans participants or their personal information and that was published in English in peer-reviewed journals. We identified all articles published between 2008 and 2015 with medical photographs of trans participants. For each reference, images were individually numbered in order to track the total number of medical photographs. We used odds ratios (OR) to assess the association between availability of the clinical photograph on Google Images and the following factors: whether the article was openly available online (open access, Researchgate.net, or Academia.edu), whether the article included genital images, if the photographs were published in color, and whether the photographs were located on the journal article landing page. RESULTS: We identified 94 articles with medical photographs of trans participants, including a total of 605 photographs. Of the 94 publications, 35 (37%) included at least one medical photograph that was found on Google Images. The ability to locate the article freely online contributes to the availability of at least one image from the article on Google Images (OR 2.99, 95% CI 1.20-7.45). CONCLUSIONS: This is the first study to document the existence of medical photographs from peer-reviewed journals appearing in Google Images search results. Almost all of the images we searched for included sensitive photographs of patient genitals, chests, or breasts. Given that it is unlikely that patients consented to sharing their personal health information in these ways, this constitutes a risk to patient privacy. Based on the impact of current practices, revisions to informed consent policies and guidelines are required. PMID- 29483072 TI - Margaret McCartney: Clinical errors need a systemic response. PMID- 29483071 TI - Evaluating the Effect of a Web-Based E-Learning Tool for Health Professional Education on Clinical Vancomycin Use: Comparative Study. AB - BACKGROUND: Internet-based learning for health professional education is increasing. It offers advantages over traditional learning approaches, as it enables learning to be completed at a time convenient to the user and improves access where facilities are geographically disparate. We developed and implemented the Vancomycin Interactive (VI) e-learning tool to improve knowledge on the clinical use of the antibiotic vancomycin, which is commonly used for treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA). OBJECTIVE: The aims of this study were to evaluate the effect of the VI e learning tool on (1) survey knowledge scores and (2) clinical use of vancomycin among health professionals. METHODS: We conducted a comparative pre-post intervention study across the 14 hospitals of two health districts in New South Wales, Australia. A knowledge survey was completed by nurses, doctors, and pharmacists before and after release of a Web-based e-learning tool. Survey scores were compared with those obtained following traditional education in the form of an email intervention. Survey questions related to dosing, administration, and monitoring of vancomycin. Outcome measures were survey knowledge scores among the three health professional groups, vancomycin plasma trough levels, and vancomycin approvals recorded on a computerized clinical decision support system. RESULTS: Survey response rates were low at 26.87% (577/2147) preintervention and 8.24% (177/2147) postintervention. The VI was associated with an increase in knowledge scores (maximum score=5) among nurses (median 2, IQR 1-2 to median 2, IQR 1-3; P<.001), but not among other professional groups. The comparator email intervention was associated with an increase in knowledge scores among doctors (median 3, IQR 2-4 to median 4, IQR 2 4; P=.04). Participants who referred to Web-based resources while completing the e-learning tool achieved higher overall scores than those who did not (P<.001). The e-learning tool was not shown to be significantly more effective than the comparator email in the clinical use of vancomycin, as measured by plasma levels within the therapeutic range. CONCLUSIONS: The e-learning tool was associated with improved knowledge scores among nurses, whereas the comparator email was associated with improved scores among doctors. This implies that different strategies may be required for optimizing the effectiveness of education among different health professional groups. Low survey response rates limited conclusions regarding the tool's effectiveness. Improvements to design and evaluation methodology may increase the likelihood of a demonstrable effect from e-learning tools in the future. PMID- 29483070 TI - Enhancing Survivorship Care Planning for Patients With Localized Prostate Cancer Using a Couple-Focused mHealth Symptom Self-Management Program: Protocol for a Feasibility Study. AB - BACKGROUND: This project explores a new model of care that enhances survivorship care planning and promotes health for men with localized prostate cancer transitioning to posttreatment self-management. Survivorship care planning is important for patients with prostate cancer because of its high incidence rate in the United States, the frequent occurrence of treatment-related side effects, and reduced quality of life (QOL) for both men and their partners. A key component of comprehensive survivorship care planning is survivorship care plans (SCPs), documents that summarize cancer diagnosis, treatment, and plans for follow-up care. However, research concerning the effectiveness of SCPs on patient outcomes or health service use has thus far been inconclusive. SCPs that are tailored to individual patients' needs for information and care may improve effectiveness. OBJECTIVE: This study aims to examine the feasibility of an enhanced survivorship care plan (ESCP) that integrates a symptom self-management mHealth program called Prostate Cancer Education and Resources for Couples (PERC) into the existing standardized SCP. The specific aims are to (1) examine the feasibility of delivering ESCPs and (2) to estimate the magnitude of benefit of ESCPs. METHODS: We will use a two-group randomized controlled pretest-posttest design and collect data at baseline (T1) and 4 months later (T2) among 50 patients completing initial treatment for localized prostate cancer and their partners. First, we will assess the feasibility of ESCP by recruitment, enrollment, and retention rates; program satisfaction with the ESCP; and perceived ease of use of the ESCP. To achieve the secondary aim, we will compare the ESCP users with the standardized SCP users and assess their primary outcomes of QOL (overall, physical, emotional, and social QOL); secondary outcomes (reduction in negative appraisals and improvement in self-efficacy, social support, and health behaviors to manage symptoms); and number of visits to posttreatment care services between T1 and T2. We will assess the primary and secondary outcomes using measurements with sound psychometrical properties. We will use a qualitative and quantitative mixed methods approach to achieve the research aims. RESULTS: This project is ongoing and will be completed by the end of 2018. CONCLUSIONS: The results from this study will help design a definitive randomized trial to test the efficacy of the ESCPs, a potentially scalable program, to enhance supportive care for prostate cancer patients and their families. PMID- 29483074 TI - Trainee GP who falsified timesheet is suspended for four months after GMC intervened. PMID- 29483073 TI - The Combined Association of Modifiable Risk Factors with Breast Cancer Risk in the Women's Health Initiative. AB - Although several modifiable risk factors have been independently associated with risk of breast cancer, few studies have investigated their joint association with breast cancer risk. Using a healthy lifestyle index (HLI) score, we assessed the association of a combination of selected modifiable risk factors (diet, alcohol, physical activity, BMI, and smoking) with risk of invasive breast cancer in the Women's Health Initiative (WHI). This study comprised 131,833 postmenopausal women, of whom 8,168 had breast cancer, who were enrolled in the WHI Observational Study or the WHI clinical trials. Cox proportional hazards regression was used to estimate the HRs and 95% confidence intervals (CI) for the association of the score with the risk of developing breast cancer overall and according to specific breast cancer clinicopathologic characteristics. There was a 4% reduction in the risk of breast cancer per unit increase in the HLI score. Compared with those with an HLI score in the lowest quintile level, those in the highest quintile level had 30%, 37%, and 30% lower risk for overall, ER+/PR+, and HER2+ breast cancer, respectively (HR = 0.70; 95% CI, 0.64-0.76; 0.63, 0.57-0.69; and 0.70; 0.55-0.90, respectively). We also observed inverse associations between the score and risk of breast cancer irrespective of nodal status, tumor grade, and stage of the disease. Most individual lifestyle factors were independently associated with the risk of breast cancer. Our findings support the view that promoting healthy lifestyle practices may be beneficial with respect to lowering risk of breast cancer among postmenopausal women. Cancer Prev Res; 11(6); 317-26. (c)2018 AACRSee related editorial by Friedenreich and McTiernan, p. 313. PMID- 29483075 TI - pH controls spermatozoa motility in the Pacific oyster (Crassostrea gigas). AB - Investigating the roles of chemical factors stimulating and inhibiting sperm motility is required to understand the mechanisms of spermatozoa movement. In this study, we described the composition of the seminal fluid (osmotic pressure, pH, and ions) and investigated the roles of these factors and salinity in initiating spermatozoa movement in the Pacific oyster, Crassostrea gigas The acidic pH of the gonad (5.82+/-0.22) maintained sperm in the quiescent stage and initiation of flagellar movement was triggered by a sudden increase of spermatozoa external pH (pHe) when released in seawater (SW). At pH 6.4, percentage of motile spermatozoa was three times higher when they were activated in SW containing 30 mM NH4Cl, which alkalinizes internal pH (pHi) of spermatozoa, compared to NH4Cl-free SW, revealing the role of pHi in triggering sperm movement. Percentage of motile spermatozoa activated in Na+-free artificial seawater (ASW) was highly reduced compared to ASW, suggesting that change of pHi triggering sperm motility was mediated by a Na+/H+ exchanger. Motility and swimming speed were highest in salinities between 33.8 and 42.70/00 (within a range of 0 to 50 0/00), and pH values above 7.5 (within a range of 4.5 to 9.5). PMID- 29483076 TI - Factors influencing recording of drug misuse in primary care: a qualitative study of GPs in England. AB - BACKGROUND: Drug misuse is a serious public health problem. Evidence from previous epidemiological studies show that GPs are recording drug misuse in electronic patient records (EPR). However, although the recording trends are similar to national surveys, recording rates are much lower. AIM: To explore the factors that influence GPs to record drug misuse in the EPR, and to gain a clearer understanding of the gap between the amount of drug misuse recorded in primary care and that in national surveys and other studies. DESIGN AND SETTING: A semi-structured qualitative interview study of GPs working in general practices across England. METHOD: Purposive sampling was employed to recruit 12 GPs, both with and without a special interest in drug misuse, from across England. Semi structured face-to-face interviews were conducted to consider whether and why GPs record drug misuse, which methods GPs use for recording, GPs' actions if a patient asks for the information not to be recorded, and GPs' actions if they think a patient misuses drugs but does not disclose the information. Resulting data were analysed using a combination of inductive and deductive thematic analysis. RESULTS: The complexity of asking about drug misuse preceded GPs' decision to record. They described how the context of the general practice protocols, interaction between GP and patient, and the questioning process affected whether, how, and in which circumstances they asked about drug use. This led to GPs making a clinical decision on whether, who, and how to record in the EPR. CONCLUSION: When making decisions about whether or not to record drug misuse, GPs face complex choices. Aside from their own views, they reported feelings of pressure from the general practice environment in which they worked and their clinical commissioning group, as well as government policies. PMID- 29483077 TI - Reducing risk of type 2 diabetes after gestational diabetes: a qualitative study to explore the potential of technology in primary care. AB - BACKGROUND: Despite the seven-fold increased risk of type 2 diabetes mellitus (T2DM) among females previously diagnosed with gestational diabetes (GD), annual rates of follow-up in primary care are low. There is a need to consider how to reduce the incidence of progression to T2DM among this high-risk group. AIM: To examine the views of females diagnosed with GD to ascertain how to improve primary care support postnatally, and the potential role of technology in reducing the risk of progression to T2DM. DESIGN AND SETTING: A qualitative study of a purposive sample of 27 postnatal females leaving secondary care with a recent diagnosis of GD. METHOD: Semi-structured interviews were conducted with 27 females, who had been previously diagnosed with GD, at around 6-12 weeks postnatally. Interviews were audiotaped, transcribed, and analysed thematically. RESULTS: Facilitators and barriers to engaging in a healthy postnatal lifestyle were identified, the most dominant being competing demands on time. Although females were generally satisfied with the secondary care they received antenatally, they felt abandoned postnatally and were uncertain what to expect from their GP in terms of follow-up and support. Females felt postnatal care could be improved by greater clarity regarding this, and enhanced by peer support, multidisciplinary input, and subsidised facilities. Technology was seen as a potential adjunct by providing information, enabling flexible and personalised self-management, and facilitating social support. CONCLUSION: A more tailored approach for females previously diagnosed with GD may help reduce the risk of progression to T2DM. A need for future research to test the efficacy of using technology as an adjunct to current care was identified. PMID- 29483079 TI - Urgent reversal of vitamin K antagonists. PMID- 29483078 TI - Point-of-care urine culture for managing urinary tract infection in primary care: a randomised controlled trial of clinical and cost-effectiveness. AB - BACKGROUND: The effectiveness of using point-of-care (POC) urine culture in primary care on appropriate antibiotic use is unknown. AIM: To assess whether use of the FlexicultTM SSI-Urinary Kit, which quantifies bacterial growth and determines antibiotic susceptibility at the point of care, achieves antibiotic use that is more often concordant with laboratory culture results, when compared with standard care. DESIGN AND SETTING: Individually randomised trial of females with uncomplicated urinary tract infection (UTI) in primary care research networks (PCRNs) in England, the Netherlands, Spain, and Wales. METHOD: Multilevel regression compared outcomes between the two groups while controlling for clustering. RESULTS: In total, 329 participants were randomised to POC testing (POCT) and 325 to standard care, and 324 and 319 analysed. Fewer females randomised to the POCT arm than those who received standard care were prescribed antibiotics at the initial consultation (267/324 [82.4%] versus 282/319 [88.4%], odds ratio [OR] 0.56, 95% confidence interval [CI] = 0.35 to 0.88). Clinicians indicated the POCT result changed their management for 190/301 (63.1%). Despite this, there was no statistically significant difference between study arms in antibiotic use that was concordant with laboratory culture results (primary outcome) at day 3 (39.3% POCT versus 44.1% standard care, OR 0.84, 95% CI = 0.58 to 1.20), and there was no evidence of any differences in recovery, patient enablement, UTI recurrences, re-consultation, antibiotic resistance, and hospitalisations at follow-up. POCT culture was not cost-effective. CONCLUSION: Point-of-care urine culture was not effective when used mainly to adjust immediate antibiotic prescriptions. Further research should evaluate use of the test to guide initiation of 'delayed antibiotics'. PMID- 29483080 TI - Efficacy and safety of monotherapy with sirukumab compared with adalimumab monotherapy in biologic-naive patients with active rheumatoid arthritis (SIRROUND H): a randomised, double-blind, parallel-group, multinational, 52-week, phase 3 study. AB - OBJECTIVE: This randomised, double-blind, parallel-group, phase 3 study compared monotherapy with sirukumab, an anti-interleukin-6 cytokine monoclonal antibody, with adalimumab monotherapy in patients with rheumatoid arthritis (RA). METHODS: Biologic-naive patients with active RA who were inadequate responders or were intolerant to, or inappropriate for, methotrexate were randomised to subcutaneous sirukumab 100 mg every 2 weeks (n=187), sirukumab 50 mg every 4 weeks (n=186) or adalimumab 40 mg every 2 weeks (n=186). Primary endpoints at week 24 were change from baseline in Disease Activity Score in 28 joints (DAS28) using erythrocyte sedimentation rate (ESR) and proportion of patients achieving an American College of Rheumatology (ACR) 50 response; these endpoints were tested in sequential order. This study is registered at EudraCT (number: 2013-001417-32) and ClinicalTrials.gov (number: NCT02019472). RESULTS: Significantly greater improvements from baseline in mean (SD) DAS28 (ESR) were observed at week 24 with sirukumab 100 mg every 2 weeks (-2.96 (1.580)) versus adalimumab 40 mg every 2 weeks (-2.19 (1.437); P<0.001). Sirukumab 50 mg every 4 weeks also showed significantly greater improvement from baseline at week 24 in DAS28 (ESR) (-2.58 (1.524)) compared with adalimumab (P=0.013). The ACR50 response rates with the 100 mg (35.3%) and 50 mg (26.9%) doses of sirukumab were comparable to that with adalimumab (31.7%) at week 24. The safety profile of sirukumab was consistent with that observed with anti-interleukin-6 receptor antibodies. A dose-related effect on the incidence of injection-site reactions was observed with sirukumab. CONCLUSION: Sirukumab monotherapy showed greater improvements in DAS28 (ESR), but similar ACR50 response rates, versus adalimumab monotherapy. PMID- 29483081 TI - Progressive idiopathic unilateral corneal endothelial failure of unknown aetiology in phakic eyes. AB - AIM: To describe a cohort of patients with irreversible unilateral bullous keratopathy (BK) of undetermined aetiology. METHOD: Retrospective, single-centre case series in a tertiary corneal referral centre. RESULTS: Eleven consecutive patients (nine females; mean age 71.7 years) presented from 1999 to 2009 with acute onset unilateral visual loss. At presentation, the best-corrected visual acuity of the affected eyes was 6/9 or worse with mean central corneal thickness (CCT) of 684 (SD 66) MUm. Specular microscopy was not possible in the affected eyes. There was no other ocular pathology in the affected eye. The fellow eye remained normal throughout the study (mean endothelial cell density (ECD) of 1980 (SD 736) cells/mm2 and CCT of 536 (SD 34) MUm). Topical steroid, antiviral treatments (both topical and systemic) or a combination of both did not yield any improvement. After a mean follow-up of 82.2 months, eight eyes had penetrating keratoplasty (PK). One required two regrafts. Histology showed typical BK features, with endothelial cell (EC) loss and thickened Descemet's membrane (DM). Transmission electron microscopy revealed DM abnormalities in a non-consistent pattern, featuring variable collagen deposition posterior to the non-banded zone. The ECs were degenerated, reduced or absent. Neither viruses nor pseudoexfoliation material was identified. CONCLUSION: While medical treatment is not beneficial, PK appears to offer good results. Non-guttate Fuchs' corneal endothelial dystrophy merits consideration but it would be unusual to see an exclusively unilateral presentation. DM thickening is reflective of a chronic EC loss but the cause of this loss remains elusive. PMID- 29483083 TI - There is no excuse for homelessness in Britain in 2018. PMID- 29483084 TI - Out-of-Hospital Cardiac Arrest Resuscitation Systems of Care: A Scientific Statement From the American Heart Association. AB - The American Heart Association previously recommended implementation of cardiac resuscitation systems of care that consist of interconnected community, emergency medical services, and hospital efforts to measure and improve the process of care and outcome for patients with cardiac arrest. In addition, the American Heart Association proposed a national process to develop and implement evidence-based guidelines for cardiac resuscitation systems of care. Significant experience has been gained with implementing these systems, and new evidence has accumulated. This update describes recent advances in the science of cardiac resuscitation systems and evidence of their effectiveness, as well as recent progress in dissemination and implementation throughout the United States. Emphasis is placed on evidence published since the original recommendations (ie, including and since 2010). PMID- 29483082 TI - Inhibition of the IRE-1alpha/XBP-1 pathway prevents chronic GVHD and preserves the GVL effect in mice. AB - Hematopoietic stem cell transplantation (HCT) is a curative procedure for hematological malignancies, but chronic graft-versus-host disease (cGVHD) remains a major complication after allogeneic HCT. Because donor B cells are essential for cGVHD development and B cells are sensitive to endoplasmic reticulum (ER) stress, we hypothesized that the IRE-1alpha/XBP-1 pathway is required for B-cell activation and function and for the development of cGVHD. To test this hypothesis, we used conditional knock-out mice deficient of XBP-1 specifically in B cells. Recipients transplanted with donor grafts containing XBP-1-deficient B cells displayed reduced cGVHD compared with controls. Reduction of cGVHD correlated with impaired B-cell functions, including reduced production of anti double-stranded DNA immunoglobulin G antibodies, CD86, Fas, and GL7 surface expression, and impaired T-cell responses, including reduced interferon-gamma production and follicular helper T cells. In a bronchiolitis obliterans cGVHD model, recipients of transplants containing XBP-1-deficient B cells demonstrated improved pulmonary function correlated with reduced donor splenic follicular helper T cells and increased B cells compared with those of wild-type control donor grafts. We then tested if XBP-1 blockade via an IRE-1alpha inhibitor, B I09, would attenuate cGVHD and preserve the graft-versus-leukemia (GVL) effect. In a cutaneous cGVHD model, we found that prophylactic administration of B-I09 reduced clinical features of cGVHD, which correlated with reductions in donor T cell and dendritic cell skin infiltrates. Inhibition of the IRE-1alpha/XBP-1 pathway also preserved the GVL effect against chronic myelogenous leukemia mediated by allogeneic splenocytes. Collectively, the ER stress response mediated by the IRE-1alpha/XBP-1 axis is required for cGVHD development but dispensable for GVL activity. PMID- 29483085 TI - Low-Calorie Vegetarian Versus Mediterranean Diets for Reducing Body Weight and Improving Cardiovascular Risk Profile: CARDIVEG Study (Cardiovascular Prevention With Vegetarian Diet). AB - BACKGROUND: Only a few randomized dietary intervention studies that investigated the effects of lacto-ovo vegetarian diet (Vd) in clinically healthy omnivorous subjects are available. METHODS: We randomly assigned to overweight omnivores with a low-to-moderate cardiovascular risk profile a low-calorie Vd compared with a low-calorie Mediterranean diet (MD), each lasting 3 months, with a crossover design. The primary outcome was the difference in body weight, body mass index, and fat mass changes between the 2 groups. Secondary outcomes were differences in circulating cardiovascular disease risk parameters changes between the 2 groups. RESULTS: One hundred eighteen subjects (mean age: 51.1 years, females: 78%) were enrolled. The total participation rate at the end of the study was 84.7%. No differences between the 2 diets in body weight were observed, as reported by similar and significant reductions obtained by both Vd (-1.88 kg) and MD (-1.77 kg). Similar results were observed for body mass index and fat mass. In contrast, significant differences between the 2 interventions were obtained for low-density lipoprotein cholesterol, triglycerides, and vitamin B12 levels. The difference between the Vd and MD groups, in terms of end-of-diet values, was recorded at 9.10 mg/dL for low-density lipoprotein cholesterol (P=0.01), 12.70 mg/dL for triglycerides (P<0.01), and 32.32 pg/mL for vitamin B12 (P<0.01). Finally, no significant difference was found between Vd and MD interventions in oxidative stress markers and inflammatory cytokines, except for interleukin-17, which improved only in the MD group. Forty-six participants during the Vd period and 35 during the MD period reached the target values for >=1 cardiovascular risk factor. CONCLUSIONS: Both Vd and MD were effective in reducing body weight, body mass index, and fat mass, with no significant differences between them. However, Vd was more effective in reducing low-density lipoprotein cholesterol levels, whereas MD led to a greater reduction in triglyceride levels. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02641834. PMID- 29483087 TI - Dietary Patterns to Reduce Weight and Optimize Cardiovascular Health: Persuasive Evidence for Promoting Multiple, Healthful Approaches. PMID- 29483089 TI - Ontario outlines how law on doctors' industry ties will work. PMID- 29483086 TI - Impact of Bystander Automated External Defibrillator Use on Survival and Functional Outcomes in Shockable Observed Public Cardiac Arrests. AB - BACKGROUND: Survival following out-of-hospital cardiac arrest (OHCA) with shockable rhythms can be improved with early defibrillation. Although shockable OHCA accounts for only ~25% of overall arrests, ~60% of public OHCAs are shockable, offering the possibility of restoring thousands of individuals to full recovery with early defibrillation by bystanders. We sought to determine the association of bystander automated external defibrillator use with survival and functional outcomes in shockable observed public OHCA. METHODS: From 2011 to 2015, the Resuscitation Outcomes Consortium prospectively collected detailed information on all cardiac arrests at 9 regional centers. The exposures were shock administration by a bystander-applied automated external defibrillator in comparison with initial defibrillation by emergency medical services. The primary outcome measure was discharge with normal or near-normal (favorable) functional status defined as a modified Rankin Score <=2. Survival to hospital discharge was the secondary outcome measure. RESULTS: Among 49 555 OHCAs, 4115 (8.3%) observed public OHCAs were analyzed, of which 2500 (60.8%) were shockable. A bystander shock was applied in 18.8% of the shockable arrests. Patients shocked by a bystander were significantly more likely to survive to discharge (66.5% versus 43.0%) and be discharged with favorable functional outcome (57.1% versus 32.7%) than patients initially shocked by emergency medical services. After adjusting for known predictors of outcome, the odds ratio associated with a bystander shock was 2.62 (95% confidence interval, 2.07-3.31) for survival to hospital discharge and 2.73 (95% confidence interval, 2.17-3.44) for discharge with favorable functional outcome. The benefit of bystander shock increased progressively as emergency medical services response time became longer. CONCLUSIONS: Bystander automated external defibrillator use before emergency medical services arrival in shockable observed public OHCA was associated with better survival and functional outcomes. Continued emphasis on public automated external defibrillator utilization programs may further improve outcomes of OHCA. PMID- 29483090 TI - Highest billing US doctor sentenced to 17 years for Medicare fraud. PMID- 29483091 TI - Removing the blindfold on medicines pricing. PMID- 29483092 TI - Airn Regulates Igf2bp2 Translation in Cardiomyocytes. AB - RATIONALE: Increasing evidence indicates the presence of lncRNAs in various cell types. Airn is an imprinting gene transcribed from the paternal chromosome. It is in antisense orientation to the imprinted, but maternally derived, Igf2r gene, on which Airn exerts its regulation in cis. Although Airn is highly expressed in the heart, functions aside from imprinting remain unknown. OBJECTIVE: Here, we studied the functions of Airn in the heart, especially cardiomyocytes. METHODS AND RESULTS: Silencing of Airn via siRNAs augmented cell death, vulnerability to cellular stress, and reduced cell migration. To find the cause of such phenotypes, the potential binding partners of Airn were identified via RNA pull down followed by mass spectrometry, which indicated Igf2bp2 (insulin-like growth factor 2 mRNA-binding protein 2) and Rpa1 (replication protein A1) as potential binding partners. Further experiments showed that Airn binds to Igf2bp2 to control the translation of several genes. Moreover, silencing of Airn caused less binding of Igf2bp2 to other mRNAs and reduced translation of Igf2bp2 protein. CONCLUSIONS: Our study uncovers a new function of Airn and demonstrates that Airn is important for the physiology of cardiomyocytes. PMID- 29483095 TI - IRAK1 Augments Cancer Stemness and Drug Resistance via the AP-1/AKR1B10 Signaling Cascade in Hepatocellular Carcinoma. AB - Frequent relapse and drug resistance in patients with hepatocellular carcinoma (HCC) can be attributed to the existence of tumor-initiating cells (TIC) within the tumor bulk. Therefore, targeting liver TICs may improve the prognosis of these patients. From transcriptome sequencing of 16 pairs of clinical HCC samples, we report that interleukin-1 receptor-associated kinase 1 (IRAK1) in the TLR/IRAK pathway is significantly upregulated in HCC. IRAK1 overexpression in HCC was further confirmed at the mRNA and protein levels and correlated with advanced tumor stages and poor patient survival. Interestingly, IRAK4, an upstream regulator of IRAK1, was also consistently upregulated. IRAK1 regulated liver TIC properties, including self-renewal, tumorigenicity, and liver TIC marker expression. IRAK1 inhibition sensitized HCC cells to doxorubicin and sorafenib treatment in vitro via suppression of the apoptotic cascade. Pharmacological inhibition of IRAK1 with a specific IRAK1/4 kinase inhibitor consistently suppressed liver TIC populations. We identified aldo-keto reductase family 1 member 10 (AKR1B10) as a novel downstream target of IRAK1, which was found to be overexpressed in HCC and significantly correlated with IRAK1 expression. Knockdown of AKR1B10 negated IRAK1-induced TIC functions via modulation of the AP 1 complex. Inhibition of IRAK1/4 inhibitor in combination with sorafenib synergistically suppressed tumor growth in an HCC xenograft model. In conclusion, targeting the IRAK4/IRAK1/AP-1/AKR1B10 signaling pathway may be a potential therapeutic strategy against HCC.Significance: IRAK4/IRAK1/AP-1/AKR1B10 signaling pathway regulates cancer stemness and drug resistance and may be a novel therapeutic target in HCC. Cancer Res; 78(9); 2332-42. (c)2018 AACR. PMID- 29483093 TI - Desmin Phosphorylation Triggers Preamyloid Oligomers Formation and Myocyte Dysfunction in Acquired Heart Failure. AB - RATIONALE: Disrupted proteostasis is one major pathological trait that heart failure (HF) shares with other organ proteinopathies, such as Alzheimer and Parkinson diseases. Yet, differently from the latter, whether and how cardiac preamyloid oligomers (PAOs) develop in acquired forms of HF is unclear. OBJECTIVE: We previously reported a rise in monophosphorylated, aggregate-prone desmin in canine and human HF. We now tested whether monophosphorylated desmin acts as the seed nucleating PAOs formation and determined whether positron emission tomography is able to detect myocardial PAOs in nongenetic HF. METHODS AND RESULTS: Here, we first show that toxic cardiac PAOs accumulate in the myocardium of mice subjected to transverse aortic constriction and that PAOs comigrate with the cytoskeletal protein desmin in this well-established model of acquired HF. We confirm this evidence in cardiac extracts from human ischemic and nonischemic HF. We also demonstrate that Ser31 phosphorylated desmin aggregates extensively in cultured cardiomyocytes. Lastly, we were able to detect the in vivo accumulation of cardiac PAOs using positron emission tomography for the first time in acquired HF. CONCLUSIONS: Ser31 phosphorylated desmin is a likely candidate seed for the nucleation process leading to cardiac PAOs deposition. Desmin post-translational processing and misfolding constitute a new, attractive avenue for the diagnosis and treatment of the cardiac accumulation of toxic PAOs that can now be measured by positron emission tomography in acquired HF. PMID- 29483094 TI - A Soft Microenvironment Protects from Failure of Midbody Abscission and Multinucleation Downstream of the EMT-Promoting Transcription Factor Snail. AB - Multinucleation is found in more than one third of tumors and is linked to increased tolerance for mutation, resistance to chemotherapy, and invasive potential. The integrity of the genome depends on proper execution of the cell cycle, which can be altered through mechanotransduction pathways as the tumor microenvironment stiffens during tumorigenesis. Here, we show that signaling downstream of matrix metalloproteinase-3 (MMP3) or TGFbeta, known inducers of epithelial-mesenchymal transition (EMT), also promotes multinucleation in stiff microenvironments through Snail-dependent expression of the filament-forming protein septin-6, resulting in midbody persistence, abscission failure, and multinucleation. Consistently, we observed elevated expression of Snail and septin-6 as well as multinucleation in a human patient sample of metaplastic carcinoma of the breast, a rare classification characterized by deposition of collagen fibers and active EMT. In contrast, a soft microenvironment protected mammary epithelial cells from becoming multinucleated by preventing Snail-induced upregulation of septin-6. Our data suggest that tissue stiffening during tumorigenesis synergizes with oncogenic signaling to promote genomic abnormalities that drive cancer progression.Significance: These findings reveal tissue stiffening during tumorigenesis synergizes with oncogenic signaling to promote genomic abnormalities that drive cancer progression. Cancer Res; 78(9); 2277-89. (c)2018 AACR. PMID- 29483096 TI - hPCL3s Promotes Hepatocellular Carcinoma Metastasis by Activating beta-Catenin Signaling. AB - Two isoforms of human Polycomb-like protein 3 (hPCL3) have been reported as components of the nuclear Polycomb repressive complex 2 (PRC2), with the short isoform (hPCL3s) showing a dominant cytoplasmic localization. The function of cytoplasmic hPCL3s has, however, not been addressed. In this study, we report that hPCL3s is upregulated in clinical hepatocellular carcinoma (HCC) samples and its expression correlated with HCC clinical features. hPCL3s positively regulated the migration, invasion, and metastasis of HCC cells. hPCL3s interacted with components of the cytoplasmic beta-catenin destruction complex, inhibited beta catenin degradation, and activated beta-catenin/T-cell factor signaling. Downstream of the beta-catenin cascade, IL6 mediated the motility-promoting functions of hPCL3s. Forced expression of hPCL3s in the liver of a HCC mouse model promoted tumorigenesis and metastasis. Taken together, these data show that hPCL3s promotes the metastasis of HCC by activating the beta-catenin/IL6 pathway.Significance: hPCL3s has an oncogenic role in hepatocellular carcinoma by activating the beta-catenin/IL6 signaling axis to promote metastasis. Cancer Res; 78(10); 2536-49. (c)2018 AACR. PMID- 29483097 TI - Patient-Customized Drug Combination Prediction and Testing for T-cell Prolymphocytic Leukemia Patients. AB - The molecular pathways that drive cancer progression and treatment resistance are highly redundant and variable between individual patients with the same cancer type. To tackle this complex rewiring of pathway cross-talk, personalized combination treatments targeting multiple cancer growth and survival pathways are required. Here we implemented a computational-experimental drug combination prediction and testing (DCPT) platform for efficient in silico prioritization and ex vivo testing in patient-derived samples to identify customized synergistic combinations for individual cancer patients. DCPT used drug-target interaction networks to traverse the massive combinatorial search spaces among 218 compounds (a total of 23,653 pairwise combinations) and identified cancer-selective synergies by using differential single-compound sensitivity profiles between patient cells and healthy controls, hence reducing the likelihood of toxic combination effects. A polypharmacology-based machine learning modeling and network visualization made use of baseline genomic and molecular profiles to guide patient-specific combination testing and clinical translation phases. Using T-cell prolymphocytic leukemia (T-PLL) as a first case study, we show how the DCPT platform successfully predicted distinct synergistic combinations for each of the three T-PLL patients, each presenting with different resistance patterns and synergy mechanisms. In total, 10 of 24 (42%) of selective combination predictions were experimentally confirmed to show synergy in patient-derived samples ex vivo The identified selective synergies among approved drugs, including tacrolimus and temsirolimus combined with BCL-2 inhibitor venetoclax, may offer novel drug repurposing opportunities for treating T-PLL.Significance: An integrated use of functional drug screening combined with genomic and molecular profiling enables patient-customized prediction and testing of drug combination synergies for T-PLL patients. Cancer Res; 78(9); 2407-18. (c)2018 AACR. PMID- 29483099 TI - February 26th Question. PMID- 29483098 TI - So you think you can return to sport? PMID- 29483100 TI - Coagulation factor XII in thrombosis and inflammation. AB - Combinations of proinflammatory and procoagulant reactions are the unifying principle for a variety of disorders affecting the cardiovascular system. The factor XII-driven contact system starts coagulation and inflammatory mechanisms via the intrinsic pathway of coagulation and the bradykinin-producing kallikrein kinin system, respectively. The biochemistry of the contact system in vitro is well understood; however, its in vivo functions are just beginning to emerge. Challenging the concept of the coagulation balance, targeting factor XII or its activator polyphosphate, provides protection from thromboembolic diseases without interfering with hemostasis. This suggests that the polyphosphate/factor XII axis contributes to thrombus formation while being dispensable for hemostatic processes. In contrast to deficiency in factor XII providing safe thromboprotection, excessive FXII activity is associated with the life threatening inflammatory disorder hereditary angioedema. The current review summarizes recent findings of the polyphosphate/factor XII-driven contact system at the intersection of procoagulant and proinflammatory disease states. Elucidating the contact system offers the exciting opportunity to develop strategies for safe interference with both thrombotic and inflammatory disorders. PMID- 29483103 TI - Estimates of Within-Person Biological Variation and Reference Change Values of Serum S100B and NSE Proteins. PMID- 29483101 TI - Depth and durability of response to ibrutinib in CLL: 5-year follow-up of a phase 2 study. AB - The safety and efficacy of ibrutinib (420 mg) in chronic lymphocytic leukemia (CLL) were evaluated in a phase 2 study; 51 patients had TP53 aberration (TP53 cohort) and 35 were enrolled because of age 65 years or older (elderly cohort). Both cohorts included patients with treatment-naive (TN) and relapsed/refractory (RR) CLL. With the median follow-up of 4.8 years, 49 (57.0%) of 86 patients remain on study. Treatment was discontinued for progressive disease in 20 (23.3%) patients and for adverse events in 5 (5.8%). Atrial fibrillation occurred in 18 (20.9%) patients for a rate of 6.4 per 100 patient-years. No serious bleeding occurred. The overall response rate at 6 months, the primary study endpoint, was 95.8% for the TP53 cohort (95% confidence interval, 85.7%-99.5%) and 93.9% for the elderly cohort (95% confidence interval, 79.8%-99.3%). Depth of response improved with time: at best response, 14 (29.2%) of 48 patients in the TP53 cohort and 9 (27.3%) of 33 in the elderly cohort achieved a complete response. Median minimal residual disease (MRD) in peripheral blood was 3.8 * 10-2 at 4 years, with MRD-negative (<10-4) remissions in 5 (10.2%) patients. In the TP53 cohort, the estimated 5-year progression-free survival (PFS) was 74.4% in TN-CLL compared with 19.4% in RR-CLL (P = .0002), and overall survival (OS) was 85.3% vs 53.7%, respectively (P = .023). In the elderly cohort, the estimated 5-year PFS and OS in RR-CLL were 64.8% and 71.6%, respectively, and no event occurred in TN CLL. Long-term administration of ibrutinib was well tolerated and provided durable disease control for most patients. This trial was registered at www.clinicaltrials.gov as #NCT01500733. PMID- 29483104 TI - The NanoDisk-MS Assay: A New Frontier in Biomarker-Based Tuberculosis Diagnostics? PMID- 29483102 TI - A Ser725Arg mutation in Band 3 abolishes transport function and leads to anemia and renal tubular acidosis. PMID- 29483105 TI - Biological Variation of Creatinine, Cystatin C, and eGFR over 24 Hours. AB - BACKGROUND: Estimated glomerular filtration rate (eGFR) is widely used in clinical practice. This study assessed the within-subject biological variation (CVI) of different eGFR equations in people with chronic kidney disease (CKD) and people without CKD. The aims of this study were (a) to determine the 24-h biological variation profiles of creatinine, cystatin C, and eGFR and (b) to determine whether CVI of creatinine, cystatin C, and eGFR changes on deterioration of glomerular filtration. METHODS: Hourly blood samples were analyzed from 37 individuals (17 without CKD, 20 with CKD) during 24 h. Creatinine (enzymatic method) and cystatin C were measured using a Cobas 8000 (Roche Diagnostics). eGFR was estimated using the Modification of Diet in Renal Disease and the Chronic Kidney Disease Epidemiology Collaboration based on creatinine and/or cystatin C. Plasma samples were stored at -80 degrees C before analysis. Outlier and homogeneity analyses were checked before performing a nested ANOVA to determine biological variation. RESULTS: CVI of creatinine was higher in people without CKD than in those with CKD (6.4% vs 2.5%) owing primarily to the more profound effect of meat consumption on creatinine variability in individuals with lower baseline creatinine concentrations. Unlike creatinine, cystatin C concentrations were unaffected by meat consumption. Cystatin C showed some diurnal rhythmic variation and less in people with CKD. Reference change values (RCVs) of all eGFR equations were within 13% to 20% in both study groups. CONCLUSIONS: Despite differences in CVI of creatinine, the CVI and RCV of the eGFR equations were relatively similar for people with or without CKD. PMID- 29483106 TI - Endogenous Heparin Interferes with Quantification of MicroRNAs by RT-qPCR. PMID- 29483107 TI - Liquid Profiling of Circulating Tumor DNA in Plasma of Melanoma Patients for Companion Diagnostics and Monitoring of BRAF Inhibitor Therapy. AB - BACKGROUND: The current standard for determining eligibility of patients with metastatic melanoma for BRAF-targeted therapy is tissue-based testing of BRAF mutations. As patients are rarely rebiopsied, detection in blood might be advantageous by enabling a comprehensive assessment of tumor mutational status in real time and thereby representing a noninvasive biomarker for monitoring BRAF therapy. METHODS: In all, 634 stage I to IV melanoma patients were enrolled at 2 centers, and 1406 plasma samples were prospectively collected. Patients were assigned to 3 separate study cohorts: study 1 for assessment of circulating tumor DNA (ctDNA) as part of companion diagnostics, study 2 for assessment of ctDNA for patients with low tumor burden and for follow-up, and study 3 for monitoring of resistance to BRAF inhibitor (BRAFi) or mitogen-activated protein kinase inhibitor therapy. RESULTS: Overall, a high degree of concordance between plasma and tissue testing results was observed at 90.9% (study 1) and 90.1% (study 2), respectively. Interestingly, discrepant results were in some cases associated with nonresponse to BRAFi (n = 3) or a secondary BRAF-mutant malignancy (n = 5). Importantly, ctDNA results correlated with the clinical course of disease in 95.7% and with response to treatment. Significantly, the detection of BRAF mutant ctDNA preceded relapse assessed by Response Evaluation Criteria in Solid Tumors, and was more specific than serum S100 and lactate dehydrogenase. CONCLUSIONS: Blood-based testing compares favorably with standard-of-care tissue-based BRAF mutation testing. Importantly, blood-based BRAF testing correlates with the clinical course, even for early-stage patients, and may be used to predict response to treatment, recurrence, and resistance before radioimaging under BRAFi therapy, thereby enabling considerable improvements in patient treatment. PMID- 29483108 TI - Potential of STAT Somatic Mutation Testing at Resection. PMID- 29483109 TI - Resistome Analysis of a Carbapenemase (OXA-48)-Producing and Colistin-Resistant Klebsiella pneumoniae Strain. PMID- 29483111 TI - In Vitro Susceptibility of Ceftolozane-Tazobactam against Burkholderia pseudomallei. PMID- 29483110 TI - Evidence for Inhibition of Topoisomerase 1A by Gold(III) Macrocycles and Chelates Targeting Mycobacterium tuberculosis and Mycobacterium abscessus. AB - Mycobacterium tuberculosis and the fast-growing species Mycobacterium abscessus are two important human pathogens causing persistent pulmonary infections that are difficult to cure and require long treatment times. The emergence of drug resistant M. tuberculosis strains and the high level of intrinsic resistance of M. abscessus call for novel drug scaffolds that effectively target both pathogens. In this study, we evaluated the activity of bis(pyrrolide-imine) gold(III) macrocycles and chelates, originally designed as DNA intercalators capable of targeting human topoisomerase types I and II (Topo1 and Topo2), against M. abscessus and M. tuberculosis We identified a total of 5 noncytotoxic compounds active against both mycobacterial pathogens under replicating in vitro conditions. We chose one of these hits, compound 14, for detailed analysis due to its potent bactericidal mode of inhibition and scalable synthesis. The clinical relevance of this compound was demonstrated by its ability to inhibit a panel of diverse M. tuberculosis and M. abscessus clinical isolates. Prompted by previous data suggesting that compound 14 may target topoisomerase/gyrase enzymes, we demonstrated that it lacked cross-resistance with fluoroquinolones, which target the M. tuberculosis gyrase. In vitro enzyme assays confirmed the potent activity of compound 14 against bacterial topoisomerase 1A (Topo1) enzymes but not gyrase. Novel scaffolds like compound 14 with potent, selective bactericidal activity against M. tuberculosis and M. abscessus that act on validated but underexploited targets like Topo1 represent a promising starting point for the development of novel therapeutics for infections by pathogenic mycobacteria. PMID- 29483112 TI - Plasma Levels of Rifampin Correlate with the Tuberculosis Drug Activity Assay. AB - The plasma tuberculosis drug activity (TDA) assay may be an alternative tool for therapeutic drug monitoring in resource-limited settings. In tuberculosis (TB) patients (n = 30), TDA and plasma levels of first-line drugs were analyzed 2 h postdose, 2 weeks after treatment initiation. Patients with plasma levels of rifampin lower than 8 mg/liter had a significantly lower median TDA (1.40 versus 1.68, P = 0.0013). TDA may be used to identify TB patients with suboptimal rifampin levels during TB treatment. PMID- 29483113 TI - The Amphibian Antimicrobial Peptide Temporin B Inhibits In Vitro Herpes Simplex Virus 1 Infection. AB - The herpes simplex virus 1 (HSV-1) is widespread in the population, and in most cases its infection is asymptomatic. The currently available anti-HSV-1 drugs are acyclovir and its derivatives, although long-term therapy with these agents can lead to drug resistance. Thus, the discovery of novel antiherpetic compounds deserves additional effort. Naturally occurring antimicrobial peptides (AMPs) represent an interesting class of molecules with potential antiviral properties. To the best of our knowledge, this study is the first demonstration of the in vitro anti-HSV-1 activity of temporin B (TB), a short membrane-active amphibian AMP. In particular, when HSV-1 was preincubated with 20 MUg/ml TB, significant antiviral activity was observed (a 5-log reduction of the virus titer). Such an effect was due to the disruption of the viral envelope, as demonstrated by transmission electron microscopy. Moreover, TB partially affected different stages of the HSV-1 life cycle, including the attachment and the entry of the virus into the host cell, as well as the subsequent postinfection phase. Furthermore, its efficacy was confirmed on human epithelial cells, suggesting TB as a novel approach for the prevention and/or treatment of HSV-1 infections. PMID- 29483114 TI - Evaluation of the In Vitro Activity of Eravacycline against a Broad Spectrum of Recent Clinical Anaerobic Isolates. AB - The novel fluorocycline antibiotic eravacycline is in development for use in the treatment of serious infections caused by susceptible and multidrug-resistant (MDR) aerobic and anaerobic Gram-negative and Gram-positive pathogens. Eravacycline and 11 comparator antibiotics were tested against recent anaerobic clinical isolates, including MDR Bacteroides spp. and Clostridium difficile Eravacycline was potent in vitro against all the isolates tested, including strains with tetracycline-specific resistance determinants and MDR anaerobic pathogens resistant to carbapenems and/or beta-lactam-beta-lactamase inhibitor combinations. PMID- 29483115 TI - An Antibiotic Stewardship Program Blueprint for Optimizing Verigene BC-GN within an Institution: a Tale of Two Cities. AB - Rapid diagnostic tests (RDTs) have revolutionized the management of Gram-negative bacteremia by allowing antimicrobial stewardship teams the ability to escalate therapy and improve patient outcomes through timely organism identification and detection of certain resistance determinants. However, given the complex nature of Gram-negative resistance, stewardship teams are left without clear direction for how to respond when resistance determinants are absent, as the safety of de escalation in this setting is unknown. The primary purpose of this analysis was to determine the negative predictive values (NPVs) of resistance marker absence for predicting susceptibility in target bug-drug scenarios at two geographically distinct institutions. A total of 1,046 Gram-negative bloodstream isolates that were analyzed with the Verigene BC-GN platform were assessed. Except for Pseudomonas aeruginosa, the absence of resistance determinants as reported by the RDT largely predicted susceptibility to target antibiotics at both institutions. NPVs for ceftriaxone susceptibility in Escherichia coli and Klebsiella pneumoniae in the absence of either CTX-M or a carbapenemase gene were 98% and 93 to 94%, respectively. Similar results were seen with other target bug-drug scenarios, with NPVs of 94 to 100% demonstrated at both institutions, with the exception of P. aeruginosa, for which NPVs were poor, likely due to the more complex nature of resistance in this pathogen. The results of this study show that clinicians at both institutions should have confidence in de-escalation in the absence of resistance determinant detection by Verigene BC-GN testing, and the methodology described within this article can serve as a blueprint for other stewardship programs to employ at their institutions to optimize management of Gram-negative bacteremia. PMID- 29483116 TI - MEDI3902 Correlates of Protection against Severe Pseudomonas aeruginosa Pneumonia in a Rabbit Acute Pneumonia Model. AB - Pseudomonas aeruginosa is among the most formidable antibiotic-resistant pathogens and is a leading cause of hospital-associated infections. With dwindling options for antibiotic-resistant infections, a new paradigm for treatment and disease resolution is required. MEDI3902, a bispecific antibody targeting the P. aeruginosa type III secretion (T3S) protein PcrV and Psl exopolysaccharide, was previously shown to mediate potent protective activity in murine infection models. With the current challenges associated with the clinical development of narrow-spectrum agents, robust preclinical efficacy data in multiple animal species are desirable. Here, we sought to develop a rabbit P. aeruginosa acute pneumonia model to further evaluate the activity of MEDI3902 intervention. In the rabbit model of acute pneumonia, prophylaxis with MEDI3902 exhibited potent dose-dependent protection, whereas those receiving control IgG developed fatal hemorrhagic necrotizing pneumonia between 12 and 54 h after infection. Blood biomarkers (e.g., partial pressure of oxygen [pO2], partial pressure of carbon dioxide [pCO2], base excess, lactate, and creatinine) were grossly deranged for the vast majority of control IgG-treated animals but remained within normal limits for MEDI3902-treated animals. In addition, MEDI3902 treated animals exhibited a profound reduction in P. aeruginosa organ burden and a marked reduction in the expression of proinflammatory mediators from lung tissue, which correlated with reduced lung histopathology. These results confirm that targeting PcrV and Psl via MEDI3902 is a promising candidate for immunotherapy against P. aeruginosa pneumonia. PMID- 29483117 TI - Identification and Characterization of Key Charged Residues in the Cofilin Protein Involved in Azole Susceptibility, Apoptosis, and Virulence of Aspergillus fumigatus. AB - Through some specific amino acid residues, cofilin, a ubiquitous actin depolymerization factor, can significantly affect mitochondrial function related to drug resistance and apoptosis in Saccharomyces cerevisiae; however, this modulation in a major fungal pathogen, Aspergillus fumigatus, was still unclear. Hereby, it was found, first, that mutations on several charged residues in cofilin to alanine, D19A-R21A, E48A, and K36A, increased the formation of reactive oxygen species and induced apoptosis along with typical hallmarks, including mitochondrial membrane potential depolarization, cytochrome c release, upregulation of metacaspases, and DNA cleavage, in A. fumigatus Two of these mutations (D19A-R21A and K36A) increased acetyl coenzyme A and ATP concentrations by triggering fatty acid beta-oxidation. The upregulated acetyl coenzyme A affected the ergosterol biosynthetic pathway, leading to overexpression of cyp51A and -B, while excess ATP fueled ATP-binding cassette transporters. Besides, both of these mutations reduced the susceptibility of A. fumigatus to azole drugs and enhanced the virulence of A. fumigatus in a Galleria mellonella infection model. Taken together, novel and key charged residues in cofilin were identified to be essential modules regulating the mitochondrial function involved in azole susceptibility, apoptosis, and virulence of A. fumigatus. PMID- 29483118 TI - Integrase-Mediated Recombination of the bel-1 Gene Cassette Encoding the Extended Spectrum beta-Lactamase BEL-1. AB - Integrons are genetic elements that can acquire and rearrange gene cassettes. The blaBEL-1 gene encodes an extended-spectrum beta-lactamase, BEL-1, that is present at the second position of the variable region of class 1 integrons identified in Pseudomonas aeruginosa The mobility of the bel-1 gene cassette was analyzed under physiological conditions and with the integrase gene being overexpressed. Cassette mobility in Escherichia coli was detected by excision/integration into the recipient integron In3 on the conjugative plasmid R388 with the overproduced integrase. Despite several antibiotic pressures, the bel-1 cassette remained at the second position in the integron, highlighting its stability in P. aeruginosa Overexpression of the integrase gene in E. coli induced bel-1 cassette recombination. However, cassettes containing two genes (blaBEL-1 and smr2 or blaBEL-1 and aacA4) were excised, suggesting that the bel-1 cassette attC site was defective. We show that bel-1 is a stable gene cassette under physiological growth conditions, irrespective of the selective antibiotic pressure, that may be mobilized upon overexpression of the integrase gene. PMID- 29483119 TI - Efficacy of Human-Simulated Exposures of Ceftolozane-Tazobactam Alone and in Combination with Amikacin or Colistin against Multidrug-Resistant Pseudomonas aeruginosa in an In Vitro Pharmacodynamic Model. AB - Combination therapy is an attractive option for the treatment of multidrug resistant (MDR) Pseudomonas aeruginosa infections; however, limited data are available on combinations with ceftolozane-tazobactam (C-T). The in vitro pharmacodynamic chemostat model was employed to compare human-simulated exposures of C-T at 3 g every 8 h alone or in combination with amikacin at 25 mg/kg of body weight daily or colistin at 360 mg daily against four MDR P. aeruginosa isolates. C-T alone resulted in 24-h changes in the number of CFU of -0.02 +/- 0.21, -1.81 +/- 0.55, -1.44 +/- 0.40, and +0.62 +/- 0.05 log10 CFU/ml against isolates with C T MICs of 4, 4, 8, and 16 MUg/ml, respectively. Amikacin and colistin monotherapy displayed various results. The addition of amikacin to C-T resulted in -2.00 +/- 0.23 (P < 0.001, additive)-, -1.50 +/- 0.83 (P = 0.687, indifferent)-, -2.84 +/- 0.08 (P = 0.079, indifferent)-, and -2.67 +/- 0.54 (P < 0.001, synergy)-log10 CFU/ml reductions, respectively. The addition of colistin to C-T resulted in 3.02 +/- 0.22 (P < 0.001, additive)-, -3.21 +/- 0.24 (P > 0.05, indifferent)-, 4.6 +/- 0.11 (P = 0.002, synergy)-, and -3.01 +/- 0.28 (P < 0.001, synergy)-log10 CFU/ml reductions, respectively, against the MDR P. aeruginosa isolates with these MICs. Greater overall reductions in bacterial burden, including additive or synergistic interactions at 24 h, with C-T plus amikacin or colistin were observed against 3 out of 4 MDR P. aeruginosa strains tested, particularly those strains that were intermediate or resistant to C-T. Further studies assessing combination regimens containing C-T against MDR P. aeruginosa are warranted. PMID- 29483121 TI - Characterization of the Complete Nucleotide Sequences of IMP-4-Encoding Plasmids, Belonging to Diverse Inc Families, Recovered from Enterobacteriaceae Isolates of Wildlife Origin. AB - The complete nucleotide sequences of six IMP-4-encoding plasmids recovered from Enterobacteriaceae isolates of wildlife origin were characterized. Sequencing data showed that plasmids of different incompatibility groups (IncM, IncI1, IncF, and nontypeable [including an IncX5_2 and two pPrY2001-like]) carried the blaIMP 4-carrying integrons In809 or In1460. Most of the plasmids carried an mph(A) region, and chrA-like, aac(3)-IId, and blaTEM-1b genes. Finally, plasmid analysis revealed the involvement of two different IS26- and Tn1696-associated mechanisms in the mobilization of IMP-4-encoding integrons. PMID- 29483120 TI - Characteristics of Carbapenemase-Producing Enterobacteriaceae in Wastewater Revealed by Genomic Analysis. AB - Wastewater is considered a major source of antibiotic-resistant bacteria released into the environment. Here, we characterized carbapenemase-producing Enterobacteriaceae (CPE) in wastewater by whole-genome analysis. Wastewater samples (n = 40) were collected from municipal wastewater treatment plants and hospital wastewater in Japan and Taiwan. Samples were screened for CPE using selective media, and the obtained isolates were sequenced using an Illumina MiSeq. The isolates (n = 45) included the following microorganisms: Klebsiella quasipneumoniae (n = 12), Escherichia coli (n = 10), Enterobacter cloacae complex (n = 10), Klebsiella pneumoniae (n = 8), Klebsiella variicola (n = 2), Raoultella ornithinolytica (n = 1), Citrobacter freundii (n = 1), and Citrobacter amalonaticus (n = 1). Among the 45 isolates, 38 harbored at least one carbapenemase-encoding gene. Of these, the blaGES (blaGES-5, blaGES-6, and blaGES 24) genes were found in 29 isolates. The genes were situated in novel class 1 integrons, but the integron structures were different between the Japanese (In1439 with blaGES-24 and In1440 with blaGES-5) and Taiwanese (In1441 with blaGES-5 and In1442 with blaGES-6) isolates. Other carbapenemase-encoding genes (blaVIM-1, blaNDM-5, blaIMP-8, blaIMP-19, and blaKPC-2) were found in one to three isolates. Notably, class 1 integrons previously reported among clinical isolates obtained in the same regions as the present study, namely, In477 with blaIMP-19 and In73 with blaIMP-8, were found among the Japanese and Taiwanese isolates, respectively. The results indicate that CPE with various carbapenemase encoding genes in different genetic contexts were present in biologically treated wastewater, highlighting the need to monitor for antibiotic resistance in wastewater. PMID- 29483122 TI - Aminomethyl Spectinomycins as Therapeutics for Drug-Resistant Gonorrhea and Chlamydia Coinfections. AB - Bacterial sexually transmitted infections are widespread and common, with Neisseria gonorrhoeae (gonorrhea) and Chlamydia trachomatis (chlamydia) being the two most frequent causes. If left untreated, both infections can cause pelvic inflammatory disease, infertility, ectopic pregnancy, and other sequelae. The recommended treatment for gonorrhea is ceftriaxone plus azithromycin (to empirically treat chlamydial coinfections). Antibiotic resistance to all existing therapies has developed in gonorrheal infections. The need for new antibiotics is great, but the pipeline for new drugs is alarmingly small. The aminomethyl spectinomycins, a new class of semisynthetic analogs of the antibiotic spectinomycin, were developed on the basis of a computational analysis of the spectinomycin binding site of the bacterial 30S ribosome and structure-guided synthesis. The compounds display particular potency against common respiratory tract pathogens as well as the sexually transmitted pathogens that cause gonorrhea and chlamydia. Here, we demonstrate the in vitro potencies of several compounds of this class against both bacterial species; the compounds displayed increased potencies against N. gonorrhoeae compared to that of spectinomycin and, significantly, demonstrated activity against C. trachomatis that is not observed with spectinomycin. Efficacies of the compounds were compared to those of spectinomycin and gentamicin in a murine model of infection caused by ceftriaxone/azithromycin-resistant N. gonorrhoeae; the aminomethyl spectinomycins significantly reduced the colonization load and were as potent as the comparator compounds. In summary, data produced by this study support aminomethyl spectinomycins as a promising replacement for spectinomycin and antibiotics such as ceftriaxone for treating drug-resistant gonorrhea, with the added benefit of treating chlamydial coinfections. PMID- 29483123 TI - Micafungin Enhances the Human Macrophage Response to Candida albicans through beta-Glucan Exposure. AB - Micafungin belongs to the antifungal family of echinocandins, which act as noncompetitive inhibitors of the fungal cell wall beta-1,3-d-glucan synthase. Since Candida albicans is the most prevalent pathogenic fungus in humans, we study the involvement of micafungin in the modulation of the inflammatory response developed by human tissue macrophages against C. albicans The MIC for micafungin was 0.016 MUg/ml on the C. albicans SC5314 standard strain. Micafungin induced a drastic reduction in the number of exponential SC5314 viable cells, with the fungicidal effect being dependent on the cellular metabolic activity. Notably, micafungin also caused a structural remodelling of the cell wall, leading to exposure of the beta-glucan and chitin content on the external surface. At the higher doses used (0.05 MUg/ml), the antifungal also induced the blowing up of budding yeasts. In addition, preincubation with micafungin before exposure to human tissue macrophages enhanced the secretion of tumor necrosis factor alpha (TNF-alpha), interleukin-17A (IL-17A), and IL-10 cytokines. Our results strongly suggest that in C. albicans treatment with micafungin, in addition to having the expected toxic antifungal effect, it potentiates the immune response, improving the interaction and activation of human macrophages, probably through the unmasking of beta-glucans on the cell wall surface. PMID- 29483124 TI - In Situ Validation of the Endothelial Cell Receptor GRP78 in a Case of Rhinocerebral Mucormycosis. PMID- 29483125 TI - Treatment of Clostridium difficile Infection with a Small-Molecule Inhibitor of Toxin UDP-Glucose Hydrolysis Activity. AB - Clostridium difficile infection (CDI) is the leading cause of hospital-acquired infectious diarrhea, with significant morbidity, mortality, and associated health care costs. The major risk factor for CDI is antimicrobial therapy, which disrupts the normal gut microbiota and allows C. difficile to flourish. Treatment of CDI with antimicrobials is generally effective in the short term, but recurrent infections are frequent and problematic, indicating that improved treatment options are necessary. Symptoms of disease are largely due to two homologous toxins, TcdA and TcdB, which are glucosyltransferases that inhibit host Rho GTPases. As the normal gut microbiota is an important component of resistance to CDI, our goal was to develop an effective nonantimicrobial therapy. Here, we report a highly potent small-molecule inhibitor (VB-82252) of TcdA and TcdB. This compound inhibits the UDP-glucose hydrolysis activity of TcdB and protects cells from intoxication after challenge with either toxin. Oral dosing of the inhibitor prevented inflammation in a murine intrarectal toxin challenge model. In a murine model of recurrent CDI, the inhibitor reduced weight loss and gut inflammation during acute disease and did not cause the recurrent disease that was observed with vancomycin treatment. Lastly, the inhibitor demonstrated efficacy similar to that of vancomycin in a hamster disease model. Overall, these results demonstrate that small-molecule inhibition of C. difficile toxin UDP glucose hydrolysis activity is a promising nonantimicrobial approach to the treatment of CDI. PMID- 29483126 TI - The Clarithromycin Susceptibility Genotype Affects the Treatment Outcome of Patients with Mycobacterium abscessus Lung Disease. AB - Mycobacterium abscessus accounts for a large proportion of lung disease cases caused by rapidly growing mycobacteria. The association between clarithromycin sensitivity and treatment outcome is clear. However, M. abscessus culture and antibiotic susceptibility testing are time-consuming. Clarithromycin susceptibility genotyping offers an alternate, rapid approach to predicting the efficacy of clarithromycin-based antibiotic therapy. M. abscessus lung disease patients were divided into two groups based upon the clarithromycin susceptibility genotype of the organism isolated. A retrospective analysis was conducted to compare the clinical features, microbiological characteristics, and treatment outcomes of the two groups. Several other potential predictors of the response to treatment were also assessed. Sixty-nine patients were enrolled in the clarithromycin-resistant genotype group, which included 5 infected with rrl 2058-2059 mutants and 64 infected with erm(41)T28-type M. abscessus; 31 were in the clarithromycin-sensitive group, i.e., 6 and 25 patients infected with genotypes erm(41)C28 and erm(41) M type, respectively. The results showed that lung disease patients infected with clarithromycin-sensitive and -resistant M. abscessus genotypes differed significantly in clarithromycin-based combination treatment outcomes. Patients infected with the clarithromycin-sensitive genotype exhibited higher initial and final sputum-negative conversion and radiological improvement rates and better therapeutic outcomes. Multivariate analysis demonstrated that genotyping was a reliable and, more importantly, rapid means of predicting the efficacy of clarithromycin-based antibiotic treatment for M. abscessus lung disease. PMID- 29483127 TI - Sustained Persistence of IL2 Signaling Enhances the Antitumor Effect of Peptide Vaccines through T-cell Expansion and Preventing PD-1 Inhibition. AB - Peptide vaccines can be a successful and cost-effective way of generating T-cell responses against defined tumor antigens, especially when combined with immune adjuvants such as poly-IC. However, strong immune adjuvants can induce a collateral increase in numbers of irrelevant, nonspecific T cells, which limits the effectiveness of the peptide vaccines. Here, we report that providing prolonged IL2 signaling in the form of either IL2/anti-IL2 complexes or pegylated IL2 overcomes the competitive suppressive effect of irrelevant T cells, allowing the preferential expansion of antigen-specific T cells. In addition to increasing the number of tumor-reactive T cells, sustained IL2 enhanced the ability of T cells to resist PD-1-induced negative signals, increasing the therapeutic effectiveness of the vaccines against established tumors. This vaccination strategy using peptides and sustained IL2 could be taken into the clinic for the treatment of cancer. Cancer Immunol Res; 6(5); 617-27. (c)2018 AACR. PMID- 29483128 TI - ApoE facilitates the microglial response to amyloid plaque pathology. AB - One of the hallmarks of Alzheimer's disease is the presence of extracellular diffuse and fibrillar plaques predominantly consisting of the amyloid-beta (Abeta) peptide. Apolipoprotein E (ApoE) influences the deposition of amyloid pathology through affecting the clearance and aggregation of monomeric Abeta in the brain. In addition to influencing Abeta metabolism, increasing evidence suggests that apoE influences microglial function in neurodegenerative diseases. Here, we characterize the impact that apoE has on amyloid pathology and the innate immune response in APPPS1DeltaE9 and APPPS1-21 transgenic mice. We report that Apoe deficiency reduced fibrillar plaque deposition, consistent with previous studies. However, fibrillar plaques in Apoe-deficient mice exhibited a striking reduction in plaque compaction. Hyperspectral fluorescent imaging using luminescent conjugated oligothiophenes identified distinct Abeta morphotypes in Apoe-deficient mice. We also observed a significant reduction in fibrillar plaque associated microgliosis and activated microglial gene expression in Apoe deficient mice, along with significant increases in dystrophic neurites around fibrillar plaques. Our results suggest that apoE is critical in stimulating the innate immune response to amyloid pathology. PMID- 29483131 TI - Retraction. PMID- 29483132 TI - Otopetrin-1: A sour-tasting proton channel. PMID- 29483129 TI - Autophagy in stem cells: repair, remodelling and metabolic reprogramming. AB - Autophagy is a catabolic pathway by which cellular components are delivered to the lysosome for degradation and recycling. Autophagy serves as a crucial intracellular quality control and repair mechanism but is also involved in cell remodelling during development and cell differentiation. In addition, mitophagy, the process by which damaged mitochondria undergo autophagy, has emerged as key regulator of cell metabolism. In recent years, a number of studies have revealed roles for autophagy and mitophagy in the regulation of stem cells, which represent the origin for all tissues during embryonic and postnatal development, and contribute to tissue homeostasis and repair throughout adult life. Here, we review these studies, focussing on the latest evidence that supports the quality control, remodelling and metabolic functions of autophagy during the activation, self-renewal and differentiation of embryonic, adult and cancer stem cells. PMID- 29483134 TI - Drug Combo Bests Sunitinib in RCC. AB - The phase III IMmotion151 trial found that the combination of atezolizumab and bevacizumab boosts progression-free survival compared with sunitinib in patients with advanced or metastatic renal cell carcinoma. The increase was 2.8 months in all patients and 3.5 months in patients with PD-L1-positive tumors. PMID- 29483133 TI - An allosteric inhibitor of Mycobacterium tuberculosis ArgJ: Implications to a novel combinatorial therapy. AB - The existing treatment regime against tuberculosis is not adequate, and novel therapeutic interventions are required to target Mycobacterium tuberculosis (Mtb) pathogenesis. We report Pranlukast (PRK) as a novel allosteric inhibitor of Mtb's arginine biosynthetic enzyme, Ornithine acetyltransferase (MtArgJ). PRK treatment remarkably abates the survival of free as well as macrophage-internalized Mtb, and shows enhanced efficacy in combination with standard-of-care drugs. Notably, PRK also reduces the 5-lipoxygenase (5-LO) signaling in the infected macrophages, thereby surmounting an enhanced response against intracellular pathogen. Further, treatment with PRK alone or with rifampicin leads to significant decrease in Mtb burden and tubercular granulomas in Mtb-infected mice lungs. Taken together, this study demonstrates a novel allosteric inhibitor of MtArgJ, which acts as a dual edged sword, by targeting the intracellular bacteria as well as the bacterial pro survival signaling in the host. PRK is highly effective against in vitro and in vivo survival of Mtb and being an FDA-approved drug, it shows a potential for development of advanced combinatorial therapy against tuberculosis. PMID- 29483135 TI - Allele-Specific Mechanisms of Activation of MEK1 Mutants Determine Their Properties. AB - Mutations at multiple sites in MEK1 occur in cancer, suggesting that their mechanisms of activation might be different. We analyzed 17 tumor-associated MEK1 mutants and found that they drove ERK signaling autonomously or in a RAS/RAF dependent manner. The latter are sensitive to feedback inhibition of RAF, which limits their functional output, and often cooccur with RAS or RAF mutations. They act as amplifiers of RAF signaling. In contrast, another class of mutants deletes a hitherto unrecognized negative regulatory segment of MEK1, is RAF- and phosphorylation-independent, is unaffected by feedback inhibition of upstream signaling, and drives high ERK output and transformation in the absence of RAF activity. Moreover, these RAF-independent mutants are insensitive to allosteric MEK inhibitors, which preferentially bind to the inactivated form of MEK1. All the mutants are sensitive to an ATP-competitive MEK inhibitor. Thus, our study comprises a novel therapeutic strategy for tumors driven by RAF-independent MEK1 mutants.Significance: Mutants with which MEK1 mutants coexist and their sensitivity to inhibitors are determined by allele-specific properties. This study shows the importance of functional characterization of mutant alleles in single oncogenes and identifies a new class of MEK1 mutants, insensitive to current MEK1 inhibitors but treatable with a new ATP-competitive inhibitor. Cancer Discov; 8(5); 648-61. (c)2018 AACR.See related commentary by Maust et al., p. 534This article is highlighted in the In This Issue feature, p. 517. PMID- 29483136 TI - Genomic and Functional Fidelity of Small Cell Lung Cancer Patient-Derived Xenografts. AB - Small cell lung cancer (SCLC) patient-derived xenografts (PDX) can be generated from biopsies or circulating tumor cells (CTC), though scarcity of tissue and low efficiency of tumor growth have previously limited these approaches. Applying an established clinical-translational pipeline for tissue collection and an automated microfluidic platform for CTC enrichment, we generated 17 biopsy derived PDXs and 17 CTC-derived PDXs in a 2-year timeframe, at 89% and 38% efficiency, respectively. Whole-exome sequencing showed that somatic alterations are stably maintained between patient tumors and PDXs. Early-passage PDXs maintain the genomic and transcriptional profiles of the founder PDX. In vivo treatment with etoposide and platinum (EP) in 30 PDX models demonstrated greater sensitivity in PDXs from EP-naive patients, and resistance to EP corresponded to increased expression of a MYC gene signature. Finally, serial CTC-derived PDXs generated from an individual patient at multiple time points accurately recapitulated the evolving drug sensitivities of that patient's disease. Collectively, this work highlights the translational potential of this strategy.Significance: Effective translational research utilizing SCLC PDX models requires both efficient generation of models from patients and fidelity of those models in representing patient tumor characteristics. We present approaches for efficient generation of PDXs from both biopsies and CTCs, and demonstrate that these models capture the mutational landscape and functional features of the donor tumors. Cancer Discov; 8(5); 600-15. (c)2018 AACR.This article is highlighted in the In This Issue feature, p. 517. PMID- 29483137 TI - B3GNT3 overexpression is associated with unfavourable survival in non-small cell lung cancer. AB - OBJECTIVE: The aim of this study was to evaluate the expression of beta-1,3-N acetylglucosaminyltransferase-3 (B3GNT3) in non-small cell lung cancer (NSCLC) patients and to investigate the relevance of B3GNT3 expression in tumour prognosis. METHODS: In this study, B3GNT3 expression was examined in five pairs of resectable NSCLC tissue by Western blot and in 42 pairs of resectable NSCLC tissue by quantitative real-time PCR (qRT-PCR). Immunohistochemistry and statistical analysis were performed to assess the relationship between B3GNT3 expression scores and clinicopathological parameters, as well as clinical prognosis in a retrospective cohort of 176 NSCLC patients. RESULTS: Both B3GNT3 mRNA and protein expression levels were significantly higher in NSCLC tissue than in adjacent normal tissue. In the 176 NSCLC cases, a high B3GNT3 expression level was positively correlated with lymph node metastasis (P<0.001) and advanced TNM stage (P=0.043). Kaplan-Meier analysis indicated that patients with high B3GNT3 expression had significantly lower disease-free survival (DFS) (P<0.001) and overall survival (OS) (P<0.001) than those with low B3GNT3 expression. Moreover, in the multivariate analyses, B3GNT3 expression was an independent prognostic factor for DFS (HR 0.329, 95% CI 0.213 to 0.508, P<0.001) and OS (HR 0.383, 95% CI 0.249 to 0.588, P<0.001). CONCLUSIONS: Our study demonstrated that high expression of B3GNT3 was associated with unfavourable DFS and OS in NSCLC patients, suggesting that B3GNT3 might be a potential prognostic biomarker for NSCLC. PMID- 29483138 TI - Mechanisms, Clinical Implications, and Treatment of Intradialytic Hypotension. AB - Individuals with ESKD requiring maintenance hemodialysis face a unique hemodynamic challenge, typically on a thrice-weekly basis. In an effort to achieve some degree of euvolemia, ultrafiltration goals often involve removal of the equivalent of an entire plasma volume. Maintenance of adequate end-organ perfusion in this setting is dependent on the institution of a variety of complex compensatory mechanisms. Unfortunately, secondary to a myriad of patient- and dialysis-related factors, this compensation often falls short and results in intradialytic hypotension. Physicians and patients have developed a greater appreciation for the breadth of adverse outcomes associated with intradialytic hypotension, including higher cardiovascular and all-cause mortality. In this review, we summarize the evidence for adverse outcomes associated with intradialytic hypotension, explore the underlying pathophysiology, and use this as a basis to introduce potential strategies for its prevention and treatment. PMID- 29483140 TI - Vocalization in caterpillars: a novel sound-producing mechanism for insects. AB - Insects have evolved a great diversity of sound-producing mechanisms largely attributable to their hardened exoskeleton, which can be rubbed, vibrated or tapped against different substrates to produce acoustic signals. However, sound production by forced air, while common in vertebrates, is poorly understood in insects. We report on a caterpillar that 'vocalizes' by forcing air into and out of its gut. When disturbed, larvae of the Nessus sphinx hawkmoth (Sphingidae: Amphion floridensis) produce sound trains comprising a stereotyped pattern of long (370 ms) followed by multiple short-duration (23 ms) units. Sounds are emitted from the oral cavity, as confirmed by close-up videos and comparing sound amplitudes at different body regions. Numerical models using measurements of the caterpillar foregut were constructed to test hypotheses explaining sound production. We propose that sound is generated by ring vortices created as air flows through the orifice between two foregut chambers (crop and oesophagus), a mechanism analogous to a whistling kettle. As air flows past the orifice, certain sound frequencies are amplified by a Helmholtz resonator effect of the oesophagus chamber. Long sound units occur during inflation, while short sound units occur during deflation. Several other insects have been reported to produce sounds by forced air, but the aeroacoustic mechanisms of such sounds remain elusive. Our results provide evidence for this mechanism by showing that caterpillars employ mechanisms similar to rocket engines to produce sounds. PMID- 29483139 TI - BP Measurement Techniques: What They Mean for Patients with Kidney Disease. AB - Patients with CKD typically have hypertension. Manual BP measurement in the office setting was used to define hypertension, establish eligibility, and assess BP targets in the epidemiologic studies and early randomized, controlled trials that inform current management of hypertension. Use of automated oscillometric devices has largely replaced manual BP measurement in the office and clinical trials. These newer devices may reduce the white coat effect and facilitate guideline-adherent measurement protocols. Obtaining BP measurements outside of the office with home and ambulatory BP monitoring is now more common. Out of office BPs are especially important in patients with CKD, because reduced GFR and proteinuria are associated with masked hypertension (normal office BP and elevated BP outside of the office), elevated nighttime BP, and abnormal diurnal variation in BP, all of which are associated with higher risk for target organ damage and adverse outcomes. Also, it is now feasible to routinely measure central BP and central hemodynamics. These measures are of greater importance to patients with CKD given the higher prevalence of increased sympathetic tone, arteriosclerosis, and inflammation as well as impaired sodium excretion and endothelial dysfunction, which lead to alterations in central BPs in this population. In this review, we describe various BP measurement techniques and how they apply to the care of patients with CKD. PMID- 29483141 TI - Pre-existing depression predicts survival in cardiovascular disease and cancer. AB - BACKGROUND: Previous studies have found depression to be negatively associated with the prognosis of both cardiovascular disease (CVD) and cancer, but this may partly reflect reverse causality. We limited the possibility of reverse causality by measuring depression before the first diagnosis of CVD or cancer. METHODS: We used an 11% longitudinal random sample of the Finnish population aged 25 years or older who are residents of Finland for at least 1 year between 1987 and 2007, with an 80% oversample of those who died during this period. Those who had their first incidence of coronary heart disease (CHD) (n=107 966), stroke (n=68 685) or cancer (n=113 754) between 1998 and 2012 were followed up for cause-specific mortality from the date of diagnosis until the end of 2012. Depression was defined as having antidepressant purchases two to three calendar years before the incidence. Logistic and Cox regression models were used to examine short-term and long-term mortality by depression status. RESULTS: Long-term mortality after diagnosis was 1.34 (95% CI 1.25 to 1.44) for CHD, 1.26 (95% CI 1.15 to 1.37) for stroke and 1.10 (95% CI 1.04 to 1.16) for cancer in those who had used antidepressants in two consecutive calendar years as compared with those with no purchases. Short-term mortality from CHD was elevated among persons with depression (OR=1.30; 95% CI 1.06 to 1.61), but no association was found for stroke. CONCLUSION: Pre-existing depression is associated with a worse prognosis of CHD, stroke and cancer. More attention in the healthcare system is needed for patients with chronic diseases who have a history of depression. PMID- 29483142 TI - STAT5A/B Blockade Sensitizes Prostate Cancer to Radiation through Inhibition of RAD51 and DNA Repair. AB - Purpose: The standard treatment for organ-confined prostate cancer is surgery or radiation, and locally advanced prostate cancer is typically treated with radiotherapy alone or in combination with androgen deprivation therapy. Here, we investigated whether Stat5a/b participates in regulation of double-strand DNA break repair in prostate cancer, and whether Stat5 inhibition may provide a novel strategy to sensitize prostate cancer to radiotherapy.Experimental Design: Stat5a/b regulation of DNA repair in prostate cancer was evaluated by comet and clonogenic survival assays, followed by assays specific to homologous recombination (HR) DNA repair and nonhomologous end joining (NHEJ) DNA repair. For HR DNA repair, Stat5a/b regulation of Rad51 and the mechanisms underlying the regulation were investigated in prostate cancer cells, xenograft tumors, and patient-derived prostate cancers ex vivo in 3D explant cultures. Stat5a/b induction of Rad51 and HR DNA repair and responsiveness to radiation were evaluated in vivo in mice bearing prostate cancer xenograft tumors.Results: Stat5a/b is critical for Rad51 expression in prostate cancer via Jak2-dependent mechanisms by inducing Rad51 mRNA levels. Consistent with this, genetic knockdown of Stat5a/b suppressed HR DNA repair while not affecting NHEJ DNA repair. Pharmacologic Stat5a/b inhibition potently sensitized prostate cancer cell lines and prostate cancer tumors to radiation, while not inducing radiation sensitivity in the neighboring tissues.Conclusions: This work introduces a novel concept of a pivotal role of Jak2-Stat5a/b signaling for Rad51 expression and HR DNA repair in prostate cancer. Inhibition of Jak2-Stat5a/b signaling sensitizes prostate cancer to radiation and, therefore, may provide an adjuvant therapy for radiation to reduce radiation-induced damage to the neighboring tissues. Clin Cancer Res; 24(8); 1917-31. (c)2018 AACR. PMID- 29483144 TI - Wanted: a WhatsApp alternative for clinicians. PMID- 29483143 TI - Phase I Study of LY2940680, a Smo Antagonist, in Patients with Advanced Cancer Including Treatment-Naive and Previously Treated Basal Cell Carcinoma. AB - Purpose: The purpose of this study was to determine a recommended phase II dose and schedule of LY2940680 (taladegib) for safe administration to patients with locally advanced/metastatic cancer.Experimental Design: This was a phase I, multicenter, open-label study of oral LY2940680. The maximum tolerable dose (MTD) was determined using a 3+3 design, the dose was confirmed, and then treatment naive and previously hedgehog (Hh)-inhibitor-treated patients with basal cell carcinoma (BCC) were enrolled.Results: Eighty-four patients were treated (dose escalation, n = 25; dose confirmation, n = 19; and BCC dose expansion, n = 40). Common treatment-emergent adverse events were dysgeusia [41 (48.8%)], fatigue [40 (47.6%)], nausea [38 (45.2%)], and muscle spasms [34 (40.5%)]. Four patients experienced events (3 were grade 3; 1 was grade 2) that were considered dose limiting toxicities (DLT). The MTD was determined to be 400 mg because of DLTs and dose reductions. Pharmacokinetic analyses showed no clear relationship between exposure and toxicity. Analysis of Gli1 mRNA from skin biopsies from unaffected areas suggested that all doses were biologically active [inhibition median of 92.3% (80.9% to 95.7%)]. All clinical responses (per RECIST 1.1) were in patients with BCC (n = 47); the overall and estimated response rate was 46.8% (95% confidence interval, 32.1%-61.9%). Responses were observed in patients previously treated with Hh therapy (11/31) and in Hh treatment-naive (11/16) patients.Conclusions: LY2940680 treatment resulted in an acceptable safety profile in patients with advanced/metastatic cancer. Clinical responses were observed in patients with locally advanced/metastatic BCC who were previously treated with Hh therapy and in Hh treatment-naive patients. Clin Cancer Res; 24(9); 2082-91. (c)2018 AACR. PMID- 29483145 TI - BBSome trains remove activated GPCRs from cilia by enabling passage through the transition zone. AB - A diffusion barrier at the transition zone enables the compartmentalization of signaling molecules by cilia. The BBSome and the small guanosine triphosphatase Arl6, which triggers BBSome coat polymerization, are required for the exit of activated signaling receptors from cilia, but how diffusion barriers are crossed when membrane proteins exit cilia remains to be determined. In this study, we found that activation of the ciliary G protein-coupled receptors (GPCRs) Smoothened and SSTR3 drove the Arl6-dependent assembly of large, highly processive, and cargo-laden retrograde BBSome trains. Single-molecule imaging revealed that the assembly of BBSome trains enables the lateral transport of ciliary GPCRs across the transition zone. However, the removal of activated GPCRs from cilia was inefficient because a second periciliary diffusion barrier was infrequently crossed. We conclude that exit from cilia is a two-step process in which BBSome/Arl6 trains first move activated GPCRs through the transition zone before a periciliary barrier can be crossed. PMID- 29483146 TI - Properties of Triheteromeric N-Methyl-d-Aspartate Receptors Containing Two Distinct GluN1 Isoforms. AB - N-Methyl-d-aspartate (NMDA)-type glutamate receptors mediate excitatory synaptic transmission in the central nervous system and play critical roles in many neuronal processes. The physiologic roles of NMDA receptors are shaped by their functional properties, which are highly dependent on subunit composition. Most NMDA receptors are assembled from two GluN1 and two GluN2 subunits, but diversity in subunit composition is made possible by eight GluN1 splice variants (i.e., isoforms) and four distinct GluN2 subunits (GluN2A-D). We demonstrate using Forster resonance energy transfer and fluorescence lifetime imaging that GluN1-1a and GluN1-1b isoforms, which include or lack residues encoded by exon 5, form triheteromeric GluN1-1a/GluN1-1b/GluN2A (1a/1b/2A) and GluN1-1a/GluN1-1b/GluN2B (1a/1b/2B) receptors. We describe the selective expression of NMDA receptors containing two different GluN1 isoforms, and show that triheteromeric 1a/1b/2A and 1a/1b/2B receptors exhibit intermediate deactivation kinetics and pharmacological properties compared with the respective diheteromeric GluN1 1a/GluN1-1a/GluN2 and GluN1-1b/GluN1-1b/GluN2 receptors. These results highlight the intriguing possibility that neurons can finely tune NMDA receptor signaling by shifting the ratio of expressed GluN1-1a and GluN1-1b isoforms. Furthermore, we evaluate the contribution of channel pore residues to magnesium block and calcium permeability. These data point to the asymmetric contribution of pore residues in GluN1 and GluN2 to magnesium block, and reveal that a single copy of pore residues from GluN3 subunits strongly attenuates magnesium block and calcium permeability of NMDA receptors. Thus, the selective expression of NMDA receptors containing two distinct GluN1 isoforms provides new opportunities to study functional properties relevant to neuronal receptors. PMID- 29483147 TI - Modulation of Plant Salicylic Acid-Associated Immune Responses via Glycosylation of Dihydroxybenzoic Acids. AB - Salicylic acid (SA) plays a crucial role in plant innate immunity. The deployment of SA-associated immune responses is primarily affected by SA concentration, which is determined by a balance between SA biosynthesis and catabolism. However, the mechanisms regulating SA homeostasis are poorly understood. In this study, we characterized a unique UDP-glycosyltransferase, UGT76D1, which plays an important role in SA homeostasis and associated immune responses in Arabidopsis (Arabidopsis thaliana). Expression of UGT76D1 was induced by treatment with both the pathogen Pseudomonas syringae pv. tomato (Pst) DC3000 and SA. Overexpression of UGT76D1 resulted in high SA accumulation, significant up-regulation of pathogen-related genes, and a hypersensitive response (HR)-like lesion mimic phenotype. This HR-like phenotype was not observed following UGT76D1 overexpression in SA-deficient NahG transgenic or sid2 plants, suggesting that the phenotype is SA dependent. Biochemical assays showed that UGT76D1 glycosylated 2,3-dihydroxybenzoic acid (2,3-DHBA) and 2,5-dihydroxybenzoic acid (2,5-DHBA), the major catabolic forms of SA, to their Glc and Xyl conjugates in vitro and in vivo. Moreover, in a mutant background blocked in the formation of 2,3-DHBA and 2,5-DHBA, UGT76D1 overexpression did not cause a HR-like lesion mimic phenotype. Following infection with Pst DC3000, UGT76D1 knockout mutants displayed a delayed immune response, with reduced levels of DHBA glycosides and SA, and down-regulated SA synthase expression. By contrast, UGT76D1 overexpression lines showed an enhanced immune response and increased SA biosynthesis before and after pathogen infection. Thus, we propose that UGT76D1 plays an important role in SA homeostasis and plant immune responses by facilitating glycosylation of dihydroxybenzoic acids. PMID- 29483148 TI - Be tick aware: when and where to check cats and dogs for ticks. PMID- 29483149 TI - Evidence of longer life; a cohort of 39 labrador retrievers. PMID- 29483150 TI - Serum creatinine levels and risk of incident type 2 diabetes mellitus or dysglycemia in middle-aged Japanese men: a retrospective cohort study. AB - OBJECTIVE: To assess the association between low serum creatinine levels and an increased risk of type 2 diabetes mellitus and dysglycemia. RESEARCH DESIGN AND METHODS: We conducted a retrospective cohort study of 3313 Japanese male workers aged 30-55 years, who underwent annual health check-ups during 2001-2008 and showed no type 2 diabetes mellitus, and underwent follow-up examinations until March 2013. Dysglycemia was defined as a fasting plasma glucose concentration of >=110 mg/dL (6.1 mmol/L), or a non-fasting plasma glucose concentration of >=140 mg/dL (7.8 mmol/L). A Cox proportional model was used to calculate HRs and 95% CIs for developing type 2 diabetes mellitus or dysglycemia. RESULTS: During the median 6.7-year follow-up, there were 207 cases of incident type 2 diabetes mellitus and 596 cases of incident dysglycemia, including 115 cases of type 2 diabetes mellitus among the subjects with normal glucose concentrations at baseline. After adjustment for age, body mass index and known diabetes risk factors, the multivariable HR of type 2 diabetes mellitus for the lowest category of serum creatinine (<0.7 mg/dL) vs the highest category (0.9-1.1 mg/dL) was 1.9 (95% CI 1.2 to 2.9; P for trend 0.03). The multivariable HRs of dysglycemia for the lowest category of serum creatinine versus the highest category was 1.5 (95% CI 1.1 to 1.9; P for trend 0.01). CONCLUSIONS: Low serum creatinine levels were associated with an increased risk of type 2 diabetes mellitus and dysglycemia. PMID- 29483151 TI - E-patients hold key to the future of healthcare. PMID- 29483152 TI - C. elegans ADARs antagonize silencing of cellular dsRNAs by the antiviral RNAi pathway. AB - Cellular dsRNAs are edited by adenosine deaminases that act on RNA (ADARs). While editing can alter mRNA-coding potential, most editing occurs in noncoding sequences, the function of which is poorly understood. Using dsRNA immunoprecipitation (dsRIP) and RNA sequencing (RNA-seq), we identified 1523 regions of clustered A-to-I editing, termed editing-enriched regions (EERs), in four stages of Caenorhabditis elegans development, often with highest expression in embryos. Analyses of small RNA-seq data revealed 22- to 23-nucleotide (nt) siRNAs, reminiscent of viral siRNAs, that mapped to EERs and were abundant in adr 1;adr-2 mutant animals. Consistent with roles for these siRNAs in silencing, EER associated genes (EAGs) were down-regulated in adr-1;adr-2 embryos, and this was dependent on associated EERs and the RNAi factor RDE-4. We observed that ADARs genetically interact with the 26G endogenous siRNA (endo-siRNA) pathway, which likely competes for RNAi components; deletion of factors required for this pathway (rrf-3 or ergo-1) in adr-1;adr-2 mutant strains caused a synthetic phenotype that was rescued by deleting antiviral RNAi factors. Poly(A)+ RNA-seq revealed EAG down-regulation and antiviral gene induction in adr-1;adr-2;rrf-3 embryos, and these expression changes were dependent on rde-1 and rde-4 Our data suggest that ADARs restrict antiviral silencing of cellular dsRNAs. PMID- 29483153 TI - Discoidin domain receptor 1 (DDR1) ablation promotes tissue fibrosis and hypoxia to induce aggressive basal-like breast cancers. AB - The discoidin domain receptor 1 (DDR1) is overexpressed in breast carcinoma cells. Low DDR1 expression is associated with worse relapse-free survival, reflecting its controversial role in cancer progression. We detected DDR1 on luminal cells but not on myoepithelial cells of DDR1+/+ mice. We found that DDR1 loss compromises cell adhesion, consistent with data that older DDR1-/- mammary glands had more basal/myoepithelial cells. Basal cells isolated from older mice exerted higher traction forces than the luminal cells, in agreement with increased mammary branches observed in older DDR1-/- mice and higher branching by their isolated organoids. When we crossed DDR1-/- mice with MMTV-PyMT mice, the PyMT/DDR1-/- mammary tumors grew faster and had increased epithelial tension and matricellular fibrosis with a more basal phenotype and increased lung metastases. DDR1 deletion induced basal differentiation of CD90+CD24+ cancer cells, and the increase in basal cells correlated with tumor cell mitoses. K14+ basal cells, including K8+K14+ cells, were increased adjacent to necrotic fields. These data suggest that the absence of DDR1 provides a growth and adhesion advantage that favors the expansion of basal cells, potentiates fibrosis, and enhances necrosis/hypoxia and basal differentiation of transformed cells to increase their aggression and metastatic potential. PMID- 29483154 TI - Transcription elongation rate affects nascent histone pre-mRNA folding and 3' end processing. AB - Transcription elongation rate influences cotranscriptional pre-mRNA maturation, but how such kinetic coupling works is poorly understood. The formation of nonadenylated histone mRNA 3' ends requires recognition of an RNA structure by stem-loop-binding protein (SLBP). We report that slow transcription by mutant RNA polymerase II (Pol II) caused accumulation of polyadenylated histone mRNAs that extend past the stem-loop processing site. UV irradiation, which decelerates Pol II elongation, also induced long poly(A)+ histone transcripts. Inhibition of 3' processing by slow Pol II correlates with failure to recruit SLBP to histone genes. Chemical probing of nascent RNA structure showed that the stem-loop fails to fold in transcripts made by slow Pol II, thereby explaining the absence of SLBP and failure to process 3' ends. These results show that regulation of transcription speed can modulate pre-mRNA processing by changing nascent RNA structure and suggest a mechanism by which alternative processing could be controlled. PMID- 29483155 TI - A mechanism for epigenetic control of DNA replication. AB - DNA replication origins in hyperacetylated euchromatin fire preferentially during early S phase. However, how acetylation controls DNA replication timing is unknown. TICRR/TRESLIN is an essential protein required for the initiation of DNA replication. Here, we report that TICRR physically interacts with the acetyl histone binding bromodomain (BRD) and extraterminal (BET) proteins BRD2 and BRD4. Abrogation of this interaction impairs TICRR binding to acetylated chromatin and disrupts normal S-phase progression. Our data reveal a novel function for BET proteins and establish the TICRR-BET interaction as a potential mechanism for epigenetic control of DNA replication. PMID- 29483156 TI - NBCe1-A Regulates Proximal Tubule Ammonia Metabolism under Basal Conditions and in Response to Metabolic Acidosis. AB - Renal ammonia metabolism is the primary mechanism through which the kidneys maintain acid-base homeostasis, but the molecular mechanisms regulating renal ammonia generation are unclear. In these studies, we evaluated the role of the proximal tubule basolateral plasma membrane electrogenic sodium bicarbonate cotransporter 1 variant A (NBCe1-A) in this process. Deletion of the NBCe1-A gene caused severe spontaneous metabolic acidosis in mice. Despite this metabolic acidosis, which normally causes a dramatic increase in ammonia excretion, absolute urinary ammonia concentration was unaltered. Additionally, NBCe1-A deletion almost completely blocked the ability to increase ammonia excretion after exogenous acid loading. Under basal conditions and during acid loading, urine pH was more acidic in mice with NBCe1-A deletion than in wild-type controls, indicating that the abnormal ammonia excretion was not caused by a primary failure of urine acidification. Instead, NBCe1-A deletion altered the expression levels of multiple enzymes involved in proximal tubule ammonia generation, including phosphate-dependent glutaminase, phosphoenolpyruvate carboxykinase, and glutamine synthetase, under basal conditions and after exogenous acid loading. Deletion of NBCe1-A did not impair expression of key proteins involved in collecting duct ammonia secretion. These studies demonstrate that the integral membrane protein NBCe1-A has a critical role in basal and acidosis-stimulated ammonia metabolism through the regulation of proximal tubule ammonia-metabolizing enzymes. PMID- 29483157 TI - Mechanism of Hyperkalemia-Induced Metabolic Acidosis. AB - Background Hyperkalemia in association with metabolic acidosis that are out of proportion to changes in glomerular filtration rate defines type 4 renal tubular acidosis (RTA), the most common RTA observed, but the molecular mechanisms underlying the associated metabolic acidosis are incompletely understood. We sought to determine whether hyperkalemia directly causes metabolic acidosis and, if so, the mechanisms through which this occurs.Methods We studied a genetic model of hyperkalemia that results from early distal convoluted tubule (DCT) specific overexpression of constitutively active Ste20/SPS1-related proline alanine-rich kinase (DCT-CA-SPAK).Results DCT-CA-SPAK mice developed hyperkalemia in association with metabolic acidosis and suppressed ammonia excretion; however, titratable acid excretion and urine pH were unchanged compared with those in wild type mice. Abnormal ammonia excretion in DCT-CA-SPAK mice associated with decreased proximal tubule expression of the ammonia-generating enzymes phosphate dependent glutaminase and phosphoenolpyruvate carboxykinase and overexpression of the ammonia-recycling enzyme glutamine synthetase. These mice also had decreased expression of the ammonia transporter family member Rhcg and decreased apical polarization of H+-ATPase in the inner stripe of the outer medullary collecting duct. Correcting the hyperkalemia by treatment with hydrochlorothiazide corrected the metabolic acidosis, increased ammonia excretion, and normalized ammoniagenic enzyme and Rhcg expression in DCT-CA-SPAK mice. In wild-type mice, induction of hyperkalemia by administration of the epithelial sodium channel blocker benzamil caused hyperkalemia and suppressed ammonia excretion.Conclusions Hyperkalemia decreases proximal tubule ammonia generation and collecting duct ammonia transport, leading to impaired ammonia excretion that causes metabolic acidosis. PMID- 29483158 TI - IL-17C/IL-17 Receptor E Signaling in CD4+ T Cells Promotes TH17 Cell-Driven Glomerular Inflammation. AB - The IL-17 cytokine family and the cognate receptors thereof have a unique role in organ-specific autoimmunity. Most studies have focused on the founding member of the IL-17 family, IL-17A, as the central mediator of diseases. Indeed, although pathogenic functions have been ascribed to IL-17A and IL-17F in the context of immune-mediated glomerular diseases, the specific functions of the other IL-17 family members in immunity and inflammatory kidney diseases is largely unknown. Here, we report that compared with healthy controls, patients with acute Anti neutrophil cytoplasmatic antibody (ANCA)-associated crescentic glomerulonephritis (GN) had significantly elevated serum levels of IL-17C (but not IL-17A, F, or E). In mouse models of crescentic GN (nephrotoxic nephritis) and pristane-induced lupus nephritis, deficiency in IL-17C significantly ameliorated the course of GN in terms of renal tissue injury and kidney function. Deficiency of the unique IL 17C receptor IL-17 receptor E (IL-17RE) provided similar protection against crescentic GN. These protective effects associated with a reduced TH17 response. Bone marrow transplantation experiments revealed that IL-17C is produced by tissue-resident cells, but not by lymphocytes. Finally, IL-17RE was highly expressed by CD4+ TH17 cells, and loss of this expression prevented the TH17 responses and subsequent tissue injury in crescentic GN. Our findings indicate that IL-17C promotes TH17 cell responses and immune-mediated kidney disease via IL-17RE expressed on CD4+ TH17 cells. Targeting the IL-17C/IL-17RE pathway may present an intriguing therapeutic strategy for TH17-induced autoimmune disorders. PMID- 29483160 TI - Oxygen-permeable microwell device maintains islet mass and integrity during shipping. AB - Islet transplantation is currently the only minimally invasive therapy available for patients with type 1 diabetes that can lead to insulin independence; however, it is limited to only a small number of patients. Although clinical procedures have improved in the isolation and culture of islets, a large number of islets are still lost in the pre-transplant period, limiting the success of this treatment. Moreover, current practice includes islets being prepared at specialized centers, which are sometimes remote to the transplant location. Thus, a critical point of intervention to maintain the quality and quantity of isolated islets is during transportation between isolation centers and the transplanting hospitals, during which 20-40% of functional islets can be lost. The current study investigated the use of an oxygen-permeable PDMS microwell device for long distance transportation of isolated islets. We demonstrate that the microwell device protected islets from aggregation during transport, maintaining viability and average islet size during shipping. PMID- 29483159 TI - Growth Hormone Research Society perspective on biomarkers of GH action in children and adults. AB - OBJECTIVE: The Growth Hormone Research Society (GRS) convened a Workshop in 2017 to evaluate clinical endpoints, surrogate endpoints and biomarkers during GH treatment of children and adults and in patients with acromegaly. PARTICIPANTS: GRS invited 34 international experts including clinicians, basic scientists, a regulatory scientist and physicians from the pharmaceutical industry. EVIDENCE: Current literature was reviewed and expert opinion was utilized to establish the state of the art and identify current gaps and unmet needs. CONSENSUS PROCESS: Following plenary presentations, breakout groups discussed questions framed by the planning committee. The attendees re-convened after each breakout session to share the group reports. A writing team compiled the breakout session reports into a document that was subsequently discussed and revised by participants. This was edited further and circulated for final review after the meeting. Participants from pharmaceutical companies were not part of the writing process. CONCLUSIONS: The clinical endpoint in paediatric GH treatment is adult height with height velocity as a surrogate endpoint. Increased life expectancy is the ideal but unfeasible clinical endpoint of GH treatment in adult GH-deficient patients (GHDA) and in patients with acromegaly. The pragmatic clinical endpoints in GHDA include normalization of body composition and quality of life, whereas symptom relief and reversal of comorbidities are used in acromegaly. Serum IGF-I is widely used as a biomarker, even though it correlates weakly with clinical endpoints in GH treatment, whereas in acromegaly, normalization of IGF-I may be related to improvement in mortality. There is an unmet need for novel biomarkers that capture the pleiotropic actions of GH in relation to GH treatment and in patients with acromegaly. PMID- 29483161 TI - Regulatory Role of an Interdomain Linker in the Bacterial Chemotaxis Histidine Kinase CheA. AB - The histidine kinase CheA plays a central role in signal integration, conversion, and amplification in the bacterial chemotaxis signal transduction pathway. The kinase activity is regulated in chemotaxis signaling complexes formed via the interactions among CheA's regulatory domain (P5), the coupling protein CheW, and transmembrane chemoreceptors. Despite recent advancements in the understanding of the architecture of the signaling complex, the molecular mechanism underlying this regulation remains elusive. An interdomain linker that connects the catalytic (P4) and regulatory domains of CheA may mediate regulatory signals from the P5-CheW-receptor interactions to the catalytic domain. To investigate whether this interdomain linker is capable of both activating and inhibiting CheA, we performed in vivo screens to search for P4-P5 linker mutations that result in different CheA autokinase activities. Several CheA variants were identified with kinase activities ranging from 30% to 670% of the activity of wild-type CheA. All of these CheA variants were defective in receptor-mediated kinase activation, indicating that the natural receptor-mediated signal transmission pathway was simultaneously affected by these mutations. The altered P4-P5 linkers were sufficient for making significant changes in the kinase activity even in the absence of the P5 domain. Therefore, the interdomain linker is an active module that has the ability to impose regulatory effects on the catalytic activity of the P4 domain. These results suggest that chemoreceptors may manipulate the conformation of the P4-P5 linker to achieve CheA regulation in the platform of the signaling complex.IMPORTANCE The molecular mechanism underlying kinase regulation in bacterial chemotaxis signaling complexes formed by the regulatory domain of the histidine kinase CheA, the coupling protein CheW, and chemoreceptors is still unknown. We isolated and characterized mutations in the interdomain linker that connects the catalytic and regulatory domains of CheA and found that the linker mutations resulted in different CheA autokinase activities in the absence and presence of the regulatory domain as well as a defect in receptor-mediated kinase activation. These results demonstrate that the interdomain linker is an active module that has the ability to impose regulatory effects on CheA activity. Chemoreceptors may manipulate the conformation of this interdomain linker to achieve CheA regulation in the platform of the signaling complex. PMID- 29483162 TI - PhdA Catalyzes the First Step of Phenazine-1-Carboxylic Acid Degradation in Mycobacterium fortuitum. AB - Phenazines are a class of bacterially produced redox-active metabolites that are found in natural, industrial, and clinical environments. In Pseudomonas spp., phenazine-1-carboxylic acid (PCA)-the precursor of all phenazine metabolites facilitates nutrient acquisition, biofilm formation, and competition with other organisms. While the removal of phenazines negatively impacts these activities, little is known about the genes or enzymes responsible for phenazine degradation by other organisms. Here, we report that the first step of PCA degradation by Mycobacterium fortuitum is catalyzed by a phenazine-degrading decarboxylase (PhdA). PhdA is related to members of the UbiD protein family that rely on a prenylated flavin mononucleotide cofactor for activity. The gene for PhdB, the enzyme responsible for cofactor synthesis, is present in a putative operon with the gene encoding PhdA in a region of the M. fortuitum genome that is essential for PCA degradation. PhdA and PhdB are present in all known PCA-degrading organisms from the ActinobacteriaM. fortuitum can also catabolize other Pseudomonas-derived phenazines such as phenazine-1-carboxamide, 1 hydroxyphenazine, and pyocyanin. On the basis of our previous work and the current characterization of PhdA, we propose that degradation converges on a common intermediate: dihydroxyphenazine. An understanding of the genes responsible for degradation will enable targeted studies of phenazine degraders in diverse environments.IMPORTANCE Bacteria from phylogenetically diverse groups secrete redox-active metabolites that provide a fitness advantage for their producers. For example, phenazines from Pseudomonas spp. benefit the producers by facilitating anoxic survival and biofilm formation and additionally inhibit competitors by serving as antimicrobials. Phenazine-producing pseudomonads act as biocontrol agents by leveraging these antibiotic properties to inhibit plant pests. Despite this importance, the fate of phenazines in the environment is poorly understood. Here, we characterize an enzyme from Mycobacterium fortuitum that catalyzes the first step of phenazine-1-carboxylic acid degradation. Knowledge of the genetic basis of phenazine degradation will facilitate the identification of environments where this activity influences the microbial community structure. PMID- 29483163 TI - A self-assembling whole cell vaccine antigen presentation platform. AB - Diarrhea is the most common infection in children under the age of five worldwide. In spite of this, only a few vaccines to treat infectious diarrhea exist, and many of the available vaccines are sparingly and sporadically administered. Major obstacles to the development and widespread implementation of vaccination include the ease and cost of production, distribution, and delivery. Here we present a novel, customizable and self-assembling vaccine platform that exploits the Vibrio cholerae bacterial biofilm matrix for antigen presentation. We use this technology to create a proof-of-concept, live-attenuated whole cell vaccine that is boosted by spontaneous association of a secreted protein antigen with the cell surface. Sublingual administration of this live-attenuated vaccine to mice confers protection against V. cholerae challenge and elicits production of antigen-specific stool IgA. The platform presented here enables development of antigen-boosted vaccines that are simple to produce and deliver, addressing many of the obstacles to vaccination against diarrheal diseases. This may also serve as a paradigm for the development of broadly protective, biofilm-based vaccines against other mucosal infections.Importance Diarrheal disease is the most common infection afflicting children worldwide. In resource-poor settings, these infections are correlated with cognitive delay, stunted growth, and premature death. With the development of efficacious, affordable, and easily administered vaccines, such infections could be prevented. While a major focus of biofilm research has been their elimination, here we harness the bacterial biofilm to create a customizable platform for cost-effective, whole cell mucosal vaccines that self-incorporate secreted protein antigens. We use this platform to develop a sublingually administered, live-attenuated prototype vaccine based on Vibrio cholerae. This serves not only as a proof-of-concept for a multivalent vaccine against common bacterial enteric pathogens but also as a paradigm for vaccines utilizing other bacterial biofilms to target mucosal infections. PMID- 29483166 TI - The 24th Annual Midwest Microbial Pathogenesis Meeting. AB - The 24th Annual Midwest Microbial Pathogenesis Conference (MMPC) was held at the University of Notre Dame from August 25-27, 2017. The conference provided an opportunity for scientists from the Midwest to discuss new advances in microbial pathogenesis, including how pathogens promote disease, and how they interact with each other, the microbiome and the host. This commentary highlights the MMPC history, the topics presented at the conference and the reports in this issue. PMID- 29483165 TI - Electron transfer to nitrogenase in different genomic and metabolic backgrounds. AB - Nitrogenase catalyzes the reduction of dinitrogen (N2) using low potential electrons from ferredoxin (Fd) or flavodoxin (Fld) through an ATP dependent process. Since its emergence in an anaerobic chemoautotroph, this oxygen (O2) sensitive enzyme complex has evolved to operate in a variety of genomic and metabolic backgrounds including those of aerobes, anaerobes, chemotrophs, and phototrophs. However, whether pathways of electron delivery to nitrogenase are influenced by these different metabolic backgrounds is not well understood. Here, we report the distribution of homologs of Fds, Flds, and Fd/Fld-reducing enzymes in 359 genomes of putative N2 fixers (diazotrophs). Six distinct lineages of nitrogenase were identified and their distributions largely corresponded to differences in the host cells' ability to integrate O2 or light into energy metabolism. Predicted pathways of electron transfer to nitrogenase in aerobes, facultative anaerobes, and phototrophs varied from those in anaerobes at the level of Fds/Flds used to reduce nitrogenase, the enzymes that generate reduced Fds/Flds, and the putative substrates of these enzymes. Proteins that putatively reduce Fd with hydrogen or pyruvate were enriched in anaerobes, while those that reduce Fd with NADH/NADPH were enriched in aerobes, facultative anaerobes, and anoxygenic phototrophs. The energy metabolism of aerobic, facultatively anaerobic, and anoxygenic phototrophic diazotrophs often yields reduced NADH/NADPH that is not sufficiently reduced to drive N2 reduction. At least two mechanisms have been acquired by these taxa to overcome this limitation and to generate electrons with potentials capable of reducing Fd. These include the bifurcation of electrons or the coupling of Fd reduction to reverse ion translocation.IMPORTANCE Nitrogen fixation supplies fixed nitrogen to cells from a variety of genomic and metabolic backgrounds including those of aerobes, facultative anaerobes, chemotrophs, and phototrophs. Here, using informatics approaches applied to genomic data, we show that pathways of electron transfer to nitrogenase in metabolically diverse diazotrophic taxa have diversified primarily in response to host cells' acquired ability to integrate O2 or light into their energy metabolism. Acquisition of two key enzyme complexes enabled aerobic and facultatively anaerobic phototrophic taxa to generate electrons of sufficiently low potential to reduce nitrogenase: the bifurcation of electrons via the Fix complex or the coupling of Fd reduction to reverse ion translocation via the Rhodobacter nitrogen fixation (Rnf) complex. PMID- 29483164 TI - The many lives of nontuberculous mycobacteria. AB - Nontuberculous mycobacteria (NTM) include species that colonize human epithelia, as well as species that are ubiquitous in soil and aquatic environments. NTM that primarily inhabit soil and aquatic environments include the Mycobacterium avium complex (MAC, M. avium and Mycobacterium intracellulare) and the Mycobacterium abscessus complex (MABSC, M. abscessus subspecies abscessus, massiliense, and bolletii), and can be free-living, biofilm-associated, or amoeba-associated. Although NTM are rarely pathogenic in immunocompetent individuals, those who are immunocompromised - due to either an inherited or acquired immunodeficiency - are highly susceptible to NTM infection (NTMI). Several characteristics such as biofilm formation and the ability of select NTM species to form distinct colony morphotypes all may play a role in pathogenesis not observed in the related, well characterized pathogen Mycobacterium tuberculosis The recognition of different morphotypes of NTM has been established and characterized since the 1950s, but the mechanisms that underlie colony phenotype change and subsequent differences in pathogenicity are just beginning to be explored. Advances in genomic analysis have led to progress in identifying genes important to the pathogenesis and persistence of MAC disease as well as illuminating genetic aspects of different colony morphotypes. Here we review recent literature regarding NTM ecology and transmission, as well as the factors which regulate colony morphotype and pathogenicity. PMID- 29483168 TI - Global Impact of the 2017 American College of Cardiology/American Heart Association Hypertension Guidelines: A Perspective From Canada. PMID- 29483167 TI - Stress Suppressor Screening Leads to Detection of Regulation of Cyclic di-AMP Homeostasis by a Trk Family Effector Protein in Streptococcus pneumoniae. AB - Cyclic di-AMP (c-di-AMP) is a newly discovered bacterial second messenger. However, regulation of c-di-AMP homeostasis is poorly understood. In Streptococcus pneumoniae, a sole diadenylate cyclase, CdaA, produces c-di-AMP and two phosphodiesterases, Pde1 and Pde2, cleave the signaling dinucleotide. To expand our knowledge of the pneumococcal c-di-AMP signaling network, we performed whole-genome sequencing of Deltapde1 Deltapde2 heat shock suppressors. In addition to their effects on surviving heat shock, these suppressor mutations restored general stress resistance and improved growth in rich medium. Mutations in CdaA or in the potassium transporter TrkH paired with an insertion leading to a frameshift at the C terminus of CdaA significantly reduced c-di-AMP levels. These observations indicate that the elevated c-di-AMP levels in the Deltapde1 Deltapde2 mutant enhance susceptibility of S. pneumoniae to the stress conditions. Interestingly, we have previously shown that TrkH complexes with a Trk family c-di-AMP-binding protein, CabP, to mediate potassium uptake. In this study, we found that deletion of cabP significantly reduced pneumococcal c-di-AMP levels. This is the first observation that a c-di-AMP effector protein modulates bacterial c-di-AMP homeostasis.IMPORTANCE Second messengers, including c-di-AMP, are prevalent among bacterial species. In S. pneumoniae, c-di-AMP phosphodiesterase-encoding gene null mutants are attenuated during mouse models of infection, but the role of c-di-AMP signaling in pneumococcal pathogenesis is enigmatic. In this work, we found that heat shock suppressor mutations converge on undermining c-di-AMP toxicity by changing intracellular c-di-AMP concentrations. These mutations improve the growth and restore the stress response generally in c-di-AMP phosphodiesterase-deficient pneumococci, thereby demonstrating the essentiality for tight regulation of c-di-AMP homeostasis in order to respond to stress. Likewise, this work demonstrates that a c-di-AMP effector protein, CabP, affects c-di-AMP homeostasis, which provides new perception into c-di-AMP regulation. This study has implications for c-di-AMP producing bacteria since many species contain CabP homologs. PMID- 29483169 TI - Perspective From Sweden on the Global Impact of the 2017 American College of Cardiology/American Heart Association Hypertension Guidelines: A "Sprint" Beyond Evidence in the United States. PMID- 29483170 TI - Global Impact of the 2017 American College of Cardiology/American Heart Association Hypertension Guidelines: A Perspective From Italy. PMID- 29483171 TI - Autonomic Nervous System in Pulmonary Arterial Hypertension: Time to Rest and Digest. PMID- 29483173 TI - Gene-Editing Technology Accelerates Cardiovascular Research: Clinical Applications Being Explored. PMID- 29483172 TI - 2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials. AB - This publication describes uniform definitions for cardiovascular and stroke outcomes developed by the Standardized Data Collection for Cardiovascular Trials Initiative and the US Food and Drug Administration (FDA). The FDA established the Standardized Data Collection for Cardiovascular Trials Initiative in 2009 to simplify the design and conduct of clinical trials intended to support marketing applications. The writing committee recognizes that these definitions may be used in other types of clinical trials and clinical care processes where appropriate. Use of these definitions at the FDA has enhanced the ability to aggregate data within and across medical product development programs, conduct meta-analyses to evaluate cardiovascular safety, integrate data from multiple trials, and compare effectiveness of drugs and devices. Further study is needed to determine whether prospective data collection using these common definitions improves the design, conduct, and interpretability of the results of clinical trials. PMID- 29483174 TI - Reduced Blood Lipid Levels With In Vivo CRISPR-Cas9 Base Editing of ANGPTL3. PMID- 29483175 TI - Outcomes of Patients With Hypoplastic Left Heart Syndrome Reaching Adulthood After Fontan Palliation: Multicenter Study. PMID- 29483176 TI - Letter by Tampaki et al Regarding Article, "Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors)". PMID- 29483177 TI - Letter by Koh Regarding Article, "Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors)". PMID- 29483178 TI - Letter by Taegtmeyer and Karlstaedt Regarding Article, "Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors)". PMID- 29483179 TI - Letter by Jin-shan and Xue-bin Regarding Article, "Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors)". PMID- 29483180 TI - Response by Kosiborod et al to Letters Regarding Article, "Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors)". PMID- 29483181 TI - Publishing in an ASPET Journal - What's in It for You? PMID- 29483182 TI - A Novel Strategy to Prevent Advanced Atherosclerosis and Lower Blood Glucose in a Mouse Model of Metabolic Syndrome. AB - Cardiovascular disease caused by atherosclerosis is the leading cause of mortality associated with type 2 diabetes and metabolic syndrome. Insulin therapy is often needed to improve glycemic control, but it does not clearly prevent atherosclerosis. Upon binding to the insulin receptor (IR), insulin activates distinct arms of downstream signaling. The IR-Akt arm is associated with blood glucose lowering and beneficial effects, whereas the IR-Erk arm might exert less desirable effects. We investigated whether selective activation of the IR-Akt arm, leaving the IR-Erk arm largely inactive, would result in protection from atherosclerosis in a mouse model of metabolic syndrome. The insulin mimetic peptide S597 lowered blood glucose and activated Akt in insulin target tissues, mimicking insulin's effects, but only weakly activated Erk and even prevented insulin-induced Erk activation. Strikingly, S597 retarded atherosclerotic lesion progression through a process associated with protection from leukocytosis, thereby reducing lesional accumulation of inflammatory Ly6Chi monocytes. S597 mediated protection from leukocytosis was accompanied by reduced numbers of the earliest bone marrow hematopoietic stem cells and reduced IR-Erk activity in hematopoietic stem cells. This study provides a conceptually novel treatment strategy for advanced atherosclerosis associated with metabolic syndrome and type 2 diabetes. PMID- 29483184 TI - Childhood BMI and Adult Type 2 Diabetes, Coronary Artery Diseases, Chronic Kidney Disease, and Cardiometabolic Traits: A Mendelian Randomization Analysis. AB - OBJECTIVE: To test the causal effect of childhood BMI on adult cardiometabolic diseases using a Mendelian randomization analysis. RESEARCH DESIGN AND METHODS: We used 15 single nucleotide polymorphisms as instrumental variables for childhood BMI to test the causal effect of childhood BMI on cardiometabolic diseases using summary-level data from consortia. RESULTS: We found that a 1-SD increase in childhood BMI (kg/m2) was associated with an 83% increase in risk of type 2 diabetes (odds ratio [OR] 1.83 [95% CI 1.46, 2.30]; P = 2.5 * 10-7) and a 28% increase in risk of coronary artery disease (CAD) (OR 1.28 [95% CI 1.17, 1.39]; P = 2.1 * 10-8) at the Bonferroni-adjusted level of significance (P < 0.017) in adults. In addition, a 1-SD increase in childhood BMI was associated with a 0.587-SD increase in adulthood BMI (kg/m2), a 0.062-SD increase in hip circumference (cm), a 0.602-SD increase in waist circumference (cm), a 0.111 pmol/L increase in log fasting insulin, a 0.068 increase in log-transformed HOMA of beta-cell function (%), a 0.126 increase in log-transformed HOMA of insulin resistance (%), and a 0.109-SD increase in triglyceride (mg/dL) but a 0.138-SD decrease in HDL (mg/dL) in adults at the Bonferroni-adjusted level of significance (P < 0.0026). CONCLUSIONS: A genetic predisposition to higher childhood BMI was associated with increased risk of type 2 diabetes and CAD in adult life. These results provide evidence supportive of a causal association between childhood BMI and these outcomes. PMID- 29483183 TI - HLA-B*07, HLA-DRB1*07, HLA-DRB1*12, and HLA-C*03:02 Strongly Associate With BMI: Data From 1.3 Million Healthy Chinese Adults. AB - Strong associations between HLA alleles and infectious and autoimmune diseases are well established. Although obesity is also associated with these diseases, the relationship between HLA and obesity has not been systematically investigated in a large cohort. In the current study, we analyzed the association of HLA alleles with BMI using data from 1.3 million healthy adult donors from the Chinese Marrow Donor Program (CMDP). We found 23 HLA alleles, including 12 low resolution and 11 high-resolution alleles, were significantly associated with BMI after correction for multiple testing. Alleles associated with high BMI were enriched in haplotypes that were common in both Chinese and European populations, whereas the alleles associated with low BMI were enriched in haplotypes common only in Asians. Alleles B*07, DRB1*07, DRB1*12, and C*03:02 provided the strongest associations with BMI (P = 6.89 * 10-10, 1.32 * 10-9, 1.52 * 10-9, and 4.45 * 10-8, respectively), where B*07 and DRB1*07 also had evidence for sex specific effects (Pheterogeneity = 0.0067 and 0.00058, respectively). These results, which identify associations between alleles of HLA-B, DRB1, and C with BMI in Chinese young adults, implicate a novel biological connection between HLA alleles and obesity. PMID- 29483186 TI - Erratum: Cellular and Molecular Mechanisms of Centromere Drive. PMID- 29483185 TI - Efficacy and Safety of IDegLira Versus Basal-Bolus Insulin Therapy in Patients With Type 2 Diabetes Uncontrolled on Metformin and Basal Insulin: The DUAL VII Randomized Clinical Trial. AB - OBJECTIVE: In patients with uncontrolled type 2 diabetes on basal insulin, prandial insulin may be initiated. We assessed the efficacy and safety of initiating insulin degludec/liraglutide fixed-ratio combination (IDegLira) versus basal-bolus insulin. RESEARCH DESIGN AND METHODS: A phase 3b trial examined patients with uncontrolled type 2 diabetes on insulin glargine (IGlar U100) 20-50 units/day and metformin, randomized to IDegLira or IGlar U100 and insulin aspart <=4 times per day. RESULTS: Glycated hemoglobin (HbA1c) decreased from 8.2% (66 mmol/mol) to 6.7% (50 mmol/mol) with IDegLira and from 8.2% (67 mmol/mol) to 6.7% (50 mmol/mol) with basal-bolus (estimated treatment difference [ETD] -0.02% [95% CI -0.16, 0.12]; -0.2 mmol/mol [95% CI -1.7, 1.3]), confirming IDegLira noninferiority versus basal-bolus (P < 0.0001). The number of severe or blood glucose-confirmed symptomatic hypoglycemia events was lower with IDegLira versus basal-bolus (risk ratio 0.39 [95% CI 0.29, 0.51]; rate ratio 0.11 [95% CI 0.08, 0.17]). Body weight decreased with IDegLira and increased with basal-bolus (ETD 3.6 kg [95% CI -4.2, -2.9]). Fasting plasma glucose reductions were similar; lunch, dinner, and bedtime self-monitored plasma glucose measurements were significantly lower with basal-bolus. Sixty-six percent of patients on IDegLira vs. 67.0% on basal-bolus achieved HbA1c <7.0% (53 mmol/mol). Total daily insulin dose was lower with IDegLira (40 units) than basal-bolus (84 units total; 52 units basal). CONCLUSIONS: In patients with uncontrolled type 2 diabetes on IGlar U100 and metformin, IDegLira treatment elicited HbA1c reductions comparable to basal-bolus, with statistically superior lower hypoglycemia rates and weight loss versus weight gain. PMID- 29483187 TI - Comparative and integrative metabolomics reveal that S-nitrosation inhibits physiologically relevant metabolic enzymes. AB - Cysteine S-nitrosation is a reversible post-translational modification mediated by nitric oxide (*NO)-derived agents. S-Nitrosation participates in cellular signaling and is associated with several diseases such as cancer, cardiovascular diseases, and neuronal disorders. Despite the physiological importance of this nonclassical *NO-signaling pathway, little is understood about how much S nitrosation affects protein function. Moreover, identifying physiologically relevant targets of S-nitrosation is difficult because of the dynamics of transnitrosation and a limited understanding of the physiological mechanisms leading to selective protein S-nitrosation. To identify proteins whose activities are modulated by S-nitrosation, we performed a metabolomics study comparing WT and endothelial nitric-oxide synthase knockout mice. We integrated our results with those of a previous proteomics study that identified physiologically relevant S-nitrosated cysteines, and we found that the activity of at least 21 metabolic enzymes might be regulated by S-nitrosation. We cloned, expressed, and purified four of these enzymes and observed that S-nitrosation inhibits the metabolic enzymes 6-phosphogluconate dehydrogenase, Delta1-pyrroline-5 carboxylate dehydrogenase, catechol-O-methyltransferase, and d-3-phosphoglycerate dehydrogenase. Furthermore, using site-directed mutagenesis, we identified the predominant cysteine residue influencing the observed activity changes in each enzyme. In summary, using an integrated metabolomics approach, we have identified several physiologically relevant S-nitrosation targets, including metabolic enzymes, which are inhibited by this modification, and we have found the cysteines modified by S-nitrosation in each enzyme. PMID- 29483188 TI - A step-by-step in crystallo guide to bond cleavage and 1,6-anhydro-sugar product synthesis by a peptidoglycan-degrading lytic transglycosylase. AB - Lytic transglycosylases (LTs) are a class of enzymes important for the recycling and metabolism of peptidoglycan (PG). LTs cleave the beta-1,4-glycosidic bond between N-acetylmuramic acid (MurNAc) and GlcNAc in the PG glycan strand, resulting in the concomitant formation of 1,6-anhydro-N-acetylmuramic acid and GlcNAc. No LTs reported to date have utilized chitins as substrates, despite the fact that chitins are GlcNAc polymers linked via beta-1,4-glycosidic bonds, which are the known site of chemical activity for LTs. Here, we demonstrate enzymatically that LtgA, a non-canonical, substrate-permissive LT from Neisseria meningitidis utilizes chitopentaose ((GlcNAc)5) as a substrate to produce three newly identified sugars: 1,6-anhydro-chitobiose, 1,6-anhydro-chitotriose, and 1,6 anhydro-chitotetraose. Although LTs have been widely studied, their complex reactions have not previously been visualized in the crystalline state because macromolecular PG is insoluble. Here, we visualized the cleavage of the glycosidic bond and the liberation of GlcNAc-derived residues by LtgA, followed by the synthesis of atypical 1,6-anhydro-GlcNAc derivatives. In addition to the newly identified anhydro-chitin products, we identified trapped intermediates, unpredicted substrate rearrangements, sugar distortions, and a conserved crystallographic water molecule bound to the catalytic glutamate of a high resolution native LT. This study enabled us to propose a revised alternative mechanism for LtgA that could also be applicable to other LTs. Our work contributes to the understanding of the mechanisms of LTs in bacterial cell wall biology. PMID- 29483189 TI - Deletion of the neural tube defect-associated gene Mthfd1l disrupts one-carbon and central energy metabolism in mouse embryos. AB - One-carbon (1C) metabolism is a universal folate-dependent pathway essential for de novo purine and thymidylate synthesis, amino acid interconversion, universal methyl-donor production, and regeneration of redox cofactors. Homozygous deletion of the 1C pathway gene Mthfd1l encoding methylenetetrahydrofolate dehydrogenase (NADP+-dependent) 1-like, which catalyzes mitochondrial formate production from 10-formyltetrahydrofolate, results in 100% penetrant embryonic neural tube defects (NTDs), underscoring the central role of mitochondrially derived formate in embryonic development and providing a mechanistic link between folate and NTDs. However, the specific metabolic processes that are perturbed by Mthfd1l deletion are not known. Here, we performed untargeted metabolomics on whole Mthfd1l-null and wildtype mouse embryos in combination with isotope tracer analysis in mouse embryonic fibroblast (MEF) cell lines to identify Mthfd1l deletion-induced disruptions in 1C metabolism, glycolysis, and the TCA cycle. We found that maternal formate supplementation largely corrects these disruptions in Mthfd1l-null embryos. Serine tracer experiments revealed that Mthfd1l-null MEFs have altered methionine synthesis, indicating that Mthfd1l deletion impairs the methyl cycle. Supplementation of Mthfd1l-null MEFs with formate, hypoxanthine, or combined hypoxanthine and thymidine restored their growth to wildtype levels. Thymidine addition alone was ineffective, suggesting a purine synthesis defect in Mthfd1l-null MEFs. Tracer experiments also revealed lower proportions of labeled hypoxanthine and inosine monophosphate in Mthfd1l-null than in wildtype MEFs, suggesting that Mthfd1l deletion results in increased reliance on the purine salvage pathway. These results indicate that disruptions of mitochondrial 1C metabolism have wide-ranging consequences for many metabolic processes, including those that may not directly interact with 1C metabolism. PMID- 29483191 TI - A biparatopic agonistic antibody that mimics fibroblast growth factor 21 ligand activity. AB - Bispecific antibodies have become important formats for therapeutic discovery. They allow for potential synergy by simultaneously engaging two separate targets and enable new functions that are not possible to achieve by using a combination of two monospecific antibodies. Antagonistic antibodies dominate drug discovery today, but only a limited number of agonistic antibodies (i.e. those that activate receptor signaling) have been described. For receptors formed by two components, engaging both of these components simultaneously may be required for agonistic signaling. As such, bispecific antibodies may be particularly useful in activating multicomponent receptor complexes. Here, we describe a biparatopic (i.e. targeting two different epitopes on the same target) format that can activate the endocrine fibroblast growth factor (FGF) 21 receptor (FGFR) complex containing beta-Klotho and FGFR1c. This format was constructed by grafting two different antigen-specific VH domains onto the VH and VL positions of an IgG, yielding a tetravalent binder with two potential geometries, a close and a distant, between the two paratopes. Our results revealed that the biparatopic molecule provides activities that are not observed with each paratope alone. Our approach could help address the challenges with heterogeneity inherent in other bispecific formats and could provide the means to adjust intramolecular distances of the antibody domains to drive optimal activity in a bispecific format. In conclusion, this format is versatile, is easy to construct and produce, and opens a new avenue for agonistic antibody discovery and development. PMID- 29483190 TI - SbnI is a free serine kinase that generates O -phospho-l-serine for staphyloferrin B biosynthesis in Staphylococcus aureus. AB - Staphyloferrin B (SB) is an iron-chelating siderophore produced by Staphylococcus aureus in invasive infections. Proteins for SB biosynthesis and export are encoded by the sbnABCDEFGHI gene cluster, in which SbnI, a member of the ParB/Srx superfamily, acts as a heme-dependent transcriptional regulator of the sbn locus. However, no structural or functional information about SbnI is available. Here, a crystal structure of SbnI revealed striking structural similarity to an ADP dependent free serine kinase, SerK, from the archaea Thermococcus kodakarensis We found that features of the active sites are conserved, and biochemical assays and 31P NMR and HPLC analyses indicated that SbnI is also a free serine kinase but uses ATP rather than ADP as phosphate donor to generate the SB precursor O phospho-l-serine (OPS). SbnI consists of two domains, and elevated B-factors in domain II were consistent with the open-close reaction mechanism previously reported for SerK. Mutagenesis of Glu20 and Asp58 in SbnI disclosed that they are required for kinase activity. The only known OPS source in bacteria is through the phosphoserine aminotransferase activity of SerC within the serine biosynthesis pathway, and we demonstrate that an S. aureus serC mutant is a serine auxotroph, consistent with a function in l-serine biosynthesis. However, the serC mutant strain could produce SB when provided l-serine, suggesting that SbnI produces OPS for SB biosynthesis in vivo These findings indicate that besides transcriptionally regulating the sbn locus, SbnI also has an enzymatic role in the SB biosynthetic pathway. PMID- 29483192 TI - Alternative splicing variant of the scaffold protein APPL1 suppresses hepatic adiponectin signaling and function. AB - Adiponectin is an adipocyte-derived hormone with antidiabetic activities that include increasing the sensitivity of cells to insulin. Adaptor protein containing pleckstrin homology domain, phosphotyrosine-binding domain, and leucine zipper motif (APPL1) stimulates adiponectin signaling and promotes adiponectin's insulin-sensitizing effects by binding to two adiponectin receptors, AdipoR1 and AdipoR2, and the insulin receptor. In this study, we report an alternative splicing variant of APPL1 (APPL1sv) that is highly expressed in mouse liver, pancreas, and spleen tissues. The expression levels of APPL1sv in liver tissues were enhanced in a mouse model of obesity and diabetic dyslipidemia (i.e. db/db mice) and reduced in calorie-restricted mice compared with ad libitum-fed mice. APPL1sv overexpression or suppression inhibited or enhanced, respectively, adiponectin-stimulated phosphorylation of AMP protein kinase (AMPK) in mouse hepatocytes. We also found that APPL1sv binds to AdipoR1 and AdipoR2 under basal conditions and that adiponectin treatment reduces this binding. Overexpression of APPL1sv blocked adiponectin-induced interactions of APPL1 with the adiponectin receptors. Moreover, adenovirus-mediated and short hairpin RNA-based suppression of APPL1sv greatly reduced high fat diet-induced insulin resistance and hepatic glucose production in mice. Our study identifies a key suppressor of hepatic adiponectin signaling and insulin sensitivity, a finding that may shed light on identifying effective therapeutic targets for treating insulin resistance and type 2 diabetes. PMID- 29483193 TI - Lafora disease offers a unique window into neuronal glycogen metabolism. AB - Lafora disease (LD) is a fatal, autosomal recessive, glycogen-storage disorder that manifests as severe epilepsy. LD results from mutations in the gene encoding either the glycogen phosphatase laforin or the E3 ubiquitin ligase malin. Individuals with LD develop cytoplasmic, aberrant glycogen inclusions in nearly all tissues that more closely resemble plant starch than human glycogen. This Minireview discusses the unique window into glycogen metabolism that LD research offers. It also highlights recent discoveries, including that glycogen contains covalently bound phosphate and that neurons synthesize glycogen and express both glycogen synthase and glycogen phosphorylase. PMID- 29483194 TI - The regulation of glycogenolysis in the brain. AB - The key regulatory enzymes of glycogenolysis are phosphorylase kinase, a hetero oligomer with four different types of subunits, and glycogen phosphorylase, a homodimer. Both enzymes are activated by phosphorylation and small ligands, and both enzymes have distinct isoforms that are predominantly expressed in muscle, liver, or brain; however, whole-transcriptome high-throughput sequencing analyses show that in brain both of these enzymes are likely composed of subunit isoforms representing all three tissues. This Minireview examines the regulatory properties of the isoforms of these two enzymes expressed in the three tissues, focusing on their potential regulatory similarities and differences. Additionally, the activity, structure, and regulation of the remaining enzyme necessary for glycogenolysis, glycogen-debranching enzyme, are also reviewed. PMID- 29483195 TI - The dynamic life of the glycogen granule. AB - Glycogen, the primary storage form of glucose, is a rapid and accessible form of energy that can be supplied to tissues on demand. Each glycogen granule, or "glycosome," is considered an independent metabolic unit composed of a highly branched polysaccharide and various proteins involved in its metabolism. In this Minireview, we review the literature to follow the dynamic life of a glycogen granule in a multicompartmentalized system, i.e. the cell, and how and where glycogen granules appear and the factors governing its degradation. A better understanding of the importance of cellular compartmentalization as a regulator of glycogen metabolism is needed to unravel its role in brain energetics. PMID- 29483196 TI - Grouper iridovirus GIV66 is a Bcl-2 protein that inhibits apoptosis by exclusively sequestering Bim. AB - Programmed cell death or apoptosis is a critical mechanism for the controlled removal of damaged or infected cells, and proteins of the Bcl-2 family are important arbiters of this process. Viruses have been shown to encode functional and structural homologs of Bcl-2 to counter premature host-cell apoptosis and ensure viral proliferation or survival. Grouper iridovirus (GIV) is a large DNA virus belonging to the Iridoviridae family and harbors GIV66, a putative Bcl-2 like protein and mitochondrially localized apoptosis inhibitor. However, the molecular and structural basis of GIV66-mediated apoptosis inhibition is currently not understood. To gain insight into GIV66's mechanism of action, we systematically evaluated its ability to bind peptides spanning the BH3 domain of pro-apoptotic Bcl-2 family members. Our results revealed that GIV66 harbors an unusually high level of specificity for pro-apoptotic Bcl-2 and displays affinity only for Bcl-2-like 11 (Bcl2L11 or Bim). Using crystal structures of both apo GIV66 and GIV66 bound to the BH3 domain from Bim, we unexpectedly found that GIV66 forms dimers via an interface that results in occluded access to the canonical Bcl-2 ligand-binding groove, which breaks apart upon Bim binding. This observation suggests that GIV66 dimerization may affect GIV66's ability to bind host pro-death Bcl-2 proteins and enables highly targeted virus-directed suppression of host apoptosis signaling. Our findings provide a mechanistic understanding for the potent anti-apoptotic activity of GIV66 by identifying it as the first single-specificity, pro-survival Bcl-2 protein and identifying a pivotal role of Bim in GIV-mediated inhibition of apoptosis. PMID- 29483197 TI - The pseudophosphatase phogrin enables glucose-stimulated insulin signaling in pancreatic beta cells. AB - Autocrine insulin signaling is critical for pancreatic beta-cell growth and activity and is at least partially controlled by protein-tyrosine phosphatases (PTPs) that act on insulin receptors (IRs). The receptor-type PTP phogrin primarily localizes on insulin secretory granules in pancreatic beta cells. We recently reported that phogrin knockdown decreases the protein levels of insulin receptor substrate 2 (IRS2), whereas high-glucose stimulation promotes formation of a phogrin-IR complex that stabilizes IRS2. However, the underlying molecular mechanisms by which phogrin affects IRS2 levels are unclear. Here, we found that relative to wildtype mice, IRS2 levels in phogrin-knockout mice islets decreased by 44%. When phogrin was silenced by shRNA in pancreatic beta-cell lines, glucose induced insulin signaling led to proteasomal degradation of IRS2 via a negative feedback mechanism. Phogrin overexpression in a murine hepatocyte cell line consistently prevented chronic insulin treatment-induced IRS2 degradation. In vitro, phogrin directly bound the IR without the assistance of other proteins and protected recombinant PTP1B from oxidation to potentiate its activity toward the IR. Furthermore, phogrin expression suppressed insulin-induced local generation of hydrogen peroxide and subsequent PTP1B oxidation, which allowed progression of IR dephosphorylation. Together, these results suggest that a transient interaction of phogrin with the IR enables glucose-stimulated autocrine insulin signaling through the regulation of PTP1B activity, which is essential for suppressing feedback-mediated IRS2 degradation in pancreatic beta cells. PMID- 29483199 TI - AAP Publication Reaffirmed. PMID- 29483198 TI - Epidemic Childhood Obesity: Not Yet the End of the Beginning. PMID- 29483200 TI - Guidelines for Adolescent Depression in Primary Care (GLAD-PC): Part I. Practice Preparation, Identification, Assessment, and Initial Management. AB - OBJECTIVES: To update clinical practice guidelines to assist primary care (PC) clinicians in the management of adolescent depression. This part of the updated guidelines is used to address practice preparation, identification, assessment, and initial management of adolescent depression in PC settings. METHODS: By using a combination of evidence- and consensus-based methodologies, guidelines were developed by an expert steering committee in 2 phases as informed by (1) current scientific evidence (published and unpublished) and (2) draft revision and iteration among the steering committee, which included experts, clinicians, and youth and families with lived experience. RESULTS: Guidelines were updated for youth aged 10 to 21 years and correspond to initial phases of adolescent depression management in PC, including the identification of at-risk youth, assessment and diagnosis, and initial management. The strength of each recommendation and its evidence base are summarized. The practice preparation, identification, assessment, and initial management section of the guidelines include recommendations for (1) the preparation of the PC practice for improved care of adolescents with depression; (2) annual universal screening of youth 12 and over at health maintenance visits; (3) the identification of depression in youth who are at high risk; (4) systematic assessment procedures by using reliable depression scales, patient and caregiver interviews, and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria; (5) patient and family psychoeducation; (6) the establishment of relevant links in the community, and (7) the establishment of a safety plan. CONCLUSIONS: This part of the guidelines is intended to assist PC clinicians in the identification and initial management of adolescents with depression in an era of great clinical need and shortage of mental health specialists, but they cannot replace clinical judgment; these guidelines are not meant to be the sole source of guidance for depression management in adolescents. Additional research that addresses the identification and initial management of youth with depression in PC is needed, including empirical testing of these guidelines. PMID- 29483201 TI - Guidelines for Adolescent Depression in Primary Care (GLAD-PC): Part II. Treatment and Ongoing Management. AB - OBJECTIVES: To update clinical practice guidelines to assist primary care (PC) in the screening and assessment of depression. In this second part of the updated guidelines, we address treatment and ongoing management of adolescent depression in the PC setting. METHODS: By using a combination of evidence- and consensus based methodologies, the guidelines were updated in 2 phases as informed by (1) current scientific evidence (published and unpublished) and (2) revision and iteration among the steering committee, including youth and families with lived experience. RESULTS: These updated guidelines are targeted for youth aged 10 to 21 years and offer recommendations for the management of adolescent depression in PC, including (1) active monitoring of mildly depressed youth, (2) treatment with evidence-based medication and psychotherapeutic approaches in cases of moderate and/or severe depression, (3) close monitoring of side effects, (4) consultation and comanagement of care with mental health specialists, (5) ongoing tracking of outcomes, and (6) specific steps to be taken in instances of partial or no improvement after an initial treatment has begun. The strength of each recommendation and the grade of its evidence base are summarized. CONCLUSIONS: The Guidelines for Adolescent Depression in Primary Care cannot replace clinical judgment, and they should not be the sole source of guidance for adolescent depression management. Nonetheless, the guidelines may assist PC clinicians in the management of depressed adolescents in an era of great clinical need and a shortage of mental health specialists. Additional research concerning the management of depressed youth in PC is needed, including the usability, feasibility, and sustainability of guidelines, and determination of the extent to which the guidelines actually improve outcomes of depressed youth. PMID- 29483202 TI - Prevalence of Obesity and Severe Obesity in US Children, 1999-2016. AB - OBJECTIVES: To provide updated prevalence data on obesity trends among US children and adolescents aged 2 to 19 years from a nationally representative sample. METHODS: We used the NHANES for years 1999 to 2016. Weight status was determined by using measured height and weight from the physical examination component of the NHANES to calculate age- and sex-specific BMI. We report the prevalence estimates of overweight and obesity (class I, class II, and class III) by 2-year NHANES cycles and compared cycles by using adjusted Wald tests and linear trends by using ordinary least squares regression. RESULTS: White and Asian American children have significantly lower rates of obesity than African American children, Hispanic children, or children of other races. We report a positive linear trend for all definitions of overweight and obesity among children 2-19 years old, most prominently among adolescents. Children aged 2 to 5 years showed a sharp increase in obesity prevalence from 2015 to 2016 compared with the previous cycle. CONCLUSIONS: Despite previous reports that obesity in children and adolescents has remained stable or decreased in recent years, we found no evidence of a decline in obesity prevalence at any age. In contrast, we report a significant increase in severe obesity among children aged 2 to 5 years since the 2013-2014 cycle, a trend that continued upward for many subgroups. PMID- 29483203 TI - Lipid Transfer Proteins: Introduction to the Thematic Review Series. PMID- 29483204 TI - miR-103/107 promote ER stress-mediated apoptosis via targeting the Wnt3a/beta catenin/ATF6 pathway in preadipocytes. AB - Both miR-103 and miR-107 have been demonstrated to restrain cell proliferation and regulate lipid metabolism and inflammation. However, the effects of miR 103/107 on preadipocyte apoptosis remain unknown. In the present research, we have investigated how miR-103/107 regulated preadipocyte apoptosis. We found that miR-103/107 aggravated endoplasmic reticulum (ER) stress-mediated apoptosis in preadipocytes. We confirmed that miR-103/107 targeted WNT family member 3a (Wnt3a) in preadipocytes. It was found that overexpressing Wnt3a resulted in suppression of ER stress-mediated apoptosis, while restoration of miR-103/107 counteracted the effects of Wnt3a in preadipocytes. Moreover, bioinformatics and luciferase assays indicated that activating transcription factor (ATF)6 is a key player linking miR-103/107-induced ER stress to apoptosis. ATF6 is regulated by lymphoid enhancer-binding factor 1, a transcription factor downstream of the Wnt3a/beta-catenin signaling pathway, and ATF6 binds to the B-cell lymphoma 2 (Bcl2) promoter to regulate apoptosis further. In conclusion, miR-103/107 promoted ER stress-mediated apoptosis by targeting the Wnt3a/beta-catenin/ATF6 signaling pathway in preadipocytes. This study revealed that the miR-103/107 Wnt3a/beta-catenin-ATF6 pathway is critical to the progression of apoptosis in preadipocytes, which suggested that approaches to activate miR-103/107 could potentially be useful as new therapies for treating obesity and metabolic syndrome-related disorders. PMID- 29483205 TI - Decreasing mortality and changes in treatment patterns in patients with acromegaly from a nationwide study. AB - CONTEXT: New therapeutic strategies have developed for the management of acromegaly over recent decades. Whether this has improved mortality has not been fully elucidated. OBJECTIVE: The primary aim was to investigate mortality in a nationwide unselected cohort of patients with acromegaly. Secondary analyses included time trends in mortality and treatment patterns. DESIGN: A total of 1089 patients with acromegaly were identified in Swedish National Health Registries between 1987 and 2013. To analyse time trends, the cohort was divided into three periods (1987-1995, 1996-2004 and 2005-2013) based on the year of diagnosis. MAIN OUTCOME MEASURES: Using the Swedish population as reference, standardized mortality ratios (SMRs) were calculated with 95% confidence intervals (CIs). RESULTS: Overall SMR was 2.79 (95% CI: 2.43-3.15) with 232 observed and 83 expected deaths. Mortality was mainly related to circulatory diseases (SMR: 2.95, 95% CI: 2.35-3.55), including ischemic heart disease (2.00, 1.35-2.66) and cerebrovascular disease (3.99, 2.42-5.55) and malignancy (1.76, 1.27-2.26). Mortality decreased over time, with an SMR of 3.45 (2.87-4.02) and 1.86 (1.04 2.67) during the first and last time period, respectively (P = .015). During the same time periods, the frequency of pituitary surgery increased from 58% to 72% (P < 0.001) and the prevalence of hypopituitarism decreased from 41% to 23% (P < 0.001). CONCLUSIONS: Excess mortality was found in this nationwide cohort of patients with acromegaly, mainly related to circulatory and malignant diseases. Although still high, mortality significantly declined over time. This could be explained by the more frequent use of pituitary surgery, decreased prevalence of hypopituitarism and the availability of new medical treatment options. PMID- 29483206 TI - Combined Inhibition of mTOR and CDK4/6 Is Required for Optimal Blockade of E2F Function and Long-term Growth Inhibition in Estrogen Receptor-positive Breast Cancer. AB - The cyclin dependent kinase (CDK)-retinoblastoma (RB)-E2F pathway plays a critical role in the control of cell cycle in estrogen receptor-positive (ER+) breast cancer. Small-molecule inhibitors of CDK4/6 have shown promise in this tumor type in combination with hormonal therapies, reflecting the particular dependence of this subtype of cancer on cyclin D1 and E2F transcription factors. mTOR inhibitors have also shown potential in clinical trials in this disease setting. Recent data have suggested cooperation between the PI3K/mTOR pathway and CDK4/6 inhibition in preventing early adaptation and eliciting growth arrest, but the mechanisms of the interplay between these pathways have not been fully elucidated. Here we show that profound and durable inhibition of ER+ breast cancer growth is likely to require multiple hits on E2F-mediated transcription. We demonstrate that inhibition of mTORC1/2 does not affect ER function directly, but does cause a decrease in cyclin D1 protein, RB phosphorylation, and E2F mediated transcription. Combination of an mTORC1/2 inhibitor with a CDK4/6 inhibitor results in more profound effects on E2F-dependent transcription, which translates into more durable growth arrest and a delay in the onset of resistance. Combined inhibition of mTORC1/2, CDK4/6, and ER delivers even more profound and durable regressions in breast cancer cell lines and xenografts. Furthermore, we show that CDK4/6 inhibitor-resistant cell lines reactivate the CDK-RB-E2F pathway, but remain sensitive to mTORC1/2 inhibition, suggesting that mTORC1/2 inhibitors may represent an option for patients that have relapsed on CDK4/6 therapy. Mol Cancer Ther; 17(5); 908-20. (c)2018 AACR. PMID- 29483207 TI - Impact of Chemical-Induced Mutational Load Increase on Immune Checkpoint Therapy in Poorly Responsive Murine Tumors. AB - A recurring historic finding in cancer drug development is encouraging antitumor effects observed in tumor-bearing mice that fail to translate into the clinic. An intriguing exception to this pattern is immune checkpoint therapy, as the sustained tumor regressions observed in subsets of cancer patients are rare in mice. Reasoning that this may be due in part to relatively low mutational loads of mouse tumors, we mutagenized transplantable mouse tumor cell lines EMT-6/P, B16F1, RENCA, CT26, and MC38 in vitro with methylnitro-nitrosoguanidine (MNNG) or ethylmethane sulfonate (EMS) and tested their responsiveness to PD-L1 blockade. Exome sequencing confirmed an increase in somatic mutations by mutagen treatment, an effect mimicked in EMT-6 variants chronically exposed in vivo to cisplatin or cyclophosphamide. Certain mutagenized variants of B16F1, EMT-6/P, CT26, and MC38 (but not RENCA) were more immunogenic than their parents, yet anti-PD-L1 sensitization developed only in some EMT-6/P and B16F1 variants. Treatment response patterns corresponded with changes in immune cell infiltration and especially increases in CD8+ T cells. Chronically cisplatin-exposed EMT-6 variants were also more responsive to anti-PD-L1 therapy. Although tumor PD-L1 expression was upregulated in in vivo chemotherapy-exposed variants, PD-L1 expression levels were not consistently associated with anti-PD-L1 treatment activity across mutagenized or chemotherapy-exposed variants. In summary, mutagenized and more immunogenic mouse tumors were not universally sensitized to PD-L1 blockade. Chemically mutagenized variants may be useful to evaluate the impact of immunologically "hot" or "cold" tumors with a high mutational load, to which certain chemotherapy agents may contribute, on immunotherapy outcomes. Mol Cancer Ther; 17(4); 869-82. (c)2018 AACR. PMID- 29483208 TI - Characterization of ABBV-221, a Tumor-Selective EGFR-Targeting Antibody Drug Conjugate. AB - Depatuxizumab mafodotin (depatux-m, ABT-414) is a tumor-selective antibody drug conjugate (ADC) comprised of the anti-EGFR antibody ABT-806 and the monomethyl auristatin F (MMAF) warhead. Depatux-m has demonstrated promising clinical activity in glioblastoma multiforme (GBM) patients and is currently being evaluated in clinical trials in first-line and recurrent GBM disease settings. Depatux-m responses have been restricted to patients with amplified EGFR, highlighting the need for therapies with activity against tumors with nonamplified EGFR overexpression. In addition, depatux-m dosing has been limited by corneal side effects common to MMAF conjugates. We hypothesized that a monomethyl auristatin E (MMAE) ADC utilizing an EGFR-targeting antibody with increased affinity may have broader utility against tumors with more modest EGFR overexpression while mitigating the risk of corneal side effects. We describe here preclinical characterization of ABBV-221, an EGFR-targeting ADC comprised of an affinity-matured ABT-806 conjugated to MMAE. ABBV-221 binds to a similar EGFR epitope as depatux-m and retains tumor selectivity with increased binding to EGFR positive tumor cells and greater in vitro potency. ABBV-221 displays increased tumor uptake and antitumor activity against wild-type EGFR-positive xenografts with a greatly reduced incidence of corneal side effects relative to depatux-m. ABBV-221 has similar activity as depatux-m against an EGFR-amplified GBM patient derived xenograft (PDX) model and is highly effective alone and in combination with standard-of-care temozolomide in an EGFRvIII-positive GBM xenograft model. Based on these results, ABBV-221 has advanced to a phase I clinical trial in patients with advanced solid tumors associated with elevated levels of EGFR. Mol Cancer Ther; 17(4); 795-805. (c)2018 AACR. PMID- 29483209 TI - Analysis of Tissue and Circulating Tumor DNA by Next-Generation Sequencing of Hepatocellular Carcinoma: Implications for Targeted Therapeutics. AB - Hepatocellular carcinoma (HCC) has limited treatment options. Molecular analysis of its mutational landscape may enable the identification of novel therapies. However, biopsy is not routinely performed in HCC. The utility of analyzing cell free circulating tumor DNA (ctDNA) by next-generation sequencing (NGS) is not established. We performed 32 ctDNA NGS analyses on 26 patients; 10 of these patients had tissue NGS (236 to 626 genes). ctDNA was evaluated using an assay that detects single nucleotide variants, amplifications, fusions, and specific insertion/deletion alterations in 54 to 70 genes. The ctDNA demonstrated that 23 of 26 patients (88.5%) had >=1 characterized alteration, and all these individuals had >=1 potentially actionable alteration. The most frequently mutated gene was TP53 (16 of 26 patients, 61.5%). There were 47 unique characterized molecular alterations among 18 total gene alterations [variants of unknown significance (VUS) excluded)]. ctDNA and tissue NGS frequently showed different profiles, perhaps due to length of time between tissue and blood samples [median = 370 days (range, 29 to 876 days)]. Serial ctDNA evaluation in an illustrative patient treated with capecitabine demonstrated emergence of a new TP53 alteration after progression. In conclusion, ctDNA profiling is feasible in advanced HCC, and serial assessment using ctDNA NGS can reveal genomic changes with time. NGS of ctDNA provides a minimally invasive alternative for identifying potentially actionable gene alterations and potential molecular targeted therapies. Dynamic changes in molecular portfolio associated with therapeutic pressure in difficult-to-biopsy patients can be observed. Mol Cancer Ther; 17(5); 1114-22. (c)2018 AACR. PMID- 29483210 TI - EGF Receptor and mTORC1 Are Novel Therapeutic Targets in Nonseminomatous Germ Cell Tumors. AB - Germ cell tumors (GCT) are malignant tumors that arise from pluripotent embryonic germ cells and occur in children and young adults. GCTs are treated with cisplatin-based regimens which, while overall effective, fail to cure all patients and cause significant adverse late effects. The seminoma and nonseminoma forms of GCT exhibit distinct differentiation states, clinical behavior, and response to treatment; however, the molecular mechanisms of GCT differentiation are not fully understood. We tested whether the activity of the mTORC1 and MAPK pathways were differentially active in the two classes of GCT. Here we show that nonseminomatous germ cell tumors (NSGCT, including embryonal carcinoma, yolk sac tumor, and choriocarcinoma) from both children and adults display activation of the mTORC1 pathway, while seminomas do not. In seminomas, high levels of REDD1 may negatively regulate mTORC1 activity. In NSGCTs, on the other hand, EGF and FGF2 ligands can stimulate mTORC1 and MAPK signaling, and members of the EGF and FGF receptor families are more highly expressed. Finally, proliferation of NSGCT cells in vitro and in vivo is significantly inhibited by combined treatment with the clinically available agents erlotinib and rapamycin, which target EGFR and mTORC1 signaling, respectively. These results provide an understanding of the signaling network that drives GCT growth and a rationale for therapeutic targeting of GCTs with agents that antagonize the EGFR and mTORC1 pathways. Mol Cancer Ther; 17(5); 1079-89. (c)2018 AACR. PMID- 29483211 TI - Antitumor Activity of Osimertinib, an Irreversible Mutant-Selective EGFR Tyrosine Kinase Inhibitor, in NSCLC Harboring EGFR Exon 20 Insertions. AB - EGFR exon 20 insertions (Ex20Ins) account for 4% to 10% of EGFR activating mutations in non-small cell lung cancer (NSCLC). EGFR Ex20Ins tumors are generally unresponsive to first- and second-generation EGFR inhibitors, and current standard of care for NSCLC patients with EGFR Ex20Ins is conventional cytotoxic chemotherapy. Therefore, the development of an EGFR TKI that can more effectively target NSCLC with EGFR Ex20Ins mutations represents a major advance for this patient subset. Osimertinib is a third-generation EGFR TKI approved for the treatment of advanced NSCLC harboring EGFR T790M; however, the activity of osimertinib in EGFR Ex20Ins NSCLC has yet to be fully assessed. Using CRISPR-Cas 9 engineered cell lines carrying the most prevalent Ex20Ins mutations, namely Ex20Ins D770_N771InsSVD (22%) or Ex20Ins V769_D770InsASV (17%), and a series of patient-derived xenografts, we have characterized osimertinib and AZ5104 (a circulating metabolite of osimertinib) activities against NSCLC harboring Ex20Ins. We report that osimertinib and AZ5104 inhibit signaling pathways and cellular growth in Ex20Ins mutant cell lines in vitro and demonstrate sustained tumor growth inhibition of EGFR-mutant tumor xenograft harboring the most prevalent Ex20Ins in vivo The antitumor activity of osimertinib and AZ5104 in NSCLC harboring EGFR Ex20Ins is further described herein using a series of patient-derived xenograft models. Together these data support clinical testing of osimertinib in patients with EGFR Ex20Ins NSCLC. Mol Cancer Ther; 17(5); 885-96. (c)2018 AACR. PMID- 29483212 TI - Inhibition of the Histone H3K27 Demethylase UTX Enhances Tumor Cell Radiosensitivity. AB - The processes mediating the repair of DNA double-strand breaks (DSB) are critical determinants of radiosensitivity and provide a source of potential targets for tumor radiosensitization. Among the events required for efficient DSB repair are a variety of post-translational histone modifications, including methylation. Because trimethylation of histone H3 on lysine 27 (H3K27me3) has been associated with chromatin condensation, which can influence DSB repair, we determined the effects of radiation on H3K27me3 levels in tumor and normal cell lines. Irradiation of tumor cells resulted in a rapid loss of H3K27me3, which was prevented by the siRNA-mediated knockdown of the H3K27 demethylase UTX. Knockdown of UTX also enhanced the radiosensitivity of each tumor cell line. Treatment of tumor cells with the H3K27 demethylase inhibitor GSKJ4 immediately before irradiation prevented the radiation-induced decrease in H3K27me3 and enhanced radiosensitivity. As determined by neutral comet analysis and gammaH2AX expression, this GSKJ4 treatment protocol inhibited the repair of radiation induced DSBs. Consistent with in vitro results, treatment of mice bearing leg tumor xenografts with GSKJ4 significantly enhance radiation-induce tumor growth delay. In contrast with results generated from tumor cell lines, radiation had no effect on H3K27me3 levels in normal fibroblast cell lines and GSKJ4 did not enhance their radiosensitivity. These data suggest that H3K27me3 demethylation contributes to DSB repair in tumor cells and that UTX, the demethylase responsible, provides a target for selective tumor cell radiosensitization. Mol Cancer Ther; 17(5); 1070-8. (c)2018 AACR. PMID- 29483213 TI - Anti-HER2 scFv-Directed Extracellular Vesicle-Mediated mRNA-Based Gene Delivery Inhibits Growth of HER2-Positive Human Breast Tumor Xenografts by Prodrug Activation. AB - This paper deals with specific targeting of the prodrug/enzyme regimen, CNOB/HChrR6, to treat a serious disease, namely HER2+ human breast cancer with minimal off-target toxicity. HChrR6 is an improved bacterial enzyme that converts CNOB into the cytotoxic drug MCHB. Extracellular vesicles (EV) were used for mRNA based HchrR6 gene delivery: EVs may cause minimal immune rejection, and mRNA may be superior to DNA for gene delivery. To confine HChrR6 generation and CNOB activation to the cancer, the EVHB chimeric protein was constructed. It contains high-affinity anti-HER2 scFv antibody (ML39) and is capable of latching on to EV surface. Cells transfected with EVHB-encoding plasmid generated EVs displaying this protein ("directed EVs"). Transfection of a separate batch of cells with the new plasmid, XPort/HChrR6, generated EVs containing HChrR6 mRNA; incubation with pure EVHB enabled these to target the HER2 receptor, generating "EXO-DEPT" EVs. EXO-DEPT treatment specifically enabled HER2-overexpressing BT474 cells to convert CNOB into MCHB in actinomycin D-independent manner, showing successful and specific delivery of HChrR6 mRNA. EXO-DEPTs-but not undirected EVs-plus CNOB caused near-complete growth arrest of orthotopic BT474 xenografts in vivo, demonstrating for the first time EV-mediated delivery of functional exogenous mRNA to tumors. EXO-DEPTs may be generated from patients' own dendritic cells to evade immune rejection, and without plasmids and their potentially harmful genetic material, raising the prospect of clinical use of this regimen. This approach can be used to treat any disease overexpressing a specific marker. Mol Cancer Ther; 17(5); 1133-42. (c)2018 AACR. PMID- 29483214 TI - Preclinical Activity of Abemaciclib Alone or in Combination with Antimitotic and Targeted Therapies in Breast Cancer. AB - The cyclinD:CDK4/6:Rb axis is dysregulated in a variety of human cancers. Targeting this pathway has proven to be a successful therapeutic approach in ER+ breast cancer. In this study, in vitro and in vivo preclinical breast cancer models were used to investigate the expanded use of the CDK4/6 inhibitor, abemaciclib. Using a panel of 44 breast cancer cell lines, differential sensitivity to abemaciclib was observed and was seen predominately in the luminal ER+/HER2- and ER+/HER2+ subtypes. However, a subset of triple-negative breast cancer (TNBC) cell lines with intact Rb signaling were also found to be responsive. Equivalent levels of tumor growth inhibition were observed in ER+/HER2-, ER+/HER2+ as well as biomarker selected TNBC xenografts in response to abemaciclib. In addition, abemaciclib combined with hormonal blockade and/or HER2 targeted therapy induced significantly improved antitumor activity. CDK4/6 inhibition with abemaciclib combined with antimitotic agents, both in vitro and in vivo, did not antagonize the effect of either agent. Finally, we identified a set of Rb/E2F-regulated genes that consistently track with growth inhibitory response and constitute potential pharmacodynamic biomarkers of response to abemaciclib. Taken together, these data represent a comprehensive analysis of the preclinical activity of abemaciclib, used alone or in combination, in human breast cancer models. The subtypes most likely to respond to abemaciclib-based therapies can be identified by measurement of a specific set of biomarkers associated with increased dependency on cyclinD:CDK4/6:Rb signaling. These data support the clinical development of abemaciclib as monotherapy or as a combination partner in selected ER+/HER2-, HER2+/ER+, and TNBCs. Mol Cancer Ther; 17(5); 897-907. (c)2018 AACR. PMID- 29483215 TI - MCT4 Expression Is a Potential Therapeutic Target in Colorectal Cancer with Peritoneal Carcinomatosis. AB - Monocarboxylate transporters (MCT) are transmembrane proteins that control the lactate metabolism and are associated with poor prognosis in solid tumors, including colorectal cancer. Here, we aimed to investigate the biological and clinical role of MCTs in colorectal cancer and to assess the potential of therapeutic application. A total of 16 human colorectal cancer cell lines, 11 patient-derived cells from malignant ascites [patient-derived cells (PDC)], and 39 matched pairs of primary colorectal cancer and normal colorectal tissues were used to assess the role of MCT in vitro and in vivo siRNA methodology was used to determine the effect of MCT inhibition and molecular mechanism of hypoxia- and angiogenesis-related factors in addition to MCT4. The effect of MCT inhibition was confirmed in mouse xenograft models. MCT4 expression in surgical tissue was evaluated by IHC and used for survival analysis. Expression of MCTs was demonstrated in colorectal cancer cell lines. siRNA-mediated MCT silencing caused significant decline of cell proliferation both in vitro and in vivo An additive effect of MCT inhibition was induced by combined treatment with chemotherapy or radiotherapy. In particular, the expression of MCT4 was markedly increased in PDCs, and MCT4 inhibition significantly decreased PDC proliferation. Hypoxia inducible factor 1-alpha (HIF1alpha) was also highly expressed in PDCs, whereas HIF1alpha knockdown reduced MCT4 expression and of other angiogenesis-related mediators. The patients with high MCT4 expression by IHC showed shorter relapse free survival compared with low expression. These findings suggest that MCT4 may represent a new therapeutic target for colorectal cancer with peritoneal carcinomatosis and serve as a prognostic indicator. Mol Cancer Ther; 17(4); 838 48. (c)2018 AACR. PMID- 29483216 TI - Nigericin Exerts Anticancer Effects on Human Colorectal Cancer Cells by Inhibiting Wnt/beta-catenin Signaling Pathway. AB - Nigericin, an antibiotic derived from Streptomyces hygroscopicus, which works by acting as an H+, K+, and Pb2+ ionophore, has exhibited promising anticancer activity. The main purpose of this study is to investigate its inhibitory effects on Wnt/beta-catenin signaling pathway in colorectal cancer cells and clarify the underlying mechanism. We exposed two colorectal cancer lines (SW620 and KM12) to increasing concentrations of nigericin for different time periods and the 50% inhibiting concentration (IC50) values were evaluated. Our data showed that nigericin treatment significantly reduced tumor cell proliferation in dose- and time-dependent manners in colorectal cancer cells. The subsequent experiments in vitro and in vivo implied that nigericin could significantly suppress the tumor growth, migration, and invasion, and induce the apoptosis of colorectal cancer cells. Our results of Western blot and immunofluorescence assay showed that nigericin could suppress the Wnt/beta-catenin signaling pathway in colorectal cancer cells with dose-dependent increased expressions of downstream effectors and target proteins. To further elucidate the inhibitory effects of nigericin via a beta-catenin-dependent signaling mechanism, we established the stably beta catenin overexpression colorectal cancer cells. Western blot, SuperTOPFlash luciferase reporter, and immunoprecipitation assays all confirmed beta-catenin as a critical intermediary and player in Wnt/beta-catenin pathway, and nigericin exerted anticancer effects on colorectal cancer cells by directly targeting the beta-catenin destruction complex. These results suggested that Wnt/beta-catenin signaling might have an essential role in colorectal cancer progression. Nigericin targeting Wnt/beta-catenin signaling might provide new insight into the molecular mechanism of nigericin toward cancer cells, and suggest possible clinical application in colorectal cancer. Mol Cancer Ther; 17(5); 952-65. (c)2018 AACR. PMID- 29483217 TI - The Unfolded Protein Response: A Novel Therapeutic Target for Poor Prognostic BRAF Mutant Colorectal Cancer. AB - BRAFV600E mutations occur in ~10% of colorectal cancer cases, are associated with poor survival, and have limited responses to BRAF/MEK inhibition with or without EGFR inhibition. There is an unmet need to understand the biology of poor prognostic BRAFMT colorectal cancer. We have used differential gene expression and pathway analyses of untreated stage II and stage III BRAFMT (discovery set: n = 31; validation set: n = 26) colorectal cancer, and an siRNA screen to characterize the biology underpinning the BRAFMT subgroup with poorest outcome. These analyses identified the unfolded protein response (UPR) as a novel and druggable pathway associated with the BRAFMT colorectal cancer subgroup with poorest outcome. We also found that oncogenic BRAF drives endoplasmic reticulum (ER) stress and UPR pathway activation through MEK/ERK. Furthermore, inhibition of GRP78, the master regulator of the UPR, using siRNA or small molecule inhibition, resulted in acute ER stress and apoptosis, in particular in BRAFMT colorectal cancer cells. In addition, dual targeting of protein degradation using combined Carfilzomib (proteasome inhibitor) and ACY-1215 (HDAC6-selective inhibitor) treatment resulted in marked accumulation of protein aggregates, acute ER stress, apoptosis, and therapeutic efficacy in BRAFMT in vitro and xenograft models. Mechanistically, we found that the apoptosis following combined Carfilzomib/ACY-1215 treatment is mediated through increased CHOP expression. Taken together, our findings indicate that oncogenic BRAF induces chronic ER stress and that inducers of acute ER stress could be a novel treatment strategy for poor prognostic BRAFMT colorectal cancer. Mol Cancer Ther; 17(6); 1280-90. (c)2018 AACR. PMID- 29483218 TI - Targeting Polo-like Kinase 1 by a Novel Pyrrole-Imidazole Polyamide-Hoechst Conjugate Suppresses Tumor Growth In Vivo. AB - The serine/threonine kinase Polo-like kinase 1 (Plk1) plays a pivotal role in cell proliferation and has been validated as a promising anticancer drug target. However, very limited success has been achieved in clinical applications using existing Plk1 inhibitors, due to lack of sufficient specificity toward Plk1. To develop a novel Plk1 inhibitor with high selectivity and efficacy, we designed and synthesized a pyrrole-imidazole polyamide-Hoechst conjugate, PIP3, targeted to specific DNA sequence in the PLK1 promoter. PIP3 could specifically inhibit the cell cycle-regulated Plk1 expression and consequently retard tumor cell growth. Cancer cells treated with PIP3 exhibited severe mitotic defects and increased apoptosis, whereas normal cells were not affected by PIP3 treatment. Furthermore, subcutaneous injection of PIP3 into mice bearing human cancer xenografts induced significant tumor growth suppression with low host toxicity. Therefore, PIP3 exhibits the potential as an effective agent for targeted cancer therapy. Mol Cancer Ther; 17(5); 988-1002. (c)2018 AACR. PMID- 29483219 TI - Targeting PRPK Function Blocks Colon Cancer Metastasis. AB - The biological functions of the p53-related protein kinase (PRPK) remain unclear. We have previously demonstrated that PRPK is phosphorylated by the T-LAK cell originated protein kinase (TOPK) and that phosphorylated PRPK (p-PRPK) promotes colon cancer metastasis. Here, we analyzed colon adenocarcinomas from 87 patients and found that higher expression levels of p-PRPK were associated with later stages of metastatic dissemination (stage III and IV) as compared with earlier stages (stages I and II). Indeed, levels of p-PRPK were higher in metastatic versus malignant human colon adenocarcinomas. Knocking down PRPK expression attenuated colorectal liver and lung metastasis of colon cancer cells in vivo An in vitro kinase assay indicated that active PRPK does not phosphorylate p53 directly. We found that PRPK phosphorylates survivin, a regulator of colon cancer metastasis. PRPK phosphorylates survivin at Thr34, which is important for survivin stability. Taken together, our data strongly suggest that the PRPK signaling pathway promotes colon cancer metastasis by modulating survivin stability, and that PRPK could be a new prognostic marker for the survival of colon cancer patients. In addition, we identified an FDA-approved bacteriostatic antibiotic, fusidic acid sodium salt (fusidic acid or FA) as an inhibitor of PRPK, and show that FA combined with 5-fluorouracil (5-FU) inhibited PRPK activity and colon cancer metastasis to the lung in mice. We contend that the combination of FA with 5-FU could be an alternative therapeutic strategy to traditional chemotherapy for colon cancer patients with poor prognosis. Mol Cancer Ther; 17(5); 1101-13. (c)2018 AACR. PMID- 29483220 TI - p110alpha Inhibition Overcomes Stromal Cell-Mediated Ibrutinib Resistance in Mantle Cell Lymphoma. AB - Acquired resistance to cancer drugs is common, also for modern targeted drugs like the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, a new drug approved for the treatment of the highly aggressive and relapsing mantle cell lymphoma (MCL). The tumor microenvironment often impacts negatively on drug response. Here, we demonstrate that stromal cells protect MCL cells from ibrutinib-induced apoptosis and support MCL cell regrowth after drug removal by impairing ibrutinib mediated downregulation of PI3K/AKT signaling. Importantly, the stromal cell mediated ibrutinib resistance was overcome in vitro by inhibiting AKT activity using the PI3K catalytic p110alpha subunit-specific inhibitor BYL719. This was seen both for MCL cell lines and primary MCL cells. Furthermore, inhibition of p110alpha activity by BYL719 potentiated the ability of ibrutinib to inhibit MCL tumor growth in vivo in a mouse xenograft model. The stromal cell-mediated ibrutinib resistance was found to be due to a direct interaction with MCL cells and involves the integrin VLA-4, as disrupting stromal cell-MCL cell interaction using a VLA-4 blocking antibody abrogated the ibrutinib resistance. This suggests that combined treatment with ibrutinib and a p110alpha inhibitor, alternatively by disrupting stromal cell-MCL cell interaction, may be a promising therapeutic strategy to overcome stromal cell-mediated ibrutinib resistance in MCL. Mol Cancer Ther; 17(5); 1090-100. (c)2018 AACR. PMID- 29483221 TI - A Tricin Derivative from Deschampsia antarctica Desv. Inhibits Colorectal Carcinoma Growth and Liver Metastasis through the Induction of a Specific Immune Response. AB - In colorectal carcinoma patients, distant metastatic disease is present at initial diagnosis in nearly 25% of them. The majority of patients with metastatic colorectal carcinoma have incurable disease; therefore, new therapies are needed. Agents derived from medicinal plants have already demonstrated therapeutic activities in human cancer cells. Antartina is an antitumor agent isolated from Deschampsia antarctica Desv. This study aimed to evaluate the antitumor properties of Antartina in colorectal carcinoma models. We used human and murine colorectal carcinoma cell lines for investigating proliferation, apoptosis, and cell-cycle effects of Antartina therapy in vitro Avatar and immunocompetent colorectal carcinoma animal models were applied for evaluating the effects of Antartina in vivo Immune response against colorectal carcinoma model was investigated using CTL assay, analyzing dendritic cell activation and intratumor T-cell subpopulation, and by tumor rechallenge experiments. Antartina inhibits in vitro human colorectal carcinoma cell proliferation; however, in vivo experiments in Avatar colorectal carcinoma model Antartina display a limited antitumor effect. In an immunocompetent colorectal carcinoma mice model, Antartina potently inhibited tumor growth and liver metastases, leading to complete tumor regressions in >30% of mice and increased animal survival. In addition, Antartina induced a potent specific cytotoxic T-cell response against colorectal carcinoma and a long-lasting antitumor immunity. Interestingly, Antartina increased tumor immunogenicity and stimulated dendritic cell activation. No toxic effects were observed at the doses employed. Our findings showed that Antartina has the ability to induce antitumor immunity against colorectal carcinoma and can be used to develop new tools for the treatment of colorectal carcinoma. Mol Cancer Ther; 17(5); 966-76. (c)2018 AACR. PMID- 29483222 TI - Prognostic Value of Echocardiography in Hypertensive Versus Nonhypertensive Participants From the General Population. AB - Hypertension may be the most significant cardiovascular risk factor. Few studies have assessed the prognostic value of echocardiography in hypertensive individuals. This study examines the incremental prognostic value of adding echocardiographic parameters to established risk factors in individuals from the general population with and without hypertension. A total of 1294 individuals from the general population underwent a health examination and an echocardiogram including 2-dimensional speckle tracking. Outcome was a composite of ischemic heart disease and heart failure. The prevalence of hypertension was 38.3%. During a median follow-up of 12.5 years (interquartile range, 9.4-12.8 years), 222 participants (17.2%) developed the outcome. Out of these 222 events, 145 (65%) occurred in hypertensive participants, whereas 77 (35%) occurred in nonhypertensive individuals, corresponding to an incidence rate of 32/(1000*person-years) and 8/(1000*person-years), respectively. Follow-up was 100%. After multivariable adjustment, only left ventricular mass index predicted the outcome in hypertensive individuals, whereas only global longitudinal strain predicted the outcome in nonhypertensive individuals. In hypertensive individuals the prognostic value of left ventricular mass index was incremental to SCORE and abnormal ECG status. In nonhypertensive individuals the prognostic value of global longitudinal strain was incremental to SCORE and abnormal ECG status. The prognostic value of echocardiography in predicting cardiovascular outcomes in the general population is altered by hypertension. In hypertensive individuals, left ventricular mass index added incremental prognostic value in addition to established risk factors. In nonhypertensive individuals, global longitudinal strain added incremental prognostic value in addition to established risk factors. PMID- 29483223 TI - Medical Versus Surgical Treatment of Primary Aldosteronism. PMID- 29483224 TI - Adrenalectomy Lowers Incident Atrial Fibrillation in Primary Aldosteronism Patients at Long Term. AB - Primary aldosteronism (PA) causes cardiovascular damage in excess to the blood pressure elevation, but there are no prospective studies proving a worse long term prognosis in adrenalectomized and medically treated patients. We have, therefore, assessed the outcome of PA patients according to treatment mode in the PAPY study (Primary Aldosteronism Prevalence in Hypertension) patients, 88.8% of whom were optimally treated patients with primary (essential) hypertension (PH), and the rest had PA and were assigned to medical therapy (6.4%) or adrenalectomy (4.8%). Total mortality was the primary end point; secondary end points were cardiovascular death, major adverse cardiovascular events, including atrial fibrillation, and total cardiovascular events. Kaplan-Meier and Cox analysis were used to compare survival between PA and its subtypes and PH patients. After a median of 11.8 years, complete follow-up data were obtained in 89% of the 1125 patients in the original cohort. Only a trend (P=0.07) toward a worse death-free survival in PA than in PH patients was observed. However, at both univariate (90.0% versus 97.8%; P=0.002) and multivariate analyses (hazard ratio, 1.82; 95% confidence interval, 1.08-3.08; P=0.025), medically treated PA patients showed a lower atrial fibrillation-free survival than PH patients. By showing that during a long-term follow-up adrenalectomized aldosterone-producing adenoma patients have a similar long-term outcome of optimally treated PH patients, whereas, at variance, medically treated PA patients remain at a higher risk of atrial fibrillation, this large prospective study emphasizes the importance of an early identification of PA patients who need adrenalectomy as a key measure to prevent incident atrial fibrillation. PMID- 29483226 TI - Role of AT2R (Angiotensin Type 2 Receptor) in Maintaining Sodium-Potassium Balance. PMID- 29483225 TI - AT2R (Angiotensin II Type 2 Receptor)-Mediated Regulation of NCC (Na-Cl Cotransporter) and Renal K Excretion Depends on the K Channel, Kir4.1. AB - AT2R (AngII [angiotensin II] type 2 receptor) is expressed in the distal nephrons. The aim of the present study is to examine whether AT2R regulates NCC (Na-Cl cotransporter) and Kir4.1 of the distal convoluted tubule. AngII inhibited the basolateral 40 pS K channel (a Kir4.1/5.1 heterotetramer) in the distal convoluted tubule treated with losartan but not with PD123319. AT2R agonist also inhibits the K channel, indicating that AT2R was involved in tonic regulation of Kir4.1. The infusion of PD123319 stimulated the expression of tNCC (total NCC) and pNCC (phosphorylated NCC; Thr53) by a time-dependent way with the peak at 4 days. PD123319 treatment (4 days) stimulated the basolateral 40 pS K channel activity, augmented the basolateral K conductance, and increased the negativity of distal convoluted tubule membrane. The stimulation of Kir4.1 was essential for PD123319-induced increase in NCC because inhibiting AT2R increased the expression of tNCC and pNCC only in wild-type but not in the kidney-specific Kir4.1 knockout mice. Renal clearance study showed that thiazide-induced natriuretic effect was larger in PD123319-treated mice for 4 days than untreated mice. However, this effect was absent in kidney-specific Kir4.1 knockout mice which were also Na wasting under basal conditions. Finally, application of AT2R antagonist decreased the renal ability of K excretion and caused hyperkalemia in wild-type but not in kidney-specific Kir4.1 knockout mice. We conclude that AT2R-dependent regulation of NCC requires Kir4.1 in the distal convoluted tubule and that AT2R plays a role in stimulating K excretion by inhibiting Kir4.1 and NCC. PMID- 29483227 TI - Incremental Value of Echocardiography in Patients With or Without Hypertension: Which (Death)Star to Hitch the Wagon? PMID- 29483228 TI - VEGFR (Vascular Endothelial Growth Factor Receptor) Inhibition Induces Cardiovascular Damage via Redox-Sensitive Processes. AB - Although VEGF (vascular endothelial growth factor) inhibitors (VEGFIs), are effective anticancer therapies, they cause hypertension through unknown mechanisms. We questioned whether changes in vascular redox state may be important, because VEGF signaling involves nitric oxide (NO) and reactive oxygen species. Molecular mechanisms, including NOS, NADPH oxidase (Nox)-derived reactive oxygen species, antioxidant systems, and vasoconstrictor signaling pathways, were probed in human endothelial cells and vascular smooth muscle exposed to vatalanib, a VEGFI. Vascular functional effects of VEGFI were assessed ex vivo in mouse arteries. Cardiovascular and renal in vivo effects were studied in vatalanib- or gefitinib (EGFI [epidermal growth factor inhibitor])-treated mice. In endothelial cells, vatalanib decreased eNOS (Ser1177) phosphorylation and reduced NO and H2O2 production, responses associated with increased Nox derived O2- and ONOO- formation. Inhibition of Nox1/4 (GKT137831) or Nox1 (NoxA1ds), prevented vatalanib-induced effects. Nrf-2 (nuclear factor erythroid 2 related factor 2) nuclear translocation and expression of Nrf-2-regulated antioxidant enzymes were variably downregulated by vatalanib. In human vascular smooth muscles, VEGFI increased Nox activity and stimulated Ca2+ influx and MLC20 phosphorylation. Acetylcholine-induced vasodilatation was impaired and U46619 induced vasoconstriction was enhanced by vatalanib, effects normalized by N acetyl-cysteine and worsened by L-NAME. In vatalanib-, but not gefitinib-treated mice vasorelaxation was reduced and media:lumen ratio of mesenteric arteries was increased with associated increased cardiovascular and renal oxidative stress, decreased Nrf-2 activity and downregulation of antioxidant genes. We demonstrate that inhibition of VEGF signaling induces vascular dysfunction through redox sensitive processes. Our findings identify Noxs and antioxidant enzymes as novel targets underling VEGFI-induced vascular dysfunction. These molecular processes may contribute to vascular toxicity and hypertension in VEGFI-treated patients. PMID- 29483229 TI - Cocaine-Responsive miRNA and Blood Pressure Elevation. PMID- 29483231 TI - Management of a Pregnant Woman With Fibromuscular Dysplasia. PMID- 29483230 TI - Cocaine Exposure Increases Blood Pressure and Aortic Stiffness via the miR-30c-5p Malic Enzyme 1-Reactive Oxygen Species Pathway. AB - Cocaine abuse increases the risk of cardiovascular mortality and morbidity; however, the underlying molecular mechanisms remain elusive. By using a mouse model for cocaine abuse/use, we found that repeated cocaine injection led to increased blood pressure and aortic stiffness in mice associated with elevated levels of reactive oxygen species (ROS) in the aortas, a phenomenon similar to that observed in hypertensive humans. This ROS elevation was correlated with downregulation of Me1 (malic enzyme 1), an important redox molecule that counteracts ROS generation, and upregulation of microRNA (miR)-30c-5p that targets Me1 expression by directly binding to its 3'UTR (untranslated region). Remarkably, lentivirus-mediated overexpression of miR-30c-5p in aortic smooth muscle cells recapitulated the effect of cocaine on Me1 suppression, which in turn led to ROS elevation. Moreover, in vivo silencing of miR-30c-5p in smooth muscle cells resulted in Me1 upregulation, ROS reduction, and significantly suppressed cocaine-induced increases in blood pressure and aortic stiffness-a similar effect to that produced by treatment with the antioxidant N-acetyl cysteine. Discovery of this novel cocaine-?miR-30c-5p-?Me1-?ROS pathway provides a potential new therapeutic avenue for treatment of cocaine abuse-related cardiovascular disease. PMID- 29483233 TI - AEDs are problematic, but Mrs A is a misleading case. PMID- 29483232 TI - Whole Exome Sequencing Reveals a Monogenic Cause of Disease in ~43% of 35 Families With Midaortic Syndrome. AB - Midaortic syndrome (MAS) is a rare cause of severe childhood hypertension characterized by narrowing of the abdominal aorta in children and is associated with extensive vascular disease. It may occur as part of a genetic syndrome, such as neurofibromatosis, or as consequence of a pathological inflammatory disease. However, most cases are considered idiopathic. We hypothesized that in a high percentage of these patients, a monogenic cause of disease may be detected by evaluating whole exome sequencing data for mutations in 1 of 38 candidate genes previously described to cause vasculopathy. We studied a cohort of 36 individuals from 35 different families with MAS by exome sequencing. In 15 of 35 families (42.9%), we detected likely causal dominant mutations. In 15 of 35 (42.9%) families with MAS, whole exome sequencing revealed a mutation in one of the genes previously associated with vascular disease (NF1, JAG1, ELN, GATA6, and RNF213). Ten of the 15 mutations have not previously been reported. This is the first report of ELN, RNF213, or GATA6 mutations in individuals with MAS. Mutations were detected in NF1 (6/15 families), JAG1 (4/15 families), ELN (3/15 families), and one family each for GATA6 and RNF213 Eight individuals had syndromic disease and 7 individuals had isolated MAS. Whole exome sequencing can provide conclusive molecular genetic diagnosis in a high fraction of individuals with syndromic or isolated MAS. Establishing an etiologic diagnosis may reveal genotype/phenotype correlations for MAS in the future and should, therefore, be performed routinely in MAS. PMID- 29483234 TI - Obligation for transparency regarding treating physician credentials at academic health centres. AB - Academic health centres have historically treated patients with the most complex of diseases, served as training grounds to teach the next generations of physicians and fostered an innovative environment for research and discovery. The physicians who hold faculty positions at these institutions have long understood how these key academic goals are critical to serve their patient community effectively. Recent healthcare reforms, however, have led many academic health centres to recruit physicians without these same academic expectations and to partner with non-faculty physicians at other health systems. There has been limited transparency in regard to the expertise among the physicians and the academic faculty within these larger entities. Such lack of transparency may lead to confusion among patients regarding the qualifications of who is actually treating them. This could threaten the ethical principles of patient autonomy, benevolence and non-maleficence as patients risk making uninformed decisions that might lead to poorer outcomes. Furthermore, this lack of transparency unjustly devalues the achievements of physician faculty members as well as potentially the university they represent. In this paper, it is suggested that academic health centres have an obligation to foster total transparency regarding what if any role a physician has at a university or medical school when university or other academic monikers are used at a hospital. PMID- 29483235 TI - SMARCB1 Deficiency Integrates Epigenetic Signals to Oncogenic Gene Expression Program Maintenance in Human Acute Myeloid Leukemia. AB - SWI/SNF is an evolutionarily conserved multi-subunit chromatin remodeling complex that regulates epigenetic architecture and cellular identity. Although SWI/SNF genes are altered in approximately 25% of human malignancies, evidences showing their involvement in tumor cell-autonomous chromatin regulation and transcriptional plasticity are limiting. This study demonstrates that human primary acute myeloid leukemia (AML) cells exhibit near complete loss of SMARCB1 (BAF47 or SNF5/INI1) and SMARCD2 (BAF60B) associated with nucleation of SWI/SNFDelta SMARCC1 (BAF155), an intact core component of SWI/SNFDelta, colocalized with H3K27Ac to target oncogenic loci in primary AML cells. Interestingly, gene ontology (GO) term and pathway analysis suggested that SMARCC1 occupancy was enriched on genes regulating Rac GTPase activation, cell trafficking, and AML-associated transcriptional dysregulation. Transcriptome profiling revealed that expression of these genes is upregulated in primary AML blasts, and loss-of-function studies confirmed transcriptional regulation of Rac GTPase guanine nucleotide exchange factors (GEF) by SMARCB1. Mechanistically, loss of SMARCB1 increased recruitment of SWI/SNFDelta and associated histone acetyltransferases (HAT) to target loci, thereby promoting H3K27Ac and gene expression. Together, SMARCB1 deficiency induced GEFs for Rac GTPase activation and augmented AML cell migration and survival. Collectively, these findings highlight tumor suppressor role of SMARCB1 and illustrate SWI/SNFDelta function in maintaining an oncogenic gene expression program in AML.Implications: Loss of SMARCB1 in AML associates with SWI/SNFDelta nucleation, which in turn promotes Rac GTPase GEF expression, Rac activation, migration, and survival of AML cells, highlighting SWI/SNFDelta downstream signaling as important molecular regulator in AML. Mol Cancer Res; 16(5); 791-804. (c)2018 AACR. PMID- 29483236 TI - Penetrance estimates for BRCA1, BRCA2 (also applied to Lynch syndrome) based on presymptomatic testing: a new unbiased method to assess risk? AB - PURPOSE: The identification of BRCA1, BRCA2 or mismatch repair (MMR) pathogenic gene variants in familial breast/ovarian/colorectal cancer families facilitates predictive genetic testing of at-risk relatives. However, controversy still exists regarding overall lifetime risks of cancer in individuals testing positive. METHODS: We assessed the penetrance of BRCA1, BRCA2, MLH1 and MSH2 mutations in men and women using Bayesian calculations based on ratios of positive to negative presymptomatic testing by 10-year age cohorts. Mutation position was also assessed for BRCA1/BRCA2. RESULTS: Using results from 2264 presymptomatic tests in first-degree relatives (FDRs) of mutation carriers in BRCA1 and BRCA2 and 646 FDRs of patients with MMR mutations, we assessed overall associated cancer penetrance to age of 68 years as 73% (95% CI 61% to 82%) for BRCA1, 60% (95% CI 49% to 71%) for BRCA2, 95% (95% CI 76% to 99%) for MLH1% and 61% (95% CI 49% to 76%) for MSH2. There was no evidence for significant penetrance for males in BRCA1 or BRCA2 families and males had equivalent penetrance to females with Lynch syndrome. Mutation position and degree of family history influenced penetrance in BRCA2 but not BRCA1. CONCLUSION: We describe a new method for assessing penetrance in cancer-prone syndromes. Results are in keeping with published prospective series and present modern-day estimates for overall disease penetrance that bypasses retrospective series biases. PMID- 29483237 TI - A Novel Tool for Visualizing Composite Endpoint Associations. PMID- 29483238 TI - Prebiotic prevents impaired kidney and renal Oat3 functions in obese rats. AB - Obesity is health issue worldwide, which can lead to kidney dysfunction. Prebiotics are non-digestible foods that have beneficial effects on health. This study aimed to investigate the effects of xylooligosaccharide (XOS) on renal function, renal organic anion transporter 3 (Oat3) and the mechanisms involved. High-fat diet was provided for 12 weeks in male Wistar rats. After that, the rats were divided into normal diet (ND); normal diet treated with XOS (NDX); high-fat diet (HF) and high-fat diet treated with XOS (HFX). XOS was given daily at a dose of 1000 mg for 12 weeks. At week 24, HF rats showed a significant increase in obesity and insulin resistance associated with podocyte injury, increased microalbuminuria, decreased creatinine clearance and impaired Oat3 function. These alterations were improved by XOS supplementation. Renal MDA level and the expression of AT1R, NOX4, p67phox, 4-HNE, phosphorylated PKCalpha and ERK1/2 were significantly decreased after XOS treatment. In addition, Nrf2-Keap1 pathway, SOD2 and GCLC expression as well as renal apoptosis were also significantly reduced by XOS. These data suggest that XOS could indirectly restore renal function and Oat3 function via the reduction of oxidative stress and apoptosis through the modulating of AT1R-PKCalpha-NOXs activation in obese insulin resistant rats. These attenuations were instigated by the improvement of obesity, hyperlipidemia and insulin resistance. PMID- 29483239 TI - How the science of injury prevention contributes to advancing home fire safety in the USA: successes and opportunities. AB - BACKGROUND: In the decades since the landmark report-America Burning-was published in 1973, the number of home fire deaths has shrunk from >5500 per year to 2650 in 2015. This paper: (1) describes how science and practice in injury prevention and fire and life safety contributed to successful interventions, and (2) identifies emerging strategies and future opportunities to prevent home fire related deaths. METHODS: The aims are addressed through the lens of population health research, with a focus on the work of selected Centers for Disease Control and Prevention-funded Injury Control Research Centers. Results are organised using the Haddon Matrix and an ecological model. RESULTS: We found evidence to support interventions that address all components of both the matrix and the model, including: reduced ignition propensity cigarettes, stop smoking campaigns, housing codes, residential sprinkler systems, smoke alarms, community risk reduction, school-based educational programmes, and fire and burn response systems. Future reductions are likely to come from enhancing residential sprinkler and smoke alarm technology, and increasing their utilisation; expanding the use of community risk reduction methods; and implementing new technological solutions. Despite the successes, substantial disparities in home fire death rates remain, reflecting underlying social determinants of health. CONCLUSION: Most of the evidence-supported interventions were focused on changing the policy and community environments to prevent home fires and reduce injury when a fire occurs. Future prevention efforts should give high priority to addressing the continued disparities in home fire deaths. PMID- 29483240 TI - Optimal location of emergency stations in underground mine networks using a multiobjective mathematical model. AB - Background Every year, many mining accidents occur in underground mines all over the world resulting in the death and maiming of many miners and heavy financial losses to mining companies. Underground mining accounts for an increasing share of these events due to their special circumstances and the risks of working therein. Thus, the optimal location of emergency stations within the network of an underground mine in order to provide medical first aid and transport injured people at the right time, plays an essential role in reducing deaths and disabilities caused by accidents Objective The main objective of this study is to determine the location of emergency stations (ES) within the network of an underground coal mine in order to minimize the outreach time for the injured. Methods A three-objective mathematical model is presented for placement of ES facility location selection and allocation of facilities to the injured in various stopes. Results Taking into account the radius of influence for each ES, the proposed model is capable to reduce the maximum time for provision of emergency services in the event of accident for each stope. In addition, the coverage or lack of coverage of each stope by any of the emergency facility is determined by means of Floyd-Warshall algorithm and graph. To solve the problem, a global criterion method using GAMS software is used to evaluate the accuracy and efficiency of the model. Conclusions 7 locations were selected from among 46 candidates for the establishment of emergency facilities in Tabas underground coal mine. PMID- 29483241 TI - Maternal depression is associated with injuries in children aged 2-4 years: the Pelotas 2004 Birth Cohort. AB - INTRODUCTION: Injuries during childhood, which mostly consist of falls, burns, drowning, poisonings and car crashes, are among the main causes of death among children and young adults in several countries. OBJECTIVES: To investigate the association between maternal depression and the incidence of injuries during childhood. METHODS: In 2004, children who were born in the municipality of Pelotas, Brazil, were enrolled in a population-based birth cohort, with evaluations at birth and at 3, 12, 24 and 48 months of age. Maternal depression during pregnancy was evaluated at the time of delivery. At 12 and 24 months post partum, the Edinburgh Postnatal Depression Scale (EPDS) was used. The injuries incidence rates at ages of 24-48 months and the crude and adjusted IRRs were calculated with 95% CI through Poisson's regression. RESULTS: A total of 3533 children were analysed. The incidence of injuries was higher among children whose mothers presented depressive symptoms during pregnancy and at 12 and 24 months compared with those whose mothers did not present any symptoms. In the adjusted analysis, the IRR among girls whose mothers presented depressive symptoms during pregnancy and EPDS >=13 at 12 and 24 months was 1.31 (1.15-1.50); and, among boys, 1.18 (1.03-1.36). INTERPRETATION: Maternal depression is associated with higher incidence of injuries between 24 and 48 months of age, in both sexes. PMID- 29483243 TI - Strain-induced accelerated asymmetric spatial degradation of polymeric vascular scaffolds. AB - Polymer-based bioresorbable scaffolds (BRS) seek to eliminate long-term complications of metal stents. However, current BRS designs bear substantially higher incidence of clinical failures, especially thrombosis, compared with metal stents. Research strategies inherited from metal stents fail to consider polymer microstructures and dynamics--issues critical to BRS. Using Raman spectroscopy, we demonstrate microstructural heterogeneities within polymeric scaffolds arising from integrated strain during fabrication and implantation. Stress generated from crimping and inflation causes loss of structural integrity even before chemical degradation, and the induced differences in crystallinity and polymer alignment across scaffolds lead to faster degradation in scaffold cores than on the surface, which further enlarge localized deformation. We postulate that these structural irregularities and asymmetric material degradation present a response to strain and thereby clinical performance different from metal stents. Unlike metal stents which stay patent and intact until catastrophic fracture, BRS exhibit loss of structural integrity almost immediately upon crimping and expansion. Irregularities in microstructure amplify these effects and can have profound clinical implications. Therefore, polymer microstructure should be considered in earliest design stages of resorbable devices, and fabrication processes must be well-designed with microscopic perspective. PMID- 29483242 TI - Convergence of marine megafauna movement patterns in coastal and open oceans. AB - The extent of increasing anthropogenic impacts on large marine vertebrates partly depends on the animals' movement patterns. Effective conservation requires identification of the key drivers of movement including intrinsic properties and extrinsic constraints associated with the dynamic nature of the environments the animals inhabit. However, the relative importance of intrinsic versus extrinsic factors remains elusive. We analyze a global dataset of ~2.8 million locations from >2,600 tracked individuals across 50 marine vertebrates evolutionarily separated by millions of years and using different locomotion modes (fly, swim, walk/paddle). Strikingly, movement patterns show a remarkable convergence, being strongly conserved across species and independent of body length and mass, despite these traits ranging over 10 orders of magnitude among the species studied. This represents a fundamental difference between marine and terrestrial vertebrates not previously identified, likely linked to the reduced costs of locomotion in water. Movement patterns were primarily explained by the interaction between species-specific traits and the habitat(s) they move through, resulting in complex movement patterns when moving close to coasts compared with more predictable patterns when moving in open oceans. This distinct difference may be associated with greater complexity within coastal microhabitats, highlighting a critical role of preferred habitat in shaping marine vertebrate global movements. Efforts to develop understanding of the characteristics of vertebrate movement should consider the habitat(s) through which they move to identify how movement patterns will alter with forecasted severe ocean changes, such as reduced Arctic sea ice cover, sea level rise, and declining oxygen content. PMID- 29483244 TI - Multiscale approach reveals that Cloudina aggregates are detritus and not in situ reef constructions. AB - The earliest metazoans capable of biomineralization appeared during the late Ediacaran Period (635-541 Ma) in strata associated with shallow water microbial reefs. It has been suggested that some Ediacaran microbial reefs were dominated (and possibly built) by an abundant and globally distributed tubular organism known as Cloudina If true, this interpretation implies that metazoan framework reef building-a complex behavior that is responsible for some of the largest bioconstructions and most diverse environments in modern oceans-emerged much earlier than previously thought. Here, we present 3D reconstructions of Cloudina populations, produced using an automated serial grinding and imaging system coupled with a recently developed neural network image classifier. Our reconstructions show that Cloudina aggregates are composed of transported remains while detailed field observations demonstrate that the studied reef outcrops contain only detrital Cloudina buildups, suggesting that Cloudina played a minor role in Ediacaran reef systems. These techniques have wide applicability to problems that require 3D reconstructions where physical separation is impossible and a lack of density contrast precludes tomographic imaging techniques. PMID- 29483245 TI - Reforestation can sequester two petagrams of carbon in US topsoils in a century. AB - Soils are Earth's largest terrestrial carbon (C) pool, and their responsiveness to land use and management make them appealing targets for strategies to enhance C sequestration. Numerous studies have identified practices that increase soil C, but their inferences are often based on limited data extrapolated over large areas. Here, we combine 15,000 observations from two national-level databases with remote sensing information to address the impacts of reforestation on the sequestration of C in topsoils (uppermost mineral soil horizons). We quantify C stocks in cultivated, reforesting, and natural forest topsoils; rates of C accumulation in reforesting topsoils; and their contribution to the US forest C sink. Our results indicate that reforestation increases topsoil C storage, and that reforesting lands, currently occupying >500,000 km2 in the United States, will sequester a cumulative 1.3-2.1 Pg C within a century (13-21 Tg C.y-1). Annually, these C gains constitute 10% of the US forest sector C sink and offset 1% of all US greenhouse gas emissions. PMID- 29483246 TI - Citywide cluster randomized trial to restore blighted vacant land and its effects on violence, crime, and fear. AB - Vacant and blighted urban land is a widespread and potentially risky environmental condition encountered by millions of people on a daily basis. About 15% of the land in US cities is deemed vacant or abandoned, an area roughly the size of Switzerland. In a citywide cluster randomized controlled trial, we investigated the effects of standardized, reproducible interventions that restore vacant land on the commission of violence, crime, and the perceptions of fear and safety. Quantitative and ethnographic analyses were included in a mixed-methods approach to more fully test and explicate our findings. A total of 541 randomly sampled vacant lots were randomly assigned into treatment and control study arms; outcomes from police and 445 randomly sampled participants were analyzed over a 38-month study period. Participants living near treated vacant lots reported significantly reduced perceptions of crime (-36.8%, P < 0.05), vandalism (-39.3%, P < 0.05), and safety concerns when going outside their homes (-57.8%, P < 0.05), as well as significantly increased use of outside spaces for relaxing and socializing (75.7%, P < 0.01). Significant reductions in crime overall (-13.3%, P < 0.01), gun violence (-29.1%, P < 0.001), burglary (-21.9%, P < 0.001), and nuisances (-30.3%, P < 0.05) were also found after the treatment of vacant lots in neighborhoods below the poverty line. Blighted and vacant urban land affects people's perceptions of safety, and their actual, physical safety. Restoration of this land can be an effective and scalable infrastructure intervention for gun violence, crime, and fear in urban neighborhoods. PMID- 29483248 TI - Natural diamond formation by self-redox of ferromagnesian carbonate. AB - Formation of natural diamonds requires the reduction of carbon to its bare elemental form, and pressures (P) greater than 5 GPa to cross the graphite diamond transition boundary. In a study of shocked ferromagnesian carbonate at the Xiuyan impact crater, we found that the impact pressure-temperature (P-T) of 25-45 GPa and 800-900 degrees C were sufficient to decompose ankerite Ca(Fe2+,Mg)(CO3)2 to form diamond in the absence of another reductant. The carbonate self-reduced to diamond by concurrent oxidation of Fe2+ to Fe3+ to form a high-P polymorph of magnesioferrite, MgFe3+2O4 Discovery of the subsolidus carbonate self-reduction mechanism indicates that diamonds could be ubiquitously present as a dominant host for carbon in the Earth's lower mantle. PMID- 29483247 TI - A comprehensive genomic history of extinct and living elephants. AB - Elephantids are the world's most iconic megafaunal family, yet there is no comprehensive genomic assessment of their relationships. We report a total of 14 genomes, including 2 from the American mastodon, which is an extinct elephantid relative, and 12 spanning all three extant and three extinct elephantid species including an ~120,000-y-old straight-tusked elephant, a Columbian mammoth, and woolly mammoths. Earlier genetic studies modeled elephantid evolution via simple bifurcating trees, but here we show that interspecies hybridization has been a recurrent feature of elephantid evolution. We found that the genetic makeup of the straight-tusked elephant, previously placed as a sister group to African forest elephants based on lower coverage data, in fact comprises three major components. Most of the straight-tusked elephant's ancestry derives from a lineage related to the ancestor of African elephants while its remaining ancestry consists of a large contribution from a lineage related to forest elephants and another related to mammoths. Columbian and woolly mammoths also showed evidence of interbreeding, likely following a latitudinal cline across North America. While hybridization events have shaped elephantid history in profound ways, isolation also appears to have played an important role. Our data reveal nearly complete isolation between the ancestors of the African forest and savanna elephants for ~500,000 y, providing compelling justification for the conservation of forest and savanna elephants as separate species. PMID- 29483249 TI - Effects of maturation on the conformational free-energy landscape of SOD1. AB - Amyotrophic lateral sclerosis (ALS) is a devastating fatal syndrome characterized by very rapid degeneration of motor neurons. A leading hypothesis is that ALS is caused by toxic protein misfolding and aggregation, as also occurs in many other neurodegenerative disorders, such as prion, Alzheimer's, Parkinson's, and Huntington's diseases. A prominent cause of familial ALS is mutations in the protein superoxide dismutase (SOD1), which promote the formation of misfolded SOD1 conformers that are prone to aberrant interactions both with each other and with other cellular components. We have shown previously that immature SOD1, lacking bound Cu and Zn metal ions and the intrasubunit disulfide bond (apoSOD12SH), has a rugged free-energy surface (FES) and exchanges with four other conformations (excited states) that have millisecond lifetimes and sparse populations on the order of a few percent. Here, we examine further states of SOD1 along its maturation pathway, as well as those off-pathway resulting from metal loss that have been observed in proteinaceous inclusions. Metallation and disulfide bond formation lead to structural transformations including local ordering of the electrostatic loop and native dimerization that are observed in rare conformers of apoSOD12SH; thus, SOD1 maturation may occur via a population switch mechanism whereby posttranslational modifications select for preexisting structures on the FES. Metallation and oxidation of SOD1 stabilize the native, mature conformation and decrease the number of detected excited conformational states, suggesting that it is the immature forms of the protein that contribute to misfolded conformations in vivo rather than the highly stable enzymatically active dimer. PMID- 29483250 TI - Brain-to-brain coupling during handholding is associated with pain reduction. AB - The mechanisms underlying analgesia related to social touch are not clear. While recent research highlights the role of the empathy of the observer to pain relief in the target, the contribution of social interaction to analgesia is unknown. The current study examines brain-to-brain coupling during pain with interpersonal touch and tests the involvement of interbrain synchrony in pain alleviation. Romantic partners were assigned the roles of target (pain receiver) and observer (pain observer) under pain-no-pain and touch-no-touch conditions concurrent with EEG recording. Brain-to-brain coupling in alpha-mu band (8-12 Hz) was estimated by a three-step multilevel analysis procedure based on running window circular correlation coefficient and post hoc power of the findings was calculated using simulations. Our findings indicate that hand-holding during pain administration increases brain-to-brain coupling in a network that mainly involves the central regions of the pain target and the right hemisphere of the pain observer. Moreover, brain-to-brain coupling in this network was found to correlate with analgesia magnitude and observer's empathic accuracy. These findings indicate that brain-to-brain coupling may be involved in touch-related analgesia. PMID- 29483251 TI - Grip and slip of L1-CAM on adhesive substrates direct growth cone haptotaxis. AB - Chemical cues presented on the adhesive substrate direct cell migration, a process termed haptotaxis. To migrate, cells must generate traction forces upon the substrate. However, how cells probe substrate-bound cues and generate directional forces for migration remains unclear. Here, we show that the cell adhesion molecule (CAM) L1-CAM is involved in laminin-induced haptotaxis of axonal growth cones. L1-CAM underwent grip and slip on the substrate. The ratio of the grip state was higher on laminin than on the control substrate polylysine; this was accompanied by an increase in the traction force upon laminin. Our data suggest that the directional force for laminin-induced growth cone haptotaxis is generated by the grip and slip of L1-CAM on the substrates, which occur asymmetrically under the growth cone. This mechanism is distinct from the conventional cell signaling models for directional cell migration. We further show that this mechanism is disrupted in a human patient with L1-CAM syndrome, suffering corpus callosum agenesis and corticospinal tract hypoplasia. PMID- 29483252 TI - Infants expect ingroup support to override fairness when resources are limited. AB - Recent research suggests that the foundations of human moral cognition include abstract principles of fairness and ingroup support. We examined which principle 1.5-y-old infants and 2.5-y-old toddlers would prioritize when the two were pitted against each other. In violation-of-expectation tasks, a puppet distributor brought in either two (two-item condition) or three (three-item condition) items and faced two potential recipients, an ingroup and an outgroup puppet. In each condition, the distributor allocated two items in one of three events: She gave one item each to the ingroup and outgroup puppets (equal event), she gave both items to the ingroup puppet (favors-ingroup event), or she gave both items to the outgroup puppet (favors-outgroup event). Children in the two item condition looked significantly longer at the equal or favors-outgroup event than at the favors-ingroup event, suggesting that when there were only enough items for the group to which the distributor belonged, children detected a violation if she gave any of the items to the outgroup puppet. In the three-item condition, in contrast, children looked significantly longer at the favors ingroup or favors-outgroup event than at the equal event, suggesting that when there were enough items for all puppets present, children detected a violation if the distributor chose to give two items to one recipient and none to the other, regardless of which recipient was advantaged. Thus, infants and toddlers expected fairness to prevail when there were as many items as puppets, but they expected ingroup support to trump fairness otherwise. PMID- 29483253 TI - Social norm enforcement in ethnically diverse communities. AB - Recent waves of immigration to Western nations have fueled a debate over the consequences of ethnic diversity for social cohesion. One prominent argument in this debate holds that diversity is detrimental to trust and cooperation because individuals in heterogeneous communities face difficulties in enforcing social norms across ethnic lines. We examine this proposition in a field experiment involving real-life interactions among residents of multiethnic German neighborhoods. We find significant ethnic asymmetries in the pattern of norm enforcement: Members of the majority "native" German population are more active in sanctioning norm violations, while ethnic minorities are more likely to find themselves the target of sanctions. We interpret these results in light of prevailing status inequalities between ethnic minorities and the native majority. We further calculate that, as a result of ethnic discrimination, social control is likely to rise in communities with moderate minority population shares. PMID- 29483254 TI - Optimal multiguidance integration in insect navigation. AB - In the last decades, desert ants have become model organisms for the study of insect navigation. In finding their way, they use two major navigational routines: path integration using a celestial compass and landmark guidance based on sets of panoramic views of the terrestrial environment. It has been claimed that this information would enable the insect to acquire and use a centralized cognitive map of its foraging terrain. Here, we present a decentralized architecture, in which the concurrently operating path integration and landmark guidance routines contribute optimally to the directions to be steered, with "optimal" meaning maximizing the certainty (reliability) of the combined information. At any one time during its journey, the animal computes a path integration (global) vector and landmark guidance (local) vector, in which the length of each vector is proportional to the certainty of the individual estimates. Hence, these vectors represent the limited knowledge that the navigator has at any one place about the direction of the goal. The sum of the global and local vectors indicates the navigator's optimal directional estimate. Wherever applied, this decentralized model architecture is sufficient to simulate the results of quite a number of diverse cue-conflict experiments, which have recently been performed in various behavioral contexts by different authors in both desert ants and honeybees. They include even those experiments that have deliberately been designed by former authors to strengthen the evidence for a metric cognitive map in bees. PMID- 29483255 TI - Health effects of banning beehive coke ovens and implementation of the ban in China. AB - Environmental legislation and proper implementation are critical in environmental protection. In the past, beehive coke ovens (BCOs) were popular in China, resulting in enormous emissions of benzo[a]pyrene (BaP), a common indicator of carcinogenic polycyclic aromatic hydrocarbons. BCOs were banned by the Coal Law in 1996. Although BCO numbers have declined since the ban, they were not eliminated until 2011 due to poor implementation. Here, we present the results of a quantitative evaluation of the health effects of historical BCO operation, the health benefits of the ban, and the adverse impacts of the poor implementation of the ban. With only limited official statistics available, historical and geospatial data about BCOs were reconstructed based on satellite images. Emission inventories of BaP from BCOs were compiled and used to model atmospheric transport, nonoccupational population exposure, and induced lung cancer risk. We demonstrated that more than 20% of the BaP in ambient air was from BCOs in the peak year. The cumulative nonoccupational excess lung cancer cases associated with BaP from BCOs was 3,500 (+/-1,500) from 1982 to 2015. If there was no ban, the cases would be as high as 9,290 (+/-4,300), indicating the significant health benefits of the Coal Law. On the other hand, if the ban had been fully implemented immediately after the law was enforced in 1996, the cumulative cases would be 1,500 (+/-620), showing the importance of implementing the law. PMID- 29483256 TI - Forecasting the spatial transmission of influenza in the United States. AB - Recurrent outbreaks of seasonal and pandemic influenza create a need for forecasts of the geographic spread of this pathogen. Although it is well established that the spatial progression of infection is largely attributable to human mobility, difficulty obtaining real-time information on human movement has limited its incorporation into existing infectious disease forecasting techniques. In this study, we develop and validate an ensemble forecast system for predicting the spatiotemporal spread of influenza that uses readily accessible human mobility data and a metapopulation model. In retrospective state level forecasts for 35 US states, the system accurately predicts local influenza outbreak onset,-i.e., spatial spread, defined as the week that local incidence increases above a baseline threshold-up to 6 wk in advance of this event. In addition, the metapopulation prediction system forecasts influenza outbreak onset, peak timing, and peak intensity more accurately than isolated location specific forecasts. The proposed framework could be applied to emergent respiratory viruses and, with appropriate modifications, other infectious diseases. PMID- 29483257 TI - Human aging and disease: Lessons from age-related macular degeneration. AB - Aging is the most significant risk factor associated with chronic disease in humans. The accumulation of genetic damage throughout life leads to a variety of biological aberrations, including disrupted protein homeostasis, metabolic dysfunction, and altered cellular signaling. Such changes ultimately result in cellular senescence, death, or transformation to uncontrolled proliferation, thereby compromising human health. Events contributing to age-dependent physiological decline also occur in the context of hormonal and metabolic changes, affecting interconnected cellular networks. This complexity often confounds the development of effective treatments for aging and age-related diseases. In contrast to monotherapy and polypharmacology, an innovative systems pharmacology approach can identify synergistic combinations of drugs that modulate distinct mechanistic nodes within a network, minimizing off-target side effects and enabling better therapeutic outcomes. G protein-coupled receptors (GPCRs) are particularly good targets for the application of systems pharmacology, because they activate different signal transduction pathways that can culminate in a common response. Here, we describe a systems pharmacology strategy for the treatment of age-related macular degeneration (AMD), a multifactorial chronic disease of the eye. By considering the retina as part of a large, interconnected network, systems pharmacology will enable the identification of combination therapies targeting GPCRs to help restore genomic, proteomic, and endocrine homeostasis. Such an approach can be advantageous in providing drug regimens for the treatment of AMD, while also having broader ramifications for ameliorating adverse effects of chronic, age-related disease in humans. PMID- 29483258 TI - OCT4/POU5F1 is required for NANOG expression in bovine blastocysts. AB - Mammalian preimplantation development involves two lineage specifications: first, the CDX2-expressing trophectoderm (TE) and a pluripotent inner cell mass (ICM) are separated during blastocyst formation. Second, the pluripotent epiblast (EPI; expressing NANOG) and the differentiated primitive endoderm (PrE; expressing GATA6) diverge within the ICM. Studies in mice revealed that OCT4/POU5F1 is at the center of a pluripotency regulatory network. To study the role of OCT4 in bovine preimplantation development, we generated OCT4 knockout (KO) fibroblasts by CRISPR-Cas9 and produced embryos by somatic cell nuclear transfer (SCNT). SCNT embryos from nontransfected fibroblasts and embryos produced by in vitro fertilization served as controls. In OCT4 KO morulae (day 5), ~70% of the nuclei were OCT4 positive, indicating that maternal OCT4 mRNA partially maintains OCT4 protein expression during early development. In contrast, OCT4 KO blastocysts (day 7) lacked OCT4 protein entirely. CDX2 was detected only in TE cells; OCT4 is thus not required to suppress CDX2 in the ICM. Control blastocysts showed a typical salt-and-pepper distribution of NANOG- and GATA6-positive cells in the ICM. In contrast, NANOG was absent or very faint in the ICM of OCT4 KO blastocysts, and no cells expressing exclusively NANOG were observed. This mimics findings in OCT4-deficient human blastocysts but is in sharp contrast to Oct4 null mouse blastocysts, where NANOG persists and PrE development fails. Our study supports bovine embryogenesis as a model for early human development and exemplifies a general strategy for studying the roles of specific genes in embryos of domestic species. PMID- 29483259 TI - Molecular machines with bio-inspired mechanisms. AB - The widespread use of molecular-level motion in key natural processes suggests that great rewards could come from bridging the gap between the present generation of synthetic molecular machines-which by and large function as switches-and the machines of the macroscopic world, which utilize the synchronized behavior of integrated components to perform more sophisticated tasks than is possible with any individual switch. Should we try to make molecular machines of greater complexity by trying to mimic machines from the macroscopic world or instead apply unfamiliar (and no doubt have to discover or invent currently unknown) mechanisms utilized by biological machines? Here we try to answer that question by exploring some of the advances made to date using bio inspired machine mechanisms. PMID- 29483261 TI - Correction for Meslin et al., Structural complexity and molecular heterogeneity of a butterfly ejaculate reflect a complex history of selection. PMID- 29483260 TI - Early anthropogenic impact on Western Central African rainforests 2,600 y ago. AB - A potential human footprint on Western Central African rainforests before the Common Era has become the focus of an ongoing controversy. Between 3,000 y ago and 2,000 y ago, regional pollen sequences indicate a replacement of mature rainforests by a forest-savannah mosaic including pioneer trees. Although some studies suggested an anthropogenic influence on this forest fragmentation, current interpretations based on pollen data attribute the ''rainforest crisis'' to climate change toward a drier, more seasonal climate. A rigorous test of this hypothesis, however, requires climate proxies independent of vegetation changes. Here we resolve this controversy through a continuous 10,500-y record of both vegetation and hydrological changes from Lake Barombi in Southwest Cameroon based on changes in carbon and hydrogen isotope compositions of plant waxes. [Formula: see text]13C-inferred vegetation changes confirm a prominent and abrupt appearance of C4 plants in the Lake Barombi catchment, at 2,600 calendar years before AD 1950 (cal y BP), followed by an equally sudden return to rainforest vegetation at 2,020 cal y BP. [Formula: see text]D values from the same plant wax compounds, however, show no simultaneous hydrological change. Based on the combination of these data with a comprehensive regional archaeological database we provide evidence that humans triggered the rainforest fragmentation 2,600 y ago. Our findings suggest that technological developments, including agricultural practices and iron metallurgy, possibly related to the large-scale Bantu expansion, significantly impacted the ecosystems before the Common Era. PMID- 29483262 TI - Direct observation of backbone planarization via side-chain alignment in single bulky-substituted polythiophenes. AB - The backbone conformation of conjugated polymers affects, to a large extent, their optical and electronic properties. The usually flexible substituents provide solubility and influence the packing behavior of conjugated polymers in films or in bad solvents. However, the role of the side chains in determining and potentially controlling the backbone conformation, and thus the optical and electronic properties on the single polymer level, is currently under debate. Here, we investigate directly the impact of the side chains by studying the bulky substituted poly(3-(2,5-dioctylphenyl)thiophene) (PDOPT) and the common poly(3 hexylthiophene) (P3HT), both with a defined molecular weight and high regioregularity, using low-temperature single-chain photoluminescence (PL) spectroscopy and quantum-classical simulations. Surprisingly, the optical transition energy of PDOPT is significantly (~2,000 cm-1 or 0.25 eV) red-shifted relative to P3HT despite a higher static and dynamic disorder in the former. We ascribe this red shift to a side-chain induced backbone planarization in PDOPT, supported by temperature-dependent ensemble PL spectroscopy. Our atomistic simulations reveal that the bulkier 2,5-dioctylphenyl side chains of PDOPT adopt a clear secondary helical structural motif and thus protect conjugation, i.e., enforce backbone planarity, whereas, for P3HT, this is not the case. These different degrees of planarity in both thiophenes do not result in different conjugation lengths, which we found to be similar. It is rather the stronger electronic coupling between the repeating units in the more planar PDOPT which gives rise to the observed spectral red shift as well as to a reduced calculated electron-hole polarization. PMID- 29483263 TI - For Black men, being tall increases threat stereotyping and police stops. AB - Height seems beneficial for men in terms of salaries and success; however, past research on height examines only White men. For Black men, height may be more costly than beneficial, primarily signaling threat rather than competence. Three studies reveal the downsides of height in Black men. Study 1 analyzes over 1 million New York Police Department stop-and-frisk encounters and finds that tall Black men are especially likely to receive unjustified attention from police. Then, studies 2 and 3 experimentally demonstrate a causal link between perceptions of height and perceptions of threat for Black men, particularly for perceivers who endorse stereotypes that Black people are more threatening than White people. Together, these data reveal that height is sometimes a liability for Black men, particularly in contexts in which threat is salient. PMID- 29483264 TI - Rapid regulatory evolution of a nonrecombining autosome linked to divergent behavioral phenotypes. AB - In the white-throated sparrow (Zonotrichia albicollis), the second chromosome bears a striking resemblance to sex chromosomes. First, within each breeding pair of birds, one bird is homozygous for the standard arrangement of the chromosome (ZAL2/ZAL2) and its mate is heterozygous for a different version (ZAL2/ZAL2m). Second, recombination is profoundly suppressed between the two versions, leading to genetic differentiation between them. Third, the ZAL2m version is linked with phenotypic traits, such as bright plumage, high aggression, and low parental behavior, which are usually associated with males. These similarities to sex chromosomes suggest that the evolutionary mechanisms that shape sex chromosomes, in particular genetic degeneration of the heterogametic version due to the suppression of recombination, are likely important in this system as well. Here, we investigated patterns of protein sequence evolution and gene expression evolution between the ZAL2 and ZAL2m chromosomes by whole-genome sequencing and transcriptome analyses. Patterns of protein evolution exhibited only weak signals of genetic degeneration, and few genes harbored signatures of positive selection. We found substantial evidence of transcriptome evolution, such as significant expression divergence between ZAL2 and ZAL2m alleles and signatures of dosage compensation for highly expressed genes. These results suggest that, early in the evolution of heteromorphic chromosomes, gene expression divergence and dosage compensation can prevail before large-scale genetic degeneration. Our results show further that suppression of recombination between heteromorphic chromosomes can lead to the evolution of alternative (sex-like) behavioral phenotypes before substantial genetic degeneration. PMID- 29483265 TI - Expanded cellular clones carrying replication-competent HIV-1 persist, wax, and wane. AB - The latent reservoir for HIV-1 in resting CD4+ T cells is a major barrier to cure. Several lines of evidence suggest that the latent reservoir is maintained through cellular proliferation. Analysis of this proliferative process is complicated by the fact that most infected cells carry defective proviruses. Additional complications are that stimuli that drive T cell proliferation can also induce virus production from latently infected cells and productively infected cells have a short in vivo half-life. In this ex vivo study, we show that latently infected cells containing replication-competent HIV-1 can proliferate in response to T cell receptor agonists or cytokines that are known to induce homeostatic proliferation and that this can occur without virus production. Some cells that have proliferated in response to these stimuli can survive for 7 d while retaining the ability to produce virus. This finding supports the hypothesis that both antigen-driven and cytokine-induced proliferation may contribute to the stability of the latent reservoir. Sequencing of replication-competent proviruses isolated from patients at different time points confirmed the presence of expanded clones and demonstrated that while some clones harboring replication-competent virus persist longitudinally on a scale of years, others wax and wane. A similar pattern is observed in longitudinal sampling of residual viremia in patients. The observed patterns are not consistent with a continuous, cell-autonomous, proliferative process related to the HIV-1 integration site. The fact that the latent reservoir can be maintained, in part, by cellular proliferation without viral reactivation poses challenges to cure. PMID- 29483266 TI - Host biotin is required for liver stage development in malaria parasites. AB - Acetyl-CoA carboxylase (ACC) is a biotin-dependent enzyme that is the target of several classes of herbicides. Malaria parasites contain a plant-like ACC, and this is the only protein predicted to be biotinylated in the parasite. We found that ACC is expressed in the apicoplast organelle in liver- and blood-stage malaria parasites; however, it is activated through biotinylation only in the liver stages. Consistent with this observation, deletion of the biotin ligase responsible for ACC biotinylation does not impede blood-stage growth, but results in late liver-stage developmental defects. Biotin depletion increases the severity of the developmental defects, demonstrating that parasite and host biotin metabolism are required for normal liver-stage progression. This finding may link the development of liver-stage malaria parasites to the nutritional status of the host, as neither the parasite nor the human host can synthesize biotin. PMID- 29483267 TI - FLOWERING LOCUS T mRNA is synthesized in specialized companion cells in Arabidopsis and Maryland Mammoth tobacco leaf veins. AB - Flowering is triggered by the transmission of a mobile protein, FLOWERING LOCUS T (FT), from leaves to the shoot apex. FT originates in the phloem of leaf veins. However, the identity of the FT-synthesizing cells in the phloem is not known. As a result, it has not been possible to determine whether the complex regulatory networks that control FT synthesis involve intercellular communication, as is the case in many aspects of plant development. We demonstrate here that FT in Arabidopsis thaliana and FT orthologs in Maryland Mammoth tobacco (Nicotiana tabacum) are produced in two unique files of phloem companion cells. These FT activating cells, visualized by fluorescent proteins, also activate the GALACTINOL SYNTHASE (CmGAS1) promoter from melon (Cucumis melo). Ablating the cells by expression of the diphtheria toxin gene driven by the CmGAS1 promoter delays flowering in both Arabidopsis and Maryland Mammoth tobacco. In Arabidopsis, toxin expression reduces expression of FT and flowering-associated genes downstream, but not upstream, of FT Our results indicate that specific companion cells mediate the essential flowering function. Since the identified cells are present in the minor veins of two unrelated dicotyledonous species, this may be a widespread phenomenon. PMID- 29483268 TI - Transitory microbial habitat in the hyperarid Atacama Desert. AB - Traces of life are nearly ubiquitous on Earth. However, a central unresolved question is whether these traces always indicate an active microbial community or whether, in extreme environments, such as hyperarid deserts, they instead reflect just dormant or dead cells. Although microbial biomass and diversity decrease with increasing aridity in the Atacama Desert, we provide multiple lines of evidence for the presence of an at times metabolically active, microbial community in one of the driest places on Earth. We base this observation on four major lines of evidence: (i) a physico-chemical characterization of the soil habitability after an exceptional rain event, (ii) identified biomolecules indicative of potentially active cells [e.g., presence of ATP, phospholipid fatty acids (PLFAs), metabolites, and enzymatic activity], (iii) measurements of in situ replication rates of genomes of uncultivated bacteria reconstructed from selected samples, and (iv) microbial community patterns specific to soil parameters and depths. We infer that the microbial populations have undergone selection and adaptation in response to their specific soil microenvironment and in particular to the degree of aridity. Collectively, our results highlight that even the hyperarid Atacama Desert can provide a habitable environment for microorganisms that allows them to become metabolically active following an episodic increase in moisture and that once it decreases, so does the activity of the microbiota. These results have implications for the prospect of life on other planets such as Mars, which has transitioned from an earlier wetter environment to today's extreme hyperaridity. PMID- 29483270 TI - Decline and poleward shift in Indian summer monsoon synoptic activity in a warming climate. AB - Cyclonic atmospheric vortices of varying intensity, collectively known as low pressure systems (LPS), travel northwest across central India and produce more than half of the precipitation received by that fertile region and its ~600 million inhabitants. Yet, future changes in LPS activity are poorly understood, due in part to inadequate representation of these storms in current climate models. Using a high-resolution atmospheric general circulation model that realistically simulates the genesis distribution of LPS, here we show that Indian monsoon LPS activity declines about 45% by the late 21st century in simulations of a business-as-usual emission scenario. The distribution of LPS genesis shifts poleward as it weakens, with oceanic genesis decreasing by ~60% and continental genesis increasing by ~10%; over land the increase in storm counts is accompanied by a shift toward lower storm wind speeds. The weakening and poleward shift of the genesis distribution in a warmer climate are confirmed and attributed, via a statistical model, to the reduction and poleward shift of low-level absolute vorticity over the monsoon region, which in turn are robust features of most coupled model projections. The poleward shift in LPS activity results in an increased frequency of extreme precipitation events over northern India. PMID- 29483269 TI - RNA self-assembly contributes to stress granule formation and defining the stress granule transcriptome. AB - Stress granules are higher order assemblies of nontranslating mRNAs and proteins that form when translation initiation is inhibited. Stress granules are thought to form by protein-protein interactions of RNA-binding proteins. We demonstrate RNA homopolymers or purified cellular RNA forms assemblies in vitro analogous to stress granules. Remarkably, under conditions representative of an intracellular stress response, the mRNAs enriched in assemblies from total yeast RNA largely recapitulate the stress granule transcriptome. We suggest stress granules are formed by a summation of protein-protein and RNA-RNA interactions, with RNA self assembly likely to contribute to other RNP assemblies wherever there is a high local concentration of RNA. RNA assembly in vitro is also increased by GR and PR dipeptide repeats, which are known to increase stress granule formation in cells. Since GR and PR dipeptides are involved in neurodegenerative diseases, this suggests that perturbations increasing RNA-RNA assembly in cells could lead to disease. PMID- 29483271 TI - Multifrequency AFM reveals lipid membrane mechanical properties and the effect of cholesterol in modulating viscoelasticity. AB - The physical properties of lipid bilayers comprising the cell membrane occupy the current spotlight of membrane biology. Their traditional representation as a passive 2D fluid has gradually been abandoned in favor of a more complex picture: an anisotropic time-dependent viscoelastic biphasic material, capable of transmitting or attenuating mechanical forces that regulate biological processes. In establishing new models, quantitative experiments are necessary when attempting to develop suitable techniques for dynamic measurements. Here, we map both the elastic and viscous properties of the model system 1,2-dipalmitoyl-sn glycero-3-phosphocholine (DPPC) lipid bilayers using multifrequency atomic force microscopy (AFM), namely amplitude modulation-frequency modulation (AM-FM) AFM imaging in an aqueous environment. Furthermore, we investigate the effect of cholesterol (Chol) on the DPPC bilayer in concentrations from 0 to 60%. The AM AFM quantitative maps demonstrate that at low Chol concentrations, the lipid bilayer displays a distinct phase separation and is elastic, whereas at higher Chol concentration, the bilayer appears homogenous and exhibits both elastic and viscous properties. At low-Chol contents, the Estorage modulus (elastic) dominates. As the Chol insertions increases, higher energy is dissipated; and although the bilayer stiffens (increase in Estorage), the viscous component dominates (Eloss). Our results provide evidence that the lipid bilayer exhibits both elastic and viscous properties that are modulated by the presence of Chol, which may affect the propagation (elastic) or attenuation (viscous) of mechanical signals across the cell membrane. PMID- 29483272 TI - The influence of a competition on noncompetitors. AB - We report a series of experimental studies that investigate the influence of a competition on noncompetitors who do not participate in it but are aware of it. Our work is highly relevant across many domains of social life where competitions are prevalent, as it is typical in a competition that the competitors are far outnumbered by these noncompetitors. In our field experiment involving pay-what you-want entrance at a German zoo (n = 22,886), customers who were aware of a competition over entrance payments, but did not participate in it, paid more than customers who were unaware of the competition. Further experiments provide confirmatory and process evidence for this contagion effect, showing that it is driven by heightened social comparison motivation due to mere awareness of the competition. Moreover, we find evidence that the reward level for the competitors could moderate the contagion effect on the noncompetitors. Even if an individual does not participate in a competition, their behavior can still be influenced by it, and this influence can change with the characteristics of the competition in an intriguing way. PMID- 29483273 TI - Population trends in Vermivora warblers are linked to strong migratory connectivity. AB - Migratory species can experience limiting factors at different locations and during different periods of their annual cycle. In migratory birds, these factors may even occur in different hemispheres. Therefore, identifying the distribution of populations throughout their annual cycle (i.e., migratory connectivity) can reveal the complex ecological and evolutionary relationships that link species and ecosystems across the globe and illuminate where and how limiting factors influence population trends. A growing body of literature continues to identify species that exhibit weak connectivity wherein individuals from distinct breeding areas co-occur during the nonbreeding period. A detailed account of a broadly distributed species exhibiting strong migratory connectivity in which nonbreeding isolation of populations is associated with differential population trends remains undescribed. Here, we present a range-wide assessment of the nonbreeding distribution and migratory connectivity of two broadly dispersed Nearctic Neotropical migratory songbirds. We used geolocators to track the movements of 70 Vermivora warblers from sites spanning their breeding distribution in eastern North America and identified links between breeding populations and nonbreeding areas. Unlike blue-winged warblers (Vermivora cyanoptera), breeding populations of golden-winged warblers (Vermivora chrysoptera) exhibited strong migratory connectivity, which was associated with historical trends in breeding populations: stable for populations that winter in Central America and declining for those that winter in northern South America. PMID- 29483274 TI - Inorganic phosphate, arsenate, and vanadate enhance exonuclease transcript cleavage by RNA polymerase by 2000-fold. AB - Inorganic Pi is involved in all major biochemical pathways. Here we describe a previously unreported activity of Pi We show that Pi and its structural mimics, vanadate and arsenate, enhance nascent transcript cleavage by RNA polymerase (RNAP). They engage an Mg2+ ion in catalysis and activate an attacking water molecule. Pi, vanadate, and arsenate stimulate the intrinsic exonuclease activity of the enzyme nearly 2,000-fold at saturating concentrations of the reactant anions and Mg2+ This enhancement is comparable to that of specialized transcript cleavage protein factors Gre and TFIIS (3,000- to 4,000-fold). Unlike these protein factors, Pi and its analogs do not stimulate endonuclease transcript cleavage. Conversely, the protein factors only marginally enhance exonucleolytic cleavage. Pi thus complements cellular protein factors in assisting hydrolytic RNA cleavage by extending the repertoire of RNAP transcript degradation modes. PMID- 29483275 TI - d-Sedoheptulose-7-phosphate is a common precursor for the heptoses of septacidin and hygromycin B. AB - Seven-carbon-chain-containing sugars exist in several groups of important bacterial natural products. Septacidin represents a group of l-heptopyranoses containing nucleoside antibiotics with antitumor, antifungal, and pain-relief activities. Hygromycin B, an aminoglycoside anthelmintic agent used in swine and poultry farming, represents a group of d-heptopyranoses-containing antibiotics. To date, very little is known about the biosynthesis of these compounds. Here we sequenced the genome of the septacidin producer and identified the septacidin gene cluster by heterologous expression. After determining the boundaries of the septacidin gene cluster, we studied septacidin biosynthesis by in vivo and in vitro experiments and discovered that SepB, SepL, and SepC can convert d sedoheptulose-7-phosphate (S-7-P) to ADP-l-glycero-beta-d-manno-heptose, exemplifying the involvement of ADP-sugar in microbial natural product biosynthesis. Interestingly, septacidin, a secondary metabolite from a gram positive bacterium, shares the same ADP-heptose biosynthesis pathway with the gram-negative bacterium LPS. In addition, two acyltransferase-encoding genes sepD and sepH, were proposed to be involved in septacidin side-chain formation according to the intermediates accumulated in their mutants. In hygromycin B biosynthesis, an isomerase HygP can recognize S-7-P and convert it to ADP-d glycero-beta-d-altro-heptose together with GmhA and HldE, two enzymes from the Escherichia coli LPS heptose biosynthetic pathway, suggesting that the d heptopyranose moiety of hygromycin B is also derived from S-7-P. Unlike the other S-7-P isomerases, HygP catalyzes consecutive isomerizations and controls the stereochemistry of both C2 and C3 positions. PMID- 29483277 TI - STPs: from sticky toffee puddings to just plain fudge. PMID- 29483276 TI - Interferometric mapping of material properties using thermal perturbation. AB - Optical phase changes induced by transient perturbations provide a sensitive measure of material properties. We demonstrate the high sensitivity and speed of such methods, using two interferometric techniques: quantitative phase imaging (QPI) in transmission and phase-resolved optical coherence tomography (OCT) in reflection. Shot-noise-limited QPI can resolve energy deposition of about 3.4 mJ/cm2 in a single pulse, which corresponds to 0.8 degrees C temperature rise in a single cell. OCT can detect deposition of 24 mJ/cm2 energy between two scattering interfaces producing signals with about 30-dB signal-to-noise ratio (SNR), and 4.7 mJ/cm2 when SNR is 45 dB. Both techniques can image thermal changes within the thermal confinement time, which enables accurate single-shot mapping of absorption coefficients even in highly scattering samples, as well as electrical conductivity and many other material properties in biological samples at cellular scale. Integration of the phase changes along the beam path helps increase sensitivity, and the signal relaxation time reveals the size of hidden objects. These methods may enable multiple applications, ranging from temperature controlled retinal laser therapy or gene expression to mapping electric current density and characterization of semiconductor devices with rapid pump-probe measurements. PMID- 29483278 TI - Nigrostriatal and Mesolimbic D2/3 Receptor Expression in Parkinson's Disease Patients with Compulsive Reward-Driven Behaviors. AB - The nigrostriatal and mesocorticolimbic dopamine networks regulate reward-driven behavior. Regional alterations to mesolimbic dopamine D2/3 receptor expression are described in drug-seeking and addiction disorders. Parkinson's disease (PD) patients are frequently prescribed D2-like dopamine agonist (DAgonist) therapy for motor symptoms, yet a proportion develop clinically significant behavioral addictions characterized by impulsive and compulsive behaviors (ICBs). Until now, changes in D2/3 receptor binding in both striatal and extrastriatal regions have not been concurrently quantified in this population. We identified 35 human PD patients (both male and female) receiving DAgonist therapy, with (n = 17) and without (n = 18) ICBs, matched for age, disease duration, disease severity, and dose of dopamine therapy. In the off-dopamine state, all completed PET imaging with [18F]fallypride, a high affinity D2-like receptor ligand that can measure striatal and extrastriatal D2/3 nondisplaceable binding potential (BPND). Striatal differences between ICB+/ICB- patients localized to the ventral striatum and putamen, where ICB+ subjects had reduced BPND In this group, self-reported severity of ICB symptoms positively correlated with midbrain D2/3 receptor BPND Group differences in regional D2/3 BPND relationships were also notable: ICB+ (but not ICB-) patients expressed positive correlations between midbrain and caudate, putamen, globus pallidus, and amygdala BPNDs. These findings support the hypothesis that compulsive behaviors in PD are associated with reduced ventral and dorsal striatal D2/3 expression, similar to changes in comparable behavioral disorders. The data also suggest that relatively preserved ventral midbrain dopaminergic projections throughout nigrostriatal and mesolimbic networks are characteristic of ICB+ patients, and may account for differential DAgonist therapeutic response.SIGNIFICANCE STATEMENT The biologic determinants of compulsive reward-based behaviors have broad clinical relevance, from addiction to neurodegenerative disorders. Here, we address biomolecular distinctions in Parkinson's disease patients with impulsive compulsive behaviors (ICBs). This is the first study to image a large cohort of ICB+ patients using positron emission tomography with [18F]fallypride, allowing quantification of D2/3 receptors throughout the mesocorticolimbic network. We demonstrate widespread differences in dopaminergic networks, including (1) D2-like receptor distinctions in the ventral striatum and putamen, and (2) a preservation of widespread dopaminergic projections emerging from the midbrain, which is associated with the severity of compulsive behaviors. This clearly illustrates the roles of D2/3 receptors and medication effects in maladaptive behaviors, and localizes them specifically to nigrostriatal and extrastriatal regions. PMID- 29483279 TI - Choice for Drug or Natural Reward Engages Largely Overlapping Neuronal Ensembles in the Infralimbic Prefrontal Cortex. AB - Cue-reward associations form distinct memories that can drive appetitive behaviors and are involved in craving for both drugs and natural rewards. Distinct sets of neurons, so-called neuronal ensembles, in the infralimbic area (IL) of the medial prefrontal cortex (mPFC) play a key role in alcohol seeking. Whether this ensemble is specific for alcohol or controls reward seeking in general remains unclear. Here, we compared IL ensembles formed upon recall of drug (alcohol) or natural reward (saccharin) memories in male Wistar rats. Using an experimental framework that allows identification of two distinct reward associated ensembles within the same animal, we found that cue-induced seeking of either alcohol or saccharin activated ensembles of similar size and organization, whereby these ensembles consist of largely overlapping neuronal populations. Thus, the IL seems to act as a general integration hub for reward seeking behavior, but also contains subsets of neurons that encode for the different rewards.SIGNIFICANCE STATEMENT Cue-reward associations form distinct memories that can act as drivers of appetitive behaviors and are involved in craving for natural rewards as well as for drugs. Distinct sets of neurons, so-called neuronal ensembles, in the infralimbic area of the mPFC play a key role in cue triggered reward seeking. However, it is unclear whether these ensembles act as broadly tuned controllers of approach behavior or represent the learned associations between specific cues and rewards. Using an experimental framework that allows identification of two distinct reward-associated ensembles within the same animal we find largely overlapping neuronal populations. Repeated activation by two distinct events could reflect the linking of the two memory traces within the same neuron. PMID- 29483281 TI - Differential Synaptic Remodeling by Dopamine in Direct and Indirect Striatal Projection Neurons in Pitx3-/- Mice, a Genetic Model of Parkinson's Disease. AB - In toxin-based models of Parkinson's disease (PD), striatal projection neurons (SPNs) exhibit dendritic atrophy and spine loss concurrent with an increase in excitability. Chronic l-DOPA treatment that induces dyskinesia selectively restores spine density and excitability in indirect pathway SPNs (iSPNs), whereas spine loss and hyperexcitability persist in direct pathway SPNs (dSPNs). These alterations have only been characterized in toxin-based models of PD, raising the possibility that they are an artifact of exposure to the toxin, which may engage compensatory mechanisms independent of the PD-like pathology or due to the loss of dopaminergic afferents. To test all these, we studied the synaptic remodeling in Pitx3-/- or aphakia mice, a genetic model of PD, in which most of the dopamine neurons in the substantia nigra fail to fully differentiate and to innervate the striatum. We made 3D reconstructions of the dendritic arbor and measured excitability in identified SPNs located in dorsal striatum of BAC-Pitx3-/- mice treated with saline or l-DOPA. Both dSPNs and iSPNs from BAC-Pitx3-/- mice had shorter dendritic trees, lower spine density, and more action potentials than their counterparts from WT mice. Chronic l-DOPA treatment restored spine density and firing rate in iSPNs. By contrast, in dSPNs, spine loss and hyperexcitability persisted following l-DOPA treatment, which is similar to what happens in 6-OHDA WT mice. This indicates that dopamine-mediated synaptic remodeling and plasticity is independent of dopamine innervation during SPN development and that Pitx3-/- mice are a good model because they develop the same pathology described in the toxins-based models and in human postmortem studies of advanced PD.SIGNIFICANCE STATEMENT As the only genetic model of Parkinson's disease (PD) that develops dyskinesia, Pitx3-/- mice reproduce the behavioral effects seen in humans and are a good system for studying dopamine-induced synaptic remodeling. The studies we present here establish that the structural and functional synaptic plasticity that occur in striatal projection neurons in PD and in l-DOPA-induced dyskinesia are specifically due to modulation of the neurotransmitter dopamine and are not artifacts of the use of chemical toxins in PD models. In addition, our findings provide evidence that synaptic plasticity in the Pitx3-/- mouse is similar to that seen in toxin models despite its lack of dopaminergic innervation of the striatum during development. Pitx3-/- mice reproduced the alterations described in patients with advanced PD and in well accepted toxin-based models of PD and dyskinesia. These results further consolidate the fidelity of the Pitx3-/- mouse as a PD model in which to study the morphological and physiological remodeling of striatal projection neurons by administration of l-DOPA and other drugs. PMID- 29483280 TI - Swedish Nerve Growth Factor Mutation (NGFR100W) Defines a Role for TrkA and p75NTR in Nociception. AB - Nerve growth factor (NGF) exerts multiple functions on target neurons throughout development. The recent discovery of a point mutation leading to a change from arginine to tryptophan at residue 100 in the mature NGFbeta sequence (NGFR100W) in patients with hereditary sensory and autonomic neuropathy type V (HSAN V) made it possible to distinguish the signaling mechanisms that lead to two functionally different outcomes of NGF: trophic versus nociceptive. We performed extensive biochemical, cellular, and live-imaging experiments to examine the binding and signaling properties of NGFR100W Our results show that, similar to the wild-type NGF (wtNGF), the naturally occurring NGFR100W mutant was capable of binding to and activating the TrkA receptor and its downstream signaling pathways to support neuronal survival and differentiation. However, NGFR100W failed to bind and stimulate the 75 kDa neurotrophic factor receptor (p75NTR)-mediated signaling cascades (i.e., the RhoA-Cofilin pathway). Intraplantar injection of NGFR100W into adult rats induced neither TrkA-mediated thermal nor mechanical acute hyperalgesia, but retained the ability to induce chronic hyperalgesia based on agonism for TrkA signaling. Together, our studies provide evidence that NGFR100W retains trophic support capability through TrkA and one aspect of its nociceptive signaling, but fails to engage p75NTR signaling pathways. Our findings suggest that wtNGF acts via TrkA to regulate the delayed priming of nociceptive responses. The integration of both TrkA and p75NTR signaling thus appears to regulate neuroplastic effects of NGF in peripheral nociception.SIGNIFICANCE STATEMENT In the present study, we characterized the naturally occurring nerve growth factor NGFR100W mutant that is associated with hereditary sensory and autonomic neuropathy type V. We have demonstrated for the first time that NGFR100W retains trophic support capability through TrkA, but fails to engage p75NTR signaling pathways. Furthermore, after intraplantar injection into adult rats, NGFR100W induced neither thermal nor mechanical acute hyperalgesia, but retained the ability to induce chronic hyperalgesia. We have also provided evidence that the integration of both TrkA- and p75NTR-mediated signaling appears to regulate neuroplastic effects of NGF in peripheral nociception. Our study with NGFR100W suggests that it is possible to uncouple trophic effect from nociceptive function, both induced by wild-type NGF. PMID- 29483283 TI - Neuronal Organization in the Inferior Colliculus Revisited with Cell-Type Dependent Monosynaptic Tracing. AB - The inferior colliculus (IC) is a critical integration center in the auditory pathway. However, because the inputs to the IC have typically been studied by the use of conventional anterograde and retrograde tracers, the neuronal organization and cell-type-specific connections in the IC are poorly understood. Here, we used monosynaptic rabies tracing and in situ hybridization combined with excitatory and inhibitory Cre transgenic mouse lines of both sexes to characterize the brainwide and cell-type-specific inputs to specific neuron types within the lemniscal IC core and nonlemniscal IC shell. We observed that both excitatory and inhibitory neurons of the IC shell predominantly received ascending inputs rather than descending or core inputs. Correlation and clustering analyses revealed two groups of excitatory neurons in the shell: one received inputs from a combination of ascending nuclei, and the other received inputs from a combination of descending nuclei, neuromodulatory nuclei, and the contralateral IC. In contrast, inhibitory neurons in the core received inputs from the same combination of all nuclei. After normalizing the extrinsic inputs, we found that core inhibitory neurons received a higher proportion of inhibitory inputs from the ventral nucleus of the lateral lemniscus than excitatory neurons. Furthermore, the inhibitory neurons preferentially received inhibitory inputs from the contralateral IC shell. Because IC inhibitory neurons innervate the thalamus and contralateral IC, the inhibitory inputs we uncovered here suggest two long-range disinhibitory circuits. In summary, we found: (1) dominant ascending inputs to the shell, (2) two subpopulations of shell excitatory neurons, and (3) two disinhibitory circuits.SIGNIFICANCE STATEMENT Sound undergoes extensive processing in the brainstem. The inferior colliculus (IC) core is classically viewed as the integration center for ascending auditory information, whereas the IC shell integrates descending feedback information. Here, we demonstrate that ascending inputs predominated in the IC shell but appeared to be separated from the descending inputs. The presence of inhibitory projection neurons is a unique feature of the auditory ascending pathways, but the connections of these neurons are poorly understood. Interestingly, we also found that inhibitory neurons in the IC core and shell preferentially received inhibitory inputs from ascending nuclei and contralateral IC, respectively. Therefore, our results suggest a bipartite domain in the IC shell and disinhibitory circuits in the IC. PMID- 29483282 TI - BMP-Responsive Protease HtrA1 Is Differentially Expressed in Astrocytes and Regulates Astrocytic Development and Injury Response. AB - Astrocytes perform a wide array of physiological functions, including structural support, ion exchange, and neurotransmitter uptake. Despite this diversity, molecular markers that label subpopulations of astrocytes are limited, and mechanisms that generate distinct astrocyte subtypes remain unclear. Here we identified serine protease high temperature requirement A 1 (HtrA1), a bone morphogenetic protein 4 signaling regulated protein, as a novel marker of forebrain astrocytes, but not of neural stem cells, in adult mice of both sexes. Genetic deletion of HtrA1 during gliogenesis accelerates astrocyte differentiation. In addition, ablation of HtrA1 in cultured astrocytes leads to altered chondroitin sulfate proteoglycan expression and inhibition of neurite extension, along with elevated levels of transforming growth factor-beta family proteins. Brain injury induces HtrA1 expression in reactive astrocytes, and loss of HtrA1 leads to an impairment in wound closure accompanied by increased proliferation of endothelial and immune cells. Our findings demonstrate that HtrA1 is differentially expressed in adult mouse forebrain astrocytes, and that HtrA1 plays important roles in astrocytic development and injury response.SIGNIFICANCE STATEMENT Astrocytes, an abundant cell type in the brain, perform a wide array of physiological functions. Although characterized as morphologically and functionally diverse, molecular markers that label astrocyte subtypes or signaling pathways that lead to their diversity remain limited. Here, after examining the expression profile of astrocytes generated in response to bone morphogenetic protein signaling, we identify high temperature requirement A 1 (HtrA1) as an astrocyte-specific marker that is differentially expressed in distinct adult mouse brain regions. HtrA1 is a serine protease that has been linked to cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, a small blood vessel disease in humans. Understanding the role of HtrA1 during development and after injury will provide insights into how distinct astrocyte populations are generated and their unique roles in injury and disease. PMID- 29483284 TI - Challenge to Promote Change: The Neural Basis of the Contextual Interference Effect in Young and Older Adults. AB - Motor performance deteriorates with age. Hence, studying the effects of different training types on performance improvement is particularly important. Here, we investigated the neural correlates of the contextual interference (CI) effect in 32 young (YA; 16 female) and 28 older (OA; 12 female) human adults. Participants were randomly assigned to either a blocked or a random practice schedule, practiced three variations of a bimanual visuomotor task over 3 d, and were retested 6 d later. Functional magnetic resonance imaging data were acquired during the first and last training days and during retention. Although the overall performance level was lower in OA than YA, the typical CI effects were observed in both age groups, i.e., inferior performance during acquisition but superior performance during retention for random relative to blocked practice. At the neural level, blocked practice showed higher brain activity in motor-related brain regions compared with random practice across both age groups. However, although activity in these regions decreased with blocked practice in both age groups, it was either preserved (YA) or increased (OA) as a function of random practice. In contrast, random compared with blocked practice resulted in greater activations in visual processing regions across age groups. Interestingly, in OA, the more demanding random practice schedule triggered neuroplastic changes in areas of the default mode network, ultimately leading to better long-term retention. Our findings may have substantial implications for the optimization of practice schedules, and rehabilitation settings in particular.SIGNIFICANCE STATEMENT In aging societies, it is critically important to understand how motor skills can be maintained or enhanced in older adults, with the ultimate goal to prolong functional independence. Here, we demonstrated that a more challenging random as opposed to a blocked practice environment temporarily reduced performance during the acquisition phase but resulted in lasting benefits for skill retention. In older adults, learning success was critically dependent on reduction of activation in areas of the default mode network, pointing to plastic functional changes in brain regions that are vulnerable to aging effects. The random practice context led to increased economy of brain activity and better skill retention. This provides new perspectives for reversing the negative consequences of aging. PMID- 29483286 TI - Correction for Zhao et al., "Outer Membrane Proteins Ail and OmpF of Yersinia pestis Are Involved in the Adsorption of T7-Related Bacteriophage Yep-phi". PMID- 29483285 TI - Heteromeric KV2/KV8.2 Channels Mediate Delayed Rectifier Potassium Currents in Primate Photoreceptors. AB - Silent voltage-gated potassium channel subunits (KVS) interact selectively with members of the KV2 channel family to modify their functional properties. The localization and functional roles of these silent subunits remain poorly understood. Mutations in the KVS subunit, KV8.2 (KCNV2), lead to severe visual impairment in humans, but the basis of these deficits remains unclear. Here, we examined the localization, native interactions, and functional properties of KV8.2-containing channels in mouse, macaque, and human photoreceptors of either sex. In human retina, KV8.2 colocalized with KV2.1 and KV2.2 in cone inner segments and with KV2.1 in rod inner segments. KV2.1 and KV2.2 could be coimmunoprecipitated with KV8.2 in retinal lysates indicating that these subunits likely interact directly. Retinal KV2.1 was less phosphorylated than cortical KV2.1, a difference expected to alter the biophysical properties of these channels. Using voltage-clamp recordings and pharmacology, we provide functional evidence for Kv2-containing channels in primate rods and cones. We propose that the presence of KV8.2, and low levels of KV2.1 phosphorylation shift the activation range of KV2 channels to align with the operating range of rod and cone photoreceptors. Our data indicate a role for KV2/KV8.2 channels in human photoreceptor function and suggest that the visual deficits in patients with KCNV2 mutations arise from inadequate resting activation of KV channels in rod and cone inner segments.SIGNIFICANCE STATEMENT Mutations in a voltage-gated potassium channel subunit, KV8.2, underlie a blinding inherited photoreceptor dystrophy, indicating an important role for these channels in human vision. Here, we have defined the localization and subunit interactions of KV8.2 channels in primate photoreceptors. We show that the KV8.2 subunit interacts with different Kv2 channels in rods and cones, giving rise to potassium currents with distinct functional properties. Our results provide a molecular basis for retinal dysfunction in patients with mutations in the KCNV2 gene encoding KV8.2. PMID- 29483287 TI - Correction for Liu et al., "Endoplasmic Reticulum Protein SCAP Inhibits Dengue Virus NS2B3 Protease by Suppressing Its K27-Linked Polyubiquitylation". PMID- 29483288 TI - Human Interleukin-32gamma Plays a Protective Role in an Experimental Model of Visceral Leishmaniasis in Mice. AB - Visceral leishmaniasis (VL) is a chronic parasitic disease caused by Leishmania infantum in the Americas. During VL, several proinflammatory cytokines are produced in spleen, liver, and bone marrow. However, the role of interleukin-32 (IL-32) has not been explored in this disease. IL-32 can induce production of proinflammatory cytokines in innate immune cells and polarize the adaptive immune response. Herein, we discovered that L. infantum antigens induced expression of mRNA mainly for the IL-32gamma isoform but also induced low levels of the IL 32beta transcript in human peripheral blood mononuclear cells. Furthermore, infection of human IL-32gamma transgenic mice (IL-32gammaTg mice) with L. infantum promastigote forms increased IL-32gamma expression in the spleen and liver. Interestingly, IL-32gammaTg mice harbored less parasitism in the spleen and liver than wild-type (WT) mice. In addition, IL-32gammaTg mice showed increased granuloma formation in the liver compared to WT mice. The protection against VL was associated with increased production of nitric oxide (NO), interferon gamma (IFN-gamma), IL-17A, and tumor necrosis factor alpha by splenic cells restimulated ex vivo with L. infantum antigens. In parallel, there was an increase in the number of Th1 and Th17 T cells in the spleens of IL-32gammaTg mice infected with L. infantum IL-32gamma induction of IFN-gamma and IL-17A expression was found to be essential for NO production by splenic cells of infected animals. These data indicate that IL-32gamma potentiates the Th1/Th17 immune response during experimental VL, thus contributing to the control of L. infantum infection. PMID- 29483289 TI - Prostaglandin E2 Induction Suppresses the Th1 Immune Responses in Cattle with Johne's Disease. AB - Johne's disease, caused by Mycobacterium avium subsp. paratuberculosis, is a bovine chronic infection that is endemic in Japan and many other countries. The expression of immunoinhibitory molecules is upregulated in cattle with Johne's disease, but the mechanism of immunosuppression is poorly understood. Prostaglandin E2 (PGE2) is immunosuppressive in humans, but few veterinary data are available. In this study, functional and kinetic analyses of PGE2 were performed to investigate the immunosuppressive effect of PGE2 during Johne's disease. In vitro PGE2 treatment decreased T-cell proliferation and Th1 cytokine production and upregulated the expression of immunoinhibitory molecules such as interleukin-10 and programmed death ligand 1 (PD-L1) in peripheral blood mononuclear cells (PBMCs) from healthy cattle. PGE2 was upregulated in sera and intestinal lesions of cattle with Johne's disease. In vitro stimulation with Johnin purified protein derivative (J-PPD) induced cyclooxygenase-2 (COX-2) transcription, PGE2 production, and upregulation of PD-L1 and immunoinhibitory receptors in PBMCs from cattle infected with M. avium subsp. paratuberculosis Therefore, Johnin-specific Th1 responses could be limited by the PGE2 pathway in cattle. In contrast, downregulation of PGE2 with a COX-2 inhibitor promoted J-PPD stimulated CD8+ T-cell proliferation and Th1 cytokine production in PBMCs from the experimentally infected cattle. PD-L1 blockade induced J-PPD-stimulated CD8+ T-cell proliferation and interferon gamma production in vitro Combined treatment with a COX-2 inhibitor and anti-PD-L1 antibodies enhanced J-PPD-stimulated CD8+ T cell proliferation in vitro, suggesting that the blockade of both pathways is a potential therapeutic strategy to control Johne's disease. The effects of COX-2 inhibition warrant further study as a novel treatment of Johne's disease. PMID- 29483290 TI - Animal and Human Tissue Models of Vertical Listeria monocytogenes Transmission and Implications for Other Pregnancy-Associated Infections. AB - Intrauterine infections lead to serious complications for mother and fetus, including preterm birth, maternal and fetal death, and neurological sequelae in the surviving offspring. Improving maternal and child heath is a global priority. Yet, the development of strategies to prevent and treat pregnancy-related diseases has lagged behind progress made in other medical fields. One of the challenges is finding tractable model systems that replicate the human maternal fetal interface. Animal models offer the ability to study pathogenesis and host defenses in vivo However, the anatomy of the maternal-fetal interface is highly divergent across species. While many tools are available to study host responses in the pregnant mouse model, other animals have placentas that are more similar to that of humans. Here we describe new developments in animal and human tissue models to investigate the pathogenesis of listeriosis at the maternal-fetal interface. We highlight gaps in existing knowledge and make recommendations on how they can be filled. PMID- 29483291 TI - Salmonella-Mediated Inflammation Eliminates Competitors for Fructose-Asparagine in the Gut. AB - Salmonella enterica elicits intestinal inflammation to gain access to nutrients. One of these nutrients is fructose-asparagine (F-Asn). The availability of F-Asn to Salmonella during infection is dependent upon Salmonella pathogenicity islands 1 and 2, which in turn are required to provoke inflammation. Here, we determined that F-Asn is present in mouse chow at approximately 400 pmol/mg (dry weight). F Asn is also present in the intestinal tract of germfree mice at 2,700 pmol/mg (dry weight) and in the intestinal tract of conventional mice at 9 to 28 pmol/mg. These findings suggest that the mouse intestinal microbiota consumes F-Asn. We utilized heavy-labeled precursors of F-Asn to monitor its formation in the intestine, in the presence or absence of inflammation, and none was observed. Finally, we determined that some members of the class Clostridia encode F-Asn utilization pathways and that they are eliminated from highly inflamed Salmonella infected mice. Collectively, our studies identify the source of F-Asn as the diet and that Salmonella-mediated inflammation is required to eliminate competitors and allow the pathogen nearly exclusive access to this nutrient. PMID- 29483292 TI - Coxiella burnetii Subverts p62/Sequestosome 1 and Activates Nrf2 Signaling in Human Macrophages. AB - Coxiella burnetii is the causative agent of human Q fever, a debilitating flu like illness that can progress to chronic disease presenting as endocarditis. Following inhalation, C. burnetii is phagocytosed by alveolar macrophages and generates a lysosome-like replication compartment termed the parasitophorous vacuole (PV). A type IV secretion system (T4SS) is required for PV generation and is one of the pathogen's few known virulence factors. We previously showed that C. burnetii actively recruits autophagosomes to the PV using the T4SS but does not alter macroautophagy. In the current study, we confirmed that the cargo receptor p62/sequestosome 1 (SQSTM-1) localizes near the PV in primary human alveolar macrophages infected with virulent C. burnetii p62 and LC3 typically interact to select cargo for autophagy-mediated degradation, resulting in p62 degradation and LC3 recycling. However, in C. burnetii-infected macrophages, p62 was not degraded when cells were starved, suggesting that the pathogen stabilizes the protein. In addition, phosphorylated p62 levels increased, indicative of activation, during infection. Small interfering RNA experiments indicated that p62 is not absolutely required for intracellular growth, suggesting that the protein serves a signaling role during infection. Indeed, the Nrf2-Keap1 cytoprotective pathway was activated during infection, as evidenced by sustained maintenance of Nrf2 levels and translocation of the protein to the nucleus in C. burnetii-infected cells. Collectively, our studies identify a new p62-regulated host signaling pathway exploited by C. burnetii during intramacrophage growth. PMID- 29483293 TI - Enterococcus faecalis Demonstrates Pathogenicity through Increased Attachment in an Ex Vivo Polymicrobial Pulpal Infection. AB - This study investigated the host response to a polymicrobial pulpal infection consisting of Streptococcus anginosus and Enterococcus faecalis, bacteria commonly implicated in dental abscesses and endodontic failure, using a validated ex vivo rat tooth model. Tooth slices were inoculated with planktonic cultures of S. anginosus or E. faecalis alone or in coculture at S. anginosus/E. faecalis ratios of 50:50 and 90:10. Attachment was semiquantified by measuring the area covered by fluorescently labeled bacteria. Host response was established by viable histological cell counts, and inflammatory response was measured using reverse transcription-quantitative PCR (RT-qPCR) and immunohistochemistry. A significant reduction in cell viability was observed for single and polymicrobial infections, with no significant differences between infection types (~2,000 cells/mm2 for infected pulps compared to ~4,000 cells/mm2 for uninfected pulps). E. faecalis demonstrated significantly higher levels of attachment (6.5%) than S. anginosus alone (2.3%) and mixed-species infections (3.4% for 50:50 and 2.3% for 90:10), with a remarkable affinity for the pulpal vasculature. Infections with E. faecalis demonstrated the greatest increase in tumor necrosis factor alpha (TNF alpha) (47.1-fold for E. faecalis, 14.6-fold for S. anginosus, 60.1-fold for 50:50, and 25.0-fold for 90:10) and interleukin 1beta (IL-1beta) expression (54.8 fold for E. faecalis, 8.8-fold for S. anginosus, 54.5-fold for 50:50, and 39.9 fold for 90:10) compared to uninfected samples. Immunohistochemistry confirmed this, with the majority of inflammation localized to the pulpal vasculature and odontoblast regions. Interestingly, E. faecalis supernatant and heat-killed E. faecalis treatments were unable to induce the same inflammatory response, suggesting E. faecalis pathogenicity in pulpitis is linked to its greater ability to attach to the pulpal vasculature. PMID- 29483295 TI - A novel rhodopsin phosphodiesterase from Salpingoeca rosetta shows light-enhanced substrate affinity. AB - It is since many years textbook knowledge that the concentration of the second messenger cGMP is regulated in animal rod and cone cells by type II rhodopsins via a G-protein signaling cascade. Microbial rhodopsins with enzymatic activity for regulation of cGMP concentration were only recently discovered: in 2014 light activated guanylyl-cyclase opsins in fungi and in 2017 a novel rhodopsin phosphodiesterase (RhoPDE) in the protist Salpingoeca rosetta (SrRhoPDE). The light regulation of SrRhoPDE, however, seemed very weak or absent. Here, we present strong evidence for light regulation by studying SrRhoPDE, expressed in Xenopus laevis oocytes, at different substrate concentrations. Hydrolysis of cGMP shows an ~100-fold higher turnover than that of cAMP. Light causes a strong decrease in the Km value for cGMP from 80 to 13 uM but increases the maximum turnover only by ~30%. The PDE activity for cAMP is similarly enhanced by light at low substrate concentrations. Illumination does not affect the cGMP degradation of Lys296 mutants that are not able to form a covalent bond of Schiff base type to the chromophore retinal. We demonstrate that SrRhoPDE shows cytosolic N- and C-termini, most likely via an eight-transmembrane helix structure. SrRhoPDE is a new optogenetic tool for light-regulated cGMP manipulation which might be further improved by genetic engineering. PMID- 29483296 TI - Evidence for a carbohydrate-binding module (CBM) of Tannerella forsythia NanH sialidase, key to interactions at the host-pathogen interface. AB - Bacterial sialidases cleave terminal sialic acid from a variety of host glycoproteins, and contribute to survival and growth of many human-dwelling bacterial species, including various pathogens. Tannerella forsythia, an oral, Gram-negative, fastidious anaerobe, is a key organism in periodontal disease and possesses a dedicated sialic acid utilisation and scavenging (nan) operon, including NanH sialidase. Here, we describe biochemical characterisation of recombinant NanH, including its action on host-relevant sialoglycans such as sialyl Lewis A and sialyl Lewis X (SLeA/X), and on human cell-attached sialic acids directly, uncovering that it is a highly active broad specificity sialidase. Furthermore, the N-terminal domain of NanH was hypothesised and proved to be capable of binding to a range of sialoglycans and non-sialylated derivatives with Kd in the micromolar range, as determined by steady-state tryptophan fluorescence spectroscopy, but it has no catalytic activity in isolation from the active site. We consider this domain to represent the founding member of a novel subfamily of carbohydrate-binding module (CBM), involved in glycosidase-ligand binding. In addition, we created a catalytically inactive version of the NanH enzyme (FRIP -> YMAP) that retained its ability to bind sialic acid-containing ligands and revealed for the first time that binding activity of a CBM is enhanced by association with the catalytic domain. Finally, we investigated the importance of Lewis-type sialoglycans on T. forsythia-host interactions, showing that nanomolar amounts of SLeA/X were capable of reducing invasion of oral epithelial cells by T. forsythia, suggesting that these are key ligands for bacterial-cellular interactions during periodontal disease. PMID- 29483294 TI - Type IV Pili Promote Clostridium difficile Adherence and Persistence in a Mouse Model of Infection. AB - Cyclic diguanylate (c-di-GMP) is a second messenger that regulates the transition from motile to sessile lifestyles in numerous bacteria and controls virulence factor production in a variety of pathogens. In Clostridium difficile, c-di-GMP negatively regulates flagellum biosynthesis and swimming motility and promotes the production of type IV pili (TFP), biofilm formation, and surface motility in vitro Flagella have been identified as colonization factors in C. difficile, but the role of TFP in adherence to host cells and in colonization of the mammalian gut is unknown. Here we show that c-di-GMP promotes adherence to epithelial cells in vitro, which can be partly attributed to the loss of flagella. Using TFP-null mutants, we demonstrate that adherence to epithelial cells is partially mediated by TFP and that this TFP-mediated adherence requires c-di-GMP regulation. In a mouse model of colonization, the TFP-null mutants initially colonized the intestine as well as the parental strain but were cleared more quickly. Moreover, compared to the parent strain, C. difficile strains lacking TFP were particularly deficient in association with the cecal mucosa. Together these data indicate that TFP and their positive regulation by c-di-GMP promote attachment of C. difficile to the intestinal epithelium and contribute to persistence of C. difficile in the host intestine. PMID- 29483297 TI - In vivo studies on the mechanism of methylene cyclopropyl acetic acid and methylene cyclopropyl glycine-induced hypoglycemia. AB - Exposure to the toxins methylene cyclopropyl acetic acid (MCPA) and methylene cyclopropyl glycine (MCPG) of unripe ackee and litchi fruit can lead to hypoglycemia and death; however, the molecular mechanisms by which MCPA and MCPG cause hypoglycemia have not been established in vivo To determine the in vivo mechanisms of action of these toxins, we infused them into conscious rodents and assessed rates of hepatic gluconeogenesis and ketogenesis, hepatic acyl-CoA and hepatic acetyl-CoA content, and hepatocellular energy charge. MCPG suppressed rates of hepatic beta-oxidation as reflected by reductions in hepatic ketogenesis, reducing both short- and medium-chain hepatic acyl-CoA concentrations. Hepatic acetyl-CoA content decreased, and hepatic glucose production was inhibited. MCPA also suppressed beta-oxidation of short-chain acyl CoAs, rapidly inhibiting hepatic ketogenesis and hepatic glucose production, depleting hepatic acetyl-CoA content and ATP content, while increasing other short-chain acyl-CoAs. Utilizing a recently developed positional isotopomer NMR tracer analysis method, we demonstrated that MCPA-induced reductions in hepatic acetyl-CoA content were associated with a marked reduction of hepatic pyruvate carboxylase (PC) flux. Taken together, these data reveal the in vivo mechanisms of action of MCPA and MCPG: the hypoglycemia associated with ingestion of these toxins can be ascribed mostly to MCPA- or MCPG-induced reductions in hepatic PC flux due to inhibition of beta-oxidation of short-chain acyl-CoAs by MCPA or inhibition of both short- and medium-chain acyl-CoAs by MCPG with resultant reductions in hepatic acetyl-CoA content, with an additional contribution to hypoglycemia through reduced hepatic ATP stores by MCPA. PMID- 29483298 TI - Hydrolytic activity of human Nudt16 enzyme on dinucleotide cap analogs and short capped oligonucleotides. AB - Human Nudt16 (hNudt16) is a member of the Nudix family of hydrolases, comprising enzymes catabolizing various substrates including canonical (d)NTPs, oxidized (d)NTPs, nonnucleoside polyphosphates, and capped mRNAs. Decapping activity of the Xenopus laevis (X29) Nudt16 homolog was observed in the nucleolus, with a high specificity toward U8 snoRNA. Subsequent studies have reported cytoplasmic localization of mammalian Nudt16 with cap hydrolysis activity initiating RNA turnover, similar to Dcp2. The present study focuses on hNudt16 and its hydrolytic activity toward dinucleotide cap analogs and short capped oligonucleotides. We performed a screening assay for potential dinucleotide and oligonucleotide substrates for hNudt16. Our data indicate that dinucleotide cap analogs and capped oligonucleotides containing guanine base in the first transcribed nucleotide are more susceptible to enzymatic digestion by hNudt16 than their counterparts containing adenine. Furthermore, unmethylated dinucleotides (GpppG and ApppG) and respective oligonucleotides (GpppG-16nt and GpppA-16nt) were hydrolyzed by hNudt16 with greater efficiency than were m7GpppG and m7GpppG-16nt. In conclusion, we found that hNudt16 hydrolysis of dinucleotide cap analogs and short capped oligonucleotides displayed a broader spectrum specificity than is currently known. PMID- 29483299 TI - Induction of the p53 Tumor Suppressor in Cancer Cells through Inhibition of Cap Dependent Translation. AB - The p53 tumor suppressor plays a critical role in protecting normal cells from malignant transformation. Development of small molecules to reactivate p53 in cancer cells has been an area of intense research. We previously identified an internal ribosomal entry site (IRES) within the 5' untranslated region of p53 mRNA that mediates translation of the p53 mRNA independent of cap-dependent translation. Our results also show that in response to DNA damage, cells switch from cap-dependent translation to cap-independent translation of p53 mRNA. In the present study, we discovered a specific inhibitor of cap-dependent translation, 4EGI-1, that is capable of inducing the accumulation of p53 in cancer cells retaining wild-type p53. Our results show that 4EGI-1 causes an increase in p53 IRES activity, leading to increased translation of p53 mRNA. We also observed that 4EGI-1 induces cancer cell apoptosis in a p53-dependent manner. Furthermore, 4EGI-1 induces p53 in cancer cells without causing DNA double-strand breaks. In conclusion, we discovered a mechanistic link between inhibition of cap-dependent translation and enhanced p53 accumulation. This leads to apoptosis of cancer cells without causing collateral damage to normal cells, thus providing a novel and effective therapeutic strategy for cancer. PMID- 29483300 TI - The Histone Variant MacroH2A Blocks Cellular Reprogramming by Inhibiting Mesenchymal-to-Epithelial Transition. AB - Transcription factor-induced reprogramming of somatic cells to pluripotency is mediated via profound alterations in the epigenetic landscape. The histone variant macroH2A1 (mH2A1) is a barrier to the cellular reprogramming process. We demonstrate here that mH2A1 blocks reprogramming and contributes to the preservation of cell identity by trapping cells at the very early stages of the process, namely, at the mesenchymal-to-epithelial transition (MET). We provide a comprehensive analysis of the genomic sites occupied by the mH2A1 nucleosomes in human fibroblasts and embryonic stem (ES) cells and how they affect the reprogramming of fibroblasts to pluripotency. We have integrated chromatin immunoprecipitation sequencing (ChIP-seq) data with transcriptome sequencing (RNA seq) data using cells containing reduced levels of mH2A1 and have inferred mH2A1 centered gene-regulatory networks that support the fibroblast and ES cell fates. We found that the exact positions of mH2A1 nucleosomes in regulatory regions of specific network genes with key regulatory roles guarantee the functional robustness of the regulatory networks. Using the reconstructed networks, we can predict and validate several components and their interactions in the establishment of stable cell types by limiting progression to alternative cell fates. PMID- 29483301 TI - PPARgamma and its Role in Adipocyte Homeostasis and Thiazolidinedione-Mediated Insulin Sensitization. AB - Adipose tissue is a dynamic organ that makes critical contributions to whole body metabolic homeostasis. Although recent studies have revealed that different fat depots have distinct molecular signatures, metabolic functions and adipogenic mechanisms, PPARgamma is still widely viewed as the master regulator of adipogenesis and critical for maintaining mature adipocyte function. Using an inducible, adipocyte-specific knockout system, we explored the role of PPARgamma in mature adipocytes in vivo Short-term PPARgamma deficiency in adipocytes reduces whole body insulin sensitivity, but adipocytes are viable both in vitro and in vivo However, after high fat diet exposure, even short-term PPARgamma deficiency leads to rapid adipocyte death. When mature adipocytes are depleted for both PPARgamma and C/EBPalpha, they are rapidly depleted of lipids and undergo adipocyte death, both in vitro and in vivo Surprisingly, although thiazolidinediones (TZDs -- PPARgamma agonists) are thought to act mainly on PPARgamma, PPARgamma in adipocytes is not required for the whole-body insulin sensitizing effect of TZDs. This offers new mechanistic aspects of PPARgamma/TZD action and its effect on whole body metabolic homeostasis. PMID- 29483303 TI - Single-cell RNAseq reveals seven classes of colonic sensory neuron. AB - OBJECTIVE: Integration of nutritional, microbial and inflammatory events along the gut-brain axis can alter bowel physiology and organism behaviour. Colonic sensory neurons activate reflex pathways and give rise to conscious sensation, but the diversity and division of function within these neurons is poorly understood. The identification of signalling pathways contributing to visceral sensation is constrained by a paucity of molecular markers. Here we address this by comprehensive transcriptomic profiling and unsupervised clustering of individual mouse colonic sensory neurons. DESIGN: Unbiased single-cell RNA sequencing was performed on retrogradely traced mouse colonic sensory neurons isolated from both thoracolumbar (TL) and lumbosacral (LS) dorsal root ganglia associated with lumbar splanchnic and pelvic spinal pathways, respectively. Identified neuronal subtypes were validated by single-cell qRT-PCR, immunohistochemistry (IHC) and Ca2+-imaging. RESULTS: Transcriptomic profiling and unsupervised clustering of 314 colonic sensory neurons revealed seven neuronal subtypes. Of these, five neuronal subtypes accounted for 99% of TL neurons, with LS neurons almost exclusively populating the remaining two subtypes. We identify and classify neurons based on novel subtype-specific marker genes using single-cell qRT-PCR and IHC to validate subtypes derived from RNA sequencing. Lastly, functional Ca2+-imaging was conducted on colonic sensory neurons to demonstrate subtype-selective differential agonist activation. CONCLUSIONS: We identify seven subtypes of colonic sensory neurons using unbiased single-cell RNA-sequencing and confirm translation of patterning to protein expression, describing sensory diversity encompassing all modalities of colonic neuronal sensitivity. These results provide a pathway to molecular interrogation of colonic sensory innervation in health and disease, together with identifying novel targets for drug development. PMID- 29483302 TI - Molecular and Structural Traits of Insulin Receptor Substrate 1/LC3 Nuclear Structures and Their Role in Autophagy Control and Tumor Cell Survival. AB - Insulin receptor substrate 1 (IRS-1) is a common cytosolic adaptor molecule involved in signal transduction from insulin and insulin-like growth factor I (IGF-I) receptors. IRS-1 can also be found in the nucleus. We report here a new finding of unique IRS-1 nuclear structures, which we observed initially in glioblastoma biopsy specimens and glioblastoma xenografts. These nuclear structures can be reproduced in vitro by the ectopic expression of IRS-1 cDNA cloned in frame with the nuclear localization signal (NLS-IRS-1). In these structures, IRS-1 localizes at the periphery, while the center harbors a key autophagy protein, LC3. These new nuclear structures are highly dynamic, rapidly exchange IRS-1 molecules with the surrounding nucleoplasm, disassemble during mitosis, and require a growth stimulus for their reassembly and maintenance. In tumor cells engineered to express NLS-IRS-1, the IRS-1/LC3 nuclear structures repress autophagy induced by either amino acid starvation or rapamycin treatment. In this process, IRS-1 nuclear structures sequester LC3 inside the nucleus, possibly preventing its cytosolic translocation and the formation of new autophagosomes. This novel mechanism provides a quick and reversible way of inhibiting autophagy, which could counteract autophagy-induced cancer cell death under severe stress, including anticancer therapies. PMID- 29483304 TI - High-Flow Nasal Cannula: Where Does It Fit? PMID- 29483305 TI - High-Flow Nasal Cannula Devices: Noisier Than We Realize. PMID- 29483308 TI - What's happening in Neurology(r). PMID- 29483306 TI - Does Tracheostomy Remain an Option in Neuromuscular Patients? PMID- 29483309 TI - What's Happening in Neurology(r)Clinical Practice. PMID- 29483311 TI - What's happening in Neurology(r)Neuroimmunology & Neuroinflammation. PMID- 29483310 TI - What's happening in Neurology(r)Genetics. PMID- 29483312 TI - What's happening in Without Borders. PMID- 29483314 TI - The unseen but felt. PMID- 29483313 TI - Lawful physician-hastened death: AAN position statement. PMID- 29483315 TI - Resident & Fellow Rounds. PMID- 29483316 TI - Clinical Reasoning: Subacute paresis in a 28-year-old man with HIV. PMID- 29483317 TI - Editors' note: Visual discrimination training improves Humphrey perimetry in chronic cortically induced blindness. PMID- 29483318 TI - Reader response: Visual discrimination training improves Humphrey perimetry in chronic cortically induced blindness. PMID- 29483319 TI - Author response: Visual discrimination training improves Humphrey perimetry in chronic cortically induced blindness. PMID- 29483320 TI - Editors' note: MRI-guided focused ultrasound thalamotomy in non-ET tremor syndromes. PMID- 29483321 TI - Reader response: MRI-guided focused ultrasound thalamotomy in non-ET tremor syndromes. PMID- 29483322 TI - Author response: MRI-guided focused ultrasound thalamotomy in non-ET tremor syndromes. PMID- 29483324 TI - Mystery Case: Superior oblique myokymia: An uncommon cause of intermittent diplopia. PMID- 29483323 TI - Clinical features, course, and outcomes of a UK cohort of pediatric moyamoya. AB - OBJECTIVE: To describe characteristics and course of a large UK cohort of children with moyamoya from multiple centers and examine prognostic predictors. METHODS: Retrospective review of case notes/radiology, with use of logistic regression to explore predictors of outcome. RESULTS: Eighty-eight children (median presentation age 5.1 years) were included. Thirty-six presented with arterial ischemic stroke (AIS) and 29 with TIA. Eighty had bilateral and 8 unilateral carotid circulation disease; 29 patients had posterior circulation involvement. Acute infarction was present in 36/176 hemispheres and chronic infarction in 86/176 hemispheres at the index presentation. Sixty-two of 82 with symptomatic presentation had at least one clinical recurrence. Fifty-five patients were treated surgically, with 37 experiencing fewer recurrences after surgery. Outcome was categorized as good using the Recovery and Recurrence Questionnaire in 39/85 patients. On multivariable analysis, presentation with TIA (odds ratio [OR] 0.09, 95% confidence interval [CI] 0.02-0.35), headache (OR 0.10, 95% CI 0.02-0.58), or no symptoms (OR 0.08, 95% CI 0.01-0.68) was less likely to predict poor outcome than AIS presentation. Posterior circulation involvement predicted poor outcome (OR 4.22, 95% CI 1.23-15.53). Surgical revascularization was not a significant predictor of outcome. CONCLUSIONS: Moyamoya is associated with multiple recurrences, progressive arteriopathy, and poor outcome in half of patients, especially with AIS presentation and posterior circulation involvement. Recurrent AIS is rare after surgery. Surgery was not a determinant of overall outcome, likely reflecting surgical case selection and presentation clinical status. PMID- 29483325 TI - Pearls & Oy-sters: Paraneoplastic cerebral vasculitis: Rare cause of spontaneous convexity subarachnoid hemorrhage. PMID- 29483326 TI - Teaching NeuroImages: Cerebral syphilitic gumma with numerous spirochetes in immunohistochemical staining. PMID- 29483327 TI - Epilepsy and risk of injury. PMID- 29483328 TI - Comparing Canadian health care to that in other countries: looking beyond the headlines. PMID- 29483330 TI - "Is there a doctor on board?": Practical recommendations for managing in-flight medical emergencies. PMID- 29483331 TI - Hepatopulmonary syndrome. PMID- 29483329 TI - Demographic predictors of active tuberculosis in people migrating to British Columbia, Canada: a retrospective cohort study. AB - BACKGROUND: Canadian tuberculosis (TB) guidelines recommend targeting postlanding screening for and treatment of latent tuberculosis infection (LTBI) in people migrating to Canada who are at increased risk for TB reactivation. Our objectives were to calculate robust longitudinal estimates of TB incidence in a cohort of people migrating to British Columbia, Canada, over a 29-year period, and to identify groups at highest risk of developing TB based on demographic characteristics at time of landing. METHODS: We included all individuals (n = 1 080 908) who became permanent residents of Canada between Jan. 1, 1985, and Dec. 31, 2012, and were resident in BC at any time between 1985 and 2013. Multiple administrative databases were linked to the provincial TB registry. We used recursive partitioning models to identify populations with high TB yield. RESULTS: Active TB was diagnosed in 2814 individuals (incidence rate 24.2/100 000 person-years). Demographic factors (live-in caregiver, family, refugee immigration classes; higher TB incidence in country of birth; and older age) were strong predictors of TB incidence in BC, with elevated rates continuing many years after entry into the cohort. Recursive partitioning identified refugees 18 64 years of age from countries with a TB incidence greater than 224/100 000 population as a high-yield group, with 1% developing TB within the first 10 years. INTERPRETATION: These findings support recommendations in Canadian guidelines to target postlanding screening for and treatment of LTBI in adult refugees from high-incidence countries. Because high-yield populations can be identified at entry via demographic data, screening at this point may be practical and high-impact, particularly if the LTBI care cascade can be optimized. PMID- 29483332 TI - Green urine. PMID- 29483333 TI - Insurance helps to brush physician depression under the rug. PMID- 29483334 TI - Electronic health records: physicians must lead. PMID- 29483335 TI - Do students enter medicine for money and prestige or to be of service? PMID- 29483336 TI - Quebec medical residents threaten strike over hours and pay. PMID- 29483337 TI - Health on the Hill: Parliament mulls vaping regulations. PMID- 29483338 TI - Taxonomies of psychological individual differences: biological perspectives on millennia-long challenges. AB - This Editorial highlights a unique focus of this theme issue on the biological perspectives in deriving psychological taxonomies coming from neurochemistry, neuroanatomy, neurophysiology, genetics, psychiatry, developmental and comparative psychology-as contrasted to more common discussions of socio-cultural concepts (personality) and methods (lexical approach). It points out the importance of the distinction between temperament and personality for studies in human and animal differential psychophysiology, psychiatry and psycho pharmacology, sport and animal practices during the past century. It also highlights the inability of common statistical methods to handle nonlinear, feedback, contingent, dynamical and multi-level relationships between psychophysiological systems of consistent psychological traits discussed in this theme issue.This article is part of the theme issue 'Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'. PMID- 29483339 TI - Opinion on monoaminergic contributions to traits and temperament. AB - This article critically reviews evidence relating temperamental traits and personality factors to the monoamine neurotransmitters, especially dopamine and serotonin. The genetic evidence is not yet considered to be conclusive and it is argued that basic neuroscience research on the neural basis of behaviour in experimental animals should be taken more into account. While questionnaire and lexical methodology including the 'Five Factor' theory has been informative (mostly for the traits relevant to social functioning, i.e. personality), biologically oriented approaches should be employed with more objective, theoretically grounded measures of cognition and behaviour, combined with neuroimaging and psychopharmacology, where appropriate. This strategy will enable specific functions of monoamines and other neuromodulators such as acetylcholine and neuropeptides (such as orexin) to be defined with respect to their roles in modulating activity in specific neural networks-leading to a more realistic definition of their interactive roles in complex, biologically based traits (i.e. temperament).This article is part of the theme issue 'Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'. PMID- 29483340 TI - Inter-individual differences in the impulsive/compulsive dimension: deciphering related dopaminergic and serotonergic metabolisms at rest. AB - Several impulse control disorders such as ADHD, mania, personality disorders or substance abuse share common behavioural traits, like impulsiveness, risk-taking or inflexible behaviour. These disorders are treated with drugs targeting dopamine (DA) and/or serotonin (5-HT). However, the patient's monoamine imbalance that these neurotransmitters compensate is unclear. This study aims to investigate the patterns of DA and 5-HT metabolisms at rest within selected brain regions related to inter-individual variability in six main components of impulsivity/compulsivity (anticipatory hyperactivity, premature responses, delay discounting, risk-taking, perseveration, flexibility). Rats with adaptive and highly inadaptive behaviours were identified in each task and a sensitive biochemical approach allowed mapping of post-mortem endogenous monoamine tissue content in 20 brain areas. Distinct patterns of 5-HT and DA metabolisms were revealed according to the behavioural traits. Except for hyperactive responses, lower control of actions was mainly associated with a lower DA or 5-HT metabolism in prefrontal and/or subcortical areas (i.e. in orbitofrontal cortex (DA), amygdala and anterior cingulate cortex (5-HT) for inflexible and risk-prone rats). Our results reveal the complex nature of behavioural traits related to impulse control disorders through their associated monoaminergic networks at rest, paving the way for understanding the link between mental disorders and drug therapeutic actions.This article is part of the theme issue 'Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'. PMID- 29483341 TI - Traits of empathy and anger: implications for psychopathy and other disorders associated with aggression. AB - Empathy and anger are two social emotions that modulate an individual's risk for aggression. Empathy is an emotional reaction to another individual's emotional state. Anger is an emotional reaction to threat, frustration or social provocation. Reduced empathy, seen in psychopathy, increases the risk for goal directed aggression. Atypically increased anger (i.e. irritability), seen in conditions like disruptive mood dysregulation disorder and borderline personality disorder, increases the risk for reactive aggression. In this paper, I will outline core neurocognitive functions that correspond to empathy and which are compromised in individuals with psychopathic traits. In addition, I will outline neurocognitive functions involved in either the generation or regulation of anger and which are compromised in psychiatric conditions at increased risk for irritability/reactive aggression. It can be hoped that improved understanding of empathy and anger will lead to better assessment tools and improved interventions to reduce aggression risk.This article is part of the theme issue 'Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'. PMID- 29483342 TI - Brain neuroreceptor density and personality traits: towards dimensional biomarkers for psychiatric disorders. AB - Positron emission tomography has, for 30 years, been used in numerous case control studies searching for hypothesized differences in the density of neuroreceptor or transporter proteins in psychiatric disorders such as schizophrenia and depression. In most cases, the results have not been conclusive. One reason could be the sizeable interindividual variability in biochemical markers, which in twin studies have shown to emanate from both environmental and genetic factors, leading to low statistical power for the detection of group effects. On the other hand, the same interindividual variability has served as an opportunity for correlative studies on the biological underpinning of behaviour. Using this approach, a series of studies has linked markers for the dopamine and serotonin system to personality traits associated with psychiatric conditions. Based on increasing evidence for the view that many psychopathological states represent extremes of a continuum rather than distinct categories, this research strategy may lead to new biological insights about the vulnerability to and pathophysiology of major psychiatric disorders.This article is part of the theme issue 'Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'. PMID- 29483343 TI - Perspectives on two temperamental biases. AB - This paper describes the contribution of two infant temperamental biases to variation in behaviour and biology over the first 18 years in a sample of middle class Caucasian children. One bias, called high reactive, is defined by frequent display of limb activity and crying in four-month-old infants to unexpected or unfamiliar events. The other, called low reactive, is defined by the opposite pair of behaviours to the same incentives. High reactive infants are likely to display cautious, avoidant responses and signs of an excitable amygdala to unexpected experiences. Low reactives are characterized by a sociable, emotionally spontaneous profile to the same experiences and a minimally excitable amygdala. However, each bias is a better predictor of the future traits that are unlikely to develop than the ones that do. The final pattern of traits is a function of the person's temperaments, life history, and current circumstances.This article is part of the theme issue 'Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'. PMID- 29483345 TI - The neural correlates of temperamental inhibitory control in toddlers. AB - The current study examined the association between effortful control and a well studied neural index of self-regulation, the N2 event-related potential (ERP) component, in toddlers. Participants included 107 toddlers (44 girls) assessed at 30, 36 and 42 months of age. Participants completed a Go/NoGo task while electroencephalography data were recorded. The study focused on the N2 ERP component. Parent-reported effortful control was examined in association with the NoGo N2 ERP component. Findings suggest a positive association between the NoGo N2 component and the inhibitory control subscale of the wider effortful control dimension, suggesting that the N2 component may index processes associated with temperamental effortful control.This article is part of the theme issue 'Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'. PMID- 29483344 TI - Neurohormones and temperament interact during infant development. AB - The infant's psycho-physiological regulatory system begins to develop prenatally and continues to mature during the postnatal period. Temperament is a construct comprising tonic individual differences in dispositional physiological and behavioural reactions as well as an evolving ability to regulate to environmental conditions. Theoretical models and research have shown that neurohormonal and physiological factors contribute to individual development and impact infant behaviours as well as the developing regulatory system. Moreover, prenatal maternal risks such as stress and depression are thought to programme fetal regulatory tendencies and that influences neural and behavioural functioning in infancy. The purpose of this review is to examine the theories and research that link infant temperament to neurohormonal and -physiological development in typically developing infants and in those exposed to environmental risk. Research has demonstrated associations between individual variation in physiological stress responses and regulation (measured with cortisol). Moreover, studies have noted an association with physiological regulation and socio-emotional interaction (as measured by the touch-oxytocin link) that may buffer emotional dysregulation. The interaction between individual differences in temperamental tendencies, neurohormonal and -physiological patterns will be discussed by presenting data from studies that have shown that infant neurohormonal and physiological functioning sets an important trajectory for the development of the individual.This article is part of the theme issue 'Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'. PMID- 29483346 TI - The functional highly sensitive brain: a review of the brain circuits underlying sensory processing sensitivity and seemingly related disorders. AB - During the past decade, research on the biological basis of sensory processing sensitivity (SPS)-a genetically based trait associated with greater sensitivity and responsivity to environmental and social stimuli-has burgeoned. As researchers try to characterize this trait, it is still unclear how SPS is distinct from seemingly related clinical disorders that have overlapping symptoms, such as sensitivity to the environment and hyper-responsiveness to incoming stimuli. Thus, in this review, we compare the neural regions implicated in SPS with those found in fMRI studies of-Autism Spectrum Disorder (ASD), Schizophrenia (SZ) and Post-Traumatic Stress Disorder (PTSD) to elucidate the neural markers and cardinal features of SPS versus these seemingly related clinical disorders. We propose that SPS is a stable trait that is characterized by greater empathy, awareness, responsivity and depth of processing to salient stimuli. We conclude that SPS is distinct from ASD, SZ and PTSD in that in response to social and emotional stimuli, SPS differentially engages brain regions involved in reward processing, memory, physiological homeostasis, self other processing, empathy and awareness. We suggest that this serves species survival via deep integration and memory for environmental and social information that may subserve well-being and cooperation.This article is part of the theme issue 'Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'. PMID- 29483347 TI - Genetics of biologically based psychological differences. AB - In recent years, substantial effort has gone into disentangling the genetic contribution to individual differences in behaviour (such as personality and temperament traits). Heritability estimates from twin and family studies, and more recently using whole genome approaches, suggest a substantial genetic component to these traits. However, efforts to identify the genes that influence these traits have had relatively little success. Here, we review current work investigating the heritability of individual differences in behavioural traits and provide an overview of the results from genome-wide association analyses of these traits to date. In addition, we discuss the implications of these findings for the potential applications of Mendelian randomization.This article is part of the theme issue 'Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'. PMID- 29483348 TI - What is the natural measurement unit of temperament: single traits or profiles? AB - There is fundamental doubt about whether the natural unit of measurement for temperament and personality corresponds to single traits or to multi-trait profiles that describe the functioning of a whole person. Biogenetic researchers of temperament usually assume they need to focus on individual traits that differ between individuals. Recent research indicates that a shift of emphasis to understand processes within the individual is crucial for identifying the natural building blocks of temperament. Evolution and development operate on adaptation of whole organisms or persons, not on individual traits or categories. Adaptive functioning generally depends on feedback among many variable processes in ways that are characteristic of complex adaptive systems, not machines with separate parts. Advanced methods of unsupervised machine learning can now be applied to genome-wide association studies and brain imaging in order to uncover the genotypic-phenotypic architecture of traits like temperament, which are strongly influenced by complex interactions, such as genetic epistasis, pleiotropy and gene-environment interactions. We have found that the heritability of temperament can be nearly fully explained by a large number of genetic variants that are unique for multi-trait profiles, not single traits. The implications of this finding for research design and precision medicine are discussed.This article is part of the theme issue 'Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'. PMID- 29483349 TI - Benefits and limitations of drug studies in temperament research: biochemical responses as indicators of temperament. AB - This paper presents a discussion of principles and problems of neurotransmitter challenge tests using examples of experiments, most of which were performed in the author's laboratory. Drugs targeting synthesis, release, receptors or reuptake of dopamine, serotonin and noradrenergic transmitter (TM) systems were used for characterizing or discriminating certain temperament or personality traits and their sub-factors. Any personality or temperament trait is characterized by multiple TM responses, thus constellations of hormone responses to drugs acting on different TM systems or on different sources of TM activity were investigated within individuals in crossover designs. The major conclusions are: (i) intra-individual patterns of hormone responses to different TM-related drugs, or to agonists and antagonists, can help to discriminate subtypes of temperament dimensions, and (ii) the latency and shape of response curves may help specify processes of biological responses related to psychological dimensions and reveal common TM sensitivities in clusters of traits. TM sensitivity, defined by hormone responses, does not always correspond to accompanying behavioural indicators, but may provide more specific information on underlying mechanisms. Additional consideration of drug doses and experimental induction of stressors may serve to identify temperament-related susceptibilities to certain drugs. Limitations of the challenge approach and recommendations for future research are discussed.This article is part of the theme issue 'Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'. PMID- 29483350 TI - Functional systems theory and the activity-specific approach in psychological taxonomies. AB - This brief opinion contribution reflects on the application of Anokhin's functional systems theory in the development of models of temperament in Russian differential psychophysiology. It points to the benefits of using an activity specific approach in temperament theory. This approach suggests separating traits related to physical, communicative and mental aspects of behaviour.This article is part of the theme issue 'Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'. PMID- 29483351 TI - Functionality versus dimensionality in psychological taxonomies, and a puzzle of emotional valence. AB - This paper applies evolutionary and functional constructivism approaches to the discussion of psychological taxonomies, as implemented in the neurochemical model Functional Ensemble of Temperament (FET). FET asserts that neurochemical systems developed in evolution to regulate functional-dynamical aspects of construction of actions: orientation, selection (integration), energetic maintenance, and management of automatic behavioural elements. As an example, the paper reviews the neurochemical mechanisms of interlocking between emotional dispositions and performance capacities. Research shows that there are no specific neurophysiological systems of positive or negative affect, and that emotional valence is rather an integrative product of many brain systems during estimations of needs and the capacities required to satisfy these needs. The interlocking between emotional valence and functional aspects of performance appears to be only partial since all monoamine and opioid receptor systems play important roles in non-emotional aspects of behaviour, in addition to emotionality. This suggests that the Positive/Negative Affect framework for DSM/ICD classifications of mental disorders oversimplifies the structure of non-emotionality symptoms of these disorders. Contingent dynamical relationships between neurochemical systems cannot be represented by linear statistical models searching for independent dimensions (such as factor analysis); nevertheless, these relationships should be reflected in psychological and psychiatric taxonomies.This article is part of the theme issue 'Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'. PMID- 29483352 TI - Assessing the continuum between temperament and affective illness: psychiatric and mathematical perspectives. AB - Temperament of healthy people and mental illnesses, particularly affective disorders, have been conjectured to lie along a continuum of neurobehavioural regulation. Understanding the nature of this continuum may better inform the construction of taxonomies for both categories of behaviour. Both temperament and mental illness refer to patterns of behaviour that manifest over long time scales (weeks to years) and they appear to share many underlying neuroregulatory systems. This continuum is discussed from the perspectives of nonlinear dynamical systems theory, neurobiology and psychiatry as applied to understanding such multiscale time-series behaviour. Particular emphasis is given to issues of generativity, fungibility, metastability, non-stationarity and contextuality. Implications of these dynamical properties for the development of taxonomies will be discussed. Problems with the over-reliance of psychologists on statistical and mathematical methods in deriving their taxonomies (particularly those based on factor analysis) will be discussed from a dynamical perspective. An alternative approach to temperament based upon functionality, and its discriminative capabilities in mental illness, is presented.This article is part of the theme issue 'Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'. PMID- 29483353 TI - Culture, morality and individual differences: comparability and incomparability across species. AB - Major routes to identifying individual differences (in diverse species) include studies of behaviour patterns as represented in language and neurophysiology. But results from these approaches appear not to converge on some major dimensions. Identifying dimensions of human variation least applicable to non-human species may help to partition human-specific individual differences of recent evolutionary origin from those shared across species. Human culture includes learned, enforced social-norm systems that are symbolically reinforced and referenced in displays signalling adherence. At a key juncture in human evolution bullying aggression and deception-based cheating apparently became censured in the language of a moral community, enabling mutual observation coordinated in gossip, associated with external sanctions. That still-conserved cultural paradigm moralistically regulates selfish advantage-taking, with shared semantics and explicit rules. Ethics and moral codes remain critical and universal components of human culture and have a stronger imprint in language than most aspects of the currently popular Big-Five taxonomy, a model that sets out five major lines of individual-differences variation in human personality. In other species (e.g. chimpanzees), human observers might see apparent individual differences in morality-relevant traits, but not because the animals have human analogue sanctioning systems. Removing the moral dimension of personality and other human-specific manifestations (e.g. religion) may aid in identifying those other bases of individual differences more ubiquitous across species.This article is part of the theme issue 'Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'. PMID- 29483354 TI - Taxonomic models of individual differences: a guide to transdisciplinary approaches. AB - Models and constructs of individual differences are numerous and diverse. But detecting commonalities, differences and interrelations is hindered by the common abstract terms (e.g. 'personality', 'temperament', 'traits') that do not reveal the particular phenomena denoted. This article applies a transdisciplinary paradigm for research on individuals that builds on complexity theory and epistemological complementarity. Its philosophical, metatheoretical and methodological frameworks provide concepts to differentiate various kinds of phenomena (e.g. physiology, behaviour, psyche, language). They are used to scrutinize the field's basic concepts and to elaborate methodological foundations for taxonomizing individual variations in humans and other species. This guide to developing comprehensive and representative models explores the decisions taxonomists must make about which individual variations to include, which to retain and how to model them. Selection and reduction approaches from various disciplines are classified by their underlying rationales, pinpointing possibilities and limitations. Analyses highlight that individuals' complexity cannot be captured by one universal model. Instead, multiple models phenotypically taxonomizing different kinds of variability in different kinds of phenomena are needed to explore their causal and functional interrelations and ontogenetic development that are then modelled in integrative and explanatory taxonomies. This research agenda requires the expertise of many disciplines and is inherently transdisciplinary.This article is part of the theme issue 'Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'. PMID- 29483355 TI - Diversity in action: exchange of perspectives and reflections on taxonomies of individual differences. AB - Throughout the last 2500 years, the classification of individual differences in healthy people and their extreme expressions in mental disorders has remained one of the most difficult challenges in science that affects our ability to explore individuals' functioning, underlying psychobiological processes and pathways of development. To facilitate analyses of the principles required for studying individual differences, this theme issue brought together prominent scholars from diverse backgrounds of which many bring unique combinations of cross-disciplinary experiences and perspectives that help establish connections and promote exchange across disciplines. This final paper presents brief commentaries of some of our authors and further scholars exchanging perspectives and reflecting on the contributions of this theme issue.This article is part of the theme issue 'Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'. PMID- 29483356 TI - Temperament and brain networks of attention. AB - The attention networks of the human brain are important control systems that develop from infancy into adulthood. While they are common to everyone, they differ in efficiency, forming the basis of individual differences in attention. We have developed methods for measuring the efficiency of these networks in older children and adults and have also examined their development from infancy. During infancy the alerting and orienting networks are dominant in control of the infant's actions, but later an executive network dominates. Each network has been associated with its main neuromodulator and these have led to associations with genes related to that network neuromodulator. The links between parent reports of their child's effortful control and the executive attention network allow us to associate molecular mechanisms to fundamental behavioural outcomes.This article is part of the theme issue 'Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'. PMID- 29483357 TI - A network model of behavioural performance in a rule learning task. AB - Humans demonstrate differences in performance on cognitive rule learning tasks which could involve differences in properties of neural circuits. An example model is presented to show how gating of the spread of neural activity could underlie rule learning and the generalization of rules to previously unseen stimuli. This model uses the activity of gating units to regulate the pattern of connectivity between neurons responding to sensory input and subsequent gating units or output units. This model allows analysis of network parameters that could contribute to differences in cognitive rule learning. These network parameters include differences in the parameters of synaptic modification and presynaptic inhibition of synaptic transmission that could be regulated by neuromodulatory influences on neural circuits. Neuromodulatory receptors play an important role in cognitive function, as demonstrated by the fact that drugs that block cholinergic muscarinic receptors can cause cognitive impairments. In discussions of the links between neuromodulatory systems and biologically based traits, the issue of mechanisms through which these linkages are realized is often missing. This model demonstrates potential roles of neural circuit parameters regulated by acetylcholine in learning context-dependent rules, and demonstrates the potential contribution of variation in neural circuit properties and neuromodulatory function to individual differences in cognitive function.This article is part of the theme issue 'Diverse perspectives on diversity: multi disciplinary approaches to taxonomies of individual differences'. PMID- 29483358 TI - Bruton's Tyrosine Kinase Is Not Essential for B Cell Survival beyond Early Developmental Stages. AB - Bruton's tyrosine kinase (Btk) is a crucial regulator of B cell signaling and is a therapeutic target for lymphoma and autoimmune disease. BTK-deficient patients suffer from humoral immunodeficiency, as their B cells fail to progress beyond the bone marrow. However, the role of Btk in fully developed, mature peripheral B cells is not well understood. Analysis using BTK inhibitors is complicated by suboptimal inhibition, off-target effects, or failure to eliminate BTK's adaptor function. Therefore a Btkflox/Cre-ERT2 mouse model was developed and used to excise Btk after B cell populations were established. Mice lacking Btk from birth are known to have reduced follicular (FO) compartments, with expanded transitional populations, suggesting a block in development. In adult Btkflox/Cre ERT2 mice, Btk excision did not reduce FO B cells, which persisted for weeks. Autoimmune-prone B1 cells also survived conditional Btk excision, contrasting their near absence in global Btk-deficient mice. Therefore, Btk supports BCR signaling during selection into the FO and B1 compartments, but is not needed to maintain these cell populations. B1-related natural IgM levels remained normal, contrasting global Btk deficiency, but B cell proliferation and T-independent type II immunization responses were blunted. Thus, B cells have nuanced signaling responses that are differentially regulated by Btk for development, survival, and function. These findings raise the possibility that Btk may also be expendable for survival of mature human B cells, therefore requiring prolonged dosing to be effective, and that success of BTK inhibitors may depend in part on off-target effects. PMID- 29483359 TI - FHR5 Binds to Laminins, Uses Separate C3b and Surface-Binding Sites, and Activates Complement on Malondialdehyde-Acetaldehyde Surfaces. AB - Factor H related-protein 5 (CFHR5) is a surface-acting complement activator and variations in the CFHR5 gene are linked to CFHR glomerulonephritis. In this study, we show that FHR5 binds to laminin-521, the major constituent of the glomerular basement membrane, and to mesangial laminin-211. Furthermore, we identify malondialdehyde-acetaldehyde (MAA) epitopes, which are exposed on the surface of human necrotic cells (Homo sapiens), as new FHR5 ligands. Using a set of novel deletion fragments, we show that FHR5 binds to laminin-521, MAA epitopes, heparin, and human necrotic cells (HUVECs) via the middle region [short consensus repeats (SCRs) 5-7]. In contrast, surface-bound FHR5 contacts C3b via the C-terminal region (SCRs8-9). Thus, FHR5 uses separate domains for C3b binding and cell surface interaction. MAA epitopes serve as a complement-activating surface by recruiting FHR5. The complement activator FHR5 and the complement inhibitor factor H both bind to oxidation-specific MAA epitopes and FHR5 competes with factor H for binding. The C3 glomerulopathy-associated FHR21-2-FHR5 hybrid protein is more potent in MAA epitope binding and activation compared with wild type FHR5. The implications of these results for pathology of CFHR glomerulonephritis are discussed. In conclusion, we identify laminins and oxidation-specific MAA epitopes as novel FHR5 ligands and show that the surface binding site of FHR5 (SCRs5-7) is separated from the C3b binding site (SCRs8-9). Furthermore, FHR5 competes with factor H for binding to MAA epitopes and activates complement on these modified structures. PMID- 29483362 TI - Correction to: 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. PMID- 29483363 TI - Correction to: Accuracy of Prediction Instruments for Diagnosing Large Vessel Occlusion in Individuals With Suspected Stroke: A Systematic Review for the 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke. PMID- 29483360 TI - Peptide-MHC Class I Tetramers Can Fail To Detect Relevant Functional T Cell Clonotypes and Underestimate Antigen-Reactive T Cell Populations. AB - Peptide-MHC (pMHC) multimers, usually used as streptavidin-based tetramers, have transformed the study of Ag-specific T cells by allowing direct detection, phenotyping, and enumeration within polyclonal T cell populations. These reagents are now a standard part of the immunology toolkit and have been used in many thousands of published studies. Unfortunately, the TCR-affinity threshold required for staining with standard pMHC multimer protocols is higher than that required for efficient T cell activation. This discrepancy makes it possible for pMHC multimer staining to miss fully functional T cells, especially where low affinity TCRs predominate, such as in MHC class II-restricted responses or those directed against self-antigens. Several recent, somewhat alarming, reports indicate that pMHC staining might fail to detect the majority of functional T cells and have prompted suggestions that T cell immunology has become biased toward the type of cells amenable to detection with multimeric pMHC. We use several viral- and tumor-specific pMHC reagents to compare populations of human T cells stained by standard pMHC protocols and optimized protocols that we have developed. Our results confirm that optimized protocols recover greater populations of T cells that include fully functional T cell clonotypes that cannot be stained by regular pMHC-staining protocols. These results highlight the importance of using optimized procedures that include the use of protein kinase inhibitor and Ab cross-linking during staining to maximize the recovery of Ag specific T cells and serve to further highlight that many previous quantifications of T cell responses with pMHC reagents are likely to have considerably underestimated the size of the relevant populations. PMID- 29483364 TI - Correction to: Effect of Dysphagia Screening Strategies on Clinical Outcomes After Stroke: A Systematic Review for the 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke. PMID- 29483365 TI - Correction to: Effect of Smoking and Folate Levels on the Efficacy of Folic Acid Therapy in Prevention of Stroke in Hypertensive Men. PMID- 29483366 TI - Correction to: Risk of Stroke With Various Types of Menopausal Hormone Therapies: A National Cohort Study. PMID- 29483368 TI - Correction to: Predictors of In-Hospital Death After Aneurysmal Subarachnoid Hemorrhage: Analysis of a Nationwide Database (Swiss SOS [Swiss Study on Aneurysmal Subarachnoid Hemorrhage]). PMID- 29483367 TI - Correction to: Surgical Management of Moyamoya Disease. PMID- 29483370 TI - Outcomes in morbidly obese adolescent patients undergoing laparoscopic sleeve gastrectomy in the Indian subcontinent: A retrospective review. AB - Introduction: There is a worldwide increase in the prevalence of obesity among the adolescent population in India from 16.3% in 2001 to 19.3% in 2010. Recent evidence suggests that bariatric surgery leads to resolution of comorbidities and associated long-term complications in adolescent patients with morbid obesity. Aim: The aim of this study is to determine the impact of bariatric surgery on the weight loss and comorbidities of morbidly obese adolescents. Materials and Methods: A retrospective review of the data of 10 adolescent patients, who underwent Laparoscopic Sleeve Gastrectomy at our institute (tertiary care hospital), from July 2009 to July 2016 was carried out. Results: Of the 10 patients, 4 patients had syndromic forms of obesity. The median age was 16.54 years. The median pre-operative weight and height were 112 kg and 154 cm, respectively, with a body mass index of 47.2 kg/m2. There was no intra-operative or post-operative complication except for suspected methylene blue toxicity in one patient which was treated conservatively. Median follow-up period was 1 year (0-5 years). The patients had an increase in excess weight loss (EWL) of 54.5% until the end of 1 year. There was a regain of weight between the 1st and 2nd year, followed by a sustained weight loss achieving 44.8% EWL at 3 years and 60% at the end of 5 years (only two patients followed up at 5 years). Similar results were found in syndromic patients. Among the four diabetic patients, three had complete resolution and one had improvement in diabetes status. Among the three patients with obstructive sleep apnoea, two patients had complete resolution, while one patient had improvement in symptoms. One patient with hypocortisolism improved after surgery with a decrease in the steroid requirement. Among the hypothyroid patients, one patient had a complete resolution, one patient had improvement in hypothyroid status while two patients had no change. Conclusion: Bariatric surgery is effective for morbidly obese adolescents, leading to significant resolutions of comorbid illness. PMID- 29483371 TI - End-stage renal disease is a risk factor for complex laparoscopic cholecystectomy in patients waiting for renal transplantation. AB - Introduction: : To date, there are no studies investigating whether laparoscopic cholecystectomy (LC) is technically more complex in patients waiting for kidney transplant. The aim of this study is to create a user-friendly score to identify high-risk cases for complex LC integrating end-stage renal disease (ESRD). Materials and Methods: We retrospectively analysed 321 patients undergoing LC during the period 2014-2016. Two groups were compared: ESRD group (n = 25) versus control group (n = 296). Concerning statistical analysis, continuous variables were compared using Kruskal-Wallis' test, dummy variables with Chi-square test or Fisher's exact test when appropriate. A multivariable logistic regression analysis was performed to identify risk factors for complex LC. A backward conditional method was used to design the final model. Results: : Seventy out of 321 (21.8%) cases were considered as complex, with a higher prevalence in the ESRD group (32.0 vs. 20.9%; P = 0.2). Using a multivariable logistic regression analysis, we formulated a score based on the independent risk factors for complex LC: 4*(previous cholecystitis) +5 * (previous ESRD) +1 * (age per decade) +2 * (previous open abdominal surgery). High-risk cases (score >= 10) were more commonly reported in the ESRD group (72.0 vs. 24.7%; P < 0.0001). Conclusion: : Although several scores investigating the risk for complex LC have been proposed, none of them has focused on ESRD. This is the first series demonstrating that ESRD is an independent risk factor for technical complexity in LC. We developed a score to offer surgeons an extra tool for pre-operative evaluation of patients requiring LC. PMID- 29483369 TI - Maternal obesity increases the risk of metabolic disease and impacts renal health in offspring. AB - Obesity, together with insulin resistance, promotes multiple metabolic abnormalities and is strongly associated with an increased risk of chronic disease including type 2 diabetes (T2D), hypertension, cardiovascular disease, non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD). The incidence of obesity continues to rise in astronomical proportions throughout the world and affects all the different stages of the lifespan. Importantly, the proportion of women of reproductive age who are overweight or obese is increasing at an alarming rate and has potential ramifications for offspring health and disease risk. Evidence suggests a strong link between the intrauterine environment and disease programming. The current review will describe the importance of the intrauterine environment in the development of metabolic disease, including kidney disease. It will detail the known mechanisms of fetal programming, including the role of epigenetic modulation. The evidence for the role of maternal obesity in the developmental programming of CKD is derived mostly from our rodent models which will be described. The clinical implication of such findings will also be discussed. PMID- 29483372 TI - Is robot-assisted radical cystectomy superior to standard open radical cystectomy? An Indian perspective. AB - Introduction: Open radical cystectomy (ORC) has been the standard treatment for muscle-invasive bladder cancer, but this is associated with significant morbidity and mortality. Robot-assisted radical cystectomy (RARC) has been proposed as minimally invasive alternative with improved morbidity and acceptable oncological outcomes, but a large series featuring RARC and their comparison with ORC is still lacking in India despite more than a decade of its inception. We have conducted this study with an objective to see the feasibility of RARC in the Indian context and compare it with contemporary standard. Methods: This is a prospective cohort study conducted at two tertiary cancer institutes. We have evaluated the patients pertaining to operative and early post-operative factors from January 2014 to December 2015. Necessary statistical tests applied to see comparability of the arms and their outcomes. Results: A total of 170 patients underwent surgery for carcinoma bladder (45 ORC while 125 RARC). Intraoperative blood loss (RARC and ORC: 228 and 529 ml) and average transfusion rate were lower with RARC. A trend towards benefit was noted in favour of robotic arm in terms of mean complication rate (RARC and ORC: 54 and 39%). Conclusions: The present study has shown comparable surgical and early post-operative outcomes with clear advantage of robotic approach in terms of intraoperative blood transfusion and lymph node yield. Although the study was non-randomised in nature, it should provide substantial evidence on safety and feasibility of RARC in the Indian context and a reference point of evidence to look ahead. PMID- 29483374 TI - Repeated laparoscopic resection of extra-regional lymph node metastasis after laparoscopic radical resection for rectal cancer. AB - Here, we report a case of repeated laparoscopic resection of extra-regional lymph node metastases in a patient after laparoscopic surgery for rectal cancer. A 72 year-old woman was diagnosed with upper rectal cancer and underwent laparoscopic low anterior resection and D3 dissection. The pathological stage was considered as T3, N2b, M0, Stage IIIC. Six months after the operation, positron emission tomography-computed tomography (PET-CT) showed fluorodeoxyglucose (FDG) accumulation in the infra-renal para-aortic lymph nodes (PALNs). Systemic chemotherapy was administered; however, chemotherapy was discontinued due to hemoptysis related to her pulmonary disease. Therefore, we performed laparoscopic PALN resection. Pathologically, one lymph node was diagnosed with a metastasis. Three months after the second operation, PET-CT identified FDG accumulation in the left lateral pelvic lymph nodes (LPLNs) and a PALN. Laparoscopic LPLN dissection and PALN resection through minilaparotomy were performed. Pathologically, lymph node metastases were diagnosed in both fields. Sixteen months after the 3rd operation, there is no recurrence. PMID- 29483373 TI - Short- and long-term outcomes of laparoscopic-assisted surgery, mini-laparotomy and conventional laparotomy in patients with Stage I-III colorectal cancer. AB - Background: Three operative techniques have been used for colorectal cancer (CRC) resection: Conventional laparotomy (CL) and the mini-invasive techniques (MITs)- laparoscopic-assisted surgery (LAS) and mini-laparotomy (ML). The aim of the study was to compare the short- and long-term outcomes of patients undergoing the three surgical approaches for Stage I-III CRC resection. Patients and Methods: This study enrolled 688 patients with Stage I-III CRC undergoing curative resection. The primary endpoints were perioperative quality and outcomes. The secondary endpoints were oncological outcomes including disease-free survival (DFS), overall survival (OS) and local recurrence (LR). Results: Patients undergoing LAS had significantly less blood loss (P < 0.001), earlier first flatus (P = 0.002) and earlier resumption of normal diet (P = 0.025). Although post-operative complication rates were remarkably higher in patients undergoing CL than in those undergoing MITs (P = 0.002), no difference was observed in the post-operative mortality rate (P = 0.099) or 60-day re-intervention rate (P = 0.062). The quality of operation as assessed by the number of lymph nodes harvested and rates of R0 resection did not differ among the groups (all P > 0.05). During a median follow-up of 5.42 years, no significant difference was observed among the treatment groups in the rates of 3-year late morbidity, 3-year LR, 5-year LR, 5-year OS or 5-year DFS (all P > 0.05). Conclusions: Patients undergoing CL had higher post-operative morbidities. Moreover, the study findings confirm the favourable short-term and comparable long-term outcomes of LAS and ML for curative CRC resection. Therefore, both MITs may be feasible and safe alternatives to CL for Stage I-III CRC resection. PMID- 29483375 TI - Minimally invasive surgery for salvage of malfunctioning peritoneal dialysis catheters. AB - Background: Malfunction of continuous ambulatory peritoneal dialysis (CAPD) catheters is a frequent complication and has traditionally been treated with a laparotomy. We present our experience with minimally invasive surgical (laparoscopic and thoracoscopic) salvage of CAPD catheters. Materials and Methods: Between October 2003 and June 2013, 19 patients (13 males and 6 females with a mean age of 37 years [range 28-64]) underwent minimally invasive laparoscopic salvage of malfunctioning CAPD catheters. These catheters had been placed with either a percutaneous or open technique and had been in place for a mean of 4.5 months (range 2-18 months). All the salvage procedures were performed under general anaesthesia using one 10 mm and two or three 5 mm ports. The various manoeuvres undertaken to re-establish catheter function included correct positioning the catheter and anchoring it to the pelvic peritoneum, clearing the fibrin clot/sheath, freeing up the omentum/bowel/taenia coli. In addition, all patients underwent an omentopexy. Results: Laparoscopic salvage could be completed in 18 patients with good catheter inflow and outflow established at the end of the surgery and one patient underwent thoracoscopic salvage. The median operative time was 63 min (range 45-96 min) and median post-operative hospital stay was 2 days (range 2-5 days). Low volume dialysis was commenced the day after surgery and full volume dialysis by the 10th day. There were no intra- or post operative complications. All the catheters were functioning at the end of 6-month follow-up. Conclusions: Minimally invasive surgery is a valid, safe and efficacious way of salvaging malfunctioning CAPD catheters. This modality reduces the chances of re-formation of adhesions, ensures rapid recovery, reduced wound related complications and allows for early institution of peritoneal dialysis. PMID- 29483376 TI - Robotic buccal mucosa graft ureteroplasty (inlay and onlay) for upper ureteric stricture: Point of technique. AB - Ureteral stricture resulting from chronic inflammations such as tuberculosis, recurrent stone disease and multiple endourological interventions are complex in nature; these may lead to severe adhesions to surrounding structures. Endourological management of these cases is difficult with poorer outcomes. In such situations, reconstructive surgical corrections remain a reliable option. We describe the technique of onlay and inlay buccal mucosal graft ureteroplasty using a robotic platform in management of complex ureteral strictures. PMID- 29483377 TI - Laparoscopic management of retroperitoneal injuries from penetrating abdominal trauma in haemodynamically stable patients. AB - Background: Laparoscopy is increasingly utilised in the trauma setting. However, its safety and reliability in evaluating and managing retroperitoneal injuries are not known. Aim: The aim of this study was to analyse our experience with laparoscopic management of retroperitoneal injuries due to penetrating abdominal trauma (PAT) and to investigate its feasibility, safety and accuracy in haemodynamically stable patients. Methods: Over a 4-year period, patients approached laparoscopically with retroperitoneal injuries were analysed. Mechanism, location and severity of injuries were recorded. Surgical procedures, conversion rate and reasons for conversion and outcomes were described. Results: Of the 284 patients with PAT, 56 patients had involvement of retroperitoneum. Stab wounds accounted 62.5% of patients. The mean Injury Severity Score was 7.4 (4-20). Among retroperitoneal injuries, the colon (27%) was the most commonly involved hollow viscera followed by duodenum (5%). The kidney (5%) and the pancreas (4%) were the injured solid organs. The conversion rate was 19.6% and was mainly due to active bleeding (73%). Significantly more patients with gunshot wound were converted to laparotomy (38% vs. 9%). Therapeutic laparoscopy was performed in 36% of patients. There were no recorded missed injuries or mortality. Five (9%) patients developed the Clavien-Dindo Grade 3 complications, three were managed with reoperation, one with drainage/debridement and one with endovascular technique. Conclusion: Laparoscopic management of retroperitoneal injuries is safe and feasible in haemodynamically stable patients with PAT. However, a high conversion rate indicates difficulties in managing these injuries. The requirements are the dexterity in laparoscopy and readiness to convert in the event of bleeding. PMID- 29483378 TI - Single-incision laparoscopic approach for linea alba hernia in children. AB - Objective: The aim of this study is to describe the technique and to evaluate the outcome of single-incision laparoscopic (SILC) approach for linea alba hernia in children. Materials and Methods: A 2 cm vertical umbilical incision was made and stretched horizontally. A 5-mm trocar was inserted through middle port for the telescope. Another extra-long 5-mm 30 degrees trocar was inserted through the lateral port, 5 mm beside the middle port. The extraperitoneal fat was removed, and the defect of linea alba was repaired after hernial sac was excised. The peritoneum was reconstructed with interrupted suture. Results: From May 2014 to May 2015, eight children with linea alba hernia underwent SILC. Pre-operative abdominal ultrasound showed the average diameter of hernia ring was 3.2 +/- 0.7 cm. Mean operation time was 32.5 min (range = 30-45 min). Oral intake was resumed during anaesthesia recovery period. All could endure pain and discharge on the post-operative 12 h. There was no post-operative wound infection. The follow-up period was 1-12 months, no recurrence and other complications occurred. Conclusions: SILC approach for linea alba hernia is a safe and effective, minimally invasive new technology. The linea alba hernia could be repaired with a cosmetic outcome. PMID- 29483379 TI - Changes of serum and peritoneal inflammatory mediators in laparoscopic radical resection for right colon carcinoma. AB - Objective: The objective of this study is to investigate the effects of laparoscopic and open operation on serum and peritoneal inflammatory mediators in patients with right colon carcinoma. Patients and Methods: : A total of 100 patients were randomly divided into laparoscopic group (n = 50) and open group (n = 50). The age, sex, operation time, operation blood loss, post-operative Dukes stage, time to first passage of flatus and post-operative hospital stay were recorded. The levels of hypersensitive C reactive protein (hsCRP) and tumour necrosis factor-alpha (TNF-alpha) in serum and abdominal exudate were measured by ELISA at the time of pre-operative 2 h and post-operative 6 h and 24 h. Results: There was no significant difference in age, sex, Dukes stage and pre-operative inflammatory mediators between the two groups (P > 0.05). The operation time, intraoperative blood loss, time to first passage of flatus and post-operative hospital stay were significantly better in laparoscopic group than those in open operation group. At 6 h and 24 h after operation, the levels of hsCRP and TNF alpha in serum and abdominal exudate in laparoscopic group were significantly lower than those in open operation group. Conclusions: Laparoscopic surgery for the treatment of right colon carcinoma has the advantages of fewer traumas, less systemic and local inflammatory response, rapider post-operative recovery and shorter hospital stay. It is worthy of clinical application. PMID- 29483380 TI - Concomitant bariatric surgery and component separation: Historical advance or a blunder? PMID- 29483381 TI - Bedside diagnostic laparoscopy for critically ill patients in the Intensive Care Unit: Retrospective study and review of literature. AB - Background: Bedside diagnostic laparoscopy could be helpful in extremely critically ill patients. The aim of this retrospective study is to evaluate the safety and diagnostic accuracy of bedside diagnostic laparoscopy in the identification of intra-abdominal pathology in critically ill patients and to compare its accuracy and outcomes with the ones of laparotomy. Patients and Methods: A retrospective review was conducted on the medical records of patients admitted to the Intensive Care Unit (ICU) of Careggi University Hospital and submitted to bedside diagnostic laparoscopy between January 2006 and May 2017. This group of patients was compared with a group of patients that were admitted to the ICU and submitted directly to explorative laparotomy for suspected intra abdominal pathologies. Results: One hundred and twenty-nine patients (M/F = 81/48, mean age = 71.64 years) underwent bedside diagnostic laparoscopy in ICU. 154 patients instead were submitted directly to explorative laparotomy in operatory room (mean age 75.70 years, M/F = 94/60). Among the 129 patients submitted to bedside laparoscopy, 53.49% were positive for intra-abdominal pathologies whereas 46.51% were negative, while among the 154 patients submitted directly to laparotomy, 76.62% were positive for intra-abdominal pathologies whereas 23.38% were negative. In 55.03% of all patients submitted to bedside laparoscopy, a non-therapeutic laparotomy was avoided, while the 33.76% of patients submitted directly to laparotomy had a non-therapeutic laparotomy that could be avoidable. Conclusions: Our results pinpoint the advantages of performing bedside diagnostic laparoscopy in the ICU setting, which can be considered an option every time there is the suspicion of an intra-abdominal pathology. PMID- 29483382 TI - Current Status and Future Direction of Transcatheter Mitral Valve Replacement. PMID- 29483383 TI - A Multicenter, Randomized, Double-Blind, and Placebo-Controlled Study of the Effects of Tongxinluo Capsules in Acute Coronary Syndrome Patients with High On Treatment Platelet Reactivity. AB - Background: High platelet reactivity (HPR) during clopidogrel treatment predicts postpercutaneous coronary intervention (PCI) ischemic events strongly and independently. Tongxinluo capsules (TCs) are a traditional Chinese medicine formulation used as antiplatelet treatment. However, its efficacy against HPR is not known. The aim of the present study was to evaluate the effects of TCs in acute coronary syndrome (ACS) patients with HPR. Methods: This multicenter, randomized, double-blind, placebo-controlled study prospectively analyzed 136 ACS patients with HPR who underwent PCI. The patients were enrolled from November 2013 to May 2014 and randomized to receive placebo or TCs in addition to standard dual antiplatelet therapy (DAPT) with aspirin and clopidogrel. The primary end points were the prevalence of HPR at 30 days and the mean change in P2Y12reaction units (PRUs) between baseline and 30 days. Survival curves were constructed with Kaplan-Meier estimates and compared by log-rank tests between the two groups. Results: Both groups had a significantly reduced prevalence of HPR at 30 days versus baseline, but the TC group, compared with the placebo group, had greater reduction (15.8% vs. 24.8%, P = 0.013), especially among patients with one cytochrome P450 2C19 loss of function (LOF) allele (chi2 = 2.931, P = 0.047). The TC group also had a lower prevalence of HPR (33.3% vs. 54.2%, t = 5.284, P = 0.022) and superior performance in light transmittance aggregometry and higher levels of high-sensitivity C-reactive protein (hsCRP), but the composite prevalence of ischemic events did not differ significantly (chi2 = 1.587, P = 0.208). Conclusions: In addition to standard DAPT with aspirin and clopidogrel, TCs further reduce PRU and hsCRP levels, especially in patients carrying only one LOF allele. The data suggest that TCs could be used in combination therapy for ACS patients with HPR undergoing PCI. PMID- 29483384 TI - Astragalus Membranaceus Improving Asymptomatic Left Ventricular Diastolic Dysfunction in Postmenopausal Hypertensive Women with Metabolic Syndrome: A Prospective, Open-Labeled, Randomized Controlled Trial. AB - Background: Postmenopausal women with metabolic syndrome (MetS) have increased cardiovascular morbidity and left ventricular diastolic dysfunction (LVDD). The various protective effects of astragalus membranaceus (AM) have been described in previous studies. Therefore, this study aimed to evaluate the effects of different doses of AM on diastolic function in postmenopausal hypertensive women with MetS. Methods: This was a prospective, randomized controlled study. The postmenopausal hypertensive patients with MetS were enrolled from Lanzhou University Second Hospital from March 2014 to April 2015. Patients were divided into three groups: control group (received conventional medical treatment), AM Group 1 (received AM capsules at 5 g/d additionally), and AM Group 2 (received AM capsules at 10 g/d additionally). Echocardiographic and clinical characteristics were evaluated before and 12 months after treatment. Quantitative data were analyzed using unpaired t-test, analysis of variance, and multiple linear regression analysis. Results: A total of 154 patients were subjected to final analysis. In the AM Group 2, significant improvements were noted in diastolic function 12 months after treatment than those of the control group, including the early diastolic mitral annular velocity (E'; 0.065 +/- 0.007 m/s vs. 0.061 +/- 0.008 m/s, P = 0.014), the ratio of the early diastolic mitral peak flow velocity to the late diastolic mitral peak flow velocity (E/A; 0.81 +/- 0.05 vs. 0.80 +/- 0.06, P = 0.012), the ratio of E' to the late diastolic mitral annular velocity (E'/A'; 0.56 +/- 0.12 vs. 0.51 +/- 0.13, P = 0.048), and the ratio of the early diastolic mitral peak flow velocity (E) to E' (E/E'; 10.70 +/- 1.30 vs. 11.37 +/- 1.73, P = 0.031). After treatment, E/E' (10.70 +/- 1.30 vs. 11.24 +/- 1.56, P = 0.021), deceleration time (DT; 261.49 +/- 44.41 ms vs. 268.74 +/- 53.87 ms, P = 0.046), and E'/A' (0.56 +/- 0.12 vs. 0.52 +/- 0.13, P = 0.019) values improved more significantly than those of AM Group 2 before treatment. Besides, waist circumference was positively correlated with E' (r = 0.472; P = 0.003) and E'/A' (r = 0.321; P = 0.047). In addition, the waist-to-hip ratio was a significant predictor of DT (r = 0.276; P = 0.041), E' (r = -0.590; P < 0.001), E/E' (r = 0.454; P = 0.004), and E'/A' (r = -0.377; P = 0.018). Conclusions: Conventional medical plus AM therapy improved diastolic function. Moreover, WC and WHR might be risk factors for LVDD. Chinese Clinical Trial Register: ChiCTR-TRC-11001747. http://www.chictr.org.cn/showprojen.aspx?proj=7798. PMID- 29483385 TI - Comparison of Clinical Effects between Percutaneous Transluminal Septal Myocardial Ablation and Modified Morrow Septal Myectomy on Patients with Hypertrophic Cardiomyopathy. AB - Background: Percutaneous transluminal septal myocardial ablation (PTSMA) and modified Morrow septal myectomy (MMSM) are two invasive strategies used to relieve obstruction in patients with hypertrophic cardiomyopathy (HCM). This study aimed to determine the clinical outcome of these two strategies. Methods: From January 2011 to January 2015, 226 patients with HCM were treated, 68 by PTSMA and 158 by MMSM. Both ultrasonic cardiograms and heart functional class were recorded before, after operations and in the follow-up. Categorical variables were compared using Chi-square or Fisher's exact tests. Quantitative variables were compared using the paired samples t-test. Results: Interventricular septal thickness was significantly reduced in both groups (21.27 +/- 4.43 mm vs. 18.72 +/- 4.13 mm for PTSMA, t = 3.469, P < 0.001, and 21.83 +/- 5.03 mm vs. 16.57 +/- 3.95 mm for MMSM, t = 10.349, P < 0.001, respectively). The left ventricular outflow tract (LVOT) pressure gradient (PG) significantly decreased after the operations in two groups (70.30 +/- 44.79 mmHg vs. 39.78 +/- 22.07 mmHg for PTSMA, t = 5.041, P < 0.001, and 74.58 +/- 45.52 mmHg vs. 13.95 +/ 9.94 mmHg for MMSM, t = 16.357, P < 0.001, respectively). Seven patients (10.29%) in the PTSMA group required a repeat operation in the follow-up. Eight (11.76%) patients were evaluated for New York Heart Association (NYHA) III/IV in the PTSMA group, which was significantly more than the five (3.16%) in the same NYHA classes for the MMSM group at follow-up. Less than 15% of patients in the PTSMA group and none of the patients in the MMSM group complained of chest pain during follow-up. Conclusions: Both strategies can not only relieve LVOT PG but also improve heart function in patients with HCM. However, MMSM might provide a more reliable reduction in gradients compared to PTSMA. PMID- 29483386 TI - Protection Effect of Exogenous Fibroblast Growth Factor 21 on the Kidney Injury in Vascular Calcification Rats. AB - Background: Chronic kidney disease (CKD) is closely related to the cardiovascular events in vascular calcification (VC). However, little has known about the characteristics of kidney injury caused by VC. Fibroblast growth factor 21 (FGF21) is an endocrine factor, which takes part in various metabolic actions with the potential to alleviate metabolic disorder diseases. Even FGF21 has been regarded as a biomarker in CKD, the role of FGF21 in CKD remains unclear. Therefore, in this study, we evaluate the FGF21 on the kidney injury in VC rats. Methods: The male Sprague-Dawley rats were divided into three groups: (1) control group, (2) Vitamin D3 plus nicotine (VDN)-induced VC group, (3) FGF21-treated VDN group. After 4 weeks, the rats were killed and the blood was collected for serum creatinine, urea nitrogen, calcium, and phosphate measurement. Moreover, the renal tissues were homogenized for alkaline phosphatases (ALPs) activity and calcium content. The levels of FGF21 protein were measured by radioimmunoassay. The levels of beta-Klotho and FGF receptor 1 (FGFR1) protein were measured by enzyme-linked immunosorbent assay (ELISA). The structural damage and calcifications in aortas were stained by Alizarin-red S. Moreover, the structure of kidney was observed by hematoxylin and eosin staining. Results: The renal function impairment caused by VDN modeling was ameliorated by FGF21 treatment, inhibited the elevated serum creatinine and urea level by 20.5% (34.750 +/- 4.334 MUmol/L vs. 27.630 +/- 2.387 MUmol/L) and 4.0% (7.038 +/- 0.590 mmol/L vs. 6.763 +/- 0.374 mmol/L; P < 0.01), respectively, together with the structural damages of glomerular atrophy and renal interstitial fibrosis. FGF21 treatment downregulated the ALP activity, calcium content in the kidney of VC rats by 42.1% (P < 0.01) and 11.7% (P < 0.05) as well as ameliorated the aortic injury and calcification as compared with VDN treatment alone group, indicating an ameliorative effect on VC. ELISA assays showed that the expression of beta Klotho, a component of FGF21 receptor system, was increased in VDN-treated VC rats by 37.4% (6.588 +/- 0.957 pg/mg vs. 9.054 +/- 0.963 pg/mg; P < 0.01), indicating an FGF21-resistant state. Moreover, FGF21 treatment downregulated the level of beta-Klotho in renal tissue by 16.7% (9.054 +/- 0.963 pg/mg vs. 7.544 +/ 1.362 pg/mg; P < 0.05). However, the level of FGFR1, the receptor of FGF21, kept unchanged under VDN and VDN plus FGF21 administration (0.191 +/- 0.0376 ng/mg vs. 0.189 +/- 0.032 ng/mg vs. 0.181 +/- 0.034 ng/mg; P > 0.05). Conclusions: In the present study, FGF21 was observed to ameliorate the kidney injury in VDN-induced VC rats. FGF21 might be a potential therapeutic factor in CKD by cutting off the vicious circle between VC and kidney injury. PMID- 29483387 TI - Sigma-1 Receptor Stimulation with PRE-084 Ameliorates Myocardial Ischemia Reperfusion Injury in Rats. AB - Background: The sigma receptors are a relatively novel receptor group with respect to knowledge of their effect on health. Although the sigma-1 receptor agonist PRE-084 exhibits a cardioprotective effect in some studies, the benefits in cases of myocardial ischemia/reperfusion (I/R) are not clear. The aim of this study was to explore the mechanism of action and assess the effect of PRE-084 on myocardial I/R injury in rats. Methods: In this study, rats were assigned randomly to three groups with computer (n = 14 for each group): a sham group, an I/R group, and a PRE-084 group. In the PRE-084 group, rats were administered PRE 084 1 h before operation. In the myocardial I/R model, the left anterior descending branch of rats was ligated and opened half an hour later. Cardiac function was assessed, and the apoptosis index was evaluated. The mechanisms of the cardioprotective effects of PRE-084 were explored. Results: PRE-084 pretreatment preserved cardiac function and reduced myocardial apoptosis (F = 86.0, P < 0.01) with Western blotting analysis, showing significantly reduced expression of Bax (F = 75.7, P < 0.01) and cleaved-caspase 3 (F = 44.7, P < 0.01), along with increased expression of the Bcl-2 protein (P < 0.01) and phosphorylated protein kinase B (p-Akt) (P < 0.01) and phosphorylated-endothelial nitric oxide synthase (p-eNOS; P < 0.01). Conclusion: PRE-084 preserved cardiac function and reduced myocardial apoptosis through the activation of Akt and eNOS. PMID- 29483388 TI - Tongxinluo Improves Apolipoprotein E-Deficient Mouse Heart Function. AB - Background: Our previous studies have shown that Tongxinluo (TXL), a compound Chinese medicine, can decrease myocardial ischemia-reperfusion injury, protect capillary endothelium function, and lessen cardiac ventricle reconstitution in animal models. The aim of this study was to illuminate whether TXL can improve hypercholesterolemia-impaired heart function by protecting artery endothelial function and increasing microvascular density (MVD) in heart. Furthermore, we will explore the underlying molecular mechanism of TXL cardiovascular protection. Methods: After intragastric administration of TXL (0.1 ml/10 g body weight) to C57BL/6J wild-type mice (n = 8) and ApoE-/- mice (n = 8), total cholesterol, high density lipoprotein-cholesterol, very-low-density lipoprotein (VLDL)-cholesterol, triglyceride, and blood glucose levels in serum were measured. The parameters of heart rate (HR), left ventricular diastolic end diameter, and left ventricular systolic end diameter were harvested by ultrasonic cardiogram. The left ventricular ejection fraction, stroke volume, cardiac output, and left ventricular fractional shortening were calculated. Meanwhile, aorta peak systolic flow velocity (PSV), end diastolic flow velocity, and mean flow velocity (MFV) were measured. The pulsatility index (PI) and resistant index were calculated in order to evaluate the vascular elasticity and resistance. The endothelium dependent vasodilatation was evaluated by relaxation of aortic rings in response to acetylcholine. Western blotting and real-time quantitative reverse transcription polymerase chain reaction were performed for protein and gene analyses of vascular endothelial growth factor (VEGF). Immunohistochemical detection was performed for myocardial CD34 expression. Data in this study were compared by one-way analysis of variance between groups. A value of P < 0.05 was considered statistically significant. Results: Although there was no significant decrease of cholesterol level (F = 2.300, P = 0.240), TXL inhibited the level of triglyceride and VLDL (F = 9.209, P = 0.024 and F = 9.786, P = 0.020, respectively) in ApoE-/- mice. TXL improved heart function of ApoE-/- mice owing to the elevations of LVEF, SV, CO, and LVFS (all P < 0.05). TXL enhanced aortic PSV and MFV (F = 10.774, P = 0.024 and F = 11.354, P = 0.020, respectively) and reduced PI of ApoE-/- mice (1.41 +/- 0.17 vs. 1.60 +/- 0.17; P = 0.037). After incubation with 10 MUmol/L acetylcholine, the ApoE-/- mice treated with TXL aortic segment relaxed by 44% +/- 3%, significantly higher than control group mice (F = 9.280, P = 0.040). TXL also restrain the angiogenesis of ApoE-/- mice aorta (F = 21.223, P = 0.010). Compared with C57BL/6J mice, the MVD was decreased in heart tissue of untreated ApoE-/- mice (54.0 +/- 3.0/mm2 vs. 75.0 +/- 2.0/mm2; F = 16.054, P = 0.010). However, TXL could significantly enhance MVD (65.0 +/- 5.0/mm2 vs. 54.0 +/- 3.0/mm2; F = 11.929, P = 0.020) in treated ApoE-/- mice. In addition, TXL obviously increased the expression of VEGF protein determined by Western blot (F = 20.247, P = 0.004). Conclusions: TXL obviously improves the ApoE-/- mouse heart function from different pathways, including reduces blood fat to lessen atherosclerosis; enhances aortic impulsivity, blood supply capacity, and vessel elasticity; improves endothelium-dependent vasodilatation; restraines angiogenesis of aorta-contained plaque; and enhances MVD of heart. The molecular mechanism of MVD enhancement maybe relate with increased VEGF expression. PMID- 29483389 TI - Management of Urinary Incontinence before and after Total Pelvic Reconstruction for Advanced Pelvic Organ Prolapse with and without Incontinence. AB - Background: The effectiveness of an anti-incontinence procedure concomitant with prolapse reconstruction for pelvic organ prolapse (POP) in preventing urinary incontinence (UI) after surgery remains controversial. Our study aimed to describe the incidence of pre- and postoperative UI for pelvic reconstructive surgery and evaluate the management of POP associated with UI. Methods: A total of 329 patients who underwent total pelvic reconstruction between June 2009 and February 2015 at a single institution were identified. These patients were divided into two groups (Group A [Prolift reconstruction]: n = 190 and Group B [modified total pelvic reconstruction]: n = 139). Data regarding surgical procedures and patient demographic variables were recorded. Chi-square and Student's t-tests were used for two independent samples. Results: A total of 115 patients presented with UI preoperatively. The average follow-up time was 46.5 months, with 20 patients lost to follow-up (6.1%). The cure rates of stress UI (SUI), urgency UI (UUI), and mixed UI (MUI) were 51% (30/59), 80% (16/20), and 48% (14/29), respectively. The cure rate of UUI after total pelvic reconstruction (80% [16/20]) was higher than that of SUI (50.8% [30/59], chi2 = 5.219, P = 0.03), and the cure rate of MUI (48%, 14/29) was the lowest. The cure rate of patients with UI symptoms postoperatively was lower than that of those with symptoms preoperatively (9.1% [28/309] vs. 16.2% [50/309], chi2 = 7.101, P = 0.01). There was no difference in the incidence of UI postoperatively between Groups A and B (P > 0.05). The cure rate of SUI in patients undergoing tension free vaginal tape-obturator was not higher than that in those who did not undergo the procedure (42.9% [6/14] vs. 53.3% [24/45], chi2 = 0.469, P = 0.49). There were no differences in the cure rate for POP or UI between these two types of reconstructions (P > 0.05). Conclusions: No correlation between the incidence of UI and POP was identified. The results suggest that UI treatment should be performed after POP surgery for patients with both conditions. PMID- 29483390 TI - Identification of Circular RNAs as a Novel Biomarker for Ovarian Endometriosis. AB - Background: Endometriosis is a challenging disease with symptoms such as dysmenorrhea and infertility. However, its etiology is still vague and there is still no effective markers or treatment. This study aimed to profile the circular RNAs (circRNAs) expressed in eutopic endometrium from patients with ovarian endometriosis and explore potential clues to the pathogenesis of endometriosis, providing an evidence for clinical diagnosis and treatment. Methods: A total of 63 clinical samples, including control endometrium (n = 22) and eutopic endometrium (n = 41), were collected from Peking Union Medical College Hospital between May 1, 2016, and December 31, 2016. Of them, four samples in each group were used for circRNA microarray. Then, four upregulated circRNAs were screened out for quantitative real-time polymerase chain reaction (qRT-PCR) validation. After that, bioinformatics analysis was performed to predict miRNAs targeted by validated circRNAs and investigate the circRNA-miRNA-mRNA interactions. Results: Among 88 differentially expressed circRNAs, 11 were upregulated and 77 were downregulated in eutopic endometrium of patients with endometriosis. qRT-PCR validation results for two upregulated circRNAs (circ_0004712 and circ_0002198) matched the microarray results. The area under the receiver operating characteristic curve of circ_0002198 for distinguishing ovarian endometriosis was 0.846 (95% confidence interval [CI]: 0.752-0.939; P < 0.001) while that of circ_0004712 was 0.704 (95% CI: 0.571-0.837; P = 0.008). On the basis of target prediction, we depicted the molecular interactions between the identified circRNAs and their dominant target miRNAs, as well as constructed a circRNA-miRNA mRNA network. Conclusions: This study provides evidence that circRNAs are differentially expressed between eutopic and normal endometrium, which suggests that circRNAs are candidate factors in the activation of endometriosis. circ_0002198 and circ_0004712 may be potential novel biomarkers for the diagnosis of ovarian endometriosis. PMID- 29483391 TI - Impaired Coagulation Status in the Crohn's Disease Patients Complicated with Intestinal Fistula. AB - Background: Intestinal fistula is one of the common complications of Crohn's disease (CD) that might require surgical treatment. The clinical characteristics and outcomes of CD with intestinal fistula are much different from CD alone. This study was to investigate whether the coagulation status of CD is changed by intestinal fistula. Methods: Data were retrospectively analyzed for 190 patients with a definitive diagnosis of CD who were registered at the Jinling Hospital between January 2014 and September 2015. Baseline clinical characteristics and laboratory indices of initial admission and 7 days after intestinal fistula resections were collected. Student's t-test and the Wilcoxon rank-sum test were used to compare differences between the two groups. Results: Compared with CD patients without intestinal fistula, prothrombin time (PT) in patients with intestinal fistula was significantly longer (12.13 +/- 1.27 s vs. 13.18 +/- 1.51 s, P < 0.001 in overall cohort; 11.56 +/- 1.21 s vs. 12.61 +/- 0.73 s, P = 0.001 in females; and 12.51 +/- 1.17 s vs. 13.37 +/- 1.66 s, P = 0.003 in males). Platelet (PLT) count was much lower in intestinal fistula group than in nonintestinal fistula group (262.53 +/- 94.36 * 109/L vs. 310.36 +/- 131.91 * 109/L, P = 0.009). Multivariate logistic regression showed that intestinal fistula was significantly associated with a prolonged PT (odds ratio [OR] = 1.900, P < 0.001), a reduced amount of PLT (OR = 0.996, P = 0.024), and an increased operation history (OR = 5.408, P < 0.001). Among 65 CD patients receiving intestinal fistula resections, PT was obviously shorter after operation than baseline (12.28 +/- 1.16 s vs. 13.02 +/- 1.64 s, P = 0.006). Conclusions: Intestinal fistula was significantly associated with impaired coagulation status in patients complicated with CD. Coagulation status could be improved after intestinal fistula resections. PMID- 29483392 TI - Impact of Temperature in Summer on Emergency Transportation for Heat-Related Diseases in Japan. AB - Background: In Japan, the demand for emergency transportation for people with heat-related illness has recently increased. The purpose of this study was to investigate the relationship between incidents of heat-related illness and the daily maximum temperature. Methods: The daily maximum temperatures in Japan's 11 districts over the past 10 years were classified into four categories, with cutoff points at the 50th, 75th, 95th, and higher than 95th percentiles. We then conducted a logistic regression analysis of emergency transportation demand in each temperature category by age group, using the 50th percentile as the reference category for each area. Results: There were 42,931 cases of emergency transportation due to heat-related diseases during the study period. Classified by age, 12.5%, 43.4%, and 44.1% of cases involved children, adults, and elderly people, respectively. The analysis showed that the number of cases of emergency transportation for people with heat-related diseases (per 100,000 people; corresponding to a 1.0 degrees C increase in the daily maximum temperature) was 0.016-0.106 among children (24.9-169.9 children required emergency transportation for heat-related diseases), from 0.013 to 0.059 among adults (19.8-98.2 adults required emergency transportation), and from 0.045 to 0.159 among elderly persons (30.0-145.4 elderly people required emergency transportation). The risk was highest for elderly persons, followed by children and finally adults. Cases of emergency transportation due to heat-related illness increased by 2.4-8.9 times when the daily maximum temperature was approximately 1.5 degrees C above the mean daily maximum temperature. In fact, the daily maximum temperature had a larger effect than the daily relative humidity level on emergency transportation for people with heat-related diseases. Conclusion: Public health organizations and health-care services should support elderly people and children, two high-risk groups for heat-related diseases. PMID- 29483393 TI - Patient-Specific Instruments Based on Knee Joint Computed Tomography and Full Length Lower Extremity Radiography in Total Knee Replacement. AB - Background: Restoring good alignment after total knee replacement (TKR) is still a challenge globally, and the clinical efficiency of patient-specific instruments (PSIs) remains controversial. In this study, we aimed to explore the value and significance of three-dimensional printing PSIs based on knee joint computed tomography (CT) and full-length lower extremity radiography in TKR. Methods: Between June 2013 and October 2014, 31 TKRs were performed using PSIs based on knee joint CT and full-length lower extremity radiography in 31 patients (5 males and 26 females; mean age: 67.6 +/- 7.9 years; body mass index [BMI]: 27.4 +/- 3.5 kg/m2). Thirty-one matched patients (4 males and 27 females; mean age: 67.4 +/- 7.2 years; mean BMI: 28.1 +/- 4.6 kg/m2) who underwent TKR using conventional instruments in the same period served as the control group. The mean follow-up period was 38 months (31-47 months). Knee Society Score (KSS), surgical time, and postoperative drainage volume were recorded. Coronal alignment was measured on full-length radiography. Results: Twenty-three (74.2%) and 20 (64.5%) patients showed good postoperative alignment in the PSI and control groups, respectively, without significant difference between the two groups (chi2 = 0.68, P = 0.409). The mean surgical time was 81.48 +/- 16.40 min and 72.90 +/- 18.10 min for the PSI and control groups, respectively, without significant difference between the two groups (t = 0.41, P = 0.055). The postoperative drainage volume was 250.9 +/- 148.8 ml in the PSI group, which was significantly less than that in the control group (602.1 +/- 230.6 ml, t = 6.83, P < 0.001). No significant difference in the KSS at the final follow-up was found between the PSI and control groups (91.06 +/ 3.26 vs. 90.19 +/- 3.84, t = 0.95, P = 0.870). Conclusions: The use of PSIs based on knee joint CT and standing full-length lower extremity radiography in TKR resulted in acceptable alignment compared with the use of conventional instruments, although the marginal advantage was not statistically different. Surgical time and clinical results were also similar between the two groups. However, the PSI group had less postoperative drainage. PMID- 29483394 TI - Basic and Clinical Evidence of an Alternative Method to Produce Vivo Nanofat. AB - Background: Fat grafting technologies are popularly used in plastic and reconstructive surgery. Due to its size limitation, it is hard to directly inject untreated fat tissue into the dermal layer. Nanofat, which was introduced by Tonnard, solves this problem by mechanically emulsifying fat tissue. However, the viability of the cells was greatly destroyed. In this study, we reported a new method by "gently" digesting the fat tissue to produce viable adipocytes, progenitors, and stromal stem cells using collagenase I digestion and centrifugation. This was named "Vivo nanofat". Methods: Human liposuction aspirates were obtained from five healthy female donors with mean age of 28.7 +/- 5.6 years. Colony-forming assay, flow cytometry analysis, and adipogenic and osteogenic induction of the adherent cells from the Vivo nanofat were used to characterize the adipose mesenchymal stem cells (MSCs). To investigate in vivo survival, we respectively injected Vivo nanofat and nanofat subcutaneously to the back of 8-week-old male BALB/c nude mice. Samples were harvested 2 days, 2 weeks, and 4 weeks postinjection for measurement, hematoxylin and eosin staining, and immunostaining. Results: Our results showed that the Vivo nanofat contained a large number of colony-forming cells. These cells expressed MSC markers and had multi-differentiative potential. In vivo transplantation showed that the Vivo nanofat had lower resorption ratio than that of nanofat. The size of the transplanted nanofat was obviously smaller than that of Vivo nanofat 4 weeks postinjection (0.50 +/- 0.17 cm vs. 0.81 +/- 0.07 cm, t = -5783, P = 0.01). Conclusion: Vivo nanofat may serve as a cell fraction injectable through a fine needle; this could be used for cosmetic applications. PMID- 29483396 TI - Corrigendum: Two Different Total Hip Arthroplasties for Hartofilakidis Type C1 Developmental Dysplasia of Hip in Adults. AB - [This corrects the article DOI: 10.4103/0366-6999.174507]. PMID- 29483395 TI - Acute Fornix Deep Brain Stimulation Improves Hippocampal Glucose Metabolism in Aged Mice. AB - Background: A beneficial memory effect of acute fornix deep brain stimulation (DBS) has been reported in clinical studies. The aim of this study was to investigate the acute changes in glucose metabolism induced by fornix DBS. Methods: First, the Morris water maze test and novel object recognition memory test were used to confirm declined memory in aged mice (C57BL/6, 20-22 months old). Then, four groups of mice were used as follows: aged mice with stimulation (n = 12), aged mice with sham-stimulation (n = 8), adult mice (3-4 months old) with stimulation (n = 12), and adult mice with sham-stimulation (n = 8). Ipsilateral hippocampal glucose metabolism and glutamate levels were measured in vivo by microdialysis before, during, and after fornix DBS treatment. Histological staining was used to verify the localization of electrodes and mice with inaccurate placement were excluded from subsequent analyses. The effects of fornix DBS on extracellular glucose, lactate, pyruvate, and glutamate levels over time were analyzed by repeated-measures analysis of variance followed by Fisher's least significant difference post hoc test. Results: The aged mice had a higher basal lactate/pyruvate ratio (LPR) and lactate/glucose ratio (LGR) than the adult mice (LPR: 0.34 +/- 0.04 vs. 0.13 +/- 0.02, t = 4.626, P < 0.0001; LGR: 6.06 +/- 0.59 vs. 4.14 +/- 0.36, t = 2.823, P < 0.01). Fornix DBS decreased the ipsilateral hippocampal pyruvate and lactate levels (P < 0.05), but the glucose levels were not obviously changed in aged mice. Similarly, the LGR and LPR also decreased in aged mice after fornix DBS treatment (P < 0.05). Glucose metabolism in adult mice was not significantly influenced by fornix DBS. In addition, fornix DBS significantly decreased the ipsilateral hippocampal extracellular levels of glutamate in aged mice (P < 0.05), while significant alterations were not found in the adult mice. Conclusions: The present study provides experimental evidence that fornix DBS could significantly improve hippocampal glucose metabolism in aged mice by promoting cellular aerobic respiration activity. PMID- 29483397 TI - Drug-Eluting Balloon versus New-Generation Drug-Eluting Stent for the Treatment of In-Stent Restenosis: An Updated Systematic Review and Meta-Analysis. AB - Background: Currently, drug-eluting balloon (DEB) appears to be an attractive alternative option for the treatment of in-stent restenosis (ISR). Nevertheless, the clinical outcomes of DEB have seldom been compared to those of new-generation drug-eluting stent (DES). Thus, this meta-analysis aimed to evaluate the safety and efficacy of DEB compared to those of new-generation DES in the treatment of ISR. Methods: A comprehensive search of electronic databases including PubMed, EMBASE, and Cochrane Library up to November 2, 2017 was performed to identify pertinent articles comparing DEB to new-generation DES for the treatment of ISR. In addition, conference proceedings for the scientific sessions of the American College of Cardiology, American Heart Association, European Society of Cardiology, Transcatheter Cardiovascular Therapeutics, and EuroPCR were also searched. The primary endpoint was target lesion revascularization (TLR) at the longest follow-up. Dichotomous variables were presented as risk ratios (RR s) with 95% confidence intervals (CI s), while the overall RR s were estimated using the Mantel-Haenszel random-effects model. Results: Five randomized controlled trials (RCTs) and eight observational studies involving 2743 patients were included in the present meta-analysis. Overall, DEB was comparable to new generation DES in terms of TLR (RR = 1.24, 95% CI: 0.89-1.72, P = 0.21), cardiac death (RR = 1.55, 95% CI: 0.89-2.71, P = 0.12), major adverse cardiovascular event (RR = 1.21, 95% CI: 0.98-1.48, P = 0.07), myocardial infarction (RR = 1.12, 95% CI: 0.72-1.76, P = 0.62), and stent thrombosis (RR = 0.95, 95% CI: 0.38-2.42, P = 0.92). However, DEB was associated with higher risk of all-cause mortality than new-generation DES (RR = 1.65, 95% CI: 1.09-2.50, P = 0.02). This was especially true in the real-world observational studies (RR = 1.79, 95% CI: 1.12 2.88, P = 0.02). In RCTs, however, no significant difference was found between the two treatment strategies in the risk of all-cause mortality. Conclusions: The current meta-analysis showed that DEB and new-generation DES had comparable safety and efficacy for the treatment of ISR in RCTs. However, treatment with DEB was associated with higher risk of all-cause mortality in the real-world nonrandomized studies. PMID- 29483398 TI - Research Progress on the Relationship between Coronary Artery Calcification and Chronic Renal Failure. AB - Objective: Coronary artery calcification (CAC) is thought to be a controlled metabolic process that is very similar to the formation of new bone. In patients with chronic renal failure (CRF), CAC is very common, and CAC severity correlates with the deterioration of renal function. We summarized the current understanding and emerging findings of the relationship between CAC and CRF. Data Sources: All studies were identified by systematically searching PubMed, Embase, and CNKI databases for the terms "coronary calcification", "chronic renal failure", "vascular smooth muscle cell", and their synonyms until September 2017. Study Selection: We examined the titles and abstracts of all studies that met our search strategy thoroughly. The full text of relevant studies was evaluated. Reference lists of retrieved articles were also scrutinized for the additional relevant studies. Results: CRF can accelerate CAC progression. CRF increases the expression of pro-inflammatory factors, electrolyte imbalance (e.g., of calcium, phosphorus), parathyroid hormone, and uremic toxins and their ability to promote calcification. These factors, through the relevant signaling pathways, trigger vascular smooth muscle cells to transform into osteoblast-like cells while inhibiting the reduction of vascular calcification factors, thus inducing further CAC. Conclusions: Coronary heart disease in patients with CRF is due to multiple factors. Understanding the mechanism of CAC can help interventionists to protect the myocardium and reduce the prevalence of coronary heart disease and mortality. PMID- 29483400 TI - Brain Impairment in Chronic Schizophrenia Patients with Depressive Symptoms Differs from Brain Impairment in Chronic Depression Patients with Psychotic Symptoms. PMID- 29483399 TI - Hypertension-Induced Cerebral Small Vessel Disease Leading to Cognitive Impairment. AB - Objective: Alzheimer's disease and vascular dementia are responsible for more than 80% of dementia cases. These two conditions share common risk factors including hypertension. Cerebral small vessel disease (CSVD) is strongly associated with both hypertension and cognitive impairment. In this review, we identify the pathophysiological changes in CSVD that are caused by hypertension and further explore the relationship between CSVD and cognitive impairment. Data Sources: We searched and scanned the PubMed database for recently published literatures up to December 2017. We used the keywords of "hypertension", "cerebral small vessel disease", "white matter lesions", "enlarged perivascular spaces", "lacunar infarcts", "cerebral microbleeds", and "cognitive impairment" in the database of PubMed. Study Selection: Articles were obtained and reviewed to analyze the hypertension-induced pathophysiological changes that occur in CSVD and the correlation between CSVD and cognitive impairment. Results: In recent years, studies have demonstrated that hypertension-related changes (e.g., small vascular lesions, inflammatory reactions, hypoperfusion, oxidative stress, damage to autoregulatory processes and the blood-brain barrier, and cerebral amyloid angiopathy) can occur over time in cerebral small vessels, potentially leading to lower cognitive function when blood pressure (BP) control is poor or lacking. Both isolated and co-occurrent CSVD can lead to cognitive deterioration, and this effect may be attributable to a dysfunction in either the cholinergic system or the functionality of cortical and subcortical tracts. Conclusions: We explore the currently available evidence about the hypertensive vasculopathy and inflammatory changes that occur in CSVD. Both are vital prognostic indicators of the development of cognitive impairment. Future studies should be performed to validate the relationship between BP levels and CSVD progression and between the numbers, volumes, and anatomical locations of CSVD and cognitive impairment. PMID- 29483401 TI - Attitudes, Knowledge, and Practices Regarding Blood Glucose Control: A Survey of Intensive Care Unit Professionals. PMID- 29483402 TI - Primary Pulmonary Germ Cell Tumor with Bone Metastasis. PMID- 29483403 TI - Expression Pattern of the Hippo Pathway Effector TAZ in Cellular and Fibrotic Nonspecific Interstitial Pneumonia. PMID- 29483404 TI - Clonorchiasis or Paragonimiasis? PMID- 29483405 TI - Reply to "Clonorchiasis or Paragonimiasis?" PMID- 29483406 TI - [New Opioid Options in Japan - Methadone, Tapentadol and Hydromorphone]. AB - In 2010s, several opioids became available in Japan, including methadone, tapentadol and hydromorphone. Methadone was approved in September 2012 by Japanese regulatory authority. Since methadone is positioned as so-called "step 4 opioid" in Japan, it must be prescribed as alternative opioid switched from another of 60mg/day or greater equivalent dose of oral morphine. Diversity of pharmacokinetics among individuals and various drug interactions require close monitoring of adverse events. In spite of these cautions, unique characteristics such as inhibiting N-methyl-D-aspartate(NMDA)and in- ducing internalization/degradation of mu-delta opioid receptor heterodimers underline the value of methadone in opioid switching. Tapentadol, a dual-acting opioid which inhibits noradrenaline(norepinephrine)reuptake, was approved in Japan in March 2014. In a double-blind randomized study comparing withoxycodone, tapentadol showed relatively better tolerability. Advantages such as having no active metabolites and minimal drug interactions also ease the administration of tapentadol to the patients with comorbidities. Hydromorphone, approved in March 2017, has a profile similar to morphine. Higher potency than morphine lead to less production of 3-glucronide metabolite(H3G)whichaccumulates in patients withrenal failure and causes neurotoxicity. Because there is no concluding evidence about effect of hydromorphone on dyspnea or tolerability in patients withrenal insufficiency, organized studies are still needed. We expect these"new in Japan" opioids contribute to long-term, stable pain control for patients withcancer. PMID- 29483407 TI - [Recent Advances in Immunotherapy for Non-Small Cell Lung Cancer]. AB - Cancer immunotherapy for non-small cell lung cancer began around 1970 with nonspecific immunomodulators and cytokine therapies. This has since developed into cell therapy including lymphokine-activated killer cells(LAK)and tumor infiltrating lymphocytes(TIL), as well as cancer vaccine therapy. However, no clear indication of effectiveness has been reported. Despite the high expectation over the effectiveness of cancer vaccine therapy, the treatment strategy was deemed unsuccessful, and focus turned to the study of immune escape mechanism, which is now regarded as standard treatment for non-small cell lung cancer. With the advent of immune checkpoint inhibitors, cancer immunotherapy has finally become a standard treatment for non-small cell lung cancer. There are still several obstacles to overcome including the identification of a predictive biomarker for improved efficacy, as well as the establishment of multidrug or multimodality combination therapy. PD-L1 expression is currently used as a predictive biomarker for anti-PD-1 therapy, but does not meet the expectations of the aimed results. Although tumor mutation burden is considered another promising biomarker, there remain clinical problems, for example the need of next generation sequencer. It was reported that combination therapy of immune checkpoint inhibitor after chemoradiation therapy was also effective. However, it remains unclear of what is required to further improve the clinical effects. In this article, we will review the history of cancer immunotherapy for non-small cell lung cancer and discuss the future prospects. PMID- 29483408 TI - [Significance of Immune-Cell Infiltration in Gastric]. AB - There are many reports on the association between infiltrating immune cells andcancer prognosis. It is generally thought that cancer cells escape from the immune surveillance system in vivo. Cells associatedwith tumor immunosuppressive mechanisms include macrophages, regulatory T cells, bone marrow-derived immunosuppressive cells(MDSC), andneutrophils. These immunosuppressive cells enhance the production of TGF-b andIL -10 andthe expression of PDL-1 by cytokines producedby stromal cells such as cancer cells andfibroblasts, thereby inducing cytotoxic T cells lymphocytes(CTL). On the other hand, it has been proved that CD8+ T cells react in an antigen-specific manner even in advanced gastric cancer, suggesting the possibility that memory T cells, NK cells andNKT cells in gastric cancer tissues correlate with goodprognosis. Recently, it has been reportedthat the presence of follicular lymphoidstructure calledtertiary lymphoidstructure(TLS)in gastric cancer tissue is associatedwith favorable prognosis. Although immune responses are suppressedin gastric cancer tissues, the effectiveness of an immune checkpoint inhibitor(anti-PD-1 antibody)has been provedin 2017. The tumor-infiltrating immune cells is known as a predictive effect biomarker. As cancer genome research progresses, which type of immune response is induced is gradually being elucidated in near future. Thus, assessing the invasive morphology and function of various tumorinfiltrating immune cells is considered to be extremely important in Precision Medicine for gastric cancer. PMID- 29483409 TI - [Immunosuppressive Environment in Tumors]. AB - Tumor cells establish a unique circumstance called tumor microenvironment(TME)suitable for tumor development and progression. One ofthe most important advantages ofTME for tumor cells is immunosuppressive environment such as higher presence ofregulatory T(Treg)cells, which play a central role for establishment and maintenance of immunological selftolerance and homeostasis. CTLA-4 expressed by Treg cells prevents the maturation ofAPCs resulting in suppression ofT -cell activation. Inhibitory cytokines and adenosine produced by Treg cells are also responsible for their suppressive functions. Indeed, high infiltration of Treg cells has been observed in many tumor tissues and is associated with poor clinical outcomes. Treg cells are recruited into tumors via chemokines secreted by tumor cells and immune cells, and further expand in TME. It has recently been shown that the metabolism oftumor cells and infiltrated immune cells in TME is also important component for tumor immunosuppressive environment. Effector T(Teff)cells rely on glycolysis for their proliferation and effector function, whereas Treg cells predominantly employ oxidative phosphorylation for suppressive function. In TME, tumor cells uptake and utilize large amounts ofglucose and glutamine and the concentration ofthose nutrients is much lower than that in normal tissues or peripheral blood. Under low glucose conditions, Teff cells fail to drive glycolysis for their survival and effector function. While the shortage of glutamine causes inhibition of Teff-cell proliferation and cytokines production, it is favorable for Treg cells. High consumption of glucose through glycolysis by tumor cells results in lactate accumulation in TME, resulting in suppression to proliferation and function of Teff cells. By contrast, high lactate level increases Treg cells with suppressive function. Furthermore, adenosine generated by tumor cells and Treg cells is known to impair the function of Teff cells. Together, various factors in TME including the metabolism of tumor cells and infiltrated immune cells allow Treg cells to infiltrate, proliferate and exhibit strong suppressive function, leading to dysfunction of Teff cells. PMID- 29483410 TI - [Enhancement of Cytotoxic T Lymphocytes(CTLs)Infiltration into the Cancer Tissues]. AB - Recently, with the rapid development of elucidating the tumor immunological status, it has become clear that various lymphocytes, which are infiltrating tumor, are deeply involved in not only tumor growth but also its elimination. The interest and importance of cytotoxic T cells(CTLs)for cancer immunotherapy has been further increased, since CTLs play an important role in eliminating cancer cells by having high cytotoxic activity and high proliferation ability. To achieve potent antitumor effects, in addition to the anti-tumor immune response induced by various methods such as cancer peptide vaccine and immune checkpoint inhibitor, it is thought to be essential that CTLs should migrate and invade into localized cancer tissues. In this article, we will introduce the latest immunotherapies related to CTLs infiltration, and various methods to enhancement of CTLs infiltration into the cancer tissues. PMID- 29483411 TI - [Gynecologic Tumor Chemotherapy for Rare Tumors in Gynecologic Malignancies]. PMID- 29483412 TI - [I. Clinical Development and Prospect of Chemotherapy for Uterine Carcinosarcoma]. PMID- 29483413 TI - [II. Chemotherapy for Small Cell Carcinoma of the Uterus]. PMID- 29483414 TI - [III. Chemotherapy, Targeted Therapy and Immunotherapy for Uterine Leiomyosarcoma]. PMID- 29483415 TI - [IV. Current Status and Future Perspectives in Low-Grade Serous Cancer of the Ovary]. PMID- 29483416 TI - [Result of Clinical Trials of Ceritinib in Patients with ALK-Rearranged Non-Small Cell Lung Cancer and Management of the Adverse Events]. AB - The advent of anaplastic lymphoma kinase(ALK)inhibitors has revolutionized treatment of ALK fusion gene-positive nonsmall cell lung cancer(NSCLC). Nevertheless, it has become clear that cases refractory and resistant to ALK inhibitors occur at a certain incidence, and how to treat such cases is a current issue. Following crizotinib and alectinib, ceritinib(Zykadia(r) capsules)is the third ALK inhibitor approved in Japan, and it is expected to be useful for patients who have developed crizotinib resistance. However, ceritinib has been pointed out to have a high incidence of gastrointestinal adverse events that impact patients' quality of life. Accordingly, in this paper, we report the clinical results and incidence of gastrointestinal adverse reactions with ceritinib in treatment of ALK-positive NSCLC patients. We also present management methods of the adverse events. PMID- 29483417 TI - [A Retrospective Investigation of Lacrimation in Patients Treated with S-1]. AB - Lacrimation is among the typical adverse drug reactions associated with S-1 treatment. However, lacrimation frequencies differ between reports, and a clear consensus regarding reaction times, risk factors, and symptomatic treatment for lacrimation is lacking. We retrospectively investigated the reaction times, risk factors, and outcomes of symptomatic treatment for lacrimation in 202 patients treated with S-1. The median estimated creatinine clearance noted upon initiation of cancer treatment was 75.8mL/min. The median of the relative treatment intensity was 87.1%, while the incidence of lacrimation was 26.7%. The median cumulative dose of S-1 before the onset of lacrimation was 23,520 mg in all patients, and 5,050 mg in those who developed lacrimation. Of the patients who developed lacrimation, 40.7% developed this symptom within 2 months after starting S-1 treatment. There were no apparent risk factors. The most frequently employed symptomatic treatment was a physiological saline ophthalmic solution provided as a hospital preparation. After treatment with this ophthalmic solution, 29.4% of the affected patients showed improvement and 70.6% showed no change; none however, experienced worsening of symptoms. These results suggest that clinicians should assess the presence of lacrimation after starting treatment with S-1. Symptomatic treatment with an ophthalmic solution that does not have a tear retention capacity may be useful in patients who have developed lacrimation. PMID- 29483418 TI - [Surgical Resection of an Intraductal Papillary Mucinous Carcinoma Observed on Imaging Four Years after the Initial Diagnosis]. AB - We herein report a 75-year-old woman who presented with an intraductal papillary mucinous carcinoma(IPMC)who was treated with surgical resection 4 years after the initial diagnosis was made. She previously underwent a high anterior resection of the rectum for rectal cancer at 71 years of age. Preoperative CT revealed a multilocular cystic mass measuring 6 cm in size in the body of the pancreas, which was considered benign. We followed up the intraductal papillary mucinous neoplasm(IPMN) by using annual CT imaging for 4 years. CT revealed a gradual increase in the size of the mass and the development of an intramural nodule in the IPMN. Endoscopic retrograde pancreatography revealed dilatations of the main pancreatic duct communicating with the multilocular cystic lesion. The cytology of the pancreatic juice demonstrated class III b. We therefore diagnosed the patient as having IPMC and performed total pancreatectomy. The postoperative course was uneventful without any recurrence. To our knowledge, only few reports have described the natural history of IPMNs. This resected case of IPMC is rare on the basis of our observation of the natural history of an IPMN using long-term imaging studies. PMID- 29483419 TI - [A Case of Unknown Primary Carcinoma with Dermatomyositis]. AB - A 50-year-old woman was diagnosed with dermatomyositis at the department of neurology in our hospital; she then received steroid pulse therapy. A positron emission computed tomography(PET-CT)revealed swollen lymph nodes near the aorta and in the left inguinal region. She presented at our institution for examination to determine the cause of her lymphadenopathy, but the primary site of the carcinoma was unknown. A histopathological examination of the lymph node specimen obtained using endoscopic ultrasonography-guided fine-needle aspiration(EUS FNA)revealed a moderately to poorly differentiated adenocarcinoma. The patient underwent lymphadenectomy. After the surgery, a new lymph node metastasis appeared in the lower abdomen. We initiated a combination treatment with chemotherapy and radiotherapy. The patient died because of disease progression 31 months after her first visit. PMID- 29483420 TI - [Clinical Outcome of Eight Patients with Perforated Colorectal Cancer]. AB - We studied the clinicopathological findings of 8 patients with perforated colorectal cancer. Four patients were male. In 7 patients, the primary cancer site was left side colon. Chief complaints were abdominal pain in 7 patients and diarrhea in 1 patient. The emergent operation was performed in all cases. The final stages of 8 patients were as follows: 5 patients with Stage II, 2 patients with Stage III, 1 patient with Stage IV. All patients were discharged from our hospital. Postoperative chemotherapy was performed for 5 patients. Of these 8 patients, 1 patient had peritoneal dissemination and 1 patient had local recurrence. Two patients were died of cancer and 6 patients were alive. In conclusion, patient with perforated colorectal cancer were high risk cases for recurrence. PMID- 29483421 TI - [Evaluation of Body Temperature during Pancreaticoduodenectomy for Pancreatic Cancer in Elderly Patients Aged over 75 Years Old]. AB - BACKGROUND: Body temperatures in elderly patients undergoing a pancreaticoduodenectomy(PD)for treatment of pancreatic cancer have not been fully evaluated. We aimed to compare body temperature during a PD between elderly(75 years old)and non-elderly patients. METHODS: This retrospective study included patients who underwent PD between April 2012 and April 2014 at the Kanasgawa Cancer Center. Patients were categorized into 2 groups: elderly patients(>=75 years of age: group A)and non-elderly patients(<75 years of age: group B). Body temperatures were compared between the groups. RESULTS: We evaluated 58 patients 14 were classified into group A, and 44 into group B. Preoperative clinicopathological outcomes demonstrated no significant differences between patients. A comparison of body temperatures between the groups showed 36.3 degrees C(before surgery)/36.1 degrees C(at 1 hr)/36.3 degrees C(at 2 hr)/36.7 degrees C(at 3 hr)/36.8 degrees C(at 4 hr)/37.1 degrees C(at 5 hr)/37.4 degrees C(at 6 hr)in group A compared to 36.2 degrees C(before surgery)/36.2 degrees C(at 1 hr)/36.4 degrees C(at 2 hr)/36.6 degrees C(at 3 hr)/ 36.9 degrees C(at 4 hr)/37.0 degrees C(at 5 hr)/37.3 degrees C(at 6 hr)in group B. Results did not significantly differ between the groups. CONCLUSIONS: Our study suggests that body temperature is not affected by a patient's age. PMID- 29483422 TI - [Multimodality Therapy against the Lateral Lymph Node Recurrence of Rectal Cancer]. AB - BACKGROUND: The local recurrence of rectal cancer classifies 4 types, anterior, posterior, lateral compartment and anastomotic site. This study evaluates outcome of laparoscopic lateral lymph node dissection(LLND)against the lateral lymph node recurrence. METHOD: Five patients were diagnosed as the lateral lymph node recurrence and underwent laparoscopic LLND. We diagnosed the lateral lymph node recurrence by CT, MRI and PET-CT. All cases revealed abnormal uptake on PET-CT. RESULT: The median of age is 63. Three patients are male. About primary tumor, 4 patients had tumor below peritoneal reflection and one patient above it. Two patients received neoadjuvant(chemo)radiotherapy(RT group)and one of them underwent laparoscopic LLND at the first operation. The median period from operation to recurrence was 25 months. Before re-operation, 3 patients received chemotherapy. Pathological assessments confirmed pathological complete response(pCR) in all three cases. The median of operation time and bleeding were 257 min and 0 mL, respectively. No complications, more than Grade III(Clavien Dindo classification)happened. The median follow-up period from re-operation was 34 months. Four patients have no recurrence and one presents lung metastasis. All 5 patients are alive. CONCLUSION: Laparoscope magnifies various pelvic structures. Therefore we perform operation more exactly and safety. In the case of local recurrence, especially lateral compartment, tumor is easy to invade adjacent structures. Then, it is often difficult to do R0 resection. If we find the recurrence lesions earlier and induce neoadjuvant chemotherapy, we can improve R0 resection rate. PMID- 29483423 TI - [A Case of Laparoscopic Distal Gastrectomy after Abdominal Incisional Hernia Repair]. AB - Re-laparotomy with resection of the mesh after abdominal incisional hernia repair may cause recurrence of the hernia and infection of the mesh. In the present study, we performed laparoscopic distal gastrectomy(LDG)for early gastric cancer without the resection of the mesh in such a case. A 82-year-old man who had undergone abdominal vascular replacement, cholecystectomy, abdominal incisional hernia repair with the mesh, sigmoidectomy had local recurrence of gastric cancer after endoscopic submucosal resection. We diagnosed as cStage IA and performed LDG without resection of the mesh. He had no recurrence of hernia nor infection of the mesh. Minimizing damage to the abdominal wall by laparoscopic surgery can prevent them. PMID- 29483424 TI - [A Resected Case of Long-Term Survival of Pancreatic Cancer with Simultaneous Multiple Lung Metastasis with Systemic Chemotherapy]. AB - The patient was a 78-year-old man with resection of distal pancreatectomy for pancreatic cancer with simultaneous multiple lung metastasis. They were papillary and tubular adenocarcinoma, Pt, TS3, infiltrative type, ly0, v0, pT3, CH0, DU0, S1, RP1, PV0, A1(Asp), PL0, OO0 and pN0, M1(PUL), pStage IV. He was received gemcitabine after the surgery. S-1 was added because of lung metastasis progression. Chemotherapy was continued for about 10 years from resection, and intra-abdominal recurrence was not observed and good performance status was maintained. 5-year survival rate of pancreatic cancer is as low as about 6.5%in Stage IV. There are cases where lung resection to isolated lung metastasis are performed after resection of pancreas and long-term-survival are obtained. A resected case of long-term-survival of pancreatic cancer with simultaneous multiple lung metastasis is rare, so we will report with a few literature considerations. PMID- 29483425 TI - [A Case of Sjogren's Syndrome Associated with Thyroid Cancer]. AB - A 42-year-old woman who had a history of Sjogren's syndrome was admitted to our hospital because of a mass lesion in the left cervical region. A hard tumor in the left lobe and a smaller mass in the central area was detected by ultrasonography and computed tomography. Subtotal thyroidectomy with lymph node dissection was performed. The central mass was minimal thyroid carcinoma. The minimal thyroid carcinoma was discovered accidentally during therapy for Sjogren's syndrome. Because the symptoms decreased, surgery of the thyroid carcinoma could be performed. When it was aggravated, it was thought to be diagnosed carefully. PMID- 29483426 TI - [A Case of a Long-Term Survivor Who Underwent Surgical Intervention for Hepatocellular Carcinoma Combined with Tumor Thrombus in the Main Trunkof the Portal Vein]. AB - We reported a patient survived more than 7years after undergoing hepatectomy accompanied by tumor thrombectomy in the main trunk of the portal vein after preoperative hepatic arterial chemotherapy for hepatocellular carcinoma combined with tumor thrombus in the main portal vein. A 58-year-old man underwent hepatic arterial infusion therapy with 5-fluorouracil( 5-FU)plus cisplatin(CDDP)for 6 weeks for a solitary 7cm nodule of hepatocellular carcinoma on the liver(S6) with tumor thrombus in the main portal vein. Although hepatic arterial infusion therapy was effective and the tumor shrank markedly, the tumor thrombus of the main portal vein still existed and the existence of portal hypertension was predicted from lower platelet values. Therefore, we performed hepatectomy accompanied by tumor thrombectomy in the main portal vein. Four months after surgery, staining of a single tumor was observed in the residual liver by contrast computed tomography (CT)and Lipiodol-TAI was performed. There was no recurrence of cancer for about 4 years, when a single recurrent lesion was found in the liver caudate lobe and a single lung metastatic lesion was also found in the left lower lobe section. We performed hepatectomy of the caudate lobe, and furthermore, we performed the left basilar segmentectomy. After these operations, the patient remained cancer free and died suddenly of another disease 7years after the first treatment for the hepatoma. PMID- 29483427 TI - [A Case of Transduodenal Ampullectomy for an Ampullary Neoplasm Coexisting with Gastric and Colon Cancer]. AB - We present here a case of transduodenal ampullectomy for an ampullary neoplasm coexisting with gastric and colon cancer. The patient was a 72-year-old man who was referred to our hospital with a positive fecal blood test. Colonoscopy revealed advanced cancer in the descending colon. As part of the preoperative examination, for the colonic cancer, upper gastrointestinal endoscopy was performed. Endoscopy showed a 2 cm elevated lesion(0'-II a type)with subserosalinfil tration on the small curvature side of the upper part of the stomach, and a 2 cm elevated lesion on the papilla of Vater. Histopathological examination showed that the former was a well differentiated tubular adenocarcinoma and the latter was a villous tubular adenoma with severe atypia. First, laparoscopic colectomy for advanced descending colon cancer was performed. Totalgastrectomy with Roux-en-Y reconstruction, cholecystectomy, and transduodenal ampullectomy for the ampullary neoplasm 21 days after the first surgery. The patient was discharged without any complications, such as postoperative suture failure. According to pathological tissue diagnosis, the degrees of progress of the colorectal cancer and the gastric cancer were pT2(MP)and pT1b(SM2), respectively, and there was no lymph node metastasis. The duodenal papillary tumor was a tubular villous adenoma(high grade). Local excision of the papilla is minimally invasive, leaves easy-to-secure stumps, and has less risk of complications such as bleeding and pancreatitis. Taking into account the balance with coexisting gastrointestinal cancer treatment, local excision of the papilla in this case was considered to be an appropriate treatment. PMID- 29483428 TI - [A Case of Ischemic Colitis Four Months after Laparoscopic Left Hemicolectomy Preserving Superior Rectal Artery]. AB - The case was for a male at the age of 80. We performed laparoscopic left hemicolectomy and D3 lymph node dissection for descending colon cancer. He had a good postoperative prognosis and was discharged on the 14th day after the operation. Later, he was receiving the treatment on an outpatient basis without postoperative adjuvant chemotherapy during the followup period. He visited the hospital for sudden abdominal pain and melena as chief complaint approximately 4 months after the operation. We found prominent edematous wall thickening and increased surrounding fat concentration in the anal side of colon from the anastomosis site with plain abdominal CT scan. We also found that the anal side of colon from the anastomosis site an edematous change broadly in the lower gastrointestinal endoscopy. We conducted conservative treatment with the diagnosis of ischemic colitis at the anal side of colon from the anastomosis site. He was discharged on the 11th day after the hospitalization. Later, we conducted a follow-up examination for him on an outpatient basis. We recognized the symptom improvement approximately 2 months after the onset of the ischemic colitis. PMID- 29483429 TI - [A Case of a Bulky Axillary Ectopic Breast Cancer Which Successfully Resected after Chemotherapy(Docetaxel)]. AB - A 78-year-old woman presented with a right axillary mass.With an incisional biopsy a diagnosis of invasive ductal carcinoma was achieved.In the whole body search, any primary focus including the breast was unclear, advanced occult breast cancer with supraclavicular lymph node metastases was diagnosed.Administration of 3 courses of docetaxel achieved disappearance of supraclavicular lymph node and reduction of an axillary mass.Right axillary lymph node dissection could be successfully performed.Pathological report showed a right ectopic cancer with right axillary lymph node metastases.The patient has been well without any relapse for 3 years. PMID- 29483430 TI - [Clinicopathological Study of Perforated Gastric Cancer Treated with Surgery]. AB - This retrospective study evaluated an appropriate surgical treatment in patients with perforated gastric cancer. The clinicopathological and survival data on 17 perforated gastric cancer patients treated with surgery were analyzed. The one stage or two-stage gastrectomy was performed in 8 and 5 patients, respectively. The omental patch repair was performed in 4 patients. In univariate analysis, non curative(R2)resection with gross residual tumor(p<0.01)and postoperative complications( p=0.01)were found to be significant unfavorable factors for overall survival(OS). In multivariate analysis, R2 resection was identified to be an only independent significant unfavorable factor for OS. Patients who underwent curative(R0) resection had long-term survival, while patients with R2 resection and postoperative complication had limited survival times. These results suggest that R0 resection may be optimal to improve survival in patients with perforated gastric cancer, regardless of whether patients underwent a one-stage or two-stage gastrectomy based on the patient's condition. PMID- 29483431 TI - [Prolonged Survival Achieved with Surgical Resection and Multidisciplinary Therapy for Acinar Cell Carcinoma of the Pancreas with Liver Metastases]. AB - We report 2 cases of prolonged survival achieved with surgical resection and multidisciplinary therapy for acinar cell carcinoma of the pancreas with liver metastases.Case 1: The patient was a 55-year-old woman.She presented with upper right abdominal pain and anemia.We diagnosed a tumor originating from the pancreas and multiple liver metastases.To avoid death caused by bleeding from the tumor, we performed pancreaticoduodenectomy and right-hemi hepatectomy, and a rapid diagnosis of acinar cell carcinoma of the pancreas was confirmed intraoperatively.After the hospital discharge, we administered hepatic intra arterial chemotherapy and performed microwave ablation for the remnant liver metastases.Additionally, systemic chemotherapy with gemcitabine was administered; however, multiple metastases of the lung and liver became uncontrollable and she died 2 and half years postoperatively.Case 2: The patient was a 42-year-old woman.Through a medical checkup, gastric varix and elevated tumor markers were detected.The examination revealed a tumor at the tail of the pancreas and liver metastasis.We performed distal pancreatomy and partial liver resection.The pathological diagnosis was acinar cell carcinoma and liver metastasis.We administered adjuvant chemotherapy by using gemcitabine and achieved 5 years of relapse-free survival.The prognosis of ACC is better than that for PDAC.However, prognosis of unresectable cases is still unfavorable.Therapeutic strategies including aggressive surgical resection for metastatic ACC are worthy of consideration. PMID- 29483432 TI - [The Surgical Experience for Bulky Serous Cystic Neoplasm of Pancreas]. AB - A 74-year-old femalewas admitted to our hospital dueto thebulky abdominal tumor pointed out by ultrasonography of medical screening. Abdominal CT revealed the tumor, in a diameter 20 cm, replaced the total pancreas and compressed the surrounding organs and portal vein. We diagnosed as a pancreatic serous cystic neoplasm with a possibility of malignancy. The operative findings showed the tumor tightly adhered to stomach, duodenum, liver, transverse colon mesenterium, retroperitoneum and the surrounding main vessels. Total pancreatectomy, cholecystectomy, splenectomy and distal gastrectomy were performed. As a histopathological finding, thetumor surfacewas smooth and theinsidewas sponge likeappe arancemixe d with microcystic and solid components. No malignant finding was observed. The patient was discharged without major complications on postoperative day 42, and remains alive with no recurrence for 9 months after surgery. PMID- 29483433 TI - [A Case of Metastatic Colorectal Cancer with Brain Metastasis Treated with Combined TFTD and Bevacizumab Therapy]. AB - A woman in her 70s was confirmed as presenting with multiple liver and lung metastases from transverse colon cancer. After undergoing resection of the primary lesion, partial response(PR)was achieved after undergoing the first regimen (sLV5FU2 and bevacizumab[Bmab]); therefore, partial hepatectomy was performed. Adjuvant chemotherapy was administered for 7 months, but liver metastasis recurrence, multiple lung metastases, and brain metastasis were confirmed. As the brain metastasis was a single lesion and was accompanied by symptoms, resection of the lesion was performed. Treatment with regorafenib was initiated, but Grade 3 severe erythema multiforme was detected, and the treatment had to be discontinued. Therefore, combined TFTD and Bmab therapy was initiated as the third regimen. Liver and lung metastases were maintained as stable disease(SD), and the treatment was continued for approximately 1 year together with stereotaxic radiation therapy for the newbrain metastatic lesion. The utility of combined TFTD and Bmab therapy has been reported in a phase II trial, and it has also been indicated that Bmab is effective for reducing brain edema. As this treatment was effective in this case, we will report on it together with a discussion of the literature. PMID- 29483434 TI - [Local Control by Mastectomy in Advanced Breast Cancer with Liver Metastasis after Chemotherapy, Radiotherapy, and Hyperthermia - A Case Report]. AB - Advanced breast cancer has a poor prognosis compared to early breast cancer; however, quality of life and radical operation can be improved in some case by using multidisciplinary treatment. A 54-year-old woman was examined at the hospital because of an enlarging tumor in the left breast. She was aware of a lump for 3 years. Results of the initial examination indicated invasive ductal carcinoma with liver metastasis. She first received chemotherapy(AC followed by weekly paclitaxel). After 4 courses of weekly paclitaxel, computed tomography revealed axillary lymph nodes involved in the axillary vein. Operation was difficult and conversion therapy was administered. The patient underwent radiotherapy, hyperthermia, and hormone therapy. After 1 year from the start of hormone therapy, the metastasis had disappeared and the patient underwent operation in our unit. Eight months after operation, no recurrence was observed. PMID- 29483435 TI - [A Case of Thoracic Esophageal Cancer That Caused Necrosis of a Reconstructed Colon Ten Years after Esophagectomy]. AB - Necrosis of a reconstructed organ after esophageal cancer surgery is a very serious complication that often occurs soon after the surgery. We report a case of emergency surgery that was performed to treat necrosis of a reconstructed colon 10 years after esophagectomy. A 73-year-old man was admitted to our hospital with complaints of chest pain. His history included a proximal gastrectomy for gastric cancer. His present illness includes endoscopic mucosal resection for superficial esophageal cancer in 1995. Subtotal esophagectomy and right colon interposition through the retrosternal route were performed due to a recurrence in the same lesion in 2005. The patient was immediately hospitalized due to chest pain in 2015. An upper gastrointestinal endoscopy revealed extensive necrosis in the colon. He underwent an emergency operation. The surgical operations included reconstructed colonic resection by longitudinal sternotomy, esophagostomy, gastrostomy, and drainage procedure. The patient is currently under rehabilitation at a referral hospital. There has been no report on the occurrence of necrosis in the reconstructed colon 10 years after esophagectomy. PMID- 29483436 TI - [A Case of Thyroid Metastasis from Rectal Cancer]. AB - The patient was a 68-year-old man who underwent Hartmann's procedure for a fistula due to rectal cancer in August 2012. The cancer was tub2>tub1, pSE, pN2, pH2, pM1(intrapulmonary metastasis), stage IV. The patient received 5 courses of FOLFOX and bevacizumab as adjuvant chemotherapy. In December 2012, the patient was seen by Otolaryngology for hoarseness. A neck examination revealed induration of the left lobe of the thyroid, and FNA biopsy strongly suggested metastasis of rectal cancer to the thyroid. FDG-PET was performed and revealed extensive accumulation of FDG at the same site. The patient was diagnosed with thyroid metastasis of rectal cancer and underwent a left thyroid lobectomy and lymph node dissection in January 2013. Histopathology confirmed the thyroid metastasis of rectal cancer. Thyroid metastasis of rectal cancer is extremely rare: there are 11 such cases in the Japanese literature, including the case encountered by the current authors. This case is reported here, along with a discussion of some of the literature. PMID- 29483437 TI - [Efficacy of Palliative Radiotherapy for Unresectable Advanced Gastric Cancer with Bleeding]. AB - Bleeding and obstruction negativelyimpact qualityof life for patients with unresectable advanced gastric cancer. There are several choices against bleeding and obstruction such as surgery, endoscopic therapy, radiotherapy and interventional radiology. We report on an 85-year-old woman with StageIV gastric cancer with tumor bleeding. Radiation therapyof 30 Gyin 10 fractions was performed. Anyadverse events were not confirmed. Bleeding or obstruction did not occur for 7 months after radiation therapy. Palliative radiation therapy to gastric cancer can be a reasonable option for patients with unsuitable general conditions for surgical intervention. PMID- 29483438 TI - [A Case of Myocardial Metastasis of Esophageal Squamous Cell Carcinoma]. AB - Myocardial metastasis for esophageal squamous cell carcinoma(ESCC)is relatively rare and it is diagnosed as a part of widespread metastasis in the terminal stage. We experienced a case of myocardial metastasis of ESCC treated effectively with chemoradiotherapy. A 56-year-old man was diagnosed ESCC(clinical T3N2M0, Stage III). He received neoadjuvant chemotherapy of 5-fluorouracil plus cisplatin followed by subtotal esophagectomy with dissection of the 3 regional lymph nodes. The pathological diagnosis was moderate differentiated squamous cell carcinoma, CT-pT3(T3), pN1, sM0, fStage III. Four months after surgery, he had no clinical symptom, however myocardial metastasis located in the apex was detected on the follow up positron emission tomography(PET). Chemoradiotherapy was performed for the myocardial metastasis. Myocardial metastasis treated effectively with chemoradiotherapy almost disappeared on the PET and computed tomography taken 3 months after chemoradiotherapy. He died, however, of multiple liver and bone metastases 15 months after the initial surgery. PMID- 29483440 TI - [Status of Hepatic Lymph Node Involvement in Patients with Resectable Liver Metastasis of Colorectal Cancer after Preoperative Chemotherapy]. AB - The liver is the most common metastatic site for colorectal cancer(CRC).The 5 year survival rate of resected cases has been reported to be about 40%.Hepatic lymph node metastasis is reportedly associated with a poor prognosis in patients with liver metastases of CRC.The incidence of hepatic lymph node involvement in patients with liver metastases of CRC ranges from 5% to 28%.However, few reports have focused on hepatic lymph node involvement in patients with resectable liver metastasis who have undergone preoperative chemotherapy.This retrospective study was undertaken to address this issue.The subjects were 33 consecutive patients who had undergone the resection of liver metastases of CRC with hepatic lymph node sampling after preoperative chemotherapy between 2001 and 2016. Hepatic lymph node metastasis was confirmed in only one patient(3%).There was no significant difference in the frequency of hepatic lymph node metastasis between the cases with or without preoperative chemotherapy.The further collection of data is warranted to elucidate the significance of hepatic lymph node involvement in patients with liver metastases of CRC treated with preoperative chemotherapy. PMID- 29483439 TI - [Indication of Palliative Gastrojejunostomy for Unresectable Advanced Gastric Cancer with Obstruction from the View Point of Preoperative Inflammatory Biomarkers]. AB - Palliative surgery for advanced gastric cancer with serious symptoms such as hemorrhage or obstruction may be meaningful in the point of improving quality of life(QOL). However, the meaning of palliative gastrojejunostomy for unresectable gastric cancer with obstruction is controversial. We retrospectively evaluated the effectiveness of gastrojejunostomy for unresectable gastric cancer with obstruction using preoperative inflammatory biomarkers. Blood lymphocyte monocyte ratio(LMR), neu- trophill ymphocyte ratio(NLR)and C-reactive protein/albumin ratio(CAR)were analyzed as inflammatory biomarkers in this study. The percentage of improvement in food intake, discharge from the hospitaland performance of chemotherapy were significantly higher in the patients without any preoperative inflammatory reaction compared to those with any inflammation. Moreover, the survival of the patients without any inflammatory change was significantly longer compared to those with any inflammation. In conclusion, preoperative status of inflammation may be a useful marker to predict the effect and outcome of palliative gastrojejunostomy for unresectable gastric cancer with obstruction. Especially when there is any inflammation, the surgical indication should be carefully judged. PMID- 29483441 TI - [A Case of Repeated Surgical Resections for Tumor Seeding of Hepatocellular Carcinoma after Radiofrequency Ablation]. AB - We report a case of repeated surgical resections for the tumor seeding of hepatocellular carcinoma(HCC)after radiofrequency ablation(RFA). A 79-year-old man, who had an intrahepatic recurrence of HCC(segment 2)5 months after RFA, was referred to our hospital for surgery, and underwent a laparoscopic lateral segmentectomy. Histological examination showed a poorly differentiated HCC(pStage II). Eight months after RFA, subcutaneous nodules along the RFA needle tract were pointed out by abdominal CT, and a tumorectomy was performed. Nineteen months after RFA, abdominal CT showed a 33mm tumor on the side of the spleen, leading to the diagnosis of the peritoneal dissemination following RFA. The tumor has been growing up to 49mm in size in spite of a radiation therapy. Accordingly, a laparoscopic tumorectomy was performed 26 months after RFA. His resected tumors were morphologically identical to the intrahepatic recurrence of HCC. The patient had remained recurrence-free for 4 months after the second tumorectomy. Our case demonstrated the utility of surgical resection for the tumor seeding of HCC following RFA. PMID- 29483442 TI - [Surgery for Lower Intestinal Perforation Due to Peritoneal Dissemination]. AB - INTRODUCTION: we examined the cases in which surgery was performed for the lower intestinal perforation due to peritoneal dissemination in our hospital. SUBJECTS: Four cases of lower intestinal perforation of patients with peritoneal dissemination who underwent emergency operation in our hospital were enrolled. RESULTS: Two males and 2 females patients with median age of 65.5 year old(63 71)were included. The perforated sites were 3 cases of small intestine and 1 case of ascending colon, and the APACHE II score at the visit was 14.5(10-16)points. The surgical procedure was performed in 3 cases of resection of the perforated site and 3 cases of stoma creation. In 2 out of 4 cases, it became difficult to control bacterial peritonitis and died on the 16th postoperative day. One case could discharge hospital and continued BSC, survived 4 months after surgery. CONCLUSION: Although long-term prognosis could not be expected, there were cases in which it was possible to restart the oral intake after surgery or discharge. Surgical treatment might be selected for the lower intestinal perforation due to peritoneal dissemination. PMID- 29483443 TI - [Conversion Surgery for Pancreatic Head Cancer with Peritoneal Dissemination Following Chemotherapy for Two Years - A Case Report]. AB - Here we report a case of pancreatic cancer(PC)with peritoneal dissemination, underwent conversion surgery following chemotherapy for 2 years. A5 5-year-old woman was referred to our hospital for treatment of PC. Abdominal CT scan revealed 3.0 cm of a pancreatic head tumor with abutment of the portal vein and the hepatic artery, classified as borderline resectable. Staging laparoscopy(SL)showed positive peritoneal cytology(CY). Gemcitabine(Gem)plus S-1 therapy(GS) was performed. Ten months after initial GS, SL revealed the disseminated nodule and positive CY. The regimen was changed to Gem plus nab paclitaxel therapy(Gem plus nab-PTX). Since right ovarian tumor was detected by CT scan 6 months after initial Gem plus nab-PTX, laparoscopic oophorectomy was performed. Histological findings showed positive CY and ovarian metastasis of PC. Afterward, Gem plus nab-PTX has been continued for 8 months. Since SL after 2 years from initial chemotherapy showed negative CY and no metastatic lesion, pancreaticoduodenectomy with portal vein resection was performed as conversion surgery. According to General Rules for the Study of Pancreatic Cancer the 7th edition by Japan Pancreas Society, histological findings showed ypT3, ypN0, R0, and Grade 1b of histological effect. The patient is alive without recurrence 6 months after the resection. PMID- 29483444 TI - [Significance of Transcatheter Arterial Chemoembolization for BCLC Stage B Hepatocellular Carcinoma with Mal-Nutrition]. AB - : BackgroundandAim: The recommendedind ication of transcatheter arterial chemoembolization(TACE)for hepatocellular carcinoma(HCC)is Barcelona Clinic Liver Cancer(BCLC)stage B HCC. But there are some cases in which we do not perform TACE because of liver damage with malnutrition in stage B. So we examined whether branched-chain amino acid (BCAA)improve nutritional status and perform TACE to contribute the prolongation of HCC survival. METHODS: This study included8 8 patients treatedfor liver cirrhosis with HCC. All patients initially receivedBCAA granules. In patients with unchangedor decreasedAlb levels, BCAA granules were discontinuedandBCAA enrichednutrient was started. TACE for HCC were performedin those with an improvedChild -Pugh score. RESULTS: TACE were performedfollowing the aggressive intervention with BCAA nutritional education in 66 of 88(75%)patients. Finally, overall survival time was significantly extended in TACE group(p<0.0001). CONCLUSION: Timely aggressive nutritional intervention in BCLC stage B HCC, early partial replacement with BCAA enrichednutrient before TACE may consequently contribute to improvement of the treatment outcome of HCC. PMID- 29483445 TI - [A Case of Surgery after Chemotherapy for Cecal Cancer with Onset of the Stenosis of the Colostomy]. AB - The patient was 55-year-old woman, undergoing Hartmann operation by the sigmoid colon diverticulum perforation, 2 years later visited our hospital with abdominal pain. Although lower endoscopy and histological examination could not be performed due to stoma stenosis, we diagnosed cecal carcinoma, liver metastasis, distant lymph node metastasis from CT and PET-CT, CapeOX plus Bmabtherapy and IRIS plus Bmabtherapy were performed. After that, repeated intestinal obstruction due to exacerbated stoma stenosis, metastatic lesion increased in CT examination, furthermore the patient had hope of stoma closure, we decided to resect the primacy tumor, performed subtotal colonectomy and stoma closure. Pathological diagnosis revealed RAS wild type. After surgery, Pmabplus CPT-11 therapy was performed and the metastatic lesion was temporarily shrunk but re-exacerbated, the patient died 2 years 2 months after the first treatment started, 7 months after the primary tumor resection. In the treatment of colorectal cancer, when metastatic lesion is unresectable, chemotherapy is often carried out except when the primary tumor is symptomatic. In our case, although the primary tumor was asymptomatic, an intestinal obstruction due to stoma stenosis was developed and it was necessary to examine whether to use anti-EGFR antibody drugs, therefore we performed operation. PMID- 29483446 TI - [Three Long-Surviving Cases of Peritoneal Metastasis after Colorectal Cancer Resection]. AB - We experienced 3 impressive colorectal cancer patients who developed peritoneal recurrences and underwent surgery several times and survived for more than 5 years. Case No. 1 was of a 44-year-old woman who underwent right hemicolectomy for her stage II A ascending colon cancer. She developed left ovarian metastasis, which was resected 3 years later. Five years later, she developed a pelvic peritoneal recurrence, which was resected successfully. Thirteen years later, she is doing well. Case No. 2 was of a 61-year-old man who underwent transverse colectomy for his stage II B colon cancer. He developed ileus 2 years 9 months later due to peritoneal recurrence, which was removed successfully. He underwent another resection for peritoneal metastasis 2 years 6 months later. He was administered 15 courses of FOLFOX6. He has remained cancer-free since 2009. Case No. 3 was of a 62-year-old man who underwent sigmoidectomy for his stage II A colon cancer. One year 8 months later, he underwent resection for a painful abdominal wall metastasis. Eight months later, he developed another abdominal wall recurrence, which was resected successfully. He underwent thoracoscopic resection 4 times for lung metastases and was given 16 courses of FOLFOX6. In 2009, he developed pelvic peritoneal nodules, which were resected. He later needed lymphadenectomy twice. He has remained cancer-free for the last 5 years and 6 months. Curative resection must be performed for a patient with peritoneal recurrence of colorectal cancer when surgery is indicated. PMID- 29483447 TI - [A Case of Resection for Lymph Node Recurrence around the Inferior Vena Cava after Radical Surgery of Undifferentiated Carcinoma of the Pancreatic Head Region]. AB - A 60-year-old man underwent palliative surgery with a diagnosis of unresectable cancer, and he visited our hospital for further treatment. Since the cancer was unresectable and multiple hepatic tumors were revealed in CT images that were not metastases, we decided to perform curative surgery for the pancreatic cancer accompanied by partial liver invasion. Pancreaticoduodenectomy plus partial hepatectomy were performed, and 2 tumors were detected in the resected specimen: one in the pancreas-duodenum region and a submucosal tumor in the duodenum bulb. The large tumor that occupied the pancreasduodenum region was histologically diagnosed as an undifferentiated carcinoma, and the duodenal submucosal tumor was consistent with findings of a poorly differentiated adenocarcinoma. Two years after surgery, CT examination revealed a mass extending into the inferior vena cava(IVC)from near the right renal vein. We eventually diagnosed lymph node recurrence with tumor thrombosis inthe IVC and started chemotherapy(FOLFIRINOX). After the tumor decreased, we performed salvage surgery involving resection of the lymph node, thrombectomy, and right nephrectomy. The tumor revealed atypical cells in the region of thrombosis, and the pathological findings were not in conflict with the findings of metastases from pancreatic cancer 2 years prior. After the treatment, chemotherapy was administered and he survived without any recurrence for 15 months after surgery. PMID- 29483448 TI - [Hemosuccus Pancreaticus Due to Pancreatic Head Invasive Pancreatic Duct Carcinoma]. AB - A 51-year-old man was admitted to our hospital because of anorexia and jaundice. Abdominal CT and MRCP taken after admission revealed tumor in the pancreatic head. Upper gastrointestinal endoscopy showed bleeding from the orifice of the major papilla. In angiography, an irregular image was found in the branch of the gastroduodenal artery, and a coil embolization surgery was performed mainly on the same part. We diagnosed pancreatic cancer and pancreaticoduodenectomy was performed. Pancreatic cancer with bleeding from the orifice of major papilla is very rare. We describe our case with known reports. PMID- 29483449 TI - [A Case of the Locally Advanced Breast Cancer with Serious Comorbidities Obtained a Good Local Control]. AB - A 66-years-old woman was referred to our hospital with the chief complaint of a huge exposed left breast mass, associated massive exudates, bleedingand foul smelling discharge. Invasive ductal carcinoma was diagnosed by core needle biopsy. The computed tomography showed left axillary lymph node metastases and no distant metastasis. Her performance status(PS) was Grade 3. She had serious comorbidities such as non-alcoholic steatohepatitis and liver cirrhosis, renal dysfunction. DMpC therapy and Mohs paste therapy were started since her overall status was improved. The huge left breast tumor and left axillary lymph node metastases were reduced remarkably. Total mastectomy and axillary lymph node dissection and free skin grafting was perfomed, and PS was improved to Grade 0, She received DMpC therapy for 4 months postoperatively, and radiotherapy at left chest wall and supraclavicular fossa. PMID- 29483450 TI - [A Case of Advanced Breast Cancer Effectively Treated with Bevacizumab and Letrozole]. AB - We report a case of primary advanced breast cancer that was locally controlled by treatment with bevacizumab. A 69-yearold woman presented at our hospital complaining of left breast hemorrhage. Her left breast had a large mass with an ulcer, and there was bleeding. Breast ultrasonography showed a large tumor that involved the whole left breast, and some swollen axillary lymph nodes. Breast MRI showed a mass of 77mm and skin invasion around the medial area of the left breast. Histopathological examination indicated invasive ductal carcinoma, ER(+), PgR(+), HER2(-), Ki-67 20%. We diagnosed left breast carcinoma, T4bN1M0, stage III B. She received paclitaxel plus bevacizumab as first-line therapy. Breast MRI showed a reduction in the primary tumor and axillary lymph node swelling. Adverse events including hypertension(Grade 3) and peripheral neuropathy(Grade 2)were observed. She received letrozole as second-line therapy. After commencing letrozole, the tumor reduced further, and the local ulcer disappeared showing only induration. Four years from the start of treatment, the woman has obtained good local control and has not developed other metastases. PMID- 29483451 TI - [Radiofrequency Ablation under Computed Tomography during Arterial Portography for Hypovascular Liver Metastases from Advanced Pancreatic Cancer]. AB - A 70's man had been treated with gemcitabine(GEM)and nab paclitaxel(nabPTX)combination for advanced pancreatic tail cancer with splenic invasion and liver metastases. However, the primary lesion was not controlled, then intensity-modulat- ed radiation therapy(76.5 Gy/17 Fr)was performed for primary lesion. Three grown hypovascular liver metastases were detected by follow up EOB-MRI and PET-computed tomography(CT)imaging with 18F-FDG. Unfortunately, these lesions were not detected by intravenous injection of contrast media with CT nor ultrasonography. Radiofrequency ablation(RFA) under computed tomography during arterial portography(CTAP)guidance was performed. The patient has been alive for 1 year after RFA with no recurrence. CTAP could be a feasible image guidance for the treatment of hypovascular liver metastases with RFA. PMID- 29483452 TI - [A Case of Transverse Colon Cancer with Liver Metastasis and Tumor Thrombosis of Portal Vein Effectively Treated with Chemotherapy]. AB - The patient was a 70-year-old man. He was diagnosed with advanced transverse colon cancer. A computed tomography (CT)revealed liver metastasis and tumor thrombosis of portal vein. We started combination chemotherapy with capecita- bine/oxaliplatin(CapeOX). Perforation of the tumor was observed 5 days after CapeOX therapy was started. Treatment with abscess drainage and ileostmy, infection was controlled and general condition was improved. After 9 courses of CapeOX, we changed chemotherapy regimen to irinotecan/tegafur-gimeracil oteracilpotassium (IRIS)due to strong side effects. In CT and FDG-PET examination after 8 courses of IRIS, the tumor of transverse colon, liver metastasis, and the tumor thrombosis of portalvein became unclear. A year and 6 months have passed since chemotherapy was started, recurrence was not observed. For the patients with unresectable colorectal cancer, it is necessary to consider multidisciplinary treatments including chemotherapy while considering the general condition of them. PMID- 29483454 TI - [Three Cases of Long-Term Surviving Stage IV Gastric Cancer after Conversion Surgery]. AB - The standard therapy for Stage IV gastric cancer is chemotherapy. It is not certain, but conversion surgery is expected to be effective. We report the cases of 3 patients who achieved long-term survival after conversion surgery. Case 1 was of a 59- year-old woman. The tumor was classified as L-Less Post, Type 2, tub1, cT3N2M1(#16a2lat), Stage IV. Then, we initiated S-1 plus cisplatin and the LN achieved PRafter 4 courses. We performed distal gastrectomy with D2 lymph node dissection in February 2011. It was classified as ypT2N2 and the primary lesion was histologically classified as Grade 1a. Case 2 was of a 74- year-old man. The tumor was classified as UM-Less Ant, Type 3, por1, cT3N2H0P1CY1, Stage IV. Then, we initiated docetaxel plus cisplatin plus S-1 and the primary tumor achieved PRafter 6 courses. There were no new tumors and we conducted a laparoscopic examination. After the decision of P0CY0, we performed total gastrectomy with D2 lymph node dissection in April 2012. It was classified as ypT3N1 and the primary lesion was histologically classified as Grade 2. Case 3 was of a 64-yearold woman. The tumor was classified as UM-Less, Type 3, por1, cT3N2H1M0(liver), Stage IV. Then, we initiated capecitabin plus cisplatin and liver metastasis achieved PRafter 6 courses. We performed total gastrectomy with D2 lymph node dissection in July 2012. It was classified as ypT3N1 and the primary lesion was histologically classified as Grade 1b. All postoperative chemotherapy courses were of only S-1. In case 1, the para aortic LN exhibited recurrence 6 months postoperatively. We initiated weekly paclitaxel as second-line therapy. It achieved CRafter 6 courses, and the same trend was maintained. In cases 2 and 3, no therapy was administered after 8 S-1 courses, but no recurrences occurred. All patients survived after 62-77 months postoperatively. A new clinical trial is needed to prove the improvement in prognosis for Stage IV gastric cancer after conversion surgery. PMID- 29483453 TI - [A Case of Gastric Cancer Underwent Two-Stage Gastrectomy after Chemotherapy Induced Perforation]. AB - A 70's man presenting with a chief complaint of stomachache was found to have advanced gastric cancer with a deep ulcer and some lymph-node metastases. We decided performing a curative operation after 2 courses of S-1 plus cisplatin. On the first course day 13 of chemotherapy, he complained of severe epigastralgia, and we diagnosed as generalized peritonitis due to perforation of gastric cancer. We performed an urgent laparoscopic operation, which made perforation simple closure and omentopexy. Curative distal gastrectomy with D2 lymph node dissection was successfully performed on postoperative day 16. PMID- 29483455 TI - [A Case of Laparoscopy Assisted Ileocecal Resection for Large Appendiceal Mucinous Adenocarcinoma]. AB - Appendiceal mucinous adenocarcinoma accompanied by cysts ruptures by surgical operation and leakage of mucus into the peritoneal cavity results in deterioration of prognosis.We report a case where the appendix mucinous adenocarcinoma was safely excised by laparoscopically preceding vascular treatment, lymph node dissection and intestinal dissection.The case was a woman in her forty-age suffering from the right lower quadrant and fever; no improvement was observed even when antibiotics were administered.A cystic lesion with a maximum diameter of 75mm was found on the right side of the pelvis with CT, and numerous lymph adenopathy was observed along the iliac artery.Preoperative diagnosis was diagnosed as appendiceal mucinous adenocarcinoma suspected and laparoscopic resection of the cecum was performed with the above procedure without breaking the cyst.Pathological diagnosis was findings of appendicular mucinous adenocarcinoma.She was discharged on the 7th postoperative day after surgery, 6 months after surgery without relapse survival.In order to resect a cystic tumor by laparoscopic surgery, it is considered to be useful to take care to prevent the forceps from touching the tumor, and perform a procedure that precedes vascular dissection and intestinal dissection. PMID- 29483456 TI - [A Case of Long-Term Survival of the Pancreatic Tail Cancer with the Concomitant Small Liver Metastasis]. AB - We hereby report a case of long-term survival of the pancreatic tail cancer with a synchronous small liver metastasis. A 62- year-old male with pancreatic tail cancer was incidentally diagnosed with single tiny metastasis in the left medial section of the liver duringthe distal pancreatectomy. The lesion was also resected together with primary lesion. Since then, systemic chemotherapies such as gemcitabine(GEM)plus S-1 combination therapy, GEM alone therapy and S-1 alone therapy had been given to escape from recurrence. However, the recurrences were found in the liver at 21 months after surgery. Left hepatectomy was performed for metastatic lesions. Afterwards, proton radiation therapy was twice performed for the metastatic lesions in the liver which were unable to be removed by surgery alone. Partial resection of transverse colon was also needed to be performed for the bowel obstruction caused by recurrence on the surgical margin of the liver. Systemic chemotherapies includingS -1 therapy, FOLFIRINOX therapy and GEM plus nab-paclitaxel therapy have been continued throughout his entire treatment history after recurrence. He has been keepingin good physical condition with these multidisciplinary therapies, even though 51 months have passed since the first evidence of liver metastasis was diagnosed. PMID- 29483457 TI - [Resection for the Recurrence of Hepatocellular Carcinoma in the Inferior Vena Cava and Right Atrium under Deep Hypothermic Circulatory Arrest]. AB - A 77-year-old man underwent extended right lobectomy of the liver for rupture of hepatocellular carcinoma. Recurrence in the inferior vena cava andright atrium was noted 30 months after surgery. We performedextirpation of this tumor thrombosis under retrograde cerebral perfusion during deep hypothermic circulatory arrest. The pericardium was cut through sternotomy, and cooling was initiated. After cardiac arrest at 20.4 degrees C, the inferior vena cava was separated. An incision was made in the right atrium andthe tumor thrombus was extirpated. In the meantime, brain protection was maintainedby retrograde cerebral perfusion. The patient was discharged on day 12 without postoperative complications. He remains alive 6 months after surgery without recurrence. This procedure prevented pulmonary embolism due to tumor thrombosis release. It was also possible to perform the procedure with retrograde cerebral perfusion. PMID- 29483458 TI - [Postoperative Atrial Fibrillation in Patients who Underwent Thoracic Aortic Surgery]. AB - PURPOSE: Postoperative atrial fibrillation (POAF) is a very common and important complication occurring after open heart surgery. Risk factors and prevention measure including beta blocker use have been reported mainly in regard to patients who underwent coronary artery bypass grafting, while little is known about POAF following thoracic aortic surgery. In the present study, we examined risk factors related to POAF and effective prevention of POAF in patients who underwent thoracic aortic surgery. PATIENTS AND METHODS: We evaluated 95 consecutive patients who underwent thoracic aortic surgery since 2010. We analyzed the relationship between perioperative factors and occurrence of POAF in the study cohort, as well as in 62 patients who had perioperative intravenous beta blocker (landiolol) administration. RESULTS: Following surgery, 21 (22%) of the patients had new onset POAF. The occurrence of POAF was related to that of stroke. Univariate analysis showed that age was a risk factor for POAF. In patients with landiolol, risk factors for POAF were age, arch aneurysm, and timing of landiolol administration. Six patients developed POAF during landiolol administration. However, of 56 patients who had not have POAF during landiolol administration, 8 developed POAF after stopping landiolol. CONCLUSION: Our findings show that the risk factor of POAF after thoracic aortic surgery is age, while perioperative administration of landiolol may reduce POAF incidence. PMID- 29483459 TI - [Video-assisted Transaortic Left Ventricular Thrombectomy]. AB - A 50-year-old woman visited a previous hospital because of aphasia. She was diagnosed as having cardiogenic embolism and left ventricular thrombus. Anticoagulant therapy was performed but was unsuccessful because of hypermenorrhea due to the myoma of the uterus. She was transferred to our hospital to receive surgical treatment. After uterine myomectomy, we performed video-assisted transaortic left ventricular thrombectomy. Her postoperative course was uneventful. Left ventriculotomy has been the standard approach for left ventricular thrombectomy. However, this approach carries a risk of ventricular dysfunction. We report our experience of a successful outcome with video-assisted transaortic left ventricular thrombectomy, thereby avoiding a left ventriculotomy. PMID- 29483460 TI - [Usefulness of Continuous Suction Unit in Detecting Air Leakage for Pneumothorax]. AB - A 66-year-old male with spontaneous pneumothorax underwent chest tube drainage in other hospital. After tube drainage, chest X-ray showed that the lung fully expanded and an air leakage was not visible. However, clamping the chest tube led to the collapse of the lung, and he transferred to our hospital. A continuous suction unit with pressure and bubbling time history monitoring system was used to detect intermittent air leakages( MS-009T). He underwent video-assisted thoracoscopic surgery. An air leakage from the right lung successfully closed. A new continuous suction unit was useful in detecting an air leakage which could not be confirmed by visual inspection. PMID- 29483461 TI - [Significance of Thoraco-laparoscopic Observation in Repairing Diaphragmatic Injury by the Penetrating Trauma]. AB - A 53-year-old man with a penetrating trauma was admitted to our hospital. Thoracoabdominal computed tomography (CT) on admission showed left diaphragmatic injury and peritoneal fat in the left thoracic cavity. Under a diagnosis of the traumatic diaphragmatic injury, an emergency operation was performed, and the left diaphragm was repaired. No other injuries were found in the thoracic and abdominal organs by thoraco-laparoscopic observation. The postoperative course was uneventful, and the patient left hospital on the 14th day after surgery. In case of the diaphragm injury, it is important to confirm the probable injuries of other organs by thoraco-laparoscopic observation. PMID- 29483462 TI - [Infectious Endocarditis due to Methicillin-sensitive Bovine Staphylococcus aureus;Report of a Case]. AB - A 19-year-old male patient was admitted to our hospital after developing infectious endocarditis associated with methicillin-sensitive bovine Staphylococcus aureus septicemia. Brain magnetic resonance imaging confirmed occipital lobe cerebral bleeding. An echocardiogram showed severe mitral regurgitation with vegetation on the posterior mitral leaflet. We performed mitral valve replacement. However, a hepatic artery aneurysm and a ruptured splenic artery aneurysm was found on the 5th postoperative day and coil embolization was accordingly performed. The patient suffered repeated cerebral bleeding and received external decompression. He was discharged on the 92nd day after the valve replacement. Our case is rare in that methicillin-sensitive bovine Staphylococcus aureus isolated from human is extremely unusual especially complicated by multiple peripheral aneurysms. This is the 1st reported case of methicillin-sensitive bovine Staphylococcus aureus isolated from human in the Japanese literature. PMID- 29483463 TI - [Aortoesophageal Fistula with Infected Thoracic Aortic Aneurysm Rupture;Report of a Case]. AB - A 67-year-old man was referred to our hospital because of fever and discomfort of the throat. Gastrointestinal endoscopy revealed hematoma at the middle thoracic esophagus. Computed tomography revealed posterior mediastinal hematoma extending the descending aorta. Bacillus was detected in the blood culture. Aortoesophageal fistula with an infected thoracic aortic aneurysm rupture was diagnosed. First, thoracic endovascular aortic repair (TEVAR) was performed. Resection of the thoracic esophagus and omentopexy was conducted 15 days after TEVAR. Esophageal reconstruction using a gastric tube was performed 43 days after esophagectomy. He has been doing well since then. PMID- 29483464 TI - [Surgical Experience of Distal Aortic Arch Aneurysm Suspected to be Associated with Pre-existing Coarctation of the Aorta]. AB - A 45 year-old-man who had undergone ventricular septal defect repair during childhood presented with hoarseness. He was diagnosed as having a distal aortic arch aneurysm by using computed tomography, and was referred to our hospital for surgical treatment. The operation was performed via a 4th intercostal thoracotomy in the right lateral position. The aortic aneurysm occupied the upper pleural cavity. The aortic arch was pressed up by the aortic aneurysm, so visual identification and clamping of the proximal aorta and the left subclavian artery were extremely difficult. Extracorporeal circulation was established via the right femoral artery and vein. Aneurysmal resection and graft replacement were performed using the open proximal method and retrograde cerebral circulation. The aneurysmal wall and proximal aorta were fragile and the proximal aorta was narrow, although the distal aorta was normal. The difference in diameters between the proximal and distal aorta suggested the presence of coarctation of the aorta. PMID- 29483465 TI - [Coronary Artery Bypass Surgery for the Patient with a History of Anaphylaxis due to Neuromuscular Blocking Agent ; Report of a Case]. AB - We present herein a patient with rocuronium anaphylaxis, which had been identified using skin test, underwent conventional coronary artery bypass surgery without any neuromuscular blocking agent. Immobility was achieved with sedatives and analgesics. PMID- 29483466 TI - [Asymptomatic Cardiac Myxoma Complicated with Carney Complex;Report of a Case]. AB - Carney complex(CNC) is a rare genetic syndrome, characterized by spotty pigmentation of the skin, cardiac myxomas and multiple endocrine tumors. We present a case of asymptomatic cardiac myxoma associated with CNC. She was 49 year-old healthy woman whose son was known to have CNC. She was also diagnosed as CNC due to her family history, typical cutaneous findings and screening endocrine test. Screening ultrasound echocardiography resulted in discovering her asymptomatic left atrial myxoma of 30 mm size. Tumor was successfully resected via median sternotomy and no signs of recurrence were observed at 1 year follow up. Periodical follow up is mandatory because of its high recurrence rate. PMID- 29483467 TI - [Primary Malignant Pericardial Mesothelioma;Report of a Case]. AB - A 69-year-old male was referred to our hospital after being diagnosed as having pericarditis with pericardial effusion. The symptoms of tamponade disappeared after the effusion was drained;although the cause of pericarditis remained unidentified. About 4 months later, the tamponade symptoms recurred due to the thickened nodular pericardium. Partial pericardiectomy was performed, however the patient died on the 52nd day after surgery. Immunohistological examination with calretinin led to the diagnosis of primary malignant pericardial mesothelioma, which was an extremely rare pathology. Because the hyaluronic acid content of the effusion has been reported as a diagnostic aid for malignant mesothelioma, routine examination of the hyaluronic acid content for pericarditis with pericardial effusion may be necessary for early diagnosis and to improve prognosis. PMID- 29483468 TI - [One-stage Operation through the Same Skin Incision for Synchronous Double Primary Breast and Lung Cancer;Report of a Case]. AB - A 75-year-old woman noticed a small mass in the right side breast and consulted our hospital. The results of the detailed examination indicated the synchronous double primary right breast cancer and the same side lung cancer (rS5). One-stage operation from the same skin incision was scheduled. Volume rendering (VR) of computed tomography (CT)-scan was very useful in deciding the position and the length of the skin incision. The breast tumor resection and the right middle lobe resection were successfully performed through 6.5 cm skin incision. PMID- 29483469 TI - [Lung Cancer Associated with Hamartoma;Report of a Case]. AB - A 65-year-old male was admitted to our hospital for evaluation of an abnormal shadow in the left lung field of chest roentgenogram. A chest computed tomography scan revealed an ill-defined nodule in the superior lingular segment of left lung and a calcified nodule in the left pulmonary apex region. A diagnosis of lung adenocarcinoma in the left lingular was made by transbronchial cytology and the left upper lobectomy with lymph node dissection was performed. Pathological diagnosis was primary lung adenocarcinoma in the superior lingular segment of left lung (pT1aN0M0, stage I A) and hamartoma in the left pulmonary apex region. It was considered to be important to discriminate a hamartoma from a metastasic lesion in order to conduct correct treatment. PMID- 29483470 TI - [Empyema Successfully Treated by Plombage with Abdominal Rectus Muscle and Omental Flap after Open-window Thoracostomy;Report of a Case]. AB - The partient was 76-year-old male. He had acute empyema due to lung abscess and open-window thoracotomy was performed to control infection. 3 years and 9 months later, the bronchial fistula was closed with abdominal rectus muscle and greater omentum. These are very useful when other muscles such as latissimus dorsi muscle, serratus anterior muscle and pectoralis major muscle are not available. PMID- 29483471 TI - [Tracheal Injury Successfully Treated without Surgery;Report of a Case]. AB - A 73-year-old man was injured after crashing his automobile into a concrete wall, and was admitted to our hospital with breathing difficulties. Chest computed tomography showed extensive mediastinal emphysema, right traumatic pneumothorax, and a suspected tracheal injury at the membranous region. Because of the associated tracheomalacia, the site of the tracheal injury was difficult to find by bronchoscopy. In addition, as the patient's respiratory condition was stable, surgical treatment was not chosen. Due to the continuous air leakage from the right lung, the patient underwent surgery after mediastinal and subcutaneous emphysema improved. The postoperative course was uneventful. PMID- 29483472 TI - [Hemothorax Occurring after Chest Drainage for Tension Pneumothorax;Report of a Case]. AB - A 23-year-old man was transported to our hospital complaining of chest pain and dyspnea. Chest X-ray revealed the right side tension pneumothorax with pleural effusion. A 12 Fr. chest tube was inserted. After 6 hours of chest drainage, the sign of intrathoracic bleeding appeared and the emergency operation was performed. The bleeding point was successfully coagulated with electrocautery. The postoperative course was uneventful. PMID- 29483473 TI - [Giant Cell Tumor of the Rib;Report of a Case]. AB - We report a rare case of giant cell tumor of the rib. A 33-year-old man was admitted to our hospital because of a recently appearing mass and pain in the right chest wall. Chest computed tomography and magnetic resonance imaging revealed a heterogeneous mass of 8-cm in diameter arising from and destroying the right 7th rib. The tumor was resected together with the 6th, 7th, and 8th ribs and the adjacent muscle and diaphragm. The pathological diagnosis was giant cell tumor of the bone. The patient has been free from recurrence or metastasis for 4 years after the operation. PMID- 29483474 TI - [Aortic Root Replacement for Patients with Aortic Root Aneurysms;Clinical Outcomes Compared Among Different Types of Abnormality and Operative Procedures]. AB - Aortic root operations are established procedures for patients with aortic root aneurysms, however there is a little insight for comparative long-term outcomes among different types of anatomical abnormalities and procedures. In this study, we sought to compare the results of patients with aortic abnormalities undergoing different procedures. From January 2008 to March 2017, a total of 105 patients without aortic dissection were performed the elective aortic root surgery. Patients with bicuspid aortic valve had enlarged annulus, and those with Marfan syndrome had enlarged Valsalva without enlarged annulus. Bentall operation with mechanical valve or bioprothetic valve was performed for patients with enlarged annulus and/or abnormal aortic cusp, and David operations for patients with normal cusps. This comparative study showed that these different procedures according to our policy were associated with reduced cardiac mortality and valve related complications. The results suggest David procedure is the treatment of choice for young patients with aortic root aneurysm and normal aortic cusps, however, careful patient selection is paramount. PMID- 29483475 TI - [Surgical Results of Aortic Root Replacement;Technical Modification and Geometric Analysis of Aortic Root after Aortic Valve-sparing Procedure]. AB - BACKGROUND: The Bentall procedure is a reliable treatment of various types of aortic root pathology. Furthermore, the aortic valve-sparing aortic root replacement also has been accepted as an ideal procedure especially in young patients. Recently, we have developed a simple valve-sparing operation focused on standardization and reproducibility. METHODS: From 2011 to 2017, 44 consecutive patients underwent aortic root replacement( Bentall 17, David 27)in our institution. Surgical results of these patients were evaluated retrospectively. Geometric parameters of reconstructed aortic root were analyzed to evaluate aortic valve function. RESULTS: There were 2 operative death( Bentall 2, David 0). Valve-sparing procedure was completed without conversion to valve replacement and no significant aortic insufficiency was noted soon after the operation. Patients underwent David operation were divided into 2 groups according to the annular diameter. There were 15 patients with large annulus and 12 with small annulus. The postoperative valve function was reproduced in both large and small annulus groups. From the results of geometric analysis of the aortic root, patients with large annulus and sino-tubular(ST) junction were anatomically more suitable and better treated with reimplantation technique. On the other hand, even in patients with small annulus, effective plication of ST junction and adequate suspension of commissure posts might be contribute to restore the valve competency with reimplantation technique. Two patients had aortic valve replacement 6 and 12 months after reimplantation, respectively. CONCLUSIONS: The acceptable outcome was demonstrated in patients underwent aortic root replacement. Aortic valve was reproduced well with our simple modification of valve-sparing operation. Although our modified technique is considered to be safe, reproducible and technically less demanding, close observation would be mandatory in this particular circumstance. PMID- 29483476 TI - [Valve-sparing Replacement in Patients with Aortic Root Dilatation]. AB - Valve-sparing root replacement is increasingly used to overcome drawbacks associated with valvular prostheses. In our institution, 7 patients underwent valve-sparing root replacement from August 2016 to July 2017. The mean age was 45 years (range, 14~69 years). Three patients had Marfan syndrome and 1 had Loeys Dietz syndrome with acute aortic dissection. All patients underwent surgery with reimplantation technique using a Valsalva graft. Two patients required repair of aortic valve leaflet prolapse. All patients had an excellent clinical course, with mild or no aortic regurgitation and a decrease in end-diastolic volume on echocardiography. These results support the continued use of valve-sparing root replacement in selected patients. PMID- 29483477 TI - [Results of Valve Sparing Aortic Root Replacement]. AB - Ninety-nine patients underwent valve sparing aortic root replacement, mostly using reimplantation technique. Mean age was 56.1+/-13.4 years. Indication of this type of operation was extended to patients with significant aortic regurgitation (AR) accompanied by sinus Valsalva diameter more than 40 mm. Bicuspid valve presented in 17 patients. The proportion of severe AR was 55%. Valve plasty technique included central plication (n=61) and pericardial patch (n=7). Operative mortality was 1%. AR grade at discharge was none or trivial in 87 patients (88%). Five-year survival rate was 96%. There were 5 reoperation and 2 patients underwent re-repair. Five-year reoperation free rate was 96%. PMID- 29483478 TI - [Surgical Outcomes for Aortic Root Repair in Patients Undergoing Type A Acute Aortic Dissection]. AB - We evaluated retrospectively 11 consecutive patients who underwent emergent aortic root operations for acute aortic dissection from April 2012 to March 2017. We underwent Bentall operation in 6 patients and Florida Sleeve repair in 3 patients and aortic root replacement with a Freestyle stentless porcine valve in 2 patients. The 30-day mortality of emergent aortic root operations was 9.1%(1 of 11), and the hospital mortality was 18.2%(2 of 11). The Overall survival at 5 years was 90.0%. In conclusion, the aortic root repair can be performed safely in acute aortic dissection. PMID- 29483479 TI - [Future Aspects of Bio-Bentall Procedure]. AB - The Bentall procedures using biological valved conduit is expanding owing to the increasing incidence of aortic valve disease in the aging population and usage for young generation. The long-term durability of the biological valve including the risks of structural valve deterioration(SVD) is the major concern of the bio Bentall procedure. Bio-Bentall in our hospital are reviewed and literature review are added. Our surgical results of long-term survival in bio-Bentall patients is acceptable compare to other study and freedom from SVD and reoperation is better than other results. There was no experience of SVD complication so far. Modification using double sewing ring technique is useful to put larger valve, keep better hemostasis, easy to do reoperation for further SVD and expect for future valve in valve situation. PMID- 29483480 TI - [Aortic Root Replacement with Cryopreserved Allograft Aortic Valve]. AB - Aortic root replacement with a cryopreserved allograft aortic valve is effective for active infectious endocarditis and prosthetic valve endocarditis, especially with a perivalvular abscess, since an allograft seems to be resistant to infection by maintaining viable cells under the process of programmed freezing. From December 1998 to March 2017, aortic root replacement with allograft aortic valves were performed in 38 patients in the University of Tokyo. The in-hospital mortality was 18%, the 5-year survival rate was 68%, and the 5-year freedom rate of reoperation was 75%. Although the clinical outcome was improved as institutional experiences increased recently, pseudoaneurysm during the long-term follow-up period needs special attention. The health-insurance system was applied to this allograft treatment in April 2016 by the Ministry of Health, Labour and Welfare. There are still some hurdles for obtaining institutional certification and financial resources, and enough number of donor allografts, so as to use them more commonly. PMID- 29483481 TI - [Aortic Valve Repair with Reimplantation in Small Aortic Root]. AB - Annular fixation has an important role aortic valve repair for aortic regurgitation. We have used the reimplantation procedure as annular fixation combined with cusp repair rechniques for aortic valve repair even in small aortic root( <50 mm) since 2010. Freedom from aortic valve reoperation was 93% at 5 years and 79% at 8 years. Freedom from greater than moderate aortic regurgitation was 80% at 5 years and 71% at 8 years. Although the outcomes were not satisfactory and should be improved, this technique would be one of choices in selected patients, considering durability of bioprostheses and anticoagulation related events in mechanical valves. PMID- 29483482 TI - [Current Status and Future Prospect of Robot-assisted Thoracoscopic Surgery]. AB - As surgical robots have widely spread, verification of their usefulness in the general thoracic surgery field is required. The most favorable advantage of robot assisted surgery is the markedly free movement of joint-equipped robotic forceps under 3-dimensional high-vision. Accurate operation makes complex procedures straightforward and may overcome weak points of previous thoracoscopic surgery. Robot-assisted surgery for lung cancer and mediastinal disease have been safely introduced and initial results have shown favorable. It is still at the stage of clinical research, but recently a lot of merits of robot-assisted thoracic surgery are proved. Although safety management, education and significant cost are also important issues, the robotic-assisted thoracoscopic surgery will become one of the surgical options in minimally invasive surgery. PMID- 29483483 TI - [Hepatoid Adenocarcinoma of the Lung with High Serum AFP and CEA Values;Report of a Case]. AB - A 60-year-old man exhibited an abnormal shadow in the right upper lobe. He was diagnosed with lung cancer by percutaneous computed tomography-guided lung tumor biopsy. Preoperative blood test showed high serum alpha-fetoprotein(AFP) and carcinoembryonic antigen(CEA) values. Right upper lobectomy was performed and histlogical diagnosis was AFP producing hepatoid adenocarcinoma with immunohistochemically positive HEP-PAR1. After the surgery, AFP and CEA values decreased to normal range. PMID- 29483484 TI - Ethnic Similarities and Differences in the Relationship between Beta Cell Mass and Diabetes. AB - Recent evidence has revealed that a change of functional beta cell mass is an essential factor of the pathophysiology of type 2 diabetes (T2DM). Since beta cell dysfunction is not only present in T2DM but also progressively worsens with disease duration, to preserve or recover functional beta cell mass is important in both prevention of the development of T2DM and therapeutic strategies for T2DM. Furthermore, ethnic difference in functional beta cell mass may also need to be taken into account. Recent evidences suggest that Asians have less beta cell functional capacity compared with Caucasians. Preservation or recovery of functional beta cell mass seems to be further emphasized for Asians because of the limited capacity of beta cell. This review summarizes the current knowledge on beta cell dysfunction in T2DM and discusses the similarities and differences in functional beta cell mass between ethnicities in the face of obesity and T2DM. PMID- 29483485 TI - Efficacy of Laminoplasty in Patients with Cervical Kyphosis. AB - BACKGROUND The efficacy of laminoplasty in patients with cervical kyphosis is controversial. The purpose of this study was to investigate the impact of the initial pathogenesis on the clinical outcomes of laminoplasty in patients with cervical kyphosis. MATERIAL AND METHODS A total of 137 patients with cervical spondylotic myelopathy (CSM) or ossification of the posterior longitudinal ligament (OPLL) underwent laminoplasty from April 2013 to May 2015. The patients were divided into the following 4 groups: lordosis with CSM (LC), kyphosis with CSM (KC), lordosis with OPLL (LO), and kyphosis with OPLL (KO). The clinical outcome measures included the visual analogue scale (VAS) and modified Japanese Orthopedic Association (mJOA) scores, the range of motion (ROM), and the cervical global angle (CGA). RESULTS The mean VAS and mJOA scores improved significantly in all groups after surgery. The changes in VAS and mJOA scores were significantly smaller, and the JOA recovery rate was significantly lower, in the KC group than in the LC and KO groups. The mean change in the CGA was greatest in the KC group (>8 degrees towards kyphosis). The preoperative ROM was negatively correlated with the change in CGA and the JOA recovery rate in the KO and KC groups. CONCLUSIONS We found that laminoplasty is suitable for patients with cervical lordosis and those with mild cervical kyphosis and OPLL, but is not recommended for patients with kyphosis and CSM, particularly those with a large ROM preoperatively. PMID- 29483486 TI - Treatment of Donor Rat Hearts Prior to Transplantation with FLIP (FADD-Like Interleukin Beta-Converting Enzyme (FLICE)-Like Inhibitory Protein) in Cardioplegic Solution Decreased Apoptosis at Thirty Minutes Post-transplantation and Decreased Total Tyrosine Phosphorylation Levels. AB - BACKGROUND Heart transplantation is a therapeutic option for patients with severe coronary artery disease or heart failure. One of the difficulties to overcome is the apoptosis of cardiomyocytes in the donor organ. To prevent apoptosis in the donor organ, we developed a fusion protein containing FLIP (FADD-like interleukin beta-converting enzyme (FLICE)-like inhibitory protein) to inhibit caspase-8. MATERIAL AND METHODS We linked the cDNA coding for the FLIP protein to the transduction domain of HIV (human immunodeficiency virus) to allow the protein to enter cells. The recombinant protein was used at two different concentrations, 3 nM and 30 nM, for treatment of the donor heart in rat transplantation experiments. After transplantation, apoptosis was measured by ELISA, and the levels of active caspase-3, caspase-8, Bid, and PUMA were determined by western blotting using specific antibodies. RESULTS We observed that treatment of the donor organ with a solution containing this protein reduced the apoptosis level in the donor organ after 30 minutes post-transplantation as measured by the total of apoptotic cells with ELISA assay, and caspase-8 and caspase-3 activation and decreased levels of BH3-only proteins such as Bid and PUMA. Furthermore, this treatment also reduced the total tyrosine phosphorylation levels, which may be a possible measurement of lower oxidative stress levels in cardiomyocytes. CONCLUSIONS Protein FLIP solution reduced apoptosis at 30 minutes post transplantation and decreased levels of several regulators of apoptosis. PMID- 29483487 TI - A Rare Case of Cardiac Calcified Amorphous Tumor: Multi-Modality Imaging Evaluation. AB - BACKGROUND Cardiac calcified amorphous tumors (CAT) are rarely presented and featured as calcification and eosinophilic amorphous material in dense collagenous fibrous tissue. CASE REPORT Our case report describes a 47-year-old man presenting cardiac CAT with only chronic cough and occasional dizziness. Preoperative multi-modality imaging was used to evaluate it and postoperative histological study was used to confirm the diagnosis. The mass was resected and the patient was fully recovered and discharged on the 7th postoperative day. In the 1-year follow-up, transthoracic echography showed no further pathological changes. CONCLUSIONS Cardiac CAT is a non-neoplastic cardiac tumor of unknown etiology. The tumor is commonly an incidental finding and the treatment of choice is complete surgical resection. In this case, we found that that multi-modality images were helpful in evaluating and diagnosing the cardiac CAT. PMID- 29483488 TI - Influence of exogenous lactoferrin on the oxidant/antioxidant balance and molecular profile of hormone receptor-positive and -negative human breast cancer cells in vitro. AB - AIM: To investigate the mechanisms of cytotoxic activity and pro-/antioxidant effect of lactoferrin on hormone receptor-positive and receptor-negative breast cancer cells in vitro. MATERIALS AND METHODS: The study was performed on receptor positive (MCF-7, T47D) and receptor-negative (MDA-MB-231, MDA-MB-468) human breast cancer cell lines. Immunocytochemical staining, flow cytometry, low temperature electron paramagnetic resonance, and the Comet assay were used. RESULTS: Upon treatment with lactoferrin, the increased levels of reactive oxygen species (ROS) (p < 0.05), NO generation rate by inducible NO-synthase (p < 0.05) and the level of "free" iron (p < 0.05) were observed. Moreover, the effects of lactoferrin were more pronounced in receptor-negative MDA-MB-231 and MDA-MB-468 cells. These changes resulted in increased expression of proapoptotic Bax protein (p < 0.05), reduced expression of the antiapoptotic Bcl-2 protein (p < 0.05) and level of not-oxidized mitochondrial cardiolipin (1.4-1.7-fold, p < 0.05). This, in turn, caused an increase in the percentage of apoptotic cells (by 14-24%, p < 0.05). Cytotoxic effects of lactoferrin were accompanied by an increase in the percentage of DNA in the comet tail and blocking cell cycle at G2/M phase, especially in receptor-negative cell lines. CONCLUSION: The study showed that exogenous lactoferrin causes a violation of an antioxidant balance by increasing the level of ROS, "free" iron and NO generation rate, resalting in the blocking of cell cycle at G2/M-phase and apoptosis of malignant cells. PMID- 29483489 TI - Genome-wide association study of loss of heterozygosity and metastasis-free survival in breast cancer patients. AB - : One of the factors providing the diversity and heterogeneity of malignant tumors, particularly breast cancer, are genetic variations, due to gene polymorphism, and, especially, the phenomenon of loss of heterozygosity (LOH). It has been shown that LOH in some genes could be a good prognostic marker. AIM: To perform genome-wide study on LOH in association with metastasis-free survival in breast cancer. MATERIALS AND METHODS: The study involved 68 patients with breast cancer. LOH status was detected by microarray analysis, using a high density DNA chip CytoScanTM HD Array (Affymetrix, USA). The Chromosome Analysis Suite 3.1 (Affymetrix, USA) software was used for result processing. RESULTS: 13,815 genes were examined, in order to detect LOH. The frequency of LOH varied from 0% to 63%. The association analysis identified four genes: EDA2R, PGK1, TAF9B and CYSLTR1 that demonstrated the presence of LOH associated with metastasis-free survival (log-rank test, p < 0.03). CONCLUSIONS: The presence of LOH in EDA2R, TAF9B, and CYSLTR1 genes is associated with metastasis-free survival in breast cancer patients, indicating their potential value as prognostic markers. PMID- 29483490 TI - Impact of lactic acidosis on the survival of Lewis lung carcinoma cells. AB - AIM: To investigate the effect of lactic acidosis on the survival of Lewis lung carcinoma cells under glucose-deprived conditions. MATERIALS AND METHODS: LLC/R9 variant of Lewis lung carcinoma cells was cultured in glucose deficit or complete culture medium. Conditions of lactic acidosis, lactosis, and acidosis were generated in glucose deficit medium. Cell survival, cell cycle, apoptosis, autophagy, and the content of glucose, lactate, vascular endothelial growth factor in the culture medium were determined. Light and fluorescent microscopy, flow cytometry, spectrophotometry, and ELISA were used. RESULTS: It has been found that 24 h incubation of tumor cells under lactic acidosis caused (i) the reduction of the number of living cells by 33% (p < 0.05) and 56% (p < 0.05); (ii) the inhibition of apoptosis by 4.3-fold (p < 0.05) and 3.3-fold (p < 0.05); (iii) the reduction of the rate of glucose consumption by 2-fold (p < 0.05) and 2.5-fold (p < 0.05); (iv) an increase of lactate production more than twice (p < 0.05) and 1.6-fold (p < 0.05) compared with these indexes under conditions of glucose deficiency or complete glucose-containing medium, respectively. However, on the second day of culture under lactic acidosis, the number of viable cells reached a maximum, in contrast to culture in the complete medium. The number of live cells on the seventh day of culture under lactic acidosis exceeded almost 2 3 times (p < 0.05) that in the culture under conditions of the glucose deprivation or in complete medium. On the third day under lactic acidosis the autophagolysosomes count was 54% (p < 0.05) lower that that under glucose deficit. CONCLUSIONS: Lactic acidosis promoted the survival and proliferation of Lewis lung carcinoma cells by energy system reprogramming directed on inhibition of apoptosis and autophagy, a significant decrease in the rate of glucose utilization and activation of glutaminolysis and, consequently, increase of the lactate production rate. Inhibition of lactate production by tumor cells may be considered as a promising approach for more efficient antiangiogenic treatment of cancer. PMID- 29483491 TI - Determination of cisplatin in human blood plasma and urine using liquid chromatography-mass spectrometry for oncological patients with a variety of fatty tissue mass for prediction of toxicity. AB - AIM: The research was aimed to analyze a level of triglycerides in blood serum as a possible new marker of toxicity, particularly in patients with excess body weight, receiving cisplatin. MATERIALS AND METHODS: Study involved 20 oncological patients with stage III lung cancer, who received palliative treatment with cisplatin. High-performance liquid chromatography was used for quantitative determination of pure cisplatin in urine and blood samples. Cisplatin concentration of the test samples was determined based on the data obtained from the calibration graph. RESULTS: Quantitative determination of pure cisplatin is quite complicated. The elimination half-time for one of the groups was observed higher almost by half than for other patients. Higher dose of cisplatin showed a significant association with increase in triglyceride levels. We found a close correlation between body mass index and triglyceride changes during chemotherapy (p = 0.001; r = 0.67). The results indicate that a higher body mass index gives higher fluctuations of triglyceride levels in blood serum. Analyses of correlation between level of triglycerides and elimination half-time show that by an increase in the level of triglycerides in the blood serum cisplatin elimination half-time is prolonged (R2 Linear = 0.596). Cisplatin concentration in urine is higher and elimination takes longer time at elevated levels of triglycerides, where close correlation between fraction of excreted substance in urine and concentration parameters was seen (p < 0.01). Also good correlation for body mass index with fraction of excreted substance in urine and concentration parameters was observed (p < 0.05). CONCLUSION: Clearance of cisplatin, which was determined by the chromatographic method, is reduced in individuals with increased adipose tissue mass. Research data suggest that overweight affects cisplatin elimination from the body. The greater body fat mass can contribute to a greater rise of triglyceride level in blood serum. Triglycerides in blood plasma may serve as an additional indicator of higher cisplatin toxicity as a cardiotoxicity marker. PMID- 29483493 TI - Materials of a mini-symposium "New trends in cancer research and innovative tumor vaccines" held on May 11, 2017 during the VACTRAIN summer school in Kyiv, Ukraine. PMID- 29483492 TI - Experimental study of liposomal docetaxel analysis of docetaxel incorporation and stability. AB - AIM: The article presents the results of developing the composition and technology of obtaining the liposomal form of docetaxel. The effect of the phospholipid composition of the membrane, ionic strength, pH, temperature, cryoprotectant type, and other factors on the stability of liposomes and the docetaxel incorporation has been considered. RESULTS: Reduction of toxicity of the liposomal form of docetaxel (LD50 - 137 +/- 7.7 mg/kg) was found in comparison with its free form (LD50 - 101 +/- 6.3 mg/kg). Preservation of nanosize particle after lyophilization has been shown. CONCLUSIONS: As a result of the studies, the optimal composition and technological scheme for obtaining liposomes containing docetaxel have been developed allowing large-scale production of docetaxel in liposomal form. PMID- 29483494 TI - Generic imatinib in the treatment of chronic myeloid leukemia: two years' experience in Latvia. AB - BACKGROUND: Imatinib is tyrosine kinase inhibitor (TKI) and as a targeted anti cancer agent has significantly changed chronic myeloid leukemia (CML) prognosis and patient survival. Currently TKI is the main therapy in CML Philadelphia chromosome-positive (Ph-positive) cases. When generics of imatinib appeared in the pharmaceuticals market, reimbursement policies in many countries switched to using generics or encouraged use of generic imatinib to lower the expenses. Cost savings were substantial; however, for doctors and CML patients the efficacy, safety and quality of generic imatinib were an issue of concern. OBJECTIVE: Since the global number of CML patients, who in the future will have to switch from original imatinib to generic imatinib, is high, the aim of study was to monitor, whether during 24 months of generic imatinib usage patients maintain the achieved major molecular response (MMR) or whether the treatment results are inferior. METHODS: We conducted a retrospective study, which included CML patients, who were above 18 years of age and who until May 2013 had used at least for 2 years (24 months) the original imatinib, and following that used at least for 24 months one of the generic imatinib medicines. In 2013, before switching to generic imatinib, all patients had reached MMR in accordance with European LeukemiaNet (ELN) Guidelines. Every three months blood count, BCR-ABL fusion gene (BCR-ABL), biochemical analysis and side effect were monitored. RESULTS: Our study proved that CML patients, who had achieved MMR by original imatinib therapy, retained MMR during 24 months of generic imatinib therapy. Nobody was switched to second line generation TKI. During observation period neither haematological, nor non hematological toxicity was found. CONCLUSION: Our study proved that CML patients, who had achieved MMR by original imatinib therapy, retained MMR during 24 months of generic imatinib therapy. This demonstrates that generic imatinib is not inferior to original imatinib. As to expenses, the annual costs of generic imatinib are lower by 96%, which is a significant benefit to health-care financing. PMID- 29483495 TI - Adenocarcinoma of the lung with rare insertion mutation in EGFR exon 19 that had partial response to gefitinib: a case report. AB - AIM: Classic activating mutations L858R and deletions in exon 19 (19del) in the gene for epidermal growth factor receptor (EGFR) are associated with sensitivity of the non-small cell lung cancer (NSCLC) to therapy with tyrosine kinase inhibitors (TKI). Insertions in EGFR exon 19 (19ins) are rare mutations in NSCLC; response of cases with 19ins to TKI is not well studied. Here we report a case of NSCLC with 19ins in a Russian patient who was treated with gefitinib. We also overview cases of 19ins reported in the literature. CASE DESCRIPTION: A 48 years old female Russian patient was diagnosed with adenocarcinoma of the lung (T3N2M1, stage IV). Mutation 19ins was detected in the tumor biopsy by fragment analysis and genotyped by Sanger sequencing as p.I744_K745insKIPVAI. Treatment with gefitinib (250 mg/day) resulted in clinical and radiological improvements scored as partial response that lasted 12 months. CONCLUSION: Treatment with gefitinib of lung adenocarcinoma that carries mutation EGFR 19ins can result in durable response. PMID- 29483496 TI - Comparison of chromosomal rearrangements in bone marrow cells and blast transformed B-cells in relapse of B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma. AB - AIM: The genetic mechanisms of resistance to chemotherapy in B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL) are not clear. We aimed to determine the peculiarities of abnormal karyotype formation in bone marrow (BM) cells and peripheral blood (PB) blast transformed B-cells in relapse of B-CLL/SLL. MATERIALS AND METHODS: Cytogenetic GTG banding technique and molecular cytogenetic in interphase cells (i-FISH) studies of BM cells and PB blast transformed B-lymphocytes were performed in 14 patients (10 males and 4 females) with B-CLL/SLL. RESULTS: The results of karyotyping BM and PB cells revealed the heterogeneity of cytogenetic abnormalities in combined single nosological group of B-CLL/SLL. In PB B-cells, chromosome abnormalities related to a poor prognosis group were registered 2.5 times more often than in BM cells. Additional near tetraploid clones that occurred in 57.1% cases were the peculiar feature of BM cell karyotypes. Chromosomal rearrangements characteristic of the group of adverse cytogenetic prognosis were revealed in all cases from which in 2 cases by karyotyping BM cells, in 6 cases in PB B-cells and in 8 cases by the i FISH method in BM cells, i.e. their detection frequency was 3 times higher in PB B-cells and 4 times higher when analyzing by i-FISH in BM cells. CONCLUSIONS: Mismatch in abnormal karyotypes in BM and PB B-cells by the presence of quantitative and structural chromosomal rearrangements may be indicative of simultaneous and independent processes of abnormal clone formation in the lymph nodes and BM hematopoietic cells. Accumulation the information about previously unidentified chromosomal rearrangements in relapse of the disease may help to understand the ways of resistance formation to chemotherapy. PMID- 29483497 TI - Lectin binding patterns in normal, dysplastic and Helicobacter pylori infected gastric mucosa. AB - AIM: To analyze the glycoprotein binding sites of the gastric mucosa and its secreted mucus using lectin histochemistry in patients with chronic non-atrophic gastritis (CNAG) associated or not-associated with Helicobacter pylori infection with or without dysplasia. MATERIALS AND METHODS: In order to identify the areas with glycoconjugates expression in gastric mucosa, 6 lectins (Canavalia ensiformis agglutinin - Con A, Sambucus nigra agglutinin - SNA, wheat germ agglutinin - WGA, soybean agglutinin - SBA, Helix pomatia agglutinin - HPA, peanut agglutinin - PNA) were used. Carbohydrate determinants were visualized according to the lectin-peroxidase-diaminobenzidine staining protocol. Biopsy material was obtained and processed by conventional histological methods. The samples from 84 patients (54 with CNAG) with low (n = 34) and high grade (n = 20) dysplasia, 38 patients were H. pylori-infected and 26 patients - H. pylori noninfected) were used. The comparison group included 30 persons with CNAG without dysplasia (16 patients H. pylori-infected and 14 - noninfected). RESULTS: In comparison to normal gastric mucosa, a low affinity of Con A was shown in 80% of patients with non-infected CNAG and 90% of H. pylori associated CNAG. In 70% of H. pylori-infected patients with CNAG and low grade dysplasia there was an increase of SNA expression compared with non-infected patients (p < 0.05). Regarding SBA labeling no differences were detected in the studied groups (p < 0.05). In H. pylori infected patients with CNAG and low grade dysplasia, WGA, HPA and PNA showed a strong reactivity with the gastric mucosa cells in 80; 75%, and 60% of patients, respectively. CONCLUSION: We suggest that a set of lectins in reaction with gastric epithelial and glandular cells can be used as a tool to obtain information about the dysplastic changes of the gastric mucosa and may offer new insight into gastric carcinogenesis and precancerous lesions treatment. PMID- 29483498 TI - Expression of cancer-associated genes in prostate tumors. AB - BACKGROUND: Prostate cancer is one of the most common male cancers in Western countries and takes the third place in morbidity in Ukraine. It is a highly heterogeneous disease. AIM: To analyze relative expression levels of the TGFB1, IL1B, FOS, EFNA5, TAGLN, PLAU, and EPDR1 genes in malignant and non-malignant prostate tissues. MATERIALS AND METHODS: Total RNA was isolated from 16 prostate adenomas, 37 prostate adenocarcinomas, and 29 conventionally normal prostate tissues. To analyze relative gene expression levels the quantitative real-time polymerase chain reaction was performed. RESULTS: The significant alterations in the relative expression levels were found in all analyzed sample groups for 4 genes: FOS, EFNA5, IL1B, and TGFB1. We have found that FOS and EFNA5 were more frequently overexpressed in carcinomas with Gleason score <= 7, compared with adenomas. On contrary, PLAU expression levels were decreased more frequently in prostate cancers, compared with conventionally normal tissues. Noteworthy, we found positive correlation between IL1B expression level and PSA (for patients with slight PSA increase, no more than 20.0 ng/ml). CONCLUSION: The EFNA5, FOS, IL1B, PLAU, and TGFB1 genes that showed significant expression alterations in prostate tumors, compared with conventionally normal prostate tissue, may play role in prostate cancer development and should be further investigated. PMID- 29483499 TI - Multiple-field interstitial photodynamic therapy of subcutaneously transplanted cholangiocellular carcinoma RS-1 in rats. AB - : The aim of present study was to investigate an antitumor efficacy of multiple field interstitial photodynamic therapy (iPDT) in vivo. MATERIALS AND METHODS: The study was performed on 15 white random-bred rats with subcutaneously transplanted cholangiocellular carcinoma RS-1. Chlorine-based photosensitizer (PS) Ce6CPPPS was administered via single injection at a dose of 2.5 mg/kg into the animal's caudal vein. Photoirradiation (PI) of tumors was carried out 3 h after PS administration using 7 optical fibers SMA-905 with diode laser with 660 +/- 5 nm wavelength at exposure doses of 150 and 300 J/cm2 with 0.21 W/cm2 fluency rate. The total power density was 360 mW and treatment time was 12 and 24 min. Antitumor efficacy of iPDT was assessed by evaluation of necrosis areas and depth of necrosis in experimental tumors. RESULTS: The results have shown that interstitial PI with multi-field low power density enhanced the antitumor effect of PDT in the RS-1 model. Necrosis areas in tumor tissues after PI with exposure doses 150 and 300 J/cm2 24 h and 96 h after treatment were 83.78 +/- 4.25 and 100% (p = 0.00074); 56.79 +/- 3.24 and 95.46 +/- 1.64% (p < 0.00001), respectively. CONCLUSION: An analysis of the literature data and the results obtained in this study evidence on high effectiveness of the method of multiple field. PMID- 29483500 TI - Current epidemiological knowledge about the role of flavonoids in prostate carcinogenesis. AB - Numerous experimental studies have demonstrated anticancer action of polyphenolic plant metabolites. However, data about associations between dietary intake of plant-derived flavonoids and prostate cancer risk are still sparse and inconsistent. This minireview compiles the epidemiological findings published to date on the role of flavonoids in prostate tumorigenesis, discusses the reasons of inconsistencies and elicits the promising results for chemoprevention of this malignancy. Long-term consumption of high doses of soy isoflavones can be the reason of markedly lower clinically detectable prostate cancer incidence among Asian men compared to their counterparts in the Western world. The ability to metabolize daidzein to equol, the most biologically active isoflavone, by the certain intestinal bacteria also seems to contribute to this important health benefit. The increasing incidence rate of prostate cancer related to adoption of westernized lifestyle and dietary habits makes the issue of chemoprevention ever more important and directs the eyes to specific food components in the Eastern diet. If further large-scale epidemiological studies will confirm the protective effects of isoflavones against prostate cancer, this could provide an important way for prostate cancer prevention, as diet is a potentially modifiable factor in our behavioral pattern. PMID- 29483501 TI - The influence of the molecular packing on the room temperature phosphorescence of purely organic luminogens. AB - Organic luminogens with persistent room temperature phosphorescence (RTP) have attracted great attention for their wide applications in optoelectronic devices and bioimaging. However, these materials are still very scarce, partially due to the unclear mechanism and lack of designing guidelines. Herein we develop seven 10-phenyl-10H-phenothiazine-5,5-dioxide-based derivatives, reveal their different RTP properties and underlying mechanism, and exploit their potential imaging applications. Coupled with the preliminary theoretical calculations, it is found that strong pi-pi interactions in solid state can promote the persistent RTP. Particularly, CS-CF3 shows the unique photo-induced phosphorescence in response to the changes in molecular packing, further confirming the key influence of the molecular packing on the RTP property. Furthermore, CS-F with its long RTP lifetime could be utilized for real-time excitation-free phosphorescent imaging in living mice. Thus, our study paves the way for the development of persistent RTP materials, in both the practical applications and the inherent mechanism. PMID- 29483502 TI - Non-catalytic hydrogenation of VO2 in acid solution. AB - Hydrogenation is an effective way to tune the property of metal oxides. It can conventionally be performed by doping hydrogen into solid materials with noble metal catalysis, high-temperature/pressure annealing treatment, or high-energy proton implantation in vacuum condition. Acid solution naturally provides a rich proton source, but it should cause corrosion rather than hydrogenation to metal oxides. Here we report a facile approach to hydrogenate monoclinic vanadium dioxide (VO2) in acid solution at ambient condition by placing a small piece of low workfunction metal (Al, Cu, Ag, Zn, or Fe) on VO2 surface. It is found that the attachment of a tiny metal particle (~1.0 mm) can lead to the complete hydrogenation of an entire wafer-size VO2 (>2 inch). Moreover, with the right choice of the metal a two-step insulator-metal-insulator phase modulation can even be achieved. An electron-proton co-doping mechanism has been proposed and verified by the first-principles calculations. PMID- 29483503 TI - Allelic decomposition and exact genotyping of highly polymorphic and structurally variant genes. AB - High-throughput sequencing provides the means to determine the allelic decomposition for any gene of interest-the number of copies and the exact sequence content of each copy of a gene. Although many clinically and functionally important genes are highly polymorphic and have undergone structural alterations, no high-throughput sequencing data analysis tool has yet been designed to effectively solve the full allelic decomposition problem. Here we introduce a combinatorial optimization framework that successfully resolves this challenging problem, including for genes with structural alterations. We provide an associated computational tool Aldy that performs allelic decomposition of highly polymorphic, multi-copy genes through using whole or targeted genome sequencing data. For a large diverse sequencing data set, Aldy identifies multiple rare and novel alleles for several important pharmacogenes, significantly improving upon the accuracy and utility of current genotyping assays. As more data sets become available, we expect Aldy to become an essential component of genotyping toolkits. PMID- 29483504 TI - Sodium enhances indium-gallium interdiffusion in copper indium gallium diselenide photovoltaic absorbers. AB - Copper indium gallium diselenide-based technology provides the most efficient solar energy conversion among all thin-film photovoltaic devices. This is possible due to engineered gallium depth gradients and alkali extrinsic doping. Sodium is well known to impede interdiffusion of indium and gallium in polycrystalline Cu(In,Ga)Se2 films, thus influencing the gallium depth distribution. Here, however, sodium is shown to have the opposite effect in monocrystalline gallium-free CuInSe2 grown on GaAs substrates. Gallium in diffusion from the substrates is enhanced when sodium is incorporated into the film, leading to Cu(In,Ga)Se2 and Cu(In,Ga)3Se5 phase formation. These results show that sodium does not decrease per se indium and gallium interdiffusion. Instead, it is suggested that sodium promotes indium and gallium intragrain diffusion, while it hinders intergrain diffusion by segregating at grain boundaries. The deeper understanding of dopant-mediated atomic diffusion mechanisms should lead to more effective chemical and electrical passivation strategies, and more efficient solar cells. PMID- 29483505 TI - Control over multiple molecular states with directional changes driven by molecular recognition. AB - Recently, ligand-metal coordination, stimuli-responsive covalent bonds, and mechanically interlinked molecular constructs have been used to create systems with a large number of accessible structural states. However, accessing a multiplicity of states in sequence from more than one direction and doing so without the need for external energetic inputs remain as unmet challenges, as does the use of relatively weak noncovalent interactions to stabilize the underlying forms. Here we report a system based on a bispyridine-substituted calix[4]pyrrole that allows access to six different discrete states with directional control via the combined use of metal-based self-assembly and molecular recognition. Switching can be induced by the selective addition or removal of appropriately chosen ionic guests. No light or redox changes are required. The tunable nature of the system has been established through a combination of spectroscopic techniques and single crystal X-ray diffraction analyses. The findings illustrate a new approach to creating information-rich functional materials. PMID- 29483506 TI - A dual mechanism promotes switching of the Stormorken STIM1 R304W mutant into the activated state. AB - STIM1 and Orai1 are key components of the Ca2+-release activated Ca2+ (CRAC) current. Orai1, which represents the subunit forming the CRAC channel complex, is activated by the ER resident Ca2+ sensor STIM1. The genetically inherited Stormorken syndrome disease has been associated with the STIM1 single point R304W mutant. The resulting constitutive activation of Orai1 mainly involves the CRAC activating domain CAD/SOAR of STIM1, the exposure of which is regulated by the molecular interplay between three cytosolic STIM1 coiled-coil (CC) domains. Here we present a dual mechanism by which STIM1 R304W attains the pathophysiological, constitutive activity eliciting the Stormorken syndrome. The R304W mutation induces a helical elongation within the CC1 domain, which together with an increased CC1 homomerization, destabilize the resting state of STIM1. This culminates, even in the absence of store depletion, in structural extension and CAD/SOAR exposure of STIM1 R304W leading to constitutive CRAC channel activation and Stormorken disease. PMID- 29483507 TI - Lkb1 deficiency confers glutamine dependency in polycystic kidney disease. AB - Polycystic kidney disease (PKD) is a common genetic disorder characterized by the growth of fluid-filled cysts in the kidneys. Several studies reported that the serine-threonine kinase Lkb1 is dysregulated in PKD. Here we show that genetic ablation of Lkb1 in the embryonic ureteric bud has no effects on tubule formation, maintenance, or growth. However, co-ablation of Lkb1 and Tsc1, an mTOR repressor, results in an early developing, aggressive form of PKD. We find that both loss of Lkb1 and loss of Pkd1 render cells dependent on glutamine for growth. Metabolomics analysis suggests that Lkb1 mutant kidneys require glutamine for non-essential amino acid and glutathione metabolism. Inhibition of glutamine metabolism in both Lkb1/Tsc1 and Pkd1 mutant mice significantly reduces cyst progression. Thus, we identify a role for Lkb1 in glutamine metabolism within the kidney epithelia and suggest that drugs targeting glutamine metabolism may help reduce cyst number and/or size in PKD. PMID- 29483508 TI - Protease nexin-1 prevents growth of human B cell lymphoma via inhibition of sonic hedgehog signaling. PMID- 29483509 TI - Fatty Acid Synthase induced S6Kinase facilitates USP11-eIF4B complex formation for sustained oncogenic translation in DLBCL. AB - Altered lipid metabolism and aberrant protein translation are strongly associated with cancerous outgrowth; however, the inter-regulation of these key processes is still underexplored in diffuse large B-cell lymphoma (DLBCL). Although fatty acid synthase (FASN) activity is reported to positively correlate with PI3K-Akt-mTOR pathway that can modulate protein synthesis, the precise impact of FASN inhibition on this process is still unknown. Herein, we demonstrate that attenuating FASN expression or its activity significantly reduces eIF4B (eukaryotic initiation factor 4B) levels and consequently overall protein translation. Through biochemical studies, we identified eIF4B as a bonafide substrate of USP11, which stabilizes and enhances eIF4B activity. Employing both pharmacological and genetic approaches, we establish that FASN-induced PI3K S6Kinase signaling phosphorylates USP11 enhancing its interaction with eIF4B and thereby promoting oncogenic translation. PMID- 29483510 TI - EGFL7 reduces CNS inflammation in mouse. AB - Extracellular matrix (ECM) proteins secreted by blood-brain barrier (BBB) endothelial cells (ECs) are implicated in cell trafficking. We discovered that the expression of ECM epidermal growth factor-like protein 7 (EGFL7) is increased in the CNS vasculature of patients with multiple sclerosis (MS), and in mice with experimental autoimmune encephalomyelitis (EAE). Perivascular CD4 T lymphocytes colocalize with ECM-bound EGFL7 in MS lesions. Human and mouse activated T cells upregulate EGFL7 ligand alphavbeta3 integrin and can adhere to EGFL7 through integrin alphavbeta3. EGFL7-knockout (KO) mice show earlier onset of EAE and increased brain and spinal cord parenchymal infiltration of T lymphocytes. Importantly, EC-restricted EGFL7-KO is associated with a similar EAE worsening. Finally, treatment with recombinant EGFL7 improves EAE, reduces MCAM expression, and tightens the BBB in mouse. Our data demonstrate that EGFL7 can limit CNS immune infiltration and may represent a novel therapeutic avenue in MS. PMID- 29483511 TI - MSD1 regulates pedicellate spikelet fertility in sorghum through the jasmonic acid pathway. AB - Grain number per panicle (GNP) is a major determinant of grain yield in cereals. However, the mechanisms that regulate GNP remain unclear. To address this issue, we isolate a series of sorghum [Sorghum bicolor (L.) Moench] multiseeded (msd) mutants that can double GNP by increasing panicle size and altering floral development so that all spikelets are fertile and set grain. Through bulk segregant analysis by next-generation sequencing, we identify MSD1 as a TCP (Teosinte branched/Cycloidea/PCF) transcription factor. Whole-genome expression profiling reveals that jasmonic acid (JA) biosynthetic enzymes are transiently activated in pedicellate spikelets. Young msd1 panicles have 50% less JA than wild-type (WT) panicles, and application of exogenous JA can rescue the msd1 phenotype. Our results reveal a new mechanism for increasing GNP, with the potential to boost grain yield, and provide insight into the regulation of plant inflorescence architecture and development. PMID- 29483512 TI - A cryptic RNA-binding domain mediates Syncrip recognition and exosomal partitioning of miRNA targets. AB - Exosomal miRNA transfer is a mechanism for cell-cell communication that is important in the immune response, in the functioning of the nervous system and in cancer. Syncrip/hnRNPQ is a highly conserved RNA-binding protein that mediates the exosomal partition of a set of miRNAs. Here, we report that Syncrip's amino terminal domain, which was previously thought to mediate protein-protein interactions, is a cryptic, conserved and sequence-specific RNA-binding domain, designated NURR (N-terminal unit for RNA recognition). The NURR domain mediates the specific recognition of a short hEXO sequence defining Syncrip exosomal miRNA targets, and is coupled by a non-canonical structural element to Syncrip's RRM domains to achieve high-affinity miRNA binding. As a consequence, Syncrip mediated selection of the target miRNAs implies both recognition of the hEXO sequence by the NURR domain and binding of the RRM domains 5' to this sequence. This structural arrangement enables Syncrip-mediated selection of miRNAs with different seed sequences. PMID- 29483513 TI - Clonally diverse CD38+HLA-DR+CD8+ T cells persist during fatal H7N9 disease. AB - Severe influenza A virus (IAV) infection is associated with immune dysfunction. Here, we show circulating CD8+ T-cell profiles from patients hospitalized with avian H7N9, seasonal IAV, and influenza vaccinees. Patient survival reflects an early, transient prevalence of highly activated CD38+HLA-DR+PD-1+ CD8+ T cells, whereas the prolonged persistence of this set is found in ultimately fatal cases. Single-cell T cell receptor (TCR)-alphabeta analyses of activated CD38+HLA DR+CD8+ T cells show similar TCRalphabeta diversity but differential clonal expansion kinetics in surviving and fatal H7N9 patients. Delayed clonal expansion associated with an early dichotomy at a transcriptome level (as detected by single-cell RNAseq) is found in CD38+HLA-DR+CD8+ T cells from patients who succumbed to the disease, suggesting a divergent differentiation pathway of CD38+HLA-DR+CD8+ T cells from the outset during fatal disease. Our study proposes that effective expansion of cross-reactive influenza-specific TCRalphabeta clonotypes with appropriate transcriptome signatures is needed for early protection against severe influenza disease. PMID- 29483515 TI - Population-specific expression of antimicrobial peptides conferring pathogen resistance in the invasive ladybird Harmonia axyridis. AB - The harlequin ladybird Harmonia axyridis has emerged as a model species in the context of invasion biology and possesses an expanded repertoire of antimicrobial peptides (AMPs). Here we measured the expression of 22 AMP genes in adult beetles from native and introduced populations, and from a biocontrol population, allowing us to compare populations differing in terms of invasive performance. Strikingly, we observed population-specific expression profiles for particular AMPs. Following an immune challenge, the genes for Coleoptericin1 (Col1), Coleoptericin-likeB and Defensin1 were induced up to several thousand times more strongly in the invasive populations compared to the native and biocontrol populations. To determine the role of Col1 in pathogen resistance, the corresponding gene was silenced by RNA interference (RNAi), causing higher mortality in beetles subsequently infected with the entomopathogen Pseudomonas entomophila. The RNAi-triggered susceptibility to this pathogen was reversed by the injection of a synthetic Col1 peptide. We show that a native population is more susceptible to P. entomomophila infection than an invasive population. This is the first study demonstrating population-specific differences in the immune system of an invasive species and suggests that rapid gene expression changes and a highly adaptive immune system could promote pathogen resistance and thereby invasive performance. PMID- 29483514 TI - Spatiotemporal regulation of Aurora B recruitment ensures release of cohesion during C. elegans oocyte meiosis. AB - The formation of haploid gametes from diploid germ cells requires the regulated two-step release of sister chromatid cohesion (SCC) during the meiotic divisions. Here, we show that phosphorylation of cohesin subunit REC-8 by Aurora B promotes SCC release at anaphase I onset in C. elegans oocytes. Aurora B loading to chromatin displaying Haspin-mediated H3 T3 phosphorylation induces spatially restricted REC-8 phosphorylation, preventing full SCC release during anaphase I. H3 T3 phosphorylation is locally antagonized by protein phosphatase 1, which is recruited to chromosomes by HTP-1/2 and LAB-1. Mutating the N terminus of HTP-1 causes ectopic H3 T3 phosphorylation, triggering precocious SCC release without impairing earlier HTP-1 roles in homolog pairing and recombination. CDK-1 exerts temporal regulation of Aurora B recruitment, coupling REC-8 phosphorylation to oocyte maturation. Our findings elucidate a complex regulatory network that uses chromosome axis components, H3 T3 phosphorylation, and cell cycle regulators to ensure accurate chromosome segregation during oogenesis. PMID- 29483516 TI - MicroRNA Contents in Matrix Vesicles Produced by Growth Plate Chondrocytes are Cell Maturation Dependent. AB - Chondrocytes at different maturation states in the growth plate produce matrix vesicles (MVs), membrane organelles found in the extracellular matrix, with a wide range of contents, such as matrix processing enzymes and receptors for hormones. We have shown that MVs harvested from growth zone (GC) chondrocyte cultures contain abundant small RNAs, including miRNAs. Here, we determined whether RNA also exists in MVs produced by less mature resting zone (RC) chondrocytes and, if so, whether it differs from the RNA in MVs produced by GC cells. Our results showed that RNA, small RNA specifically, was present in RC MVs, and it was well-protected from RNase by the phospholipid membrane. A group of miRNAs was enriched in RC-MVs compared RC-cells, suggesting that miRNAs are selectively packaged into MVs. High throughput array and RNA sequencing showed that ~39% miRNAs were differentially expressed between RC-MVs and GC-MVs. Individual RT-qPCR also confirmed that miR-122-5p and miR-150-5p were expressed at significantly higher levels in RC-MVs compared to GC-MVs. This study showed that growth plate chondrocytes at different differentiation stages produce different MVs with different miRNA contents, further supporting extracellular vesicle miRNAs play a role as "matrisomes" that mediate the cell-cell communication in cartilage and bone development. PMID- 29483517 TI - A comparative analysis of surface and bulk contributions to second-harmonic generation in centrosymmetric nanoparticles. AB - Second-harmonic generation (SHG) from nanoparticles made of centrosymmetric materials provides an effective tool to characterize many important properties of photonic structures at the subwavelength scale. Here we study the relative contribution of surface and bulk effects to SHG for plasmonic and dielectric nanostructures made of centrosymmetric materials in both dispersive and non dispersive regimes. Our calculations of the far-fields generated by the nonlinear surface and bulk currents reveal that the size of the nanoparticle strongly influences the amount and relative contributions of the surface and bulk SHG effects. Importantly, our study reveals that, whereas for plasmonic nanoparticles the surface contribution is always dominant, the bulk and surface SHG effects can become comparable for dielectric nanoparticles, and thus they both should be taken into account when analyzing nonlinear optical properties of all-dielectric nanostructures. PMID- 29483519 TI - High-resolution 3D photopolymerization assisted by upconversion nanoparticles for rapid prototyping applications. AB - Three-dimensional (3D) rapid prototyping technology based on near-infrared light induced polymerization of photocurable compositions containing upconversion nanomaterials has been explored. For this aim, the rationally-designed core/shell upconversion nanoparticles NaYF4:Yb3+,Tm3+/NaYF4, with the distinct ultraviolet emitting lines and unprecedentedly high near-infrared to ultraviolet conversion efficiency of [Formula: see text] have been used. The upconverted ultraviolet photons were capable to efficiently activate photoinitiators contained in light sensitive resins under moderate intensities of NIR excitation below 10 W cm-2 and induce generation of radicals and photopolymerization in situ. Near infrared activated polymerization process, both at the millimeter and sub-micron scales, was investigated. Polymeric macro- and microstructures were fabricated by means of near infrared laser scanning photolithography in the volume of liquid photocurable compositions with focused laser light at 975 nm wavelength. Examination of the polymerization process in the vicinity of the nanoparticles shows strong differences in the rate of polymer shell growth on flat and edge nanoparticle sides. This phenomenon mainly defines the resolution of the demonstrated near infrared - ultraviolet 3D printing technology at the micrometer scale level. PMID- 29483518 TI - Cardiolipin exposure on the outer mitochondrial membrane modulates alpha synuclein. AB - Neuronal loss in Parkinson's disease (PD) is associated with aberrant mitochondrial function and impaired proteostasis. Identifying the mechanisms that link these pathologies is critical to furthering our understanding of PD pathogenesis. Using human pluripotent stem cells (hPSCs) that allow comparison of cells expressing mutant SNCA (encoding alpha-synuclein (alpha-syn)) with isogenic controls, or SNCA-transgenic mice, we show that SNCA-mutant neurons display fragmented mitochondria and accumulate alpha-syn deposits that cluster to mitochondrial membranes in response to exposure of cardiolipin on the mitochondrial surface. Whereas exposed cardiolipin specifically binds to and facilitates refolding of alpha-syn fibrils, prolonged cardiolipin exposure in SNCA-mutants initiates recruitment of LC3 to the mitochondria and mitophagy. Moreover, we find that co-culture of SNCA-mutant neurons with their isogenic controls results in transmission of alpha-syn pathology coincident with mitochondrial pathology in control neurons. Transmission of pathology is effectively blocked using an anti-alpha-syn monoclonal antibody (mAb), consistent with cell-to-cell seeding of alpha-syn. PMID- 29483520 TI - Cytoplasmic Transport Machinery of the SPF27 Homologue Num1 in Ustilago maydis. AB - In the phytopathogenic basidiomycete Ustilago maydis, the Num1 protein has a pivotal function in hyphal morphogenesis. Num1 functions as a core component of the spliceosome-associated Prp19/CDC5 complex (NTC). The interaction of Num1 with the kinesin motor Kin1 suggests a connection between a component of the splicing machinery and cytoplasmic trafficking processes. Previously it was shown that Num1 localizes predominantly in the nucleus; however, due to the diffraction limited spatial resolution of conventional optical microscopy, it was not possible to attribute the localization to specific structures within the cytoplasm. We have now employed super-resolution localization microscopy to visualize Num1 in the cytoplasm by fusing it to a tandem dimeric Eos fluorescent protein (tdEosFP). The Num1 protein is localized within the cytoplasm with an enhanced density in the vicinity of microtubules. Num1 movement is found predominantly close to the nucleus. Movement is dependent on its interaction partner Kin1, but independent of Kin3. Our results provide strong evidence that, in addition to its involvement in splicing in the nucleus, Num1 has an additional functional role in the cytosol connected to the Kin1 motor protein. PMID- 29483521 TI - Improving prediction of heart transplantation outcome using deep learning techniques. AB - The primary objective of this study is to compare the accuracy of two risk models, International Heart Transplantation Survival Algorithm (IHTSA), developed using deep learning technique, and Index for Mortality Prediction After Cardiac Transplantation (IMPACT), to predict survival after heart transplantation. Data from adult heart transplanted patients between January 1997 to December 2011 were collected from the UNOS registry. The study included 27,860 heart transplantations, corresponding to 27,705 patients. The study cohorts were divided into patients transplanted before 2009 (derivation cohort) and from 2009 (test cohort). The receiver operating characteristic (ROC) values, for the validation cohort, computed for one-year mortality, were 0.654 (95% CI: 0.629 0.679) for IHTSA and 0.608 (0.583-0.634) for the IMPACT model. The discrimination reached a C-index for long-term survival of 0.627 (0.608-0.646) for IHTSA, compared with 0.584 (0.564-0.605) for the IMPACT model. These figures correspond to an error reduction of 12% for ROC and 10% for C-index by using deep learning technique. The predicted one-year mortality rates for were 12% and 22% for IHTSA and IMPACT, respectively, versus an actual mortality rate of 10%. The IHTSA model showed superior discriminatory power to predict one-year mortality and survival over time after heart transplantation compared to the IMPACT model. PMID- 29483522 TI - Fe-oxide mineralogy of the Jiujiang red earth sediments and implications for Quaternary climate change, southern China. AB - Diffuse reflectance spectrophotometry (DRS) is a new, fast, and reliable method to characterize Fe-oxides in soils. The Fe-oxide mineralogy of the Jiujiang red earth sediments was investigated using DRS to investigate the climate evolution of southern China since the mid-Pleistocene. The DRS results show that hematite/(hematite + goethite) ratios [Hm/(Hm + Gt)] exhibit an upward decreasing trend within the Jiujiang section, suggesting a gradual climate change from warm and humid in the middle Pleistocene to cooler and drier in the late Pleistocene. Upsection trends toward higher (orthoclase + plagioclase)/quartz ratios [(Or + Pl)/Q] and magnetic susceptibility values (chilf) support this inference, which accords with global climate trends at that time. However, higher-frequency climatic subcycles observed in loess sections of northern China are not evident in the Jiujiang records, indicating a relatively lower climate sensitivity of the red earth sediments in southern China. PMID- 29483523 TI - Indomethacin Disrupts Autophagic Flux by Inducing Lysosomal Dysfunction in Gastric Cancer Cells and Increases Their Sensitivity to Cytotoxic Drugs. AB - NSAIDs inhibit tumorigenesis in gastrointestinal tissues and have been proposed as coadjuvant agents to chemotherapy. The ability of cancer epithelial cells to adapt to the tumour environment and to resist cytotoxic agents seems to depend on rescue mechanisms such as autophagy. In the present study we aimed to determine whether an NSAID with sensitizing properties such as indomethacin modulates autophagy in gastric cancer epithelial cells. We observed that indomethacin causes lysosomal dysfunction in AGS cells and promotes the accumulation of autophagy substrates without altering mTOR activity. Indomethacin enhanced the inhibitory effects of the lysosomotropic agent chloroquine on lysosome activity and autophagy, but lacked any effect when both functions were maximally reduced with another lysosome inhibitor (bafilomycin B1). Indomethacin, alone and in combination with chloroquine, also hindered the autophagic flux stimulated by the antineoplastic drug oxaliplatin and enhanced its toxic effect, increasing the rate of apoptosis/necrosis and undermining cell viability. In summary, our results indicate that indomethacin disrupts autophagic flux by disturbing the normal functioning of lysosomes and, by doing so, increases the sensitivity of gastric cancer cells to cytotoxic agents, an effect that could be used to overcome cancer cell resistance to antineoplastic regimes. PMID- 29483524 TI - Inhibition of Heat Shock proteins HSP90 and HSP70 induce oxidative stress, suppressing cotton fiber development. AB - Cotton fiber is a specialized unicellular structure useful for the study of cellular differentiation and development. Heat shock proteins (HSPs) have been shown to be involved in various developmental processes. Microarray data analysis of five Gossypium hirsutum genotypes revealed high transcript levels of GhHSP90 and GhHSP70 genes at different stages of fiber development, indicating their importance in the process. Further, we identified 26 and 55 members of HSP90 and HSP70 gene families in G. hirsutum. The treatment of specific inhibitors novobiocin (Nov; HSP90) and pifithrin/2-phenylethynesulfonamide (Pif; HSP70) in in-vitro cultured ovules resulted in a fewer number of fiber initials and retardation in fiber elongation. The molecular chaperone assay using bacterially expressed recombinant GhHSP90-7 and GhHSP70-8 proteins further confirmed the specificity of inhibitors. HSP inhibition disturbs the H2O2 balance that leads to the generation of oxidative stress, which consequently results in autophagy in the epidermal layer of the cotton ovule. Transmission electron microscopy (TEM) of inhibitor-treated ovule also corroborates autophagosome formation along with disrupted mitochondrial cristae. The perturbations in transcript profile of HSP inhibited ovules show differential regulation of different stress and fiber development-related genes and pathways. Altogether, our results indicate that HSP90 and HSP70 families play a crucial role in cotton fiber differentiation and development by maintaining cellular homeostasis. PMID- 29483525 TI - The Cue-Approach Task as a General Mechanism for Long-Term Non-Reinforced Behavioral Change. AB - Recent findings show that preferences for food items can be modified without external reinforcements using the cue-approach task. In the task, the mere association of food item images with a neutral auditory cue and a speeded button press, resulted in enhanced preferences for the associated stimuli. In a series of 10 independent samples with a total of 255 participants, we show for the first time that using this non-reinforced method we can enhance preferences for faces, fractals and affective images, as well as snack foods, using auditory, visual and even aversive cues. This change was highly durable in follow-up sessions performed one to six months after training. Preferences were successfully enhanced for all conditions, except for negative valence items. These findings promote our understanding of non-reinforced change, suggest a boundary condition for the effect and lay the foundation for development of novel applications. PMID- 29483526 TI - Widespread erosion on high plateaus during recent glaciations in Scandinavia. AB - Glaciers create some of Earth's steepest topography; yet, many areas that were repeatedly overridden by ice sheets in the last few million years include extensive plateaus. The distinct geomorphic contrast between plateaus and the glacial troughs that dissect them has sustained two long-held hypotheses: first, that ice sheets perform insignificant erosion beyond glacial troughs, and, second, that the plateaus represent ancient pre-glacial landforms bearing information of tectonic and geomorphic history prior to Pliocene-Pleistocene global cooling (~3.5 Myr ago). Here we show that the Fennoscandian ice sheets drove widespread erosion across plateaus far beyond glacial troughs. We apply inverse modelling to 118 new cosmogenic 10Be and 26Al measurements to quantify ice sheet erosion on the plateaus fringing the Sognefjorden glacial trough in western Norway. Our findings demonstrate substantial modification of the pre glacial landscape during the Quaternary, and that glacial erosion of plateaus is important when estimating the global sediment flux to the oceans. PMID- 29483527 TI - The influence of a high fat diet on bone and soft tissue formation in Matrix Gla Protein knockout mice. AB - Studies suggest bone growth and development are influenced by maternal nutrition, during intrauterine and early postnatal life. This study assessed the role of MGP and a maternal high fat diet on vitamin K-dependent proteins' gene expression and their impact on bone formation. Knockout (KO) offspring were smaller than wild type (WT) littermates, yet possessed the same volume of intrascapular brown adipose tissue. The total proportion of body fat was reduced, but only in animals on a control diet. Lung air volume was observed to be comparable in both KO and WT animals on the same diet. The degree of aortic calcification was reduced in KO animals maintained on a HF diet. KO females on the high fat diet showed reduced cortical bone volume and thickness in the femur and tibia. Gene expression levels of GGCX and VKOR were reduced in control fed KO animals suggesting a potential link between gene expression levels of MGP, GGCX, and VKOR and total volumes of bone, calcified soft tissue, and iBAT; with implications for modulation of body length and mass. Our results confirm the important role for vitamin K in bone and calcified soft tissue, but now extend this role to include iBAT. PMID- 29483528 TI - Characterization of the quinol-dependent nitric oxide reductase from the pathogen Neisseria meningitidis, an electrogenic enzyme. AB - Bacterial nitric oxide reductases (NORs) catalyse the reduction of NO to N2O and H2O. NORs are found either in denitrification chains, or in pathogens where their primary role is detoxification of NO produced by the immune defense of the host. Although NORs belong to the heme-copper oxidase superfamily, comprising proton pumping O2-reducing enzymes, the best studied NORs, cNORs (cytochrome c dependent), are non-electrogenic. Here, we focus on another type of NOR, qNOR (quinol-dependent). Recombinant qNOR from Neisseria meningitidis, a human pathogen, purified from Escherichia coli, showed high catalytic activity and spectroscopic properties largely similar to cNORs. However, in contrast to cNOR, liposome-reconstituted qNOR showed respiratory control ratios above two, indicating that NO reduction by qNOR was electrogenic. Further, we determined a 4.5 A crystal structure of the N. meningitidis qNOR, allowing exploration of a potential proton transfer pathway from the cytoplasm by mutagenesis. Most mutations had little effect on the activity, however the E-498 variants were largely inactive, while the corresponding substitution in cNOR was previously shown not to induce significant effects. We thus suggest that, contrary to cNOR, the N. meningitidis qNOR uses cytoplasmic protons for NO reduction. Our results allow possible routes for protons to be discussed. PMID- 29483529 TI - Increased mechanical loading through controlled swimming exercise induces bone formation and mineralization in adult zebrafish. AB - Exercise promotes gain in bone mass through adaptive responses of the vertebrate skeleton. This mechanism counteracts age- and disease-related skeletal degradation, but remains to be fully understood. In life sciences, zebrafish emerged as a vertebrate model that can provide new insights into the complex mechanisms governing bone quality. To test the hypothesis that musculoskeletal exercise induces bone adaptation in adult zebrafish and to characterize bone reorganization, animals were subjected to increased physical exercise for four weeks in a swim tunnel experiment. Cellular, structural and compositional changes of loaded vertebrae were quantified using integrated high-resolution analyses. Exercise triggered rapid bone adaptation with substantial increases in bone forming osteoblasts, bone volume and mineralization. Clearly, modeling processes in zebrafish bone resemble processes in human bone. This study highlights how exercise experiments in adult zebrafish foster in-depth insight into aging related bone diseases and can thus catalyze the search for appropriate prevention and new treatment options. PMID- 29483530 TI - An olfactory virtual reality system for mice. AB - All motile organisms use spatially distributed chemical features of their surroundings to guide their behaviors, but the neural mechanisms underlying such behaviors in mammals have been difficult to study, largely due to the technical challenges of controlling chemical concentrations in space and time during behavioral experiments. To overcome these challenges, we introduce a system to control and maintain an olfactory virtual landscape. This system uses rapid flow controllers and an online predictive algorithm to deliver precise odorant distributions to head-fixed mice as they explore a virtual environment. We establish an odor-guided virtual navigation behavior that engages hippocampal CA1 "place cells" that exhibit similar properties to those previously reported for real and visual virtual environments, demonstrating that navigation based on different sensory modalities recruits a similar cognitive map. This method opens new possibilities for studying the neural mechanisms of olfactory-driven behaviors, multisensory integration, innate valence, and low-dimensional sensory spatial processing. PMID- 29483531 TI - Agrochemicals increase risk of human schistosomiasis by supporting higher densities of intermediate hosts. AB - Schistosomiasis is a snail-borne parasitic disease that ranks among the most important water-based diseases of humans in developing countries. Increased prevalence and spread of human schistosomiasis to non-endemic areas has been consistently linked with water resource management related to agricultural expansion. However, the role of agrochemical pollution in human schistosome transmission remains unexplored, despite strong evidence of agrochemicals increasing snail-borne diseases of wildlife and a projected 2- to 5-fold increase in global agrochemical use by 2050. Using a field mesocosm experiment, we show that environmentally relevant concentrations of fertilizer, a herbicide, and an insecticide, individually and as mixtures, increase densities of schistosome infected snails by increasing the algae snails eat and decreasing densities of snail predators. Epidemiological models indicate that these agrochemical effects can increase transmission of schistosomes. Identifying agricultural practices or agrochemicals that minimize disease risk will be critical to meeting growing food demands while improving human wellbeing. PMID- 29483532 TI - Genetic loci simultaneously controlling lignin monomers and biomass digestibility of rice straw. AB - Lignin content and composition are crucial factors affecting biomass digestibility. Exploring the genetic loci simultaneously affecting lignin relevant traits and biomass digestibility is a precondition for lignin genetic manipulation towards energy crop breeding. In this study, a high-throughput platform was employed to assay the lignin content, lignin composition and biomass enzymatic digestibility of a rice recombinant inbred line population. Correlation analysis indicated that the absolute content of lignin monomers rather than lignin content had negative effects on biomass saccharification, whereas the relative content of p-hydroxyphenyl unit and the molar ratio of p-hydroxyphenyl unit to guaiacyl unit exhibited positive roles. Eight QTL clusters were identified and four of them affecting both lignin composition and biomass digestibility. The additive effects of clustered QTL revealed consistent relationships between lignin-relevant traits and biomass digestibility. Pyramiding rice lines containing the above four positive alleles for increasing biomass digestibility were selected and showed comparable lignin content, decreased syringyl or guaiacyl unit and increased molar percentage of p hydroxyphenyl unit, the molar ratio of p-hydroxyphenyl unit to guaiacyl unit and sugar releases. More importantly, the lodging resistance and eating/cooking quality of pyramiding lines were not sacrificed, indicating the QTL information could be applied to select desirable energy rice lines. PMID- 29483534 TI - Osteocyte morphology and orientation in relation to strain in the jaw bone. AB - Bone mass is important for dental implant success and is regulated by mechanoresponsive osteocytes. We aimed to investigate the relationship between the levels and orientation of tensile strain and morphology and orientation of osteocytes at different dental implant positions in the maxillary bone. Bone biopsies were retrieved from eight patients who underwent maxillary sinus-floor elevation with beta-tricalcium phosphate prior to implant placement. Gap versus free-ending locations were compared using 1) a three-dimensional finite-element model of the maxilla to predict the tensile strain magnitude and direction and 2) histology and histomorphometric analyses. The finite-element model predicted larger, differently directed tensile strains in the gap versus free-ending locations. The mean percentage of mineralised residual native-tissue volume, osteocyte number (mean +/- standard deviations: 97 +/- 40/region-of-interest), and osteocyte shape (~90% elongated, ~10% round) were similar for both locations. However, the osteocyte surface area was 1.5-times larger in the gap than in the free-ending locations, and the elongated osteocytes in these locations were more cranially caudally oriented. In conclusion, significant differences in the osteocyte surface area and orientation seem to exist locally in the maxillary bone, which may be related to the tensile strain magnitude and orientation. This might reflect local differences in the osteocyte mechanosensitivity and bone quality, suggesting differences in dental implant success based on the location in the maxilla. PMID- 29483535 TI - Age variation in the body coloration of the orb-weaver spider Alpaida tuonabo and its implications on foraging. AB - Spiders show a repertoire of strategies to increase their foraging success. In particular, some orb-weaver spiders use attractive body colorations to lure prey. Interestingly, coloration varies with age in many species, which may result in ontogenetic variation of foraging success. By using field observations, laboratory experiments and spectrophotometric analysis, we investigated whether pale juveniles and bright adults of the orb-weaver Alpaida tuonabo use different foraging strategies due to ontogenetic variation in coloration. Field observations revealed that foraging success of juveniles and adults was influenced by web properties. However, foraging success increased with body size only in adults, supporting the idea that larger individuals produce a stronger visual signal for prey. The attractiveness of the adult coloration for prey was confirmed in the laboratory with frame-web-choice experiments, in which webs bearing a spider intercepted more bees than empty webs. Our spectrophotometric analysis suggests that the yellow coloration may produce the deceiving signal for prey. Moreover, we identified potential alternative foraging strategies: cryptic juveniles at higher heights and 'attractive' adults at lower heights. This study reveals how ontogenetic colour variation may favour the use of alternative foraging strategies in orb-weaver spiders and reduces intraspecific competition. PMID- 29483533 TI - Comprehensive integrative analyses identify GLT8D1 and CSNK2B as schizophrenia risk genes. AB - Recent genome-wide association studies (GWAS) have identified multiple risk loci that show strong associations with schizophrenia. However, pinpointing the potential causal genes at the reported loci remains a major challenge. Here we identify candidate causal genes for schizophrenia using an integrative genomic approach. Sherlock integrative analysis shows that ALMS1, GLT8D1, and CSNK2B are schizophrenia risk genes, which are validated using independent brain expression quantitative trait loci (eQTL) data and integrative analysis method (SMR). Consistently, gene expression analysis in schizophrenia cases and controls further supports the potential role of these three genes in the pathogenesis of schizophrenia. Finally, we show that GLT8D1 and CSNK2B knockdown promote the proliferation and inhibit the differentiation abilities of neural stem cells, and alter morphology and synaptic transmission of neurons. These convergent lines of evidence suggest that the ALMS1, CSNK2B, and GLT8D1 genes may be involved in pathophysiology of schizophrenia. PMID- 29483536 TI - Spider dragline silk composite films doped with linear and telechelic polyalanine: Effect of polyalanine on the structure and mechanical properties. AB - Spider dragline silks have attracted intensive attention as eco-friendly tough materials because of their excellent mechanical property and biomass-based origin. Composite films based on a recombinant spider dragline silk protein (ADF3) from Araneus diadematus were prepared by doping with linear or telechelic poly(L-alanine) (L- or T-polyA, respectively) as a reinforcing agent. Higher tensile strength and toughness of the composite films were achieved with the addition of polyA compared with the tensile strength and toughness of the silk only film. The difference in the reinforcing behavior between L- and T-polyA was associated with their primary structures, which were revealed by wide angle X-ray diffraction analysis. L-polyA showed a tendency to aggregate in the composite films and induce crystallization of the inherent silk beta-sheet to afford rigid but brittle films. By contrast, T-polyA dispersion in the composite films led to the formation of beta-sheet crystal of both T-polyA and the inherent silk, which imparted high strength and toughness to the silk films. PMID- 29483537 TI - Correlation between the timing of autonomous selfing and floral traits: a comparative study from three selfing Gentianopsis species (Gentianaceae). AB - About 20% of angiosperms employ self-fertilization as their main mating strategy. In this study, we aimed to examine how the selfing timing correlated with floral traits in three Gentianopsis species in which autonomous selfing is achieved through filament elongation. Although the three Gentianopsis species exhibit no significant variation in their capacity for autonomous selfing, flowers of G. grandis last longer, are larger and have a higher corolla biomass, P/O ratios and male biomass allocation than those of G. paludosa, and especially those of G. contorta. Autonomous selfing occurs in the early floral life of G. paludosa and G. contorta and in the later floral life of G. grandis. Seed production mainly results from autonomous selfing in G. paludosa and G. contorta; however, G. grandis could be more described as having a mixed mating system. We suggest that autonomous selfing in later floral life increases the chance of cross-pollination prior to this, while autonomous selfing in early floral life offers a selective advantage to plants by reducing the resource investment in traits that may increase pollinator attraction and visitation. PMID- 29483538 TI - Morphine induces changes in the gut microbiome and metabolome in a morphine dependence model. AB - Opioid analgesics are frequently prescribed in the United States and worldwide. However, serious comorbidities, such as dependence, tolerance, immunosuppression and gastrointestinal disorders limit their long-term use. In the current study, a morphine-murine model was used to investigate the role of the gut microbiome and metabolome as a potential mechanism contributing to the negative consequences associated with opioid use. Results reveal a significant shift in the gut microbiome and metabolome within one day following morphine treatment compared to that observed after placebo. Morphine-induced gut microbial dysbiosis exhibited distinct characteristic signatures, including significant increase in communities associated with pathogenic function, decrease in communities associated with stress tolerance and significant impairment in bile acids and morphine-3 glucuronide/morphine biotransformation in the gut. Moreover, expansion of Enterococcus faecalis was strongly correlated with gut dysbiosis following morphine treatment, and alterations in deoxycholic acid (DCA) and phosphatidylethanolamines (PEs) were associated with opioid-induced metabolomic changes. Collectively, these results indicate that morphine induced distinct alterations in the gut microbiome and metabolome, contributing to negative consequences associated with opioid use. Therapeutics directed at maintaining microbiome homeostasis during opioid use may reduce the comorbidities associated with opioid use for pain management. PMID- 29483539 TI - Genome sequencing and analysis of Alcaligenes faecalis subsp. phenolicus MB207. AB - Bacteria within the genus Alcaligenes, exhibit diverse properties but remain largely unexplored at genome scale. To shed light on the genome structure, heterogeneity and traits of Alcaligenes species, the genome of a tannery effluent isolated Alcaligenes faecalis subsp. phenolicus MB207 was sequenced and assembled. The genome was compared to the whole genome sequences of genus Alcaligenes present in the National Centre for Biotechnology Information database. Core, pan and species specific gene sequences i.e. singletons were identified. Members of this genus did not portray exceptional genetic heterogeneity or conservation and out of 5,166 protein coding genes from pooled genome dataset, 2429 (47.01%) contributed to the core, 1193 (23.09%) to singletons and 1544 (29.88%) to accessory genome. Secondary metabolite forming apparatus, antibiotic production and resistance was also profiled. Alcaligenes faecalis subsp. phenolicus MB207 genome consisted of a copious amount of bioremediation genes i.e. metal tolerance and xenobiotic degrading genes. This study marks this strain as a prospective eco-friendly bacterium with numerous benefits for the environment related research. Availability of the whole genome sequence heralds an opportunity for researchers to explore enzymes and apparatus for sustainable environmental clean-up as well as important compounds/substance production. PMID- 29483540 TI - An automated method for the analysis of food intake behaviour in Caenorhabditis elegans. AB - The study of mechanisms that govern feeding behaviour and its related disorders is a matter of global health interest. The roundworm Caenorhabditis elegans is becoming a model organism of choice to study these conserved pathways. C. elegans feeding depends on the contraction of the pharynx (pumping). Thanks to the worm transparency, pumping can be directly observed under a stereoscope. Therefore, C. elegans feeding has been historically investigated by counting pharyngeal pumping or by other indirect approaches. However, those methods are short-term, time consuming and unsuitable for independent measurements of sizable numbers of individuals. Although some particular devices and long-term methods have been lately reported, they fail in the automated, scalable and/or continuous aspects. Here we present an automated bioluminescence-based method for the analysis and continuous monitoring of worm feeding in a multi-well format. We validate the method using genetic, environmental and pharmacological modulators of pharyngeal pumping. This flexible methodology allows studying food intake at specific time points or during longer periods of time, in single worms or in populations at any developmental stage. Additionally, changes in feeding rates in response to differential metabolic status or external environmental cues can be monitored in real time, allowing accurate kinetic measurements. PMID- 29483541 TI - Factors influencing intention to obtain the HPV vaccine in South East Asian and Western Pacific regions: A systematic review and meta-analysis. AB - Since licensing in 2006, there has been poor uptake of the HPV vaccine among the targeted population in the South East Asia Region (SEAR) and Western Pacific Region (WPR). A systematic review was conducted to identify the studies exploring the relationship between factors and intention for HPV vaccination among women in SEAR and WPR countries. Nineteen studies were identified as suitable for qualitative synthesis, and three as suitable for meta-analysis. Most women had a positive intention to have an HPV vaccine (range 57%-85%). Having a positive intention to vaccinate was significantly higher among women not aware of HPV infection (OR: 1.34, 95% CI: 1.02-1.76) and HPV vaccine (OR: 1.57, 95% CI: 1.26 1.96). Lower knowledge level and less confidence in safety and efficacy of the vaccine, negatively affected intention to vaccinate. Perceiving the vaccine to be expensive, low perception of contracting HPV infection and cervical cancer, and lack of concrete recommendations from healthcare providers also negatively affected intention to vaccinate. This review suggests the decision-making processes of women in SEAR and WPR is influenced by the cost of vaccination, perceived efficacy and safety of vaccine, provision of information on vaccination, and the awareness about HPV infection and the HPV vaccine. PMID- 29483543 TI - Fermentation and kinetics characteristics of a bioflocculant from potato starch wastewater and its application. AB - Potato starch wastewater was used as fermentation medium for Rhodococcus erythropolis to produce bioflocculant. Kinetics of cell growth and bioflocculant production were firstly constructed. After fermentation for 60 h, 0.97 g of bioflocculant with polysaccharides nature was extracted from 1 L of fermentation liquor. Kinetics characteristics showed that cell growth and bioflocculant production could be simulated well with Logistic and Luedeking-Piret equations, respectively. When R. erythropolis was in logarithm growth phase, COD, ammonium, and TP of the potato starch wastewater medium were rapidly down to 1736, 188, and 146 mg/L, respectively, from 7836, 975, and 712 mg/L, while the medium's exactly pH value was almost not changed. Furthermore, bioflocculant flocculation can be used as an effective pretreatment way for potato starch wastewater, and it was feasible in actual treatment projects in Ronghua Starch Co., Ltd., Sichuan Province. PMID- 29483542 TI - Understanding the high L-valine production in Corynebacterium glutamicum VWB-1 using transcriptomics and proteomics. AB - Toward the elucidation of the advanced mechanism of L-valine production by Corynebacterium glutamicum, a highly developed industrial strain VWB-1 was analyzed, employing the combination of transcriptomics and proteomics methods. The transcriptional level of 1155 genes and expression abundance of 96 proteins were changed significantly by the transcriptome and proteome comparison of VWB-1 and ATCC 13869. It was indicated that the key genes involved in the biosynthesis of L-valine, ilvBN, ilvC, ilvD, ilvE were up-regulated in VWB-1, which together made prominent contributions in improving the carbon flow towards L-valine. The L leucine and L-isoleucine synthesis ability were weakened according to the down regulation of leuB and ilvA. The up-regulation of the branched chain amino acid transporter genes brnFE promoted the L-valine secretion capability of VWB-1. The NADPH and ATP generation ability of VWB-1 were strengthened through the up regulation of the genes involved in phosphate pentose pathway and TCA pathway. Pyruvate accumulation was achieved through the weakening of the L-lactate, acetate and L-alanine pathways. The up-regulation of the genes coding for elongation factors and ribosomal proteins were beneficial for L-valine synthesis in C. glutamicum. All information acquired were useful for the genome breeding of better industrial L-valine producing strains. PMID- 29483545 TI - High-performance Platinum-free oxygen reduction reaction and hydrogen oxidation reaction catalyst in polymer electrolyte membrane fuel cell. AB - The integration of polymer electrolyte membrane fuel cell (PEMFC) stack into vehicles necessitates the replacement of high-priced platinum (Pt)-based electrocatalyst, which contributes to about 45% of the cost of the stack. The implementation of high-performance and durable Pt metal-free catalyst for both oxygen reduction reaction (ORR) and hydrogen oxidation reaction (HOR) could significantly enable large-scale commercialization of fuel cell-powered vehicles. Towards this goal, a simple, scalable, single-step synthesis method was adopted to develop palladium-cobalt alloy supported on nitrogen-doped reduced graphene oxide (Pd3Co/NG) nanocomposite. Rotating ring-disk electrode (RRDE) studies for the electrochemical activity towards ORR indicates that ORR proceeds via nearly four-electron mechanism. Besides, the mass activity of Pd3Co/NG shows an enhancement of 1.6 times compared to that of Pd/NG. The full fuel cell measurements were carried out using Pd3Co/NG at the anode, cathode in conjunction with Pt/C and simultaneously at both anode and cathode. A maximum power density of 68 mW/cm2 is accomplished from the simultaneous use of Pd3Co/NG as both anode and cathode electrocatalyst with individual loading of 0.5 mg/cm2 at 60 degrees C without any backpressure. To the best of our knowledge, the present study is the first of its kind of a fully non-Pt based PEM full cell. PMID- 29483544 TI - Clinical Utility of FDG PET/CT in Patients with Autoimmune Pancreatitis: a Case Control Study. AB - Autoimmune pancreatitis (AIP) shares overlapping clinical features with pancreatic cancer (PC). Importantly, treatment of the two conditions is different. We investigated the clinical usefulness of 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in patients with suspected AIP before treatment. From September 2008 to July 2016, 53 patients with suspected AIP at National Taiwan University Hospital had PET/CT prior to therapy to exclude malignancy and evaluate the extent of inflammation. Their scans were compared with those from 61 PC patients. PET imaging features were analyzed using logistic regression. Significant differences in pancreatic tumor uptake morphology, maximum standardized uptake value, high-order primary tumor texture feature (i.e. high-gray level zone emphasis value), and numbers and location of extrapancreatic foci were found between AIP and PC. Using the prediction model, the area under curve of receiver-operator curve was 0.95 (P < 0.0001) with sensitivity, specificity, positive predictive, and negative predictive values of 90.6%, 84.0%, 87.9%, and 87.5% respectively, in differentiating AIP from PC. FDG PET/CT offers high sensitivity, albeit slightly lower specificity in differentiating AIP from PC. Nonetheless, additional systemic inflammatory foci detected by the whole body PET/CT help confirm diagnosis of AIP in these patients before initiating steroid therapy, especially when biopsy is inconclusive. PMID- 29483546 TI - Elastic net regularized regression for time-series analysis of plasma metabolome stability under sub-optimal freezing condition. AB - In this paper, the stability of the plasma metabolome at -20 degrees C for up to 30 days was evaluated using liquid chromatography-high resolution mass spectrometric metabolomics analysis. To follow the time-series deterioration of the plasma metabolome, the use of an elastic net regularized regression model for the prediction of storage time at -20 degrees C based on the plasma metabolomic profile, and the selection and ranking of metabolites with high temporal changes was demonstrated using the glmnet package in R. Out of 1229 (positive mode) and 1483 (negative mode) metabolite features, the elastic net model extracted 32 metabolites of interest in both positive and negative modes. L-gamma-glutamyl-L (iso)leucine (tentative identification) was found to have the highest time dependent change and significantly increased proportionally to the storage time of plasma at -20 degrees C (R2 = 0.6378 [positive mode], R2 = 0.7893 [negative mode], p-value < 0.00001). Based on the temporal profiles of the extracted metabolites by the model, results show only minimal deterioration of the plasma metabolome at -20 degrees C up to 1 month. However, majority of the changes appeared at around 12-15 days of storage. This allows scientists to better plan logistics and storage strategies for samples obtained from low-resource settings, where -80 degrees C storage is not guaranteed. PMID- 29483547 TI - Influent factors of gestational vitamin D deficiency and its relation to an increased risk of preterm delivery in Chinese population. AB - Gestational vitamin D deficiency (VDD) has been linked with adverse pregnant outcomes. To investigate influent factors of gestational VDD and its relation to the incidence of preterm delivery, total 3598 eligible mother-and-singleton offspring pairs were recruited. For serum 25(OH)D concentration, 941 pregnant women were sufficient, 1260 insufficient, and 1397 deficient. Further analysis showed that VDD was more prevalent in winter than in other seasons. Underweight but not overweight was a risk factor for gestational VDD. Multivitamin use reduced risk of gestational VDD. Interestingly, 8.23% delivered preterm infants among subjects with VDD (adjusted RR: 4.02; 95% CI: 2.33, 6.92) and 3.81% among subjects with gestational vitamin D insufficiency (VDI) (adjusted RR: 2.07; 95% CI: 1.16, 3.71). Moreover, 2.59% delivered early preterm infants among subjects with VDD (adjusted RR: 2.97; 95% CI: 1.41, 6.24) and 0.49% among subjects with VDI (adjusted RR: 0.54; 95% CI: 0.19, 1.51). The incidence of late preterm delivery was 5.64% among subjects with VDD (adjusted RR: 3.90; 95% CI: 2.26, 6.72) and 3.32% among subjects with VDI (adjusted RR: 2.09; 95% CI: 1.17, 3.74). In conclusion, pre-pregnancy BMI, seasonality and multivitamin use are influent factors of gestational vitamin D status. Gestational VDD is associated with an increased risk of preterm delivery in Chinese population. PMID- 29483549 TI - Magnetic properties and magnetocrystalline anisotropy of Nd2Fe17, Nd2Fe17X3, and related compounds. AB - The electronic and magnetic properties of Nd2Fe17 and Nd2Fe17X3 (X = C or N) compounds have been calculated using the first-principles density functional calculations. Among these, the nitrogen and carbon interstitial compounds exhibit all of the required properties such as a saturation moment of 1.6 T, Curie temperature of 700-750 K, however easy magnetic axis lies in the planar direction making them less attractive for permanent magnet applications. The calculated magnetocrystalline anisotropy energy is found to be -2.7 MJ/m3 for Nd2Fe17C3 and 4.7 MJ/m3 for Nd2Fe17N3. We further explored the possibility of changing the easy axis direction through La/Ce alloying at Nd site. Although the MAE is found to be smaller in magnitude for all the La/Ce alloys it still maintains planar direction. PMID- 29483548 TI - Sculpting nanoparticle dynamics for single-bacteria-level screening and direct binding-efficiency measurement. AB - Particle trapping and binding in optical potential wells provide a versatile platform for various biomedical applications. However, implementation systems to study multi-particle contact interactions in an optical lattice remain rare. By configuring an optofluidic lattice, we demonstrate the precise control of particle interactions and functions such as controlling aggregation and multi hopping. The mean residence time of a single particle is found considerably reduced from 7 s, as predicted by Kramer's theory, to 0.6 s, owing to the mechanical interactions among aggregated particles. The optofluidic lattice also enables single-bacteria-level screening of biological binding agents such as antibodies through particle-enabled bacteria hopping. The binding efficiency of antibodies could be determined directly, selectively, quantitatively and efficiently. This work enriches the fundamental mechanisms of particle kinetics and offers new possibilities for probing and utilising unprecedented biomolecule interactions at single-bacteria level. PMID- 29483550 TI - Oligonucleotide conjugated multi-functional adeno-associated viruses. AB - Recombinant adeno-associated viruses (AAVs) are among the most commonly used vehicles for in vivo gene delivery. However, their tropism is limited, and additionally their efficacy can be negatively affected by prevalence of neutralizing antibodies in sera. Methodologies to systematically engineer AAV capsid properties would thus be of great relevance. In this regard, we develop here multi-functional AAVs by engineering precision tethering of oligonucleotides onto the AAV surface, and thereby enabling a spectrum of nucleic-acid programmable functionalities. Towards this, we engineered genetically encoded incorporation of unnatural amino acids (UAA) bearing bio-orthogonal chemical handles onto capsid proteins. Via these we enabled site-specific coupling of oligonucleotides onto the AAV capsid surface using facile click chemistry. The resulting oligo-AAVs could be sequence specifically labeled, and also patterned in 2D using DNA array substrates. Additionally, we utilized these oligo conjugations to engineer viral shielding by lipid-based cloaks that efficaciously protected the AAV particles from neutralizing serum. We confirmed these 'cloaked AAVs' retained full functionality via their ability to transduce a range of cell types, and also enable robust delivery of CRISPR-Cas9 effectors. Taken together, we anticipate this programmable oligo-AAV system will have broad utility in synthetic biology and AAV engineering applications. PMID- 29483551 TI - Somatic Mitochondrial DNA Mutations in Diffuse Large B-Cell Lymphoma. AB - Diffuse Large B-Cell Lymphoma (DLBCL) is an aggressive hematological cancer for which mitochondrial metabolism may play an important role. Mitochondrial DNA (mtDNA) encodes crucial mitochondrial proteins, yet the relationship between mtDNA and DLBCL remains unclear. We analyzed the functional consequences and mutational spectra of mtDNA somatic mutations and private constitutional variants in 40 DLBCL tumour-normal pairs. While private constitutional variants occurred frequently in the D-Loop, somatic mutations were randomly distributed across the mitochondrial genome. Heteroplasmic constitutional variants showed a trend towards loss of heteroplasmy in the corresponding tumour regardless of whether the reference or variant allele was being lost, suggesting that these variants are selectively neutral. The mtDNA mutational spectrum showed minimal support for ROS damage and revealed strand asymmetry with increased C > T and A > G transitions on the heavy strand, consistent with a replication-associated mode of mutagenesis. These heavy strand transitions carried higher proportions of amino acid changes - which were also more pathogenic - than equivalent substitutions on the light strand. Taken together, endogenous replication-associated events underlie mtDNA mutagenesis in DLBCL and preferentially generate functionally consequential mutations. Yet mtDNA somatic mutations remain selectively neutral, suggesting that mtDNA-encoded mitochondrial functions may not play an important role in DLBCL. PMID- 29483552 TI - Activation of AMPK inhibits TGF-beta1-induced airway smooth muscle cells proliferation and its potential mechanisms. AB - The aims of the present study were to examine signaling mechanisms underlying transforming growth factor beta1 (TGF-beta1)-induced airway smooth muscle cells (ASMCs) proliferation and to determine the effect of adenosine monophosphate activated protein kinase (AMPK) activation on TGF-beta1-induced ASMCs proliferation and its potential mechanisms. TGF-beta1 reduced microRNA-206 (miR 206) level by activating Smad2/3, and this in turn up-regulated histone deacetylase 4 (HDAC4) and consequently increased cyclin D1 protein leading to ASMCs proliferation. Prior incubation of ASMCs with metformin induced AMPK activation and blocked TGF-beta1-induced cell proliferation. Activation of AMPK slightly attenuated TGF-beta1-induced miR-206 suppression, but dramatically suppressed TGF-beta1-caused HDAC4 up-expression and significantly increased HDAC4 phosphorylation finally leading to reduction of up-regulated cyclin D1 protein expression. Our study suggests that activation of AMPK modulates miR 206/HDAC4/cyclin D1 signaling pathway, particularly targeting on HDAC4, to suppress ASMCs proliferation and therefore has a potential value in the prevention and treatment of asthma by alleviating airway remodeling. PMID- 29483553 TI - Network Motifs Capable of Decoding Transcription Factor Dynamics. AB - Transcription factors (TFs) can encode the information of upstream signal in terms of its temporal activation dynamics. However, it remains unclear how different types of TF dynamics are decoded by downstream signalling networks. In this work, we studied all three-node transcriptional networks for their ability to distinguish two types of TF dynamics: amplitude modulation (AM), where the TF is activated with a constant amplitude, and frequency modulation (FM), where the TF activity displays an oscillatory behavior. We found two sets of network topologies: one set can differentially respond to AM TF signal but not to FM; the other set to FM signal but not to AM. Interestingly, there is little overlap between the two sets. We identified the prevalent topological features in each set and gave a mechanistic explanation as to why they can differentially respond to only one type of TF signal. We also found that some network topologies have a weak (not robust) ability to differentially respond to both AM and FM input signals by using different values of parameters for AM and FM cases. Our results provide a novel network mechanism for decoding different TF dynamics. PMID- 29483554 TI - Co-exposure to environmental carcinogens in vivo induces neoplasia-related hallmarks in low-genotoxicity events, even after removal of insult. AB - Addressing the risk of mixed carcinogens in vivo under environmentally-realistic scenarios is still a challenge. Searching for adequate biomarkers of exposure requires understanding molecular pathways and their connection with neoplasia related benchmark pathologies. Subjecting the zebrafish model to realistic concentrations of two genotoxicants and carcinogens, cadmium and benzo[a]pyrene, isolated and combined, yielded low levels of DNA damage. Altogether, the organisms' mechanisms of DNA repair, oxidative stress and phases I and II were not overwhelmed after two weeks of treatment. Still, transcriptional responses related to detoxification (epoxide hydrolase and UDP-glucuronosyltransferase) were higher in animals subjected to the combination treatment, inclusively following depuration. Nonetheless, inflammation and formation of hyperplasic foci in fish epithelia were more severe in animals exposed to the combined substances, showing slower recovery during depuration. Additionally, the combination treatment yielded unexpected increased expression of a ras-family oncogene homologue after depuration, with evidence for increased tp53 counter-response in the same period. The findings indicate that oncogene expression, cell proliferation and inflammation, may not require noticeable DNA damage to occur. Furthermore, albeit absent proof for neoplasic growth, the removal of chemical insult may promote tissue recovery but does not entirely clear molecular and histopathological endpoints that are commonly associated to neoplasia. PMID- 29483555 TI - Effect of friction on oxidative graphite intercalation and high-quality graphene formation. AB - Oxidative wet-chemical delamination of graphene from graphite is expected to become a scalable production method. However, the formation process of the intermediate stage-1 graphite sulfate by sulfuric acid intercalation and its subsequent oxidation are poorly understood and lattice defect formation must be avoided. Here, we demonstrate film formation of micrometer-sized graphene flakes with lattice defects down to 0.02% and visualize the carbon lattice by transmission electron microscopy at atomic resolution. Interestingly, we find that only well-ordered, highly crystalline graphite delaminates into oxo functionalized graphene, whereas other graphite grades do not form a proper stage 1 intercalate and revert back to graphite upon hydrolysis. Ab initio molecular dynamics simulations show that ideal stacking and electronic oxidation of the graphite layers significantly reduce the friction of the moving sulfuric acid molecules, thereby facilitating intercalation. Furthermore, the evaluation of the stability of oxo-species in graphite sulfate supports an oxidation mechanism that obviates intercalation of the oxidant. PMID- 29483556 TI - Signatures of human impact on self-organized vegetation in the Horn of Africa. AB - In many dryland environments, vegetation self-organizes into bands that can be clearly identified in remotely-sensed imagery. The status of individual bands can be tracked over time, allowing for a detailed remote analysis of how human populations affect the vital balance of dryland ecosystems. In this study, we characterize vegetation change in areas of the Horn of Africa where imagery taken in the early 1950s is available. We find that substantial change is associated with steep increases in human activity, which we infer primarily through the extent of road and dirt track development. A seemingly paradoxical signature of human impact appears as an increase in the widths of the vegetation bands, which effectively increases the extent of vegetation cover in many areas. We show that this widening occurs due to altered rates of vegetation colonization and mortality at the edges of the bands, and conjecture that such changes are driven by human-induced shifts in plant species composition. Our findings suggest signatures of human impact that may aid in identifying and monitoring vulnerable drylands in the Horn of Africa. PMID- 29483557 TI - Development of a numerical model to predict physiological strain of firefighter in fire hazard. AB - This paper aims to develop a numerical model to predict heat stress of firefighter under low-level thermal radiation. The model integrated a modified multi-layer clothing model with a human thermoregulation model. We took the coupled radiative and conductive heat transfer in the clothing, the size dependent heat transfer in the air gaps, and the controlling active and controlled passive thermal regulation in human body into consideration. The predicted core temperature and mean skin temperature from the model showed a good agreement with the experimental results. Parametric study was conducted and the result demonstrated that the radiative intensity had a significant influence on the physiological heat strain. The existence of air gap showed positive effect on the physiological heat strain when air gap size is small. However, when the size of air gap exceeds 6 mm, a different trend was observed due to the occurrence of natural convection. Additionally, the time length for the existence of the physiological heat strain was greater than the existence of the skin burn under various heat exposures. The findings obtained in this study provide a better understanding of the physiological strain of firefighter and shed light on textile material engineering for achieving higher protective performance. PMID- 29483558 TI - Radiosensitization Effect of Talazoparib, a Parp Inhibitor, on Glioblastoma Stem Cells Exposed to Low and High Linear Energy Transfer Radiation. AB - Despite continuous improvements in treatment of glioblastoma, tumor recurrence and therapy resistance still occur in a high proportion of patients. One underlying reason for this radioresistance might be the presence of glioblastoma cancer stem cells (GSCs), which feature high DNA repair capability. PARP protein plays an important cellular role by detecting the presence of damaged DNA and then activating signaling pathways that promote appropriate cellular responses. Thus, PARP inhibitors (PARPi) have recently emerged as potential radiosensitizing agents. In this study, we investigated the preclinical efficacy of talazoparib, a new PARPi, in association with low and high linear energy transfer (LET) irradiation in two GSC cell lines. Reduction of GSC fraction, impact on cell proliferation, and cell cycle arrest were evaluated for each condition. All combinations were compared with a reference schedule: photonic irradiation combined with temozolomide. The use of PARPi combined with photon beam and even more carbon beam irradiation drastically reduced the GSC frequency of GBM cell lines in vitro. Furthermore, talazoparib combined with irradiation induced a marked and prolonged G2/M block, and decreased proliferation. These results show that talazoparib is a new candidate that effects radiosensitization in radioresistant GSCs, and its combination with high LET irradiation, is promising. PMID- 29483559 TI - The effectiveness, reproducibility, and durability of tailored mobile coaching on diabetes management in policyholders: A randomized, controlled, open-label study. AB - This randomized, controlled, open-label study conducted in Kangbuk Samsung Hospital evaluated the effectiveness, reproducibility, and durability of tailored mobile coaching (TMC) on diabetes management. The participants included 148 Korean adult policyholders with type 2 diabetes divided into the Intervention Maintenance (I-M) group (n = 74) and Control-Intervention (C-I) group (n = 74). Intervention was the addition of TMC to typical diabetes care. In the 6-month phase 1, the I-M group received TMC, and the C-I group received their usual diabetes care. During the second 6-month phase 2, the C-I group received TMC, and the I-M group received only regular information messages. After the 6-month phase 1, a significant decrease (0.6%) in HbA1c levels compared with baseline values was observed in only the I-M group (from 8.1 +/- 1.4% to 7.5 +/- 1.1%, P < 0.001 based on a paired t-test). At the end of phase 2, HbA1c levels in the C-I group decreased by 0.6% compared with the value at 6 months (from 7.9 +/- 1.5 to 7.3 +/ 1.0, P < 0.001 based on a paired t-test). In the I-M group, no changes were observed. Both groups showed significant improvements in frequency of blood glucose testing and exercise. In conclusion, addition of TMC to conventional treatment for diabetes improved glycemic control, and this effect was maintained without individualized message feedback. PMID- 29483560 TI - Light Emission from Plasmonic Nanostructures Enhanced with Fluorescent Nanodiamonds. AB - In the surface-enhanced fluorescence (SEF) process, it is well known that the plasmonic nanostructure can enhance the light emission of fluorescent emitters. With the help of atomic force microscopy, a hybrid system consisting of a fluorescent nanodiamond and a gold nanoparticle was assembled step-by-step for in situ optical measurements. We demonstrate that fluorescent emitters can also enhance the light emission from gold nanoparticles which is judged through the intrinsic anti-Stokes emission owing to the nanostructures. The light emission intensity, spectral shape, and lifetime of the hybrid system were dependent on the coupling configuration. The interaction between gold nanoparticles and fluorescent emitter was modelled based on the concept of a quantised optical cavity by considering the nanodiamond and the nanoparticle as a two-level energy system and a nanoresonator, respectively. The theoretical calculations reveal that the dielectric antenna effect can enhance the local field felt by the nanoparticle, which contributes more to the light emission enhancement of the nanoparticles rather than the plasmonic coupling effect. The findings reveal that the SEF is a mutually enhancing process. This suggests the hybrid system should be considered as an entity to analyse and optimise surface-enhanced spectroscopy. PMID- 29483561 TI - Lightning initiation: Strong pulses of VHF radiation accompany preliminary breakdown. AB - We analyze lightning initiation process using magnetic field waveforms of preliminary breakdown (PB) pulses observed at time scales of a few tens of microseconds by a broad-band receiver. We compare these pulses with sources of narrow-band very high frequency (VHF) radiation at 60-66 MHz recorded by two separate Lightning Mapping Arrays (LMAs). We find that almost none of the observed PB pulses correspond to geo-located VHF radiation sources, in agreement with previous results and with the hypothesis that processes generating VHF radiation and PB pulses are only weakly related. However, our detailed analysis discovers that individual peaks of strong VHF radiation seen by separate LMA stations correspond surprisingly well to the PB pulses. This result shows that electromagnetic radiation generated during fast stepwise extension of developing lightning channels is spread over a large interval of frequencies. We also show that intense VHF radiation abruptly starts with the first PB pulse and that it is then continuously present during the entire PB phase of developing discharges. PMID- 29483562 TI - Morphological evidence of telocytes in human synovium. AB - A new cell type named telocyte (i.e. cell with distinctive prolongations called telopodes) has recently been identified in the stroma of various organs in humans. However, no study has yet reported the existence of telocytes in the synovial membrane of diarthrodial joints. This work was therefore undertaken to search for telocytes in the normal human synovium using transmission electron microscopy, immunohistochemistry and immunofluorescence. Ultrastructural analyses demonstrated the presence of numerous spindle-shaped telocytes in the whole synovial sublining layer. Synovial telocytes exhibited very long and thin moniliform telopodes and were particularly concentrated at the boundary between the lining and sublining layers and around blood vessels. Light microscopy confirmed the presence of CD34-positive telocytes in the aforementioned locations. Moreover, synovial telocytes coexpressed CD34 and platelet-derived growth factor receptor alpha. Double immunostaining further allowed to unequivocally differentiate synovial telocytes (CD34-positive/CD31-negative) from vascular endothelial cells (CD34-positive/CD31-positive). The in vitro examination of fibroblast-like synoviocyte primary cultures revealed the coexistence of different cell types, including CD34-positive telocytes projecting typical moniliform telopodes. In conclusion, our work provides the first evidence that telocytes do exist in the human synovium and lays the groundwork for future studies on synovial telocytes in a variety of degenerative and destructive joint diseases. PMID- 29483563 TI - The competing effects of microbially derived polymeric and low molecular-weight substances on the dispersibility of CeO2 nanoparticles. AB - To understand the competing effects of the components in extracellular substances (ES), polymeric substances (PS) and low-molecular-weight small substances (SS) <1 kDa derived from microorganisms, on the colloidal stability of cerium dioxide nanoparticles (CeNPs), we investigated their adsorption to sparingly soluble CeNPs at room temperature at pH 6.0. The ES was extracted from the fungus S. cerevisiae. The polypeptides and phosphates in all components preferentially adsorbed onto the CeNPs. The zeta potentials of ES + CeNPs, PS + CeNPs, and SS + CeNPs overlapped on the plot of PS itself, indicating the surface charge of the polymeric substances controls the zeta potentials. The sizes of the CeNP aggregates, 100-1300 nm, were constrained by the zeta potentials. The steric barrier derived from the polymers, even in SS, enhanced the CeNP dispersibility at pH 1.5-10. Consequently, the PS and SS had similar effects on modifying the CeNP surfaces. The adsorption of ES, which contains PS + SS, can suppress the aggregation of CeNPs over a wider pH range than that for PS only. The present study addresses the non-negligible effects of small-sized molecules derived from microbial activity on the migration of CeNP in aquatic environments, especially where bacterial consortia prevail. PMID- 29483564 TI - Functional Brain States Measure Mentor-Trainee Trust during Robot-Assisted Surgery. AB - Mutual trust is important in surgical teams, especially in robot-assisted surgery (RAS) where interaction with robot-assisted interface increases the complexity of relationships within the surgical team. However, evaluation of trust between surgeons is challenging and generally based on subjective measures. Mentor Trainee trust was defined as assessment of mentor on trainee's performance quality and approving trainee's ability to continue performing the surgery. Here, we proposed a novel method of objectively assessing mentor-trainee trust during RAS based on patterns of brain activity of surgical mentor observing trainees. We monitored the EEG activity of a mentor surgeon while he observed procedures performed by surgical trainees and quantified the mentor's brain activity using functional and cognitive brain state features. We used methods from machine learning classification to identity key features that distinguish trustworthiness from concerning performances. Results showed that during simple surgical task, functional brain features are sufficient to classify trust. While, during more complex tasks, the addition of cognitive features could provide additional accuracy, but functional brain state features drive classification performance. These results indicate that functional brain network interactions hold information that may help objective trainee specific mentorship and aid in laying the foundation of automation in the human-robot shared control environment during RAS. PMID- 29483565 TI - Soil organic carbon and total nitrogen pools in permafrost zones of the Qinghai Tibetan Plateau. AB - There are several publications related to the soil organic carbon (SOC) on the Qinghai-Tibetan Plateau (QTP). However, most of these reports were from different parts of the plateau with various sampling depth. Here, we present the results from a systematic sampling and analysis of 200 soil pits. Most of the pits were deeper than 2 m from an east-west transect across the plateau. The SOC and total nitrogen (TN) pools of the 148 * 104 km2, the area of the permafrost zone, for the upper 2 m soils calculated from the vegetation map were estimated to be 17.07 Pg (interquartile range: 11.34-25.33 Pg) and 1.72 Pg (interquartile range: 1.08 2.06 Pg), respectively. We also predicted the distribution of land cover types in 2050 and 2070 using decision tree rules and climate scenarios, and then predicted SOC and TN pools of this region. The results suggested that the SOC and TN pools will decrease in the future. The results not only contribute to the carbon and nitrogen storage and stocks in the permafrost regions as a whole but most importantly, to our knowledge of the possible changes of C and N storage on the QTP in the future. PMID- 29483566 TI - Serum folate levels and urinary arsenic methylation profiles in the US population: NHANES, 2003-2012. AB - Arsenic is a prevalent environmental contaminant, and its folate-dependent methylation is important for detoxification in the body. In this study, we investigated the association between serum folate levels and methylation using data from the US National Health and Nutrition Examination Survey (NHANES) (2003 2012) (N = 11,016). Multivariate linear regression and penalized spline regression models were used to examine the association and possible upper limit of folate level regarding its impact on methylation in children (<=18 years) and adults (>18 years), respectively. Serum folate levels, methylation metabolites including urinary monomethylarsonic acid (MMA(V)) and dimethylarsinic acid (DMA(V)), and demographic variables were extracted from NHANES. Results showed that urinary percentage of DMA(V) (%DMA(V)) was positively associated with log(serum folate levels) after adjustment in children (beta = 1.93, p < 0.01); urinary percentage of MMA(V) (%MMA(V)) was positively associated with log (serum folate levels) after adjustment in adults (beta = 0.40, p < 0.01). No upper limit of folate level regarding its impact on arsenic methylation was identified. More than 50% of Non-Hispanic black and smokers with high total urinary arsenic levels had low serum folate levels. Our results indicate that folate promotes arsenic methylation, but the patterns are different in children versus in adults. Future interventions may be needed for the population exposed to high level of arsenic but with low serum folate to protect against the potential adverse health effects of arsenic. PMID- 29483567 TI - Simulation and spatiotemporal pattern of air temperature and precipitation in Eastern Central Asia using RegCM. AB - Central Asia is a region that has a large land mass, yet meteorological stations in this area are relatively scarce. To address this data issues, in this study, we selected two reanalysis datasets (the ERA40 and NCEP/NCAR) and downscaled them to 40 * 40 km using RegCM. Then three gridded datasets (the CRU, APHRO, and WM) that were extrapolated from the observations of Central Asian meteorological stations to evaluate the performance of RegCM and analyze the spatiotemporal distribution of precipitation and air temperature. We found that since the 1960s, the air temperature in Xinjiang shows an increasing trend and the distribution of precipitation in the Tianshan area is quite complex. The precipitation is increasing in the south of the Tianshan Mountains (Southern Xinjiang, SX) and decreasing in the mountainous areas. The CRU and WM data indicate that precipitation in the north of the Tianshan Mountains (Northern Xinjiang, NX) is increasing, while the APHRO data show an opposite trend. The downscaled results from RegCM are generally consistent with the extrapolated gridded datasets in terms of the spatiotemporal patterns. We believe that our results can provide useful information in developing a regional climate model in Central Asia where meteorological stations are scarce. PMID- 29483568 TI - Skew in ovarian activation depends on domicile size in phyllode-glueing thrips. AB - Costs and benefits of group living are a fundamental topic in behavioural ecology. Resource availability affects individuals' breeding prospects alone and in groups, as well as how reproduction is distributed within groups ("reproductive skew"). Here, in facultatively social thrips, we provide correlational evidence that breeding resources are associated with (1) whether solitary or social living is favoured, and (2) the degree of ovarian skew. Dunatothrips aneurae (Thysanoptera, Phlaeothripidae) cooperatively build silk "domiciles" on Australian Acacias, feeding exclusively from internal phyllode surfaces. Per capita productivity scaled differently with group size depending on domicile volume - females in small domiciles did better alone than in groups, whereas in large domiciles single and group-nesting females did equally well. Ovarian dissections revealed that in small domiciles some females were nonreproductive, indicating ovarian (i.e. reproductive) skew. Skew increased as domicile size decreased and group size increased. Breeders had smaller oocyte volume in smaller domiciles, especially those containing nonreproductives. These findings suggest group formation and reproductive skew in D. aneurae may be influenced by reproductive competition for breeding resources. Nonreproductive females in small domiciles may be reproductively suppressed, subfertile, or accumulating resources to reproduce. PMID- 29483569 TI - What's the harm? Risks and benefits of evolving rule-out sepsis practices. AB - Asymptomatic term and late-preterm newborns with risk factors for early onset sepsis commonly undergo laboratory evaluation and receive empiric antibiotic therapy. Some have challenged the rationale for current "rule-out sepsis" practices, arguing that they lead to unnecessary overtreatment and healthcare costs. A series of recent clinical studies has explored scheduled serial observations as an alternative to laboratory testing and empiric antibiotics for asymptomatic newborns with historical risk factors for sepsis. These studies have shared the conclusion that serial observation is safe and cost-effective for well appearing term and late-preterm babies, but they are also somewhat speculative because culture-proven early onset sepsis is an extremely low prevalence diagnosis. Here, we review the evolving consensus of optimal rule-out sepsis practices. We examine chorioamnionitis as an example of a problematic risk factor that has contributed to the controversy surrounding this topic. We also discuss how introduction of online sepsis risk calculators has allowed more precise delineation of a patient's chances of developing culture-proven infection. Finally, we analyze existing data from published studies to estimate the number needed to harm (NNH) when an observation-based strategy is used instead of a risk based approach. We conclude that, if harm is defined as death or serious sepsis complications such as hemodynamic instability or neurologic injury, the NNH is 1610, compared to an NNH of 7 and 2.9 for IV infiltrates and delayed breastfeeding, respectively-two common and potentially consequential complications of NICU admission for a rule-out sepsis. We believe that the differential between risk of serious harm from observing a well-appearing term or late-preterm newborn with risk factors for sepsis and the risk of less significant but common NICU complications argues in favor of the ongoing trend toward less aggressive management of newborns with sepsis risks. PMID- 29483570 TI - Protective humoral and CD4+ T cellular immune responses of Staphylococcus aureus vaccine MntC in a murine peritonitis model. AB - Staphylococcus aureus can cause different types of diseases from mild skin infections to life-threatening sepsis worldwide. Owing to the emergence and transmission of multidrug-resistant strains, developing an impactful immunotherapy especially vaccine control approach against S. aureus infections is increasingly encouraged and supported. S. aureus manganese transport protein C (MntC), which is a highly-conserved cell surface protein, can elicit protective immunity against S. aureus and Staphylococcus epidermidis. In this study, we evaluated the humoral immune response and CD4+ T cell-mediated immune responses in a mouse peritonitis model. The results showed that MntC-specific antibodies conferred an essential protection for mice to reduce invasion of S. aureus, which was corroborated via the opsonophagocytic killing assay and passive immunization experiment in mice, and moreover MntC-induced Th17 played a remarkable part in preventing S. aureus infection since the MntC-induced protective immunity decreased after neutralization of IL-17 by antibody in vivo and the Th17 adoptive transferred-mice could partly resist S. aureus challenge. In conclusion, we considered that the MntC-specific antibodies and MntC-specific Th17 cells play cooperative roles in the prevention of S. aureus infection. PMID- 29483571 TI - A small molecule inhibitor of Nicotinamide N-methyltransferase for the treatment of metabolic disorders. AB - Nicotinamide N-methyltransferase (NNMT) is a cytosolic enzyme that catalyzes the transfer of a methyl group from the co-factor S-adenosyl-L-methionine (SAM) onto the substrate, nicotinamide (NA) to form 1-methyl-nicotinamide (MNA). Higher NNMT expression and MNA concentrations have been associated with obesity and type-2 diabetes. Here we report a small molecule analog of NA, JBSNF-000088, that inhibits NNMT activity, reduces MNA levels and drives insulin sensitization, glucose modulation and body weight reduction in animal models of metabolic disease. In mice with high fat diet (HFD)-induced obesity, JBSNF-000088 treatment caused a reduction in body weight, improved insulin sensitivity and normalized glucose tolerance to the level of lean control mice. These effects were not seen in NNMT knockout mice on HFD, confirming specificity of JBSNF-000088. The compound also improved glucose handling in ob/ob and db/db mice albeit to a lesser extent and in the absence of weight loss. Co-crystal structure analysis revealed the presence of the N-methylated product of JBSNF-000088 bound to the NNMT protein. The N-methylated product was also detected in the plasma of mice treated with JBSNF-000088. Hence, JBSNF-000088 may act as a slow-turnover substrate analog, driving the observed metabolic benefits. PMID- 29483572 TI - Overexpression of preeclampsia induced microRNA-26a-5p leads to proteinuria in zebrafish. AB - So far the pathomechanism of preeclampsia in pregnancy is focussed on increased circulating levels of soluble fms-like tyrosin kinase-1 (sFLT-1) that neutralizes glomerular VEGF-A expression and prevents its signaling at the glomerular endothelium. As a result of changed glomerular VEGF-A levels endotheliosis and podocyte foot process effacement are typical morphological features of preeclampsia. Recently, microRNA-26a-5p (miR-26a-5p) was described to be also upregulated in the preeclamptic placenta. We found that miR-26a-5p targets VEGF-A expression by means of PIK3C2alpha in cultured human podocytes and that miR-26a 5p overexpression in zebrafish causes proteinuria, edema, glomerular endotheliosis and podocyte foot process effacement. Interestingly, recombinant zebrafish Vegf-Aa protein could rescue glomerular changes induced by miR-26a-5p. In a small pilot study, preeclamptic patients with podocyte damage identified by podocyturia, expressed significantly more urinary miR-26a-5p compared to healthy controls. Thus, functional and ultrastructural glomerular changes after miR-26a 5p overexpression can resemble the findings seen in preeclampsia and indicate a potential pathophysiological role of miR-26a-5p in addition to sFLT-1 in this disease. PMID- 29483573 TI - Social status and parasitism in male and female vertebrates: a meta-analysis. AB - Social status is an important predictor of parasite risk in vertebrates. To date, general frameworks to explain status-related variation in parasitism have remained elusive. In this meta-analysis, we evaluated five hypotheses proposed to explain status-related variation in parasitism in male and female vertebrates by leveraging variation in hierarchy type, mating system, parasite transmission mode, and allostatic load to test associated predictions. Our meta-analyses span 66 analyses (26 studies) of male vertebrates (two orders and five classes), and 62 analyses (13 studies) of female vertebrates (four vertebrate orders). Contrary to the prevailing paradigm that low status is linked to poor health, we found that dominant animals typically faced higher parasite risk than subordinates. This pattern was especially well-supported in analyses of males versus females, in linear versus egalitarian hierarchies, in mating systems where dominance rank predicts mating effort, and for contact- and environmentally-transmitted parasites rather than vector-borne parasites. These findings supported the priority-of-access and tradeoffs hypotheses suggesting that variation in parasitism is driven by rank-associated differences in exposure to parasites and mating effort. Together, these results suggest that high parasite risk might sometimes be an unappreciated cost of high rank, and conversely, reduced parasite risk might be a benefit of social subordination. PMID- 29483574 TI - Elevated FGF23 Levels in Mice Lacking the Thiazide-Sensitive NaCl cotransporter (NCC). AB - Fibroblast growth factor 23 (FGF23) participates in the orchestration of mineral metabolism by inducing phosphaturia and decreasing the production of 1,25(OH)2D3. It is known that FGF23 release is stimulated by aldosterone and extracellular volume depletion. To characterize this effect further in a model of mild hypovolemia, we studied mice lacking the thiazide sensitive NaCl cotransporter (NCC). Our data indicate that NCC knockout mice (KO) have significantly higher FGF23, PTH and aldosterone concentrations than corresponding wild type (WT) mice. However, 1,25(OH)2D3, fractional phosphate excretion and renal brush border expression of the sodium/phosphate co-transporter 2a were not different between the two genotypes. In addition, renal expression of FGF23 receptor FGFR1 and the co-receptor Klotho were unaltered in NCC KO mice. FGF23 transcript was increased in the bone of NCC KO mice compared to WT mice, but treatment of primary murine osteoblasts with the NCC inhibitor hydrochlorothiazide did not elicit an increase of FGF23 transcription. In contrast, the mineralocorticoid receptor blocker eplerenone reversed excess FGF23 levels in KO mice but not in WT mice, indicating that FGF23 upregulation in NCC KO mice is primarily aldosterone-mediated. Together, our data reveal that lack of renal NCC causes an aldosterone-mediated upregulation of circulating FGF23. PMID- 29483576 TI - Abrogation of TGF-beta signalling in TAGLN expressing cells recapitulates Pentalogy of Cantrell in the mouse. AB - Pentalogy of Cantrell (PC) is a rare multi-organ congenital anomaly that impedes ventral body wall closure and results in diaphragmatic hernia, intra- and pericardial defects. The underlying cellular and molecular changes that lead to these severe developmental defects have remained unknown largely due to the lack of representative animal models. Here we provide in depth characterization of a mouse model with conditional ablation of TGFbetaRII in Transgelin (Tagln) expressing cells. We show that Tagln is transiently expressed in a variety of cells that participate in the embryonic development and patterning of ventral structures. Genetic ablation of TGFbetaRII in these cells leads to ventral midline closure defect, diaphragmatic hernia, dilated cardiac outflow tract and aberrant cardiac septation, providing a reliable model to study the morphological changes leading to PC. We show that myogenisis in the diaphragm is independent of TGFbeta and the diaphragmatic hernia arises from fibroblast-specific migration defect. In the dorsal body wall Tagln expression is initiated after the closure process, revealing a remarkable difference between ventral and dorsal body walls development. Our study demonstrates the use of micro-CT scanning to obtain a 3 dimensional high-resolution overview of embryonic anomalies and provides the first mechanistic insight into the development of PC. PMID- 29483575 TI - Self-interaction of NPM1 modulates multiple mechanisms of liquid-liquid phase separation. AB - Nucleophosmin (NPM1) is an abundant, oligomeric protein in the granular component of the nucleolus with roles in ribosome biogenesis. Pentameric NPM1 undergoes liquid-liquid phase separation (LLPS) via heterotypic interactions with nucleolar components, including ribosomal RNA (rRNA) and proteins which display multivalent arginine-rich linear motifs (R-motifs), and is integral to the liquid-like nucleolar matrix. Here we show that NPM1 can also undergo LLPS via homotypic interactions between its polyampholytic intrinsically disordered regions, a mechanism that opposes LLPS via heterotypic interactions. Using a combination of biophysical techniques, including confocal microscopy, SAXS, analytical ultracentrifugation, and single-molecule fluorescence, we describe how conformational changes within NPM1 control valency and switching between the different LLPS mechanisms. We propose that this newly discovered interplay between multiple LLPS mechanisms may influence the direction of vectorial pre ribosomal particle assembly within, and exit from the nucleolus as part of the ribosome biogenesis process. PMID- 29483577 TI - ThMn12-type phases for magnets with low rare-earth content: Crystal-field analysis of the full magnetization process. AB - Rare-earth (R)-iron alloys are a backbone of permanent magnets. Recent increase in price of rare earths has pushed the industry to seek ways to reduce the R content in the hard magnetic materials. For this reason strong magnets with the ThMn12 type of structure came into focus. Functional properties of R(Fe,T)12 (T element stabilizes the structure) compounds or their interstitially modified derivatives, R(Fe,T)12-X (X is an atom of hydrogen or nitrogen) are determined by the crystal-electric-field (CEF) and exchange interaction (EI) parameters. We have calculated the parameters using high-field magnetization data. We choose the ferrimagnetic Tm-containing compounds, which are most sensitive to magnetic field and demonstrate that TmFe11Ti-H reaches the ferromagnetic state in the magnetic field of 52 T. Knowledge of exact CEF and EI parameters and their variation in the compounds modified by the interstitial atoms is a cornerstone of the quest for hard magnetic materials with low rare-earth content. PMID- 29483578 TI - Targeting Ligand Specificity Linked to Tumor Tissue Topological Heterogeneity via Single-Cell Micro-Pharmacological Modeling. AB - Targeted therapy has held promise to be a successful anticancer treatment due to its specificity towards tumor cells that express the target receptors. However, not all targeting drugs used in the clinic are equally effective in tumor eradication. To examine which biochemical and biophysical properties of targeted agents are pivotal for their effective distribution inside the tumor and their efficient cellular uptake, we combine mathematical micro-pharmacological modeling with in vivo imaging of targeted human xenograft tumors in SCID mice. The mathematical model calibrated to experimental data was used to explore properties of the targeting ligand (diffusion and affinity) and ligand release schemes (rates and concentrations) with a goal to identify the properties of cells and ligands that enable high receptor saturation. By accounting for heterogeneities typical of in vivo tumors, our model was able to identify cell- and tissue-level barriers to efficient drug uptake. This work provides a base for utilizing experimentally measurable properties of a ligand-targeted agent and patient specific attributes of the tumor tissue to support the development of novel targeted imaging agents and for improvement in their delivery to individual tumor cells. PMID- 29483579 TI - Hypoxia-inducible factor 2-alpha-dependent induction of amphiregulin dampens myocardial ischemia-reperfusion injury. AB - Myocardial ischemia-reperfusion injury (IRI) leads to the stabilization of the transcription factors hypoxia-inducible factor 1-alpha (HIF1-alpha) and hypoxia inducible factor 2-alpha (HIF2-alpha). While previous studies implicate HIF1 alpha in cardioprotection, the role of HIF2-alpha remains elusive. Here we show that HIF2-alpha induces the epithelial growth factor amphiregulin (AREG) to elicit cardioprotection in myocardial IRI. Comparing mice with inducible deletion of Hif1a or Hif2a in cardiac myocytes, we show that loss of Hif2-alpha increases infarct sizes. Microarray studies in genetic models or cultured human cardiac myocytes implicate HIF2-alpha in the myocardial induction of AREG. Likewise, AREG increases in myocardial tissues from patients with ischemic heart disease. Areg deficiency increases myocardial IRI, as does pharmacologic inhibition of Areg signaling. In contrast, treatment with recombinant Areg provides cardioprotection and reconstitutes mice with Hif2a deletion. These studies indicate that HIF2 alpha induces myocardial AREG expression in cardiac myocytes, which increases myocardial ischemia tolerance. PMID- 29483580 TI - How ligand binds to the type 1 insulin-like growth factor receptor. AB - Human type 1 insulin-like growth factor receptor is a homodimeric receptor tyrosine kinase that signals into pathways directing normal cellular growth, differentiation and proliferation, with aberrant signalling implicated in cancer. Insulin-like growth factor binding is understood to relax conformational restraints within the homodimer, initiating transphosphorylation of the tyrosine kinase domains. However, no three-dimensional structures exist for the receptor ectodomain to inform atomic-level understanding of these events. Here, we present crystal structures of the ectodomain in apo form and in complex with insulin-like growth factor I, the latter obtained by crystal soaking. These structures not only provide a wealth of detail of the growth factor interaction with the receptor's primary ligand-binding site but also indicate that ligand binding separates receptor domains by a mechanism of induced fit. Our findings are of importance to the design of agents targeting IGF-1R and its partner protein, the human insulin receptor. PMID- 29483581 TI - Quantitative Assessment of Liver Steatosis and Affected Pathways with Molecular Imaging and Proteomic Profiling. AB - Current assessment of non-alcoholic fatty liver disease (NAFLD) with histology is time-consuming, insensitive to early-stage detection, qualitative, and lacks information on etiology. This study explored alternative methods for fast and quantitative assessment of NAFLD with hyperspectral stimulated Raman scattering (SRS) microscopy and nanofluidic proteomics. Hyperspectral SRS microscopy quantitatively measured liver composition of protein, DNA, and lipid without labeling and sensitively detected early-stage steatosis in a few minutes. On the other hand, nanofluidic proteomics quantitatively measured perturbations to the post-translational modification (PTM) profiles of selective liver proteins to identify affected cellular signaling and metabolic pathways in a few hours. Perturbations to the PTM profiles of Akt, 4EBP1, BID, HMGCS2, FABP1, and FABP5 indicated abnormalities in multiple cellular processes including cell cycle regulation, PI3K/Akt/mTOR signaling cascade, autophagy, ketogenesis, and fatty acid transport. The integrative deployment of hyperspectral SRS microscopy and nanofluidic proteomics provided fast, sensitive, and quantitative assessment of liver steatosis and affected pathways that overcame the limitations of histology. PMID- 29483582 TI - Superplastic nanoscale pore shaping by ion irradiation. AB - Exposed to ionizing radiation, nanomaterials often undergo unusual transformations compared to their bulk form. However, atomic-level mechanisms of such transformations are largely unknown. This work visualizes and quantifies nanopore shrinkage in nanoporous alumina subjected to low-energy ion beams in a helium ion microscope. Mass transport in porous alumina is thus simultaneously induced and imaged with nanoscale precision, thereby relating nanoscale interactions to mesoscopic deformations. The interplay between chemical bonds, disorders, and ionization-induced transformations is analyzed. It is found that irradiation-induced diffusion is responsible for mass transport and that the ionization affects mobility of diffusive entities. The extraordinary room temperature superplasticity of the normally brittle alumina is discovered. These findings enable the effective manipulation of chemical bonds and structural order by nanoscale ion-matter interactions to produce mesoscopic structures with nanometer precision, such as ultra-high density arrays of sub-10-nm pores with or without the accompanying controlled plastic deformations. PMID- 29483583 TI - A randomized and open-label phase II trial reports the efficacy of neoadjuvant lobaplatin in breast cancer. AB - Currently, one sixth of triple-negative breast cancer (TNBC) patients who receive docetaxel (T) and epirubicin (E) as neoadjuvant chemotherapy achieve a pathologic complete response (pCR). This study evaluates the impact of adding lobaplatin (L) to the TE regimen. Here, we show data from 125 patients (63 TE and 62 TEL patients). Four patients did not complete all the cycles. Two-sided P values show that the addition of L (38.7% vs. 12.7%, P = 0.001) significantly increases the rate of pCR in the breast and the axilla (TpCR) and the overall response rate (ORR; 93.5% vs. 73.0%, P = 0.003). The occurrence of grade 3-4 anemia and thrombocytopenia is higher in the TEL group (52.5% vs. 10.0% and 34.4% vs. 1.7% respectively). These results demonstrate that the addition of L to the TE regimen as neoadjuvant chemotherapy improves the TpCR and the ORR rates of TNBC but with increased side effects. PMID- 29483584 TI - Localization of lipopolysaccharide from Escherichia Coli into human atherosclerotic plaque. AB - Experimental studies showed that gut-derived lipopolysaccharide (LPS) is pro atherogenic, however, its relationship with human atherosclerosis is still to be defined. We investigate if gut-derived LPS from Escherichia Coli localizes in human carotid plaque and its potential role as pro-inflammatory molecule in the atherosclerotic lesion. LPS from Escherichia Coli and Toll-like receptor 4 (TLR4) were studied in specimens from carotid and thyroid arteries of 10 patients undergoing endarterectomy and 15 controls matched for demographic and clinical characteristics. Blood LPS were significantly higher in patients compared to controls. Immunochemistry analysis revealed positivity for antibodies against LPS and TLR4 coincidentally with positivity for CD68 only in the atherosclerotic plaque of carotid arteries but not in thyroid arteries; the positivity for LPS and TLR4 was greater in the area with activated macrophages. LPS concentration similar to that detected in atherosclerotic plaque resulted in a dose-dependent TLR4-mediated Nox2 up-regulation by human monocytes. These data provide the first evidence that LPS from Escherichia Coli localizes in human plaque and may contribute to atherosclerotic damage via TLR4-mediated oxidative stress. PMID- 29483585 TI - The use of classification tree analysis to assess the influence of surgical timing on neurological recovery following severe cervical traumatic spinal cord injury. AB - STUDY DESIGN: Post hoc analysis of prospectively collected data. OBJECTIVES: Assess the influence of surgical timing on neurological recovery using classification tree analysis in patients sustaining cervical traumatic spinal cord injury. SETTING: Hopital du Sacre-Coeur de Montreal METHODS: 42 patients sustaining cervical SCI were followed for at least 6 months post injury. Neurological status was assessed from the American Spinal Injury Association impairment scale (AIS) and neurological level of injury (NLI) at admission and at follow-up. Age, surgical timing, AIS grade at admission and energy of injury were the four input parameters. Neurological recovery was quantified by the occurrence of improvement by at least one AIS grade, at least 2 AIS grades and at least 2 NLI. RESULTS: Proportion of patients that improved at least one ASIA grade was higher in the group that received early surgery (75 vs. 41 %). The proportion of patients that improved two AIS grades was also higher in the group that received early surgery (67 vs. 38 %). Finally, 30 % of the patients that received early decompression improved two NLI as compared with 0% in the other group. Early surgery was also associated with a non-statistically significant improvement in functional recovery. CONCLUSIONS: Neurological recovery of patients sustaining cervical traumatic spinal cord injury can be improved by early decompression surgery performed within 19 h post trauma. SPONSORSHIP: U.S. Army Medical Research and Material Command, Rick Hansen Institute. PMID- 29483586 TI - Changes in psychotropic prescription medication use and their relationship with mortality among people with traumatic spinal cord injury. AB - STUDY DESIGN: Prospective cohort study. OBJECTIVE: To identify the relationship of frequency of prescription medication use to treat pain, spasticity, sleep, and depression/stress, and change in prescription medication use with risk of all cause mortality. SETTING: This study was initiated at a specialty hospital in the Southeastern USA, with follow-up and data analysis at an academic medical center in the Southeastern United States. METHODS: Prospective data were collected in 1997-1998 (Time 1) and 2007-2009 (Time 2), with mortality determined as of 31 December 2014. The initial participant cohort was comprised of 1386 participants with traumatic SCI who were adults and a minimum of 1-year post-injury at enrollment in 1997-1998. Of these, 863 participated at follow-up and 861 were included in the current mortality analysis. RESULTS: The frequency of taking prescription medication increased over the 10-year timeframe, particularly for sleep and pain. Each type of prescription medication at Time 1 was associated with later mortality, and an increase in medication use over time was associated with a greater risk of mortality for three of the four conditions (all except spasticity). A decrease in the frequency of pain medication use over time was associated with a decreased risk of all-cause mortality. CONCLUSIONS: More frequent use of prescription medication to treat pain, sleep, and depression/stress is related to all-cause mortality, and increases in the use of medications to treat these conditions is associated with elevated risk of all cause mortality. PMID- 29483587 TI - Adiposity, physical activity, and risk of hypertension: prospective data from the population-based HUNT Study, Norway. AB - Adiposity and inactivity have been associated with increased risk of hypertension. However, reports on the joint effect of these two risk factors in relation to hypertension are scarce and their interaction poorly understood. We prospectively examined both independent and joint effects of measured body mass index (BMI) and self-reported physical activity on the risk of hypertension. We conducted a longitudinal study of 11,238 men and 15,301 women who participated in the Nord-Trondelag Health Study (HUNT) in Norway. Poisson regression was used to estimate adjusted risk ratios (RRs) of hypertension (>=140/90 mmHg) according to BMI and physical activity. BMI was positively associated with risk of hypertension in both sexes (Ptrends < 0.001), whereas the independent effect of physical activity was less clear. Obese men who reported no physical activity had a RR of 1.50 (95% confidence interval (CI): 1.27-1.77) compared to normal weight men with a high activity level, whereas obese men who reported high activity levels had a RR of 1.16 (95% CI: 0.79-1.70). Correspondingly, obese and inactive women had a RR of 1.55 (95% CI: 1.35-1.77), whereas obese and highly active women had RRs of 1.41 (95% CI: 1.18-1.69). Our data suggest that high levels of physical activity could to some extent attenuate the unfavorable effect of adiposity on hypertension, particularly in men. PMID- 29483588 TI - Prevalence and risk factors of hypertension in acclimatized lowlanders staying at high altitude for different durations. AB - Hypoxic exposure at high-altitude (HA) modulates blood pressure (BP). High prevalence of hypertension among native highlanders (NH) has been reported. However, information on prevalence and determinants of hypertension in acclimatized young lowlanders (ALL) staying at HA for different durations is sparse. We aimed to determine the prevalence of hypertension in ALL staying at HA for different durations and its association with cardiovascular risk factors. Male volunteers were categorized on the basis of their duration of stay at HA; Lowlanders (LL) (0 months; n = 151), ALL (1-24 months; n = 519) and NH (n = 103). ALL were sub grouped into ALL 1 (1-6 months; n = 165), ALL 2 (6-12 months; n = 181), and ALL 3 (12-24 months; n = 173). BP, sympathetic activity, arterial stiffness, lipid profile, and homocysteine were estimated. Regression analysis was performed to determine association of risk factors with hypertension. Prevalence of hypertension among ALL was highest with 17.53% followed by NH (11.6%) and LL (9.27%). Prevalence of hypertension in ALL sub group was in order ALL 1 < ALL 2 < ALL 3. Hypertension was significantly associated with sympathetic dominance (p < 0.001) in ALL 1. Hypertension in ALL 2 was associated with dyslipidemia (p < 0.01) while in ALL 3 hypertension was associated with hyperhomocysteinemia (hHCY, p < 0.001), arterial stiffness and dyslipidemia (p < 0.01). In conclusion, our report suggests higher prevalence of hypertension in ALL. The association of studied risk factors and hypertension in different ALL sub groups varied significantly. Our findings suggest the need for a differential clinical approach to control hypertension in ALL considering their duration of stay at HA. PMID- 29483590 TI - Marangoni-driven flower-like patterning of an evaporating drop spreading on a liquid substrate. AB - Drop motility at liquid surfaces is attracting growing interest because of its potential applications in microfluidics and artificial cell design. Here we report the unique highly ordered pattern that sets in when a millimeter-size drop of dichloromethane spreads on an aqueous substrate under the influence of surface tension, both phases containing a surfactant. Evaporation induces a Marangoni flow that forces the development of a marked rim at the periphery of the spreading film. At some point this rim breaks up, giving rise to a ring of droplets, which modifies the aqueous phase properties in such a way that the film recoils. The process repeats itself, yielding regular large-amplitude pulsations. Wrinkles form at the film surface due to an evaporative instability. During the dewetting stage, they emit equally spaced radial strings of droplets which, combined with those previously expelled from the rim, make the top view of the system resemble a flower. PMID- 29483589 TI - The interdependence of excitation and inhibition for the control of dynamic breathing rhythms. AB - The preBotzinger Complex (preBotC), a medullary network critical for breathing, relies on excitatory interneurons to generate the inspiratory rhythm. Yet, half of preBotC neurons are inhibitory, and the role of inhibition in rhythmogenesis remains controversial. Using optogenetics and electrophysiology in vitro and in vivo, we demonstrate that the intrinsic excitability of excitatory neurons is reduced following large depolarizing inspiratory bursts. This refractory period limits the preBotC to very slow breathing frequencies. Inhibition integrated within the network is required to prevent overexcitation of preBotC neurons, thereby regulating the refractory period and allowing rapid breathing. In vivo, sensory feedback inhibition also regulates the refractory period, and in slowly breathing mice with sensory feedback removed, activity of inhibitory, but not excitatory, neurons restores breathing to physiological frequencies. We conclude that excitation and inhibition are interdependent for the breathing rhythm, because inhibition permits physiological preBotC bursting by controlling refractory properties of excitatory neurons. PMID- 29483591 TI - GourdBase: a genome-centered multi-omics database for the bottle gourd (Lagenaria siceraria), an economically important cucurbit crop. AB - GourdBase is an integrative data platform for the bottle gourd to examine its multifarious intuitive morphology and annotated genome. GourdBase consists of six main modules that store and interlink multi-omic data: the genome (with transcriptomic data integrated) module, the phenome module, the markers/QTLs module, the maps (genetic, physical and comparative) module, the cultivars module, and the publications module. These modules provide access to various type of data including the annotated reference genome sequence, gene models, transcriptomic data from various tissues, physical and comparative genome maps, molecular markers in different types, phenotypic data for featuring traits including fruit shape and umami taste, and quantitative trait loci (QTLs) that underlie these traits. GourdBase is intuitive, user-friendly and interlinked and is designed to allow researchers, breeders and trained farmers to browse, search and fetch information on interests and assist in genomics-driven studies and breeding. The knowledge base and web interface can be accessed at http://www.gourdbase.cn/ . PMID- 29483592 TI - High motor variability in DYT1 dystonia is associated with impaired visuomotor adaptation. AB - For the healthy motor control system, an essential regulatory role is maintaining the equilibrium between keeping unwanted motor variability in check whilst allowing informative elements of motor variability. Kinematic studies in children with generalised dystonia (due to mixed aetiologies) show that movements are characterised by increased motor variability. In this study, the mechanisms by which high motor variability may influence movement generation in dystonia were investigated. Reaching movements in the symptomatic arm of 10 patients with DYT1 dystonia and 12 age-matched controls were captured using a robotic manipulandum and features of motor variability were extracted. Given that task-relevant variability and sensorimotor adaptation are related in health, markers of variability were then examined for any co-variance with performance indicators during an error-based learning visuomotor adaptation task. First, we confirmed that motor variability on a trial-by-trial basis was selectively increased in the homogenous and prototypical dystonic disorder DYT1 dystonia. Second, high baseline variability predicted poor performance in the subsequent visuomotor adaptation task offering insight into the rules which appear to govern dystonic motor control. The potential mechanisms behind increased motor variability and its corresponding implications for the rehabilitation of patients with DYT1 dystonia are highlighted. PMID- 29483593 TI - Human Epicardial Adipose Tissue cTGF Expression is an Independent Risk Factor for Atrial Fibrillation and Highly Associated with Atrial Fibrosis. AB - Epicardial adipose tissue (EAT) is associated with the incidence, perpetuation, and recurrence of atrial fibrillation (AF), with elusive underlying mechanisms. We analyzed adipokine expression in samples from 20 patients with sinus rhythm (SR) and 16 with AF. Quantitative real-time PCR showed that connective tissue growth factor (cTGF) expression was significantly higher in EAT than in subcutaneous adipose tissue (SAT) or paracardial adipose tissue (PAT) from patients with AF, and in EAT from patients with SR (P < 0.001). Galectin-3 expression was significantly higher in EAT than in SAT or PAT (P < 0.001), with no significant differences between patients with AF and SR (P > 0.05). Leptin and vaspin expression were lower in EAT than in PAT (P < 0.001). Trichrome staining showed that the fibrosis was much more severe in patients with AF than SR (P < 0.001). We found a linear relationship between cTGF mRNA expression level and collagen volume fraction (y = 1.471x + 27.330, P < 0.001), and logistic regression showed that cTGF level was an independent risk factor for AF (OR 2.369, P = 0.027). In conclusion, highly expressed in EAT, cTGF is associated with atrial fibrosis, and can be an important risk factor for AF. PMID- 29483594 TI - Dynamic control of particle separation in deterministic lateral displacement separator with viscoelastic fluids. AB - We proposed an innovative method to achieve dynamic control of particle separation by employing viscoelastic fluids in deterministic lateral displacement (DLD) arrays. The effects of shear-thinning and elasticity of working fluids on the critical separation size in DLD arrays are investigated. It is observed that each effect can lead to the variation of the critical separation size by approximately 40%. Since the elasticity strength of the fluid is related to the shear rate, the dynamic control can for the first time be easily realized through tuning the flow rate in microchannels. PMID- 29483596 TI - Selective state spectroscopy and multifractality in disordered Bose-Einstein condensates: a numerical study. AB - We propose to apply a modified version of the excitation scheme introduced by Volchkov et al. on bosons experiencing hyperfine state dependent disorder to address the critical state at the mobility edge of the Anderson localization transition, and to observe its intriguing multifractal structure. An optimally designed, spatially focused external radio frequency pulse can be applied to generate transitions to eigenstates in a narrow energy window close to the mobility edge, where critical scaling and multifractality emerge. Alternatively, two-photon laser scanning microscopy is proposed to address individual localized states even close to the transition. The projected image of the cloud is shown to inherit multifractality and to display universal density correlations. Interactions - unavoidably present - are taken into account by solving the Gross Pitaevskii equations, and their destructive effect on the spectral resolution and the multifractal spectrum is analyzed. Time of flight images of the excited states are predicted to show interference fringes in the localized phase, while they allow one to map equal energy surfaces deep in the metallic phase. PMID- 29483595 TI - RANKL deletion in periodontal ligament and bone lining cells blocks orthodontic tooth movement. AB - The bone remodeling process in response to orthodontic forces requires the activity of osteoclasts to allow teeth to move in the direction of the force applied. Receptor activator of nuclear factor-kappaB ligand (RANKL) is essential for this process although its cellular source in response to orthodontic forces has not been determined. Orthodontic tooth movement is considered to be an aseptic inflammatory process that is stimulated by leukocytes including T and B lymphocytes which are presumed to stimulate bone resorption. We determined whether periodontal ligament and bone lining cells were an essential source of RANKL by tamoxifen induced deletion of RANKL in which Cre recombinase was driven by a 3.2 kb reporter element of the Col1alpha1 gene in experimental mice (Col1alpha1.CreERTM+.RANKLf/f) and compared results with littermate controls (Col1alpha1.CreERTM-.RANKLf/f). By examination of Col1alpha1.CreERTM+.ROSA26 reporter mice we showed tissue specificity of tamoxifen induced Cre recombinase predominantly in the periodontal ligament and bone lining cells. Surprisingly we found that most of the orthodontic tooth movement and formation of osteoclasts was blocked in the experimental mice, which also had a reduced periodontal ligament space. Thus, we demonstrate for the first time that RANKL produced by periodontal ligament and bone lining cells provide the major driving force for tooth movement and osteoclastogenesis in response to orthodontic forces. PMID- 29483597 TI - Regulation of age-associated B cells by IRF5 in systemic autoimmunity. AB - Age-associated B cells (ABCs) are a subset of B cells dependent on the transcription factor T-bet that accumulate prematurely in autoimmune settings. The pathways that regulate ABCs in autoimmunity are largely unknown. SWAP-70 and DEF6 (also known as IBP or SLAT) are the only two members of the SWEF family, a unique family of Rho GTPase-regulatory proteins that control both cytoskeletal dynamics and the activity of the transcription factor IRF4. Notably, DEF6 is a newly identified human risk variant for systemic lupus erythematosus. Here we found that the lupus syndrome that developed in SWEF-deficient mice was accompanied by the accumulation of ABCs that produced autoantibodies after stimulation. ABCs from SWEF-deficient mice exhibited a distinctive transcriptome and a unique chromatin landscape characterized by enrichment for motifs bound by transcription factors of the IRF and AP-1 families and the transcription factor T bet. Enhanced ABC formation in SWEF-deficient mice was controlled by the cytokine IL-21 and IRF5, whose variants are strongly associated with lupus. The lack of SWEF proteins led to dysregulated activity of IRF5 in response to stimulation with IL-21. These studies thus elucidate a previously unknown signaling pathway that controls ABCs in autoimmunity. PMID- 29483598 TI - Objective Test of Cochlear Dead Region: Electrophysiologic Approach using Acoustic Change Complex. AB - The goal of this study was to develop an objective and neurophysiologic method of identifying the presence of cochlear dead region (CDR) by combining acoustic change complex (ACC) responses with threshold-equalizing noise (TEN) test. The goal of the first study was to confirm whether ACC could be evoked with TEN stimuli and to also optimize the test conditions. The goal of the second study was to determine whether the TEN-ACC test is capable of detecting CDR(s). The ACC responses were successfully recorded from all study participants. Both behaviorally and electrophysiologically obtained masked thresholds (TEN threshold and TEN-ACC threshold) were similar and below 10 and 12 dB SNR in NH listeners, respectively. HI listeners were divided into HI (non-CDR) and CDR groups based on the behavioral TEN test. For the non-CDR group, TEN-ACC thresholds were below 12 dB which were similar to NH listeners. However, for the CDR group, TEN-ACC thresholds were significantly higher (>=12 dB SNR) than those in the NH and HI groups, indicating that CDR(s) can be objectively detected using the ACC. Results of this study demonstrate that it is possible to detect the presence of CDR using an electrophysiologic method. PMID- 29483599 TI - Spatially controlled doping of two-dimensional SnS2 through intercalation for electronics. AB - Doped semiconductors are the most important building elements for modern electronic devices 1 . In silicon-based integrated circuits, facile and controllable fabrication and integration of these materials can be realized without introducing a high-resistance interface2,3. Besides, the emergence of two dimensional (2D) materials enables the realization of atomically thin integrated circuits4-9. However, the 2D nature of these materials precludes the use of traditional ion implantation techniques for carrier doping and further hinders device development 10 . Here, we demonstrate a solvent-based intercalation method to achieve p-type, n-type and degenerately doped semiconductors in the same parent material at the atomically thin limit. In contrast to naturally grown n type S-vacancy SnS2, Cu intercalated bilayer SnS2 obtained by this technique displays a hole field-effect mobility of ~40 cm2 V-1 s-1, and the obtained Co SnS2 exhibits a metal-like behaviour with sheet resistance comparable to that of few-layer graphene 5 . Combining this intercalation technique with lithography, an atomically seamless p-n-metal junction could be further realized with precise size and spatial control, which makes in-plane heterostructures practically applicable for integrated devices and other 2D materials. Therefore, the presented intercalation method can open a new avenue connecting the previously disparate worlds of integrated circuits and atomically thin materials. PMID- 29483600 TI - Charge splitters and charge transport junctions based on guanine quadruplexes. AB - Self-assembling circuit elements, such as current splitters or combiners at the molecular scale, require the design of building blocks with three or more terminals. A promising material for such building blocks is DNA, wherein multiple strands can self-assemble into multi-ended junctions, and nucleobase stacks can transport charge over long distances. However, nucleobase stacking is often disrupted at junction points, hindering electric charge transport between the two terminals of the junction. Here, we show that a guanine-quadruplex (G4) motif can be used as a connector element for a multi-ended DNA junction. By attaching specific terminal groups to the motif, we demonstrate that charges can enter the structure from one terminal at one end of a three-way G4 motif, and can exit from one of two terminals at the other end with minimal carrier transport attenuation. Moreover, we study four-way G4 junction structures by performing theoretical calculations to assist in the design and optimization of these connectors. PMID- 29483601 TI - Phosphorus speciation in a prairie soil amended with MBM and DDG ash: Sequential chemical extraction and synchrotron-based XANES spectroscopy investigations. AB - Sequential chemical extraction and synchrotron-based XANES spectroscopy techniques were used to identify P species in two ashes before and after addition to a prairie soil. The used ashes were: meat and bone meal ash (MBMA) and dried distillers grains ash (DDGA) plus mineral P fertilizer (MP) for comparison. Soil treated with MP contained higher content of resin-Pi and NaHCO3-Pi followed by DDGA and MBMA. The MBMA amended soil had the highest (47%) proportion of the soil P contained in recalcitrant HCl extractable fraction, reflecting more Ca-bound P present and being formed in soil after application. Analysis of both ashes with XANES spectroscopy before application to soil revealed that MBMA had strong spectral features consistent with hydroxyapatite (Ca5(PO4)3(OH)). DDGA exhibited spectral features consistent with a mixture of several Mg and K phosphate salts rather than a single mineral species. The distinctive features in the XANES spectra of both ashes largely disappeared after amendment to the soil, suggesting transformation to different P forms in the soil after application. It is also possible that the added amount of P to the studied soil via DDGS or MBMA was small enough so that P speciation is not different from the background P level. PMID- 29483602 TI - Strength of tremor patches along deep transition zone of a megathrust. AB - Deep low frequency tremors are indicators of slow slip transients in the brittle ductile transition zone along subducting plates. Investigation of comprehensive tremor activities is therefore an important issue for understanding the seismic/aseismic characteristics in transition zones. Here, we focus on the radiated energy from tremors to reveal the along-strike heterogeneity in the strength of tremor patches. Based on a tremor catalog that more accurately evaluates radiated energy, we examine the spatio-temporal activity of tremors accompanied by slow slip events (SSEs) in western Shikoku, southwestern Japan. The new finding of this study is that the energy radiated from tremors is positively correlated with the speed of tremor migration front and the slip rate along the plate interface during a SSE. This can be qualitatively explained by a stress diffusion model, which consists of along-strike heterogeneities in the effective strength of tremor patches embedded in a ductile shear zone. This effective strength heterogeneity is supported by a lateral variation in the stress drop of a SSE; it is consistent with the fluid pressure distribution along the plate boundary fault and the tidal sensitivity of tremors. Accurate evaluation of tremor activities, especially the radiated energy, can be used to infer the spatial distribution of the strength of tremor patches in transition zones worldwide. PMID- 29483603 TI - Bumetanide for autism: more eye contact, less amygdala activation. AB - We recently showed that constraining eye contact leads to exaggerated increase of amygdala activation in autism. Here, in a proof of concept pilot study, we demonstrate that administration of bumetanide (a NKCC1 chloride importer antagonist that restores GABAergic inhibition) normalizes the level of amygdala activation during constrained eye contact with dynamic emotional face stimuli in autism. In addition, eye-tracking data reveal that bumetanide administration increases the time spent in spontaneous eye gaze during in a free-viewing mode of the same face stimuli. In keeping with clinical trials, our data support the Excitatory/Inhibitory dysfunction hypothesis in autism, and indicate that bumetanide may improve specific aspects of social processing in autism. Future double-blind placebo controlled studies with larger cohorts of participants will help clarify the mechanisms of bumetanide action in autism. PMID- 29483604 TI - The prevalence of underweight, overweight and obesity in children and adolescents from Ukraine. AB - The aim of this study was to evaluate the prevalence of overweight, obesity and underweight in children from Ukraine. A cross-sectional study was performed on data collected from a representative sample of Ukraine children (13,739 children (boys 48%, girls 52%) aged 6.0-18.9 years). The measurement of body weight was performed with medical scales and height was measured using a stadiometer. Based on the results obtained, body mass index (BMI) was calculated. Three criteria were used to define childhood underweight, overweight and obesity: The International Obesity Task Force (IOTF) reference, World Health Organization (WHO) child growth standard and The US Center for Disease Control and Prevention (CDC). The combined prevalence of obesity and overweight among children aged 6-18 years old was 12.1%, 17.6%, and 12.6% based on the IOTF reference, WHO growth standard, and the CDC, respectively. Obesity was 2.1%, 4.2%, and 3.6% respectively. Significantly more girls were underweight than boys. Furthermore, a higher prevalence of overweight and obesity was diagnosed in younger that older Ukrainian population. PMID- 29483605 TI - Charge-spin mutual entanglement: A case study by exact diagonalization of the one hole doped t-J loop. AB - We investigate the ground state and excitations of finite-size Heisenberg loops doped with one hole as the simplest example to illustrate the nature of strong correlations in a doped Mott insulator. We show that the doped hole form a peculiar long-range entanglement with the surrounding spins as revealed by inspecting the mutual correlations between the charge and spin using exact diagonalization (ED). In particular, the one-hole ground state acquires a series of non-trivial total momenta depending on the ratio J/t (J and t denote the superexchange coupling and hopping integral, respectively), which gives rise to distinct quantum phases separated by critical points (CPs). Interestingly the novel total momentum and correlations completely disappear once a singular sign structure is turned off in the t-J model, indicating the latter is the true original source for strong correlation via many-body quantum interference. We emphasize that the novelties discovered here are not restricted to the one dimensional loop. We introduce a new charge-spin mutual entanglement that can well characterize these exotic properties, which can be then easily generalized to more realistic situations like two dimensions. PMID- 29483606 TI - Clinicopathologic characteristics of poorly differentiated chordoma. AB - Chordoma is a rare malignant tumor of bone with high morbidity and mortality. Recently, aggressive pediatric poorly differentiated chordoma with SMARCB1 loss has been described. This study summarizes the clinicopathologic features of poorly differentiated chordoma with SMARCB1 loss in the largest series to date. A search of records between 1990-2017 at MGH identified 19 patients with poorly differentiated chordoma. Immunohistochemical stains were evaluated. Kaplan-Meier survival statistics and log-rank (Mantel Cox) tests compared survival with other subtypes. The patients (n = 19) were diagnosed at a median age of 11 years (range: 1-29). Tumors arose in the skull base and clivus (n = 10/19; 53%); cervical spine (n = 6/19; 32%); and sacrum or coccyx (n = 3/19; 16%). The clinical stage of these patients (AJCC 7e) was stage 2A (n = 7/16; 44%); stage 2B (n = 6/16; 38%); stage 4A (n = 1/16; 6%); and stage 4B (n = 2/16; 13%). The tumors were composed of sheets of epithelioid cells with nuclear pleomorphism, abundant eosinophilic cytoplasm, and increased mitoses. Tumors were positive for cytokeratin (n = 18/18; 100%) and brachyury (n = 18/18; 100%). Patients were treated with a combination of excision, radiation therapy, and chemotherapy. No difference in overall survival, progression free survival, local control time, and metastasis free survival was identified between poorly differentiated chordoma of the skull base and of the spine. Compared to other chordoma subtypes, poorly differentiated chordoma has a significantly decreased mean overall survival after stratification by site (p = 0.037). Pediatric poorly differentiated chordoma has a distinct clinical and immunohistochemical profile, with characteristic SMARCB1 loss and decreased survival compared to conventional/chondroid chordoma. Recognition of this subtype is important because these malignancies should be treated aggressively with multimodality therapy. PMID- 29483607 TI - Acute Kidney Injury in Trauma Patients Admitted to Critical Care: Development and Validation of a Diagnostic Prediction Model. AB - Acute Kidney Injury (AKI) complicating major trauma is associated with increased mortality and morbidity. Traumatic AKI has specific risk factors and predictable time-course facilitating diagnostic modelling. In a single centre, retrospective observational study we developed risk prediction models for AKI after trauma based on data around intensive care admission. Models predicting AKI were developed using data from 830 patients, using data reduction followed by logistic regression, and were independently validated in a further 564 patients. AKI occurred in 163/830 (19.6%) with 42 (5.1%) receiving renal replacement therapy (RRT). First serum creatinine and phosphate, units of blood transfused in first 24 h, age and Charlson score discriminated need for RRT and AKI early after trauma. For RRT c-statistics were good to excellent: development: 0.92 (0.88 0.96), validation: 0.91 (0.86-0.97). Modelling AKI stage 2-3, c-statistics were also good, development: 0.81 (0.75-0.88) and validation: 0.83 (0.74-0.92). The model predicting AKI stage 1-3 performed moderately, development: c-statistic 0.77 (0.72-0.81), validation: 0.70 (0.64-0.77). Despite good discrimination of need for RRT, positive predictive values (PPV) at the optimal cut-off were only 23.0% (13.7-42.7) in development. However, PPV for the alternative endpoint of RRT and/or death improved to 41.2% (34.8-48.1) highlighting death as a clinically relevant endpoint to RRT. PMID- 29483608 TI - HIF1alpha-dependent glycolysis promotes macrophage functional activities in protecting against bacterial and fungal infection. AB - Macrophages are important innate immune defense system cells in the fight against bacterial and fungal pathogenic infections. They exhibit significant plasticity, particularly with their ability to undergo functional differentiation. Additionally, HIF1alpha is critically involved in the functional differentiation of macrophages during inflammation. However, the role of macrophage HIF1alpha in protecting against different pathogenic infections remains unclear. In this study, we investigated and compared the roles of HIF1alpha in different macrophage functional effects of bacterial and fungal infections in vitro and in vivo. We found that bacterial and fungal infections produced similar effects on macrophage functional differentiation. HIF1alpha deficiency inhibited pro inflammatory macrophage functional activities when cells were stimulated with LPS or curdlan in vitro or when mice were infected with L. monocytogenes or C. albicans in vivo, thus decreasing pro-inflammatory TNFalpha and IL-6 secretion associated with pathogenic microorganism survival. Alteration of glycolytic pathway activation was required for the functional differentiation of pro inflammatory macrophages in protecting against bacterial and fungal infections. Thus, the HIF1alpha-dependent glycolytic pathway is essential for pro inflammatory macrophage functional differentiation in protecting against bacterial and fungal infections. PMID- 29483609 TI - Heterogeneous localisation of membrane proteins in Staphylococcus aureus. AB - The bacterial cytoplasmic membrane is the interface between the cell and its environment, with multiple membrane proteins serving its many functions. However, how these proteins are organised to permit optimal physiological processes is largely unknown. Based on our initial findings that 2 phospholipid biosynthetic enzymes (PlsY and CdsA) localise heterogeneously in the membrane of the bacterium Staphylococcus aureus, we have analysed the localisation of other key membrane proteins. A range of protein fusions were constructed and used in conjunction with quantitative image analysis. Enzymes involved in phospholipid biosynthesis as well as the lipid raft marker FloT exhibited a heterogeneous localisation pattern. However, the secretion associated SecY protein, was more homogeneously distributed in the membrane. A FRET-based system also identified novel colocalisation between phospholipid biosynthesis enzymes and the respiratory protein CydB revealing a likely larger network of partners. PlsY localisation was found to be dose dependent but not to be affected by membrane lipid composition. Disruption of the activity of the essential cell division organiser FtsZ, using the inhibitor PC190723 led to loss of PlsY localisation, revealing a link to cell division and a possible role for FtsZ in functions not strictly associated with septum formation. PMID- 29483610 TI - Input-Independent Energy Harvesting in Bistable Lattices from Transition Waves. AB - We demonstrate the utilisation of transition waves for realising input-invariant, frequency-independent energy harvesting in 1D lattices of bistable elements. We propose a metamaterial-inspired design with an integrated electromechanical transduction mechanism to the unit cell, rendering the power conversion capability an intrinsic property of the lattice. Moreover, focusing of transmitted energy to desired locations is demonstrated numerically and experimentally by introducing engineered defects in the form of perturbation in mass or inter-element forcing. We achieve further localisation of energy and numerically observe a breather-like mode for the first time in this type of lattice, improving the harvesting performance by an order of magnitude. Our approach considers generic bistable unit cells and thus provides a universal mechanism to harvest energy and realise metamaterials effectively behaving as a capacitor and power delivery system. PMID- 29483611 TI - Intragenic DNA methylation in buccal epithelial cells and intellectual functioning in a paediatric cohort of males with fragile X. AB - Increased intragenic DNA methylation of the Fragile X Related Epigenetic Element 2 (FREE2) in blood has been correlated with lower intellectual functioning in females with fragile X syndrome (FXS). This study explored these relationships in a paediatric cohort of males with FXS using Buccal Epithelial Cells (BEC). BEC were collected from 25 males with FXS, aged 3 to 17 years and 19 age-matched male controls without FXS. Methylation of 9 CpG sites within the FREE2 region was examined using the EpiTYPER approach. Full Scale IQ (FSIQ) scores of males with FXS were corrected for floor effect using the Whitaker and Gordon (WG) extrapolation method. Compared to controls, children with FXS had significant higher methylation levels for all CpG sites examined (p < 3.3 * 10-7), and within the FXS group, lower FSIQ (WG corrected) was associated with higher levels of DNA methylation, with the strongest relationship found for CpG sites within FMR1 intron 1 (p < 5.6 * 10-5). Applying the WG method to the FXS cohort unmasked significant epi-genotype-phenotype relationships. These results extend previous evidence in blood to BEC and demonstrate FREE2 DNA methylation to be a sensitive epigenetic biomarker significantly associated with the variability in intellectual functioning in FXS. PMID- 29483612 TI - Rapid oxygen diffusion during high temperature alteration of zircon. AB - The mineral zircon through its isotopic and elemental signatures comprises the greatest archive recording the evolution of Earth's continental crust. Recognising primary from secondary zircon compositional signatures is thus important for the accurate interpretation of this archive. We report two examples of metasedimentary rocks from high-grade shear zones within the Southern Granulite Belt of India, where anomalously high and homogeneous oxygen isotope signatures indicate disturbance of this isotopic system. Utilising the combined U Pb-Hf-O and trace element signatures from these zircon grains, we postulate that fluid-assisted alteration has led to complete resetting of the oxygen isotope signatures. This case study presents a rarely observed natural example of potentially fast diffusion of oxygen under hydrous conditions. Given the pervasive nature of fluid interaction within high-grade and highly deformed rocks, we expect that such isotopic disturbance might be more common to nature than is currently reported. A lack of correlation between isotopic disturbance with cathodoluminescence or Th/U values, suggests that these altered zircon grains would not clearly be classified as metamorphic, in which case they would be expected to yield primary compositions. Caution is therefore advised when using detrital delta18O zircon compilations without a high level of scrutiny for primary versus secondary compositions. PMID- 29483613 TI - Superamphiphobic coatings based on liquid-core microcapsules with engineered capsule walls and functionality. AB - Microcapsules with specific functional properties, related to the capsule wall and core, are highly desired in a number of applications. In this study, hybrid cellulose microcapsules (1.2 +/- 0.4 um in diameter) were prepared by nanoengineering the outer walls of precursor capsules. Depending on the preparation route, capsules with different surface roughness (raspberry or broccoli-like), and thereby different wetting properties, could be obtained. The tunable surface roughness was achieved as a result of the chemical and structural properties of the outer wall of a precursor capsule, which combined with a new processing route allowed in-situ formation of silica nanoparticles (30-40 nm or 70 nm in diameter). By coating glass slides with "broccoli-like" microcapsules (30-40 nm silica nanoparticles), static contact angles above 150 degrees and roll-off angles below 6 degrees were obtained for both water and low surface tension oil (hexadecane), rendering the substrate superamphiphobic. As a comparison, coatings from raspberry-like capsules were only strongly oleophobic and hydrophobic. The liquid-core of the capsules opens great opportunities to incorporate different functionalities and here hydrophobic superparamagnetic nanoparticles (SPIONs) were encapsulated. As a result, magnetic broccoli-like microcapsules formed an excellent superamphiphobic coating-layer on a curved geometry by simply applying an external magnetic field. PMID- 29483614 TI - HLA-DQB1*06 is a risk marker for chlamydia reinfection in African American women. AB - Associations between human leukocyte antigen (HLA) variants and chlamydia-related outcomes have been inconsistent. We previously identified HLA-DQB1*06 as a risk marker for chlamydia reinfection in a cohort of predominately HIV-infected adolescents. As chlamydia reinfection can lead to reproductive complications, validation of this finding in HIV-seronegative women may help reveal the underlying biology. We performed HLA-DQB1 genotyping in HIV-seronegative, chlamydia-infected African American women who were evaluated for reinfection at 3 and 6-month visits after treatment. Of 185 evaluable women for whom HLA-DQB1 genotyping was performed, only HLA-DQB1*06 was associated with chlamydia reinfection (P = 0.009), with no evidence of a dose-response effect for this allele. African American women with HLA-DQB1*06 may warrant more frequent chlamydia screening. More comprehensive genotyping of HLA class II and neighboring genes is needed to establish whether HLA-DQB1*06 is a causal variant for chlamydia reinfection or a surrogate for other causal variants in the major histocompatibility complex. PMID- 29483615 TI - CRISPR/cas9 mediated knockout of an intergenic variant rs6927172 identified IL 20RA as a new risk gene for multiple autoimmune diseases. AB - Genetic variants near the tumor necrosis factor-alpha-induced protein 3 gene (TNFAIP3) at the chromosomal region 6q23 demonstrated significant associations with multiple autoimmune diseases. The signals of associations have been explained to the TNFAIP3 gene, the most likely causal gene. In this study, we employed CRISPR/cas9 genome-editing tool to generate cell lines with deletions including a candidate causal variant, rs6927172, at 140 kb upstream of the TNFAIP3 gene. Interestingly, we observed alterations of multiple genes including IL-20RA encoding a subunit of the receptor for interleukin 20. Using Electrophoretic mobility shift assay (EMSA), Western blotting, and chromatin conformation capture we characterized the molecular mechanism that the DNA element carrying the variant rs6927172 influences expression of IL-20RA and TNFAIP3 genes. Additionally, we developed a new use of the transcription activator-like effector (TALE) to study the role of the variant in regulating expressions of its target genes. In summary, we generated deletion knockouts that included the candidate causal variant rs6927172 in HEK293T cells provided new evidence and mechanism for IL-20RA gene as a risk factor for multiple autoimmune diseases. PMID- 29483616 TI - Pharmacological Mobilization of Endogenous Bone Marrow Stem Cells Promotes Liver Regeneration after Extensive Liver Resection in Rats. AB - Rapid regeneration of the remnant liver is critical for preventing liver failure and promoting recovery after extensive liver resection. Numerous studies have demonstrated the involvement of bone marrow-derived stem cells in liver regeneration and the potential benefits of bone marrow stem cell therapy. To avoid the preparation of stem cells, we proposed in this study to mobilize endogenous bone marrow stem cells pharmacologically with a combination of AMD3100 (A), an antagonist of CXCR4 and low-dose FK506 (F). Here we show that AF combination therapy significantly increased lineage negative (Lin-) CD34+ and Lin CD133+ stem cells in peripheral blood and enhanced recruitment of CD133+ cells into the remnant liver in a rat model of 85% partial hepatectomy. Recruiting CD133+ stem cells in the remnant liver was associated with increased proliferation of hepatic oval cells and paralleled the increased SDF-1, CXCR4 and HGF expression. Importantly, AF combination therapy increased the number of Ki67 positive hepatocytes and BrdU incorporation in the remnant liver and improved serum levels of albumin. Our results demonstrate that pharmacological mobilization of endogenous bone marrow stem cells with AF combination therapy can enhance endogenous stem cell mobilization to promote liver regeneration and improve liver function after extensive hepatectomy. PMID- 29483618 TI - Real-time energy/mass transfer mapping for online 4D dose reconstruction. AB - In this work we describe an ultra-fast, low-latency implementation of the energy/mass transfer (EMT) mapping method to accumulate dose on deforming geometries such as lung using the central processing unit (CPU). It enables the computation of the actually delivered dose for intensity-modulated radiation therapy on 4D image data in real-time at 25 Hz. In order to accumulate the delivered dose onto a reference phase a pre-calculated deformable vector field is used. The aim of this study is to present an online dose accumulation technique that can be carried out in less than 40 ms to accommodate the machine log update rate of our research linac. Three speed optimisation strategies for the CPU are discussed: single-core optimisation, parallelisation for multiple cores and vectorisation. The single-core implementation accumulates dose in about 1.1 s on a typical high resolution grid for a lung stereotactic body radiation therapy case. Adding parallelisation decreased the runtime to about 50 ms while adding vectorisation satisfied our real-time constraint by further reducing the dose accumulation time to 15 ms without compromising on resolution or accuracy. The presented method allows real-time dose accumulation on deforming patient geometries and has the potential to enable online dose evaluation and re-planning scenarios. PMID- 29483617 TI - Dysregulation of RNF213 promotes cerebral hypoperfusion. AB - RNF213 is a susceptibility gene for moyamoya disease, yet its exact functions remain unclear. To evaluate the role of RNF213 in adaptation of cerebral blood flow (CBF) under cerebral hypoperfusion, we performed bilateral common carotid artery stenosis surgery using external microcoils on Rnf213 knockout (KO) and vascular endothelial cell-specific Rnf213 mutant (human p.R4810K orthologue) transgenic (EC-Tg) mice. Temporal CBF changes were measured by arterial spin labelling magnetic resonance imaging. In the cortical area, no significant difference in CBF was found before surgery between the genotypes. Three of eight (37.5%) KO mice died after surgery but all wild-type and EC-Tg mice survived hypoperfusion. KO mice had a significantly more severe reduction in CBF on day 7 than wild-type mice (KO, 29.7% of baseline level; wild-type, 49.3%; p = 0.038), while CBF restoration on day 28 was significantly impaired in both KO (50.0%) and EC-Tg (56.1%) mice compared with wild-type mice (69.5%; p = 0.031 and 0.037, respectively). Changes in the subcortical area also showed the same tendency as the cortical area. Additionally, histological analysis demonstrated that angiogenesis was impaired in both EC-Tg and KO mice. These results are indicative of the essential role of RNF213 in the maintenance of CBF. PMID- 29483619 TI - Normalization of cell associated antiretroviral drug concentrations with a novel RPP30 droplet digital PCR assay. AB - Quantification of antiretroviral (ARV) drug concentrations in peripheral blood mononuclear cells (PBMCs) and tissue isolated mononuclear cells (TIMCs) from lymph node (LNMC) and rectum (RMC) is an important measure of bio-distribution. Normalization of drug concentrations is critical to represent tissue drug concentrations and to analyze both intra-individual and inter-individual variability in drug distribution. However, a molecular method to normalize intracellular drug concentrations in PBMCs and TIMCs methanol extracts is currently unavailable. In this study, a novel droplet digital PCR (ddPCR) assay was designed to amplify RPP30 gene sequence conserved in human and non-human primates (NHP). Genomic DNA (gDNA) isolated from 70 percent methanol embedded PBMCs and TIMCs was used as ddPCR template to quantitate precise RPP30 copies to derive cell counts. The novel molecular method quantitated RPP30 copies in human and rhesus macaque gDNA templates with greater accuracy and precision than qPCR. RPP30 ddPCR derived cell counts are strongly correlated with automated cytometer based cell counts in PBMC (R = 0.90, p = 0.001 and n = 20); LNMC (R = 0.85 p = 0.0001 and n = 22) and RMC (R = 0.92, p = 0.0001 and n = 20) and achieved comparable normalized drug concentrations. Therefore, the RPP30 ddPCR assay is an important normalization method in drug bio-distribution and pharmacokinetic studies in humans and NHPs. PMID- 29483620 TI - Novel 3D Liquid Cell Culture Method for Anchorage-independent Cell Growth, Cell Imaging and Automated Drug Screening. AB - Cells grown in three-dimensional (3D) cultures are more likely to have native cell-cell and cell-matrix interactions than in 2D cultures that impose mechanical constraints to cells. However, most 3D cultures utilise gel matrix which, while serving as a scaffold, limits application due to its solid and opaque nature and inconsistency in cell exposure to exogenous signals. In 3D culture without gel matrix, cells tend to adhere to each other and form clumps with necrotic zone at the centre, making them unsuitable for analyses. Here we report that addition of low-molecular-weight agar named LA717 to culture media allows cells to grow as dispersed clonal spheroids in 3D. LA717 maintains cells dispersed and settled to the bottom of the medium while keeping the medium clear with little additional viscosity, making it suitable for microscopic observation. Importantly, cancer spheroids formed in LA717-containing medium show higher sensitivity to anti cancer drugs such as Trametinib and MK-2206 that are not as effective in 2D. Because of the small and consistent size of spheroids, cell viability and drug toxicity are readily detectable in automated imaging analysis. These results demonstrate that LA717 offers a novel 3D culture system with great in vivo reflection and practicality. PMID- 29483622 TI - TSG-6 secreted by bone marrow mesenchymal stem cells attenuates intervertebral disc degeneration by inhibiting the TLR2/NF-kappaB signaling pathway. AB - Inflammation has been correlated with intervertebral disc degeneration (IDD). Recent evidence suggests that TNF-alpha-stimulated gene 6 protein (TSG-6) secreted by bone marrow mesenchymal stem cells (BMSCs) displays a remarkable ability to inhibit inflammatory processes in a variety of diseases. However, it is unknown whether BMSCs exert their therapeutic effect against IDD by secreting TSG-6. Here we investigated the effects of BMSCs and TSG-6 on IDD and explored the possible underlying mechanisms in vitro and in vivo. We found that BMSCs and TSG-6 reduced the expression of MMP-3 and MMP-13, and increased the expression of collagen II and aggrecan in the IL-1beta-treated nucleus pulposus cells (NPCs), but the protective effects of BMSCs and TSG-6 were attenuated when TSG-6 expression was silenced. We also found that the activation of the TLR2/NF-kappaB pathway was inhibited by BMSCs and TSG-6. The levels of IL-6 and TNF-alpha in the degenerated NPCs were reduced and the proliferation of IL-1beta-treated NPCs was increased in the presence of BMSCs and TSG-6. Furthermore, in vivo experiments showed that BMSCs and TSG-6 restored the MRI T2-weighted signal intensity and increased collagen II and aggrecan expression in the degenerated nucleus pulposus (NP) tissues. Finally, our results showed that BMSCs and TSG-6 downregulated the TLR2/NF-kappaB signaling and reduced the expression of MMPs and inflammatory cytokines in the degenerated NP tissues. The present study is the first to demonstrate the involvement of TLR2/NF-kappaB pathway in the potential anti-IDD therapeutic effect of TSG-6, and the results provide new insight into the beneficial effect of BMSCs in the treatment of IDD. PMID- 29483623 TI - Upper arm anthropometrics versus DXA scan in survivors of acute respiratory distress syndrome. AB - Survivors of acute respiratory distress syndrome (ARDS) experience severe muscle wasting. Upper arm anthropometrics can provide a quick, non-invasive estimate of muscle status, but its accuracy is unknown. This study examines the accuracy of upper arm percent muscle area (UAMA) with reference measures of lean mass from dual energy X-ray absorptiometry (DXA). Data are from 120 ARDS survivors participating in a multicenter national study. Receiver operating characteristic (ROC) curves, by patient sex, demonstrated that UAMA did no better than chance in discriminating low appendicular skeletal muscle mass identified using DXA findings (c-statistics, 6 months: 0.50-0.59, 12 months: 0.54-0.57). Modest correlations of UAMA with DXA measures (whole-body: r = 0.46-0.49, arm-specific: r = 0.50-0.51, p < 0.001) and Bland-Altman plots indicate poor precision. UAMA is not an appropriate screening measure for estimating muscle mass when compared to a DXA reference standard. Alternate screening measures should be evaluated in ARDS survivors. PMID- 29483621 TI - The efficacy of Ranolazine on E1784K is altered by temperature and calcium. AB - E1784K is the most common mixed syndrome SCN5a mutation underpinning both Brugada syndrome type 1 (BrS1) and Long-QT syndrome type 3 (LQT3). The charge reversal mutant enhances the late sodium current (INa) passed by the cardiac voltage-gated sodium channel (NaV1.5), delaying cardiac repolarization. Exercise-induced triggers, like elevated temperature and cytosolic calcium, exacerbate E1784K late INa. In this study, we tested the effects of Ranolazine, the late INa blocker, on voltage-dependent and kinetic properties of E1784K at elevated temperature and cytosolic calcium. We used whole-cell patch clamp to measure INa from wild type and E1784K channels expressed in HEK293 cells. At elevated temperature, Ranolazine attenuated gain-of-function in E1784K by decreasing late INa, hyperpolarizing steady-state fast inactivation, and increasing use-dependent inactivation. Both elevated temperature and cytosolic calcium hampered the capacity of Ranolazine to suppress E1784K late INa. In-silico action potential (AP) simulations were done using a modified O'Hara Rudy (ORd) cardiac model. Simulations showed that Ranolazine failed to shorten AP duration, an effect augmented at febrile temperatures. The drug-channel interaction is clearly affected by external triggers, as reported previously with ischemia. Determining drug efficacy under various physiological states in SCN5a cohorts is crucial for accurate management of arrhythmias. PMID- 29483624 TI - Synaptic and transcriptionally downregulated genes are associated with cortical thickness differences in autism. AB - Differences in cortical morphology-in particular, cortical volume, thickness and surface area-have been reported in individuals with autism. However, it is unclear what aspects of genetic and transcriptomic variation are associated with these differences. Here we investigate the genetic correlates of global cortical thickness differences (DeltaCT) in children with autism. We used Partial Least Squares Regression (PLSR) on structural MRI data from 548 children (166 with autism, 295 neurotypical children and 87 children with ADHD) and cortical gene expression data from the Allen Institute for Brain Science to identify genetic correlates of DeltaCT in autism. We identify that these genes are enriched for synaptic transmission pathways and explain significant variation in DeltaCT. These genes are also significantly enriched for genes dysregulated in the autism post-mortem cortex (Odd Ratio (OR) = 1.11, Pcorrected 10-14), driven entirely by downregulated genes (OR = 1.87, Pcorrected 10-15). We validated the enrichment for downregulated genes in two independent data sets: Validation 1 (OR = 1.44, Pcorrected = 0.004) and Validation 2 (OR = 1.30; Pcorrected = 0.001). We conclude that transcriptionally downregulated genes implicated in autism are robustly associated with global changes in cortical thickness variability in children with autism. PMID- 29483626 TI - Vasopressin-secreting neurons derived from human embryonic stem cells through specific induction of dorsal hypothalamic progenitors. AB - Arginine-vasopressin (AVP) neurons exist in the hypothalamus, a major region of the diencephalon, and play an essential role in water balance. Here, we established the differentiation method for AVP-secreting neurons from human embryonic stem cells (hESCs) by recapitulating in vitro the in vivo embryonic developmental processes of AVP neurons. At first, the differentiation efficiency was improved. That was achieved through the optimization of the culture condition for obtaining dorsal hypothalamic progenitors. Secondly, the induced AVP neurons were identified by immunohistochemistry and these neurons secreted AVP after potassium chloride stimulation. Additionally, other hypothalamic neuropeptides were also detected, such as oxytocin, corticotropin-releasing hormone, thyrotropin-releasing hormone, pro-opiomelanocortin, agouti-related peptide, orexin, and melanin-concentrating hormone. This is the first report describing the generation of secretory AVP neurons derived from hESCs. This method will be applicable to research using disease models and, potentially, for regenerative medicine of the hypothalamus. PMID- 29483628 TI - Substance Index for Volume 70. PMID- 29483625 TI - New considerations for hiPSC-based models of neuropsychiatric disorders. AB - The development of human-induced pluripotent stem cells (hiPSCs) has made possible patient-specific modeling across the spectrum of human disease. Here, we discuss recent advances in psychiatric genomics and post-mortem studies that provide critical insights concerning cell-type composition and sample size that should be considered when designing hiPSC-based studies of complex genetic disease. We review recent hiPSC-based models of SZ, in light of our new understanding of critical power limitations in the design of hiPSC-based studies of complex genetic disorders. Three possible solutions are a movement towards genetically stratified cohorts of rare variant patients, application of CRISPR technologies to engineer isogenic neural cells to study the impact of common variants, and integration of advanced genetics and hiPSC-based datasets in future studies. Overall, we emphasize that to advance the reproducibility and relevance of hiPSC-based studies, stem cell biologists must contemplate statistical and biological considerations that are already well accepted in the field of genetics. We conclude with a discussion of the hypothesis of biological convergence of disease-through molecular, cellular, circuit, and patient level phenotypes-and how this might emerge through hiPSC-based studies. PMID- 29483627 TI - Virtual Touch IQ elastography reduces unnecessary breast biopsies by applying quantitative "rule-in" and "rule-out" threshold values. AB - Our purpose was to evaluate Virtual Touch IQ (VTIQ) elastography and identify quantitative "rule-in" and "rule-out" thresholds for the probability of malignancy, which can help avoid unnecessary breast biopsies. 189 patients with 196 sonographically evident lesions were included in this retrospective, IRB approved study. Quantitative VTIQ images of each lesion measuring the respective maximum Shear Wave Velocity (SWV) were obtained. Paired and unpaired, non parametric statistics were applied for comparisons as appropriate. ROC-curve analysis was used to analyse the diagnostic performance of VTIQ and to specify "rule-in" and "rule-out" thresholds for the probability of malignancy. The standard of reference was either histopathology or follow-up stability for >24 months. 84 lesions were malignant and 112 benign. Median SWV of benign lesions was significantly lower than that of malignant lesions (p < 0.001). The application of a "rule-out" threshold of 1.9 m/s lead to a sensitivity of >98% with a concomitant significant (p = 0.032) reduction in false positive cases of almost 15%, whereas a "rule-in" threshold of 6.5 m/s suggested a probability of malignancy of >95%. In conclusion, VTIQ elastography accurately differentiates malignant from benign breast lesions. The application of quantitative "rule-in" and "rule-out" thresholds is feasible and allows reduction of unnecessary benign breast biopsies by almost 15%. PMID- 29483630 TI - First profiling of lysine crotonylation of myofilament proteins and ribosomal proteins in zebrafish embryos. AB - Zebrafish embryos are translucent and develop rapidly in individual eggs ex utero; they are widely used as models for embryogenesis and organ development for human diseases and drug discovery. Lysine crotonylation (Kcr) is a type of histone post-translational modifications discovered in 2011. Kcr dynamics are involved in gene expression regulation and acute kidney injury; however, little is known about the effects of Kcr on non-histone proteins. In the present study, we conducted the first proteome-wide profiling of Kcr in zebrafish larvae and identified 557 Kcr sites on 218 proteins, representing the Kcr event in zebrafish. We identified two types of Kcr motifs containing hydrophobic (Leu, Ile, Val) and acidic (Asp and Glu) amino acids near the modified lysine residues. Our results show that both crotonylated proteins and sites of crotonylation were evolutionarily conserved between zebrafish embryos and humans. Specifically, Kcr on ribosomal proteins and myofilament proteins, including myosin, tropomyosin and troponin, were widely enriched. Interestingly, 55 lysine crotonylation sites on myosin were distributed throughout coiled coil regions. Therefore, Kcr may regulate muscle contraction and protein synthesis. Our results provide a foundation for future studies on the effects of lysine crotonylation on aging and heart failure. PMID- 29483631 TI - Antibiotic growth promoters virginiamycin and bacitracin methylene disalicylate alter the chicken intestinal metabolome. AB - Although dietary antibiotic growth promoters have long been used to increase growth performance in commercial food animal production, the biochemical details associated with these effects remain poorly defined. A metabolomics approach was used to characterize and identify the biochemical compounds present in the intestine of broiler chickens fed a standard, unsupplemented diet or a diet supplemented with the antibiotic growth promoters, virginiamycin or bacitracin methylene disalicylate. Compared with unsupplemented controls, the levels of 218 biochemicals were altered (156 increased, 62 decreased) in chickens given the virginiamycin-supplemented diet, while 119 were altered (96 increased, 23 decreased) with the bacitracin-supplemented diet. When compared between antibiotic-supplemented groups, 79 chemicals were altered (43 increased, 36 decreased) in virginiamycin- vs. bacitracin-supplemented chickens. The changes in the levels of intestinal biochemicals provided a distinctive biochemical signature unique to each antibiotic-supplemented group. These biochemical signatures were characterized by increases in the levels of metabolites of amino acids (e.g. 5-hydroxylysine, 2-aminoadipate, 5-hydroxyindoleaceate, 7 hydroxyindole sulfate), fatty acids (e.g. oleate/vaccenate, eicosapentaenoate, 16 hydroxypalmitate, stearate), nucleosides (e.g. inosine, N6-methyladenosine), and vitamins (e.g. nicotinamide). These results provide the framework for future studies to identify natural chemical compounds to improve poultry growth performance without the use of in-feed antibiotics. PMID- 29483632 TI - The chejuenolide biosynthetic gene cluster harboring an iterative trans-AT PKS system in Hahella chejuensis strain MB-1084. AB - Hahella chejuensis MB-1084 is a Gram-negative marine bacterial strain that produces unusual 17-membered carbocyclic tetraenes, chejuenolide A and B. Two fosmid clones responsible for chejuenolide production were identified from the genomic DNA library of the MB-1084 strain. Systematic inactivation of the open reading frames (ORFs) in the sequenced region defines the boundaries of the chejuenolide (che) biosynthetic gene cluster (24.9 kbp) that encodes one non ribosomal peptide synthase (NRPS)-polyketide synthase (PKS) hybrid protein, three modular PKSs, two PKS domains, and an amine oxidase homolog. Based on the results, we found that the che PKSs have non-canonical features such as trans-AT system and insufficient number of KS domains (five KS domains) for chejuenolide production (requires eight rounds of Claisen condensation reaction). Heterologous expression of the che PKSs in the E. coli BAP1 strain provides strong evidence of the iterative characteristic of the modular PKSs. Additionally, the phylogenetic relatedness of the KS domains of che PKSs and other trans-AT PKSs was analyzed to propose a possible pathway for chejuenolide biosynthesis. PMID- 29483634 TI - The role of reticular chemistry in the design of CO2 reduction catalysts. AB - The problem with current state-of-the-art catalysts for CO2 photo- or electroreduction is rooted in the notion that no single system can independently control, and thus optimize, the interplay between activity, selectivity and efficiency. At its core, reticular chemistry is recognized for its ability to control, with atomic precision, the chemical and structural features (activity and selectivity) as well as the output optoelectronic properties (efficiency) of porous, crystalline materials. The molecular building blocks that are in a reticular chemist's toolbox are chosen in such a way that the structures are rationally designed, framework chemistry is performed to integrate catalytically active components, and the manner in which these building blocks are connected endows the material with the desired optoelectronic properties. The fact that these aspects can be fine-tuned independently lends credence to the prospect of reticular chemistry contributing to the design of next-generation CO2 reduction catalysts. PMID- 29483633 TI - Targeted Mutation of NGN3 Gene Disrupts Pancreatic Endocrine Cell Development in Pigs. AB - The domestic pig is an attractive model for biomedical research because of similarities in anatomy and physiology to humans. However, key gaps remain in our understanding of the role of developmental genes in pig, limiting its full potential. In this publication, the role of NEUROGENIN 3 (NGN3), a transcription factor involved in endocrine pancreas development has been investigated by CRISPR/Cas9 gene ablation. Precomplexed Cas9 ribonucleoproteins targeting NGN3 were injected into in vivo derived porcine embryos, and transferred into surrogate females. On day 60 of pregnancy, nine fetuses were collected for genotypic and phenotypic analysis. One of the piglets was identified as an in frame biallelic knockout (Delta2/Delta2), which showed a loss of putative NGN3 downstream target genes: NEUROD1 and PAX4, as well as insulin, glucagon, somatostatin and pancreatic polypeptide-Y. Fibroblasts from this fetus were used in somatic cell nuclear transfer to generate clonal animals to qualify the effect of mutation on embryonic lethality. Three live piglets were born, received colostrum and suckled normally, but experienced extreme weight loss over a 24 to 36-hour period requiring humane euthanasia. Expression of pancreatic endocrine hormones: insulin, glucagon, and somatostatin were lost. The data support a critical role of NGN3 in porcine endocrine pancreas development. PMID- 29483635 TI - Insight into doping efficiency of organic semiconductors from the analysis of the density of states in n-doped C60 and ZnPc. AB - Doping plays a crucial role in semiconductor physics, with n-doping being controlled by the ionization energy of the impurity relative to the conduction band edge. In organic semiconductors, efficient doping is dominated by various effects that are currently not well understood. Here, we simulate and experimentally measure, with direct and inverse photoemission spectroscopy, the density of states and the Fermi level position of the prototypical materials C60 and zinc phthalocyanine n-doped with highly efficient benzimidazoline radicals (2 Cyc-DMBI). We study the role of doping-induced gap states, and, in particular, of the difference Delta1 between the electron affinity of the undoped material and the ionization potential of its doped counterpart. We show that this parameter is critical for the generation of free carriers and influences the conductivity of the doped films. Tuning of Delta1 may provide alternative strategies to optimize the electronic properties of organic semiconductors. PMID- 29483637 TI - Observation of the adsorption and desorption of vibrationally excited molecules on a metal surface. AB - The most common mechanism of catalytic surface chemistry is that of Langmuir and Hinshelwood (LH). In the LH mechanism, reactants adsorb, become thermalized with the surface, and subsequently react. The measured vibrational (relaxation) lifetimes of molecules adsorbed at metal surfaces are in the range of a few picoseconds. As a consequence, vibrational promotion of LH chemistry is rarely observed, with the exception of LH reactions occurring via a molecular physisorbed intermediate. Here, we directly detect adsorption and subsequent desorption of vibrationally excited CO molecules from a Au(111) surface. Our results show that CO (v = 1) survives on a Au(111) surface for ~1 * 10-10 s. Such long vibrational lifetimes for adsorbates on metal surfaces are unexpected and pose an interesting challenge to the current understanding of vibrational energy dissipation on metal surfaces. They also suggest that vibrational promotion of surface chemistry might be more common than is generally believed. PMID- 29483636 TI - Acoustically modulated magnetic resonance imaging of gas-filled protein nanostructures. AB - Non-invasive biological imaging requires materials capable of interacting with deeply penetrant forms of energy such as magnetic fields and sound waves. Here, we show that gas vesicles (GVs), a unique class of gas-filled protein nanostructures with differential magnetic susceptibility relative to water, can produce robust contrast in magnetic resonance imaging (MRI) at sub-nanomolar concentrations, and that this contrast can be inactivated with ultrasound in situ to enable background-free imaging. We demonstrate this capability in vitro, in cells expressing these nanostructures as genetically encoded reporters, and in three model in vivo scenarios. Genetic variants of GVs, differing in their magnetic or mechanical phenotypes, allow multiplexed imaging using parametric MRI and differential acoustic sensitivity. Additionally, clustering-induced changes in MRI contrast enable the design of dynamic molecular sensors. By coupling the complementary physics of MRI and ultrasound, this nanomaterial gives rise to a distinct modality for molecular imaging with unique advantages and capabilities. PMID- 29483638 TI - Chemical evolution of atmospheric organic carbon over multiple generations of oxidation. AB - The evolution of atmospheric organic carbon as it undergoes oxidation has a controlling influence on concentrations of key atmospheric species, including particulate matter, ozone and oxidants. However, full characterization of organic carbon over hours to days of atmospheric processing has been stymied by its extreme chemical complexity. Here we study the multigenerational oxidation of alpha-pinene in the laboratory, characterizing products with several state-of-the art analytical techniques. Although quantification of some early generation products remains elusive, full carbon closure is achieved (within measurement uncertainty) by the end of the experiments. These results provide new insights into the effects of oxidation on organic carbon properties (volatility, oxidation state and reactivity) and the atmospheric lifecycle of organic carbon. Following an initial period characterized by functionalization reactions and particle growth, fragmentation reactions dominate, forming smaller species. After approximately one day of atmospheric aging, most carbon is sequestered in two long-lived reservoirs-volatile oxidized gases and low-volatility particulate matter. PMID- 29483639 TI - Encapsulation of catalyst in block copolymer micelles for the polymerization of ethylene in aqueous medium. AB - The catalytic emulsion polymerization of ethylene has been a long-lasting technical challenge as current techniques still suffer some limitations. Here we report an alternative strategy for the production of semi-crystalline polyethylene latex. Our methodology consists of encapsulating a catalyst precursor within micelles composed of an amphiphilic block copolymer. These micelles act as nanoreactors for the polymerization of ethylene in water. Phosphinosulfonate palladium complexes were used to demonstrate the success of our approach as they were found to be active for hours when encapsulated in micelles. Despite this long stability, the activity of the catalysts in micelles remains significantly lower than in organic solvent, suggesting some catalyst inhibition. The inhibition strength of the different chemicals present in the micelle were determined and compared. The combination of the small volume of the micelles, and the coordination of PEG appear to be the culprits for the low activity observed in micelles. PMID- 29483640 TI - Resistance to nonribosomal peptide antibiotics mediated by D-stereospecific peptidases. AB - Nonribosomal peptide antibiotics, including polymyxin, vancomycin, and teixobactin, most of which contain D-amino acids, are highly effective against multidrug-resistant bacteria. However, overusing antibiotics while ignoring the risk of resistance arising has inexorably led to widespread emergence of resistant bacteria. Therefore, elucidation of the emerging mechanisms of resistance to nonribosomal peptide antibiotics is critical to their implementation. Here we describe a networking-associated genome-mining platform for linking biosynthetic building blocks to resistance components associated with biosynthetic gene clusters. By applying this approach to 5,585 complete bacterial genomes spanning the entire domain of bacteria, with subsequent chemical and enzymatic analyses, we demonstrate a mechanism of resistance toward nonribosomal peptide antibiotics that is based on hydrolytic cleavage by D-stereospecific peptidases. Our finding reveals both the widespread distribution and broad spectrum resistance potential of D-stereospecific peptidases, providing a potential early indicator of antibiotic resistance to nonribosomal peptide antibiotics. PMID- 29483641 TI - Trp-ing upon new repressors. PMID- 29483643 TI - Directed evolution of a synthetic phylogeny of programmable Trp repressors. AB - As synthetic regulatory programs expand in sophistication, an ever increasing number of biological components with predictable phenotypes is required. Regulators are often 'part mined' from a diverse, but uncharacterized, array of genomic sequences, often leading to idiosyncratic behavior. Here, we generate an entire synthetic phylogeny from the canonical allosteric transcription factor TrpR. Iterative rounds of positive and negative compartmentalized partnered replication (CPR) led to the exponential amplification of variants that responded with high affinity and specificity to halogenated tryptophan analogs and novel operator sites. Fourteen repressor variants were evolved with unique regulatory profiles across five operators and three ligands. The logic of individual repressors can be modularly programmed by creating heterodimeric fusions, resulting in single proteins that display logic functions, such as 'NAND'. Despite the evolutionarily limited regulatory role of TrpR, vast functional spaces exist around this highly conserved protein scaffold and can be harnessed to create synthetic regulatory programs. PMID- 29483642 TI - A robotic multidimensional directed evolution approach applied to fluorescent voltage reporters. AB - We developed a new way to engineer complex proteins toward multidimensional specifications using a simple, yet scalable, directed evolution strategy. By robotically picking mammalian cells that were identified, under a microscope, as expressing proteins that simultaneously exhibit several specific properties, we can screen hundreds of thousands of proteins in a library in just a few hours, evaluating each along multiple performance axes. To demonstrate the power of this approach, we created a genetically encoded fluorescent voltage indicator, simultaneously optimizing its brightness and membrane localization using our microscopy-guided cell-picking strategy. We produced the high-performance opsin based fluorescent voltage reporter Archon1 and demonstrated its utility by imaging spiking and millivolt-scale subthreshold and synaptic activity in acute mouse brain slices and in larval zebrafish in vivo. We also measured postsynaptic responses downstream of optogenetically controlled neurons in C. elegans. PMID- 29483645 TI - ERK5 is activated by oncogenic BRAF and promotes melanoma growth. AB - Malignant melanoma is among the most aggressive cancers and its incidence is increasing worldwide. Targeted therapies and immunotherapy have improved the survival of patients with metastatic melanoma in the last few years; however, available treatments are still unsatisfactory. While the role of the BRAF-MEK1/2 ERK1/2 pathway in melanoma is well established, the involvement of mitogen activated protein kinases MEK5-ERK5 remains poorly explored. Here we investigated the function of ERK5 signaling in melanoma. We show that ERK5 is consistently expressed in human melanoma tissues and is active in melanoma cells. Genetic silencing and pharmacological inhibition of ERK5 pathway drastically reduce the growth of melanoma cells and xenografts harboring wild-type (wt) or mutated BRAF (V600E). We also found that oncogenic BRAF positively regulates expression, phosphorylation, and nuclear localization of ERK5. Importantly, ERK5 kinase and transcriptional transactivator activities are enhanced by BRAF. Nevertheless, combined pharmacological inhibition of BRAFV600E and MEK5 is required to decrease nuclear ERK5, that is critical for the regulation of cell proliferation. Accordingly, combination of MEK5 or ERK5 inhibitors with BRAFV600E inhibitor vemurafenib is more effective than single treatments in reducing colony formation and growth of BRAFV600E melanoma cells and xenografts. Overall, these data support a key role of the ERK5 pathway for melanoma growth in vitro and in vivo and suggest that targeting ERK5, alone or in combination with BRAF-MEK1/2 inhibitors, might represent a novel approach for melanoma treatment. PMID- 29483644 TI - The ablation of the matricellular protein EMILIN2 causes defective vascularization due to impaired EGFR-dependent IL-8 production affecting tumor growth. AB - EMILIN2 is an extracellular matrix constituent playing an important role in angiogenesis; however, the underlying mechanism is unknown. Here we show that EMILIN2 promotes angiogenesis by directly binding epidermal growth factor receptor (EGFR), which enhances interleukin-8 (IL-8) production. In turn, IL-8 stimulates the proliferation and migration of vascular endothelial cells. Emilin2 null mice were generated and exhibited delayed retinal vascular development, which was rescued by the administration of the IL-8 murine ortholog MIP-2. Next, we assessed tumor growth and tumor-associated angiogenesis in these mice. Tumor cell growth in Emilin2 null mice was impaired as well as the expression of MIP-2. The vascular density of the tumors developed in Emilin2 null mice was prejudiced and vessels perfusion, as well as response to chemotherapy, decreased. Accordingly, human tumors expressing high levels of EMILIN2 were more responsive to chemotherapy. These results point at EMILIN2 as a key microenvironmental cue affecting vessel formation and unveil the possibility to develop new prognostic tools to predict chemotherapy efficacy. PMID- 29483646 TI - LINC01410-miR-532-NCF2-NF-kB feedback loop promotes gastric cancer angiogenesis and metastasis. AB - Dysregulation of non-coding RNAs, including miRNAs and lncRNAs has been reported to play vital roles in gastric cancer (GC) carcinogenesis, but the mechanism involved is largely unknown. Using the cancer genome atlas (TCGA) data set and bioinformatics analyses, we identified miR-532-5p as a potential tumor suppressor in GC, and found that lncRNA LINC01410 might be a negative regulator of miR-532 5p. We then conducted a series of in vivo and in vitro assays to explore the effect of LINC01410 on miR-532-5p-mediated GC malignancy and the underlying mechanism involved. MiR-532-5p overexpression inhibited GC metastasis and angiogenesis in vitro and in vivo, whereas miR-532-5p silencing had the opposite effect. Further study showed that miR-532-5p attenuated NF-kappaB signaling by directly inhibiting NCF2 expression, while miR-532-5p silencing in GC enhanced NF kappaB activity. Furthermore, we demonstrated miR-532-5p down-regulation was caused by aberrantly high expression of LINC01410 in GC. Mechanistically, overexpression of LINC01410 promoted GC angiogenesis and metastasis by binding to and suppressing miR-532-5p, which resulted in up-regulation of NCF2 and sustained NF-kappaB pathway activation. Interestingly, NCF2 could in turn increase the promoter activity and expression of LINC01410 via NF-kappaB, thus forming a positive feedback loop that drives the malignant behavior of GC. Finally, high expression of LINC01410, along with low expression of miR-532-5p, was associated with poor survival outcome in GC patients. Our studies uncover a mechanism for constitutive LINC1410-miR-532-5p-NCF2-NF-kappaB feedback loop activation in GC, and consequently, as a potential therapeutic target in GC treatment. PMID- 29483647 TI - MicroRNA degradation by a conserved target RNA regulates animal behavior. AB - microRNAs (miRNAs) repress target transcripts through partial complementarity. By contrast, highly complementary miRNA-binding sites within viral and artificially engineered transcripts induce miRNA degradation in vitro and in cell lines. Here, we show that a genome-encoded transcript harboring a near-perfect and deeply conserved miRNA-binding site for miR-29 controls zebrafish and mouse behavior. This transcript originated in basal vertebrates as a long noncoding RNA (lncRNA) and evolved to the protein-coding gene NREP in mammals, where the miR-29-binding site is located within the 3' UTR. We show that the near-perfect miRNA site selectively triggers miR-29b destabilization through 3' trimming and restricts its spatial expression in the cerebellum. Genetic disruption of the miR-29 site within mouse Nrep results in ectopic expression of cerebellar miR-29b and impaired coordination and motor learning. Thus, we demonstrate an endogenous target-RNA-directed miRNA degradation event and its requirement for animal behavior. PMID- 29483648 TI - Screening, large-scale production and structure-based classification of cystine dense peptides. AB - Peptides folded through interwoven disulfides display extreme biochemical properties and unique medicinal potential. However, their exploitation has been hampered by the limited amounts isolatable from natural sources and the expense of chemical synthesis. We developed reliable biological methods for high throughput expression, screening and large-scale production of these peptides: 46 were successfully produced in multimilligram quantities, and >600 more were deemed expressible through stringent screening criteria. Many showed extreme resistance to temperature, proteolysis and/or reduction, and all displayed inhibitory activity against at least 1 of 20 ion channels tested, thus confirming their biological functionality. Crystal structures of 12 confirmed proper cystine topology and the utility of crystallography to study these molecules but also highlighted the need for rational classification. Previous categorization attempts have focused on limited subsets featuring distinct motifs. Here we present a global definition, classification and analysis of >700 structures of cystine-dense peptides, providing a unifying framework for these molecules. PMID- 29483649 TI - Structural basis for GTP hydrolysis and conformational change of MFN1 in mediating membrane fusion. AB - Fusion of the outer mitochondrial membrane is mediated by the dynamin-like GTPase mitofusin (MFN). Here, we determined the structure of the minimal GTPase domain (MGD) of human MFN1 in complex with GDP-BeF3-. The MGD folds into a canonical GTPase fold with an associating four-helix bundle, HB1, and forms a dimer. A potassium ion in the catalytic core engages GDP and BeF3- (GDP-BeF3-). Enzymatic analysis has confirmed that efficient GTP hydrolysis by MFN1 requires potassium. Compared to previously reported MGD structures, the HB1 structure undergoes a major conformational change relative to the GTPase domains, as they move from pointing in opposite directions to point in the same direction, suggesting that a swing of the four-helix bundle can pull tethered membranes closer to achieve fusion. The proposed model is supported by results from in vitro biochemical assays and mitochondria morphology rescue assays in MFN1-deleted cells. These findings offer an explanation for how Charcot-Marie-Tooth neuropathy type 2 A (CMT2A)-causing mutations compromise MFN-mediated fusion. PMID- 29483650 TI - Accurate H3K27 methylation can be established de novo by SUZ12-directed PRC2. AB - Polycomb repressive complex 2 (PRC2) catalyzes methylation on lysine 27 of histone H3 (H3K27) and is required for maintaining transcriptional patterns and cellular identity, but the specification and maintenance of genomic PRC2 binding and H3K27 methylation patterns remain incompletely understood. Epigenetic mechanisms have been proposed, wherein pre-existing H3K27 methylation directs recruitment and regulates the catalytic activity of PRC2 to support its own maintenance. Here we investigate whether such mechanisms are required for specifying H3K27 methylation patterns in mouse embryonic stem cells (mESCs). Through re-expression of PRC2 subunits in PRC2-knockout cells that have lost all H3K27 methylation, we demonstrate that methylation patterns can be accurately established de novo. We find that regional methylation kinetics correlate with original methylation patterns even in their absence, and specification of the genomic PRC2 binding pattern is retained and specifically dependent on the PRC2 core subunit SUZ12. Thus, the H3K27 methylation patterns in mESCs are not dependent on self-autonomous epigenetic inheritance. PMID- 29483652 TI - Oocyte DNA damage quality control requires consecutive interplay of CHK2 and CK1 to activate p63. AB - The survival rate of cancer patients is steadily increasing, owing to more efficient therapies. Understanding the molecular mechanisms of chemotherapy induced premature ovarian insufficiency (POI) could identify targets for prevention of POI. Loss of the primordial follicle reserve is the most important cause of POI, with the p53 family member p63 being responsible for DNA-damage induced apoptosis of resting oocytes. Here, we provide the first detailed mechanistic insight into the activation of p63, a process that requires phosphorylation by both the priming kinase CHK2 and the executioner kinase CK1 in mouse primordial follicles. We further describe the structural changes induced by phosphorylation that enable p63 to adopt its active tetrameric conformation and demonstrate that previously discussed phosphorylation by c-Abl is not involved in this process. Inhibition of CK1 rescues primary oocytes from doxorubicin and cisplatin-induced apoptosis, thus uncovering a new target for the development of fertoprotective therapies. PMID- 29483651 TI - Cryo-EM and X-ray structures of TRPV4 reveal insight into ion permeation and gating mechanisms. AB - The transient receptor potential (TRP) channel TRPV4 participates in multiple biological processes, and numerous TRPV4 mutations underlie several distinct and devastating diseases. Here we present the cryo-EM structure of Xenopus tropicalis TRPV4 at 3.8-A resolution. The ion-conduction pore contains an intracellular gate formed by the inner helices, but lacks any extracellular gate in the selectivity filter, as observed in other TRPV channels. Anomalous X-ray diffraction analyses identify a single ion-binding site in the selectivity filter, thus explaining TRPV4 nonselectivity. Structural comparisons with other TRP channels and distantly related voltage-gated cation channels reveal an unprecedented, unique packing interface between the voltage-sensor-like domain and the pore domain, suggesting distinct gating mechanisms. Moreover, our structure begins to provide mechanistic insights to the large set of pathogenic mutations, offering potential opportunities for drug development. PMID- 29483653 TI - Human TGF-beta1 deficiency causes severe inflammatory bowel disease and encephalopathy. AB - Transforming growth factor (TGF)-beta1 (encoded by TGFB1) is the prototypic member of the TGF-beta family of 33 proteins that orchestrate embryogenesis, development and tissue homeostasis1,2. Following its discovery 3 , enormous interest and numerous controversies have emerged about the role of TGF-beta in coordinating the balance of pro- and anti-oncogenic properties4,5, pro- and anti inflammatory effects 6 , or pro- and anti-fibrinogenic characteristics 7 . Here we describe three individuals from two pedigrees with biallelic loss-of-function mutations in the TGFB1 gene who presented with severe infantile inflammatory bowel disease (IBD) and central nervous system (CNS) disease associated with epilepsy, brain atrophy and posterior leukoencephalopathy. The proteins encoded by the mutated TGFB1 alleles were characterized by impaired secretion, function or stability of the TGF-beta1-LAP complex, which is suggestive of perturbed bioavailability of TGF-beta1. Our study shows that TGF-beta1 has a critical and nonredundant role in the development and homeostasis of intestinal immunity and the CNS in humans. PMID- 29483654 TI - The human noncoding genome defined by genetic diversity. AB - Understanding the significance of genetic variants in the noncoding genome is emerging as the next challenge in human genomics. We used the power of 11,257 whole-genome sequences and 16,384 heptamers (7-nt motifs) to build a map of sequence constraint for the human species. This build differed substantially from traditional maps of interspecies conservation and identified regulatory elements among the most constrained regions of the genome. Using new Hi-C experimental data, we describe a strong pattern of coordination over 2 Mb where the most constrained regulatory elements associate with the most essential genes. Constrained regions of the noncoding genome are up to 52-fold enriched for known pathogenic variants as compared to unconstrained regions (21-fold when compared to the genome average). This map of sequence constraint across thousands of individuals is an asset to help interpret noncoding elements in the human genome, prioritize variants and reconsider gene units at a larger scale. PMID- 29483655 TI - RNA-dependent chromatin targeting of TET2 for endogenous retrovirus control in pluripotent stem cells. AB - Ten-eleven translocation (TET) proteins play key roles in the regulation of DNA methylation status by oxidizing 5-methylcytosine (5mC) to generate 5 hydroxymethylcytosine (5hmC), which can both serve as a stable epigenetic mark and participate in active demethylation. Unlike the other members of the TET family, TET2 does not contain a DNA-binding domain, and it remains unclear how it is recruited to chromatin. Here we show that TET2 is recruited by the RNA-binding protein Paraspeckle component 1 (PSPC1) through transcriptionally active loci, including endogenous retroviruses (ERVs) whose long terminal repeats (LTRs) have been co-opted by mammalian genomes as stage- and tissue-specific transcriptional regulatory modules. We found that PSPC1 and TET2 contribute to ERVL and ERVL associated gene regulation by both transcriptional repression via histone deacetylases and post-transcriptional destabilization of RNAs through 5hmC modification. Our findings provide evidence for a functional role of transcriptionally active ERVs as specific docking sites for RNA epigenetic modulation and gene regulation. PMID- 29483657 TI - DSYB catalyses the key step of dimethylsulfoniopropionate biosynthesis in many phytoplankton. AB - Dimethylsulfoniopropionate (DMSP) is a globally important organosulfur molecule and the major precursor for dimethyl sulfide. These compounds are important info chemicals, key nutrients for marine microorganisms, and are involved in global sulfur cycling, atmospheric chemistry and cloud formation1-3. DMSP production was thought to be confined to eukaryotes, but heterotrophic bacteria can also produce DMSP through the pathway used by most phytoplankton 4 , and the DsyB enzyme catalysing the key step of this pathway in bacteria was recently identified 5 . However, eukaryotic phytoplankton probably produce most of Earth's DMSP, yet no DMSP biosynthesis genes have been identified in any such organisms. Here we identify functional dsyB homologues, termed DSYB, in many phytoplankton and corals. DSYB is a methylthiohydroxybutryate methyltransferase enzyme localized in the chloroplasts and mitochondria of the haptophyte Prymnesium parvum, and stable isotope tracking experiments support these organelles as sites of DMSP synthesis. DSYB transcription levels increased with DMSP concentrations in different phytoplankton and were indicative of intracellular DMSP. Identification of the eukaryotic DSYB sequences, along with bacterial dsyB, provides the first molecular tools to predict the relative contributions of eukaryotes and prokaryotes to global DMSP production. Furthermore, evolutionary analysis suggests that eukaryotic DSYB originated in bacteria and was passed to eukaryotes early in their evolution. PMID- 29483658 TI - Muscarinic M5 receptors modulate ethanol seeking in rats. AB - Despite the cost to both individual and society, alcohol use disorders (AUDs) remain a major health risk within society, and both relapse and heavy drinking are still poorly controlled with current medications. Here we demonstrate for the first time that a centrally active and selective negative allosteric modulator for the rat M5 muscarinic acetylcholine receptor (mAChR), ML375, decreases ethanol self-administration and attenuates cue-induced reinstatement of ethanol seeking in ethanol-preferring (iP) rats. Importantly, ML375 did not affect sucrose self-administration or general locomotor activity indicative of a selective effect on ethanol seeking. Based on the expression profile of M5 mAChRs in the brain and the distinct roles different aspects of the dorsal striatum have on long-term and short-term ethanol use, we studied whether intra-striatal microinjection of ML375 modulated ethanol intake in rats. We show in iP rats with an extensive history of ethanol intake that intra-dorsolateral (DL), but not intra-dorsomedial, striatal injections of ML375 reduced ethanol self administration to a similar extent as the nicotinic acetylcholine receptor ligand varenicline, which has preclinical and clinical efficacy in reducing the reinforcing effects of ethanol. These data implicate the DL striatum as a locus for the effects of cholinergic-acting drugs on ethanol seeking in rats with a history of long-term ethanol use. Accordingly, we demonstrate in rats that selectively targeting the M5 mAChR can modulate both voluntary ethanol intake and cue-induced ethanol seeking and thereby provide direct evidence that the M5 mAChR is a potential novel target for pharmacotherapies aimed at treating AUDs. PMID- 29483659 TI - At-risk individuals display altered brain activity following stress. AB - Stress is a major risk factor for almost all psychiatric disorders, however, the underlying neurobiological mechanisms remain largely elusive. In healthy individuals, a successful stress response involves an adequate neuronal adaptation to a changing environment. This adaptive response may be dysfunctional in vulnerable individuals, potentially contributing to the development of psychopathology. In the current study, we investigated brain responses to emotional stimuli following stress in healthy controls and at-risk individuals. An fMRI study was conducted in healthy male controls (N = 39) and unaffected healthy male siblings of schizophrenia patients (N = 39) who are at increased risk for the development of a broad range of psychiatric disorders. Brain responses to pictures from the International Affective Picture System (IAPS) were measured 33 min after exposure to stress induced by the validated trier social stress test (TSST) or a control condition. Stress-induced levels of cortisol, alpha-amylase, and subjective stress were comparable in both groups. Yet, stress differentially affected brain responses of schizophrenia siblings versus controls. Specifically, control subjects, but not schizophrenia siblings, showed reduced brain activity in key nodes of the default mode network (PCC/precuneus and mPFC) and salience network (anterior insula) as well as the STG, MTG, MCC, vlPFC, precentral gyrus, and cerebellar vermis in response to all pictures following stress. These results indicate that even in the absence of a psychiatric disorder, at-risk individuals display abnormal functional activation following stress, which in turn may increase their vulnerability and risk for adverse outcomes. PMID- 29483660 TI - Multiple long-range inputs evoke NMDA currents in prefrontal cortex fast-spiking interneurons. AB - Several aspects of schizophrenia can be mimicked acutely in healthy human volunteers via administration of NMDA glutamate receptor (NMDAR) antagonists. As these agents decrease firing rates in prefrontal cortical (PFC) GABAergic fast spiking interneurons (FSI) in animal studies, a leading hypothesis on schizophrenia pathophysiology is that NMDAR in FSI are impaired. However, whole cell recordings of FSI in slices of adult mouse PFC revealed limited amounts of NMDAR-mediated current. Since those studies used local electrical stimulation to activate a heterogeneous set of synaptic inputs to the recorded cell, it is unclear whether specific afferent inputs may preferentially drive NMDAR responses in FSI. Here, we expressed opsins in discrete brain regions projecting to the PFC in adult male mice, enabling light-activation of defined, homogenous sets of long range inputs to FSI and pyramidal neurons recorded in slices containing medial PFC (mPFC). Stimulation of axons originating from either the contralateral mPFC, ventral hippocampus, or mediodorsal thalamus evoked NMDAR-mediated currents in the vast majority of FSI and in all pyramidal neurons recorded. The observation that multiple long-range inputs to mPFC FSI elicit NMDAR currents suggests that the NMDAR-hypofunction model of schizophrenia may still imply a loss of interneuron inputs, but the sources of reduced excitation may originate from sites upstream of the PFC. PMID- 29483661 TI - Cell-subtype-specific changes in adenosine pathways in schizophrenia. AB - Prior work in animal models implicates abnormalities of adenosine metabolism in astrocytes as a possible pathophysiological mechanism underlying the symptoms of schizophrenia. In the present study, we sought to reverse-translate these findings back to the human brain in schizophrenia, focusing on the following questions: (1) Which components of the adenosine system are dysregulated in schizophrenia, and (2) are these changes limited to astrocytes? To address these questions, we captured enriched populations of DLPFC pyramidal neurons and astrocytes from schizophrenia and control subjects using laser capture microdissection and assessed expression of adenosine system components using qPCR. Interestingly, we found changes in enriched populations of astrocytes and neurons spanning metabolic and catabolic pathways. Ectonucleoside triphosphate diphosphohydrolase-1 (ENTPD1) and ENTPD2 mRNA levels were significantly decreased (p < 0.05, n = 16 per group) in enriched populations of astrocytes; in pyramidal neurons equilibrative nucleoside transporter 1 (ENT1) and adenosine A1 receptor mRNA levels were significantly decreased, with an increase in adenosine deaminase (ADA) (p < 0.05, n = 16 per group). Rodent studies suggest that some of our findings (A1R and ENTPD2) may be due to treatment with antipsychotics. Our findings suggest changes in expression of genes involved in regulating metabolism of ATP in enriched populations of astrocytes, leading to lower availability of substrates needed to generate adenosine. In pyramidal neurons, changes in ENT1 and ADA mRNA may suggest increased catabolism of adenosine. These results offer new insights into the cell-subtype-specific pathophysiology of the adenosine system in this illness. PMID- 29483662 TI - Historical changes in grassland area determined the demography of semi-natural grassland butterflies in Japan. AB - Semi-natural grassland areas expanded worldwide several thousand years ago following an increase in anthropogenic activities. However, semi-natural grassland habitat areas have been declining in recent decades due to changes in landuse, which have caused a loss of grassland biodiversity. Reconstructing historical and recent demographic changes in semi-natural grassland species will help clarify the factors affecting their population decline. Here we quantified past and recent demographic histories of Melitaea ambigua (Lepidoptera; Nymphalidae), an endangered grassland butterfly species in Japan. We examined changes in demography over the past 10,000 years based on 1378 bp of mitochondrial COI gene. We then examined changes in its genetic diversity and structure during the last 30 years using nine microsatellite DNA markers. The effective population size of M. ambigua increased about 3000-6000 years ago. In contrast, the genetic diversity and effective population sizes of many populations significantly declined from the 1980s to 2010s, which is consistent with a recent decline in the species population size. Our data suggest that the M. ambigua demography can be traced to changes in area covered by semi-natural grasslands throughout the Holocene. PMID- 29483656 TI - Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. AB - Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation intolerant genes and suggest a mechanism by which common risk variants persist in the population. PMID- 29483663 TI - Feedback determines the structure of correlated variability in primary visual cortex. AB - The variable responses of sensory neurons tend to be weakly correlated (spike count correlation, rsc). This is widely thought to reflect noise in shared afferents, in which case rsc can limit the reliability of sensory coding. However, it could also be due to feedback from higher-order brain regions. Currently, the relative contributions of these sources are unknown. We addressed this by recording from populations of V1 neurons in macaques performing different discrimination tasks involving the same visual input. We found that the structure of rsc (the way rsc varied with neuronal stimulus preference) changed systematically with task instruction. Therefore, even at the earliest stage in the cortical visual hierarchy, rsc structure during task performance primarily reflects feedback dynamics. Consequently, previous proposals for how rsc constrains sensory processing need not apply. Furthermore, we show that correlations between the activity of single neurons and choice depend on feedback engaged by the task. PMID- 29483664 TI - A common neural circuit mechanism for internally guided and externally reinforced forms of motor learning. AB - The complex skills underlying verbal and musical expression can be learned without external punishment or reward, indicating their learning is internally guided. The neural mechanisms that mediate internally guided learning are poorly understood, but a circuit comprising dopamine-releasing neurons in the midbrain ventral tegmental area (VTA) and their targets in the basal ganglia are important to externally reinforced learning. Juvenile zebra finches copy a tutor song in a process that is internally guided and, in adulthood, can learn to modify the fundamental frequency (pitch) of a target syllable in response to external reinforcement with white noise. Here we combined intersectional genetic ablation of VTA neurons, reversible blockade of dopamine receptors in the basal ganglia, and singing-triggered optogenetic stimulation of VTA terminals to establish that a common VTA-basal ganglia circuit enables internally guided song copying and externally reinforced syllable pitch learning. PMID- 29483665 TI - The association between cancer family history and ovarian cancer risk in BRCA1/2 mutation carriers: can it be explained by the mutation position? AB - This observational study aimed to investigate whether the reported association between family history (FH) of breast cancer (BC) or ovarian cancer (OC) and OC risks in BRCA1/2 mutation carriers can be explained by mutation position on the gene. In total, 3310 female BRCA1/2 mutation carriers participating in a nationwide prospective cohort (Hereditary Breast and Ovarian Cancer in the Netherlands) were included. FH was classified according to cancer occurrence in first-degree relatives (BC only, OC only, both, neither) and mutations were classified according to their position on the gene (OC cluster region (OCCR), BC cluster region, neither). The main outcome was OC occurrence. Cox proportional hazard models were applied to investigate the association between FH and OC risks before and after adjusting for mutation position. Of all women included, 202 were diagnosed with OC. A BC-only FH tended to be associated with lower OC risks when compared with a FH without BC/OC (HR: 0.79, 95% CI: 0.52-1.17; HR: 0.59, 95% CI: 0.33-1.07 for BRCA1 and BRCA2, respectively) while an OC-only FH tended to be associated with higher risks (HR: 1.58, 95% CI: 0.90-2.77; HR: 1.75, 95% CI: 0.70 4.37 for BRCA1 and BRCA2, respectively). After adjusting for mutation position, association between FH and OC risks was slightly smaller in magnitude (HR: 0.85, 95% CI: 0.55-1.30; HR: 0.64, 95% CI: 0.34-1.21 for BC-only FH in BRCA1 and BRCA2, respectively; HR: 1.46, 95% CI: 0.80-2.68; HR: 1.49, 95% CI: 0.44-4.02 for OC only FH in BRCA1 and BRCA2, respectively), indicating that mutation position explains only part of the association. Considering the magnitude of the observed trend, we do not believe FH should be used to change counseling regarding OC prevention. PMID- 29483666 TI - Uncovering the genetic lesions underlying the most severe form of Hirschsprung disease by whole-genome sequencing. AB - Hirschsprung disease (HSCR) is a complex birth defect characterized by the lack of ganglion cells along a variable length of the distal intestine. A large proportion of HSCR patients remain genetically unexplained. We applied whole genome sequencing (WGS) on 9 trios where the probands are sporadically affected with the most severe form of the disorder and harbor no coding sequence variants affecting the function of known HSCR genes. We found de novo protein-altering variants in three intolerant to change genes-CCT2, VASH1, and CYP26A1-for which a plausible link with the enteric nervous system (ENS) exists. De novo single nucleotide and indel variants were present in introns and non-coding neighboring regions of ENS-related genes, including NRG1 and ERBB4. Joint analysis with those inherited rare variants found under recessive and/or digenic models revealed both patient-unique and shared genetic features where rare variants were found to be enriched in the extracellular matrix-receptor (ECM-receptor) pathway (p = 3.4 * 10-11). Delineation of the genetic profile of each patient might help finding common grounds that could lead to the discovery of shared molecules that could be used as drug targets for the currently ongoing cell therapy effort which aims at providing an alternative to the surgical treatment. PMID- 29483667 TI - gamma-glutamyl transpeptidase deficiency caused by a large homozygous intragenic deletion in GGT1. AB - gamma-Glutamyl transpeptidase deficiency (glutathionuria, OMIM 231950) is a rare disease, with only six patients reported in the literature, although this condition has probably been underdiagnosed due the difficulty to routinely analyze glutathione in clinical samples and to the fact that no genetic defect has been coupled to the disease so far. We report two siblings with mild psychomotor developmental delay and mild neurological symptoms, who presented a markedly increased excretion of glutathione in urine and a very low gamma glutamyl transpeptidase activity in serum. Whole-genome sequencing revealed the presence of a 16.9 kb homozygous deletion in GGT1, one of the genes encoding enzymes with gamma-glutamyl transpeptidase activity in the human genome. Close analysis revealed the presence of a 13 bp insertion at the deletion junction. This is the first report of a genetic variant as the cause of glutathionuria. In addition, genetic characterization of the patients' parents and a healthy sibling has provided direct genetic evidence regarding the autosomal recessive nature of this disease. PMID- 29483668 TI - Whole-exome sequence analysis highlights the role of unmasked recessive mutations in copy number variants with incomplete penetrance. AB - Several hypotheses have been proposed to explain the phenotypic variability between parent and offspring carrying the same genomic imbalance, including unmasking of a recessive variant by a chromosomal deletion. Here, 19 patients with neurodevelopmental disorders harboring a rare deletion inherited from a healthy parent were investigated by whole-exome sequencing to search for SNV on the contralateral segment. This strategy allowed us to identify a candidate variant in two patients in the NUP214 and NCOR1 genes. This result demonstrates that the analysis of the genes included in non-deleted contralateral allele is a key point in the etiological investigation of patients harboring a deletion inherited from a parent. Finally, this strategy is also an interesting approach to identify new recessive intellectual disability genes. PMID- 29483669 TI - Genetic determinants of glycated hemoglobin levels in the Greenlandic Inuit population. AB - We previously showed that a common genetic variant leads to a remarkably increased risk of type 2 diabetes (T2D) in the small and historically isolated Greenlandic population. Motivated by this, we aimed at discovering novel genetic determinants for glycated hemoglobin (HbA1C) and at estimating the effect of known HbA1C-associated loci in the Greenlandic population. We analyzed genotype data from 4049 Greenlanders generated using the Illumina Cardio-Metabochip. We performed the discovery association analysis by an additive linear mixed model. To estimate the effect of known HbA1C-associated loci, we modeled the effect in the European and Inuit ancestry proportions of the Greenlandic genome (EAPGG and IAPGG, respectively). After correcting for multiple testing, we found no novel significant associations. When we investigated loci known to associate with HbA1C levels, we found that the lead variant in the GCK locus associated significantly with HbA1C levels in the IAPGG ([Formula: see text]). Furthermore, for 10 of 15 known HbA1C loci, the effects in IAPGG were similar to the previously reported effects. Interestingly, the ANK1 locus showed a statistically significant ancestral population differential effect, with opposing directions of effect in the two ancestral populations. In conclusion, we found only 1 of the 15 known HbA1C loci to be significantly associated with HbA1C levels in the IAPGG and that two-thirds of the loci showed similar effects in Inuit as previously found in European and East Asian populations. Our results shed light on the genetic effects across ethnicities. PMID- 29483670 TI - Novel variants in Nordic patients referred for genetic testing of telomere related disorders. AB - Telomere-related disorders are a clinically and genetically heterogeneous group of disorders characterized by premature telomere shortening and proliferative failure of a variety of tissues. This study reports the spectrum of telomere related gene variants and telomere length in Nordic patients referred for genetic testing due to suspected telomere-related disorder. We performed Sanger sequencing of the genes TERT, TERC, DKC1, and TINF2 on 135 unrelated index patients and measured telomere length by qPCR on DNA from peripheral blood leukocytes. We identified pathogenic or likely pathogenic variants in 10 index patients, all of which had short telomeres compared to age-matched healthy controls. Six of the 10 variants were novel; three in TERC (n.69_74dupAGGCGC, n.122_125delGCGG, and n.407_408delinsAA) and three in TERT (p.(D684G), p.(R774*), and p.(*1133Wext*39)). The high proportion of novel variants identified in our study highlights the need for solid interpretation of new variants that may be detected. Measurement of telomere length is a useful approach for evaluating pathogenicity of genetic variants associated with telomere-related disorders. PMID- 29483671 TI - New insights from Thailand into the maternal genetic history of Mainland Southeast Asia. AB - Tai-Kadai (TK) is one of the major language families in Mainland Southeast Asia (MSEA), with a concentration in the area of Thailand and Laos. Our previous study of 1234 mtDNA genome sequences supported a demic diffusion scenario in the spread of TK languages from southern China to Laos as well as northern and northeastern Thailand. Here we add an additional 560 mtDNA genomes from 22 groups, with a focus on the TK-speaking central Thai people and the Sino-Tibetan speaking Karen. We find extensive diversity, including 62 haplogroups not reported previously from this region. Demic diffusion is still a preferable scenario for central Thais, emphasizing the expansion of TK people through MSEA, although there is also some support for gene flow between central Thai and native Austroasiatic speaking Mon and Khmer. We also tested competing models concerning the genetic relationships of groups from the major MSEA languages, and found support for an ancestral relationship of TK and Austronesian-speaking groups. PMID- 29483672 TI - A rice class-XIV kinesin enters the nucleus in response to cold. AB - Higher plants possess a large number of kinesins, but lack the minus-end directed dynein motors. However, the kinesin class XIV has strongly expanded, and minus end directed motors from this class may have taken over functions of cytoplasmic dyneins. In this study, we address the functional aspects of a novel rice homologue of the Arabidopsis class-XIV kinesins ATK1 and ATK5. Since a loss-of function rice mutant of this kinesin is not viable, the function was studied in tobacco BY-2 as heterologous system. OsDLK-GFP stably expressed in BY-2 cells decorates cortical microtubules, but also can shift into the nucleus of interphase cells. Because of this peculiar localisation, we coined the name Dual Localisation Kinesin (DLK). The nuclear import of this protein is strongly and reversibly promoted in response to cold. During mitosis, OsDLK is repartitioned between spindle and phragmoplast. Motility assays in vitro using show that OsDLK can convey mutual sliding of microtubules and moves at a velocity comparable to other class-XIV kinesins. When tobacco cells overexpressing OsDLK are synchronised, they exhibit a delayed entry into metaphase, while the later phases of mitosis are accelerated. The data are discussed in relation to additional functions of this kinesin type, beyond their transport along microtubules. PMID- 29483674 TI - Prediabetes and diabetes in a cohort of Qatari women screened for polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is associated with an increased risk of type 2 diabetes mellitus (T2DM) but its association with prediabetes and T2DM is unknown in Qatar. A cross sectional analysis of 3,017 Qatari subjects from the Qatar Biobank, identified 749 women aged 18-40 years, 720 of whom were assessed by the National Institute for Health (NIH) Guidelines for PCOS. Prediabetes (HbA1c 5.7 6.4% and/or impaired fasting glucose (IFG): fasting plasma glucose (FPG) 100-125 mg/dL (5.6-6.9 mmol/L)), and T2DM (fasting plasma glucose > 125 mg/dL (>=7 mmol/L), and/or HbA1c >= 6.5%) were determined. The prevalence of prediabetes was 10.6% and the prevalence of undiagnosed diabetes was found to be 4.0% in the total population. Overall, 12.1% of 720 women had PCOS, of whom FPG and HbA1c were available in 62 women with PCOS: 19.4% had prediabetes and 9.7% had diabetes. An adverse cardiovascular risk profile for IFG women compared to normal women was found. Women with PCOS alone had a similar adverse cardiovascular profile as those with IFG alone and T2DM. Thus, the risk of prediabetes and diabetes is increased in Qatari women with PCOS, with an adverse cardiovascular risk profile similar to that seen in prediabetes and T2DM. PMID- 29483673 TI - Deep brain stimulation for treatment-resistant depression: an integrative review of preclinical and clinical findings and translational implications. AB - Although deep brain stimulation (DBS) is an established treatment choice for Parkinson's disease (PD), essential tremor and movement disorders, its effectiveness for the management of treatment-resistant depression (TRD) remains unclear. Herein, we conducted an integrative review on major neuroanatomical targets of DBS pursued for the treatment of intractable TRD. The aim of this review article is to provide a critical discussion of possible underlying mechanisms for DBS-generated antidepressant effects identified in preclinical studies and clinical trials, and to determine which brain target(s) elicited the most promising outcomes considering acute and maintenance treatment of TRD. Major electronic databases were searched to identify preclinical and clinical studies that have investigated the effects of DBS on depression-related outcomes. Overall, 92 references met inclusion criteria, and have evaluated six unique DBS targets namely the subcallosal cingulate gyrus (SCG), nucleus accumbens (NAc), ventral capsule/ventral striatum or anterior limb of internal capsule (ALIC), medial forebrain bundle (MFB), lateral habenula (LHb) and inferior thalamic peduncle for the treatment of unrelenting TRD. Electrical stimulation of these pertinent brain regions displayed differential effects on mood transition in patients with TRD. In addition, 47 unique references provided preclinical evidence for putative neurobiological mechanisms underlying antidepressant effects of DBS applied to the ventromedial prefrontal cortex, NAc, MFB, LHb and subthalamic nucleus. Preclinical studies suggest that stimulation parameters and neuroanatomical locations could influence DBS-related antidepressant effects, and also pointed that modulatory effects on monoamine neurotransmitters in target regions or interconnected brain networks following DBS could have a role in the antidepressant effects of DBS. Among several neuromodulatory targets that have been investigated, DBS in the neuroanatomical framework of the SCG, ALIC and MFB yielded more consistent antidepressant response rates in samples with TRD. Nevertheless, more well-designed randomized double-blind, controlled trials are warranted to further assess the efficacy, safety and tolerability of these more promising DBS targets for the management of TRD as therapeutic effects have been inconsistent across some controlled studies. PMID- 29483676 TI - The second point mutation in PREPL: a case report and literature review. AB - Prolyl endopeptidase-like (PREPL) deficiency (MIM# 616224) is a rare autosomal recessive inherited congenital myasthenic syndrome characterized by neonatal hypotonia, feeding problems, mild dysmorphism, and neuromuscular symptoms, followed by hyperphagia and obesity in later childhood. Some patients also exhibit growth deficits, sexual hormone deficiency, and cognitive impairments. This syndrome is caused by biallelic mutations in PREPL. To date, only one nucleotide deletion and seven small microdeletions in PREPL have been reported. Here we report a female patient with a novel homozygous frameshift mutation in PREPL (NM_006036.4, c.342delA:p.Val115Leufs*39). Her clinical features are similar to those of previously reported cases. The mutation is the first homozygous point mutation reported in humans. PMID- 29483675 TI - Nature vs. nurture in human sociality: multi-level genomic analyses of social conformity. AB - Social conformity is fundamental to human societies and has been studied for more than six decades, but our understanding of its mechanisms remains limited. Individual differences in conformity have been attributed to social and cultural environmental influences, but not to genes. Here we demonstrate a genetic contribution to conformity after analyzing 1,140 twins and single-nucleotide polymorphism (SNP)-based studies of 2,130 young adults. A two-step genome-wide association study (GWAS) revealed replicable associations in 9 genomic loci, and a meta-analysis of three GWAS with a sample size of ~2,600 further confirmed one locus, corresponding to the NAV3 (Neuron Navigator 3) gene which encodes a protein important for axon outgrowth and guidance. Further multi-level (haplotype, gene, pathway) GWAS strongly associated genes including NAV3, PTPRD (protein tyrosine phosphatase receptor type D), ARL10 (ADP ribosylation factor like GTPase 10), and CTNND2 (catenin delta 2), with conformity. Magnetic resonance imaging of 64 subjects shows correlation of activation or structural features of brain regions with the SNPs of these genes, supporting their functional significance. Our results suggest potential moderate genetic influence on conformity, implicate several specific genetic elements in conformity and will facilitate further research on cellular and molecular mechanisms underlying human conformity. PMID- 29483678 TI - Northwest passage to Scandinavia. PMID- 29483677 TI - Could inherited predisposition drive non-obese fatty liver disease? Results from German tertiary referral centers. AB - Non-alcoholic fatty liver disease (NAFLD) is frequent among obese individuals with metabolic syndrome. Variants PNPLA3 p.I148M, TM6SF2 p.E167K and MBOAT7 rs641738 are associated with higher liver fat contents. Here we analyzed 63 biopsied non-obese, non-diabetic patients with NAFLD (39 men, age: 20-72 years) recruited within the German NAFLD CSG program. The frequencies of the PNPLA3, TM6SF2 and MBOAT7 polymorphisms were compared with the remaining patients in the NAFLD CSG cohort and with a control population (n = 174). Serum CK18-M30 was measured by ELISA. In non-obese NAFLD patients, the frequency of the PNPLA3 p.I148M allele (74.6%), but not of the TM6SF2 or MBOAT7 polymorphisms, was significantly (P < 0.05) higher as compared to the other patients in the NAFLD CSG cohort (54.9%) or controls (40.2%). The presence of the minor PNPLA3 p.I148M risk allele increased the risk of developing NAFLD (OR = 3.29, P < 0.001) and was associated with higher steatosis, fibrosis, and serum CK18-M30 levels (all P < 0.05). According to the population attributable fraction (PAF), 49.8% of NAFLD cases could be eliminated if the PNPLA3 mutation was absent. The MBOAT7 polymorphism was more frequent (P = 0.019) in patients with severe hepatic steatosis. In conclusion, PNPLA3, and to a lesser extent, MBOAT7 variants are associated with NAFLD risk and modulate liver injury in non-obese patients without diabetes. PMID- 29483679 TI - The science and ethics of extinction. PMID- 29483680 TI - The large mean body size of mammalian herbivores explains the productivity paradox during the Last Glacial Maximum. AB - Large herbivores are a major agent in ecosystems, influencing vegetation structure, and carbon and nutrient flows. During the last glacial period, a mammoth steppe ecosystem prevailed in the unglaciated northern lands, supporting a high diversity and density of megafaunal herbivores. The apparent discrepancy between abundant megafauna and the expected low vegetation productivity under a generally harsher climate with a lower CO2 concentration, termed the productivity paradox, requires large-scale quantitative analysis using process-based ecosystem models. However, most of the current global dynamic vegetation models (DGVMs) lack explicit representation of large herbivores. Here we incorporated a grazing module in a DGVM based on physiological and demographic equations for wild large grazers, taking into account feedbacks of large grazers on vegetation. The model was applied globally for present-day and the Last Glacial Maximum (LGM). The present-day results of potential grazer biomass, combined with an empirical land use map, infer a reduction in wild grazer biomass by 79-93% owing to anthropogenic land replacement of natural grasslands. For the LGM, we find that the larger mean body size of mammalian herbivores than today is the crucial clue to explain the productivity paradox, due to a more efficient exploitation of grass production by grazers with a large body size. PMID- 29483682 TI - Crop exports desiccate deserts. PMID- 29483681 TI - The exceptional value of intact forest ecosystems. AB - As the terrestrial human footprint continues to expand, the amount of native forest that is free from significant damaging human activities is in precipitous decline. There is emerging evidence that the remaining intact forest supports an exceptional confluence of globally significant environmental values relative to degraded forests, including imperilled biodiversity, carbon sequestration and storage, water provision, indigenous culture and the maintenance of human health. Here we argue that maintaining and, where possible, restoring the integrity of dwindling intact forests is an urgent priority for current global efforts to halt the ongoing biodiversity crisis, slow rapid climate change and achieve sustainability goals. Retaining the integrity of intact forest ecosystems should be a central component of proactive global and national environmental strategies, alongside current efforts aimed at halting deforestation and promoting reforestation. PMID- 29483683 TI - Precision genome engineering through adenine and cytosine base editing. AB - Adenine base editors (ABEs), composed of an engineered deaminase and a catalytically impaired CRISPR-Cas9 variant, are powerful new tools for targeted base editing in cells and organisms. Together with cytosine base editors (CBEs), ABEs enable single-nucleotide conversions cleanly, efficiently and reversibly without double-stranded DNA cleavage, advancing genome editing in a new dimension. PMID- 29483684 TI - An apoplastic peptide activates salicylic acid signalling in maize. AB - Localized control of cell death is crucial for the resistance of plants to pathogens. Papain-like cysteine proteases (PLCPs) regulate plant defence to drive cell death and protection against biotrophic pathogens. In maize (Zea mays), PLCPs are crucial in the orchestration of salicylic acid (SA)-dependent defence signalling. Despite this central role in immunity, it remains unknown how PLCPs are activated, and which downstream signals they induce to trigger plant immunity. Here, we discover an immune signalling peptide, Z. mays immune signalling peptide 1 (Zip1), which is produced after salicylic acid (SA) treatment. In vitro studies demonstrate that PLCPs are required to release bioactive Zip1 from its propeptide precursor. Conversely, Zip1 treatment strongly elicits SA accumulation in leaves. Moreover, transcriptome analyses revealed that Zip1 and SA induce highly overlapping transcriptional changes. Consequently, Zip1 promotes the infection of the necrotrophic fungus Botrytis cinerea, while it reduces virulence of the biotrophic fungus Ustilago maydis. Thus, Zip1 represents the previously missing signal that is released by PLCPs to activate SA defence signalling. PMID- 29483685 TI - Computational analysis of the productivity potential of CAM. AB - There is considerable interest in transferring crassulacean acid metabolism (CAM) to C3 crops to improve their water-use efficiency. However, because the CAM biochemical cycle is energetically costly, it is unclear what impact this would have on yield. Using diel flux balance analysis of the CAM and C3 leaf metabolic networks, we show that energy consumption is three-fold higher in CAM at night. However, this additional cost of CAM can be entirely offset by the carbon concentrating effect of malate decarboxylation behind closed stomata during the day. Depending on the resultant rates of the carboxylase and oxygenase activities of rubisco, the productivity of the PEPCK-CAM subtype is 74-100% of the C3 network. We conclude that CAM does not impose a significant productivity penalty and that engineering CAM into C3 crops is likely to lead to a major increase in water-use efficiency without substantially affecting yield. PMID- 29483686 TI - The power of a positive approach to realizing change in an animal facility. PMID- 29483687 TI - Post-publication problems: how to proceed when there's no record of IACUC approval? PMID- 29483689 TI - Honesty is the best policy. PMID- 29483688 TI - A Word from OLAW. PMID- 29483690 TI - Investigation, reporting, and program improvement. PMID- 29483691 TI - Phased arrays & the Egyptian fruit bat. PMID- 29483693 TI - Harm-Benefit Analysis: opportunities for enhancing ethical review in animal research. PMID- 29483694 TI - New technologies for developing second generation retinal prostheses. AB - Inherited or age-dependent retinal dystrophies such as Retinitis pigmentosa (RP) and macular degeneration (MD) are among the most prevalent causes of blindness. Despite enormous efforts, no established pharmacological treatment to prevent or cure photoreceptor degeneration has been identified. Given the relative survival of the inner retina, attempts have been made to restore vision with optogenetics or with retinal neuroprostheses to allow light-dependent stimulation of the inner retinal network. While microelectrode and photovoltaic devices based on inorganic technologies have been proposed and in many cases implanted in RP patients, a new generation of prosthetics based on organic molecules, such as organic photoswitches and conjugated polymers, is demonstrating an unexpected potential for visual rescue and intimate interactions with functioning tissue. Organic devices are starting a new era of tissue electronics, in which light-sensitive molecules and live tissues integrate and tightly interact, producing a new ecosystem of organic prosthetics and intelligent biotic/abiotic interfaces. In addition to the retina, the applications of these interfaces might be extended in the future to other biomedical fields. PMID- 29483695 TI - Independent nerves. PMID- 29483696 TI - The social transmission of stress. PMID- 29483697 TI - Nanoparticles vs. viruses. PMID- 29483698 TI - Acoustic reporters. PMID- 29483699 TI - Virus stamping in single cells. PMID- 29483700 TI - Shrinkage in worm genomes. PMID- 29483701 TI - Fish concussions. PMID- 29483702 TI - The sooty mangabey's sequence. PMID- 29483703 TI - Loads take off the lbs. PMID- 29483704 TI - Hybridization controls. PMID- 29483706 TI - Difficult situation=difficult solution. PMID- 29483707 TI - Nanobody-Displaying Flagellar Nanotubes. AB - In this work we addressed the problem how to fabricate self-assembling tubular nanostructures displaying target recognition functionalities. Bacterial flagellar filaments, composed of thousands of flagellin subunits, were used as scaffolds to display single-domain antibodies (nanobodies) on their surface. As a representative example, an anti-GFP nanobody was successfully inserted into the middle part of flagellin replacing the hypervariable surface-exposed D3 domain. A novel procedure was developed to select appropriate linkers required for functional internal insertion. Linkers of various lengths and conformational properties were chosen from a linker database and they were randomly attached to both ends of an anti-GFP nanobody to facilitate insertion. Functional fusion constructs capable of forming filaments on the surface of flagellin-deficient host cells were selected by magnetic microparticles covered by target GFP molecules and appropriate linkers were identified. TEM studies revealed that short filaments of 2-900 nm were formed on the cell surface. ITC and fluorescent measurements demonstrated that the fusion protein exhibited high binding affinity towards GFP. Our approach allows the development of functionalized flagellar nanotubes against a variety of important target molecules offering potential applications in biosensorics and bio-nanotechnology. PMID- 29483708 TI - An "off-the-shelf" fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. AB - T cell malignancies represent a group of hematologic cancers with high rates of relapse and mortality in patients for whom no effective targeted therapies exist. The shared expression of target antigens between chimeric antigen receptor (CAR) T cells and malignant T cells has limited the development of CAR-T because of unintended CAR-T fratricide and an inability to harvest sufficient autologous T cells. Here, we describe a fratricide-resistant "off-the-shelf" CAR-T (or UCART7) that targets CD7+ T cell malignancies and, through CRISPR/Cas9 gene editing, lacks both CD7 and T cell receptor alpha chain (TRAC) expression. UCART7 demonstrates efficacy against human T cell acute lymphoblastic leukemia (T-ALL) cell lines and primary T-ALL in vitro and in vivo without the induction of xenogeneic GvHD. Fratricide-resistant, allo-tolerant "off-the-shelf" CAR-T represents a strategy for treatment of relapsed and refractory T-ALL and non Hodgkin's T cell lymphoma without a requirement for autologous T cells. PMID- 29483709 TI - Prognostic significance of circulating plasma cells by multi-parametric flow cytometry in light chain amyloidosis. AB - We evaluated the prognostic impact of clonal circulating plasma cells (cPCs) detected by six-color multi-parametric flow cytometry (MFC) in light chain (AL) amyloidosis at diagnosis. Of the 154 patients who underwent MFC, cPCs were detected in 42% (n = 65) patients. Median number of cPCs was 81 per 150,000 events (range: 6-17,844). High bone marrow plasma cell percentage was an independent predictor of presence of cPCs. Presence of cPCs at diagnosis was associated with inferior overall survival (OS) (90 vs. 98 months, p = 0.003) and inferior progression free survival (PFS) (31 vs. 52 months, p = 0.02). Estimated 1, 2 and 5 year OS in the two groups was: 74, 64 and 57 and 89, 87, and 80%, respectively. Estimated PFS at 1, 2, and 5 years was: 69, 56, and 23% and 80, 74, and 37%, respectively. Furthermore, the presence of cPCs at diagnosis was an independent adverse predictor of OS in multivariable analysis. Achieving a very good partial response, or better, was able to overcome the adverse impact of cPCs at diagnosis. Patients with cPCs at diagnosis may warrant closer monitoring post treatment, especially if they do not achieve a deep hematologic response. PMID- 29483710 TI - (In)convenience of adding age and comorbidities to prognostic models in myelodysplastic syndromes. PMID- 29483711 TI - Universal genetic testing for inherited susceptibility in children and adults with myelodysplastic syndrome and acute myeloid leukemia: are we there yet? AB - Comprehensive genomic profiling of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) cases have enabled the detection and differentiation of driver and subclonal mutations, informed risk prognostication, and defined targeted therapies. These insights into disease biology, and management have made multigene-acquired mutation testing a critical part of the diagnostic assessment of patients with sporadic MDS and AML. More recently, our understanding of the role of an increasing number of inherited genetic factors on MDS/AML risk and management has rapidly progressed. In recognition of the growing impact of this field, clinical guidelines and disease classification systems for both MDS and AML have recently incorporated familial MDS/AML predisposition syndromes into their diagnostic algorithms. In this perspective piece, we contemplate the advantages, disadvantages, and barriers that would need to be overcome to incorporate inherited MDS/AML genetic testing into the upfront molecular diagnostic work-up of every MDS/AML patient. For centers already performing panel based tumor-only testing, including genes associated with familial forms of MDS/AML (e.g., RUNX1, CEBPA, GATA2, TP53), we advocate optimizing these tests to detect all types of germline variants in these genes and moving toward upfront paired tumor/germline testing to maximize detection and streamline patient care. PMID- 29483712 TI - Anti-CD69 therapy induces rapid mobilization and high proliferation of HSPCs through S1P and mTOR. AB - CD69 regulates lymphocyte egress from the thymus and lymph nodes through cis interactions and the downregulation of surface sphingosine-1-phosphate (S1P) receptor-1 (S1P1). However, its role in the regulation of cell egress from bone marrow has not been extensively studied. We show here that CD69 targeting induced rapid and massive mobilization of BM leukocytes, which was inhibited by desensitization to S1P with FTY720. This mobilization was reproduced with anti human CD69 mAb treatment of mice expressing human CD69. In this strain, the mobilization occurred to the same extent as that induced by AMD3100. The anti human CD69 treatment highly increased LSK and CLP cell proliferation and numbers, both in the periphery and in the BM, and also augmented S1P1 and CXCR4 expression. Additionally, increased mTOR, p70S6K, S6, and 4E-BP1 phosphorylation was detected after in vivo anti-CD69 treatment in the bone marrow. Importantly, mTOR inhibition with rapamycin inhibited anti-huCD69-induced mobilization of hematopoietic stem and progenitor cells (HSPCs). Together, our results indicated that CD69 targeting induces not only mobilization but also high proliferation of HSPCs, and thus is crucial for precursor cell replenishment over time. These results suggest that anti-CD69 mAbs are putative novel candidates for mobilization strategies. PMID- 29483714 TI - [A 20-year study on microvascular autologous transplantation of submandibular gland for treatment of severe dry eye]. AB - Severe dry eye is a refractory ophthalmologic disease. Our multidisciplinary research group treated severe dry eye by microvascular autologous transplantation of submandibular gland (SMG) during the past 20 years. The SMG, with its blood vessels and Wharton's duct, was harvested from the submandibular triangle and transferred to the temporal area. The blood vessels in the SMG were anastomosed with the temporal blood vessels using a microsurgical technique. Then, the distal end of Wharton's duct was sutured to form an opening in the upper lateral conjunctival fold. The tear was replaced by the secretion of the transplanted SMG to lubricate the ocular surface. In our study, the surgical techniques of blood vessel management were continuously modified to increase the survival rate of the transplanted SMG. A novel surgical modality of partial transplantation of SMG was established to prevent postoperative epiphora. A clinical study with the largest case number in the world was conducted and the effectiveness of transplantation of SMG for severe dry eye was fully confirmed. In order to resolve two main clinical problems including ductal obstruction resulted from low secretion rate during the latent period, and epiphora due to over secretion of the transplanted SMG in the later term of transplantation, the regulation of the secretion mechanism of the normal and transplanted SMG were investigated. New opinions on mechanisms of saliva secretion were provided. Based on the priniciple of translational medicine, the results of related basic research were applied in the clinic. The clinical guidelines for secretion regulation of transplanted SMG were established. A concept of chronic obstructive sialadenitis of transplanted SMG was provided and its diagnostic criteria, diagnostic technique of sialography, and therapeutic regimen were established. As a result, the surgical success rate was obviously elevated, the surgical complications were decreased, and life quality of the patients was greatly improved. PMID- 29483713 TI - MicroRNA-101 expression is associated with JAK2V617F activity and regulates JAK2/STAT5 signaling. PMID- 29483715 TI - [Salivary microbiome in people with obesity: a pilot study]. AB - OBJECTIVE: To investigate the characterization of the salivary microbiome in people with obesity and the differences in microbial composition, gene function and metabolic pathways of salivary microbiome between people with obesity and normal weight controls. METHODS: The study was carried out in people with obesity and age- and sex-matched normal weight controls. None of these selected participants had the systemic disease, oral mucosal disease or periodontal disease. Unstimulated saliva samples were collected and oral examination was conducted. DNAs from saliva samples were extracted and sequenced in an Illumina NextSeq 500 platform. Community composition, linear discriminant analysis of taxonomic differences,gene prediction, gene set construction and annotation of gene function were performed. RESULTS: The classified bacterial reads of the samples were 2 630 428 for each sample. A total of 11 phyla, 19 classes, 26 orders, 41 families, 62 genera and 164 species were detected ultimately. All samples had the same predominant phyla (Proteobacteria, Firmicutes, Bacteroidetes, Actinobacteria and Fusobacteria). There were statistical differences between the groups at the class, order, family, genus and species levels. At the class level, Negativicutes and Erysipelotrichia were more abundant in the obesity group, while Flavobacteriia and Bateroidetes dominated in normal weight group (P<0.05). At the species level, 16 showed significant differences in relative abundance among the groups, in which Prevotella melaninogenica,Prevotella salivae,Solobacterium moorei and Atopobium parvulum ware more abundant in the obesity group, whereas Streptococcus sanguinis dominated in normal weight group (P<0.05). The people with obesity had a higher number of salivary microbial genes (P<0.05). We produced statistics on gene prediction and found salivary microbiome of obesity group had a higher number of genes (P < 0.05). Genes associated with the pathways of metabolism and environmental information processing and human diseases were significantly enriched in the saliva samples of people with obesity (P < 0.01). CONCLUSION: Significant differences were seen in composition, gene function and metabolic pathways of salivary microbiome between people with obesity and normal weight people. We hope to go on further study with larger sample size in the near future. PMID- 29483716 TI - [Influence of vitamin D receptor FokI polymorphism on expression of CYP24A1 in periodontal cells]. AB - OBJECTIVE: There is asingle nucleotide polymorphism (SNP) in the exon 2 of the vitamin D receptor (VDR) gene that can be distinguished using the restriction endonuclease FokI, and accordingly divided into three genotypes: FF, Ff and ff. VDR-FokI polymorphism was the only known SNP that could alter the protein structure of VDR. CYP24A1 is the gene encoding vitamin D 24 hydroxylase and is a vitamin D responsive gene. The influence of rs2228570 on transcriptional activation by VDR in human gingival fibroblasts (hGF) and periodontal ligament cells (hPDLC) was investigated in this study. METHODS: hGF and hPDLC of 12 donors' were primarily cultured and genomic DNA was extracted. A part of genomic DNA with the length of 267 bp was obtained using PCR, which contained the SNP. VDR-Fok I genotypes were determined according to the results of restriction fragment length polymorphism. hGF and hPDLC were stimulated with 10 nmol/L 1alpha,25 dihydroxy vitamin D3 (1,25OH2D3) or 1 000 nmol/L 25 hydroxy vitamin D3 (25OHD3) for 48 h before RNA was extracted. Then VDR antagonist ZK159222 was used or not used during 1,25OH2D3 or 25OHD3 stimulation with hGF and hPDLC. After 1,25OH2D3 stimulation for 48 h, the proteins in hGF and hPDLC were also collected. The protein expressions of CYP24A1 and VDR were detected using Western blot. RESULTS: Among the 12 donors' cell cultures, the number of FF, ff and Ff genotypes was 4, 3 and 5, respectively.After stimulation with 1,25OH2D3 or 25OHD3 for 48 h,CYP24A1 mRNA levels in FF-hGF were significantly higher than those in other hGF genotypes(1,25OH2D3: F=31.147, P<0.01; 25OHD3: F= 32.061,P <0.01), as was in FF-hPDLC (1,25OH2D3: F=23.347, P<0.01; 25OHD3: F=32.569,P<0.01). When ZK159222 was used before 1,25OH2D3 stimulation, this statistically significant difference disappeared (hGF: F=0.246, P=0.787; hPDLC: F=0.574, P=0.583). When ZK159222 was used before 25OHD3 stimulation, the trend was similar (hGF: F=1.636, P=0.248; hPDLC: F=0.582, P=0.578).After stimulation with 1,25OH2D3 for 48 h, CYP24A1 protein levels in FF-hGF were significantly higher than those in the other hGF genotypes (F=12.368, P <0.01), as was in FF-hPDLC (F=15.749, P <0.01). In hGF and hPDLC, the mRNA or protein expression of VDR of different genotypes was not significantly different under different stimulation conditions.The paired comparison showed that there was no statistically significant difference between the expression of CYP24A1 in hGF and that in hPDLC under all the stimulation conditions, as was the expression of VDR. CONCLUSION: In hGF and hPDLC, the FF VDR genotype is associated with the more remarkable up-regulation of CYP24A1than the other genotypes, indicating that transcriptional activation of FF-VDR might be higher than those of other vitamin D receptors. PMID- 29483717 TI - [Role of vitamin K-dependent protein Gas6 in the expression of endothelial cell adhesion molecule-1 and chemokines induced by Porphyromonas gingivalis lipopolysaccharide]. AB - OBJECTIVE: Growth-arrest-specific protein 6 (Gas6) is a vitamin K-dependent protein and involved in cell proliferation, survival, adhesion and migration . Also it has been shown to play an important role in the inflammatory response .The aim of present study was to investigate the role of Gas6 in the process of the expression of adhesion molecules and chemokines of human umbilical vein endothelial cells (HUVECs) induced by Porphyromonas gingivalis lipopolysaccharide(P.g-LPS). METHODS: After up-regulation and down-regulation of the expression of Gas6, the vascular endothelial cells were stimulated with 1 mg/L P.g-LPS for 3 h and 24 h. Real-time quantitative polymerase chain reaction(real-time PCR) was taken to detect the expression of the cell adhesion molecules:intercellular adhesion molecule-1 (ICAM-1) and E-selectin, as well as chemokines:interleukin-8 (IL-8) and monocyte chemoattractant protein 1 (MCP-1). Wound healing assay was taken to observe the migration ability of endothelium cells in different groups. RESULTS: After 3 h of P.g-LPS stimulation, the expression of adhesion molecules and chemokine in the down-regulation group was not significantly different from that in the control group,while in the up regulation group the decrease of E-selectin, ICAM-1, IL-8 and MCP-1 was 81%+/-0%, 47%+/-3%, 76% +/- 3%, 26% +/- 6% respectively. After 24 h of P.g-LPS stimulation, the expression of adhesion molecules and chemokine in down-regulation group was significantly higher than that in control group (2.06+/-0.07, 1.99+/-0.11, 3.14+/ 0.15, 1.84+/-0.03 flod), while these molecules in the down-regulation group was significantly lower than in the control group (29%+/-1%, 62%+/-3%, 69%+/-1%, 41%+/-2%). Differences were statistically significant (P<0.01). Wounding healing assay showed that down-regulation of Gas6 enhanced migration ability of endothelial cells while up-regulation of Gas6 weakened this ability,which was consistent with the trend of real-time PCR result. CONCLUSION: Down-regulation of the Gas6 gene enhanced the expression of ICAM-1, E-selectin, IL-8 and MCP-1 in HUVECs after P.g- LPS stimulating, while up-regulaiton of the Gas6 gene weakened the expression of ICAM-1, E-selectin, IL-8 and MCP-1 in HUVECs after P.g-LPS stimulating,suggesting that Gas6 may play a role in the process of endothelial cell adhesion. PMID- 29483718 TI - [Expression of hypoxia-inducible factor 1alpha is associated with lymph node metastasis in oral squamous cell carcinoma]. AB - OBJECTIVE: To explore the association between hypoxia-inducible factor 1alpha (HIF-1alpha) expression and lymph node metastasis in oral squamous cell carcinoma (OSCC). METHODS: Tumor specimens from 125 patients with histologically-proven, surgically-treated OSCC were examined by immunohistochemical staining for expression of HIF-1alpha. The patients were divided into two groups by the expression of HIF-1alpha, high expression of HIF -1alpha group (H-group) and low expression of HIF-1alpha group (L-group). The main assessment parameters were lymph node metastasis rate and disease-specific survival (DSS). The lymph node metastasis rate and clinicopathologic features were compared using Mann-Whitney test. The Kaplan-Meier curve was generated for each group and compared using the log-rank test. Cox proportional hazard models were utilized for multivariate analyses of HIF-1alpha expression and other baseline factors with DSS. All calculations and analyses were performed using the SPSS 17.0 software package. RESULTS: The protein expression levels of HIF-1alpha were up-regulated in OSCC and two patients were unable to evaluate. There were 48 patients in L-group and 75 patients in H-group. Lymph node metastasis rate was 37.5% (18/48) for L-group and 58.7% (44/75) for H-group (P=0.027). Expression of HIF-1alpha was significantly correlated with lymph node metastasis. The patients of L-group had a significantly better DSS than the patients of H-group (70.8% vs. 46.7%, P=0.005), while the patients of L-group had a significantly better disease-free survival (DFS) than the patients of H-group (60.4% vs. 36.0%, P=0.009) by Kaplan Meier method. A multivariate survival analysis also showed that HIF-1alpha expression (HR=2.164, 95%CI: 1.150-4.074, P=0.017) and T-stage (HR=1.387, 95%CI: 1.066-1.804, P=0.015) both were the independent factors associated with prognosis. CONCLUSION: HIF-1alpha expression is significantly correlated with lymph node metastasis in OSCC. HIF-1alpha expression is an independent predictive factor for prognosis of OSCC patients, and may serve as a potential biomarker for molecular diagnosis and targeted therapy in future. PMID- 29483719 TI - [Decreased phosphorylation of mitogen activated protein kinase and protein kinase B contribute to the inhibition of osteogenic differentiation mediated by activation of Toll like receptor in human periodontal ligament stem cells]. AB - OBJECTIVE: To investigate the effects of Toll like receptors on the osteogenesis of human pe-riodontal ligament stem cells (hPDLSCs) and probable molecular mechanism. METHODS: Real-time PCR and flow cytometry were applied to test the expression of TLRs in hPDLSCs and the positive cell percentage of TLR. hPDLSCs were cultured in osteogenic medium for 7 to 14 days with different TLR agonists at various concentrations . The effect of different TLR on osteogenic differentiation of hPDLSCs was evaluated by alizarin red S staining, alkaline phosphatase (ALP) staining and ALP activity assay. Western blotting was used to analyze the phosphorylation levels of extracellular regulated protein kinases (ERK), c-Jun N-terminal protein kinase (JNK), P38, AKT and expression of Runx2 an osteogenic related gene after treatment with TLR agonists, compared with the effect of inhibitors of mitogen activated protein kinase (MAPK) or protein kinase B (PKB or AKT) on Runx2 expression of hPDLSCs cultured in osteogenic medium. RESULTS: Higher expressions of TLR1,3,4,6 were found in hPDLSCs through real-time PCR. Positive cell percentage of TLR was determined by flow cytometry and described as TLR1: 2.82%+/-0.68%; TLR2: 1.26%+/-0.09%; TLR3: 13.23%+/-2.05%; TLR4: 3.64%+/-0.79%; TLR6: 3.21%+/-1.64%, whose tendency was comparable to their mRNA expression in hPDLSCs. Most TLR ligands had no effect on the ALP staining, activity and mineralization of hPDLSCs at lower concentration except for 0.1 mg/L PolyI:C could induce the osteogenic ability of hPDLSCs. On the contrary, Higher concentration of TLR ligands (PolyI:C: 10 mg/L, LPS: 10 mg/L , Pam3CSK4: 1 mg/L, FSL-1: 50 MUg/L) had obviously inhibitory effect on osteogenic differentiation of hPDLSCs. Activation of TLR using higher concentration of TLR ligands could downregulate the phosphorylation levels of ERK, P38, JNK and AKT, and also reduced the expression of Runx2, compared with the untreated control. The inhibitors of MAPK (U0126, SP600125,SB203580) and inhibitor of AKT (perifosine) could also inhibit Runx2 expression. CONCLUSION: Higher concentration of TLR ligands could inhibit osteogenic differentiation of hPDLSCs. This inhibitory effect seemed to be related to decreased phosphorylation of MAPK and AKT. PMID- 29483720 TI - [Nano-sized bioactive glass enhances osteogenesis of critical bone defect in rabbits]. AB - OBJECTIVE: To compare the osteogenic effects of a nano-sized 58S bioactive glass (nano-58S BG) and a traditional 45S5 bioactive glass(45S5 BG) in penetrating parietal critical bone defects. METHODS: Critical bone defect with 9 mm diameter was created in the parietal bone of New Zealand rabbits. The bone defects were then filled with either nano-58S BG, or 45S5 BG, or nothing but the newly-formed blood clot as the blank control at random. For histological observation, specimens were gained 4 and 8 weeks after the surgery, sectioned and stained by HE. The amount of collagen type I was observed with Picric-Sirius Red staining through polarimetry. To observe the new bone formation with fluorescence under the laser confocal microscope, we injected fluorescent markers 14, 28, and 42 days after the surgery. The markers were tetracycline hydrochloride, alizarin red and calcin individually in chronological order. Image J software was used to quantify the bone regeneration. RESULTS: HE staining showed that BG particulates were integrated with the surrounding tissue without any inflammatory cells infiltration 4 weeks after surgery. New bone regeneration was observed both from the border and in the center of the defects in both BG groups. No bone regeneration in defect center was observed in control group. At the end of 8 weeks, there was more bone regeneration in nano-58S group compared with 45S5 group and control group. The structure of the new bone in BG groups was hollow, which was similar to the natural normal parietal bone. No hollow structure was observed in the new bone of control group. Picric-sirius Red polarimetry showed that more amount of collagen type I was found in nano-58S group than in either 45S5 or control group. The fluorescent observation of the hard tissue slices at the end of 8 weeks showed statistically larger scope and faster new bone formation in nano-58S group with (29.4+/-4.48) MUm thickness from 4-6 weeks and (35.3+/-3.74) MUm from 6-8 weeks compared with 45S5 group [(13.43+/-3.44) MUm and (17.64+/-4.13) MUm] and control group [(5.88+/-2.92) MUm and (6.07+/-3.02) MUm, P<0.01]. CONCLUSION: Compared with the traditional 45S5 bioactive glass, 58S nano sized bioactive glass showed better osteogenic effect in bone regeneration in parietal bones of rabbits. PMID- 29483721 TI - [Effect of different surface treatments on the crystal structure and properties of zirconia]. AB - OBJECTIVE: To investigate the effects of 3 surface different treatments on the crystal structure, shear bond strength,roughness value and flexural strength of zirconia. METHODS: The zirconia specimens were prepared and randomly divided into 4 groups and received the following treatments: (1) blank control group,the specimens without treatments; (2)sandblasting with alumina group, sandblasting the specimens with 110 MUm alumina particles for 21 s as working pressure 0.25 MPa and working distance 10 mm; (3)laser etching group, coating the surface of the specimens with graphite powder and using Er:Yttrium Aluminum Garnet (Er:YAG) laser to irradiate the surface 30 s; (4) hot-etching group, putting the specimens in a closed reactor within a 1:1 mixture of 40% (mass traction) nitric acid and 68%(mass traction) hydrofluoric acid liquid, the reaction of 30 min in a water bath at 100 degrees centigrade. The changes of crystal structure, shear bond strength(SBS) and flexural strength of zirconia after different surface treatments were tested. RESULTS: The X-ray diffractometer (XRD) patterns showed that the volume percentage of monoclinic phase of the 4 groups was 0.91%, 12.50%, 6.64% and 17.81% respectively. The roughness value for the four groups were as follows: blank control group,(0.29+/-0.01) MUm; sandblasting with alumina group, (1.05+/-0.11) MU m; laser etching group, (0.73+/-0.04) MUm; hot-etching group, (1.31+/-0.06) MUm, respectively(P<0.05). Mean SBS was (7.09+/-0.46) MPa in blank control group, (12.14+/-1.51) MPa in sandblasting with alumina group, (8.82+/ 0.74) MPa in laser etching group and (11.97+/-0.99) MPa in hot-etching group. There was no statistically significant difference between sandblasting with alumina group and hot-etching group (P>0.05), but the difference between the other groups were statistically significant(P<0.05). Mean three-point bending was (933.70+/-44.13) MPa in blank control group, (850.95+/-60.66) MPa in sandblasting with alumina group, (771.53+/-68.08) MPa in laser etching group and (766.27+/ 57.49) MPa in hot-etching group. There was no statistically significant difference between sandblasting with alumina group and hot-etching group (P>0.05), but the difference between the other groups were statistically significant (P<0.05). CONCLUSION: After different surface treatments, the surface of zirconia has changed from tetrago-nal to monoclinic phases in varying degrees. In addition, surface treatments could improve the bond strength of zirconia to resin cement, and also lead to a decrease in the flexural strength of zirconia. PMID- 29483722 TI - [Effects of different surface treatments on the zirconia-resin cement bond strength]. AB - OBJECTIVE: To evaluate the effects of different surface treatments on the shear bond strength between zirconia and resin cement. METHODS: Forty zirconia discs were randomly divided into four groups (10 discs in each group) for different surface treatments: control, no surface treatment; sandblast, applied air abrasion with aluminum oxide particles; ultraviolet (UV), the zirconia sample was placed in the UV sterilizer at the bottom of the UV lamp at 10 mm, and irradiated for 48 h; cold plasma, the discs were put in the cold plasma cabinet with the cold plasma generated from the gas of He for 30 s. Specimens of all the groups were surface treated prior to cementation with Panavia F 2.0 cement. The surface morphology and contact angle of water were measured. The shear bond strengths were tested and the failure modes were examined with a stereomicroscope. RESULTS: Surface morphology showed no difference between the UV/cold plasma group and the control group. Sandblasted zirconia displayed an overall heterogeneous distribution of micropores. The contact angle of the control group was 64.1 degrees +/-2.0 degrees . After sandblasting, UV irradiation and cold plasma exposure, the values significantly decreased to 48.8 degrees +/-2.6 degrees , 27.1 degrees +/-3.6 degrees and 32.0 degrees +/-3.3 degrees . The values of shear bond strength of the specimens with sandblasted (14.82+/-2.01) MPa were higher than those with no treatment (9.41+/-1.07) MPa with statistically significant difference (P<0.05). The values of shear bond strength of the specimens with UV irradiation (10.02+/-0.64) MPa were higher than those with no treatment (9.41+/-1.07) MPa, but without statistically significant difference (P>0.05). The values of cold plasma group (18.34+/-3.05) MPa were significantly higher than those of control group (9.41+/-1.07) MPa, even more than those with sandblast(14.82+/-2.01) MPa (P<0.05). X-ray photoelectron spectroscopy (XPS) showed increase in oxygen (O) and decrease in carbon (C) elements after UV and cold plasma treatment. The surface C/O ratio also decreased after UV and cold plasma treatment. CONCLUSION: Zirconia specimens treated with UV and cold plasma could significantly improve the hydrophilicity. The surface morphology was unaffected by the UV irradiation and cold plasma treatments. The improvements of ziconia shear bond strength were slight in UV group without statistically significant difference. Cold plasma treatment significantly improved the shear bond strength between zirconia and resin cement. PMID- 29483723 TI - [Influence of setting time on bond strength of different bioactive pulp capping materials with dental adhesive]. AB - OBJECTIVE: To investigate influence of setting time on bond strength of different bioactive pulp capping materials with self-etch or etch-and-rinse adhesive. METHODS: Sixty specimens were prepared for each of the three tested capping materials, namely mineral trioxide aggregate (MTA), iRoot BP Plus (BP) and iRoot FS (FS). Specimens of each material were divided into three groups and bonded at three setting time points of the materials respectively: initial setting time (4 h for MTA, 2 h for BP and 20 min for FS), 24 h after application and 7 d after application. The specimen surfaces of each group were treated with self-etch mode or etch-and-rinse mode of one universal adhesive (Single Bond Universal, SBU) (n=10). The bonding area was restricted to a round area with 3 mm diameter, on which composite cylinders were build up with flowable composite and light cured completely. The shear bond strength was tested immediately with a shear strength tester and fracture mode was observed under stereo microscope and recorded. The mean shear bond strength for each group was analyzed with SPSS 19.0 software ANOVA method. The surface morphology of each material was observed after setting and acid treatment under scanning electron microscope. RESULTS: There was no significant difference among the three tested materials at either initial setting point or 7 d after application (P<0.05). The bond strength of MTA was significantly higher than those of BP and FS 24 h after application in both bonding modes (P<0.05). For all the three tested materials, shear bond strength was significantly higher for complete setting group than for initial setting group of the same material (P<0.05). Under scanning electron microscope, the characteristic crystal patterns could be observed on the three bioactive materials surfaces after complete setting, the size of which was bigger for MTA than for BP and FS. These features were lost to some extent after self-etch primer application or phosphoric acid etching. CONCLUSION: Based on the present results, adequate bond strength can be obtained for FS at initial setting time, which is comparable with BP and MTA. This implies that clinically composite restoration can be placed over bioactive direct capping materials after shortened initial setting process in one visit. PMID- 29483724 TI - [Cleaning efficacy of different solvents on sealer-contaminated dentin surface]. AB - OBJECTIVE: To evaluate the influence of an epoxy resin-based sealer on the bond strength of adhesive resins to dentin and the cleaning efficacy of different solvents in removing sealer residues. METHODS: The occlusal enamel of 25 freshly extracted human third molars without caries were removed to expose flat surfaces of dentin. The teeth were randomly divided into five groups according to the treatment received: For negative control group, the dentin surfaces were not contaminated with AH-Plus; For the other 4 experimental groups, the samples were contaminated with AH-Plus for 5 min and different measures were taken: For positive control group, the sealer were wiped with dry cotton pellets; For solvents experimental groups: cotton pellets saturated with 95% (volume fraction) ethanol, 99.5% (volume fraction) acetone or 99% (volume fraction) amyl acetate were used to wipe the sealer until the surface appeared clean when viewed through a stereomicroscope under *10 magnification, then rinsed with de-ionized water for 3 s. After sealer removal, a self-etching adhesive system was applied on the surfaces with resin composite. The samples were sectioned into 1.0 mm*1.0 mm stick specimens (n=45) for microtensile test. Failure modes at the dentin-resin interface were observed using a stereomicroscope. The samples were sectioned into 1.0 mm piece specimens (n=4) for scanning electron microscope observation. The microtensile bond strength data were analyzed by one-way ANOVA. Chi-square test were used to analyse the failure modes between the groups. RESULTS: There was significant difference among the five groups (P<0.001). For dry cotton pellet group (38.69+/-8.60) MPa and the ethanol group (37.14+/-12.01) MPa, the microtensile bond strength significantly declined when compared with negative control group (43.86+/-7.99) MPa (P<0.05). No significant difference of bond strength was found between the dry cotton pellet group and the ethanol group (P=0.426). There was no statistical significant difference among acetone group, amyl acetate group and negative control group (P>0.05). The bond strength of acetone group and amyl acetate group were (45.94+/-10.37) MPa and (43.99+/-7.01) MPa, respectively. The ethanol group exhibited lower bond strength than that of acetone group and amyl acetate group (P<0.05). Scanning electronic microscope observation revealed that in dry cotton pellet group and ethanol group, the resin tags were short and loose. Moreover, sealer residues were identified in the interface in the ethanol group samples, while the resin tags in the acetone and amyl acetate group were as dense and uniform as in negative control group. The distribution of failure modes showed no significant difference in the five groups (P=0.086). CONCLUSION: The microtensile bond strength of dentin to composite resin was lower after exposure to sealer. Compared with ethanol and dry cotton pellets, the cleaning effect of acetone and amyl acetate on sealer-contaminated dentin surface were better. PMID- 29483725 TI - [Effect of acid etching of retropreparation cavities on seal of retrofill materials]. AB - OBJECTIVE: To evaluate the effect of acid etching of retropreps on seal of different retrofill materials. METHODS: In the study, 80 freshly extracted lower molar teeth were used. They were examined under 3.5* magnifying glass to rull out fractures. They were cleaned and stored in distilled water before use. The distal roots were sectioned off and underwent root canal treatment. Rotary nickel titanium instruments were used during instrumentation and the roots were obturated using lateral condensation technique. The apical portion (3 mm in length) was removed with a fine grit diamond bur, the root tip was retroprepared with a ultrasonic tip (3 mm in depth). The retroprepared roots were randomly assigned to 4 groups and retrofilled with amalgam, intermediate restorative material (IRM), iRoot BP Plus and mineral trioxide aggregate (MTA). The groups were further divided into subgroups according to treatment of the root end cavity (etch and non-etch). The root tips were covered with alginate impression material and were left to set in PBS solution for a week and stained with methylene blue for a week. The roots were removed from the dye solution, thoroughly rinsed and dried, split in halves along the long axis with a diamond disk and observed under a stereoscope. The linear dye leakage was measured and analyzed. One way ANOVA and Tamhane's T2 method were used to analyze the data. The significance level was set at 0.05. RESULTS: The dye leakage results (mean+/-standard deviation) according to the treatment groups were: amalgam etch (2.80+/-0.72) mm, amalgam non-etch (2.07+/-0.86) mm, IRM etch (1.54+/-0.19) mm, IRM non-etch (1.12+/-0.28) mm , iRoot BP Plus etch (0.20+/-0.20) mm, iRoot BP Plus non-etch (0.11+/-0.08) mm, MTA etch (0.19+/-0.19) mm, and MTA non-etch (0.17+/-0.14) mm. One way ANOVA showed significant differences between the groups. Comparison between the groups using Tamhane's T2 method showed roots retrofilled with iRoot BP Plus and MTA had significant less leakage than those retrofilled with amalgam and IRM (P<0.05); There was no significant difference in terms of leakage between iRoot BP Plus and MTA; Acid etching increased leakage of IRM but did not affect MTA, iRoot BP Plus or amalgam retrofillings. CONCLUSION: Acid etching is not shown to benefit apical sealing of retrofill materials. PMID- 29483726 TI - [Wear intensity and surface roughness of microhybrid composite and ceramic occlusal veneers on premolars after the thermocycling and cyclic mechanical loading tests]. AB - OBJECTIVE: To evaluate the wear intensity and surface roughness of occlusal veneers on premolars made of microhybrid composite resin or two kinds of ceramics in vitro after the thermocycling and cyclic mechanical loading tests. METHODS: In the study,24 fresh extracted human premolars without root canal treatment were prepared (cusps reduction of 1.5 mm in thickness to simulate middle to severe tooth wear, the inclinations of cusps were 20 degrees ). The prepared teeth were restored with occlusal veneers made of three different materials: microhybrid composite, heat-pressed lithium disilicate ceramic and computer-aided design/computer-aided manufacturing (CAD/CAM) lithium disilicate ceramic in the thickness of 1.5 mm. The occlusal veneers were cemented with resin cement. The specimens were fatigued using the thermocycling and cyclic mechanical loading tests after being stored in water for 72 h. The wear of specimens was measured using gypsum replicas and 3D laser scanner before and after the thermocycling and cyclic mechanical loading tests and the mean lost distance (mm) was used to indicate the level of wear. The surfaces of occlusal contact area were observed and the surface roughness was recorded using 3D laser scanning confocal microscope before and after the fatigue test. Differences between the groups were compared using ONE-way ANOVA(P<0.05). RESULTS: All the specimens successfully survived after the thermocycling and cyclic mechanical loading tests. The mean wear of microhybrid composite group, heat-pressed lithium disilicate ceramic group, and CAD/CAM lithium disilicate ceramic group was (-0.13+/-0.03) mm, ( 0.05+/-0.01) mm and (-0.05+/-0.01) mm, the wear of microhybrid composite was significantly higher than the two ceramic groups(P<0.001).The mean surface roughness(Ra)before the fatigue test was(1.24+/-0.20) MUm, (0.75+/-0.09) MUm, (0.73+/-0.14) MUm and it became (1.81+/-0.24) MUm, (1.53+/-0.26) MUm and (1.77+/ 0.23) MUm after the test . Before the fatigue test, the surface roughness of microhybrid composite was significantly higher than the two ceramic groups(P<0.001) and after the test, the surface roughness of heat-pressed lithium disilicate ceramic was significantly lower than microhybrid composite(P=0.005) and CAD/CAM lithium disilicate ceramic (P=0.010). CONCLUSION: From the view of wear speed, microhybrid composite was significantly higher than the two kinds of ceramics, but it was similar to enamel when the opposing tooth was natural. The surface roughness before the themocycling and cyclic mechanical loading test of microhybrid composite was significantly higher than that of the two ceramic groups. After the test, the surface roughness of heat-pressed ceramic was significantly lower than that of the other two groups. From the view of surface roughness, heat-pressed ceramic has more advantage. PMID- 29483727 TI - [Application of digital design of orthodontic-prosthodontic multidisciplinary treatment plan in esthetic rehabilitation of anterior teeth]. AB - OBJECTIVE: To develop a digital workflow of orthodontic-prosthodontic multidisciplinary treatment plan which can be applied in complicated anterior teeth esthetic rehabilitation, in order to enhance the efficiency of communication between dentists and patients, and improve the predictability of treatment outcome. METHODS: Twenty patients with the potential needs of orthodontic-prosthodontic multidisciplinary treatment to solve their complicated esthetic problems in anterior teeth were recruited in this study. Digital models of patients' both dental arches and soft tissues were captured using intra oral scanner. Direct prosthodontic (DP) treatment plan and orthodontic-prosthodontic (OP) treatment plan were carried out for each patient. For DP treatment plans, digital wax-up models were directly designed on original digital models using prosthodontic design system. For OP treatment plans, virtual-setups were performed using orthodontic analyze system according to orthodontic and esthetic criteria and imported to prosthodontic design system to finalize the digital wax up models. These two treatment plans were shown to the patients and demonstrated elaborately. Each patient rated two treatment plans using visual analogue scales and the medians of scores of two treatment plans were analyzed using signed Wilcoxon test. Having taken into consideration various related factors, including time, costs of treatment, each patient chose a specific treatment plan. For the patients chose DP treatment plans, digital wax-up models were exported and printed into resin diagnostic models which would be utilized in the prosthodontic treatment process. For the patients chose OP treatment plans, virtual-setups were used to fabricate aligners or indirect bonding templates and digital wax-up models were also exported and printed into resin diagnostic models for prosthodontic treatment after orthodontic treatment completed. RESULTS: The medians of scores of DP treatment plan and OP treatment plan were calculated and analyzed by IBM SPSS 20. The median of scores of DP treatment plan was 8.4, the minimum value was 6.9 and the maximum value was 9.3. The median of scores of OP treatment plan was 9.0, the minimum value was 7.9 and the maximum value was 9.6. The median of scores of OP was significantly higher than that of DP (Z=-3.23, P<0.01). Finally, 12 patients chose OP treatment plans and 8 patients chose DP treatment plans. CONCLUSION: For cases with complex esthetic problems in anterior teeth, a digital workflow can demonstrate final treatment outcome and help patients make suitable treatment decisions. In our study, the orthodontic prosthodontic multidisciplinary treatment plan is feasible which can provide predictions of treatment outcome and improve esthetic outcome with patients' satisfaction. PMID- 29483728 TI - [Comparison of the translucency and color masking effect of the zirconia ceramics made by milling and gel deposition]. AB - OBJECTIVE: Three kinds of zirconia specimens were made respectively by milling of the prisintered blocks and by three dimensional (3D) gel deposition for in vitro evaluation of their optical translucency under three different thicknesses and their color masking effect on discolored teeth. The study aims for establishing the principle for guiding the materials selection in clinical practice. METHODS: Ninety A2-colored zirconia disc specimens with diameter of 14 mm were prepared and were divided into three groups (n=30). (1) Group CZ, by milling of the presintered blanks; (2) Group NZW, by 3D gel deposition, without a color masking opaque inner layer; (3) Group NZY, by 3D gel deposition, with a color masking opaque inner layer. Furthermore, each group was divided into three sub-groups (n=10) according to the sample thickness, i.e., 0.6, 1.0 and 1.5 mm, respectively. The maxillary anterior teeth with severe discoloration, extracted owing to periodontal disease, were collected and embedded. By gentle gridding and polishing a plane, larger than 6 mm2*6 mm2, was generated on the labial surface of each tooth. Chromatic values(CIE1976-L*a*b*) of the zirconia samples in the nine sub-groups were measured by the spectrophotometer Crystaleye in front of the black or white background in a cassette, and the translucency parameter (TP) values were calculated for each sample. Thereafter the zirconia specimens were bonded onto the labial surface of the polished teeth for measuring the chromatic values, using the chromatic value of the medium 1/3 of the standardized Vita A2 as a control. The color aberration DeltaE between each zirconia specimen and the control value was calculated, respectively. The results were statistically analyzed by One-way ANOVA and Bonferroni. RESULTS: (1) The optical transparency of the three kinds of zirconia disc specimens with the thickness of 0.6, 1.0 and 1.5 mm was 14.09, 12.31 and 10.45 for group CZ; 19.84, 16.54 and 12.44 for group NZW;14.81, 13.16 and 11.92 for group NZY. In each group, the degree of optical transparency of the specimens showed a clear tendency as in the sub-group 0.6 mm >1.0 mm >1.5 mm. The TP value of the specimens in the three groups with the same thickness showed a tendency of the group NZW >group NZY >group CZ. (2) After bonding onto the polished labial surface of the teeth, the color aberration DeltaE of the specimens with the thickness of 0.6, 1.0 and 1.5 mm was calculated to be 10.77, 9.94 and 8.50 for group CZ; 6.84, 5.89 and 5.29 for group NZW; 4.16, 3.92 and 3.67 for group NZY. In each group, the color aberration of the specimens showed a clear tendency as in the sub-group 0.6 mm >1.0 mm >1.5 mm; the color aberration of the three groups with the same thickness was in the order of the group CZ >group NZW >group NZY. CONCLUSION: In all the specimen groups with a fixed specimen thickness, the optical translucency of the specimen was the highest in group NZW made by 3D gel deposition, and the best color masking effect was obtained in specimens with a color masking opaque inner layer in group NZY, where a thickness of 0.6 mm was sufficient enough for obtaining the ideal color masking effect. PMID- 29483729 TI - [Preliminary study on the accuracy of infrabony root surface area of single-root teeth by periapical films]. AB - OBJECTIVE: To explore the accuracy of periapical film in evaluating the infrabone root surface area of single-root teeth with different types of resorption of the alveolar bone. METHODS: In this study, the medical records and imaging data of patients in Department of Periodontology of Peking University Hospital of Stomatology from January 2014 to December 2016 were retrospectively analysed. The involved teeth were divided into two groups: horizontal bone loss group and vertical bone loss group. Digital three-dimensional models of teeth were segmented from cone beam computed tomography (CBCT) data, and the percentage of the infrabone root surface area was measured. While the percentage of the residual alveolar bone was measured on the periapical films. The correlation of the two percentages were analyzed, and the differences between the two percentages of each group were compared. RESULTS: Thirty-two patients and 79 single-root teeth were involved totally, in whom there were 25 men and 7 women, aged 26-60 years, and of which there were 41 teeth in the horizontal bone loss group and 38 teeth in the vertical bone loss group. The remaining alveolar bone height percentages were 45.13%-90.39% on the periapical films, and at the same time, the infrabone root surface area percentages were 36.27%-93.03% on CBCT. The residual alveolar bone height percentage of the horizontal bone loss group was not subject to normal distribution, so the residual alveolar bone height percentage and the infrabone root surface area percentage were analyzed by Wilcoxon matched pair rank test (P=0.382), and the result showed no statistically significant difference. The mean value of difference value of the two measurements was 0, and the consistency limit of 95 % was -9.7%-9.8%, between the clinical consistency limit (-15%-15%).The residual alveolar bone height percentage and the infrabone root surface area percentage of the vertical bone loss group were analyzed by paired T test (P< 0.001), and the result showed statistically significant difference. The mean value of difference value of the two measurements was 7.2 %, and the consistency limit of 95% was -13.1%-27.5%, beyond clinical consistency limit (-15%-15%). CONCLUSION: For the teeth with horizontal bone loss, the proximal residual alveo-lar bone height reflected on the periapical films could show the infrabone root surface area relatively accurately. For the teeth with vertical bone loss, the periapical films could not show the degree of periodontal tissue loss accurately, and it would underestimate the extent of bone destruction usually, so CBCT might be taken to show the bone destruction condition of this type of teeth if necessary. PMID- 29483730 TI - [Morphological analysis of alveolar bone of anterior mandible in high-angle skeletal class II and class III malocclusions assessed with cone-beam computed tomography]. AB - OBJECTIVE: To evaluate the difference of features of alveolar bone support under lower anterior teeth between high-angle adults with skeletal class II malocclusions and high-angle adults presenting skeletal class III malocclusions by using cone-beam computed tomography (CBCT). METHODS: Patients who had taken the images of CBCT were selected from the Peking University School and Hospital of Stomatology between October 2015 and August 2017. The CBCT archives from 62 high-angle adult cases without orthodontic treatment were divided into two groups based on their sagittal jaw relationships: skeletal class II and skeletal class III. vertical bone level (VBL), alveolar bone area (ABA), and the width of alveolar bone were measured respectively at the 2 mm, 4 mm, 6 mm below the cemento-enamel junction (CEJ) level and at the apical level. After that, independent samples t-tests were conducted for statistical comparisons. RESULTS: The ABA of the mandibular alveolar bone in the area of lower anterior teeth was significantly thinner in the patients of skeletal class III than those of skeletal class II, especially in terms of the apical ABA, total ABA on the labial and lingual sides and the ABA at 6 mm below CEJ level on the lingual side (P<0.05). The thickness of the alveolar bone of mandibular anterior teeth was significantly thinner in the subjects of skeletal class III than those of skeletal class II, especially regarding the apical level on the labial and lingual side and at the level of 4 mm, 6 mm below CEJ level on the lingual side (P<0.05). CONCLUSION: The ABA and the thickness of the alveolar bone of mandibular anterior teeth were significantly thinner in the group of skeletal class III adult patients with high-angle when compared with the sample of high angle skeletal class II adult cases. We recommend orthodontists to be more cautious in treatment of high-angle skeletal class III patients, especially pay attention to control the torque of lower anterior teeth during forward and backward movement, in case that the apical root might be absorbed or fenestration happen in the area of lower anterior teeth. PMID- 29483731 TI - [Accuracy analysis of alveolar dehiscence and fenestration of maxillary anterior teeth of Angle class III by cone-beam CT]. AB - OBJECTIVE: To evaluate the accuracy and reliability of detecting alveolar bone dehiscence and fenestration of maxillary anterior teeth of Angle class III by cone-beam computed tomography (CBCT). METHODS: Eighteen Angle class III patients with 108 maxillary anterior teeth were included (3 males and 15 females) who accepted modified corticotomy in orthodontic therapy. The mean age was 23.6 years (18-30 years). The clinical detection of dehiscence and fenestration was done when modified corticotomy was performed by the same periodontist. The CBCT examination was conducted pre-operation and the detection of dehiscence and fenestration by CBCT was done by two periodontists. The data in modified corticotomy were used as the golden standard to calculate the parameters, such as sensitivity, specificity, positive and negative predictive values, Youden index (YI), positive and negative likelihood ratio. Kappa statistic was used to analyze the agreement between the clinical detection and the CBCT detection. RESULTS: The incidence of dehiscence and fenestration was about 10.19% and 13.89% respectively, which mainly occurred on lateral incisors and canines. The median values of length and width of dehiscence were about 5 mm and 4 mm, and the median values of length and width of fenestration were 3 mm and 2 mm, respectively. Most fenestrations were detected on the middle third to the apical third of the root. For dehiscence, the agreement between clinical detection and CBCT detection was statistically significant (P<0.05). For fenestration, the agreement between clinical detection and CBCT detection was statistically significant (P<0.05). The values of sensitivity and specificity for detecting dehiscence were more than 0.7. The values of positive and negative predictive values for detecting dehiscence were 0.44 and 0.97. The values of sensitivity and specificity for detecting fenestration were 0.93 and 0.52. The values of positive and negative predictive values for detecting fenestration were 0.24 and 0.98. CONCLUSION: For dehiscence, the agreement between clinical detection and CBCT detection was good. For fenestration, the agreement between clinical detection and CBCT detection was general. Detection of dehiscence and fenestration of maxillary anterior teeth of Angle class III by CBCT had limited diagnostic value in clinical practice with overestimation of dehiscence and fenestration incidence. PMID- 29483732 TI - [Evaluation of using cone beam computed tomography as a regular test before and after periodontal regenerative surgery]. AB - OBJECTIVE: To test the accuracy and credibility of cone-beam computed tomography (CBCT) on measuring the height and volume of alveolar bone defects before periodontal regeneration surgery. By comparing the bone density measured by CBCT before and after the operation, the time to evaluate the efficacy of the periodontal regenerative surgery would be determined. METHODS: Periodontal regenerative surgeries were performed on three-wall bone defects of ten teeth in nine patients. The height of bone defects was measured using both periapical film of distant parallel technique and CBCT before periodontal regenerative surgery. Before the surgery, CBCT data were used to measure the volume of the bone defects and the bone density around the defective areas. The height of the bone defects was measured during periodontal regeneration surgery, and the volume of the defective areas was obtained with bone wax in operation. CBCT was taken 6, 12 and 24 weeks after surgery to measure the bone density in the regenerated region. RESULTS: The Wilcoxon test showed that the height of the bone defects measured preoperatively using periapical film was (0.822+/-0.222) mm deeper than the intraoperative measurement results, and the difference was statistically significant (P<0.05). Whereas CBCT measurement results was (0.150+/-0.171) mm less than the intraoperative measurement results, without statistical significant (P>0.05). The regression analysis and the Bland-Altman method also showed that the results of CBCT measurement were more accurate. The Wilcoxon test showed that the bone defect volume measured by CBCT preoperatively was accurate, and the difference between the preoperative and the intraoperative measurements was not statistically significant, ranging from 0.38 to 2.83 mm3 (P>0.05). The bone density of the regenerated areas measured by CBCT was (0.49+/-0.03) times in the sixth week, (0.74+/-0.09) times in the twelfth week and (1.16+/-0.11) times in the twentieth week as that of the areas around the bone defects after the surgery. CONCLUSION: The present data suggest that using CBCT before periodontal regenerative surgery could result in accurate measurement of height and volume of alveolar bone defects. For the purpose of evaluating the effectiveness of regenerative surgery, CBCT could be taken 24 weeks after surgery. PMID- 29483733 TI - [Influence of implants prepared by selective laser melting on early bone healing]. AB - OBJECTIVE: To evaluate the influence of the rough surface of dental implants prepared by selective laser melting (SLM) on early bone healing around titanium implants. METHODS: A total of sixteen titanium implants were involved in our research, of which eight implants were prepared by SLM (TIXOS Cylindrical, Leader Novaxa, Milan, Italy; 3.3 mm*10 mm, internal hex) and the other eight were sandblasted, large-grit and acid-etched (SLA) implants (IMPLUS Cylindrical, Leader-Novaxa, Milan, Italy; 3.3 mm*10 mm, internal hex). All of the dental implants were inserted into the healed extraction sockets of the mandible of two adult male Beagle dogs. Half of the dental implants were designed to be healed beneath the mucosa and the other half were intended to be healed transgingivally and were immediately loaded by acrylic resin bridge restoration. Three types of tetracycline fluorescent labels, namely calcein blue, alizarin complexone and calcein, were administered into the veins of the Beagle dogs 2, 4, and 8 weeks after implant placement respectively for fluorescent evaluation of newly formed bone peri-implant. Both Beagle dogs were euthanized 12 weeks after implant insertion and the mandible block specimens containing the titanium implants and surrounding bone and soft tissue of each dog were carefully sectioned and dissected. A total of 16 hard tissue slices were obtained and stained with toluidine blue for microscopic examination and histomorphometric measurements. Histological observation was made for each slice under light microscope and laser scanning confocal microscope (LSCM). Comparison on new bone formation around titanium implants of each group was made and mineral apposition rate (MAR) was calculated for each group. RESULTS: Dental implants prepared by selective laser melting had achieved satisfying osseointegration to surrounding bone tissue after the healing period of 12 weeks. Newly formed bone tissue was observed creeping on the highly porous surface of the SLM implant and growing into the pores of surface structure. Higher MAR values were shown for SLM implants compared with SLA implants (P<0.01). CONCLUSION: Dental implants prepared by selective laser melting could promote early bone healing and improve mineral apposition rate. PMID- 29483734 TI - [A prognostic model for assessment of outcome of root canal treatment in teeth with pulpitis or apical periodontitis]. AB - OBJECTIVE: To present a prognostic model for evaluating the outcome of root canal treatment in teeth with pulpitis or apical periodontitis 2 years after treatment. METHODS: The implementation of this study was based on a retrospective study on the 2-year outcome of root canal treatment. A cohort of 360 teeth, which received treatment and review, were chosen to build up the total sample size. In the study, 143 teeth with vital pulp and 217 teeth with apical periodontitis were included. About 67% of the samples were selected randomly to derive a training date set for modeling, and the others were used as validating date set for testing. Logistic regression models were used to produce the prognostic models. The dependent variable was defined as absence of periapical lesion or reduction of periapical lesion. The predictability of the models was evaluated by the area under the receiver-operating characteristic (ROC) curve (AUC). RESULTS: Four predictors were included in model one (absence of apical lesion): pre-operative periapical radiolucency, canal curvature, density and apical extent of root fillings. The AUC was 0.802 (95%CI: 0.744-0.859). And the AUC of the testing date was 0.688. Only the density and apical extent of root fillings were included to present model two (reduction of apical lesion). The AUC of training dates and testing dates were 0.734 (95%CI: 0.612-0.856) and 0.681, respectively. As predicted by model one, the probability of absence of periapical lesion 2 years after endodontic treatment was 90% in pulpitis teeth with sever root-canal curvature and adequate root canal fillings, but 51% in teeth with apical periodontitis. When using prognostic model two for prediction, in teeth with apical periodontitis, the probability of detecting lesion reduction with adequate or inadequate root fillings was 95% and 39% 2 years after treatment. CONCLUSION: The pre-operative periapical status, canal curvature and quality of root canal treatment could be used to predict the 2-year outcome of root canal treatment. PMID- 29483735 TI - [Simulation of dose distribution in bone medium of 125I photon emitting source with Monte Carlo method]. AB - OBJECTIVE: To present a theoretical analysis of how the presence of bone in interstitial brachytherapy affects dose rate distributions with MCNP4C Monte Carlo code and to prepare for the next clinical study on the dose distribution of interstitial brachytherapy in head and neck neoplasm. METHODS: Type 6711,125I brachytherapy source was simulated with MCNP4C Monte Carlo code whose cross section library was DLC-200. The dose distribution along the transverse axis in water and dose constant were compared with the American Association of Physicists in Medicine (AAPM) TG43UI update dosimetry formalism and current literature. The validated computer code was then applied to simple homogeneous bone tissue model to determine the affected different bone tissue had on dose distribution from 125I interstitial implant. RESULTS: 125I brachytherapy source simulated with MCNP4C Monte Carlo code met the requirements of TG43UI report. Dose rate constant, 0.977 78 cGy/(h*U), was in agreement within 1.32% compared with the recommended value of TG43UI. There was a good agreement between TG43UI about the dosimetric parameters at distances of 1 to 10 cm along the transverse axis of the 125I source established by MCNP4C and current published data. And the dose distribution of 125I photon emitting source in different bone tissue was calculated. Dose-deposition capacity of photons was in decreasing order: cortical bone, spongy bone, cartilage, yellow bone marrow, red bone marrow in the same medium depth. Photons deposited significantly in traversal axis among the phantom material of cortical bone and sponge bone relevant to the dose to water. In the medium depth of 0.01 cm, 0.1 cm, and 1 cm, the dose in the cortical bone was 12.90 times, 9.72 times, and 0.30 times of water respectively. CONCLUSION: This study build a 125I source model with MCNP4C Monte Carlo code, which is validated, and could be used in subsequent study. Dose distribution of photons in different bone medium is not the same as water, and its main energy deposits in bone medium surface, so we should consider the effect of bone medium when we design the target area adjacent to the bone tissue in 125I sources implantation plan. PMID- 29483736 TI - [Influence of intraoral scan and dental cast scan on occlusal quantitative analysis of virtual dental model]. AB - OBJECTIVE: To make more accurate occlusal quantitative analysis of three dimensional (3D) virtual dental models and to compare the occlusal contact obtained by intraoral and dental cast scan. METHODS: In this study, 5 subjects were intraoral scanned using laser scanner (3 shapes, Germany) to obtain the 3D virtual models of one tooth (the first molar), two teeth (the second premolar and the first molar), three teeth (the premolars and the first molar) and their opposite teeth, respectively. The silicone impressions were made and dental stone models were poured for each of them. The dental casts were scanned and then they were fixed to the maximum intercuspal position with a special locating jig for a rescanning of occlusal position. The virtual models taken intraorally and obtained with dental cast scan were introduced to a 3D quantitative analysis system, and some criteria regarding to occlusal contact were calculated and analyzed. The occlusal criteria were mean values of occlusal clearance space between the upper and lower occlusal surface (clearance), occlusal contact area (area), and cusp inclination (angle) of the mandibular first molar. Paired t tests were used to evaluate differences of occlusal criteria between the virtual models obtained with the intraoral scan and dental cast scan (alpha=0.05). RESULTS: The mean values of occlusal clearance of one to three teeth obtained by way of intraoral scan were smaller than those obtained by way of cast scan by 0.134 mm, 0.177 mm, and 0.207 mm, respectively. While the occlusal contact areas were greater than the cast scan by 8.65 mm2, 10.28 mm2, and 11.46 mm2. No statistically significant differences were found between the cusps inclinations obtained with the two scanning methods, and the interclass correlations were high. CONCLUSION: Occlusal clearance obtained by intraoral scan was less than that by cast scan while the occlusal contact area was greater than the latter, indicating that intraoral occlusal contact was closer. The difference of the standard deviations of occlusal clearance measured by the two methods were small and that of occlusal contact area was influenced by the number of teeth scanned intraorally. There was no statistical difference in cusp inclination between the two methods. PMID- 29483737 TI - [Stress change of periodontal ligament of the anterior teeth at the stage of space closure in lingual appliances: a 3-dimensional finite element analysis]. AB - OBJECTIVE: To analyze the stress distribution in the periodontal ligament (PDL) under different loading conditions at the stage of space closure by 3D finite element model of customized lingual appliances. METHODS: The 3D finite element model was used in ANSYS 11.0 to analyze the stress distribution in the PDL under the following loading conditions: (1) buccal sliding mechanics (0.75 N,1.00 N,1.50 N), (2) palatal sliding mechanics (0.75 N,1.00 N,1.50 N), (3) palatal buccal combined sliding mechanics (buccal 1.00 N + palatal 0.50 N, buccal 0.75 N + palatal 0.75 N, buccal 0.50 N+ palatal 1.00 N). The maximum principal stress, minimum principal stress and von Mises stress were evaluated. RESULTS: (1) buccal sliding mechanics(0.75 N,1.00 N,1.50 N): maximum principal stress: at the initial of loading, maximum principal stress, which was the compressed stress, distributed in labial PDL of cervix of lateral incisor, and palatal distal PDL of cervix of canine. With increasing loa-ding, the magnitude and range of the stress was increased. Minimum principal stress: at the initial of loading, minimum principal stress which was tonsil stress, distributed in palatal PDL of cervix of lateral incisor and mesial PDL of cervix of canine. With increasing loading, the magnitude and range of minimum principal stress was increased. The area of minimum principal stress appeared in distal and mesial PDL of cervix of central incisor. von Mises stress:it distributed in labial and palatal PDL of cervix of lateral incisor and distal PDL of cervix of canine initially. With increasing loading, the magnitude and range of stress was increased towards the direction of root. Finally, there was stress concentration area at mesial PDL of cervix of canine. (2) palatal sliding mechanics(0.75 N,1.00 N,1.50 N): maximum principal stress: at the initial of loading, maximum principal stress which was the compressed stress, distributed in palatal and distal PDL of cervix of canine, and distal-buccal and palatal PDL of cervix of lateral incisor. With increasing loading, the magnitude and range of the stress was increased. Minimum principal stress: at the initial of loading, minimum principal stress which was tonsil stress, distributed in distal-interproximal PDL of cervix of lateral incisor and mesial-interproximal PDL of cervix of canine. With increasing loading, the magnitude and range of the stress was increased.von Mises stress: von Mises stress distributed in palatal and interproximal PDL of cervix of canine. With increasing loading, the magnitude and range of stress was increased. Finally, von Mises stress distributing area appeared at distal-palatal PDL of cervix of canine. (3) palatal-buccal combined sliding mechanics: maximum principal stress: maximum principal stress still distributed in distal-palatal PDL of cervix of canine. Minimum principal stress: minimum principal stress distributed in palatal PDL of cervix of lateral incisor when buccal force was more than palatal force. As palatal force increased, the stress concentrating area transferred to mesial PDL of cervix of canine.von Mises stress: it was lower and more well-distributed in palatal-buccal combined sliding mechanics than palatal or buccal sliding mechanics. CONCLUSION: Using buccal sliding mechanics,stress majorly distributed in PDL of lateral incisor and canine, and magnitude and range of stress increased with the increase of loading; Using palatal sliding mechanics, stress majorly distributed in PDL of canine, and magnitude and range of stress increased with the increase of loading; With palatal-buccal combined sliding mechanics, the maximum principal stress distributed in the distal PDL of canine. Minimum principal stress distributed in palatal PDL of cervix of lateral incisor when buccal force was more than palatal force. As palatal force was increasing, the minimum principal stress distributing area shifted to mesial PDL of cervix of canine. When using 1.00 N buccal force and 0.50 N palatal force, the von Mises stress distributed uniformly in PDL and minimal stress appeared. PMID- 29483738 TI - [Glide path management of rotary nickel-titanium instruments in simulated root canals]. AB - OBJECTIVE: To compare the shaping ability of ProGlider, HyFlex EDM Glidepath File and RaCe ISO 10 with that of PathFile and stainless steel K-file hand instruments in simulated root canals. METHODS: A total of 60 simulated resin blocks were divided randomly into five groups (n=12), each group prepared with each instrument, respectively. Preparation time was recorded. Pre- and post-operative images were obtained using a scanner and superimposed using Photoshop. The material removal from the inner and outer canal walls beginning from 0 mm at the end point of the canal were measured using ImageJ. Centering ability was determined, accordingly. The data were analyzed using the One-Way ANOVA at a significance level of P<0.05. RESULTS: Preparation time for ProGlider was (61.018+/-5.020) s, significantly the fastest (P < 0.05), that for SS K-file (111.100+/-6.987) s, the slowest (P<0.05), and the differences among the other 3 groups were not significant (P>0.05). The removal of resin from the outer wall at the apical portion was significantly lower for HyFlex EDM Glidepath File than for ProGlider (P<0.05), both of them were significantly lower than the other 3 groups (P<0.05). For the removal from the inner wall at the curvature portion, ProGlider was the least whilst SS K-file the most (P<0.05). At the straight portion, RaCe ISO 10 removed the most not only from the inner but also the outer wall (P<0.05), HyFlex EDM Glidepath File the second most, and the other 3 groups among the same levels. As far as the centering ability was concerned, at the apical portion, HyFlex EDM Glidepath File was the best, ProGlider the second best, no significant difference identified among the other 3 groups. At the curvature portion, ProGlider and HyFlex EDM Glidepath File were the best, PathFile the second, RaCe ISO 10 the third, the worst was the SS K-file. At the straight portion, the difference amongt the 5 groups was not significant. CONCLUSION: The shaping abilities of ProGlider, HyFlex EDM Glidepath File and RaCe ISO 10 were better or comparable to that of PathFile, while the preparation time for ProGlider reduced significantly, and HyFlex EDM Glidepath File and RaCe ISO 10 removed significantly more resin at the straight portion of the canal. PMID- 29483739 TI - [Evaluation of accuracy of virtual occlusal definition in Angle class I molar relationship]. AB - OBJECTIVE: To evaluate the accuracy of virtual occlusal definition in non-Angle class I molar relationship, and to evaluate the clinical feasibility. METHODS: Twenty pairs of models of orthognathic patients were included in this study. The inclusion criteria were: (1) finished with pre-surgical orthodontic treatment and (2) stable final occlusion. The exclusion criteria were: (1) existence of distorted teeth, (2) needs for segmentation, (3) defect of dentition except for orthodontic extraction ones, and (4) existence of tooth space. The tooth extracted test group included 10 models with two premolars extracted during preoperative orthodontic treatment. Their molar relationships were not Angle class I relationship. The non-tooth-extracted test group included another 10 models without teeth extracted, therefore their molar relationships were Angle class I. To define the final occlusion in virtual environment, two steps were included: (1) The morphology data of upper and lower dentition were digitalized by surface scanner (Smart Optics/Activity 102; Model-Tray GmbH, Hamburg, Germany); (2) the virtual relationships were defined using 3Shape software. The control standard of final occlusion was manually defined using gypsum models and then digitalized by surface scanner. The final occlusion of test group and control standard were overlapped according to lower dentition morphology. Errors were evaluated by calculating the distance between the corresponding reference points of testing group and control standard locations. RESULTS: The overall errors for upper dentition between test group and control standard location were (0.51+/-0.18) mm in non-tooth-extracted test group and (0.60+/-0.36) mm in tooth extracted test group. The errors were significantly different between these two test groups (P<0.05). However, in both test groups, the errors of each tooth in a single dentition does not differ from one another. There was no significant difference between errors in tooth-extracted test group and 1 mm (P>0.05); and the accuracy of non-tooth-extracted group was significantly smaller than 1 mm (P<0.05). CONCLUSION: The error of virtual occlusal definition of none class I molar relationship is higher than that of class I relationship, with an accuracy of 1 mm. However, its accuracy is still feasible for clinical application. PMID- 29483740 TI - [Endoscopy-assisted sialodochoplasty for the treatment of severe sialoduct stenosis]. AB - OBJECTIVE: To evaluate the effects of endoscopy-assisted sialodochoplasty for the treatment of severe sialoduct stenosis with concurrent megaducts. METHODS: From Jul.2010 to Dec. 2016, 8 patients presenting with severe parotid duct stenosis and 3 patients with occlusion of the Wharton's duct underwent endoscopy-assisted sialodochoplasty.All these patients had concurrent severe ductal ectasiaand manifested a painful swelling of the involved salivary glands.The diameter of ectasia and length of stenosis of the sialoducts were measured preoperatively by sialography, computed tomography, or ultrasonography. The megaducts were opened transorally and sutured to the buccal or oral floor mucosa, therefore creating a neo-ostium. All the patients were followed up periodically after operation. The treatment effects were evaluated by clinical signs, sialogram and sialometry. RESULTS: The length of the Stensen's duct stenosis was 5-12 mm, and the diameter of the concurrent ectasia was 8-16 mm. The length of the Wharton's duct stenosis was 10-20 mm, and the diameter of the concurrent ectasia was 6-8 mm.The neo ostiums healed uneventfully 2 weeks after operation. The duration of the follow up varied from 6 to 78 months (median: 24 months). Among the 8 patients with Stensen's duct stenosis, two experienced re-obliteration of the neo-ostium, but the buccal bulge and clinical symptoms disappeared; one reported recurrent clinical symptoms after initial alleviation, which could be controlled with self massaging; the remaining 5 patients had satisfactory clinical results, i.e., disappearance of the obstruction symptoms and buccal bulge, patent ostium,clean saliva and improvement of the ductal ectasia on sialogram. Three patients with Wharton's duct occlusion were asymptomatic with clear saliva and patent ostium;two exhibited approximately normal appearance and one showed improvement of the sialogram.Sialometry was performed in 9 patients with patent neo-ostium of the involved glands,the resting saliva flow rate of the affected glands showed no differences compared with the normal side, and stimulated flow rate showed a significant increase, though less than the control side.The clinical results included good in 5 patients, fair in 4 patients, and poor in 2 patients, with a total effective rate of 82% (9/11). CONCLUSION: Endoscopy-assisted sialodochoplasty appears to be effective and can be a viable option for patients presenting with severe sialoducts tenosis and concurrent ectasia. PMID- 29483741 TI - [Preemptive analgesia with loxoprofen sodiumorally in extraction of impacted teeth]. AB - OBJECTIVE: To investigate the effectiveness of preemptive analgesia with loxoprofen sodium orally, which was a kind of non-steroid anti-inflammatory drugs, in extractions of mandibular impacted third teeth. METHODS: There were questionnaires about postoperative pain for patients whose mandibular impacted third teeth were extracted from July 2017 to August 2017 in First Clinical Division of Peking University School and Hospital of Stomatology. All the patients did their routine clinical examinations and imaging examinations. After their mandibular impacted third teeth were extracted, the questionnaires were sent to them. The questionnaires were filled in by the patients on their own and returned one week later. There were 120 questionnaires that were sent and 105 questionnaires returned, of which 98 questionnaires were filled in completely. According to the inclusive criteria and exclusion criteria, 66 questionnaires were totally selected in this study. According to the time when the patients took their loxoprofen sodium orally firstly, the patients were divided into 3 groups. The first group was for patients who didn't take loxoprofen sodium during their extractions (non-medicine group). The second group was for patients who took 60 mg loxoprofen sodium 30 min before their extractions (preoperative group). The third group was for patients who took 60 mg loxoprofen sodium 30 min after their extractions (postoperative group). The operation time among the 3 groups was analyzed by Kruskal-Wallis method. The postoperative time points were 2, 4, 12,24 and 48 h after operation. The scores of visual analogue scales (VAS) for postoperative pain in each group at different postoperative time points were analyzed by Friedman method. At each postoperative time point, VAS scores in the different groups were analyzed by Kruskal-Wallis me-thod. The numbers of the patients taking loxoprofen sodium home and drug adverse reactions were also analyzed. RESULTS: The operation time of the 3 groups was 15.0 (5.0,30.0) min and had no significant differences (P=0.848).VAS scores of non-medicine group 2,4, 12,24 and 48 h after operation were 1.75 (0.1,10.0), 6.25 (1.5,10.0), 2.00 (0.1,8.0), 2.00 (0.1,6.0) and 0.5 (0.1,5.5) separately and had significant differences (P<0.001).The VAS score at 4 h after operation was higher than the VAS scores at other time points after operation (P<0.005). Four hours after the operations, the VAS scores of preoperative group [2.0 (0.1,10.0)] and postoperative group [2.0 (0.1,5.0)] were lower significantly than those of non medicine group [6.25 (1.5,10.0)] (P<0.001).The numbers of the patients taking loxoprofen sodium home were 9(40.9%) in non-medicine group,5(21.8%) in preoperative group and 7(33.3%) in postoperative group. The number of the patients who had drug adverse reactions in preoperative group (n=3,13.0%) and in postoperative group (n=4,19.0%) was less than the number of the patients who had drug adverse reactions in non-medicine group (n=8,36.4%). CONCLUSION: There were two protocols of preemptive analgesia with loxoprofen sodium orally in extractions of mandibular impacted third teeth, which were taking 60 mg loxoprofen sodium orally 30 min before the extractions and taking 60 mg loxoprofen sodium orally 30 min after the extractions. Both of the two preemptive analgesia protocols could decrease the postoperative pain significantly. PMID- 29483742 TI - [Two-year outcomes of pulpotomy in primary molars using mineral trioxide aggregate: a retrospective study]. AB - OBJECTIVE: To evaluate the two-year outcomes of primary molars pulpotomy using mineral trioxided aggregate (MTA) and to find out the potential influence factor, with the help of electronic medical record database. METHODS: Children who received primary molars pulpotomy in the Department of Pediatric Dentistry in Peking University School and Hospital of Stomatology from May, 2014 to November, 2015 were searched in the Electronic Medical Record Database of Peking University School and Hospital of Stomatology, via the database for scientific research provided by the corporation of Kaientai. The children who were healthy, no more than 8 years old and followed up over 1.5 years were selected as the subjects of this study. At the same time, those children who didn't have complete medical records and X-rays before and after treatment were removed. Basic information, the relevant medical records and radiographic records of those children were collected. All molars were examined clinically and radiographically, and classified into 1 of 5 outcomes: N, H, P0, PX, PY. Molars classified into P0, PX and PY were regarded as failed. Survival analysis was applied. The survival rate and survival time of the deciduous teeth were calculated.Multivariate analysis was performed by using Cox proportional hazard model. RESULTS: One hundred and fifteen children were finally included,aged from 2.6 to 8.2 years, with the mean age of (4.5+/-1.1) years. 211 primary molars were included, and the average follow up time was (880+/-154) days. A good level of agreement between the raters was found for molars with five outcomes(kappa=0.913). Intrarater reliability was good for molars with five outcomes (kappa=0.916). Forty-nine molars failed by September, 2017. Forty-three molars had abnormal radiographic manifestation. Six molars suffered premature loss. Only fourteen molars had an associated gingival swelling or parulis, or pathologic mobility upon clinical examination. The cumulative survival probability of half a year, one year, one year and a half, two years, two year and a half for the pulpotomy was 100%, 98.5%, 92.9%, 90.5%,73.8% through the Kaplan-Meier method, respectively. Through the analysis of Cox proportional hazard model, the survival probability was significantly higher when the age was younger. When sodium hypochlorite and the saline were used as the irrigation at the same time, the survival probability was not improved for those teeth with more bleeding in the operation compared with that used saline only. The teeth with preformed metal crown (PMC) gained longer median survival time than those restored with resin composite and others, but the difference was not significant, either. What's more, gender, the restoration time of PMC, the restoration of the opposite teeth were not found to be associated with the success of the treatment. CONCLUSION: The cumulative survival probability of two years after the primary pulpotomy was 90.5%, complying the current instructions in our department. The survival probability of the molars after the treatment was significantly affected by the age. PMID- 29483743 TI - [Effects of RGD peptides-grafted porous tantalum on morphological change of MG63 osteoblasts-tantalum conjunctive interface and expression of osteogenesis factors]. AB - OBJECTIVE: To investigate the effects of the Arg-Gly-Asp polypeptedes (RGD) peptides-modified porous tantalum surface on osteoblasts morphology and expressions of osteogenesis factors, and to evaluate RGD peptides promotes junctura ossium of tantalum-bone interface in vivo. METHODS: RGD peptides of different concentrations (1 g/L, 5 g/L, and 10 g/L) were loaded to porous tantalum slices with a diameter of 10 mm and a thickness of 3 mm by physical absorption. The 3rd generation of MG63 cells were co-cultured with tantalum and divided into 4 groups: Ta-cells (control) group, 1 g/L cells/Ta/RGD group, 5 g/L cells/Ta/RGD group, and 10 g/L cells/Ta/RGD group. Porous tantalum compo-sites and osteoblasts-tantalum interface were observed by scanning electron microscopy. The adhesion rate of osteoblasts was detected and immunocytochemistry was used to detect the expressions of filamentous actin (F-actin), osteocalcin (OC) and fibronectin (FN). RESULTS: The scanning electron microscope (SEM) revealed that osteoblasts distributed on the surface of porous tantalum and secreted extracellular matrix on outside and inner of micro-pores. The osteoblasts adhesion rate on porous tantalum modified with RGD was higher than that in the unmodified porous tantalum at the end of 24, 48, and 72 hours. The best adhesion effect was got in 5 g/L cells/Ta/RGD group at hour 48 [(68.07+/-3.80) vs. (23.40+/-4.39), P<0.05]. The results of immunocytochemistry showed that the expressions intensity of F-actin, OC and FN in osteoblasts on porous tantalum modified groups with RGD were stronger than that in the unmodified groups, and the expressions of 5 g/L cells/Ta/RGD group were significantly higher than those in the 10 g/L group and 1 g/L group [OC: (18.08+/-0.08) vs. (15.14+/-0.19), P<0.05; (18.08+/-0.08) vs. (14.04+/-0.61), P<0.05. FN: (24.60+/-0.98) vs. (15.90+/-0.53), P<0.05; (24.60+/-0.98) vs. (15.30+/-0.42), P<0.05. F-actin: (29.20+/-1.31) vs. (24.50+/-1.51), P<0.05; (29.20+/-1.31) vs. (16.92+/-0.40), P<0.05]. Correspondingly F-actin in osteoblasts was showed in longitudinal arrangement, and the expressions intensity was stronger than those OC and FN. CONCLUSION: The RGD peptides is beneficial to enhance adhesion of osteoblast, spreading and reorganization of cytoskeleton on porous tantalum surface and improve the interface morphology, further promoting osteoblasts-tantalum conjunctive interface osseointegration. PMID- 29483744 TI - [Segmental vena cava resection for the treatment of renal tumor with invading tumor thrombus]. AB - OBJECTIVE: To investigate the safety and perioperative experience of the segmental resection of the vena cava. METHODS: From May 2015 to July 2017, 92 renal tumor patients with venous tumor thrombus were treated in Peking University Third Hospital, of whom 17 underwent nephrectomy with resection of the invaded vena cava for renal tumor with tumor thrombus invading vena cava. The preoperative features included that 15 patients were male and 2 female, the mean age was (59.2+/-12.9) years (31-84 years), 6 cases were left sided and 11 right sided, and the mean diameter of the renal tumor was (9.1+/-3.7) cm (3-14.5 cm). RESULTS: In this group of 17 cases, 5 patients underwent resection of the vena cava via laparoscopy (including 2 open conversions), and 12 via open procedures (including 2 cardiopulmonary bypasses). The mean operation time was (430.4+/ 120.7) min (284-694 min) and the mean intraoperative blood loss was (2 918.8+/-2 608.2) mL (300-10 000 mL). The vena cava from the bottom to the top was transected. The median length of the tumor thrombus in the vena cava was 10 cm (3 21 cm). Postoperative complications were found in 11 patients, including grade I in 1 case, grade II in 7 cases, grade IV in 2 cases and grade V in 1 case according to the Clavien system. The median postoperative creatinine was 116 MUmol/L (79-645 MUmol/L) with 2 patients needing dialysis. The postoperative pathology revealed that renal clear cell carcinoma in 10 cases, papillary carcinoma in 5 cases, urothelial carcinoma in 1 case and fusiform cell sarcoma in 1 case. During the median follow-up of 8 (1-28) months, 1 patient died during perioperative period, 1 patient died from multiple metastasis in 9 months postoperatively, 3 patients found distant metastasis and 2 cases remained lower extremity edema after operation. CONCLUSION: The segmental resection of the vena cava may be a good choice for non-metastatic renal tumors with tumor thrombus invading vena cava. The short term follow-up results revealed a satisfactory safety and feasibility. PMID- 29483745 TI - [Dosimetric analysis of volumetric modulated arc therapy and intensity modulated radiotherapy for patients undergone breast-conserving operation]. AB - OBJECTIVE: To compare the dosimetric differences between volumetric modulated arc therapy and intensity modulated radiotherapy for breast cancer patients after breast-conserving surgery. METHODS: Ten patients who received radiotherapy after breast-conserving surgery were selected. Eclipse planning system was used to design volumetric rotating intensity-modulated (2F-RapidArc) and two field intensity-modulated radiation therapy (2F-IMRT) planning for each patient. 2F RapidArc plans were made using two partial arcs with gantry rotation from 287 degrees -293 degrees to 152 degrees -162 degrees , and 0 degrees to 90 degrees was avoidance sector. The gantry angle of 2F-IMRT were 301 degrees -311 degrees and 125 degrees -135 degrees . The prescription dose was 46 Gy/23 fractions. All plans required 95% of the target volume receiving the prescription dose. The dose distribution of the target, organs at risk, machine unit (MU) and treatment time were compared. RESULTS: 2F-RapidArc and 2F-IMRT plans' uniformity index was 1.12+/-0.02 and 1.11+/-0.03 (P=0.282), respectively; conformal index was 0.80+/ 0.03 and 0.65+/-0.04 (P<0.001), respectively. V110 of plan target volume was 20.98%+/-14.47% and 10.43%+/-10.49% (P=0.030), respectively. Compared with the 2F IMRT, 2F-RapidArc plans had a higher dosimetric parameters for left lung: V5 (48.06%+/-17.32% vs. 24.23%+/-6.56%,P=0.001), V10 (28.89+/-9.28 vs.17.07+/ 4.78%,P=0.004), Dmean [(9.70+/-2.14) Gy vs. (6.86+/-1.77) Gy, P=0.002], increased the double lung: V5 (22.85%+/-7.55% vs. 11.01%+/- 2.95%,P=0.001), V10 (13.16%+/ 4.33% vs. 7.76%+/- 2.16%, P=0.006), Dmean [(4.66+/-0.95) Gy vs. (3.17+/-0.82) Gy, P=0.001], reduced the left lung: V40 (3.58%+/-1.46% vs. 6.19%+/-3.04%, P=0.006), reduced the double lung: V40 (1.61%+/-0.64% vs. 2.81%+/- 1.39%,P=0.005), increased cardiac: V5 (39.3%+/-17.19% vs. 8.79%+/-4.24%, P<0.001), V10 (21.31%+/ 13.8% vs. 5.73%+/-3.42%, P=0.002), V20 (7.80%+/-6.08% vs. 4.05%+/-2.85%,P=0.018), Dmean [(0.64+/-0.25) Gy vs. (0.29+/-1.39) Gy,P<0.001],reduced the heart: V40(0.50%+/-0.40% vs. 1.86%+/-1.94%,P=0.037),increased the contralateral breast Dmean [(1.63+/-1.26) Gy vs. (0.09+/-0.05) Gy, P=0.004]. Compared with 2F IMRTplan, 2F-RapidArc increased the treatment time [(132.9+/-7.2) s vs. (140.3+/ 11.6) s, P=0.030]. Both the machine units were almost the same [(467.0+/-30.4) MU vs. (494.7+/-44.9) MU, P=0.094]. CONCLUSION: Both 2F-RapidArc and 2F-IMRT plans could reach the clinical requirements. 2F-RapidArc had a better conformal index, reduced the high dose area, but increased the low dose regions of the lung, heart, body area, and increased the average dose of the contralateral breast. The treatment time of 2F-RapidArc was longer than that of 2F-IMRT, and the MU of 2F RapidArc and 2F-IMRT plans were almost the same. PMID- 29483746 TI - [Prevalance of peri-anesthesia allergy and its related risk factor: a retrospective survey from 2012-2017]. AB - OBJECTIVE: To investigate the incidence of peri-anesthesia allergy in a tertiary teaching hospital. METHODS: This was a retrospective cohort study. Patients who received anesthesia in operation rooms at Peking University First Hospital from January 2012 to April 2017 were enrolled. Researchers reviewed all the patients' electronic records and screened suspect allergy cases. Allergy was diagnosed according to the definition in Consensus on Management of Perioperative Allergy (China) and Scandinavian Clinical Practice Guidelines on the Diagnosis, Management and Follow-up of Anaphylaxis during Anesthesia. After obtaining the electronic records, two researchers began to screen and supplement missing data according medical records independently, then they checked out each other's data. The final data were reviewed by another two researchers. We collected the patients' basic characteristics, surgery type, anesthesia type, peri-anesthesia use of drugs, prognosis and other data. Univariate logistic regression was employed to screen potential factors of allergy. Factors with statistical significance (P<0.05) in univariate Logistic regression were entered into multivariate Logistic regression to identify independent risk factors of allergy. RESULTS: In the study, 106 074 patients entered final statistic analysis. The incidence of peri-anesthesia allergy was about 1.5/1 000 (156/106 074). The incidence of Grades I, II and III allergy was 64.1% (100/156), 30.1% (47/156), and 5.8% (9/156) respectively. Multivariate logistic regression showed 5 independent risk factors of allergy including history of allergy (OR=6.836, 95%CI: 4.461-10.474, P<0.001), intraoperative use of sufentanil (OR=1.993, 95%CI: 1.228-3.232, P=0.005), intraoperative use of cis-atracuronium (OR=2.495, 95%CI: 1.599-3.893, P<0.001), intraoperative infusion of antibiotics (OR=2.005, 95%CI: 1.375-2.924, P<0.001) and frozen fresh plasma (OR=3.055, 95%CI: 1.842-5.068, P<0.001). CONCLUSION: The incidence of peri-anesthesia allergy is high and further attempt is needed to establish standard operation process of diagnosis and treatment of allergy. PMID- 29483747 TI - Our centenary issue. PMID- 29483748 TI - World blindness and visual impairment: despite many successes, the problem is growing. PMID- 29483749 TI - The epidemiology of blindness in children: changing priorities. PMID- 29483750 TI - Integrating child eye health within primary health care: a case study. PMID- 29483751 TI - Changing techniques in cataract surgery: how have patients benefited? PMID- 29483752 TI - Cataract indicators: their development and use over the last 30 years. PMID- 29483754 TI - Cataract surgical rates. PMID- 29483753 TI - Facing the crisis in human resources for eye health in sub-Saharan Africa. PMID- 29483755 TI - Trachoma then and now: update on mapping and control. PMID- 29483756 TI - Onchocerciasis then and now: achievements, priorities and challenges. PMID- 29483757 TI - Open education in eye health: transforming access to learning. PMID- 29483758 TI - Eye care in South Asia, 1988-2018: developments, achievements and future challenges. PMID- 29483759 TI - "Without this journal, I am in utter darkness". PMID- 29483761 TI - Fascia Suture Technique and Suture-mediated Closure Devices: Systematic Review. AB - Background The aim of the present study is to review the available data on suture-mediated closure devices (SMCDs) and fascia suture technique (FST), which are alternatives for minimizing the invasiveness of percutaneous endovascular aortic aneurysm repair (p-EVAR) and reduce the complications related to groin dissections. Methods The Medline, ClinicalTrials.gov, and Cochrane library - Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched for publications regarding SMCD and FST between January 1999 and December 2016. Results We review 37 original articles, 30 referring to SMCDs (Prostar XL and Proglide), which included 3,992 patients, and 6 articles referring to FST, which include 426 patients. The two techniques are compared only in one article (100 patients). The two types of SMCDs were Prostar and Proglide. In most studies on SMCDs, the reported technical success rates were between 89 and 100%, but the complication rates varied greatly between 0 and 25%. Concerning FST, the technical success rates were also high, ranging between 87 and 99%. However, intraoperative complication rates ranged between 1.2 and 13%, whereas postoperative complication rates varied from 0.9 to 6.2% for the short-term and from 1.9 to 13.6% for the long-term. Conclusions SMCDs and FST seem to be effective and simple methods for closing common femoral artery (CFA) punctures after p-EVAR. FST can reduce the access closure time and the procedural costs with a quite short learning curve, whereas it can work as a bailout procedure for failed SMCDs suture. The few failures of the SMCDs and FST that may occur due to bleeding or occlusion can easily be managed. PMID- 29483762 TI - Overutilization of Cross-Sectional Imaging in the Lower Extremity Trauma Setting. AB - Objective In an era of managed care and cost savings, we are faced with the question of whether another test is necessary to confirm our clinical suspicion. We hypothesized that a few computed tomography angiographies (CTAs) are necessary to identify lower extremity vascular injuries (LEVIs). We reviewed our trauma center's experience in the management of LEVI. Methods A retrospective review of all trauma patients between 2012 and 2016 was performed. Four-thousand nine hundred fourteen trauma patients were evaluated with 46 suspected LEVIs (either with cross-sectional imaging and/or operative exploration). Our primary end point was the utility of CTA in the setting of LEVI. Receiver operating characteristic curves were performed to evaluate sensitivity and specificity for hard signs and CTA identification of LEVI. Results Out of the initial 46 patients with suspected LEVI, 41 (89%) had a CTA as part of their initial evaluation. Sixteen patients (35%) with LEVI were due to penetrating injuries. Seventeen patients (41%) had a CTA with LEVI. Fourteen of the 17 patients (82%) with injury on CTA also had hard signs of LEVI. Twenty-two patients (48%) underwent operative exploration: three had no LEVI that was previously believed to be on CTA; operative exploration identified two missed injuries not observed on CTA. Seven of forty-one (17%) CTA studies provided a false assumption of the presence/absence of LEVI. One patient (2%) underwent operative exploration and was found to have LEVI in the absence of hard signs, but with a CTA identifying LEVI. Conclusion The recognition of hard signs through physical examination is paramount to assessing need for operative intervention with suspicion of LEVI. CTA should be reserved as an adjunct for identification of LEVI in patients with high clinical suspicion and absence of hard signs, rather than utilizing CTA as an initial screening tool for the identification of LEVI. PMID- 29483760 TI - AGE-RAGE Stress, Stressors, and Antistressors in Health and Disease. AB - Adverse effects of advanced glycation end-products (AGEs) on the tissues are through nonreceptor- and receptor-mediated mechanisms. In the receptor-mediated mechanism, interaction of AGEs with its cell-bound receptor of AGE (RAGE) increases generation of oxygen radicals, activates nuclear factor-kappa B, and increases expression and release of pro-inflammatory cytokines resulting in the cellular damage. The deleterious effects of AGE and AGE-RAGE interaction are coined as "AGE-RAGE stress." The body is equipped with defense mechanisms to counteract the adverse effects of AGE and RAGE through endogenous enzymatic (glyoxalase 1, glyoxalase 2) and AGE receptor-mediated (AGER1, AGER2) degradation of AGE, and through elevation of soluble receptor of AGE (sRAGE). Exogenous defense mechanisms include reduction in consumption of AGE, prevention of AGE formation, and downregulation of RAGE expression. We have coined AGE and RAGE as "stressors" and the defense mechanisms as "anti-stressors." AGE-RAGE stress is defined as a shift in the balance between stressors and antistressors in the favor of stressors. Measurements of stressors or antistressors alone would not assess AGE-RAGE stress. For true assessment of AGE-RAGE stress, the equation should include all the stressors and antistressors. The equation for AGE-RAGE stress, therefore, would be the ratio of AGE + RAGE/sRAGE + glyoxalase1 + glyoxalase 2 + AGER1 +AGER2. This is, however, not practical in patients. AGE RAGE stress may be assessed simply by the ratio of AGE/sRAGE. A high ratio of AGE/sRAGE indicates a relative shift in stressors from antistressors, suggesting the presence of AGE-RAGE stress, resulting in tissue damage, initiation, and progression of the diseases and their complications. PMID- 29483763 TI - Evaluation of Experience with Lower Extremity Arterial Injuries at an Urban Trauma Center. AB - Lower extremity arterial injuries (LEAIs) can be complicated injuries resulting in limb loss and death. Patients with LEAI often have multiple injuries increasing the risk for morbidity and mortality. We sought to evaluate the incidence and management of LEAI and to define associations between injuries and outcomes. We performed a retrospective review of LEAI at an urban level-1 trauma center from April 2005 to April 2015. Chi-square tests were used to compare independent groups with respect to mortality and amputation. Means were compared between independent groups using two-sample t -tests. From April 2005 to April 2015, 208 arterial injuries occurred in 163 patients. The majority (80.4%) suffered concomitant lower extremity injuries with 35.6% suffering systemic injuries. Surgical intervention was required for 72.1% of injuries. Amputation rate was 14.7%. Mortality rate was 8.0%. Data from 2010 to 2015 were more specifically analyzed. Injury severity score (ISS) was higher with fatalities (37 +/- 13.16 vs. 11.8 +/- 8.51, p < 0.0001) and in patients requiring an amputation (25.4 +/- 15.32 compared with 11.6 +/- 9.05, p = 0.0015). Popliteal artery injury was most likely to require an amputation (odds ratio [OR] = 2.9, p = 0.04). Mortality was more likely when systemic injuries were present (OR = 18.1, p = 0.0005). The majority of patients with arterial injuries require surgical management, most often with open surgical techniques. Arterial injuries associated with systemic injuries, blunt injury mechanisms, and higher ISS are at a significantly increased risk of mortality. PMID- 29483764 TI - Erythrocyte Aggregation and Blood Viscosity is Similar in Homozygous Sickle Cell Disease Patients with and without Leg Ulcers. AB - Background There is no consensus regarding the role of red blood cell (RBC) aggregation in the pathogenesis of leg ulcers (LUs) in sickle cell disease (SCD). Objectives We sought to evaluate whether the cross-sectional determination of RBC aggregation and hematological indices were associated with the presence of LU in homozygous SCD. Methods Twenty-seven patients with LU and 23 with no history of ulceration were recruited into the study. A laser-assisted rotational red cell analyzer (LoRRca) was used in the determination of the aggregation index (AI), aggregation half-time ( t1/2 ), and the RBC aggregate strength (AMP). Hematological indices were determined using a CELL-DYN Ruby analyzer. Whole blood viscosity (WBV) and plasma viscosity (PV) were measured using a Vilastic bioprofiler. The data were presented as means +/- standard deviation or median, interquartile range. Two-sample t -test was used to test for associations between the AIs, WBV, and PV in patients with and without LU. Statistical significance was taken as p < 0.05. All analyses were conducted using Stata/SE v . 12.1 (StataCorp, College Station, TX). Results The AI was comparable in the group with and without ulcers (68.6, 16.7 versus 67.7, 16.9; p = 0.74); t1/2 (1.7, 1.3 versus 1.8, 1.3; p = 0.71); AMP (18.8, 14.5 versus 19.1, 13.3; p = 0.84), WBV (3.8, 1.2 versus 3.8, 0.7; p = 0.77); and the PV (1.3, 0.08 versus 1.4, 0.1; p = 0.31) and were also not statistically different between the groups of participants. Conclusion RBC aggregation and aggregate strength are not associated with leg ulceration in SCD. PMID- 29483765 TI - Clinical Use of the Amplatzer Device in the Management of Intracardiac Defects: A Single-Center Experience. AB - Device therapy is a viable alternative to open heart surgery in the management of intracardiac defects. The Amplatzer septal occluder (ASO) is one such device that has been adapted to close a wide variety of cardiac defects with few complications and a high success rate. This is a retrospective review of all the patients who received the ASO between 2012 and 2016 at the University of Kentucky. In total, 169 patients underwent percutaneous closure of a septal defect with Amplatzer during the timeframe studied, and of those, 91% received the device for an atrial septal defect or patent foramen ovale. Patients presented with stroke, transient ischemic attack, migraine, dyspnea or other symptoms and were diagnosed by transesophageal echocardiography and cardiac catheterization. All Amplatzer devices achieved successful closure without requiring a second procedure. Four patients sustained complications of the procedure, with two experiencing tamponade, one with hematoma, and one with cellulitis. The Amplatzer device was not directly implicated in the three fatalities that occurred within 30 days of the septal occlusion procedure. The ASO has performed very well at our institution and we expect it to serve additional functions as the field of transcatheter cardiology develops. PMID- 29483766 TI - Left Ventricular Myxoma with Embolization Causes Acute Infrarenal Aortic Occlusion. AB - Atrial myxoma is the most common benign tumor of the heart; moreover, atrial myxoma embolization to the peripheral vessels is rare. We present an unusual case of total acute infrarenal aortic occlusion resulting from embolic implantation from a left ventricular myxoma. A 37-year-old man with acute lower limbs ischemia, spinal cord ischemia, and acute renal insufficiency was urgently operated and discharged after surgery. PMID- 29483767 TI - Hypogastric Chimney Patency in Aortic Monoiliacal Endograft Thrombosis: A Life Saved by Collateral Pelvic Circulation. AB - Background To report a case of a high-risk patient treated with hypogastric chimney and aortic endograft for a native infrarenal aorta aneurysmal degeneration, 20 years after an aortobifemoral bypass procedure for severe iliac occlusive disease. Methods A two-stage procedure was planned. The first stage was right internal iliac artery (IIA) embolization and simple angioplasty of left IIA. The second stage consisted of aortouniiliac endograft with femoral crossover and left IIA chimney. Results Femoral crossover complicated with early thrombosis, but a decision on conservative medical treatment with anticoagulation was made based on no rest pain or severe claudication. After 3 months the patient presented with moderate claudication alone. Scheduled computed tomography scan showed femoral crossover graft and aortic endograft thrombosis with left IIA patency. The axillofemoral bypass was scheduled a week later, and the patient discharged home. Conclusion Preservation of pelvic circulation is mandatory to avoid life-threatening complications. The chimney technique demonstrates good patency and should be considered in the endovascular approach armamentarium for hypogastric artery revascularization. PMID- 29483768 TI - Hybrid Strategy for High-Risk Neonates with Interrupted Aortic Arch: A Can Well Worth Kicking? AB - The use of hybrid techniques to avoid neonatal cardiopulmonary bypass in high risk individuals is well reported in the setting of hypoplastic left heart syndrome. We describe the use of that technique as a bridging procedure in high risk neonates with an interrupted aortic arch. We report three cases where hybrid branch pulmonary artery banding and ductal stent implantation has been successfully used to defer complete repair, allowing recovery, maturity, and weight gain. This strategy may be considered for patients deemed at high risk for primary neonatal repair. PMID- 29483770 TI - Comparison of the long-term efficacy and safety of generic tacrolimus, Tacrobell, with Prograf in liver transplant recipients. AB - Introduction: The purpose of this study was to compare the safety and efficacy of generic tacrolimus (Tacrobell [TCB]) and a reference tacrolimus (Prograf [PGF]) in liver transplant recipients. Patients and methods: We retrospectively analyzed 167 patients who used TCB or PGF between January 2009 and March 2016 for >1 year (TCB group, n=86; PGF group, n=81). To assess the efficacy and safety of TCB, we evaluated the relationship between drug dose and trough level, survival, rejection, infection, kidney function, and side effects. Results: There was no difference in the preoperative demographics between the two groups. Moreover, there was no difference in the drug dose and trough level between the groups at 1 week after surgery. Coefficient of variation (CV) values were obtained at the drug trough level for each patient and no differences in CV values were identified within 1 year (p=0.587) and up to 5 years (p=0.824) in both groups. Rehospitalization (p=0.1) and total rejection (p=0.915) did not differ between the two groups, but the rejection severity, recorded as the rejection activity index value, was worse in the PGF group (p=0.039). No difference was found in the infection rate (p=0.818), and with regard to nephrotoxicity, there was no difference in the rate of patients with chronic kidney disease stage 3 and above during the follow-up period. No differences were found between the two groups in terms of drug side effects and adverse events. Conclusion: The generic tacrolimus, TCB, is a comparable alternative to the original tacrolimus, PGF, as a main immunosuppressive drug for liver transplantation. PMID- 29483769 TI - Asthma and poly(ADP-ribose) polymerase inhibition: a new therapeutic approach. AB - Asthma is a chronic lung disease affecting people of all ages worldwide, and it frequently begins in childhood. Because of its chronic nature, it is characterized by pathological manifestations, including airway inflammation, remodeling, and goblet cell hyperplasia. Current therapies for asthma, including corticosteroids and beta-2 adrenergic agonists, are directed toward relieving the symptoms of the asthmatic response, with poor effectiveness against the underlying causes of the disease. Asthma initiation and progression depends on the T helper (Th) 2 type immune response carried out by a complex interplay of cytokines, such as interleukin (IL) 4, IL5, and IL13, and the signal transducer and activator of transcription 6. Much of the data resulting from different laboratories support the role of poly(ADP-ribose) polymerase (PARP) 1 and PARP14 activation in asthma. Indeed, PARP enzymes play key roles in the regulation and progression of the inflammatory asthma process because they affect the expression of genes and chemokines involved in the immune response. Consistently, PARP inhibition achievable either upon genetic ablation or by using pharmacological agents has shown a range of therapeutic effects against the disease. Indeed, in the last two decades, several preclinical studies highlighted the protective effects of PARP inhibition in various animal models of asthma. PARP inhibitors showed the ability to reduce the overall lung inflammation acting with a specific effect on immune cell recruitment and through the modulation of asthma-associated cytokines production. PARP inhibition has been shown to affect the Th1-Th2 balance and, at least in some aspects, the airway remodeling. In this review, we summarize and discuss the steps that led PARP inhibition to become a possible future therapeutic strategy against allergic asthma. PMID- 29483771 TI - Foot health-related quality of life among elderly with and without lesser toe deformities: a case-control study. AB - Purpose: The aim of this study was to compare the health-related quality of life impact related to foot health and health in general in older adults with lesser toe deformities (LTD) and without any foot conditions. Methods: A case-control observational study was carried out following the Strengthening the Reporting of Observational Studies in Epidemiology criteria. A total of 100 older adults with a mean age of 74.39+/-6.02 years were recruited at an outpatient clinic; 50 of these subjects had LTD (case group) and 50 subjects were without any foot conditions (control group). Presence of LTD was determined in both feet using the Kelikian push-up test, and the Foot Health Status Questionnaire scores were self reported. Results: The case group showed lower scores in quality of life in relation to health in general and to foot health specifically. Statistically significant differences (p<0.05) between case and control groups were shown by means of the Wicoxon test. Conclusion: A negative impact in quality of life in relation to foot health should be considered in older adults with LTD, regardless of gender. PMID- 29483772 TI - Falls prevention in community care: 10 years on. AB - Background: A million older people living in Australia receive community care services each year due to experiencing functional or mental health difficulties. This group may be at greater risk of falling than similar-aged people not receiving services. However, there is limited falls prevention research for this population. Purpose: The aim of this study was to identify the falls prevalence rates of older people from 10 Australian community care organizations and compare current falls prevention data to a study 10 years prior that utilized the same 10 organizations. This study also identified factors associated with falling for this population. Patients and methods: This is a cross-sectional descriptive study, in which 5,338 questionnaires were mailed to a random sample of community care recipients aged >=65 years. Results: A total of 1,991 questionnaires were returned (37.3%), with 47.7% of respondents having fallen in the previous year, and 32.7% in the month prior to completing the questionnaire, similar to 10 years prior. Community care clients had a 50% higher falls rate than that reported for similar-aged people not receiving services, and this remained unchanged over the last 10 years. Eighty-six per cent of fallers had fallen once or twice, and 60% reported being injured. Thirty-six per cent of respondents reported not being able to get up independently, and only 27.4% of fallers were referred to a falls prevention program (significantly fewer than 10 years ago; 95% CI: 0.821-6.366, p=0.01). Balance issues (odds ratio [OR]: 2.06, 95% CI: 1.288-3.290, p=0.003) and perceived risk of falling in the future being "definite" (OR: 6.42, 95% CI: 1.890 21.808, p=0.003) or "unsure" (OR: 3.31, 95% CI: 1.144-9.544, p=0.027) were risk factors associated with falling. In contrast, individuals referred to a falls prevention intervention had a 47% reduced likelihood of having fallen (95% CI: 0.281-0.988, p=0.046). Conclusion: Community care clients should have their falls risk routinely assessed, and at-risk individuals be offered falls prevention advice and referral to fall prevention programs. PMID- 29483773 TI - Psychological effects of exercise on community-dwelling older adults. AB - Background: In recent years, there have been an increasing number of older adults who suffer from mental disorders globally. Objective: The objective of this study was to examine the effect of an intervention that consisted of an exercise program to improve the mental health of community-dwelling older adults. Participants and methods: The recruited participants of this study were community dwelling older adults aged >=60 years who participated in a comprehensive health promotion program in Kakogawa, Japan. Participants in the intervention group received an exercise program that was developed for older adults using Thera Band. To measure participants' mental health status, a Japanese version of the short form of the Profile of Mood States (POMS-SF) was used. Stress markers were measured, such as salivary cortisol, alpha-amylase, and sIgA levels. All participants provided salivary samples and completed psychological questionnaires at baseline and 6-month follow-up. Results: No significant differences were observed between the intervention and control groups with respect to POMS-SF score and salivary biomarker profile at baseline. After the intervention, the intervention group showed a significant decrease in the POMS-SF "fatigue" score and cortisol level. No significant changes were observed in the control group. Conclusion: Simultaneous changes in feelings of fatigue and cortisol levels were observed among subjects who had received the intervention of regular exercise. Further research is needed to investigate the effectiveness of exercise intervention in improving mental health among older adults. PMID- 29483775 TI - Timing of psychoeducation for patients with depression who were treated with antidepressants: when should patients receive psychoeducation. AB - Background: We analyzed data on the understanding of depression among patients who were prescribed antidepressants to determine when psychoeducation should be provided. Patients and methods: A total of 424 outpatients were enrolled in this study. We used an original self-administered questionnaire consisting of eight categories: (A) depressive symptoms, (B) the course of depression, (C) causes of depression, (D) the treatment plan, (E) the duration of antidepressant use, (F) discontinuation of antidepressants, (G) the side effects of antidepressants, and (H) psychotherapy. Each category was assessed with the following two questions: "Have you received an explanation of this topic from the doctor in charge?" and "How much do you understand about your treatment?" The level of understanding of patients was rated on a scale from 0 to 10 (no understanding to full understanding; 11 anchor points). Symptoms were evaluated using the Quick Inventory for Depressive Symptomatology, Japanese version (QIDS-J) and other scales. Participants were divided into two groups: patients receiving psychoeducation at their first visit vs patients receiving psychoeducation after their first visit. Results: Of the patients who had received an explanation of each psychoeducation item, a greater proportion were in the first visit group than in the after first visit group for nearly all items. Compared with the after first visit group, the first visit group showed a better understanding of each psychoeducation item and significantly lower QIDS scores for those receiving explanations of Items A and C. There was no significant difference between the two groups in remittance rates. Conclusion: Psychoeducation on depression, especially regarding the symptoms and causes of depression, should be provided at patients' first visit. PMID- 29483774 TI - Mixed Th2 and non-Th2 inflammatory pattern in the asthma-COPD overlap: a network approach. AB - Introduction: The asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) is a clinical condition that combines features of those two diseases, and that is difficult to define due to the lack of understanding of the underlying mechanisms. Determining systemic mediators may help clarify the nature of inflammation in patients with ACO. Objectives: We aimed at investigating the role and interaction of common markers of systemic inflammation (IL-6, IL-8, and tumor necrosis factor-alpha), Th2-related markers (periostin, IL-5, and IL-13), and IL 17 in asthma, COPD, and ACO. Methods: This is a cross-sectional study of patients aged >=40 years with a post-bronchodilator forced expiratory volume in the first second/forced vital capacity <0.70 recruited from outpatient clinics in tertiary hospitals with a clinical diagnosis of asthma, COPD, or ACO. ACO was defined by a history of smoking >10 pack-years in a patient with a previous diagnosis of asthma or by the presence of eosinophilia in a patient with a previous diagnosis of COPD. Clinical, functional, and inflammatory parameters were compared between categories using discriminant and network analysis. Results: In total, 109 ACO, 89 COPD, and 94 asthma patients were included. Serum levels (median [interquartile range]) of IL-5 were higher in asthma patients than in COPD patients (2.09 [0.61-3.57] vs 1.11 [0.12-2.42] pg/mL, respectively; p=0.03), and IL-8 levels (median [interquartile range]) were higher in COPD patients than in asthma patients (9.45 [6.61-13.12] vs 7.03 [4.69-10.44] pg/mL, respectively; p<0.001). Their values in ACO were intermediate between those in asthma and in COPD. Principal component and network analysis showed a mixed inflammatory pattern in ACO in between asthma and COPD. IL-13 was the most connected node in the network, with different weights among the three conditions. Conclusion: Asthma and COPD are two different inflammatory conditions that may overlap in some patients, leading to a mixed inflammatory pattern. IL-13 could be central to the regulation of inflammation in these conditions. PMID- 29483776 TI - Chronic dialysis patients with infectious spondylodiscitis have poorer outcomes than non-dialysis populations. AB - Purpose: Infectious spondylodiscitis is a serious disease that can lead to permanent neurological deficit. Because there were only a few case reports or series featuring infectious spondylodiscitis in chronic dialysis patients, we investigated the epidemiology and outcome in the chronic dialysis patients versus general population. Materials and methods: We retrospectively identified chronic dialysis patients admitted for infectious spondylodiscitis between January 2002 and December 2015. A total of 105 chronic dialysis patients were included, and we performed a 1:2 case-control match on propensity score in non-dialysis patients with infectious spondylodiscitis. The demographic features, clinical manifestation, infection focus, and disease outcome were recorded. Results: A total of 302 patients entered the final analysis. Chronic dialysis patients less frequently had fever (34.3%), and in the majority, bacterial entry was through dialysis vascular access (30.5%). Methicillin-resistant Staphylococcus aureus (MRSA) comprised the majority of causative pathogen. The chronic dialysis group had longer hospital stay, higher in-hospital mortality, and higher 1-year mortality. The odds ratio of in-hospital mortality was 2.20 compared with the non dialysis group. Conclusions: The study highlighted poorer outcome and high frequency of resistant Staphylococcus of infectious spondylodiscitis in chronic dialysis patients. Therefore, high vigilance, prompt recognition, and empiric coverage of MRSA will be important in the management of infectious spondylodiscitis in chronic dialysis patients. PMID- 29483777 TI - Antitumor effect of triptolide in T-cell lymphoblastic lymphoma by inhibiting cell viability, invasion, and epithelial-mesenchymal transition via regulating the PI3K/AKT/mTOR pathway. AB - Introduction: T-cell lymphoblastic lymphoma (T-LBL) is a widely disseminated disease worldwide. Triptolide (TPL) is purified from Chinese herb and displays anti-inflammatory, anti-fertility, anti-tumor and immunosuppressive effects. Materials and methods: Here, in vitro and in vivo experiments were conducted to investigate the anti-tumor effect of TPL treatment in T-LBL and the potential mechanism in T-LBL progression. Results: TPL inhibited cell proliferation of T LBL cells (Jurkat cells and Molt-3 cells) in a dose-dependent manner. Flow cytometry analysis showed that cell apoptosis rate was increased by TPL treatment. TPL also up-regulated the expression of Caspase-3, Bax and down regulated the expression of Bcl-2, indicating that TPL promoted apoptosis in Jurkat cells. Moreover, TPL inhibited invasion ability of Jurkat cells and down regulated the expression of MMP-3 and MMP-9 in a dose-dependent manner. The expression of Snail, Slug, Twist and Integrin alphaVbeta6 was decreased and the expression of E-cadherin was increased by TPL treatment, indicating that TPL inhibited EMT of Jurkat cells. Apart from that, TPL treatment attenuated the phoslevels of PI3K, Akt and mTOR and suppressed AKT activation compared with control group, suggesting that TPL inhibited PI3K/Akt/mTOR signal pathway in T LBL. In vivo experiments showed that TPL inhibited tumor growth of T-LBL and promoted apoptosis of tumor cells. The expression of PCNA, Bcl-2, Snail, p-PI3K, p-Akt and mTOR was suppressed by TPL in a dose-dependent manner, suggesting that TPL suppressed tumor growth and promoted apoptosis of tumor cells by inhibiting PI3K/Akt/mTOR signal pathway in T-LBL. Conclusion: In conclusion, TPL exerted anti-tumor effect in T-LBL by inhibiting cell viability, invasion and EMT via regulating the PI3K/AKT/mTOR pathway. PMID- 29483778 TI - A review on stem cell therapy for multiple sclerosis: special focus on human embryonic stem cells. AB - Multiple sclerosis (MS), a complex disorder of the central nervous system (CNS), is characterized with axonal loss underlying long-term progressive disability. Currently available therapies for its management are able to slow down the progression but fail to treat it completely. Moreover, these therapies are associated with major CNS and cardiovascular adverse events, and prolonged use of these treatments may cause life-threatening diseases. Recent research has shown that cellular therapies hold a potential for CNS repair and may be able to provide protection from inflammatory damage caused after injury. Human embryonic stem cell (hESC) transplantation is one of the promising cell therapies; hESCs play an important role in remyelination and help in preventing demylenation of the axons. In this study, an overview of the current knowledge about the unique properties of hESC and their comparison with other cell therapies has been presented for the treatment of patients with MS. PMID- 29483779 TI - Skin bacterial flora as a potential risk factor predisposing to late bacterial infection after cross-linked hyaluronic acid gel augmentation. AB - Introduction: Cross-linked hyaluronic acid (HA) gel is widely used in esthetic medicine. Late bacterial infection (LBI) is a rare, but severe complication after HA augmentation. The aim of this study was to determine whether patients who underwent the HA injection procedure and developed LBI had qualitatively different bacterial flora on the skin compared to patients who underwent the procedure without any complications. Methods: The study group comprised 10 previously healthy women with recently diagnosed, untreated LBI after HA augmentation. The control group comprised 17 healthy women who had a similar amount of HA injected with no complications. To assess the difference between the two groups, their skin flora was cultured from nasal swabs, both before and after antibiotic treatment in the study group. Results: A significant increase in the incidence of Staphylococcus epidermidis was detected in the control group (P=0.000) compared to the study group. The study group showed a significantly higher incidence of Staphylococcus aureus (P=0.005), Klebsiella pneumoniae (P=0.006), Klebsiella oxytoca (P=0.048), and Staphylococcus haemolyticus (P=0.048) compared to the control group. Conclusion: The bacterial flora on the skin differed in patients with LBI from the control group. The control group's bacterial skin flora was dominated by S. epidermidis. Patients with LBI had a bacterial skin flora dominated by potentially pathogenic bacteria. PMID- 29483780 TI - High-dose amikacin for achieving serum target levels in critically ill elderly patients. AB - Introduction: To achieve target concentrations, the application of higher-than standard doses of amikacin is proposed for the treatment of sepsis due to an increase in volume of distribution and clearance, but little data are available on aminoglycoside administration in critically ill elderly patients. Patients and methods: Forty critically ill elderly patients (aged over 65 years) who required amikacin therapy due to severe documented, or suspected gram-negative infections, were randomly assigned to two treatment groups. Group A (20 patients) received 15 mg/kg amikacin and Group B (20 patients) received 25 mg/kg amikacin per day as a single daily dose. All the patients were monitored for renal damage by the daily monitoring of serum creatinine. The amikacin peak (Cmax) and trough (Cmin) serum concentrations were measured on Days 3 and 7 postadministration. Results: Data from 18 patients in Group A and 15 patients in Group B were finally analyzed. On Day 3, the amikacin mean Cmax levels in the standard and high-dose treatment groups were 30.4+/-11 and 52.3+/-16.1 ug/mL (P<0.001), and the Cmin levels were 3.2+/-2.1 and 5.2+/-2.8 ug/mL, respectively (P=0.035). On Day 7, the Cmax levels in the standard and high-dose groups were 33+/-7.3 and 60.0+/-17.6 ug/mL (P=0.001), and the Cmin levels were 3.2+/-2.9 and 9.3+/-5.6 ug/mL, respectively (P=0.002). In only six (40%) of the patients in the high-dose groups and none of the patients in the standard-dose group, amikacin Cmax reached the target levels (>64 ug/mL), whereas the amikacin mean Cmin levels in the high-dose group were above the threshold of toxicity (5 ug/mL). Conclusion: Our results suggest that the optimum dose of amikacin should be determined for elderly critically ill patients. It seems that higher-than-standard doses of amikacin with more extended intervals might be more appropriate than standard once-daily dosing in the elderly critically ill patients. PMID- 29483782 TI - Single dose oral midazolam for minor emergency department procedures in children: a retrospective cohort study. AB - Background: In the pediatric emergency department, patients are commonly treated with a single dose of oral midazolam for minor procedures. We sought to evaluate the effect of this treatment on procedure completion rates. Methods: We conducted a single-center retrospective cohort study of all patients who were treated with pre-procedure oral midazolam between January 2011 and June 2016. The primary outcome was the procedure completion rate. Results: During the study period, 1,504 patients were treated with oral midazolam as per department protocol; 1,467 received midazolam and 37 declined midazolam. Oral midazolam was used in 14 different types of emergency department procedures. The procedure completion rates in the treatment and non-treatment groups were 1,402/1,467 (95.6%) and 24/37 (64.8%), respectively (difference 30.7%; 95% confidence interval [CI] 17.3% 46.8%); p<0.0001. Treatment group patients had procedure completion rates of 25/33 (75.8%), 165/188 (87.8%%), 1,154/1,187 (97.2%), and 58/59 (98.3%), in the less than 0.3 mg/kg group, 0.3 to less than 0.5 mg/kg group, 0.5 to less than 0.7 mg/kg group, and 0.7 to less than 0.9 mg/kg group, respectively. Multivariate regression did not demonstrate an association between sex, ethnicity, dosage of 0.5 mg/kg or greater, type of procedure, and failure to complete procedure. Severe adverse events were not recorded. A dose of less than 0.3 mg/kg was significantly associated with an increased risk of failure to complete a procedure (adjusted odds ratio 8.34, 95% CI 3.32-20.9; p<0.0001). Conclusion: The findings suggest that oral midazolam in a single dose of 0.5 mg/kg or greater is associated with successful completion of minor pediatric procedures. PMID- 29483781 TI - NOD2 and inflammation: current insights. AB - The nucleotide-binding oligomerization domain (NOD) protein, NOD2, belonging to the intracellular NOD-like receptor family, detects conserved motifs in bacterial peptidoglycan and promotes their clearance through activation of a proinflammatory transcriptional program and other innate immune pathways, including autophagy and endoplasmic reticulum stress. An inactive form due to mutations or a constitutive high expression of NOD2 is associated with several inflammatory diseases, suggesting that balanced NOD2 signaling is critical for the maintenance of immune homeostasis. In this review, we discuss recent developments about the pathway and mechanisms of regulation of NOD2 and illustrate the principal functions of the gene, with particular emphasis on its central role in maintaining the equilibrium between intestinal microbiota and host immune responses to control inflammation. Furthermore, we survey recent studies illustrating the role of NOD2 in several inflammatory diseases, in particular, inflammatory bowel disease, of which it is the main susceptibility gene. PMID- 29483783 TI - Acupuncture versus titrated morphine in acute renal colic: a randomized controlled trial. AB - Objective: The objective of this study was to compare the analgesic effect and tolerance profile of acupuncture versus intravenous (IV) titrated morphine in patients presenting to the emergency department (ED) with renal colic. Materials and methods: A total of 115 patients were randomized into two groups. Patients in the IV titrated-morphine group (n=61) received 0.1 mg/kg morphine every 5 minutes until pain score dropped by at least 50% of its baseline value. Patients in the acupuncture group (n=54) received an acupuncture session of 30 minutes following a prespecified protocol. The visual analog scale (VAS) was used to assess pain intensity at baseline and at 10, 20, 30, 45, and 60 minutes following the start of the treatment protocol. Possible treatment side effects were also recorded. Results: No significant differences were found between the two groups concerning age, sex, or baseline VAS score. From the 10th minute until the end of the intervention, acupuncture was associated with a deeper analgesic effect than titrated morphine (P<0.05 from the 10th minute and over). Analgesia was also faster in the acupuncture group, with time to obtain 50% reduction of baseline VAS of 14 minutes in the acupuncture group versus 28 minutes in the IV titrated morphine group (P<0.001). Only three patients in the acupuncture group experienced minor side effects versus 42 in the morphine group (P<0.001). No major side effects were observed in this study. Conclusion: In ED patients with renal colic, acupuncture was associated with a much faster and deeper analgesic effect and a better tolerance profile in comparison with titrated IV morphine. PMID- 29483784 TI - The role of cytokines and chemokines in the microenvironment of the blood-brain barrier in leukemia central nervous system metastasis. AB - Aim: Central nervous system (CNS) metastasis is a major obstacle in the treatment of leukemia, and the underlying mechanisms of leukemia CNS metastasis are not fully understood. The present study is an investigation of the role of the CNS microenvironment in leukemia CNS metastasis. Methods: Analog blood-brain barrier (BBB) was set by coculturing human brain microvascular endothelial cells (HBMVECs) and leukemia cells (U937 and IL-60), as well as HBMVECs and sera from leukemia patients, in vitro. The permeability of the HBMVEC monolayer and the levels of tight junction proteins, cytokines and chemokines (C&Ckines) were measured. Results: The permeability of HBMVECs increased when cocultured with leukemia sera. The expression of C&Ckines was significantly upregulated in HBMVECs cocultured with leukemia sera or leukemia cells, compared to the normal sera (P<0.05, respectively). Specifically, significantly higher levels of vascular endothelial growth factor A (VEGF-A) and matrix metalloprotease 9 (MMP 9) were found in HBMVECs and leukemia cells/sera coculturing systems. Conclusion: Both leukemia cells and the molecules in leukemia sera play an important role in leukemia CNS metastasis. VEGF-A and MMPs may be the main factors resulting in the degradation of the BBB and inducing the CNS migration of leukemia cells. PMID- 29483785 TI - The effect of endometrial thickness on pregnancy outcome in patients with Asherman's syndrome post-hysteroscopic adhesiolysis. AB - Background: Hysteroscopic adhesiolysis anatomically restores the uterine cavity in cases of Asherman's syndrome (AS); however, the extent of endometrial fibrosis could determine the pregnancy outcome. Objectives: To determine whether endometrial thickness could influence pregnancy outcome of hysteroscopic adhesiolysis in women with a history of AS. Subjects and methods: This was a retrospective cohort study that included 41 women who attended Women's Specialized Hospital, King Fahad Medical City from December 2008 to December 2015, presented with a history of infertility or recurrent pregnancy loss, and were diagnosed with intrauterine adhesions and treated by hysteroscopic adhesiolysis. To analyze the causative factors of AS, history of curettage, miscarriage, postpartum hemorrhage, hysteroscopy, endometritis, and any uterine surgery were recorded. Patients were followed up for 2 years to account for pregnancy. Patients were divided into two groups based on measurement of endometrial thickness in the midsagittal plane at mid-cycle of a menstrual period. Group A consisted of 26 patients with endometrial thickness <=5 mm, and group B included 15 patients with endometrial thickness >5 mm. The main outcome measures included endometrial thickness and pregnancy outcome. Results: Group A had significantly (P<0.001) lower pregnancy rates compared with group B (38.4% versus 80%, respectively). Five of 10 pregnancies (50%) from group A miscarried, compared with 1 of 12 (8.3%) pregnancies in group B. This was statistically significant (P<0.001). Conclusion: Pregnancy rates were observed to be higher when the endometrium was >5 mm in thickness among patients with AS and miscarriage rates may be reduced in this group. PMID- 29483786 TI - Reliability and validity of the revised Gibson Test of Cognitive Skills, a computer-based test battery for assessing cognition across the lifespan. AB - Purpose: The purpose of the current study is to evaluate the validity and reliability of the revised Gibson Test of Cognitive Skills, a computer-based battery of tests measuring short-term memory, long-term memory, processing speed, logic and reasoning, visual processing, as well as auditory processing and word attack skills. Methods: This study included 2,737 participants aged 5-85 years. A series of studies was conducted to examine the validity and reliability using the test performance of the entire norming group and several subgroups. The evaluation of the technical properties of the test battery included content validation by subject matter experts, item analysis and coefficient alpha, test retest reliability, split-half reliability, and analysis of concurrent validity with the Woodcock Johnson III Tests of Cognitive Abilities and Tests of Achievement. Results: Results indicated strong sources of evidence of validity and reliability for the test, including internal consistency reliability coefficients ranging from 0.87 to 0.98, test-retest reliability coefficients ranging from 0.69 to 0.91, split-half reliability coefficients ranging from 0.87 to 0.91, and concurrent validity coefficients ranging from 0.53 to 0.93. Conclusion: The Gibson Test of Cognitive Skills-2 is a reliable and valid tool for assessing cognition in the general population across the lifespan. PMID- 29483787 TI - The use of ibuprofen and acetaminophen for acute headache in the postconcussive youth: A pilot study. AB - Objective: Acute postconcussive headaches are problematic for children after mild traumatic brain injury. There are no evidence-based guidelines for their management. This pilot study aims to assess the feasibility and efficacy of routine analgesia administration. Methods: A four-arm open-label randomized controlled trial pilot/feasibility study was conducted: (i) acetaminophen, (ii) ibuprofen, (iii) alternating acetaminophen and ibuprofen and (iv) a control group. Children and youth 8 to 18 years of age presenting to emergency department with headache within 48 hours of their first concussion were recruited consecutively and sequentially randomized. Children with abnormal neuroimaging, history of previous concussions and bleeding disorder were excluded. A headache survey was administered at recruitment. All participants were provided with standard concussion management education and were also instructed on how to use the headache diary for the 1-week study follow-up period. The diary captures (i) headache days, (ii) number of headaches, (iii) headache intensity and (iv) return to-school information. Feasibility was assessed based on study recruitment and compliance. Results: There were no feasibility concerns with the recruitment and no major compliance issues. Patients on acetaminophen, ibuprofen or both had significantly less headache days, episodes of headache and lower headache intensity than did the standard care group. Patients on both ibuprofen and acetaminophen (79.0%) and on ibuprofen alone (61.0%) were more likely to be back at school 1 week postinjury as compared with the acetaminophen group (33.3%) and the standard care group (21.1%). Conclusion: Results showed routine analgesia administration was feasible and effective for postconcussive headache management. A larger full-scale randomized controlled trial is required to further assess the efficacy with longer follow-up, a wider variety of patients and more concussion related outcomes. PMID- 29483788 TI - Frequent marijuana use and driving risk behaviours in Canadian youth. AB - Background: A better understanding of the relations between patterns of marijuana use and driving risks in young adulthood is needed. Methods: Secondary analyses of self-report data from the Victoria Healthy Youth Survey. Youth (baseline ages 12 to 18; N=662; 52% females) were interviewed biannually (on six occasions) from 2003 to 2013 and classified as abstainers (i.e., used no marijuana in past 12 months), occasional users (i.e., used at most once per week), and frequent users (i.e., used more than once a week). Results: In the frequent user group, 80% of males and 75% of females reported 'being in a car driven by driver (including themselves) using marijuana or other drugs in the last 30 days', 64% of males and 33% of females reported that they were 'intoxicated' with marijuana while operating a vehicle and 50% of males and 42% of females reported being in a car driven by a driver using alcohol. In addition, 28% of occasional users and also a small proportion of abstainers reported 'being in a car driven by a driver using marijuana or other drugs in the last 30 days'. Interpretation: The high frequency of driving risk behaviours, particularly for frequent users, suggest that plans for legalization of recreational use should anticipate the costs of preventive education efforts that present an accurate picture of potential risks for driving. Youth also need to understand risks for dependence, and screening for and treatment of marijuana use disorders is needed. PMID- 29483789 TI - Effect of measuring vital signs on recognition and treatment of septic children. AB - Background and objectives: A majority of children presenting with sepsis do not receive adequate fluid resuscitation and have a delay in antibiotic administration despite recommendations from the Surviving Sepsis Campaign. The objective of this study was to evaluate the association of measuring a complete set of five vital signs in the emergency department (ED) with recognition and treatment of septic children presenting to the ED. Methods: Records of 218 patients aged 1 month to 17 years treated between February 2011 and December 2011 in a single academic centre with clinical criteria of sepsis, severe sepsis or septic shock were retrospectively evaluated. The presence or absence of complete vital signs was analyzed in relation to timing of fluid resuscitation, and if antibiotics were given in the first hour of medical evaluation. Results: Seventy six per cent of children who had all five vital signs measured in the ED received fluid resuscitation in the first hour after medical evaluation as opposed to 61% of those who had an incomplete set of vital signs (P<0.04). Twenty per cent of children who had all five vital signs measured received antibiotics in the first hour as opposed to 9% in children who had fewer vital signs measured (P<0.02). Conclusion: In our study population, the measurement of all vital signs in the ED, including blood pressure, was associated with faster administration of antibiotics and improved compliance with existing fluid bolus recommendations, which may have been the result of better recognition of sepsis in children through vital signs measurement. PMID- 29483790 TI - Increasing Canadian paediatricians' awareness and use of the new Canadian Physical Activity and Sedentary Behaviour Guidelines for ages 0 to 17 years. AB - Objective: To examine changes in the awareness, use, feasibility, and barriers associated with the Canadian Physical Activity and Sedentary Behaviour Guidelines for Children and Youth ages 0-17 years in a sample of Canadian paediatricians, and to assess tools/resources developed by the Canadian Paediatric Society (CPS). Methods: Practicing paediatricians who were members of the CPS were invited to complete an on-line survey in February 2013. In response to survey findings, the CPS developed and promoted tools/resources to increase and improve paediatricians' counselling of the guidelines. The CPS membership was surveyed again in September-October 2014. Findings are based on responses from 331 and 217 (23% and 16% participation rate) Canadian paediatricians who completed the survey in 2013 and 2014, respectively. Results: No significant differences were observed for awareness, use, or feasibility associated with the physical activity or sedentary behaviour guidelines between 2013 and 2014. However, a lack of knowledge/training was reported as a barrier sometimes/often/always by paediatricians significantly less in 2014 (14%) compared to 2013 (32%). Insufficient motivation/lack of support from parents/caregivers/youth was also reported as a barrier less frequently in 2014 (64%) compared to 2013 (75%) but it was borderline non-significant (P=0.05). Only 9% of paediatricians were unaware of the new CPS tools/resources. Conclusions: The new tools/resources developed by the CPS appeared to reduce some barriers experienced by paediatricians in counselling families about the guidelines. However, this did not appear to translate into greater awareness or use of the guidelines. Continued tool/resource development and training initiatives may be required. PMID- 29483791 TI - Expand your HEADS, follow the THRxEADS! AB - Adolescence can be a particularly challenging period for individuals with a chronic health condition or disability. We present a new mnemonic, THRxEADS (T for Transition, H for Home, Rx for Medication and Treatment, E for Education and Eating, A for Activities and Affect, D for Drugs and S for Sexuality), which can be used as a complement to the adolescent HEADS (Home-Education-Activities-Drugs Sexuality) assessment. THRxEADS may serve as a clinical tool to explore key issues that are often not covered in subspecialty clinic visits such as transition, coping, adherence and understanding of illness, as they apply to youth with special health care needs. THRxEADS may be used as a vehicle to highlight successes and to promote resilience. It may also be used as an educational tool with medical trainees to allow a deeper understanding of the realities of adolescents with chronic health care needs. A short list of sample chronic illness and disability-specific questions is provided. PMID- 29483792 TI - The paediatrician and middle childhood parenting. AB - The 'forgotten years' of middle childhood, from age 6 to 12, represent a critical period in child development. Emotional, social and physical development during this time have a lifelong impact on health and adult contributions to society. Mental health conditions have displaced physical illness as the leading childhood disability. Positive parenting can improve child behaviour, prevent early-onset conduct problems and provide a buffer from adverse childhood events resulting in decreased toxic stress and improved health. Medical homes can play a key role in supporting parents with positive parenting skills that are practical, evidence based and useful in everyday life. Paediatricians need to explore the domains that promote healthy development, including caring environments, fundamental needs and nurturing relationships. Our objective is to promote high-quality positive parenting through middle childhood by identifying opportunities for paediatricians to frame parenting discussions in the context of development, behaviour and safety and to provide access to valuable parenting resources. PMID- 29483793 TI - Taking the sting out of school-based immunizations. AB - Pain and fear widely contribute to negative experiences for students during school-based immunizations. In this preliminary research, we used a pre-existing network of 50 schools across Canada that participated in a biannual national immunization poster competition for grade 6 students organized by Immunize Canada to survey principals, teachers and students about their experiences with immunization pain and fear, how they want to learn about managing pain and fear and opportunities to include this information in the process of immunization. Responses revealed that both pain and fear are relevant to the immunization experience and that education and interventions are welcome by students and school staff. This may lead to improved attitudes about immunization, as well as future compliance with recommended immunizations. PMID- 29483795 TI - The relationship between paediatric practitioners and 'industry'. AB - Paediatric practitioners interact with industry representatives for many purposes but most often to receive information on new and existing products. While practitioners believe they are immune to the marketing influences exerted by these representatives, research has demonstrated otherwise. The literature suggests that the public is aware of such influences and that most people feel industry influence on practitioners is inappropriate. National guidelines go some way toward regulating practitioner-industry interactions, although they are not always clear or sufficient. The present practice point explores the context for these relationships, raises some ethical issues specific to paediatric practitioners and provides recommendations for maintaining professional integrity in the patient-physician relationship. Paediatric practitioners have a professional duty to ensure that their own interactions with industry are conducted with the best interests of the patient front and centre. PMID- 29483794 TI - Recommendations for the use of rotavirus vaccines in infants. AB - The present statement provides information concerning the clinical rotavirus disease and rotavirus vaccines in Canada. Since the implementation of publically funded rotavirus vaccine programs in Canada, increasing evidence has been accumulating globally as to the effectiveness of rotavirus vaccines in the prevention of acute gastroenteritis. Current data estimate vaccine effectiveness to be in the order of 85% for preventing severe disease, including hospitalizations and emergency department visits, when vaccine coverage is high. Also, substantial herd protection in older children has been documented. Post marketing surveillance has detected a very small increased risk of intussusception (one to three per 100,000) in children, usually occurring within 1 week of vaccination. Infants who have an identified significant immune deficiency or are suspected of having such a condition should not receive rotavirus vaccine. PMID- 29483796 TI - A 15-year-old boy with anemia and leg bruising. PMID- 29483797 TI - Vascular toxicity of urea, a new "old player" in the pathogenesis of chronic renal failure induced cardiovascular diseases. AB - Chronic kidney disease in children is an irreversible process that may lead to end-stage renal disease. The mortality rate in children with end-stage renal disease who receive dialysis increased dramatically in the last decade, and it is significantly higher compared with the general pediatric population. Furthermore, dialysis and transplant patients, who have developed end-stage renal disease during childhood, live respectively far less as compared with age/race-matched populations. Different reports show that cardiovascular disease is the leading cause of death in children with end-stage renal disease and in adults with childhood-onset chronic kidney disease, and that children with chronic kidney disease are in the highest risk group for the development of cardiovascular disease. Urea, which is generated in the liver during catabolism of amino acids and other nitrogenous metabolites, is normally excreted into the urine by the kidneys as rapidly as it is produced. When renal function is impaired, increasing concentrations of blood urea will steadily accumulate. For a long time, urea has been considered to have negligible toxicity. However, the finding that plasma urea is the only significant predictor of aortic plaque area fraction in an animal model of chronic renal failure -accelerated atherosclerosis, suggests that the high levels of urea found in chronic dialysis patients might play an important role in accelerated atherosclerosis in this group of patients. The aim of this review was to provide novel insights into the role played by urea in the pathogenesis of accelerated cardiovascular disease in renal failure. PMID- 29483798 TI - Electrocardiographic changes in children with diabetic ketoacidosis and ketosis. AB - Aim: We aimed to study electrocardiographic changes in children with diabetic ketoacidosis and ketosis and to evaluate the relation of the changes with serum electrolyte levels and ketosis. Material and Methods: This study was performed in Istanbul Medical Faculty, Pediatric Emergency and Intensive Care Department between May 2008 and May 2009. The electrocardiographic parameters and QT length of children with diabetic ketoacidosis and ketosis were evaluated at diagnosis and after the treatment. Results: Forty patients were included in the study; 16 (40%) were diagnosed as having diabetic ketosis and 24 (60%) had diabetic ketoacidosis. Twenty-four (60%) patients were male and 16 (40%) were female and the mean age was 9.21+/-4.71 years (range, 1-16 years). Twelve (30%) cases of diabetic ketoacidosis were mild, three (7.5%) were moderate, and nine (22.5%) were severe. One patient had premature ventricular beats, and four had ST depression. The electrocardiographic parameters were all normal beyond the QTC length prolongation. The mean QTC length was 447+/-45 ms (380-560 ms) at diagnosis and 418+/-32 ms (350-500 ms) after treatment. The change in the QTC length was statistically significant. None of the patients had significant electrolyte disturbance and the prolongation of QTc length was not correlated with serum electrolyte levels. The prolongation of QTc length was statistically correlated with anion gap (r=0.33, p=0.03). Conclusions: In our study, we showed QTc length prolongation and the importance of performing electrocardiography during the diagnosis of diabetic ketoacidosis and ketosis. We also demonstrated that ketosis was responsible for the prolongation of QTc length. PMID- 29483799 TI - The effect of phototherapy on sister chromatid exchange with different light density in newborn hyperbilirubinemia. AB - Aim: Concerns of possible genotoxic effects of hyperbilirubinemia and phototherapy were raised from experimental and observational studies in neonates. The purpose of this study was to assess the effect of hyperbilirubinemia and phototherapy with three different methods on DNA damage by investigating sister chromatid exchange frequency. Material and Methods: Patients whose gestational ages were >37 weeks and bilirubin levels above phototherapy limits were enrolled into three groups and each group was planned to receive 25 babies. Group 1 received enhanced light-emitting diode phototherapy, group 2 had light-emitting diode phototherapy, and group 3 received conventional phototherapy. Infants with hyperbilirubinemia but did not require phototherapy comprised the control group, which was subdivided into two groups regarding bilirubin levels (10mg/dL). Blood samples were collected before and after phototherapy for sister chromatid exchange frequency and samples were examined by a biologist who was blinded to the study groups. Results: The mean pre-treatment sister chromatid exchange frequency was 1.41+/-0.34/cell, post-treatment 2.65+/-0.68/cell, and 1.61+/ 0.61/cell for the control group (p<0.05). A statistically significant increase in sister chromatid exchange frequency after phototherapy was observed in all three intervention groups (p values: 0.01, 0.01, and 0.008, respectively). When the treatment groups were compared with each other in terms of irradiance, no significant difference was found (p=0.08). Conclusions: Phototherapy causes an increase in the frequency of sister chromatid exchange regardless of the irradiance. Phototherapy could have some genotoxic adverse effects on chromosomes; however, further investigations are warranted to enlighten as to whether these effects are permanent or clinically important. PMID- 29483800 TI - Levels of inflammatory cytokines from peripheral blood mononuclear cells of children with cow's milk protein allergy. AB - Aim: The aim of the study was to investigate the level of cytokines in cultures of cow's milk protein- stimulated peripheral blood mononuclear cells of patients with cow's milk protein allergy. Material and Methods: Eleven children with cow's milk protein allergy and 11 non-allergic controls were studied. Their peripheral blood mononuclear cells were cultured alone and in the presence of cow's milk alpha-lactalbumin; beta-lactoglobulin; alphaS 1, alphaS 2, beta, and kappa-casein fraction mixtures; and a cow's protein mixture from whole milk. Production of cytokines, tumor necrosis factor-alpha, interleukin-10, and interleukin-12 were determined in culture supernatants. Results: In cow's milk protein-stimulated peripheral blood mononuclear cell cultures of children with cow's milk protein allergy, tumor necrosis factor-alpha, interleukin-10, and interleukin-12 production was significantly higher than in non-allergic controls (p<0.05). No difference in cytokine production was found between cultures obtained from unstimulated peripheral blood mononuclear cell cultures of both cow's milk protein allergy and non-allergic controls. Conclusions: The findings of this preliminary study align with data from the literature suggesting that the investigation of tumor necrosis factor-alpha, interleukin-10, and interleukin-12 in cow's milk protein-stimulated peripheral blood mononuclear cell cultures of children may be taken in further consideration to explore whether they might have a predictive role for cow's milk protein allergy. Further studies are therefore needed to extensively investigate this issue. PMID- 29483801 TI - Evaluation of febrile neutropenic attacks of pediatric hematology-oncology patients. AB - Aim: Febrile neutropenia is an important cause of mortality and morbidity in hematology-oncology patients undergoing chemotherapy. The objective of this study was to evaluate febrile neutropenic episodes in children with malignancy. Material and Methods: Sixty-eight children who received chemotherapy for malignancy between 2010 and 2015 were retrospectively reviewed. The demographic characteristics, laboratory data, infection foci, and frequency of microorganisms grown in culture were examined. Also, the frequency of febrile neutropenic attacks was investigated according to the chemotherapy periods. Results: Of the total 200 episodes, 81 (40.5%) were clinically documented, and 73 (36.5%) were microbiologically documented infections. Fever of unknown origin was observed in 46 (23%) episodes. The most frequently clinically documented focus were mucositis (33.4%) and pneumonia (24.7%). Blood culture was positive in 55 (75.3%) episodes of microbiologically documented infections. The most commonly isolated microorganisms in blood culture were Gram-negative bacteria (47.2%). C-reactive protein levels in microbiologically documented infections were higher than in clinically documented infections, and fever of unknown origin (p<0.05, for both). The most common underlying malignancy was acute lymphoblastic leukemia (73.5%). The highest proportions (34.6%) of febrile neutropenic episodes were observed during the reinduction period for these children. Nine (13.2%) children died of neutropenic sepsis. Conclusions: Febrile neutropenia continues to be an important cause of mortality in pediatric patients with malignancy. C-reactive protein levels may be an indicator for predicting bacterial infection in children with febrile neutropenia without apparent focus. The most frequently isolated agents in our center were Gram-negative microorganisms. Determining the microbial flora of each center may be beneficial to improving survival rates. PMID- 29483802 TI - Evaluation of patients with orbital infections. AB - Aim: Orbital tissue infections are common infections of childhood that can lead to severe complications. Herein, we aimed to evaluate the etiologic factors, diagnosis, follow-up, and treatment procedures in pediatric patients with orbital infections. Material and Methods: This study was performed retrospectively between January 2014 and December 2015 in Cerrahpasa Medical Faculty Pediatric Infectious Disease Unit. Patients were studied for age, ophthalmologic examination features, laboratory and radiology results, treatment modalities, and the response to these treatments. Results: Thirty-six patients (21 males, 15 females) with an average age of 71.43+/-42.24 months (5-168 months) participated in the study in the two-year period. Thirty-two patients (88.9%) had preseptal cellulitis, and four (11.9%) had orbital cellulitis. All patients had eyelid hyperemia, edema, and ocular pain, with chemosis in seven and proptosis in four cases. Twenty-five patients were admitted with fever. All cases were unilateral and 44.4% occurred secondary to paranasal sinusitis. All cases were treated with intravenous cefazolin-amikacin. The mean of duration of hospitalization was 12.02+/-8.75 days (range, 3-28 days) and the duration of parental antibiotics was 12.83+/-8.18 days (range, 7-21 days). All patients recovered without any vision loss, only one patient experienced subdural empyema complicating preseptal cellulitis. Conclusions: Most orbital tissue infections occur secondary to paranasal sinusitis in childhood. Orbital tissue infections can be complicated by brain abscess, cavernous sinus thrombophlebitis, and vision loss. Early diagnosis and proper antibiotic treatment are essential to prevent these life-threatening complications. PMID- 29483803 TI - A case of Donohue syndrome "Leprechaunism" with a novel mutation in the insulin receptor gene. AB - Donohue syndrome (Leprechaunism) is characterized by severe insulin resistance, hyperinsulinemia, postprandial hyperglycemia, preprandial hypoglycemia, intrauterine and postnatal growth retardation, dysmorphic findings, and clinical and laboratory findings of hyperandrogenemia due to homozygous or compound heterozygous inactivating mutations in the insulin receptor gene. A female newborn presented with lack of subcutaneous fat tissue, bilateral simian creases, hypertrichosis, especially on her face, gingival hypertrophy, cliteromegaly, and prominent nipples. Her laboratory tests revealed hyperandrogenism, postprandial hyperglycemia and preprandial hypoglycemia, and very high concurrent insulin levels. She was diagnosed as having Donohue syndrome. Metformin and continuous nasogastric feeding were administrated. During follow-up, relatively good glycemic control was obtained. However, severe hypertrophic obstructive cardiomyopathy and severe malnutrition developed. She died aged 75 days of severe heart failure and pneumonia. Her insulin receptors gene analysis revealed a compound heterozygous mutation. One of these mutations was a p.R813 (c.2437C>T) mutation, which was defined previously and shown also in her father, the other mutation was a novel p.777-790delVAAFPNTSSTSVPT mutation, also shown in her mother. The parents were heterozygous for these mutations. PMID- 29483804 TI - Two patients with Apert syndrome with different mutations: the importance of early diagnosis. AB - Apert syndrome is an autosomal dominant craniosynostosis syndrome accompanied by limb anomalies. The fibroblast growth factor receptor 2 (FGFR2) gene is responsible for the disease and two different heterozygous mutations, p.Pro253Arg and p.Ser252Trp, have been defined as responsible in the majority of cases of Apert syndrome. In this case report, two patients with Apert syndrome with two different FGFR2 gene mutations are presented. Case-1, a 4-month-old boy with craniosynostosis and syndactyly was referred to pediatric genetic clinic. The molecular analysis revealed p.Pro253Arg mutation in the FGFR2 gene, which confirmed the diagnosis of Apert syndrome. Case-2, a 16-year-old girl with developmental delay, cleft palate, syndactyly, and craniosynostosis, was also diagnosed as having Apert syndrome. A molecular diagnosis identified a p.Ser252Trp heterozygous mutation in the FGFR2 gene. Case-1 underwent surgery for craniosynostosis at age 10 months and he was developmentally normal during the 2 year follow-up period. As a conclusion, early surgical intervention should be considered in cases of Apert syndrome to prevent intellectual disability. PMID- 29483805 TI - A rare cause of vomiting: annular pancreas. AB - Annular pancreas is a rare congenital anomaly that consists of a ring of pancreatic tissue partially or completely encircling the second part of the duodenum. It can affect anyone from neonates to adults, and is difficult to diagnose because it can present in a wide range of clinical conditions. Although cases have also been reported in adults, symptomatic cases are often referred in infancy or early childhood. A 17-year-old female patient who was diagnosed as having annular pancreas is reported. The patient had had non-bilious vomiting accompanied by abdominal pain, especially 5-10 minutes after meals, for seven years. Annular pancreas, which may be seen at any age, should be considered in the differential diagnosis of patients with non-bilious vomiting, particularly after meals, over a long period. PMID- 29483806 TI - Evaluation of two non-myasthenic patients with ptosis. AB - Decreased height of the eyelid or the narrowing of the lid is called ptosis. Ptosis has several causes. Malignancy-related conditions such as Horner's syndrome, which causes unilateral ptosis in the pediatric age group, and patients with malignancy receiving chemotherapeutic treatment, are often secondary to these drugs and ptosis is a clue of underlying diseases. Underlying pathologies can lead to different clinical conditions such as cognitive impairment from coma, the presence of ptosis should be cautionary. In this study, we present two patients with malignancy who were admitted with ptosis. The first patient was diagnosed as having neuroblastoma and treated with neuroblastoma-directed chemotherapeutics. The second patient was diagnosed as having acute lymphoblastic leukemia and developed vincristine-induced ptosis and recovered on treatment with pyridoxine and pyridostigmine. In conclusion, non-myasthenic ptosis may develop due to involvement of the central nervous system during malignancy or neurotoxic effects of chemotherapeutic agents. Therefore, patients who present with ptosis should be evaluated for the etiologic diagnosis. PMID- 29483807 TI - Neonatal Grave's disease: a caution while treating. PMID- 29483808 TI - Re: Neonatal Grave's disease: a caution while treating. PMID- 29483809 TI - Cell Therapy Clinical Trials for Stress Urinary Incontinence: Current Status and Perspectives. AB - Stress urinary incontinence (SUI) affects 200 million people worldwide. Standard therapies often provide symptomatic relief, but without targeting the underlying etiology, and show tremendous patient-to-patient variability, limited success and complications associated with the procedures. We review in this article the latest clinical trials performed to treat SUI using cell-based therapies. These therapies, despite typically including only a small number of patients and short term evaluation of results, have proven to be feasible and safe. However, there is not yet a consensus for the best cell source to be used to treat SUI and not all patients may be suitable for these therapies. Therefore, more clinical trials should be promoted recruiting large number of patients and evaluating long term results. PMID- 29483810 TI - Mitochondrial stress and redox failure in steroid-associated osteonecrosis. AB - The purpose of the role of antioxidant enzymes and mitochondria in the developmental mechanism of steroid-associated osteonecrosis in the femur. In the present study Japanese white rabbits (mean weight 3.5kg) were injected into the gluteus with methylprednisolone (MP) 20mg/kg, and killed after 3 days (MP3 group), 5 days (MP5 group), and 14 days (MP14 group) (n=3 each). As a Control group (C group) Japanese white rabbits not administered MP were used. In experiment 1, the expression of the antioxidant enzymes Superoxide dismutade (SOD) and catalase was compared in liver, kidney, heart, humerus, and femur in C group, and the presence/absence of mitochondria transcription factor A (TFAM) expression was determined by Western blotting (WB) and used to evaluate the number of mitochondria and their function. In experiment 2, the presence/absence of necrosis was determined by immunohistochemistry, while changes in the expression of SOD, catalase, and TFAM in the femur after steroid administration were determined by Western blotting (WB). In experiment 1, intense expression of all of SOD, catalase, and TFAM was found in the liver, kidney, and heart as compared to the humerus and femur. In experiment 2, the expression of all of SOD, catalase, and TFAM in MP3 and MP5 groups was decreased on WB as compared with C group, while in MP14 group a tendency to improvement was seen. Accordingly, steroid-associated mitochondrial injury and redox failure are concluded to be important elements implicated in the pathogenesis of osteonecrosis. PMID- 29483811 TI - Increased Levels of Serum Protein Complexes Are Associated with Type 2 Diabetes. AB - Objective: To screen novel biomarkers in the levels of protein complexes for type 2 diabetes mellitus (T2DM). Methods: Serum immunoinflammation-related protein complexes (IIRPCs) and diabetes-related protein complexes (DRPCs) in 1537 serum samples including 504 healthy controls, 320 patients with prediabetes, and 713 patients with T2DM were analyzed using an optimized native polyacrylamide gel electrophoresis (native-PAGE). Results: Seven patterns of serum IIRPCs and four patterns of serum DRPCs were observed in the study population, respectively. Significant increase in the levels of serum IIRPCs in T2DM was detected relative to healthy controls. Change trends of serum DRPCs are as below: patients with T2DM>patients with prediabetes> healthy controls. Conclusion: Our findings suggest that increased levels of serum IIRPCs and DRPCs were associated with T2DM. PMID- 29483813 TI - Comparison of Floaters after Cataract Surgery with Different Viscoelastics. AB - Purpose: To investigate whether there is a difference between symptoms of floaters according to the type of ophthalmic viscosurgical devices(OVDs) used during phacoemulsification. Methods: A total of 112 eyes had undergone standard phacosurgery with the dispersive OVDs(Group1). Group2 comprised 117 eyes that underwent phacosurgery with the dispersive OVDs, but between continuous curvilinear capsulorhexis and hydrodissection, some OVDs had been removed. Group3 included 120 eyes that had undergone phacosurgery with the cohesive OVDs. Results: 14 eyes (12.5%) of Group1 had new-onset floater after surgery whereas 6 eyes (5.13%) in Group2, and 7 eyes (5.83%) in Group3 at the day after and a week after surgery. This was significantly higher in Group1 than Group2 and Group3, respectively (p=0.047,0.049). Conclusion: Cataract surgery with dispersive OVD can predispose the eye to an increased floater symptom. Therefore, surgeons should consider release some OVDs during hydrodissection with dispersive viscoelastics and keep trying to avoid IOP surge during surgery. PMID- 29483812 TI - Association of Genetic Variants of Small Non-Coding RNAs with Survival in Colorectal Cancer. AB - Background: Single nucleotide polymorphisms (SNPs) of small non-coding RNAs (sncRNAs) can influence sncRNA function and target gene expression to mediate the risk of certain diseases. The aim of the present study was to evaluate the prognostic relevance of sncRNA SNPs for colorectal cancer, which has not been well characterized to date. Methods: We comprehensively examined 31 common SNPs of sncRNAs, and assessed the impact of these variants on survival in a cohort of 188 patients with colorectal cancer. Results: Three SNPs were significantly associated with survival of patients with colorectal cancer after correction for multiple testing, and two of the SNPs (hsa-mir-196a-2 rs11614913 and U85 rs714775) remained significant in multivariate analyses. Additional in silico analysis provided further evidence of this association, since the expression levels of the target genes of the hsa-miR-196a (HOXA7, HOXB8, and AKT1) were significantly correlated with colorectal cancer progression. Furthermore, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated that hsa-miR-196a is associated with well-known oncogenic pathways, including cellular protein modification process, mitotic cell cycle, adherens junction, and extracellular matrix receptor interaction pathways. Conclusion: Our results suggest that SNPs of sncRNAs could play a critical role in cancer progression, and that hsa-miR-196a might be a valuable biomarker or therapeutic target for colorectal cancer patients. PMID- 29483814 TI - Pioglitazone Use and Risk of Bladder Cancer: an In Vitro Study. AB - Aims: Whether pioglitazone (PIO), a peroxisome proliferator-activated receptor gamma agonist, increases the risk of developing bladder cancer has been debated for several years. The aim of this study was to investigate the in vitro effects of PIO on normal urothelial transitional epithelium (NUTE) cells and bladder cancer (J82) cells to further evaluate the risk. Methods: NUTE cells were obtained from Sprague-Dawley rats. NUTE and J82 cells were treated with different concentrations of PIO for various time periods. Cell proliferation was tested by the MTT assay. Cell apoptosis was evaluated by flow cytometry. The expressions of p53, cyclin D1, Bcl-2, and Bax were determined by qRT-PCR and western blots. Results: After 24 hours, the treatment of NUTE cells with 10 MUmol/L PIO led to morphological changes, without changes in J82 cells. Moreover, PIO inhibited the proliferation and induced apoptosis of NUTE cells, but not J82 cells, in a time- and dose-dependent manner. However, PIO did not alter the growth of cells from other tissues. In addition, treatment with PIO for up to 72 hours did not result in changes in the expressions of p53, cyclin D1, Bcl-2, and Bax in NUTE cells and J82 cells. Interestingly, PIO significantly downregulated the protein levels of p53 and cyclin D1 in J82 cells, but not NUTE cells after more than 192 hours of treatment. Conclusions: PIO did not promote malignant alterations of NUTE cells or stimulate proliferation of J82 cells. PIO decreased the expression of p53 and cyclin D1 in J82 cells after long-term culture, which suggested that PIO may be helpful for diabetic patients with bladder cancer. PMID- 29483815 TI - Platelet-Rich Plasma Injection in Burn Scar Areas Alleviates Neuropathic Scar Pain. AB - Objective: No effective treatments have yet been developed for burn-induced neuropathic pain. Platelet-rich plasma (PRP) has been reported to ameliorate various types of inflammation pain. However, the effect of PRP on burn-induced neuropathic pain is unclear. Methods: Burn-induced neuropathic pain Sprague Dawley rat model was confirmed using a mechanical response test 4 weeks after the burn injuries were sustained, following which PRP was injected in the scar area. The rats were divided into four groups (n = 6) as following: Group A, Sham; Group B, Sham + PRP; Group C, Burn; and Group D, Burn + PRP. Four weeks after the PRP injection, the animals were subjected to behavior tests and then sacrificed; specimens were collected for inflammation tests, Masson's trichrome stain and chromosome 10 (PTEN) in the injured skin; and PTEN, phosphorylated mammalian target of rapamycin (p-mTOR), p38, nuclear factor kappaB (NFkappaB), chemokine (CC motif) ligand 2 (CCL2), and CCL2 cognate receptor (CCR2) in spinal cord dorsal horns through immunohistochemistry and immunofluorescence staining. Results: PRP significantly alleviated allodynia in burn-induced neuropathic pain 4 weeks after treatment, and PTEN expression in the skin and spinal cord were significantly increased in group D compared with the group C. p-PTEN, p-mTOR, and CCL2 expression in neuron cells; p-p38 and p-NFkappaB expression in microglia; and p-JNK and p-NFkappaB activation in spinal astrocytes decreased significantly in the group D compared with the group C. Conclusions: PRP is effective in treating burn-induced neuropathic pain and may be used in clinical practice. PMID- 29483816 TI - Recent insights into mitochondrial targeting strategies in liver transplantation. AB - Ischemia/reperfusion (I/R) injury in liver transplantation can disrupt the normal activity of mitochondria in the hepatic parenchyma. This potential dysfunction of mitochondria after I/R injury could be responsible for the initial poor graft function or primary nonfunction observed after liver transplantation. Thus, determining the mechanisms that lead to human hepatic mitochondrial dysfunction might contribute to improving the outcome of liver transplantation. Furthermore, early identification of novel prognostic factors involved in I/R injury could serve as a key endpoint to predict the outcome of liver grafts and also to promote the early adoption of novel strategies that protect against I/R injury. Here, we briefly review recent advances in the study of mitochondrial dysfunction and I/R injury, particularly in relation to liver transplantation. Next, we highlight various pharmacological therapeutic strategies that could be applied, and discuss their relationship to relevant mitochondrion-related processes and targets. Lastly, we note that although considerable progress has been made in our understanding of I/R injury and mitochondrial dysfunction, further investigation is required to elucidate the cellular and molecular mechanisms underlying these processes, thereby identifying biomarkers that can help in evaluating donor organs. PMID- 29483817 TI - Effects of Matrix Stiffness on the Morphology, Adhesion, Proliferation and Osteogenic Differentiation of Mesenchymal Stem Cells. AB - BMMSCs have drawn great interest in tissue engineering and regenerative medicine attributable to their multi-lineage differentiation capacity. Increasing evidence has shown that the mechanical stiffness of extracellular matrix is a critical determinant for stem cell behaviors. However, it remains unknown how matrix stiffness influences MSCs commitment with changes in cell morphology, adhesion, proliferation, self-renewal and differentiation. We employed fibronectin coated polyacrylamide hydrogels with variable stiffnesses ranging from 13 to 68 kPa to modulate the mechanical environment of BMMSCs and found that the morphology and adhesion of BMMSCs were highly dependent on mechanical stiffness. Cells became more spread and more adhesive on substrates of higher stiffness. Similarly, the proliferation of BMMSCs increased as stiffness increased. Sox2 expression was lower during 4h to 1 week on the 13-16 kPa and 62-68 kPa, in contrast, it was higher during 4h to 1 week on the 48-53 kPa. Oct4 expression on 13-16 kPa was higher than 48-53 kPa at 4h, and it has no significant differences at other time point among three different stiffness groups. On 62-68 kPa, BMMSCs were able to be induced toward osteogenic phenotype and generated a markedly high level of RUNX2, ALP, and Osteopontin. The cells exhibited a polygonal morphology and larger spreading area. These results suggest that matrix stiffness modulates commitment of BMMSCs. Our findings may eventually aid in the development of novel, effective biomaterials for the applications in tissue engineering. PMID- 29483818 TI - Olfactory stimulation modulates the blood glucose level in rats. AB - In both humans and animals, chemosensory stimuli, including odors and tastes, induce a variety of physiologic and mental responses related to energy homeostasis, such as glucose kinetics. The present study examined the importance of olfactory function in glucose kinetics following ingestion behavior in a simplified experimental scenario. We applied a conventional glucose tolerance test to rats with and without olfactory function and analyzed subsequent blood glucose (BG) curves in detail. The loss of olfactory input due to experimental damage to the olfactory mucosa induced a marked decrease in the area under the BG curve. Exposure to grapefruit odor and its main component, limonene, both of which activate the sympathetic nerves, before glucose loading also greatly depressed the BG curve. Pre-loading exposure to lavender odor, a parasympathetic activator, stabilized the BG level. These results suggest that olfactory function is important for proper glucose kinetics after glucose intake and that certain fragrances could be utilized as tools for controlling BG levels. PMID- 29483819 TI - Risks of Using Sterilization by Gamma Radiation: The Other Side of the Coin. AB - The standard sterilization method for most medical devices over the past 40 years involves gamma irradiation. During sterilization, gamma rays efficiently eliminate microorganisms from the medical devices and tissue allografts, but also significantly change molecular structure of irradiated products, particularly fragile biologics such as cytokines, chemokines and growth factors. Accordingly, gamma radiation significantly alters biomechanical properties of bone, tendon, tracheal, skin, amnion tissue grafts and micronized amniotic membrane injectable products. Similarly, when polymer medical devices are sterilized by gamma radiation, their physico-chemical characteristics undergo modification significantly affecting their clinical use. Several animal studies demonstrated that consummation of irradiated food provoked genome instability raising serious concerns regarding oncogenic potential of irradiated consumables. These findings strongly suggest that new, long-term, prospective clinical studies should be conducted in near future to investigate whether irradiated food is safe for human consumption. In this review, we summarized current knowledge regarding molecular mechanisms responsible for deleterious effects of gamma radiation with focusing on its significance for food safety and biomechanical characteristics of medical devices, and tissue allografts, especially injectable biologics. PMID- 29483820 TI - Vital Roles of beta-catenin in Trans-differentiation of Chondrocytes to Bone Cells. AB - A recent breakthrough showing that direct trans-differentiation of chondrocytes into bone cells commonly occurs during endochondral bone formation in the growth plate, articular cartilage, and mandibular condylar cartilage suggests that chondrogenesis and osteogenesis are likely one continuous biological process instead of two separate processes. Yet, gene regulation of this cell transformation is largely unclear. Here, we employed cartilage-specific beta catenin loss-of-function (beta-catenin fx/fx ) and gain-of-function (beta-catenin fx(exon3)/ fx(exon3) ) models in the R26RTomato background (for better tracing the cell fate of chondrocytes) to study the role of beta-catenin in cell trans differentiation. Using histological, immunohistochemical, and radiological methods combined with cell lineage tracing techniques, we showed that deletion of beta-catenin by either Acan-CreERT2 or Col10a1-Cre resulted in greatly reduced cell trans-differentiation with a significant decrease in subchondral bone volume during mandibular condylar growth. Molecular studies demonstrated severe defects in cell proliferation and differentiation in both chondrocytes and bone cells. The gain of function studies (constitutive activation of beta-catenin with Acan CreERT2 at ages of postnatal day 7, 4-weeks and 6-months) led to more bone cell trans-differentiation of chondrocytes in the mandibular condyle due to increased proliferation and accelerated chondrocyte differentiation with incipient osteogenic changes within the cartilage matrix, resulting in an increased volume of poorly-formed immature subchondral bone. These results support the notion that chondrogenesis and osteogenesis are one continuous process, in which beta-catenin signaling plays an essential role in the cell trans-differentiation of chondrocytes into bone cells during mandibular condylar development and growth. PMID- 29483821 TI - Disruption of Gen1 Causes Congenital Anomalies of the Kidney and Urinary Tract in Mice. AB - Congenital anomalies of the kidney and urinary tract (CAKUT) are among the most common developmental defects in humans. Despite of several known CAKUT-related loci (HNF1B, PAX2, EYA1, etc.), the genetic etiology of CAKUT remains to be elucidated for most patients. In this study, we report that disruption of the Holliday Junction resolvase gene Gen1 leads to renal agenesis, duplex kidney, hydronephrosis, and vesicoureteral reflux (VUR) in mice. GEN1 interacts with SIX1 and enhances the transcriptional activity of SIX1/EYA1, a key regulatory complex of the GDNF morphogen. Gen1 mutation impairs Grem1 and Gdnf expression, resulting in excessive ureteric bud formation and defective ureteric bud branching during early kidney development. These results revealed an unidentified role of GEN1 in kidney development and suggested its contribution to CAKUT. PMID- 29483822 TI - Human Papillomavirus Types 16 and 18 Early-expressed Proteins Differentially Modulate the Cellular Redox State and DNA Damage. AB - Oxidative stress has been proposed as a risk factor for cervical cancer development. However, few studies have evaluated the redox state associated with human papillomavirus (HPV) infection. The aim of this work was to determine the role of the early expressed viral proteins E1, E2, E6 and E7 from HPV types 16 and 18 in the modulation of the redox state in an integral form. Therefore, generation of reactive oxygen species (ROS), concentration of reduced glutathione (GSH), levels and activity of the antioxidant enzymes catalase and superoxide dismutase (SOD) and deoxyribonucleic acid (DNA) damage, were analysed in epithelial cells ectopically expressing the viral proteins. Our research shows that E6 oncoproteins decreased GSH and catalase protein levels, as well as its enzymatic activity, which was associated with an increase in ROS production and DNA damage. In contrast, E7 oncoproteins increased GSH, as well as catalase protein levels and its activity, which correlated with a decrease in ROS without affecting DNA integrity. The co-expression of both E6 and E7 oncoproteins neutralized the effects that were independently observed for each of the viral proteins. Additionally, the combined expression of E1 and E2 proteins increased ROS levels with the subsequent increase in the marker for DNA damage phospho histone 2AX (gammaH2AX). A decrease in GSH, as well as SOD2 levels and activity were also detected in the presence of E1 and E2, even though catalase activity increased. This study demonstrates that HPV early expressed proteins differentially modulate cellular redox state and DNA damage. PMID- 29483823 TI - The metabonomics study of P-selectin glycoprotein ligand-1 (PSGL-1) deficiency inhibiting the progression of atherosclerosis in LDLR-/- mice. AB - Atherosclerosis (AS) is a multi-factorial chronic disease commonly associated with the mechanisms of metabolism disorder, endothelial dysfunction and chronic inflammation. AS an inflammatory molecule, p-selectin glycoprotein ligand-1 (PSGL 1) played an important role in the inflammatory process of atherogenesis involving the recruitment of leukocyte and transmitting signals to activate leukocyte during the adhesion process. So far, there has been little study regarding the effects of PSGL-1 on AS progression and the metabolic regulation. In this report, we studied the effect of PSGL-1 deficiency on the formation and progression of AS and the metabolic regulation by use of LDLR-/-, PSGL-1-/- transgenic mice based on metabonomics. It was found that the PSGL-1 deficiency reduced the atherosclerotic plaque area, inflammatory cells infiltration and fiber hyperplasia during the AS development. The serum metabonomics study showed that the LDLR-/- ,PSGL-1-/- mice had higher levels of HDL, valine, acetate, pyruvate, choline, PC, GPC and glycine, and lower levels of LDL+VLDL and lactate at the early stage of atherosclerosis, while lactate, citrate and glutamine showed statistical significance at the late stage of atherosclerosis. These results showed that the PSGL-1 deficiency inhibited the AS progression and regulated glucose metabolism, lipid metabolism, amino acid and phospholipid metabolism in LDLR-/- mice. PMID- 29483824 TI - Dioscin overcome TKI resistance in EGFR-mutated lung adenocarcinoma cells via down-regulation of tyrosine phosphatase SHP2 expression. AB - Resistance to tyrosine kinase inhibitors (TKIs) results in tumor relapse and poor prognosis in patients with lung adenocarcinoma. TKI resistance caused by epidermal growth factor receptor (EGFR) mutations at T790M and c-Met amplification occurs through persistent activation of the MEK/ERK and PI3K/AKT signaling pathways. We therefore expected that dual inhibitors of both signaling pathways could overcome TKI resistance in lung adenocarcinoma. Here, dioscin was selected from a product library of Chinese naturally occurring compounds and overcame TKI resistance in EGFR-mutated lung adenocarcinoma cells. Mechanistically, dioscin may down-regulate the expression of SH2 domain containing phosphatase-2 (SHP2) at the transcription level by increasing p53 binding to the SHP2 promoter due to reactive oxygen species (ROS). Simultaneous inhibition of MEK/ERK and PI3K/AKT activation via decreased SHP2 expression and its interaction with GAB1 may be responsible for dioscin-mediated TKI sensitivity. A higher unfavorable response to TKI therapy occurred more commonly in patients with high SHP2 mRNA expression than in patients with low SHP2 mRNA expression. Therefore, we suggest that dioscin may act as a dual inhibitor of the MEK/ERK and PI3K/AKT signaling pathways to overcome TKI resistance via dysregulation of SHP2 expression in lung adenocarcinoma. PMID- 29483825 TI - Angiotensin 1-7 Overexpression Mediated by a Capsid-optimized AAV8 Vector Leads to Significant Growth Inhibition of Hepatocellular Carcinoma In vivo. AB - Background: Angiotensin-(1-7) [Ang-(1-7)] has been identified to inhibit the growth of many types of tumor cells both in vitro and in vivo. However, the rapid degradation of Ang-(1-7) in vivo limits its clinical application. Adeno associated virus (AAV) serotype-8 is a remarkable vector for long-term in vivo gene delivery. Method: This study was designed to investigate the effects of AAV mediated Ang-(1-7) overexpression on hepatocellular carcinoma. We first generated three different tyrosine (Y) to phenylalanine (F) mutants of AAV8 (Y447F, Y703F, Y708F) and evaluated their in vivo transduction efficiencies. Results: The data indicated that the Y703F mutant elicited a significant enhancement of liver gene delivery when compared with wild-type AAV8 (wtAAV8). The anti-tumor effect of Ang (1-7) mediated by this optimized vector was evaluated in H22 hepatoma-bearing mice. Our results demonstrated that AAV-Ang-(1-7) persistently inhibited the growth of hepatocellular carcinoma by significantly downregulating angiogenesis. This was confirmed by observed decreases in the levels of the proangiogenic factors VEGF and PIGF. Conclusion: Collectively, these data suggest that Ang-(1 7) overexpression mediated by the optimized vector may be an effective alternative for hepatocellular carcinoma therapy due to its long-term and significant anti-tumor activity. PMID- 29483826 TI - Aryl Hydrocarbon Receptor Activation Modulates Intestinal Epithelial Barrier Function by Maintaining Tight Junction Integrity. AB - Activation of Aryl hydrocarbon receptor (AhR) is involved in the control of intestinal mucosal homeostasis. Intestinal barrier dysfunction contributes to the development of many intestinal diseases, such as inflammatory bowel disease (IBD). In this study, we investigated the mechanisms of AhR activation in the maintenance of intestinal barrier function. Adult C57BL/6 mice were treated with dextran sulphate sodium (DSS) for 7 days, with or without 6-Formylindolo(3,2 b)carbazole (FICZ), a ligand of AhR. We found that AhR activation by FICZ attenuated the decreased TJ protein expression in the colonic mucosa of the DSS induced mice. Further, the increase of both MLC phosphorylation and MLCK expression in the mice with DSS-induced colitis was also significantly inhibited by FICZ induced AhR activation. For in vitro experiments, Caco-2 cells were treated with tumour necrosis factor alpha (TNF-alpha)/interferon gamma (IFN gamma) for 48 h, with or without FICZ. AhR activation prevented TNF-alpha/IFN gamma-induced decrease in TER and morphological disruption of the TJs in Caco-2 monolayers. It also inhibited TNF-alpha/IFN-gamma-induced increase in MLCK expression and MLC phosphorylation by suppression of NF-kappaB p65 signaling pathway. Thus, AhR-activating factors might have potential as therapeutic agents for the treatment of patients with IBD. PMID- 29483827 TI - Fam60al as a novel factor involved in reprogramming of somatic cell nuclear transfer in zebrafish (Danio rerio). AB - The main reason for abnormal development of cloned animals or embryos, and inefficient animal cloning, is a poor understanding of the reprogramming mechanism. To better comprehend reprogramming and subsequent generation of pluripotent stem cells, we must investigate factors related to reprogramming of somatic cells as nuclear donors. As we know, fam60al (family with sequence similarity 60, member A, like) is a coding gene only found in zebrafish and frog (Xenopus laevis) among vertebrates. However, until now, its functions have remained unknown. Here, we generated a zebrafish fam60al-/- mutant line using transcription activator-like effector nucleases (TALENs), and found that both nanog and klf4b expression significantly decreased while myca expression significantly increased in fam60al-/- mutant embryos. Concurrently, we also uncovered that in developmentally arrested embryos of somatic cell nuclear transfer, nanog, klf4b and myca expression was down-regulated, accompanying a decrease of fam60al expression. Interestingly, we identified a long noncoding RNA (lncRNA) of fam60al, named fam60al-AS, which negatively regulated fam60al by forming double-stranded RNA (dsRNA). RNase protection assay and real-time PCR confirmed these findings. Taken together, these results suggest that fam60al is a novel factor related to the reprogramming of somatic cell nuclear transfer in zebrafish, which is regulated by its reverse lncRNA. PMID- 29483828 TI - Comparison of microRNA Profiles between Bovine Mammary Glands Infected with Staphylococcus aureus and Escherichia coli. AB - MicroRNAs (miRNAs) play crucial roles in regulating innate and adaptive immunity in humans and animals. Infection with E. coli or S. aureus can cause inflammation of the mammary glands, which results in significant economic losses in dairy cattle. However, the regulatory mechanisms of miRNAs in response to E. coli or S. aureus infection in bovine mammary glands have not been thoroughly explored. To discover the differential expression of miRNA in bovine mammary gland challenged with E. coli or S. aureus, we performed miRNA sequencing on tissue samples. A total of 1838 miRNAs were identified, including 580 known-miRNAs (included in the miRbase database) and 1258 predicted novel miRNAs. The miRNA expression patterns indicated that, compared with control samples, 279 miRNAs and 305 miRNAs were differentially expressed miRNAs (DIE-miRNA) in S. aureus and E. coli infected tissues, respectively. Moreover, the results of comparison the DIE-miRNAs between the E. coli and S. aureus infected groups showed that 197 DIE-miRNAs are identical, 108 DIE-miRNAs are specific to the E. coli group, and 82 DIE-miRNAs are specific to the S. aureus group. Many DIE-miRNAs, such as bta-miR-144, bta miR-451 and bta-miR-7863, might be the useful biomarkers of mastitis caused by E. coli and S. aureus. In addition, target genes of the DIE-miRNAs were predicted. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis indicated that these DIE-miRNAs are likely involved in many immune signaling pathways, including the Toll-like receptor signaling pathways, MAPK signaling pathway, cell adhesion molecules, TGF-beta signaling pathway, leukocyte trans endothelial migration, cytokine-cytokine receptor interaction, and chemokine signaling pathways. This study has provided supportive evidence that miRNAs may serve as diagnostic biomarkers of mastitis in dairy cows, and suggests potentially of effective strategies to combat mastitis. PMID- 29483829 TI - MiR-21-mediated Metabolic Alteration of Cancer-associated Fibroblasts and Its Effect on Pancreatic Cancer Cell Behavior. AB - In this study, we investigated whether the metabolic alteration of cancer associated fibroblasts (CAFs) occurs via miR-21 remodeling and the effect of this alteration on pancreatic cancer cells. CAFs and normal fibroblasts (NFs) were isolated and cultured. Glucose consumption and lactic acid production were tested, and lactate dehydrogenase (LDHA), pyruvate kinase m2 (PKM2), and miR-21 expression were examined. The level of glycolysis in CAFs was determined after treatment with a miR-21 inhibitor. Primary miR-21-NC CAFs and miR-21-inhibitor CAFs were indirectly co-cultured with BxPc-3 in vitro, and the invasion capacity of these cells was determined. The aerobic oxidation index of cancer cells and the expression of succinodehydrogenase (SDH) and fumarate hydratase (FH) were assessed. Compared with NFs, CAFs showed enhanced glucose uptake capacity, lactic acid production, and elevated LDHA, PKM2, and miR-21 expression. After miR-21 inhibitor treatment, the extent of glycolysis in CAFs was reduced. After indirect co-culture with CAFs, oxidative phosphorylation and SDH, FH, and MCT expression increased in BxPc-3 cells. After co-culture with miR-21-inhibitor-CAFs, oxidative phosphorylation and invasion ability of the pancreatic cancer cells decreased. MiR-21 was involved in metabolic alteration of CAFs and affected the development of cancer cells. This metabolic alteration may be an important mechanism by which the microenvironment promotes tumor progression in a nonvascular manner. PMID- 29483831 TI - Ten hub genes associated with progression and prognosis of pancreatic carcinoma identified by co-expression analysis. AB - Since the five-year survival rate is less than 5%, pancreatic ductal adenocarcinoma (PDAC) remains the 4th cause of cancer-related death. Although PDAC has been repeatedly researched in recent years, it is still predicted to be the second leading cause of cancer death by year 2030. In our study, the differentially expressed genes in dataset GSE62452 were used to construct a co expression network by WGCNA. The yellow module related to grade of PDAC was screened. Combined with co-expression network and PPI network, 36 candidates were screened. After survival and regression analysis by using GSE62452 and TCGA dataset, we identified 10 real hub genes (CCNA2, CCNB1, CENPF, DLGAP5, KIF14, KIF23, NEK2, RACGAP1, TPX2 and UBE2C) tightly related to progression of PDAC. According to Oncomine database and The Human Protein Atlas (HPA), we found that all real hub genes were overexpressed in pancreatic carcinoma compared with normal tissues on transcriptional and translational level. ROC curve was plotted and AUC was calculated to distinguish recurrent and non-recurrent PDAC and every AUC of the real hub gene was greater than 0.5. Finally, functional enrichment analysis and gene set enrichment (GSEA) was performed and both of them showed the cell cycle played a vital role in PDAC. PMID- 29483830 TI - The role of TGF-beta/SMAD4 signaling in cancer. AB - Transforming growth factor beta (TGF-beta) signaling pathway plays important roles in many biological processes, including cell growth, differentiation, apoptosis, migration, as well as cancer initiation and progression. SMAD4, which serves as the central mediator of TGF-beta signaling, is specifically inactivated in over half of pancreatic duct adenocarcinoma, and varying degrees in many other types of cancers. In the past two decades, multiple studies have revealed that SMAD4 loss on its own does not initiate tumor formation, but can promote tumor progression initiated by other genes, such as KRAS activation in pancreatic duct adenocarcinoma and APC inactivation in colorectal cancer. In other cases, such as skin cancer, loss of SMAD4 plays an important initiating role by disrupting DNA damage response and repair mechanisms and enhance genomic instability, suggesting its distinct roles in different types of tumors. This review lists SMAD4 mutations in various types of cancer and summarizes recent advances on SMAD4 with focuses on the function, signaling pathway, and the possibility of SMAD4 as a prognostic indicator. PMID- 29483832 TI - A Prognostic Model Based on Circulating Tumour Cells is Useful for Identifying the Poorest Survival Outcome in Patients with Metastatic Colorectal Cancer. AB - Background: There is an urgency to develop robust prognostic biomarkers for metastatic colorectal cancer (mCRC) patients receiving chemotherapy. The current study aimed to examine the prognostic significance of circulating tumour cells (CTCs) and to develop a prognostic model incorporating CTCs in predicting the outcomes of mCRC patients treated with chemotherapy. Methods: Our study prospectively enrolled 55 mCRC patients who had undergone palliative chemotherapy between 2011 and 2014. Baseline CTCs and clinicopathological variables predictive of survival outcome were identified using univariate analysis. Negative selection based protocol plus flow cytometry was used for CTC identification. Results: The median overall survival (OS) and progression-free survival (PFS) were 24.2 months and 8.7 months, respectively. CTCs were detected in all the patients, and the median number of CTCs was 30.8/mL (range: 5.8-431.3/mL). The median OS and PFS were 37.1 and 13.3 months, respectively, for patients with CTC number <=30/mL, while the median OS and PFS were 14.9 months and 5.1 months, respectively, for patients with CTC number >30/mL (both P<0.001). A prognostic model using CTCs in conjunction with other independent clinical variables further stratified patients into good and poor prognostic groups. The median OS and PFS were 32.4 and 11.5 months, respectively, in the good prognostic group and 5.4 and 2.7 months, respectively, in the poor prognostic group. Conclusions: We developed a reliable CTC-based prognostic model for the prediction of clinical outcomes in mCRC patients treated with chemotherapy. This model may be used to assist clinicians in identifying those with the poorest prognosis before treatment. PMID- 29483833 TI - NLRP12 Promotes Mouse Neutrophil Differentiation through Regulation of Non canonical NF-kappaB and MAPKERK1/2 Signaling. AB - Neutrophils are the most important component of the innate immune system. Mechanistic understanding of the mechanism underlying neutrophil differentiation remains elusive. Using genome-wide RNA-seq, we identified genes whose expression is dramatically up-regulated during neutrophil differentiation. Among them is nucleotide-binding leucine-rich repeat and pyrindomain-containing receptor 12 (NLRP12), which plays a role in immune inflammatory responses. Genetic ablation of NLRP12 suppresses NF-kappaB inducing kinase (NIK) stabilization, RelB nuclear translocation and neutrophil differentiation in vitro. At a mechanistic level, NLRP12 inhibits the activity of mitogen-activated protein kinases (MAPK)/extracellular signal-regulated kinases (ERK1/2), relieves ERK1/2 suppression of NIK protein levels. Thus, NLRP12 enhances noncanonical NF-kappaB signaling through inhibition of ERK1/2 signaling, thereby promoting neutrophil differentiation. PMID- 29483834 TI - Analysis of early stage osteonecrosis of the human femoral head and the mechanism of femoral head collapse. AB - We explored the mechanism of early stage osteonecrotic femoral head collapse by analyzing and comparing different regions in human osteonecrotic femoral head samples. Eight osteonecrotic femoral heads (ARCO II-III) were obtained from patients undergoing total hip arthroplasty. Bone structure was observed and evaluated by micro-computed tomography (CT) scans and pathology. Osteoblast and osteoclast activities were detected by tartrate-resistant acid phosphatase, alkaline phosphatase, and immunofluorescent staining. Some trabeculae had microfractures in the subchondral bone and necrotic region, which had lower bone mineral density, as well as trabecular thickness and number, but greater osteoclast activity. A sclerotic band had already appeared in certain samples which had greater trabecular thickness and number, bone mineral density, and osteoblast activity. The appearance of the femoral head did not change significantly in the early stage of osteonecrosis of the femoral head. However, osteoblast and osteoclast activities had already changed in different regions of the osteonecrotic femoral head, which may lead to eventual collapse of the femoral head. Therefore, osteonecrosis of the femoral head must be treated during the early stage. In addition, osteoblast activity should be promoted and osteoclast activity inhibited as early as possible to prevent collapse of an osteonecrotic femoral head. PMID- 29483835 TI - Loss of p21 promoted tumorigenesis in the background of telomere dysfunctions induced by TRF2 and Wrn deficiency. AB - Werner syndrome (WS) is a rare autosomal recessive progeria disease with genetic instability/cancer predisposition, thus a good model in understanding aging related carcinogenesis. Telomere dysfunction induced cellular senescence is essential in the manifestation of the WS phenotype. Our previous data has shown that p21 (encoded by Cdkn1a gene) could induce cellular senescence and suppress cellular growth of ALT (alternative lengthening of telomere) tumors derived from WS, suggested that p21 might play a key role in maintaining senescence of WS cells. To confirm the role of p21 in suppressing telomere dysfunction induced tumorigenesis, we overexpressed dominant negative protein TRF2DeltaBDeltaM in p21 /- mouse embryonic fibroblasts (MEFs). To further stress the cell, we crossed Wrn /- mice with p21-/- mice to obtained p21-/-Wrn-/- MEFs, and overexpressed TRF2DeltaBDeltaM in these MEFs to induce telomere dysfunction similar to that in WS cells. Our data showed that, in the context of p21-/- TRF2DeltaBDeltaM, loss of p21 function rescued cellular senescence, and induced p53 mutation, but did not induce tumorigenesis. However, in the set of p21-/-Wrn-/- TRF2DeltaBDeltaM, loss of p21 function induced p53 mutation and tumorigenesis. To further verify the role of p21 in suppressing telomere dysfunction related tumorigenesis, we knocked down p21 in non-tumorigenic immortalized cells derived from WS MEFs (mTerc -/-Wrn-/- ), and found that loss of p21 could induce ALT tumorigenesis, which displayed typical smear pattern of telomere length and arc-shaped telomeric DNA. In another hand, recovering telomerase activity in these MEFs could also induce tumorigenesis without affecting p21 expression level. Together our data suggested that p21 controlled cell cycle regulation played an essential role in suppressing telomere dysfunction-related tumorigenesis. These data also suggested that the genetic context is essential in determining the role of p21 in cancer prevention. Therefore, targeting p21 in the treatment of human degenerative diseases would require a personalized genetic background screen. PMID- 29483836 TI - MicroRNA-21-5p mediates TGF-beta-regulated fibrogenic activation of spinal fibroblasts and the formation of fibrotic scars after spinal cord injury. AB - Little regeneration of transected axons occurs after the damage caused by traumatic spinal cord injury (SCI), and unidirectional and irreversible fibrotic scars are thought to be the main chemical and physical obstacle for axonal regrowth in SCI pathology. We previously demonstrated that microRNA (miR)-21-5p and transforming growth factor (TGF)-beta1, a central pathological mediator of fibrotic diseases, were significantly up-regulated in the lesion epicenter after SCI. Here, we found that TGF-beta1 enhanced miR-21-5p expression in primary spinal fibroblasts, and regulated the expression of fibrosis-related genes. The overexpression of miR-21-5p promoted the pro-fibrogenic activity of TGF-beta1 in spinal fibroblasts, while miR-21-5p knockdown attenuated this activity. We identified Smad7 as a target gene of miR-21-5p, suggesting a potential mechanism for the role of miR-21-5p in spinal fibrosis through regulating Smad7 expression. Furthermore, miR-21-5p knockdown in a mouse model significantly improved motor functional recovery after spinal cord injury. These data demonstrate that miR-21 5p functions in an amplifying circuit to enhance TGF-beta signaling events in the activation of spinal fibroblasts and suggest that miR-21-5p is a potential therapeutic target in the treatment of fibrotic scar formation after SCI. PMID- 29483837 TI - The Role of G Protein-coupled Receptor Kinases in Cancer. AB - G protein-coupled receptors (GPCRs) are the largest family of plasma membrane receptors. Emerging evidence demonstrates that signaling through GPCRs affects numerous aspects of cancer biology such as vascular remolding, invasion, and migration. Therefore, development of GPCR-targeted drugs could provide a new therapeutic strategy to treating a variety of cancers. G protein-coupled receptor kinases (GRKs) modulate GPCR signaling by interacting with the ligand-activated GPCR and phosphorylating its intracellular domain. This phosphorylation initiates receptor desensitization and internalization, which inhibits downstream signaling pathways related to cancer progression. GRKs can also regulate non-GPCR substrates, resulting in the modulation of a different set of pathophysiological pathways. In this review, we will discuss the role of GRKs in modulating cell signaling and cancer progression, as well as the therapeutic potential of targeting GRKs. PMID- 29483839 TI - Trichosanthin enhances sensitivity of non-small cell lung cancer (NSCLC) TRAIL resistance cells. AB - Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has a specific antitumour activity against many malignant tumours. However, more than half of lung cancer cells are resistant to TRAIL-relevant drugs. Trichosanthin (TCS) is a traditional Chinese medicine with strong inhibitive effects on various malignancies. Nevertheless, its function on TRAIL resistance has not been revealed in non-small cell lung cancer (NSCLC). To examine the molecular mechanisms of TCS-induced TRAIL sensitivity, we administrated TCS to TRAIL resistance NSCLC cells, and found that the combination treatment of TCS and TRAIL inhibited cancer cell proliferation and invasion, and induced cell apoptosis and S-phase arrest. This combined therapeutic method regulated the expression levels of extrinsic apoptosis-associated proteins Caspase 3/8 and PARP; intrinsic apoptosis-associated proteins BCL-2 and BAX; invasion-associated proteins E cadherin, N-cadherin, Vimentin, ICAM-1, MMP-2 and MMP-9; and cell cycle associated proteins P27, CCNE1 and CDK2. Up-expression and redistribution of death receptors (DRs) on the cell surface were also observed in combined treatment. In conclusion, our results indicated that TCS rendered NSCLC cells sensitivity to TRAIL via upregulating and redistributing DR4 and DR5, inducing apoptosis, and regulating invasion and cell cycle related proteins. Our results provided a potential therapeutic method to enhance TRAIL-sensitivity. PMID- 29483838 TI - Combination Strategies Using EGFR-TKi in NSCLC Therapy: Learning from the Gap between Pre-Clinical Results and Clinical Outcomes. AB - Although epidermal growth factor receptor (EGFR) inhibitors have been used to treat non-small cell lung cancer (NSCLC) for decades with great success in patients with EGFR mutations, acquired resistance inevitably occurs after long term exposure. More recently, combination therapy has emerged as a promising strategy to overcome this issue. Several experiments have been carried out to evaluate the synergism of combination therapy both in vitro and in vivo. Additionally, many clinical studies have been carried out to investigate the feasibility of treatment with EGFR-tyrosine kinase inhibitors (TKi) combined with other NSCLC treatments, including radiotherapy, cytotoxic chemotherapies, targeted therapies, and emerging immunotherapies. However, a significant gap still exists when applying pre-clinical results to clinical scenarios, which hinders the development and use of these strategies. This article is a literature review analysing the rationalities and controversies in the transition from pre clinical investigation to clinical practice associated with various combination strategies. It also highlights clues and challenges regarding future combination therapeutic options in NSCLC treatment. PMID- 29483840 TI - MiR-519d suppresses breast cancer tumorigenesis and metastasis via targeting MMP3. AB - Breast cancer (BC) is the most common cause of death in women throughout the world. Although microRNAs (miRNAs) have been identified as novel regulators in carcinogenesis, there are still abundant hidden treasure needed to be excavated. In the present study, we found that miR-519d expression was remarkably decreased in both human BC tissues and MCF-7 cells. CCK8 and 5-Ethynyl-2'-deoxyuridine (EdU) assays were used to evaluate cell proliferation. Wound-healing and transwell assays were performed for detection of cell migration and invasion. The results demonstrated miR-519d overexpression dramatically suppressed MCF-7 cells proliferation, migration and invasion. While downregulation of miR-519d by miR 519d inhibitor substantially increased MCF-7 cell carcinogenesis. Further analysis identified Matrix Metalloproteinase-3 (MMP3) as a direct target of miR 519d. QRT-PCR and western blot results indicated the correlative expression of miR-519d and MMP3 in BC tissues and MCF-7 cells. In summary, our data uncovered the novel molecular interaction between miR-519d and MMP3, indicating a therapeutic strategy of miR-519d for BC. PMID- 29483841 TI - Prevalence and Determinants of Peripheral Microvascular Endothelial Dysfunction in Rheumatoid Arthritis Patients: A Multicenter Cross-Sectional Study. AB - Objectives: To define the prevalence and determinants of peripheral microvascular endothelial dysfunction (ED) in a large series of rheumatoid arthritis (RA) patients free of previous cardiovascular events. Materials and Methods: Data from 874 RA patients enrolled in the EDRA study (Endothelial Dysfunction Evaluation for Coronary Heart Disease Risk Estimation in Rheumatoid Arthritis ClinicalTrials.gov: NCT02341066) were analyzed. Log-transformed reactive hyperemia index (Ln-RHI) was evaluated by peripheral arterial tonometry (PAT) using the EndoPAT2000 device: values of Ln-RHI < 0.51 were considered indicative of peripheral ED. Results: Peripheral microvascular ED was documented in one third of RA patients (33.5%); in multiple logistic regression analysis, ACPA negativity and higher triglycerides concentrations were independently associated with the presence of peripheral ED [OR (95% CI) = 1.708 (1.218-2.396), p < 0.01 and OR (95% CI) = 1.005 (1.002-1.009), p < 0.01, respectively]. Multiple regression analysis showed a positive correlation between Ln-RHI values and systolic blood pressure and HDL cholesterol levels; furthermore, higher values of Ln-RHI were associated with ACPA positivity, while smoking habit was associated with lower Ln-RHI values. Conclusions: This study demonstrates for the first time a high prevalence of peripheral microvascular ED in patients with RA free of previous cardiovascular events that appear to be only partially driven by traditional cardiovascular risk factors. The association between ACPA negativity and ED warrants further exploration. PMID- 29483842 TI - Whole-Body Cryotherapy Decreases the Levels of Inflammatory, Oxidative Stress, and Atherosclerosis Plaque Markers in Male Patients with Active-Phase Ankylosing Spondylitis in the Absence of Classical Cardiovascular Risk Factors. AB - Objective: The aim of the study was to estimate the impact of whole-body cryotherapy (WBC) on cardiovascular risk factors in patients with ankylosing spondylitis (AS). Material and Methods: We investigated the effect of WBC with subsequent kinesiotherapy on markers of inflammation, oxidative stress, lipid profile, and atherosclerosis plaque in male AS patients (WBC group). To assess the disease activity, the BASDAI and BASFI were also calculated. The results from the WBC group were compared with results from the kinesiotherapy (KT) group. Results: The results showed that in the WBC group, the plasma hsCRP level decreased without change to the IL-6 level. The ICAM-1 level showed a decreasing tendency. The CER concentration, as well as the BASDAI and BASFI, decreased in both groups, but the index changes of disease activity were higher in the WBC than KT patients. Additionally, in the WBC group, we observed a decrease in oxidative stress markers, changes in the activity of some antioxidant enzymes and nonenzymatic antioxidant parameters. In both groups, the total cholesterol and LDL cholesterol, triglycerides, sCD40L, PAPP-A, and PLGF levels decreased, but the parameter changes were higher in the WBC group. Conclusion: WBC appears to be a useful method of atherosclerosis prevention in AS patients. PMID- 29483843 TI - The role of tonsillectomy in the Periodic Fever, Aphthous stomatitis, Pharyngitis and cervical Adenitis syndrome; a literature review. AB - Background: Tonsillectomy (TE) or adenotonsillectomy (ATE) may have a beneficial effect on the clinical course in children with the Periodic Fever, Aphthous stomatitis, Pharyngitis and cervical Adenitis (PFAPA) syndrome. However, an immunological reason for this effect remains unknown. This literature review summarizes the current knowledge of the effect of TE or ATE in the PFAPA syndrome. Methods: A search of PubMed, Medline, EMBASE and Cochrane was conducted for papers written in English dated from 1 January 1987 to 31 December 2016. The search included all studies reporting outcomes after TE or ATE from children aged 0 to 18 years with PFAPA. Results: Two randomized controlled trials reported significantly faster resolution of febrile episodes after TE or ATE in children with PFAPA compared to controls (non-surgery groups). We identified 28 case series including 555 children with PFAPA. The diagnosis was set prospectively before surgery in 440 children and retrospectively after surgery in 115 of the children. TE or ATE had a curative effect in 509 of the 555 children with PFAPA (92%), but few studies were of high quality. Conclusion: TE or ATE may have a curative effect on children with PFAPA, but the evidence is of moderate quality. Further high-quality randomized controlled studies are still needed. PMID- 29483844 TI - To what extent has doctoral (PhD) education supported academic nurse educators in their teaching roles: an integrative review. AB - Background: A doctoral degree, either a PhD or equivalent, is the academic credential required for an academic nurse educator position in a university setting; however, the lack of formal teaching courses in doctoral programs contradict the belief that these graduates are proficient in teaching. As a result, many PhD prepared individuals are not ready to meet the demands of teaching. Methods: An integrative literature review was undertaken. Four electronic databases were searched including the Cumulative Index to Nursing & Allied Health Literature (CINAHL), PubMed, Educational Resources Information Center (ERIC) and ProQuest. Date range and type of peer-reviewed literature was not specified. Results: Conditions and factors that influenced or impacted on academic nurse educators' roles and continue to perpetuate insufficient pedagogical preparation include the requirement of a research focused PhD, lack of mentorship in doctoral programs and the influence of epistemic cultures (including institutional emphasis and reward system). Other factors that have impacted the academic nurse educator's role are society's demand for highly educated nurses that have increased the required credential, the assumption that all nurses are considered natural teachers, and a lack of consensus on the practice of the scholarship of teaching. Conclusions: Despite recommendations from nursing licensing bodies and a major US national nursing education study, little has been done to address the issue of formal pedagogical preparation in doctoral (PhD) nursing programs. There is an expectation of academic nurse educators to deliver quality nursing education yet, have very little or no formal pedagogical preparation for this role. While PhD programs remain research intensive, the PhD degree remains a requirement for a role in which teaching is the major responsibility. PMID- 29483845 TI - MLL2/KMT2D and MLL3/KMT2C expression correlates with disease progression and response to imatinib mesylate in chronic myeloid leukemia. AB - Background: Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm whose pathogenesis is linked to the Philadelphia chromosome presence that generates the BCR-ABL1 fusion oncogene. Tyrosine kinase inhibitors (TKI) such as imatinib mesylate (IM) dramatically improved the treatment efficiency and survival of CML patients by targeting BCR-ABL tyrosine kinase. The disease shows three distinct clinical-laboratory stages: chronic phase, accelerated phase and blast crisis. Although patients in the chronic phase respond well to treatment, patients in the accelerated phase or blast crisis usually show therapy resistance and CML relapse. It is crucial, therefore, to identify biomarkers to predict CML genetic evolution and resistance to TKI therapy, considering not only the effects of genetic aberrations but also the role of epigenetic alterations during the disease. Although dysregulations in epigenetic modulators such as histone methyltrasnferases have already been described for some hematologic malignancies, to date very limited data is available for CML, especially when considering the lysine methyltransferase MLL2/KMT2D and MLL3/KMT2C. Methods: Here we investigated the expression profile of both genes in CML patients in different stages of the disease, in patients showing different responses to therapy with IM and in non neoplastic control samples. Imatinib sensitive and resistant CML cell lines were also used to investigate whether treatment with other tyrosine kinase inhibitors interfered in their expression. Results: In patients, both methyltransferases were either upregulated or with basal expression level during the chronic phase compared to controls. Interestingly, MLL3/KMT2C and specially MLL2/KMT2D levels decreased during disease progression correlating with distinct clinical stages. Furthermore, MLL2/KMT2D was decreased in patients resistant to IM treatment. A rescue in the expression of both MLL genes was observed in KCL22S, a CML cell line sensitive to IM, after treatment with dasatinib or nilotinib which was associated with a higher rate of apoptosis, an enhanced expression of p21 (CDKN1A) and a concomitant decrease in the expression of CDK2, CDK4 and Cyclin B1 (CCNB1) in comparison to untreated KCL22S control or IM resistant KCL22R cell line, which suggests involvement of p53 regulated pathway. Conclusion: Our results established a new association between MLL2/KMT2D and MLL3/KMT2C genes with CML and suggest that MLL2/KMT2D is associated with disease evolution and may be a potential marker to predict the development of therapy resistance. PMID- 29483846 TI - Integrated TCGA analysis implicates lncRNA CTB-193M12.5 as a prognostic factor in lung adenocarcinoma. AB - Background: Lung cancer is a malignant tumor with the highest incidence and mortality around the world. Recent advances in RNA sequencing technology have enabled insights into long non-coding RNAs (lncRNAs), a previously largely overlooked species in dissecting lung cancer pathology. Methods: In this study, we used a comprehensive bioinformatics analysis strategy to identify lncRNAs closely associated with lung adenocarcinoma, using the RNA sequencing datasets collected from more than 500 lung adenocarcinoma patients and deposited at The Cancer Genome Atlas (TCGA) database. Results: Differential expression analysis highlighted lncRNAs CTD-2510F5.4 and CTB-193M12.5, both of which were significantly upregulated in cancerous specimens. Moreover, network analyses showed highly correlated expression levels of both lncRNAs with those of differentially expressed protein-coding genes, and suggested central regulatory roles of both lncRNAs in the gene co-expression network. Importantly, expression of CTB-193M12.5 showed strong negative correlation with patient survival. Conclusions: Our study mined existing TCGA datasets for novel factors associated with lung adenocarcinoma, and identified a largely unknown lncRNA as a potential prognostic factor. Further investigation is warranted to characterize the roles and significance of CTB-193M12.5 in lung adenocarcinoma biology. PMID- 29483847 TI - Unique CD44 intronic SNP is associated with tumor grade in breast cancer: a case control study and in silico analysis. AB - Background: CD44 encoded by a single gene is a cell surface transmembrane glycoprotein. Exon 2 is one of the important exons to bind CD44 protein to hyaluronan. Experimental evidences show that hyaluronan-CD44 interaction intensifies the proliferation, migration, and invasion of breast cancer cells. Therefore, the current study aimed at investigating the association between specific polymorphisms in exon 2 and its flanking region of CD44 with predisposition to breast cancer. Methods: In the current study, 175 Iranian female patients with breast cancer and 175 age-matched healthy controls were recruited in biobank, Breast Cancer Research Center, Tehran, Iran. Single nucleotide polymorphisms of CD44 exon 2 and its flanking were analyzed via polymerase chain reaction and gene sequencing techniques. Association between the observed variation with breast cancer risk and clinico-pathological characteristics were studied. Subsequently, bioinformatics analysis was conducted to predict potential exonic splicing enhancer (ESE) motifs changed as the result of a mutation. Results: A unique polymorphism of the gene encoding CD44 was identified at position 14 nucleotide upstream of exon 2 (A37692->G) by the sequencing method. The A > G polymorphism exhibited a significant association with higher-grades of breast cancer, although no significant relation was found between this polymorphism and breast cancer risk. Finally, computational analysis revealed that the intronic mutation generated a new consensus-binding motif for the splicing factor, SC35, within intron 1. Conclusions: The current study results indicated that A > G polymorphism was associated with breast cancer development; in addition, in silico analysis with ESE finder prediction software showed that the change created a new SC35 binding site. PMID- 29483848 TI - Incorporating economies of scale in the cost estimation in economic evaluation of PCV and HPV vaccination programmes in the Philippines: a game changer? AB - Background: Many economic evaluations ignore economies of scale in their cost estimation, which means that cost parameters are assumed to have a linear relationship with the level of production. Economies of scale is the situation when the average total cost of producing a product decreases with increasing volume caused by reducing the variable costs due to more efficient operation. This study investigates the significance of applying the economies of scale concept: the saving in costs gained by an increased level of production in economic evaluation of pneumococcal conjugate vaccines (PCV) and human papillomavirus (HPV) vaccinations. Methods: The fixed and variable costs of providing partial (20% coverage) and universal (100% coverage) vaccination programs in the Philippines were estimated using various methods, including costs of conducting questionnaire survey, focus-group discussion, and analysis of secondary data. Costing parameters were utilised as inputs for the two economic evaluation models for PCV and HPV. Incremental cost-effectiveness ratios (ICERs) and 5-year budget impacts with and without applying economies of scale to the costing parameters for partial and universal coverage were compared in order to determine the effect of these different costing approaches. Results: The program costs of the partial coverage for the two immunisation programs were not very different when applying and not applying the economies of scale concept. Nevertheless, the program costs for universal coverage were 0.26 and 0.32 times lower when applying economies of scale compared to not applying economies of scale for the pneumococcal and human papillomavirus vaccinations, respectively. ICERs varied by up to 98% for pneumococcal vaccinations, whereas the change in ICERs in the human papillomavirus vaccination depended on both the costs of cervical cancer screening and the vaccination program. This results in a significant difference in the 5-year budget impact, accounting for 30 and 40% of reduction in the 5-year budget impact for the pneumococcal and human papillomavirus vaccination programs. Conclusions: This study demonstrated the feasibility and importance of applying economies of scale in the cost estimation in economic evaluation, which would lead to different conclusions in terms of value for money regarding the interventions, particularly with population-wide interventions such as vaccination programs. The economies of scale approach to costing is recommended for the creation of methodological guidelines for conducting economic evaluations. PMID- 29483849 TI - Comparative transcriptome reveal the potential adaptive evolutionary genes in Andrias davidianus. AB - To search the evidence of molecular evolution mechanism for aquatic and cave habitat in Andrias davidianus, the evolution analysis was carried out among several species transcriptome data. The transcriptome data of Notophthalmus viridescens, Xenopus tropicalis, Cynops pyrrhogaster, Hynobius chinensis and A. davidianus were obtained from the Genbank and reassembled except Xenopus tropicalis. The BLAST search of transcriptome data obtained 1244 single-copy orthologous genes among five species. A phylogenetic tree showed A. davidianus to have the closest relationship to H. chinensis. Fourteen positively selected genes were detected in A. davidianus and N. vridescens group and fifteen in A. davidianus and H. chinensis group. Five genes were shared in the both groups which involved in the immune system, suggesting that A. davidianus adaptation to an aquatic and cave environment required rapid evolution of the immune system compared to N. viridescens and H. chinensis. PMID- 29483850 TI - Gold-catalyzed Fluorination of Alkynyl Esters and Ketones: Efficient Access to Fluorinated 1,3-Dicarbonyl Compounds. AB - We developed an efficient synthesis of 2-fluoro-1,3-dicarbonyl compounds using readily available alkynyl ketones or esters as starting material. The key step is the insertion of hydrogen fluoride (HF) to the gold carbene intermediate generated from cationic gold catalyzed addition of N-oxides to alkynyl ketones or esters. This method gives excellent chemical yields and regioselectivity with good functional group tolerance. PMID- 29483851 TI - Ultrasonography of uterine leiomyomas. AB - Uterine leiomyomas or uterine fibroids are the most common gynaecological tumours and occur in about 20-50% of women around the world. Ultrasonography (USG) is the first-line imaging examination in suspected fibroids and shows high sensitivity and specificity in diagnosing this condition. Ultrasound scans can be performed transvaginally (transvaginal scan - TVS) or transabdominally (transabdominal scan - TAS); both scans have advantages and limitations, but, in general, transvaginal sonography is superior to transabdominal sonography in most cases of pelvic pathology. Whether a leiomyoma is symptomatic or not depends primarily on its size and location. During ultrasound examination, leiomyomas usually appear as well-defined, solid, concentric, hypoechoic masses that cause a variable amount of acoustic shadowing. During the examination of leiomyomas differential diagnosis is important. Some of the most common misdiagnosed pathologies are adenomyosis, solid tumours of adnexa, and endometrial polyps. Misdiagnosis of a leiomyosarcoma has the most negative consequences, presenting symptoms are very similar to benign leiomyoma, and there is no pelvic imaging technique that can reliably differentiate between those pathologies. Magnetic resonance and computer tomography might be helpful in the diagnostics of uterine leiomyoma; however, ultrasound examination is the basic imaging test confirming the existence of leiomyomas, allowing the differentiation of myomas with adenomyosis, endometrial polyps, ovarian tumours, and pregnant uterus. PMID- 29483852 TI - 3D Power Doppler vascular indices as a novel technique in assessing the outcome of minimally invasive techniques in uterine fibroids treatment. AB - Uterine fibroids are considered to be the most frequent female benign tumours. The most common reported symptoms of fibroids are heavy menstrual bleeding and painful menstruation, pelvic pain, urinary problems, constipation, as well as infertility and recurrent pregnancy loss. The mainstay of fibroid treatment is surgery, but nowadays minimally-invasive techniques are growing in popularity. Vascularity of fibroids may play a role in the outcome of these techniques, which is why it is important to find an objective, reproducible technique to measure the vascularization before and after the procedure. The 3D Power Doppler vascular indices (3DPDVI) allow objective assessment of vascularization in the entire volume of the tumour. Initially this technique was mostly used in experimental imaging phantoms, but recently many studies focus on the clinical utility of this technique. Power Doppler allows to obtain information on vascularity in the area of interest, while 3DPDVI can be objectively calculated by the Virtual Organ Computer-aided AnaLysis (VOCALTM) software. 3DPDVI showed high reproducibility in most of the studies. This technique has an important role in monitoring the outcome of minimally invasive procedures in fibroid treatment, because they affect vascularity of the tumours. Although there are some limitations of 3DPDVI, it seems that their application may be an effective tool in objective assessment of vascularity of fibroids. However further studies are required to consolidate the usage of 3DPDVI in clinical practice. PMID- 29483853 TI - Minimally invasive procedures in the management of uterine fibroids. AB - Uterine fibroids are benign uterine tumors. In women during the reproductive period, uterine fibroids occur in about 25%, whereas after this time, they are observed in more than 40% of women. In the majority of women (about 20-50%), such tumors do not cause discomfort and do not require treatment. Asymptomatic uterine fibroids usually undergo only regular medical control, whereas symptomatic fibroids are an indication for treatment. Current treatment methods include surgical, pharmacological and minimally invasive treatment. Among the current commonly used methods, there are minimally invasive treatment options, which include Uterine Artery Embolization (UAE), Magnetic Resonance Guided Ultrasound Surgery (MRgFUS), MR-guided High Intensity Focused Ultrasound (MR-HIFU) and Laparoscopic Uterine Artery Occlusion (LUAO). The minimally invasive Ultrasound guided High Intensity Focused Ultrasound method (US-HIFU) is new, but still experimental. The use of MRgFUS/MR-HIFU for the thermoablative treatment of fibroids was approved by the FDA (Food and Drug Administration) in 2004. As a minimally invasive method, it enables preservation of the uterus and eliminates the need for general anesthesia. LUAO is based on the use of the vascular clip, which is placed on the uterine artery at the level of the internal iliac artery. This procedure is performed bilaterally. The use of UAE in obstetrics and gynecology was first described in 1987 as an effective method in the treatment of hemorrhage, which allows avoiding surgical intervention and enables the uterus to be preserved. An appropriate qualification of patients is crucial for high clinical efficacy and prevention of complications after UAE. The candidates should be women with symptomatic uterine fibroids, without other pathologies within the pelvis, who do not plan to get pregnant in the future. The variety of uterine fibroids as for the location, size, and symptoms they can evoke, has enforced a very individual approach to each patient, to begin with observation and regular gynecological control, through a number of pharmacological and minimally invasive treatment methods, and ending with the removal of the uterus. It gives the doctors the tools, which, if used properly, can manage uterine fibroids and fulfil the expectations of the patient. PMID- 29483854 TI - Hysteroscopic myomectomy. AB - A new International Federation of Gynecology and Obstetrics classification for myomas was recently described. Type 0, 1 and 2 are the submucosal fibroids. Submucous myomas represent one of the main indications for operative hysteroscopy. Hysteroscopic resection of submucous fibroids should be a simple, well-tolerated procedure and ideally finished in a single surgical step. Hysteroscopic myomectomy is an effective procedure. Fertility outcome and menorrhagia are improved by this procedure. However, for menorrhagia, a recurrence can occur mainly during the first year following the surgery. For bleeding outcome, a success rate from 70 to 99% has been reported by different studies. The success rate seems to decline as the follow- up period increases. For fertility outcome, submucosal fibroids have negative impact on pregnancy rates. The size of the fibroids plays a crucial role in completing the hysteroscopic myomectomy in a single step. A diameter greater than 3 cm in type 2 myomas results in a higher risk of a multiple procedure. PMID- 29483855 TI - The role of levonorgestrel intrauterine systems in the treatment of symptomatic fibroids. AB - Uterine fibroids are considered to be the most frequently occurring tumours in females. The majority of fibroids do not require any treatment. When symptomatic, the major ailments include abnormal uterine bleeding, painful menstruation, pelvic pressure or pain, urinary problems, constipation, infertility, and recurrent pregnancy loss. Surgery remains a mainstay of symptomatic uterine fibroids therapy; however, minimally-invasive techniques and pharmacological management have become more available. The levonorgestrel intrauterine system (LNG-IUS) is a T-shaped device with a vertical stem containing a reservoir of levonorgestrel and is widely known for its contraception effect. Moreover, the non-contraceptive benefits of the LNG-IUS have been previously confirmed by numerous studies. LNG-IUS causes reduction of the duration and the amount of menstrual bleeding, with minimal side effects due to release of hormones at the targeted organ. Currently, results from systematic reviews show that LNG-IUS may be an effective and safe treatment for symptomatic uterine fibroids in premenopausal women. However, further studies are required to consolidate the usage of LNG-IUS in the treatment of symptomatic uterine fibroids. PMID- 29483856 TI - Ulipristal acetate as a treatment option for uterine fibroids. AB - Uterine fibroids are the most common benign uterine tumours. Clinical symptoms include abnormal bleeding, pelvic pressure, pelvic pain, infertility and obstetric complications. Approximately one third of women with fibroids will require treatment. The management also depends on the number, size, and location of the fibroids. There are surgical and non-surgical treatment options. The choice of therapy depends on different factors, such as the severity of symptoms, tumour characteristics, age, and wish to preserve the uterus and fertility. There is growing evidence of the main role of progesterone pathways in the pathophysiology of uterine fibroids due to the use of selective progesterone receptor modulators such as ulipristal acetate. The efficacy of long-term intermittent use of UPA was recently demonstrated by randomised controlled studies. There is great demand for alternatives to surgical intervention, especially in women seeking to preserve their fertility. One of these alternatives is ulipristal acetate, which is proven to treat fibroid symptoms effectively. PMID- 29483857 TI - Fertility impairment associated with uterine fibroids - a review of literature. AB - Uterine fibroids (also known as leiomyomas or myomas) are the most common benign tumors affecting reproductive organs in women. They are monoclonal tumors of the uterine smooth muscle, which spring from myometrium. It is estimated that they occur in 50-60% of the female population and rise to 70% by the age of 50. While mostly asymptomatic, myomas can be connected with several conditions, including abnormal bleeding with subsequent anemia, pelvic masses, pelvic pain, bulk symptoms, unfavorable impact on fertility and obstetric complications. Factors, which predispose the emergence of fibroids are: hormones, Afro-American ethnicity, age, obesity, adverse pregnancy outcome history, early menarche, genetic factors, alcohol, caffeine or eating too much red meat. On the other hand, there are factors, which can decrease this risk: pregnancy, early menopause and tobacco smoking. There are several mechanisms of fertility impairment in females with fibroids: alternations in uterus function (flawed blood supply, increased contractility), changes in the normal uterus anatomy, local hormonal changes induced by fibroids. In this review the connection between fibroids and infertility is analyzed. PMID- 29483858 TI - Comparison of Treatment for Metabolic Disorders Associated with Autism:Reanalysis of Three Clinical Trials. AB - Autism spectrum disorder (ASD) affects about 1 in 45 individuals in the United States, yet effective treatments are yet to be defined. There is growing evidence that ASD is associated with abnormalities in several metabolic pathways, including the inter-connected folate, methylation and glutathione pathways. Several treatments that can therapeutically target these pathways have been tested in preliminary clinical trials. The combination of methylcobalamin (mB12) with low-dose folinic acid (LDFA) and sapropterin, a synthetic form of tetrahydrobiopterin (BH4) have been studied in open-label trials while high-dose folinic acid has been studied in a double-blind placebo controlled trial. All of these treatments have the potential to positively affect folate, methylation and glutathione pathways. Although the effect of mB12/LDFA and BH4 on methylation and glutathione metabolism have been examined in the open-label studies, these changes have not been compared to controls who received a placebo in order to account for the natural variation in the changes in these pathways. Furthermore, the recent study using high-dose folinic acid (HDFA) did not analyze the change in metabolism resulting from the treatment. Thus, we compared changes in methylation and glutathione metabolism and biomarkers of chronic oxidative stress as a result of these three treatments to individuals receiving placebo. In general, mB12/LDFA treatment had a significant effect on glutathione and cysteine metabolism with a medium effect size while BH4 had a significant effect on methylation and markers of chronic oxidative stress with a large effect size. HDFA treatment did not significantly influence biomarkers of methylation, glutathione or chronic oxidative stress. One caveat was that participants in the mB12/LDFA and BH4 studies had significantly worse markers of glutathione metabolism and chronic oxidative stress at baseline, respectively. Thus, the participants selected in these two clinical trials may have been those with the most severe metabolic abnormalities and most expected to respond to these treatments. Overall this study supports the notion that metabolic abnormalities in individuals with ASD may be amenable to targeted treatments and provide some insight into the mechanism of action of these treatments. PMID- 29483859 TI - Editorial: Closed-Loop Systems for Next-Generation Neuroprostheses. PMID- 29483861 TI - Therapeutic Effects of Electrical Stimulation: Interpretations and Predictions Based on the Visceral Theory of Sleep. PMID- 29483860 TI - The Histamine H3 Receptor Antagonist DL77 Ameliorates MK801-Induced Memory Deficits in Rats. AB - The role of Histamine H3 receptors (H3Rs) in memory, and the prospective of H3R antagonists in pharmacological control of neurodegenerative disorders, e.g., Alzheimer disease (AD) is well-accepted. For that reason, the procognitive effects of the H3R antagonist DL77 on cognitive impairments induced with MK801 were tested in an inhibitory passive avoidance paradigm (PAP) and novel object recognition (NOR) task in adult male rats, using donepezil (DOZ) as a standard drug. Acute systemic pretreatment with DL77 (2.5, 5, and 10 mg/kg, i.p.) significantly ameliorated memory deficits induced with MK801 in PAP (all P < 0.05, n = 7). The ameliorative effect of most promising dose of DL77 (5 mg/kg, i.p.) was reversed when rats were co-injected with the H3R agonist R-(alpha) methylhistamine (RAMH, 10 mg/kg, i.p.) (p = 0.701 for MK801-amnesic group vs. MK801+DL77+RAMH group, n = 6). In the NOR paradigm, DL77 (5 mg/kg, i.p.) counteracted long-term memory (LTM) deficits induced with MK801 (P < 0.05, n = 6 8), and the DL77-provided effect was similar to that of DOZ (p = 0.788, n = 6-8), and was reversed when rats were co-injected with RAMH (10 mg/kg, i.p.) (p = 0.877, n = 6, as compared to the (MK801)-amnesic group). However, DL77 (5 mg/kg, i.p.) did not alter short-term memory (STM) impairment in NOR test (p = 0.772, n = 6-8, as compared to (MK801)-amnesic group). Moreover, DL77 (5 mg/kg) failed to modify anxiety and locomotor behaviors of animals innate to elevated-plus maze (EPM) (p = 0.67 for percentage of time spent exploring the open arms, p = 0.52 for number of entries into the open arms, p = 0.76 for percentage of entries into the open arms, and p = 0.73 number of closed arm entries as compared to saline treated groups, all n = 6), demonstrating that the procognitive effects observed in PAP or NOR tests were unconnected to alterations in emotions or in natural locomotion of tested animals. These results signify the potential involvement of H3Rs in modulating neurotransmitters related to neurodegenerative disorders, e.g., AD. PMID- 29483862 TI - Cocaine Effects on Dopaminergic Transmission Depend on a Balance between Sigma-1 and Sigma-2 Receptor Expression. AB - Sigma sigma1 and sigma2 receptors are targets of cocaine. Despite sharing a similar name, the two receptors are structurally unrelated and their physiological role is unknown. Cocaine increases the level of dopamine, a key neurotransmitter in CNS motor control and reward areas. While the drug also affects dopaminergic signaling by allosteric modulations exerted by sigma1R interacting with dopamine D1 and D2 receptors, the potential regulation of dopaminergic transmission by sigma2R is also unknown. We here demonstrate that sigma2R may form heteroreceptor complexes with D1 but not with D2 receptors. Remarkably sigma1, sigma2, and D1 receptors may form heterotrimers with particular signaling properties. Determination of cAMP levels, MAP kinase activation and label-free assays demonstrate allosteric interactions within the trimer. Importantly, the presence of sigma2R induces bias in signal transduction as sigma2R ligands increase cAMP signaling whereas reduce MAP kinase activation. These effects, which are opposite to those exerted via sigma1R, suggest that the D1 receptor-mediated signaling depends on the degree of trimer formation and the differential balance of sigma receptor and heteroreceptor expression in acute versus chronic cocaine consumption. Although the physiological role is unknown, the heteroreceptor complex formed by sigma1, sigma2, and D1 receptors arise as relevant to convey the cocaine actions on motor control and reward circuits and as a key factor in acquisition of the addictive habit. PMID- 29483863 TI - Differential Expression of Dopamine D5 Receptors across Neuronal Subtypes in Macaque Frontal Eye Field. AB - Dopamine signaling in the prefrontal cortex (PFC) is important for cognitive functions, yet very little is known about the expression of the D5 class of dopamine receptors (D5Rs) in this region. To address this, we co-stained for D5Rs, pyramidal neurons (neurogranin+), putative long-range projection pyramidal neurons (SMI-32+), and several classes of inhibitory interneuron (parvalbumin+, calbindin+, calretinin+, somatostatin+) within the frontal eye field (FEF): an area within the PFC involved in the control of visual spatial attention. We then quantified the co-expression of D5Rs with markers of different cell types across different layers of the FEF. We show that: (1) D5Rs are more prevalent on pyramidal neurons than on inhibitory interneurons. (2) D5Rs are disproportionately expressed on putative long-range projecting pyramidal neurons. The disproportionately high expression of D5Rs on long-range projecting pyramidals, compared to interneurons, was particularly pronounced in layers II III. Together these results indicate that the engagement of D5R-dependent mechanisms in the FEF varies depending on cell type and cortical layer, and suggests that non-locally projecting neurons contribute disproportionately to functions involving the D5R subtype. PMID- 29483864 TI - Differential Regulation of Bladder Pain and Voiding Function by Sensory Afferent Populations Revealed by Selective Optogenetic Activation. AB - Bladder-innervating primary sensory neurons mediate reflex-driven bladder function under normal conditions, and contribute to debilitating bladder pain and/or overactivity in pathological states. The goal of this study was to examine the respective roles of defined subtypes of afferent neurons in bladder sensation and function in vivo via direct optogenetic activation. To accomplish this goal, we generated transgenic lines that express a Channelrhodopsin-2-eYFP fusion protein (ChR2-eYFP) in two distinct populations of sensory neurons: TRPV1-lineage neurons (Trpv1Cre;Ai32, the majority of nociceptors) and Nav1.8+ neurons (Scn10aCre;Ai32, nociceptors and some mechanosensitive fibers). In spinal cord, eYFP+ fibers in Trpv1Cre;Ai32 mice were observed predominantly in dorsal horn (DH) laminae I-II, while in Scn10aCre;Ai32 mice they extended throughout the DH, including a dense projection to lamina X. Fiber density correlated with number of retrogradely-labeled eYFP+ dorsal root ganglion neurons (82.2% Scn10aCre;Ai32 vs. 62% Trpv1Cre;Ai32) and degree of DH excitatory synaptic transmission. Photostimulation of peripheral afferent terminals significantly increased visceromotor responses to noxious bladder distension (30-50 mmHg) in both transgenic lines, and to non-noxious distension (20 mmHg) in Scn10aCre;Ai32 mice. Depolarization of ChR2+ afferents in Scn10aCre;Ai32 mice produced low- and high amplitude bladder contractions respectively in 53% and 27% of stimulation trials, and frequency of high-amplitude contractions increased to 60% after engagement of low threshold (LT) mechanoreceptors by bladder filling. In Trpv1Cre;Ai32 mice, low-amplitude contractions occurred in 27% of trials before bladder filling, which was pre-requisite for light-evoked high-amplitude contractions (observed in 53.3% of trials). Potential explanations for these observations include physiological differences in the thresholds of stimulated fibers and their connectivity to spinal circuits. PMID- 29483865 TI - Altered Processing and Integration of Multisensory Bodily Representations and Signals in Eating Disorders: A Possible Path Toward the Understanding of Their Underlying Causes. AB - According to the Diagnostic and Statistical Manual of Mental Disorders (DSM V) eating problems are the clinical core of eating disorders (EDs). However, the importance of shape and weight overvaluation symptoms in these disorders underlines the critical role of the experience of the body in the etiology of EDs. This article suggests that the transdiagnostic centrality of these symptoms in individuals with EDs may reflect a deficit in the processing and integration of multisensory bodily representations and signals. Multisensory body integration is a critical cognitive and perceptual process, allowing the individual to protect and extend her/his boundaries at both the homeostatic and psychological levels. To achieve this goal the brain integrates sensory data arriving from real time multiple sensory modalities and internal bodily information with predictions made using the stored information about the body from conceptual, perceptual, and episodic memory. In this view the emotional, visual, tactile, proprioceptive and interoceptive deficits reported by many authors in individuals with EDs may reflect a broader impairment in multisensory body integration that affects the individual's abilities: (a) to identify the relevant interoceptive signals that predict potential pleasant (or aversive) consequences; and (b) to modify/correct the autobiographical allocentric (observer view) memories of body related events (self-objectified memories). Based on this view, the article also proposes a strategy, based on new technologies (i.e., virtual reality and brain/body stimulation), for using crossmodal associations to reactivate and correct the multisensory body integration processes. PMID- 29483866 TI - Non-Uniform Sample Assignment in Training Set Improving Recognition of Hand Gestures Dominated with Similar Muscle Activities. AB - So far, little is known how the sample assignment of surface electromyogram (sEMG) features in training set influences the recognition efficiency of hand gesture, and the aim of this study is to explore the impact of different sample arrangements in training set on the classification of hand gestures dominated with similar muscle activation patterns. Seven right-handed healthy subjects (24.2 +/- 1.2 years) were recruited to perform similar grasping tasks (fist, spherical, and cylindrical grasping) and similar pinch tasks (finger, key, and tape pinch). Each task was sustained for 4 s and followed by a 5-s rest interval to avoid fatigue, and the procedure was repeated 60 times for every task. sEMG were recorded from six forearm hand muscles during grasping or pinch tasks, and 4 s sEMG from each channel was segmented for empirical mode decomposition analysis trial by trial. The muscle activity was quantified with zero crossing (ZC) and Wilson amplitude (WAMP) of the first four resulting intrinsic mode function. Thereafter, a sEMG feature vector was constructed with the ZC and WAMP of each channel sEMG, and a classifier combined with support vector machine and genetic algorithm was used for hand gesture recognition. The sample number for each hand gesture was designed to be rearranged according to different sample proportion in training set, and corresponding recognition rate was calculated to evaluate the effect of sample assignment change on gesture classification. Either for similar grasping or pinch tasks, the sample assignment change in training set affected the overall recognition rate of candidate hand gesture. Compare to conventional results with uniformly assigned training samples, the recognition rate of similar pinch gestures was significantly improved when the sample of finger-, key-, and tape-pinch gesture were assigned as 60, 20, and 20%, respectively. Similarly, the recognition rate of similar grasping gestures also rose when the sample proportion of fist, spherical, and cylindrical grasping was 40, 30, and 30%, respectively. Our results suggested that the recognition rate of hand gestures can be regulated by change sample arrangement in training set, which can be potentially used to improve fine-gesture recognition for myoelectric robotic hand exoskeleton control. PMID- 29483869 TI - Increased Amplitude of the P3a ERP Component as a Neurocognitive Marker for Differentiating Amnestic Subtypes of Mild Cognitive Impairment. AB - The event-related potential (ERP) technique has been shown to be useful for evaluating changes in brain electrical activity associated with different cognitive processes, particularly in Alzheimer's disease (AD). Longitudinal studies have shown that a high proportion of people with amnestic mild cognitive impairment (aMCI) go on to develop AD. aMCI is divided into two subtypes according to the presence of memory impairment only (single-domain aMCI: sdaMCI) or impairment of memory and other cognitive domains (multi-domain aMCI: mdaMCI). The main aim of this study was to examine the effects of sdaMCI and mdaMCI on the P3a ERP component associated with the involuntary orientation of attention toward unattended infrequent novel auditory stimuli. Participants performed an auditory visual distraction-attention task, in which they were asked to ignore the auditory stimuli (standard, deviant, and novel) and to attend to the visual stimuli (responding to some of them: Go stimuli). P3a was identified in the Novel minus Standard difference waveforms, and reaction times (RTs) and hits (in response to Go stimuli) were also analyzed. Participants were classified into three groups: Control, 20 adults (mean age (M): 65.8 years); sdaMCI, 19 adults (M: 67 years); and mdaMCI, 11 adults (M: 71 years). In all groups, the RTs were significantly longer when Go stimuli were preceded by novel (relative to standard) auditory stimuli, suggesting a distraction effect triggered by novel stimuli; mdaMCI participants made significantly fewer hits than control and sdaMCI participants. P3a comprised two consecutive phases in all groups: early P3a (e-P3a), which may reflect the orienting response toward the irrelevant stimuli, and late-P3a (l-P3a), which may be a correlate of subsequent evaluation of these stimuli. The e-P3a amplitude was significantly larger in mdaMCI than in sdaMCI participants, and the l-P3a amplitude was significantly larger in mdaMCI than in sdaMCI and Control participants, indicating greater involuntary capture of attention to unattended novel auditory stimuli and allocation of more attentional resources for the subsequent evaluation of these stimuli in mdaMCI participants. The e-P3a and l-P3a components showed moderate to high sensitivity and specificity for distinguishing between groups, suggesting that both may represent optimal neurocognitive markers for differentiating aMCI subtypes. PMID- 29483870 TI - Bayesian Optimization for Neuroimaging Pre-processing in Brain Age Classification and Prediction. AB - Neuroimaging-based age prediction using machine learning is proposed as a biomarker of brain aging, relating to cognitive performance, health outcomes and progression of neurodegenerative disease. However, even leading age-prediction algorithms contain measurement error, motivating efforts to improve experimental pipelines. T1-weighted MRI is commonly used for age prediction, and the pre processing of these scans involves normalization to a common template and resampling to a common voxel size, followed by spatial smoothing. Resampling parameters are often selected arbitrarily. Here, we sought to improve brain-age prediction accuracy by optimizing resampling parameters using Bayesian optimization. Using data on N = 2003 healthy individuals (aged 16-90 years) we trained support vector machines to (i) distinguish between young (<22 years) and old (>50 years) brains (classification) and (ii) predict chronological age (regression). We also evaluated generalisability of the age-regression model to an independent dataset (CamCAN, N = 648, aged 18-88 years). Bayesian optimization was used to identify optimal voxel size and smoothing kernel size for each task. This procedure adaptively samples the parameter space to evaluate accuracy across a range of possible parameters, using independent sub-samples to iteratively assess different parameter combinations to arrive at optimal values. When distinguishing between young and old brains a classification accuracy of 88.1% was achieved, (optimal voxel size = 11.5 mm3, smoothing kernel = 2.3 mm). For predicting chronological age, a mean absolute error (MAE) of 5.08 years was achieved, (optimal voxel size = 3.73 mm3, smoothing kernel = 3.68 mm). This was compared to performance using default values of 1.5 mm3 and 4mm respectively, resulting in MAE = 5.48 years, though this 7.3% improvement was not statistically significant. When assessing generalisability, best performance was achieved when applying the entire Bayesian optimization framework to the new dataset, out performing the parameters optimized for the initial training dataset. Our study outlines the proof-of-principle that neuroimaging models for brain-age prediction can use Bayesian optimization to derive case-specific pre-processing parameters. Our results suggest that different pre-processing parameters are selected when optimization is conducted in specific contexts. This potentially motivates use of optimization techniques at many different points during the experimental process, which may improve statistical sensitivity and reduce opportunities for experimenter-led bias. PMID- 29483867 TI - Ethnopharmacological Approaches for Dementia Therapy and Significance of Natural Products and Herbal Drugs. AB - Dementia is a clinical syndrome wherein gradual decline of mental and cognitive capabilities of an afflicted person takes place. Dementia is associated with various risk factors and conditions such as insufficient cerebral blood supply, toxin exposure, mitochondrial dysfunction, oxidative damage, and often coexisting with some neurodegenerative disorders such as Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD). Although there are well established (semi-)synthetic drugs currently used for the management of AD and AD associated dementia, most of them have several adverse effects. Thus, traditional medicine provides various plant-derived lead molecules that may be useful for further medical research. Herein we review the worldwide use of ethnomedicinal plants in dementia treatment. We have explored a number of recognized databases by using keywords and phrases such as "dementia", "Alzheimer's," "traditional medicine," "ethnopharmacology," "ethnobotany," "herbs," "medicinal plants" or other relevant terms, and summarized 90 medicinal plants that are traditionally used to treat dementia. Moreover, we highlight five medicinal plants or plant genera of prime importance and discuss the physiological effects, as well as the mechanism of action of their major bioactive compounds. Furthermore, the link between mitochondrial dysfunction and dementia is also discussed. We conclude that several drugs of plant origin may serve as promising therapeutics for the treatment of dementia, however, pivotal evidence for their therapeutic efficacy in advanced clinical studies is still lacking. PMID- 29483868 TI - Microglia Polarization, Gene-Environment Interactions and Wnt/beta-Catenin Signaling: Emerging Roles of Glia-Neuron and Glia-Stem/Neuroprogenitor Crosstalk for Dopaminergic Neurorestoration in Aged Parkinsonian Brain. AB - Neuroinflammatory processes are recognized key contributory factors in Parkinson's disease (PD) physiopathology. While the causes responsible for the progressive loss of midbrain dopaminergic (mDA) neuronal cell bodies in the subtantia nigra pars compacta are poorly understood, aging, genetics, environmental toxicity, and particularly inflammation, represent prominent etiological factors in PD development. Especially, reactive astrocytes, microglial cells, and infiltrating monocyte-derived macrophages play dual beneficial/harmful effects, via a panel of pro- or anti-inflammatory cytokines, chemokines, neurotrophic and neurogenic transcription factors. Notably, with age, microglia may adopt a potent neurotoxic, pro-inflammatory "primed" (M1) phenotype when challenged with inflammatory or neurotoxic stimuli that hamper brain's own restorative potential and inhibit endogenous neurorepair mechanisms. In the last decade we have provided evidence for a major role of microglial crosstalk with astrocytes, mDA neurons and neural stem progenitor cells (NSCs) in the MPTP- (1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine-) mouse model of PD, and identified Wnt/beta-catenin signaling, a pivotal morphogen for mDA neurodevelopment, neuroprotection, and neuroinflammatory modulation, as a critical actor in glia neuron and glia-NSCs crosstalk. With age however, Wnt signaling and glia-NSC neuron crosstalk become dysfunctional with harmful consequences for mDA neuron plasticity and repair. These findings are of importance given the deregulation of Wnt signaling in PD and the emerging link between most PD related genes, Wnt signaling and inflammation. Especially, in light of the expanding field of microRNAs and inflammatory PD-related genes as modulators of microglial proinflammatory status, uncovering the complex molecular circuitry linking PD and neuroinflammation will permit the identification of new druggable targets for the cure of the disease. Here we summarize recent findings unveiling major microglial inflammatory and oxidative stress pathways converging in the regulation of Wnt/beta-catenin signaling, and reciprocally, the ability of Wnt signaling pathways to modulate microglial activation in PD. Unraveling the key factors and conditons promoting the switch of the proinflammatory M1 microglia status into a neuroprotective and regenerative M2 phenotype will have important consequences for neuroimmune interactions and neuronal outcome under inflammatory and/or neurodegenerative conditions. PMID- 29483871 TI - A Novel Tetramethylpyrazine Derivative Prophylactically Protects against Glutamate-Induced Excitotoxicity in Primary Neurons through the Blockage of N Methyl-D-aspartate Receptor. AB - The over-activation of NMDA receptor via the excessive glutamate is believed to one of the most causal factors associated with Alzheimer's disease (AD), a progressive neurodegenerative brain disorder. Molecules that could protect against glutamate-induced neurotoxicity may hold therapeutic values for treating AD. Herein, the neuroprotective mechanisms of dimeric DT-010, a novel derivative of naturally occurring danshensu and tetramethylpyrazine, were investigated using primary rat cerebellar granule neurons (CGNs) and hippocampal neurons. It was found that DT-010 (3-30 MUM) markedly prevented excitotoxicity of CGNs caused by glutamate, as evidenced by the promotion of neuronal viability as well as the reversal of abnormal morphological changes. While its parent molecules did not show any protective effects even when their concentration reached 50 MUM. Additionally, DT-010 almost fully blocked intracellular accumulation of reactive oxygen species caused by glutamate and exogenous oxidative stimulus. Moreover, Western blot results demonstrated that DT-010 remarkably attenuated the inhibition of pro-survival PI3K/Akt/GSK3beta pathway caused by glutamate. Ca2+ imaging with Fluo-4 fluorescence analysis further revealed that DT-010 greatly declined glutamate-induced increase in intracellular Ca2+. Most importantly, with the use of whole-cell patch clamp electrophysiology, DT-010 directly inhibited NMDA-activated whole-cell currents in primary hippocampal neurons. Molecular docking simulation analysis further revealed a possible binding mode that inhibited NMDA receptor at the ion channel, showing that DT-010 favorably binds to Asn602 of NMDA receptor via arene hydrogen bond. These results suggest that DT 010 could be served as a novel NMDA receptor antagonist and protect against glutamate-induced excitotoxicity from blocking the upstream NMDA receptors to the subsequent Ca2+ influx and to the downstream GSK3beta cascade. PMID- 29483872 TI - Herbal Components of a Novel Formula PSORI-CM02 Interdependently Suppress Allograft Rejection and Induce CD8+CD122+PD-1+ Regulatory T Cells. AB - A recipient usually rejects a transplanted organ and thus needs immunosuppressive treatments to prevent rejection. Achieving long-term allograft survival without continuous global immunosuppression is highly desirable in transplantation as long-term immunosuppression causes various side effects. Therefore, it is necessary to search for medicine with potentially less side effects. Traditional Chinese medicine PSORI-CM01 (Yin Xie Ling), a formula with seven natural herbs, has been used to treat patients with psoriasis. Here, we investigated a "sharpened" formula, PSORI-CM02 consisting of only five herbs from PSORI-CM01: Curcumae rhizoma, Radix paeoniae rubra, Rhizoma smilacis glabrae, Mume fructus, and Sarcandrae herba. We examined whether or not PSORI-CM02 would suppress alloimmunity and found that PSORI-CM02 significantly inhibited murine skin allograft rejection and reduced graft-infiltration of CD3+ T cells. Interestingly, omitting any single herbal component rendered the whole formula ineffective in suppression, indicating that these herbal components exert their effects cooperatively as a whole. Moreover, PSORI-CM02 increased CD8+CD122+PD-1+ Treg frequency with CD4+FoxP3+ Tregs remaining unchanged in recipient mice, whereas CsA reduced CD4+FoxP3+ Treg frequency. PSORI-CM02 also hindered CD11c+ DC maturation posttransplantation. Importantly, PSORI-CM02-induced CD8+CD122+PD-1+ Tregs were more potent in suppression of allograft rejection in Rag-/- mice than control Tregs. On the other hand, PSORI-CM02 suppressed T cell proliferation in vitro and reduced their phosphorylation of P70S6K and P50/P65, suggesting that it inhibits both mTOR and NFkappaB signaling pathways. It also increased IL-10 production while reducing IFNgamma level in the supernatant of activated T cells co-cultured with CD8+CD122+PD-1+ Tregs. Furthermore, HPLC fingerprinting ruled out that PSORI-CM02 contained CsA or rapamycin. PSORI-CM02 also did not cause any illness and toxic injury in recipient mice. Thus, we demonstrate that PSORI-CM02 formula suppresses allograft rejection without toxicity. PMID- 29483873 TI - Usage of Mitogen-Activated Protein Kinase Small Molecule Inhibitors: More Than Just Inhibition! AB - We have identified a phenomenon occurring in the usage of proposed "specific" Mitogen-activated protein kinase (MAPK) inhibitors. We found that especially inhibitors of p38 potentiate the activation of other MAPKs in various cell types. This finding will have tremendous impact on the interpretation of all former studies using MAPK inhibitors. PMID- 29483875 TI - Macrophage Depletion Protects against Cigarette Smoke-Induced Inflammatory Response in the Mouse Colon and Lung. AB - Cigarette smoke (CS) is considered as a major risk factor for pulmonary and intestinal inflammation. CS leads to macrophage infiltration in the mucosae of the lung and colon, inducing the uncontrolled secretion of inflammatory mediators, and thus promoting inflammatory response. In this study, we investigated whether macrophage depletion modulates cigarette smoke (CS)-induced inflammatory response in both the lung and colon. The mice were exposed to CS for 30 min, after which they were rested in a fresh air environment for 30 min. The total duration of exposure to CS was 2 h per day for 4 weeks. Macrophage depletion state was made with the injection of clodronate containing liposome. Individual body weights were measured twice a week, and the mice were sacrificed on day 28. Hematoxylin and eosin (H&E) staining was performed in the lung and colon tissue to determine histological changes. Inflammatory mediators' synthesis was analyzed using ELISA and western blotting. Clodronate liposome treatment ameliorated pathological changes associated with the infiltration of immune cells in the lung and colon. Also, clodronate liposome injected mice showed significantly lower level of inflammatory mediators, including cytokines and chemokine and proteases. Our results indicated that macrophage depletion by clodronate liposome treatment attenuates CS-induced inflammatory response in both the lung and colon. PMID- 29483874 TI - Cardiac Autonomic Modulations and Psychological Correlates in the Yukon Arctic Ultra: The Longest and the Coldest Ultramarathon. AB - Studies on human physical performance in extreme environments have effectively approached the investigation of adaptation mechanisms and their physiological limits. As scientific interest in the interplay between physiological and psychological aspects of performance is growing, we aimed to investigate cardiac autonomic control, by means of heart rate variability, and psychological correlates, in competitors of a subarctic ultramarathon, taking place over a 690 km course (temperatures between +5 and -47 degrees C). At baseline (PRE), after 277 km (D1), 383 km (D2), and post-race (POST, 690 km), heart rate (HR) recordings (supine, 15 min), psychometric measurements (Profile of Mood States/POMS, Borg fatigue, and Karolinska Sleepiness Scale scores both upon arrival and departure) were obtained in 16 competitors (12 men, 4 women, 38.6 +/- 9.5 years). As not all participants reached the finish line, comparison of finishers (FIN, n = 10) and non-finishers (NON, n = 6), allowed differential assessment of performance. Resting HR increased overall significantly at D1 (FIN +15.9; NON +14.0 bpm), due to a significant decrease in parasympathetic drive. This decrease was in FIN only partially recovered toward POST. In FIN only, baseline HR was negatively correlated with mean velocity [r -0.63 (P.04)] and parasympathetic drive [pNN50+: r -0.67 (P.03)], a lower HR and a higher vagal tone predicting a better performance. Moreover, in FIN, a persistent increase of the long-term self-similarity coefficient, assessed by detrended fluctuation analysis (DFAalpha2), was retrieved, possibly due to higher alertness. As for psychometrics, at D1, POMS Vigor decreased (FIN: -7.0; NON: -3.8), while Fatigue augmented (FIN: +6.9; NON: +5.0). Sleepiness increased only in NON, while Borg scales did not exhibit changes. Baseline comparison of mood states with normative data for athletes displayed significantly higher positive mood in our athletes. Results show that: the race conditions induced early decreases in parasympathetic drive; the extent of vagal withdrawal, associated to the timing of its recovery, is crucial for success; pre-competition lower resting HR predicts a better performance; psychological profile is reliably depicted by POMS, but not by Borg fatigue scales. Therefore, assessment of heart rate variability and psychological profile may monitor and partly predict performance in long-duration ultramarathon in extreme cold environment. PMID- 29483876 TI - Pyridostigmine Improves the Effects of Resistance Exercise Training after Myocardial Infarction in Rats. AB - Myocardial infarction (MI) remains the leading cause of morbidity and mortality worldwide. Exercise training and pharmacological treatments are important strategies to minimize the deleterious effects of MI. However, little is known about the effects of resistance training combined with pyridostigmine bromide (PYR) treatment on cardiac and autonomic function, as well as on the inflammatory profile after MI. Thus, in the present study, male Wistar rats were randomly assigned into: control (Cont); sedentary infarcted (Inf); PYR - treated sedentary infarcted rats (Inf+P); infarcted rats undergoing resistance exercise training (Inf+RT); and infarcted rats undergoing PYR treatment plus resistance training (Inf+RT+P). After 12 weeks of resistance training (15-20 climbs per session, with a 1-min rest between each climb, at a low to moderate intensity, 5 days a week) and/or PYR treatment (0.14 mg/mL of drink water), hemodynamic function, autonomic modulation, and cytokine expressions were evaluated. We observed that 3 months of PYR treatment, either alone or in combination with exercise, can improve the deleterious effects of MI on left ventricle dimensions and function, baroreflex sensitivity, and autonomic parameters, as well as systemic and tissue inflammatory profile. Furthermore, additional benefits in a maximal load test and anti-inflammatory state of skeletal muscle were found when resistance training was combined with PYR treatment. Thus, our findings suggest that the combination of resistance training and PYR may be a good therapeutic strategy since they promote additional benefits on skeletal muscle anti-inflammatory profile after MI. PMID- 29483877 TI - Participation of Arachidonic Acid Metabolism in the Aortic Aneurysm Formation in Patients with Marfan Syndrome. AB - Marfan syndrome (MFS) is a pleiotropic genetic disease involving the cardiovascular system where a fibrillin-1 mutation is present. This mutation is associated with accelerated activation of transforming growth factor beta (TGFbeta1) which contributes to the formation of aneurysms in the root of the aorta. There is an imbalance in the synthesis of thromboxane A2 (TXA2) and prostacyclin, that is a consequence of a differential protein expression of the isoforms of cyclooxygenases (COXs), suggesting an alteration of arachidonic acid (AA) metabolism. The aim of this study was to analyze the participation of AA metabolism associated with inflammatory factors in the dilation and dissection of the aortic aneurysm in patients with MFS. A decrease in AA (p = 0.02), an increase in oleic acid (OA), TGFbeta1, tumor necrosis factor alpha (TNFalpha), prostaglandin E2 (PGE2) (p < 0.05), and COXs activity (p = 0.002) was found. The expressions of phospholipase A2 (PLA2), cytochrome P450 (CYP450 4A), 5 lipoxygenase (5-LOX), COX2 and TXA2R (p < 0.05) showed a significant increase in the aortic aneurysm of patients with MFS compared to control subjects. COX1, 6 keto-prostaglandin 1 alpha (6-keto-PG1alpha) and 8-isoprostane did not show significant changes. Histological examination of the aortas showed an increase of cystic necrosis, elastic fibers and collagen in MFS. The results suggest that there are inflammatory factors coupled to genetic factors that predispose to aortic endothelial dysfunction in the aortic tissue of patients with MFS. There is a decrease in the percentage of AA, associated with an increase of PLA2, COX2/TXA2R, CYP450 4A, and 5-LOX which leads to a greater synthesis of PGE2 than of 6-keto-PGF1alpha, thus contributing to the formation of the aortic aneurysm. The evident loss of the homeostasis in these mechanisms confirms that there is a participation of the AA pathway in the aneurysm progression in MFS. PMID- 29483878 TI - Salinity Effects on Strategies of Glycogen Utilization in Livers of Euryhaline Milkfish (Chanos chanos) under Hypothermal Stress. AB - The fluctuation of temperature affects many physiological responses in ectothermic organisms, including feed intake, growth, reproduction, and behavior. Changes in environmental temperatures affect the acquisition of energy, whereas hepatic glycogen plays a central role in energy supply for the homeostasis of the entire body. Glycogen phosphorylase (GP), which catalyzes the rate-limiting step in glycogenolysis, is also an indicator of environmental stress. Here, we examined the effects of salinity on glycogen metabolism in milkfish livers under cold stress. A reduction of feed intake was observed in both freshwater (FW) and seawater (SW) milkfish under cold adaptation. At normal temperature (28 degrees C), compared to the FW milkfish, the SW milkfish exhibited greater mRNA abundance of the liver isoform of GP (Ccpygl), higher GP activity, and less glycogen content in the livers. Upon hypothermal (18 degrees C) stress, hepatic Ccpygl mRNA expression of FW milkfish surged at 3 h, declined at 6 and 12 h, increased again at 24 h, and increased significantly after 96 h. Increases in GP protein, GP activity, and the phosphorylation state and the breakdown of glycogen were also found in FW milkfish livers after 12 h of exposure at 18 degrees C. Conversely, the Ccpygl transcript levels in SW milkfish were downregulated after 1 h of exposure at 18 degrees C, whereas the protein abundance of GP, GP activity, and glycogen content were not significantly altered. Taken together, under 18 degrees C cold stress, FW milkfish exhibited an acute response with the breakdown of hepatic glycogen for maintaining energy homeostasis of the entire body, whereas no change was observed in the hepatic glycogen content and GP activity of SW milkfish because of their greater tolerance to cold conditions. PMID- 29483879 TI - Effect of Inhaled Nebulized Furosemide (40 and 120 mg) on Breathlessness during Exercise in the Presence of External Thoracic Restriction in Healthy Men. AB - Inhalation of nebulized furosemide has been shown to alleviate breathlessness provoked experimentally in health and disease; however, it remains unclear whether the efficacy of nebulized furosemide on breathlessness is dose-dependent. We tested the hypothesis that inhaled nebulized furosemide would be associated with a dose-dependent relief of breathlessness during exercise testing in the setting of abnormal restrictive constraints on tidal volume (VT) expansion. In a randomized, double-blind, crossover study, 24 healthy men aged 25.3 +/- 1.2 years (mean +/- SE) completed a symptom-limited constant-load cycle endurance exercise test in the setting of external thoracic restriction via chest wall strapping to reduce vital capacity by ~20% following single-dose inhalation nebulized furosemide (40 and 120 mg) and 0.9% saline. Compared with 0.9% saline, neither 40 nor 120 mg of inhaled nebulized furosemide had an effect on ratings of perceived breathlessness during exercise or an effect on cardiometabolic, ventilatory, breathing pattern, or dynamic operating lung volume responses during exercise. Urine production rate, the percentage of participants reporting an "urge to urinate" and the intensity of perceived "urge to urinate" were all significantly greater after inhaling the 120 mg furosemide solution compared with both 0.9% saline and 40 mg furosemide solutions. We concluded that, under the experimental conditions of this study, inhalation of nebulized furosemide at doses of 40 and 120 mg did not alleviate breathlessness during exercise in healthy men. PMID- 29483881 TI - Phenotypic Modulation of Cultured Primary Human Aortic Vascular Smooth Muscle Cells by Uremic Serum. AB - Patients with chronic kidney disease (CKD) have a markedly increased incidence of cardiovascular disease (CVD). The high concentration of circulating uremic toxins and alterations in mineral metabolism and hormone levels produce vascular wall remodeling and significant vascular damage. Medial calcification is an early vascular event in CKD patients and is associated to apoptosis or necrosis and trans-differentiation of vascular smooth muscle cells (VSMC) to an osteogenic phenotype. VSMC obtained from bovine or rat aorta and cultured in the presence of increased inorganic phosphate (Pi) have been extensively used to study these processes. In this study we used human aortic VSMC primary cultures to compare the effects of increased Pi to treatment with serum obtained from uremic patients. Uremic serum induced calcification, trans-differentiation and phenotypic remodeling even with normal Pi levels. In spite of similar calcification kinetics, there were fundamental differences in osteochondrogenic marker expression and alkaline phosphatase induction between Pi and uremic serum treated cells. Moreover, high Pi induced a dramatic decrease in cell viability, while uremic serum preserved it. In summary, our data suggests that primary cultures of human VSMC treated with serum from uremic patients provides a more informative model for the study of vascular calcification secondary to CKD. PMID- 29483880 TI - Glial Cells in the Genesis and Regulation of Circadian Rhythms. AB - Circadian rhythms are biological oscillations with a period of ~24 h. These rhythms are orchestrated by a circadian timekeeper in the suprachiasmatic nucleus of the hypothalamus, the circadian "master clock," which exactly adjusts clock outputs to solar time via photic synchronization. At the molecular level, circadian rhythms are generated by the interaction of positive and negative feedback loops of transcriptional and translational processes of the so-called "clock genes." A large number of clock genes encode numerous proteins that regulate their own transcription and that of other genes, collectively known as "clock-controlled genes." In addition to the sleep/wake cycle, many cellular processes are regulated by circadian rhythms, including synaptic plasticity in which an exquisite interplay between neurons and glial cells takes place. In particular, there is compelling evidence suggesting that glial cells participate in and regulate synaptic plasticity in a circadian fashion, possibly representing the missing cellular and physiological link between circadian rhythms with learning and cognition processes. Here we review recent studies in support of this hypothesis, focusing on the interplay between glial cells, synaptic plasticity, and circadian rhythmogenesis. PMID- 29483882 TI - Fluid Metabolism in Athletes Running Seven Marathons in Seven Consecutive Days. AB - Purpose: Hypohydration and hyperhydration are significant disorders of fluid metabolism in endurance performance; however, little relevant data exist regarding multi-stage endurance activities. The aim of the present study was to examine the effect of running seven marathons in 7 consecutive days on selected anthropometric, hematological and biochemical characteristics with an emphasis on hydration status. Methods: Participants included 6 women and 20 men (age 42.6 +/- 6.2 years). Data was collected before day 1 (B1) and after day 1 (A1), 4 (A4), and 7 (A7). Results: The average marathon race time was 4:44 h:min (ranging from 3:09 - 6:19 h:min). Plasma sodium, plasma potassium and urine sodium were maintained during the race. Body mass (p < 0.001, eta2 = 0.501), body fat (p < 0.001, eta2 = 0.572) and hematocrit (p < 0.001, eta2 = 0.358) decreased. Plasma osmolality (Posm) (p < 0.001, eta2 = 0.416), urine osmolality (Uosm) (p < 0.001, eta2 = 0.465), urine potassium (p < 0.001, eta2 = 0.507), urine specific gravity (Usg) (p < 0.001, eta2 = 0.540), plasma urea (PUN) (p < 0.001, eta2 = 0.586), urine urea (UUN) (p < 0.001, eta2 = 0.532) and transtubular potassium gradient (p < 0.001, eta2 = 0.560) increased at A1, A4, and A7 vs. B1. Posm correlated with PUN at A1 (r = 0.59, p = 0.001) and A4 (r = 0.58, p = 0.002). The reported post race fluid intake was 0.5 +/- 0.2 L/h and it correlated negatively with plasma [Na+] (r = -0.42, p = 0.007) at A4 and (r = -0.50, p = 0.009) at A7. Uosm was associated with UUN at A1 (r = 0.80, p < 0.001), at A4 (r = 0.81, p < 0.001) and at A7 (r = 0.86, p < 0.001) and with Usg (r = 0.71, p < 0.001) at A1, (r = 0.52, p = 0.006) at A4 and (r = 0.46, p = 0.02) at A7. Conclusions: Despite the decrease in body mass, fluid and electrolyte balance was maintained with no decrease in plasma volume after running seven marathons in seven consecutive days. Current findings support the hypothesis that body mass changes do not reflect changes in the hydration status during prolonged exercise. PMID- 29483883 TI - Adipsin Concentrations Are Associated with Back Pain Independently of Adiposity in Overweight or Obese Adults. AB - Objective: To compare cardiometabolic risk factors including cytokine and adipokine concentrations between individuals with and without back pain. Methods: In 62 overweight/obese adults (BMI >= 25 kg/m2; 23F/39M), we collected data on: self-reported back pain; anthropometry [BMI, waist circumference, body composition (dual energy X-ray absorptiometry-DEXA)]; metabolic parameters [fasting glucose; insulin sensitivity (hyperinsulinaemic-euglycaemic clamps)]; cardiovascular parameters (blood pressure, lipids); serum inflammation markers [high-sensitivity C-reactive protein (hsCRP; immunoturbidimetric-assay), tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and IL-10 (multiplex assay)]; and adipokines [leptin, adipsin, resistin, and adiponectin (multiplex assay)]. Results: Participants who reported having back pain in the past month (n = 24; 39%) had higher BMI (mean +/- SD = 33.8 +/- 6.3 vs. 30.2 +/- 4.1 kg/m2, p = 0.008), fat-mass (39.9 +/- 12.3 vs. 33.9 +/- 9.8%, p = 0.04), and waist circumference (109.6 +/- 16.8 vs. 101.0 +/- 9.3 cm, p = 0.01) compared to those without back pain (n = 38; 61%). No differences were observed in cardiometabolic parameters, inflammatory markers, or adiponectin or resistin concentrations. Those reporting back pain had higher adipsin concentrations compared to those without back pain [median (IQR) = 744 (472-2,804) vs. 721 (515-867) ng/ml, p = 0.03], with a trend for higher leptin [5.5 (1.5-24.3) vs. 2.3 (1.5-6.7) ng/ml, p = 0.05], both of which persisted after adjustment for age and sex. Adipsin remained associated with back pain independently of adiposity (BMI, waist, fat mass, or total %body fat; all p <= 0.03). Conclusions: Greater obesity, and higher adipsin and leptin concentrations were observed in those who reported back pain in the past month compared to those without back pain, and adipsin was associated with back pain independently of adiposity. Larger studies are needed to determine if adipsin could be a novel therapeutic target for prevention and/or treatment of back pain. PMID- 29483884 TI - Opioid Overdose Education for Individuals Prescribed Opioids for Pain Management: Randomized Comparison of Two Computer-Based Interventions. AB - Background: Opioid overdose (OD) rates in the United States have reached unprecedented levels. Current OD prevention strategies largely consist of distribution of naloxone and in-person trainings, which face obstacles to expedient, widespread dissemination. Web-based interventions have increased opioid-OD response knowledge in patients with opioid-use disorders; however, these interventions have not been tested in the larger population of individuals that are prescribed opioid analgesics. This study assessed a web-based intervention providing education across three knowledge domains: opioid effects, opioid-OD symptoms, and opioid-OD response. Methods: Participants (N = 197) were adults recruited on Amazon Mechanical Turk from May to June 2017, who were prescribed an opioid medication for pain. Participants were randomly assigned to a Presentation (n = 97) intervention communicating relevant facts in each knowledge domain, or a Presentation + Mastery (n = 100) intervention including the same facts but requiring that participants respond correctly to >=80% of embedded questions in each module before advancing. Participants completed the Brief Opioid Overdose Knowledge (BOOK) measure before and after the interventions, and provided feedback on acceptability. Results: Both versions of the intervention resulted in significant pre to postintervention increases in BOOK scores across all knowledge domains (p < 0.001), with no significant knowledge differences between groups. The Presentation intervention took significantly less time to complete (p < 0.001) and was completed by significantly more participants than the Presentation + Mastery intervention (p < 0.001). Most participants rated both interventions as highly acceptable. Conclusion: Results replicate a previous study (1) and suggest the web-based Presentation intervention may be a convenient, cost-effective method for disseminating crucial public health information for preventing opioid OD. PMID- 29483885 TI - Causal Cognition, Force Dynamics and Early Hunting Technologies. AB - With this contribution we analyze ancient hunting technologies as one way to explore the development of causal cognition in the hominin lineage. Building on earlier work, we separate seven grades of causal thinking. By looking at variations in force dynamics as a central element in causal cognition, we analyze the thinking required for different hunting technologies such as stabbing spears, throwing spears, launching atlatl darts, shooting arrows with a bow, and the use of poisoned arrows. Our interpretation demonstrates that there is an interplay between the extension of human body through technology and expanding our cognitive abilities to reason about causes. It adds content and dimension to the trend of including embodied cognition in evolutionary studies and in the interpretation of the archeological record. Our method could explain variation in technology sets between archaic and modern human groups. PMID- 29483886 TI - Are Psychotic Experiences Related to Poorer Reflective Reasoning? AB - Background: Cognitive biases play an important role in the formation and maintenance of delusions. These biases are indicators of a weak reflective mind, or reduced engaging in reflective and deliberate reasoning. In three experiments, we tested whether a bias to accept non-sense statements as profound, treat metaphorical statements as literal, and suppress intuitive responses is related to psychotic-like experiences. Methods: We tested deliberate reasoning and psychotic-like experiences in the general population and in patients with a former psychotic episode. Deliberate reasoning was assessed with the bullshit receptivity scale, the ontological confabulation scale and the cognitive reflection test (CRT). We also measured algorithmic performance with the Berlin numeracy test and the wordsum test. Psychotic-like experiences were measured with the Community Assessment of Psychic Experience (CAPE-42) scale. Results: Psychotic-like experiences were positively correlated with a larger receptivity toward bullshit, more ontological confabulations, and also a lower score on the CRT but not with algorithmic task performance. In the patient group higher psychotic-like experiences significantly correlated with higher bullshit receptivity. Conclusion: Reduced deliberate reasoning may contribute to the formation of delusions, and be a general thinking bias largely independent of a person's general intelligence. Acceptance of bullshit may be facilitated the more positive symptoms a patient has, contributing to the maintenance of the delusions. PMID- 29483887 TI - How Much Do Adolescents Cybergossip? Scale Development and Validation in Spain and Colombia. AB - Cybergossip is the act of two or more people making evaluative comments via digital devices about somebody who is not present. This cyberbehavior affects the social group in which it occurs and can either promote or hinder peer relationships. Scientific studies that assess the nature of this emerging and interactive behavior in the virtual world are limited. Some research on traditional gossip has identified it as an inherent and defining element of indirect relational aggression. This paper adopts and argues for a wider definition of gossip that includes positive comments and motivations. This work also suggests that cybergossip has to be measured independently from traditional gossip due to key differences when it occurs through ICT. This paper presents the Colombian and Spanish validation of the Cybergossip Questionnaire for Adolescents (CGQ-A), involving 3,747 high school students (M = 13.98 years old, SD = 1.69; 48.5% male), of which 1,931 were Colombian and 1,816 were Spanish. Test models derived from item response theory, confirmatory factor analysis, content validation, and multi-group analysis were run on the full sample and subsamples for each country and both genders. The obtained optimal fit and psychometric properties confirm the robustness and suitability of a one-dimensional structure for the cybergossip instrument. The multi-group analysis shows that the cybergossip construct is understood similarly in both countries and between girls and boys. The composite reliability ratifies convergent and divergent validity of the scale. Descriptive results show that Colombian adolescents gossip less than their Spanish counterparts and that boys and girls use cybergossip to the same extent. As a conclusion, this study confirmes the relationship between cybergossip and cyberbullying, but it also supports a focus on positive cybergossip in psychoeducational interventions to build positive virtual relationships and prevent risky cyberbehaviors. PMID- 29483888 TI - Fighting Depression: Action Video Game Play May Reduce Rumination and Increase Subjective and Objective Cognition in Depressed Patients. AB - Cognitive deficits are common in depression and may persist following the resolution of affective symptoms. However, therapeutic strategies that successfully target cognitive impairments are lacking. Recent work has demonstrated that playing action video games leads to improvements in cognition, in particular executive function, in healthy individuals. We therefore set out to test whether playing video games can reduce symptoms associated with depression. We focussed on depressive symptoms and on rumination, since rumination is a good predictor of depression and may contribute to triggering depression. We recruited 68 clinically depressed individuals (mean age: 46 years, 47 females) that were randomized into the training group playing a fast paced action video game for 6 weeks or a waitlist control group. Before and after training participants completed online questionnaires and a neuropsychological test battery. Only participants who actually played the game were included in the analysis. The final sample consisted of n = 21 training group and n = 29 waitlist control group. The training group showed significantly higher subjective cognitive ability, as well as lower self-reported rumination at posttest in contrast to the control group (although these findings do not survive Bonferroni correction). On a subsample with cognitive performance data (n = 19) we detected an improvement in executive function (Trail Making Task A and B) in the training compared with the control group. The results show that the fast paced action video game employed in the present study improved Trail Making performance and may reduce rumination and enhance subjective cognitive ability. Future research may focus on the investigation of the precise cognitive profile of effects. PMID- 29483889 TI - Perspective: Stepping Stones to Unraveling the Pathophysiology of Mal de Debarquement Syndrome with Neuroimaging. AB - Mal de debarquement syndrome (MdDS) is a neurological condition typically characterized by a sensation of motion, which in most cases manifests after disembarking from a vehicle (e.g., boat, plane, and car). However, the same symptoms can also occur spontaneously. Two main theories of the pathophysiology of MdDS are briefly summarized here. In this perspective, we aimed to report the most recent findings on neuroimaging studies related to MdDS, as well as to suggest further potential research questions that could be addressed with the use of neuroimaging techniques. A detailed analysis of previous work on MdDS has led to five main research questions that could be addressed in new neuroimaging studies. Furthermore, in this perspective, we propose new stepping-stones to addressing critical research questions related to MdDS and its pathophysiology. We propose considerations for new studies, as well as a detailed analysis of the current limitations and challenges present when studying MdDS patients. We hope that our examination of the nuances of MdDS as a neurological disorder will contribute to more directed research on this topic. PMID- 29483890 TI - Microangiopathy-A Potential Contributing Factor to Idiopathic Polyneuropathy: A Mini Review. AB - Chronic idiopathic axonal polyneuropathy (CIAP) is a slowly progressive predominantly sensory axonal polyneuropathy. The prevalence of CIAP increases with age. The pathogenic cause of CIAP is unknown although there are several prevailing etiological hypotheses. In this mini review, we focus on the hypothesis of disturbed microcirculation in the vasa nervorum of peripheral nerves as a pathogenic cause of CIAP. There is an association between CIAP and metabolic risk factors. Furthermore, the phenotype of CIAP resembles diabetic neuropathy both clinically and electrophysiologically. In sural nerve biopsies from patients with diabetes mellitus, structural abnormalities indicating microangiopathy in the endoneurial microvessels are well documented. Similarly, sural microvessel abnormalities have been shown in patients with atherosclerotic non-diabetic peripheral vascular disease. However, the reported histopathological alterations of microvasculature in sural nerves of CIAP patients are inconsistent. Two studies report microangiopathic changes in CIAP sural nerves comparable with those found in patients with diabetic neuropathy. Conversely, another recent study showed no significant differences in the microangiopathic parameters in the endoneurial microvessels in the sural nerve biopsies from CIAP patients compared to controls without polyneuropathy. However, this CIAP patient group was younger compared to the patient groups in the other two studies. A general limitation with the published morphological studies are that different methods have been used in the assessment of microangiopathy, and there is also a risk of subjectivity in the results. Immunohistochemistry studies of sural nerves with verification of microangiopathy using specific biomarkers would be of great interest to develop. PMID- 29483891 TI - Effects of Head Position on Perception of Gravity in Vestibular Neuritis and Lateral Medullary Infarction. AB - Objective: Internal representation of gravity can be quantified by measuring the subjective visual vertical (SVV). Modulation of verticality perception during head tilts may be perturbed in vestibular disorders causing SVV tilts in the upright head position. This study aimed to determine the influence of head tilts on the estimation of SVV in acute vestibular disorders. Methods: We measured the SVV in 37 patients with acute vestibular symptoms due to unilateral vestibular neuritis (VN) (n = 28) and lateral medullary infarction (LMI) (n = 9). Measurements of the SVV were performed under head upright, head tilt 30 degrees and 60 degrees in each direction. Seventeen normal subjects served as the control. Results: In controls, head tilt of 30 degrees produced a contraversive shift of the SVV (the E-effect), and head tilt of 60 degrees generated an ipsiversive shift (the A-effect). Patients with VN showed only the A-effect irrespective of the direction and amplitude of head tilt. Patients with LMI could estimate earth verticality accurately during head tilts. Patients with VN during the recovery phase showed the patterns of SVV modulation similar to those observed in the controls either with head upright or tilted. Conclusion: Given the absence of the E-effect in acute VN, the peripheral otolithic inputs appear to be essential in the perception of earth vertical during small static head tilts. PMID- 29483892 TI - Efficacy of Modified Atkins Ketogenic Diet in Chronic Cluster Headache: An Open Label, Single-Arm, Clinical Trial. AB - Introduction: Drug-resistant cluster headache (CH) is still an open clinical challenge. Recently, our group observed the clinical efficacy of a ketogenic diet (KD), usually adopted to treat drug-resistant epilepsies, on migraine. Aim: Here, we aim to detect the effect of KD in a group of drug-resistant chronic CH (CCH) patients. Materials and methods: Eighteen drug-resistant CCH patients underwent a 12-week KD (Modified Atkins Diet, MAD), and the clinical response was evaluated in terms of response (>=50% attack reduction). Results: Of the 18 CCH patients, 15 were considered responders to the diet (11 experienced a full resolution of headache, and 4 had a headache reduction of at least 50% in terms of mean monthly number of attacks during the diet). The mean monthly number of attacks for each patient at the baseline was 108.71 (SD = 81.71); at the end of the third month of diet, it was reduced to 31.44 (SD = 84.61). Conclusion: We observed for the first time that a 3-month ketogenesis ameliorates clinical features of CCH. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03244735. PMID- 29483893 TI - Mathematical Methods for Measuring the Visually Enhanced Vestibulo-Ocular Reflex and Preliminary Results from Healthy Subjects and Patient Groups. AB - Background: Visually enhanced vestibulo-ocular reflex (VVOR) is a well-known bedside clinical test to evaluate visuo-vestibular interaction, with clinical applications in patients with neurological and vestibular dysfunctions. Owing to recently developed diagnostic technologies, the possibility to perform an easy and objective measurement of the VVOR has increased, but there is a lack of computational methods designed to obtain an objective VVOR measurement. Objectives: To develop a method for the assessment of the VVOR to obtain a gain value that compares head and eye velocities and to test this method in patients and healthy subjects. Methods: Two computational methods were developed to measure the VVOR test responses: the first method was based on the area under curve of head and eye velocity plots and the second method was based on the slope of the linear regression obtained for head and eye velocity data. VVOR gain and vestibulo-ocular reflex (VOR) gain were analyzed with the data obtained from 35 subjects divided into four groups: healthy (N = 10), unilateral vestibular with vestibular neurectomy (N = 8), bilateral vestibulopathy (N = 12), and cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) (N = 5). Results: Intra-class correlation index for the two developed VVOR analysis methods was 0.99. Statistical differences were obtained by analysis of variance statistical method, comparing the healthy group (VVOR mean gain of 1 +/- 0) with all other groups. The CANVAS group exhibited (VVOR mean gain of 0.4 +/- 0.1) differences when compared to all other groups. VVOR mean gain for the vestibular bilateral group was 0.8 +/- 0.1. VVOR mean gain in the unilateral group was 0.6 +/- 0.1, with a Pearson's correlation of 0.52 obtained when VVOR gain was compared to the VOR gain of the operated side. Conclusion: Two computational methods to measure the gain of VVOR were successfully developed. The VVOR gain values appear to objectively characterize the VVOR alteration observed in CANVAS patients, and also distinguish between healthy subjects and patients with some vestibular disorders. PMID- 29483894 TI - Clinical Characteristics of Wolfram Syndrome in Chinese Population and a Novel Frameshift Mutation in WFS1. AB - Objective: Wolfram syndrome (WS) is a rare, degenerative, and hereditary disorder characterized by ear diabetes mellitus (DM) and optic atrophy (OA). We aim to characterize clinical features in Chinese patients who had been poorly studied until now. Methods: We performed a retrospective review of patients with WS seen in the Peking Union Medical College Hospital from 2002 to 2017. Data including demographic data, clinical presentations, examination results, family history, and genetic analysis were described. Results: Six patients with WS were identified, meeting the diagnostic criteria of the coincidence of DM and OA before 15 years old or the existence of two WFS1 mutations. All were male, with the median age of 14.5 years (range 10-19 years). Blood glucose impairment, OA, and diabetes insipidus were present in all (100%), hearing impairment in four (66.7%), urological abnormalities in four (66.7%), neurological abnormalities in one (16.7%), and endocrine disorder in one (16.7%). Rare presentation includes cataract, glaucoma, and spina bifida occulta. Diabetes was insulin-dependent and not ketosis onset, with antibody to glutamic acid decarboxylase and islet cell negative. Genetic analysis revealed mutations in WFS1 in three patients. A novel frameshift mutation (p.Asp151Glufs*93) was identified in exon 4 of WFS1. Conclusion: Our series of WS patients indicated that WS is a degenerative disease with a wide and variable spectrum, characterized by ear non-autoimmune DM and bilateral OA. Genetic analysis is recommended when suspected of WS. PMID- 29483895 TI - Involvement of Corticotropin-Releasing Factor and Receptors in Immune Cells in Irritable Bowel Syndrome. AB - Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder defined by ROME IV criteria as pain in the lower abdominal region, which is associated with altered bowel habit or defecation. The underlying mechanism of IBS is not completely understood. IBS seems to be a product of interactions between various factors with genetics, dietary/intestinal microbiota, low-grade inflammation, and stress playing a key role in the pathogenesis of this disease. The crosstalk between the immune system and stress in IBS mechanism is increasingly recognized. Corticotropin-releasing factor (CRF), a major mediator in the stress response, is involved in altered function in GI, including inflammatory processes, colonic transit time, contractile activity, defecation pattern, pain threshold, mucosal secretory function, and barrier functions. This mini review focuses on the recently establish local GI-CRF system, its involvement in modulating the immune response in IBS, and summarizes current IBS animal models and mapping of CRF, CRFR1, and CRFR2 expression in colon tissues. CRF and receptors might be a key molecule involving the immune and movement function via brain-gut axis in IBS. PMID- 29483897 TI - A Comprehensive Overview of the Cyclodipeptide Synthase Family Enriched with the Characterization of 32 New Enzymes. AB - Cyclodipeptide synthases (CDPSs) use as substrates two amino acids activated as aminoacyl-tRNAs to synthesize cyclodipeptides in secondary metabolites biosynthetic pathways. Since the first description of a CDPS in 2002, the number of putative CDPSs in databases has increased exponentially, reaching around 800 in June 2017. They are likely to be involved in numerous biosynthetic pathways but the diversity of their products is still under-explored. Here, we describe the activity of 32 new CDPSs, bringing the number of experimentally characterized CDPSs to about 100. We detect 16 new cyclodipeptides, one of which containing an arginine which has never been observed previously. This brings to 75 the number of cyclodipeptides formed by CDPSs out of the possible 210 natural ones. We also identify several consensus sequences related to the synthesis of a specific cyclodipeptide, improving the predictive model of CDPS specificity. The improved prediction method enables to propose the main product synthesized for about 80% of the CDPS sequences available in databases and opens the way for the deciphering of CDPS-dependent pathways. Analysis of phylum distribution and predicted activity for all CDPSs identified in databases shows that the experimentally characterized set is representative of the whole family. Our work also demonstrates that some cyclodipeptides, precursors of diketopiperazines with interesting pharmacological properties and previously described as being synthesized by fungal non-ribosomal peptide synthetases, can also be produced by CDPSs in bacteria. PMID- 29483896 TI - Association between Serum Cholesterol Level and Osteoporotic Fractures. AB - Objective: Previous epidemiological studies have found an association between serum cholesterol level and bone mineral density. However, epidemiological studies evaluating the association between serum cholesterol level and the incidence of osteoporotic fracture are scant. Therefore, the objective of this study was to investigate whether serum cholesterol levels in Chinese participants aged 55 years or older was associated with an increased risk of osteoporotic fracture. Materials and methods: We performed a cross-sectional study, including 1,791 participants (62.1% postmenopausal women and 213 fractures). Standardized self-administered questionnaires, physical examination, laboratory tests, and dual-energy X-ray absorptiometry examination were performed. Multivariate adjusted logistic regression models were used to evaluate associations between serum cholesterol [total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL-C), and low-density lipoprotein (LDL-C)] levels and the osteoporotic fracture risk. Results: After adjusting for potential confounding factors, there were no associations between per SD increase in TC and LDL level and an increased risk of osteoporotic fracture in total participants, and in men and women as individual groups. There was a significant association between per SD increase in HDL-C level and an increased risk of osteoporotic fracture in total participants [odds ratios (OR) 1.20, 95% confidence interval (CI) 1.03, 1.40, P = 0.023] and in women (OR 1.37, 95% CI 1.12, 1.68, P = 0.003), whereas no association was observed in men (OR 1.01, 95% CI 0.73, 1.40, P = 0.951). Additionally, we found a significant association between per SD increase in TG level and an increased risk of osteoporotic fracture in total participants (OR 1.20, 95% CI 1.04, 1.38, P = 0.015). In women, a nonlinear relationship was observed between per SD increase in TG level and an increased risk of osteoporotic fracture. The risk of osteoporotic fracture in women increased with TG level >1.64 mmol/L (OR 1.93, 95% CI 1.24, 3.00, P = 0.004). Conclusion: Among Chinese older adults, serum HDL-C level is significantly associated with a risk of osteoporotic fractures in women, and serum TG level is significantly associated with a risk of osteoporotic fractures in total participants and in women with TG >1.64 mmol/L. PMID- 29483898 TI - Competitive Traits Are More Important than Stress-Tolerance Traits in a Cadmium Contaminated Rhizosphere: A Role for Trait Theory in Microbial Ecology. AB - Understanding how biotic and abiotic factors govern the assembly of rhizosphere microbial communities is a long-standing goal in microbial ecology. In phytoremediation research, where plants are used to remediate heavy metal contaminated soils, a deeper understanding of rhizosphere-microbial ecology is needed to fully exploit the potential of microbial-assisted phytoremediation. This study investigated whether Grime's competitor/stress-tolerator/ruderal (CSR) theory could be used to describe the impact of cadmium (Cd) and the presence of a Cd-accumulating plant, Carpobrotus rossii (Haw.) Schwantes, on the assembly of soil-bacterial communities using Illumina 16S rRNA profiling and the predictive metagenomic-profiling program, PICRUSt. Using predictions based on CSR theory, we hypothesized that Cd and the presence of a rhizosphere would affect community assembly. We predicted that the additional resource availability in the rhizosphere would enrich for competitive life strategists, while the presence of Cd would select for stress-tolerators. Traits identified as competitive followed CSR predictions, discriminating between rhizosphere and bulk-soil communities whilst stress-tolerance traits increased with Cd dose, but only in bulk-soil communities. These findings suggest that a bacterium's competitive attributes are critical to its ability to occupy and proliferate in a Cd-contaminated rhizosphere. Ruderal traits, which relate to community re-colonization potential, were synergistically decreased by the presence of the rhizosphere and Cd dose. Taken together this microcosm study suggests that the CSR theory is broadly applicable to microbial communities. Further work toward developing a simplified and robust strategy for microbial CSR classification will provide an ecologically meaningful framework to interpret community-level changes across a range of biomes. PMID- 29483899 TI - Growth Rate and Biofilm Formation Ability of Clinical and Laboratory-Evolved Colistin-Resistant Strains of Acinetobacter baumannii. AB - Two different mechanisms of resistance to colistin in Acinetobacter baumannii have been described. The first involves the total loss of lipopolysaccharide (LPS) due to mutations in the lpxACD operon, which is involved in the lipid A biosynthesis pathway. The second entails the addition of ethanolamine to the lipid A of the LPS resulting from mutations in the PmrAB two-component system. To evaluate the impact of colistin resistance-associated mutations on antimicrobial resistance and virulence properties, four pairs of clinical and laboratory evolved colistin-susceptible/colistin-resistant (ColS/ColR) A. baumannii isolates were used. Antimicrobial susceptibility, surface motility, in vitro and in vivo biofilm-forming capacity, in vitro and in vivo expression levels of biofilm associated genes, and in vitro growth rate were analyzed in these strains. Growth rate, in vitro and in vivo biofilm formation ability, as well as expression levels of biofilm-associated gene were reduced in ColR LPS-deficient isolate (the lpxD mutant) when compared with its ColS partner, whereas there were not such differences between LPS-modified isolates (the pmrB mutants) and their parental isolates. Mutation in lpxD was accompanied by a greater reduction in minimum inhibitory concentrations of azithromycin, vancomycin, and rifampin than mutation in pmrB. Besides, loss of LPS was associated with a significant reduction in surface motility without any change in expression of type IV pili. Collectively, colistin resistance through loss of LPS causes a more considerable cost in biological features such as growth rate, motility, and biofilm formation capacity relative to LPS modification. Therefore, ColR LPS-modified strains are more likely to spread and transmit from one patient to another in hospital settings, which results in more complex treatment and control. PMID- 29483900 TI - Recent Developments of the Synthetic Biology Toolkit for Clostridium. AB - The Clostridium genus is a large, diverse group consisting of Gram-positive, spore-forming, obligate anaerobic firmicutes. Among this group are historically notorious pathogens as well as several industrially relevant species with the ability to produce chemical commodities, particularly biofuels, from renewable biomass. Additionally, other species are studied for their potential use as therapeutics. Although metabolic engineering and synthetic biology have been instrumental in improving product tolerance, titer, yields, and feed stock consumption capabilities in several organisms, low transformation efficiencies and lack of synthetic biology tools and genetic parts make metabolic engineering within the Clostridium genus difficult. Progress has recently been made to overcome challenges associated with engineering various Clostridium spp. For example, developments in CRISPR tools in multiple species and strains allow greater capability to produce edits with greater precision, faster, and with higher efficiencies. In this mini-review, we will highlight these recent advances and compare them to established methods for genetic engineering in Clostridium. In addition, we discuss the current state and development of Clostridium-based promoters (constitutive and inducible) and reporters. Future progress in this area will enable more rapid development of strain engineering, which would allow for the industrial exploitation of Clostridium for several applications including bioproduction of several commodity products. PMID- 29483901 TI - Rewriting the Metabolic Blueprint: Advances in Pathway Diversification in Microorganisms. AB - Living organisms have evolved over millions of years to fine tune their metabolism to create efficient pathways for producing metabolites necessary for their survival. Advancement in the field of synthetic biology has enabled the exploitation of these metabolic pathways for the production of desired compounds by creating microbial cell factories through metabolic engineering, thus providing sustainable routes to obtain value-added chemicals. Following the past success in metabolic engineering, there is increasing interest in diversifying natural metabolic pathways to construct non-natural biosynthesis routes, thereby creating possibilities for producing novel valuable compounds that are non natural or without elucidated biosynthesis pathways. Thus, the range of chemicals that can be produced by biological systems can be expanded to meet the demands of industries for compounds such as plastic precursors and new antibiotics, most of which can only be obtained through chemical synthesis currently. Herein, we review and discuss novel strategies that have been developed to rewrite natural metabolic blueprints in a bid to broaden the chemical repertoire achievable in microorganisms. This review aims to provide insights on recent approaches taken to open new avenues for achieving biochemical production that are beyond currently available inventions. PMID- 29483902 TI - Community Composition of Nitrous Oxide-Related Genes in Salt Marsh Sediments Exposed to Nitrogen Enrichment. AB - Salt marshes provide many key ecosystem services that have tremendous ecological and economic value. One critical service is the removal of fixed nitrogen from coastal waters, which limits the negative effects of eutrophication resulting from increased nutrient supply. Nutrient enrichment of salt marsh sediments results in higher rates of nitrogen cycling and, commonly, a concurrent increase in the flux of nitrous oxide, an important greenhouse gas. Little is known, however, regarding controls on the microbial communities that contribute to nitrous oxide fluxes in marsh sediments. To address this disconnect, we generated profiles of microbial communities and communities of micro-organisms containing specific nitrogen cycling genes that encode several enzymes (amoA, norB, nosZ) related to nitrous oxide flux from salt marsh sediments. We hypothesized that communities of microbes responsible for nitrogen transformations will be structured by nitrogen availability. Taxa that respond positively to high nitrogen inputs may be responsible for the elevated rates of nitrogen cycling processes measured in fertilized sediments. Our data show that, with the exception of ammonia-oxidizing archaea, the community composition of organisms involved in the production and consumption of nitrous oxide was altered under nutrient enrichment. These results suggest that previously measured rates of nitrous oxide production and consumption are likely the result of changes in community structure, not simply changes in microbial activity. PMID- 29483903 TI - Prolactin and Autoimmunity. AB - The great asymmetry of autoimmune diseases between genders represents one of the most enigmatic observations among the mosaic of autoimmunity. Sex hormones are believed to play a crucial role on this dimorphism. The higher prevalence of autoimmunity among women at childbearing ages, disease onset/relapses during pregnancy, and post-partum are some of the arguments that support this hypothesis. Certainly, motherhood represents one of the most remarkable challenges for the immune system, which not only has to allow for the conceptus, but also has to deal with complex endocrine alterations. Hormonal homeostasis is known to exert a crucial influence in achieving a competent and healthy immune system. Prolactin (PRL) has a bioactive function acting as a hormone and a cytokine. It interferes with immune system modulation, mainly inhibiting the negative selection of autoreactive B lymphocytes. Likewise, hyperprolactinemia has been described in relation to the pathogenesis and activity of several autoimmune disorders. Dopamine is an effective inhibitor of PRL secretion due to either a direct influence on the hypophysis or stimulation of postsynaptic dopamine receptors in the hypothalamus, arousing the release of the PRL inhibitory factor. Hence, dopamine agonists have proven to offer clinical benefits among autoimmune patients and represent a promising therapy to be explored. In this review, we attempt to provide a critical overview of the link between PRL, autoimmune diseases, and motherhood. PMID- 29483904 TI - Exosomes in Pathogen Infections: A Bridge to Deliver Molecules and Link Functions. AB - Exosomes are extracellular vesicles derived from cell endocytosis which act as transmitters between cells. They are composed of proteins, lipids, and RNAs through which they participate in cellular crosstalk. Consequently, they play an important role in health and disease. Our view is that exosomes exert a bidirectional regulatory effect on pathogen infections by delivering their content. First, exosomes containing proteins and RNAs derived from pathogens can promote infections in three ways: (1) mediating further infection by transmitting pathogen-related molecules; (2) participating in the immune escape of pathogens; and (3) inhibiting immune responses by favoring immune cell apoptosis. Second, exosomes play anti-infection roles through: (1) inhibiting pathogen proliferation and infection directly; (2) inducing immune responses such as those related to the function of monocyte-macrophages, NK cells, T cells, and B cells. We believe that exosomes act as "bridges" during pathogen infections through the mechanisms mentioned above. The purpose of this review is to describe present findings regarding exosomes and pathogen infections, and highlight their enormous potential in clinical diagnosis and treatment. We discuss two opposite aspects: infection and anti-infection, and we hypothesize a balance between them. At the same time, we elaborate on the role of exosomes in immune regulation. PMID- 29483907 TI - Human Properdin Opsonizes Nanoparticles and Triggers a Potent Pro-inflammatory Response by Macrophages without Involving Complement Activation. AB - Development of nanoparticles as tissue-specific drug delivery platforms can be considerably influenced by the complement system because of their inherent pro inflammatory and tumorigenic consequences. The complement activation pathways, and its recognition subcomponents, can modulate clearance of the nanoparticles and subsequent inflammatory response and thus alter the intended translational applications. Here, we report, for the first time, that human properdin, an upregulator of the complement alternative pathway, can opsonize functionalized carbon nanotubes (CNTs) via its thrombospondin type I repeat (TSR) 4 and 5. Binding of properdin and TSR4+5 is likely to involve charge pattern/polarity recognition of the CNT surface since both carboxymethyl cellulose-coated carbon nanotubes (CMC-CNT) and oxidized (Ox-CNT) bound these proteins well. Properdin enhanced the uptake of CMC-CNTs by a macrophage cell line, THP-1, mounting a robust pro-inflammatory immune response, as revealed by qRT-PCR, multiplex cytokine array, and NF-kappaB nuclear translocation analyses. Properdin can be locally synthesized by immune cells in an inflammatory microenvironment, and thus, its interaction with nanoparticles is of considerable importance. In addition, recombinant TSR4+5 coated on the CMC-CNTs inhibited complement consumption by CMC-CNTs, suggesting that nanoparticle decoration with TSR4+5, can be potentially used as a complement inhibitor in a number of pathological contexts arising due to exaggerated complement activation. PMID- 29483905 TI - A New Classification System for IgG4 Autoantibodies. AB - IgG4 autoimmune diseases are characterized by the presence of antigen-specific autoantibodies of the IgG4 subclass and contain well-characterized diseases such as muscle-specific kinase myasthenia gravis, pemphigus, and thrombotic thrombocytopenic purpura. In recent years, several new diseases were identified, and by now 14 antigens targeted by IgG4 autoantibodies have been described. The IgG4 subclass is considered immunologically inert and functionally monovalent due to structural differences compared to other IgG subclasses. IgG4 usually arises after chronic exposure to antigen and competes with other antibody species, thus "blocking" their pathogenic effector mechanisms. Accordingly, in the context of IgG4 autoimmunity, the pathogenicity of IgG4 is associated with blocking of enzymatic activity or protein-protein interactions of the target antigen. Pathogenicity of IgG4 autoantibodies has not yet been systematically analyzed in IgG4 autoimmune diseases. Here, we establish a modified classification system based on Witebsky's postulates to determine IgG4 pathogenicity in IgG4 autoimmune diseases, review characteristics and pathogenic mechanisms of IgG4 in these disorders, and also investigate the contribution of other antibody entities to pathophysiology by additional mechanisms. As a result, three classes of IgG4 autoimmune diseases emerge: class I where IgG4 pathogenicity is validated by the use of subclass-specific autoantibodies in animal models and/or in vitro models of pathogenicity; class II where IgG4 pathogenicity is highly suspected but lack validation by the use of subclass specific antibodies in in vitro models of pathogenicity or animal models; and class III with insufficient data or a pathogenic mechanism associated with multivalent antigen binding. Five out of the 14 IgG4 antigens were validated as class I, five as class II, and four as class III. Antibodies of other IgG subclasses or immunoglobulin classes were present in several diseases and could contribute additional pathogenic mechanisms. PMID- 29483909 TI - Agonistic Autoantibodies to the beta2-Adrenergic Receptor Involved in the Pathogenesis of Open-Angle Glaucoma. AB - Glaucoma is a frequent ocular disease that may lead to blindness. Primary open angle glaucoma (POAG) and ocular hypertension (OHT) are common diseases with increased intraocular pressure (IOP), which are mainly responsible for these disorders. Their pathogenesis is widely unknown. We screened the sera of patients with POAG and OHT for the prevalence of autoantibodies (AAb) against G protein coupled receptors (GPCRs) in comparison to controls. Employing frequency modulation of spontaneously contracting neonatal rat cardiomyocytes in vitro, agonistic GPCR AAb were to be detected in roughly 75% of the patients with POAG and OHT, however, not in controls. Using inhibitory peptides the AAb' target was identified as beta2 adrenergic receptor (beta2AR). The AAb interact with the second extracellular loop of beta2AR. The peptides 181-187 and 186-192 were identified as binding sites of the AAb within the extracellular loop II. The binding of the AAb to beta2ARs was verified by surface-plasmon-resonance analysis. The isotype of the AAb was (immunoglobulin) IgG3. In an additional pilot principal-of-proof study, including four patients with POAG, the removal of the AAb against the beta2AR and other immunoglobulins G by immunoadsorption resulted in a transient reduction of IOP. These findings might indicate a possible role of agonistic AAb directed against beta2ARs in the dynamics of aqueous humor and might support a contribution of adaptive autoimmunity in the etiopathogenesis of POAG and OHT. PMID- 29483906 TI - Twenty Years of AIRE. AB - About two decades ago, cloning of the autoimmune regulator (AIRE) gene materialized one of the most important actors on the scene of self-tolerance. Thymic transcription of genes encoding tissue-specific antigens (ts-ags) is activated by AIRE protein and embodies the essence of thymic self-representation. Pathogenic AIRE variants cause the autoimmune polyglandular syndrome type 1, which is a rare and complex disease that is gaining attention in research on autoimmunity. The animal models of disease, although not identically reproducing the human picture, supply fundamental information on mechanisms and extent of AIRE action: thanks to its multidomain structure, AIRE localizes to chromatin enclosing the target genes, binds to histones, and offers an anchorage to multimolecular complexes involved in initiation and post-initiation events of gene transcription. In addition, AIRE enhances mRNA diversity by favoring alternative mRNA splicing. Once synthesized, ts-ags are presented to, and cause deletion of the self-reactive thymocyte clones. However, AIRE function is not restricted to the activation of gene transcription. AIRE would control presentation and transfer of self-antigens for thymic cellular interplay: such mechanism is aimed at increasing the likelihood of engagement of the thymocytes that carry the corresponding T-cell receptors. Another fundamental role of AIRE in promoting self-tolerance is related to the development of thymocyte anergy, as thymic self-representation shapes at the same time the repertoire of regulatory T cells. Finally, AIRE seems to replicate its action in the secondary lymphoid organs, albeit the cell lineage detaining such property has not been fully characterized. Delineation of AIRE functions adds interesting data to the knowledge of the mechanisms of self-tolerance and introduces exciting perspectives of therapeutic interventions against the related diseases. PMID- 29483908 TI - Cow's Milk and Immune Function in the Respiratory Tract: Potential Mechanisms. AB - During the last decades, the world has witnessed a dramatic increase in allergy prevalence. Epidemiological evidence shows that growing up on a farm is a protective factor, which is partly explained by the consumption of raw cow's milk. Indeed, recent studies show inverse associations between raw cow's milk consumption in early life and asthma, hay fever, and rhinitis. A similar association of raw cow's milk consumption with respiratory tract infections is recently found. In line with these findings, controlled studies in infants with milk components such as lactoferrin, milk fat globule membrane, and colostrum IgG have shown to reduce respiratory infections. However, for ethical reasons, it is not possible to conduct controlled studies with raw cow's milk in infants, so formal proof is lacking to date. Because viral respiratory tract infections and aeroallergen exposure in children may be causally linked to the development of asthma, it is of interest to investigate whether cow's milk components can modulate human immune function in the respiratory tract and via which mechanisms. Inhaled allergens and viruses trigger local immune responses in the upper airways in both nasal and oral lymphoid tissue. The components present in raw cow's milk are able to promote a local microenvironment in which mucosal immune responses are modified and the epithelial barrier is enforced. In addition, such responses may also be triggered in the gut after exposure to allergens and viruses in the nasal cavity that become available in the GI tract after swallowing. However, these immune cells that come into contact with cow's milk components in the gut must recirculate into the blood and home to the (upper and lower) respiratory tract to regulate immune responses locally. Expression of the tissue homing associated markers alpha4beta7 and CCR9 or CCR10 on lymphocytes can be influenced by vitamin A and vitamin D3, respectively. Since both vitamins are present in milk, we speculate that raw milk may influence homing of lymphocytes to the upper respiratory tract. This review focuses on potential mechanisms via which cow's milk or its components can influence immune function in the intestine and the upper respiratory tract. Unraveling these complex mechanisms may contribute to the development of novel dietary approaches in allergy and asthma prevention. PMID- 29483910 TI - Respiratory Disease following Viral Lung Infection Alters the Murine Gut Microbiota. AB - Alterations in the composition of the gut microbiota have profound effects on human health. Consequently, there is great interest in identifying, characterizing, and understanding factors that initiate these changes. Despite their high prevalence, studies have only recently begun to investigate how viral lung infections have an impact on the gut microbiota. There is also considerable interest in whether the gut microbiota could be manipulated during vaccination to improve efficacy. In this highly controlled study, we aimed to establish the effect of viral lung infection on gut microbiota composition and the gut environment using mouse models of common respiratory pathogens respiratory syncytial virus (RSV) and influenza virus. This was then compared to the effect of live attenuated influenza virus (LAIV) vaccination. Both RSV and influenza virus infection resulted in significantly altered gut microbiota diversity, with an increase in Bacteroidetes and a concomitant decrease in Firmicutes phyla abundance. Although the increase in the Bacteroidetes phylum was consistent across several experiments, differences were observed at the family and operational taxonomic unit level. This suggests a change in gut conditions after viral lung infection that favors Bacteroidetes outgrowth but not individual families. No change in gut microbiota composition was observed after LAIV vaccination, suggesting that the driver of gut microbiota change is specific to live viral infection. Viral lung infections also resulted in an increase in fecal lipocalin-2, suggesting low-grade gut inflammation, and colonic Muc5ac levels. Owing to the important role that mucus plays in the gut environment, this may explain the changes in microbiota composition observed. This study demonstrates that the gut microbiota and the gut environment are altered following viral lung infections and that these changes are not observed during vaccination. Whether increased mucin levels and gut inflammation drive, or are a result of, these changes is still to be determined. PMID- 29483911 TI - Molecular Basis for the Recognition of Herpes Simplex Virus Type 1 Infection by Human Natural Killer Cells. AB - Primary infection with Herpes simplex virus type 1 (HSV1) is subclinical or only mildly symptomatic in normal individuals, yet the reason for the body's effective immune defense against this pathogen in the absence of antigen-specific immunity has not been well understood. It is clear that human natural killer (NK) cells recognize and kill HSV1-infected cells, and those individuals who either lack or have functionally impaired NK cells can suffer severe, recurrent, and sometimes fatal HSV1 infection. In this article, we review what is known about the recognition of HSV1 by NK cells, and describe a novel mechanism of innate immune surveillance against certain viral pathogens by NK cells called Fc-bridged cell mediated cytotoxicity. PMID- 29483912 TI - Infective Larvae of Brugia malayi Induce Polarization of Host Macrophages that Helps in Immune Evasion. AB - Filarial parasites suppress, divert, or polarize the host immune response to aid their survival. However, mechanisms that govern the polarization of host MPhis during early filarial infection are not completely understood. In this study, we infected BALB/c mice with infective larvae stage-3 of Brugia malayi (Bm-L3) and studied their effect on the polarization of splenic MPhis. Results showed that MPhis displayed M2-phenotype by day 3 p.i. characterized by upregulated IL-4, but reduced IL-12 and Prostaglandin-D2 secretion. Increased arginase activity, higher arginase-1 but reduced NOS2 expression and poor phagocytic and antigen processing capacity was also observed. M2 MPhis supported T-cell proliferation and characteristically upregulated p-ERK but downregulated NF-kappaB-p65 and NF kappaB-p50/105. Notably, Bm-L3 synergized with host regulatory T-cells (Tregs) and polarized M2 MPhis to regulatory MPhis (Mregs) by day 7 p.i., which secreted copious amounts of IL-10 and prostaglandin-E2. Mregs also showed upregulated expression levels of MHC-II, CD80, and CD86 and exhibited increased antigen processing capacity but displayed impaired activation of NF-kappaB-p65 and NF kappaB-p50/105. Neutralization of Tregs by anti-GITR + anti-CD25 antibodies checked the polarization of M2 MPhis to Mregs, decreased accumulation of regulatory B cells and inflammatory monocytes, and reduced secretion of IL-10, but enhanced IL-4 production and percentages of eosinophils, which led to Bm-L3 killing. In summary, we report hitherto undocumented effects of early Bm-L3 infection on the polarization of splenic MPhis and show how infective larvae deftly utilize the functional plasticity of host MPhis to establish themselves inside the host. PMID- 29483914 TI - Pathogenicity and Viral Shedding of MERS-CoV in Immunocompromised Rhesus Macaques. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) has recently emerged in the Middle East. Since 2012, there have been approximately 2,100 confirmed cases, with a 35% case fatality rate. Disease severity has been linked to patient health status, as people with chronic diseases or an immunocompromised status fare worse, although the mechanisms of disease have yet to be elucidated. We used the rhesus macaque model of mild MERS to investigate whether the immune response plays a role in the pathogenicity in relation to MERS-CoV shedding. Immunosuppressed macaques were inoculated with MERS-CoV and sampled daily for 6 days to assess their immune statues and to measure viral shedding and replication. Immunosuppressed macaques supported significantly higher levels of MERS-CoV replication in respiratory tissues and shed more virus, and virus disseminated to tissues outside of the respiratory tract, whereas viral RNA was confined to respiratory tissues in non-immunosuppressed animals. Despite increased viral replication, pathology in the lungs was significantly lower in immunosuppressed animals. The observation that the virus was less pathogenic in these animals suggests that disease has an immunopathogenic component and shows that inflammatory responses elicited by the virus contribute to disease. PMID- 29483915 TI - The NLRP3 Inflammasome Is Upregulated in HIV-Infected Antiretroviral Therapy Treated Individuals with Defective Immune Recovery. AB - Background: Inflammasome-mediated activation of caspase-1 regulates inflammatory responses and pyroptosis. We analyzed possible associations between inflammasome related genes and immune reconstitution in HIV-infected antiretroviral therapy (ART)-treated patients. Methods: Cross-sectional, case-control study. HIV infected patients on ART for >=24 months with HIV-RNA<50 cp/mL for >=12 months were enrolled and defined as immunological responders (IR) or non-responders (INR) if CD4 count was >=500 or <=350 cells/MUL, respectively. Expression of inflammasome genes, caspases 1, 3, 4, 5 and gamma-interferon-inducible protein 16 (IFI16) was measured in unstimulated and LPS- or aldrithiol-2-treated HIV-1BaL virions-stimulated peripheral blood mononuclear cells. Microbial translocation markers were evaluated. Results: Thirty-nine patients (22 IRs; 17 INRs) were enrolled. LPS-stimulated inflammasome genes were significantly upregulated in INRs. Whereas HIV-1BaL stimulation induced (NOD)-like receptor (NLR) family pyrin domain containing 3 (NLRP3) expression in both IRs and INRs, NLRP3 and IL-18 expression was significantly increased in INRs compared to IRs. Significant higher caspase-1 expression was seen as well, whereas caspase 3, 4, and 5 expression was similar in both groups. No differences in microbial translocation markers (LPS and soluble CD14) were detected in the two groups. Conclusion: Upregulation of NLRP3 and caspase-1 is observed in INR patients. This could play a role in persistent immune activation that characterize INRs. Caspase-1 upregulation could induce CD4 T-cell loss via pyroptosis, contributing to unsatisfactory CD4 T-cells recovery. PMID- 29483913 TI - Abnormal Epigenetic Regulation of Immune System during Aging. AB - Epigenetics refers to the study of mechanisms controlling the chromatin structure, which has fundamental role in the regulation of gene expression and genome stability. Epigenetic marks, such as DNA methylation and histone modifications, are established during embryonic development and epigenetic profiles are stably inherited during mitosis, ensuring cell differentiation and fate. Under the effect of intrinsic and extrinsic factors, such as metabolic profile, hormones, nutrition, drugs, smoke, and stress, epigenetic marks are actively modulated. In this sense, the lifestyle may affect significantly the epigenome, and as a result, the gene expression profile and cell function. Epigenetic alterations are a hallmark of aging and diseases, such as cancer. Among biological systems compromised with aging is the decline of immune response. Different regulators of immune response have their promoters and enhancers susceptible to the modulation by epigenetic marks, which is fundamental to the differentiation and function of immune cells. Consistent evidence has showed the regulation of innate immune cells, and T and B lymphocytes by epigenetic mechanisms. Therefore, age-dependent alterations in epigenetic marks may result in the decline of immune function and this might contribute to the increased incidence of diseases in old people. In order to maintain health, we need to better understand how to avoid epigenetic alterations related to immune aging. In this review, the contribution of epigenetic mechanisms to the loss of immune function during aging will be discussed, and the promise of new means of disease prevention and management will be pointed. PMID- 29483916 TI - Hepatitis B Virus-Specific CD8+ T Cells Maintain Functional Exhaustion after Antigen Reexposure in an Acute Activation Immune Environment. AB - Chronic hepatitis B virus (HBV) infection is characterized by the presence of functionally exhausted HBV-specific CD8+ T cells. To characterize the possible residual effector ability of these cells, we reexposed CD8+ T cells from chronically HBV replicating mice to HBV antigens in an acute activation immune environment. We found that after transfer into naive mice, exhausted CD8+ T cells reexpanded in a comparable magnitude as naive CD8+ T cells in response to acute HBV infection; however, their proliferation intensity was significantly lower than that of CD8+ T cells from acute-resolving HBV replicating mice (AR mice). The differentiation phenotypes driven by acute HBV replication of donor exhausted and naive CD8+ T cells were similar, but were different from those of their counterparts from AR mice. Nevertheless, exhausted CD8+ T cells maintained less activated phenotype, an absence of effector cytokine production and poor antiviral function after HBV reexposure in an acute activation immune environment. We thus conclude that exhausted CD8+ T cells undergo a stable form of dysfunctional differentiation during chronic HBV replication and switching immune environment alone is not sufficient for the antiviral functional reconstitution of these cells. PMID- 29483917 TI - More than Decoration: Roles for Natural Killer Group 2 Member D Ligand Expression by Immune Cells. AB - The activating immune receptor natural killer group 2 member D (NKG2D), which is expressed by natural killer cells and T cell subsets, recognizes a number of ligands expressed by "stressed" or damaged cells. NKG2D has been extensively studied for its role in tumor immunosurveillance and antiviral immunity. To date, the majority of studies have focused on NKG2D-mediated killing of target cells expressing NKG2D ligands. However, with a number of reports describing expression of NKG2D ligands by cells that are not generally considered stressed, it is becoming clear that some healthy cells also express NKG2D ligands. Expression of these ligands by cells within the skin, intestinal epithelium, and the immune system suggests other immune functions for NKG2D ligand expression in addition to its canonical role as a "kill me" signal. How NKG2D ligands function in this capacity is just now starting to be unraveled. In this review, we examine the expression of NKG2D ligands by immune cells and discuss current literature describing the effects of this expression on immunity and immune regulation. PMID- 29483918 TI - Unique Immune Gene Expression Patterns in Bronchoalveolar Lavage and Tumor Adjacent Non-Neoplastic Lung Tissue in Non-Small Cell Lung Cancer. AB - Background: The immune cells in the local environments surrounding non-small cell lung cancer (NSCLC) implicate the balance of pro- and antitumor immunity; however, their transcriptomic profiles remain poorly understood. Methods: A transcriptomic microarray study of bronchoalveolar lavage (BAL) cells harvested from tumor-bearing lung segments was performed in a discovery group. The findings were validated (1) in published microarray datasets, (2) in an independent group by RT-qPCR, and (3) in non-diseased and tumor adjacent non-neoplastic lung tissue by immunohistochemistry and in BAL cell lysates by immunoblotting. Result: The differential expression of 129 genes was identified in the discovery group. These genes revealed functional enrichment in Fc gamma receptor-dependent phagocytosis and circulating immunoglobulin complex among others. Microarray datasets analysis (n = 607) showed that gene expression of BAL cells of tumor-bearing lung segment was also the unique transcriptomic profile of tumor adjacent non-neoplastic lung of early stage NSCLC and a significantly gradient increase of immunoglobulin genes' expression for non-diseased lungs, tumor adjacent non-neoplastic lungs, and tumors was identified (ANOVA, p < 2 * 10-16). A 53-gene signature was determined with significant correlation with inhibitory checkpoint PDCD1 (r = 0.59, p = 0.0078) among others, where the nine top genes including IGJ and IGKC were RT-qPCR validated with high diagnostic performance (AUC: 0.920, 95% CI: 0.831-0.985, p = 2.98 * 10-7). Increased staining and expression of IGKC revealed by immunohistochemistry and immunoblotting in tumor adjacent non-neoplastic lung tissues (Wilcoxon signed-rank test, p < 0.001) and in BAL cell lysates (p < 0.01) of NSCLC, respectively, were noted. Conclusion: The BAL cells of tumor-bearing lung segments and tumor adjacent non-neoplastic lung tissues present a unique gene expression characterized by IGKC in relation to inhibitory checkpoints. Further study of humoral immune responses to NSCLC is warranted. PMID- 29483919 TI - Human gamma-Herpesvirus Infection, Tumorigenesis, and Immune Control in Mice with Reconstituted Human Immune System Components. AB - The human gamma-herpesviruses Epstein-Barr virus (EBV or HHV4) and Kaposi sarcoma associated herpesvirus (KSHV or HHV8) are each associated with around 2% of all tumors in humans worldwide. However, investigations into their infection, oncogenesis, and immune responses that protect from the associated tumors have been hampered by the exclusive tropism of these pathogens for humans. Mice with reconstituted human immune system components (HIS mice) provide the unique opportunity to study persistent infection, virus associated lymphoma formation, and cell-mediated immune control of EBV and KSHV. Moreover, since these pathogens are unique stimuli for cytotoxic human lymphocyte responses, they also allow us to characterize long-lasting cell-mediated immune control and the requirements for its initiation, which would also be desirable to achieve during antitumor vaccination in general. Thus, human gamma-herpesvirus infection of HIS mice provides unique insights into the biology of these important human pathogens and human cell-mediated immune responses that are considered to be the main protective entity against tumors. PMID- 29483920 TI - Vgamma4 T Cells Inhibit the Pro-healing Functions of Dendritic Epidermal T Cells to Delay Skin Wound Closure Through IL-17A. AB - Dendritic epidermal T cells (DETCs) and dermal Vgamma4 T cells engage in wound re epithelialization and skin inflammation. However, it remains unknown whether a functional link between Vgamma4 T cell pro-inflammation and DETC pro-healing exists to affect the outcome of skin wound closure. Here, we revealed that Vgamma4 T cell-derived IL-17A inhibited IGF-1 production by DETCs to delay skin wound healing. Epidermal IL-1beta and IL-23 were required for Vgamma4 T cells to suppress IGF-1 production by DETCs after skin injury. Moreover, we clarified that IL-1beta rather than IL-23 played a more important role in inhibiting IGF-1 production by DETCs in an NF-kappaB-dependent manner. Together, these findings suggested a mechanistic link between Vgamma4 T cell-derived IL-17A, epidermal IL 1beta/IL-23, DETC-derived IGF-1, and wound-healing responses in the skin. PMID- 29483921 TI - Abiotic Stresses Modulate Landscape of Poplar Transcriptome via Alternative Splicing, Differential Intron Retention, and Isoform Ratio Switching. AB - Abiotic stresses affect plant physiology, development, growth, and alter pre-mRNA splicing. Western poplar is a model woody tree and a potential bioenergy feedstock. To investigate the extent of stress-regulated alternative splicing (AS), we conducted an in-depth survey of leaf, root, and stem xylem transcriptomes under drought, salt, or temperature stress. Analysis of approximately one billion of genome-aligned RNA-Seq reads from tissue- or stress specific libraries revealed over fifteen millions of novel splice junctions. Transcript models supported by both RNA-Seq and single molecule isoform sequencing (Iso-Seq) data revealed a broad array of novel stress- and/or tissue specific isoforms. Analysis of Iso-Seq data also resulted in the discovery of 15,087 novel transcribed regions of which 164 show AS. Our findings demonstrate that abiotic stresses profoundly perturb transcript isoform profiles and trigger widespread intron retention (IR) events. Stress treatments often increased or decreased retention of specific introns - a phenomenon described here as differential intron retention (DIR). Many differentially retained introns were regulated in a stress- and/or tissue-specific manner. A subset of transcripts harboring super stress-responsive DIR events showed persisting fluctuations in the degree of IR across all treatments and tissue types. To investigate coordinated dynamics of intron-containing transcripts in the study we quantified absolute copy number of isoforms of two conserved transcription factors (TFs) using Droplet Digital PCR. This case study suggests that stress treatments can be associated with coordinated switches in relative ratios between fully spliced and intron-retaining isoforms and may play a role in adjusting transcriptome to abiotic stresses. PMID- 29483922 TI - New Insights into Different Reproductive Effort and Sexual Recruitment Contribution between Two Geographic Zostera marina L. Populations in Temperate China. AB - Seagrasses are important components of global coastal ecosystems, and the eelgrass Zostera marina L. is widely distributed along the Atlantic and Pacific coasts in the temperate northern hemisphere, but limited datum related to the contribution of sexual reproduction to population recruitment have been reported. This study aimed to understand eelgrass sexual reproduction and population recruitment in Swan Lake (SLL), and Huiquan Bay (HQB) was included for comparison. Random sampling, permanent quadrats or cores and laboratory seed germination-based experimental methods were employed. The flowering, seed production, seed banks, seed germination, seedling survival, and seedling growth of eelgrass were investigated from July 2014 to December 2015 to evaluate the contribution of sexual reproduction to population recruitment. Results indicated a dominant role of asexual reproduction in HQB, while sexual reproduction played a relatively important role in SLL. The highest flowering shoot density in SLL was 517.27 +/- 504.29 shoots m-2 (June) and represented 53.34% of the total shoots at the center site. The potential seed output per reproductive shoot and per unit area in SLL were 103.67 +/- 37.95 seeds shoot-1 and 53,623.66 +/- 19,628.11 seeds m-2, respectively. The maximum seed bank density in SLL was 552.21 +/- 204.94 seeds m-2 (October). Seed germination mainly occurred from the middle of March to the end of May, and the highest seedling density was 296.88 +/ 274.27 seedlings m-2 in April. The recruitment from seedlings accounted for 41.36% of the Z. marina population recruitment at the center site, while the sexual recruitment contribution at the patch site (50.52%) was greater than that at the center site. Seeds in SLL were acclimated to spring germination, while in HQB, they were acclimated to autumn germination (early October-late November). Seed bank density in HQB was very low, with a value of 254.35 +/- 613.34 seeds m 2 (early October). However, seeds in HQB were significantly larger and heavier than those in SLL (size: P = 0.004; weight: P < 0.001). The recruitment from seedlings accounted for as low as 2.53% of the Z. marina population recruitment in HQB. Our laboratory seed germination experiment, which was conducted in autumn, showed that the seed germination percent in HQB was significantly greater than in SLL at optimal germination temperatures (10 and 15 degrees C; P < 0.001). A laboratory seed germination test at suitable temperature may be a potential novel approach to identify the ecological differences among different geographic populations. It is suggested that the Z. marina population recruitment may have different strategies and adapt to specific local conditions, such as in SLL and HQB, and the temperature regime may control morphological and phonological variations. PMID- 29483923 TI - Research Advances in the Correlation between Peroxisome Proliferator-Activated Receptor-gamma and Digestive Cancers. AB - Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a class of ligand activated nuclear transcription factors, which is a member of type II nuclear receptor superfamily. Previous studies demonstrate that PPARgamma is expressed in a variety of tumor tissues and is closely associated with the proliferation and prognosis of digestive system tumors by its roles in mediation of cell differentiation, induction of cell apoptosis, and inhibition of cell proliferation. PMID- 29483924 TI - Portulaca Extract Attenuates Development of Dextran Sulfate Sodium Induced Colitis in Mice through Activation of PPARgamma. AB - Portulaca oleracea L. is a traditional Chinese medicine, which has been used as adjuvant therapy for inflammatory bowel disease (IBD). However, the mechanism of its activity in IBD still remains unclear. Since previous studies have documented the anti-inflammatory effect of peroxisome proliferator activated receptors-gamma (PPAR-gamma), Portulaca regulation of PPAR-gamma in inflammation was examined in current study. Ulcerative colitis (UC) was generated by 5% dextran sulfate sodium (DSS) in mice and four groups were established as normal control, DSS alone, DSS plus mesalamine, and DSS plus Portulaca. Severity of UC was evaluated by body weight, stool blood form, and length of colorectum. Inflammation was examined by determination of inflammatory cytokines (TNF-a, IL-6, and IL-1a). Portulaca extract was able to attenuate development of UC in DSS model similar to the treatment of mesalazine. Moreover, Portulaca extract inhibited proinflammatory cytokines release and reduced the level of DSS-induced NF-kappaB phosphorylation. Furthermore, Portulaca extract restored PPAR-gamma level, which was reduced by DSS. In addition, Portulaca extract protected DSS induced apoptosis in mice. In conclusion, Portulaca extract can alleviate colitis in mice through regulation of inflammatory reaction, apoptosis, and PPAR-gamma level; therefore, Portulaca extract can be a potential candidate for the treatment of IBD. PMID- 29483925 TI - ENO1 Overexpression in Pancreatic Cancer Patients and Its Clinical and Diagnostic Significance. AB - We investigated in this study the expression of ENO1 in tissues and plasma of PDAC patients to evaluate its clinicopathological and diagnostic significance. ENO1 protein expression was detected in tissue microarray of human PDAC and adjacent noncancer tissues. Electrochemiluminescence immunoassay and amplified luminescent proximity homogeneous assay (AlphaLISA) were performed to measure CA19-9 and ENO1 concentration in plasma from PDAC patients and healthy controls. We demonstrated that ENO1 overexpression is positively correlated with clinical stage, lymph node metastasis, and poor prognosis of PDAC; ENO1 may function as a hopeful candidate diagnostic marker in combination with CA19-9 in PDAC diagnosis. PMID- 29483926 TI - The Effect of Marital Status on Survival of Patients with Gastrointestinal Stromal Tumors: A SEER Database Analysis. AB - Background: Marital status has been reported to be a prognostic factor in multiple malignancies. However, its prognostic value on gastrointestinal stromal tumors (GISTs) have not yet been determined. The objective of the present analysis was to assess the effects of marital status on survival in patients with GISTs. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to analyze 6195 patients who were diagnosed with GISTs from 2001 to 2014. We also use Kaplan-Meier analysis and Cox regression to analyze the impact of marital status on cancer-specific survival (CSS). Results: Patients in the married group had more frequency in white people, more high/moderate grade tumors, and were more likely to receive surgery. Widowed patients had a higher proportion of women, a greater proportion of older patients (>60 years), and more common site of the stomach. Multivariate analysis demonstrated that marital status was an independent prognostic factor for GISTs (P < 0.001). Married patients had better CSS than unmarried patients (P < 0.001). Subgroup analysis suggested that widowed patients had the lowest CSS compared with all other patients. Conclusions: Marital status is a prognostic factor for survival in patients with GISTs, and widowed patients are at greater risk of cancer-specific mortality. PMID- 29483927 TI - Scaffolds for Pelvic Floor Prolapse: Logical Pathways. AB - Pelvic organ prolapse (POP) has borrowed principles of treatment from hernia repair and in the last two decades we saw reinforcement materials to treat POP with good outcomes in terms of anatomy but with alarming complication rates. Polypropylene meshes to specifically treat POP have been withdrawn from market by manufactures and a blank space was left to be filled with new materials. Macroporous monofilament meshes are ideal candidates and electrospinning emerged as a reliable method capable of delivering production reproducibility and customization. In this review, we point out some pathways that seem logical to be followed but have been only researched in last couple of years. PMID- 29483928 TI - C-fos upregulates P-glycoprotein, contributing to the development of multidrug resistance in HEp-2 laryngeal cancer cells with VCR-induced resistance. AB - Background: Laryngeal cancer tends to have a very poor prognosis due to the unsatisfactory efficacy of chemotherapy for this cancer. Multidrug resistance (MDR) is the main cause of chemotherapy failure. The proto-oncogene c-fos has been shown to be involved in the development of MDR in several tumor types, but few studies have evaluated the relationship between c-fos and MDR in laryngeal cancer. We investigated the role of c-fos in MDR development in laryngeal cancer cells (cell line: human epithelial type 2, HEp-2) using the chemotherapeutic vincristine (VCR). Methods: HEp-2/VCR drug resistance was established by selection against an increasing drug concentration gradient. The expressions of c fos and multidrug resistance 1 (mdr1) were measured using qPCR and western blot. C-fos overexpression or knockdown was performed in various cells. The intracellular rhodamine-123 (Rh-123) accumulation assay was used to detect the transport capacity of P-glycoprotein (P-gp, which is encoded by the mdr1 gene). Results: HEp-2 cells with VCR-induced resistance (HEp-2/VCR cells) were not only resistant to VCR but also evolved cross-resistance to other chemotherapeutic drugs. The expressions of the c-fos and mdr1genes were significantly higher in the HEp-2/VCR cells than in control cells. C-fos overexpression in HEp-2 cells (c fos WT) resulted in increased P-gp expression and increased the IC50 for 5-FU. C fos knockdown in the HEp-2/VCR cells (c-fos shRNA) resulted in decreased P-gp expression and decreased IC50 for 5-FU. An intracellular Rh-123 accumulation assay showed that the mean intracellular fluorescence intensity (MFI) was lower in the HEp-2/VCR cells than in HEp-2 cells. C-fos WT cells also showed lower MFI. By contrast, c-fos shRNA cells exhibited a higher MFI than the control group. Conclusion: C-fos increased the expression of P-gp and mdr1 in the HEp-2/VCR cells, and enhanced the efflux function of the cells, thereby contributing to the development of MDR. PMID- 29483929 TI - Downregulation of microRNA-448 inhibits IL-1beta-induced cartilage degradation in human chondrocytes via upregulation of matrilin-3. AB - Background: Osteoarthritis is characterized by the continuous degradation of the articular cartilage. The microRNA miR-448 has been found to be broadly involved in cellular processes, including proliferation, apoptosis, invasion and EMT. While aberrant expression of miR-448 has been found in multiple cancers, its level in osteoarthritis cartilage and its role in the progression of this disease are still unknown. Here, we examined the functional roles of miR-448 and its expression in osteoarthritis tissues, including IL-1beta-stimulated osteoarthritis chondrocytes. Methods: Chondrocytes were isolated from human articular cartilage and stimulated with IL-1beta. The expression levels of miR 448 in the cartilage and chondrocytes were both determined. After transfection with an miR-448 mimic or inhibitor, the mRNA levels of aggrecan, type II collagen and MMP-13 were determined. Luciferase reporter assay, qRT-PCR and western blot were performed to explore whether matrilin-3 was a target of miR-448. Furthermore, we co-transfected chondrocytes with miR-448 inhibitor and siRNA for matrilin-3 and then stimulated them with IL-1beta to determine whether miR-448 mediated IL-1beta-induced cartilage matrix degradation resulted from directly targeting matrilin-3. Results: The level of miR-448 was significantly higher and matrilin-3 expression was significantly lower in osteoarthritis cartilage and IL 1beta-induced chondrocytes than in normal tissues and cells. Furthermore, matrilin-3 expression was reduced by miR-448 overexpression. MiR-448 downregulation significantly alleviated the IL-1beta-induced downregulation of aggrecan and type II collagen expression, and upregulation of MMP-13 expression. MiR-448 overexpression had the opposite effects. Knockdown of matrilin-3 reversed the effects of the miR-448 inhibitor on the expressions of aggrecan, type II collagen and MMP-13. Conclusion: The findings showed that miR-448 contributed to the progression of osteoarthritis by directly targeting matrilin-3. This indicates that it has potential as a therapeutic target for the treatment of osteoarthritis. PMID- 29483930 TI - Treatment with combined dabrafenib and trametinib in BRAFV600E-mutated metastatic malignant melanoma: a case of long-term complete response after treatment cessation. AB - Here, we report the case of a patient, diagnosed with BRAFV600E-mutated metastatic malignant melanoma M1a, who achieved a complete metabolic response after 7 months of treatment with the combination of dabrafenib and trametinib. After 31 months, the treatment was interrupted for patient's decision. To date October 2017, 18 months after the interruption of the treatment with the combination of dabrafenib and trametinib, follow-up Positron Emission Tomography (PET) scans are still documenting complete metabolic response. PMID- 29483931 TI - Preventive Effects of Velvet Antler (Cervus elaphus) against Lipopolysaccharide Induced Acute Lung Injury in Mice by Inhibiting MAPK/NF-kappaB Activation and Inducing AMPK/Nrf2 Pathways. AB - Velvet antler (Cervus elaphus) is a typical traditional animal medicine. It is considered to have various pharmacological effects including stimulation of the immune system, increase in the physical strength, and enhancement of sexual function. This paper aims to investigate the aqueous extract of velvet antler (AVA) in the mouse models of LPS-induced ALI. Inhibition of NO, TNF-alpha, IL 1beta, IL-6, and IL-10 productions contributes to the attenuation of LPS-induced lung inflammation by AVA. A 5-day pretreatment of AVA prevented histological alterations and enhanced antioxidant enzyme activity in lung tissues. AVA significantly reduced the material (total number of cells and proteins) in the BALF. Western blot analysis revealed that the expression of iNOS and COX-2 and phosphorylation of IkappaB-alpha and MAPKs proteins are blocked in LPS-stimulated macrophages as well as LPS-induced lung injury in mice. Consistent with this concept, the phosphorylation of CaMKKbeta, LKB1, AMPK, Nrf2, and HO-1 was activated after AVA treatment. The results from this study indicate AVA has anti inflammatory effects in vivo and AVA is a potential model for the development of health food. In addition, its pathways may be at least partially associated with inhibiting MAPK/NF-kappaB activation and upregulating AMPK/Nrf2 pathways and the regulation of antioxidant enzyme activity. PMID- 29483932 TI - Effect of Resveratrol Dry Suspension on Immune Function of Piglets. AB - Resveratrol, a polyphenolic plant antitoxin, has a wide range of pharmacological activities. In this study, we systematically evaluated the effects of resveratrol dry suspension (RDS) on immune function in piglets that were treated with different doses of RDS for 2 weeks. The results showed that the RDS has significant effects on the development, maturation, proliferation, and transformation of T lymphocytes. RDS could regulate humoral immune responses by upregulating the release of IFN-gamma and downregulating the release of TNF alpha. After piglets were vaccinated against classical swine fever virus and foot and-mouth disease virus, the antibody titers were significantly increased. RDS treatment showed an excellent resistance to enhance T-SOD activity. Values of blood routine and blood biochemistry showed no toxicity. These results suggested that RDS could be considered as an adjuvant to enhance immune responses to vaccines, as well as dietary additives for animals to enhance humoral and cellular immunity. PMID- 29483933 TI - Novel metrics for growth model selection. AB - Background: Literature surrounding the statistical modeling of childhood growth data involves a diverse set of potential models from which investigators can choose. However, the lack of a comprehensive framework for comparing non-nested models leads to difficulty in assessing model performance. This paper proposes a framework for comparing non-nested growth models using novel metrics of predictive accuracy based on modifications of the mean squared error criteria. Methods: Three metrics were created: normalized, age-adjusted, and weighted mean squared error (MSE). Predictive performance metrics were used to compare linear mixed effects models and functional regression models. Prediction accuracy was assessed by partitioning the observed data into training and test datasets. This partitioning was constructed to assess prediction accuracy for backward (i.e., early growth), forward (i.e., late growth), in-range, and on new-individuals. Analyses were done with height measurements from 215 Peruvian children with data spanning from near birth to 2 years of age. Results: Functional models outperformed linear mixed effects models in all scenarios tested. In particular, prediction errors for functional concurrent regression (FCR) and functional principal component analysis models were approximately 6% lower when compared to linear mixed effects models. When we weighted subject-specific MSEs according to subject-specific growth rates during infancy, we found that FCR was the best performer in all scenarios. Conclusion: With this novel approach, we can quantitatively compare non-nested models and weight subgroups of interest to select the best performing growth model for a particular application or problem at hand. PMID- 29483934 TI - Two predominant MUPs, OBP3 and MUP13, are male pheromones in rats. AB - Background: In rats, urine-borne male pheromones comprise organic volatile compounds and major urinary proteins (MUPs). A number of volatile pheromones have been reported, but no MUP pheromones have been identified in rat urine. Results: We used sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), isoelectric focusing electrophoresis (IEF), nano-liquid chromatography-tandem mass spectrometry (nLC-MS/MS) after in gel digestion of the proteins and quantitative real-time PCR (qRT-PCR) and showed that the levels of two MUPs, odorant-binding protein 3 (OBP3) (i.e. PGCL4) and MUP13 (i.e. PGCL1), in urine and their mRNAs in liver were higher in males than in females and were suppressed by orchidectomy and restored by testosterone treatment (T treatment). We then generated recombinant MUPs (rMUPs) and found that the sexual attractiveness of urine from castrated males to females significantly increased after the addition of either recombinant OBP3 (rOBP3) or recombinant MUP13 (rMUP13). Using c-Fos immunohistochemistry, we further examined neuronal activation in the brains of female rats after they sniffed rOBP3 or rMUP13. Both rOBP3 and rMUP13 activated the accessory olfactory bulb (AOB), medial preoptic area (MPA), bed nucleus of the stria terminalis (BST), medial amygdala (MeA), posteromedial cortical amygdala (PMCo) and ventromedial nucleus of the hypothalamus (VMH), which participate in the neural circuits responsible for pheromone-induced sexual behaviours. In particular, more c-Fos-immunopositive (c-Fos-ir) cells were observed in the posterior AOB than in the anterior AOB. Conclusions: The expression of OBP3 and MUP13 was male-biased and androgen-dependent. They attracted females and activated brain areas related to sexual behaviours in female rats, suggesting that both OBP3 and MUP13 are male pheromones in rats. Particularly, an OBP excreted into urine was exemplified to be a chemical signal. PMID- 29483935 TI - Breastfeeding knowledge and attitudes of health professional students: a systematic review. AB - Background: Breastfeeding support from health professionals can be effective in influencing a mother's decision to initiate and maintain breastfeeding. However, health professionals, including nursing students, do not always receive adequate breastfeeding education during their foundational education programme to effectively help mothers. In this paper, we report on a systematic review of the literature that aimed to describe nursing and other health professional students' knowledge and attitudes towards breastfeeding, and examine educational interventions designed to increase breastfeeding knowledge and attitudes amongst health professional students. Methods: A systematic review of peer reviewed literature was performed. The search for literature was conducted utilising six electronic databases, CINAHL, MEDLINE, ProQuest, PubMed, Scopus, and Cochrane, for studies published in English from January 2000 to March 2017. Studies focused on nursing students' or other health professional students' knowledge, attitudes or experiences related to breastfeeding. Intervention studies to improve knowledge and attitudes, were also included. All papers were reviewed using the relevant Critical Appraisal Skills Programme (CASP) checklist. Results: Fourteen studies were included in the review. This review indicates that in some settings, health professional students demonstrated mid-range scores on breastfeeding attitudes, and their knowledge of breastfeeding was limited, particularly in relation to breastfeeding assessment and management. All of the studies that tested a specialised breastfeeding education programme, appeared to increase nursing students' knowledge overall or aspects of their knowledge related to breastfeeding. Several factors were found to influence breastfeeding knowledge and attitudes, including timing of maternal and child health curriculum component, previous personal breastfeeding experience, gender, cultural practices and government legislation. Conclusions: Based on this review, it appears that nursing curriculum, or specialised programmes that emphasise the importance of breastfeeding initiation, can improve breastfeeding knowledge and attitudes and students' confidence in helping and guiding breastfeeding mothers. PMID- 29483936 TI - A simple and rapid method for preparing the whole section of starchy seed to investigate the morphology and distribution of starch in different regions of seed. AB - Background: Storage starch in starchy seed influences the seed weight and texture, and determines its applications in food and nonfood industries. Starch granules from different plant sources have significantly different shapes and sizes, and even more the difference exists in the different regions of the same tissue. Therefore, it is very important to in situ investigate the morphology and distribution of starch in the whole seed. However, a simple and rapid method is deficient to prepare the whole section of starchy seed for investigating the morphology and distribution of starch in the whole seeds for a large number of samples. Results: A simple and rapid method was established to prepare the whole section of starchy seed, especially for floury seed, in this study. The whole seeds of translucent and chalky rice, vitreous and floury maize, and normal barley and wheat were sectioned successfully using the newly established method. The iodine-stained section clearly exhibited the shapes and size of starch granules in different regions of seed. The starch granules with different morphologies and iodine-staining colors existed regionally in the seeds of high amylose rice and maize. The sections of lotus and kidney bean seeds also showed the feasibility of this method for starchy non-cereal seeds. Conclusion: The simple and rapid method was proven effective for preparing the whole sections of starchy seeds. The whole section of seed could be used to investigate the morphology and distribution of starch granules in different regions of the whole seed. The method was especially suitable for large sample numbers to investigate the starch morphology in short time. PMID- 29483937 TI - Protocol: high-efficiency in-planta Agrobacterium-mediated transgenic hairy root induction of Camellia sinensis var. sinensis. AB - Background: Camellia sinensis var. sinensis is widely grown for tea beverages that possess significant health promoting effects. Studies on tea plant genetics and breeding are hindered due to its recalcitrance to Agrobacterium-mediated genetic transformation. Among the possible reasons, oxidation of phenolics released from explant tissues and bactericidal effects of tea polyphenols during the process of transformation play a role in the plant recalcitrance. The aim of the present study was to alleviate the harmful effects of phenolic compounds using in-planta transformation. Results: Two-month old seedlings of tea cultivar "Nong Kangzao" were infected at the hypocotyl with wild type Agrobacterium rhizogenes and maintained in an environment of high humidity. 88.3% of infected plants developed hairy roots at the wounded site after 2 months of infection. Our data indicated that transgenic hairy root induction of tea can be achieved using A. rhizogenes following the optimized protocol. Conclusion: With this method, composite tea plants containing wild-type shoots with transgenic roots can be generated for "in root" gene functional characterization and root-shoot interaction studies. Moreover, this method can be applied to improve the root system of composite tea plants for a better resistance to abiotic and biotic stresses. PMID- 29483938 TI - Ginsenoside G-Rh2 synergizes with SMI-4a in anti-melanoma activity through autophagic cell death. AB - Background: Melanoma is a leading cause of cancer death worldwide, and SMI-4a and G-Rh2 exert anti-tumor activity in multiple cancer. However, SMI-4a as well as a synergistic relationship between SMI-4a and G-Rh2 in anti-melanoma capacity are still unknown. Therefore, we investigated the effects of SMI-4a and combined SMI 4a with G-Rh2 on the viability, apoptosis and autophagy of melanoma, and to preliminarily explore the underlying mechanism of SMI-4a and combined SMI-4a with G-Rh2 in inhibiting tumor growth. Methods: Cell viability was examined with cell counting Kit 8 assay and colony formation assay; Apoptosis was evaluated by flow cytometry and Caspase 3/7 activity assay; Western blotting was used to test proteins related to autophagy and the AKT/mammalian target of rapamycin (mTOR) signaling pathway; Tumor xenograft model in BALB/c nude mice was performed to evaluate the effects of SMI-4a and combined SMI-4a with G-Rh2 in anti-melanoma in vivo. Results: SMI-4a, a pharmacological inhibitor of PIM-1, could decrease cell viability, induce apoptosis, and promote Caspase 3/7 activity in both A375 and G361 melanoma cells, and SMI-4a inhibited tumor growth by inducing autophagy via down-regulating AKT/mTOR axis in melanoma cells. Furthermore, G-Rh2 amplified the anti-tumor activity of SMI-4a in melanoma cells via strengthening autophagy. Conclusions: Our results suggested that SMI-4a could enhance autophagy-inducing apoptosis by inhibiting AKT/mTOR signaling pathway in melanoma cells, and G-Rh2 could enhance the effects of SMI-4a against melanoma cancer via amplifying autophagy induction. This study demonstrates that combined SMI-4a and G-Rh2 might be a novel alternative strategy for melanoma treatment. PMID- 29483939 TI - A transgene design for enhancing oil content in Arabidopsis and Camelina seeds. AB - Background: Increasing the oil yield is a major objective for oilseed crop improvement. Oil biosynthesis and accumulation are influenced by multiple genes involved in embryo and seed development. The leafy cotyledon1 (LEC1) is a master regulator of embryo development that also enhances the expression of genes involved in fatty acid biosynthesis. We speculated that seed oil could be increased by targeted overexpression of a master regulating transcription factor for oil biosynthesis, using a downstream promoter for a gene in the oil biosynthesis pathway. To verify the effect of such a combination on seed oil content, we made constructs with maize (Zea mays) ZmLEC1 driven by serine carboxypeptidase-like (SCPL17) and acyl carrier protein (ACP5) promoters, respectively, for expression in transgenic Arabidopsis thaliana and Camelina sativa. Results: Agrobacterium-mediated transformation successfully generated Arabidopsis and Camelina lines that overexpressed ZmLEC1 under the control of a seed-specific promoter. This overexpression does not appear to be detrimental to seed vigor under laboratory conditions and did not cause observable abnormal growth phenotypes throughout the life cycle of the plants. Overexpression of ZmLEC1 increased the oil content in mature seeds by more than 20% in Arabidopsis and 26% in Camelina. Conclusion: The findings suggested that the maize master regulator, ZmLEC1, driven by a downstream seed-specific promoter, can be used to increase oil production in Arabidopsis and Camelina and might be a promising target for increasing oil yield in oilseed crops.0. PMID- 29483940 TI - Microbial effects of part-stream low-frequency ultrasonic pretreatment on sludge anaerobic digestion as revealed by high-throughput sequencing-based metagenomics and metatranscriptomics. AB - Background: Part-stream low-frequency ultrasound (LFUS) was one of the common practices for sludge disintegration in full-scale anaerobic digestion (AD) facilities. However, the effectiveness of part-stream LFUS treatment and its effect on AD microbiome have not been fully elucidated. Methods: Here we testified the effectiveness of part-stream LFUS pretreatment by treating only a fraction of feed sludge (23% and 33% total solid of the feed sludge) with 20 Hz LFUS for 70 s. State-of-the-art metagenomic and metatranscriptomic analysis was used to investigate the microbial process underpinning the enhanced AD performance by part-stream LFUS pretreatment. Results: By pretreating 33% total solid of the feed sludge, methane yield was increased by 36.5%, while the volatile solid reduction ratio remained unchanged. RNA-seq of the microbiome at stable stage showed that the continuous dosage of easy-degradable LFUS-pretreated feed sludge had gradually altered the microbial community by selecting Bacteroidales hydrolyzer with greater metabolic capability to hydrolyze cellulosic biomass without substrate attachment. Meanwhile, Thermotogales with excellent cell mobility for nutrient capturing was highly active within the community. Foremost proportion of the methanogenesis was contributed by the dominant Methanomicrobiales via carbon dioxide reduction. More interestingly, a perceivable proportion of the reverse electron flow of the community was input from Methanoculleus species other than syntrophic acetate-oxidizing bacteria. In addition, metagenomic binning retrieved several interesting novel metagenomic assembled genomes (MAGs): MAG-bin6 of Alistipes shahii showed exceptional transcriptional activities towards protein degradation and MAG-bin11 of Candidatus Cloacimonetes with active cellulolytic GH74 gene detected. Conclusions: In summary, despite the unchanged sludge digestibility, the applied part-stream LFUS pretreatment strategy was robust in adjusting the microbial pathways towards more effective substrate conversion enabled by free-living hydrolyser and beta-oxidation-capable methanogens. PMID- 29483941 TI - Genome-resolved metagenomics of sugarcane vinasse bacteria. AB - Background: The production of 1 L of ethanol from sugarcane generates up to 12 L of vinasse, which is a liquid waste containing an as-yet uncharacterized microbial assemblage. Most vinasse is destined for use as a fertilizer on the sugarcane fields because of the high organic and K content; however, increased N2O emissions have been observed when vinasse is co-applied with inorganic N fertilizers. Here we aimed to characterize the microbial assemblage of vinasse to determine the gene potential of vinasse microbes for contributing to negative environmental effects during fertirrigation and/or to the obstruction of bioethanol fermentation. Results: We measured chemical characteristics and extracted total DNA from six vinasse batches taken over 1.5 years from a bioethanol and sugar mill in Sao Paulo State. The vinasse microbial assemblage was characterized by low alpha diversity with 5-15 species across the six vinasses. The core genus was Lactobacillus. The top six represented bacterial genera across the samples were Lactobacillus, Megasphaera and Mitsuokella (Phylum Firmicutes, 35-97% of sample reads); Arcobacter and Alcaligenes (Phylum Proteobacteria, 0-40%); Dysgonomonas (Phylum Bacteroidetes, 0-53%); and Bifidobacterium (Phylum Actinobacteria, 0-18%). Potential genes for denitrification but not nitrification were identified in the vinasse metagenomes, with putative nirK and nosZ genes the most represented. Binning resulted in 38 large bins with between 36.0 and 99.3% completeness, and five small mobile element bins. Of the large bins, 53% could be classified at the phylum level as Firmicutes, 15% as Proteobacteria, 13% as unknown phyla, 13% as Bacteroidetes and 6% as Actinobacteria. The large bins spanned a range of potential denitrifiers; moreover, the genetic repertoires of all the large bins included the presence of genes involved in acetate, CO2, ethanol, H2O2, and lactose metabolism; for many of the large bins, genes related to the metabolism of mannitol, xylose, butyric acid, cellulose, sucrose, "3-hydroxy" fatty acids and antibiotic resistance were present based on the annotations. In total, 21 vinasse bacterial draft genomes were submitted to the genome repository. Conclusions: Identification of the gene repertoires of vinasse bacteria and assemblages supported the idea that organic carbon and nitrogen present in vinasse together with microbiological variation of vinasse might lead to varying patterns of N2O emissions during fertirrigation. Furthermore, we uncovered draft genomes of novel strains of known bioethanol contaminants, as well as draft genomes unknown at the phylum level. This study will aid efforts to improve bioethanol production efficiency and sugarcane agriculture sustainability. PMID- 29483942 TI - Optimization of cellulolytic enzyme components through engineering Trichoderma reesei and on-site fermentation using the soluble inducer for cellulosic ethanol production from corn stover. AB - Background: Cellulolytic enzymes produced by Trichoderma reesei are widely studied for biomass bioconversion, and enzymatic components vary depending on different inducers. In our previous studies, a mixture of glucose and disaccharide (MGD) was developed and used to induce cellulase production. However, the enzymatic profile induced by MGD is still not defined, and further optimization of the enzyme cocktail is also required for efficient ethanol production from lignocellulosic biomass. Results: In this study, cellulolytic enzymes produced by T. reesei Rut C30 using MGD and alkali-pretreated corn stover (APCS) as inducer were compared. Cellular secretome in response to each inducer was analyzed, which revealed a similar enzyme profile. However, significant difference in the content of cellulases and xylanase was detected. Although MGD induction enhanced beta-glucosidase production, its activity was still not sufficient for biomass hydrolysis. To overcome such a disadvantage, aabgl1 encoding beta-glucosidase in Aspergillus aculeatus was heterologously expressed in T. reesei Rut C30 under the control of the pdc1 promoter. The recombinant T. reesei PB-3 strain showed an improved beta-glucosidase activity of 310 CBU/mL in the fed-batch fermentation, 71-folds higher than that produced by the parent strain. Meanwhile, cellulase activity of 50 FPU/mL was detected. Subsequently, the crude enzyme was applied for hydrolyzing corn stover with a solid loading of 20% through separate hydrolysis and fermentation (SHF) and simultaneous saccharification and fermentation, respectively, for ethanol production. Better performance was observed in the SHF process, through which a total of 119.9 g/L glucose was released within 12 h for concomitant ethanol production of 54.2 g/L. Conclusions: The similar profile of cellulolytic enzymes was detected under the induction of MGD and APCS, but higher amount of cellulases was present in the crude enzyme induced by MGD. However, beta-glucosidase activity induced by MGD was not sufficient for hydrolyzing lignocellulosic biomass. High titers of cellulases and beta-glucosidase were achieved simultaneously by heterologous expression of aabgl1 in T. reesei and fed-batch fermentation through feeding MGD. We demonstrated that on-site cellulase production by T. reesei PB-3 has a potential for efficient biomass saccharification and ethanol production from lignocellulosic biomass. PMID- 29483943 TI - Complete genome sequence of Lactobacillus rhamnosus Pen, a probiotic component of a medicine used in prevention of antibiotic-associated diarrhoea in children. AB - Background: Lactobacillus rhamnosus Pen is a human endogenous strain with well documented health promoting properties that is used for production of probiotics. It has a long safety history of application, and its effectiveness in the prevention of antibiotic-associated diarrhoea has also been confirmed in clinical trials. Results: Here we present the complete genome sequence of L. rhamnosus Pen, which consists of a circular 2,884,4966-bp chromosome with a GC content of 46.8%. Within 2907 open reading frames (ORFs), genes involved with probiotic properties were identified. A CRISPR locus, consisting of a 1092-nt region with 16 spacers, was also detected. Finally, an intact prophage of ~ 40.7 kb, 57 ORFs, GC content 44.8% was identified. Conclusions: Genomic analysis confirmed the probiotic properties of L. rhamnosus Pen and may indicate new biotechnological applications of this industrially important strain. PMID- 29483944 TI - Molecular detection of human enteric viruses circulating among children with acute gastroenteritis in Valencia, Venezuela, before rotavirus vaccine implementation. AB - Background: The role of rotavirus as main etiologic agent of diarrhea has been well documented worldwide, including in Venezuela. However, information about the prevalence of gastrointestinal viruses such as calicivirus, adenovirus and astrovirus is limited and the contribution of other agents as Aichi virus and klassevirus is largely unknown. To explore the etiological spectrum of diarrhea associated with agents other than rotaviruses, 227 stool samples from children under 5 years old with acute gastroenteritis, collected in Valencia (Venezuela) from 2001 to 2005, and previously tested as rotavirus-negative, were analyzed for caliciviruses, adenoviruses, astroviruses, Aichi viruses, klasseviruses, picobirnaviruses and enteroviruses by specific RT-PCRs. Results: At least one viral agent was detected in 134 (59%) of the samples analyzed, mainly from children under 24 months of age and most of them belonging to the lowest socioeconomic status. Overall, enterovirus was identified as the most common viral agent (37.9%), followed by calicivirus (23.3%), adenovirus (11.5%), astrovirus (3.5%), klassevirus (1.3%) and Aichi virus (0.4%), while no picobirnavirus was detected. Klasseviruses were found during 2004 and 2005 and Aichi viruses only in 2005, indicating their circulation in Venezuela; meanwhile, the rest of the viruses were detected during the whole study period. Coinfections with two or more viruses were found in 39 (29.1%) of the infected children, most under 24 months of age. Adenovirus was involved as the coinfecting agent in at least 46.9% of the cases, but no differences concerning socio-demographic variables were observed between the coinfected and the single infected children. Conclusions: The results show that various enteric viruses, including enteroviruses, caliciviruses and adenoviruses, accounted for a significant proportion of infantile diarrhea cases in Venezuela before rotavirus vaccine implementation. In addition, emerging viruses as Aichi virus and klassevirus were found, indicating the need to continue monitoring their spreading into the communities. Efforts are needed to develop more accurate methods to identify the major causes of diarrhea and to provide tools for more effective preventive measures. PMID- 29483945 TI - Molecular epidemiology of genogroup II norovirus infections in acute gastroenteritis patients during 2014-2016 in Pudong New Area, Shanghai, China. AB - Background: Norovirus (NoV), a member of the Caliciviridae, is now recognized as the leading cause of acute gastroenteritis (AGE) worldwide. Globally, the GII.4 Sydney_2012 variant has predominated in NoV-related AGE since 2012, although the novel variant GII.17 has also been reported as responsible for gastroenteritis outbreaks in East Asia since 2014. This study aimed to disclose the recent genotype patterns of NoV genogroup II (GII) presenting in AGE patients in Pudong New Area of Shanghai through a laboratory-based syndromic surveillance system. The study further aimed to delineate the predominant strains circulating in the population. Methods: Pudong New Area is located in eastern Shanghai and covers 20.89% of the Shanghai population. The laboratory-based syndromic surveillance system is composed of 12 sentinel hospitals among the 68 general hospitals in this area. AGE patients who sought medical care were sampled following an AGE surveillance protocol. Stool samples were collected from participating patients, and a standardized questionnaire was given to each patient by trained nurses to gain information on the disease profiles and demographics of the patients. Real time reverse transcription polymerase chain reaction (qRT-PCR) was used to screen the GI nd GII NoV and RT-PCR was used to amplify NoV GII partial capsid protein open reading frame 2 (ORF2). NoV Genotyping Tool (version 1.0, RIVM, MA Bilthoven, Netherlands) was used for genotyping, and a phylogenetic analysis was conducted by MEGA 7.0. Results: During 2014-2016, among the 2069 virus-infected AGE cases, 65.88% were caused by NoV. NoV-AGE occurred most frequently in the periods from October to March. The patients with more severe diarrheal symptoms and vomiting were more likely to be infected by NoV. The main genotypes were GII.17 (44.69%) and GII.4 (39.26%), which dominated the NoV-AGE epidemics jointly or in turn, whereas a slight increase in GII.2 was observed beginning in May 2016. The GII.17 strains tended to cluster more with the Hu/JP/2014/GII.P17_GII.17/Kawasaki323 variants, representing novel prevalent strains. Among the GII.4 strains, the GII.4 Sydney_2012 variant was still the predominant strain. Conclusions: NoV GII has become the main cause of virus infected AGE in Pudong New Area, Shanghai. The predominant genotypes of NoV GII were GII.17 and GII.4. Comprehensive laboratory-based surveillance is important for clinical diagnosis and treatment. Identification of emerging new genotypes is also crucial for the prevention and control of NoV-infected AGE. PMID- 29483946 TI - The prevalence and risk factors of peripheral neuropathy among patients with type 2 diabetes mellitus; the case of Jordan. AB - Background: Peripheral neuropathy is one of the most common microvascular complication of diabetes mellitus. This study is conducted to determine the prevalence of diabetic peripheral neuropathy (DPN) and its associated factors among patients with type 2 diabetes mellitus in Jordan. Methods: A cross sectional study was conducted at the National Center for Diabetes, Endocrinology and Genetics, Jordan. A total of 1003 patients with type 2 diabetes were recruited. Data were collected from participants during a face-to-face structured interview. DPN was assessed using the translated version of Michigan Neuropathy Screening Instrument (MNSI). Results: The overall prevalence of DPN based on MNSI was 39.5%. The most frequently reported symptoms were numbness (32.3%) and pain with walking (29.7%), while the least reported symptoms were the history of amputation (1.3%) and loss of sensation in legs/feet while walking (3.8%). Logistic regression analysis revealed that unemployment, cardiovascular disease, dyslipidemia, diabetic retinopathy and long standing DM (diabetes of >= 5 years) were significantly associated with DPN. Conclusion: Peripheral Neuropathy is highly prevalent among Jordanian patients with type 2 diabetes mellitus. DPN was significantly associated with duration of DM, dyslipidemia, diabetic retinopathy, cardiovascular disease, and unemployment. Early detection and appropriate intervention are mandatory among high-risk groups. PMID- 29483948 TI - Prevalence and predictors of metabolic syndrome among people living with human immunodeficiency virus (PLWHIV). AB - Background: Use of combination antiretroviral therapy (cART) has led to significant reductions in morbidity and mortality. However, there is a growing concern about metabolic syndromes (MS), among patients receiving cART. Despite this fact, there is limited evidence for the prevalence of the MS among HIV infected persons receiving cART in developing countries, particularly Ethiopia. Objective: To determine the prevalence and predictors of MS among people living with HIV/AIDS in Jimma health centre, Jimma Zone south west Ethiopia. Methods: A cross-sectional study was conducted on people living with HIV/AIDS (PLWHA) in Jimma health centre that fulfilled the inclusion criteria. Data on demographic and anthropometric characteristics were collected using World health organization (WHO) stepwise approach. Fasting blood glucose and lipid profile was measured. The Third Report of National Cholesterol Education Program-adult treatment panel III (NCEP-ATP III)-2001, the International Diabetes Federation (IDF)-2005 and the Joint interim statement-2009 (JIS) criteria were used to define MS. Data were analyzed using statistical software package (SPSS) version 20.0. Logistic regression analysis was done to identify predictors of MS and predictors with p value < 0.05 were used to declare statistical significance. Results: Of 268 HIV infected participants included in the analysis, 211 (78.7%) were women. The mean age of the participants was 39.32 +/- 10.626 years. Using the NCEP-ATP III criteria, the prevalence of MS was found to be 23.5% (63 patients). While it was 20.5% (55 patients) and 27.6% (74 patients) with IDF and JIS criteria respectively. Enrollment in formal education resulted in 75% increment in the odds of MS (AOR = 0.25, 95% CI [0.072-0.879]). The odds of MS in patients with body mass index > 25 kg/m2 was elevated to 13.4 times (AOR = 13.39, 95% CI [3.943 45.525]) and exposure to D-drugs was attributed to 59% increment in the odds of MS (AOR = 1.59, 95% CI [0.58-4.56]), although the finding lacks statistical significance. Conclusions: Metabolic syndromes was relatively common to the study population. Hence, promoting health education and monitoring patient's clinical and laboratory parameters at every visit and taking appropriate measure is ideal. PMID- 29483947 TI - Metabolic syndrome and the skin: a more than superficial association. Reviewing the association between skin diseases and metabolic syndrome and a clinical decision algorithm for high risk patients. AB - There is ongoing scientific interest regarding comorbidities associated with the metabolic syndrome (MeTS). MeTS comprises a combination of parameters that predispose individuals to the development of type 2 diabetes and cardiovascular disease (CVD). Three or more of the following criteria are necessary: fasting glucose > 110 mg/dl (5.6 mmol/l), hypertriglyceridemia > 150 mg/dl (1.7 mmol/l), HDL levels < 40 mg/dl (men)/< 50 mg/dl (women), blood pressure > 130/85 mmHg, waist circumference (values for Mediterranean populations > 94 cm (men)/> 89 cm (women). In this review we attempted to summarize relevant data by searching dermatological literature regarding associations between various skin conditions and MeTS. A multitude of studies was retrieved and a further goal of the present article is to present plausible mechanistic connections. The severity of skin conditions like psoriasis has been linked with MeTS. Parameters of MeTS like insulin resistance are present in patients with early onset androgenic alopecia, hidradenitis suppurativa acne and rosacea. Since MeTS can lead to CVD and type 2 diabetes early detection of patients would be very important. Also therapeutic intervention on MeTS could lead to improvement on the severity of skin conditions. This reciprocal relationship between skin diseases and MeTS in our opinion holds great interest for further investigation. PMID- 29483949 TI - The Unknown microRNA Expression of Male Breast Cancer. Similarities and Differences with Female Ductal Carcinoma. Their Role as Tumor Biomarker. AB - : Mature microRNAs (miRNAs) are small non-protein coding RNAs that modulate gene expression after transcription. Few studies have shown that male breast cancer (MBC) shows distinctive miRNAs pattern, suggesting its relevance in this pathology. To study this, we performed a profile of 800 miRNAs in 9 MBC samples and in normal epithelial cells of 3 MBC cases. EXPERIMENTAL DESIGN: Of FFPE tissues, miRNA was extracted for profiles using the NanoString method. miRNAs were obtained by comparing tumor samples versus normal epithelium. Quantitative real-time PCR analyzes were performed by the TaqMan approach for specific miRNAs. RESULTS: The profile of 800 miRNAs showed a different microRNA expression pattern between MBC and its normal counterpart, suggesting a specific microRNA cancer expression profile for MBC. Forty-nine miRNAs showed greater expression, while 26 were found to be down-regulated in MBC, compared to normal tissue. The lower expression of miR-125b correlated significantly with tumors> 2 cm, suggesting that its down-regulation may be implicated in mechanisms to more aggressive tumors. CONCLUSIONS: These results suggest that MBC has a unique expression profile compared to normal breast tissue and expression profile of female breast cancer. Differentially expressed miRNAs provide insights of this uncommon but highly aggressive pathology. PMID- 29483950 TI - MK2 and ETV1 Are Prognostic Factors in Esophageal Adenocarcinomas. AB - Background. Esophageal cancer is ranked in the top ten of diagnosed tumors worldwide. Even though improvements in survival could be noticed over the last years, prognosis remains poor. ETS translocation variant 1 (ETV1) is a member of a family of transcription factors and is phosphorylated by mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2). Aim of this study was to evaluate the prognostic role of MK2 and ETV1 in esophageal cancer. Methods. Consecutive patients that underwent surgical resection at the department of surgery at the Medical University of Vienna between 1991 and 2012 were included into this study. After microscopic analysis, tissue micro arrays (TMAs) were created and immunohistochemistry was performed with antibodies against MK2 and ETV1. Results. 323 patients were included in this study. Clinical data was achieved from a prospective patient data base. Nuclear overexpression of MK2 was observed in 143 (44.3%) cases for nuclear staining and in 142 (44.0%) cases a cytoplasmic overexpression of MK2 was observed. Nuclear and cytoplasmic ETV1 overexpression was detected in 20 cases (6.2%) and 30 cases (9.3%), respectively. In univariate survival analysis, cMK2 and nETV1 were found to be significantly associated with patients' overall survival. Whereas overexpression of cMK2 was associated with shorter, nETV1 was associated with longer overall survival. In multivariate survival analysis, both cMK2 and nETV1 were found to be independent prognostic factors for the subgroup of EAC as well. Discussion. Expression of MK2 and ETV1 are prognostic factors in patients, with esophageal adenocarcinoma. PMID- 29483951 TI - Exploration of Racial Differences in Reproductive Factors for Breast Cancer among Women aged 55-74. AB - Background Reproductive factors have been well-documented risk factors for breast cancer. Few studies have examined whether the associations between reproductive factors and breast cancer differed across races/ethnicities. Methods We analyzed a sub-sample (70, 734) of the Prostate, Lung, Colorectal, and Ovarian (PLCO) dataset. Participants with valid baseline questionnaire and without breast cancer at enrollment were included into analysis. We stratified the participants into subgroups based on their races/ethnicities then estimated the effects of the reproductive factors on breast cancer within each group using Cox-proportion regression models. Results Oral contraceptive use (HR=1.09, 95% confidence interval or CI=1.01, 1.18), advanced age at natural menopause (HR=1.25, 95% CI=1.06, 1.49) were associated with increased risk of breast cancer in non Hispanic Caucasians group only. Long term use of menopausal hormone therapy (more than five years) was associated with increased risk of breast cancer in both of the non-Hispanic Caucasian (HR=1.44, 95% CI=1.31, 1.59) group and the non Hispanic Asian/Pacific Islander (HR=1.98, 95% CI=1.23, 3.20) group, but not in other race/ethnic groups. Hispanics who tried to become pregnant for a year or more had increased risk of breast cancer (HR=2.60, 95% CI=1.05, 6.46) than their counterparts without difficulty in getting pregnancy. In addition, surgery induced menopause was found to be a protective factor for breast cancer in non Hispanic Caucasian (HR=0.88, 95% CI=0.79, 0.98) group only. Conclusions We concluded that different races/ethnicities had different breast cancer related reproductive risk factors. Non-Hispanic Caucasians had the most breast cancer related reproductive risk factors, while the minorities had none or few breast cancer related reproductive risk factors and among these few factors only 1 was also risk factor for non-Hispanic Caucasians. PMID- 29483952 TI - Clinicopathological Characteristics of the primary and metastatic Hepatic Neuroendocrine Tumors and the relevant Prognosis-Related Factors: A Retrospective Study of 81 Cases in a Single Chinese Center. AB - Aims: We aim to describe the clinicopathological characteristics of hepatic neuroendocrine tumors (HNETs) and evaluate the relevant prognosis-related factors. Methods: The clinical data of 81 consecutive patients with primary or metastatic HNETs from March 2000 to July 2014 were retrospectively analyzed. Results: The mean (SD) age was 59.68 (11.64) years, 69.15% were men. The percentages of Grade G1, G2 and G3 tumors were 4.94%, 25.93% and 69.13%, respectively. Thirty-five cases were primary HNETs. Primary HNETs were more common in patients with larger tumors, lymph nodes invasions, tumor necrosis and portal vein tumor thrombus. The 1-, 3-, and 5-year overall survival rate were 88.89%, 32.10%, and 8.64%, separately. The relapse rate was 81.48% (66/81) and the mean (SD) relapse time was 18.79 (10.99) months. Reduced survival rate was associated with lymph node metastases (P=0.034), tumor necrosis (P=0.048), hard texture of tumor character (P=0.001), multifocality of tumor numbers (P=0.043), and the immunohistochemical expression of NSE (P=0.000) and Syn (P=0.037). Patients with metastatic HNETs were demonstrated with a more decreased period of Progression-free Survival (PFS) and Overall survival (OS) than their primary HNETs counterparts (P<0.05). Conclusion: Primary HNETs cohort patients were more common with aggressive clinical presentation. The hard texture of tumor character, multifocality of tumor numbers, and the immunohistochemical expression of NSE and Syn were independent predictive factors. Patients who were pathologically diagnosed as the primary HNETs seemed to achieve a long-term survival. PMID- 29483953 TI - Influence of diabetes on the risk of urothelial cancer according to body mass index: a 10-year nationwide population-based observational study. AB - To examine the association between obesity and urothelial cancer, we used a representative data from the National Health Insurance System (NHIS). Participants included 826,170 men aged 20 years and older who experienced a health examination at least one time between 2004 and 2008. The study thus excluded people aged <20 years and women. We used a multivariate adjusted Cox regression analysis to examine the association between urothelial cancer and body mass index (BMI) via a hazard ratio (HR) and 95% confidence interval (CI). The age- or multivariable-adjusted HR for urothelial cancer was stratified by BMI. Men with a higher BMI were more likely to acquire urothelial cancer independent of variables. In the population with diabetes, there showed a considerable, increasing trend in the risk of urothelial cancer in the overweight and obesity group, compared to the group with the same BMI but without diabetes. This population-based study showed evidence of an association between obesity and the development of urothelial cancer, where the presence of diabetes increased the risk of urothelial cancer. Additionally, the higher the BMI, the higher the risk for urothelial cancer. PMID- 29483954 TI - Clinical significance and diagnostic capacity of serum TK1, CEA, CA 19-9 and CA 72-4 levels in gastric and colorectal cancer patients. AB - Despite extensive progress in treatment for cancer in recent decades, the early diagnosis for gastric cancer (GC) and colorectal cancer (CRC) remains poor. In this study, we explore the diagnostic value of joint detection of thymidine kinase 1 (TK1), carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19 9) and carbohydrate antigen 72-4 (CA 72-4) in the diagnosis of GC and CRC, and to evaluated the relationship between TK1 expression and clinical pathological characteristics in the patients. Serum TK1, CA 19-9, CA 72-4 and CEA levels were measured in 169 patients with GC, 344 patients with CRC and 75 healthy controls using electro-chemiluminescence. The TK1 concentration was significantly higher in patients with cancer than in healthy controls and patients with clinical stage III+IV had higher TK1 levels than clinical stage I+II (P<0.05). The levels of TK1 is significantly associated with tumor stage, lymph node metastasis, distant metastasis, tumor differentiation and age (P<0.05). When the tumor markers (TK1, CA 19-9 and CA 72-4) were detected respectively, the area under receiver operating characteristics curve (AUC) of TK1 for three cancers was the highest (0.823-0.895). However, the combination of AUC was higher than that for each tumor marker detected respectively (0.934-0.953), and the Hosmer-Lemeshow test showed an adequate model of calibration (P>0.05). Moreover, the AUCs varied significantly between the combination tests and single biomarker tests (Z test, P<0.01). In conclusion, serum TK1 may be an independent tumor marker for GC and CRC patients, and the combination of TK1, CA 19-9 and CA 72-4 and CEA performed even better. This study suggests that combination detection of four tumor markers may prove to be useful for the diagnosis of GC and CRC. PMID- 29483955 TI - Recombinant nanocomposites by the clinical drugs of Abraxane(r) and Herceptin(r) as sequentially dual-targeting therapeutics for breast cancer. AB - Breast cancer greatly threatens the health of women all over the word despite of several effective drugs. Targeted therapy for breast cancer is limited to human epidermal growth factor receptor 2 (HER2). Herceptin(r), monoclonal antibody against HER2, is now widely used in HER2(+) breast cancer. Abraxane(r), the current gold standard for paclitaxel (PTX) delivery, has shown superiority in breast cancer based on nanoparticle albumin bound technology. Despite these advances, further novel targeted therapy with more improved anti-tumor efficacy for breast cancer is still urgently needed. Here, we report the recombinant nanocomposites (NPs) composed of the above two clinical drugs of Abraxane(r) and Herceptin(r) (Abra/anti-HER2), which at first migrates to the tumor region through the unique targeting mechanism of human serum albumin (HSA) of Abraxane(r), and sequentially further precisely recognize the HER2(+) breast cancer cells due to Herceptin(r). The Abra/anti-HER2 NPs were fabricated by a "one-step" synthesis using EDC/NHS. In vitro analysis of cell viability, apoptosis and cell cycle revealed that Abra/anti-HER2 NPs showed more anti-tumor efficacy against HER2(+) SK-BR-3 cells than Abraxane(r) at equivalent PTX concentration. In addition, in HER2(+) breast cancer xenograft model, Abra/anti HER2 NPs significantly inhibited tumor growth with less side effects. Moreover, the properties of more precise target and delayed release of PTX were proved by NIRF imaging. Thus, our results indicate that Abra/anti-HER2 NPs could represent a next-generation sequentially dual-targeting therapeutic agent for HER2(+) breast cancer. PMID- 29483956 TI - Elevated baseline serum lactate dehydrogenase indicates a poor prognosis in primary duodenum adenocarcinoma patients. AB - Purpose: Tumour cells produce energy through glycolysis and lactate dehydrogenase (LDH) is a key part of glycolysis. Elevation of serum LDH may indicate poor prognosis in primary duodenum adenocarcinoma. We aim to explore the prognostic significance of LDH in this disease. Methods and materials: Two hundred forty four patients diagnosed with primary duodenum adenocarcinoma who were treated at the Sun Yat-sen Cancer Center from February 1996 to January 2016 were retrospectively analysed. We collected routine clinical data, including baseline LDH. Patients were classified into a normal LDH group (<= 245U/L) and higher LDH group (>245U/L). Correlations of the LDH level and other clinicopathological characteristics were explored using the Chi-square test. Prognostic factors for overall survival were identified using univariate and multivariate analyses. Results: Two hundred seven patients (84.9%) had normal LDH levels, while 37 patients (15.1%) had abnormally high LDH levels. Higher LDH levels were significantly associated with more distant metastasis, node metastasis, poor differentiation and TNM stage III-IV (P<0.05). Consistently, patients with node metastasis, poor differentiation and TNM stageIII-IV had a significantly higher median LDH level (P<0.05). The median survival of patients in the higher LDH group was significantly shorter than that of the patients in the normal LDH group (16.3 m vs. 42.5 m, P=0.02). Using multivariate analysis, LDH, age and radical surgery were independent prognostic factors associated with overall survival(OS) (HR=1.571, P=0.036 for LDH; HR=1.514, P=0.013 for age; HR=0.248, P<0.0001 for radical surgery, respectively). Conclusions: For the first time, our research suggests that baseline serum LDH is an independent prognostic factor in primary duodenum adenocarcinoma patients and elevated baseline serum LDH indicates a poor prognosis. PMID- 29483957 TI - Overexpression of MICAL2, a novel tumor-promoting factor, accelerates tumor progression through regulating cell proliferation and EMT. AB - Molecule interacting with CasL 2 (MICAL2), a microtubule associated monooxygenase, is involved in cell growth, axon guidance, vesicle trafficking and apoptosis. Recent studies have demonstrated that MICAL2 is highly expressed in tumor and accelerates tumor progression and it is deemed to be a novel tumor promoting factor. MICAL2 overexpression increases cell proliferation to accelerate tumor growth, and MICAL2 also promotes epithelial-mesenchymal transition (EMT)-related proteins to increase cancer cell metastasis. On mechanism, MICAL2 induces EMT by regulating SRF (serum response factor)/MRTF-A (myocardin related transcription factor A) signaling, Semaphorin/Plexin pathway and inducing ROS (Reactive oxygen species) production. In the present review, we introduced MICAL family, expatiated the structure and functions of MICALs, and summarized the mechanisms of MICAL2 involving tumor progression. The challenges and perspectives for MICAL2 in tumor are also discussed. PMID- 29483958 TI - Impact of Weight Loss at Presentation on Survival in Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKI) Sensitive Mutant Advanced Non small Cell Lung Cancer (NSCLC) Treated with First-line EGFR-TKI. AB - Purpose The aim of this study is to evaluate the impact of weight loss at presentation on treatment outcomes of first-line EGFR-tyrosine kinase inhibitors (EGFR-TKI) in EGFR-TKI sensitive mutant NSCLC patients. Methods We retrospectively analyzed the clinical outcomes of 75 consecutive advanced NSCLC patients with EGFR-TKI sensitive mutations (exon 19 deletion or exon 21 L858R) received first-line gefitinib or erlotinib therapy according to weight loss status at presentation in our single center. Results Of 75 EGFR-TKI sensitive mutant NSCLC patients, 49 (65.3%) patients had no weight loss and 26 (34.7%) had weight loss at presentation, the objective response rate (ORR) to EGFR-TKI treatment were similar between the two groups (79.6% vs. 76.9%, p = 0.533). Patients without weight loss at presentation had significantly longer median progression free survival (PFS) (12.4 months vs. 7.6 months; hazard ratio [HR] 0.356, 95% confidence interval [CI] 0.212-0.596, p < 0.001) and overall survival (OS) (28.5 months vs. 20.7 months; HR 0.408, 95% CI 0.215-0.776, p = 0.006) than those with weight loss at presentation; moreover, the stratified analysis by EGFR TKI sensitive mutation types also found similar trend between these two groups except for OS in EGFR exon 21 L858R mutation patients. Multivariate analysis identified weight loss at presentation and EGFR-TKI sensitive mutation types were independent predictive factors for PFS and OS. Conclusions Weight loss at presentation had a detrimental impact on PFS and OS in EGFR-TKI sensitive mutant advanced NSCLC patients treated with first-line EGFR-TKI. It should be considered as an important factor in the treatment decision or designing of EGFR-TKI clinical trials. PMID- 29483959 TI - Association between NEFL Gene Polymorphisms and Neuroblastoma Risk in Chinese Children: A Two-Center Case-Control Study. AB - Neuroblastoma is a lethal tumor that mainly occurs in children. To date, the genetic etiology of sporadic neuroblastoma remains obscure. A previous study identified three neuroblastoma susceptibility loci (rs11994014 G>A, rs2979704 T>C, rs1059111 A>T) in neurofilament light (NEFL) gene. Here, we attempted to evaluate the contributions of these three single nucleotide polymorphisms to neuroblastoma susceptibility in Chinese children. We genotyped these three polymorphisms using subjects from Guangdong province (256 cases and 531 controls) and Henan province (118 cases and 281 controls). Logistic regression models were performed to generate odds ratios and 95% confidence intervals to access the association of these three polymorphisms with neuroblastoma risk. Overall, we failed to provide any evidence supporting the association between these three polymorphisms and neuroblastoma susceptibility, either in single center population or in the combined population. Moreover, such null association was also observed when the samples were stratified by age, gender, tumor sites, and clinical stages. In the future, larger samples from different ethnicities are needed to clarify the role of NEFL gene polymorphisms in neuroblastoma risk. PMID- 29483960 TI - Clinical study on the prevalence and comparative analysis of metabolic syndrome and its components among Chinese breast cancer women and control population. AB - Metabolic syndrome has been previously identified as a risk factor for breast cancer and is increasingly a public health concern. This study aims to investigate the prevalence of metabolic syndrome and its components among primary breast cancer and control population. The clinical data of metabolic syndrome and its components in the breast cancer (605 cases) and control population (3212 cases), from Breast Cancer Center and Physical Examination Center of Chongqing, China, from July 2015 to February 2017, were collected for comparative analysis. This study was prospectively registered in Chinese Clinical Trial Registry (http://www.chictr.org.cn/, number: ChiCTR-OOB-15007543). The prevalence of metabolic syndrome in breast cancer (32.6%) was obviously higher than that in control population (18.2%) (p<0.001; OR: 2.173, 95%CI: 1.793 to 2.633). With age stratification, the prevalence of metabolic syndrome in breast cancer group aged below 60 years (24.9%, p<0.001; OR: 2.216, 95%CI: 1.744 to 2.816) and equal/above 60 years (58.3%, p<0.001; OR: 2.291, 95%CI: 1.580 to 3.322) were also statistically higher than those (13.0% & 37.9%) in control population, respectively. Breast cancer women were more likely to have preobese (BMI 25.0 29.9) or obesity (BMI >=30.0), broader waist circumference, lower HDL-C level, higher systolic and/or diastolic blood pressure and higher fasting blood glucose level compared to the control population, corresponding prevalence were 31.7%vs.19.4%, 76.0%vs.29.6%, 37.4%vs.30.4%, 34.2%/27.3%vs.27.6%/14.2% and 25.0%vs.20.1%, respectively (p<0.01). In summary, there is high prevalence of metabolic syndrome and its components in Chinese breast cancer women, and metabolic syndrome is closely related with breast cancer. Therefore, screening and prevention strategy of metabolic syndrome should be carried out in the management of breast cancer. PMID- 29483961 TI - The prognostic value of Niemann-Pick C1-like protein 1 and Niemann-Pick disease type C2 in hepatocellular carcinoma. AB - Niemann-Pick C1-like 1 (NPC1L1) and Niemann-Pick C2 (NPC2) is a critical mediator of cholesterol absorption. The aim of the present study was to investigate the prognostic value of NPC1L1 and NPC2 in human primary hepatocellular carcinoma (HCC). The expression level of NPC1L1 and NPC2 were evaluated by Immunohistochemistry, Westen blot and Real-time Quantitative PCR. Protein expression level in tissue was represented by integral optic density (IOD). For prognosis analyses, outcome-based cut-point was calculated by X-tile software. Kaplan-Meier analysis, Cox regression analysis were used evaluate prognostic value of NPC1L1 and NPC2 and NPC1L1/NPC2 combination. Both of NPC1L1 and NPC2 were significantly decreased in HCC tissues than peritumoral liver tissues (61 pairs of tissue for Immunohistochemistry and 10 pairs of tissues for Western blot and Real-time Quantitative PCR), respectively. (n=61: p=0.0005 for NPC1L1 and p=0.0001 for NPC2; n=10: p=0.0002 for NPC1L1 and p=0.0489 for NPC2). Kaplan-Meier analyses in 265 HCC cases were showed that the low expression level of NPC1L1 and NPC2 and NPC1L1/NPC2 combination were significantly correlated with poor overall survival (OS) and shorter time to recurrence (TTR). In addition, univariate and multivariate Cox analyses showed that the expression level of NPC1L1/NPC2 combination in HCC was an independent prognostic factor for OS and TTR. Conclusion: NPC1L1 and NPC2 were lowly expressed in HCC compared with peritumoral liver tissues, and low expression of NPC1L1 and NPC2 in HCC tissues may indicate poor outcome of HCC patients after surgery. NPC1L1/NPC2 combination is an independent prognostic factor for OS and TTR in postoperative HCC patients. PMID- 29483962 TI - Folic acid-modified diatrizoic acid-linked dendrimer-entrapped gold nanoparticles enable targeted CT imaging of human cervical cancer. AB - It has been a great challenge to develop multifunctional fluorescent nanoprobes for tumor-targeted imaging. In this study, we developed folic acid (FA) gold nanoparticles (AuNPs) through diatrozic acid (DTA) linking for in vitro and in vivo targeted imaging of HeLa cervical cancer cells by computed tomography (CT). G5 dendrimers were used as templates to synthesize AuNPs within the interiors of dendrimers. The synthesized AuNPs were then sequentially modified by fluorescein isothiocyanate, FA, and DTA and the remaining terminal amines on the dendrimers were acetylated. We further performed hematoxylin and eosin staining, cell viability assay, flow cytometric analysis of cell cycle and apoptosis, and hemolytic assay to examine the cytotoxicity and hemocompatibility of the particles. The specific uptake of the nanoparticles by HeLa cells was determined through inductively coupled plasma atomic emission spectroscopy determination of silver and transmission electron microscopy. Lastly, HeLa cells and a xenografted HeLa tumor model were employed to evaluate the in vitro and in vivo targeted CT imaging performances of the nanoparticles, respectively. We showed that Au DENPs FA-DTA does not cause cytotoxic effects on both HeLa cancer cells and healthy normal cells in mice, demonstrating the superior biocompatibility and stability of the particles in the given concentration range. Micro-CT images documented that HeLa cells incubated with Au DENPs-FA-DTA in vitro could be identified by X ray examinations and that HeLa cells xenografts in BALB/c nude mice could be imaged after the mice were administered with the particles intravenously or intratumorally. The FA-modified AuNPs enabled targeted CT imaging of HeLa cells overexpressing FA receptors in vitro and in vivo. Taken together, our results showed that the AuNPs we developed exhibit great potentials as imaging probes for targeted CT imaging of human cervical cancer. PMID- 29483963 TI - Down-expression of CD36 in pancreatic adenocarcinoma and its correlation with clinicopathological features and prognosis. AB - Recent studies show that CD36 plays a key role in the occurrence and development of tumors, especially in the metastasis of tumors. However, the expression and role of CD36 has not been reported in pancreatic cancer. This study is aimed to explore the expression of CD36 in pancreatic cancer and corresponding non-tumor normal tissues, and its correlation with clinicopathological features and prognosis of pancreatic cancer patients. By analyzing the chip results of database GSE16515, we found that there was significant differential expression of CD36 in pancreatic cancer and corresponding non-tumor normal tissues. In this study, western blot and immunohistochemistry were used to show that the expression of CD36 in pancreatic cancer cells and tissues is significantly lower than that in corresponding non-tumor normal tissues. By statistically analyzing clinical and pathological data, we found that low expression of CD36 predicts lower TNM staging and CA19-9 levels, but larger tumor size and poor survival prognosis. These findings indicated that CD36 can be used as a predictor of clinicopathological features and prognosis, but the contradiction is worthy of our further study. PMID- 29483964 TI - Role of Postoperative Concurrent Chemoradiotherapy for Esophageal Carcinoma: A meta-analysis of 2165 Patients. AB - Purpose: This meta-analysis was aimed to evaluate the role of postoperative concurrent chemoradiotherapy (post-CCRT) for esophageal cancer patients after surgery. Methods: We systematically searched PubMed, PMC, EMBASE, Cochrane Central Register of Controlled Trials, Chinese National Knowledge Infrastructure and Wanfang databases. Studies which compared CCRT with non-CCRT treatment for esophageal cancer patients after surgery were eligible. Outcomes of interest were odds ratios (OR) for overall survival (OS), local-regional recurrence rate, distant metastasis rate and adverse-event rate. Results: Thirteen studies with 2165 patients were included in this meta-analysis. Post-CCRT significantly improved OS for esophageal cancer patients. Comparing the CCRT group with the non CCRT one, the OR and 95% confidence interval (CI) for 1-year, 3-year and 5-year OS were 1.66 [1.30-2.11], 1.50 [1.24-1.81] and 1.54 [1.22-1.94], respectively. The local-regional recurrence rate was significantly reduced in the CCRT group (OR=0.58, 95% CI=0.46-0.72), but no significant difference was observed in the distant metastasis rate between the CCRT and non-CCRT groups (OR=0.94, 95% CI=0.68-1.30). Post-CCRT didn't increase the risk of pneumonitis, anastomotic stenosis or severe hematologic toxicities. Mild esophagitis in the CCRT group was increased but could be well tolerated. Conclusions: This meta-analysis based on the largest-scale of published literature confirms that post-CCRT yields significant survival benefit and improves local-regional control with tolerable toxicity for patients with esophageal carcinoma. PMID- 29483965 TI - Additional induction chemotherapy to concurrent chemotherapy and intensity modulated radiotherapy with or without nimotuzumab in first-line treatment for locoregionally advanced nasopharyngeal carcinoma: a propensity score matched analysis. AB - Background: The aim of this study is to assess the survival benefits of additional induction chemotherapy before concurrent chemotherapy, intensity modulated radiotherapy and nimotuzumab in patients with locoregionally advanced nasopharyngeal carcinoma. Methods: Clinical data from 1104 nonmetastatic nasopharyngeal carcinoma patients diagnosed between May 2008 and April 2014 were retrospectively reviewed. All patients received addition of induction chemotherapy to concurrent chemoradiotherapy with or without nimotuzumab. A propensity score matched method was used to identify paired patients according to various covariates. Results: In total, 120 pairs were selected by propensity score matched method. At a median follow-up time of 56 months (10-99 months), the 5-year locoregional relapse-free survival, distant metastases-free survival, progression-free survival and overall survival rates in patients treated with nimotuzumab vs. without nimotuzumab were 91.6% vs. 91.1% (P= 0.957), 95.8% vs. 83.9% (P= 0.007), 87.4% vs. 81.3% (P= 0.225), 94.5% vs. 85.6% (P= 0.058), respectively. Multivariate analysis revealed that nimotuzumab was an independent prognosticator of OS and DMFS. Conclusions: Nimotuzumab is an effective treatment option for locoregionally advanced nasopharyngeal carcinoma, and the addition of induction chemotherapy to concurrent chemoradiotherapy and nimotuzumab could obtain the best survival benefits. PMID- 29483966 TI - Differential expression and clinical significance of epithelial-mesenchymal transition markers among different histological types of triple-negative breast cancer. AB - Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease closely associated with epithelial-to-mesenchymal transition (EMT). This study aimed to investigate the role of EMT in metaplastic carcinoma. Methods: E cadherin, Slug, Twist and Vimentin levels were detected by immunohistochemistry in 167 TNBC tumors, including 145 invasive carcinomas of no special type (ICONSTs), 14 spindle cell carcinomas (SpCCs) and 8 matrix-producing carcinomas (MPCs). Results: Nuclear Slug and Twist were more frequently detected in SpCC and MPC tumors than that in ICONST tumors (p<0.001). The rate of E-cadherin loss was much lower in the ICONST tumors than that in the SpCC and MPC tumors (p<0.001). Vimentin was expressed in all SpCC and MPC tumors. Furthermore, nuclear expression of Slug and Twist was positively associated with the cytoplasmic localization of Vimentin (p<0.001) and was inversely associated with membranous staining of E-cadherin (p<0.001). These trends were more apparent in the SpCC and MPC tumors than in the ICONST tumors. Follow-up data were available for 151 patients. The follow-up times ranged from 1 month to 11 years (mean: 74 m; median: 21 m). The median progression-free survival and overall survival times were 24 months (mean: 32 months) and 22 months (mean: 35 months), respectively. Tumor size, TNM stage and E-cadherin were found to be independent prognostic factors of TNBC. Conclusions: EMT may play an important role in TNBC, especially in MPC and SpCC. Further researches are needed to confirm this finding. The results of this study may facilitate the future development of targeted therapies based on alterations in the EMT and stem cell markers. PMID- 29483967 TI - The role of cancer-associated fibroblast MRC-5 in pancreatic cancer. AB - Background: Our previous study showed that cancer-associated fibroblast MRC-5 promoted hepatocellular carcinoma progression by enhancing migration and invasion capability. However, few studies have explored the role of MRC-5 in pancreatic cancer (PC). In this study, we examined the exact role and associated mechanisms of MRC-5. Methods: The conditioned media for MRC-5 was used to culture PC cell lines SW1990 and PANC-1. Cell proliferation was compared based on colony formation assays of PC cells in normal media and of PC cells cultured with conditioned media of MRC-5. Cell migration and invasion were assayed by transwell chambers. The expression of EMT-related proteins and apoptosis-related proteins was evaluated using Western blot. And confocal microscopy was used to further detect the expression of EMT-related proteins. qRT-PCR was used to confirm the expression changes of related genes at the mRNA level. We also used flow cytometry to examine the cell cycle, apoptotic rate, and expression of CD3, CD4, CD14, CD25, CD45, CD61, CD90, TLR1, and TLR4. Results: MRC-5 repressed the colony formation ability of PC cells and significantly inhibited cell migration and invasion potential. MRC-5 induced S-phase cell cycle arrest but did not augment the apoptotic effects in PC cells. We hypothesized that the weakened malignant biological behavior of PC cells was correlated with MRC-5-induced altered expression of the cancer stem cell marker CD90; the immune-related cell surface molecules CD14, CD25, TLR4, and TLR1; and cell polarity complexes Par, Scribble, and Crumbs. Conclusion: MRC-5 limits the malignant activities of PC cells by suppressing cancer stem cell expansion, remolding epithelial polarity, and blocking the protumoral cascade reaction coupled to TLR4, TLR1, CD14, and CD25. PMID- 29483968 TI - High Quality Draft Genomes of the Type Strains Geobacillus thermocatenulatus DSM 730T, G. uzenensis DSM 23175T And Parageobacillus galactosidasius DSM 18751T. AB - The thermophilic 'Geobacilli' are important sources of thermostable enzymes and other biotechnologically relevant macromolecules. The present work reports the high quality draft genome sequences of previously unsequenced type strains of Geobacillus uzenensis (DSM 23175T), G. thermocatenulatus (DSM 730T) and Parageobacillus galactosidasius (DSM 18751T). Phylogenomic analyses revealed that DSM 18751T and DSM 23175T represent later heterotypic synonyms of P. toebii and G. subterraneus, respectively, while DSM 730T represents the type strain for the species G. thermocatenulatus. These genome sequences will contribute towards a deeper understanding of the ecological and biological diversity and the biotechnological exploitation of the 'geobacilli'. PMID- 29483969 TI - Innovations and Innovative Approaches or Pseudo-Innovations in the Context of General Globalization? It's Time to Wake Up! AB - Globalisation, scientific and technical progress are the basis of numerous innovative therapies for oncologic and non-oncologic diseases. It is another matter how much and by whom they are desired, and whether they have to be applied. When and how often? Innovative approaches should go towards simplification, universal distribution and application while at the same time analysis between the potential initial investment and the achieved final result should be made. An illustrative example for this is the targeted therapy for melanoma with its low baseline criteria or basic rules for its surgical treatment. Another example could be the confocal microscopy in the context of dysplastic nevus syndrome. Therapies for various autoimmune diseases should also be considered critically. In the current OAMJMS issue, as well as in some of our other ideas and statements reported also in OAMJMS, we are trying to answer at least to a part of these dilemmas, to provoke a critical point of view and to ask some simple questions: "Should any innovation be considered as a face value? Which is potentially beneficial for our patients? How could we regulate the processes to minimise the need for expensive medications for certain diseases? And, of course, we are also turning to our own mistakes by visualising the results of them! PMID- 29483970 TI - Early Regenerative Modifications of Human Postmenopausal Atrophic Vaginal Mucosa Following Fractional CO2 Laser Treatment. AB - BACKGROUND: Postmenopausal women experience undesired symptoms that adversely affect their quality of life. In the recent years, a specific 12 - week fractional CO2 laser treatment has been introduced, with highly significant relief of symptoms. AIM: The aim of this paper is the identification of the early modifications of structural components of atrophic vaginal mucosa induced by laser irradiation, which is responsible for the restorative processes. MATERIAL AND METHODS: We investigated by microscopical, ultrastructural and biochemical methods the modifications of the structural components of postmenopausal atrophic vaginal mucosa tissues after 1 hour following a single fractional laser CO2 application. RESULTS: In one hour, the mucosal epithelium thickens, with the maturation of epithelial cells and desquamation at the epithelial surface. In the connective tissue, new papillae indenting the epithelium with newly formed vessels penetrating them, new thin fibrils of collagen III are also formed in a renewed turnover of components due to the increase of metalloproteinase - 2. Specific features of fibroblasts support stimulation of their activity responsible of the renewal of the extracellular matrix, with an increase of mechanical support as connective tissue and stimulation of growth and maturation to epithelium thanks to new vessels and related factors delivered. CONCLUSION: We found the activation of regenerative mechanisms expressed both in the connective tissue - with the formation of new vessels, new papillae, and new collagen - and in the epithelium with the associated thickening and desquamation of cells at the mucosal surface. PMID- 29483971 TI - In Vitro Evaluation of the Biosafety of Hyaluronic Acid PEG Cross-Linked with Micromolecules of Calcium Hydroxyapatite in Low Concentration. AB - OBJECTIVE: Neauvia Stimulate is biocompatible, injectable hyaluronic acid (HA) filler (26 mg/ml) PEG cross-linked with 1% of calcium hydroxyapatite (CaHA) for facial soft-tissue augmentation that provides volume to tissues, followed by process of neocollagenesis for improving skin quality. AIM: The aim of the present study is to evaluate the biosafety of the product (Lot. 160517-26-1/2 PEG) on human keratinocytes cultured in vitro. MATERIAL AND METHODS: The experimental model proposed, despite being an in vitro system, allows the derivation of useful information to predict the possible activity of the product in further in vivo application. Human keratinocytes (HaCaT cells) were treated with the product for 24h at increasing concentrations of product respect to control (untreated cells). RESULTS: The biosafety of the product to be tested has been evaluated performing different methods: MTT test, NRU test, Kenacid Blue assay. Moreover, any possible effect on the structure, morphology, and viability of cells has been evaluated. CONCLUSION: In conclusion, the results obtained by the different methods show that the product Neauvia Stimulate(r) does not cause any cytotoxic effect and does not affect the correct structure and morphology of cells cultures. PMID- 29483972 TI - In Vitro Evaluation of the Sensitivity of a Hyaluronic Acid PEG Cross-Linked to Bovine Testes Hyaluronidase. AB - Neauvia Intense is biocompatible, injectable hyaluronic acid (HA) filler PEG cross-linked for facial soft-tissue augmentation that provides volume to tissues. The aim of the present study is to evaluate the sensitivity of Neauvia Intense in hyaluronidase from bovine testes in a time-course analysis. The test is based on the colourimetric determination of the N-acetyl - D - glucosamine (NAG) released by the hyaluronidase in standardised conditions. The in vitro conditions involve the treatment of Neauvia Intense with a known concentration of the enzyme (6080U/ml). The NAG content was determined at different times to assess the kinetics of the degradation (1h, 3h, 6h, 24h, 48h, 72h, 120h, and 168h); the Ehrlich's reagent was used for the colourimetric quantification, by the method described by Reissing and colleagues. The intensity of the violet colour developed after the chemical reaction was proportional to the NAG present in each sample. A microplate reader at 585 nm read the absorbance. The amount of NAG released by the product was proportional to the time of incubation with bovine hyaluronidase, reaching a plateau after 168 hours. PMID- 29483973 TI - Carbon Dioxide with a New Pulse Profile and Shape: A Perfect Tool to Perform Labiaplasty for Functional and Cosmetic Purpose. AB - OBJECTIVE: To describe the benefits and safety of using Carbon Dioxide Laser in multi-pulse modalities when performing labiaplasty and anatomical variants approach for functional and cosmetic indications. DESIGN: This is a prospective, descriptive case series study. SETTING: Private Practice Quirofano Calculaser Megacentro Pinares Pereira Colombia. POPULATION: One Hundred and twelve women seeking labia minora labiaplasty for functional and cosmetic reasons were enrolled in the study protocol from June 2013 to June 2016. Labia minora labioplasty and anatomical variants approach were performed with Carbon Dioxide laser Multi-pulse modalities DEKA M.EL.A Florence Italy. MAIN OUTCOME MEASURES: Good Cosmetic results, functional and sexuality improvement. RESULTS: Dramatic changes in the VAS and VSQ were detected after the surgical procedure. All the participants reported a high degree of satisfaction, felt more confident with their partners during sexual encounters, and the procedure was well tolerated. CONCLUSION: Laser Carbon Dioxide Laser with a new pulse profile and shape seems to be a safe and precise surgical tool to perform this type of procedures, optimal biophysical and bio stimulative laser-tissue interactions allow delicate vulvar tissues to shorten downtime. PMID- 29483974 TI - Epidermoid Cysts - A Wide Spectrum of Clinical Presentation and Successful Treatment by Surgery: A Retrospective 10-Year Analysis and Literature Review. AB - Epidermoid cysts are common benign lesions of hair-bearing, and less often glabrous skin. They can also occur in oral mucosa and internal organs. In case of cutaneous lesions, an epidermal punctum is a clinical diagnostic hallmark. The clinical presentation is variable leading to some differential diagnoses. Diagnosis of epidermoid cysts needs histopathological confirmation - not only of the potential of malignant transformation. The treatment of choice is surgery. We report a retrospective analysis of 2159 epidermoid cysts treated surgically. Most of the cases can be performed under local anaesthesia. The complication rate of 2.2% is low. To avoid relapses, the cyst wall has to be removed completely. Rare genetic disorders with multiple cysts are Gardner and Lowe syndrome. PMID- 29483975 TI - Intralesional Diode Laser 1064 nm for the Treatment of Hidradenitis Suppurativa: A Report of Twenty Patients. AB - AIM: Hidradenitis suppurativa (HS) is a chronic inflammatory disease, commonly characterized by painful, deep dermal abscesses and chronic draining sinus tracts. Recently, laser and light-based therapies have become more commonly used in the management of HS. MATERIAL AND METHODS: We report 20 HS patients treated with a 1064 nm wavelength, emitted from a diode laser, launched in an optical fibre through intracavitary modalities. RESULTS: Each patient underwent four laser sessions, one every two weeks. we recorded a significative reduction (31%) of Sartorius score from 28.55 +/- 13.04 to 19.75 +/- 12.29 after 4 laser sessions (p < 0.05). No one has had a worsening of the disease. CONCLUSION: Intralesional diode laser 1064 nm can be a good treatment option for patients with moderate and localized hidradenitis suppurativa, because it is minimally invasive, doesn't have significant complications and provides a rapid post-treatment recovery. PMID- 29483976 TI - Dermatofibrosarcoma Protuberans: Retrospective Single Center Analysis Over 16 Years. AB - Dermatofibrosarcoma protuberans (DFSP) is rare mesenchymal neoplasia with a high risk of local recurrence but a low risk of metastatic spread. Tumor cells express CD34 and show a characteristic translocation t(17;22)(q22;q13). We analysed the documented cases at the Department of Dermatology and Allergology between 08/2001 and 08/2017. The diagnosis had been confirmed by histology and immunohistology in all cases. We identified four adults and a pediatric patient with DFSP. All patients were treated by wide surgical excision and controlled by three dimensional histologic margin control. We observed no recurrence and no metastatic spread. We discuss prognostic factors and emerging treatments. PMID- 29483977 TI - Automatic Artificial Hair Implant: Safety and Efficacy in Androgenetic Alopecia. A Prospective Study with a Highly Biocompatible Fiber. AB - AIM: A multi - centre two years the long prospective open clinical study was conducted in five countries located in four different continents from May 2015 to evaluate the clinical safety and efficacy of Automatic Biofibre hair implant in male and female androgenetic alopecia. Biofibre(r)is a CE/TGA certified medical grade polyamide fibre suitable for implantation. MATERIAL AND METHODS: A total of 213 patients were enrolled in the study. Patients were assessed pre -operatively by Hamilton scale grading and the percentage of scalp covered by hair. All the patients underwent Biofibre hair implantation by a standardised surgical technique followed by adequate post-operative care. Efficacy of the implant was evaluated by surgeons and patients bimonthly for the first year and trimonthly during the second year. Any adverse effects were recorded during these visits. RESULTS: At the completion of the study period, a total of 194 patients concluded the trial and the results were statistically evaluated. Both Hamilton scale grading and covered area percent improved at the end of the study, and subjective and objective evaluations revealed satisfactory results. Side effects were reported in only 18 cases (9.27%) which were easily controlled by either topical or systemic treatment in 8 to 10 days. CONCLUSION: Overall a successful result was noticed in 97.94% of patients with great psychological satisfaction. PMID- 29483978 TI - Successful Treatment with UVA 1 Laser of Non - Responder Vitiligo Patients. AB - The Authors discuss their experience in treating non-responder vitiligo patients with a UVA-1 laser. Laser Alba 355(r) is an innovative device of target UVA - 1 phototherapy. The present report suggests that UVA1 laser could be an applicable therapeutic option in patients with vitiligo, also for the ones who did not respond to the more conventional phototherapies. PMID- 29483979 TI - Micro - Focused Phototherapy Associated To Janus Kinase Inhibitor: A Promising Valid Therapeutic Option for Patients with Localized Vitiligo. AB - BACKGROUND: Vitiligo is an acquired pigmentary cutaneous disease, characterised by the progressive loss of melanocytes, resulting in hypopigmented skin areas which progressively become amelanotic. Classically, vitiligo treatments are unsatisfactory and challenging. Despite the continuous introduction of new therapies, phototherapy is still the mainstay for vitiligo repigmentation. AIM: The aim of this multicenter observational retrospective study was to evaluate the efficacy and safety of the nb - UVB micro - phototherapy (BIOSKIN EVOLUTION(r)), used alone or in associations with an oral Janus kinase inhibitor (Tofacitinib citrate), in the treatment of stable or active forms of localised vitiligo. MATERIAL AND METHODS: Fifty eight patients had been treated with n-UVB micro photootherapy (Group A); 9 patients had been treated with phototherapy plus Tofacitinb citrate (Group B). RESULTS: Among Group A, 42 patients (72%) obtained a re-pigmentation rate higher than 75%, with a medium value of 77%. 11 patients (19%) achieved a marked improvement of the clinical findings with a repigmentation rate between 50-75%; 4 patients (8%) showed a moderate response with a lesional repigmentation of 25-50%. Only one patient (1%) had a poor response to the phototherapeutic treatment. CONCLUSION: Nb - UVB micro-focused phototherapy is one of the most effective therapeutic options for vitiligo treatment. The association of micro-focused phototherapy to Tofacitinib citrate seems to provide better clinical results in term of repigmentation rate. PMID- 29483980 TI - An Innovative Therapeutic Protocol for Vitiligo: Experience with the Use of Fraxel Herbium Laser, Topical Latanoprost and Successive Irradiation with UVA - 1 Laser. AB - Despite the continuous introduction of innovative therapies for vitiligo, today none of them provide constant and excellent results in term of repigmentation. The authors report their experience in treating a localised form of vitiligo with a new protocol consisting in the use of a Fraxel Herbium laser, and in the following application of topical Latanoprost solution and, one day after, in lesional irradiation with UVA1 laser. PMID- 29483981 TI - Subungual Exostosis in a Young Soccer Player. AB - BACKGROUND: Subungual exostosis is a relatively uncommon, benign osteocartilaginous tumor of the distal phalanx of the toes or fingers in young adults, considered as a rare variant of osteochondroma. Differential diagnoses include subungual verruca (viral wart), pyogenic granuloma, osteochondroma, amelanotic subungual melanoma and glomus tumour. Misdiagnosis and total onychodystrophy frequently occur as a result of late treatment or inadequate treatment strategy. Dermoscopy could be a useful technique, involved in the diagnostic process, although X-ray examination and histopathology are mandatory for the diagnosis. CASE REPORT: We report a rare case of subungual exostosis of the great toe associated with repeated trauma of the nail bed. The lack of radiographic and histopathological examination could lead to misdiagnosis and inadequate treatment. Although completely benign, subungual exostosis should be considered in differential diagnosis of nail bed tumors in young adults, in order to avoid associated complications and unneeded aggressive surgical interventions. CONCLUSION: Complete excision of the lesion and delicate separation from the underlying nail bed structures results in total resolve of the problem, by providing the lowest risk of recurrences. PMID- 29483982 TI - Chronic Scalp Ulcer 35 Years after Skull Trepanation Surgery and Radiotherapy for Oligodendroglioma: A Further Example of Immunocompromised Cutaneous Districts. AB - BACKGROUND: Chronic ulcers of the scalp have a variety of underlying pathologies. In case of cancer patients, a second malignancy must be excluded. CASE REPORT: A 78-year-old female patient presented to our department with a large soft tissue defect on the frontotemporal left side. The lesion was about 3 cm in diameter with exposed bone and inflammatory soft tissue on the edges of the defect. About 35 years ago, she had undergone a combined neurosurgery with skull trepanation and radiotherapy for an oligodendroglioma. Three years ago, sandwich transplantation with the dermal template and meshed skin graft failed. Now she re presented with inflammatory ulcer borders. A complex defect repair was performed after exclusion of a second malignancy. CONCLUSION: Chronic scalp ulcers may be the result immunocompromised cutaneous districts and need a complex reconstruction. PMID- 29483983 TI - Successful Treatment of Reticular Blue Veins of the Lower Eyelid by Long-Pulse Nd: YAG - Case Report with 8-Year Follow-Up. AB - BACKGROUND: Facial reticular blue veins are of esthetic concern. Most often these veins develop on the lower lids. The safest and most effective way of treatment is by vascular lasers. CASE REPORT: We report on a successful reticular vein treatment using a long-pulsed 1064 nm Nd: YAG laser. We present a follow-up of 8 years with constant esthetic improvement without unwanted adverse events. CONCLUSION: There was no relapse demonstrating the efficacy of Nd: YAG laser. PMID- 29483984 TI - Simultaneous Occurrence of Balanoposthitis Circumscripta Plasmacellularis Zoon, Phimosis and in Situ Carcinoma of the Penis: Case Report with An Unusual Ulcerated Polypoid Variant of Zoon's Disease and a Carcinoma in Situ of Reserve Cell Type. AB - BACKGROUND: Zoon's balanitis is a benign disease characterized by an asymptomatic, chronic, solitary, shiny, red-orange plaque of the glans and/ or prepuce. In rare cases of Zoon's disease, penile squamous cell carcinoma developed in the chronic inflammatory lesions. CASE REPORT: We report on a 68 year-old male patient presenting with phimosis and coexistent Zoon's disease and penile carcinoma in situ treated successfully by circumcision. CONCLUSION: Coexistence of both lesions in contrast to the development of cancerous lesions within pre-existent Zoon's disease is a very rare observation. PMID- 29483985 TI - Advanced Pretibial Melanoma (APM): Clinicians Behaviour As Triggering Factor? AB - BACKGROUND: Pigmented lesions represent a broad spectrum of clinical conditions, both benign and malignant. The precise diagnosis is often a challenge, while the clinical diagnostic criteria could be misleading, as a result of the frequently atypical presentation of otherwise completely benign in nature lesions. The variety of therapeutic options for benign pigmented lesions including shave curettage, local laser destruction, electrocoagulation removal could sound enticingly both for the physician and patient, but they destroy the possibility for histological examination and provide a deceptively feeling of calm, that the problem is solved. If there is even a minimum chance for misdiagnosis, the risk could be a human life. Furthermore, a simple surgical excision could provide total resolution of the problem, with correct histological verification and further therapeutic measurements, if needed. CASE REPORT: We present a case of a patient, with advanced pretibial melanoma with multiple lung metastases, misdiagnosed as a seborrheic keratosis, treated with shave-curettage 6 months earlier, as we want to emphasize the importance of the correct therapeutic method in all cases with pigmented lesions with unknown origin, in order to minimize the risk of dramatic consequences of misdiagnosis of melanoma. So, we want to ask you is this risk justified? CONCLUSION: So, we want to ask you - is this risk justified? PMID- 29483986 TI - The Role of Complex Treatment in Mixed Leg Ulcers - A Case Report of Vascular, Surgical and Physical Therapy. AB - BACKGROUND: Leg ulcers are a burden to patients, their families and society. The second most common cause of chronic leg ulcers is the mixed arterio-venous type. An 80-year-old female patient presented to our department due to painful enlarging chronic leg ulcer of mixed arteriovenous origin on her left lower leg. She suffered from peripheral arterial occlusive disease stage I and chronic venous insufficiency Widmer grade IIIa, and a number of comorbidities. AIM: The aim of our ulcer treatment was a complete and stable wound closure that was hampered by arterial occlusion, exposed tendon, and renal insiffuciency. CASE REPORT: To improve the prognosis for ulcer surgery, we performed percutaneous transluminal angioplasty, transcutaneous CO2 and deep ulcer shaving. The wound was closed by sandwich transplantation using elastin-collagen dermal template and meshed split skin graft. She had a 100% graft take with rapid reduction of severe wound pain. CONCLUSION: Complex approaches are necessary, to gain optimum results in leg ulcer therapy in mixed leg ulcers. Therapeutic nihilism should be abandonend. PMID- 29483988 TI - Van Lohuizen Syndrome - A Case Report with a Diagnostic Delay of Four Years. AB - BACKGROUND: Cutis marmorata telangiectatic congenital or Van Lohuizen syndrome is a rare vascular disorder that may be associated with other congenital malformations. Around 300 cases have been reported so far. CASE REPORT: We present a 4-year-old girl with Van Lohuizen syndrome of the leg, but without any other malformations. CONCLUSION: Neonatal lupus erythematosus may resemble congenital vasculopathy, but histopathology and immune-serology are characteristic. PMID- 29483987 TI - Neurofibromatosis Type 1 with Massive Ventricular Polyposis: First Report in the Medical Literature. AB - BACKGROUND: Neurofibromatosis type 1 (NF1) is a multisystemic disorder with genetic background, characterised by specific cutaneous findings, skeletal dysplasias, and growth of both benign and malignant nervous system tumours. NF1 is caused by mutations in the NF1 gene, situated in chromosome 17q11.2, with an autosomal dominant pattern of inheritance and clinical manifestation of neurofibromas, malignant peripheral nerve sheath tumour, optic and non-optic nerve gliomas, congenital heart disease, cardiovascular and cerebrovascular disease and orthopaedic disorders. The incidence of gastrointestinal manifestations of NF1 is relatively low, compared to neurological disorders, presenting approximately in 5 to 25% of the patient, but later in life. CASE REPORT: We present a patient with NF1, ventricular polyposis and attentional disorders with cognitive phenotype, while both of her daughters also present with cutaneous manifestations of NF1. CONCLUSION: To the best of our knowledge, this is the first reported case of NF1 with ventricular polyposis as a gastrointestinal manifestation in the mother and NF1 with no signs of inner organ involvement in both of her daughters. PMID- 29483989 TI - A "Yellow Submarine" in Dermoscopy. AB - BACKGROUND: Histiocytic sarcoma (HS) is an extremely rare, non-Langerhans cell tumor. HS affects especially adults, its etiology is unknown yet. Skin could be interested by papules or nodules, single or multiple. CASE REPORT: A Caucasian man in his late 40s came to our clinic for a naevi evaluation. During the visit, a rose papulonodular lesion was observed in the lumbar region. This lesion was completely asymptomatic, and it had been there for an indefinite period. The clinical evaluation revealed that the lesion appeared elevated, of 9 x 15 mm in dimension, symmetrical and of a homogeneous pinkish colour. The videodermoscopical evaluation revealed a homogeneous yellow central pattern, polymorphic vessels, an eccentric peripheral pigmentation and a white collar. An excisional biopsy was performed. The morphology and the expression of CD163, CD68 and/or lysozyme to the immunophenotypic analysis, revealed the true nature of the lesion. CONCLUSION: HS is usually diagnosed at an already advanced clinical stage and it has a high mortality rate even today. Dermoscopy, showing a yellow and distributed homogeneously colour, can facilitate its hard diagnosis. PMID- 29483990 TI - Segmental Erythema Multiforme-Like Drug Eruption by Aromatase Inhibitor Anastrozole - First Case Report and another Example of an Immunocompromised District. AB - Anastrozole is a non-selective aromatase inhibitor for adjuvant breast cancer therapy in postmenopausal women. Cutaneous adverse events have been reported. We observed a 64-year-old female patient with a medical history of locally advanced breast cancer of her right breast that was treated with radiotherapy and adjuvant drug therapy with anastrozole. She developed a segmental bullous eruption limited to the cancer-affected breast. Cessation of the aromatase inhibitor and systemic therapy with prednisolone cleared the lesions completely. This is the first report of a segmental erythema multiforme like drug eruption by anastrozole and another example of the concept of the immunocompromised district of skin. PMID- 29483991 TI - Chronic Encapsulated Seroma Persisting for Three Years after Abdominoplasty and a Successful Surgical Solution. AB - Abdominoplasty is listed among five most common esthetic surgical procedures in the Western World. Despite all efforts, abdominoplasty bears a high risk of complications. We observed a 39-year-old-woman with previous classical abdominoplasty performed elsewhere three years ago. Clinical examination demonstrated a swollen and tense abdominal mass. Laboratory findings were normal. Clinical examination was completed by abdominal ultrasonography which demonstrated both, a significant fluid volume in this area and a dense fibrous "capsule". The diagnosis was a late or chronic encapsulated seroma with a thick pseudocapsule or "bursa". We performed a revision abdominoplasty with a standard supra-fascial dissection. Surgical resection of infra-umbilical flap containing skin, subcutaneous tissue and capsulectomy were performed under general anaesthesia. A new umbilicus was created attaching small skin flaps in the muscular fascia. No drains were used. We observed no seroma formation. Follow up after six and ten months was unremarkable. The fibrous pseudocapsule of chronic seroma results in different degrees of deformities, abdominal scar deviation and asymmetry. Surgical capsulectomy combined with revision abdominoplasty with preservation of Scarpa's fascia and placement of progressive tension sutures resulted in being effective and leads an esthetic outcome without seroma recurrence. PMID- 29483992 TI - Acute Forefoot Phlegmon - A Complication of Intravenous Heroin-Addiction. AB - Infections of the skin and soft tissues (SSTI) are clinical entities with variable presentations, causes, and levels of clinical severity. They are frequent in emergency departments. The most common pathogen in the Western World is Staphylococcus aureus. SSTI may provide a hint to underlying pathologies such as diabetes and other states of immune compromise. Here we present a 41-year-old non-diabetic male patient with pain and swelling of the left forefoot but not any recent trauma. Microbiology identified streptococci. The medical history was positive for intravenous heroin abuse. The diagnosis of forefoot phlegm due to drug addition was confirmed. Treatment was realised by a combination of intravenous antibiosis and drainage. Intravenous drug addiction is a significant risk factor for SSTI. PMID- 29483993 TI - Neglected Under Lip Cancer. AB - The lip represents an anatomical area of the interface between the skin and oral mucosa. It is, therefore, not entirely surprising that SCC of the lip exhibits mixed features between cutaneous and oral mucosal SCC, namely regarding risk factors and biological behaviour. The main risk factors for lip SCC include ultraviolet radiation exposure, low phototype, tobacco and alcohol use, and immunosuppression. Lip SCC usually presents clinically as a nodule or a tumour with a keratotic surface that commonly ulcerates. There is often a background of actinic cheilitis. The particularly exuberant presentation of our case can most probably be explained by the long evolution of a tumour before the patient reached medical attention. Patients with regional lymph node metastasis are usually offered regional lymph node dissection (usually of the neck). Radiotherapy and/or chemotherapy may be used in advanced cases, particularly in unresectable tumours, tumours with high-risk features and metastatic disease. The large size of a tumour in our case, most probably due to its long evolution, highlights the importance of timely diagnosis to avoid such extreme presentations and the consequent need for more aggressive treatment. PMID- 29483994 TI - Cutaneous Leishmaniasis - A Case Series from Dresden. AB - Leishmaniasis is world-wide one of the most common infectious disorders caused by protozoa. Due to the climate change, there is a risk of further spread of the disease to central and northern Europe. Another important issue is the high number of refugees from Syria since Syria is one of the hot spots of Old World leishmaniasis. We report on single-centre experience with leishmaniasis in the capital of Saxony, Dresden, during the years 2001 to 2017. We noted a substantial increase in the last five years. Once a very rare exotic disorder in Germany, cutaneous leishmaniasis has become a reality and physicians should be aware of it. A significant number of cases are from Syrian refugees; other cases had been acquired by tourists in the Mediterranean region! PMID- 29483995 TI - Lip Repair after Mohs Surgery for Squamous Cell Carcinoma by Bilateral Tissue Expanding Vermillion Myocutaneous Flap (Goldstein Technique Modified by Sawada). AB - Squamous cell carcinoma is the most common malignancy of the lower lip. Environmental factors such as ultraviolet light exposure, arsenic and smoking are contributing factors to the increasing incidence. Mohs surgery is the treatment of choice ensuring the lowest recurrence rates. The closure of the surgical defects, however, can be a challenge. Multiple and versatile methods of reconstructing vermilion defects have been described. Among these options, Goldstein developed the adjacent ipsilateral vermilion flap based on an arterialized myocutaneous flap. The original technique was modified by Sawada based on bilateral adjacent vermilion advancement flap for closure of central vermilion defects. We report the use of bilateral flaps - Sawada's technique (instead of unilateral as suggested by Goldstein) in medium (2 cm of extension) to large defects (> 2 cm) to achieve an effective and functional reconstruction of vermillion defects after Mohs surgery for lip cancer. PMID- 29483996 TI - Ulcerating Lichen Planopilaris - Successful Treatment by Surgery. AB - Lichen planus is a T-cell mediated autoimmune disorder affecting the skin and mucous membranes. Ulcerating lichen planus is uncommon mostly on oral and genital mucosa but not skin. Lichen planopilaris, however, is a subtype of lichen planus affection hair follicles and leading to permanent scarring alopecia. We report a case of lichen planopilaris of the scalp with multiple alopecic patches ulceration - a hitherto unreported clinical feature. The patient was treated surgically, and the defect could be closed by combined tissue advancement and extension. PMID- 29483997 TI - Sarcoidosis in A. C. Milan (1899)? AB - The pathogenesis, diagnosis and therapy of sarcoidosis as an autonomous disease are subjects of spirited discussions, which haven't found definitive conclusion yet. Distinguishing between sarcoidosis and sarcoid-like reactions (sarcoid - type granulomas) is not currently a medical "gold standard" and is not implemented in clinical practice. This leads to 1) misinterpretation of numerous available data; 2) difficulty in the interpretation of other unverified data, which is often followed by 3) inappropriate or inadequate therapeutic approach. Similarly to many other diseases, in sarcoidosis and sarcoid - types of reactions the concept of personalised approach and therapy should also be introduced. This methodology of clinical guidance is difficult, complex and not always achievable in the current medical status and relations (doctor-patient relationship; financial factor; time factor). It is appropriate to note that in some cases the guidelines or the so-called standards are neglected or not possible to put into practice with the aim of better therapeutic practices and strategies, as well as the achievement of optimal final clinical results (especially in patients with sarcoid granulomas). The sarcoid granuloma, even when it is sterile, should not be considered as the equivalent of sarcoidosis, i.e., sarcoidosis as an autonomous disease. Sure enough, exactly because of this fact, the personalised approach should not be an exception, but it has to gradually become a rule in medical practice. When clinical decisions are conformed to some of the latest modern concepts, officialised in the international databases, often the achieved results can be much better. We present a patient with a tattoo of AC Milan (1899) on his right arm, who subsequently developed localised sterile sarcoid granulomas in the area of the tattoo. Later the process became generalised on his whole body's skin, lungs and lymph nodes. It is unclear for the moment whether this condition should be interpreted as sarcoidosis as an autonomous disease or, instead, as a sarcoidal type of reaction with subsequent generalisation due to cross-reactivity against antigens present in other tissues with similarities to the exogenous pigments. Following the modern concepts regarding the pathogenesis of these two conditions, we introduced, in this case, an innovative, non-standard approach: 1) systemic and local immunosuppressive therapy, combined with 2) recommendation for immediate surgical excision of the tattoo to remove the possible trigger of molecular and antigen mimicry. PMID- 29483998 TI - Unilateral Palmar Callus and Irritant Hand Eczema - Underreported Signs of Dependency on Crutches. AB - Leg amputees who can't use prostheses and patients with arthritis are often dependent on crutches. Their chronic use can exert significant friction forces. The palmar skin will respond by forming a hyperkeratotic callus. We report for the first time unilateral palmar callus formation caused by friction from using crutches. Another possible adverse effect is the triggering of irritant contact dermatitis by the handholes of crutches. We report two cases with hand dermatitis due to the chronic dependence on crutches and discuss treatment options. PMID- 29483999 TI - Sweet's Syndrome (SS) in the Course of Acute Myeloid Leukaemia (AML). AB - Firstly described by Robert Douglas Sweet in 1964, febrile neutrophilic dermatosis is a disabling, not only cutaneous disorder, clinically characterised by fever and painful erythematous nodules, with a typical background of neutrophilia. Sweet's syndrome (SS) is a chronic inflammatory reactive disorder of unknown cause and incompletely established pathogenesis, although an interplay between genetic and environmental factors, including infections, is likely to occur. A significant part of cases has been demonstrated to be linked with malignancies, especially in the hematologic setting. Because of the underlying disease and related therapeutic measures, SS may present atypical clinical course, whereas the response to treatment is strictly dependent on the concurrent hematologic disease. Herein we describe a case of a lady who had a refractory form of SS, resulted in a paraneoplastic cutaneous disease, and AML. Surprisingly, clinical remission of SS followed cytotoxic chemotherapy while hematologic disorder obtained a further complete response. PMID- 29484000 TI - Idiopathic Scrotal Calcinosis - A Case Report. AB - Idiopathic scrotal calcinosis is a rare disorder presenting with firm and painless nodules on the scrotal skin. The most common site is the frontal aspect of the scrotum whereas the dorsal aspect with the transition to the perineum is rarely involved. Surgery is the gold standard of treatment. PMID- 29484001 TI - Para - And Intraurethral Penile Tumor - Like Condilomatosis. AB - Condyloma acuminata represents an epidermal manifestation, associated with the epidermotropic human papillomavirus (HPV). They have been reported as the most common sexually transmitted disease, with prevalence exceeding 50%, increased up to 4 times, within the last two decades, as the most common side of affection are the penis, vulva, vagina, cervix, perineum, and perianal area, with increased prevalence in young, sexually active individuals. Increased attention should be focused on lesions, caused by types, with moderate (33, 35, 39, 40, 43, 45, 51 56, 58) or high risk potential (types 16, 18) for malignant transformation, leading to further development of cancers of anus, vagina, vulva and penis, as well as cancers of the head and neck. A provident of coexistence of many of these types in the same patient could be seen in approximately 10-15% of patients, as the lack of adequate information on the oncogenic potential of many other types complicated the treatment and the further outcome. Although the variety of treatment options, genital condylomata acuminata still show high recurrent rate to destructive topical regiments, because of the activation of the viruses at some point, which emphasise the importance of virus- eradication, instead only of the topical destruction of the lesions. Despite decreasing the recurrent rate, the most important goal of immunisation is the reduction of the incidence of HPV associated squamous cell carcinomas using either the quadrivalent (Silgard/Gardasil) or the bivalent (Cervarix) HPV (human papillomavirus) vaccine. We present a patient with periurethral condylomata acuminate, who refused performing of a biopsy for determining the virus type, as we want to emphasize the importance of the virus - treatment in all cases of genital warts, instead only of topical destruction of the lesions, not only because of the recurrence incidence rate, but also because of the well - known oncogenic potential of some HPV - types, as well as the unknown potential of various underestimated types, in contrast. PMID- 29484002 TI - Giant Pendulous Carcinosarcoma - Squamous Cell Carcinoma-Type - of the Leg - A Case Report and Review of the Literature. AB - Cutaneous carcinosarcoma (CCS) is a rare non-melanoma skin cancer with a biphasic growth pattern. A tumour is composed of epithelial and mesenchymal cells that show clonality. In most cases, CCS develops in the head-and-neck region on the chronic sun-exposed skin of males. Here, we describe an 80-year-old female patient who developed a giant, pendulous CCS on the leg. A tumour was surgically removed. We found no evidence of metastatic spread. PMID- 29484003 TI - Another Case of Interdigital Located "Metastasing Hematoma"? AB - Interdigital spaces could be an area of affection of a various cutaneous conditions, most of them with benign origin. The spectrum of differential diagnosis of pigmented interdigital lesions with a recent occurrence is not so wide, in contrast. When considering pigmented lesions in the interdigital area, the most harmless differential diagnosis is a traumatic hematoma. But what would happen if we based our therapeutic behaviour or suspicious and unconfirmed harmless diagnosis, instead of considering the real life-threatening once with priority, if we kept in mind that acral lentiginous melanoma has rather an aggressive course and is the main cause of death in skin cancer patients? We present a case of misdiagnosed interdigital melanoma, treated as a hemangioma with curettage, with almost fatal consequences, in regard to uncontrolled tumor progression as a result of the wrong traumatic procedure in one hand, and the lack of adequate screening and follow up, leading to progress of the disease with lymph node metastasis and poor prognosis in general. We want to emphasise the importance of acral lentiginous melanoma with an unusual location in the differential diagnostic plan because, despite the early detection, early eradication with simple excision could save a life, or at least could provide a better prognosis. PMID- 29484004 TI - Psoriasiform Dermatophytosis in a Bulgarian Child. AB - Although tinea capitis is the most common fungal infection in children, significant changes have been reported in its epidemiology worldwide, as a result from certain geographic, climatic and cultural differences in one hand, as well as the changes in its etiologic pattern. The clinical manifestation of the infection and the stage of inflammation vary from mild desquamation to severe suppurative indurated plaques in kerion - like the pattern, depending on the nature of the etiologic agent and the host-immune response. We report a case of tinea capitis profunda, caused by Trichophyton verrucosum in a 5 - year - old male patient, presented as a severe scalp and cutaneous desquamation, resembling histopathologically psoriasis, associated with severely indurated ringworm plaque in the temporal area. The performed histological examination revealed a psoriasiform pattern, without the typical Munro abscesses or Kogoj pustules. With the presented case, we want to emphasize the importance of the host's immune reaction to zoophilic dermatophytes, such as Trichophyton verrucosum, resulting in severe and often atypical clinical manifestation, as well as the possible "Id reaction", to avoid or minimise misdiagnosis and delayed therapy. The presented patient was treated with topical oleum acidy salicylic 10% and Terbinafine 125 mg daily with significant resolution of the complaints within the following two months. PMID- 29484005 TI - A Patient with Multiple Keratinocytic Cancers (MKC): Uncommon Presentation in a Bulgarian Patient. AB - Keratinocyte skin cancers, including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), are the most common cancer occurring in people with fair skin, worldwide. Despite all known triggers, several suggested contributors are still investigated. We will focus our attention on the personal history of previous cancers and radiation exposure as occupational risk factors, as in the presented case. We report a patient, with multiple BCCs, and subsequent occurrence of a SCC on photo-exposed area of the face, as we want to emphasize the importance of strict following up of these patients, regarding the risk for developing new tumors in short periods of time, no matter if the triggering exposure factor is known from the history, or not. Although keratinocytes tumours are associated with the low mortality rate, we focus the attention on the fact, that the history of non-melanoma skin cancer is associated with increased mortality. PMID- 29484006 TI - Diffuse Normolipemic Plane Xanthoma (DNPX) of the Neck without Xanthelasma Palpebrum. AB - Diffuse normolipemic plane xanthoma (DNPX) is an uncommon subtype of non Langerhans histiocytosis. DNPX is characterised by xanthelasma palpebrarum, diffuse plane xanthoma of the head, neck, trunk, or extremities, and normal plasma lipid levels. The neck is the most common site. We report about a 62-year old female Caucasian patient, who developed an asymptomatic fine wrinkling and loose skin on the neck and decollete about three years ago. The skin colour became yellowish. Xanthelasma was absent. Histopathology of a skin biopsy confirmed the diagnosis of DNPX. The patient had a medical history of chronic myeloblastic leukaemia. No other laboratory abnormalities were found. Laser treatment was offered but opposed by the patient. PMID- 29484007 TI - Locally Advanced Basal Cell Carcinoma with Intraocular Invasion. AB - We present a 103 - year - old patient, with duration of complaints of about ten years. The initial complaint had been presented as a small nodule, located on the eyebrow, which subsequently ulcerated and encompassed larger regions of the upper and lower eyelids. For the past three years, the patient also had complaints of a worsening of his vision, without seeking for medical help. Within the dermatological examination, an intraocular and periocular localised tumour was established, characterised by a raised peripheral edge and central ulceration. More careful examination revealed that the bulb was fully consumed. The patient refused further diagnosis and treatment. Advanced basal cell carcinomas with intraocular invasion are rare in general. If the patient refuses surgery, radiotherapy and systemic therapy with modern medications such as Vismodegib or Sonidegib are available as treatment options. PMID- 29484008 TI - Seborrheic Pemphigus, Antigen Mimicry and the Subsequent-Wrong Diagnostic and Therapeutic Approach? AB - It is well-established that drugs could be leading cause of occurrence of numerous diseases, including pemphigus, being either inducer or triggering factor of the autoimmunity. Despite medications, it should be kept in mind that chronic or acute infections are also capable of being a trigger in various types of cutaneous eruptions, including pemphigus. The rapidly obtained and uncompleted history for accompanied medication leads to general mistakes in the subsequent treatment approach, as the first step in such cases is discontinuation of the drug-inductor. The absence of this information guaranties the fail of the treatment. On the other hand, the lack of performed screening for chronic or acute hepatitis and tuberculosis is not the only mistake, regarding the high dosage of immunosuppressors that have been planned as regiment and the possible fatal effect on the infection's spread or exacerbation, but also because of the possible triggering ability of chronic or acute infection, which may play also a key role in the generation of antigen- or molecular- mimicry, as a potential source of antibodies reactive with various tissue antigens. It turns out that although the diagnosis of pemphigus in regular cases is usually not a challenge, the treatment occasionally could be, just because of a simple pitfall in anamnesis and screening, as in the presented case. Herein, we present a case of a patient with seborrheic pemphigus, which is strongly demonstrative for these statements, as we want to emphasise the importance of the first and the most powerful clinician's weapons - the patient's history and thorough examination. PMID- 29484009 TI - Peri - and Intraocular Mutilating Advanced Squamous Cell Carcinoma: "Monsters Inside Your Body"? AB - Periocular malignancies represent between 5% and 10% of all types of skin cancers. The incidence of eyelid (but also the periocular located) malignancies seems to differ in distribution across the continents. The incidence of eyelid tumours (but also the periocular located tumours) in a predominantly white population determined that BCC is the most common malignant periocular eyelid tumour in whites. This finding has been replicated consistently throughout the literature, with BCC representing 85-95% of all eyelid malignancies, SCC representing 3.4 - 12.6%, Seb Ca representing 0.6 - 10.2%, and both melanoma and Merkel cell carcinoma representing less than 1%. Most periocular skin cancers are associated with ultraviolet radiation (UVR) exposure. Ultraviolet radiation causes local immune suppression, which, coupled with DNA abnormalities in tumour suppressor genes and oncogenes, leads to the development of skin cancers. We are presenting a 62 - year - old patient with a small nodule about 2 cm away from the lower lid of his left eye. A tumour was surgically treated. Several years later there was a tumour relapse, treated with radiotherapy and subsequent chemotherapy with Endoxan and Cisplatin. After the second relapse, he was treated surgically in general anaesthesia by orbital exenteration, removal of the orbital floor and resection of zygomatic bone and the maxillary sinus. A couple of months later, he developed a tumour relapse in the scars and the area of a primary tumour with tumour progression. A possible therapy with Cetuximab or radiation therapy was discussed as a possible treatment option. PMID- 29484010 TI - Mucoepidermoid Carcinoma (MEC) of Parotid Gland with Massive Cutaneous Involvement: Bilateral Pedicle Advancement Flap (U - Plasty) As Adequate Surgical Approach. AB - Neoplasms of the major and minor salivary glands are morphologically and a clinically diverse group of neoplasms which lead the clinician to diagnostic and management challenges. This article aims to report a case of mucoepidermoid carcinoma in 83 - year - old woman who presented in the dermatology clinic with a tumour mass in the left auricular area. The patient complained of pain and abnormal bleeding of the mass. The lesion was examined, and surgical treatment was performed. A tumour was extirpated, and partial resection of both the parotid gland and the sternocleidomastoid muscle was done. Lymphatic dissection was performed. Post recovery was uneventful with no functional defects and abnormalities. The pathohistological result confirmed the diagnosis of mucoepidermoid carcinoma of the parotid gland with massive infiltration of the skin and the subcutaneous tissue. Lymph nodules with total metastasis of mucoepidermoid carcinoma and capsular invasion were additionally presented. Postoperative radiation therapy was planned. PMID- 29484011 TI - Violet - Colored Inguinal Located Cutaneous Tumour? AB - Anaplastic large cell lymphoma (ALCL) represents an aggressive CD30 - positive T cell lymphoma, as it is the second most common T cell lymphoma and 2% to 5% of all non - Hodgkin lymphomas. The cutaneous involvement can be primary or secondary within systemic ALCL, resembling inflammatory and other neoplastic lesions both clinically and cytologically. Various pigmented cutaneous tumours with a different origin, cutaneous metastasis and B-cell lymphoma must be carefully considered in the differential diagnostic plan. While simple surgical excision is usually curative, with good prognosis, systemic involvement must also be excluded. We present a case of a patient, with clinically unspecific single violet nodular lesion, as the only clinical manifestation of ALCL. The diagnosis was confirmed histologically, as the surgical excision was enough therapeutic management, regarding the early disease stage. Further following up with the patient is mandatory, because of the high recurrence rate. We want to emphasise the diversity of clinical manifestation of ALCL, regarding the importance of its early diagnosis and treatment. PMID- 29484012 TI - Disseminated Porokeratosis with Idiopathic Thrombocytopenia - Case Report and Literature Review of Porokeratosis and Related Disorders. AB - BACKGROUND: Porokeratosis is characterised by one or more atrophic patches surrounded by a distinctive peripheral keratotic ridge, typically found on sun exposed areas, with several clinical variants and typical histological findings. Despite ultraviolet radiation, varies antibody - related autoimmune disease treated with systemic steroids and other immunosuppressive conditions such as chronic liver disease, HIV and organ transplantations have been implicated in its etiopathology. CASE REPORT: We present a case of porokeratosis, associated with idiopathic thrombocytopenia in 74 - year old, otherwise healthy male patient, as we discuss the previously reported associated disorders. CONCLUSION: Regarding all of the polymorphism of clinical presentation, associated disorders and treatment responses, we could conclude that disseminated porokeratosis is still an unknown well disorder, which will continue to surprise the physicians in future. The screening and follow up of the patients is mandatory in all cases because as we see, porokeratosis has multiple unexpected faces, which require circumstantial clinical and paraclinical behaviour. PMID- 29484013 TI - Medium Sized Congenital Melanocytic Nevus with Suspected Progression to Melanoma during Pregnancy: What's the Best for the Patient? AB - BACKGROUND: Congenital melanocytic nevi (CMN) are pigmented skin lesions usually present at birth. Rare varieties can develop and become clinically very large. Although they are benign nevomelanocytic neoplasms, all CMN may be precursors of the melanoma, regardless of their size. Individual risk of malignant transformation of melanocyte is determined by simultaneous action of exogenous and endogenous factors. The major exogenous risk factor is ultraviolet radiation. Leading roles among the endogenous factors are attributed to skin phenotype, gene mutation, sex hormones and their significance. CASE REPORT: We present a case of a 27 - year - old pregnant female patient with a congenital melanocytic nevus, which increased significantly in size, during her pregnancy. Estrogen levels increase during pregnancy and clinical evidence has suggested that melanocytes are estrogen - responsive. Nevi in a pregnant patient would exhibit increased expression of estrogen receptor beta (ERbeta) and thus enhanced the potential to respond to altered estrogen levels. CONCLUSION: All pigmented skin lesions should be carefully observed during pregnancy by a dermatologist due to the increased risk of malignant transformation, associated with the endocrine dependence. All lesions with visible changes should be removed surgically with appropriative anaesthesia. PMID- 29484014 TI - Once in a Blue Moon ... Rare Adnexal Tumor: From the Clinical and Videodermoscopical Aspects to the Mohs Surgery and the Histological Diagnosis. AB - The adnexal tumours are a very heterogeneous group of lesions, more and more studied in the literature. The squamoid eccrine ductal carcinoma (SEDC) is a rare malignant variant that combines ductal structures with squamous differentiation. We report a case of dermoscopic and histological diagnosis of SEDC, treated with Mohs Surgery and with no recurrence of a tumour after 12 months of follow up. PMID- 29484015 TI - Small Dysplastic Congenital Melanocytic Nevi in Childhood as Possible Melanoma Imitators. AB - Small pigmented lesions in children can represent a significant diagnostic challenge. If the diagnostic features and therapeutic approach are relatively well established in large and giant nevi, there is still much controversy regarding small and intermediate-sized congenital pigmented lesions that can lead to significant diagnostic challenges, both clinically and dermoscopically, and consequently to difficulty in defining the optimal approach in such cases. Although dermoscopy can be useful in the diagnosis of pigmented lesions, the diversity of clinical and dermoscopic features of pigmented nevi in children usually hinder the differentiation between them and melanoma. Histological findings after resection often show surprising results that do not correspond either to the clinical nor the dermoscopic features. With the present case, we want to emphasise the variable natural behaviour of melanocytic lesions in children, which sometimes leads to unnecessary surgical excisions, which should be avoided in pediatric patients. PMID- 29484016 TI - Chimeric Monoclonal Antibody Cetuximab Targeting Epidermal Growth Factor-Receptor in Advanced Non-Melanoma Skin Cancer. AB - BACKGROUND: Non-melanoma skin cancer (NMSC) is the most common malignancy in humans. Targeted therapy with monoclonal antibody cetuximab is an option in case of advanced tumor or metastasis. AIM: We present and update of the use of cetuximab in NMSC searching PUBMED 2011-2017. METHODS: The monoclonal antibody cetuximab against epidermal growth factor receptor (EGFR) has been investigated for its use in NMSC during the years 2011 to 2017 by a PUBMED research using the following items: "Non-melanoma skin cancer AND cetuximab," "cutaneous squamous cell carcinoma AND cetuximab," and "basal cell carcinoma AND cetuximab", and "cetuximab AND skin toxicity". Available data were analyzed including case reports. RESULTS: Current evidence of cetuximab efficacy in NMSC was mainly obtained in cutaneous SCC and to a lesser extend in BCC. Response rates vary for neoadjuvant, adjuvant, mono- and combined therapy with cetuximab. Management of cutaneous toxicities is necessary. Guidelines are available. CONCLUSIONS: Cetuximab is an option for recurrent or advanced NMSC of the skin. It seems to be justified particularly in very high-risk tumors. There is a need for phase III trials. PMID- 29484017 TI - Artificial Hair: By the Dawn to Automatic Biofibre(r) Hair Implant. AB - Since the beginning of the twentieth century, there have been attempts at creating artificial hair to treat baldness. Major evolution took place at the end of 1970's when, unfortunately, artificial hair treatments were applied without appropriate medical controls, resulting in sub-standard results from the use of unsuitable materials and technique. The large improper use of this technique in North America from no medical personnel and with dangerous fibres led the Food and Drug Administration (FDA) to suspend the procedure in 1983. In Europe, a new trial on artificial hair procedure started at the beginning of 1990's. In 1995 the European Union (UE) recognised the artificial hair implant as a legitimate medical treatment and outlined the rules related to that procedure. In 1996, biocompatible fibres (Biofibre(r)) produced by Medicap(r) Italy were approved by the UE Authorities and by the Australian Therapeutic Goods Administration (TGA) as medical devices for hair implant. An effective medical protocol was developed during the following years to provide correct guidelines for appropriate treatment, and to reduce possible related complications. Automatic Biofibre(r) hair implant represents the last achievement in this hair restoration technique with significant advantages for the patients. PMID- 29484018 TI - Health and Illness in History, Science and Society. AB - Health is a fundamental human right. The World Health Organization defines it as a "state of complete physical, psychological and social well - being and not merely the absence of disease or infirmity". The health of individuals, however, is also linked to the environment in which they live and especially to their ability to adapt and integrate into their life context. The relationship with the environment is extremely important because it is that interaction that outlines the concept of normality compared to pathology. Such normality needs to be contextualised by gender, geographical origin and by the individuals' living conditions: as a matter of fact, what is normal for a young person may differ from what is normal for a senior one. That is to say, the concept of health is indeed relative and it is the result of an interesting evolution of the concept of illness. From the first approaches - dealing with the mere treatment of the symptoms - to the promise of a free-from-pain society, science and economics have played a significant role in redefining the dualism health/ illness. The article reflects on these two concepts, health and illness, in history and nowadays, and discusses the future of the medical science. PMID- 29484019 TI - Cutaneous Microembolism of Fingers and Toes. AB - A macro vascular embolism is a well-known emergency. In contrast, cutaneous microembolism is a lesser known symptom. However, cutaneous microembolism of fingers and toes is a red flag symptom for vascular emergencies. The underlying cause may involve infectious, immunological, metabolic and physical disorders, coagulation disorders and malignancies. Early recognition can help to live safe. PMID- 29484021 TI - Arthrospira Platensis - Potential in Dermatology and Beyond. AB - The search for natural products with benefits for health in general and of potential for treating human disease has gained wider interest world-wide. Here, we analyse current data on the microalga Arthrospira platensis (AP), that has been used in nutrition since ancient times in Fare East and African communities, for medical purposes with a focus on dermatology. Extracts of AP have been investigated in vitro and in vivo. The alga is rich in proteins, lipopolysaccharides and gamma-linolenic acid. AP extracts, phycocyanin compounds and polysaccharide calcium spirulan (Ca-SP) have been evaluated in various models. It could be demonstrated, that AP has significant antioxidant activity, prevents viruses from entry into target cells and inhibits the colonisation of wounds by multi-resistant bacteria. Furthermore, anti-cancer activity was documented in models of oral cancer, melanoma, and UV-induced non-melanoma skin cancer. PMID- 29484020 TI - Unconventional Treatments for Vitiligo: Are They (Un) Satisfactory? AB - The authors show a brief overview of the vitiligo's unconventional therapies. A part for well-documented effectiveness of L-phenylalanine, PGE2 and antioxidant agents in the treatment of vitiligo, for the other therapeutical approaches more investigations are needed. PMID- 29484022 TI - Vitiligo in Children: A Better Understanding of the Disease. AB - Vitiligo is an important skin disease of childhood. The authors briefly discuss the etiopathobiology, clinics and comorbidities of the disease. PMID- 29484023 TI - Integrative Dermatology - The Use of Herbals and Nutritional Supplements to Treat Dermatological Conditions. AB - From humble beginnings at the dawn of time to it's advanced and successful status today, this essay traces the history of natural medicine and the development of integrated dermatology to what it is today. Some of the most well-known natural (international and Australian) products with an application in dermatology are discussed. The history and functions of the Psoriasis Eczema Clinic and the products developed by its founder, Prof. Michael Tirant, are explained. PMID- 29484024 TI - Herbal Compounds for the Treatment of Vitiligo: A Review. AB - An overview of unconventional therapies for vitiligo is presented. Some herbal compounds may be considered as valid therapeutic tools for the treatment of vitiligo. PMID- 29484025 TI - Acrocyanosis - A Symptom with Many Facettes. AB - Acrocyanosis is an uncommon complaint belonging to the acro-syndromes. It typically presents with coolness and bluish discolourations of hands, feet, ears, nose, lips and nipple. The most frequently affected parts of the body are the hands. This review discusses physical factors, vascular disorders, infectious diseases, haematological disorders, solid tumours genetic disorders, drugs, eating disorders, and spinal disease presenting as or leading to acrocyanosis. PMID- 29484026 TI - Vitiligo in Children: A Review of Conventional Treatments. AB - Vitiligo is an important skin disease of childhood, which may lead to deep psychological trauma, resulting in a poor quality of life and low self-esteem. The Authors discuss a short review of the more conventional therapies available for the treatment of vitiligo in children. PMID- 29484027 TI - Use of Curcumin in Psoriasis. AB - Curcumin is a polyphenol derived from the golden spice turmeric, which is widely used for different purposes, such as culinary spice and alimentary addictive, make - up and, finally, as a natural product for the treatment of different diseases, especially for the chronic inflammatory ones. Recently, curcumin has been proposed as a valid and safe therapeutic option for psoriasis. PMID- 29484028 TI - Vitiligo in Children: What's New in Treatment? AB - Vitiligo is an acquired chronic hypopigmentary disorder, which usually stars in childhood. The Authors discuss a short review of the more innovative therapies for childhood vitiligo. PMID- 29484029 TI - Comment on a Primary Cutaneous Nocardiosis of the Hand. AB - Nocardia spp. are gram-positive, partially acid-fast bacteria which are lives in environmental sources and cause of various infection that called nocardiosis in animals and humans. Identification of this group of bacteria was important due to accurate diagnosis, patient management and prevention of antibiotic resistant among of bacteria. Molecular methods including PCR-RFLP and sequencing using housekeeping genes such as 16S rRNA, hsp65, rpoB and gyrB are recommended to accurate and reliable identification of nocardiosis. PMID- 29484030 TI - Guidelines for Biomarker of Food Intake Reviews (BFIRev): how to conduct an extensive literature search for biomarker of food intake discovery. AB - Identification of new biomarkers of food and nutrient intake has developed fast over the past two decades and could potentially provide important new tools for compliance monitoring and dietary intake assessment in nutrition and health science. In recent years, metabolomics has played an important role in identifying a large number of putative biomarkers of food intake (BFIs). However, the large body of scientific literature on potential BFIs outside the metabolomics area should also be taken into account. In particular, we believe that extensive literature reviews should be conducted and that the quality of all suggested biomarkers should be systematically evaluated. In order to cover the literature on BFIs in the most appropriate and consistent manner, there is a need for appropriate guidelines on this topic. These guidelines should build upon guidelines in related areas of science while targeting the special needs of biomarker methodology. This document provides a guideline for conducting an extensive literature search on BFIs, which will provide the basis to systematically validate BFIs. This procedure will help to prioritize future work on the identification of new potential biomarkers and on validating these as well as other biomarker candidates, thereby providing better tools for future studies in nutrition and health. PMID- 29484031 TI - FTO genotype, dietary protein intake, and body weight in a multiethnic population of young adults: a cross-sectional study. AB - Background: Variation in the fat mass and obesity-associated gene (FTO) has been associated with susceptibility to obesity, but the association appears to be modified by diet. We investigated whether dietary protein intake modifies the association between FTO variant rs1558902 and body mass index (BMI) and waist circumference in young adults (n = 1491) from the cross-sectional Toronto Nutrigenomics and Health Study. Results: Lifestyle, genetic, anthropometric, and biochemical data were collected and diet was assessed using a Toronto-modified Willett Food Frequency Questionnaire. General linear models stratified by ethnicity and adjusted for age, sex, and total energy intake were used to examine the association between FTO genotypes and measures of body weight, and whether protein intake modified any of the associations. East Asians who were homozygous for the rs1558902 risk allele (A) had a greater BMI (p = 0.004) and waist circumference (p = 0.03) than T allele carriers. This association was not observed in individuals of Caucasian or South Asian ancestry. Among East Asians, a significant FTO-protein interaction was observed for BMI (p = 0.01) and waist circumference (p = 0.007). Those with low protein intake (<= 18% total energy intake) who were homozygous for the rs1558902 risk allele (A) had significantly higher BMI (p < 0.0001) and waist circumference (p = 0.0006) compared to carriers of the T allele. These associations were absent in the high protein intake group (> 18% total energy intake). Compared to Caucasians and South Asians, East Asians consumed a significantly higher ratio of animal-to-plant protein (p < 0.05). Conclusions: These findings suggest that high dietary protein intake may protect against the effects of risk variants in the FTO gene on BMI and waist circumference. PMID- 29484032 TI - Matching and Imputation Methods for Risk Adjustment in the Health Insurance Marketplaces. AB - New state-level health insurance markets, denoted Marketplaces, created under the Affordable Care Act, use risk-adjusted plan payment formulas derived from a population ineligible to participate in the Marketplaces. We develop methodology to derive a sample from the target population and to assemble information to generate improved risk-adjusted payment formulas using data from the Medical Expenditure Panel Survey and Truven MarketScan databases. Our approach requires multi-stage data selection and imputation procedures because both data sources have systemic missing data on crucial variables and arise from different populations. We present matching and imputation methods adapted to this setting. The long-term goal is to improve risk-adjustment estimation utilizing information found in Truven MarketScan data supplemented with imputed Medical Expenditure Panel Survey values. PMID- 29484033 TI - Is ZFP57 binding to H19/IGF2:IG-DMR affected in Silver-Russell syndrome? AB - Background: Loss of paternal methylation (LOM) of the H19/IGF2 intergenic differentially methylated region (H19/IGF2:IG-DMR) causes alteration of H19/IGF2 imprinting and Silver-Russell syndrome (SRS). Recently, internal deletions of the H19/IGF2:IG-DMR have been associated with LOM and SRS when present on the paternal chromosome. In contrast, previously described deletions, most of which cause gain of methylation (GOM) and Beckwith-Wiedemann syndrome (BWS) on maternal transmission, were consistently associated with normal methylation and phenotype if paternally inherited. Presentation of the hypothesis: The presence of several target sites (ZTSs) and three demonstrated binding regions (BRs) for the imprinting factor ZFP57 in the H19/IGF2:IG-DMR suggest the involvement of this factor in the maintenance of methylation of this locus. By comparing the extension of the H19/IGF2:IG-DMR deletions with the binding profile of ZFP57, we propose that the effect of the deletions on DNA methylation and clinical phenotype is dependent on their interference with ZFP57 binding. Indeed, deletions strongly affecting a ZFP57 BR result in LOM and SRS, while deletions preserving a significant number of ZFPs in each BR do not alter methylation and are associated with normal phenotype. Testing the hypothesis: The generation of transgenic mouse lines in which the endogenous H19/IGF2:IG-DMR is replaced by the human orthologous locus including the three ZFP57 BRs or their mutant versions will allow to test the role of ZFP57 binding in imprinted methylation and growth phenotype. Implications of the hypothesis: Similarly to what is proposed for maternally inherited BWS mutations and CTCF and OCT4/SOX2 binding, we suggest that deletions of the H19/IGF2:IG-DMR result in SRS with LOM if ZFP57 binding on the paternal chromosome is affected. PMID- 29484034 TI - A robust internal control for high-precision DNA methylation analyses by droplet digital PCR. AB - Background: Droplet digital PCR (ddPCR) allows absolute quantification of nucleic acids and has potential for improved non-invasive detection of DNA methylation. For increased precision of the methylation analysis, we aimed to develop a robust internal control for use in methylation-specific ddPCR. Methods: Two control design approaches were tested: (a) targeting a genomic region shared across members of a gene family and (b) combining multiple assays targeting different pericentromeric loci on different chromosomes. Through analyses of 34 colorectal cancer cell lines, the performance of the control assay candidates was optimized and evaluated, both individually and in various combinations, using the QX200TM droplet digital PCR platform (Bio-Rad). The best-performing control was tested in combination with assays targeting methylated CDO1, SEPT9, and VIM. Results: A 4Plex panel consisting of EPHA3, KBTBD4, PLEKHF1, and SYT10 was identified as the best-performing control. The use of the 4Plex for normalization reduced the variability in methylation values, corrected for differences in template amount, and diminished the effect of chromosomal aberrations. Positive Droplet Calling (PoDCall), an R-based algorithm for standardized threshold determination, was developed, ensuring consistency of the ddPCR results. Conclusion: Implementation of a robust internal control, i.e., the 4Plex, and an algorithm for automated threshold determination, PoDCall, in methylation-specific ddPCR increase the precision of DNA methylation analysis. PMID- 29484036 TI - Genetic Association of Interleukin-31 Gene Polymorphisms with Epithelial Ovarian Cancer in Chinese Population. AB - Roles of interleukin-31 (IL-31) in the development and progression of human epithelial ovarian cancer are largely unknown. Studies report that the polymorphisms, rs7977932 C>G and rs4758680 C>A in IL-31, affect the expression level of IL-31. In the present study, we examined 412 patients with epithelial ovarian cancer and 428 healthy individuals to explore whether these polymorphisms are associated with the epithelial ovarian cancer in Chinese women. The genotype of the polymorphisms in each individual was identified. The associations of the polymorphisms with patients' clinical characteristics and outcomes were evaluated. For rs7977932, the frequency of the CG/GG was significantly decreased in patients with epithelial ovarian cancer. However, the frequency of the rs4758680 CA/AA was significantly increased in those patients. Moreover, the frequency of rs7977932 CG/GG genotype was significantly higher in patients with less advanced FIGO stages. Kaplan-Meier curve showed that patients with CG/GG genotypes of rs7977932 had a decreased risk for recurrence compared to those with CC genotype. Our findings suggested that rs7977932 and rs4758680 of IL-31 may be associated with the development and progression of the epithelial ovarian cancer in the Chinese population. IL-31, therefore, may be a potential therapeutic target for the development of drugs to treat the disease. PMID- 29484035 TI - Epigenome-wide analysis in newborn blood spots from monozygotic twins discordant for cerebral palsy reveals consistent regional differences in DNA methylation. AB - Background: Cerebral palsy (CP) is a clinical description for a group of motor disorders that are heterogeneous with respect to causes, symptoms and severity. A diagnosis of CP cannot usually be made at birth and in some cases may be delayed until 2-3 years of age. This limits opportunities for early intervention that could otherwise improve long-term outcomes. CP has been recorded in monozygotic twins discordant for the disorder, indicating a potential role of non-genetic factors such as intrauterine infection, hypoxia-ischaemia, haemorrhage and thrombosis. The aim of this exploratory study was to utilise the discordant monozygotic twin model to understand and measure epigenetic changes associated with the development of CP. Methods: We performed a genome-wide analysis of DNA methylation using the Illumina Infinium Human Methylation 450 BeadChip array with DNA from newborn blood spots of 15 monozygotic twin pairs who later became discordant for CP. Quality control and data preprocessing were undertaken using the minfi R package. Differential methylation analysis was performed using the remove unwanted variation (RUVm) method, taking twin pairing into account in order to identify CP-specific differentially methylated probes (DMPs), and bumphunter was performed to identify differentially methylated regions (DMRs). Results: We identified 33 top-ranked DMPs based on a nominal p value cut-off of p < 1 * 10-4 and two DMRs (p < 1 * 10-3) associated with CP. The top-ranked probes related to 25 genes including HNRNPL, RASSF5, CD3D and KALRN involved in immune signalling pathways, in addition to TBC1D24, FBXO9 and VIPR2 previously linked to epileptic encephalopathy. Gene ontology and pathway analysis of top-ranked DMP associated genes revealed enrichment of inflammatory signalling pathways, regulation of cytokine secretion and regulation of leukocyte-mediated immunity. We also identified two top-ranked DMRs including one on chromosome 6 within the promoter region of LTA gene encoding tumour necrosis factor-beta (TNF-beta), an important regulator of inflammation and brain development. The second was within the transcription start site of the LIME1 gene, which plays a key role in inflammatory pathways such as MAPK signalling. CP-specific differential DNA methylation within one of our two top DMRs was validated using an independent platform, MassArray EpiTyper. Conclusions: Ours is the first epigenome-wide association study of CP in disease-discordant monozygotic twin pairs and suggests a potential role for immune dysfunction in this condition. PMID- 29484038 TI - Inflammatory breast cancer in accessory abdominal breast tissue. AB - Accessory breast tissue results from failure of the embryologic mammary ridge, also known as the milk line, to involute. As a result, ectopic breast tissue can develop anywhere along this ridge, which extends from the axilla-the most common location-to the groin. Primary breast cancer in accessory breast tissue is uncommon but has been reported in multiple prior studies. We present a rare case of inflammatory breast cancer presenting in upper abdominal accessory breast tissue in women with a personal history of ipsilateral breast cancer, and highlight the challenges of both diagnosis and treatment of breast cancer in accessory breast tissue. PMID- 29484037 TI - A Novel Polymorphism in the Promoter of the CYP4A11 Gene Is Associated with Susceptibility to Coronary Artery Disease. AB - Enzymes CYP4A11 and CYP4F2 are involved in biosynthesis of vasoactive 20 hydroxyeicosatetraenoic acid and may contribute to pathogenesis of coronary artery disease (CAD). We investigated whether polymorphisms of the CYP4A11 and CYP4F2 genes are associated with the risk of CAD in Russian population. DNA samples from 1323 unrelated subjects (637 angiographically confirmed CAD patients and 686 age- and sex-matched healthy individuals) were genotyped for polymorphisms rs3890011, rs9332978, and rs9333029 of CYP4A11 and rs3093098 and rs1558139 of CYP4F2 by using the Mass-ARRAY 4 system. SNPs rs3890011 and rs9332978 of CYP4A11 were associated with increased risk of CAD in women: OR = 1.26, 95% CI: 1.02-1.57, P = 0.004, and Q = 0.01 and OR = 1.45, 95% CI: 1.13 1.87, P = 0.004, and Q = 0.01, respectively. Haplotype G-C-A of CYP4A11 was associated with increased risk of CAD (adjusted OR = 1.41, 95% CI: 1.12-1.78, and P = 0.0036). Epistatic interactions were found between rs9332978 of CYP4A11 and rs1558139 of CYP4F2 (Pinteraction = 0.025). In silico analysis allowed identifying that SNP rs9332978 is located at a binding site for multiple transcription factors; many of them are known to regulate the pathways involved in the pathogenesis of CAD. This is the first study in Europeans that reported association between polymorphism rs9332978 of CYP4A11 and susceptibility to coronary artery disease. PMID- 29484039 TI - Nodular fasciitis of the breast in an elderly woman. AB - Nodular fasciitis is a benign proliferation of fibroblasts and myofibroblasts most commonly found in the soft tissues of the upper extremities and the trunk of young to middle-aged adults. Nodular fasciitis is infrequently encountered in the breast and in the elderly. We report a case of a 69-year-old woman presenting with a palpable breast mass with imaging features that mimicked malignancy. Knowledge of this entity is important to allow proper radiological and pathologic concordance and patient management. PMID- 29484040 TI - Malignant phyllodes breast tumor. AB - Malignant phyllodes tumor is a rare tumor of the breast occurring in females usually between the ages of 35 and 55 years. It is often difficult to distinguish benign from malignant phyllodes tumors from other benign entities such as fibroadenomas. This case presentation demonstrates a woman with malignant phyllodes tumor treated with mastectomy with abdominal skin flap reconstruction. PMID- 29484041 TI - Primary breast osteosarcoma mimicking calcified fibroadenoma on screening digital breast tomosynthesis mammogram. AB - Primary breast osteosarcoma is a rare malignancy, with mostly case reports in the literature. The appearance of breast osteosarcoma on digital breast tomosynthesis imaging has not yet been described. A 69-year-old woman presents for routine screening mammography and is found to have a calcified mass in her right breast. Pattern of calcification appeared "sunburst" on digital breast tomosynthesis images. This mass was larger than on the previous year's mammogram, at which time it had been interpreted as a benign calcified fibroadenoma. The subsequent workup demonstrated the mass to reflect primary breast osteosarcoma. The patient's workup and treatment are detailed in this case. Primary breast osteosarcoma, although rare, should be included as a diagnostic consideration for breast masses with a sunburst pattern of calcifications, particularly when the mammographic appearance has changed. PMID- 29484042 TI - Fetal MRI diagnosis of 2 types of left pulmonary artery sling. AB - We report on 2 different types of left pulmonary artery sling (LPAS), types IA and IIB, diagnosed by fetal magnetic resonance imaging (MRI). We suggest that fetal MRI is an effective tool for accurately diagnosing LPAS and helping guide its perinatal management. Fetal MRI is relatively unaffected by the conditions that limit visualization by echocardiography. When prenatal ultrasound detects either a possible anomalous origin of the left pulmonary artery or a tracheobronchial anomaly, fetal MRI may provide additional information to confirm the LPAS diagnosis and classify its type. To our knowledge, these are the first reports of prenatally diagnosed LPAS by fetal MRI. PMID- 29484043 TI - Cardiac magnetic resonance imaging and a rare case of an atrial myxoma causing an atrial septal defect. AB - A 40 year-old athletic woman presented with worsening dyspnea on exertion over the preceding several months. Chest radiograph showed borderline cardiomegaly and subsequent echocardiography demonstrated a 5.0-cm left atrial mass as well as left-to-right interatrial shunting through a patent foramen ovale. Cardiac magnetic resonance imaging was performed, which demonstrated signal characteristics consistent with an atrial myxoma. The patient then underwent urgent surgical treatment with good technical and clinical outcome. Histologic examination confirmed an atrial myxoma. Cardiac magnetic resonance imaging was valuable in characterizing the nature of the atrial mass and patent foramen ovale, helping guide the surgical approach. PMID- 29484044 TI - Interarterial course of anomalous right coronary artery: Pathophysiology, diagnosis, and treatment. AB - Anomalous coronary artery from the opposite sinus is a rare congenital anomaly that can present with symptoms similar to coronary artery disease, and sudden cardiac death. Management of anomalous coronary artery from the opposite sinus varies; however, current guidelines suggest surgery in symptomatic patients. Our patient is a middle-aged male with a history of coronary artery disease and status post coronary artery bypass graft. He presented with complaints of vague chest pain. After a positive stress test, he was sent to the catheterization suite. Diagnosis of an anomalous right coronary artery from the left coronary sinus was made. The patient underwent surgical revascularization and was awaiting follow-up with cardiology at the time of study. A timely diagnosis of an anomalous coronary artery is critical in symptomatic patients because of the risk of sudden cardiac death, especially in patients with arteries with an interarterial course. This case demonstrates the importance of making the correct diagnosis, as appropriate surgical management can drastically improve outcomes. PMID- 29484045 TI - Radiopathologic correlation of a tricuspid valve papillary fibroelastoma detected in an infant. AB - Papillary fibroelastomas are benign primary cardiac tumors that usually arise from the valve apparatus and are rare in the pediatric population. Involvement of the tricuspid valve is even less common with only a few cases reported in the literature. Cardiac magnetic resonance imaging is a valuable examination that aids in differentiating a tumor from a thrombus. We present the case of an 11 month-old girl referred by her pediatrician to investigate a murmur noted since birth. To our knowledge, this is the first report of a pathologically proven papillary fibroelastoma arising from the tricuspid valve characterized by magnetic resonance imaging in an infant. PMID- 29484046 TI - Bifid sternum in a young woman: Multimodality imaging features. AB - Bifid sternum is a rare fusion anomaly of the chest wall that accounts for 0.15% of all chest deformities and may be associated with cardiac or vascular anomalies. It is usually diagnosed and surgically corrected at birth or within the first month of life. Being a diagnosis made during the neonatal period, computed tomography scan and magnetic resonance imaging are not often performed; not so many cases in literature have been studied with II level diagnostic imaging, such as computed tomography or magnetic resonance. We describe a case of bifid sternum, rarely diagnosed in adults, discovered in a 21-year-old woman who came to our Diagnostic Imaging Department to perform a chest magnetic resonance after a chest X-ray. PMID- 29484047 TI - Occult lawn mower projectile injury presenting with hemoptysis. AB - We present the case of a 72-year-old man with hemoptysis after a thoracic projectile injury, which occurred while mowing the lawn. Chest radiograph followed by a computed tomography angiogram revealed a metallic foreign body in the right middle lobe of the lung. The patient underwent a right anterolateral thoracotomy where the object was successfully retrieved. The patient had an uneventful postoperative recovery. PMID- 29484048 TI - Primary septic arthritis of the manubriosternal joint in an immunocompetent young patient: A case report. AB - The aim of this article was to illustrate a case of primary septic arthritis of the manubriosternal joint, due to Staphylococcus aureus infection, in an immunocompetent 28-year-old male patient. The manubriosternal joint can be rarely involved in inflammatory processes, but pyarthrosis is even more unusual in an otherwise healthy adult. Although rare, pyarthrosis could be associated with significant morbidity and mortality, first of all because of spreading to mediastinal structures. Diagnosis is generally made thanks to imaging findings after clinical suspicion in a patient with anterior chest pain and swelling, fever, and raised inflammatory markers, especially when any risk factors are known. Management is generally aggressive because intravenous antibiotics and surgical debridement are necessary. PMID- 29484049 TI - Delayed recurrence of ulcerative colitis manifested by tracheobronchitis, bronchiolitis, and bronchiolectasis. AB - Ulcerative colitis can cause inflammation of small and large airways, characterized by mucosal inflammation, tracheobronchial stenosis, bronchiestasis, and bronchiolitis. We present a case of tracheobronchitis and bronchiolitis associated with ulcerative colitis in a 58-year-old nonsmoking man, 17 years after the total colectomy and complete resolution of intestinal findings. Computed tomography demonstrated wall thickening of trachea and left main stem bronchus, and multiple bronchi around the both hilum with mild to moderate stenosis. Fiberoptic bronchial biopsy showed inflammation of the airways, similar to histologic findings of ulcerative colitis within colon. PMID- 29484050 TI - Displacement of a power-injectable PICC following computed tomography pulmonary angiogram. AB - Displacement of peripherally inserted central catheter (PICC) lines during contrast-enhanced computed tomography examinations is an underappreciated phenomenon. We report a case of iatrogenic PICC line displacement following the power injection of contrast during a computed tomography pulmonary angiogram. During the study, the PICC line was shown to move on 2 occasions, resulting in 2 nondiagnostic studies. We review the available literature on the topic and suggest possible strategies to avoid this phenomenon. Radiologists should be aware of PICC line migration, and it should become common practice to review the catheter tip position after computed tomography examinations. PMID- 29484051 TI - Colonic angiodysplasia on CT colonography: case report and characteristic imaging findings. AB - Gastrointestinal angiodysplasia represents the cause of 6% of lower gastrointestinal tract bleeding, particularly in the elderly. Because of the common presentation and age range of affected patients, often patients with occult or massive gastrointestinal bleedings are investigated with colonoscopy, in the suspect of colonic cancer. Other methods are capsule enteroscopy, angiography, double-contrast barium enema, computed tomography angiography, and radionuclide scanning. In this contribution, we describe a case of colonic angiodysplasia first suspected during computed tomography colonography performed after an incomplete colonoscopy in a patient with recent anemization. The purpose is to highlight the computed tomography colonography imaging characteristics of this rare finding during such examination performed due to suspected colon carcinoma as a complementary or substitutive method of colonoscopy. PMID- 29484052 TI - Computed tomography findings of diffuse gastrointestinal mantle cell lymphoma. AB - Multiple lymphomatous polyposis is an uncommon type of primary non-Hodgkin's lymphoma, characterized by multiple lymphomatous polyps along the gastrointestinal tract. We present 2 cases of diffuse gastrointestinal involvement and illustrate radiological and pathologic findings. PMID- 29484053 TI - Mucinous carcinoma of the gallbladder with signet ring cells. AB - Most gallbladder carcinomas are adenocarcinomas, of which mucinous carcinoma (MC) is a rare pathologic subtype. Signet ring cells are seldom found in MCs. We report an extremely rare case of gallbladder MC with signet ring cells. This is the first radiological case report about this rare type of histologic entity with detailed discussion of imaging findings in the English literature. In addition to the features of MC, linitis plastica-like invasion, which is the key feature of signet ring cells, was confirmed by both imaging and histopathologic analysis. Furthermore, radiologists should know how the imaging findings of MC differ from those of other major subtypes of adenocarcinoma, as there is a risk of delays in diagnosis and underestimation of tumor spread. PMID- 29484054 TI - Paroxysmal nocturnal haemoglobinuria (PNH) manifesting on CT as a pathologic segment of small bowel. AB - Paroxysmal nocturnal haemoglobinuria, a rare, acquired, life-threatening disease of the blood, is characterised by a triad of haemolysis previously believed to occur mainly at night, bone marrow dysfunction, and thrombophilia. Paroxysmal nocturnal haemoglobinuria is customarily regarded to manifest clinically as haemolytic anaemia and haemoglobinuria experienced as reddened urine in the morning, pancytopenia, and thrombosis. We describe a case in which an abnormal segment of small bowel as visualised on computed tomography was the principal sign of the disease process on presentation. PMID- 29484055 TI - Small bowel intussusception in 2 adults caused by inflammatory polyps. AB - Inflammatory fibroid polyps are rare, benign pseudotumors of the gastrointestinal tract of unknown etiology, which may rarely present as bowel intussusception and obstruction. The authors describe the clinical, radiologic, and pathologic features of 2 patients with ileal inflammatory fibroid polyps presenting as small bowel intussusception. PMID- 29484056 TI - Primary hepatic mucosa-associated lymphoid tissue lymphoma in a patient with no chronic liver disease: Case report. AB - Extramarginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) is a non Hodgkin lymphoma of low-grade malignancy. The most common localization is the stomach, and the common nongastric sites are salivary glands, the skin, orbits, the conjunctiva, the lung, breasts, upper airways, other gastrointestinal sites, and the liver. Primary hepatic MALT lymphoma is a rare disease and the diagnostic can be challenging. The clinical presentation is nonspecific and may range from no symptoms to end-stage liver disease. The radiological aspect of hepatic lymphoma may indicate this diagnosis; however, the final diagnosis is made by hepatic biopsy. We report the case of a 47-year-old woman with no chronic liver disease, incidentally found with a focal liver mass at ultrasound examination. The only clinical symptom was fatigue. The blood tests were normal and tumoral markers were negative. Computed tomography and magnetic resonance imaging were performed. However, because the hepatic lesion was first described as a benign entity and, at second opinion, the suspicion of lymphoma was raised, the patient decided to undergo surgery first, without prior biopsy. The histopathologic analysis confirmed the diagnosis: hepatic MALT lymphoma positive for CD 20 and negative for CD 5, BCL6, cyclin D1, and CD 23. No lymph node involvement was noted and follow-up imaging with positron emission tomography-computed tomography did not show any other site of disease, thus confirming the diagnosis of primary hepatic MALT lymphoma. The aim of this paper was to highlight the imagistic features of primary hepatic lymphoma to contribute to the early diagnosis of this rare disease entity. PMID- 29484057 TI - Ureterovaginal fistula secondary to retained vaginal foreign body in a young girl. AB - We present the case of a 13-year-old girl with a recurrent urinary tract infection, malodorous vaginal discharge, and urinary incontinence caused by a retained vaginal foreign body. The foreign body, an aerosol cap retained for over 2 years, resulted in the formation of a ureterovaginal fistula, an extremely rare complication. The critical value of ultrasound and magnetic resonance urography in delineating the foreign body, the fistulous tract, and the intraperitoneal urine leak is described. Through this unique diagnostic dilemma, we wish to highlight that the evaluation of persistent unusual urinary symptoms and vaginal discharge in a young girl must include a thorough pelvic examination and focused imaging to look for retained vaginal foreign bodies. PMID- 29484058 TI - A report of two deep-seated noncutaneous penile tumors: more than meets the eye. AB - Penile cancer is an uncommon primary genitourinary malignancy, the vast majority representing superficial squamous cell carcinomas. However, less common skin cancers, secondary malignancies, mesenchymal neoplasms, and hematopoietic tumors do affect the penis. Medical history, atypical presentation, and deep epicenter of a penile mass may raise question of a nonepithelial neoplasm. We describe and discuss 2 examples of rare deep-seated penile malignancies, leiomyosarcoma and B cell lymphoma. PMID- 29484059 TI - Triparametric ultrasound in differentiating multicystic renal masses: a rare presentation of unilateral focal renal lymphangioma. AB - We describe a rare case of renal lymphangioma presenting as a focal unilateral multicystic renal mass and document the first reported use of triparametric ultrasound (B-mode, Doppler, and contrast-enhanced ultrasound) in its diagnosis and discrimination from other focal multicystic lesions. Renal lymphangiomas are rare, benign, typically developmental lesions composed of cystic dilatation of the lymphatic ducts, usually occurring bilaterally as perinephric collections or parapelvic cysts mimicking hydronephrosis. Radiologists have an important role in suggesting the diagnosis, as clinical presentation can be nonspecific. Management is usually conservative; however, nephron-sparing surgery may be recommended in symptomatic individuals. PMID- 29484060 TI - Large presacral epidermoid cyst in an asymptomatic woman. AB - An epidermoid cyst is an infrequent entity among cysts found in the presacral region, frequently coexistent with a meningocele. Diffusion-weighted imaging is known to be a useful diagnostic measure for differentiating presacral epidermoid cysts. Here, we present a large but asymptomatic case found in the presacral region. Epidermoid cysts should be considered in patients with presacral cysts. PMID- 29484061 TI - Massive endometrioma presenting with dyspnea and abdominal symptoms. AB - An abdominal mass may present with a myriad of symptoms resulting from compression of surrounding organs. A major clinical challenge with practical implications is accurate preoperative identification of the origin of the mass. Here, we present the case of a 29-year-old female patient with abdominal distension and shortness of breath for approximately 6 weeks before presentation. A large abdominal mass compressing the surrounding organs was observed on abdominal x-ray and computed tomography of the abdomen and pelvis. Preoperative imaging was unable to identify the organ of origin; pathologic and histologic analyses of the tumor ultimately identified a rare, massive intra-abdominal endometrioma, freely floating within the peritoneum and fed by an omental blood supply. This case highlights the importance of considering an atypical presentation of endometriosis in women of reproductive age with abdominal complaints. PMID- 29484062 TI - Multiparametric ultrasound findings of tuberculous orchitis following bacillus Calmette-Guerin therapy. AB - Granulomatous bacillus Calmette-Guerin (BCG) infection, both localized and disseminated, as a complication of intravesical therapy for transitional cell carcinoma of the bladder is a recognized but highly unusual phenomenon. We report the case of an 89-year-old gentleman with a history of bladder transitional cell carcinoma and subsequent intravesical BCG instillation of the bladder who presented to his general practitioner with a non-tender lump in his left testis. Histopathologic and microbiological evaluation of the subsequent orchidectomy specimen revealed granuloma formation secondary to BCG infection. The use of bubble contrast agents and elastography in ultrasound to evaluate focal testicular lesions is a relatively novel concept, and we aim to highlight the imaging features of testicular BCG infection using these techniques. PMID- 29484063 TI - Wandering carotid arteries: Reciprocating change between normal and retropharyngeal positions on serial CT studies. AB - Positional change in the retropharyngeal carotid artery, a rare phenomenon over time, is even rarer in previous reports, and it is important to be aware of this before any neck surgical procedure. A woman in her 50s underwent an anterior maxillectomy for upper gingival cancer, without neck dissection. The patient had medical histories of diabetes mellitus and liver dysfunction, with unremarkable family histories. Serial neck contrast-enhanced computed tomography for detecting locoregional recurrence had been performed as a follow-up during 4 years. A radiological course of moving carotid arteries in serial computed tomography studies showed reciprocating positional changes (wandering) between normal and retropharyngeal regions. There was no locoregional recurrence of the gingival cancer. This is the first case to describe a so-rare presentation of wandering carotid arteries. It is important for clinicians to be aware of a wandering carotid artery to avoid potentially fatal complications. PMID- 29484064 TI - Peripheral osteoma, compound odontoma, focal cemento-osseous dysplasia, and cemento-ossifying fibroma in the same hemimandible: CBCT findings of an unusual case. AB - Peripheral osteoma is the most common subtype of osteoma that arises most frequently in the craniofacial bones. It may occur at any age with a male-to female ratio of 2:1. Peripheral osteoma may affect the mandible, particularly the ramus and the condyle. Compound odontoma is a subtype of odontoma that occurs in young subjects without gender predilection. It affects the maxilla more frequently than the mandible. Focal cemento-osseous dysplasia and cemento ossifying fibroma are 2 benign fibro-osseous lesions with a female predominance that occur most commonly in the posterior region of the mandible. We report the first case involving the simultaneous occurrence of these 4 benign lesions in the same hemimandible diagnosed by CBCT. PMID- 29484065 TI - A successful case of a para-aortic lymphocele treated with autologous peripheral blood injection. AB - A lymphocele is one of the complications of systematic pelvic or para-aortic lymphadenectomy. Although most patients are entirely asymptomatic, our patient exhibited an obstructive ileus at the jejunum compressed by a lymphocele. We report here a case of a subsequent para-aortic lymphocele treated with autologous peripheral blood injection. A 68-year-old woman with sigmoid colon cancer (T3N2bM1a) underwent laparoscopic sigmoidectomy. After 4 courses of chemotherapy (CapeOX + Bmab), para-aortic lymphadenectomy was additionally performed. One month later, an obstructive ileus occurred suddenly due to a lymphocele. A drainage catheter was placed into the lymphocele and a total of 35 mL of autologous peripheral blood was injected in 4 divided doses through the catheter. The volume of the lymphocele gradually reduced and the ileus improved after blood injection. This is the first report of a successful case of a subsequent para aortic lymphocele treated with autologous peripheral blood injection without any complications. PMID- 29484066 TI - Percutaneous radiofrequency ablation for a recurrent metastasis after resection of liver metastases from an ileal clear-cell sarcoma: Long-term local tumor control. AB - Clear-cell sarcomas (CCSs) in the gastrointestinal tract are extremely rare and aggressive tumors. We present the first case of a CCS arising in the ileum and metastasizing to the liver; our patient was a 60-year-old man. After the resection of the CCS and the liver metastases, a new liver metastasis developed, which was treated via percutaneous radiofrequency ablation only. At the 5-year follow-up, the ablated region was stable without local tumor progression. Percutaneous radiofrequency ablation is a viable local treatment option for recurrent metastases from an ileal CCS if they are detected when small and at an early stage in follow-up studies. PMID- 29484067 TI - Endovascular retrieval of foreign body in persistent left-sided superior vena cava. AB - Endovascular retrieval of a foreign body is becoming an increasingly common procedure in the management of complications resulting from more frequent endovascular procedures. Many procedures are performed on a regular basis in assessment of vascular anatomy, endovascular-guided therapy, and catheter placement. This case report depicts a complication of a chemoport placement resulting in a foreign body. Evaluation of the foreign body raised attention to aberrant anatomy, a persistent left-sided superior vena cava. We further discuss briefly the embryology behind a persistent left-sided superior vena cava, technical errors leading to the foreign body, and assessing the nature of the foreign body through different imaging modalities. This is followed by the subsequent endovascular retrieval by Interventional Radiology and a literature review and individual case assessment of endovascular foreign body retrieval. We discuss considerations for practice based upon our literature review. PMID- 29484068 TI - Rigid inflatable gastrostomy tube malposition. AB - Rigid inflatable gastrostomy (RIG) tubes are widely used in contemporary clinical practice for a variety of indications. Insertion of RIG tubes is associated with a high technical success rate and low incidence of mortality. In this case report, a procedural pitfall associated with intraperitoneal-extragastric malposition is described. Rigorous assessment of abdominal radiographs, as well as awareness of the expected appearance of the RIG tube and gastropexy T fasteners, allows the abdominal radiologist to detect early RIG position in the early postprocedural period. Abdominal radiography is a widely available and inexpensive technique. The high spatial resolution it provides makes it a valuable tool in determining hardware position. PMID- 29484069 TI - Successful selective arterial embolizations for bone metastases in renal cell carcinoma integrated with systemic therapies: A case report. AB - Herein is described the case of a 64-year-old patient affected by metastatic clear-cell carcinoma, with exclusive bone disease, subjected after the initial cytoreductive nephrectomy to 3 successive lines of medical treatment (sunitinib, everolimus, and sorafenib) and multiple locoregional treatments (spinal surgery, radiation therapy, and selective arterial embolization), resulting in a surprisingly long survival of over 75 months. In the era of target therapy, integration strategies, including additional locoregional treatment to medical therapy, are essential to optimize the clinical benefit, to maximize treatment duration overcoming focal progressive disease, and to improve the quality of life. In this context, we would highlight that selective transcatheter embolization of bone metastases from renal cell carcinoma should be considered as an effective and safe option in the palliative setting for patients with bone metastasis, especially for pain relief. PMID- 29484070 TI - Embolization of congenital intercostobronchial trunk-pulmonary artery fistula using Amplatzer vascular plugs. AB - We present the case of a 54-year-old male patient diagnosed with a right upper lobe lung cancer and was referred for resection. Positron emission tomography computed tomography scan showed a prominent vascular structure in the right lung, suspicious for vascular malformation. A computed tomography angiography was done, demonstrating an intercostobronchial trunk-pulmonary artery fistula. There was also non-tapering dilated wandering pulmonary artery coursing through the right lower lung without any abnormal connection with pulmonary veins and were supplying normal lung parenchyma. Amplatzer vascular plugs were used for the treatment of the intercostobronchial trunk-pulmonary artery fistula. Our case highlights these very rare vascular anomalies, and their management. PMID- 29484071 TI - Percutaneous embolization of cystic duct stump leak following failed endoscopic management. AB - A case of a 79-year-old man, status post laparoscopic cholecystectomy with a drainage catheter placed at the gallbladder fossa is presented. The case was complicated postoperatively by abdominal pain and bilious discharge from the drainage catheter. Endoscopic retrograde cholangio-pancreatography demonstrated leakage through the cystic duct stump into the gallbladder fossa. Placement of a covered metal stent endoscopically failed to seal the leak. We performed percutaneous embolization of the cystic duct stump using a combination of coils and gelatin sponge through the drainage catheter in the gallbladder fossa. To our knowledge, this technique has not been previously described in the literature. PMID- 29484072 TI - Percutaneous transgastric interventional radiology-operated duodenoscopy for the identification of duodenal perforation and Graham patch dehiscence. AB - Patients with a Roux-en-Y gastric bypass may be challenging diagnostic and therapeutic dilemmas for gastroenterologists and endoscopists due to anatomic considerations. Pancreaticobiliary limb pathology is particularly difficult to diagnose from standard endoscopic approaches as it often requires double balloon enteroscopy. Percutaneous access and gastrostomy placement into the gastric remnant, however, is a commonly performed procedure by interventional radiology. This report describes the identification of duodenal perforation and Graham patch dehiscence in the pancreaticobiliary limb of a patient with a prior Roux-en-Y gastric bypass who had failed traditional endoscopic measures, using transgastric remnant interventional duodenoscopy and confirmed with methylene blue injection into a periduodenal abscess. PMID- 29484073 TI - Hemiazygous-accessory hemiazygous continuation of double inferior vena cava. AB - We report a case of hemiazygous-accessory hemiazygous continuation of a double IVC with absent azygous vein, incidentally discovered in an adult patient. PMID- 29484074 TI - Bilateral trampoline fracture of the proximal tibia in a child. AB - Trampoline fractures are transversely oriented impaction fractures of the proximal tibia sustained by young children jumping on a trampoline. Unaware of the mechanism of this specific nontraumatic fracture, physicians may fail to detect these fractures on plain radiographs, as radiological findings may be very subtle. In this case report, we present a rare case of bilateral trampoline fractures with an explanation of the trauma mechanism. PMID- 29484075 TI - Chronic expanding hematoma of the left flank mimicking a soft-tissue neoplasm. AB - Soft-tissue hematomas are a common clinical entity often associated with trauma, surgery, and bleeding disorders. In the majority of cases, soft-tissue hematomas acutely appear and spontaneously resolve, but sometimes, they present as swellings that slowly expand and progressively increase with time. We present a case of a 70-year-old man with chronic expanding hematoma of the left flank without any history of recent trauma or other medical disease. The diagnosis could not be confirmed on imaging features alone, so the patient was taken to surgery for open biopsy and excision. In patients with slowly growing extremity masses without recent trauma or chronic medical disorders, the differential diagnosis becomes challenging, and chronic expanding hematoma should be considered in addition to soft-tissue sarcomas and other malignancies. PMID- 29484076 TI - Angiosarcoma of the hand associated with pseudoaneurysm. AB - Angiosarcoma is a rare malignancy of vascular endothelial origin. We describe a case of angiosarcoma of the hand initially histopathologically diagnosed as a pseudoaneurysm, emphasizing the diagnostic importance of radiological pathologic concordance. Here we highlight the distinctive imaging and the histopathologic features of angiosarcoma, invaluable to its accurate and timely diagnosis. PMID- 29484077 TI - Myxoid-round cell liposarcoma: MRI appearance after radiation therapy and relationship to response. AB - Liposarcomas are classified into 4 different subtypes, with the myxoid-round cell variant demonstrating increased morbidity and metastatic potential dependent on cell composition. Unique to sarcomas, the myxoid-round cell liposarcoma is remarkably sensitive to radiation therapy in the pretreatment setting, owing to the tumor morphology and vascular distribution. Herein we report a case of myxoid round cell liposarcoma within the deep soft tissues of the thigh of an 81-year old male with excellent neoadjuvant response to radiation. We briefly review treatment options. PMID- 29484079 TI - Acetabular paralabral cyst causing compression of the sciatic nerve. AB - Acetabular paralabral cysts are common. They vary in their clinical presentation and may be asymptomatic or cause pain and restriction at the hip joint. In rare instances they may cause symptoms by compressing local neurovascular structures. We report a case of symptomatic compression of the sciatic nerve by a posteriorly displaced acetabular paralabral cyst. PMID- 29484078 TI - Denervation pseudohypertrophy of calf muscles associated with diabetic neuropathy. AB - Denervation of muscle usually leads to muscle atrophy with fatty replacement but, uncommonly, also results in muscle hypertrophy or pseudohypertrophy with fatty replacement. We report the ultrasonographic and magnetic resonance imaging (MRI) findings of a patient with diffuse fatty infiltration of calf muscles as a result of denervation pseudohypertrophy. The elevated fasting glucose, neurogenic electromyographic changes, and muscle atrophy with adipose tissue infiltration are consistent with diabetic neuropathy as the cause of denervation pseudohypertrophy. Lumbosacral radiculopathy and plexopathy were excluded by MRI. The imaging features reported in the literature are reviewed. The important differential diagnosis of infiltrating lipoma and denervation hypertrophy, as well as other causes of monomelic hypertrophy or swelling, is discussed. This case report demonstrates the importance of MRI, with clinical, biochemical, electrophysiological, and histologic correlation in the diagnosis of denervation pseudohypertrophy. Correct diagnosis of denervation pseudohypertrophy has an important role in guiding further investigations and treatment of the disease and the underlying cause. PMID- 29484080 TI - Clinical usefulness of multiphase arterial spin labeling imaging for evaluating cerebral hemodynamic status in a patient with symptomatic carotid stenosis by comparison with single-photon emission computed tomography: A case study. AB - Multiphase arterial spin labeling (ASL), which obtains the imaged slices with various postlabeling delays, allows for the noninvasive assessment of cerebral hemodynamics that cannot be adequately acquired by single-photon emission computed tomography (SPECT) imaging. We describe the clinical usefulness of multiphase ASL in a patient with symptomatic carotid stenosis by comparison with SPECT at rest using iodoamphetamine. A 75-year-old man was referred to our hospital with severe stenosis of the left internal carotid artery (ICA). While SPECT showed no significant laterality of cerebral blood flow (CBF), multiphase ASL demonstrated relatively delayed perfusion in the left ICA territory. The patient underwent stent placement for the left ICA stenosis. Postoperatively, while SPECT demonstrated no significant laterality of CBF, multiphase ASL revealed improved perfusion in the left ICA territory. This case showed that multiphase ASL could accurately evaluate the cerebral hemodynamic status which could not be detected using pre- and postoperative SPECT. PMID- 29484081 TI - Biologically aggressive regions within glioblastoma identified by spin-lock contrast T1 relaxation in the rotating frame (T1rho) MRI. AB - Spin-lattice relaxation in the rotating frame magnetic resonance imaging allows for the quantitative assessment of spin-lock contrast within tissues. We describe the utility of spin-lattice relaxation in the rotating frame metrics in characterizing glioblastoma biological heterogeneity. A 84-year-old man presented to our institution with a right frontal temporal mass. Prior tissue sampling from a peripheral nonenhancing lesion was nondiagnostic. Stereotactic image-guided tissue sampling of the nonenhancing T2-fluid-attenuated inversion recovery hyperintense region involving the anterior cingulate gyrus with elevated spin lattice relaxation in the rotating frame metrics provided a pathologic diagnosis of glioblastoma. This case illustrates the utility of spin-lattice relaxation in the rotating frame magnetic resonance imaging in identifying biologically aggressive regions within glioblastoma. PMID- 29484082 TI - Arterial spin labeling perfusion imaging demonstrates cerebral hyperperfusion in anti-NMDAR encephalitis. AB - Anti-N-methyl-d-aspartate receptor encephalitis is an increasingly recognized autoimmune disorder that results in substantial morbidity, prolonged hospital stays, and even death. The diagnosis is often delayed or unrecognized entirely as a result of absent or only subtle initial magnetic resonance imaging findings and a nonspecific clinical syndrome. The discovery of early imaging findings in this disease may help clinicians to more aggressively treat this autoimmune encephalitis and to potentially lessen morbidity and mortality. We report a novel case of anti-N-methyl-d-aspartate receptor encephalitis characterized by early evidence of increased cerebral perfusion on arterial spin labeling perfusion imaging, a finding that preceded laboratory diagnosis and conventional magnetic resonance imaging abnormalities. Further investigation is needed to firmly establish the pathologic basis of this finding. PMID- 29484083 TI - Adrenal mass of unusual etiology: Ewing sarcoma in a young man. AB - Ewing sarcoma and peripheral primitive neuroectodermal tumor belong to the Ewing sarcoma (ES) family of tumors originating from a primitive neural tube. We report a 31-year-old man who was admitted to the urology clinic with complaints of fever, nausea, and dysuria. A right-sided adrenal mass was detected during ultrasonography. The lesion was then evaluated with magnetic resonance imaging, which showed areas of necrosis amid heterogeneous solid areas. Whole body scan with 2-deoxy-2-[fluorine-18]fluoro-D-glucose integrated with computed tomography and bone scan studies showed pulmonary and osseous metastatic foci. The mass and right kidney were removed by an open approach. An immunohistochemical and molecular workup enabled the diagnosis of ES. The patient also underwent radiotherapy and chemotherapy. The patient remained in fairly good health during the 18-month follow-up period, but showed progression of all metastatic foci and died 26 months after treatment. In conclusion, adrenal ES should be included in the differential diagnosis of nonfunctional adrenal lesions despite its rare occurrence. PMID- 29484084 TI - Radiological findings of two neoplasms with perivascular epithelioid cell differentiation. AB - Perivascular epithelioid cell tumors (PEComas) constitute a rare subset of mesenchymal neoplasms classified by the World Health Organization in 2002. We present two cases of PEComas; the first is a cervical PEComa in a 35-year-old woman with no known past medical history who presented with a palpable pelvic mass; the second is an adnexal PEComa in a 39-year-old woman with a history of colitis who presented with abdominal pain and diarrhea. The rarity of these tumors has led to little information about imaging characteristics which we hope these two cases will help expand. PMID- 29484085 TI - Pamidronate "zebra lines": A treatment timeline. AB - Osteogenesis imperfecta is a hereditary bone dysplasia characterized by bone fragility, deformity, and short stature. Treatment focuses on preventing bone fractures and symptom relief. Pamidronate, a second-generation bisphosphonate drug that minimizes bone loss, is the chosen treatment in osteogenesis imperfecta. Radiologically, each cycle of pamidronate treatment is depicted as a line of sclerosed nondecalcified cartilage at the metaphysis, termed a pamidronate line. In this case report, we demonstrate that a treatment timeline can be visualized on plain radiographs as the number and spacing of pamidronate lines reflects the number and timing of treatment cycles. The educational value of this is to reassure physicians of the benign nature of "zebra lines," to demonstrate that the pamidronate lines migrate and fade with bone growth, and alert physicians that the lack of expected pamidronate lines during treatment may reflect a change in the patient's condition that reduces the effectiveness of bisphosphonate infusions. PMID- 29484086 TI - The Ferroelectric Domain Structures Induced by Electron Beam Scanning in Lithium Niobate. AB - Ferroelectric domain structure has been formed under the action of electron beam scanning in congruent lithium niobate single crystal covered by surface dielectric layer. The obtained types of the domain patterns have been considered as subsequent stages of domain structure evolution. The dependence on irradiated charge density of domain density, length, and period of domain rays and stripe domain width was used for characterization of the domain structure evolution. The threshold irradiated charge density necessary for the formation of solid stripe domain has been revealed. All obtained results have been discussed in terms of kinetic approach based on the analogy between domain structure evolution and first-order phase transition. PMID- 29484087 TI - Vapocoolant Anesthesia for Cosmetic Facial Rejuvenation Injections: A Randomized, Prospective, Split-Face Trial. AB - Background: Minimally invasive cosmetic procedures are the most commonly performed aesthetic techniques by plastic surgeons. Patients are interested in a pain-free experience. Surgeons desire patient satisfaction and time-efficient utilization of office staff and resources. Clinical evidence exists for use of vapocoolant technology to reduce pain associated with intravenous cannulation in the pediatric population and in hemodialysis patients. Applying vapocoolant technology to facial rejuvenation is a novel approach to decrease pain associated with neurotoxin or filler injection. Methods: A randomized, prospective study was conducted, testing 15 subjects receiving filler injections and another 15 patients receiving neurotoxin injections using a split-face model. The vapocoolant spray used was composed of a 95:5 ratio of 1,1,1,3,3 pentafluoropropane and 1,1,1,2-tetrafluoroethane. Within each group, individual patients randomly received injection (filler or neurotoxin) alone versus injection (filler or neurotoxin) plus vapocoolant on an equivalent half of his or her face. An independent examiner recorded from each patient on a scale of 1 to 10 perceived pain for injection alone versus injection plus vapocoolant spray. Results were calculated as a percentage change of pain scores experienced after injection for each person between the control (nonvapocoolant) and treatment (vapocoolant) sides of the face. Results: Vapocoolant spray at the time of cosmetic facial injections leads to a 59% decrease in perceived pain score with neurotoxin injections (range, 0%-100% change) and 64% decrease in perceived pain score with filler injections (range, 0%-100% change). These results were statistically significant with P < .05. Conclusion: Vapocoolant spray reduces pain associated with facial rejuvenation procedures. PMID- 29484088 TI - Effect of glycation focusing on the process of epidermal lipid synthesis in a reconstructed skin model and membrane fluidity of stratum corneum lipids. AB - We previously reported that epidermal glycation causes an increase in saturated fatty acid (FA) content in a differentiated reconstructed skin model and HaCaT cells. However, the relationship between ceramides (CERs) and glycation and their effects on stratum corneum (SC) barrier function was not elucidated. In this study, we investigated the effect of glycation on lipid content in 6-day-old cultured reconstructed skin. We used the EPISKIN RHE 6D model and induced glycation using glyoxal. In addition to transepidermal water loss, content of CERs, cholesterol and FA in the reconstructed epidermal model were analyzed by high performance thin layer chromatography. Expression of genes related to ceramide metabolism was determined by real time RT-PCR. Membrane fluidity of stratum corneum lipid liposomes (SCLL) that mimic glycated epidermis was analyzed using an electron spin resonance technique. It was found that FA was significantly increased by glycation. CER[NS], [AP], and cholesterol were decreased in glycated epidermis. Expression of ceramide synthase 3 (CERS3) was significantly decreased while fatty acid elongase 3 was increased by glyoxal in a dose dependent manner. Membrane fluidity of SCLL mimicking the lipid composition of glycated epidermis was increased compared with controls. Therefore, disruption of CER and FA content in glycated epidermis may be regulated via CERS3 expression and contribute to abnormal membrane fluidity. PMID- 29484089 TI - RIS-1/psoriasin expression in epithelial skin cells indicates their selective role in innate immunity and in inflammatory skin diseases including acne. AB - OBJECTIVE: RIS-1/psoriasin/S100A7 is an epithelial antimicrobial peptide, whose expression is upregulated in inflammatory skin diseases and is induced by retinoids. Its molecular expression was investigated in skin cell cultures and in skin specimens to better understand its role in inflammatory procedures of the pilosebaceous unit. METHODS: rtPCR and northern blotting of RIS-1/psoriasin and the retinoid-metabolizing genes CYP26AI and CRABP-II were performed in cells cultures (keratinocytes, sebocytes, fibroblasts, endothelial cells, melanocytes, lymphocytes and prostate cells; native and treated with retinoids) and in situ hybridization in normal and inflamed skin (acne, psoriasis). RESULTS: a) RIS 1/psoriasin is expressed in keratinocytes and fibroblasts in vitro and in keratinocytes of the stratum granulosum in vivo. Retinoids in vitro and inflammatory conditions in vivo increase the levels of RIS-1/psoriasin in keratinocytes (both), sebocytes (inflammation only) and fibroblasts (retinoids). Sebocytes and fibroblasts are the metabolically most active skin cells, since they can upregulate the expression of CRABP-II and CYP26AI, genes responsible for retinoid metabolism. Inflammation modifies the compartmentation of RIS 1/psoriasin in sebaceous glands and the follicular root sheaths. CONCLUSION: The present data indicate that anti-inflammatory treatment targeting the epithelial compartments of the skin, including such with antibacterial peptides, may be promising for inflammatory skin diseases. PMID- 29484091 TI - Special types of folliculitis which should be differentiated from acne. AB - Because both acne vulgaris and folliculitis can present as inflammatory erythematous papules, pustules or nodules, they are often hard to distinguish. The importance to distinguish between these 2 shall be stressed as their pathogenesis and therapies are different and misdiagnosis or missed diagnosis may lead to improper treatment. We will introduce several special types of folliculitis that should be differentiated from acne to increase our knowledge of the disorders with an acne-like manifestation. PMID- 29484090 TI - Insulin and Insulin-like growth factor-1 can activate the phosphoinositide-3 kinase /Akt/FoxO1 pathway in T cells in vitro. AB - Hyper-glycemic food increases insulin-like growth factor 1 (IGF-1) and insulin signaling and regulates endocrine responses and thereby may modulate the course of acne. Inflammation and adaptive immune responses have a pivotal role in all stages of acne. Recent hypothesis suggests that hyperglycemic food reduces nuclear forkhead box-O1 (FoxO1) transcription factor and may eventually induces acne. The aim of our study was to investigate the role of IGF-1 and insulin on the phosphoinositide-3-kinase (PI3K)/Akt/FoxO1 pathway in human primary T cells and on the molecular functions of T cells in vitro. T cells were stimulated with 0.001 MUM IGF-1 or 1 MUM insulin +/- 20 MUM PI3K inhibitor LY294002. T cells were also exposed to SZ95 sebocyte supernatants which were pre-stimulated with IGF-1 or insulin. We found that 0.001 uM IGF-1 and 1 uM insulin activate the PI3K pathway in T cells leading to up-regulation of p-Akt and p-FoxO1 at 15 and 30 minutes. Nuclear FoxO1 was decreased and FoxO transcriptional activity was reduced. 0.001 uM IGF-1 and 1 uM insulin increased T cell proliferation but have no significant effect on Toll-like receptor2/4 (TLR) expression. Interestingly, supernatants from IGF-1- or insulin-stimulated sebocytes activated the PI3K pathway in T cells but reduced T cell proliferation. Taken together, this study helps to support that high glycemic load diet may contribute to induce activation of the PI3K pathway and increase of proliferation in human primary T cells. Factors secreted by IGF-1- and insulin-stimulated sebocytes induce the PI3K pathway in T cells and reduce T cell proliferation, which probably can reflect a protective mechanism of the sebaceous gland basal cells. PMID- 29484092 TI - Seeking new acne treatment from natural products, devices and synthetic drug discovery. AB - Despite lots of research on the pathogenesis of acne, the development of new therapeutic agents is still stagnant. Conventional agents which target multiple pathological processes have some serious side effects and this makes seeking new treatment options important for treating acne. As new therapeutic options, researchers are focusing on natural products, synthetic drugs and devices. From natural products, epigallocatechin-3 gallate, lupeol, cannabidiol and Lactobacillus fermented Chamaecyperis obtusa were reported to be possible candidates for novel drugs, targeting multiple pathogenic factors. Synthetic anti P.acnes agent, nitric oxide nanoparticles and alpha-mangostin nanoparticles are shown to be effective in acne treatment. Device or procedural methods such as fractional microneedling radiofrequency, cryolysis, photothermolysis and daylight photodynamic therapy have potential as new treatment options for acne. Further large clinical trials comparing these new treatments with existing agents will be necessary in the future. PMID- 29484093 TI - Modulation of Toll Like Receptor-2 on sebaceous gland by the treatment of adult female acne. AB - Adult female acne is a chronic inflammatory, immune-mediated disease that affects the pilosebaceous unit in women in their 20s to 40s, and is considered different from acne vulgaris. Propionibacterium acnes is recognized by TLR-2, resulting in activation of this receptor and an inflammatory response through the NFkappa B pathway. This therapeutic, interventional, open, randomized, evaluator-blinded and comparative trial included 38 adult women with moderate facial acne and 10 age-matched controls, all aged between 26 and 44 years. Two treatments were performed over six months: 15% azelaic acid gel (AA) bid (n = 18) and oral contraceptive (COC) drospirenone 3 mg/ethinylestradiol .02 mg (n = 20). Biopsies were taken at baseline (control, lesion, perilesional) and at the conclusion (lesion and perilesional) of the study to evaluate TLR-2 expression by immunohistochemistry. Lesion count and blind photographic evaluation were used for efficacy. The groups were homogeneous: 70% of lesions were located in the submandibular area, 95% of participants had inflammatory lesions; of these, 50% had persistent and 50% had late-onset acne. The mean ages were 33.7 +/- 5.5 and 33.1 +/- 5.3 years (COC and AA group, respectively). A moderate clinical improvement was observed in both groups. No difference in TLR-2 expression in the lesion or perilesional areas was observed; however, reduced TLR-2 expression was seen in the control group. A significant reduction in expression was observed after both treatments, with no difference between the groups. This finding suggests an anti-inflammatory effect of COCs and AA in adult female acne, via modulation of the TLR-2 receptor. PMID- 29484094 TI - The effect on acne quality of life of topical azelaic acid 15% gel versus a combined oral contraceptive in adult female acne: A randomized trial. AB - Acne vulgaris is a chronic inflammatory disease that affects the pilosebaceous unit. Recent studies have shown an increasing number of cases of acne in adult women. These cases are predominantly normoandrogenic and have show some clinical differences compared to adolescent acne. In addition to the physical aspects, acne has a strong psychosocial impact and can lead to the onset of signs and symptoms of depression, such as anger. Our objective was to evaluate the effect on acne-specific quality of life in adult women treated with topical azelaic acid versus a combined oral contraceptive. The study population consisted of 38 adult women with acne and without any features of hyperandrogenism recruited from the clinic of Dermatology Hospital Division of Sao Paulo, Federal University of Sao Paulo from January 2012 to September 2014. Patients were randomized into two different groups: one receiving containing 20 ug of ethinylestradiol and 3 mg drospirenone in a regimen of 24 days of medication, a combined oral contraceptive (COC), and the other group topical 15% azelaic acid (AA) gel, twice daily, both for six months. The quality of life was evaluated at baseline and end of treatment with an acne specific measure (Acne-QoL). Before treatment, our data revealed a significant impact of the presence of acne on quality of life. Both treatments resulted in improvement with significant statistical values in quality of life scores. Comparing the four domains of Acne-QoL, patients treated with an oral contraceptive showed greater improvement in two domains (self-perception and acne symptoms) than those treated with azelaic acid. PMID- 29484095 TI - Cutaneous fungal microbiome: Malassezia yeasts in seborrheic dermatitis scalp in a randomized, comparative and therapeutic trial. AB - Malassezia spp in skin microbiome scalp has been implicated in seborrheic dermatitis pathogenesis. Thus, treatment based in antifungal combined to topical keratolitic agents have been indicated as well as oral isotretinoin as it reduces the sebum production, glandular's size and possesses anti-inflammatory properties. This randomized, comparative and therapeutic trial aimed toper form the genotypic identification of Malassezia species before and after low-dose oral isotretinoin or topical antifungal treatments for moderate to severe seborrhea and/or seborrheic dermatitis on scalp. Scales and sebum of the scalp were seeded in the middle of modified Dixon and incubated at 32 degrees C. For genotypic identification polymerase chain reaction primers for the ITS and D1/D2 ribossomal DNA were used and followed by samples sequencing. The procedure was conducted before and after therapeutic and randomized intervention for moderate to severe seborrhea/seborrheic dermatitis on the scalp, including oral isotretinoin, 10 mg, every other day and anti-seborrheic shampoo (piroctone olamine), over six months. The M. globosa and M. restricta were the most frequent species isolated on the scalp before and after both treatments. Other non-Malassezia species were also identified. The Malassezia spp. were maintained in the scalp after both treatments that were equally effective for the control of seborrhea/seborrheic dermatitis clinical signs. PMID- 29484097 TI - Clinical and histopathological characteristics in patients with scarring folliculitis type of acne inversa. AB - Objective: This study was designed to study the clinical and histopathological characteristics of patients with the scarring folliculitis type acne inversa in Chinese population. Methods: A total of 21 patients with acne inversa and 6 controls without known dermatological disease were recruited from outpatient department of dermatology and orthopedic surgery. Two-millimeter punch biopsies were taken from 8 patients with acne inversa and 6 controls, fixed in formalin, embedded in paraffin and stained with haematoxylin and eosin prior to histopathological analysis. Results: There were 12 patients (57.14%) belonging to the scarring folliculitis type presented with double comedones, papules, nodules, depressed scars, and were mainly Hurley stage I (66.67%). Many of the scarring folliculitis type were smokers (58.33%), some had a history of occupational exposure (41.67%) and some were overweight (50%), the mean BMI of which is 25.18+/-3.16 kg/m2. Histopathological changes such as perifollicular inflammation can be observed in scarring folliculitis type of acne inversa and controls as well. However, epidermal hyperplasia, follicular hyperplasia, sebaceous gland disappearance, destruction of hair follicle and sebaceous gland, collagen hyperplasia, perivascular inflammation, granulomatous inflammation, Micro thrombus were only seen in scarring folliculitis type. The mean surface area in patients (8073.36+/-15798.43 MUm2) was smaller than that in controls (302059.08+/ 502813.78 MUm2), with statistically significant difference. (P = 0.024). Conclusion: The scarring folliculitis type in acne inversa in Chinese population could be characterized by depressed scars, double-ended comedones, epidermal cysts and had high proportion of smokers, or occupational exposure with lower Hurley stage, as well as diminished sebaceous gland. Further studies are needed to clarify the relations between the clinical subtypes of acne inversa and their corresponding genetypes. PMID- 29484096 TI - Rosacea: Epidemiology, pathogenesis, and treatment. AB - Rosacea is a chronic relapsing inflammatory skin disease with a high prevalence among adults of Northern European heritage with fair skin. Symptoms present in various combinations and severity, often fluctuating between periods of exacerbation and remission. Based on morphological characteristics, rosacea is generally classified into four major subtypes: erythematotelangiectatic, papulopustular, phymatous, and ocular. Diverse environmental and endogenous factors have been shown to stimulate an augmented innate immune response and neurovascular dysregulation; however, rosacea's exact pathogenesis is still unclear. An evidence-based approach is essential in delineating differences between the many available treatments. Because of the diverse presentations of rosacea, approaches to treatment must be individualized based on the disease severity, quality-of-life implications, comorbidities, trigger factors, and the patient's commitment to therapy. PMID- 29484098 TI - Recent advances in the endocrinology of the sebaceous gland. AB - The sebaceous gland, long considered an evolutionary relic with little-to-no physiological relevance in humans, has emerged in recent decades as a key orchestrator and contributor to many cutaneous functions. In addition to the classical physico-chemical barrier function of the skin against constant environmental challenges, a more novel, neuro-immune modulatory role has also emerged. As part of the complex intercellular communication network of the integumentary system, the sebaceous gland acts as a "relay station" in the skin for many endocrine factors. This review aims to offer a comprehensive overview of endocrine effects and subsequent interactions on this much maligned mini-organ. PMID- 29484099 TI - Sunbeds with UVB radiation can produce physiological levels of serum 25 Hydroxyvitamin D in healthy volunteers. AB - Vitamin D3 is produced in the skin in response to UVB irradiation, from either sun exposure or UVB sunbeds. The objective of the current study was to characterize serum 25(OH)D response to regular sunbed use from several lamp outputs following their respective time exposure recommendations. There were three groups that tanned over 12 weeks during the winter months in dedicated sunbeds based on lamp outputs (100 W and 160 W low pressure fluorescent and 700 W high pressure filtered metal halide lamps) and a control group provided serum 25(OH)D samples at baseline and end-of-study. Tanning session lengths were calculated based on Health Canada guidelines to stay below the erythema levels. Mean 25(OH)D were increased by an average of 42 nmol/L in the sunbeds that used 100 W and 160 W fluorescents. Change in 25(OH)D was dependent on baseline 25(OH)D levels and sunbed (p = 0.003) and age (p = 0.03), but was not affected by gender, BMI, Fitzpatrick type or cumulative length of tanning sessions. There was no significant increase in 25(OH)D levels in participants using the 700 W filtered metal halide lamp sunbed or in the control participants. Skin pigmentation, [Formula: see text], was markedly increased in all tanners and skin lightness, L*, significantly decreased at 12 weeks. Both L* and [Formula: see text] were significantly correlated with 25(OH)D concentrations for the sunbeds with fluorescent lamps emitting UVB (100 W and 160W). Participants following standardized exposure schedules meeting Health Canada regulations in sunbeds irradiating adequate UVB showed continuous increases of 25(OH)D to physiological levels even after producing a tan in a controlled manner. ClinicalTrials.gov Registration: NCT02334592. PMID- 29484100 TI - Sebaceous-immunobiology is orchestrated by sebum lipids. AB - The major role of sebaceous glands in mammals is to produce sebum, which coats the epidermis and the hair providing waterproofing, thermoregulation and photoprotection. However, as the need for these functions decreased along the evolutionary changes in humans, a relevant question has been raised: are sebaceous glands and sebum the remnants of our mammalian heritage or do they have overtaken a far more complex role in human skin biology? Trying to provide answers to this question, this review introduces the evolving field of sebaceous immunobiology and puts into the focus the pathways that sebum lipids use to influence the immune milieu of the skin. By introducing possible modifiers of sebaceous lipogenesis and discussing the - human-specific - alterations in composition and amount of sebum, the attribute of sebum as a sensitive tool, which is capable of translating multiple signalling pathways into the dermal micro environment is presented. Further their interaction with macrophages and keratinocytes involves sebum lipid fractions into disease pathogenesis, which could lead - on the other side - to the development of novel sebum-based therapeutic strategies. PMID- 29484102 TI - Differential biological effects of dehydroepiandrosterone (DHEA) between mouse (B16F10) and human melanoma (BLM) cell lines. AB - Dehydroepiandrosterone (DHEA) is a weak androgen and had been shown to have anti cancer, anti-adipogenic and anti-inflammatory effects on mouse and other rodent models, but not on humans, suggesting a systemic level difference between mouse and human. Our previous study on DHEA biological functions involving a variety of cell lines, suggested that the functional differences between mouse and human existed even at the cellular level. Hence, using mouse and human melanoma cell models, in-vitro effects of DHEA on cell growth, mechanism of cell death and mechanism of DHEA action were studied. Results indicated a differential biological effects of DHEA between mouse and human melanoma cell lines. These in vitro studies also suggested that the differential biological effects observed between these two cell lines could be due to the difference in the way DHEA was processed or metabolized inside the cell. PMID- 29484103 TI - Cutaneous manifestations of diabetic peripheral neuropathy. AB - There is a rise in number of people diagnosed with Diabetes Mellitus. The incidence is rising in modern Indian society because of Industrial development and drastically changing lifestyles. Diabetic neuropathies are microvascular disorders that are usually associated with the duration of Diabetes. Among the various forms, the most common is Diabetic Peripheral Neuropathy. The disease if neglected leads to chronic ulcer formation leading to amputations frequently. Hence the aim of this study is to document the early cutaneous changes and create an early awareness in the importance of controlling Diabetes. The study consisted of 205 patients with Type 2 DM. Participant's neuropathy status was determined based on Neuropathy Disability Score and Diabetic Neuropathy Symptom Score. Among the Skin changes documented, the common changes seen were: Peripheral hair loss in 185 (90.2%), Xerosis in 168 (82%), Anhydrosis in 162 (79%), Plantar Fissures in 136 (66.3%), Plantar Ulcer in 80 (39%), common nail changes documented were Onychomycosis in 165 (80.5%) and Onychauxis in 53 (25.8%) patients in relation to the occupation and duration of Diabetes mellitus. In conclusion, it is important to control glycemic levels in the all stages of Diabetes and institute foot care measures to prevent the complications of neuropathy. PMID- 29484104 TI - Thyroid autoimmunity in female post-adolescent acne: A case-control study. PMID- 29484101 TI - Untangling the most probable role for vitamin D3 in autism. AB - Recent studies indicate an important role for vitamin D3 in autism spectrum disorder (ASD), although its mechanism is not completely understood. The most puzzling aspect of ASD is that identical twins, who share identical DNA, do not have 100% concordance rates (~88% for identical and ~31% for fraternal twins). These findings provide major clues into the etiology: ASD must involve an environmental factor present in the prenatal milieu that both identical twins are not always exposed to because they do not always share it (i.e., placentas). Combined with the exponential increasing rates of ASD around the world, these observations suggest a contagious disease is probably transferred to the fetus via the placenta becoming infected by a cervical virus. Vitamin D3 boosts immune responses clearing viral infections and increases serotonin and estrogen brain levels. Here we review the different roles and untangle the most probable one vitamin D3 plays in ASD. PMID- 29484105 TI - Local cortisol activation is involved in EGF-induced immunosuppression. AB - The major effects of the epidermal growth factor receptor (EGFR) signalling pathway on keratinocytes are cell proliferation, cell differentiation, and wound healing. In addition to these effects, an immunosuppressive effect of EGFR signalling has been reported. However, the precise mechanism of immunosuppression by EGFR signalling is not well understood. In this study, we clarified the involvement of increased local cortisol activation in EGFR signalling-induced immunosuppression in keratinocytes. EGF treatment up-regulated the expression of 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) and supernatant cortisol levels in a dose-dependent manner in keratinocytes. 11beta-HSD1 is an enzyme that catalyses the conversion of cellular hormonally inactive cortisone into active cortisol. qRT-PCR and ELISA assays indicated that EGF significantly decreased tumour necrosis factor alpha (TNF- alpha)-induced interleukin-6 (IL-6) expression in keratinocytes. Similarly, 11beta-HSD1 overexpression significantly decreased TNF-alpha-induced IL-6 expression. We evaluated the role of 11beta-HSD1 in immunosuppression through EGFR signalling. Blockade of 11beta-HSD1 via 11beta HSD1 inhibitor reversed both the expression and production of TNF-alpha-induced IL-6, which was decreased by EGF in keratinocytes. Therefore, increased local cortisol activation by 11beta-HSD1 is involved in EGFR signalling-induced immunosuppression in keratinocytes. Finally, we evaluated whether EGFR inhibition by cetuximab affects the expression of 11beta-HSD1. We found that 0.1 ug cetuximab decreased 11beta-HSD1 transcript levels in keratinocytes. The changes in 11beta-HSD1 were more apparent in TNF-alpha-treated cells. As 11beta-HSD1 expression in keratinocytes is associated with inflammation and cell proliferation, this mechanism may be associated with adverse skin reactions observed in patients treated with EGFR inhibitors. PMID- 29484108 TI - Competing risks and cancer-specific mortality: why it matters. PMID- 29484106 TI - Age-Related Macular Degeneration: New Paradigms for Treatment and Management of AMD. AB - Age-related macular degeneration (AMD) is a well-characterized and extensively studied disease. It is currently considered the leading cause of visual disability among patients over 60 years. The hallmark of early AMD is the formation of drusen, pigmentary changes at the macula, and mild to moderate vision loss. There are two forms of AMD: the "dry" and the "wet" form that is less frequent but is responsible for 90% of acute blindness due to AMD. Risk factors have been associated with AMD progression, and they are taking relevance to understand how AMD develops: (1) advanced age and the exposition to environmental factors inducing high levels of oxidative stress damaging the macula and (2) this damage, which causes inflammation inducing a vicious cycle, altogether causing central vision loss. There is neither a cure nor treatment to prevent AMD. However, there are some treatments available for the wet form of AMD. This article will review some molecular and cellular mechanisms associated with the onset of AMD focusing on feasible treatments for each related factor in the development of this pathology such as vascular endothelial growth factor, oxidative stress, failure of the clearance of proteins and organelles, and glial cell dysfunction in AMD. PMID- 29484107 TI - Granulocyte Colony-Stimulating Factor Alleviates Bacterial-Induced Neuronal Apoptotic Damage in the Neonatal Rat Brain through Epigenetic Histone Modification. AB - Bacterial meningitis during the perinatal period may cause long-term neurological deficits. The study investigated whether bacterial lipopolysaccharide (LPS) derived from E. coli. led to neuronal apoptosis with an impaired performance of long-term cognitive function involving the activation of histone modification in the TNF-alpha gene promoter. Further, we looked into the therapeutic efficacy of granulocyte colony-stimulating factor (G-CSF) in a neonatal brain suffering from perinatal bacterial meningitis. We applied the following research techniques: neurobehavioral tasks, confocal laser microscopy, chromatin immunoprecipitation, and Western blotting. At postnatal day 10, the animals were subjected to LPS and/or G-CSF. The target brain tissues were then collected at P17. Some animals (P45) were studied using neurobehavioral tasks. The LPS-injected group revealed significantly increased expression of NF-kappaB phosphorylation and trimethylated H3K4 in the TNFA gene promoter locus. Furthermore, the caspase-3, neuronal apoptosis expression, and an impaired performance in cognitive functions were also found in our study. Such deleterious outcomes described above were markedly alleviated by G-CSF therapy. This study suggests that selective therapeutic action sites of G-CSF through epigenetic regulation in the TNFA gene promoter locus may exert a potentially beneficial role for the neonatal brain suffering from perinatal bacterial-induced meningitis. PMID- 29484109 TI - A novel suicide gene therapy for the treatment of p16Ink4a-overexpressing tumors. AB - p16Ink4a is a potent cell cycle inhibitor engaged to support cell cycle arrest during cellular senescence. However, in tumors carrying mutations in key downstream effectors, p16Ink4a is highly expressed but fails to block cell proliferation. p16Ink4a-overexpressing tumor cells are highly aggressive and no targeted interventions are available. To study the effect of specific therapies, we generated murine sarcomas by overexpressing RAS oncogene and disrupting p53 activity. We observed that p16Ink4a-overxpressing murine sarcoma cells were resistant to ABT-263 and ABT-737, anti-cancer small molecules previously shown to eliminate p16Ink4a+ senescent cells. We then generated sarcoma cells carrying a suicide and reporter gene, called 3MR, under the regulation of the full p16Ink4a promoter. Activation of the suicide efficiently killed p16Ink4a-overxpressing sarcoma cells in vitro and in vivo. These data suggest that suicide gene therapy could represent an important therapeutic approach for the treatment of highly aggressive p16Ink4a+ cancers. PMID- 29484110 TI - Inhibition of Mdmx (Mdm4) in vivo induces anti-obesity effects. AB - Although cell-cycle arrest, senescence and apoptosis remain as major canonical activities of p53 in tumor suppression, the emerging role of p53 in metabolism has been a topic of great interest. Nevertheless, it is not completely understood how p53-mediated metabolic activities are regulated in vivo and whether this part of the activities has an independent role beyond tumor suppression. Mdmx (also called Mdm4), like Mdm2, acts as a major suppressor of p53 but the embryonic lethality of mdmx-null mice creates difficulties to evaluate its physiological significance in metabolism. Here, we report that the embryonic lethality caused by the deficiency of mdmx, in contrast to the case for mdm2, is fully rescued in the background of p533KR/3KR , an acetylation-defective mutant unable to induce cell-cycle arrest, senescence and apoptosis. p533KR/3KR/mdmx-/- mice are healthy but skinny without obvious developmental defects. p533KR/3KR/mdmx-/- mice are resistant to fat accumulation in adipose tissues upon high fat diet. Notably, the levels of p53 protein are only slightly increased and can be further induced upon DNA damage in p533KR/3KR/mdmx-/- mice, suggesting that Mdmx is only partially required for p53 degradation in vivo. Further analyses indicate that the anti obesity phenotypes in p533KR/3KR/mdmx-/- mice are caused by activation of lipid oxidation and thermogenic programs in adipose tissues. These results demonstrate the specific effects of the p53/Mdmx axis in lipid metabolism and adipose tissue remodeling and reveal a surprising role of Mdmx inhibition in anti-obesity effects beyond, commonly expected, tumor suppression. Thus, our study has significant implications regarding Mdmx inhibitors in the treatment of obesity related diseases. PMID- 29484111 TI - Endurance exercise prevents high-fat-diet induced heart and mobility premature aging and dsir2 expression decline in aging Drosophila. AB - High-Fat-Diet (HFD)-induced obesity is a major contributor to heart and mobility premature aging and mortality in both Drosophila and humans. The dSir2 genes are closely related to aging, but there are few directed reports showing that whether HFD could inhibit the expression dSir2 genes. Endurance exercise can prevent fat accumulation and reverse HFD-induced cardiac dysfunction. Endurance also delays age-relate functional decline. It is unclear whether lifetime endurance exercise can combat lifetime HFD-induced heart and mobility premature aging, and relieve the harmful HFD-induced influence on the dSir2 gene and lifespan yet. In this study, flies are fed a HFD and trained from when they are 1 week old until they are 5 weeks old. Then, triacylglycerol levels, climbing index, cardiac function, lifespan, and dSir2 mRNA expressions are measured. We show that endurance exercise improves climbing capacity, cardiac contraction, and dSir2 expression, and it reduces body and heart triacylglycerol levels, heart fibrillation, and mortality in both HFD and aging flies. So, lifelong endurance exercise delays HFD induced accelerated age-related locomotor impairment, cardiac dysfunction, death, and dSir2 expression decline, and prevents HFD-induced premature aging in Drosophila. PMID- 29484112 TI - Evidence that PP2A activity is dispensable for spindle assembly checkpoint dependent control of Cdk1. AB - Progression through mitosis, the cell cycle phase deputed to segregate replicated chromosomes, is granted by a protein phosphorylation wave that follows an activation-inactivation cycle of cyclin B-dependent kinase (Cdk) 1, the major mitosis-promoting enzyme. To ensure correct chromosome segregation, the safeguard mechanism spindle assembly checkpoint (SAC) delays Cdk1 inactivation by preventing cyclin B degradation until mitotic spindle assembly. At the end of mitosis, reversal of bulk mitotic protein phosphorylation, downstream Cdk1 inactivation, is required to complete mitosis and crucially relies on the activity of major protein phosphatases like PP2A. A role for PP2A, however, has also been suggested in spindle assembly and SAC-dependent control of Cdk1. Indeed, PP2A was found in complex with SAC proteins while small interfering RNAs (siRNAs)-mediated downregulation of PP2A holoenzyme components affected mitosis completion in mammalian cells. However, whether the SAC-dependent control of Cdk1 required the catalytic activity of PP2A has never been directly assessed. Here, using two PP2A inhibitors, okadaic acid and LB-100, we provide evidence that PP2A activity is dispensable for SAC control of Cdk1 in human cells. PMID- 29484113 TI - The prevention of chemotherapy induced peripheral neuropathy by concurrent treatment with drugs used for bipolar disease: a retrospective chart analysis in human cancer patients. AB - Peripheral neuropathy is a major adverse effect in the use of chemotherapeutic drugs. In nearly 50% of patients, chemotherapy induced peripheral neuropathy (CIPN) has been reported as irreversible. With increasing numbers of patients surviving treatment as well as increasing duration of survival after treatment, reducing the side effects of chemotherapy and improving the quality of life has become a major focus of cancer survivorship. Multiple classes of chemotherapeutic drugs including taxanes, platinum agents and vinka alkaloids list peripheral neuropathy as the main dose-limiting side effect of treatment. We previously found that drugs that interfere with the microtubule function, including taxanes and vinca alkaloids, bind to neuronal calcium sensor 1 (NCS1), leading to aberrant calcium signaling. The altered calcium signaling can be mitigated by application of drugs used to treat bipolar disease (e.g., lithium and valproic acid) prior to initiation of chemotherapy. Because pre-treatment with these drugs prevented CIPN in mice treated with taxanes, we sought clinical evidence by performing a retrospective chart review study of the VA electronic health record to see whether or not there would be evidence to support our scientific belief that patients treated with lithium or valproic acid while receiving chemotherapy have a lower risk for development of CIPN than patients who received chemotherapy alone. Our data did provide evidence supporting the belief that treatment with lithium or valproic acid concurrently with chemotherapy was associated with a decreased incidence of developing CIPN. PMID- 29484114 TI - Single cell whole genome sequencing reveals that NFKB1 mutation affects radiotherapy sensitivity in cervical cancer. AB - Cervical cancer is the third most common cancer in women. Radiotherapy resistance remains a major obstacle for patients with cervical cancer. Somatic alterations in human genomes are responsible for radiotherapy resistance. Here, we performed single cell whole genome sequencing on 13 cells before radiotherapy and 12 cells after radiotherapy from a Chinese woman patient with cervical carcinoma. We identified one damaging mutation in NFKB1 (G430E), which showed significantly increased mutant allele frequency after radiotherapy than that before radiotherapy. Further functional assays showed that NFKB1 was a tumour suppressor in cervical cancer by inhibiting cell proliferation, colony formation and migration, while the mutation in NFKB1 could weaken the tumour suppressing functions of NFKB1. NFKB1 enhanced the sensitivity of cervical cancer cells to the effects of irradiation, and the mutation in NFKB1 weakened this effect. These results suggested that NFKB1 may be a potential molecular target in cervical cancer radiation therapy in the future. PMID- 29484115 TI - Transcriptomes define distinct subgroups of salivary gland adenoid cystic carcinoma with different driver mutations and outcomes. AB - The relative rarity of salivary gland adenoid cystic carcinoma (ACC) and its slow growing yet aggressive nature has complicated the development of molecular markers for patient stratification. To analyze molecular differences linked to the protracted disease course of ACC and metastases that form 5 or more years after diagnosis, detailed RNA-sequencing (RNA-seq) analysis was performed on 68 ACC tumor samples, starting with archived, formalin-fixed paraffin-embedded (FFPE) samples up to 25 years old, so that clinical outcomes were available. A statistical peak-finding approach was used to classify the tumors that expressed MYB or MYBL1, which had overlapping gene expression signatures, from a group that expressed neither oncogene and displayed a unique phenotype. Expression of MYB or MYBL1 was closely correlated to the expression of the SOX4 and EN1 genes, suggesting that they are direct targets of Myb proteins in ACC tumors. Unsupervised hierarchical clustering identified a subgroup of approximately 20% of patients with exceptionally poor overall survival (median less than 30 months) and a unique gene expression signature resembling embryonic stem cells. The results provide a strategy for stratifying ACC patients and identifying the high risk, poor-outcome group that are candidates for personalized therapies. PMID- 29484116 TI - A common molecular signature of intestinal-type gastric carcinoma indicates processes related to gastric carcinogenesis. AB - Gastric carcinoma (GC) is one of the most aggressive cancers and the second leading cause of cancer death in the world. According to the Lauren classification, this adenocarcinoma is divided into two subtypes, intestinal and diffuse, which differ in their clinical, epidemiological and molecular features. Several studies have attempted to delineate the molecular signature of gastric cancer to develop new and non-invasive screening tests that improve diagnosis and lead to new treatment strategies. However, a consensus signature has not yet been identified for each condition. Thus, this work aimed to analyze the gene expression profile of Brazilian intestinal-type GC tissues using microarrays and compare the results to those of non-tumor tissue samples. Moreover, we compared our intestinal-type gastric carcinoma profile with those obtained from populations worldwide to assess their similarity. The results identified a molecular signature for intestinal-type GC and revealed that 38 genes differentially expressed in Brazilian intestinal-type gastric carcinoma samples can successfully distinguish gastric tumors from non-tumor tissue in the global population. These differentially expressed genes participate in biological processes important to cell homeostasis. Furthermore, Kaplan-Meier analysis suggested that 7 of these genes could individually be able to predict overall survival in intestinal-type gastric cancer patients. PMID- 29484117 TI - Paeoniflorin regulates osteoclastogenesis and osteoblastogenesis via manipulating NF-kappaB signaling pathway both in vitro and in vivo. AB - The metabolic balance between synthesis and resorption of the bone is maintained by osteoblasts and osteoclasts, respectively. Identification of agents that stimulate bone formation and suppress excessive osteoclast formation, may aid in preventing and treating conditions like osteoporosis and periprosthetic loosening. Paeoniflorin is a natural product derived from Paeonia lactiflora Pall with anti-inflammatory, analgesic, and diuretic properties. However, the effect of paeoniflorin on osteoclastogenesis and osteoblastogenesis is unknown. Herein, we demonstrated that paeoniflorin has a dose-dependent suppressive action on RANKL-evoked osteoclast differentiation and bone resorption, achieved by inhibiting the NF-kappaB pathway and subunit p65 nuclear translocation. Simultaneously, paeoniflorin was also found to stimulate osteoblast differentiation and bone mineralization, in addition to rescuing TNFalpha impaired osteoblastogenesis. At the molecular level, paeoniflorin was found to inhibit NF-kappaB transcriptional activity and stimulate osteoblastogenesis related marker gene expression (ALP, osteocalcin, OPN and Runx2), a trend that was inhibited by p65 overexpression. In ovariectomized mice, paeoniflorin was found to improve osteoblast activity, inhibit osteoclast activity, and thus, reduce ovariectomy-induced osteoporosis. Our study demonstrated that paeoniflorin simultaneously suppressed osteoclastogenesis and facilitated osteoblastogenesis by manipulating the actions of NF-kappaB. Therefore, paeoniflorin may serve as an ideal therapeutic antidote for osteoporosis. PMID- 29484118 TI - Genetic correction improves prediction efficiency of serum tumor biomarkers on digestive cancer risk in the elderly Chinese cohort study. AB - Although serum tumor biomarkers alpha-fetoprotein (AFP), carbohydrate antigen 19 9 (CA19-9) and carcinoembryonic antigen (CEA) have been used in digestive cancer risk prediction, the prediction efficiency remains unsatisfactory. The aim of this study was to evaluate whether genetic correction could improve the efficiency of these biomarkers for prediction of digestive cancer risk. We conducted a prospective analysis in 9,808 healthy individuals based on a cohort study in the elderly Chinese population. The genotypes of reported single nucleotide polymorphisms (SNPs) associated with serum AFP, CA19-9 and CEA were used to estimate the genetic corrected levels of these markers. Unconditional logistic regression analysis was performed to evaluate the risk of digestive cancer. The Harrell's C-statistic was used to evaluate the discriminative ability of the raw levels and genetic corrected levels of biomarkers on digestive cancer risk. Up to October 2013, a total of 172 individuals were newly diagnosed with digestive cancer. With the genetic correction, higher odds ratios (ORs) for digestive cancer risk were found for the genetic corrected levels of tumor biomarkers compared with their raw serum levels (1.57 vs. 1.65 for AFP; 1.19 vs. 1.21 for CA19-9; 1.09 vs. 1.10 for CEA, respectively). The same results were observed in the Harrell's C-statistic analyses. Genetic correction improved the prediction efficiency of tumor biomarkers on the digestive cancer risk in an elderly Chinese population. Our findings provide evidence for further studies of genetic effects on tumor biomarker to improve the predictive efficiency on cancer risk. PMID- 29484119 TI - Breast cancer cell-derived exosomes and macrophage polarization are associated with lymph node metastasis. AB - Crosstalk between breast cancer and macrophages has potential implications for tumor metastasis. This study investigates macrophage polarization induced by triple-negative breast cancer (TNBC) cell-derived exosomes that promote lymph node (LN) metastasis in orthotopic TNBC models. The MDA-MB-231 cancer cell line expressing the exosomal CD63-red fluorescence (RFP) fusion protein was generated to noninvasively visualize exosome transfer into cancer cells and macrophages. Administration of RFP-tagged exosomes enhanced migration of macrophages and induced macrophage polarization in vitro. In orthotopic TNBC models, noninvasive bioluminescent imaging, ultrasound-guided photoacoustic imaging, and histological analysis revealed that intravenous injection of RFP-tagged exosomes promoted primary tumor growth and axillary LN metastasis in which expression of CD206, a marker or alternatively activated type 2 (M2) macrophages, was significantly higher than expression of NOS2, a marker of classically activated type 1 (M1) macrophages. These results suggest breast cancer cell-derived exosomes stimulate macrophage polarization that creates favorable conditions for LN metastatic processes in TNBC. PMID- 29484120 TI - Epigallocatechin-3-gallate suppresses differentiation of adipocytes via regulating the phosphorylation of FOXO1 mediated by PI3K-AKT signaling in 3T3-L1 cells. AB - Epigallocatechin-3-gallate (EGCG) is a pivotal effective component of green tea. It is known that EGCG has antioxidant activity, anti-angiogenesis, anti-tumor, cardiovascular protection and blood lipid regulation functions. Forkhead box-O1 (FOXO1) is one of the downstream signals of protein kinase B (AKT) and takes part in adipogenesis. The purpose of this study is to investigate the effects of EGCG on adipose differentiation and the likely mechanisms. 3T3-L1 cells were induced by DMI for 2, 4, 6 and 8 days, respectively. During induction, the cells were treated with EGCG (5 MUM, 10 MUM, 50 MUM and 100 MUM) or DMSO for the first 2 days. In addition, another batch of 3T3-L1cells were treated with SC-3036 (PI3K activator, 10 uM), or LY294002 (PI3K inhibitor, 10 uM) alone or combined with EGCG (100 MUM) for the indicated times. Medium glucose concentration, lipid accumulation, the levels of TNF-alpha, resistin, adiponectin and leptin and the expression of FOXO1, phosphorylated-FOXO1 (P-FOXO1), PPARgamma, fatty acid synthase (FAS) were detected, respectively. The present study demonstrated that EGCG inhibited glucose uptake, lipid accumulation and adipokine secretion in a concentration-dependent manner during adipogenesis, which suggests that EGCG inhibits adipocyte's differentiation, maturation and functions. Moreover, EGCG also down-regulated the expression levels of PPARgamma and P-FOXO1. Conversely, the PI3K activator reversed these changes caused by EGCG, suggesting that the inhibitory effects of EGCG may be mediated by PI3K-AKT-FOXO1 pathway to negatively regulate the expression of PPARgamma. The findings will provide a solid foundation for EGCG to prevent and cure the obesity-associated diseases. PMID- 29484122 TI - SALL1 expression in acute myeloid leukemia. AB - Similar signaling pathways could operate in both normal hematopoietic stem and progenitor cells (HSPCs) and leukemia stem cells (LSCs). Thus, targeting LSCs signaling without substantial toxicities to normal HSPCs remains challenging. SALL1, is a member of the transcriptional network that regulates stem cell pluripotency, and lacks significant expression in most adult tissues, including normal bone marrow (NBM). We examined the expression and functional characterization of SALL1 in NBM and in acute myeloid leukemia (AML) using in vitro and in vivo assays. We showed that SALL1 is expressed preferentially in LSCs- enriched CD34+CD38- cell subpopulation but not in NBM. SALL1 inhibition resulted in decreased cellular proliferation and in inferior AML engraftment in NSG mice and it was also associated with upregulation of PTEN and downregulation of m-TOR, beta-catenin, and NF-?B expression. These findings suggest that SALL1 inhibition interrupts leukemogenesis. Further studies to validate SALL1 as a potential biomarker for minimal residual disease (MRD) and to determine SALL1's role in prognostication are ongoing. Additionally, pre-clinical evaluation of SALL1 as a therapeutic target in AML is warranted. PMID- 29484121 TI - Novel mutational landscapes and expression signatures of lung squamous cell carcinoma. AB - Lung squamous cell carcinoma (LUSC) is a major subtype of Non-Small Cell Lung Cancer. To increase our understanding of the LUSC pathobiology, we performed exome sequencing and RNA-seq in 16 murine carcinogen-induced LUSC tumors and 8 normal murine lung tissue samples. Additionally, we conducted single-cell RNA-seq on two independent tumors from the same murine model. We identified a list of 59 cancer genes recurrently mutated in the mice LUSC tumors, 47 (80%) of which were also mutated in human LUSCs. At the single cell level, we detected unique clonal mutation patterns for each of the two LUSC tumors, being initiated from clones carrying the mutant Igfbp7 and Trp53 genes, respectively. We also identified an expression signature serving as an effective classifier for LUSC tumors and a strong predictor of survival outcomes of lung cancer patients. Lastly, we found that some of the mutant LUSC genes were associated with the significantly altered tumoral expression of inhibitory immune checkpoint genes such as PD-L1, VISTA, TIM3 and LAG3 in human LUSCs. The novel findings of clonal evolution, mutational landscapes and expression signatures of LUSC suggested new targets for the overall LUSC therapy and the immunotherapy of LUSC. PMID- 29484123 TI - Expression of uc.189 and its clinicopathologic significance in gynecological cancers. AB - In recent decades, emerging evidence demonstrates that ultraconserved elements (UCEs) encoding noncoding RNAs serve as regulators of gene expression. Until now, the role of uc.189 in human cancers remains undefined and the clinical significance of uc.189 in gynecological cancers remains unknown. This study was to identify the prognostic value of uc.189 expression in gynecological cancers. Tissue microarrays were constructed with 243 samples including 116 cervical squamous cell carcinomas (CSCCs), 98 endometrial adenocarcinomas (EACs), 29 ovarian cystoadenocarcinomas(OCAs), and corresponding normal tissues. In CSCC, uc.189 expression was increased in 78.5% of cases (91/116), decreased in 4.3% (5/116), and unchanged in 17.2% (20/116). In EAC its expression was increased in 74.5% (73/98), decreased in 3.1% (3/98), and unchanged in 22.4% (22/98). Expression of uc.189 was increased in 23, and unchanged/decreased in 6, of 29 cases of ovarian cystoadenocarcinomas. Univariate and multivariate Cox regression analysis demonstrated that over-expression of uc.189 predicted poor prognosis in CSCC and EAC. Thus, these findings suggested uc.189 might be an evaluating prognosis marker of gynecological tumors. PMID- 29484124 TI - Involvement of the FOXO6 transcriptional factor in breast carcinogenesis. AB - In mammals, FOXO transcriptional factors form a family of four members (FOXO1, 3, 4, and 6) involved in the modulation proliferation, apoptosis, and carcinogenesis. The role of the FOXO family in breast cancer remains poorly elucidated. According to the cellular context and the stage of the disease, FOXOs can have opposite effects on carcinogenesis. To study the role of FOXOs in breast carcinogenesis in more detail, we examined their expression in normal tissues, breast cell lines, and a large series of breast tumours of human origin. We found a very low physiological level of FOXO6 expression in normal adult tissues and high levels of expression in foetal brain. FOXO gene expressions fluctuate specifically in breast cancer cells compared to normal cells, suggesting that these genes may have different roles in breast carcinogenesis. For the first time, we have shown that, among the various FOXO genes, only FOXO6 was frequently highly overexpressed in breast cell lines and tumours. We also found that inhibition of the endogenous expression of FOXO6 by a specific siRNA inhibited the growth of the human breast cell lines MDA-MB-468 and HCC-38. FACS and Western blot analysis showed that inhibition of endogenous expression of FOXO6 induced accumulation of cells in G0/G1 phase of the cell cycle, but not apoptosis. These results tend to demonstrate that the overexpression of the human FOXO6 gene that we highlighted in the breast tumors stimulates breast carcinogenesis by activating breast cancer cell proliferation. PMID- 29484125 TI - Oncogene c-Myc promotes epitranscriptome m6A reader YTHDF1 expression in colorectal cancer. AB - Recent studies that have emerged on the diversity of RNA modification in tumors suggest their eligibility as bona fide targets in diagnosis and drug discovery. N6-methyladenosine (m6A) was first reported and is most common in epitranscriptome modification of various RNAs. The YT521-B homology (YTH) domain family are representative m6A-binding proteins, but how the YTH domain family is involved in cancer remains to be clearly understood. Given that clinical sequence data in colorectal cancer indicate that overexpression of YTHDF1 is outstanding among other family members, we studied the role of Ythdf1 and the transcriptional control of YTHDF1. Immunostaining of Ythdf1 showed that its expression was associated with various malignant tumor behaviors, such as depth, lymph node metastasis, and poorer cancer stages. The study of patient survival indicated that patients with high Ythdf1 expression had significantly poorer overall survival. The results indicated that Ythdf1 expression is an independent prognostic factor of patients. The in vitro study showed that the knockdown of YTHDF1 resulted in the suppression of cancer proliferation and sensitization to the exposure of anticancer drugs such as fluorouracil and oxaliplatin. Importantly, the study upstream of the YTHDF1 gene indicated that an oncogenic transcription factor c-Myc was associated with YTHDF1 in both expression and chromatin immunoprecipitation data. Moreover, the knockdown experiments of c-Myc showed the inhibition of YTHDF1, supporting a notion of c-Myc-driven YTHDF1 axis significance. These data suggest that m6A reader Ythdf1 plays a significant role in colorectal cancer progression. PMID- 29484126 TI - Retargeting of UniCAR T cells with an in vivo synthesized target module directed against CD19 positive tumor cells. AB - Recent treatments of leukemias with T cells expressing chimeric antigen receptors (CARs) underline their impressive therapeutic potential but also their risk of severe side effects including cytokine release storms and tumor lysis syndrome. In case of cross-reactivities, CAR T cells may also attack healthy tissues. To overcome these limitations, we previously established a switchable CAR platform technology termed UniCAR. UniCARs are not directed against typical tumor associated antigens (TAAs) but instead against a unique peptide epitope: Fusion of this peptide epitope to a recombinant antibody domain results in a target module (TM). TMs can cross-link UniCAR T cells with tumor cells and thereby lead to their destruction. So far, we constructed TMs with a short half-life. The fast turnover of such a TM allows to rapidly interrupt the treatment in case severe side effects occur. After elimination of most of the tumor cells, however, longer lasting TMs which have not to be applied via continous infusion would be more convenient for the patient. Here we describe and characterize a TM for retargeting UniCAR T cells to CD19 positive tumor cells. Moreover, we show that the TM can efficiently be produced in vivo from producer cells housed in a sponge like biomimetic cryogel and, thereby, serving as an in vivo TM factory for an extended retargeting of UniCAR T cells to CD19 positive leukemic cells. PMID- 29484127 TI - MALAT1/miR-101-3p/MCL1 axis mediates cisplatin resistance in lung cancer. AB - In this study, we investigated the mechanism by which lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) mediates cisplatin resistance in lung cancer. Lung cancer patients with high MALAT1 levels were associated with cisplatin resistance and low overall survival. Moreover, cisplatin-resistant A549/DDP cells showed higher MALAT1 expression than cisplatin sensitive lung cancer cells (A549, H460, H1299 and SPC-A1). Dual luciferase reporter and RNA immunoprecipitation assays showed direct binding of miR-101-3p to MALAT1. MALAT1 knockdown in lung cancer cells resulted in miR-101-3p upregulation and increased cisplatin sensitivity. In addition, miR-101-3p decreased myeloid cell leukemia 1 (MCL1) expression by binding to the 3' untranslated region (3'-UTR) of its mRNA. These results demonstrate that MALAT1/miR-101-3p/MCL1 signaling underlies cisplatin resistance in lung cancer. PMID- 29484128 TI - Early hyperbaric oxygen effects on neuropathic pain and nitric oxide synthase isoforms in CCI rats. AB - Neuropathic pain is pain caused by injury or dysfunction in the central and/or peripheral nervous system. Neuropathic pain has a high incidence with a complex mechanism, but effective treatment remains elusive. Hyperbaric oxygen (HBO) therapy has been widely used in the treatment of a variety of neurological diseases. The current study used a rat model of neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve. We observed the effects of early use of 2.5 absolute atmosphere (ATA) HBO on neuropathic pain-related behaviors and the expression of nitric oxide synthase (NOS) isoforms in the spinal dorsal horn. In the CCI group, mechanical withdrawal threshold (MWT) was decreased, Thermal withdrawal latency (TWL) was shortened, and mRNA and protein levels of iNOS and nNOS were significantly increased compared to the sham group. MWT was increased, TWL was enhanced, and iNOS and nNOS levels were significantly decreased in the HBO group compared to the CCI group. There was no change in eNOS levels across all groups. HBO treatment at early stages can improve hyperalgesia. PMID- 29484129 TI - Diagnostic value of HE4+ circulating tumor cells in patients with suspicious ovarian cancer. AB - Lacking a satisfactory screening test, ovarian cancer is frequently diagnosed at a late stage, leading to poor patient outcomes. This study investigated the diagnostic value of circulating tumor cells (CTCs) in peripheral blood from patients with suspected ovarian tumors. Sixty-one women suspected of having an ovarian mass were prospectively enrolled in this study. CTCs were identified and counted using microfluidic isolation and immunofluorescent staining of CD45, HE4, and epithelial and mesenchymal (E&M) markers (epithelial cell adhesion molecule, cytokeratins, and vimentin). Thirty (49%) of the patients were diagnosed with ovarian cancer. DAPI+/E&M+/CD45-/HE4+ CTC counts were higher in these patients than in patients with benign tumors (p = 0.016). The receiver operating characteristic (ROC) curve showed that the sensitivity of CTCs was 73.3%, which was superior to that of CA125 (56.7%). In patients with elevated CA125 levels (>=35 U/ml), CTC counts still showed good specificity (86.7%). Our findings suggest the DAPI+/E&M+/CD45-/HE4+ CTC count is a useful diagnostic indicator in patients with suspected ovarian cancer. PMID- 29484130 TI - Prognostic factors associated with a stable MR4.5 achievement in chronic myeloid leukemia patients treated with imatinib. AB - Deep molecular response in chronic myeloid leukemia (CML) patients treated with imatinib is a prerequisite for possible discontinuation. We identify clinico biologic features linked with the probability of reaching MR4.5 (BCR-ABL/ABL <= 0.0032% IS) as a stable response (confirmed on two or more consecutive determinations). In a series of 208 patients treated with imatinib first-line outside clinical trials, after a median follow-up of 7 years the incidence of stable MR4.5 was 34.6%, obtained in median time of 5.4 years. In univariate analysis, female gender (p = 0.02), lower median age (56.4 vs 58.6, p = 0.03), Sokal risk stratification (p = 0.01) and e14a2 type of transcript (43% vs 31%, p = 0.02) are associated to achievement of a stable MR4.5. In multivariate regression analysis, female gender (HR 1.6, 95% CI: 1.1-2.6; P = 0.022), Sokal risk (HR 1.4, 95% CI: 1.1-2.3; p = 0.03), type of transcript (e14a2 vs e13a2 type, HR 1.6, 95% CI: 1.3-2.9; P = 0.03) and achievement of an early molecular response (EMR) at 3 months (HR 1.5, 95% CI: 1.2-2.8; P = 0.01), retained statistical significance. These clinical and biologic features associated with the achievement of a stable deep molecular response should be taken into account at a time when treatment-free remission strategies are being actively pursued in the management of CML. PMID- 29484131 TI - Dual targeting of mitochondrial function and mTOR pathway as a therapeutic strategy for diffuse intrinsic pontine glioma. AB - Diffuse Intrinsic Pontine Gliomas (DIPG) are the most devastating of all pediatric brain tumors. They mostly affect young children and, as there are no effective treatments, almost all patients with DIPG will die of their tumor within 12 months of diagnosis. A key feature of this devastating tumor is its intrinsic resistance to all clinically available therapies. It has been shown that glioma development is associated with metabolic reprogramming, redox state disruption and resistance to apoptotic pathways. The mitochondrion is an attractive target as a key organelle that facilitates these critical processes. PENAO is a novel anti-cancer compound that targets mitochondrial function by inhibiting adenine nucleotide translocase (ANT). Here we found that DIPG neurosphere cultures express high levels of ANT2 protein and are sensitive to the mitochondrial inhibitor PENAO through oxidative stress, while its apoptotic effects were found to be further enhanced upon co-treatment with mTOR inhibitor temsirolimus. This combination therapy was found to act through inhibition of PI3K/AKT/mTOR pathway, HSP90 and activation of AMPK. In vivo experiments employing an orthotopic model of DIPG showed a marginal anti-tumour effect likely due to poor penetration of the inhibitors into the brain. Further testing of this anti-DIPG strategy with compounds that penetrate the BBB is warranted. PMID- 29484132 TI - Cryoablation with drug-loaded bead embolization in the treatment of unresectable hepatocellular carcinoma: safety and efficacy analysis. AB - This study aimed to explore the efficacy and safety of drug-eluting bead (DEB) embolization (DEB-TACE) when combined with cryoablation in the treatment of unresectable hepatocellular carcinoma (HCC). The study was a single-center randomized controlled trial comprised of 60 patients with HCC conducted between August 2015 and October 2017. The patients were randomly divided into two groups: DEB-TACE combined with cryoablation (DEB-TACE-Cryo group) or cryoablation alone (Cryo group). Inter-group differences in overall survival, progression-free survival, and adverse reactions were assessed. The operative success rates were 82.7% and 77.4% in the DEB-TACE-Cryo group and Cryo group, respectively, with no operative mortality. The overall survival and progression-free survival in the DEB-TACE-Cryo group were significantly higher than those in the Cryo group (16.8 months vs.13.4 months, P = 0.0493; 8.1 months vs. 6.0 months, P = 0.0089, respectively). The postoperative complications in the two groups were rated as grade 1 or grade 2, according to guidelines set by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE V4.0). We demonstrated that DEB-TACE combined with cryoablation was effective, well tolerated, and had a low complication rate. Therefore, this combination therapy may be a better choice for the treatment of unresectable hepatocellular carcinoma. PMID- 29484133 TI - SCD5 restored expression favors differentiation and epithelial-mesenchymal reversion in advanced melanoma. AB - Our previous data supported a role for the Stearoyl-CoA desaturase (SCD5) in protection against malignancy, whereby it appears to functionally modify tumor stroma impairing tumor spread. SCD5 is significantly expressed in primary melanoma, but becomes barely detectable at tumor advanced stages. Looking for the regulatory mechanisms underlying SCD5 reduced expression during melanoma progression, we demonstrated a significantly lower stability of SCD5 protein as well as the direct targeting of SCD5 mRNA by the oncogenic miR-221&222 in metastatic cell lines. Moreover, our results indicated the existence of a negative feedback loop between SCD5 and miR-221&222, in good agreement with their opposite functions. Also, we showed how SCD5 re-expression and the direct supplementation of its main product oleic acid (OA) can drive advanced melanoma cell lines toward differentiation and reversion of the epithelial-mesenchymal (EMT)-like process, eventually inducing a less malignant phenotype. Indeed, SCD5 re-established the sensitivity to all-trans retinoic acid in A375M metastatic melanoma, associated with increased levels of Tyrosinase, melanin production and reduced proliferation. As evidenced by the correct modulation of some key transcription factors, SCD5 managed by favoring a partial mesenchymal-to epithelial (MET) transition in in vitro studies. Interestingly, a more complete MET, including E-cadherin re-expression correctly localized at cell membranes, was obtained in in vivo xenograft models, thus indicating the requirement of direct contacts between tumor cells and the surrounding microenvironment as well as the presence of some essential factors for SCD5 complete function. PMID- 29484134 TI - Interaction of renin-angiotensin system gene polymorphisms with hypertension in Chinese patients with type 1 diabetes and retinopathy. AB - Background: The objective of this research was to investigate the interaction of RAS gene polymorphisms in Chinese patients with type 1 diabetes mellitus (T1DM) and diabetic retinopathy (DR). Methods: Genomic DNA was extracted from peripheral blood leukocytes and genotyping for the angiotensin converting enzyme (ACE) gene I/D and angiotensinogen (AGT) gene M/T polymorphisms was performed using the polymerase chain reaction method. 311 T1DM patients were recruited for the assessment of ACE and AGT polymorphisms relating to DR. Results: Compared with the diabetic non-retinopathy (DNR) patients, DR patients had lower proportion of diabetic nephropathy (p<0.001) and M allele (p=0.013). Intriguingly, the frequency D allele (p=0.035) was lower in DR patients with hypertension, as well as DD (p=0.003) and DI genotype (p=0.012) in DR patients with normal blood pressure after multiple tests with Bonferroni correction, but D allele (p=0.025) displayed higher in normotensive patients with T1DM. Logistic regression analyses indicated that no significant relationship existed about the genotype and allele polymorphisms with the progress of DR after adjusting for confounding factors. Conclusions: Interaction of hypertension and the RAS gene polymorphisms might have a role in the DR development in Chinese T1DM patients. PMID- 29484135 TI - Interaction between physical activity, PITX1 rs647161 genetic polymorphism and colorectal cancer risk in a Korean population: a case-control study. AB - This study assessed the interaction between physical activity and colorectal cancer (CRC) risk based on a polymorphism in the paired-like homeodomain 1 (PITX1) gene in Koreans. In total, 923 cases and 1,846 controls were enrolled at the National Cancer Center, Korea. Subjects who did regular exercise showed a significantly reduced risk of CRC than those did not exercise regularly (OR = 0.37, 95% CI = 0.30-0.45). Subjects in the highest tertile of metabolic equivalents of task (MET)-minutes per week showed a significantly lower risk of CRC (OR = 0.62, 95% CI = 0.48-0.79, p-trend < 0.001). In the dominant model, minor allele carriers showed a significantly higher risk of CRC than subjects homozygous for the major allele (OR = 1.46, 95% CI = 1.18-1.80). The PITX1 genetic variant showed significant interactions with regular exercise and CRC risk (p-interaction = 0.018) and colon cancer risk (p-interaction = 0.029) among all subjects. Subjects who carried at least one minor allele and did not regularly exercise showed a greater risk of CRC (OR = 1.81, 95% CI = 1.37-2.41). Subjects who were homozygous for the major allele with high physical activity showed a significantly reduced risk of CRC (OR = 0.56, 95% CI = 0.38-0.82). Thus, individuals with PITX1 genetic variants can have benefit from physical activity regarding prevention of CRC risk in a Korean population. PMID- 29484136 TI - SOX9 is a driver of aggressive prostate cancer by promoting invasion, cell fate and cytoskeleton alterations and epithelial to mesenchymal transition. AB - Aggressive lethal prostate cancer is characterised by tumour invasion, metastasis and androgen resistance. Understanding the mechanisms by which localised disease progresses to advanced lethal stages is key to the development of effective therapies. Here we have identified a novel role for the transcription factor, SOX9, as a driver of aggressive invasive prostate cancer. Using genetically modified mouse models, we show that increased Sox9 expression in the prostate epithelia of animals with Pten loss leads to a highly invasive phenotype and metastasis. In depth analysis of these mice and related in vitro models reveals that SOX9 acts a key regulator of various processes that together promote tumour progression. We show that this factor promotes cell lineage plasticity with cells acquiring properties of basal stem cells and an increase in proliferation. In addition, increased SOX9 leads to changes in cytoskeleton and adhesion, deposition of extracellular matrix and epithelia to mesenchyme transition, properties of highly invasive cells. Analysis of castrated mice showed that the invasive phenotype driven by SOX9 is independent of androgen levels. Our study has identified a novel driver of prostate cancer progression and highlighted the cellular and molecular processes that are regulated by Sox9 to achieve invasive disease. PMID- 29484137 TI - Alzheimer's disease is associated with prostate cancer: a population-based study. AB - Alzheimer's disease and cancer are increasingly prevalent with advancing age. However, the association between Alzheimer's disease and prostate cancer remains unclear. The aim of this study was to examine the relationship between prior Alzheimer's disease and subsequent prostate cancer using a population-based dataset in Taiwan. Data for this study were sourced from the Taiwan Longitudinal Health Insurance Database 2005. This case-control study included 2101 prostate cancer patients as cases and 6303 matched controls. We used conditional logistic regression analyses to calculate the odds ratio (OR) and corresponding 95% confidence interval (CI) for Alzheimer's disease between prostate cancer patients and controls. We found that of the 8404 sampled patients, 128 (1.5%) had been diagnosed with Alzheimer's disease prior to the index date. A Chi-squared test showed that there was a significant difference in the prevalences of prior Alzheimer's disease between prostate cancer patients and controls (2.1% vs. 1.3%, p < 0.001). The conditional logistic regression analysis showed that the OR of prior Alzheimer's disease for prostate cancer patients was 1.53 (95% CI: 1.06~2.21) compared to controls. Furthermore, the OR of prior Alzheimer's disease for prostate cancer patients was 1.52 (95% CI: 1.04~2.22) compared to controls after adjusting for hypertension, diabetes, coronary heart disease, hyperlipidemia, obesity, prostatitis, gonorrhea or chlamydia infection, testitis or epididymitis, and alcohol abuse/alcohol dependency syndrome. This study revealed an association between prior Alzheimer's disease and prostate cancer. We suggest that clinicians be alert to the increased risk of prostate cancer when caring for elderly individuals with Alzheimer's disease. PMID- 29484138 TI - Impact of atrial fibrillation on the development of ischemic stroke among cancer patients classified by CHA2DS2-VASc score-a nationwide cohort study. AB - Purpose: The current study aimed to explore the impact of atrial fibrillation (AF) on risk of ischemic stroke among cancer patients classified by CHA2DS2-VASc score. Methods: Study participants were identified from Registry for Catastrophic Illness Patient Database. All cancer patients whether they had comorbid AF or not were divided into 4 groups according to their CHA2DS2-VASc score-a score of 0-1, 2-3, 4-5 and >5. Competing risk analysis was used to evaluate the subhazard ratios (SHRs) and 95% confidence intervals (CIs) of incident ischemic stroke between cancer patients with and without AF according to their CHA2DS2-VASc score. Results: A total of 781473 patients with cancer were identified. Of them, 21134 had comorbid AF whereas the remaining 760339 patients did not. After controlling for the confounding factors and the competing risk of death, among cancer patients, those with AF were associated with the highest risk of ischemic stroke than those without AF while their CHA2DS2-VASc score was 0~1 (adjusted SHR [aSHR] = 4.15, 95% CI = 3.29-5.23). Among those with a CHA2DS2-VASc score of >5, the AF group exhibited a 1.82-fold higher risk of ischemic stroke than the non-AF group (95% CI = 1.34-2.47). Conclusions: The impact of AF on risk of ischemic stroke was attenuated with advancing CHA2DS2-VASc score in patients with cancer. PMID- 29484139 TI - S100A9+ MDSC and TAM-mediated EGFR-TKI resistance in lung adenocarcinoma: the role of RELB. AB - Background: Monocytic myeloid-derived suppressor cells (MDSCs), particularly the S100A9+ subset, has been shown initial clinical relevance. However, its role in EGFR-mutated lung adenocarcinoma, especially to EGFR-tyrosine kinase inhibitor (EGFR-TKI) is not clear. In a clinical setting of EGFR mutated lung adenocarcinoma, a role of the MDSC apart from T cell suppression was also investigated. Results: Blood monocytic S100A9+ MDSC counts were higher in lung cancer patients than healthy donors, and were associated with poor treatment response and shorter progression-free survival (PFS). S100A9+ MDSCs in PBMC were well correlated to tumor infiltrating CD68+ and S100A9+ cells, suggesting an origin of TAMs. Patient's MDMs, mostly from S100A9+ MDSC, similar to primary alveolar macrophages from patients, both expressed S100A9 and CD206, attenuated EGFR-TKI cytotoxicity. Microarray analysis identified up-regulation of the RELB signaling genes, confirmed by Western blotting and functionally by RELB knockdown. Conclusions: In conclusion, blood S100A9+ MDSC is a predictor of poor treatment response to EGFR-TKI, possibly via its derived TAMs through activation of the non-canonical NF-kappaB RELB pathway. Methods: Patients with activating EGFR mutation lung adenocarcinoma receiving first line EGFR TKIs were prospectively enrolled. Peripheral blood mononuclear cells (PBMCs) were collected for MDSCs analysis and for monocyte-derived macrophages (MDMs) and stored tissue for TAM analysis by IHC. A transwell co-culture system of MDMs/macrophages and H827 cells was used to detect the effect of macrophages on H827 and microarray analysis to explore the underlying molecular mechanisms, functionally confirmed by RNA interference. PMID- 29484140 TI - A Taiwanese population-based study on the association between chronic tonsillitis and tonsil cancer. AB - Although it is known that inflammatory processes elevate the risk of cancer, to date the association between chronic tonsillitis and tonsil cancer remains unknown. This study aimed to evaluate the association of chronic tonsillitis with tonsil cancer based on a population-based database in Taiwan. We retrieved data for this study from the Longitudinal Health Insurance Database 2005. This case control study included 489 patients with tonsil cancer and 2445 matched controls. We used conditional logistic regression analyses to calculate the odds ratio (OR) and corresponding 95% confidence interval (CI) for having been previously diagnosed with chronic tonsillitis between patients with tonsil cancer and the controls. We found that of the 2934 sampled patients, 22 (0.75%) had received a diagnosis of chronic tonsillitis. A Chi-squared test further revealed that there was a significant difference in the prevalences of prior chronic tonsillitis between tonsil cancer patients and controls (2.45% vs. 0.41%, p<0.001). The conditional logistic regression suggested that after adjusting for hypertension, diabetes, hyperlipidemia, obesity, tobacco use disorder, and alcohol abuse/alcohol dependency syndrome, the OR of having previously been diagnosed with chronic tonsillitis for patients with tonsil cancer was 8.07 (95% CI: 3.32~19.64; p<0.001) compared to controls. It is also noteworthy that alcohol abuse/alcohol dependency syndrome was significantly associated with TC (adjusted OR=9.88). We demonstrated that patients with chronic tonsillitis were more likely to have tonsil cancer, and our findings support tonsillitis as a possible risk factor for tonsil cancer. PMID- 29484141 TI - Association between PIK3CA alteration and prognosis of gastric cancer patients: a meta-analysis. AB - Background: Increasing evidence suggests that dysregulation of phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) plays an important role in carcinogenesis. However, the relationship between PIK3CA expression and gastric cancer (GC) prognosis remains controversial. Methods: We searchedPubMed, Embase, Web of Science, and the Cochrane Library databases for relevant studies up to June 30, 2017. Primary outcomes were hazard ratio (HR), odds ratio (OR), and 95% confidence intervals (CI) for association with overall survival and clinicopathological features. Results: Eleven studies comprising 2481 GC patients were analyzed. Pooled analysis showed that PIK3CA upregulation was significantly associated with worse overall survival (HR = 1.79, 95% CI 1.42-2.27, p< 0.001) at the protein (HR = 1.94, 95% CI 1.52-2.47, p< 0.001) but not the gene (HR = 1.57, 95% CI 0.92-2.69, p= 0.097) level. PIK3CA gene mutation did not correlate with overall survival (HR = 1.05, 95% CI 0.83 1.34, p= 0.666) but was significantly associated with poor tumor differentiation (OR = 0.37, 95% CI 0.17-0.76, p= 0.011). Conclusion: High PIK3CA protein expression predicted poor prognosis in GC, whereas PIK3CA gene amplification or mutation did not. Moreover, PIK3CA mutation was an indicator of poorly differentiated tumors. PMID- 29484142 TI - Prognostic value of endoglin-assessed microvessel density in cancer patients: a systematic review and meta-analysis. AB - Background: Endoglin (ENG, CD105), an auxiliary receptor for several TGF-beta superfamily ligands, is constitutively expressed in tumor microvessels. The prognostic value of ENG-assessed microvessel density (MVD) has not been systemically analyzed. This meta-analysis reviews and evaluates the association between ENG expression and prognosis in cancer patients. Materials and Methods: Thirty published studies involving in 3613 patients were included after searching of PubMed, Web of Science, and EMBASE. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS) were calculated using random-effects models. The publication bias was detected by a Begg's test and Egger's test. The outcome stability was verified by sensitivity analysis. Results: The high ENG assessed MVD was significantly associated with poor OS (HR = 2.14, 95% CI 1.62 2.81; P < 0.001), DFS (HR = 3.23, 95% CI 2.10-4.95; P < 0.001), CSS (HR = 3.33, 95% CI 1.32-8.37; P < 0.001). Furthermore, subgroup analysis revealed that the association between the overexpression of ENG in tumor microvessels and the outcome endpoints (OS or DFS) were also significant in the Asians and Caucasians patients with different cancer types. Conclusions: ENG of tumor microvessels is a predictor of poor OS, DFS and CSS and may be a prognostic marker of patients with cancer. PMID- 29484143 TI - Anti-PD-1/PD-L1 antibodies versus docetaxel in patients with previously treated non-small-cell lung cancer. AB - Anti-PD-1/PD-L1 antibodies have been proved one of the most promising treatments against non-small cell lung cancer (NSCLC); however, whether anti-PD-1/PD-L1 antibodies can provide added benefits for pretreated patients with advanced NSCLC and which patients are most likely to benefit from anti-PD-1/PD-L1 therapy remain controversial. This meta-analysis evaluated the efficacy and safety between anti PD-1/PD-L1 antibodies and docetaxel in previously treated, advanced NSCLC. PubMed, EMBASE and Cochrane library databases were systematically searched for eligible studies. Five studies with a total of 3,025 patients were included. Our results showed that, for all patients, anti-PD-1/PD-L1 therapy prolonged overall survival (OS) (hazard ratio [HR] = 0.69; 95% CI, 0.63-0.75) and progression-free survival (PFS) (HR = 0.87; 95% CI, 0.80-0.94). For patients with PD-L1 expression >=1%, anti-PD-1/PD-L1 therapy had higher objective response rates. In subgroup analysis according to the tumor PD-L1 expression level, anti-PD-1/PD-L1 therapy was associated with longer OS and PFS in patients with high PD-L1 expression (>=1%, >=5%, >=10% and >=50%), but not in those with low expressions. In subgroup analysis of patients' characteristics, anti-PD-1/PD-L1 antibodies showed OS benefits across most prespecified subgroups, except for patients with EGFR mutation-positive and never smokers. For patients with EGFR mutation, anti-PD 1/PD-L1 therapy was an unfavorable factor of PFS. The grade 3 or 4 adverse events rates of anti-PD-1/PD-L1 treatment were significantly lower than that of docetaxel. Our results suggest that anti-PD-1/PD-L1 therapy significantly improves survival compared with docetaxel in patients with previously treated, PD L1-positive, advanced NSCLC, and has a distinct safety profile from chemotherapy. PMID- 29484144 TI - Association between PD-L1 expression and driver gene status in non-small-cell lung cancer: a meta-analysis. AB - Objective: To assess the association between PD-L1 expression and driver gene mutations in patients with non-small-cell lung cancer (NSCLC). Method: We performed a meta-analysis of 26 studies (7541 patients) which were published from 2015 to 2017. Pooled odds ratios (ORs) with 95% confidence intervals (CI) were calculated to describe the correlation. Subgroup analysis was performed based on population characteristics, types of PD-L1 antibodies and quality of individual studies. Results: A lower frequency of PD-L1 positivity was observed in NSCLCs harboring EGFR mutation (OR: 0.64, 95% CI, 0.45-0.91, p = 0.014). A negative correlation was also found at 1% (OR: 0.35, 95% CI, 0.22-0.55, p = 0.000) and 50% (OR: 0.33, 95% CI, 0.14-0.81, p = 0.015) cutoff for PD-L1 positive, elderly age group (OR: 0.56, 95% CI, 0.35-0.89, p = 0.013), female dominant group (OR: 0.55, 95% CI, 0.29-0.94, p = 0.030) and smoker dominant group (OR: 0.52, 95% CI, 0.29 0.96, p = 0.035). No significant differences in PD-L1 expression were observed among patients with different ALK, BRAF, HER2, PIK3CA status and MET expression level. Higher level of PD-L1 was found in tumors with KRAS mutation (OR: 1.45, 95% CI, 1.18-1.80, p = 0.001). PD-L1 expression level was not significantly different between triple (EGFR/ALK/KRAS) wild type NSCLCs and those with EGFR/ALK/KRAS mutation. Conclusions: PD-L1 expression in EGFR mutated NSCLCs were lower than those in EGFR wild type NSCLCs, while tumors with KRAS mutation showed higher levels of PD-L1. PMID- 29484145 TI - Prevalence of infant sneezing without colds and prediction of childhood allergy diseases in a prospective cohort study. AB - Background: Allergy sensitization may begin during the perinatal period, but predicting allergic diseases in infancy remains difficult. This study attempted to identify early predictors of childhood allergy diseases in a prospective cohort study. Materials and Methods: In a prospective birth cohort study at southern Taiwan locating in a subtropical region, questionnaire surveys of sneezing or cough without colds at 6 and 18 months of age were recorded, and the correlation with allergy diseases was assessed at 3 and 6 years of age. Results: A total of 1812 pregnant women and 1848 newborn infants were prenatally enrolled, and 1543, 1344, 1236, and 756 children completed the follow-up at ages 6 months, 18 months, 3 years and 6 years, respectively. The prevalence of infant sneezing without colds at 6 and 18 months of age was 30.3% and 19.2%, respectively. The prevalence of infant cough without colds at 6 and 18 months of age was 10.6% and 5.7%, respectively. Infant sneezing without colds at 18 months of age was significantly correlated with atopic dermatitis, allergic rhinitis and asthma at 6 years of age. Infant cough without colds at 18 months of age significantly predicted asthma but not atopic dermatitis or allergic rhinitis at 6 years of age. Conclusions: Infant sneezing without colds predicted all allergy diseases at 6 years of age in a subtropical country. This highlights a potential non-invasive clue in a subtropical region for the early prediction, treatment and prevention of childhood allergy diseases in infancy. PMID- 29484147 TI - Low- to high-density lipoprotein cholesterol ratio followed by coronary computed tomography angiography improves coronary plaque classification accuracy. AB - Coronary computed tomography angiography (CCTA) is a noninvasive test for detection and analysis of coronary plaques morphology and classification. The low to high-density lipoprotein cholesterol (L/H) ratio is associated with plaques vulnerability. The study aims to investigate the diagnostic accuracy of CCTA and L/H ratio for plaques classification. We enrolled 212 patients with coronary artery single-vessel disease who performed preoperative CCTA and Intravascular ultrasound (IVUS)-guided invasive coronary angiography. Patients were assigned to the acute coronary syndrome (ACS) group (n = 129) and stable angina pectoris (SAP) group (n = 83). CCTA showed that patients with ACS had more soft plaque and less calcific plaque than those with SAP. The plaque volume and remodeling index measured by CCTA showed good correlation with those measured by IVUS. IVUS identified 91 soft, 58 mixed and 63 calcific plaques in this cohort. For diagnosis of noncalcified plaque (soft and mixed), CCTA had the sensitivity and specificity of 87.9% and 90.4%, respectively. While refer to the further diagnosis of mixed plaque from noncalcified plaque, the sensitivity and specificity was 88.4% and 88.8%, respectively. The L/H ratio was gradually decreased from soft plaque to calcific plaque. If the patients had both the two characteristics (L/H >= 2.55 and CCTA), the sensitivity, and specificity were improved in diagnosing noncalcified plaque or mixed plaque. In conclusion, a combined application of CCTA and L/H ratio improves the diagnostic accuracy for coronary noncalcified plaque or mixed plaque as compared to CCTA along. PMID- 29484146 TI - Biomarkers for cognitive decline in patients with diabetes mellitus: evidence from clinical studies. AB - Diabetes mellitus is considered as an important factor for cognitive decline and dementia in recent years. However, cognitive impairment in diabetic patients is often underestimated and kept undiagnosed, leading to thousands of diabetic patients suffering from worsening memory. Available reviews in this field were limited and not comprehensive enough. Thus, the present review aimed to summarize all available clinical studies on diabetic patients with cognitive decline, and to find valuable biomarkers that might be applied as diagnostic and therapeutic targets of cognitive impairment in diabetes. The biomarkers or risk factors of cognitive decline in diabetic patients could be classified into the following three aspects: serum molecules or relevant complications, functional or metabolic changes by neuroimaging tools, and genetic variants. Specifically, factors related to poor glucose metabolism, insulin resistance, inflammation, comorbid depression, micro-/macrovascular complications, adipokines, neurotrophic molecules and Tau protein presented significant changes in diabetic patients with cognitive decline. Besides, neuroimaging platform could provide more clues on the structural, functional and metabolic changes during the cognitive decline progression of diabetic patients. Genetic factors related to cognitive decline showed inconsistency based on the limited studies. Future studies might apply above biomarkers as diagnostic and treatment targets in a large population, and regulation of these parameters might shed light on a more valuable, sensitive and specific strategy for the diagnosis and treatment of cognitive decline in diabetic patients. PMID- 29484148 TI - Review on comparative efficacy of bevacizumab, panitumumab and cetuximab antibody therapy with combination of FOLFOX-4 in KRAS-mutated colorectal cancer patients. AB - Colorectal cancer, fourth leading form of cancer worldwide and is increasing in alarming rate in the developing countries. Treating colorectal cancer has become a big challenge worldwide and several antibody therapies such as bevacizumab, panitumumab and cetuximab are being used with limited success. Moreover, mutation in KRAS gene which is linked with the colorectal cancer initiation and progression further interferes with the antibody therapies. Considering median progression free survival and overall survival in account, this review focuses to identify the most efficient antibody therapy in combination with chemotherapy (FOLFOX-4) in KRAS mutated colorectal cancer patients. The bevacizumab plus FOLFOX-4 therapy shows about 9.3 months and 8.7 months of progression free survival for KRAS wild and mutant type, respectively. The overall survival is about 34.8 months for wild type whereas for the mutant it is inconclusive for the same therapy. In comparison, panitumumab results in better progression-free survival which is about (9.6 months) and overall survival is about (23.9 months) for the wild type KRAS and the overall survival is about 15.5 months for the mutant KRAS. Cetuximab plus FOLFOX-4 therapy shows about 7.7 months and 5.5 months of progression-free survival for wild type KRAS and mutant type, respectively. Thus, panitumumab shows significant improvement in overall survival rate for wild type KRAS, validating as a cost effective therapeutic for colorectal cancer therapy. This review depicts that panitumumab along with FOLFOX 4 has a higher response in colorectal cancer patients than the either of the two monoclonal antibodies plus FOLFOX-4. PMID- 29484150 TI - Insulin receptor sensitization restores neocortical excitation/inhibition balance in a mouse model of autism. AB - Background: Met receptor tyrosine kinase regulates neurogenesis, differentiation, migration, connectivity, and synaptic plasticity. The human Met gene has been identified as a prominent risk factor for autism spectrum disorder (ASD). Met gene-altered mice serve as useful models for mechanistic studies of ASD. Inactivation of Met in excitatory cortical neurons in mice (Emx1cre/Metflox mice) yields a phenotype in which significantly decreased GABAA receptor-mediated inhibition shifts the excitation/inhibition (E/I) balance toward excitation in the somatosensory cortex. Further, unlike that seen in wild-type mice, insulin does not increase inhibition in the mutant cortex, suggesting that one of the consequences of kinase inactive Met gene could be desensitization of insulin receptors. To test this hypothesis, we investigated the effects of insulin receptor sensitizer, pioglitazone, on inhibition in the somatosensory thalamocortical circuitry. Methods: We used whole-cell patch clamp electrophysiology and analyzed excitatory and inhibitory responses of cortical layer IV excitatory cells following stimulation of their thalamic input in thalamocortical pathway intact brain slices. We applied insulin alone and insulin + a thiazolidinedione, pioglitazone (PIO), to test the effects of sensitizing insulin receptors on inhibitory responses mediated by GABAA receptors in the somatosensory cortex of Emx1cre/Metflox mice. Results: In WT brain slices, application of insulin together with PIO did not enhance the effect of insulin alone. In contrast, PIO application induced a much larger inhibition than that of insulin alone in Met-defective cortex. Thus, insulin resistance of GABAA receptor mediated response in Met mutant mice may result from desensitized insulin receptors. Conclusions: Sporadic clinical studies reported improved behavioral symptoms in children with autism following PIO treatment. We show that PIO can aid in normalization of the E/I balance in the primary somatosensory cortex, a potential physiological mechanism underlying the positive effects of PIO treatment. PMID- 29484151 TI - Warming increases the sensitivity of seedling growth capacity to rainfall in six temperate deciduous tree species. AB - Predicting the effects of climate change on tree species and communities is critical for understanding the future state of our forested ecosystems. We used a fully factorial precipitation (three levels; ambient, -50 % ambient, +50 % ambient) by warming (four levels; up to +4 degrees C) experiment in an old-field ecosystem in the northeastern USA to study the climatic sensitivity of seedlings of six native tree species. We measured whole plant-level responses: survival, total leaf area (TLA), seedling insect herbivory damage, as well as leaf-level responses: specific leaf area (SLA), leaf-level water content (LWC), foliar nitrogen (N) concentration, foliar carbon (C) concentration and C:N ratio of each of these deciduous species in each treatment across a single growing season. We found that canopy warming dramatically increased the sensitivity of plant growth (measured as TLA) to rainfall across all species. Warm, dry conditions consistently reduced TLA and also reduced leaf C:N in four species (Acer rubrum, Betula lenta, Prunus serotina, Ulmus americana), primarily as a result of reduced foliar C, not increased foliar N. Interestingly, these conditions also harmed the other two species in different ways, increasing either mortality (Populus grandidentata) or herbivory (Quercus rubra). Specific leaf area and LWC varied across species, but did not show strong treatment responses. Our results indicate that, in the northeastern USA, dry years in a future warmer environment could have damaging effects on the growth capacity of these early secondary successional forests, through species-specific effects on leaf production (total leaves and leaf C), herbivory and mortality. PMID- 29484149 TI - Randomised controlled trial of simvastatin treatment for autism in young children with neurofibromatosis type 1 (SANTA). AB - Background: Neurofibromatosis 1 (NF1) is a monogenic model for syndromic autism. Statins rescue the social and cognitive phenotype in animal knockout models, but translational trials with subjects > 8 years using cognition/behaviour outcomes have shown mixed results. This trial breaks new ground by studying statin effects for the first time in younger children with NF1 and co-morbid autism and by using multiparametric imaging outcomes. Methods: A single-site triple-blind RCT of simvastatin vs. placebo was done. Assessment (baseline and 12-week endpoint) included peripheral MAPK assay, awake magnetic resonance imaging spectroscopy (MRS; GABA and glutamate+glutamine (Glx)), arterial spin labelling (ASL), apparent diffusion coefficient (ADC), resting state functional MRI, and autism behavioural outcomes (Aberrant Behaviour Checklist and Clinical Global Impression). Results: Thirty subjects had a mean age of 8.1 years (SD 1.8). Simvastatin was well tolerated. The amount of imaging data varied by test. Simvastatin treatment was associated with (i) increased frontal white matter MRS GABA (t(12) = - 2.12, p = .055), GABA/Glx ratio (t(12) = - 2.78, p = .016), and reduced grey nuclei Glx (ANCOVA p < 0.05, Mann-Whitney p < 0.01); (ii) increased ASL perfusion in ventral diencephalon (Mann-Whitney p < 0.01); and (iii) decreased ADC in cingulate gyrus (Mann-Whitney p < 0.01). Machine-learning classification of imaging outcomes achieved 79% (p < .05) accuracy differentiating groups at endpoint against chance level (64%, p = 0.25) at baseline. Three of 12 (25%) simvastatin cases compared to none in placebo met 'clinical responder' criteria for behavioural outcome. Conclusions: We show feasibility of peripheral MAPK assay and autism symptom measurement, but the study was not powered to test effectiveness. Multiparametric imaging suggests possible simvastatin effects in brain areas previously associated with NF1 pathophysiology and the social brain network. Trial registration: EU Clinical Trial Register (EudraCT) 2012-005742-38 (www.clinicaltrialsregister.eu). PMID- 29484152 TI - Inter- and intraspecific variation in leaf economic traits in wheat and maize. AB - Leaf Economics Spectrum (LES) trait variation underpins multiple agroecological processes and many prominent crop yield models. While there are numerous independent studies assessing trait variation in crops, to date there have been no comprehensive assessments of intraspecific trait variation (ITV) in LES traits for wheat and maize: the world's most widespread crops. Using trait databases and peer-reviewed literature, we compiled over 700 records of specific leaf area (SLA), maximum photosynthetic rates (Amax) and leaf nitrogen (N) concentrations, for wheat and maize. We evaluated intraspecific LES trait variation, and intraspecific trait-environment relationships. While wheat and maize occupy the upper 90th percentile of LES trait values observed across a global species pool, ITV ranged widely across the LES in wheat and maize. Fertilization treatments had strong impacts on leaf N, while plant developmental stage (here standardized as the number of days since planting) had strong impacts on Amax; days since planting, N fertilization and irrigation all influenced SLA. When controlling for these factors, intraspecific responses to temperature and precipitation explained 39.4 and 43.7 % of the variation in Amax and SLA, respectively, but only 5.4 % of the variation in leaf N. Despite a long history of domestication in these species, ITV in wheat and maize among and within cultivars remains large. Intraspecific trait variation is a critical consideration to refine regional to global models of agroecosystem structure, function and food security. Considerable opportunities and benefits exist for consolidating a crop trait database for a wider range of domesticated plant species. PMID- 29484153 TI - Orthopraxy, not orthodoxy. PMID- 29484154 TI - Cyclic vomiting syndrome: a case series and review of the literature. AB - Objective: Cyclic vomiting syndrome (CVS) is under-recognised. Treatment is difficult as the pathophysiology is incompletely understood. We report our experience of treating patients with amitriptyline, and review the literature to summarise symptoms and associated features, epidemiology, potential pathophysiological mechanisms, differential diagnoses and treatment. Design: Consecutive adult patients with CVS were identified during a 5-year period from January 2010 until December 2015. Medical records were reviewed retrospectively, and age and sex of the patient, symptoms, associated features and response to treatment with amitriptyline were recorded. Setting: A luminal gastroenterology clinic at a teaching hospital. Results: Seventeen patients were identified (mean age 29.8 years, 13 (76.5%) female). Five had a history of cannabis use. Duration of symptoms prior to diagnosis ranged from 5 months to 15 years. Fourteen patients commenced amitriptyline, and in eight (57.1%) symptoms either ceased entirely or improved. Review of the literature suggested the prevalence of CVS was 0.5%. Symptoms are stereotypical, with acute episodes of nausea and vomiting, interspersed by periods when the patient is symptom-free. Proposed pathophysiologies include neuroendocrine dysfunction, mutations in mitochondrial DNA and re-intoxication effects from cannabis stored in fat tissues. Treatment during the acute phase is supportive, with rehydration, sedation and antiemetics. Prophylaxis to prevent future attacks with antihistamines, antimigraine drugs, antiepileptics and tricyclic antidepressants may be beneficial. Complete cessation of cannabis smoking should be advised. Conclusions: Diagnosis of CVS is often delayed in adults. Once identified, patients respond well to amitriptyline. PMID- 29484155 TI - A practical guide to thiopurine prescribing and monitoring in IBD. AB - Thiopurines are often the mainstay of treatment for many patients with inflammatory bowel disease. As such, a general understanding of the evidence behind their use and of their metabolism is extremely useful in clinical practice. This review gives a practical overview of thiopurine metabolism, the importance of thiopurine S-methyltransferase testing prior to the start of therapy and the monitoring of thioguanine nucleotide levels while on treatment, guiding a personalised approach to optimising thiopurine therapy. PMID- 29484156 TI - How are we managing fistulating perianal Crohn's disease? Results of a national survey of consultant gastroenterologists. AB - Objective: Fistulating perianal Crohn's disease represents a significant challenge to both clinicians and patients. This survey set out to describe current practice and variation in the medical management of this condition. Design: A survey was designed by an expert group of gastroenterologists and surgeons with an inflammatory bowel disease (IBD) interest. The questionnaire aimed to capture opinions from consultant gastroenterologists with a UK practice on the management of acutely symptomatic fistula, assessment of a new fistula presentation, medical management strategies and surgical intervention. The survey was piloted at the British Society of Gastroenterology Clinical Research Group meeting, and distributed at UK gastroenterology meetings. Results: There were 111 completed responses (response rate 55%). Following clearance of sepsis, 22.1% of respondents would wait 6 weeks or more before commencing medical therapy. Antibiotics were used by 89.2%, with a variable duration. First-line medical therapy was thiopurine for 48% and antitumour necrosis factor (TNF) for 50% of respondents. These were used in combination by 44.4%. Interval to escalation of therapy (if required) varied from 1 month to a year. Anti-TNF therapies were favoured in deteriorating patients. An IBD multidisciplinary team was accessible to 98%, although only 23.6% routinely discussed these patients. Optimisation strategies for anti-TNF and thiopurines were used by 70% of respondents. Recurrent sepsis, refractory disease and patient choice are indications for surgical referral. Conclusion: These results illustrate the huge variation in practice and lack of consensus among physicians for the optimal medical management of perianal Crohn's disease. There are gaps in knowledge that require targeted research. PMID- 29484157 TI - Can faecal calprotectin predict relapse in inflammatory bowel disease: a mini review. AB - Crohn's disease and ulcerative colitis are chronic inflammatory disorders affecting the gastrointestinal tract. Faecal calprotectin is a protein complex of the S-100 family of calcium-binding proteins present in inflammatory cells that can be measured in stool samples, which act as a biomarker for bowel inflammation. Elevated faecal calprotectin has been shown to reflect the presence of ongoing mucosal inflammation, which improves with mucosal healing. The aim of this review was to evaluate the available evidence on the ability of faecal calprotectin to predict a relapse in inflammatory bowel disease. Multiple retrospective studies have shown that patients who relapse have significantly higher levels of calprotectin in their stool compared with non-relapsers, especially in ulcerative colitis. Elevated faecal calprotectin postoperatively in Crohn's disease was also shown to be indicative of a relapse. However, the association of a raised faecal calprotectin and relapse is not universal and may be explained by the different patterns of mucosal inflammatory activity that exist. In conclusion, we put forward our hypothesis that changes such as a rise in faecal calprotectin levels may be more predictive of a relapse than absolute values. PMID- 29484158 TI - Establishing the aims, format and function for multidisciplinary team-driven care within an inflammatory bowel disease service: a multicentre qualitative specialist-based consensus study. AB - Objective: To obtain a specialist-based consensus on the aims, format and function for MDT-driven care within an inflammatory bowel disease (IBD) service. Design: This was a prospective, multicentre study using a Delphi formal consensus building methodology. Setting: Participants were recruited nationally across 13 centres from July to August 2014. Participants: 24 participants were included into the Delphi Specialist Consensus Panel. They included six consultant colorectal surgeons, six gastroenterologists, five consultant radiologists, three consultant histopathologists and 4 IBD nurse specialists. Interventions: Panellists ranked items on a Likert scale (1=not important to 5=very important). Items with a median score >3 were considered eligible for inclusion. Main outcome measures: Consensus was defined with an IQR <=1. Consensus on categorical responses was defined by an agreement of >60%. Results: A consensus on items (median; IQR) that described the aims of the MDT-driven care that were considered very important included: advance patient care (5;5-5), provide multidisciplinary input for the patient's care plan (5;5-5), provide shared experience and expertise (5;5-5), improve patient outcome (5;5-5), deliver the best possible care for the patient (5;5-5) and to obtain consensus on management for a patient with IBD (5;4-5). A consensus for being a core MDT member was demonstrated for colorectal surgeons (24/24), radiologists (24/24), gastroenterologists (24/24), nurse specialists (24/24), dieticians (14/23), histopathologists (21/23) and coordinators (21/24). Conclusions: This study has provided a consensus for proposed aims, overall design, format and function MDT-driven care within an IBD service. This can provide a focus for core members, and aid a contractual recognition to ensure attendance and proactive contribution. PMID- 29484159 TI - Monitoring adolescents and young people with inflammatory bowel disease during transition to adult healthcare. AB - The transition of adolescents and young people (AYP) with inflammatory bowel disease (IBD) from paediatric to adult healthcare requires coordination between healthcare care providers to achieve optimum outcomes. Transition into adulthood is a time of major challenges physically, developmentally, emotionally and psychosocially for AYP living with IBD. Healthcare professionals must monitor the AYP progress proactively with attention to each of these parameters throughout the transition period to ensure that milestones are attained, and skills for self management are formed. Thus, achieving the desired goals in both clinical and pastoral areas requires intensive monitoring from a multidisciplinary team across healthcare providers. PMID- 29484160 TI - Meeting update: faecal microbiota transplantation--bench, bedside, courtroom? PMID- 29484161 TI - Conference report: improving outcomes for gastrointestinal cancer in the UK. PMID- 29484162 TI - Reassessing the value of gastroscopy for the investigation of dyspepsia. AB - Objective: To evaluate the diagnostic yield of investigating dyspepsia with oesophagogastroduodenoscopy (OGD) with or without mucosal biopsy. Design: Retrospective service evaluation study. Setting: Two teaching hospitals: The Royal Hallamshire Hospital and Northern General Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, UK. Patients: 500 patients, 55 years of age and over, who underwent OGD to investigate dyspepsia were included. The study period included a 3-month window. All OGDs were performed on an outpatient basis. Interventions: Data were extracted from electronic OGD records within the study period. Main outcome measures: Diagnostic yield provided by endoscopic examination and histological assessment. Results: 378 patients (75.6%) were reported to have some form of endoscopic abnormality, and 417 patients (83.4%) had biopsies taken. The most common findings at OGD were gastritis (47.2%) and oesophagitis (24.4%). Oesophagogastric malignancy was seen in 1%. Diagnoses made endoscopically or histologically that would not have been appropriately managed by empirical therapies were seen in 16.2%. Conclusion: OGD in dyspepsia influences patient management in approximately one-sixth of cases. However, the majority of patients are sufficiently managed with Helicobacter pylori testing and eradication and/or a trial of proton pump inhibitor therapy. Further non invasive approaches are needed to identify patients who need endoscopy for biopsy or therapy. PMID- 29484163 TI - Do non-targeted gastric biopsies affect the management of patients, and can a simple protocol and education reduce the rate? AB - Objective: To determine whether development of localised protocol could reduce the number of non-targeted gastric biopsies taken at endoscopy, without risking harm from non-detection of malignant conditions. Design: Retrospective analysis of patient records over a 3-month period in 2013, repeated in 2015 following intervention. Setting: Two UK teaching hospitals. Patients: Patient record data on indication for endoscopy, endoscopy findings, histopathology results and patient outcome. Interventions: Guidance on upper gastrointestinal biopsy in the form of a new trust-wide protocol, as well as lecture-based education. Main outcome measures: Rates of non-targeted and targeted biopsies before and after intervention, and differences between grade of endoscopist. Results: Between 2013 and 2015, there was a 36% reduction in non-targeted biopsies (10.4% vs 6.7%, p=0.001), predominantly within registrar and nurse endoscopist groups, with reduction in non-targeted biopsies of 9.5% and 64%, respectively. Percentage of targeted biopsies remained relatively static, 7.9% and 8.2%. In 2013, 92% of non targeted biopsies had no management change based on histology; in 2015 this was 90%. Of patients with alteration to management, only 0.4% and 0.7% were due to malignancy, in known high-risk patients. Reduction in non-targeted biopsies resulted in estimated annual savings in this trust of L36,000. Conclusion: Development of local protocol reduces the numbers of non-targeted biopsies taken, without risk of harm from non-detection of malignant conditions, enabling a significant reduction in workload within busy histopathology services, with significant cost savings. Localised protocols are adaptable to local population demographics. PMID- 29484164 TI - Does rectal diclofenac reduce post-ERCP pancreatitis? A district general hospital experience. AB - Introduction: There is controversy in the literature recently regarding the efficacy of rectal non-steroidal anti-inflammatory drugs (NSAID) to prevent post ERCP pancreatitis (PEP). The aim of this study was to compare the incidence of PEP in three distinct groups of patients at the Royal United Hospital, Bath: no use of rectal diclofenac, selective use and blanket use without contraindication. Method: Readmission data, blood results, radiology reports and discharge summaries were used to identify patients with PEP from August 2010 to December 2015. The administration of rectal diclofenac postprocedure was recorded from the endoscopy reporting system. Results: 1318 endoscopic retrograde cholangiopancreatographies (ERCP) were performed by four endoscopists during the study period with 66 (5.0%) cases of pancreatitis. 445 ERCPs were performed prior to the introduction of NSAID use during which time, with an incidence of 35 (7.9%) episodes of PEP. During the selective period of NSAID use (high-risk patients) 539 ERCPs were performed and 72 (13.4%) patients received NSAIDs. 17 (3.2%) developed PEP. 334 ERCPs were performed when NSAIDs were given to all patients without contraindication. 289 (86.5%) of patients received rectal diclofenac and 13 (3.9%) developed pancreatitis. There is a statistically significant decrease in PEP comparing the groups of patients receiving NSAIDs selectively (p=0.0009) or routinely (p=0.0172) when compared with none. There is no difference between the selective and routine group (p=0.571). Conclusion: Our data demonstrate that the introduction of a selective or routine use of NSAIDs for PEP in a District General Hospital (DGH) significantly decreases the risk of pancreatitis (risk reduction 43.7%). PMID- 29484166 TI - Successful management of an aorto-gastric fistula occurring 15 years after oesophagectomy with covered aortic stent graft placement followed by open surgery. AB - Aorto-gastric fistula (AGF) is an uncommon and life threatening complication of oesophagectomy. Usually occurring in the immediate weeks following the procedure at anastomosis lines, this case describes a rare development of an AGF 15 years after an oesophagectomy due to the presence of a benign ulcer. Initially successful endovascular stenting of the thoracic aorta was followed by re-bleed, further stenting but eventually open surgery was required. PMID- 29484165 TI - Management of chronic hepatitis B before and after liver transplantation. AB - Chronic hepatitis B infection is a global public health problem associated with significant morbidity and mortality. Persistent infection may evolve to liver cirrhosis and hepatocellular carcinoma, and hepatitis B-related liver disease is a common indication for liver transplantation. Patients with advanced liver disease should be treated with antiviral therapy which may result in clinical improvement. The management of patients after liver transplant then focuses on preventing hepatitis B recurrence in the graft. With the introduction of prophylactic treatment, patient and graft survival has improved significantly. In this review, we will discuss the management of patients with hepatitis B-related cirrhosis, both compensated and decompensated. We also review the management of hepatitis B after liver transplantation. PMID- 29484167 TI - A surgical case of inflammatory abdominal aortic aneurysm that responded remarkably to preoperative steroid therapy. AB - We describe the surgical management of a 58-year-old man with inflammatory abdominal aortic aneurysm (IAAA) following treatment with preoperative steroids. The patient was transferred to our institution for abdominal pain and fever. Contrast-enhanced computed tomography showed juxtarenal abdominal aortic aneurysm surrounded by dense perianeurysmal fibrous tissue. Under a diagnosis of IAAA, steroid therapy with prednisolone was initiated to control the perianeurysmal inflammation. It continued for 3 weeks with a decreasing dose schedule, with remarkable decrease in the soft tissue mass. The patient underwent elective surgery 21 days after commencing steroid therapy. During surgery, adjacent organs were adherent to the aneurysmal wall, but fibrotic change to the retroperitoneum was very limited. He recovered uneventfully, and was discharged on postoperative Day 10. Therefore, it can be concluded that preoperative steroid therapy could minimize the operative risk for IAAAs, and improve surgical outcome. PMID- 29484168 TI - Tracheo-oesophageal fistula: a delayed complication of missed inhaled magnetic toys. AB - Delayed diagnosis of tracheobronchial foreign body (FB) aspiration is not uncommon in children. It occurs when symptoms are underappreciated and/or radiological findings are overlooked. In such cases serious complications can arise, which make the diagnosis and removal of the FB much more difficult. Here, we present a case where FB aspiration was misdiagnosed as asthma after a radio opaque FB on the chest radiograph was missed, leading to formation of a tracheo oesophageal fistula as a rare delayed complication. PMID- 29484169 TI - Dimerized translationally controlled tumor protein increases interleukin-8 expression through MAPK and NF-kappaB pathways in a human bronchial epithelial cell line. AB - Background: Histamine releasing factor (HRF) is a unique cytokine known to regulate a variety of immune cells in late allergic reactions. In the previous study, we revealed that the biologically active form of HRF is the dimerized translationally controlled tumor protein (dTCTP) for the first time, and confirmed the secretion of IL-8 cytokine by dTCTP in human bronchial epithelial cells. However, the signaling pathway by which dTCTP promotes the secretion of IL 8 is not known. Results: When the cells were stimulated with dTCTP, the canonical NF-kappaB pathway and ERK, JNK and p38 MAPK become activated. dTCTP promoted transcription of IL-8, which involved NF-kappaB and AP-1 transcription factors. NF-kappaB was found to be essential for the transcriptional activation of IL-8, while AP-1 was partially responsible for the transcriptional activation by dTCTP. p38 MAPK was found to be involved in post-transcriptional regulation of dTCTP by stabilizing IL-8 mRNA. Conclusions: This study demonstrated that dTCTP induces IL 8 secretion in BEAS-2B cells through transcriptional and post-transcriptional regulation of MAPK and NF-kappaB pathways. This study provides insight into the mechanism by which dTCTP induces inflammation. PMID- 29484170 TI - Correlation between hepatic human males absent on the first (hMOF) and viral persistence in chronic hepatitis B patients. AB - Background: Chronic hepatitis B (CHB) remains a global health dilemma with high morbidity and mortality. Human males absent on the first (hMOF) (a histone acetyltransferase) is responsible for DNA damage repair, tumorigenesis and cell cycle regulation. Persistence of HBV DNA contributes to cirrhosis and hepatocellular carcinoma (HCC) in CHB patients. Histone acetyltransferase enhances HBV replication, however the precise underlying mechanism of hMOF in HBV replication in CHB patients remains to be explored. This study aims to investigate the correlation between hepatic hMOF and HBV DNA replication in CHB patients, and may provide new insights towards the treatment of CHB patients. Methods: hMOF in liver biopsy (CHB, n = 33 HBeAg+; n = 20 HBeAg-, and three healthy controls) was determined, using immunohistochemistry, qPCR and Western blot. The correlation between hMOF and HBsAg, as well as, HBeAg were determined. Results: A positive correlation between hMOF and HBV DNA in overall CHB patients was observed. A distinct positive correlation between hMOF and HBsAg and/or HBeAg in HBeAg+ CHB patients was also detected, however not observed between hMOF and HBsAg in HBeAg- CHB patients. No correlation was observed between hMOF and hepatic inflammation severity and fibrotic stage in CHB patients. Conclusions: Hepatic hMOF might contribute to host HBV clearance in CHB patients and possible pathogenesis. PMID- 29484171 TI - Publication trends of Allergy, Pediatric Allergy and Immunology, and Clinical and Translational Allergy journals: a MeSH term-based bibliometric analysis. AB - We performed a MeSH term-based bibliometric analysis aiming to assess the publication trends of EAACI journals, namely Allergy, Pediatric Allergy and Immunology (PAI) (from 1990 to 2015) and Clinical and Translational Allergy (CTA) (from its inception in 2011 to 2015). We also aimed to discuss the impact of the creation of CTA in the publication topics of Allergy and PAI. We analysed a total of 1973 articles and 23,660 MeSH terms. Most MeSH terms in the three journals fell in the category of "basic immunology and molecular biology" (BIMB). During the studied period, we observed an increase in the proportion of MeSH terms on BIMB, and a decreasing proportion of terms on allergic rhinitis and aeroallergens. The observed changes in Allergy and PAI publication topics hint at a possible impact from CTA creation. PMID- 29484172 TI - Apnoeic oxygenation by nasal cannula during airway management in children undergoing general anaesthesia: a pilot randomised controlled trial. AB - Background: Airway management is a core clinical skill in anaesthesia. Pre oxygenation prior to induction of anaesthesia is a standard practice to prevent desaturation. Apnoeic oxygenation in adults is effective and prolongs the time to desaturation. The effectiveness of apnoeic oxygenation in the adult is well documented; however, evidence in the paediatric is lacking. Therefore, the aim of this study was to investigate the effectiveness of apnoeic oxygenation during airway management in children. Methods: This was a pilot randomised controlled trial. Patients were randomised to receive either apnoeic oxygenation or standard care during the induction of anaesthesia. The primary outcome was the duration of safe apnoea, defined as a composite of the time to first event, either time for SpO2 to drop to 92% or time to successfully secure the airway, and the lowest SpO2 observed during airway management. Secondary outcomes were the number of patients whose SpO2 dropped below 95% and the number of patients whose SpO2 dropped below 92%. Results: A total of 30 patients were randomised, 15 to apnoeic oxygenation and 15 to standard care. No significant difference was observed in the time to first event (p = 0.870). However, patients randomised to apnoeic oxygenation had significantly higher SpO2 observed compared to the standard care group (p = 0.004). All patients in the apnoeic oxygenation group maintained SpO2 of 100% during airway management, compared to only six in the standard care group. SpO2 dropped below 92% in one patient, with the lowest SPO2 recorded 73%. Conclusion: This study suggests that providing 3 l/min oxygen by nasal cannula following pre-oxygenation contributes to maintaining high levels of oxygen saturation during airway management in children, contributing to increased patients' safety during general anaesthesia. Trial registration: Retrospectively registered at ClinicalTrials.gov, NCT03271827. Registered: 4 September 2017. PMID- 29484173 TI - Prevalence of extended-spectrum-beta-lactamase-producing Enterobacteriaceae: first systematic meta-analysis report from Pakistan. AB - Background: South-Asia is known as a hub for multidrug-resistant (MDR) bacteria. Unfortunately, proper surveillance and documentation of MDR pathogens is lacking in Pakistan. The alarming increase in the prevalence of extended-spectrum beta lactamase (ESBL)-producing Enterobacteriaceae is a serious problem. From this perspective, we analysed published data regarding ESBL-producing Enterobacteriaceae in different regions of Pakistan. Methods: A meta-analysis was performed to determine the prevalence of ESBL-producing Enterobacteriaceae in Pakistan. A Web-based search was conducted in electronic databases, including PubMed, Scopus and PakMedi Net (for non-indexed Pakistani journals). Articles published (in either indexed or non-indexed journals) between January 2002 and July 2016 were included in the study. Relevant data were extracted, and statistical analysis was performed using the Metaprop command of STATA version 14.1. Results: A total of 68 studies were identified from the electronic data base search, and 55 of these studies met our inclusion criteria. Pakistan's overall pooled proportion of ESBL-producers was 0.40 (95% CI: 0.34-0.47). The overall heterogeneity was significant (I2 = 99.75%, p < 0.001), and significant ES = 0 (Z = 18.41, p < 0.001) was found. OXA, SHV, TEM and CTX-M were the most commonly found gene variants for ESBLs in these studies. Conclusion: The prevalence of ESBL-producing Enterobacteriaceae is high in Pakistan. Little is known about the annual frequency of ESBLs and their prevalence in different provinces of Pakistan. No data are available regarding ESBL frequency in Baluchistan. This underscores an urgent demand for regular surveillance to address this antimicrobial resistance problem. Surveillance to better understand the annual ESBL burden is crucial to improve national and regional guidelines. PMID- 29484174 TI - Comparing and optimizing ultraviolet germicidal irradiation systems use for patient room terminal disinfection: an exploratory study using radiometry and commercial test cards. AB - Background: Ultraviolet germicidal irradiation (UVGI) systems are gaining popularity, however objective comparisons of their characteristics are lacking. While environmental cultures and reduction of hospital-associated infections rates are excellent study endpoints, they are impractical for centers with limited resources who want to compare or optimize UVGI systems use. Methods: We evaluated radiometry and commercial test cards, two simple and low cost tools, to compare 2 full size UVGI systems (Tru-D and Optimum-UV Enlight) and 2 small units (Lumalier EDU 435 and MRSA-UV Turbo-UV). Results: Radiometry-derived output curves show that if both large devices emit enough energy to reach C. difficile lethal doses at 10 ft, the reduction in output in distance is almost perfectly logarithmic. In a patient room environment, Enlight and Tru-D performed similarly when compared using radiometry and commercial test cards. The two small devices reached C. difficile range around the bathroom with the device raised above the floor, but longer times are needed. Conclusions: Despite different workflows and price points, no clear superiority emerges between Tru-D and Enlight. Bathroom disinfection should be dealt with separately from the main room and small, cheaper units can be used. Radiometry and commercial test cards are promising ways to compare UVGI systems, but further validation is needed using correlation with environmental cultures. Trial registration: Not applicable. PMID- 29484175 TI - Superbugs in the supermarket? Assessing the rate of contamination with third generation cephalosporin-resistant gram-negative bacteria in fresh Australian pork and chicken. AB - Background: Antibiotic misuse in food-producing animals is potentially associated with human acquisition of multidrug-resistant (MDR; resistance to >= 3 drug classes) bacteria via the food chain. We aimed to determine if MDR Gram-negative (GNB) organisms are present in fresh Australian chicken and pork products. Methods: We sampled raw, chicken drumsticks (CD) and pork ribs (PR) from 30 local supermarkets/butchers across Melbourne on two occasions. Specimens were sub cultured onto selective media for third-generation cephalosporin-resistant (3GCR) GNBs, with species identification and antibiotic susceptibility determined for all unique colonies. Isolates were assessed by PCR for SHV, TEM, CTX-M, AmpC and carbapenemase genes (encoding IMP, VIM, KPC, OXA-48, NDM). Results: From 120 specimens (60 CD, 60 PR), 112 (93%) grew a 3GCR-GNB (n = 164 isolates; 86 CD, 78 PR); common species were Acinetobacter baumannii (37%), Pseudomonas aeruginosa (13%) and Serratia fonticola (12%), but only one E. coli isolate. Fifty-nine (36%) had evidence of 3GCR alone, 93/163 (57%) displayed 3GCR plus resistance to one additional antibiotic class, and 9/163 (6%) were 3GCR plus resistance to two additional classes. Of 158 DNA specimens, all were negative for ESBL/carbapenemase genes, except 23 (15%) which were positive for AmpC, with 22/23 considered to be inherently chromosomal, but the sole E. coli isolate contained a plasmid-mediated CMY-2 AmpC. Conclusions: We found low rates of MDR GNBs in Australian chicken and pork meat, but potential 3GCR-GNBs are common (93% specimens). Testing programs that only assess for E. coli are likely to severely underestimate the diversity of 3GCR organisms in fresh meat. PMID- 29484177 TI - Comparing performance of mothers using simplified mid-upper arm circumference (MUAC) classification devices with an improved MUAC insertion tape in Isiolo County, Kenya. AB - Background: A novel approach for improving community case-detection of acute malnutrition involves mothers/caregivers screening their children for acute malnutrition using a mid-upper arm circumference (MUAC) insertion tape. The objective of this study was to test three simple MUAC classification devices to determine whether they improved the sensitivity of mothers/caregivers at detecting acute malnutrition. Methods: Prospective, non-randomised, partially blinded, clinical diagnostic trial describing and comparing the performance of three "Click-MUAC" devices and a MUAC insertion tape. The study took place in twenty-one health facilities providing integrated management of acute malnutrition (IMAM) services in Isiolo County, Kenya. Mothers/caregivers classified their child (n=1040), aged 6-59 months, using the "Click-MUAC" devices and a MUAC insertion tape. These classifications were compared to a "gold standard" classification (the mean of three measurements taken by a research assistant using the MUAC insertion tape). Results: The sensitivity of mother/caregiver classifications was high for all devices (>93% for severe acute malnutrition (SAM), defined by MUAC < 115 mm, and > 90% for global acute malnutrition (GAM), defined by MUAC < 125 mm). Mother/caregiver sensitivity for SAM and GAM classification was higher using the MUAC insertion tape (100% sensitivity for SAM and 99% sensitivity for GAM) than using "Click-MUAC" devices. Younden's J for SAM classification, and sensitivity for GAM classification, were significantly higher for the MUAC insertion tape (99% and 99% respectively). Specificity was high for all devices (>96%) with no significant difference between the "Click-MUAC" devices and the MUAC insertion tape. Conclusions: The results of this study indicate that, although the "Click-MUAC" devices performed well, the MUAC insertion tape performed best. The results for sensitivity are higher than found in previous studies. The high sensitivity for both SAM and GAM classification by mothers/caregivers with the MUAC insertion tape could be due to the use of an improved MUAC tape design which has a number of new design features. The one-on-one demonstration provided to mothers/caregivers on the use of the devices may also have helped improve sensitivity. The results of this study provide evidence that mothers/caregivers can perform sensitive and specific classifications of their child's nutritional status using MUAC. Trial registrations: Clinical trials registration number: NCT02833740. PMID- 29484178 TI - Obstructive sleep apnea knowledge and attitudes among recent medical graduates training in Ecuador. AB - Background: We aimed to assess recent Latin American medical school graduates' knowledge and attitudes about OSA and examine whether their knowledge and attitudes about OSA differed from practicing physicians. Methods: Recent medical graduates completed the Spanish translation of the OSA Knowledge and Attitudes (OSAKA) questionnaire at the 2013 national primary-care residency-placement meeting in Ecuador. The OSAKA includes 18 knowledge and five attitudinal items about OSA. We compared recent graduates' data with data collected in 2010-2011 from practicing physicians using chi-square tests of associations among categorical variables and analysis of variance of differences in mean knowledge and attitude scores. Unadjusted logistic regression models tested the odds that recent graduates (vs. practicing physicians) answered each item correctly. Results: Of 265 recent graduates, 138 (52.1%) were male, and mean age was 25.9 years. Although mean knowledge was low overall, scores were lower for recent graduates than for the 367 practicing physicians (53.5% vs. 60.4%; p < 0.001). Practicing physicians were significantly more likely to answer specific items correctly with one exception-recent graduates were more likely to know that < 5 apneas-hypopneas/h is normal (OR 1.47, 1.03-2.07). Physicians in practice attributed greater importance to OSA as clinical disorder and the need for identifying patients with OSA; but recent graduates reported greater confidence in managing patients with OSA and CPAP. Conclusions: OSA-focused educational interventions during medical school should help to improve recent medical graduates' abilities to diagnose and treat OSA. We recommend a greater number of hours of medical students' exposure to sleep education. PMID- 29484176 TI - Factors that influence adult neurogenesis as potential therapy. AB - Adult neurogenesis involves persistent proliferative neuroprogenitor populations that reside within distinct regions of the brain. This phenomenon was first described over 50 years ago and it is now firmly established that new neurons are continually generated in distinct regions of the adult brain. The potential of enhancing the neurogenic process lies in improved brain cognition and neuronal plasticity particularly in the context of neuronal injury and neurodegenerative disorders. In addition, adult neurogenesis might also play a role in mood and affective disorders. The factors that regulate adult neurogenesis have been broadly studied. However, the underlying molecular mechanisms of regulating neurogenesis are still not fully defined. In this review, we will provide critical analysis of our current understanding of the factors and molecular mechanisms that determine neurogenesis. We will further discuss pre-clinical and clinical studies that have investigated the potential of modulating neurogenesis as therapeutic intervention in neurodegeneration. PMID- 29484180 TI - A vaccine to prevent cervical cancer: academic and industrial collaboration and a Lasker award. PMID- 29484179 TI - Genome-wide association studies in Crohn's disease: Past, present and future. AB - Over the course of the past decade, genome-wide association studies (GWAS) have revolutionised our understanding of complex disease genetics. One of the diseases that has benefitted most from this technology has been Crohn's disease (CD), with the identification of autophagy, the IL-17/IL-23 axis and innate lymphoid cells as key players in CD pathogenesis. Our increasing understanding of the genetic architecture of CD has also highlighted how a failure to suppress aberrant immune responses may contribute to disease development - a realisation that is now being incorporated into the design of new treatments. However, despite these successes, a significant proportion of disease heritability remains unexplained. Similarly, most of the causal variants at associated loci have not yet been identified, and even fewer have been functionally characterised. Because of the inarguable rise in the incidence of CD in regions of the world that previously had low disease rates, GWAS studies will soon have to shift from a largely Caucasian focus to include populations from other ethnic backgrounds. Future studies should also move beyond conventional studies of disease susceptibility into phenotypically driven 'within-cases' analyses in order to explore the role of genetics in other important aspects of disease biology. These studies are likely to include assessments of prognosis and/or response to treatments and may be critical if personalised medicine is ever to become a reality. PMID- 29484181 TI - Rapid loss of group 1 innate lymphoid cells during blood stage Plasmodium infection. AB - Objectives: Innate lymphoid cells (ILCs) share many characteristics with CD4+ T cells, and group 1 ILCs share a requirement for T-bet and the ability to produce IFNgamma with T helper 1 (Th1) cells. Given this similarity, and the importance of Th1 cells for protection against intracellular protozoan parasites, we aimed to characterise the role of group 1 ILCs during Plasmodium infection. Methods: We quantified group 1 ILCs in peripheral blood collected from subjects infected with with Plasmodium falciparum 3D7 as part of a controlled human malaria infection study, and in the liver and spleens of Pc AS-infected mice. We used genetically modified mouse models, as well as cell-depletion methods in mice to characterise the role of group 1 ILCs during Pc AS infection. Results: In a controlled human malaria infection study, we found that the frequencies of circulating ILC1s and NK cells decreased as infection progressed but recovered after volunteers were treated with antiparasitic drug. A similar observation was made for liver and splenic ILC1s in P. chabaudi chabaudi AS (Pc AS)-infected mice. The decrease in mouse liver ILC1 frequencies was associated with increased apoptosis. We also identified a population of cells within the liver and spleen that expressed both ILC1 and NK cell markers, indicative of plasticity between these two cell lineages. Studies using genetic and cell-depletion approaches indicated that group 1 ILCs have a limited role in antiparasitic immunity during Pc AS infection in mice. Discussion: Our results are consistent with a previous study indicating a limited role for natural killer (NK) cells during Plasmodium chabaudi infection in mice. Additionally, a recent study reported the redundancy of ILCs in humans with competent B and T cells. Nonetheless, our results do not rule out a role for group 1 ILCs in human malaria in endemic settings given that blood stage infection was initiated intravenously in our experimental models, and thus bypassed the liver stage of infection, which may influence the immune response during the blood stage. Conclusion: Our results show that ILC1s are lost early during mouse and human malaria, and this observation may help to explain the limited role for these cells in controlling blood stage infection. PMID- 29484182 TI - Regulatory T cells in renal disease. AB - The kidney is vulnerable to injury, both acute and chronic from a variety of immune and metabolic insults, all of which at least to some degree involve inflammation. Regulatory T cells modulate systemic autoimmune and allogenic responses in glomerulonephritis and transplantation. Intrarenal regulatory T cells (Tregs), including those recruited to the kidney, have suppressive effects on both adaptive and innate immune cells, and probably also intrinsic kidney cells. Evidence from autoimmune glomerulonephritis implicates antigen-specific Tregs in HLA-mediated dominant protection, while in several human renal diseases Tregs are abnormal in number or phenotype. Experimentally, Tregs can protect the kidney from injury in a variety of renal diseases. Mechanisms of Treg recruitment to the kidney include via the chemokine receptors CCR6 and CXCR3 and potentially, at least in innate injury TLR9. The effects of Tregs may be context dependent, with evidence for roles for immunoregulatory roles both for endogenous Tbet expressing Tregs and STAT-3-expressing Tregs in experimental glomerulonephritis. Most experimental work and some of the ongoing human trials in renal transplantation have focussed on unfractionated thymically derived Tregs (tTregs). However, induced Tregs (iTregs), type 1 regulatory T (Tr1) cells and in particular antigen-specific Tregs also have therapeutic potential not only in renal transplantation, but also in other kidney diseases. PMID- 29484183 TI - Human FOXP3+ T regulatory cell heterogeneity. AB - FOXP3-expressing CD4+ T regulatory (Treg) cells are instrumental for the maintenance of self-tolerance. They are also involved in the prevention of allergy, allograft rejection, foetal rejection during pregnancy and of exaggerated immune response towards commensal pathogens in mucosal tissues. They can also prevent immune responses against tumors and promote tumor progression. FOXP3-expressing Treg cells are not a homogenous population. The different subsets of Treg cells can have different functions or roles in the maintenance of immune homeostasis and can therefore be differentially targeted in the management of autoimmune diseases or in cancer. We discuss here how Treg cell subsets can be differentiated phenotypically, functionally and developmentally in humans. PMID- 29484184 TI - Endoplasmic reticulum stress in the development of multiple myeloma and drug resistance. AB - Multiple myeloma (MM) is a haematological malignancy of mature antibody-secreting plasma cells. Currently, MM is incurable, but advances in drug treatments have increased patient lifespan. One of the characteristics of MM is the excessive production of monoclonal immunoglobulin (also referred to as paraprotein). This high level of protein production induces endoplasmic reticulum (ER) stress, and proteasomal degradation of the paraprotein is required to avoid ER stress-induced cell death. Consequently, proteasomal inhibitors such as bortezomib have been particularly effective therapies. Unfortunately development of resistance to bortezomib is common. In this review, we address how control of endoplasmic reticulum stress is important in the development of MM and how the unfolded protein response and its associated stress response pathways are involved in the development of bortezomib resistance. PMID- 29484185 TI - Accumulation of IL-17+ Vgamma6+ gammadelta T cells in pregnant mice is not associated with spontaneous abortion. AB - Introduction: Pregnancy is an immune paradox. While the immune system is required for embryo implantation, placental development and progression of gestation, excessive inflammation is associated with pregnancy failure. Similarly, the cytokine IL-17A plays an important role in defence against extracellular pathogens, but its dysregulation can lead to pathogenic inflammation and tissue damage. Although expression of IL-17 has been reported during pregnancy, the cellular source of this cytokine and its relevance to gestation are not clear. Objectives: Here we define the kinetics and cellular source of IL-17A in the uterus during healthy and abortion-prone murine pregnancy. Methods: The CBA/J x DBA/2J abortion-prone mating was used and compared to CBA/J x BALB/c control mating. Results: We demonstrate that, irrespective of gestational health, the number of IL-17-producing cells peaks during midterm pregnancy and is largely derived from the gammadelta T-cell lineage. We identify gammadelta T, Th17, CD8 T and NKT cells as the cellular source of IL-17A in pregnant mice. Furthermore, we positively identify the Vgamma6+ subset of uterine gammadelta T cells as the main producer of IL-17A during both healthy pregnancy and abortive pregnancy. Conclusions: To conclude, the accumulation of uterine IL-17+ innate-like T cells appears not to adversely impact the developing foetus. Collectively, our results show that IL-17+ gammadelta T cells are present in the uterus throughout the course of normal gestation and therefore may play an important role in healthy pregnancy. PMID- 29484186 TI - Characterisation of anti-alpha toxin antibody levels and colonisation status after administration of an investigational human monoclonal antibody, MEDI4893, against Staphylococcus aureus alpha toxin. AB - Objectives: MEDI4893 is a novel, long-acting human monoclonal antibody targeting Staphylococcus aureus (SA) alpha toxin (AT). This report presents the results of the exploratory analyses from a randomised phase 1 dose-escalation study in healthy human subjects receiving single intravenous MEDI4893 doses or placebo. Methods: Anti-AT antibodies and AT expression were measured as described previously. Nasal swabs were analysed by culture and PCR. Data were summarised by treatment groups and visits by using SAS System Version 9.3. Results: Subjects receiving 2250 or 5000 mg of MEDI4893 had the highest serum anti-AT neutralising antibody (NAb) levels: approximately 180- to 240-, 70- to 100- and sevenfold to 10-fold higher than respective baseline levels at peak, 30 and 360 days, respectively. In these subjects, levels of serum anti-AT NAbs were >3.2 International Units (IU) mL-1 for at least 211 days. In the upper respiratory tract, anti-AT NAb levels increased with MEDI4893 dose. No apparent effect of MEDI4893 on SA nasal colonisation, hla gene sequence or AT expression was observed. Five AT variants were detected, their lytic activity was fully neutralised by MEDI4893. Discussion: Our results indicate that (1) MEDI4893 administration at 2250 and 5000 mg would provide effective immunoprophylaxis against systemic SA disease; (2) MEDI4983 distributes to the upper respiratory tract and retains neutralising activity against AT; and (3) potential for emergence of MEDI4893 resistance is low. Conclusion: Intravenous administration of MEDI4893 maintained levels of anti-AT NAbs in serum and nasal mucosa that may provide effective immunoprophylaxis against SA disease and support continued clinical development of MEDI4893. PMID- 29484188 TI - The safety of a novel early mobilization protocol conducted by ICU physicians: a prospective observational study. AB - Background: There are numerous barriers to early mobilization (EM) in a resource limited intensive care unit (ICU) without a specialized team or an EM culture, regarding patient stability while critically ill or in the presence of medical devices. We hypothesized that ICU physicians can overcome these barriers. The aim of this study was to investigate the safety of EM according to the Maebashi EM protocol conducted by ICU physicians. Methods: This was a single-center prospective observational study. All consecutive patients with an unplanned emergency admission were included in this study, according to the exclusion criteria. The observation period was from June 2015 to June 2016. Data regarding adverse events, medical devices in place during rehabilitation, protocol adherence, and rehabilitation outcomes were collected. The primary outcome was safety. Results: A total of 232 consecutively enrolled patients underwent 587 rehabilitation sessions. Thirteen adverse events occurred (2.2%; 95% confidence interval, 1.2-3.8%) and no specific treatment was needed. There were no instances of dislodgement or obstruction of medical devices, tubes, or lines. The incidence of adverse events associated with mechanical ventilation or extracorporeal membrane oxygenation (ECMO) was 2.4 and 3.6%, respectively. Of 587 sessions, 387 (66%) sessions were performed at the active rehabilitation level, including sitting out of the bed, active transfer to a chair, standing, marching, and ambulating. ICU physicians attended over 95% of these active rehabilitation sessions. Of all patients, 143 (62%) got out of bed within 2 days (median 1.2 days; interquartile range 0.1-2.0). Conclusions: EM according to the Maebashi EM protocol conducted by ICU physicians, without a specialized team or EM culture, was performed at a level of safety similar to previous studies performed by specialized teams, even with medical devices in place, including mechanical ventilation or ECMO. Protocolized EM led by ICU physicians can be initiated in the acute phase of critical illness without serious adverse events requiring additional treatment. PMID- 29484187 TI - Vaccinating for natural killer cell effector functions. AB - Vaccination has proved to be highly effective in reducing global mortality and eliminating infectious diseases. Building on this success will depend on the development of new and improved vaccines, new methods to determine efficacy and optimum dosing and new or refined adjuvant systems. NK cells are innate lymphoid cells that respond rapidly during primary infection but also have adaptive characteristics enabling them to integrate innate and acquired immune responses. NK cells are activated after vaccination against pathogens including influenza, yellow fever and tuberculosis, and their subsequent maturation, proliferation and effector function is dependent on myeloid accessory cell-derived cytokines such as IL-12, IL-18 and type I interferons. Activation of antigen-presenting cells by live attenuated or whole inactivated vaccines, or by the use of adjuvants, leads to enhanced and sustained NK cell activity, which in turn contributes to T cell recruitment and memory cell formation. This review explores the role of cytokine activated NK cells as vaccine-induced effector cells and in recall responses and their potential contribution to vaccine and adjuvant development. PMID- 29484190 TI - A rare case of avascular necrosis in sickle cell trait: a case report. AB - Background: Sickle cell trait is usually an asymptomatic presentation of a patient with slightly different hemoglobin molecule makeup than normal. It is similar to a more serious disease, sickle cell disease, in which a person's hemoglobin is mutated in such a way that causes their red blood cells to easily change shape in certain environmental and internal states; this causes red blood cells to adhere to the walls and occlude the lumen of the arteries in which they travel, leading to downstream effects secondary to ischemia. Sickle cell trait does not have these ischemic effects, usually. Case presentation: In this case, a young African American female patient presents to the clinic with severe right hip pain. Her past medical history includes sickle cell trait and asthma. She has not been symptomatic of her asthma for years and is not on therapy for it. The pain has lasted for several months and has not improved with anti-inflammatory medication. There is severe pain with internal and external rotation of the hip. The neurovascularity of the lower extremities is intact bilaterally. MRI of the femur shows stage 2 or 3 avascular necrosis of the femoral head, while X-rays of the femur are unremarkable. Non weight-bearing for several weeks was unsuccessful; shortly thereafter, the patient underwent core decompression of the right femoral head as well as starting bisphosphonates. The patient improved temporarily but regressed shortly thereafter. Her avascular necrosis worsened radiographically over the next several months. At this point, the only other option would be to do a total hip arthroplasty, but the patient may need several more throughout her lifetime due to the lifespan of the artificial replacement. Conclusion: There have only been scarce reports of avascular necrosis in patients with sickle cell trait. This manuscript presents such a case and includes the trials and tribulations associated with its management. PMID- 29484189 TI - Race affects SVR12 in a large and ethnically diverse hepatitis C-infected patient population following treatment with direct-acting antivirals: Analysis of a single-center Department of Veterans Affairs cohort. AB - Hepatitis C virus (HCV) infection is a major cause of chronic liver disease. HCV cure has been linked to improved patient outcomes. In the era of direct-acting antivirals (DAAs), HCV cure has become the goal, as defined by sustained virological response 12 weeks (SVR12) after completion of therapy. Historically, African-Americans have had lower SVR12 rates compared to White people in the interferon era, which had been attributed to the high prevalence of non-CC interleukin 28B (IL28B) type. Less is known about the association between race/ethnicity and SVR12 in DAA-treated era. The aim of the study is to evaluate the predictors of SVR12 in a diverse, single-center Veterans Affairs population. We conducted a retrospective study of patients undergoing HCV therapy with DAAs from 2014 to 2016 at the VA Greater Los Angeles Healthcare System. We performed a multivariable logistic regression analysis to determine predictors of SVR12, adjusting for age, HCV genotype, DAA regimen and duration, human immunodeficiency virus (HIV) status, fibrosis, nonalcoholic fatty liver disease (NAFLD) fibrosis score, homelessness, mental health, and adherence. Our cohort included 1068 patients, out of which 401 (37.5%) were White people and 400 (37.5%) were African American. Genotype 1 was the most common genotype (83.9%, N = 896). In the adjusted models, race/ethnicity and the presence of fibrosis were statistically significant predictors of non-SVR. African-Americans had 57% lower odds for reaching SVR12 (adj.OR = 0.43, 95% CI = 1.5-4.1) compared to White people. Advanced fibrosis (adj.OR = 0.40, 95% CI = 0.26-0.68) was also a significant predictor of non-SVR. In a single-center VA population on DAAs, African-Americans were less likely than White people to reach SVR12 when adjusting for covariates. PMID- 29484191 TI - Psychometric properties of the Zephyr bioharness device: a systematic review. AB - Background: Technological development and improvements in Wearable Physiological Monitoring devices, have facilitated the wireless and continuous field-based monitoring/capturing of physiologic measures in healthy, clinical or athletic populations. These devices have many applications for prevention and rehabilitation of musculoskeletal disorders, assuming reliable and valid data is collected. The purpose of this study was to appraise the quality and synthesize findings from published studies on psychometric properties of heart rate measurements taken with the Zephyr Bioharness device. Methods: We searched the Embase, Medline, PsycInfo, PuMed and Google Scholar databases to identify articles. Articles were appraised for quality using a structured clinical measurement specific appraisal tool. Two raters evaluated the quality and conducted data extraction. We extracted data on the reliability (intra-class correlation coefficients and standard error of measurement) and validity measures (Pearson/Spearman's correlation coefficients) along with mean differences. Agreement parameters were summarised by the average biases and 95% limits of agreement. Results: A total of ten studies were included: quality ratings ranged from 54 to 92%. The intra-class correlation coefficients reported ranged from 0.85-0.98. The construct validity coefficients compared against gold standard calibrations or other commercially used devices, ranged from 0.74-0.99 and 0.67 0.98 respectively. Zephyr Bioharness agreement error ranged from - 4.81 (under estimation) to 3.00 (over-estimation) beats per minute, with varying 95% limits of agreement, when compared with gold standard measures. Conclusion: Good to excellent quality evidence from ten studies suggested that the Zephyr Bioharness device can provide reliable and valid measurements of heart rate across multiple contexts, and that it displayed good agreements vs. gold standard comparators - supporting criterion validity. PMID- 29484193 TI - Serological biomarker testing helps avoiding unnecessary endoscopies in obese patients before bariatric surgery. AB - Background: To assess the value of serological biomarker testing as a substitute for esophagogastroduodenoscopy (EGDS) in pre-operative assessment of patients referred for bariatric surgery. Methods: Sixty-five obese patients with a mean age of 43 years (range: 21-65) and a mean body mass index (BMI) of 44 (range: 36 59) were studied. The patients were tested with a four-biomarker panel: pepsinogen I and II, gastrin-17 (basal and stimulated), and Helicobacter pylori (HP) antibodies (GastroPanel(r), Biohit Oyj, Finland). On the basis of the biomarker test, the patients were classified into the HS (healthy stomach) group (n = 22) with the normal biomarker profile and the NHS (non-healthy stomach) group (n = 43). The classification of patients into HS and NHS was evaluated against the gold standard, i.e. EGDS with biopsies. Results: The concordance (Cohen's kappa) between the biomarker test and gastric histology was 0.68; 95% CI 0.504-0.854, with an overall agreement of 84.6% (95% CI 73.9-91.4%). In the NHS group, all 43 patients had biopsy-confirmed chronic gastritis: 39 non-atrophic HP gastritis, 4 atrophic antrum gastritis (AGA) of moderate severity.In the HS group only 6 patients had mild superficial H.pylori negative gastritis. Of the 22 HS subjects with the normal biomarker profile, 20 (31% of all 65) had no complaints either, while the remaining two had reflux symptoms with esophagitis. In the NHS group 10 patients had esophagitis and 8 had also reflux symptoms. Conclusions: The normal biomarker profile is an excellent surrogate for healthy stomach, implicating that pre-operative EGDS could have been avoided in 31% of our asymptomatic bariatric surgery patients who had the normal biomarker profile. PMID- 29484194 TI - In-transit development of color abnormalities in turkey breast meat during winter season. AB - Background: The poultry industry suffers losses from problems as pale, soft and exudative (PSE), and dark, firm and dry (DFD) meat can develop in meat as a result of short- and long-term stress, respectively. These abnormalities are impacted by pre-slaughter animal welfare. Methods: This work evaluated the effects of open vehicle container microclimate, throughout the 38 +/- 10 km journey from the farm to the slaughterhouse, on commercially turkey transported during the Brazilian winter season. The journey was initiated immediately after water bath in truck fitted with portable Kestrel anemometers to measure air ventilation, relative humidity, temperature and ventilation. Results: The inferior compartments of the middle and rear truck regions showed highest temperature and relative humidity, and lower air ventilation. In addition, the superior compartments of the front truck regions presented lower temperature and wind chill, and highest air ventilation. The breast meat samples from animals located at the inferior compartments of the middle and rear truck regions and subjected to with water bath (WiB) treatment presented highest DFD-like and had lowest PSE-like meat incidence than those from animals located at other compartments within the container. Lower incidence of PSE-like meat was observed in birds without water bath (WoB). Conclusions: Assessment on turkeys transported under Brazilian southern winter conditions revealed that breast meat quality can be affected by relative humidity, air ventilation, temperature, and transport under subtropical conditions promoting color abnormalities and the formation of simultaneously PSE-like and DFD-like meat. PMID- 29484192 TI - The negative impact of sugar-sweetened beverages on children's health: an update of the literature. AB - While sugar sweetened beverage (SSB) consumption has declined in the last 15 years, consumption of SSBs is still high among children and adolescents. This research synthesis updates a prior review on this topic and examines the evidence regarding the various health impacts of SSBs on children's health (overweight/obesity, insulin resistance, dental caries, and caffeine-related effects). We searched PubMed, CAB Abstracts and PAIS International to identify cross-sectional, longitudinal and intervention studies examining the health impacts of SSBs in children published after January 1, 2007. We also searched reference lists of relevant articles. Overall, most studies found consistent evidence for the negative impact of SSBs on children's health, with the strongest support for overweight/obesity risk and dental caries, and emerging evidence for insulin resistance and caffeine-related effects. The majority of evidence was cross-sectional highlighting the need for more longitudinal and intervention studies to address this research question. There is substantial evidence that SSBs increase the risk of overweight/obesity and dental caries and developing evidence for the negative impact of SSBs on insulin resistance and caffeine related effects. The vast majority of literature supports the idea that a reduction in SSB consumption would improve children's health. PMID- 29484195 TI - Culling in served females and farrowed sows at consecutive parities in Spanish pig herds. AB - Background: The objectives of our study were 1) to characterize culling and retention patterns in parities 0 to 6 in served females and farrowed sows in two herd groups, and 2) to quantify the factors associated with by-parity culling risks for both groups in commercial herds. Lifetime data from first-service to removal included 465,947 service records of 94,691 females served between 2008 and 2013 in 98 Spanish herds. Herds were categorized into two groups based on the upper 25th percentile of the herd means of annualized lifetime pigs weaned per sow: high-performing (> 24.7 pigs) and ordinary herds (<= 24.7 pigs). Two-level log-binomial regression models were used to examine risk factors and relative risk ratios associated with by-parity culling risks. Results: Mean by-parity culling risks (+/- SE) for served females and farrowed sows were 5.9 +/- 0.03 and 12.4 +/- 0.05%, respectively. Increased culling risks were associated with sows that farrowed 8 or fewer pigs born alive (PBA). Also, farrowed sows in high performing herds in parities 2 to 6 had 1.5-5.6% higher culling risk than equivalent parity sows in ordinary herds (P < 0.05). Furthermore, sows in parities 1 to 6 that farrowed 3 or more stillborn piglets had 2.2-4.8% higher culling risk than for sows that did not farrow any stillborn piglets (P < 0.05). For served sows, culling risk in parity 1 to 6 sows with a weaning-to-first service interval (WSI) of 7 days or more were 2.2-3.9% higher than equivalent parity sows with WSI 0-6 days (P < 0.05). With regard to relative risk ratios, served sows with WSI 7 days or more were 1.56-1.81 times more likely to be culled than those with WSI 0-6 days. Conclusion: Producers should reduce non-productive days by culling sows after weaning, instead of after service or during pregnancy. Also, producers should pay special attention to sows farrowing stillborn piglets or having prolonged WSI, and reconsider culling policy for mid-parity sows when they farrow 8 or fewer PBA. PMID- 29484197 TI - Feasibility and assessment of outcome measures for yoga as self-care for minorities with arthritis: a pilot study. AB - Background: While there is a growing interest in the therapeutic benefits of yoga, minority populations with arthritis tend to be under-represented in the research. Additionally, there is an absence of guidance in the literature regarding the use of multicultural teams and sociocultural health beliefs, when designing yoga studies for a racially diverse population with arthritis. This pilot study examined the feasibility of offering yoga as a self-care modality to an urban, bilingual, minority population with osteoarthritis (OA) or rheumatoid arthritis (RA), in the Washington, DC area. Methods: The primary objective of the study was to assess the feasibility of offering an 8-week, bilingual yoga intervention adapted for arthritis to a convenience sample of primarily Hispanic and Black/African-American adults. A racially diverse interdisciplinary research team was assembled to design a study to facilitate recruitment and retention. The second objective identified outcome measures to operationalize potential facilitators and barriers to self-care and self-efficacy. The third objective determined the feasibility of using computer-assisted self-interview (CASI) for data collection. Results: Enrolled participants (n = 30) were mostly female (93%), Spanish speaking (69%), and diagnosed with RA (88.5%). Feasibility was evaluated using practicality, acceptability, adaptation, and expansion of an arthritis-adapted yoga intervention, modified for this population. Recruitment (51%) and participation (60%) rates were similar to previous research and clinical experience with the study population. Of those enrolled, 18 started the intervention. For adherence, 12 out of 18 (67%) participants completed the intervention. All (100%), who completed the intervention, continued to practice yoga 3 months after completing the study. Using nonparametric tests, selected outcome measures showed a measurable change post-intervention suggesting appropriate use in future studies. An in-person computerized questionnaire was determined to be a feasible method of data collection. Conclusions: Findings from this pilot study confirm the feasibility of offering yoga to this racially/ethnically diverse population with arthritis. This article provides recruitment/retention rates, outcome measures with error rates, and data collection recommendations for a previously under-represented population. Suggestions include allocating resources for translation and using a multicultural design to facilitate recruitment and retention. Trial registration: ClinicalTrials.gov, NCT01617421. PMID- 29484196 TI - Targeted full energy and protein delivery in critically ill patients: a study protocol for a pilot randomised control trial (FEED Trial). AB - Background: Current guidelines for the provision of protein for critically ill patients are based on incomplete evidence, due to limited data from randomised controlled trials. The present pilot randomised controlled trial is part of a program of work to expand knowledge about the clinical effects of protein delivery to critically ill patients. The primary aim of this pilot study is to determine whether an enteral feeding protocol using a volume target, with additional protein supplementation, delivers a greater amount of protein and energy to mechanically ventilated critically ill patients than a standard nutrition protocol. The secondary aims are to evaluate the potential effects of this feeding strategy on muscle mass and other patient-centred outcomes. Methods: This prospective, single-centred, pilot, randomised control trial will include 60 participants who are mechanically ventilated and can be enterally fed. Following informed consent, the participants receiving enteral nutrition in the intensive care unit (ICU) will be allocated using a randomisation algorithm in a 1:1 ratio to the intervention (high-protein daily volume-based feeding protocol, providing 25 kcal/kg and 1.5 g/kg protein) or standard care (hourly rate-based feeding protocol providing 25 kcal/kg and 1 g/kg protein). The co-primary outcomes are the average daily protein and energy delivered to the end of day 15 following randomisation. The secondary outcomes include change in quadriceps muscle layer thickness (QMLT) from baseline (prior to randomisation) to ICU discharge and other nutritional and patient-centred outcomes. Discussion: This trial aims to examine whether a volume-based feeding protocol with supplemental protein increases protein and energy delivery. The potential effect of such increases on muscle mass loss will be explored. These outcomes will assist in formulating larger randomised control trials to assess mortality and morbidity. Trial registration: Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN: 12615000876594 UTN: U1111-1172-8563. PMID- 29484199 TI - Project HELP: a study protocol to pilot test a shared decision-making tool about treatment options for patients with hepatitis C and chronic kidney disease. AB - Background: Recent advances in treatment have given patients with chronic kidney disease (CKD) access to safer and more effective medications to treat comorbid hepatitis C virus (HCV) infection. Given the variety and complexity of treatment options that depend on patients' clinical characteristics and personal preferences, education and decision support are needed to prepare patients better to discuss treatment options with their clinicians. Methods: Drawing on International Patient Decision Aids Standards guidelines, literature reviews, and guidance from a diverse expert advisory group of nephrologists, hepatologists, and patients, we will develop and test a HCV and CKD decision support tool. Named Project HELP (Helping Empower Liver and kidney Patients), this tool will support patients with HCV and CKD during decisions about whether, when, and how to treat each illness. The tool will (1) explain information using plain language and graphics; (2) provide a step-by-step process for thinking about treating HCV and CKD; (3) tailor relevant information to each user by asking about the individual's stage of CKD, stage of fibrosis, prior treatment, and comorbidities; (4) assess user knowledge and values for treatment choices; and (5) help individuals use and consider information appropriate to their values and needs to discuss with a clinician. A pilot study including 70 individuals will evaluate the tool's efficacy, usability, and likelihood of using it in clinical practice. Eligibility criteria will include individuals who understand and read English, who are at least 18 years old, have a diagnosis of HCV (any genotype) and CKD (any stage), and are considering treatment options. Discussion: This study can identify particular characteristics of individuals or groups that might experience challenges initiating treatment for HCV in the CKD population. This tool could provide a resource to facilitate patient-clinician discussions regarding HCV and CKD treatment options. PMID- 29484200 TI - Participants' perspectives of weekly telephonic mood monitoring in South Africa: a feasibility study. AB - Background: Mood and anxiety disorders have a high lifetime prevalence, and their chronicity adds to the management burden of already scarce and strained mental health care resources, particularly in developing countries. Non-professional assisted interventions and technology (such as weekly telephonic mood monitoring) could assist in the early identification of symptoms of relapse and hospitalization prevention. The present study aimed to determine participants' perspectives and the feasibility of weekly telephonic mood monitoring in order to inform the development of the full study. Method: Semi-structured telephonic interviews (n = 37; 89.2% female; mean age = 33.1 years) were conducted as part of the full-scale feasibility study (N = 61; named the Bipolar Disorder Mood Monitoring (BDMM) Study). The BDMM Study was conducted to determine the viability of weekly telephonic mood monitoring, spanning 26 weeks and starting 1 week post discharge. Frequency and descriptive statistical analyses (using SPSS version 24) were undertaken, and qualitative data were analyzed using thematic content analysis. Results: This article presents the findings from the semi-structured interview section of the BDMM Study. Participants generally expressed positive experiences and perceptions of weekly telephonic mood monitoring, stating that they would advise others to also take part in weekly telephonic mood monitoring. Nonetheless, some participants did make suggestions for improvement of mood monitoring while others expressed negative experiences of weekly telephonic mood monitoring. Conclusion: The results of the semi-structured interviews of the BDMM Study indicated that participants perceived weekly telephonic mood monitoring to be helpful in lightening the burden of mood and anxiety disorders (e.g., having someone to talk to, providing insight into their disorders). Not only did it help them, but they also perceived mood monitoring to be potentially helpful to future participants. However, weekly mood monitoring was also burdensome in itself (including being too time consuming and having to answer questions when feeling down). Importantly, the findings highlighted that participants' and researchers' perceptions and experiences may not be congruent (especially in terms of therapeutic misconception). The current findings may inform researchers' future approach to study design and participant relationships. PMID- 29484198 TI - Physical therapy and deep brain stimulation in Parkinson's Disease: protocol for a pilot randomized controlled trial. AB - Background: Subthalamic nucleus deep brain stimulation (STN-DBS) reduces tremor, muscle stiffness, and bradykinesia in people with Parkinson's Disease (PD). Walking speed, known to be reduced in PD, typically improves after surgery; however, other important aspects of gait may not improve. Furthermore, balance may worsen and falls may increase after STN-DBS. Thus, interventions to improve balance and gait could reduce morbidity and improve quality of life following STN DBS. Physical therapy (PT) effectively improves balance and gait in people with PD, but studies on the effects of PT have not been extended to those treated with STN-DBS. As such, the efficacy, safety, and feasibility of PT in this population remain to be determined. The purpose of this pilot study is to address these unmet needs. We hypothesize that PT designed to target balance and gait impairment will be effective, safe, and feasible in this population. Methods/design: Participants with PD treated with STN-DBS will be randomly assigned to either a PT or control group. Participants assigned to PT will complete an 8-week, twice-weekly PT program consisting of exercises designed to improve balance and gait. Control group participants will receive the current standard of care following STN-DBS, which does not include prescription of PT. The primary aim is to assess preliminary efficacy of PT on balance (Balance Evaluation Systems Test). A secondary aim is to assess efficacy of PT on gait (GAITRite instrumented walkway). Participants will be assessed OFF medication/OFF stimulation and ON medication/ON stimulation at baseline and at 8 and 12 weeks after baseline. Adverse events will be measured over the duration of the study, and adherence to PT will be measured to determine feasibility. Discussion: To our knowledge, this will be the first study to explore the preliminary efficacy, safety, and feasibility of PT for individuals with PD with STN-DBS. If the study suggests potential efficacy, then this would justify larger trials to test effectiveness and safety of PT for those with PD with STN-DBS. Trial registration: NCT03181282 (clinicaltrials.gov). Registered on 7 June 2017. PMID- 29484201 TI - Differentiated osteoblasts derived decellularized extracellular matrix to promote osteogenic differentiation. AB - Background: The extracellular matrix (ECM) can directly or indirectly influence on regulation of cell functions such as cell adhesion, migration, proliferation and differentiation. The cell derived ECM (CD-ECM) is a useful in vitro model for studying the comprehensive functions of CD-ECM because it maintains a native-like structure and composition. In this study, the CD-ECM is obtained and a test is carried out to determine the effectiveness of several combinations of decellularized methods. These methods were used to regulate the optimal ECM compositions to be induced by osteogenic differentiation using primary isolated osteoblasts. Result: We investigated the effect of osteoblasts re-seeded onto normal osteoblast ECM under the growth medium (GM-ECM) and the osteogenic differentiation medium (OD-ECM). The osteoblasts were then cultured statically for 1, 2, and 4 weeks in a growth medium or differentiation medium. Before osteoblast culture, we performed immunostaining with filamentous actin and nuclei, and then performed DNA quantification. After each culture period, the osteogenic differentiation of the osteoblasts re-seeded on the OD-ECMs was enhanced osteogenic differentiation which confirmed by alkaline phosphatase staining and quantification, Alizarin Red S staining and quantification, and von Kossa staining. The OD-ECM-4 W group showed more effective osteogenic differentiation than GM-ECM and OD-ECM-2 W. Conclusions: The OD-ECM-4 W has a better capacity in a microenvironment that supports osteogenic differentiation on the GM-ECM and OD-ECM-2 W. The ECM substrate has a wide range of applications as cell culture system or direct differentiation of stem cell and excellent potential as cell-based tissue repair in orthopedic tissue engineering. PMID- 29484202 TI - Fusion of piggyBac-like transposons and herpesviruses occurs frequently in teleosts. AB - Background: Endogenous viral elements play important roles in eukaryotic evolution by giving rise to genetic novelties. Herpesviruses are a large family of DNA viruses, most of which do not have the ability to endogenize into host genomes. Recently, we identified a novel type of endogenous herpesvirus, which we named "Teratorn", from the medaka (Oryzias latipes) genome, in which the herpesvirus is fused with a piggyBac-like DNA transposon, forming a novel mobile element. Teratorn is a unique herpesvirus that retains its viral genes intact and has acquired the endogenized lifestyle by hijacking the transposon system. However, it is unclear how this novel element evolved in the teleost lineage and whether fusion of two mobile elements is a general phenomenon in vertebrates. Results: Here we performed a comprehensive genomic survey searching for Teratorn like viruses in publicly available genome data and found that they are widely distributed in teleosts, forming a clade within Alloherpesviridae. Importantly, at least half of the identified Teratorn-like viruses contain piggyBac-like transposase genes, suggesting the generality of the transposon-herpesvirus fusion in teleosts. Phylogenetic tree topologies between the piggyBac-like transposase gene and herpesvirus-like genes are nearly identical, supporting the idea of a long-term evolutionary relationship between them. Conclusion: We propose that piggyBac-like elements and Teratorn-like viruses have co-existed for a long time, and that fusion of the two mobile genetic elements occurred frequently in teleosts. PMID- 29484203 TI - Unravelling the complicated evolutionary and dissemination history of HIV-1M subtype A lineages. AB - Subtype A is one of the rare HIV-1 group M (HIV-1M) lineages that is both widely distributed throughout the world and persists at high frequencies in the Congo Basin (CB), the site where HIV-1M likely originated. This, together with its high degree of diversity suggests that subtype A is amongst the fittest HIV-1M lineages. Here we use a comprehensive set of published near full-length subtype A sequences and A-derived genome fragments from both circulating and unique recombinant forms (CRFs/URFs) to obtain some insights into how frequently these lineages have independently seeded HIV-1M sub-epidemics in different parts of the world. We do this by inferring when and where the major subtype A lineages and subtype A-derived CRFs originated. Following its origin in the CB during the 1940s, we track the diversification and recombination history of subtype A sequences before and during its dissemination throughout much of the world between the 1950s and 1970s. Collectively, the timings and numbers of detectable subtype A recombination and dissemination events, the present broad global distribution of the sub-epidemics that were seeded by these events, and the high prevalence of subtype A sequences within the regions where these sub-epidemics occurred, suggest that ancestral subtype A viruses (and particularly sub-subtype A1 ancestral viruses) may have been genetically predisposed to become major components of the present epidemic. PMID- 29484204 TI - The influence of a full-time, immersive simulation-based clinical placement on physiotherapy student confidence during the transition to clinical practice. AB - Background: Novice students may have limited learning opportunities during their early exposure to complex clinical environments, due to the priorities of patient care. Immersive, high-fidelity simulation provides an opportunity for physiotherapy students to be exposed to relatively complex scenarios in a safe learning environment before transitioning to the clinical setting. The present study evaluated the influence of immersive simulation on student confidence and competence. Methods: Sixty penultimate year physiotherapy students completed an 18-day full-time immersive simulation placement. The placement involved students spending 6 days working in each of three core practice areas (cardiopulmonary, musculoskeletal, neurological) in which they interacted with simulated patients portrayed by professional role-play actors. The patient scenarios were developed by groups of expert practitioners and incorporated full documentary and imaging information. Students completed a questionnaire to evaluate their confidence in the clinical environment at the start and completion of each 6-day rotation. Their clinical competence was evaluated at the end of each 6-day rotation using the Assessment of Physiotherapy Practice (APP) tool. In a secondary analysis, the clinical competence of this cohort was evaluated in comparison to a matched cohort of students from the same year group that had not completed an immersive simulation placement. Results: Student confidence improved significantly in each 6-day rotation (p < 0.001); however, it reduced again at the commencement of the next rotation, and there was no cumulative improvement in confidence over the 18 day placement (p = 0.22). Students who had completed the immersive simulation placement achieved higher APP (p < 0.001) scores in an evaluation of their competence to practice during their subsequent clinical placement. Conclusion: Immersive simulation provides a beneficial learning environment to enable physiotherapy students to transition from university-based education to working in the clinical environment. PMID- 29484205 TI - Fitting Tips and Visual Rehabilitation of Irregular Cornea with a New Design of Corneoscleral Contact Lens: Objective and Subjective Evaluation. AB - Objectives: To study the fitting and the visual rehabilitation obtained with a corneoscleral contact lens, namely, Rose K2 XL in patients with irregular cornea. Methods: This prospective study included 36 eyes of 36 patients with irregular cornea fitted with Rose K2 XL. Refractive and visual outcomes and mesopic and aberrometric parameters of fitted eyes were assessed at 2 weeks, 3 months, and 6 months after the initial lens use. Objective and subjective parameters of patient satisfaction and lens comfort were noted. Causes of lens discontinuation and complications were also recorded. Results: Average logMAR VA improved significantly from 0.95 +/- 0.09 without correction to 0.04 +/- 0.05 six months after lens wear. Similarly, mesopic and aberrometric measures were significantly improved. Statistical analysis of the subjective patients' responses showed a significant acceptance of the lens by most of them. At the end of follow-up, the mean wearing time was 9.9 +/- 2.9 hours per day. The most common cause of wearing discontinuation was persistent discomfort (16.7%) and high lens expenses(16.7%). Self-assessed questionnaire showed statistically significant improvement in nearly all measured subjective parameters. Conclusion: Rose K2 XL lenses provide patients with irregular cornea with both quantitative and qualitative optimal visual function with high degree of patient comfort and satisfaction. PMID- 29484206 TI - Effect of Coronary Slow Flow on Intrinsicoid Deflection of QRS Complex. AB - Coronary slow flow is a rare, clinically important entity observed in acute coronary syndrome. The pathophysiological mechanism is not fully elucidated. We investigated patients with chest pain who had angiographic features consistent with the coronary slow flow. One hundred ten patients were included. Electrocardiography, echocardiography, and angiography results were retrospectively noted. The mean age was 56.4. Fifty-eight were male, and fifty two were female. The control group consisted of patients with normal angiography. Patients had higher diastolic blood pressure, lower mean ejection fraction, higher average left ventricular end-diastolic diameter, and higher mean left atrial size than the control group (p=0.009, p=0.017, p=0.041, andp < 0.001, resp.). Patients had higher average V1 ID, V6 ID, P wave dispersion, TFC LAD, TFC Cx, TFC RCA, and TFC levels than the control group. A significant linear positive relationship was found between the V1 ID and the TFC LAD, TFC Cx, TFC RCA, and TFC; also between the V6 ID and the TFC LAD, TFC Cx, TFC RCA, and TFC. Angiographic and electrocardiographic features are suggestive and diagnostic for the coronary slow flow syndrome. Although when regarded as a benign condition, coronary slow flow should be diagnosed, followed up, and treated as many of laboratory features suggest ischemic events. PMID- 29484208 TI - Synthesis, Characterization, and Antimicrobial Activity of a Novel Trisazo Dye from 3-Amino-4H-thieno[3,4-c][1]benzopyran-4-one. AB - A new trisazo dye has been synthesized by coupling the diazonium ion of 3-amino 4H thieno[3,4-c][1]benzopyran-4-one with 2-tert-butyl-4-methoxyphenol. The newly prepared trisazo dye was characterized by its physical, elemental, and spectroscopic data. 2D-NMR (COSY, HSQC, and HMBC) techniques were used to secure the structural assignments. The new trisazo dye (compound 7) along with precursors 3, 4, and 6 was screened by microdilution susceptibility assay for antibacterial and antifungal activities towards eight bacterial strains and three yeasts selected on the basis of their relevance as human pathogens. The results showed that compound 7 (MIC = 2-128 MUg/mL) was the most active as compared with its precursors. The most resistant microorganisms were V. cholerae NB2 and V. cholerae SG24, whereas the most sensitive microorganism was C. neoformans. The overall results of this study indicated that compound 7 had the greatest potential value against both yeasts and multidrug-resistant bacteria, so further investigation is warranted. PMID- 29484209 TI - Adverse Effects of Carbetocin versus Oxytocin in the Prevention of Postpartum Haemorrhage after Caesarean Section: A Randomized Controlled Trial. AB - Purpose: To compare the incidence of nausea, vomiting, and arterial hypotension between carbetocin and oxytocin to prevent haemorrhage after caesarean section (CS). Methods: A randomized controlled trial in term pregnant women undergoing planned CS. Groups were randomized to carbetocin or oxytocin. Blood pressure (BP), heart rate, presence of nausea/vomitus, and need for vasopressors were evaluated throughout surgery. Preoperative and postoperative haemoglobin and haematocrit levels were compared. Results: Fifty-eight women were randomized (carbetocin n = 32; oxytocin n = 26). Both medications had hypotensive effect, difference in BP for carbetocin versus oxytocin: systolic (14.4 +/- 2.4 mmHg versus 8.5 +/- 1.8 mmHg); diastolic (7.8 +/- 1.6 mmHg versus 8.9 +/- 3.0 mmHg) without significant difference between the drugs (p = 0.1 and p = 0.7). Both groups had similar needs for vasopressors. The presence of nausea was not rare, but the difference was not statistically significant (p = 0.4). Average blood loss was slightly lower in the carbetocin group but not statistically significant (p = 0.8). Conclusion: In planned CS, a possible clinical significant lower incidence of nausea after carbetocin was noted but this was not statistically significant. There were no differences regarding BP, heart rate, the need for vasopressor, and blood loss. The study was registered in the International Journal of Clinical Trials (ISRCTN 95504420, 2/2017). PMID- 29484207 TI - Cardiac Development and Transcription Factors: Insulin Signalling, Insulin Resistance, and Intrauterine Nutritional Programming of Cardiovascular Disease. AB - Programming with an insult or stimulus during critical developmental life stages shapes metabolic disease through divergent mechanisms. Cardiovascular disease increasingly contributes to global morbidity and mortality, and the heart as an insulin-sensitive organ may become insulin resistant, which manifests as micro- and/or macrovascular complications due to diabetic complications. Cardiogenesis is a sequential process during which the heart develops into a mature organ and is regulated by several cardiac-specific transcription factors. Disrupted cardiac insulin signalling contributes to cardiac insulin resistance. Intrauterine under- or overnutrition alters offspring cardiac structure and function, notably cardiac hypertrophy, systolic and diastolic dysfunction, and hypertension that precede the onset of cardiovascular disease. Optimal intrauterine nutrition and oxygen saturation are required for normal cardiac development in offspring and the maintenance of their cardiovascular physiology. PMID- 29484211 TI - Establishing the Role of Stereotactic Ablative Body Radiotherapy in Early-Stage Breast Cancer. AB - Stereotactic ablative body radiotherapy (SABR) has a role as definitive therapy in many tumor sites; however, its role in the treatment of breast cancer is less well explored. Currently, SABR has been investigated in the neoadjuvant and adjuvant setting with a number of ongoing feasibility studies. However, its use comes with a number of radiobiological and technical challenges that require further evaluation. We have learned much from other extracranial disease sites such as lung, brain, and spine, where definitive treatment with SABR has shown encouraging outcomes. In women with breast cancer, SABR may eliminate the need for invasive surgery, reducing healthcare costs and hospital stays and providing an additional curative option for early-stage disease. This poses the following question: is there a role for SABR as a definitive therapy in breast cancer? PMID- 29484210 TI - Evaluating Stress during Pregnancy: Do We Have the Right Conceptions and the Correct Tools to Assess It? AB - Gestational stress is believed to increase the risk of pregnancy failure and perinatal and adult morbidity and mortality in both the mother and her child or children. However, some contradictions might arise from methodological issues or even from differences in the philosophical grounds that guide the studies on gestational stress. Biased perspectives could lead us to use and/or design inadequate/incomplete panels of biochemical determinations and/or psychological instruments to diagnose it accurately during pregnancy, a psychoneuroimmune endocrine state in which allostatic loads may be significant. Here, we review these notions and propose a model to evaluate and diagnose stress during pregnancy. PMID- 29484212 TI - A Very Rare Case: HPV-Negative Vulvar Cancer in an Adolescent. AB - Carcinoma of the vulva is usually regarded as a disease of older women, with the typical age of 65-85 years. There are a limited number of reports of vulvar cancer cases younger than 30 years. These patients have usually risk factors such as human papillomavirus (HPV) infection and immunosuppression. Herein, we present a case of invasive squamous vulvar cancer in an 18-year-old patient without any risk factor. Vulvar radical local excision and bilateral inguinal sentinel lymph node biopsies were performed. The clitoris was preserved during the surgery. Patient did not receive adjuvant therapy. Follow-up after 12 months of the disease showed no evidence of disease. Vulvar carcinoma in very young women may develop without any predisposing factor. Early detection will result in better survival. So, there should be a high index of suspicion when a vulvar lesion is seen, even if the patient falls below the typical age range and does not carry any well-known risk factors such as HPV infection and immunodeficiency. PMID- 29484213 TI - Nonvolatile Chemical Constituents from the Leaves of Ligusticopsis wallichiana (DC.) Pimenov & Kljuykov and Their Free Radical-Scavenging Activity. AB - Different plant parts of Ligusticopsis wallichiana (family: Apiaceae) are widely used as traditional medicines. Although many volatile constituents are already identified from the leaves of L. wallichiana, there is no detailed report on the nonvolatile constituents. In the present study, we aimed to isolate and identify the major chemical constituents from the leaves. Bhutkesoside A (1), falcarindiol (2), ferulic acid (3), cnidioside A (4), quercetin 3-O-beta-D-glucopyranoside (5), rutin (6), 4'-O-methylquercetin 3-O-beta-D-glucopyranoside (7), scopoletin (8), umbelliferone (9), eugenol 4-O-beta-D-glucopyranoside (10) and pumilaside A (11) were isolated from the 70% MeOH extract. The structures of isolated compounds were elucidated on the basis of 1H- and 13C-NMR spectroscopic data. Compounds 4-11 are reported for the first time from L. wallichiana. Compounds 5 and 6 showed potent free radical-scavenging activity. PMID- 29484214 TI - Comparison of Three Sample Preparation Procedures for the Quantification of L Arginine, Asymmetric Dimethylarginine, and Symmetric Dimethylarginine in Human Plasma Using HPLC-FLD. AB - Increased asymmetric dimethylarginine (ADMA) in human plasma has been associated with reduced generation of nitric oxide, leading to atherosclerotic diseases. ADMA may therefore be an important biomarker for cardiovascular disease. In the present study, three sample preparation techniques were compared regarding the quantification of L-arginine and ADMA in human plasma: (A) protein precipitation (PP) based on aqueous trichloroacetic acid (TCA), (B) PP using a mixture of ammonia and acetonitrile, and (C) solid-phase extraction (SPE). The samples were analysed by using high-performance liquid chromatography with fluorescence detection (HPLC-FLD). The analytical performance of (A) was comparable with that of (C), demonstrating recoveries of >90%, coefficient of variations (CVs, %) of <8, and a resolution (Rs ) between ADMA and symmetric dimethylarginine (SDMA) of 1.2. (B) was disregarded due to recoveries below 75%. (A) was validated with good results regarding linearity (>0.994), precision (<5%), and sensitivity (lower limit of quantification (LLOQ)) of 0.14 uM and 12 nM for L-arginine and ADMA, respectively. Due to the simplicity and speed of procedure (A), this approach may serve as preferred sample preparation of human plasma samples before HPLC-FLD in providing important information regarding elevated ADMA concentrations. PMID- 29484215 TI - Simple and Selective HPLC-UV/Vis Bioanalytical Method to Determine Aluminum Phthalocyanine Chloride in Skin Permeation Studies. AB - Considering the feasibility of the aluminum phthalocyanine chloride (AlPcCl) application in the topical photodynamic therapy of cutaneous tumors and the lack of HPLC methods capable of supporting skin permeation experiments using this compound, the aim of this study was to obtain a simple and selective chromatographic method for AlPcCl determination in skin matrices. A HPLC-UV/Vis method was developed using a normal-phase column operating at 30 degrees C, an isocratic mobile phase of methanol : phosphoric acid (0.01 M) at 1.5 mL/min, and detection at 670 nm. The method exhibited (i) selectivity against various contaminants found in the different skin layers, (ii) high drug extraction capacity from the hair follicle (>70%) and remaining skin (>80%), and (iii) low limits of detection and of quantification (0.03 and 0.09 MUg/mL, resp.). The method was also linear in the range from 0.1 to 5.0 ug/mL (r = 0.9994) and demonstrated robustness with regard to experimental chromatographic parameters according to a factorial design. Lastly, the developed method was successfully tested in in vitro skin permeation studies of AlPcCl, proving its effectiveness in the development of pharmaceutical delivery systems containing this drug for topical photodynamic therapy of skin cancers. PMID- 29484216 TI - Physical Characteristics of Tetrahydroxy and Acylated Derivatives of Jojoba Liquid Wax in Lubricant Applications. AB - Jojoba liquid wax is a mixture of esters of long-chain fatty acids and fatty alcohols mainly C38:2-C46:2. The oil exhibits excellent emolliency on the skin and, therefore, is a component in many personal care cosmetic formulations. The virgin oil is a component of the seed of the jojoba (Simmondsia chinensis) plant which occurs naturally in the Sonora Desert in the United States and northwestern Mexico as well as in the northeastern Sahara desert. The seed contains 50-60% oil by dry weight. The plant has been introduced into Australia, Argentina, and Israel for commercial production of the jojoba oil. As a natural lubricant, we are seeking to explore its potential as a renewable industrial lubricant additive. Thus, we have chemically modified the carbon-carbon double bonds in the oil structure in order to improve its already good resistance to air oxidation so as to enhance its utility as well as its shelf life in nonpersonal care applications. To achieve this goal, we have hydroxylated its -C=C- bonds. Acylation of the resulting hydroxyl moieties has generated short-chain vicinal acyl substituents on the oil which keep the wax liquid, improving its cold flow properties and also protecting it from auto-oxidation and rancidity. PMID- 29484217 TI - Ecological and Phytochemical Studies on Euphorbia retusa (Forssk.) from Egyptian Habitat. AB - This study deals with the ecology, phytochemistry, and biological activity investigation of Euphorbia retusa, belonging to Euphorbiaceae family, obtained from Egypt. Ecologically, Euphorbia retusa secretes white sap inhibiting the growth of the other species, so Euphorbia retusa is forming complete patches. Phytochemical study of the plant was visualized intensively based on its extraction with a protic organic solvent, working up and purifying its entire bioactive compounds using a series of different chromatographic techniques. A broad range of diverse compounds were isolated, namely, 1-hexacosanol (1), 3beta hydroxy-24-methylene-9,19-cyclolanostane; 24-methylenecycloartanol (2), 3beta hydroxy-9,19-cyclolanostane; cyclolaudanol (3), 3beta,24S-Ergost-5-en-ol (4), and methyllinoleate. Additionally, GC-MS analysis of the unpolar fractions detected the existence of n-dodecane, methyllaurate, 6,10,14-trimethyl-pentadecan-2-one (5), 6,10-dimethyl-undecan-2-one (6), 2-methyl-hexadecanal (7), methylpalmitate, methyl-9,12,15-octadecatrienoate (8), and n-heneicosane (9). A full assignment for compounds 2 and 3 using 1 and 2 DNMR was carried out herein for the first time. The antimicrobial activity of the strain extract and obtained compounds was studied using a panel of pathogenic bacterial strains. The in vitro cytotoxicity of the compounds as well as the crude extract was studied against the human cervix carcinoma cell line (KB-3-1). PMID- 29484218 TI - Personalized cancer screening: helping primary care rise to the challenge. AB - With their longitudinal patient relationships, primary care physicians and their care teams are uniquely situated to promote preventive medicine, including cancer screening. A confluence of forces is driving the demand for the personalization of cancer screening recommendations. Recommendations are increasingly based on individual patient preferences, medical history, genetic and environmental risk factors, and level of interaction with the healthcare system. Current examples include choices between colonoscopy, fecal testing, and emerging tests for colorectal cancer (CRC) screening; the use of genetic information and availability of home self-testing in cervical cancer screening; the integration of multiple risk factors and patient preferences to decide the intensity and length of breast cancer screening; and the issues of smoking cessation and competing priorities when deciding whether or not to pursue lung cancer screening. These changes will inevitably increase the burden on primary care of providing high-quality cancer screening to their patients. To address, primary care physicians need access to continuously updated evidence reviews including prioritization of strongly supported recommendations, training in shared decision making and tools for preference diagnosis, and an electronic health record (EHR) and reimbursement model that allow for population health management and team based care. Only by reinforcing cancer screening in primary care can we ensure that personalized cancer screening is accessible and evidence-based. PMID- 29484219 TI - Sperm DNA and detection of DNA fragmentations in sperm. AB - The questionable effectiveness of routine sperm parameters in determining male factor infertility problems and increasing the success rates of assisted reproductive techniques have led to the investigation of more detailed sperm parameters that could affect the male fertility and reproduction. Thus, the effects of different sperm parameters such as sperm DNA integrity was started to be investigated thanks to the previously described methods such as single cell gel electrophoresis (COMET) assay, sperm chromatin structure assay (SCSA), acridine orange test (AOT), terminal deoxynucleotidyl transferase-mediated deoxyuridine (TdT) triphosphate (dUTP) nick end labeling (TUNEL) assay and sperm chromatin dispersion (SCD) test. However, studying on sperm DNA might be very complex because the sperm DNA differs from the somatic cell DNA with its unique structure. Also, the sperm DNA undergoes many changes during spermatogenesis and it is condensed by being packaged tightly with different types and numbers of protamines in different species. Despite all these difficulties, these methods provide important information about the reasons and consequences of DNA damages in sperm and the effects of these damages on reproduction. PMID- 29484220 TI - 3D printing in urology: Is it really promising? AB - Three-dimensional (3D) printings are gaining a place in a variety of the medical sectors. With applications in urogenital diseases, 3D printing is a new tool that present difficulties at stages of imaging, planning, and carry out therapeutic interventions. In this review we tried to find answers to the questions that come to mind on this new topic by empasizing the suitable 3D printing models in urology, their clinical usage, and the limitations. PMID- 29484221 TI - Peyronie's disease surgery: Surgical outcomes of 268 cases. AB - Objective: To assess the outcomes of the surgical techniques used in Peyronie's disease (PD) surgery. Material and methods: Two hundred and sixty-eight patients received surgical treatment for PD. Fifty four and 144 patients underwent simple corporoplasties (shortening procedure, SP, group 1) or plaque incision and grafting surgery (lengthening surgery, LP, group 2), respectively, whereas 70 patients with erectile dysfunction underwent penile prosthesis implantation. Results: Penile plication and Nesbit surgeries were performed in 5 (9%) and 42 (78%) patients out of total 54 patients. In the remaining 7 (13%) patients, Nesbit and plication suture combination was required for complete penile straightening. Mean curvature degree was 52.2+/-12.3 degrees. Follow up time was 36.1+/-29.4 months. No significant difference was demonstrated between the two groups in the baseline features and co-morbidities except age. In 144 patients who underwent plaque incision and grafting, mean age and PD onset duration were 54.1+/-9.2 years and 28.2+/-17.3 months respectively. Mean curvature degree was 58.4+/-18.9 degrees. Post-operative follow up time of the second group was 51.1+/ 39.6 months. Additional plication suture was used in 48 patients (33%) patients. Degree of curvature improvement was 37.9+/-19.1 and 52.1+/-23.5 in SP and LP respectively (p=0.01). The initial anatomic success rates were 90.4% and 87.5% at their early post-operative follow-ups for group 1 and 2 respectively. These rates dropped to 82.7% and 83.6% at the long term follow-up (36 and 51 months) respectively (p=0.9). Although the average follow-up time of LP group was longer than SP group (52.1 mo vs. 37.0 mo), recurrence rates of these two groups were comparable. The combined functional and anatomical success of patients were demonstrated to be 79% and 75% in shortening and grafting surgery. Shortening surgery was not statistically superior to grafting surgery for patients in terms of having erection with or without the aid of PDE-5 inhibitors (94.4% vs. 88.2%, p=0.28). Shortening surgery makes a difference in the long term follow-up for patients who had erections without the aid of PDE-5 inhibitors (90.7% vs. 67.3%, p=0.02). Conclusion: Both SP and LP are successful in terms of penile straightening in the short and long-term follow-up. Curvature degree improvement is greater in LP. Patients who undergo LP surgery may suffer from ED in the long term follow-ups. Greater percentage of patients who underwent LP require PDE-5 inhibitors usage for sexual intercourse. Despite stated shortcomings, combined success (anatomic and functional) is achieved in three out of four patients for both groups. Penile prosthesis implantation should be preferred for patients with ED and penile deformity. PMID- 29484222 TI - Investigation of the effects of curcumin, vitamin E and their combination in cisplatin-induced testicular apoptosis using immunohistochemical technique. AB - Objective: Cisplatin is an effective antineoplastic agent used in cancer therapy. However, the use of cisplatin is restricted due to its toxic side effects. Alleviation of its side effects which restricts cisplatin use is highly important. We aimed to investigate the effects of curcumin, vitamin E and their combination in cisplatin induced testicular apoptosis. Material and methods: Thirty-five Wistar albino male adult rats, weighing 300-350 g were divided randomly into five groups including seven rats in each as control, cisplatin, curcumin, vitamin E, and curcumin + vitamin E. On the posttest 5th day, rats were sacrificed, and their testes were removed. 4-5 MUm sections from formalin fixed paraffin embedded testis tissues were stained both hematoxylin-eosin to analyze histologically and immunohistochemically to determine the expression of the apoptotic pathway proteins (Bax, Cas-3, Bcl-2). Results: Increased histological damage with cisplatin administration was reduced in treatment, especially in combination therapy. Cas-3 and Bax protein immunostaining intensities H-scores were significantly increased but Bcl-2 was slightly decreased in the cisplatin group compared to the control. In all treatment groups Bax, Cas-3 decreased compared to cisplatin group however Bcl-2 decreased in the curcumin and vitamin E groups. Bax/Bcl-2 was the highest in the cisplatin, and decreased in all treatment groups in favor of control. Conclusion: Cas-3 expression increased by cisplatin administration suggests that cisplatin causes apoptosis of germ cells. According to the present findings, cisplatin mainly caused testicular apoptosis through the Cas-3 and Bax apoptotic protein pathways. Cisplatin-induced testicular apoptosis can be prevented by administration of curcumin, vitamin E, and combination therapy. PMID- 29484223 TI - The association between variant urothelial histologies, pathological stage and disease specific survival in patients with bladder cancer. AB - Objective: We aimed to compare the oncological outcomes of patients with variant urothelial histologies (VH) with pure urothelial histology (PUH) in bladder cancer (BC) patients. Material and methods: This study includes 223 patients who underwent radical cystectomies (RCs) between September 2006 and July 2016 with complete follow-up data A retrospective screening was performed to identify the patients with PUH and VH. The primary outcomes of interest were pathological stage of disease at RC and disease-specific survival (DSS). For comparison of categorical variables, Fisher's exact test and Pearson chi- square and for continuous variables Wilcoxon rank-sum and Mann-Whitney U tests were used. Kaplan Meier (KM) method was used for survival analysis and log-rank test was used for comparison of survival rates. Predictors of survival were detected with mulitivariable Cox-proportional hazards model including the variables such as gender, age, existence of VH, lymph node dissection (LND) type and pathological stage of the disease. Results: A moderate-degree correlation was detected between VH and pathological stages of RC (r=0.45, p<0.001). In PUH group, 39 (25.8%) of 151 patients died after a median follow-up of 20 (0-107) months; whereas 37 (51.4%) of 72 patients with VH died after a median follow-up of 16.5 (0-104) months (p<0.001). In terms of pathological stage, the number of patients with PUH and VH were at stages pT0-2 (n=100; 66.2% vs. n=19; 26.4%), pT3-4 (n=35; 23.2% vs. 38; 52.8%, and in 16 (10.6%) and 15 (20.8%) patients with LN positivity, respectively (p<0.001). KM survival analysis revealed a significantly decreased DSS in patients with VH compared to PUH (p<0.001). Meanwhile, pathological disease stage and existence of VH were found to be associated with decreased DSS in the multivariate model. Conclusion: The present study revealed that VH is associated with advanced pathological tumor stage at RC and decreased DSS compared to patients with PUH in patients with BC. PMID- 29484224 TI - Immunohistochemical study of C-kit expression in subtypes of renal cell carcinoma. AB - Objective: Renal cell carcinomas (RCCs) include about 2% of adult neoplasms and 90-95% of all renal tumors. Mostly, it is possible to distinguish RCC subtypes using hematoxylin-eosin staining. However, overlapping morphologic features cause some difficulties in making a precise diagnosis. In order to render an accurate diagnosis, additional methods such as immunohistochemical staining for c-kit have been recommended. In this study, we aimed to investigate c-kit gene expression in various subtypes of RCC. Material and methods: We reviewed 65 diagnosed RCC cases. Formalin- fixed, paraffin- embedded specimens were available for the cases. The expression of c-kit was evaluated using immunohistochemistry. The correlation between c-kit expression and clinicopathological parameters including patients' age and gender in addition to grade, stage, and size of the tumor were investigated. Results: Six cases of 39 clear cell types (15.4%), 8 of 13 papillary types (61.5%), 11 of 12 chromophobe types (91.7%), and no sarcomatoid type were positive for c-kit expression. Based on chi-square test results, there was a significant relationship between RCC subtypes and c-kit expression (p=0.001). There was no significant correlation between age, sex, grade, stage, and size of the tumor and c-kit expression. Conclusion: The expression of c-kit in RCC may have diagnostic significance in subtypes of RCC especially papillary and chromophobe subtypes of RCC. PMID- 29484225 TI - Rearrangement of the Guy's stone score improves prediction of stone-free rate after percutaneous nephrolithotomy. AB - Objective: We propose a modification of the original Guy's Stone Score (GSS) to hold on 20 % of prognostic discrimination among groups which makes this score a more reliable resource for risk assessment in patients undergoing percutaneous nephrolithotomy (PCNL). Material and methods: Historical cohort of 126 patients undergoing PCNL from December 2010 to November 2014 was included in the survey. Every patient was classified according to the original GSS. For the new classification of Guy Stone Score (GSS-M) all of the subgroups included in the scale were analyzed individually and then ranked from better to worst according to the postoperative stone- free rates (SFRs). This ranking led us to reclassify all the original subgroups, clustering them in three new categories according to their SFRs as subgroups of good, intermediate and poor prognosis, trying to achieve at least 20% of prognostic discrimination among the groups. Results: Hundred and twenty-six PCNL procedures were evaluated, but only 124 were included for statistical analysis and classified based on SFR according to the GSS as follows: 76% for grade 1, 71% for grade 2, 55% for grade 3 and 20% for grade 4. The SFRs were also assessed for the GSS-M obtaining the following predictive values as 93%, 67% and 44% for the good, intermediate and poor prognostic groups, respectively. The prognostic difference among the GSS-M groups was always >20% (p<0.05). Conclusion: The original GSS has limitations to predict SFR because of its poor discrimination power among prognostic groups. This rearrangement improves prediction of SFR and better discriminates risk groups in PCNL. PMID- 29484226 TI - Efficacy of oral steroids after optical internal urethrotomy in reducing recurrence of urethral strictures. AB - Objective: Optical internal urethrotomy is a feasible modality of treatment for short segment bulbar urethral strictures. Recurrence is an important problem after urethrotomy. This study aimed at evaluating the efficacy of oral steroid (deflazocort) in reducing the recurrence of strictures after urethrotomy. Up to date, no study has evaluated the role of oral steroids after urethrotomy. Material and methods: In this case-control study, patients undergoing urethrotomy (bulbar urethral strictures <2 cm) were divided into two groups according to patients receiving (Group 1) or not receiving (Group 2) oral steroid (deflazocort 6 mg tablets) after operation. Both groups were controlled at 1, 3 and 6 months after catheter removal (usually 5-6 days after operation) with uroflowmetry, and the flow rates were statistically compared. Deflazocort was given after catheter removal, at first 6 mg twice daily for two weeks, then 6 mg once daily for another two weeks (self-obturation was not performed). Results: A total of 72 patients were selected for the study as per inclusion criteria. They were divided into 2 groups as those receiving (Group 1: deflazocort group; n=36) or not receiving (Group 2; n=36) deflazocort. Median postoperative maximum flow rates in the deflazocort group were 26.2, 22.3 and 18.2 mL/sec, and in the control group was 24.4, 17.1 and 13.7 mL/sec at postoperative 1., 3. and 6. months, respectively. Lesser patients in the deflazocort group had recurrence. The difference was statistically significant only at postoperative 3 (p value=0.03), and 6. months (p value=0.02) (p value=0.15). Conclusion: Oral steroids can be used after internal urethrotomy to reduce the recurrence of urethral strictures. PMID- 29484227 TI - Dynamic MRI and isotope renogram in the functional evaluation of pelviureteric junction obstruction: A comparative study. AB - Objective: The aim of this study was to evaluate and compare the diagnostic accuracy of dynamic contrast- enhanced magnetic resonance imaging (dMRI) and isotope renogram in the functional evaluation of pelviureteric junction obstruction (PUJO). Material and methods: Forty-two patients included in the study were investigated with isotope renogram and subsequently, subjected to dMRI. Time-activity curves were generated for both isotope renogram and dMRI. Out of the 42 cases, 9 cases were conservatively managed. Thirty-three cases were taken up for surgical intervention. Results: Of 33 patients taken up for surgical intervention, 12 underwent laparoscopic nephrectomy and 21 of them pyeloplasty. The mean glomerular filtration rates (GFRs) as measured by isotope renogram and dMRI were 22.5+4.2 mL/min and 23.8+3.1 mL/min respectively. The calculation of GFR by isotope renogram, showed good correlation with that of dMRI with correlation coefficient of 0.93. The dMRI was able to reveal the functional status of the renal unit accurately. dMRI did not yield false positive results with 20 of 21 patients scheduled for pyeloplasty and 11 of 12 patients scheduled for nephrectomy. Isotope renogram had a false positive result in 3 cases compared with surgical diagnosis. Conclusion: Analysis of renal function using dMRI yielded results comparable to those of renal scintigraphy, with superior spatial and contrast resolution. It was also better in prompting management decisions with respect to the obstructed systems. dMRI can be used as a "one stop imaging examination" that can replace different imaging methods used for morphological, etiological and functional evaluation of PUJO. PMID- 29484228 TI - The adverse effects of oral desmopressin lyophilisate (MELT): personal experience on enuretic children. AB - Objective: The aim of this study was to evaluate adverse effects of oral desmopressin lyophilisate (MELT) in enuretic children. Material and methods: We enrolled 260 children with nocturnal enuresis (NE) referred to the Pediatric Service, 'Campus Bio-Medico' University of Rome, from April 2014 to April 2017 in the study, of these 23 were excluded. The study was characterized by 2 phases. During Phase 1 a careful patient's medical history was obtained and physical examination was performed. After 3 months of treatment with MELT (Minirin/DDAVP(r)) at the dose of 120 mcg a day, a micturition diary was kept, adherence to therapy and any possible adverse effects were checked during the Phase 2. The study was carried out in compliance with the Helsinki Declaration. Results: Among 237 patients included in the study 11 male and 6 female (n=17; 7.2%) patients with a mean age 10.06+/-2.49 years, reported 22 adverse effects, with an absolute risk of 7.17%. In particular, 5 neurological symptoms, 3 gastrointestinal effects, 4 sleep disturbances, 8 psycho-behavioral disorders, 2 symptoms of fatigue were reported. Conclusion: In our study MELT with its higher bioavailability guaranteed lower frequency of adverse effects which resolved spontaneously and rapidly. The MELT formulation actually represents the first line and safe treatment for the NE. PMID- 29484229 TI - Comparison of outcomes of tubed versus tubeless percutaneous nephrolithotomy in children: A single center study. AB - Objective: To evaluate and compare the effectiveness of tubeless percutaneous nephrolithotomy (PCNL) and tubed PCNL by using small bore nephrostomy tube (12Fr) in children for the management of nephrolithiasis. Material and methods: This study was a retrospective analysis of 35 children where tubed PCNL (Group 1) was done in 18, and tubeless PCNL (group 2) in 17 patients from January 2010 to December 2016. Charts were reviewed for age, mass, stone size, operative time, hospital stay and stone-free rates. These variables were compared between the two groups. SPSS version 21 was used for data analysis. The data were shown as mean+/ standard deviation for continuous variables. Categorical variables were presented in percentages. Results: There is no difference in terms of age, stone sizes, operative times, hospital stays, stone-free rates and post-PCNL complications between the two groups (p>0.05). The mean drop in hemoglobin level was 0.7+/-0.1 g/dL and 1.3+/-0.2 g/dL in Groups 1 and 2, respectively (p=0.01). Conclusion: Tubeless PCNL in children is a safe option in well selected cases. PMID- 29484230 TI - Bacterial isolates and their antimicrobial susceptibility patterns among pediatric patients with urinary tract infections. AB - Objective: Urinary tract infection is a common pediatric problem with the potential to produce long-term morbidity. Therefore, appropriate diagnosis and prompt treatment is required. However, studies about magnitude of uropathogenicity and antimicrobial resistance pattern of pediatric urinary tract infection (UTI) are lacking in resource limited countries including Ethiopia. This study was aimed to determine bacterial isolates, antimicrobial susceptibility pattern among pediatric patients with UTI. Material and methods: A cross- sectional study was conducted. Pathogenic bacterial isolates were identified by culture and biochemical methods following standard procedures. Antimicrobial susceptibility testing of the isolates for commonly used antibiotics was done using the standard disc diffusion method on Muller Hinton agar. Associations between dependent and independent variables were measured using chi-square test and within 95% confidence interval. P values <0.05 were considered as statistically significant. Results: A total of 310 pediatric patients were included in the study, and 82 (26.45%) bacterial isolates were detected. Gram- negative bacteria were predominant etiologic agents of UTI in this study. E. coli was the most frequently occurring pathogen (n=45; 54.88%) followed by S. aureus and P.aeruginosa (n=8; 9.75% for both), P. vulgaris, P.aeruginosa (n=4; 4.88%, for both) and Enterococcus species (n=3; 3.66%). All K. pneumoniae, P. mirabilis, and K. ozanae straines were 100% resistance to ampicillin, followed by P. aeruginosa (87.5%) and E. coli (69%). While all Gram- positive bacterial isolates were 100% sensitive to ciprofloxacin. Malnutrition, history of catherization and previous history of UTI were independently associated with UTI (p=0.000). Conclusion: There was a high prevalence of uropathogenic bacteria and drug resistance particularly to ampicillin (72%) and tetracycline (37.80%). This condition indicates that antibiotic selection should be based on knowledge of the local prevalence of bacterial organisms and antibiotic sensitivities rather than empirical treatment. PMID- 29484231 TI - The role of the neurometer CPT/C in sacral neuromodulation. AB - Objective: The aim of the current research project was to study the role of the Neurometer(r) as a tool to predict responders to sacral neuromodulation therapy (SNM). Material and methods: This was a prospective, open study in male and female patients, aged 18 and over with voiding dysfunction [non-obstructive retention and/or frequency/ urgency syndrome]. The first group underwent a screening test to evaluate percutaneous nerve functions (PNE) and to determine whether they are candidates for SNM with the InterStim(r). Prior to PNE testing, all patients were evaluated with the pain tolerance test (PTT) using the electro diagnostic Neurometer(r) CPT/C device. An InterStim(r) implant was placed in patients who were responders to PNE testing underwent. On the other hand, non responders underwent a staged implant placement. The second group consisted of patients who already had InterStim(r) implanted for voiding dysfunction. During the routine office follow-up, the patients implanted with Interstim(r) underwent a PTT using the Neurometer(r) CPT/C device. All the testing using the Neurometer CPT/C was performed on the day of the PNE for the first group, and the day of the routine follow-up visit for the second group. All of the results for the Neurometer(r) testing were kept blinded from the PNE results, and those of the outcome of the follow-up visit. The study received approval by the Research Ethics Board of the University Health Network (No. 14-8196). Results: We recruited a total of 123 patients. The results presented here include 110 patients who completed the study, 48 of whom were in the first group, and 62 in the second group. The statistical analysis used was as follows: Group 1: Simple linear regression analysis and the linear discriminate analysis were preformed. It was found that for patients without the InterStim(r) implant with a combined CPT/CPD of 800 and above, the Neurometer(r) could predict the test screening results with an accuracy of 71%. Group 2: Same analysis and tests were conducted for patients with the InterStim(r) implant, and the results showed that if the patient had a combined CPT/CPD of 600 and above, the Neurometer(r) could predict the patients satisfaction or dissatisfaction with an accuracy of 72%. Conclusion: Neurometer(r) may play a role in predicting test trial positive responders and patient satisfaction after the placement of InterStim(r) implant. PMID- 29484232 TI - Supraclavicular lymph node as the first presentation and late skin metastasis: an unusual clinical course for prostate cancer. AB - Prostate cancer is the most common non-cutaneous malignancy and the second cause of cancer death in men. Despite improvements in diagnostic methods, the primary diagnosis of a number of patients may still be on metastatic stage. Cutaneous and supraclavicular lymph nodes are very rare metastatic sites for prostate cancer. In this report we present an extremely rare prostate cancer case diagnosed with supraclavicular lymph node and then developed cutaneous metastasis. A 64 year-old man was admitted to an internal medicine outpatient clinic with supraclavicular lymph node and biopsy of lymph node showed an adenocarcinoma. After prostate cancer diagnosis, patient was treated with androgen deprivation therapy, docetaxel chemotherapy and abiraterone acetate, respectively. While abiraterone treatment, cutaneous metastasis developed in inguinal area and diagnosis was confirmed by skin biopsy. In some cases, atypical symptoms may guide us to find disease with aggressive clinics. That's why, physical rectal examination and prostate specific antigen measurements should be kept in mind for prostate cancer in male patients with supraclavicular lymph node or atypical metastasis. PMID- 29484233 TI - Giant malignant fibrous histiocytoma of the testis. AB - We present a case of malignant fibrous histiocytoma of the testis in a 59 year- old male who admitted to our hospital with left testicular painless mass presenting for two months. A scrotal ultrasound examination and magnetic resonance imaging revealed a 9 cm left testicular solid mass. Serum tumor markers were unremarkable. The patient underwent left radical orchiectomy. Histopathologic diagnosis was giant cell variant of malignant fibrous histiocytoma which composed of varying amounts of a mixture of spindled, rounded and osteoclastic type giant cells. Hemorrhagic and necrotic areas were seen between tumor nodules. In immunohystochemical staining, vimentin, CD68 were positive and SMA was focally positive. The patient then received adjuvant chemoterapy and currently, he has no sign of recurrence. PMID- 29484234 TI - Foreign body mimicking neoplasia of the renal pelvis on magnetic resonance imaging. AB - A 65-year-old male presented with an incidental magnetic resonance imaging (MRI) finding of a right renal pelvis (RP) tumor-like mass. He was subjected to nephrostomy tube (NT) placement due to hydronephrosis secondary to an impacted ureteral stone. NT was removed after successful Ho:YAG laser lithotripsy. Abdominal MRI performed 19 months later for another indication showed RP wall thickening/enhancement and an intrapelvic low-intensity linear structure presenting as a magnetic susceptibility artifact. He underwent diagnostic ureterorenoscopy/retrograde intrarenal surgery. A calcified NT locking suture remnant was found within the pelvis surrounded by reactive edema without evidence of tumor. Foreign body (FB) was removed after disintegration of surrounding calcifications using Ho:YAG laser. This is the first case of a calcified NT locking suture remnant mimicking RP tumor on MRI. The case underlies the importance of safe NT removal. Specific MRI findings may prove valuable for preoperative diagnosis of intrarenal FBs in cases with history of endourological interventions evaluated for upper urinary tract masses. Multidisciplinary uroradiological approach of such cases is essential. PMID- 29484235 TI - Benign diaphragmatic neurilemmoma mimicking a left adrenal cyst. AB - Neurilemmomas are benign, slow growing, encapsulated nerve sheath tumor. These tumors arise from the schwann cells of neural crest. Neurilemmomas can manifest in various form according to site, extent and severity of involvement of organ. Diaphragmatic neurilemmomas are very unusual and even difficult to diagnose on preoperative imaging. We will report a case of 39 year old male, who presented with complaints of occasional left flank pain for one year and subsequently investigated, which showed left adrenal cyst with haemorrhagic fluid content. On the contrary, when surgical exploration of the lesion was done, it showed a cyst within the diaphragm, completely separated from left kidney and left adrenal with haemorrhagic content in situ. Histopathological examination of the lesion showed it to be a benign neurilemmoma with cystic degeneration. Post opearatively patient did well. We believe that this is the first case report, which is addressing such kind of initial manifestation of diaphragmatic neurilemmomas. PMID- 29484236 TI - EFFICACY OF THE STRETCH BAND ANKLE TRACTION TECHNIQUE IN THE TREATMENT OF PEDIATRIC PATIENTS WITH ACUTE ANKLE SPRAINS: A RANDOMIZED CONTROL TRIAL. AB - Background: Ankle injuries account for up to 40% of all sport related injuries. These injuries can result in weeks to months of missed sport or work. The PRICE (Protection, Rest, Ice, Compression, Elevation) treatment is standard care for most acute ankle sprains. Recently, early mobilization in adults has been shown to decrease time off from sport or work, and the likelihood of developing chronic instability. To date, no research has been performed assessing the effectiveness of early mobilization in pediatric patients (<18 years). Purpose: There were two objectives of this study: (1) to determine if early ankle joint mobilization using elastic band traction is effective and (2) assess the occurrence of adverse events with this technique in the pediatric population. Methods: Patients with an acute ankle sprain of <7 days referred to physical therapy were randomly assigned to receive early mobilization or PRICE. Early mobilization was performed using a stretch band ankle traction technique. Both groups received a standardized rehabilitation program. Pain, edema, ankle strength using hand-held dynamometry, and Foot and Ankle Disability Index (FADI) were measured at both initial evaluation and at discharge. The number of days before return to sport and the number of treatment sessions were also variables of interest. Results: Forty-one pediatric patients were recruited for participation (mean age 14.6 + 1.9 years). Both treatment groups had clinically significant improvements in pain, edema, strength, and FADI scores. No significant differences in outcomes were noted between treatment groups. Mean number of days for return to sport for the PRICE group was 26.33 + 7.14 and the early mobilization group was 26.63 + 14.82, the difference between groups was not significant (p = 0.607). The number of total visits for the PRICE group of 8.07 + 2.63 and the early mobilization groups of 8.5 + 1.57, was also not statistically significantly different (p = 0.762). There were no reported adverse events with early mobilization. Conclusion: Early mobilization appears to be a safe intervention in pediatric patients with an acute ankle sprain. Early mobilization resulted in similar outcomes when compared to traditional PRICE treatment. A high drop-out rate in both treatment groups was a limitation of this randomized trial. Level of evidence: 1b. PMID- 29484237 TI - ACUTE LATERAL ANKLE SPRAIN PREDICTION IN COLLEGIATE WOMEN'S SOCCER PLAYERS. AB - Background: Women's soccer has among the highest injury rates in collegiate sports, and lateral ankle sprains (LAS) are among the most commonly occurring injuries in that athletic population. However, no established LAS prediction model exists for collegiate women's soccer players.The purpose of this study was to develop a prediction model for acute LAS injuries in collegiate women's soccer players utilizing previous ankle sprain history, height, mass, and BMI as potential predictors.The authors' hypothesized that collegiate women's soccer players with greater height, mass, and body mass index (BMI), as well as a previous history of ankle sprain would have greater odds of sustaining a LAS. Study Design: Prospective cohort study. Methods: Forty-three NCAA Division I women's soccer players' (19.7 +/- 1.1yrs, 166.8 +/- 3.7cm, 60.8 +/- 4.4kg) height, mass, and BMI were measured one week before beginning preseason practices. Additionally, participants reported whether or not they had sustained a previous ankle sprain. The team athletic trainer tracked LASs over the competitive season. Independent t-tests, binary logistic regression analyses, receiver operating characteristic (ROC) curves, and diagnostic statistics assessed the ability of the variables to differentiate between those that did and did not sustain a LAS. Results: Participants that sustained a LAS (n = 8) were significantly taller than those that did not sustain a LAS (n = 35) (t41 = -2.87, p = 0.01, d = 0.83[0.03,1.60]). A logistic regression analysis (odds ratio=1.30[1.00,1.70]) and area under the ROC curve analysis (AUROC=0.73[0.58,0.89], p=0.04) further exhibited predictive value of height. A height cutoff score of 167.6cm demonstrated excellent sensitivity (0.88), moderate specificity (0.51), and a favorable diagnostic odds ratio (7.5). A logistic regression analysis (odds ratio=1.87[1.22,1.98]) exhibited predictive value of previous ankle sprain history. That variable was also associated with good sensitivity (0.75) and specificity (0.71) within the model, as well as a favorable DOR (7.37). Mass and BMI demonstrated no predictive value for LAS. Conclusion: Taller collegiate women's soccer players and those with previous ankle sprain history may have a greater predisposition to LAS. Level of evidence: 1b. PMID- 29484238 TI - THE RELIABILITY OF A NOVEL HEEL-RISE TEST VERSUS GONIOMETRY TO ASSESS PLANTARFLEXION RANGE OF MOTION. AB - Background: Ankle plantarflexion (PF) active range of motion (ROM) is traditionally assessed in a non-weight-bearing (NWB) position with a universal goniometer. However, a convenient, reliable, low-cost means of assessing functional PF active ROM in a weight-bearing (WB) position has yet to be established. Purpose: To compare the intra- and interrater reliability of PF active ROM measurements obtained from a goniometric NWB assessment, and a functional heel-rise test (FHRT) performed in WB. Study Design: Reliability study. Methods: Two physical therapy student examiners, blinded to each other's measurements, assessed PF active ROM through a NWB goniometric technique and a FHRT on all subjects within the same test session. Intra- and interrater reliability values were calculated using an intraclass correlation coefficient (ICC2,1, ICC2,k) and 95% confidence intervals. Standard error of measurement (SEM) and minimal detectable change (MDC) were recorded for each method. Results: 43 healthy participants (mean +/- SD, age: 22.7 +/- 1.7 years, height: 1.7 +/- 0.1 m, mass: 77.8 +/- 17.2 kg) completed testing procedures. The within-session intrarater reliability (ICC2,1) estimates were observed for goniometry (right: 0.96, left: 0.95 - 0.97) and FHRT (right: 0.99, left: 0.99), as well as the interrater reliability (ICC2,k) of goniometry (right: 0.79, left: 0.79) and FHRT (right: 0.79, left: 0.87). Goniometry SEM (3.3 - 3.6 degrees ) and MDC (9.2 - 9.8 degrees ) were observed, in addition to FHRT SEM (0.6 cm) and MDC (1.6 - 1.7 cm). A weak correlation was found between FHRT and goniometric measurements (r = 0.03 - 0.13). Conclusions: The FHRT was found to have good to excellent intra- and interrater reliability, similar to goniometric measurement. The lack of agreement between these measurements requires further exploration of a WB assessment of ankle PF active ROM. Level of Evidence: 2b. PMID- 29484239 TI - ULTRASONOGRAPHIC ASSESSMENT OF NECK MUSCULAR SIZE AND RANGE OF MOTION IN RUGBY PLAYERS. AB - Background: World Rugby Union laws are constantly evolving towards stringent injury-prevention, particularly for contested scrums, since front row players are most at risk of cervical spine injuries. Recently, some countries have also introduced tailored training programs and minimum performance requirements for playing in the front row. Nevertheless, these approaches lack an objective assessment of each cervical muscle that would provide protective support. Objective: Since front row players are the most at risk for cervical spine injuries due to the specific type of contact during scrums, the purpose of this study was to ascertain whether significant differences exist in neck muscle size and range of motion between front row players and players of other positions, across playing categories. Study Design: Cross-sectional controlled laboratory study. Methods: 129 sub-elite male subjects from various first-team squads of Belgian Rugby clubs were recruited. Subjects were grouped according to age: Junior (J) < 19 years old, Senior (S) 19 to 35 years old and Veteran (V) > 35 years old; as well as playing position: Front row players (J = 10, S = 12, V = 11 subjects), (Rest of the) pack (J = 12, S = 12, V = 10), backs (J = 10, S = 11, V = 11). An age-matched control group of non-rugby players was also recruited (J = 10, S = 10, V = 10).For each subject, the total neck circumference (NC) and the cervical range of motion (CROM) were measured. In addition, the thickness of the trapezius (T), splenius capitis (SCa), semispinalis capitis (SCb), semispinalis cervicis (SPC), sternocleidomastoid muscles (SCOM), and the total thickness of all four structures (TT), were measured using ultrasonography. Results: In each age category, compared to controls, rugby players were found to have decreased CROM, an increase in neck circumference (NC), and increased total thickness (TT), trapezius (T), semispinalis capitis (SCb) and sternocleidomastoid muscles (SCOM) sizes. For junior players, the thickness of the semispinalis cervicis (SPC) was also increased compared to controls. The CROM was decreased in front row players compared to pack and back players for all age categories; Front row seniors also showed an increase in trapezius (T), splenius capitis (SCa), semispinalis capitis (SCb) and total thickness (TT), compared to back players. Conclusion: In regard of the differences in cervical values found between player positions, the implementation of both range of motion and echography muscle thickness assessments could serve to create an additional measurement for all front row players, that could complement current pre-participation screening used by rugby federations by objectively monitoring muscular size and motion amplitude around the cervical spine. PMID- 29484240 TI - A COMPARATIVE STUDY OF PASSIVE SHOULDER ROTATION RANGE OF MOTION, ISOMETRIC ROTATION STRENGTH AND SERVE SPEED BETWEEN ELITE TENNIS PLAYERS WITH AND WITHOUT HISTORY OF SHOULDER PAIN. AB - Background: Glenohumeral internal rotation deficit and external rotation strength have been associated with the development of shoulder pain in overhead athletes. Objective: To examine the bilateral passive shoulder rotational range of motion (ROM), the isometric rotational strength and unilateral serve speed in elite tennis players with and without shoulder pain history (PH and NPH, respectively) and compare between dominant and non-dominant limbs and between groups. Study Design: Cohort study. Methods: Fifty-eight elite tennis players were distributed into the PH group (n = 20) and the NPH group (n = 38). Serve velocity, dominant and non-dominant passive shoulder external and internal rotation (ER and IR) ROM, total arc of motion (TAM: the sum of IR and ER ROM), ER and IR isometric strength, bilateral deficits and ER/IR strength ratio were measured in both groups. Questionnaires were administered in order to classify characteristics of shoulder pain. Results: The dominant shoulder showed significantly reduced IR ROM and TAM, and increased ER ROM compared to the non-dominant shoulder in both groups. Isometric ER strength and ER/IR strength ratio were significantly lower in the dominant shoulder in the PH group when compared with the NPH group. No significant differences between groups were found for serve speed. Conclusion: These data show specific adaptations in the IR, TAM and ER ROM in the dominant shoulder in both groups. Isometric ER muscle weakness and ER/IR strength ratio deficit appear to be associated with history of shoulder injuries in elite tennis players. It would be advisable for clinicians to use the present information to design injury prevention programs. Level of evidence: 2. PMID- 29484241 TI - SHOULDER EXTERNAL ROTATOR STRENGTH IN RESPONSE TO VARIOUS SITTING POSTURES: A CONTROLLED LABORATORY STUDY. AB - Background: The forward head rounded shoulder (FHRS) sitting posture has been associated with decreased shoulder complex muscle strength and function. Upon clinical observation, the adverse effects of the FHRS sitting posture on shoulder complex isometric muscle strength is also present when testing controls for scapular position. Hypothesis/Purpose: The purpose of the study was to assess the effect of various sitting postures on shoulder external rotator muscle isometric strength when the strength testing controls for scapular position. Study Design: A cohort study, with subjects serving as their own controls. Methods: One hundred subjects ages 20-26 participated in the study. Each subject was placed in a neutral cervical sitting (NCS) posture which was maintained for five minutes after which the strength of the dominant shoulder external rotators was immediately tested with the glenohumeral joint in the neutral position using a Micro-FET3 Hand Held Muscle Testing Dynamometer (HHMTD). Each subject was returned to the NCS posture for subsequent external rotator strength testing after five minutes in a FHRS sitting posture, five additional minutes in the NCS posture and five minutes in a retracted cervical sitting (RCS) posture resulting in each subjects' external rotator strength being tested on four occasions. Subjects were randomized for order between the FHRS and RCS postures. Results: Mean strength values for each condition were normalized to the mean strength value for the 1st NCS condition for each subject. A statistically significant decline in shoulder external rotator strength following the FHRS sitting posture occurred compared to the appropriate postural conditions (p<.05). A frequency analysis revealed that 36% of the subjects demonstrated greater than 10% decline in external rotator strength following five minutes in the FHRS sitting posture. The average percentage of strength decline in those with greater than a 10% reduction in external rotator strength was 19%. Sixty-four percent of the subjects experienced less than a 10% decline in shoulder external rotator strength in response to the FHRS sitting posture. Conclusion: Shoulder external rotator strength declined 8% following five minutes in the FHRS sitting posture. A sub-population of 36% demonstrated an average decline of 19% in shoulder external rotator strength following five minutes in the FHRS sitting posture. The strength decline appears to resolve over the short-term by returning to the NCS posture. Level of Evidence: Level III. PMID- 29484242 TI - TRUNK LEAN DURING A SINGLE-LEG SQUAT IS ASSOCIATED WITH TRUNK LEAN DURING PITCHING. AB - Background: Impaired trunk motion during pitching may be a risk factor for upper extremity injuries. Specifically, increased forces about the shoulder and elbow have been observed in pitchers with excessive contralateral trunk lean during pitching. Because of the difficulty in identifying abnormal trunk motions during a high-speed task such as pitching, a clinical screening test is needed to identify pitchers who have impaired trunk motion during pitching. Hypothesis/Purpose: The purpose of this study was to determine the relationship between the degree of lateral trunk lean during the single-leg squat and amount of trunk lean during pitching and if trunk lean during pitching can be predicted from lean during the single-leg squat. Study Design: Controlled Laboratory Study; Cross-sectional. Methods: Seventy-three young baseball pitchers (11.4 +/- 1.7 years; 156.3 +/- 11.9 cm; 50.5 +/- 8.8 kg) participated. An electromagnetic tracking system was used to obtain trunk kinematic data during a single-leg squat task (lead leg) and at maximum shoulder external rotation of a fastball pitch. Pearson correlation coefficients for trunk lean during the single-leg squat and pitching were calculated. A linear regression analysis was performed to determine if trunk lean during pitching can be predicted from lean during the single-leg squat. Results: There was a positive correlation between trunk lean during the single-leg squat and trunk lean during pitching (r = 0.53; p<0.001). Lateral trunk lean during the single-leg squat predicted the amount of lateral trunk lean during pitching (R2 = 0.28; p < 0.001). Conclusions: A moderate positive correlation was observed between trunk lean during an SLS and pitching. Trunk lean during the single-leg squat explained 28% of the variance in trunk lean during pitching. Level of Evidence: Diagnosis, level 3. PMID- 29484243 TI - MAXIMAL HIP AND KNEE MUSCLE STRENGTH ARE NOT RELATED TO NEUROMUSCULAR PRE ACTIVITY DURING SIDECUTTING MANEUVER: A CROSS-SECTIONAL STUDY. AB - Background: Reduced lower extremity muscle strength as well as reduced lower extremity muscle pre-activity (defined as muscular activity just prior to initial ground contact) during high-risk movements are factors related to increased risk of non-contact ACL injury in adolescent female athletes. A strong relationship exists between muscle strength and muscle activity obtained during an isometric contraction, however, whether these two measures are related when muscle activity is obtained during a movement associated with a high risk of non-contact ACL injury is not known. Absence or presence of such a relationship may have implications for which training modalities to choose in the prevention of ACL injuries. Purpose: The purpose of this study was to examine the relationship between maximal muscle strength of the hip extensors, hip abductors and knee flexors and the pre-activity of these muscle groups recorded during a sidecutting maneuver (high-risk movement) in adolescent female soccer and handball athletes. Study design: Cross-sectional study. Methods: Eighty-five adolescent (age 16.9 +/ 1.2 years) female elite handball and soccer athletes were assessed for maximal hip extensor, hip abductor and knee flexor muscle strength; and muscle pre activity (electromyography recordings over a 10 ms time interval prior to foot ground contact) of the gluteus maximus (Gmax), gluteus medius (Gmed), biceps femoris (BF) and semitendinosus (ST) during a standardized sidecutting maneuver. Results: The results of the correlation analyses demonstrated poor and statistically non-significant correlations. Maximal hip extensor force (N/kg bw) and Gmax pre-activity [rs = 0.012 (95% CI -0.202 - 0.224), p = 0.91], maximal hip abductor force (N/kg bw) and Gmed pre-activity [rs = 0.171 (95% CI -0.044 - 0.371), p = 0.11], maximal knee flexor force (N/kg bw) and BF pre-activity [rs = 0.049 (95% CI -0.166 - 0.259), p = 0.65], and maximal knee flexor force and ST pre-activity [rs = 0.085 (95% CI -0.131 - 0.293), p = 0.44]. Conclusion: In the present exploratory study, the results imply that no relationship exists between maximal lower extremity isometric muscle strength and lower extremity muscle pre activity during sidecutting. This means that athletes with low muscle strength may not necessarily demonstrate high (or low) muscle pre-activity during sidecutting - a well-known risk movement for sustaining non-contact ACL injury. Levels of evidence: Level 3. PMID- 29484244 TI - 2D AND 3D KINEMATICS DURING LATERAL STEP-DOWN TESTING IN INDIVIDUALS WITH ANTERIOR CRUCIATE LIGAMENT RECONSTRUCTION. AB - Background: The lateral step-down test is an established clinical evaluation tool to assess quality of movement in patients with knee disorders. However, this test has not been investigated in individuals after anterior cruciate ligament reconstruction (ACLR) in association with quantitative 3D motion analysis. Purposes: The purpose of this study was to determine the strength of association between visually-assessed quality of movement during the lateral step-down test and 3D lower limb kinematics in patients with history of ACLR. A second purpose was to compare kinematics between subgroups based on the presence or absence of faulty alignments during the task. The final purpose was to compare visually assessed quality of movement scores between box heights during lateral step-down testing. Methods: Twenty subjects at least one year status post-ACLR (18 females, age of 24.5 +/- 4.6 years and body mass index of 23.4 +/- 2.3 kg/m2) performed the lateral step-down test unilaterally on the surgical limb atop four and six inch boxes. A board-certified orthopedic physical therapist scored overall quality of movement during the lateral step-down test using established criteria during 2D video playback. Lower limb kinematics were simultaneously collected using 3D motion capture. An alpha level of 0.05 was used for all statistical treatments. Results: Overall 2D quality of movement score significantly correlated (r =0.47-0.57) with 3D hip adduction and hip internal rotation across box heights. Across box heights, the presence of faulty pelvic alignment differentiated a subgroup exhibiting less peak knee flexion, and the presence of faulty knee alignment differentiated a subgroup exhibiting greater peak hip adduction. The six inch box elicited worse quality of movement compared to the four inch box. Conclusions: These results suggest that visually-assessed quality of movement is associated with several kinematic variables after ACLR. 2D movement deviations at the pelvis appear to consistently relate to less knee flexion, and 2D deviations at the knee appear to suggest greater hip adduction. Generally, poorer quality of movement was observed for the six inch box height. Clinically, these data suggest that interventions targeting hip abductor and knee extensor strength and neuromuscular control may be useful in the presence of poor quality of movement during lateral step-down testing. Level of Evidence: 2b. PMID- 29484245 TI - QUANTIFYING FRONTAL PLANE KNEE KINEMATICS IN SUBJECTS WITH ANTERIOR KNEE PAIN: THE RELIABILITY AND CONCURRENT VALIDITY OF 2D MOTION ANALYSIS. AB - Background: Two-dimensional (2D) analysis has the potential to identify individuals at risk for knee injury by measuring genu valgus during sport related tasks. The reliability of 2D mobile motion analysis in measuring genu valgus during a single leg hop test on individuals with anterior knee pain has not been examined. Purpose: To assess the reliability and concurrent validity of 2D mobile motion analysis and compare it to visual observation while analyzing dynamic genu valgus during a single leg hop test in subjects with anterior knee pain. Study Design: Cohort study; repeated measures. Methods: Nineteen subjects experiencing anterior knee pain completed a single leg hop test with both lower extremities. Two investigators independently estimated the degrees of genu valgus with visual observation alone during the subjects' single leg hop. After the visual estimation, the investigators watched the video again using the 2D Spark Motion ProTM application to pause the video and measured the amount of knee valgus with a virtual goniometer tool on the application. Interrater reliability was calculated using intraclass correlation coefficients (ICC) model 2, k and intrarater rater reliability using model 3, k. Minimal detectable change, concurrent validity and limits of agreement were calculated. Results: Visual observation alone demonstrated interrater reliability ICCs of 0.682-0.685 on the symptomatic and non-symptomatic lower extremities respectively. The interrater reliability using the 2D application had ICC's of 0.927 and 0.792 on the symptomatic and non-symptomatic lower extremities respectively. The concurrent validity for 2D analysis and visual observation on the symptomatic lower extremity had ICC values of 0.96 (rater A) and 0.85 (rater B). The non symptomatic lower extremity demonstrated concurrent validity ICC values of 0.95(rater A) and 0.65(rater B). The standard error of measurement(SEM) was 3.898 and 3.258 for the symptomatic and non-symptomatic lower extremity(LE) respectively for visual observation. When using the Spark Motion ProTM application the SEM was 1.648 and 2.718 for the symptomatic and non-symptomatic LE respectively. The minimal detectable change (MDC) using visual observation alone was 5.58 and 4.68. When using the application, it was noted at 2.328 and 3.838 on the symptomatic and non-symptomatic LE respectively. Conclusion: The results of this study support the use of a 2D mobile application as a reliable tool for measuring knee valgus in symptomatic subjects and offers reduced error (SEM = 1.648) when compared to visual observation alone (SEM = 3.898). Level of evidence: 2B. PMID- 29484246 TI - ISOKINETIC ASSESSMENT OF MUSCULAR STRENGTH AND BALANCE IN BRAZILIAN ELITE FUTSAL PLAYERS. AB - Purpose/Background: Strength asymmetries are related to knee injuries in intermittent sports players. The purpose of this study was to examine whether elite futsal players demonstrate strength asymmetries during knee isokinetic testing applying the Croisier et al.21 criteria. Methods: Forty male elite (27.9 +/- 6.5 years) Brazilian futsal players participated in the study. The testing protocol required players to perform concentric contractions of both quadriceps and hamstring muscles at angular velocities of 60 degrees .s-1 and 240 degrees .s-1 and eccentric contractions of hamstring at 30 degrees .s-1 and 120 degrees .s-1. Conventional (concentric:concentric) and mixed (eccentric:concentric) hamstrings/quadriceps (H/Q) ratios were calculated. Subjects were determined to have an imbalanced strength profile if an athlete had at least two parameters that were asymmetrical across speeds and conditions. Asymmetry was operationally defined as peak torque asymmetry greater than 15% in bilateral comparison, and H/Q ratio less than 0.47 for conventional and 0.80 for mixed conditions. Results: Significant differences were observed between preferred and nonpreferred limbs in the concentric contractions of flexors at 240 degrees .s-1 and eccentric contractions of extensors and flexors at 30 degrees .s-1 and 120 degrees .s-1. However, these asymmetries did not exceed 15%. The conventional and mixed H/Q ratios were greater in the preferred than in nonpreferred limbs, but only the mixed hamstringsecc/quadricepsconc in the nonpreferred limbs showed values lower than recommended (<0.80). In addition, 50% of elite futsal players had preseason strength imbalances per the developed criteria. Conclusion: The studied elite futsal players had preseason strength imbalances, which may increase the risk of hamstring injuries. Level of evidence: 3. PMID- 29484247 TI - ACUTE EFFECTS OF DIFFERENT ANTERIOR THIGH SELF-MASSAGE ON HIP RANGE-OF-MOTION IN TRAINED MEN. AB - Background: Self-massage is a ubiquitous intervention similar to massage, but performed by the recipient him- or herself rather than by a therapist, most often using a tool (e.g., foam roller, roller massager). Self-massage has been found to have a wide range of effects. It is particularly known for increasing flexibility acutely, although not always. The variability of the results in previous studies may potentially be a function of the tool used. Recent findings also suggest that self-massage exerts global effects. Therefore, increased flexibility should be expected in the areas adjacent to the ones treated. Purpose: To investigate the acute effects of foam rolling and rolling massage of anterior thigh on hip range of-motion (ROM) - i.e., hip extension and hip flexion - in trained men. Methods: Eighteen recreationally active, resistance trained males visited the lab on two occasions over a 4-day period separated by at least a day. Each session included two baseline ROM measures of passive hip flexion and extension taken in a randomized fashion. Recording of baseline measures was followed by the intervention of the day, which was either foam rolling or rolling massage of the anterior thigh as per randomization. Immediately post intervention, passive hip flexion and hip extension ROM were reassessed. In order to assess the time course of improvements in ROM, hip flexion and hip extension ROM were reevaluated at 10, 20, and 30 minutes post-intervention. Results: Hip flexion and hip extension ROM increased immediately following both interventions (foam rolling or roller massager) and remained increased for 30 minutes post intervention. Foam rolling was statistically superior in improving hip flexion and hip extension ROM immediately post intervention. However, immediately post-intervention was the only time point that measurements exceeded the minimum detectable change for both interventions. Conclusion: Both foam rolling and rolling massage appear to be effective interventions for improving hip flexion and extension ROM when applied to the anterior thigh, but the observed effects are transient in nature. Level of evidence: 2b. PMID- 29484248 TI - STRENGTHENING THE GLUTEUS MAXIMUS IN SUBJECTS WITH SACROILIAC DYSFUNCTION. AB - Study design: Case series. Background and purpose: The literature has emphasized the use of exercise as an intervention for individuals with lumbopelvic pain. However, there is limited information to guide clinicians in exercise selection for those with sacroiliac (SI) joint dysfunction. Altered function of the gluteus maximus has been found in those with SI joint dysfunction. The objective of this case series was to assess the effectiveness of an exercise program directed at increasing gluteus maximus strength in those with clinical tests positive for SI joint dysfunction. Case descriptions: The eight subjects in this series presented with lumbopelvic pain and clinical evidence of SI joint dysfunction. Each subject underwent 10 treatments over five weeks consisting of five exercises directed at strengthening the gluteus maximus. Radiological assessment and clinical examination were performed to rule out potential concurrent pathologies. Visual analog pain scale, the Oswestry Disability Index, and strength assessed via hand held dynamometry were measured pre- and post-intervention. Outcomes: A significant (p<0.001) weakness in gluteus maximus was noted when comparing the uninvolved and involved sides pre-intervention. After completing the strengthening exercise program over 10 visits, statistically significant (p<0.002) increases in gluteus maximus strength and function were found, as well as a decrease in pain. All subjects were discharged from physical therapy and able to return to their normal daily activities. Discussion: The results of this case series support the use of gluteus maximus strengthening exercises in those with persistent lumbopelvic pain and clinical tests positive for SI joint dysfunction. PMID- 29484249 TI - THE UTILIZATION OF MULLIGAN CONCEPT THORACIC SUSTAINED NATURAL APOPHYSEAL GLIDES ON PATIENTS CLASSIFIED WITH SECONDARY IMPINGEMENT SYNDROME: A MULTI-SITE CASE SERIES. AB - Background and Purpose: Secondary impingement syndrome (SIS) is a common complaint in the sporting population particularly among athletes engaging in overhead activities. While symptoms may be present at the shoulder with patients complaining of SIS, spinal alignment or dysfunction can influence scapular positioning and overall shoulder girdle function. As an adjunct therapy to traditional interventions for SIS, thoracic high-velocity low-amplitude (HVLA) thrusts have been utilized and correlated with patient reported decreases in pain. Mulligan Concept (MC) thoracic sustained natural apophyseal glides (SNAGs) are an emerging treatment intervention utilized to treat patients with shoulder pain and dysfunction as the evidence supporting an interdependent relationship between the thoracic spine and the shoulder is growing. The purpose of this case series was to investigate the effects of one MC thoracic SNAG treatment session on subjects classified with SIS, while utilizing a classification-based treatment protocol. Case Descriptions: Seven subjects classified with SIS were treated utilizing a MC thoracic SNAG. The Numeric Rating Scale (NRS) was administered at initial evaluation, immediately following intervention, and at the 48-h follow-up to identify patient-reported pain during range of motion, manual strength testing, and special tests of the shoulder. Investigators collected the Shoulder Pain and Disability Index (SPADI) at initial evaluation and the 48-h follow-up to identify patient-reported dysfunction. Outcomes: Following one MC thoracic SNAG treatment (3 sets of 10 repetitions), minimal clinically important differences (MCIDs) were reported utilizing the NRS. A decrease in pain during active shoulder abduction (ABD) was detected immediately post-treatment, and the NRS change scores for resisted external rotation (RER) and active ABD were statistically different and clinically important at the 48-h follow-up. Discussion: Based on the results of this case series, thoracic SNAGs may influence short-term pain levels and shoulder mobility in the included subjects with SIS and support the concept of regional interdependence (RI) between the thoracic spine and glenohumeral joint. Continued exploration into the proposed benefits of the MC thoracic SNAG treatment as an adjunct therapy when treating patients complaining of SIS is warranted. Level of Evidence: 4 (Case Series). PMID- 29484250 TI - PATELLOFEMORAL CHONDRAL DEFECT IN A PREADOLESCENT SKIER: A CASE REPORT IN EARLY SPORT SPECIALIZATION. AB - Background and Purpose: Early sport specialization (ESS) refers to intense training year round in a specific sport starting at a young age with no or limited participation in other sports. This approach to training is highly controversial; recent literature suggests that this type of specialized training could be a contributing source to overuse injuries in youth athletes. The purpose of this case report was to describe a patellofemoral articular cartilage defect of the knee in a preadolescent skier due to overuse and repetitive microtrauma as a result of ESS. Study Design: Case Report. Case Description: A healthy 11-year old male competitive alpine skier presented with recurrent swelling of his right knee and persistent anterior knee pain while skiing without evidence of any specific history of injury or traumatic event. The patient failed a conservative treatment regimen including rest and formal physical therapy focused on generalized knee strengthening. Magnetic resonance imaging was ordered and revealed an articular cartilage defect of the medial patellar facet. The patient was treated with an arthroscopic debridement of his articular cartilage defect. Outcome: At 12 weeks postoperatively, the patient presented with a normalized gait pattern, no evidence of knee effusion, full knee range of motion and patellar mobility symmetric to his contralateral limb, and no patellar crepitation or painful palpation on physical exam. The patient was released to begin return to sport progression at 12 weeks, and was cleared for full activities/returned to competitive skiing at 15 weeks postoperatively. At 16 weeks postoperatively, he won an international alpine ski race in Europe for his age group. Discussion: Cartilage injuries and osteochondral defects are very common in adolescent athletes and often go undiagnosed. Allied healthcare professionals must be educated on the known causes of recurrent knee effusions and how early sport specialization may result in overuse injuries to knee joint cartilage. Level of Evidence: 4. PMID- 29484251 TI - Graph theory analysis of cortical thickness networks in adolescents with d transposition of the great arteries. AB - Objective: Adolescents with d-transposition of the great arteries (d-TGA) who had the arterial switch operation in infancy have been found to have structural brain differences compared to healthy controls. We used cortical thickness measurements obtained from structural brain MRI to determine group differences in global brain organization using a graph theoretical approach. Methods: Ninety-two d-TGA subjects and 49 controls were scanned using one of two identical 1.5-Tesla MRI systems. Mean cortical thickness was obtained from 34 regions per hemisphere using Freesurfer. A linear model was used for each brain region to adjust for subject age, sex, and scanning location. Structural connectivity for each group was inferred based on the presence of high inter-regional correlations of the linear model residuals, and binary connectivity matrices were created by thresholding over a range of correlation values for each group. Graph theory analysis was performed using packages in R. Permutation tests were performed to determine significance of between-group differences in global network measures. Results: Within-group connectivity patterns were qualitatively different between groups. At lower network densities, controls had significantly more long-range connections. The location and number of hub regions differed between groups: controls had a greater number of hubs at most network densities. The control network had a significant rightward asymmetry compared to the d-TGA group at all network densities. Conclusions: Using graph theory analysis of cortical thickness correlations, we found differences in brain structural network organization among d-TGA adolescents compared to controls. These may be related to the white matter and gray matter differences previously found in this cohort, and in turn may be related to the cognitive deficits this cohort presents. PMID- 29484253 TI - Progressive multiple sclerosis, cognitive function, and quality of life. AB - Background: Patients with progressive multiple sclerosis (MS) often have cognitive impairment in addition to physical impairment. The burden of cognitive and physical impairment progresses over time, and may be major determinants of quality of life. The aim of this study was to assess to which degree quality of life correlates with physical and cognitive function in progressive MS. Methods: This is a retrospective study of 52 patients with primary progressive (N = 18) and secondary progressive MS (N = 34). Physical disability was assessed using the Expanded Disability Status Scale, Timed 25 Foot Walk (T25FW) test and 9-Hole Peg Test (9HPT). Cognitive function was assessed using Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test, and Trail Making Test B (TRAIL-B). In addition, quality of life was assessed by the Short Form 36 (SF-36) questionnaire. Results: Only measures of cognitive function correlated with the overall SF-36 quality of life score and the Mental Component Summary score from the SF-36. The only physical measure that correlated with a measure of quality of life was T25FW test, which correlated with the Physical Component Summary from the SF-36. We found no other significant correlations between the measures of cognitive function and the overall physical measures but interestingly, we found a possible relationship between the 9HPT score for the nondominant hand and the SDMT and TRAIL-B. Conclusion: Our findings support inclusion of measures of cognitive function in the assessment of patients with progressive MS as these correlated closer with quality of life than measures of physical impairment. PMID- 29484252 TI - Coupled changes in hippocampal structure and cognitive ability in later life. AB - Introduction: The hippocampus plays an important role in cognitive abilities which often decline with advancing age. Methods: In a longitudinal study of community-dwelling adults, we investigated whether there were coupled changes in hippocampal structure and verbal memory, working memory, and processing speed between the ages of 73 (N = 655) and 76 years (N = 469). Hippocampal structure was indexed by hippocampal volume, hippocampal volume as a percentage of intracranial volume (H_ICV), fractional anisotropy (FA), mean diffusivity (MD), and longitudinal relaxation time (T1). Results: Mean levels of hippocampal volume, H_ICV, FA, T1, and all three cognitive abilities domains decreased, whereas MD increased, from age 73 to 76. At baseline, higher hippocampal volume was associated with better working memory and verbal memory, but none of these correlations survived correction for multiple comparisons. Higher FA, lower MD, and lower T1 at baseline were associated with better cognitive abilities in all three domains; only the correlation between baseline hippocampal MD and T1, and change in the three cognitive domains, survived correction for multiple comparisons. Individuals with higher hippocampal MD at age 73 experienced a greater decline in all three cognitive abilities between ages 73 and 76. However, no significant associations with changes in cognitive abilities were found with hippocampal volume, FA, and T1 measures at baseline. Similarly, no significant associations were found between cognitive abilities at age 73 and changes in the hippocampal MRI biomarkers between ages 73 and 76. Conclusion: Our results provide evidence to better understand how the hippocampus ages in healthy adults in relation to the cognitive domains in which it is involved, suggesting that better hippocampal MD at age 73 predicts less relative decline in three important cognitive domains across the next 3 years. It can potentially assist in diagnosing early stages of aging-related neuropathologies, because in some cases, accelerated decline could predict pathologies. PMID- 29484254 TI - Rest but busy: Aberrant resting-state functional connectivity of triple network model in insomnia. AB - Introduction: One classical hypothesis among many models to explain the etiology and maintenance of insomnia disorder (ID) is hyperarousal. Aberrant functional connectivity among resting-state large-scale brain networks may be the underlying neurological mechanisms of this hypothesis. The aim of current study was to investigate the functional network connectivity (FNC) among large-scale brain networks in patients with insomnia disorder (ID) during resting state. Methods: In the present study, the resting-state fMRI was used to evaluate whether patients with ID showed aberrant FNC among dorsal attention network (DAN), frontoparietal control network (FPC), anterior default mode network (aDMN), and posterior default mode network (pDMN) compared with healthy good sleepers (HGSs). The Pearson's correlation analysis was employed to explore whether the abnormal FNC observed in patients with ID was associated with sleep parameters, cognitive and emotional scores, and behavioral performance assessed by questionnaires and tasks. Results: Patients with ID had worse subjective thought control ability measured by Thought Control Ability Questionnaire (TCAQ) and more negative affect than HGSs. Intriguingly, relative to HGSs, patients with ID showed a significant increase in FNC between DAN and FPC, but a significant decrease in FNC between aDMN and pDMN. Exploratory analysis in patients with ID revealed a significantly positive correlation between the DAN-FPC FNC and reaction time (RT) of psychomotor vigilance task (PVT). Conclusion: The current study demonstrated that even during the resting state, the task-activated and task-deactivated large scale brain networks in insomniacs may still maintain a hyperarousal state, looking quite similar to the pattern in a task condition with external stimuli. Those results support the hyperarousal model of insomnia. PMID- 29484255 TI - Brain resting-state networks in adolescents with high-functioning autism: Analysis of spatial connectivity and temporal neurodynamics. AB - Introduction: Autism spectrum disorder (ASD) is mainly characterized by functional and communication impairments as well as restrictive and repetitive behavior. The leading hypothesis for the neural basis of autism postulates globally abnormal brain connectivity, which can be assessed using functional magnetic resonance imaging (fMRI). Even in the absence of a task, the brain exhibits a high degree of functional connectivity, known as intrinsic, or resting state, connectivity. Global default connectivity in individuals with autism versus controls is not well characterized, especially for a high-functioning young population. The aim of this study is to test whether high-functioning adolescents with ASD (HFA) have an abnormal resting-state functional connectivity. Materials and Methods: We performed spatial and temporal analyses on resting-state networks (RSNs) in 13 HFA adolescents and 13 IQ- and age-matched controls. For the spatial analysis, we used probabilistic independent component analysis (ICA) and a permutation statistical method to reveal the RSN differences between the groups. For the temporal analysis, we applied Granger causality to find differences in temporal neurodynamics. Results: Controls and HFA display very similar patterns and strengths of resting-state connectivity. We do not find any significant differences between HFA adolescents and controls in the spatial resting-state connectivity. However, in the temporal dynamics of this connectivity, we did find differences in the causal effect properties of RSNs originating in temporal and prefrontal cortices. Conclusion: The results show a difference between HFA and controls in the temporal neurodynamics from the ventral attention network to the salience-executive network: a pathway involving cognitive, executive, and emotion-related cortices. We hypothesized that this weaker dynamic pathway is due to a subtle trigger challenging the cognitive state prior to the resting state. PMID- 29484256 TI - Catechol-O-methyltransferase Val158Met polymorphism associates with affect and cortisol levels in women. AB - Introduction: We tested the extent to which the catechol-O-methyltransferase (COMT) Val158Met polymorphism is associated with affective state and evening cortisol levels. We limited our study to women as previous research suggests that the link between COMT genotype and psychological health is entangled by sex differences. Materials and Methods: The participants were assessed on measures of anxiety, mood disturbance, depressive symptomatology, and perceived stress. We also evaluated participants on a quality of life measures that included two emotion domains and two physical domains (physical health and environment). Results: We found that under normal (nonstress) conditions, the COMT A allele (Met carriers, higher dopamine) associates with healthier affect and lower afternoon cortisol levels in women. These effects were limited to affective measures and not to physical or environmental quality of life. Conclusions: These findings help to shed light on the complex nature of COMT and emotion, and suggest that both sex and task condition (stress vs. nonstress) should be considered when examining the relationship between COMT genotype and emotion. PMID- 29484257 TI - High-definition transcranial direct current stimulation (HD-tDCS) of left dorsolateral prefrontal cortex affects performance in Balloon Analogue Risk Task (BART). AB - Background: Studies on risk preferences have long been of great concern and have examined the neural basis underlying risk-based decision making. However, studies using conventional transcranial direct current stimulation (tDCS) revealed that bilateral stimulation could change risk propensity with limited evidence of precisely focalized unilateral high-definition transcranial direct current stimulation (HD-tDCS). The aim of this experiment was to investigate the effect of HD-tDCS focalizing the left dorsal lateral prefrontal cortex (DLPFC) on risk taking behavior during the Balloon Analogue Risk Task (BART). Methods: This study was designed as a between-subject, single-blind, sham-controlled experiment. University students were randomly assigned to three groups: the anodal group (F3 anode, AF3, F1, F5, FC3 returned), the cathodal group (F3 cathodal, AF3, F1, F5, FC3 returned) and the sham group. Subsequently, 1.5-mA 20-min HD-tDCS was applied during the BART, and the Positive Affect and Negative Affect Scale (PANAS), the Sensation Seeking Scale-5 (SSS-5), and the Behavioral Inhibition System and Behavioral Approach System scale (BIS/BAS) were measured as control variables. Results: The cathodal group earned less total money than the sham group, and no significant difference was observed between the anodal group and the sham group. Conclusions: These results showed that, to some extent, focalized unilateral cathodal HD-tDCS on left DLPFC could change performance during risky tasks and diminish risky decision making. Further studies are needed to investigate the dose effect and electrode distribution of HD-tDCS during risky tasks and examine synchronous brain activity to show the neural basis. PMID- 29484259 TI - Poststroke emotional disturbances and a tryptophan hydroxylase 2 gene polymorphism. AB - Objectives: Emotional dysfunction is a common finding in stroke patients. Despite reports on serotonergic involvement in the etiology of poststroke emotional dysfunction (PSED), the role of serotonin synthesizing tryptophan hydroxylase 2 (TPH2) genes in the development of PSED remains unclear. Methods: Genotyping of TPH2 rs4641528 and rs10879355 was performed from genomic DNA of 383 stroke patients collected previously and stored at -70 degrees C. Potential associations between TPH2 genes and poststroke depression (PSD), poststroke emotional incontinence (PSEI), and poststroke anger proneness (PSAP) were investigated 3 months poststroke. Results: Among the 383 patients, 69 (18%) had PSD, 41 (11%) had PSEI, and 93 (24%) had PSAP. The TPH2 rs4641528 genotype frequencies differed significantly between patients with and without either PSD or PSEI, although no significant differences were found between the patients with and without PSAP. In multiple logistic regression analysis, PSD was related to the National Institutes of Health Stroke Scale (NIHSS) score at admission (95% confidence interval [CI]: 1.047-1.230, p < .01), modified Rankin scale score at 3 months (95% CI: 0.135 0.848, p < .05), and TPH2 rs4641528 C allele (95% CI: 1.039-5.631, p < .05), whereas PSEI was associated only with the NIHSS score at admission (95% CI: 1.053 1.259, p < .01) and the TPH2 rs4641528 C allele (95% CI: 1.029-11.678, p < .05). Conclusions: Our findings suggest that the TPH2 rs4641528 C allele may play a role in the pathogenesis of PSD and PSEI but not PSAP in Korean stroke patients. PMID- 29484260 TI - Using Delphi methodology in the development of a new patient-reported outcome measure for stroke survivors with visual impairment. AB - Introduction: The aim of this study was to ascertain what items stroke survivors and stroke care professionals think are important when assessing quality of life for stroke survivors with visual impairment for inclusion in the new patient reported outcome measure. Methods: A reactive Delphi process was used in a three round electronic-based survey. The items presented consisted of 62 items originally sourced from a systematic review of existing vision-related quality of life instruments and stroke survivor interviews, reduced and refined following a ranking exercise and pilot with stroke survivors with visual impairment. Stakeholders (stroke survivors/clinicians) were invited to take part in the process. A consensus definition of >=70% was decided a priori. Participants were asked to rank importance on a 9-point scale and categorize the items by relevance to types of visual impairment following stroke or not relevant. Analysis of consensus, stability, and agreement was conducted. Results: In total, 113 participants registered for the Delphi survey of which 47 (41.6%) completed all three rounds. Response rates to the three rounds were 78/113 (69.0%), 61/76 (81.3%), and 49/64 (76.6%), respectively. The participants included orthoptists (45.4%), occupational therapists (44.3%), and stroke survivors (10.3%). Consensus was reached on 56.5% of items in the three-round process, all for inclusion. A consensus was reached for 83.8% in the categorization of items. The majority (82.6%) of consensus were for relevant to 'all visual impairment following stroke'; two items were deemed 'not relevant'. Conclusion: The lack of item reduction achieved by this Delphi process highlights the need for additional methods of item reduction in the development of a new PROM for visual impairment following stroke. These results will be considered alongside Rasch analysis to achieve further item reduction. However, the Delphi survey remains important as it provides clinical and patient insight into each item rather than purely relying on the psychometric data. PMID- 29484258 TI - Relationship between serum vitamin D levels and inflammatory markers in acute stroke patients. AB - Introduction: Low serum vitamin D levels are associated with the development of poststroke depression (PSD). Inflammatory markers play an important role in pathophysiology of PSD. The relationship between vitamin D levels and inflammatory markers has been discussed in nonstroke individuals. The purposes of this study were to explore the relationship between vitamin D levels and inflammatory markers in acute stroke patients and examine the effect of vitamin D and inflammatory markers on PSD. Methods: A total of 152 acute stroke patients were recruited. Serum levels of 25-hydroxyvitamin D and inflammatory markers were measured by standardized laboratory methods. Depression symptoms were assessed with the 17-item Hamilton Depression Scale (HAMD-17). Patients with the HAMD-17 scores >=7 were identified to have depression symptoms. Results: Serum vitamin D levels were negatively correlated with serum levels of interleukin-6 and high sensitivity C-reactive protein (hsCRP) (r = -.244, p = .002; r = -.231, p = .004). Multiple regression analysis showed that interleukin-6 and hsCRP levels were associated with vitamin D levels (B = -0.355, p = .003; B = -2.085, p = .006), whereas age, height, weight, leukocyte count, neutrophil ratio, and lymphocyte rate could be omitted without changing the results. In multivariate analyses, the serum levels of vitamin D and interleukin-6 were associated with the development of PSD after adjusted possible variables (OR = 0.976, 95% CI: 0.958-0.994, p = .009; OR = 1.029, 95% CI: 1.003-1.055, p = .027). Conclusions: Serum vitamin D levels are inversely associated with the levels of interleukin-6 and hsCRP, suggesting a potential anti-inflammatory role for vitamin D in stroke individuals. PMID- 29484261 TI - Validation of intracranial hemorrhage in the Norwegian Patient Registry. AB - Objectives: Administrative health registries need to have accurate diagnoses and sufficient coverage in the population they serve in order to be useful in research. In this study, we investigated the proportion of discharge diagnoses of intracranial hemorrhage (ICH) that were coded correctly in the Norwegian Patient Registry (NPR). Materials and Methods: We reviewed the electronic medical records and diagnostic imaging of all admissions to St. Olavs University Hospital, Trondheim, Norway, between January 1, 2008, to December 31, 2014, with a discharge diagnosis of ICH in the NPR, and estimated positive predictive values (PPVs) for primary and secondary diagnoses. Separate calculations were made for inpatient and outpatient admissions. Results: In total, 1,419 patients with 1,458 discharge diagnoses of ICH were included in our study. Overall, 1,333 (91.4%) discharge diagnoses were coded correctly. For inpatient admissions, the PPVs for primary discharge codes were 96.9% for hemorrhagic stroke, 95.3% for subarachnoid hemorrhage, and 97.9% for subdural hemorrhage. The most common cause of incorrect diagnosis was previous stroke that should have been coded as rehabilitation or sequela after stroke. There were more false-positive diagnoses among outpatient consultations and secondary diagnoses. Conclusion: Coding of ICH discharge diagnoses in the NPR is of high quality, showing that data from this registry can safely be used for medical research. PMID- 29484262 TI - Cooperate or not cooperate EEG, autonomic, and behavioral correlates of ineffective joint strategies. AB - Introduction: The neural activity in response to ineffective joint actions was explored in the present study. Subjects involved in a cooperative but frustrating task (poor performance as manipulated by an external feedback) were required to cooperate (T1) during an attentional task in a way to synchronize their responses and obtain better outcomes. Methods: We manipulated their strategies by providing false feedbacks (T2) signaling the incapacity to create a synergy, which was reinforced by a general negative evaluation halfway through the game. A control condition was provided (no cooperation required, T0) as well as a check for possible learning effect (time series analysis). The effects of the feedback in modulating subjects' behavioral performance and electrocortical activity were explored by means of brain oscillations (delta, theta, alpha, beta) and autonomic activity (heart rate, HR; skin conductance activity, SCR). Results: Results showed a specific pattern of behavioral, neural, and peripheral responses after the social feedback. In fact, within this condition, worse behavioral outcomes emerged, with longer response times with respect to the prefeedback one. In parallel, a specific right-lateralized effect was observed over the dorsolateral prefrontal cortex (DLPFC), with increased delta and theta power compared to the previous condition. Moreover, increased SCR was observed with respect to the first part. Conclusions: Two interpretations are put forward to explain the present findings: 1) the contribution of negative emotions in response to failing interactions or 2) a motivational disengagement toward goal-oriented cooperation elicited by frustrating evaluations. PMID- 29484263 TI - Neurodegenerative disease biomarkers Abeta1-40, Abeta1-42, tau, and p-tau181 in the vervet monkey cerebrospinal fluid: Relation to normal aging, genetic influences, and cerebral amyloid angiopathy. AB - Background: The Caribbean vervet monkey (Chlorocebus aethiops sabaeus) is a potentially valuable animal model of neurodegenerative disease. However, the trajectory of aging in vervets and its relationship to human disease is incompletely understood. Methods: To characterize biomarkers associated with neurodegeneration, we measured cerebrospinal fluid (CSF) concentrations of Abeta1 40, Abeta1-42, total tau, and p-tau181 in 329 members of a multigenerational pedigree. Linkage and genome-wide association were used to elucidate a genetic contribution to these traits. Results: Abeta1-40 concentrations were significantly correlated with age, brain total surface area, and gray matter thickness. Levels of p-tau181 were associated with cerebral volume and brain total surface area. Among the measured analytes, only CSF Abeta1-40 was heritable. No significant linkage (LOD > 3.3) was found, though suggestive linkage was highlighted on chromosomes 4 and 12. Genome-wide association identified a suggestive locus near the chromosome 4 linkage peak. Conclusions: Overall, these results support the vervet as a non-human primate model of amyloid related neurodegeneration, such as Alzheimer's disease and cerebral amyloid angiopathy, and highlight Abeta1-40 and p-tau181 as potentially valuable biomarkers of these processes. PMID- 29484264 TI - Propranolol can induce PTSD-like memory impairments in rats. AB - Introduction: One hallmark symptom of post-traumatic stress disorder (PTSD) is an inability to restrict fear responses to the appropriate predictor. An infusion of glucocorticoids (GCs) after a high-intensity shock has been shown to induce PTSD like memory impairments. In addition to GCs, noradrenergic signalling is also recognized as a key biomarker underlying PTSD symptomatology. Methods: To explore the role of the noradrenergic system in PTSD-like memory impairments, in this study, various doses of the beta-adrenoceptor antagonist propranolol were systemically or bilaterally injected into the dorsal hippocampus immediately after unpaired cue-shock contextual fear conditioning, and then the rats were tested 24 h later. Results: Interestingly, we found that only low-dose propranolol could induce PTSD-like memory impairments, as rats showed reduced freezing to the correct predictor and generalized fear responses to the safe cues, accompanied by increased NE levels in the hippocampus and altered neural activity within the frontal-subcortical circuit. Conclusion: These findings demonstrate that the noradrenergic system is involved in regulating the consolidation of contextual fear memory and that propranolol can dose-dependently induce PTSD-like memory impairments. PMID- 29484265 TI - Atypical presentation of dopa-responsive dystonia in Taiwan. AB - The typical clinical presentation of dopa-responsive dystonia, which is also called Segawa disease, is a young age of onset, with predominance in females, diurnal fluctuation of lower limb dystonia, and fair response to low-dose levodopa. This disease has both autosomal dominant and autosomal recessive inheritance. Autosomal dominant Segawa disease is caused by GCH1 mutation on chromosome 14q22.1-q22.2. Here, we report the case of a male patient with genetically confirmed Segawa disease and atypical presentations including no diurnal symptom fluctuation and insufficient response to levodopa. The patient's father who had the same mutation presented parkinsonism in old age. We also review the literature to address the broad clinical heterogeneity of Segawa disease and the influence of onset age on clinical presentation. PMID- 29484266 TI - Stress reactivity and pain-mediated stress regulation in remitted patients with borderline personality disorder. AB - Objective: Patients with borderline personality disorder (BPD) use nonsuicidal self-injury (NSSI) to cope with states of elevated inner tension. It is unclear to what extent remitted BPD patients experience these states and whether the experience of pain still regulates emotion. The purpose of this study was the investigation of baseline stress levels, stress reactivity, and pain-mediated stress regulation in remitted BPD patients. Method: Subjective and objective stress parameters were assessed in 30 remitted BPD patients, 30 current BPD patients, and 30 healthy controls. After stress induction, a non-nociceptive tactile stimulus, a tissue-injuring, or a noninvasive pain stimulus was applied to the right volar forearm. Results: Baseline stress levels of remitted BPD patients lie in between the stress levels of current BPD patients and healthy controls. Urge for NSSI increased significantly more in current than remitted BPD patients. The experience of pain led to a greater decrease of arousal in current compared to remitted BPD patients and healthy controls. Conclusions: States of increased tension still seem to appear in remitted BPD patients. The role of pain mediated stress regulation appears to be reduced in remitted patients. PMID- 29484267 TI - POCD in patients receiving total knee replacement under deep vs light anesthesia: A randomized controlled trial. AB - Objectives: Clinical observation, as well as randomized controlled trials, indicated an increasing rate of postoperative cognitive dysfunction (POCD) with increasing depth of general anesthesia. However, the findings are subject to bias due to varying degree of analgesia. In this trial, we compared the rate of POCD between patients receiving light versus high anesthesia while holding analgesia comparable using nerve block. Methods: Elderly patients (?60 years) receiving elective total knee replacement were randomized to receive the surgery under general anesthesia at BIS 40-50 (LOBIS group) or BIS 55-65 (HIBIS group). The femoral nerve and the sciatic nerve were blocked under ultrasonic guidance in all patients before induction. Cognitive performance was assessed with Montreal cognitive assessment (MoCA) at the baseline and 1d, 3d, and 7d after the surgery. POCD was defined by Z score of >1.96 using cross-reference. The extubation time and recovery time were also compared. Results: A total of 66 patients were randomized; 60 (n = 30 per group) completed trial as the protocol specified. POCD occurred in six patients (20%) in the LOBIS group vs. in one patient (3.3%) in the HIBIS group (Figure 3, p = .04). In all seven cases, the diagnosis of POCD was based on MoCA assessment on 1d after the surgery. Assessment in 3d and 7d after surgery did not reveal POCD in any case. Extubation time was longer in the LOBIS group (12.16 +/- 2.58 vs. 5.77 +/- 3.01 min in the HIBIS group (p < .001)). The time of comeback of directional ability was 13.47 +/- 3.14 and 6.17 +/- 3.23 min in the LOBIS and HIBIS groups, respectively (p < .001). Conclusions: In elderly patients receiving a total knee replacement, lighter anesthesia could reduce the rate of POCD with complete analgesia during surgery. PMID- 29484268 TI - Is reappraisal always effective in modifying emotional reactions in females? The role of regulatory timing and goals. AB - Introduction: Numerous studies have explored the effect of cognitive reappraisal before or after emotion-inducing events. However, only a few studies have examined the influence of regulatory timing on the effectiveness of reappraisal. Thus, the aim of this study was to investigate the role of regulatory timing and goals in reappraisal regulation, which would help promote the specific application of cognitive reappraisal in emotion regulation. We hypothesized that decrease reappraisal would be more effective when initiated early rather than late, but increase reappraisal would be more effective when initiated in the emotional high-activation phase. Methods: This study, via event-related potential (ERP) technique, probed the influence of the timing and regulatory goal on negative emotion when reappraisal was introduced, respectively 500 ms before (anticipatory), 2,000 ms after (online 2,000 ms) picture onset (in Experiment 1), 500 ms after (online 500 ms) picture onset, and 1,500 ms after (online 1,500 ms) picture onset (in Experiment 2). Results: Based on the ERP results, under the anticipatory regulation condition, the LPP amplitude in the parietal area was significantly reduced by decrease reappraisal during 700-2,100 ms after picture onset, and under the online 500 ms regulation condition, the LPP in central and parietal areas was significantly enhanced by increase reappraisal during 450-750 ms after regulatory cue onset. Moreover, our results showed that increase reappraisal evoked a larger prefrontal or frontal LPP than decrease reappraisal beginning at about 700 ms after picture onset under the anticipatory regulation condition and beginning at 450 ms after regulatory cue onset under the online 500 ms regulation condition, which may reflect increased cognitive effort and mental conflict associated with increase reappraisal. Conclusion: The anticipatory reappraisal successfully decreased negative emotion, and online 500 ms reappraisal successfully increased negative emotion. Our results support the hypothesis. PMID- 29484269 TI - Altered functional networks in long-term unilateral hearing loss: A connectome analysis. AB - Introduction: In neuroimaging studies, long-term unilateral hearing loss (UHL) is associated with functional changes in specific brain regions and connections; however, little is known regarding alterations in the topological organization of whole-brain functional networks and whether these alterations are related to hearing behavior in UHL patients. Methods: We acquired resting-state fMRI data from 21 patients with UHL caused by acoustic neuromas and 21 matched healthy controls. Whole-brain functional networks were constructed by measuring interregional temporal correlations of 278 brain regions. Alterations in interregional functional connectivity and topological properties (e.g., small world, efficiency, and nodal centrality) were identified using graph-theory analysis. The subjects also completed a battery of hearing behavior measures. Results: Both UHL patients and controls exhibited efficient small-world properties in their functional networks. Compared with controls, UHL patients showed increased and decreased nodal centrality in distributed brain regions. Furthermore, the brain regions with significantly increased and decreased functional connections associated with UHL were components of the following important networks: (1) visual network; (2) higher-order functional networks, including the default-mode and attention networks; and (3) subcortical network and cerebellum. Intriguingly, the changes in intranetwork connections in UHL were significantly correlated with disease duration and hearing level. Conclusions: This study revealed connectome-level alterations involved in multiple large-scale networks related to sensory and higher-level cognitive functions in long-term UHL patients. These reorganizations of the brain in UHL patients may depend on the stage of deafness and hearing level. Together, our findings provided empirical evidence for understanding the neuroplastic mechanisms underlying hearing impairment, establishing potential biomarkers for monitoring the progression and further treatment effects for UHL patients. PMID- 29484270 TI - DLGAP1 and NMDA receptor-associated postsynaptic density protein genes influence executive function in attention deficit hyperactivity disorder. AB - Objective: To explore the association of DLGAP1 gene with executive function (EF) in attention deficit hyperactivity disorder (ADHD) children. Method: A total of 763 ADHD children and 140 healthy controls were enrolled. The difference of EF between ADHD and controls was analyzed using the analysis of covariance (ANCOVA), with IQ, sex, and age as covariates. Both the associations of SNPs with EF and three symptom traits of ADHD were conducted using an additive linear regression model by PLINK with the same covariates as ANCOVA. Results: Compared with controls, children with ADHD showed poorer cognitive flexibility and inhibition. Two SNPs (rs2049161, p-value = 5.08e-7, adjusted p-value = 1.63e-4, rs16946051, p value = 5.18e-7, adjusted p-value = 1.66e-4) survived multiple tests in Trail Making Test. Both SNPs also showed association with TOH (rs2049161, p = 6.82e-4, rs16946051, p = 7.91e-4). Set-based analysis for gene DLGAP1 and its functional pathway DLGAP1-DLG4-NMDA showed they were associated with cognitive flexibility at both gene (p = .0057) and pathway level (p = .0321). Furthermore, the gene and pathway also showed association with ADHD symptom score. The associated SNPs and their LD proxies were related to the expression of DLGAP1 in medulla and frontal cortex. Conclusion: Children with ADHD showed deficit in EF, especially, cognitive flexibility and inhibition. DLGAP1 was associated with cognitive flexibility and plan, and the role of DLGAP1 might be implemented through the complex of DLGAP1-DLG4-NMDA. PMID- 29484272 TI - Curcumin protects neural cells against ischemic injury in N2a cells and mouse brain with ischemic stroke. AB - Background and Purpose: Curcumin, a natural antioxidant isolated from Curcuma longa, has been reported to exert neuroprotective effect in animal models of ischemic stroke. However, the underlying mechanism is still not fully understood. The purpose of this study was to investigate the effect of curcumin treatment on neuronal apoptosis in the periinfarct cortex after cerebral ischemia/reperfusion (I/R) injury and in mouse N2a cells after oxygen-glucose deprivation/reoxygenation (OGD/R) injury and its underlying mechanism. Methods: The cerebral I/R injury was established by 1-hr middle cerebral artery occlusion (MCAO) and reperfusion in mice. Infarct volume was determined by TTC staining, and neurological score was evaluated by mNSS. Cell morphology in the ischemic boundary zone were detected by HE staining. The number and apoptotic rate of neurons in ischemic boundary zone were assayed by immunohistochemistry and TUNEL, respectively. Mouse neuroblastoma N2a cells were subjected to OGD/R. Cell viability was assessed with CCK-8. The mitochondrial membrane potential was measured using JC-1 staining. The expression of Bax, Bcl-2, and caspase-3 was detected using Western blotting. Besides, cellular distribution of Bax was determined by immunofluorescence assays. Results: Curcumin treatment reduced infarct volume, improved neurological function, alleviated the morphological damage of neurons, and increased neuronal survival rate after I/R injury in vivo. Moreover, curcumin treatment improved cell viability, reduced cell apoptosis, increased Bcl-2 protein levels while decreased Bax and caspase-3 expressions in mouse N2a cells after OGD/R injury. Besides, curcumin treatment inhibited Bax activation and maintained mitochondrial membrane integrity. Conclusion: Curcumin promotes neuron survival in vivo and in vitro to exert neuroprotective effects against ischemia injury. Moreover, our results for the first time demonstrated curcumin inhibited ischemia-induced mitochondrial apoptosis via restricting Bax activation, which may be one of the possible mechanisms underlying the neuroprotective effects of curcumin. PMID- 29484273 TI - Home versus hospital immunoglobulin treatment for autoimmune neuropathies: A cost minimization analysis. AB - Background: Prior clinical trials have suggested that home-based Ig treatment in multifocal motor neuropathy (MMN) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and its variant Lewis-Sumner syndrome (LSS) is safe and effective and is less costly than hospital-administered intravenous immunoglobulin (IVIg). Methods: A French prospective, dual-center, cost minimization analysis was carried out to evaluate IVIg administration (5% concentrated) at home versus in hospital with regard to costs, patients' autonomy, and patients' quality of life. The primary endpoint was the overall cost of treatment, and we adopted the perspective of the payer (French Social Health Insurance). Results: Twenty-four patients aged 52.3 (12.2) years were analyzed: nine patients with MMN, eight with CIDP, and seven with LSS. IVIg (g/kg) dosage was 1.51 +/- 0.43 in hospital and 1.52 +/- 0.4 at home. Nine-month total costs per patient extrapolated to 1 year of treatment were ?48,189 +/- 26,105 versus ?91,798 +/- 51,125 in the home and hospital groups, respectively (p < .0001). The most frequently reported factors for choosing home treatment were the good tolerance and absence of side effects of IVIg administration, as well as a good understanding of the advantages and drawbacks of home treatment (75% of respondents). The mRankin scores before and after switch to home treatment were 1.61 +/- 0.72 and 1.36 +/- 0.76, respectively (p = .027). Discussion: The switch from hospital-based to home-based IVIg treatment for patients with immune neuropathy represents potentially significant savings in the management of the disease. PMID- 29484274 TI - Cardiac repolarization during fingolimod treatment in patients with relapsing remitting multiple sclerosis. AB - Background: Fingolimod is a sphingosine-1-phosphate receptor modulator for the treatment of relapsing-remitting multiple sclerosis (RRMS). Despite an established effect on heart rate, the effect of fingolimod on cardiac repolarization is not completely known. Methods: Twenty-seven patients with RRMS underwent 24-hr ambulatory ECG before fingolimod (baseline), at the day of fingolimod initiation (1D) and after three-month treatment (3M). The mean values of RR-interval as well as QT-interval corrected by Bazzet's (QTcBaz) and Fridericia's (QTcFri) formula were compared between baseline, 1D, and 3M over 24 hr period as well as at daytime and nighttime. Results: QTcBaz over 24-hr was shorter at 1D (414 +/- 20 ms, p < .001) and at 3M (414 +/- 20 ms, p < .001) than at baseline (418 +/- 20 ms). In contrast, QTcFri over 24-hr was longer at 1D (410 +/- 19 ms, p < .001) but similar at 3M (406 +/- 19 ms, p = .355) compared to baseline (407 +/- 19 ms). Daytime QTcBaz was shorter at 1D (p < .001) and at 3M (p = .007), whereas daytime QTcFri was longer at 1D (p < .05) but similar at 3M (p = ns) compared to baseline. During the night, changes were observed neither in QTcBaz nor in QTcFri between baseline, 1D, and 3M. Conclusions: Changes in cardiac repolarization after fingolimod initiation were mild and occurred at daytime. Ambiguously, QTcBaz demonstrated shortening, whereas QTcFri showed prolongation in cardiac repolarization after fingolimod initiation. The formula applied for QT-interval correction needs to be taken carefully into account as evaluating pharmacovigilance issues related to fingolimod. PMID- 29484271 TI - Maternal hormonal milieu influence on fetal brain development. AB - An adverse maternal hormonal environment during pregnancy can be associated with abnormal brain growth. Subtle changes in fetal brain development have been observed even for maternal hormone levels within the currently accepted physiologic ranges. In this review, we provide an update of the research data on maternal hormonal impact on fetal neurodevelopment, giving particular emphasis to thyroid hormones and glucocorticoids. Thyroid hormones are required for normal brain development. Despite serum TSH appearing to be the most accurate indicator of thyroid function in pregnancy, maternal serum free T4 levels in the first trimester of pregnancy are the major determinant of postnatal psychomotor development. Even a transient period of maternal hypothyroxinemia at the beginning of neurogenesis can confer a higher risk of expressive language and nonverbal cognitive delays in offspring. Nevertheless, most recent clinical guidelines advocate for targeted high-risk case finding during first trimester of pregnancy despite universal thyroid function screening. Corticosteroids are determinant in suppressing cell proliferation and stimulating terminal differentiation, a fundamental switch for the maturation of fetal organs. Not surprisingly, intrauterine exposure to stress or high levels of glucocorticoids, endogenous or synthetic, has a molecular and structural impact on brain development and appears to impair cognition and increase anxiety and reactivity to stress. Limbic regions, such as hippocampus and amygdala, are particularly sensitive. Repeated doses of prenatal corticosteroids seem to have short-term benefits of less respiratory distress and fewer serious health problems in offspring. Nevertheless, neurodevelopmental growth in later childhood and adulthood needs further clarification. Future studies should address the relevance of monitoring the level of thyroid hormones and corticosteroids during pregnancy in the risk stratification for impaired postnatal neurodevelopment. PMID- 29484275 TI - THRIVE-c score predicts clinical outcomes in Chinese patients after thrombolysis. AB - Objectives: Total Health Risks in Vascular Events-calculation score (THRIVE-c) is an easy use and patient-specific outcome predictive score by computing the logistic equation with patients' continuous variables. We validated its performance in Chinese ischemic stroke patients receiving intravenous thrombolysis (IVT) therapy. Materials and Methods: We used data from the Thrombolysis Implementation and Monitor of Acute Ischemic Stroke in China (TIMS China) registry to validate the THRIVE-c score in patients receiving IVT therapy. We evaluated the score performance using area under the receiver operating characteristic curve (AUC). Receiver operator characteristic curve (ROC) was used to compare THRIVE-c score performance with other scores in predicting clinical outcome and symptomatic intracranial hemorrhage (SICH). Calibration was assessed by Pearson correlation coefficient and Hosmer-Lemeshow test. Results: Among the 1,128 patients receiving IVT therapy included in this study, AUC of the THRIVE-c score for 3-month SICH, poor functional outcome, and mortality rate was 0.70 (95% CI: 0.63-0.76), 0.75 (95% CI: 0.73-0.78) and 0.81 (95% CI: 0.77-0.85), respectively. The increased THRIVE-c score was associated with higher risk of developing SICH, poor functional outcome, or mortality in patients with acute ischemic stroke at 3 months after thrombolysis. The performance of the THRIVE-c score was similar to or superior to other predictive scores (THRIVE score, SEDAN score, DRAGON score, HIAT2 score). Conclusions: The THRIVE-c score reliably predicts the risks of 3-month SICH, poor functional outcome, and mortality after IVT therapy in Chinese patients with ischemic stroke. PMID- 29484276 TI - Potential added value of a RT-qPCR method of SOX 11 expression, in the context of a multidisciplinary diagnostic assessment of B cell malignancies. AB - Background: Expression of SRY [sex-determining region Y]-box11 (SOX11) is specific to mantle cell lymphoma (MCL) and contributes, in conjunction with immunoglobulin variable heavy chain gene mutation status, to the identification of two forms of this disease. Methods: The aim of this report was firstly, to design an easy and suitable RT-qPCR method to quantify SOX11 mRNA expression in mantle cell lymphoma and other B cell malignancies with the proper reference gene; secondly, to define the best threshold of relative quantity of SOX11 mRNA in order to reach the best compromise between sensitivity and specificity. Results: For best discrimination of MCL and non-MCL groups we determined an area under the curve (AUC) of 0.9750 and a threshold of 1.76 with 100% sensitivity and 88% specificity. AUC and threshold values of respectively 0.91/1.346 [87% sensitivity, 80% specificity] and 0.9525/1.7120 [100% sensitivity, 88% specificity] for GAPDH and RPLP0 respectively denote that the RPLP0 reference gene alone is sufficient for PCR housekeeping gene. Conclusion: This work describes an RT-qPCR assay for SOX11 expression in order to better characterize MCL at diagnosis. Further studies on larger cohorts are needed to evaluate this molecular tool, especially for the follow-up of minimal residual disease. PMID- 29484277 TI - World market and biotechnological production of itaconic acid. AB - The itaconic acid (IA) world market is expected to exceed 216 million of dollars by 2020 as a result of an increasing demand for bio-based chemicals. The potential of this organic acid produced by fermentation mainly with filamentous fungi relies on the vast industrial applications of polymers derived from it. The applications may be as a superabsorbent polymer for personal care or agriculture, unsaturated polyester resin for the transportation industry, poly(methyl methacrylate) for electronic devices, among many others. However, the existence of other substitutes and the high production cost limit the current IA market. IA manufacturing is done mainly in China and other Asia-Pacific countries. Higher economic feasibility and production worldwide may be achieved with the use of low cost feedstock of local origin and with the development of applications targeted to specific local markets. Moreover, research on the biological pathway for IA synthesis and the effect of medium composition are important for amplifying the knowledge about the production of that biochemical with great market potential. PMID- 29484278 TI - Simple isolation and characterization of seminal plasma extracellular vesicle and its total RNA in an academic lab. AB - Extracellular vesicles (EVs) are small membrane-bound sacs, identified in many body fluids of humans. Standard extracellular vesicle separation methods such as differential and ultracentrifugation are very expensive, not affordable in academic labs. So, the current research tried to isolate seminal plasma EVs using polyethylene glycol (PEG) precipitation process. Normospermia semen from "Milann The Fertility Center" processed to isolate EVs by PEG method. Nanodrop spectrophotometer showed presence of EVs by indirectly measuring protein content of precipitated EVs. EVs isolated by PEG precipitation showed a wide size range from 30 to 1000 nm with Z average of 75.4 nm and a PI of 0.464, whereas ultracentrifuge sample showed size range of 60-1000 nm with Z average of 501.3 nm with a PI of 0.692. Edax analysis also showed good elemental pattern. Total RNA extraction from PEG EVs analysed with nanodrop spectrophotometer, showed presence of RNA content in varying concentrations obtained from different ratios in nanograms. Thus, the current study concludes that seminal plasma EVs isolated by PEG precipitation is simple, reproducible and non-sensitive to carry out at academic labs. PMID- 29484279 TI - Construction of chloroplast transformation vector and its functional evaluation in Momordica charantia L. AB - Chloroplast transformation vectors require an expression cassette flanked by homologous plastid sequences to drive plastome recombination. The rrn16-rrn23 plastome region was selected and using this region, a new species-specific plastid transformation vector CuIA was developed with pKS+II as a backbone by inserting the rrn16-trnI and trnA-rrn23 sequences from Cucumis sativus L. An independent expression cassette with aadA gene encoding aminoglycoside 3' adenylyltransferase with psbA controlling elements is added into the trnI-trnA intergenic region that confers resistance to spectinomycin. An efficient plastid transformation in bitter melon (Momordica charantia L.) was achieved by bombardment of petiole segments. The frequency of transplastomic plants yielded using standardized biolistic parameters with CuIA vector was two per 15 bombarded plates, each containing 20 petiole explants. Integration of aadA gene was verified by PCR analysis in transplastomes. Transplastomic technology developed may be a novel approach for high level expression of pharmaceutical traits. PMID- 29484280 TI - Effect of nanozeolite and plant growth promoting rhizobacteria on maize. AB - Plant growth promoting rhizobacteria are key to soil and plant health maintenance. In the present study, two PGPR strains which were identified as Bacillus spp. (accession number KX650178 and KX650179) with nanozeolite (50 ppm) were applied to the seeds in different combinations and tested on growth profile of maize crop. Various growth related parameters, including plant height, leaf area, number of leaves chlorophyll and total protein were positively increased up to twofold by the nanocompound treatment. GC-MS results reveal increase in total phenolic and acid ester compounds after the treatment of nanozeolite and PGPR, which are responsible for stress tolerance mechanism. Soil physicochemical parameters (organic carbon, phosphorous, potassium, ammoniacal nitrogen and nitrate nitrogen) were assessed qualitatively and a shift towards higher amount was observed. Various biochemical parameters of soil health like dehydrogenase, fluorescein diacetate hydrolysis and alkaline phosphatase activity were significantly enhanced up to threefold with the application of different treatments. The results, for the first time, demonstrate successful use of nanozeolite in enhancing growth of Zea mays, under controlled conditions and present a viable alternative to GM crop for ensuring food security. PMID- 29484281 TI - Energy assessment of second generation (2G) ethanol production from wheat straw in Indian scenario. AB - Impact of second-generation ethanol (2G) use in transportation sector mainly depends upon energy efficiency of entire production process. The objective of present study was to determine energy efficiency of a potential lignocellulosic feedstock; wheat straw and its conversion into cellulosic ethanol in Indian scenario. Energy efficiency was determined by calculating Net energy ratio (NER), i.e. ratio of output energy obtained by ethanol and input energy used in ethanol production. Energy consumption and generation at each step is calculated briefly (11,837.35 MJ/ha during Indian dwarf irrigated variety of wheat crop production and 7.1148 MJ/kg straw during ethanol production stage). Total energy consumption is calculated as 8.2988 MJ/kg straw whereas energy generation from ethanol is 15.082 MJ/kg straw; resulting into NER > 1. Major portion of agricultural energy input is contributed by diesel and fertilisers whereas refining process of wheat straw feedstock to ethanol and by-products require mainly in the form of steam and electricity. On an average, 1671.8 kg water free ethanol, 930 kg lignin rich biomass (for combustion), and 561 kg C5-molasses (for fodder) per hectare are produced. Findings of this study, net energy ratio (1.81) and figure of merit (14.8028 MJ/nil kg carbon) proves wheat straw as highest energy efficient lignocellulosic feedstock for the country. PMID- 29484282 TI - Genetic diversity in the candidate trees of Madhuca indica J. F. Gmel. (Mahua) revealed by inter-simple sequence repeats (ISSRs). AB - Madhuca indica provides livelihood to several tribal people in India, where the flowers are used for extraction of sweet juices having multiple applications. Certain trees have more value as judged by the tribal people mainly based on yield and quality performance of the trees, and these trees were selected for the genetic diversity analyses. Genetic diversity of 48 candidate Mahua trees from Etapalli, Dadagaon, and Jawhar, Maharashtra, India, was assessed using ISSR markers. Fourteen ISSR primers revealed a total of 132 polymorphic bands giving overall 92% polymorphism. Genetic diversity, in terms of expected number of alleles (Ne), the observed number of alleles (Na), Nei's genetic diversity (H), and Shannon's information index (I) was 1.921, 1.333, 0.211, and 0.337, respectively, and suggested lower genetic diversity. Region wise analysis revealed higher genetic diversity for site Etapalli (H = 0.206) and lowest at Dhadgaon (H = 0.140). Etapalli area possesses higher forest cover than Dhadgaon and Jawhar. Additionally, in Dhadgaon and Jawhar M. indica trees are restricted to field bunds; both reasons might contribute to lower genetic diversity in these regions. The dendrogram and the principal coordinate analyses showed no region specific clustering. The clustering patterns were supported by AMOVA where higher genetic variance was observed within trees and lower variance among regions. Long distance dispersal and/or higher human interference might be responsible for low diversity and higher genetic variance within the candidate trees. PMID- 29484283 TI - Comparison of relative efficiency of genomic SSR and EST-SSR markers in estimating genetic diversity in sugarcane. AB - Twenty-five primer pairs developed from genomic simple sequence repeats (SSR) were compared with 25 expressed sequence tags (EST) SSRs to evaluate the efficiency of these two sets of primers using 59 sugarcane genetic stocks. The mean polymorphism information content (PIC) of genomic SSR was higher (0.72) compared to the PIC value recorded by EST-SSR marker (0.62). The relatively low level of polymorphism in EST-SSR markers may be due to the location of these markers in more conserved and expressed sequences compared to genomic sequences which are spread throughout the genome. Dendrogram based on the genomic SSR and EST-SSR marker data showed differences in grouping of genotypes. A total of 59 sugarcane accessions were grouped into 6 and 4 clusters using genomic SSR and EST SSR, respectively. The highly efficient genomic SSR could subcluster the genotypes of some of the clusters formed by EST-SSR markers. The difference in dendrogram observed was probably due to the variation in number of markers produced by genomic SSR and EST-SSR and different portion of genome amplified by both the markers. The combined dendrogram (genomic SSR and EST-SSR) more clearly showed the genetic relationship among the sugarcane genotypes by forming four clusters. The mean genetic similarity (GS) value obtained using EST-SSR among 59 sugarcane accessions was 0.70, whereas the mean GS obtained using genomic SSR was 0.63. Although relatively lower level of polymorphism was displayed by the EST SSR markers, genetic diversity shown by the EST-SSR was found to be promising as they were functional marker. High level of PIC and low genetic similarity values of genomic SSR may be more useful in DNA fingerprinting, selection of true hybrids, identification of variety specific markers and genetic diversity analysis. Identification of diverse parents based on cluster analysis can be effectively done with EST-SSR as the genetic similarity estimates are based on functional attributes related to morphological/agronomical traits. PMID- 29484284 TI - Correction to: Extraction and bioactive profile of the compounds produced by Rhodococcus sp. VLD-10. AB - [This corrects the article DOI: 10.1007/s13205-016-0576-6.]. PMID- 29484285 TI - Utility of Glioblastoma Patient-Derived Orthotopic Xenografts in Drug Discovery and Personalized Therapy. AB - Despite substantial effort and resources dedicated to drug discovery and development, new anticancer agents often fail in clinical trials. Among many reasons, the lack of reliable predictive preclinical cancer models is a fundamental one. For decades, immortalized cancer cell cultures have been used to lay the groundwork for cancer biology and the quest for therapeutic responses. However, cell lines do not usually recapitulate cancer heterogeneity or reveal therapeutic resistance cues. With the rapidly evolving exploration of cancer "omics," the scientific community is increasingly investigating whether the employment of short-term patient-derived tumor cell cultures (two- and three dimensional) and/or patient-derived xenograft models might provide a more representative delineation of the cancer core and its therapeutic response. Patient-derived cancer models allow the integration of genomic with drug sensitivity data on a personalized basis and currently represent the ultimate approach for preclinical drug development and biomarker discovery. The proper use of these patient-derived cancer models might soon influence clinical outcomes and allow the implementation of tailored personalized therapy. When assessing drug efficacy for the treatment of glioblastoma multiforme (GBM), currently, the most reliable models are generated through direct injection of patient-derived cells or more frequently the isolation of glioblastoma cells endowed with stem-like features and orthotopically injecting these cells into the cerebrum of immunodeficient mice. Herein, we present the key strengths, weaknesses, and potential applications of cell- and animal-based models of GBM, highlighting our experience with the glioblastoma stem-like patient cell-derived xenograft model and its utility in drug discovery. PMID- 29484287 TI - Long-term Non-Invasive Ventilation in Infants: A Systematic Review and Meta Analysis. AB - Background: The use of long-term non-invasive ventilation (NIV) to treat sleep and breathing disorders in children has increased substantially in the last decade; however, less data exist about its use in infants. Given that infants have distinct sleep and breathing patterns when compared to older children, the outcomes of infants on long-term NIV may differ as well. The aim of this study is to systematically review the use and outcomes of long-term NIV in infants. Methods: Ovid Medline, Ovid Embase, CINAHL (via EbscoHOST), PubMed, and Wiley Cochrane Library were systematically searched from January 1990 to July 2017. Studies on infants using long-term NIV outside of an acute care setting were included. Data were extracted on study design, population characteristics, and NIV outcomes. Results: A total of 327 studies were full-text reviewed, with final inclusion of 60. Studies were distributed across airway (40%), neuromuscular (28%), central nervous system (10%), cardio-respiratory (2%), and multiple (20%) disease categories. Of the 18 airway studies reporting on NIV outcomes, 13 (72%) reported improvements in respiratory parameters. Of the 12 neuromuscular studies exclusively on spinal muscular atrophy type 1 (SMA1), six (50%) reported decreased hospitalizations and nine (75%) reported on mortality outcomes. Risk of bias was moderate to serious, and quality of the evidence was low to very low for all studies. Most studies had an observational design with no control group, limiting the potential for a meta-analysis. Conclusion: The outcomes reported in studies differed by the disease category being studied. Studies on airway conditions showed improvements in respiratory parameters for infants using NIV. Studies on neuromuscular disorder, which were almost exclusively on SMA1, reported decreased hospitalizations and prolonged survival. Overall, it appears that NIV is an effective long-term therapy for infants. However, the high risk of bias and low quality of the available evidence limited strong conclusions. PMID- 29484288 TI - Ventilation Strategies during Neonatal Cardiopulmonary Resuscitation. AB - Approximately, 10-20% of newborns require breathing assistance at birth, which remains the cornerstone of neonatal resuscitation. Fortunately, the need for chest compression (CC) or medications in the delivery room (DR) is rare. About 0.1% of term infants and up to 15% of preterm infants receive these interventions, this will result in approximately one million newborn deaths annually worldwide. In addition, CC or medications (epinephrine) are more frequent in the preterm population (~15%) due to birth asphyxia. A recent study reported that only 6 per 10,000 infants received epinephrine in the DR. Further, the study reported that infants receiving epinephrine during resuscitation had a high incidence of mortality (41%) and short-term neurologic morbidity (57% hypoxic-ischemic encephalopathy and seizures). A recent review of newborns who received prolonged CC and epinephrine but had no signs of life at 10 min following birth noted 83% mortality, with 93% of survivors suffering moderate-to severe disability. The poor prognosis associated with receiving CC alone or with medications in the DR raises questions as to whether improved cardiopulmonary resuscitation methods specifically tailored to the newborn could improve outcomes. PMID- 29484289 TI - Neonatal Safety of Elective Family-Centered Caesarean Sections: A Cohort Study. AB - Background: Although little data are available concerning safety for newborns, family-centered caesarean sections (FCS) are increasingly implemented. With FCS mothers can see the delivery of their baby, followed by direct skin-to-skin contact. We evaluated the safety for newborns born with FCS in the Leiden University Medical Center (LUMC), where FCS was implemented in June 2014 for singleton pregnancies with a gestational age (GA) >=38 weeks and without increased risks for respiratory morbidity. Methods: The incidence of respiratory pathology, unplanned admission, and hypothermia in infants born after FCS in LUMC were retrospectively reviewed and compared with a historical cohort of standard elective cesarean sections (CS). Results: From June 2014 to November 2015, 92 FCS were performed and compared to 71 standard CS in 2013. Incidence of respiratory morbidity, hypothermia, temperatures at arrival at the department, GA, and birth weight were comparable (ns). Unplanned admission occurred more often after FCS when compared to standard CS (21 vs 7%; p = 0.03), probably due to peripheral oxygen saturation (SpO2) monitoring. There was no increase in respiratory pathology (8 vs 6%, ns). One-third of the babies were separated from their mother during or after FCS. Conclusion: Unplanned neonatal admissions after elective CS increased after implementing FCS, without an increase in respiratory morbidity or hypothermia. SpO2 monitoring might have a contribution. Separation from the mother occurred often. PMID- 29484290 TI - Association of Picky Eating with Growth, Nutritional Status, Development, Physical Activity, and Health in Preschool Children. AB - Background: This study aimed to assess the prevalence of picky eating among preschool children and to evaluate the association between eating behavior and growth, physical activity, development, and health status. Methods: A structured questionnaire was used to conduct a cross-sectional descriptive study of 300 primary caregivers of children aged 2-4 years in Taiwan. Data collected included: demographics, food preferences, eating behavior, body weight, and height, development, physical activity, and records of medical illness. Data from children defined as picky or non-picky eaters based on parental' questionnaire responses were analyzed and compared using standard statistical tests. Results: The mean age of the children was 2.95 years; 162 (54%) were picky eaters. Compared with non-picky eaters, z-score of weight-for-age, height-for-age, and body mass index (BMI)-for-age in picky eaters was 0.91, 0.73, and 0.44 SD lower, respectively. There were significant differences of rates in the weight-for-age, height-for-age, and BMI-for-age percentiles <15, between picky and non-picky eaters (P = 0.04, 0.023, and 0.005, respectively). Fear of unfamiliar places, poor physical activity, constipation, and high frequency (>2 times in the past 3 months) of medical illness were significantly higher in picky eaters (P = 0.01, 0.001, 0.044, and <0.001, respectively). Conclusion: The prevalence of picky eaters in preschool children was high, resulting in significant detrimental impacts on growth, nutritional status, development, physical activity, and health status. PMID- 29484291 TI - Ethical and Legal Considerations in Biometric Data Usage-Bulgarian Perspective. AB - Ethical and legal considerations with regards to biometric data usage are directly related to the right to protection of personal data, which is part of the rights protected under the European Convention of human rights. Specific protection is required to the process and use of sensitive data which reveals certain personal characteristic and is related to the health status of individuals. Biometric data and information on individual upon which people could be identified based on specifics and distinguishing signs. Bulgaria, as a country progressing in terms of integration of digital technologies and as a European Union member state has adopted international and universal legal instruments related on the procession and use of digital data and data protection. On legislative and ethical grounds, it has been established the particular importance of not violating human rights and individual freedoms when processing and using personal data. It has been noted that the processing of special categories of personal data may be necessary for reasons of public interest in the field of public health and that is why under such circumstances it has been permitted the procession to be carried on without the consent of the data subject. Lack of transparency and lawfulness of the processing of personal data could lead to physical, tangible, or intangible damages where processing could lead to discrimination, identity theft, or identity fraud as a result of which may be significant adverse economic or social consequences. Increasingly, widespread use of biometrics in the implementation of medical activities requires the application of a new approach in terms of awareness regarding existing risks to the rights, ethics, and freedoms of all of us, as a user of medical service. PMID- 29484286 TI - Multifaceted Role of the Urokinase-Type Plasminogen Activator (uPA) and Its Receptor (uPAR): Diagnostic, Prognostic, and Therapeutic Applications. AB - The plasminogen activator (PA) system is an extracellular proteolytic enzyme system associated with various physiological and pathophysiological processes. A large body of evidence support that among the various components of the PA system, urokinase-type plasminogen activator (uPA), its receptor (uPAR), and plasminogen activator inhibitor-1 and -2 (PAI-1 and PAI-2) play a major role in tumor progression and metastasis. The binding of uPA with uPAR is instrumental for the activation of plasminogen to plasmin, which in turn initiates a series of proteolytic cascade to degrade the components of the extracellular matrix, and thereby, cause tumor cell migration from the primary site of origin to a distant secondary organ. The components of the PA system show altered expression patterns in several common malignancies, which have identified them as ideal diagnostic, prognostic, and therapeutic targets to reduce cancer-associated morbidity and mortality. This review summarizes the various components of the PA system and focuses on the role of uPA-uPAR in different biological processes especially in the context of malignancy. We also discuss the current state of knowledge of uPA uPAR-targeted diagnostic and therapeutic strategies for various malignancies. PMID- 29484292 TI - Aqueous Binder Enhanced High-Performance GeP5 Anode for Lithium-Ion Batteries. AB - GeP5 is a recently reported new anode material for lithium ion batteries (LIBs), it holds a large theoretical capacity about 2300 mAh g-1, and a high rate capability due to its bi-active components and superior conductivity. However, it undergoes a large volume change during its electrochemical alloying and de alloying with Li, a suitable binder is necessary to stable the electrode integrity for improving cycle performance. In this work, we tried to apply aqueous binders LiPAA and NaCMC to GeP5 anode, and compared the difference in electrochemical performance between them and traditional binder PVDF. As can be seen from the test result, GeP5 can keep stable in both common organic solvents and proton solvents such as water and alcohol solvents, it meets the application requirements of aqueous binders. The electrochemistry results show that the use of LiPAA binder can significantly improve the initial Coulombic efficiency, reversible capacity, and cyclability of GeP5 anode as compared to the electrodes based on NaCMC and PVDF binders. The enhanced electrochemical performance of GeP5 electrode with LiPAA binder can be ascribed to the unique high strength long chain polymer structure of LiPAA, which also provide numerous uniform distributed carboxyl groups to form strong ester groups with active materials and copper current collector. Benefit from that, the GeP5 electrode with LiPAA can also exhibit excellent rate capability, and even at low temperature, it still shows attractive electrochemical performance. PMID- 29484293 TI - Five Days Granulocyte Colony-Stimulating Factor Treatment Increases Bone Formation and Reduces Gap Size of a Rat Segmental Bone Defect: A Pilot Study. AB - Bone is an organ with high natural regenerative capacity and most fractures heal spontaneously when appropriate fracture fixation is provided. However, additional treatment is required for patients with large segmental defects exceeding the endogenous healing potential and for patients suffering from fracture non-unions. These cases are often associated with insufficient vascularization. Transplantation of CD34+ endothelial progenitor cells (EPCs) has been successfully applied to promote neovascularization of bone defects, however including extensive ex vivo manipulation of cells. Here, we hypothesized, that treatment with granulocyte colony-stimulating factor (G-CSF) may improve bone healing by mobilization of CD34+ progenitor cells into the circulation, which in turn may facilitate vascularization at the defect site. In this pilot study, we aimed to characterize the different cell populations mobilized by G-CSF and investigate the influence of cell mobilization on the healing of a critical size femoral defect in rats. Cell mobilization was investigated by flow cytometry at different time points after five consecutive daily G-CSF injections. In a pilot study, bone healing of a 4.5-mm critical femoral defect in F344 rats was compared between a saline-treated control group and a G-CSF treatment group. In vivo microcomputed tomography and histology were applied to compare bone formation in both treatment groups. Our data revealed that leukocyte counts show a peak increase at the first day after the last G-CSF injection. In addition, we found that CD34+ progenitor cells, including EPCs, were significantly enriched at day 1, and further increased at day 5 and day 11. Upregulation of monocytes, granulocytes and macrophages peaked at day 1. G-CSF treatment significantly increased bone volume and bone density in the defect, which was confirmed by histology. Our data show that different cell populations are mobilized by G-CSF treatment in cell specific patterns. Although in this pilot study no bridging of the critical defect was observed, significantly improved bone formation by G-CSF treatment was clearly shown. PMID- 29484294 TI - Formic Acid Formation by Clostridium ljungdahlii at Elevated Pressures of Carbon Dioxide and Hydrogen. AB - Low productivities of bioprocesses using gaseous carbon and energy sources are usually caused by the low solubility of those gases (e.g., H2 and CO). It has been suggested that increasing the partial pressure of those gases will result in higher dissolved concentrations and should, therefore, be helpful to overcome this obstacle. Investigations of the late 1980s with mixtures of hydrogen and carbon monoxide showed inhibitory effects of carbon monoxide partial pressures above 0.8 bar. Avoiding any effects of carbon monoxide, we investigate growth and product formation of Clostridium ljungdahlii at absolute process pressures of 1, 4, and 7 bar in batch stirred tank reactor cultivations with carbon dioxide and hydrogen as sole gaseous carbon and energy source. With increasing process pressure, the product spectrum shifts from mainly acetic acid and ethanol to almost only formic acid at a total system pressure of 7 bar. On the other hand, no significant changes in overall product yield can be observed. By keeping the amount of substance flow rate constant instead of the volumetric gas feed rate when increasing the process pressure, we increased the overall product yield of 7.5 times of what has been previously reported in the literature. After 90 h of cultivation at a total pressure of 7 bar a total of 4 g L-1 of products is produced consisting of 82.7 % formic acid, 15.6 % acetic acid, and 1.7 % ethanol. PMID- 29484296 TI - Quantification of Wine Mixtures with an Electronic Nose and a Human Panel. AB - In this work, an electronic nose and a human panel were used for the quantification of wines formed by binary mixtures of four white grape varieties and two varieties of red wines at different percentages (from 0 to 100% in 10% steps for the electronic nose and from 0 to 100% in 25% steps for the human panel). The wines were prepared using the traditional method with commercial yeasts. Both techniques were able to quantify the mixtures tested, but it is important to note that the technology of the electronic nose is faster, simpler, and more objective than the human panel. In addition, better results of quantification were also obtained using the electronic nose. PMID- 29484295 TI - Biology of Vascular Endothelial Growth Factor C in the Morphogenesis of Lymphatic Vessels. AB - Because virtually all tissues contain blood vessels, the importance of hemevascularization has been long recognized in regenerative medicine and tissue engineering. However, the lymphatic vasculature has only recently become a subject of interest. Central to the task of growing a lymphatic network are lymphatic endothelial cells (LECs), which constitute the innermost layer of all lymphatic vessels. The central molecule that directs proliferation and migration of LECs during embryogenesis is vascular endothelial growth factor C (VEGF-C). VEGF-C is therefore an important ingredient for LEC culture and attempts to (re)generate lymphatic vessels and networks. During its biosynthesis VEGF-C undergoes a stepwise proteolytic processing, during which its properties and affinities for its interaction partners change. Many of these fundamental aspects of VEGF-C biosynthesis have only recently been uncovered. So far, most-if not all applications of VEGF-C do not discriminate between different forms of VEGF-C. However, for lymphatic regeneration and engineering purposes, it appears mandatory to understand these differences, since they relate, e.g., to important aspects such as biodistribution and receptor activation potential. In this review, we discuss the molecular biology of VEGF-C as it relates to the growth of LECs and lymphatic vessels. However, the properties of VEGF-C are similarly relevant for the cardiovascular system, since both old and recent data show that VEGF-C can have a profound effect on the blood vasculature. PMID- 29484297 TI - IgE-Selective Immunoadsorption for Severe Atopic Dermatitis. AB - Introduction: Recent reports proposed the application of immunoadsorption (IA) for patients with recalcitrant atopic dermatitis (AD) and high-serum IgE levels. However, experience with this novel treatment approach, especially with the newly available IgE-specific adsorber, is limited and recommendation for its use in clinical practice awaits evidence from more studies. Materials and methods: Patients with severe AD (SCORAD >= 60) and total serum IgE levels >=750 kU/L were included in this study. The treatment protocol consisted of two cycles of five consecutive treatments with IgE-selective IA 3 weeks apart. Results: Ten patients were enrolled and four patients completed the study. The mean SCORAD was significantly improved by up to 43% within a few weeks and until the end of a 6 month follow-up period, with 50% of patients achieving an at least 50% individual reduction of the baseline SCORAD. Each IA cycle induced a temporal average decrement of total serum levels of IgE, IgM, IgA, and IgG by 92, 43, 38, and 35%, respectively. Except for one case of Staphylococcus aureus septicemia, no major adverse events occurred. Conclusion: Although limited by a considerable withdrawal rate, our observations strengthen our and other recent results further suggesting that IgE-selective IA is an effective treatment option for patients severely affected by AD with highly elevated IgE levels. PMID- 29484298 TI - Improved Exercise Tolerance with Caffeine Is Associated with Modulation of both Peripheral and Central Neural Processes in Human Participants. AB - Background: Caffeine has been shown to enhance exercise performance and capacity. The mechanisms remain unclear but are suggested to relate to adenosine receptor antagonism, resulting in increased central motor drive, reduced perception of effort, and altered peripheral processes such as enhanced calcium handling and extracellular potassium regulation. Our aims were to investigate how caffeine (i) affects knee extensor PCr kinetics and pH during repeated sets of single-leg knee extensor exercise to task failure and (ii) modulates the interplay between central and peripheral neural processes. We hypothesized that the caffeine induced extension of exercise capacity during repeated sets of exercise would occur despite greater disturbance of the muscle milieu due to enhanced peripheral and corticospinal excitatory output, central motor drive, and muscle contractility. Methods: Nine healthy active young men performed five sets of intense single-leg knee extensor exercise to task failure on four separate occasions: for two visits (6 mg.kg-1 caffeine vs placebo), quadriceps 31P magnetic resonance spectroscopy scans were performed to quantify phosphocreatine kinetics and pH, and for the remaining two visits (6 mg.kg-1 caffeine vs placebo), femoral nerve electrical and transcranial magnetic stimulation of the quadriceps cortical motor area were applied pre- and post exercise. Results: The total exercise time was 17.9 +/- 6.0% longer in the caffeine (1,225 +/- 86 s) than in the placebo trial (1,049 +/- 73 s, p = 0.016), and muscle phosphocreatine concentration and pH (p < 0.05) were significantly lower in the latter sets of exercise after caffeine ingestion. Voluntary activation (VA) (peripheral, p = 0.007; but not supraspinal, p = 0.074), motor-evoked potential (MEP) amplitude (p = 0.007), and contractility (contraction time, p = 0.009; and relaxation rate, p = 0.003) were significantly higher after caffeine consumption, but at task failure MEP amplitude and VA were not different from placebo. Caffeine prevented the reduction in M-wave amplitude that occurred at task failure (p = 0.039). Conclusion: Caffeine supplementation improved high-intensity exercise tolerance despite greater-end exercise knee extensor phosphocreatine depletion and H+ accumulation. Caffeine-induced increases in central motor drive and corticospinal excitability were attenuated at task failure. This may have been induced by the afferent feedback of the greater disturbance of the muscle milieu, resulting in a stronger inhibitory input to the spinal and supraspinal motor neurons. However, causality needs to be established through further experiments. PMID- 29484299 TI - Alternative Splicing in Neurogenesis and Brain Development. AB - Alternative splicing of precursor mRNA is an important mechanism that increases transcriptomic and proteomic diversity and also post-transcriptionally regulates mRNA levels. Alternative splicing occurs at high frequency in brain tissues and contributes to every step of nervous system development, including cell-fate decisions, neuronal migration, axon guidance, and synaptogenesis. Genetic manipulation and RNA sequencing have provided insights into the molecular mechanisms underlying the effects of alternative splicing in stem cell self renewal and neuronal fate specification. Timely expression and perhaps post translational modification of neuron-specific splicing regulators play important roles in neuronal development. Alternative splicing of many key transcription regulators or epigenetic factors reprograms the transcriptome and hence contributes to stem cell fate determination. During neuronal differentiation, alternative splicing also modulates signaling activity, centriolar dynamics, and metabolic pathways. Moreover, alternative splicing impacts cortical lamination and neuronal development and function. In this review, we focus on recent progress toward understanding the contributions of alternative splicing to neurogenesis and brain development, which has shed light on how splicing defects may cause brain disorders and diseases. PMID- 29484300 TI - Tailoring the Variational Implicit Solvent Method for New Challenges: Biomolecular Recognition and Assembly. AB - Predicting solvation free energies and describing the complex water behavior that plays an important role in essentially all biological processes is a major challenge from the computational standpoint. While an atomistic, explicit description of the solvent can turn out to be too expensive in large biomolecular systems, most implicit solvent methods fail to capture "dewetting" effects and heterogeneous hydration by relying on a pre-established (i.e., guessed) solvation interface. Here we focus on the Variational Implicit Solvent Method, an implicit solvent method that adds water "plasticity" back to the picture by formulating the solvation free energy as a functional of all possible solvation interfaces. We survey VISM's applications to the problem of molecular recognition and report some of the most recent efforts to tailor VISM for more challenging scenarios, with the ultimate goal of including thermal fluctuations into the framework. The advances reported herein pave the way to make VISM a uniquely successful approach to characterize complex solvation properties in the recognition and binding of large-scale biomolecular complexes. PMID- 29484302 TI - The Effect of Thyroid Dysfunction on the Cardiovascular Risk of Type 2 Diabetes Mellitus Patients in Ghana. AB - Background: Thyroid dysfunction is known to exaggerate the coronary heart disease (CHD) risk associated with type 2 diabetes mellitus (T2DM) among whites. The effect is yet to be studied among African populations. Methods: This is a cross sectional study involving 780 T2DM patients enrolled in a diabetes clinic in Kumasi, Ghana. CHD risk was estimated using the Framingham and UKPDS risk scores. Risks were categorised as low (<10%), intermediate (10-19%), and high (>=20%). Associations between metabolic risk factors, thyroid dysfunction, and CHD risk were measured using Spearman's partial correlation analysis while controlling for age and gender. Differences were considered statistically significant at p < 0.05. Results: 780 T2DM patients (57.7% females), mean +/- SD age of 57.4 +/- 9.4 was analysed. The median (IQR) 10-year CHD score estimated using the Framingham and UKPDS risk engines for males and females was 12 (8-20), 9.4 (5.7-13.4), p < 0.0001 and 3 (1-6), 5.8 (3.4-9.6), p < 0.0001, respectively. Positive correlation was found between CHD risk and HbA1c, total cholesterol, low-density lipoprotein cholesterol, systolic blood pressure, and thyroid stimulating hormone. Conclusion: The presence of thyroid dysfunction significantly increased the CHD risk associated with T2DM patients in Ghana. PMID- 29484301 TI - The One Health Concept: 10 Years Old and a Long Road Ahead. AB - Over the past decade, a significant increase in the circulation of infectious agents was observed. With the spread and emergence of epizootics, zoonoses, and epidemics, the risks of pandemics became more and more critical. Human and animal health has also been threatened by antimicrobial resistance, environmental pollution, and the development of multifactorial and chronic diseases. This highlighted the increasing globalization of health risks and the importance of the human-animal-ecosystem interface in the evolution and emergence of pathogens. A better knowledge of causes and consequences of certain human activities, lifestyles, and behaviors in ecosystems is crucial for a rigorous interpretation of disease dynamics and to drive public policies. As a global good, health security must be understood on a global scale and from a global and crosscutting perspective, integrating human health, animal health, plant health, ecosystems health, and biodiversity. In this study, we discuss how crucial it is to consider ecological, evolutionary, and environmental sciences in understanding the emergence and re-emergence of infectious diseases and in facing the challenges of antimicrobial resistance. We also discuss the application of the "One Health" concept to non-communicable chronic diseases linked to exposure to multiple stresses, including toxic stress, and new lifestyles. Finally, we draw up a list of barriers that need removing and the ambitions that we must nurture for the effective application of the "One Health" concept. We conclude that the success of this One Health concept now requires breaking down the interdisciplinary barriers that still separate human and veterinary medicine from ecological, evolutionary, and environmental sciences. The development of integrative approaches should be promoted by linking the study of factors underlying stress responses to their consequences on ecosystem functioning and evolution. This knowledge is required for the development of novel control strategies inspired by environmental mechanisms leading to desired equilibrium and dynamics in healthy ecosystems and must provide in the near future a framework for more integrated operational initiatives. PMID- 29484303 TI - Liraglutide, a GLP-1 Receptor Agonist, Which Decreases Hypothalamic 5-HT2A Receptor Expression, Reduces Appetite and Body Weight Independently of Serotonin Synthesis in Mice. AB - A recent report suggested that brain-derived serotonin (5-HT) is critical for maintaining weight loss induced by glucagon-like peptide-1 (GLP-1) receptor activation in rats and that 5-HT2A receptors mediate the feeding suppression and weight loss induced by GLP-1 receptor activation. Here, we show that changes in daily food intake and body weight induced by intraperitoneal administration of liraglutide, a GLP-1 receptor agonist, over 4 days did not differ between mice treated with the tryptophan hydroxylase (Tph) inhibitor p-chlorophenylalanine (PCPA) for 3 days and mice without PCPA treatment. Treatment with PCPA did not affect hypothalamic 5-HT2A receptor expression. Despite the anorexic effect of liraglutide disappearing after the first day of treatment, the body weight loss induced by liraglutide persisted for 4 days in mice treated with or without PCPA. Intraperitoneal administration of liraglutide significantly decreased the gene expression of hypothalamic 5-HT2A receptors 1 h after injection. Moreover, the acute anorexic effects of liraglutide were blunted in mice treated with the high affinity 5-HT2A agonist (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl) methylamine hydrobromide 14 h or 24 h before liraglutide injection. These findings suggest that liraglutide reduces appetite and body weight independently of 5-HT synthesis in mice, whereas GLP-1 receptor activation downregulates the gene expression of hypothalamic 5-HT2A receptors. PMID- 29484305 TI - Abdominal Abscess Related to Endoscopically Placed AspireAssist(r) Device. AB - We report a 55-year-old diabetic woman with abdominal pain, pyrexia, and leukocytosis 3 months after aspiration tube placement. Abdominal computed tomography revealed a hypodense mass (10.8 * 7.2 cm) extending into the right anterior abdominal wall. Aspiration of the abscess revealed purulent fluid that grew Streptococcus intermedius. The aspiration tube was removed and 4 endoclips were deployed to close the intragastric stoma. The patient recovered well with 21 days of antibiotics, with resolution of the abscess and full wound healing. PMID- 29484304 TI - Role of MicroRNAs in Obesity-Induced Metabolic Disorder and Immune Response. AB - In all living organisms, metabolic homeostasis and the immune system are the most fundamental requirements for survival. Recently, obesity has become a global public health issue, which is the cardinal risk factor for metabolic disorder. Many diseases emanating from obesity-induced metabolic dysfunction are responsible for the activated immune system, including innate and adaptive responses. Of note, inflammation is the manifest accountant signal. Deeply studied microRNAs (miRNAs) have participated in many pathways involved in metabolism and immune responses to protect cells from multiple harmful stimulants, and they play an important role in determining the progress through targeting different inflammatory pathways. Thus, immune response and metabolic regulation are highly integrated with miRNAs. Collectively, miRNAs are the new targets for therapy in immune dysfunction. PMID- 29484306 TI - Conundrum of a Large Bowel Neoplasm: Collision Tumor. AB - A 79-year-old Hispanic man was admitted to the intensive care unit with symptomatic iron-deficiency anemia and watery diarrhea. Radiological images revealed diffuse colonic wall thickening, a soft-tissue fullness in the ascending colon, and multiple mesenteric lymphadenopathies. Colonoscopy showed multiple aphthous ulcers throughout the colon and a large deep ulcer with irregular raised borders in the rectosigmoid area. Histological exam of the ulcers showed severe ulcerative colitis, while biopsy of the deep ulcer revealed a well-differentiated adenocarcinoma. Colectomy specimen was consistent with colliding diffuse large B cell lymphoma and adenocarcinoma. PMID- 29484307 TI - Migration of a Lumen-Apposing Metal Stent into the Colon. AB - The introduction of lumen-apposing metal stents (LAMS) has been an important development in the management of pancreatic fluid collections. Stent migration out of pancreatic fluid collections into the stomach has been reported, despite the special anti-migratory design of the bi-flanged stent. Data on stent migration rates remain sparse, with some studies suggesting a migration rate of 3.3-5%. There have been no reported cases of LAMS migration outside of the stomach. We describe the first reported case of a transgastric LAMS migrating from the stomach and passing into the colon. PMID- 29484308 TI - Short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms in NMOSD. PMID- 29484309 TI - Balancing Autophagy for a Healthy Heart. AB - Autophagy is a well-known intracellular degradation process involved in clearing damaged or unnecessary components in cells. Functional autophagy is important for cardiac homeostasis. Given this, it is not surprising that dysregulation of autophagy has been implicated in the aging process and in various cardiovascular diseases. Therefore, understanding the functional role of autophagy in the heart under various conditions and whether manipulation of the pathway has therapeutic benefits have been a major focus of many investigations in recent years. Although consensus exists that autophagy is a critical cellular quality control pathway in the heart, its role in disease remains controversial. Whether altered autophagy is protective or detrimental in the heart seems to depend on the context and the disease. Here, we review the latest insights into autophagy in cardiovascular homeostasis and disease and its role in disease development. PMID- 29484310 TI - Performance and marginal bone level alteration around immediately loaded narrow diameter implants. A prospective clinical study: Results after 1 year. AB - OBJECTIVE: The aim of the present prospective clinical study was to assess the survival rate and the radiologic crestal bone level alteration around four interforaminal immediately loaded narrow-diameter implants (NDIs) in the edentulous mandible. METHOD AND MATERIALS: A total of 20 participants received each 4 NDIs (MDI, 3M Espe; diameter 1.8 mm, length 13 or 15 mm) in the edentulous mandible. Immediate loading was performed if insertion torque was 35 Ncm or higher. The implants were loaded the same day by converting the existing full denture into an implant overdenture. Follow-up visits were performed five times (baseline to 52 weeks). Standardized radiographs were taken at baseline and 12, 26, and 52 weeks post-loading. Clinical parameters (Plaque Index, probing depth, bleeding on probing) were assessed. The nonparametric ANOVA test was used to assess crestal bone level changes. RESULTS: In all 20 patients the healing of the total 80 implants was uneventful and no implant was lost. Sixty-eight (85%) implants were loaded immediately. All clinical parameters showed healthy, stable, and well-maintained peri-implant soft tissue conditions. The mean (+/- standard deviation) radiographic bone loss after 1 year was 0.78 (+/- 0.64) mm. CONCLUSION: According to the 1-year results of this prospective clinical study, NDIs seem to be a reliable alternative to support prostheses in edentulous patients with a reduced horizontal mandibular bone volume. PMID- 29484311 TI - In-vivo performance of impedance spectroscopy, laser fluorescence, and bitewing radiographs for occlusal caries detection. AB - OBJECTIVE: To evaluate the clinical performance of impedance spectroscopy, laser fluorescence, and bitewing radiographs in detecting occlusal caries and compare them with visual scores. METHOD AND MATERIALS: In 62 adults, one occlusal surface per person was selected and independently examined by two examiners using the visual ICDAS scoring system, CarieScan PRO (ACIS), DIAGNOdent pen (LF-pen), and bitewing radiographs. The procedures were repeated within 1 to 4 weeks. The diagnostic performance was expressed as sensitivity, specificity, predictive values, accuracy, and diagnostic odds ratio (DOR) using ICDAS as gold standard. Intra- and inter-examiner reproducibility was assessed with intra-class correlation coefficients (ICC) for numerical results and kappa values for categorical data. Five patients dropped out due to no-shows or restorative care. RESULTS: In total, 54% of the teeth had early or no lesions (ICDAS 0 to 2) while 46% exhibited moderate to extensive lesions (ICDAS 3 to 5). The Spearman correlation coefficients were 0.65, 0.60, and 0.71 for ICDAS vs ACIS, LF-pen, and bitewing radiographs, respectively. ACIS demonstrated high specificity and positive predictive values but low sensitivity, whereas LF-pen had moderate sensitivity and high specificity. Accuracy and DOR was highest for bitewing radiographs. The ICC values ranged between 0.65 and 0.88 for ACIS and 0.89 and 0.94 for LF-pen. The weighted kappa values were 0.81 to 0.91 for ICDAS and 0.90 to 0.92 for bitewing radiographs. CONCLUSION: All three methods were useful for detecting occlusal caries but bitewing radiography exhibited the best performance when compared with visual scoring. ACIS displayed the highest specificity and positive predictive value but the sensitivity was low and the clinical handling was less convenient. Further clinical studies are needed to evaluate the long term effects of early caries detection on dental health. PMID- 29484312 TI - Is liberal independent dental practice in danger? Assessing forms of dental practice in the European Regional Organization (ERO) zone of the FDI World Dental Federation. AB - OBJECTIVE: A trend towards increasingly new forms of dental practice has been observed in the FDI World Dental Federation. Elementary foundations such as the free dentist and therapy choice, and independent, free, self-responsible professional practice may be undermined. The current study is aimed at analyzing the general training framework, organization, and professional types of dental practice in the European Regional Organization (ERO) zone and at critically discussing selected aspects of changes in the dental profession. METHOD AND MATERIALS: A questionnaire was developed by the ERO Working-Group "Liberal Dental Practice." Information about dental schools, professional organizations, dental practice regulations, and ambulatory healthcare centers was analyzed. RESULTS: Self-employed dental practice is the most common type of practice (51.7%). Dentists are allowed to work independently immediately after graduation (72.7%). Approximately one-third are organized as compulsory members in chambers/corporations. The density of dentists has a mean of 1,570 inhabitants per dentist. In most countries, there are no special rules for founding dental ambulatory healthcare centers. In a total of 353 universities of the ERO countries surveyed, 16,619 dentists per year were trained, with a trend toward a higher percentage of female students (63%). CONCLUSIONS: Despite modern forms of dental practice, the charter of the individual liberal dental profession (CED et al, 2013) should be respected and taken into account on the basis of ethical principles. The commercialization of the dental profession can be neutralized only by establishing and following well-defined ethical principles; oral healthcare quality can thus be ensured without the influence of third parties. PMID- 29484314 TI - On the cononsolvency behaviour of hydrophobic clusters in water-methanol solutions. AB - Simple calculations, grounded on the geometric approach to hydrophobic interaction, confirm the occurrence of a minimum in the Gibbs free energy change associated with the formation of several hard sphere clusters in water-methanol solutions with a methanol molar fraction of around 0.3, at room temperature and atmospheric pressure. This finding is in line with the computer simulation results of Mochizuki and Koga [Phys. Chem. Chem. Phys., 2016, 18, 16188]. However, it is underscored that these results cannot be the basis for a rationalization of the cononsolvency phenomenon of the polymers in water-methanol solutions. In fact, there is no Gibbs free energy minimum for the processes more closely resembling polymer collapse, i.e., those involving solely a change in the spatial organization of the same number of hard spheres. PMID- 29484313 TI - Fingerprints of electronic, spin and structural dynamics from resonant inelastic soft X-ray scattering in transient photo-chemical species. AB - We describe how inversion symmetry separation of electronic state manifolds in resonant inelastic soft X-ray scattering (RIXS) can be applied to probe excited state dynamics with compelling selectivity. In a case study of Fe L3-edge RIXS in the ferricyanide complex Fe(CN)63-, we demonstrate with multi-configurational restricted active space spectrum simulations how the information content of RIXS spectral fingerprints can be used to unambiguously separate species of different electronic configurations, spin multiplicities, and structures, with possible involvement in the decay dynamics of photo-excited ligand-to-metal charge transfer. Specifically, we propose that this could be applied to confirm or reject the presence of a hitherto elusive transient Quartet species. Thus, RIXS offers a particular possibility to settle a recent controversy regarding the decay pathway, and we expect the technique to be similarly applicable in other model systems of photo-induced dynamics. PMID- 29484315 TI - Correction: Organic semiconductor perylenetetracarboxylic diimide (PTCDI) electrodes for electrocatalytic reduction of oxygen to hydrogen peroxide. AB - Correction for 'Organic semiconductor perylenetetracarboxylic diimide (PTCDI) electrodes for electrocatalytic reduction of oxygen to hydrogen peroxide' by Magdalena Warczak et al., Chem. Commun., 2018, DOI: . PMID- 29484316 TI - Asymmetric vinylogous Mukaiyama aldol reaction of isatins under bifunctional organocatalysis: enantioselective synthesis of substituted 3-hydroxy-2-oxindoles. AB - A highly enantioselective organocatalytic vinylogous Mukaiyama aldol reaction of silyloxy dienes and isatins under bifunctional organocatalysis is presented. Substituted 3-hydroxy-2-oxindoles are synthesised in good yields and enantioselectivities. These synthetic intermediates are used for the construction of more complex molecules with biological properties such as the formal synthesis of a CB2 agonist presented. PMID- 29484317 TI - Artificial molecular and nanostructures for advanced nanomachinery. AB - Artificial nanomachines can be broadly defined as manmade molecular and nanosystems that are capable of performing useful tasks, very often, by means of doing mechanical work at the nanoscale. Recent advances in nanoscience allow these tiny machines to be designed and made with unprecedented sophistication and complexity, showing promise in novel applications, including molecular assemblers, self-propelling nanocarriers and in vivo molecular computation. This Feature Article overviews and compares major types of nanoscale machines, including molecular machines, self-assembled nanomachines and hybrid inorganic nanomachines, to reveal common structural features and operating principles across different length scales and material systems. We will focus on systems with feature size between 1 and 100 nm, where classical laws of physics meet those of quantum mechanics, giving rise to a spectrum of exotic physiochemical properties. Concepts of nanomachines will be illustrated by selected seminal work along with state-of-the-art progress, including our own contribution, across the fields. The Article will conclude with a brief outlook of this exciting research area. PMID- 29484318 TI - An intramolecular ortho-assisted activation of the silicon-hydrogen bond in arylsilanes: an experimental and theoretical study. AB - An intramolecular activation of the Si-H bond in arylsilanes by selected ortho assisting functional groups based on boron, carbon and phosphorus was investigated experimentally and by means of theoretical calculations. The major conclusion drawn is that the presence of a negatively charged oxygen atom in the functional group is essential for providing effective chelation to the silicon atom which in turn results in the increased hydridic character of a resulting five-coordinated species. In contrast, an intermolecular attack of hydroxide on the silicon atom in aryldimethylsilane results in the activation of the silicon aryl bond. This increased reactivity of the Si-H bond in intramolecularly coordinated arylsilanes can be ascribed to a significant trans effect which operates in the preferred configuration. Hydrolytic cleavage of the Si-H bond results in dihydrogen elimination and the formation of various silicon heterocyclic systems such as benzosiloxaboroles, spiro-bis(siloxa)borinate, benzosilalactone and benzophosphoxasilole. In addition, intermolecular reduction of benzaldehydes with ortho-boronated arylsilane was observed whereas compounds bearing other reducible functional groups (COMe, COOEt, CN and NO2) were inert under comparable conditions. Specifically, an intramolecular reduction of the CN group in an ortho-silylated benzonitrile derivative was observed. The mechanism of Si-H bond activation was investigated by the DFT theoretical calculations. The calculations showed that the intramolecular coordination of the silicon atom effectively prevents the cleavage of the Si-aryl bond. Furthermore, the reaction is favored in anionic systems bearing COO-, B(OH)3- or CH2O- groups, while in the case of neutral functional groups such as PO(OEt)2 the process is much slower. PMID- 29484319 TI - The quest for determining one-electron redox potentials of azulene-1 carbonitriles by calculation. AB - Electrochemical processes drive many chemical and biochemical reactions. Theoretical methods to accurately predict redox potentials are therefore crucial for understanding these reactions and designing new chemical species with desired properties. We have investigated a theoretical methodology using electronic structure methods based on density functional theory and continuum solvation models. These methods have been validated with linear correlation plots comparing theoretical and experimental results for the redox properties of a series of azulene derivatives. The results showed excellent correlations despite only minor structural variations of the azulenes, which support this rather simple theoretical methodology for determining redox potentials of organic molecules. Furthermore, we have estimated the absolute redox potential of the ferrocene/ferrocenium redox couple to be 4.8 +/- 0.1 V in dichloromethane, which is slightly lower than previous estimates. PMID- 29484320 TI - An electrochemiluminescent sensor based on functionalized conjugated polymer dots for the ultrasensitive detection of Cu2. AB - An ultrasensitive electrochemiluminescence (ECL) detection for Cu2+ was explored using the carboxyl functionalized poly(9,9-dioctylfluorenyl-2,7-diyl) (PS-COOH-co PFO) dots as the signal label without adding any coreactant. PMID- 29484321 TI - Room temperature chiral reorganization of interfacial assembly of achiral double decker phthalocyanine. AB - The modulation of solid-state supramolecular assemblies at room temperature is still challenging even though it potentially has very important application prospects. Herein, based on the possibility of overall conformational changes in double-decker phthalocyanine, the room temperature chiral reorganization of solid state assemblies was investigated. LS (Langmuir-Schaefer) films of achiral double decker cerium phthalocyanine were fabricated via air-water interfacial assembly and the dependence of supramolecular chirality on the assembly of the achiral double-decker molecules was identified. Interestingly, the corresponding supramolecular chirality in the solid-state can be reorganized with amplification of the Cotton effect and formation of helical nanostructures upon storage at room temperature and atmospheric pressure. These results open new perspectives for the regulation of supramolecular assemblies. PMID- 29484322 TI - Influence of the hydrogen-bond interactions on the excited-state dynamics of a push-pull azobenzene dye: the case of Methyl Orange. AB - The excited-state dynamics of the push-pull azobenzene Methyl Orange (MO) were investigated in several solvents and water/glycerol mixtures using a combination of ultrafast time-resolved fluorescence and transient absorption in both the UV visible and the IR regions, as well as quantum chemical calculations. Optical excitation of MO in its trans form results in the population of the S2 pipi* state and is followed by internal conversion to the S1 npi* state in ~50 fs. The population of this state decays on the sub-picosecond timescale by both internal conversion to the trans ground state and isomerisation to the cis ground state. Finally, the cis form converts thermally to the trans form on a timescale ranging from less than 50 ms to several minutes. Significant differences depending on the hydrogen-bond donor strength of the solvents, quantified by the Kamlet Taft parameter alpha, were observed: compared to the other solvents, in highly protic solvents (alpha > 1), (i) the viscosity dependence of the S1 state lifetime is less pronounced, (ii) the S1 state lifetime is shorter by a factor of ~1.5 for the same viscosity, (iii) the trans-to-cis photoisomerisation efficiency is smaller, and (iv) the thermal cis-to-trans isomerisation is faster by a factor of >=103. These differences are explained in terms of hydrogen-bond interactions between the solvent and the azo nitrogen atoms of MO, which not only change the nature of the S1 state but also have an impact on the shape of ground- and excited-state potentials, and, thus, affect the deactivation pathways from the excited state. PMID- 29484323 TI - Conformational properties and the entropic barrier in the "head-on" adsorption of a single polymer chain towards a flat surface. AB - This work investigates the change in conformations and the entropic free energy barrier in the "head-on" adsorption process of a flexible polymer chain towards a flat surface in the framework of the Gaussian chain model. Analytical expressions are reported for the distribution of chain end, the mean square end-to-end distance, the entropic free energy barrier and the adsorption equilibrium constant at low surface coverage (the "mushroom" regime). Theoretical results are discussed in the context of polyoxyethylene-phosphonate-type polymer dispersants, possessing a non-adsorbing polyoxyethylene chain and an adsorbing head-group. PMID- 29484324 TI - Ionic liquid syntheses via click chemistry: expeditious routes toward versatile functional materials. AB - Since the introduction of click chemistry by K. B. Sharpless in 2001, its exploration and exploitation has occurred in countless fields of materials sciences in both academic and industrial spheres. Click chemistry is defined as an efficient, robust, and orthogonal synthetic platform for the facile formation of new carbon-heteroatom bonds, using readily available starting materials. Premier examples of click reactions are copper(i)-catalyzed azide-alkyne Huisgen cycloaddition (CuAAC) and the thiol-X (X = ene and yne) coupling reactions to form C-N and C-S bonds, respectively. The emphasis of this review is centered on the rapidly expanding area of click chemistry-mediated synthesis of functional ionic liquids via CuAAC, thiol-X and oxime formation, and selected examples of nucleophilic ring-opening reactions, while offering some thoughts on emerging challenges, opportunities and ultimately the evolution of this field. Click chemistry offers tremendous opportunities, and introduces intriguing perspectives for efficient and robust generation of tailored task-specific ionic liquids - an important class of soft materials. PMID- 29484325 TI - Visible-light and thermal driven double hydrophosphination of terminal alkynes using a commercially available iron compound. AB - A commercially available iron compound, [CpFe(CO)2]2 (1) (Cp = eta5-C5H5), is an efficient catalyst for the double hydrophosphination of terminal aryl alkynes with diphenylphosphine under visible light irradiation or thermal conditions with a reduction of reaction times of up to two orders of magnitude for some substrates over literature reports. The 1,2-bis(diphenylphosphino)ethane products generated in these reactions are readily isolated in high yields. PMID- 29484326 TI - Excitation spectra of retinal by multiconfiguration pair-density functional theory. AB - Retinal is the chromophore in proteins responsible for vision. The absorption maximum of retinal is sensitive to mutations of the protein. However, it is not easy to predict the absorption spectrum of retinal accurately, and questions remain even after intensive investigation. Retinal poses a challenge for Kohn Sham density functional theory (KS-DFT) because of the charge transfer character in its excitations, and it poses a challenge for wave function theory because the large size of the molecule makes multiconfigurational perturbation theory methods expensive. In this study, we demonstrate that multiconfiguration pair-density functional theory (MC-PDFT) provides an efficient way to predict the vertical excitation energies of 11-Z retinal, and it reproduces the experimentally determined absorption band widths and peak positions better than complete active space second-order perturbation theory (CASPT2). The consistency between complete active space self-consistent field (CASSCF) and KS-DFT dipole moments is demonstrated to be a useful criterion in selecting the active space. We also found that the nature of the terminal groups and the conformations of retinal play a significant role in the absorption spectrum. By considering a thermal distribution of conformations, we predict an absorption spectrum of retinal that is consistent with the experimental gas-phase spectrum. The location of the absorption peak and the spectral broadening based on MC-PDFT calculations agree better with experiments than those of CASPT2. PMID- 29484328 TI - Phonon transport in Janus monolayer MoSSe: a first-principles study. AB - Transition Metal Dichalcogenide (TMD) monolayers are very widely studied due to their unique physical properties. Recently, Janus TMD monolayer MoSSe, with a sandwiched S-Mo-Se structure, has been synthesized by replacing the top S atomic layer in MoS2 with Se atoms. In this work, we systematically investigate the phonon transport and lattice thermal conductivity (kappaL) in MoSSe monolayers using first-principles calculations and the linearized phonon Boltzmann equation within the single-mode relaxation time approximation (RTA). The calculated results show that the kappaL of MoSSe monolayers is much lower than that of MoS2 monolayers, and higher than that of MoSe2 monolayers. The corresponding thermal sheet conductance of MoSSe monolayers is 342.50 W K-1 at room temperature. This can be understood by studying the phonon group velocities and lifetimes. Compared to MoS2 monolayers, the smaller group velocities and shorter phonon lifetimes of MoSSe monolayers give rise to a lower kappaL. The larger group velocities of MoSSe compared to those of MoSe2 monolayers are the main reason for the higher kappaL. The elastic properties of MoS2, MoSSe and MoSe2 monolayers are also calculated, and the order of the Young's modulus is identical to that of the kappaL. The calculated results show that isotope scattering leads to a 5.8% reduction of the kappaL. The size effects on the kappaL are also considered, and are usually used in device implementation. When the characteristic length of the MoSSe monolayer is about 110 nm, the kappaL reduces to half. These results may offer perspectives on thermal management of MoSSe monolayers, for applications in thermoelectrics, thermal circuits and nanoelectronics, and may motivate further theoretical or experimental efforts to investigate thermal transport in Janus TMD monolayers. PMID- 29484327 TI - The effect of geometric isomerism on the anticancer activity of the monofunctional platinum complex trans-[Pt(NH3)2(phenanthridine)Cl]NO3. AB - A trans-DDP based monofunctional phenanthridine Pt(ii) complex was synthesized and characterized. Its anticancer activity was studied in vitro on a panel of human cancer cell lines and mouse intestinal cancer organoids. This complex displays significant antitumor properties, with a different spectrum of activity than that of classic bifunctional cross-linking agents like cisplatin. PMID- 29484329 TI - A solvent-directed stereoselective and electrocatalytic synthesis of diisoeugenol. AB - A stereoselective and electrocatalytic coupling reaction of isoeugenol has been reported for the first time in a 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP)/boron doped diamond (BDD) electrode system. This particular C-C bond formation and diastereoselectivity is driven by a solvate interaction between the radical species and another isoeugenol molecule. Due to an electrocatalytic cycle, only understoichiometric amounts of charge are necessary. Since electric current is directly employed as the oxidant, the reaction is metal and reagent-free. In addition, the electrolysis can be conducted in a very simple undivided beaker type cell under constant current conditions. Therefore, the protocol is easy to use, suitable for scale-up, and inherently safe. PMID- 29484330 TI - Overcoming drug-resistant lung cancer by paclitaxel loaded tetrahedral DNA nanostructures. AB - Paclitaxel (PTX) is an effective drug against diseases such as lung cancer, ovarian cancer, and breast cancer. However, multidrug resistance limits the clinical applications of this drug. Tetrahedral DNA nanostructures (TDNs) offer great promise as a drug delivery candidate. In our study, we prepared TDNs that were subsequently loaded with PTX (PTX/TDNs). The cytotoxicity of PTX/TDNs and PTX alone on non-small cell lung cancer (NSCLC) cells (A549) and the PTX resistant cell line (A549/T) was determined using a cell count kit-8 (CCK-8) assay. PTX/TDNs exerted strong lethality on both cell lines. Moreover, drug resistance was overcome. Furthermore, the mechanisms used by PTX/TDNs to overcome drug resistance were studied. The expression of mdr 1 gene and P-glycoprotein (P gp) in A549/T was found to be downregulated, thus indicating that TDNs serve as a P-gp inhibitor. We also showed that PTX/TDNs killed cancer cells via apoptosis. Thus, PTX/TDNs have great potential for use as a nanodelivery system for the treatment of PTX-resistant NSCLC. PMID- 29484331 TI - Scalable chemical-vapour-deposition growth of three-dimensional graphene materials towards energy-related applications. AB - Three-dimensional (3D) graphene materials, which are integrated using graphene structural units, show great promise for energy-related applications because of the high specific surface area, fast electron transport, and low density. Beyond solution-phase assembly of graphene sheets, chemical vapour deposition (CVD) has been recently introduced as a scalable, high-yield, and facile strategy for preparing 3D graphene materials with relatively high crystallinity and controllable layer numbers. Such 3D graphene structures have served as ideal platforms for constructing next-generation energy storage and conversion devices such as supercapacitors, batteries, and fuel cells. In this tutorial review, we focus on recent progress in the scalable CVD growth of 3D graphene materials (e.g., foams, shells, and hierarchical structures) as well as their applications in energy-related fields. First, we emphasize the role of substrate shape and composition (metal or non-metal) in the CVD growth of diverse 3D graphene materials. The related growth mechanisms of these 3D graphene materials are also analysed and discussed. Second, we demonstrate the applications of the CVD derived 3D graphene materials in various energy-related devices. Finally, we conclude this review with our insights into the challenges and future opportunities for CVD synthesis as well as the application of such intriguing 3D graphene materials. PMID- 29484332 TI - Viable aromatic BenHn stars enclosing a planar hypercoordinate boron or late transition metal. AB - Monocyclic Bn rings can act as n-electron sigma-donors to stabilize a non classical planar hypercoordinate atom at ring center, forming wheel-like structures. Herein, we report that BenHn rings can also serve as n-electron sigma donors to construct star-like structures including B(c)Be6H6+ and TM(c)Be7H7q (TM is a group 10-12 metal with q = -1, 0, and 1, respectively) by complying with octet or 18-electron rules. Electronic structure analyses show that these species are stabilized by the sigma-donation and pi-backdonation between the central atom and the peripheral BenHn ring, the favorable Coulomb attraction due to the negative-positive-negative charge population pattern on the central atom, the middle Ben layer, and the outer Hn layer, as well as the sigma-pi double aromaticity. Importantly, three of the ten species, including B(c)Be6H6+, Cu(c)Be7H7, and Au PMID- 29484333 TI - Synthesis of tRNA analogues containing a terminal ribose locked in the South conformation to study tRNA-dependent enzymes. AB - We report here the synthetic route of two constrained dinucleotides and the determination of the sugar puckering by NMR analyses of the starting nucleosides. Enzymatic ligation to microhelix-RNAs provide access to tRNA analogues containing a 3' terminal A76 locked in South conformation. Biological evaluation of our tRNA analogues has been performed using amino-acyl tRNA-dependent transferase FemXWv, which mediates non-ribosomal incorporation of amino acids into the bacterial cell wall. We have shown that our tRNA analogues inhibited the aminoacyl transfer reaction catalyzed by FemXWv with IC50s of 10 and 8 MUM. These results indicate that FemXWv displays a moderate preference for tRNAs containing a terminal A76 locked in the South conformation and that a South to North switch in the conformation of the terminal ribose might contribute to the release of the uncharged tRNAAla product of the aminoacyl transfer reaction catalyzed by FemXwv. PMID- 29484334 TI - Bioinspired microstructures of chitosan hydrogel provide enhanced wear protection. AB - We describe the fabrication of physical chitosan hydrogels exhibiting a layered structure. This bilayered structure, as shown by SEM and confocal microscopy, is composed of a thin dense superficial zone (SZ), covering a deeper zone (DZ) containing microchannels orientated perpendicularly to the SZ. We show that such structure favors diffusion of macromolecules within the hydrogel matrix up to a critical pressure, sigmac, above which channels were constricted. Moreover, we found that the SZ provided a higher wear resistance than the DZ which was severely damaged at a pressure equal to the elastic modulus of the gel. The coefficient of friction (CoF) of the SZ remained independent of the applied load with MUSZ = 0.38 +/- 0.02, while CoF measured at DZ exhibited two regimes: an initial CoF close to the value found on the SZ, and a CoF that decreased to MUDZ = 0.18 +/- 0.01 at pressures higher than the critical pressure sigmac. Overall, our results show that internal structuring is a promising avenue in controlling and improving the wear resistance of soft materials such as hydrogels. PMID- 29484335 TI - Shedding light on tau protein aggregation: the progress in developing highly selective fluorophores. AB - Historically, in Alzheimer's disease research, a lot of attention has been paid to the development of highly selective fluorophores for beta amyloid plaques. With a shift in the understanding of the disease and the importance of a network of cross-talk interactions, the development of small-molecule fluorescent dyes with high selectivity for (hyperphosphorylated) tau protein aggregates in neurofibrillary tangles has been gaining increasing attention. Fluorescent dyes for the selective labelling of tau aggregates in histological AD brain sections have been described, spanning the entire visible range of the electromagnetic spectrum. Despite the relatively early stages of the development of the field, a large diversity in probe architectures has been reported. Importantly, a handful of near-infrared-emissive dyes have been described as well, and some of these have exhibited good pharmacological profiles, with a significant blood-brain barrier permeability, and a demonstrated ability to label tau tangles in vivo in small-animal models of Alzheimer's disease and other tauopathies. The developments summarized in the current work are expected to aid the unravelling of the diverse set of players in the etiology of Alzheimer's disease. In this tutorial review, we seek to provide the reader with an overview of the most important recent developments and hope to provide some guidelines for the design of future probes. PMID- 29484336 TI - Sub-MUL measurements of the thermal conductivity and heat capacity of liquids. AB - We present the analysis of the thermal conductivity, kappa, and heat capacity, Cp, of a wide variety of liquids, covering organic molecular solvents, ionic liquids and water-polymer mixtures. These data were obtained from ~0.6 MUL samples, using an experimental development based on the 3omega method, capable of the simultaneous measurement of kappa and Cp. In spite of the different type and strength of interactions, expected in a priori so different systems, the ratio of kappa to the sound velocity is approximately constant for all of them. This is the consequence of a similar atomic density for all these liquids, notwithstanding their different molecular structures. This was corroborated experimentally by the observation of a Cp/V ~ 1.89 * 106 J K-1 m-3 (~3R/2 per atom), for all liquids studied in this work. Finally, the very small volume of the sample required in this experimental method is an important advantage for the characterization of systems like nanofluids, in which having a large amount of the dispersed phase is sometimes extremely challenging. PMID- 29484337 TI - Thermo-responsive recoverable polymeric inhibitors for the resolution of racemic amino acids. AB - Novel polymeric inhibitors with lower critical solution temperatures in water were prepared and used to mediate the crystallization of racemic asparagine monohydrate, leading to chiral separation with 88.6 ee%. They could be recollected by simply elevating the temperature with a high yield of around 95% and reused without compromising the stereoselectivity and stability. PMID- 29484338 TI - Polydatin inhibits the IL-1beta-induced inflammatory response in human osteoarthritic chondrocytes by activating the Nrf2 signaling pathway and ameliorates murine osteoarthritis. AB - Osteoarthritis (OA), which is characterized by progressive degradation of the articular cartilage, is the most prevalent form of human arthritis. Accumulating evidence has shown that polydatin (PD) exerts special biological functions in a variety of diseases. However, whether it protects against OA development has remained unknown. Here, we investigated the anti-inflammatory and chondroprotective effects of PD on interleukin (IL)-1beta-induced human osteoarthritic chondrocytes and in the surgical destabilization of medial meniscus mouse (DMM) OA models. In vitro, PD treatment completely suppressed the over-production of pro-inflammatory mediators, including prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF-alpha), nitric oxide (NO), cyclooxygenase-2 (COX 2), inducible nitric oxide synthase (iNOS), and IL-6 in IL-1beta-induced human OA chondrocytes. Moreover, PD exerted a suppressive effect on the expression of matrix-degrading proteases, including matrix metalloproteinase 13 (MMP13) and thrombospondin motifs 5 (ADAMTS-5), which leads to the degradation of the extracellular matrix (ECM). Meanwhile, specific inhibition of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) level by short-interfering RNA (siRNA) strongly reversed the anti-inflammatory and chondroprotective effects of PD in human OA chondrocytes. The protective effects of PD were also observed in vivo. In conclusion, our studies demonstrate that PD holds novel therapeutic potential for the development of OA. PMID- 29484339 TI - Metallomic study on the metabolism of RAPTA-C and cisplatin in cell culture medium and its impact on cell accumulation. AB - Metal-based anticancer agent development can be improved with advanced metallomics methods that allow for quick and efficient screening of metallodrugs for their metabolites in biological media. Cellular accumulation in in vitro settings is not always correlated with cytotoxicity; and protein binding, particularly with albumin and transferrin, can have an important influence on metallodrug transportation, selectivity, and efficacy. We contrast the time dependent cellular accumulation of both cisplatin and the pre-clinically investigated RAPTA-C in terms of cell uptake and speciation in culture medium via CE-ICP-MS analysis. Despite RAPTA-C being administered at 40-fold higher dose than cisplatin, owing to its much higher IC50 value, the accumulation over time was only 10-fold higher. An optimised CE-ICP-MS method, through the coating of the capillary to prevent protein-capillary surface interactions, resulted in superior resolution and metal-protein adduct identification. It was then used for extracellular speciation in conjunction with [tris(acetylacetonato)cobalt(iii)] as an internal standard. RAPTA-C was found to be more inert to extracellular reactions than cisplatin which could be used to rationalise the observed cellular uptake patterns. While for cisplatin both transferrin and albumin were identified as the main binding partners, RAPTA-C was found to react nearly exclusively with albumin. Moreover, this behaviour was time-dependent and our results also demonstrate that cancer cells have an influence on metal species distribution in the cell culture medium over time. PMID- 29484340 TI - Lipopeptidomimetics derived from teixobactin have potent antibacterial activity against Staphylococcus aureus. AB - A series of lipopeptidomimetics derived from teixobactin have been prepared that probe the role of residues (1-6) as a membrane anchor and the function of enduracididine. The most active compounds, with a farnesyl tail and End10 to Lys10 or Orn10 substitution have potent activity (MIC 8 MUg mL-1) against S. aureus. These results pave the way for the synthesis of simple, cost-effective yet potent lipopeptidomimetic antimicrobials. PMID- 29484342 TI - Editorial: Defining Undernutrition (Malnutrition) in Older Persons. PMID- 29484341 TI - The teleos of metallo-reduction and metallo-oxidation in eukaryotic iron and copper trafficking. AB - Eukaryotic cells, whether free-living or organismal, rely on metallo-reductases to process environmental ferric iron and cupric copper prior to uptake. In addition, some free-living eukaryotes (e.g. fungi and algae) couple ferri reduction to ferro-oxidation, a process catalyzed by a small cohort of multi copper oxidases; in these organisms, the ferric iron product is a ligand for cell iron uptake via a ferric iron permease. In addition to their support of iron uptake in lower eukaryotes, ferroxidases support ferrous iron efflux in Chordata; in this process the release of the ferrous iron from the efflux transporter is catalyzed by its ferroxidation. Last, ferroxidases also catalyze the oxidation of cuprous copper and, as metallo-oxidases, mirror the dual activity of the metallo reductases. This Perspective examines the teleos of the yin-yang of this redox cycling of iron and copper in their metabolism. PMID- 29484343 TI - Association of Spicy Food Consumption Frequency with Serum Lipid Profiles in Older People in China. AB - OBJECTIVES: There has been recent interest in spicy foods and their bioactive ingredients for cardiovascular health. This study aims to explore relationship between spicy food consumption frequency and serum lipid profiles in a cross sectional sample of older Chinese from China Health and Nutrition Survey (CHNS). METHODS: A total of 1549 participant aged 65 years and above from CHNS 2009 were included in the analysis. Information on spicy food consumption was obtained using a questionnaire survey and 24h dietary recalls over three consecutive days combined with weighted food inventory. Fasting blood samples were analyzed for total cholesterol (TC), triglycerides, high density lipoprotein cholesterol (HDL C), low density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (apoA1) and apolipoprotein B (apoB). Correlations between spicy food consumption frequency and serum lipid profiles were evaluated by multivariate linear regression models. RESULTS: The result shows a significant positive association between frequency of spicy food consumption estimated by the frequency question and daily spicy food intake calculated from 24h recall. After adjustment for potential lifestyle and dietary confounding factors, men with higher frequency of spicy food consumption showed higher apoA1 level, and lower ratio of LDL-C/apoB (p for trend <0.05). For female, frequency of spicy food consumption was significantly associated with TC, LDL-C, apoB, LDL-C/HDL-C, and apoB/apoA1 in an inverse manner, and positively correlated with apoA1 level (p for trend <0.05). CONCLUSION: In this study with Chinese aged 65y and above, increased spicy food consumption frequency may favorably associated with some risk factors for cardiovascular diseases. PMID- 29484344 TI - Prevalence of Risk Factors for the Refeeding Syndrome in Older Hospitalized Patients. AB - OBJECTIVES: The incidence of refeeding syndrome (RFS) in older patients is not well-known. The aim of the study was to determine the prevalence of known risk factors for RFS in older individuals during hospitalization at geriatric hospital departments. DESIGN AND SETTING: 342 consecutive older participants (222 females) who admitted at acute geriatric hospital wards were included in a cross-sectional study. We applied the National Institute for Health and Clinical Excellence (NICE) criteria for determining patients at risk of RFS. In addition, Mini Nutritional Assessment Short Form (MNA(r)-SF) was used to identify patients at risk of malnutrition. Weight and height were assessed. The degree of weight loss was obtained by interview. Serum phosphate, magnesium, potassium, sodium, calcium, creatinine and urea were analyzed according to standard procedures. RESULTS: Of 342 older participants included in the study (mean age 83.1 +/- 6.8, BMI range of 14.7-43.6 kg/m2), 239 (69.9%) were considered to be at risk of RFS, in which 43.5% and 11.7% were at risk of malnutrition and malnourished, respectively, according to MNA-SF. Patients in the risk group had significantly higher weight loss, lower phosphate and magnesium levels. In a multivariate logistic regression analysis, low levels of phosphate and magnesium followed by weight loss were the major risk factors for fulfilling the NICE criteria. CONCLUSION: The incidence of risk factors for RFS was relatively high in older individuals acutely admitted in geriatric hospital units, suggesting that, RFS maybe more frequent among older persons than we are aware of. Patients with low serum levels of phosphate and magnesium and higher weight loss are at increased risk of RFS. The clinical characteristics of the older participants at risk of RFS indicate that these patients had a relatively poor nutritional status which can help us better understand the potential scale of RFS on admission or during the hospital stay. PMID- 29484345 TI - Hospitalization Drug Regimen Changes in Geriatric Patients and Adherence to Modifications by General Practitioners in Primary Care. AB - OBJECTIVES: To evaluate the overall rate of adherence by general practitioners (GPs) to treatment modifications suggested at discharge from hospital and to assess the way communication between secondary and primary care could be improved. DESIGN: Observational prospective cohort study. SETTING: Patients hospitalized from the emergency department to the acute geriatric care unit of a university hospital. PARTICIPANTS: 206 subjects with a mean age of 85 years. MEASUREMENTS: Changes in drug regimen undertaken during hospitalization were collected with the associated justifications. Adherence at one month by GPs to treatment modifications was assessed as well as modifications implemented in primary care with their rationale in case of non-adherence. Community pharmacists' and GPs' opinions about quality of communication and information transfer at hospital-general practice interface were investigated. RESULTS: 5.5 +/- 2.8 drug regimen changes were done per patient during hospitalization. The rate of adherence by GPs to treatment modifications suggested at discharge from hospital was 83%. In most cases, non-adherence by GPs to treatment modifications done during hospitalization was due to dosage adjustments, symptoms resolution but also worsening of symptoms. The last of which was particularly true for psychotropic drugs. All GPs received their patients' discharge letters but the timely dissemination still needs to be improved. Only 6.6% of community pharmacists were informed of treatment modifications done during their patients' hospitalization. CONCLUSION: Our findings showed a successful rate of adherence by GPs to treatment modifications suggested at discharge from hospital, due to the fact that optimization was done in a collaborative way between geriatricians and hospital pharmacists and that justifications for drug regimen changes were systematically provided in discharge letters. Communication processes at the interface between secondary and primary care, particularly with community pharmacists, must be strengthened to improve seamless care. PMID- 29484346 TI - Factors Associated with Pre-Event Hydration Status and Drinking Behavior of Middle-Aged Cyclists. AB - OBJECTIVES: Water is an essential nutrient for thermoregulation, metabolism, cognition, and overall physiological homeostatic function. However, aging adults display a blunted thirst mechanism and subsequently have an increased risk for dehydration or hyponatremia. Fluid consumption behaviors are modifiable and the importance of practicing adequate drinking behaviors for aging adults is amplified during exercise. Identification of aging adult's hydration beliefs and how they attain hydration advice could provide valuable information into ways to promote better drinking habits to reduce fluid imbalances. Thus, this investigation evaluated the knowledge, beliefs and behaviors of middle-aged cyclists (MA) that were associated with hydration status and drinking behavior, before and during a 164-km mass-participation event (ambient temperature, 33.3+/ 2.8oC(mean+/-SD)). DESIGN: This cross-sectional field study retrospectively grouped participants by their second urine specific gravity (Usg) measurement of the event morning prior to a mass participation cycling event. Usg was assessed via handheld refractometer. SETTING: The Hotter N' Hell Hundred 164-km cycling event in Wichita Falls, Texas during the month of August. PARTICIPANTS: 36 male recreational cyclists (age, 53+/-9 y(mean+/-SD)). MEASUREMENTS: Participants were grouped according their urine specific gravity as either slightly hyperhydrated (SH; n=12, Usg<=1.014), euhydrated (EUH; n=12, Usg, 1.015-1.020), or slightly dehydrated (SD; n=12, Usg>=1.021). Exercise histories and questionnaires were recorded 24-48 h prior to the cycling event. RESULTS: Regardless of pre-event hydration status, all groups experienced a similar body mass loss during the 164 km event and finished with statistically similar exercise times; also, drinking behavior within all groups was influenced by multiple factors. The primary factors associated with MA cyclist drinking behavior were trial and error/personal history and thirst; further, the majority of cyclists (>=65%) in SH, EUH, and SD believed that dehydration affects performance negatively. The least important factors included rehydration recommendations from scientific and sports medicine organizations, plus information from sports drink manufacturers. CONCLUSION: Considering the complexity of the present findings and the physiological changes that accompany aging such as delayed thirst perception, we recommend that MA cyclists formulate an individualized drinking plan that is based on observations during exercise. PMID- 29484347 TI - Subjective Well-Being Is Associated with Food Behavior and Demographic Factors in Chronically Ill Older Japanese People Living Alone. AB - OBJECTIVES: This study aimed to examine the relationships among subjective well being, food and health behaviors, socioeconomic factors, and geography in chronically ill older Japanese adults living alone. DESIGN: The design was a cross-sectional, multilevel survey. A questionnaire was distributed by post and self-completed by participants. SETTING: The sample was drawn from seven towns and cities across Japan. PARTICIPANTS: A geographic information system was used to select a representative sample of older people living alone based on their proximity to a supermarket. Study recruitment was conducted with municipal assistance. MEASUREMENTS: To assess subjective well-being and food and health behaviors of respondents with disease, a logistic regression analysis was performed using stepwise variable analyses, adjusted for respondent age, socioeconomic status, and proximity to a supermarket. The dependent variable was good or poor subjective well-being. RESULTS: In total, 2,165 older people (744 men, 1,421 women) completed the questionnaire (63.5% response rate). Data from 737 men and 1,414 women were used in this study. Among people with a chronic disease, individuals with good subjective well-being had significantly higher rates than those with poor subjective well-being for satisfaction with meal quality and chewing ability, food diversity, food intake frequency, perception of shopping ease, having someone to help with food shopping, eating home-produced vegetables, preparing breakfast themselves, eating with other people, and high alcohol consumption. A stepwise logistic analysis showed that the factors strongly related to poor subjective well-being were shopping difficulty (men: odds ratio [OR] = 3.19, 95% confidence interval [CI], 1.94-5.23; P < 0.0001; women: OR = 2.20, 95% CI, 1.54-3.14; P < 0.0001), not having someone to help with food shopping (women: OR = 1.41, 95% CI, 1.01-1.97; P = 0.043), not preparing breakfast (women: OR = 2.36, 95% CI, 1.40-3.98; P = 0.001), and eating together less often (women: OR = 1.99, 95% CI, 1.32-3.00; P = 0.002). CONCLUSION: Subjective well-being of people with chronic diseases is associated with food intake and food behavior. The factors that affect poor subjective well-being in chronically ill older Japanese people living alone include food accessibility and social communication. PMID- 29484348 TI - Associations between Proportion of Plasma Phospholipid Fatty Acids, Depressive Symptoms and Major Depressive Disorder. Cross-Sectional Analyses from the AGES Reykjavik Study. AB - BACKGROUND: Deficits in n-3 fatty acids may be associated with depression. However, data are scarce from older adults who are at greater risk of poor dietary intake and of developing depression. OBJECTIVE: To investigate proportion of plasma phospholipid fatty acids with respect to depressive symptoms and major depressive disorder in community dwelling older adults. METHODS: Cross-sectional analyses of 1571 participants in the Age, Gene/Environment Susceptibility (AGES) Reykjavik Study aged 67-93 years. Depressive symptoms were measured using the 15 item Geriatric Depression Scale (GDS-15). Major depressive disorder was assessed according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria using the Mini-International Neuropsychiatric Interview (MINI). RESULTS: Depressive symptoms were observed in 195 (12.4%) subjects and there were 27 (1.7%) cases of major depressive disorder. Participants with depressive symptoms were less educated, more likely to be smokers, less physically active and consumed cod liver oil less frequently. Difference in GDS-15 scores by tertiles of n-3 fatty acid proportion was not significant. Proportion of long chain n-3 fatty acids (Eicosapentaenoic- + Docosahexaenoic acid) were inversely related to major depressive disorder, (tertile 2 vs. tertile 1) OR: 0.31 (95% CI: 0.11, 0.86); tertile 3 vs. tertile 1, OR: 0.45 (95% CI: 0.17, 1.21). CONCLUSION: In our cross sectional analyses low proportions of long chain n-3 fatty acids in plasma phospholipids appear to be associated with increased risk of major depressive disorder. However, the results from this study warrant further investigation in prospective setting with sufficiently long follow-up. PMID- 29484349 TI - High Fructose and High Fat Exert Different Effects on Changes in Trabecular Bone Micro-structure. AB - OBJECTIVES: To compare the effects of high-fat diet (HFD) and high-fructose diet (HFrD) on bone metabolism at different time points, dynamically observe the bone histology and femur trabecular micro-architecture, and analyze the underlying mechanisms. METHODS: Sixty -Five male 6- to 7-week-old C57BL/6J mice were given HFD, HFrD, or standard diets (SD) for 8, 16, and 24 weeks. Micro-computed tomography (MUCT) and bone histology were used to measure bone mass and trabecular micro-structure. Quantitative real-time polymerase chain reaction (qRT PCR) was used to determine the expression of genes related to bone and lipid metabolisms. RESULTS: Compared to SD mice, femoral trabecular bone mass was significantly increased in both HFrD mice and HFD mice at 8 weeks, it continued to be higher in HFrD mice at 16 and 24 weeks with the highest level at 16 weeks, but it was significantly decreased in HFD mice at 16 and 24 weeks. HFD mice showed more epididymal fat accumulation than HFrD mice. mRNA expression of Runx2 was up-regulated at 8 and 16 weeks, but down-regulated at 24 weeks similarly in both HFrD mice and HFD mice. mRNA expression of MMP9 and CTSK was up-regulated at 8 and 16 weeks in HFD mice, but down-regulated at 24 weeks in both HFrD mice and HFD mice. CONCLUSIONS: Our data indicated that the HFrD and HFD had different modulating effects on bone mass. After short-term feeding, both HFrD and HFD showed positive effects on bone mass; however, after long-term feeding, bone mass was decreased in HFD mice. In contrast, the bone mass was first increased and then decreased in the HFrD mice. On the basis of these findings, we speculated that chronic consumption of fat and fructose would exert detrimental effects on bone mass which might a combination action of body mass, fat mass, and bone formation/bone resorption along with proinflammatory factor and bone marrow environment. PMID- 29484350 TI - Osteoarthristis Increases the Risk of Cardiovascular Disease: Data from the Osteoarthritis Initiative. AB - OBJECTIVES: Although osteoarthritis (OA) is a common condition in older adults, the role of OA in increasing cardiovascular disease (CVD) incidence is still debated. The aim of this study was to investigate the association between OA and the onset of CVD in a large database of American adults. DESIGN: Longitudinal. SETTING: Community-dwelling. PARTICIPANTS: People with OA or at high risk of OA. MEASUREMENTS: Osteoarthritis was defined as the presence of OA of the hand, knee, hip, back/neck or of other sites. CVD was defined as self-reported presence of heart attack, heart failure, stroke and other cerebral atherosclerotic conditions, and peripheral artery disease. RESULTS: A total 4,265 persons without CVD (mean age=60.8 years, females=59.2%) at baseline were analyzed (1,775 with OA versus 2,490 without). Over a mean of 8.2 years, according to an adjusted Cox's regression analysis for 11 potential baseline confounders, study participants with OA of any joint had a significantly higher risk of developing CVD compared to those without OA (Hazard ratio (HR): =1.27; 95% CI: 1.03-1.56). The presence of hand OA was associated with a higher risk of developing CVD (HR=1.31; 95%CI: 1.01-1.68) with respect to those who had no OA. Knee, hip and back/neck OA did not, instead, increase the risk of developing CVD. The association between OA and CVD was significant in the women, but not in the men. CONCLUSIONS: OA, in particular, when it affects the hand and in women, was associated with a higher risk of developing CVD. PMID- 29484351 TI - Assessment of Physical Activity of Hospitalised Older Adults: A Systematic Review. AB - BACKGROUND: The assessment of physical activity levels of hospitalised older people requires accurate and reliable measures. Physical activities that older people in hospital commonly engage in include exercises and walking. Measurement of physical activity levels of older inpatients is essential to evaluate the impact of interventions to improve physical activity levels and to determine associations between physical activity in hospital and other health-related outcome measures. OBJECTIVE: To determine which measures are used to measure physical activity of older people in hospital, and to describe their properties and applications. METHOD: A systematic review of four databases: Medline, Embase, CINAHL and AMED was conducted for papers published from 1996 to 2016. Inclusion criteria were participants aged >= 65 years and studies which included measures of physical activity in the acute medical inpatient setting. Studies which specifically assessed the activity levels of surgical patients or patients with neurological conditions such as stroke or brain injury were excluded. All study designs were included in the review. RESULTS: 18 studies were included from 127 articles selected for full review. 15 studies used objective measures to measure the physical activity of older inpatients: 11 studies used accelerometers and four used direct systematic observations. Seven accelerometers were identified including the StepWatch Activity Monitor, activPAL, GENEActiv, Kenz Lifecorder EX, Actiwatch-L, Tractivity and AugmenTech Inc. Pittsburgh accelerometer. Three studies used a subjective measure (interviews with nurses and patients) to classify patients into low, intermediate and high mobility groups. The StepWatch Activity Monitor was reported to be most accurate at step-counting in patients with slow gait speed or altered gait. The activPAL was reported to be highly accurate at classifying postures. CONCLUSION: Physical activity levels of older inpatients can be measured using accelerometers. The accuracy of the accelerometers varies between devices and population-specific validation studies are needed to determine their suitability in measuring physical activity levels of hospitalised older people. Subjective measures are less accurate but can be a practical way of measuring physical activity in a larger group of patients. PMID- 29484352 TI - Interrelatioship between Diet Quality and Depressive Symptoms in Elderly. AB - BACKGROUND: Several observational studies have shown association between diet quality and depression, but few studies have explored the interrelationship between these variables. OBJECTIVE: The aim of this study was to assess the interrelationship between diet quality and depressive symptoms in elderly. DESIGN: Cross-sectional study. SETTING: Population based. PARTICIPANTS: 1,378 elderly in the city of Pelotas, Brazil. MEASUREMENTS: The diet quality was assessed by a short food frequency questionnaire and the prevalence of depressive symptoms was estimated by the abbreviated Brazilian version of the Geriatric Depression Scale (GDS). The association between diet quality and depressive symptoms was assessed using logistic regression. RESULTS: The prevalence of depressive symptoms was 15.3%. Elderly with low-quality diet were more likely to experience depressive symptoms, and the association was almost twice higher in males than in females (men OR = 3.8, 95% CI 1.4, 10.6; women OR = 2.1, 95% CI: 1.4, 3.3). On the other hand, depressive elderly had higher odds of consuming a low-quality diet (OR 2.4, 95% CI: 1.7, 3.8). LIMITATIONS: Self-reported data and cross-sectional design limit our conclusions. CONCLUSIONS: The choice of a low quality diet was associated to a higher risk of depressive symptoms in elderly, and vice-versa. These results highlight the importance of encouraging the choice of healthy food habits, especially in depressed elderly, in order to promote healthy aging. PMID- 29484353 TI - Community-Living Older Adults' Perceptions of Body Weight, Signs of Malnutrition and Sources of Information: a Descriptive Analysis of Survey Data. AB - BACKGROUND: Community-living older adults may be susceptible to malnutrition (undernutrition) due to both physiological and non-physiological causes. The condition develops over time and the early signs and symptoms may not be obvious. Therefore awareness and early identification of nutrition risk factors may prevent, or at least slow, the progression of malnutrition. OBJECTIVE: To describe community-living older adults' understanding of the signs of malnutrition, where they would seek malnutrition information and their self perception of body weight. DESIGN: Older adults (aged >= 65 years) living in the community setting completed an online or paper based questionnaire between May and August 2016. The questionnaire contained a mix of closed and open questions which related to weight perception, weight changes, perceived signs of malnutrition and sources of malnutrition information. Body mass index (BMI) from self-reported data was classified using BMI reference ranges for older adults and compared to self-perceived weight status. Textual data regarding the signs of malnutrition were analysed and reviewed by two authors using content analysis. Descriptive statistics were used to describe participant characteristics. RESULTS: A total of 344 responses were received, the majority (90%) completed online. Mean participant age was 73 years and 57% of participants were female. Most (92%) reported their health to be good/very good. Body weight was perceived to be just right or more than it should be by 87% of underweight women and 97% of underweight men. Although 71% of the participants indicated their body weight had remained stable in the past six months, 37% reported they had been trying to change their weight. Signs of malnutrition resulted in four key categories of (i) psychological, (ii) physical appearance, (ii) bodily function and (iv) weight change. Very few reported the need to locate malnutrition information and indicated the top three sources for information would be (i) general practitioner, (ii) dietitian or (iii) internet. CONCLUSION: This paper has presented useful data about malnutrition from the perspective of the community living older adult. We found there may be uncertainty about the best weight, for older age. As many indicated they had been trying to change their weight, awareness needs to be raised regarding the impact of weight changes on health outcomes in this population. In this study, the internet appeared to be a key provider of nutrition information. Healthcare professionals need to consider how this can be used in an informative manner among community living older adults as a tool for raising awareness about nutrition risk and malnutrition. PMID- 29484354 TI - Temporal Associations between Caregiving Approach, Behavioral Symptoms and Observable Indicators of Aspiration in Nursing Home Residents with Dementia. AB - OBJECTIVES: Dysphagia, or impaired swallowing, is common in nursing home (NH) residents with dementia and contributes to malnutrition and diminished quality of life. Dysphagia also commonly leads to aspiration or passage of food or fluids into the airway, which can result in aspiration pneumonia-a leading cause of death for people with dementia. Currently available interventions for dysphagia aim to modify the risk of aspiration events primarily by modifying diet and positioning to improve the safety of an individual's swallow. However other potentially modifiable contextual factors relevant to mealtime care within NH settings that may influence the occurrence of aspiration events, such as the nature of caregiving interactions or occurrence of dementia-related behavioral symptoms, have not been examined. To address this gap, we examined the temporal associations between caregiving approach and behavioral symptoms as antecedents to observable indicators of aspiration among nursing home (NH) residents with dementia. DESIGN: Secondary analysis of coded, timed-event behavioral data from 33 video-recorded observations of mealtime interactions between NH residents with dementia and caregivers. SETTING/PARTICIPANTS: Residents with dementia who required assistance with mealtime care (n=12) and nursing assistants (n=8) from Memory Care Units (MCU) in 2 Midwestern NHs. RESULTS: Observable indicators of aspiration were significantly more likely to occur during or following task centered caregiver actions than person-centered actions (12% likelihood; Yule's Q 0.89; OR 95% CI 12.70-23.75) and 15-30 seconds after a behavioral symptom (5% likelihood; Yule's Q 0.65; OR 95% CI 4.18-8.57). CONCLUSIONS: These findings provide compelling preliminary evidence that caregiver approach may influence the occurrence of aspiration. Provided the urgent need for more approaches to mitigate the complications associated with dysphagia in people with dementia, even a moderate reduction in aspiration events may be clinically meaningful. Further, well-designed observational studies with individuals with well characterized dysphagia are needed to better understand and characterize these relationships, their temporal structures and their impacts on other relevant outcomes such as eating performance and malnutrition. PMID- 29484356 TI - The impact of Fruit-Vegetable Diet on High Signal Resolution Pulse Wave (HSR-PW) Parameters. AB - OBJECTIVES: The diet and lifestyle affect our life. Inadequate nutrition can cause various diseases including cardiovascular diseases. The aim of this study was to show the correlations between the fruit and vegetable diet and high signal resolution pulse wave parameters. DESIGN: This was an observational study. SETTINGS: The study was done during two-weeks rehabilitation treatment. PARTICIPANTS: In this study 154 people using the fruit and vegetable diet have been examined. MEASUREMENTS: The participants were monitored using a new diagnostic method high signal resolution pulseoximetry (HSR-PW). They were examined two times: before starting the diet and after two weeks of using it. The high signal resolution pulse wave and its characteristic parameters have been compared. RESULTS: Analyzing the research results at the beginning and after two weeks of using this diet, the improvement of selected parameters has been noticed. With the improvement in the pulse wave was observed weight loss, improved blood counts (e.g. cholesterol, triglycerides) as well as decreased blood pressure particularly in people with treated hypertension. CONCLUSIONS: The study shows that applied fruit and vegetable diet influenced favorably the people using it and contributed to the improvement of the HSR-PW parameters which are the source of information about the state of the cardiovascular system. PMID- 29484355 TI - Association between Salivary Hypofunction and Food Consumption in the Elderlies. A Systematic Literature Review. AB - OBJECTIVES: This systematic literature review aims to summarize the existing scientific evidence about the association between a reduced salivary function and food consumption in elderly people. METHODS: A validated search strategy in two databases (PubMed and ISI Web of Knowledge) was carried out and retrieved papers together with their reference lists were screened by two independent reviewers. The quality of the included studies was critically appraised via the Quality Assessment Criteria for Evaluating Primary Research Papers. RESULTS: From the originally identified studies (n=391), only 15 articles (all cross-sectional studies) met the pre-fixed inclusion/exclusion criteria. The methodological quality of the included studies was in general good, although only 3 from 15 obtained the maximum score. The control of confounding factors was the quality variable more poorly rated in the selected studies. Salivary hypofunction was associated with a decrease of the objective chewing and swallowing abilities and taste perception. Moreover, most of the selected studies showed a relationship between salivary hypofunction and food consumption (in terms of appetite loss, unbalanced dietary intake and malnutrition), although no causality could be established. CONCLUSIONS: This study highlights the fact that salivary hypofunction definition and measurements are different across the studies. Therefore, future research efforts should focus on establishing a gold standard to define and identify salivary hypofunction throughout life and on performing longitudinal studies controlling for confounding factors to establish causality. PMID- 29484357 TI - Physical Activity and Changes in White Matter Hyperintensities over Three Years. AB - OBJECTIVES: Since physical activity (PA) has demonstrated benefits for cardiovascular health, it is possible to hypothesize that higher or increasing PA slows the progression of white matter hyperintensities (WMH). We investigated the association between PA and the progression of WMH in non-demented older adults with memory complaints. DESIGN: We included 152 participants (mean age 74.7+/-3.8 years; 63.8% women) in the analyses, in whom information on self-reported PA and MRI was available at both baseline and 3-year follow-up. From the PA questionnaire, the baseline metabolic equivalent of task (MET-minute/week) and changes in MET-minute/week over three years were separately calculated for overall, leisure-time, and non-leisure time PA. WMH volume at baseline and 3-year follow-up was obtained by using an automated segmentation algorithm. RESULTS: Mixed-effect linear regression models showed that none of the baseline PA variables was associated with progression of WMH over time. People who had decreased their PA levels over three years tended to show greater progression of WMH compared with those who had maintained PA levels of >=1200 MET-min/week (roughly equivalent to >=300 minutes of brisk walking) in the unadjusted model (beta+/-SE=4.85+/-2.42, p=0.045); however, this association was no longer significant after adjustment for confounders (beta+/-SE =3.63+/-2.18, p=0.096). CONCLUSIONS: We did not find any significant association between PA and WMH in non-demented older adults with memory complaints. However, decrease over time in PA levels tended to be associated with progression of WMH. A larger longitudinal study with data on PA assessed using objective measures would provide important information in this field. PMID- 29484358 TI - High-Intensity Multimodal Resistance Training Improves Muscle Function, Symmetry during a Sit-to-Stand Task, and Physical Function Following Hip Fracture. AB - OBJECTIVES: Post rehabilitation, older adults with hip fracture display low vertical ground reaction force (vGRF) on the involved lower extremity during a sit-to-stand task and low physical function. The purpose of this study was to test whether muscle performance, involved side vGRF during a sit-to-stand task, and physical function improved following multimodal high-intensity resistance training, when initiated after usual care (2 to 6 months after hip fracture). DESIGN: Case series study, 12 weeks extended high-intensity strength training intervention following hip fracture. SETTING: University hospital outpatient facility. PARTICIPANTS: Twenty-four community-dwelling older adults (mean age 78.4 years (SD 10.4), 16 female/8 male), 3.6 (SD 1.2) months post-hip fracture and discharged from physical therapy participated. Intervention/Measurement: All participants performed sit-to-stand tasks, muscle performance tests, and modified physical performance test (mPPT) before and after 12 weeks (3x/wk) of training. Variables were compared using paired t-tests. RESULTS: The vGRF rate of force development (RFD) and magnitude of discrepancy between limb loading during rising phase of sit-to-stand task (AREA) variables improved post-training (RFD ratio = Pre: 0.78 - Post: 0.82, AREA ratio = Pre: 0.79 - Post: 0.86). Surgical leg extension power gains were large (~65%) while strength gains were moderate (~34%); yielding improved symmetry in both strength (Pre: 0.74 - Post: 0.88) and power (Pre: 0.75 - Post: 0.82). Physical function improved pre-training 25 (SD 5.2) to post training 30 (SD 4.3), (p < 0.001). CONCLUSION: Unique to this study, participants recovering from hip fracture demonstrated improved symmetry in sit to-stand vGRFs, muscle function, and physical function after training. However, a high percentage of patients continued to experience persistently low vGRF of the involved side compared to previous studies of healthy elderly controls. Developing alternative strategies to improve involved side vGRF may be warranted. PMID- 29484359 TI - Trends of Activities of Daily Living Disability Situation and Association with Chronic Conditions among Elderly Aged 80 Years and Over in China. AB - OBJECTIVES: In China, few studies reported the disability situation and the association between disabilities with chronic conditions in aged people. This study investigates the cross-sectional trends of prevalence and severity of activities of daily living disability (ADL) in Chinese oldest-old people from 1998 to 2008, and identified the potential risk factors of disability. DESIGN: A combination of population-based longitudinal prospective study and probabilistically sampling cross-sectional studies. SETTING: The Chinese Longitudinal Healthy Longevity Survey (CLHLS) was based on a random sampling of aged people from twenty-two provinces in China. PARTICIPANTS: A total of 52,667 participants aged from 80 years old to 105 years old sampled in the year of 1998 (n=8,768), 2000 (n=10,940), 2002 (n=10,905), 2005 (n=10,396) and 2008 (n=11,658) were analyzed respectively. RESULTS: The prevalence of ADL disability decreased from the year of 1998 (18%) to 2008 (12%). The disability prevalence significantly increased in 2002 and decreased in 2008 (P<0.001) in total participants than the year of 1998. The prevalence trends of low ADL disability level were almost identical with that of the total ADL disability. Stroke/cerebrovascular disease (CVD) and cognitive impairment were the strongest risk factors of disability. Vision impairment became less associated with ADL disability (P=0.045), while the association between multimorbidity and ADL disability became stronger (P=0.033). CONCLUSIONS: The prevalence of ADL disability declined among the oldest-old population in China from the year of 1998 to 2008 without obeying a linear pattern. Temporal trends of ADL disability mainly attributed to the change of low disability level prevalence. Stroke/CVD and cognitive impairment were the most common risk factors of disability. Vision impairment caused disability has become less common, while risks of multimorbidity related disability increased. PMID- 29484360 TI - The Effects of Green Tea Extract on Working Memory in Healthy Women. AB - OBJECTIVES: This study aimed to examine the effects of green tea extract on working memory in healthy younger (21 - 29 y) and older (50 - 63 y) women. DESIGN: A single-blind, placebo-controlled, crossover design was used. SETTING: A university laboratory. PARTICIPANTS: Twenty non-smoking Caucasian women were recruited in the younger (10) and older (10) age group. INTERVENTION: Subjects received 5.4 g green tea extract (at least 45% epigallocatechin-3-gallate) or placebo (cornstarch) within a 24-hour period. MEASUREMENTS: Working memory was measured by reading span and N-back task paradigm. Blood sample (20 mL) was collected and measured for plasma malondialdehyde (MDA) and total antioxidant capacity (TEAC) concentration. A 24-hour recall was conducted for each treatment period to ensure similar dietary patterns. RESULTS: Green tea extract significantly improved reading span performance in older women, indicated by higher absolute and partial scores of reading span. No significant changes were observed in the younger group. N-back latencies and accuracies were not significantly different after green tea treatment in either age group. Plasma concentration of MDA and TEAC were not different after green tea extract in either group. CONCLUSION: Acute supplementation of decaffeinated green tea extract may enhance working memory capacity of women between 50 to 63 years of age. This study provides preliminary evidence that consumption of green tea extract may enhance the cognitive performance in older adults and thus provide potential chemopreventive benefits in this group. The mechanism should be explored in future research. PMID- 29484361 TI - Frailty Severity and Dietary Variety in Japanese Older Persons: A Cross-Sectional Study. AB - Providing older person individuals with an appropriate intervention at the time of frailty onset is important to prevent the progression of the condition and the need for long-term care. However, the proper timing of starting nutritional and dietary interventions for frail older person subjects has not been fully elucidated. Therefore, in this cross-sectional study, we aimed to clarify the association between frailty and dietary variety among older persons in Japan. We surveyed sex, age, body height, body weight, body mass index, serum albumin level, dietary variety, and nutritional intake indexes in 747 community-dwelling older person individuals who underwent a comprehensive health examination in October 2014. Frailty was determined using the Kihon Checklist (25 questions). Kihon Checklist is widely used to assess frailty in Japan, and their physical, cognitive and social function was evaluated. After excluding those who did not complete the Kihon Checklist and those who required long-term care, frailty status was analyzed in 665 older person individuals. The numbers and percentages of frail, pre-frail and robust older persons were found to be 77 (11.6%), 182 (27.4%) and 406 (61.0%) respectively. Significant differences among robust, pre frail, and frail subjects were observed in terms of age, serum albumin level, alcohol consumption, smoking, and history of diabetes. Among the nutrition related indexes, only the dietary variety showed a significant difference. The results of ordinal logistic regression analysis showed a significant association between frailty and sex, age, smoking status, diabetes, and dietary variety score. Dietary variety was significantly associated with the progression of frailty among older persons in the community. PMID- 29484362 TI - An Initial Investigation of the Neural Correlates of Word Processing in Preschoolers With Specific Language Impairment. AB - Purpose: Previous behavioral studies have found deficits in lexical-semantic abilities in children with specific language impairment (SLI), including reduced depth and breadth of word knowledge. This study explored the neural correlates of early emerging familiar word processing in preschoolers with SLI and typical development. Method: Fifteen preschoolers with typical development and 15 preschoolers with SLI were presented with pictures followed after a brief delay by an auditory label that did or did not match. Event-related brain potentials were time locked to the onset of the auditory labels. Children provided verbal judgments of whether the label matched the picture. Results: There were no group differences in the accuracy of identifying when pictures and labels matched or mismatched. Event-related brain potential data revealed that mismatch trials elicited a robust N400 in both groups, with no group differences in mean amplitude or peak latency. However, the typically developing group demonstrated a more robust late positive component, elicited by mismatch trials. Conclusions: These initial findings indicate that lexical-semantic access of early acquired words, indexed by the N400, does not differ between preschoolers with SLI and typical development when highly familiar words are presented in isolation. However, the typically developing group demonstrated a more mature profile of postlexical reanalysis and integration, indexed by an emerging late positive component. The findings lay the necessary groundwork for better understanding processing of newly learned words in children with SLI. PMID- 29484363 TI - Influence of Language Load on Speech Motor Skill in Children With Specific Language Impairment. AB - Purpose: Children with specific language impairment (SLI) show particular deficits in the generation of sequenced action: the quintessential procedural task. Practiced imitation of a sequence may become rote and require reduced procedural memory. This study explored whether speech motor deficits in children with SLI occur generally or only in conditions of high linguistic load, whether speech motor deficits diminish with practice, and whether it is beneficial to incorporate conditions of high load to understand speech production. Method: Children with SLI and typical development participated in a syntactic priming task during which they generated sentences (high linguistic load) and, then, practiced repeating a sentence (low load) across 3 sessions. We assessed phonetic accuracy, speech movement variability, and duration. Results: Children with SLI produced more variable articulatory movements than peers with typical development in the high load condition. The groups converged in the low load condition. Children with SLI continued to show increased articulatory stability over 3 practice sessions. Both groups produced generated sentences with increased duration and variability compared with repeated sentences. Conclusions: Linguistic demands influence speech motor production. Children with SLI show reduced speech motor performance in tasks that require language generation but not when task demands are reduced in rote practice. PMID- 29484364 TI - Scientific basis of ISO standards on biomechanical risk factors. AB - Among other purposes, companies and regulatory agencies from around the world often adopt International Standard Organization (ISO) standards to determine acceptable practices, equipment and criteria for preventing occupational injuries and illnesses. ISO standards are based on a consensus among individuals who participate in the process. This discussion paper examines the scientific process for the development of several ISO standards on biomechanical factors, comparing it with processes used by other professional organizations, including scientific committees working on the development of clinical guidelines. While the ISO process has value, it also has clear limitations when it comes to developing occupational health and safety standards that should be based on scientific principles. PMID- 29484365 TI - LicA induces autophagy through ULK1/Atg13 and ROS pathway in human hepatocellular carcinoma cells. AB - Chemotherapy is the best choice for the vast majority of hepatocellular carcinoma patients at late stage, but few effective chemotherapy drugs are available in clinic. Licochalcone A (LicA) is a new chemotherapy drug inducing apoptosis as Bcl-2 inhibitor, but few studies report on LicA-induced autophagy. This study investigated the phenomenon and mechanisms of LicA-induced autophagy looking for a targeted combination drug. Human hepatocellular carcinoma cells (HCCs) were treated with LicA, to detect markers of autophagy and to investigate the mechanisms. In order to investigate the role of reactive oxygen species (ROS) in LicA-induced autophagy, ROS, glutathione (GSH) and O2- were measured in LicA treated HCCs, and antioxidant N-Acetyl-L-cysteine (NAC) was cotreated with LicA in HCCs, then mechanisms of ROS-induced autophagy was investigated in LicA or LicA combined with NAC treated HCCs. Finally, the LicA-induced apoptosis was detected in LicA combined with NAC treated HCCs. We first report that LicA can induce autophagy through ULK1/Atg13 and ROS pathway in HCCs, suppression of LicA induced ROS through antioxidant NAC can enhance LicA-induced apoptosis, promoting the function of LicA killing HCCs. LicA can activate the ULK1/Atg13 complex which is upstream of autophagy, additionally, LicA also can promote ROS generation, ROS trigger the expression level of TSC1/2 complex, PRAS40, CTMP, PP2A, PDK1 and Rubicon change, these molecules are upstream of autophagy. In conclusion, LicA can induce autophagy through ULK1/Atg13 and ROS pathway in HCCs, LicA combined with NAC can enhance LicA-induced apoptosis. Our results may provide a novel design for clinical hepatocellular carcinoma therapy trials. PMID- 29484366 TI - BAG3 promotes the phenotypic transformation of primary rat vascular smooth muscle cells via TRAIL. AB - Under normal physiological condition, the mature vascular smooth muscle cells (VSMCs) show differentiated phenotype. In response to various environmental stimuluses, VSMCs convert from the differentiated phenotype to dedifferentiated phenotype characterized by the increased ability of proliferation/migration and the reduction of contractile ability. The phenotypic transformation of VSMCs played an important role in atherosclerosis. Both Bcl-2-associated athanogene 3 (BAG3) and tumor necrosis factor-related apopt-osis inducing ligand (TRAIL) involved in apoptosis. The relationship between BAG3 and TRAIL and their effects the proliferation and migration in VSMCs are rarely reported. This study investigated the effects of BAG3 on the phenotypic modulation and the potential underlying mechanisms in primary rat VSMCs. Primary rat VSMCs were extracted and cultured in vitro. Cell proliferation was detected by cell counting, real-time cell analyzer (RTCA) and EdU incorporation. Cell migration was detected by wound healing, Transwell and RTCA. BAG3 and TRAIL were detected using real-time PCR and western blotting and the secreted proteins in the cultured media by dot blot. The expression of BAG3 increased with continued passages in cultured primary VSMCs. BAG3 promoted the proliferation and migration of primary rat VSMC in a time dependent manner. BAG3 significantly increased the expression of TRAIL while had no effects on its receptors. TRAIL knockdown or blocking by neutralizing antibody inhibited the proliferation of VSMCs induced by BAG3. TRAIL knockdown exerted no obvious influence on the migration of VSMCs. Based on this study, we report for the first time that BAG3 was expressed in cultured primary rat VSMCs and the expression of BAG3 increased with continued passages. Furthermore, BAG3 promoted the proliferation of VSMCs via increasing the expression of TRAIL. In addition, we also demonstrated that BAG3 promoted the migration of VSMCs independent of TRAIL upregulation. PMID- 29484367 TI - Differential effects of alpha-catenin on the invasion and radiochemosensitivity of human colorectal cancer cells. AB - Driven by genetic and epigenetic alterations, progression, therapy resistance and metastasis are frequent events in colorectal cancer (CRC). Although often speculated, the function of cell-cell contact for radiochemosensitivity, particularly associated with E-cadherin/catenin complex, warrants further clarification. In this study, we investigated the role of the E-cadherin/catenin complex proteins under more physiological three-dimensional (3D) cell culture conditions in a panel of CRC cell lines. In contrast to floating spheroids and growth in the laminin-rich matrix, collagen type 1 induced the formation of two distinct growth phenotypes, i.e., cell groups and single cells, in 5 out of the 8 CRC cell lines. Further characterization of these subpopulations revealed that, intriguingly, cell-cell contact proteins are important for invasion, but negligible for radiochemosensitivity, proliferation and adhesion. Despite the generation of genomic and transcriptomic data, we were unable to elucidate the mechanisms through which alpha-catenin affects collagen type 1 invasion. In a retrospective analysis of patients with rectal carcinoma, a low alpha-catenin expression trended with overall survival, as well as locoregional and distant control. Our results suggest that the E-cadherin/catenin complex proteins forming cell-cell contacts are mainly involved in the invasion, rather than the radiochemosensitivity of 3D grown CRC cells. Further studies are warranted in order to provide a better understanding of the molecular mechanisms controlling cell-cell adhesion in the context of radiochemoresistance. PMID- 29484368 TI - DFMG attenuates the activation of macrophages induced by co-culture with LPC injured HUVE-12 cells via the TLR4/MyD88/NF-kappaB signaling pathway. AB - 7-difluoromethoxy-5,4'-dimethoxy-genistein (DFMG) is a novel active chemical entity, which modulates the function and signal transduction of endothelial cells and macrophages (MPs), and is essential in the prevention of atherosclerosis. In the present study, the activity and molecular mechanism of DFMG on MPs was investigated using a Transwell assay to construct a non-contact co-culture model. Human umbilical vein endothelial cells (HUVE-12), which were incubated with lysophosphatidylcholine (LPC), were seeded in the upper chambers, whereas PMA induced MPs were grown in the lower chambers. The generation of reactive oxygen species (ROS) and the release of lactate dehydrogenase (LDH) were measured using the corresponding assay kits. The proliferation and migration were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and wound healing assays, respectively. Foam cell formation was examined using oil red O staining and a total cholesterol assay. The protein expression levels of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88) and nuclear factor (NF)-kappaB p65 were detected by western immunoblotting. The secretion of interleukin (IL)-1beta was examined using an enzyme-linked immunosorbent assay. It was found that LPC significantly increased the generation of ROS and the release of LDH in HUVE-12 cells. The LPC-injured HUVE-12 cells activated MPs under co-culture conditions and this process was inhibited by DFMG treatment. LPC upregulated the expression levels of TLR4, MyD88 and NF-kappaB p65, and the secretion of IL-1beta in the supernatant of the co-cultured HUVE-12 cells and MPs. These effects were reversed by the application of DFMG. Furthermore, CLI-095 and IL-1Ra suppressed the activation of MPs that was induced by co-culture with injured HUVE-12 cells. These effects were further enhanced by co-treatment with DFMG, and DFMG exhibited synergistic effects with a TLR4-specific inhibitor. Take together, these findings revealed that DFMG attenuated the activation of MP induced by co-culture with LPC-injured HUVE-12 cells. This process was mediated via inhibition of the TLR4/MyD88/NF-kappaB signaling pathway in HUVE-12 cells. PMID- 29484369 TI - AMP-activated protein kinase stimulates osteoblast differentiation and mineralization through autophagy induction. AB - Previous studies have reported that adenosine monophosphate-activated protein kinase (AMPK) activation can enhance osteoblast differentiation and mineralization; however, the underlying mechanism is not fully understood. Autophagy also serves an important role in osteoblast mineralization and bone homeostasis. The present study aimed to explore whether activation of AMPK could enhance osteoblast differentiation and mineralization via the induction of autophagy. The fracture healing and nonunion animal models were established and verified by X-ray imaging. Bone maturation was measured by Masson staining and the expression of AMPK, p-AMPK, microtubule-associated proteins 1A/1B light chain 3B II, and p62 in the fracture ends were detected by immunohistochemical staining. The mRNA expression levels of alkaline phosphatase (ALP), osteocalcin ,runt-related transcription factor 2 and BCN1 were determined by reverse transcription-quantitative polymerase chain reaction. 5-Bromo-4-chloro-3-indolyl phosphate/nitro blue tetrazolium staining was used to determine ALP activity and alizarin red staining was adopted to examine mineralization. Western blot analysis was performed to detect protein expression. Autophagosome was observed by Transmission electron microscopy. Small interfering (si)RNA was used to knock down the expression of target gene. In vivo experiments demonstrated that new bone mineralization and maturation was markedly restrained in the nonunion group, alongside decreased AMPK activation and autophagic activity, compared with in the fracture healing group. The results of an in vitro study indicated that AMPK activation stimulated the osteogenic differentiation of MC3T3-E1 cells, with increases in ALP activity, mineralization, and the mRNA expression levels of ALP, osteocalcin and runt-related transcription factor 2. Furthermore, AMPK activation induced autophagy, as determined by upregulation of microtubule-associated proteins 1A/1B light chain 3B, increased autophagosome density and downregulation of p62. In addition, inhibition of autophagy reversed the effects of AMPK activation on osteoblast differentiation. These results suggested that AMPK activation may stimulate osteoblast differentiation and mineralization via the induction of autophagy, and provides evidence to suggest that enhancing AMPK activation and autophagic activity may be a potential novel approach to promote fracture healing. PMID- 29484370 TI - The antitumor activity screening of chemical constituents from Camellia nitidissima Chi. AB - Chemotherapy is the preferred and most common treatment for cancer in clinical practice. An increasing number of researchers all over the world are focusing on natural medicines to find new antitumor drugs, and several reports have shown that Camellia nitidissima (C. nitidissima) Chi could reduce blood-lipid, decrease blood pressure, resist oxidation, prevent carcinogenesis and inhibit tumors. Therefore, the pharmacodynamics of the chemical constituents in C. nitidissima need to be investigated further. In the present study, 16 chemical constituents were isolated from the leaves of C. nitidissima, of which 6 compounds are reported to be found in this plant for the first time. Furthermore, all these phytochemicals were screened for antitumor activity on 4 common cancer cell lines, while compound 3, one oleanane-type triterpene, exhibited the most potential antitumor effects. Interestingly, to our knowledge, this was the first report that compound 3 inhibits cancer cells. Compound 3 inhibited EGFR-mutant lung cancer cell line, NCI-H1975 via apoptosis effect, with an IC50 of 13.37+/ 2.05 uM at 48 h. Based on the data, compound 3 showed potential for antitumor drug development, suggesting the scientific basis for the antitumor activity of C. nitidissima. PMID- 29484371 TI - Ang-(1-7) protects HUVECs from high glucose-induced injury and inflammation via inhibition of the JAK2/STAT3 pathway. AB - Angiotensin (Ang)-1-7, which is catalyzed by angiotensin-converting enzyme 2 (ACE2) from angiotensin-II (Ang-II), exerts multiple biological and pharmacological effects, including cardioprotective effects and endothelial protection. The Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway has been demonstrated to be involved in diabetes associated cardiovascular complications. The present study hypothesized that Ang (1-7) protects against high glucose (HG)-induced endothelial cell injury and inflammation by inhibiting the JAK2/STAT3 pathway in human umbilical vein endothelial cells (HUVECs). HUVECs were treated with 40 mmol/l glucose (HG) for 24 h to establish a model of HG-induced endothelial cell injury and inflammation. Protein expression levels of p-JAK2, t-JAK2, p-STAT3, t-STAT3, NOX-4, eNOS and cleaved caspase-3 were tested by western blotting. CCK-8 assay was performed to assess cell viability of HUVECs. Apoptotic cell death was analyzed by Hoechst 33258 staining. Mitochondrial membrane potential (MMP) was obtained using JC-1. Superoxide dismutase (SOD) activity was tested by SOD assay kit. Interleukin (IL) 1beta, IL-10, IL-12 and TNF-alpha levels in culture media were tested by ELISA. The findings demonstrated that exposure of HUVECs to HG for 24 h induced injury and inflammation. This injury and inflammation were significantly ameliorated by pre-treatment of cells with either Ang-(1-7) or AG490, an inhibitor of the JAK2/STAT3 pathway, prior to exposure of the cells to HG. Exposure of the cells to HG also increased the phosphorylation of JAK2/STAT3 (p-JAK2 and p-STAT3). Increased activation of the JAK2/STAT3 pathway was attenuated by pre-treatment with Ang-(1-7). To the best of our knowledge, the findings from the present study provided the first evidence that Ang-(1-7) protects against HG-induced injury and inflammation by inhibiting activation of the JAK2/STAT3 pathway in HUVECs. PMID- 29484372 TI - Sphingosine kinase inhibitors: A patent review. AB - Sphingosine kinases (SphKs) catalyze the conversion of the sphingosine to the promitogenic/migratory product, sphingosine-1-phosphate (S1P). SphK/S1P pathway has been linked to the progression of cancer and various other diseases including allergic inflammatory disease, cardiovascular diseases, rejection after transplantation, the central nervous system, and virus infections. Therefore, SphKs represent potential new targets for developing novel therapeutics for these diseases. The history and development of SphK inhibitors are discussed, summarizing SphK inhibitors by their structures, and describing some applications of SphK inhibitors. We concluded: i) initial SphK inhibitors based on sphingosine have low specificity with several important off-targets. Identification the off targets that would work synergistically with SphKs, and developing compounds that target the unique C4 domain of SphKs should be the focus of future studies. ii) The modifications of SphK inhibitors, which are devoted to increasing the selectivity to one of the two isoforms, now focus on the alkyl length, the spacer between the head and linker rings, and the insertion and the position of lipidic group in tail region. iii) SphK/S1P signaling pathway holds therapeutic values for many diseases. To find the exact function of each isoform of SphKs increasing the number of SphK inhibitor clinical trials is necessary. PMID- 29484373 TI - Metabolic changes associated with papillary thyroid carcinoma: A nuclear magnetic resonance-based metabolomics study. AB - Papillary thyroid carcinoma (PTC) is the most common thyroid cancer. Nuclear magnetic resonance (NMR)-based metabolomic technique is the gold standard in metabolite structural elucidation, and can provide different coverage of information compared with other metabolomic techniques. Here, we firstly conducted NMR based metabolomics study regarding detailed metabolic changes especially metabolic pathway changes related to PTC pathogenesis. 1H NMR-based metabolomic technique was adopted in conju-nction with multivariate analysis to analyze matched tumor and normal thyroid tissues obtained from 16 patients. The results were further annotated with Kyoto Encyclopedia of Genes and Genomes (KEGG), and Human Metabolome Database, and then were analyzed using modules of pathway analysis and enrichment analysis of MetaboAnalyst 3.0. Based on the analytical techniques, we established the models of principal component analysis (PCA), partial least squares-discriminant analysis (PLS-DA), and orthogonal partial least-squares discriminant analysis (OPLS-DA) which could discriminate PTC from normal thyroid tissue, and found 15 robust differentiated metabolites from two OPLS-DA models. We identified 8 KEGG pathways and 3 pathways of small molecular pathway database which were significantly related to PTC by using pathway analysis and enrichment analysis, respectively, through which we identified metabolisms related to PTC including branched chain amino acid metabolism (leucine and valine), other amino acid metabolism (glycine and taurine), glycolysis (lactate), tricarboxylic acid cycle (citrate), choline metabolism (choline, ethanolamine and glycerolphosphocholine) and lipid metabolism (very-low-density lipoprotein and low-density lipoprotein). In conclusion, the PTC was characterized with increased glycolysis and inhibited tricarboxylic acid cycle, increased oncogenic amino acids as well as abnormal choline and lipid metabolism. The findings in this study provide new insights into detailed metabolic changes of PTC, and hold great potential in the treatment of PTC. PMID- 29484375 TI - [Corrigendum] Candidate of metastasis 1 regulates in vitro growth and invasion of bladder cancer cells. AB - We noted an accidental error in Fig. 5 in the above-mentioned article. The image of the apoptotic analysis of the pEF control cells was accidently duplicated during composition of the final figure, such that it overlapped with the RT112 COM1rib result. A new version of Fig. 5 in featured here, in which the error has been corrected (the correct data for the RT112 COM1rib experiment are now included). It was regrettable that this accidental error occurred. The authors are grateful to the Editor for affording us with the opportunity to publish this corrigendum, and we apologize to the readership of the Journal for any inconvenience caused. [the original article was published in the International Journal of Oncology 42: 1249-1256, 2013; DOI: 10.3892/ijo.2013.1802]. PMID- 29484376 TI - Zoledronate suppresses VEGF-induced capillary tube formation and inhibits expression of interferon-induced transmembrane protein-1 in human umbilical vein endothelial cells. AB - Interferon-induced transmembrane protein 1 (IFITM1) is a member of the interferon induced transmembrane protein family and has recently been identified as a novel protein participant in angiogenesis. Zoledronate (ZON), a nitrogen-containing bisphosphonate, is widely used in the treatment of osteoporosis and to prevent bone metastases of certain cancer types. However, the association between ZON and IFITM1 has remained elusive. The present study investigated the effect of ZON on the expression of IFITM1 during vascular endothelial growth factor (VEGF)-induced capillary tube formation in human umbilical vein endothelial cells. It was observed that cell proliferation and VEGF-induced tube formation were significantly inhibited by treatment with 10 uM ZON. The expression of IFITM1 increased during VEGF-induced tube formation. However, the VEGF-induced increase in IFITM1 expression exhibited a dose- and time-dependent decrease with ZON treatment at the mRNA and protein level. Furthermore, matrix metalloproteinase-9 activation was markedly decreased by ZON treatment. These results suggest that induction of IFITM1 expression may be involved in the anti-angiogenic activity of ZON. PMID- 29484377 TI - GLP-1R agonists ameliorate peripheral nerve dysfunction and inflammation via p38 MAPK/NF-kappaB signaling pathways in streptozotocin-induced diabetic rats. AB - The present study aimed to investigate the mechanism of glucagon-like peptide-1 receptor (GLP-1R) agonists in the progression of diabetic peripheral neuropathy (DPN) in streptozotocin (STZ)-induced diabetic rats, through inflammatory signaling pathways. The DPN rat model was generated by intraperitoneal injection of STZ and then treated with the GLP-1R agonist liraglutide or saline for 8 weeks. These animals were randomly divided into 4 groups (10 rats in each): The normal control + saline group, the normal control + liraglutide group, the diabetic + saline (DM) group and the diabetic + liraglutide (DML) group. The nerve conduction velocity (NCV) in the sciatic nerves of the rats was monitored over a period of 8 weeks. Peripheral serum was obtained for the measurement of blood glucose, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and IL-1beta level. The protein levels of phosphorylated (p-) and total extracellular signal-regulated kinase, c-Jun NH2-terminal kinases, p38 mitogen-activated protein kinases (MAPK), and nuclear and cytoplasmic nuclear factor-kappaB (NF kappaB) were measured through western blot analysis. Sciatic nerve mRNA expression levels of proinflammatory chemokines (TNF-alpha, IL-6 and IL-1beta), chemokines [monocyte chemoattractant protein-1 (MCP-1)], adhesion molecules [intercellular adhesion molecule 1 (ICAM-1)], neurotrophic factors [neuritin, nerve growth factor (NGF) and neuron-specific enolase (NSE)] and NADPH oxidase 4 (NOX4) were evaluated by reverse transcription-quantitative polymerase chain reaction. Subsequent to 8 weeks of treatment with liraglutide, the density of myelin nerve fibers was partially restored in the DML group. The delayed motor NCV and sensory NCV in the DML group were improved. The IOD value of NOX4 staining in the DML group (24.43+/-9.01) was reduced compared with that in the DM group (56.60+/-6.91). The levels of TNF-alpha, IL-1beta and IL-6 in the peripheral serum of the DML group were significantly suppressed compared with those of the DM group. It was also observed that the mRNA expression levels of TNF-alpha, IL-6, IL-1beta, MCP-1, ICAM-1 and NOX4 in the sciatic nerve were attenuated in the DML group. The mRNA expression of neuritin and NGF was significantly increased in the DML group compared with that of the DM group; NSE was reduced in the sciatic nerves of the DML group compared with that of the DM group. Additionally, the protein expression of p-p38 MAPK and NF-kappaB in the DML group was significantly suppressed. These data demonstrated that GLP-1R agonists may prevent nerve dysfunction in the sciatic nerves of diabetic rats via p38 MAPK/NF-kappaB signaling pathways independent of glycemic control. GLP-1R agonists may be a useful therapeutic strategy for slowing the progression of DPN. PMID- 29484378 TI - Exosomes derived from human umbilical cord mesenchymal stem cells improve myocardial repair via upregulation of Smad7. AB - It has been previously reported that exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC)-exosomes exhibit cardioprotective effects on the rat acute myocardial infarction (AMI) models and cardiomyocyte hypoxia injury models in vitro, however the exact mechanisms involved require further investigation. The present study aimed to investigate the repair effects of hucMSC-exosomes on myocardial injury via the regulation of mothers against decapentaplegic homolog 7 (Smad7) expression. Compared with sham or normoxia groups (in vivo and in vitro, respectively), western blotting demonstrated that Smad7 expression was significantly decreased in the borderline area of infraction myocardium and in H9C2(2-1) cells following hypoxia-induced injury. Additionally, microRNA (miR)-125b-5p expression was markedly increased using reverse transcription-quantitative polymerase chain reaction, but was reversed by hucMSC exosomes. Trypan blue staining and lactate dehydrogenase release detection demonstrated that cell injury was significantly increased in the AMI + PBS and hypoxia group compared with in the sham and normoxia groups and was inhibited by hucMSC-exosomes. A dual luciferase reporter gene assay confirmed that Smad7 is a target gene of miR-125b-5p. In addition, miR-125b-5p mimics promoted H9C2(2-1) cell injury following 48 h exposure to hypoxia. Downregulation of Smad7 expression under hypoxia was increased by miR-125b-5p mimics compared with the mimic negative control, and hucMSC-exosomes partially alleviated this phenomenon. In conclusion, hucMSC-exosomes may promote Smad7 expression by inhibiting miR 125b-5p to increase myocardial repair. The present study may provide a potential therapeutic approach to improve myocardial repair following AMI. PMID- 29484374 TI - The post-translational modification, SUMOylation, and cancer (Review). AB - SUMOylation is a reversible post-translational modification which has emerged as a crucial molecular regulatory mechanism, involved in the regulation of DNA damage repair, immune responses, carcinogenesis, cell cycle progression and apoptosis. Four SUMO isoforms have been identified, which are SUMO1, SUMO2/3 and SUMO4. The small ubiquitin-like modifier (SUMO) pathway is conserved in all eukaryotes and plays pivotal roles in the regulation of gene expression, cellular signaling and the maintenance of genomic integrity. The SUMO catalytic cycle includes maturation, activation, conjugation, ligation and de-modification. The dysregulation of the SUMO system is associated with a number of diseases, particularly cancer. SUMOylation is widely involved in carcinogenesis, DNA damage response, cancer cell proliferation, metastasis and apoptosis. SUMO can be used as a potential therapeutic target for cancer. In this review, we briefly outline the basic concepts of the SUMO system and summarize the involvement of SUMO proteins in cancer cells in order to better understand the role of SUMO in human disease. PMID- 29484379 TI - Early intervention with mesenchymal stem cells prevents nephropathy in diabetic rats by ameliorating the inflammatory microenvironment. AB - Diabetic nephropathy (DN) is a major complication of diabetes and represents the leading cause of end-stage renal disease. Mesenchymal stem cell (MSC) treatment has been demonstrated to be effective in DN models by reducing albuminuria and attenuating glomerular injury; however, limited in-depth understanding of the underlying mechanism and a lack of clinical trials hinders its clinical use. Additionally, most of these experimental studies were conducted on the advanced stage of nephropathy, which is difficult to reverse and consequently showed limited therapeutic efficacy. We sought to evaluate whether early intervention by MSCs has the potential to prevent DN onset and progression as well as protect kidney function when intravenously administered to rats with diabetes. Diabetes was induced in adult male SD rats by streptozotocin (STZ) injection (55 mg/kg, i.p.). The diabetic rats were injected with or without bone marrow-derived MSCs (5x106 per rat), via tail vein at 2, 4, 5 and 7 weeks after diabetes onset. Fasting blood glucose (FBG), blood urea nitrogen (BUN) and serum creatinine (Scr) levels in serum samples and glycosuria (GLU), microalbumin (MAU), and albumin to creatinine ratio (ACR) in urine samples were determined. Renal pathology and immunohistochemistry (IHC) for CD68, MCP-1, fibronectin (FN), transforming growth factor-beta (TGF-beta) and pro-inflammatory cytokines were also performed. Expression levels of the above factors as well as interleukin-10 (IL-10), and epidermal growth factor (EGF) were assessed by qPCR and multiplex bead-based suspension array system, respectively. Additionally, MSC tracing in vivo was performed. Ex vivo, peritoneal macrophages were co-cultured with MSCs, and expression of inflammatory cytokines was detected as well. MSC treatment profoundly suppressed renal macrophage infiltration and inflammatory cytokine secretion in diabetic rats, resulting in prominently improved kidney histology, systemic homeostasis, and animal survival, although no significant effect on hyperglycemia was observed. Engrafted MSCs were primarily localized in deteriorated areas of the kidney and immune organs 48 h after infusion. MSC treatment upregulated serum anti-inflammatory cytokines IL-10 and EGF. Ex vivo, MSCs inhibited lipopolysaccharide (LPS)-stimulated rat peritoneal macrophage activation via the downregulation of inflammatory-related cytokines such as IL-6, MCP-1, tumor necrosis factor-alpha (TNF-alpha) and IL-1beta. Our results demonstrated that early intervention with MSCs prevented renal injury via immune regulation in diabetic rats, which restored the homeostasis of the immune microenvironment, contributing to the prevention of kidney dysfunction and glomerulosclerosis. PMID- 29484380 TI - Black rice (Oryza sativa L.) extract modulates ultraviolet-induced expression of matrix metalloproteinases and procollagen in a skin cell model. AB - Exposure of the skin to ultraviolet (UV) radiation causes extracellular matrix (ECM) collapse in the dermis, owing to an increase in matrix metalloproteinase (MMP) production in both the epidermis and dermis, and a decrease in type I collagen expression in the dermis. Recently, black rice (Oryza sativa L.) was reported to have a wide range of pharmacological effects in various settings. However, the effects of black rice extract (BRE) on UV-irradiated skin cells have not yet been characterized. BRE treatment did not affect cell morphology and viability of HaCaT and human dermal fibroblasts (HDF). We demonstrated that BRE downregulated basal and UV-induced MMP-1 expression in HaCaT cells. Furthermore, BRE significantly increased type I procollagen expression, and decreased MMP-1 and MMP-3 expression in UV-irradiated HDF. The underlying mechanisms of these results involve a decrease in p38 and c-Jun N-terminal kinase activity, and suppression of UV-induced activation of activator protein-1 (AP-1). BRE reduced UV-induced reactive oxygen species production in HaCaT cells in a dose-dependent manner. Indeed, mass spectrometry revealed that BRE contained antioxidative flavonoid components such as cyanidin-3-O-beta-D-glycoside and taxifolin-7-O glucoside. These findings suggest that BRE attenuates UV-induced ECM damage by modulating mitogen-activated protein kinase and AP-1 signaling, and could be used as an active ingredient for preventing photoaging of the skin. PMID- 29484381 TI - Sitagliptin ameliorates diabetic nephropathy by blocking TGF-beta1/Smad signaling pathway. AB - Diabetic nephropathy (DN) is the leading cause of end-stage failure of the kidney, but the efficacy of current strategies available for the prevention of DN remains unsatisfactory. The purpose of this study was to assess whether sitagliptin (SIT) has therapeutic potential for prevention of DN and to investigate its possible mechanism. The effects of SIT on DN were investigated in rats with type 2 diabetes mellitus (T2DM) and rat mesangial cells (MCs) induced by high glucose. T2DM rats were administered at a dose of 10 mg/kg SIT. The kidney index, 24 h urinary protein, blood urea nitrogen (BUN), serum creatinine (Cr), accumulation of glycogen and collagens were investigated by different methods. MCs were administered with SIT at doses of 0.1, 1 and 10 umol/ml. The possible mechanism of SIT on protection of diabetic kidney injury was examined by expression of transforming growth factor-beta1 (TGF-beta1)/Smad pathway. The results showed that the SIT-treated diabetic rats significantly reduced diabetic kidney injury by inhibiting the kidney index and attenuating 24 h urinary protein, reducing BUN and serum creatinine, inhibiting progressive renal fibrosis and increassing extracellular matrix including collagen IV and fibronectin. Further studies showed that inhibition of renal fibrosis in SIT-treated diabetic rats and MCs were associated with rebalancing of TGF-beta1/Smad pathway. Sitagliptin may be a potent agent for preventing the progression of DN through inhabiting TGF-beta1/Smad-mediated renal fibrosis. PMID- 29484382 TI - Human umbilical cord mesenchymal stem cells inhibit proliferation of hepatic stellate cells in vitro. AB - The effect of human umbilical cord mesenchymal stem cells (hUC-MSCs) on the proliferation of hepatic stellate cells (HSCs) is largely unknown. The purpose of this study was to explore the mechanism of action of hUC-MSCs on the proliferation of HSCs in vitro. The upper and lower double-cell co-culture system was established between hUC-MSCs and HSCs in the experimental group. HSCs were cultured alone as a negative control group. Cell proliferation and apoptosis were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry, respectively. Cell supernatants were harvested to determine the concentration of transforming growth factor-beta1 (TGF-beta1) by ELISA. mRNA and protein of TGF-beta1, Smad3 and Smad7 in HSCs were determined by reverse transcription-polymerase chain reaction and western blotting, respectively. In the co-culture group, the proliferation of HSCs was significantly inhibited compared with the negative control group at 24 and 48 h (p<0.05). Apoptosis of HSCs in the co-culture group increased compared with that in the negative control group, which was more obvious at 48 h (p<0.05). The concentration of TGF-beta1 in the co-culture group was significantly lower than in the HSCs cultured alone (p<0.05). After HSCs were co-cultured with hUC-MSCs for 48 h, expression of TGF-beta1 and Smad3 mRNA and protein was reduced and expression of Smad7 mRNA and protein was increased compared with the negative control group (p<0.05). hUC-MSCs inhibited proliferation of HSCs, possibly through inhibiting TGF-beta1 and Smad3 expression and increasing Smad7 protein expression. PMID- 29484383 TI - The transcription factor cMaf is targeted by mTOR, and regulates the inflammatory response via the TLR4 signaling pathway. AB - cMaf is a leucine-zipper transcription factor that is involved in cell differentiation, oncogenic transformation, and human diseases; however, the functions of cMaf in inflammatory responses in macrophages are still not fully understood. Western blot analysis showed that cMaf expression was induced by lipopolysaccharide (LPS) stimulation in mouse macrophages. An enzyme-linked immunosorbent assay was performed to detect the level of expression of inflammatory cytokines after knockdown of cMaf expression in macrophages using a small interfering RNA (siRNA). Signaling pathway inhibitor analyses indicated that extracellular signal-related kinase and phosphoinositide 3-kinase contribute to mammalian target of rapamycin phosphorylation (mTOR), which controls cMaf expression at the translational level by regulating the expression of eIF4E binding protein 1 and S6 ribosomal kinase 1 in response to Toll-like receptor 4 signaling. Histopathological findings of the lung and a survival analysis showed that mice transplanted with cMaf-knockdown macrophages were more susceptible to LPS challenge. Taken together, our study revealed that the control of cMaf expression at the translational level by mTOR regulated the expression of inflammatory genes in response to LPS challenge. Moreover, cMaf protected mice from septic shock indicating that cMaf may improve host fitness, thereby enabling the survival of certain infectious diseases. PMID- 29484385 TI - Downregulation of SOX3 leads to the inhibition of the proliferation, migration and invasion of osteosarcoma cells. AB - Sex determining region Y-box protein 3 (SOX3) is involved in embryonic development and tumorigenesis. However, the expression and precise role of SOX3 in osteosarcoma remain unclear. In this study, we reported that SOX3 expression was upregulated in osteosarcoma tissues compared with non-cancerous bone cyst tissues. To elucidate the cellular and molecular function of SOX3, we examined the consequences of SOX3 knockdown in osteosarcoma cells. We found that the downregulation of SOX3 inhibited the proliferation, migration and invasion of osteosarcoma cells. SOX3 downregulation also increased the cell population in the G1 phase and induced cell apoptosis. SOX3 knockdown-mediated cell cycle arrest and cell apoptosis were associated with decreased levels of Cdc25A, cyclin D1, proliferating cell nuclear antigen (PCNA) and Bcl-2, as well as an increased Bax expression. We also found that the downregulation of SOX3 decreased the expression of Snail, Twist and matrix metalloproteinase-9 (MMP-9), and increased E-cadherin expression, resulting in the inhibition of cell migration and invasion. Taken together, our data indicate that SOX3 may serve as an oncogene in osteosarcoma, and SOX3 downregulation may prove to be a novel approach for the inhibition of osteosarcoma progression. PMID- 29484384 TI - Inhibition of cell migration by focal adhesion kinase: Time-dependent difference in integrin-induced signaling between endothelial and hepatoblastoma cells. AB - angiogenesis plays an important role in the development and progression of tumors, and it involves a series of signaling pathways contributing to the migration of endothelial cells for vascularization and to the invasion of cancer cells for secondary tumor formation. Among these pathways, the focal adhesion kinase (FAK) signaling cascade has been implicated in a variety of human cancers in connection with cell adhesion and migration events leading to tumor angiogenesis, metastasis and invasion. Therefore, the inhibition of FAK in endothelial and/or cancer cells is a potential target for anti-angiogenic therapy. In the present study, a small-molecule FAK inhibitor, 1,2,4,5 benzenetetramine tetrahydrochloride (Y15), was used to study the effects of FAK inhibition on the adhesion and migration behaviors of vascular endothelial cells (VECs) and human hepatoblastoma cells. Furthermore, the time-dependent differences in proteins associated with the integrin-mediated FAK/Rho GTPases signaling pathway within 2 h were examined. The results indicated that the inhibition of FAK significantly decreased the migration ability of VECs and human hepatoblastoma cells in a dose-dependent manner. Inhibition of FAK promoted cell detachment by decreasing the expression of focal adhesion components, and blocked cell motility by reducing the level of Rho GTPases. However, the expression of crucial proteins involved in integrin-induced signaling in two cell lines exhibited a time-dependent difference with increased duration of FAK inhibitor treatment, suggesting different mechanisms of FAK-mediated cell migration behavior. These results suggest that the mechanism underlying FAK-mediated adhesion and migration behavior differs among various cells, which is expected to provide evidence for future FAK therapy targeted against tumor angiogenesis. PMID- 29484386 TI - Mangiferin inhibits apoptosis and oxidative stress via BMP2/Smad-1 signaling in dexamethasone-induced MC3T3-E1 cells. AB - Mangiferin is a xanthone glucoside, which possesses antioxidant, antiviral, antitumor and anti-inflammatory functions, and is associated with gene regulation. However, it remains unknown whether mangiferin protects osteoblasts, such as the MC3T3-E1 cell line, against glucocorticoid-induced damage. In the present study, MC3T3-E1 cells were treated with dexamethasone (Dex), which is a well-known synthetic glucocorticoid, in order to establish a glucocorticoid induced cell injury model. After Dex and/or mangiferin treatment, cell viability, apoptosis and reactive oxygen species (ROS) production was measured by Cell Counting kit-8 (CCK-8) and flow cytometry, respectively, and the concentration of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and macrophage colony stimulating factor (M-CSF) was measured by ELISA. The expression of bone morphogenetic protein 2 (BMP2), phosphorylated-SMAD family member 1 (p-Smad-1), t Smad-1, osterix (OSX), osteocalcin (OCN), osteoprotegerin (OPG), receptor activator of nuclear factor-kappaB (RANK), RANK ligand (RANKL), B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) was measured by real-time PCR and/or western blot analysis. The results indicated that pretreatment of MC3T3-E1 cells with mangiferin for 3 h prior to exposure to Dex for 48 h significantly attenuated Dex-induced injury and inflammation, as demonstrated by increased cell viability, and decreases in apoptosis, ROS generation, and the secretion of TNF alpha, IL-6 and M-CSF. In addition, pretreatment with mangiferin markedly reduced Dex-induced BMP2 and p-Smad-1 downregulation, and corrected the expression of differentiation- and apoptosis-associated markers, including alkaline phosphatase, OSX, OCN, OPG, RANK, RANKL, Bcl-2 and Bax, which were altered by Dex treatment. Similar to the protective effects of mangiferin, overexpression of BMP2 suppressed not only Dex-induced cytotoxicity, but also ROS generation, and the secretion of TNF-alpha, IL-6 and M-CSF. In conclusion, the results of the present study are the first, to the best of our knowledge, to demonstrate that mangiferin protects MC3T3-E1 cells against Dex-induced apoptosis and oxidative stress by activating the BMP2/Smad-1 signaling pathway. PMID- 29484387 TI - Upregulation of AKAP12 with HDAC3 depletion suppresses the progression and migration of colorectal cancer. AB - A-kinase anchor protein 12 (AKAP12; also known as Gravin) functions as a tumor suppressor in several human primary cancers. However, the potential correlation between histone deacetylase 3 (HDAC3) and AKAP12 and the underlying mechanisms remain unclear. Thus, in this study, in an aim to shed light into this matter, the expression levels of HDAC3 and AKAP12 in 96 colorectal cancer (CRC) and adjacent non-cancerous tissues, as well as in SW480 cells were examined by immunohistochemical, RT-qPCR and western blot analyses. The effects of HDAC3 and AKAP12 on the proliferation, apoptosis and metastasis of CRC cells were examined by cell counting kit-8 (CCK-8) assay, colony formation assays, flow cytometry, cell cycle analysis and Transwell assays. The results revealed that the reduction or loss of AKAP12 expression was detected in 69 (71.8%) of the 96 tissue specimens, whereas HDAC3 was upregulated in 50 (52.1%) of the 96 tumor tissue specimens. AKAP12 expression was markedly increased upon treatment with the HDAC3 inhibitors, trichostatin A (TSA) and RGFP966, at both the mRNA and protein level. Mechanistically, the direct binding of HDAC3 within the intron-1 region of AKAP12 was identified to be indispensable for the inhibition of AKAP12 expression. Moreover, the proliferation, colony-forming ability, cell cycle progression and the migration of the CRC cells were found to be promoted in response to AKAP12 silencing or AKAP12/HDAC3 co-silencing, whereas transfection with si-HDAC3 yielded opposite effects. Apart from the elevated expression of the anti apoptotic protein, Bcl-2, after AKAP12 knockdown, the increased activity of PI3K/AKT signaling was found to be indispensable for AKAP12-mediated colony formation and migration. On the whole, these findings indicate that AKAP12 may be a potential prognostic predictor and therapeutic target for the treatment of CRC in combination with HDAC3. PMID- 29484388 TI - Increased cytomegalovirus replication by 5-Azacytidine and viral-induced cytoplasmic expression of DNMT-1 in medulloblastoma and endothelial cells. AB - Among all brain tumors diagnosed in children, medulloblastomas (MBs) are associated with a poor prognosis. The etiology of MB is not fully understood, yet the impact of epigenetic alterations of oncogenes has previously been established. During the past decade, the human cytomegalovirus (HCMV) has been detected in several types of cancer, including MB. Since DNA methylation occurs in the cell nucleus and this is considered a host defence response, we studied the impact of HCMV infection on DNA methyltransferase (DNMT-1) in MB (D324) cells, human umbilical vein endothelial cells (HUVECs) as well as in MB tissue sections. We hypothesized that infection and DNMT-1 intracellular localization are linked. Uninfected and HCMV-infected D324 cells and HUVECs were analyzed for HCMV immediate early (HCMV-IE) protein, HCMV-glycoprotein B (HCMV-gB) and DNMT-1 using immunofluorescence staining and quantitative ELISA. DNMT-1 localized to the nucleus of uninfected and HCMV-IE- expressing D324 cells and HUVECs, but accumulated in the extra nuclear space in all HCMV-gB-positive cells. Inhibition of HCMV late protein expression by Cymevene(r) (ganciclovir) prevented the cytoplasmic localization of DNMT-1. Treatment of HCMV- infected D324 cells and HUVECs with the methylation inhibitor 5-Azacytidine (5AZA), significantly increased HCMV-IE and HCMV-gB gene transcription and protein expression. Immunohistochemical staining of DNMT-1 and HCMV proteins in MB cancer tissue sections revealed both nuclear and cytoplasmic DNMT-1 localization. In conclusion, DNMT-1 resides in the cytoplasm of HCMV-gB-expressing HUVECs and D324 cells. Increased viral protein synthesis in 5AZA-treated cells suggests that HCMV replication may benefit from a DNA methyltransferase-free cellular environment. Our findings emphasize the importance of assessing potential viral activation in the treatment of MB patients with epigenetic drugs. PMID- 29484389 TI - mTOR is involved in stroke-induced seizures and the anti-seizure effect of mild hypothermia. AB - Stroke is considered an underlying etiology of the development of seizures. Stroke leads to glucose and oxygen deficiency in neurons, resulting in brain dysfunction and injury. Mild hypothermia is a therapeutic strategy to inhibit stroke-induced seizures, which may be associated with the regulation of energy metabolism of the brain. Mammalian target of rapamycin (mTOR) signaling and solute carrier family 2, facilitated glucose transporter member (GLUT)-1 are critical for energy metabolism. Furthermore, mTOR overactivation and GLUT-1 deficiency are associated with genetically acquired seizures. It has been hypothesized that mTOR and GLUT-1 may additionally be involved in seizures elicited by stroke. The present study established global cerebral ischemia (GCI) models of rats. Convulsive seizure behaviors frequently occurred during the first and the second days following GCI, which were accompanied with seizure discharge reflected in the EEG monitor. Expression of phosphor (p)-mTOR and GLUT-1 were upregulated in the cerebral cortex and hippocampus, as evidenced by immunohistochemistry and western blot analyses. Mild hypothermia and/or rapamycin (mTOR inhibitor) treatments reduced the number of epileptic attacks, seizure severity scores and seizure discharges, thereby alleviating seizures induced by GCI. Mild hypothermia and/or rapamycin treatments reduced phosphorylation levels of mTOR and the downstream effecter p70S6 in neurons, and the amount of GLUT-1 in the cytomembrane of neurons. The present study revealed that mTOR is involved in stroke-induced seizures and the anti-seizure effect of mild hypothermia. The role of GLUT-1 in stroke-elicited seizures appears to be different from the role in seizures induced by other reasons. Further studies are necessary in order to elucidate the exact function of GLUT-1 in stroke-elicited seizures. PMID- 29484390 TI - Paeoniflorin inhibits IL-1beta-induced chondrocyte apoptosis by regulating the Bax/Bcl-2/caspase-3 signaling pathway. AB - Apoptosis serves a pivotal role in the pathogenesis of osteoarthritis (OA). Increasing evidence has demonstrated that paeoniflorin exerts key properties (including anticancer, anti-inflammation and neuroprotective) for clinical applications. However, the precise role of paeoniflorin in articular cartilage apoptosis remains unknown. The present study explored the effects and potential molecular mechanism of paeoniflorin on rat chondrocyte apoptosis. Rat articular chondrocytes were cultured in monolayers. The lactate dehydrogenase (LDH) release rate of cells was determined by an LDH release assay. Annexin V-fluorescein isothiocyanate and propidium iodide staining were performed to detect early and advanced apoptotic cells by flow cytometry. The activity of caspase-3 in chondrocytes was determined using a caspase-3 activity assay. The expression of B cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein (Bax) was examined by reverse transcription-quantitative polymerase chain and western blotting. The present study also examined the protein kinase B (Akt) signaling pathway by western blotting. Treatment with 25 or 50 uM paeoniflorin markedly decreased the release of LDH and the ratio of apoptotic cells in interleukin (IL)-1beta-induced rat chondrocytes. Paeoniflorin treatment decreased the mRNA and protein levels of Bax, and increased the level of Bcl-2. Paeoniflorin also reduced the activity of caspase-3 in chondrocytes. Furthermore, paeoniflorin was determined to regulate the Akt signaling pathway by increasing Akt phosphorylation. Therefore, paeoniflorin may exert its protective effect by inhibiting apoptosis in IL-1beta induced rat chondrocytes and thus, may be an effective agent in the prevention and treatment of OA. PMID- 29484391 TI - Melatonin attenuated inflammatory reaction by inhibiting the activation of p38 and NF-kappaB in taurocholate-induced acute pancreatitis. AB - The aim of the present study was to investigate the protective mechanism underlying of melatonin in severe acute pancreatitis (SAP). A total of 64 male Sprague-Dawley rats were randomly divided into four groups: The sham operation (SO) group, SAP group, melatonin treatment (MLT) group and p38 inhibitor (SB203580) treatment (SB) group. Acute pancreatitis was induced by 5% taurocholate through retrograde infusion into the biliopancreatic ducts. The melatonin and SB203580 treatment groups were administered with MLT and SB 30 min before operation the induction of SAP. Rats in each group were euthanized at 6 and 12 h following SAP induction. Blood and pancreatic tissues were removed for inflammatory examination. Peripheral blood mononuclear cells (PBMCs) were isolated following sacrifice to measure the phosphorylation of p38 and nuclear factor-kappaB (NF-kappaB was measured as p65 and phosphorylation of p65). The pretreatment of melatonin significantly attenuated the severity of pancreatitis. In addition, melatonin also reduced serum amylase and proinflammatory cytokine levels, including tumor necrosis factor-alpha, interleukin (IL)-1 and IL-6. The mean pathological scores for pancreatic tissues in the MLT group were higher than those for samples in the SO group, but were lower than those for samples in the SAP group at each time-point. Phosphorylation of p38 and p65 levels in the melatonin treatment group were lower than that in the SAP group, and higher in the SAP group than in the SO group, and the SB203580 treatment group. Furthermore, melatonin significantly inhibited the activation of p38 and NF kappaB in PBMCs. The authors revealed that melatonin may attenuate inflammatory reactions by inhibiting the activation of p38 MAPK and NF-kappaB in both acute pancreatitis rats and PBMCs. SAP is a severe disease with a high risk of morbidity and mortality. It is important to attenuated inflammatory reaction in acute pancreatitis. Thus, the authors studied melatonin, which is synthesized by the pineal gland and released into the blood. Previous studies have shown that melatonin serves a protective role in the early course of human acute pancreatitis, and melatonin concentration variations are closely related to the severity of acute pancreatitis. It may be concluded that melatonin may attenuates inflammatory reactions by inhibiting the activation of p38 MAPK and NF-kappaB in both acute pancreatitis rats and PBMCs. PMID- 29484392 TI - Melatonin induces anti-inflammatory effects via endoplasmic reticulum stress in RAW264.7 macrophages. AB - Melatonin, which is predominantly secreted by the pineal gland and is released into the blood, appears to have anti-inflammatory properties. Several studies have shown that melatonin can relieve lipopolysaccharide-induced inflammatory responses of RAW264.7 cells. However, the mechanisms underlying this anti inflammatory effect remain to be fully elucidated, particularly the association between melatonin and endoplasmic reticulum (ER) stress (ERS). Therefore, the present study examined the anti-inflammatory activity of melatonin in RAW264.7 cells and analyzed its molecular mechanisms in ERS. The RAW264.7 cells were stimulated by lipopolysaccharide and treated with melatonin. A Cell Counting Kit 8 assay was used to assess the toxicity of melatonin. The degree of inflammation was evaluated using ELISA. The expression levels of ERS-associated protein molecules were examined using reverse transcription-quantitative polymerase chain reaction and western blot analyses. The results revealed that melatonin had no toxic effect on the RAW264.7 cells at the range of concentrations used in the experiment. Lipo-polysaccharide stimulated the cells to produce inflammatory molecules; in the early stage, proteins associated with ERS increased, and then apoptosis occurred. The cells treated with melatonin exhibited attenuated inflammation, decreased expression of ERS-associated proteins and inhibition of apoptosis. Taken together, the results of the present study showed that melatonin may attenuate the inflammatory response by inhibiting the activation of ERS in RAW264.7 macrophages. PMID- 29484393 TI - Spontaneous adipogenic differentiation potential of adipose-derived stem cells decreased with increasing cell passages. AB - Primary adipose-derived stem cells (ADSCs) are a mixture of cell types including preadipocytes having the ability to spontaneously differentiate into adipocytes. The aim of the present study was to compare the spontaneous adipogenic differentiation potential of ADSCs at different passages to determine whether it decreased with continuous cell passages. Mouse ADSCs (mADSCs) were harvested and cells from passages 1 to 5 were used for experiments. The proliferation of mADSCs at different passages was tested using the cell counting kit-8 assay. Reverse transcription-quantitative polymerase chain reaction was used to determine relative mRNA expression levels of CCAAT/enhancer binding protein alpha (Cebpa and C/EBPalpha) and peroxisome proliferator-activated receptor gamma (Pparg and PPARgamma), and western blot analysis was used to investigate C/EBPalpha and PPARgamma protein expression. The cells were cultured using DMEM. The fixed cells were then stained using Oil Red O on days 14 and 28, and the obtained extracted dye was monitored for absorbance. The 510 nm absorbance from passages 1 to 5 was observed to be statistically different. The relative expression levels of Cebpa and Pparg for mADSCs from passage 1 were significantly higher when compared with those for mADSCs from passages 2 to 5 on days 3, 5 and 7. However, no difference was identified in the expression levels of proteins C/EBPalpha and PPARgamma for different passages. Although the mRNA expression levels of Pparg from passages 4 to 5 were significantly higher when compared with those from passage 1, the results of Oil Red O absorbance, mRNA expression levels of Cebpa, and the protein expression levels of C/EBPalpha and PPARgamma exhibited no difference between mADSCs from passages 1 to 5 when cultured with induced adipogenic differentiation medium. Therefore, it was concluded that the spontaneous adipogenic differentiation potential of ADSCs decreased with continuous cell passages. PMID- 29484394 TI - Anti-cancer effects of a novel Pan-RAF inhibitor in a hepatocellular carcinoma cell line. AB - The RAF/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK (RAF/MEK/ERK) signaling cascade serves a prominent role in hepatocellular carcinoma (HCC) proliferation. Sorafenib (BAY 43-9006) is a potent multikinase inhibitor of RAF kinases and a few receptor tyrosine kinases. Additionally, sorafenib causes apoptosis in a number of human tumor cell lines such as leukemia cell lines. Sorafenib is the first targeted drug to prolong the overall survival of patients with advanced HCC. However, sorafenib activity is less favorable in certain cancers, including sarcomas and melanomas, due to patient insensitivity and drug resistance. In the present study, a novel bi-aryl urea, N-(3-trifluoromethylphenyl)-N'-(2-methyl-4-(6 cyclopropanecarboxamido-pyrimidin-4-yl) oxyphenyl) urea (CBI-5725), is shown to be a potential candidate for the treatment of liver cancer. In the present study, the in vitro activities of CBI-5725 and sorafenib in PLC/PRF/5 HCC cells were examined and the corresponding in vivo antitumor activities in PLC/PRF/5 human tumor xenografts. An alamar blue assay confirmed that CBI-5725 was more cytotoxic than sorafenib to PLC/PRF/5 cells, suggesting that CBI-5725 inhibited tumor cell proliferation more potently than sorafenib. CBI-5725 inhibited the RAF/MEK/ERK signaling pathway to the same extent as sorafenib. In addition, CBI-5725 elicited cell cycle arrest in the G2/M phase, while sorafenib did not markedly alter the cell cycle. Furthermore, CBI-5725 induced apoptosis more strongly than sorafenib in a dose-dependent manner, which may be attributed to greater caspase-3 and poly(adenosine 5'-diphosphate-ribose) polymerase activation by CBI-5725. In the PLC/PRF/5 xenograft model, 2 mg/kg CBI-5725 inhibited tumor growth by 73%. At doses ranging from 6 to 18 mg/kg, CBI-5725 nearly completely prevented tumor growth. These results imply that the antitumor efficacy of CBI-5725 in HCC models may result from the suppression of the RAF/MEK/ERK signaling pathway, the induction of cell cycle arrest in the G2/M phase, and the initiation of caspase-3 dependent apoptosis. These observations suggested that CBI-5725 may be a potent novel compound for the treatment of HCC. PMID- 29484395 TI - Identification of candidate genes and long non-coding RNAs associated with the effect of ATP5J in colorectal cancer. AB - The incidence and development of colorectal cancer (CRC) is a process with multiple gene interactions. We have previously demonstrated that ATP synthase coupling factor 6, mitochondrial (ATP5J) is associated with CRC migration and 5 fluorouracil resistance; nevertheless, the exact molecular mechanism remains unclear. The following study uses microarray and bioinformatics methods to identify candidate genes and long non-coding RNAs (lncRNAs) in CRC cells (two pairs) with upregulated and downregulated ATP5J. Briefly, a total of 2,190 differentially expressed mRNAs (DEmRNAs) were sorted. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was performed for 4 DEmRNAs to validate the results of microarray analysis. Functional annotation and pathway enrichment were analyzed for DEmRNAs using the Database for Annotation, Visualization and Integrated Discovery. Significantly enriched pathways included the regulation of gene expression and cell growth. The protein-protein interaction network was constructed, and AKT serine/threonine kinase 2 (AKT2) was considered as one of the hub genes. For further analysis, 51 DEmRNAs and 30 DElncRNAs were selected that were positively or negatively associated with the expression of ATP5J in the two cell pairs. X-inactive specific transcript (XIST), premature ovarian failure 1B (POF1B) and calmin (CLMN) were identified in the DEmRNA-DElncRNA co-expression network. The expression of AKT2 and XIST in CRC cells was confirmed by RT-qPCR. To sum up, the candidate genes and lncRNAs, as well as potential signaling pathways, which were identified using integrated bioinformatics analysis, could improve the understanding of molecular events involved in the function of ATP5J in CRC. PMID- 29484396 TI - Effects of sheep/goat whey protein dietary supplementation on the redox status of rats. AB - The purpose of the present study is to estimate the effects of sheep/goat whey protein dietary supplementation on the redox status of blood and tissues of rats. Twelve male Wistar rats were divided into the control group (standard commercial diet) and whey group [standard commercial diet + sheep/goat whey protein (1 g kg b.w/day)] (6 rats/group). The animals were maintainted on their respective diet for 28 days. At the end of the experimental period, reduced glutathione, catalase activity, total antioxidant capacity, thiobarbituric reactive substances, protein carbonyls and the decomposition rate of H2O2 were measured in blood and tissues of rats. According to the results, the rats fed with the sheep/goat whey protein exhibited improved antioxidant status and decreased free radical-induced toxic effects on lipids and proteins. Specifically, in blood, GSH and CAT levels were significantly increased while TBARS and protein carbonyl levels were significantly decreased compared to the control group. Regarding the effects on tissues, it was observed that GSH levels were significantly increased in small intestine, quadriceps muscle, pancreas and lung tissue compared to the control group. The decomposition rate of H2O2 was significantly decreased in liver, brain and quadriceps muscle, but was significantly increased in spleen tissue compared to the control group. TBARS levels were significantly decreased in liver, brain, quadriceps muscle, pancreas, lung and spleen tissue compared to the control group. Finally, protein carbonyl levels were significantly decreased in brain, small intestine, kidney, pancreas and spleen tissue compared to the control group. Thus, the present findings show the beneficial effects of sheep/goat whey protein, a by-product of cheese manufacturing, on the redox status in an in vivo model. PMID- 29484397 TI - Adenoviruses-mediated RNA interference targeting cytosolic phospholipase A2alpha attenuates focal ischemic brain damage in mice. AB - Cerebral ischemia injury is a clinical, frequently occurring disease, which causes a heavy burden on society and families. It has been demonstrated that cytosolic phospholipase A2alpha (cPLA2alpha) is significant in neurological injury caused by ischemic brain injury, and inhibition of cPLA2alpha may reduce stroke injury. In the present study, the role of cPLA2alpha was investigated in a mouse model of middle cerebral artery occlusion and/or reperfusion (MCAO/R) using an effective cPLA2alpha inhibitor and adenoviruses-mediated RNA interference. The most effective recombinant adenovirus encoding cPLA2alpha small interfering RNA (pAd-siRNA-cPLA2alpha) was constructed and selected. MCAO/R surgery is used to construct the model of focal ischemic brain damage in mice. Adenoviruses-mediated RNA interference targeting cPLA2alpha was administered by stereotactic surgery 2 h before the MCAO/R. The expression/activity of cPLA2alpha and cPLA2alpha-derived injurious lipid mediators was assessed. pAd-siRNA-cPLA2alpha-treated animals (RNA interference; RNAi group) were compared with pAd-siRNA-control-treated animals (negative group) with regard to neurological deficit, motor function, pathological changes, apoptosis, and infarct volume. The RNAi group animals reduced the expression level of cPLA2alpha, as determined by western blotting and reverse transcription-quantitative polymerase chain reaction, the improvement of locomotor function was evaluated by rotarod test, and the decrease of apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end-labeling staining. The decreased infarct areas were evaluated by 2,3,5 triphenyltetrazolium chloride staining. The expression levels of prostaglandin E2, leukotrienes B4, lysophosphatidylcholine and free fatty acids were reduced in the RNAi group when compared with the negative control group. Thus, the data indicates that the expression level of cPLA2alpha was effectively controlled by pAd-siRNA-cPLA2alpha treatment. pAd-siRNA-cPLA2alpha treatment, in reducing the levels of inflammatory factors, neurological deficit and tissue damage, represents an effective potential therapeutic strategy. pAd-siRNA-cPLA2alpha reduces cPLA2alpha expression levels with long-term efficacy, thereby improving functional deficits and effectively attenuating ischemic brain damage. Thus, pAd siRNA-cPLA2alpha shows potential value for therapeutic evaluation in ischemic brain damage. PMID- 29484398 TI - Pannexin-1 is involved in neuronal apoptosis and degeneration in experimental intracerebral hemorrhage in rats. AB - Pannexins serve an important role in the regulation of extracellular neuronal regenerative currents and cellular signal transduction of glial cells; however, the effects of pannexins in various cerebrovascular diseases have not been reported. The present study focused on the expression and influence of pannexins in a rat model of intracerebral hemorrhage (ICH), and confirmed that pannexins (including Pannexin-1, Pannexin-2 and Pannexin-3) are expressed in rat brain tissues. However, only the expression of Pannexin-1 was significantly increased and peaked 48 h post-ICH. Following treatment with carbenoxolone (CBX), which is an inhibitor of Pannexin-1, apoptosis and neuronal degeneration in the brain tissues around the ICH hematoma decreased. The extent of secondary brain injury due to ICH was also alleviated. Compared with rats in the ICH-only group, recovery of neurocognitive functions improved significantly in the CBX-treated groups. Results from the present study suggested that the upregulation of Pannexin-1 expression may be involved in apoptosis and degeneration of neurons in the rat brain following ICH, and may contribute to subsequent cognitive dysfunction. PMID- 29484399 TI - Generation of an anti-angiogenic endothelial progenitor cell line via endostatin gene transfer. AB - The viability of endothelial progenitor cells (EPCs) as a therapeutic treatment for neovascularization (NV) was subject to investigation in the present study. Furthermore, endostatin has previously been demonstrated to be an inhibitor of angiogenesis and a suppressant of vascular leakage. The aim of the present study was to generate transgenic EPCs with anti-angiogenic effects for the treatment of ocular NV. EPCs were obtained from rat peripheral blood samples and then verified. A lentiviral-endostatin-green fluorescent protein recombinant construct was generated and used to infect EPCs. Transfected cells were then subjected to puromycin selection. Reverse transcription-quantitative polymerase chain reaction and a western blot assay were then applied in order to determine both the endostatin mRNA and protein expression levels, respectively. In addition, vascular endothelial growth factor (VEGF) expression levels were also detected in order to observe the anti-angiogenic effect of the endostatin-transfected EPCs. Following puromycin (1 ug/ml) selection for 4 days, a stable endostatin transfected EPC line was generated. In this stable endostatin-transfected EPC line, the expression levels of endostatin increased; whereas the expression levels of VEGF decreased. The results of the present study revealed that EPCs can be genetically modified to overexpress endostatin, which may provide the cells with an anti-angiogenic effect via increased expression of endostatin and decreased expression of VEGF. Thus, EPCs genetically modified to overexpress endostatin may serve as a potential therapeutic agent for ocular NV treatment. PMID- 29484400 TI - Gli family zinc finger 1 is associated with endothelin receptor type B in Hirschsprung disease. AB - Hirschsprung disease (HSCR) is a newborn colorectal disease characterized by an absence of ganglia in the distal gut. Hedgehog (Hh) and endothelin signaling serve important roles in gastrointestinal tract formation. Alterations in the signaling pathways disrupt the development of enteric neural crest cells (ENCCs). It is not known whether there is any coordination between these pathways in the pathogenesis of HSCR. In the present study, tissue samples from 35 patients with HSCR, including stenotic aganglionosis gut and normal ganglionic gut, were obtained. The expression of Gli family zinc finger 1 (Gli1) and endothelin receptor type B (EDNRB) was determined using reverse transcription-quantitative polymerase chain reaction, immunohistochemistry and western blotting. In addition, the SK-N-SH cell line was used to investigate the association between Hh signaling and the expression of EDNRB. The results revealed aberrant expression of Gli1 in the aganglionic segments, as well as decreased expression of Gli1 in tissues from 7 patients with HSCR exhibited, whereas tissues from 9 patients with HSCR exhibited increased Gli1 expression compared with the expression in the normal tissues. There was a negative association between EDNRB expression and Gli1 expression in the same sample. Knockdown of Gli1 by small interfering RNA and inhibition of Hh signaling by Vismodegib in SK-N-SH cells increased EDNRB expression. By contrast, upregulation of Gli1 expression by plasmids and activation of Hh signaling by Purmorphamine decreased EDNRB expression. Furthermore, premature enteric ganglia were observed in 4 patients with HSCR with decreased Gli1 expression. Thus, the results of the present study suggest that altered Gli1 expression negatively regulates EDNRB expression in patients with HSCR. The increased expression of EDNRB induced by decreased Gli1 expression may represent a novel mechanism in HSCR. PMID- 29484401 TI - MicroRNA-210 promotes angiogenesis in acute myocardial infarction. AB - MicroRNA-210 (miRNA-210) has been reported to be associated with angiogenesis and may serve important roles in acute myocardial infarction (AMI), which remain unclear. The present study sought to evaluate the efficacy of miRNA-210 in AMI and to examine the potential associated mechanisms. AMI models were established in Sprague-Dawley rats. The expression of miRNA-210 was upregulated via transfection with lentivirus-mediated agonists and quantitative analysis was performed using the reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Immunoblotting and RT-qPCR were separately used to detect the expression levels of hepatocyte growth factor (HGF) in heart samples, while only the protein expression level of beta-myosin heavy chain (beta-MHC) was assessed. The expression of HGF in human umbilical vein endothelial cells under hypoxic conditions was silenced by transfecting with small interfering RNA, as demonstrated by the determination of associated protein expression levels. The microvessel density (MVD) of the infarcted myocardium was selected to be the angiogenesis efficacy endpoint, which was evaluated by platelet endothelial cell adhesion molecule immunostaining. Markedly increased expression of HGF was observed among the AMI rats receiving miRNA-210 agonists, demonstrated via quantitative analyses using RT-qPCR or western blotting. Promotion of angiogenesis was observed with the increased MVD. Improved cardiac function in the rats was subsequently noted, as they exhibited improved left ventricular fractional shortening and left ventricular ejection fraction percentages, which may result from improved cardiac contractility indicated by attenuating the increase in beta-MHC protein expression. Overexpression of miRNA-210 appeared to be an advantageous therapeutic tool for treating AMI, primarily due to its promoting effects on angiogenesis in the infarcted myocardium by stimulating HGF expression and inducing improved left ventricular remodeling, leading to improved cardiac function. PMID- 29484402 TI - Pharmacological activities of a novel plant species, Huernia Sp. Nov. aff. Boleana growing in the high mountains of southwest Saudi Arabia. AB - Huernia Sp. Nov. aff. Boleana, Apocynaceae, grows in the high mountains of southwest Saudi Arabia and is widely used as a remedy for the treatment of diabetes. The present study investigated the anti-inflammatory, wound healing and inhibitory effects on migration of Huernia Sp. Nov. aff. Boleana. The anti inflammatory effect was assessed in mice using formalin-induced edema. Wound healing effects were assessed in rats using a circular excision wound model. An in vitro 'scratch' test was used to investigate the inhibitory effects on melanoma cell (B16-F10) migration. The anti-inflammatory effects of total extract, hexane and chloroform fractions were greater or equal to indomethacin (control). The relatively non-polar fractions (hexane and chloroform) exhibited higher anti-inflammatory activities compared with the aqueous fraction. The percentage of wound contraction among animals treated with the plant extract was higher compared with the control; however, this difference was not statistically significant (P>0.05). The total plant extract increased wound healing by inhibiting the inflammatory response, promoting angiogenesis, and significantly promoting the proliferation of fibroblasts, particularly on days 7 and 14 post wounding. Furthermore, the plant extract promoted wound repair via the enhancement of collagen synthesis, and complete epithelization with well-formed and differentiated epithelial tissues. The in vitro 'scratch' test indicated the inhibitory effects of this plant on melanoma cell migration in a dose-dependent manner. The present study indicated that Huernia Sp. Nov. aff. Boleana may have potential as an anti-inflammatory, wound-healing and migration-inhibiting ethno medicine. PMID- 29484403 TI - [Corrigendum] Inhibition of BTK protects lungs from trauma-hemorrhagic shock induced injury in rats. AB - Subsequent to the publication of the above paper, the authors realize that they did not acknowledge their funders in their paper. Consequently, the following information should have been included in the published article: "Funding: This study was supported by a grant from the National Natural Science Foundation of China (no. 81401586)". The authors sincerely apologize for this mistake, and regret the inconvenience this omission has caused, including that to the funders of this study. [the original article was published in the Molecular Medicine Reports 16: 192-200, 2017; DOI: 10.3892/mmr.2017.6553]. PMID- 29484404 TI - Novel compound heterozygous SPTA1 mutations in a patient with hereditary elliptocytosis. AB - Hereditaryelliptocytosis (HE) is a hereditary hemolytic disease, characterized by the presence of many elliptical erythrocytes in the peripheral blood that is caused by abnormal cytoskeletal proteins in the erythrocyte membrane. In the present study, a novel, causal HE mutation was reported. Routine blood examinations were performed on the proband and their family, and the fluorescence intensity of eosin-5-maleimide (EMA)-labeled erythrocytes was determined via flow cytometry. Subsequently, DNA was extracted from the peripheral blood of the proband and their family members, and amplified by quantitative polymerase chain reaction. The Sanger sequencing approach was used to determine and identify gene mutations, which were verified by matrix-assisted laser desorption-ionization time of flight (MALDI-TOF) mass spectrometry. To exclude genetic polymorphisms, newly identified mutations were subjected to large-scale gene screening using high-resolution melt analysis. Protein expression levels in the erythrocyte membrane of the proband were determined via SDS-PAGE, which demonstrated that, compared with healthy controls, the proband exhibited a reduction in EMA-labeled erythrocytes. In addition, DNA analysis demonstrated that the proband carried three mutations in the spectrin alpha chain erythrocytic 1 (SPTA1) gene: c.161A>C, c.5572C>G and 6531-12C>T. The corresponding mutant polypeptides were also analyzed by MALDI-TOF mass spectroscopy. SDS-PAGE analysis indicated that the proband exhibited normal levels of erythrocyte membrane proteins. In the present study, a novel HE case with a His54Pro mutation in the SPTA1 gene was reported. The results suggested that the His54Pro mutation influenced the role of erythrocyte membrane proteins without reducing its level of expression. PMID- 29484405 TI - Downregulation of G-protein-coupled receptor 30 in the hippocampus attenuates the neuroprotection of estrogen in the critical period hypothesis. AB - The aim of the present study was to investigate the role of G-protein-coupled receptor 30 (GPR30) in long-term 17beta-estradiol (E2) deprivation (LTED) in a rat model with global cerebral ischemia (GCI), and its therapeutic target for ischemic stroke in the clinical setting. Following bilateral ovariectomy, GCI was induced in rats 1 or 10 weeks post-surgery. To determine the protein and mRNA expression levels of GPR30 in the hippocampal CA1 region of LTED rats, short-term E2 deprivation (STED) rats and naturally aging rats, western blot analysis and reverse transcription-quantitative polymerase chain reaction were performed. The results of the present study demonstrated that E2 treatment revealed significant neuroprotection post-GCI in STED rats, but not in LTED rats, as well as a decrease in the expression levels of GPR30 in the hippocampal CA1 region. In LTED rats,. Notably, no effects were observed on the ubiquitination of GPR30 following investigation in STED or LTED rats. While the protein and mRNA expression levels of GPR30 were also decreased in the hippocampal CA1 region of female 24-month-old rats compared with 3-month-old rats. E2 treatment initiated for the entire ovariectomy period elevated GPR30 mRNA and protein expression levels, and attenuated the loss of hippocampal neurons in the GCI-induced CA1 region, indicating that E2 treatment exerted robust neuroprotection within LTED rats. However, the neuroprotective effect of E2 may be blocked by G15. The results of the present study revealed that downregulation of GPR30 expression may attenuate the neuroprotection of E2 within LTED conditions in rats post-ovariectomy by leading to neuronal insensitivity to E2 neuroprotection following cerebral ischemia. These results provide evidence that GPR30 may have potential as a novel therapeutic target for the treatment of clinical ischemic stroke. PMID- 29484406 TI - Pre-B cell leukemia transcription factor 3 induces inflammatory responses in human umbilical vein endothelial cells and murine sepsis via acting a competing endogenous RNA for high mobility group box 1 protein. AB - The present study investigated the roles of pre-B cell leukemia transcription factor 3 (PBX3) in sepsis. Reverse transcription-quantitative polymerase chain reaction and western blot analysis indicated that overexpression of the PBX 3' untranslated region (UTR) promoted high mobility group box 1 (HMGB1) protein expression in human umbilical vein endothelial cells (HUVECs) (P<0.01). Furthermore, post-treatment of PBX3 small interfering (si)RNA suppressed lipopolysaccharide (LPS)-mediated HMGB1 release and attenuated HMGB1-mediated hyperpermeability and leukocyte migration in HUVECs and septic mice (P<0.01). Additionally, post-injection of PBX3 siRNA also induced the downregulation of cecal ligation and puncture-induced HMGB1 release, production of IL-6 and mortality (P<0.01). Mechanistically, the 3'UTRs of PBX3 and HMGB1 were identified to harbor six common micro (mi)RNA binding sites, and PBX 3'UTR increased HMGB1 expression in a 3'UTR- and miRNA-dependent manner. Notably, the coding sequence of PBX3 did not increase HMGB1 expression in HUVECs. Collectively, the present study indicates that PBX 3'UTR may induce inflammatory responses and sepsis via acting as a competing endogenous RNA for HMGB1. PMID- 29484407 TI - Regulation of angiotensin II-induced B-cell lymphoma-2-associated athanogene 3 expression in vascular smooth muscle cells. AB - Previous studies have demonstrated that angiotensin II (Ang II) is involved in the process of atherosclerosis and vascular restenosis through its proinflammatory effect. Bcl-2-associated athanogene 3 (BAG3) had been suggested to be associated with proliferation, migration and invasion in many types of tumor. However, the role of BAG3 among the proliferative process of vascular smooth muscle cells (VSMCs) induced by Ang II, to the best of our knowledge, remains to be investigated. The present study demonstrated that in growth arrested VSMCs, Ang II-induced VSMC proliferation, accompanied by increased BAG3 mRNA and protein expression levels in a dose- and time-dependent manner. BAG3 expression levels were measured in VSMCs treated in the presence or absence of Ang II. The proliferation of VSMCs was assessed using manual cell counting and Cell Counting kit-8 assays. mRNA and protein expression levels of BAG3, Toll-like receptor 4 (TLR4), proliferating cell nuclear antigen, nuclear factor (NF)-kappaB p65, smooth muscle protein 22alpha and phosphorylated NF-kappaB p65 were assessed by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. In non-transfected or scramble short hairpin RNA (shRNA) transfected VSMCs cells, Ang II significantly induced VSMC proliferation. However, this Ang II-induce proliferation was attenuated when BAG3 was silenced, suggesting that inhibition of BAG3 may somehow reduce proliferation in Ang II induced VSMCs. Furthermore, the TLR4/NF-kappaB p65 signaling pathway was involved in BAG3 gene upregulation. In conclusion, to the best of our knowledge, the present study demonstrated for the first time that inhibition of BAG3 attenuates cell proliferation. Furthermore, Ang II induced VSMCs proliferation through regulation of BAG3 expression via the TLR4/NF-kappaB p65 signaling pathway. PMID- 29484408 TI - BAG3 promotes chondrosarcoma progression by upregulating the expression of beta catenin. AB - To investigate the roles of B-cell lymphoma-2 associated athanogene 3 (BAG3) in human chondrosarcoma and the potential mechanisms, the expression levels of BAG3 were detected in the present study, and the associations between BAG3 and clinical pathological parameters, clinical stage as well as the survival of patients were analyzed. The present study detected BAG3 mRNA and protein expression in the normal cartilage cell line HC-a and in SW1353 chondrosarcoma cells by reverse transcription-quantitative polymerase chain reaction and western blot analysis. The BAG3 protein expression in 59 cases of chondrosarcoma, 30 patients with endogenous chondroma and 8 cases of normal cartilage was semi quantitatively analyzed using the immunohistochemical method. In addition, the BAG3 protein expression level, the clinical pathological parameters, clinical stage and the survival time of patients with chondrosarcoma were analyzed. The plasmid transfection method was employed to upregulate the expression BAG3 and small RNA interference to downregulate the expression of BAG3 in SW1353 cells. The expression levels of BAG3 protein and mRNA were significantly increased in the chondrosarcoma cell line when compared with the normal cartilage cell line. The immunohistochemistry results indicated that BAG3 protein was overexpressed in the tissue of human chondrosarcoma. Statistical analysis showed that the expression level of BAG3 was significantly increased in the different Enneking staging of patients with chondrosarcoma and Tumor staging, and there were no statistical differences in age, gender, histological classification and tumor size. In the in vitro experiments, the data revealed that BAG3 significantly promoted chondrosarcoma cell proliferation, colony-formation, migration and invasion; however, it inhibited chondrosarcoma cell apoptosis. It was observed that BAG3 upregulated beta-catenin expression at the mRNA and protein levels. In addition, BAG3 induced the expression of runt-related transcription factor 2 (RUNX2) in chondrosarcoma cells by upregulating beta-catenin. These clinical analyses revealed a positive association between beta-catenin and BAG3 in chondrosarcoma tumors. BAG3 was significantly increased in chondrosarcoma cells and tissues compared with the normal cartilage cells, tissue and cartilage benign tumors. Thus, BAG3 may serve as an oncogene in the development of chondrosarcoma via the induction of RUNX2 expression. The results of the present study contribute to further research on the biological development of chondrosarcoma. PMID- 29484410 TI - [Corrigendum] Inhibition of sphingosine-1-phosphate phosphatase 1 promotes cancer cells migration in gastric cancer: Clinical implications. AB - We have recently noticed an accidental error in part of a figure which appeared in the above-mentioned article. In Fig. 3A, the image for the HGC27-pEF, 15 h panel was mistakenly replicated as the HGC27-KD, 0 h panel in the same figure, and the AGS-pEF, 15 h and AGS KD, 0 h panels were mistakenly switched with each other. We have reviewed the original files and the individual figures for the submitted composite figure, and realized that the error occurred when we produced the composite figure by marrying the individual images to the final figure. The same image was accidentally pasted twice without us being fully aware of the error. We have identified all the original images, and the corrected version of Fig. 3 is shown below. We regret that this error occurred, and thank the Editor for affording us the opportunity to publish this Corrigendum. [the original article was published in the Oncology Reports 34: 1977-1987, 2015; DOI: 10.3892/or.2015.4162]. PMID- 29484409 TI - Suppression of the NF-kappaB signaling pathway in colon cancer cells by the natural compound Riccardin D from Dumortierahirsute. AB - Colorectal cancer (CRC) is a major cause of mortality and morbidity. Chronic inflammation is closely associated with the development, progression and prognosis of the majority of intestinal malignancies. In recent years, targeting the nuclear factor (NF)-kappaB signaling pathway for CRC therapy has become an attractive strategy. Riccardin D, a novel macrocyclicbis (bibenzyl) compound, was isolated from the Chinese liverwort plant. Previous studies have suggested that Riccardin D exerted chemo-preventative effects against the intestinal malignancy formation. In the present study, cell counting kit-8, Hochest 33258 staining, mitochondria membrane permeability assay, western blotting analysis, reverse transcription-polymerase chain reaction, luciferase reporter gene assay and molecular modeling analysis were performed to detect the effect and mechanisms of Riccardin D on human colon cancer cells. The results demonstrated that Riccardin D significantly inhibited the growth of HT-29 cells. In addition, the cDNA expression of cyclooxygenase-2, and the protein expression and activity of NF kappaB and tumor necrosis factor-alpha were downregulated; however, the protein expression of cleaved caspase-3 and -9, and cleaved poly (adenosine diphosphate ribose) polymerase, and the B-cell lymphoma (Bcl)-2: Bcl-2-associated X protein ratio were upregulated. Furthermore, Auto Dock analysis identified binding sites between Riccardin D and NF-kappaB. These results indicated that Riccardin D may inhibit cell proliferation and induce apoptosis in HT-29 cells, which may be associated with the blocking of the NF-kappaB signaling pathway. Thus, Riccardin D should be investigated as an NF-kappaB inhibitor in cancer therapy. PMID- 29484411 TI - miR-16 inhibits hyperoxia-induced cell apoptosis in human alveolar epithelial cells. AB - The identification and development of novel therapeutic strategies for acute lung injury is urgently required. It has been previously demonstrated that microRNA (miR)-16 suppresses the level of transforming growth factor (TGF)-beta in acute lung injury (ALI). Therefore, the present study investigated the role of miR-16 in the phenotype, cell proliferation and apoptosis, and the involvement of TGF beta/Smad family member 2 (Smad2) and JAK/signal transducer and activator of transcription (STAT)3 signaling, of primary human alveolar type II epithelial cells (AECII). Following transfection with miR-16 mimics, AECII cells were exposed to hyperoxia for 24 h. Subsequently, immunofluorescence staining of surfactant protein-A (SP-A) was performed, and cell proliferation and apoptosis were investigated by Cell Counting Kit-8 assays and annexin V-fluorescein isothiocyanate/propidium iodide staining, respectively. Furthermore, the expression levels of miR-16, TGF-beta, Smad2, phosphorylated-Smad2, JAK and STAT3 were detected by western blotting and/or reverse transcription-quantitative polymerase chain reaction. The results demonstrated that miR-16 levels and SP-A fluorescence were markedly inhibited by hyperoxia. Furthermore, transfection of AECII cells with miR-16 mimics increased SP-A fluorescence in hyperoxia-treated AECII cells, significantly reversed hyperoxia-induced reductions in cell proliferation and inhibited hyperoxia-induced apoptosis. Finally, miR-16 mimics modulated the mRNA and protein expression of components of the TGF-beta/Smad2 and JAK/STAT3 pathways in AECII cells following hyperoxia. In conclusion, the results of the present study indicate that overexpression of miR-16 may exert a protective effect in AECII cells against cell apoptosis and ALI, which may be associated with TGF-beta/Smad2 and JAK/STAT3 signaling pathways. This may also represent a promising target for novel therapeutic strategies for acute lung injury. PMID- 29484412 TI - Melatonin induces the apoptosis and inhibits the proliferation of human gastric cancer cells via blockade of the AKT/MDM2 pathway. AB - Globally, gastric cancer (GC) is one of the most common types of cancer and the third leading cause of cancer-related death. In China, gastric and liver cancers have the highest mortality rates. Melatonin, also known as N-acetyl-5 methoxytryptamine, is a hormone that is produced by the pineal gland in animals and regulates sleep and wakefulness. Melatonin has been shown to inhibit various carcinomas, including GC. There are many different hypotheses to explain the anticancer effects of melatonin, including stimulation of apoptosis, inhibition of cell growth, regulation of anticancer immunity, induction of free-radical scavenging, and the competitive inhibition of estrogen. However, the underlying mechanism by which these effects are elicited remains elusive. The aim of the present study was to investigate the effects of melatonin on human GC cells and determine the underlying molecular mechanism. We treated SGC-7901 GC cells with melatonin and analyzed the resulting protein changes using protein chip technology. Several proteins related to cell apoptosis and proliferation were identified and further tested in SGC-7901 GC cells. We found that melatonin induced cell cycle arrest and the downregulation of CDC25A, phospho-CDC25A (at Ser75), p21 (p21Cip1/p21Waf1) and phospho-p21 (at Thr145). Melatonin also induced upregulation of Bax, downregulation of Bcl-xL, an increase in cleaved caspase-9 level and activation of caspase-3, which confirmed the involvement of the mitochondria in melatonin-induced apoptosis. Upstream regulators of the above proteins, MDM2, phospho-MDM2 (at Ser166) and AKT, phospho-AKT (at Thr308) were all attenuated by melatonin, which led to an increase in p53. The present study demonstrated that the oncostatic effects of melatonin on SGC-7901 GC cells are mediated via the blockade of the AKT/MDM2 intracellular pathway. PMID- 29484413 TI - Knockdown of EPCR inhibits the proliferation and migration of human gastric cancer cells via the ERK1/2 pathway in a PAR-1-dependent manner. AB - Endothelial protein C receptor (EPCR) has been implicated in the carcinogenesis of diverse tumor types. This tumor-promoting effect of EPCR is associated with the upregulation of activated protein C and the activation of protease-activated receptor 1 (PAR-1). However, the exact role of EPCR in gastric cancer (GC) and the mechanisms underlying the regulation of EPCR remain elusive. In the present study, we investigated the effects of EPCR on human GC cells, as well as the underlying mechanisms. An siRNA inference system was used to knock down the expression of EPCR in GC cells, and CCK-8, colony formation and Transwell assays were performed to determine the effects of EPCR knockdown on the proliferation and migration of the tumor cells. Additionally, cell cycle distribution and apoptosis were assessed by flow cytometry, and activated PAR-1 levels were determined by cell ELISA. The results indicated that the proliferation, clonogenicity and migration were significantly reduced and that the cell cycle was arrested in the Gap 1 phase by EPCR knockdown in SGC7901 and AGS cells. Meanwhile, apoptosis was promoted by EPCR knockdown in the two cell lines. The activation of PAR-1 on the cell surface of SGC7901 and AGS cells was significantly reduced after the knockdown of EPCR. By contrast, blockade of PAR-1 reduced the proliferation and migration of gastric cells in vitro. Additionally, after the knockdown of EPCR or treatment with PAR-1 antibody, the expression of pERK1/2 was significantly downregulated in the SGC7901 and AGS cells, while the expression levels of p-AKT (S473) and p-AKT (T308) were unchanged. The findings of the present study demonstrated that EPCR exerts pro-carcinogenic effects in GC cells in a PAR-1-dependent manner via the ERK1/2-MAPK pathway. Thus, EPCR may be a potential molecular diagnostic or therapeutic target for GC. PMID- 29484414 TI - Raf1 is a prognostic factor for progression in patients with non-small cell lung cancer after radiotherapy. AB - Raf-1 proto-oncogene, serine/threonine kinase (Raf1) acts as a part of the RAS/RAF/MEK/ERK signaling pathway and regulates cell migration, apoptosis and differentiation. However, few studies are available on the expression and clinical significance of Raf1 in non-small cell lung cancer (NSCLC). This study investigated the clinical value and prognostic significance of Raf1 in NSCLC patients, following radiotherapy. We evaluated the Raf1 expression using immunohistochemical analyses of samples from 110 NSCLC patients who received radiotherapy. The association between Raf1 expression and clinicopathological variables was also analyzed. The multivariate Cox proportional hazard model was used to determine the prognostic value of Raf1 in regards to progression and 3 year survival. Significant associations between Raf1 expression and invasion and metastasis capability in lung cancer A549 and H1299 cell lines were identified. Results showed that 44.5% (49/110) of the NSCLC patient specimens demonstrated Raf1 expression, which was found to be positively correlated with lymph node metastasis (P=0.014), T stage (P=0.038) and poor histological differentiation (P=0.029). Later progression was observed in patients with negative or low Raf1 expression than in patients with high Raf1 expression (P=0.002). The multivariate analysis indicated that Raf1 is an independent prognostic factor for time to progression (TTP) (HR, 1.94; 95% CI, 1.16-3.25; P=0.01). A high Raf1 expression was found to result in a poor 3-year overall survival (OS)(HR, 1.64; 95% CI, 0.98 2.75; P=0.06). Raf1 overexpression was correlated with early progression in NSCLC. Raf1 may serve as a novel prognostic factor and potential target for improving the long-term outcome of NSCLC patients. PMID- 29484415 TI - Metformin facilitates BG45-induced apoptosis via an anti-Warburg effect in cholangiocarcinoma cells. AB - Cholangiocarcinoma (CCA) is a highly lethal malignancy with an often late diagnosis and consequent poor prognosis. Chemotherapy is the only therapeutic strategy for most patients. Compared to normal cells, tumor cells preferentially metabolize glucose to lactate, even in aerobic conditions. Such metabolic alterations not only support the growth and invasion of tumor cells, but also promote their chemoresistance. The purpose of our study was to explore the role of metformin in regulating the metabolism of CCA, as well as to investigate whether metformin could act as a chemosensitizer of the HDAC3 inhibitor BG45, and therefore have potential for the treatment of CCA. Through bioinformatic analysis, we found that aberrant metabolism contributed to the proliferation of CCA cells. Seahorse XF96 Extracellular Flux Analyzer analysis and lactate production analysis showed that metformin could act as a suppressor of the Warburg effect in CCA cells. Western blotting showed that metformin decreased the expression of LDHA, which plays a key role in the Warburg effect. However, suppression of the Warburg effect was not sufficient to induce CCA cellular apoptosis. According to our previous research, which showed that an HDAC3 inhibitor (MI192) was involved in CCA apoptosis, we observed that metformin combined with BG45 (a novel specific HDAC3 inhibitor) effectively induced the apoptosis of CCA cells in vitro. Furthermore, in vivo experiments revealed that the combined treatment with metformin and BG45 markedly reduced CCA growth in a CCA xenograft model. Our data revealed that reversing the Warburg effect with metformin sensitizes cells to the antitumor effects of HDAC3 inhibitors. This provides a rationale for using the combination of metformin and BG45 as a new therapeutic strategy in the treatment of CCA. PMID- 29484416 TI - Prognostic impact of sarcopenia and its correlation with circulating miR-21 in colorectal cancer patients. AB - Severe malnutrition accompanied by sarcopenia and cachexia, is strongly associated with the surgical and oncological outcomes in cancer patients. The aim of the present study was to clarify the clinical significance of sarcopenia and its correlation with sarcopenia-associated miRNA in colorectal cancer (CRC). A total of 167 CRC patients were enrolled in the present study. We evaluated psoas muscle mass index (PMI) and intramuscular adipose tissue content (IMAC). The expression of miR-21 in CRC tissues and preoperative serum was evaluated using quantitative PCR. Despite the lack of significant correlation between IMAC and disease-correlated factors, decreased PMI was significantly associated with well established clinicopathological factors for disease progression. Decreased PMI was an independent prognostic factor for both overall survival and disease-free survival and was an independent risk factor for various types of metastasis. In contrast to the expression of tissue miR-21, the expression of serum miR-21 was significantly increased in CRC patients with low PMI. Furthermore, postoperative PMI was drastically improved compared with preoperative PMI in CRC patients with potentially curative resections. In conclusion, skeletal muscle mass may be a prognostic and predictive biomarker for distant metastasis in CRC patients and quantification of serum miR-21 expression could help clinicians make decisions regarding nutrition intervention strategies in CRC patients. PMID- 29484417 TI - miRNA-320a inhibits glioma cell invasion and migration by directly targeting aquaporin 4. AB - Glioma is the most aggressive and malignant type of primary intracranial tumor. In recent decades, despite the rapid development of modern surgery and therapeutic strategies available for brain tumors, the prognosis of glioma remains poor and the median survival time is <15 months. In this study, we found that the levels of miRNA-320a were significantly decreased in patients with glioma, and that elevated miRNA-320a expression was associated with a better prognosis. In addition, aquaporin 4 (AQP4) was identified as a direct target of miRNA-320a. Overexpression of miRNA-320a led to the inhibition of cell invasion and migration via targeting of AQP4. Therefore, our results suggested that miRNA 320a could suppress the aggressive capacity of tumors by targeting AQP4, and that miRNA-320a could serve as a new effective therapeutic target for glioma surgical and therapeutic strategies. PMID- 29484418 TI - Prognostic and predictive value of HURP in non-small cell lung cancer. AB - Previous studies have revealed that HURP (also known as DLGAP5 or KIAA0008) is overexpressed in many types of human cancers, such as hepatocellular carcinoma, squamous cell bladder cancer, and transitional cell carcinoma, indicating that HURP is a putative oncoprotein that promotes carcinogenesis through various molecular mechanisms. However, the role of HURP in the pathogenesis of non-small cell lung cancer (NSCLC) has not been reported. In the present study, we investigated the prognostic value of HURP among NSCLC patients through the GEO database. The online tool of KM-plotter was used to identify the correlation of HURP expression and the survival of NSCLC patients. We found the HURP expression at the mRNA level was correlated with the clinicopathologic characteristics and prognosis of NSCLC patients. HURP was highly expressed in aggressive NSCLC cells, and its higher expression was associated with shorter survival. Further cytological experiments revealed that the silencing of HURP caused cell cycle arrest and inhibited the proliferation of NSCLC cells. Transwell assay showed that HURP shRNA inhibited cell migration and invasion in vitro. The bioinformatic analysis suggests that HURP promotes carcinogenesis in multiple manners. Taken together, we revealed the prognostic value of HURP in NSCLC patients and HURP may be a potential therapeutic target for NSCLC. PMID- 29484419 TI - Itraconazole inhibits invasion and migration of pancreatic cancer cells by suppressing TGF-beta/SMAD2/3 signaling. AB - Pancreatic cancer is the fourth leading cause of cancer-associated mortality worldwide, with an overall 5-year survival rate <8%. We studied the therapeutic effect of itraconazole (ITZ), a commonly used broad-spectrum anti-fungal agent, in the treatment of pancreatic cancer, and to reveal the underlying anticancer mechanisms. Effects of ITZ on cell proliferation, apoptosis, invasion and migration were observed by MTT assays and colony formation assays, flow cytometry, wound scratch assays and transwell assays, respectively. Western blotting and immunofluorescence were performed to investigate the effect of ITZ on the epithelial to mesenchymal transition (EMT) of pancreatic cancer cells. Recombinant transforming growth factor-beta (TGF-beta) and TGF-beta neutralizing antibody were used to study the effect of ITZ on the TGF-beta/SMAD2/3 signaling. Transgenic engineered mice which harboring the spontaneous pancreatic cancer was applied to investigate the therapeutic role of ITZ in vivo. We report that ITZ inhibited the viability and induced apoptosis of pancreatic cancer cells. Furthermore, ITZ suppressed the invasion and migration of pancreatic cancer cells. We found that ITZ treatment was efficient in suppressing EMT and that the effect of ITZ was partially mediated by impaired TGF-beta/SMAD2/3 signaling. The role of TGF-beta/SMAD2/3 signaling in mediating the effect of ITZ was confirmed based on the results that recombinant TGF-beta induced, but the TGF-beta neutralizing antibody inhibited EMT as well as the invasion and migration of pancreatic cancer cells. Also, the anticancer effect of ITZ could be partially reversed by recombinant TGF-beta. Furthermore, treatment with ITZ suppressed growth of tumor in vivo. Taken together, we suggest that ITZ may potentially serve as a new chemotherapeutic agent for the treatment of pancreatic cancer. PMID- 29484420 TI - lncRNA NEAT1 promotes cell proliferation and invasion by regulating miR-365/RGS20 in oral squamous cell carcinoma. AB - Long non-coding RNAs (lncRNAs) have emerged as critical regulators of tumor progression. However, the function and mechanism of lncRNA NEAT1 in oral squamous cell carcinoma (OSCC) are unclear. In the present study, NEAT1 was significantly upregulated in OSCC cells and tissues. High expression of NEAT1 was correlated with advanced TNM stage and poor survival of patients. Using bioinformatics prediction and experimental analysis, we determined that NEAT1 could negatively regulate the expression of miR-365. The expression of miR-365 was decreased in OSCC tissues and inversely correlated with NEAT1 in tumors. Functionally, knockdown of NEAT1 significantly inhibited cell proliferation and invasion and induced cell cycle arrest at the G0/G1 phase and apoptosis, whereas inhibition of miR-365 abolished the suppressive effect of NEAT1 knockdown on cellular processes. RGS20, a direct target of miR-365, could reverse the tumor suppressive role of miR-365 mimic by enhancing cell viability and motility. Moreover, the protein levels of RGS20, cyclin D1, E-cadherin, N-cadherin and vimentin could be regulated by the NEAT1/miR-365 axis. NEAT1 silencing also inhibited tumor growth in vivo. Collectively, we revealed that the NEAT1/miR-365/RGS20 axis may be a novel mechanism or therapeutic strategy for OSCC treatment. PMID- 29484421 TI - High expression of TRAIL by osteoblastic differentiated dental pulp stem cells affects myeloma cell viability. AB - Cells from dental tissues have a mesenchymal stem cell (MSC) phenotype, are multipotent and can differentiate into osteoblastic cells, as we have previously found. MSCs, due to their tumor-homing ability, are currently being used as cell based delivery systems for cancer protein therapeutics, such as the TNF-related apoptosis-inducing ligand (TRAIL). In the present study we revealed that dental pulp stem cells (DPSCs) expressed TRAIL to a greater extent when they were differentiated into the osteoblastic lineage. TRAIL affected the viability of undifferentiated DPSCs, while osteoblastic differentiated DPSCs were not sensitive to TRAIL. The expression trend of TRAIL receptors underwent changes during the osteoblastic differentiation of DPSCs exhibiting low DcR2 and high DR5 levels in the undifferentiated DPSCs and an opposite scenario was presented in the differentiated cells. The sensitivity of the undifferentiated DPSCs to the TRAIL-apoptotic effect was also associated with low levels of intracellular anti apoptotic proteins, such as c-FLIP, XIAP and the activation of caspase-8 and -3. DPSC-differentiated osteoblasts expressing high TRAIL levels were capable to affect the cell viability of the human myeloma cell line H929, thus representing an effective anticancer therapeutic method. PMID- 29484422 TI - Serum microRNA miR-206 is decreased in hyperthyroidism and mediates thyroid hormone regulation of lipid metabolism in HepG2 human hepatoblastoma cells. AB - The actions of thyroid hormone (TH) on lipid metabolism in the liver are associated with a number of genes involved in lipogenesis and lipid metabolism; however, the underlying mechanisms through which TH impacts on lipid metabolism remain to be elucidated. The present study aimed to investigate the effects of hyperthyroidism on the serum levels of the microRNA (miR) miR-206 and the role of miR-206 on TH-regulated lipid metabolism in liver cells. Serum was obtained from 12 patients diagnosed with hyperthyroidism and 10 healthy control subjects. Human hepatoblastoma (HepG2) cells were used to study the effects of triiodothyronine (T3) and miR-206 on lipid metabolism. Expression of miR-206 in serum and cells was determined by reverse transcription-quantitative polymerase chain reaction analysis. Lipid accumulation in HepG2 cells was assessed with Oil Red O staining. Suppression or overexpression of miR-206 was performed via transfection with a miR-206 mimic or miR-206 inhibitor. Serum miR-206 was significantly decreased in patients with hyperthyroidism compared with euthyroid controls. Treatment of HepG2 cells with T3 led to reduced total cholesterol (TC) and triglyceride (TG) content, accompanied by reduced miR-206 expression. Inhibition of endogenous miR 206 expression decreased intracellular TG and TC content in HepG2 cells. By contrast, overexpression of miR-206 in HepG2 partially prevented the reduction in TG content induced by treatment with T3. In conclusion, serum miR-206 expression is reduced in patients with hyperthyroidism. In addition, miR-206 is involved in T3-mediated regulation of lipid metabolism in HepG2 cells, indicating a role for miR-206 in thyroid hormone-induced disorders of lipid metabolism in the liver. PMID- 29484423 TI - High expression of hnRNPA1 promotes cell invasion by inducing EMT in gastric cancer. AB - Advanced gastric cancer (GC) has a poor prognosis and its treatment strategies are not very efficient. Heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) has emerged as a plausible GC marker, however the role and molecular mechanism of hnRNPA1 in cell invasion and migration remains unknown. In the present study, the gene expression across normal and tumor tissue (GENT) database was used to evaluate the mRNA expression of hnRNPA1 in various types of cancer. Western blot analysis (WB) and immunohistochemistry (IHC) were performed to detect the protein expression of hnRNPA1 in GC tissues and adjacent non-tumor tissues. The expression of multiple oncogenes was detected by western blot analysis and quantitative RT-PCR in hnRNPA1 overexpressing GC cells. Soft agar colony formation, EdU incorporation, wound healing and invasion assays were applied to verify the role of hnRNPA1 in anchorage-independent cell growth, migration and invasion in GC cells. Epithelial-to-mesenchymal transition (EMT) markers were detected by immunofluorescence, western blot analysis and IHC in vitro. A nude mice model of metastasis carcinoma was established to confirm the role of hnRNPA1 during EMT in vivo. Our results revealed that hnRNPA1 was significantly upregulated in GC tissue. HnRNPA1 overexpression significantly induced cell growth, migration and invasion ability in GC cells. In addition, hnRNPA1 promoted EMT of GC cells in vitro and in vivo. These findings indicated that hnRNPA1 is highly expressed in GC and promoted invasion by inducing EMT transition in GC cells. Thus, hnRNPA1 may be a potential therapeutic target for GC. PMID- 29484424 TI - Knockdown of end-binding protein 1 induces apoptosis in radioresistant A549 lung cancer cells via p38 kinase-dependent COX-2 upregulation. AB - The role of end-binding protein 1 (EB1) in lung cancer tumorigenesis and radiotherapy remains poorly understood. In the present study, we observed that EB1 was highly expressed in lung tumor tissues compared with normal non-tumor tissues based on immunohistochemical analysis of lung cancer tissue samples obtained from human tissue microarrays. EB1 was also highly overexpressed in radioresistant lung and cervical cancer cells, which exhibited increased cell death after EB1 silencing. The cytotoxicity induced by EB1 gene knockdown was due to the activation and generation of reactive oxygen species by p38 mitogen activated protein kinase. Notably, this signaling cascade, however not nuclear factor-kappaB-mediated signaling, induced the expression of cyclooxygenase-2, a key effector of apoptotic death. Our results provided new molecular evidence supporting the use of EB1 as a novel target in lung cancer therapy, especially in the case of radioresistance. PMID- 29484425 TI - Effect of placental sex hormone-binding globulin single nucleotide polymorphism rs6259 on protein and function in gestational diabetes mellitus. AB - Sex hormone-binding globulin (SHBG) has a key role in the occurrence and development of the gestational diab-etes mellitus (GDM). Single nucleotide polymorphism (SNP) rs6259 is a functional site in SHBG gene, which is suspected to regulate the SHBG level. The present study explored the placental SHBG SNP rs6259 distribution in Chinese pregnant women and the influence on placental SHBG concentrations, to assess the relationship of SHBG rs6259 in the occurrence and development of GDM. We screened the SHBG rs6259 allele in 210 healthy and 180 GDM gravidas by PCR-RFLP and restriction enzyme and measured placental SHBG concentrations in each genotypic group with western blot analysis. The mechanisms of SHBG rs6259 function were analyzed by cell culture, recombinant lentivirus transfection, real-time PCR, and western blot analysis. We found the differences of SHBG Asn327 allele frequency and the genotype distribution in GDM and control groups were statistically significant (P<0.05). Western blot analysis results showed that the Asn327 allele group was associated with a higher placental SHBG level than the Asp327 allele homozygote group (P<0.05). In HTR8-SVneo cell transfection, the positive transfection groups (SHBG-rs6259 Asn) led to an obviously higher tendency of SHBG mRNA and protein expression than the negative control groups (SHBG-rs6259 Asp), the normal cell group, and the blank control group (blank lentivirus LV-5) (P<0.05). Our data, therefore, reflected that SHBG SNP rs6259 causes changes in placental SHBG concentration and may play a functional role in the molecular mechanisms of GDM etiology. PMID- 29484426 TI - miR-27a-3p promotes the malignant phenotypes of osteosarcoma by targeting ten eleven translocation 1. AB - Osteosarcoma has become one of the most common primary malignant tumors affecting children and adolescents. Although increasing evidence has indicated that microRNAs (miRNAs or miRs) play important roles in the development of osteosarcoma, the expression of miR-27a-3p and its effects on osteosarcoma are not yet fully understood. In the present study, our data demonstrated that the expression of miR-27a-3p in osteosarcoma cell lines was significantly higher than that in the normal human osteoblastic cell line, hFOB 1.19 cell (P<0.01). In order to explore the role of miR-27a-3p in the development and progression of osteosarcoma, the expression of miR-27a-3p was inhibited by transfection of the MG-63 cells with miR-27a-3p inhibitor. The results revealed that the cell proliferative ability significantly decreased (P<0.01), the number of apoptotic cells significantly increased (P<0.01) and the number of cells passing through the Transwell membrane was significantly reduced in the group transfected with the miR-27a-3p inhibitor (P<0.01). At the same time, the expression of E-cadherin and alpha-catenin was significantly upregulated (P<0.01), while the expression of vimentin was significantly downregulated in the group transfected with the miR 27a-3p inhibitor (P<0.01). Our results also revealed that the mRNA expression of ten-eleven translocation 1 (TET1) in the osteosarcoma cells was significantly downregulated compared with that in the hFOB 1.19 cells (P<0.01). Luciferase reporter system analysis indicated that miR-27a-3p recognized the TET1 3'-UTR. The protein expression of TET1 significantly increased in the group transfected with the miR-27a-3p inhibitor. The results from CCK-8 assay, flow cytometric assay and Transwell invasion analysis revealed that TET1 knockdown inhibited the biological effects induced by the downregulation of miR-27a-3p. Taken together, the findings of this study indicate that miR-27a-3p is upregulated, while TET1 is downregulated in human osteosarcoma cells. miR-27a-3p inhibition suppresses the proliferation and invasion of osteosarcoma cells, and promotes cell apoptosis via the negative regulation of TET1. miR-27a-3p/TET1 may thus be a potential target for the treatment of osteosarcoma. PMID- 29484427 TI - Fingerprint analysis and pharmacological evaluation of Ailanthus altissima. AB - Ailanthus altissima (AA) has been used in various anticancer prescriptions and showed excellent therapeutic effect. However, there is no report on the method of quality control and the anti-glioblastoma activity. In this study, we used a combinative method approach consisting of chromatographic fingerprinting and quantitative methods to analyze quality of different samples. The anti glioblastoma activity and the possible mechanisms were studied by pharmacological methods. The samples were separated on a Kromasil 100-5 C18 column and the flow rate was 0.8 ml/min at 25C. The mobile phase was composed of 1% formic acid and 1% methanol-water at a flow rate of 0.8 ml/min. The method was validated and applied to the quantification of different samples. Ten batches of AA from different provinces in China were detected, and we found that the contents of Ailanthone (AT) ranged from 0.21-1.78 mg/g and the relative retention times were similar in different origins. Ten batches of AA were analyzed by the high performance liquid chromatography (HPLC) fingerprinting method and 19 common peaks were detected. The similarity of 10 batches is <1.5%. The peak areas in different samples were significantly different (0.682-0.954). We also found that AA induced oxidative stress first in U87 cells, then induced ER stress, finally activated the caspases which caused cell apoptosis. In conclusion, a method combining chromatographic fingerprinting and quantitative analysis can be used to control the quality of AA. AA could be used as a medicine or a constituent part of herb prescription to treat glioblastoma. PMID- 29484428 TI - Euphorbia supina extract results in inhibition of high-fat-diet-induced obesity in mice. AB - The present study was undertaken to investigate the anti-obesity effect of a 50% ethanol extract of Euphorbia supina (ESEE) in high-fat-diet (HFD)-induced obese C57BL/6J mice. Mice were fed a HFD with or without ESEE (2, 10, or 50 mg/kg) or with Garcinia cambogia (positive control) for 6 weeks. ESEE supplementation significantly reduced body, epididymal white adipose tissue (eWAT), and organ weights (P<0.05). ESEE also reduced hepatic steatosis and improved serum lipid profiles. In addition, ESEE significantly reduced serum leptin levels and increased adiponectin levels, and significantly downregulated the mRNA and protein levels of proliferator-activated receptor gamma (PPARgamma) and CCAAT/enhancer-binding protein alpha (C/EPBalpha) in eWAT and liver tissues (all P<0.05). These results suggested that ESEE supplementation protects against HFD induced obesity by downregulating PPARgamma and C/EPBalpha, and that ESEE may be beneficial for the prevention and treatment of obesity and associated diseases. PMID- 29484429 TI - Downregulated miR-23b-3p expression acts as a predictor of hepatocellular carcinoma progression: A study based on public data and RT-qPCR verification. AB - Mounting evidence has shown that miR-23b-3p, which is associated with cell proliferation, invasion, and apoptosis, acts as a biomarker for diagnosis and outcomes in numerous cancers. However, the clinicopathological implication of miR 23b-3p in hepatocellular carcinoma (HCC) remains unclear. Our study evaluated the role of miR-23b-3p in HCC and investigated its potential application as a marker for preliminary diagnosis and therapy in HCC. High-throughput data from the NCBI Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) were collected and analyzed. One hundred and one tissue sections of HCC were paired with adjacent non-cancerous HCC as further supplements. miR-23b-3p expression was detected using quantitative real-time PCR. Additionally, the relationship between miR-23b-3p expression and HCC progression and Time-to-recurrence (months) was explored. Ten algorithms were applied to predict the prospective target genes of miR-23b-3p. Next, we conducted bioinformatics analysis for further study. miR-23b 3p expression was pronouncedly decreased in HCC tissues in contrast with their paired adjacent non-cancerous HCC (P<0.001) with RT-qPCR. In total, 405 targets, acquired with consistent prediction from at least five databases, were used for the bioinformatics analysis. According to the Gene Ontology (GO) analysis, all targets were classified into biological processes, cellular components and molecular functions. In the pathway analysis, targets of miR-23b-3p were primarily enriched in the signaling pathways of renal cell carcinoma, hepatitis B and pancreatic cancer (corrected P-value <0.05). In the protein-protein interaction (PPI) network for miR-23b-3p, a total of 8 targets, including SRC, AKT1, EGFR, CTNNB1, BCL2, SMAD3, PTEN and KDM6A, were located in the key nodes with high degree (>35). In conclusion, this study provides impressive illumination of the potential role of miR-23b-3p in HCC tumorigenesis and progression. Furthermore, miR-23b-3p may act as a predictor of HCC and could be a new treatment target. PMID- 29484430 TI - A novel variant in MITF in a child from Yunnan-Guizhou Plateau with autosomal dominant inheritance of nonsyndromic hearing loss: A case report. AB - Deafness and hearing loss may have functional, economic, social and emotional impacts on humans, including the ability of an individual to communicate with others, feelings of isolation and frustration, and health sector costs. The World Health Organization reported that there are 32 million children worldwide with hearing loss. In order to investigate genetic mutations in children of 26 nationalities with hearing loss in Yunnan, Sanger sequencing was employed to screen for mutations in four of the most common pathological genes, including gap junction protein beta2 and 3, solute carrier family 26 member 4 and mitochondrial DNA. Whole exome sequencing was used to detect the mutation in the proband of a family in which these four genes were normal. Subsequently, the mutation was identified by Sanger sequencing. The present study reports a novel mutation, c.718C>G; p. (Arg240Gly) in the melanogenesis associated transcription factor gene, in Han people with hearing loss. The results of the present study may provide parents and children an accurate diagnosis, which may allow physicians to how to rehabilitate children's hearing. PMID- 29484431 TI - Downregulation of microRNA-181a attenuates hydrogen peroxide-induced human lens epithelial cell apoptosis in vitro. AB - Apoptosis of human lens epithelial (HLE) cells is a process closely associated with cataract formation. The aim of the present study was to explore the effects of microRNA (miR)-181a against hydrogen peroxide (H2O2)-induced apoptosis in HLE cells in vitro. The recombinant lentiviral plasmid pLKO. 1-puro-miR-181a was constructed and used to transfect human HLE-B3 cells with the short hairpin (sh)RNA to silence the expression of miR-181a. The apoptotic rate of both HLE-B3 cells in which miR-181a expression was stably silenced and in untransfected HLE B3 cells was assessed in the presence of H2O2 using flow cytometry. The mRNA expression levels of the apoptosis-related genes caspase-3 (CASP3) and B-cell lymphoma-2-associated X protein (BAX), and of the potential target genes for miR 181a, c-MET, cyclooxygenase 2 (COX-2) and snail family transcriptional repressor 2 (SNAI2) were measured using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Malondialdehyde (MDA), superoxide dismutase (SOD) and catalase (CAT) levels were assessed using ELISA. RT-qPCR analysis revealed that miR-181a expression was downregulated in HLE-B3 cells following transfection with miR-181a-shRNA. Treatment with H2O2 significantly reduced the viability of HLE-B3 cells, whereas miR-181a knockdown was revealed to attenuate the effects on cell viability following H2O2 treatment. In addition, the downregulation of miR-181a expression significantly decreased H2O2-induced cell apoptosis, which was accompanied by a downregulation in CASP3 and BAX and COX-2 expression. Furthermore, the levels of MDA were decreased, whereas the levels of SOD and CAT were increased following miR-181a silencing. The present findings suggested that miR-181a knockdown may protect HLE-B3 cells against H2O2-induced apoptosis in vitro. The molecular mechanisms involved in the protective effects of miR-181a silencing may involve the suppression of CASP3, BAX and COX-2 expression, and the inhibition of MDA generation. PMID- 29484432 TI - miR-15a represses cancer cell migration and invasion under conditions of hypoxia by targeting and downregulating Bcl-2 expression in human osteosarcoma cells. AB - Osteosarcoma is a common, high-risk primary bone malignancy that mostly affects the younger population. There has been no marked improvement in the clinical outcomes of osteosarcoma patients to date, and cancer recurrence and metastasis are common in high-grade osteosarcoma. Therefore, identifying new biomarkers and novel therapeutic targets is crucial for improving the prognosis of osteosarcoma patients. In the present study, the MG63 human osteosarcoma cell line was employed to examine the role of microRNA (miR)-15a in regulating cellular activities under hypoxic conditions. It was demonstrated that hypoxia stimulates migration and invasion in MG63 cells, which was correlated with the downregulation of miR-15a and upregulation of B-cell lymphoma 2 (Bcl-2) expression. Introduction of miR-15a or knockdown of endogenous Bcl-2 may reduce hypoxia-induced cell invasion and migration through the regulation of matrix metalloproteinases. Analysis of the expression of miR-15a indicated that hypoxia repressed the transcription of deleted in lymphocytic leukemia 2 (DLEU2), which is the host gene of miR-15a. These findings indicated that miR-15a may be a valuable target for the treatment of osteosarcoma, particularly for patients with high-grade cancer or heavy tumor burden. PMID- 29484433 TI - The polyaromatic hydrocarbon beta-naphthoflavone alters binding of YY1, Sp1, and Sp3 transcription factors to the Dp71 promoter in hepatic cells. AB - The smallest product of the Duchenne muscular dystrophy gene, dystrophin (Dp)71, is ubiquitously expressed in nonmuscle tissues. We previously showed that Dp71 expression in hepatic cells is modulated in part by stimulating factor 1 (Sp1), stimulating protein 3 (Sp3), and yin yang 1 (YY1) transcription factors, and that the polyaromatic hydrocarbon, beta-naphthoflavone (beta-NF), downregulates Dp71 expression. The aim of the present study was to determine whether beta-NF represses Dp71 expression by altering mRNA stability or its promoter activity. Reverse transcription-quantitative polymerase chain reaction was used to measure half-life mRNA levels in beta-NF-treated cells exposed to actinomycin D, an inhibitor of transcription, for 0, 4, 8, 12 and 16 h. Transient transfections with a plasmid carrying the Dp71 basal promoter fused to luciferase reporter gene were carried out in control and beta-NF-treated cells. Electrophoretic mobility shift assays (EMSAs) were performed with labeled probes, corresponding to Dp71 promoter sequences, and nuclear extracts of control and beta-NF-treated cells. To the best of our knowledge, the results demonstrated for the first time that this negative regulation takes place at the promoter level rather than the mRNA stability level. Interestingly, using EMSAs, beta-NF reduced binding of YY1, Sp1, and Sp3 to the Dp71 promoter. It also suggests that beta-NF may modulate the expression of other genes regulated by these transcription factors. In conclusion, beta-NF represses Dp71 expression in hepatic cells by altering binding of YY1, Sp1, and Sp3 to the Dp71 promoter. PMID- 29484434 TI - miR-33a-5p enhances the sensitivity of lung adenocarcinoma cells to celastrol by regulating mTOR signaling. AB - MicroRNAs (miRNAs or miRs) have recently become a popular focus of cancer research due to their ability to act as oncogenes or tumor suppressors. In the present study, miR-33a-5p expression was identified to be downregulated in lung adenocarcinoma samples compared with normal, which suggested that miR-33a-5p may serve as a tumor suppressor gene. Transfection with miR-33a-5p mimics inhibited the proliferation and migration of A549 and LTEP-a-2 cells and increased cellular apoptosis. A luciferase reporter assay confirmed that miR-33a-5p targets the 3' untranslated region of the mechanistic target of rapamycin (mTOR) gene. mTOR expression was decreased in A549 and LTEP-a-2 cells treated with miR-33a-5p mimics, as well as the expression of its downstream effectors phosphorylated (p) p70 ribosomal protein S6 kinase (p70S6K) and p-eukaryotic translation initiation factor 4E binding protein 1 (4EBP1). Following treatment with celastrol, miR-33a 5p expression was upregulated, and miR-33a-5p could enhance cellular sensitivity to celastrol. Western blot analysis revealed that the expression of mTOR, p p70S6K and p-4EBP1 decreased following celastrol treatment. These results suggested that mTOR was involved in the mechanism by which miR-33a-5p enhanced the sensitivity of lung adenocarcinoma cells to celastrol. Furthermore, LTEP-a-2 cells were xenografted subcutaneously into nude mice, to examine the effect of celastrol and miR-33a-5p on the growth of LTEP-a-2 cells in vivo. The results demonstrated that tumor growth in the celastrol-treated or miR-33a-5p-treated group was attenuated compared with the control group. Notably, tumor growth in the combination treatment group was almost arrested after 2 weeks. In addition, celastrol upregulated the expression of miR-33a-5p, and high expression of miR 33a-5p inhibited mTOR and its downstream effectors. In summary, miR-33a-5p inhibited the proliferation of lung adenocarcinoma cells, enhanced the antitumor effect of celastrol, and improved sensitivity to celastrol by targeting mTOR in lung adenocarcinoma in vitro and in vivo. PMID- 29484435 TI - Syndecan-1 suppresses epithelial-mesenchymal transition and migration in human oral cancer cells. AB - Epithelial-mesenchymal transition (EMT) is one of the major processes that contribute to the occurrence of cancer metastasis. EMT has been associated with the development of oral cancer. Syndecan-1 (SDC1) is a key cell-surface adhesion molecule and its expression level inversely correlates with tumor differentiation and prognosis. In the present study, we aimed to determine the role of SDC1 in oral cancer progression and investigate the molecular mechanisms through which SDC1 regulates the EMT and invasiveness of oral cancer cells. We demonstrated that basal SDC1 expression levels were lower in four oral cancer cell lines (KB, Tca8113, ACC2 and CAL-27), than in normal human periodontal ligament fibroblasts. Ectopic overexpression of SDC1 resulted in morphological transformation, decreased expression of EMT-associated markers, as well as decreased migration, invasiveness and proliferation of oral cancer cells. In contrast, downregulation of the expression of SDC1 caused the opposite results. Furthermore, the knockdown of endogenous SDC1 activated the extracellular signal-regulated kinase (ERK) cascade, upregulated the expression of Snail and inhibited the expression of E cadherin. In conclusion, our findings revealed that SDC1 suppressed EMT via the modulation of the ERK signaling pathway that, in turn, negatively affected the invasiveness of human oral cancer cells. Our results provided useful evidence about the potential use of SDC1 as a molecular target for therapeutic interventions in human oral cancer. PMID- 29484436 TI - Resveratrol protects late endothelial progenitor cells from TNF-alpha-induced inflammatory damage by upregulating Kruppel-like factor-2. AB - Cardiovascular risk factors can negatively influence late endothelial progenitor cell (EPCs) number and functions, thus EPCs biology is a clinical implications for cardiovascular diseases. The present study aimed to investigate the potential protective effects of resveratrol (RES) on tumor necrosis factor (TNF)-alpha induced inflammatory damage in late endothelial progenitor cells (EPCs) and to elucidate the underlying mechanisms. Late EPCs at passages 3-5 were pretreated with RES at a concentration of 20 umol/l for 12 h and subsequently incubated with TNF-alpha (10 ng/ml) for 24 h. The adhesion, migration, proliferation and vasculogenesis of EPCs were subsequently detected. Furthermore, the mRNA expression levels of intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) were measured by reverse transcription quantitative polymerase chain reaction (RT-qPCR). Nitric oxide (NO) levels in the supernatant were determined using a colorimetric assay kit. Additionally, the mRNA and protein expression of Kruppel-like factor-2 (KLF2) was determined by RT qPCR and western blot analysis, respectively. The results indicated that TNF alpha markedly inhibited the proliferation, adhesion, migration and vasculogenesis of late EPCs. However, RES ameliorated the effects induced by TNF alpha. Furthermore, exposure of EPCs to TNF-alpha decreased the levels of NO secretion and KLF2 expression at the mRNA and protein levels, but upregulated the levels of inflammatory factors, including ICAM-1 and MCP-1, compared with the control group. RES significantly inhibited TNF-alpha-induced inflammatory damage through upregulation of KLF2 expression and downregulation of the expression of ICAM-1 and MCP-1. In conclusion, RES may exert protective effects on the cardiovascular system, as demonstrated by the amelioration of TNF-alpha-induced inflammation in EPCs following RES treatment, and may therefore be used in the future for the prevention of cardiovascular disease. PMID- 29484437 TI - miR-181 regulates cisplatin-resistant non-small cell lung cancer via downregulation of autophagy through the PTEN/PI3K/AKT pathway. AB - A number of miRNAs have been found to be abnormally expressed or mutated in numerous cancers and thus, are considered to act as oncogenes or tumor suppressor genes. The aim of the present study was to investigate the effect of miR-181 on cisplatin-resistant non-small cell lung cancer (NSCLC). In patients with cisplatin-resistant NSCLC, miR-181 expression was found to be markedly decreased. In addition, in the cisplatin-resistant human lung adenocarcinoma cell line A549/DDP, miR-181 downregulation promoted cell growth and metastasis and inhibited cell apoptosis, whereas miR-181 overexpression exerted the opposite effects. Furthermore, miR-181 downregulation suppressed LC3 and ATG5 protein expression in A549/DDP cells through suppression of the PTEN/PI3K/AKT/mTOR pathway, whereas miR-181 overexpression recovered LC3 and ATG5 protein expression by promoting PTEN/PI3K/AKT/mTOR signaling. In turn, PTEN inhibitors reduced the anticancer effects of miR-181 overexpression on A549/DDP cell growth via the regulation of autophagy through the PI3K/AKT/mTOR pathway. Therefore, miR-181 may be a novel and important regulator of cisplatin-resistant NSCLC by serving a role in the regulation of apoptosis, as an established rate-limiting miRNA target. PMID- 29484438 TI - Semaphorin 3A enhances osteogenesis of MG63 cells through interaction with Schwann cells in vitro. AB - Bone remodeling is under the control of various signals and systems in the body, including the nervous system. Semaphorin (Sema) 3A is a chemorepellent protein which regulates bone mass. Schwann cells, having a pivotal role following nerve injury, interact with Sema3A under numerous circumstances. The present study established a co-culture system of MG63 and Schwann cells to investigate the role of the interaction between Sema3A and Schwann cells in osteogenesis. The results from the alkaline phosphatase assay, calcium nodule staining and the analysis of the osteogenic gene expression revealed that Sema3A inhibits osteogenic differentiation of MG63 cells in single-cell culture and promotes osteogenic differentiation of MG63 cells in co-culture with Schwann cells, in a concentration-dependent manner. These findings suggest that the presence of Schwann cells induces Sema3A-associated osteogenic differentiation in bone cells, and also reveals the pivotal role of Sema3A as a regulator in the skeletal and nervous systems, thus contributing to a better understanding of the interaction between these systems. PMID- 29484439 TI - Amino acid starvation culture condition sensitizes EGFR-expressing cancer cell lines to gefitinib-mediated cytotoxicity by inducing atypical necroptosis. AB - The maintenance of the intracellular level of amino acids is crucial for cellular homeostasis. This is carried out via the regulation of both the influx from the extracellular environment and the recycling of intracellular resources. Since epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors, including gefitinib (GEF) have been reported to induce the apoptosis of several cancer cell lines, in the present study, we examined whether the cytotoxic effects of GEF are further enhanced under amino acid starvation (AAS) culture conditions. Under AAS culture conditions, the cell killing effect of GEF was synergistically pronounced in the EGFR-expressing cell lines, namely, CAL 27, Detroit 562, A549 and PANC-1 cells compared with those treated with either GEF or AAS alone. The addition of essential amino acids, but not non-essential amino acids to the cell culture medium resulted in the cancellation of this pronounced cytotoxicity. The knockdown of L-type amino acid transporter 1 (LAT-1) by siRNA also enhanced GEF induced cytotoxicity. Therefore, the shortage of the intracellular amino acid pool appears to determine the sensitivity to GEF. Notably, this enhanced cytotoxicity is not mediated by the induction of apoptosis, but is accompanied by the pronounced induction of autophagy. The presence of necrostatin-1, an inhibitor of receptor-interacting serine/threonine-protein kinase 1 (RIPK-1), but not that of Z-VAD-fmk, attenuated the cytotoxic effects of GEF under AAS culture conditions. Electron microscopy demonstrated that the CAL 27 cells treated with GEF under AAS culture conditions exhibited swelling of the cytosol and organelles with an increased number of autophagosomes and autolysosomes, but without chromatin condensation and nuclear fragmentation. Autophagic cell death was excluded as the inhibition of autophagy did not attenuate the cytotoxicity. These results strongly suggest the induction of necroptosis in response to GEF under AAS culture conditions. However, we could not detect any phosphorylation of RIPK 1 and mixed lineage kinase domain like pseudokinase (MLKL), as well as any necrosome formation. Therefore, the enhanced cytotoxic effect of GEF under AAS culture conditions is thought to be mediated by atypical necroptosis. PMID- 29484441 TI - A disintegrin and metalloprotease 10-containing exosomes derived from nasal polyps promote angiogenesis and vascular permeability. AB - Abnormal angiogenesis and vascular permeability is important for the formation of nasal polyps (NPs). Increasing evidence has indicated that exosomes serve a vital role in modulating angiogenesis and vascular permeability. A disintegrin and metalloprotease 10 (ADAM10), an important type of proteinase that is overexpressed in various diseases, can influence angiogenesis and vascular permeability and has been observed in healthy nasal exosomes. To the best of our knowledge, the expression levels and the function of ADAM10 in NLF-derived exosomes from NPs has not been demonstrated previously. In order to determine the influence of exosomes derived from nasal lavage fluid (NLF) on angiogenesis and vascular permeability, 25 nasal polyp patients and 15 healthy volunteers were enrolled in the present study. NLF was collected from all of the subjects. Exosomes were isolated from NLF, visualized under transmission electron microscope and identified using western blot analysis. The effect of exosomes on human umbilical vein endothelial cells (HUVECs) was measured by tube formation and permeability assays in vitro. The expression of exosomal ADAM10 was also analyzed by western blotting. NLF-derived exosomes from NPs influenced proliferation, tube formation and the permeability of HUVECs. ADAM10 was highly expressed in NLF-derived exosomes from NPs when compared with healthy volunteers. Thus, NLF-derived exosomes from NPs promoted angiogenesis and vascular permeability, which may be associated with abundant ADAM10 in NP exosomes. PMID- 29484442 TI - DFMG reverses proliferation and migration of vascular smooth muscle cells induced by co-culture with injured vascular endothelial cells via suppression of the TLR4 mediated signaling pathway. AB - 7-Difluoromethoxy-5,4'-dimethoxy-genistein (DFMG) is a novel chemical compound synthesized using genistein. Previous studies have indicated that DFMG can reverse the apoptosis of vascular endothelial cells (VECs) by regulating the mitochondrial apoptosis pathway. The present study aimed to investigate the activity and molecular mechanism underlying DFMG-mediated protection of vascular smooth muscle cell (VSMCs) using a non-contact co-culture model established by using Transwell insert. Secretion of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were measured by ELISA. Proliferation and migration of VSMCs were assessed using a Cell Counting kit-8 and wound healing assays, respectively. Toll-like receptor 4 (TLR4) mRNA and protein levels were detected by reverse transcription-quantitative polymerase chain reaction and western blotting analyses, respectively. In the present study, lysophosphatidylcholine (LPC) significantly increased the secretion of IL-6 and TNF-alpha in VECs. VECs treated with LPC markedly increased proliferation and migration of VSMCs, which were inhibited by DFMG. Transfection of either TLR4 short hairpin RNA (shRNA) or TLR4 cDNA in VECs inhibited and increased proliferation and migration of VSMCs, respectively. Furthermore, transfection of VECs with TLR4 shRNA suppressed the proliferation and migration of VSMCs induced by co-culture with injured VECs, which was further enhanced by treatment with DFMG. By contrast, transfection of VECs with TLR4 cDNA enhanced proliferation and migration of VSMCs and this effect was inhibited by treatment with DFMG. Taken together, the results of the present study demonstrated that DFMG can reverse proliferation and migration of VSMCs induced by co-culture with injured VECs via suppression of the TLR4-mediated signaling pathway. PMID- 29484443 TI - Lentivirus-mediated MDA7/IL24 expression inhibits the proliferation of hepatocellular carcinoma cells. AB - MDA7/IL24 is a member of the IL-10 gene family that functions as a cytokine. Notably, supra-physiological endogenous MDA7 levels have been indicated to suppress tumor growth and induce apoptosis in different cancer types. In the present study, MDA7 roles were investigated during the proliferation of hepatocellular carcinoma (HCC) cells and the molecular mechanisms underlying this process. A lentiviral vector expressing MDA7/IL24 (LV-MDA7/IL24) was constructed and used to infect HCC SMMC-7721 cells. The expression levels of MDA7/IL24 in these cells were determined using RT-qPCR and western blot analysis. The effects of LV-MDA7/IL24 on cell proliferation were analyzed using MTT and colony formation assays. Furthermore, the influence of LV-MDA7/IL24 on cell apoptosis and cell cycle distribution were detected using flow cytometry. The underlying molecular mechanisms were investigated using microarray and western blot analysis. The expression of MDA7/IL24 was confirmed to be significantly increased in the cells infected with LV-MDA7/IL24 compared with that the negative-control infected group. Lentivirus-mediated MDA7/IL24 expression was found to inhibit HCC cell proliferation and colony formation, and it also induced cell arrest and apoptosis. Microarray analysis and western blotting results indicated that multiple cancer-associated pathways and oncogenes are regulated by MDA7/IL24, including cell cycle regulatory and apoptosis activation pathway. In conclusion, it was determined that MDA7/IL24 inhibits the proliferation and reduces the tumorigenicity of HCC cells by regulating cell cycle progression and inducing apoptosis, indicating that it may be used as a potential prognostic and therapeutic target in HCC. PMID- 29484444 TI - Autophagy-mediated adaptation of hepatocellular carcinoma cells to hypoxia mimicking conditions constitutes an attractive therapeutic target. AB - Hepatocellular carcinoma has extremely poor prognosis. In cancerous liver tissues, aberrant proliferation of cancer cells leads to the creation of an area where an immature vascular network is formed. Since oxygen is supplied to cancer tissues through the bloodstream, a part of the tumor is exposed to hypoxic conditions. As hypoxia is known to severely reduce the effectiveness of existing anticancer agents, novel valid therapeutic targets must be identified for the treatment of hepatocellular carcinoma. Generally, autophagy has been reported to play an important role in the adaptation of cancer cells to hypoxia. However, the exact role and significance of this process vary depending on the cancer type, requiring detailed analysis in individual primary tumors and cell lines. In the present study, we examined autophagy induced by cobalt chloride, a hypoxia mimicking agent, in hepatocellular carcinoma cells with the aim to evaluate the validity of this process as a potential therapeutic target. We observed that treatment with cobalt chloride induced autophagy, including the intracellular quality control mechanism, in an AMPK-dependent manner. Furthermore, treatment with autophagy inhibitors (bafilomycin and LY294002) resulted in significant, highly-selective cytotoxicity and apoptosis activation under hypoxia-mimicking conditions. The knockdown of AMPK also revealed significant cytotoxicity in hypoxia-mimicking conditions. These results clearly demonstrated that autophagy, especially mitophagy, was induced by the AMPK pathway when hepatocellular carcinoma cells were subjected to hypoxic conditions and played an important role in the adaptation of these cells to such conditions. Thus, autophagy may constitute an attractive therapeutic target for the treatment of hepatocellular carcinoma. PMID- 29484440 TI - Importance of immune monitoring approaches and the use of immune checkpoints for the treatment of diffuse intrinsic pontine glioma: From bench to clinic and vice versa (Review). AB - On the basis of immunological results, it is not in doubt that the immune system is able to recognize and eliminate transformed cells. A plethora of studies have investigated the immune system of patients with cancer and how it is prone to immunosuppression, due in part to the decrease in lymphocyte proliferation and cytotoxic activity. The series of experiments published following the demonstration by Dr Allison's group of the potential effect of anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) paved the way for a new perception in cancer immunotherapy: Immune checkpoints. Several T cell-co-stimulatory molecules including cluster of differentiation (CD)28, inducible T cell co-stimulatory, 4 1BB, OX40, glucocorticoid-induced tumor necrosis factor receptor-related gene and CD27, and inhibitory molecules including T cell immunoglobulin and mucin domain containing-3, programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD L1), V-domain immunoglobulin suppressor of T cells activation, T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain, and B and T lymphocyte attenuator have been described in regulating T cell functions, and have been demonstrated to be essential targets in immunotherapy. In preclinical studies, glioblastoma multiforme, a high-grade glioma, the monotherapy targeting PD-1/PD-L1 and CTLA-4 resulted in increased survival times. An improved understanding of the pharmacodynamics and immune monitoring on glioma cancers, particularly in diffuse intrinsic pontine glioma (DIPG), an orphan type of cancer, is expected to have a major contribution to the development of novel therapeutic approaches. On the basis of the recent preclinical and clinical studies of glioma, but not of DIPG, the present review makes a claim for the importance of investigating the tumor microenvironment, the immune response and the use of immune checkpoints (agonists or antagonists) in preclinical/clinical DIPG samples by immune monitoring approaches and high-dimensional analysis. Evaluating the potential predictive and correlative biomarkers in preclinical and clinical studies may assist in answering certain crucial questions that may be useful to improve the clinical response in patients with DIPG. PMID- 29484445 TI - The WOMAC score can be reliably used to classify patient satisfaction after total knee arthroplasty. AB - PURPOSE: The primary aim of this study was to define a classification in the WOMAC score after total knee arthroplasty (TKA) according to patient satisfaction. The secondary aims were to describe patient demographics for each level of satisfaction. METHODS: A retrospective cohort consisting of 2589 patients undergoing a primary TKA were identified from an established arthroplasty database. Patient demographics, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and short form (SF) 12 scores were collected pre-operatively and 1 year post-operatively. In addition, patient satisfaction was assessed at 1 year with four responses: very satisfied, satisfied, dissatisfied or very dissatisfied. Receiver operating characteristic (ROC) curves were used to identify values in the components and total WOMAC scores that were predictive of each level of satisfaction, which were used to define the categories of excellent, good, fair and poor. RESULTS: At 1 year, there were 1740 (67.5%) very satisfied, 572 (22.2%) satisfied, 190 (7.4%) dissatisfied and 76 (2.9%) very dissatisfied patients. ROC curve analysis identified excellent, good, fair and poor categories for the pain (> 78, 59-78, 44-58, < 44), function (> 72, 54-72, 41-53, < 41), stiffness (> 69, 56-69, 43-55, < 43) and total (> 75, 56-75, 43-55, < 43) WOMAC scores, respectively. Patients with lung disease, diabetes, gastric ulcer, kidney disease, liver disease, depression, back pain, with worse pre-operative functional scores (WOMAC and SF 12) and those with less of an improvement in the scores, had a significantly lower level of satisfaction. CONCLUSION: This study has defined a post-operative classification of excellent, good, fair and poor for the components and total WOMAC scores after TKA. The predictors of level of satisfaction should be recognised in clinical practice and patients at risk of a lower level of satisfaction should be made aware in the pre-operative consent process. LEVEL OF EVIDENCE: III. PMID- 29484446 TI - Effects of the Antibiotic Amoxicillin on Key Species of the Terrestrial Environment. AB - The antibiotic amoxicillin (AMX) is globally important for human and animal health. Although AMX is considered as a threat for the aquatic and terrestrial environment, limited data are present for its toxicity against key species such as denitrifying bacteria in soil, earthworms and plants. In the present research, the OECD protocols for environmental risk assessment were applied to study AMX acute toxicity, at nominal concentrations, close to the environmentally relevant, in soil bacteria responsible for nitrogen cycling, in the earthworm species Eisenia fetida and six plant species. The results revealed no significant effects of the antibiotic on the parameters related to the end-points of each respective test, at the selected concentration range. Therefore, the antibiotic did not present acute toxicity for the species, under the framework of the OECD tests. Further research is essential to be conducted also considering the patterns of degradation of AMX during the experimental periods. PMID- 29484448 TI - [Atopic eczema]. PMID- 29484447 TI - Enhancer DNA methylation in acute myeloid leukemia and myelodysplastic syndromes. AB - DNA methylation (CpG methylation) exerts an important role in normal differentiation and proliferation of hematopoietic stem cells and their differentiated progeny, while it has also the ability to regulate myeloid versus lymphoid fate. Mutations of the epigenetic machinery are observed in hematological malignancies including acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) resulting in hyper- or hypo-methylation affecting several different pathways. Enhancers are cis-regulatory elements which promote transcription activation and are characterized by histone marks including H3K27ac and H3K4me1/2. These gene subunits are target gene expression 'fine-tuners', are differentially used during the hematopoietic differentiation, and, in contrast to promoters, are not shared by the different hematopoietic cell types. Although the interaction between gene promoters and DNA methylation has extensively been studied, much less is known about the interplay between enhancers and DNA methylation. In hematopoiesis, DNA methylation at enhancers has the potential to discriminate between fetal and adult erythropoiesis, and also is a regulatory mechanism in granulopoiesis through repression of neutrophil-specific enhancers in progenitor cells during maturation. The interplay between DNA methylation at enhancers is disrupted in AML and MDS and mainly hyper-methylation at enhancers raising early during myeloid lineage commitment is acquired during malignant transformation. Interactions between mutated epigenetic drivers and other oncogenic mutations also affect enhancers' activity with final result, myeloid differentiation block. In this review, we have assembled recent data regarding DNA methylation and enhancers' activity in normal and mainly myeloid malignancies. PMID- 29484449 TI - Assessment of Multi Fragment Melting Analysis System (MFMAS) for the Identification of Food-Borne Yeasts. AB - Multi Fragment Melting Analysis System (MFMAS) is a novel approach that was developed for the species-level identification of microorganisms. It is a software-assisted system that performs concurrent melting analysis of 8 different DNA fragments to obtain a fingerprint of each strain analyzed. The identification is performed according to the comparison of these fingerprints with the fingerprints of known yeast species recorded in a database to obtain the best possible match. In this study, applicability of the yeast version of the MFMAS (MFMAS-yeast) was evaluated for the identification of food-associated yeast species. For this purpose, in this study, a total of 145 yeast strains originated from foods and beverages and 19 standard yeast strains were tested. The DNAs isolated from these yeast strains were analyzed by the MFMAS, and their species were successfully identified with a similarity rate of 95% or higher. It was shown that the strains belonged to 43 different yeast species that are widely found in the foods. A clear discrimination was also observed in the phylogenetically related species. In conclusion, it might be suggested that the MFMAS-yeast seems to be a highly promising approach for a rapid, accurate, and one-step identification of the yeasts isolated from food products and/or their processing environments. PMID- 29484450 TI - Safety of mFOLFOX6/XELOX as adjuvant chemotherapy after curative resection of stage III colon cancer: phase II clinical study (The FACOS study). AB - PURPOSE: Adjuvant chemotherapy with oxaliplatin combined with a fluoropyrimidine derivative is widely accepted as standard therapy for patients with stage III colon cancer, since few clinical data are available for Japanese patients. The FACOS trial investigated the tolerability of modified FOLFOX6 (mFOLFOX6) and XELOX regimens in Japanese colon cancer patients. METHODS: Twelve cycles of mFOLFOX6 or 8 cycles of XELOX were given to patients with eligibility: stage III curatively resected colon cancer, performance status of 0-1, age from 20 to 75 years, and adequate organ function. The primary endpoint was 3-year disease-free survival. Secondary endpoints were the incidence of adverse events (AEs) and the completion rate of study therapy. RESULTS: From April 2010 to April 2014, a total of 132 patients were enrolled. Safety was analyzed in 130 patients, with finalized data from 73 patients receiving mFOLFOX6 and 57 patients receiving XELOX. A total of 130 patients (100%) experienced AEs (any grade), and 52 patients (40.0%) experienced AEs of grade >= 3. No significant difference in the frequency of grade >= 3 AEs was observed between mFOLFOX6 and XELOX groups. Continuation of the planned cycle rate of protocol treatment was 69.9% in the mFOLFOX6 group and 68.4% in the XELOX group. Treatment was discontinued because of AEs in 14 patients (19.2%) in the mFOLFOX6 group and 8 (14.0%) in the XELOX group. Mean relative dose intensity for oxaliplatin was 78.0% in the mFOLFOX6 group and 82.8% in the XELOX group. CONCLUSION: As adjuvant chemotherapy for stage III colon cancer, mFOLFOX6/XELOX regimens are acceptable. PMID- 29484451 TI - PRRT genomic signature in blood for prediction of 177Lu-octreotate efficacy. AB - BACKGROUND: Peptide receptor radionuclide therapy (PRRT) utilizes somatostatin receptor (SSR) overexpression on neuroendocrine tumors (NET) to deliver targeted radiotherapy. Intensity of uptake at imaging is considered related to efficacy but has low sensitivity. A pretreatment strategy to determine individual PRRT response remains a key unmet need. NET transcript expression in blood integrated with tumor grade provides a PRRT predictive quotient (PPQ) which stratifies PRRT "responders" from "non-responders". This study clinically validates the utility of the PPQ in NETs. METHODS: The development and validation of the PPQ was undertaken in three independent 177Lu-PRRT treated cohorts. Specificity was tested in two separate somatostatin analog-treated cohorts. Prognostic value of the marker was defined in a cohort of untreated patients. The developmental cohort included lung and gastroenteropancreatic [GEP] NETs (n = 72) from IRST Meldola, Italy. The majority were GEP (71%) and low grade (86% G1-G2). Prospective validation cohorts were from Zentralklinik Bad Berka, Germany (n = 44), and Erasmus Medical Center, Rotterdam, Netherlands (n = 42). Each cohort included predominantly well differentiated, low grade (86-95%) lung and GEP-NETs. The non-PRRT comparator cohorts included SSA cohort I, n = 28 (100% low grade, 100% GEP-NET); SSA cohort II, n = 51 (98% low grade; 76% GEP-NET); and an untreated cohort, n = 44 (64% low grade; 91% GEP-NET). Baseline evaluations included clinical information (disease status, grade, SSR) and biomarker (CgA). NET blood gene transcripts (n = 8: growth factor signaling and metabolism) were measured pre-therapy and integrated with tumor Ki67 using a logistic regression model. This provided a binary output: "predicted responder" (PPQ+); "predicted non-responder" (PPQ-). Treatment response was evaluated using RECIST criteria [Responder (stable, partial and complete response) vs Non-Responder)]. Sample measurement and analyses were blinded to study outcome. Statistical evaluation included Kaplan-Meier survival and standard test evaluation analyses. RESULTS: In the developmental cohort, 56% responded to PRRT. The PPQ predicted 100% of responders and 84% of non-responders (accuracy: 93%). In the two validation cohorts (response: 64-79%), the PPQ was 95% accurate (Bad Berka: PPQ + =97%, PPQ- = 93%; Rotterdam: PPQ + =94%, PPQ- = 100%). Overall, the median PFS was not reached in PPQ+ vs PPQ- (10-14 months; HR: 18-77, p < 0.0001). In the comparator cohorts, the predictor (PPQ) was 47-50% accurate for SSA-treatment and 50% as a prognostic. No differences in PFS were respectively noted (PPQ+: 10-12 months vs. PPQ-: 9-15 months). CONCLUSION: The PPQ derived from circulating NET specific genes and tumor grade prior to the initiation of therapy is a highly specific predictor of the efficacy of PRRT with an accuracy of 95%. PMID- 29484453 TI - Six-Position, Frontal View Photography in Blepharoplasty: A Simple Method. AB - BACKGROUND: Photography plays a pivotal role in patient education, photo documentation, preoperative planning and postsurgical evaluation in plastic surgeries. It has long been serving as a bridge that facilitated communication not only between patients and doctors, but also among plastic surgeons from different countries. Although several basic principles and photographic methods have been proposed, there is no internationally accepted photography that could provide both static and dynamic information in blepharoplasty. In this article, we introduced a novel six-position, frontal view photography for thorough assessment in blepharoplasty. METHODS: From October 2013 to January 2017, 1068 patients who underwent blepharoplasty were enrolled in our clinical research. All patients received six-position, frontal view photography. Pictures were taken of the patients looking up, looking down, squeezing, smiling, looking ahead and with closed eyes. Conventionally, frontal view photography only contained the last two positions. Then, both novel six-position photographs and conventional two position photographs were used to appraise postsurgical outcomes. RESULTS: Compared to conventional two-position, frontal view photography, six-position, frontal view photography can provide more detailed, thorough information about the eyes. It is of clinical significance in indicating underlying adhesion of skin/muscle/fat according to individual's features and assessing preoperative and postoperative dynamic changes and aesthetic outcomes. CONCLUSION: Six-position, frontal view photography is technically uncomplicated while exhibiting static, dynamic and detailed information of the eyes. This innovative method is favorable in eye assessment, especially for revision blepharoplasty. We suggest using six position, frontal view photography to obtain comprehensive photographs. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29484452 TI - Requirement or exclusion of inverted repeat sequences with cruciform-forming potential in Escherichia coli revealed by genome-wide analyses. AB - Inverted repeat (IR) sequences are DNA sequences that read the same from 5' to 3' in each strand. Some IRs can form cruciforms under the stress of negative supercoiling, and these IRs are widely found in genomes. However, their biological significance remains unclear. The aim of the current study is to explore this issue further. We constructed the first Escherichia coli genome-wide comprehensive map of IRs with cruciform-forming potential. Based on the map, we performed detailed and quantitative analyses. Here, we report that IRs with cruciform-forming potential are statistically enriched in the following five regions: the adjacent regions downstream of the stop codon-coding sites (referred to as the stop codons), on and around the positions corresponding to mRNA ends (referred to as the gene ends), ~ 20 to ~45 bp upstream of the start codon-coding sites (referred to as the start codons) within the 5'-UTR (untranslated region), ~ 25 to ~ 60 bp downstream of the start codons, and promoter regions. For the adjacent regions downstream of the stop codons and on and around the gene ends, most of the IRs with a repeat unit length of >= 8 bp and a spacer size of <= 8 bp were parts of the intrinsic terminators, regardless of the location, and presumably used for Rho-independent transcription termination. In contrast, fewer IRs were present in the small region preceding the start codons. In E. coli, IRs with cruciform-forming potential are actively placed or excluded in the regulatory regions for the initiation and termination of transcription and translation, indicating their deep involvement or influence in these processes. PMID- 29484454 TI - Evolutionary games under incompetence. AB - The adaptation process of a species to a new environment is a significant area of study in biology. As part of natural selection, adaptation is a mutation process which improves survival skills and reproductive functions of species. Here, we investigate this process by combining the idea of incompetence with evolutionary game theory. In the sense of evolution, incompetence and training can be interpreted as a special learning process. With focus on the social side of the problem, we analyze the influence of incompetence on behavior of species. We introduce an incompetence parameter into a learning function in a single population game and analyze its effect on the outcome of the replicator dynamics. Incompetence can change the outcome of the game and its dynamics, indicating its significance within what are inherently imperfect natural systems. PMID- 29484455 TI - Survival analysis of patients with Hodgkin lymphoma who failed high dose chemotherapy and autologous stem cell transplant. AB - Hodgkin lymphoma (HL) patients failing after high dose chemotherapy (HDC) and auto-SCT have a poor outcome. Some patients may still benefit from further treatments. From 1996 to 2016, 137 HL patients (39.5%) out of 347 transplanted experienced post auto-SCT failure. Males/female 61%:39%, median age at auto-SCT 23.4 years and median follow-up 55.6 months (9-153). Type of failure was progressive (46%), relapsed (35%) or persistent disease/refractory disease (19%). Median overall survival (OS) from the time of failure is 20 months; 35 patients (25.5%) are alive. One hundred and four patients received treatment; the response rate was 45%; complete remission in 41 (30%) and partial remission in 21 (15%) patients. 1st interventions post auto-SCT were chemotherapy (39%), radiation therapy (35%) or best supportive care (24%). Twenty-seven patients with 2nd-SCT (allogeneic (15), auto-SCT (2)) and/or brentuximab (18 patients) had superior OS (50.6 months) vs other treatments (22.5 months, P value 0.037). COX regression multivariate analysis identified post auto-SCT treatment failure before 12 months (hazard ratio (HR) 3.37, CI 1.7-6.6, P value < 0.001), presence of B symptoms (HR 2.55, CI 1.4-4.6, P value 0.002), stages III-IV (HR 2.7, CI 1.5-4.9, P value 0.001), albumin < 4 g/dl (HR 1.76, CI 1.1-2.9, P value 0.027) and tumor > 5 cm (HR 1.1.9, CI 1.13-3.25, P value 0.015) as significant risk factors; P value < 0.001. KM OS with 0-1 factor (148.6 months): 2 factors (23.6 months) and 3-5 factors (9.4 months) (P value < 0.001). OS was 63%:25%:7% respectively with 0 1:2:3-5 factors respectively (P value < 0.001). Despite high-risk factors, 2nd SCT/brentuximab use post HDC auto-SCT failure may result in durable survival. PMID- 29484456 TI - Very late erosion of Amplatzer occluder device resulting in Cardiac tamponade after 15 years. PMID- 29484457 TI - Stimulus duration has little effect on auditory, visual and audiovisual temporal order judgement. AB - Some classical studies on temporal order judgments (TOJ) suggested a single central process comparing stimulus onsets across modalities. The prevalent current view suggests that there is modality-specific timing estimation followed by a cross-modal stage. If the latter view is correct, TOJ's may vary depending on stimulus modality. Further, if TOJ is based only on onsets, stimulus duration should be irrelevant. To address these issues, we used both unisensory and multisensory stimuli to test whether unisensory duration processing influences cross-modal TOJ's. The stimuli were auditory noise bursts, visual squares, and their cross-modal combinations presented at 10, 40 and 500 ms durations, and various stimulus onset asynchronies. Psychometric functions were measured with an identical task in all conditions: On each trial, two stimuli were presented, one to the left, the other to the right of fixation. The participants judged which one started first. TOJ's were little affected by stimulus duration, implying that they are mainly determined by stimulus onsets. Throughout, the cross-modal just noticeable differences were larger than the unisensory ones. In accordance with the current view, our results suggest that cross-modal TOJ's require a comparison of timing after modality-specific estimations. PMID- 29484458 TI - Vessel architecture in human knee cartilage in children: an in vivo susceptibility-weighted imaging study at 7 T. AB - OBJECTIVES: To evaluate the clinical feasibility of ultrahigh field 7-T SWI to visualize vessels and assess their density in the immature epiphyseal cartilage of human knee joints. METHODS: 7-T SWI of 12 knees (six healthy volunteers, six patients with osteochondral abnormalities; mean age 10.7 years; 3 female, 9 male) were analysed by two readers, classifying intracartilaginous vessel densities (IVD) in three grades (no vessels, low IVD and high IVD) in defined femoral, tibial and patellar zones. Differences between patients and volunteers, IVDs in different anatomic locations, differences between cartilage overlying osteochondral abnormalities and corresponding normal zones, and differences in age groups were analysed. RESULTS: Interrater reliability showed moderate agreement between the two readers (kappa = 0.58, p < 0.001). The comparison of IVDs between patients and volunteers revealed no significant difference (p = 0.706). The difference between zones in the cartilage overlying osteochondral abnormalities to corresponding normal zones showed no significant difference (p = 0.564). IVDs were related to anatomic location, with decreased IVDs in loading areas (p = 0.003). IVD was age dependent, with more vessels present in the younger participants (p = 0.001). CONCLUSIONS: The use of SWI in conjunction with ultrahigh field MRI makes the in vivo visualization of vessels in the growing cartilage of humans feasible, providing insights into the role of the vessel network in acquired disturbances. KEY POINTS: * SWI facilitates in vivo visualization of vessels in the growing human cartilage. * Interrater reliability of the intracartilaginous vessel grading was moderate. * Intracartilaginous vessel densities are dependent on anatomical location and age. PMID- 29484460 TI - [Human papillomavirus and penile cancer : Thinking about measures for prevention]. AB - Two major pathways of penile carcinogenesis are known: human papillomavirus (HPV) induced penile cancer and HPV-negative cancers associated with chronic dermatoses. Therefore, modern measures for prevention of penile cancer may for example include prophylactic HPV vaccination. The resulting B-cell-mediated immunity to HPV capsid proteins is effective protection against future HPV infections. Contrarily when treating existing HPV infections or HPV-associated cancers an antigen-specific T-cell immunity is necessary. To date, screening and treatment of precancerous lesions to prevent penile cancer are not established in the German health care program and the highly expected therapeutic HPV vaccines are still on the horizon. In this article, we focus on possible strategies to prevent HPV-related penile cancer on different levels of carcinogenesis. PMID- 29484459 TI - Simultaneous multislice diffusion-weighted imaging in whole-body positron emission tomography/magnetic resonance imaging for multiparametric examination in oncological patients. AB - OBJECTIVES: The aim of this study was to compare the diagnostic performance of simultaneous multislice diffusion-weighted imaging (DWI-SMS) with that of standard DWI (DWI-STD) in whole-body 3-T PET/MRI examination protocols in oncological patients. METHODS: In a phantom study, we evaluated the apparent diffusion coefficients (ADC) from the two techniques. In ten volunteers, we assessed ADC values in different organs. In 20 oncological patients, we evaluated subjective image quality (Likert scale, 5 indicating excellent) and artefacts in different body regions. We also rated the conspicuity and acquired the ADC values of PET-positive tumorous lesions. RESULTS: The scan time for the whole-body DWI SMS examinations was 40% shorter than the scan time for the DWI-STD examinations (84 s vs. 140 s per table position). The phantom and volunteer studies showed lower ADC values from DWI-SMS in the liver and muscle (psoas muscle 1.4 vs. 1.3). In patients, DWI-SMS provided poorer subjective image quality in the thoracoabdominal region (3.0 vs. 3.8, p = 0.02) and overall more artefacts (138 vs. 105). No significant differences regarding conspicuity and ADC values of lesions were found. CONCLUSIONS: DWI-SMS seems to provide reliable conspicuity and ADC values of tumorous lesions similar to those provided by DWI-STD. Therefore, although providing poorer image quality in certain regions, DWI-SMS can clearly reduce PET/MRI scan times in oncological patients. KEY POINTS: * DWI SMS can reduce PET/MRI scan times in oncological patients. * DWI-SMS provides reliable ADC values and good lesion conspicuity similar to those provided by DWI STD. * DWI-SMS may provide poorer image quality in regions with low signal. PMID- 29484461 TI - [Long-term changes in multimodal intensive tinnitus therapy : A 5-year follow-up. German version]. AB - BACKGROUND: We present 5-year follow-up data for tinnitus-specific and comorbid depressive symptoms as well as stress-related outcome variables of an intensive multimodal 7-day tinnitus therapy. METHOD: Tinnitus burden (Tinnitus Questionnaire), stress (Perceived Stress Questionnaire), and depressive symptomatology (General Depression Scale) were measured at the 5-year follow-up after a multimodal intensive 7-day intervention. In all, 94 patients participated in the study. RESULTS: All outcome variables showed significant improvement at the end of the 7-day intensive treatment. These effects remained significant after 5 years. CONCLUSION: The results of the present study support the effectiveness of the 7-day multimodal intensive therapy for tinnitus. Posttreatment improvements were related to both tinnitus burden as well as stress and depressive symptoms and were maintained at the 5-year follow-up. PMID- 29484462 TI - Accuracy of CT chest without oral contrast for ruling out esophageal perforation using fluoroscopic esophagography as reference standard: a retrospective study. AB - PURPOSE: Esophageal perforation has a high mortality rate. Fluoroscopic esophagography (FE) is the procedure of choice for diagnosing esophageal perforation. However, FE can be difficult to perform in seriously ill patients. METHODS: We retrospectively reviewed charts and scans of all patients who had undergone thoracic CT (TCT) without oral contrast and FE for suspicion of esophageal perforation at our hospital between October, 2010 and December, 2015. Scans were interpreted by a single consultant radiologist having > 5 years of relevant experience. Statistical analysis was performed using SPSS version 20. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of TCT were computed using FE as reference standard. RESULTS: Of 122 subjects, 106 (83%) were male and their median age was 42 [inter-quartile range (IQR) 29-53] years. Esophageal perforation was evident on FE in 15 (8%) cases. Sensitivity, specificity, PPV and NPV of TCT for detecting esophageal perforation were 100, 54.6, 23.4 and 100%, respectively. When TCT was negative (n = 107), an alternative diagnosis was evident in 65 cases. CONCLUSION: Thoracic computed tomography (TCT) had 100% sensitivity and negative predictive value for excluding esophageal perforation. FE may be omitted in patients who have no evidence of mediastinal collection, pneumomediastinum or esophageal wall defect on TCT. However, in the presence of any of these features, FE is still necessary to confirm or exclude the presence of an esophageal perforation. PMID- 29484463 TI - Medial humeral condyle fracture in childhood: a rare but often overlooked injury. AB - The medial condyle fracture of the humerus is-in comparison to the lateral condyle fracture-a very rare Salter-Harrison IV-fracture of the elbow. In this prospective study 14 children were included and reviewed. One child had minimal displacement fracture type I, one child had type II, and 12 children had type III fractures. One patient was treated conservatively by an upper arm cast; thirteen were surgically treated using open reduction and osteosynthetical treatment. Postoperatively the elbow was immobilized in 90 degrees flexion and neutral position in a long-arm cast for 4-6 weeks. In 11 children the diagnosis was made immediately after trauma, in 3 children the fracture was overlooked initially. Medial condyle fractures may be difficult to diagnose in children younger than 6 years and the lesion may be mistaken for a simple avulsion of the medial epicondyle or even missed. The C-sign is a hint for a medial condyle fracture. The development of nonunion happens in consequence of failure to recognize the fractures. Results after an average follow-up of 36 months showed that children who were diagnosed immediately and received operative stabilization had very good functional and aesthetical results. Three children with delayed diagnosis of the fracture had open surgery with reposition and osteosynthetical fixation. In two of the overlooked cases a slight contracture and angular misalignment persisted. If in this injury the diagnosis is made without delay, an appropriate therapy is implemented and radiographical controls are performed until consolidation, good results can be expected. The main risk in medial condyle fractures of the humerus is to overlook them. This can lead to the development of a nonunion with joint malformations. PMID- 29484464 TI - PD-L1, B7-H3, and PD-1 expression in immunocompetent vs. immunosuppressed patients with cutaneous squamous cell carcinoma. AB - BACKGROUND: To characterize the expression of co-signaling molecules PD-L1, PD-1, and B7-H3 in cutaneous squamous cell carcinoma (cSCC) by immune status. METHODS: We retrospectively analyzed 66 cases of cSCC treated with surgical resection from 2012 to 2015. Immunostained tumor sections were analyzed for percent of tumor cells expressing PD-L1 (Tum-PD-L1%), B7-H3 (Tum-B7-H3%), density of peri and intratumoral CD8 T cells (CD8 density), proportion of CD8 T cells expressing PD-1 (CD8-PD-1%) and of tumor-infiltrating immune cells (TII) expressing PD-L1 (TII-PD L1%). RESULTS: Of 66 cases, 42 were immunocompetent, 24 immunosuppressed (13 organ transplant, 8 HIV+, 3 other). Defining positive expression at > 5%, 26% of tumors were positive for PD-L1, 85% for B7-H3, 80% had CD8 T cells that expressed PD-1 and 55% had TII that expressed PD-L1. Tum-B7-H3% was significantly higher (median 60 vs. 28%, p = 0.025) in immunocompetent vs. immunosuppressed patients, including when factoring in cause of immunosuppression. No significant difference in Tum-PD-L1%, TII-PD-L1%, CD8 density, or CD8-PD-1% was observed. Tumors from HIV+ patients lacked PD-L1 expression, and had lower B7-H3% (median 2.5 vs. 60%, p = 0.007), and higher CD8 density (median 75% vs. 40%, p = 0.04) compared to immunocompetent patients. Higher tumor grade (Rs = 0.34, p = 0.006) and LVI (Rs = 0.61, p < 0.001) were both associated with higher Tum-PD-L1%. CONCLUSION: cSCC showed expression of PD-L1 on tumor in 26% of cases, and high tumor B7-H3 expression (85%) and PD-1 expression on CD8 TILs (80%). Tumor B7-H3 expression was significantly higher in immunocompetent vs. immunosuppressed patients, largely driven by very low expression in HIV+ patients. PMID- 29484465 TI - Combined Static and Dynamic Computed Tomography Angiography of Peripheral Artery Occlusive Disease: Comparison with Magnetic Resonance Angiography. AB - PURPOSE: To compare in patients with known peripheral artery occlusive disease (PAOD), image quality of a combined CTA to a combined MRA protocol, including both static and dynamic acquisitions. MATERIALS AND METHODS: Twenty-two patients with PAOD were examined with a combined CTA and MRA protocol consisting of static acquisitions (s-CTA, s-MRA) of the entire runoff and dynamic acquisitions (d-CTA, d-MRA) of the calves. Two radiologists compared image quality of the s-MRA versus s-CTA as well as d-MRA versus d-CTA. Image quality was assessed on a segmental basis using a 4-point Likert scale. RESULTS: For s-CTA, 76% of segments were rated as excellent or good. For s-MRA, 50% of segments were rated as excellent or good (p < 0.0001). For d-CTA, median image quality score for all segments was rated as excellent for both readers. For d-MRA, median image quality for the different segments ranged from moderate to good. For both d-CTA and d-MRA, the median image quality scores were significantly higher for all segments of the lower limb compared with the static examinations of the lower limb segments (all p values < 0.0001). In patients with PAOD category 4-6, 80% of segments were rated as excellent or good for d-CTA, while 45% of segments were rated as poor or non-diagnostic for d-MRA. CONCLUSION: In patients with known PAOD, a combined static and dynamic CTA examination improves image quality relative to static and dynamic MRA and should be considered as an alternative to MRA, particularly in patients with advanced stage PAOD. PMID- 29484466 TI - Radiofrequency Ablation of Liver Tumors: No Difference in the Ablation Zone Volume Between Cirrhotic and Healthy Liver. AB - PURPOSE: The "oven effect" theory assumes that radiofrequency ablation (RFA) would be more efficient on tumors of cirrhotic livers. The aim of the study was to compare the size and volume of the ablation zone following RFA on tumors of cirrhotic versus healthy livers. METHODS: One hundred and eleven patients who underwent RFA from 2011 to 2013 for the treatment of 140 liver tumors (83 hepatocellular carcinomas developed on a cirrhotic liver, i.e., "cirrhosis group," and 57 tumors developed on a healthy liver, mainly liver metastasis, i.e., "healthy liver group") using the same RFA device were retrospectively selected. The diameter and volume of the ablation zone were compared between groups at the end of the procedure (FU0), at first (FU1) and second follow-up (FU2) performed 1.6 months (+/- 19 days) and 4.7 months (+/- 40 days) post-RFA, respectively. RESULTS: No differences in the size or volume of the ablation zone were found between groups at FU0 (36.5 +/- 12 mm vs. 34.3 +/- 10 mm, p = 0.5; and 28 +/- 16 mm3 vs. 26.5 +/- 16 mm3, p = 0.6, respectively), FU1, or FU2. Similarly, no differences were found at FU0, FU1, or FU2 in the subgroups of tumors treated using a single radiofrequency application. The mean volume of the ablation zone decreased over time, by 33.3% at FU1 and 48.5% at FU2, without any difference between groups. CONCLUSION: In contradiction to the "oven effect" theory, RFA achieves ablation zones of a comparable size and volume in cirrhotic and healthy livers. PMID- 29484467 TI - Factors Predicting a Good Symptomatic Outcome After Prostate Artery Embolisation (PAE). AB - INTRODUCTION: As prostate artery embolisation (PAE) becomes an established treatment for benign prostatic obstruction, factors predicting good symptomatic outcome remain unclear. Pre-embolisation prostate size as a predictor is controversial with a handful of papers coming to conflicting conclusions. We aimed to investigate if an association existed in our patient cohort between prostate size and clinical benefit, in addition to evaluating percentage volume reduction as a predictor of symptomatic outcome following PAE. MATERIALS OR METHODS: Prospective follow-up of 86 PAE patients at a single institution between June 2012 and January 2016 was conducted (mean age 64.9 years, range 54-80 years). Multiple linear regression analysis was performed to assess strength of association between clinical improvement (change in IPSS) and other variables, of any statistical correlation, through Pearson's bivariate analysis. RESULTS: No major procedural complications were identified and clinical success was achieved in 72.1% (n = 62) at 12 months. Initial prostate size and percentage reduction were found to have a significant association with clinical improvement. Multiple linear regression analysis (r2 = 0.48) demonstrated that percentage volume reduction at 3 months (r = 0.68, p < 0.001) had the strongest correlation with good symptomatic improvement at 12 months after adjusting for confounding factors. CONCLUSION: Both the initial prostate size and percentage volume reduction at 3 months predict good symptomatic outcome at 12 months. These findings therefore aid patient selection and counselling to achieve optimal outcomes for men undergoing prostate artery embolisation. PMID- 29484468 TI - Results of minimally invasive surgical treatment of allograft lithiasis in live donor renal transplant recipients: a single-center experience of 3758 renal transplantations. AB - Allograft lithiasis is a rare urologic complication of renal transplantation (RT). Our aim is to present our experience with minimally invasive surgical treatment of allograft lithiasis in our series of live-donor renal transplant recipients. In a retrospective analysis of 3758 consecutive live-donor RTs performed in our center between November 2009 and January 2017, the results of minimally invasive surgery for the treatment of renal graft lithiasis diagnosed at follow-up were evaluated. Twenty-two (0.58%) patients underwent minimally invasive surgery for renal graft lithiasis. The mean age was 41.6 years, and duration between RT and surgical intervention was 27.3 months (range 3-67). The mean stone size was 11.6 mm (range 4-29). Stones were located in the urethra in 1, bladder in 2, ureter in 9, renal pelvis in 7 and calices in 3 patients. Surgical treatment included percutaneous nephrolithotomy in 1, cystoscopic lithotripsy in 3, flexible ureteroscopic lithotripsy in 6 and rigid ureteroscopic lithotripsy in 12 patients. No major complications were observed. One patient (4.5%) who underwent flexible ureteroscopy developed postoperative urinary tract infection. All patients were stone-free except two (9%) patients who required a second-look procedure after flexible ureteroscopic lithotripsy for residual stones. Stone recurrence was not observed in any patient during a mean follow-up duration of 30.2 months (range 8-84). Renal transplant lithiasis is uncommon and minimally invasive surgical treatment is rarely performed for its treatment. Endourological surgery may be performed safely, effectively and with a high success rate in these patients. PMID- 29484470 TI - Prediction of clamp-derived insulin sensitivity from the oral glucose insulin sensitivity index. AB - AIMS/HYPOTHESIS: The euglycaemic-hyperinsulinaemic clamp is the gold-standard method for measuring insulin sensitivity, but is less suitable for large clinical trials. Thus, several indices have been developed for evaluating insulin sensitivity from the oral glucose tolerance test (OGTT). However, most of them yield values different from those obtained by the clamp method. The aim of this study was to develop a new index to predict clamp-derived insulin sensitivity (M value) from the OGTT-derived oral glucose insulin sensitivity index (OGIS). METHODS: We analysed datasets of people that underwent both a clamp and an OGTT or meal test, thereby allowing calculation of both the M value and OGIS. The population was divided into a training and a validation cohort (n = 359 and n = 154, respectively). After a stepwise selection approach, the best model for M value prediction was applied to the validation cohort. This cohort was also divided into subgroups according to glucose tolerance, obesity category and age. RESULTS: The new index, called PREDIcted M (PREDIM), was based on OGIS, BMI, 2 h glucose during OGTT and fasting insulin. Bland-Altman analysis revealed a good relationship between the M value and PREDIM in the validation dataset (only 9 of 154 observations outside limits of agreement). Also, no significant differences were found between the M value and PREDIM (equivalence test: p < 0.0063). Subgroup stratification showed that measured M value and PREDIM have a similar ability to detect intergroup differences (p < 0.02, both M value and PREDIM). CONCLUSIONS/INTERPRETATION: The new index PREDIM provides excellent prediction of M values from OGTT or meal data, thereby allowing comparison of insulin sensitivity between studies using different tests. PMID- 29484469 TI - Short-course antibiotic therapy for critically ill patients treated for postoperative intra-abdominal infection: the DURAPOP randomised clinical trial. AB - PURPOSE: Shortening the duration of antibiotic therapy (ABT) is a key measure in antimicrobial stewardship. The optimal duration of ABT for treatment of postoperative intra-abdominal infections (PIAI) in critically ill patients is unknown. METHODS: A multicentre prospective randomised trial conducted in 21 French intensive care units (ICU) between May 2011 and February 2015 compared the efficacy and safety of 8-day versus 15-day antibiotic therapy in critically ill patients with PIAI. Among 410 eligible patients (adequate source control and ABT on day 0), 249 patients were randomly assigned on day 8 to either stop ABT immediately (n = 126) or to continue ABT until day 15 (n = 123). The primary endpoint was the number of antibiotic-free days between randomisation (day 8) and day 28. Secondary outcomes were death, ICU and hospital length of stay, emergence of multidrug-resistant (MDR) bacteria and reoperation rate, with 45-day follow up. RESULTS: Patients treated for 8 days had a higher median number of antibiotic free days than those treated for 15 days (15 [6-20] vs 12 [6-13] days, respectively; P < 0.0001) (Wilcoxon rank difference 4.99 days [95% CI 2.99-6.00; P < 0.0001). Equivalence was established in terms of 45-day mortality (rate difference 0.038, 95% CI - 0.013 to 0.061). Treatments did not differ in terms of ICU and hospital length of stay, emergence of MDR bacteria or reoperation rate, while subsequent drainages between day 8 and day 45 were observed following short course ABT (P = 0.041). CONCLUSION: Short-course antibiotic therapy in critically ill ICU patients with PIAI reduces antibiotic exposure. Continuation of treatment until day 15 is not associated with any clinical benefit. CLINICALTRIALS. GOV IDENTIFIER: NCT01311765. PMID- 29484471 TI - Computed tomography of bicondylar tibial plateau fractures after distraction with a bridging external fixation. AB - BACKGROUND: The goal of this study was to compare the inter- and intra-observer reliabilities of computed tomography (CT) scans of bicondylar tibial plateau fractures (Bi-TPFs) with or without distraction with a bridging external fixation (EF) as interpreted by inexperienced surgeons. METHODS: Patients that underwent CT after distraction with a bridging EF were allocated to group 1 (n = 18), and patients that underwent CT before distraction with a bridging EF were allocated to group 2 (n = 18). Five observers were given plain radiographs and CT images to assess (survey 1) and this assessment was repeated six weeks later (survey 2). Agreements regarding fracture classification and pre-operative planning were evaluated using kappa coefficients. In addition, to evaluate fracture severity, we designed a severity score. RESULTS: Inter-observer reliabilities for fracture classification and pre-operative planning were higher in group 1 than in group 2. Surveys 1 and 2 revealed similar kappa coefficients in the two study groups. The mean absolute difference (MAD) in severity scores allocated at the two surveys was significantly different between the two groups (P = 0.045). Intra-observer reliabilities of fracture classification and pre-operative planning were also higher in group 1 than in group 2. In addition, level of training was found to have a significant impact on the MAD in severity scores (P = 0.007). CONCLUSIONS: Inter- and intra-observer reliabilities for fracture classification and pre operative planning were better for inexperienced surgeons when CT was performed after distraction with a bridging EF for Bi-TPFs. Thus, when staged treatment using EF is selected in Bi-TPF patients, the authors suggest that CT scans be performed after distraction with a bridging EF especially for inexperienced surgeons. PMID- 29484472 TI - Evaluation of the three-dimensional bony coverage before and after rotational acetabular osteotomy. AB - PURPOSE: Rotational acetabular osteotomy is a type of pelvic osteotomy that involves rotation of the acetabular bone to improve the bony coverage of the femoral head for patients with acetabular dysplasia. Favourable post-operative long-term outcomes have been reported in previous studies. However, there is a paucity of published data regarding three-dimensional bony coverage. The present study investigated the three-dimensional bony coverage of the acetabulum covering the femoral head in hips before and after rotational acetabular osteotomy and in normal hips. METHODS: The computed tomography data of 40 hip joints (12 joints before and after rotational acetabular osteotomy; 16 normal joints) were analyzed. The three-dimensional bony coverage of each joint was evaluated using original software. RESULTS: The post-operative bony coverage improved significantly compared with pre-operative values. In particular, the anterolateral aspect of the acetabulum tended to be dysplastic in patients with acetabular dysplasia compared to those with normal hip joints. However, greater bony coverage at the anterolateral aspect was obtained after rotational acetabular osteotomy. Meanwhile, the results of the present study may indicate that the bony coverage in the anterior aspect may be excessive. CONCLUSION: Three dimensional analysis indicated that rotational acetabular osteotomy achieved favorable bony coverage. Further investigations are necessary to determine the ideal bony coverage after rotational acetabular osteotomy. PMID- 29484473 TI - Clinical and radiological outcomes of trabecular metal systems and antiprotrusion cages in acetabular revision surgery with severe defects: a comparative study. AB - INTRODUCTION: Acetabular revision surgery poses a challenge due to the increased frequency of severe defects and poor quality of the remaining bone. We compare the clinical and radiological outcomes, complications, and survival of two systems commonly used in complex acetabular revisions (AAOS types II, III, and IV): trabecular metal system (TM) and Burch-Schneider antiprotrusion cages (BS). METHODS: Eighty-four patients underwent acetabular revision surgery with TM or BS in our centre between 2008 and 2014. Comparison was made of demographic and clinical characteristics, satisfaction, radiographic parameters, complications, and survival of the implants. A BS was implanted in 30.9% of the patients, while 69.1% received a TM implant. The mean follow-up was 4.77 years. RESULTS: The BS group required a significantly greater number of constrained implants (p = 0.001) and more walking aids (p = 0.04). The mean satisfaction (p = 0.02) and HHS scores at the end of the follow-up were higher in the TM group (p = 0.003). No differences were observed in the incidence of complications, though the only two cases of implant rupture corresponded to the BS group. The overall survival rate was 88.1% after 7.5 years. CONCLUSION: TM implants afforded better clinical outcomes and greater patient satisfaction than antiprotrusion cages in the treatment of severe acetabular defects. PMID- 29484474 TI - No association between vitamin C and E supplementation and grip strength over 5 years: the Colaus study. AB - PURPOSE: To assess the cross-sectional and longitudinal association between self reported vitamin C + E dietary supplementation and markers of grip strength and frailty in community-dwelling Swiss adults. METHODS: Population-based study including 3277 participants (1722 women) aged 40-80 years at baseline. The associations between vitamin C + E dietary supplementation and grip strength were examined cross-sectionally and after a follow-up of 5.2 years on average. RESULTS: There were 253 (7.7%) self-reported vitamin C + E supplement users. Female users had significantly lower grip strength than non-users (average +/- standard deviation: 24.3 +/- 6.1 versus 25.6 +/- 6.1 kg, respectively). However, the association disappeared after multivariate adjustment (24.7 +/- 0.5 versus 25.6 +/- 0.1 kg, for users versus non-users, respectively). No differences were found in men regarding grip strength. No differences were found in the highest quintile of grip strength or prevalence of low grip strengthin in users versus non-users during cross-sectional analysis for both genders. After 5.2 years of follow-up, no associations were found between vitamin C + E supplementation and change in grip strength for raw values (difference between baseline and follow up: 1.2 +/- 5.0 versus 0.4 +/- 5.2 kg for female and 0.6 +/- 6.5 versus 1.1 +/- 6.8 kg for male users and non-users, respectively) or after multivariable adjustment (1.2 +/- 0.5 versus 0.4 +/- 0.1 kg for female and 0.6 +/- 0.8 versus 1.1 +/- 0.2 kg for male users and non-users, respectively) when taking baseline vitamin C + E supplementation into account. No association was also found for incidence of low grip strength. CONCLUSION: In a sample of community-dwelling Swiss adults, vitamin C + E supplementation neither improved grip strength nor prevented low-grip strength over a 5-year period. PMID- 29484476 TI - Memories of the Future. PMID- 29484475 TI - Medullary Thyroid Carcinoma: Survival Analysis and Evaluation of Mutation Specific Immunohistochemistry in Detection of Sporadic Disease. AB - INTRODUCTION: Medullary thyroid cancer (MTC) is a rare tumour of neuroendocrine origin with a more aggressive profile than differentiated thyroid cancer. Familial cases of MTC are associated with RET mutations whilst RAS mutations appear to be a frequent finding in RET negative tumours. The aims of this study were to analyse survival outcomes in MTC and to evaluate the role of RAS immunohistochemistry in the identification of sporadic disease. MATERIALS AND METHODS: A retrospective cohort study of consecutive patients with MTC was undertaken. The primary outcome measures were overall survival and disease-free survival. Survival analysis was performed on the basis of sporadic and familial disease. Patients had routine RET testing using the capillary (Sanger) sequencing method. Histopathological MTC slides from 100 patients were tested for HRASQ61R, a common somatic RAS mutation in MTC, with mutation-specific immunohistochemistry (IHC). RESULTS: A total of 195 patients had surgical treatment of MTC in the period 1980 to 2016. There were 83 males and 112 females with a mean age of 53.0 years. A total of 39 (20%) patients had familial disease. Sporadic cases had a higher median pre-op calcitonin (969.5 vs. 257.5 pg/ml), greater mean primary tumour size (23.5 vs. 12.5 mm) and more distant metastases (12.8 vs. 10.3%). Multivariate analysis showed age (p = 0.005), Multiple Endocrine Neoplasia Type 2 (MEN2) status (p = 0.021) and distant metastasis (p = 0.002) to be significant independent predictors of survival. Significant independent predictors for disease-free survival were age (p = 0.015), MEN2 (p = 0.002), pre-op calcitonin (p = 0.033) and venous invasion (p = 0.001). The overall 5-year survival was 100% for familial MTC and 78% for sporadic MTC. The 10-year disease-free survival was 94% for familial MTC and 61% for sporadic cases. A total of 100 cases of MTC underwent mutation-specific IHC for HRASQ61R. Of these, 18 had confirmed MEN2. IHC had 100% specificity in excluding MEN2. Twelve (12%) of 100 patients stained positive for HRASQ61R mutation. CONCLUSION: In the era of genetic testing, RET status significantly influences disease-specific survival in MTC. Mutation specific IHC for HRASQ61R may have a role in the identification of patients presenting with sporadic disease. PMID- 29484477 TI - Screening for single-chain variable fragment antibodies against multiple Cry1 toxins from an immunized mouse phage display antibody library. AB - Single-chain variable fragment (scFv) is a kind of antibody that possess only one chain of the complete antibody while maintaining the antigen-specific binding abilities and can be expressed in prokaryotic system. In this study, scFvs against Cry1 toxins were screened out from an immunized mouse phage displayed antibody library, which was successfully constructed with capacity of 6.25 * 107 CFU/mL. Using the mixed and alternative antigen coating strategy and after four rounds of affinity screening, seven positive phage-scFvs against Cry1 toxins were selected and characterized. Among them, clone scFv-3H9 (MG214869) showing relative stable and high binding abilities to six Cry1 toxins was selected for expression and purification. SDS-PAGE indicated that the scFv-3H9 fragments approximately 27 kDa were successfully expressed in Escherichia coli HB2151 strain. The purified scFv-3H9 was used to establish the double antibody sandwich enzyme-linked immunosorbent assay method (DAS-ELISA) for detecting six Cry1 toxins, of which the lowest detectable limits (LOD) and the lowest quantitative limits (LOQ) were 3.14-11.07 and 8.22-39.44 ng mL-1, respectively, with the correlation coefficient higher than 0.997. The average recoveries of Cry1 toxins from spiked rice leaf samples were ranged from 84 to 95%, with coefficient of variation (CV) less than 8.2%, showing good accuracy for the multi-residue determination of six Cry1 toxins in agricultural samples. This research suggested that the constructed phage display antibody library based on the animal which was immunized with the mixture of several antigens under the same category can be used for the quick and effective screening of generic antibodies. PMID- 29484478 TI - Nematicidal protease genes screened from a soil metagenomic library to control Radopholus similis mediated by Pseudomonas fluorescens pf36. AB - Controlling Radopholus similis, an important phytopathogenic nematode, is a challenge worldwide. Herein, we constructed a metagenomic fosmid library from the rhizosphere soil of banana plants, and six clones with protease activity were obtained by functionally screening the library. Furthermore, subclones were constructed using the six clones, and three protease genes with nematicidal activity were identified: pase1, pase4, and pase6. The pase4 gene was successfully cloned and expressed, demonstrating that the protease PASE4 could effectively degrade R. similis tissues and result in nematode death. Additionally, we isolated a predominant R. similis-associated bacterium, Pseudomonas fluorescens (pf36), from 10 R. similis populations with different hosts. The pase4 gene was successfully introduced into the pf36 strain by vector transformation and conjugative transposition, and two genetically modified strains were obtained: p4MCS-pf36 and p4Tn5-pf36. p4MCS-pf36 had significantly higher protease expression and nematicidal activity (p < 0.05) than p4Tn5-pf36 in a microtiter plate assay, whereas p4Tn5-pf36 was superior to p4MCS-pf36 in terms of genetic stability and controlling R. similis in growth pot tests. This study confirmed that R. similis is inhibited by the associated bacterium pf36-mediated expression of nematicidal proteases. Herein, a novel approach is provided for the study and development of efficient, environmentally friendly, and sustainable biocontrol techniques against phytonematodes. PMID- 29484479 TI - Two or three domains: a new view of tree of life in the genomics era. AB - The deep phylogenetic topology of tree of life is in the center of a long-time dispute. The Woeseian three-domain tree theory, with the Eukarya evolving as a sister clade to Archaea, competes with the two-domain tree theory (the eocyte tree), with the Eukarya branched within Archaea. Revealed by the ongoing debate over the last three decades, sophisticated and proper phylogenetic methods should necessarily be paid with more emphasis, especially these are focusing on the compositional heterogeneity of sites and lineages, and the heterotachy issue. The newly emerging archaeal lineages with numerous eukaryotic-like features, such as membrane trafficking and cellular compartmentalization, are phylogenetically the closest to eukaryotes currently. These findings highlight the evolutionary history from an ancient archaeon to a more complex archaeon with protoeukaryotic like features and complex cellular structures, thus providing clues to understand eukaryogenesis process. The increasing repertoire of precise genomic contents provides great advantages on understanding the deep phylogeny of tree of life and ancient evolutionary events on Eukarya branching process. PMID- 29484480 TI - Quantification of elemental area densities in multiple metal layers (Au/Ni/Cu) on a Cr-coated quartz glass substrate for certification of NMIJ CRM 5208-a. AB - Area densities of Au/Ni/Cu layers on a Cr-coated quartz substrate were characterized to certify a multiple-metal-layer certified reference material (NMIJ CRM5208-a) that is intended for use in the analysis of the layer area density and the thickness by an X-ray fluorescence spectrometer. The area densities of Au/Ni/Cu layers were calculated from layer mass amounts and area. The layer mass amounts were determined by using wet chemical analyses, namely inductively coupled plasma mass spectrometry (ICP-MS), isotope-dilution (ID-) ICP MS, and inductively coupled plasma optical emission spectrometry (ICP-OES) after dissolving the layers with diluted mixture of HCl and HNO3 (1:1, v/v). Analytical results of the layer mass amounts obtained by the methods agreed well with each another within their uncertainty ranges. The area of the layer was determined by using a high-resolution optical scanner calibrated by Japan Calibration Service System (JCSS) standard scales. The property values of area density were 1.84 +/- 0.05 MUg/mm2 for Au, 8.69 +/- 0.17 MUg/mm2 for Ni, and 8.80 +/- 0.14 MUg/mm2 for Cu (mean +/- expanded uncertainty, coverage factor k = 2). In order to assess the reliability of these values, the density of each metal layer calculated from the property values of the area density and layer thickness measured by using a scanning electron microscope were compared with available literature values and good agreement between the observed values and values obtained in previous studies. PMID- 29484481 TI - Development of a sensitive and quantitative capillary LC-UV method to study the uptake of pharmaceuticals in zebrafish brain. AB - The present study explores the potential of 10-day-old zebrafish (Danio rerio) as a predictive blood-brain-barrier model using a set of 7 pharmaceutical agents. For this purpose, zebrafish were incubated with each of these 7 drugs separately via the route of immersion and the concentration reaching the brain was determined by applying a brain extraction procedure allowing isolation of the intact brain from the head of the zebrafish larvae. Sample analysis was performed utilizing capillary ultra-high performance liquid chromatography (cap-UHPLC) on a Pepmap RSLC C18 capillary column (150 mm * 300 MUm, dp = 2 MUm) coupled to a variable wavelength UV detector. Gradient separation was performed in 28 min at a flow rate of 5 MUL/min and the optimal injection volume was determined to be 1 MUL. The brain extraction procedure was established for the zebrafish strain TG898 exhibiting red fluorescence of the brain, allowing control of the integrity of the extracted parts. Quantitative experiments carried out on pooled samples of six zebrafish (n = 6) demonstrated the selective semipermeable nature of the blood-brain barrier after incubating the zebrafish at the maximum tolerated concentration for the investigated pharmaceuticals. The obtained brain-to-trunk ratios ranged between 0.3 for the most excluded compound and 1.2 for the pharmaceutical agent being most accumulated in the brain of the fish. Graphical abstract Workflow of brain extraction to study the uptake of pharmaceuticals in the brain of zebrafish larvae. PMID- 29484482 TI - New interplay between interstitial and alveolar macrophages explains pulmonary alveolar proteinosis (PAP) induced by indium tin oxide particles. AB - Occupational exposure to indium tin oxide (ITO) particles has been associated with the development of severe lung diseases, including pulmonary alveolar proteinosis (PAP). The mechanisms of this lung toxicity remain unknown. Here, we reveal the respective roles of resident alveolar (Siglec-Fhigh AM) and recruited interstitial (Siglec-Flow IM) macrophages contributing in concert to the development of PAP. In mice treated with ITO particles, PAP is specifically associated with IL-1alpha (not GM-CSF) deficiency and Siglec-Fhigh AM (not Siglec Flow IM) depletion. Mechanistically, ITO particles are preferentially phagocytosed and dissolved to soluble In3+ by Siglec-Flow IM. In contrast, Siglec Fhigh AM weakly phagocytose or dissolve ITO particles, but are sensitive to released In3+ through the expression of the transferrin receptor-1 (TfR1). Blocking pulmonary Siglec-Flow IM recruitment in CCR2-deficient mice reduces ITO particle dissolution, In3+ release, Siglec-Fhigh AM depletion, and PAP formation. Restoration of IL-1-related Siglec-Fhigh AM also prevented ITO-induced PAP. We identified a new mechanism of secondary PAP development according to which metal ions released from inhaled particles by phagocytic IM disturb IL-1alpha-dependent AM self-maintenance and, in turn, alveolar clearance. PMID- 29484483 TI - Nicotine and exercise performance: another tool in the arsenal or curse for anti doping? PMID- 29484484 TI - Foundational insights into the estimation of whole-body metabolic rate. AB - Since 2013, this journal has promoted the publication of thematic reviews (Taylor in Eur J Appl Physiol 113:1634, 2013), where leading groups were invited to review the critical literature within each of several sub-topics. The current theme is historically based, and is focussed on estimating the metabolic rate in humans. This review charts the development of our understanding of those methods, from the discovery of oxygen and carbon dioxide, to the introduction of highly sophisticated modern apparatus to examine the composition of expired gas and determine respiratory minute volume. An historical timeline links the six thematic vignettes on this theme. Modern advances have greatly enhanced data collection without significant decrements in measurement accuracy. At the same time, however, conceptual errors, particularly steady-state requirements, are too often ignored. Indeed, it is recognised that we often neglect the past, leading to errors in research design, experimental observations and data interpretation, and this appears to be increasingly prevalent within the open-access literature. Accordingly, the Editorial Board, in recognition of a widening gap between our experimental foundations and contemporary research, embarked on developing a number of thematic review series, of which this series is the first. The intent of each accompanying overview is to introduce and illuminate seminal investigations that led to significant scientific or intellectual breakthroughs, and to thereby whet the appetite of readers to delve more deeply into the historical literature; for it is only when the foundations are understood that we can best understand where we are now, and in which directions we should head. PMID- 29484485 TI - Near Infrared-Emitting Cr3+/Eu3+ Co-doped Zinc Gallogermanate Persistence Luminescent Nanoparticles for Cell Imaging. AB - Near infrared (NIR)-emitting persistent luminescent nanoparticles have been developed as potential agents for bioimaging. However, synthesizing uniform nanoparticles with long afterglow for long-term imaging is lacking. Here, we demonstrated the synthesis of spinel structured Zn3Ga2Ge2O10:Cr3+ (ZGGO:Cr3+) and Zn3Ga2Ge2O10:Cr3+,Eu3+ (ZGGO:Cr3+,Eu3+) nanoparticles by a sol-gel method in combination with a subsequent reducing atmosphere-free calcination. The samples were investigated via detailed characterizations by combined techniques of XRD, TEM, STEM, selected area electron diffraction, photoluminescence excitation (PLE)/photoluminescence (PL) spectroscopy, and temperature-dependent PL analysis. The single-crystalline nanoparticles are homogeneous solid solution, possessing uniform cubic shape and lateral size of ~ 80-100 nm. Upon UV excitation at 273 nm, ZGGO:Cr3+,Eu3+ exhibited a NIR emission band at 697 nm (2E -> 4A2 transition of distorted Cr3+ ions in gallogermanate), in the absence of Eu3+ emission. NIR persistent luminescence of the sample can last longer than 7200 s and still hold intense intensity. Eu3+ incorporation increased the persistent luminescence intensity and the afterglow time of ZGGO:Cr3+, but it did not significantly affect the thermal stability. The obtained ZGGO:Cr3+,Eu3+-NH2 nanoparticles possessed an excellent imaging capacity for cells in vitro. PMID- 29484486 TI - Computational Design of Flat-Band Material. AB - Quantum mechanics states that hopping integral between local orbitals makes the energy band dispersive. However, in some special cases, there are bands with no dispersion due to quantum interference. These bands are called as flat band. Many models having flat band have been proposed, and many interesting physical properties are predicted. However, no real compound having flat band has been found yet despite the 25 years of vigorous researches. We have found that some pyrochlore oxides have quasi-flat band just below the Fermi level by first principles calculation. Moreover, their valence bands are well described by a tight-binding model of pyrochlore lattice with isotropic nearest neighbor hopping integral. This model belongs to a class of Mielke model, whose ground state is known to be ferromagnetic with appropriate carrier doping and on-site repulsive Coulomb interaction. We have also performed a spin-polarized band calculation for the hole-doped system from first principles and found that the ground state is ferromagnetic for some doping region. Interestingly, these compounds do not include magnetic element, such as transition metal and rare-earth elements. PMID- 29484487 TI - 'In Vitro', 'In Vivo' and 'In Silico' Investigation of the Anticancer Effectiveness of Oxygen-Loaded Chitosan-Shelled Nanodroplets as Potential Drug Vector. AB - PURPOSE: Chitosan-shelled/decafluoropentane-cored oxygen-loaded nanodroplets (OLN) are a new class of nanodevices to effectively deliver anti-cancer drugs to tumoral cells. This study investigated their antitumoral effects 'per se', using a mathematical model validated on experimental data. METHODS: OLN were prepared and characterized either in vitro or in vivo. TUBO cells, established from a lobular carcinoma of a BALB-neuT mouse, were investigated following 48 h of incubation in the absence/presence of different concentrations of OLN. OLN internalization, cell viability, necrosis, apoptosis, cell cycle and reactive oxygen species (ROS) production were checked as described in the Method section. In vivo tumor growth was evaluated after subcutaneous transplant in BALB/c mice of TUBO cells either without treatment or after 24 h incubation with 10% v/v OLN. RESULTS: OLN showed sizes of about 350 nm and a positive surface charge (45 mV). Dose-dependent TUBO cell death through ROS-triggered apoptosis following OLN internalization was detected. A mathematical model predicting the effects of OLN uptake was validated on both in vitro and in vivo results. CONCLUSIONS: Due to their intrinsic toxicity OLN might be considered an adjuvant tool suitable to deliver their therapeutic cargo intracellularly and may be proposed as promising combined delivery system. PMID- 29484489 TI - SGLT-2 inhibitors and the risk of infections: a systematic review and meta analysis of randomized controlled trials. AB - AIMS: There is concern about the infection-related safety profile of sodium glucose co-transporter 2 (SGLT-2) inhibitors. We aimed to determine the effect of SGLT-2 inhibitors on genitourinary and other infections via systematic review and meta-analysis of randomized controlled trials (RCTs). METHODS: We conducted a systematic search of Medline, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov to identify double-blinded RCTs enrolling >= 50 patients with type 2 diabetes which compared an SGLT-2 inhibitor to placebo or active comparator. Two independent reviewers extracted data and appraised study quality. Data were pooled using random-effects models. RESULTS: Eighty-six RCTs enrolling 50,880 patients were included. SGLT-2 inhibitors increased the risk of genital infections compared to placebo (relative risk [RR] 3.37, 95% CI 2.89 3.93, I2 0%) and active comparator (RR 3.89, 95% CI 3.14-4.82, I2 0.3%). The risk of urinary tract infection (UTI) was not increased with SGLT-2 inhibitors compared to placebo (RR 1.03, 95% CI 0.96-1.11, I2 0%) or active comparator (RR 1.08, 95% CI 0.93-1.25, I2 22%). In drug-specific analyses, only dapagliflozin 10 mg daily was associated with a significantly increased risk of UTI compared to placebo (RR 1.33, 95% CI 1.10-1.61, I2 0%). SGLT-2 inhibitors were associated with a reduced risk of gastroenteritis (RR 0.38, 95% CI 0.20-0.72, I2 0%) but did not affect the risk of respiratory tract infections. CONCLUSIONS/INTERPRETATION: SGLT-2 inhibitors are associated with an increased risk of genital tract infections. Although there is no association overall between SGLT-2 inhibitors and UTI, higher doses of dapagliflozin are associated with an increased risk. PMID- 29484491 TI - Simultaneous measurements of dissolved CH4 and H2 in wetland soils. AB - Biogeochemical processes in wetland soils are complex and are driven by a microbiological community that competes for resources and affects the soil chemistry. Depending on the availability of various electron acceptors, the high carbon input to wetland soils can make them important sources of methane production and emissions. There are two significant pathways for methanogenesis: acetoclastic and hydrogenotrophic methanogenesis. The hydrogenotrophic pathway is dependent on the availability of dissolved hydrogen gas (H2), and there is significant competition for available H2. This study presents simultaneous measurements of dissolved methane and H2 over a 2-year period at three tidal marshes in the New Jersey Meadowlands. Methane reservoirs show a significant correlation with dissolved organic carbon, temperature, and methane emissions, whereas the H2 concentrations measured with dialysis samplers do not show significant relationships with these field variables. Data presented in this study show that increased dissolved H2 reservoirs in wetland soils correlate with decreased methane reservoirs, which is consistent with studies that have shown that elevated levels of H2 inhibit methane production by inhibiting propionate fermentation, resulting in less acetate production and hence decreasing the contribution of acetoclastic methanogenesis to the overall production of methane. PMID- 29484490 TI - Out-of-pocket expenditure on maternity care for hospital births in Uttar Pradesh, India. AB - BACKGROUND AND OBJECTIVE: The studies measured Out-of-Pocket Expenditure (OOPE) for hospital births previously suffer from serious data limitations. To overcome such limitations, we designed a hospital-based study for measuring the levels and factors of OOPE on maternity care for hospital births by its detailed components. METHODS: Data were collected from women for non-complicated deliveries 24-h before the survey and complicated deliveries 48-h prior to the survey at the hospital settings in Uttar Pradesh, India during 2014. The simple random sampling design was used in the selection of respondents. Bivariate analyses were used to estimate mean expenditure on Antenatal care services (ANCs), Delivery care and Total Maternity Expenditure (TME). Multivariate linear regression was employed to examine the factor associated with the absolute and relative share of expenditure in couple's annual income on ANCs, delivery care, and TME. RESULTS: The findings show that average expenditure on maternal health care is high ($155) in the study population. Findings suggest that factors such as income, place, and number of ANCs, type, and place of institutional delivery are significantly associated with both absolute and relative expenditure on maternity care. The likelihood of incidence of catastrophic expenditure on maternity care is significantly higher for women delivered in private hospitals (beta = 2.427, p < 0.001) compared to the government hospital (beta = 0). Also, it is higher among caesarean or forceps deliveries (beta = 0.617, p < 0.01), deliveries conducted on doctor advise (beta = 0.598, p < 0.01), than in normal deliveries (beta = 0) and self or family planned deliveries (beta = 0). CONCLUSIONS: The findings of this study suggest that the OOPE on maternity care for hospital births reported in this study is much higher as it was collected with a better methodology, although with smaller sample size. Therefore, ongoing maternity benefit scheme in India in general and Uttar Pradesh in particular need to consider the levels of OOPE on maternity care and demand-side and supply-side factors determining it for a more effective policy to reduce the catastrophic burden on households and help women to achieve better maternity health outcomes in poor regional settings like Uttar Pradesh in India. PMID- 29484492 TI - Peristome as a potential tool for delimiting Bryum Hedw. (Bryaceae) from India. AB - The peristome, an interesting and important taxonomic structure used in the systematics of mosses, is for the first time studied in detail for 21 taxa of Bryum, which constitute a fraction of Indian representatives. Macro- and micro morphological characters including color, size and length of two components of peristome, tapering pattern, median line, and papillosity at upper part under light microscope; width of exostome border, number and inner surface of ventral trabeculae, presence or absence of longitudinal/oblique septae between ventral trabeculae, pattern of exostome surface and height of endostomial basal membrane, adherence, perforations, and surface of cilia under scanning electron microscope were examined to bring out submicroscopic differences. Detail surface structure of eight taxa, viz., B. apalodictyoides, B. evanidinerve, B. pachytheca, B. pseudotriquetrum var. subrotundum, B. reflexifolium, B. thomsonii, B. tuberosum, and B. turbinatum, under LM and nine species, namely, B. apalodictyoides, B. apiculatum, B. argenteum, B. billarderi, B. dichotomum, B. evanidinerve, B. recurvulum, B. turbinatum, and B. uliginosum, under SEM is being provided for the first time. Description of peristome surface and a key based on SEM and other taxonomical features is also being provided. The data obtained from the present study suggest that the species of this genus can easily be distinguished on the basis of peristomial surface pattern. PMID- 29484488 TI - TRPs et al.: a molecular toolkit for thermosensory adaptations. AB - The ability to sense temperature is crucial for the survival of an organism. Temperature influences all biological operations, from rates of metabolic reactions to protein folding, and broad behavioral functions, from feeding to breeding, and other seasonal activities. The evolution of specialized thermosensory adaptations has enabled animals to inhabit extreme temperature niches and to perform specific temperature-dependent behaviors. The function of sensory neurons depends on the participation of various types of ion channels. Each of the channels involved in neuronal excitability, whether through the generation of receptor potential, action potential, or the maintenance of the resting potential have temperature-dependent properties that can tune the neuron's response to temperature stimuli. Since the function of all proteins is affected by temperature, animals need adaptations not only for detecting different temperatures, but also for maintaining sensory ability at different temperatures. A full understanding of the molecular mechanism of thermosensation requires an investigation of all channel types at each step of thermosensory transduction. A fruitful avenue of investigation into how different molecules can contribute to the fine-tuning of temperature sensitivity is to study the specialized adaptations of various species. Given the diversity of molecular participants at each stage of sensory transduction, animals have a toolkit of channels at their disposal to adapt their thermosensitivity to their particular habitats or behavioral circumstances. PMID- 29484493 TI - Secondary sclerosing cholangitis in critically ill patients after a traffic accident-a new entity that should be considered in death classification. AB - A 49-year-old female sustained a polytrauma after being hit by a vehicle in a traffic accident. Following the incident, the woman had various surgical interventions and underwent intensive care over a 6-week period. Eight months later, she died after developing secondary sclerosing cholangitis (SSC). Autopsy revealed liver failure and hepatic encephalopathy due to SSC caused by the polytrauma and the subsequent intensive care. Prior to the accident, there was no evidence of a pre-existing liver or biliary system disease. The death of the patient was classified as non-natural as a causal consequence of the traffic accident. SSC has been clinically described as a complication of intensive care. Since it has a high mortality rate, it is important that forensics and pathologists are aware of the condition. PMID- 29484494 TI - Treatment of mediastinal lymphatic malformation in children: an analysis of a nationwide survey in Japan. AB - PURPOSE: Clinical guidelines on lymphatic malformation (LM) influencing the airway have been crafted in the Research Project for Intractable Diseases. We herein report an analysis of a nationwide survey of mediastinal LM and the therapeutic recommendations. METHODS: Eighty-seven registered cases with mediastinal involvement were analyzed with a review of the literature. RESULTS: Mediastinal LM was located more often in the upper and anterior mediastinum and was found without any accompanying symptoms in 56/87 cases. Tracheostomy was required in 23/87 cases, mostly < 2 years of age (87%). All patients who needed tracheostomy had a lesion in contact with the airway, while only 55% of those without tracheostomy had contact. Tracheostomy tended to be placed more when the longer segment of the airway was in contact with the LM. Multimodal treatments were performed in 29 patients, but the lesions remained in most cases, and chylothorax, hemorrhaging, nerve palsy, and infections were noted as complications. CONCLUSIONS: In patients with mediastinal LM, tracheostomy may be necessary, especially when the lesion is extensive and contacts the airway. Extirpation of the mediastinal LM may be the only therapeutic option, but in cases with few or no symptoms, non-surgical treatment should be considered in light of potential postoperative complications. PMID- 29484495 TI - An observational study of rotigotine transdermal patch and other currently prescribed therapies in patients with Parkinson's disease. AB - Real-world data from large cohorts of patients with Parkinson's disease on the long-term effectiveness of different dopamine-substituting drug therapies are rare. The objective of this study was to obtain information on real-world management of PD with dopamine-substituting drugs. SP0854 (NCT00599339) was a prospective, multicenter, non-interventional, multiple-cohort, post-authorization safety study of rotigotine versus other dopaminergic therapies. The study was also part of a European Medicines Agency risk-management plan for the non ergoline dopamine agonist rotigotine, focussing on cardiovalvular fibrosis. Eligible patients requiring monotherapy with a dopamine agonist, or levodopa in combination with a dopamine agonist were followed for <= 33 months; 1531 of 2195 patients completed the study. Mean motor scores improved for all dopamine substituting treatments. Patients with more severe motor-symptoms/increased disability were more likely to receive levodopa alone or in combination with a DA at study onset. More patients who started on combination therapy with levodopa remained on this treatment versus those starting on dopaminergic monotherapy. This real-world study showed that the dopamine-substituting therapies were efficacious, with a safety profile consistent with that expected of dopaminergic treatments. Cardiovalvular pathology was rare and not found to be causally related to rotigotine. PMID- 29484496 TI - The femoral component alignment resulting from spacer block technique is not worse than after intramedullary guided technique in medial unicompartimental knee arthroplasty. AB - PURPOSE: Although the spacer block technique has been recommended for the implantation of unicompartmental knee arthroplasty (UKA), there is still a lack of data concerning the resulting component positioning. METHODS: This retrospective study included 193 consecutive patients who had undergone medial UKA using the spacer technique. On the basis of the postoperative long standing radiographs, the coronal component alignment was determined in relation to the mechanical axes and the sagittal component alignment in relation to the anatomical axes of the tibia and femur. The coronal alignment of the femoral component was determined through post hoc 3D planning with the CAD data projected onto the radiograph. RESULTS: The angle of the tibial component was on the average 2.3 degrees +/- 2.8 degrees in varus, the femoral component on the average 2.6 degrees +/- 3.7 degrees in varus. Only 4 implants (2%) were outside an assumed tolerance range of 10 degrees varus-10 degrees valgus. A tilting from the femoral to the tibial component of more than 10 degrees was observed in 8 cases (4%). A valgus positioning of the tibial component was followed by a valgus alignment of the femoral component (R = - 0.194, p = 0.007). An increased posterior slope of the tibial component led to an extended positioning of the femoral component (R = - 0.230, p = 0.001). CONCLUSIONS: The spacer block technique produces results comparable to the intramedullary guided technique. However, the precision is low and outlier frequent. Due to the possibility of transferring a tibial malalignment to a femoral malalignment, even greater attention should be paid to the precision of tibial resection. PMID- 29484498 TI - Bendamustine and G-CSF support. PMID- 29484497 TI - The potential for host switching via ecological fitting in the emerald ash borer host plant system. AB - The traits used by phytophagous insects to find and utilize their ancestral hosts can lead to host range expansions, generally to closely related hosts that share visual and chemical features with ancestral hosts. Host range expansions often result from ecological fitting, which is the process whereby organisms colonize and persist in novel environments, use novel resources, or form novel associations with other species because of the suites of traits that they carry at the time they encounter the novel environment. Our objective in this review is to discuss the potential and constraints on host switching via ecological fitting in emerald ash borer, Agrilus planipennis, an ecologically and economically important invasive wood boring beetle. Once thought of as an ash (Fraxinus spp.) tree specialist, recent studies have revealed a broader potential host range than was expected for this insect. We discuss the demonstrated host-use capabilities of this beetle, as well as the potential for and barriers to the adoption of additional hosts by this beetle. We place our observations in the context of biochemical mechanisms that mediate the interaction of these beetles with their host plants and discuss whether evolutionary host shifts are a possible outcome of the interaction of this insect with novel hosts. PMID- 29484499 TI - Sleep disturbance among Chinese breast cancer survivors living in the USA. AB - PURPOSE: Emerging evidence suggests Chinese breast cancer survivors, a largely understudied population, are at increased risk of sleep disturbance which can have significant impacts on quality of life and other important outcomes. This study aims to describe sleep disturbance among Chinese breast cancer survivors and to examine demographic and clinical correlates as well as psychosocial correlates of sleep disturbance. METHODS: Data from 80 Chinese breast cancer survivors in the USA completed the Chinese version of the Pittsburgh Sleep Quality Index as well as measures of quality of life, depressive symptoms, and perceived stress. Participants also completed measures of demographic factors and acculturation. RESULTS: Two thirds (66%) of survivors experienced elevated sleep disturbance. Approximately half (49%) reported sleep efficiency, the percentage of time in bed that is spent asleep, that was below the recommended cutoff. Compared to those without sleep disturbance, those with sleep disturbance had worse quality of life, more depressive symptoms, and more perceived stress (ps <= .01). CONCLUSIONS: This study is among the first to examine sleep disturbance among any Asian cancer population in the USA. Findings indicate Chinese breast cancer survivors may experience significant disparities in sleep disturbance relative to non-Hispanic Whites and suggest an urgent need for interventions to address sleep disturbance among Chinese breast cancer survivors. PMID- 29484500 TI - Rice nitrate transporter OsNPF7.2 positively regulates tiller number and grain yield. AB - BACKGROUND: Rice tiller number is one of the most important factors that determine grain yield, while nitrogen is essential for the crop growth and development, especially for tiller formation. Genes involved in nitrogen use efficiency processes have been identified in the previous studies, however, only a small number of these genes have been found to improve grain yield by promoting tillering. RESULTS: We constructed over-expression (OX) lines and RNA interference (Ri) lines, and selected a mutant of OsNPF7.2, a low-affinity nitrate transporter. Our analyses showed that rice tiller number and grain yield were significantly increased in OX lines, whereas Ri lines and mutant osnpf7.2 had fewer tiller number and lower grain yield. Under different nitrate concentrations, tiller buds grew faster in OX lines than in WT, but they grew slower in Ri lines and mutant osnpf7.2. These results indicated that altered expression of OsNPF7.2 plays a significant role in the control of tiller bud growth and regulation of tillering. Elevated expression of OsNPF7.2 also improved root length, root number, fresh weight, and dry weight. However, reduced expression of OsNPF7.2 had the opposite result on these characters. OsNPF7.2 OX lines showed more significantly enhanced influx of nitrate and had a higher nitrate concentration than WT. The levels of gene transcripts related to cytokinin pathway and cell cycle in tiller bud, and cytokinins concentration in tiller basal portion were higher in OX lines than that in WT, suggesting that altered expression of OsNPF7.2 controlled tiller bud growth and root development by regulating cytokinins content and cell cycle in plant cells. Altered expression of OsNPF7.2 also was responsible for the change in expression of the genes involved in strigolactone pathway, such as D27, D17, D10, Os900, Os1400, D14, D3, and OsFC1. CONCLUSION: Our results suggested that OsNPF7.2 is a positive regulator of nitrate influx and concentration, and that it also regulates cell division in tiller bud and alters expression of genes involved in cytokinin and strigolactone pathways, resulting in the control over rice tiller number. Since elevated expression of OsNPF7.2 is capable of improving rice grain yield, this gene might be applied to high-yield rice breeding. PMID- 29484501 TI - Integrated spatiotemporal trends using TRMM 3B42 data for the Upper Sao Francisco River basin, Brazil. AB - Trend analysis is an important issue for the decision-making processes. Thus, trends of rainfall, consecutive dry days (CDD), and consecutive wet days (CWD) in the Upper Sao Francisco River basin, Brazil, using daily rainfall data from the Tropical Rainfall Measuring Mission (TRMM) for recent 18 years, were analyzed. Instead of analyzing the trend of one average time series for one specific confidence level, a spatiotemporal analysis over the entire area with 169 continuous time series is done by applying the nonparametric Mann-Kendall and Sen tests for simultaneously 13 confidence levels and a new integrated confidence classification is proposed. The results show that the rainfall has increased during the less rainy periods (from June to October) and has decreased in the rainy periods (from November to May), with the highest and lowest confidence levels, respectively. An analysis of CDD and CWD shows that the number of CDD has decreased, while the number of CWD has increased, which revealed that the dry periods are more frequently interrupted for the period studied. PMID- 29484503 TI - Proliferation of human aortic endothelial cells on Nitinol thin films with varying hole sizes. AB - In this paper, we present the effect of micron size holes on proliferation and growth of human aortic endothelial cells (HAECs). Square shaped micron size holes (5, 10, 15, 20 and 25 MUm) separated by 10 MUm wide struts are fabricated on 5 MUm thick sputter deposited Nitinol films. HAECs are seeded onto these micropatterned films and analyzed after 30 days with fluorescence microscopy. Captured images are used to quantify the nucleus packing density, size, and aspect ratio. The films with holes ranging from 10 to 20 MUm produce the highest cell packing densities with cell nucleus contained within the hole. This produces a geometrically regular grid like cellular distribution pattern. The cell nucleus aspect ratio on the 10-20 MUm holes is more circular in shape when compared to aspect ratio on the continuous film or larger size holes. Finally, the 25 MUm size holes prevented the formation of a continuous cell monolayer, suggesting the critical length that cells cannot bridge is between 20 to 25 MUm. PMID- 29484502 TI - p63 isoforms in triple-negative breast cancer: DeltaNp63 associates with the basal phenotype whereas TAp63 associates with androgen receptor, lack of BRCA mutation, PTEN and improved survival. AB - The TP63 gene encodes two major protein variants that differ in their N-terminal sequences and have opposing effects. In breast, DeltaNp63 is expressed by immature stem/progenitor cells and mature myoepithelial/basal cells and is a characteristic feature of basal-like triple-negative breast cancers (TNBCs). The expression and potential role of TAp63 in the mammary gland and breast cancers is less clear, partly due to the lack of studies that employ p63 isoform-specific antibodies. We used immunohistochemistry with DeltaNp63-specific or TAp63 specific monoclonal antibodies to investigate p63 isoforms in 236 TNBCs. TAp63, but not DeltaNp63, was seen in tumour-associated lymphocytes and other stromal cells. Tumour cells showed nuclear staining for DeltaNp63 in 17% of TNBCs compared to 7.3% that were positive for TAp63. Whilst most TAp63+ tumours also contained DeltaNp63+ cells, the levels of the two isoforms were independent of each other. DeltaNp63 associated with metaplastic and medullary cancers, and with a basal phenotype, whereas TAp63 associated with androgen receptor, BRCA1/2 wild type status and PTEN positivity. Despite the proposed effects of p63 on proliferation, Ki67 did not correlate with either p63 isoform, nor did they associate with p53 mutation status. DeltaNp63 showed no association with patient outcomes, whereas TAp63+ patients showed fewer recurrences and improved overall survival. These findings indicate that both major p63 protein isoforms are expressed in TNBCs with different tumour characteristics, indicating distinct functional activities of p63 variants in breast cancer. Analysis of individual p63 isoforms provides additional information into TNBC biology, with TAp63 expression indicating improved prognosis. PMID- 29484504 TI - The effect of multidisciplinary extracorporeal membrane oxygenation team on clinical outcomes in patients with severe acute respiratory failure. AB - BACKGROUND: The Extracorporeal Life Support Organization (ELSO) has suggested that extracorporeal membrane oxygenation (ECMO) patients should be managed by a multidisciplinary team. However, there are limited data on the impact of ECMO team on the outcomes of patients with severe acute respiratory failure. METHODS: All consecutive patients with severe acute respiratory failure who underwent ECMO for respiratory support from January 2012 through December 2016 were divided into the pre-ECMO team period (before January 2014, n = 70) and the post-ECMO team period (after January 2014, n = 46). Clinical characteristics and outcomes were compared between the two groups. RESULTS: The mortality rates in the intensive care unit (72.9 vs. 50.0%, P = 0.012) and hospital (75.7 vs. 52.2%, P = 0.009) were significantly decreased in the post-ECMO team period compared to the pre ECMO team period. The median duration of ECMO support was not different between the two periods. However, the proportion of patients successfully weaned off ECMO was higher in the post-ECMO team period (42.9 vs. 65.2%, P = 0.018). During ECMO support, the incidence of cannula problems (32.9 vs. 15.2%, P = 0.034) and cardiovascular events (88.6 vs. 65.2%, P = 0.002) was reduced after implementation of the ECMO team. The 1-year mortality was significantly different between the pre-ECMO team and post-ECMO team periods (37.8 vs. 14.3%, P = 0.005). CONCLUSION: After implementing a multidisciplinary ECMO team, survival rate in patients treated with ECMO for severe acute respiratory failure was significantly improved. PMID- 29484505 TI - Woody forages effect the intestinal bacteria diversity of golden pompano Trachinotus ovatus. AB - To understand the effect of woody forages on golden pompano (Trachinotus ovatus) intestinal bacteria diversity and exploit new aquafeed ingredients, the diets of Moringa oleifera Lam (MOL), Broussonetia papyrifera (BP), Neolamarckia cadamba (NC) and Folium mori (FM) formulated with 70% of reference (Ref) diet and 30% of the four woody plants leaves were fed to golden pompano with initial body weight of 34.4 +/- 0.5 g for 56 days, respectively. Bacteria diversity of golden pompano intestine and tank water (W) samples were analyzed using high-throughput illumina sequencing and the result indicated that the dominate phyla of golden pompano intestine were Proteobacteria, Bacteroidetes, Firmicutes and Fusobacteria. Proteobacteria in BP was significantly higher than those in NC (P < 0.05). Firmicutes in NC were significantly higher than those in BP and FM (P < 0.05). At genera level, Lactobacillus in NC was significantly higher than those in BP, MOL and FM groups (P < 0.05). The PCoA and heat map analyses showed that the intestinal bacteria community of golden pompano fed with woody forages and Ref diet presented higher similarity and the bacteria community of golden pompano intestine were clearly distinguished from those of W. Phylogenetic investigation of communities by reconstruction of unobserved states showed that the intestinal bacteria dominant metabolism pathways of golden pompano fed with woody forages and Ref diet were biosynthesis of amino acids and carbon metabolism. Overall, the present study first successfully characterized the intestinal bacteria diversity of golden pompano. PMID- 29484506 TI - Caco-2 Cell Conditions Enabling Studies of Drug Absorption from Digestible Lipid Based Formulations. AB - PURPOSE: To identify conditions allowing the use of cell-based models for studies of drug absorption during in vitro lipolysis of lipid-based formulations (LBFs). METHODS: Caco-2 was selected as the cell-based model system. Monolayer integrity was evaluated by measuring mannitol permeability after incubating Caco-2 cells in the presence of components available during lipolysis. Pure excipients and formulations representing the lipid formulation classification system (LFCS) were evaluated before and after digestion. Porcine mucin was evaluated for its capacity to protect the cell monolayer. RESULTS: Most undigested formulations were compatible with the cells (II-LC, IIIB-LC, and IV) although some needed mucin to protect against damaging effects (II-MC, IIIB-MC, I-LC, and IIIA-LC). The pancreatic extract commonly used in digestion studies was incompatible with the cells but the Caco-2 monolayers could withstand immobilized recombinant lipase. Upon digestion, long chain formulations caused more damage to Caco-2 cells than their undigested counterparts whereas medium chain formulations showed better tolerability after digestion. CONCLUSIONS: Most LBFs and components thereof (undigested and digested) are compatible with Caco-2 cells. Pancreatic enzyme is not tolerated by the cells but immobilized lipase can be used in combination with the cell monolayer. Mucin is beneficial for critical formulations and digestion products. PMID- 29484507 TI - Correction to: Basophils activated via TLR signaling may contribute to pathophysiology of type 1 autoimmune pancreatitis. AB - In the original publication of this article, the Table 2 was published incorrectly. PMID- 29484509 TI - Preparation of a flood-risk environmental index: case study of eight townships in Changhua County, Taiwan. AB - To evaluate flood-prone areas, correlation analysis of flooding factors for the quantitative evaluation of hazard degree was determined to assist in further disaster prevention management. This study used flood-prone areas in 35 villages over eight townships (Changhua, Huatan, Yuanlin, Xiushui, Puyan, Hemei, Dacun, and Erlin) in Changhua County as research samples. Linear combination was used to evaluate flood-prone environmental indices, and an expert questionnaire was designed by using the analytic hierarchy process and the Delphi method to determine the weights of factors. These factors were then used to calculate the eigenvector of a pairwise comparison matrix to obtain the weights for the risk assessment criteria. Through collection of disaster cases, with particular focus on specifically protected areas where flooding has occurred or is likely to occur, public adaptation and response capabilities were evaluated by using an interview questionnaire that contains the items of perceived disaster risk, resource acquisition capability, adaptation capability, and environment understanding and disaster prevention education. Overlays in a geographic information system were used to analyze the flood-risk degree in villages and to construct a distribution map that contains flood-prone environment indices. The results can assist local governments in understanding the risk degree of various administrative areas to aid them in developing effective mitigation plans. PMID- 29484508 TI - Undifferentiated headache: broadening the approach to headache in children and adolescents, with supporting evidence from a nationwide school-based cross sectional survey in Turkey. AB - BACKGROUND: Headache is a leading disabler in adults worldwide. In children and adolescents, the same may be true but the evidence is much poorer. It is notable that published epidemiological studies of these age groups have largely ignored headaches not fulfilling any specific set of ICHD criteria, although such headaches appear to be common. A new approach to these is needed: here we introduce, and investigate, a diagnostic category termed "undifferentiated headache" (UdH), defined in young people as recurrent mild-intensity headache of < 1 h's duration. METHODS: We conducted a nationwide cross-sectional survey in 31 schools in six regions of Turkey selected by mixed convenience-based and purposive modified cluster-sampling. A validated, standardised self-completed structured questionnaire was administered by a physician-investigator to entire classes of pupils aged 6-17 years. RESULTS: Of the identified sample of 7889 pupils, 7088 (89.8%) participated. The 1-year prevalence of UdH was 29.2%, of migraine (definite and probable) 26.7%, and of tension-type headache (TTH) (definite and probable) 12.9%. UdH differed with respect to almost all headache features and associated symptoms from both migraine and TTH. Burden of headache and use of acute medication were lower in UdH than in migraine and TTH. Headache yesterday was less common in UdH than migraine (OR 0.32; 95% CI 0.28-0.37) and TTH (OR 0.64; 95% CI 0.56-0.77). Quality of life (QoL) was better in UdH (33.6 +/ 5.2) than in migraine (30.3 +/- 5.6; p < 0.001) and TTH (32.4 +/- 5.3; p < 0.001), but worse than in pupils without headache (35.7 +/- 4.7; p < 0.001). CONCLUSIONS: This large nationwide study in Turkey of pupils aged 6-17 years has shown that many children and adolescents have a headache type that does not conform to existing accepted diagnostic criteria. This new diagnostic category of presumably still-evolving headache (undifferentiated headache) is common. UdH differs in almost all measurable respects from both migraine and TTH. Although characterised by mild headaches lasting < 1 h, UdH is associated with significant adverse impact on QoL. Longitudinal cohort studies are needed to evaluate the prognosis of UdH but, meanwhile, recognition of UdH and its distinction from migraine and TTH has implications for epidemiological studies, public-health policy and routine clinical practice. PMID- 29484510 TI - Impact of Quran in Treatment of the Psychological Disorder and Spiritual Illness. AB - This paper studies the effect of Quranic therapy on psychological diseases and spiritual diseases. The experiments have been conducted on a random sample with 121 patients from both genders. The procedures that have been followed were different sessions with the patients, who were given some verses from the Holy Quran to listen within a specific period of time. After that, each patient was given a remedy program. This study aimed to measure the effectiveness and responsiveness of patients to receive treatment through Quran. This study highlighted the employment of a quantitative research, which achieved its objective through validity and reliability. The results of the effectiveness factor came after ability and willingness and gave a result of 92.6% for those who support the contention that the Quran has a significant healing influence. Also, some of the patients who regularly attended Quranic therapy sessions have been successfully cured, 81.8% of the sample believe that Quranic therapy sessions support their health needs. This study has empirically proved that the sound of the Holy Quran is an effective treatment for those who suffer from spiritual and psychological issues. Folk medicine and other traditional methods of treatment are important field of study that require further investigation. The study also illustrates that it's highly important for patient to have confidence in his doctor or healer. Furthermore, our results show that the ability and willingness positively and significantly are related to the effectiveness and responsiveness, also effectiveness positively and significantly related to the responsiveness. Therefore, the patients satisfied to receive treatment through Quran and they have the ability and willingness to do so as they believe that Quran is an essential part of their life. PMID- 29484511 TI - When Fear of Childbirth is Pathological: The Fear Continuum. AB - OBJECTIVES: Given that prepartum psychiatric symptoms have been reported to be associated with postpartum disorders, focusing on the prepartum period appears of prime importance. The aim of the current study was threefold: (a) to identify the prevalence rates of women suffering from fear of childbirth (FOC) and tokophobia (b) to explore the association between FOC, obstetrical and psychopathological variables and (c) to identify the independent predictors of the intensity of FOC symptoms, FOC and tokophobia. METHODS: at 36 weeks' gestation, 98 women completed questionnaires assessing FOC, pretraumatic stress, fear of pain, depressive and anxiety symptomatology as well as perceived social support. Socio-demographic and gynecological data were also gathered. RESULTS: 22.45% of women reported a probable FOC and 20.41% suffered from a potential tokophobia. Epidural anesthesia (beta = 5.62, p < 0.05), and the intensity of pretraumatic stress symptoms (beta= 0.69, p < 0.05), were independently associated with the intensity of FOC symptoms. Planning a c-section was significantly related to FOC (beta = 0.09, p = 0.03). Planning an epidural anesthesia was also an independent predictor of both FOC and tokophobia (beta = 1.33, p = 0.03; beta = 1.26, p = 0.04, respectively). CONCLUSIONS: Given the high rates of FOC and tokophobia highlighted, developing an appropriate preparation to childbirth is of great relevance. Longitudinal studies should be developed in order to provide an in-depth examination of the course of prepartum psychiatric disorders, maintenance of symptoms and their impact on subsequent infant development. PMID- 29484513 TI - New Perspectives in Clinical Pharmacokinetics-1: the Importance of Updating the Teaching in Pharmacokinetics that both Clearance and Elimination Rate Constant Approaches Are Mathematically Proven Equally Valid. AB - The healing professions have only about four main therapeutic tools at their disposal-surgery, drugs, physical therapy, and psychotherapy. For the general profession of internal medicine, drug therapy is its primary tool. Providing an understanding of the state-of-the-art in therapeutic methods, grounded in solid scientific and mathematical rigor, is therefore of the utmost clinical importance for both physicians and clinical pharmacists. This is particularly true where rapidly evolving scientific changes require an up-to-date education upon which students can rely. Unfortunately, relatively little attention has been paid to training clinical pharmacokineticists and physicians to manage drug therapy optimally for patients under their care in their everyday practice. In this paper, we discuss one of these basic deficiencies from the perspective of the longstanding controversy in pharmacokinetic modeling: whether the volume and clearance approach or the volume and rate constant approach is somehow "better". We examine this controversy using the mathematical principle of invariance, which to our knowledge has not been done before. The conclusion of this analysis is that both approaches are rigorously proven mathematically to be equally valid. We also discuss some implications of these equally valid approaches from the framework of mechanistic and non-compartmental models. Ultimately, the conclusion is that the choice of one parameterization over the other is based on preference or usefulness for research or clinical practice, but no longer, because of this analysis, on science. PMID- 29484512 TI - CrossFit Overview: Systematic Review and Meta-analysis. AB - BACKGROUND: CrossFit is recognized as one of the fastest growing high-intensity functional training modes in the world. However, scientific data regarding the practice of CrossFit is sparse. Therefore, the objective of this study is to analyze the findings of scientific literature related to CrossFit via systematic review and meta-analysis. METHODS: Systematic searches of the PubMed, Web of Science, Scopus, Bireme/MedLine, and SciELO online databases were conducted for articles reporting the effects of CrossFit training. The systematic review followed the PRISMA guidelines. The Oxford Levels of Evidence was used for all included articles, and only studies that investigated the effects of CrossFit as a training program were included in the meta-analysis. For the meta-analysis, effect sizes (ESs) with 95% confidence interval (CI) were calculated and heterogeneity was assessed using a random-effects model. RESULTS: Thirty-one articles were included in the systematic review and four were included in the meta-analysis. However, only two studies had a high level of evidence at low risk of bias. Scientific literature related to CrossFit has reported on body composition, psycho-physiological parameters, musculoskeletal injury risk, life and health aspects, and psycho-social behavior. In the meta-analysis, significant results were not found for any variables. CONCLUSIONS: The current scientific literature related to CrossFit has few studies with high level of evidence at low risk of bias. However, preliminary data has suggested that CrossFit practice is associated with higher levels of sense of community, satisfaction, and motivation. PMID- 29484514 TI - A Description of Advertisements for Alcohol on LinkNYC Kiosks in Manhattan, New York City: A Pilot Study. AB - Excessive alcohol consumption compromises health and increases risk of mortality. Advertisements for alcohol in city environments have been shown to influence consumption. The aim of this pilot study was to estimate the prevalence of alcohol advertisements displayed on LinkNYC kiosks, a new communication channel that provides outdoor Wi-Fi access and advertising on streets within urban environments. Direct observations were conducted to document advertisements on a 20% random sample of the 500 LinkNYC kiosks in Manhattan, NYC. From May to September of 2017, each of the 100 selected kiosks was observed for a 10-min period to document advertisements for alcohol. In addition, differences in prevalence of alcohol advertisements were examined by the location of the kiosk based on NYC zip codes' median annual income. Of the 2025 advertisements observed, 5.09% (N = 103) were for an alcohol product (including duplicates). Such advertisements were observed on 17% of the kiosks. No health warnings or age warnings were presented in any of the alcohol advertisements. Compared with kiosks located in zip codes with lower median annual income, significantly more alcohol advertisements were displayed in zip codes with higher median annual income. This is the first study to estimate the prevalence of alcohol advertising on the LinkNYC Wi-Fi and telecommunication system, now ubiquitous on Manhattan's sidewalks. This study adds to the current literature that suggests New York City residents could benefit from health-promoting versus health-compromising advertising. The findings also highlight the potential of LinkNYC kiosk marketing to undermine health-related social marketing efforts by City government and other organizations. PMID- 29484515 TI - Early stage non-small cell lung cancer patients need brain imaging regardless of symptoms. AB - BACKGROUND: Japanese Lung Cancer Society and ESMO guideline recommends screening for brain metastasis in all patients with non-small cell lung cancer (NSCLC), while NCCN/ACCP guidelines do not recommend screening patients who are asymptomatic and with clinical stage I NSCLC. However, brain metastasis sometimes occurs in early stage NSCLC patients without any neurological symptoms. METHODS: We retrospectively reviewed medical records of 124 patients admitted to the University of Tokyo Hospital with stage IV NSCLC from January 2012 to April 2016. We analyzed clinical stage, the presence of the central nervous system manifestations and the number of brain metastases. RESULTS: Forty-six out of 124 cases had brain metastasis at presentation. The brain metastasis group had larger number of female, never smokers and patients with EGFR mutation compared with extracranial metastasis group. Twenty-one of 35 adenocarcinoma cases with brain metastasis had EGFR mutations. Out of 46 brain metastasis patients, 29 patients (63%) were asymptomatic and patients with EGFR mutations were significantly less likely to have neurological symptoms (4/21 vs. 7/14, p = 0.049). Six out of 46 cases with brain metastasis (13%) were clinical T1-2aN0. In clinical T1-2aN0 cases, only one patient had neurological symptoms at presentation. CONCLUSION: In clinical T1-2aN0 lung cancer patients with brain metastasis, almost all patients were asymptomatic. Patients with EGFR mutations and brain metastasis were likely to be asymptomatic. Regardless of central nervous system symptoms, routine brain imaging seems warranted in all NSCLC patients, especially in areas where patients have a higher frequency of EGFR mutations. PMID- 29484517 TI - Arthroscopic bone graft procedure combined with arthroscopic subscapularis augmentation (ASA) for recurrent anterior instability with glenoid bone defect: a cadaver study. AB - BACKGROUND: Glenoid bone loss and capsular deficiency represent critical points of arthroscopic Bankart repair failures. The purpose of this study was to evaluate an all-arthroscopic bone block procedure associated with arthroscopic subscapularis augmentation (ASA) for treating gleno-humeral instability with glenoid bone loss (GBL) and anterior capsulo-labral deficiency. Our hypothesis was that these two procedures could be combined arthroscopically. The feasibility of this technique and its reproducibility, and potential neurovascular complications were evaluated. METHODS: A tricortical bone graft was harvested from the cadaveric clavicle, and in one case a Xenograft was used. An anterior inferior GBL of about 25% was created. Two glenoid tunnels were set up from the posterior to the anterior side using a dedicated bone block guide, and four buttons were used to fix the graft to the glenoid. The subscapularis tenodesis was performed using a suture tape anchor. Afterwards, the shoulder was dissected to study the relationship between all portals and nerves. The size of the bone block, its position on the glenoid and the relationship with the subscapularis tendon were investigated. RESULTS: In all seven specimens (five left and two right shoulders), the bone block was flush with the cartilage and fixed to the anterior-inferior part of the glenoid. No lesions of the surrounding neurovascular structures were observed. No interference was found between the two bone block tunnels and the anchor tunnel used for the tenodesis. CONCLUSIONS: This study demonstrated the feasibility and reproducibility of this combined arthroscopic technique (bone block associated with ASA) in the treatment of anterior shoulder instability associated with anterior bone loss and anterior capsular deficiency. PMID- 29484516 TI - Natural history of neurological abnormalities in cerebrotendinous xanthomatosis. AB - OBJECTIVES: Cerebrotendinous xanthomatosis (CTX) is a rare inherited neurodegenerative disorder in bile acid synthesis. The natural history of neurological abnormalities in CTX is not well understood. The object of this study was to determine neurological progression in CTX. METHODS: A literature search on PubMed for "cerebrotendinous xanthomatosis" yielded 91 publications that reported cases of CTX patients. Two independent reviewers abstracted information about the presence and age of onset of neurological abnormalities in published CTX cases. For each neurological abnormality, we estimated the probability of its onset at any given age using cumulative incidence function analysis. We also present our own case series, in which five CTX patients were evaluated. RESULTS: The literature search yielded 194 CTX cases (ages ranging from newborn to 67 years old). The most common neurological abnormalities were corticospinal tract abnormalities including weakness, hyperreflexia, spasticity, Babinski sign (59.8%), ataxia (58.8%), cognitive decline (46.4%), and gait difficulty (38.1%); 68 (35.0%) had baseline cognitive problems. Cumulative incidence function analysis revealed that ataxia, gait difficulties, and corticospinal tract abnormalities developed throughout life, while cognitive decline tended to develop later in life. Of the less common neurological abnormalities, seizures, psychiatric changes and speech changes developed throughout life, while parkinsonism and sensory changes tended to develop later in life. Our case series corroborated this temporal pattern of neurological abnormalities. CONCLUSION: We provide estimates for the neurological progression of CTX, categorizing neurological abnormalities according to time and probability of development. Our approach may be applicable to other rare disorders. PMID- 29484518 TI - Paracoccus pueri sp. nov., isolated from Pu'er tea. AB - A Gram-stain negative, aerobic, short rod-shaped, motile by flagella bacterial strain (THG-N2.35T), was isolated from Pu'er tea. Growth occurred at 10-40 degrees C (optimum 28 degrees C), at pH 4-7 (optimum 7) and at 0-5% NaCl (optimum 1%). Based on 16S rRNA gene sequence analysis, the near phylogenetic neighbours of strain THG-N2.35T were identified as Paracoccus hibisci KACC 18632T (99.0%), Paracoccus tibetensis CGMCC 1.8925T (98.7%), Paracoccus beibuensis CGMCC 1.7295T (98.2%), Paracoccus aestuarii KCTC 22049T (98.2%), Paracoccus rhizosphaerae LMG 26205T (98.1%), Paracoccus zeaxanthinifaciens ATCC 21588T (97.1%), Paracoccus marcusii DSM 11574T (97.0%). Levels of similarity between strain THG-N2.35T and other Paracoccus species were lower than 97.0%. DNA-DNA hybridization values between strain THG-N2.35T and P. hibisci KACC 18632T, P. tibetensis CGMCC 1.8925T, P. beibuensis CGMCC 1.7295T, P. aestuarii KCTC 22049T, P. rhizosphaerae LMG 26205T, P. zeaxanthinifaciens ATCC 21588T, P.marcusii DSM 11574T were 47.5% (42.3%, reciprocal analysis), 36.1% (32.3%), 24.7% (22.1%), 19.2% (16.3%), 11.3% (8.8%), 11.1% (10.8%), 6.1% (5.8%), respectively. The DNA G+C content of strain THG-N2.35T was 62.3 mol%. The polar lipids were diphosphatidylglycerol, phosphatidyl-N-methylethanolamine, phosphatidylethanolamine, phosphatidylglycerol and phosphatidylcholine. The quinone was ubiquinone-10 (Q-10). The major fatty acids were C10:0 3OH, C16:0, C18:0 and C18:1 omega7sigma. On the basis of the phylogenetic analysis, chemotaxonomic data, physiological characteristics and DNA-DNA hybridization data, strain THG-N2.35T represent a novel species of the genus Paracoccus, for which the name Paracoccus pueri sp. nov. is proposed. The type strain is THG N2.35T (= KACC 18934T = CCTCC AB 2016177T). PMID- 29484519 TI - Perspective on the interpretation of research and translation to clinical care with therapy-associated metastatic breast cancer progression as an example. AB - This commentary was written as a collaboration between the Board of the Metastasis Research Society and two patients with metastatic breast cancer. It was conceived in response to how preclinical scientific research is sometimes presented to non-scientists in a way that can cause stress and confusion. Translation of preclinical findings to the clinic requires overcoming multiple barriers. This is irrespective of whether the findings relate to exciting responses to new therapies or problematic effects of currently used therapies. It is important that these barriers are understood and acknowledged when research findings are summarized for mainstream reporting. To minimize confusion, patients should continue to rely on their oncology care team to help them interpret whether research findings presented in mainstream media have relevance for their individual care. Researchers, both bench and clinical, should work together where possible to increase options for patients with metastatic disease, which is still in desperate need of effective therapeutic approaches. PMID- 29484520 TI - Reporting, Visualization, and Modeling of Immunogenicity Data to Assess Its Impact on Pharmacokinetics, Efficacy, and Safety of Monoclonal Antibodies. AB - The rapidly increasing number of therapeutic biologics in development has led to a growing recognition of the need for improvements in immunogenicity assessment. Published data are often inadequate to assess the impact of an antidrug antibody (ADA) on pharmacokinetics, safety, and efficacy, and enable a fully informed decision about patient management in the event of ADA development. The recent introduction of detailed regulatory guidance for industry should help address many past inadequacies in immunogenicity assessment. Nonetheless, careful analysis of gathered data and clear reporting of results are critical to a full understanding of the clinical relevance of ADAs, but have not been widely considered in published literature to date. Here, we review visualization and modeling of immunogenicity data. We present several relatively simple visualization techniques that can provide preliminary information about the kinetics and magnitude of ADA responses, and their impact on pharmacokinetics and clinical endpoints for a given therapeutic protein. We focus on individual sample and patient-level data, which can be used to build a picture of any trends, thereby guiding analysis of the overall study population. We also discuss methods for modeling ADA data to investigate the impact of immunogenicity on pharmacokinetics, efficacy, and safety. PMID- 29484521 TI - Diagnosis of non-osseous spinal metastatic disease: the role of PET/CT and PET/MRI. AB - The spine is the third most common site for distant metastasis in cancer patients with approximately 70% of patients with metastatic cancer having spinal involvement. Positron emission tomography (PET), combined with computed tomography (CT) or magnetic resonance imaging (MRI), has been deeply integrated in modern clinical oncology as a pivotal component of the diagnostic work-up of patients with cancer. PET is able to diagnose several neoplastic processes before any detectable morphological changes can be identified by anatomic imaging modalities alone. In this review, we discuss the role of PET/CT and PET/MRI in the diagnostic management of non-osseous metastatic disease of the spinal canal. While sometimes subtle, recognizing such disease on FDG PET/CT and PET/MRI imaging done routinely in cancer patients can guide treatment strategies to potentially prevent irreversible neurological damage. PMID- 29484522 TI - Circulating matrix metalloproteinases and procollagen propeptides in inguinal hernia. AB - PURPOSE: Degradation of collagen has been suggested involved in the pathogenesis of inguinal hernia. In this study, we aim to evaluate circulating biomarkers of procollagen type I N-terminal propeptide (PINP), procollagen type III N-terminal propeptide (PIIINP), matrix metalloproteinases (MMP)-2, MMP-9, copper and zinc in primary and recurrent inguinal hernia patients. METHODS: This study included 110 inguinal hernia patients: 45 patients had primary indirect inguinal hernia, 40 patients had primary direct inguinal hernia, 15 patients had recurrent indirect inguinal hernia and 10 patients had recurrent direct inguinal hernia. Additional 45 patients operated for reasons other than hernia were included as a control group. All blood samples were obtained preoperatively. Circulating PINP, PIIINP, MMP-2 and MMP-9 were investigated using enzyme-linked immunoabsorbent assay (ELISA) methods, and copper and zinc were measured using an air acetylene flame atomic absorption spectrometer. RESULTS: Serum MMP-2 levels in patients with direct and recurrent inguinal hernias were significantly higher than controls. The ratios of PINP/PIIINP decreased more apparent in recurrent indirect or direct inguinal hernia group than primary indirect or direct inguinal hernia group. Based on receiver operating characteristic curve analysis, PINP/PIIINP can effectively diagnose recurrent inguinal hernia from primary inguinal hernia with area under the curve (AUC) of 0.919 for recurrent indirect inguinal hernia and 0.808 for recurrent direct inguinal hernia, respectively. CONCLUSION: The ratio of serum PINP/PIIINP was lower in patients with recurrent inguinal hernia, demonstrating more serious damage of collagen metabolism in these patients. Serologic ratio of PINP/PIIINP may be used to identify the presence of recurrent inguinal hernia in patients. PMID- 29484523 TI - Muscarinic Receptor-Dependent Long Term Depression in the Perirhinal Cortex and Recognition Memory are Impaired in the rTg4510 Mouse Model of Tauopathy. AB - Neurodegenerative diseases affecting cognitive dysfunction, such as Alzheimer's disease and fronto-temporal dementia, are often associated impairments in the visual recognition memory system. Recent evidence suggests that synaptic plasticity, in particular long term depression (LTD), in the perirhinal cortex (PRh) is a critical cellular mechanism underlying recognition memory. In this study, we have examined novel object recognition and PRh LTD in rTg4510 mice, which transgenically overexpress tauP301L. We found that 8-9 month old rTg4510 mice had significant deficits in long- but not short-term novel object recognition memory. Furthermore, we also established that PRh slices prepared from rTg4510 mice, unlike those prepared from wildtype littermates, could not support a muscarinic acetylcholine receptor-dependent form of LTD, induced by a 5 Hz stimulation protocol. In contrast, bath application of the muscarinic agonist carbachol induced a form of chemical LTD in both WT and rTg4510 slices. Finally, when rTg4510 slices were preincubated with the acetylcholinesterase inhibitor donepezil, the 5 Hz stimulation protocol was capable of inducing significant levels of LTD. These data suggest that dysfunctional cholinergic innervation of the PRh of rTg4510 mice, results in deficits in synaptic LTD which may contribute to aberrant recognition memory in this rodent model of tauopathy. PMID- 29484524 TI - Significance of mandibular molar replacement with a dental implant: a theoretical study with nonlinear finite element analysis. AB - BACKGROUND: Dental implants are frequently applied to unilateral defects in the mandible. However, implant placement in the molar region of the mandible can be difficult due to anatomical structure. The aim of this study was to evaluate the distribution of occlusal force in a mandibular shortened dental arch (SDA) with implants. METHODS: Three-dimensional finite element (FE) models of the mandible with varying numbers of teeth and implants were constructed. Models Im6 and Im67 contained one and two implants in the defect of the left molar region, respectively. Models Im456 and Im4567 contained three and four implants in the defect of the left premolar and molar regions, respectively. Model MT67 contained a defect in the molar region with no implant placed. Model MT7 represented natural dentition without a left second molar, as a control. Modification of the condition of occlusal contacts assuming the intercuspal position was performed before analysis under load 400 N; therefore, the load condition as total force on the occlusal surface was 400 N. FE analyses were subsequently performed under load conditions of loads 100, 200, and 800 N. The distribution of reaction forces on the occlusal surface and the mandibular condyle was investigated. RESULTS: Force distribution in models Im67 and Im4567 appeared to be symmetrical under all load conditions. Occlusal force distribution in models Im6 and Im456 was similar to that in model MT7. However, the occlusal force at the second premolars on the defect side in those models was larger under loads 100 and 200 N. Conversely, the occlusal force on the first molars was much larger than that in model MT7 under load 800 N. CONCLUSIONS: Within the limitations of this theoretical study, we demonstrated that restoration with the same number of implants as missing teeth will show almost symmetric occlusal force distribution, and it will produce less biomechanically stress for a unilateral defect of the mandible. However, if restoration of a missing second molar with an implant is impossible or difficult, then an SDA with implants may also be acceptable except for individuals with severe bruxism. PMID- 29484526 TI - miR-146a down-regulation alleviates H2O2-induced cytotoxicity of PC12 cells by regulating MCL1/JAK/STAT pathway : miR-146a down-regulation relieves H2O2-induced PC12 cells cytotoxicity by MCL1/JAK/STAT. AB - Oxidative stress and miRNAs have been confirmed to play an important role in neurological diseases. The study aimed to explore the underlying effect and mechanisms of miR-146a in H2O2-induced injury of PC12 cells. Here, PC12 cells were stimulated with 200 MUM of H2O2 to construct oxidative injury model. Cell injury was evaluated on the basis of the changes in cell viability, migration, invasion, apoptosis, and DNA damage. Results revealed that miR-146a expression was up-regulated in H2O2-induced PC12 cells. Functional analysis showed that down regulation of miR-146a alleviated H2O2-induced cytotoxicity in PC12 cells. Dual luciferase reporter and western blot assay verified that MCL1 was a direct target gene of miR-146a. Moreover, anti-miR-146a-mediated suppression on cell cytotoxicity was abated following MCL1 knockdown in H2O2-induced PC12 cells. Furthermore, MCL1 activated JAK/STAT signaling pathway and MCL1 overexpression attenuated H2O2-induced cytotoxicity in PC12 cells by JAK/STAT signaling pathway. In conclusion, this study suggested that suppression of miR-146a abated H2O2 induced cytotoxicity in PC12 cells via regulating MCL1/JAK/STAT pathway. PMID- 29484525 TI - Effect of factor XIII levels and polymorphisms on the risk of myocardial infarction in young patients. AB - Factor XIII (FXIII) stabilizes and protects the fibrin network. Its role in myocardial infarction (MI) is still to be clarified. To evaluate the association of FXIII levels with MI in young patients and to investigate how the FXIII-A p.Val34Leu, FXIII-B p.His95Arg, and IVS11, c.1952 + 144 C>G (Intron K) polymorphisms influence FXIII levels and MI risk. Patients with ST elevation MI below 40 years of age (MI, n = 119), age-matched clinical controls (CC, n = 101) without MI and coronary artery disease, and healthy controls (HC, n = 120) were investigated for FXIII activity, FXIII-A2B2, FXIII-B concentrations and for the polymorphisms. FXIII activity and FXIII-A2B2 antigen were significantly elevated in MI. FXIII activity and antigen were significantly elevated in Arg95, while decreased in Intron K "G" carriers. Smoking had an independent increasing effect on FXIII activity and FXIII-A2B2 antigen. Intron K C>G polymorphism significantly decreased the risk of MI in patients with elevated fibrinogen. Among the investigated factors Intron K C>G polymorphism and smoking have the most powerful effect on FXIII levels and on the risk of MI in the young. The effect of smoking on coronary thrombus formation may partially be attributed to its FXIII increasing effect. PMID- 29484527 TI - History, applications, and challenges of immune repertoire research. AB - The diversity of T and B cells in terms of their receptor sequences is huge in the vertebrate's immune system and provides broad protection against the vast diversity of pathogens. Immune repertoire is defined as the sum of T cell receptors and B cell receptors (also named immunoglobulin) that makes the organism's adaptive immune system. Before the emergence of high-throughput sequencing, the studies on immune repertoire were limited by the underdeveloped methodologies, since it was impossible to capture the whole picture by the low throughput tools. The massive paralleled sequencing technology suits perfectly the researches on immune repertoire. In this article, we review the history of immune repertoire studies, in terms of technologies and research applications. Particularly, we discuss several aspects of challenges in this field and highlight the efforts to develop potential solutions, in the era of high throughput sequencing of the immune repertoire. PMID- 29484528 TI - Variable Cell Line Pharmacokinetics Contribute to Non-Linear Treatment Response in Heterogeneous Cell Populations. AB - We develop a combined experimental-mathematical framework to investigate heterogeneity in the context of breast cancer treated with doxorubicin. We engineer a cell line to over-express the multi-drug resistance 1 protein (MDR1), an ATP-dependent pump that effluxes intracellular drug. Co-culture experiments mixing the MDR1-overexpressing line with its parental line are evaluated via fluorescence microscopy. To quantify the impact of population heterogeneity on therapy response, these data are analyzed with a coupled pharmacokinetics/pharmacodynamics model. The proliferation and death rates of each line vary with co-culture condition (the relative fraction of each cell line at the time of seeding). For example, the death rate in the parental line under low-dose doxorubicin treatment is increased from 0.64 (+/- 0.22) * 10-2 to 1.46 (+/- 0.58) * 10-2 h-1 with increasing fractions of MDR1-overexpressing cells. The growth rate of the MDR1-overexpressing line increases 29% as its relative fraction is decreased. Simulations of the pharmacokinetics/pharmacodynamics model suggest increased efflux from MDR1-overexpressing cells contributes to the increased death rate in the parental cells. Experimentally, the death rate of parental cells is constant across co-culture conditions under co-treatment with an MDR1 inhibitor. These data indicate that intercellular pharmacokinetic variability should be considered in analyzing treatment response in heterogeneous populations. PMID- 29484530 TI - In situ forming phase-inversion implants for sustained ocular delivery of triamcinolone acetonide. AB - The objectives of this study were to develop biodegradable poly-lactic-co glycolic acid (PLGA) based injectable phase inversion in situ forming system for sustained delivery of triamcinolone acetonide (TA) and to conduct physicochemical characterisation including in vitro drug release of the prepared formulations. TA (at 0.5%, 1% and 2.5% w/w loading) was dissolved in N-methyl-2-pyrrolidone (NMP) solvent and then incorporated 30% w/w PLGA (50/50 and 75/25) polymer to prepare homogenous injectable solution. The formulations were evaluated for rheological behaviour using rheometer, syringeability by texture analyser, water uptake and rate of implant formation by optical coherence tomography (OCT) microscope. Phase inversion in situ forming formulations were injected into PBS pH 7.3 to form an implant and release samples were collected and analysed for drug content using a HPLC method. All formulations exhibited good syringeability and rheological properties (viscosity: 0.19-3.06 Pa.s) by showing shear thinning behaviour which enable them to remain as free-flowing solution for ease administration. The results from OCT microscope demonstrated that thickness of the implants were increased with the increase in time and the rate of implant formation indicated the fast phase inversion. The drug release from implants was sustained over a period of 42 days. The research findings demonstrated that PLGA/NMP-based phase inversion in situ forming implants can improve compliance in patient's suffering from ocular diseases by sustaining the drug release for a prolonged period of time and thereby reducing the frequency of ocular injections. PMID- 29484529 TI - Journal of Clinical Monitoring and Computing 2017 end of year summary: cardiovascular and hemodynamic monitoring. AB - Hemodynamic monitoring provides the basis for the optimization of cardiovascular dynamics in intensive care medicine and anesthesiology. The Journal of Clinical Monitoring and Computing (JCMC) is an ideal platform to publish research related to hemodynamic monitoring technologies, cardiovascular (patho)physiology, and hemodynamic treatment strategies. In this review, we discuss selected papers published on cardiovascular and hemodynamic monitoring in the JCMC in 2017. PMID- 29484531 TI - P and T wave detection and delineation of ECG signal using differential evolution (DE) optimization strategy. AB - Generally, P and T waves in an electrocardiogram (ECG) signal are lower in amplitude compared to amplitude of QRS complex and contaminated with noises from various sources. Due to these problems and lack of universal delineation rule, the automated detection and delineation of T and P waves (on, off, and peak position of T and P wave) in the ECG signal are challenging task. The effectiveness for detection of on, off, and peak position of T and P wave by using differential evolution (DE) algorithm with the denoising technique has been verified in this manuscript. The denoising operation of the ECG signal has been performed by extended Kalman smoother (EKS) framework. DE algorithm is used for selection of optimized width and phase of five waves of the ECG signal. These parameters are used in EKS for initialization of the process noise covariance matrix and also development of the state equation. The new algorithm (an intelligent process of searching and subtraction) for detection of on, off and peak location of P and T waves without using amplitude threshold is developed by using the optimized parameters computed by the DE algorithm and denoised ECG signal with the help of the EKS framework. The effectiveness of the proposed technique has been validated using real-time QT database. Our proposed method shows better sensitivity, predicitvity and accuracy compared to other well-known methods for detection of on, off, peak location of P and T wave. PMID- 29484532 TI - Using Community-Based Participatory Research to Develop Geospatial Models Toward Improving Community Health for Disadvantaged Hispanic Populations in Charlotte, NC. AB - Hispanic immigrant communities across the U.S. experience persistent health disparities and barriers to primary care. We examined whether community-based participatory research (CBPR) and geospatial modeling could systematically and reproducibly pinpoint neighborhoods in Charlotte, North Carolina with large proportions of Hispanic immigrants who were at-risk for poor health outcomes and health disparities. Using a CBPR framework, we identified 21 social determinants of health measures and developed a geospatial model from a subset of those measures to identify neighborhoods with large proportions of Hispanic immigrant populations at risk for poor health outcomes. The geospatial model included four measures-poverty, English ability, acculturation and violent crime-which comprised our Hispanic Health Risk Index (HHRI). We developed a Primary Care Barrier Index (PCBI) to determine (1) how well the HHRI correlated with a statistically derived composite measure incorporating all 21 measures identified through the CBPR process as being associated with access to primary care; (2) whether the HHRI predicted primary care access as well as the statistically derived composite measure in a statistical model; and (3) whether the HHRI identified similar neighborhoods as the statistically derived composite measure. We collapsed 17 of the 21 social determinants using principal components analysis to develop the PCBI. We determined the correlation of each index with inappropriate emergency department (ED) visits, a proxy for primary care access, using logistic generalized estimating equations. Results from logistic regression models showed positive associations of both the HHRI and the PCBI with the use of the ED for primary care treatable conditions. Enhanced by the knowledge of the local community, the CBPR process with geospatial modeling can guide the multi tiered validation of social determinants of health and identify neighborhoods that are at-risk for poor health outcomes and health disparities. PMID- 29484533 TI - The Spatial Musical Association of Response Codes does not depend on a normal visual experience: A study with early blind individuals. AB - Converging evidence suggests that the perception of auditory pitch exhibits a characteristic spatial organization. This pitch-space association can be demonstrated experimentally by the Spatial Musical Association of Response Codes (SMARC) effect. This is characterized by faster response times when a low positioned key is pressed in response to a low-pitched tone, and a high positioned key is pressed in response to a high-pitched tone. To investigate whether the development of this pitch-space association is mediated by normal visual experience, we tested a group of early blind individuals on a task that required them to discriminate the timbre of different instrument sounds with varying pitch. Results revealed a comparable pattern in the SMARC effect in both blind participants and sighted controls, suggesting that the lack of prior visual experience does not prevent the development of an association between pitch height and vertical space. PMID- 29484535 TI - Psychologists and Neoliberal School Reforms: Multi-Faceted Problems Calling for Multi-Faceted Interventions. AB - This paper extends on six aspects of an article on neoliberal school reforms, their possible influences on schools and school psychologists, and options for dealing with these challenges (Szulevicz, Integrative Psychological and Behavioral Sciences 2018). First, the reductions implied in the neoliberal view of the student as homo economicus and of an ideal student as self-regulated learner are described and alternative views of the student as a person (e.g., homo moralis) and of the ideal student (e.g., as intentional self-developer) are presented. Secondly, several promoting and inhibiting influences on neoliberal school reforms are discussed: competence-based school education, output-oriented school governance, and standardized school performance testing on the one hand, and critical discourses about these phenomena on the other. Third, attention is directed towards impending disadvantages of the aforementioned reforms (e.g., insufficient preparation of students for the fullness of life). Fourth, goals for interventions are discussed (e.g., reducing neoliberal influences on schools, creating an awareness of the disadvantages of neoliberal reforms, forming coalitions to promote alternatives to these reforms). Fifth, some intervention approaches for reaching these goals are considered with special emphasis on different system levels and stakeholders at which these interventions may be targeted (e.g., education policy makers, teachers and parents associations). Sixth, evaluations of the interventions are called for to monitor their effects and to refine the guiding goals, problem analyses, and strategies. In closing, some transferable principles of the preceding approach are highlighted that could be used to better understand and manage other educational problems as well. PMID- 29484536 TI - Agreement between retrospectively and contemporaneously collected patient reported outcome measures (PROMs) in hip and knee replacement patients. AB - PURPOSE: To investigate the relationship between retrospectively and contemporaneously collected patient-reported outcome measures (PROMs) and the influence on this relationship of patients' age and socio-economic status and the length of time. METHODS: Patients undergoing hip or knee replacement in four hospitals who had completed a pre-operative questionnaire were invited to recall their pre-operative health status shortly after surgery. The questionnaires included a disease-specific (Oxford Hip Score; Oxford Knee Score) and generic (EQ 5D-3L) PROM. Consistency and absolute agreement between contemporary and retrospective reports were investigated using intraclass correlations (ICCs). Differences were visualised using Bland-Altman plots. Linear regression analysis explored whether retrospective can predict contemporary PROMs. RESULTS: Patients' recalled health statuses were similar to their contemporaneous reports, with no significant systematic bias. Absolute agreement for disease-specific PROMs was very strong (ICC 0.82) and stronger than for the generic PROM (ICC 0.60, 0.62). Agreement was consistently strong across the range of severity of a patient's condition, age and socio-economic status. Patients' age and socio-economic status had no significant influence on size of difference and direction of recall, although reliability of recall was slightly worse among the over-75s versus under 60s for hips (Oxford Hip Score ICC 0.88 vs. 0.78). Mean retrospective PROMs for groups or populations of patients can reliably predict what mean contemporary reports of PROMs would have been. CONCLUSION: Retrospective PROMs can be used to obtain a baseline assessment of health status when contemporary collection is not feasible or cost effective. Research is needed to determine the feasibility of retrospective PROMs in emergency admissions. PMID- 29484537 TI - Establishment of two basal-like breast cancer cell lines with extremely low tumorigenicity from Taiwanese premenopausal women. AB - The research of carcinogenetic mechanisms of breast cancer in different ethnic backgrounds is an interesting field, as clinical features of breast cancers vary among races. High premenopausal incidence is distinctive in East-Asian breast cancer. However, human cell lines derived from Asian primary breast tumor are rare. To provide alternative cell line models with a relevant genetic background, we aimed to establish breast cancer cell lines from Taiwanese patients of Han Chinese ethnicity. Fresh tissue from mammary tumors were digested into organoids, plated and grown in basal serum-free medium of human mammary epithelial cells (HuMEC) with supplements. Cells were further enriched by positive selection with CD326 (epithelial cell adhesion molecule; EpCAM)-coated micro-magnetic beads. Two breast cancer cell lines derived from premenopausal women were successfully established by this method, and named Chang-Gung Breast Cancer 01 (CGBC 01) and 02 (CGBC 02). These two cell lines had a similar phenotype with weak expression of estrogen receptor (ER), progesterone receptor (PR), and without amplification of receptor tyrosine protein kinase erbB-2 (HER2/neu). Genome-wide Single Nucleotide Polymorphism (SNP) array showed multiple copy number alterations in both cell lines. Based on gene expression profiles, CGBC 01 and 02 were clustered into basal-like subtype with reference to the breast cancer cell line gene expression database. The tumorigenicity of both cell lines was extremely low in both anchorage-independence assay and transplantation into the mammary fat pads of nude mice. CGBC 01 and CGBC 02 are low tumorigenic breast cancer cell lines, established from Han-Chinese premenopausal breast cancer patients, which serve as in vitro models in studying the biological features of Asian breast cancer. PMID- 29484539 TI - Mechanical Properties and Composition of the Basal Leaflet-Annulus Region of the Tricuspid Valve. AB - The Tricuspid valve (TV) annulus is a transition structure from the leaflets to the myocardium, with 3 different annulus segments corresponding to the TV leaflets, which includes both basal leaflets and bordering myocardium. The objective of this study was to understand TV annulus mechanical properties and correlate it to the biological composition. The uniaxial testing of the annulus segments from ten porcine TVs was performed to measure Young's modulus (E) and extensibility (epsilonT). Western blotting and histology were executed. The septal annulus E value (208.7 +/- 67.2 kPa) was statistically greater (p < 0.01) than that of the anterior (92.0 +/- 66.8 kPa) and the posterior annulus segment (136.8 +/- 56.9 kPa) (p < 0.05), respectively. epsilonT among the 3 segments were equivalent (p values < 0.05). Western blotting and histology indicated that collagen was greatest along the septal annulus segment, which is correlated to E values. Collagen fibers from the leaflets inserted into the myocardium and faded out. Collagen content explains greater E and suture strength in the surgical annulus repair and larger resistance to annulus dilation in the septal annulus as compared with other segments. This study elucidates new knowledge of mechanical properties of the basal leaflet-annulus region of the TV annulus, which can be useful for future TV repair techniques. PMID- 29484538 TI - Intestinal calcium transport and its regulation in thalassemia: interaction between calcium and iron metabolism. AB - Osteoporosis and derangement of calcium homeostasis are common complications of thalassemia. Despite being an important process for bone and calcium metabolism, little is known about intestinal calcium transport in thalassemia. Recent reports of decreases in both intestinal calcium transport and bone mineral density in thalassemic patients and animal models suggested that defective calcium absorption might be a cause of thalassemic bone disorder. Herein, the possible mechanisms associated with intestinal calcium malabsorption in thalassemia are discussed. This includes alterations in the calcium transporters and hormonal controls of the transcellular and paracellular intestinal transport systems in thalassemia. In addition, the effects of iron overload on intestinal calcium absorption, and the reciprocal interaction between iron and calcium transport in thalassemia are elaborated. Understanding the mechanisms underlining calcium malabsorption in thalassemia would lead to development of therapeutic agents and mineral supplements that restore calcium absorption as well as prevent osteoporosis in thalassemic patients. PMID- 29484540 TI - Vitamin D supplementation improves endothelial dysfunction in patients with non dialysis chronic kidney disease. AB - PURPOSE: Hypovitaminosis D is common in chronic kidney disease (CKD) and is associated with endothelial dysfunction and cardiovascular events. This study aimed to investigate the effects of vitamin D supplementation on endothelial dysfunction in non-dialysis CKD patients. MATERIALS AND METHODS: Seventy-one non dialysis CKD patients with low vitamin D (serum 25(OH)D < 30 ng/mL) were recruited. Patients received oral cholecalciferol 50,000 units once a week for 12 weeks. Changes in endothelial function by brachial artery flow-mediated dilation (FMD), soluble vascular cell adhesion molecule-1 (sVCAM-1), and sE-selectin were studied. RESULTS: There was a significant increase in serum levels of 25(OH)D after cholecalciferol supplementation (33.7 +/- 12.1 vs. 13.2 +/- 5.4 ng/mL, P < 0.001). Multivariable regression analysis showed that higher proteinuria (beta = 0.548, P < 0.001) and lower levels of 25(OH)D (beta = 0.360, P < 0.001) at baseline were related to lower 25(OH)D level after supplementation. FMD increased significantly from 4.4 +/- 1.3 to 5.1 +/- 1.5% (P < 0.001), and soluble endothelial biomarkers decreased: sVCAM-1 from 926.9 +/- 158.0 to 867.0 +/- 129.0 ng/mL (P < 0.001), and sE-selectin 69.7 +/- 15.8 to 63.3 +/- 14.7 ng/mL (P < 0.001). CONCLUSIONS: Vitamin D supplementation can improve endothelial dysfunction in pre-dialysis CKD patients. PMID- 29484541 TI - Taking an insect-inspired approach to bird navigation. AB - Navigation is an essential skill for many animals, and understanding how animal use environmental information, particularly visual information, to navigate has a long history in both ethology and psychology. In birds, the dominant approach for investigating navigation at small-scales comes from comparative psychology, which emphasizes the cognitive representations underpinning spatial memory. The majority of this work is based in the laboratory and it is unclear whether this context itself affects the information that birds learn and use when they search for a location. Data from hummingbirds suggests that birds in the wild might use visual information in quite a different manner. To reconcile these differences, here we propose a new approach to avian navigation, inspired by the sensory driven study of navigation in insects. Using methods devised for studying the navigation of insects, it is possible to quantify the visual information available to navigating birds, and then to determine how this information influences those birds' navigation decisions. Focusing on four areas that we consider characteristic of the insect navigation perspective, we discuss how this approach has shone light on the information insects use to navigate, and assess the prospects of taking a similar approach with birds. Although birds and insects differ in many ways, there is nothing in the insect-inspired approach of the kind we describe that means these methods need be restricted to insects. On the contrary, adopting such an approach could provide a fresh perspective on the well studied question of how birds navigate through a variety of environments. PMID- 29484542 TI - Evolution of neurocognitive function in long-term survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only. AB - PURPOSE: The purpose of this study was to determine the evolution of neurocognitive problems from therapy completion to long-term follow-up in survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only. METHODS: We evaluated whether attention problems observed at therapy completion evolve into long-term executive dysfunction in 158 survivors treated on a single institution protocol. Treatment data (high-dose intravenous methotrexate exposure [serum concentration] and triple intrathecal chemotherapy injections) were collected. Parent report of behavior and direct cognitive testing of survivors was conducted at end of therapy, and survivors completed neurocognitive testing when > 5 years post-diagnosis. RESULTS: At the end of chemotherapy, survivors (52% female; mean age 9.2 years) demonstrated higher frequency of impairment in sustained attention (38%) and parent-reported inattention (20%) compared to population expectations (10%). At long-term follow up, survivors (mean age 13.7 years; 7.6 years post-diagnosis) demonstrated higher impairment in executive function (flexibility 24%, fluency 21%), sustained attention (15%), and processing speed (15%). Sustained attention improved from end of therapy to long-term follow-up (p < 0.001). Higher methotrexate AUC and greater number of intrathecal injections were associated with attention problems (p = 0.009, p = 0.002, respectively) at the end of chemotherapy and executive function (p < 0.001, p = 0.02, respectively) problems at long-term follow-up. Attention problems at the end of therapy were not associated with executive function problems at long-term follow-up (p's > 0.05). The direct effect of chemotherapy exposure predicted outcomes at both time points. CONCLUSIONS AND IMPLICATIONS FOR CANCER SURVIVORS: Survivors should be monitored for neurocognitive problems well into long-term survivorship, regardless of whether they show attention problems at the end of therapy. Treatment exposures are the best predictor of long-term complications. PMID- 29484543 TI - Improved diagnostic accuracy of thallium-201 myocardial perfusion single-photon emission computed tomography with CT attenuation correction. AB - BACKGROUND: The benefits of attenuation correction (AC) in technetium-99m myocardial perfusion imaging (MPI) have been well established. However, the value of thallium (Tl-201) AC and routine computed tomography AC (CTAC) were less well established. The aims of this study were to evaluate the diagnostic performance of thallium (Tl-201) MPI with additional CTAC and to determine which participants would benefit most. METHODS AND RESULTS: A total of 108 consecutive patients who underwent Tl-201 MPI and received coronary angiography within 3 months were enrolled. Diagnostic performance was determined by sensitivity, specificity, and receiver operating characteristic curve analysis. Subgroup analyses were performed using gender and obesity. CTAC improved the area under the curve (0.84 vs. 0.77, P = 0.037 at patient level), primarily due to a significant improvement in specificity (0.78 vs. 0.57, P = 0.013) and no significant difference in sensitivity (0.79 vs. 0.82, P = 0.75). In subgroup analysis, CTAC was most helpful in obese subjects, men, and especially right coronary artery lesions. CONCLUSIONS: CTAC significantly improved diagnostic performance primarily by increasing the specificity, and the improvements were significantly greater in obese patients and male patients. These findings suggest that CTAC should be applied to Tl-201 MPI as routine clinical practice. PMID- 29484544 TI - Response to "Limited capacity to retain phosphorus in the Baltic proper offshore sediments" by Karlsson and Malmaeus. PMID- 29484545 TI - Biochemical Properties of alpha-Amylase from Midgut of Alphitobius diaperinus (Panzer) (Coleoptera: Tenebrionidae) Larvae. AB - The lesser mealworm, Alphitobius diaperinus (Panzer), is the main insect pest in the poultry industry, thus causing serious damage to production. In this work, the properties of midgut alpha-amylase from larvae of A. diaperinus were characterized, and its in vitro activity to proteinaceous preparations from different cultivars of common bean (Phaseolus vulgaris) was determined, as well as the amylolitic activity of insects reared on different types of poultry diet. In order to establish some assay conditions, time course and enzyme concentration upon the reaction rate were determined. Product proceeded linearly with time, and the activity was directly proportional to the enzyme concentration. Banding patterns in mildly denaturing electrophoresis showed a single band with apparent molecular weight of 42 kDa. alpha-Amylase reached optimal temperature at 45 degrees C and pH 5.0 as the optimal one. It maintained 34.6% of the activity after being kept at 60 degrees C for 5 min, and 23%, after 60 min. However, at 80 degrees C, only 14 and 6% remained after 5 and 60 min, respectively. The presence of Ca2+ and Na+ ions decreased the enzyme activity at concentrations higher than 2 and 100 mM, respectively. The activity was significantly inhibited by some proteinaceous extracts from common bean cultivars, and it declined with increasing proteinaceous concentration. No significant difference was observed when the amylolytic activity was determined in A. diaperinus reared on different poultry diets, offered to broilers in the starter, grower, finisher, and layer phases. PMID- 29484546 TI - A randomized triple-blind crossover trial of a hydrocolloid-containing dentifrice as a controlled-release system for fluoride. AB - OBJECTIVE: To evaluate retention of intraoral fluoride in biofilm and saliva, an experimental dentifrice containing hydrocolloid (tara gum) was used as a controlled-release system for fluoride (F). MATERIALS AND METHODS: In a triple blind randomized crossover trial with washout, 18 individuals used the following different dentifrices for a week: 100-TGF (sodium fluoride NaF associated with tara gum, 1100 mg/L), 50-TGF (50% NaF associated with tara gum + 50% free NaF, 1100 mg/L), PC (free NaF, 1100 mg/L), TG (with tara gum and without F), and placebo (without F or tara gum). On the seventh day of dentifrice use, biofilm was collected at 1 and 12 h, and saliva was collected up to 60 min and 12 h after the last toothbrushing. F concentrations were determined by physico-chemical analysis of fluoride using the hexamethyldisiloxane-facilitated diffusion technique. Data were subjected to two-way analysis of variance (repeated measures) and Spearman's correlation coefficient (p < 0.05) testing. RESULTS: No significant difference was observed with the same dentifrice regarding F retention in biofilm at 1 and 12 h after toothbrushing for the 100-TGF, placebo, and TG groups (p > 0.05). The highest area under the curve values in saliva were found for the 50-TGF, 100-TGF, and PC groups. CONCLUSION: The dentifrice containing hydrocolloid as a controlled-release system for F promoted F retention in the oral cavity, even at 12 h after brushing. CLINICAL RELEVANCE: Hydrocolloid added to dentifrices as a controlled-release system for F might contribute to a higher anti-caries effect. TRIAL REGISTRATION: NCT02809014. PMID- 29484547 TI - Adaptation to new complete dentures-is the neuromuscular system outcome-oriented or effort-oriented? AB - OBJECTIVE: The aim of this study was to observe the adaptation strategy of the stomatognathic system during the adaptation of complete dentures, comprising masticatory parameters and subjective measures. Our hypothesis was that with new dentures, masticatory performance would increase while the effort of the system is kept constant. MATERIAL AND METHODS: Thirty-two patients received standardized new complete dentures. Masticatory performance tests were conducted with old dentures (T1), immediately after incorporation of new dentures (T2) and after an adaptation period of 3 months (T3). Patients habitually chewed the silicone-based artificial test food Optocal. The comminuted test food was analyzed and mean particle sizes (x50) were calculated. Simultaneously, surface EMGs of the anterior temporalis and masseter muscles were recorded. Specific (SMW) and total muscle work (TMW) were determined. Patients filled in the OHIP-49 questionnaire. Test conditions were compared using repeated-measures ANOVA with SPSS 22 (SPSS Inc.) RESULTS: Masticatory performance increased (P = 0.016) between old (x50 = 4.99 +/- 0.28) and adapted new dentures (x50 = 4.80 +/- 0.33). TMW deteriorated (P = 0.004) at T2 (from TMW1 = 119.77 +/- 56.49 to TMW2 = 92.12 46.27), and increased again (P = 0.028) at T3 (TMW3 = 107.66 +/- 44.65). OHIP scores decreased significantly in all subscales (P < 0.001...P = 0.046); the total score was reduced (P < 0.001) from 56.24 +/- 29.05 (T1) to 34.66 +/- 24.74 (T3). CONCLUSION: In complete denture wearers, masticatory performance improves over an adaptation period. Muscle work initially decreased before reaching its original level again after adaptation. Subjective parameters overestimated the functional improvements. CLINICAL SIGNIFICANCE: The subjective evaluation does not adequately reflect functional improvements. The assessment of function requires an adaptation period. PMID- 29484548 TI - Inflammatory serum markers up to 5 years after comprehensive periodontal therapy of aggressive and chronic periodontitis. AB - AIM: The aim of the study is to assess the long-term effect of active periodontal therapy on serum inflammatory parameters in patients with aggressive (AgP) and chronic (ChP) periodontitis in a non-randomised clinical study. METHODS: Twenty five ChP and 17 AgP were examined clinically prior to (baseline), 12 weeks and 60 months after subgingival debridement of all pockets within 2 days. Systemic antibiotics were prescribed if Aggregatibacter actinomycetemcomitans was detected (10 AgP, 8 ChP), flap surgery was rendered if required. Neutrophil elastase (NE), C-reactive protein (CRP), lipopolysaccharide binding protein, interleukin 6, 8, and leukocyte counts were assessed at baseline, 12 weeks and 60 months. RESULTS: Clinical parameters improved significantly in both groups from 12 weeks to 60 months. Eleven AgP and 18 ChP patients received surgical treatment after the 12 weeks examination. Only 3 patients in each group attended >= 2 supportive maintenance visits per year. NE and CRP were significantly higher in AgP than ChP at baseline and 60 months (p < 0.01). For leukocyte counts in ChP, significant changes were observed (baseline: 6.11 +/- 1.44 nl-1; 12 weeks: 5.34 +/- 1.40 nl 1; 60 months: 7.73 +/- 2.89 nl-1; p < 0.05). Multiple regression analysis identified African origin, surgical treatment and female sex to correlate with better clinical improvement. CONCLUSION: Despite comprehensive periodontal treatment, AgP patients exhibit higher NE and CRP levels than ChP patients up to 5 years after therapy. CLINICAL RELEVANCE: Systemic inflammatory burden in AgP patients is higher than in ChP patients even 5 years after periodontal treatment. PMID- 29484549 TI - Morphological and molecular identification of Sarcocystis spp. from the sika deer (Cervus nippon), including two new species Sarcocystis frondea and Sarcocystis nipponi. AB - Diaphragm muscles of 25 sika deer (Cervus nippon) farmed in Lithuania were examined for sarcocysts of Sarcocystis species. Two new Sarcocystis species, Sarcocystis frondea and Sarcocystis nipponi, were observed using light microscopy (LM) and transmission electron microscopy (TEM) and characterized by 18S ribosomal DNA (rDNA) and subunit I of cytochrome c oxidase (cox1) sequence analyses. By LM, sarcocysts of S. frondea and S. nipponi were ribbon-shaped and had finger-like sarcocyst wall protrusions, respectively. Under TEM, protrusions of S. frondea were about 9 * 1-1.5 MUm, filled with clearly visible electron dense substance and microtubules, type 39-like. Whereas, protrusions (about 9 * 0.2 MUm) of S. nipponi arose from dome-shaped bases were filled with microtubules extending to the ground substance layer, type 9o-like. Moreover, three known Sarcocystis spp., Sarcocystis entzerothi, Sarcocystis ovalis, and Sarcocystis truncata previously described in other cervids as intermediate hosts, were characterized in sika deer. The cox1 was more suitable than 18S rDNA delimitating closely related Sarcocystis species from cervids. The phylogenetic results suggest that scavenger birds could be definitive hosts of S. frondea. According to the summarized morphological data on Sarcocystis found in the sika deer, such host should harbor at least nine different Sarcocystis species. PMID- 29484550 TI - Genetic uniqueness of Cryptosporidium parvum from dairy calves in Colombia. AB - Fecal specimens from 432 pre-weaned calves younger than 35 days were collected over a 2-year period (2010-2012) from 74 dairy cattle farms in the central area of Colombia. These samples were microscopically examined for the presence of Cryptosporidium oocysts, and positive specimens were selected for molecular examination. Microscopy revealed that 115 calves (26.6%) from 44 farms (59.5%) tested positive. Oocyst shedding was recorded in calves aged 3-day-old onwards, although the infection rate peaked at 8-14 days (40.7%). Infection rates were higher in diarrheic (52.2%) than in non-diarrheic calves (19.9%) (p < 0.0001, chi2), and infected calves had up to seven times more probability of having diarrhea than non-infected calves. Cryptosporidium species and subtypes were successfully identified in 73 samples from 32 farms. Restriction and sequence analyses of the SSU rRNA gene revealed C. parvum in all but two isolates identified as Cryptosporidium bovis. Sequence analyses of the 60-KDa glycoprotein (gp60) gene revealed eight subtypes within the IIa family. An unusual subtype (IIaA18G5R1) was the most prevalent and widely distributed (more than 66% specimens and 68% farms) while the subtype most frequently reported in cattle worldwide (IIaA15G2R1) was found in less than 13% of specimens and 16% farms. The remaining subtypes (IIaA16G2R1, IIaA17G4R1, IIaA20G5R1, IIaA19G6R1, IIaA20G6R1, and IIaA20G7R1) were restricted to 1-3 farms. This is the first large-sample size study of Cryptosporidium species and subtypes in Colombia and demonstrates the genetic uniqueness of this protozoan in cattle farms in this geographical area. PMID- 29484551 TI - Teaching clinical reasoning through hypothetico-deduction is (slightly) better than self-explanation in tutorial groups: An experimental study. AB - BACKGROUND: Self-explanation while individually diagnosing clinical cases has proved to be an effective instructional approach for teaching clinical reasoning. The present study compared the effects on diagnostic performance of self explanation in small groups with the more commonly used hypothetico-deductive approach. METHODS: Second-year students from a six-year medical school in Saudi Arabia (39 males; 49 females) worked in small groups on seven clinical vignettes (four criterion cases representing cardiovascular diseases and three 'fillers', i.e. cases of other unrelated diagnoses). The students followed different approaches to work on each case depending on the experimental condition to which they had been randomly assigned. Under the self-explanation condition, students provided a diagnosis and a suitable pathophysiological explanation for the clinical findings whereas in the hypothetico-deduction condition students hypothesized about plausible diagnoses for signs and symptoms that were presented sequentially. One week later, all students diagnosed eight vignettes, four of which represented cardiovascular diseases. A mean diagnostic accuracy score (range: 0-1) was computed for the criterion cases. One-way ANOVA with experimental condition as between-subjects factor was performed on the mean diagnostic accuracy scores. RESULTS: Students in the hypothetico-deduction condition outperformed those in the self-explanation condition (mean = 0.22, standard deviation = 0.14, mean = 0.17; standard deviation = 0.12; F(1, 88) = 4.90, p = 0.03, partial eta2 = 0.06, respectively). CONCLUSIONS: Students in the hypothetico-deduction condition performed slightly better on a follow-up test involving similar cases, possibly because they were allowed to formulate more than one hypothesis per case during the learning phase. PMID- 29484552 TI - Self-efficacy beliefs of medical students: a critical review. AB - INTRODUCTION: Self-efficacy is a theoretically and empirically robust motivation belief that has been shown to play an important role in the learning and development of new skills and knowledge. In this article, we critically review research on the self-efficacy beliefs of medical students, with a goal to evaluate the existing research and to strengthen future work. In particular, we sought to describe the state of research on medical student self-efficacy and to critically examine the conceptualization and measurement of the construct. Finally, we aimed to provide directions for future self-efficacy research. METHODS: We critically reviewed 74 published articles that included measures of self-efficacy beliefs of medical students. RESULTS: Our review showed that (a) research on the self-efficacy beliefs of medical students is growing and is becoming increasingly international, and (b) that nearly half (46%) of self efficacy measures showed conceptual and operational flaws. DISCUSSION: Our critical review of 74 research studies on self-efficacy of medical students found that although research in the field is increasing, nearly half of measures labelled as self-efficacy were incongruent with the conceptual guidelines set by self-efficacy experts. We provide five suggestions for future research on the self-efficacy of medical students. PMID- 29484553 TI - Approaching the superior mesenteric artery from the right side using the proximal dorsal jejunal vein preisolation method during laparoscopic pancreaticoduodenectomy. AB - BACKGROUND: Although the artery-first approach is widely used in open pancreaticoduodenectomy, it is difficult to laparoscopically expose the origin of the inferior pancreaticoduodenal artery (IPDA) from the left side of the superior mesenteric artery (SMA). By contrast, damaging the inferior pancreaticoduodenal veins (IPDVs) is possible when approaching the IPDA from the right side of the SMA. To facilitate the artery-first approach in laparoscopic pancreaticoduodenectomy (LPD), we focused on the proximal-dorsal jejunal vein (PDJV) that branched from the superior mesenteric vein (SMV) dorsal side and drained the IPDVs. This study aimed to clarify the usefulness of the right SMA approach using the PDJV preisolation method. METHODS: The PDJV was first isolated, and the IPDVs were divided along the PDJV on the right side of the SMA. Then, the IPDA was divided at the root without first separating the pancreatic head from the portal vein and the SMV. Overall, 21 patients underwent this approach, and the results were retrospectively compared with those of 21 patients who underwent the artery-first approach, which was performed on the left side of the SMA. Anatomical characteristics of the PDJV were evaluated using multidetector computed tomography for the two groups. RESULTS: Operative times and resection times were significantly lower for the PDJV preisolation group than for the conventional LPD group (489.3 vs. 541.7 min, respectively; p = 0.002). During anatomical evaluation, 41 patients (97.6%) had a PDJV that drained from the SMV dorsally and was in contact with the anterior aspect of the uncinate process. The PDJV was confirmed as the first jejunal vein in 31 patients (73.8%) and as the second jejunal vein in 10 patients (23.8%). CONCLUSIONS: This approach facilitates dissection of the IPDA on the right side of the SMA, thereby reducing operative times. PMID- 29484554 TI - Diagnostic evaluation of sentinel lymph node biopsy using indocyanine green and infrared or fluorescent imaging in gastric cancer: a systematic review and meta analysis. AB - BACKGROUND: Sentinel node navigation surgery (SNNS) for gastric cancer using infrared visualization of indocyanine green (ICG) is intriguing because it may limit operative morbidity. We are the first to systematically review and perform meta-analysis on the diagnostic utility of ICG and infrared electronic endoscopy (IREE) or near infrared fluorescent imaging (NIFI) for SNNS exclusively in gastric cancer. METHODS: A search of electronic databases MEDLINE, EMBASE, SCOPUS, Web of Science, and the Cochrane Library using search terms "gastric/stomach" AND "tumor/carcinoma/cancer/neoplasm/adenocarcinoma/malignancy" AND "indocyanine green" was completed in May 2017. Articles were selected by two independent reviewers based on the following major inclusion criteria: (1) diagnostic accuracy study design; (2) indocyanine green was injected at tumor site; (3) IREE or NIFI was used for intraoperative visualization. 327 titles or abstracts were screened. The quality of included studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2. RESULTS: Ten full text studies were selected. 643 patients were identified with the majority of patients possessing T1 tumors (79.8%). Pooled identification rate, diagnostic odds ratio, sensitivity, and specificity were 0.99 (0.97-1.0), 380.0 (68.71-2101), 0.87 (0.80 0.93), and 1.00 (0.99-1.00), respectively. The summary receiver operator characteristic for ICG + IREE/NIFI demonstrated a test accuracy of 98.3%. Subgroup analysis found improved test performance for studies with low-risk QUADAS-2 scores, studies published after 2010 and submucosal ICG injection. IREE had improved diagnostic odds ratio, sensitivity, and identification rate compared to NIFI. Heterogeneity among studies ranged from low (I2 < 25%) to high (I2 > 75%). CONCLUSIONS: We found encouraging results regarding the accuracy, diagnostic odds ratio, and specificity of the test. The sensitivity was not optimal but may be improved by a strict protocol to augment the technique. Given the number and heterogeneity of studies, our results must be viewed with caution. PMID- 29484555 TI - Laparoscopic versus open surgery for the repair of congenital duodenal obstructions in infants and children. AB - BACKGROUND: Laparoscopic repair of congenital duodenal obstruction (LCDO) was described more than 15 years ago. However, studies comparing outcomes of LCDO with open repair (OCDO) are rare. Standardized assessments of complications using the Clavien-Dindo classification (CDC) and the comprehensive complication index (CCI) are not available. METHODS: All patients undergoing OCDO or LCDO between 2004 and 2017 were identified from the institutional database by retrospective analysis. Postoperative outcomes were assessed, including all complications using the CDC and the CCI. RESULTS: Forty-seven consecutive patients were identified; 27 patients underwent LCDO and 20 patients had OCDO. Both groups did not differ regarding demographics, associated congenital anomalies, intraoperative pathologic findings, and operative procedures. LCDO was associated with a longer operative time [mean (SD), 202 (89) vs. 112 (41) min, P < 0.0001], shorter time to initiation of feeds [median (range), 1 (0-4) vs. 3 (1-12) days, P = 0.0027], and shorter time to full feeds [mean (SD), 8.2 (4.1) vs. 12.2 (6.4) days, P = 0.0243] compared to OCDO. Shorter length of postoperative hospital stay in LCDO group was achieved for patients without cardiac anomalies [mean (SD), 9.4 (3.1) days in LCDO group vs. 17.2 (9.4) days in OCDO, P = 0.0396] and patients without other anomalies [median (range), 12 (3-38) days in LCDO group vs. 21 (7-31) days in OCDO, P = 0.0460]. LCDO was associated with a lower CCI [median (range) 0 (0 39.7) vs. 4.3 (0-100), P = 0.0270]. CONCLUSIONS: Despite a longer operative time for LCDO, a number of advantages of LCDO over OCDO were recognized comparing both approaches in the repair of congenital duodenal obstruction. Such advantages include a lower morbidity, reduced time to initiation and completion of full enteral feeds, and shorter length of postoperative hospitalization for patients without concomitant cardiac anomalies and for patients without other anomalies when operated laparoscopic. In view of the present results, LCDO, performed in selected patients, appears to represent a viable alternative to OCDO. PMID- 29484556 TI - Minimally invasive versus open surgery in the Medicare population: a comparison of post-operative and economic outcomes. AB - BACKGROUND: Despite strong evidence demonstrating the clinical and economic benefits of minimally invasive surgery (MIS), utilization of MIS in the Medicare population is highly variable and tends to be lower than in the general population. We sought to compare the post-operative and economic outcomes of MIS versus open surgery for seven common surgical procedures in the Medicare population. METHODS: Using the 2014 Medicare Provider Analysis and Review Inpatient Limited Data Set, patients undergoing bariatric, cholecystectomy, colectomy, hysterectomy, inguinal hernia, thoracic, and ventral hernia procedures were identified using DRG and ICD-9 codes. Adjusting for patient demographics and comorbidities, the odds of complication and all-cause 30-day re-admission were compared among patients undergoing MIS versus open surgery stratified by operation type. A generalized linear model was used to calculate the estimated difference in length of stay (LOS), Medicare claim cost, and Medicare reimbursement. RESULTS: Among 233,984 patients, 102,729 patients underwent an open procedure versus 131,255 who underwent an MIS procedure. The incidence of complication after MIS was lower for 5 out of the 7 procedures examined (OR 0.36 0.69). Re-admission was lower for MIS for 6 out of 7 procedures (OR 0.43-0.87). MIS was associated with shorter LOS for 6 procedures (point estimate range 0.35 2.47 days shorter). Medicare claim costs for MIS were lower for 4 (range $3010.23 $4832.74 less per procedure) and Medicare reimbursements were lower for 3 (range $841.10-$939.69 less per procedure). CONCLUSIONS: MIS benefited Medicare patients undergoing a range of surgical procedures. MIS was associated with fewer complications and re-admissions as well as shorter LOS and lower Medicare costs and reimbursements versus open surgery. MIS may represent a better quality and cost proposition in the Medicare population. PMID- 29484557 TI - Transthoracic echocardiography in patients undergoing mitral valve repair: comparison of new transthoracic 3D techniques to 2D transoesophageal echocardiography in the localization of mitral valve prolapse. AB - Successful mitral valve (MV) repair for degenerative mitral regurgitation (DMR) is mainly related to surgical expertise and MV anatomy. Although 2D echocardiography, specifically transoesophageal (TOE), provides precise information regarding MV anatomy, recent advancements in matrix technology meant a decisive step forward to the point where segmental MV analysis can be accurately performed from a noninvasive 3D transthoracic (TTE) approach. The aims of this study were: (a) to evaluate the feasibility and time required for real time 3D TTE in a large consecutive cohort of patients with severe DMR in the assessment of MV anatomy; (b) to compare the accuracy of 3D TTE and 2D TOE versus surgical inspection in the recognition and localization of all components of the MV leaflets; (c) to establish the added diagnostic value of 3D colourDoppler examination to pure 3D morphologic evaluation. 149 consecutive patients with severe DMR underwent complete 3D TTE before surgery and 2D TOE in the operating room. Echocardiographic data obtained by the different techniques were compared with surgical inspection. 3D TTE was feasible in a relatively short time (8 +/- 4 min), with good (49%) and optimal (33%) imaging quality in the majority of cases. 3D TTE had significant better overall accuracy compared to 2D TOE (93 and 91%, p < 0.05, respectively). 2D TOE was significantly more specific than 3D TTE in the identification of A3 prolapse (99 vs. 96%). The colourDoppler mode did not improve significantly the accuracy of 3D TTE, albeit it determined a better sensitivity in the detection of A2 prolapse if compared to 2D TOE (95 vs. 85%). 3D TTE with or without colourDoppler is a feasible and useful method in the analysis of MV prolapse; it allows a preoperative and noninvasive description of the pathology as accurate as the 2D TOE. PMID- 29484558 TI - Targeting Inflammatory Vasculature by Extracellular Vesicles. AB - Extracellular vesicles (EVs) are cell membrane-derived compartments that regulate physiology and pathology in the body. Naturally secreted EVs have been well studied in their biogenesis and have been exploited in targeted drug delivery. Due to the limitations on production of EVs, nitrogen cavitation has been utilized to efficiently generate EV-like drug delivery systems used in treating inflammatory disorders. In this short review, we will discuss the production and purification of EVs, and we will summarize what technologies are needed to improve their production for translation. We describe the drug-loading processes in EVs and their applications as drug delivery systems for inflammatory therapies, focusing on a new type of EVs made from neutrophil membrane using nitrogen cavitation. PMID- 29484559 TI - The effect of non-neovascular age-related macular degeneration on face recognition performance. AB - PURPOSE: There is a well-established research base surrounding face recognition in patients with age-related macular degeneration (AMD). However, much of this existing research does not differentiate between results obtained for 'wet' AMD and 'dry' AMD. Here, we test the hypothesis that face recognition performance is worse in patients with dry AMD compared with visually healthy peers. METHODS: Patients (>60 years of age, logMAR binocular visual acuity 0.7 or better) with dry AMD of varying severity and visually healthy age-related peers (controls) completed a modified version of the Cambridge Face Memory Test (CFMT). Percentage of correctly identified faces was used as an outcome measure for performance for each participant. A 90% normative reference limit was generated from the distribution of CFMT scores recorded in the visually healthy controls. Scores for AMD participants were then specifically compared to this limit, and comparisons between average scores in the AMD severity groups were investigated. RESULTS: Thirty patients (median [interquartile range] age of 76 [70, 79] years) and 34 controls (median age of 70 [64, 75] years) were examined. Four, seventeen and nine patients were classified as having early, intermediate and late AMD (geographic atrophy) respectively. Five (17%) patients recorded a face recognition performance worse than the 90% limit (Fisher's exact test, p = 0.46) set by controls; four of these had geographic atrophy. Patients with geographic atrophy identified fewer faces on average (+/-SD) (61% +/- 22%) than those with early and intermediate AMD (75 +/- 11%) and controls (74% +/- 11%). CONCLUSIONS: People with dry AMD may not suffer from problems with face recognition until the disease is in its later stages; those with late AMD (geographic atrophy) are likely to have difficulty recognising faces. The results from this study should influence the management and expectations of patients with dry AMD in both community practice and hospital clinics. PMID- 29484560 TI - The effects of 3% diquafosol sodium eye drop application on meibomian gland and ocular surface alterations in the Cu, Zn-superoxide dismutase-1 (Sod1) knockout mice. AB - PURPOSE: The purpose of the study is to investigate the effect of 3% diquafosol sodium eye drops on meibomian gland and ocular surface alterations in the superoxide dismutase-1 (Sod1 -/- ) mice in comparison to the wild-type mouse. METHODS: Three percent diquafosol sodium eye drop was instilled to 20 eyes of 10 50-week-old male Sod1 -/- mice and 22 eyes of 11 C57BL/6 strain 50-week-old wild type (WT) male mice six times a day for 2 weeks. Aqueous tear secretion quantity was measured with phenol red-impregnated cotton threads without anesthesia. Tear film stability and corneal epithelial damage were assessed by fluorescein and lissamine green staining. We also performed oil red O (ORO) lipid staining to evaluate the lipid changes in the meibomian glands. Meibomian gland specimens underwent hematoxylin and eosin staining to examine histopathological changes and meibomian gland acinar unit density after sacrifice. Immunohistochemistry staining was performed using cytokeratin 4, cytokeratin 13, and transglutaminase 1 antibodies. Quantitative real-time polymerase chain reaction for cytokeratin 4, cytokeratin 13, and transglutaminase-1 mRNA expression was also performed. RESULTS: The aqueous tear quantity, the mean tear film breakup time, and the number of lipid droplets significantly improved in the Sod1 -/- mice with treatment. The mean meibomian acinar unit density did not change in the Sod1 -/- mice and WT mice after treatment. Application of 3% diquafosol sodium eye drop significantly decreased the corneal fluorescein and lissamine green staining scores in the Sod1 -/- mice after 2 weeks. We showed a notable increase in cytokeratin 4, cytokeratin 13 immunohistochemistry staining, and cytokeratin 4, cytokeratin 13 mRNA expressions with a marked decrease in immunohistochemistry staining and significant decline in mRNA expression of transglutaminase-1 after 3% diquafosol sodium treatment. CONCLUSION: Topical application of 3% diquafosol sodium eye drop improved the number of lipid droplets, tear stability, and tear production which in turn appeared to have a favorable effect on the ocular surface epithelium. Three percent diquafosol sodium eye drop may be a potential treatment for age-related meibomian gland and dry eye disease based on the observations of the current study. PMID- 29484562 TI - Concurrent Versus Sequential Chemoradiation Therapy in Completely Resected Pathologic N2 Non-Small Cell Lung Cancer: Propensity-Matched Analysis of the National Cancer Data Base. AB - BACKGROUND: Following complete resection of pN2 non-small cell lung cancer (NSCLC), national guidelines recommend either sequential (sCRT) or concurrent chemoradiotherapy (cCRT). This is the largest study to date evaluating survival between both approaches. In sCRT patients, sequencing 'chemotherapy first' versus 'radiotherapy first' was also addressed. METHODS: The National Cancer Data Base (NCDB) was queried for patients with primary NSCLC undergoing surgery (without neoadjuvant radiotherapy or chemotherapy), pN2 disease with negative surgical margins, and receiving postoperative CRT. Multivariable logistic regression ascertained factors associated with cCRT administration. Kaplan-Meier analysis evaluated overall survival (OS), and Cox proportional hazards modeling determined variables associated with OS. Propensity matching was performed to address group imbalances and indication biases. RESULTS: Of 1924 total patients, 1115 (58%) received sCRT and 809 (42%) underwent cCRT. Median OS in the sCRT and cCRT cohorts was 53 months versus 37 months (p < 0.001); differences persisted following propensity matching (p = 0.002). In the sCRT population, there was a trend for higher OS in the 'chemotherapy first' group, relative to 'radiotherapy first' (55 vs. 44 months, p = 0.079), but there were no statistically apparent differences following propensity matching (p = 0.302). CONCLUSIONS: For completely resected pN2 NSCLC, delivering adjuvant sCRT was associated with improved survival over cCRT. Toxicity-related factors may help to explain these results but need to be better addressed in further investigations. Differential sequencing of sCRT did not appear to affect survival. PMID- 29484561 TI - Bactibilia in diseases of the biliary tract and pancreatic gland in patients older than 80 years: a STROBE-retrospective cohort study in a teaching hospital in Italy. AB - Bile is a lipid-rich sterile solution produced in the liver that can be infected resulting in bactibilia. A higher incidence of postoperative infectious complications has been seen in patients with bactibilia. Recently, gram-negative bacteria have been linked to a tumor-associated inflammatory status. This study is a retrospective cohort study of 39 patients, who are over 80 years of age only (53.85% males and 46.15% females), hospitalized with diseases of the biliopancreatic system in one teaching hospital in Italy from January 2011 to December 2012 with a follow-up of 5 years. The most common biliary diseases after surgery were pancreatic head cancer (p < 0.0001) and gallbladder cancer (p = 0.0051), while the most common bacteria in the bile were E. coli (p = 0.0180) and Pseudomonas spp. (p < 0.0001). Uni- and multivariate linear correlation analysis revealed that patients with pancreatic head cancer had low survival times compared to patients with other diseases. Moreover, the bacterium type was a positive predictor of survival time compared to other variables. Our data confirm E. coli as a pathogen in patients with gallbladder and pancreatic cancer. Although the influence of bactibilia in developing surgical complications is limited, we consider that its composition is crucial to properly address the antibiotic treatment in biliary tract infections, especially in the elderly. PMID- 29484563 TI - 4D-CT is Superior to Ultrasound and Sestamibi for Localizing Recurrent Parathyroid Disease. AB - BACKGROUND: Recurrent primary hyperparathyroidism (PHPT) presents a diagnostic challenge in localizing a hyperfunctioning gland. Although several imaging modalities are available for preoperative localization, 4D-CT is increasingly utilized for its ability to locate both smaller and previously unlocalized lesions. Currently, there is a paucity of data evaluating the utility of 4D-CT in the reoperative setting compared with ultrasound (US) and sestamibi. We aimed to determine the sensitivity of 4D-CT in localizing parathyroid adenomas in recurrent or persistent PHPT. METHODS: We performed a retrospective review of prospectively collected data from a tertiary-care hospital, and identified 58 patients who received preoperative 4D-CT with US and/or sestamibi between May 2008 and March 2016. Data regarding the size, shape, and number of parathyroid lesions were collected for each patient. RESULTS: A total of 62 lesions were identified intraoperatively among the 58 patients (6 with multigland disease) included in this investigation. 4D-CT missed 13 lesions identified intraoperatively, compared with 32 and 22 lesions missed by US and sestamibi, respectively. Sensitivity for correct lateralization of culprit lesions was 77.4% for 4D-CT, 38.5% for US, and 46% for sestamibi. 4D-CT was superior in lateralizing adenomas (49/62) compared with US (20/52; p < 0.001) and sestamibi (18/47; p < 0.001). The overall cure rate (6-month postoperative calcium < 10.7 mg/dL) was 89.7%. All patients with lesions correctly lateralized by 4D-CT were cured at 6 months. CONCLUSION: 4D-CT localized parathyroid adenomas with higher sensitivity among patients with recurrent or persistent PHPT compared with sestamibi or US-based imaging. PMID- 29484564 TI - Single-Axillary-Incision Endoscopic-Assisted Hybrid Technique for Nipple-Sparing Mastectomy: Technique, Preliminary Results, and Patient-Reported Cosmetic Outcome from Preliminary 50 Procedures. AB - BACKGROUND: A new hybrid technique for single-axillary-incision endoscopic assisted nipple-sparing mastectomy (E-NSM) was introduced. Preliminary results are reported. METHODS: Patients who received single-axillary-incision E-NSM from August 2013 to August 2017 were searched from a single institution. Data were analyzed to determine the effectiveness and oncologic safety of single-axillary incision E-NSM. Patient-oriented cosmetic outcome report was also obtained. RESULTS: During the study period, a total of 50 E-NSM with single-incision procedures were performed in 41 female patients with breast cancer, including 11 (26.8%) patients with bilateral disease. Their mean age was 45.3 +/- 8.4 years. The mean size of tumors encountered during the 50 single-incision E-NSM procedures was 2.3 +/- 1.8 (0.1-7.3) cm for invasive tumors and 2.6 +/- 1.7 (0.2 5.7) cm for carcinoma in situ lesions. Six (12%) of those tumors were multifocal/multicentric. Lymph node metastasis was found during 12% of the procedures. Forty-five (90%) received immediate breast reconstruction with gel implant. Mean operating time was 244.3 +/- 82.8 min. The overall complication rate was 6%, and no total nipple necrosis or implant loss was observed. No locoregional recurrence or distant metastasis was found during mean follow-up of 21.6 months. About 94.4% of patients were satisfied with the postoperative scar location and wound length. All patients who responded would choose the same operation again. CONCLUSIONS: The proposed single-axillary-incision endoscopic hybrid technique for nipple-sparing mastectomy was a safe procedure with low morbidity and associated with high patient satisfaction. PMID- 29484566 TI - Ablation of idiopathic ventricular arrhythmias. PMID- 29484565 TI - Cytoreductive Surgery Plus Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Metastases From a Small Bowel Adenocarcinoma: Multi-Institutional Experience. AB - BACKGROUND: The multi-institutional registry in this study evaluated the outcome after cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with peritoneal metastases (PM) from small bowel adenocarcinoma (SBA). METHODS: A multi-institutional data registry including 152 patients with PM from SBA was established. The primary end point was overall survival (OS) after CRS plus HIPEC. RESULTS: Between 1989 and 2016, 152 patients from 21 institutions received a treatment of CRS plus HIPEC. The median follow-up period was 20 months (range 1-100 months). Of the 152 patients, 70 (46.1%) were women with a median age of 54 years. The median peritoneal cancer index (PCI) was 10 (mean 12; range 1-33). Completeness of cytoreduction (CCR) 0 or 1 was achieved for 134 patients (88.2%). After CRS and HIPEC, the median OS was 32 months (range 1-100 months), with survival rates of 83.2% at 1 year, 46.4% at 3 years, and 30.8% at 5 years. The median disease-free survival after CCR 0/1 was 14 months (range 1-100 months). The treatment-related mortality rate was 2%, and 29 patients (19.1%) experienced grades 3 or 4 operative complications. The period between detection of PM and CRS plus HIPEC was 6 months or less (P = 0.008), and multivariate analysis identified absence of lymph node metastasis (P = 0.037), well-differentiated tumor (P = 0.028), and PCI of 15 or lower (P = 0.003) as independently associated with improved OS. CONCLUSION: The combined treatment strategy of CRS plus HIPEC achieved prolonged survival for selected patients who had PM from SBA with acceptable morbidity and mortality. PMID- 29484567 TI - Development of 3D printed fibrillar collagen scaffold for tissue engineering. AB - Collagen is widely used in tissue engineering because it can be extracted in large quantities, and has excellent biocompatibility, good biodegradability, and weak antigenicity. In the present study, we isolated printable collagen from bovine Achilles tendon and examined the purity of the isolated collagen using sodium dodecyl sulfate polyacrylamide gel electrophoresis. The bands obtained corresponded to alpha1, alpha2 and beta chains with little contamination from other small proteins. Furthermore, rheological measurements of collagen dispersions (60 mg per ml of PBS) at pH 7 revealed values of viscosity of 35.62 +/- 1.42 Pa s at shear rate of 10 s - 1 and a shear thinning behavior. Collagen gels and solutions can be used for building scaffolds by three-dimensional (3D) printing. After designing and fabricating a low-cost 3D printer we assayed the collagen printing and obtaining 3D printed scaffolds of collagen at pH 7. The porosity of the scaffold was 90.22% +/- 0.88% and the swelling ratio was 1437% +/ 146%. The microstructure of the scaffolds was studied using scanning electron microscopy, and a porous mesh of fibrillar collagen was observed. In addition, the 3D printed collagen scaffold was not cytotoxic with cell viability higher than 70% using Vero and NIH 3 T3 cells. In vitro evaluation using both cells lines demonstrated that the collagen scaffolds had the ability to support cell attachment and proliferation. Also a fibrillar collagen mesh was observed after two weeks of culture at 37 degrees C. Overall, these results are promising since they show the capability of the presented protocol to obtain printable fibrillar collagen at pH 7 and the potential of the printing technique for building low cost biocompatible 3D plotted structures which maintained the fibrillar collagen structure after incubation in culture media without using additional strategies as crosslinking. PMID- 29484568 TI - Usefulness of Bisacodyl Testing on Therapeutic Outcomes in Refractory Constipation. AB - BACKGROUND: Although chronically constipated patients usually respond to medical treatment, there is a subgroup with scarce/no response, generally labeled as refractory or intractable. However, whether this lack of response is real or due to ancillary causes (suboptimal dosage, lack of compliance etc.) is unknown. AIMS: To see whether a pharmacologic test (bisacodyl colonic intraluminal infusion during manometric assessment) may predict the therapeutic outcome. METHODS: Data of patients undergoing 24/h colonic manometry for severe intractable constipation in whom the bisacodyl test (10 ml of drug dissolved into saline and injected through the more proximal recording port) had been carried out were retrieved and analysed, and correlations with the therapeutic outcome made. RESULTS: Overall, charts from 38 patients (5 men) were available; of these, only 21% displayed naive high-amplitude propagated contractions (average, less than 2/24 h), mostly meal-induced, during the recordings. A bisacodyl response was present in 31.6% patients, with a mean number of events of 1.8 per patient. After bisacodyl testing, 47.3% patients underwent intensive medical treatment, 44.7% surgery (medical failures), and 8% transanal irrigation, a procedure employed to treat refractory patients. The presence of naive propulsive contractions significantly correlated with the response to bisacodyl infusion (p < 0.0001), and with a favourable outcome to intensive medical treatment (p < 0.0001). CONCLUSIONS: The bisacodyl test may be clinically useful to better categorize constipated patients erroneously labelled as intractable and to exclude true colonic inertia, thus avoiding surgery in more than 30% of these subjects. PMID- 29484569 TI - Profiles: Benjamin Lebwohl, MD, MS. PMID- 29484570 TI - Non-evidence-Based Medicine: The Gastroenterologist's Role and Responsibility. PMID- 29484571 TI - Effects of Vedolizumab Therapy on Extraintestinal Manifestations in Inflammatory Bowel Disease. AB - BACKGROUND: Approximately 15-20% of ulcerative colitis patients and 20-40% of those with Crohn's disease experience extraintestinal manifestations (EIMs) of their inflammatory bowel disease (IBD). Clinicians who treat IBD must manage EIMs affecting multiple organs that variably correlate with intestinal disease activity. Vedolizumab is a monoclonal antibody for the treatment of IBD with a gut-selective mechanism of action. AIMS: This report evaluates whether vedolizumab is an effective treatment of EIMs, given its gut-specific mechanism of action. METHODS: We report 8 case studies of patients with various EIMs, including pyoderma gangrenosum, peripheral arthralgia/arthritis, axial arthropathies, erythema nodosum, and uveitis, who received vedolizumab therapy. RESULTS: Vedolizumab therapy was effective for pyoderma gangrenosum in ulcerative colitis, uveitis, erythema nodosum, polyarticular arthropathy, and ankylosing spondylitis/sacroiliitis but did not provide sustained benefit for the treatment of pyoderma gangrenosum in a patient with Crohn's disease. CONCLUSIONS: These cases demonstrate the potential of vedolizumab as a treatment of EIMs in patients with IBD. PMID- 29484572 TI - Low-Dose Sofosbuvir Is Safe and Effective in Treating Chronic Hepatitis C in Patients with Severe Renal Impairment or End-Stage Renal Disease. AB - BACKGROUND AND AIMS: There is sparse data on the use of Sofosbuvir based directly acting antiviral (DAA) drug regimens in chronic hepatitis C (CHC) patients with chronic kidney disease (CKD) with estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m2. We evaluated the safety and efficacy of low-dose Sofosbuvir plus full-dose Daclatasvir in CHC patients with CKD. METHODS: Sixty five CHC patients with CKD with eGFR less than 30 mL/min/1.73 m2 [54 (83%) patients with ESRD on hemodialysis] were included. All patients irrespective of genotype were treated with half-dose Sofosbuvir [200 mg (half tablet of 400 mg)] plus full-dose Daclatasvir (60 mg) given daily for either 12 or 24 weeks given in patients with genotype 3 cirrhosis. The efficacy was assessed by the sustained virological response (SVR12) with negative HCV RNA 12 weeks after the end of treatment (ETR). RESULTS: The median HCV RNA level in 65 patients (Males 40, mean age 42.9 +/- 13 years) was 1.65 * 106 (1.2 * 103-1.73 * 108) IU/mL with 42 (64.6%) patients having HCV genotype 1, followed by genotype 3 and 2 in 22 (34%) and 1 (1.4%) patients, respectively. Twenty-one (32%) patients had evidence of cirrhosis, and ten (15.4%) patients were treatment experienced. Sixty-four (98.5%) patients achieved ETR, and 65 (100%) patients attained SVR12. All patients tolerated the DAAs well with none of the patients reporting any serious adverse events. Minor side effects noted were nausea seen in five (7.7%) patients, insomnia and headache in four (6.2%) patients each, and pruritus in one (1.5%) patient. CONCLUSION: Low-dose Sofosbuvir and full-dose Daclatasvir are safe and effective in treating CHC in patients with CKD with eGFR less than 30 mL/min/1.73 m2. PMID- 29484574 TI - Capsule Commentary on Burke et al., Evaluating the Quality of Patient Decision making Regarding Post-acute Care. PMID- 29484573 TI - Genetic and Structural Analysis of a SKIV2L Mutation Causing Tricho-hepato enteric Syndrome. AB - BACKGROUND: Advances in genomics have facilitated the discovery of monogenic disorders in patients with unique gastro-intestinal phenotypes. Syndromic diarrhea, also called tricho-hepato-enteric (THE) syndrome, results from deleterious mutations in SKIV2L or TTC37 genes. The main features of this disorder are intractable diarrhea, abnormal hair, facial dysmorphism, immunodeficiency and liver disease. AIM: To report on a patient with THE syndrome and present the genetic analysis that facilitated diagnosis. METHODS: Whole-exome sequencing (WES) was performed in a 4-month-old female with history of congenital diarrhea and severe failure to thrive but without hair anomalies or dysmorphism. Since the parents were first-degree cousins, the analysis focused on an autosomal recessive model. Sanger sequencing was used to validate suspected variants. Mutated protein structure was modeled to assess the effect of the mutation on protein function. RESULTS: We identified an autosomal recessive C.1891G > A missense mutation (NM_006929) in SKIV2L gene that was previously described only in a compound heterozygous state as causing THE syndrome. The mutation was determined to be deleterious in multiple prediction models. Protein modeling suggested that the mutation has the potential to cause structural destabilization of SKIV2L, either through conformational changes, interference with the protein's packing, or changes at the protein's interface. CONCLUSIONS: THE syndrome can present with a broad range of clinical features in the neonatal period. WES is an important diagnostic tool in patients with congenital diarrhea and can facilitate diagnosis of various diseases presenting with atypical features. PMID- 29484575 TI - Direct-to-Consumer Broadcast Advertisements for Pharmaceuticals: Off-Label Promotion and Adherence to FDA Guidelines. AB - BACKGROUND: Direct-to-consumer (DTC) advertisements for prescription drugs in the United States are regulated by the Food and Drug Administration (FDA). Off-label promotion, or the advertisement of a drug for an indication not approved by the FDA, is prohibited. Our objective was to examine the presence of off-label promotion in broadcast DTC ads and to assess their adherence to FDA guidelines mandating fair balance in presentation of risks and benefits and prohibiting misleading advertisement claims. METHODS: All English-language broadcast DTC ads for prescription drugs that aired in the United States from January 2015 to July 2016 were obtained from AdPharm, an online collection of healthcare advertisements. Ad length was measured and adherence to FDA guidelines was assessed for several categories: key regulatory items, indicators of false or misleading ads, and indicators of fair balance in presentation of risks and benefits. RESULTS: Our sample included 97 unique DTC ads, representing 60 unique drugs and 67 unique drug-indication combinations. No ads described drug risks quantitatively, whereas drug efficacy was presented quantitatively in 25 (26%) ads. Thirteen (13%) ads, all for diabetes medications, suggested off-label uses for weight loss and blood pressure reduction. The most commonly advertised drugs were indicated for the treatment of inflammatory conditions (n = 12; 18%), diabetes or diabetic neuropathy (n = 11; 16%), bowel or bladder dysfunction (n = 6; 9%), and infections or allergic reaction (n = 6; 9%). More than three-quarters (n = 51; 76%) advertised drugs to treat chronic conditions. CONCLUSIONS: Few broadcast DTC ads were fully compliant with FDA guidelines. The overall quality of information provided in ads was low, and suggestions of off-label promotion were common for diabetes medications. The impact of current DTC ads and off-label marketing on patient and prescriber decisions merits further scrutiny. PMID- 29484576 TI - A Subjective Assessment of the Prevalence and Factors Associated with Poor Sleep Quality Amongst Elite Japanese Athletes. AB - BACKGROUND: The amount, quality, and timing of sleep are considered important for athletes' ability to train, maximize training responses, and recover. However, some research has shown that elite athletes do not obtain sufficient sleep. Based on this background, researchers recently started to assess and manage sleep in elite athletes. The purpose of this study was to clarify the prevalence of poor sleep quality and its associated factors amongst elite Japanese athletes. METHODS: Eight hundred and ninety-one candidates for the 17th Asian Games Incheon 2014, who were over 20 years old, participated in this study. They completed a questionnaire that included the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale, two-question case-finding instruments, and a checklist for sleep hygiene. Data from 817 of the 891 athletes (91.7%) with no missing values were analyzed. RESULTS: The mean time in bed was 7 h and 29 min. Two hundred and twenty-nine (28.0%) athletes showed a PSQI global score above the clinical criteria. A multiple logistic analysis revealed that sleep quality was significantly associated with five factors: "time in bed," "eating breakfast every morning," "avoiding the use of electronic devices (PC, smartphone, etc.) just before bedtime," "depressive mood", and "not thinking about troubles while in bed." Forty percent of athletes reported they had been informed by someone about "snoring loudly" and/or "leg twitching or jerking during sleep." CONCLUSIONS: The results of this study demonstrate that 28% of the athletes showed the PSQI score above the cutoff for poor sleep quality (> 5.5), which suggests that there may be a high prevalence of poor sleep quality in this population of athletes. To improve athletes' sleep, the five factors associated with sleep quality should be emphasized in athletes' sleep education. Furthermore, in medical evaluations of athletes, it may be desirable to include screening for sleep disorders. PMID- 29484577 TI - Evaluation of Diversity Based on Morphological Variabilities and ISSR Molecular Markers in Iranian Cynodon dactylon (L.) Pers. Accessions to Select and Introduce Cold-Tolerant Genotypes. AB - The main goals of the present study were to screen Iranian common bermudagrasses to find cold-tolerant accessions and evaluate their genetic and morphological variabilities. In this study, 49 accessions were collected from 18 provinces of Iran. One foreign cultivar of common bermudagrass was used as control. Morphological variation was evaluated based on 14 morphological traits to give information about taxonomic position of Iranian common bermudagrass. Data from morphological traits were evaluated to categorize all accessions as either cold sensitive or tolerant using hierarchical clustering with Ward's method in SPSS software. Inter-Simple Sequence Repeat (ISSR) primers were employed to evaluate genetic variability of accessions. The results of our taxonomic investigation support the existence of two varieties of Cynodon dactylon in Iran: var. dactylon (hairless plant) and var. villosous (plant with hairs at leaf underside and/or upper side surfaces or exterior surfaces of sheath). All 15 primers amplified and gave clear and highly reproducible DNA fragments. In total, 152 fragments were produced, of which 144 (94.73%) being polymorphic. The polymorphic information content (PIC) values ranged from 0.700 to 0.928. The average PIC value obtained with 15 ISSR primers was 0.800, which shows that all primers were informative. Probability identity (PI) and discriminating power between all primers ranged from 0.029 to 0.185 and 0.815 to 0.971, respectively. Genetic data were converted into a binary data matrix. NTSYS software was used for data analysis. Clustering was done by the unweighted pair-group method with arithmetic averages and principle coordinate analysis, separated the accessions into six main clusters. According to both morphological and genetic diversity investigations of accessions, they can be clustered into three groups: cold sensitive, cold semi tolerant, and cold tolerant. The most cold-tolerant accessions were: Taft, Malayear, Gorgan, Safashahr, Naein, Aligoudarz, and the foreign cultivar. This study may provide useful information for further breeding programs on common bermudagrass. Selected genotypes can be evaluated for other abiotic stresses such as drought and salinity. PMID- 29484578 TI - Value-Based Care in Hematopoietic Cell Transplantation and Cellular Therapy: Challenges and Opportunities. AB - PURPOSE OF REVIEW: Improved tolerability and outcomes after hematopoietic cell transplantation (HCT), along with the availability of alternative donors, have expanded its use. With this growth, and the development of additional cellular therapies, we also aim to increase effectiveness, efficiency, and the quality of the care provided. Fundamentally, the goal of value-based care is to have better health outcomes with streamlined processes, improved patient experience, and lower costs for both the patients and the health care system. HCT and cellular therapy treatments are multiphase treatments which allow for interventions at each juncture. RECENT FINDINGS: We present a summary of the current literature with focus on program structure and overall system capacity, coordination of therapy across providers, standardization across institutions, diversity and disparities in care, patient quality of life, and cost implications. Each of these topics provides challenges and opportunities to improve value-based care for HCT and cellular therapy patients. PMID- 29484580 TI - Five-year clinical outcomes of everolimus-eluting stents from the post marketing study of CoCr-EES (XIENCE V/PROMUS) in Japan. AB - : The Cobalt Chromium Everolimus-Eluting Stent (CoCr-EES) Post Marketing Surveillance (PMS) Japan study is a prospective multicenter registry designed to evaluate the safety and efficacy of XIENCE V/PROMUS everolimus-eluting stents in routine clinical practice at 47 centers representative of the clinical environment in Japan. We enrolled 2010 consecutive patients (2649 lesions) who underwent percutaneous coronary intervention using CoCr-EES. Clinical outcomes were evaluated through 5 years. Mean age was 68.8 years, 41.9% had diabetes, 4.9% received hemodialysis. Five-year clinical follow up was available for 1704 (84.8%) patients. Major adverse cardiovascular events (MACE) occurred in 10.7% of patients, including cardiac death (3.8%), myocardial infarction (1.8%), and clinically driven target lesion revascularization (TLR) (6.0%). Beyond 1 year, annual incidence of clinically driven TLR was 0.5-0.8%. Definite or probable stent thrombosis occurred in 9 (0.5%) patients at 5 years. After 1 year, definite stent thrombosis occurred in only 1 patient. Significant predictors for MACE were dialysis (ODDs ratio 4.58, 95% CI 2.75-7.64), prior cardiac intervention (ODDs ratio 2.47, 95% CI 1.75-3.49), total stent length (ODDs ratio 1.01, 95% CI 1.01 1.02), and number of diseased vessels (ODDs ratio 1.66, 95% CI 1.08-2.55). Five year clinical outcomes from the CoCr-EES PMS Japan study demonstrated a low incidence of clinical events in the daily practice up to 5 years. CLINICAL TRIAL REGISTRATION INFORMATION: https://clinicaltrials.gov/ct2/show/NCT01086228 . PMID- 29484579 TI - Predicting eye-movement characteristics across multiple tasks from working memory and executive control. AB - Individual differences in working memory (WM) and executive control are stable, related to cognitive task performance, and clinically predictive. Between participant differences in eye movements are also highly reliable (Carter & Luke, Journal of Experimental Psychology: Human Perception and Performance, 2018; Henderson & Luke, Journal of Experimental Psychology: Human Perception and Performance, 40(4), 1390-1400, 2014). However, little is known about how higher order individual differences in cognition are related to these eye-movement characteristics. In the present study, healthy college-age participants performed several individual difference tasks to measure WM span and executive control. Participants also performed three eye-movement tasks: reading, visual search, and scene viewing. Across all tasks, higher WM scores were related to reduced skewness in fixation duration distributions. In reading, higher WM scores predicted longer saccades. In scene viewing, higher WM scores predicted longer fixations. Theoretical and clinical implications of these findings are discussed. PMID- 29484581 TI - Is Clinical Anxiety a Risk or a Protective Factor for Executive Functioning in Youth with ADHD? A Meta-regression Analysis. AB - Comorbidity rates between ADHD and anxiety disorders (AD) are high, but little is known about the nature of this co-occurrence. A dominant idea is that AD may intensify some (i.e., attention and working memory) and attenuate other (i.e., inhibition) ADHD symptoms. Results are mixed, potentially because of between study differences. To investigate this further we performed a meta-regression analysis on 11 studies (n 'ADHD-only' = 695; n 'ADHD + AD' = 608), containing 35 effect sizes on attention, inhibition and working memory. Main results were: (1) no evidence of a negative effect of AD on attention and working memory; (2) better response inhibition in children with ADHD with AD than those with only ADHD (medium ES g = - .40); (3) medication moderated this association: the effect seemed limited to studies that included medication-naive participants; (4) the difference between the two groups increased with age for attention and with proportion of boys for working memory ability. There was no effect of comorbid disruptive behavior disorder. In conclusion, AD seems to be a protective factor for inhibition problems as assessed with laboratory tasks in ADHD, especially in children who are medication naive. Further, AD may have a protective function for attention in older children, and for working memory in boys with ADHD. It is therefore important to screen for AD when diagnosing ADHD, and to educate those with comorbid AD about the possible positive function of feeling anxious. Potential negative effects of ADHD medication on inhibition in children with comorbid AD should be considered. PMID- 29484582 TI - Prolonged Microcatheter-Based Local Thrombolytic Infusion as a Salvage Treatment After Failed Endovascular Treatment for Cerebral Venous Thrombosis: A Multicenter Experience. AB - BACKGROUND AND PURPOSE: To determine the effectiveness of prolonged microcatheter based local thrombolytic infusion in treatment of patients with cerebral venous thrombosis who achieved no or suboptimal recanalization with transvenous endovascular treatment. METHODS: Data collection: Prospectively registries supplemented by retrospective review. SETTINGS: Three hospitals with tertiary referral base. PATIENTS: Patients who underwent transvenous endovascular treatment for cerebral venous thrombosis. INTERVENTION: Prolonged microcatheter based local thrombolytic infusion of alteplase at the rate of 0.5-1 mg/h in patients in whom initial angiographic outcome was deemed suboptimal, either due to incomplete or no recanalization. RESULTS: Serial angiograms were performed to assess treatment response as follows: grade I, partial recanalization of one or more occluded dural sinuses with improved flow or visualization of branches; grade II, complete recanalization of one sinus but persistent occlusion of the other sinuses (A-no residual flow, B-nonocclusive flow); grade III, complete recanalization. Clinical outcome was determined at 1-3 months using modified Rankin scale. A total of 14 patients underwent 15 transvenous endovascular treatments. Initial treatment was considered suboptimal in 12/15 procedures due to no recanalization in five (grade 0), partial recanalization (grade I) in four, complete recanalization of one sinus but persistent occlusion of the other sinuses (grade 2A in two and 2B in one). A prolonged microcatheter-based local recombinant tissue plasminogen activator infusion was used following ten of the 15 procedures for a median duration of 18 h (range 13-22 h). Follow-up angiography demonstrated complete recanalization in four procedures and improvement in grades of partial recanalization in six procedures (final grades 2A in three and 2B in three procedures). None of the patients developed new symptomatic intracranial hemorrhage associated with local thrombolytic infusion. At follow-up, patients in five of ten procedures had achieved a modified Rankin scale of 0 and one patient had achieved a score of 1 (no neurological deficits but had residual headaches). CONCLUSION: Prolonged microcatheter-based local thrombolytic infusion appeared to be effective treatment in patients who have suboptimal response to acute transvenous endovascular treatment without any additional adverse events. PMID- 29484584 TI - Workflow for a Computational Analysis of an sRNA Candidate in Bacteria. AB - Computational methods can often facilitate the functional characterization of individual sRNAs and furthermore allow high-throughput analysis on large numbers of sRNA candidates. This chapter outlines a potential workflow for computational sRNA analyses and describes in detail methods for homolog detection, target prediction, and functional characterization based on enrichment analysis. The cyanobacterial sRNA IsaR1 is used as a specific example. All methods are available as webservers and easily accessible for nonexpert users. PMID- 29484583 TI - Association of Seizure Occurrence with Aneurysm Treatment Modality in Aneurysmal Subarachnoid Hemorrhage Patients. AB - BACKGROUND: Data on new-onset seizures after treatment of aneurysmal subarachnoid hemorrhage (aSAH) patients are limited and variable. We examined the association between new-onset seizures after aSAH and aneurysm treatment modality, as well their relationship with initial clinical severity of aSAH and outcomes. METHODS: This is a retrospective cohort study of all aSAH patients admitted to our institution over a 6-year period. 'Seizures' were defined as any observed clinical seizure or electrographic seizure on continuous electroencephalogram (cEEG) recordings, as determined by the reviewing neurophysiologist. Subgroup analyses were performed in low-grade (Hunt-Hess 1-3) and high-grade (Hunt-Hess 4 5) patients. Outcomes measures were Glasgow Coma Score (GCS) at intensive care unit (ICU) discharge and modified Rankin Scale (mRS) at outpatient follow-up. RESULTS: There were 282 patients with aSAH; 203 (72.0%) suffered low-grade and 79 (28%) high-grade aSAH. Patients were treated with endovascular coiling (N = 194, 68.8%) or surgical clipping (N = 66, 23.4%). Eighteen (6.4%) patients had seizures, of whom 10 (5.5%) had aneurysm coiling and 7 (10.6%) underwent clipping (p = 0.15). In low-grade patients, seizures occurred less frequently (p = 0.016) and were more common after surgical clipping (p = 0.0089). Seizures correlated with lower GCS upon ICU discharge (p < 0.001), in clipped (p = 0.011) and coiled (p < 0.001) patients and in low-grade aSAH (p < 0.001). Seizures correlated with higher mRS on follow-up (p < 0.001), in clipped (p = 0.032) and coiled (p = 0.004) patients and in low-grade aSAH (p = 0.003). CONCLUSIONS: New-onset seizures after aSAH occurred infrequently, and their incidence after aneurysm clipping versus coiling was not significantly different. However, in low-grade patients, new seizures were more frequently associated with clipping than coiling. Additionally, non-convulsive seizures did not occur in low-grade patients treated with coiling. These findings may explain, in part, previous work suggesting better outcomes in coiled patients and encourage physicians to have a lower threshold for cEEG utilization in low-grade patients suspected to have acute seizures after surgical clipping. PMID- 29484585 TI - Guidelines for Inferring and Characterizing a Family of Bacterial trans-Acting Small Noncoding RNAs. AB - So far, every sequenced bacterial transcriptome encompasses hundreds of small regulatory noncoding RNAs (sRNAs). From those sRNAs that have been already characterized, we learned that their regulatory functions could span over almost every bacterial process, mostly acting at the posttranscriptional control of gene expression (Wagner and Romby, Adv Genet 90:133-208, 2015). Canonical molecular mechanisms of sRNA action have been described to rely on both sequence and/or structural traits of the RNA molecule. As for protein-coding genes, the conservation of sRNAs among species suggests conserved and adjusted functions across evolution. Knowing the phylogenetic distribution of an sRNA gene and how its functional traits have evolved may help to get a broad picture of its biological role in each single species. Here, we present a simple computational workflow to identify close and distant sRNA homologs present in sequenced bacterial genomes, which allows defining novel sRNA families. This strategy is based on the use of Covariance Models (CM) and assumes the conservation of sequence and structure of functional sRNA genes throughout evolution. Moreover, by carefully inspecting the conservation of the close genomic context of every member of the RNA family and how the patterns of microsynteny follow the path of species evolution, it is possible to define subgroups of sRNA orthologs, which in turn enables the definition of RNA subfamilies. PMID- 29484586 TI - Bioinformatic Approach for Prediction of CsrA/RsmA-Regulating Small RNAs in Bacteria. AB - CsrA/RsmA is a RNA-binding protein that functions as a global regulator controlling important processes such as virulence, secondary metabolism, motility, and biofilm formation in diverse bacterial species. The activity of CsrA/RsmA is regulated by small RNAs that contain multiple binding sites for the protein. The expression of these noncoding RNAs effectively sequesters the protein and reduces free cellular levels of CsrA/RsmA. While multiple bacterial small RNAs that bind to and regulate CsrA/RsmA levels have been discovered, it is anticipated that there are several such small RNAs that remain undiscovered. To assist in the discovery of these small RNAs, we have developed a bioinformatics approach that combines sequence- and structure-based features to predict small RNA regulators of CsrA/RsmA. This approach analyzes structural motifs in the ensemble of low energy secondary structures of known small RNA regulators of CsrA/RsmA and trains a binary classifier on these features. The proposed machine learning approach leads to several testable predictions for small RNA regulators of CsrA/RsmA, thereby complementing and accelerating experimental efforts aimed at discovery of noncoding RNAs in the CsrA/RsmA pathway. PMID- 29484587 TI - Host-Pathogen Transcriptomics by Dual RNA-Seq. AB - Transcriptomics, i.e., the quantification of cellular RNA transcripts, is a powerful way to gauge the physiological state of either bacterial or eukaryotic cells under a given condition. However, traditional approaches were unsuitable to measure the abundance of transcripts across kingdoms, which is relevant for biological processes such as bacterial infections of mammalian host cells. This changed with the establishment of "Dual RNA-seq," which profiles gene expression simultaneously in an infecting bacterium and its infected host. Here, we describe a detailed Dual RNA-seq protocol optimized for-but not restricted to-the study of human cell culture models infected with the Gram-negative model pathogen Salmonella Typhimurium. Furthermore, we provide experimental data demonstrating the benefits of some of the key steps of this protocol, including transcriptome stabilization (RNA fixation), FACS-based enrichment of invaded cells, and double rRNA depletion. While our focus is on data generation, we also include a section describing suitable computational methods to analyze the obtained datasets. PMID- 29484588 TI - Identification of New Bacterial Small RNA Targets Using MS2 Affinity Purification Coupled to RNA Sequencing. AB - Small regulatory RNAs (sRNAs) are ubiquitous regulatory molecules expressed in living cells. In prokaryotes, sRNAs usually bind to target mRNAs to either promote their degradation or interfere with translation initiation. Because a single sRNA can regulate a considerable number of target mRNAs, we seek to identify those targets rapidly and reliably. Here, we present a robust method based on the co-purification of target mRNAs bound to MS2-tagged sRNAs expressed in vivo. After purification of the tagged-sRNA, we use RNAseq to determine the identity of all RNA interacting partners and their enrichment level. We describe how to analyze the RNAseq data through the Galaxy Project Platform bioinformatics tools to identify new mRNA targets. This technique is applicable to most sRNAs of E. coli and Salmonella. PMID- 29484589 TI - Assessment of External Guide Sequences' (EGS) Efficiency as Inducers of RNase P Mediated Cleavage of mRNA Target Molecules. AB - RNase P is a ribozyme consisting of a catalytic RNA molecule and, depending on the organism, one or more cofactor proteins. It was initially identified as the enzyme that mediates cleavage of precursor tRNAs at the 5'-end termini to generate the mature tRNAs. An important characteristic of RNase P is that its specificity depends on the structure rather than the sequence of the RNA substrate. Any RNA species that interacts with an antisense molecule (called external guide sequence, EGS) and forms the appropriate structure can be cleaved by RNase P. This property is the basis for EGS technology, an antisense methodology for inhibiting gene expression by eliciting RNase P-mediated cleavage of a target mRNA molecule. EGS technology is being developed to design therapies against a large variety of diseases. An essential milestone in developing EGSs as therapies is the assessment of the efficiency of antisense molecules to induce cleavage of the target mRNA and evaluate their effect in vivo. Here, we describe simple protocols to test the ability of EGSs to induce cleavage of a target mRNA in vitro and to induce a phenotypic change in growing cells. PMID- 29484590 TI - Evaluating the Effect of Small RNAs and Associated Chaperones on Rho-Dependent Termination of Transcription In Vitro. AB - Besides their well-known posttranscriptional effects on mRNA translation and decay, sRNAs and associated RNA chaperones (e.g., Hfq, CsrA) sometimes regulate gene expression at the transcriptional level. In this case, the sRNA-dependent machinery modulates the activity of the transcription termination factor Rho, a ring-shaped RNA translocase/helicase that dissociates transcription elongation complexes at specific loci of the bacterial genome. Here, we describe biochemical assays to detect Rho-dependent termination signals in genomic regions of interest and to assess the effects of sRNAs and/or associated RNA chaperones on such signals. PMID- 29484591 TI - Mapping Changes in Cell Surface Protein Expression Through Selective Labeling of Live Cells. AB - ncRNAs are key players in the adaptation of bacteria to new environments, by modulating the composition of the membrane upon changes in the environment. Nevertheless, monitoring the changes in surface protein expression is still a challenge, since these proteins are present in low abundance, and are difficult to extract. Here is described a method to easily, reproducibly, and specifically enrich total protein extracts in surface proteins. This method comprises a direct labeling of surface proteins on living cells using fluorescent dyes, followed by total protein extraction and subsequent separation of these extracts by 2D gel electrophoresis. PMID- 29484592 TI - Fluorescence-Based Methods for Characterizing RNA Interactions In Vivo. AB - Fluorescence-based tools that measure RNA-RNA and RNA-protein interactions in vivo offer useful experimental approaches to probe the complex and dynamic physiological behavior of bacterial RNAs. Here we document the step-by-step design and application of two fluorescence-based methods for studying the regulatory interactions RNAs perform in vivo: (i) the in vivo RNA Structural Sensing System (iRS3) for measuring RNA accessibility and (ii) the trifluorescence complementation (TriFC) assay for measuring RNA-protein interactions. PMID- 29484593 TI - Mutational Analysis of sRNA-mRNA Base Pairing by Electrophoretic Mobility Shift Assay. AB - Small regulatory RNAs (sRNAs) in bacteria often act by base pairing to mRNAs. Direct interactions between an sRNA and its target mRNA can be investigated by electrophoretic mobility shift assay. In this assay, regions engaged in base pairing are analyzed by introducing mutations in one of the RNAs that prevent sRNA-mRNA complex formation, followed by the introduction of complementary mutations in its partner RNA that restore base pairing. Here, we describe the design of a mutational strategy used to analyze the base pairing between two CU rich regions of the sRNA Rli22 and the AG-rich Shine-Dalgarno region of the mRNA oppA in Listeria monocytogenes. The protocol can be employed for mutational studies of base pairing between any sRNA and its mRNA target(s). PMID- 29484594 TI - An Integrated Cell-Free Assay to Study Translation Regulation by Small Bacterial Noncoding RNAs. AB - Posttranscriptional regulation of gene expression by small noncoding RNAs (sRNAs) is an important control mechanism that modulates bacterial metabolism, motility, and pathogenesis. Using the bacterial carbon storage regulator/regulator of secondary metabolism (Csr/Rsm) system, we here describe an E. coli-based cell free translation assay that allows a quantitative analysis of translation regulation by ncRNAs and their corresponding translation repressor proteins. The assay quantifies the translation of chloramphenicol acetyltransferase in cell free expression reactions that contain defined amounts of ncRNA and repressor protein. We demonstrate our protocol with a comparative translation activation analysis of the RsmX, RsmY, and RsmZ sRNAs from Pseudomonas protegens, which reveals a superior efficacy of RsmZ over RsmX and RsmY. PMID- 29484595 TI - Quantitative Super-Resolution Imaging of Small RNAs in Bacterial Cells. AB - We present a method for the quantification of small regulatory RNAs (sRNAs) in bacteria, by combining single-molecule fluorescence in situ hybridization (smFISH), super-resolved single-fluorophore microscopy, and clustering analysis. Compared to smFISH imaging with diffraction-limited fluorescence microscopy, our method provides better quantification for short and abundant RNA (such as sRNAs) in a small volume of bacterial cells. Our method can also be directly used for the quantification of messenger RNAs (mRNAs). PMID- 29484597 TI - Absolute Regulatory Small Noncoding RNA Concentration and Decay Rates Measurements in Escherichia coli. AB - Regulation of RNA turnover is of utmost importance for controlling the concentration of transcripts and consequently cellular protein levels. Among the processes controlling RNA decay, small noncoding regulatory RNAs (sRNAs) have recently emerged as major new players. In this chapter, we describe and discuss protocols that can be used to measure sRNA concentration in vivo and to assess sRNA decay rates in Gram-negative bacteria. Precisely, we focus our analyses on the Escherichia coli Gram-negative bacterium as a model. The information described in this chapter provides a guideline to help develop a protocol in order to assess these important parameters and to identify RNA-processing enzymes involved in sRNA degradation processes. PMID- 29484596 TI - Extraction and Analysis of RNA Isolated from Pure Bacteria-Derived Outer Membrane Vesicles. AB - Outer membrane vesicles (OMVs) are released by commensal as well as pathogenic Gram-negative bacteria. These vesicles contain numerous bacterial components, such as proteins, peptidoglycans, lipopolysaccharides, DNA, and RNA. To examine if OMV-associated RNA molecules are bacterial degradation products and/or are functionally active, it is necessary to extract RNA from pure OMVs for subsequent analysis. Therefore, we describe here an isolation method of ultrapure OMVs and the subsequent extraction of RNA and basic steps of RNA-Seq analysis. Bacterial culture, extracellular supernatant concentration, OMV purification, and the subsequent RNA extraction out of OMVs are described. Specific pitfalls within the protocol and RNA contamination sources are highlighted. PMID- 29484598 TI - High-Resolution, High-Throughput Analysis of Hfq-Binding Sites Using UV Crosslinking and Analysis of cDNA (CRAC). AB - Small regulatory nonprotein-coding RNAs (sRNAs) have emerged as ubiquitous and abundant regulators of gene expression in a diverse cross section of bacteria. They play key roles in most aspects of bacterial physiology, including central metabolism, nutrient acquisition, virulence, biofilm formation, and outer membrane composition. RNA sequencing technologies have accelerated the identification of bacterial regulatory RNAs and are now being employed to understand their functions. Many regulatory RNAs require protein partners for activity, or modulate the activity of interacting proteins. Understanding how and where proteins interact with the transcriptome is essential to elucidate the functions of the many sRNAs. Here, we describe the implementation in bacteria of a UV-crosslinking technique termed CRAC that allows stringent, transcriptome-wide recovery of bacterial RNA-protein interaction sites in vivo and at base-pair resolution. We have used CRAC to map protein-RNA interaction sites for the RNA chaperone Hfq and ribonuclease RNase E in pathogenic E. coli, and toxins from toxin-antitoxin systems in Mycobacterium smegmatis, demonstrating the broad applicability of this technique. PMID- 29484599 TI - Producing Hfq/Sm Proteins and sRNAs for Structural and Biophysical Studies of Ribonucleoprotein Assembly. AB - Hfq is a bacterial RNA-binding protein that plays key roles in the post transcriptional regulation of gene expression. Like other Sm proteins, Hfq assembles into toroidal discs that bind RNAs with varying affinities and degrees of sequence specificity. By simultaneously binding to a regulatory small RNA (sRNA) and an mRNA target, Hfq hexamers facilitate productive RNA???RNA interactions; the generic nature of this chaperone-like functionality makes Hfq a hub in many sRNA-based regulatory networks. That Hfq is crucial in diverse cellular pathways-including stress response, quorum sensing, and biofilm formation-has motivated genetic and "RNAomic" studies of its function and physiology (in vivo), as well as biochemical and structural analyses of Hfq???RNA interactions (in vitro). Indeed, crystallographic and biophysical studies first established Hfq as a member of the phylogenetically conserved Sm superfamily. Crystallography and other biophysical methodologies enable the RNA-binding properties of Hfq to be elucidated in atomic detail, but such approaches have stringent sample requirements, viz.: reconstituting and characterizing an Hfq.RNA complex requires ample quantities of well-behaved (sufficient purity, homogeneity) specimens of Hfq and RNA (sRNA, mRNA fragments, short oligoribonucleotides, or even single nucleotides). The production of such materials is covered in this chapter, with a particular focus on recombinant Hfq proteins for crystallization experiments. PMID- 29484600 TI - Single-Molecule FRET Assay to Observe the Activity of Proteins Involved in RNA/RNA Annealing. AB - In recent years, single-molecule fluorescence resonance energy transfer (smFRET) has emerged as a powerful technique to study macromolecular interactions. The chief advantages of smFRET analysis compared to bulk measurements include the possibility to detect sample heterogeneities within a large population of molecules and the facility to measure kinetics without needing the synchronization of intermediate states. As such, the methodology is particularly well adapted to observe and analyze RNA/RNA and RNA/protein interactions involved in small noncoding RNA-mediated gene regulation networks. In this chapter, we describe and discuss protocols that can be used to measure the dynamics of these interactions, with a particular emphasis on the advantages-and experimental pitfalls-of using the smFRET methodology to study sRNA-based biological systems. PMID- 29484601 TI - Techniques to Analyze sRNA Protein Cofactor Self-Assembly In Vitro. AB - Post-transcriptional control of gene expression by small regulatory noncoding RNA (sRNA) needs protein accomplices to occur. Past research mainly focused on the RNA chaperone Hfq as cofactor. Nevertheless, recent studies indicated that other proteins might be involved in sRNA-based regulations. As some of these proteins have been shown to self-assemble, we describe in this chapter protocols to analyze the nano-assemblies formed. Precisely, we focus our analysis on Escherichia coli Hfq as a model, but the protocols presented here can be applied to analyze any polymer of proteins. This chapter thus provides a guideline to develop commonly used approaches to detect prokaryotic protein self-assembly, with a special focus on the detection of amyloidogenic polymers. PMID- 29484602 TI - Sequence-Specific Affinity Chromatography of Bacterial Small Regulatory RNA Binding Proteins from Bacterial Cells. AB - Bacterial small RNA molecules (sRNAs) are increasingly recognized as central regulators of bacterial stress responses and pathogenesis. In many cases, RNA binding proteins are critical for the stability and function of sRNAs. Previous studies have adopted strategies to genetically tag an sRNA of interest, allowing isolation of RNA-protein complexes from cells. Here we present a sequence specific affinity purification protocol that requires no prior genetic manipulation of bacterial cells, allowing isolation of RNA-binding proteins bound to native RNA molecules. PMID- 29484603 TI - Identification of Small RNA-Protein Partners in Plant Symbiotic Bacteria. AB - The identification of the protein partners of bacterial small noncoding RNAs (sRNAs) is essential to understand the mechanistic principles and functions of riboregulation in prokaryotic cells. Here, we describe an optimized affinity chromatography protocol that enables purification of in vivo formed sRNA-protein complexes in Sinorhizobium meliloti, a genetically tractable nitrogen-fixing plant symbiotic bacterium. The procedure requires the tagging of the desired sRNA with the MS2 aptamer, which is affinity-captured by the MS2-MBP protein conjugated to an amylose resin. As proof of principle, we show recovery of the RNA chaperone Hfq associated to the strictly Hfq-dependent AbcR2 trans-sRNA. This method can be applied for the investigation of sRNA-protein interactions on a broad range of genetically tractable alpha-proteobacteria. PMID- 29484604 TI - A Modular Genetic System for High-Throughput Profiling and Engineering of Multi Target Small RNAs. AB - RNA biology and RNA engineering are subjects of growing interest due to recent advances in our understanding of the diverse cellular functions of RNAs, including their roles as genetic regulators. The noncoding small RNAs (sRNAs) of bacteria are a fundamental basis of regulatory control that can regulate gene expression via antisense base-pairing to one or more target mRNAs. The sRNAs can be customized to generate a range of mRNA translation rates and stabilities. The sRNAs can be applied as a platform for metabolic engineering, to control expression of genes of interest by following relatively straightforward design rules (Kushwaha et al., ACS Synth Biol 5:795-809, 2016). However, the ab initio design of functional sRNAs to precise specifications of gene control is not yet possible. Consequently, there is a need for tools to rapidly profile uncharacterized sRNAs in vivo, to screen sRNAs against "new/novel" targets, and (in the case of metabolic engineering) to develop engineered sRNAs for regulatory function against multiple desired mRNA targets. To address this unmet need, we previously constructed a modular genetic system for assaying sRNA activity in vivo against specifiable mRNA sequences, using microtiter plate assays for high throughput productivity. This sRNA design platform consists of three modular plasmids: one plasmid contains an inducible sRNA and the RNA chaperone Hfq; the second contains an inducible fluorescent reporter protein and a LacY mutant transporter protein for inducer molecules; and the third plasmid contains a second inducible fluorescent reporter protein. The second reporter gene makes it possible to screen for sRNA regulators that have activity against multiple mRNAs. We describe the protocol for engineering sRNAs with novel regulatory activity using this system. This sRNA prototyping regimen could also be employed for validating predicted mRNA targets of uncharacterized, naturally occurring sRNAs or for testing hypotheses about the predicted roles of genes, including essential genes, in cellular metabolism and other processes, by using customized antisense sRNAs to knock down or tune down gene expression. PMID- 29484605 TI - The effects of systemic oxygenation on cerebral oxygen saturation and its relationship to mixed venous oxygen saturation: A prospective observational study comparison of the INVOS and ForeSight Elite cerebral oximeters. AB - PURPOSE: The present study aimed to test the hypothesis that cerebral oxygen saturation (ScO2) measurements with the INVOS-5100-C and the ForeSight-Elite cerebral oximeters vary in their correlation with mixed venous oxygen saturation (SvO2) upon changes in systemic oxygenation in extubated cardiac surgical patients. Additionally, we aimed to elucidate whether the ScO2 measurements of both devices can be used interchangeably to detect reduced SvO2. METHODS: Forty eight spontaneously breathing patients extubated after cardiac surgery were included in this prospective observational study. The patients were exposed to both high (10 oxygen L.min-1 via face mask) and low (room air) inspiratory oxygen concentrations. Bi-hemispherical ScO2 was determined with the INVOS and ForeSight Elite cerebral oximeters. The SvO2 was measured with a pulmonary artery catheter. RESULTS: Significant changes in oxygen delivery, ScO2 (by both cerebral oximeters), and SvO2 were observed upon variation of oxygenation. The minimum mean (standard deviation) ScO2 (ScO2min) using the INVOS and ForeSight did not differ significantly during high oxygen delivery [63.1 (8.6) % vs 65.8 (4.7) %, respectively; P = 0.07], but during low oxygen delivery, the INVOS value was significantly lower than that of the ForeSight oximeter [56.7 (8.9) % vs 61.3 (4.4) %, respectively; P = 0.003]. Both devices differed in the correlation between ScO2min and SvO2 for the combined oxygenation data (0.59, INVOS vs 0.28, ForeSight; correlation difference, 0.31; Bonferroni-adjusted 95% confidence interval [CI], 0.08 to 0.54; P = 0.008). The receiver-operating curve analysis revealed an area under the curve of 0.83 (95% CI, 0.74 to 0.9; P = 0.005) for detecting an SvO2 below 50% by ScO2min with the INVOS and 0.51 (95% CI, 0.41 to 0.62; P = 0.92), respectively, with the ForeSight. CONCLUSIONS: These findings suggest that the cerebral oximeters tested react differently to variations in systemic oxygenation and in their relationship with SvO2 and thus give different information on cardiopulmonary function. These findings raise doubt about whether these devices should be used interchangeably. PMID- 29484606 TI - Author Correction to: Recent Perioperative Pharmacological Prevention of Acute Kidney Injury after Cardiac Surgery: A Narrative Review. AB - Acute kidney injury (AKI) is a common and severe complication of cardiac surgery, and related rates of both hospitalization and long-term mortality are increasing. A number of studies have explored the preventive effects of perioperative pharmacological therapy on AKI after cardiac surgery. PMID- 29484608 TI - Effectiveness of a Functional Rehabilitation Program After Bariatric Surgery: a Pilot Study. AB - BACKGROUND: Beyond obesity-related comorbidities, overweight patients have a high risk of developing osteoarticular pathologies. Moreover, weight loss following bariatric surgery induces a decrease in fat mass but also in muscle mass, thus affecting the physical capacities of these patients. Functional rehabilitation is a solution to correct these imbalances. The aim of this study was to evaluate the effectiveness of a functional rehabilitation program after bariatric surgery. METHODS: Twenty-three patients with severe obesity (BMI = 37.9 +/- 5.7 kg/m2; 41.1 +/- 12.9 years) participated in a functional rehabilitation protocol, 2 months after sleeve gastrectomy. Rehabilitation program consisted of 20 sessions of 1h30 (two sessions per week), based on endurance training, muscle strengthening, and proprioception work. An initial and final assessment included bioelectrical impedance measurements, questionnaires, and physical function tests. RESULTS: All impedance parameters were significantly improved in 20 sessions: % excess weight loss (%EWL) from 27.6 +/- 9.1 to 51.1 +/- 13.4% and % fat-free mass from 52.7 +/- 5.6 to 57.6 +/- 6.7%. Waist and hip circumferences were significantly reduced in 20 sessions: from 107.4 +/- 13.7 to 94.5 +/- 12.6 cm and from 120.5 +/- 12.4 to 108.7 +/- 11.7 cm, respectively (p < 0.001). Physical function tests were significantly improved between the 1st and the 20th sessions (p < 0.001). The cycloergometer stress test progressed from 77.7 +/- 24.1 to 93.6 +/- 27.2 W, and the sit-to-stand test from 20 +/- 5.2 to 24.8 +/- 7.6 flexions in 30 s. The Quality Of Life, Obesity and Dietetics (QOLOD) scale increased by 12.6%. CONCLUSIONS: The functional rehabilitation protocol of 20 sessions significantly improved patients' body composition, functional tests, and quality of life. The standardization of tests and sessions allowed to objectively assess progress. PMID- 29484609 TI - Elipse Balloon: the Pitfalls of Excessive Simplicity. PMID- 29484607 TI - Treatment of Tardive Dyskinesia: A General Overview with Focus on the Vesicular Monoamine Transporter 2 Inhibitors. AB - Tardive dyskinesia (TD) encompasses the spectrum of iatrogenic hyperkinetic movement disorders following exposure to dopamine receptor-blocking agents (DRBAs). Despite the advent of atypical or second- and third-generation antipsychotics with a presumably lower risk of complications, TD remains a persistent and challenging problem. Prevention is the first step in mitigating the risk of TD, but early recognition, gradual withdrawal of offending medications, and appropriate treatment are also critical. As TD is often a persistent and troublesome disorder, specific antidyskinetic therapies are often needed for symptomatic relief. The vesicular monoamine transporter 2 (VMAT2) inhibitors, which include tetrabenazine, deutetrabenazine, and valbenazine, are considered the treatment of choice for most patients with TD. Deutetrabenazine-a deuterated version of tetrabenazine-and valbenazine, the purified parent product of one of the main tetrabenazine metabolites, are novel VMAT2 inhibitors and the only drugs to receive approval from the US FDA for the treatment of TD. VMAT2 inhibitors deplete presynaptic dopamine and reduce involuntary movements in many hyperkinetic movement disorders, particularly TD, Huntington disease, and Tourette syndrome. The active metabolites of the VMAT2 inhibitors have high affinity for VMAT2 and minimal off-target binding. Compared with tetrabenazine, deutetrabenazine and valbenazine have pharmacokinetic advantages that translate into less frequent dosing and better tolerability. However, no head-to-head studies have compared the various VMAT2 inhibitors. One of the major advantages of VMAT2 inhibitors over DRBAs, which are still being used by some clinicians in the treatment of some hyperkinetic disorders, including TD, is that they are not associated with the development of TD. We also briefly discuss other treatment options for TD, including amantadine, clonazepam, Gingko biloba, zolpidem, botulinum toxin, and deep brain stimulation. Treatment of TD and other drug induced movement disorders must be individualized and based on the severity, phenomenology, potential side effects, and other factors discussed in this review. PMID- 29484610 TI - Sensitivity and Specificity of 50% Excess Weight Loss (50%EWL) and Twelve Other Bariatric Criteria for Weight Loss Success. AB - BACKGROUND: Criteria for bariatric weight loss success are numerous. Most of them are arbitrary. None of them is evidence-based. Our objective was to determine their sensitivity and specificity. METHODS: Thirteen common bariatric weight loss criteria were compared to a benchmark reflecting the gold standard in bariatric surgery. We used an elaborate baseline BMI-independent weight loss percentile chart, based on retrospective data after laparoscopic Roux-en-Y gastric bypass (LRYGB), performed between 2007 and 2017. Percentile curves p31.6 (patients' expectation), p25 (interquartile range), p15.9 (1 standard deviation (SD) below median), and p10.9 (surgeons' goal) were used as possible cutoff for success to determine true or false positive and negative results beyond 1 year. RESULTS: We operated 4497 primary LRYGB patients, with mean follow-up 22 (+/- 1 SD 19; range 0-109) months, 3031 patients with last result >= 1 year, 518 >= 5 years. For all four cutoff percentile curves for success, specificities were low (2-72%) for criteria < 35 body mass index (BMI), >= 25percentage excess BMI loss (%EBMIL), >= 50%EBMIL, >= 15 percentage total weight loss (%TWL), >= 20%TWL, >= 25 percentage excess weight loss (%EWL), and high (83-96%) for < 30 BMI. No criterion had > 80% specificity and sensitivity for a cutoff above p15.9. For p15.9, they were both > 80% for criteria >= 10 BMI reduction and >= 50%EWL, both > 90% for >= 25%TWL and >= 35 percentage alterable weight loss (%AWL). All criteria had high sensitivities for all cutoff percentile curves (87-100%), except < 30 BMI (65 78%). CONCLUSIONS: For the first time, common bariatric criteria for weight loss success were systematically validated. Most criteria recognized success very well (high sensitivities), but >= 15%TWL, >= 20%TWL, < 35BMI, >= 25%EWL, >= 25%EBMIL, and >= 50%EBMIL left too many poor responders unnoticed (low specificities). Bariatric weight loss success is best assessed by comparing results to percentile curve 1 SD below median (p15.9) in a bariatric baseline BMI-independent weight loss percentile chart. Criteria >= 35%AWL and >= 25%TWL came close to that curve, both with > 90% sensitivity and specificity. Among others, criterion >= 50%EBMIL did not. PMID- 29484611 TI - The Risk for Lung Cancer Incidence with Calcium Channel Blockers: A Systematic Review and Meta-Analysis of Observational Studies. AB - INTRODUCTION: There are conflicting findings regarding the association between the use of calcium channel blockers (CCBs) and the risk of lung cancer. Considering the public health importance of lung cancer prevention, and emerging evidence of a significant biologic role of calcium channel regulation in the development of lung cancer, we conducted a meta-analysis to assess the risk of lung cancer in CCB users compared with non-CCB users. MATERIALS AND METHODS: We conducted a comprehensive systematic search of leading medical databases for observational studies published up to December 2017 that examined CCB use and the risk of lung cancer. We used random-effects models to pool results. The impact of duration of CCB use on the estimated effect size was explored using random effects meta-regression. RESULTS: Ten studies (six cohort and four case-control studies) that evaluated the overall cancer risk among 38,758 CCB users were included in the analysis. Overall risk ratio (RR) for CCB use and lung cancer was 1.15 (95% confidence interval [CI] 1.01-1.32). Subgroup analysis by duration of CCB use suggested that the observed increase in lung cancer risk was driven by the results of five studies with prolonged (>= 4 years) exposure (RR 1.18; 95% CI 1.08-1.30). CONCLUSIONS: Our analysis suggests exposure to CCBs is associated with an increased risk of lung cancer. Considering their widespread use, and the paucity of data on the long-term effects of chronic exposure to CCBs, these results are reason for concern and warrant further investigation. SYSTEMATIC REVIEW REGISTRATION: The protocol for this study was registered at the PROSPERO registry of systematic reviews (registry number: CRD42017056362). PMID- 29484612 TI - Sex Differences in Reported Adverse Drug Reactions of Selective Serotonin Reuptake Inhibitors. AB - INTRODUCTION: Several studies have investigated sex as a risk factor for the occurrence of adverse drug reactions (ADRs) and found that women are more likely to experience ADRs than men. OBJECTIVE: The aim of this explorative study was to investigate whether differences exist in reported ADRs of selective serotonin reuptake inhibitors (SSRIs) for men and women in the database of the Netherlands Pharmacovigilance Centre Lareb. METHODS: A ratio of reports concerning women and men, corrected for the number of users, was calculated for all the ADRs reported on SSRIs. RESULTS: We found that 16 ADRs were statistically significantly more reported in women than men, and four ADRS were reported more in men than women. CONCLUSION: ADRs more reported in women than men when using SSRIs were usually dose-related ADRs or commonly occurring ADRs. Differences in the pharmacokinetics of SSRIs between men and women may explain why these reports of dose-related ADRs when using SSRIs concern women more than men. PMID- 29484614 TI - Influence of a Combination of Chemical Enhancers and Iontophoresis on In Vitro Transungual Permeation of Nystatin. AB - To promote transungual permeation of nystatin (NYST), molecule with high molecular weight, no water-soluble, amphoteric by iontophoresis. The synergic effect of the combination of cetylpyridinium chloride, CPC, or polyoxyethylene (20) sorbitan monooleate, TW80, and iontophoresis was investigated. In vitro permeation experiments were carried out through bovine hoof slices using vertical diffusion cells. A low current density (0.2 mA/cm2) was applied by introducing Ag/AgCl electrodes in the donor (anode) and receptor (cathode) chambers. The donor phase consisted of a solution, a suspension, or gel-type vehicles containing NYST and surfactants in pH 5.6 HEPES buffer. The addition of CPC to NYST suspension (SOSP) produced a fivefold increase on the permeability of the bovine hoof membrane to the drug. The application of anodal iontophoresis further improved NYST flux. Conversely, NYST transungual permeation was not influenced by TW80 either in the passive diffusion or iontophoretic flux. Furthermore, the iontophoretic treatment does not appear to induce irreversible alterations to the hoof bovine membranes. The present work demonstrated the efficacy of iontophoresis as a treatment for different nail pathologies with large molecules very slightly soluble in water without irreversibly affecting the nail structure. A synergistic effect between CPC and iontophoresis was observed. PMID- 29484613 TI - Limited Evidence for Risk Factors for Proarrhythmia and Sudden Cardiac Death in Patients Using Antidepressants: Dutch Consensus on ECG Monitoring. AB - Currently, there is a lack of international and national guidelines or consensus documents with specific recommendations for electrocardiogram (ECG) screening and monitoring during antidepressant treatment. To make a proper estimation of the risk of cardiac arrhythmias and sudden (cardiac) death during antidepressant use, both the drug and patient-specific factors should be taken into account; however, solid evidence on how this should be done in clinical practice is lacking. Available recommendations on the management of QT(c) prolongation (with antidepressant treatment) emphasize that special attention should be given to high-risk patients; however, clinicians are in need of more concrete suggestions about how to select patients for ECG screening and monitoring. Based on a review of the literature, a Dutch multidisciplinary expert panel aimed to formulate specific guidelines to identify patients at risk for cardiac arrhythmias and sudden death by developing a consensus statement regarding ECG screening before, and monitoring during, antidepressant use. We first reviewed the literature to identify the relative risks of various risk factors on cardiac arrhythmia and sudden (cardiac) death during antidepressant use. These relative contributions of risk factors could not be determined since no systematic reviews or meta-analyses quantitatively addressed this topic. Because evidence was insufficient, additional expert opinion was used to formulate recommendations. This resulted in readily applicable recommendations for clinical practice for selection of high risk patients for ECG screening and monitoring. ECG screening and monitoring is recommended before and following the start of QTc-prolonging antidepressants in the presence of vulnerability to QTc prolongation or two or more risk factors (age > 65 years, female sex, concomitant use of a QTc-prolonging drug or concomitant use of a drug that influences the metabolism of a QTc-prolonging drug, cardiac disease, excessive dosing and specific electrolyte disturbances). PMID- 29484615 TI - Application of an Optimized Tape Stripping Method for the Bioequivalence Assessment of Topical Acyclovir Creams. AB - This study indicates the application of tape stripping (TS) for bioequivalence (BE) assessment of a topical cream product containing 5% acyclovir. A TS method, previously used successfully to assess BE of topical clobetasol propionate and clotrimazole formulations, was used to assess BE of an acyclovir cream (5%) formulation as well as a diluted acyclovir formulation (1.5%) applied to the skin of healthy humans. An appropriate application time was established by conducting a dose duration study using the innovator product, Zovirax(r) cream. Transepidermal water loss was measured and used to normalize thicknesses between subjects. The area under the curve (AUC) from a plot of amount of acyclovir/strip vs cumulative fraction of stratum corneum (SC) removed was calculated for each application site. BE was assessed using Fieller's theorem in accordance with FDA's guidance for assessment of BE of topical corticosteroids. Adco-acyclovir cream (5%) was found to be BE to Zovirax(r) cream, where the mean test/reference (T/R) ratio of the AUC's was 0.96 and the bioequivalence interval using a 90% confidence interval was 0.91-1.01 with a statistical power > 95%, whereas the diluted test product fell outside the BE acceptance criteria with T/R ratio of AUC of 0.23 and a 90% CI of 0.20-0.26. This study indicates that the data resulting from the application of this TS procedure has reinforced the potential for its use to assess BE of topical drug products intended for local action, thereby obviating the necessity to undertake clinical trials in patients. PMID- 29484616 TI - A Review About the Drug Delivery from Microsponges. AB - Microparticulate drug delivery systems have shown a great interest in the pharmaceutical area. They allow the increase of drug therapeutic efficacy and the reduction of side effects. In this context, microsponges represent a new model of porous polymer microspheres, which allow the entrapment of a wide range of active agents. During the development, it is necessary the characterization of the system and among of the most important tests are the release and permeation profile analysis. They can demonstrate the behavior of drug in a specific site with a particular application condition and are related to therapeutic efficacy. Therefore, this review provides an overview of drug delivery profile from microsponges. Methods for determination of in vitro release and ex vivo permeation studies are detailed. Examples of drug delivery from microsponges administered in different sites are also discussed with aim to provide an understanding of the use of this strategy to modify the drug delivery. PMID- 29484618 TI - Pyrolysis of wastewater sludge and composted organic fines from municipal solid waste: laboratory reactor characterisation and product distribution. AB - Sludge from municipal wastewater treatment plants and organic fines from mechanical sorting of municipal solid waste (MSW) are two common widespread waste streams that are becoming increasingly difficult to utilise. Changing perceptions of risk in food production has limited the appeal of sludge use on agricultural land, and outlets via landfilling are diminishing rapidly. These factors have led to interest in thermal conversion technologies whose aim is to recover energy and nutrients from waste while reducing health and environmental risks associated with material re-use. Pyrolysis yields three output products: solid char, liquid oils and gas. Their relative distribution depends on process parameters which can be somewhat optimised depending on the end use of product. The potential of pyrolysis for the conversion of wastewater sludge (SS) and organic fines of MSW (OF) to a combustion gas and a carbon-rich char has been investigated. Pyrolysis of SS and OF was done using a laboratory fixed-bed reactor. Herein, the physical characterisation of the reactor is described, and results on pyrolysis yields are presented. Feedstock and chars have been characterised using standard laboratory methods, and the composition of pyrolysis gases was analysed using micro gas chromatography. Product distribution (char/liquid/gas) from the pyrolysis of sewage sludge and composted MSW fines at 700 degrees C for 10 min were 45/26/29 and 53/14/33%, respectively. The combustible fractions of pyrolysis gases range from 36 to 54% for SS feedstock and 62 to 72% from OF. The corresponding lower heating value range of sampled gases were 11.8-19.1 and 18.2-21.0 MJ m-3, respectively. PMID- 29484617 TI - Ascorbic acid protects male rat brain from oral potassium dichromate-induced oxdative DNA damage and apoptotic changes: the expression patterns of caspase-3, P 53, Bax, and Bcl-2 genes. AB - Our study designed to study the potential of potassium dichromate (K2Cr2O7) oral exposure to induce damage in male rat brain and to compare the possible protective role of vitamin C (VC) either pre and/or concurrent supply against (K2Cr2O7) induced changes. Thirty male rats were divided into five groups. First control group received distilled water (C), second received 120 mg/kg b.wt (VC), third received 25 mg/kg b.wt K2Cr2O7 (Cr), fourth group received VC together with K2Cr2O7 by the same former doses (VC + Cr), and the fifth group received the same oral doses of VC 2 weeks prior to and along with K2Cr2O7 for 6 weeks (VC + Cr pro/co treated). The obtained results revealed that K2Cr2O7 induced a significant decrease in cholinergic activity, glutathione reductase GR activity, reduced glutathione content GSH and ATP levels. Furthermore, K2Cr2O7 induced a significant increase in oxidative DNA damage indicated by 8-hydroxy 2' deoxyguanosine (8OH2'dG) and formation of apoptotic DNA ladders, significant increase in malondialdehyde (MDA), protein carbonyl, and lactate dehydrogenase enzyme. Increased mRNA expression of pro-apoptotic genes, including caspase-3, p53, and Bax, unlike Bcl-2 expression, was decreased. K2Cr2O7 increased caspase-3 and decreased Bcl-2 immuno-labeling. VC supply noticeably ameliorates K2Cr2O7 induced changes which were more significantly in VC pro and concurrent supplement rather than VC concurrent supply only. Finally, it is concluded that K2Cr2O7 oral administration induced oxidative apoptotic changes in rat brain and confirms the usefulness of VC pre and concurrent supply for the amelioration of K2Cr2O7 induced events more significantly than VC concurrent supply only. PMID- 29484619 TI - Fate of perfluorooctanoic acid (PFOA) in sewage sludge during microwave-assisted persulfate oxidation treatment. AB - The fate of perfluorooctanoic acid (PFOA) has been investigated for an emerging sludge treatment technique using microwave heating-assisted persulfate (PS) oxidation. The effect of heating temperature (20, 50, and 70 degrees C) and PS dose (PS1: 0.01; PS2: 0.1; PS3: 0.2 g/g wet sludge) was studied in sludge spiked with PFOA at an environmentally relevant concentration (200 ng/g wet weight). Control degradation experiments using spiked sludge without PS addition and background sludge (no PFOA spike) with PS addition were also conducted at each temperature. Sludge samples were analyzed for eight perfluorocarboxylic acids (PFCAs) (C4 - C11) using LC-MS/MS. At 20 degrees C (PS2 dose), minimal (~ 5%) removal of the spiked PFOA was observed after 72 h, suggesting the need for elevated treatment temperature. For the same PS dose (0.1 g /g sludge), treatment at 50 and 70 degrees C showed a decrease in PFOA concentration with increasing temperature, with ~ 28 and ~ 42% removal following 4 h of treatment. No significant increase in degradation was observed for the highest dose (PS3) after 2 h, possibly indicating self-scavenging of PS at high dosage. Due to the low initial spiking concentration of PFOA and low extraction recovery, all shorter chain PFCAs (< C8), the degradation products of PFOA, were below quantification limits in all sludge samples. PMID- 29484621 TI - Fluorinated waste and firefighting activities: biodegradation of hydrocarbons from petrochemical refinery soil co-contaminated with halogenated foams. AB - Perfluorinated compounds, including fluorotelomers, are important constituents of firefighting foams to extinguish fuel fires in the petrochemical industry, airports, and at fire-training sites. In this study, we monitored the biodegradation process in a co-contamination scenario with monoaromatic hydrocarbons commonly found in fuels (benzene, toluene) and fluorotelomers. The CO2 production rates were evaluated by a factorial design taking into account the effect of seasonality at in situ natural attenuation processes. Headspace analysis by gas chromatography with a thermal conductivity detector (GC-TCD) was applied to detect CO2 production, whereas monoaromatics were analyzed by gas chromatography coupled to mass spectrometry (GC-MS). According to our results, seasonality had a detectable effect during summer, yielding different CO2 production rates. Higher temperatures increased CO2 production rate, while higher concentrations of fluorotelomer inhibited the biodegradation process. On average, benzene and toluene were depleted 17.5 days earlier in control assays without fluorotelomers. Toluene removal efficiency was also notably higher than benzene. The noticeable decrease in degradation rates of monoaromatics was caused by perfluorinated compounds that are possibly linked to metabolic inhibition mechanisms. Fluorotelomer diminished catabolism in all of our batch cultures. In addition to this, an alternative production of by-products could be detected. Thus, we propose that transient components of the benzene and toluene degradation may be differentially formed, causing the benzene, toluene, and perfluorinated co contaminations to go through switched metabolic stages under the presence of fluoride in a contamination scenario. PMID- 29484620 TI - Air pollution from industrial waste gas emissions is associated with cancer incidences in Shanghai, China. AB - Outdoor air pollution may be associated with cancer risk at different sites. This study sought to investigate outdoor air pollution from waste gas emission effects on multiple cancer incidences in a retrospective population-based study in Shanghai, China. Trends in cancer incidence for males and females and trends in waste gas emissions for the total waste gas, industrial waste gas, other waste gas, SO2, and soot were investigated between 1983 and 2010 in Shanghai, China. Regression models after adjusting for confounding variables were constructed to estimate associations between waste gas emissions and multiple cancer incidences in the whole group and stratified by sex, Engel coefficient, life expectancy, and number of doctors per 10,000 populations to further explore whether changes of waste gas emissions were associated with multiple cancer incidences. More than 550,000 new cancer patients were enrolled and reviewed. Upward trends in multiple cancer incidences for males and females and in waste gas emissions were observed from 1983 to 2010 in Shanghai, China. Waste gas emissions came mainly from industrial waste gas. Waste gas emissions was significantly positively associated with cancer incidence of salivary gland, small intestine, colorectal, anus, gallbladder, thoracic organs, connective and soft tissue, prostate, kidney, bladder, thyroid, non-Hodgkin's lymphoma, lymphatic leukemia, myeloid leukemia, and other unspecified sites (all p < 0.05). Negative association between waste gas emissions and the esophagus cancer incidence was observed (p < 0.05). The results of the whole group were basically consistent with the results of the stratified analysis. The results from this retrospective population-based study suggest ambient air pollution from waste gas emissions was associated with multiple cancer incidences. PMID- 29484622 TI - Enhancing denitrification with waste sludge carbon source: the substrate metabolism process and mechanisms. AB - Using waste sludge internal carbon source for nitrogen removal in wastewater has drawn much attention, due to its economic advantages and sludge reduction. In this study, the performance of enhanced denitrification with waste sludge thermal hydrolysate and fermentation liquid as carbon sources at different SCOD/N (soluble chemical oxygen demand/NO3--N) was investigated. The optimum SCOD/N was 8 for sludge thermal hydrolysate and 7 for fermentation liquid, with NO3--N removal efficiency of 92.3 and 98.9%, respectively, and no NO2--N accumulation. To further understand the fate of sludge carbon source during denitrification, the changes of SCOD, proteins, carbohydrates, and volatile fatty acids (VFAs) were analyzed, and three-dimensional fluorescence excitation-emission matrix (EEM) spectroscopy with fluorescence regional integration (FRI) analysis was introduced. The utilization of SCOD was consistent with NO3--N reduction, and the utilization efficiency of different organic matter was as follows: VFAs > proteins > carbohydrates. The soluble organic-like materials (region IV) were the most readily utilized organic matter according to three-dimensional fluorescence EEM spectroscopy. Regarding denitrification mechanisms, the denitrification rate (VDN), denitrification potential (PDN), heterotroph anoxic yield (YH), and the most readily biodegradable COD (SS) were also investigated. PMID- 29484623 TI - Polycyclic aromatic hydrocarbons in a bakery indoor air: trends, dynamics, and dispersion. AB - Indoor air pollution assessment in work environments remains challenging due to a combination of logistic reasons and availability of costly instrumentation for data acquisition and post-processing. Existing literature focuses on energy production environments, hospitals, and less so on food production spaces. Studies on indoor air quality in bakeries are scarce or even absent. Motivated by this, the present study investigates indoor air quality in a bakery located in Bari province in South Italy, using a combination of approaches including analytical chemistry analyses and computational fluid dynamics to reconstruct the air ventilation in response to air temperature gradients within the working environment. PM2.5 indoor samplings were collected every 6 h from 7 to 19 April 2013 in the proximity of two bakery ovens powered by gas and wood, respectively. For each sampling day, 4 PM2.5 samples were collected: from 3:00 to 9:00 h (first), from 9:00 to 13:30 h (second), from 14:00 to 21:00 h (third), and from 21:00 to 3:00 h (fourth). In total, 40 samples were collected. On each sample, several polycyclic aromatic hydrocarbons (PAHs) were determined such as benzo[a]anthracene (228), benzo[b]fluoranthene (252), benzo[k]fluoranthene (252), benzo[a]pyrene (252), benzo[g,h,i]perylene (276), indeno[1,2,3-cd]pyrene (276), and dibenzo[a,h]anthracene (278), the main compounds of 16 priority US Environmental Protection Agency (US-EPA) PAHs in particulate phase. The PAH mean concentrations showed higher values during the first (from 3:00 to 9:00 h) and fourth (from 21:00 to 3:00 h) sampling intervals than the other two with benzo[a]pyrene mean values exceeding the Italian law limit of 1 ng/m3. Taking into account benzo[a]pyrene mean concentration for the first interval and the first plus the second one, which are the hours with the largest working activity, we have estimated that the baker and co-workers are exposed to a cancer risk of 4.3 * 10-7 and 5.8 * 10-7, respectively (these values are lower than US-EPA recommended guideline of 10-6). Our study was complemented by numerical analyses using state-of-the-art computational fluid dynamics to reconstruct at high resolution air movement from the various working places, i.e., the bakery and the selling area which were connected via a door. The numerical simulations were possible given that surface temperature using infrared thermography as well as air temperature was continuously recorded throughout the sampling acquisition. The use of this approach allowed us to estimate the transport and diffusion of benzo[a]pyrene from one area to the other thus complementing the point sampling information. Computational fluid dynamic simulation results confirm the presence of benzo[a]pyrene in the laboratory as obtained from the measurements and suggests its presence in the sales' area of the bakery with concentrations similar those found in the laboratory. PMID- 29484625 TI - Biomechanical problems related to pedicle screw system. AB - AIM: Many studies have reported the results of spinal instrumentation using pedicle screw (PS) systems. However, few biomechanical reports have compared the intact spine with instrumented spine. The purpose of this study was to investigate the biomechanical problems related to PS systems. MATERIAL AND METHODS: Functional spinal units (L3-4) of deer were evaluated using a 6-axis material testing machine. For the specimen models, we prepared an intact model, a damaged model, a PS model, and a crosslink model. We checked the range of motion (ROM) during bending and rotation tests. Eight directions were measured in the bending test: anterior, right-anterior, right, right-posterior, posterior, left posterior, left, and left-anterior, and 2 directions were measured in the rotation test (right and left). RESULTS: ROMs of the PS model were smaller than those of the intact model in all directions. However, ROMs of the PS model in the rotation test were smaller than those of the damaged model and larger than those of the intact model. The stability of the crosslink model was better than that of the PS model during the bending test, but ROMs of the crosslink model were larger than those of the intact model during the rotation test. CONCLUSION: Excessive bending rigidity and rotational instability are the biomechanical problems related to PS systems. Based on these results, we speculate that one of the most significant causes of adjacent segment disease is excessive bending rigidity and one of the most important causes of instrumentation failure is rotational instability. PMID- 29484624 TI - Deep sequencing reveals the molecular pathology characteristics between primary uterine leiomyoma and pulmonary benign metastasizing leiomyoma. AB - PURPOSE: Pulmonary benign metastasizing leiomyoma (PBML), a rare condition of smooth muscle tumor, originates from women with a history of uterine leiomyoma (LM). Numerous genetic studies of uterine LM have been reported; however, there are few cytogenetic and molecular descriptions of PBML. Therefore, molecular subtyping is necessary to understand the pathogenesis of metastasizing sites. METHODS: Driver gene exon-capture sequencing was performed on one patient's peripheral blood, paraffin samples from primary uterine LM, and lung metastasizing leiomyoma 8 years later. RESULTS: The results showed that the same missense mutations of BLMH, LRP2, MED12, SMAD2, and UGT1A8 were concurrently mutated in the primary uterine LM and the PBML. Moreover, a splice mutation of PTEN (c.492+1G>A) was uniquely identified in the lung metastasis of the patient. CONCLUSION: This study indicates that the metastatic lung lesions were derived from the same malignant cell clone of uterine LMs and later acquired the novel driver mutations in the evolution of the tumor. In addition, driver gene sequencing can discriminate somatic driver mutations as biological indicators of potential malignant leiomyoma and can identify pathogenic variation driver mutations, which could be used for individualized therapy. PMID- 29484626 TI - Are specific gene expressions of extracellular matrix and nucleus pulposus affected by primary cell cultures prepared from intact or degenerative intervertebral disc tissues? AB - AIM: In this scientific research project, the researchers aimed to determine the gene expression patterns of nucleus pulposus (NP) in cell cultures obtained from degenerated or intact tissues. MATERIAL AND METHODS: Whereas 12 of the cases were diagnosed with lumbar disc hernia and had undergone lumbar microdiscectomy, 12 cases had undergone traumatic intervertebral discectomy and corpectomy, along with discectomy after spinal trauma. NP-specific markers and gene expressions of the reagents of the extracellular matrix in the experimental setup were tested at the 0th, 24th, and 48th hours by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Visual evaluations were simultaneously made in all samples using invert and fluorescence microscopy. Vitality and proliferation analyses were evaluated by UV spectrophotometer. As a method of statistical evaluation, Spearman was used for categorical variants, and the Pearson correlation was used for variants with numerical and plain distribution. RESULTS: No association was found either between the tissue type and times (r=0.000; p=1.000) or between the region that the tissue was obtained from and hypoxia transcription factor-1 alpha (HIF-1alpha) gene expression (r=0.098; p=0.245). There was no correlation between cell proliferation and chondroadherin (CHAD) expression or between type II collagen (COL2A1) and CHAD gene expressions. It was found that CHAD and HIF-1alpha gene expressions and HIF-1alpha and COL2A1 gene expressions affected cell proliferation. CONCLUSION: Cell culture setups are of paramount importance because they may influence the pattern of changes in the gene expressions of the cells used in these setups. PMID- 29484627 TI - New Entity of Skull Lesions due to Birth Trauma: Kanat (Wing) Fractures. AB - AIM: To discuss a special type of skull lesion detected after delivery. We reviewed our experience on scalp swelling in term neonates to further investigate the relationship between cranial injuries and labor process. MATERIAL AND METHODS: A total of 55 newborns with scalp swellings were assessed with medical records retrospectively between January 2007-July 2017. A radiologist and a pediatric neurosurgeon re-analyzed all skull X-ray images via picture archiving and communication system of the hospital. RESULTS: A special type of skull fracture, called Kanat (wing) fracture, was detected. The fractures appeared unique, were located in the midline parietal bone, and were difficult to detect by X-ray. Kanat fractures accounted for 12.7% of the 55 cases (n=7). Patients without (group-1) and patients with (group-2) Kanat fractures were compared based on the head circumference of the newborns (p=0.881), fetal birth weight (p=0.20), maternal age (p=0.04), duration of second stage of labor (p=0.217), maternal body mass index (p=0.278), total labor time (p=0.922) and parity (p=0.375). No statistically significant difference between the two groups was determined for the compared parameters. CONCLUSION: The present study is the first research describing and discussing the possible effects of maternal, fetal and delivery characteristics on Kanat fractures. Designing clinical and experimental researches to enhance awareness and acknowledgement of skull injuries and labor process could improve the clinical outcome of the newborns. PMID- 29484628 TI - A Hybrid Operation for the Treatment of Extracranial Carotid Artery Aneurysm with a 2-year Follow-up. AB - Extracranial carotid artery aneurysms (ECAA) are less commonly seen disease. It is still difficult to determine the optimal treatment strategy because of limitations in reporting of results and confounding by indications based on the available literature. We depict a hybrid operation combining surgery with balloon occlusion to achieve distal outlet control, aneurysm resection, and reconstruction of parent internal carotid artery for the treatment of extracranial carotid artery aneurysms with good outcomes according to a 2-year follow up. We conclude that a hybrid operation combining surgery with endovascular assistance yields a safe and effective choice for the treatment of extracranial carotid artery aneurysms. PMID- 29484629 TI - The geometry of the circle of Willis anatomical variants as a potential cerebrovascular risk factor. AB - AIM: Anatomical variants of the circle of Willis are diverse and frequent and, although they are not a direct cause of cerebrovascular diseases, they are risk factors for impaired collateral perfusion and wall shear stress. This study aimed to correlate the anatomical variants with their effects on the hemodynamic and geometrical parameters responsible for the pathogenesis of neurological diseases. MATERIAL AND METHODS: The circle of Willis and the proximal segments of the main arteries were dissected and measured on ten formalin-fixed human brains. The anatomical variants were systematized using descriptive statistics. The mathematical models for brain perfusion and wall shear stress were developed by optimally approximating resistance to flow, vascular conductance, and branching. RESULTS: 80% of the brains presented asymmetries, especially in the posterior communicating (70%) and anterior cerebral (40%) arteries. The posterior circulation had more variations (65.21%). Nine hypoplastic vessels were found in 7 brains. Atypical origins were observed in eight cases. According to the mathematical models, which integrated each anatomical change in the global circle of Willis anatomy, the circle of Willis' geometry could represent a risk factor for intracranial aneurysms and atherosclerosis, mostly when hypoplastic arteries are present, due to high resistance to flow and imbalanced bifurcation geometry. Accessory vessels are less associated with cerebrovascular risk. CONCLUSION: We described anatomical variants of both the anterior and posterior circulations and their specific effects on the hemodynamic balance of cerebral blood flow. PMID- 29484630 TI - Co-Innervation of Triceps Brachii Muscle with Variant Branch of Ulnar Nerve. AB - AIM: To evaluate the existence of nerve innervation of the triceps brachii muscle via the ulnar nerve and its clinical importance in terms of nerve transfer or susceptibility to iatrogenic injuries during surgical procedures. MATERIAL AND METHODS: Thirty-five skeletally mature upper extremities of adult cadavers were included in the present study. The ulnar nerve was revealed from the medial cord to the distal part of the cubital fossa. The existence of the branches of the ulnar nerve and communicant branch of the radial nerve was examined in the brachium. The diameter and length of the variant nerve branches were measured. RESULTS: A nerve branch from the ulnar nerve to the triceps brachii muscle was found in five of the dissected extremities (14.7%). The mean length and diameter of the variant nerve branch were 20.2 mm and 1.46 mm, respectively. The mean distance of the muscle entry point of the variant nerve branch from the bi condylar line was 8.18 cm. CONCLUSION: A variant nerve branch via the ulnar nerve can innervate the medial head of the triceps brachii at the distal third of the brachium. This variant nerve branch will be under risk of iatrogenic injury during elbow surgery and it seems to be an option for nerve grafts. PMID- 29484631 TI - Temperature and aridity regulate spatial variability of soil multifunctionality in drylands across the globe. AB - The relationship between the spatial variability of soil multifunctionality (i.e., the capacity of soils to conduct multiple functions; SVM) and major climatic drivers, such as temperature and aridity, has never been assessed globally in terrestrial ecosystems. We surveyed 236 dryland ecosystems from six continents to evaluate the relative importance of aridity and mean annual temperature, and of other abiotic (e.g., texture) and biotic (e.g., plant cover) variables as drivers of SVM, calculated as the averaged coefficient of variation for multiple soil variables linked to nutrient stocks and cycling. We found that increases in temperature and aridity were globally correlated to increases in SVM. Some of these climatic effects on SVM were direct, but others were indirectly driven through reductions in the number of vegetation patches and increases in soil sand content. The predictive capacity of our structural equation modelling was clearly higher for the spatial variability of N- than for C- and P-related soil variables. In the case of N cycling, the effects of temperature and aridity were both direct and indirect via changes in soil properties. For C and P, the effect of climate was mainly indirect via changes in plant attributes. These results suggest that future changes in climate may decouple the spatial availability of these elements for plants and microbes in dryland soils. Our findings significantly advance our understanding of the patterns and mechanisms driving SVM in drylands across the globe, which is critical for predicting changes in ecosystem functioning in response to climate change. PMID- 29484632 TI - Organ-on-Chip Recapitulates Thrombosis Induced by an anti-CD154 Monoclonal Antibody: Translational Potential of Advanced Microengineered Systems. AB - Clinical development of Hu5c8, a monoclonal antibody against CD40L intended for treatment of autoimmune disorders, was terminated due to unexpected thrombotic complications. These life-threatening side effects were not discovered during preclinical testing due to the lack of predictive models. In the present study, we describe the development of a microengineered system lined by human endothelium perfused with human whole blood, a "Vessel-Chip." The Vessel-Chip allowed us to evaluate key parameters in thrombosis, such as endothelial activation, platelet adhesion, platelet aggregation, fibrin clot formation, and thrombin anti-thrombin complexes in the Chip-effluent in response to Hu5c8 in the presence of soluble CD40L. Importantly, the observed prothrombotic effects were not observed with Hu5c8-IgG2sigma designed with an Fc domain that does not bind the FcgammaRIIa receptor, suggesting that this approach may have a low potential risk for thrombosis. Our results demonstrate the translational potential of Organs-on-Chips, as advanced microengineered systems to better predict human response. PMID- 29484633 TI - A Person-Centered Approach to Child Temperament and Parenting. AB - The aim of this study was to examine how variations in children's temperamental reactivity and mothers' parenting stress relate to parenting behavior. A sample of 3,001 mother-child dyads was assessed when children were 14, 24, 36, and 54 months. Latent profile analysis identified a group of temperamentally "easy" children whose mothers experienced little parenting stress, along with two groups of highly reactive children differentiated by mothers' stress levels. Maternal negative regard over time was highest in the group of reactive children with highly stressed mothers. Mothers in this group also perceived more child behavior problems and had less knowledge of child development. Results are discussed relative to Person * Environment interactions and the complex interplay between parent and child characteristics. PMID- 29484634 TI - Exploring the structure characteristics and major channels of cytochrome P450 2A6, 2A13, and 2E1 with pilocarpine. AB - The majority of cytochromes P450 play a critical role in metabolism of endogenous and exogenous substrates, some of its products are carcinogens. Therefore, inhibition of P450 enzymes activity can promote the detoxification and elimination of chemical carcinogens. In this study, molecular dynamics (MD) simulations and adaptive steered molecular dynamics (ASMD) simulations were performed to explore the structure features and channel dynamics of three P450 isoforms 2A6, 2A13, and 2E1 bound with the common inhibitor pilocarpine. The binding free energy results combined with the PMF calculations give a reasonable ranking of binding affinity, which are consistent with the experimental data. Our results uncover how a sequence divergence of different CYP2 enzymes causes individual variations in major channel selections. On the basis of channel bottleneck and energy decomposition analysis, we propose a gating mechanism of their respective major channels in three enzymes, which may be attributed to a reversal of Phe209 in CYP2A6/2A13, as well as the rotation of Phe116 and Phe298 in CYP2E1. The hydrophobic residues not only make strong hydrophobic interactions with inhibitor, but also act as gatekeeper to regulate the opening of channel. The present study provides important insights into the structure-function relationships of three cytochrome P450s and the molecular basis for development of potent inhibitors. PMID- 29484635 TI - Dipeptidyl Peptidase 1 Inhibitor AZD7986 Induces a Sustained, Exposure-Dependent Reduction in Neutrophil Elastase Activity in Healthy Subjects. AB - Neutrophil serine proteases (NSPs), such as neutrophil elastase (NE), are activated by dipeptidyl peptidase 1 (DPP1) during neutrophil maturation. High NSP levels can be detrimental, particularly in lung tissue, and inhibition of NSPs is therefore an interesting therapeutic opportunity in multiple lung diseases, including chronic obstructive pulmonary disease (COPD) and bronchiectasis. We conducted a randomized, placebo-controlled, first-in-human study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of the DPP1 inhibitor AZD7986 in healthy subjects. Pharmacokinetic and pharmacodynamic data were analyzed using nonlinear mixed effects modeling and showed that AZD7986 inhibits whole blood NE activity in an exposure-dependent, indirect manner-consistent with in vitro and preclinical predictions. Several dose-dependent, possibly DPP1-related, nonserious skin findings were observed, but these were not considered to prevent further clinical development. Overall, the study results provided confidence to progress AZD7986 to phase II and supported selection of a clinically relevant dose. PMID- 29484637 TI - Child Sleep and Socioeconomic Context in the Development of Cognitive Abilities in Early Childhood. AB - Despite a robust literature examining the association between sleep problems and cognitive abilities in childhood, little is known about this association in toddlerhood, a period of rapid cognitive development. The present study examined the association between various sleep problems, using actigraphy, and performance on a standardized test of cognitive abilities, longitudinally across three ages (30, 36, and 42 months) in a large sample of toddlers (N = 493). Results revealed a between-subject effect in which the children who had more delayed sleep schedules on average also showed poorer cognitive abilities on average but did not support a within-subjects effect. Results also showed that delayed sleep explains part of the association between family socioeconomic context and child cognitive abilities. PMID- 29484638 TI - Safety, Pharmacokinetics, and Pharmacodynamics in Healthy Volunteers Treated With GDC-0853, a Selective Reversible Bruton's Tyrosine Kinase Inhibitor. AB - GDC-0853 is a small molecule inhibitor of Bruton's tyrosine kinase (BTK) that is highly selective and noncovalent, leading to reversible binding. In double-blind, randomized, and placebo-controlled phase I healthy volunteer studies, GDC-0853 was well tolerated, with no dose-limiting adverse events (AEs) or serious AEs. The maximum tolerated dose was not reached during dose escalation (<=600 mg, single ascending dose (SAD) study; <=250 mg twice daily (b.i.d.) and <=500 mg once daily, 14-day multiple ascending dose (MAD) study). Plasma concentrations peaked 1-3 hours after oral administration and declined thereafter, with a steady state half-life ranging from 4.2-9.9 hours. Independent assays demonstrated dose dependent BTK target engagement. Based on pharmacokinetic/pharmacodynamic (PK/PD) simulations, a once-daily dosing regimen (e.g., 100 mg, q.d.) is expected to maintain a high level of BTK inhibition over the dosing interval. Taken together, the safety and PK/PD data support GDC-0853 evaluation in rheumatoid arthritis, lupus, and other autoimmune or inflammatory indications. PMID- 29484639 TI - Quantitative axial myology in two constricting snakes: Lampropeltis holbrooki and Pantherophis obsoletus. AB - A snake's body represents an extreme degree of elongation with immense muscle complexity. Snakes have approximately 25 different muscles on each side of the body at each vertebra. These muscles serially repeat, overlap, interconnect, and rarely insert parallel to the vertebral column. The angled muscles mean that simple measurements of anatomical cross-sectional area (ACSA, perpendicular to the long-axis of the body) serve only as proxies for the primary determinant of muscle force, physiological cross-sectional area (PCSA, area perpendicular to the muscle fibers). Here, I describe and quantify the musculature of two intraguild constrictors: kingsnakes (Lampropeltis holbrooki) and ratsnakes (Pantherophis obsoletus) whose predation performance varies considerably. Kingsnakes can produce significantly higher constriction pressures compared with ratsnakes of similar size. In both snakes, I provide qualitative descriptions, detail previously undescribed complexity, identify a new lateral muscle, and provide some of the first quantitative measures of individual muscle and whole-body PCSA. Furthermore, I compare measurements of ACSA with measurements of PCSA. There was no significant difference in PCSA of muscles between kingsnakes and ratsnakes. There is, however, a strong relationship between ACSA and PCSA measurements. I could not identify a significant difference in musculature between kingsnakes and ratsnakes that explains their different levels of constriction performance. Unmeasured components of muscle function, such as endurance and force production, might account for differences in performance between two species with similar muscle structure. PMID- 29484640 TI - Helicopter vs. ground transportation of patients bound for primary percutaneous coronary intervention. AB - BACKGROUND: Implementation of the first Danish helicopter emergency medical service (HEMS) was associated with reduced time from first medical contact to treatment at a specialized centre for patients with suspected ST elevation myocardial infarction (STEMI). We aimed to investigate effects of HEMS on mortality and labour market affiliation in patients admitted for primary percutaneous coronary intervention (PCI). METHODS: In this prospective observational study, we included patients with suspected STEMI within the region covered by the HEMS from January 1, 2010, to April 30, 2013, transported by either HEMS or ground emergency medical services (GEMS) to the regional PCI centre. The primary outcome was 30-day mortality. RESULTS: Among the 384 HEMS and 1220 GEMS patients, time from diagnostic ECG to PCI centre arrival was lower with HEMS (median 71 min vs. 78 min with GEMS; P = 0.004). Thirty-day mortality was 5.0% and 6.2%, respectively (adjusted OR = 0.82, 95% CI 0.44-1.51, P = 0.52. Involuntary early retirement rates were 0.62 (HEMS) and 0.94 (GEMS) per 100 PYR (adjusted IRR = 0.68, 0.15-3.23, P = 0.63). The proportion of patients on social transfer payments longer than half of the follow-up time was 22.1% (HEMS) vs. 21.2% (adjusted OR = 1.10, 0.64-1.90, P = 0.73). CONCLUSION: In an observational study of patients with suspected STEMI in eastern Denmark, no significant beneficial effect of helicopter transport could be detected on mortality, premature labour market exit or work ability. Only a study with random allocation to one system vs. another, along with a large sample size, will allow determination of superiority of helicopter transport. PMID- 29484641 TI - Acute Respiratory Distress Syndrome: Bench-to-Bedside Approaches to Improve Drug Development. AB - Despite 50 years of extensive research, no definite drug is currently available to treat acute respiratory distress syndrome (ARDS), and the supportive therapies remain the mainstay of treatment. To improve drug development for ARDS, researchers need to deeply analyze the "omics" approaches, reevaluate the suitable therapeutic targets, resolve the problems of inadequate animal modeling, develop the strategies to reduce the heterogeneity, and reconsider new therapeutic and analytical approaches for better designs of clinical trials. PMID- 29484642 TI - Using Meta-analytic Structural Equation Modeling to Study Developmental Change in Relations Between Language and Literacy. AB - The purpose of this review was to introduce readers of Child Development to the meta-analytic structural equation modeling (MASEM) technique. Provided are a background to the MASEM approach, a discussion of its utility in the study of child development, and an application of this technique in the study of reading comprehension (RC) development. MASEM uses a two-stage approach: first, it provides a composite correlation matrix across included variables, and second, it fits hypothesized a priori models. The provided MASEM application used a large sample (N = 1,205,581) of students (ages 3.5-46.225) from 155 studies to investigate the factor structure and relations among components of RC. The practical implications of using this technique to study development are discussed. PMID- 29484643 TI - Alouatta pigra males ignore A. palliata loud calls: A case of failed rival recognition? AB - OBJECTIVES: When closely related species overlap geographically, selection may favor species-specific mate recognition traits to avoid hybridization costs. Conversely, the need to recognize potential same-sex rivals may select for lower specificity, creating the possibility that selection in one domain constrains evolution in the other. Despite a wealth of data on mate recognition, studies addressing rival recognition between hybridizing species are limited to a few bird species. Using naive populations, we examine the extent to which failed rival recognition might have affected hybridization patterns when two species of howler monkeys (Alouatta pigra and A. palliata) first met after diverging in allopatry. METHODS: We simulated first contact between naive subjects using playback experiments in allopatric populations of the two purebred species. Using linear mixed models, we compared their look, move, and vocal responses to conspecific and heterospecific loud calls. RESULTS: Although not different in overall response strength to playbacks, the two species differed in reaction to heterospecific callers. Male A. pigra ignored calls from male A. palliata, but the reverse was not true. DISCUSSION: Despite striking differences in vocalizations, A. palliata respond equally to calls from both species whereas A. pigra respond only to conspecifics. This apparent failure of A. pigra males to recognize interspecific rivals might have biased hybridization (F1 hybrids = male A. palliata x female A. pigra), a pattern previously hypothesized based on genetic analysis of hybrids. Given that A. pigra males could be losing reproductive opportunities to heterospecific males, our findings add to growing evidence of potential costs for overly specific species recognition. PMID- 29484644 TI - More Similar Than Different: Gender Differences in Children's Basic Numerical Skills Are the Exception Not the Rule. AB - This study investigates gender differences in basic numerical skills that are predictive of math achievement. Previous research in this area is inconsistent and has relied upon traditional hypothesis testing, which does not allow for assertive conclusions to be made regarding nonsignificant findings. This study is the first to compare male and female performance (N = 1,391; ages 6-13) on many basic numerical tasks using both Bayesian and frequentist analyses. The results provide strong evidence of gender similarities on the majority of basic numerical tasks measured, suggesting that a male advantage in foundational numerical skills is the exception rather than the rule. PMID- 29484645 TI - Comparative iTRAQ analysis of protein abundance in the human sinoatrial node and working cardiomyocytes. AB - Our objective was to assess the changes in protein abundance in the human sinoatrial node (SAN) compared with working cardiomyocytes to identify SAN specific protein signatures. Four pairs of samples (the SAN and working cardiomyocytes) were obtained postmortem from four human donors with no evidence of cardiovascular disease. We performed protein identification and quantitation using two-dimensional chromatography-tandem mass spectrometry with isobaric peptide labeling (iTRAQ). We identified 451 different proteins expressed in both the SAN and working cardiomyocytes, 166 of which were differentially regulated (110 were upregulated in the SAN and 56 in the working cardiomyocytes). We identified sarcomere structural proteins in both tissues, although they were differently distributed among the tested samples. For example, myosin light chain 4, myosin regulatory light chain 2-atrial isoform, and tropomyosin alpha-3 chain levels were twofold higher in the SAN than in working cardiomyocytes, and myosin light chain 3 and myosin regulatory light chain 2-ventricular/cardiac muscle isoform levels were twofold higher in the ventricle tissue than in SAN. We identified many mitochondrial oxidative phosphorylation, beta-oxidation, and tricarboxylic acid cycle proteins that were predominantly associated with working cardiomyocytes tissue. We detected upregulation of the fatty acid omega activation pathway proteins in the SAN samples. Some proteins specific for smooth muscle tissue were highly upregulated in the SAN (e.g. transgelin), which indicates that the SAN tissue might act as the bridge between the working myocardium and the smooth muscle. Our results show possible implementation of proteomic strategies to identify in-depth functional differences between various heart sub-structures. PMID- 29484646 TI - A microbial-enzymatic strategy for producing chondroitin sulfate glycosaminoglycans. AB - Chondroitin sulfate has been widely used in both medical and clinical applications. Commercial chondroitin sulfate has been mainly acquired from animal tissue extraction. Here we report a new two-step biological strategy for producing chondroitin sulfate A and chondroitin sulfate C. First, the chondroitin biosynthesis pathway in a recombinant Bacillus subtilis strain using sucrose as carbon source was systematically optimized and the titer of chondroitin was significantly enhanced to 7.15 g/L. Then, specific sulfation transformation systems were successfully constructed and optimized by combining the purified aryl sulfotransferase IV (ASST IV), chondroitin 4-sulfotransferase (C4ST) and chondroitin 6-sulfotransferase (C6ST). Chondroitin sulfate A and C were enzymatically transformed from chondroitin at conversion rates of 98% and 96%, respectively. The present biological strategy has great potential to be scaled up for biosynthesis of chondroitin sulfate A and C from cheap carbon sources. PMID- 29484647 TI - Gene-based evaluation of low-frequency variation and genetically-predicted gene expression impacting risk of keloid formation. AB - Keloids are benign dermal tumors occurring approximately 20 times more often in individuals of African descent as compared to individuals of European descent. While most keloids occur sporadically, a genetic predisposition is supported by both familial aggregation of some keloids and large differences in risk among populations. Despite Africans and African Americans being at increased risk over lighter-skinned individuals, little genetic research exists into this phenotype. Using a combination of admixture mapping and exome analysis, we reported multiple common variants within chr15q21.2-22.3 associated with risk of keloid formation in African Americans. Here we describe a gene-based association analysis using 478 African American samples with exome genotyping data to identify genes containing low-frequency variants associated with keloids, with evaluation of genetically-predicted gene expression in skin tissues using association summary statistics. The strongest signal from gene-based association was located in C15orf63 (P-value = 6.6 * 10-6 ) located at 15q15.3. The top result from gene expression was increased predicted DCAF4 expression (P-value = 5.5 * 10-4 ) in non-sun-exposed skin, followed by increased predicted OR10A3 expression in sun exposed skin (P-value = 6.9 * 10-4 ). Our findings identify variation with putative roles in keloid formation, enhanced by the use of predicted gene expression to support the biological roles of variation identified only though genetic association studies. PMID- 29484648 TI - Architectonic features and relative locations of primary sensory and related areas of neocortex in mouse lemurs. AB - Mouse lemurs are the smallest of the living primates, and are members of the understudied radiation of strepsirrhine lemurs of Madagascar. They are thought to closely resemble the ancestral primates that gave rise to present day primates. Here we have used multiple histological and immunochemical methods to identify and characterize sensory areas of neocortex in four brains of adult lemurs obtained from a licensed breeding colony. We describe the laminar features for the primary visual area (V1), the secondary visual area (V2), the middle temporal visual area (MT) and area prostriata, somatosensory areas S1(3b), 3a, and area 1, the primary motor cortex (M1), and the primary auditory cortex (A1). V1 has "blobs" with "nonblob" surrounds, providing further evidence that this type of modular organization might have evolved early in the primate lineage to be retained in all extant primates. The laminar organization of V1 further supports the view that sublayers of layer 3 of primates have been commonly misidentified as sublayers of layer 4. S1 (area 3b) is proportionately wider than the elongated area observed in anthropoid primates, and has disruptions that may distinguish representations of the hand, face, teeth, and tongue. Primary auditory cortex is located in the upper temporal cortex and may include a rostral area, R, in addition to A1. The resulting architectonic maps of cortical areas in mouse lemurs can usefully guide future studies of cortical connectivity and function. PMID- 29484649 TI - Reply from Luca Ruggiero, Alexandra F. Yacyshyn, Jane Nettleton and Chris J. McNeil. PMID- 29484650 TI - Has the attention deficit hyperactivity disorder phenotype become more common in children between 2004 and 2014? Trends over 10 years from a Swedish general population sample. AB - BACKGROUND: Studies have reported increases in clinically diagnosed and treated attention deficit hyperactivity disorder (ADHD) during the last decade, but it is unclear if this reflects an increase in the underlying ADHD phenotype. We aimed to clarify if there has been an increase in the prevalence of ADHD-like traits in the general population from 2004 to 2014. METHOD: Data were collected from 9-year old twins (19,271), participating in the population-based Child and Adolescent Twin Study in Sweden between 2004 and 2014. We assessed lifetime ADHD symptoms using the Autism-Tics, ADHD and other Comorbidities inventory. Research proxies for diagnostic-level ADHD and subthreshold ADHD were derived from this scale. We modeled the lifetime prevalence of diagnostic-level and subthreshold ADHD with logistic regression, and assessed mean ADHD scores each year with linear regression. Lifetime prevalence of clinically diagnosed ADHD was retrieved from the National Patient Register and modeled with logistic regression. RESULTS: The prevalence of diagnostic-level ADHD based on parent ratings did not differ significantly over time from 2004 to 2014 (OR 1.37; 95% CI: 0.77-2.45; p-value .233). Both subthreshold ADHD and mean ADHD scores increased significantly over time (both p-values <.001). Clinically diagnosed ADHD increased more than fivefold from 2004 to 2014 (OR 5.27, 95% CI: 1.85-14.96). CONCLUSIONS: We found no evidence of an increase in ADHD-like traits at the extreme end of the distribution from 2004 to 2014, but small increases in normal and subthreshold variations of ADHD-like traits were observed. This suggests that the increased rates of clinically diagnosed ADHD might reflect changes in diagnostic and treatment practices of ADHD, administrative changes in reporting diagnoses, greater awareness of ADHD, better access to healthcare, or current overdiagnosis, rather than an increase in the ADHD phenotype. PMID- 29484651 TI - Reply to Grant, William: Obesity and vitamin D status may help explain the racial and ethnic disparities in ampullary cancer survival rates. PMID- 29484652 TI - TrpM8-mediated somatosensation in mouse neocortex. AB - Somatosensation is a complex sense mediated by more than a dozen distinct neural subtypes in the periphery. Although pressure and touch sensation have been mapped to primary somatosensory cortex in rodents, it has been controversial whether pain and temperature inputs are also directed to this area. Here we use a well defined somatosensory modality, cool sensation mediated by peripheral TrpM8 receptors, to investigate the neural substrate for cool perception in the mouse neocortex. Using activation of cutaneous TrpM8 receptor-expressing neurons, we identify candidate neocortical areas responsive for cool sensation. Initially, we optimized TrpM8 stimulation and determined that menthol, a selective TrpM8 agonist, was more effective than cool stimulation at inducing expression of the immediate-early gene c-fos in the spinal cord. We developed a broad-scale brain survey method for identification of activated brain areas, using automated methods to quantify c-fos immunoreactivity (fos-IR) across animals. Brain areas corresponding to the posterior insular cortex and secondary somatosensory (S2) show elevated fos-IR after menthol stimulation, in contrast to weaker activation in primary somatosensory cortex (S1). In addition, menthol exposure triggered fos IR in piriform cortex, the amygdala, and the hypothalamus. Menthol-mediated activation was absent in TrpM8-knock-out animals. Our results indicate that cool somatosensory input broadly drives neural activity across the mouse brain, with neocortical signal most elevated in the posterior insula, as well as S2 and S1. These findings are consistent with data from humans indicating that the posterior insula is specialized for somatosensory information encoding temperature, pain, and gentle touch. PMID- 29484653 TI - Hedychium spicatum: a systematic review on traditional uses, phytochemistry, pharmacology and future prospectus. AB - OBJECTIVES: Hedychium spicatum Buch. Ham. ex D.Don. (Family Zingiberaceae) is a rhizomatous herb, used in medicines, food, cosmetics and perfumery industries. Traditionally, it is widely used in treating inflammation, pain, asthma, foul breath, vomiting, diarrhoea, bronchitis, hiccough and blood diseases. This study systematically reviewed traditional and folk uses, pharmacological properties, bioactive compounds and market potential of H. spicatum. Research gaps and potential of future research have also been discussed. KEY FINDINGS: Available literature indicates that research on this species is largely focused on phytochemical and pharmacological studies; however, propagation and modern interventions for high productivity have been contravened. These studies demonstrated that the rhizome of the species exhibited many valuable and medicinally important compounds, such as labdane terpenes, hedychinone and polyphenols. Many of the traditional uses of the species have been validated through the findings of pharmacological studies and biological properties of the extracts and pure compounds. Phytochemical constituents and related pharmacological activities have provided some suggestive scientific evidences for the various ethnomedicinal uses of the species in the treatment, control and management of diseases and for new drug discovery. SUMMARY: Literature reveals that the species is lacking in exact scientific basis of the beneficial properties. Although, some other distinct biological properties identified in this species also opened new door way for its new applications. Therefore, the mentioned phytochemical constituents such as phenolic and flavonoids compounds; and related pharmacological activities such as antimicrobial, anti-inflammatory and antioxidant activity of the species have provided some suggestive scientific evidences for its potential in pharmaceutical, food and aromatic industries. PMID- 29484654 TI - Ablation approach for primary liver tumors: Peri-operative outcomes. AB - BACKGROUND AND OBJECTIVES: Ablation is a common treatment modality for malignant primary liver tumors(PLTs), outcomes following laparoscopic (LA) versus open ablation (OA) are ill-defined. This project compares peri-procedural outcomes of LA versus OA for PLTs. MATERIALS AND METHODS: Patients with PLTs undergoing radiofrequency ablation were queried from ACS NSQIP Database (2005-2013) using CPT codes. Patients undergoing percutaneous ablation or hepatic resection were excluded. Multivariable logistic regression analyses determined the association of ablation approach with 30-day morbidity and mortality. RESULTS: Of 5747 with PLTs, 655 (11.4%) ablations were identified: 177 (27.0%) underwent OA, 478 (73.0%) underwent LA. Patients undergoing LA had lower mortality (1.9% vs 5.1%, P = 0.026), lower minor morbidity (2.3% vs 5.7%, P = 0.031), and lower major morbidity (4.2% vs 17.0%, P < 0.001). Adjusting for demographics, disease specific variables (preoperative ascites, total bilirubin, platelet count, albumin, and INR), 30-day mortality (OR 3.85, 95%CI: 1.38-10.80, P = 0.010), minor morbidity (OR 2.98, 95%CI: 1.16-7.67, P = 0.024), and major morbidity (OR 4.59 95%CI: 2.41-8.76, P < 0.001) were statistically lower in LA. OA demonstrated increased length of stay(LOS) (5 vs 2 days, P < 0.001), and longer operative time (152 vs 112 min, P < 0.001). CONCLUSION: LA offers decreased peri-procedural morbidity, mortality, and reduced LOS. LA should be the preferred method for hepatic ablation. PMID- 29484655 TI - Delineation of human prostate cancer evolution identifies chromothripsis as a polyclonal event and FKBP4 as a potential driver of castration resistance. AB - Understanding the evolutionary mechanisms and genomic events leading to castration-resistant (CR) prostate cancer (PC) is key to improve the outcome of this otherwise deadly disease. Here, we delineated the tumour history of seven patients progressing to castration resistance by analysing matched prostate cancer tissues before and after castration. We performed genomic profiling of DNA content-based flow-sorted populations in order to define the different evolutionary patterns. In one patient, we discovered that a catastrophic genomic event, known as chromothripsis, resulted in multiple CRPC tumour populations with distinct, potentially advantageous copy number aberrations, including an amplification of FK506 binding protein 4 (FKBP4, also known as FKBP52), a protein enhancing the transcriptional activity of androgen receptor signalling. Analysis of FKBP4 protein expression in more than 500 prostate cancer samples revealed increased expression in CRPC in comparison to hormone-naive (HN) PC. Moreover, elevated FKBP4 expression was associated with poor survival of patients with HNPC. We propose FKBP4 amplification and overexpression as a selective advantage in the process of tumour evolution and as a potential mechanism associated with the development of CRPC. Furthermore, FKBP4 interaction with androgen receptor may provide a potential therapeutic target in PC. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29484656 TI - Maternal depression impacts child psychopathology across the first decade of life: Oxytocin and synchrony as markers of resilience. AB - BACKGROUND: While maternal depression is known to carry long-term negative consequences for offspring, very few studies followed children longitudinally to address markers of resilience in the context of maternal depression. We focused on oxytocin (OT) and mother-child synchrony - the biological and behavioral arms of the neurobiology of affiliation - as correlates of resilience among children of depressed mothers. METHOD: A community birth-cohort was recruited on the second postbirth day and repeatedly assessed for maternal depression across the first year. At 6 and 10 years, mothers and children underwent psychiatric diagnosis, mother-child interactions were coded for maternal sensitivity, child social engagement, and mother-child synchrony, children's OT assayed, and externalizing and internalizing problems reported. RESULTS: Exposure to maternal depression markedly increased child propensity to develop Axis-I disorder at 6 and 10 years. Child OT showed main effects for both maternal depression and child psychiatric disorder at 6 and 10 years, with maternal or child psychopathology attenuating OT response. In contrast, maternal depression decreased synchrony at 6 years but by 10 years synchrony showed only child disorder effect, highlighting the shift from direct to indirect effects as children grow older. Path analysis linking maternal depression to child externalizing and internalizing problems at 10 years controlling for 6-year variables indicated that depression linked with decreased maternal sensitivity and child OT, which predicted reduced child engagement and synchrony, leading to higher externalizing and internalizing problems. OT and synchrony mediated the effects of maternal depression on child behavior problems and an alternative model without these resilience components provided less adequate fit. CONCLUSIONS: Maternal depression continues to play a role in children's development beyond infancy. The mediating effects of OT and synchronous, mutually regulated interactions underscore the role of plasticity in resilience. Results emphasize the need to follow children of depressed mothers across middle childhood and construct interventions that bolster age-appropriate synchrony. PMID- 29484657 TI - Melatonin provides protection against heat stroke-induced myocardial injury in male rats. AB - OBJECTIVES: This study aimed to investigate the cardioprotective effects of melatonin on heat stroke (HS) induced acute myocardial infarction in rats and to explore the underlying mechanisms. METHODS: Myocardial injury was induced by subjecting the anaesthetized rats to a high ambient temperature of 43 degrees C for 70 min. Such a high ambient temperature caused hyperthermia, hypotension and myocardial injury in rats. Rats were treated with melatonin (3 mg/kg) intravenously one hour before and followed by an additional dose immediately after heat stress. KEY FINDINGS: At the onset of HS, animals displayed myocardial injury evidenced by increased levels of cardiac damage indicators (e.g. total lactate dehydrogenase, cardiac troponin I and creatine kinase-MB), increased cardiac damage scores and suppressed left ventricular performance. Animals with HS also had increased cardiac oxidative stress evidenced by increased levels of lipid peroxidation (e.g. increased thiobarbituric acid reactive substances) and decreased levels of antioxidant enzymes (e.g. superoxide dismutase, catalase and reduced glutathione) and activated inflammation (e.g. increased levels of interleukin-6 and tumour necrosis factor-alpha). Pretreatment with melatonin significantly reversed the HS-induced myocardial injury, cardiac oxidative stress and cardiac inflammation. CONCLUSIONS: Melatonin may protect against HS-induced myocardial injury in male rats by mitigating oxidative stress and inflammation. PMID- 29484658 TI - Nasolabial propeller perforator flap: Anatomical study and case series. AB - PURPOSE: The previous cadaveric studies of facial artery perforators have frequently reported high variability, and those results remain to be validated in the Colombian population. Thus, we aimed to describe the vascular anatomy of the lateral nasal artery cutaneous branches and their clinical applications using Colombian cadavers. MATERIALS AND METHODS: Nine hemifaces from six fresh cadavers were included in the study. Terminal branches of the facial artery and cutaneous perforators of the lateral nasal artery were dissected. The quality, number, and distribution of the perforators were assessed. In addition, we present results of seven clinical cases for nasal alar reconstruction. RESULTS: Cutaneous perforators were found in all hemifaces, and zone 2 was the most common location. In our clinical case series, all flaps used to reconstruct the nasal alar defects survived. There were two cases of venous congestion but no additional procedures were needed. CONCLUSIONS: Although nasal alar reconstruction continues to be a challenging plastic surgery procedure, the nasolabial propeller perforator flap is an excellent choice for such because it allows a precise skin island design, is less bulky, has a wide arc of rotation, and facilitates one-staged reconstruction without increasing the rate of complications. PMID- 29484659 TI - Development and prospective validation of a model estimating risk of readmission in cancer patients. AB - INTRODUCTION: Hospital readmissions among cancer patients are common. While several models estimating readmission risk exist, models specific for cancer patients are lacking. METHODS: A logistic regression model estimating risk of unplanned 30-day readmission was developed using inpatient admission data from a 2-year period (n = 18 782) at a tertiary cancer hospital. Readmission risk estimates derived from the model were then calculated prospectively over a 10 month period (n = 8616 admissions) and compared with actual incidence of readmission. RESULTS: There were 2478 (13.2%) unplanned readmissions. Model factors associated with readmission included: emergency department visit within 30 days, >1 admission within 60 days, non-surgical admission, solid malignancy, gastrointestinal cancer, emergency admission, length of stay >5 days, abnormal sodium, hemoglobin, or white blood cell count. The c-statistic for the model was 0.70. During the 10-month prospective evaluation, estimates of readmission from the model were associated with higher actual readmission incidence from 20.7% for the highest risk category to 9.6% for the lowest. CONCLUSIONS: An unplanned readmission risk model developed specifically for cancer patients performs well when validated prospectively. The specificity of the model for cancer patients, EMR incorporation, and prospective validation justify use of the model in future studies designed to reduce and prevent readmissions. PMID- 29484661 TI - Hyperthermic isolated limb perfusion, preoperative radiotherapy, and surgery (PRS) a new limb saving treatment strategy for locally advanced sarcomas. AB - BACKGROUND: This feasibility study presents the results of a new intensive treatment regimen for locally advanced extremity soft tissue sarcomas (ESTS), consisting of hyperthermic isolated limb perfusion (HILP), preoperative external beam radiotherapy (EBRT), and surgical resection. METHODS: From 2011 to 2016, 11 high grade locally advanced ESTS patients underwent this treatment regimen. Preoperative EBRT (12 * 3 Gy) started <4 weeks following the HILP (TNF-alpha and melphalan) and the surgical resection was planned to take place <2 weeks following the end of the EBRT. RESULTS: All patients completed the treatment. After a median follow-up of 32 (23-50) months, the limb was saved in 10 patients (91%), 1 patient (9%) developed a local recurrence, 5 patients (45%) developed distant metastases, and 3 patients (27%) died of their disease. During follow-up two patients (18%) developed a pathologic fracture of the treated limb and three patients (27%) developed a major wound complication requiring surgical intervention. The median overall treatment time (OTT) was 56 (49-69) days. CONCLUSIONS: This intensive treatment regimen is feasible and safe in locally advanced ESTS, and it achieves oncological results that are comparable with conventional HILP treatment. In addition, the major wound complication risk is comparable and the OTT is reduced. PMID- 29484662 TI - Melanoma patterns of care in Ontario: A call for a strategic alignment of multidisciplinary care-Response to letter. PMID- 29484660 TI - The dual-gate model for pentameric ligand-gated ion channels activation and desensitization. AB - Pentameric ligand-gated ion channels (pLGICs) mediate fast neurotransmission in the nervous system. Their dysfunction is associated with psychiatric, neurological and neurodegenerative disorders such as schizophrenia, epilepsy and Alzheimer's disease. Understanding their biophysical and pharmacological properties, at both the functional and the structural level, thus holds many therapeutic promises. In addition to their agonist-elicited activation, most pLGICs display another key allosteric property, namely desensitization, in which they enter a shut state refractory to activation upon sustained agonist binding. While the activation mechanisms of several pLGICs have been revealed at near atomic resolution, the structural foundation of desensitization has long remained elusive. Recent structural and functional data now suggest that the activation and desensitization gates are distinct, and are located at both sides of the ion channel. Such a 'dual gate mechanism' accounts for the marked allosteric effects of channel blockers, a feature illustrated herein by theoretical kinetics simulations. Comparison with other classes of ligand- and voltage-gated ion channels shows that this dual gate mechanism emerges as a common theme for the desensitization and inactivation properties of structurally unrelated ion channels. PMID- 29484663 TI - Number of nodes in sentinel lymph node biopsy for breast cancer: Are surgeons still biased? AB - BACKGROUND AND OBJECTIVES: The purpose of this study was to assess the number of lymph nodes removed at SLNB, and what factors might bias a surgeon's decision to remove additional nodes. METHODS: A prospectively maintained database was reviewed. All patients that had SLNB for primary treatment of breast cancer between January 2012 and March 2016 were identified. Clinicopathologic factors were used to compare the number of LNs and rates of node positivity. RESULTS: One thousand six hundred and three patients were included. The average number of SLNs, non-SLNs, and total LNs was 2.53, 0.54, 3.08, respectively. Significantly more LNs were removed in age <40 versus age >40 (3.73, 3.04 P < 0.01), invasive versus DCIS (3.13, 2.73 P < 0.001), Grade III versus Grade II (3.42, 2.99 P < 0.01), T2 versus T1 (3.40, 2.96 P < 0.01), and ER- versus ER+ (3.45, 3.05 P < 0.05). SLN positivity was significantly higher (P < 0.05) in invasive versus DCIS (27%, 4%), T2 versus T1 (30%. 17%), Grade II versus Grade I (42%, 18%), and ILC versus IDC (38%, 26%). CONCLUSIONS: There was a significant difference in the number of lymph nodes removed at SLNB in certain groups however; node positivity was not necessarily higher in these groups. Surgeons must be cognizant of potential bias when performing SLNB. PMID- 29484664 TI - Considering the cost of a simultaneous versus staged approach to resection of colorectal cancer with synchronous liver metastases in a publicly funded healthcare model. AB - BACKGROUND: Simultaneous resection for colorectal cancer with synchronous liver metastases is an established alternative to a staged approach. This study aimed to compare these approaches with regards to economic parameters and short-term outcomes. METHODS: A retrospective cohort analysis was conducted between 2005 and 2016. The primary outcome was cost per episode of care. Secondary measures included 30-day clinical outcomes. A multivariate analysis was performed to determine the adjusted effect of a simultaneous surgical approach on total cost of care. RESULTS: Fifty-three cases were identified; 27 in the staged approach, and 26 in the simultaneous group. Age (P = 0.49), sex (P = 0.20), BMI (P = 0.74), and ASA class (P = 0.44) were comparable between groups. Total cost ($20297 vs $27522), OR ($6830 vs $10376), PACU ($675 vs $1182), ward ($7586 vs $11603) and pharmacy costs ($728 vs $1075) were significantly less for the simultaneous group (P < 0.05). The adjusted rate ratio for total cost of care in the staged group compared to simultaneous group was 1.51 (95%CI: 1.16-1.97, P < 0.05). The groups had comparable Clavien-Dindo scores (P = 0.89), 30-day readmissions (P = 0.44), morbidity (P = 0.50) and mortality (P = 1.00). CONCLUSIONS: Our study demonstrates that a simultaneous approach is associated with a significantly lower total cost while maintaining comparable short-term outcomes. PMID- 29484665 TI - Obesity and vitamin D status may help explain the racial and ethnic disparities in ampullary cancer survival rates. PMID- 29484666 TI - Chlortetracycline and related tetracyclines: detection in wheat and rye grain. AB - BACKGROUND: Antibiotic drugs are excreted to a large proportion by livestock. Thus, antibiotics are distributed on fields with slurry and can be taken up by plants. In the present study, hydroponic experiments were performed to reveal whether the widely administered chlortetracycline is taken up into wheat grain in a concentration-dependent manner. A further goal was to determine (chlor)tetracyclines in wheat and rye grain from agricultural practice. RESULTS: Increasing chlortetracycline deposition in wheat grain was observed with a rising chlortetracycline spiking level in the hydroponic solution. In 371 selected wheat and rye samples from three growing years of agricultural practice, the overall detection frequency was 21% for tetracyclines. In the most highly contaminated sample, tetracyclines occurred at 18.2 MUg kg-1 . Tetracycline residues were also found in rye grain. Conversion and degradation products of (chlor)tetracycline such as tetracycline, doxycycline and demeclocycline were detected in grains from hydroponic experiments and from agricultural practice. CONCLUSION: Concentrations of tetracyclines found in wheat and rye grains were of no concern with respect to toxicity regarding human consumption. However, antibiotic concentrations below the minimum inhibitory concentration can select for antibiotic resistance in bacteria. Thus, low levels of different tetracycline residues contained in food should be taken into account regarding risk assessment. (c) 2018 Society of Chemical Industry. PMID- 29484667 TI - It's more than skin-deep: The relationship between social victimization and telomere length in adolescence. AB - This study examined the relationship between peer victimization and telomere length (TL), an indicator of biological aging that is associated with stressors (Epel, 2009). It was predicted that social victimization would have a greater impact upon TL, as well as the frequency and severity of health complaints than physical victimization. Adolescents (Mage = 15.91 years, SDage = 1.65) and their parents completed measures of peer victimization and physical health problems; adolescents also submitted a DNA sample for telomere analysis. Greater instances of being socially, but not physically, victimized were associated with shorter telomeres, as well as more frequent and severe health complaints. TL was also negatively related to both the frequency and severity of health problems, even after controlling for BMI, age, and sex of participant. The relationship between social victimization and health complaints via TL held only at higher levels of social victimization. These findings are the first to find an association between peer victimization and shortened telomeres. PMID- 29484668 TI - Acute hemolytic transfusion reaction due to a warm reactive anti-A1. AB - BACKGROUND: Anti-A1 are regularly observed by reverse testing and are generally considered clinically irrelevant. For compatibility testing and the selection of blood, we use the type-and-screen (T&S) strategy, in which ABO confirmation of patients with a definitive blood group is performed by forward grouping only. Because anti-A1 seem clinically irrelevant, it is our policy to provide group A blood in patients with an anti-A1 . STUDY DESIGN AND METHODS: This is a case report of a 96-year-old woman who died shortly after transfusion of blood group A red blood cells (RBCs). She was known to have blood group A2 with an anti-A1 and the absence of other RBC antibodies. Directly after starting transfusion, acute dyspnea was observed, while other clinical signs for a transfusion reaction were absent. In the laboratory, indications for a severe hemolytic transfusion reaction (HTR) triggered serologic investigations and complement deposition experiments. RESULTS: Analyses revealed that the anti-A1 was present as a high titer IgM class immunoglobulin that induced complement deposition on A1 RBCs. The anti-A1 reacted in a wide temperature amplitude up to 37 degrees C with A1 RBCs, while weak agglutination was observed with A2 RBCs at room temperature. CONCLUSION: A pretransfusion detectable anti-A1 caused a severe HTR that, in view of the rapid onset of clinical symptoms and concomitant deterioration, contributed to the death of the patient. Considering its clinical significance in this case, we encourage an unambiguous procedure for patients with an anti-A1 , especially when T&S is used for donor RBC selection. PMID- 29484669 TI - In transit sentinel node drainage as a prognostic factor for patients with cutaneous melanoma. AB - BACKGROUND: Minor basin or in transit node drainage can be found in patients with cutaneous melanoma who undergo sentinel node biopsy. Its clinical impact is still unclear. Our objective is to evaluate clinical outcomes in patients who presented with in transit sentinel node (ITN) drainage. MATERIAL AND METHODS: Retrospective analysis of patients who underwent sentinel node biopsy (SNB) in a single Brazilian institution between 2000 and 2015. RESULTS: Our cohort comprised 1223 SNB. There were 64 patients (5.2%) with ITN. Melanoma of the limbs (OR 10.61, P < 0.0001) and acral subtype (OR 3.49, P < 0.0001) were associated with ITN drainage. Among these 64 patients, 14 (21.9%) had a positive SNB. The ITN was positive for metastases in five patients, four in a popliteal basin and one on the trunk. Regarding completion node dissection (CND), two patients had positive non-sentinel nodes (NSN), both in major basins. In patients who developed recurrence, time to recurrence was shorter (mean time 18 vs 31.4 months, P = 0.001) and time to death was shorter (mean time 31.6 vs 40 months, P = 0.039) in those who had ITN drainage. CONCLUSION: ITN drainage was associated with earlier recurrences and deaths from melanoma. PMID- 29484670 TI - Plasma temperature during methylene blue/light treatment influences virus inactivation capacity and product quality. AB - BACKGROUND: Photodynamic treatment using methylene blue (MB) and visible light is in routine use for pathogen inactivation of human plasma in different countries. Ambient and product temperature conditions for human plasma during production may vary between production sites. The influence of different temperature conditions on virus inactivation capacity and plasma quality of the THERAFLEX MB-Plasma procedure was investigated in this study. METHODS: Plasma units equilibrated to 5 +/- 2 degrees C, room temperature (22 +/- 2 degrees C) or 30 +/- 2 degrees C were treated with MB/light and comparatively assessed for the inactivation capacity for three different viruses, concentrations of MB and its photoproducts, activity of various plasma coagulation factors and clotting time. RESULTS: Reduced solubility of the MB pill was observed at 5 +/- 2 degrees C. Photocatalytic degradation of MB increased with increasing temperature, and the greatest formation of photoproducts (mainly azure B) occurred at 30 +/- 2 degrees C. Inactivation of suid herpesvirus, bovine viral diarrhoea virus and vesicular stomatitis virus was significantly lower at 5 +/- 2 degrees C than at higher temperatures. MB/light treatment affected clotting times and the activity of almost all investigated plasma proteins. Factor VIII (-17.7 +/- 8.3%, 22 +/- 2 degrees C) and fibrinogen (-14.4 +/- 16.4%, 22 +/- 2 degrees C) showed the highest decreases in activity. Increasing plasma temperatures resulted in greater changes in clotting time and higher losses of plasma coagulation factor activity. CONCLUSIONS: Temperature conditions for THERAFLEX MB-Plasma treatment must be carefully controlled to assure uniform quality of pathogen-reduced plasma in routine production. Inactivation of cooled plasma is not recommended. PMID- 29484671 TI - Longitudinal Associations Between Alcohol-Related Cognitions and Use in African American and European American Adolescent Girls. AB - BACKGROUND: African American (AA) girls initiate alcohol use later and drink less than European American (EA) girls, potentially reflecting differences in the development of drinking behaviors. This study examined alcohol-related cognitions: expectancies, attitudes, and intention to drink, as possible sources of variation by race in alcohol use. The aim of this study was to characterize the nature and degree of association between cognitions and use over time and by race in EA and AA girls. METHODS: Data were drawn from the longitudinal Pittsburgh Girls Study (N = 2,450), an urban population-based sample of girls and their caregivers recruited when girls were between ages 5 and 8, and assessed annually through adolescence. Cross-lagged panel models were conducted separately by race (56.2% AA, 43.8% EA) to identify patterns of association between alcohol use and cognitions from ages 12 to 17 in 2,173 girls. RESULTS: Endorsement of cognitions and use was higher overall in EA than AA girls but the magnitude of cross-lagged path coefficients did not differ significantly by race. In both groups, bidirectional effects emerged between intentions and use, and alcohol use largely predicted cognitions across ages. However, intention to drink was the only alcohol-related cognition that consistently predicted subsequent use (odds ratios ranged from 1.55 to 2.71). CONCLUSIONS: Although rates of alcohol use and endorsement of cognitions were greater in EA than AA girls, the anticipated racial differences in longitudinal associations between cognitions and use did not emerge, indicating that variation in associations between use and cognitions does not account for the lower prevalence of alcohol use in AA compared with EA girls. Furthermore, our finding that intention to drink is a consistent, robust predictor of subsequent alcohol use suggests the need to investigate potentially modifiable factors that influence intention to drink across racial groups. PMID- 29484672 TI - In vitro evaluation of a simulated pneumoperitoneum environment using carbon dioxide on canine transitional cell carcinoma. AB - OBJECTIVE: To assess the impact of a simulated CO2 pneumoperitoneum environment on the viability and proliferation of canine transitional cell carcinoma (TCC) cells in vitro. STUDY DESIGN: In vitro study. METHODS: A control Madin-Darby canine kidney (MDCK) cell line and 3 canine TCC cell lines were exposed to 100% CO2 at pressure of 0, 5, 10, or 15 mmHg for 2 hours by using an airtight chamber and a mechanical insufflator at 37 degrees C. Culture media pH was measured. Viability and proliferation were assessed by using a resazurin assay and trypan blue dye, respectively. RESULTS: The pH in the media significantly decreased immediately after CO2 exposure but returned to normal within 1 hour. The viability of the cell lines was variably affected at the evaluated pressures. Insufflation pressure of 10 mmHg resulted in significantly decreased cell viability compared with control. The impact of 15 mmHg CO2 was comparable to 0 mmHg and control. CO2 insufflation pressure had no significant effects on proliferation up to 7 days postexposure. Conclusion/Clinical significance: A positive pressure CO2 environment significantly decreased the viability of TCC and MDCK cells under specific conditions without influencing their proliferation up to 7 days postexposure. Investigating these effects in clinical patients undergoing CO2 laparoscopy is essential to assess for port site metastasis or peritoneal carcinomatosis in order to translate these in vitro results to clinical recommendations. PMID- 29484673 TI - The DHS Program's Modeled Surfaces Spatial Datasets. AB - Spatially interpolated map surface datasets for key development indicators are being produced and publicly shared using population-based surveys from the USAID funded Demographic and Health Survey (DHS) Program. Each modeled surface is produced with standardized geostatistical modeling methods. For each indicator, a package is available that includes spatial raster grids of 5 * 5 km pixels for the point estimate surface and an uncertainty surface, along with validation statistics and other model diagnostic data. The maps are publicly available for download on the DHS Program Spatial Data Repository at http://spatialdata.dhsprogram.com/. The modeled surfaces are produced with publicly available geo-referenced data on each indicator as collected by the DHS Program, augmented with other relevant spatial data sources that act as covariates. A Bayesian model-based geostatistical (MBG) approach is used to generate the modeled surfaces. Spatially modeled surfaces can be used to support and improve decision-making at multiple levels within many development programs including health, population, family planning, nutrition, and water and sanitation. The modeled surfaces can be used in their original 5 * 5 km pixel format, operationalized to other geographic areas as relevant for the program, or linked to DHS or other survey data for additional analysis. PMID- 29484674 TI - Smartphones & microfluidics: Marriage for the future. AB - Smartphones have become widely recognized as a very interesting detection and controlling tool in microfluidics. They are portable devices with built-in cameras and internal microprocessors which carry out image processing. In this case, the external computers are not needed and phones can provide fast and accurate results. Moreover, the connectivity of smartphones gives the possibility to share and provide real-time results when needed, whether in health diagnostics, environmental monitoring, immunoassays or food safety. Undoubtedly, the marriage of smartphones and microfluidics has a brilliant future in building low cost and easily operable systems for analysis in the field, realizing the idea of people's "smartlife". The aim of this review is to present and summarize the main advantages and disadvantages of the use of smartphones as well as to take a closer look at some novel achievements published during the last couple of years. In the next paragraphs, readers will find specific uses of a combination of smartphones and microfluidics such as water analysis, health analysis (virus and bacteria detection), and measurement of physical properties or smartphone liquid control in polymer devices. PMID- 29484675 TI - Quantitative separation of hesperidin, chrysin, epicatechin, epigallocatechin gallate, and morin using ionic liquid as a buffer additive in capillary electrophoresis. AB - Recently, an increasing interest has been observed in ionic liquids (ILs) due to their potentialities in various chemical processes. ILs have some unique properties making them excellent additives in CE. In this work a simple, rapid, and reliable CZE method has been developed and validated using 1-butyl-3-methyl imidazolium hexafluorophosphate (BMIM-PF6 ) ionic liquid as a buffer additive for the determination/separation of five flavonoids including hesperedin, epicatechin (EC), epigallocatechin gallate (EGCG), and morin using photodiode array (PDA) detector. The effect of several parameters such as concentration and pH of the running buffer, applied voltage, and concentration of ionic liquid were optimized. CZE at 25 degrees C with 25 mM borate buffer of pH 9.0 at an applied voltage of 17 kV by adding 17.5 mM of IL was found to be suitable for the separation/determination of all five analytes within 08 min. Validation of the method was performed in terms of linearity, accuracy, precision, and limit of detection and quantification. The calibration curves were plotted in the concentration range of 1-200 MUg/mL for all five analytes. The response was linear with R2 = 0.990 for EC, chrysin, and hesperidin, 0.992 for morin, and 0.988 for EGCG. LOD and LOQ were obtained within the range of 0.4-0.5 and 1.4-1.7 MUg/mL, respectively. The proposed method showed good reproducibility with RSD of less than 3% for both migration time and peak height. The method was successfully applied for the determination of flavonoids from citrus fruits and tea samples. PMID- 29484676 TI - Parametric models to compute tryptophan fluorescence wavelengths from classical protein simulations. AB - Fluorescence spectroscopy is an important method to study protein conformational dynamics and solvation structures. Tryptophan (Trp) residues are the most important and practical intrinsic probes for protein fluorescence due to the variability of their fluorescence wavelengths: Trp residues emit in wavelengths ranging from 308 to 360 nm depending on the local molecular environment. Fluorescence involves electronic transitions, thus its computational modeling is a challenging task. We show that it is possible to predict the wavelength of emission of a Trp residue from classical molecular dynamics simulations by computing the solvent-accessible surface area or the electrostatic interaction between the indole group and the rest of the system. Linear parametric models are obtained to predict the maximum emission wavelengths with standard errors of the order 5 nm. In a set of 19 proteins with emission wavelengths ranging from 308 to 352 nm, the best model predicts the maximum wavelength of emission with a standard error of 4.89 nm and a quadratic Pearson correlation coefficient of 0.81. These models can be used for the interpretation of fluorescence spectra of proteins with multiple Trp residues, or for which local Trp environmental variability exists and can be probed by classical molecular dynamics simulations. (c) 2018 Wiley Periodicals, Inc. PMID- 29484677 TI - Mitogen-activated protein kinase signaling is involved in nonylphenol-induced proinflammatory cytokines secretion by BV2 microglia. AB - Microglia (MG) are the key cells involved in the innate immune response in the central nervous system, and their activation has been linked to inflammation and neurotoxicity by the production of proinflammatory cytokines. Recently, researchers have found that nonylphenol (NP), a ubiquitous endocrine disrupting chemical, could impair neurodevelopment and cognitive memory performance. However, whether NP affects the inflammatory responses of MG remains to be elucidated. The aim of this study was to explore the effects of NP on the inflammatory responses of BV2 MG and the underlying mechanisms. Our results showed that NP increased the secretion of interleukin (IL)-6 and IL-1beta in BV2 MG. Increased phosphorylation of Akt, JNK and p38 mitogen-activated protein kinase and decreased phosphorylation of ERK were observed in NP-treated MG. The inflammatory transcription factor activator protein 1 was also activated in NP treated BV2 MG. These results suggest that NP may activate Akt/mitogen-activated protein kinase/activator protein 1 signaling in MG and subsequently increase IL-6 and IL-1beta secretion. PMID- 29484679 TI - Hypobaric hypoxia causes impairment of spermatogenesis in developing rats at pre puberty. AB - The effect of hypoxia on the spermatogenesis of male Wistar rats (n = 32) at pre puberty was studied using a hypobaric chamber simulating an altitude of 5,000 metres above sea level. Persistent hypoxic exposure with brief interruption for 3 weeks caused significant decreases in body and testis weights and testosterone level compared to the normobaric controls. Histologically, spermatogenic development was arrested; arrays of spermatids were misshaped; numbers of spermatogonia, Sertoli and Leydig cells were reduced; and apoptotic spermatocytes were increased substantially in the germinal epithelium of testis in the hypoxic exposed group. These hormonal and histopathological changes did not improve remarkably after 3 weeks of normobaric conditions. There was a significant decrease in sperm production when the rats in the hypoxia/oxygen-resuming group were examined at 63 days of post-natal age. Exposing rats to hypoxic conditions at pre-puberty induced damages on spermatogenesis, which could affect sperm production after sex mature. PMID- 29484678 TI - Simultaneous isolation and preconcentration of exosomes by ion concentration polarization. AB - Exosomes carry microRNA biomarkers, occur in higher abundance in cancerous patients than in healthy ones, and because they are present in most biofluids, including blood and urine, these can be obtained noninvasively. Standard laboratory techniques to isolate exosomes are expensive, time consuming, provide poor purity, and recover on the order of 25% of the available exosomes. We present a new microfluidic technique to simultaneously isolate exosomes and preconcentrate them by electrophoresis using a high transverse local electric field generated by ion-depleting ion-selective membrane. We use pressure-driven flow to deliver an exosome sample to a microfluidic chip such that the transverse electric field forces them out of the cross flow and into an agarose gel which filters out unwanted cellular debris while the ion-selective membrane concentrates the exosomes through an enrichment effect. We efficiently isolated exosomes from 1* PBS buffer, cell culture media, and blood serum. Using flow rates from 150 to 200 MUL/h and field strengths of 100 V/cm, we consistently captured between 60 and 80% of exosomes from buffer, cell culture media, and blood serum as confirmed by both fluorescence spectroscopy and nanoparticle tracking analysis. Our microfluidic chip maintained this recovery rate for more than 20 min with a concentration factor of 15 for 10 min of isolation. PMID- 29484680 TI - Hypoxia induces production of citrullinated proteins in human fibroblast-like synoviocytes through regulating HIF1alpha. AB - Hypoxia is a prominent microenvironment feature in a range of disorders including cancer, rheumatoid arthritis (RA), atherosclerosis, inflammatory bowel disease (IBD), infection and obesity. Hypoxia promotes biological functions of fibroblast like synoviocytes via regulating hypoxia-inducible factor 1alpha (HIF1alpha). Dysregulated protein citrullination in RA drives the production of antibodies to citrullinated proteins, a highly specific biomarker of RA. However, the mechanisms promoting citrullination in RA are not yet fully elucidated. In this study, we investigated whether pathophysiological hypoxia as found in the rheumatoid synovium modulates the citrullination in human fibroblast-like synoviocytes (HFLS). Here, we found that peptidylarginine deiminase 2 (PAD2) and citrullinated proteins were increased in HFLS after exposure to hypoxia. Moreover, knocking down HIF1alpha by HIF1alpha siRNA ameliorated the expression of PAD2 and citrullinated proteins. Collectively, this study provides a new mechanism involved in generating citrullinated proteins: hypoxia promotes citrullination and PAD production in HFLS. Concurrently, we also proposed a novel hypoxia involved mechanism in RA pathogenesis. This study deepens our understanding of the role of hypoxia in the pathogenesis of RA and provides a potential therapeutic strategy for RA. PMID- 29484681 TI - Comorbidity of the congenital absence of the vas deferens. AB - Congenital absence of the vas deferens (CAVD) is a relatively rare anomaly that may contribute to male infertility. The aim of this study was to evaluate the clinical features of patients with CAVD and to emphasise some pathological conditions that may be detected during the infertility work-up or follow-up of these patients. The charts of 150 males with the diagnosis of CAVD were evaluated retrospectively. The demographic characteristics, reasons for attendance, the way of diagnosis, interventions for infertility before and after attendance, physical examination findings, reproductive hormone levels, semen analysis results, genetical analysis results and resultant live birth events were all included in the study. There were 101 bilateral and 43 unilateral CAVD cases. Thirty-two males (30.2%) had some renal abnormalities. Two cases, one with bilateral and one with unilateral agenesis, died because of colon cancer at a young age. One case with CUAVD had acute lymphoblastic leukaemia. Congenital absence of the vas deferens should not be seen only as a fertility problem because of the many genotypic or phenotypic disorders that may be present with it. These disorders can cause serious general health problems either presently or in future and can also be transmitted to future generations. PMID- 29484682 TI - Efficacy and safety of uninterrupted low-intensity warfarin for cryoballoon ablation of atrial fibrillation in the elderly: A pilot study. AB - WHAT IS KNOWN AND OBJECTIVE: Uninterrupted warfarin during cryoballoon ablation (CB-A) of atrial fibrillation (AF) has been widely accepted. However, to our knowledge, no previous studies exist investigating the optimal intensity of anticoagulation with warfarin for CB-A. This study aimed to evaluate the efficacy and safety of uninterrupted low-intensity warfarin for CB-A of AF in the elderly. METHODS: Paroxysmal AF patients (age >= 70 years) who underwent CB-A were enrolled prospectively. The participants were stratified into 2 groups based on international normalized ratio (INR) before ablation (INR in group A: 1.5 to 2.0; INR in group B: 2.0-2.5). Primary endpoints included periprocedural thromboembolic complications and major bleeding. Secondary endpoints were new asymptomatic cerebral emboli (ACE) and minor bleeding. RESULTS AND DISCUSSION: A total of 144 patients were enrolled (group A: 65; group B: 79). In group A, the use of concomitant antiplatelet drugs was more common. Also, the mean HAS-BLED score was significantly higher (2.4 +/- 0.8 vs 2.0 +/- 0.6, P < .01) and the mean activated clotting time (ACT) during the procedure was significantly lower (302 +/- 14 s vs 311 +/- 11 s, P < .01). Other clinical characteristics were balanced between the 2 groups. No thromboembolic complications and major bleeding occurred in either group. The incidence of periprocedural ACE was comparable between the 2 groups (9.2% vs 6.3%, P = .74). The incidence of minor bleeding in group A and group B was 4.6% and 11.4%, respectively (P = .14). WHAT IS NEW AND CONCLUSION: Compared with standard-intensity warfarin, uninterrupted low-intensity warfarin might not increase the incidence of thromboembolic complications and might be associated with less bleeding risk during the perioperative period of cryoballoon ablation in the elderly. Large trials are needed to confirm these results. PMID- 29484684 TI - Clinical, pathological, and biological characterization of Richter syndrome developing after ibrutinib treatment for relapsed chronic lymphocytic leukemia. AB - Richter syndrome, a transformation of chronic lymphocytic leukemia (CLL) into a diffuse large B-cell lymphoma, is a rare complication of patients treated with chemo-immunotherapy. Richter syndrome might be both clonally related or unrelated to the underlying CLL and often showed mutations of the TP53 and NOTCH1 genes. Recently, ibrutinib was approved for patients with relapsed/refractory CLL or for untreated CLL patients with del 17p or TP53 mutation. The clinical picture, pathology, and genetics of Richter transformation after IBR treatment are largely unknown. Here, we report 2 cases of Richter transformation after Ibrutinib treatment. As just reported by previous report, Richter syndrome developing after ibrutinib therapy lacked resistance mutations of the BTK and PLCG2 genes, which are clonally related to the pre-existent CLL phase representing transformation from CLL. Richter syndrome after ibrutinib seems to have some peculiar clinical findings as the bone marrow predilection, severe hypercalcemia, and a more aggressive outcome. PMID- 29484683 TI - Association of Protein Kinase B (AKT) DNA Hypermethylation with Maintenance Atypical Antipsychotic Treatment in Patients with Bipolar Disorder. AB - STUDY OBJECTIVE: Atypical antipsychotics cause insulin resistance that leads to an increased risk of diabetes mellitus and cardiovascular disease. Skeletal muscle is the primary tissue for uptake of glucose, and its dysfunction is considered one of the primary defects in the development of insulin resistance. Protein kinase B (AKT) plays an important role in overall skeletal muscle health and glucose uptake into the muscle. The objective of this study was to measure AKT isoform-specific gene methylation differences in the skeletal muscle of patients with bipolar disorder treated with atypical antipsychotic or mood stabilizer maintenance therapy. DESIGN: Cross-sectional observational study. SETTING: Clinical research services center at an academic center. PATIENTS: Thirty patients with a confirmed diagnosis of bipolar disorder who were treated with either an atypical antipsychotic (16 patients) or mood stabilizer (14 patients) at a consistent dose for at least 3 months. INTERVENTIONS: A fasting skeletal muscle biopsy was performed in the vastus lateralis in each patient. Patients also underwent fasting blood sample collection and a standard 75-g oral glucose tolerance test. MEASUREMENTS AND MAIN RESULTS: Skeletal muscle DNA methylation near the promoter region for three genes, AKT1, AKT2, and AKT3, was measured by methylation-sensitive high-resolution melting. Gene methylation was analyzed based on atypical antipsychotic versus mood stabilizer maintenance therapy. Associations between gene methylation, insulin resistance, and glucose tolerance were also analyzed. In patients treated with atypical antipsychotics, AKT1 and AKT2 methylation was increased compared with patients treated with mood stabilizers (p=0.03 and p=0.02, respectively). In addition, for patients receiving atypical antipsychotics, a positive trend for AKT2 hypermethylation with increasing insulin resistance was observed, whereas for patients receiving mood stabilizers, a trend for decreased AKT2 methylation with increasing insulin resistance was observed. CONCLUSION: Overall, our findings suggest that the AKT gene is differentially methylated in the skeletal muscle of patients taking atypical antipsychotics or mood stabilizer maintenance therapy. These results may direct future approaches to reduce the harmful adverse effects of atypical antipsychotic treatment. PMID- 29484685 TI - Evaluation of oxidative stress and antioxidant status: Correlation with the severity of sepsis. AB - Sepsis is a condition caused by infection followed by unregulated inflammatory response which may lead to the organ dysfunction. During such condition, over production of oxidants is one of the factors which contribute cellular toxicity and ultimately organ failure and mortality. Antioxidants having free radicals scavenging activity exert protective role in various diseases. This study has been designed to evaluate the levels of oxidative and antioxidative activity in sepsis patients and their correlation with the severity of the sepsis. A total of 100 sepsis patients and 50 healthy controls subjects were enrolled in this study from the period October 2016 to June 2017. The investigation included measurements of oxidative enzyme, myeloperoxidase (MPO), antioxidant enzymes including superoxide dismutase activity (SOD) and catalase activity (CAT) and cytokines (TNF-alpha, IL-8 and IFN-gamma). Furthermore, the level of these activities was correlated with severity of sepsis. Augmented levels of oxidants were found in sepsis as demonstrated by DMPO nitrone adduct formation and plasma MPO level activity (1.37 +/- 0.51 in sepsis vs 0.405 +/- 0.16 in control subjects). Cytokines were also found to be increased in sepsis patients. However, plasma SOD and CAT activities were significantly attenuated (P < .001) in the sepsis patients compared with controls subjects. Moreover, inverse relation between antioxidant enzymes (SOD and CAT) and organ failure assessment (SOFA), physiological score (APACHE II), organ toxicity specific markers have been observed as demonstrated by Pearson's correlation coefficient. This study suggests that imbalance between oxidant and antioxidant plays key role in the severity of sepsis. PMID- 29484686 TI - Predictors of Gabapentin Overuse With or Without Concomitant Opioids in a Commercially Insured U.S. Population. AB - OBJECTIVE: Research suggests the medical consequences of gabapentin overuse depend on whether gabapentin is abused alone or with opioids to potentiate an opioid "high." The objective of this study was to assess predictors of gabapentin overuse with or without concomitant opioids. METHODS: Data were obtained from the Truven Health MarketScan(r) Commercial Claims and Encounters database for 2013 through 2015. Eligibility criteria were gabapentin utilization, with or without opioids, for 120 days or longer throughout a 12-month observation period. Cohort identification was based on patterns of overuse exceeding thresholds of 3600 mg of gabapentin and/or 50 morphine-mg equivalents of opioids; sustained overuse was defined as three or more quarters exceeding threshold. Diagnostic predictors were measured in the 6 months pretreatment in inpatient (IP) or emergency department (ED) settings. Indications were measured in IP, ED, or ambulatory settings. Logistic regression analyses adjusted for age, sex, indication, use of benzodiazepine or z-hypnotics (i.e., zaleplon, zolpidem, eszopiclone) during gabapentin treatment, pretreatment ED/IP use, and pretreatment diagnoses of anxiety or depression. RESULTS: Criteria for sustained overuse were met by 2.0% of 44,148 patients treated with gabapentin without opioids and by 11.7% of 15,335 patients treated with concomitant gabapentin-opioid. The top three predictors of sustained overuse for gabapentin-only patients were insomnia (7.0%), euphoria (4.5%), and bipolar disorder (4.5%), and were detoxification (35.6%), altered mental status (26.3%), and addiction (21.6%) for gabapentin-opioid patients. In adjusted analyses, concomitant opioid use multiplied the odds of sustained misuse by 6.32 (95% confidence interval [CI] = 5.80-6.89) and the interaction of addiction with opioid use by 1.88 (95% CI = 1.32-2.66). Among gabapentin-only patients, sustained misuse was predicted by a history of anxiety (odds ratio = 1.56, 95% CI = 1.02-2.38) but not by a history of addiction. CONCLUSIONS: The likelihood of gabapentin overuse alone is low but significantly increases with concomitant opioid use, especially when coupled with a history of addiction. History of addiction does not appear to increase risk of gabapentin misuse among those with gabapentin alone. PMID- 29484687 TI - Endogenous protein and enzyme fragments induce immunoglobulin E-independent activation of mast cells via a G protein-coupled receptor, MRGPRX2. AB - Mast cells play a central role in inflammatory and allergic reactions by releasing inflammatory mediators through 2 main pathways, immunoglobulin E dependent and E-independent activation. In the latter pathway, mast cells are activated by a diverse range of basic molecules (collectively known as basic secretagogues) through Mas-related G protein-coupled receptors (MRGPRs). In addition to the known basic secretagogues, here, we discovered several endogenous protein and enzyme fragments (such as chaperonin-10 fragment) that act as bioactive peptides and induce immunoglobulin E-independent mast cell activation via MRGPRX2 (previously known as MrgX2), leading to the degranulation of mast cells. We discuss the possibility that MRGPRX2 responds various as-yet unidentified endogenous ligands that have specific characteristics, and propose that MRGPRX2 plays an important role in regulating inflammatory responses to endogenous harmful stimuli, such as protein breakdown products released from damaged or dying cells. PMID- 29484688 TI - Moving beyond the comprehensive in vitro proarrhythmia assay: Use of human induced pluripotent stem cell-derived cardiomyocytes to assess contractile effects associated with drug-induced structural cardiotoxicity. AB - Drug-induced cardiotoxicity is a potentially severe side effect that can adversely affect myocardial contractility through structural or electrophysiological changes in cardiomyocytes. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a promising human cardiac in vitro model system to assess both proarrhythmic and non-proarrhythmic cardiotoxicity of new drug candidates. The scalable differentiation of hiPSCs into cardiomyocytes provides a renewable cell source that overcomes species differences present in current animal models of drug toxicity testing. The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative represents a paradigm shift for proarrhythmic risk assessment, and hiPSC-CMs are an integral component of that paradigm. The recent advancements in hiPSC-CMs will not only impact safety decisions for possible drug-induced proarrhythmia, but should also facilitate risk assessment for non-proarrhythmic cardiotoxicity, where current non-clinical approaches are limited in detecting this risk before initiation of clinical trials. Importantly, emerging evidence strongly suggests that the use of hiPSC CMs with cardiac physiological relevant measurements in vitro improves the detection of structural cardiotoxicity. Here we review high-throughput drug screening using the hiPSC-CM model as an experimentally feasible approach to assess potential contractile and structural cardiotoxicity in early phase drug development. We also suggest that the assessment of structural cardiotoxicity can be added to electrophysiological tests in the same platform to complement the Comprehensive in vitro Proarrhythmia Assay for regulatory use. Ideally, application of these novel tools in early drug development will allow for more reliable risk assessment and lead to more informed regulatory decisions in making safe and effective drugs available to the public. PMID- 29484689 TI - Intravesicular taxane-induced dermatotoxicity in a 78-year-old man with urothelial carcinoma and primary cutaneous anaplastic large cell lymphoma. AB - Patients treated with intravesical bacillus Calmette-Guerin therapy for urothelial carcinoma often become refractory and experience recurrent disease, thus necessitating alternative intravesical treatment modalities if the patient is to be spared the morbidities associated with radical cystectomy. Intravesical treatment with taxane-based chemotherapy, such as docetaxel, has gained traction in urologic oncology, proving to be an effective salvage therapy in such patients. Systemic taxane-based chemotherapeutic regimens have long been used in several advanced malignancies, and their systemic side-effects and associated histologic correlates have been extensively documented. In contrast to adverse effects associated with systemic administration, intravesical taxane administration has thus far proven to be well-tolerated, with little to no systemic absorption. To our knowledge, features of taxane-induced systemic effects have not been reported in this setting. Herein, we report a case of a patient with recurrent urothelial carcinoma treated with intravesical docetaxel, along with primary cutaneous anaplastic large cell lymphoma, who developed characteristic dermatotoxic histologic findings associated with intravenous taxane administration. As such histopathologic findings often represent close mimickers of neoplastic and infectious etiologies, knowledge of the potential for systemic manifestations of taxane therapy in patients treated topically may prevent potentially costly diagnostic pitfalls. PMID- 29484690 TI - Lymphomas and thyroid: Bridging the gap. AB - The thyroid gland is often involved in the development of neoplastic diseases, including lymphoproliferative disorders. The aim of this paper is to provide a comprehensive overview of the multiple interactions between lymphoma and thyroid. Through an extensive research among the literature, the relationship between lymphomas and thyroid can be established at various levels, and the possible interconnections are here summarized in 5 points: (1) the greater risk of lymphoma development in some thyroid diseases; (2) the primary thyroid lymphoma, with focus on issues related to the diagnosis, differential diagnosis, and treatment; (3) the incidence of thyroid involvement in primitive nodal lymphomas or in extranodal lymphomas of the other sites; (4) thyroid changes after treatment of lymphoma, in relation to the effects of radiation therapy and immuno chemotherapy; (5) the incidental findings of thyroid changes, on imaging, in patients with lymphoma, without a direct involvement of the gland in malignant disease. In conclusion, issues that until now have been dealt with separately will therefore be analyzed in a unique paper, allowing a global view of the topic and emphasizing the need of a multidisciplinary approach. Future learning areas in this topic mainly relate to rapidly increasing the knowledge of imaging studies together with expanding the armamentarium of novel biological and targeting agents in lymphoma patients. PMID- 29484691 TI - Relationships of working conditions, health problems and vehicle accidents in bus rapid transit (BRT) drivers. AB - BACKGROUND: The aim of this study was to estimate accident risk rates and mental health of bus rapid transit (BRT) drivers based on psychosocial risk factors at work leading to increased stress and health problems. METHODS: A cross-sectional research design utilized a self-report questionnaire completed by 524 BRT drivers. RESULTS: Some working conditions of BRT drivers (lack of social support from supervisors and perceived potential for risk) may partially explain Bogota's BRT drivers' involvement in road accidents. Drivers' mental health problems were associated with higher job strain, less support from co-workers, fewer rewards and greater signal conflict while driving. CONCLUSIONS: To prevent bus accidents, supervisory support may need to be increased. To prevent mental health problems, other interventions may be needed such as reducing demands, increasing job control, reducing amount of incoming information, simplifying current signals, making signals less contradictory, and revising rewards. PMID- 29484692 TI - How to take better photomicrographs: A step-wise approach. AB - The objective of our study was to establish a detailed photomicrographing protocol for pathologists and dermatopathologists using standard overhead camera and image editing packages. Through a trial-and-error approach we devised a series of steps that comprise our photomicrographing protocol. Descriptive and interpretive data analyses were performed to highlight how each step improves tinctorial quality of digital photomicrographs. PMID- 29484693 TI - A 3-level Bayesian mixed effects location scale model with an application to ecological momentary assessment data. AB - Ecological momentary assessment studies usually produce intensively measured longitudinal data with large numbers of observations per unit, and research interest is often centered around understanding the changes in variation of people's thoughts, emotions and behaviors. Hedeker et al developed a 2-level mixed effects location scale model that allows observed covariates as well as unobserved variables to influence both the mean and the within-subjects variance, for a 2-level data structure where observations are nested within subjects. In some ecological momentary assessment studies, subjects are measured at multiple waves, and within each wave, subjects are measured over time. Li and Hedeker extended the original 2-level model to a 3-level data structure where observations are nested within days and days are then nested within subjects, by including a random location and scale intercept at the intermediate wave level. However, the 3-level random intercept model assumes constant response change rate for both the mean and variance. To account for changes in variance across waves, as well as clustering attributable to waves, we propose a more comprehensive location scale model that allows subject heterogeneity at baseline as well as across different waves, for a 3-level data structure where observations are nested within waves and waves are then further nested within subjects. The model parameters are estimated using Markov chain Monte Carlo methods. We provide details on the Bayesian estimation approach and demonstrate how the Stan statistical software can be used to sample from the desired distributions and achieve consistent estimates. The proposed model is validated via a series of simulation studies. Data from an adolescent smoking study are analyzed to demonstrate this approach. The analyses clearly favor the proposed model and show significant subject heterogeneity at baseline as well as change over time, for both mood mean and variance. The proposed 3-level location scale model can be widely applied to areas of research where the interest lies in the consistency in addition to the mean level of the responses. PMID- 29484694 TI - Colliding, colonizing or combining? Four cases illustrating the unique challenges presented by melanoma arising in conjunction with basal cell carcinoma. AB - Biphasic lesions comprised of melanocytic and epithelial components are rare entities believed to arise either as a collision of 2 histologically distinct lesions in the same anatomic location or as a singular progenitor tumor differentiating along 2 differing lineages. Regardless of mechanism of origin, these tumors present unique challenges in pathologic interpretation and in determining appropriate measurements, which assigns subsequent prognosis to the patient. We present 4 tumors of melanoma co-existing with basal cell carcinoma (BCC) and discuss relevant literature regarding these biphasic entities. Patients consisted of 3 males and 1 female, ranging in age from 62 to 93, with lesions located on the shoulder, frontal scalp, forearm and nose. Three of 4 lesions showed melanoma cells limited to BCC tumor lobules, without evidence of direct dermal invasion by melanoma cells, raising the question of whether or not these tumors should be classified as in situ or invasive melanoma. These cases highlight the complexity that such lesions pose to dermatopathologists, in terms of their uncertain origin and variable microscopic appearance. In the absence of data regarding outcomes for these tumors (given their rarity), it is important to utilize a case-by-case approach, with careful clinical correlation and appropriate use of ancillary techniques. PMID- 29484695 TI - Advances in Structural Biology and the Application to Biological Filament Systems. AB - Structural biology has experienced several transformative technological advances in recent years. These include: development of extremely bright X-ray sources (microfocus synchrotron beamlines and free electron lasers) and the use of electrons to extend protein crystallography to ever decreasing crystal sizes; and an increase in the resolution attainable by cryo-electron microscopy. Here we discuss the use of these techniques in general terms and highlight their application for biological filament systems, an area that is severely underrepresented in atomic resolution structures. We assemble a model of a capped tropomyosin-actin minifilament to demonstrate the utility of combining structures determined by different techniques. Finally, we survey the methods that attempt to transform high resolution structural biology into more physiological environments, such as the cell. Together these techniques promise a compelling decade for structural biology and, more importantly, they will provide exciting discoveries in understanding the designs and purposes of biological machines. PMID- 29484696 TI - Lessons learned: a different approach to teaching electrocardiogram interpretation. PMID- 29484697 TI - Risk of new-onset diabetes mellitus during treatment with low-dose statins in Japan: A retrospective cohort study. AB - WHAT IS KNOWN AND OBJECTIVE: The risk of new-onset diabetes mellitus (NODM) in Japanese patients using low-dose hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) has not been previously examined. The aim of this study was to assess the risk of NODM associated with use of high- and low-potency statins in Japanese patients taking low-dose statins. METHODS: A retrospective cohort study of 2554 Japanese patients who started treatment with a statin was conducted. Only patients taking the same dose of the same statin were enrolled, and patients were separated into high- and low-potency statin groups. The outcome was incidence of NODM during statin treatment. RESULTS: The incidence rate of NODM in the cohort was 7.4% (n = 190). Kaplan-Meier survival curves showed a significantly higher rate of NODM in patients taking high-potency statins compared with those taking low-potency statins (P < .001, log-rank test). Baseline fasting plasma glucose levels, use of high-potency statins, male gender and combination treatment with calcium channel blockers, immunosuppressants or steroids were identified as factors that significantly increased the risk for NODM using Cox proportional hazard regression analysis. WHAT IS NEW AND CONCLUSION: The use of high-potency statins at a low standard daily dose significantly increased the risk of NODM in Japanese patients compared with low potency statins. Furthermore, clinicians should also be careful when prescribing statins in combination with steroids or immunosuppressants due to the increased risk of NODM. PMID- 29484698 TI - Intra-operative evaluation of prophylactic hysterectomy and salpingo-oophorectomy specimens in hereditary gynaecological cancer syndromes. AB - AIMS: Prophylactic total hysterectomy (TH) and bilateral salpingo-oophorectomy (BSO) have become routine procedures in women at genetic risk for gynaecological malignancies. Intra-operative pathology diagnosis of an occult malignancy provides the opportunity for immediate surgical staging and helps to avoid a second surgery. However, no standard guidelines exist for optimal intra-operative evaluation (IOE) of these specimens. We performed a retrospective analysis of prophylactic TH and BSO cases to assess the presence of gross findings, frozen and permanent section sampling practices, frozen section diagnoses and diagnostic discrepancies. METHODS AND RESULTS: All prophylactic TH and BSO cases between 1990 and 2017 were retrieved from our departmental archives. A total of 413 cases were included in the study: 27 with Lynch syndrome (LS), 222 with germline BRCA 1 or 2 mutations and 164 cases with strong family or personal history (non Lynch/non-BRCA). Only fewer than half of all cases (159 of 413; 38.5%) were sent for IOE, 15 of 27 (56%) LS cases, 93 of 222 (42%) BRCA cases and 51 of 164 (31%) non-Lynch/non-BRCA cases. A total of 19 patients (4.6% of patients combining all three groups) had a final diagnosis of malignancy or premalignancy on permanent sections. Of these 19 cases, eight had a corresponding gross lesion (42%) and could have been diagnosed on frozen section; however, only one of them underwent IOE. CONCLUSIONS: Our results highlight the potential benefits and challenges of IOE in this setting and may provide a basis for future practice recommendations. PMID- 29484699 TI - Lowering the barriers to teaching online. PMID- 29484700 TI - From authoritarian enclave to deliberative space: governance logics in post disaster reconstruction. AB - One would be hard-pressed nowadays to find any practitioners and scholars in the field of post-disaster reconstruction who would argue against the virtues of community participation. In practice, however, the legacy of community participation has been mixed. This paper pursues this line of inquiry by examining the manifestations of participation in three communities affected by Typhoon Haiyan that struck the Philippines on 8 November 2013. The findings suggest that different governance logics emerge in each of the three case studies: authoritarian; communitarian; and deliberative. These logics promote particular understandings of who should participate in the reconstruction process and the appropriate scope of action for citizens to express discontent, provide feedback, and perform democratic agency. The paper contends that design interventions in participatory procedures, as well as contingencies in wider social contexts, shape the character and legacies of community participation. It concludes by comparing the legacies of these three 'governance enclaves' and imagining possibilities for participatory politics in post-disaster settings. PMID- 29484701 TI - Trabecular and subchondral bone development of the talus and distal tibia from foal to adult in the warmblood horse. AB - Horses are precocial animals and able to stand and walk within hours after birth. To cope with associated loading, intrauterine bone development has shown to be anticipative. This study provides further insight into the post-natal development of structurally important features of trabecular and subchondral bone of the talus and sagittal ridge of the tibia of warm-blooded horses. In all areas studied, the average bone volume fraction showed a gradual increase over time, which was the result of a significant increase in trabecular thickness, without significant changes in the degree of anisotropy. Similar to the mineralised part of the bone, collagen content, measured as average retardation using polarised light microscopy, increased significantly, but the degree of anisotropy of the collagen type I network did not. At birth, the subchondral bone layer had a more trabecular aspect, gradually changing to an even surface with only a few vascular canals at an age of 2 months. Presented results indicate the necessity for a stronger structure, but not for a different structural design after birth, providing further evidence for anticipatory bone development in the horse. More knowledge about the strategies used to cope with mechanical loading after birth might be helpful in understanding the developmental bone and joint diseases. PMID- 29484702 TI - Review of parental activation interventions for parents of children with special health care needs. AB - BACKGROUND: A large number of U.S. children are identified as having special health care needs (CSHCN). Despite parents' central role in managing their child's needs, many parents report difficulties in navigating service systems, finding information about their child's condition, and accessing health care and community resources. Therefore, there is a need for interventions that "activate" parents of children with special health care needs to increase their knowledge, skills, and confidence in managing, coordinating, and advocating for their child's needs. This study sought to review the existing literature and examine the effects of parent support interventions that focus on parental activation either in part or whole, on child, parent, or family outcomes. Specific aims included (a) summarizing the nature and content of interventions; (b) describing changes in relevant outcomes; (c) identifying limitations and making recommendations for future research. METHODS: Following electronic databases were searched: MEDLINE, EMBASE, PsycINFO via ProQuest, PubMed, Cumulative Index to Nursing and Allied Health via EBSCO, Education Resources Information Center (ERIC) via ProQuest, The Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register), and Google Scholar. Twenty-two studies were selected, data were extracted, and quality was assessed using standardized procedures. RESULTS: Five intervention categories were identified: parent-to-parent supports, psycho educational groups, content-specific groups, community health worker model, and self-management-based interventions. Although most studies showed positive effects of the intervention, evidence was inconsistent for parental outcomes such as self-efficacy, confidence, strain, depression, and perceived social support. Evidence was more consistent in showing improvement in parent coping and in use of community-based services and resources. CONCLUSIONS: There is a need to boost active ingredients of interventions that specifically target enhancing parent skill sets relevant to areas of self-efficacy, confidence, and empowerment. Future studies must also adapt intervention and study design to recruit socioeconomically vulnerable families. PMID- 29484703 TI - Identifying taxonomic and functional surrogates for spring biodiversity conservation. AB - Surrogate approaches are widely used to estimate overall taxonomic diversity for conservation planning. Surrogate taxa are frequently selected based on rarity or charisma, whereas selection through statistical modeling has been applied rarely. We used boosted-regression-tree models (BRT) fitted to biological data from 165 springs to identify bryophyte and invertebrate surrogates for taxonomic and functional diversity of boreal springs. We focused on these 2 groups because they are well known and abundant in most boreal springs. The best indicators of taxonomic versus functional diversity differed. The bryophyte Bryum weigelii and the chironomid larva Paratrichocladius skirwithensis best indicated taxonomic diversity, whereas the isopod Asellus aquaticus and the chironomid Macropelopia spp. were the best surrogates of functional diversity. In a scoring algorithm for priority-site selection, taxonomic surrogates performed only slightly better than random selection for all spring-dwelling taxa, but they were very effective in representing spring specialists, providing a distinct improvement over random solutions. However, the surrogates for taxonomic diversity represented functional diversity poorly and vice versa. When combined with cross-taxon complementarity analyses, surrogate selection based on statistical modeling provides a promising approach for identifying groundwater-dependent ecosystems of special conservation value, a key requirement of the EU Water Framework Directive. PMID- 29484704 TI - The functional impact of amblyopia. AB - Amblyopia is the most common disorder managed in paediatric ophthalmic practice in industrialised countries. Reports on the impact of amblyopia on tasks relevant to the activities of children, or on skills pertinent to their education and quality of life, is leading to greater understanding of the functional disabilities associated with the condition. This review considers the extent to which amblyopia affects the ability to carry out everyday tasks, with particular attention to studies of motor skills and reading proficiency in children. Collectively, these studies show that amblyopia results in poorer outcomes on tests of skills required for proficiency in everyday tasks and which relate to childhood academic performance. However, the relative contributions that the documented vision anomalies inherent in amblyopia contribute to various functional disabilities is not fully determined. Recent reports have demonstrated improvement following treatment in standardised measures of fine motor skills involved in practical, everyday tasks. Including measurement of functional performance skills in amblyopia treatment trials is desirable to show treatment effect on crucial, real-world activities. PMID- 29484705 TI - What should be the laboratory approach against isolated prolongation of a activated partial thromboplastin time? AB - BACKGROUND: This study is a retrospective evaluation of patients who were subject to mixing study in our laboratory due to prolonged APTT. The preliminary diagnoses, clinical manifestations, and results of additional ordered tests were reviewed. The study aims to investigate whether repeating APTT test with a different assay prior to performing mixed study in patients with prolonged APTT would be a better alternative algorithmic approach in order to save both time and costs. METHODS: We retrospectively evaluated 166 patients (65 females and 101 males) who were subject to mixing study due to isolated prolonged APTT. Additional ordered tests to identify the etiology and clinical findings were reviewed. All patients who had prolonged APTT as a result of testing with Hemosil Synthasil APTT reagent in ACL TOP analyzer were repeated with Stago Cephascreen APTT reagent in STA-R coagulation analyzer. RESULTS: APTT test was requested preoperatively in 72.2% of cases. Only 6.6% of the cases had history of bleeding. Correction with mixing study was achieved in 122 (73.5%) cases, among which 75 (45%) cases were found to have APTT test results within reference range when tested with Cephascreen reagent. In 44 (26.5%) cases, mixing study did not result in correction. Only 4 cases were confirmed to have lupus anticoagulants (LA), while 4 cases were diagnosed with hemophilia with inhibitors. CONCLUSION: Prolonged APTT results should always be retested using a different assay prior to mixing study. The clinician and the laboratory specialist should collaborate at the postanalytical phase. PMID- 29484706 TI - Identification of a novel truncating mutation in PALB2 gene by a multigene sequencing panel for mutational screening of breast cancer risk-associated and related genes. AB - BACKGROUND: Breast cancer (BC) is the most common neoplasm in women, with 5%-10% patients showing a familial predisposition, where germline mutations in BRCA1/BRCA2 genes are found in -20% of cases. Next-generation sequencing (NGS) is among the best available options for genetic screening, providing several benefits that include enhanced sensitivity and unbiased mutation detection. PALB2 (partner and localizer of BRCA2) is a cancer predisposing gene recently described that encodes a protein partner of BRCA2 involved in DNA double-strand break repair and cell cycle control. The DNA damage response represents a key cellular event, targeted by innovative anticancer therapies, including those based on poly (ADP-ribose) polymerase (PARP) inhibitors targeting PARP1 and PARP2 enzymes, activated by DNA damage and involved in single-strand break and base excision repair. METHODS: Genomic DNA was isolated from 34 patient samples and four BC cell lines, as controls, and 27 breast cancer predisposing genes belonging to the BRCA1/BRCA2 and PARP pathways were sequenced by NGS. RESULTS: The panel described here allowed identification of several sequence variations in most investigated genes, among which we found a novel truncating mutation in PALB2. CONCLUSIONS: The NGS-based strategy designed here for molecular analysis of a customized panel of BC predisposing and related genes was found to perform effectively, providing a comprehensive exploration of all genomic sequences of the investigated genes. It is thus useful for BC molecular diagnosis, in particular for familiar cases where alterations in routinely investigated genes, such as BRCAs, result to be absent. PMID- 29484707 TI - 2-AG limits Theiler's virus induced acute neuroinflammation by modulating microglia and promoting MDSCs. AB - The innate immune response is mediated by primary immune modulators such as cytokines and chemokines that together with immune cells and resident glia orchestrate CNS immunity and inflammation. Growing evidence supports that the endocannabinoid 2-arachidonoylglycerol (2-AG) exerts protective actions in CNS injury models. Here, we used the acute phase of Theiler's virus induced demyelination disease (TMEV-IDD) as a model of acute neuroinflammation to investigate whether 2-AG modifies the brain innate immune responses to TMEV and CNS leukocyte trafficking. 2-AG or the inhibition of its hydrolysis diminished the reactivity and number of microglia at the TMEV injection site reducing their morphological complexity and modulating them towards an anti-inflammatory state via CB2 receptors. Indeed, 2-AG dampened the infiltration of immune cells into the CNS and inhibited their egress from the spleen, resulting in long-term beneficial effects at the chronic phase of the disease. Intriguingly, it is not a generalized action over leukocytes since 2-AG increased the presence and suppressive potency of myeloid derived suppressor cells (MDSCs) in the brain resulting in higher apoptotic CD4+ T cells at the injection site. Together, these data suggest a robust modulatory effect in the peripheral and central immunity by 2-AG and highlight the interest of modulating endogenous cannabinoids to regulate CNS inflammatory conditions. PMID- 29484708 TI - Comparing different estimated glomerular filtration rate equations in assessing glomerular function in children based on creatinine and cystatin C. AB - BACKGROUND: Glomerular filtration rate (GFR) is the best marker used to assess renal function. Estimated GFR (eGFR) equations have been developed, and the ideal formula is still under discussion. We wanted to find the most practical and reliable GFR in eGFR formulas. We compared serum creatinine (Scr)- and cystatin C (cysC)-based eGFR formulas in the literature. We also aimed to determine the suitability and the reliability of cysC for practical use in determining GFR in children. METHODS: We have enrolled 238 children in the study. Measurement of 24 hour creatinine clearance was compared with eGFR equations which are based on Scr, cysC, and creatinine plus cysC. RESULTS: Of the patients (n = 238), 117 were males (49.2%), and 121 (50.8%) were females with a median age of 9.0 years. The areas under the ROC curves of Counahan-Barratt and Bedside Schwartz were equal and 0.89 (with a 95% CI 0.80-0.97). The areas under the ROC curves were not significantly different in all cystatin C-based eGFR equations. The highest AUC values for differentiating normal vs abnormal renal functions according to CrCl24 were for the CKiD-cysC and CKiD-Scr-cysC equations. CONCLUSIONS: In our study, compared with creatinine-based ones, the cystatin C-based formulas did not show much superiority in predicting eGFR. Still, we think Bedside Schwartz is a good formula to provide ease of use because, in this equation, the constant k is same for all age groups. However, the most valuable equations in determining chronic kidney disease are the CKiD-cysC and CKiD-Scr-cysC equations. PMID- 29484709 TI - A pragmatic approach to amblyopia diagnosis: evidence into practice. AB - Amblyopia is a common cause of reduced vision in children. The clinical diagnosis is complicated and requires consideration of the severity of vision loss relative to the characteristics of the disrupting amblyogenic factor. Added to the challenge of a thorough examination of very young children, is the weight of consequence if the amblyogenic factor is not identified and treated appropriately within clinically recommended time frames. Further, the poor visual function may be a symptom of more sinister underlying pathology impacting the visual pathway. This review presents an evidence-based, pragmatic approach to the diagnosis of amblyopia, as a means for guiding best practice for the care of children who present with reduced vision. PMID- 29484710 TI - An in vitro evaluation of fracture load of implant-supported zirconia-based prostheses fabricated with different veneer materials. AB - OBJECTIVES: The purpose of this in vitro study was to evaluate fracture loads of implant-supported zirconia-based prostheses fabricated with different veneer materials (resin-based material and lithium disilicate ceramics). MATERIAL AND METHODS: Forty-four zirconia-based molar prostheses were fabricated on dental implants and divided into four groups (n = 11): zirconia-based prostheses veneered with feldspathic porcelain (ZVF), zirconia-based prostheses bonded with the lithium disilicate glass-ceramic veneer (ZBD), zirconia-based prostheses veneered with indirect composite resin (ZVC), and zirconia-based prostheses bonded with composite materials fabricated from a CAD/CAM resin block (ZBC). The zirconia-based prostheses and abutments were adhesively bonded with a dual polymerized resin-based luting material. Fracture load was determined using compression load to the prostheses with a universal testing machine. The data were analyzed with one-way analysis of variance (ANOVA) and Tukey's HSD test (alpha = .05). RESULTS: The mean fracture load was significantly higher in the ZBC group (3.95 kN) than in the ZVC group (3.28 kN). No significant difference in fracture load was found among the ZVF (3.52 kN), ZBD (3.48 kN), and ZVC groups. CONCLUSIONS: The adhesively bonded veneering technique enhances fracture resistance of implant-supported zirconia-based prostheses fabricated with a resin based material. All implant-supported zirconia-based restorations tested should resist physiologic masticatory forces in the oral environment. PMID- 29484711 TI - In vivo characterization of pustules in Malassezia Folliculitis by reflectance confocal microscopy and optical coherence tomography. A case series study. AB - BACKGROUND AND OBJECTIVE: Malassezia Folliculitis (MaF) is an inflammatory condition of hair follicles caused by Malassezia yeast. Optical coherence tomography (OCT) and reflectance confocal microscopy (RCM) are imaging technologies enabling in vivo visualization of superficial skin layers. This study explores morphology of pustules in MaF imaged by OCT and RCM. METHODS: Patients with microscopically verified MaF were included in this case series. Morphology was evaluated qualitatively with RCM and OCT, focusing on shape, border and content of selected pustules. RESULTS: Nine patients with MaF were included. Clinically, six patients presented monomorphic MaF with multiple superficial pustules, while three patients showed more polymorph MaF appearance. In total 13 pustules were investigated by RCM and OCT. In RCM images, pustules varied from having a well-defined border with homogenous content to ill-defined borders with heterogeneous content. A distinct black halo was occasionally observed around pustules as were dilated vessels. In OCT images, pustules appeared polymorphic, showing both well- and ill-defined structures with oval or irregular shape and more or less homogenous content. Malassezia fungi were not discernible by either RCM or OCT. Specific morphological image features in RCM and OCT did not reflect different clinical manifestations of MaF. CONCLUSION: RCM and OCT images identify morphological aspects of MaF pustules, and confirm that MaF is a folliculitis with clinical as well as morphological variance. PMID- 29484712 TI - Alveolar ridge preservation in the esthetic zone. AB - In the esthetic zone, in the case of tooth extraction, the clinician is often confronted with a challenge regarding the optimal decision-making process for providing a solution using dental implants. This is because, after tooth extraction, alveolar bone loss and structural and compositional changes of the covering soft tissues, as well as morphological alterations, can be expected. Ideally, the therapeutic plan starts before tooth extraction and it offers three options: spontaneous healing of the extraction socket; immediate implant placement; and techniques for preserving the alveolar ridge at the site of tooth removal. The decision-making process mainly depends on: (i) the chosen time-point for implant placement and the ability to place a dental implant; (ii) the quality and quantity of soft tissue in the region of the extraction socket; (iii) the remaining height of the buccal bone plate; and (iv) the expected rates of implant survival and success. Based on scientific evidence, three time-periods for alveolar ridge preservation are described in the literature: (i) soft-tissue preservation with 6-8 weeks of healing after tooth extraction (for optimization of the soft tissues); (ii) hard- and soft-tissue preservation with 4-6 months of healing after tooth extraction (for optimization of the hard and soft tissues); and (iii) hard-tissue preservation with > 6 months of healing after tooth extraction (for optimization of the hard tissues). PMID- 29484713 TI - What trainees grapple with: a study of threshold concepts on the medicine ward. AB - OBJECTIVES: Socialisation theories of professional identity formation (PIF) consider clinical rotations to be critically intense transformative experiences. However, few studies have explored what trainees grapple with during these transformative experiences or their influence on performance. Applying a threshold concepts (TCs) lens, this study investigates and documents 'troublesome' and 'transformative' concepts that junior trainees may encounter during a clinical rotation. Insights gained are essential for supporting trainee development. METHODS: Constructivist grounded theory was used to guide the collection and analysis of data for this two-phase study. Phase 1 involved direct observation and field interviews with 17 junior trainees over two observation periods and phase 2 involved in-depth interviews with 13 attending physicians. The theory of TCs was used as a sensitising concept. RESULTS: In total, nine TCs were identified and thematically grouped under the headings: Developing as a Professional, Providing Patient Care and Working Collectively. Across the interviewed attending physicians, there appeared to be a shared understanding of TCs strong trainees had crossed and weaker trainees struggled with. Observational and field interview data suggested that individual trainee actions were strongly influenced by the identified TC and whether or not the trainee appeared to have crossed any given threshold. Moreover, individual clinical practices could be influenced by more than one TC. Trainees were also observed to vary in the thresholds they had already crossed or struggled with. CONCLUSIONS: The identified TCs offer important insights into the relationship between trainee actions and how they conceptualise practice. At their heart, many appeared to represent ideals of practice that trainees should incorporate into their developing identities as they explore what it means to be a physician. Future research should explore how to incorporate TCs into assessment and the support of trainee development. PMID- 29484714 TI - Implant placement in the esthetic area: criteria for positioning single and multiple implants. AB - Patient expectations from implant treatment have changed over the years and esthetics plays an important role in defining what is now called success of rehabilitation. Of the many factors that influence the outcome of the rehabilitation, the two main ones are the bone and soft-tissue deficiencies at the intended implant site. Many surgical approaches are described in terms of timing of implant placement and management of regenerative procedures. The aim of this article is to discuss the different implant placement alternatives in the esthetic area, in particular: (i) the timing of implant placement/regenerative procedures/skeletal growth/altered passive eruption; (ii) the correct three dimensional position of the fixture between the cuspids and in the premolar area; (iii) multiple missing teeth in the esthetic area with single tooth/pontic or cantilevered options/prosthetic compensation; (iv) placement of implants into infected sites; and (v) the influence of abutment and crown morphology on implant position. Combining our long-standing clinical experience and the pertinent literature, the following conclusions can be drawn: Immediate implant placement can be a successful procedure in terms of esthetics but it is technique sensitive and requires an experienced team. Immediate placement is less traumatic to the patient as fewer surgical procedures are involved and patients tend to prefer this clinical approach with regards to quality of life. The diagnostic phase is of utmost importance, with not only bone and soft tissue deficiencies being addressed but also: skeletal growth, dental/implant soft tissue parameters such as altered passive eruption and the morphology of the roots adjacent to the edentulous area. Post-extraction immediate loading is feasible in infected sites. The correct position of the fixture should follow widely accepted guidelines but the abutment morphologies play a role in the vestibular/palatal position of the implant. The long axis of the implant, aiming at the incisal edge of the future restorations, is the most appropriate implant position when a shoulder-less abutment is used and allows a restorative crown morphology with a cervical contour resembling a natural tooth. The use of a shoulder-less abutment gives more space for the tissue to grow compared with the traditional abutment with shoulder finish line. PMID- 29484715 TI - 3D Jet Writing: Functional Microtissues Based on Tessellated Scaffold Architectures. AB - The advent of adaptive manufacturing techniques supports the vision of cell instructive materials that mimic biological tissues. 3D jet writing, a modified electrospinning process reported herein, yields 3D structures with unprecedented precision and resolution offering customizable pore geometries and scalability to over tens of centimeters. These scaffolds support the 3D expansion and differentiation of human mesenchymal stem cells in vitro. Implantation of these constructs leads to the healing of critical bone defects in vivo without exogenous growth factors. When applied as a metastatic target site in mice, circulating cancer cells home in to the osteogenic environment simulated on 3D jet writing scaffolds, despite implantation in an anatomically abnormal site. Through 3D jet writing, the formation of tessellated microtissues is demonstrated, which serve as a versatile 3D cell culture platform in a range of biomedical applications including regenerative medicine, cancer biology, and stem cell biotechnology. PMID- 29484716 TI - Ultrafast Processing of Hierarchical Nanotexture for a Transparent Superamphiphobic Coating with Extremely Low Roll-Off Angle and High Impalement Pressure. AB - Low roll-off angle, high impalement pressure, and mechanical robustness are key requirements for super-liquid-repellent surfaces to realize their potential in applications ranging from gas exchange membranes to protective and self-cleaning materials. Achieving these properties is still a challenge with superamphiphobic surfaces, which can repel both water and low-surface-tension liquids. In addition, fabrication procedures of superamphiphobic surfaces are typically slow and expensive. Here, by making use of liquid flame spray, a silicon dioxide titanium dioxide nanostructured coating is fabricated at a high velocity up to 0.8 m s-1 . After fluorosilanization, the coating is superamphiphobic with excellent transparency and an extremely low roll-off angle; 10 uL drops of n hexadecane roll off the surface at inclination angles even below 1 degrees . Falling drops bounce off when impacting from a height of 50 cm, demonstrating the high impalement pressure of the coating. The extraordinary properties are due to a pronounced hierarchical nanotexture of the coating. PMID- 29484717 TI - Necklace-Like Microfibers with Variable Knots and Perfusable Channels Fabricated by an Oil-Free Microfluidic Spinning Process. AB - Fiber materials with different structural features, which in many cases endow the fibers extraordinary functions, are drawing considerable attention from biomedical and material researchers. Here, perfusable necklace-like knotted microfibers are presented for the first time. Additionally, a novel microfluidic spinning method facilitates the production of variable knots and channels. Not only spindle-, but also hemisphere- and petal-knotted microfibers can be controllably fabricated. Generation and perfusion of both Janus channels and helical channel in the knotted microfibers are also shown. With no need of oil and surfactant, the spinning process is highly cytocompatible. The potential bioengineering and biomedical application of the knotted hollow microfiber is demonstrated by its cell-encapsulation feasibility and the unique liver acinus like diffusion gradient in the knot. The merits of perfusability, cytocompatibility, and structural diversity of the microfibers may open more avenues for further material and biomedical investigation. PMID- 29484718 TI - Comparing deregression methods for genomic prediction of test-day traits in dairy cattle. AB - We aimed to investigate the performance of three deregression methods (VanRaden, VR; Wiggans, WG; and Garrick, GR) of cows' and bulls' breeding values to be used as pseudophenotypes in the genomic evaluation of test-day dairy production traits. Three scenarios were considered within each deregression method: (i) including only animals with reliability of estimated breeding value (RELEBV ) higher than the average of parent reliability (RELPA ) in the training and validation populations; (ii) including only animals with RELEBV higher than 0.50 in the training and RELEBV higher than RELPA in the validation population; and (iii) including only animals with RELEBV higher than 0.50 in both training and validation populations. Individual random regression coefficients of lactation curves were predicted using the genomic best linear unbiased prediction (GBLUP), considering either unweighted or weighted residual variances based on effective records contributions. In summary, VR and WG deregression methods seemed more appropriate for genomic prediction of test-day traits without need for weighting in the genomic analysis, unless large differences in RELEBV between training population animals exist. PMID- 29484719 TI - Lipase-Triggered Water-Responsive "Pandora's Box" for Cancer Therapy: Toward Induced Neighboring Effect and Enhanced Drug Penetration. AB - Insufficient drug release as well as poor drug penetration are major obstacles for effective nanoparticles (NPs)-based cancer therapy. Herein, the high aqueous instability of amorphous calcium carbonate (ACC) is employed to construct doxorubicin (DOX) preloaded and monostearin (MS) coated "Pandora's box" (MS/ACC DOX) NPs for lipase-triggered water-responsive drug release in lipase overexpressed tumor tissue to induce a neighboring effect and enhance drug penetration. MS as a solid lipid can prevent potential drug leakage of ACC-DOX NPs during the circulatory process, while it can be readily be disintegrated in lipase-overexpressed SKOV3 cells to expose the ACC-DOX core. The high aqueous instability of ACC will lead to burst release of the encapsulated DOX to induce apoptosis and cytotoxicity to kill the tumor cells. The liberated NPs from the dead or dying cells continue to respond to the ubiquitous aqueous environment to sufficiently release DOX once unpacked, like the "Pandora's box", leading to severe cytotoxicity to neighboring cells (neighboring effect). Moreover, the continuously released free DOX molecules can readily diffused through the tumor extracellular matrix to enhance drug penetration to deep tumor tissue. Both effects contribute to achieve elevated antitumor benefits. PMID- 29484720 TI - Facilitated Water Transport through Graphene Oxide Membranes Functionalized with Aquaporin-Mimicking Peptides. AB - Water purification by membranes is widely investigated to address concerns related to the scarcity of clean water. Achieving high flux and rejection simultaneously is a difficult challenge using such membranes because these properties are mutually exclusive in common artificial membranes. Nature has developed a method for this task involving water-channel membrane proteins known as aquaporins. Here, the design and fabrication of graphene oxide (GO)-based membranes with a surface-tethered peptide motif designed to mimic the water selective filter of natural aquaporins is reported. The short RF8 (RFRFRFRF, where R and F represent arginine and phenylalanine, respectively) octapeptide is a concentrated form of the core component of the Ar/R (aromatic/arginine) water selective filter in aquaporin. The resulting GO-RF8 shows superior flux and high rejection similar to natural aquaporins. Molecular dynamics simulation reveal the unique configuration of RF8 peptides and the transport of water in GO-RF8 membranes, supporting that RF8 effectively emulates the core function of aquaporins. PMID- 29484721 TI - Low Thermal Conductivity through Dense Particle Packings with Optimum Disorder. AB - Heat transport plays a critical role in modern batteries, electrodes, and capacitors. This is caused by the ongoing miniaturization of such nanotechnological devices, which increases the local power density and hence temperature. Even worse, the introduction of heterostructures and interfaces is often accompanied by a reduction in thermal conductivity, which can ultimately lead to the failure of the entire device. Surprisingly, a fundamental understanding of the governing heat transport processes even in simple systems, such as binary particle mixtures is still missing. This contribution closes this gap and elucidates how strongly the polydispersity of a model particulate system influences the effective thermal conductivity across such a heterogeneous system. In a combined experimental and modeling approach, well-defined mixtures of monodisperse particles with varying size ratios are investigated. The transition from order to disorder can reduce the effective thermal conductivity by as much as ~50%. This is caused by an increase in the thermal transport path length and is governed by the number of interparticle contact points. These results are of general importance for many particulate and heterostructured materials and will help to conceive improved device layouts with more reliable heat dissipation or conservation properties in the future. PMID- 29484722 TI - Effective Carrier-Concentration Tuning of SnO2 Quantum Dot Electron-Selective Layers for High-Performance Planar Perovskite Solar Cells. AB - The carrier concentration of the electron-selective layer (ESL) and hole selective layer can significantly affect the performance of organic-inorganic lead halide perovskite solar cells (PSCs). Herein, a facile yet effective two step method, i.e., room-temperature colloidal synthesis and low-temperature removal of additive (thiourea), to control the carrier concentration of SnO2 quantum dot (QD) ESLs to achieve high-performance PSCs is developed. By optimizing the electron density of SnO2 QD ESLs, a champion stabilized power output of 20.32% for the planar PSCs using triple cation perovskite absorber and 19.73% for those using CH3 NH3 PbI3 absorber is achieved. The superior uniformity of low-temperature processed SnO2 QD ESLs also enables the fabrication of ~19% efficiency PSCs with an aperture area of 1.0 cm2 and 16.97% efficiency flexible device. The results demonstrate the promise of carrier-concentration-controlled SnO2 QD ESLs for fabricating stable, efficient, reproducible, large-scale, and flexible planar PSCs. PMID- 29484723 TI - Multi-modal imaging of long-term recovery post-stroke by positron emission tomography and matrix-assisted laser desorption/ionisation mass spectrometry. AB - RATIONALE: Stroke is a leading cause of disability worldwide. Understanding the recovery process post-stroke is essential; however, longer-term recovery studies are lacking. In vivo positron emission tomography (PET) can image biological recovery processes, but is limited by spatial resolution and its targeted nature. Untargeted mass spectrometry imaging offers high spatial resolution, providing an ideal ex vivo tool for brain recovery imaging. METHODS: Magnetic resonance imaging (MRI) was used to image a rat brain 48 h after ischaemic stroke to locate the infarcted regions of the brain. PET was carried out 3 months post-stroke using the tracers [18 F]DPA-714 for TSPO and [18 F]IAM6067 for sigma-1 receptors to image neuroinflammation and neurodegeneration, respectively. The rat brain was flash-frozen immediately after PET scanning, and sectioned for matrix-assisted laser desorption/ionisation mass spectrometry (MALDI-MS) imaging. RESULTS: Three months post-stroke, PET imaging shows minimal detection of neurodegeneration and neuroinflammation, indicating that the brain has stabilised. However, MALDI-MS images reveal distinct differences in lipid distributions (e.g. phosphatidylcholine and sphingomyelin) between the scar and the healthy brain, suggesting that recovery processes are still in play. It is currently not known if the altered lipids in the scar will change on a longer time scale, or if they are stabilised products of the brain post-stroke. CONCLUSIONS: The data demonstrates the ability to combine MALD-MS with in vivo PET to image different aspects of stroke recovery. PMID- 29484724 TI - Water Transport through Ultrathin Polyamide Nanofilms Used for Reverse Osmosis. AB - Thin-film composite membranes comprising a polyamide nanofilm separating layer on a support material are state of the art for desalination by reverse osmosis. Nanofilm thickness is thought to determine the rate of water transport through the membranes; although due to the fast and relatively uncontrolled interfacial polymerization reaction employed to form these nanofilms, they are typically crumpled and the separating layer is reported to be ~50-200 nm thick. This crumpled structure has confounded exploration of the independent effects of thickness, permeation mechanism, and the support material. Herein, smooth sub-8 nm polyamide nanofilms are fabricated at a free aqueous-organic interface, exhibiting chemical homogeneity at both aqueous and organic facing surfaces. Transfer of these ultrathin nanofilms onto porous supports provides fast water transport through the resulting nanofilm composite membranes. Manipulating the intrinsic nanofilm thickness from ~15 down to 8 nm reveals that water permeance increases proportionally with the thickness decrease, after which it increases nonlinearly to 2.7 L m-2 h-1 bar-1 as the thickness is further reduced to ~6 nm. PMID- 29484725 TI - CMOS Enabled Microfluidic Systems for Healthcare Based Applications. AB - With the increased global population, it is more important than ever to expand accessibility to affordable personalized healthcare. In this context, a seamless integration of microfluidic technology for bioanalysis and drug delivery and complementary metal oxide semiconductor (CMOS) technology enabled data-management circuitry is critical. Therefore, here, the fundamentals, integration aspects, and applications of CMOS-enabled microfluidic systems for affordable personalized healthcare systems are presented. Critical components, like sensors, actuators, and their fabrication and packaging, are discussed and reviewed in detail. With the emergence of the Internet-of-Things and the upcoming Internet-of-Everything for a people-process-data-device connected world, now is the time to take CMOS enabled microfluidics technology to as many people as possible. There is enormous potential for microfluidic technologies in affordable healthcare for everyone, and CMOS technology will play a major role in making that happen. PMID- 29484726 TI - Soft Somatosensitive Actuators via Embedded 3D Printing. AB - Humans possess manual dexterity, motor skills, and other physical abilities that rely on feedback provided by the somatosensory system. Herein, a method is reported for creating soft somatosensitive actuators (SSAs) via embedded 3D printing, which are innervated with multiple conductive features that simultaneously enable haptic, proprioceptive, and thermoceptive sensing. This novel manufacturing approach enables the seamless integration of multiple ionically conductive and fluidic features within elastomeric matrices to produce SSAs with the desired bioinspired sensing and actuation capabilities. Each printed sensor is composed of an ionically conductive gel that exhibits both long term stability and hysteresis-free performance. As an exemplar, multiple SSAs are combined into a soft robotic gripper that provides proprioceptive and haptic feedback via embedded curvature, inflation, and contact sensors, including deep and fine touch contact sensors. The multimaterial manufacturing platform enables complex sensing motifs to be easily integrated into soft actuating systems, which is a necessary step toward closed-loop feedback control of soft robots, machines, and haptic devices. PMID- 29484727 TI - Thermally Carbonized Porous Silicon and Its Recent Applications. AB - Recent progress in research on thermally carbonized porous silicon (TCPSi) and its applications is reported. Despite a slow start, thermal carbonization has now started to gain interest mainly due to new emerging areas for applications. These new areas, such as optical sensing, drug delivery, and energy storage, require stable surface chemistry and physical properties. TCPSi is known to have all of these desired properties. Herein, the above-listed properties of TCPSi are summarized, and the carbonization processes, functionalization, and characterization of TCPSi are reviewed. Moreover, some of the emerging fields of TCPSi applications are discussed and recent advances in the fields are introduced. PMID- 29484728 TI - A Bioinspired Interface Design for Improving the Strength and Electrical Conductivity of Graphene-Based Fibers. AB - Graphene-based fibers (GBFs) are attractive for next-generation wearable electronics due to their potentially high mechanical strength, superior flexibility, and excellent electrical and thermal conductivity. Many efforts have been devoted to improving these properties of GBFs in the past few years. However, fabricating GBFs with high strength and electrical conductivity simultaneously remains as a great challenge. Herein, inspired by nacre-like multilevel structural design, an interface-reinforced method is developed to improve both the mechanical property and electrical conductivity of the GBFs by introducing polydopamine-derived N-doped carbon species as resistance enhancers, binding agents, and conductive connection "bridges." Remarkably, both the tensile strength and electrical conductivity of the obtained GBFs are significantly improved to ~724 MPa and ~6.6 * 104 S m-1 , respectively, demonstrating great superiority compared to previously reported similar GBFs. These outstanding integrated performances of the GBFs provide it with great application potential in the fields of flexible and wearable microdevices such as sensors, actuators, supercapacitors, and batteries. PMID- 29484729 TI - Pinus densiflora bark extract ameliorates 2,4-dinitrochlorobenzene-induced atopic dermatitis in NC/Nga mice by regulating Th1/Th2 balance and skin barrier function. AB - Korean red pine (Pinus densiflora) bark has been traditionally used in Korea and other parts of East Asia to relieve inflammatory diseases. Although many studies using P. densiflora bark have been reported, its effect on atopic dermatitis (AD) has not been elucidated. Thus, we investigated whether the P. densiflora bark extract (PBE) has potential to attenuate AD symptoms and elucidated the molecular mechanism. Oral administration of PBE to mice with 2,4-dinitrochlorobenzene (DNCB)-induced AD lessened dermatitis scores and scratching behavior and significantly reduced measures of epidermal thickness, infiltration of mast cells and eosinophils, levels of immunoglobulin E (IgE), and IgG1 /IgG2a ratio in serum. PBE not only inhibited IL-4, IL-5, and IL-13 but also increased IFN-gamma in splenic production. Furthermore, PBE significantly suppressed mRNA expression of thymic stromal lymphopoietin and further downregulated the mRNA expression of Th2 and Th17 cytokines such as IL-4, IL-13, IL-17, IL-31, and TNF-alpha. In addition, the protein expressions of filaggrin, involucrin, and loricrin in lesional skin were recovered by PBE. These results suggest that PBE attenuates DNCB-induced AD via regulating Th1/Th2 balance and skin barrier function. PMID- 29484730 TI - Effect of dissolved organic nitrogen contamination on delta15 N-NH4 determination in water samples by modification of the diffusion method with gas-phase trapping. AB - RATIONALE: The isotopic tracer technique is widely used to identify the sources and fate of nitrogen (N) in order to understand the N cycle and contamination in water environments. The stable isotope ratio of ammonium is expected to greatly enhance the tracing analysis by combining it with the traditional nitrate isotope ratio. Diffusion followed by gas-phase trapping is the most commonly applied method for ammonium isotope ratio measurement. Although dissolved organic nitrogen (DON) is abundant in natural water and its breakdown in the diffusion procedure has been reported, the interference of DON with the measurement of ammonium isotope ratios has not been fully examined. METHODS: This study aims to test the effect of DON contamination by using organic N compounds, viz. humic acid and alanine. A series of diffusion experiments was conducted at a temperature of 80 degrees C for a maximum of 7 days. Ammonia was transferred from alkaline solution and trapped with an acidic filter. This method was applied for samples with ammonium concentrations between 0.5 and 2.0 mg-N/L. RESULTS: There was no difference between the ammonium N stable isotope ratios for samples with and without added DON compounds; the fractionation between the observed value and the actual value was negligible, in the range of 0.2 to 1.00/00. The modifications of previous studies, i.e. shorter diffusion period, no vigorous shaking and using gas-phase trapping, successfully avoided any breakdown of DON in fresh water samples. CONCLUSIONS: The modified method provides high precision and accuracy and it is recommended for the analysis of anthropogenically influenced water samples, such as paddy fields, ground water, rivers and lakes. PMID- 29484731 TI - Reducing bias in the dairy cattle single-step genomic evaluation by ignoring bulls without progeny. AB - The number of genotyped animals has increased rapidly creating computational challenges for genomic evaluation. In animal model BLUP, candidate animals without progeny and phenotype do not contribute information to the evaluation and can be discarded. In theory, genotyped candidate animal without progeny can bring information into single-step BLUP (ssGBLUP) and affect the estimation of other breeding values. We studied the effect of including or excluding genomic information of culled bull calves on genomic breeding values (GEBV) from ssGBLUP. In particular, GEBVs of genotyped bulls with daughters and GEBVs of young bulls selected into AI to be progeny tested (test bulls) were studied. The ssGBLUP evaluation was computed using Nordic test day (TD) model and TD data for the Nordic Red Dairy Cattle. The results indicate that genomic information of culled bull calves does not affect the GEBVs of progeny tested reference animals, but if genotypes of the culled bulls are used in the TD ssGBLUP, the genetic trend in the test bulls is considerably higher compared to the situation when genomic information of the culled bull calves is excluded. It seems that by discarding genomic information of culled bull calves without progeny, upward bias of GEBVs of test bulls is reduced. PMID- 29484732 TI - Sodium Chloride Crystal-Induced SERS Platform for Controlled Highly Sensitive Detection of Illicit Drugs. AB - A sodium chloride crystal-driven spontaneous 'hot spot' structure was demonstrated as a SERS-active platform, to get reproducible SERS signals, and eliminate the need for mapping large areas, in comparison with solution phase testing. During the process of solvent evaporation, the crystals produced induced silver aggregates to assemble around themselves. The micro-scale crystals can also act as a template to obtain an optical position, such that the assembled hot area is conveniently located during SERS measurements. More importantly, the chloride ions added in colloids can also replace the citrate and on the surface of the silver sol, and further decrease the background interference. High quality SERS spectra from heroin, methamphetamine (MAMP), and cocaine have been obtained on the crystal-driven hot spot structure with high sensitivity and credible reproducibility. This approach can not only bring the nanoparticles to form plasmonic hot spots in a controlled way, and thus provide high sensitivity, but also potentially be explored as an active substrate for label-free detection of other illicit drugs or additives. PMID- 29484733 TI - Antifungal constituents of the plant family Amaryllidaceae. AB - Globalization, the modern lifestyle, immuno-suppressive agents, invasive surgical procedures, the loss of efficacies of existing drugs, and multidrug resistance are some of the factors used to explain the rise in fungal infections in recent years. Significant advances have been made in attempts to replace existing antifungal schedules, especially with synthetic targets. The identification of other platforms for drug discovery is now entrenched in research programs across the globe. Plants offer significant benefits owing to their numerical superiority, exceedingly broad chemical basis and appealing sustainability characteristics. Furthermore, plants have a long and rich historical association with traditional approaches towards fungal diseases. These have in numerous instances served as markers in the bioassay-guided identification of the active constituents. Although the plant family Amaryllidaceae is conventionally associated with cancer and motor-neuron disease chemotherapies, around 30 of its species have been examined for antifungal activities with microgram per millilitre inhibitory activities detected in several instances. This review focuses on the nearly 40 constituents from the family, mainly isoquinoline alkaloids, which have been screened against around 50 fungal pathogens. Encouragingly, microgram per millilitre growth inhibitory activities were applicable for several of the compounds with a minimum inhibitory concentration of 4 MUg/ml seen to be the lowest. PMID- 29484734 TI - Ultrafast Coherent Absorption in Diamond Metamaterials. AB - Diamond is introduced as a material platform for visible/near-infrared photonic metamaterials, with a nanostructured polycrystalline diamond metasurface only 170 nm thick providing an experimental demonstration of coherent light-by-light modulation at few-optical-cycle (6 fs) pulse durations. "Coherent control" of absorption in planar (subwavelength-thickness) materials has emerged recently as a mechanism for high-contrast all-optical gating, with a speed of response that is limited only by the spectral width of the absorption line. It is shown here that a free-standing diamond membrane structured by focused ion beam milling can provide strong, spectrally near-flat absorption over a visible to near-infrared wavelength range that is wide enough (wider than is characteristically achievable in plasmonic metal metasurfaces) to facilitate coherent modulation of ultrashort optical pulses comprising only a few oscillations of electromagnetic field. PMID- 29484735 TI - Treatment of intrahepatic cholestasis of pregnancy with ursodeoxycholic acid associated with improvement of fetal first-degree atrioventricular block. PMID- 29484736 TI - Pharmacological or transcriptional inhibition of both HDAC1 and 2 leads to cell cycle blockage and apoptosis via p21Waf1/Cip1 and p19INK4d upregulation in hepatocellular carcinoma. AB - OBJECTIVES: Histone deacetylases (HDACs) are commonly dysregulated in cancer and represent promising therapeutic targets. However, global HDAC inhibitors have shown limited efficacy in the treatment of solid tumours, including hepatocellular carcinoma (HCC). In this study, we investigated the therapeutic effect of selectively inhibiting HDAC1 and 2 in HCC. METHODS: HDAC1 inhibitor Tacedinaline (CI994), HDAC2 inhibitor Santacruzamate A (CAY10683), HDAC1/2 common inhibitor Romidepsin (FK228) and global HDAC inhibitor Vorinostat (SAHA) were used to treat HCC cells. Cell cycle, apoptosis and the protein levels of CDKs and CDKNs were performed to evaluate HCC cell growth. Inhibition of HDAC1/2 by RNAi was further investigated. RESULTS: Combined inhibition of HDAC1/2 led to HCC cell morphology changes, growth inhibition, cell cycle blockage and apoptosis in vitro and suppressed the growth of subcutaneous HCC xenograft tumours in vivo. p21Waf1/Cip1 and p19INK4d , which play roles in cell cycle blockage and apoptosis induction, were upregulated. Inhibition of HDAC1/2 by siRNA further demonstrated that HDAC1 and 2 cooperate in blocking the cell cycle and inducing apoptosis via p19INK4d and p21Waf1/Cip1 upregulation. Finally, H3K18, H3K56 and H4K12 in the p19INK4d and p21Waf1/Cip1 promoter regions were found to be targets of HDAC1/2. CONCLUSIONS: Pharmacological or transcriptional inhibition of HDAC1/2 increases p19INK4d and p21Waf1/Cip1 expression, decreases CDK expression and arrests HCC growth. These results indicated a potential pharmacological mechanism of selective HDAC1/2 inhibitors in HCC therapy. PMID- 29484737 TI - The BRAF activated non-coding RNA: A pivotal long non-coding RNA in human malignancies. AB - Long non-coding RNAs (lncRNAs) participate in the complex network of cancer and play an important role in tumourigenesis and progression. BRAF activated non coding RNA (BANCR), a 4-exon transcript of 693-bp, was first discovered as an oncogenic long non-coding RNA in BRAFV600E melanomas cells in 2012 and was related to melanoma cell migration. Besides melanoma, increasing evidence has explored the potential role of BANCR in the development and progression of multiple other human malignancies, such as retinoblastoma, lung cancer, gastric cancer etc. since its discovery. The expression pattern of BANCR varies in different types of cancers, either as a tumour suppressor or as an accelerator. Functional BANCR may serve as a promising biomarker for cancer diagnosis as well as prognosis evaluation. BANCR-targeted intervention may also become a valuable novel therapeutic tool against human malignancies. This review summarized the advanced research progresses concerning the expression and role of BANCR in different human malignancies. PMID- 29484739 TI - A new comprehensive paradigm for prenatal diagnosis: seeing the forest through the trees. PMID- 29484738 TI - Anti-cancer therapy with TNFalpha and IFNgamma: A comprehensive review. AB - Tumour necrosis factor alpha (TNFalpha) and interferon gamma (IFNgamma) were originally found to be produced by inflammatory cells and play important roles in the immune system and surveillance of tumour growth. By activating distinct signalling pathways of nuclear factor-kappaB (NF-kappaB), mitogen-activated protein kinase (MAPK), and JAK/STAT, TNFalpha and IFNgamma were reported to effectively trigger cell death and perform powerful anti-cancer effects. In this review, we will discuss the new advancements of TNFalpha and IFNgamma in anti cancer therapy. PMID- 29484740 TI - Physical appearance concerns are uniquely associated with the severity of steroid dependence and depression in anabolic-androgenic steroid users. AB - INTRODUCTION AND AIMS: Emerging research suggests that the sub-population of anabolic-androgenic steroid (AAS) users who experience physical appearance concerns may suffer greater psychological dysfunction than other sub-populations, including users with athletic or occupational concerns. Thus, among current AAS users, we sought to determine whether, and to what extent, social physique anxiety-an established measure of appearance concern-was associated with psychological dysfunction. DESIGN AND METHODS: Interviews were conducted with a sample of 74 male AAS users living in Australia. Users completed self-report instruments of the severity of AAS dependence, depression, hazardous and risky drinking, use of non-AAS illicit drugs, psychological side-effects due to AAS use and abnormal test results due to AAS use. RESULTS: Multivariate analyses revealed that greater social physique anxiety was uniquely associated with more severe symptoms of both AAS dependence and depression. Moreover, the effect size of these relationships was large. Social physique anxiety was not associated with hazardous or risky drinking, non-AAS illicit drug use, psychological side-effects or abnormal test results. DISCUSSION AND CONCLUSIONS: Limitations notwithstanding, the study is consistent with the notion that AAS users who experience appearance concerns are at heightened risk of co-morbid psychological dysfunction. Given trends indicating an increase in the prevalence of AAS use in Australia and elsewhere, the findings suggest that health-care systems may need to consider prioritising the sub-population of AAS users who experience appearance concerns. Further investigation of the clinical syndrome of AAS dependence is required, including its relation to body image and eating disorders. PMID- 29484741 TI - Interpretation of results from the competitive Biacore procedure for characterizing immunochemical interactions in solution. AB - Rigorous consideration of the consequences of antibody bivalence in the published competitive kinetic procedure for quantifying the solution characteristics of an antigen-antibody interaction in solution has rendered redundant the practice of substituting the Fab fragment for the antibody to ensure validity of the analysis of results in terms of theory developed for a univalent analyte. Although the quantitative expressions differ for univalent and bivalent analytes, the additional contribution arising from bivalence is likely to be well within the limits of experimental uncertainty in the measured binding constant. PMID- 29484743 TI - Automated analysis of fetal cardiac function using color tissue Doppler imaging in the second half of normal pregnancy. AB - OBJECTIVES: Color tissue Doppler imaging (cTDI) is a promising tool for the assessment of fetal cardiac function. However, the analysis of myocardial velocity traces is cumbersome and time-consuming limiting its application in clinical practice. The aim of this study was to evaluate fetal cardiac function during the second half of pregnancy and to develop reference ranges using a newly developed automated method to analyze cTDI recordings from a cardiac four-chamber view. METHODS: This was a cross-sectional study including 201 normal singleton pregnancies between 18 and 42 weeks of gestation. During fetal echocardiography, a four-chamber view of the heart was visualized and cTDI performed. Regions of interest were placed at the atrioventricular plane in the left ventricular (LV), right ventricular (RV) and septal walls of the fetal heart to obtain myocardial velocity traces that were analyzed off-line using an automated algorithm. Peak myocardial velocities during atrial contraction (Am), ventricular ejection (Sm), rapid ventricular filling, i.e. early diastole (Em), Em/Am ratio, mechanical cardiac time intervals and myocardial performance index (cMPI) were evaluated and gestational age specific reference ranges were constructed. Differences between female and male fetuses were assessed using Mann-Whitney U-test. RESULTS: At 18 weeks of gestation the peak myocardial velocities (cm/s) presented as fitted mean with 95% confidence intervals were: LV Am 3.39 (3.09-3.70), LV Sm 1.62 (1.46 1.79), LV Em 1.95 (1.75-2.15), septal Am 3.07 (2.80-3.36), septal Sm 1.93(1.81 2.06), septal Em 2.57 (2.32-2.84), RV Am 4.89 (4.59-5.20), RV Sm 2.31 (2.16-2.46) and RV Em 2.94 (2.69-3.21). At 42 weeks of gestation the peak myocardial velocities (cm/s) had increased to: LV Am 4.25 (3.87-4.65), LV Sm 3.53 (3.19 3.89), LV Em 4.55 (4.18-4.94), septal Am 4.49 (4.17-4.82), septal Sm 3.36 (3.17 3.55), septal Em 3.76 (3.51-4.03), RV Am 6.52 (6.09-6.96), RV Sm 4.95 (4.59-5.32) and RV Em 5.42 (4.99-5.88). Regression equations used for the construction of gestational age specific reference ranges for peak myocardial velocities, Em/Am ratios, mechanical cardiac time intervals, and cMPI are presented. Differences between female and male fetuses were seen in variables describing late diastolic and systolic fetal cardiac function. CONCLUSION: All peak myocardial velocities showed an increase with gestational age. The mechanical time intervals remained more stable throughout the second half of pregnancy. It was possible to construct reference ranges using cTDI-derived myocardial velocity traces which is a pre requisite to distinguish between normal and abnormal fetal cardiac function. PMID- 29484742 TI - A tutorial on conducting genome-wide association studies: Quality control and statistical analysis. AB - OBJECTIVES: Genome-wide association studies (GWAS) have become increasingly popular to identify associations between single nucleotide polymorphisms (SNPs) and phenotypic traits. The GWAS method is commonly applied within the social sciences. However, statistical analyses will need to be carefully conducted and the use of dedicated genetics software will be required. This tutorial aims to provide a guideline for conducting genetic analyses. METHODS: We discuss and explain key concepts and illustrate how to conduct GWAS using example scripts provided through GitHub (https://github.com/MareesAT/GWA_tutorial/). In addition to the illustration of standard GWAS, we will also show how to apply polygenic risk score (PRS) analysis. PRS does not aim to identify individual SNPs but aggregates information from SNPs across the genome in order to provide individual level scores of genetic risk. RESULTS: The simulated data and scripts that will be illustrated in the current tutorial provide hands-on practice with genetic analyses. The scripts are based on PLINK, PRSice, and R, which are commonly used, freely available software tools that are accessible for novice users. CONCLUSIONS: By providing theoretical background and hands-on experience, we aim to make GWAS more accessible to researchers without formal training in the field. PMID- 29484744 TI - Transcriptional regulation of the vitellogenin gene through a fecundity-related single nucleotide polymorphism within a GATA-1 binding motif in the brown planthopper, Nilaparvata lugens. AB - Identifying the Single Nucleotide Polymorphisms (SNPs) with functions in insect fecundity promises to provide novel insight into genetic mechanisms of adaptation and to aid in effective control of insect populations. We previously identified several SNPs within the vitellogenin (Vg) promoter region between a high fecundity population (HFP) and a low-fecundity population (LFP) of the brown planthopper, Nilaparvata lugens Stal (Hemiptera: Delphacidae). Here, we found that an A-to-T (HFP allele to LFP allele) transversion at nucleotide -953 upstream of Vg in a Nilaparvata lugens GATA-1 (NlGATA-1) binding motif is associated with the level of Vg transcription. We also characterized NlGATA-1, containing a double CX2 CX17 CX2 C zinc finger, which has been implicated in the activation of Vg gene expression. Knockdown of the NlGATA-1 gene results in a reduced basal level of expression of the Vg gene and fewer offspring of N. lugens in vivo, whereas overexpression of NlGATA-1 in cells increased Vg promoter activity. Moreover, upon cotransfection with NlGATA-1 expression vector, the luciferase activities of Vg reporter vectors with the A allele were significantly higher than those with the T allele. These findings support a mechanism in which a SNP within the promoter of Vg is associated with the level of Vg transcription by altering the binding activity of NlGATA-1 and subsequently affecting fecundity in N. lugens. PMID- 29484745 TI - The fourth ventricle index - a sonographic marker for severe fetal vermian dysgenesis / agenesis. AB - OBJECTIVE: Prenatal diagnosis of midbrain-hindbrain malformations rely primarily on abnormal size and shape of the cerebellum and retrocerebellar space. The aim of this study was to present the 4th ventricle index (4VI), and to evaluate its role as a marker of severe vermian dysgenesis / agenesis cases without an open 4th ventricle (4v). METHODS: This prospective cross-sectional study included 384 healthy fetuses between 14 to 37 gestational weeks. Axial images of the 4v were obtained and the 4VI was calculated as the ratio between the latero-lateral and anteroposterior diameters. Reference ranges were constructed and the normal values compared to 44 fetuses with confirmed anomalies including severe vermian dysgenesis/agenesis, as Joubert syndrome and related disorders, rhombencephalosynapsis, cobblestone malformations and cerebellar hypoplasia. RESULTS: The 4VI in normal fetuses was constantly >1. In affected fetuses, measurements were below -2SD and always <1. CONCLUSIONS: The 4VI is sonographic marker for severe fetal vermian dysgenesis / agenesis in the absence of an open 4v. It may be easily incorporated into the routine brain scan and a 4VI <1 indicate the need of dedicated fetal neuroimaging studies for appropriate diagnosis and prenatal counseling. PMID- 29484746 TI - The association of IgA deficiency on infection rate, self-perceived health, and levels of C-reactive protein in healthy blood donors. AB - The clinical importance of immunoglobulin A (IgA) deficiency in otherwise healthy individuals is not well described. We aimed to investigate the self-reported mental and physical health and the risk of infection in IgA-deficient blood donors compared to healthy control blood donors. Infectious events, recorded in public health registries either as prescriptions filled of any antimicrobial medicine or as hospital infections, were compared between 177 IgA-deficient blood donors and 1770 control blood donors. A subset of the IgA-deficient donors were further characterized by self-reported health (Short Form-12, n = 28) and circulating C-reactive protein (CRP) (n = 10). IgA-deficient individuals had lower self-reported mental health (p = 0.01) and higher CRP (p < 0.05). A strong trend was found regarding prescription of antimicrobial medicine (hazard ratio = 1.19, p = 0.05). No association was found with hospital infections (hazard ratio = 1.02, p = 0.95) or self-reported physical health (p = 0.86). IgA-deficient blood donors have impaired self-reported mental health, enhanced inflammation and possibly an increased risk of infection. Despite these findings, this study does not provide sufficient evidence to warrant specific health precautions for donors with IgA deficiency. PMID- 29484747 TI - Bacterial isolates exhibiting multidrug resistance, hemolytic activity, and high 16S rRNA gene similarity with well-known pathogens found in camel milk samples of Riyadh region. AB - Customary consumption of unpasteurized milk by the population in the central Najed region of Saudi Arabia may pose a health risk. Therefore, 80 camel milk samples were collected aseptically from seven different stations of Riyadh region. The biochemical and microbiological properties of these milk samples were determined. Nutrient agar and brain heart infusion agar were used to determine mesophilic aerobic counts (MACs). The MAC in each mL of milk varied from 60 to 16 * 104 CFU/mL on nutrient agar. Based on the colony morphology, 176 colonies were collected from different samples, and these isolates were de-replicated into 80 unique isolates using rep-PCR analysis. Surprisingly, the 16S rRNA sequence analysis of these strains revealed that more than one-third of the collected milk samples contained strains that share maximum sequence similarities with well known pathogens, such as Brucella, Bacillus anthracis, Listeria monocytogenes, and MRSA. Furthermore, many strains exhibit 16S rRNA gene similarity with opportunistic pathogens such as Citrobacter freundii and Kytococcus schroeteri. Many strains exhibit beta-hemolytic activity and resistant to six different antibiotics. Our study suggested that consumption of raw camel milk from this region constitutes a great health risk. PMID- 29484748 TI - Eosinophilia is a favorable prognostic marker for oral cavity and lip squamous cell carcinoma. AB - Eosinophils are frequently encountered with squamous cell carcinomas (SCC) and it has been proposed that tumor-associated tissue eosinophilia (TATE) could be of prognostic significance in oral SCC. The aim was to evaluate TATE in 83 oral cavity and 16 lip SCCs as well as the best possible use of TATE as a prognostic marker. The number of eosinophils was counted per high power fields (HPF, *400) in three different representative areas of the tumor and its stroma. The degree of TATE was analyzed in relation to clinicopathological features of tumors and patients' survival (follow-up mean 40.7 months) using Fisher's exact test. TATE was detected in 58 (70%) oral and 8 (50%) lip SCC samples. The median number of eosinophils between oral and lip SCC was different (p = 0.028) but TATE was similar per HPF (p = 0.085). Totally, 6% of lip and 21% of oral SCC patients died during the follow-up. The patients with the higher TATE had significantly better survival than the patients with the lower TATE (p = 0.0136). The best cut-off value predicting the survival was 4 eosinophils/HPF. TATE is a prognostic marker for oral and lip SCC: more than 4 eosinophils/HPF may predict more favorable prognosis. PMID- 29484749 TI - rpoB gene mutations among Mycobacterium tuberculosis isolates from extrapulmonary sites. AB - The aim of this study was to analyze mutations occurring in the rpoB gene of Mycobacterium tuberculosis (MTB) isolates from clinical samples of extrapulmonary tuberculosis (EPTB). Seventy formalin-fixed, paraffin-embedded samples and fresh tissue samples from confirmed EPTB cases were analyzed. Nested PCR based on the rpoB gene was performed on the extracted DNAs, combined with cloning and subsequent sequencing. Sixty-seven (95.7%) samples were positive for nester PCR. Sequence analysis of the 81 bp region of the rpoB gene demonstrated mutations in 41 (61.2%) of 67 sequenced samples. Several point mutations including deletion mutations at codons 510, 512, 513 and 515, with 45% and 51% of the mutations in codons 512 and 513 respectively were seen, along with 26% replacement mutations at codons 509, 513, 514, 518, 520, 524 and 531. The most common alteration was Gln -> His, at codon 513, presented in 30 (75.6%) isolates. This study demonstrated sequence alterations in codon 513 of the 81 bp region of the rpoB gene as the most common mutation occurred in 75.6% of molecularly confirmed rifampin-resistant strains. In addition, simultaneous mutation at codons 512 and 513 was demonstrated in 34.3% of the isolates. PMID- 29484750 TI - Costunolide suppresses an inflammatory angiogenic response in a subcutaneous murine sponge model. AB - Costunolide is known to possess anti-inflammatory and antitumor activity, but its role in tumor angiogenesis, the key step involved in tumor growth and metastasis, and the involved molecular mechanism is still unknown. We aimed to investigate the effects of costunolide on key components of inflammatory angiogenesis in the murine cannulated sponge implant angiogenesis model. Polyester-polyurethane sponges, used as a framework for fibrovascular tissue growth, were implanted in Swiss albino mice and costunolide (5, 10 and 20 mg/kg/day) was administered for 14 days through installed cannula. The implants collected at day 14 post implantation were processed for the assessment of hemoglobin (Hb), myeloperoxidase (MPO), N-acetylglucosaminidase (NAG) and collagen, which were used as indices for angiogenesis, neutrophil and macrophage accumulation, and extracellular matrix deposition, respectively. Relevant inflammatory, angiogenic and fibrogenic cytokines were also determined. Costunolide treatment attenuated the main components of the fibrovascular tissue, wet weight, vascularization (Hb content), macrophage recruitment (NAG activity), collagen deposition, and the levels of vascular endothelial growth factor (VEGF), interleukin (IL)-1beta, IL 6, IL-17, tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF beta). Regulatory function of costunolide on multiple parameters of the main components of inflammatory angiogenesis has been revealed giving insight into the potential therapeutic benefit underlying the anti-angiogenic actions of costunolide. PMID- 29484751 TI - 'Are The Times A-Changin'? Trends in adolescent substance use in Europe. AB - AIMS: To estimate temporal trends in adolescents' current cigarette, alcohol and cannabis use in Europe by gender and region, test for regional differences and evaluate regional convergence. DESIGN AND SETTING: Five waves of the European School Survey Project on Alcohol and Other Drugs (ESPAD) from 28 countries between 1999 and 2015. Countries were grouped into five regions [northern (NE), southern (SE), western (WE), eastern Europe (EE) and the Balkans (BK)]. PARTICIPANTS: A total of 223 814 male and 211 712 female 15-16-year-old students. MEASUREMENTS: Daily cigarette use, weekly alcohol use, monthly heavy episodic drinking (HED) and monthly cannabis use. Linear and quadratic trends were tested using multi-level mixed-effects logistic regression; regional differences were tested using pairwise Wald tests; mean absolute differences (MD) of predicted prevalence were used for evaluating conversion. FINDINGS: Daily cigarette use among boys in EE showed a declining curvilinear trend, whereas in all other regions a declining linear trend was found. With the exception of BK, trends of weekly drinking decreased curvilinear in both genders in all regions. Among girls, trends in WE, EE and BK differed from trends in NE and SE. Monthly HED showed increasing curvilinear trends in all regions except in NE (both genders), WE and EE (boys each). In both genders, the trend in EE differed from the trend in SE. Trends of cannabis use increased in both genders in SE and BK; differences were found between the curvilinear trends in EE and BK. MD by substance and gender were generally somewhat stable over time. CONCLUSIONS: Despite regional differences in prevalence of substance use among European adolescents from 1999 to 2015, trends showed remarkable similarities, with strong decreasing trends in cigarette use and moderate decreasing trends in alcohol use. Trends of cannabis use only increased in southern Europe and the Balkans. Trends across all substance use indicators suggest no regional convergence. PMID- 29484752 TI - Outcome of fetuses with prenatal diagnosis of isolated severe bilateral ventriculomegaly: systematic review and meta-analysis. AB - OBJECTIVE: To quantify from the published literature survival and neurodevelopmental outcome of fetuses with prenatally detected isolated severe bilateral ventriculomegaly. METHODS: MEDLINE, EMBASE and the Cochrane Library were searched electronically. Only cases with a prenatal diagnosis of apparently isolated severe ventriculomegaly and postnatal neurodevelopmental assessment were selected and included. Severe ventriculomegaly was defined as enlargement of the ventricular atria, with a diameter of greater than 15 mm in the transventricular plane. All cases in which the investigators were unable to detect associated structural abnormality, chromosomal abnormality or fetal infection, and in which the ventriculomegaly was therefore regarded as apparently isolated, were included. Those for which the etiology was identified prenatally were excluded, whereas those with postnatal identification of the underlying cause were not excluded, since this information was not available prenatally. The quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS) for cohort studies. Pregnancy outcomes such as termination, stillbirth, neonatal survival and developmental outcome of the baby, were recorded. The degree of disability was classified as no, mild or severe disability. Statistical assessment was performed by meta-analysis of proportions to combine data, weighting the studies using the inverse variance method and a random-effects model. Proportions and CIs were reported. RESULTS: Eleven studies including 137 fetuses were found. Twenty seven pregnancies underwent termination and were excluded. The remaining 110 fetuses with apparently isolated severe ventriculomegaly for which continuation of pregnancy was intended, form the study population. Overall quality assessed using NOS for cohort studies was good. Survival was reported in 95/110 (pooled proportion 87.9% (95% CI, 75.6-96.2%)) cases. In 15/110 (pooled proportion 12.1% (95% CI, 3.8-24.4%)), either stillbirth or neonatal demise was reported. No disability was reported in 41/95 survivors (pooled proportion 42.2% (95% CI, 27.5 57.6%)). However, 17/95 showed mild/moderate disability (pooled proportion 18.6% (95% CI, 7.2-33.8%)) and 37/95 were reported to have severe disability (pooled proportion 39.6% (95% CI, 30.0-50.0%)). CONCLUSIONS: Four-fifths of fetuses with severe ventriculomegaly survive and, of these, just over two-fifths show normal neurodevelopment. The overall survivors without disability account for more than one third of the total. Given that many cases undergo termination of pregnancy and require longer follow-up in order to detect subtle abnormalities, mortality and prevalence of developmental delay may be even higher than that reported in this paper. Copyright (c) 2018 ISUOG. Published by John Wiley & Sons Ltd. PMID- 29484753 TI - The long non-coding RNA SPRY4-IT1: An emerging player in tumorigenesis and osteosarcoma. AB - Accumulating evidence from genome-wide analysis and functional studies has begun to unveil the important role of long non-coding RNAs (lncRNAs) in cancer development. The lncRNA SPRY4-IT1 is derived from an intron of SPRY4 gene and was originally reported to be upregulated in melanoma in which it functioned as an oncogene. Since this discovery, an increasing number of studies have investigated the expression and function of SPRY4-IT1 in human cancers. Aberrant expression of SPRY4-IT1 has now been documented in different cancer types, including osteosarcoma, breast, renal, oesophageal and prostate cancers. However, its deregulation and function in lung and gastric cancers remain controversial. Pertinent to clinical practice, SPRY4-IT1 expression has been shown to predict survival of cancer patients. In this review, we summarize recent evidence concerning SPRY4-IT1 deregulation and the associated mechanisms in human cancers. We also discuss the potential clinical utilization of this lncRNA as a diagnostic and prognostic biomarker for cancer patients. PMID- 29484754 TI - Integrated analytical methodology to investigate bioactive compounds in Crocus sativus L. flowers. AB - INTRODUCTION: The increasing interest on Crocus sativus L. over the last decades is caused by its potential employment as a source of biologically active molecules, endowed with antioxidant and nutraceutical properties. These molecules are present mainly in stigmas and tepals, these last generally considered as byproducts. OBJECTIVE: To characterise bioactive compounds in stigmas, stamens, and tepals of Crocus sativus L. for quality, cross-contamination of tissues or fraudulent addition, joining spectroscopic and chromatographic techniques. METHODOLOGY: Fourier transform infrared (FT-IR) and Raman spectroscopies were initially employed, being very rapid in response; volatiles were more appropriately investigated by gas chromatography with mass spectrometry (GC-MS), while finally nuclear magnetic resonance (NMR) and high-performance liquid chromatography with a diode array detector (HPLC-DAD) were adopted for a more thorough characterisation of secondary metabolites. NMR was also used to investigate the anthocyanins content in tepals upon acid extraction. RESULTS: The results obtained highlighted the drying method as the dominant factor affecting the content of volatile constituents and contributing to the quality of saffron, while only slight differences were observed in the most abundant metabolites of stigmas, as well as in the anthocyanin content of tepals. In particular, for the first time, delphinidin and petunidin were detected by NMR in this latter tissue. CONCLUSION: The integrated analytical methodology here proposed, allowed to achieve a deeper level of compositional and structural details of secondary metabolites in Crocus sativus L. flowers. PMID- 29484755 TI - Defining the patient safety attitudes and influencing factors of health professionals working at maternity hospitals. AB - AIM: To determine patient safety attitudes of midwives, nurses and physicians and to examine the difference or correlation in patient safety attitudes of midwives, nurses and physicians working in maternity hospitals. BACKGROUND: It has been suggested that it is necessary to define the factors affecting patient safety attitudes of health professionals working in maternity hospitals. METHODS: A descriptive and correlational design was employed.The sample comprised 58 midwives, 134 nurses and 63 physicians (255) in two maternity hospitals in Istanbul, Turkey. The data were collected using an 'information form' and a 'Patient Safety Attitude Questionnaire'. RESULTS: The safety attitudes of participants were generally found to be negative. However, midwives had more positive patient safety attitudes and the age, unit, adequacy of patient safety training and the importance of patient safety were the most effective variables. CONCLUSIONS: As health professionals working in maternity hospitals generally have negative patient safety attitudes and because patient safety training provided better attitudes among the participants, these training programmes should be developed and implemented considering the differences among age groups and units. IMPLICATIONS FOR PRACTICE: Health professionals have different views on the patient safety culture; therefore, training needs to involve everyone to create a shared vision for patient safety. PMID- 29484756 TI - Regulation of the ovarian inflammatory response at ovulation by nuclear progesterone receptor. AB - PROBLEM: The nuclear progesterone receptor (PGR) transcription factor is essential for ovulation; however, the exact mechanisms by which PGR controls ovulation are not known. The aim of this study was to determine whether PGR regulates inflammatory mediators in the ovary. METHOD OF STUDY: Ovaries from mice lacking PGR (PRKO) and heterozygous PR+/- littermates were subjected to microarray analysis of a large panel of inflammatory genes. Immune cell subsets were detected by gene expression; and neutrophils by immunohistochemistry and chemotaxis assay. RESULTS: PRKO ovaries exhibited dysregulated expression of vasodilator (Edn1), cytokine (Il-6, Tgfb1), adhesion receptor (Cd34), apoptotic factor (Bax) and transcription factors (Nfkb2, Socs1, Stat3). Ptgs2 was also reduced in PRKO ovaries, but mRNA and protein were not different in granulosa cells. There were reduced neutrophils in ovaries of PRKO mice at ovulation; however, chemotaxis assays showed PRKO neutrophils migrate normally and that PRKO ovarian extracts exhibit chemotactic properties in vitro. CONCLUSION: Specific inflammatory mediators are altered in the ovaries of PRKO mice indicating that progesterone regulates features of inflammation at ovulation. PMID- 29484757 TI - Rhodium-Catalyzed Cascade Synthesis of Benzofuranylmethylidene-Benzoxasiloles: Elucidating Reaction Mechanism and Efficient Solid-State Fluorescence. AB - A new synthetic route to highly fluorescent benzofuranylmethylidenebenzoxasiloles through cationic rhodium(I)/binap complex-catalyzed cascade cycloisomerization of bis(2-ethynylphenol)silanes has been developed involving 1,2-silicon and 1,3 carbon (alkyne) migrations followed by oxycyclization. The present synthesis requires only three steps, starting from commercially available dichlorodiisopropylsilane, which is markedly shorter than our previous synthesis (eight steps starting from commercially available chlorodiisopropylsilane). Theoretical calculations elucidated the mechanism of the above cascade cycloisomerization. This reaction is initiated by the formation of a rhodium vinylidene not through direct 1,2-silicon migration but rather through an unprecedented stepwise 1,5-silicon migration followed by C-Si bond-forming cyclization from a dearomatized allenylrhodium complex. Subsequent 1,3-carbon (alkyne) migration leading to a eta3 -allenyl/propargyl-rhodium complex followed by oxycyclization through pi-bond (alkyne) activation with the cationic rhodium(I) complex affords the benzofuranylmethylidenebenzoxasilole product. The structure-fluorescence property relationships of the thus obtained benzofuranylmethylidenebenzoxasiloles were investigated, which revealed that good fluorescence quantum yields were generated in the solution state (phiF =69-87 %) by introduction of electron-donating alkyl and phenyl groups on two phenoxy groups. In the powder state, 4-methyl- and 4-methoxy-phenoxy derivatives exhibited efficient blue fluorescence (phiF =52 % and 46 %, respectively). Especially, the 4-methylphenoxy derivative was thermally stable, and exhibited strong narrow-band fluorescence in the film state (blue, phiF =95 %) and redshifted strong narrow-band fluorescence (green, phiF =90 %) in the crystalline state as a result of the formation of an offset pi-stacked dimer; the latter was confirmed by X-ray crystallographic analysis and by theoretical calculations. PMID- 29484758 TI - Forskolin-mediated BeWo cell fusion involves down-regulation of miR-92a-1-5p that targets dysferlin and protein kinase cAMP-activated catalytic subunit alpha. AB - PROBLEM: To study the role of miRNA(s) during trophoblastic BeWo cell fusion. METHOD OF STUDY: Changes in miRNA(s) profile of BeWo cells treated with forskolin were analyzed using Affymetrix miRNA microarray platform. Down-regulated miRNA, miR-92a-1-5p, was overexpressed in BeWo cells followed by forskolin treatment to understand its relevance in the process of BeWo cell fusion by desmoplakin I+II staining and hCG secretion by ELISA. Predicted targets of miR-92a-1-5p were also confirmed by qRT-PCR/Western blotting. RESULTS: The miRNA profiling of BeWo cells after forskolin (25 MUmol/L) treatment identified miR-92a-1-5p as the most significantly down-regulated miRNA both at 24 and 48 hours time points. Overexpression of miR-92a-1-5p in these cells led to a significant decrease in forskolin-mediated cell fusion and hCG secretion. miRNA target prediction software, TargetScan, revealed dysferlin (DYSF) and protein kinase cAMP-activated catalytic subunit alpha (PRKACA), as target genes of miR-92a-1-5p. Overexpression of miR-92a-1-5p in BeWo cells showed reduction in forskolin-induced transcripts for DYSF and PRKACA. Further, reduction in DYSF (~2.6-fold) at protein level and PRKACA-encoded protein kinase A catalytic subunit alpha (PKAC-alpha; ~1.6-fold) were also observed. CONCLUSION: These observations suggest that miR-92a-1-5p regulates forskolin-mediated BeWo cell fusion and hCG secretion by regulating PKA signaling pathway and dysferlin expression. PMID- 29484759 TI - General nutrition knowledge among carers at group homes for people with intellectual disability. AB - BACKGROUND: Good nutrition knowledge among carers of people with intellectual disability (ID) living in group homes is essential as they have a primary role in food provision for residents. Research on the nutrition knowledge of carers is limited. METHOD: This cross-sectional study assessed the level of general nutrition knowledge in a convenience sample of Australian carers (C) of people with ID and compared this to the general Australian community (CM). Nutrition knowledge was evaluated using the validated General Nutrition Knowledge Questionnaire. Total knowledge score as well as performance on instrument sub sections (dietary guidelines, nutrient sources, healthy food choices and diet disease relationships) were assessed (expressed as %). Knowledge scores were adjusted for known confounders (age, sex, education level, BMI, living arrangement and English spoken at home) using generalised linear modelling. RESULTS: A total of 589 participants were recruited (C: n = 40; CM: n = 549). Age (C: 40.8 +/- 12.1 year; CM: 37.8 +/- 13.3 years; P = 0.145), sex distribution (C: 62.5%; CM: 67.2% female; P = 0.602) and English spoken at home (C: 82.5%; CM: 89.6%; P = 0.183) were similar between groups, but BMI (C: 28.5 +/- 5.7 kgm-2 ; CM: 25.3 kgm-2 ; P = 0.002) was significantly lower and tertiary education (C: 52.5%; CM: 85.1%; P < 0.0005) significantly higher for CM. Total knowledge score (C: 56.6 +/- 12.6%; CM: 67.2 +/- 12.6%; P < 0.0005) and performance on all instrument sub-sections (P <= 0.004) were significantly lower for carers. This remained after confounder adjustment except for the knowledge of dietary guidelines sub-section (P = 0.116). CONCLUSION: Limited carer nutrition knowledge may compromise their ability to plan and adapt meals to support a healthy and appropriate diet for people with ID in group homes. PMID- 29484760 TI - Disruption in neural phase synchrony is related to identification of inattentional deafness in real-world setting. AB - Individuals often have reduced ability to hear alarms in real world situations (e.g., anesthesia monitoring, flying airplanes) when attention is focused on another task, sometimes with devastating consequences. This phenomenon is called inattentional deafness and usually occurs under critical high workload conditions. It is difficult to simulate the critical nature of these tasks in the laboratory. In this study, dry electroencephalography is used to investigate inattentional deafness in real flight while piloting an airplane. The pilots participating in the experiment responded to audio alarms while experiencing critical high workload situations. It was found that missed relative to detected alarms were marked by reduced stimulus evoked phase synchrony in theta and alpha frequencies (6-14 Hz) from 120 to 230 ms poststimulus onset. Correlation of alarm detection performance with intertrial coherence measures of neural phase synchrony showed different frequency and time ranges for detected and missed alarms. These results are consistent with selective attentional processes actively disrupting oscillatory coherence in sensory networks not involved with the primary task (piloting in this case) under critical high load conditions. This hypothesis is corroborated by analyses of flight parameters showing greater maneuvering associated with difficult phases of flight occurring during missed alarms. Our results suggest modulation of neural oscillation is a general mechanism of attention utilizing enhancement of phase synchrony to sharpen alarm perception during successful divided attention, and disruption of phase synchrony in brain networks when attentional demands of the primary task are great, such as in the case of inattentional deafness. PMID- 29484761 TI - Heme oxygenase-1 deficiency results in splenic T-cell dysregulation in offspring of mothers exposed to late gestational inflammation. AB - PROBLEM: Infection during pregnancy can disrupt regulatory/effector immune system balance, resulting in adverse pregnancy and fetal-neonatal outcomes. Heme oxygenase-1 (HO-1) is a major regulatory enzyme in the immune system. We observed maternal immune response dysregulation during late gestational inflammation (LGI), which may be mediated by HO-1. Here, we extend these studies to examine the immune response of offspring. METHOD OF STUDY: Pregnant wild-type (Wt) and HO 1 heterozygote (Het) dams were treated with lipopolysaccharide (LPS) or vehicle at E15.5. Pups' splenic immune cells were characterized using flow cytometry. RESULTS: CD3+ CD4+ CD25+ (Tregs) and CD3+ CD8+ (Teffs) T cells in Wt and Het were similar in control neonates and increased with age. We showed not only age- but also genotype-specific and long-lasting T-cell dysregulation in pups after maternal LGI. The persistent immune dysregulation, mediated by HO-1 deficiency, was reflected as a decrease in Treg FoxP3 and CD3+ CD8+ T cells, and an increase in CD4+ /CD8+ T-cell and Treg/Teff ratios in Hets compared with Wt juvenile mice after maternal exposure to LGI. CONCLUSION: Maternal exposure to LGI can result in dysregulation of splenic T cells in offspring, especially in those with HO-1 deficiency. We speculate that these immune alterations are the basis of adverse outcomes in neonates from mothers exposed to low-grade (subclinical) infections. PMID- 29484762 TI - Coroglaucigenin induces senescence and autophagy in colorectal cancer cells. AB - OBJECTIVES: Coroglaucigenin (CGN), a natural product isolated from Calotropis gigantean by our research group, has been identified as a potential anti-cancer agent. However, the molecular mechanisms involved remain poorly understood. MATERIALS AND METHODS: Cell viability and cell proliferation were detected by MTT and BrdU assays. Flow cytometry, SA-beta-gal assay, western blotting and immunofluorescence were performed to determine CGN-induced apoptosis, senescence and autophagy. Western blotting, siRNA transfection and coimmunoprecipitation were carried out to investigate the mechanisms of CGN-induced senescence and autophagy. The anti-tumour activities of combination therapy with CGN and chloroquine were observed in mice tumour models. RESULTS: We demonstrated that CGN inhibits the proliferation of colorectal cancer cells both in vitro and in vivo. We showed that the inhibition of cell proliferation by CGN is independent of apoptosis, but is associated with cell-cycle arrest and senescence in colorectal cancer cells. Notably, CGN induces protective autophagy that attenuates CGN-mediated cell proliferation. Functional studies revealed that CGN disrupts the association of Hsp90 with both CDK4 and Akt, leading to CDK4 degradation and Akt dephosphorylation, eventually resulting in senescence and autophagy, respectively. Combination therapy with CGN and chloroquine resulted in enhanced anti-tumour effects in vivo. CONCLUSIONS: Our results demonstrate that CGN induces senescence and autophagy in colorectal cancer cells and indicate that combining it with an autophagy inhibitor may be a novel strategy suitable for CGN mediated anti-cancer therapy. PMID- 29484763 TI - Distances from vocal cords to mid-trachea for optimizing endotracheal tubes depth markers according to gestational age. AB - BACKGROUND: Adequate endotracheal tube positioning in preterm infants is complicated by the short length of the airway. Distal markers were designed to help with the insertion of endotracheal tubes at an appropriate depth below the vocal cords. However, those markers are not standardized between manufacturers, each tube size displays only one (sometimes 2) markers to provide information for infants of various gestational ages, and indicated distances are often too long for extremely preterm infants. AIMS: The study aims to describe vocal cords to mid-tracheal distance for different gestational ages and determine if depth markers should be adjusted accordingly. METHODS: Half the tracheal length added to the height of the posterior lamina of the cricoids approximates the distance between vocal cords and mid-trachea. Those dimensions were retrospectively retrieved from a database of laryngo-tracheal measurements obtained during autopsies of fetuses and newborn infants free of upper airway malformations. The equation of correlation between gestational age and distance from vocal cords to mid-trachea was used to calculate those distances for different gestational ages. RESULTS: Data were derived from 114 patients. Vocal cords to mid-trachea distance is linearly correlated with gestational age (r = .90; distance = 2.831 + 0.6208 * gestational age). We suggest depth markers at 17.7, 19.0, 20.8, 22.7, 24.6, and 26.4 mm for gestational ages of 24, 26, 29, 32, 35, and 38 weeks, respectively, indicated by contrasting colors. CONCLUSION: The linear relationship between laryngo-tracheal size and gestational age offers the opportunity to revise endotracheal tube depth markers for the smallest patients. Trials comparing those suggested markers with those currently in use are needed before implementation. PMID- 29484765 TI - Intentional tracheoesophageal fistula cannulation for gastric decompression in type C esophageal atresia. AB - We describe a nonsurgical technique for managing gastric distention in infants with type C esophageal atresia, involving intubating the trachea with an umbilical catheter and entering the stomach through the fistula as soon as a flexible bronchoscope found its wide-open orifice. This technique might have a special role when gastric distention precedes other commonly used preventive measures. PMID- 29484764 TI - Prognostic value of T-wave morphology parameters in coronary artery disease in current treatment era. AB - BACKGROUND: The prognostic value of T-wave morphology parameters in coronary artery disease in the current treatment era is not well established. METHODS: The Innovation to reduce Cardiovascular Complications of Diabetes at the Intersection (ARTEMIS) study included 1,946 patients with angiographically verified coronary artery disease (CAD). The study patients underwent thorough examinations including 12-lead digital electrocardiogram (ECG) at baseline. RESULTS: During a follow-up period of 73 +/- 22 months, a total of 201 (10.3%) patients died. Of the study patients, 95 (4.9%) experienced cardiac death (CD) consisting of 44 (2.3%) sudden cardiac deaths (SCD) and 51 (2.6%) nonsudden cardiac deaths (NSCD), and 106 (5.4%) patients experienced noncardiac death (NCD). T-wave morphology dispersion (TMD), T-wave area dispersion (TWAD), and total cosine R-to-T (TCRT) had a significant association with CD even after adjustment with relevant clinical risk markers in the Cox regression analysis (multivariate HRs: 1.015, 95% CI 1.007-1.023, p = .0003; 0.474, 95% CI 0.305-0.737, p = .0009; 0.598, 95% CI 0.412-0.866, p = .006, respectively). When including these parameters to the clinical risk model for CD, the C-index increased from 0.810 to 0.823 improving the discrimination significantly (integrated discrimination index [IDI] = 0.0118, 95% CI 0.0028-0.0208, p = .01). These parameters were more closely associated with NSCD (multivariate p-values from .016 to .001) than with SCD (univariate/multivariate p-values for TMD .015/.197 and for TCRT .012/.43). CONCLUSION: T-wave morphology parameters describing repolarization heterogeneity improve the predictive power of the clinical risk model for CD in patients with CAD in the current treatment era. PMID- 29484766 TI - Comparative SEM and LM foliar epidermal and palyno-morphological studies of Amaranthaceae and its taxonomic implications. AB - Palynological features as well as comparative foliar epidermal using light and scanning electron microscope (SEM) of 17 species (10genera) of Amaranthaceae have been studied for its taxonomic significance. Different foliar and palynological micro-morphological characters were examined to explain their value in resolving the difficulty in identification. All species were amphistomatic but stomata on abaxial surface were more abundant. Taxonomically significant epidermal character including stomata type, trichomes (unicellular, multicellular, and capitate) and epidermal cells shapes (polygonal and irregular) were also observed. Pollens of this family are Polypantoporate, pores large, spheroidal, mesoporous region is sparsely to scabrate, densely psilate, and spinulose. All these characters can be active at species level for identification purpose. This study indicates that at different taxonomic levels, LM and SEM pollen and epidermal morphology is explanatory and significant to identify species and genera. PMID- 29484767 TI - Dissociable meta-analytic brain networks contribute to coordinated emotional processing. AB - Meta-analytic techniques for mining the neuroimaging literature continue to exert an impact on our conceptualization of functional brain networks contributing to human emotion and cognition. Traditional theories regarding the neurobiological substrates contributing to affective processing are shifting from regional- towards more network-based heuristic frameworks. To elucidate differential brain network involvement linked to distinct aspects of emotion processing, we applied an emergent meta-analytic clustering approach to the extensive body of affective neuroimaging results archived in the BrainMap database. Specifically, we performed hierarchical clustering on the modeled activation maps from 1,747 experiments in the affective processing domain, resulting in five meta-analytic groupings of experiments demonstrating whole-brain recruitment. Behavioral inference analyses conducted for each of these groupings suggested dissociable networks supporting: (1) visual perception within primary and associative visual cortices, (2) auditory perception within primary auditory cortices, (3) attention to emotionally salient information within insular, anterior cingulate, and subcortical regions, (4) appraisal and prediction of emotional events within medial prefrontal and posterior cingulate cortices, and (5) induction of emotional responses within amygdala and fusiform gyri. These meta-analytic outcomes are consistent with a contemporary psychological model of affective processing in which emotionally salient information from perceived stimuli are integrated with previous experiences to engender a subjective affective response. This study highlights the utility of using emergent meta-analytic methods to inform and extend psychological theories and suggests that emotions are manifest as the eventual consequence of interactions between large-scale brain networks. PMID- 29484768 TI - The Vasoreparative Function of Myeloid Angiogenic Cells Is Impaired in Diabetes Through the Induction of IL1beta. AB - Myeloid angiogenic cells (MACs) promote revascularization through the paracrine release of angiogenic factors and have been harnessed as therapeutic cells for many ischemic diseases. However, their proangiogenic properties have been suggested to be diminished in diabetes. This study investigates how the diabetic milieu affects the immunophenotype and function of MACs. Both MACs isolated from diabetic conditions and healthy cells exposed to a diabetic environment were used to determine the potential of MACs as a cell therapy for diabetic-related ischemia. MACs were isolated from human peripheral blood and characterized alongside proinflammatory macrophages M (LPS + IFNgamma) and proangiogenic macrophages M (IL4). Functional changes in MACs in response to high-d-glucose were assessed using an in vitro 3D-tubulogenesis assay. Phenotypic changes were determined by gene and protein expression analysis. Additionally, MACs from type 1 diabetic (T1D) patients and corresponding controls were isolated and characterized. Our evidence demonstrates MACs identity as a distinct macrophage subtype that shares M2 proangiogenic characteristics, but can be distinguished by CD163hi expression. High-d-glucose treatment significantly reduced MACs proangiogenic capacity, which was associated with a significant increase in IL1beta mRNA and protein expression. Inhibition of IL1beta abrogated the antiangiogenic effect induced by high-d-glucose. IL1beta was also significantly upregulated in MACs isolated from T1D patients with microvascular complications compared to T1D patients without microvascular complications or nondiabetic volunteers. This study demonstrates that Type 1 diabetes and diabetic-like conditions impair the proangiogenic and regenerative capacity of MACs, and this response is mediated by IL-1beta. Stem Cells 2018;36:834-843. PMID- 29484769 TI - Early Blood-Brain Barrier Disruption after Mechanical Thrombectomy in Acute Ischemic Stroke. AB - BACKGROUND AND PURPOSE: The impact of blood-brain barrier (BBB) disruption can be detected by intraparenchymal hyperdense lesion on the computed tomography (CT) scan after endovascular stroke therapy. The purpose of this study was to determine whether early BBB disruption predicts intracranial hemorrhage and poor outcome in patients with acute ischemic stroke treated with mechanical thrombectomy. METHODS: We analyzed patients with anterior circulation stroke treated with mechanical thrombectomy and identified BBB disruption on the noncontrast CT images immediately after endovascular treatment. Follow-up CT or magnetic resonance imaging scan was performed at 24 hours to assess intracranial hemorrhage. We dichotomized patients into those with moderate BBB disruption versus those with minor BBB disruption and no BBB disruption. We evaluated the association of moderate BBB disruption after mechanical thrombectomy with intracranial hemorrhage and clinical outcomes. RESULTS: Moderate BBB disruption after mechanical thrombectomy was found in 56 of 210 patients (26.7%). Moderate BBB disruption was independently associated with higher rates of hemorrhagic transformation (OR 25.33; 95% CI 9.93-64.65; P < .001), parenchymal hematoma (OR 20.57; 95% CI 5.64-74.99; P < .001), and poor outcome at discharge (OR 2.35; 95% CI 1.09-5.07; P = .03). The association of BBB disruption with intracranial hemorrhage remained in patients with successful reperfusion after mechanical thrombectomy. The location of BBB disruption was not associated with intracranial hemorrhage and poor outcome. CONCLUSIONS: Moderate BBB disruption is common after mechanical thrombectomy in a quarter of patients with acute ischemic stroke and increases the risk of intracranial hemorrhage and poor outcome. PMID- 29484770 TI - The relationship between the therapeutic alliance and clinical outcomes in cognitive behaviour therapy for adults with depression: A meta-analytic review. AB - Research consistently provides evidence for the relationship between the therapeutic alliance (TA) and outcome across various therapies and presenting problems. Depression is considered the leading cause of disability worldwide, and there is substantial evidence for the efficacy for Cognitive Behaviour Therapy (CBT) in its treatment. At present, there is lack of clarity specifically about the relationship between the TA and outcome in CBT for depression. The present review is the first meta-analytic review to explore this relationship and also considering moderators. Within a random-effects model, an overall mean effect size of r = 0.26 (95% CI [.19-.32]) was found, indicating that the TA was moderately related to outcome in CBT for depression. The mean TA-outcome correlation is consistent with existing meta-analysis that looked across a broad range of presenting problems and psychological therapies. A secondary exploratory analysis of moderators suggested the TA-outcome relationship varied according to the TA rater, where the relationship was weaker for therapist raters compared with clients and observer raters. Additionally, the results indicated that the TA outcome relationship marginally increased over the course of CBT treatment. The results of the meta-analysis are discussed in reference to the wider body of research, methodological limitations, clinical implications, and future directions for research. PMID- 29484771 TI - Developmental outcomes of Japanese children born through Assisted Reproductive Technology (ART) in toddlerhood. AB - AIM: This study aimed to investigate developmental outcomes of Japanese babies born through Assisted Reproductive Technology (ART) at ages 2 and 3. METHODS: The data were gathered from 1085 children in a hospital-based cohort study conducted in Japan. The children's level of development was assessed through a parent-rated questionnaire, the Kinder Infant Development Scale, which consists of nine developmental domains. We compared the development of children born through ART and those born naturally by conducting analyses of covariance. For the analyses, the effect of maternal age, family income, parental education and multiple birth were controlled for. RESULTS: At 24 months, no significant difference was found between children born through ART and those born naturally in development in any domain. At 36 months, a significant difference was found in development of Receptive language (F (1, 845) = 6.148, P = 0.013), Expressive language (F (1, 845) = 4.060, P = 0.044) and Language concept (F (1, 845) = 6.968, P = 0.008). For these domains, children born through ART had a significantly higher developmental age compared to children born naturally. CONCLUSION: At age 2, no significant difference was found between the children born through ART and those born naturally in nine developmental domains, although at age 3, the children born through ART showed significantly better language development than the children born naturally. PMID- 29484772 TI - Concise Review: Regulatory Influence of Sleep and Epigenetics on Adult Hippocampal Neurogenesis and Cognitive and Emotional Function. AB - Neural stem and progenitor cells continue to generate new neurons in particular regions of the brain during adulthood. One of these neurogenic regions is the dentate gyrus (DG) of the hippocampus, which plays an important role in cognition and emotion. By exploiting this innate neuronal regeneration mechanism in the DG, new technologies have the potential to promote resistance to or recovery from brain dysfunction or degeneration. However, a deeper understanding of how adult DG neurogenesis is regulated by factors such as sleep and epigenetic modifications of gene expression could lead to further breakthroughs in the clinical application of neural stem and progenitor cells. In this review, we discuss the functions of adult-born DG neurons, describe the epigenetic regulation of adult DG neurogenesis, identify overlaps in how sleep and epigenetic modifications impact adult DG neurogenesis and memory consolidation, and suggest ways of using sleep or epigenetic interventions as therapies for neurodegenerative and psychiatric disorders. By knitting together separate strands of the literature, we hope to trigger new insights into how the functions of adult-generated neurons are directed by interactions between sleep-related neural processes and epigenetic mechanisms to facilitate novel approaches to preventing and treating brain disorders such as depression, post-traumatic stress disorder, and Alzheimer's disease. Stem Cells 2018;36:969-976. PMID- 29484773 TI - Congenital lymphangioma circumscriptum of vulva presenting as multiple giant mass lesions: a case report and literature review. AB - A G2L2 33-year-old woman presented to our clinic with large verrucous warty masses in labia major, perinea and the end portion of her spine measuring about 15 * 7, 9 * 7 and 8 * 8 cm, which had been enlarged following puberty and pregnancy. Her right upper and left lower limbs had gross congenital lymphedema. The masses were removed by superficial partial vulvectomy with a qualified margin and repaired without skin graft. Pathology report showed lymphangioma circumscriptum. Several months of follow up revealed normal healing and no recurrence. In conclusion, congenital vulvar lymphangioma, which is a rare disorder, can be highly triggered by hormonal-stimulating situations like puberty and pregnancy. Thus, it is better to visit the affected cases in a timely manner in order to excise these lesions before massive enlargement. In our experience, a superficial partial vulvectomy without skin graft can be a sufficient procedure. Obviously, an appropriate approach during and after surgery would be very important for obtaining a desirable healing. PMID- 29484774 TI - Are individuals with loss-of-control eating more prone to dietary lapse in behavioural weight loss treatment? An ecological momentary assessment study. AB - OBJECTIVE: Individuals with overweight/obesity and loss-of-control eating (LOC) may experience poorer outcomes from behavioural weight loss due to reactivity to internal (e.g., affective and physical) states that impact treatment adherence (e.g., dietary lapses). This study examined (a) whether the presence of LOC increased risk for dietary lapses and (b) the moderating role of LOC on the relation between internal states and dietary lapses. METHOD: Individuals (n = 189) with overweight and obesity completed ecological momentary assessment early in behavioural weight loss. RESULTS: LOC was positively associated with dietary lapse. LOC did not moderate the relation between momentary changes in internal states and dietary lapses. However, the effect of average levels of internal states on lapses was attenuated for those with LOC. DISCUSSION: Results suggest that those with LOC are at higher risk of dietary lapse, whereas elevated average levels of internal states may contribute to early inadherence for those without LOC. PMID- 29484775 TI - Anesthesia of thoracic surgery in children. AB - Providing anesthesia in children with thoracic disease is a challenging task. The effects of the underlying disease, the surgical interventions, and preexisting condition of the patient need to be considered when planning perioperative care. The perioperative care for children undergoing thoracic surgery requires specific techniques adapted to the pediatric physiology and anatomy. This review is focused on anesthetic strategies for thoracic surgery with an emphasis on perioperative analgesia including neuraxial techniques. PMID- 29484776 TI - The Effects of Fresh Detox Juices on Color Stability and Roughness of Resin-Based Composites. AB - PURPOSE: To evaluate the effects of three fresh detox juices, including an orange, green, and red beverage, on the color stability and surface roughness of three anterior esthetic resin-based composites (RBCs). MATERIALS AND METHODS: Disk-shaped specimens were prepared with three different esthetic RBCs (Amaris, G aenial Anterior, Clearfil Majesty ES-2) according to the manufacturers' instructions. Forty specimens were prepared for each RBC, and all specimens were stored in artificial saliva at 37 degrees C for 24 hours. The initial color values and surface roughness measurements of the specimens were taken using a spectrophotometer and a profilometer. The specimens were then divided into 4 subgroups (n = 10). All specimens except the control specimens were immersed in their designated fresh detox juices (green, red, or orange) for 10 minutes twice a day. Color and surface roughness measurements were taken on day 15 and day 30, and the results were analyzed by one-way ANOVA and Tukey HSD test. The association between color change and surface roughness was evaluated by Spearman's Rank Correlation analysis. RESULTS: Color changes and surface roughness increased upon exposure to fresh detox juices for 15 and 30 days for all of the RBCs. All of the G-aenial and Amaris groups displayed color changes above the threshold of acceptability, whereas Clearfil Majesty ES-2 displayed a color change above the threshold of acceptability only after exposure to the red beverage for 30 days (DeltaE > 3.7). With regard to surface roughness, Clearfil Majesty ES-2 outperformed the other RBCs (p < 0.001). According to Spearman's Rank Correlation analysis, there was no correlation between color change and surface roughness (p > 0.001). CONCLUSIONS: Exposure to the fresh detox juices used in this study led to similar color changes in the RBCs used in this study. PMID- 29484777 TI - Veteran status, disability rating, and public sector employment. AB - This paper used microdata from the 2013-2015 American Community Survey to examine differences in federal government, state and local government, private sector, and self-employment among employed veterans and nonveterans. The U.S. federal and state governments have hiring preferences to benefit veterans, especially disabled veterans. Other factors may also push veterans toward public sector employment. I found that veteran status substantially increased the likelihood of federal employment, with the largest magnitudes for severely disabled veterans. Differences in state and local government employment were modest and exhibited heterogeneity by disability severity. PMID- 29484778 TI - Walking performance in adolescents and young adults with Down syndrome: the role of obesity and sleep problems. AB - BACKGROUND: High prevalence of obesity and features of obstructive sleep apnea (OSA) are major health issues in individuals with Down syndrome (DS), and both may also affect adversely on their daily activities. Further, lower levels of physical work capacity (PWC) have been reported in this population compared to their peers with intellectual disabilities. However, no study examines the relationships between obesity and sleep problems with PWC in individuals with DS. Thus, this study investigated the influence of body mass index (BMI) and different types of sleep problems on PWC in adolescents and young adults with DS (14-31 years). METHODS: The incremental treadmill walking trial was used to assess PWC. RESULTS: The negative associations were indicated between BMI and walking steps (p = .03) as well as features with OSA and walking steps (p = .04). Thus, BMI and OSA were included in the regression analysis to estimate the walking steps achieved during walking trials. In addition, Bland-Altman plots demonstrated no overestimation and underestimation of variability in the difference between actual and estimated walking steps developed by using BMI and OSA. CONCLUSIONS: Obesity and sleep problem are potentially detrimental to walking performance (i.e., fewer walking steps) in individuals with DS. Thus, individuals with DS may adopt a slow walk speed due to the increased balance deficits and physical fatigue that result from obesity and sleep fragmentation, respectively. Exercise interventions, which have the potential to reduce obesity and OSA, are recommended to improve the accomplishment of PWC in individuals with DS. PMID- 29484779 TI - Critical appraisal of nonrandomized studies-A review of recommended and commonly used tools. AB - RATIONALE, AIMS, AND OBJECTIVES: When randomized controlled trial data are limited or unavailable, or to supplement randomized controlled trial evidence, health technology assessment (HTA) agencies may rely on systematic reviews of nonrandomized studies (NRSs) for evidence of the effectiveness of health care interventions. NRS designs may introduce considerable bias into systematic reviews, and several methodologies by which to evaluate this risk of bias are available. This study aimed to identify tools commonly used to assess bias in NRS and determine those recommended by HTA bodies. METHODS: Appraisal tools used in NRS were identified through a targeted search of systematic reviews (January 2013 March 2017; MEDLINE and EMBASE [OVID SP]). Recommendations for the critical appraisal of NRS by expert review groups and HTA bodies were reviewed. RESULTS: From the 686 studies included in the narrative synthesis, 48 critical appraisal tools were identified. Commonly used tools included the Newcastle-Ottawa Scale, the methodological index for NRS, and bespoke appraisal tools. Neither the Cochrane Handbook nor the Centre for Reviews and Dissemination recommends a particular instrument for the assessment of risk of bias in NRS, although Cochrane has recently developed their own NRS critical appraisal tool. Among HTA bodies, only the Canadian Agency for Drugs and Technologies in Health recommends use of a specific critical appraisal tool-SIGN 50 (for cohort or case-control studies). Several criteria including reporting, external validity, confounding, and power were examined. CONCLUSION: There is no consensus between HTA groups on the preferred appraisal tool. Reviewers should select from a suite of tools on the basis of the design of studies included in their review. PMID- 29484780 TI - A functional polymorphism in the pre-miR-146a gene is associated with the risk of nonsyndromic orofacial cleft. AB - microRNAs (miRNAs) are widely involved in craniofacial development, and genetic variants of miRNAs may be associated with the risk of nonsyndromic orofacial cleft (NSOC). Here, we systematically selected five single nucleotide polymorphisms (SNPs) of miRNAs and investigated the associations between these variants and NSOC susceptibility in a two-stage case-control study including 1,406 NSOC patients and 1,578 controls from the Chinese population. We found that compared with the C allele, the rs2910164 G allele of pre-miR-146a was associated with an increased risk of NSOC (additive model: odds ratio [OR] = 1.17, 95% confidence interval [CI]: 1.06-1.30, P = 0.002), including both cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO). Bioinformatic prediction and functional assays revealed that the C allele of rs2910164 was significantly associated with inhibited HEK-293 and HEPM cell proliferation and decreased abundance of TRAF6. Both miR-146a and TRAF6 were expressed in the lip tissue samples of NSOC patients, and a moderate inverse correlation was observed between them. Taken together, these results demonstrated that miR-146a/rs2910164 is associated with susceptibility to NSOC, providing novel insights into the genetic etiology and underlying biology of NSOC. PMID- 29484782 TI - Diabetic ketoacidosis incidence in children at first presentation of type 1 diabetes at an Australian regional hospital: The effect of health professional education. AB - BACKGROUND: Diabetic ketoacidosis (DKA) is an acute life threatening, resource intensive preventable complication of type 1 diabetes which has major biopsychosocial effects on patients and families. Incidence of pediatric DKA has been studied nationally and internationally in metropolitan centers. This study analyzed the DKA incidence at first presentation of type 1 diabetes at Townsville Hospital, before and after an educational intervention. This is the first study of its kind in a regional center in Queensland, Australia. METHOD: The inclusion criteria consisted of children (0-18 years) diagnosed with type 1 diabetes from January, 2006 to December, 2016. Medical and laboratory patient data was retrospectively collected. Quantitative analysis was conducted using SPSS. Education sessions were delivered to health professionals by a pediatric endocrinologist during 2015 and 2016. DKA and its severity were defined by the International Society of Pediatric Diabetes 2014 Guidelines. RESULTS: In total, 106 patients met inclusion criteria. Average incidence of DKA at first presentation of type 1 diabetes was 48.10%. Pre- and post-intervention incidences were 54.90% and 25%, respectively (P = 0.01). DKA severity pre- and post intervention were severe (48.88%, 33.33%), moderate (26.67%, 16.67%), and mild (24.44%, 50%), respectively (P = 0.53). CONCLUSIONS: DKA incidence at first presentation of type 1 diabetes prior to intervention, is higher than that reported by other studies in Australia: Brisbane (31.8%) and Sydney (37.7%). DKA incidence at first presentation of type 1 diabetes decreased significantly during the period of health professional education. PMID- 29484783 TI - High frequencies of dermatological complications in children using insulin pumps or sensors. AB - BACKGROUND: Dermatological complications in children and adolescents that are related to continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM) have not been well-characterized. This study examined the prevalence and characteristics of different types of dermatological complications. METHODS: Online questionnaires regarding dermatological complications related to CSII and/or CGM were returned from a total of 144 children and adolescents, aged 2 to 20 years. Both previous and current skin problems were reported along with their clinical characteristics. Descriptive statistics, chi2 tests, and multivariate analyses were used to evaluate the data. RESULTS: Of 143 patients using CSII, 90% had previous and 63% reported current dermatological complications. Non-specific eczema was most frequently reported and was currently present in 25.7% of the patients. These results were independent of age and current CGM use. Among the 76 patients using CGM, 46% reported current dermatological complications. A history of atopy was associated with dermatological complications in individuals using CSII, but not CGM. The patients rated CGM-related dermal issues as significantly worse than those associated with CSII (P < .05). CONCLUSIONS: Dermatological complications can be a serious problem in treating pediatric and adolescent patients of all ages with CSII and/or CGM. Only a few clinical characteristics associated with these complications were identified in this study, highlighting the need for prospective studies that might lead to improvements in the prevention and treatment of dermatological problems. PMID- 29484784 TI - Retrospective analysis: Conservative treatment of placenta increta with methotrexate. AB - AIM: To evaluate the efficacy of conservative treatment with methotrexate against placenta increta by two different routes of administration through retrospective analysis. METHODS: A total of 54 women diagnosed with placenta increta after vaginal delivery were enrolled in this retrospective study. The participants accepted conservative management with methotrexate through either intravenous injection or local multi-point injection under ultrasound guidance. The treatment was considered effective if no hysterectomy was mandatory during the follow-up period. RESULTS: Out of the 54 cases, 21 patients were treated with methotrexate intravenously (group 1), and 33 patients received local multi-point injection to the placenta increta under ultrasound guidance (group 2). No maternal death occurred. In group 1, 10 patients expelled the placentas spontaneously, 7 patients underwent uterine curettage and 4 patients underwent hysterectomy for uncontrollable post-partum hemorrhage and infection. In group 2, 25 patients expelled placentas spontaneously and 8 patients underwent uterine curettage with no incidence of hysterectomy. The success rate in group 1 and group 2 was 17/21 and 33/33, respectively. The average time of the spontaneous placenta expulsion was 79.13 +/- 29.87 days in group 1 and 42.42 +/- 31.83 days in group 2. CONCLUSION: Local multi-point methotrexate injection under ultrasound guidance is a better alternative for patients with placenta increta, especially for preserving fertility. PMID- 29484785 TI - Interleukin-7 receptor alpha-chain haplotypes differentially affect soluble IL-7 receptor and IL-7 serum concentrations in children with type 1 diabetes. AB - BACKGROUND: Interleukin-7 receptor alpha-chain (IL7RA) haplotypes are associated with susceptibility for development of autoimmune diseases, including type 1 diabetes (T1D). A protective IL7RA haplotype which causes lower soluble IL-7R (sIL-7R) serum levels is hypothesized to restrict IL-7-availability for self reactive T cells. Functional mechanisms affected by a risk-associated IL7RA haplotype are unknown. METHODS: We investigated the influence of IL7RA haplotypes (tagged by rs6897932T for the protective or by rs1494555G for the risk haplotype) on sIL-7R and IL-7 serum concentrations as well as disease manifestation of children with T1D (n = 259). Possible effects of differential IL-7 serum concentrations on IL-7-mediated in vitro T cell functions (i.e. IL-7R regulation and cytokine expression) were measured in a second study group of children with T1D (n = 42). RESULTS: We detected lower sIL-7R serum concentrations in children with T1D carrying protective or risk haplotypes as compared to reference haplotypes. sIL-7R levels were lowest in T1D children with the protective haplotype and lower IL-7 serum levels were exclusively detected in this study group. We found no evidence for dependency between IL-7 and sIL-7R serum concentrations and no association with T1D manifestation. Neither IL-7 nor sIL-7R serum levels were associated with mIL-7R regulation or IL-7-promoted T cell cytokine expression. CONCLUSIONS: Children with T1D carrying autoimmunity risk- or protection-associated IL7RA haplotypes had both lower sIL-7R serum concentrations as compared to the reference haplotype, but only T1D children with the protective haplotype had lower IL-7 serum levels. Our results suggest additional functional mechanisms of autoimmunity-associated IL7RA variants independent from sIL-7R mediated regulation of IL-7 availability for T cells. PMID- 29484786 TI - Accuracy and reproducibility of fetal-fraction measurement using relative quantitation at polymorphic loci with microarray. AB - OBJECTIVES: Various methods of fetal-fraction measurement have been employed in conjunction with different approaches to cell-free DNA testing for fetal aneuploidy. In this study, we determined the accuracy and reproducibility of fetal-fraction measurement using polymorphic assays that are incorporated into the test design as part of the Harmony(r) prenatal test and evaluated whether the single nucleotide polymorphisms selected for and used in these assays can be applied broadly to all patient populations. METHODS: Clinical maternal plasma samples were assayed using a custom microarray with Digital ANalysis of Selected Regions (DANSR) assays designed to cover non-polymorphic targets on chromosomes of interest for aneuploidy assessment (13, 18, 21, X and Y) and polymorphic targets for fetal-fraction assessment. In a consecutive series of 47 512 maternal plasma samples, fetal-fraction measurements based on polymorphic assays were compared with those from Y-sequence quantitation. Reproducibility was examined between first- and second-tube measurements for the same patient sample in 734 cases. The fraction of informative loci was calculated for 13 988 samples. RESULTS: There was a strong correlation between fetal fractions determined using the polymorphic assays and using Y-chromosome sequence quantitation (r = 0.97). Fetal-fraction measurement between the first and second tubes was highly reproducible (r = 0.98). The fraction of informative loci observed in a clinical series was consistent with predictions based on assay design. CONCLUSIONS: The method based on relative quantitation at polymorphic loci on a microarray is accurate and reproducible for fetal-fraction estimation and is equally informative across global populations. This study provides a useful benchmark for ensuring the reliability and accuracy of fetal-fraction measurement. (c) 2018 Roche Sequencing Solutions. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology. PMID- 29484787 TI - Transforming clinical practice guidelines and clinical pathways into fast-and frugal decision trees to improve clinical care strategies. AB - BACKGROUND: Contemporary delivery of health care is inappropriate in many ways, largely due to suboptimal Q5 decision-making. A typical approach to improve practitioners' decision-making is to develop evidence-based clinical practice guidelines (CPG) by guidelines panels, who are instructed to use their judgments to derive practice recommendations. However, mechanisms for the formulation of guideline judgments remains a "black-box" operation-a process with defined inputs and outputs but without sufficient knowledge of its internal workings. METHODS: Increased explicitness and transparency in the process can be achieved by implementing CPG as clinical pathways (CPs) (also known as clinical algorithms or flow-charts). However, clinical recommendations thus derived are typically ad hoc and developed by experts in a theory-free environment. As any recommendation can be right (true positive or negative), or wrong (false positive or negative), the lack of theoretical structure precludes the quantitative assessment of the management strategies recommended by CPGs/CPs. RESULTS: To realize the full potential of CPGs/CPs, they need to be placed on more solid theoretical grounds. We believe this potential can be best realized by converting CPGs/CPs within the heuristic theory of decision-making, often implemented as fast-and-frugal (FFT) decision trees. This is possible because FFT heuristic strategy of decision making can be linked to signal detection theory, evidence accumulation theory, and a threshold model of decision-making, which, in turn, allows quantitative analysis of the accuracy of clinical management strategies. CONCLUSIONS: Fast-and frugal provides a simple and transparent, yet solid and robust, methodological framework connecting decision science to clinical care, a sorely needed missing link between CPGs/CPs and patient outcomes. We therefore advocate that all guidelines panels express their recommendations as CPs, which in turn should be converted into FFTs to guide clinical care. PMID- 29484789 TI - Why bipolar II disorder does not deserve its status as the overlooked middle child. PMID- 29484788 TI - Iron deficiency impairs contractility of human cardiomyocytes through decreased mitochondrial function. AB - AIMS: Iron deficiency is common in patients with heart failure and associated with a poor cardiac function and higher mortality. How iron deficiency impairs cardiac function on a cellular level in the human setting is unknown. This study aims to determine the direct effects of iron deficiency and iron repletion on human cardiomyocytes. METHODS AND RESULTS: Human embryonic stem cell-derived cardiomyocytes were depleted of iron by incubation with the iron chelator deferoxamine (DFO). Mitochondrial respiration was determined by Seahorse Mito Stress test, and contractility was directly quantified using video analyses according to the BASiC method. The activity of the mitochondrial respiratory chain complexes was examined using spectrophotometric enzyme assays. Four days of iron depletion resulted in an 84% decrease in ferritin (P < 0.0001) and significantly increased gene expression of transferrin receptor 1 and divalent metal transporter 1 (both P < 0.001). Mitochondrial function was reduced in iron deficient cardiomyocytes, in particular ATP-linked respiration and respiratory reserve were impaired (both P < 0.0001). Iron depletion affected mitochondrial function through reduced activity of the iron-sulfur cluster containing complexes I, II and III, but not complexes IV and V. Iron deficiency reduced cellular ATP levels by 74% (P < 0.0001) and reduced contractile force by 43% (P < 0.05). The maximum velocities during both systole and diastole were reduced by 64% and 85%, respectively (both P < 0.001). Supplementation of transferrin-bound iron recovered functional and morphological abnormalities within 3 days. CONCLUSION: Iron deficiency directly affects human cardiomyocyte function, impairing mitochondrial respiration, and reducing contractility and relaxation. Restoration of intracellular iron levels can reverse these effects. PMID- 29484790 TI - Inversion of Configuration at the Phosphorus Nucleophile in the Diastereoselective and Enantioselective Synthesis of P-Stereogenic syn Phosphiranes from Chiral Epoxides. AB - Nucleophilic substitution results in inversion of configuration at the electrophilic carbon center (SN 2) or racemization (SN 1). The stereochemistry of the nucleophile is rarely considered, but phosphines, which have a high barrier to pyramidal inversion, attack electrophiles with retention of configuration at P. Surprisingly, cyclization of bifunctional secondary phosphine alkyl tosylates proceeded under mild conditions with inversion of configuration at the nucleophile to yield P-stereogenic syn-phosphiranes. DFT studies suggested that the novel stereochemistry results from acid-promoted tosylate dissociation to yield an intermediate phosphenium-bridged cation, which undergoes syn-selective cyclization. PMID- 29484791 TI - Neutropenia in 6 cases of childhood onset type 1 diabetes and its possible mechanisms. AB - OBJECTIVE: Type 1 diabetes (T1D) is a chronic inflammatory disease caused by a selective destruction of the pancreatic beta-cells. There are few reports on peripheral neutropenia in T1D for different reasons. We reported 6 cases of childhood onset T1D combined with neutropenia and explored its possible mechanisms. METHODS: The clinical diagnosis and treatment course of 6 cases of childhood onset T1D combined with neutropenia, who were hospitalized in our hospital from January 2013 to December 2016, were studied retrospectively. RESULTS: We have diagnosed and treated 38 cases of childhood onset T1D during this period, while only 6 cases (15.79%) had neutropenia. The diagnostic ages of the 6 cases ranged from 5 to 12 years. Diabetic ketoacidosis (DKA) was complicated in 5 cases. Neutropenia happened within 14 to 21 days of the onset of disease and 3 to 11 days after using insulin, respectively, and returned spontaneously to normal range within 5 to 9 days. The serum levels of granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF) increased slightly before the usage of insulin in all 6 cases, and decreased to normal range after the usage of insulin. CONCLUSION: Neutropenia can be seen in childhood onset T1D, and can return spontaneously to normal range without special treatments. The possible mechanisms might be the regulation effects of insulin on G-CSF and GM-CSF. PMID- 29484792 TI - Intermolecular C(sp3 )-H Amination of Complex Molecules. AB - A general and operationally convenient method for intermolecular amination of C(sp3 )-H bonds is described. This technology allows for efficient functionalization of complex molecules, including numerous pharmaceutical targets. The combination of pivalonitrile as a solvent, Al2 O3 as an additive, and phenyl sulfamate as a nitrogen source affords differential reaction performance and substrate scope. Mechanistic data strongly implicate a pathway for catalyst decomposition that initiates with solvent oxidation, thus providing rationale for the marked influence of pivalonitrile on this reaction process. PMID- 29484793 TI - Low-Coordinate Single-Ion Magnets by Intercalation of Lanthanides into a Phenol Matrix. AB - It is very challenging to synthesize stable trivalent rare-earth complexes in which the coordination number is lower than 3 for the high oxidation state, there is a large ion radius and nearly non-bonding character of trivalent lanthanide ions. The bulky phenol ligand ArOH (Ar=2,6-Dipp2 C6 H3 , Dipp=2,6 diisopropylphenyl) was utilized to construct low-coordinate lanthanide compound [(ArO)Ln(OAr')] (Ar'=6-Dipp-2-(2'-i Pr-6'-CHMe(CH2- )C6 H3 )C6 H3 O- ; Ln=Tb, Dy, Ho, Er, Tm). These complexes and the free ligand ArOH were isostructural. Magnetic measurements and theoretical studies demonstrated that both the oblate type dysprosium and prolate-type erbium analogues exhibited single-ion magnet (SIM) behavior. The bulky phenol ligands provided strong uniaxial ligand field, making the dysprosium SIM possessing blocking barrier up to 961 K. PMID- 29484794 TI - Prostate cancer screening: Beliefs and practices of the Brazilian physicians with different specialties. AB - RATIONALE, AIMS, AND OBJECTIVES: Prostate cancer (PC) presents with a high prevalence, but a low mortality. The evaluation of the risk-benefit ratio of current screening methods has led to conflicting results, which are reflected in some contradictory recommendations proposed by scientific and governmental entities. In this context of uncertainty, our objective is to verify the practices and beliefs of Brazilian physicians of different specialties regarding screening for PC. METHODS: A cross-sectional study was conducted through a self administered questionnaire survey during the main events of the target specialties (general practitioner, geriatrics, and urology) during the year 2016. We evaluated the practices on 6 main points of conduct in PC screening: previous discussion to informed decision, exams indicated, age of onset with and without additional risk factors, repeat interval, and age when screening is suspended. Responses were analysed with descriptive statistics and correlation, using the Statistical Package for the Social Sciences program (IBM SPSS Statistics version 20, 2010). RESULTS: The screening recommendation for PC differs significantly among specialists in association with previous discussion of benefits/harm (P = 0.026), exams used (P < 0.001), age of beginning screening with and without additional risk (P < 0.001), and age of suspension of the screening program (P < 0.001). CONCLUSIONS: Our findings indicate that there is a significant difference of conduct between doctors in different specialties. To the best of the author's knowledge, this is the first study that directly compares the practices of these different specialists in relation to the main points involved in screening for PC. PMID- 29484796 TI - Maternal perceptions of advice on sleep in young children: How, what, and when? AB - OBJECTIVES: Parental knowledge on sleep hygiene in children may be a contributing factor for sleep difficulties in preschoolers. As sleep is crucial for healthy development, it is important to understand how parental knowledge can be improved. The aim of this qualitative study was to develop an understanding of advice available in the United Kingdom (UK) on sleep in young children. DESIGN: This study employed constructivist grounded theory methodology. METHODS: Participants were recruited via social media and a previously constructed participant database. Interviews were audio-recorded, transcribed, and analysed. RESULTS: Fourteen mothers were interviewed independently, whilst one mother was interviewed together with her husband. Themes relating to how UK mothers wish advice on sleep to be formulated, what they believe it should include and when they would like to receive it, were identified from the data. Specifically, this study suggests that UK mothers value experience and thus recommends that advice be made through collaboration projects involving both professionals and parents. It also suggests that advice should be readily available and given to expecting parents prior to the arrival of their baby as well as at regular follow-ups. In addition, the participating mothers wanted advice to be balanced and non judgemental. CONCLUSION: This study looks at the views of mainly White British mothers currently residing within the United Kingdom. Thus, it may not represent the views of everyone in the United Kingdom. Nevertheless, it still makes important recommendations for practice. For example, relationships between health professionals and parents need to be improved and information on different sleeping practices widely dispersed. Statement of contribution What is already known on this subject? Poor sleep is common in young children. Young children's sleep quality can be affected by parental behaviours. Parents lack knowledge of sleep in young children. What does this study add? According to this study: It would be beneficial for professionals to work in partnership with parents when formulating advice. Mothers want advice to appreciate individual differences, be free of stigma, and manage expectations. Mothers want advice both prenatally and throughout their child's development. PMID- 29484797 TI - Synthesis and Applications of Compartmentalised Molecular Polymer Brushes. AB - Polymer science is rapidly advancing towards the precise construction of synthetic macromolecules of formidable complexity. Beyond the impressive advances in control over polymer composition and uniformity enabled by the living polymerisation revolution, the introduction of compartmentalisation within polymer architectures can elevate their functionality beyond that of their constituent parts, thus offering immense potential for the production of tailor made nanomaterials. In this Minireview, we discuss synthetic routes to complex molecular brushes with discrete chemical compartments and highlight their potential in the development of advanced materials with applications in nanofabrication, optics and functional materials. PMID- 29484798 TI - Identification of Adult Mesodermal Progenitor Cells and Hierarchy in Atherosclerotic Vascular Calcification. AB - The nature of calcifying progenitor cells remains elusive. In this study, we investigated the developmental hierarchy and dynamics of progenitor cells. In vitro and in vivo reconstitution assays demonstrated that Sca-1+/PDGFRalpha- cells in the bone marrow (BM) are the ancestors of Sca-1+/PDGFRalpha+ cells. Cells of CD29 + Sca-1+/PDGFRalpha- lineage in the BM showed both hematopoietic potential with osteoclastic differentiation ability as well as mesenchymal stem cell-like properties with osteoblastic differentiation potential. Clonally isolated BM-derived artery-infiltrated Sca-1+/PDGFRalpha- cells maintained osteoblastic/osteoclastic bipotency but lost hematopoietic activity. In hypercholesterolemic apolipoprotein-E-deficient (Apoe-/-) mice, the mobilization from BM to peripheral circulation, followed by migration into atherosclerotic plaques of Sca-1+/PDGFRalpha- cells, but not Sca-1+/PDGFRalpha+ cells, were significantly decreased, and Interleukin-1beta (IL-1beta) and Interleukin-5 (IL 5) mediated this response. Here, we demonstrated that Sca-1+/PDGFRalpha- cells are mesodermal progenitor cells in adults, and the dynamics of progenitor cells were regulated by atherosclerosis-related humoral factors. These results may contribute to better understanding of vascular homeostasis and assist in the development of novel therapies for atherosclerosis. Stem Cells 2018;36:1075-1096. PMID- 29484799 TI - Daphnia females adjust sex allocation in response to current sex ratio and density. AB - Cyclical parthenogenesis presents an interesting challenge for the study of sex allocation, as individuals' allocation decisions involve both the choice between sexual and asexual reproduction, and the choice between sons and daughters. Male production is therefore expected to depend on ecological and evolutionary drivers of overall investment in sex, and those influencing male reproductive value during sexual periods. We manipulated experimental populations, and made repeated observations of natural populations over their growing season, to disentangle effects of population density and the timing of sex from effects of adult sex ratio on sex allocation in cyclically parthenogenetic Daphnia magna. Male production increased with population density, the major ecological driver of sexual reproduction; however, this response was dampened when the population sex ratio was more male-biased. Thus, in line with sex ratio theory, we show that D. magna adjust offspring sex allocation in response to the current population sex ratio. PMID- 29484795 TI - Parahydrogen-Based Hyperpolarization for Biomedicine. AB - Magnetic resonance (MR) is one of the most versatile and useful physical effects used for human imaging, chemical analysis, and the elucidation of molecular structures. However, its full potential is rarely used, because only a small fraction of the nuclear spin ensemble is polarized, that is, aligned with the applied static magnetic field. Hyperpolarization methods seek other means to increase the polarization and thus the MR signal. A unique source of pure spin order is the entangled singlet spin state of dihydrogen, parahydrogen (pH2 ), which is inherently stable and long-lived. When brought into contact with another molecule, this "spin order on demand" allows the MR signal to be enhanced by several orders of magnitude. Considerable progress has been made in the past decade in the area of pH2 -based hyperpolarization techniques for biomedical applications. It is the goal of this Review to provide a selective overview of these developments, covering the areas of spin physics, catalysis, instrumentation, preparation of the contrast agents, and applications. PMID- 29484801 TI - Brain injury markers: S100 calcium-binding protein B, neuron-specific enolase and glial fibrillary acidic protein in children with diabetic ketoacidosis. AB - BACKGROUND: To investigate serum levels of brain injury markers in diabetic ketoacidosis (DKA) and the relation of these markers with clinical and radiological findings of brain injury and laboratory results. METHODS: Twenty nine patients with DKA, 30 with type 1 diabetes mellitus (T1DM), and 35 healthy children were included. Clinical and laboratory findings, and the Glasgow Coma Scale (GCS) were recorded. In the DKA group, neuron-specific enolase (NSE), S100 calcium-binding protein B (S100B) and glial fibrillary acidic protein (GFAP) levels were measured at baseline and 6 and 12 hours after treatment. Magnetic resonance imaging was performed in the DKA group to demonstrate any brain injury. RESULTS: No clinical or radiological findings of brain injury were found in any of the patients with DKA. In the DKA group, S100B was significantly higher than the healthy control and T1DM groups, while GFAP and NSE levels were not different from controls and T1DM patients. No significant differences were found in GFAP, NSE and S100B levels according to severity of DKA, diabetes duration and GCS. CONCLUSION: NSE and GFAP levels do not increase in DKA patients without overt brain injury. Elevated levels of S100B, which is also synthesized from non neuronal tissues, might arise from peripheral sources. A lack of concurrent increase in serum levels of these brain injury markers might result from the yet intact blood brain barrier or a true absence of neuronal damage. In order to reveal subclinical brain injury related to DKA, there is a need for studies concurrently assessing neurocognitive functions. PMID- 29484800 TI - Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver. AB - Increasing evidence suggests that regulation of heterochromatin at the nuclear envelope underlies metabolic disease susceptibility and age-dependent metabolic changes, but the mechanism is unknown. Here, we profile lamina-associated domains (LADs) using lamin B1 ChIP-Seq in young and old hepatocytes and find that, although lamin B1 resides at a large fraction of domains at both ages, a third of lamin B1-associated regions are bound exclusively at each age in vivo. Regions occupied by lamin B1 solely in young livers are enriched for the forkhead motif, bound by Foxa pioneer factors. We also show that Foxa2 binds more sites in Zmpste24 mutant mice, a progeroid laminopathy model, similar to increased Foxa2 occupancy in old livers. Aged and Zmpste24-deficient livers share several features, including nuclear lamina abnormalities, increased Foxa2 binding, de repression of PPAR- and LXR-dependent gene expression, and fatty liver. In old livers, additional Foxa2 binding is correlated to loss of lamin B1 and heterochromatin (H3K9me3 occupancy) at these loci. Our observations suggest that changes at the nuclear lamina are linked to altered Foxa2 binding, enabling opening of chromatin and de-repression of genes encoding lipid synthesis and storage targets that contribute to etiology of hepatic steatosis. PMID- 29484803 TI - Controlled Attachment of Pseudomonas aeruginosa with Binary Colloidal Crystal Based Topographies. AB - Micro- and nanotopographies can interfere with bacteria attachment, however, the interplay existing between surface chemistry and topography remains unclear. Here, self-assembled spherical micrometer- silica and nanometer poly(methyl methacrylate) (PMMA)-sized particles are used to make binary colloidal crystal (BCC) topographical patterns to study bacterial attachment. A uniform surface chemistry of allylamine plasma polymer (AAMpp) is coated on the top of the BCCs to study only the topography effects. The uncoated and coated BCCs are exposed to Pseudomonas aeruginosa, and the surfaces and bacteria are characterized using scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and fluorescence microscopy. It is found that bacteria attachment to the uncoated BCCs is delayed and individual cells are attracted to the small particle regions of the patterns. Surprisingly, this phenomenon is also observed for the AAMpp coated BCCs, with bacteria attaching to the small particle regions of the pattern, in stark contrast to uniform flat films of AAMpp that are highly adhesive toward P. aeruginosa. Also, the overall levels of bacterial attachment are significantly reduced by the BCC patterns compared to controls. Thus, there is a trade-off that exists between chemistry and topography that can be exploited to delay the onset of P. aeruginosa biofilm formation on surfaces. PMID- 29484802 TI - System and path planning algorithm for low-kV X-ray free-form surface irradiation. AB - OBJECTIVE: Intraoperative radiotherapy (IORT) after surgical resection using a low-kV-X-ray source is a proven method used in cancer treatment. However, the shape and size of the targeted surface area are limited to the size of the available applicators. This can lead to nonconformal and therefore suboptimal treatment for many patients. METHODS: A system is proposed comprising an X-ray source with an applicator for surface irradiation mounted on a robotic arm. This is controlled by an algorithm designed for planning the required continuous path, enabling irradiation of any desired shape with a controlled dose distribution. RESULTS: The system is shown to be capable of irradiating areas composed of rectangles on a flat surface with a homogeneity index of less than 7% inside the targeted area. CONCLUSION: The presented results demonstrate the potential of the proposed setup to eliminate the current limitations, leading to better treatment of patients. PMID- 29484804 TI - Response to 'Letter to "Repair of damaged ligaments with tissue fixation system minisling is sufficient to cure major prolapse in all three compartments: 5-year data'". PMID- 29484805 TI - Identifying mechanisms that structure ecological communities by snapping model parameters to empirically observed tradeoffs. AB - Theory predicts that interspecific tradeoffs are primary determinants of coexistence and community composition. Using information from empirically observed tradeoffs to augment the parametrisation of mechanism-based models should therefore improve model predictions, provided that tradeoffs and mechanisms are chosen correctly. We developed and tested such a model for 35 grassland plant species using monoculture measurements of three species characteristics related to nitrogen uptake and retention, which previous experiments indicate as important at our site. Matching classical theoretical expectations, these characteristics defined a distinct tradeoff surface, and models parameterised with these characteristics closely matched observations from experimental multi-species mixtures. Importantly, predictions improved significantly when we incorporated information from tradeoffs by 'snapping' characteristics to the nearest location on the tradeoff surface, suggesting that the tradeoffs and mechanisms we identify are important determinants of local community structure. This 'snapping' method could therefore constitute a broadly applicable test for identifying influential tradeoffs and mechanisms. PMID- 29484806 TI - Application of response surface methodology to vortex-assisted dispersive liquid liquid extraction for the determination of nicotine and cotinine in urine by gas chromatography-tandem mass spectrometry. AB - A method of vortex-assisted dispersive liquid-liquid extraction coupled with gas chromatography and tandem mass spectrometry for the determination of nicotine and cotinine in urine was developed. Response surface methodology was applied to obtain the optimum extraction conditions. In this method, Plackett-Burman design was utilized to evaluate the impact of five selected factors on pretreatment procedure. Then, three main factors were optimized using a Box-Behnken design. The optimized method showed good linearities at 1-2000 MUg/L with correlation coefficients of 0.9998 for nicotine and 0.9986 for cotinine. Recovery was 91.4 106 and 91.7-108% for nicotine and cotinine, respectively. The intraday relative standard derivations of determination were 1.47-4.06% for nicotine and 0.41-3.16% for cotinine, and interday relative standard derivations were 3.03-6.70% for nicotine and 1.64-6.38% for cotinine. The method detection limits for nicotine and cotinine were 0.33 and 0.34 MUg/L, respectively. A total of 87 urine samples from smokers and nonsmokers were tested with the proposed method. Urinary nicotine and cotinine were 23.0-6.67 * 103 and 18.4-4.17 * 103 MUg/(g.cr) for smokers and 1.31-286 and 1.39-131 MUg/(g.cr) for nonsmokers, respectively. The method is sensitive, suitable and reliable for the determination of nicotine and cotinine in urine and meets the requirements for evaluating short-term tobacco exposure. PMID- 29484807 TI - A Flexible Stretchable Hydrogel Electrolyte for Healable All-in-One Configured Supercapacitors. AB - The development of integrated high-performance supercapacitors with all-in-one configuration, excellent flexibility and autonomously intrinsic self-healability, and without the extra healable film layers, is still tremendously challenging. Compared to the sandwich-like laminated structures of supercapacitors with augmented interfacial contact resistance, the flexible healable integrated supercapacitor with all-in-one structure could theoretically improve their interfacial contact resistance and energy densities, simplify the tedious device assembly process, prolong the lifetime, and avoid the displacement and delamination of multilayered configurations under deformations. Herein, a flexible healable all-in-one configured supercapacitor with excellent flexibility and reliable self-healing ability by avoiding the extra healable film substrates and the postassembled sandwich-like laminated structures is developed. The healable all-in-one configured supercapacitor is prepared from in situ polymerization and deposition of nanocomposites electrode materials onto the two sided faces of the self-healing hydrogel electrolyte separator. The self-healing hydrogel film is obtained from the physically crosslinked hydrogel with enormous hydrogen bonds, which can endow the healable capability through dynamic hydrogen bonding. The assembled all-in-one configured supercapacitor exhibits enhanced capacitive performance, good cycling stability, reliable self-healing capability, and excellent flexibility. It holds broad prospects for obtaining various flexible healable all-in-one configured supercapacitors for working as portable energy storage devices in wearable electronics. PMID- 29484808 TI - Effects of resveratrol supplementation on liver fat content in overweight and insulin-resistant subjects: A randomized, double-blind, placebo-controlled clinical trial. AB - We performed the largest randomized, placebo-controlled clinical trial to date (N = 112, 12-week intervention) to investigate the effects and safety of resveratrol supplementation on liver fat content and cardiometabolic risk parameters in overweight and obese and insulin-resistant subjects. At baseline the variability in liver fat content was very large, ranging from 0.09% to 37.55% (median, 7.12%; interquartile range, 3.85%-12.94%). Mean (SD) liver fat content was 9.22 (6.85) % in the placebo group and 9.91 (7.76) % in the resveratrol group. During the study liver fat content decreased in the placebo group (-0.7%) but not in the resveratrol group (-0.03%) (differences between groups: P = .018 for the intention-to-treat [ITT] population; N = 54, resveratrol, N = 54, placebo and P = .0077 for the per protocol [PP] population). No effects of resveratrol supplementation on cardiometabolic risk parameters were observed. Resveratrol supplementation was well tolerated and safe. In conclusion, these data suggest that resveratrol supplementation is safe and that it does not considerably impact liver fat content or cardiometabolic risk parameters in humans. PMID- 29484809 TI - Living with schizophrenia in rural communities in north-east Thailand. AB - In the rural villages of Thailand, rich social support networks exist that bond the community members to help each other. This study explored the barriers and facilitators of living with schizophrenia in Thai villages. A descriptive qualitative study was conducted using semi-structured interviews with individuals with schizophrenia, family members, and significant others. Content analysis of transcripts involved examining the data, recording observations, data reduction, and coding themes. Four main themes emerged from the narratives: (i) keep doing day-to-day activities as a way of life; (ii) support sustains day-to-day living; (iii) controlling medication side effects maintains daily living; and (iv) managing self maintains daily living. Self-regulation and social support are keys to moving from dependence to a normative life goal in rural communities. The patterns of living in the rural communities provide a strong social network as people with schizophrenia learn to lead successful lives. Using supportive families and community members as resources is an alternative and effective way of providing supportive care. PMID- 29484810 TI - Dual Effects of Nanostructuring and Oxygen Vacancy on Photoelectrochemical Water Oxidation Activity of Superstructured and Defective Hematite Nanorods. AB - An Ar atmospheric treatment is rationally used to etch and activate hematite nanoflakes (NFs) as photoanodes toward enhanced photoelectrochemical water oxidation. The formation of a highly ordered hematite nanorods (NRs) array containing a high density of oxygen vacancy is successfully prepared through in situ reduction of NFs in Ar atmosphere. Furthermore, a hematite (104) plane and an iron suboxide layer at the absorber/back-contact interface are formed. The material defects produced by a thermal oxidation method can be critical for the morphology transformation from 2D NFs to 1D NRs. The resulting hematite NR photoanodes show high efficiency toward solar water splitting with improved light harvesting capabilities, leading to an enhanced photoresponse due to the artificially formed oxygen vacancies. PMID- 29484811 TI - Cucurbit[8]uril-Regulated Colloidal Dispersions Exhibiting Photocontrolled Rheological Behavior. AB - In situ photocontrol over shear-thickening of condensed colloidal dispersions is of paramount importance in a wide range of applications including process technology and photorheological fluids. Its development and practicability, however, are hampered by the lack of well-designed photoresponsive systems. Here, a colloidal suspension whose rheological behavior is readily switchable between shear-thinning and shear-thickening using an external light stimulus is reported. This smart colloidal solution contains hybrid raspberry-like colloids prepared by employing cucurbit[8]uril as a supramolecular linker to assemble functional Fe3 O4 nanoparticles onto a silica core. The formed raspberry colloids are photoresponsive and can be reversibly disassembled under UV irradiation. PMID- 29484812 TI - Chronic pain in the workplace: A diary study of pain interference at work and worker strain. AB - Chronic pain is both prevalent and one of the leading causes of work-related disability. Somatic experiences of pain and pain interference with daily activities at work may lead to psychological distress and strain in workers. In accordance with the appraisal theory of stress, we proposed a model in which pain interference mid-workday predicts negative affect and end-of-workday emotional exhaustion in workers who interact with customers. Further, we proposed that pain interference predicts variance in negative affect and exhaustion beyond somatic experiences of pain, based on our theoretical proposition that pain interference represents a secondary stress appraisal. Participants (N = 86 full-time workers with chronic pain) completed 2 online surveys per day for 5 consecutive workdays. Results from multilevel path analysis supported our hypotheses; pain interference predicted both negative affect and end-of-day emotional exhaustion while controlling for somatic experiences of pain (pain severity). Further, pain interference indirectly predicted end-of-day emotional exhaustion via negative affect while controlling for somatic pain experiences. Results highlight the importance of pain interference as a stressor at work for individuals working with chronic pain and point to the need for effective interventions for this working population. PMID- 29484813 TI - Plant genetics enters the nano age? AB - Plant transformation has for many years relied on agrobacterium infection or biolistic particle delivery. However, these two methods are limited to model plant systems or a small number of crop species. This commentary highlights recent developments in the nanoparticle-mediated transformation that have the potential to revolutionize how plants are transformed. PMID- 29484814 TI - Determination of ultraviolet filter compounds in environmental water samples using membrane-protected micro-solid-phase extraction. AB - A method based on membrane-protected micro-solid-phase extraction coupled with gas chromatography and mass spectrometry was developed for the determination of six ultraviolet filter compounds in various aqueous media. Multiwalled carbon nanotubes as the sorbent were encapsulated in a sealed polypropylene membrane packet and immersed in the sample to extract the analytes, and then dichloromethane was used for desorption purpose. The method was sensitive enough for quantitative analysis of the target analytes, with limits of quantification between 0.01 and 0.06 MUg/L, and produced a linear response (R2 > 0.991) over the calibration range (0.05-6 MUg/L). The obtained reproducibility was practically suitable with relative standard deviation values of less than 14% in pure water (spiked at 0.20/MUg L) and less than 15% in real samples. The optimized method was applied for the analysis of real water samples with varying matrix complexity: tap, river, and dam water; geothermal spa; and sewage treatment plant effluent. Various levels and patterns of contamination were observed in the examined samples, while the sample from spa was the most contaminated, regarding the target analytes. Matrix spikes and matrix spike replicates were also analyzed to validate the technique for analysis of real aqueous samples, and satisfactory results were achieved. PMID- 29484815 TI - Modified triangular hepatic vein reconstruction for preventing hepatic venous outflow obstruction in pediatric living donor liver transplantation using left lateral segment grafts. AB - HVOO can be a critical complication in pediatric LDLT. The aim of this study was to evaluate a modified triangular technique of hepatic vein reconstruction for preventing HVOO in pediatric LDLT. A total of 298 pediatric LDLTs were performed using a left lateral segment graft by 2 methods for reconstruction of the hepatic vein. In 177 recipients, slit-shaped anastomosis was indicated with partial clamp of the IVC. A total of 121 recipients subjected to the modified triangular anastomosis with total clamp of the IVC. We compared the incidence of hepatic vein anastomotic complications between these 2 methods. Nine of the 177 cases (5.3%) treated with the conventional technique were diagnosed with outflow obstruction. All 9 cases underwent hepatic vein reconstruction with the slit shaped hepatic vein anastomosis. In contrast, there were no cases of outflow obstruction in the 121 cases treated with the modified triangular anastomosis. The modified triangular technique of hepatic vein reconstruction with total clamping of the IVC was useful for preventing HVOO in pediatric LDLT. PMID- 29484816 TI - Synergistic Nanotubular Copper-Doped Nickel Catalysts for Hydrogen Evolution Reactions. AB - Developing highly active electrocatalysts with low cost and high efficiency for hydrogen evolution reactions (HERs) is of great significance for industrial water electrolysis. Herein, a 3D hierarchically structured nanotubular copper-doped nickel catalyst on nickel foam (NF) for HER is reported, denoted as Ni(Cu), via facile electrodeposition and selective electrochemical dealloying. The as prepared Ni(Cu)/NF electrode holds superlarge electrochemical active surface area and exhibits Pt-like electrocatalytic activity for HER, displaying an overpotential of merely 27 mV to achieve a current density of 10 mA cm-2 and an extremely small Tafel slope of 33.3 mV dec-1 in 1 m KOH solution. The Ni(Cu)/NF electrode also shows excellent durability and robustness in both continuous and intermittent bulk water electrolysis. Density functional theory calculations suggest that Cu substitution and the formation of NiO on the surface leads to more optimal free energy for hydrogen adsorption. The lattice distortion of Ni caused by Cu substitution, the increased interfacial activity induced by surface oxidation of nanoporous Ni, and numerous active sites at Ni atom offered by the 3D hierarchical porous structure, all contribute to the dramatically enhanced catalytic performance. Benefiting from the facile, scalable preparation method, this highly efficient and robust Ni(Cu)/NF electrocatalyst holds great promise for industrial water-alkali electrolysis. PMID- 29484817 TI - Pre-registration pharmacist tutor training: a pilot study. AB - BACKGROUND: The quality and variability of pre-registration pharmacist training has been questioned in recent years, with many trainees reporting dissatisfaction with their training experiences. A pilot training event aimed at pre-registration tutors from all sectors of practice was developed by Health Education England North East (HEENE) in 2016 to address some of these issues, with the overall aim of developing and preparing new tutors for the role of the tutor. CONTEXT: Quantitative data were collected via questionnaires given to the participants before and after training. The questions focused on participants' perceptions of their competence as a tutor across a range of domains, such as assessing trainee progress in the workplace, providing feedback and reflective practice. Interviews were subsequently held with a subset of participants to help understand the key themes and responses. INNOVATION: Results were overwhelmingly positive, with participants reporting an increased level of confidence in their role, having made positive changes to their practice as a tutor. The only domain that did not show a positive shift after training was 'undertaking of reflective practice'. Participants attributed this to the lack of protected time in the workplace to support reflective practice. The quality and variability of pre-registration pharmacist training has been questioned in recent years IMPLICATIONS: Results from this evaluation imply that this tutor training event was felt to be worthwhile, met the needs that it was developed to address and has the potential to have a positive impact on the standardisation of pharmacist pre-registration tutor training nationally. Areas for improvement centre on external factors relevant to pharmacists' daily practice, such as being allocated time in (or outside of) the workplace to support personal development. PMID- 29484818 TI - Resilience training is just a band-aid solution for doctor well-being: No. PMID- 29484819 TI - Are we allowing impact factor to have too much impact: The need to reassess the process of academic advancement in pediatric cardiology? AB - Impact factor has been used as a metric by which to gauge scientific journals for several years. A metric meant to describe the performance of a journal overall, impact factor has also become a metric used to gauge individual performance as well. This has held true in the field of pediatric cardiology where many divisions utilize impact factor of journals that an individual has published in to help determine the individual's academic achievement. This subsequently can impact the individual's promotion through the academic ranks. We review the purpose of impact factor, its strengths and weaknesses, discuss why impact factor is not a fair metric to apply to individuals, and offer alternative means by which to gauge individual performance for academic promotion. PMID- 29484820 TI - Comparative analyses of simple sequence repeats (SSRs) in 23 mosquito species genomes: Identification, characterization and distribution (Diptera: Culicidae). AB - Simple sequence repeats (SSRs) exist in both eukaryotic and prokaryotic genomes and are the most popular genetic markers, but the SSRs of mosquito genomes are still not well understood. In this study, we identified and analyzed the SSRs in 23 mosquito species using Drosophila melanogaster as reference at the whole genome level. The results show that SSR numbers (33 076-560 175/genome) and genome sizes (574.57-1342.21 Mb) are significantly positively correlated (R2 = 0.8992, P < 0.01), but the correlation in individual species varies in these mosquito species. In six types of SSR, mono- to trinucleotide SSRs are dominant with cumulative percentages of 95.14%-99.00% and densities of 195.65/Mb 787.51/Mb, whereas tetra- to hexanucleotide SSRs are rare with 1.12%-4.22% and 3.76/Mb-40.23/Mb. The (A/T)n, (AC/GT)n and (AGC/GCT)n are the most frequent motifs in mononucleotide, dinucleotide and trinucleotide SSRs, respectively, and the motif frequencies of tetra- to hexanucleotide SSRs appear to be species specific. The 10-20 bp length of SSRs are dominant with the number of 110 561 +/- 93 482 and the frequency of 87.25% +/- 5.73% on average, and the number and frequency decline with the increase of length. Most SSRs (83.34% +/- 7.72%) are located in intergenic regions, followed by intron regions (11.59% +/- 5.59%), exon regions (3.74% +/- 1.95%), and untranslated regions (1.32% +/- 1.39%). The mono-, di- and trinucleotide SSRs are the main SSRs in both gene regions (98.55% +/- 0.85%) and exon regions (99.27% +/- 0.52%). An average of 42.52% of total genes contains SSRs, and the preference for SSR occurrence in different gene subcategories are species-specific. The study provides useful insights into the SSR diversity, characteristics and distribution in 23 mosquito species of genomes. PMID- 29484821 TI - The G-quadruplex-stabilizing ligand RHPS4 enhances sensitivity of U251MG glioblastoma cells to clinical carbon ion beams. AB - The pentacyclic acridine RHPS4 is a highly potent and specific G-quadruplex (G4) ligand, which binds and stabilizes telomeric G4 leading to the block of the replication forks at telomeres and consequently to telomere dysfunctionalization. In turn, the cell recognizes unprotected telomeres as DNA double-strand breaks with consequent activation of DNA repair response at telomeres, cellular growth impairment, and death. Data from the literature showed the capability of this compound to sensitize U251MG glioblastoma radioresistant cell line to X-rays sparsely ionizing radiations. In the present paper, it was investigated whether RHPS4 is also able to increase the effect of clinical carbon ion beams (cells irradiated in the middle of a spread-out Bragg peak, in the energy range of 246 312 MeV.MUm-1 and a dose-averaged linear energy transfer of 46 keV.MUm-1 ). Interestingly, also for charged particles whose damage inflicted to DNA is more complex than that of sparsely ionizing radiations and results in higher Relative Biological Effectiveness (RBE), RHPS4 significantly potentiated the radiation effect in terms of cell killing, delayed rejoining of DNA double-strand breaks (gamma-H2AX and 53BBP1 immunofluorescence staining), chromosome aberrations (pan centromeric/telomeric FISH and multicolor FISH), and G2 /M-phase accumulation in GBM cells. Overall, the results provide the first evidence that the combined administration of the G4-ligand RHPS4 with charged particles interfere with cellular processes involved in cell survival leading to radiosensitization of highly radioresistant tumor cells. PMID- 29484822 TI - Impact of interpersonal relations on learning and development of professional identity: A study of residents' perceptions. AB - OBJECTIVES: Informal learning includes all occurrences during one's life when learning is not deliberate. Prior research on informal learning in healthcare contexts examined learning happening outside of the formal curriculum, yet still in the workplace. This study explores residents' perceptions about extracurricular factors outside of the workplace that contribute to their learning and development of professional identity, whether interpersonal relations are recognised as such factors, and positive and negative impacts of interpersonal relations. METHODS: In this qualitative study, all 21 residents in our Emergency Medicine programme were asked, in a web-based survey with open ended questions, to identify extracurricular sources outside of the workplace perceived as contributing to their learning and professional identity development, and list positive and negative impacts of interpersonal relations outside of work on learning and identity development. Themes were extracted through content analysis of the narrative responses. Two reviewers coded all data. RESULTS: Thirteen (62%) residents identified 37 factors grouped under five themes: learning activity, role modelling, support, non-clinical academic roles, and social interactions. Interpersonal relations were perceived as having positive and negative impacts, including creating support, positive role modelling and mentoring, increasing concrete learning, as well as lapses in teaching skills, deficits in professional role training, and loss of personal time. CONCLUSIONS: Several extracurricular factors outside of the workplace contribute to resident learning and identity development, including interpersonal relations, which have positive and negative impacts. The most often noted negative impact of interpersonal relations outside of work between residents and faculty related to perceived lapses in teaching skills. PMID- 29484823 TI - Pain management using photobiomodulation: Mechanisms, location, and repeatability quantified by pain threshold and neural biomarkers in mice. AB - Photobiomodulation (PBM) is a simple, efficient and cost-effective treatment for both acute and chronic pain. We previously showed that PBM applied to the mouse head inhibited nociception in the foot. Nevertheless, the optimum parameters, location for irradiation, duration of the effect and the mechanisms of action remain unclear. In the present study, the pain threshold in the right hind paw of mice was studied, after PBM (810 nm CW laser, spot size 1 or 6 cm2 , 1.2-36 J/cm2 ) applied to various anatomical locations. The pain threshold, measured with von Frey filaments, was increased more than 3-fold by PBM to the lower back (dorsal root ganglion, DRG), as well as to other neural structures along the pathway such as the head, neck and ipsilateral (right) paw. On the other hand, application of PBM to the contralateral (left) paw, abdomen and tail had no effect. The optimal effect occurred 2 to 3 hours post-PBM and disappeared by 24 hours. Seven daily irradiations showed no development of tolerance. Type 1 metabotropic glutamate receptors decreased, and prostatic acid phosphatase and tubulin-positive varicosities were increased as shown by immunofluorescence of DRG samples. These findings elucidate the mechanisms of PBM for pain and provide insights for clinical practice. PMID- 29484824 TI - Simpson's paradox: A statistician's case study. AB - Gender equality and workforce diversity has recently been in the forefront of College discussions. Reasons for the difference between various groups may not be as they initially appeared. The results of comparing the outcome between two groups can sometimes be confounded and even reversed by an unrecognised third variable. This concept is known as Simpson's Paradox, and is illustrated here using a renowned case study on potential gender bias for acceptance to Graduate School at the University of California, Berkeley. The investigation showed that males were 1.8 times more likely to be admitted to Graduate School than females in 1973. Initially it appeared that women were discriminated against in the selection process. However, when admissions were re-examined at individual Departments of the School, admission tended to be better for women than men in four of six Departments. This contradiction or paradox tells us that the association between admission and gender was dependent upon on Department. The confounding effect of Department was defined by two characteristics. Firstly, a strong association between Department and admission: some Departments admitted much smaller percentages of applicants than others. Secondly, a strong association between Department and gender: females tended to apply to Departments with lower admission rates. The explanation of differences between groups can be multifactorial. A search for possible confounders will assist in this understanding. This could apply whenever two groups initially appear to differ, but on closer analysis this difference is either unfounded, or even reversed by reference to a third, confounding variable. PMID- 29484825 TI - "One-Pot" Sample Processing Method for Proteome-Wide Analysis of Microbial Cells and Spores. AB - PURPOSE: Bacterial endospores, the transmissible forms of pathogenic bacilli and clostridia, are heterogeneous multilayered structures composed of proteins. These proteins protect the spores against a variety of stresses, thus helping spore survival, and assist in germination, by interacting with the environment to form vegetative cells. Owing to the complexity, insolubility, and dynamic nature of spore proteins, it has been difficult to obtain their comprehensive protein profiles. EXPERIMENTAL DESIGN: The intact spores of Bacillus subtilis, Bacillus cereus, and Peptoclostridium difficile and their vegetative counterparts were disrupted by bead beating in 6 m urea under reductive conditions. The heterogeneous mixture was then double digested with LysC and trypsin. Next, the peptide mixture was pre-fractionated with zwitterionic hydrophilic interaction liquid chromatography (ZIC-HILIC) followed by reverse-phase LC-FT-MS analysis of the fractions. RESULTS: "One-pot" method is a simple, robust method that yields identification of >1000 proteins with high confidence, across all spore layers from B. subtilis, B. cereus, and P. difficile. CONCLUSIONS AND MEDICAL RELEVANCE: This method can be employed for proteome-wide analysis of non-spore-forming as well as spore-forming pathogens. Analysis of spore protein profile will help to understand the sporulation and germination processes and to distinguish immunogenic protein markers. PMID- 29484826 TI - Integration of Enzymatic and Heterogeneous Catalysis for One-Pot Production of Fructose from Glucose. AB - The search for efficient routes for the production of fructose from biomass derived glucose is of great interest and importance, as fructose is a highly attractive substrate in the conversion of cellulosic biomass into biofuels and chemicals. In this study, a one-pot, multistep procedure involving enzyme catalyzed oxidation of glucose at C2 and Ni/C-catalyzed hydrogenation of d glucosone at C1 selectively gives fructose in 77 % yield. Starting from upstream substrates such as alpha-cellulose and starch, fructose was also generated with similar efficiency and selectivity by the combination of enzymatic and heterogeneous catalysis. This method constitutes a new means of preparing fructose from biomass-derived substrates in an efficient fashion. PMID- 29484827 TI - A closer look at the antibiotic-resistant bacterial community found in urban wastewater treatment systems. AB - The conventional biological treatment process can provide a favorable environment for the maintenance and dissemination of antibiotic-resistant bacteria and the antibiotic resistance genes (ARG) they carry. This study investigated the occurrence of antibiotic resistance in three wastewater treatment plants (WWTP) to determine the role they play in the dissemination of ARGs. Bacterial isolates resistant to tetracycline were collected, and tested against eight antibiotics to determine their resistance profiles and the prevalence of multiple antibiotic resistance. It was found that bacteria resistant to tetracycline were more likely to display resistance to multiple antibiotics compared to those isolates that were not tetracycline resistant. Polymerase chain reaction (PCR) was used to identify the tetracycline resistance determinants present within the bacterial communities of the WWTPs and receiving waters, and it was found that ARGs may not be released from the treatment process. Identification of isolates showed that there was a large diversity of species in both the tetracycline-resistant and tetracycline-sensitive populations and that the two groups were significantly different in composition. Antibiotic resistance profiles of each population showed that a large diversity of resistance patterns existed within genera suggesting that transmission of ARG may progress by both horizontal gene and vertical proliferation. PMID- 29484828 TI - Measuring person-centred care in nurse-led outpatient rheumatology clinics. AB - BACKGROUND: Measurement of person-centred care (PCC) outcomes is underdeveloped owing to the complexity of the concept and lack of conceptual clarity. A framework conceptualizing outpatient PCC in rheumatology nurse-led clinics has therefore been suggested and operationalized into the PCC instrument for outpatient care in rheumatology (PCCoc/rheum). OBJECTIVE: The aim of the present study was to test the extent to which the PCCoc/rheum represents the underpinning conceptual outpatient PCC framework, and to assess its measurement properties as applied in nurse-led outpatient rheumatology clinics. METHODS: The 24-item PCCoc/rheum was administered to 343 persons with rheumatoid arthritis from six nurse-led outpatient rheumatology clinics. Its measurement properties were tested by Rasch measurement theory. RESULTS: Ninety-two per cent of individuals (n = 316) answered the PCCoc/rheum. Items successfully operationalized a quantitative continuum from lower to higher degrees of perceived PCC. Model fit was generally good, including lack of differential item functioning (DIF), and the PCCoc/rheum was able to separate individuals with a reliability of 0.88. The four response categories worked as intended, with the exception of one item. Item ordering provided general empirical support of a priori expectations, with the exception of three items that were omitted owing to multidimensionality, dysfunctional response categories and unexpected ordering. The 21-item PCCoc/rheum showed good accordance with the conceptual framework, improved fit, functioning response categories and no DIF, and its reliability was 0.86. CONCLUSION: We found general support for the appropriateness of the PCCoc/rheum as an outcome measure of patient-perceived PCC in nurse-led outpatient rheumatology clinics. While in need of further testing, the 21-item PCCoc/rheum has the potential to evaluate outpatient PCC from a patient perspective. PMID- 29484829 TI - Taste sensitivity and divergence in host plant acceptance between adult females and larvae of Papilio hospiton. AB - On the island of Sardinia the lepidopteran Papilio hospiton uses Ferula communis as exclusive host plant. However, on the small island of Tavolara, adult females lay eggs on Seseli tortuosum, a plant confined to the island. When raised in captivity on Seseli only few larvae grew beyond the first-second instar. Host specificity of lepidopterans is determined by female oviposition preferences, but also by larval food acceptance, and adult and larval taste sensitivity may be related to host selection in both cases. Aim of this work was: (i) to study the taste sensitivity of larvae and ovipositing females to saps of Ferula and Seseli; (ii) to cross-compare the spike activity of gustatory receptor neurons (GRNs) to both taste stimuli; (iii) to evaluate the discriminating capability between the two saps and determine which neural code/s is/are used. The results show that: (i) the spike responses of the tarsal GRNs of adult females to both plant saps are not different and therefore they cannot discriminate the two plants; (ii) larval L-lat GRN shows a higher activity in response to Seseli than Ferula, while the opposite occurs for the phagostimulant neurons, and larvae may discriminate between the two saps by means of multiple neural codes; (iii) the number of eggs laid on the two plants is the same, but the larval growth performance is better on Ferula than Seseli. Taste sensitivity differences may explain the absence of a positive relationship between oviposition preferences by adult females and plant acceptance and growth performance by larvae. PMID- 29484830 TI - Microwave-Assisted Preparation and Characterization of a Polyoxometalate-Based Inorganic 2D Framework Anode for Enhancing Lithium-Ion Battery Performance. AB - A pure inorganic 2D network molybdophosphate, [Mn3 Mo12 O24 (OH)6 (HPO3 )8 (H2 O)6 ]4- (1 a), synthesized through microwave irradiation with the existence of Mn2+ and organic cations and isolated as [(CH3 )2 NH2 ]3 Na[Mn3 Mo12 O24 (OH)6 (HPO3 )8 (H2 O)6 ]?12 H2 O (1), is found to possess highly enhanced performance in lithium-ion batteries' anode materials. The molecule shows multielectron redox properties suitable for producing anode materials with a specific capacity of 602 mA h g-1 at 100 mA g-1 after 50 cycles in lithium-ion batteries, although its specific capacity is the highest among all the reported pure inorganic 2D polyoxometalates to date, the cyclic stability is not that satisfactory. A hybrid nanocomposite of this 2D network and polypyrrole cations effectively reduces the capacity fading in initial cycles, and increases the stability and improves the electrochemical performance of lithium-ion batteries as well. PMID- 29484831 TI - Construction of a Triangle-Shaped Trimer and a Tetrahedron Using an alpha-Helix Inserted Circular Permutant of Cytochrome c555. AB - Highly-ordered protein structures have gained interest for future uses for biomaterials. Herein, we constructed a building block protein (BBP) by the circular permutation of the hyperthermostable Aquifex aeolicus cytochrome (cyt) c555 , and assembled BBP into a triangle-shaped trimer and a tetrahedron. The angle of the intermolecular interactions of BBP was controlled by cleaving the domain-swapping hinge loop of cyt c555 and connecting the original N- and C terminal alpha-helices with an alpha-helical linker. We obtained BBP oligomers up to ~40 mers, with a relatively large amount of trimers. According to the X-ray crystallographic analysis of the BBP trimer, the N-terminal region of one BBP molecule interacted intermolecularly with the C-terminal region of another BBP molecule, resulting in a triangle-shaped structure with an edge length of 68 A. Additionally, four trimers assembled into a unique tetrahedron in the crystal. These results demonstrate that the circular permutation connecting the original N and C-terminal alpha-helices with an alpha-helical linker may be useful for constructing organized protein structures. PMID- 29484832 TI - Endoplasmic reticulum, Golgi, and lysosomes are disorganized in lung fibroblasts from chronic obstructive pulmonary disease patients. AB - Chronic Obstructive Pulmonary Disease (COPD) is often caused by smoking and other stressors. This causes oxidative stress, which induces numerous changes on both the transcriptome and proteome of the cell. We aimed to examine if the endomembrane pathway, including the endoplasmic reticulum (ER), Golgi, and lysosomes, was disrupted in fibroblasts from COPD patients as opposed to healthy ever-smokers or never-smokers, and if the response to stress differed. Different cellular compartments involved in the endomembrane pathway, as well as mRNA expression and apoptosis, were examined before and after the addition of stress in lung fibroblasts from never-smokers, ever-smokers, and patients with COPD. We found that the ER, Golgi, and lysosomes were disorganized in fibroblasts from COPD patients under baseline conditions. After a time course with ER stress inducing chemicals, changes to the phenotypes of cellular compartments in COPD patient fibroblasts were observed, and the expression of the ER stress-induced gene ERP72 was upregulated more in the COPD patient's cells compared to ever smokers or never-smokers. Lastly, a tendency of increased active Caspase-3 was observed in COPD fibroblasts. Our results show that COPD patients have phenotypic changes in the lung fibroblasts endomembrane pathway, and respond differently to stress. Furthermore, these fibroblasts were cultured for several weeks outside the body, but they were not able to regain proper ER structure, indicating that the internal changes to the endomembrane system are permanent in smokers. This vulnerability to cellular stress might be a cause as to why some smokers develop COPD. PMID- 29484833 TI - The unfolding of plant growth form-defence syndromes along elevation gradients. AB - Understanding the functional economics that drives plant investment of resources requires investigating the interface between plant phenotypes and the variation in ecological conditions. While allocation to defence represents a large portion of the carbon budget, this axis is usually neglected in the study of plant economic spectrum. Using a novel geometrical approach, we analysed the co variation in a comprehensive set of functional traits related to plant growth strategies, as well as chemical defences against herbivores on all 15 Cardamine species present in the Swiss Alps. By extracting geometrical information of the functional space, we observed clustering of plants into three main syndromes. Those different strategies of growth form and defence were also distributed within distinct elevational bands demonstrating an association between the functional space and the ecological conditions. We conclude that plant strategies converge into clear syndromes that trade off abiotic tolerance, growth and defence within each elevation zone. PMID- 29484834 TI - Detection and genetic characterization of porcine pegivirus in pigs in the United States. AB - Using next-generation sequencing on vesicular swab and serum from swine from the USA exhibiting lameness and vesicles, porcine pegivirus (PPgV) was first identified and genetically characterized in the United States. Further screening using RT-PCR revealed that 24 of 159 (15.1%) serum samples were positive for PPgV. Future studies are needed to understand clinical impacts of the virus. PMID- 29484835 TI - Quantifying intracellular Mycobacterium tuberculosis: An essential issue for in vitro assays. AB - Many studies about intracellular microorganisms which are important regarding diseases affecting public health have been focused on the recognition of host pathogen interactions, thereby ascertaining the mechanisms by which the pathogen invades a cell and makes it become its host. Such knowledge enables understanding the immunological response triggered by these interactions for obtaining useful information for developing vaccines and drugs. Quantitative cell infection assay protocols are indispensable regarding studies involving Mycobacterium tuberculosis, which takes the lives of more than 2 million people worldwide every year; however, sometimes these are limited by the pathogen's slow growth. Concerning such limitation, a detailed review is presented here regarding the different methods for quantifying and differentiating an intracellular pathogen, the importance of mycobacteria aggregate dissociation and multiplicity of infection (MOI) in infection assays. The methods' differences, advantages, and disadvantages are discussed regarding intra and extracellular bacteria (on cell surface) differentiation, current problems are outlined, as are the solutions provided using fluorophores and projections made concerning quantitative infection assays. PMID- 29484836 TI - Primary murine mucosal response during cephalosporin-induced intestinal colonization by Enterococcus faecium. AB - Hospitalized patients are often administered antibiotics that perturb the gastrointestinal commensal microbiota, leading to outgrowth of antibiotic resistant bacteria, like multidrug-resistant Enterococcus faecium, subsequent spread, and eventually infections. However, the events that occur at the initial stage of intestinal colonization and outgrowth by multidrug-resistant E. faecium within the antibiotic-treated host have not been thoroughly studied. Here, we describe and visualize that only 6 hr after cephalosporin treatment of mice, the Muc-2 mucus layer is reduced and E-cadherin junctions were altered. In contrast, the cadherin-17 junctions were unaffected in antibiotic treated mice during E. faecium colonization or in untreated animals. E. faecium was capable to colonize the mouse colon already within 6 hr after inoculation, and agglutinated at the apical side of the intestinal epithelium. During the primary stage of gastrointestinal colonization the number of IgA+ cells and CD11b+ IgA+ cells increased in the lamina propria of the colon and mediated an elevated IgA response upon E. faecium colonization. PMID- 29484837 TI - Elevated GLUT4 and glycogenin protein abundance correspond to increased glycogen content in the soleus muscle of mdx mice with no benefit associated with taurine supplementation. AB - Duchenne muscular dystrophy (DMD) patients and the dystrophic mdx mouse have an elevated demand for ATP requiring processes, including Ca2+ regulation and skeletal muscle regeneration. As a key substrate for cellular ATP production, altered glycogen metabolism may contribute significantly to dystrophic pathology and explain reports of mild glucose intolerance. We compare the soleus and extensor digitorum longus (EDL) muscles of the mdx mouse during active muscle necrosis (at 28 days) and at 70 days where pathology is stable. We further investigate the impact of taurine (tau) on dystrophic glycogen metabolism to identify if the benefit seen with tau in a previous study (Barker et al. ) was in part owed to altered glycogen handling. The soleus muscle of 28- and 70-day-old mdx mice had elevated glucose transporter type 4 (GLUT4), glycogenin protein abundances and glycogen content compared to WT (C57BL10/ScSn) controls. Mdx tau mice exhibited modestly reduced glycogen compared to their respective mdx group. The EDL muscle of 28 days mdx tau mice had a ~70% increase in glycogenin protein abundance compared to the mdx but 50% less glycogen content. A twofold greater phosphorylated glycogen synthase (p-GS) and glycogen phosphorylase (p-GP) protein abundance was observed in the 70-day-old mdx soleus muscle than in the 28-day-old mdx soleus muscle. Glycogen debranching enzyme (GDE) protein abundance was elevated in both 28- and 70-day-old mdx soleus muscles compared to WT controls. We identified an increase in proteins associated with glucose uptake and utilization specific to the predominantly slow-twitch soleus muscle of mdx mice regardless of age and that taurine affords no obvious benefit to glycogen metabolism in the mdx mouse. PMID- 29484838 TI - Efficacy, cost effectiveness, and sustainability of a pediatric high risk asthma clinic. AB - AIM: At our institution, a pediatric High Risk Asthma clinic has been in operation for over 15 years, targeting children with poorly controlled, and difficult to treat asthma. This study evaluates the outcomes and cost effectiveness of the High Risk Asthma clinic from 2000 through 2014. METHODS: A retrospective chart review was performed on all patients entering High Risk Asthma clinic from 2000-2014, and total hospitalizations and Emergency Department visits were tallied for the year prior to entering clinic and the year after. Costs incurred, and reimbursements obtained from payors were tallied to determine cost-effectiveness and sustainability. RESULTS: Consistent decreases in hospitalizations (51.2% decrease, P < 0.001) and Emergency Department visits (23.0% decrease, P = 0.048) were seen for patients entering High Risk Asthma clinic, with commensurate significant decreases in related costs. Reimbursements received for outpatient services were sufficient to offset operational costs of the High Risk Asthma clinic, when both clinic visit, and pulmonary function testing charges were included. CONCLUSIONS: A pediatric High Risk Asthma clinic model is efficacious in decreasing hospitalizations and Emergency Department visits for a difficult to treat population, and such a model can be cost effective and sustainable. PMID- 29484839 TI - Microbial diversity in biodeteriorated Greek historical documents dating back to the 19th and 20th century: A case study. AB - Paper documents in archives, libraries, and museums often undergo biodeterioration by microorganisms. Fungi and less often bacteria have been described to advance paper staining, so called "foxing" and degradation of paper substrates. In this study, for the first time, the fungal and bacterial diversity in biodeteriorated paper documents of Hellenic General State Archives dating back to the 19th and 20th century has been assessed by culture-dependent and independent methods. The internally transcribed spacer (ITS) region and 16S rRNA gene were amplified by PCR from fungal and bacterial isolates and amplicons were sequenced. Sequence analysis and phylogeny revealed fungal phylotypes like Penicillium sp., Cladosporium sp., Penicillium citrinum, Alternaria infectoria, Alternaria alternata, Epicoccum nigrum, and Penicillium chrysogenum which are often implicated in paper deterioration. Bacterial phylotypes closely related to known biodeteriogenic bacteria such as Bacillus spp., Micrococcus spp., Kocuria sp. in accordance with previous studies were characterized. Among the fungal phylotypes described in this study are included well-known allergens such as Penicillium spp., Alternaria spp., and Cladosporium spp. that impose a serious health threat on staff members and scholars. Furthermore, fungal isolates such as Chalastospora gossypii and Trametes ochracea have been identified and implicated in biodeterioration of historical paper manuscripts in this study for the first time. Certain new or less known fungi and bacteria implicated in paper degradation were retrieved, indicating that particular ambient conditions, substrate chemistry, or even location might influence the composition of colonizing microbiota. PMID- 29484840 TI - NF-kappaB/p53-activated inflammatory response involves in diquat-induced mitochondrial dysfunction and apoptosis. AB - Inflammation generated by environmental toxicants including pesticides could be one of the factors underlying neuronal cell damage in neurodegenerative diseases. In this study, we investigated the mechanisms by which inflammatory responses contribute to apoptosis in PC12 cells treated with diquat. We found that diquat induced apoptosis, as demonstrated by the activation of caspases and nuclear condensation, inhibition of mitochondrial complex I activity, and decreased ATP level in PC12 cells. Diquat also reduced the dopamine level, indicating that cell death induced by diquat is due to cytotoxicity of dopaminergic neuronal components in these cells. Exposure of PC12 cells to diquat led to the production of reactive oxygen species (ROS), and the antioxidant N-acetyl-cystein attenuated the cytotoxicity of caspase-3 pathways. These results demonstrate that diquat induced apoptosis is involved in mitochondrial dysfunction through production of ROS. Furthermore, diquat increased expression of cyclooxygenase-2 (COX-2) and tumor necrosis factor-alpha (TNF-alpha) via inflammatory stimulation. Diquat induced nuclear accumulation of NF-kappaB and p53 proteins. Importantly, an inhibitor of NF-kappaB nuclear translocation blocked the increase of p53. Both NF kappaB and p53 inhibitors also blocked the diquat-induced inflammatory response. Pretreatment of cells with meloxicam, a COX-2 inhibitor, also blocked apoptosis and mitochondrial dysfunction. These results represent a unique molecular characterization of diquat-induced cytotoxicity in PC12 cells. Our results demonstrate that diquat induces cell damage in part through inflammatory responses via NF-kappaB-mediated p53 signaling. This suggests the potential to generate mitochondrial damage via inflammatory responses and inflammatory stimulation-related neurodegenerative disease. PMID- 29484841 TI - New indices of arterial stiffness measured with an upper-arm oscillometric device in active versus inactive women. AB - Arterial velocity pulse index (AVI) and arterial pressure-volume index (API), new indicators of arterial stiffness, are risk factors for the development of cardiovascular disease. Regular aerobic exercise decreases arterial stiffness. In fact, pulse wave velocity (PWV), index of arterial stiffness, is lower in endurance-trained than in untrained young adults. However, the effect of regular aerobic exercise on AVI and API remains unknown. This study investigates the effect of regular aerobic exercise on AVI and API, new indicators of arterial stiffness. We gathered data from 18 recreationally active females (active group, age: 18 +/- 1 years, 2 +/- 2 h/week, 3 +/- 2 times/week, >=2 years of aerobic endurance training) and 18 recreationally inactive females (inactive group, age: 18 +/- 1 years, >=2 years without such training) in a cross-sectional study. Height, body weight, body mass index, AVI, API, brachial blood pressure, heart rate, and 20-m multistage shuttle run test were measured in a quiet room at a temperature between 24 degrees C and 25 degrees C. AVI and API were lower in the active group than in the inactive group (P < 0.01). Number of 20-m shuttles was negatively correlated with AVI (P < 0.01, r = -0.8) and API (P < 0.01, r = -0.8). These results suggest that regular aerobic exercise training decreases AVI and API in young females. PMID- 29484843 TI - Clinical trial in China: The status and challenge of data management and statistical analysis. PMID- 29484842 TI - Quantitative Systems Pharmacology Analysis of KRAS G12C Covalent Inhibitors. AB - KRAS has proven difficult to target pharmacologically. Two strategies have recently been described for covalently targeting the most common KRAS mutant in lung cancer, KRAS G12C. Previously, we developed a computational model of the processes that regulate Ras activation. Here, we use this model to investigate KRAS G12C covalent inhibitors. We updated the model to include Ras protein turnover, and validation demonstrates that our model performs well in areas of G12C targeting where conventional wisdom struggles. We then used the model to investigate possible strategies to improve KRAS G12C inhibitors and identified GEF loading as a mechanism that could improve efficacy. Our simulations also found resistance-promoting mutations may reverse which class of KRAS G12C inhibitor inhibits the system better, suggesting that there may be value to pursuing both types of KRAS G12C inhibitors. Overall, this work demonstrates areas in which systems biology approaches can inform Ras drug development. PMID- 29484844 TI - The BPSC: A prospective study investigating the clinical effect of interventional therapy and the risk factors for bladder cancer and benign prostatic hyperplasia in Chinese population. AB - Bladder cancer and benign prostatic hyperplasia have been two very common diseases among the elderly men, especially with the aging of the population in the world. We have designed a study to investigate the clinical effect of interventional therapy for plasmakinetic resection of the prostate and plasmakinetic resection of the bladder, which is called "BPSC" (The bladder cancer and benign prostatic hyperplasia study in Chinese population). The BPSC is not only a specific study, it is made up of many studies. In this article, we introduced the research background, source, name, study framework, study management and further direction of BPSC project. We hope this process will contribute to the growth of the database through sharing data and enriching the evidence of bladder cancer and benign prostatic hyperplasia in the Chinese population, thereby finally improving the accessibility of these important findings for doctors, researchers, and patients. PMID- 29484845 TI - Cochrane in 2017: Opportunities for the research community in China. PMID- 29484846 TI - The habit cough: Diagnosis and treatment. PMID- 29484847 TI - Lung epithelial-specific TRIP-1 overexpression maintains epithelial integrity during hyperoxia exposure. AB - The onset and degree of injury occurring in animals that develop hyperoxic acute lung injury (HALI) is dependent on age at exposure, suggesting that developmentally regulated pathways/factors must underlie initiation of the epithelial injury and subsequent repair. Type II TGFbeta receptor interacting protein-1 (TRIP-1) is a negative regulator of TGFbeta signaling, which we have previously shown is a developmentally regulated protein with modulatory effects on epithelial-fibroblastic signaling. The aim of this study was to assess if type II alveolar epithelial cells overexpressing TRIP-1 are protected against hyperoxia-induced epithelial injury, and in turn HALI. Rat lung epithelial cells (RLE) overexpressing TRIP-1 or LacZ were exposed to 85% oxygen for 4 days. A surfactant protein C (SPC)-driven TRIP-1 overexpression mouse (TRIP-1AECTg+ ) was generated and exposed to hyperoxia (>95% for 4 days) at 4 weeks of age to assess the effects TRIP-1 overexpression has on HALI. RLE overexpressing TRIP-1 resisted hyperoxia-induced apoptosis. Mice overexpressing TRIP-1 in their lung type II alveolar epithelial cells (TRIP-1AECTg+ ) showed normal lung development, increased phospho-AKT level and E-cadherin, along with resistance to HALI, as evidence by less TGFbeta activation, apoptosis, alveolar macrophage influx, KC expression. Taken together, these findings point to existence of a TRIP-1 mediated molecular pathway affording protection against epithelial/acute lung injury. PMID- 29484848 TI - Treatment of severe bronchiolitis: A survey of Canadian pediatric intensivists. AB - OBJECTIVE: To describe management practices and the factors guiding admission and treatment decisions for viral bronchiolitis across Canadian pediatric intensive care units (PICUs). DESIGN: Cross-sectional survey. SETTING: Canadian PICUs. SUBJECTS: Pediatric intensivists. MEASUREMENTS AND MAIN RESULTS: A survey using two case scenarios (non-intubated vs intubated patients) was developed using focus groups and a literature review. We analyzed our results using descriptive statistics and multivariate logistic regression. Our response rate was 55% (57/103). Regarding bronchiolitis management, 75% (42/56) of respondents would use inhaled therapies, with nebulized epinephrine (33/56, 59%) and salbutamol (20/56, 36%) being the most common. Antibiotic use within the first hour of admission to PICU almost doubled in frequency (36% vs 71%) in patients who required mechanical ventilation (p 0.0004). High flow nasal cannula (HFNC; 32/56, 57%) and continuous positive airway pressure (CPAP; 16/56, 29%) were the preferred modes of non-invasive ventilation (NIV). CONCLUSION: The management of severe viral bronchiolitis is similar across Canadian PICUs. The use of NIV, inhaled treatments, and antibiotics is frequent, which differs from the recommendations made by published guidelines. Canadian pediatric intensivists use homogeneous PICU admission criteria based on patients' characteristics and severity of the clinical picture. Clinical practice guidelines for children with viral bronchiolitis should address the management of patients with severe clinical disease. PMID- 29484849 TI - Resilience training is just a band-aid solution for doctor well-being: Yes. PMID- 29484850 TI - Genetic variations on SETD5 underlying autistic conditions. AB - The prevalence of autism spectrum disorders (ASD) and the number of identified ASD-related genes have increased in recent years. The SETD5 gene encodes a SET containing-domain 5 protein, a likely reader enzyme. Genetic evidences suggest that SETD5 malfunction contributes to ASD phenotype, such as on intellectual disability (ID) and facial dysmorphism. In this review, we mapped the clinical phenotypes of individuals carrying mutations on the SETD5 gene that are associated with ASD and other chromatinopathies (mutation in epigenetic modifiers that leads to the development of neurodevelopmental disorders such as ASD). After a detailed systematic literature review and analysis of public disease-related databank, we found so far 42 individuals carrying mutations on the SETD5 gene, with 23.8% presenting autistic-like features. Furthermore, most of mutations occurred between positions 9,480,000-9,500,000 bp on chromosome 3 (3p25.3) at the SETD5 gene locus. In all males, mutations in SETD5 presented high penetrance, while in females the clinical phenotype seems more variable with two reported cases showing normal female carriers and not presenting ASD or any ID-like symptoms. At the molecular level, SETD5 interacts with proteins of PAF1C and N CoR complexes, leading to a possible involvement with chromatin modification pathway, which plays important roles for brain development. Together, we propose that mutations on the SETD5 gene could lead to a new syndromic condition in males, which is linked to 3p25 syndrome, and can leads to ASD-related intellectual disability and facial dysmorphism. (c) 2018 Wiley Periodicals, Inc. Develop Neurobiol 78: 500-518, 2018. PMID- 29484851 TI - Validation of the Mandarin Chinese version of the Leicester Cough Questionnaire in non-small cell lung cancer patients after surgery. AB - BACKGROUND: There are no validated and reliable cough-specific instruments to assess health-related quality of life with respect to postoperative cough in non small cell lung cancer (NSCLC) patients. We used the Leicester Cough Questionnaire in Mandarin-Chinese (LCQ-MC) and investigated the validity, reliability, and repeatability of this instrument. METHODS: A total of 130 NSCLC patients (average age 58.75 +/- 9.43 years, 65 men, 65 women) completed the LCQ MC, cough Visual Analogue Scale (VAS), Cough Symptom Score (CSS), Hospital Anxiety and Depression Scale (HADS), and Medical Outcomes Study 36-item Short Form Health Survey (SF-36). Forty patients completed the LCQ-MC again one week later. Concurrent validity, internal consistency, and repeatability were assessed. RESULTS: Analyses of concurrent validity showed significant correlations between the LCQ-MC and the cough VAS (r = -0.488 to -0.660) and CSS (r = -0.495 to -0.601). The corresponding domains of the LCQ-MC and the SF-36 exhibited moderate correlations (r = 0.421-0.432). However, there was no significant correlation between the LCQ-MC and the HADS (P > 0.05). Internal consistency was acceptable (Cronbach's alpha of 0.74-0.90). Test-retest reliability was high (intraclass correlation coefficients of 0.89-0.95). CONCLUSION: The LCQ-MC is a reliable, valid instrument for assessing postoperative cough in NSCLC patients. PMID- 29484852 TI - Skeletal muscle fiber-type-specific changes in markers of capillary and mitochondrial content after low-volume interval training in overweight women. AB - High-intensity interval training (HIIT) enhances skeletal muscle oxygen delivery and utilization but data are limited regarding fiber-specific adaptations in humans. We examined the effect of 18 sessions of HIIT (10 * 60-sec cycling intervals at ~90% HRmax , interspersed by 60-sec of recovery) over 6 weeks on markers of microvascular density and oxidative capacity in type I and II fibers in healthy but sedentary young women (Age: 26 +/- 7 years; BMI: 30 +/- 4 kg.m-2 ; VO2peak : 2.16 +/- 0.45 L.m-1 ). Immunohistochemical analyses of muscle cross sections revealed a training-induced increase in capillary contacts per fiber in type I fibers (PRE: 4.38 +/- 0.37 vs. POST: 5.17 +/- 0.80; main effect, P < 0.05) and type II fibers (PRE: 4.24 +/- 0.55 vs. POST: 4.92 +/- 0.54; main effect, P < 0.05). The capillary-to-fiber ratio also increased after training in type I fibers (PRE: 1.53 +/- 1.44 vs. POST: 1.88 +/- 0.38; main effect, P < 0.05) and type II fibers (PRE: 1.45 +/- 0.19 vs. POST: 1.76 +/- 0.27; main effect, P < 0.05). Muscle oxidative capacity as reflected by the protein content of cytochrome oxidase IV also increased after training in type I fibers (PRE: 3500 +/- 858 vs. POST: 4442 +/- 1377 arbitrary units; main effect, P < 0.01) and type II fibers (PRE: 2632 +/- 629 vs. POST: 3863 +/- 1307 arbitrary units; main effect, P < 0.01). We conclude that short-term HIIT in previously inactive women similarly increases markers of capillary density and mitochondrial content in type I and type II fibers. PMID- 29484853 TI - Impulse oscillometry at preschool age is a strong predictor of lung function by flow-volume spirometry in adolescence. AB - BACKGROUND: The transition from early childhood wheezing to persistent asthma is linked to lung function impairment over time. Little is known how the methods used to study lung function at different ages correlate longitudinally. METHODS: Sixty-four children with a history of hospitalization for bronchiolitis before 6 months of age were prospectively studied with impulse oscillometry (IOS) at the mean age of 6.3 years and these preschool IOS results were compared with flow volume spirometry (FVS) measurements at mean age of 11.4 years. RESULTS: The baseline respiratory system resistance at 5 Hz (Rrs5) showed a modest statistically significant correlation with all baseline FVS parameters except FVC. The post-bronchodilator (post-BD) Rrs5 showed a modest statistically significant correlation with post-BD FEV1 and FEV1 /FVC. The bronchodilator induced decrease in Rrs5 showed a modest statistically significant correlation with the percent increase in FEV1 . Baseline and post-BD respiratory reactance at 5 Hz (Xrs5) showed a modest statistically significant correlation with baseline and post-BD FVS parameters except post-BD FEV1 /FVC, respectively, and post-BD Xrs5 showed a strong correlation with post-BD FVC (rho = 0.61) and post-BD FEV1 (rho = 0.59). In adjusted linear regression, preschool Xrs5 remained as a statistically significant independent predictor of FVS parameters in adolescence; the one-unit decrease in the Z-score of preschool post-BD Xrs5 predicted 9.6% lower post-BD FEV1 , 9.3% lower post-BD FVC, and 9.7% lower post-BD MEF50 when expressed as %-predicted parameters. CONCLUSION: Persistent post-BD small airway impairment in children with a history of bronchiolitis detected with IOS at preschool age predicted FVS results measured in early adolescence. PMID- 29484854 TI - Microbial dynamics during harmful dinoflagellate Ostreopsis cf. ovata growth: Bacterial succession and viral abundance pattern. AB - Algal-bacterial interactions play a major role in shaping diversity of algal associated bacterial communities. Temporal variation in bacterial phylogenetic composition reflects changes of these complex interactions which occur during the algal growth cycle as well as throughout the lifetime of algal blooms. Viruses are also known to cause shifts in bacterial community diversity which could affect algal bloom phases. This study investigated on changes of bacterial and viral abundances, bacterial physiological status, and on bacterial successional pattern associated with the harmful benthic dinoflagellate Ostreopsis cf. ovata in batch cultures over the algal growth cycle. Bacterial community phylogenetic structure was assessed by 16S rRNA gene ION torrent sequencing. A comparison between bacterial community retrieved in cultures and that one co-occurring in situ during the development of the O. cf. ovata bloom from where the algal strain was isolated was also reported. Bacterial community growth was characterized by a biphasic pattern with the highest contributions (~60%) of highly active bacteria found at the two bacterial exponential growth steps. An alphaproteobacterial consortium composed by the Rhodobacteraceae Dinoroseobacter (22.2%-35.4%) and Roseovarius (5.7%-18.3%), together with Oceanicaulis (14.2-40.3%), was strongly associated with O. cf. ovata over the algal growth. The Rhodobacteraceae members encompassed phylotypes with an assessed mutualistic-pathogenic bimodal behavior. Fabibacter (0.7%-25.2%), Labrenzia (5.6%-24.3%), and Dietzia (0.04%-1.7%) were relevant at the stationary phase. Overall, the successional pattern and the metabolic and functional traits of the bacterial community retrieved in culture mirror those ones underpinning O. cf. ovata bloom dynamics in field. Viral abundances increased synoptically with bacterial abundances during the first bacterial exponential growth step while being stationary during the second step. Microbial trends also suggest that viruses induced some shifts in bacterial community composition. PMID- 29484855 TI - Paternal high-fat diet enhances offspring whole-body insulin sensitivity and skeletal muscle insulin signaling early in life. AB - Evidence suggests that paternal diet can predispose offspring to metabolic dysfunction. Despite this knowledge, little is known regarding the effects of paternal high-fat feeding on offspring insulin sensitivity. The purpose of this study was to investigate for the first time the effects of paternal high-fat feeding on whole-body and skeletal muscle insulin action in young and adult offspring. At 4 weeks of age, founder C57BL6/N males (F0) were fed a high-fat diet or control diet for 12 weeks and then bred with females on a control diet. Offspring (F1) were euthanized at 6 weeks, 6 months, or 12 months and insulin stimulated insulin signaling was measured ex vivo in isolated soleus muscle. At 6 weeks of age, paternal high fat offspring (HFO) had enhanced whole-body insulin sensitivity (35%, P < 0.05), as well as, increased insulin-stimulated skeletal muscle phosphorylation of Akt threonine 308 (70%, P < 0.05) and AS160 threonine 642 (80%, P < 0.05) compared to paternal control fed offspring (CFO), despite both offspring groups consuming standard chow. At 6 months of age, HFO had increased percent body fat compared to CFO (74%, P < 0.005) and whole-body and skeletal muscle insulin signaling normalized to CFO. Body fat was inversely related with insulin signaling in HFO, but not CFO. These findings suggest that paternal high-fat feeding contributes to enhanced whole-body and skeletal muscle insulin sensitivity in HFO early in life; however, these benefits are lost by early adulthood, potentially due to premature increases in body fat. PMID- 29484856 TI - Degenerate-disc Infection Study with Contaminant Control: Discussion on the Research Methods. AB - OBJECTIVE: The role of bacterial infection in the causation of disc degeneration and its consequences is controversial. The current evidence is limited to underpowered studies, with the majority of such studies having only an internal contaminant arm, and only one study having a control arm with a non-degenerate disc population. The Degenerate-disc Infection Study with Contaminant Control (DISC) study includes a control arm and an internal contaminant control to resolve these shortcomings. METHODS: The study is designed as a case-control study: cases are patients undergoing surgery for degenerated disc pathology and controls are patients undergoing surgery for non-degenerate pathology, such as trauma, scoliosis or tumor cases. RESULTS: This study is part of a multi-centric trial involving six spine centers with 15 spine surgeons contributing. The DISC study methodology, rationale and controversies are presented here. The predominant issue is how to interpret contamination. We present our algorithm for the DISC study to address this. For disc samples that are positive concurrently with positive paraspinal tissue sample, the result will be interpreted as contamination. For positive disc samples with a negative paraspinal tissue culture result, the interpretation of this result will be infection. If cultures for both disc sample and paraspinal tissue sample are negative, then the result is interpreted as non-infected. If the disc culture is negative but paraspinal tissue culture is positive, then it is treated as a contaminant. CONCLUSIONS: Future large-scale studies are required with a good control arm, a contamination arm, and histopathological correlations. PMID- 29484857 TI - Biomechanical Analysis of a Novel Intercalary Prosthesis for Humeral Diaphyseal Segmental Defect Reconstruction. AB - OBJECTIVE: To study the biomechanical properties of a novel modular intercalary prosthesis for humeral diaphyseal segmental defect reconstruction, to establish valid finite element humerus and prosthesis models, and to analyze the biomechanical differences in modular intercalary prostheses with or without plate fixation. METHODS: Three groups were set up to compare the performance of the prosthesis: intact humerus, humerus-prosthesis and humerus-prosthesis-plate. The models of the three groups were transferred to finite element software. Boundary conditions, material properties, and mesh generation were set up for both the prosthesis and the humerus. In addition, 100 N or 2 N.m torsion was loaded to the elbow joint surface with the glenohumeral joint surface fixed. Humeral finite element models were established according to CT scans of the cadaveric bone; reverse engineering software Geomagic was used in this procedure. Components of prosthetic models were established using 3-D modeling software Solidworks. To verify the finite element models, the in vitro tests were simulated using a mechanical testing machine (Bionix; MTS Systems Corporation, USA). Starting with a 50 N preload, the specimen was subjected to 5 times tensile (300 N) and torsional (5 N.m) strength; interval time was 30 min to allow full recovery for the next specimen load. Axial tensile and torsional loads were applied to the elbow joint surface to simulate lifting heavy objects or twisting something, with the glenohumeral joint surface fixed. RESULTS: Stress distribution on the humerus did not change its tendency notably after reconstruction by intercalary prosthesis whether with or without a plate. The special design which included a plate and prosthesis effectively diminished stress on the stem where aseptic loosening often takes place. Stress distribution major concentrate upon two stems without plate addition, maximum stress on proximal and distal stem respectively diminish 27.37% and 13.23% under tension, 10.66% and 11.16% under torsion after plate allied. CONCLUSION: The novel intercalary prosthesis has excellent ability to reconstruct humeral diaphyseal defects. The accessory fixation system, which included a plate and prosthesis, improved the rigidity of anti-tension and anti torsion, and diminished the risk of prosthetic loosening and dislocation. A finite element analysis is a kind of convenient and practicable method to be used as the confirmation of experimental biomechanics study. PMID- 29484858 TI - [AN EDUCATIONAL INTERVENTION TO REDUCE THE RATE OF CONTAMINANTS IN BLOOD CULTURES AND IMPROVE APPROPRIATE ANTIBIOTIC TREATMENT]. AB - INTRODUCTION: Blood cultures' contamination (BCC) is associated with unnecessary processing of cultures, higher cost, and occasionally, unjustified antibiotic treatment. We aimed to reduce the rate of BCC by educational intervention. In parallel, we also strove to expand the use of aminoglycosides (AMG) and reduce the utilization of beta-lactam antibiotics. The rate of BCC was assessed prospectively in the study department - the Emergency Department (ED) and in control departments - Medical Departments A, B and Geriatrics. Data was collected continuously during the study period and educational interventions were performed in the ED but not in the control departments. The intervention included meetings with ED staff, emphasizing proper blood culture collection technique, and post intervention result updates. The utilization of AMG was encouraged in cases of suspected gram-negative bacteremia. The empirical and definitive antibiotic regimen was assessed. During the study period, a 30% decrease in BCC rate [33/564 (5.9%) to 30/734 (4.1%), p=0.143] was noted in the study department whereas a small increase in BCC rate was noted in the control departments. Logistic regression analysis revealed significantly different trends in BCC rate between the study and control departments (p<0.001). Additionally, an increase in AMG utilization was observed (7% to 40%) in patients with suspected gram-negative bacteremia with normal renal function (p=0.16). Educational intervention was successful in reducing the rate of BCC and in parallel, increasing the utilization of AMG. Repeat and frequent interventions are required to maintain such achievements. PMID- 29484859 TI - [FETAL WEIGHT CHARTS IN THE ISRAELI POPULATION]. AB - BACKGROUND: Sonographic estimated fetal weight is performed by measuring the fetal organs' biometry and introducing the data into a formula. The calculated value is then compared with reference charts and serves as a critical component in pregnancy follow-up. Ideally the charts should be appropriate to the specific population. OBJECTIVES: To display and validate sonographic based Israeli matched, intrauterine fetal weight curves. METHODS: The international Hadlock and Souka formulas, were chosen and assessed using over 70,000 ultrasound examinations from Israel. Since the Souka formula is appropriate only after 30 weeks of pregnancy, we used Hadlock's formula for pregnancies under 30 weeks and the comparison between the Hadlock and Souka formulas was made thereafter. In order to evaluate the Israeli population charts, 6389 pregnant women were examined sonographically in the last three days of pregnancy, and the estimated fetal weights were compared with the actual newborn weights. RESULTS: Fetal weight charts were constructed. Both equations were efficient, but the combination of Hadlock formula until 30 weeks and Souka between 31 to 42 weeks tended to be more accurate. CONCLUSIONS: We described fetal weight charts based on common equations, using biometric measurements derived from the Israeli population. We recommend the charts presented here as the universal reference for all the professionals involved in perinatal care in Israel. DISCUSSION: Fetal growth abnormalities are determined by the curve chosen. Birthweight curves may underdiagnose restrictions in fetal growth because of the disorders associated with preterm delivery. Sonographic biometric curves represent physiological growth more reliably. PMID- 29484860 TI - [COPING WITH DEPRESSION AND ANXIETY AMONG HEART FAILURE PATIENTS]. AB - BACKGROUND: Research shows that high levels of depression and anxiety have a negative effect on the quality of life of people with heart failure. Family and social support are an important source for coping with the emotional distress derived from an illness. It is important to reach a deeper understanding about the relationship between family and social support and levels of depression and anxiety among heart failure patients. OBJECTIVES: To examine the associations between function, social support, depression and anxiety among heart failure patients. METHODS: A total of 50 heart failure patients from the hospital day unit of the Cardiovascular Department in Rambam Healthcare Center answered a structured questionnaire that included measures of depression and anxiety and levels of difficulty in function, family and social support. RESULTS: A total of 15% (n=7) of the participants reported a high level of anxiety and 33% (n=16) reported a high level of depression. The average score for difficulty in functioning was high on a scale of 1-12 (mean=7.16; SD=2.86). The average score on family support was also high on a scale of 1-7 (Mean=6.21;SD=1.14) but social support was very low (mean=3.20; SD=2.06). Positive associations were found between difficulty in functioning, depression (r=.54) and anxiety (r=.39) and a negative association was found between social and family support and anxiety (r= .30). CONCLUSIONS: Heart failure patients and their families might experience functional and emotional burdens when trying to cope with their illness. Early and inclusive intervention is important and should include combined treatment of both physicians and social workers cooperating in order to identify patients in need and treat the different aspects of the illness in a sensitive and culturally adapted manner. PMID- 29484861 TI - [STEVENS-JOHNSON SYNDROME AND TOXIC EPIDERMAL NECROLYSIS AS A PARA-NEOPLASTIC SYNDROME FOR B-CELL LYMPHOMA]. PMID- 29484862 TI - [SCARPA FASCIA AND ABDOMINAL WALL DEEP ADIPOSE COMPARTMENT PRESERVATION IN ABDOMINOPLASTY - CURRENT CLINICAL AND ANATOMICAL REVIEW]. AB - INTRODUCTION: During the last two decades, in parallel to the increased prevalence of bariatric procedures, there has been a marked increase in the prevalence of abdominoplasty surgery in the United States, and in accordance an increase in the scientific and clinical research related to all aspects of this technique. The most common complication of abdominoplasty is the formation of post-operative seroma. Various theories have been raised regarding the pathophysiology of seroma formation, and numerous methods for seroma prevention have been employed and tested. In the early 90's, a new theory argued that post operative seroma formation is secondary to damage caused to the abdominal wall's lymphatic drainage during flap undermining. In light of this theory, a new surgical technique was suggested to execute the flap undermining in a more superficial plane. This enabled the preservation of the scarpa fascia and the deep adipose compartment, which preserved the integrity of the abdominal wall lymphatic collectors. This method was successful in reducing the rate of postoperative seroma formation. Recent studies have shed new light on the anatomy of the abdominal lymphatic collectors, pathophysiology of seroma formation and methods of its prevention. This new data undermines the foundations of the scarpa fascia preservation theory, and the surgical technique that was derived from it. A new theory that tries to settle the contradiction between the clinical success of the technique in reducing seromas and the new findings regarding abdominal wall's lymphatic collectors anatomy, is the presence of a 'sticky interface' between the deep adipose compartment and the flap. PMID- 29484863 TI - [DYSMENORRHEA - ITS PREVALENCE, CAUSES, INFLUENCE ON THE AFFECTED WOMEN AND POSSIBLE TREATMENTS]. AB - INTRODUCTION: Dysmenorrhea is a common condition among young menstruating women. It is defined as menstrual pains, which sometimes, may be so severe, as to completely cripple the affected woman in every aspect of her daily function. Dysmenorrhea may further cause female infertility problems. This disease is divided into two forms: primary - where no accompanying pelvic pathology is found, and secondary - where pelvic pathology is demonstrated. The most prevalent cause of the latter form is endometriosis. Treatment comprises of medication, such as NSAIDs or various hormonal preparations or several methods of complementary medicine, as well as surgery. Generally, medical and complementary forms of treatment have been found effective in alleviating the pain, while surgery was found effective in treating infertility. Dysmenorrhea, in general, and endometriosis, in particular, has a further immense financial burden on society - both in terms of medical cost, as well as absence from studies or work by young women. To date, no absolute effective treatment, in terms of pain prevention or long standing fertility preservation, has been found. PMID- 29484864 TI - [DEVELOPMENT AND CHALLENGES IN TREATMENT OF UVEAL MELANOMA]. AB - INTRODUCTION: Uveal melanoma, the most common primary intraocular malignancy in adults, is potentially a lethal tumour. Since the development of local radiotherapy, tumour control is achieved in the majority of cases and most eyes are salvaged. Despite this, more than 50% of patients develop distant metastatic spread, mainly to the liver, and in the absence of efficient treatments to extend life, die soon after. A great deal of effort has been put into developing prognostic markers for metastatic spread and survival. Novel genetic prognostic tests, recently introduced, are now being clinically used in many ocular oncology centres worldwide. In addition, in most centres, patients are referred for systemic surveillance programs for early detection of liver metastasis. Novel treatment modalities to battle metastatic uveal melanoma are being developed and used in clinical trials. Their efficacy is yet to be proved. This review summarizes the recent developments and current challenges related to uveal melanoma management. PMID- 29484865 TI - [THE RELATIONSHIP BETWEEN INJURIES, SHOES AND STYLE IN THE RUNNER'S POPULATION]. AB - INTRODUCTION: We are now standing four decades after the 'running revolution' which occurred during the 70's of the previous century. Despite the developments that have occurred in medicine and the large budgets invested in the development of the sport's equipment, the runner's morbidity has not changed. In this article, we would like to review the changes in running that occurred throughout the years, as well as the common risk factors for running injuries. Furthermore, we would like to examine the scientific point of view regarding running shoes and running technique as risk factors for running injuries. A new trend, the "minimalist running", characterized by a unique technique and rigid shod might be the "game changer" in diminishing the injury rates in runners. Note, that minimalist running is not yet a common technique and thus, we might encounter a new set of injuries which we still have to evaluate. PMID- 29484866 TI - [MALLET FINGER - DIAGNOSIS, CLASSIFICATION AND TREATMENT]. AB - INTRODUCTION: Mallet finger is a common injury involving the extensor mechanism of the finger. It presents as an inability to extend the distal phalanx of the digit. In the right clinical setting, a thorough examination should be performed and supplemented by adequate radiographs. The mechanism of injury is usually a direct blow to an extended finger causing hyperflexion or hyperextension of the distal phalanx. Common occurrences are in young adults during sporting activities or in minor falls or trauma in osteoporotic individuals. Treatment includes use of a splint which maintains the distal phalanx in extension allowing for tendon healing or surgical intervention when indicated. In the vast majority of cases, prompt diagnosis and avid conservative treatment will result in a good outcome. Neglecting or missing this seemingly minor injury may result in a formidable functional handicap. PMID- 29484867 TI - [NEUROSURGICAL INTERVENTIONS FOR INTRACTABLE ONCOLOGICAL PAIN]. AB - INTRODUCTION: Pain is one of the most common symptoms among cancer patients, and particularly in those who suffer from metastatic or terminal disease. There is great importance in delivering good pain management to these patients in order to alleviate their suffering, improve their functional status and their overall quality of life. In most cases, pain management is based on pharmacotherapy with opioids and other medications. However, there are selected patients for whom pharmacotherapy does not achieve acceptable pain relief or is associated with marked side effects. These patients, who suffer from refractory cancer pain, may benefit from neurosurgical procedures selectively intervening in different locations along the pain signaling pathways. This article summarizes several of these neurosurgical procedures: percutaneous cordotomy for unilateral pain, punctuate midline myelotomy for visceral pain and stereotactic cingulotomy for diffuse pain syndromes. This article demonstrates the use of careful patient selection by an interdisciplinary team which is critical for the success of these procedures. The team consists of palliative care specialists, pain specialists and a neurosurgeon. These neurosurgical interventions are presented through representative clinical cases, followed by a discussion of the clinical considerations that guided the choice of the therapeutic approach for each case. PMID- 29484868 TI - [GENE THERAPY POTENTIAL AS A TREATMENT FOR HEART FAILURE]. AB - INTRODUCTION: Advances in understanding the molecular biology of heart failure, the evolution of vector technology, as well as defining the targets for therapeutic interventions has placed heart failure within the reach of gene-based therapy. During the last decade the concept of delivering cDNA encoding a therapeutic gene to failing cardiomyocytes has moved from hypothesis to the bench of preclinical applications and clinical trials. However, despite significant promise, several obstacles exist, which are described in this review. We anticipate that advances in the field will improve gene therapy in heart failure in future clinical approaches. PMID- 29484869 TI - [DIAGNOSIS AND TREATMENT OF BRONCHIECTASIS: POSITION PAPER OF THE ISRAELI PULMONOLOGY SOCIETY AND THE ISRAELI PEDIATRIC PULMONOLOGY SOCIETY]. AB - INTRODUCTION: Bronchiectasis is anatomically defined by irreversible distortion of the bronchi. Clinically, its manifestations are cough with sputum production and a predisposition to pulmonary infections. Unlike asthma and COPD, where ample clinical data are present regarding the course and effective treatment, knowledge of bronchiectasis has yet to evolve. Lately, bronchiectasis is gaining renewed attention among the medical community, with growing basic and clinical research based data. In Israel, no registered treatments exist for bronchiectasis, which makes it difficult to treat these patients. This paper is a summary of the position of the Israeli Pulmonology Association and the Israeli Pediatric Pulmonology Association for diagnosis and treatment of bronchiectasis. PMID- 29484871 TI - [Infectious Diseases of Israel]. PMID- 29484870 TI - [ENDOTHELIAL DYSFUNCTION: A POSITION PAPER OF THE ISRAEL HEART SOCIETY]. AB - INTRODUCTION: Prediction of cardiovascular adverse events is challenging. It became apparent that traditional coronary artery disease (CAD) risk factors are the cornerstones of the European 10-year CAD risk SCRORE and the Framingham score. However, despite their importance, the prediction value of general assessment tools such as the SCORE and Framingham options in an individual subject is limited, especially in young adults and women. The trend toward personalized medicine and individualized risk assessment during recent years is growing strong and various functional and imaging screening tests, including endothelial function studies, have been suggested to improve accuracy and provide the functional implications of these risk factors. Endothelial dysfunction is an early stage of atherosclerosis and has been associated with adverse cardiovascular outcome events, including myocardial infarction, stroke and death. The purpose of this position paper is to review the scientific background, methods available for assessment of endothelial function and the interpretation of test results. The current manuscript also suggest some meaningful clinical guidelines on potential integration of these tests into our practice. PMID- 29484872 TI - [Chapters in the History of Psychiatry]. PMID- 29484873 TI - [Is it safe to perform epidural anesthesia during labor in women with lumbar tattoos?] PMID- 29484874 TI - [The influence of Gluten on the Sharpness of Vision]. PMID- 29484875 TI - [Family Physicians are Busy with Administrative Issues - New Data and Call for Change]. PMID- 29484876 TI - Automated differentiation between meningioma and healthy brain tissue based on optical coherence tomography ex vivo images using texture features. AB - Brain tissue analysis is highly desired in neurosurgery, such as tumor resection. To guarantee best life quality afterward, exact navigation within the brain during the surgery is essential. So far, no method has been established that perfectly fulfills this need. Optical coherence tomography (OCT) is a promising three-dimensional imaging tool to support neurosurgical resections. We perform a preliminary study toward in vivo brain tumor removal assistance by investigating meningioma, healthy white, and healthy gray matter. For that purpose, we utilized a commercially available OCT device (Thorlabs Callisto) and measured eight samples of meningioma, three samples of healthy white, and two samples of healthy gray matter ex vivo directly after removal. Structural variations of different tissue types, especially meningioma, can already be seen in the raw OCT images. Nevertheless, an automated differentiation approach is desired, so that neurosurgical guidance can be delivered without a-priori knowledge of the surgeon. Therefore, we employ different algorithms to extract texture features and apply pattern recognition methods for their classification. With these postprocessing steps, an accuracy of nearly 98% was found. PMID- 29484877 TI - Neurologic music therapy in upper-limb rehabilitation in children with severe bilateral cerebral palsy: a randomized controlled trial. AB - BACKGROUND: After receiving neurologic music therapy, functional improvements in children with severe bilateral cerebral palsy have not been found in the literature. Musical training with instruments allows interrelationships between movement, emotions and cognition for task-based learning, in order to improve motor control. AIM: To understand whether neurologic music therapy has an impact on the functionality of children with severe cerebral palsy. DESIGN: A randomized controlled assessor-blind trial was carried out. SETTING: Children were recruited and treated in their own community center. POPULATION: Eighteen children with severe bilateral cerebral palsy between 4 and 16 years old were studied. METHODS: The intervention group (n=18) received music therapy for 16 weeks, in addition to its usual physiotherapy input. Two music therapists implemented a neurologic music therapy program of therapeutic instrumental music performance. The control group (n=9) received its usual therapeutic input, similar to the intervention group, but not neurologic music therapy. Overall and specific "Chailey levels of Ability" were quantified, as well as the Locomotor Stages. RESULTS: Significant improvements in the overall and specific "arm and hand position" as well as "activities" from the Chailey Levels of Ability and the Locomotor Stages were observed (p<.05) in the group which received the music therapy (corregir si se acepta en la editing proofs). All these improvements persisted after 4 months. The control group showed no improvements after a four-month follow-up. CONCLUSIONS: Optimized intervention of neurologic music therapy can improve the functionality of children with severe bilateral cerebral palsy. REHABILITATION IMPACT: Music therapy is a useful tool in rehabilitation and its positive effects remain four months after completing the treatment. PMID- 29484878 TI - Off-Plane Dielectric Screening of Few-Layer Graphdiyne and Its Family. AB - We performed first-principles calculations on few-layer graphdiyne (GDY) and its family, sp-sp2 hybrid carbon atomic layers, for an off-plane, static dielectric screening. The vertical dielectric constants of semiconducting GDY structures are finite and independent of the thickness. However, unlike the widely accepted wisdom that the static metallic screening is infinite, those of metallic GDY structures are finite and dependent on their thickness. Furthermore, the vertical dielectric screening can be tuned by varying the interlayer distance. We also studied the dielectric properties of heterostructures of GDY/its family; the vertical dielectric constant has an equivalent value from the two distinct values of the two distinct monostructures. The dielectric screening behaviors are well described by the uniform dielectric slab model. In addition, the band gaps can be widely tuned from 0 to 0.8 eV, by varying the thickness and electric field. Our results provide a method for engineering the dielectric constant and band gap of GDY and its family for applications of supercapacitors and nanodevices. PMID- 29484879 TI - Monitoring the Swelling Behavior of PEDOT:PSS Electrodes under High Humidity Conditions. AB - Polymer electrodes made of poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) are used in many applications but are also sensitive to humidity. We study humidity-induced changes of PEDOT:PSS electrodes as monitored with in situ time-of-flight neutron reflectivity (TOF-NR) measurements under high humidity conditions. The influence of the solvent additive Zonyl and a post-treatment of PEDOT:PSS films with ethylene glycol (EG) serving as electrodes are analyzed with respect to the swelling ratio and water uptake. Depending on the applied PEDOT:PSS treatment, PEDOT and PSS enrichment layers are clearly identified with TOF-NR at the substrate-polymer and polymer-air interface, respectively. The additive Zonyl reduces the water uptake and limits film swelling. EG post treatment further increases hydrophobicity and thereby water incorporation into the PEDOT:PSS film is strongly suppressed. The characteristic time constants and effective interaction parameters extracted from the kinetic NR data show that additive and post-treatment reduce the sensitivity of the PEDOT:PSS electrodes to humidity. PMID- 29484880 TI - Copper(II)-Mediated [11C]Cyanation of Arylboronic Acids and Arylstannanes. AB - A copper-mediated method for the transformation of diverse arylboron compounds and arylstannanes to aryl-[11C]-nitriles is reported. This method is operationally simple, uses commercially available reagents, and is compatible with a wide variety of substituted aryl- and heteroaryl substrates. This method is applied to the automated synthesis of high specific activity [11C]perampanel in 10% nondecay-corrected radiochemical yield (RCY). PMID- 29484881 TI - Rubidium Doping for Enhanced Performance of Highly Efficient Formamidinium-Based Perovskite Light-Emitting Diodes. AB - Organometal halide perovskites (OHPs) have become the most promising optoelectronic material in the past few years with a myriad of applications in the photovoltaic, light-emitting, and laser fields. However, for light-emitting applications, the low photoluminescence quantum yield (PLQY) of OHP film is critical to hinder the efficiency improvement of OHP-film-based light-emitting diodes (PeLEDs). Herein, we study the effects of rubidium incorporation on the crystal growth, structure, and photoelectric and optical properties of formamidinium-lead-bromide-based (FAPbBr3-based) perovskite films and light emission performance of PeLEDs. It is found that rubidium incorporation can significantly enhance the PLQY of FAPbBr3 film by suppressing the trap density and thus improve the withstand voltage as well as the performance of PeLEDs. When FAPbBr3 film with optimal Rb doping ratio is employed as the light emitter of PeLEDs, the maximum luminance and current efficiency is enhanced by ~10-fold and ~5-fold to 66 353 cd/m2 and 24.22 cd/A compared to the controlled device, respectively, the record performance based on FAPbBr3 PeLEDs so far. The enhanced performance can be chiefly attributed to the increase of PLQY and decrease of trap defect density of perovskite film with rubidium incorporation. Our research is expected to stimulate the development of OHPs for the next-generation lighting and display fields. PMID- 29484882 TI - Designable Immune Therapeutical Vaccine System Based on DNA Supramolecular Hydrogels. AB - Immunotherapy is believed to be an ideal method to treat cancer because it can break the immunotolerance of tumor and induce robust immunoresponse. However, constructing a wide antigen-adaptive, easy-handling, and biodegradable system that can recruit and activate antigen-presenting cells (APCs) much effectively is still a challenge. Herein, we show an injectable DNA supramolecular hydrogel vaccine (DSHV) system which could efficiently recruit and activate APCs in vitro and in vivo. The in vitro processes have been visualized by fluorescence microscopy. Through intraperitoneal or subcutaneous injection, the DSHV system can mimic the function of a lymph node where the APCs are recruited and activated by the high local concentration of cytosine-phosphate-guanine. Subsequently, strong immune response and obvious antitumor effects have been obtained. Our findings demonstrated that the DSHV system could serve as a general platform for tumor vaccination and benefit the personalized cancer therapy in the near future. PMID- 29484883 TI - Bioinspired Synthesis of Chiral 3,4-Dihydropyranones via S-to-O Acyl-Transfer Reactions. AB - A bioinspired synthesis of chiral 3,4-dihydropyranones via S-to-O acyl-transfer reactions is described. Asymmetric Michael addition-lactonization reactions of beta,gamma-unsaturated alpha-keto esters with thioesters are catalyzed by proline derived urea, providing 3,4-dihydropyranones and spiro-3,4-dihydrocoumarin-fused 3',4'-dihydropyranones in high yield (up to 94%) with excellent stereoselectivities (up to >20:1 dr, 99% ee) under catalyst loadings as low as 1 mol %. PMID- 29484885 TI - Sulfonamide-Directed Chemo- and Site-Selective Oxidative Halogenation/Amination Using Halogenating Reagents Generated in Situ from Cyclic Diacyl Peroxides. AB - The combination of cyclic diacyl peroxides with commercially available halide salts as a unique halogenating system is utilized in Hofmann-Loffler-Freytag-type reaction. This strategy allows for the formation of N-chloroamides, delta brominated products, and even biologically relevant pyrrolidines under mild conditions in moderate to excellent yields. Meanwhile, the preliminary structure of the in situ formed brominating reagent is investigated by NMR and UV/vis analysis. PMID- 29484884 TI - One-Pot Synthesis of Ginsenoside Rh2 and Bioactive Unnatural Ginsenoside by Coupling Promiscuous Glycosyltransferase from Bacillus subtilis 168 to Sucrose Synthase. AB - Ginsenosides, the major effective ingredients of Panax ginseng, exhibit various biological properties. UDP-glycosyltransferase (UGT)-mediated glycosylation is the last biosynthetic step of ginsenosides and contributes to their immense structural and functional diversity. In this study, UGT Bs-YjiC from Bacillus subtilis 168 was demonstrated to transfer a glucosyl moiety to the free C3-OH and C12-OH of protopanaxadiol (PPD) and PPD-type ginsenosides to synthesize natural and unnatural ginsenosides. In vitro assays showed that unnatural ginsenoside F12 (3- O-beta-d-glucopyranosyl-12- O-beta-d-glucopyranosyl-20( S)-protopanaxadiol) exhibited remarkable activity against diverse human cancer cell lines. A one-pot reaction by coupling Bs-YjiC to sucrose synthase (SuSy) was performed to regenerate UDP-glucose from sucrose and UDP. With PPD as the aglycon, an unprecedented high yield of ginsenosides F12 (3.98 g L-1) and Rh2 (0.20 g L-1) was obtained by optimizing the conversion conditions. This study provides an efficient approach for the biosynthesis of ginsenosides using a UGT-SuSy cascade reaction. PMID- 29484886 TI - Cascade Dehydrogenative Hydroboration for the Synthesis of Azaborabenzofulvenes. AB - Tandem dehydrogenative hydroboration has been established to be highly effective in the synthesis of BN isosteres of benzofulvene and derivatives. The scope of this synthetic method is applicable to a variety of substrates. Spectroscopic and computational studies indicate that the new azaborabenzofulvenes have similar electronic properties as their carbonaceous analogues. PMID- 29484887 TI - Synthesis of Nitrosobenzene Derivatives via Nitrosodesilylation Reaction. AB - The electrophilic ipso-substitution of trimethylsilyl-substituted benzene derivatives into nitrosobenzene derivatives is reported. The optimization of the reaction conditions was performed for moderately electron-deficient, electron rich, and sterically hindered starting materials by varying reaction time, temperature, and equivalents of NOBF4. Also, a stable intermediate of the nitrosation reaction could be characterized by 19F NMR which can be assigned to a NO+ adduct with the nitrosobenzene derivative. This complex decomposes upon aqueous workup and liberates the desired nitrosobenzene derivative. PMID- 29484888 TI - Preparation of 5-Fluoropyrazoles from Pyrazoles and N-Fluorobenzenesulfonimide (NFSI). AB - Facile synthesis of 5-fluoropyrazoles by direct fluorination of pyrazoles with N fluorobenzenesulfonimide (NFSI) was elaborated. This approach was used to prepare the unsubstituted 5-fluoro-1 H-pyrazole, the known fungicide Penflufen, and many functionalized 5-fluoropyrazoles: building blocks for medicinal chemistry and agrochemistry. PMID- 29484889 TI - Correction to The Chemical Reaction of Glutathione and trans-2-Hexenal in Grape Juice Media To Form Wine Aroma Precursors: The Impact of pH, Temperature, and Sulfur Dioxide. PMID- 29484890 TI - Novel Solid Lipid Nanoparticle with Endosomal Escape Function for Oral Delivery of Insulin. AB - Although nanoparticles (NPs) have been demonstrated as promising tools for improving oral absorption of biotherapeutics, most of them still have very limited oral bioavailability. Lyso-endosomal degradation in epithelial cells is one of the important but often-neglected physiological barriers, limiting the transport of cargoes across the intestinal epithelium. We herein reported a solid lipid nanoparticle (SLN) platform with a unique feature of endosomal escape for oral protein drug delivery. The SLNs consisted of a solid-lipid shell, which contained an endosomal escape agent (GLFEAIEGFIENGWEGMIDGWYG, HA2), and an aqueous core that is loaded with insulin (INS HA2-O-SLNs). SLNs without and with the HA2 peptide in the aqueous core (INS SLNs and INS HA2-W-SLNs, respectively) were used as the control groups. Our study showed that INS HA2-O-SLNs effectively facilitated the escape of the loaded insulin from the acidic endosomes, which preserved the biological activity of insulin to a greater extent during the intracellular transport. The spatial location of the HA2 peptide was demonstrated to determine the endosomal escape efficiency. As demonstrated in the intracellular trafficking of SLNs, INS HA2-O-SLNs displayed much less distribution in late endosomes and lysosomes. Meanwhile, insulin in INS HA2-O SLNs exhibited the highest transepithelial permeation efficiency, with 2.19 and 1.72 folds higher accumulated amount in the basolateral side as compared to that in INS SLNs and INS HA2-W-SLNs. In addition, insulin from INS HA2-O-SLNs exhibited the highest insulin permeation in various regions of small intestines. INS HA2-O-SLNs generated an excellent hypoglycemic response following oral administration in diabetic rats. Thus, such functional SLNs demonstrated a great potency for oral delivery of peptide/protein drugs. PMID- 29484891 TI - Optical Properties of Low-Loss Ag Films and Nanostructures on Transparent Substrates. AB - We demonstrate the fabrication of a low-loss single-crystalline Ag nanostructure deposited on transparent substrates. Our approach is based on an epitaxial growth technique in which a NaCl(001) substrate is used. The NaCl substrate is dissolved in water to allow the Ag film to be transferred onto the desired substrates. Focused ion beam milling is subsequently employed to pattern a nanoarray structure consisting of 200 nanorods. The epitaxial Ag films with nanoarray structures grown in the study exhibited very flat and smooth surfaces having excellent crystallinity and local misorientation of less than 1 degrees . Further, spectroscopic ellipsometry measurements indicated that the imaginary part of the dielectric constant of the single-crystalline film was smaller than that of a conventional polycrystalline film. Moreover, we used the three dimensional finite-difference time-domain method to analyze the plasmonic properties of the nanoarray structure by considering the actual processed structure. Characteristically, when the SiO2 substrate was etched by ion beam milling to a depth of 30 nm, the spectrum showed a spectral shape 20% sharper than that of the substrate with no etching (depth: 0 nm). The plasmonic performance of the single-crystalline Ag nanostructure was largely determined by its structural precision and the dielectric properties of the metal. PMID- 29484893 TI - Generalized Pustular Psoriasis Induced by Infliximab in a Patient With Inflammatory Bowel Disease. AB - The incidence of anti-tumour necrosis factor (TNF)-induced psoriasiform eruptions has ranged in the literature between 0.5% and 10.9% of patients with inflammatory bowel disease (IBD). The morphology of the rash varies, with plaque psoriasis being the most common form. Generalized pustular eruption is reported in 10.2% of cases of anti-TNF-induced psoriasis. We are reporting a unique case of anti-TNF associated psoriasiform eruption due to the severity of the rash presenting as a generalized pustular eruption in association with plaque psoriasiform rash requiring systemic therapy. PMID- 29484892 TI - Deriving Field-Based Ecological Risks for Bird Species. AB - Ecological risks (ERs) of pollutants are typically assessed using species sensitivity distributions (SSDs), based on effect concentrations obtained from bioassays with unknown representativeness for field conditions. Alternatively, monitoring data relating breeding success in bird populations to egg concentrations may be used. In this study, we developed a procedure to derive SSDs for birds based on field data of egg concentrations and reproductive success. As an example, we derived field-based SSDs for p, p'-DDE and polychlorinated biphenyls (PCBs) exposure to birds. These SSDs were used to calculate ERs for these two chemicals in the American Great Lakes and the Arctic. First, we obtained field data of p, p'-DDE and PCBs egg concentrations and reproductive success from the literature. Second, these field data were used to fit exposure-response curves along the upper boundary (right margin) of the response's distribution (95th quantile), also called quantile regression analysis. The upper boundary is used to account for heterogeneity in reproductive success induced by other external factors. Third, the species-specific EC10/50s obtained from the field-based exposure-response curves were used to derive SSDs per chemical. Finally, the SSDs were combined with specific exposure data for both compounds in the two areas to calculate the ER. We found that the ERs of combined exposure to these two chemicals were a factor of 5-35 higher in the Great Lakes compared to Arctic regions. Uncertainty in the species-specific exposure-response curves and related SSDs was mainly caused by the limited number of field exposure-response data for bird species. With sufficient monitoring data, our method can be used to quantify field-based ecological risks for other chemicals, species groups, and regions of interest. PMID- 29484895 TI - In Vivo Evaluation of Withania somnifera-Based Indian Traditional Formulation ( Amukkara Choornam), Against Chikungunya Virus-Induced Morbidity and Arthralgia. AB - Chikungunya viral fever results in extreme morbidity and arthralgia in affected individuals. Currently, modern medicines providing symptomatic relief for the acute febrile phase and the chronic arthritic phase are only options available. Traditional Indian medical system, however, uses specific formulations for treatment of this infection; one such polyherbal formulation used to treat the postpyretic phase of chikungunya is amukkara choornam. The current study was undertaken to study the efficacy of amukkara choornam in the treatment of chikungunya in C57BL/6J mice. The formulation when administered to chikungunya infected mice relieved morbidity and joint swelling. Analysis of virus clearance in brain and joint tissues on formulation treatment revealed a direct correlation of viral load in brain to morbidity during infection; likewise, joint swelling receded prior to complete viral clearance explaining possible immunomodulatory effect of amukkara choornam. This study provides insight into the possible mode of action of amukkara choornam during chikungunya. PMID- 29484896 TI - Three cases of transient hyperthyroidism after triptorelin treatment - case report and literature review. AB - The impacts of gonadtropin-releasing hormone (GnRH) agonists on thyroid function have long been observed and the conclusions were controversial. We here reported three cases of transient hyperthyroidisms after triptorelin therapy. The three patients showed decreased thyroid-stimulating hormone (TSH), with or without elevated free triiodothyronine (FT3) and free thyroxine (FT4) 2 weeks after injection of triptorelin. Thyroid-specific autoantibody assays showed antithyroid microsome autoantibody (TMAb) and (or) antithyroglobulin autoantibody (TgAb) were positive in two patients while and antithyrotropin receptor autoantibody (TRAb) were negative in all three cases. One patient with all thyroid-specific autoantibodies negative showed enlarged thyroid in thyroid ultrasound scanning. Only mild symptoms of hyperthyroidism presented in one patient. Four weeks after triptorelin injection, thyroid function returned to normal in all three patients. These observations indicated transient hyperthyroidism due to thyroid destruction in patients receive triptorelin therapy. The hyperthyroidism was most possibly due to onset of the autoimmune thyroiditis, emphasizing monitoring thyroid function during triptorelin treatment in females. PMID- 29484897 TI - miR-124 antagonizes the antidepressant-like effects of standardized gypenosides in mice. AB - Our previous study demonstrated that gypenosides produced antidepressant-like effects in mice exposed to chronic mild stress in a brain-derived neurotrophic factor-dependent manner. However, whether other mechanisms are involved in the antidepressant-like effects of gypenosides is not clear. miR-124 is one of the most abundant microRNAs in the hippocampus, and its dysregulation is related to the pathophysiology of depression. The glucocorticoid receptor is dysfunctional in depression, and it is a direct target of miR-124. Therefore, the present study used corticosterone-induced mice as a model to evaluate the role of miR-124 on the antidepressant-like effects of gypenosides. miR-124 agomir was intracerebrally injected prior to administration of gypenosides and corticosterone injection. Sucrose preference and forced swimming tests were performed 21 days later. Proteins related to glucocorticoid receptors and brain derived neurotrophic factor-tyrosine receptor kinase B signaling in the hippocampus were evaluated. Our results demonstrated that gypenosides reversed the chronic corticosterone injection-induced decreased sucrose preference and increased immobility time. In contrast, this effect was antagonized by miR-124 injection. In addition, gypenosides increased glucocorticoid receptor and tyrosine receptor kinase B expression in the hippocampus, which activated brain derived neurotrophic factor signaling. miR-124 also blocked these effects. In conclusion, this study demonstrated that a reduction in miR-124 was required for the antidepressant-like effects of gypenosides induced by chronic corticosterone injection in mice. PMID- 29484898 TI - An overview of the clinical management of cyclic vomiting syndrome in childhood. AB - This narrative review provides an update on cyclic vomiting syndrome pathogenesis, diagnosis and management, based upon studies published after the 2008 North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) official recommendations. The review began with a comprehensive PubMed/Medline search for "cyclic vomiting syndrome", "periodic syndromes" and "pediatrics" from 2000 up to October 2017. Additional papers were identified by reviewing the re-ference lists of retrieved publications. Cyclic vomiting syndrome is a severe, debilitating disorder of the brain-gut axis with unclear pathogenesis, that significantly affects long-term quality of life of affected children and their families. The 2008 NASPGHAN recommendations defined the major clinical, diagnostic and therapeutic peculiarities. Over the last 10 years, advancements in pathogenesis and diagnostic criteria have been made, and new prophylactic and therapeutic strategies have been proposed. These aspects are discussed in this manuscript. For the pediatrician, the major aim is to have early clinical suspicion to avoid diagnostic delay and to start adequate, phase related, symptom-tailored management. PMID- 29484899 TI - lnjuries in wrestling: systematic review. AB - OBJECTIVES: To identify all studies of injuries in wrestling, assess risk of bias and compute weighted average injury rates. METHODS: 17 online databases and nine grey literature resources were searched with no language/date limitations. Abstracts were assessed for inclusion and data abstracted independently by two reviewers. RESULTS: Eleven studies of competitions, 27 databases, four surveys (699 wrestlers) and seventeen case reports (604 cases) were included. Studies provided varying completeness of data. Weighted average injury rates of 16.3/1000AE (AE = Athletic encounter) could be computed for 8/11 studies of competitions and 69.5/1000AE for 5/27 databases. Eleven of the databases focused on specific injuries. Weighted average injury rates by location for 8/11 competition studies and 7/16 databases were similar for the upper extremities (competitions 26%, databases 24%) and torso (15%, 12%), but dissimilar for head/neck (31%, 20%) and lower extremities (24%, 39%). Weighted average injury rates by injury type varied from 6/11 to 2/11 competition studies and 6/16 to 3/16 database studies. Percentages were similar for fractures (6%, 7%), dislocations/subluxations (6%, 6%), ligament tears/cartilage injuries (12%, 17%) and concussions/1000AE (2 competition studies, 1 database) in competitions (25%, 27%) and training (5.7%, 7.1%). Percentages were dissimilar for lacerations/abrasions/contusions (23%, 4%) and sprains/strains (38%, 26%). The differences may be due to the small number of databases providing specific data and the unknown proportion of training injuries. Databases extrapolating injuries to the national US level reported high annual numbers. CONCLUSIONS: Average injury rates weighted by sample size are 16.3/1000AE for 8/11 competition studies and 69.5/1000AE for 5/27 databases. Competition data are likely to be accurate because they were observed by physicians, trainers and referees and the completeness and accuracy of database studies vary. Databases which extrapolated data to provide annual national rates estimated large numbers. Few studies provided data about the situations in which injuries occur and the causes of injuries. PMID- 29484900 TI - Incidental Flexor Carpi Radialis Tendinopathy on Magnetic Resonance Imaging. AB - BACKGROUND: Wrist pain is often nonspecific. Magnetic resonance imaging (MRI) is regularly obtained to evaluate wrist pain. Variations and pathophysiology identified on MRI may not account for patient's clinical symptoms. This study aims to quantify the prevalence of flexor carpi radialis (FCR) tendinopathy on MRI and the coexistence of trapeziometacarpal (TMC) or scaphotrapeziotrapezoid (STT) osteoarthritis. METHODS: Using an institutional research database, we identified 3631 adult patients who obtained an MRI of the wrist during a 15-year period. Text search in the radiology reports identified 302 patients with possible FCR signal abnormalities. After reviewing the medical records, 98 patients were identified with FCR tendinopathy. Furthermore, medical records were used to identify pain located on the volar radial part of the wrist. In the absence of a documented examination consistent with FCR tendinopathy, we considered any signal change in the FCR incidental. RESULTS: We identified 55 patients (55%) with incidental FCR tendinopathy. In a bivariate analysis, we found FCR signal changes on the MRI were associated with older age, white race, clinically suspected FCR tendinopathy, volar-radial sided wrist pain, and TMC and STT arthritis. Using multivariable logistic regression to account for confounding, older age and volar-radial sided wrist pain were independently associated with FCR signal changes on MRI. CONCLUSIONS: Signal changes in the FCR are infrequent and often incidental (asymptomatic) or associated with peritrapezial osteoarthritis. PMID- 29484901 TI - Complications of Radial Column Plating of the Distal Radius. AB - BACKGROUND: Distal radius fractures treated with open reduction and internal fixation are commonly stabilized with a volar locking plate; however, more complex fracture patterns may require supplemental fixation with fragment specific implants. The objective of this study was to evaluate the outcomes of distal radius fractures treated with radial column plates. METHODS: A consecutive series of 61 patients who sustained distal radius fractures underwent radial column plating alone or in conjunction with other implants between August 2006 and January 2014. Thirty-one patients returned for follow-up or returned a mailed questionnaire at an average of 4.1 years. The outcomes measures included Visual Analog Scale (VAS); Disabilities of the Arm, Shoulder and Hand (DASH); and Patient-Rated Wrist Evaluation (PRWE) scores. RESULTS: Sixty-one patients with a mean age of 55 years (range, 20-87) met inclusion criteria and were available for follow-up or chart review at an average of 5.2 years (range, 1.6-9.0 years). Seventeen of 61 (28%) underwent radial column plate removal. Twenty patients returned for final follow-up examination, and 11 completed questionnaires via mail. Subjective scores included a mean postoperative VAS of 0.72, DASH score of 17.2, and PRWE score of 15.7. Hardware sensitivity and wrist stiffness were the most common complications at final follow-up. CONCLUSIONS: Radial column plating of the distal radius is a safe treatment modality and a valuable adjunct in the setting of complex distal radius fractures, but patients should be counseled that there is a 28% chance that hardware removal may be required. Our retrospective review found evidence of few complications and objective scores consistent with return to normal function. PMID- 29484902 TI - Two new bis-C20-diterpenoid alkaloids with anti-inflammation activity from Aconitum bulleyanum. AB - Two new bis-C20-diterpenoid alkaloids, bulleyanines A and B (1 and 2), were isolated from Aconitum bulleyanum. Their structures were elucidated by comprehensive spectroscopic analyses including UV, IR, MS, 1D and 2D NMR. Biological activity tests indicated that compound 1 exhibited significant inhibitory activity against nitric oxide (NO) production in lipopolysaccharide (LPS)-activated RAW264.7 macrophages with the inhibition rate of 74.60% (40 MUmol/L), while positive control dexamethasone gave 78.70% inhibition at 100 MUg/ml. PMID- 29484903 TI - Complex Interaction of Hb Q-Thailand (HBA1: c.223G>C) with beta-Thalassemia/Hb E (HBB: c.79G>A) Disease. AB - Hb Q-Thailand [alpha74(EF3)Asp->His (alpha1), GAC>CAC, HBA1: c.223G>C] is an abnormal hemoglobin (Hb) frequently found in Thailand and Southeast Asian countries. The association of the alphaQ-Thailand allele with other globin gene disorders has important implications in diagnosis. Here, we report how to diagnose the coinheritance of Hb Q-Thailand with beta-thalassemia (beta-thal)/Hb E disease in four Thai samples from high performance liquid chromatography (HPLC) and capillary electrophoresis (CE) testing results. Understanding of the HPLC chromatogram and CE electropherogram patterns of this complex mutation is important for interpretation of testing results and providing genetic counseling. PMID- 29484904 TI - Dual effect biodegradable ciprofloxacin loaded implantable matrices for osteomyelitis: controlled release and osteointegration. AB - Ciprofloxacin biodegradable implantable matrices (CPX-IMs) of tailored porous surfaces were fabricated by hot melt injection molding of poly-l-lactic acid (PLLA) followed by coating with PLLA/sodium chloride. CPX-IDs were designed to have a non-porous coat (NPC) or a porous coat of small pore size (SPC; 150-250 um) or a large pore size (LPC; 250-350 um). CPX-IMs surface pore size was confirmed by scanning electron microscope. The hardness of NPC, LPC, and SPC CPX IMs were 58 +/- 2.8, 53 +/- 1.9, and 50 +/- 2.1 N, respectively. The measured porosity values were 41.2 +/- 1.53, 65.2 +/- 1.1, and 60.7 +/- 1.2%, respectively. Differential scanning calorimetry was employed to study the compatibility of ingredients, the effect of injection molding on polymer properties, and implants degradation. Coating of CPX-IMs prolonged drug release to reach a value of 90% release in 40 days. Antibacterial activity tests showed sufficiency of CPX to inhibit pathogens known to cause osteomyelitis. The in vivo study showed tissue compatibilities of the inserted matrices in tested rats with no sign of infection throughout the experiment period. SPC and LPC CPX-IMs demonstrated a better osteointegration, cell adhesion, and infiltration of different types of bone cells within implants structure compared to the non porous matrix. Furthermore, LPC CPX-IMs showed a superior bone cell attachment and osteointegration relative to SPC CPX-IMs. Findings of this study confirmed the impact of porosity and pore sizes on cell proliferation and fracture healing concurrently with the sustained local antibiotic therapy for treatment or prevention of osteomyelitis. PMID- 29484905 TI - Biomimetic nanoparticles delivered hedgehog pathway inhibitor to modify tumour microenvironment and improved chemotherapy for pancreatic carcinoma. AB - The unique tumour microenvironment (TM) of pancreatic ductal adenocarcinoma (PDA) including highly desmoplastic ECM and low tumour perfusion supports a considerable barrier for effective delivery of nanomedicines. Effectively modulating PDA microenvironment to enhance tumour drug delivery represents a pinpoint in the field of PDA treatment. In this study, it was the first time that biomimetic nanoparticles, which were designed in the form of erythrocyte membrane camouflaged PLGA nanoparticles (MNP), were utilized for PDA microenvironment modulation. Cyclopamine (CYC), an inhibitor of Hedgehog pathway that contributed a lot to desmoplastic ECM of PDA, was selected as the model drug and successfully encapsulated into MNP. Advantages of CYC-loaded MNP (CMNP) included favourable biocompatibility, long circulation time, and powerful TM modulation effect. CMNP could effectively deliver CYC to the tumour site, disrupt tumour ECM, increase functional vessels, and improve tumour perfusion significantly. The combination treatment with CMNP and PTX-loaded MNP (PMNP) successfully improved PTX delivery to tumour, resulting in remarkable tumour growth inhibition in vivo. Therefore, biomimetic nanoparticles provide a new strategy for modulating PDA TM and will have great potential to improve the therapeutic effects of nanomedicines for PDA patients. PMID- 29484906 TI - The Roles of Family and Teacher Support in Moderating and Mediating Externalized and Internalized Outcomes of Exposure to Community Violence Among Arab and Jewish Adolescents in Israel. AB - The study examined family and teacher support as factors that can protect adolescents from internalized and externalized problems after exposure to community violence (ECV). Self-administered questionnaires were filled out by a sample of 1,832 Arab and Jewish Israeli high school students. The Arab adolescents reported significantly higher levels of community violence victimization, internalized problems, externalized problems, family support, and teacher support than the Jewish adolescents. The girls reported higher levels of internalized problems, and the boys reported higher levels of externalized problems. ECV predicted high levels of internalized and externalized problems, family support predicted low levels of internalized and externalized problems, and teacher support had no predictive role. Path analysis confirmed the significance of the relationships between ECV effects, support variables, and gender. The limitations of the study and implications of the findings for future research and for the development of family care and family intervention programs are discussed. PMID- 29484907 TI - Re-emergence of measles: ongoing current outbreak in south-western Greece since December 2017 and onwards. PMID- 29484908 TI - Pseudoaneurysm of the basilar artery presenting with epistaxis. AB - The internal carotid artery is the most commonly affected artery in pseudoaneurysm presenting with epistaxis. Basilar arterial pseudoaneurysm is usually associated with intracranial haemorrhage. We report a basilar artery pseudoaneurysm after endoscopic surgery for clival chordoma, leading to epistaxis. The mechanism of epistaxis and strategy of embolisation are discussed. PMID- 29484909 TI - Propranolol for treating emotional, behavioural, autonomic dysregulation in children and adolescents with autism spectrum disorders. AB - OBJECTIVES: To date, there is no single medication prescribed to alleviate all the core symptoms of Autism Spectrum Disorder (ASD; National Institute of Health and Care Excellence, 2016). Both serotonin reuptake inhibitors and drugs for psychosis possess therapeutic drawbacks when managing anxiety and aggression in ASD. This review sought to appraise the use of propranolol as a pharmacological alternative when managing emotional, behavioural and autonomic dysregulation (EBAD) and other symptoms. MATERIALS AND METHODS: Sixteen reports examined the administration of propranolol in the context of ASD. RESULTS: Sixteen reports broadly covered cognitive domains, neural correlates, and behavioural domains. From the eight single-dose clinical trials, propranolol led to significant improvements in cognitive performance - verbal problem solving, social skills, mouth fixation, and conversation reciprocity; and changes in neural correlates - improvement in semantic networks and functional connectivity. The remaining eight case series and single case reports showed improvements in EBAD, anxiety, aggressive, self-injurious and hypersexual behaviours. Additionally, propranolol significantly improved similar behavioural domains (aggression and self-injury) for those with acquired brain injury. CONCLUSION: This review indicates that propranolol holds promise for EBAD and cognitive performance in ASD. Given the lack of good quality clinical trials, randomised controlled trials are warranted to explore the efficacy of propranolol in managing EBAD in ASD. PMID- 29484911 TI - Relationship between depth of approximal caries lesions and presence of bacteria in the dentine in primary and permanent posterior teeth: a radiographic examination with microbiological evaluation. AB - OBJECTIVES: We aimed to determine the relation between the radiographical depth of approximal lesions and the presence of bacteria in the dentine in posterior teeth in both dentitions. MATERIAL AND METHODS: Sample 1 consisted of 34 approximal lesions in primary molars in children aged 5-7 years old. Sample 2 consisted of 48 approximal lesions in molars and premolars in adult patients aged 18-67 years old. All lesions were in need of restorative treatment according to the dentists. During the operative interventions dentine biopsies were collected with a sterile bur just pulpally of the enamel-dentin junction. Two authors evaluated the presence/absence of bacterial colonies. The lesions depth on bitewing radiographs (RSCORING) were assessed independently by two examiners twice using the ICCMS classification system: RI=initial-; RM=moderate-; RE=extensive caries. RESULTS: In sample 1, the RSCORING was distributed as follows: RI=15; RM=12; RE = 7. In 9 cases the lesions were clinically cavitated. Bacteria were visible on the agar plates in one case (7%) of the RI lesion, 86% of the RM lesions and in all the RE lesions, (p < .001). In sample 2, RSCORING was distributed as follows RI=14; RM=23; RE=9. In 15 cases, the lesions were clinically cavitated. In 2 cases (14%), there were visible bacteria on the agar plates among the RI lesions, while this was the case in 86% of RM lesions and in 100% of RE lesions (p < .001). CONCLUSIONS: RM and RE lesions seem to harbor bacteria in the dentine and are candidates for invasive treatment. In contrast, RI lesions should in general be managed non-invasively. PMID- 29484910 TI - Chitosan-based liposomal thermogels for the controlled delivery of pingyangmycin: design, optimization and in vitro and in vivo studies. AB - Pingyangmycin (PYM) has been applied clinically for many years to treat vascular malformations (VM) in China. The major limitation of PYM injections is quick diffusion from the injection site, which increases side effects, especially the possibility of pulmonary injury. In this paper, chitosan/glycerophosphate disodium (CS/GP) thermogels containing liposomes for sustained and localized PYM delivery were prepared and optimized by a three-level three-factorial Box-Behnken experimental design to evaluate the effects of different variables (the PYM concentration, CS amount and GP content), on the selected responses (cumulative percentage PYM released in 1 day, 9 days and the rate constant k). The results revealed that the optimized PYM liposomal thermogels had a controlled PYM release for 14 days in vitro, which confirmed the validity of optimization. In vitro morphological observation, cell cycle and apoptosis analysis showed an effective anti-proliferation action of PYM liposomal thermogels on human vascular endothelial cells (EA.hy926). In vivo pharmacokinetics research in rabbits displayed that compared with PYM liposomes and PYM thermogels, PYM liposomal thermogels had a better controlled delivery of PYM. Histological examination of rabbit ear veins showed that after local application with PYM lipsomal thermogels for 21 days, obvious vein thrombosis and inflammatory reaction could be observed. The above results indicated that PYM-loaded lipsomal CS/GP thermogels might have a good prospect for the treatment of VM. PMID- 29484912 TI - Umbilical Lesions: Clinicopathologic Features of 99 Tumors. AB - BACKGROUND: Umbilical lesions are rare, and can be benign or malignant. This retrospective study was conducted to assess the epidemiological, clinical, and histologic characteristics of umbilical masses. METHODS: Cases of umbilical masses from January 1994 to August 2016 were retrieved from our institution's pathology databases, and their clinicopathological features were reviewed. RESULTS: There were a total of 99 cases of umbilical masses, 78 women (78.8%) and 21 men (21.2%). Of these, 59 were malignant (59.6%) and 40 were benign (40.4%). Among the malignant cases, 48 were women with a mean age of 65 years and 11 were men with a mean age of 66 years. All malignant lesions were secondary tumors. Twenty-five patients (42.3%) had a metastatic tumor to the umbilicus with an average of 7 months from the original diagnosis (12 gynecological, 8 pancreatic/gastrointestinal, 2 lymphomas, and a case each of breast, prostate, and melanoma). Of the patients with a benign diagnosis, 30 were women (75%) with a mean age of 52 years and 10 were men (25%) with a mean age of 43 years. The benign lesions included epidermal inclusion cysts (15/40), endometriosis (11/40), lipomas (3/40), neurofibromas (3/40), fibromas (3/40), abscesses (2/40), and 1 case each of tubular apocrine adenoma, serous cystadenoma, and calcified nodule. CONCLUSION: The most common metastatic tumors to the umbilicus are from the adjacent organs with the gynecologic tract as the most frequent primary followed by the gastrointestinal system. Primary malignant tumors of the umbilical region are rarely identified in clinical practice. PMID- 29484913 TI - Correlates of Illicit Drug Use Among Indigenous Peoples in Canada: A Test of Social Support Theory. AB - Relying on a national stratified random sample of Indigenous peoples aged 19 years old and above in Canada, this study investigates the correlates of illicit drug use among Indigenous peoples, paying special attention to the association between social support measures and illegal drug use. Results from multivariate logistical regression show that measures of social support, such as residential mobility, strength of ties within communities, and lack of timely counseling, are statistically significant correlates of illicit drug use. Those identifying as Christian are significantly less likely to use illegal drugs. This is the first nationwide analysis of the illicit drug usage of Indigenous peoples in Canada. The results are robust because we have controlled for a range of comorbidity variables as well as a series of sociodemographic variables. Policy implications from these findings are discussed. PMID- 29484914 TI - The Otolaryngologist's Role in Providing Gender-Affirming Care: An Opportunity for Improved Education and Training. AB - Currently, there are limited resources and training available for otolaryngologists and otolaryngology practice personnel to provide gender affirming care for transgender or gender nonconforming patients. This unique patient population may present to our offices for gender-specific care or with complaints of the ear, nose, and throat unrelated to gender identity. Our current practice has unintentional but direct consequences on our patients care, as transgender patients often report negative experiences in the healthcare setting related to their gender identity. The absence of resources and training is also seen in other specialties. Physicians who create an environment where patients of all gender identities feel welcome can better meet their patients' health care needs. In addition, otolaryngologists can play a role in easing the gender dysphoria experienced by transgender patients. We suggest educational content should be created for and made available to otolaryngologists and office staff to provide gender-affirming care. PMID- 29484915 TI - Race Characterization of Phytophthora Root Rot on Capsicum in Taiwan as a Basis for Anticipatory Resistance Breeding. AB - Peppers (Capsicum sp.) are an increasingly important crop because of their use as a vegetable, spice, and food colorant. The oomycete Phytophthora capsici is one of the most devastating pathogens to pepper production worldwide, causing more than $100 million in losses annually. Developing cultivars resistant to P. capsici is challenging because of the many physiological races that exist and new races that are continuously evolving. This problem is confounded by the lack of a universal system of race characterization. As a basis to develop a global anticipatory breeding program, New Mexico recombinant inbred lines (NMRILs) functioned as a host differential for Phytophthora root rot to characterize the race structure of P. capsici populations in Taiwan. Using the NMRILs, 24 new races were identified, illustrating the utility and usefulness of the NMRILs for anticipatory breeding. Virulence of P. capsici was observed to be geographically specific and in two virulence clusters. Interestingly, all but two isolates collected in 2016 were the A2 mating type, which is a shift from the predominantly A1 mating type isolates collected prior to 2008. The NMRILs host differential provides an approach for scientists to work together on a global scale when breeding for resistance as well as on a local level for regional gene deployment. Additionally, we propose that the current race numbering system, which has no biological meaning, be supplemented with the virulence phenotype, based on the susceptible NMRILs to a given isolate. This work provides insights into the population dynamics of P. capsici and interactions within the highly complex Capsicum-Phytophthora pathosystem, and offers a basis for similar research in other crops. PMID- 29484916 TI - Audiometric Testing Guideline Adherence in Children Undergoing Tympanostomy Tubes: A Population-Based Study. AB - Objective Tympanostomy tube (TT) insertion is the most common ambulatory surgery performed on children. American Academy of Otolaryngology-Head and Neck Surgery Founda-tion (AAO-HNSF) Clinical Practice Guidelines (CPGs) recommend hearing testing for all pediatric TT candidates. The aim of this study was to assess audiometric testing in this population. Study Design Retrospective population based cohort study. Setting All hospitals in the Canadian province of Ontario. Subjects and Methods All patients 12 years of age and younger who underwent at least 1 TT procedure between January 1993 and June 2016. The primary outcomes were the percentage of patients who underwent a hearing test within 1 year before and/or 1 year after surgery. Results A total of 316,599 bilateral TT procedures were performed during the study period (1993 to 2016). Presurgical hearing tests increased from 55.7% to 74.9%, and postsurgical hearing tests increased from 42.2% to 68.9%. Younger surgeons demonstrated a greater adherence to the CPGs (relative risk [RR], 1.22; 95% CI, 1.08-1.38; P = .001). Remarkably, there was not a spike in preoperative hearing tests following the introduction of the CPGs in 2013 (RR, 1.12; 95% CI, 0.85-1.47; P = .432). Presurgical hearing testing ranged from 26.1% to 83.5% across health regions. Conclusion In this cohort of children who underwent TT placement, the trends of preoperative and postoperative audiometric testing are increasing but are still lower than recommended by the CPGs, despite a tripling of practicing audiologists. This study describes the current state of testing in Ontario and highlights issues of access to audiology services, possible parent preferences, and the importance of ongoing continuing medical education for all health care practitioners. PMID- 29484918 TI - Equality Promotes Wellness. AB - Women otolaryngologists face issues that interfere with their wellness on a regular basis. Over the course of my career-in positions of leadership in academic practice and at the Academy's Board of Governors and Women in Otolaryngology Section and as past president of the AAO-HNS/F-I have had experiences and observations that I feel can help move the needle forward on these very important conversations. PMID- 29484917 TI - Brevundimonas spp: Emerging global opportunistic pathogens. AB - Non-fermenting Gram-negative bacteria are problematic in clinical locations, being one of the most prevalent causes of nosocomial infections. Many of these non-fermenting Gram-negative bacteria are opportunistic pathogens that affect patients that are suffering with underlying medical conditions and diseases. Brevundimonas spp., in particular Brevundimonas diminuta and Brevundimonas vesicularis, are a genus of non-fermenting Gram-negative bacteria considered of minor clinical importance. Forty-nine separate instances of infection relating to Brevundimonas spp were found in the scientific literature along with two pseudo infections. The majority of these instances were infection with Brevundimonas vesicularis (thirty-five cases - 71%). The major condition associated with Brevundimonas spp infection was bacteraemia with seventeen individual cases/outbreaks (35%). This review identified forty-nine examples of Brevundimonas spp. infections have been discussed in the literature. These findings indicate that infection review programs should consider investigation of possible Brevundimonas spp outbreaks if these bacteria are clinically isolated in more than one patient. PMID- 29484919 TI - Types and sources of social support among adults living with type 2 diabetes in rural communities in the Dominican Republic. AB - Type 2 diabetes management hinges on various determinants, including the role of interpersonal relationships in self-management behaviours. The aim of this study was to explore the types and sources of social support received by adults in the diabetes diagnosis and self-management processes. We conducted qualitative interviews with 28 men and women at two rural clinics in the Dominican Republic and used a combination of narrative and thematic analytic techniques to identify key sources and types of social support in their diabetes experiences. Participants described three stages in their diabetes experience: diagnosis, programme-enrolment, and long-term management. During diabetes diagnosis, most participants described receiving no support. At the programme-enrolment stage, friends and neighbours frequently provided informational or instrumental support to get to the clinic. In long-term management, cohabiting partners provided the most support, which was often assistance with their diet. Our findings highlight he need to assess and leverage distinct types and sources of social support at different stages of the diabetes experience. PMID- 29484920 TI - Music Appreciation after Cochlear Implantation in Adult Patients: A Systematic Review. AB - Objective The cochlear implant (CI) improves quality of life for people who are severely and profoundly deafened, allowing implantees to perceive speech at levels similar to those of individuals with normal hearing. However, patients with CIs generally report a reduced appreciation of music after implantation. We aimed to systematically review the English-language literature for studies evaluating music enjoyment and perception among adult patients with CIs. Data Sources A systematic review of PubMed/MEDLINE, Scopus, Embase, and the Cochrane Library. Review Methods The PRISMA statement was utilized to identify English language studies reporting music appreciation among adults with CIs. Two independent reviewers performed searches through May 2017. Included studies investigated parameters related to music enjoyment and music perception, including (1) pitch and timbre perception, (2) noise-canceling algorithms, and (3) the presence of dissonant chords, lyrics, or visual cues. Results A total of 508 articles were screened for relevance. Forty-one full-text articles were evaluated, and 18 met final inclusion criteria. Studies used heterogeneous methods of outcome measurement for identifying music appreciation. The outcome measures suggest that rhythm and lyrics are important components of enjoyment. Patients with CIs had difficulty with pitch and timbre perception. Conclusion The heterogeneous outcome measures identified in this systematic review suggest that rhythm and lyrics are important components of enjoyment, while patients with CIs had difficulty with pitch and timbre perception. Because there is no standardized reporting metric for music appreciation among adult patients with CIs, a standardized validated outcome-measuring tool is warranted. PMID- 29484921 TI - Power Corrupts, but Control Does Not: What Stands Behind the Effects of Holding High Positions. AB - People seek high positions not to gain influence over others but to satisfy their need for personal control. Personal control tends to have positive interpersonal consequences. If this is the case, does power indeed corrupt? We argue that holding a high position is associated both with perceptions of power (influence over others) and personal control (influence over one's life). Three studies showed that these two aspects might have opposite consequences: Power over others positively predicted aggressiveness (Study 1, N = 793) and exploitativeness (Study 2, N = 445), whereas personal control predicted these outcomes negatively. In Study 3 ( N = 557), conducted among employees at various organizational positions, the effects of holding a high position on exploitativeness and aggressiveness were differentially mediated by power over others and personal control. We discuss these findings in light of contradicting evidence on the corruptive effects of power. PMID- 29484922 TI - Antithrombotic Therapy for Venous Thromboembolism and Prevention of Thrombosis in Otolaryngology-Head and Neck Surgery: State of the Art Review. AB - Objective The aim of this report is to present a cohesive evidence-based approach to reducing venous thromboembolism (VTE) in otolaryngology-head and neck surgery. VTE prevention includes deep venous thrombosis and pulmonary embolism. Despite national efforts in VTE prevention, guidelines do not exist for otolaryngology head and neck surgery in the United States. Data Sources PubMed/MEDLINE. Review Methods A comprehensive review of literature pertaining to VTE in otolaryngology head and neck surgery was performed, identifying data on incidence of thrombotic complications and the outcomes of regimens for thromboprophylaxis. Data were then synthesized and compared with other surgical specialties. Conclusions We identified 29 articles: 1 prospective cohort study and 28 retrospective studies. The overall prevalence of VTE in otolaryngology appears lower than that of most other surgical specialties. The Caprini system allows effective individualized risk stratification for VTE prevention in otolaryngology. Mechanical and chemoprophylaxis ("dual thromboprophylaxis") is recommended for patients with a Caprini score >=7 or patients with a Caprini score of 5 or 6 who undergo major head and neck surgery, when prolonged hospital stay is anticipated or mobility is limited. For patients with a Caprini score of 5 or 6, we recommend dual thromboprophylaxis or mechanical prophylaxis alone. Patients with a Caprini score <=4 should receive mechanical prophylaxis alone. Implications for Practice Otolaryngologists should consider an individualized and risk-stratified plan for perioperative thromboprophylaxis in every patient. The risk of bleeding must be weighed against the risk of VTE when deciding on chemoprophylaxis. PMID- 29484923 TI - Palliative Head and Neck Cancer Treatment for Asymptomatic Disease. PMID- 29484924 TI - A Multidisciplinary Approach to a Pediatric Difficult Airway Simulation Course. AB - Objective To design and assess an advanced pediatric airway management course, through simulation-based team training and with multiple disciplines, to emphasize communication and cooperation across subspecialties and to provide a common skill set and knowledge base. Methods Trainees from anesthesiology, emergency medicine, critical care, pediatric surgery, and otolaryngology at a tertiary children's hospital participated in a 1-day workshop emphasizing airway skills and complex airway simulations. Small groups were multidisciplinary to promote teamwork. Participants completed pre- and postworkshop questionnaires. Results Thirty-nine trainees participated over the 3-year study period. Compared with their precourse responses, participants' postcourse responses indicated either agreement or strong agreement that the multidisciplinary format (1) helped in the development of team communication skills and (2) was preferred over single discipline training. Improvement in confidence in managing critical airway situations and in advanced airway management skills was significant ( P < .05). Eighty-one percent of participants had improved confidence in following the hospital's critical airway protocol, and 64% were better able to locate advanced airway management equipment. Discussion Multiple subspecialists manage pediatric respiratory failure, where successful care requires complex handoffs and teamwork. Multidisciplinary education to teach advanced airway management, teamwork, and communication skills is practical and preferred by learners and is possible to achieve despite differences in experience. Future study is required to better understand the impact of this course on patient care outcomes. Implications for Practice Implementation of a pediatric difficult airway course through simulation-based team training is feasible and preferred by learners among multiple disciplines. A multidisciplinary approach exposes previously unrecognized knowledge gaps and allows for better communication and collaboration among the fields. PMID- 29484925 TI - Comparison of Pediatric Intracapsular Tonsillectomy and Extracapsular Tonsillectomy: A Cost and Utility Decision Analysis. AB - Objectives To use decision analysis modeling to compare utility and cost outcomes of intracapsular tonsillectomy (ICT) and extracapsular tonsillectomy (ECT). To use sensitivity analysis to determine the most important factors influencing outcomes favoring one surgical method versus another. Study Design Decision analysis model. Setting Hypothetical cohort. Subjects and Methods A decision analysis model was created with computer software comparing the results of ICT and ECT. The model featured complications with completion tonsillectomy, such as postsurgical bleed, dehydration, and tonsillar regrowth. Outcomes were quantified with a utility scale ranging from 0.95 (1 surgical procedure without complications) to 0.55 (ICT, regrowth requiring completion ECT, post-ECT bleeding). Costs measured out-of-pocket costs for an insured patient and factored in different recovery times for ECT versus ICT. Results Based on baseline parameters, ECT had higher cumulative utility than ICT. Utility model results were highly dependent on the value of having a single uncomplicated surgery, as well as on the tonsillar regrowth rate. Utility was equal at a regrowth rate of 1.64%; rates above this value favored ECT. The base cost model showed that ICT ($4177.92) was less expensive than ECT ($4546.91), although ICT with regrowth had the highest outcome cost ($8393.91). ECT and ICT costs were equal at a tonsil regrowth rate of 17.8% and at a recovery period of 7.4 days. Conclusion Utility decision modeling based on best estimates for baseline parameters suggests that ECT may be slightly superior to ICT, but cost analysis suggests the opposite. However, the comparative results are highly dependent on subtle changes in the tonsil regrowth rate and the potential difference in recovery time. PMID- 29484926 TI - Giant gastrointestinal stromal tumour of the stomach: a case report with surgical treatment. AB - We report a case of giant gastrointestinal stromal tumour of the stomach in a 71 year-old woman, with emphasis on its going through surgical resection. The physical examination and radiological findings revealed that a giant mass occupied most of the abdominal cavity. The patient underwent an en-block resection of the mass, partial resection of the distal stomach and Billroth II gastrojejunostomy. The pathological diagnosis was gastrointestinal stromal tumour. The patient had a long-term disease-free survival. We emphasise that complete surgical resection is the only effective radical treatment approach for giant gastrointestinal stroma of the stomach. In some cases, we still have the opportunity for resection of these tumours because of their expansive growth, even though the lesions are very large. PMID- 29484927 TI - Is sarcopenia a useful predictor of outcome in patients after emergency laparotomy? A study using the NELA database. AB - Introduction Studies have reported on the use of frailty as a prognostic indicator in patients undergoing elective surgery. Similar data do not exist for patients undergoing emergency surgery. The aim of this study was to evaluate the effect of preoperative sarcopenia measured by computed tomography (CT) on outcome following emergency laparotomy. Materials and methods Data from the National Emergency Laparotomy Audit database were retrieved for patients who had undergone an emergency laparotomy over 12 months at York NHS Foundation Trust. Sarcopenia was assessed by psoas density and area on preoperative CT. Mortality rates at 30 days and 1 year were recorded. Secondary outcomes included discharge rates to non independent living. Results A total of 259 patients were included. Overall cohort 30-day and 1-year mortality was 13.9% (36/259) and 28.2% (73/259), respectively. Sarcopenia measured by psoas density was associated with increased mortality compared with patients who did not develop sarcopenia at 30 days (29.7%, 19/64, vs. 8.7%, 17/195; P < 0.001; odds ratio, OR, 4.42; 95% confidence interval, CI 2.13-9.26) and at 1 year (57.8%, 37/64, vs. 18.5%, (36/195; P < 0.001; OR 6.05; 95%CI 3.28-11.18). An increase in mortality was seen in patients with sarcopenia measured by psoas area at 30 days (21.3%, 13/61, vs. 9.1%, 17/187; OR 2.71; 95%CI 1.23-5.96, P = 0.013) and at 1 year (42.6%, 26/61, vs. 20.9%, 39/187; OR 2.82; 95% CI 1.52-5.23, P < 0.001). Conclusions Sarcopenia assessed by measurement of psoas density and area on CT is associated with increased mortality following emergency laparotomy. The use of sarcopenia as a predictive tool merits further attention and may be useful in patients undergoing emergency surgery. PMID- 29484928 TI - Comparison of gait kinetics in total and unicondylar knee replacement surgery. AB - Introduction The aim of this study was to compare kinetical data from gait analysis of patients who have undergone total and uni-condylar knee replacement. Materials and methods Thirteen patients with unilateral total knee arthroplasty (TKA) and 13 unicondylar knee arthroplasty (UKA), were included, all performed by the same surgeon more than one year prior. The Vicon gait analysis system was used. Statistical power was calculated using SPSS. Results No significant difference was found in the spatiotemporal parameters of gait and survival years of the knee prosthesis between the two groups. The UKA group was found to have significantly larger moments than the TKA group in knee adduction on the operated side and knee flexion moment on the unoperated side during the loading phase. The maximum and minimum sagittal plane moments of the operated sides in the TKA group were significantly lower than the unoperated side. The difference was most significant at pre-swing. The maximum and minimum moments on the operated sides in the UKA group were significantly lower for the knee flexion and adduction moments when compared with the unoperated side and were most prevalent during the loading phase. Conclusions These results are relevant in terms of prosthesis wear. The TKA knees had smaller magnitude moments than the UKA knees in the sagittal and coronal planes. This could explain the higher revision rates for UKA. In both groups, the non-operated knees had significantly larger moments than the operated knees, which implies that after unilateral knee replacement of either type, the non-operated knee is being put under greater stress. PMID- 29484929 TI - Cervical tuberculous lymphadenitis: diagnosis and demographics, a five-year case series in the UK. AB - Introduction Cervical tuberculous lymphadenitis is a low-volume condition in the UK with a potential for delayed diagnosis. This study describes typical demographic and clinical features of patients diagnosed with cervical tuberculous lymphadenitis in a UK population. The utility of cytological, histological and microbiological investigations is reviewed with comparison between fine-needle aspiration and open biopsy. This information can facilitate recognition of new cases and guide initial management. Methods Patients diagnosed with cervical tuberculous lymphadenitis between January 2009 and December 2013 at two district general hospitals were identified from local infectious disease databases. Retrospective case-note review was undertaken to collect demographic and diagnostic data and associated complications. Results Full data were available for 51 patients aged 19-70 years (mean 32.4 years) with mean follow-up of 370 days; 49/51 patients were immigrants to the UK with a wide geographic spread in the countries of origin and time since arrival; 42/51 had no significant comorbidities, although two patients had coexistent HIV infection. The clinical presentation was most frequently without constitutional symptoms (39/51) and often with no history of tuberculosis contact. Posterior triangle neck nodes were most commonly involved (26/51). Conclusion The 'typical' patient with cervical tuberculous lymphadenitis in our region is a young healthy individual who came to the UK from a high-risk country several years earlier. Diagnosis by fine-needle aspiration is as effective as open biopsy if fluid/pus is aspirated. Open biopsy is potentially associated with complications but does not appear to increase chronic wound discharge rates in our series. PMID- 29484930 TI - Giant central lumbar disc herniations: a case for the transdural approach. AB - Giant central lumbar disc protrusions can pose a significant operative challenge. Clinically, these patients are at risk of permanent disability, due not only to preoperative neural compromise caused by the protrusion itself but also to the potential iatrogenic risks associated with the standard extradural microdiscectomy technique. This is the first report to date of a giant central L3/4 disc protrusion being successfully treated through a transdural microdiscectomy approach. Prior to this report, there have been just two cases describing its application in the lumbar spine. However, neither of these reports has described its use below the level of L2/3. We compare our surgical technique with these authors and discuss the pros and cons of this surgical approach relative to the standard extradural microdiscectomy technique. Overall, we have observed encouraging results from this approach and this report would support a role for further investigation into this rarely used technique. PMID- 29484931 TI - Gastric lipoma: a rare cause of haematemesis. AB - Gastric lipomas are rare benign tumours of the stomach, representing less than 3% of all benign gastric neoplasms. They are usually asymptomatic but larger lesions can present with abdominal pain, gastric outlet obstruction and haematemesis. Malignant transformation is extremely rare. Accurate preoperative diagnosis can be established with computed tomography. Being benign, extensive surgery is not necessary and simple excision of the lesion is adequate. Small asymptomatic lesions can be followed up. We present a case of 80-year-old woman with gastric submucosal lipoma who presented with haematemesis. PMID- 29484932 TI - Massive intussusception caused by a solitary Peutz-Jeghers type hamartomatous polyp. AB - Intussusception is a rare cause of intestinal obstruction in adults and represents a diagnostic challenge for the surgeon. In the majority of cases, presenting symptoms are not specific, making preoperative diagnosis difficult. Several medical conditions may cause intestinal intussusception. We present the case of a 16-year-old female patient with intussusception due to a hamartomatous Peutz-Jeghers type polyp. This is an extremely rare case in which the first manifestation of the intestinal polyp was jejunojejunal intussusception very close to the duodenojejunal junction, with a necrotic intussusceptum about 50 cm long. The patient was treated successfully with enterectomy and end-to-end anastomosis. Postoperative course was uneventful and the patient is currently under gastroenterological and genetic investigation to exclude the diagnosis of Peutz-Jeghers syndrome. PMID- 29484933 TI - Bowel obstruction caused by broad ligament hernia sucessfully repaired by laparoscopy. AB - Internal hernais are rare bowel obstructions. We present a case of small bowel obstruction in a 37-year-old woman caused by internal herniation through a defect in broad ligament, which was managed by laparoscopic surgery. PMID- 29484934 TI - Routine blood group and antibody screening prior to emergency laparoscopy. AB - Introduction Studies show that rates of blood transfusion associated with general surgical laparoscopy are low. Currently, there are no national guidelines in the UK regarding blood group and antibody screening (G&S) for patients undergoing emergency laparoscopy. The aim of this study was to assess whether using G&S before emergency laparoscopic general surgery routinely is worthwhile by identifying rates of perioperative transfusion. Methods Data were collected retrospectively on all emergency laparoscopic procedures at a single district general hospital between January 2014 and 31 December 2016. Emergency laparoscopic general surgical cases were included and gynaecological cases excluded. Records were reviewed to ascertain whether G&S was performed, whether antibodies were detected and whether patients were transfused. Results A total of 562 emergency laparoscopic cases were performed. The median age was 28 years (range: 6-95 years). Laparoscopic appendicectomy (n=446), diagnostic laparoscopy (n=47) and laparoscopic cholecystectomy (n=25) were the most common procedures. Of the total patient cohort, 514 (91.5%) and 349 (70.1%) had a first and second G&S respectively while 30 (5.3%) had no G&S. Four patients (0.71%) had antibodies detected. One patient (0.18%) received a transfusion. This patient had undergone laparoscopic repair of a perforated duodenal ulcer and there was no major intraoperative haemorrhage but he was transfused perioperatively for chronic anaemia. Conclusions These results demonstrate a low rate of blood transfusion in emergency laparoscopic general surgery. The majority of these patients had a low risk of major intraoperative haemorrhage and we therefore argue that G&S was not warranted. We propose a more targeted approach to the requirement for preoperative G&S and the use of O negative blood in the event of acute haemorrhage from major vessel injury. PMID- 29484935 TI - A comparison of operative and margin outcomes from surgeon learning curves in robot assisted radical prostatectomy in a changing referral practice. AB - Introduction The aim of this study was to explore the impact of increasing proportions of high risk referrals on surgical margin outcomes of a surgeon's learning curve in robotic prostatectomy. Methods All patients in this study underwent robot assisted radical prostatectomy (RARP) performed by three different consultant urological surgeons. Data collected included preoperative clinical stage, Gleason score and prostate specific antigen levels, which were used to risk stratify patients according to National Institute for Health and Care Excellence criteria. Oncological clearance was assessed by overall and stage specific positive margin status. Comparisons were made between each surgeon for the first and second 50 consecutive cases. Results For the three surgeons, there was a progressive increase in the proportion of high risk cases referred accompanied by a corresponding decline in low risk disease (p<0.001). Postoperative pathology also showed an upward trend in pT3 cases across the three eras. There was no statistical difference in overall positive margin rates between the surgeons. The overall rates were 12%, 20% and 23% for the first 50 cases, and 32%, 36% and 21% for the second 50 cases for the three surgeons respectively. Conclusions Our series demonstrates an upward trend in the risk profile of men referred for robotic prostatectomy over a nine-year period. Despite this, there was minimal impact on pathological and surgical outcomes among our surgeons, who were at the initial stages of their RARP learning curve. Our results suggest that there is no requirement for an active case selection bias against patients with high risk disease for surgeons newly embarking on their RARP learning experience. PMID- 29484936 TI - The surgical arrest of post-tonsillectomy haemorrhage: Hospital Episode Statistics 12 years on. AB - Introduction The risk of returning to theatre for arrest of haemorrhage following tonsillectomy can be determined from analysis of the Hospital Episode Statistics data provided by the Department of Health website. This method was employed previously for data between 1998-2002 and was repeated in this study to observe any changes over this time period. Materials and methods Hospital Episode Statistics data for England from 2010-2016 were used. The number of tonsillectomies and surgical arrest of post-tonsillectomy haemorrhage were considered for children and adults. Results Of 267,159 tonsillectomies performed over the six-year period, 5027 (1.88%) returned to theatre for control of bleeding. This was 3.5 times more likely in adults than children (P < 0.0001). Comparison with the previous study showed an increase in return to theatre rates following tonsillectomy of 1.06%, from 0.82% to 1.88%. Conclusion Adults are more likely than children to require and arrest of haemorrhage post-tonsillectomy. Return to theatre rates have increased since 2004 at an estimated additional cost to NHS England of L1,415,056 per annum. The causes of this observed increase have yet to be determined. PMID- 29484937 TI - Ductal carcinoma in-situ arising within benign phyllodes tumours. AB - Ductal carcinoma in situ arising within a benign phyllodes tumour is a rare neoplasm of the breast. We present a case of a 19-year-old woman who had a right breast lump for six months with the above diagnosis together with a mini-review of the literature. Ultrasound revealed a 5-cm breast lump and core biopsy revealed ductal carcinoma in situ. She underwent wide local excision of the breast lump with clear margins. Final histology confirmed ductal carcinoma in situ within a fibroepithelial lesion consistent with a benign phyllodes tumour. To our knowledge, this is the youngest case of ductal carcinoma in situ arising in a phyllodes tumour to have been reported so far. PMID- 29484938 TI - The spectrum and outcome of blunt trauma related enteric hollow visceral injury. AB - Introduction This audit focused on patients who sustained enteric injury following blunt abdominal trauma. Methods Our prospectively maintained electronic registry was interrogated retrospectively, and all patients who had sustained blunt abdominal trauma between December 2011 and January 2016 were identified. Results Overall, 2,045 patients had sustained blunt abdominal trauma during the period under review. Seventy per cent were male. The median age was 28 years. Sixty patients (2.9%) sustained a small bowel injury (SBI). Thirty-five of these were peritonitic on presentation. All patients with a SBI had a chest x-ray and free air was present in seven. In 18 patients with a SBI, computed tomography (CT) was performed, which revealed isolated free fluid in 12 and free intraperitoneal air in 5. In five cases, the CT was normal. A total of 32 patients (1.5%) sustained blunt duodenal trauma (BDT). All patients with BDT had a chest x-ray on presentation. Free intraperitoneal air was not present in any. CT was performed on 17 patients with BDT. This revealed isolated free fluid or retroperitoneal air in 12. The median delay between injury and presentation for these enteric injures was 15.5 hours (interquartile range [IQR]: 8-25 hours) while between presentation at hospital and operation, the median delay was 6 hours (IQR: 3-13 hours). Conclusions Blunt trauma related enteric hollow visceral injury remains associated with delayed diagnosis and significant morbidity. It can be caused by a disparate array of mechanisms and is difficult to diagnose even with modern imaging strategies. PMID- 29484939 TI - The use of a novel adhesive tissue patch as an aid to anastomotic healing. AB - Introduction One of the most feared complications of colorectal surgery is anastomotic leak. Numerous techniques have been studied in the hope of decreasing leakage. This study was designed to assess the handling characteristics of a novel adhesive tissue patch (TissuePatchTM; Tissuemed, Leeds, UK) applied to colorectal anastomoses in a pilot study. This was with a view to assessing its potential role in aiding anastomotic healing in subsequent trials. Methods A patch was applied to colorectal anastomoses after the surgeon had completed the anastomosis and prior to abdominal closure. Handling characteristics and patient outcomes were recorded prospectively. Results Nine patients were recruited before the study was prematurely terminated. In one patient, the patch fell off and in another patient, the surgeon omitted to apply it. Six patients had significant postoperative problems (1 confirmed leak necessitating return to theatre and excision anastomosis, 3 suspicious of leak on computed tomography delaying discharge, 2 perianastomotic collections). One patient had an uneventful recovery. Conclusions Although the handling characteristics of this novel tissue patch were deemed satisfactory, it appears that wrapping a colorectal anastomosis with an adhesive hydrophilic patch has significant deleterious effects on anastomotic healing. This could be a consequence of the creation of a microenvironment between the patch and the anastomosis that impairs healing. Further research is required to better understand the mechanisms involved. At present, the use of such patches on colorectal anastomoses should be discouraged outside the confines of a well monitored trial. PMID- 29484941 TI - Umbilical tailoring in abdominoplasty: a simple and consistent way of shortening a post-bariatric umbilicus. PMID- 29484940 TI - Early outcomes of patients transferred with ruptured suprarenal aneurysm or dissection. AB - Objective Despite centralisation of the provision of vascular care, not all areas in England and Wales are able to offer emergency treatment for patients with acute conditions affecting the aorta proximal to the renal arteries. While cardiothoracic centres have made network arrangements to coordinate care for the repair of type A dissections, a similar plan for vascular care is lacking. This study investigates early outcomes in patients with ruptured suprarenal aortic aneurysm or dissection (rSRAD) transferred to a specialist centre. Methods Retrospective observational study over a five-year period (2009-2014) assessing outcomes of patients with ruptured sRAD diagnosed at their local hospital and then transferred to a tertiary centre capable of offering such treatment. Results Fifty-two patients (median age 73 years, 32 male) with rSRAD were transferred and a further four died during transit. The mean distance of patient transfer was 35 miles (range 4-211 miles). One patient did not undergo intervention due to frailty and two died before reaching the operating theatre. A total of 23 patients underwent endovascular repair, 9 hybrid repair and 17 open surgery. Median follow-up was 12 months (range 1-43 months). Complications included paraplegia (n = 3), stroke (n = 2), type IA endoleak (n = 4); 30-day and in hospital mortality were 16% and 27%. For patients discharged alive from hospital, one-year survival was 67%. Conclusions Although the number of patients with rSRAD is low and those who are transferred alive are a self-selecting group, this study suggests that transfer of such patients to a specialist vascular centre is associated with acceptable mortality rates following emergency complex aortic repair. PMID- 29484942 TI - Synchronous subcutaneous granular cell tumours, a rare presentation. AB - We describe a unique presentation of a rare disease presentation of a granular cell tumour. A 36-year-old woman presents with a large symptomatic left flank mass that had been slowly increasing in size. Multiple synchronous subcutaneous masses were found at presentation on the left breast, right auricle and right cheek. After diagnosis of granular cell tumour by core needle biopsy, the masses were excised with histopathological and immunohistochemical analysis of both specimens confirming the presence of non-malignant granular cell tumours. Granular cell tumours are rare Schwann cell derived tumours that are typically asymptomatic and benign. These tumours are most often located in the head and neck, with multifocal disease present in approximately 5-16% of patients. Final pathology is necessary for diagnosis and frozen section is rarely helpful. Malignancy is present in approximately 2% of cases and can be diagnosed by the presence of a high mitotic rate, large nucleoli, necrosis, spindling and pleomorphism are other suspicious features. Granular cell tumours do not generally require adjuvant treatment. The mainstay of therapy is surgical resection with surveillance. PMID- 29484943 TI - Hartmann's procedure, reversal and rate of stoma-free survival. AB - Background Hartmann's procedure is a commonly performed operation for complicated left colon diverticulitis or malignancy. The timing for reversal of Hartmann's is not well defined as it is technically challenging and carries a high complication rate. Methods This study is a retrospective audit of all patients who underwent Hartmann's procedure between 2008 and 2014. Reversal of Hartmann's rate, timing, American Society of Anesthesiologists grade, length of stay and complications (Clavien-Dindo) including 30-day mortality were recorded. Results Hartmann's procedure (n = 228) indications were complicated diverticular disease 44% (n = 100), malignancy 32% (n = 74) and other causes 24%, (n = 56). Reversal of Hartmann's rate was 47% (n = 108). Median age of patients was 58 years (range 21 84 years), American Society of Anesthesiologists grade 2 (range 1-4), length of stay was eight days (range 2-42 days). Median time to reversal of Hartmann's was 11 months (range 4-96 months). The overall complication rate from reversal of Hartmann's was 21%; 3.7% had a major complication of IIIa or above including three anastomotic leaks and one deep wound dehiscence. Failure of reversal and permanent stoma was less than 1% (n = 2). Thirty-day mortality following Hartmann's procedure was 7% (n = 15). Where Hartmann's procedure wass not reversed, for 30% (n = 31) this was the patient's choice and 70% (n = 74) were either high risk or unfit. Conclusions Hartmann's procedure is reversed less frequently than thought and consented for. Only 46% of Hartmann's procedures were stoma free at the end of the audit period. The anastomotic complication rate of 1% is also low for reversal of Hartmann's procedure in this study. PMID- 29484944 TI - Risk stratification of 282 differentiated thyroid cancers found incidentally in 1369 total thyroidectomies according to the 2015 ATA guidelines; implications for management and treatment. AB - Introduction The purpose of this study was to evaluate the incidence of incidental differentiated thyroid carcinoma in thyroid operations for a benign preoperative diagnosis, to identify the risk factors involved and to risk stratify the cancer patients according to the 2015 American Thyroid Association (ATA) guidelines. Materials and methods The study was a retrospective review of all thyroidectomy operations performed in a single institution (January 2004 to January 2009). We excluded patients with a preoperative diagnosis of thyroid malignancy. Results Incidental differentiated thyroid carcinoma was diagnosed in 282/1369 patients (21%). The incidental group had a significantly higher number of males (19% vs 14%, P = 0.033) and a higher number of patients with histopathological evidence of thyroiditis (35% vs 25%, P = 0.004). There was a higher number of lymph nodes present in the incidental group but numbers did not reach statistical significance (17% vs 13%, P = 0.079). There were 270 cases in the ATA low-risk group (96%) and 12 cases in the ATA intermediate-risk group (4%). Patients with an ATA intermediate risk had a statistically higher number of capsule invasion, extrathyroidal extension and angioinvasion (P < 0.001, P < 0.001 and P < 0.001, respectively). Overall, 22% of patients with an incidental differentiated thyroid carcinoma should be considered for radioactive iodine 131I treatment. 29 of the 191 patients in American Joint Committee on Cancer stage I should be considered for radioactive iodine treatment (15%). Conclusions Males and patients with thyroiditis are at a higher risk for an incidental differentiated thyroid carcinoma. One of every five of patients diagnosed with cancer will need radioactive iodine treatment, even some patients with stage I disease. PMID- 29484945 TI - Laparoscopic cholecystectomy: a prospective cohort study assessing the impact of grade of operating surgeon on operative time and 30-day morbidity. AB - Introduction There is an increasing trend towards day case surgery for uncomplicated gallstone disease. The challenges of maximising training opportunities are well recognised by surgical trainees and the need to demonstrate timely progression of competencies is essential. Laparoscopic cholecystectomy provides the potential for excellent trainee learning opportunities. Our study builds upon previous work by assessing whether measures of outcome are still affected when cases are stratified based on procedural difficulty. Material and methods A prospective cohort study of all laparoscopic cholecystectomies conducted at a district general hospital between 2009 and 2014, performed under the care of a single consultant. The operative difficulty was determined using the Cuschieri classification. The primary endpoint was duration of operation. Secondary endpoints included length of hospital stay, delayed discharge rate and 30-day morbidity. Results A total of 266 laparoscopic cholecystectomies were performed during the study period. Mean operative time for all consultant-led cases was 52.5 minutes compared with 51.4 minutes for trainees (P = 0.67 unpaired t-test). When cases were stratified for difficulty, consultant led cases were on average 5 minutes faster. Median duration of hospital stay was equivalent in both groups and there was no statistical difference in re attendance (12.9% vs. 15.3% P = 0.59) or re-admission rates (3.2% vs. 8.1% P = 0.10) at 30 days. Conclusions Our study provides evidence that laparoscopic cholecystectomy provides a good training opportunity for surgical trainees without being detrimental to patient outcome. We recommend that, in selected patients, under consultant supervision, laparoscopic cholecystectomy can be performed primarily by the surgical trainee without impacting on patient outcome or theatre scheduling. PMID- 29484946 TI - Gastric liposarcoma in a patient with severe obesity. AB - Liposarcoma is the most common soft tissue sarcoma in adults. Predominant locations are the limbs and retroperitoneum. Intra-abdominal liposarcoma represents only 2% of all cases and visceral location is exceptional. Gastric liposarcoma is extremely rare, with fewer than 20 cases reported. The treatment of choice is wide en-bloc surgical resection. If the tumour arises in the area of the cardia, resection involves resection of the proximal stomach as well as the distal oesophagus. Traditional reconstruction with oesophagogastrostomy often leads to troublesome reflux. We report a case of gastric liposarcoma arising in the gastro-oesophageal junction in a severely obese patient. PMID- 29484947 TI - Urinary Leukotriene E4 Levels in Children with Sleep-Disordered Breathing. AB - Objective Due to limitations of polysomnography (PSG), novel ways to evaluate pediatric obstructive sleep apnea (OSA) are needed. Urinary leukotriene E4 (LTE4), an inflammatory marker, has been identified as a potential biomarker for pediatric OSA. The objective of the study was to assess whether urinary LTE4 levels correlate with OSA severity, as determined by obstructive apnea-hypopnea index (AHI) and nadir oxygen saturation. Study Design Prospective trial. Setting Tertiary care children's hospital. Subjects and Methods Children (age, 3-16 years) with sleep-disordered breathing (SDB) who were referred for PSG were included. Urine samples were obtained the morning following PSG, and urinary LTE4 levels were quantified with enzyme-linked immunoassay kits. Results A total of 113 children were enrolled, and the mean age was 7.3 years. Thirty-nine percent (n = 44) were obese, and the majority were white (53%, n = 58). Seventy-eight percent (n = 88) were diagnosed with OSA (AHI >1), with 27% (n = 30) having severe disease (AHI >10). The mean urinary LTE4 level was 91.3 ng/mM. Urinary LTE4 levels did not correlate with AHI ( P = .77) or nadir oxygen saturation ( P = .64). There was a significant difference in urinary LTE4 levels between patients with mild SDB and those with moderate to severe OSA ( P = .03). Conclusion Urinary LTE4 levels do not correlate with AHI in children with SDB. Compared with children with severe OSA, children with mild SDB have higher urinary LTE4 levels. Further research is needed determine whether urinary LTE4 is a satisfactory biomarker for pediatric OSA. PMID- 29484950 TI - The Psychiatry Ashes Test March update. PMID- 29484948 TI - Movies in mind: 'Mother!': a maelstrom that reveals much about humankind. PMID- 29484951 TI - Taking action to reduce mental disorders: Clinical intervention and beyond. PMID- 29484952 TI - Impact of roll compaction design, process parameters, and material deformation behaviour on ribbon relative density. AB - Ribbons from microcrystalline cellulose (MCC), mannitol, and their 50:50% mixture were produced using the roll compactors AlexanderWerk BT120, Hosokawa Alpine Pharmapaktor C250, L.B. Bohle BRC 25, and Gerteis Mini-Pactor in the frame of multilevel full factorial experimental plans. The specific compaction force (SCF)/hydraulic pressure (HP), gap width (GW), roll speed, and fraction of MCC were analyzed as quantitative factors, whereas the roll surface and sealing system were examined as qualitative factors. Ribbon relative density was investigated as response of the models. The SCF/HP is found to be the most significant factor in each model. A significant inverse effect of the GW is obtained in the models of AlexanderWerk BT120, Pharmapaktor C250, and BRC 25 roll compactors, using smooth rolls. The principle of the establishment of a conversion factor (cf) is introduced based on the obtained data sets of AlexanderWerk BT120 and Mini-Pactor. This can facilitate the transfer of a roll compaction process between different types of roll compactors. PMID- 29484953 TI - Echocardiographic Guidance of AMPLATZER Amulet Left Atrial Appendage Occlusion Device Placement. AB - In this report, we provided details of periprocedural echocardiographic guidance for patients undergoing Amplatzer-Amulet device left atrial closure. Familiarity with left atrial appendage (LAA) occlusion devices and the required left atrial examination and measurements are key before device placement. Device placement is assisted by transesophageal echocardiography (TEE) and fluoroscopy, but TEE will be the main guide for patients with renal insufficiency in whom contrast dye use needs to be minimal. TEE is also used to confirm LAA occlusion with the device and finally detect complications throughout the procedure and into the postoperative period. PMID- 29484954 TI - Studies on the correlation between physicochemical properties of fly ash and its sorption of gas-phase arsenic. AB - This study investigated the adsorption behaviors of gas-phase arsenic on four kinds of fly ashes through using a fixed-bed reactor, and analyzed the correlation between sorption of gas-phase arsenic and physicochemical properties of fly ashes at different adsorption temperatures. The results showed that different fly ashes all had an adsorption effect on arsenic. The carbon content and specific surface area had a promoting effect on arsenic adsorption at the low temperature of 400C, but there was no obvious correlation between arsenic adsorption and the contents of Fe2O3 and CaO. However, it was exactly the opposite at the high temperature of 600C. So the correlation between physicochemical properties of fly ash and its sorption of arsenic was proved to vary with temperature. It was further revealed that the physical adsorption predominated in temperatures ranging between 200C and 400C, while the chemical adsorption predominated at further higher temperatures. The optimal temperature to maintain a high arsenic capture efficiency should be around 600C. PMID- 29484955 TI - Correction to: Funken, Heinrich, Willwacher, Muller, Bocker, Hobara, Bruggemann, & Potthast, Leg amputation side determines performance in curve sprinting: a case study on a Paralympic medalist. PMID- 29484956 TI - Targeting the GPI biosynthetic pathway. AB - The GPI (Glycosylphosphatidylinositol) biosynthetic pathway is a multistep conserved pathway in eukaryotes that culminates in the generation of GPI glycolipid which in turn anchors many proteins (GPI-APs) to the cell surface. In spite of the overall conservation of the pathway, there still exist subtle differences in the GPI pathway of mammals and other eukaryotes which holds a great promise so far as the development of drugs/inhibitors against specific targets in the GPI pathway of pathogens is concerned. Many of the GPI structures and their anchored proteins in pathogenic protozoans and fungi act as pathogenicity factors. Notable examples include GPI-anchored variant surface glycoprotein (VSG) in Trypanosoma brucei, GPI-anchored merozoite surface protein 1 (MSP1) and MSP2 in Plasmodium falciparum, protein-free GPI related molecules like lipophosphoglycans (LPGs) and glycoinositolphospholipids (GIPLs) in Leishmania spp., GPI-anchored Gal/GalNAc lectin and proteophosphoglycans in Entamoeba histolytica or the GPI-anchored mannoproteins in pathogenic fungi like Candida albicans. Research in this active area has already yielded encouraging results in Trypanosoma brucei by the development of parasite-specific inhibitors of GlcNCONH2-beta-PI, GlcNCONH2-(2-O-octyl)-PI and salicylic hydroxamic acid (SHAM) targeting trypanosomal GlcNAc-PI de-N-acetylase as well as the development of antifungal inhibitors like BIQ/E1210/gepinacin/G365/G884 and YW3548/M743/M720 targeting the GPI specific fungal inositol acyltransferase (Gwt1) and the phosphoethanolamine transferase-I (Mcd4), respectively. These confirm the fact that the GPI pathway continues to be the focus of researchers, given its implications for the betterment of human life. PMID- 29484957 TI - Occupational predictors of urinary dialkyl phosphate concentrations in Mexican flower growers. AB - Background Flower growers have high potential for exposures to pesticides. Occupational factors, such as tasks performed, the production method (organic or conventional), the use of personal protective equipment (PPE), and workplace characteristics influence the intensity of pesticide exposure. Objective To evaluate occupational characteristics affecting urinary concentration of dialkylphosphate (DAP) metabolites of organophosphate pesticides among a group of Mexican floricultural workers. Methods A questionnaire was administered to 117 workers who also provided a first morning urine sample. According to tasks performed and the production methods, pesticide contact was defined as low, medium, or high. PPE use was categorized as acceptable, fairly acceptable, and unacceptable. Urinary concentration of DAP metabolites were determined using gas liquid chromatography. Association between occupational characteristics and DAP urinary concentrations was assessed by means of linear regression models. Results After adjusting for potential confounders, the workers in the medium and high contact categories had significantly higher DAP concentrations than those in the low contact category (beta: 0.3, CI 95%: 0.1-0.5). Greenhouse workers had greater DAP concentrations than outdoors workers (beta: 0.3, CI 95%: 0.1-0.5). Compared with non-acceptable use of PPE, acceptable use of PPE was associated with lower DAP concentrations (beta: -0.4, CI 95% -0.6 to -0.1). Conclusion Improved safety training is needed for correct PPE usage, especially among flower growers who use conventional pest control methods and who work in a greenhouse environment. PMID- 29484958 TI - Hybrid treatment of multilevel revascularization in patients with peripheral arterial disease - a multi-centre study in Korea. AB - BACKGROUND: Endovascular treatment is an alternative first-line management for peripheral artery disease (PAD). Hybrid treatment (HT) is defined as a combined treatment for patients with PAD using endovascular and open surgery, simultaneously performed in an operating room. The results of HT are reportedly good for multilevel revascularization (MR) in patients with chronic limb ischaemia, and even in older high-risk patients. The goal of this study was to examine the clinical and haemodynamic outcomes of HT in patients who need MR. PATIENTS AND METHODS: Nine university hospitals in Korea participated in this multicentre study. A total of 134 patients with multilevel PAD underwent HT and MR. Patients were enrolled from July 2014 to June 2015 and were followed for 18 months. RESULTS: The mean age of the patients was 68.8 +/- 9.93 years and 88.1 % were men. Patients with Rutherford category 2 to 3 and 4 to 6 comprised 59.0 % and 42.0 % of the group, respectively. The technical success rate was 100 %. The primary patency rates at 12 and 18 months were 77.6 % and 63.9 %, respectively. The primary-assisted patency rates at 12 and 18 months were both 90.0 %. The pre operative mean ankle brachial index (0.43 +/- 0.23) increased to 0.87 +/- 0.23 at six months post-operatively (t-test, p < 0.05). The amputation free survival rate was 97.1 %. CONCLUSIONS: Although outcomes of multilevel PAD are reportedly poor when endovascular treatment alone is used, we have shown that HT is a feasible alternative modality for patients with multilevel PAD, with satisfactory amputation-free survival and freedom from re-intervention rates. PMID- 29484959 TI - Chronic Total Occlusion Crossing Approach Based on Plaque Cap Morphology: The CTOP Classification. AB - PURPOSE: To present the chronic total occlusion (CTO) crossing approach based on plaque cap morphology (CTOP) classification system and assess its ability to predict successful lesion crossing. METHODS: A retrospective analysis was conducted of imaging and procedure data from 114 consecutive symptomatic patients (mean age 69+/-11 years; 84 men) with claudication (Rutherford category 3) or critical limb ischemia (Rutherford category 4-6) who underwent endovascular interventions for 142 CTOs. CTO cap morphology was determined from a review of angiography and duplex ultrasonography and classified into 4 types (I, II, III, or IV) based on the concave or convex shape of the proximal and distal caps. RESULTS: Statistically significant differences among groups were found in patients with rest pain, lesion length, and severe calcification. CTOP type II CTOs were most common and type III lesions the least common. Type I CTOs were most likely to be crossed antegrade and had a lower incidence of severe calcification. Type IV lesions were more likely to be crossed retrograde from a tibiopedal approach. CTOP type IV was least likely to be crossed in an antegrade fashion. Access conversion, or need for an alternate access, was commonly seen in types II, III, and IV lesions. Distinctive predictors of access conversion were CTO types II and III, lesion length, and severe calcification. CONCLUSION: CTOP type I lesions were easiest to cross in antegrade fashion and type IV the most difficult. Lesion length >10 cm, severe calcification, and CTO types II, III, and IV benefited from the addition of retrograde tibiopedal access. PMID- 29484960 TI - Spirulina effect on modulation of toxins provided by food, impact on hepatic and renal functions. AB - Spirulina platensis, is an alga rich in phycocyanin (potent antioxidant), is effective in regulating the balance of oxidative stress. The objective of this study is to observe the impact of ingestion of a highly oxidised vegetable oil, by rats of Wistar strain. Finally, we observe the effect of Spirulina used as an antioxidant treatment, on rats having ingested a diet rich in highly oxidised oil. Physiological, biochemical and histological studies have been carried out; the oxidative stress parameters evaluated and a dosing of Cytochrome P450 2E1 was finally carried out. Following the introduction of highly oxidised vegetable oil, rats showed deterioration in their metabolic state, an imbalance in the balance of oxidative stress, an increase in serum concentrations of Cytochrome P450 2E1 and significant hepatic lesions. The administration of a daily dose of Spirulina reduces the deleterious effect of oxidative stress induced by a diet enriched with lipid peroxides. PMID- 29484961 TI - Core/shell PLGA microspheres with controllable in vivo release profile via rational core phase design. AB - Highly soluble drugs tend to release from preparations at high speeds, which make them need to be taken at frequent intervals. Additionally, some drugs need to be controlled to release in vivo at certain periods, so as to achieve therapeutic effects. Thus, the objective of this study is to design injectable microparticulate systems with controllable in vivo release profile. Biodegradable PLGA was used as the matrix material to fabricate microspheres using the traditional double emulsification-solvent evaporation method as well as improved techniques, with gel (5% gelatine or 25% F127) or LP powders as the inner phases. Their physicochemical properties were systemically investigated. Microspheres prepared by modified methods had an increase in drug loading (15.50, 16.72, 15.66%, respectively) and encapsulation efficiencies (73.46, 79.42, 74.40%, respectively) when compared with traditional methods (12.01 and 57.06%). The morphology of the particles was characterized by optical microscope (OM) and scanning electron microscopy (SEM), and the amorphous nature of the encapsulated drug was confirmed by differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analysis. To evaluate their release behaviour, the in vitro degradation, in vitro release and in vivo pharmacodynamics were subsequently studied. Traditional microspheres prepared in this study with water as the inner phase had a relatively short release period within 16 d when compared with modified microspheres with 5% gelatine as the inner phase, which resulted in a smooth release profile and appropriate plasma LP concentrations over 21 d. Thus this type of modified microspheres can be better used in drugs requiring sustained release. The other two formulations containing 25% F127 and LP micropowders presented two-stage release profiles, resulting in fluctuant plasma LP concentrations which may be suitable for drugs requiring controlled release. All the results suggested that drug release rates from the microspheres prepared by various methods were mainly controlled by either the porosity inside the microspheres or the degradation of materials, which could, therefore, lead to different release behaviours. This results indicated great potential of the PLGA microsphere formulation as an injectable depot for controllable in vivo release profile via rational core phase design. Core/shell microspheres fabricated by modified double emulsification-solvent evaporation methods, with various inner phases, to obtain high loading drugs system, as well as appropriate release behaviours. Accordingly, control in vivo release profile via rational core phase design. PMID- 29484962 TI - Application and optimization of minimally invasive cell-free DNA techniques in oncogenomics. AB - The conventional method of measuring biomarkers in malignant tissue samples has already given subversive growth in cancer diagnosis, prognosis, and therapy selection. However, the regression and heterogeneity associated with tumor tissue biopsy have urged for the development of an alternative approach. Considering the limitations, cell-free DNA has emerged as a surrogate alternative, facilitating preoperative chemoradiotherapy (p < 0.0001) treatment response in rectal cancer and detection of biomarker in lung cancer. This potential of cell-free DNA in several other cancers has yet to be explored based on clinical relevance by optimizing the preanalytical factors. This review has highlighted the crucial parameters from blood collection to cell-free DNA analysis that has a significant impact on the accuracy and reliability of clinical data. The quantity of cell free DNA is also a limiting factor. Therefore, a proper preanalytical factor for blood collection, its stability, centrifugation speed, and plasma storage condition are to be optimized for developing cancer-specific biomarkers useful for clinical purpose. Liquid biopsy-based origin of cell-free DNA has revolutionized the area of cancer research. Lack of preanalytical and analytical procedures may be considered for identification of novel biomarkers through next generation sequencing of tumor-originated cell-free DNA in contradiction to tissue biopsy for cancer-specific biomarkers. PMID- 29484963 TI - Chaga ( Inonotus obliquus), a Future Potential Medicinal Fungus in Oncology? A Chemical Study and a Comparison of the Cytotoxicity Against Human Lung Adenocarcinoma Cells (A549) and Human Bronchial Epithelial Cells (BEAS-2B). AB - BACKGROUND: Inonotus obliquus, also known as Chaga, is a parasitic fungus growing on birches and used in traditional medicine (especially by Khanty people) to treat various health problems. In this study, we aimed to quantify the 3 metabolites frequently cited in literature, that is, betulin, betulinic acid, and inotodiol in the Chaga recently discovered in forests located in Normandy (France), and to compare their concentrations with Ukrainian and Canadian Chaga. This study also explores the cytotoxicity of the French Chaga against cancer derived cells and transformed cells. METHODS: A quantification method by HPLC-MS MS (high-performance liquid chromatography-tandem mass spectrometry) of betulin, betulinic acid, and inotodiol was developed to study the French Chaga and compare the concentration of these metabolites with extracts provided from Chaga growing in Canada and Ukraine. This method was also used to identify and quantify those 3 compounds in other traditional preparations of Chaga (aqueous extract, infusion, and decoction). Among these preparations, the aqueous extract that contains betulin, betulinic acid, and inotodiol was chosen to evaluate and compare its cytotoxic activity toward human lung adenocarcinoma cells (A549 line) and human bronchial epithelial cells (BEAS-2B line). RESULTS: French Chaga contains betulin and betulinic acid at higher levels than in other Chaga, whereas the concentration of inotodiol is greater in the Canadian Chaga. Moreover, the results highlighted a cytotoxic activity of the Chaga's aqueous extract after 48 and 72 hours of exposure with a higher effect on cancer-derived cells A549 than on normal transformed cells BEAS-2B ( P = 0.025 after 48 hours of exposure and P = 0.004 after 72 hours of exposure). PMID- 29484964 TI - Innovating for Transformation in First Nations Health Using Community-Based Participatory Research. AB - Community-based participatory research (CBPR) provides the opportunity to engage communities for sustainable change. We share a journey to transformation in our work with eight Manitoba First Nations seeking to improve the health of their communities and discuss lessons learned. The study used community-based participatory research approach for the conceptualization of the study, data collection, analysis, and knowledge translation. It was accomplished through a variety of methods, including qualitative interviews, administrative health data analyses, surveys, and case studies. Research relationships built on strong ethics and protocols to enhance mutual commitment to support community-driven transformation. Collaborative and respectful relationships are platforms for defining and strengthening community health care priorities. We further discuss how partnerships were forged to own and sustain innovations. This article contributes a blueprint for respectful CBPR. The outcome is a community-owned, widely recognized process that is sustainable while fulfilling researcher and funding obligations. PMID- 29484965 TI - Advancing progressive health policy to reduce NCDs amidst international commercial opposition: Tobacco standardised packaging in Australia. AB - This study examines how health advocates and the Australian government responded to international commercial pressure during the implementation of tobacco standardised packaging (SP) as a measure to reduce non-communicable diseases (NCDs). Relevant government and NGO documents, and media items were reviewed. Policymakers and health advocates (n = 19) in Australia were interviewed. In 2009, Australia's National Health Taskforce recommended SP, which the Australian government announced in April 2010. In response, tobacco companies threatened the government with litigation in both domestic and international courts, claiming that SP would violate their investment and intellectual property rights. However, these legal threats were unsuccessful in forcing the government to withdrawal the SP proposal. Tobacco companies legally challenged SP, but as of February 2018 failed with each legal challenge. The political success of enacting and implementing SP against international commercial pressure was supported by legal preparation and support, and a whole-of-government approach. The Australian SP case illustrates how, against international commercial opposition, governments can build and maintain political and official support to enact and implement progressive public health measures to reduce NCDs. PMID- 29484966 TI - Public Discourses of Ebola Contagion and Courtesy Stigma: The Real Risk to International Health Care Workers Returning Home From the West Africa Ebola Outbreak? AB - This article explores the homecoming experiences of international health care workers who responded to the 2014 to 2016 West African Ebola outbreak. Interviews with 11 frontline international medical staff were undertaken and data thematically analyzed. It was found that international health care workers faced an unforeseen risk of stigmatization upon their return home, related to others' fears of their infectious status. Media representations of the disease appear to have played a significant role in heightening societal perceptions of the risks associated with the returning health care workers, resulting in public hostility toward them. For participants, these social risks overtook concerns about biological risks during the immediate postmission period. The participants developed different strategies to cope with courtesy stigma, by rationalizing stigmatizing attitudes, educating people, or simply through an avoidance of others. PMID- 29484969 TI - Erratum. PMID- 29484968 TI - DNA Methylation Markers Improve the Sensitivity of Endoscopic Retrograde Cholangiopancreatography-Based Brushing Cytology in Extrahepatic Cholangiocarcinoma. AB - Endoscopic retrograde cholangiopancreatography with brushed cytology is still the standard method for the diagnosis of extrahepatic cholangiocarcinoma in obstructive jaundice; however, the diagnostic yield is limited. To improve the diagnostic sensitivity, DNA methylation analysis is an attractive candidate, since this may constitute a stable marker in brushed specimens. Therefore, this study aims to evaluate the importance of such epigenetic markers in brushed biliary cells from patients with obstructive jaundice for the diagnosis of extrahepatic cholangiocarcinoma. The cells examined were those that were left over from brushed cytology done during routine endoscopic retrograde cholangiopancreatography of patients with extrahepatic cholangiocarcinoma. The methylation states of HOXA1, RASSF1A, P16, and NEUROG1 genes in extrahepatic cholangiocarcinoma were measured by quantitative methylation-specific polymerase chain reaction and compared between brushed biliary cells and normal gall bladder epithelial cells. The results showed that the sensitivity of the methylation index measurements of HOXA1 and NEUROG1 genes from brushed samples was markedly superior to that of standard cytology. In conclusion, measurement of the DNA methylation status of HOXA1 and NEUROG1 genes in leftover brushed biliary cells might serve as a useful supplement in the detection of malignant biliary obstruction by increasing the sensitivity of diagnosis by routine cytology. PMID- 29484970 TI - The effects of anionic and non-ionic surfactant on anaerobic co-digestion of sludge, food wastes and green wastes. AB - Surfactants are widely used and discharged into wastewater treatment plants, which might influence the anaerobic digestion (AD) treatment of municipal waste. In this study, the effects of typical anionic surfactants sodium dodecyl benzene6 sulfonate (SDBS) and non-ionic surfactants APG, on mesophilic anaerobic co digestion of sludge, food waste, and green waste were investigated. Results indicated that at 5 mg/g, the biogas production was inhibited in SDBS supplemented systems while stimulated in APG-added reactors, with the methane yield of 146.58 L/g VS consumed. At 15 mg/g, the biogas production in both SDBS and APG supplemented reactors was both inhibited. It means the negative or positive effect of APG on AD depends on the dose of APG supplementation. The 16S rRNA gene analysis demonstrated the microbial community structure in the digester was changed due to the addition of surfactant. Bacteroidia significantly increased with the addition of APG and SBDS, while the increase of Clostridia only occurred in APG-added system. The variation of microbial Communities' structure in APG and SDBS-added digesters might give an explanation for the different efficiencies in these two systems. Thus, the effects of surfactants on the efficiency of AD should be considered during the disposal of municipal organic waste. PMID- 29484972 TI - A Novel Pathologic Variant in OTOF in an Iranian Family Segregating Hereditary Hearing Loss. AB - Objective Hearing loss (HL) is the most common sensory-neural defect and the most heterogeneous trait in humans, with the involvement of >100 genes, which make a molecular diagnosis problematic. Next-generation sequencing (NGS) is a new strategy that can overcome this problem. Study Design Descriptive experimental study. Setting Diagnostic laboratory. Subjects and Methods A comprehensive family history was obtained, and clinical evaluations and pedigree analysis were performed in a family with multiple individuals with HL. As the first tier, GJB2 was sequenced, and genetic linkage analysis of DFNB1A/B was performed to rule out the most common cause of the disease. Targeted NGS was used to unravel the molecular etiology of the disease in the HL-associated genes in the proband. Two homozygous variants remained in OTOF after proper filtration. Cosegregation and in silico analysis were done. Preimplantation genetic diagnosis (PGD) was accomplished via linkage analysis and direct sequencing of the pathogenic variant. Results Clinical evaluations suggested autosomal recessive nonsyndromic HL. Two homozygous variants, c.367G>A (p.Gly123Ser) and c.1392+1G>A, were identified in cis status. c.1392+1G>A met the criteria for being pathogenic according to the variant interpretation guideline of the American College of Medical Genetics and Genomics. PGD was successfully performed to prevent the recurrence of the disease in the related family. Conclusion A novel OTOF mutation causing HL was identified. Here, we report the effectiveness of the combined application of targeted NGS and PGD in diagnosis and prevention of hereditary HL. PMID- 29484973 TI - Organic fluorescent dye-based nanomaterials: Advances in the rational design for imaging and sensing applications. AB - Self-assembled fluorescent nanomaterials based on small-molecule organic dyes are gaining increasing popularity in imaging and sensing applications over the past decade. This is primarily due to their ability to combine spectral property tunability and biocompatibility of small molecule organic fluorophores with brightness, chemical, and colloidal stability of inorganic materials. Such a unique combination of features comes with rich versatility of dye-based nanomaterials: from aggregates of small molecules to sophisticated core-shell nanoarchitectures involving hyperbranched polymers. Along with the ongoing discovery of new materials and better ways of their synthesis, it is very important to continue systematic studies of fundamental factors that regulate the key properties of fluorescent nanomaterials: their size, polydispersity, colloidal stability, chemical stability, absorption and emission maxima, biocompatibility, and interactions with biological interfaces. In this review, we focus on the systematic description of various types of organic fluorescent nanomaterials, approaches to their synthesis, and ways to optimize and control their characteristics. The discussion is built on examples from reports on recent advances in design and applications of such materials. Conclusions made from this analysis allow a perspective on future development of fluorescent nanomaterials design for biomedical and related applications. PMID- 29484971 TI - Music Training Can Improve Music and Speech Perception in Pediatric Mandarin Speaking Cochlear Implant Users. AB - Due to limited spectral resolution, cochlear implants (CIs) do not convey pitch information very well. Pitch cues are important for perception of music and tonal language; it is possible that music training may improve performance in both listening tasks. In this study, we investigated music training outcomes in terms of perception of music, lexical tones, and sentences in 22 young (4.8 to 9.3 years old), prelingually deaf Mandarin-speaking CI users. Music perception was measured using a melodic contour identification (MCI) task. Speech perception was measured for lexical tones and sentences presented in quiet. Subjects received 8 weeks of MCI training using pitch ranges not used for testing. Music and speech perception were measured at 2, 4, and 8 weeks after training was begun; follow-up measures were made 4 weeks after training was stopped. Mean baseline performance was 33.2%, 76.9%, and 45.8% correct for MCI, lexical tone recognition, and sentence recognition, respectively. After 8 weeks of MCI training, mean performance significantly improved by 22.9, 14.4, and 14.5 percentage points for MCI, lexical tone recognition, and sentence recognition, respectively ( p < .05 in all cases). Four weeks after training was stopped, there was no significant change in posttraining music and speech performance. The results suggest that music training can significantly improve pediatric Mandarin-speaking CI users' music and speech perception. PMID- 29484974 TI - UDP-glucuronosyltransferases: Structure, Function and Drug Design Studies. AB - UDP-glucuronosyltransferases (UGTs) are important phase II metabolic enzymes responsible for approximately 40-70% of endo and xenobiotic reactions. It catalyzes the transfer of glucuronic acid to lipophilic substrates, converting them into hydrophilic compounds that are excreted. There are 22 active human UGTs that belong to 4 families. This review focuses on human UGTs, highlighting the most current issues in order to connect all information available and allowing a discussion on the challenges already solved and those in which we need to move forward. Although, several UGTs studies have been conducted, the most recent ones addressing drug-drug interactions and polymorphism issues, there are still bottlenecks to overcome. Tridimensional structure is difficult to obtain due to overexpression, purification, and crystallization problems as well as the action mechanism - since overlapping of substrate specificities renders impasses on the identification of which isoform is responsible for a particular drug metabolic pathway. For this reason, bioinformatic tools are gaining more space, since it is a faster and less expensive reliable methodology that complements in vitro and in vivo researches. Combinations of quantum and molecular methods have become increasingly common, leading to the incorporation of enzyme features comprising their structure, dynamics and chemical reactions. Breakthroughs related to the enzyme, not only enable the discovery of new drugs essential for the treatment of various diseases, but also provide an improved action of the existing drugs. PMID- 29484975 TI - The Clustered DNA Lesions - Types, Pathways of Repair and Relevance to Human Health. AB - The clustered DNA lesions are a characteristic feature of ionizing radiation and are defined as two or more damage sites formed within 20 bps after the passage of a single radiation track. The clustered DNA lesions are divided into two major groups: double-stranded breaks (DSBs) and non-DSB clusters also known as Oxidatively-induced Clustered DNA Lesions (OCDLs), which could involve either two opposing strands or the same strand. As irradiation is gaining greater interest in cancer treatment as well as in imaging techniques, the detailed knowledge of its genotoxicity and the mechanisms of repair of radiation-induced DNA damage remain issues to explore. In this review we look at the ways the cell copes with clustered DNA lesions, especially with 5',8-cyclo-2'-deoxypurines. As the base excision repair deals with isolated lesions, complex damage is more difficult to repair. Depending on the number of lesions within a cluster, their types and mutual distribution, long-patch BER or NER are activated. During the repair of opposing lesions, DSBs could be generated, which are repaired either by nonhomologous end joining (NHEJ) or homologous recombination (HR). The repair of individual lesions within a cluster progresses gradually. This slower processing of particular damage might lead to severe biological consequences such as misrepair, mutations and chromosomal rearrengement as it enhances the plausibility of a cluster encountering a replication fork prior to its repair. The consequences of clustered DNA lesions on cell survival and their relevance to the efficacy and safety of radiotherapy and radiodiagnosis will also be discussed. PMID- 29484976 TI - New Life to an Old Treatment: Pegylated Interferon Beta 1a in the Management of Multiple Sclerosis. AB - BACKGROUND: In the 1990s, the beta interferons and glatiramer acetate were introduced for treating relapsing-remitting multiple sclerosis. These medications have a demonstrated record of efficacy and safety, although they require frequent administration via injection and are only partially effective. The optimization of treatment in patients who do not respond adequately to this first-line therapy is essential for attaining the best long-term outcomes. Switching to the recently approved emergent therapies is a strategy to consider for treatment of patients with a suboptimal response. OBJECTIVE: This review summarizes the mechanisms of action, clinical benefits, and safety profiles of current multiple sclerosis disease-modifying therapies, including highly efficacious monoclonal antibodies or convenient oral therapies, and with a special focus on the pegylated interferon beta 1a formulation. METHODS: We reviewed the recent literature and human clinical trials on multiple sclerosis therapies by bibliographic search in PubMed and clinicaltrials.gov. RESULTS AND CONCLUSION: Although the first-line interferon beta exhibits a favorable benefit-torisk profile, treatment compliance is compromised potentially due to its known adverse events and frequent injectable administration. Less frequent dosing and improved pharmacological properties have been achieved by reaction of interferon beta with chemically activated polyethylene glycol. Provided that none of the available therapies show better effectiveness for all outcomes and their safety in clinical practice is of a fundamental concern, the pegylated form of interferon beta seems to keep its place as a competitive therapeutic option. PMID- 29484977 TI - Toward Computational Understanding of Molecular Recognition in the Human Metabolizing Cytochrome P450s. AB - Cytochrome P450s are enzymes capable of metabolizing a wide variety of drugs. Their significant impact in drug discovery has led to extensive research, computationally and experimentally, in order to explore how a chemical entity responds to metabolizing enzymes. We present an overview of ligand-based and structure-based methodologies, along with pertinent information on the structures, biology, and relevance of these enzymes. PMID- 29484978 TI - RAS in the Central Nervous System: Potential Role in Neuropsychiatric Disorders. AB - BACKGROUND: The Renin-Angiotensin System (RAS) is a key regulator of cardiovascular and renal homeostasis, but also plays important roles in mediating physiological functions in the central nervous system (CNS). The effects of the RAS were classically described as mediated by angiotensin (Ang) II via angiotensin type 1 (AT1) receptors. However, another arm of the RAS formed by the angiotensin converting enzyme 2 (ACE2), Ang-(1-7) and the Mas receptor has been a matter of investigation due to its important physiological roles, usually counterbalancing the classical effects exerted by Ang II. OBJECTIVE: We aim to provide an overview of effects elicited by the RAS, especially Ang-(1-7), in the brain. We also aim to discuss the therapeutic potential for neuropsychiatric disorders for the modulation of RAS. METHOD: We carried out an extensive literature search in PubMed central. RESULTS: Within the brain, Ang-(1-7) contributes to the regulation of blood pressure by acting at regions that control cardiovascular functions. In contrast with Ang II, Ang-(1-7) improves baroreflex sensitivity and plays an inhibitory role in hypothalamic noradrenergic neurotransmission. Ang-(1-7) not only exerts effects related to blood pressure regulation, but also acts as a neuroprotective component of the RAS, for instance, by reducing cerebral infarct size, inflammation, oxidative stress and neuronal apoptosis. CONCLUSION: Pre-clinical evidence supports a relevant role for ACE2/Ang-(1-7)/Mas receptor axis in several neuropsychiatric conditions, including stress-related and mood disorders, cerebrovascular ischemic and hemorrhagic lesions and neurodegenerative diseases. However, very few data are available regarding the ACE2/Ang-(1-7)/Mas receptor axis in human CNS. PMID- 29484979 TI - Role of Autophagy in Parkinson's Disease. AB - Autophagy is an essential catabolic mechanism that delivers misfolded proteins and damaged organelles to the lysosome for degradation. Autophagy pathways include macroautophagy, chaperone-mediated autophagy and microautophagy, each involving different mechanisms of substrate delivery to lysosome. Defects of these pathways and the resulting accumulation of protein aggregates represent a common pathobiological feature of neurodegenerative disorders such as Alzheimer, Parkinson and Huntington disease. This review provides an overview of the role of autophagy in Parkinson's disease (PD) by summarizing the most relevant genetic and experimental evidence showing how this process can contribute to disease pathogenesis. Given lysosomes take part in the final step of the autophagic process, the role of lysosomal defects in the impairment of autophagy and their impact on disease will be also discuss. A glance on the role of non-neuronal autophagy in the pathogenesis of PD will be included. Moreover, we will examine novel pharmacological targets and therapeutic strategies that, by boosting autophagy, may be theoretically beneficial for PD. Special attention will be focused on natural products, such as phenolic compounds, that are receiving increasing consideration due to their potential efficacy associated with low toxicity. Although many efforts have been made to elucidate autophagic process, the development of new therapeutic interventions requires a deeper understanding of the mechanisms that may lead to autophagy defects in PD and should take into account the multifactorial nature of the disease as well as the phenotypic heterogeneity of PD patients. PMID- 29484980 TI - Innovative Therapeutic Potential of Cannabinoid Receptors as Targets in Alzheimer's disease and Less Well-Known Diseases. AB - The discovery of cannabinoid receptors at the beginning of the 1990s, CB1 being cloned in 1990 and CB2 cloned in 1993, and the availability of selective and potent cannabimimetics could only be justified by the existence of endogenous ligands that are capable of binding to them. Thus, the characterisation and cloning of the first cannabinoid receptor (CB1) led to the isolation and characterisation of the first endocannabinoid, arachidonoylethanolamide (AEA), two years later and the subsequent identification of a family of lipid transmitters known as the fatty acid ester 2-arachidonoylglycerol (2-AG). The endogenous cannabinoid system is a complex signalling system that comprises transmembrane endocannabinoid receptors, their endogenous ligands (the endocannabinoids), the specific uptake mechanisms and the enzymatic systems related to their biosynthesis and degradation. The endocannabinoid system has been implicated in a wide diversity of biological processes, in both the central and peripheral nervous systems, including memory, learning, neuronal development, stress and emotions, food intake, energy regulation, peripheral metabolism, and the regulation of hormonal balance through the endocrine system. In this context, this article will review the current knowledge of the therapeutic potential of cannabinoid receptor as a target in Alzheimer's disease and other less well-known diseases that include, among others, multiple sclerosis, bone metabolism, and Fragile X syndrome. The therapeutic applications will be addressed through the study of cannabinoid agonists acting as single drugs and multi-target drugs highlighting the CB2 receptor agonist. PMID- 29484981 TI - Development of an Aqueous Ophthalmic Solution with an Enhanced-Solubility Enrofloxacin Crystal, and its Clinical Evaluation in Dogs. AB - BACKGROUND: The concern about the frequent use of ciprofloxacin in veterinary medicine is linked to increased antimicrobial resistance. The corresponding fluoroquinolone for veterinary use is enrofloxacin. A new solvate form of enrofloxacin, as dihydrate-hydrochloride (enro-C) with higher water solubility than the parent compound, was formulated as an ophthalmic solution (pH 5). A multicentre, longitudinal, non-inferiority clinical study in a non-hospital environment was designed to treat 36 dogs affected by tobramycin-unresponsive conjunctivitis with either the experimental 0.5% enro-C ophthalmic preparation (enro-CG) or a commercial preparation of ciprofloxacin (cipro-G). Other causes of conjunctivitis were ruled out. Pathogens were isolated and minimum inhibitory concentration (MIC) studies of tobramycin were carried out. Three blocks of bacterial resistance were set up, beginning at the established breakpoint i.e., 4 ug/mL; 8 ug/mL and 16 ug/mL. Eighteen dogs were randomly assigned to each block. The enro-CG group was treated with two drops of the referred preparation (10 mg/eye) twice a day for 7 days, and the cipro-G group was treated with four drops of a 0.3% commercially available ciprofloxacin eye-drop preparation (9 mg/eye) twice a day, also for 7 days. Clinical and bacteriological cure rates were evaluated. RESULTS: Enro-C-treated dogs achieved a clinical cure one day earlier than ciprofloxacin-treated dogs, and unlike this latter group, enro-CG achieved bacteriological cure in all cases. No side effects were observed in either group, but dogs treated with enro-C showed no discomfort, allowing easier treatment compliance. CONCLUSION: This is the first study reported on the successful formulation of enrofloxacin as an ophthalmic solution. Clinical assessment reveals outstanding clinical efficacy. It is necessary to conduct further research on clinical efficacy and toxicity, with the chronic use of this preparation under different clinical challenges. PMID- 29484982 TI - Leukocyte Imaging of the Diabetic Foot. AB - BACKGROUND: Diagnosing diabetic foot infection is often difficult, despite several available diagnostic methods. Amongst these, several imaging modalities exist to evaluate the diabetic foot in case of a suspected osteomyelitis. Nuclear Medicine, in particular, offers a variety of radiopharmaceuticals and techniques. Nowadays the gold standard radionuclide procedure, when an osteomyelitis is suspected, is represented by the use of radiolabelled leukocytes with either 99mTc-HMPAO or 111In-oxine. METHODS: In this review, we describe the correct acquisition and interpretation of white blood cell scintigraphy and we provide an overview of the existing literature data of the use of this technique in the infected diabetic foot. If images are correctly acquired, displayed and interpreted, this modality reaches very high diagnostic accuracy (>95%) in detecting osteomyelitis and it allows the differential diagnosis with a soft tissue infection or inflammation. Single-photon emission computed tomography/computed tomography (SPECT/CT) in addition to planar images is mandatory to determine the extent and exact location of the infective process in both fore foot and midhint foot. With the addition of bone marrow scintigraphy using radiolabelled nanocolloids, radiolabelled white blood cell scintigraphy is also able to differentiate between Charcot neuroarthropathy and osteomyelitis, which is a challenge in the evaluation of diabetic foot. Radiolabelled anti granulocyte monoclonal antibodies and their fragments can also be used instead of white blood cells although there is a limited experience on their usefulness in diabetic foot infection. PMID- 29484983 TI - New Imaging Tracers for the Infected Diabetic Foot (Nuclear and Optical Imaging). AB - Diabetic Foot Infections (DFIs) are associated with increased morbidity, an economic burden on patients, their families and healthcare systems and increased mortality. Early diagnosis with prompt, appropriate and adequate treatment of the infected diabetic foot is crucial. The determination of DFIs, however, may be quite perplexing and invasive. Imaging is useful in the evaluation of certain cases of DFIs, especially in suspected instances with no overt clinical features, or in the diagnosis of osteomyelitis. Nuclear medicine imaging is currently used in the evaluation of DFIs; however, like all the imaging techniques now available, it has its limitations. Several radiopharmaceuticals presently available play useful roles in the management of DFIs, while new ones are being evaluated. Optical imaging techniques have recently demonstrated promising results in the evaluation of many infections including DFIs. Using the same molecule, a tracer can be labeled with a radioisotope or an optical imaging dye. This enables infections to be evaluated both pre- and intra-operatively when surgery is required in their management. In some cases, tracers have been simultaneously labeled with both a radioisotope and an optical imaging dye to produce a hybrid tracer. These new tracers potentially provide powerful and new opportunities in the management of DFIs. In this review, we briefly examine tracers that have been used in the evaluation of the infected diabetic foot. We then explore the potential of new imaging tracers currently under development for infection that may be useful in the management of DFIs. PMID- 29484984 TI - Diabetic Foot Infection: The Role of PET/CT Imaging. AB - Osteomyelitis in the diabetic foot can be difficult to diagnose and has serious consequences. Although 2-deoxy-2-[18F]-fluoro-D-glucose (FDG) positron emission tomography (PET) was traditionally used in oncology, it is emerging as a useful method in inflammatory and infectious entities. In this chapter, original research articles, meta-analyses, and reviews on the performance of FDG PET in diagnosing osteomyelitis in the diabetic foot will be discussed. In addition, PET available data in comparison to different imaging methods, different analysis methods, and impact of other co-existing conditions such as hyperglycemia, and long-term antibiotic treatment on the performance of FDG PET will be reviewed. Studies published in the last two decades showed variable performance of FDG PET in the assessment of diabetic foot infection with a relatively high specificity (67-93%) but a wide range of sensitivity (29-100%). More recent studies showed better sensitivity, probably due to improved imaging technology and analysis methods and use of hybrid imaging with positron emission tomography/ computed tomography (PET/CT). FDG PET/CT has several advantages compared to other anatomical and functional imaging methods, including short acquisition time, high resolution, low radiation dose, and better tolerability. Further research is required to establish its role in the clinical practice. PMID- 29484985 TI - A Dual Targeting Drug Delivery System for Penetrating Blood-Brain Barrier and Selectively Delivering siRNA to Neurons for Alzheimer's Disease Treatment. AB - BACKGROUND: Alzheimer's disease (AD) is one of most serious threats to human beings, however, the treatment is hindered by blood-brain barrier and poor intra brain cell selectivity. METHODS: In this study, we developed a novel dual targeting drug delivery system by modification of NL4 peptide and apolipoprotein A-I (ApoA-I) onto dendrimer particles that may efficiently deliver siRNA into neuron cells to down-regulate BACE1 and inhibit Abeta formation. The constructed ANNP/ siRNA was approximately 79.26 nm with a spherical structure and a zeta potential of 3.53 mV. At N/P ratio of 10, the siRNA could be completely packaged into particles to avoid degradation by RNAase. RESULTS: In vitro, the modification with ApoA-I considerably increased bEnd.3 cell uptake and NL-4 considerably increased PC12 cell uptake. As a result, ANNP/siRNA showed higher uptake in both the cells. In addition, ANNP/siRNA could efficiently penetrate through bEnd.3 monolayers, which was 2.4-fold higher than unmodified complexes. In PC12 cells, the ANNP/siRNA could escape from endosomes and transport into cytoplasm after 8 h incubation, resulting in 87.5% BACE1 gene knockdown capacity, which was better than PEI. Additionally, the particles showed low cytotoxicity to both bEnd.3 and PC12 cells. CONCLUSION: In conclusion, this study preliminarily demonstrated that ApoA-I and NL4 dual modified dendrimer nanoparticles were efficient carriers for siRNA delivery to AD bearing brain. PMID- 29484986 TI - Characterization of Biologically Active Substances from Calendula officinalis. AB - BACKGROUND: The aim of this work was to compare water and organic extracts, infusions and tinctures from flowers and leaves of Calendula officinalis in terms of their biological activity and composition. The purpose of work was investigation whether the leaves and stems are really the waste or they contain interesting substances which could be utilized. Antimicrobial, antifungal, antioxidant and anti-inflammatory activities were studied. Then, the ability to inhibit collagenase was studied as well. Cytotoxicity was tested for all the samples on mammalian cell lines. METHODS: To determine the composition of extracts, infusions and tinctures phytochemical analysis (the set of colour reactions for the detection of groups of biologically active compounds) was carried out and showed that samples from flowers and leaves contain the same groups of biologically active substances (proteins and amino acids, reducing sugars, flavonoids, saponins, phenolics, terpenoids, steroids, glycosides). The antimicrobial activity of tested samples was proved, where the most sensitive bacterium was Micrococcus luteus and the most sensitive yeast was Geotrichum candidum. RESULTS: The study of anti-collagenase activity has shown that the enzymatic reaction of collagenase was affected by all tested samples and their effect was concentration dependent. Cytotoxicity of water and methanol extracts at cell lines HEK 293T and HepG2 was observed. CONCLUSION: Cells HepG2 were more sensitive than cells HEK 293T. Using cell line RAW 264.7, antiinflammatory activity of all samples was observed. Tincture of leaves was the most effective. PMID- 29484987 TI - Determination and Isolation of Four Anti-tumour Saponins from Lonicera macranthoides by HPLC-ESI-QTOF/MS and HSCCC. AB - BACKGROUND: Lonicera macranthoides is a Chinese herb that contains a large number of bioactive spanions possessing important pharmacological activities, such as anti-tumour activity. However, detailed information about their anti-tumor activity and bioactive compounds is limited. METHODS: In order to evaluate the scientific basis, the method of high-speed counter-current chromatography (HSCCC) combined with high performance liquid chromatography mass spectrometry (HPLC-ESI QTOF/MS) has been developed to separate, purify and analyze saponins from Lonicera macranthoides. Four main saponins, Macranthoidin B (I), Macranthoidin A (II), Macranthoides B (III) and Akebia saponin D (IV) were separated by HSCCC with the solvent systems of ethyl acetate-nbutanol- water (3:2:5) and n-butanol water-methanol-ethyl acetate (1:6:0.5:4). The purities of these four bioactive ingredients (I-IV) identified and detected by HPLC-ESI-QTOF/MS were 95.1%, 92.7%, 91.8% and 96.3%, respectively. The separated saponins were evaluated for their cytotoxic activities against six tumor cell lines (MCF-7, Hela, A549, HepG2, HT29 and Eca109). RESULTS: Results show that compounds I-IV exhibited particular significant anti-tumor activities against human mammary adenocarcinoma MCF-7 cell with IC50 values ranging from 12.7 to 30.8 uM. CONCLUSION: It was demonstrated that the combinative method using HPLC-ESI-QTOF/MS and HSCCC was suitable for rapid screening and isolating saponins of Lonicera macranthoides and the isolated compounds have great potential for the development of new antitumor drugs. PMID- 29484988 TI - Separate Toxin-Antidote Stabilization System in Two Plasmids for Recombinant Protein Production. AB - BACKGROUND: Expression vector is an important component in the production of therapeutic recombinant proteins. Most of the commercialized expression vectors apply antibiotic-based selection system. Meanwhile, World Health Organization highly recommends for the alternative system due to its potentials to cause spreading of resistance gene and hypersensitivity to some people. METHODS: In current work, we developed an expression system for Escherichia coli using the toxinantidote system in two separated plasmids. An antidote gene (ccdA) with its natural promoter and terminator was constructed in a plasmid (pDCSAsod) containing a DNA fragment encoding recombinant superoxide dismutase from Staphylococcus equorum (rMnSODSeq) as a model. The gene expression was directed under T7 promoter and regulated by lac operator. The toxin gene (ccdB) was located in a separate plasmid (pDCSB) under PBAD promoter. This study aimed to study the growth profile of the host in the presence of both plasmids, to determine plasmids stability, and the effect of the toxinantidote system on rMnSODSeq production and activity. RESULTS: The presence of both plasmids did not affect the growth profile of E. coli BL21(DE3), while the plasmid stability was 94% for pDCSAsod and 68% for pDCSB at the end of protein production time. The yield of purified rMnSODSeq was 3.2 mg/ml and the enzyme was shown to be active by a zymography assay. CONCLUSION: In conclusion, for the first time, we show that toxin-antidote system in two separated plasmids has the potential for the production of recombinant therapeutic proteins and is more flexible in choosing the E. coli strain compared to established chromosomally integrated toxin antidote selection system. PMID- 29484989 TI - An Atlas of Anionic Antimicrobial Peptides from Amphibians. AB - Anionic antimicrobial peptides (AAMPs) with net charges ranging from -1 to -8 have been identified in frogs, toads, newts and salamanders across Africa, South America and China. Most of these peptides show antibacterial activity and a number of them are multifunctional, variously showing antifungal activity, anticancer action, neuropeptide function and the ability to potentiate conventional antibiotics. Antimicrobial mechanisms proposed for these AAMPs, include toroidal pore formation and the Shai-Huang-Matsazuki model of membrane interaction along with pH dependent amyloidogenesis and membranolysis via tilted peptide formation. The potential for therapeutic and biotechnical application of these AAMPs has been demonstrated, including the development of amyloid-based nanomaterials and antiviral agents. It is concluded that amphibian AAMPs represent an untapped potential source of biologically active agents and merit far greater research interest. PMID- 29484990 TI - Biosynthesis of Carnosine and Related Dipeptides in Vertebrates. AB - Carnosine (beta-alanyl-L-histidine) and its methylated derivatives: anserine (beta-alanyl-Npi- methyl-L-histidine) and balenine (beta-alanyl-Ntau-methyl-L histidine) are abundant constituents of excitable tissues of vertebrates. While carnosine and anserine are present at high concentrations and in variable proportions in skeletal muscle and brain of most vertebrates, balenine appears to be rather more abundant in marine mammals and certain reptilian species. Since the discovery of these compounds at the beginning of 20th century, numerous studies have been devoted to identification of the biochemical and physiological properties of carnosine and related dipeptides. These led to the discovery of the pHbuffering, metal-chelation and antioxidant, capabilities of carnosine and anserine, although no definitive ideas concerning their physiological role has yet been formulated. Only recently the molecular identities of the enzymes catalyzing synthesis of carnosine (carnosine synthase, EC 6.3.2.11) and anserine (carnosine N-methyltransferase, EC 2.1.1.22) have been elucidated, which has given a new insight into their metabolism in vertebrates. These findings have opened new research areas and provide authentic opportunities for understanding the biological function of these "enigmatic" dipeptides. This review aims to summarize recent advances in our knowledge concerning enzymes responsible for the biosynthesis of carnosine and related dipeptides and to evaluate their importance in vertebrate physiology. PMID- 29484991 TI - A New Investigational Perspective for Purines Against Glioblastoma Invasiveness. AB - BACKGROUND: Glioblastoma Multiforme (GBM) is the most common and lethal brain malignancy. Recent evidence suggests that the presence of stem-like cells (GSCs) inside the tumor with high self-renewal, resistance to chemotherapy and invasiveness/migration potential is associated with poor GBM prognosis. GSC aggressiveness seems to be linked to an important process involved in tumorigenesis and cancer metastasis called Epithelial-to-Mesenchymal Transition (EMT), which is responsible for several biochemical changes and the acquisition of a more mesenchymal phenotype by GSCs, that enhance their migration, invasiveness and resistance to apoptosis. OBJECTIVE: Since previous reports demonstrated that purines, interacting with their own receptors, exerted anti tumor effects in GBM and derived cells, we tried to investigate the ability of these compounds to reduce tumor cell migration/invasion acting on EMT-associated genes/activators and/or signal pathways. METHODS: Search in the literature of relevant articles related to the objective. RESULTS: Papers examining the activity of purines on EMT signaling pathways/markers in GSCs are still few whereas literature is more abundant as for other kinds of tumors. CONCLUSION: Considering the significance of EMT in GBM aggressiveness and the promising involvement of purines in this process, we think that further research in this regard may open the way towards a new therapeutic approach for the control of GBM invasiveness/recurrence. PMID- 29484992 TI - Potential of Liquid Biopsy in Papillary Thyroid Carcinoma in Context of miRNA, BRAF and p53 Mutation. AB - BACKGROUND: Liquid biopsy is a minimally invasive detection method for molecular biomarkers such as miRNA and cell free DNA in body fluids. Deregulations of miRNA are involved in papillary thyroid carcinoma (PTC), one the most common endocrine malignancy. The most widespread common mutations detected in papillary thyroid cancers are BRAF mutations. Many studies indicate that the BRAF mutation is related to deregulation of miRNA. p53 has an important role in cell cycle control, DNA repair and apoptosis. Moreover, the p53 can regulate the expression of miRNAs and thus participate in thyroid oncogenesis. OBJECTIVE: In this review, we briefly summarize the present state of knowledge about miRNA, BRAF and p53 mutation in the development of PTC and the possibility of using detecting BRAF mutation and miRNA expression in liquid biopsy. RESULTS: The use of the plasma miRNA expression profile in combination with the BRAF mutation analysis in cf-DNA may be a valuable tool in management of PTC. CONCLUSION: Numerous molecular variation characterize recent diagnostic and prognostic markers and therapeutic targets for this type of cancer, which offer unique chances for further research and clinical development of innovative treatment strategies for thyroid cancer. PMID- 29484993 TI - The Use of Antidepressants for Physical and Psychological Symptoms in Cancer. AB - : Cancer patients are commonly associated with various physical and psychological symptoms. In palliative setting, the aims are to relieve those symptoms, improve quality of life, and increase medication adherence among cancer patients. Antidepressants are generally accepted for the treatment of depression among patients with or without cancer. Some other potential benefits of the antidepressants have been reported in cancer patients. OBJECTIVE: This study aims to review the use of antidepressants for physical and psychological symptoms in cancer patients. RESULTS: Our findings showed the mixed result of positive and negative findings in various symptoms associated with cancer patients. These studies are categorised according to the hierarchy of evidence from high to low level, namely randomised controlled trials, cohort studies, case-control studies, case series, case reports, as well as other type of publications. The majority of antidepressants used in cancer patients seem to be beneficial for the treatment of depression, anxiety, hot flashes and other symptoms such as sexual dysfunction, fatigue, nicotine dependence, vasomotor symptoms, executive functions, sleep problems, pruritus, as well as for hypochondriasis. While fluoxetine was found to be associated with the reduction of antiemetic property in ondansetron, mirtazapine was identified to be a good alternative in treating nausea and cachexia among cancer patients. CONCLUSION: More research studies with adequate statistical power are warranted to validate the use of antidepressants among cancer patients in treating these physical and psychological symptoms. PMID- 29484994 TI - Antifungal Activity of Eugenol Loaded Electrospun PAN Nanofiber Mats Against Candida Albicans. AB - BACKGROUND: Eugenol, as the major phenolic component of clove essential oil due to its desired properties in medical field, was loaded into polyacrylonitrile (PAN) nanofibers with various percentages. OBJECTIVE: Our main purpose in this study was to determine the in vitro antifungal activity of eugenol loaded on PAN nanofibers against Candida albicans as the most common causative agent for candidiasis. METHOD: Also, the surface morphology and the mechanical properties of nanofibers were studied by scanning electron microscope (SEM) and a tensile tester, respectively. The average diameters of nanofibers in pure PAN nanofibers were found to be 127 nm. RESULTS: The results showed that the average diameter of nanofibers after increasing the eugenol ratio (from 127 to 179-218 nm) was increased. Drug release profile of the samples was gradual and was completed after 150 hours. CONCLUSION: According to the results, these nanofiber mats loaded with eugenol can be used for treating cutaneous mucocutaneous candidiasis in high risk patients as a coating on a fabric substrate or temporary wound dressing. PMID- 29484995 TI - Biodegradable Microspheres as Intravitreal Delivery Systems for Prolonged Drug Release. What is their Eminence in the Nanoparticle Era? AB - Drug administration to the posterior segment of the eye has many challenges due to the natural barriers and consequent problems of low and unpredictable bioavailability. There is an increasing need for managing severe posterior eye diseases, such as age-related macular degeneration, diabetic retinopathy, etc. Most of these diseases, if left untreated, lead to blindness. Traditional ocular formulations and topical administrations are almost inefficient and the drug delivery to the back of the eye requires direct administrations through intravitreal injections of innovative drug delivery systems. These systems must be easily injectable, able to release the drug for a prolonged period of time (to overcome the problem of repeated administrations) and made of biodegradable/biocompatible polymers. Among these delivery systems, microspheres still have an important role. This overview wants to highlight the use of microspheres as intravitreal systems to overcome the challenges of back of the eye diseases. Studies have shown that microspheres are able to enhance the intravitreal half-life and thus bioavailability of many drugs, protecting them from degradation. Furthermore, personalized therapies can be made by changing the amount of administered microspheres. This review focuses on the materials (polymers) used for the preparation of the microparticulate systems and comparative remarks are made with respect to the use of nanoparticles. PMID- 29484996 TI - Enhancing Solubility and Bioavailability of Rosuvastatin into Self Nanoemulsifying Drug Delivery System. AB - OBJECTIVE: The aim of this study was to develop new Rosuvastatin calcium (RCa) self nanoemulsifying drug delivery system (SNEDDS) and to evaluate the bioavailability and pharmacodynamic effect of RCa-SNEDDS in Yorkshire pigs. METHODS: Firstly, SNEDDS was developed and prepared then RCa was incorporated into SNEDDS which was evaluated regarding their characterization, stability properties, drug release profiles, permeation and cytotoxicity studies. Finally, in vivo performance of RCa-SNEDDS (F1-RCa-SNEDDS) was examined by pharmacokinetic and pharmacodynamics studies. The average droplet size of RCa- SNEDDS ranged between 200 and 250 nm. RCa-SNEDDS that contained 12.8% Oleic acid, 11 % Labrafil M, 3.3 % Labrasol and 4.4 % Transcutol HP were found to be stable and exhibited approximately 4-fold higher permeation than commercial tablet (Crestor(r) 20 mg tablet). RESULTS: In pharmacokinetic studies, when F1-RCa-SNEDDS and commercial tablet were administered orally, F1-RCa-SNEDDS showed higher bioavailability of RCa than commercial tablet. Respectively, in pharmacodynamic studies, triglyceride and total cholesterol levels were significantly reduced with F1- RCa SNEDDS formulation by 37% and 19% when compared to baseline values. CONCLUSION: However, these decreases with commercial formulation were only 6% and 2% respectively. According to these findings, development formulation could be potentially used to enhance the oral absorption of RCa. PMID- 29484997 TI - Insights into the Influences of Carboxymethyl-beta-Cyclodextrin on DNA Formulations Characteristics and Gene Transfection Efficiency. AB - BACKGROUND: Gene therapy is an expanding field and it can treat genetic and acquired diseases. OBJECTIVE: It was found that formulations with DNA: CM-beta-CD (Carboxymethyl-beta-cyclodextrin): Pluronic-F127 1:3:3 and 1:3 DNA: CM-beta-CD are the most stable formulations indicating high incorporation of DNA within CM beta -CD. METHOD: Gel electrophoresis revealed DNA with low CM-beta -CD concentration has formed a more stable complex. Samples 1:3 DNA: CM-beta-CD and 1:3:3 DNA: CM-beta-CD: Pluronic-127 show no DNA fragment, suggesting good condensation of DNA inside cyclodextrin cavity. RESULTS: This was confirmed by fluorescence data where fluorescence intensity was reduced for samples DNA: CM beta-CD 1:3. Overall, the findings showed that Carboxymethyl-beta-cyclodextrin (as a novel non-viral gene vector) was able to provide condensation and protection to the DNA, with and without Pluronic-F127, at low concentration. CONCLUSION: pDNA/CM-beta-CD complex has not only shown to be able to transfect COS 7 and SHSY5Y cell lines, but it gives a higher transfection efficiency than that produced by the TransIT-LT1 commercial transfection reagent. PMID- 29484998 TI - FOXP2 Promotes Tumor Proliferation and Metastasis by Targeting GRP78 in Triple negative Breast Cancer. AB - BACKGROUND: FOXP2, a member of the forkhead box P (FOXP) family, has been reported to be important in breast cancer. However, its exact mechanisms and pathways remain unclear. OBJECTIVE: To investigate the effect of FOXP2 on tumor proliferation and metastasis in triplenegative breast cancer (TNBC) and study its underlying molecular mechanism. METHODS: We first used qRT-PCR to detect FOXP2 expression in TNBC cell lines and tissues. Then we conducted cell proliferation assays, colony formation assays, and transwell assays to analyze the effects of FOXP2 expression in TNBC cells. Mouse xenograft model was performed to further confirm the role of FOXP2 in TNBC. Moreover, we used qRT-PCR and Western blot to access the effect of FOXP2 on GRP78 expression and qRT-PCR to analyze GRP78 expression in TNBC tissues. We conducted IHC analysis to detect both FOXP2 and GRP78 expressions in transplanted tumors and used the correlation analysis to further analyze the link between them. RESULTS: FOXP2 was found to be highly expressed in TNBC cell lines and tissues. FOXP2 knockdown attenuated the growth and invasiveness of TNBC in vitro as well as tumor progression and metastasis in vivo. Moreover, FOXP2 knockdown downregulated glucose-regulated protein of molecular mass 78 (GRP78) expression in TNBC cells and transplanted tumors. Correlation analysis showed that GRP78 expression was positively associated with FOXP2 expression in TNBC cells. CONCLUSION: FOXP2 plays a crucial role in TNBC, partly through modulating GRP78, and could act as a potential target for TNBC treatment. PMID- 29484999 TI - The Immunomodulatory Role of G2013 (a-L-Guluronic acid) on the Expression of TLR2 and TLR4 in HT29 cell line. AB - BACKGROUND/OBJECTIVES: The non-steroidal anti-inflammatory drugs (NSAIDs) play crucial role in controlling of inflammatory diseases. But due to the vast side effects of NSAIDs, its use is limited. G2013 or alpha-L-Guluronic acid is a new NSAID with immunomodulatory features. Considering the leading role of TLRs in inflammatory responses, in this study we aimed to evaluate G2013 cytotoxicity and its effect on the expression of TLR2 and TLR4 molecules. METHOD: HEK293-TLR2 and HEK293-TLR4 cells were cultured and seeded on 96-well cell plate and MTT assay was performed for detection the viability of the cells after treatment with different concentrations of G2013. HT29 cells were grown and treated with low and high doses of G2013. After total RNA extraction and cDNA synthesis, quantitative real-time PCR were performed to assess the TLR2 and TLR4 mRNA synthesis. RESULTS: We found that concentrations of <=125 ug/ml of G2013 had no apparent cytotoxicity effect on the HEK293-TLR2 and -TLR4 cells. Our results indicated that after G2013 treatment (5 ug/ml) in HT29 cells, TLR2 and TLR4 mRNA expression was decreased significantly compared with untreated control group (p=0.02 and p=0.001 respectively). CONCLUSION: The results of this study revealed that G2013 is able to down regulate the TLR2 and TLR4 gene expression and exerts its inhibitory effect. Our findings are parallel to our previous finding which showed G2013 ability to down regulate the signaling pathway of TLRs. However, further studies are needed to identify the molecular mechanism of G2013. PMID- 29485000 TI - Transient Secondary Hypothyroidism and Thyroid Hormone Replacement Therapy in Pediatric Postoperative Cardiopulmonary Bypass. AB - BACKGROUND: To develop an understanding of current practices in the management of transient secondary hypothyroidism in pediatric postoperative cardiopulmonary bypass (CPB) patients. METHODS: Electronic survey comprising a 10-item questionnaire was sent to sixty-four high volume pediatric heart centers in the United States and United Kingdom. Survey participants included cardiologists, intensivists, cardiothoracic surgeons, and advanced practice providers. A retrospective chart review was also performed at a large regional referral center in the Midwest on subjects 0-18 years old who underwent CPB from 2005-2015. Information obtained included a unique identifier, date of birth, age, procedure performed, CPB time, date of surgery and date and type of Thyroid Function Test (TFT) ordered. RESULTS: 1,153 individuals from 64 congenital heart centers were contacted via email to participate in the electronic survey. In the 3-month response window, 129 completed surveys were received from cardiologists (55%), intensivists (17%), surgeons (15%), "other" (8%), and advanced practice providers (5%). This yielded a response rate of 11.2%. Of the 129 respondents, only 10 providers routinely order TFTs prior to (n=7) and after (n=1) CPB or when clinically indicated (n=2). All 10 providers order thyroid stimulating hormone test, 7 order thyroxine, and 3 order triiodothyronine. Only 1 provider routinely treats children with prophylactic thyroid hormone replacement therapy after CPB. Our retrospective review included 502 CPB events with 442 unique patients. Of the events, 20 patients received preoperative TFT testing while 11 received postoperative testing. CONCLUSIONS: There is a general lack of uniformity in the evaluation, diagnosis, and treatment of transient secondary hypothyroidism in pediatric postoperative CPB patients. PMID- 29485001 TI - Design and Synthesis of 3,4-diarylpyrrole Analogues as Potent Topoisomerase Inhibitors. AB - BACKGROUND: The natural products containing a common 3,4-diarylpyrrole skeleton have attracted considerable attention due to their unique structures and multiplex biological activities. In our previous study, lycogarubin C was synthesized and showed cytotoxicity against MDAMB- 231, A549, PC3 and HeLa cell lines and topoisomerase II inhibitory activities. OBJECTIVE: We present the design, synthesis and antitumor studies of 3,4-diarylprrole derivatives. Their antitumor activities and inhibitory activities against Topo I and Topo IIalpha of these compounds were assayed. METHODS: A series of 3,4-diarylpyrrole analogues have been designed and synthesized. Their antiproliferation activities were evaluated by sulforhodamine B assay on human breast cancer MDAMB- 231, MDA-MB-435 and human cervical cancer HeLa cells. RESULTS: Four compounds showed modest inhibitory activities against the growth of the three cell lines with IC50 below 50 MUM. DNA relaxation assay revealed that compound 19o showed potent inhibitory activity against Topo IIalpha in vitro. 19o also induced DNA breaks in MDA-MB-435 cells evidenced by comet tails and the accumulation of gamma-H2AX foci. The ability of 19o in inducing DNA breaks mediated by Topo IIalpha resulted in G2/M phase arrest and apoptosis. CONCLUSION: This work indicates that 3,4 diarylpyrrole derivatives represent a novel type of Topo IIalpha inhibitory scaffold for developing new antitumor chemotherapeutic agents. PMID- 29485002 TI - Emerging Roles of Purinergic Signaling in Diabetes. AB - BACKGROUND: Purinergic signaling accounts for a complex network of receptors and extracellular enzymes responsible for the generation, recognition and degradation of extracellular ATP and adenosine. The main components of this system include P2X, P2Y and Adenosine Receptors, ectonucleotidases CD39 and CD73 and Adenosine Deaminase. The purinergic network recently emerged as a central player in several physiopathological conditions particularly those linked to immune system regulation including type 1 and type 2 diabetes. METHODS: Here, we give an overview of recent findings linking purinergic signaling with diabetes pathogenesis, including purines roles in altered glucose homeostasis, impaired metabolic control, and immune system-mediated pancreatic beta cells destruction. We particularly focused our attention on established preclinical experimental models of diabetes development and therapy including NOD mice, streptozotocin induced beta islets degeneration, and islet transplantation. RESULTS: The summarized studies delineate a central role of purines, their receptors and degrading enzymes in diabetes by demonstrating that manipulation of the purinergic axis at different levels can prevent or exacerbate the insurgency and evolution of both type 1 and type 2 diabetes. CONCLUSION: The reported preclinical data and the availability of several effective compounds targeting the different steps of the purinergic response strongly suggest that P2 and Adenosine Receptors or ecto-nucleotidases will be feasible therapeutic targets for the treatment of diabetes. PMID- 29485003 TI - Activity of Diosgenyl 2-amino-2-deoxy-beta-D-glucopyranoside, its Hydrochloride, and N,N-dialkyl Derivatives Against Non-albicans Candida Isolates. AB - BACKGROUND: Candida albicans belongs to the most common fungal pathogens in humans, but recently an increased proliferation of strains called non-albicans Candida has been reported. Species belonging to this group are often characterised by a reduced susceptibility to antifungal agents. OBJECTIVE: In view of the emergence of non-albicans Candida and their resistance to available antifungals, an attempt has been made to develop novel effective agents. Biological activities of the N,N-dialkyl diosgenyl glycosides, which were previously synthesized, were determined. METHOD: Minimum inhibitory concentration (MIC) was determined for group of clinical nonalbicans Candida isolates by serial dilution method in Sabouraud liquid medium. In order to assess the toxicity towards human cells the minimum haemolytic concentration (MHC) was determined on human erythrocytes by serial dilution method in phosphoric buffer. RESULTS: The saponins exhibited a strong activity towards clinical isolates of C. glabrata and C. parapsilosis comparable or even stronger than that of conventional antimicrobials. A high rate of resistance to fluconazole was shown among C. glabrata isolates. Among clinical strains of C. krusei and C. tropicalis, isolates with a decreased susceptibility to saponins were identified. All the tested C. krusei isolates showed resistance to fluconazole, while among C. tropicalis numerous strains were resistant to all tested azoles. The saponins did not show haemolytic activities at their microbiologically active concentrations. CONCLUSION: Results of the present work encourage to continue the study on steroidal saponins and their potential application for the treatment of candidemia. PMID- 29485004 TI - Design, Synthesis and Biological Evaluation of 7-arylbenzo[c]acridine-5,6- diones as Potential Anti-Leishmanial and anti-trypanosomal Agents. AB - BACKGROUND: Leishmaniasis is endemic in 98 countries and is closely associated with poverty. On the basis of current evidence, it may be safely suggested that over time Leishmania spp. have evolved coexistence in different macrophage types and developed adaptations in order to ensure their intracellular survival. Considering new drugs, the need of the hour the present study deals with the synthesis of novel compounds of biological importance based on naturally occurring scaffolds. OBJECTIVE: Synthesis, anti-leishmanial and anti-trypanosomal activities of a series of thirty three (eighteen newly synthesized and fifteen previously reported) 7-arylbenzo[c]acridine-5,6-diones. METHOD: A series of thirty-three 7-arylbenzo[c]acridine-5,6-diones was designed and synthesized. The anti-leishmanial and anti-trypanosomal activities of the newly synthesized compounds were done. RESULTS: Seven compounds (14, 17, 19, 26, 27, 38 and 39) were found to exhibit excellent antiparasitic activities. Compound 14 was identified as the most potent compound against L. donovani promastigotes while compound 27 showed most significant inhibition activity against amastigotes. Compounds 14 and 27 showed remarkable inhibitory activity with IC50 values of 0.38 and 0.53 uM, respectively, when tested in human macrophage cell line (THP) infected with L. donovani amastigotes. Against trypanomastigotes, six compounds (15, 17, 19, 25, 26 and 43) demonstrated remarkable inhibition. CONCLUSION: Compound 19 was found to be the best anti-trypanosomal agent and showed 300-fold superior inhibitory activity to that of the standard drug DFMO. Significant anti leishmanial and anti-trypanosomal activities combined with the non-cytotoxic profile presents 7-arylbenzo[c]acridine- 5,6-diones as new candidates with therapeutic potential in the treatment of parasitic diseases. PMID- 29485005 TI - Vaping versus Smoking: A Quest for Efficacy and Safety of E-cigarette. AB - BACKGROUND: Electronic Cigarettes (ECIGs) are devices with a heating element which produces aerosol for inhalation. They have been propagated as a healthier alternative to tobacco smoking and a potential device for smoking cessation, despite non-documentation of their long-term adverse health effects. OBJECTIVES: With the glorification of ECIG, its use has increased even among non-tobacco users. This makes it critical to understand and discuss a true picture of safety and utility of ECIGs by reviewing the literature. METHODS: Literature search for narrative review was done on PubMed, Scopus and Web of Science databases using the keywords viz electronic cigarette, e-cigarette, electronic nicotine delivery systems, NRT, vaping and electronic nicotine delivery device. The review was sub categorized into four themes (potential role in smoking cessation, chemicals in the smoke of traditional cigarette and ECIGs, pharmacology of nicotine delivery via ECIG and current regulatory status across the globe). RESULTS: Search revealed a total of 40 articles out of which 29 were included in the review. ECIGs achieved modest cessation rates with benefits of behavioral and sensory gratification. On the contrary, in many studies where ECIGs were introduced as an intervention, participants continued to use them to maintain their habit instead of quitting. A total of 22 toxic substances apart from nicotine were reported in liquid of ECIG cartridges and its emissions. Many compounds had lower concentrations in ECIG compared to tobacco smoke. There existed a wide variation in the content of ECIG cartridges and strengths of nicotine in refill solutions. It has been observed that the second generation ECIGs delivered nicotine with a similar kinetic profile as conventional cigarettes. In 2013, US FDA gave market authorization to ECIG as substitutes for quitting smoking and cigarette substitutes. The United Kingdom also advocates ECIGs as a medicinal quit aid but bans it from workplaces and other public spaces. India along with many other countries still need to come up with a formal regulatory stand regarding ECIGs. CONCLUSION: There is a need to conduct large long-term global clinical trials in real life settings to ascertain the potential uses, adverse effects of ECIG and achieve harmonization of nicotine solution concentration. PMID- 29485006 TI - Risks Associated with SGLT2 Inhibitors: An Overview. AB - BACKGROUND: Sodium glucose co-transport 2 inhibitors (SGLT2-i) are the new class of antidiabetic medications which are recently approved (2013) by the Food and Drug Administration (FDA) for the treatment of diabetes. These inhibitors block the SGLT2 protein which involved glucose reabsorption from proximal renal tubule resulting in increased glucose excretion and lower blood glucose levels. These inhibitors exert favourable effects beyond glucose control such as consistent body weight, blood pressure and serum uric acid reductions. Canagliflozin, Dapagliflozin and empagliflozin belong to the class of SGLT2 inhibitors. RESULTS AND CONCLUSION: All these drugs are giving promising results in the treatment of diabetes mellitus, but emerging data from post-marketing studies indicate their adverse effects such as diabetic ketoacidosis, genital and urinary tract infection, cancer, bone fracture and foot and leg amputation. Thus, there is a need for better understanding the risk profile of SGLT2 inhibitors. In this review, we have compiled the risk profile of SGLT2 inhibitors by collecting information from various sources such as case reports, published literature and from various regulatory websites. Further, the proposed mechanism of risks has also been discussed. PMID- 29485007 TI - Pinpoint Localized Odynophagia (PLO) as a Specific Symptom of Pill-induced Oesophagitis (PIO) in the Evaluation of Acute Retrosternal Chest Pain. AB - INTRODUCTION: 36 out of 100 cases of retrosternal chest pains are due to oesophageal pathologies, and Pill-induced Oesophagitis (PIO) is one of them. PIO can present as retrosternal chest pain associated with various Gastrointestinal (GI) symptoms and require a high index of suspicion. PIO is a clinical diagnosis; and oesophagogastroscopy is required for confirmation of the diagnosis, to find out complications of PIO and to rule out other oesophageal disorders. Our aims of the present study were to study clinical profile, risk factors and endoscopic features of PIO. MATERIALS AND METHODS: We have done a cross-sectional study of 1000 patients with acute retrosternal chest pain, and all patients of suspected upper gastrointestinal system involvement were subjected to oesophagogastroscopy. Patients having a history of pill ingestion followed by retrosternal chest pain with GI symptoms of less than 10 days duration and having typical endoscopy findings like kissing ulcer, multiple small discrete ulcers or erosion of esophagus were diagnosed as PIO after excluding other oesophageal pathologies. RESULTS AND CONCLUSION: Among 1000 retrosternal chest pain patients, 450(45%) cardiovascular, 255(25.5%) respiratory, 248(24.85%) upper GI and 47(0.47%) had other system involvement. Among 248 GI patients, the frequency of symptoms was as follows: Pinpoint localized odynophagia (8.46%), non-localised odynophagia (12.09%), nausea (62.09%), vomiting (44.35%), dysphagia (3.62%), dyspepsia (13.70%) and hematemesis (0.8%). PLO, dysphagia, and hematemesis were significant symptoms of PIO (p<0.05). Endoscopic findings suggestive of PIO such as kissing ulcer, multiple small discrete ulcers, oesophageal erosions were observed in 91.30%, 47.83%, and 34.78% patients, respectively. Involvement of the middle third of esophagus was present in 74.19% and the lower third in 25.81% patients. Most of the patients with PLO had kissing oesophageal ulcer seen on endoscopy (pvalue =0.0002). The habit of consuming pill with less than 100 ml of water and consumption of night pill dose 10 minutes or less before sleeping were observed as significant risk factors for PIO (p value<0.05). PLO is a newly established and highly specific symptom of PIO of our study and it matches with kissing ulcer of the esophagus by endoscopy. PMID- 29485008 TI - Pharmacology, Systematic Review and Recent Clinical Trials of Metadoxine. AB - BACKGROUND: Metadoxine is composed of pyroglutamic acid and vitamin B6. Administrations of metadoxine are indicated in cases of acute alcohol intoxication or in chronic alcoholism. OBJECTIVES: To reference all available clinical trials investigating the effects of metadoxine on humans. A focus was put on alcohol intoxication and chronic alcoholism, alcohol abstinence and survival rates. Adverse events were also taken into consideration. Finally, potential roles of metadoxine in treating disorders of the central nervous system will be assessed. METHODS: PRISMA guidelines were followed. Computerised literature searches were performed in July 2017 to retrieve all clinical trials investigating metadoxine from the MEDLINE(r), the European Union Clinical Trials Register and the ClinicalTrials.gov databases, using the following equation: "metadoxine". Inclusion criteria were all published clinical trials investigating metadoxine in humans, regardless of outcome measures. Exclusion criteria were articles not abstracted, in vitro studies, studies in rodents, retrospective studies and reviews. RESULTS: Sixteen studies were included. Evidence suggests that metadoxine appears safe to use, as it rarely induced adverse events (reported in 7 out of the 7 studies measuring safety/tolerability). Moreover, metadoxine seems efficient in treating acute alcohol intoxication (2/2 studies) as well as improving liver functions following chronic alcoholism (4/5 studies). Finally, currently on-going clinical trials will reveal if metadoxine could be indicated in attention deficit and hyperactivity disorders as well as fragile X syndrome. CONCLUSION: Metadoxine appears safe to use and seems efficient to improve liver functions following alcohol-related diseases. Further clinical trials will be necessary to determine if metadoxine can be promising for treating brain disorders. PROSPERO registration number: CRD42017072964. PMID- 29485009 TI - Oral Submucous Fibrosis as an Overhealing Wound: Implications in Malignant Transformation. AB - BACKGROUND: Oral submucous fibrosis is an oral potentially malignant disorder with high incidence of malignant transformation and rising global prevalence. However, the genesis of oral submucous fibrosis is still unclear despite superfluity of literature. In the background of ineffective treatment, it is necessary to decode its onset and progression before designing customized treatment regimens. OBJECTIVE: The objective of this article is to decipher the pathogenesis of oral submucous fibrosis in order to identify novel drug targets. METHODS: A thorough literature review based on oral submucous fibrosis being an overhealing wound was conducted; several related patents were identified and herewith reviewed. Necessary pathways were elaborated and deliberated in the manuscript in the form of schemas, keeping our hypothesis in mind. Several novel molecular targets were identified and discussed in detail. RESULTS: Several patents demonstrating inhibition of fibrosis via chemokine ligand mimetics, anticonnexon antibodies, stem cell therapy, fibronectin blocking peptides, HIF inhibitors, recombinant erythropoietin, xanthine oxidase inhibitors, long non coding RNAs, targeting inflammation, increasing TH-1/TH-2 cytokine ratio, t-box protein 4, chromium containing compositions, Iron-based nanocomposites, Lactate Dehydrogenase-5 inhibitors, Carbonic Anhdrase-9 inhibitors, proton pump inhibitors, liposomal encapsulated glutathione, monocarboxylate-4 inhibitors, autophagy inhibitors, Submucosal anti-IL-6 antibodies, fibrin degradation products for monitoring of malignancy and fibrosis, small molecule antagonists like vorapaxar, tiplaxtinin, and TM-5275, TGF-beta signalling inhibitors were identified as future therapeutic avenues. CONCLUSION: Considering, oral submucous fibrosis as an overhealing wound explains both pathogenesis and malignant transformation. Certainly, abnormalities in coagulation and fibrinolytic system are a common denominator in the profibrotic milieu and associated malignancy. PMID- 29485010 TI - The Application of lncRNAs in Cancer Treatment and Diagnosis. AB - BACKGROUND: It is increasingly evident that lncRNAs have various biological functions playing as essential regulators, getting involved in diverse cellular processes. Many of the lncRNAs show aberrant expression in cancer, which is associated with different cancer types. The dysregulation of lncRNAs has been increasingly linked to cancer carcinogenesis and progression. OBJECTIVE: Due to their tissue-specific expression and key role in cancer, lncRNAs have the potential to be novel biomarkers or effective drug targets for cancer. This review aims to present the application of lncRNAs in cancer diagnosis and targeted cancer therapies, elaborates molecular mechanisms and provides a deeper understanding of cancer-related lncRNA functions. METHODS: Relevant recent patents are collected to summarize the application of lncRNAs in cancer. Combined with published articles, functions and mechanisms of lncRNAs are elaborated. RESULTS: Patents revealed that a series of reagents and kits have been applied for early cancer diagnosis by detecting specific lncRNAs, having the advantages of high sensitivity, specificity and stability. In addition, lncRNAs as effective targets have been applied in developing targeted cancer drugs. With regard to their role in cancer, lncRNAs regulate target genes, thus to medicate cancer physiological and pathological processes through diverse mechanisms at epigenetic, transcriptional and posttranscriptional levels. CONCLUSION: Current knowledge of lncRNAs presents prosperous prospects in cancer. However, functions of lncRNAs are still far from fully being understood. Therefore, further study is needed to advance imminent applications of these findings to the clinic. PMID- 29485011 TI - Fibrinolytic Protease from Marine Streptomyces rubiginosus VITPSS1. AB - INTRODUCTION: Fibrinolytic enzymes must currently originate a significant product in the arena of medical research. Very limited studies are stated on fibrinolyticenzyme production from actinomycetes. METHODS: Streptomyces sp. isolated from marine soil was chosen to optimize its fibrinolytic protease production.16s rRNA sequencing confirmed the isolated potent strain to be Streptomyces rubiginosus VITPSS1. A fibrinolytic protease was then purified from Streptomyces rubiginosus VITPSS1, with the target of producing a cost effective feasible enzyme from a potential actinomycete. RESULTS: SDS-PAGE results exhibited a protein band of about 45 kDa and the fibrinolytic band was detected by zymography. Optimization of physical and nutritional parameters for fibrinolytic protease production from a marine soil isolate Streptomyces strain was done by response surface methodology. The optimal cultural condition for fibrinolytic protease production was obtained with response surface methodology was based on OFAT results, it was inferred that glycerol, Soyabean meal, pH 7.2 and temperature 37 degrees C. The optimization of the production of fibrinolytic protease with response surface methodology bring about two-folds increase in production by Streptomyces rubiginosus VITPSS1. CONCLUSION: Thus, this study presents its novelty by highlighting the potential of marine Streptomyces as a significant source for fibrinolytic enzyme production. PMID- 29485012 TI - Sodium-glucose Cotransporter 2 Inhibitors: Potential Cardiovascular and Mortality Benefits. AB - BACKGROUND: The impact of overt diabetes and poor glycemic control on the risk of cardiovascular disease is well established. Among patients with type 2 diabetes, several studies demonstrated a significant increase in coronary artery disease related death and cardiovascular events associated with HbA1c levels of greater than 7% compared with lower levels. Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are a novel class of anti-diabetic drugs that lower blood glucose levels through the suppression of renal glucose reabsorption thereby promoting renal glucose excretion. OBJECTIVES: To summarize data on the potential mechanisms of SGLT-2 inhibition that could exert cardiovascular benefits in patients with diabetes mellitus. METHOD: We conducted an in-depth literature search of SGLT-2 inhibitors and potential cardiovascular benefits and mechanisms that mediate those effects. RESULTS: In diabetes, expression of the SGLT-2 genes is up-regulated and renal threshold increased, resulting in increased glucose reabsorption from glomerular filtrate, reducing urinary glucose excretion and worsening hyperglycemia. SGLT-2 inhibition should offer potential cardiovascular protection in diabetic patients via attenuating hyperglycemia, blood pressure, body weight, hyperuricemia, and diabetic nephropathy. CONCLUSION: The initial data of SGLT-2 inhibitors suggest beneficial effects on cardiovascular risk among patients with diabetes mellitus. Several mechanisms are hypothesized to mediate the abovementioned benefits. Future randomized, controlled studies are needed in order to unveil the contribution of each mechanism to these outcomes. PMID- 29485013 TI - Development of Microemulsion Based Nabumetone Transdermal Delivery for Treatment of Arthritis. AB - BACKGROUND: Nabumetone is biopharmaceutics classification system (BCS) class II drug, widely used in the treatment of osteoarthritis and rheumatoid arthritis. The most frequently reported adverse reactions for the drug involve disturbance in gastrointestinal tract, diarrhea, dyspepsia and abdominal pain. Microemulgel has advantages of microemulsion for improving solubility for hydrophobic drug. Patent literature had shown that the work for drug has been carried on spray chilling, enteric coated tablet, and topical formulation which gave an idea for present research work for the development of transdermal delivery. OBJECTIVE: The objective of the present research work was to optimize transdermal microemulgel delivery for Nabumetone for the treatment of arthritis. METHODS: Oil, surfactant and co-surfactant were selected based on solubility study of the drug. Gelling agents used were Carbopol 934 and HPMC K100M. Optimization was carried out using 32 factorial design. Characterization and evaluation were carried out for microemulsion and microemulsion based gel. RESULTS: Field emission-scanning electron microscopy (FE-SEM) study of the microemulsion revealed globules of 50 200 nm size. Zeta potential -9.50 mV indicated good stability of microemulsion. Globule size measured by dynamic light scattering (zetasizer) was 160nm. Design expert gave optimized batch as F7 which contain 0.2% w/w drug, 4.3% w/w liquid paraffin, 0.71% w/w tween 80, 0.35% w/w propylene glycol, 0.124% w/w Carbopol 934, 0.187% w/w HPMC K100M and 11.68% w/w water. In-vitro diffusion study for F7 batch showed 99.16+/-2.10 % drug release through egg membrane and 99.15+/-2.73% drug release in ex-vivo study. CONCLUSION: Nabumetone microemulgel exhibiting good in-vitro and ex-vivo controlled drug release was optimized. PMID- 29485014 TI - In vitro And In vivo Immunomodulating Properties of Mesenchymal Stem Cells. AB - BACKGROUND: Mesenchymal Stem Cells (MSCs) are self-renewing, multipotent progenitor cells with multilineage potential to differentiate into all cell types of mesodermal origin, such as adipocytes, osteocytes and chondrocytes. Mesenchymal Stem Cells (MSCs) are adult stem cells which can be isolated from human and animal sources. OBJECTIVE: Besides the differentiation potential of MSCs, these also regulate the immune response in numerous ailments. The present review expedites the immunomodulating prospective of MSCs. METHODS: Scrupulous search of the literature and patents available on MSCs and their role in the immunomodulation was carried out using Medline, PubMed, PubMed Central, Science Direct and other scientific databases. The retrieved information has been analyzed and compiled. RESULTS: MSCs have unique regulation of microenvironment in the host tissue by secreting cytokines and immune-receptors which results in immunomodulatory effects. MSCs can be used as an effective tool in the treatment of chronic diseases because of its property to secrete anti-inflammatory molecules, having multilineage potential and immunomodulation. CONCLUSION: The present review is focused on the use of MSCs due to their unique immunomodulatory characteristics. MSCs reach to the site of inflammation and interact with immune cells to bring immunosuppressive and anti-inflammatory effects. Along with these unique therapeutic properties, MSCs may be a useful therapeutic approach for various disorders. PMID- 29485015 TI - Protein Tyrosine Phosphatase as Potential Therapeutic Target in various Disorders. AB - BACKGROUND: Tyrosine-protein phosphatase is an enzyme that functions in a unit with tyrosine kinases to regulate signaling pathways. Several members of the PTP family link to human disease predisposition such as PTP1B, SH2, DEP1, and inhibition of these enzymes may represent an effective palliative therapy. OBJECTIVE: This review aims to summarize the rapidly developing role of the PTPs in various physiological and pathological states. RESULTS: Pharmacological inhibition of protein tyrosine phosphatase has been found to reduce endothelial dysfunction in different cardiovascular diseases related to metabolic disorders and it can be helpful for the management of other brain disorders associated with perhaps even in normal, agerelated cognitive decline. Tyrosine-protein phosphates have both stimulatory and inhibitory consequences on cancer-associated signaling pathways and deregulation of PTKs involves tumorgenesis. CONCLUSION: Inhibition of protein tyrosine phosphatase plays an important function in the improvement of various diseases such as metabolic, cardiovascular disorders, cancer and autoimmune disease. PMID- 29485016 TI - Comparing the Bioburden Measured by Adenosine Triphosphate (ATP) Luminescence Technology to Contact Plate-Based Microbiologic Sampling to Assess the Cleanliness of the Patient Care Environment. AB - The correlation between ATP concentration and bacterial burden in the patient care environment was assessed. These findings suggest that a correlation exists between ATP concentration and bacterial burden, and they generally support ATP technology manufacturer-recommended cutoff values. Despite relatively modest discriminative ability, this technology may serve as a useful proxy for cleanliness.Infect Control Hosp Epidemiol 2018;39:622-624. PMID- 29485017 TI - The Epidemiology of Community Clostridium difficile Infection: A Five-Year Population-Based Study on the Bailiwick of Jersey, Channel Islands. AB - We studied healthcare-associated and community-associated Clostridium difficile infection (CDI) in Jersey, Channel Islands (2008-2012). The Island's stable population has reliable denominator data, a clearly defined at-risk population, and healthcare contact that is easily followed. The vast majority of CDI cases had had recent healthcare contact, and true community-associated disease is extremely rare.Infect Control Hosp Epidemiol 2018;39:603-607. PMID- 29485018 TI - Outpatient Antibiotic Prescription Trends in the United States: A National Cohort Study. AB - OBJECTIVETo characterize trends in outpatient antibiotic prescriptions in the United StatesDESIGNRetrospective ecological and temporal trend study evaluating outpatient antibiotic prescriptions from 2013 to 2015SETTINGNational administrative claims data from a pharmacy benefits manager PARTICIPANTS. Prescription pharmacy beneficiaries from Express Scripts Holding CompanyMEASUREMENTSAnnual and seasonal percent change in antibiotic prescriptionsRESULTSApproximately 98 million outpatient antibiotic prescriptions were filled by 39 million insurance beneficiaries during the 3-year study period. The most commonly prescribed antibiotics were azithromycin, amoxicillin, amoxicillin/clavulanate, ciprofloxacin, and cephalexin. No significant changes in individual or overall annual antibiotic prescribing rates were found during the study period. Significant seasonal variation was observed, with antibiotics being 42% more likely to be prescribed during February than September (peak-to-trough ratio [PTTR], 1.42; 95% confidence interval [CI], 1.39-1.61). Similar seasonal trends were found for azithromycin (PTTR, 2.46; 95% CI, 2.44-3.47), amoxicillin (PTTR, 1.52; 95% CI, 1.42-1.89), and amoxicillin/clavulanate (PTTR, 1.78; 95% CI, 1.68-2.29).CONCLUSIONSThis study demonstrates that annual national outpatient antibiotic prescribing practices remained unchanged during our study period. Furthermore, seasonal peaks in antibiotics generally used to treat viral upper respiratory tract infections remained unchanged during cold and influenza season. These results suggest that inappropriate prescribing of antibiotics remains widespread, despite the concurrent release of several guideline-based best practices intended to reduce inappropriate antibiotic consumption; however, further research linking national outpatient antibiotic prescriptions to associated medical conditions is needed to confirm these findings.Infect Control Hosp Epidemiol 2018;39:584-589. PMID- 29485019 TI - Role of Hand Hygiene Ambassador and Implementation of Directly Observed Hand Hygiene Among Residents in Residential Care Homes for the Elderly in Hong Kong. AB - OBJECTIVEMultidrug-resistant organisms (MDROs) are increasingly reported in residential care homes for the elderly (RCHEs). We assessed whether implementation of directly observed hand hygiene (DOHH) by hand hygiene ambassadors can reduce environmental contamination with MDROs.METHODSFrom July to August 2017, a cluster-randomized controlled study was conducted at 10 RCHEs (5 intervention versus 5 nonintervention controls), where DOHH was performed at two hourly intervals during daytime, before meals and medication rounds by a one trained nurse in each intervention RCHE. Environmental contamination by MRDOs, such as methicillin-resistant Staphylococcus aureus (MRSA), carbapenem-resistant Acinetobacter species (CRA), and extended-spectrum beta-lactamse (ESBL)-producing Enterobacteriaceae, was evaluated using specimens collected from communal areas at baseline, then twice weekly. The volume of alcohol-based hand rub (ABHR) consumed per resident per week was measured.RESULTSThe overall environmental contamination of communal areas was culture-positive for MRSA in 33 of 100 specimens (33%), CRA in 26 of 100 specimens (26%), and ESBL-producing Enterobacteriaceae in 3 of 100 specimens (3%) in intervention and nonintervention RCHEs at baseline. Serial monitoring of environmental specimens revealed a significant reduction in MRSA (79 of 600 [13.2%] vs 197 of 600 [32.8%]; P<.001) and CRA (56 of 600 [9.3%] vs 94 of 600 [15.7%]; P=.001) contamination in the intervention arm compared with the nonintervention arm during the study period. The volume of ABHR consumed per resident per week was 3 times higher in the intervention arm compared with the baseline (59.3+/-12.9 mL vs 19.7+/-12.6 mL; P<.001) and was significantly higher than the nonintervention arm (59.3+/-12.9 mL vs 23.3+/-17.2 mL; P=.006).CONCLUSIONSThe direct observation of hand hygiene of residents could reduce environmental contamination by MDROs in RCHEs.Infect Control Hosp Epidemiol 2018;39:571-577. PMID- 29485021 TI - Maternal Impression Management in the Assessment of Childhood Depressive Symptomatology. AB - BACKGROUND: Self-report instruments are commonly used to assess for childhood depressive symptoms. Historically, clinicians have relied heavily on parent reports due to concerns about childrens' cognitive abilities to understand diagnostic questions. However, parents may also be unreliable reporters due to a lack of understanding of their child's symptomatology, overshadowing by their own problems, and tendencies to promote themselves more favourably in order to achieve desired assessment goals. One such variable that can lead to unreliable reporting is impression management, which is a goal-directed response in which an individual (e.g. mother or father) attempts to represent themselves, or their child, in a socially desirable way to the observer. AIMS: This study examined the relationship between mothers who engage in impression management, as measured by the Parenting Stress Index-Short Form defensive responding subscale, and parent /child-self-reports of depressive symptomatology in 106 mother-child dyads. METHODS: 106 clinic-referred children (mean child age = 10.06 years, range 7-16 years) were administered the Child Depression Inventory, and mothers (mean mother age = 40.80 years, range 27-57 years) were administered the Child-Behavior Checklist, Parenting Stress Index-Short Form, and Symptom Checklist-90-Revised. RESULTS: As predicted, mothers who engaged in impression management under reported their child's symptomatology on the anxious/depressed and withdrawn subscales of the Child Behavior Checklist. Moreover, the relationship between maternal-reported child depressive symptoms and child-reported depressive symptoms was moderated by impression management. CONCLUSIONS: These results suggest that children may be more reliable reporters of their own depressive symptomatology when mothers are highly defensive or stressed. PMID- 29485022 TI - Early Effects of Ionizing Radiation on the Collagen Hierarchical Structure of Bladder and Rectum Visualized by Atomic Force Microscopy. AB - Radiation therapy, widely used in the treatment of a variety of malignancies in the pelvic area, is associated with inevitable damage to the surrounding healthy tissues. We have applied atomic force microscopy (AFM) to track the early damaging effects of ionizing radiation on the collagen structures in the experimental animals' bladder and rectum. The first signs of the low-dose radiation (2 Gy) effect were detected by AFM as early as 1 week postirradiation. The observed changes were consistent with initial radiation destruction of the protein matrix. The alterations in the collagen fibers' packing 1 month postirradiation were indicative of the onset of fibrotic processes. The destructive effect of higher radiation doses was probed 1 day posttreatment. The severity of the radiation damage was proportional to the dose, from relatively minor changes in the collagen packing at 8 Gy to the growing collagen matrix destruction at higher doses and complete three-dimensional collagen network restructuring towards fibrotic-type architecture at the dose of 22 Gy. The AFM study appeared superior to the optical microscopy-based studies in its sensitivity to early radiation damage of tissues, providing valuable additional information on the onset and development of the collagen matrix destruction and remodeling. PMID- 29485023 TI - The Influence of Beam Broadening on the Spatial Resolution of Annular Dark Field Scanning Transmission Electron Microscopy. AB - The spatial resolution of aberration-corrected annular dark field scanning transmission electron microscopy was studied as function of the vertical position z within a sample. The samples consisted of gold nanoparticles (AuNPs) positioned in different horizontal layers within aluminum matrices of 0.6 and 1.0 um thickness. The highest resolution was achieved in the top layer, whereas the resolution was reduced by beam broadening for AuNPs deeper in the sample. To examine the influence of the beam broadening, the intensity profiles of line scans over nanoparticles at a certain vertical location were analyzed. The experimental data were compared with Monte Carlo simulations that accurately matched the data. The spatial resolution was also calculated using three different theoretical models of the beam blurring as function of the vertical position within the sample. One model considered beam blurring to occur as a single scattering event but was found to be inaccurate for larger depths of the AuNPs in the sample. Two models were adapted and evaluated that include estimates for multiple scattering, and these described the data with sufficient accuracy to be able to predict the resolution. The beam broadening depended on z 1.5 in all three models. PMID- 29485024 TI - Overexpression of MicroRNA-29b Decreases Expression of DNA Methyltransferases and Improves Quality of the Blastocysts Derived from Somatic Cell Nuclear Transfer in Cattle. AB - MicroRNA (miR)-29b plays a crucial role during somatic cell reprogramming. The aim of the current study was to explore the effects of miR-29b on the developmental competence of bovine somatic cell nuclear transfer (SCNT) embryos, as well as the underlying mechanisms of action. The expression level of miR-29b was lower in bovine SCNT embryos at the pronuclear, 8-cell, and blastocyst stages compared with in vitro fertilized embryos. In addition, miR-29b regulates the expression of DNA methyltransferases (Dnmt3a/3b and Dnmt1) in bovine SCNT embryos. We further investigated SCNT embryo developmental competence and found that miR-29b overexpression during bovine SCNT embryonic development does not improve developmental potency and downregulation inhibits developmental potency. Nevertheless, the quality of bovine SCNT embryos at the blastocyst stage improved significantly. The expression of pluripotency factors and cellular proliferation were significantly higher in blastocysts from the miR-29b overexpression group than the control and downregulation groups. In addition, outgrowth potential in blastocysts after miR-29b overexpression was also significantly greater in the miR-29b overexpression group than in the control and downregulation groups. Taken together, these results demonstrated that miR-29b plays an important role in bovine SCNT embryo development. PMID- 29485025 TI - Is the Binding Pattern of Zinc(II) Equal in Different Bryophyte Species? AB - Bryophytes are usually taken as good bioindicators. However, they represent a large group of terrestrial plants and they express an enormous range of peculiarities within the plant kingdom. With the aim to search for a common pattern of zinc binding, we established axenical in vitro cultures of a dozen bryophyte species that include hornworts, thallose, and leafy liverworts, as well as acrocarp and pleurocarp mosses. The species were grown free of contaminants for many years prior to the application of different treatments, i.e. offering Zn(II) from solid and liquid media and in combination with different anions. The localization and binding of zinc was detected by confocal microscopy using the zinc-specific dye FluoZinTM-3. In one of the species, Hypnum cupressiforme (which is widely used for atmospheric heavy metal deposition studies in biomonitoring), semi-quantitative analyses of zinc were performed by energy dispersive X-ray microspectrometry (EDX) in a scanning electron microscope. The results suggest no common pattern of Zn(II) binding in different bryophyte species. Instead, the binding pattern seems to be species specific. Zinc is located in certain areas or cellular compartments, as clearly shown by the EDX measurements in H. cupressiforme. PMID- 29485026 TI - Quantification of Olivine Using Fe Lalpha in Electron Probe Microanalysis (EPMA). AB - Quantification of first series transition metal Lalpha X-rays is hampered by absorption and in some cases transition probabilities (fluorescence yields) varying with chemical bonding. Compound mass absorption coefficients for Fe Lalpha were measured in the olivine solid solution series [Forsterite (Mg2SiO4) to Fayalite (Fe2SiO4)] and the mass absorption coefficients for Fe Lalpha absorbed by Fe were calculated. The mass absorption coefficients vary systematically between Fo83 and Fo0. Using the measured mass absorption coefficients for both standard and unknown and by correcting for a systematic discrepancy, consistent with varying partial fluorescence yields, a good agreement between calculated k-ratios and measured k-ratios is achieved. The systematic variations allow quantification of unknown k-ratios. The described method of quantification requires modification of matrix correction routines to allow standards and unknowns to have different mass absorption coefficients, and to incorporate solid solution mass absorption coefficients and partial fluorescence yield corrections derived from regression of experimental data. PMID- 29485020 TI - Suboptimality in Perceptual Decision Making. AB - Human perceptual decisions are often described as optimal. Critics of this view have argued that claims of optimality are overly flexible and lack explanatory power. Meanwhile, advocates for optimality have countered that such criticisms single out a few selected papers. To elucidate the issue of optimality in perceptual decision making, we review the extensive literature on suboptimal performance in perceptual tasks. We discuss eight different classes of suboptimal perceptual decisions, including improper placement, maintenance, and adjustment of perceptual criteria, inadequate tradeoff between speed and accuracy, inappropriate confidence ratings, misweightings in cue combination, and findings related to various perceptual illusions and biases. In addition, we discuss conceptual shortcomings of a focus on optimality, such as definitional difficulties and the limited value of optimality claims in and of themselves. We therefore advocate that the field drop its emphasis on whether observed behavior is optimal and instead concentrate on building and testing detailed observer models that explain behavior across a wide range of tasks. To facilitate this transition, we compile the proposed hypotheses regarding the origins of suboptimal perceptual decisions reviewed here. We argue that verifying, rejecting, and expanding these explanations for suboptimal behavior - rather than assessing optimality per se - should be among the major goals of the science of perceptual decision making. PMID- 29485027 TI - Polarization Microscopy and Infrared Microspectroscopy of Integument Coverings of Diapausing Larvae in Two Distantly Related Nonsocial Bees. AB - The larvae of the two distantly related nonsocial bees Ericrocis lata (Apidae) and Hesperapis (Carinapis) rhodocerata (Melittidae), which develop mostly under arid desert areas of North America, and that differ in that they either spin (E. lata) or do not spin (H. rhodocerata) protective cocoons before entering diapause, produce transparent films that cover the larval integument. To understand the nature of these films, their responses to topochemical tests and their characteristics when examined with fluorescence and high-performance polarization microscopy and microspectroscopy were studied. A positive staining by Sudan black B, birefringence of negative sign, and a Fourier transform infrared (FT-IR) spectrum typical of lipids were detected for the integument covering of both species. The FT-IR signature, particularly, suggests a wax chemical composition for these lipid coverings, resembling the waxes that are used as construction materials in the honey cells produced by social bees. Considering the arid environmental conditions under which these larvae develop, we hypothesize that their covering films may have evolved as protection against water depletion. This hypothesis seems especially appropriate for H. rhodocerata larvae, which are capable of undergoing a long diapause period in the absence of a protective cocoon. PMID- 29485028 TI - Superficial and Inner Examination of a Microwave-Irradiated Dental Acrylic Resin and Its Metal-Polymer Interface. AB - The aim of this study is to conduct an extended surface and cross-section characterization of a denture base acrylic resin subjected to 500, 650, and 750 W microwave irradiation for 2, 3, and 5 min to assess its morphological modifications. A commercial heat-cured powder was polymerized according to the manufacturer's specifications and distributed into 20 circular samples. A stainless-steel wire was partially embedded in half of the discs, in order to investigate the metal-polymer interface. High-resolution scanning electron microscopy (SEM) imaging, white light interferometry, roughness measurements and Fourier transform infrared spectrometry were employed for morphological and structural evaluation of the irradiated polymer. Superficial adaptation was discovered after 5 min exposure at 500 W, 650 W, and 750 W, revealing significant roughness correction for 750 W. SEM characterization revealed the inner alteration of the resin for the 750 W protocol and a metal-polymer gap developed regardless of the irradiation conditions. The considerable temperature fluctuations that the samples were subject to during the experiments did not essentially change the poly(methyl-methacrylate) bond structure. PMID- 29485029 TI - Construction and characterization of an infectious molecular clone of novel duck reovirus. AB - Novel duck reovirus (NDRV), the prototype strain of the species Avian orthoreovirus (ARV), is currently an infectious agent for ducks. Studies on NDRV replication and pathogenesis have been hampered by the lack of an available reverse-genetics system. In this study, a plasmid-based reverse-genetics system that is free of helper viruses has been developed. In this system, 10 full-length gene segments of wild-type NDRV TH11 strain are transfected into BSR-T7/5 cells that express bacteriophage T7 RNA polymerase. Production of infectious virus was shown by the inoculation of cell lysate derived from transfected cells into 10 day-old duck embryos. The in vivo growth kinetics and infectivity of the recombinant strains were identical to those of the wild-type strain. These viruses grew well and were genetically stable both in vitro and in vivo. Altogether, these results show the successful production of an infectious clone for NDRV. The infectious clone reported will be further used to elucidate the mechanisms of host tropism, viral replication and pathogenesis, as well as immunological changes induced by NDRV. PMID- 29485030 TI - In vitro characterization and identification of potential substrates of a low molecular weight protein tyrosine phosphatase in Streptococcus pneumoniae. AB - Streptococcus pneumoniae is a major human pathogen responsible for significant mortality and morbidity worldwide. Within the annotated genome of the pneumococcus lies a previously uncharacterized protein tyrosine phosphatase which shows homology to low molecular weight protein tyrosine phosphatases (LMWPTPs). LMWPTPs modulate many processes critical for the pathogenicity of a number of bacteria including capsular polysaccharide biosynthesis, stress response and persistence in host macrophages. Here, we demonstrate that Spd1837 is indeed a LMWPTP, by purifying the protein, and characterizing its phosphatase activity. Spd1837 showed specific tyrosine phosphatase activity, and it did not form higher order oligomers in contrast to many other LMWPTPs. Substrate-trapping assays using the wild-type and the phosphatase-deficient Spd1837 identified potential substrates/interacting proteins including major metabolic enzymes such as ATP dependent-6-phosphofructokinase and Hpr kinase/phosphorylase. Given the tight association between the bacterial basic physiology and virulence, this study hopes to prompt further investigation of how the pneumococcus controls its metabolic flux via the LMWPTP Spd1837. PMID- 29485031 TI - Effects of extended-release naltrexone on the brain response to drug-related stimuli in patients with opioid use disorder. AB - BACKGROUND: Heightened response to drug-related cues is a hallmark of addiction. Extended-release naltrexone (XR-NTX) is a US Food and Drug Administration approved pharmacotherapy for relapse prevention in patients with opioid use disorder (OUD). In these patients, XR-NTX has been shown to reduce brain responses to opioid-related visual stimuli. To assess the biomarker potential of this phenomenon, it is necessary to determine whether this effect is limited to opioid-related stimuli and whether it is associated with key OUD symptoms. METHODS: Using functional MRI (fMRI), we measured the brain responses to opioid related and control (i.e., sexual and aversive) images in detoxified patients with OUD before, during and after XR-NTX treatment. Craving and withdrawal severity were evaluated using clinician- and self-administered instruments during each session. RESULTS: We included 24 patients with OUD in our analysis. During XR-NTX treatment, we found reduced responses to opioid-related stimuli in the nucleus accumbens (NAcc) and medial orbitofrontal cortex (mOFC). The reduction in mOFC response was specific to the opioid-related stimuli. The reduced NAcc and mOFC opioid cue reactivity was correlated with reduction in clinician-assessed and self-reported withdrawal symptoms, respectively. LIMITATIONS: The study was not placebo-controlled owing to ethical, safety and feasibility concerns. CONCLUSION: Extended-release naltrexone reduces the NAcc and mOFC cue reactivity in patients with OUD. This effect is specific to opioid-related stimuli in the mOFC only. The reduction in neural response to opioid-related stimuli is more robust in patients with greater decline in withdrawal severity. Our results support the clinical utility of mesocorticolimbic cue reactivity in monitoring the XR-NTX treatment outcomes and highlight the link between opioid withdrawal symptomatology and neural opioid cue reactivity. PMID- 29485032 TI - Long-term results of protocol kidney biopsy directing steroid withdrawal in simultaneous pancreas-kidney transplant patients. AB - INTRODUCTION: We sought to determine whether protocol biopsies could be used to guide treatment and improve outcomes in simultaneous pancreas-kidney (SPK) patients. METHODS: Between 2004 and 2013, protocol biopsies were performed on SPK patients at 3-6 months and one year post-transplant. Maintenance immunosuppression consisted of a calcineurin inhibitor, anti-proliferative agent, and corticosteroid. Corticosteroid was withdrawn in negative early biopsies, maintained in subclinical/ borderline biopsies, and increased if Banff IB or greater rejection was identified. Endpoints included presence of interstitial fibrosis and tubular atrophy on biopsy at one year (IF/TA), rejection episodes, and renal and pancreas function at five years' followup. RESULTS: Forty-one SPK transplant patients were reviewed and a total of 75 protocol biopsies were identified. On early biopsy, 51% had negative biopsies, 44% had borderline rejection, and 5% had subclinical rejection. Renal and pancreas function were not significantly different at one, two, and five years post-transplant between negative vs. borderline early biopsy patients. No difference in the degree of IF/TA was found between these two groups. CONCLUSIONS: To our knowledge, this is the first study to evaluate protocol biopsies as an investigative tool prior to steroid withdrawal in SPK patients. Our study suggests that there are no detrimental functional or histological effects at five years post-transplant, despite weaning steroids in the negative biopsy group. PMID- 29485033 TI - The X-Y factor: Females and males with urological chronic pelvic pain syndrome present distinct clinical phenotypes. AB - INTRODUCTION: Urological chronic pelvic pain syndrome (UCPPS) in females is often attributed to the bladder (interstitial cystitis/ bladder pain syndrome), while UCPPS in males is often attributed to the prostate (chronic prostatitis/chronic pelvic pain syndrome). However, there is increasing awareness that bladder pain plays a role in both males and females and the degree of overlap of clinical characteristics in males and females with UCPPS is not well known. Our objective was to compare clinical phenotypes of females and males with UCPPS. METHODS: We conducted a retrospective analysis of prospectively collected data from a single centre patient population presenting between 1998 and 2016 to our UCPPS clinic. Demographics, symptom scores, pain scales, retrospectively described clinical UPOINT (urinary, psychosocial, organ-specific, infection, neurogenic, and tenderness) scoring, and presence of comorbid medical conditions were compared between females and males using comparative analyses. RESULTS: We identified 2007 subjects (1523 males, 484 females) with UCPPS. Females had increased prevalence of irritable bowel syndrome (25% vs. 11.2%), chronic fatigue syndrome (13.6% vs. 1.6%), fibromyalgia (16.9% vs. 1.6%), drug allergies (56.6% vs. 13.5%), diabetes (20.2% vs. 3.9%), depression (31% vs. 18.4%), and alcohol use (44.2% vs. 10.8%) compared to males with UCPPS (all p<0.001). In respect to UPOINT domains, females had a higher "total" (3.2 vs. 2.4), "urinary" (92.8% vs. 67.6%), "organ-specific" (90.1% vs. 51.4%), and "neurogenic" (44.7% vs. 30%) prevalence compared to males (all p<0.001). CONCLUSIONS: Females with UCPPS have greater prevalence of systemic disorders/symptoms and worse urinary symptoms than males with UCPPS. These findings demonstrate that females and males with UCPPS have distinct and different clinical phenotypes. PMID- 29485034 TI - The use of urodynamic studies for the followup of neurogenic bladders treated with onabotulinumtoxinA. AB - INTRODUCTION: Intradetrusor injection of onabotulinumtoxinA (BoNTA) is well established as treatment for patients with neurogenic bladders. Urodynamics (UDS) is used at regular intervals during followup to monitor intravesical pressure. With regards to the discomfort and risks associated with UDS, our objective was to assess if UDS done at regular intervals in the followup of neurogenic bladders treated with BoNTA had an impact on management. METHODS: We retrospectively analyzed the medical records of adult patients with neurological disorders treated with BoNTA for either detrusor overactivity or low bladder compliance at the Institut de Readaptation en Deficience Physique de Quebec (IRDPQ). At our centre, UDS was routinely performed at baseline, three months after the first treatment, then three months after every fifth set of injections. RESULTS: We identified 57 patients with neurological disorder treated with intravesical BoNTA. Each patient had between one and 19 sets of injections (mean 5.61 injections) and 1-6 followup UDS (mean 2.09). Of the 119 followup UDS reviewed at our centre, three UDS (2.5%) resulted in a modification of the urinary tract management from BoNTA to bladder augmentation. Two regimens were suspended and one was ended due to patient preference. CONCLUSIONS: Our study showed that UDS at pre-set intervals for followup of patients receiving BoNTA injections were rarely associated with modifications in the treatment course. Therefore, UDS should only be performed in cases where there are changes in the patient's symptoms or if the urologist suspects that the treatment response is suboptimal. PMID- 29485035 TI - Impact of oral hypoglycemic agents on mortality among diabetic patients with non muscle-invasive bladder cancer: A populationbased analysis. AB - INTRODUCTION: Non-muscle-invasive bladder cancer (NMIBC) accounts for 75-85% of all urothelial bladder cancers (UBC). Many UBC patients are also afflicted by diabetes mellitus (DM). It has been postulated that several oral hypoglycemic agents could impact disease-specific survival (DSS), but the data are sparse among NMIBC patients. Our primary objective was to evaluate the impact of metformin on DSS and overall survival (OS) in NMIBC patients. METHODS: This is a retrospective, population-based study that used linked administrative databases to identify diabetic patients >=66 years who were subsequently diagnosed with NMIBC in Ontario between 1992 and 2012. Cumulative use of metformin and other hypoglycemic agent were calculated before and after NMIBC diagnosis. DSS and OS were estimated using multivariable competing risk and Cox proportional hazards models, respectively. RESULTS: A total of 1742 subjects were included in the study. After a median followup of 5.2 years, 1122 (64%) had died, including 247 (15%) deaths as a result of UBC. On multivariable analysis, cumulative duration of metformin use after NMIBC diagnosis did not appear to impact DSS (hazard ratio [HR] 1.1; 95% confidence interval [CI] 0.92-1.2), whereas glyburide use appeared to have a detrimental effect (HR 1.17; 95% CI 1.02-1.3). None of the other hypoglycemic agents had an impact on OS. CONCLUSIONS: In this large, population based study, we have provided further evidence that metformin use does not significantly impact DSS among diabetic patients diagnosed with NMIBC. However, our findings demonstrate that glyburide use inversely affects DSS. The detrimental effect of glyburide on DSS will require further validation. PMID- 29485036 TI - The evolving clinical picture of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS): A look at 1310 patients over 16 years. AB - INTRODUCTION: Two decades of increasing understanding of etiopathogenesis and clinical phenotyping produces an impression the clinical face of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is changing. We sought to retrospectively analyze trends in CP/CPPS patients presenting to our clinic for evaluation over a 16-year period. METHODS: Patients with CP/CPPS presenting to a tertiary clinic were evaluated prospectively from 1998-2014 with Chronic Prostatitis Symptom Index (CPSI) and UPOINT (urinary, psychosocial, organ specific, infection, neurogenic, and tenderness) categorization. Patients were stratified in four cohorts, based on year of presentation, and we retrospectively analyzed variations in symptom scores and patterns, UPOINT categorization, and treatment modalities amongst cohorts. RESULTS: Mean age of the 1310 CP/CPPS patients was 44.7 years, while mean CPSI pain, urination, and total scores were 10.6, 4.8, and 23.3, respectively. The most prevalent UPOINT domain, urinary (U) (71.8%) was associated with a higher CPSI urination score (6.3), more frequent penile tip pain (37%), dysuria (48%), and more treatment with alpha-blockers (70%). Increase in UPOINT domains was associated with higher CPSI pain, quality of life (QoL), and total scores. Trends over time included increased prevalence of psychosocial (P), organ (O), and tenderness (T) domains, as well as increased use of alpha-blockers, neuromodulation, and phytotherapy as treatment modalities. There was little variation in age, CPSI scores, and pain locations over time. CONCLUSIONS: The changing clinical face of CP/CPPS reflects the increased recognition of psychosocial (P domain) and pelvic floor pain (T domain), along with the concomitant use of associated therapies. There was little variation of pain/urinary symptom patterns and QoL. PMID- 29485037 TI - Urinary function following radical cystectomy and orthotopic neobladder urinary reconstruction. AB - INTRODUCTION: An orthotopic neobladder urinary diversion aims to minimize the physical and psychological effects of radical cystectomy through avoidance of a stoma and maintenance of urethral voiding. Neobladder function reported in the literature ranges widely due to differences in patient selection and method of assessment. The objective of the study was to characterize functional outcomes of consecutive patients treated at a tertiary care hospital. METHODS: A historical cohort of patients who underwent radical cystectomy with a neobladder diversion performed at The Ottawa Hospital between January 2006 and December 2014 were reviewed. Outcomes of interest were urinary continence, use of clean intermittent catheterization (CIC), post-void residual volume, and uroflowmetry at three, six, and 12 months following cystectomy. RESULTS: During the study period, 158 neobladder diversions were performed. The mean age of patients was 63.1 years (standard deviation [SD] 8.1), and 81.7% were male. Significant daytime incontinence (>1 pad) three months following surgery was common (65%), but decreased to 8.6% by 12 months. Nighttime incontinence was also common at three months (54%) and improved at 12 months (20%). While no appreciable differences between men and women were observed for continence, more women performed CIC at 12 months post-surgery (59% of women; 9% of men; relative risk [RR] 0.15; 95% confidence interval [CI] 0.07-0.30). Among patients who did not catheterize, uroflowmetry and post-void residual volume parameters were stable between three and 12 months postoperative. CONCLUSIONS: Daytime and nighttime incontinence is common in neobladder patients following surgery, but improves considerably with time. Correspondingly, many female neobladder patients at our institution use CIC. PMID- 29485038 TI - A practical guide to female sexual dysfunction: An evidence-based review for physicians in Canada. PMID- 29485039 TI - The true malignancy risk of Bosniak III cystic renal lesions: Active surveillance or surgical resection? AB - INTRODUCTION: We sought to evaluate the pathological results of renal masses in comparison with Bosniak III renal cystic lesions to determine the actual malignancy risk. METHODS: A retrospective review of Bosniak III renal lesions identified by computed tomography (CT) or magnetic resonance imaging (MRI) were collected from our patients between August 1, 2013 and December 31, 2015 who underwent surgical excision. TNM stage, histology, Fuhrman grade, and maximum lesion size data was collected. Lesion size relationship with prevalence of malignancy was completed by two-tailed t-test, using the homogeneity hypothesis between malignant and benign groups. RESULTS: Fifteen of 25 (60%) of Bosniak III lesions were determined to be malignant. All malignant lesions were classified as either Fuhrman grade 1 or 2 with no evidence of progression to Bosniak IV. Average size of malignant lesions was smaller than those of benign pathology (3.52+/-1.99 cm vs. 5.66+/-2.53 cm; p=0.041). Smaller lesions (size <4 cm) were more likely to be malignant than lesions of a larger size (p=0.047). CONCLUSIONS: The malignancy risk of Bosniak III renal lesions was 60% in our study. All Bosniak III lesions were of low Fuhrman grade with no evidence of progression. No patient in this study developed metastatic disease within the three-year followup period. Smaller (<4 cm) Bosniak III cysts were more likely to be malignant and lesion size should be taken into consideration when considering management of complex cysts. Active surveillance may be a reasonable option for Bosniak III cystic lesions, regardless of overall size, based upon their universal low grade and no patient developing metastatic disease. PMID- 29485040 TI - Canadian Urological Association best practice report on chronic scrotal pain. PMID- 29485042 TI - Association Between Treatment at High-Volume Facilities and Improved Overall Survival in Soft Tissue Sarcomas. AB - PURPOSE: Soft tissue sarcomas (STS) are rare malignancies that require complex multidisciplinary management. Therefore, facilities with high sarcoma case volume may demonstrate superior outcomes. We hypothesized that STS treatment at high volume (HV) facilities would be associated with improved overall survival (OS). METHODS AND MATERIALS: Patients aged >=18 years with nonmetastatic STS treated with surgery and radiation therapy at a single facility from 2004 through 2013 were identified from the National Cancer Database. Facilities were dichotomized into HV and low-volume (LV) cohorts based on total case volume over the study period. OS was assessed using multivariable Cox regression with propensity score matching. Patterns of care were assessed using multivariable logistic regression analysis. RESULTS: Of 9025 total patients, 1578 (17%) and 7447 (83%) were treated at HV and LV facilities, respectively. On multivariable analysis, high educational attainment, larger tumor size, higher grade, and negative surgical margins were statistically significantly associated with treatment at HV facilities; conversely, black race and non-metropolitan residence were negative predictors of treatment at HV facilities. On propensity score-matched multivariable analysis, treatment at HV facilities versus LV facilities was associated with improved OS (hazard ratio, 0.87, 95% confidence interval, 0.80 0.95; P = .001). Older age, lack of insurance, greater comorbidity, larger tumor size, higher tumor grade, and positive surgical margins were associated with statistically significantly worse OS. CONCLUSIONS: In this observational cohort study using the National Cancer Database, receipt of surgery and radiation therapy at HV facilities was associated with improved OS in patients with STS. Potential sociodemographic disparities limit access to care at HV facilities for certain populations. Our findings highlight the importance of receipt of care at HV facilities for patients with STS and warrant further study into improving access to care at HV facilities. PMID- 29485041 TI - Conjunction of factors triggering waves of seasonal influenza. AB - Using several longitudinal datasets describing putative factors affecting influenza incidence and clinical data on the disease and health status of over 150 million human subjects observed over a decade, we investigated the source and the mechanistic triggers of influenza epidemics. We conclude that the initiation of a pan-continental influenza wave emerges from the simultaneous realization of a complex set of conditions. The strongest predictor groups are as follows, ranked by importance: (1) the host population's socio- and ethno-demographic properties; (2) weather variables pertaining to specific humidity, temperature, and solar radiation; (3) the virus' antigenic drift over time; (4) the host population'?TMs land-based travel habits, and; (5) recent spatio-temporal dynamics, as reflected in the influenza wave auto-correlation. The models we infer are demonstrably predictive (area under the Receiver Operating Characteristic curve 80%) when tested with out-of-sample data, opening the door to the potential formulation of new population-level intervention and mitigation policies. PMID- 29485043 TI - Inhibitors of HIF-1alpha and CXCR4 Mitigate the Development of Radiation Necrosis in Mouse Brain. AB - PURPOSE: There is mounting evidence that, in addition to angiogenesis, hypoxia induced inflammation via the hypoxia-inducible factor 1alpha (HIF-1alpha)-CXC chemokine receptor 4 (CXCR4) pathway may contribute to the pathogenesis of late onset, irradiation-induced necrosis. This study investigates the mitigative efficacy of an HIF-1alpha inhibitor, topotecan, and a CXCR4 antagonist, AMD3100, on the development of radiation necrosis (RN) in an intracranial mouse model. METHODS AND MATERIALS: Mice received a single-fraction, 50-Gy dose of hemispheric irradiation from the Leksell Gamma Knife Perfexion and were then treated with either topotecan, an HIF-1alpha inhibitor, from 1 to 12 weeks after irradiation, or AMD3100, a CXCR4 antagonist, from 4 to 12 weeks after irradiation. The onset and progression of RN were monitored longitudinally via noninvasive, in vivo magnetic resonance imaging (MRI) from 4 to 12 weeks after irradiation. Conventional hematoxylin-eosin staining and immunohistochemistry staining were performed to evaluate the treatment response. RESULTS: The progression of brain RN was significantly mitigated for mice treated with either topotecan or AMD3100 compared with control animals. MRI-derived lesion volumes were significantly smaller for both of the treated groups, and histologic findings correlated well with the MRI data. By hematoxylin-eosin staining, both treated groups demonstrated reduced irradiation-induced tissue damage compared with controls. Furthermore, immunohistochemistry results revealed that expression levels of vascular endothelial growth factor, CXC chemokine ligand 12, CD68, CD3, and tumor necrosis factor alpha in the lesion area were significantly lower in treated (topotecan or AMD3100) brains versus control brains, while ionized calcium binding adapter molecule 1 (Iba1) and HIF-1alpha expression was similar, though somewhat reduced. CXCR4 expression was reduced only in topotecan-treated mice, while interleukin 6 expression was unaffected by either topotecan or AMD3100. CONCLUSIONS: By reducing inflammation, both topotecan and AMD3100 can, independently, mitigate the development of RN in the mouse brain. When combined with first-line, antiangiogenic treatment, anti-inflammation therapy may provide an adjuvant therapeutic strategy for clinical, postirradiation management of tumors, with additional benefits in the mitigation of RN development. PMID- 29485044 TI - Associations of Genetic Variations in MicroRNA Seed Regions With Acute Adverse Events and Survival in Patients With Rectal Cancer Receiving Postoperative Chemoradiation Therapy. AB - PURPOSE: The aim of this study was to investigate the associations between single nucleotide polymorphisms (SNPs) in the seed regions of microRNAs and acute adverse events (AEs) and survival in patients with rectal cancer receiving postoperative chemoradiation therapy. METHODS AND MATERIALS: Eighteen SNPs were genotyped in 365 patients with rectal cancer receiving postoperative chemoradiation therapy. The associations between genotypes and AEs were estimated by odds ratios and 95% confidence intervals (CIs), which were computed by using multivariate logistic regression models. The hazard ratios and 95% CIs to assess the death of patients for different genotypes were calculated by Cox proportional regression models. Overall survival and disease-free survival of patients with different genotypes were estimated by Kaplan-Meier plots, and the statistical significance was determined by using the log-rank test. RESULTS: In these patients, the most common grade >=2 AEs were diarrhea (44.1%), leukopenia (29.6%), and dermatitis (18.9%). With false discovery rate correction, SNP rs2273626 was significantly associated with a decreased risk of grade >=2 leukopenia (odds ratio, 0.48; 95% CI, 0.31-0.74; P = .0009). In addition, SNP rs202195689 was associated with overall survival and disease-free survival in patients receiving postoperative chemoradiation therapy, with the hazard ratios for death being 2.02 (95% CI, 1.36-3.01; P = .0006) and 1.91 (95% CI, 1.36-2.70; P = .0002), respectively. However, no significant association between these SNPs and diarrhea and dermatitis was observed. CONCLUSIONS: These results suggest that rs2273626 and rs202195689 in microRNA seed regions might serve as independent biomarkers for predicting AEs and prognosis in patients with rectal cancer receiving postoperative chemoradiation therapy. Independent replication of these findings is required to confirm these results. PMID- 29485045 TI - Blocking Interleukin (IL)4- and IL13-Mediated Phosphorylation of STAT6 (Tyr641) Decreases M2 Polarization of Macrophages and Protects Against Macrophage-Mediated Radioresistance of Inflammatory Breast Cancer. AB - PURPOSE: To determine the role of macrophage polarization on the response of inflammatory breast cancer (IBC) cells to radiation and whether modulation of macrophage plasticity can alter radiation response. METHODS AND MATERIALS: The human THP-1 monocyte cell line and primary human monocytes isolated from peripheral blood mononuclear cells were differentiated into macrophages and polarized to either an "antitumor" (M1) or a "protumor" (M2) phenotype. These polarized macrophages were co-cultured with IBC cells (SUM149, KPL4, MDA-IBC3, or SUM190) without direct contact for 24 hours, then subjected to irradiation (0, 2, 4, or 6 Gy). Interleukin (IL)4/IL13-induced activation of STAT6 signaling was measured by Western blotting of phospho-STAT6 (Tyr641), and expression of M2 polarization gene markers (CD206, fibronectin, and CCL22) was measured by quantitative polymerase chain reaction. RESULTS: Expression of M2 polarization markers was higher in M2-polarized macrophages after IL4/IL13 treatment than in control (M0) or M1-polarized macrophages. Co-culture of IBC cell lines with M1 polarized THP-1 macrophages mediated radiosensitivity of IBC cells, whereas co culture with M2-polarized macrophages mediated radioresistance. Phosphopeptide mimetic PM37, targeting the SH2 domain of STAT6, prevented and reversed IL4/IL13 mediated STAT6 phosphorylation (Tyr641) and decreased the expression of M2 polarization markers. Pretreatment of M2-THP1 macrophages with PM37 reduced the radioresistance they induced in IBC cells after co-culture. Targeted proteomics analysis of IBC KPL4 cells using a kinase antibody array revealed induction of protein kinase C zeta (PRKCZ) in these cells only after co-culture with M2-THP1 macrophages, which was prevented by PM37 pretreatment. KPL4 cells with stable short hairpin RNA knockdown of PRKCZ exhibited lower radioresistance after M2 THP1 co-culture. CONCLUSIONS: These data suggest that inhibition of M2 polarization of macrophages by PM37 can prevent radioresistance of IBC by down regulating PRKCZ. PMID- 29485046 TI - Locally Ablative Radiation Therapy of a Primary Human Small Cell Lung Cancer Tumor Decreases the Number of Spontaneous Metastases in Two Xenograft Models. AB - PURPOSE: To investigated the influence of radiation therapy (RT), surgery (OP), radio-chemotherapy (RChT), or chemotherapy (ChT) on small cell lung cancer metastases in 2 xenograft models. METHODS AND MATERIALS: A total of 1 * 106 human small cell lung cancer cells (OH1, H69) were subcutaneously injected into severe combined immunodeficiency mice to form a local primary tumor node at the lower trunk. Radiation therapy, OP, RChT, or ChT were started after development of palpable tumors. Chemotherapy was given as a single intraperitoneal injection of cisplatin. Radiation therapy was 5 * 10 Gy on the local tumor node. Two additional groups were implemented to assess primary tumors and distant metastases in untreated mice at the beginning (control group A) and at the end of the experiment (control group B). Proapoptotic, antiproliferative, antiangiogenic, and hypoxic effects were assessed by Feulgen, Ki67, S1P1 receptor, and hypoxia-inducible factor 1alpha staining, respectively. Quantitative Alu-polymerase chain reaction was used to determine circulating tumor cells in the blood, and disseminated tumor cells in the lungs, bone marrow, liver, and brain. RESULTS: In both xenograft models, RT and RChT abrogated local tumor growth, indicated by increased apoptosis, decreased cell proliferation, and reduced microvessel density (equally affecting vessels of all diameters). Regarding metastases, RT and RChT not only counteracted the time-dependent increase of dissemination but also decreased the metastatic load pre-existing at therapy induction in the blood, lungs, and liver. Only in the case of relapse free surgery could similar effects be achieved by OP. CONCLUSIONS: Our models provide evidence that RT and RChT ablate the primary tumor and inhibit metastasis development over time. Upon local recurrence, RT showed beneficial effects compared with OP with regard to suppression of circulating tumor cells and disseminated tumor cells. PMID- 29485049 TI - Contemporary Analysis of the Prevalence of Illegal Match Questions During Medical Student Residency Interviews. PMID- 29485048 TI - Improving Quality and Consistency in NRG Oncology Radiation Therapy Oncology Group 0631 for Spine Radiosurgery via Knowledge-Based Planning. AB - PURPOSE: To use knowledge-based planning (KBP) as a method of producing high quality, consistent, protocol-compliant treatment plans in a complex setting of spine stereotactic body radiation therapy on NRG Oncology Radiation Therapy Oncology Group (RTOG) 0631. METHODS AND MATERIALS: An internally developed KBP model was applied to an external validation cohort of 22 anonymized cases submitted under NRG Oncology RTOG 0631. The original and KBP plans were compared via their protocol compliance, target conformity and gradient index, dose to critical structures, and dose to surrounding normal tissues. RESULTS: The KBP model generated plans meeting all protocol objectives in a single optimization when tested on both internal and protocol-submitted NRG Oncology RTOG 0631 cases. Two submitted plans that were considered to have a protocol-unacceptable deviation were made protocol compliant through the use of the model. There were no statistically significant differences in protocol spinal cord metrics (D10% and D0.03cc) between the manually optimized plans and the KBP plans. The volume of planning target volume receiving prescription dose increased from 93.3% +/- 3.2% to 98.3% +/- 1.4% (P = .01) when using KBP. High-dose spillage to surrounding normal tissues (V105%) showed no significant differences (2.1 +/- 7.3 cm3 for manual plans to 1.8 +/- 0.6 cm3 with KBP), and dosimetric outliers with large amounts of spillage were eliminated through the use of KBP. Knowledge-based planning plans were also found to be significantly more consistent in several metrics, including target coverage and high dose outside of the target. CONCLUSION: Incorporation of KBP models into the clinical trial setting may have a profound impact on the quality of trial results, owing to the increase in consistency and standardization of planning, especially for treatment sites or techniques that are nonstandard. PMID- 29485050 TI - In Regard to Kumar et al. PMID- 29485047 TI - American Association of Physicists in Medicine Task Group 263: Standardizing Nomenclatures in Radiation Oncology. AB - A substantial barrier to the single- and multi-institutional aggregation of data to supporting clinical trials, practice quality improvement efforts, and development of big data analytics resource systems is the lack of standardized nomenclatures for expressing dosimetric data. To address this issue, the American Association of Physicists in Medicine (AAPM) Task Group 263 was charged with providing nomenclature guidelines and values in radiation oncology for use in clinical trials, data-pooling initiatives, population-based studies, and routine clinical care by standardizing: (1) structure names across image processing and treatment planning system platforms; (2) nomenclature for dosimetric data (eg, dose-volume histogram [DVH]-based metrics); (3) templates for clinical trial groups and users of an initial subset of software platforms to facilitate adoption of the standards; (4) formalism for nomenclature schema, which can accommodate the addition of other structures defined in the future. A multisociety, multidisciplinary, multinational group of 57 members representing stake holders ranging from large academic centers to community clinics and vendors was assembled, including physicists, physicians, dosimetrists, and vendors. The stakeholder groups represented in the membership included the AAPM, American Society for Radiation Oncology (ASTRO), NRG Oncology, European Society for Radiation Oncology (ESTRO), Radiation Therapy Oncology Group (RTOG), Children's Oncology Group (COG), Integrating Healthcare Enterprise in Radiation Oncology (IHE-RO), and Digital Imaging and Communications in Medicine working group (DICOM WG); A nomenclature system for target and organ at risk volumes and DVH nomenclature was developed and piloted to demonstrate viability across a range of clinics and within the framework of clinical trials. The final report was approved by AAPM in October 2017. The approval process included review by 8 AAPM committees, with additional review by ASTRO, European Society for Radiation Oncology (ESTRO), and American Association of Medical Dosimetrists (AAMD). This Executive Summary of the report highlights the key recommendations for clinical practice, research, and trials. PMID- 29485051 TI - In Reply to Hurmuz et al. PMID- 29485052 TI - Radiation Biology and Circulating Tumor Cells. PMID- 29485053 TI - Proceedings of the National Cancer Institute Workshop on Charged Particle Radiobiology. AB - In April 2016, the National Cancer Institute hosted a multidisciplinary workshop to discuss the current knowledge of the radiobiological aspects of charged particles used in cancer therapy to identify gaps in that knowledge that might hinder the effective clinical use of charged particles and to propose research that could help fill those gaps. The workshop was organized into 10 topics ranging from biophysical models to clinical trials and included treatment optimization, relative biological effectiveness of tumors and normal tissues, hypofractionation with particles, combination with immunotherapy, "omics," hypoxia, and particle-induced second malignancies. Given that the most commonly used charged particle in the clinic currently is protons, much of the discussion revolved around evaluating the state of knowledge and current practice of using a relative biological effectiveness of 1.1 for protons. Discussion also included the potential advantages of heavier ions, notably carbon ions, because of their increased biological effectiveness, especially for tumors frequently considered to be radiation resistant, increased effectiveness in hypoxic cells, and potential for differentially altering immune responses. The participants identified a large number of research areas in which information is needed to inform the most effective use of charged particles in the future in clinical radiation therapy. This unique form of radiation therapy holds great promise for improving cancer treatment. PMID- 29485054 TI - Radiation Therapy in a Time of Disaster. PMID- 29485055 TI - Puerto Rico: After Maria. PMID- 29485056 TI - Natural Disasters and the Importance of Minimizing Subsequent Radiation Therapy Interruptions for Locally Advanced Lung Cancer. PMID- 29485057 TI - When Disaster Strikes: Mitigating the Adverse Impact on Head and Neck Cancer Patients. PMID- 29485058 TI - Role of Overall Treatment Time in the Management of Prostate Cancer Patients: How to Manage Unscheduled Treatment Interruptions. PMID- 29485059 TI - Radiation Oncology in the Face of Natural Disaster: The Experience of Houston Methodist Hospital. PMID- 29485060 TI - Radiation Oncology and Related Oncology Fields in the Face of the 2011 "Triple Disaster" in Fukushima, Japan. PMID- 29485061 TI - Our Role in Radiation Disaster Preparedness. PMID- 29485062 TI - The Impact of Academic Facility Type and Case Volume on Survival in Patients Undergoing Curative Radiation Therapy for Muscle-Invasive Bladder Cancer. AB - PURPOSE: Bladder-preserving curative radiation therapy (RT) has been established as an excellent treatment option for select patients with muscle-invasive bladder cancer (MIBC). However, some clinicians have concerns that good outcomes are only achievable at high-volume facilities (HVFs) and academic centers (ACs), questioning successful reproducibility of curative RT at smaller centers. This study sought to determine whether treatment at ACs or HVFs was associated with better overall survival (OS) than treatment at nonacademic centers or lower volume facilities. METHODS AND MATERIALS: We performed a retrospective cohort study of National Cancer Database patients (n=2763) with cT2 to cT4 N0 M0 transitional cell MIBC who received curative RT (60-70 Gy) with or without concurrent chemotherapy. Cox proportional hazards models were used to estimate the instantaneous hazard of death as a function of univariate and multivariate patient characteristics and clinical measures. RESULTS: Univariate analysis showed that academic facility type was significantly associated with improved OS (hazard ratio [HR], 0.88; 95% confidence interval [CI] 0.79-0.98; P=.02) whereas higher case volume was not associated with improved survival (HR, 0.97; 95% CI 0.92-1.01; P=.15). Multivariate analysis showed no differences in OS for treatment at ACs versus nonacademic centers (HR, 0.94; 95% CI 0.84-1.06; P=.31) or HVFs versus lower-volume facilities (HR, 0.99; 95% CI 0.94-1.04; P=.60). The 2 year OS rate was 54.5% (95% CI 52.5%-56.4%), and the 5-year OS rate was 28.9% (95% CI 27.0%-30.8%). CONCLUSIONS: Although some providers are cautious about offering curative RT at all centers, this large hospital-based study suggests that facility type and volume are not significantly associated with OS for patients undergoing curative RT after we account for other clinically relevant risk factors. The results of this study demonstrate that curative RT in the treatment of MIBC may be considered for patients regardless of facility type or volume. PMID- 29485063 TI - Dose Response and Fractionation Sensitivity of Prostate Cancer After External Beam Radiation Therapy: A Meta-analysis of Randomized Trials. AB - PURPOSE: Randomized trials of altered dose/fractionation for external beam radiation therapy are meta-analyzed with the aim of establishing the dose response and fractionation sensitivity. METHODS AND MATERIALS: Studies were identified through PubMed through April 1, 2017. Studies of any-risk prostate cancer patients and any modification of external beam radiation therapy were included. The outcomes and comparisons collected were hazard ratios for biochemical no evidence of disease (bNED) and overall survival (OS). Trial-by trial estimates of the steepness of the dose-response curve for bNED were performed for dose-escalation trials, followed by inverse variance weighting. The steepness was used to extract estimates of alpha/beta, which were subsequently synthesized. Both analyses were performed assuming no effect of overall treatment time and were repeated assuming a loss of 0.31 Gy/d for a protracted treatment time. Finally, all trials were included in the analyses of the dose response for fractionation-corrected doses. This analysis was repeated for OS. Finally, the per-trial effect on OS was compared to the effect on bNED. RESULTS: We identified 13 randomized trials involving 10,184 patients. The dose response for bNED from dose-escalation trials was gamma50 = 0.62 (95% confidence interval [CI] 0.37 0.87) and gamma50 = 0.87 (95% CI 0.53-1.21) without and with the overall treatment time effect, respectively. The corresponding estimates of alpha/beta from 8 fractionation trials (7946 patients) were 1.2 Gy (95% CI 0.8-1.7) and 2.7 Gy (95% CI 1.6-3.8). The heterogeneity in the data can be explained by the shallower dose response for bNED in trials with effective doses in the experimental arm >80 Gy equivalent dose in 2-Gy fractions (EQD2) (P = .04). No indication was found of a dose response for OS or a correlation with improvement in bNED. CONCLUSIONS: The reported data of moderate hypofractionation are consistent with a low alpha/beta value with narrow CIs. Dose-escalation trials have demonstrated a dose response for bNED. Escalating doses to >80 Gy EQD2 might not improve bNED. A correlation between benefit in bNED and OS was not found. PMID- 29485064 TI - 4 Weeks Versus 5 Weeks of Hypofractionated High-dose Radiation Therapy as Primary Therapy for Prostate Cancer: Interim Safety Analysis of a Randomized Phase 3 Trial. AB - PURPOSE: Hypofractionated radiation therapy (HFRT) for localized prostate cancer is safe and effective. The question that remains is which hypofractionation schedule to implement. We compared 2 different HFRT regimens in the present study. METHODS AND MATERIALS: From June 2013 to July 2016, 160 patients with prostate cancer were randomly assigned (1:1), within this single-center phase III trial, to 56 Gy (16 fractions of 3.5 Gy; arm A) or 67 Gy (25 fractions of 2.68 Gy; arm B). Randomization was performed using computer-generated permuted blocks, stratified by previous transurethral resection of the prostate and the presence of a dominant intraprostatic lesion. Treatment allocation was not masked, and the clinicians were not blinded. The primary endpoint was acute gastrointestinal (GI) toxicity, assessed using the Common Terminology Criteria for Adverse Events, version 4.0, and Radiation Therapy Oncology Group toxicity scale. An interim analysis of acute toxicity was planned at 160 patients to prove the safety of both treatment regimens. If >=22 of 72 patients had grade >=2 GI toxicity, the study arm would be rejected. The study is registered at ClinicalTrials.gov (NCT01921803). RESULTS: In arm A, 20 patients (26%) and 1 patient (1%) developed acute grade 2 and grade 3 GI toxicity. In arm B, 16 patients (20%) reported acute grade 2 GI toxicity. In arm A, 42 (55%) and 5 (6%) patients developed acute grade 2 and grade 3 urinary toxicity. In arm B, 40 (49%) and 7 (9%) patients reported acute grade 2 and grade 3 urinary toxicity. Toxicity peaked during radiation therapy and resolved in the months after radiation therapy. CONCLUSIONS: With acute grade >=2 GI toxicity reported in 21 of 77 patients in arm A and 16 of 82 patients in arm B, both treatment arms can be considered safe. PMID- 29485065 TI - Are We Now Able to Define Guidelines for Moderate Hypofractionation in Prostate Cancer Radiation Therapy? PMID- 29485066 TI - A Phase 2 Study of 2 Weeks of Adjuvant Whole Breast/Chest Wall and/or Regional Nodal Radiation Therapy for Patients With Breast Cancer. AB - PURPOSE: To report the results in terms of feasibility and early toxicity of hypofractionated adjuvant whole breast/chest wall and/or regional nodal radiation therapy for patients with breast cancer. METHODS AND MATERIALS: From June 2013 to October 2014, 50 patients with breast cancer after mastectomy or after breast conservation surgery (BCS) were prospectively included. The institutional ethics committee approved the study, which was registered with ClinicalTrials.gov (ClinicalTrials.gov identifier no. NCT02460744). Treatment planning was performed using a simulator with 2 tangential fields to the breast/chest wall and an incident field to the supraclavicular fossa. The radiation dose delivered was 34 Gy in 10 fractions within 2 weeks, followed by a boost of 10 Gy in 5 fractions within 1 week for patients who underwent BCS. Acute skin toxicities were recorded during and after treatment according to the Radiation Therapy Oncology Group acute radiation toxicity scoring criteria. The primary objective was to obtain estimates of the acute toxicity rates and cosmetic outcomes that could be used to design a subsequent phase III comparative study. Acute skin and late toxicities were recorded during and after treatment. Cosmetic outcomes were assessed before and after treatment and during the regular follow-up period. A cost/benefit analysis was also performed and compared with that for standard treatment of 35 Gy in 15 fractions within 3 weeks. RESULTS: The median follow-up was 39 months (range 14-48). The mean age was 51 years (range 26-75). A left-sided tumor was present in 25 patients (50%). Total mastectomy with axillary clearance was performed in 40 (80%) and BCS in 10 (20%) patients. Acute grade 2 and 3 skin toxicity was seen in 16 (32%) and 1 (2%) patient, respectively. In the BCS patients, grade 2 skin and subcutaneous toxicity was seen in 2 (20%) and 1 (10%) patient, respectively. Grade 2 edema was seen in 1 patient (10%). The cosmesis was excellent or good in 8 (80%) and fair or poor in 2 (20%) patients. The cost/benefit analysis revealed significantly less financial burden on the patients with 2 weeks of treatment. Disease-free and overall survival at 3 years was 94% and 96%, respectively. CONCLUSIONS: Hypofractionated radiation therapy within 2 weeks appears to be feasible for patients with breast cancer and was associated with acute and late skin toxicity profiles similar to those observed with 3 weeks of treatment. The financial burden on the patient and family could be reduced with 2 weeks of treatment. Long-term follow-up data and a prospective comparative study are needed to strengthen these results. Hypofractionation might help radiation centers worldwide to meet the increasing need for radiation for breast cancer, especially in developing countries where resources are limited and patients must travel long distances for treatment. PMID- 29485068 TI - Delineation of Neck Clinical Target Volume Specific to Nasopharyngeal Carcinoma Based on Lymph Node Distribution and the International Consensus Guidelines. AB - PURPOSE: To establish the regional lymph node (LN) distribution probability map and draw the neck clinical target volume specific to nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: One thousand patients with pathologically proven NPC were enrolled from January 2010 to December 2011. The center point of the LNs with a minimal axial diameter of >=4 mm was marked on a single treatment planning computed tomography scan. The neck LN levels I to X using the 2013 updated international consensus guidelines were also contoured. LN distribution probability maps and distribution curves were established. The relationships between the LN distribution and consensus guidelines were analyzed to propose modifications for clinical target volume boundaries specific to NPC. RESULTS: A total of 10,651 LNs from 959 patients were marked. Based on the distribution of LNs and consensus guidelines, most of the LN levels defined in the 2013 updated consensus guidelines were confirmed to be comprehensive and applicable for NPC. However, for level Vb, 13.3% of cases (11 of 83) had LNs beyond the posteromedial border. For level VIIa (retropharyngeal LN), 1.5% of cases (12 of 819) had LNs above the cranial boundary, and 5 cases had LNs that emerged in the medial group. Moreover, we confirmed that no LN had been detected in certain areas of levels Ib, II, IVa, and Vc. Accordingly, a new level VIIc was proposed to include the medial group of retropharyngeal LNs, moderately extended boundaries for levels Vb and VIIa were recommended, and reduced boundaries are possibly adaptable for levels Ib, II, IV, and Vc. CONCLUSIONS: Most LN levels in the 2013 updated consensus guidelines are comprehensive and applicable for NPC. We have proposed a new level VIIc to include a medial group of retropharyngeal LNs, recommended moderate extended boundaries for levels Vb and VIIa, and suggested that the boundaries for levels Ib, II, IV, and Vc might be reduced. PMID- 29485067 TI - Long-term Patient-Reported Outcomes in Older Breast Cancer Survivors: A Population-Based Survey Study. AB - PURPOSE: For older women with breast cancer, local therapy options may include lumpectomy plus whole-breast irradiation (Lump + WBI), lumpectomy plus brachytherapy (Lump + Brachy), lumpectomy alone (Lump alone), mastectomy without radiation therapy (Mast alone), and mastectomy plus radiation therapy (Mast + RT). We surveyed a population-based cohort of older breast cancer survivors to assess the association of local therapy with long-term quality-of-life outcomes. METHODS AND MATERIALS: We used nationally comprehensive Medicare claims to identify women aged >=67 years in whom nonmetastatic breast cancer was diagnosed in 2009, who were treated with 1 of the 5 aforementioned treatment options, and who were still alive in 2015. From this cohort, 1650 patients (330 patients per treatment) were randomly selected. A survey that included the CanSORT (Cancer Surveillance and Outcomes Research Team) Satisfaction with Breast Cosmetic Outcome, BREAST-Q, Decisional Regret Scale, and EQ-5D-3L was mailed to potential participants. We used multivariable linear regression to assess associations between local therapy and outcomes after adjusting for patient, disease, and treatment covariates. RESULTS: Among the 489 women who returned the surveys (30% response rate), the median age at diagnosis was 72 years (range, 67-87 years). The interval from diagnosis to survey completion was approximately 6 years for all patients. Compared with Lump + WBI (adjusted score, 3.40), the CanSORT cosmetic satisfaction scores were higher for Lump + Brachy (score, 3.77; P = .007) and Lump alone (score, 3.80; P = .04) and lower for Mast + RT (score, 3.01; P = .006). Similar trends were seen for BREAST-Q cosmetic satisfaction. BREAST-Q psychosocial, sexual, and physical well-being and EQ-5D-3L global health status tended to be better in patients treated with less irradiation and less surgery. BREAST-Q adverse radiation effects were worse for Lump + WBI compared with Lump + Brachy. Decisional regret regarding surgery and radiation therapy did not differ across groups. Compared with patients treated with Lump + WBI, patients treated with Lump + Brachy and Lump alone reported slightly higher rates of in-breast recurrence (excess risk of 5.8% and 6.4%, respectively; P = .01). CONCLUSIONS: In this nationally diverse cohort, less irradiation and less surgery were associated with better long-term quality-of-life outcomes. However, patient regret regarding surgery and radiation therapy was similar across all groups. PMID- 29485069 TI - CTV Guidance for Head and Neck Cancers. PMID- 29485070 TI - Phase 1 Dose Escalation Trial of Ipilimumab and Stereotactic Body Radiation Therapy in Metastatic Melanoma. AB - PURPOSE: To report the results of a phase 1 trial evaluating the safety of the ipilimumab/radiation therapy combination in patients with metastatic melanoma. PATIENTS AND METHODS: Thirteen patients with metastatic melanoma were enrolled. Trial treatment consisted of 4 cycles of ipilimumab in combination with concurrent dose-escalated high-dose radiation therapy to 1 lesion administered before the third cycle of ipilimumab. RESULTS: Grade 3 or 4 ipilimumab-related adverse events occurred in 25% of patients. The maximum tolerated radiation therapy dose was not reached. Local control of the irradiated lesions was achieved in 11 of 12 irradiated patients (1 patient had progressive disease before irradiation and dropped out of the trial). Evaluation of the nonirradiated lesions demonstrated that 3 of 13 patients experienced clinical benefit, with 1 patient developing a partial response and 2 patients having confirmed stable disease. Immunomonitoring data showed that in patients without clinical benefit, factors linked to immunotolerance increased early after the initiation of ipilimumab, suggesting that early initiation of radiation therapy might be more effective if combined with ipilimumab. CONCLUSIONS: Our findings suggest that the combination of ipilimumab and high-dose radiation therapy is feasible and safe. PMID- 29485071 TI - Concurrent Immune Checkpoint Inhibitors and Stereotactic Radiosurgery for Brain Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma. AB - PURPOSE: To characterize the effect of concurrent stereotactic radiosurgery stereotactic radiation therapy (SRS-SRT) and immune checkpoint inhibitors on patient outcomes and safety in patients with brain metastases (BMs). METHODS AND MATERIALS: We retrospectively identified metastatic non-small cell lung cancer, melanoma, and renal cell carcinoma patients who had BMs treated with SRS-SRT from 2010 to 2016 without prior whole-brain radiation therapy. We included SRS-SRT patients who were treated with anti-cytotoxic T-lymphocyte-associated protein 4 (ipilimumab) and anti-programmed cell death protein 1 receptor (nivolumab, pembrolizumab). Patients who were given immune checkpoint inhibitors on active or unreported clinical trials were excluded, and concurrent immune checkpoint inhibition (ICI) was defined as ICI given within 2 weeks of SRS-SRT. Patients were managed with SRS-SRT, SRS-SRT with nonconcurrent ICI, or SRS-SRT with concurrent ICI. Progression-free survival and overall survival (OS) were estimated using Kaplan-Meier survival curves, and Cox proportional hazards models were used for multivariate analysis. Logistic regression was used to identify predictors of acute neurologic toxicity, immune-related adverse events, and new BMs. RESULTS: A total of 260 patients were treated with SRS-SRT to 623 BMs. Of these patients, 181 were treated with SRS-SRT alone, whereas 79 received SRS-SRT and ICI, 35% of whom were treated with concurrent SRS-SRT and ICI. Concurrent ICI was not associated with increased rates of immune-related adverse events or acute neurologic toxicity and predicted for a decreased likelihood of the development of >=3 new BMs after SRS-SRT (P=.045; odds ratio, 0.337). Median OS for patients treated with SRS-SRT, SRS-SRT with nonconcurrent ICI, and SRS-SRT with concurrent ICI was 12.9 months, 14.5 months, and 24.7 months, respectively. SRS-SRT with concurrent ICI was associated with improved OS compared with SRS-SRT alone (P=.002; hazard ratio [HR], 2.69) and compared with nonconcurrent SRS-SRT and ICI (P=.006; HR, 2.40) on multivariate analysis. The OS benefit of concurrent SRS-SRT and ICI was significant in comparison with patients treated with SRS-SRT before ICI (P=.002; HR, 3.82) or after ICI (P=.021; HR, 2.64). CONCLUSIONS: Delivering SRS-SRT with concurrent ICI may be associated with a decreased incidence of new BMs and favorable survival outcomes without increased rates of adverse events. PMID- 29485072 TI - Decision-Making Strategy for Rectal Cancer Management Using Radiation Therapy for Elderly or Comorbid Patients. AB - Rectal cancer predominantly affects patients older than 70 years, with peak incidence at age 80 to 85 years. However, the standard treatment paradigm for rectal cancer oftentimes cannot be feasibly applied to these patients owing to frailty or comorbid conditions. There are currently little information and no treatment guidelines to help direct therapy for patients who are elderly and/or have significant comorbidities, because most are not included or specifically studied in clinical trials. More recently various alternative treatment options have been brought to light that may potentially be utilized in this group of patients. This critical review examines the available literature on alternative therapies for rectal cancer and proposes a treatment algorithm to help guide clinicians in treatment decision making for elderly and comorbid patients. PMID- 29485073 TI - Deviations From Standard Chemoradiation Among Early-Stage Anal Cancer Patients. PMID- 29485075 TI - Local Control and Toxicity of External Beam Reirradiation With a Pulsed Low-dose rate Technique. AB - PURPOSE: To evaluate the efficacy and toxicity of external beam reirradiation using a pulsed low-dose-rate (PLDR) technique. METHODS AND MATERIALS: We evaluated patients treated with PLDR reirradiation from 2009 to 2016 at a single institution. Toxicity was graded using the Common Terminology Criteria for Adverse Events, version 4.0, and local control was assessed using the Response Evaluation Criteria In Solid Tumors, version 1.1. On univariate analysis (UVA), the chi2 and Fisher exact tests were used to assess the toxicity outcomes. Competing risk analysis using cumulative incidence function estimates were used to assess local progression. RESULTS: A total of 39 patients were treated to 41 disease sites with PLDR reirradiation. These patients had a median follow-up time of 8.8 months (range 0.5-64.7). The targets were the thorax, abdomen, and pelvis, including 36 symptomatic sites. The median interval from the first radiation course and reirradiation was 26.2 months; the median dose of the first and second course of radiation was 50.4 Gy and 50 Gy, respectively. Five patients (13%) received concurrent systemic therapy. Of the 39 patients, 9 (23%) developed grade >=2 acute toxicity, most commonly radiation dermatitis (5 of 9). None developed grade >=4 acute or subacute toxicity. The only grade >=2 late toxicity was late skin toxicity in 1 patient. On UVA, toxicity was not significantly associated with the dose of the first course of radiation or reirradiation, the interval to reirradiation, or the reirradiation site. Of the 41 disease sites treated with PLDR reirradiation, 32 had pre- and post-PLDR scans to evaluate for local control. The local progression rate was 16.5% at 6 months and 23.8% at 12 months and was not associated with the dose of reirradiation, the reirradiation site, or concurrent systemic therapy on UVA. Of the 36 symptomatic disease sites, 25 sites (69%) achieved a symptomatic response after PLDR, including 6 (17%) with complete symptomatic relief. CONCLUSION: Reirradiation with PLDR is effective and well tolerated. The risk of late toxicity and the durability of local control were limited by the relatively short follow-up duration in the present cohort. PMID- 29485074 TI - Comparison of Stereotactic Body Radiation Therapy and Radiofrequency Ablation in the Treatment of Intrahepatic Metastases. AB - PURPOSE: Stereotactic body radiation therapy (SBRT) and radiofrequency ablation (RFA) are widely used therapies for the treatment of intrahepatic metastases; however, direct comparisons are lacking. We sought to compare outcomes for these 2 modalities. METHODS AND MATERIALS: From 2000 to 2015, 161 patients with 282 pathologically diagnosed unresectable liver metastases were treated with RFA (n = 112) or SBRT (n = 170) at a single institution. The primary outcome was freedom from local progression (FFLP). The effect of treatment and covariates on FFLP was modeled using a mixed-effects Cox model with application of inverse probability treatment weighting to adjust for potential imbalances in treatment modality. RESULTS: The median follow-up period was 24.6 months. Patients receiving SBRT had larger tumors than those treated with RFA (median, 2.7 cm vs 1.8 cm; P < .01). On univariate analysis, tumor size was associated with worse FFLP for RFA (hazard ratio [HR]; 1.57; 95% confidence interval [CI], 1.15-2.14; P < .01) but not for SBRT (HR, 1.38; 95% CI, 0.76-2.51; P = .3). The 2-year FFLP rate was 88.2% compared with 73.9%, favoring SBRT (P = .06). For tumors >=2 cm in diameter, SBRT was associated with improved FFLP (HR, 0.28; 95% CI, 0.09-0.93; P < .01). On multivariate analysis, treatment with SBRT (HR, 0.21; 95% CI, 0.07-0.62; P = .005) and smaller tumor size (HR, 0.65; 95% CI, 0.47-0.91; P = .01) were associated with improved FFLP. The 2-year overall survival rate was 51.1%, with no difference between groups (P = .8). Grade >=3 treatment-related toxicity was rare, with no difference between SBRT (n = 4) and RFA (n = 3). CONCLUSIONS: Treatment with SBRT or RFA is well tolerated and provides excellent and similar local control for intrahepatic metastases <2 cm in size. For tumors >=2 cm in size, treatment with SBRT is associated with improved FFLP and may be the preferable treatment. PMID- 29485076 TI - Risk Factors for Malignant Transformation of Low-Grade Glioma. AB - PURPOSE: The incidence, risk factors, and outcomes of low-grade glioma patients who undergo malignant transformation (MT) in the era of temozolomide are not well known. This study evaluates these factors in a large group of World Health Organization grade 2 glioma patients treated at a tertiary-care institution. METHODS AND MATERIALS: Patient, tumor, and treatment factors were analyzed using an institutional review board-approved low-grade glioma database. Characteristics were compared using chi2 and Wilcoxon signed rank tests. Time to event was summarized using proportional hazards models. Univariate and multivariate survival analyses were performed. RESULTS: Of a total of 599 patients, 124 underwent MT; 76 (61.3%) had biopsy-proven MT. The MT incidence was 21%, and the median time to MT was 56.4 months. The 5- and 10-year progression-free survival rates were 30.6% +/- 4.2% and 4.8% +/- 1.9%, respectively, for MT patients and 60% +/- 2.4% and 38% +/- 2.7%, respectively, for non-MT patients. The 5- and 10 year overall survival rates were 75% +/- 4.0% and 46% +/- 5.0%, respectively, for MT patients and 87% +/- 1.7% and 78% +/- 2.3%, respectively, for non-MT patients. On multivariate analysis, older age (P = .001), male sex (P = .004), multiple tumor locations (P = .004), chemotherapy alone (P = .012), and extent of resection (P = .045) remained significant predictors of MT. CONCLUSIONS: MT affects survival. Risk factors include older age, male sex, multiple tumor locations, use of chemotherapy alone, and presence of residual disease. Our finding that initial interventions could affect the rate of MT is provocative, but these data should be validated using data from prospective trials. In addition to improving survival, future therapeutic efforts should focus on preventing MT. PMID- 29485077 TI - Outcomes of Patients With Primary Sacral Chordoma Treated With Definitive Proton Beam Therapy. AB - PURPOSE: To evaluate the efficacy and safety of definitive proton beam therapy (PBT) for primary sacral chordoma. METHODS AND MATERIALS: We conducted a retrospective analysis of the clinical outcomes of eligible patients with primary sacral chordoma who had undergone definitive PBT with 70.4 Gy (relative biological effectiveness) in 32 fractions at our institution from September 2009 to October 2015. Local progression-free survival, distant metastasis-free survival, disease-free survival, cause-specific survival, and overall survival were evaluated. To explore the factors that influenced local progression, the following parameters were analyzed: sex, the presence of a spacer (Gore-Tex sheets), gross tumor volume, and extent of cranial tumor extension. Adverse events were evaluated using the Common Terminology Criteria for Adverse Events, version 4.0. To assess the impact of PBT on pain relief, the change in pain grades was investigated between the initiation of PBT and the last follow-up visit. RESULTS: Thirty-three eligible patients were analyzed. The median follow up period was 37 months. The 3-year estimated local progression-free survival, distant metastasis-free survival, disease-free survival, cause-specific survival, and overall survival rates were 89.6%, 88.2%, 81.9%, 95.7%, and 92.7%, respectively. No significant association was between the patients' clinicopathologic characteristics and local progression-free survival. Four patients developed grade 3 adverse events, including acute dermatitis (n = 1), ileus (n = 1), and pain due to sacral insufficiency fractures (n = 2). The pain grades had improved, were unchanged, or had deteriorated in 15, 7, and 11 patients, respectively. CONCLUSIONS: Definitive PBT with 70.4 Gy (relative biological effectiveness) in 32 fractions is an effective treatment with acceptable toxicity for primary sacral chordoma and has the potential to reduce pain. PMID- 29485078 TI - Hippocampal Sparing During Craniospinal Irradiation: What Did We Learn About the Incidence of Perihippocampus Metastases? AB - PURPOSE: To identify the incidence of patients with perihippocampal metastases to assess the risk of brain relapse when sparing the hippocampal area. Medulloblastoma (MB) represents 20% of pediatric brain tumors. For high-risk MB patients, the 3- to 5-year event-free survival rate has recently improved from 50% to >76%. Many survivors, however, experience neurocognitive side effects. Several retrospective studies of patients receiving whole brain irradiation (WBI) have suggested a relationship between the radiation dose to the hippocampus and neurocognitive decline. The hippocampal avoidance-WBI (HA-WBI) approach could partially reduce neurocognitive impairment in children treated for high-risk MB. METHODS AND MATERIALS: From 2008 to 2011, 51 patients with high-risk MB were treated according to the French trial primitive neuroectodermal tumor HR+5. Hippocampal contouring was manually generated on 3-dimensional magnetic resonance images according to the Radiation Therapy Oncology Group 0933 atlas. The distribution of metastases was assessed relative to the hippocampus: 0 to 5 mm for the first perihippocampal area and 5 to 15 mm for the rest of the perihippocampal area. RESULTS: The median patient age was 8.79 years (33% female). After a follow-up of 2.4 years, 43 patients were alive; 28 had had brain metastasis at diagnosis and 2 at relapse, with 16% in the first perihippocampal area and 43% in the rest of the perihippocampal area. Of the 18 patients without brain metastases at diagnosis, including M1 patients, none developed secondary lesions within the first or the rest of the perihippocampal area, after receiving 36 Gy. No clinical or biological factor was significantly associated with the development of perihippocampal metastases. CONCLUSIONS: Our results suggest the HA-WBI strategy should be evaluated for the subgroup of high-risk MB patients without metastatic disease. PMID- 29485079 TI - Radiation Necrosis and White Matter Lesions in Pediatric Patients With Brain Tumors Treated With Pencil Beam Scanning Proton Therapy. AB - PURPOSE: To assess the rate of radiation necrosis (RN) and white matter lesions (WMLs) in pediatric patients with primary brain tumors treated with pencil beam scanning (PBS) proton therapy (PT) with or without concomitant chemotherapy at the PSI. METHODS AND MATERIALS: Between 1999 and 2015, 171 pediatric patients (age <18 years) were treated with PT. Median age at diagnosis was 3.3 years (range, 0.3-17.0 years), and the median delivered dose was 54 Gy (relative biological effectiveness) (range, 40.0-74.1 Gy). Radiation necrosis and WMLs were defined as a new area of abnormal signal intensity on T2-weighted images or increased signal intensity on T2-weighted images, and contrast enhancement on T1 occurring in the brain parenchyma included in the radiation treatment field, which did not demonstrate any abnormality before PT. Radiation necrosis and WMLs were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. The median follow-up period for the surviving patients was 49.8 months (range, 5.9-194.7 months). RESULTS: Twenty-nine patients (17%) developed RN at a median time of 5 months (range, 1-26 months), most of them (n = 17; 59%) being asymptomatic (grade 1). Grade 2, 4, and 5 toxicities occurred in 8, 2, and 2 patients, respectively. Eighteen patients (11%) developed WMLs at a median time of 14.5 months (range, 2-62 months), most of them (n = 13; 72%) being asymptomatic (grade 1). White matter lesion grade 2 and 3 toxicities occurred in 4 and 1 patient(s), respectively. The 5-year RN-free and WML-free survival was 83% and 87%, respectively. In univariate analysis, neoadjuvant (P = .025) or any (P = .03) chemotherapy, hydrocephalus before PT (P = .035), and ependymoma (P = .026) histology were significant predictors of RN. CONCLUSIONS: Children treated with PT demonstrated a low prevalence of symptomatic RN (7%) or WML (3%) compared with similar cohorts treated with either proton or photon radiation therapy. Chemotherapy, ependymomal tumors and hydrocephalus as an initial symptom were significant risk factors for RN. PMID- 29485080 TI - Radiation Therapy for Aggressive Fibromatosis: The Association Between Local Control and Age. AB - PURPOSE: Radiation therapy (RT) is often used in the treatment of unresectable or recurrent aggressive fibromatosis (also known as desmoid tumor) typically with excellent local control. Prior reports have suggested that local control in pediatric patients with aggressive fibromatosis is poor. We aimed to report a long-term single-institution experience with the radiotherapeutic treatment of these tumors with a focus on age-dependent outcomes. METHODS AND MATERIALS: A total of 101 patients treated with RT for aggressive fibromatosis between 1975 and 2015 at a single institution were identified. A variety of demographic and treatment-related variables were abstracted from patients' medical records. Kaplan-Meier analyses were performed to investigate the relationship between these variables and local control. RESULTS: Overall survival was excellent (98% and 95% at 5 and 10 years, respectively); local control was likewise excellent (82% and 78% at 5 and 10 years, respectively). Patients aged <20 years at diagnosis had significantly worse 5-year local control than those aged >40 years at diagnosis (72% vs 97%; hazard ratio, 9.0; P = .009). Patients treated with once-daily fractionation had significantly improved 5-year local control compared with those treated with twice-daily fractionation (90% vs 73%; hazard ratio, 0.3; P = .008). Neither the presence of gross versus microscopic residual disease, initial versus recurrent presentation, number of prior surgical procedures, nor tumor size had any effect on 5-year local control. In a total of 36.6% of patients, Common Terminology Criteria for Adverse Events grade 3 or 4 toxicity developed following treatment; the frequency of toxicities was reduced in patients treated during or after 1995 (24.5%) relative to those treated prior to 1995 (51.9%, P = .02). CONCLUSIONS: RT for aggressive fibromatosis offers excellent local control and should remain the standard of care for patients with unresectable or recurrent disease. Younger patients have diminished local control relative to older patients, suggesting possible biological differences contributing to radioresistance in the pediatric and young adult population. PMID- 29485081 TI - A time for celebration. PMID- 29485082 TI - Unavailability of old antibiotics threatens effective treatment for common bacterial infections. PMID- 29485083 TI - Corrections. PMID- 29485084 TI - Beyond one virus: vaccination against hepatitis B after hepatitis C treatment. PMID- 29485085 TI - Potential plague exportation from Madagascar via international air travel. PMID- 29485086 TI - Xpert Ultra's place in the diagnosis of tuberculous meningitis. PMID- 29485087 TI - Xpert Ultra's place in the diagnosis of tuberculous meningitis - Authors' reply. PMID- 29485088 TI - Emergence of recalcitrant dermatophytosis in India. PMID- 29485089 TI - Syndromic management of STIs and the threat of untreatable Mycoplasma genitalium. PMID- 29485090 TI - Use of prevalence data to study sepsis incidence and mortality in intensive care units. PMID- 29485091 TI - Use of prevalence data to study sepsis incidence and mortality in intensive care units - Authors' reply. PMID- 29485092 TI - Increasing malaria in Venezuela threatens regional progress. PMID- 29485093 TI - Typhoid conjugate vaccine gets WHO prequalification. PMID- 29485096 TI - Advanced Kaposi's sarcoma in a 2-year-old child. PMID- 29485097 TI - Increased Expression of Interleukin-18 mRNA is Associated with Carotid Artery Stenosis AB - Background: Carotid artery stenosis is the atherosclerotic narrowing of the proximal internal carotid artery and one of the primary causes of stroke. Elevated expression of the pleiotropic proinflammatory cytokine interleukin-18 has been demonstrated in human atherosclerotic plaques. Aims: To investigate whether the mRNA expression levels of interleukin-18 and interleukin-18-binding protein and interleukin-18 -137 G/C (rs187238) variants are associated with carotid artery stenosis development. Study Design: Case-control study. Methods: The mRNA expression levels of interleukin-18 and interleukin-18-binding protein and interleukin-18 rs187238 variants were evaluated by quantitative real-time polymerase chain reaction and real-time polymerase chain reaction, respectively, in the peripheral blood mononuclear cells of 70 patients with carotid artery stenosis (36 symptomatic, 34 asymptomatic) and 75 healthy controls. Results: Interleukin-18 mRNA expression was significantly increased in carotid artery stenosis patients compared to that in healthy controls (p=0.01). However, no significant difference was observed between interleukin-18-binding protein mRNA expression levels in patients with carotid artery stenosis and those in controls (p=0.101). Internal carotid artery stenosis severity was significantly higher in symptomatic patients than that in asymptomatic patients (p<0.001). A significant relationship was identified between interleukin-18 expression and internal carotid artery stenosis severity in patients with carotid artery stenosis (p=0.051). Interleukin-18 rs187238 polymorphism genotype frequencies did not significantly differ between patients with carotid artery stenosis and controls (p=0.246). A significant difference was identified between interleukin-18-binding protein gene expression and symptomatic and asymptomatic patients (p=0.026), but there was no difference in interleukin-18 expression between the symptomatic and asymptomatic subgroups (p=0.397). Conclusion: Interleukin-18 mRNA expression may affect carotid artery stenosis etiopathogenesis and internal carotid artery stenosis severity and also may play a mechanistic role in the pathogenesis of carotid artery stenosis, influencing the appearance of symptoms. PMID- 29485099 TI - Practice Patterns in Diagnosis and Treatment of Lower Urinary Tract Symptoms due to Benign Prostatic Hyperplasia among General Practitioners: Lessons Learnt from a Greek Survey PMID- 29485098 TI - Evaluation of the Cytotoxic and Autophagic Effects of Atorvastatin on MCF-7 Breast Cancer Cells AB - Background: Recently, cytotoxic effects of statins on breast cancer cells have been reported. However, the mechanism of anti-proliferative effects is currently unknown. Autophagy is non-apoptotic programmed cell death, which is characterized by degradation of cytoplasmic components and as having a role in cancer pathogenesis. Aims: To investigate the anti-proliferative effects of atorvastatin on MCF-7 human breast adenocarcinoma cells with respect to both autophagy and apoptosis. Study Design: Cell culture study. Methods: Cell viability was analyzed using WST-1 cell proliferation assay. Apoptosis was determined by the TUNEL method, whereas autophagy was assessed by Beclin-1 and LC3B immunofluorescence staining. Ultrastructural analysis of cells was performed by electron microscopy. Results: Atorvastatin reduced MCF-7 cell proliferation in a dose- and time dependent manner inducing TUNEL-, Beclin-1-, and LC3B-positive cells. Moreover, ultrastructural analysis showed apoptotic, autophagic, and necrotic morphological changes in treatment groups. A statistically significant increase in the apoptotic index was detected with higher concentrations of atorvastatin at 24 h and 48 h (p<0.05). Conclusion: The anti-proliferative effects of atorvastatin on breast cancer cells is mediated by the induction of both apoptosis and autophagy which shows statins as a potential treatment option for breast cancer. PMID- 29485100 TI - Magnetotransport study of topological superconductor Cu0.10Bi2Se3 single crystal. AB - We report a magnetotransport study of vortex-pinning in Cu0.10Bi2Se3 single crystal. The sample is demonstrated to be in clean limit and absent of Pauli spin limiting effect. Interestingly, the resistivity versus magnetic field shows an anomalously pronounced increase when approaching the superconducting-normal state boundary for both [Formula: see text] and [Formula: see text] configurations. We have investigated the flux-flowing behavior under various magnetic fields and temperatures, enabling us to establish its anisotropic vortex phase diagram. Our results suggest the Cu0.10Bi2Se3 can be served as one unique material for exploring exotic surface vortex states in topological superconductors. PMID- 29485101 TI - Strain tuning of electronic properties of various dimension elemental tellurium with broken screw symmetry. AB - We present a systematical study of atomic structures and electronic properties of various dimension tellurium (Te) with broken intrinsical screw symmetry by applying reasonable strain. It is demonstrated that (i) bulk trigonal Te has degenerate Weyl nodes around the H point near the Fermi energy, and this degeneracy will be broken by introducing the selenium (Se) atom through creating the inner unsymmetrical strain, instead of external shear strain. (ii) 2D structures of tetragonal Te (t-Te) and 1T-MoS2-like Te (1T-Te) show direct and indirect band gap, respectively. Under the uniform biaxial compressive (BC) strain, monolayer of t-Te shows the direct-to-indirect band gap transition, while 1T-Te monolayer has a band gap transition firstly from indirect to direct and then from direct to indirect. Their effective masses of hole and electron can be effectively tuned by BC strain. (iii) One-dimensional (1D) structures of single helix, triangular Te and hexagonal Te nanowires display the obvious quantum confinement effect on the band structure and different sensitivity to the effect of uniaxial compressive strain. PMID- 29485102 TI - Influence of experimental parameters on iron oxide nanoparticle properties synthesized by thermal decomposition: size and nuclear magnetic resonance studies. AB - A study of the experimental conditions to synthesize monodisperse iron oxide nanocrystals prepared from the thermal decomposition of iron(III) acetylacetonate was carried out in the presence of surfactants and a reducing agent. The influence of temperature, synthesis time and surfactant amounts on nanoparticle properties is reported. This investigation combines relaxometric characterization and size properties. The relaxometric behavior of the nanomaterials depends on the selected experimental parameters. The synthesis of iron oxide nanoparticles with a high relaxivity and a high saturation magnetization can be obtained with a short reaction time at high temperature. Moreover, the influence of surfactant concentrations determines the optimal value in order to produce iron oxide nanoparticles with a narrow size distribution. The optimized synthesis is rapid, robust and reproductive, and produces nearly monodisperse magnetic nanocrystals. PMID- 29485103 TI - Evaluating the in vivo glial response to miniaturized parylene cortical probes coated with an ultra-fast degrading polymer to aid insertion. AB - OBJECTIVE: Despite the feasibility of short-term neural recordings using implantable microelectrodes, attaining reliable, chronic recordings remains a challenge. Most neural recording devices suffer from a long-term tissue response, including gliosis, at the device-tissue interface. It was hypothesized that smaller, more flexible intracortical probes would limit gliosis by providing a better mechanical match with surrounding tissue. APPROACH: This paper describes the in vivo evaluation of flexible parylene microprobes designed to improve the interface with the adjacent neural tissue to limit gliosis and thereby allow for improved recording longevity. The probes were coated with an ultrafast degrading tyrosine-derived polycarbonate (E5005(2K)) polymer that provides temporary mechanical support for device implantation, yet degrades within 2 h post implantation. A parametric study of probes of varying dimensions and polymer coating thicknesses were implanted in rat brains. The glial tissue response and neuronal loss were assessed from 72 h to 24 weeks post-implantation via immunohistochemistry. MAIN RESULTS: Experimental results suggest that both probe and polymer coating sizes affect the extent of gliosis. When an appropriate sized coating dimension (100 um * 100 um) and small probe (30 um * 5 um) was implanted, a minimal post-implantation glial response was observed. No discernible gliosis was detected when compared to tissue where a sham control consisting of a solid degradable polymer shuttle of the same dimensions was inserted. A larger polymer coating (200 um * 200 um) device induced a more severe glial response at later time points, suggesting that the initial insertion trauma can affect gliosis even when the polymer shuttle degrades rapidly. A larger degree of gliosis was also observed when comparing a larger sized probe (80 um * 5 um) to a smaller probe (30 um * 5 um) using the same polymer coating size (100 um * 100 um). There was no significant neuronal loss around the implantation sites for most device candidates except the group with largest polymer coating and probe sizes. SIGNIFICANCE: These results suggest that: (1) the degree of mechanical trauma at device implantation and mechanical mismatches at the probe-tissue interface affect long term gliosis; (2) smaller, more flexible probes may minimize the glial response to provide improved tissue biocompatibility when used for chronic neural signal recording; and (3) some degree of glial scarring did not significantly affect neuronal distribution around the probe. PMID- 29485104 TI - Effect of sulphur vacancy and interlayer interaction on the electronic structure and spin splitting of bilayer MoS2. AB - Molybdenum disulfide (MoS2) is one of the candidate materials for nanoelectronics and optoelectronics devices in the future. The electronic and magnetic properties of MoS2 can be regulated by interlayer interaction and the vacancy effect. Nevertheless, the combined effect of these two factors on MoS2 is not clearly understood. In this study, we have investigated the impact of a single S vacancy combined with interlayer interaction on the properties of bilayer MoS2. Our calculated results show that an S vacancy brings impurity states in the band structure of bilayer MoS2, and the energy level of the impurity states can be affected by the interlayer distance, which finally disappears in the bulk state when the layer distance is relatively small. Moreover, during the compression of bilayer MoS2, the bottom layer, where the S vacancy stays, gets an additional charge due to interlayer charge transfer, which first increases, and then decreases due to gradually forming the interlayer S-S covalent bond, as interlayer distance decreases. The change of the additional charge is consistent with the change of the total magnetic moment of the bottom layers, no magnetic moment has been found in the top layer. The distribution of magnetic moment mainly concentrates on the three Mo atoms around the S vacancy, for each of which the magnetic moment is very much related to the Mo-Mo length. Our conclusion is that the interlayer charge transfer and S vacancy co-determine the magnetic properties of this system, which may be a useful way to regulate the electronic and magnetic properties of MoS2 for potential applications. PMID- 29485105 TI - Nanomechanical resonators based on group IV element monolayers. AB - We perform molecular dynamics simulations to investigate the energy dissipation of the resonant oscillation for the group IV monolayers of puckered configuration, in which the oscillation is driven with different actuation velocities. We find that, in the moderate actuation velocity regime, the nonlinear coupling between the resonant oscillation mode and other high-frequency modes will lead to the non-resonant motion of the system. For the larger actuation velocity, the effective strain generated during the resonant oscillating causes a structural transition from the puckered configuration into the planar configuration, which is a characteristic energy dissipation mechanism for the resonant oscillation of these group IV puckered monolayers. Our findings shed light on mechanical applications of the group IV monolayers in the nanomechanical resonator field. PMID- 29485106 TI - Evaluation of crystallographic strain, rotation and defects in functional oxides by the moire effect in scanning transmission electron microscopy. AB - Moire patterns in scanning transmission electron microscopy (STEM) images of epitaxial perovskite oxides are used to assess strain and defect densities over fields of view extending over several hundred nanometers. The patterns arise from the geometric overlap of the rastered STEM electron beam and the samples' crystal periodicities and we explore the emergence and application of these moire fringes for rapid strain analysis. Using the epitaxial functional oxide perovskites BiFeO3 and Pr1-x Ca x MnO3, we discuss the impact of large degrees of strain on the quantification of STEM moire patterns, identify defects in the fringe patterns and quantify strain and lattice rotation. Such a wide-area analysis of crystallographic strain and defects is crucial for developing structure-function relations of functional oxides and we find the STEM moire technique to be an attractive means of structural assessment that can be readily applied to low dose studies of damage sensitive crystalline materials. PMID- 29485107 TI - Inducing and manipulating magnetization in 2D zinc-oxide by strain and external voltage. AB - Two-dimensional (2D) structures that exhibit intriguing magnetic phenomena such as perpendicular magnetic anisotropy and its switchable feature are of great interests in spintronics research. Herein, the density functional theory studies reveal the critical impacts of strain and external gating on vacancy-induced magnetism and its spin direction in a graphene-like single layer of zinc oxide (ZnO). In contrast to the pristine and defective ZnO with an O-vacancy, the presence of a Zn-vacancy induces significant magnetic moments to its first neighboring O and Zn atoms due to the charge deficit. We further predict that the direction of magnetization easy axis reverses from an in-plane to perpendicular orientation under a practically achievable biaxial compressive strain of only ~1 2% or applying an electric field by means of the charge density modulation. This magnetization reversal is mainly driven by the strain- and electric-field-induced changes in the spin-orbit coupled d states of the first-neighbor Zn atom to a Zn vacancy. These findings open interesting prospects for exploiting strain and electric field engineering to manipulate magnetism and magnetization orientation of 2D materials. PMID- 29485108 TI - Fabrication, characterization and in vitro evaluation of triboelectric nanogenerator based on 317 L stainless steel and polylactic acid. AB - A novel, cost-effective biomedical triboelectric nanogenerator (TENG) has been fabricated based on biocompatible medical 317 L stainless steel (317 L SS) and polylactic acid (PLLA) films as the friction layers, whose surface roughness was designed by simple and low-cost laser etching and hot-embossing template methods, respectively. With the increase of the TENG's tribo-interface roughness and the molecular weight of the PLLA, the power output of TENG was greatly increased owing to more charges being produced and the excellent mechanical properties PLLA possessed. When the 317 L SS plate surface roughness was 66.54% measured by the image J software and the PLLA film with a larger molecular weight at 500 000 was patterned with the 1000 mesh screen template, the maximal short current, open voltage and transferred charge of TENG reached up to 60 MUA, 150 V and ~125 nC, respectively. At the optimum condition, the maximum instantaneous power of the TENG was 5.5 mW at a load resistance of ~2.5 MOmega and the saturation voltage was 20 V when the load capacitance was 0.1 MUF. The evaluation of the TENG's biocompatibility in vitro was performed by using the simulated body fluid (SBF) solution and ultrasonic wave to mimic the body environment with various vibrations, respectively. After 6 h ultrasonic bath for the directly immersed TENG, the pH of the SBF solution just changed slightly from 7.4 to 7.61 with an acceptable degradation of the output power of TENG. The cellular toxicity test also demonstrates that the mouse L929 cells grow excellently with normal morphology even after 5 d. These results indicate that the TENG has a good stability in the body environment and the output performance can still drive many micro-medical devices. PMID- 29485109 TI - How do biological systems escape 'chaotic' state? PMID- 29485110 TI - Liberating primatology. PMID- 29485111 TI - Sisyphus desperately seeking publisher. AB - As a punishment for his trickery, King Sisyphus was made to endlessly roll a huge boulder up a steep hill. The maddening nature of the punishment was reserved for King Sisyphus due to his hubristic belief that his cleverness surpassed that of Zeus himself. Today's scientists also pay a heavy price for their hubris and narcissism. They try to trick the editors of a few 'top' journals by peppering their papers with glitter and 'bling-bling', making overblown promises, and giving minimal credit to their predecessors. The editors wield their Olympian authority by making today's scientists endlessly push their weighty boulders up steep hills. By bowing to this implacable ritual, we scientists confer undue power to a handful of popular but irresponsible journals. PMID- 29485112 TI - Low concentrations of ethanol during irradiation drastically reduce DNA damage caused by very high doses of ionizing radiation. AB - Presence of low concentrations (1-2%) of ethanol during irradiation exhibited significant protection against DNA damage caused by very high doses (2-12 kGy) of 60 Co-gamma-rays in vitro. Radiation-induced DNA damage was substantially reduced in different types of DNA molecules (chromosomal DNA from Anabaena 7120 or Deinococcus radiodurans or bacteriophage Lambda, and plasmid pBluescript DNA) when irradiated in the presence of ethanol, thus indicating the generic nature of ethanol protection. The radioprotection appeared to be a consequence of the well known ability of ethanol to scavenge hydroxyl radicals. Addition of ethanol during 6 kGy irradiation also reduced DNA damage in vivo and improved post irradiation growth recovery of Anabaena 7120 cultures. To our knowledge, this is the first instance of ability of very low ethanol concentrations to protect DNA from damage triggered by extremely high doses of 60 Co-gamma rays. PMID- 29485113 TI - ATR kinase regulates its attenuation via PPM1D phosphatase recruitment to chromatin during recovery from DNA replication stress signalling. AB - In eukaryotes, in response to replication stress, DNA damage response kinase, ATR is activated, whose signalling abrogation leads to cell lethality due to aberrant fork remodelling and excessive origin firing. Here we report that inhibition of ATR kinase activity specifically during replication stress recovery results in persistent ATR signalling, evidenced by the presence of ATR-dependent phosphorylation marks (gamma H2AX, pChk1 and pRad17) and delayed cell cycle re entry. Further, such disruption of ATR signalling attenuation leads to double strand breaks, fork collapse and thereby 'replication catastrophe'. PPM1D phosphatase, a nucleolar localized protein, relocates to chromatin during replication stress and reverts back to nucleolus following stress recovery, under the control of ATR kinase action. Inhibition of ATR kinase activity, specifically during post replication stress, triggers dislodging of the chromatin-bound PPM1D from nucleus to cytoplasm followed by its degradation, thereby leading to persistence of activated ATR marks in the nuclei. Chemical inhibition of PPM1D activity or SiRNA mediated depletion of the protein during post replication stress recovery 'phenocopies' ATR kinase inhibition by failing to attenuate ATR signalling. Collectively, our observations suggest a novel role of ATR kinase in mediating its own signal attenuation via PPM1D recruitment to chromatin as an essential mechanism for restarting the stalled forks, cell-cycle re-entry and cellular recovery from replication stress. PMID- 29485115 TI - Thalassiosira mala (Bacillariophyta), a potentially harmful, marine diatom from Chilka Lake and other coastal localities of Odisha, India: Nomenclature, frustule morphology and global biogeography. PMID- 29485114 TI - An individual-level selection model for the apparent altruism exhibited by cellular slime moulds. AB - In Dictyostelium discoideum, cells that become part of the stalk or basal disc display behaviour that can be interpreted as altruistic. Atzmony et al. (Curr Sci 72:142-145, 1997) had hypothesised that this behaviour could be the outcome of an adaptive strategy based on differing intrinsic quality as reflected by phenotypes that indicate differences in potential for survival and reproduction, followed by intercellular competition among amoebae of differing qualities. Low-quality amoebae would have a poor chance of succeeding in the competition to form spores; they could enhance their chances of survival by adopting a presumptive stalk strategy. Here we extend the hypothesis by making use of recent findings. Our approach is based on the view that an evolutionary explanation for the apparent altruism of stalk cells in D. discoideum must apply broadly to other cellular slime moulds (CSMs) that exhibit stalk cell death. Further, it must be capable of being modified to cover social behaviour in CSMs with an extracellular stalk, as well as in sorocarpic amoebae whose stalk cells are viable. With regard to D. discoideum, we suggest that (a) differentiation-inducing factor, thought of as a signal that inhibits amoebae from forming spores and induces them to differentiate into basal disc cells, is better viewed as a mediator of competition among post-aggregation amoebae and (b) the products of the 'recognition genes', tgrB and tgrC, allow an amoeba to assess its quality relative to that of its neighbours and move to a position within the aggregate that optimises its reproductive fitness. From this perspective, all cells behave in a manner that is 'selfish' rather than 'altruistic', albeit with different expectations of success. PMID- 29485116 TI - PAX6 can substitute for LHX2 and override NFIA-induced astrogliogenesis in developing hippocampus in vivo. AB - In the developing central nervous system, transcription factors play a crucial role in the regulation of cell fate. Previously we demonstrated that LHX2 is a critical regulator of the neuron-glia cell fate switch in the developing mouse hippocampus. Here, we test LHX2 target gene Pax6 for a role in this process. We report that Pax6 overexpression is able to suppress the enhanced astrogliogenesis arising due to loss of functional LHX2. Furthermore, we show that like Lhx2, Pax6 is also able to suppress induced astrogliogenesis caused by overexpression of progliogenic factor Nfia. This demonstrates that overexpression of Pax6 can substitute for Lhx2 in the regulation of the neuronal versus glial cell fate in the developing hippocampus, and therefore, supports a role for PAX6 as a mediator of LHX2 function in this process. PMID- 29485117 TI - Acute pharmacogenetic activation of medial prefrontal cortex excitatory neurons regulates anxiety-like behaviour. AB - The medial prefrontal cortex (mPFC) is implicated in anxiety-like behaviour. In rodent models, perturbations of mPFC neuronal activity through pharmacological manipulations, optogenetic activation of mPFC neurons or cell-type specific pharmacogenetic inhibition of somatostatin interneurons indicate conflicting effects on anxiety-like behaviour. In the present study we examined the effects of pharmacogenetic activation of Ca 2+/calmodulin-dependent protein kinase alpha (CamKII alpha)-positive excitatory neurons on anxiety-like behaviour. We used clozapine-N-oxide (CNO) to pharmacogenetically activate virally delivered CamKII alpha-hM3Dq-DREADD in mPFC excitatory neurons. The effects of acute CNO or vehicle treatment on anxiety-like behaviour in the open field and elevated plus maze tests were examined in rats virally infected with either CamKII alpha-hM3Dq DREADD or CamKII alpha-GFP. In addition, the effects of acute CNO treatment on the expression of the neuronal activity marker c-Fos were examined in the mPFC as well as downstream target neuronal circuits using immunohistochemistry. Acute pharmacogenetic activation of mPFC excitatory neurons evoked a significant decrease in anxiety-like behaviour selectively on the elevated plus maze task, but not the open field test. Acute CNO treatment resulted in enhanced c-Fos immunopositive cell number in the infralimbic, prelimbic and cingulate subdivisions of the mPFC. This was also accompanied by enhanced c-Fos immunopositive cell number in multiple downstream circuits of the mPFC in CNO treated hM3Dq animals. Acute pharmacogenetic activation of mPFC excitatory neurons reduces anxietylike behaviour in a task-specific fashion accompanied by enhanced c-Fos expression in the mPFC and multiple target circuits implicated in the regulation of anxiety-like behaviour. PMID- 29485118 TI - Target-specific delivery of doxorubicin to human glioblastoma cell line via ssDNA aptamer. AB - Targeted drug delivery approaches have been implementing significant therapeutic gain for cancer treatment since last decades. Aptamers are one of the mostly used and highly selective targeting agents for cancer cells. Herein, we address a nano sized targeted drug delivery approach adorned with A-172 glioblastoma cell-line specific single stranded DNA (ssDNA) aptamer in which the chemotherapeutic agent Doxorubicin (DOX) had been conjugated. DNA aptamer, GMT-3, was previously selected for specific recognition of glioblastoma and represented many advantageous characteristics for drug targeting purposes. Flow cytometry analysis proved the binding efficiency of the specific aptamer to tumour cell lines. Celltype- specific toxicity of GMT-3:DOX complex was showed by XTT assay and terminated cytotoxic effects were screened for both target cell and a control breast cancer cell line. The result of this contribution demonstrated the potential utility of GMT-3 aptamer-mediated therapeutic drug transportation in the treatment of gliomas specifically. It was concluded that aptamer-mediated drug delivery can be applied successfully for clinical use. PMID- 29485119 TI - Root transcripts associated with arsenic accumulation in hyperaccumulator Pteris vittata. AB - Hyperaccumulation of arsenic (As) by brake fern Pteris vittata has been described as an important genetic trait that provides an option for development of a sustainable phytoremediation process for As mitigation. Accumulation of very high concentration of arsenic in above-ground tissues may be the result of arsenic vacuole compartmentalization, but the mechanism(s) of arsenic uptake and transport by underground tissues are largely unknown. In this study, we made an attempt towards understanding the molecular mechanism of As hyperaccumulation in this plant. A time-dependent As accumulation study indicates an exponential accumulation of As from 7 to 30 days of arsenic exposure in fronds, and day 3-7 in roots. Root transcriptome analysis identified 554,973 transcripts. Further, subsets of 824 transcripts were differentially expressed between treated and control samples. Many of the genes of critical As-stress response, transcription factors and metal transporters, biosynthesis of chelating compounds involved in uptake and accumulation mechanisms were identified. The genes that were highly expressed such as cysteine-rich RLK, and ABC transporter G family member 26 needs further studies along with arsenite transmembrane transporter. The analysis of generated transcriptome dataset has provided valuable information and platform for further functional studies. PMID- 29485120 TI - Glucohexaose-induced protein phosphatase 2C regulates cell redox status of cucumber seedling. AB - Protein Phosphatase 2C (PP2C) is an important phosphatase-like protein in eukaryotic organisms that can negatively regulate protein kinase cascade abscisic acid (ABA) signal system through phosphorylation and carry out vital roles in various cell processes. The previous study indicated that the accumulation of reactive oxygen species (ROS) is a part of mechanism of glucohexaose-induced resistance in cucumber cotyledons, and CsPP2C80s might play a crucial role in processes related to ROS produce and signal transduction. To identify the mechanism of CsPP2C80s involved in glucohexaose and ABA signaling regulating cell redox status, the effects of glucohexaose and ROS inhibitor pretreatment on endogenous ABA content and ABA signaling genes expression levels of cucumber seedlings were analysed. These results suggest that cucumber CsPP2C80s are involved in ROS accumulation and ABA signal transduction pathway induced by glucohexaose, CsPP2C80s play a positive regulatory role in process of ABA combined with ABA receptors (PYLs) to activate SNF1-related protein kinases 2 (SnRK2s) and regulate NADPH oxidase to produce extracellular hydrogen peroxide (H2O2), providing unequivocal molecular evidence of PP2C-mediated ABA response mechanisms functioning in cell redox status induced by glucohexaose. PMID- 29485121 TI - Blocking dephosphorylation at Serine 120 residue in t-SNARE SNAP-23 leads to massive inhibition in exocytosis from mast cells. AB - Mast cells (MCs) respond to allergen challenge by release of pre-stored inflammatory mediators from their secretory granules, on cross-linking of Fc(epsilon) receptor I (Fc(epsilon)RI) receptors. The target-SNARE (t-SNARE) SNAP 23 has been shown to play an important role in MC exocytosis and undergoes transient phosphorylation at Serine 95 (S95) and Serine 120 (S120), concomitant with mediator release. During current study we explored the importance of transient nature of phosphorylation at S120 in MC exocytosis. A phosphomimetic SNAP-23-S120D mutant of rodent SNAP-23 was cloned into EGFP vector and its effect on the exocytosis and the mechanisms involved was studied in RBL-2H3 MC line. Secretion reporter assay with SNAP-23-S120D transfected MCs revealed a very significant inhibition of exocytosis, and reduced ruffling in response to Fc(epsilon)RI cross-linking. Further, the effect of this mutation on localization of SNAP-23 in MCs was studied. Immunofluorescence microscopy studies and membrane cytosol fractionation of green fluorescent protein-tagged SNAP- 23-S120D (GFP SNAP-23-S120D) transfected MCs showed that a large proportion of GFP-SNAP-23 S120D was residing in cytosol unlike wild-type SNAP-23, in resting and activated MCs and even the membrane associated portion was on internal lysosomal membranes than plasma membrane. These studies imply that dephosphorylation of S120 is important for SNAP-23 membrane association dynamics and subsequently MC degranulation. PMID- 29485122 TI - Tetrahymena dynamin-related protein 6 self-assembles independent of membrane association. AB - Self-assembly on target membranes is one of the important properties of all dynamin family proteins. Drp6, a dynaminrelated protein in Tetrahymena, controls nuclear remodelling and undergoes cycles of assembly/disassembly on the nuclear envelope. To elucidate the mechanism of Drp6 function, we have characterized its biochemical and biophysical properties using size exclusion chromatography, chemical cross-linking and electron microscopy. The results demonstrate that Drp6 readily forms high-molecular-weight self-assembled structures as determined by size exclusion chromatography and chemical cross-linking. Negative stain electron microscopy revealed that Drp6 assembles into rings and spirals at physiological ionic strength. We have also shown that the recombinant Drp6 expressed in bacteria is catalytically active and its GTPase activity is not enhanced by low salt. These results suggest that, in contrast to dynamins but similar to MxA, Drp6 self-assembles in the absence of membrane templates, and its GTPase activity is not affected by ionic strength of the buffer. We discuss the self-assembly structure of Drp6 and explain the basis for lack of membrane-stimulated GTPase activity. PMID- 29485123 TI - Triacylglycerol: nourishing molecule in endurance of Mycobacterium tuberculosis. AB - The ability of Mycobacterium tuberculosis (M. tuberculosis) to accumulate lipid rich molecules as an energy source obtained from host cell debris remains interesting. Additionally, the potential of M. tuberculosis to survive under different stress conditions leading to its dormant state in pathogenesis remains elusive. The exact mechanism by which these lipid bodies generated in M. tuberculosis infection and utilized by bacilli inside infected macrophage for its survival is still not understood. In this, during bacillary infection, many metabolic pathways are involved that influence the survival of M. tuberculosis for their own support. However, the exact energy source derived from infecting host cells remain elusive. Therefore, this study highlights several alternative energy sources in the form of triacylglycerol (TAG) and fatty acids, i.e. oleic acids accumulation, which are essential in dormancy-like state under M. tuberculosis infection. The prominent stage in tuberculosis (TB) infection is re establishment of M. tuberculosis under stress conditions and deployment of a confined strategy to utilize these biomolecules for its persistence survival. So, growing in our understanding of these pathways will help us in accelerating therapies, which could reduce TB prevalence world widely. PMID- 29485125 TI - Plant reference genes for development and stress response studies. AB - Many reference genes are used by different laboratories for gene expression analyses to indicate the relative amount of input RNA/DNA in the experiment. These reference genes are supposed to show least variation among the treatments and with the control sets in a given experiment. However, expression of reference genes varies significantly from one set of experiment to the other. Thus, selection of reference genes depends on the experimental conditions. Sometimes the average expression of two or three reference genes is taken as standard. This review consolidated the details of about 120 genes attempted for normalization during comparative expression analysis in 16 different plants. Plant species included in this review are Arabidopsis thaliana, cotton (Gossypium hirsutum), tobacco (Nicotiana benthamiana and N. tabacum), soybean (Glycine max), rice (Oryza sativa), blueberry (Vaccinium corymbosum), tomato (Solanum lycopersicum), wheat (Triticum aestivum), potato (Solanum tuberosum), sugar cane (Saccharum sp.), carrot (Daucus carota), coffee (Coffea arabica), cucumber (Cucumis sativus), kiwi (Actinidia deliciosa) and grape (Vitis vinifera). The list includes model and cultivated crop plants from both monocot and dicot classes. We have categorized plant-wise the reference genes that have been used for expression analyses in any or all of the four different conditions such as biotic stress, abiotic stress, developmental stages and various organs and tissues, reported till date. This review serves as a guide during the reference gene hunt for gene expression analysis studies. PMID- 29485124 TI - Structure function relations in PDZ-domain-containing proteins: Implications for protein networks in cellular signalling. AB - Protein scaffolds as essential backbones for organization of supramolecular signalling complexes are a recurrent theme in several model systems. Scaffold proteins preferentially employ linear peptide binding motifs for recruiting their interaction partners. PDZ domains are one of the more commonly encountered peptide binding domains in several proteins including those involved in scaffolding functions. This domain is known for its promiscuity both in terms of ligand selection, mode of interaction with its ligands as well as its association with other protein interaction domains. PDZ domains are subject to several means of regulations by virtue of their functional diversity. Additionally, the PDZ domains are refractive to the effect of mutations and maintain their three dimensional architecture under extreme mutational load. The biochemical and biophysical basis for this selectivity as well as promiscuity has been investigated and reviewed extensively. The present review focuses on the plasticity inherent in PDZ domains and its implications for modular organization as well as evolution of cellular signalling pathways in higher eukaryotes. PMID- 29485127 TI - Norepinephrine Inhibits Th17 Cells via beta2-Adrenergic Receptor (beta2-AR) Signaling in a Mouse Model of Rheumatoid Arthritis. AB - BACKGROUND Norepinephrine (NE), a neurotransmitter released from the sympathetic nerves, has been shown to be involved in rheumatoid arthritis (RA). However, its role in the sympathetic nervous system in RA is divergent. Herein, we demonstrate that the sympathetic neurotransmitter NE exerts an anti-inflammatory effect in collagen-induced arthritis (CIA), a mouse model of RA, by inhibiting Th17 cell differentiation and function via beta2-adrenergic receptor (beta2-AR) signaling. MATERIAL AND METHODS CIA was prepared by intradermal injection of collagen type II in the tail base of DBA1/J mice. On the 41st day post-immunization, the mice were used as CIA models. CD4+ T cells from the spleen were purified using magnetic cell sorting and activated with anti-CD3 anti-CD28 antibodies. Th17 cells were polarized from the CD4+ T cells using various antibodies and cytokines. RESULTS Co-expression of CD4 and beta2-AR was observed in spleens of both intact and CIA mice. The beta2-AR expression in the ankle and spleen was downregulated in CIA mice. CIA induced increases in production of interleukin (IL)-17 and IL-22, CD25-IL-17+ cell percentage, and ROR-gammat expression in CD4+ T cells. Importantly, NE reduced the CIA-induced CD4+ T cell shift towards Th17 phenotype, and the beta2-AR antagonist ICI118551 blocked the NE effect. Moreover, the beta2-AR agonist terbutaline (Terb) inhibited CIA-induced CD4+ T cell proliferation and shift towards Th17 phenotype, and the protein kinase A (PKA) inhibitor H-89 abolished the agonist effect. Terb also reduced CIA-induced Th17 enhancement, and H-89 impaired the Terb effect. CONCLUSIONS NE inhibits Th17 cell differentiation and function in CIA condition by activation of beta2-AR/PKA signaling. PMID- 29485129 TI - Prostate cancer: AR-Vs not predictive in mCRPC. PMID- 29485128 TI - Position paper: Rationale for the treatment of children with CCSK in the UMBRELLA SIOP-RTSG 2016 protocol. AB - The International Society of Paediatric Oncology-Renal Tumour Study Group (SIOP RTSG) has developed a new protocol for the diagnosis, treatment, and follow-up monitoring of childhood renal tumours - the UMBRELLA SIOP-RTSG 2016 protocol (the UMBRELLA protocol). This protocol has been designed to continue international collaboration in the treatment of childhood renal tumours and will be implemented in over 50 different countries. Clear cell sarcoma of the kidney, which is a rare paediatric renal tumour that most commonly occurs in children between 2 and 4 years of age, is specifically addressed in the UMBRELLA protocol. PMID- 29485126 TI - Investigating the genetic and epigenetic basis of big biological questions with the parthenogenetic marbled crayfish: A review and perspectives. AB - In the last 15 years, considerable attempts have been undertaken to develop the obligately parthenogenetic marbled crayfish Procambarus virginalis as a new model in biology. Its main advantage is the production of large numbers of offspring that are genetically identical to the mother, making this crustacean particularly suitable for research in epigenetics. Now, a draft genome, transcriptome and genome-wide methylome are available opening new windows for research. In this article, I summarize the biological advantages and genomic and epigenetic features of marbled crayfish and, based on first promising data, discuss what this new model could contribute to answering of ''big'' biological questions. Genome mining is expected to reveal new insights into the genetic specificities of decapod crustaceans, the genetic basis of arthropod reproduction, moulting and immunity, and more general topics such as the genetic underpinning of adaptation to fresh water, omnivory, biomineralization, sexual system change, behavioural variation, clonal genome evolution, and resistance to cancer. Epigenetic investigations with the marbled crayfish can help clarifying the role of epigenetic mechanisms in gene regulation, tissue specification, adult stem cell regulation, cell ageing, organ regeneration and disease susceptibility. Marbled crayfish is further suitable to elucidate the relationship between genetic and epigenetic variation, the transgenerational inheritance of epigenetic signatures and the contribution of epigenetic phenotype variation to the establishment of social hierarchies, environmental adaptation and speciation. These issues can be tackled by experiments with highly standardized laboratory lineages, comparison of differently adapted wild populations and the generation of genetically and epigenetically edited strains. PMID- 29485130 TI - The rs626283 Variant in the MBOAT7 Gene is Associated with Insulin Resistance and Fatty Liver in Caucasian Obese Youth. AB - OBJECTIVES: Non alcoholic fatty liver disease (NAFLD) is a leading cause of liver damage in childhood, its occurrence is influenced by genetic and environmental factors. Recently, the rs626283 polymorphism in the MBOAT7 gene has been found to be associated with alcoholic liver disease and NAFLD in adults. METHODS: In a multiethnic cohort of obese children and adolescents we genotyped the rs626283 polymorphism in the MBOAT7 gene, evaluated insulin sensitivity by an oral glucose tolerance test, and measured the intra-hepatic fat content (HFF%) by magnetic resonance imaging. RESULTS: In Caucasian youth, the minor allele (C) was associated with HFF% in (P=0.003), fasting insulin (P=0.03), area under the curve of glucose (P=0.03), and lower degree of whole-body insulin sensitivity (P=0.01) independent of age, gender, and body mass index z-score. A partial correlation showed that the association between the rs626283 variant and insulin resistance was driven by the presence of hepatic steatosis (P=0.009). However, there was no association between the rs626283 and hepatic steatosis among Hispanic and African American children and youth. The association between the rs626283 in the MBOAT7 gene among Caucasians was independent of the PNPLA3 rs738409, GCKR 1260326, and TM6SF2 rs58542926 (P=0.01). The four polymorphisms combined explained~19% of the HFF% in Caucasian obese children and adolescents. CONCLUSIONS: The rs626283 variant in the MBOAT7 gene is associated with NAFLD and may affect glucose metabolism by modulating intra-hepatic fat content in Caucasian obese children and adolescents. PMID- 29485133 TI - Health policy: Towards greater equity in the global oncology workforce. PMID- 29485131 TI - ACG Clinical Guideline: Diagnosis and Management of Pancreatic Cysts. AB - Pancreatic cysts are very common with the majority incidentally identified. There are several types of pancreatic cysts; some types can contain cancer or have malignant potential, whereas others are benign. However, even the types of cysts with malignant potential rarely progress to cancer. At the present time, the only viable treatment for pancreatic cysts is surgical excision, which is associated with a high morbidity and occasional mortality. The small risk of malignant transformation, the high risks of surgical treatment, and the lack of high quality prospective studies have led to contradictory recommendations for their immediate management and for their surveillance. This guideline will provide a practical approach to pancreatic cyst management and recommendations for cyst surveillance for the general gastroenterologist. PMID- 29485134 TI - Breast cancer: Metronomic chemotherapy for elderly and/or frail patients. PMID- 29485135 TI - CNS cancer: Oncolytic adenovirus effective in patients with glioblastoma. PMID- 29485136 TI - Corrigendum: From Resistance to Sensitivity: Insights and Implications of Biphasic Modulation of Autophagy by Sunitinib. AB - [This corrects the article on p. 718 in vol. 8, PMID: 29066973.]. PMID- 29485137 TI - Erratum. AB - [This corrects the article on p. 133 in vol. 52, PMID: 29062246.]. PMID- 29485132 TI - Epigenome-based cancer risk prediction: rationale, opportunities and challenges. AB - The incidence of cancer is continuing to rise and risk-tailored early diagnostic and/or primary prevention strategies are urgently required. The ideal risk predictive test should: integrate the effects of both genetic and nongenetic factors and aim to capture these effects using an approach that is both biologically stable and technically reproducible; derive a score from easily accessible biological samples that acts as a surrogate for the organ in question; and enable the effectiveness of risk-reducing measures to be monitored. Substantial evidence has accumulated suggesting that the epigenome and, in particular, DNA methylation-based tests meet all of these requirements. However, the development and implementation of DNA methylation-based risk-prediction tests poses considerable challenges. In particular, the cell type specificity of DNA methylation and the extensive cellular heterogeneity of the easily accessible surrogate cells that might contain information relevant to less accessible tissues necessitates the use of novel methods in order to account for these confounding issues. Furthermore, the engagement of the scientific community with health-care professionals, policymakers and the public is required in order to identify and address the organizational, ethical, legal, social and economic challenges associated with the routine use of epigenetic testing. PMID- 29485138 TI - Counselling and management for anticipated extremely preterm birth. AB - Counselling couples facing the birth of an extremely preterm infant is a complex and delicate task, entailing both challenges and opportunities. This revised position statement proposes using a prognosis-based approach that takes the best estimate of gestational age into account, along with additional factors, including estimated fetal weight, receipt of antenatal corticosteroids, singleton versus multiple pregnancy, fetal status and anomalies on ultrasound and place of birth. This statement updates data on survival in Canada, long-term neurodevelopmental disability at school age and quality of life, with focus on strategies to communicate effectively with parents. It also proposes a framework for determining the prognosis-based management option(s) to present to parents when initiating the decision-making process. This statement replaces the 2012 position statement. PMID- 29485139 TI - Erratum. AB - [This corrects the article on p. 165 in vol. 52, PMID: 29062251.]. PMID- 29485140 TI - Erratum. AB - [This corrects the article on p. 401 in vol. 43, PMID: 29201499.]. PMID- 29485141 TI - Corrigendum: Changes in Blood Factors and Ultrasound Findings in Mild Cognitive Impairment and Dementia. AB - [This corrects the article on p. 427 in vol. 9, PMID: 29311909.]. PMID- 29485142 TI - Cleanser use could decrease numbers of Demodex Folliculorum in mild to moderate acne patients. AB - Objective: This study was to verify if the skin cleanser could help decrease the infection ratio of Demodex Folliculorum in acne patients. Methods: 132 participants with mild to moderate vulgaris acne participated in this monocentric, prospective, double-blind study. Dermatologists grading and Standardized Skin Surface Biopsy were performed in baseline and after using cleanser only 7 d later. Results: There was no significant difference between the 2 times for each type of acne, but the number of Demodex Folliculorum was significantly decreased compared with baseline. There was no relationship between the number of Demodex Folliculorum and the total number of acne lesions. Limitations: Short follow-up time in 7 d. Conclusion: Using the cleanser could decrease the average number of Demodex Folliculorum in only 7 d in mild to moderate acne patients. There is no relationship between Demodex and acne lesions number. PMID- 29485143 TI - Broadening health policy education in medical school. PMID- 29485144 TI - Correction to: Abstracts from the NIHR INVOLVE Conference 2017. AB - [This corrects the article DOI: 10.1186/s40900-017-0075-x.]. PMID- 29485146 TI - Erratum. AB - [This corrects the article on p. 414 in vol. 43, PMID: 29201501.]. PMID- 29485145 TI - Distortion-free measurement of electric field strength with a MEMS sensor. AB - Small-scale and distortion-free measurement of electric fields is crucial for applications such as surveying atmospheric electrostatic fields, lightning research, and safeguarding areas close to high-voltage power lines. A variety of measurement systems exist, the most common of which are field mills, which work by picking up the differential voltage of the measurement electrodes while periodically shielding them with a grounded electrode. However, all current approaches are either bulky, suffer from a strong temperature dependency, or severely distort the electric field requiring a well-defined surrounding and complex calibration procedures. Here we show that microelectromechanical system (MEMS) devices can be used to measure electric field strength without significant field distortion. The purely passive MEMS devices exploit the effect of electrostatic induction, which is used to generate internal forces that are converted into an optically tracked mechanical displacement of a spring-suspended seismic mass. The devices exhibit resolutions on the order of [Formula: see text] with a measurement range of up to tens of kilovolt per metre in the quasi-static regime (? 300 Hz).We also show that it should be possible to achieve resolutions of around [Formula: see text] by fine-tuning of the sensor embodiment. These MEMS devices are compact and could easily be mass produced for wide application. PMID- 29485147 TI - Light-triggered release of drug conjugates for an efficient combination of chemotherapy and photodynamic therapy. AB - Herein, we present a series of light-triggered porphyrin-based polymeric drug conjugates PSDTD-m for combined chemo-photodynamic therapy of cancer. The controlled release of a drug through a ROS-cleavable linker combined with photodynamic therapy showed enhanced anticancer efficacy, proving the effectiveness of this light triggered smart nanocarrier platform for enhancing the therapy efficacy. PMID- 29485148 TI - Enhancing anticancer cytotoxicity through bimodal drug delivery from ultrasmall Zr MOF nanoparticles. AB - Dual delivery of dichloroacetate and 5-fluorouracil from Zr MOFs into cancer cells is found to enhance in vitro cytotoxicity. Tuning particle size and, more significantly, surface chemistry, further improves cytotoxicity by promoting caveolae-mediated endocytosis and cytosolic cargo delivery. PMID- 29485149 TI - Reverse electrodialysis in bilayer nanochannels: salinity gradient-driven power generation. AB - To evaluate the possibility of nano-fluidic reverse electrodialysis (RED) for salinity gradient energy harvesting, we consider the behavior of ion transportation in a bilayer cylindrical nanochannel consisting of different sized nanopores connecting two large reservoirs at different NaCl concentrations. Numerical simulations to illustrate the electrokinetic behavior at asymmetric sub pore length and surface charge density are conducted, the impacts of which on transference number, osmotic current, diffusive voltage, maximum power and maximum power efficiency are systematically investigated. The results reveal that the transference number in Config. I (where high NaCl concentration is applied at the larger nanopore) is always larger than that in the opposite configuration (Config. II). At low concentration ratios, the osmotic current and maximum power have maximum values, while the maximum power efficiency decreases consistently. For Config. II, the ion transportation is impacted by the surface charge density at both sub-nanopores, while for Config. I, it is determined by the surface charge density at the downstream small nanopore. When large surface charge density is applied at the downstream small nanopore in contact with a very low concentration reservoir, there exists an interesting phenomenon: the larger surface charge density at the large nanopore induces a slight performance drop due to the impact of upstream EDL overlap. PMID- 29485150 TI - Calculation of linear and nonlinear optical properties of azobenzene derivatives with Kohn-Sham and coupled-cluster methods. AB - Linear polarizabilities (alpha) and second hyperpolarizabilities (gamma) of unsubstituted azobenzenes and 'push-pull' azobenzene derivatives are investigated using Kohn-Sham theory (KST) and coupled-cluster (CC) approaches. Various standard exchange-correlation functionals as well as a non-empirically 'tuned' long-range corrected (LC) functional with range-separated exchange are used in the KST calculations. When compared to correlated ab initio calculations and measurements, the tuned functional gives accurate low-energy excitation energies, especially for charge transfer (CT) transitions, and performs well for alpha. Basis set and solvent effects are also studied. In contrast to expectations, but in agreement with a prior study of pi-conjugated systems that do not have low energy CT excitations, the improvements of the CT excitation energies for the push-pull pi-chromophores due to tuning do not go along with clear improvements of gamma toward the CC reference data, likely due to the importance of the dynamic electron correlation for this property. PMID- 29485153 TI - Tuning protein assembly pathways through superfast amyloid-like aggregation. AB - Amyloid formation of proteins is not only relevant for neurodegenerative diseases, but has recently emerged as a groundbreaking approach in materials science and biotechnology. However, amyloid aggregation of proteins in vitro generally requires a long incubation time under extremely harsh conditions, and the understanding of the structural motif to determine amyloid assembly is extremely limited. Herein we reveal that the integration of three important building blocks in typical globular proteins is crucial for superfast protein amyloid-like assembly including the segment required for high fibrillation propensity, abundant alpha-helix structures and intramolecular S-S bonds to lock the alpha-helix. With the reduction of the S-S bond by tris(2 carboxyethyl)phosphine (TCEP), the alpha-helix was rapidly unlocked from the protein chain, and the resultant unfolded monomer underwent a fast transition to beta-sheet-rich amyloid oligomers and protofibrils in minutes, which further assembled into a macroscopic nanofilm at the air/water interface and microparticles in bulk solution, respectively. PMID- 29485151 TI - Following the electrons: peculiarities in the catalytic cycles of radical SAM enzymes. AB - Radical SAM enzymes use S-adenosyl-l-methionine as an oxidant to initiate radical mediated transformations that would otherwise not be possible with Lewis acid/base chemistry alone. These reactions are either redox neutral or oxidative leading to certain expectations regarding the role of SAM as either a reusable cofactor or the ultimate electron acceptor during each turnover. However, these expectations are frequently not realized resulting in fundamental questions regarding the redox handling and movement of electrons associated with these biological catalysts. Herein we provide a focused perspective on several of these questions and associated hypotheses with an emphasis on recently discovered radical SAM enzymes. PMID- 29485154 TI - Embryonic exposure to an aqueous coal dust extract results in gene expression alterations associated with the development and function of connective tissue and the hematological system, immunological and inflammatory disease, and cancer in zebrafish. AB - Coal mining is one of the economic activities with the greatest impact on environmental quality. At all stages contaminants are released as particulates such as coal dust. The first aim of this study was to obtain an aqueous coal dust extract and characterize its composition in terms of trace elements by ICP-MS. In addition, the developmental toxicity of the aqueous coal extract was evaluated using zebrafish (Danio rerio) after exposure to different concentrations (0-1000 ppm; MUg mL-1) to establish acute toxicity, morphology and transcriptome changes. Trace elements within the aqueous coal dust extract present at the highest concentrations (>10 ppb) included Sr, Zn, Ba, As, Cu and Se. In addition, Cd and Pb were found in lower concentrations. No significant difference in mortality was observed (p > 0.05), but a delay in hatching was found at 0.1 and 1000 ppm (p < 0.05). No significant differences in morphological characteristics were observed in any of the treatment groups (p > 0.05). Transcriptomic results of zebrafish larvae revealed alterations in 77, 61 and 1376 genes in the 1, 10, and 100 ppm groups, respectively. Gene ontology analysis identified gene alterations associated with the development and function of connective tissue and the hematological system, as well as pathways associated with apoptosis, the cell cycle, transcription, and oxidative stress including the MAPK signaling pathway. In addition, altered genes were associated with cancer; connective tissue, muscular, and skeletal disorders; and immunological and inflammatory diseases. Overall, this is the first study to characterize gene expression alterations in response to developmental exposure to aqueous coal dust residue from coal mining with transcriptome results signifying functions and systems to target in future studies. PMID- 29485156 TI - Surface induced twist in nematic and chiral nematic liquid crystals: stick-slip like and constrained motion. AB - Surface driven pattern formation is an intriguing phenomenon in the liquid crystal field. Owing to its ability to transmit torque, one can generate different patterns by propagating distortions on the optical wavelength scale in the sample from the surface. Here, we theoretically investigate (from the elasticity point of view) twist deformations induced by a rotating easy axis at one surface, by considering the anchoring energy and surface viscosity of nematic and chiral nematic samples. The model is solved analytically in the limit of strong anchoring and numerically for a low anchoring strength situation. Such rotation could be induced, in principle, by light-controlling the orientation of an azobenzene monolayer coated at one of the glass substrates or by an in-plane rotating field. We discuss the role of the surface parameters and the different distortions, and calculate light transmission using the Jones method. Three different regimes are identified: free twist, stick-slip twist, and constrained twist. The results obtained here may be relevant for liquid crystal active waveplates and for determining surface viscosity and the azimuthal anchoring energy. PMID- 29485158 TI - Pillaring of layered zeolite precursors with ferrierite topology leading to unusual molecular sieves on the micro/mesoporous border. AB - Layered zeolite materials with FER layer topology can produce various condensed and expanded structures including zeolite frameworks, FER and CDO, their interlayer expanded forms (IEZ), and organic-intercalated and pillared derivatives. This work concerns pillaring of the surfactant-swollen derivative with a gallery height of ca. 2.5 nm between layers by treatment with tetraethylorthosilicate (TEOS) at room and elevated temperatures. The materials obtained at 100 degrees C and higher showed unusual properties including 2 nm pores on the micro/mesoporous border and disordered layer packing indicated by the absence of distinct low angle interlayer peaks at d-spacing >3 nm (~3 degrees 2theta Cu Kalpha radiation) in the X-ray diffraction pattern (XRD). TEOS treatment at room temperature produced a pillared molecular sieve with the expected mesoporous characteristics, namely a pore size of around 3 nm and a high intensity low angle (001) peak at 2.3 degrees 2theta, and a d-spacing of 3.8 nm, in the XRD. The characterization aiming to elucidate the nature of the obtained unusual products included gas adsorption isotherms, aberration corrected (Cs corrected) Scanning Transmission Electron Microscopy (STEM) studies and 29Si solid state NMR. BET surface area values decreased with the temperature of TEOS treatment from approximately 1200 m2 g-1 to ~900 and 600 m2 g-1, at room temperature, 100 degrees C, and 120 degrees C, respectively. The 29Si solid state NMR revealed the presence of both Q3 ((SiO)3SiOX, X = H or minus charge) and Q4 ((SiO)4Si) centers giving separated signals up to the pillaring step. After pillaring at 100 degrees C and calcination, the nominal intensity ratios Q4 : Q3 were 2.17 and 2.61 but the signals were merged into one broad peak indicating the structural heterogeneity of Si-O coordination. The microscopy showed the presence of FER layers in the samples but the overall structure and composition were not well-defined. The observed unusual disorganization and possible partial degradation of layers during pillaring may result from the combination of high temperature, alkalinity (surfactant hydroxide) and siliceous composition of the layers. The obtained pillared products are of interest for the preparation of larger pore catalysts and sorbents or controlled drug delivery. PMID- 29485160 TI - Polyphenols in Kuding tea help prevent HCl/ethanol-induced gastric injury in mice. AB - We conducted the present study to determine the gastric injury preventive effects of polyphenols in Kuding tea (KTPs) in Kunming (KM) mice through the inhibition of gastric-acid secretion and the protection of the gastric mucosa. Mice treated with a high concentration of Kuding tea polyphenols (HKTP) had lower serum levels of interleukin-6 (IL-6), IL-12, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), motilin (MOT), substance P (SP), and endothelin-1 (ET-1), and higher serum levels of somatostatin (SS) and vasoactive intestinal peptide (VIP) than did the mice in the control group. Serum and gastric tissue levels of nitrous oxide (NO), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and GSH were higher in the HKTP-treated mice than in the control mice, but malondialdehyde (MDA) levels were lower in the HKTP-treated mice than in the control mice. The expression of occludin, epidermal growth factor (EGF), EGF receptor (EGFR), vascular endothelial growth factor (VEGF), nuclear factor of kappa-light polypeptide gene enhancer in B-cells inhibitor-alpha (IkappaBalpha), Cu/Zn-SOD (cuprozinc-superoxide dismutase), Mn-SOD (manganese-superoxide dismutase), GSH-Px (glutathione peroxidase), neuronal nitric oxide synthase (nNOS), endothelial NOS (eNOS), messenger RNA (mRNA) and protein in gastric tissue was stronger in the HKTP-treated mice than in the control mice, while the expression of p38 mitogen-activated protein kinase (P38MAPK, or p38), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB), inducible NOS (iNOS), and cyclooxygenase-2 (COX-2) was weaker in the HKTP group than in the control group. And HKTP also could reduce the TNF-alpha, IL-1beta (interleukin-1 beta), and IL-6 mRNA expression in gastric injury mice. A high performance liquid chromatography (HPLC) assay showed that Kuding tea polyphenols (KTPs) contained chlorogenic acid, cryptochlorogenic acid, and isochlorogenic acids A, B, and C. These constituents contributed to the preventive effects of KTPs on gastric injury. According to these results, KTPs are a kind of active component that have a strong preventive effect on gastric injury. PMID- 29485161 TI - Can off-centre mesogen dipoles extend the biaxial nematic range? AB - We have investigated the possibility of extending the stability range of the biaxial nematic phase by adding an off-centre dipole of various strengths and orientations to elongated biaxial Gay-Berne (GB) mesogens yielding a relatively narrow biaxial nematic (Nbx) phase, and a smectic (Sbx) phase when dipole-less. The effect of dipoles is not easy to predict, and our previous investigations have shown the limited benefits of having a central dipole. Here we show, employing molecular dynamics (MD) simulations, that a not too strong off-centre dipole positioned along the longest axis of the nematogen can extend the temperature range of stability of the biaxial nematic phase, also shifting it towards lower temperatures. PMID- 29485162 TI - Chemistry through cocrystals: pressure-induced polymerization of C2H2.C6H6 to an extended crystalline hydrocarbon. AB - The 1 : 1 acetylene-benzene cocrystal, C2H2.C6H6, was synthesized under pressure in a diamond anvil cell (DAC) and its evolution under pressure was studied with single-crystal X-ray diffraction and Raman spectroscopy. C2H2.C6H6 is stable up to 30 GPa, nearly 10* the observed polymerization pressure for molecular acetylene to polyacetylene. Upon mild heating at 30 GPa, the cocrystal was observed to undergo an irreversible transition to a mixture of amorphous hydrocarbon and a crystalline phase with similar diffraction to i-carbon, a nanodiamond polymorph currently lacking a definitive structure. Characterization of this i-carbon-like phase suggests that it remains hydrogenated and may help explain previous observations of nanodiamond polymorphs. Potential reaction pathways in C2H2.C6H6 are discussed and compared with other theoretical extended hydrocarbons that may be obtained through crystal engineering. The cocrystallization of benzene with other more inert gases may provide a novel pathway to selectively control the rich chemistry of these materials. PMID- 29485168 TI - In-silico design of nanoparticles for transdermal drug delivery application. AB - Nanoparticles are used in the medical field for various applications like cell imaging, drug delivery, gene and si-RNA delivery, to name a few. Designing nanoparticles for a given application, purely based on the trial and error experimentation, requires a lot of time and effort. In this study we show that computer simulations could help in designing nanoparticles for drug delivery thus reducing the time and cost associated with their design, development and deployment. The permeation of nanoparticles, having various surface chemistries and patterns, through the skin lipid bilayer was studied using constrained and unconstrained molecular dynamics simulations. Interestingly, the permeation mechanism of nanoparticles having the same surface chemistry but different patterns was found to be completely different. Nanoparticles (NPs) were screened based on the free energy of permeation through the skin lipid bilayer. The behavior of the screened NPs was further validated with unconstrained simulations using the skin lipid bilayer. Nanoparticles thus screened through both of the techniques were further used for the co-delivery of a model protein into the skin lipid bilayer. It was observed that the nanoparticles having a 2 : 1 homogeneous ratio of hydrophobic to hydrophilic regions were the most promising in transdermal delivery of proteins. The obtained results are in line with the results of recent permeation experiments on cell and plasma membrane. Our study could help in in-silico design of nanoparticles for delivery of actives through skin. These in-silico experiments thus could help speed up the development process by guiding formulation chemists. PMID- 29485173 TI - Quantifying orientational regeneration of injured neurons by natural product concentration gradients in a 3D microfluidic device. AB - Regeneration of injured neurons in complicated three-dimensional (3D) microenvironments is a key approach for treating neurodegenerative diseases. Microfluidics provides a versatile tool to recapitulate cellular microenvironments in vitro, but it still remains a big challenge to construct a microfluidic platform incorporating extracellular matrix (ECM) structures and highly controlled 3D gradients of soluble factors to study the regeneration of injured neurons. In this work, we developed a microfluidic device which can provide multiple adjustable gradients in a 3D ECM to investigate the regeneration of injured central nervous system (CNS) neurons in response to natural small molecules. With interconnecting but independently controlled central channels, asymmetrically designed side channels and a series of microgrooves connecting the central channels, spatially and temporally controlled 3D biochemical gradients can be generated inside collagen hydrogel in the central channels. This allows quantitative analysis of guided axon growth and the orientational regeneration of injured dopaminergic neurons by 3D chemical gradients of three natural molecules. This study demonstrates a promising microfluidic platform for the generation of highly controlled 3D biochemical gradients in an ECM to quantitatively study neuronal responses, thereby potentially facilitating drug screening and optimization of treatment protocols for neurodegenerative diseases. PMID- 29485174 TI - CO oxidative coupling to dimethyl oxalate over Pd-Me (Me = Cu, Al) catalysts: a combined DFT and kinetic study. AB - CO oxidative coupling to dimethyl oxalate (DMO) on Pd(111), Pd-Cu(111) and Pd Al(111) surfaces was systematically investigated by means of density functional theory (DFT) together with periodic slab models and micro-kinetic modeling. The binding energy results show that Cu and Al can be fine substrates to stably support Pd. The favorable pathway for DMO synthesis on these catalysts starts from the formation of two COOCH3 intermediates, followed by the coupling to each other, and the catalytic activity follows the trend of Pd-Al(111) > Pd(111) > Pd Cu(111). Additionally, the formation of DMO is far favorable than that of dimethyl carbonate (DMC) on these catalysts. The results were further demonstrated by micro-kinetic modeling. Therefore, Pd-Al bimetallic catalysts can be applied in practice to effectively enhance the catalytic performance and greatly reduce the cost. This study can help with fine-tuning and designing of high-efficient and low-cost Pd-based bimetallic catalysts. PMID- 29485180 TI - Progenitor cells in auricular cartilage demonstrate cartilage-forming capacity in 3D hydrogel culture. AB - Paramount for the generation of auricular structures of clinically-relevant size is the acquisition of a large number of cells maintaining an elastic cartilage phenotype, which is the key in producing a tissue capable of withstanding forces subjected to the auricle. Current regenerative medicine strategies utilize chondrocytes from various locations or mesenchymal stromal cells (MSCs). However, the quality of neo-tissues resulting from these cell types is inadequate due to inefficient chondrogenic differentiation and endochondral ossification, respectively. Recently, a subpopulation of stem/progenitor cells has been identified within the auricular cartilage tissue, with similarities to MSCs in terms of proliferative capacity and cell surface biomarkers, but their potential for tissue engineering has not yet been explored. This study compared the in vitro cartilage-forming ability of equine auricular cartilage progenitor cells (AuCPCs), bone marrow-derived MSCs and auricular chondrocytes in gelatin methacryloyl (gelMA)-based hydrogels over a period of 56 d, by assessing their ability to undergo chondrogenic differentiation. Neocartilage formation was assessed through gene expression profiling, compression testing, biochemical composition and histology. Similar to MSCs and chondrocytes, AuCPCs displayed a marked ability to generate cartilaginous matrix, although, under the applied culture conditions, MSCs outperformed both cartilage-derived cell types in terms of matrix production and mechanical properties. AuCPCs demonstrated upregulated mRNA expression of elastin, low expression of collagen type X and similar levels of proteoglycan production and mechanical properties as compared to chondrocytes. These results underscored the AuCPCs' tissue-specific differentiation potential, making them an interesting cell source for the next generation of elastic cartilage tissue-engineered constructs. PMID- 29485179 TI - Combining enamel matrix proteins with mechanical stimuli potentiates human periodontal ligament fibroblasts proliferation and periodontium remodeling. AB - BACKGROUND: Collagen I (Col-I) and matrix metalloproteinase-1 (MMP-1) have been implicated in the regeneration and remodeling of the periodontium. Studies have shown that enamel matrix proteins (EMPs) and mechanical stimuli can promote the synthesis and degradation, respectively, of Col-I and MMP-1. However, the effects of the combination of EMPs and mechanical stimuli on human periodontal ligament are not known. OBJECTIVE: Our aim was to test the combined effects of EMPs and mechanical stimuli on the proliferation of human periodontal ligament fibroblasts (HPDLFs) and Col-I and MMP-1 mRNA expression. METHODS: Primary HPDLFs were isolated using an enzyme digestion method. To select the optimum EMP concentration and the optimum magnitude and loading time of mechanical stimuli, HPDLFs were stimulated with gradient concentration of EMPs (0 ug/mL, 25 ug/mL, 50 ug/mL, 100 ug/mL and 200 ug/mL) and mechanical stimuli (0 kPa, 25 kPa, 50 kPa, 100 kPa, and 200 kPa for 0 h, 3 h, 6 h, 12 h, and 24 h), respectively. The cell proliferative response was tested by the MTT assay. The impact of EMPs combined with mechanical stimuli on Col-I and MMP-1 mRNA expression were measured by reverse transcription polymerase chain reaction. RESULTS: 100 ug/mL of EMPs and a 50 kPa mechanical stimulus were chosen as the optimum parameters due to the higher proliferation rates than other doses. The combination of 100 ug/mL of EMPs and a 50 kPa mechanical stimulus significantly stimulated HPDLFs proliferation and increased Col-I and MMP-1 expression levels compared with incubation with two factors alone. CONCLUSIONS: We concluded that the combination of EMPs and mechanical stimulus have synergistic effects on cell growth, cell number, collagen turnover, and periodontium remodeling. PMID- 29485181 TI - Two cases of seborrheic keratosis of the external ear canal: involvement of PIK3CA and FGFR3 genes. AB - BACKGROUND: Seborrheic keratosis (SK) of the outer ear canal is rarely described in literature. Etiological risk factors involved in SK such as exposure to human papillomavirus (HPV) and ultraviolet (UV) light are established but must still be confirmed. In recent years, new insights into the pathogenesis of SKs occurred in the area of molecular pathogenesis. Fibroblast growth factor receptor 3 (FGFR3) gene and p110alpha subunit of phosphoinositide 3-kinase (PIK3CA) oncogene mutations are known to be involved. METHODS: We describe two cases of SK of the outer ear canal. We conducted a review of literature and examined the role of etiological risk factors involved in our cases. The lesions were primarily treated with surgical resection. Postoperatively, in both patients, the lesions recurred after a considerably long disease-free interval. We tested both FGFR3 and PIK3CA genes for mutations, in the primary and recurrent lesions. RESULTS: We did not find any mutations in both genes in all samples. CONCLUSION: Additional research is needed to further establish possible etiological risk factors and to clarify the involvement of PIK3CA and FGFR3 genes in the pathogenesis of seborrheic keratosis of the outer ear canal. These cases underscore the need for meticulous diagnosis, treatment, and sufficient long-term follow-up. PMID- 29485182 TI - A new RelB-dependent CD117+ CD172a+ murine DC subset preferentially induces Th2 differentiation and supports airway hyperresponses in vivo. AB - The NF-kappaB transcription factor subunit RelB is important for the full activation of conventional dendritic cells (cDCs) during T-cell-dependent immune responses. Although the number of splenic DCs is greatly reduced in RelBnull mice, the cause and consequences of this deficiency are currently unknown. To circumvent the impact of the pleiotropic defects in RelBnull mice we used a reporter model for RelB expression (RelBKatushka mice) and conditionally deleted RelB in DCs (RelBCD11c-Cre mice). Thereby, we can show here that RelB is essential for the differentiation of a CD117+ CD172a+ cDC subpopulation that highly expresses RelB. Surprisingly, these DCs depend on p50 for their development and are negatively regulated by a constitutive p52 activation in absence of p100. The absence of p52/p100 had no influence on the homeostasis of CD117+ CD172a+ cDCs. RelB-dependent CD117+ CD172a+ DCs strongly induce the production of the type 2 cytokines IL-4 and IL-13, as well as GM-CSF from naive Th cells. Consequently, mice lacking RelB in cDCs show an attenuated bronchial hyperresponsiveness with reduced eosinophil infiltration. Taken together, we have identified a new splenic RelB-dependent CD117+ CD172a+ cDC population that preferentially induces Th2 responses. PMID- 29485183 TI - Effect of nano-scaled rabbit bone powder on physicochemical properties of rabbit meat batter. AB - BACKGROUND: To explore a new method of deep processing and to improve the value of rabbit bone, we prepared a nano-scaled rabbit bone powder by dry ball milling and compared the effect of different particle sizes of rabbit bone powder [fine scaled (236.01 +/- 5.99 MUm), superfine-scaled (65.92 +/- 1.71 MUm), nano-scaled (502.52 +/- 11.72 nm)] on the nutritional characteristics, pH, color, water holding capacity, textural and rheological attributes of rabbit meat batter. RESULTS: The rabbit bone powder significantly affected nutritional characteristics of meat batters; in particular, the contents of calcium were increased, regardless of particle size. Additionally, the rabbit meat batter, which contained 20 g kg-1 nano-scaled rabbit bone, had the lowest centrifugal and cooking losses among the treatments. CONCLUSION: Based on the textural and rheological attributes of the rabbit meat batters, the addition of 20 g kg-1 nano scaled rabbit bone was the best treatment. This represents an important finding with respect to the deep processing of rabbit bone in the rabbit meat industry. (c) 2018 Society of Chemical Industry. PMID- 29485184 TI - Necrobiotic xanthogranuloma associated with chronic lymphocytic leukemia. PMID- 29485187 TI - Imiquimod anal tampons treatment of anal intraepithelial neoplasia. PMID- 29485185 TI - Hypoxia and acidosis: immune suppressors and therapeutic targets. AB - Due to imbalances between vascularity and cellular growth patterns, the tumour microenvironment harbours multiple metabolic stressors including hypoxia and acidosis, which have significant influences on remodelling both tumour and peritumoral tissues. These stressors are also immunosuppressive and can contribute to escape from immune surveillance. Understanding these effects and characterizing the pathways involved can identify new targets for therapy and may redefine our understanding of traditional anti-tumour therapies. In this review, the effects of hypoxia and acidosis on tumour immunity will be summarized, and how modulating these parameters and their sequelae can be a useful tool for future therapeutic interventions is discussed. PMID- 29485186 TI - Concurrent renal amyloidosis and thymoma resulting in a fatal ventricular thrombus in a dog. AB - Thymoma-associated nephropathies have been reported in people but not in dogs. In this report, we describe a dog with thymoma and concurrent renal amyloidosis. A 7 year-old castrated male Weimaraner was presented for progressive anorexia, lethargy, and tachypnea. The dog was diagnosed with azotemia, marked proteinuria, and a thymoma that was surgically removed. Postoperatively, the dog developed a large left ventricular thrombus and was euthanized. Necropsy confirmed the presence of a left ventricular thrombus and histopathology revealed renal amyloidosis. We speculate that the renal amyloidosis occurred secondary to the thymoma, with amyloidosis in turn leading to nephrotic syndrome, hypercoagulability, and ventricular thrombosis. This case illustrates the potential for thymoma-associated nephropathies to occur in dogs and that dogs suspected to have thymoma should have a urinalysis and urine protein creatinine ratio performed as part of the pre-surgical database. PMID- 29485188 TI - Quantitative proteomics reveals decreased expression of major urinary proteins in the liver of apoE/eNOS-DKO mice. AB - Endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) plays an important role, not only in endothelium-dependent vasodilation but also in lipid and glucose homeostasis in the liver and exerts beneficial effects on mitochondrial biogenesis and respiration. Thus, the aim of our study was to use iTRAQ-based quantitative proteomics to investigate the changes in protein expression in the mitochondrial and cytosolic fractions isolated from the liver of the double (apolipoprotein E (apoE) and eNOS) knockout (apoE/eNOS-DKO) mice as compared to apoE KO mice (apoE-/- ) - an animal model of atherosclerosis and hepatic steatosis. Collectively, the deficiency of eNOS resulted in increased expression of proteins related to gluconeogenesis, fatty acids and cholesterol biosynthesis as well as the decreased expression of proteins participated in triglyceride breakdown, cholesterol transport, protein transcription & translation and processing in endoplasmic reticulum (ER). Moreover, one of the most downregulated proteins were major urinary proteins (MUPs), which are abundantly expressed in the liver and were shown to be involved in the regulation of lipid and glucose metabolism. The exact functional consequences of the revealed alterations require further investigation. PMID- 29485190 TI - Atomic Force Microscopy for Molecular Structure Elucidation. AB - Using scanning probe microscopy techniques, at low temperatures and in ultrahigh vacuum, individual molecules adsorbed on surfaces can be probed with ultrahigh resolution to determine their structure and details of their conformation, configuration, charge states, aromaticity, and the contributions of resonance structures. Functionalizing the tip of an atomic force microscope with a CO molecule enabled atomic-resolution imaging of single molecules, and measurement of their adsorption geometry and bond-order relations. In addition, by using scanning tunneling microscopy and Kelvin probe force microscopy, the density of the molecular frontier orbitals and the electric charge distribution within molecules can be mapped. Combining these techniques yields a high-resolution tool for the identification and characterization of individual molecules. The single molecule sensitivity and the possibility of atom manipulation to induce chemical reactions with the tip of the microscope open up unique applications in chemistry, and differentiate scanning probe microscopy from conventional methods for molecular structure elucidation. Besides being an aid for challenging cases in natural product identification, atomic force microscopy has been shown to be a powerful tool for the investigation of on-surface reactions and the characterization of radicals and molecular mixtures. Herein we review the progress that high-resolution scanning probe microscopy with functionalized tips has made for molecular structure identification and characterization, and discuss the challenges it will face in the years to come. PMID- 29485189 TI - Dynamic diffusion tensor imaging of spinal cord contusion: A canine model. AB - This study aimed to explore the dynamic diffusion tensor imaging (DTI) of changes in spinal cord contusion using a canine model of injury involving rostral and caudal levels. In this study, a spinal cord contusion model was established in female dogs using a custom-made weight-drop lesion device. DTI was performed on dogs with injured spinal cords (n=7) using a Siemens 3.0T MRI scanner at pre contusion and at 3 h, 24 h, 6 weeks and 12 weeks post-injury. The tissue sections were stained for immunohistochemical analysis. Canine models of spinal cord contusion were created successfully using the weight-drop lesion device. The fractional anisotropy (FA) value of lesion epicenter decreased, while the apparent diffusion coefficient (ADC), mean diffusivity (MD), and radial diffusivity (RD) values increased, and the extent of the curve was apparent gradually. The site and time affected the DTI parameters significantly in the whole spinal cord, ADC (site, P < 0.001 and time, P = 0.077, respectively); FA (site, P < 0.001 and time, P = 0.002, respectively). Immunohistological analysis of GFAP and NF revealed the pathologic changes of reactive astrocytes and axons, as well as the cavity and glial scars occurring during chronic SCI. DTI is a sensitive and noninvasive imaging tool useful to assess edema, hemorrhage, cavity formation, structural damage and reconstruction of axon, and myelin in dogs. The DTI parameters after contusion vary. However, the curves of ADC, MD, and RD were nearly similar and the FA curve was distinct. All the DTI parameters were affected by distance and time. PMID- 29485191 TI - Pelvis morphology suggests that early Mesozoic birds were too heavy to contact incubate their eggs. AB - Numerous new fossils have driven an interest in reproduction of early birds, but direct evidence remains elusive. No Mesozoic avian eggs can be unambiguously assigned to a species, which hampers our understanding of the evolution of contact incubation, which is a defining feature of extant birds. Compared to living species, eggs of Mesozoic birds are relatively small, but whether the eggs of Mesozoic birds could actually have borne the weight of a breeding adult has not yet been investigated. We estimated maximal egg breadth for a range of Mesozoic avian taxa from the width of the pelvic canal defined by the pubic symphysis. Known elongation ratios of Mesozoic bird eggs allowed us to predict egg mass and hence the load mass an egg could endure before cracking. These values were compared to the predicted body masses of the adult birds based on skeletal remains. Based on 21 fossil species, we show that for nonornithothoracine birds body mass was 187% of the load mass of the eggs. For Enantiornithes, body mass was 127% greater than the egg load mass, but some early Cretaceous ornithuromorphs were 179% heavier than their eggs could support. Our indirect approach provides the best evidence yet that early birds could not have sat on their eggs without running the risk of causing damage. We suggest that contact incubation evolved comparatively late in birds. PMID- 29485192 TI - Need (more than) two to Tango: Multiple tools to adapt to changes in oxygen availability. AB - Oxygen is a fundamental element for the life of a large number of living organisms allowing an efficient energetic utilization of substrates. Organisms relying on oxygen evolved complex structures for oxygen delivery and biochemical machineries dealing with its safe utilization and the ability to overcome the potentially harmful consequences of changes in oxygen availability. On fact, cells composing complex Eukaryotic organisms are set to live within an optimum narrow range of oxygen, quite specific for each cell type. Minute modifications of oxygen availability, either positive or negative, induce the expression of specific genes, the major actors of this responses being the transcription factors HIF and Nrf2 that control the attempt to cope with low oxygen (hypoxia) or to either high oxygen or to an oxygen "overflow," respectively. This review describes the interaction between these two transcription factors and their interaction with the transcription factor NF-kappaB acting as a pivotal determinant of final cell response. (c) 2018 BioFactors, 44(3):207-218, 2018. PMID- 29485193 TI - Polymorphisms in the microglial marker molecule CX3CR1 affect the blood volume of the human brain. AB - AIM: CX3CR1, a G-protein-coupled receptor, is involved in various inflammatory processes. Two non-synonymous single nucleotide polymorphisms, V249I (rs3732379) and T280M (rs3732378), are located in the sixth and seventh transmembrane domains of the CX3CR1 protein, respectively. Previous studies have indicated significant associations between T280M and leukocyte functional characteristics, including adhesion, signaling, and chemotaxis, while the function of V249I is unclear. In the brain, microglia are the only proven and widely accepted CX3CR1-expressing cells. This study aimed to specify whether there were specific brain regions on which these two single nucleotide polymorphisms exert their biological impacts through their functional effects on microglia. METHODS: Associations between the single nucleotide polymorphisms and brain characteristics, including gray and white matter volumes, white matter integrity, resting arterial blood volume, and cerebral blood flow, were evaluated among 1300 healthy Japanese individuals. RESULTS: The major allele carriers (V249 and T280) were significantly associated with an increased total arterial blood volume of the whole brain, especially around the bilateral precuneus, left posterior cingulate cortex, and left posterior parietal cortex. There were no significant associations between the genotypes and other brain structural indicators. CONCLUSION: This finding suggests that the CX3CR1 variants may affect arterial structures in the brain, possibly via interactions between microglia and brain microvascular endothelial cells. PMID- 29485194 TI - Quinoa bitterness: causes and solutions for improving product acceptability. AB - Awareness of the several agronomic, environmental, and health benefits of quinoa has led to a constant increase in its production and consumption not only in South America, where it is a native crop, but also in Europe and the USA. However, producing wheat or gluten-free based products enriched with quinoa alters some quality characteristics, including sensory acceptance. Several anti nutritional factors such as saponins are concentrated in the grain pericarp. These bitter and astringent substances may interfere with the digestion and absorption of various nutrients. Developing processes to decrease or modify the bitterness of quinoa can enhance palatability, and thus consumption, of quinoa. In addition to the production of sweet varieties of quinoa, other processes have been proposed. Some of them (i.e. washing, pearling and the combination of the two) have a direct effect on saponins, either by solubilization and/or the mechanical removal of seed layers. Others, such as fermentation or germination, are able to mask the bitterness with aroma compounds and/or sugar formation. This review presents the major sources of the undesirable sensory attributes of quinoa, including bitterness, and various ways of counteracting the negative characteristics of quinoa. (c) 2018 Society of Chemical Industry. PMID- 29485196 TI - Evaluation of laser ablation microtomy for correlative microscopy of hard tissues. AB - Laser ablation machining or microtomy (LAM) is a relatively new approach to producing slide mounted sections of translucent materials. We evaluated the method with a variety of problems from the bone, joint and dental tissues fields where we require thin undecalcified and undistorted sections for correlative light microscopy (LM) and backscattered electron scanning electron microscopy (BSE SEM). All samples were embedded in poly-methylmethacrlate (PMMA) and flat block surfaces had been previously studied by BSE-SEM and confocal scanning light microscopy (CSLM). Most were also studied by X-yay microtomography (XMT). The block surface is stuck to a glass slide with cyanoacrylate adhesive. Setting the section thickness and levelling uses inbuilt optical coherence tomographic imaging. Tight focusing of near-infrared laser radiation in the sectioning plane gives extreme intensities causing photodisruption of material at the focal point. The laser beam is moved by a fast scanner to write a cutting line, which is simultaneously moved by an XY positioning unit to create a sectioning plane. The block is thereby released from the slide, leaving the section stuck to the slide. Light, wet polishing on the finest grade (4000 grit) silicon carbide polishing paper is used to remove a 1-2 MUm thick damaged layer at the surface of the section. Sections produced by laser cutting are fine in quality and superior to those produced by mechanical cutting and can be thinner than the 'voxel' in most laboratory X-ray microtomography systems. The present extensive pilot studies have shown that it works to produce samples which we can study by both light and electron microscopy. PMID- 29485195 TI - Characterization of genetic predisposition and autoantibody profile in atypical haemolytic-uraemic syndrome. AB - We previously reported that Indian paediatric patients with atypical haemolytic uraemic syndrome (aHUS) showed high frequencies of anti-complement factor H (FH) autoantibodies that are correlated with homozygous deletion of the genes for FH related proteins 1 and 3 (FHR1 and FHR3) (FHR1/3-/- ). We now report that Indian paediatric aHUS patients without anti-FH autoantibodies also showed modestly higher frequencies of the FHR1/3-/- genotype. Further, when we characterized epitope specificities and binding avidities of anti-FH autoantibodies in aHUS patients, most anti-FH autoantibodies were directed towards the FH cell-surface anchoring polyanionic binding site-containing C-terminal short conservative regions (SCRs) 17-20 with higher binding avidities than for native FH. FH SCR17 20-binding anti-FH autoantibodies also bound the other cell-surface anchoring polyanionic binding site-containing region FH SCR5-8, at lower binding avidities. Anti-FH autoantibody avidities correlated with antibody titres. These anti-FH autoantibody characteristics did not differ between aHUS patients with or without the FHR1/3-/- genotype. Our data suggest a complex matrix of interactions between FHR1-FHR3 deletion, immunomodulation and anti-FH autoantibodies in the aetiopathogenesis of aHUS. PMID- 29485197 TI - Testing the evidence integration triangle for implementation of interventions to manage behavioral and psychological symptoms associated with dementia: Protocol for a pragmatic trial. AB - Behavioral and psychological symptoms of dementia (BPSD) include aggression, agitation, resistiveness to care, depression, anxiety, apathy, and hallucinations. BPSD are common in nursing home residents and can be ameliorated using person-centered approaches. Despite regulatory requirements, less than 2% of nursing homes consistently implement person-centered behavioral approaches. In a National Institute of Nursing Research-funded research protocol, we are implementing a pragmatic cluster randomized clinical trial designed to enable staff in nursing homes to reduce BPSD using behavioral approaches while optimizing function, preventing adverse events, and improving quality of life of residents. The implementation is based on use of the Evidence Integration Triangle (EIT), a parsimonious, community-engaged participatory framework that is well suited to the complexity and variability in the nursing home environment. A total of 50 nursing home communities will be randomized to EIT-4-BPSD or education only. Primary Aim 1 is to determine if communities exposed to EIT-4 BPSD demonstrate evidence of implementation evaluated by the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) criteria. Primary Aim 2 is to evaluate the feasibility, utility, and cost of the EIT approach in EIT-4-BPSD communities. PMID- 29485199 TI - Nonlinear Optical Microscopy for Melanoma: Challenges, Tools and Opportunities. AB - The natural pigments known as melanins are thought to play a role in the etiology and progression of melanoma, but many of their roles are currently not well understood. While quantification of melanins have, up until now, have been performed in bulk tissue ex vivo, new imaging technologies have unlocked the means to visualize and quantify melanins at the sub-cellular scale. The nonlinear imaging methods known as pump-probe, coherent Raman, and sum-frequency absorption microscopies provide subcellular resolution imaging of melanins, enabling label free, longitudinal quantification of both eumelanin and pheomelanin in situ and in vivo. These nonlinear imaging toolkits have been well proven in both animal models and human samples, moving them tantalizingly close to clinical application. Future efforts integrating these tools into practical, mobile imaging systems will provide immense benefit both to clinical research and practice. PMID- 29485198 TI - Systematic investigation for extraction and separation of polyphenols in tea leaves by magnetic ionic liquids. AB - BACKGROUND: Magnetic separation has become a mature industrial technique in many fields and its application in the food and agricultural fields is expected for further extension. Furthermore, there has been little application of magnetic ionic liquids in the preparation of bioactive products. In the present study, 0.8 mol L-1 C3 MIMFeCl4 in its aqueous solution was found to be ideal for the extraction of active constituents from tea leaves. After extraction, polyphenols, caffeine and ionic liquid were also satisfactorily separated from the crude extract by various easy operations. RESULTS: The average extraction efficiency of tea polyphenols could reach up to 185.38 g kg-1 and the recovery percent of the magnetic ionic liquid was 99.8% through an external magnetic field. The extraction process was more consistent with a pseudo-second order kinetic model. Moreover, C3 MIMFeCl4 had no effect on the stability of tea polyphenols, which was very different from ordinary ferric salt. The presence of magnetic ionic liquid had a positive effect on the antioxidant activity of the product. CONCLUSION: The developed method had a good performance for selective extraction together with separation of tea polyphenols and caffeine, which is expected in the preparation of more similar active components from food and agricultural resources as a useful multifunctional solvent. (c) 2018 Society of Chemical Industry. PMID- 29485200 TI - Tomosyn guides SNARE complex formation in coordination with Munc18 and Munc13. AB - As a SNARE binding protein, tomosyn has been reported to negatively regulate synaptic exocytosis via arresting syntaxin-1 and SNAP-25 into a nonfusogenic product that precludes synaptobrevin-2 entry, raising the question how the assembly of the SNARE complex is achieved. Here, we have investigated new functions of tomosyn in SNARE complex formation and SNARE-mediated vesicle fusion. Assisted by NSF/alpha-SNAP, syntaxin-1 escapes tomosyn arrest and assembles into the Munc18-1/syntaxin-1 complex. Munc13-1 then catalyzes the transit of syntaxin-1 from the Munc18-1/syntaxin-1 complex to the SNARE complex in a manner specific to synaptobrevin-2 but resistant to tomosyn. Our data suggest that tomosyn ensures SNARE assembly in a way amenable to tight regulation by Munc18-1 and Munc13-1. PMID- 29485201 TI - Annual Ambient UVB at Wavelengths that Induce Vitamin D Synthesis is Associated with Reduced Esophageal and Gastric Cancer Risk: A Nested Case-Control Study. AB - Vitamin D has been shown to be beneficial at reducing the risk of cancer; however, studies examining esophageal and gastric cancer have been scarce and findings inconsistent. The UK Biobank cohort was used for this nested case control study (N = 3732). Primary, incident esophageal and gastric cancer cases diagnosed after recruitment were identified via linkage to National Cancer Registries. Tropospheric Emissions Monitoring Internet Service database was used to calculate ambient annual UVB dose (D-UVB). Conditional logistic regression was used to investigate the relationship between annual ambient D-UVB and risk of esophageal and gastric cancer, and odds ratios (ORs) are reported. In total, 373 esophageal and 249 gastric cancer cases and 3110 age- and gender-matched controls were included in the study. We found a strong inverse association between annual ambient D-UVB and odds of developing esophageal or gastric cancer: Compared to the lowest tertile, OR for the highest tertile was 0.64 (95%CI:0.51-0.79) in adjusted analysis. The association was strengthened when restricted to esophageal cancer (OR = 0.60; 95%CI:0.45-0.80) and esophageal adenocarcinoma cases (OR = 0.48; 95%CI: 0.34-0.68). Similar results were found in unadjusted and stratified analysis. In conclusion, ambient UVB radiation is inversely associated with the development of esophageal and gastric cancer, even in a high-latitude country. PMID- 29485202 TI - Systems analysis of dilated cardiomyopathy in the next generation sequencing era. AB - Dilated cardiomyopathy (DCM) is a form of severe failure of cardiac muscle caused by a long list of etiologies ranging from myocardial infarction, DNA mutations in cardiac genes, to toxics. Systems analysis integrating next-generation sequencing (NGS)-based omics approaches, such as the sequencing of DNA, RNA, and chromatin, provide valuable insights into DCM mechanisms. The outcome and interpretation of NGS methods can be affected by the localization of cardiac biopsy, level of tissue degradation, and variable ratios of different cell populations, especially in the presence of fibrosis. Heart tissue composition may even differ between sexes, or siblings carrying the same disease causing mutation. Therefore, before planning any experiments, it is important to fully appreciate the complexities of DCM, and the selection of samples suitable for given research question should be an interdisciplinary effort involving clinicians and biologists. The list of NGS omics datasets in DCM to date is short. More studies have to be performed to contribute to public data repositories and facilitate systems analysis. In addition, proper data integration is a difficult task requiring complex computational approaches. Despite these complications, there are multiple promising implications of systems analysis in DCM. By combining various types of datasets, for example, RNA-seq, ChIP-seq, or 4C, deep insights into cardiac biology, and possible biomarkers and treatment targets, can be gained. Systems analysis can also facilitate the annotation of noncoding mutations in cardiac specific DNA regulatory regions that play a substantial role in maintaining the tissue- and cell-specific transcriptional programs in the heart. This article is categorized under: Physiology > Mammalian Physiology in Health and Disease Laboratory Methods and Technologies > Genetic/Genomic Methods Laboratory Methods and Technologies > RNA Methods. PMID- 29485203 TI - Cover Image, Volume 233, Number 6, June 2018. AB - Cover: The cover image, by Ji Hu et al., is based on the Mini - Review Progress and prospects of circular RNAs in Hepatocellular carcinoma: Novel insights into their function DOI: 10.1002/jcp.26154. PMID- 29485204 TI - Coloured filters and visual stress. PMID- 29485205 TI - Author's reply. PMID- 29485206 TI - Preventing falls in older people with cataract - it is not just about surgery. PMID- 29485207 TI - Clinical outcomes of low vision rehabilitation delivered by a mobile clinic. AB - PURPOSE: This prospective cohort study examined clinical outcomes of low vision rehabilitation (LVR) delivered by a mobile clinic. METHODS: Participants were recruited from those scheduled for mobile clinic LVR and met the United States definition of legal blindness. Participants completed the Massof Activity Inventory (AI) before LVR, 3 months post-LVR, and 1 year post-LVR. Change scores and measures of clinical effect (i.e. Cohen's effect size and minimum clinically important difference, MCID) were calculated for each time point and compared. Additional participant characteristics (age, acuity, contrast sensitivity, cause of visual impairment, training recommendations, and prior LVR experience) were also explored with respect to outcome measures. RESULTS: Of the 66 participants enroled in this study, 47% had no prior LVR experience. Significant differences were noted between baseline and 3-month person measures, and between baseline and 1-year person measures. There was no significant difference between 3-month and 1 year person measures, nor was there a significant difference in change score between these two time points. At 1 year post-LVR, overall visual ability effect size was 0.74. A clinically meaningful outcome was achieved in 56% of participants at 3 months and 71% at 1 year for overall visual ability. There was no significant difference in the proportion of participants achieving MCID at 3 months vs 1 year. Of participants who completed the 1-year post-LVR AI, 59% reported a subjective worsening of vision during the study period. This subgroup also tended to have smaller 1-year change scores. CONCLUSIONS: Mobile clinic LVR is effective at expanding access to care and produces clinically meaningful outcomes comparable to those seen in other outpatient LVR delivery models. PMID- 29485208 TI - Clinical characteristics and visual outcomes of sport-related open globe injuries. PMID- 29485209 TI - Limited accuracy of transurethral and periurethral intrasphincteric injections of cellular suspension. AB - AIMS: The efficacy of cell therapy in patients with stress urinary incontinence (SUI) is lower than expected. The aim of this study was to determine the injection accuracy rate both with transurethral and periurethral route. METHODS: Autologous intraurethral cell transplantation was performed in female goats. The cells were injected either periurethrally (PERI group, two depots/animal, n = 8) or transurethrally (TRANS group, eight depots/animal, n = 11). Transurethral injections were performed under endoscopic guidance. The number and distribution of cell depots in urethras were analyzed in the three-step protocol: 1) screening of whole explants by in vivo imaging system; 2) systematic microscopic analysis of raw 10 MUm cross-sections; 3) immunohistochemistry. As control, four urethras collected 1 day after transurethral transplantation were used. Episodes of cell suspension leakages after needle withdrawal were noted. RESULTS: In all experimental animals depots were identified in the urethral wall 28 days after transplantation. The mean percentage of depots located in the urethral wall in relation to all performed injections amounted to 68.7% and 67.0% for PERI and TRANS groups, respectively. The mean proportions of depots which were identified in external urethral sphincter (EUS) amounted 18.8% and 17.1%, respectively. Suspension leakage was observed in 19% of transurethral injections. CONCLUSIONS: Although majority of cell depots were administrated accurately into the urethral wall, the precise delivery of cells into EUS is limited regardless of injection method. The insufficient accuracy of cell delivery into EUS and cell suspension leakage can contribute to the low efficacy of cell therapy in human patients with SUI. PMID- 29485211 TI - Surgical treatment of hidradenitis suppurativa: an analysis of postoperative outcome, cosmetic results and quality of life in 255 patients. AB - BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with increasing incidence. Severe disease stages are seen as a therapeutic challenge and pose the threat of significant restrictions on patients' life quality. OBJECTIVES: We evaluated postoperative outcome after wide local excision for HS as well as postoperative course, cosmetic results, disease recurrence and quality of life. METHODS: All patients receiving radical surgical treatment for HS (Hurley III) between 2006 and 2015 were identified and received a letter-based survey. They were asked about postoperative course, cosmetic results, recurrence and life quality. RESULTS: Two hundred and fifty-five patients (103 men, 152 women) answered the questionnaire. Ninety-five percentage of patients reported disease-specific restrictions on everyday life. Seventy-five percentage of patients did not experience any postoperative adverse events; however, postoperative pain with need for analgesics was reported in 38%. The majority of patients (80%) were very satisfied or satisfied after surgery, and 85% of patients would recommend surgery to other affected persons. LIMITATIONS: The retrospective design of the study was a limitation. CONCLUSIONS: The well-known negative psychological and social effects are a relevant part of HS and emphasize the importance of immediate therapy. As long-lasting local disease-control can be achieved, surgery should be considered as first-line therapy. PMID- 29485210 TI - Evaluation of potential serum biomarkers of hepatic fibrosis and necroinflammatory activity in dogs with liver disease. AB - BACKGROUND: Serum interleukin 6 (IL-6), chemokine ligand 2 (CCL2), C-reactive protein (CRP), and the ratio of aspartate transaminase to alanine transaminase (AST:ALT) have been correlated with fibrosis and necroinflammatory activity in humans with various hepatopathies. HYPOTHESIS/OBJECTIVES: To determine whether increases in serum IL-6, CCL2, CRP, or AST:ALT were associated with moderate to severe fibrosis or necroinflammatory activity in dogs with various hepatopathies. ANIMALS: Forty-four client-owned dogs with clinical evidence of liver disease and 10 healthy purpose-bred dogs, all undergoing liver biopsies by laparoscopy or laparotomy. METHODS: Measurement of serum IL-6, CCL2, CRP, AST, and ALT before scheduled liver biopsy and evaluation of liver histopathology using the METAVIR scoring system used in human medicine, blinded to clinical presentation. RESULTS: Median serum IL-6 was approximately twice as high in dogs with high fibrosis scores (15.5 pg/mL; range, 1.4 to 235 pg/mL) compared to dogs with low fibrosis scores (7.6 pg/mL; range, 1.4 to 148.1 pg/mL), with marginal significance (P = .05). Median serum CCL2 was significantly higher in dogs with active necroinflammation (444 pg/mL; range, 144 to 896 pg/mL) compared to dogs without detectable necroinflammation (326 pg/mL; range, 59 to 1692 pg/mL; P = .008), but with considerable overlap between groups. Neither serum CRP nor AST:ALT ratios were significantly different based on fibrosis or necroinflammatory scores. CONCLUSIONS AND CLINICAL IMPORTANCE: Because of substantial variability among dogs, single measurements of IL-6 and CCL2 have limited diagnostic utility for identifying fibrosis or necroinflammation, respectively, in dogs with various chronic liver diseases. The value of these biomarkers should be explored further in monitoring response to treatment in individual dogs with chronic hepatopathies. PMID- 29485212 TI - A de novo mutation in the EXT2 gene associated with osteochondromatosis in a litter of American Staffordshire Terriers. AB - BACKGROUND: We aimed to identify mutations associated with osteochondromatosis in a litter of American Staffordshire Terrier puppies. HYPOTHESIS: We hypothesized that the associated mutation would be located in a gene that causes osteochondromatosis in humans. ANIMALS: A litter of 9 American Staffordshire puppies, their sire and dam, 3 of 4 grandparents, 26 healthy unrelated American Staffordshire Terriers, and 154 dogs of 27 different breeds. METHODS: Whole genome sequencing was performed on the proband, and variants were compared against polymorphisms derived from 154 additional dogs across 27 breeds, as well as single nucleotide polymorphism database 146. One variant was selected for follow-up sequencing. Parentage and genetic mosaicism were evaluated across the litter. RESULTS: We found 56,301 genetic variants unique to the proband. Eleven variants were located in or near the gene exostosin 2 (EXT2), which is strongly associated with osteochondromatosis in humans. One heterozygous variant (c.969C > A) is predicted to result in a stop codon in exon 5 of the gene. Sanger sequencing identified the identical mutation in all affected offspring. The mutation was absent in the unaffected offspring, both parents, all available grandparents, and 26 healthy unrelated American Staffordshire Terriers. CONCLUSIONS AND CLINICAL IMPORTANCE: These findings represent the first reported mutation associated with osteochondromatosis in dogs. Because this mutation arose de novo, the identical mutation is unlikely to be the cause of osteochondromatosis in other dogs. However, de novo mutations in EXT2 are common in humans with osteochondromatosis, and by extension, it is possible that dogs with osteochondromatosis could be identified by sequencing the entire EXT2 gene. PMID- 29485213 TI - Trends in bullying victimization by gender among U.S. high school students. AB - This research used four consecutive waves of data from the National Youth Risk Behavior Survey (YRBS) conducted by the Centers for Disease Control (CDC), to estimate linear time trends by gender in the prevalence of school and electronic bullying victimization among U.S. high school students (N = 61,042). Dependent variables were student self-reported school bullying victimization and electronic bullying victimization during the previous 12 months. Independent variables used to estimate multiple logistic regression models by gender were survey year, race/ethnicity, and grade level. Results showed the prevalence of school bullying increased significantly among females from 2009 (21.2%) to 2015 (24.8%), linear trend OR = 1.08 [1.04, 1.12]; and decreased significantly among males from 2009 (18.7%) to 2015 (15.8%), linear trend OR = 0.93 [0.89, 0.98]. Prevalence of electronic bullying was unchanged between 2011 to 2015 among both male and female students. Asian race, relative to White race, was associated with significantly lower rates of both school and electronic bullying victimization among females, but not males. The incidence of school and electronic bullying victimization was significantly lower among Black and Hispanic students, but not among multiple race students, regardless of student gender. Healthy People 2020 set a goal to reduce school bullying victimization 10% by 2019. As of 2015, school bullying victimization decreased significantly among males (16% decrease); it significantly increased among females (17% increase). Future research should explore underlying factors related to these divergent trends, and develop effective strategies to reverse the alarming rise in female school bullying victimization. PMID- 29485214 TI - Transcription Factor-Based Biosensors in High-Throughput Screening: Advances and Applications. AB - The molecular mechanisms that cells use to sense changes in the intra- and extracellular environment are increasingly utilized in synthetic biology to build genetic reporter constructs for various applications. Although in nature sensing can be RNA-mediated, most existing genetically-encoded biosensors are based on transcription factors (TF) and cognate DNA sequences. Here, the recent advances in the integration of TF-based biosensors in metabolic and protein engineering screens whereas distinction is made between production-driven and competitive screening systems for enzyme evolution under physiological conditions are discussed. Furthermore, the advantages and disadvantages of existing TF-based biosensors are examined with respects to dynamic range, sensitivity, and robustness, and compared to other screening approaches. The application examples discussed in this review demonstrate the promising potential TF-based biosensors hold as screening tools in laboratory evolution of proteins and metabolic pathways, alike. PMID- 29485215 TI - Insulin resistance in hidradenitis suppurativa: a case-control study. AB - BACKGROUND: The association between chronic inflammatory diseases, such as rheumatoid arthritis and psoriasis, and insulin resistance (IR) has been well established. Hidradenitis suppurativa (HS) is a chronic inflammatory cutaneous disease that affects the apocrine gland-bearing areas of the body. OBJECTIVE: We aimed to determine the prevalence of IR in patients with HS. METHODS: This cross sectional, case-control study enrolled 137 subjects, 76 patients with HS and 61 age- and gender-matched controls. Demographic data, clinical examination of HS patients, anthropometric measures, cardiovascular risk factors and laboratory studies were recorded. The homeostasis model assessment of IR (HOMA-IR) was calculated in all participants by measuring fasting plasma glucose and insulin levels. RESULTS: The median (IQR) HOMA-IR value in HS patients was significantly higher [2.0 (1.0-3.6)] than in controls [1.5 (0.9-2.3)] (P = 0.01). The prevalence of IR was significantly higher in cases (43.4%) compared with controls (16.4%) (P = 0.001). In the linear regression multivariable analysis after adjusting for age, sex and body mass index (BMI), HS remained as a significant factor for a higher HOMA-IR [2.51 (0.18) vs 1.92(0.21); P = 0.04]. The HOMA-IR value and the prevalence of IR did not differ significantly among HS patients grouped by severity of the disease. CONCLUSION: Our results show an increased frequency of IR in HS. Thus, we suggest HS patients to be evaluated for IR and managed accordingly. PMID- 29485216 TI - Detecting host-parasitoid interactions in an invasive Lepidopteran using nested tagging DNA metabarcoding. AB - Determining the host-parasitoid interactions and parasitism rates for invasive species entering novel environments is an important first step in assessing potential routes for biocontrol and integrated pest management. Conventional insect rearing techniques followed by taxonomic identification are widely used to obtain such data, but this can be time-consuming and prone to biases. Here, we present a next-generation sequencing approach for use in ecological studies which allows for individual-level metadata tracking of large numbers of invertebrate samples through the use of hierarchically organised molecular identification tags. We demonstrate its utility using a sample data set examining both species identity and levels of parasitism in late larval stages of the oak processionary moth (Thaumetopoea processionea-Linn. 1758), an invasive species recently established in the United Kingdom. Overall, we find that there are two main species exploiting the late larval stages of oak processionary moth in the United Kingdom with the main parasitoid (Carcelia iliaca-Ratzeburg, 1840) parasitising 45.7% of caterpillars, while a rare secondary parasitoid (Compsilura concinnata Meigen, 1824) was also detected in 0.4% of caterpillars. Using this approach on all life stages of the oak processionary moth may demonstrate additional parasitoid diversity. We discuss the wider potential of nested tagging DNA metabarcoding for constructing large, highly resolved species interaction networks. PMID- 29485217 TI - Multifunctional Ionic Liquids from Rhodium(I) Isocyanide Complexes: Thermochromic, Fluorescence, and Chemochromic Properties Based on Rh-Rh Interaction and Oxidative Addition. AB - Square-planar rhodium(I) isocyanide complexes exhibit unique chemical reactivities such as the formation of Rh-Rh bonds and oxidative addition. This paper details the syntheses and properties of multifunctional ionic liquids containing RhI isocyanide complexes [Rh(nBuNC)4 ]X (X=Tf2 N (=N(SO2 CF3 )2- ), Nf2 N (=N(SO2 C4 F9 )2- ), FSA (=N(SO2 F)2- ), CF3 BF3- ). Salts with Tf2 N and Nf2 N were liquids, whereas those with FSA and CF3 BF3 were solids at room temperature. The salts exhibited thermochromism in the liquid state, changing from orange at high temperatures to blue-purple at lower temperatures. This is based on the equilibrium between monomer, dimer, and other oligomers associated with Rh-Rh bond formation. The salts also exhibited fluorescence. Exposure of the Tf2 N salt to methyl iodide vapor produced ionic liquid mixtures [Rh(nBuNC)4 ]x [Rh(nBuNC)4 IMe](1-x) [Tf2 N], concomitant with a color change from purple to red, orange, and yellow, extending the thermochromic color range. The reaction of the Tf2 N salt and iodine produced mononuclear and polynuclear iodine adducts. Thus, these liquids exhibit thermochromism, fluorescence, vapochromism, chemical reactivities, and characteristic properties of ionic liquids. PMID- 29485218 TI - Corrigendum. PMID- 29485219 TI - "The Amazing Journey from Egg to Adult": An embryology exhibition at the National Museum of Nature and Science. PMID- 29485220 TI - Factors that influenced undergoing renal replacement therapy and survival in children with acute kidney injury. AB - BACKGROUND: Acute kidney injury (AKI) is an important clinical condition which is associated with increased mortality and morbidity. This study was performed to identify the factors that influence AKI stage, undergoing renal replacement therapy (RRT) and mortality. METHODS: This study was retrospectively conducted on 219 children with AKI who had been referred to paediatric nephrology division of Dr. Sami Ulus Teaching Hospital during their inpatient treatment from 2008 to 2012. AKI was defined using pRIFLE criteria. RESULTS: From the 219 enrolled patients, 131 were identified as having AKI at the time of hospital admission. Infant age group was the largest group. RRT was performed in 68 patients. Median RRT initiation time was 1.5 day (0-2) and the mortality increased significantly when RRT initiation time was >1 day. The likelihood of undergoing RRT was higher for patients who were younger, who were managed in PICU and who had intrinsic type of AKI. pRIFLE stage and AKI place did not influence the likelihood of undergoing RRT. Overall mortality was 26.9%. In log-rank tests, factors influencing survival were younger age, being treated in PICU, developing AKI during inpatient treatment, having a comorbid condition and undergoing RRT. pRIFLE stage did not influence survival. In logistic regression model, factors associated with mortality included younger age, undergoing RRT and having AKI during inpatient treatment. Having underlying disease and being managed in PICU did not influence the likelihood of death. CONCLUSIONS: AKI is an important condition in all hospitalized patients. More studies and interventions are needed on this topic to identify, treat and prevent AKI. PMID- 29485221 TI - Biological control effects of non-reproductive host mortality caused by insect parasitoids. AB - As the rate of spread of invasive species increases, consumer-resource communities are often populated by a combination of exotic and native species at all trophic levels. In parasitoid-host communities, these novel associations may lead to disconnects between parasitoid preference and performance, and parasitoid oviposition may result in death of the parasitoid offspring, death of the host, or death of both. Despite their relevance for biological control risk and efficacy assessments, the direct and indirect population-level consequences of parasitoids attacking and killing their hosts without successfully reproducing (non-reproductive mortality) are poorly understood. Non-reproductive mortality induced by egg parasitoids (parasitoid-induced host egg abortion) may be particularly important for understanding the population dynamics of the invasive agricultural pest Halyomorpha halys (Hemiptera: Pentatomidae) and endemic stink bugs in North America, which are attacked by a suite of both native and introduced egg parasitoids. It is unclear, however, how various factors controlling parasitoid foraging and developmental success manifest at the population level. We constructed two related versions of a two-host-one parasitoid model to evaluate the population-level consequences of non reproductive host mortality. Egg abortion can result in strong negative or positive enemy-mediated indirect effects, taking the form of apparent competition, apparent parasitism, apparent amensalism, or apparent commensalism. For parasitoids limited in their reproductive output by the number of eggs they can produce, higher non-reproductive host mortality can reduce the strength of the positive indirect effect in cases of apparent parasitism, and it can reduce the negative indirect effect on the more suitable host in cases of apparent competition. For time-limited parasitoids, unsuitable hosts with high levels of non-reproductive parasitoid-induced mortality can be strongly suppressed in the presence of a suitable host, while the suitable host is only negligibly impacted (i.e., apparent amensalism). We evaluate these model-derived hypotheses within the context of H. halys and its native and nonnative parasitoids in North America, and discuss their application to risk assessment in biological control programs. PMID- 29485222 TI - Structure versus time in the evolutionary diversification of avian carotenoid metabolic networks. AB - Historical associations of genes and proteins are thought to delineate pathways available to subsequent evolution; however, the effects of past functional involvements on contemporary evolution are rarely quantified. Here, we examined the extent to which the structure of a carotenoid enzymatic network persists in avian evolution. Specifically, we tested whether the evolution of carotenoid networks was most concordant with phylogenetically structured expansion from core reactions of common ancestors or with subsampling of biochemical pathway modules from an ancestral network. We compared structural and historical associations in 467 carotenoid networks of extant and ancestral species and uncovered the overwhelming effect of pre-existing metabolic network structure on carotenoid diversification over the last 50 million years of avian evolution. Over evolutionary time, birds repeatedly subsampled and recombined conserved biochemical modules, which likely maintained the overall structure of the carotenoid metabolic network during avian evolution. These findings explain the recurrent convergence of evolutionary distant species in carotenoid metabolism and weak phylogenetic signal in avian carotenoid evolution. Remarkable retention of an ancient metabolic structure throughout extensive and prolonged ecological diversification in avian carotenoid metabolism illustrates a fundamental requirement of organismal evolution - historical continuity of a deterministic network that links past and present functional associations of its components. PMID- 29485223 TI - Papillary muscle ventricular arrhythmias among patients with mitral valve prolapse. PMID- 29485224 TI - Use of oral immunosuppressive drugs in the treatment of atopic dermatitis in the Netherlands. AB - BACKGROUND: Although atopic dermatitis (AD) is a very common skin disease, data on the percentage of patients with really difficult to treat AD are scarce. From socio-economic perspective it is important to have more insight in these numbers, as new very effective, but expensive, treatment options will be available in the near future for difficult to treat AD. Estimating the number of AD patients using oral immunosuppressive drugs can give an impression of the percentage of difficult to treat patients in the total AD population. OBJECTIVE: To give an overview of the use of oral immunosuppressive drugs in patients with AD in the Netherlands. METHODS: Prescription data of oral immunosuppressive drugs in the Netherlands were extracted from a pharmaceutical database (NControl) containing data of 557 million prescriptions and 7.2 million patients. An algorithm, based on the WHO Anatomical Therapeutic Chemical (ATC) codes, was used to identify patients with AD. The prescription of oral immunosuppressive drugs in patients with AD between January 1st 2012 and January 1st 2017 was evaluated. RESULTS: Based on the algorithm, 65 943 patients with AD were selected. 943 AD patients (1.4%) used cyclosporine A, methotrexate, azathioprine or mycophenolic acid. Methotrexate was most commonly used, followed by azathioprine and cyclosporine A. A switch in medication was rarely seen. In the evaluation period a decrease in the prescription of cyclosporine A was seen, together with an increase of the prescription of methotrexate. In 31% of the patients who stopped treatment, the discontinuation took place within the first months of treatment. CONCLUSION: In this study population, 1.4% of the AD patients used oral immunosuppressive drugs for their eczema in a five year period. Methotrexate was the most commonly used systemic drug in the Netherlands for the treatment of AD. This article is protected by copyright. All rights reserved. PMID- 29485225 TI - Thumb necrotic ulcers caused by weeverfish: case report and review of the literature. PMID- 29485226 TI - Diffusion MRI visualization. AB - Modern diffusion magnetic resonance imaging (dMRI) acquires intricate volume datasets and biological meaning can only be found in the relationship between its different measurements. Suitable strategies for visualizing these complicated data have been key to interpretation by physicians and neuroscientists, for drawing conclusions on brain connectivity and for quality control. This article provides an overview of visualization solutions that have been proposed to date, ranging from basic grayscale and color encodings to glyph representations and renderings of fiber tractography. A particular focus is on ongoing and possible future developments in dMRI visualization, including comparative, uncertainty, interactive and dense visualizations. PMID- 29485227 TI - In vitro characterization of pH-sensitive Bletilla Striata polysaccharide copolymer micelles and enhanced tumour suppression in vivo. AB - OBJECTIVES: A system of stearic acid (SA)-modified Bletilla striata polysaccharide (BSP) micelles was developed for the targeted delivery of docetaxel (DTX) as a model anticancer drug (DTX-SA-BSP). METHODS: Particle size, zeta potential and DTX release in vitro were measured in release media at different pH values. Quantitative cellular uptake, cytotoxicity assay in vitro and antitumour efficacy in vivo were also evaluated. Cell apoptosis was assessed by flow cytometry. KEY FINDINGS: DTX-SA-BSP copolymer micelles displayed pH dependent properties in the respects of particle size, zeta potential and in vitro release behaviour ranging from pH 5.0 to pH 7.4. DTX-SA-BSP copolymer micelles showed higher release rate at pH 5.0 than that at pH 6.0 and 7.4. In vitro cytotoxic effect of DTX-SA-BSP copolymer micelles was higher than that of DTX injection. The results of high-performance liquid chromatography determination confirmed that DTX cellular uptake of micelles was enhanced compared with that of DTX injection. Anticancer activity in vivo further confirmed the enhanced tumour targeting and anticancer efficacy of DTX-SA-BSP copolymer micelles. CONCLUSIONS: The above results show that DTX-SA-BSP copolymer micelles have pH sensitivity. SA-BSP copolymers are a promising carrier for delivering hydrophobic anticancer drugs. PMID- 29485228 TI - Driving performance of stable outpatients with depression undergoing real-world treatment. AB - AIM: Although the effects of psychotropics on driving ability have received much attention, little research is available on driving performance of stable outpatients with depression undergoing real-world treatment. This observational study investigated driving performance, cognitive functions, and depressive symptomatology of partly remitted outpatients with depression under daily practice psychopharmacologic treatment. METHODS: Seventy stable outpatients with depression and 67 healthy volunteers were enrolled. Patients' prescriptions were not controlled in order to capture the real-world treatment environment. Participants underwent three driving tasks - road-tracking, car-following, and harsh-braking - using a driving simulator, and three cognitive tasks - Continuous Performance Test, Wisconsin Card Sorting Test, and Trail-Making Test. The Symptom Assessment Scale - Structured Interview Guide for the Hamilton Depression Rating Scale, Beck Depression Inventory-II, Social Adaptation Self-Evaluation Scale, and Stanford Sleepiness Scale were also completed. RESULTS: Although many patients received various pharmacologic treatments, there were no significant differences in the three driving tasks between outpatients with depression and healthy controls. Difficulty of maintaining set in the Wisconsin Card Sorting Test was significantly increased in patients with depression. Results on the Social Adaptation Self-Evaluation Scale were significantly associated with road-tracking and car-following performance, in contrast to results on the Hamilton Depression Rating Scale and the Beck Depression Inventory-II. CONCLUSION: We conclude that partly remitted depressive patients under steady-state pharmacologic treatment do not differ from healthy controls with respect to driving performance, which seems to be more affected by psychosocial functioning than by pharmacologic agents. This, however, should be investigated systematically in an off/on study. PMID- 29485229 TI - Development of a liquid chromatography-tandem mass spectrometry method for simultaneous determination of five isoflavonoids and seven neurochemicals in rat brain dialysate and its application to a pharmacological study. AB - Pueraria lobata is a medicinal plant widely used in traditional Chinese medicine. The total pueraria isoflavones have demonstrated positive effect against neurological disorders. In the present study, we first develop an ultra high performance liquid chromatography and tandem mass spectrometry method to quantify the multiple active pueraria isoflavonoids and neurochemical markers in brain dialysate to provide tools for further exploring the functional mechanism of pueraria isoflavones for neuroactivities. A phenomenex Luna C18 column (50 * 2.0 mm, 5 MUm) was employed with acetonitrile/0.05% formic acid in water as the mobile phase for the separation of analytes. A mass spectrometer with electrospray ionization source in positive/negative ion switching mode was used for multiple reaction monitoring of the detected compounds. The method was validated and proved acceptable. The intra- and interday precision across quality control levels was within 13.87 for all analytes, whereas the deviation of assay accuracies ranged between 0.03 and 11.53%. The method was successfully applied to a pharmacological study of pueraria isoflavones in rat brain. PMID- 29485230 TI - The Role of High-Frequency MRI Monitoring in the Detection of Brain Atrophy in Multiple Sclerosis. AB - BACKGROUND AND PURPOSE: A relatively high intraindividual variability of longitudinal magnetic resonance imaging (MRI) of brain volume loss (BVL) measurements over time renders challenging its application to individual multiple sclerosis (MS) patients. Objective of this study was to investigate if high frequency brain MRI monitoring affects identification of pathological BVL in an individual patient. METHODS: One hundred fifty-seven relapsing-remitting MS patients had seven MRI scans over 12 months follow-up. All 1,585 MRI scans were performed on the same 1.5T scanner using an identical scanning protocol. Volumetric analysis was performed by ScanView and SIENA software. Linear regression analysis was used for estimation of annualized BVL, with a cutoff greater than .4% defined as pathological. We compared proportions of patients with pathological BVL obtained by analysis of different number of MRI time points. RESULTS: An analysis of seven MRI scans (months 0, 2, 4, 6, 8, 10, and 12) showed pathological BVL in 105 (65%) of patients. When three MRI scans were included (months 0, 6, and 12), we found 10 (6.4%) false negative and 9 (5.7%) false positive results compared with the analysis of seven MRI scans, used as a reference for assessment of pathological BVL. Analysis of two MRI time-points (months 0 and 12) showed 10 (6.4%) false negative and 13 (8.3%) false positive results compared with analysis of seven MRI time-points. Change in the accuracy of pathological BVL between results obtained by analysis of seven and two time points was 14.7%. CONCLUSIONS: High-frequency MRI monitoring may have a considerable effect on improving the precision of precisely identifying pathological BVL in individual patients. However, limitations in translation to clinical practice remain. PMID- 29485231 TI - Synthesis, Characterization, Uses and Applications of Porous Clays Heterostructures: A Review. AB - Porous clay heterostructures (PCH) are obtained by the insertion of an organic bulky cation in the interlayer spacing of a smectite, causing a swelling of the clay mineral. Right after, oxides species, mainly silicon oxide, are incorporated as pillars galleries between adjacent layers to form a porous structure after the removal of the template. The ordering of the clay mineral as well the organic cation incorporated in the synthetic step favors the modulation of the textural properties of the PCH. In addition, the incorporation of heteroatoms in the pillars galleries can also modulate the acidity of the PCH. The modulation of the pore size and the acid properties provides to these materials a wide range of applications in the fields of adsorption and catalysis. This paper carries out a detailed review of the synthesis of PCH, characterization as well as uses and application reported in the literature. PMID- 29485232 TI - GABAA receptor subunit expression changes in the human Alzheimer's disease hippocampus, subiculum, entorhinal cortex and superior temporal gyrus. AB - Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. GABA type A receptors (GABAA Rs) are severely affected in Alzheimer's disease (AD). However, the distribution and subunit composition of GABAA Rs in the AD brain are not well understood. This is the first comprehensive study to show brain region- and cell layer-specific alterations in the expression of the GABAA R subunits alpha1-3, alpha5, beta1-3 and gamma2 in the human AD hippocampus, entorhinal cortex and superior temporal gyrus. In late-stage AD tissue samples using immunohistochemistry we found significant alteration of all investigated GABAA Rs subunits except for alpha3 and beta1 that were well preserved. The most prominent changes include an increase in GABAA R alpha1 expression associated with AD in all layers of the CA3 region, in the stratum (str.) granulare and hilus of the dentate gyrus. We found a significant increase in GABAA R alpha2 expression in the str. oriens of the CA1-3, str. radiatum of the CA2,3 and decrease in the str. pyramidale of the CA1 region in AD cases. In AD there was a significant increase in GABAA R alpha5 subunit expression in str. pyramidale, str. oriens of the CA1 region and decrease in the superior temporal gyrus. We also found a significant decrease in the GABAA R beta3 subunit immunoreactivity in the str. oriens of the CA2, str. granulare and str. moleculare of the dentate gyrus. In conclusion, these findings indicate that the expression of the GABAA R subunits shows brain region- and layer-specific alterations in AD, and these changes could significantly influence and alter GABAA R function in the disease. Cover Image for this issue: doi: 10.1111/jnc.14179. PMID- 29485233 TI - Survey of recognition and treatment of at-risk mental state by Japanese psychiatrists. AB - AIM: The importance of early intervention in psychiatry is widely recognized among psychiatrists. However, it is unknown whether precise knowledge of at-risk mental state has been disseminated. With this survey, we aimed to reveal how Japanese psychiatrists diagnose patients with at-risk mental state and prescribe treatment strategies for them. METHODS: Using fictional case vignettes, we conducted a questionnaire survey of psychiatrists (n = 1399) who worked in Tokyo. We mailed study documents to all eligible participants in November 2015 with a requested return date in December. RESULTS: Two hundred and sixty (19.3%) psychiatrists responded to the survey. Their correct diagnosis rates for the patients in the at-risk mental state vignettes were low (14.6% for the vignette describing at-risk mental state with attenuated positive symptom syndrome; 13.1% for the vignette describing at-risk mental state with brief intermittent psychotic syndrome). Many psychiatrists selected pharmacotherapy and antipsychotics to treat patients in the at-risk mental state vignettes. The psychiatrists who correctly diagnosed patients in the at-risk mental state vignettes had significantly fewer years of clinical psychiatric experience than did those who diagnosed them as having a non-at-risk mental state (12.5 years vs 22.7 years for the vignette describing at-risk mental state with attenuated positive symptom syndrome, P < 0.01; 14.3 years vs 22.2 years for the vignette describing at-risk mental state with brief intermittent psychotic syndrome, P < 0.01). CONCLUSION: This study suggests that precise knowledge of at-risk mental state has not been disseminated among Japanese psychiatrists. PMID- 29485234 TI - Effect of ionization, bedding, and feeding on air quality in a horse stable. AB - BACKGROUND: Organic dust is associated with Equine asthma. Ionization should reduce airborne dust levels. OBJECTIVES: To determine the effect of ionization of air, type of bedding, and feed on the levels of airborne dust, endotoxin, and fungal colonies in horse stables. ANIMALS: 24 healthy University-owned horses occupied the stables. METHODS: A randomized controlled cross-over study. Four units with 6 stables were equipped with an ionization installation (25 VA, 5000 Volt Direct Current). Horses were kept either on wood shavings and fed haylage (2 units), or on straw and fed dry hay (2 units). Measurements were performed with and without activated ionization, during daytime and nighttime, repeatedly over the course of a week and repeatedly during 4-6 weeks. Statistical analysis was performed using a mixed effect model with Akaike's Information Criterion for model reduction and 95% profile (log) likelihood confidence intervals (CI). RESULTS: Ionization did not alter concentrations of dust, endotoxin, or fungi, fewer. In the units with straw and hay, the concentration of dust, endotoxin, and fungi (difference in logarithmic mean 1.92 (95%CI 1.71-2.12); 2.86 (95%CI 2.59 3.14); 1.75 (95%CI 1.13-2.36)) were significantly higher compared to wood shavings and haylage. CONCLUSIONS AND CLINICAL IMPORTANCE: The installation of a negative air-ionizer in the horse stable did not reduce concentrations of dust, endotoxin, and viable fungal spores. The substantial effect of low dust bedding and feed is confirmed. PMID- 29485235 TI - Extension of peripheral nonperfusion in eyes with retinal vein occlusion during intravitreal dexamethasone treatment. AB - BACKGROUND: To evaluate the change in peripheral perfusion status in patients with retinal vein occlusion (RVO) during dexamethasone treatment. METHODS: Thirty five eyes of patients with macular oedema due to either branch or central retinal vein occlusion were included. At baseline, patients were treated with an intravitreal dexamethasone implant (Ozurdex(r) ) and followed until month 6. Wide field angiographies were classified as ischaemic and nonischaemic. Peripheral nonperfusion (PNP) was determined manually by calculating the percentage of nonperfusion area in relation to the total visible retina (ischaemic index). RESULTS: Thirteen eyes showed evidence of >10 disc area of PNP at baseline and were graded as ischaemic RVO. In nonischaemic eyes, the mean area of PNP was 0.3% at baseline, 0.6% after 1 month, 0.6% after 3 months and 0.6% after 6 months, respectively (p > 0.05). In ischaemic RVO, the ischaemic index was calculated to be 18% at baseline. One month after treatment, mean area of PNP was 16% and after 3 months was 19% (p = 0.8; p = 0.6). After retreatment, total PNP area was 18% (month 6; p = 0.9). During treatment, best-corrected visual acuity (BCVA) increased and central retinal thickness (CRT) decreased from baseline to final follow-up with no differences between nonischaemic/ischaemic RVO. A significant negative correlation between the total area of PNP and visual acuity was identified (r = -0.6; p = 0.04). CONCLUSION: Using 200 degrees wide-field fluorescein angiography, the ischaemic index was shown to remain stable during dexamethasone treatment. This finding was consistent in ischaemic as well as in nonischaemic conditions. PMID- 29485236 TI - Viral outbreaks linked to fresh produce consumption: a systematic review. AB - AIMS: Alpha systematic review to investigate fresh produce-borne viral outbreaks, to record the outbreak distribution worldwide and to analyse the implication of different types of fresh produce and viral types as well. METHODS AND RESULTS: Four databases (PubMed/Medline, Scopus, Eurosurveillance Journal and Spingerlink electronic journal) and a global electronic reporting system (ProMED-mail) were searched up to 2016. One hundred and fifty-two viral outbreaks linked to fresh produce consumption were identified. The majority of the reported outbreaks was reported in Europe, followed by North America, Asia, Australia, Africa and South America. A great number of the outbreaks was recorded in Denmark and Finland. The most common viral pathogens were norovirus (48.7%) and hepatitis A virus (46.1%). The most frequent type of fresh produce involved was frozen raspberries (23.7%). Differences in the reporting of outbreaks were recorded between the scientific literature and ProMED. CONCLUSIONS: The number of reported illnesses linked to fresh produce has increased in several countries. Consumption of contaminated fresh produce represents a risk to public health in both developed and developing countries, but the impact will be disproportionate and likely to compound existing health disparities. For this reason, all countries should systematically collate and report such data through a disease surveillance system, in order to adopt risk management practices for reducing the likelihood of contamination. PMID- 29485238 TI - Purification-Free, Target-Selective Immobilization of a Protein from Cell Lysates. AB - Protein immobilization has been widely used for laboratory experiments and industrial processes. Preparation of a recombinant protein for immobilization usually requires laborious and expensive purification steps. Here, a novel purification-free, target-selective immobilization technique of a protein from cell lysates is reported. Purification steps are skipped by immobilizing a target protein containing a clickable non-natural amino acid (p-azidophenylalanine) in cell lysates onto alkyne-functionalized solid supports via bioorthogonal azide alkyne cycloaddition. In order to achieve a target protein-selective immobilization, p-azidophenylalanine was introduced into an exogenous target protein, but not into endogenous non-target proteins using host cells with amber codon-free genomic DNAs. Immobilization of superfolder fluorescent protein (sfGFP) from cell lysates is as efficient as that of the purified sfGFP. Using two fluorescent proteins (sfGFP and mCherry), the authors also demonstrated that the target proteins are immobilized with a minimal immobilization of non-target proteins (target-selective immobilization). PMID- 29485239 TI - Egg-laying environment modulates offspring responses to predation risk in an amphibian. AB - Predator-induced plasticity has been in the focus of evolutionary ecological research in the last decades, but the consequences of temporal variation in the presence of cues predicting offspring environment have remained controversial. This is partly due to the fact that the role of early environmental effects has scarcely been scrutinized in this context while also controlling for potential maternal effects. In this study, we investigated how past environmental conditions, that is different combinations of risky or safe adult (prenatal) and oviposition (early post-natal) environments, affected offspring's plastic responses in hatching time and locomotor activity to predation risk during development in the smooth newt (Lissotriton vulgaris). We found that females did not adjust their reproductive investment to the perceived level of risk in the adult environment, and this prenatal environment had generally negligible effect on offspring phenotype. However, when predator cues were absent during oviposition, larvae raised in the presence of predator cues delayed their hatching and exhibited a decreased activity compared to control larvae developing without predator cues, which responses are advantageous when predators pose a threat to hatched larvae. In the presence of predator cues during oviposition, the difference in hatching time persisted, but the difference in general locomotor activity disappeared between risk-exposed and control larvae. Our findings provide clear experimental evidence that fine-scale temporal variation in a predictive cue during and after egg-laying interactively affects offspring phenotype, and highlight the importance of the early post-natal environment, which may exert a substantial influence on progeny's phenotype also under natural conditions. PMID- 29485237 TI - Recent progress in Lynch syndrome and other familial colorectal cancer syndromes. AB - The current understanding of familial colorectal cancer was limited to descriptions of affected pedigrees until the early 1990s. A series of landscape altering discoveries revealed that there were distinct forms of familial cancer, and most were related to genes previously not known to be involved in human disease. This review largely focuses on advances in our understanding of Lynch syndrome because of the unique relationship of this disease to defective DNA mismatch repair and the clinical implications this has for diagnostics, prevention, and therapy. Recent advances have occurred in our understanding of the epidemiology of this disease, and the advent of broad genetic panels has altered the approach to germline and somatic diagnoses for all of the familial colorectal cancer syndromes. Important advances have been made toward a more complete mechanistic understanding of the pathogenesis of neoplasia in the setting of Lynch syndrome, and these advances have important implications for prevention. Finally, paradigm-shifting approaches to treatment of Lynch-syndrome and related tumors have occurred through the development of immune checkpoint therapies for hypermutated cancers. CA Cancer J Clin 2018;68:217-231. (c) 2018 American Cancer Society. PMID- 29485240 TI - Site-Specific Photoconjugation of Beta-Lactamase Fragments to Monoclonal Antibodies Enables Sensitive Analyte Detection via Split-Enzyme Complementation. AB - Protein fragment complementation assays (PCA) rely on a proximity-driven reconstitution of a split reporter protein activity, typically via interaction between bait and prey units separately fused to the reporter protein halves. The PCA principle can also be formatted for use in immunossays for analyte detection, e.g., via the use of small immunoglobulin binding proteins (IgBp) as fusion partners to split-reporter protein fragments for conversion of pairs of antibodies into split-protein half-probes. However, the non-covalent binding between IgBp and antibodies is not ideal for development of robust assays. Here, the authors describe how split-enzyme reporter halves can be both site specifically and covalently photoconjugated at antibody Fc-parts for use in homogeneous dual-antibody in vitro immunoassays based on analyte-dependent split enzyme fragment complementation. The half-probes consist of parts of a beta lactamase split-protein reporter fused to an immunoglobulin Fc binding domain equipped with a unique cysteine residue at which a photoactivable maleimide benzophenone group (MBP) is attached. Using such antibody conjugates the authors obtain an analyte-driven complementation of the reporter enzyme fragments monitored via conversion of a chromogenic substrate. Results from detection of human interferon-gamma and the extracellular domain of HER2 is shown. The described principles for site-specific conjugation of proteins to antibodies should be broadly applicable. PMID- 29485241 TI - Effects of fetal hypothyroidism on uterine smooth muscle contraction and structure of offspring rats. AB - NEW FINDINGS: What is the central question of this study? Does fetal hypothyroidism in rats alter uterine contractions and structure in the adult offspring? What is the main finding and its importance? Our study indicated that maternal hypothyroidism during pregnancy increased gestational length and decreased litter size. In addition, maternal hypothyroidism caused delayed puberty onset, irregular uterine contractions and histological changes in the uterus in the female offspring. This model might contribute to a better understanding of the cellular and molecular mechanisms involved in uterine contractions in fetal hypothyroidism, studies which are not possible in humans, and might help to establish therapeutic methods for these disorders observed in uterine contractions. ABSTRACT: Thyroid hormones play an essential role in fetal growth. Hypothyroidism impairs reproductive function in both humans and animals. The aim of this study was to assess the effects of fetal hypothyroidism on uterine smooth muscle contraction and structure in the adult offspring. The control group of female Wistar rats consumed tap water, whereas the hypothyroid group received water containing 0.025% of 6-propyl-2-thiouracial throughout gestation from mating until delivery. Isometric contractility and histological changes in uterine tissue were evaluated in the adult female offspring. We tested the effects of carbachol (10-10 -10-3 m) and oxytocin (10-13 -10-8 m) on uterine smooth muscle contraction in the fetal hypothyroid (FH) and control groups. Compared with control uteri, carbachol induced contractions with lower amplitude in the FH group (area under the curve: 1820.0 +/- 250.0 versus 1370.0 +/- 125.0 a.u., control versus FH group, respectively, P < 0.001) and frequency (86.4 +/- 7.3 versus 37.0 +/- 6.1 a.u., P < 0.001). Likewise, after exposure to oxytocin the amplitude (6614.0 +/- 492.2 versus 4793.0 +/- 735.2 a.u., P < 0.001) and frequency (367.4 +/- 32.0 versus 167.0 +/- 39.0 a.u., P < 0.001) of uterine contractions in the FH group were significantly lower than in the control group. In addition, the thickness of the endometrium and smooth muscle layer and the cross-sectional area of the uterus were also significantly lower in the FH group. Gestational length was longer and litter size smaller in FH rats compared with control animals; FH offspring also had delayed puberty. In conclusion, thyroid hormone deficiency during pregnancy increased gestational length and decreased litter size; in the offspring, it delayed puberty onset, reduced uterine rhythmic contractions and resulted in uterine structural changes. PMID- 29485243 TI - Spatial scaffold effects in event memory and imagination. AB - Spatial context is a defining feature of episodic memories, which are often characterized as being events occurring in specific spatiotemporal contexts. In this review, I summarize research suggesting a common neural basis for episodic and spatial memory and relate this to the role of spatial context in episodic memory. I review evidence that spatial context serves as a scaffold for episodic memory and imagination, in terms of both behavioral and neural effects demonstrating a dependence of episodic memory on spatial representations. These effects are mediated by a posterior-medial set of neocortical regions, including the parahippocampal cortex, retrosplenial cortex, posterior cingulate cortex, precuneus, and angular gyrus, which interact with the hippocampus to represent spatial context in remembered and imagined events. I highlight questions and areas that require further research, including differentiation of hippocampal function along its long axis and subfields, and how these areas interact with the posterior-medial network. This article is categorized under: Psychology > Memory Neuroscience > Cognition. PMID- 29485242 TI - Direct Synthesis of Nano-Ferrierite along the 10-Ring-Channel Direction Boosts Their Catalytic Behavior. AB - Ferrierite zeolites with nanosized crystals and external surface areas higher than 250 m2 g-1 have been prepared at relatively low synthesis temperature (120 degrees C) by means of the collaborative effect of two organic structure directing agents (OSDA). In this way, hierarchical porosity is achieved without the use of post-synthesis treatments that usually involve leaching of T atoms and solid loss. Adjusting the synthesis conditions it is possible to decrease the crystallite size in the directions of the 8- and 10-ring channels, [010] and [001] respectively, reducing their average pore length to 10-30 nm and increasing the number of pores accessible. The small crystal size of the nano-ferrierites results in an improved accessibility of reactants to the catalytic active centers and enhanced product diffusion, leading to higher conversion and selectivity with lower deactivation rates for the oligomerization of 1-pentene into longer-chain olefins. PMID- 29485244 TI - Virtual issue-supporting people who self-harm or are suicidal-Editorial. PMID- 29485246 TI - Control of Molar Mass Distribution by Polymerization in the Analytical Ultracentrifuge. AB - Molar mass distributions are of high interest in macromolecular chemistry because they directly determine the physical and chemical properties of polymers. A principal approach to obtain and control the shape of broad molar mass distributions is adjusting the initiator concentration in free radical polymerizations. A controlled gradient of the initiator concentration should potentially lead to tailored molar mass distributions. Here we use analytical ultracentrifugation (AUC) to adjust and measure a macroinitiator's concentration gradient. Subsequent photopolymerization of a uniformly distributed monomer leads to desired chain length distributions. Resulting distributions are described and calculated by a Schulz-Flory approach. The desired concentration profiles are simulated in advance and can be detected anytime by the optical systems in the centrifuge. Therefore, tailored broad molar mass distributions can now be produced using predictions from simulations using the established theory of AUC. PMID- 29485245 TI - A morphogram for silica-witherite biomorphs and its application to microfossil identification in the early earth rock record. AB - Archean hydrothermal environments formed a likely site for the origin and early evolution of life. These are also the settings, however, were complex abiologic structures can form. Low-temperature serpentinization of ultramafic crust can generate alkaline, silica-saturated fluids in which carbonate-silica crystalline aggregates with life-like morphologies can self-assemble. These "biomorphs" could have adsorbed hydrocarbons from Fischer-Tropsch type synthesis processes, leading to metamorphosed structures that resemble carbonaceous microfossils. Although this abiogenic process has been extensively cited in the literature and has generated important controversy, so far only one specific biomorph type with a filamentous shape has been discussed for the interpretation of Archean microfossils. It is therefore critical to precisely determine the full distribution in morphology and size of these biomorphs, and to study the range of plausible geochemical conditions under which these microstructures can form. Here, a set of witherite-silica biomorph synthesis experiments in silica saturated solutions is presented, for a range of pH values (from 9 to 11.5) and barium ion concentrations (from 0.6 to 40 mmol/L BaCl2 ). Under these varying conditions, a wide range of life-like structures is found, from fractal dendrites to complex shapes with continuous curvature. The size, spatial concentration, and morphology of the biomorphs are strongly controlled by environmental parameters, among which pH is the most important. This potentially limits the diversity of environments in which the growth of biomorphs could have occurred on Early Earth. Given the variety of the observed biomorph morphologies, our results show that the morphology of an individual microstructure is a poor criterion for biogenicity. However, biomorphs may be distinguished from actual populations of cellular microfossils by their wide, unimodal size distribution. Biomorphs grown by diffusion in silica gel can be differentiated by their continuous gradient in size, spatial density, and morphology along the direction of diffusion. PMID- 29485247 TI - Structural Characterization of i-Motif Structure in the Human Acetyl-CoA Carboxylase 1 Gene Promoters and Their Role in the Regulation of Gene Expression. AB - The polypurine/polypyrimidine-rich sequences within the promoters (PI and PII) of human acetyl coenzyme A (CoA) carboxylase 1 (ACC1) gene play a vital role in determining hormone- or diet-inducible expression of ACC1. PI and PII contain consecutive runs of three and three to five G/C base pairs, respectively. In a previous study, G-rich DNA sequences of human ACC1 PI and PII were found to fold into G-quadruplex structures; these consequently acted as strong barriers to transcription and DNA replication. Typically, stretches of C-rich sequences that coexist with stretches of guanines have the capacity to form another four stranded secondary structure known as an i-motif. However, studies on the i-motif structure are limited and its functional significance is unclear. In the current study, through the use of a combination of different techniques, it is demonstrated that C-rich single-stranded DNA derived from ACC1 PI and PII form intramolecular i-motif structures and affect normal DNA metabolic processes. Additionally, the C-rich strands of PI and PII in duplex DNA adopt the i-motif conformation in crowded solution environments at neutral pH. Notably, the i-motif forming sequences of PI and PII suppressed luciferase gene transcription in HeLa cells. Furthermore, substitution of a nucleotide sequence that has no potential to form the i-motif structure increases luciferase gene expression in HeLa cells. These results support the idea that C-rich sequences within ACC1 PI and PII can form intramolecular i-motif structures, cause suppression of transcription, and thus reveal the functional significance of C-rich sequences in the regulation of ACC1 gene expression. PMID- 29485249 TI - Laparoscopic surgery using a Gigli wire saw for locally recurrent rectal cancer with concomitant intraperitoneal sacrectomy. AB - INTRODUCTION: Previous reports indicated the effectiveness of surgical resection for locally recurrent rectal cancer (LRRC). Most cases with posterior invasion patterns require concomitant sacrectomy to secure negative histologic margins, although this is a highly invasive procedure. Here, we present a new minimally invasive laparoscopic surgical technique for LRRC with concomitant sacrectomy. MATERIALS AND SURGICAL TECHNIQUE: A 64-year-old man presented with LRRC on the surface of the sacral bone. He underwent laparoscopic abdominoperineal resection with concomitant sacrectomy below the S4 vertebra. The surgical procedure, including sacrectomy, was performed laparoscopically. The distance between the estimated resection line (below the S4 vertebra) and sacral promontory was measured by preoperative imaging. Intraoperatively, a flexible ruler was employed to determine the resection line. Securing adequate space dorsal to the sacral bone was indispensable for placement of the Gigli wire saw. After the Gigli wire saw was positioned, bilateral caudal trocars were used to remove the ends of the wire. Then, the sacral bone was cut by the linear reciprocating motion of the Gigli wire saw. Pathologically confirmed curative resection was achieved. The procedure was successfully performed without transfusion or intraoperative complications. The operation time was 757 min, and blood loss volume was 890 ml. There were no severe postoperative complications. The patient is alive and well with no evidence of recurrence at 58 months after surgical resection of LRRC. DISCUSSION: Our newly developed technique demonstrates that laparoscopic intraperitoneal sacrectomy using a Gigli wire saw is a safe and useful procedure to facilitate resection of LRRC. PMID- 29485248 TI - Effects of combination of sotalol and verapamil on initiation, maintenance, and termination of ventricular fibrillation in swine hearts. AB - INTRODUCTION: Sotalol and verapamil alone reduce reentry incidence during ventricular fibrillation (VF). We tested whether the combination of these two drugs had a synergistic effect on initiation, maintenance, and termination of VF. METHODS: Six open-chest pigs received intravenous sotalol (1.5 mg/kg) followed by verapamil (0.136 mg/kg). VF threshold (VFT) was determined by a burst pacing protocol. Two 20 seconds episodes of VF were recorded from a 21 * 24 unipolar electrode plaque on the lateral posterior left ventricular epicardium before and after each drug. VF activation patterns were quantified. The duration of long duration VF (LDVF) maintenance was compared to our previously published data. RESULTS: Sotalol alone and combined with verapamil significantly increased the VFT from 12.3 +/- 4.1 to 20.3 +/- 7.1 and 26.7 +/- 8.6 mA compared with baseline (P < .05). Sotalol decreased the number of wavefronts by 20%, VF activation rate by 17% and conduction velocity 11%, while the addition of verapamil neutralized these effects. Addition of verapamil to sotalol further decreased the fractionation incidence from 14% to 29% and multiplicity from 24% to 31% compared with baseline. The combination of the two drugs increased the VF cycle length, decreased synchronicity, increased regularity index and shortened the duration of LDVF maintenance compared with our previous data of verapamil alone or no drug. Synchronicity index was lower and regularity index was higher in animals in which VF spontaneously terminated earlier than 10 minutes than in animals in which VF terminated longer than 10 minutes. CONCLUSION: The combination of sotalol and verapamil increased VFT but accelerated LDVF termination. PMID- 29485250 TI - Tying modified clinch knots during single-incision laparoscopic surgery. AB - INTRODUCTION: Recent advances in single-incision laparoscopic surgery (SILS) have caused increased difficulties when tying knots because of the limited working space. Although extracorporeal knot-tying techniques may be a practical alternative choice in SILS, it is not always appropriate. For example, sliding resistance may be encountered when tying knots for a Z-shaped suture, and it could damage the sutured tissue. MATERIALS AND SURGICAL TECHNIQUE: The clinch knot is a kind of slipknot that has been historically used by fishermen. We modified it for SILS so that it has a locking mechanism caused by knot deformation. We apply pre-tied modified clinch (MC) knots in the peritoneal cavity with a needle driver. After the suture, the needle is pulled through the knot and exits out the trocar. After the MC knot has been tightened, locking is achieved by pulling the other end of the axial thread and folding the thread in an acute angle. Because both ends of the suture thread leave the trocar together, every step can be carried out quickly through a single trocar. The MC knot can also be used to tie knots for Z-shaped sutures because of its short sliding distance. Twelve simple interrupted sutures and 55 Z-shaped sutures were tied by MC knot in SILS. All knots were successfully tied, and the mean required time to tie a knot was 27 s. DISCUSSION: The MC knot is feasible knot-tying procedure especially for a Z-shaped suture during SILS. PMID- 29485251 TI - Laparoscopic versus abdominal sacrocolpopexy for treatment of multi-compartmental pelvic organ prolapse: A systematic review. AB - Laparoscopic sacrocolpopexy (LSC) is attracting increasing attention as a minimally invasive surgery that provides excellent therapeutic effects on apical vaginal prolapse. However, its therapeutic effects on multi-compartmental pelvic organ prolapse (POP) remain unclear. Therefore, the aim of this review was to evaluate the efficacy of LSC on multi-compartmental POP compared with abdominal sacrocolpopexy (ASC). We extracted three articles on randomized controlled trials that compared LSC and ASC. A total of 247 patients (123 for LSC, 124 for ASC) were evaluated. There was no evidence of recurrence or reoperation in either group for the apical vaginal compartment. Regarding recurrence within the anterior vaginal compartment, there were no significant between-group differences in either of the two randomized controlled trials targeting vaginal vault prolapse. In contrast, in the randomized controlled trial targeting POP including cases with uteruses, there were more recurrent POP with grade II or more in the LSC group than in the ASC group (11/60 [18.3%] vs 1/60 [1.6%], P = 0.004). Reoperation for the posterior vaginal compartment was performed in three cases (2.5%) in the LSC group and in one case (0.8%) in the ASC group. The combined repeat surgery and mesh removal surgery rate was higher in the LSC group (8/119 [6.7%]) than in the ASC group (2/121 [1.7%], P = 0.049). LSC has an excellent therapeutic effect and is comparable to ASC for the treatment of apical prolapse. However, cystocele recurrence, repeat surgery of the posterior compartment, and mesh-related complications were more frequent in patients who had undergone LSC. PMID- 29485252 TI - Multiscale systems biology of trauma-induced coagulopathy. AB - Trauma with hypovolemic shock is an extreme pathological state that challenges the body to maintain blood pressure and oxygenation in the face of hemorrhagic blood loss. In conjunction with surgical actions and transfusion therapy, survival requires the patient's blood to maintain hemostasis to stop bleeding. The physics of the problem are multiscale: (a) the systemic circulation sets the global blood pressure in response to blood loss and resuscitation therapy, (b) local tissue perfusion is altered by localized vasoregulatory mechanisms and bleeding, and (c) altered blood and vessel biology resulting from the trauma as well as local hemodynamics control the assembly of clotting components at the site of injury. Building upon ongoing modeling efforts to simulate arterial or venous thrombosis in a diseased vasculature, computer simulation of trauma induced coagulopathy is an emerging approach to understand patient risk and predict response. Despite uncertainties in quantifying the patient's dynamic injury burden, multiscale systems biology may help link blood biochemistry at the molecular level to multiorgan responses in the bleeding patient. As an important goal of systems modeling, establishing early metrics of a patient's high dimensional trajectory may help guide transfusion therapy or warn of subsequent later stage bleeding or thrombotic risks. This article is categorized under: Analytical and Computational Methods > Computational Methods Biological Mechanisms > Regulatory Biology Models of Systems Properties and Processes > Mechanistic Models. PMID- 29485253 TI - Daylight photodynamic therapy with methyl aminolevulinate for the treatment of actinic keratoses of the forearms. PMID- 29485254 TI - Results of radiotherapy in minimal stage mycosis fungoides: a reappraisal after ten years. AB - BACKGROUND: Mycosis Fungoides (MF) is the most common cutaneous T cell lymphoma, accounting for 54-72 % of cases. When it presents as solitary or oligolesional picture, radiotherapy is considered potentially curative. To verify this we decided to evaluate the outcome in 15 patients studied in the period 1990-2007 after ten years. METHODS: The files of the patients were revised and they were recalled for a control. Two new cases were added. On the whole 17 patients were studied. All patients underwent histopathological ascertainment and staging investigations. All lesions were treated with conventional radiation therapy with a median dose of 25 Gy. RESULTS: After 1 month from the end of radiotherapy, complete remission (CR) occurred in 22 treatment fields (95, 6%) and partial remission(PR) in one (4,4%). Radiotherapy was always well tolerated. At the last recorded visit (median follow up 130 months) 15 patients were alive without disease, and two had localized evidence of MF lesions, with a total 5-year cure rate of 63.24% and of 66.71% if referred to the original updated series. None of the patients showed progression of the disease. CONCLUSIONS: Our results confirm that radiation therapy in the treatment of minimal stage MF contributes to afford good and durable results with negligible side effects and maintenance of good quality of life over the time. PMID- 29485255 TI - Cutaneous leukocytoclastic vasculitis in B-cell chronic lymphocytic leukaemia patients. PMID- 29485256 TI - The association between cigarettes smoke, small intestine bacterial overgrowth and rosacea. PMID- 29485257 TI - Pediatric melanoma update. AB - Pediatric melanoma is a rare disease that affects approximately 6 out of every one million children and accounts for 1-4% of all melanomas. This article reviews the epidemiology, etiology, diagnosis, treatment and prognosis of pediatric melanoma - with particular attention to recent updates in the literature. While awareness of melanoma increases among the general population, recent data suggest stable and even declining incidence rates among certain pediatric populations. Studies have examined clinical features and presentations of melanoma among the pediatric population and the conventional ABCDE criteria (asymmetrical shape, border, color, diameter, evolving lesion) used to diagnosis adult melanoma may not be entirely appropriate for pediatric melanoma; as such, additional pediatric ABCD and CUP criteria (color changing, ulceration, pyogenic granuloma-like lesions) have been proposed. Dermoscopy serves as a valuable tool to detect suggestive patterns among pediatric skin lesions, and aids in the monitoring of skin lesions and detection of melanoma among children and adolescents. The etiology and pathogenesis of the pediatric melanoma is currently being investigated; studies have examined the genetic alterations that may be involved with the development of pediatric melanomas including TERT promoter, BRAF, and NRAS among others. While genetic testing using molecular techniques such as comparative genomic hybridization and fluorescence in-situ hybridization is helpful for diagnosis in certain contexts, molecular workup is not considered standard of care among pediatric melanoma cases, and in fact has not been proven to reliably distinguish between benign and malignant spitzoid tumors in children. Our growing understanding of melanoma has informed treatment decisions regarding management of positive sentinel lymph nodes, use of adjuvant therapy, and use of immunotherapy in treatment plans. PMID- 29485258 TI - Cutaneous squamous cell carcinoma and the emerging role of sentinel lymph node biopsy. AB - Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and is usually associated with a favorable prognosis in most patients. However, a small minority of patients will be diagnosed with a high-risk cSCC (HRcSCC) and a proportion will have a poor outcome, in some cases causing death. HRcSCC is characterized by an increase in aggressiveness manifested as local recurrence, the development of lymph node metastases, and occasionally death. The utility of sentinel lymph node biopsy (SLNB) in this group of patients is unclear without high-level evidence or clear-cut recommendations. If clinicians accept as a cut off threshold of a >10% of risk of harboring occult nodal metastasis, then selected HRcSCC patients may benefit from SLNB and/or additional investigations. Herein, we performed a review of the current evidence regarding SLNB in HRcSCC. We believe that SLNB may be considered in selected HRcSCC patients to potentially better predict prognosis and influence management. However larger prospective studies are needed to better define the subset of patients that may benefit from SLNB and if early detection of occult nodal metastases is associated with an improved outcome. PMID- 29485259 TI - Osteocraniosplenic Syndrome-Hypomineralized Skull with Gracile Long Bones and Splenic Hypoplasia: A Case Report and Literature Review. AB - Osteocraniosplenic syndrome-hypomineralized skull with gracile long bones and splenic hypoplasia: a case report and literature review: We report herein an intrauterine growth-restricted preterm nwonate with a lethal bone dysplasia characterized by severe hypomineralization of the skull, absent medullary lucency flared metaphyses fishbone-like diaphysis and overtubulated long vones. Dysmorphic features included flat facies, bulging forehead, vevus flammeus, depressed nasas bridge, short philtrum, inverted U-shape mouth, mild micrometic dwarfism, and brachydactyly. The infant's lungs and spleen were hypoplastic. The findings are compatible with the 19 previously reported cases that used different terminology: osteocraniostenosis, gracile bone disorders and osteocraniosplenic syndrome. We present the clinical, pathological and cytogenetic findings of this rare disorder. PMID- 29485260 TI - Meirer-Gorlin Syndrome: A Primordial Dwarfic Rare Case with Growth and Mental Retardation in Normal Karyotype. PMID- 29485261 TI - Anthracene-Based Organic Small-Molecule Electron-Injecting Material for Inverted Organic Light-Emitting Diodes. AB - A diphenylanthracene dimethylamine derivative (9-{3,5-di( N, N dimethylaminoethoxy)phenyl}-10-phenyl-anthracene, DPAMA) was synthesized by the Suzuki-Miyaura cross-coupling reaction. Its ammonium salt, 9-{3,5 di(trimethylammonium ethoxy)phenyl}-10-phenyl-anthracene dichloride (DPAMA-Cl), was also synthesized as a reference material. DPAMA was characterized by UV-vis and fluorescence spectroscopy, cyclic voltammetry, photoelectron yield spectroscopy, and X-ray photoelectron spectroscopy to evaluate the work function modifying ability of DPAMA on indium tin oxide (ITO) and ZnO. The work functions of ITO and ZnO changed from 4.4 and 4.0 eV (pristine) to 3.8 and 3.9 eV, respectively. Using this surface modification effect of DPAMA, inverted organic light-emitting diodes were fabricated with device structures of ITO/DPAMA/Alq3/NPD/MoO3/Al (Alq3 = tris(8-hydroxyquinolinato)aluminum; NPD = N, N'-di-[(1-naphthyl)- N, N'-diphenyl]-1,1'-(biphenyl)-4,4'-diamine) and ITO/ZnO/DPAMA/Alq3/NPD/MoO3/Al. Both devices showed good performance at the range of current density, 1-300 mA/cm2. The best inverted organic light-emitting diodes device showed luminance of 7720 cd/m2, current efficiency of 4.51 cd/A, and external quantum efficiency of 1.45%. Also, poly(3-hexylthiophene):mixed phenyl C61 and C71 butyric acid methyl ester-based organic solar cells using DPAMA and DPAMA-Cl as electron-transporting materials showed power conversion efficiencies of 3.3 and 3.4%, respectively. PMID- 29485262 TI - Polycrystalline and Mesoporous 3-D Bi2O3 Nanostructured Negatrodes for High Energy and Power-Asymmetric Supercapacitors: Superfast Room-Temperature Direct Wet Chemical Growth. AB - Superfast (<=10 min) room-temperature (300 K) chemical synthesis of three dimensional (3-D) polycrystalline and mesoporous bismuth(III) oxide (Bi2O3) nanostructured negatrode (as an abbreviation of negative electrode) materials, viz., coconut shell, marigold, honey nest cross section and rose with different surface areas, charge transfer resistances, and electrochemical performances essential for energy storage, harvesting, and even catalysis devices, are directly grown onto Ni foam without and with poly(ethylene glycol), ethylene glycol, and ammonium fluoride surfactants, respectively. Smaller diffusion lengths, caused by the involvement of irregular crevices, allow electrolyte ions to infiltrate deeply, increasing the utility of inner active sites for the following electrochemical performance. A marigold 3-D Bi2O3 electrode of 58 m2.g 1 surface area has demonstrated a specific capacitance of 447 F.g-1 at 2 A.g-1 and chemical stability of 85% even after 5000 redox cycles at 10 A.g-1 in a 6 M KOH electrolyte solution, which were higher than those of other morphology negatrode materials. An asymmetric supercapacitor (AS) device assembled with marigold Bi2O3 negatrode and manganese(II) carbonate quantum dots/nickel hydrogen manganese(II)-carbonate (MnCO3QDs/NiH-Mn-CO3) positrode corroborates as high as 51 Wh.kg-1 energy at 1500 W.kg-1 power and nearly 81% cycling stability even after 5000 cycles. The obtained results were comparable or superior to the values reported previously for other Bi2O3 morphologies. This AS assembly glowed a red light-emitting diode for 20 min, demonstrating the scientific and industrial credentials of the developed superfast Bi2O3 nanostructured negatrodes in assembling various energy storage devices. PMID- 29485263 TI - Bonding inside and outside Fullerene Cages. AB - Concrete crystallographic results of endohedral metallofullerenes (EMFs) disclose that the bonding within the metallic clusters and the interactions between the metal ions and the cage carbon atoms, which are closely associated with the coordination ability of the metal ions, play essential roles in determining the stability, the molecular structure, and the chemical behavior of the hybrid EMF molecules, in addition to the previously recognized charge transfer from metal to cage. For the carbide cluster metallofullerenes, a "size effect" between the encapsulated metallic cluster and the fullerene cage has been suggested. Thus, through the geometric effect, a series of giant fullerenes (C90-C104) have been stabilized by encapsulating a large La2C2 cluster, which adopts different configurations in accordance with cage size and shape. Interestingly, the crystallographic analysis of La2C2@ D5(450)-C100 has led to the direct observation of the axial compression of short carbon nanotubes caused by the internal stress. Additionally, the defective C2(816)-C104 cage is viewed to be a precursor that can transform into the other three ideal tubular fullerene cages, presenting crystallographic evidence for the top-down formation mechanism of fullerenes. Structural characterization of Y2C2@C108 confirms a linear carbide cluster inside the large cage, indicative of a geometric effect of cage size on the bonding behavior of the internal cluster. Apart from the carbide realm, direct metal-metal bonding is observed between the two seemingly repulsive Lu2+ ions in Lu2@C82-86, adding new insights into current coordination chemistry. Meanwhile, the bonding state between the metal ions inside the cage (e.g., in La2@ I h(7)-C80) and even the configuration of the internal metallic cluster (e.g., in Sc3C2@ I h(7)-C80) can be readily controlled by exohedral radical addition, illuminating their future applications as single molecule magnets and in electronics. In addition, observation of the unexpected dimerization between two paramagnetic Y@ Cs(6)-C82 molecules suggests a spin-induced bonding behavior, which depends closely on the cage geometry. In contrast, synergistic effect of both electronic and geometric parameters has led to the formation of the unprecedented [6,6,6]-Lewis acid-base adduct of Sc3N@ I h(7)-C80. However, introduction of an oxygen atom gives rise to the corresponding normal carbene adducts for both Sc3N@ I h(7)-C80 and Lu3N@ I h(7)-C80, presenting an unexpected way of steric hindrance release. Remarkably, the Lewis acid-base complexation is demonstrated to be a facile way toward isomerically pure metallofullerene derivatives with surprisingly high regioselectivity and quantitative conversion yield for Sc2C2@ C3 v(8)-C82. This Account aims to give an advanced summary of the recent achievements in research of EMFs, focusing mainly on the interplay between the internal metallic species and the surrounding cages through bond formation or cleavage. Perspectives suggesting the future developments of EMFs are also given in the last section. PMID- 29485265 TI - Nanohybrid of Carbon Quantum Dots/Molybdenum Phosphide Nanoparticle for Efficient Electrochemical Hydrogen Evolution in Alkaline Medium. AB - The exploration of highly efficient non-noble metal electrocatalysts for hydrogen evolution reaction (HER) under alkaline conditions is highly imperative but still remains a great challenge. In this work, the nanohybrid of carbon quantum dots and molybdenum phosphide nanoparticle (CQDs/MoP) has been firstly demonstrated as an efficient alkaline HER electrocatalyst. The CQDs/MoP nanohybrid is readily prepared through a charge-directed self-assembly of CQDs with phosphomolybdic acid (H3PMo12O40) at the molecular level, followed by facile phosphatizing at 700 degrees C. The introduction of CQDs greatly helps to alleviate the agglomeration and surface oxidation of MoP nanoparticles and ensures each MoP nanoparticle to be electronically addressed, thus significantly enhancing the intrinsic catalytic activity of MoP. The optimized CQDs/MoP exhibits high-efficiency synergistic catalysis toward HER in 1 M KOH electrolyte with a low onset potential of -0.08 V and a small Tafel slope of 56 mV dec-1 as well as high durability with negligible current loss for at least 24 h. PMID- 29485264 TI - Kinetic Evidence for a Second Ligand Binding Site on Streptococcus pneumoniae Penicillin-Binding Protein 2x. AB - High molecular mass penicillin-binding proteins (PBPs, DD-peptidases) of class B, such as Streptococcus pneumoniae PBP2x, catalyze the cross-linking of peptidoglycan in bacterial cell wall biosynthesis and are thus important antibiotic targets. Despite their importance in this regard, structure-function studies of ligands of these enzymes have been impeded by the absence of useful substrates. In vitro, these enzymes do not catalyze peptide hydrolysis or aminolysis, their in vivo reaction, but some, such as PBP2x, do catalyze these reactions of certain thioesters such as PhCH2CONHCH2COSCH(D-Me)CO2- (2). We have now prepared several peptidoglycan-mimetic thioesters that we expected to more closely resemble the natural substrates of these enzymes. To our surprise, however, these compounds, although indeed substrates of PBP2x, did not, unlike 2, appear to form an acyl-enzyme intermediate during hydrolysis, and their turnover was inhibited by certain peptides and N-acylamino acids much more weakly than that of 2. An inhibitor of this type, N-benzyloxycarbonyl-d-glutamic acid, also quenched the fluorescence of PBP2x that had been labeled at the DD-peptidase active site by 6-dansylamidopenicillanic acid. These results were interpreted in terms of a model where the peptidoglycan-mimetic thioesters preferentially bound to and hydrolyzed at a site other than the classical DD-peptidase active site. This second site is likely to represent part of an extended binding site that accommodates a peptidoglycan substrate or regulator in vivo. Such a site may be a target for future inhibitor/antibiotic design. PMID- 29485266 TI - Highly Efficient Bifacial Dye-Sensitized Solar Cells Employing Polymeric Counter Electrodes. AB - Dye-sensitized solar cells (DSCs) are promising solar energy conversion devices with aesthetically favorable properties such as being colorful and having transparent features. They are also well-known for high and reliable performance even under ambient lighting, and these advantages distinguish DSCs for applications in window-type building-integrated photovoltaics (BIPVs) that utilize photons from both lamplight and sunlight. Therefore, investigations on bifacial DSCs have been done intensively, but further enhancement in performance under back-illumination is essential for practical window-BIPV applications. In this research, highly efficient bifacial DSCs were prepared by a combination of electropolymerized poly(3,4-ethylenedioxythiphene) (PEDOT) counter electrodes (CEs) and cobalt bipyridine redox ([Co(bpy)3]3+/2+) electrolyte, both of which manifested superior transparency when compared with conventional Pt and iodide counterparts, respectively. Keen electrochemical analyses of PEDOT films verified that superior electrical properties were achievable when the thickness of the film was reduced, while their high electrocatalytic activities were unchanged. The combination of the PEDOT thin film and [Co(bpy)3]3+/2+ electrolyte led to an unprecedented power conversion efficiency among bifacial DSCs under back illumination, which was also over 85% of that obtained under front-illumination. Furthermore, the advantage of the electropolymerization process, which does not require an elevation of temperature, was demonstrated by flexible bifacial DSC applications. PMID- 29485267 TI - Corrections to "Combined Effects of UV Exposure Duration and Mechanical Abrasion on Microplastic Fragmentation by Polymer Type". PMID- 29485268 TI - Binding Mode Characterization and Early in Vivo Evaluation of Fragment-Like Thiols as Inhibitors of the Virulence Factor LasB from Pseudomonas aeruginosa. AB - The increasing emergence of antibiotic resistance necessitates the development of anti-infectives with novel modes of action. Targeting bacterial virulence is considered a promising approach to develop novel antibiotics with reduced selection pressure. The extracellular collagenase elastase (LasB) plays a pivotal role in the infection process of Pseudomonas aeruginosa and therefore represents an attractive antivirulence target. Mercaptoacetamide-based thiols have been reported to inhibit LasB as well as collagenases from clostridia and bacillus species. The present work provides an insight into the structure-activity relationship (SAR) of these fragment-like LasB inhibitors, demonstrating an inverse activity profile compared to similar inhibitors of clostridial collagenase H (ColH). An X-ray cocrystal structure is presented, revealing distinct binding of two compounds to the active site of LasB, which unexpectedly maintains an open conformation. We further demonstrate in vivo efficacy in a Galleria mellonella infection model and high selectivity of the LasB inhibitors toward human matrix metalloproteinases (MMPs). PMID- 29485269 TI - Two-Dimensionally Layered p-Black Phosphorus/n-MoS2/p-Black Phosphorus Heterojunctions. AB - Layered heterojunctions are widely applied as fundamental building blocks for semiconductor devices. For the construction of nanoelectronic and nanophotonic devices, the implementation of two-dimensional materials (2DMs) is essential. However, studies of junction devices composed of 2DMs are still largely focused on single p-n junction devices. In this study, we demonstrate a novel pnp double heterojunction fabricated by the vertical stacking of 2DMs (black phosphorus (BP) and MoS2) using dry-transfer techniques and the formation of high-quality p-n heterojunctions between the BP and MoS2 in the vertically stacked BP/MoS2/BP structure. The pnp double heterojunctions allowed us to modulate the output currents by controlling the input current. These results can be applied for the fabrication of advanced heterojunction devices composed of 2DMs for nano(opto)electronics. PMID- 29485270 TI - Biomimetic Silk Scaffolds with an Amorphous Structure for Soft Tissue Engineering. AB - Fine tuning physical cues of silk fibroin (SF) biomaterials to match specific requirements for different soft tissues would be advantageous. Here, amorphous SF nanofibers were used to fabricate scaffolds with better hierarchical extracellular matrix (ECM) mimetic microstructures than previous silk scaffolds. Kinetic control was introduced into the scaffold forming process, resulting in the direct production of water-stable scaffolds with tunable secondary structures and thus mechanical properties. These biomaterials remained with amorphous structures, offering softer properties than prior scaffolds. The fine mechanical tunability of these systems provides a feasible way to optimize physical cues for improved cell proliferation and enhanced neovascularization in vivo. Multiple physical cues, such as partly ECM mimetic structures and optimized stiffness, provided suitable microenvironments for tissue ingrowth, suggesting the possibility of actively designing bioactive SF biomaterials. These systems suggest a promising strategy to develop novel SF biomaterials for soft tissue repair and regenerative medicine. PMID- 29485271 TI - Antibacterial Drug Discovery: Some Assembly Required. AB - Our limited understanding of the molecular basis for compound entry into and efflux out of Gram-negative bacteria is now recognized as a key bottleneck for the rational discovery of novel antibacterial compounds. Traditional, large-scale biochemical or target-agnostic phenotypic antibacterial screening efforts have, as a result, not been very fruitful. A main driver of this knowledge gap has been the historical lack of predictive cellular assays, tools, and models that provide structure-activity relationships to inform optimization of compound accumulation. A variety of recent approaches has recently been described to address this conundrum. This Perspective explores these approaches and considers ways in which their integration could successfully redirect antibacterial drug discovery efforts. PMID- 29485272 TI - Site-Specific Growth and in Situ Integration of Different Nanowire Material Networks on a Single Chip: Toward a Nanowire-Based Electronic Nose for Gas Detection. AB - A new method for the site-selective synthesis of nanowires has been developed to enable material growth with defined morphology and, at the same time, different composition on the same chip surface. The chemical vapor deposition approach for the growth of these nanowire-based resistive devices using micromembranes can be easily modified and represents a simple, adjustable fabrication process for the direct integration of nanowire meshes in multifunctional devices. This proof-of concept study includes the deposition of SnO2, WO3, and Ge nanowires on the same chip. The individual resistors exhibit adequate gas sensing responses toward changing gas concentrations of CO, NO2, and humidity diluted in synthetic air. The data have been processed by principal component analysis with cluster responses that can be easily separated, and thus, the devices described herein are in principle suitable for environmental monitoring. PMID- 29485274 TI - Exploring the Capacity Limit: A Layered Hexacarboxylate-Based Metal-Organic Framework for Advanced Lithium Storage. AB - Our previous work suggested that more carboxylate groups might lead to higher energy density for metal-organic frameworks. In this study, we synthesized a layered metal-organic framework (MOF) Ni-BHC by use of 1,2,3,4,5,6 benzenehexacarboxylic acid. After evacuation by thermal treatment, this MOF was employed as an anode for lithium storage. For its rich lithiation sites as well as layered fast-kinetics structure, it delivers a superior reversible capacity of 1261.3 mA h g-1 at 100 mA g-1, far exceeding the performance of previously reported MOF-based anode materials. Density functional theory calculation and O soft X-ray absorption spectroscopy suggest that the luxuriant carboxylate-metal units play an important part in the electrochemical process. PMID- 29485273 TI - Asymmetric Induction via a Helically Chiral Anion: Enantioselective Pentacarboxycyclopentadiene Bronsted Acid-Catalyzed Inverse-Electron-Demand Diels Alder Cycloaddition of Oxocarbenium Ions. AB - An enantioselective catalytic inverse-electron-demand Diels-Alder reaction of salicylaldehyde acetal-derived oxocarbenium ions and vinyl ethers to generate 2,4 dioxychromanes is described. Chiral pentacarboxycyclopentadiene (PCCP) acids are found to be effective for a variety of substrates. Computational and X-ray crystallographic analyses support the unique hypothesis that an anion with point chirality-induced helical chirality dictates the absolute sense of stereochemistry in this reaction. PMID- 29485275 TI - Smart SERS Hot Spots: Single Molecules Can Be Positioned in a Plasmonic Nanojunction Using Host-Guest Chemistry. AB - Single-molecule surface-enhanced Raman spectroscopy (SERS) offers new opportunities for exploring the complex chemical and biological processes that cannot be easily probed using ensemble techniques. However, the ability to place the single molecule of interest reliably within a hot spot, to enable its analysis at the single-molecule level, remains challenging. Here we describe a novel strategy for locating and securing a single target analyte in a SERS hot spot at a plasmonic nanojunction. The "smart" hot spot was generated by employing a thiol-functionalized cucurbit[6]uril (CB[6]) as a molecular spacer linking a silver nanoparticle to a metal substrate. This approach also permits one to study molecules chemically reluctant to enter the hot spot, by conjugating them to a moiety, such as spermine, that has a high affinity for CB[6]. The hot spot can accommodate at most a few, and often only a single, analyte molecule. Bianalyte experiments revealed that one can reproducibly treat the SERS substrate such that 96% of the hot spots contain a single analyte molecule. Furthermore, by utilizing a series of molecules each consisting of spermine bound to perylene bisimide, a bright SERS molecule, with polymethylene linkers of varying lengths, the SERS intensity as a function of distance from the center of the hot spot could be measured. The SERS enhancement was found to decrease as 1 over the square of the distance from the center of the hot spot, and the single-molecule SERS cross sections were found to increase with AgNP diameter. PMID- 29485276 TI - Lichen Biosynthetic Gene Clusters. Part I. Genome Sequencing Reveals a Rich Biosynthetic Potential. AB - Lichens are symbionts of fungi and algae that produce diverse secondary metabolites with useful properties. Little is known of lichen natural product biosynthesis because of the challenges of working with lichenizing fungi. We describe the first attempt to comprehensively profile the genetic secondary metabolome of a lichenizing fungus. An Illumina platform combined with the Antibiotics and Secondary Metabolites Analysis Shell (FungiSMASH, version 4.0) was used to sequence and annotate assembled contigs of the fungal partner of Cladonia uncialis. Up to 48 putative gene clusters are described comprising type I and type III polyketide synthases (PKS), nonribosomal peptide synthetases (NRPS), hybrid PKS-NRPS, and terpene synthases. The number of gene clusters revealed by this work dwarfs the number of known secondary metabolites from C. uncialis, suggesting that lichenizing fungi have an unexplored biosynthetic potential. PMID- 29485277 TI - Chemoselective Hydrogenation with Supported Organoplatinum(IV) Catalyst on Zn(II) Modified Silica. AB - Well-defined organoplatinum(IV) sites were grafted on a Zn(II)-modified SiO2 support via surface organometallic chemistry in toluene at room temperature. Solid-state spectroscopies including XAS, DRIFTS, DRUV-vis, and solid-state (SS) NMR enhanced by dynamic nuclear polarization (DNP), as well as TPR-H2 and TEM techniques revealed highly dispersed (methylcyclopentadienyl)methylplatinum(IV) sites on the surface ((MeCp)PtMe/Zn/SiO2, 1). In addition, computational modeling suggests that the surface reaction of (MeCp)PtMe3 with Zn(II)-modified SiO2 support is thermodynamically favorable (Delta G = -12.4 kcal/mol), likely due to the increased acidity of the hydroxyl group, as indicated by NH3-TPD and DNP enhanced 17O{1H} SSNMR. In situ DRIFTS and XAS hydrogenation experiments reveal the probable formation of a surface Pt(IV)-H upon hydrogenolysis of Pt-Me groups. The heterogenized organoplatinum(IV)-hydride sites catalyze the selective partial hydrogenation of 1,3-butadiene to butenes (up to 95%) and the reduction of nitrobenzene derivatives to anilines (up to 99%) with excellent tolerance of reduction-sensitive functional groups (olefin, carbonyl, nitrile, halogens) under mild reaction conditions. PMID- 29485278 TI - Excitation Energy Transfer Supported Amplified Charge-Transfer Emission in an Anthracenedicarboxylate- and Bipyridophenazine-Based Coordination Complex. AB - A highly luminescent tetrameric zinc(II) complex, {[Zn4(adc)3(bpz)6(HCOO)2].2H2O} (1; adc = 9,10-anthracenedicarboxylate and bpz = bipyridophenazine), was synthesized by a solvothermal technique and characterized by single-crystal X-ray diffraction. The linear tetrameric units extend into three dimensions via pi stacking of adc/bpz and bpz/bpz and multiple CH-pi interactions. The compound shows strong red emission at 597 nm (lambdaex = 480 nm), which is attributed to charge-transfer (CT) emission within an adc/bpz donor-acceptor pair. This is also supported by density functional theory computations. Interestingly, the CT emission is amplified by energy transfer from another adc linker that is not involved in the CT interaction. PMID- 29485279 TI - Development and Validation of a Hybrid Screening and Quantitative Method for the Analysis of Eight Classes of Therapeutants in Aquaculture Products by Liquid Chromatography-Tandem Mass Spectrometry. AB - A method using reverse-phase ultra-high-performance liquid chromatography coupled with tandem mass spectrometry is described for eight classes of therapeutants that are used in marine aquaculture products. Validation studies to evaluate recovery, precision, method detection limits, and measurement uncertainty were performed at three levels, using three representative matrices [salmon (fatty fish), tilapia (lean fish), and shrimp (crustaceans)] to assess the method performance for use as a screening or determinative (quantitative and confirmatory) method. A total of 16 sulfonamides (plus 2 potentiators), 2 tetracyclines, 11 (fluoro)quinolones, 7 nitroimidazoles, 3 amphenicols, 5 steroids, and 3 stilbenes met the quantitative criteria for method validation. An additional 5 triphenylmethane dyes, 2 sulfonamides, 2 tetracyclines, and 1 amphenicol met the required performance for use as a screening method. Limits of detection (LODs) for the compounds that met the quantitative criteria ranged from 0.1 to 5 MUg/kg, while LODs for compounds from the screening group ranged from 0.1 to 30 MUg/kg. This method provides a comprehensive approach to the determination of different classes of compounds in aquaculture products. PMID- 29485280 TI - Development of an Analytical Method for Analyzing Pyrrolizidine Alkaloids in Different Groups of Food by UPLC-MS/MS. AB - Suspected nontargeted pyrrolizidine alkaloids (PAs), without analytical reference standard, were observed and interfered with the determination of targeted PAs in complex food matrices, especially for spices samples. Selectivity and applicability of multiple reaction monitoring (MRM) transitions, multistage fragmentation (MS3), and MRM with differential ion mobility spectrometry (DMS) for eliminating false positive identifications were evaluated. Afterward, a selective and sensitive LC-MS/MS method for the determination of 15 PAs and 13 PA N-oxides in foodstuffs was developed. The sample preparation and cleanup are applicable to a wide range of foodstuffs, including cereal products, dairy products, meat, eggs, honey, tea infusion, and spices. Freezing-out of the raw extract and the water/acetonitrile washing steps in a solid phase extraction was found to efficiently remove complex matrices. The method was validated at 0.05 MUg kg-1 for general food and 0.5 MUg kg-1 for spices, with reference to the Eurachem Guide. The estimated limit of quantifications of different PAs was in the range of 0.010-0.087 MUg kg-1 for general food and 0.04-0.76 MUg kg-1 for spices. Isotopically labeled PAs were used as internal standards to correct the variation of PAs/PANs performance in different food commodities. Matrix effects observed in complex food matrices could be reduced by solvent dilution. Recoveries of PAs and PA N-oxides were all seen within 50-120%. PMID- 29485281 TI - Gas Chromatography-Mass Spectrometry-Olfactometry To Control the Aroma Fingerprint of Extra Virgin Olive Oil from Three Tunisian Cultivars at Three Harvest Times. AB - Gas chromatography-mass spectrometry-olfactometry was used for the analysis of volatile compounds and key odorants of three less studied Tunisian olive oil cultivars for the first time. A total of 42 aroma compounds were identified and quantified in extra virgin olive oils. The present study revealed that the most dominant volatiles in olive oil samples qualitatively and quantitatively were aldehydes and alcohols, followed by terpenes and esters. Indeed, chemometric analysis has shown a correlation between chemical compounds and sensory properties. The determination of aroma-active compounds of olive oil samples was carried out using aroma extract dilution analysis. A total of 15 aroma-active compounds were detected in the aromatic extract of extra virgin olive oil, of which 14 were identified. On the basis of the flavor dilution (FD) factor, the most potent aromatic active compound was hexanal (FD = 512) in Fakhari olive oil, (FD = 256) in Touffehi oils, and (FD = 128) in Jemri olive oil. PMID- 29485282 TI - Lichen Biosynthetic Gene Clusters Part II: Homology Mapping Suggests a Functional Diversity. AB - Lichens are renowned for their diverse natural products though little is known of the genetic programming dictating lichen natural product biosynthesis. We sequenced the genome of Cladonia uncialis and profiled its secondary metabolite biosynthetic gene clusters. Through a homology searching approach, we can now propose specific functions for gene products as well as the biosynthetic pathways that are encoded in several of these gene clusters. This analysis revealed that the lichen genome encodes the required enzymes for patulin and betaenones A-C biosynthesis, fungal toxins not known to be produced by lichens. Within several gene clusters, some (but not all) genes are genetically similar to genes devoted to secondary metabolite biosynthesis in Fungi. These lichen clusters also contain accessory tailoring genes without such genetic similarity, suggesting that the encoded tailoring enzymes perform distinct chemical transformations. We hypothesize that C. uncialis gene clusters have evolved by shuffling components of ancestral fungal clusters to create new series of chemical steps, leading to the production of hitherto undiscovered derivatives of fungal secondary metabolites. PMID- 29485283 TI - Histone Deacetylase Inhibitor (HDACi) Conjugated Polycaprolactone for Combination Cancer Therapy. AB - The short chain fatty acid, 4-phenylbutyric acid (PBA), is used for the treatment of urea cycle disorders and sickle cell disease as an endoplasmic reticulum stress inhibitor. PBA is also known as a histone deacetylase inhibitor (HDACi). We report here the effect of combination therapy on HeLa cancer cells using PBA as the HDACi together with the anticancer drug, doxorubicin (DOX). We synthesized gamma-4-phenylbutyrate-epsilon-caprolactone monomer which was polymerized to form poly(gamma-4-phenylbutyrate-epsilon-caprolactone) (PPBCL) homopolymer using NdCl3.3TEP/TIBA (TEP = triethyl phosphate, TIBA = triisobutylaluminum) catalytic system. DOX-loaded nanoparticles were prepared from the PPBCL homopolymer using poly(ethylene glycol) as a surfactant. An encapsulation efficiency as high as 88% was obtained for these nanoparticles. The DOX-loaded nanoparticles showed a cumulative release of >95% of DOX at pH 5 and 37 degrees C within 12 h, and PBA release was monitored by 1H NMR spectroscopy. The efficiency of the combination therapy can notably be seen in the cytotoxicity study carried out on HeLa cells, where only ~20% of cell viability was observed after treatment with the DOX loaded nanoparticles. This drastic cytotoxic effect on HeLa cells is the result of the dual action of DOX and PBA on the DNA strands and the HDAC enzymes, respectively. Overall, this study shows the potential of combination treatment with HDACi and DOX anticancer drug as compared to the treatment with an anticancer drug alone. PMID- 29485284 TI - Carbon Nanotube Strain Sensor Based Hemoretractometer for Blood Coagulation Testing. AB - Coagulation monitoring is essential for perioperative care and thrombosis treatment. However, existing assays for coagulation monitoring have limitations such as a large footprint and complex setup. In this work, we developed a miniaturized device for point-of-care blood coagulation testing by measuring dynamic clot retraction force development during blood clotting. In this device, a blood drop was localized between a protrusion and a flexible force-sensing beam to measure clot retraction force. The beam was featured with micropillar arrays to assist the deposition of carbon nanotube films, which served as a strain sensor to achieve label-free electrical readout of clot retraction force in real time. We characterized mechanical and electrical properties of the force-sensing beam and optimized its design. We further demonstrated that this blood coagulation monitoring device could obtain results that were consistent with those using an imaging method and that the device was capable of differentiating blood samples with different coagulation profiles. Owing to its low fabrication cost, small size, and low consumption of blood samples, the blood coagulation testing device using carbon nanotube strain sensors holds great potential as a point-of-care tool for future coagulation monitoring. PMID- 29485285 TI - An Ultrahigh-Performance Liquid Chromatography-Time-of-Flight Mass Spectrometry Metabolomic Approach to Studying the Impact of Moderate Red-Wine Consumption on Urinary Metabolome. AB - Moderate red-wine consumption has been widely described to exert several benefits in human health. This is mainly due to its unique content of bioactive polyphenols, which suffer several modifications along their pass through the digestive system, including microbial transformation in the colon and phase-II metabolism, until they are finally excreted in urine and feces. To determine the impact of moderate wine consumption in the overall urinary metabolome of healthy volunteers ( n = 41), samples from a red-wine interventional study (250 mL/day, 28 days) were investigated. Urine (24 h) was collected before and after intervention and analyzed by an untargeted ultrahigh-performance liquid chromatography-time-of-flight mass spectrometry metabolomics approach. 94 compounds linked to wine consumption, including specific wine components (tartaric acid), microbial-derived phenolic metabolites (5-(dihydroxyphenyl) gamma-valerolactones and 4-hydroxyl-5-(phenyl)-valeric acids), and endogenous compounds were identified. Also, some relationships between parallel fecal and urinary metabolomes are discussed. PMID- 29485286 TI - Volatile Compounds Related to 'Stone Fruit' Aroma Attributes in Viognier and Chardonnay Wines. AB - A 'stone fruit' aroma is important in many white wine varieties and styles, but little is known about the chemical basis of this wine aroma attribute. A set of Viognier and Chardonnay wines that featured 'stone fruit' aroma attributes were selected by a panel of wine experts. The selected wines were characterized by sensory descriptive analysis and detailed volatile chemical composition analyses. This comprehensive data also allowed Viognier wine to be profiled for the first time. By partial least-squares regression, several esters and fatty acids and benzaldehyde were indicated as contributing to the 'peach' attribute; however, a reconstitution sensory study was unsuccessful in mimicking this attribute. A mixture of gamma-lactones, monoterpenes, and aldehydes were positively correlated to the 'apricot' aroma, which were generally higher in the Viognier wines. Reconstitution studies confirmed that the monoterpenes linalool, geraniol, and nerol were the most important compounds for the mixture being perceived as having an 'apricot' aroma. PMID- 29485287 TI - Optical Humidity Sensing Using Transparent Hybrid Film Composed of Cationic Magnesium Porphyrin and Clay Mineral. AB - A transparent hybrid film composed of cationic magnesium porphyrin and clay mineral was developed, and its chromic behavior depending on relative humidity (RH) was investigated. The hybrid film was obtained via intercalation of magnesium porphyrin into clay film; magnesium porphyrin was intercalated into the interlayer spaces of the clay mineral without aggregation. The absorption spectra of the hybrid film showed red shifts compared to the aqueous solution of magnesium porphyrin because of the pi-conjugated system extension with coplanarization of the meso-substituted pyridinium group and porphyrin ring. The absorption maximum of the hybrid film was gradually shifted to a shorter wavelength, and the color of the hybrid film was changed with increasing RH. The X-ray diffraction measurement suggested that the basal space of clay was expanded with increasing RH, indicating that the interlayer space of clay was expanded by water adsorption, and the spectral shift was induced by the change in coplanarization degree between the porphyrin ring and meso-substituted pyridinium groups. PMID- 29485288 TI - Student Cyberloafing In and Out of the Classroom in China and the Relationship with Student Performance. AB - This study investigates the in-class and out-of-class cyberloafing activities of students in China, and tests the relationship between those activities and academic performance. A sample of 1,050 undergraduate students at a large University in China reported their in-class (N = 548) and out-of-class (N = 502) cyberloafing activities, which were tested against the students' academic performance. The test results show a negative relationship between in-class cyberloafing and academic performance, but an inverted U-shaped relationship between out-of-class cyberloafing and academic performance. The results support our propositions that cyberloafing is a harmful distraction in the classroom, but can have positive effects when performed in moderation outside the classroom as a means of effort recovery. PMID- 29485289 TI - Community treatment orders increase community care and delay readmission while in force: Results from a large population-based study. AB - OBJECTIVE: There is debate about the effectiveness of community treatment orders in the management of people with a severe mental illness. While some case-control studies suggest community treatment orders reduce hospital readmissions, three randomised controlled trials find no effects. These randomised controlled trials measure outcomes over a longer period than the community treatment order duration and assess the combined effectiveness of community treatment orders both during and after the intervention. This study examines the effectiveness of community treatment orders in a large population-based sample, restricting observation to the period under a community treatment order. METHODS: All persons ( n = 5548) receiving a community treatment order in New South Wales, Australia, over the period 2004-2009 were identified. Controls were matched using a propensity score based on demographic, clinical and prior care variables. A baseline period equal to each case's duration of treatment was constructed. Treatment effects were compared using zero-inflated negative binomial regression, adjusting for demographics, clinical characteristics and pre-community treatment order care. RESULTS: Compared to matched controls, people on community treatment orders were less likely to be readmitted (odds ratio = 0.90, 95% confidence interval = [0.84, 0.97]) and had a significantly longer time to their first readmission (incidence rate ratio = 1.47, 95% confidence interval = [1.36, 1.58]), fewer hospital admissions (incidence rate ratio = 0.90, 95% confidence interval = [0.84, 0.96]) and more days of community care (incidence rate ratio = 1.55, 95% confidence interval = [1.51, 1.59]). Increased community care and delayed first admission were found for all durations of community treatment order care. Reduced odds of readmission were limited to people with 6 months or less of community treatment order care, and reduced number of admissions and days in hospital to people with prolonged (>24 months) community treatment order care. CONCLUSION: In this large population-based study, community treatment orders increase community care and delay rehospitalisation while they are in operation. Some negative findings in this field may reflect the use of observation periods longer than the period of active intervention. PMID- 29485290 TI - Concussion history is negatively associated with visual-motor force complexity: evidence for persistent effects on visual-motor integration. AB - OBJECTIVES: Long-term monitoring of concussion recovery requires time- and cost effective methods. Physiologic complexity may be useful in evaluating visual motor integration following concussion. The purpose of this study was to quantify the extent to which prior number of concussions influenced visual-motor tracking force complexity. METHODS: Thirty-five individuals with a self-reported concussion history (age: 20.92 +/- 1.98) and 15 without (age: 20.92 +/- 2.21) performed an isometric visual-motor tracking task, using index finger force to trace a straight line across a computer screen. Finger force root mean square error (RMSE), multi-scale complexity, and average power from 0 to 12 Hertz (Hz) were calculated. Individual multiple regressions were fit to these outcomes. RESULTS: Force complexity decreased linearly with an increasing number of concussions (R2 = 0.101). Males had more complex force overall (R2 = 0.219) and greater 4-8 Hz average power (R2 = 0.193). The 8-12 Hz average power decreased significantly for individuals with prior loss of consciousness (LOC) and increasing numbers of concussions (R2 = 0.143). CONCLUSION: Individuals exhibited linear decreases in visual-motor tracking force complexity with increasing numbers of concussions, influenced by both gender and a history of LOC. These findings indicate cumulative changes in the ways in which previously concussed individuals process and integrate visual information to guide behaviour. PMID- 29485292 TI - Combination of Vaccine-Strain Measles and Mumps Viruses Enhances Oncolytic Activity against Human Solid Malignancies. AB - Oncolytic measles and mumps viruses (MeV, MuV) have a potential for anti-cancer treatment. We examined the anti-tumor activity of MeV, MuV, and MeV-MuV combination (MM) against human solid malignancies (HSM). MeV, MuV, and MM targeted and significantly killed various cancer cell lines of HSM but not normal cells. MM demonstrated a greater anti-tumor effect and prolonged survival in a human prostate cancer xenograft tumor model compared to MeV and MuV. MeV, MuV, and MM significantly induced the expression of immunogenic cell death markers and enhanced spleen-infiltrating immune cells. In conclusion, MM combination significantly improves the treatment of human solid malignancies. PMID- 29485291 TI - Differences Between Men and Women in Balance and Tremor in Relation to Plantar Fascia Laxity During the Menstrual Cycle. AB - CONTEXT: Although much attention has been paid to the effect of estrogen on the knee ligaments, little has been done to examine the ligaments in the foot, such as the plantar fascia, and how they may be altered during the menstrual cycle. OBJECTIVE: To (1) examine sex differences in plantar fascia thickness and laxity and postural sway and (2) identify any menstrual cycle effects on plantar fascia laxity, postural sway, and neuromuscular tremor between menstruation and the ovulation phase. DESIGN: Case-control study. SETTING: Research laboratory. PATIENTS OR OTHER PARTICIPANTS: Fifteen healthy women (age = 25.9 +/- 1.8 years) and 15 healthy men (age = 27.3 +/- 2.0 years) volunteered to participate in this study. INTERVENTION(S): We asked participants to perform 8 balance tasks on a force platform while we assessed postural sway and tremor. MAIN OUTCOME MEASURE(S): Plantar fascia length and thickness unloaded and loaded with body weight were measured via ultrasound. Postural sway and tremor were measured using a force platform. RESULTS: Plantar fascia length and thickness with pressure were greater in ovulating women compared with men ( P < .001), but no differences were found between women during menstruation and men. Postural sway and tremor were greater at ovulation than during menstruation ( P < .05), and men had less sway than ovulating women on the 3 most difficult balance tasks ( P < .01). CONCLUSIONS: Plantar fascia laxity was increased and postural sway and tremor were decreased at ovulation compared with menstruation in women. Postural sway and tremor in men were the same as in women during menstruation. These findings support the need to be aware of the effect of sex hormones on balance to prevent lower extremity injuries during sport activities. PMID- 29485293 TI - A Time to Live and a Time to Die: Heterotopian Spatialities and Temporalities in a Pediatric Palliative Care Team. AB - The death of a child creates especially poignant feelings and extreme stress, distress, and devastation for family members and healthcare providers. In addition, serious or long-term illness forces a reconstruction of our experiences with time and space. In this paper, we report on a long-term ethnographic study of a Pediatric Palliative Care Team (PPCT). Using the concepts of spatiality and temporality; Deleuze's concepts of smooth and striated spaces; Innis's concepts of space and time biases; Foucault's concept of heterotopian space-places with multiple layers of meaning; and a related concept of heterokairoi-moments in time with multiple possibilities-we consider how the PPCT constructs and reconstructs meaning in the midst of chaos, ethical dilemmas, and heartbreaking choices. PMID- 29485294 TI - Delayed intracranial hemorrhage in the patient with blunt trauma on anticoagulant or antiplatelet agents: routine repeat head computed tomography is unnecessary. AB - OBJECTIVE: We postulate that in patients with blunt trauma on anticoagulant or antiplatelet agents, incidence and complication rate of delayed intracranial hemorrhage (DICH) after an initially negative head CT is low and routine repeat head CT is not warranted. DESIGN: A retrospective, observational study performed from 2008 to 2012. PATIENTS: A total of 338 patients with blunt trauma with pre admission history of any anticoagulant use, who had an initially negative head CT, followed by a repeat CT within 48 hours. INTERVENTIONS: There were no interventions, this was an observational study only. MEASUREMENTS AND MAIN RESULTS: The sample had mean ISS of 8.6 and an average GCS of 15. 55% had obvious head trauma, 27.2% reported LOC. Incidence of DICH was 2.4% (8/338). All patients with DICH were taking aspirin (ASA) either alone or in combination with another anticoagulant. Of the eight patients with DICH, none required medical or surgical intervention and there were no mortalities. We identified no significant predictors of delayed ICH. CONCLUSIONS: Routine repeat head CT in patients with blunt trauma taking anticoagulant or antiplatelet agents is unnecessary. Incidence of DICH is low and, when found, DICH was clinically insignificant. We recommend close supervision in this population, especially those taking ASA alone or in combination with another anticoagulant. PMID- 29485295 TI - "Five-layer gasket seal" watertight closure for reconstruction of the skull base in complex bilateral traumatic intraorbital meningoencephaloceles: a case report and literature review. AB - PURPOSE: Traumatic meningoencephalocele primarily occurs as a rare but complex complication of cranial base and orbital roof fractures. Traumatic intraorbital meningoencephalocele, which is rare and easily overlooked, can be life threatening since cephalomeningitis occurs due to cerebrospinal fluid (CSF) leakage. It is obscure for the operative indications or standard surgical methods of traumatic meningoencephaloceles since the combined intricate craniofacial and basal fractures, brain injury, and CSF leak may exist. This case report proposes a new operative method for the repair of complex skull base fractures following traumatic intraorbital meningoencephalocele. METHODS: A 30-year-old male with a history of complex trauma presented with symptoms of exophthalmos and traumatic CSF rhinorrhea was evaluated via 3D CT of the skull base and brain MRI and was diagnosed with bilateral intraorbital meningoencephaloceles and multiple craniofacial bone, skull base, and orbit fractures. RESULTS: Successful resection of the meningoencephaloceles and reconstruction of the skull base defects were performed via craniotomy using a "five-layer gasket seal" technique that involved, from extracranial to intracranial, a gelatin sponge, muscular paste, vascularized periosteum, RapidSorb Orbital Floor Plate (OrbFloor), and Neuro Patch layers. CONCLUSIONS: The diagnosis and treatment of complex intraorbital meningoencephalocele require careful attention. Resection of herniated tissue is suggested due to potential contamination. The "five-layer gasket seal" watertight closure technique is recommended for successful repair of the skull base in cases involving traumatic meningoencephalocele with complex skull base fractures. PMID- 29485296 TI - Facilitation or Hindrance: Physicians' Perception on Best Practice Alerts (BPA) Usage in an Electronic Health Record System. AB - A qualitative study was conducted to examine physicians' perception on best practice alerts (BPAs) usage under the theoretical framework of technology acceptance model (TAM). In particular, 20 face-to-face in-depth interviews were conducted from September 2016 to February 2017 to collect data. Four themes emerged from the current set of data: support, de-escalation, management, and enhancement are physicians' perceived motivations of using BPAs; interactivity, timing, and interface design are key factors that influence physicians' perceived experiences of using BPAs; alert fatigue and inaccurate alters are major challenges and issues faced by physicians when using BPAs; and, control and team approach are physicians' perceptions on the future improvement of BPAs. This study not only offers a detailed description of physicians' perception of BPAs, revealing the rich meanings associated with this phenomenon, but also enriches our understanding of the TAM in the context of BPAs by uncovering the key dimensions of abstract constructs in the model. PMID- 29485298 TI - The Danish version of Lymphoedema Functioning, Disability and Health Questionnaire (Lymph-ICF) for breast cancer survivors: Translation and cultural adaptation followed by validity and reliability testing. AB - PURPOSE: To translate and culturally adapt the Lymphoedema Functioning, Disability and Health Questionnaire (Lymph-ICF) for breast cancer survivors with arm lymphedema into Danish and examine its content validity and reliability. METHODS: (1) Translation and cultural adaptation was performed in 10 steps following international guidelines (International Society for Pharmacoeconomics and Outcome Research); (2) cognitive interviewing (step 7) was conducted in 15 women with breast cancer related arm lymphedema to explore understandability, interpretation, and cultural relevance; (3) after adjustments, content validity (N = 52) was explored by interviews; and (4) reliability (N = 50) examined by intraclass correlation coefficients (ICC) statistics and Cronbach alpha analysis. RESULTS: Cognitive interviewing lead to an adapted and improved version of the translated questionnaire. Content validity was supported. Internal consistency (alpha) for all questions was .98 and ranged for the different domains between 0.92 and 0.97. Test-retest reliability for the total score was highly satisfactory, ICC = 0.95, standard error of measurement (SEM) = 4.5 and smallest detectable change = 12.5. ICC values for the domains ranged from 0.84 to 0.94. SEM values differed for the domains, 6.4 (physical function), 5.7 (mobility activities), 7.09 (life and social activities), 9.1 (mental functions), and 10.2 (household activities). CONCLUSION: The translated and adjusted Lymph-ICF DK (Denmark) is reliable and valid, allowing for assessing self-reported impairments in function, activity limitations, and participation restrictions in Danish patients with breast cancer-related arm lymphedema. PMID- 29485299 TI - Predicting Intentions to Breastfeed for Three Months, Six Months, and One Year Using the Theory of Planned Behavior and Body Satisfaction. AB - Breastfeeding is one of the top maternal priorities for many organizations, including the World Health Organization (WHO), The American Academy of Pediatrics (AAP), and the Center for Disease Control (CDC). Focusing on the goals of Healthy People 2020, as well as the recommendations of other organizations, this paper investigates the impacts on women's intentions to breastfeed newborns for 3 months, 6 months, and 1 year. This research used the theory of planned behavior (TPB) as a model to predict intentions for each duration of time. Body satisfaction was included as a moderating variable given research demonstrating a possible connection of body satisfaction to breastfeeding. A survey of 156 pregnant women was conducted. Results demonstrated the importance of the three TPB measures in predicting intentions. Further, significant interactions between body satisfaction and attitudes, as well as body satisfaction and subjective norms were present in predicting intentions to exclusively breastfeed one's baby from infant to 6 months of age. Theoretical implications are discussed, as well as practical implications for breastfeeding interventions and campaigns. PMID- 29485300 TI - Space perception, movement, and insight: attuning to the space of everyday life after major weight loss. AB - Physiotherapists are well placed to help people adjust and engage meaningfully with the world following major weight loss. Recent research indicates that the body size a patient has lived with for years can continue to affect movement and perception even after largescale weight loss. This article explores this discrepancy in depth from the perspective of phenomenology and space perception and through the concepts of body image, body schema, and affordances. It draws on an empirical example in which a nautical engineer described his lived experience of returning to work following bariatric surgery and the discrepancies he experienced while adjusting to his new situation, particularly when moving his smaller body around the ship's engine room, previously inaccessible to him. Analysis of this empirical example suggests that transitions in weight and size following bariatric surgery are both highly explicit in awareness (i.e., body image) and outside awareness (i.e., body schema). Major weight loss can open up new affordances and possibilities of being in the world, but only after adjustments in body image and body schema. The article suggests ways in which such insights can contribute to physiotherapists' clinical development and practice when working with patients undergoing major weight loss. PMID- 29485301 TI - Correlation among lipid parameters, pulse wave velocity and central blood pressure in young Korean population. AB - BACKGROUND: Central blood pressure is closely related to the important cardiovascular intermediate end points, such as vascular hypertrophy and extent of carotid atherosclerosis. Therefore it is prudent to study correlation among central aortic blood pressure, body composition, lipid profiles, and pulse wave velocity in population-based study. Consequently, we investigate the correlation between central aortic blood pressure and other risk parameters of hypertension such as body composition and lipid profile. METHODS: We recruited 20 young participants diagnosed with hypertension as well as 30 without hypertension. The study used an X-SCAN PLUS 950 machine for measurement of overall body composition. Measurements of central blood pressure and carotid-femoral pulse wave velocity were carried out using SphygmoCor XCEL. RESULTS: The hypertensive participants had significantly higher total weight without fat, body moisture mass, muscle mass, body mass index, basal metabolic rate, intracellular and extracellular water contents, protein and mineral contents along with brachial and central aortic blood pressures. In both hypertensive and non-hypertensive participants, central aortic diastolic blood pressure were significantly related to the lipid parameters. CONCLUSION: Overall, the correlations between central blood pressure, pulse wave velocity, and lipid profile in hypertensive and non hypertensive participants were substantial. PMID- 29485302 TI - Psychosocial Factors that Shape Substance Abuse and Related Mental Health of Women Military Veterans who Use Community-Based Services. AB - BACKGROUND: Women Veterans who use the Veterans Health Administration (VA) have high rates of substance abuse and poorer health than non-Veteran women. Less is known about the psychosocial needs of women Veterans who seek care in non-VA settings. OBJECTIVES: We provide a grounded description of factors that impact substance abuse, mental health, and related quality of life of women Veterans who use non-VA community-based health and social services. METHODS: Utilizing a mixed methods design, we conducted semi-structured in-person interviews with 22 women Veterans in Los Angeles in 2013-2015. RESULTS: The current health of these women Veterans was shaped by substance abuse and several other factors, including: histories of trauma (in childhood, during military service) and discrimination, and associated mental health conditions; post-military socio-economic stressors; shifting social roles and adverse social support; and lost personal identity after military service. Psychosocial factors collectively underscore areas in which delivery of health and social services to women Veterans being treated in non-VA settings could be improved: (1) diffuse, implement, and sustain evidence based gender-sensitive substance abuse treatment; (2) address traumas contributing to poor health; (3) recognize stress proliferation processes erode women's capacity to access healthcare or cope with stressors in healthy ways; (4) champion women Veterans who embody resilience and thereby can help others to form empowered personal identities of health and wellness. CONCLUSION: Findings can inform interventions and services that ameliorate vulnerability to substance abuse and other health risks among women Veterans. PMID- 29485303 TI - Scoping review of resources for integrating evidence-based supported employment into spinal cord injury rehabilitation. AB - PURPOSE: Individual placement and support (IPS), an evidence-based supported employment (SE) program, has helped Veterans with spinal cord injury (SCI) receiving care in the Veterans Health Administration to obtain work. To facilitate integration of IPS into SCI rehabilitation, resources are needed. A scoping review was conducted to identify tools and resources suitable for providers of SCI care. METHODS: Applying a modified version of Arksey and O'Malley's framework, a scoping review of literature on SE tools or resources was conducted. The original review focused on resources published between 2002 and 2015 and available in English. Prior to publication an updated review through 2017 was conducted. RESULTS: From 1822 tools and resources identified in the initial review, 24 met criteria for inclusion and were evaluated by an advisory panel of experts, who selected 16 tools that addressed five topics: IPS in SCI (n = 2) orientation to SCI (n = 3); IPS SE (n = 7), job accommodations (n = 2), and benefits planning (n = 2). The updated review yielded no tools or resources that met inclusion criteria. CONCLUSION: Despite few resources to guide implementation of IPS in SCI, 16 essential resources were identified that, combined into a toolkit, may facilitate translation of IPS in SCI from research to clinical care. Implications for rehabilitation The toolkit consists of 16 essential resources and is currently available online to all persons involved in spinal cord injury rehabilitation to educate them about this effective means of assisting persons with spinal cord injury to find employment and to facilitate translation of individual placement and support in spinal cord injury from research to clinical care. While expert-informed, the toolkit is being field tested with both clinical and vocational providers to facilitate the adoption of individual placement and support by spinal cord injury rehabilitation programs. The revised version will be made available online. PMID- 29485304 TI - Is there a need for urologist assistance in the management of abnormally invasive placenta? PMID- 29485305 TI - An Evaluation of e-CHECKUP TO GO in Canada: The Mediating Role of Changes in Social Norm Misperceptions. AB - BACKGROUND: Alcohol use and related problems are key concerns among colleges, and web-based interventions to mitigate these issues are increasingly popular across campuses. A variety of programs are commercially available and have demonstrated efficacy in reducing alcohol use and consequences; however, little is known about how these programs reduce alcohol outcomes. OBJECTIVES: The e-CHECKUP TO GO program (e-CHUG) is the briefest electronic intervention available and over 600 institutions are using it internationally. The present study evaluates the impact of the e-CHUG program on drinking outcomes and examines changes in perceived norms as a potential mediator of intervention efficacy in a sample of first-year Canadian university residence students. This is the first Canadian evaluation of e-CHUG. METHODS: First year Canadian university students (N = 245) living in residence in August 2014 participated in a randomized control trial to evaluate the efficacy of e-CHUG program compared to an assessment-only control condition. Follow-up assessments were completed at 3-months and 5-months. Norm misperceptions and drinking outcomes were measured. RESULTS: At 3-month and 5 month follow-up assessments program participants had lower norm misperceptions about peers drinking compared to control participants. Changes in norm misperceptions at 3-months mediated the effect of the program on drinking outcomes at 5-months. There were no sex differences in the associations. Conclusions/Importance: Findings suggest that e-CHECKUP TO GO may be a promising strategy for addressing norm misperceptions and subsequently drinking for Canadian students. PMID- 29485306 TI - Ankle and Midfoot Power During Walking and Stair Ascent in Healthy Adults. AB - Ankle power dominates forward propulsion of gait, but midfoot power generation is also important for successful push-off. However, it is unclear if midfoot power generation increases or stays the same in response to propulsive activities that induce larger external loads and require greater ankle power. The purpose of this study was to examine ankle and midfoot power in healthy adults during progressively more demanding functional tasks. Multisegment foot motion (tibia, calcaneus, and forefoot) and ground reaction forces were recorded as participants (N = 12) walked, ascended a standard step, and ascended a high step. Ankle and midfoot positive peak power and positive total power, and the proportion of midfoot to ankle positive total power were calculated. One-way repeated-measures analyses of variance were conducted to evaluate differences across tasks. Main effects were found for ankle and midfoot peak and total powers (all Ps < .01), but not for the proportion of midfoot-to-ankle total power (P = .33). Ankle and midfoot power significantly increased across each task. Midfoot power increased in proportion to ankle power and in congruence to the external load of a task. Study findings may serve to inform multisegment foot modeling applications and internal mechanistic theories of normal and pathological foot function. PMID- 29485307 TI - Simultaneous Superior Rectus Recession and Anterior Transposition of Inferior Oblique Muscle as a Surgical Option for Traumatically Lost Inferior Rectus Muscle. AB - PURPOSE: To evaluate the role of simultaneous superior rectus (SR) recession and anterior transposition of inferior oblique (ATIO) muscle in patients with traumatically lost inferior rectus (IR) muscle. METHODS: Six patients with history of ocular trauma, followed by sudden onset vertical diplopia along with marked hypertropia (HT) and limitation of depression in abduction in the affected eye suggestive of IR disinsertion, were included in this prospective study. The patients were treated by simultaneous SR recession and ATIO muscle in the affected eye by limbal conjunctival approach under local anesthesia. RESULTS: Preoperatively, primary position HT of 40-50 (mean 44.16 +/- 4.91) prism diopters (PD) was present in all cases which increased to 65-70 (mean 65.83 +/- 5.84) PD in down and in the ipsilateral gaze along with marked limitation of depression in abduction and A pattern. On exploration, the IR could not be traced in four cases. Fibrotic muscle sheath with retracted IR was found 10-12 mm away from the limbus in rest of the two patients. ATIO (6.5 mm from the limbus) with simultaneous recession of ipsilateral SR was done under local anesthesia. At 12 weeks postoperatively, three patients were orthophoric in primary position and vertical alignment with in 4-7 PD in primary position was achieved in rest of the three patients. CONCLUSION: Simultaneous SR recession with ATIO seems to be a good alternative to achieve satisfactory vertical alignment for patients with traumatically lost inferior rectus muscle. PMID- 29485308 TI - Rectus Muscle Resection for Vertical Strabismus in Thyroid Eye Disease. AB - PURPOSE: Rectus muscle resection in thyroid eye disease (TED) is generally avoided due to the risk of worsening restriction or reactivating inflammation. However, for some patients with large-angle strabismus or diplopia in primary gaze despite maximum recession surgery, rectus muscle resection may be beneficial. We report our surgical experience with rectus muscle resection in the management of vertical strabismus associated with TED. METHODS: Retrospective review of eight patients with TED and vertical diplopia who underwent vertical rectus muscle resection by a single surgeon (IBM) at a tertiary referral centre in Liverpool, UK, from 2001 to 2013. The goal of surgery was elimination of diplopia in primary and reading position. Vertical deviations were measured in prism dioptres (?) before and after surgery at one month, four months and final visit by prism alternate cover testing at 1/3 m and 6 m. RESULTS: The mean +/- standard deviation vertical deviation for near and distance reduced significantly from 14.2? +/- 8.4? and 15.8? +/- 8.8? pre-operatively to 5.7? +/- 4.9? and 6.7? +/- 7? at the four-month visit, respectively (p< 0.05). At the four-month follow up, five (62.5%) patients achieved binocular single vision in primary and reading position with either no prisms or prisms less than 5?. Further recession surgery, Harada-Ito procedure, or lateral rectus resection were necessary in four (50%) patients with persistent diplopia. No patient developed recurrence of inflammation or increased muscle restriction. CONCLUSIONS: Vertical rectus resection could be considered as an additional surgical strategy in the management of TED patients with vertical strabismus without adverse sequelae. PMID- 29485309 TI - Age Does Not Attenuate Maximal Velocity Adaptations in the Ipsilateral and Contralateral Limbs During Unilateral Resistance Training. AB - This study examined the effects of unilateral resistance training (RT) on maximal velocity parameters in the ipsilateral and contralateral legs in young and older males. Young (n = 22; age = 21.55 +/- 2.23 years) and older (n = 20; age = 65.10 +/- 9.65 years) males were assigned to training or control groups. Unilateral isokinetic RT of the knee extensors was performed for 4 weeks. Peak velocity and acceleration were identified during a dynamic maximal voluntary contraction before (PRE), at Week 2 (MID), and after Week 4 (POST) of RT. Age-independent increases in peak velocity (1.5%) and acceleration (4.5%) were demonstrated at POST for the trained leg. For the untrained leg, acceleration increased (4.3%) at POST similarly between training groups. These findings provide evidence for the high degree of neuromuscular plasticity, regardless of age, during the early phase of RT, and the potential for cross education of acceleration. PMID- 29485310 TI - Discriminatory Ability of Lower-Extremity Peak Torque and Rate of Torque Development in the Identification of Older Women With Slow Gait Speed. AB - The aim was to compare torque and rate of torque development of lower limb muscles between older women with functional and slow gait speeds to determine which muscle group is the best predictor of functional gait speed, and to establish strength thresholds needed for functional walking speed. Torque and rate of torque development of hip, knee, and ankle muscles were measured in older women who were divided in 2 groups according to gait speed: slow gait speed (<1.22 m.s-1) and functional gait speed (>=1.22 m.s-1). For each muscle group, 3 maximal isometric contractions were performed, and peak torque and rate of torque development were recorded. Older women with slow gait speed had lower peak torque than older women with functional gait speed for hip extension (28%), knee flexion (15%), knee extension (14%), and plantar flexion (16%) (all Ps < .05). Older women with slow gait speed had lower peak rate of torque development for hip flexion (29%), hip extension (37%), knee flexion (34%), knee extension (33%), and plantar flexion (19%) (all Ps < .05). Knee extension peak rate of torque development and hip extension peak torque were the better predictors of functional gait speed with thresholds of 2.96 N.m.s-1.kg-1 and 1.26 N.m.kg-1, respectively. PMID- 29485311 TI - Economic Significance of Tropical Theileriosis on a Holstein Friesian Dairy Farm in Pakistan. AB - The dairy industry in Pakistan is booming, and investors are anxious to fund dairy farms that are using high-milk-producing (exotic) cattle breeds such as Holstein Friesians that are not native to the country. Unfortunately, the benefits of increased milk production do not provide resistance to pathogens present in regions where the exotic breeds are introduced. Therefore, the current study was conducted to evaluate the economic impact of Theileria annulata on a commercial Holstein Friesian dairy farm in the District of Ranjanpur, in the Province of Punjab, Pakistan. The economic impact of T. annulata infection was calculated for cattle with subclinical and clinical theileriosis. Losses were estimated based on milk production, morbidity, mortality, and tick control costs (organophosphate sprays). Animals were classified into groups after screening for mastitis, teat abnormality, abnormal parturition, intestinal parasites, and hemoparasites ( T. annulata, Babesia spp., and Anaplasma spp.). Microscopy was done for hemoparasites and intestinal parasites. PCR was used to confirm microscopic identification of T. annulata. Animals were classified into 3 groups: group A (normal), group B (subclinical theileriosis), and group C (acute theileriosis). Hemoparasites were observed microscopically in 28.7% of cows. Theileria annulata was found in 8%, and the herd incidence (new cases) of T. annulata was 2.8%. Milk production, animal rectal temperature, and body condition scores between group A and groups B and C were significantly different ( P < 0.05). But the enlargement of sub-scapular lymph node and interval of body condition score of the 3 groups were not significant ( P > 0.05). The total expenditure incurred due to theileriosis was US $74.98 per animal and 13.83% of total farm costs. Hence theileriosis caused significant economic loss of US $18,743.76 (0.02 million) on this Holstein Friesian dairy. PMID- 29485312 TI - Deciphering PPARgamma activation in cardiometabolic syndrome: studies by in silico and in vivo experimental assessment. AB - Cardiometabolic syndrome (CMetS) is a consolidation of metabolic disorders characterized by insulin resistance, dyslipidemia and hypertension. Curcumin, a natural bioactive compound, has been shown to possess notable anti-oxidant activity and it has also been included as a super natural herb in the super natural herbs database. Most of the beneficial effects of Curcumin are possibly due to activation of the nuclear receptor, peroxisome proliferator-activated receptor gamma (PPARgamma). The present study investigates molecular interactions of curcumin with PPARgamma protein through molecular docking and molecular dynamics (MD) simulation studies. Further, effect of curcumin on high fat diet induced CMetS was studied in rats along with western blot for PPARgamma and nuclear factor-kappaB (NF-kappaB) expressions and histopathological studies. Computational studies presented several significant molecular interactions of curcumin including Ser289, His323, His449 and Tyr473 of PPARgamma. The in vivo results further confirmed that curcumin was able to ameliorate the abnormal changes and also, increased PPARgamma expressions. The results confirm our hypothesis that activation of PPARgamma by curcumin possesses the therapeutic potential to ameliorate the altered levels of metabolic changes in rats in the treatment of CMetS. This is the first report of CMetS treatment by curcumin and study of its underlying mechanism through in silico as well as in vivo experiments. PMID- 29485313 TI - The role of personal practice in therapist skill development: a model to guide therapists, educators, supervisors and researchers. AB - Prior to 2000, personal practice (PP) for therapists mostly meant personal therapy. Recently a new landscape of PPs has emerged, with meditation-based programs and therapy self-practice/self-reflection (SP/SR) programs playing an increasing role in training and personal/professional development. The challenge now for practitioners and researchers is to refocus on the role of PPs in training and professional development. Are PPs of value - or not? Do they have a role in therapist development? How might PPs enhance therapist skilfulness? Do different PPs act in similar or different ways? Currently, the PP literature lacks a theoretical framework to guide practitioners in their choice of PPs or researchers in their choice of research questions and measures. The purpose of this article is to provide such a framework, the Personal Practice (PP) model. The PP model proposes primary impacts of PPs in four domains: personal development/wellbeing, self-awareness, interpersonal beliefs/attitudes/skills and reflective skills. The model also suggests a secondary impact on therapists' conceptual/technical skills when therapists use reflection to consider the implications of their PP for their "therapist self". We offer some suggestions to enhance the quality of future research, and conclude that PPs may play an important and perhaps unique role in therapist training. PMID- 29485314 TI - Using the 'Social Marketing Mix Framework' to explore recruitment barriers and facilitators in palliative care randomised controlled trials? A narrative synthesis review. AB - BACKGROUND: Effective recruitment to randomised controlled trials is critically important for a robust, trustworthy evidence base in palliative care. Many trials fail to achieve recruitment targets, but the reasons for this are poorly understood. Understanding barriers and facilitators is a critical step in designing optimal recruitment strategies. AIM: To identify, explore and synthesise knowledge about recruitment barriers and facilitators in palliative care trials using the '6 Ps' of the 'Social Marketing Mix Framework'. DESIGN: A systematic review with narrative synthesis. DATA SOURCES: Medline, CINAHL, PsycINFO and Embase databases (from January 1990 to early October 2016) were searched. Papers included the following: interventional and qualitative studies addressing recruitment, palliative care randomised controlled trial papers or reports containing narrative observations about the barriers, facilitators or strategies to increase recruitment. RESULTS: A total of 48 papers met the inclusion criteria. Uninterested participants (Product), burden of illness (Price) and 'identifying eligible participants' were barriers. Careful messaging and the use of scripts/role play (Promotion) were recommended. The need for intensive resources and gatekeeping by professionals were barriers while having research staff on-site and lead clinician support (Working with Partners) was advocated. Most evidence is based on researchers' own reports of experiences of recruiting to trials rather than independent evaluation. CONCLUSION: The 'Social Marketing Mix Framework' can help guide researchers when planning and implementing their recruitment strategy but suggested strategies need to be tested within embedded clinical trials. The findings of this review are applicable to all palliative care research and not just randomised controlled trials. PMID- 29485315 TI - Aerobic exercise training normalizes central blood pressure regulation after oral glucose loading in overweight/obese men. AB - Central systolic blood pressure (cSBP) decreases after a meal or glucose challenge, but this response is impaired in obesity-related disorders. We investigated whether aerobic exercise training improves cSBP regulation during an oral glucose tolerance test (OGTT) in overweight/obese men. Thirteen overweight/obese men and six normal-weight men (as an alternative comparison instead of a no-exercise group) completed a 12-week aerobic exercise training program. Before and after the program, cSBP (i.e., radial second systolic pressure) was measured using an applanation tonometry at fasting and both 60 min and 120 min after 75 g glucose loading. Before and during the program, physical activity (PA) time was recorded using a tri-axial accelerometer. Pre-training, cSBP was significantly decreased with glucose loading in normal-weight men, while cSBP did not change in overweight/obese men. Post-training, a significant decrease in cSBP was observed in both groups following glucose loading. In addition, the increase in vigorous PA time during the exercise program was significantly correlated to the increase in area above the curve for cSBP during OGTT (demonstrating an improvement in the cSBP response to glucose loading) after the exercise program. These findings may provide novel insights into the role of PA in reducing the cardiovascular risk in obesity. PMID- 29485316 TI - Variation in perceived providers of ambulatory physical therapy in the United States, 2009-2012: An analysis using data from the Medical Expenditure Panel Survey. AB - INTRODUCTION: Little is known about public perception of physical therapy (PT) delivery by type of provider in the United States (US). PURPOSE: This study aimed to describe differences in ambulatory PT visits and expenditures according to perceived provider type, and to determine if visits and expenditures varied by provider type. METHODS: This study employed the Medical Expenditure Panel Survey (MEPS), which is a nationally representative survey of US households that used a complex, stratified, cluster sample design. Data from cross-sectional samples over 4 years of the MEPS Household Component were used to study adults with musculoskeletal conditions who reported receiving ambulatory PT. National-level, average annual estimates of numbers of visits, and reported total expenditures by perceived provider type were computed. Associations between perceived provider type and visits and expenditures were determined by linear regression, accounting for the sample design, and adjusting for demographic and clinical covariates. RESULTS: Estimated annual perceived PT visits were 60.00 million with physical therapists, 39.66 million with non-physical therapist providers, and 20.66 million with multiple providers. Estimated annual expenditures for PT were $9.37 billion with physical therapists, $4.62 billion with non-physical therapist providers, and $3.09 billion with multiple providers. Compared with non-physical therapist providers, physical therapist provider status and multiple provider status were associated with higher numbers of visits and expenditures. CONCLUSION: Non-physical therapist providers are responsible for a substantial amount of PT delivery in the US. Numbers of visits and total expenditures varied by the type of provider delivering PT. PMID- 29485317 TI - Physicians' experiences with sickness absence certification in Finland. AB - AIMS: The aim of this study was to explore Finnish physicians' perceptions of sickness absence (SA) certification. METHODS: A questionnaire was sent to 50% of the physicians in Finland who provide care to working-age patients in a clinical practice setting. Of the 8867 physicians, 3089 responded. Physicians handling SA certification patients at least a few times per month were included ( n = 2472). RESULTS: At least a few times per month, 61% of all physicians perceived SA issues as problematic, 60% had experienced a lack of time in dealing with SA matters, 36% had disagreed with a patient on SA certification, and 36% had met a patient who wanted a SA certificate for reasons other than a disease or injury. Physicians were least worried about patients filing complaints (4%), exhibiting threatening behaviour (2%), or switching physicians for SA certification reasons (1%). A total of 60% of physicians had prescribed SA for a longer period than necessary because of long waiting times for further care/measures. Non specialized physicians, general practitioners, and psychiatrists experienced problems more frequently than surgeons and occupational health physicians. Over 50% of the respondents had a fairly large or very large need to deepen their knowledge of social insurance matters. The need for national guidelines for all or some diseases was reported by 80% of the respondents. CONCLUSIONS: Many physicians perceive SA tasks as problematic and are unable to dedicate enough time to them. Shortcomings in physicians' sickness certification know-how, as well as obstacles in the healthcare and rehabilitation system, prolong the SA process. Attitudes towards the adoption of national guidelines on the duration of SA were positive. PMID- 29485319 TI - Online meditation training for people with multiple sclerosis: A randomized controlled trial. AB - BACKGROUND: Multiple sclerosis (MS) has a relevant impact on quality of life (QOL) and is associated with increased risks of psychological morbidity. Mindfulness-based interventions (MBIs) are among the most studied interventions, although few well-conducted studies have tested them in this field. Furthermore, the participation in typical MBIs may be impaired by time and logistics. OBJECTIVE: We aimed to test the efficacy of an online MBI to improve QOL, psychological well-being, sleep, and fatigue. METHODS: We conducted a randomized controlled trial, in which 139 participants were randomly assigned to an MS specific online mindfulness meditation intervention or to a psychoeducational (active control) group. Participants were assessed for QOL, depression, anxiety, sleep problems, and fatigue, at three different times: at recruitment, after 2 months, and after 6 months. RESULTS: In comparison to the control group, the experimental subjects reported higher QOL and lower depression, anxiety, and sleep problems at the end of intervention. However, after 6 months these group differences were no longer significant. CONCLUSION: An online MBI could be an effective psychological treatment for the promotion of well-being in MS in short term. However, the lack of lasting effects requires the development of new strategies to support long-term changes. PMID- 29485318 TI - Physical Activity in Relation to Sleep Among Community-Dwelling Older Adults in China. AB - This cross-sectional study was conducted to describe the physical activity and sleep in 290 community-dwelling Chinese older adults and to examine the association between physical activity and poor sleep outcomes. Almost half of the samples were poor sleepers. The majority of the samples regularly participated in walking, some household activity, and light sports, yet only a small portion were involved in work-related activity or in strenuous sports. A greater level of overall physical activity (odds ratio = 0.79; 95% confidence interval = [0.73, 0.86]), leisure-time exercise (odds ratio = 0.77; 95% confidence interval = [0.68, 0.85]), and household activity (odds ratio = 0.66; 95% confidence interval = [0.56, 0.78]) were associated with reduced likelihood of being poor sleepers and other poor sleep outcomes, independent of covariates including age, sex, education, family income, the number of children, drinking, and sleep hygiene. Future larger-scale studies that incorporate both objective and subjective measures are needed to further examine the association and to explore the effects of different types of activity on sleep and other well-beings in older adults. PMID- 29485320 TI - Decentration and Tilt of Intraocular Lens after Posterior Capsulotomy. AB - PURPOSE: To assess the effect of posterior capsular opacification (PCO) and Neodymium-doped:Yttrium Aluminium Garnet (Nd:YAG) laser capsulotomy on tilt and decentration of intraocular lens (IOL) at vertical and horizontal meridians. METHODS: The study included 64 eyes of 64 patients. IOL decentration and tilt were measured using a Scheimpflug camera before and 1 month after Nd:YAG capsulotomy. Corrected distance visual acuity (CDVA) and manifest refraction were also determined. Between-group differences of IOL position change and the effect of Nd:YAG laser capsulotomy were analyzed. RESULTS: In the PCO group, before capsulotomy, CDVA was significantly lower than that after capsulotomy and of the control group values (p = 0.001 for both). No significant difference was observed in CDVA between the control group and the PCO group after capsulotomy (p = 0.854). Before capsulotomy, the angle of tilt and decentration at both meridians was significantly higher than that in the control group (tilt: p < 0.001; for both decentrations: p = 0.001, p = 0.003, respectively). A significant decrease was observed in the angle of tilt at both meridians (horizontal p = 0.001, vertical p = 0.001) from before to after capsulotomy in the PCO group. Although decentration was increased after capsulotomy, no significant position change was observed (horizontal p = 0.350, vertical p = 0.107). The angle of tilt and decentration at both meridians was significantly higher in the PCO group after capsulotomy compared to the control group (p < 0.001 for all). CONCLUSIONS: PCO is associated with not only axial displacement, but also tilt and decentration of IOL at the vertical and horizontal meridians. Laser capsulotomy decreased IOL tilt but had no effect on decentration. However, these changes did not significantly change the visual acuity between the control group and the PCO group after capsulotomy. PMID- 29485321 TI - The dichotomous nature of dose enhancement by gold nanoparticle aggregates in radiotherapy. AB - AIM: In nanoparticle-aided radiotherapy, the computational paradigm has been that inside the cell, nanoparticles are distributed sparsely and solitarily. However, experiments reveal significant cluster formation, which affects radiosensitization and must be considered in clinical treatment planning. We characterize the impact of gold nanoparticle agglomeration on the predicted radiation dose enhancement as function of size, geometry, morphology and incident beam energy. MATERIALS & METHODS: Next-generation coupled electron-photon deterministic computations were performed using subnanometric unstructured spatial mesh. RESULTS: Unlike single nanoparticles, agglomerates develop two types of dose enhancement, smooth peripheral distributions and isolated hotspots, which depend on the cluster size and geometry in opposite ways. CONCLUSION: The peripheral dose enhancement may have less importance than the hotspots, which can have greater contribution to cell kill via radical creation. Hence, aggregate formation may be beneficial in nanoparticle-aided radiotherapy. PMID- 29485322 TI - Colorectal Cancer: Cost-effectiveness of Colonoscopy versus CT Colonography Screening with Participation Rates and Costs. AB - Purpose To compare the cost-effectiveness of computed tomographic (CT) colonography and colonoscopy screening by using data on unit costs and participation rates from a randomized controlled screening trial in a dedicated screening setting. Materials and Methods Observed participation rates and screening costs from the Colonoscopy or Colonography for Screening, or COCOS, trial were used in a microsimulation model to estimate costs and quality-adjusted life-years (QALYs) gained with colonoscopy and CT colonography screening. For both tests, the authors determined optimal age range and screening interval combinations assuming a 100% participation rate. Assuming observed participation for these combinations, the cost-effectiveness of both tests was compared. Extracolonic findings were not included because long-term follow-up data are lacking. Results The participation rates for colonoscopy and CT colonography were 21.5% (1276 of 5924 invitees) and 33.6% (982 of 2920 invitees), respectively. Colonoscopy was more cost-effective in the screening strategies with one or two lifetime screenings, whereas CT colonography was more cost-effective in strategies with more lifetime screenings. CT colonography was the preferred test for willingness-to-pay-thresholds of ?3200 per QALY gained and higher, which is lower than the Dutch willingness-to-pay threshold of ?20 000. With equal participation, colonoscopy was the preferred test independent of willingness-to pay thresholds. The findings were robust for most of the sensitivity analyses, except with regard to relative screening costs and subsequent participation. Conclusion Because of the higher participation rates, CT colonography screening for colorectal cancer is more cost-effective than colonoscopy screening. The implementation of CT colonography screening requires previous satisfactory resolution to the question as to how best to deal with extracolonic findings. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 29485323 TI - The Effect of 1 Week of a Multi-ingredient Dietary Preworkout Supplement on Resting and Postacute Resistance Exercise Vascular Function. AB - Dietary preworkout supplements are popular among recreational exercisers and athletes. However, the effects of these supplements on the vasculature, both at rest and during exercise, are not well studied. Therefore, the purpose of this study was to determine the effect of 1 week of supplementation with a multi ingredient dietary preworkout supplement on measures of vascular function at rest and immediately following acute resistance exercise in young, recreationally active adults. Twelve participants (9 males and 3 females; mean +/- SD: age = 24.5 +/- 3.4 years and body mass index = 24.3 +/- 4.7 kg/m2) completed this double-blind, randomized, crossover design study. After familiarization, participants were randomized to either a taste-matched placebo or the preworkout supplement for 1 week preceding the testing visits. Participants underwent measures of vascular function, including brachial artery flow-mediated dilation, measures of central and peripheral blood pressure, and measures of arterial stiffness via pulse wave analysis and pulse wave velocity. All measures were taken at rest and immediately following an acute bilateral leg press exercise session. Resting and postacute exercise flow-mediated dilation, blood pressure, and arterial stiffness were similar between the placebo and the preworkout supplement visits. One week of multi-ingredient preworkout supplementation does not affect vascular function at rest or in response to an acute bout of resistance exercise in young, healthy, recreationally active individuals. PMID- 29485324 TI - Protein Supplementation During a 6-Month Concurrent Training Program: Effect on Body Composition and Muscular Strength in Sedentary Individuals. AB - We examined the effect of a protein supplement on muscular strength and body composition during 6 months of a 5 days/week concurrent strength and endurance training program. Sedentary males (n = 26) and females (n = 25), 18-25 years, were randomly assigned to receive a protein (PRO, 42 g/serving) or carbohydrate (CON) supplement twice daily. Strength and body composition (dual-energy X-ray absorptiometry) were assessed at baseline, 3 (3M), and 6 (6M) months. Protein intake was higher in PRO (PRO: 2.2 g/kg; CON: 1.1 g/kg; p < .001). Females in both groups gained similar strength at 3M and 6M in bench press and hip sled. Males in PRO gained more bench press strength at 3M (PRO: 24.6 +/- 3.2 kg; CON: 14.3 +/- 3.8 kg; p = .06) and 6M (PRO: 34.4 +/- 4.3 kg; CON: 18.7 +/- 5.1 kg; p = .03) and hip sled strength at 3M (PRO: 67.7 +/- 9.2 kg; CON: 40.8 +/- 10.8 kg, p = .07) and 6M (PRO: 94.0 +/- 10.6 kg; CON: 65.1 +/- 12.4 kg; p = .09) compared with CON. Females in PRO experienced a greater reduction in fat mass over the course of the study (6M) than CON (PRO: -1.7 +/- 0.5 kg; CON: 0.1 +/- 0.5 kg; p = .06). Changes in lean mass were similar for females in PRO and CON. Loss in fat mass was similar for males in PRO and CON at 3M and 6M. Males in PRO gained more lean mass at 3M compared with CON (PRO: 3.2 +/- 0.3 kg; CON: 2.2 +/- 0.4 kg; p = .1) but similar gains at 6M (PRO: 2.6 +/- 0.4 kg; CON: 2.2 +/- 0.5 kg; p = .6). The results of this study demonstrate that PRO used during a concurrent training program may augment positive changes in body composition in young sedentary males and females, and strength gains in males. PMID- 29485325 TI - Assessing physiotherapists' communication skills for promoting patient autonomy for self-management: reliability and validity of the communication evaluation in rehabilitation tool. AB - PURPOSE: To assess the inter-rater reliability and concurrent validity of the Communication Evaluation in Rehabilitation Tool, which aims to externally assess physiotherapists competency in using Self-Determination Theory-based communication strategies in practice. MATERIALS AND METHODS: Audio recordings of initial consultations between 24 physiotherapists and 24 patients with chronic low back pain in four hospitals in Ireland were obtained as part of a larger randomised controlled trial. Three raters, all of whom had Ph.Ds in psychology and expertise in motivation and physical activity, independently listened to the 24 audio recordings and completed the 18-item Communication Evaluation in Rehabilitation Tool. Inter-rater reliability between all three raters was assessed using intraclass correlation coefficients. Concurrent validity was assessed using Pearson's r correlations with a reference standard, the Health Care Climate Questionnaire. RESULTS: The total score for the Communication Evaluation in Rehabilitation Tool is an average of all 18 items. Total scores demonstrated good inter-rater reliability (Intraclass Correlation Coefficient (ICC) = 0.8) and concurrent validity with the Health Care Climate Questionnaire total score (range: r = 0.7-0.88). Item-level scores of the Communication Evaluation in Rehabilitation Tool identified five items that need improvement. CONCLUSION: Results provide preliminary evidence to support future use and testing of the Communication Evaluation in Rehabilitation Tool. Implications for Rehabilitation Promoting patient autonomy is a learned skill and while interventions exist to train clinicians in these skills there are no tools to assess how well clinicians use these skills when interacting with a patient. The lack of robust assessment has severe implications regarding both the fidelity of clinician training packages and resulting outcomes for promoting patient autonomy. This study has developed a novel measurement tool Communication Evaluation in Rehabilitation Tool and a comprehensive user manual to assess how well health care providers use autonomy-supportive communication strategies in real world-clinical settings. This tool has demonstrated good inter-rater reliability and concurrent validity in its initial testing phase. The Communication Evaluation in Rehabilitation Tool can be used in future studies to assess autonomy-supportive communication and undergo further measurement property testing as per our recommendations. PMID- 29485326 TI - The effect of 10 days of intermittent fasting on Wingate anaerobic power and prolonged high-intensity time-to-exhaustion cycling performance. AB - Many physically active individuals have undertaken intermittent fasting to reduce their daily caloric intake. However, abstaining from meals for a specific length of time may lead to the acute disturbance of highly carbohydrate-dependent exercise performance. The purpose of this study was to observe the effect of 10 days of intermittent fasting on high-intensity type exercises, Wingate anaerobic (WT) and prolonged high-intensity time-to-exhaustion (HIT) cycling test. Twenty participants were randomised into an intermittent fasting (FAS) and a control group (CON). One day after baseline data collection on Day-0 where participants consumed their recommended daily caloric intake (FAS = 2500 +/- 143 kcal day-1; CON = 2492 +/- 20 kcal day-1) served over a course of five meals, the FAS group consumed only four meals where 40% was restricted by the omission of lunch (FAS = 1500 +/- 55 kcal day-1). This diet was then continued for 10 days. Data on exercise performance and other dependent variables were collected on Day-2, -4, 6, -8 and -10. A reduction in WT power in the FAS group was observed on Day-2 (821.74 +/- 66.07 W) compared to Day-0 (847.63 +/- 95.94 W) with a moderate effect size (p < .05, ES = 0.4), while HIT time-to-exhaustion performance declined over the 10 days with a trend of recovery from a large to a minimum effect size (p < .05, ES = 0.8-0.3). Body weight and triglyceride were consistently reduced in the FAS group (p < .01). The present study suggests that intermittent fasting must exceed 10 days to ensure that high-intensity performance does not deteriorate because this length of time seems to be required for effective adaptation to the new dietary regimen. PMID- 29485327 TI - Precision nanomedicines for prostate cancer. PMID- 29485328 TI - National Systematic Legal Review of State Policies on Emergency Medical Services Licensure Levels' Authority to Administer Opioid Antagonists. AB - OBJECTIVE: Previous research conducted in November 2013 found there were a limited number of states and territories in the United States (US) that authorize emergency medical technicians (EMTs) and emergency medical responders (EMRs) to administer opioid antagonists. Given the continued increase in the number of opioid-related overdoses and deaths, many states have changed their policies to authorize EMTs and EMRs to administer opioid antagonists. The goal of this study is to provide an updated description of policy on EMS licensure levels' authority to administer opioid antagonists for all 50 US states, the District of Columbia (DC), and the Commonwealth of Puerto Rico (PR). METHODS: State law and scopes of practice were systematically reviewed using a multi-tiered approach to determine each state's legally-defined EMS licensure levels and their authority to administer an opioid antagonist. State law, state EMS websites, and state EMS scope of practice documents were identified and searched using Google Advanced Search with Boolean Search Strings. Initial results of the review were sent to each state office of EMS for review and comment. RESULTS: As of September 1, 2017, 49 states and DC authorize EMTs to administer an opioid antagonist. Among the 40 US jurisdictions (39 states and DC) that define the EMR or a comparable first responder licensure level in state law, 37 states and DC authorize their EMRs to administer an opioid antagonist. Paramedics are authorized to administer opioid antagonists in all 50 states, DC, and PR. All 49 of the US jurisdictions (48 states and DC) that define the advanced emergency medical technician (AEMT) or a comparable intermediate EMS licensure level in state law authorize their AEMTs to administer an opioid antagonist. CONCLUSIONS: 49 out of 52 US jurisdictions (50 states, DC, and PR) authorize all existing levels of EMS licensure levels to administer an opioid antagonist. Expanding access to this medication can save lives, especially in communities that have limited advanced life support coverage. PMID- 29485329 TI - Individual and community factors associated with indications of caesarean delivery in Southern Nigeria: Pooled analyses of 2003-2013 Nigeria demographic and health surveys. AB - In this study, the researcher examines associated individual and community factors of indications of caesarean delivery in Southern Nigeria. Data were pooled from 2003-2013 Nigeria Demographic and Health Surveys. Analyses were performed using Stata 12. The multilevel mixed-effects logistic regression was applied. Indications of caesarean delivery were 4.9% over the studied period. Maternal age, parity, education, and household wealth were significantly associated with indications of caesarean delivery. Community effects on indications of caesarean delivery were significant. A public health education programme is needed to address aversion to caesarean sections among those who may have medical need for caesarean delivery. PMID- 29485330 TI - Cancer patients' experiences of living with venous thromboembolism: A systematic review and qualitative thematic synthesis. AB - BACKGROUND: Cancer-associated thrombosis is common. Recommended treatment is daily injected low-molecular-weight heparin for 6 months. Most studies focus on prophylaxis and treatment; few have explored the patients' experience. AIMS: To identify and synthesise the available literature concerning patients' experience of cancer-associated thrombosis. DESIGN: Systematic literature review and qualitative thematic synthesis. DATA SOURCE: MEDLINE, Embase, CINAHL, PsycINFO (until 10/2016; limited to English) were searched. Eligible papers were qualitative studies of adult patients' experience of cancer-associated thrombosis. Two researchers screened titles/abstracts/papers against inclusion criteria with recourse to a third for disagreements. Critical Appraisal Skills Programme qualitative checklist tool was used for quality appraisal. RESULTS: A total of 1397 articles were identified. Five qualitative studies (total n = 92; age range 32-84 years) met the inclusion criteria. Participants had various cancer types. Most had advanced disease and were receiving palliative care. Four major themes emerged from the data: knowledge deficit (patients and clinicians), effects of cancer-associated thrombosis (physical and psychological), effects of anticoagulation and coping strategies. CONCLUSION: The cancer journey is difficult in itself, but thrombosis was an additional, frightening and unexpected burden. Although the association between cancer and thromboembolism is well known, cancer patients are not routinely educated about the risk or warning symptoms/signs of thromboembolism which may otherwise be misattributed to the cancer by patient and clinician alike. This systematic review highlights the impact of cancer-associated thrombosis on the lives of cancer patients, and calls for education for patients and clinicians to be part of routine care and further work to address this patient priority. PMID- 29485331 TI - Using the Hemophilia Joint Health Score for assessment of children: Reliability of the Spanish version. AB - INTRODUCTION: Numerous measuring instruments for the evaluation of hemophilic arthropathy have been developed. One of the most used systems is the Hemophilia Joint Health Score (HJHS) given its sensitivity to clinical changes appearing in the joints because of recurrent hemarthrosis. OBJECTIVE: Assessing the interrater reliability, using the Spanish version of the HJHS (version 2.1) in children with hemophilia. DESIGN: Reliability study to assess the interrater reliability of the Spanish version of HJHS. METHODS: A sample of 36 children aged 7-13 years diagnosed with hemophilia A or B was used. Two physiotherapists performed physical assessments with the Spanish version of the HJHS. Descriptive statistics (range, mean, standard deviation) and the analysis of interrater reliability were calculated. RESULTS: The interrater reliability was heterogeneous since the Kappa coefficient range (K), although significant (p < 0.001), ranged 0.31-1.00 in the variables of HJHS (swelling, duration of swelling, muscle atrophy, crepitus on motion, flexion loss, extension loss, joint pain, strength, and global gait). In assessing the bias of observers with the Bland and Altman method, the observer 1 scored 0.41 (CI [-0.67, 1.49]) units above observer 2, and the difference between the two was significant (t(36) = 4.48), p < 0.001). CONCLUSIONS: The interrater reliability of the Spanish population version of the HJHS is high. This scale should be used generically in evaluating musculoskeletal pediatric patients with hemophilia. PMID- 29485332 TI - Feasibility of an Outdoor Mindful Walking Program for Reducing Negative Affect in Older Adults. AB - Mindful walking has emerged as a potential intervention strategy to improve mental health and promote well-being in adult and clinical populations. This strategy has not been implemented specifically with older adults to date. This study evaluated the feasibility, acceptability, sustainability, and preliminary efficacy of a mindful walking program for reducing negative affect in older adults. Community-dwelling older adults (n = 29) completed a 1-month, outdoor mindful walking program distributed across eight 30-min sessions. Responses from postprogram and follow-up questionnaires revealed that mindful walking was well accepted, highly valued, and maintained after the program ended. Analysis from the pre- and postwalk surveys also suggested the preliminary efficacy of a mindful walking program for reducing negative affect. Positive results identified in the current feasibility study indicate readiness for randomized controlled trials to further examine the efficacy and effectiveness of a mindful walking intervention for promoting health and well-being in older populations. PMID- 29485333 TI - Female Athlete Triad/Relative Energy Deficiency in Sport: A Perspective Interview With Professor Barbara Drinkwater. AB - Barbara Drinkwater has been a lifelong champion of equality for women in many areas of life well before it was widely accepted. Her "walking the walk" of women breaking barriers in traditional male roles in administration and leadership is exemplified by her election as the first woman president of the American College of Sports Medicine in 1988. Some of the controversial areas in which Barbara was vocal in the arena of women in sport, besides triad/relative energy deficiency in sport, include increased opportunity and participation, total equality, acceptance of diversity, intolerance of harassment and abuse, and fairness with transgender athletes. She co-founded the evidence-based advocacy group on the international stage known as Women Sport International. As a physiologist, Barbara has had a major influence on attention to the health of the female athlete, and she produced the original pioneering work in the field. Her impactful study, "Bone mineral density after resumption of menses in amenorrheic athletes," was published in the Journal of the American Medical Association in 1986. Since that time, the female athlete triad has set the stage for research and treatment to enhance women in physical activity at all levels. PMID- 29485335 TI - Intermittent Treadmill Running Induces Kinematic Compensations to Maintain Soccer Kick Foot Speed Despite No Change in Knee Extensor Strength. AB - Kicking is a fundamental skill and a primary noncontact mechanism of injury in soccer, with injury incidence increasing during the latter stages of match-play. Ten male professional soccer players completed a 90-minute treadmill protocol based on the velocity profile of soccer match-play. Preexercise, and at 15-minute intervals, players completed a maximal velocity kick subjected to kinematic analysis at 200 Hz. Preexercise, and at the end of each half, players also completed isokinetic concentric knee extensor repetitions at 180 degrees .s-1, 300 degrees .s-1, and 60 degrees .s-1. Kicking foot speed was maintained at ~19 m.s-1, with no main effect for exercise duration. In relation to proximal-distal sequencing during the kicking action, there was a significant increase in the duration (but not magnitude) of thigh rotation, with a compensatory decrease in the duration (but not magnitude) of shank rotation during the latter stages of the exercise protocol. In relation to long-axis rotation, pelvic orientation at ball contact was maintained at ~6 degrees , representing a total pelvic rotation in the order of ~15 degrees during the kicking action. Peak knee extensor torque at all speeds was also maintained throughout the protocol, such that kinematic modifications are not attributable to a decline in knee extensor strength. PMID- 29485334 TI - Spinal cord injury pharmacotherapy: Current research & development and competitive commercial landscape as of 2015. AB - CONTEXT: Current treatment of spinal cord injury (SCI) focuses on cord stabilization to prevent further injury, rehabilitation, management of non-motor symptoms, and prevention of complications. Currently, no approved treatments are available, and limited treatment options exist for symptoms and complications associated with chronic SCI. This review describes the pharmacotherapy landscape in SCI from both commercial and research and development (R&D) standpoints through March 2015. METHODS: Information about specific compounds has been obtained through drug pipeline monographs in the Pharmaprojects(r) (Citeline, Inc., New York, New York, USA) drug database (current as of a search on May 30, 2014), websites of individual companies with compounds in development for SCI (current as of March 24, 2015), and a literature search of published R&D studies to validate the Pharmaprojects(r) source for selected compounds (current as of March 24, 2015). RESULTS: Types of studies conducted and outcomes measured in earlier phases of development are described for compounds in clinical development Currently four primary mechanisms are under investigation and may yield promising therapeutic targets: 1) neuronal regeneration; 2) neuroprotection (including anti inflammation); 3) axonal reconnection; and 4) neuromodulation and signal enhancement. Many other compounds are no longer under investigation for SCI are mentioned; however, in most cases, the reason for terminating their development is not clear. CONCLUSION: There is urgent need to develop disease-modifying therapy for SCI, yet the commercial landscape remains small and highly fragmented with a paucity of novel late-stage compounds in R&D. PMID- 29485336 TI - Secrets, shame and discipline: School girls' experiences of sanitation and menstrual hygiene management in a peri-urban community in Ghana. AB - Women and girls need proper sanitation and hygiene facilities to maintain health and dignity. In this study we show how schoolgirls from a peri-urban community of Ghana, experience severe multidimensional 'hygiene poverty' when attending schools. Hygiene poverty was characterized by poor water and sanitation infrastructures and serious social and emotional challenges, including shaming and disciplining of their sanitation and menstrual practices, which forces girls to apply secretive coping strategies. We discuss the importance of changing the negative MHM discourses at schools and fostering supportive teaching methods in adolescent female health. PMID- 29485337 TI - A qualitative exploration of proxy decision makers' expectations of prescribed medications for people with advanced dementia. AB - BACKGROUND: Proxy decision makers often have to make decisions for people with advanced dementia. Their expectations regarding prescribed medications have the potential to influence prescription or withdrawal of medications. However, few studies to date have explored this. AIM: To explore proxy decision makers' expectations of prescribed medications for people with advanced dementia and to consider how these change with changing goals of care and dementia progression. DESIGN: This is a qualitative semi-structured interview study. SETTING/PARTICIPANTS: In total, 15 proxy decision makers of people with advanced dementia were recruited via general practitioners ( n = 9), Join Dementia Research ( n = 3) and the Alzheimer's Society Northern Ireland ( n = 3). RESULTS: Five key themes emerged: the role as advocate, attitudes to medicines and medicine taking, uncertainty over the benefit of anti-dementia medications, stopping medications, and communication and decision-making. Proxy decision makers desired more information about prescribed medicines, particularly the indications, benefits and risks of treatment. Despite uncertainty about the benefits of anti-dementia medications, proxy decision makers were reluctant for these medications to be withdrawn. Reluctance to stop other prescribed medicines was also expressed but reduced with changing goals of care and dementia progression. Although some proxy decision makers expected to be involved in medication-related decisions, the majority preferred to delegate these decisions to healthcare professionals. However, they expected to be informed of any medication-related decisions made. CONCLUSION: Proxy decision makers vary in terms of their desire for active involvement in the medication decision-making process. Healthcare professionals should facilitate proxy decision maker involvement if desired. Further research is required to consider the impact of proxy decision maker involvement in decision-making. PMID- 29485338 TI - Dexamethasone-Related Perineal Burning in the Prehospital Setting: A Case Series. AB - Dexamethasone is frequently used in the treatment of allergic reactions and airway inflammation because of its potent anti-inflammatory effects and long duration of action. As prehospital use becomes more common, it is important for providers to be aware of unique and potentially distressing associated adverse effects. We report eight cases of intravenous dexamethasone administration associated with perineal or diffuse burning sensation in female patients. PMID- 29485339 TI - Macronutrient Intakes of Male Rugby Union Players: A Review. AB - Rugby is a worldwide intermittent team sport. Players tend to be heavier than the majority of similar team sport athletes on whom the dietary guidelines have been developed. Therefore, the aim of the current review was to describe the intakes of rugby union players. Article databases were searched up to February 2017 and were included if they were published in English and reported dietary intakes of male rugby union players. Of the research articles identified, energy intakes were lower than two of three studies that reported intakes and expenditure, which would suggest the players were losing weight that is somewhat supported by the decreases in skinfolds seen during preseason. However, it should also be noted that there are errors in both the measurement of energy intakes and expenditure. Carbohydrate intakes ranged from 2.6 to 6.5 g.kg-1.day-1, which is lower than the current relative to body mass recommendations; however, this would not be classed as a low-carbohydrate diet. The consistently low intakes of carbohydrate suggest that these intake levels maybe sufficient for performance, given the players greater body mass or there are errors in the measurements. However, there is currently no evidence for the carbohydrate needs of rugby union players in terms of performance. The lower intakes than expenditure would suggest the players were losing weight. Previous research shows that rugby union players lose body fat during preseason training. PMID- 29485340 TI - Incentive spirometry and positive expiratory pressure improve ventilation and recruitment in postoperative recovery: A randomized crossover study. AB - INTRODUCTION: Impairment of global and regional pulmonary ventilations is a well known consequence of general anesthesia. Positive expiratory pressure (PEP) or incentive spirometry (IS) is commonly prescribed, albeit their efficacy is poorly demonstrated. The aim of this study was to assess the effects of PEP and IS on lung ventilation and recruitment in patients after surgery involving anesthesia using electrical impedance tomography (EIT). METHOD: Ten male subjects (age = 61.2 +/- 16.3 years; BMI = 25.3 +/- 3.8 kg/m2), free of pulmonary disease before being anesthetized, were recruited. Two series of manoeuvers (PEP and volume oriented IS) were randomly performed with quiet breathing interposed between these phases. Pulmonary ventilation (DeltaEELVVT (i - e)) and recruitment (DeltaEELI) were evaluated continuously in a semi-seated position during all phases by EIT. Comparisons between rest and treatment were performed by Wilcoxon signed rank test. Rest phases were compared by a mixed ANOVA. Bonferroni method was used for post-hoc comparisons. RESULTS: DeltaEELVVT (i - e) and DeltaEELI were significantly increased by both techniques (+422% [p < 0.001]; +138% [p = 0.040] and +296% [p < 0.001]; +638% [p < 0.001] for PEP and IS, respectively). No difference was observed between both manoeuvers neither on ventilation nor on recruitment. This positive effect disappeared during the quiet breathing phases. CONCLUSION: IS and PEP improved ventilation and recruitment instantaneously without remnant effect after stopping the exercise. PMID- 29485341 TI - Delayed clearance of cerebrospinal fluid tracer from entorhinal cortex in idiopathic normal pressure hydrocephalus: A glymphatic magnetic resonance imaging study. AB - The glymphatic system plays a key role for clearance of waste solutes from the rodent brain. We recently found evidence of glymphatic circulation in the human brain when using magnetic resonance imaging (MRI) contrast agent as cerebrospinal fluid (CSF) tracer in conjunction with multiple MRI acquisitions (gMRI). The present study explored the hypothesis that reduced glymphatic clearance in entorhinal cortex (ERC) may be instrumental in idiopathic normal pressure hydrocephalus (iNPH) dementia. gMRI acquisitions were obtained over a 24-48 h time span in cognitively affected iNPH patients and non-cognitively affected patients with suspected CSF leaks. The CSF tracer enrichment was determined as changes in normalized MRI T1 signal units. The study included 30 patients with iNPH and 8 individuals with suspected CSF leaks (i.e. reference individuals). Compared to reference individuals, iNPH patients presented with higher medial temporal lobe atrophy score and Evan's index and inferior ERC thickness. We found delayed clearance of the intrathecal CSF tracer gadobutrol from CSF, the ERC and adjacent white matter, suggesting impaired glymphatic circulation. Reduced clearance and accumulation of toxic waste product such as amyloid-beta may be a mechanism behind dementia in iNPH. Glymphatic MRI (gMRI) may become a tool for assessment of early dementia. PMID- 29485343 TI - A Simplified Approach to Select Exercise Endurance Intensity for Interventional Studies in COPD. AB - Time to exercise limitation (Tlim) in response to constant work rate (CWR) is sensitive to interventions in chronic obstructive pulmonary disease (COPD). This is particularly true when the pre-intervention test lasts between 3 and 8 min (Tlim3'-8'). There is, however, no simple method to select a work rate which is consistently associated with Tlim3'-8' across the spectrum of COPD severity. We assessed 59 GOLD stages II-IV patients who initially cycled to Tlim at 75% peak. In case of short (<3 min, low-endurance) or long (>8 min, high-endurance) tests, patients exercised after 60 min at 50% or 90%, respectively (CWR50%<=75%=>90%). Critical mechanical constraints and limiting dyspnea at 75% were reached within the desired timeframe in 27 "mid-endurance" patients (46%). Increasing work rate intensity to 90% hastened the mechanical-ventilatory responses leading to Tlim3' 8' in 23/26 (88%) "high-endurance" patients; conversely, decreasing exercise intensity to 50% slowed those responses leading to Tlim3'-8' in 5/6 (83%) "high endurance" patients. Repeating the tests at higher (60%) or lower (80%) intensities fail to consistently produce Tlim3'-8' in "low-" and "high endurance", respectively (p > 0.05). Compared to a fixed work rate at 75%, CWR50%<=75%=>90% significantly decreased Tlim's coefficient of variation; consequently, the required N to detect 100 s or 33% improvement in Tlim decreased from 82 to 26 and 41 to 14, respectively. This simplified approach to individualized work rate adjustment (CWR50%<=75%=>90%) might allow greater sensitivity in evaluating interventional efficacy in improving respiratory mechanics and exercise tolerance while simultaneously reducing sample size requirements in patients with COPD. PMID- 29485344 TI - Kinetic and Electromyographic Subphase Characteristics With Relation to Countermovement Vertical Jump Performance. AB - This study sought to identify kinetic and electromyographic subphase characteristics distinguishing good from poor jumpers during countermovement vertical jumps (CMVJs), as defined by the reactive strength index (RSI, CMVJ displacement divided by jump time; cutoff = 0.46 m.s-1). A total of 15 men (1.8 [0.6] m, 84.5 [8.5] kg, 24 [2] y) were stratified by RSI into good (n = 6; RSI = 0.57 [0.07] m.s-1) and poor (n = 9; RSI = 0.39 [0.06] m.s-1) performance groups. The following variables were compared between groups using independent t tests (alpha = .05) and Cohen's d effect sizes (d >= 0.8, large): jump height, propulsive impulse, eccentric rate of force development, and jump time, unloading, eccentric, and concentric subphase times, and average electromyographic amplitudes of 8 lower extremity muscles. Compared with the poor RSI group, the good RSI group exhibited a greater, though not statistically different CMVJ displacement (d = 1.07, P = .06). In addition, the good RSI group exhibited a significantly greater propulsive impulse (P = .04, d = 1.27) and a significantly more rapid unloading subphase (P = .04, d = 1.08). No other significant or noteworthy differences were detected. Enhanced RSI appears related to a quicker unloading phase, allowing a greater portion of the total jumping phase to be utilized generating positive net force. Poor jumpers should aim to use unloading strategies that emphasize quickness to enhance RSI during CMVJ. PMID- 29485345 TI - Erratum. PMID- 29485346 TI - Pyrethroid residue dynamics in insects depends on the circadian clock. AB - Many factors may affect pesticide effectiveness against pests. One of the factors that should be considered is circadian rhythmicity. In this study, we evaluated daily variations in pyrethroid susceptibility in the house cricket, Acheta domesticus L. Crickets were exposed to a standard dose of beta-cyfluthrin at different times of a day, and pesticide residue levels were evaluated using gas chromatography. Results demonstrate that the time of pyrethroid disappearance is correlated with the circadian clock, with the highest decomposition rate at night. Furthermore, crickets also showed the highest resistance to the insecticide at night, expressed as a high survival rate. Moreover, beta cyfluthrin induced significant changes in thermal preferences of intoxicated crickets. This is the first report showing that pyrethroid residue levels in the crickets' body depend on its circadian clock. PMID- 29485348 TI - Impairment of perceptual metacognitive accuracy and reduced prefrontal grey matter volume in first-episode psychosis. AB - INTRODUCTION: Metacognition, or "thinking about thinking", is a higher-order thought process that allows for the evaluation of perceptual processes for accuracy. Metacognitive accuracy is associated with the grey matter volume (GMV) in the prefrontal cortex (PFC), an area also impacted in schizophrenia. The present study set out to investigate whether deficits in metacognitive accuracy are present in the early stages of psychosis. METHODS: Metacognitive accuracy in first-episode psychosis (FEP) was assessed on a perceptual decision-making task and their performance compared to matched healthy control participants (N = 18). A novel signal detection theory approach was used to model metacognitive sensitivity independently from objective perceptual performance. A voxel-based morphometry investigation was also conducted on GMV. RESULTS: We found that the FEP group demonstrated significantly worse metacognitive accuracy compared to controls (p = .039). Importantly, GMV deficits were also observed in the superior frontal gyrus. The findings suggest a specific deficit in this processing domain to exist at first episode; however, no relationship was found between GMV and metacognitive accuracy. CONCLUSIONS: Our findings support the notion that an inability to accurately scrutinise perception may underpin functional deficits observed in later schizophrenia; however, the exact neural basis of metacognitive deficits in FEP remains elusive. PMID- 29485347 TI - Meningococcal vaccination in pregnancy. AB - Invasive meningococcal disease causes meningitis and septicemia worldwide with highest rates of disease occurring in children <2 years of age, and in particular young infants. Vaccination during pregnancy has been a successful strategy for prevention of other infections in young infants, most notably tetanus, pertussis and influenza. However, few studies of meningococcal vaccines in pregnancy have been undertaken, and none include the most commonly used current vaccines to prevent disease by capsular groups A, B, C, W and Y. The limited data suggest that the older polysaccharide vaccines are immunogenic, but the impact on prevention of infant disease has not been measured. Further studies of MenB protein vaccines and MenA protein-polysaccharide conjugate vaccines in particular are needed if vaccination in pregnancy is to be utilized as an approach to prevention of meningococcal disease in young infants. PMID- 29485349 TI - Parental experiences using the Therapy Outcomes by You (TOBY) application to deliver early intervention to their child with autism. AB - PURPOSE: As computer-based interventions become commonplace for parents of children with neurodevelopmental disorders, this study sought to understand the experience of using a parent-delivered supplementary early intervention therapy for children with autism spectrum disorder grounded in a variety of behavioral, sensory, developmental, and relationship-based approaches and delivered via a tablet device. METHODS: Parental experiences using the 'Therapy Outcomes by You' (TOBY) application were collected through semi-structured interviews with 17 parents. RESULTS: Parents reported TOBY facilitated parent-child engagement, provided ideas for therapeutic activities, created feelings of empowerment, and positively impacted their child's development. Barriers to use included preparation time, execution of the intervention, and individual strengths and weaknesses of their child. CONCLUSION: The overall parental experience of TOBY was positive when use of the application aligned with parental proficiency, opportunities for use, and importantly, the needs of the child. PMID- 29485350 TI - The Psychological Impact of the Great East Japan Earthquake on Japan Ground Self Defense Force Personnel: A Three-Wave, One-Year Longitudinal Study. AB - OBJECTIVE: Approximately 70,000 Japan Ground Self-Defense Force (JGSDF) personnel were dispatched in the wake of the 2011 Great East Japan Earthquake and the tsunami and nuclear disaster that followed. This study was conducted to evaluate the mental health of the JGSDF personnel and the correlates. METHODS: Data collected from 56,753 participants at three time points (one, six, and 12 months after mission completion) were analyzed. Those who scored 25 or more points on the Impact of Events Scale-Revised (IES-R) and the Kessler Psychological Distress Scale (K10) were allocated into the high posttraumatic stress response (high PTSR) group, and the high general psychological distress (high-GPD) group, respectively. RESULTS: The multiple logistic regression analysis identified the following factors as the significant risk factor related to high-PTSR or high-GPD status, with odds ratios of 2.0 or higher: deployment length of three or more months, being personally affected by the disaster, and being overworked continuously for three or more months after mission completion. No significant association was observed for duties with radiation exposure risk. CONCLUSIONS: Our findings suggest that disaster workers may be able to conduct disaster relief activities more safely with mission-related considerations of shorter deployment length and recognizing the effects on personnel personally affected by the disaster, in addition to avoiding overworking personnel after mission completion. PMID- 29485351 TI - Nanomedicine for neuroHIV/AIDS management. PMID- 29485352 TI - Convergent effects of a functional C3 variant on brain atrophy, demyelination, and cognitive impairment in multiple sclerosis. AB - BACKGROUND: Complement system activation products are present in areas of neuroinflammation, demyelination, and neurodegeneration in brains of patients with multiple sclerosis (MS). C3 is a central element in the activation of complement cascades. A common coding variant in the C3 gene (rs2230199, C3R102G) affects C3 activity. OBJECTIVES: To assess the effects of rs2230199 on MS severity using clinical, cognitive, and imaging measures. METHODS: In total, 161 relapse-onset MS patients (Expanded Disability Status Scale (EDSS) <= 6) underwent physical assessments, cognitive tests (Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT), and California Verbal Learning Test (CVLT)), and magnetic resonance imaging (MRI). Lesion volumes were quantified semi-automatically. Voxel-wise analyses were performed to assess the effects of rs2230199 genotype on gray matter (GM) atrophy ( n = 155), white matter (WM) fractional anisotropy (FA; n = 105), and WM magnetization transfer ratio (MTR; n = 90). RESULTS: While rs2230199 minor-allele dosage (C3-102G) showed no significant effect on EDSS and Multiple Sclerosis Functional Composite (MSFC), it was associated with worse cognitive performance ( p = 0.02), lower brain parenchymal fraction ( p = 0.003), and higher lesion burden ( p = 0.02). Moreover, voxel-wise analyses showed lower GM volume in subcortical structures and insula, and lower FA and MTR in several WM areas with higher copies of rs2230199 minor allele. CONCLUSION: C3-rs2230199 affects white and GM damage as well as cognitive impairment in MS patients. Our findings support a causal role for complement system activity in the pathophysiology of MS. PMID- 29485353 TI - Seasonal influenza vaccine in immunocompromised persons. AB - Immunocompromised persons are at high risk of complications from influenza infection. This population includes those with solid organ transplants, hematopoietic stem cell transplants, solid cancers and hematologic malignancy as well as those with autoimmune conditions receiving biologic therapies. In this review, we discuss the impact of influenza infection and evidence for vaccine effectiveness and immunogenicity. Overall, lower respiratory disease from influenza is common; however, vaccine immunogenicity is low. Despite this, in some populations, influenza vaccine has demonstrated effectiveness in reducing severe disease. Various strategies to improve influenza vaccine immunogenicity have been attempted including two vaccine doses in the same influenza season, intradermal, adjuvanted, and high-dose vaccines. The timing of influenza vaccine is also important to achieve optimal immunogenicity. Given the suboptimal immunogenicity, family members and healthcare professionals involved in the care of these populations should be vaccinated. Health care professional recommendation for vaccination is an important factor in vaccine coverage. PMID- 29485354 TI - 20-HETE synthesis inhibition promotes cerebral protection after intracerebral hemorrhage without inhibiting angiogenesis. AB - 20-HETE, an arachidonic acid metabolite synthesized by cytochrome P450 4A, plays an important role in acute brain damage from ischemic stroke or subarachnoid hemorrhage. We tested the hypothesis that 20-HETE inhibition has a protective effect after intracerebral hemorrhage (ICH) and then investigated its effect on angiogenesis. We exposed hippocampal slice cultures to hemoglobin and induced ICH in mouse brains by intrastriatal collagenase injection to investigate the protective effect of 20-HETE synthesis inhibitor N-hydroxy-N'-(4- n-butyl-2 methylphenyl)-formamidine (HET0016). Hemoglobin-induced neuronal death was assessed by propidium iodide after 18 h in vitro. Lesion volume, neurologic deficits, cell death, reactive oxygen species (ROS), neuroinflammation, and angiogenesis were evaluated at different time points after ICH. In cultured mouse hippocampal slices, HET0016 attenuated hemoglobin-induced neuronal death and decreased levels of proinflammatory cytokines and ROS. In vivo, HET0016 reduced brain lesion volume and neurologic deficits, and decreased neuronal death, ROS production, gelatinolytic activity, and the inflammatory response at three days after ICH. However, HET0016 did not inhibit angiogenesis, as levels of CD31, VEGF, and VEGFR2 were unchanged on day 28. We conclude that 20-HETE is involved in ICH-induced brain damage. Inhibition of 20-HETE synthesis may provide a viable means to mitigate ICH injury without inhibition of angiogenesis. PMID- 29485355 TI - Usefulness of classical homeopathy for the prophylaxis of recurrent urinary tract infections in individuals with chronic neurogenic lower urinary tract dysfunction. AB - Context/Objective to investigate the usefulness of classical homeopathy for the prevention of recurrent urinary tract infections (UTI) in patients with spinal cord injury (SCI). Design prospective study. Setting rehabilitation center in Switzerland. Participants patients with chronic SCI and >=3 UTI/year. Interventions Participants were treated either with a standardized prophylaxis alone or in combination with homeopathy. Outcome measures The number of UTI, general and specific quality of life (QoL), and satisfaction with homeopathic treatment were assessed prospectively for one year. Results Ten patients were in the control group; 25 patients received adjunctive homeopathic treatment. The median number of self-reported UTI in the homeopathy group decreased significantly, whereas it remained unchanged in the control group. The domain incontinence impact of the KHQ improved significantly (P = 0.035), whereas the general QoL did not change. The satisfaction with homeopathic care was high. Conclusions Adjunctive homeopathic treatment lead to a significant decrease of UTI in SCI patients. Therefore, classical homeopathy could be considered in SCI patients with recurrent UTI. Trial registration ClinicalTrials.gov. (NCT01477502). PMID- 29485356 TI - Effects of Corrective Training on Drop Landing Ground Reaction Force Characteristics and Lower Limb Kinematics in Older Adults With Genu Valgus: A Randomized Controlled Trial. AB - The aim of this study was to identify the effects of a corrective exercise program on landing ground reaction force characteristics and lower limb kinematics in older adults with genu valgus. A total of 26 older male adults with genu valgus were randomized into two groups. An experimental group conducted a 14 week corrective exercise program, whereas a control group did not perform any exercise. The experimental group displayed lower peak vertical, peak anterior and posterior, and peak medial ground reaction force components during the posttest compared with the pretest. The vertical loading rate, impulses, and free moment amplitudes were not statistically different between groups. In the experimental group, the peak knee abduction during the posttest was significantly smaller and the peak hip flexion angle was significantly greater than during the pretest. The authors suggest that this corrective exercise program may be a suitable intervention to improve landing ground reaction forces and lower limb kinematics in older male adults with genu valgus. PMID- 29485357 TI - Childhood trauma and anorexia nervosa: From body image to embodiment. AB - Contemporary understandings of anorexia nervosa are framed by the body image paradigm. The body-image framework considers that women's bodily experiences are reflected through distorted mental images of their bodies or disordered thinking and behavior around food and eating. Body image has come to symbolize all that can go wrong with women's relationship with their bodies, food and eating. The problem with this approach is its failure to consider the experience of women who survived childhood abuse. Women's bodily disturbances are not easily discernible through objective measures as they lie within the inner subjective realm of the embodied 'self', and embodied emotional experience. Consideration of the different ways that women inhabit their bodies inform this paper's examination of the conceptual framework embodiment as an alternate to the body image paradigm. PMID- 29485358 TI - The knowledge about autonomic dysreflexia among nursing and physiotherapy students. AB - CONTEXT/OBJECTIVE: Autonomic dysreflexia is a clinical syndrome affecting persons with spinal cord lesions. The aim of the study was to detect the level of knowledge among students about autonomic dysreflexia in persons with spinal cord lesions. DESIGN: Single centre questionnaire study. SETTING: Faculty of Health Studies, Rijeka, Croatia. PARTICIPANTS: Nursing (n = 43) and physiotherapy (n = 48) students. OUTCOME MEASURES: AD knowledge test. RESULTS: More of the half of the students (57%) had contact with persons with spinal cord lesions during work, especially nursing students. The self-estimated knowledge of autonomic dysreflexia was judged as poor or none in 73.6% of students. On the autonomic dysreflexia knowledge test, nursing students collected mean of 5.6 points and physiotherapy students 4.9 points (P = 0.173). There was no difference in the autonomic dysreflexia test results regardless of work experience or group affiliation. CONCLUSION: The level of knowledge about autonomic dysreflexia among students was low. Our results suggest the need for more education of students and health care professionals to apply adequate treatment to persons with episodes of autonomic dysreflexia. PMID- 29485359 TI - Influence of ionizing radiation on the antimicrobial activity of the antibiotics sulfamethoxazole and trimethoprim. AB - The response of the antimicrobial compounds sulfamethoxazole (SMX) and trimethoprim (TMP) - individually and in mixtures - to ionizing radiation was investigated using laboratory prepared mixtures and a commercial pharmaceutical formulation. The residual antibacterial activity of the solutions was monitored using Staphylococcus aureus and Escherichia coli test strains. Based on antibacterial activity, SMX was more susceptible to ionizing radiation as compared to TMP. The antibacterial activity of SMX and TMP was completely eliminated at 0.2 kGy and 0.8 kGy, respectively. However, when SMX and TMP were in a mixture, the dose required to eliminate the antibacterial activity was 10 kGy, implying a synergistic antibacterial activity when these are present in mixtures. Only when the antibiotic concentration was below the Minimum Inhibitory Concentration of TMP (i.e., 2 umol dm-3) did the antibacterial activity of the SMX and TMP mixture disappear. These results imply that the synergistic antimicrobial activity of antimicrobial compounds in pharmaceutical waste streams is a strong possibility. Therefore, antimicrobial activity assays should be included when evaluating the use of ionizing radiation technology for the remediation of pharmaceutical or municipal waste streams. PMID- 29485360 TI - Center of Pressure and Perceived Stability in Basketball Shoes With Soft and Hard Midsoles. AB - This study aimed to investigate the effects of varying midsole hardness on center of pressure (COP) and perceived stability during basketball-specific tasks, as well as the correlation between COP and perception measurements. A total of 20 male basketball players performed 45 degrees cutting and layup while wearing basketball shoes with soft and hard midsoles. COP trajectories were obtained from the Pedar insole system. Stability perceptions at the forefoot and rearfoot were assessed using 150-mm visual analogue scales. Results indicated greater COP mediolateral deviations in soft midsole compared with hard midsole during layup (soft: 16.6 [4.7] mm, hard: 15.8 [4.6] mm, P = .03) but not 45 degrees cutting (soft: 15.7 [5.9] mm, hard: 15.8 [5.6] mm, P = .60). While 16 out of 20 participants preferred soft midsole, no significant difference in visual analogue scale ratings was found between shoes for both tested movements. There was no significant correlation between COP and perceived stability during layup or 45 degrees cutting. In conclusion, midsole hardness of basketball shoes did not consistently affect mediolateral stability of the foot during 45 degrees cutting and layup. Subjective perception alone cannot be used to indicate mediolateral deviation of the foot when executing basketball-specific maneuvers. PMID- 29485361 TI - The attractiveness-positivity link: Let's contextualize it. AB - The statement "what is beautiful is good" reflects a persuasive heuristic that may be supported either by a general association of attractiveness with positivity or by a specific association with the perceived credibility of an attractive source. In one study (N = 58), we approach this question using an explicit and an implicit measure (Stroop Task) to assess whether attractiveness is more likely associated with valenced words when these are related (vs. unrelated) to credibility. Results show that this effect occurs but only for the implicit measure. When the word-face associations were made at an explicit level, we found a general association between positivity and attractiveness, unrestricted to the dimension of credibility. We discuss how these results inform about attractiveness as a shortcut to judgments of validity. PMID- 29485362 TI - Runners With Patellofemoral Pain Exhibit Greater Peak Patella Cartilage Stress Compared With Pain-Free Runners. AB - The primary purpose of this study is to determine whether recreational runners with patellofemoral pain (PFP) exhibit greater peak patella cartilage stress compared with pain-free runners. A secondary purpose was to determine the kinematic and/or kinetic predictors of peak patella cartilage stress during running. A total of 22 female recreational runners (12 with PFP and 10 pain-free controls) participated in this study. Patella cartilage stress profiles were quantified using subject-specific finite element models simulating the maximum knee flexion angle during the stance phase of running. Input parameters to the finite element model included subject-specific patellofemoral joint geometry, quadriceps muscle forces, and lower-extremity kinematics in the frontal and transverse planes. Tibiofemoral joint kinematics and kinetics were quantified to determine the best predictor of stress using stepwise regression analysis. Compared with the pain-free runners, those with PFP exhibited greater peak hydrostatic pressure (PFP vs control: 21.2 [5.6] MPa vs 16.5 [4.6] MPa) and maximum shear stress (PFP vs control: 11.3 [4.6] MPa vs 8.7 [2.3] MPa). Knee external rotation was the best predictor of peak hydrostatic pressure and peak maximum shear stress (38% and 25% of variances, respectively), followed by the knee extensor moment (21% and 25% of variances, respectively). Runners with PFP exhibit greater peak patella cartilage stress during running compared with pain free individuals. The combination of knee external rotation and a high knee extensor moment best predicted the elevated peak stress during running. PMID- 29485363 TI - Deep vein thrombosis and properties of the arterial wall. AB - BACKGROUND: Deep vein thrombosis (DVT) affects more than one out of 1,000 people every year, of which 50 % develop post-thrombotic syndrome (PTS). Studies indicated that patients with DVT have deteriorated arterial wall function, while less is known about the association with PTS. We therefore investigated this relationship further. PATIENTS AND METHODS: A total of 120 patients treated for DVT of the lower extremity and a control group of 40 subjects without DVT were included. We assessed the presence of PTS using the Villalta scale. Flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD) were calculated and reactive hyperaemia index (RHI) and augmentation index (AI) were obtained. RESULTS: Patients with a history of DVT had lower FMD (4.0 % vs. 8.0 %, p < 0.001), lower NMD (12 % vs. 19 %, p = 0.001), and increased diameter of brachial artery (4.8 mm vs. 4.4 mm, p = 0.017). Peripheral arterial tonometry showed higher AI in patients with DVT (22.0 vs. 6.0, p = 0.004), while there was no difference in RHI. No differences in values between PTS-positive and PTS-negative patients were found. CONCLUSIONS: We confirmed the association between DVT and deteriorated functional properties of the arterial wall. Endothelial dysfunction of the large arteries, increased arterial stiffness, and increased diameter of the brachial artery were found in patients with DVT. However, there was no association between functional capability of the arterial wall and the incidence of PTS in DVT patients. PMID- 29485364 TI - Syringobulbia: A delayed complication following spinal cord injury - case report. AB - CONTEXT: Syringobulbia is a very rare progressive disorder of central nervous system, with several possible underlying conditions. Rarely, it is also encountered as a late complication of syringomyelia. FINDINGS: In the present manuscript, a case of a paraplegic patient, due to traumatic spinal cord injury (thoracolumbar fracture), presenting after years progressively developing symptoms of the lower cranial nerves and upper extremities, owed to syringomyelia and syringobulbia, the surgical treatment applied and its outcomes are described. We performed a syringo-peritoneal shunting procedure using a T-tube. The patient's symptoms resolved postoperatively and the cavity's size was reduced to a great degree. CONCLUSION/CLINICAL RELEVANCE: The late appearance of cranial nerve deficits or symptoms-signs of the upper extremities in a patient with traumatic thoracic spinal cord injury should raise suspicion that post-traumatic syringomyelia or syringobulbia has occurred. In such cases, radiologic evaluation and early surgical drainage of the cyst as a means of preventing significant delayed neurologic deficit is advocated. PMID- 29485366 TI - Interplay of vitamin D, vitamin B12, homocysteine and bone mineral density in postmenopausal females. AB - Osteoporosis is most common age related, multifactorial disease. The aim of the researchers were to discover the association between serum homocysteine, vitamin D, vitamin B12 and bone mineral density in postmenopausal non-osteoporotic and osteoporotic females. In this cross- sectional study, 156 postmenopausal females between 50-70 years of age were recruited and divided into two groups, non osteoporotic (n = 52) and osteoporotic (n = 104). There was significant negative correlation of homocysteine with vitamin D and B12 in postmenopausal non osteoporotic and homocysteine with vitamin B12 in postmenopausal osteoporotic females. Serum homocysteine levels were predicted by vitamin D in postmenopausal non-osteoporotic and vitamin B12 in postmenopausal osteoporotic females. PMID- 29485365 TI - Childhood trauma, combat trauma, and substance use in National Guard and reserve soldiers. AB - BACKGROUND: The goal of this work was to examine associations among childhood trauma, combat trauma, and substance use (alcohol problems, frequent heavy drinking [FHD], current cigarette smoking, and current/lifetime drug use) and the interaction effects of childhood trauma and combat exposure on those associations among National Guard/reserve soldiers. METHODS: Participants (N = 248) completed an electronic survey asking questions about their military experiences, physical and mental health, and substance use. Childhood trauma and combat exposure were examined jointly in regression models, controlling for age, marital satisfaction, and number of deployments. RESULTS: Childhood trauma was associated with current drug use (trend level, odds ratio [OR] = 1.44, 95% confidence interval [CI]: 0.97, 2.14; P = .072) in the main effect model; however, there was not a significant interaction with combat. Combat exposure had a significant interaction with childhood trauma on alcohol problems (b = -0.56, 95% CI: -1.12, 0.01; P = .048), FHD (b = -0.27, 95% CI: -0.47, -0.08; P = .007), and lifetime drug use (OR = 1.78, 95% CI: 1.04, 3.04; P = .035). There were no associations with either of the trauma measures and current cigarette smoking. CONCLUSIONS: These results demonstrate that childhood and combat trauma have differential effects on alcohol use, such that combat trauma may not add to the effect on alcohol use in those with greater child maltreatment but may contribute to greater alcohol use among those with low child maltreatment. As expected, childhood and combat trauma had synergistic effects on lifetime drug use. Screening for multiple types of trauma prior to enlistment and/or deployment may help to identify at-risk individuals and allow time for early intervention to prevent future adverse outcomes. PMID- 29485367 TI - Orbital malignant meningioma: a unique presentation of a rare entity. AB - An elderly female with progressive proptosis was found to have an aggressive retrobulbar solid orbital mass. The mass was distinct from the optic nerve sheath and intracranial meninges, and produced concave erosion of the sphenoid wing. Operative findings demonstrated an orbital mass adherent to the dura of the superior orbital fissure. The mass did not demonstrate meningeal violation, infiltrate the superior orbital fissure, or display intracranial spread. The dura remained intact after gross total resection. Histopathology revealed a malignant meningioma with papillary and focal rhabdoid morphology and bony invasion (WHO grade III). The patient received 2500cGy of stereotactic radiotherapy in addition to gross total resection. Postoperatively, the signs and symptoms of orbital mass effect resolved (proptosis, relative afferent papillary defect, and periorbital edema) and the vision improved. There was no orbital recurrence or intracranial extension. The follow-up time was limited to eight months secondary to the patient succumbing to metastatic lung adenocarcinoma, which was demonstrated to be a separate process from the orbital meningioma. We propose the etiology of this tumor to be most consistent with an orbital malignant primary extradural meningioma - the first case reported in the literature. PMID- 29485369 TI - Freud's Rejection of Hypnosis, Part II: The Perpetuation of a Rift. AB - Freud's rejection of hypnosis gave rise to a rift between clinical hypnosis and psychoanalysis that has endured for over a century. A review of Freud's rationales (Kluft, 2018a/this issue) demonstrates that while some stemmed from what he considered advances, others appear strongly influenced by his promoting the superiority of his "psycho-analysis" at the expense of hypnosis. Mainstream psychoanalysis continues to endorse the perpetuation of rationales Freud asserted nearly a century ago, and an oral lore of related supportive statements. This oral lore proves difficult to sustain upon closer scrutiny. It bypasses concerns that, if studied in depth, would demonstrate significant shortcomings. Problems encountered in this oral lore include: (1) the importance of information unavailable to Freud; (2) the ongoing impact of certain errors of Freud's thinking; (3) the distorting force of Freud's compelling drive to be a "conquistador" of the mind and create a heroic theory; (4) the implausibility, upon inspection, of certain long-accepted assertions about Freud's motivations; and (5) Freud's discomfort with his own dissociative symptomatology. It is argued that the "oral lore" promulgated in connection with Freud's rejection of hypnosis, like Freud's decision to reject hypnosis itself, is not firmly grounded and deserves careful reassessment. PMID- 29485370 TI - Review of the International Literature. PMID- 29485372 TI - Editorial. PMID- 29485373 TI - Two are Better Than One: Dual-Track Interventions in Hypnotherapy. AB - The current article provides clinical conceptualizations of six dual-track interventions for dealing with stuck and resistant situations in hypnotherapy. Dual-track interventions are based on the assumption that patients habitually regard their problems as one-dimensional and thus, tend to become rigid in their attitudes toward these problems. Dual-track interventions constitute hypnotherapeutic processes for transforming patients' negative and rigid perceptions of their problems into more positive and functional mental states that provide a dual-dimensional view, thereby offering patients more options and freeing them to contend with their problems more effectively. We introduce a novel hypnotherapeutic tool from the Illness/Nonillness Model (Navon 2014). This tool, known as the differentiation tool, can transform negative perceptions of psychological and emotional conditions to positive and hopeful perceptions. PMID- 29485374 TI - Integrating Hypnosis with Other Therapies for Treating Specific Phobias: A Case Series. AB - There is a high prevalence of anxiety disorders including specific phobias and panic disorder in the United States and Europe. A variety of therapeutic modalities including pharmacotherapy, cognitive behavioral therapy, systematic desensitization, hypnosis, in vivo exposure, and virtual reality exposure therapy have been applied. No one modality has been entirely successful. There has been only a limited attempt to combine psychological therapies in the treatment of specific phobias and panic disorder and what has been done has been primarily with systematic desensitization or cognitive behavioral therapy along with hypnotherapy. I present two cases of multiple specific phobias that were successfully treated with hypnotherapy combined with virtual reality exposure therapy or in vivo exposure therapy. The rationale for this integrative therapy and the neurobiological constructs are considered. PMID- 29485375 TI - An Extension Study Using Hypnotic Suggestion as an Adjunct to Intravenous Sedation. AB - The effects of hypnosis/therapeutic suggestion in connection with intravenous sedation and surgery have been described in many clinical publications; however, few randomized, controlled, and blind studies have been performed in the outpatient area. The original study published in 2010 aimed to evaluate the use of hypnosis/therapeutic suggestion as an adjunct to intravenous sedation in patients having third molar removal in an outpatient setting. The patients were randomly assigned to a treatment or control group. The treatment group listened to a rapid conversational induction and therapeutic suggestions via headphones throughout the entire surgical procedure along with a standard sedation dose of intravenous anesthetic. The control group received intravenous anesthesia but listened to only music without any hypnotic intervention. The current replication study addressed several of the limitations of the original. Sample size was increased and selection of participants from a different geographic area in Pennsylvania. Intra-operative propofol administration, patient post-operative pain ratings, and post-operative prescription pain reliever consumption were all significantly reduced in the treatment compared to the control group. Implications of these results are discussed. PMID- 29485376 TI - Psychometric Analysis of the Barber Suggestibility Scale in a Clinical Population. AB - The aim of the study was to administer the Barber suggestibility scale to a clinical population in Spain and to examine its psychometric properties therein. The reliability and factor structure of the adapted scale was compared with that of the original (American) scale and with data from two other versions (British and Puerto Rican samples). Sex differences in suggestibility were also analyzed. The Barber suggestibility scale was administered (without preliminaries) to a sample of 283 patients (130 women, 153 men) with a range of diagnoses: anxiety disorder (33.9%), substance-related and addictive disorder (25.8%), mood disorder (12.7%), somatic symptom disorder (4.6%), trauma- and stress-related disorder (3.5%), and other disorders (19.5%). Results indicated a higher degree of suggestibility among women, with the effect size being low (d = 0.26) for the objective subscale and moderate (d = 0.55) for the subjective subscale. Therefore, normative scores were reported by sex for both subscales. As a whole, the present clinical sample showed higher suggestibility than has been reported previously for nonclinical populations (p < 0.001; d = 1.56). Reliability indices (Cronbach's alpha and split-half/Spearman-Brown) for the present adaptation in a clinical population indicated acceptable internal consistency (range 0.70-0.82). Applied to a clinical sample the Barber suggestibility scale showed a three factor structure for the objective subscale and a more complex structure for the subjective subscale. These results suggest that the Barber suggestibility scale is a suitable instrument for assessing the degree of suggestibility in persons with a clinical disorder. PMID- 29485377 TI - Freud's Rejection of Hypnosis, Part I: The Genesis of a Rift. AB - Modern psychoanalysis begins with Sigmund Freud's study of hypnosis and the treatment of the grand hysterics of the fin de siecle. In the process of developing his own paradigm, Freud came to reject the use of hypnosis and turned his attention away from the severe hysterias. These decisions began what has become, notwithstanding noteworthy exceptions, over a century of estrangement and disengagement between the fields of hypnosis and psychoanalysis. The current communication reviews the 75 archived Psychoanalytic Electronic Publishing resources from Freud's scientific work and correspondence in which reference is made to hypnosis. A close examination of Freud's stated rationales for abandoning hypnosis suggests that both the ideas he developed and the rift between hypnosis and psychoanalysis that they created may prove to have been problematic as well as innovative. They and their consequences merit thoughtful review and critical reconsideration. PMID- 29485379 TI - The Rate of Adverse Events Related to Hypnosis During Clinical Trials. AB - The rate of adverse events associated with medical and psychological interventions is important to regulators who oversee clinical research. There have been relatively few reports on the frequency of adverse events associated with hypnosis. The current article collected data from a publically available register (ClinicalTrials.gov) on adverse events reported during clinical trials that used hypnosis. The rate of serious adverse events likely attributable to hypnosis was 0%. The rate of other adverse events was 0.47%. This rate was similar to previous reports. However, several trials in the register that used hypnosis did not report adverse event data. For the trials that did report adverse events, there was substantial variability in reporting. Another limitation was the lack of generalizability as all studies included in the analysis used hypnosis to treat side-effects related to medical conditions or procedures as opposed to psychiatric conditions. Future clinical trials using hypnosis should use more precise assessment methods to report adverse events, especially when tested in samples with mental health disorders. PMID- 29485381 TI - DELLA-dependent and -independent gibberellin signaling. AB - DELLA proteins act as negative regulators in gibberellin (GA) signal transduction. GA-induced DELLA degradation is a central regulatory system in GA signaling pathway. Intensive studies have revealed the degradation mechanism of DELLA and the functions of DELLA as a transcriptional regulator. Meanwhile, recent studies suggest the existence of a DELLA-independent GA signaling pathway. In this review, we summarized the DELLA-independent GA signaling pathway together with the well-analyzed DELLA-dependent pathway. PMID- 29485382 TI - Empower, not impose!-Preventing academic procrastination. AB - In the frame of the goal setting process between supervisor and student while writing a thesis, it is hypothesized that mutually set goals (participation) and writing down the results of the meeting (recording) can prevent procrastination and increase engagement of the student. With a questionnaire relating to the latest written thesis (n = 97, academic sample), the effects of goal setting characteristics (recording, participation) and task characteristics (ambiguity, control) on engagement and procrastination were examined. Results of a multiple mediation model indicate that recording indirectly influences engagement and procrastination through its effect on ambiguity. Moreover, participation indirectly influences engagement through its effect on control. It is concluded that goal setting characteristics and task characteristics can affect student's procrastination. Thus, the present research provides criteria for how supervisors can prevent students from procrastinating. PMID- 29485383 TI - Academic procrastination and feelings toward procrastination in LD and non-LD students: Preliminary insights for future intervention. AB - Academic procrastination is a prevalent behavior that negatively influences students' performance and well-being. The growing number of students with learning disabilities (LD) in higher education communities leads to the need to study and address academic procrastination in this unique population of students and to develop ways to prevent and intervene. The present study examined the difference in academic procrastination between LD, non-LD, and supported LD college students in Israel. Findings indicated a significant difference between the three groups, both in academic procrastination and in the desire to change this behavior. Interestingly, supported LD students were similar to non-LD students in all parameters of academic procrastination; however, they expressed less desire to change this behavior than unsupported LD students. These findings highlight the effect of general academic support on academic procrastination in LD students. Future studies will need to further explore the specific elements of support that most contribute to the reduction of academic procrastination in LD students. Specific support programs for academic procrastination in LD students who take into account the findings of these future studies can then be developed and studied. PMID- 29485384 TI - Academic interventions for academic procrastination: A review of the literature. AB - Procrastination is a widespread phenomenon in academic settings. It has been studied from many different theoretical angles, and a variety of causes and consequences have been suggested. Recent studies support the notion that academic procrastination can be seen from a situational perspective and as a failure in learning self-regulation. It suggests that interventions should address situational as well as deficits in self-regulation to help students overcome their procrastinating tendencies. The present review examined the recent literature on causes and consequences of academic procrastination and the limited number of studies of academic interventions for academic procrastination. Findings of this review strengthen the need to further study the topic of academic interventions for academic procrastination and to develop effective interventions. At the end of this review, several suggestions for the development of academic interventions are outlined. PMID- 29485385 TI - "I'll stop procrastinating now!" Fostering specific processes of self-regulated learning to reduce academic procrastination. AB - Academic procrastination is considered to be a result of self-regulation failure having detrimental effects on students' well-being and academic performance. In the present study, we developed and evaluated a group training that aimed to reduce academic procrastination. We based the training on a cyclical process model of self-regulated learning, thus, focusing on improving deficient processes of self-regulated learning among academic procrastinators (e.g., time management, dealing with distractions). The training comprised five sessions and took place once a week for 90 min in groups of no more than 10 students. Overall, 106 students completed the training. We evaluated the training using a comprehensive control group design with repeated measures (three points of measurement); the control group was trained after the intervention group's training. The results showed that our training was successful. The trained intervention group significantly reduced academic procrastination and improved specific processes of self-regulated learning (e.g., time management, concentration), whereas the untrained control group showed no change regarding these variables. After the control group had also been trained, the control group also showed the expected favorable changes. The students rated the training overall as good and found it recommendable for procrastinating friends. Hence, fostering self-regulatory processes in our intervention was a successful attempt to support students in reducing academic procrastination. The evaluation of the training encourages us to adapt the training for different groups of procrastinators. PMID- 29485386 TI - Is procrastination all that "bad"? A qualitative study of academic procrastination and self-worth in postgraduate university students. AB - Most of the existing literature investigated the construct of procrastination using quantitative paradigms-primarily self-administered questionnaires. However, such approaches seem to limit insight, elaboration, and deeper understanding of central facets that might influence procrastination. The present qualitative study explored how a sample of postgraduate students from Cambridge University represented academic procrastination framed within their personal perspectives and context using semistructured interviews. This study extends the existing quantitative literature by adding students' personal narratives and voices. Ten postgraduate students were interviewed and the data were analyzed using thematic analysis. The preponderance of the literature on academic procrastination has described it as a maladaptive and detrimental behavior. However, the present study found evidence which supports the existence of a positive form of procrastination as well which suggests that procrastination can sometimes be worthwhile and allow further thinking time, allowing students to do a task and enable them to give more attention to detail which suggests a reconsideration of the negative image commonly associated with procrastination. PMID- 29485387 TI - Academic procrastination and academic performance: An initial basis for intervention. AB - Academic procrastination is a prevalent phenomenon with a range of negative outcomes. Many studies focused on causes and correlates of academic procrastination; however, the study of interventions for academic procrastination is scarce. The present study is an initial effort to study the relationship between academic procrastination, online course participation, and achievement, as a basis for developing an intervention for academic procrastination. Findings indicated that studying procrastination was negatively associated with final exam grade as well as with the three online course participation measures. Final exam grade was positively associated with two of the online course participation measures, and they positively correlated with each other. In addition, results indicated that studying procrastination, in combination with online course participation measures, explained about 50% of variance in final exam's grade. Frequency of activities in course Web site had the strongest positive effect on final exam's grade. These findings strengthen the notion that studying procrastination is an impediment to students' academic performance and outcomes and clarifies the need to develop and study academic interventions for academic procrastination as a means to decrease its prevalence in academic settings. PMID- 29485388 TI - Developing an intervention to overcome procrastination. AB - The main goal of this study was the development of a reliable intervention to overcome general procrastination orientated to college students, designed to be used in practical clinical work. The workshops involved six meetings based on behavioral and cognitive techniques, paradox intervention, and psychoeducation. 175 students participated voluntarily. Their procrastination levels were measured in a pretest, post-test, and a 3-month follow-up. After the first interview, the participants were randomly divided into three groups (Intervention A, Intervention B, and a control group with no intervention). There was a significant improvement after the intervention. After 3 months, the average score was still significantly lower than in the pretest, whereas the score of the control group remained unchanged. The participants in Workshop A scored significantly lower in the post-test than the ones in Workshop B. After 3 months, the participants in Workshop B scored significantly lower in the follow up. So both interventions resulted to be effective in reducing procrastination sustainably. PMID- 29485389 TI - Prevention and intervention for academic procrastination in academic communities. PMID- 29485390 TI - Laboratory challenges in the diagnosis of hepatitis E virus. AB - Hepatitis E virus (HEV) is an RNA virus that is an important cause of both acute and chronic hepatitis worldwide. To date, there are eight HEV genotypes that can infect mammals. HEV-1 and HEV-2 infect exclusively humans, while HEV-3 and HEV-4 infect humans and various animals, mainly pigs and deer. Additionally, two new genotypes (HEV-5 and HEV-6) infect mainly wild boar. Recently, newly discovered genotypes HEV-7 and HEV-8 were found to infect camels and possibly humans. Nevertheless, the epidemiological distribution of HEV-7 is not well established. HEV-8 is another newly discovered genotype that was identified in 2016 in Chinese Bactrian camels. Although faecal-oral transmission is the most common route of HEV transmission, HEV can be vertically transmitted from infected mothers to their fetuses. HEV may also spread by zoonotic transmission from infected animals to humans and through person-to-person contact. Nowadays, since the number of reported cases linked to blood donations is increasing annually, HEV is recognized as a transfusion-transmitted virus. Laboratory diagnostic techniques vary in their specificity and sensitivity for HEV detection. Direct techniques allow for detection of the viral proteins, antigens and viral nucleic acid, while HEV-specific IgG and IgM antibodies can help establish a diagnosis in acute and chronic infections. In this review, we will discuss recent technologies in the laboratory diagnosis of HEV, including serological and molecular methods to assess the specificity and sensitivity of currently available HEV commercial assays. PMID- 29485391 TI - Pseudonocardia soli sp. nov., isolated from mountain soil. AB - A novel actinomycete, designated strain NW8-21T, was isolated from mountain soil in Mae-Wong National Park, Nakornsawan province, Thailand, and was taxonomically characterized by using a polyphasic approach. Based on 16S rRNA gene sequence analysis, the strain was revealed to have the closest similarity to Pseudonocardia endophytica YIM 56035T with the highest 16S rRNA gene sequence similarity value of 98.7 %, followed by Pseudonocardia nantongensis KLBMP 1282T (98.0 %). The chemotaxonomic properties, i.e. arabinose and galactose as the diagnostic reducing sugar in cells, MK-8 (H4) as a major menaquinone, iso-C16 : 0 as the main cellular fatty acid component and phosphatidylethanolamine, phosphatidylmethylethanolamine, diphosphatidylglycerol, phosphatidylglycerol and phosphatidylinositol, phosphatidylcholine as the characteristic phospholipids, confirmed a taxonomic affiliation of the strain that was consistent with those of the genus Pseudonocardia. Several phenotypic differences and the DNA-DNA hybridization results (less than 40 % relatedness value) indicated that strain NW8-21T shoud be considered to represent a novel species of the genus Pseudonocardia, for which the name Pseudonocardia soli is proposed. The type strain is strain NW8-21T (=BCC 58125T=NBRC 109519T). PMID- 29485392 TI - Flavobacterium cyanobacteriorum sp. nov., isolated from cyanobacterial aggregates in a eutrophic lake. AB - A Gram-reaction-negative, aerobic, non-flagellated, non-gliding, rod-shaped and yellow-pigmented bacterium, designated strain TH021T, was isolated from cyanobacterial aggregates in a eutrophic lake, Taihu Lake, China. Optimal growth occurred at pH 7.0 (range: 5.0-10.0), 28 degrees C (range, 4-32 degrees C) and 0 % (w/v) NaCl (range, 0-1.0 %) in Reasoner's 2A broth. No growth was observed at 37 degrees C. The cells were found to be positive for oxidase and catalase activities. The major respiratory quinone was menaquinone-6. The major fatty acids (>10 %) were identified as iso-C15 : 0 and C16 : 1omega7c/C16 : 1omega6c. The major polar lipid was phosphatidylethanolamine. Phylogenetic analysis based on 16S rRNA gene sequences revealed that the isolate was affiliated with the genus Flavobacterium, with the highest sequence similarity found to Flavobacterium hauense BX12T (94.92 %), followed by Flavobacterium suzhouense XIN 1T (94.85 %), Flavobacterium arcticum SM1502T (94.79 %) and Flavobacterium beibuense F44-8T (94.30 %). The genomic G+C content of strain TH021T was 41.9 mol% based on total genome calculations. Average nucleotide identities and digital DNA-DNA hybridizations values for complete genomes ranged from 69.4 to 72.8 and 18.0 to 23.8 % between strain TH021T and strains within the genus Flavobacterium. The phenotypic, chemotaxonomic and phylogenetic properties, and genome analysis suggested that strain TH021T represents a novel species within the genus Flavobacterium, for which the name Flavobacterium cyanobacteriorum sp. nov. is proposed. The type strain is TH021T (=LMG 29720T=CGMCC 1.16325T). PMID- 29485393 TI - Transcription factor VdCmr1 is required for pigment production, protection from UV irradiation, and regulates expression of melanin biosynthetic genes in Verticillium dahliae. AB - Verticillium dahliae is a soilborne fungus that causes vascular wilt diseases on numerous plant species worldwide. The production of darkly melanized microsclerotia is crucial in the disease cycle of V. dahliae, as these structures allow for long-term survival in soil. Previously, transcriptomic and genomic analysis identified a cluster of genes in V. dahliae that encodes some dihydroxynaphthalene (DHN) melanin biosynthetic pathway homologues found in related fungi. In this study, we explored the roles of cluster-specific transcription factor VdCmr1, as well as two other genes within the cluster encoding a polyketide synthase (VdPKS1) and a laccase (VdLac1), enzymes at initial and endpoint steps in DHN melanin production. The results revealed that VdCmr1 and VdPKS1 are required for melanin production, but neither is required for microsclerotia production. None of the three genes were required for pathogenesis on tobacco and lettuce. Exposure of DeltaVdCmr1 and wild-type strains to UV irradiation, or to high temperature (40 degrees C), revealed an approx. 50 % reduction of survival in the DeltaVdCmr1 strain, relative to the wild-type strain, in response to either condition. Expression profiles revealed that expression of some melanin biosynthetic genes are in part dependent on VdCmr1. Combined data indicate VdCmr1 is a key regulator of melanin biosynthesis, and that via regulation of melanogenesis, VdCmr1 affects survival of V. dahliae in response to abiotic threats. We conclude with a model showing regulation of VdCmr1 by a high osmolarity glycerol response (Hog)-type MAP kinase pathway. PMID- 29485394 TI - Mixta gen. nov., a new genus in the Erwiniaceae. AB - The Erwiniaceae contain many species of agricultural and clinical importance. Although relationships among most of the genera in this family are relatively well resolved, the phylogenetic placement of several taxa remains ambiguous. In this study, we aimed to address these uncertainties by using a combination of phylogenetic and genomic approaches. Our multilocus sequence analysis and genome based maximum-likelihood phylogenies revealed that the arsenate-reducing strain IMH and plant-associated strain ATCC 700886, both previously presumptively identified as members of Pantoea, represent novel species of Erwinia. Our data also showed that the taxonomy of Erwinia teleogrylli requires revision as it is clearly excluded from Erwinia and the other genera of the family. Most strikingly, however, five species of Pantoea formed a distinct clade within the Erwiniaceae, where it had a sister group relationship with the Pantoea + Tatumella clade. By making use of gene content comparisons, this new clade is further predicted to encode a range of characters that it shares with or distinguishes it from related genera. We thus propose recognition of this clade as a distinct genus and suggest the name Mixta in reference to the diverse habitats from which its species were obtained, including plants, humans and food products. Accordingly, a description for Mixta gen. nov. is provided to accommodate the four species Mixta calida comb. nov., M. gaviniae comb. nov., M. intestinalis comb. nov. and M. theicola comb. nov., with M. calida as the type species for the genus. PMID- 29485395 TI - Human parainfluenza virus type 2 V protein inhibits caspase-1. AB - The multifunctional V protein of human parainfluenza virus type 2 (hPIV2) plays important roles in controlling viral genome replication, inhibiting the host interferon response and promoting virus growth. We screened a yeast two-hybrid library using V protein as bait to identify host factors that are important for other functions of V. One of several positive clones isolated from HeLa cell derived cDNA library encodes caspase-1. We found that the C-terminal region of V interacts with the C-terminal region of caspase-1 in mammalian cells. Moreover, the V protein repressed caspase-1 activity and the formation of interleukin-1beta (IL-1beta) in a dose-dependent manner. IL-1beta secretion induced by wild-type hPIV2 infection in human monocytic THP-1 cells was significantly lower than that induced by recombinant hPIV2 lacking V protein or having a mutant V. These data suggest that hPIV2 V protein inhibits caspase-1-mediated maturation of IL-1beta via its interaction with caspase-1. PMID- 29485396 TI - Proposal of Nemorincola gen. nov. to replace the illegitimate prokaryotic genus name Nemorella Chaudhary et al. 2018. AB - The prokaryotic genus name Nemorella Chaudhary et al. 2018 is illegitimate because it is a later homonym of the plant genus name Nemorella Ehrhart 1789 [Principle 2 of the Prokaryotic Code (2008 Revision)]. This name is therefore not a correct name (Principle 6). Based on Rule 54 we propose the replacement name Nemorincola with Nemorincola caseinilytica as the type species. PMID- 29485397 TI - Herbaspirillum robiniae sp. nov., isolated from root nodules of Robinia pseudoacacia in a lead-zinc mine. AB - A novel endophytic bacterium, designated strain HZ10T, was isolated from root nodules of Robinia pseudoacacia growing in a lead-zinc mine in Mianxian County, Shaanxi Province, China. The bacterium was Gram-stain-negative, aerobic, motile, slightly curved- and rod-shaped, methyl red-negative, catalase-positive, and did not produce H2S. Strain HZ10T grew at 4-45 degrees C (optimum, 25-30 degrees C), pH 5-9 (optimum, pH 7-8) and 0-1 % (w/v) NaCl. The major fatty acids were identified as C16 : 0, summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c) and summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c), and the quinone type was Q-8. The major polar lipids were diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylglycerol. The DNA G+C content of the genomic DNA was 64.9 mol% based on the whole genome sequence. According to the 16S rRNA gene sequence analysis, the closest phylogenetic relative to strain HZ10T is Herbaspirillum chlorophenolicum CPW301T (98.72 % sequence identity). Genome relatedness of the type strains H. chlorophenolicum CPW301T, Herbaspirillum seropedicae Z67T and Herbaspirillum aquaticum IEH 4430T, was quantified by using the average nucleotide identity (86.9-88.0 %) and a genome-to genome distance analysis (26.6 %-29.3 %), with both strongly supporting the notion that strain HZ10T belongs to the genus Herbaspirillum as a novel species. Based on the results from phylogenetic, chemotaxonomic and physiological analyses, strain HZ10T represents a novel Herbaspirillum species, for which the name Herbaspirillum robiniae sp. nov. is proposed. The type strain is HZ10T (=JCM 31754T=CCTCC AB 2014352T). PMID- 29485398 TI - Putative extracellular alpha-class carbonic anhydrase, EcaA, of Synechococcus elongatus PCC 7942 is an active enzyme: a sequel to an old story. AB - Carbonic anhydrase (CA) EcaA of Synechococcus elongatus PCC 7942 was previously characterized as a putative extracellular alpha-class CA, however, its activity was never verified. Here we show that EcaA possesses specific CA activity, which is inhibited by ethoxyzolamide. An active EcaA was expressed in heterologous bacterial system, which supports the formation of disulfide bonds, as a full length protein (EcaA+L) and as a mature protein that lacks a leader peptide (EcaA L). EcaA-L exhibited higher specific activity compared to EcaA+L. The recombinant EcaA, expressed in a bacterial system that does not support optimal disulfide bond formation, exhibited extremely low activity. This activity, however, could be enhanced by the thiol-oxidizing agent, diamide; while a disulfide bond reducing agent, dithiothreitol, further inactivated the enzyme. Intact E. coli cells that overexpress EcaA+L possess a small amount of processed protein, EcaA L, whereas the bulk of the full-length protein resides in the cytosol. This may indicate poor recognition of the EcaA leader peptide by protein export systems. S. elongatus possessed a relatively low level of ecaA mRNA, which varied insignificantly in response to changes in CO2 supply. However, the presence of protein in the cells is not obvious. This points to the physiological insignificance of EcaA in S. elongatus, at least under the applied experimental conditions. PMID- 29485399 TI - Glycomyces anabasis sp. nov., a novel endophytic actinobacterium isolated from roots of Anabasis aphylla L. AB - A novel endophytic actinobacterium, designated strain EGI 6500139T, was isolated from the surface-sterilized roots of Anabasis aphylla L., collected from Xinjiang, northwest PR China, and subjected to polyphasic taxonomic characterization. Strain EGI 6500139T formed sparse aerial mycelium with rod-like spores. Whole-cell hydrolysates of the isolate contained meso-diaminopimelic acid as the cell-wall diamino acid, glucose as major sugar, and mannose, galactose, xylose and ribose as minor sugars. The polar lipids were phosphatidylglycerol, diphosphatidylglycerol, phosphatidylinositol, phosphatidylinositol mannoside, one unidentified glycolipid, one unidentified phospholipid and four unidentified polar lipids. The major fatty acids identified were anteiso-C17 : 0, anteiso-C15 : 0, iso-C15 : 0 and iso-C16 : 0. The predominant menaquinones detected were MK 11 and MK-11(H2). The G+C content of the genomic DNA of strain EGI 6500139T was 70.4 mol%. Strain EGI 6500139T showed the highest 16S rRNA gene sequence similarity to Glycomyces lacisalsi XHU 5089T (96.3 %). Phylogenetic analysis showed that strain EGI 6500139T fell within the clade of the genus Glycomyces, and formed a clade with G. lacisalsi XHU 5089T and G. albus CCTCC AA 2013004T. Based on phenotypic, chemotaxonomic and phylogenetic data, strain EGI 6500139T represents a novel species of the genus Glycomyces, for which the name Glycomyces anabasis sp. nov. (type strain EGI 6500139T=JCM 30088T=KCTC 29495T) is proposed. PMID- 29485400 TI - Saccharolobus caldissimus gen. nov., sp. nov., a facultatively anaerobic iron reducing hyperthermophilic archaeon isolated from an acidic terrestrial hot spring, and reclassification of Sulfolobus solfataricus as Saccharolobus solfataricus comb. nov. and Sulfolobus shibatae as Saccharolobus shibatae comb. nov. AB - A novel hyperthermophilic archaeon of strain HS-3T, belonging to the family Sulfolobaceae, was isolated from an acidic terrestrial hot spring in Hakone Ohwaku-dani, Japan. Based on 16S rRNA gene sequence analysis, the closest phylogenetic relatives of strain HS-3T were, first, Sulfolobus solfataricus (96.4 %) and, second, Sulfolobus shibatae (96.2 %), indicating that the strain belongs to the genus Sulfolobus. However, the sequence similarity to the type species of the genus Sulfolobus (Sulfolobus acidocaldarius) was remarkably low (91.8 %). In order to determine whether strain HS-3T belongs to the genus Sulfolobus, its morphological, biochemical and physiological characteristics were examined in parallel with those of S. solfataricus and S. shibatae. Although there were some differences in chemolithotrophic growth between strain HS-3T, S. solfataricus and S. shibatae, their temperature, pH and facultatively anaerobic characteristics of growth, and their utilization of various sugars were almost identical. In contrast, the utilization of various sugars by S. acidocaldarius was quite different from that of HS-3T, S. solfataricus and S. shibatae. Phylogenetic evidence based on the 16S and the 23S rRNA gene sequences also clearly distinguished the monophyletic clade composed of strain HS-3T, S. solfataricus, and S. shibatae from S. acidocaldarius. Based on these results, we propose a new genus and species, Saccharolobus caldissimus gen. nov., sp. nov., for strain HS 3T, as well as two reclassifications, Saccharolobus solfataricus comb. nov. and Saccharolobus shibatae comb. nov. The type strain of Saccharolobus caldissimus is HS-3T (=JCM 32116T and InaCC Ar80T). The type species of the genus is Saccharolobus solfataricus. PMID- 29485401 TI - Automated analysis of long-term grooming behavior in Drosophila using a k-nearest neighbors classifier. AB - Despite being pervasive, the control of programmed grooming is poorly understood. We addressed this gap by developing a high-throughput platform that allows long term detection of grooming in Drosophila melanogaster. In our method, a k-nearest neighbors algorithm automatically classifies fly behavior and finds grooming events with over 90% accuracy in diverse genotypes. Our data show that flies spend ~13% of their waking time grooming, driven largely by two major internal programs. One of these programs regulates the timing of grooming and involves the core circadian clock components cycle, clock, and period. The second program regulates the duration of grooming and, while dependent on cycle and clock, appears to be independent of period. This emerging dual control model in which one program controls timing and another controls duration, resembles the two process regulatory model of sleep. Together, our quantitative approach presents the opportunity for further dissection of mechanisms controlling long-term grooming in Drosophila. PMID- 29485403 TI - On a mission to block transmission. AB - The controlled infection of volunteers with Plasmodium falciparum parasites could provide a platform to evaluate new drugs and vaccines aimed at blocking malaria transmission. PMID- 29485402 TI - Alterations of in vivo CA1 network activity in Dp(16)1Yey Down syndrome model mice. AB - Down syndrome, the leading genetic cause of intellectual disability, results from an extra-copy of chromosome 21. Mice engineered to model this aneuploidy exhibit Down syndrome-like memory deficits in spatial and contextual tasks. While abnormal neuronal function has been identified in these models, most studies have relied on in vitro measures. Here, using in vivo recording in the Dp(16)1Yey model, we find alterations in the organization of spiking of hippocampal CA1 pyramidal neurons, including deficits in the generation of complex spikes. These changes lead to poorer spatial coding during exploration and less coordinated activity during sharp-wave ripples, events involved in memory consolidation. Further, the density of CA1 inhibitory neurons expressing neuropeptide Y, a population key for the generation of pyramidal cell bursts, were significantly increased in Dp(16)1Yey mice. Our data refine the 'over-suppression' theory of Down syndrome pathophysiology and suggest specific neuronal subtypes involved in hippocampal dysfunction in these model mice. PMID- 29485405 TI - Cobalt sulfide aerogel prepared by anion exchange method with enhanced pseudocapacitive and water oxidation performances. AB - This work introduces the anion exchange method into the sol-gel process for the first time to prepare a metal sulfide aerogel. A porous Co9S8 aerogel with a high surface area (274.2 m2 g-1) and large pore volume (0.87 cm3 g-1) has been successfully prepared by exchanging cobalt citrate wet gel in thioacetamide and subsequently drying in supercritical ethanol. Such a Co9S8 aerogel shows enhanced supercapacitive performance and catalytic activity toward oxygen evolution reaction (OER) compared to its oxide aerogel counterpart. High specific capacitance (950 F g-1 at 1 A g-1), good rate capability (74.3% capacitance retention from 1 to 20 A g-1) and low onset overpotential for OER (220 mV) were observed. The results demonstrated here have implications in preparing various sulfide chalcogels. PMID- 29485406 TI - A deep learning approach for fetal QRS complex detection. AB - OBJECTIVE: Non-invasive foetal electrocardiography (NI-FECG) has the potential to provide more additional clinical information for detecting and diagnosing fetal diseases. We propose and demonstrate a deep learning approach for fetal QRS complex detection from raw NI-FECG signals by using a convolutional neural network (CNN) model. The main objective is to investigate whether reliable fetal QRS complex detection performance can still be obtained from features of single channel NI-FECG signals, without canceling maternal ECG (MECG) signals. APPROACH: A deep learning method is proposed for recognizing fetal QRS complexes. Firstly, we collect data from set-a of the PhysioNet/computing in Cardiology Challenge database. The sample entropy method is used for signal quality assessment. Part of the bad quality signals is excluded in the further analysis. Secondly, in the proposed method, the features of raw NI-FECG signals are normalized before they are fed to a CNN classifier to perform fetal QRS complex detection. We use precision, recall, F-measure and accuracy as the evaluation metrics to assess the performance of fetal QRS complex detection. MAIN RESULTS: The proposed deep learning method can achieve relatively high precision (75.33%), recall (80.54%), and F-measure scores (77.85%) compared with three other well-known pattern classification methods, namely KNN, naive Bayes and SVM. SIGNIFICANCE: the proposed deep learning method can attain reliable fetal QRS complex detection performance from the raw NI-FECG signals without canceling MECG signals. In addition, the influence of different activation functions and signal quality assessment on classification performance are evaluated, and results show that Relu outperforms the Sigmoid and Tanh on this particular task, and better classification performance is obtained with the signal quality assessment step in this study. PMID- 29485404 TI - Frontal cortex selects representations of the talker's mouth to aid in speech perception. AB - Human faces contain multiple sources of information. During speech perception, visual information from the talker's mouth is integrated with auditory information from the talker's voice. By directly recording neural responses from small populations of neurons in patients implanted with subdural electrodes, we found enhanced visual cortex responses to speech when auditory speech was absent (rendering visual speech especially relevant). Receptive field mapping demonstrated that this enhancement was specific to regions of the visual cortex with retinotopic representations of the mouth of the talker. Connectivity between frontal cortex and other brain regions was measured with trial-by-trial power correlations. Strong connectivity was observed between frontal cortex and mouth regions of visual cortex; connectivity was weaker between frontal cortex and non mouth regions of visual cortex or auditory cortex. These results suggest that top down selection of visual information from the talker's mouth by frontal cortex plays an important role in audiovisual speech perception. PMID- 29485407 TI - A piecewise probabilistic regression model to decode hand movement trajectories from epidural and subdural ECoG signals. AB - OBJECTIVE: The primary concern of this study is to develop a probabilistic regression method that would improve the decoding of the hand movement trajectories from epidural ECoG as well as from subdural ECoG signals. APPROACH: The model is characterized by the conditional expectation of the hand position given the ECoG signals. The conditional expectation of the hand position is then modeled by a linear combination of the conditional probability density functions defined for each segment of the movement. Moreover, a spatial linear filter is proposed for reducing the dimension of the feature space. The spatial linear filter is applied to each frequency band of the ECoG signals and extract the features with highest decoding performance. MAIN RESULTS: For evaluating the proposed method, a dataset including 28 ECoG recordings from four adult Japanese macaques is used. The results show that the proposed decoding method outperforms the results with respect to the state of the art methods using this dataset. The relative kinematic information of each frequency band is also investigated using mutual information and decoding performance. The decoding performance shows that the best performance was obtained for high gamma bands from 50 to 200 Hz as well as high frequency ECoG band from 200 to 400 Hz for subdural recordings. However, the decoding performance was decreased for these frequency bands using epidural recordings. The mutual information shows that, on average, the high gamma band from 50 to 200 Hz and high frequency ECoG band from 200 to 400 Hz contain significantly more information than the average of the rest of the frequency bands [Formula: see text] for both subdural and epidural recordings. The results of high resolution time-frequency analysis show that ERD/ERS patterns in all frequency bands could reveal the dynamics of the ECoG responses during the movement. The onset and offset of the movement can be clearly identified by the ERD/ERS patterns. SIGNIFICANCE: Reliable decoding the kinematic information from the brain signals paves the way for robust control of external devices. PMID- 29485408 TI - Surface-enhanced Raman spectroscopy with Au-nanoparticle substrate fabricated by using femtosecond pulse. AB - Au-nanoparticle (Au-NP) substrates for surface-enhanced Raman spectroscopy (SERS) were fabricated by grid-like scanning a Au-film using a femtosecond pulse. The Au NPs were directly deposited on the Au-film surface due to the scanning process. The experimentally obtained Au-NPs presented local surface plasmon resonance effect in the visible spectral range, as verified by finite difference time domain simulations and measured reflection spectrum. The SERS experiment using the Au-NP substrates exhibited high activity and excellent substrate reproducibility and stability, and a clearly present Raman spectra of target analytes, e.g. Rhodamine-6G, Rhodamine-B and Malachite green, with concentrations down to 10-9 M. This work presents an effective approach to producing Au-NP SERS substrates with advantages in activity, reproducibility and stability, which could be used in a wide variety of practical applications for trace amount detection. PMID- 29485409 TI - A stochastic differential equation model for the foraging behavior of fish schools. AB - Constructing models of living organisms locating food sources has important implications for understanding animal behavior and for the development of distribution technologies. This paper presents a novel simple model of stochastic differential equations for the foraging behavior of fish schools in a space including obstacles. The model is studied numerically. Three configurations of space with various food locations are considered. In the first configuration, fish swim in free but limited space. All individuals can find food with large probability while keeping their school structure. In the second and third configurations, they move in limited space with one and two obstacles, respectively. Our results reveal that the probability of foraging success is highest in the first configuration, and smallest in the third one. Furthermore, when school size increases up to an optimal value, the probability of foraging success tends to increase. When it exceeds an optimal value, the probability tends to decrease. The results agree with experimental observations. PMID- 29485410 TI - Volatile organic compounds discrimination based on dual mode detection. AB - We report on a volatile organic compound (VOC) sensor that can provide concentration-independent signals toward target gases. The device is based on a dual-mode detection mechanism that can simultaneously record the mechanical (resonant frequency, f r) and electrical (current, I) responses of the same gas adsorption event. The two independent signals form a unique I-f r trace for each target VOC as the concentration varies. The mechanical response (frequency shift, Deltaf r) resulting from mass load on the device is directly related to the amount of surface adsorptions, while the electrical response (current variation, DeltaI) is associated with charge transfer across the sensing interface and changes in carrier mobility. The two responses resulting from independent physical processes reflect intrinsic physical properties of each target gas. The DeltaI-Deltaf r trace combined with the concentration dependent frequency (or current) signals can therefore be used to achieve target both recognition and quantification. The dual-mode device is designed and fabricated using standard complementary metal oxide semiconductor (CMOS) compatible processes. It exhibits consistent and stable performance in our tests with six different VOCs including ethanol, methanol, acetone, formaldehyde, benzene and hexane. PMID- 29485411 TI - Response of Retinoic Acid in Patients with Radioactive Iodine-Refractory Thyroid Cancer: A Meta-Analysis. AB - PURPOSE: The purpose of this study was to evaluate the response of retinoic acid (RA) in radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC). METHODS: Systematic searches of MEDLINE (from inception to December 2016) and of EMBASE (from inception to December 2016) were performed for English-language publications on thyroid cancer treated with RA. Studies were classified according to the response criteria used: (1) 123I or 131I whole body scintigraphy (WBS), (2) serum thyroglobulin (Tg) level, (3) the response evaluation criteria in solid tumors (RECIST) version 1.0, and (4) World Health Organization (WHO) criteria. RESULTS: Disease response rates as determined by WBS ranged widely between 6.2% and 46.1% with a pooled disease response rate of 27.6% (95% confidence interval: 21.7-34.0%). Response rates as determined by Tg level ranged from 56.6% to 83.3% (pooled response rate 61.3% (51.0-70.9%)), RECIST response rates from 0% to 45.5% (pooled response rate 17.0% (1.4-44.5%)), and according to WHO criteria, the pooled response rate was 30.8% (12.7-52.7%). CONCLUSIONS: A minority of patients with RAI-refractory DTC respond to RA treatment. PMID- 29485412 TI - Volumetric Modulated Arc Therapy versus Fixed-Field Intensity-Modulated Radiotherapy in Radical Irradiation for Cervical Cancer without Lymphadenectasis: Dosimetric and Clinical Results. AB - BACKGROUND: The aim of this study was to compare the dosimetric parameters, clinical complications, and efficacy of volumetric modulated arc therapy (VMAT) and fixed-field intensity-modulated radiotherapy (f-IMRT) in radical radiotherapy for cervical cancer without lymphadenectasis. METHODS: 84 cervical cancer patients undergoing treatment with VMAT and f-IMRT were selected. Dose-volume histograms were used to evaluate the dose distribution in the planning target volume (PTV) and organs at risk. The clinical complications and efficacy were observed. RESULTS: The homogeneity index (HI) and the conformity index (CI) of VMAT plans were both superior to the HI and CI of f-IMRT plans (p = 0.043, 0.025). VMAT plans resulted in a reduction in the V30 of the rectum and V40 of the bladder (p = 0.002). Furthermore, the monitor units (MUs) for VMAT were less than a quarter of those for f-IMRT. The treatment time for VMAT was less than a half of that for f-IMRT. Both clinical complications and efficacy showed no significant differences. CONCLUSION: VMAT plans showed superior dose coverage of the PTV, better protection of the rectum and bladder in dosimetry, and significantly reduced MUs and treatment time compared with f-IMRT. Clinical results were similar for both plans. PMID- 29485413 TI - Upregulated EBI3 Correlates with Poor Outcome and Tumor Progression in Breast Cancer. AB - BACKGROUND AND AIM: So far, the understanding of the role of Epstein-Barr virus induced gene 3 (EBI3) in breast cancer has been limited. This study uncovers the functional role and clinical significance of EBI3 in breast cancer patients. PATIENTS AND METHODS: The expression levels of EBI3, IL-27p28, and IL-12p35 were measured by quantitative real-time reverse transcription (RT)-polymerase chain reaction (PCR). Correlations of EBI3 expression with IL-27p28 and IL-12p35 expression were analyzed using Pearson's correlation assay. The prognostic performance of EBI3 was assessed via Kaplan-Meier survival assay and Cox regression analysis. RESULTS: EBI3 expression was increased in cancerous tissues compared with the controls (P < 0.05). This overexpression of EBI3 was correlated with lymph node metastasis and clinical stage (both P < 0.05). Besides, elevated expression of EBI3 was usually found in patients with positive lymph node metastasis (P < 0.05), and similar results were obtained in advanced clinical stage breast cancer cases (P < 0.05). Increases in both IL-27p28 and IL-12p35 expression were identified in breast cancer tissues (all P < 0.05), and IL-12p35 expression was found to be associated with EBI3 expression (R = 0.888, P < 0.001). Survival curves revealed that high EBI3 expression was correlated with poor overall survival (log-rank P < 0.05). The Cox analysis indicated that EBI3 was an independent prognostic factor in breast cancer. CONCLUSION: Taken together, overexpression of EBI3 was associated with poor prognosis and might be involved in the progression of breast cancer. PMID- 29485414 TI - The Association between Serum 25-Hydroxyvitamin D and Cancer Risk: Results from the Prospective KORA F4 Study. AB - BACKGROUND: Many studies have examined the relationship between vitamin D and specific types of cancer with inconsistent results. Furthermore, to date, no observational studies have demonstrated a clear relationship between vitamin D and total cancer risk. METHODS: We analyzed data from a population-based prospective cohort study including 2,003 initially cancer-free participants from the KORA F4 study with baseline serum 25-hydroxyvitamin D (25(OH)D) measurements (surveyed between 2006 and 2008). We used Cox proportional hazard models to assess the association between 25(OH)D levels and incident cancer risk. RESULTS: Within a follow-up period of 7 years, 69 of the participants developed cancer. Overall, we observed no significant relationship between serum 25(OH)D levels and cancer risk. The hazard ratio (HR) per 1 ng/ml increase in 25 (OH)D for this relationship was 1.00 (95% confidence interval (CI) 0.97-1.04) adjusting for age, sex, body mass index, and season of blood draw. This was also true in subgroup analysis for prostate cancer (HR 0.95, 95% CI 0.88-1.03), breast cancer (HR 1.03, 95% CI 0.97-1.09), and colorectal cancer (HR 0.97, 95% CI 0.88-1.07). CONCLUSION: Our study found no protective effect of 25(OH)D against developing cancer. However, studies with more participants and additional measurements of 25(OH)D are still needed to accurately clarify the relationship between 25(OH)D and total cancer risk. PMID- 29485415 TI - External Validation of the Proposed Kiel Staging System and Comparison with the Old (6th Edition) and the Currently Used (7th Edition) TNM Classification in Gastric Cancer. AB - BACKGROUND: Despite the announcement of the 8th edition of TNM classification, the 7th edition (2010) is still being used for prognostic assessment in gastric cancer patients. A proposed new staging system (termed as the Kiel proposal) claims to offer a better prognostic stratification. Our objective was to retrospectively evaluate the Kiel proposal and compare it with the 6th and 7th TNM editions on a collected database. METHODS: We retrospectively analyzed gastric cancer patients who had undergone surgical resection without any previous treatment from selected randomized trials and from a cohort of patients operated at the University Hospital of Mainz, Germany. All patients were restaged using the 3 staging systems and overall survival was estimated and compared. RESULTS: A study population of 491 patients was identified. Relevant changes in stage distribution between the 6th and 7th TNM and the Kiel staging systems were observed. The 6th classification appears to display the best discriminatory measures. The Kiel staging system is slightly less prognostic than the TNM editions, but provides clearly separated strata as with the 6th edition. CONCLUSIONS: The Kiel staging system for gastric cancer appears promising in terms of simplicity, predictability and applicability and should be taken into consideration in future TNM revisions. PMID- 29485416 TI - High Levels of TRIM14 Are Associated with Poor Prognosis in Hepatocellular Carcinoma. AB - BACKGROUND: Tripartite motif containing 14 (TRIM14) has been reported to play a critical role in tumor development. However, little is known about TRIM14 expression and its clinical significance in hepatocellular carcinoma (HCC). The aim of the present study was to investigate the expression and prognostic value of TRIM14 in patients with HCC. MATERIALS AND METHODS: The mRNA and protein levels of TRIM14 in HCC were evaluated by quantitative real-time polymerase chain reaction, Western blot analysis, and immunohistochemistry. The association of TRIM14 expression with clinicopathological factors, overall survival (OS), and recurrence-free survival (RFS) was analyzed. RESULTS: TRIM14 expression was significantly upregulated in HCC-related tissues. High TRIM14 expression correlated with C-reactive protein (p = 0.01), alanine aminotransferase (p = 0.02), tumor size (p = 0.005), lesion number (p = 0.023), vascular invasion (p = 0.041), tumor/node/metastasis (TNM) stage (p = 0.001), and Barcelona Clinic Liver Cancer (BCLC) stage (p = 0.003). In addition, high TRIM14 expression was associated with poor OS and RFS (both p < 0.001). Cox regression analysis revealed that high TRIM14 expression was an independent prognostic factor for both OS (hazard ratio (HR) 1.657, 95% confidence interval (CI) 1.031-2.687; p = 0.018) and RFS (HR 2.297, 95% CI 1.184-2.312; p = 0.007). CONCLUSION: TRIM14 is a potential prognostic predictor for OS and RFS in patients with HCC. PMID- 29485417 TI - Metachronous Spontaneous Remission of Melanoma Lung Metastasis and Mediastinal Lymph Node Metastases. AB - BACKGROUND: Spontaneous remissions are rare but valid events in malignancies and in the past have led to the development of mainstay oncologic therapies. CASE REPORT: We present a rare case of spontaneous regression of a solitary pulmonary melanoma metastasis with complete remission persisting for 28 months. Concurrent mediastinal nodal metastases progressed at the time of remission of the lung metastasis, but also demonstrated regression in follow-up fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) imaging. Metastatic nodes showed only minimal residual metabolic activity after 38 months of follow up from the appearance of metastatic disease. CONCLUSION: This case report presents a rare spontaneous complete regression of a solitary pulmonary melanoma metastasis. Biological pathways involved in spontaneous regression in cancer are discussed. PMID- 29485419 TI - Meetings and Conferences. PMID- 29485418 TI - Physicochemical Properties of Magnetic Nanoparticles: Implications for Biomedical Applications In Vitro and In Vivo. AB - Magnetic and superparamagnetic iron oxide nanoparticles are emerging as promising candidates for various applications in biology and medicine, and especially in oncology. These applications, however, require that a specific set of physical, chemical, and biological properties be combined in a given sample of nanoparticles for them to act as intended. Some of these properties are fundamental: They strictly determine the nanoparticles' behavior both in vitro and in vivo. These properties are the charge, the solution stability and zeta potential, and the coating of the nanoparticles. A certain combination of these properties may satisfy a researcher in an in vitro study, but other properties should also be considered when in vivo applications are planned. For in vivo experiments, additional determinants of the quality of nanoparticles are their size, shape, modifications with targeting moieties, and degradation/excretion pathways. All these properties are in the focus of the present review. PMID- 29485420 TI - Hypocalcemia after Denosumab in a Pulmonary Hypertension Patient Receiving Epoprostenol. AB - We report the case of a 50-year-old woman with anorexigen-induced pulmonary arterial hypertension treated with epoprostenol, who presented with Trousseau's sign, leading to the diagnosis of severe hypocalcemia for which substitution was started (initially orally, followed by intravenous substitution). After further analysis, we assume that epoprostenol-induced diarrhea caused malabsorption (as other reasons were excluded), leading to nutritional osteomalacia with secondary hyperparathyroidism. We discovered that even more severe hypocalcemia was induced by the treatment with the anti-osteoporotic drug denosumab, which was started after the diagnosis of osteoporosis on bone densitometry. In our opinion, clinicians have to be aware that in patients with malabsorption, antiresorptive therapy can induce dangerous and even life-threatening hypocalcemia, even in patients with normal renal function. PMID- 29485423 TI - Targetable Immune Regulatory Molecule Expression in High-Grade Serous Ovarian Carcinomas in African American Women: A Study of PD-L1 and IDO in 112 Cases From the African American Cancer Epidemiology Study (AACES). AB - African American women with high-grade serous ovarian carcinoma have worse outcomes compared with women of European descent. Although the discrepancy is partially attributed to differences in access to care, the tumor immune microenvironment may also contribute. Expression of targetable immune regulatory molecules such as programmed cell death ligand-1 (PD-L1) and indoleamine 2,3 dioxygenase (IDO) is of particular interest as it may help guide therapy in this population. Using cases from the largest study of African American women with ovarian cancer, the African American Cancer Epidemiology Study, we characterized PD-L1 and IDO expression in 112 high-grade serous ovarian carcinomas. Immunohistochemistry for PD-L1, IDO, CD8, FOX3p, and CD68 was performed. PD-L1 and IDO were scored as the percentage of positive tumor cells and tumor associated immune cells. CD8 and FOX3p counts were averaged across 10 high-power fields. Cox proportional hazards regression was used to evaluate the association between PD-L1 and IDO expression and survival. Tumor cells were positive for PD L1 and IDO in 29% and 58% of cases, respectively. The majority showed <10% staining, and no cases exceeded 25% positivity. The majority of PD-L1-positive cases coexpressed IDO. PD-L1 and IDO expression was associated with higher CD8 and FOX3p counts (P<0.05). No association was observed between PD-L1 and IDO and survival. In summary, expression of PD-L1 and IDO is seen in a subset of high grade serous ovarian carcinoma from African American women and is correlated with elevated lymphocyte infiltration. While PD-L1 and IDO co-expression suggests a role for dual immunotherapy, diffuse expression of PD-L1 and IDO is rare, invoking caution regarding the potential for immunotherapeutic response. PMID- 29485424 TI - Incidence and Outcomes of Postoperative Atrial Fibrillation After Left Ventricular Assist Device. AB - This study sought to determine the incidence, predictors, and outcomes of postoperative atrial fibrillation (POAF) in patients undergoing implantation of left ventricular assist devices (LVADs). A retrospective analysis of all patients who underwent LVAD implantation from 2013 to 2014 was conducted. Postoperative AF, survival, and thrombotic complications were evaluated after surgery. A total of 47 patients (mean age, 56.4 +/- 12.5 years; 33 male) were included and followed for a median of 331 days. Within 30 days of surgery, 13 (28%) patients developed POAF at mean 7.9 +/- 8.5 days. Obstructive lung disease was a predictor of POAF (p = 0.01). Postoperative AF was not associated with increased mortality, length of stay, or thrombotic complication within 30 days. Postoperative AF was predictive of recurrent new AF (24 vs. 5.5%) after 30 days of LVAD implantation. Also, POAF was associated with increased risk of ischemic stroke and device thrombosis during follow-up (p = 0.01). These results show that unlike in other cardiac surgery, POAF does not have a negative impact on early postoperative morbidity or mortality. However, POAF is a predictor for future AF, ischemic stroke, and device thrombosis. PMID- 29485425 TI - Effect of Preoperative Atrial Fibrillation on Patients with Chronic Heart Failure Who Undergo Long-Term Continuous-Flow LVAD Implantation. AB - Although preoperative atrial fibrillation (AF) is common in patients undergoing continuous-flow left ventricular assist device (CF-LVAD) implantation, how AF affects outcomes remains unclear. We analyzed our single-center experience with CF-LVAD implantation to determine whether preoperative AF was associated with inferior outcomes. From November 2003 through March 2016, 526 patients with chronic heart failure underwent implantation with the HeartMate II (HMII; n = 403) or HeartWare VAD (HVAD; n = 123). We identified 229 patients (165 HMII, 65 HVAD) who had preoperative AF and compared them with non-preoperative AF patients regarding the incidence of postoperative stroke, as well as long-term survival. After implantation, 139 patients had a stroke (78 non-preoperative AF patients [26.2%], 61 preoperative AF patients [26.6%]; p = 0.84). The rate of events per patient-year was 0.19 in non-preoperative AF patients and 0.22 in preoperative AF patients (p = 0.84). Survival was not significantly different between the two groups (p = 0.60). In Cox regression, preoperative AF was not associated with postoperative stroke (odds ratio: 1.13; 95% confidence interval [CI]: 0.74-1.74; p = 0.55) or survival (hazard ratio: 0.93; 95% CI: 0.71-1.25; p = 0.66). We conclude that in CF-LVAD recipients, preoperative AF did not diminish perioperative or long-term survival or increase the risk of postoperative stroke. These findings suggest that performing concomitant AF ablation during CF-LVAD implantation may be unnecessary. PMID- 29485426 TI - The Use of Computed Tomography in Preoperative Planning for Heartware Left Ventricular Assist Device Placement. AB - Optimal left ventricular assist device (LVAD) cannula position is important for adequate ventricular unloading and LVAD function. Poor inflow cannula position predisposes to pump thrombosis, inotrope dependence, and mortality. We describe a novel technique of preoperative left ventricular apex marking using CT guidance and demonstrate in three cases the use of this method to achieve optimal inflow cannula positioning for lateral thoracotomy Heartware LVAD implantation. PMID- 29485427 TI - How hemorrhage control became common sense. AB - BACKGROUND: Just over 200 years ago, surgeons were puzzled that the use of the tourniquet to control hemorrhage as common sense during surgery was a relatively recent development. Within the last 20 years, much progress has been made to controlling hemorrhage in the prehospital context. Then, as now, it was surprising that progress on something that appeared obvious had occurred only recently, begging the question how controlling blood loss was common sense in a surgical context, but not for emergency treatment. METHODS: This article is a historical survey of the evolution of the medical understanding of hemorrhage along with technological response. RESULTS: The danger of blood loss had historically been consistently underestimated as physicians looked at other explanations for symptoms of how the human body responded to trauma. As the danger from hemorrhage became apparent, even obvious, responsibility for hemorrhage control was delegated down from the surgeon to the paramedic and eventually to individual service members and civilian bystanders with training to "stop the bleed." CONCLUSION: Hippocratic medicine assumed that blood diffused centrifugally into periphery through arteries. William Harvey's observation in 1615 that blood ran through a closed circulatory system gradually transformed conventional wisdom about blood loss, leading to the development of the tourniquet about a century later by Jean-Louis Petit, which made amputation of limbs survivable. However, physicians were cautious about their application during the First World War over concerns over effects on patient recovery. Hemorrhage had generally been seen as symptom to be managed until the patient would be seen by a surgeon who would stop the bleeding. More thorough collection and analysis of data related to case histories of soldiers wounded during the Vietnam Conflict transformed how surgeons understood the importance to hemorrhage leading to development of the doctrine of Tactical Combat Casualty Care in the late 1990s. LEVEL OF EVIDENCE: Background Information: Economic/decision study. PMID- 29485428 TI - Optimal timing of initial debridement for necrotizing soft tissue infection: A Practice Management Guideline from the Eastern Association for the Surgery of Trauma. AB - BACKGROUND: Necrotizing soft tissue infections (NSTI) are rare, life-threatening, soft-tissue infections characterized by rapidly spreading inflammation and necrosis of the skin, subcutaneous fat, and fascia. While it is widely accepted that delay in surgical debridement contributes to increased mortality, there are currently no practice management guidelines regarding the optimal timing of surgical management of this condition. Although debridement within 24 hours of diagnosis is generally recommended, the time ranges from 3 hours to 36 hours in the existing literature. Therefore, the objective of this article is to provide evidence-based recommendations for the optimal timing of surgical management of NSTI. METHODS: The MEDLINE database using PubMed was searched to identify English language articles published from January 1990 to September 2015 regarding adult and pediatric patients with NSTIs. A systematic review of the literature was performed, and the Grading of Recommendations Assessment, Development and Evaluation framework were used. A single population [P], intervention [I], comparator [C], and outcome [O] (PICO) question was applied: In patients with NSTI (P), should early (<12 hours) initial debridement (I) versus late (>=12 hours) initial debridement (C) be performed to decrease mortality (O)? RESULTS: Two hundred eighty-seven articles were identified. Of these, 42 papers underwent full text review and 6 were selected for guideline construction. A total of 341 patients underwent debridement for NSTI. Of these, 143 patients were managed with early versus 198 with late operative debridement. Across all studies, there was an overall mortality rate of 14% in the early group versus 25.8% in the late group. CONCLUSION: For NSTIs, we recommend early operative debridement within 12 hours of suspected diagnosis. Institutional and regional systems should be optimized to facilitate prompt surgical evaluation and debridement. LEVEL OF EVIDENCE: Systematic review/meta-analysis, level IV. PMID- 29485429 TI - Valid but Invalid: Suboptimal ImPACT Baseline Performance in University Athletes. AB - PURPOSE: This study aimed to investigate the frequency of valid yet suboptimal Immediate Postconcussion Assessment and Cognitive Test (ImPACT) performance in university athletes and to explore the benefit of subsequent ImPACT administrations. METHODS: This descriptive laboratory study involved baseline administration of ImPACT to 769 university athletes per the institution's concussion management protocol. Testing was proctored in groups of <=2 participants. Participants who scored below the 16th percentile according to ImPACT normative data were readministered the ImPACT test up to two additional times because these scores were thought to be potentially indicative of suboptimal effort or poor understanding of instructions. Descriptive analyses were used to examine validity indicators and individual Verbal and Visual Memory, Visual Motor Speed, and Reaction Time ImPACT composite scores in initial and subsequent administrations. RESULTS: On the basis of ImPACT's validity criteria, 1% (9/769) of administrations were invalid and 14.6% (112/769) had one or more composite score of <16th percentile but were considered valid. After one readministration, 71.4% (80/112) achieved scores of >=16th percentile and an additional 18 of 32 scored >=16th percentile after a third administration. Verbal Memory was most commonly <16th percentile on the first administration (43%), Verbal Memory and Visual Motor Speed on the second administration (44% each), and Visual Motor Speed alone on the third administration (50%). CONCLUSIONS: Approximately 16% of ImPACT records were flagged as invalid or had one or more composite scores of <16th percentile, potentially indicative of suboptimal performance. Upon readministration, 88% of those participants scored >16th percentile. Clinicians must be aware of suboptimal ImPACT performance as it limits the clinical utility of the baseline assessment. Further research is needed to address factors leading to "valid" but invalid baseline performance. PMID- 29485430 TI - [44Sc]Sc-PSMA-617 Biodistribution and Dosimetry in Patients With Metastatic Castration-Resistant Prostate Carcinoma. AB - AIM: [Sc]Sc-PSMA-617 with 3.9-hour half-life, in vitro and in vivo characteristics similar to [Lu]Lu-PSMA-617 and possibility of delayed imaging after 24 hours or later, implies it to be advantageous than [ Ga]Ga-PSMA-617 for pretherapeutic dosimetric assessment for [Lu]Lu-PSMA-617 in metastatic castration resistant prostate carcinoma (mCRPC) patients. In this study, we investigated biodistribution and radiation exposure to normal organs with [Sc]Sc-PSMA-617 in mCRPC patients. METHODS: Five mCRPC patients (mean age, 69 years) enrolled for [Lu]Lu-PSMA-617 therapy were injected with 40-62 MBq [Sc]Sc-PSMA-617 intravenously; Siemens Biograph 2 PET/CT system was used to acquire dynamic PET data (30 minutes) in list mode over the abdomen, followed by the collection of static PET/CT images (skull to mid-thigh) at 45 minutes, 2 and approximately 20 hours postinjection. Time-dependent changes in percentage activity in source organs (kidneys, bladder, salivary glands, small intestine, liver, spleen, and whole body) were determined. Bone marrow and urinary bladder contents residence time were also calculated. Source organs residence time, organ-absorbed doses, and effective doses were determined using OLINDA/EXM software. RESULTS: Physiological tracer uptake was seen in kidneys, liver, spleen, small intestine, urinary bladder, and salivary glands and in metastases. Kidneys with highest radiation absorbed dose of 3.19E-01 mSv/MBq were the critical organs, followed by urinary bladder wall (2.24E-01 mSv/MBq, spleen [1.85E-01], salivary glands [1.11E 01], and liver [1.07E-01] mSv/MBq). Red marrow dose was found to be 3.31E-02 mSv/MBq. The mean effective dose of 3.89E-02 mSv/MBq and effective dose of 1.95 mSv was estimated from 50 MBq (treatment planning dose) of [Sc]Sc-PSMA-617. CONCLUSIONS: [Sc]Sc-PSMA-617 is found to be a very promising radiopharmaceutical that can be used for pre [Lu]Lu-PSMA-617 therapeutic dosimetric assessment. PMID- 29485431 TI - FDG PET/CT Findings of Erdheim-Chester Disease: Radiologic Response to a Novel Treatment Regimen. AB - Erdheim-Chester disease (ECD) is a rare form of non-Langerhans histiocytosis with deposition of lipid-laden macrophages in numerous organs. A 74-year-old man with a history of coronary artery disease, hypertension, and hyperlipidemia presented with nonspecific symptoms including back pain, nausea, vomiting, vertigo, and left leg pain. A neutrophil-predominant elevated WBC count and a bone biopsy revealing histiocytic proliferation positive for CD68 and CD163 and negative for S100 was noted. FDG PET/CT, MRA, and CTA images were obtained. We review the radiologic hallmarks of ECD and demonstrate the radiologic manifestations of response to combined BRAF and MEK inhibitor treatment. PMID- 29485432 TI - FDG Accumulation in the Lumen of the Gallbladder Without Related Pathology. AB - FDG accumulation in the gallbladder has been reported as an indication of either malignancy or inflammation. We here report a case of FDG accumulation in the gallbladder without pathology in the gallbladder. A 15-year-old girl with Hodgkin disease underwent staging FDG PET/CT, which revealed not only the abnormal activity in the lymph nodes and left ilium, which were consistent with the malignant involvement, but also increased activity in the gallbladder. The patient had no symptoms related to hepatobiliary system at the time of scan and did not suffer any problem related to hepatobiliary system during 14 months of follow-up. PMID- 29485434 TI - Re: Low-Dose Radioactive Iodine Ablation Is Sufficient in Patients With Small Papillary Thyroid Cancer Having Minor Extrathyroidal Extension and Central Lymph Node Metastasis (T3 N1a). PMID- 29485433 TI - 18F-Fluoroestradiol PET/CT Correctly Diagnosed 18F-FDG-Avid Inflammatory Lymph Nodes in a Patient With Estrogen Receptor-Positive Breast Cancer. AB - A 77-year-old woman with left breast cancer received F-FDG PET/CT for initial staging, and F-FDG-avid lymph nodes were observed in the bilateral axillae. As estrogen receptor (ER) status of primary lesion was positive, the patient also received F-fluoroestradiol (F-FES) PET/CT. Unlike primary lesion, no remarkable F FES uptakes in the lymph nodes were observed. F-FDG uptakes in the nodes were finally interpreted as inflammation. F-FES PET that can noninvasively evaluate the ER status may have a potential to reveal the pathology of the false-positive lesion observed in F-FDG PET for patients with ER-positive breast cancer. PMID- 29485435 TI - 18F-FDG PET/CT for Molecular Imaging of Hepatoblastoma in Beckwith-Wiedemann Syndrome. AB - Beckwith-Wiedemann syndrome (BWS) is a rare congenital overgrowth disorder variably characterized by macrosomia, macroglossia, congenital hypoglycemia, and hemihyperplasia. The BWS predisposes affected individuals to embryonal tumors during childhood. The BWS is caused by abnormal gene regulation in a particular region of chromosome 11. We present the case of a 1-year-old boy with BWS who underwent an F-FDG PET/CT scan for restaging of hepatoblastoma. On the F-FDG PET scan, increased tracer accumulation was observed in hepatoblastoma lesions. In addition, marked hemihyperplasia was noted. This case highlights the usefulness of F-FDG PET/CT for restaging of hepatoblastoma in BWS. PMID- 29485436 TI - Metastasis to the Sellar/Suprasellar Region in a Patient With Endometrial Carcinoma Detected by 18F-FDG PET/CT. AB - Metastases to pituitary gland, suprasellar region or skull base from endometrial carcinoma are an extremely rare occurrence. We report the case of a 77-year-old woman with metastasis to the sellar/suprasellar region from endometrial carcinoma revealed by F-FDG PET/CT and confirmed by subsequent CT and MRI of the brain. This case highlights the usefulness of a whole-body imaging methodology such as F FDG PET/CT in the detection of distant and/or atypical sites of metastasis therefore being of help in guiding towards the correct diagnosis. PMID- 29485437 TI - Primary Hepatic Malignant Fibrous Histiocytoma on PET/CT. AB - Malignant fibrous histiocytoma is mainly presented in extremities, less commonly in posterior peritoneum, but primary presented in liver is very rare and often with a poor prognosis because of its high aggression. The features of clinical presentations and images are variable and the pre-operative diagnosis is difficult. Here, we report a primary hepatic malignant fibrous histiocytoma patient with no distant metastasis showed on pre-operative F-FDG PET/CT, however with many metastases showed on the post-operative F-FDG PET/CT. PMID- 29485438 TI - Complete Metabolic Response of Advanced Melanoma to Vemurafenib Assessed with FDG PET-CT at 85 Hours. AB - Vemurafenib improves the management of advanced melanoma due to selective inhibition of the mutated BRAF V600E kinase. FDG-PET-CT is a tool for the evaluation of the biologic impact of inhibiting mutant BRAF. With vemurafenib at day 15, all the patients had at least partial metabolic response. Reductions in uptake correlate with longer progression free survival. In this case, incomplete information provided by the patient led to the performance of his third PET 85 hours after the introduction of vemurafenib. This early case of complete metabolic response suggests that FDG-PET-CT is a useful marker of early biologic response to vemurafenib. PMID- 29485439 TI - FDG PET/CT of Chromophobe Renal Cell Carcinoma With Sarcomatoid Differentiation. AB - We report the case of a 49-year-old white man with a chromophobe renal cell carcinoma associated with sarcomatoid differentiation, an uncommon yet an aggressive form of dedifferentiated renal cell carcinoma. In opposite to the conventional renal cell carcinoma, which may not always demonstrate avid FDG activity, the sarcomatoid differentiated chromophobe renal cell carcinoma shows intense FDG uptake on PET. This case highlights the role of FDG PET/CT in staging and restaging this type of rare renal cell carcinoma. PMID- 29485441 TI - 68Ga DOTATATE PET/CT Imaging of Elastofibroma Dorsi. AB - Sixty six-year-old woman status post ileocecal resection for well-differentiated neuroendocrine tumor in the terminal ileum 7 years ago, who is on octreotide therapy for liver metastases. Ga DOTATATE PET/CT showed soft tissue masses with mildly increased radiotracer uptake in the bilateral subscapular/infrascapular regions. In retrospective image review, these soft tissue masses were first noted 7 years prior and have gradually increased in size over the years. Given the characteristic location and imaging findings, these masses are consistent with benign elastofibroma dorsi instead of metastasis. PMID- 29485440 TI - Gastric Metastasis of Prostate Cancer as an Unusual Presentation Using 68Ga Prostate-Specific Membrane Antigen PET/CT. AB - A 79-year-old man with prostate cancer underwent Ga prostate-specific membrane antigen (Ga-PSMA) dual-time-point PET/CT scan to evaluate tumor activity due to early satiety, unquantified weight loss, and elevation of prostate-specific antigen (PSA), demonstrating thickening of the gastric wall with intense tracer uptake. The immunohistochemistry of gastric biopsy showed CDX2 and CK20: negative; CK7, focal positive; PSA, positive, which confirmed metastatic disease. Metastatic disease was also found in bones, right lung, and retroperitoneal and pelvic lymphadenopathies. PMID- 29485442 TI - Should 18F-FDG PET/CT Be Routinely Performed in the Clinical Staging of Locally Advanced Gastric Adenocarcinoma? AB - PURPOSE: The aim of this study was to evaluate F-FDG PET/CT compared with conventional imaging techniques in the clinical management of patients with locally advanced gastric cancer (LAGC). METHODS: A prospective study between January 2010 and December 2011 in patients with suspected LAGC was conducted in our hospital. F-FDG PET/CT, contrast-enhanced CT (CECT), endoscopic ultrasound, and laparoscopy were performed in all cases. Standard whole-body F-FDG PET/CT images were obtained centered on the stomach at 1 and 2 hours after injection of 4.0 MBq/kg of F-FDG. Findings were confirmed by histopathology or by imaging follow-up in nonoperable patients. RESULTS: Fifty consecutive patients with confirmed LAGC (20 women, 30 men) with a mean +/- SD age of 65.7 +/- 12.1 years were included. Using Lauren classification, 24 patients were intestinal subtype, and 26 were diffuse subtype. Thirty-five patients with locoregional lymph node involvement and 22 with distant metastases were confirmed as peritoneal metastases (n = 15), retroperitoneal (n = 2) or mediastinal lymph nodes (n = 1), and liver (n = 3) or bone metastases (n = 1). Patients with signet ring carcinoma showed significantly less F-FDG uptake (P = 0.001). SUVmax correlated with tumor grading (P < 0.05). Standard and delayed F-FDG PET/CT and CECT images identified LAGC in 24, 27, and 28 of 30 patients, respectively. The sensitivity and specificity for F-FDG PET/CT and CECT to detect metastases were 68% and 100% and 64% and 93%, respectively. Contrast-enhanced CT and F-FDG PET/CT diagnosed only 6 of the 15 patients with confirmed peritoneal metastases. The impact in therapeutic management of F-FDG PET/CT and CECT was 24% and 22%, respectively. Kaplan-Meier survival curves for the LGAC showed a significant correlation between SUVmax and overall survival using an SUVmax threshold of less than 3.96 (P = 0.04). CONCLUSIONS: F-FDG PET/CT should be recommended for staging of LAGC; however, F-FDG PET/CT and CECT cannot replace laparoscopy to rule out peritoneal metastases. Delayed F-FDG PET/CT images show an increase of F-FDG uptake in most cases, improving LAGC detection. The grade of F-FDG uptake represents a significant prognostic tool in this series. PMID- 29485443 TI - 18F-FDG PET/CT Equivalent of the Hepatic Hot Spot Sign With CT Correlation. AB - A 43-year-old woman presented with an FDG-avid mediastinal Ewing sarcoma invading and nearly occluding the superior vena cava. Geographic increased FDG uptake in hepatic segment IVA was the only other site of nonphysiologic FDG activity. This focal activity was without an underlying mass, had atypical morphology for a hepatic metastasis, and correlated well with prior CT findings of abnormal segment IVA enhancement resulting from the recruitment of portocaval collaterals. In the correct setting, the F-FDG hepatic hot spot should be considered in the differential of a focal FDG-avid hepatic lesion in segment IVA. PMID- 29485444 TI - BSREM Reconstruction for Improved Detection of In-Transit Metastases With Digital FDG-PET/CT in Patients With Malignant Melanoma. AB - Block sequential regularized expectation maximization (BSREM) is a Bayesian penalized-likelihood reconstruction algorithm for PET, which reaches full convergence without the detriment of deteriorating the image quality by noise. Therefore, BSREM might have implications particularly for the detection of small lesions, which may be beneficial in melanoma patients. Our case of a 70-year-old man with metastasized malignant melanoma illustrates the impact of such a novel iterative PET reconstruction algorithm. Whereas the lymph node metastases are seen with the latest generation ordered subset expectation maximization reconstruction, the in-transit metastases are identified straightforward only with BSREM reconstruction. PMID- 29485445 TI - FDG PET/CT Findings of Polymorphic Posttransplant Lymphoproliferative Disorders in a Transplanted Kidney. AB - A 55-year-old woman underwent simultaneous liver-kidney transplantation because of polycystic liver and kidney. Six months later, FDG PET/CT was acquired to evaluate possible lesions in the renal graft, which demonstrated abnormal F-FDG accumulation in the renal pelvic lesions without other abnormality. The subsequent pathology examination after biopsy demonstrated the polymorphic posttransplant lymphoproliferative disorders. PMID- 29485446 TI - Atypical Appearance on Thyroid Scintigraphy: Achalasia. AB - We report the case of a 49-year-old woman with achalasia in whom thyroid stimulating hormone supression was incidentally detected on routine blood tests and who therefore underwent thyroid scintigraphy. Thyroid scan demonstrated low intensity diffuse technetium Tc sodium pertechnetate accumulation inferior to thyroid gland. After correlating the images with her previous barium esophagogram, tracer accumulation caudal to thyroid gland was explained on the presumption of Tc sodium pertechnetate retention within the dilated esophagus. PMID- 29485447 TI - 68Ga-DOTANOC PET/CT in Medulloblastoma. AB - Medulloblastoma, also known as cerebellar primitive neuroectodermal tumor, is the most common brain tumor in children and arises in the posterior cranial fossa. We present the case of a patient with desmoplastic type of medulloblastoma, which showed recurrence more than once. When Ga-DOTANOC PET-CT was done, the lesions showed somatostatin receptor expression, opening another potential therapeutic option for this patient. PMID- 29485448 TI - FDG PET/CT Findings in a Localized Reactive Lymphoid Hyperplasia of the Spleen. AB - A 38-year-old man with sigmoid colon cancer underwent a preoperative contrast enhanced CT which incidentally revealed a modestly enhancing splenic mass. FDG PET/CT showed mildly increased uptake in the splenic lesion in contrast to prominently increased uptake in the colonic tumor. In addition, the splenic mass demonstrated only slightly increased signal intensity in diffusion-weighted MRI, suggesting low probability of metastasis. Splenectomy nonetheless was performed at surgery of the colon cancer. The histopathologic examination showed aggregated lymphoid follicles with germinal centers in the splenic lesion and made the diagnosis of localized reactive lymphoid hyperplasia a rare benign lymphoid tumor. PMID- 29485449 TI - Recurrent Medullary Thyroid Carcinoma on 68Ga-Prostate-Specific Membrane Antigen PET/CT: Exploring New Theranostic Avenues. AB - The prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer cells. Few other malignancies have shown expression of PSMA. We present a case of 35-year-old man with medullary thyroid carcinoma, post total thyroidectomy and bilateral neck dissection, now presenting with rising calcitonin levels (doubling time 9 months) and local neck recurrence with negative I-MIBG scan. We decided to perform Ga-PSMA-HBED-CC PET/CT scan to assess PSMA expression and explore the therapeutic option in view of rising serum calcitonin. It revealed intense PSMA uptake in the soft tissue mass in left thyroid bed and cervical lymph nodes. PMID- 29485450 TI - Prediction of Overall Survival Based on Isocitrate Dehydrogenase 1 Mutation and 18F-FDG Uptake on PET/CT in Patients With Cerebral Gliomas. AB - PURPOSE: This retrospective study aimed to correlate F-FDG uptake on PET/CT with isocitrate dehydrogenase enzyme isoform 1 (IDH1) mutation in patients with cerebral gliomas. Hierarchical interactions between factors affecting overall survival (OS) were also examined. METHODS: In 59 patients with glioma, the ratio of the SUVmax of a glioma to the SUVmean of the contralateral cortex (G/C ratio) on F-FDG PET/CT and the presence of IDH1 mutation were correlated. The prognostic value of clinicopathologic factors and G/C ratio for OS were assessed using a Cox proportional hazards model and classification and regression tree models. RESULTS: The mean G/C ratio of IDH1-mutant tumors was significantly lower than that of IDH1 wild-type tumors (0.73 vs 1.14, P = 0.004). In multivariate analysis, IDH1-mutant and G/C ratio were significant for OS. The classification and regression tree modeling identified 3 risk groups for OS (group 1: IDH1 mutant [hazard ratio, 0.2]; group 2: G/C ratio <=0.8 with IDH1 wild type [hazard ratio, 0.83]; group 3: G/C ratio >0.8 with IDH1 wild type [hazard ratio, 1.9]) (overall P < 0.001). The mean OS was 37.0 months in group 1, 28.6 months in group 2, and 20.7 months in group 3, respectively, showing significant differences among the groups (group 1 vs group 2: P = 0.023, group 2 vs group 3: P = 0.049, group 1 vs group3: P < 0.001). CONCLUSIONS: F-FDG uptake of IDH1-mutant gliomas was significantly lower than that of IDH1 wild-type gliomas. IDH1 mutation was the most important factor in identifying patients with the best prognosis, whereas increased F-FDG uptake provided additional prognostic information for predicting poor OS among patients with IDH1 wild-type gliomas. PMID- 29485451 TI - About anaesthetists and artists. PMID- 29485452 TI - Maternal anaemia - the story behind the number. PMID- 29485453 TI - Reply to: maternal anaemia - the story behind the number. PMID- 29485454 TI - Is the dose and mode of administration of dipyrone associated with acute kidney injury? PMID- 29485455 TI - Reply to: is the dose and mode of administration of dipyrone associated with acute kidney injury? PMID- 29485456 TI - Does the technique of two-hand mask ventilation matter? PMID- 29485458 TI - The central venous pressure, and 'a plea for some common-sense'. PMID- 29485457 TI - Reply to: does the technique of two-hand mask ventilation matter? PMID- 29485459 TI - Reply to: the central venous pressure, and 'a plea for some common-sense'. PMID- 29485460 TI - Is the Arne risk index a valid predictor for difficult intubation with indirect laryngoscopy? PMID- 29485461 TI - Reply to: is the Arne risk index a valid predictor for difficult intubation with indirect laryngoscopy? PMID- 29485462 TI - New Bone Formation Process Using Bio-Oss and Collagen Membrane for Rat Calvarial Bone Defect: Histological Observation. AB - PURPOSE: We carried out guided bone regeneration of cranial bone defects in rats using the bovine bone substitute Bio-Oss and a collagen membrane and performed histological observations of the bone repair process. MATERIALS AND METHODS: Bone defects were created in the cranial bones of 30 15-week-old Sprague-Dawley rats. We made 3 groups. A is unfilled, B is Bio-Oss, and C is Bio-Oss plus a collagen membrane. At 4 or 8 weeks postoperatively, tissue samples were taken. The Kawamoto technique was used for histological evaluation. RESULTS: There was no new bone formation in group A. In groups B and C, new bone formation was evident around the Bio-Oss. In group C, new bone formation was evident in the centers of the bone defects, detached from the cut edge of the cranial bone. CONCLUSION: Our results suggested that the Bio-Oss acts as a scaffold for bone repair, and the use of a collagen membrane may anchor the Bio-Oss closely to the cranial bone and assist the bone repair response. PMID- 29485464 TI - Coordinating family and medical leave. PMID- 29485463 TI - Retrospective Study of 1087 Anodized Implants Placed in Private Practice: Risk Indicators Associated With Implant Failure and Relationship Between Bone Levels and Soft Tissue Health. AB - INTRODUCTION: To evaluate risk indicators associated with implant failure and relationship between bone levels and soft-tissue health of anodized implants placed in private practice. MATERIAL AND METHODS: Partially or completely edentulous patients who received an anodized implant between 2003 and 2013 were included. Univariate and multivariate analysis was used to identify the relationship between study variables and implant failure. Mean marginal bone level changes (MBLDelta) were assessed using periapical radiographs. Periimplant soft tissue was evaluated using a modified bleeding index (implant mucosal index, IMI). RESULTS: A total of 1087 implants placed in 414 patients were followed for 3.9 +/- 2.7 years. The cumulative implant survival rate after 10 years of function was 97.0%. Shorter (P = 0.0068) and maxillary implants (P = 0.0314) were associated with lower implant survival rate. Mean MBL decreased from -0.16 +/- 0.43 mm at baseline to -0.53 +/- 0.53 mm 8 to 10 years later. Implants with healthier mucosa were associated with less bone loss. CONCLUSIONS: Implants with an anodized surface showed a high long-term survival rate in a daily practice. Longer implants and implants placed in the mandible were associated with greater survival. Immediate loading and tapered design did not affect implant survival. Profuse multipoint bleeding and suppuration on recall were associated with greater bone loss. PMID- 29485465 TI - Patient portal considerations. PMID- 29485466 TI - Baby boomer retirement: Are you up to the challenge? PMID- 29485467 TI - Combating hospital-acquired C. diff. AB - A successful collaboration between clinical nurse leaders and clinical nurse specialists. PMID- 29485468 TI - Filipino nurses in the United States. AB - Demographic profile and job satisfaction. PMID- 29485469 TI - The impact of human capital management. PMID- 29485470 TI - Career development for nurse managers. AB - In this first installment of a two-part series on mentoring, we discuss organizing a mentor program for nurse managers who want to develop their careers. PMID- 29485471 TI - Staying organized in the work whirlwind. PMID- 29485472 TI - Management of delirium across an integrated health system. PMID- 29485473 TI - Cardiac Progenitors Induced from Human Induced Pluripotent Stem Cells with Cardiogenic Small Molecule Effectively Regenerate Infarcted Hearts and Attenuate Fibrosis. AB - Cardiac progenitor cells (CPCs) being multipotent offer a promising source for cardiac repair due to their ability to proliferate and multiply into cardiac lineage cells. Here, we explored a novel strategy for human CPCs generation from human induced pluripotent stem cells (hiPSCs) using a cardiogenic small molecule, isoxazole (ISX-9) and their ability to grow in the scar tissue for functional improvement in the infarcted myocardium. CPCs were induced from hiPSCs with ISX 9. CPCs were characterized by immunocytochemistry and RT-PCR. The CPC survival and differentiation in the infarcted hearts were determined by in vivo transplantation in immunodeficient mice following left anterior descending artery ligation and their effects were determined on fibrosis and functional improvement. ISX-9 simultaneously induced expression of cardiac transcription factors, NK2 homeobox 5, islet-1, GATA binding protein 4, myocyte enhancer factor 2 in hiPSCs within 3 days of treatment and successfully differentiated into three cardiac lineages in vitro. Messenger RNA and microRNA-sequencing results showed that ISX-9 targeted multiple cardiac differentiation, proliferation signaling pathways and upregulated myogenesis and cardiac hypertrophy related-microRNA. ISX 9 activated multiple pathways including transforming growth factor beta induced epithelial-mesenchymal transition signaling, canonical, and non-canonical Wnt signaling at different stages of cardiac differentiation. CPCs transplantation promoted myoangiogenesis, attenuated fibrosis, and led to functional improvement in treated mice. PMID- 29485474 TI - Precision of Optic Nerve Head and Retinal Nerve Fiber Layer Parameter Measurements by Spectral-domain Optical Coherence Tomography: Methodological Issues on Reproducibility. PMID- 29485476 TI - Iris Thickness and Severity of Neovascular Glaucoma Determined Using Swept-Source Anterior-segment Optical Coherence Tomography. AB - PURPOSE: To investigate the iris thickness (IT) in neovascular glaucoma (NVG) using swept-source anterior-segment optical coherence tomography (ASOCT). PATIENTS AND METHODS: In this retrospective, clinic-based, comparative study, we enrolled 20 NVG patients [11 with 360-degree angle-closure (AC)-NVG and 9 with NVG without AC] and 14 healthy age-matched controls. Horizontal scanning images of swept-source ASOCT were analyzed using software calipers in temporal and nasal angle areas. ITs at 1 and 2 mm from the pupil edge were measured using ASOCT. The relation between IT and the severity of NVG, the effects of intraocular pressure (IOP), intravitreal antivascular endothelial growth factor (anti-VEGF) injection, and panretinal photocoagulation (PRP) were assessed using linear regression analysis based on the corrected Akaike information criteria index. RESULTS: The IT was thinner in 360-degree AC-NVG patients, followed by NVG patients without AC and controls (0.33 vs. 0.48 vs. 0.57 mm at 1 mm and 0.31 vs. 0.43 vs. 0.49 mm at 2 mm; P<0.001 by ANOVA). Multiple linear regression analysis revealed that 360 degree AC-NVG patients-NVG patients without AC and controls (coefficient: -0.16), NVG patients without AC-control (-0.13) and underwent PRP (0.23) at 1 mm, 360 degree AC-NVG patients-NVG patients without AC and controls (-0.12), NVG patients without AC-controls (-0.08), underwent PRP (0.16), received anti-VEGF injection (0.05) and IOP (-0.001) at 2 mm were selected predictors to explain IT. CONCLUSIONS: IT decreases with the progression of the NVG stage and is thinnest in 360-degree AC-NVG patients. Our study suggests a new morphologic feature of NVG. PMID- 29485475 TI - Extensive Submacular Hemorrhage After Trabeculectomy With Mitomycin C. AB - PURPOSE: We report the occurrence of an extensive submacular hemorrhage after trabeculectomy with mitomycin C in a patient with an occult choroidal neovascular membrane (CNVM). PATIENTS AND METHODS: A 66-year-old man had a 3-year history of primary open-angle glaucoma in the left eye, which had been treated with topical antiglaucoma medication. The patient had age-related macular degeneration with an occult CNVM, for which he had received 5 intravitreal injections of ranibizumab and 5 intravitreal injections of bevacizumab in the left eye over a 3-year period. As intraocular pressure was not under control in the left eye over a 2 month period, trabeculectomy with mitomycin C was performed. RESULTS: On the first postoperative day, intraocular pressure was 8 mm Hg with a well-formed bleb in the left eye. However, extensive subretinal hemorrhage was observed, and the patient underwent pneumatic displacement and pars plana vitrectomy to remove the hemorrhage. After 7 months, extensive subretinal fibrosis was observed and visual acuity was low (hand movement only). CONCLUSIONS: To our knowledge, this is the first report of an extensive submacular hemorrhage after trabeculectomy with mitomycin C in a patient with an occult CNVM. PMID- 29485477 TI - A Pilot Test of Group Based Cognitive Behavioral Therapy to Augment Vocational Services for Persons With Serious Mental Illness: Feasibility and Competitive Work Outcomes. AB - Persons with serious mental illness (SMI) struggle with work functioning even with the assistance of vocational services. The current study sought to address this problem by examining a cognitive-behavioral therapy to augment vocational services. Fifty-two adults with SMI receiving vocational services participated in a pre-post feasibility trial of the Cognitive Behavior Therapy for Work Success (CBTw) intervention. CBTw is a 12-week manualized intervention that addresses cognitive and behavioral factors that impact work functioning. Competitive work outcomes were assessed in the 12 weeks preceding baseline and after the intervention. The results demonstrate strong session attendance and a low attrition rate. There were also significant improvements in work outcomes. Specifically, among participants unemployed at baseline, 50.0% attained work during follow-up. These findings provide preliminary evidence that CBTw may be a feasible intervention to augment vocational services; further controlled research should examine its benefit to work outcomes in people with SMI. PMID- 29485478 TI - TENON CAPSULE-VITREOUS CAVITY FISTULA AFTER HYDROGEL SCLERAL BUCKLE REMOVAL. AB - PURPOSE: To report a rare case of vitreous cavity-Tenon capsule fistula formation after removal of a symptomatic hydrogel scleral buckle. METHODS: Case report. RESULTS: A 43-year-old man presented with chronic headache and involuntary gaze deviation for over 1 year after hydrogel scleral buckle surgery 25 years prior. After removal of the scleral buckle, the patient developed a fluid-filled inflation of the buckle capsule, surrounding a previously noted area of severe scleral thinning. Ocular ultrasonography suggested a fistulous connection between the vitreous cavity and the sub-Tenon space in the area of scleral thinning. There was resolution of diplopia and headache postoperatively, with stability of the fluid collection on clinical examination. Because of high risk of further surgery and resolution of the patient's symptoms, conservative management was elected. CONCLUSION: This is the first report, to the best of our knowledge, of Tenon capsule-vitreous cavity fistula formation after scleral buckle explantation. Because of innate ability to expand, as well as tendency to become friable, hydrogel buckles have a higher risk of requiring removal and of complications from explantation, respectively. Our patient experienced relief of symptoms, without complication from the fistula, and was successfully managed conservatively. PMID- 29485479 TI - Competency-Based, Time-Variable Education in the Health Professions: Crossroads. AB - Health care systems around the world are transforming to align with the needs of 21st-century patients and populations. Transformation must also occur in the educational systems that prepare the health professionals who deliver care, advance discovery, and educate the next generation of physicians in these evolving systems. Competency-based, time-variable education, a comprehensive educational strategy guided by the roles and responsibilities that health professionals must assume to meet the needs of contemporary patients and communities, has the potential to catalyze optimization of educational and health care delivery systems. By designing educational and assessment programs that require learners to meet specific competencies before transitioning between the stages of formal education and into practice, this framework assures the public that every physician is capable of providing high-quality care. By engaging learners as partners in assessment, competency-based, time-variable education prepares graduates for careers as lifelong learners. While the medical education community has embraced the notion of competencies as a guiding framework for educational institutions, the structure and conduct of formal educational programs remain more aligned with a time-based, competency-variable paradigm.The authors outline the rationale behind this recommended shift to a competency based, time-variable education system. They then introduce the other articles included in this supplement to Academic Medicine, which summarize the history of, theories behind, examples demonstrating, and challenges associated with competency-based, time-variable education in the health professions. PMID- 29485480 TI - Time-Variable Training in Medicine: Theoretical Considerations. AB - The introduction of competency-based medical education has shifted thinking from a fixed-time model to one stressing attained competencies, independent of the time needed to arrive at those competencies. In this article, the authors explore theoretical and conceptual issues related to time variability in medical training, starting with the Carroll model from the 1960s that put time in the equation of learning. They discuss mastery learning, deliberate practice, and learning curves.While such behaviorist theories apply well to structured courses and highly structured training settings, learning in the clinical workplace is not well captured in such theories or in the model that Carroll proposed. Important in clinical training are self-regulation and motivation; neurocognitive perspectives of time and learning; professional identity formation; and entrustment as an objective of training-all of which may be viewed from the perspective of the time needed to complete training. The authors conclude that, in approaching time variability, the Carroll equation is too simplistic in its application to the breadth of medical training. The equation may be expanded to include variables that determine effective workplace learning, but future work will need to examine the validity of these additional factors. PMID- 29485481 TI - A Lack of Continuity in Education, Training, and Practice Violates the "Do No Harm" Principle. AB - The paradigm shift to competency-based medical education (CBME) is under way, but incomplete implementation is blunting the potential impact on learning and patient outcomes. The fundamental principles of CBME call for standardizing outcomes addressing population health needs, then allowing time-variable progression to achieving them. Operationalizing CBME principles requires continuity within and across phases of the education, training, and practice continuum. However, the piecemeal origin of the phases of the "continuum" has resulted in a sequence of undergraduate to graduate medical education to practice that may be continuous temporally but bears none of the integration of a true continuum.With these timed interruptions during phase transitions, learning is not reinforced because of a failure to integrate experiences. Brief block rotations for learners and ever-shorter supervisory assignments for faculty preclude the development of relationships. Without these relationships, feedback falls on deaf ears. Block rotations also disrupt learners' relationships with patients. The harms resulting from such a system include decreases in patient satisfaction with their care and learner satisfaction with their work. Learners in this block system also demonstrate an erosion of empathy compared with those in innovative longitudinal training models. In addition, higher patient mortality during intern transitions has been demonstrated.The current medical education system is violating the first principle of medicine: "Do no harm." Full implementation of competency-based, time-variable education and training, with fixed outcomes aligned with population health needs, continuity in learning and relationships, and support from a developmental program of assessment, holds great potential to stop this harm. PMID- 29485482 TI - Enhanced Requirements for Assessment in a Competency-Based, Time-Variable Medical Education System. AB - Competency-based, time-variable medical education has reshaped the perceptions and practices of teachers, curriculum designers, faculty developers, clinician educators, and program administrators. This increasingly popular approach highlights the fact that learning among different individuals varies in duration, foundation, and goal. Time variability places particular demands on the assessment data that are so necessary for making decisions about learner progress. These decisions may be formative (e.g., feedback for improvement) or summative (e.g., decisions about advancing a student). This article identifies challenges to collecting assessment data and to making assessment decisions in a time-variable system. These challenges include managing assessment data, defining and making valid assessment decisions, innovating in assessment, and modeling the considerable complexity of assessment in real-world settings and richly interconnected social systems. There are hopeful signs of creativity in assessment both from researchers and practitioners, but the transition from a traditional to a competency-based medical education system will likely continue to create much controversy and offer opportunities for originality and innovation in assessment. PMID- 29485483 TI - Learning in Practice: A Valuation of Context in Time-Variable Medical Training. AB - The logical consequence of implementing competency-based education is moving to time-variable training. Competency-based, time-variable training (CBTVT) requires an understanding of how learners interact with their learning context and how that leads to competence. In this article, the authors discuss this relationship. They first explain that the time required to achieve competence in clinical practice depends on the availability of clinical experiences that are conducive to ongoing competence development. This requires both curricular flexibility in light of the differences in individual learners' development and a balance between longitudinal placements and transitions to different environments.Along with the deliberate use of the opportunities that learning environments offer, there is value for learners in spending ample time-in-context. For instance, guided independence is possible when trainees do not progress immediately after meeting curricular learning objectives. Next, the potential implications of CBTVT can be illustrated by two learning perspectives-Sfard's acquisition and participation metaphors-which leads to the assertion that competence is both an individual characteristic and a quality that emerges from a purposeful social interaction between individuals and their context. This theory recognizes that the deliberate use of context could be used to approach learning as acquiring collective competence.Based on this relationship between learner, context, and competence, the authors propose an approach to CBTVT that recognizes that all learners will have to meet a number of standard preset learning targets in their workplace, while still having room for further context-specific competence development and personal growth within strategically organized learning environments. PMID- 29485484 TI - What Regulatory Requirements and Existing Structures Must Change If Competency Based, Time-Variable Training Is Introduced Into the Continuum of Medical Education in the United States? AB - As competency-based medical education is adopted across the training continuum, discussions regarding time-variable medical education have gained momentum, raising important issues that challenge the current regulatory environment and infrastructure of both undergraduate and graduate medical education in the United States. Implementing time-variable medical training will require recognizing, revising, and potentially reworking the multiple existing structures and regulations both internal and external to medical education that are not currently aligned with this type of system. In this article, the authors explore the impact of university financial structures, hospital infrastructures, national accrediting body standards and regulations, licensure and certification requirements, government funding, and clinical workforce models in the United States that are all intimately tied to discussions about flexible training times in undergraduate and graduate medical education. They also explore the implications of time-variable training to learners' transitions between medical school and residency, residency and fellowship, and ultimately graduate training and independent practice. Recommendations to realign existing structures to support and enhance competency-based, time-variable training across the continuum and suggestions for additional experimentation/demonstration projects to explore new training models are provided. PMID- 29485485 TI - Flexibility in Postgraduate Medical Training in the Netherlands. AB - Postgraduate medical training in the Netherlands has become increasingly individualized. In this article, the authors describe current practices for three residency programs at the University Medical Center Utrecht: anesthesiology, pediatrics, and ophthalmology. These programs are diverse yet share characteristics allowing for individualized residency training. New residents enter each program throughout the year, avoiding a large simultaneous influx of inexperienced doctors. The usual duration of each is five years. However, the actual duration of rotations or of the program as a whole can be reduced because of residents' previous medical experience or demonstration of early mastery of relevant competencies. If necessary, the duration of training can also increase.Although working hours are already restricted by the European Working Time Directive, most residents choose to train on a part-time basis. The length of their program then is extended proportionally. The extension period added for those residents training part-time can be used to develop specific competencies, complete an elective rotation or research, or explore a focus area. If the resident meets all training objectives before the extension period is completed, the program director can choose to shorten the program length. Recently, entrustable professional activities have been introduced to strengthen workplace based assessment. The effects on program duration have yet to be demonstrated.Flexible postgraduate training is feasible. Although improving work life balance for residents is a necessity, attention must be paid to ensuring that they gain the necessary experience and competencies and maintain continuity of care to ensure that high-quality patient care is provided. PMID- 29485486 TI - The University of Wisconsin-Milwaukee Flexible Option for Bachelor of Science in Nursing Degree Completion. AB - The 2010 "Future of Nursing: Leading Change, Advancing Health" report from the Institute of Medicine recommended that 80% of registered nurses (RNs) obtain a bachelor of science in nursing (BSN) degree by 2020. Hospitals with BSN nurses have reduced morbidity and mortality. In 2014, the University of Wisconsin Milwaukee and the University of Wisconsin-Extension launched the University of Wisconsin Flexible Option BSN (UW Flex BSN) as an additional model for BSN degree completion, adding to the in-person and online delivery models already being offered.In this article, the authors examine the decision to launch the UW Flex BSN program as a competency-based, time-variable approach to RN-to-BSN degree completion. They discuss the factors contributing to its success (including proactive, wraparound support for students through the use of academic success coaches and regular and substantive interaction with faculty), design and program elements and decisions, and continuing challenges that have yet to be resolved.UW Flex BSN is one version of direct-assessment, competency-based education, and it represents the first of its kind in a public institution for postlicensure BSN degree completion. The program meets all Higher Learning Commission standards and requirements and is grounded in the American Association of Colleges of Nursing Baccalaureate Essentials and program quality standards. The UW Flex BSN for degree completion is a successful example of a competency-based, time-variable education model that has been applied in a practice discipline. PMID- 29485487 TI - Describing the Journey and Lessons Learned Implementing a Competency-Based, Time Variable Undergraduate Medical Education Curriculum. AB - Oregon Health & Science University School of Medicine launched a completely new undergraduate medical education curriculum in 2014. This initiative dramatically transformed the MD degree program, changing the instructional content taught, the pedagogical methods used by the faculty, and the methods of assessment, and it added new elements such as academic coaching and programmatic entrustment to the program. One of the most exciting and impactful aspects to date of this curricular transformation has been the deliberate implementation of a competency based framework that incorporates frequent assessment, tracking of student progression using an electronic portfolio, and academic coaching to optimize learning and customize curricular elements for each student. The next major step in this process-the implementation of time-variable progression-is currently ongoing as a planning group at the school works through the conceptual, logistical, legal, and regulatory issues related to implementing such a system. When implementation is complete, MD students will graduate only once they have earned entrustment for all 13 Core Entrustable Professional Activities for Entering Residency. This article describes the school's progress to date in its curricular transformation and articulates lessons learned thus far in driving substantive and dramatic institutional changes that profoundly impact students, faculty, and administrators in one academic health center. PMID- 29485488 TI - The History of Medical Education in Europe and the United States, With Respect to Time and Proficiency. AB - In this article, the authors present a historic overview of the development of medical education in the United States and Europe (in particular the Netherlands), as it relates to the issues of time (duration of the course) and proficiency (performance requirements and examinations). This overview is necessarily limited and based largely on post hoc interpretation, as historic data on time frames are not well documented and the issue of competence has only recently been addressed.During times when there were few, if any, formal regulations, physicians were primarily "learned gentlemen" in command of few effective practical skills, and the duration of education and the competencies acquired by the end of a course simply did not appear to be issues of any interest to universities or state authorities. Though uniform criteria gradually developed for undergraduate medical education, postgraduate specialty training remained, before accreditation organizations set regulations, at the discretion of individual institutions and medical societies. This resulted in large variability in training time and acquired competencies between residency programs, which were often judged on the basis of opaque or questionable criteria. Considering the high costs of health care today and the increasing demand for patient safety and educational efficiency, continuing historic models of nonstandardized practices will no longer be feasible. Efforts to constrain, restructure, and individualize training time and licensing tracks to optimize training for safe care, both in the United States and Europe, are needed. PMID- 29485489 TI - Biological Response to Time-Controlled Adaptive Ventilation Depends on Acute Respiratory Distress Syndrome Etiology. AB - OBJECTIVES: To compare a time-controlled adaptive ventilation strategy, set in airway pressure release ventilation mode, versus a protective mechanical ventilation strategy in pulmonary and extrapulmonary acute respiratory distress syndrome with similar mechanical impairment. DESIGN: Animal study. SETTING: Laboratory investigation. SUBJECTS: Forty-two Wistar rats. INTERVENTIONS: Pulmonary acute respiratory distress syndrome and extrapulmonary acute respiratory distress syndrome were induced by instillation of Escherichia coli lipopolysaccharide intratracheally or intraperitoneally, respectively. After 24 hours, animals were randomly assigned to receive 1 hour of volume-controlled ventilation (n = 7/etiology) or time-controlled adaptive ventilation (n = 7/etiology) (tidal volume = 8 mL/kg). Time-controlled adaptive ventilation consisted of the application of continuous positive airway pressure 2 cm H2O higher than baseline respiratory system peak pressure for a time (Thigh) of 0.75 0.85 seconds. The release pressure (Plow = 0 cm H2O) was applied for a time (Tlow) of 0.11-0.18 seconds. Tlow was set to target an end-expiratory flow to peak expiratory flow ratio of 75%. Nonventilated animals (n = 7/etiology) were used for Diffuse Alveolar Damage and molecular biology markers analyses. MEASUREMENT AND MAIN RESULTS: Time-controlled adaptive ventilation increased mean respiratory system pressure regardless of acute respiratory distress syndrome etiology. The Diffuse Alveolar Damage score was lower in time-controlled adaptive ventilation compared with volume-controlled ventilation in pulmonary acute respiratory distress syndrome and lower in time-controlled adaptive ventilation than nonventilated in extrapulmonary acute respiratory distress syndrome. In pulmonary acute respiratory distress syndrome, volume-controlled ventilation, but not time-controlled adaptive ventilation, increased the expression of amphiregulin, vascular cell adhesion molecule-1, and metalloproteinase-9. Collagen density was higher, whereas expression of decorin was lower in time controlled adaptive ventilation than nonventilated, independent of acute respiratory distress syndrome etiology. In pulmonary acute respiratory distress syndrome, but not in extrapulmonary acute respiratory distress syndrome, time controlled adaptive ventilation increased syndecan expression. CONCLUSION: In pulmonary acute respiratory distress syndrome, time-controlled adaptive ventilation led to more pronounced beneficial effects on expression of biomarkers related to overdistension and extracellular matrix homeostasis. PMID- 29485490 TI - Climate of Respect Evaluation in ICUs: Development of an Instrument (ICU-CORE). AB - OBJECTIVES: To develop a valid, reliable measure that reflected the environment of respectfulness within the ICU setting. DESIGN: We developed a preliminary survey instrument based on conceptual domains of respect identified through prior qualitative analyses of ICU patient, family member, and clinician perspectives. The initial instrument consisted of 21 items. After five cognitive interviews and 16 pilot surveys, we revised the instrument to include 23 items. We used standard psychometric methods to analyze the instrument. SETTINGS: Eight ICUs serving adult patients affiliated with a large university health system. SUBJECTS: ICU clinicians. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Based on 249 responses, we identified three factors and created subscales: General Respect, Respectful Behaviors, and Disrespectful Behaviors. The General Respect subscale had seven items (alpha = 0.932) and reflected how often patients in the ICU are treated with respect, in a dignified manner, as an individual, equally to all other patients, on the "same level" as the ICU team, as a person, and as you yourself would want to be treated. The Respectful Behaviors subscale had 10 items (alpha = 0.926) and reflected how often the ICU team responds to patient and/or family anxiety, makes an effort to get to know the patient and family as people, listens carefully, explains things thoroughly, gives the opportunity to provide input into care, protects patient modesty, greets when entering room, and talks to sedated patients. The subscale measuring disrespect has four items (alpha = 0.702) and reflects how often the ICU team dismisses family concerns, talks down to patients and families, speaks disrespectfully behind their backs, and gets frustrated with patients and families. CONCLUSIONS: We created a reliable set of scales to measure the climate of respectfulness in intensive care settings. These measures can be used for ongoing quality improvement that aim to enhance the experience of ICU patients and their families. PMID- 29485491 TI - Physical and Physiological Performance Determinants of a Firefighting Simulation Test. AB - OBJECTIVE: To examine determinants of firefighting simulation test performance. METHODS: Sixty-eight (63 male; 5 female) firefighters completed a firefighting simulation (eg, equipment carry, casualty evacuation) previously validated to test occupational fitness among UK firefighters. Multiple linear regression methods were used to determine physiological and physical attributes that best predicted completion time. RESULTS: Mean (+/-SD) time taken to complete the simulation was 610 (+/-79) seconds. The prediction model combining absolute cardiorespiratory capacity (L min) and fat mass explained the greatest variance in performance and elicited the least random error (R = 0.765, R = 0.585, standard error of the estimate [SEE]: +/-52 seconds). Higher fitness and lower fat mass were associated with faster performance. CONCLUSIONS: Firefighter simulation test performance is associated with absolute cardiorespiratory fitness and fat mass. Fitter and leaner individuals perform the task more quickly. Work based interventions should enhance these attributes to promote safe and effective operational performance. PMID- 29485492 TI - Guidelines for Reporting Survey-Based Research Submitted to Academic Medicine. PMID- 29485493 TI - First-Year Students Need Time to Grieve. PMID- 29485494 TI - Building Trust in Entrustment: Pursuing Evidence-Based Progress in the Core Entrustable Professional Activities for Entering Residency. PMID- 29485495 TI - In Reply to Lomis et al. PMID- 29485496 TI - Cost, Value, and the Sustainability of Our Choices Concerning Simulation. PMID- 29485497 TI - In Reply to Maloney et al. PMID- 29485498 TI - What Do Residents Want for Burnout Prevention? ... Time. PMID- 29485499 TI - In Reply to Fortenberry et al. PMID- 29485500 TI - The Limited Value of USMLE Step 2 CS. PMID- 29485501 TI - Extending Graduation From Medical School. PMID- 29485502 TI - In Reply to Hueston et al. PMID- 29485503 TI - Could More Black Doctors Being in Primary Care Specialties Be the Result of Institutional Racism? PMID- 29485504 TI - Artist's Statement: Sixteen Anatomic Mnemonics. PMID- 29485505 TI - A Body of Work: Painting a Decade of Gross Dissection. PMID- 29485506 TI - Commentary on A Body of Work: Painting a Decade of Gross Dissection. PMID- 29485507 TI - Still My Patient. PMID- 29485509 TI - Quantity Over Quality: Metrics in Solid Organ Transplantation. PMID- 29485508 TI - International Liver Transplantation Society Consensus Statement on Immunosuppression in Liver Transplant Recipients. AB - Effective immunosupression management is central to achieving optimal outcomes in liver transplant recipients. Current immunosuppression regimens and agents are highly effective in minimizing graft loss due to acute and chronic rejection but can also produce a substantial array of toxicities. The utilization of immunosuppression varies widely, contributing to the wide disparities in posttransplant outcomes reported between transplant centers. The International Liver Transplantation Society (ILTS) convened a consensus conference, comprised of a global panel of expert hepatologists, transplant surgeons, nephrologists, and pharmacologists to review the literature and experience pertaining to immunosuppression management to develop guidelines on key aspects of immunosuppression. The consensus findings and recommendations of the ILTS Consensus guidelines on immunosuppression in liver transplant recipients are presented in this article. PMID- 29485510 TI - Management of Severe Portopulmonary Hypertension With Dual Oral Therapy Before Liver Transplantation. PMID- 29485511 TI - Small-for-size Syndrome Does Not Occur in Intestinal Transplantation Without Liver Containing Grafts. AB - BACKGROUND: The ideal donor in intestinal transplantation (ITX) is generally considered to be 50% to 70% of recipient body weight. This may be due to concerns for "small for size" syndrome as seen in liver transplantation. We report our experience using smaller donors (donor-recipient weight ratio [DRWR], < 50%) in ITX recipients. METHODS: We studied a group of ITX recipients with DRWR of 50% or less to unmatched controls who received intestinal allografts with DRWR greater than 50%. We examined patient and graft survival and enteral autonomy from parenteral nutrition as surrogate markers for safety of using smaller donors and ease of abdominal wall closure between groups to determine the value. RESULTS: There was no difference in overall patient and graft survival, time to enteral autonomy from parenteral nutrition, and weight gain after ITX over time between groups. The need for complicated abdominal closure techniques was significantly more frequent in the control group than in the study group (34.6% vs 6.9%, P = 0.01). Secondary abdominal closure occurred more frequently in the control group (15.4% vs 0%, P = 0.014). Wound revisions also occurred more frequently in the control group (15.4% vs 0%, P = 0.028). CONCLUSIONS: Our data suggest that ITX using smaller donors (DRWR <= 50%) seems to be an acceptable practice without adverse impact on surgical complications, nutritional autonomy, and patient and graft survival. Abdominal wall closure seems easier in recipients of smaller donors and "small for size" syndrome as described in liver transplantation does not occur with intestinal allografts. PMID- 29485512 TI - Survival and Quality of Life Impact of a Risk-based Allocation Algorithm for Deceased Donor Kidney Transplantation. AB - BACKGROUND: To determine the incremental gains in graft and patient survival under a risk-based, deceased donor kidney allocation compared with the current Australian algorithm. METHODS: Risk-based matching algorithms were applied to first graft, kidney only recipients (n = 7513) transplanted in Australia between 1994 and 2013. Probabilistic models were used to compare the waiting time, life, and QALYs and graft years between the 8 risk-based allocation strategies against current practice. RESULTS: Compared with current practice, Kidney Donor Risk Index-Estimated Posttransplant Survival matching of the lowest 20% of scores reduced median waiting time by 0.64 years (95% confidence interval [CI], 0.52 0.73) for recipients aged 30 years or younger, but increased waiting time by 0.94 years (95% CI, 0.79-1.09) for recipients older than 60 years. Among all age groups, the greatest gains occurred if Kidney Donor Risk Index-Estimated Posttransplant Survival matching of the lowest 30% of scores was used, incurring a median overall gain of 0.63 (95% CI, 0.03-1.25) life years and 0.78 (95% CI, 0.30-1.26) graft years compared with the current practice. A median gain in survival of 1.91 years for younger recipients (aged 30-45 years) was offset by a median reduction in survival (by 0.95 life years) among the older recipients. Prioritization of lower-quality donor kidneys for older candidates reduced the waiting time for recipients older than 45 years, but no changes in graft and patient survivals were observed. CONCLUSIONS: Risk-based matching engendered a moderate, overall increase in graft and patient survivals, accrued through benefits for recipients 45 years or younger but disadvantage to recipients older than 60 years. PMID- 29485513 TI - The Changing Epidemiology of Posttransplant Lymphoproliferative Disorder in Adult Solid Organ Transplant Recipients Over 30 Years: A Single-center Experience. AB - BACKGROUND: Posttransplant lymphoproliferative disorders (PTLD) are a complication of solid organ transplantation (SOT) associated with Epstein-Barr virus (EBV). METHODS: We analyzed the incidence of and risk factors for PTLD among adult SOT recipients at our center over 30 years (1984-2013). We also compared PTLD incidence before and after a prevention strategy of EBV viral load monitoring in EBV serology mismatched patients was adapted in 2001 (ie, transplant era 1 [1983-2001] vs era 2 [2002-2013]). RESULTS: Among 4171 SOT patients, 109 developed PTLD. Cumulative incidence at 1, 10, and 20 years posttransplant was 0.95, 2.3, and 3.5 per 100 person-years, respectively. Beyond the first year peak of almost exclusively EBV-positive PTLD, a lower incidence of PTLD, predominantly EBV negative, persisted for 20 years. Thoracic transplant (hazard ratio [HR], 2.1; P = 0.007) and negative EBV serology (HR, 7.7; P < 0.001) were independent risk factors for PTLD on multivariate Cox regression analysis. EBV seronegativity significantly increased risk of early (HR, 18.5) and EBV-positive PTLD (HR, 14.2), as well as late (HR, 4.9) and EBV-negative PTLD (HR, 3.6) on univariate analyses. Risk of early PTLD was significantly reduced in the recent transplant era (0.8% era 2 vs 1.9% era 1 at 5 years, P = 0.002); this reduction was seen in recent era EBV seropositive (P = 0.035 at 5 years) but not seronegative recipients (P = 0.90 year 5), suggesting lack of impact of viral load monitoring. CONCLUSIONS: Adult SOT recipients face a prolonged risk of late PTLD, whereas risk of early PTLD may have declined in recent years. PMID- 29485514 TI - Predicting Liver Allograft Discard: The Discard Risk Index. AB - BACKGROUND: An index that predicts liver allograft discard can effectively grade allografts and can be used to preferentially allocate marginal allografts to aggressive centers. The aim of this study is to devise an index to predict liver allograft discard using only risk factors available at the time of initial DonorNet offer. METHODS: Using univariate and multivariate analyses on a training set of 72 297 deceased donors, we identified independent risk factors for liver allograft discard. Multiple imputation was used to account for missing variables. RESULTS: We identified 15 factors as significant predictors of liver allograft discard; the most significant risk factors were: total bilirubin > 10 mg/dL (odds ratio [OR], 25.23; confidence interval [CI], 17.32-36.77), donation after circulatory death (OR, 14.13; CI, 13.30-15.01), and total bilirubin 5 to 10 mg/dL (OR, 7.57; 95% CI, 6.32-9.05). The resulting Discard Risk Index (DSRI) accurately predicted the risk of liver discard with a C statistic of 0.80. We internally validated the model with a validation set of 37 243 deceased donors and also achieved a 0.80 C statistic. At a DSRI at the 90th percentile, the discard rate was 50% (OR, 32.34; CI, 28.63-36.53), whereas at a DSRI at 10th percentile, only 3% of livers were discarded. CONCLUSIONS: The use of the DSRI can help predict liver allograft discard. The DSRI can be used to effectively grade allografts and preferentially allocate marginal allografts to aggressive centers to maximize the donor yield and expedite allocation. PMID- 29485516 TI - The Impact of Advanced Age on the Outcomes of Primary Total Hip and Knee Arthroplasty for Osteoarthritis: A Systematic Review. AB - BACKGROUND: Elective total hip arthroplasty (THA) and total knee arthroplasty (TKA) are effective options for the management of osteoarthritis that has not responded to conservative therapy, and they are increasing in utilization worldwide. Therefore, we sought to investigate how older age influences the outcomes of THA and TKA through a review of the current literature. METHODS: The Embase and MEDLINE databases were examined for relevant studies that assessed the role of older age in determining the outcomes of THA and TKA. All studies except for systematic reviews and case reports were considered for inclusion. Studies were excluded if they included data on procedures other than THA and TKA or if they focused on the effect of surgical techniques and rehabilitation programs rather than age. We excluded studies if they included data on total joint arthroplasty (TJA) performed for indications other than osteoarthritis unless osteoarthritis was the diagnosis for >90% of the patient cohort. Journal references were manually searched to identify any additional articles. RESULTS: Thirty-two articles were identified in this review. The most elderly groups in these studies were shown to experience higher mortality rates, more postoperative complications, and a longer stay in the hospital. Perioperative mortality was reported to be between 2.6% and 2.9% for nonagenarians and 1.09% and 1.54% for octogenarians. The increase in length of stay for the elderly following TJA was reported to be 0.6 to 3.1 days. Despite the increased rate of adverse events, there were gains in terms of pain relief and ability to perform activities of daily living, and overall the most elderly groups were satisfied with the THA or TKA. However, there was considerable inconsistency among studies with respect to the methodology for evaluating health-related quality of life and the level of functional ability postoperatively. CONCLUSIONS: Although TJA is considered an effective surgery for the elderly, clinicians should be aware that the elderly are at a higher risk of greater length of stay, complications, and mortality. However, the available literature contained poor data and heterogeneous patient cohorts, and reported on a wide variety of outcomes. Further research assessing the effect of older age on TJA is warranted. PMID- 29485515 TI - Maternal Mental Representations of the Child and Mobile Phone Use During Parent Child Mealtimes. AB - OBJECTIVE: Qualities of the parent-child relationship have not been explored as predictors of parent mobile device use during parent-child activities. METHODS: In 195 mother-child dyads enrolled in an ongoing cohort study, maternal mental representations of their child (ability to reflect on their child's characteristics, emotional state, and their parenting role) were evaluated through the Working Model of the Child Interview (WMCI), a validated semistructured interview. WMCI scale scores were examined as predictors of active maternal mobile device use during parent-child eating encounters (videotaped home mealtimes and a structured laboratory-based protocol) in multivariate logistic regression models. RESULTS: Children were aged 5.9 years (SD: 0.7), mothers were aged 31.5 years (SD: 7.4), and 73.3% of mothers were of white non-Hispanic race/ethnicity. During the family mealtime, 47 (24.1%) mothers actively used a mobile device at least once, whereas during the structured eating protocol, 44 (22.6%) mothers used a device. Controlling for maternal race/ethnicity, education level, and child's sex, WMCI subscales were associated with device use during home mealtimes (higher Child Difficulty) and the eating protocol (higher Child Difficulty and lower Richness of Perceptions and Caregiving Sensitivity). CONCLUSION: Maternal mental representations of their child were significantly associated with using mobile devices during eating encounters. More research studies are needed to understand directionality and longer-term associations between mobile device use and parent-child relationship characteristics. PMID- 29485517 TI - Erratum. PMID- 29485518 TI - Erratum. PMID- 29485519 TI - Evaluation of Electronic Medical Records on Nurses' Time Allocation During Cesarean Delivery. AB - BACKGROUND: The impact of the electronic medical record (EMR) on nursing workload is not well understood. The objective of this descriptive study was to measure the actual and perceived time that nurses spend on the EMR in the operating room during cesarean births. METHODS: Twenty scheduled cesarean births were observed. An observer timed the circulating nurse's EMR use during each case. Immediately after each case, the nurse completed a questionnaire to estimate EMR time allocation during the case and their desired time allocation for a typical case. They were also asked about time allotted to various activities preoperatively, intraoperatively, and postoperatively for a typical cesarean birth. RESULTS: Mean observed nurse EMR time was 36 +/- 12 minutes per case, 40% +/- 10% of the duration of the cesarean delivery. Nurses tended to estimate greater time spent on the EMR; the perceived mean proportion of time spent on the EMR (55%) was greater than the actual timed value of 40% (P = 0.020). Nurse's desired amount of time spent on the EMR was 22% +/- 15% of the case duration, significantly less than actual time spent on the EMR (P = 0.007). CONCLUSIONS: On average, nurses spent 40% of their intraoperative time on the EMR during cesarean births, and this time burden was distributed across the perioperative period. These findings highlight the time burden of EMRs and suggest that EMR functionality should be better aligned with end-user needs. Future studies are needed to better understand the impacts of intraoperative EMR use on patient safety and patient/nursing/clinician communication. PMID- 29485520 TI - Detach Yourself: The Positive Effect of Psychological Detachment on Patient Safety in Long-Term Care. AB - OBJECTIVES: Delivering health care is emotionally demanding. Emotional competencies that enable caregivers to identify and handle emotions may be important to deliver safe care, as it improves resilience and enables caregivers to make better decisions. A relevant emotional competence could be psychological detachment, which refers to the ability to psychologically detach from work and patients in off-duty hours. The objective of this study was to examine the relationship between psychological detachment and patient safety. In addition, the ability of teams to create a safe environment to discuss errors and take personal risks, i.e., psychological safety, was explored as an underlying condition for psychological detachment. METHODS: A total of 1219 caregivers (response rate = 44%) from 229 teams in two long-term care organizations completed a survey on psychological safety and psychological detachment at T0. Team managers rated patient safety of those teams at two points in time (T0 and T1). RESULTS: Two-level regression analysis showed that both psychological safety (beta = 0.72, P < 0.01) and psychological detachment (beta = 0.54, P < 0.05) relate directly to patient safety. Psychological safety relates positively to psychological detachment (beta = 0.48, P < 0.01) but was, however, not an underlying condition. CONCLUSIONS: Perceived patient safety is enhanced by emotional competencies, at individual level by psychological detachment and at team level by psychological safety. Caregivers should be aware of the important influence emotional competencies have on patient safety and be trained to develop these competencies. Future research should focus on exploring underlying conditions for emotional competencies. PMID- 29485521 TI - Novel risk factor for cardiovascular disease in women: history of trauma. PMID- 29485522 TI - Commentary: Quantifying the Impact of Maternal Influenza Vaccination-Beyond Laboratory-Confirmed Efficacy. PMID- 29485523 TI - Theory for advances in health care management research. PMID- 29485524 TI - Active Video Games as a Training Tool for Individuals With Chronic Respiratory Diseases: A SYSTEMATIC REVIEW. AB - PURPOSE: Exercise is an effective treatment for reducing symptom severity and improving quality of life for patients with chronic respiratory diseases. Active video games offer a new and enjoyable way to exercise and have gained popularity in a rehabilitation setting. However, it is unclear whether they achieve comparable physiological and clinical effects as traditional exercise training. METHODS: A systematic literature search was performed to identify studies that included an active video game component as a form of exercise training and a comparator group in chronic respiratory disease. Two assessors independently reviewed study quality using the Cochrane risk of bias tool and extracted data for exercise capacity, quality of life, and preference of exercise model. RESULTS: Six studies were included in this review. Because of the heterogeneity of the populations, study designs, length of intervention, and outcome measures, meta-analysis could not be performed. Active video game training resulted in comparable training maximal heart rate and dyspnea levels to those achieved when exercising using a treadmill or cycle (n = 5). There was insufficient evidence (n = 3) to determine whether active video game training improved exercise capacity as measured by 6-min walk test or treadmill endurance walking. CONCLUSIONS: Although the quality of evidence was low, in a small number of studies active video games induced peak heart rates and dyspnea levels comparable with traditional exercise training. Larger and longer-term randomized controlled trials are needed to establish the impact of video game training for individuals with chronic respiratory diseases.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 29485525 TI - Using 6-Min Walk Distance Expressed as a Percentage of Reference to Evaluate the Effect of Pulmonary Rehabilitation in Elderly Patients With Interstitial Lung Disease. AB - PURPOSE: The aim of this study was to investigate the effect of outpatient pulmonary rehabilitation (PR) program and the use of 6-min walk distance (6MWD), expressed as a percentage of the predicted value (%6MWD), to quantify response to PR in elderly patients with interstitial lung disease (ILD). METHODS: This was a prospective, nonrandomized controlled study. Forty eligible patients with stable ILD (>=65 y old) were advised to attend an outpatient PR program for 3 mo. Thirteen patients completed the PR program and formed the PR group. Ten patients who did not attend the PR program were evaluated after 3 mo and formed the control group. Patients in the PR group underwent a comprehensive 3-mo hospital based outpatient PR program, consisting of educational support and supervised exercise training, and attended the rehabilitation unit weekly. RESULTS: Change in the absolute 6MWD (Delta6MWD) in the PR group was not significantly different compared with the control group (P = .062). Change in %6MWD (Delta%6MWD) was greater in the PR group than in the control group. Baseline 6MWD was not correlated with Delta6MWD, but baseline %6MWD was significantly correlated with Delta6MWD and Delta%6MWD. CONCLUSION: PR had a beneficial effect on elderly patients with ILD in terms of exercise endurance. %6MWD might be more useful than the absolute 6MWD as an outcome measure of PR and as a predictor of response to PR in elderly patients with ILD. PMID- 29485526 TI - Symptoms of Depression and Anxiety as Barriers to Participation in Cardiac Rehabilitation Programs Among Arab and Jewish Patients in Israel. AB - PURPOSE: Despite its proven efficacy, low participation rates in cardiac prevention and rehabilitation programs (CPRPs) prevail worldwide, especially among ethnic minorities. This is strongly evident in Israel's Arab minority. Since psychological distress has been found to be associated with CPRP participation and minorities are subjected to higher levels of distress, it is plausible that distress may be an important barrier for CPRP participation among minority patients. The current prospective study assessed the contribution of depression and anxiety symptoms to participation in a CPRP after acute coronary syndrome, both in the enrollment phase and when considering adherence over time, among Jewish (majority) and Arab (minority) patients in Israel. METHODS: Patients were interviewed during hospitalization about their emotional status and at a 6 mo follow-up concerning participation in a CPRP. Analyses were performed on 397 patients. The Brief Symptom Inventory was used. Logistic regression modeling was applied. RESULTS: Symptoms of depression, but not anxiety, were frequently observed among Arab patients compared with their Jewish counterparts. In analyses adjusted for age, sex, ethnicity, and sociodemographic and clinical characteristics, having symptoms of anxiety was associated with less participation in a CPRP, evident for both Jews and Arabs; this association was less evident for symptoms of depression. Multivariable adjusted models did not show a significant association of symptoms of anxiety or depression with adherence in a CPRP. Accounting for psychological distress did not reduce the sharp difference between Jews and Arabs in CPRP participation. CONCLUSION: Symptoms of distress may serve as barriers to CPRP participation, regardless of ethnic origin. PMID- 29485527 TI - Association Between Severity of Depression and Cardiac Risk Factors Among Women Referred to a Cardiac Rehabilitation and Prevention Clinic. AB - PURPOSE: Depression comorbid with cardiovascular disease is associated with higher rates of morbidity and mortality, with studies suggesting that this is especially true among women. This study examined depressive symptoms and their relationship to cardiac risk factors among women referred to a women's cardiac rehabilitation and primary prevention program. METHODS: A secondary analysis of data collected between 2004 and 2014 for 1075 women who completed a baseline assessment at the Women's Cardiovascular Health Initiative, a women-only cardiac rehabilitation and prevention program in Toronto, Canada. Descriptive statistics for sociodemographic variables, quality of life (SF-36), and cardiac risk factors were stratified by depression symptom severity using cutoff scores from the Beck Depression Inventory-2nd version (BDI-II) and compared with analysis of variance and chi statistics. Prevalence of antidepressant use among those with moderate to high depressive symptoms was assessed as an indicator of under- or untreated depression. RESULTS: Overall, 38.6% of women scored above the BDI-II cutoff for depression; 23.6% in the moderate or severe range. Socioeconomic status and quality of life decreased with increasing depression severity. Body mass index increased with depressive severity (P < .001), as did the percentage of individuals with below target age predicted fitness (P < .001). Only 39.0% of women in the moderate and severe BDI-II groups were taking antidepressants. CONCLUSION: In this sample, we found a significant prevalence of untreated and undertreated depressive symptoms among women with, or at high risk of developing, cardiovascular disease. Additional strategies are needed to identify these patients early and link them to appropriate treatment. PMID- 29485528 TI - A Qualitative Study of Experiences of Participants in Cardiac Rehabilitation. AB - PURPOSE: Maintenance of lifestyle changes after cardiac rehabilitation (CR) is suboptimal. In addition, partners of cardiac patients are invited to participate in CR educational sessions and implicitly expected to assist patients with their lifestyle changes. The purpose of this study was to qualitatively examine patient and partner perceptions of phase 2 CR 3 mo after completion of the program. METHODS: A purposive sample of 11 couples (patients post-heart surgery and their spouses) was interviewed following completion of CR. Semistructured, in-person interviews were conducted with patients and spouses separately. Data were analyzed using line-by-line coding to identify themes. RESULTS: Themes were identified in relation to program elements of CR. Exercise themes were as follows: (1) benefitted from exercise and (2) felt held back. Education themes were as follows: (1) received basic education and (2) needed more personalized information. CR environment themes were as follows: (1) developed confidence; (2) made social comparisons; and (3) helped to have partner there. CONCLUSION: Overall, participant perceptions of exercise, education, and the CR environment were very positive. Nevertheless, there is a need to improve educational efforts within CR to rely less on "canned" presentations and more on participants developing their own self-management methods to maintain a healthy lifestyle after CR. PMID- 29485529 TI - Incorporating Longitudinal Comorbidity and Acute Physiology Data in Template Matching for Assessing Hospital Quality: An Exploratory Study in an Integrated Health Care Delivery System. AB - OBJECTIVE: We sought to build on the template-matching methodology by incorporating longitudinal comorbidities and acute physiology to audit hospital quality. STUDY SETTING: Patients admitted for sepsis and pneumonia, congestive heart failure, hip fracture, and cancer between January 2010 and November 2011 at 18 Kaiser Permanente Northern California hospitals. STUDY DESIGN: We generated a representative template of 250 patients in 4 diagnosis groups. We then matched between 1 and 5 patients at each hospital to this template using varying levels of patient information. DATA COLLECTION: Data were collected retrospectively from inpatient and outpatient electronic records. PRINCIPAL FINDINGS: Matching on both present-on-admission comorbidity history and physiological data significantly reduced the variation across hospitals in patient severity of illness levels compared with matching on administrative data only. After adjustment for longitudinal comorbidity and acute physiology, hospital rankings on 30-day mortality and estimates of length of stay were statistically different from rankings based on administrative data. CONCLUSIONS: Template matching-based approaches to hospital quality assessment can be enhanced using more granular electronic medical record data. PMID- 29485530 TI - Nontraditional Surrogate Decision Makers for Hospitalized Older Adults. AB - BACKGROUND: Without advanced preparation of legal documents, state law determines who may serve as a surrogate decision maker for patients in hospitals. OBJECTIVES: To examine the relationship characteristics associated with traditional versus nontraditional health care surrogates who are making medical decisions for patients in hospitals. RESEARCH DESIGN: Secondary analysis of a baseline cross-sectional survey of a larger prospective observational study. SUBJECTS: In total, 364 patient/surrogate dyads consisting of patients aged 65 years and older admitted to the medical or medical intensive care unit services who lacked decision-making capacity based on a physician assessment and also had a surrogate available. RESULTS: This study of surrogate decision makers for hospitalized older adults found that the relationships of nontraditional surrogates such as, nieces, nephews, and friends serving in the surrogate role is nearly identical to those of traditional, first degree relatives serving as a surrogate. Over two-thirds (71.2%) of nontraditional surrogates saw the patient in-person at least weekly compared with 80.8% of legal surrogates (P-value, 0.9023). Almost all traditional and nontraditional surrogates discussed the patient's medical preferences with the patient (96.9% of legal surrogates and 89.2% of nontraditional surrogates; P=0.0510). CONCLUSIONS: This study shows that both traditional and nontraditional surrogates, who are a patient's primary care giver have similar relationships with patients. The findings of this study suggest that requiring family members such as grandchildren to take the extra step of formal appointment through a legal channel may not be necessary to protect patients. Therefore, broader state laws expanding the list of surrogates authorized by state statute to include more nontraditional surrogates may be necessary. PMID- 29485531 TI - Sarcoid-like reactions in patients receiving modern melanoma treatment. AB - The development of cancer immunotherapy and targeted therapy has reached an important inflection point in the history of melanoma. Immune checkpoint inhibitors and kinase inhibitors are today's standard of care treatments in advanced melanoma patients. Treatment-related toxicities can be very intriguing and quite challenging. Sarcoidosis is a multisystemic granulomatous disease characterized by an aberrant immune response to unknown antigens, whereas sarcoid like reactions (SLRs) refer to localized clinical features. We carried out a single-center observational study in patients with stage IIB-IV melanoma treated with BRAF/MEK inhibitors and immune checkpoint inhibitors. A description of the sarcoidosis-related manifestations was provided from patients' records. We observated eight cases of SLRs in a cohort of 200 patients. The clinical courses were characterized by a variety of symptoms, accompanied by cutaneous signs and extracutaneous manifestations such as bilateral, hilar lymphadenopathy. We identified a histologically granulomatous inflammation involving the skin, the lungs, and the lymph nodes. Two patients presented with cutaneous lesions only, and three patients had lung involvement only. Three patients achieved complete and partial response of the melanoma disease, and three patients had stable disease. Disease progression was documented in two patients. The reported immune related adverse events were mild to severe and in most of the cases were continued without any treatment cessation. SLRs appear during treatment with both kinase and immune checkpoint inhibitors. Awareness of these can avoid misdiagnosis of disease progression and unnecessary treatment changes. PMID- 29485533 TI - Satisfaction With an Intensive Interdisciplinary Pain Treatment for Children and Adolescents: An Independent Outcome Measure? AB - OBJECTIVES: Although treatment satisfaction is recommended in the Pediatric Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (PedIMMPACT) as a core outcome measure in pediatric chronic pain clinical trials, no results regarding this outcome measure have been reported to date for intensive interdisciplinary pain treatment in children and adolescents. The aim of the present study was to close this gap and investigate the treatment satisfaction of pediatric patients with different chronic pain disorders who received intensive interdisciplinary pain treatment and who were followed up over 4 years. METHODS: Treatment satisfaction and treatment outcome were assessed immediately after and 6, 12, and 48 months after intensive interdisciplinary pain treatment for N=104 patients (Mage=13.5; SD=2.2). RESULTS: Patients and their parents were highly satisfied with the treatment and strongly agreed in their ratings. Emotional distress before treatment and younger age increased the risk of being dissatisfied. Analyses revealed that treatment satisfaction was independent of treatment outcome. DISCUSSION: Taken together, the results show that treatment satisfaction is not associated with treatment outcome. A global judgment of satisfaction seems to be an independent outcome measure but may be inappropriate for measuring the multifaceted construct of satisfaction. Instead, separate satisfaction ratings in specific areas, for example, treatment methods or outcome, may be more suitable. PMID- 29485532 TI - STAT5 expression correlates with recurrence and survival in melanoma patients treated with interferon-alpha. AB - Interferons (IFN) have a direct growth-inhibiting effect on tumor cells through Janus kinase-dependent activation of the transcription factor signal transducer and activator of transcription (STAT1). In vitro, signaling through STAT5 has been demonstrated to counteract this effect and lead to IFN resistance of melanoma cell lines. In 32 patients treated with IFN-alpha in an adjuvant setting, we investigated paraffin-embedded tumor tissue from primary melanomas and melanoma metastases for expression of STAT3 and STAT5, by immunohistochemistry, and for expression of phosphorylated signaling transduction activating transcription factor (pSTAT)3 and pSTAT5, by immunofluorescence. Tumor cell expression levels of these proteins were correlated with patient characteristics and clinical outcomes. The patient cohort consisted of 12 (37.5%) patients at AJCC stage I/II (primary melanoma) and 20 (62.5%) at stage III/IV (metastatic melanoma). Recurrence was observed for 25 (78.1%) either during or after IFN-alpha therapy. chi Correlation of staining intensities with clinical data revealed association of pSTAT3 and STAT5 expression with sex (P=0.003 and 0.016, respectively) and of STAT3 with tumor stage (P=0.019). Recurrence of melanoma was found to be associated with high STAT5 expression (P=0.017). Multivariable regression analysis revealed STAT5 expression as an independent factor for predicting progression-free survival (P<0.0001) and overall survival (P=0.022). In summary, high expression of STAT5 correlated with melanoma recurrence and survival of patients treated with IFN-alpha in the adjuvant setting. Recently, it has been suggested that mutations of Janus kinases are involved in resistance to immune checkpoint blocker treatments implying a possible role of STAT5 for immune checkpoint resistance. PMID- 29485534 TI - Prevalence of Pain in COPD Patients and Associated Factors: Report From a Population-based Study. AB - OBJECTIVES: To assess the prevalence of chronic neck pain (CNP), chronic low back pain (CLBP), and migraine among Spanish adults with chronic obstructive pulmonary disease (COPD) compared with non-COPD patients matched by age and sex; and to identify predictors for each of these types of pains among COPD sufferers. MATERIALS AND METHODS: A cross-sectional study conducted with data collected from the European Health Interview Surveys for Spain (EHSS) conducted in years 2009/2010 (n=22,188) and 2014 (n=22,842). Data were analyzed using multivariable logistic models. RESULTS: The prevalence of COPD among patients aged 35 years or above were 7.6% (n=1328) for the EHSS 2009 and 5.4% (n=1008) for the EHSS 2014. We matched 2251 COPD patients with age and sex controls. The prevalence of all types of pain were significantly higher among those suffering COPD than those without COPD. For CNP the figures were 40.5% versus 26.1%, for CLBP 44.8% versus 28.4%, and for migraine 22.5% versus 13.2%. Multivariable analysis showed that COPD was associated to a 1.21 (95% confidence interval [CI], 1.02-1.45) higher risk of CNP, 1.38 (95% CI, 1.16-1.64) of CLBP, and 1.36 (95% CI, 1.12-1.65) of migraine. Associated factors with the presence of these types of pain among COPD patients included younger age (not for CLBP), female sex (not for CLBP), "fair/poor/very poor" self-rated health (not for migraine), high blood pressure (not for CNP), mental disorders, obesity (not for migraine), and use of pain medication. DISCUSSION: The prevalence of CNP, CLBP, and migraine was significantly higher among COPD patients in comparison with controls. Associated factors to suffering these types of pain in patients with COPD included age, sex, self-rated health, certain comorbidities including mental disorders, obesity, and using pain medication. PMID- 29485535 TI - The Impact of Perceived Injustice on Pain-related Outcomes: A Combined Model Examining the Mediating Roles of Pain Acceptance and Anger in a Chronic Pain Sample. AB - OBJECTIVE: Perceived injustice (PI) has been identified as an important risk factor for pain-related outcomes. To date, research has shown that pain acceptance and anger are mediators of the association between PI and pain-related outcomes. However, a combined conceptual model that addresses the interrelationships between these variables is currently lacking. Therefore, the current study aimed to examine the potential mediating roles of pain acceptance and anger on the association between PI and adverse pain-related outcomes (physical function, pain intensity, opioid use status). MATERIALS AND METHOD: This cross-sectional study used a sample of 354 patients with chronic pain being treated at a tertiary pain treatment center. Participants completed measures of PI, pain acceptance, anger, physical function, pain intensity, and opioid use status. Mediation analyses were used to examine the impact of pain acceptance and anger on the association between PI and pain-related outcomes. RESULTS: Examination of the specific indirect effects revealed that pain acceptance fully mediated the relationship between PI and physical function, as well as the relationship between PI and opioid use status. Pain acceptance emerged as a partial mediator of the relationship between PI and pain intensity. DISCUSSION: This is the first study to provide a combined conceptual model investigating the mediating roles of pain acceptance and anger on the relationship between PI and pain outcomes. On the basis of our findings, low levels of pain acceptance associated with PI may help explain the association between PI and adverse pain outcomes. Clinical and theoretical implications are discussed. PMID- 29485536 TI - Virtual Reality as a Distraction Intervention to Relieve Pain and Distress During Medical Procedures: A Comprehensive Literature Review. AB - OBJECTIVES: This review aims to provide a framework for evaluating the utility of virtual reality (VR) as a distraction intervention to alleviate pain and distress during medical procedures. We first describe the theoretical bases underlying the VR analgesic and anxiolytic effects and define the main factors contributing to its efficacy, which largely emerged from studies on healthy volunteers. Then, we provide a comprehensive overview of the clinical trials using VR distraction during different medical procedures, such as burn injury treatments, chemotherapy, surgery, dental treatment, and other diagnostic and therapeutic procedures. METHODS: A broad literature search was performed using as main terms "virtual reality," "distraction," and "pain." No date limit was applied and all the retrieved studies on immersive VR distraction during medical procedures were selected. RESULTS: VR has proven to be effective in reducing procedural pain, as almost invariably observed even in patients subjected to extremely painful procedures, such as patients with burn injuries undergoing wound care, and physical therapy. Moreover, VR seemed to decrease cancer-related symptoms in different settings, including during chemotherapy. Only mild and infrequent side effects were observed. DISCUSSION: Despite these promising results, future long term randomized controlled trials with larger sample sizes and evaluating not only self-report measures but also physiological variables are needed. Further studies are also required both to establish predictive factors to select patients who can benefit from VR distraction and to design hardware/software systems tailored to the specific needs of different patients and able to provide the greatest distraction at the lowest cost. PMID- 29485537 TI - Is Screening for Chlamydia and Gonorrhea in Men Who Have Sex With Men Associated With Reduction of the Prevalence of these Infections? A Systematic Review of Observational Studies. AB - BACKGROUND: Neisseria gonorrhoeae (gonorrhea) could become untreatable in the near future. Indeed, while the treatment of symptomatic gonorrhea in core groups, such men who have sex with men (MSM), is crucial for gonorrhea control programs, screening for and treating asymptomatic gonorrhea/Chlamydia trachomatis(chlamydia) in MSM may contribute to antibiotic resistance in gonorrhea. In this systematic review, we aim to assess if there is evidence that screening MSM for gonorrhea/chlamydia is associated with a decline in the prevalence of these infections. METHODS: We conducted a systematic review in PubMed and Web of Science for relevant studies including uncontrolled observational studies and reported the results following the PRISMA guidelines. The change in estimated prevalences for chlamydia and gonorrhea across the different time points for 3 anatomical sites (oral, urethral and anal) were collected and examined. RESULTS: Twelve studies met our entry criteria. We were able to statistically assess the change in prevalence in 10 of 12 studies. In 3 studies, there was a significant increase in chlamydia prevalence, whereas for gonorrhea, 2 studies reported a significant increase and 2 others a decrease. Our review provides little evidence that screening for gonorrhea and chlamydia in MSM has an effect on the prevalence of these infections. No evidence was found that more frequent screening reduces prevalence more effectively than annual screening. CONCLUSIONS: Our study was not able to provide evidence that screening for chlamydia and gonorrhea lowers the prevalence of these infections in MSM. Randomized controlled trials are required to assess the risks and benefits of gonorrhea/chlamydia screening in high- and low-risk MSM. PMID- 29485538 TI - Practical Considerations for Implementing a New Syphilis Action Plan. PMID- 29485539 TI - The Changing Paradigm of Sexually Transmitted Disease Prevention. PMID- 29485540 TI - Practical Considerations for Health Care Systems Involvement in a Renewed Syphilis Initiative. PMID- 29485541 TI - Prenatal HIV Testing and the Impact of State HIV Testing Laws, 2004 to 2011. AB - OBJECTIVE: This study aimed to analyze prenatal human immunodeficiency virus (HIV) testing rates over time and describe the impact of state HIV testing laws on prenatal testing. METHODS: During 2004-2011, self-reported prenatal HIV testing data for women with live births in 35 states and New York City were collected. Prevalence of testing was estimated overall and by state and year. An annual percent change was calculated in states with at least 6 years of data to analyze testing changes over time. An attorney-coder used WestlawNext to identify states with laws that direct prenatal care providers to screen all pregnant women or direct all women to be tested for HIV and document changes in laws to meet this threshold. RESULTS: The overall prenatal HIV testing rate for 2004 through 2011 combined was 75.7%. State-level data showed a wide range of testing rates (43.2%-92.8%) for 2004 through 2011 combined. In areas with 6 years of data, 4 experienced an annual drop in testing (Alaska, Arkansas, Colorado, and Illinois). States that changed laws to meet the threshold generally had the highest testing rates, averaging 80%, followed by states with a preexisting law, at approximately 70%. States with no law, or no law meeting the threshold, had an average prenatal testing rate of 65%. CONCLUSIONS: Prenatal HIV testing remained stable between 2004 and 2011 but remained below universal recommendations. Testing varied widely across states and was generally higher in areas that changed their laws to meet the threshold or had preexisting prenatal HIV testing laws, compared with those with no or limited prenatal HIV testing language. PMID- 29485542 TI - The Black-White Disparity in Sexually Transmitted Diseases During Pregnancy: How Do Racial Segregation and Income Inequality Matter? AB - BACKGROUND: We investigate the roles of residential racial segregation and income inequality for the black-white disparity in acquiring sexually transmitted diseases (STD) during pregnancy in a multilevel framework. METHODS: The analytic sample consisted of non-Hispanic white (n = 79,271) and non-Hispanic black (n = 17,669) mothers from 2012 population birth data from Pennsylvania. We used the 2009 to 2013 American Community Survey for neighborhood characteristics of mothers; we used multilevel models. RESULTS: First, neighborhood-level factors are important for understanding this disparity because racial segregation and income inequality are significantly associated with acquiring STD during pregnancy, regardless of race. Second, racial segregation moderates the relationships between race/ethnicity and the acquisition of STD during pregnancy. White mothers are more vulnerable to neighborhood segregation than black mothers, and black mothers are less likely to acquire STD during pregnancy than white mothers if they reside with co-ethnics. Third, mothers residing in the most socioeconomically disadvantaged neighborhoods-as indicated by both absolute and relative measures of income inequality-have the highest odds of acquiring STD during pregnancy, regardless of race. CONCLUSIONS: Neighborhood-level segregation and income inequality are important for understanding the acquisition of STDs during pregnancy. Our findings have important implications for future research and for place-specific prevention and intervention to reduce the racial disparity in STD during pregnancy. PMID- 29485543 TI - Factors Associated With Pharyngeal Gonorrhea in Young People: Implications for Prevention. AB - BACKGROUND: The objective of this study was to examine the proportion of missed infections and correlates of pharyngeal gonorrhea among young people attending public sexually transmitted disease (STD) clinics. METHODS: We conducted a case control study of 245 young men and women between April 2012 and May 2014. Participants were eligible for inclusion if they (1) were 15 to 29 years of age, (2) reported giving oral sex to a partner of the opposite sex in the past 90 days, and (3) attended 1 of 12 public STD clinics in Los Angeles County. Computer assisted self-interviews were used to collect information on sexual behaviors and tests were conducted for pharyngeal and urogenital gonorrhea. RESULTS: Most participants were younger than 25 years (69%) and more than half were female (56%). We identified a total of 64 cases (27%) of gonorrhea, of which 29 (45%) were a urogenital only infection, 18 (28%) were a pharyngeal only, and 17 (27%) were dually infected at both sites. Pharyngeal testing increased case finding by 39% from 46 to 64 cases. After adjusting for age, sex, and number of sex partners, those who reported consistent pharyngeal exposure to ejaculate/vaginal fluids were 3 times as likely to have pharyngeal gonorrhea as compared with those without this exposure (adjusted odds ratio, 3.1; 95% confidence interval, 1.3 7.5). CONCLUSIONS: A large proportion of gonorrhea cases among young people would be missed in the absence of pharyngeal testing. These results have implications for those who provide medical care to clients at STD clinics and highlight the need for pharyngeal screening recommendations and counseling messages related to strategies to reduce exposure to infected fluids. PMID- 29485544 TI - Patient Disengagement From an HIV Preexposure Prophylaxis Program in a Sexually Transmitted Disease Clinic. AB - Among 307 patients enrolled in an HIV preexposure prophylaxis (PrEP) program in the Public Health-Seattle & King County STD Clinic, 52 patients (17%) did not fill their PrEP prescription and 40% of those who started PrEP discontinued it at least once within 12 months. PMID- 29485545 TI - Development of Hypertrophic Pachymeningitis in a Patient With Antineutrophil Cytoplasmic Antibody-Negative Eosinophilic Granulomatosis With Polyangiitis. PMID- 29485546 TI - Remission of Refractory Systemic-Onset Juvenile Idiopathic Arthritis After Treatment With Siltuximab. PMID- 29485547 TI - Neuromyelitis Optica Spectrum Disorder in a Patient With Systemic Lupus Erythematosus. PMID- 29485548 TI - Adult-Onset Still Disease and Macrophage Activation Syndrome Following Chikungunya and Hepatitis E Coinfection. PMID- 29485549 TI - Pleuritis and Pericarditis Following Silicone Breast Implants as Part of Autoimmune Syndrome Induced by Adjuvants. PMID- 29485550 TI - Fulminant type 1 diabetes associated with nivolumab in a patient with metastatic melanoma. PMID- 29485551 TI - Aged-looking skin and encorafenib: an adverse event of BRAF inhibitors. PMID- 29485552 TI - Clinical, dermoscopic, and confocal features of nevi and melanomas in a multiple primary melanoma patient with the MITF p.E318K homozygous mutation. PMID- 29485553 TI - Does the Degree of the Mastoid Pneumatization Affect the Side of Bell Palsy? AB - OBJECTIVE: The aim is to investigate the impact of degree of mastoid pneumatization on the affected side of Bell palsy (BP). STUDY DESIGN: Retrospective study in tertiary academic hospital. METHODS: In total, 52 patients who were diagnosed with as BP were included in the study. Each patient was staged using House-Brackmann (HB) staging system. All patients underwent temporal bone computed tomography imaging. House-Brackmann scores, side of the BP, and mastoid pneumatization of all of patients were evaluated in the present study. RESULTS: Regarding the degree of the mastoid pneumatization, there were no significant differences between the affected side and the unaffected side (P = 0.439). The degree of the mastoid pneumatization of the affected side and the unaffected side did not differ between males and females (P = 0.918 for the affected side, P = 0.765 for the unaffected side, respectively). A negative correlation between the age and mastoid pneumatization of each side was found (P = 0.001, P = 0.025, respectively). There was no significant correlation between HB score and the degree of the mastoid pneumatization of each side (P = 0.789, P = 0.703). CONCLUSION: As a conclusion, the degree of the mastoid pneumatization is not one of the risk factors for BP. Further randomized studies with larger numbers of patients are needed to confirm these findings. PMID- 29485554 TI - Improvement of Color Vision Following Posterior Cranial Vault Distraction for Crouzon Syndrome. AB - Crouzon syndrome (CS) is one of the craniosynostosis syndromes that leads to early fusion of cranial sutures and increased intracranial pressure. Intracranial hypertension is a serious complication that may lead to vision loss and cognitive impairment. Early detection and management are necessary to prevent complications. The authors present a patient with CS who underwent posterior cranial vault reconstruction with internal distraction after multiple episodes of headache and papilledema. The patient was unaware of any loss of color vision before the surgery; however, he noted an improvement in his color vision after the surgery. Color vision deficits may be an early sign of intracranial hypertension and finding these deficits using noninvasive testing methods may be an indication for early intervention. PMID- 29485555 TI - Dental Anomalies in Different Types of Cleft Lip and Palate: Is There Any Relation? AB - AIM: The aims of this study were to evaluate the prevalence of dental anomalies in Turkish patients with different types of cleft lip and palate (CLP) and investigate the relationship between the type of cleft and the dental anomaly. METHODS: Eighty-eight patients with cleft lip and/or palate (mean age: 14.1 +/- 6.4 years) were enrolled in this retrospective study. Dental models, panoramic radiographs, and intraoral photographs of these patients were evaluated to detect any maxillary dental anomaly (number and size anomalies). Two hundred fifty unaffected subjects (mean age: 15.2 +/- 7.2 years) composed the control group. Data were evaluated using the independent t test, chi, Fischer exact test, and the odds ratio. RESULTS: Dental anomaly frequency was significantly higher in the cleft group compared with the control group. Tooth agenesis was the most common dental anomaly, followed by microdontia and supernumerary tooth. Lateral incisor agenesis was seen in 69% of the unilateral CLP, in 78% of the bilateral CLP, and in 18% of the cleft palate patients. A significant association was revealed between the right unilateral CLP and the right lateral incisor agenesis (P = 0.0001), the left unilateral CLP and the left lateral incisor agenesis (P = 0.002), and the bilateral CLP and the bilateral lateral incisor agenesis (P = 0.0001). CONCLUSION: Dental anomalies are more frequently seen in patients with CLP compared with the general population. There is a relationship between the cleft type and the ipsilateral lateral incisor agenesis. PMID- 29485556 TI - Cervical Spine Dysmorphism in Congenital Muscular Torticollis. AB - BACKGROUND: Congenital muscular torticollis is a common childhood musculoskeletal anomaly that might result in permanent craniofacial deformity, facial asymmetry, and changes in the cervical vertebrae, if not treated during early childhood. Although there have been many studies on cervical vertebral changes, their onset in children has not been previously studied. METHODS: Fifteen patients (aged <8 years) with a confirmed diagnosed of torticollis were included. Three-dimensional computed tomography scans were obtained, and segmentation of the cervical vertebrae was done. Division of the atlas and axis across the midsagittal plane was done to compare the anatomical changes. The volumes of each halves of the atlas and axis were measured. RESULTS: An apparent change was observed in the axis of the vertebral column when compared with that of the skull. There were progressive anatomical changes affecting the upper cervical vertebrae, which started to develop around the age of 8 months and became more evident in older children. The axis vertebra was the first to be affected. Rotational and bending deformities were the most likely changes to occur. Pearson correlation analysis showed a statistically significant trend in the volume and height changes for both halves of the atlas and axis (P < 0.001 and P < 0.001). CONCLUSIONS: Children with untreated congenital muscular torticollis show progressive anatomical changes of the cervical vertebrae which started at the age of 8 months. The severity of the deformity increased with the advance of age as well as with the severity of sternocleidomastoid tightness, which might result in permanent deformities. PMID- 29485557 TI - Closure of Oroantral Communication With Plasma-Rich Fibrin Membrane. AB - Oroantral communication (OAC) is the opening between the maxillary sinus and oral cavity. It may cause oroantral fistula or maxillary sinusitis if left untreated. The surgical closure of the OAC within 48 hours was recommended to avoid the complications like sinus infections. The aim of this study is to evaluate the treatment of OACs with plasma-rich fibrin (PRF) which is safe and easy to implement in the OACs.This study was conducted with the patients, who required the treatment of the OAC, which was developed after the posterior maxillary tooth extraction in the Dental and Maxillofacial Department of the Faculty of Dentistry in Adnan Menderes University.Plasma-rich fibrin membranes were inserted in layers into the tooth socket so that they covered the OAC. Then these membranes were fixated with the sutures to the surrounding gingiva. Antibiotic (amoxicillin/clavulanic acid 1000 mg), analgesic (dexketoprofen trometamol and/or paracetamol), and oral rinse (0.2% chlorhexidine digluconate) agents were prescribed to all patients. The patients were examined in the 3rd and 7th days and 2 months after the operation.All patients tolerated PRF perfectly, and the soft tissue recovery was completed without any problem. Full epithelization was observed in the defect area in all patients. The OAC did not relapse in any patient.Plasma-rich fibrin technique is a simple and effective method, which can be used in the treatment of OACs with a diameter of 5 mm or less with a low risk of complications. PMID- 29485558 TI - Robin Sequence: Continuing Heterogeneity in Nomenclature and Diagnosis. AB - OBJECTIVE: Heterogeneity in both nomenclature and diagnostic criteria has hindered the interpretation of research into the congenital condition most widely known as (Pierre) Robin syndrome or sequence. In 2009, the discussion regarding its diagnosis and nosology was reopened to converge on a uniform eponym and standard set of diagnostic criteria. The objective of this study was to assess the impact of this debate. MATERIALS AND METHODS: This is a retrospective review of the nomenclature and diagnostic criteria employed in studies about this condition that were indexed in the MEDLINE literature database (PubMed) and published during 2009 to 2016. RESULTS: A total of 440 studies were retrieved of which the majority used the eponyms "Pierre Robin sequence" (62.0%) or "Robin sequence" (23.4%). During the study period, there was a significant shift toward the use of "sequence" in preference over "syndrome." Only 71.4% of studies mentioned their criteria for diagnosis, which remained heterogeneous throughout the study period. CONCLUSION: Since 2009, the debate has not produced a consensus eponym and standard diagnosis. This is unfortunate given the enduring controversies over the optimal management of a condition associated with a high morbidity and mortality. A renewed effort is needed to arrive at a workable consensus to enhance the retrievability of relevant literature and facilitate the interpretation of outcome studies. PMID- 29485559 TI - Innovate Global Plastic and Reconstructive Surgery: Cleft Lip and Palate Charity Database. AB - BACKGROUND: There is an emerging interest in global surgery. The Lancet Commission on Global Surgery recognizes the important role that nongovernmental organizations (NGOs) play in the delivery of cleft lip and/or palate (CLP) surgical care. To better address the unmet burden of surgical disease, the commissioners propose the use of a centralized registry to maximize coordination of global surgical volunteerism efforts. This study aims to create a comprehensive database of CLP organizations. METHODS: A systematic search of the following resources was conducted: The Plastic Surgery Foundation, Smile Train, Wikipedia, Google, and lists of surgical NGOs. A secondary review of each organization's website was performed to verify inclusion criteria and to extract data. Organizations were classified as providing surgical or nonsurgical care. RESULTS: Thirty-one organizations providing CLP care were reviewed, with 30 that met inclusion criteria. Of the 20 surgical NGOs, 50% use a diagonal approach of international outreach, 40% a vertical one-way approach, and 10% a horizontal approach. All 10 of the nonsurgical NGOs provide care through a horizontal approach. Their offices are distributed across North America (43%), Asia (27%), Europe (23%), and Australia (7%). Forty-three percent of the organizations provide CLP surgeries or services in more than 1 country; 93% do so with a multidisciplinary team. A majority of the organizations established collaborations with host institutions (80%). CONCLUSION: To the authors' best knowledge, this database includes the largest collection of CLP organizations. This list will be made publicly available to inform surgical care planning, facilitate collaboration, and promote further research. PMID- 29485560 TI - Comment on Orbital Fat Prolapse Into the Nasal Cavity in Orbital Blowout Fracture. PMID- 29485561 TI - Scanning Electron Microscopy Evaluation of Root Surfaces After Instrumentation With Two Piezoelectric Devices. AB - Scanning electron microscopy evaluation of root surfaces after ultrasonic instrumentation was performed with 2 different metallic tips on piezoelectric devices. Fresh extracted teeth were collected for experimental observation and randomly divided into 2 groups: Test Group, where the root surfaces were treated using an iron, rough, double nano-structural coated (T-Black), corindone-treated tip, and Control Group where the root surfaces were treated with a conventional iron smooth tip. A scanning electronic microscope analysis was performed and the surface roughness and the amount of residual debris were evaluated. Descriptive and inferential statistics were performed. Twenty specimens were analyzed, 10 per group and a total of 21.4 * 10 MUm has been observed. On treated area percentage of debris after ultrasonic scaling in Test Group was 1.9 +/- 1.8%, while in Control Group it was 5.7 +/- 4.3%. Within the limits of the study, it seems that the efficacy of the novel iron, rough, double nano-structural coated (T-Black), corindone-treated structure tip showed greater performance in terms of root surface debridement than the conventional iron smooth tip. The possibility to use a single tool (ultrasonic device with a specific tip) for the root planing procedure within the nonsurgical mechanical therapy may represent a significant advantage for the clinicians. The tested novel tip seems to be able to show the requested ideal characteristics. However, further clinical studies are needed to demonstrate the in vitro results. PMID- 29485562 TI - Osteofascial Radial Forearm Free Flap Reconstruction of Midface Defect After Resection of Intraosseous Hemangioma. AB - INTRODUCTION: Intraosseous hemangiomas of the midface are rare with few reported cases in the literature. Various reconstructive methods have been previously described, but none using vascularized bone graft secondary to the benign nature of the tumor and often relatively limited defect size. CLINICAL REPORT: The authors present the case of a 47-year-old man with a biopsy proven enlarging right maxillary intraosseous cavernous hemangioma which was resected primarily, resulting in a large defect involving the entire zygomaticomaxillary buttress and a portion of the right orbital floor and malar prominence. Given the structural involvement and the significant bony defect size, this was simultaneously reconstructed using an osteofascial radial forearm free flap and orbital floor titanium implant with satisfactory outcome. PMID- 29485563 TI - Spontaneous Resolution of an Orbital Mass After Delivery: A Diagnostic Challenge. AB - The authors report a 35-year-old woman who presented 1 month after delivery with the complaint of pain behind her left eye which started during her pregnancy. The patient described increased fullness with dependent head position and pain on left gaze but she had no proptosis and her ocular examination was normal. Magnetic resonance imaging (MRI) revealed an intraconal mass with inhomogeneous contrast enhancement. As the authors did not suspect malignity and her ocular examination was normal without any signs of inflammation, the authors followed the patient closely. Repeat MRI obtained 6 months after delivery revealed complete resolution of the mass. Upon disappearance of the lesion, the authors reviewed the case thoroughly and decided that orbital venous anomaly with intralesional hemorrhage/thrombosis was the most probable diagnosis. As hemorrhage or thrombosis occurring in orbital vascular anomalies may be a diagnostic challenge because of the localized lesion and distinct borders, careful interpretation of clinical characteristics and MRI findings and close follow-up is important in interpretation of orbital mass lesions, especially in pregnant or puerperal women. PMID- 29485564 TI - Comparison of the Effects of Cigarette Smoking on Male and Female Vocal Folds. AB - OBJECTIVE: To investigate effects of smoking cigarette on male and female larynges and compare them. METHOD: Eighteen adult Wistar Albino rats were included to study; 9 were male and 9 female. The exposure groups each contained 6 rats, and the control groups 3 rats. Six male constituted group 1 and 6 female constituted group 2. Group 1 and 3 were exposed to smoke. Group 2 and 4 were composed of 3 males and 3 females, respectively. Smoke from 10 cigarettes was delivered in each of the morning and afternoon daily for 1 month. At the end of 4 weeks, all rats were sacrificed and their larynges were evaluated histopathologically. RESULTS: Microscobic evaluation of epithelium of vocal folds revealed no significant difference between study groups. There was also no difference between study and control groups. Subepitelial tissue showed no difference between study groups but angiogenesis and inflammation were higher in study groups. Epithelial analysis of false vocal folds showed significant difference between study groups. Female epithelium showed more hyperplastic and metaplastic changes. CONCLUSION: Cigarette smoke damaged both the vocal folds and false vocal folds. The female false vocal folds were more susceptible to damage than the males. PMID- 29485565 TI - The Guiding Lateral Z Osteotomy for the Correction of Vertical Orbital Dystopia. AB - Transcranial vertical orbital translocation is useful for correcting vertical orbital dysplasia. However, the technique is limited by the degree of uncertainty regarding the amount of vertical movement required after the osteotomy. As for landmark movement, Z osteotomy is performed as part of a box osteotomy. This technique is useful in that it is easy to know how far the orbit should be moved, and stabilization can be obtained. PMID- 29485566 TI - Large-Scale Skin Resurfacing of the Upper Extremity in Pediatric Patients Using a Pre-Expanded Intercostal Artery Perforator Flap. AB - BACKGROUND: The repair of extensive upper limb skin lesions in pediatric patients is extremely challenging due to substantial limitations of flap size and donor site morbidity. We aimed to create an oversize preexpanded flap based on intercostal artery perforators for large-scale resurfacing of the upper extremity in children. METHOD: Between March 2013 and August 2016, 11 patients underwent reconstructive treatment for extensive skin lesions in the upper extremity using a preexpanded intercostal artery perforator flap. Preoperatively, 2 to 4 candidate perforators were selected as potential pedicle vessels based on duplex ultrasound examination. After tissue expander implantation in the thoracodorsal area, regular saline injections were performed until the expanded flap was sufficient in size. Then, a pedicled flap was formed to resurface the skin lesion of the upper limb. The pedicles were transected 3 weeks after flap transfer. Flap survival, complications, and long-term outcome were evaluated. RESULT: The average time of tissue expansion was 133 days with a mean final volume of 1713 mL. The thoracoabdominal flaps were based on 2 to 6 pedicles and used to resurface a mean skin defect area of 238 cm ranging from 180 to 357 cm. In all cases, primary donor-site closure was achieved. Marginal necrosis was seen in 5 cases. The reconstructed limbs showed satisfactory outcome in both aesthetic and functional aspects. CONCLUSION: The preexpanded intercostal artery perforator flap enables 1-block repair of extensive upper limb skin lesions. Due to limited donor-site morbidity and a pedicled technique, this resurfacing approach represents a useful tool especially in pediatric patients. PMID- 29485567 TI - Craniovertebral Junction Abnormalities in Surgical Patients With Congenital Muscular Torticollis. AB - Our clinical experience led us to realize that craniovertebral junction (CVJ) abnormalities were common in surgical patients with congenital muscular torticollis (CMT). This study aimed to report the concurrence rate of CVJ abnormalities in surgical patients with CMT, along with comprehensive evaluation of type of concurrent CVJ abnormalities. This was a retrospective cohort study in a tertiary hospital, including 41 subjects who underwent surgical release for CMT at the mean age of 8.38 years. The presence of CVJ abnormalities was analyzed, using craniofacial 3-dimensional computed tomography images. The concurrence rate of CVJ abnormalities was 70% in surgical patients with CMT. Subjects with CVJ abnormalities had, on average, 1.48 abnormalities. The CVJ abnormalities were rotation and lateral shift of the atlanto-axial joint along with rotation of atlanto-occipital joint, where rotation of the atlanto-axial joint was most common (82.76%). There is no patient with anterior shift of the atlanto-axial joint. Chronic mechanical tension by the contracted unilateral sternocleidomastoid muscle of CMT could be responsible for concurrent CVJ abnormalities. The CVJ abnormalities are more common in the atlanto-axial joint than in the atlanto-occipital joint. In conclusions, CVJ abnormality seems to be a common concurrent skeletal complication of CMT, at least, in surgical patients. The CVJ abnormality might be included in the list of skeletal complications of CMT. If CVJ abnormalities are significantly more common in surgical patients with CMT, CVJ abnormalities might be one of predictors of surgical patients with CMT. PMID- 29485568 TI - Comment on: Facial Artery Myomucosal Flap, Pedicled Solely on the Facial Artery: Experimental Design Study on Survival. PMID- 29485569 TI - Ligaments of the Face: Past, Present, and Future. AB - The aim of this study is to search for the origin of the term "ligament' in the face, present its status, and suggest a principle to rectify the use of unclear terminology.The structure that connects the zygoma to the skin was first presented by McGregor (1959). Kaye (1981), in describing his "extended facelift," wrote that the adherent area of the cheek over the malar eminence (McGregor's patch) usually requires sharp dissection. Bosse (1987) reported that the zygomatic ligament is quite solidly bound to the malar eminence and usually requires sharp dissection to release it. The origin of the term was introduced later by Furnas, who stated that when Preddy, a medical artist, prepared drawings for McGregor's slide presentations, she insisted on naming it "McGregor's patch." With the idea that "perhaps" the "retaining ligaments" of the face share a teleologic kinship with Cleland's ligaments or Grayson's ligaments of the hands, Furnas (1989) observed the structure that anchors the skin of the cheek to the inferior border of the zygoma just posterior to the origin of the zygomaticus minor muscle, and named it "the zygomatic ligaments." Subsequently, numerous articles have been published using different terminologies that cause confusion.To rectify the present confusing terminology of the ligament of face, the histologically proven structures should be designated by one term only following the Nomina Anatomica principles. PMID- 29485570 TI - Pulling and Pushing Stem Cells to Control Their Differentiation. AB - Much has already been done to achieve precisely controlled and customised regenerative therapies. Thanks to recent advances made in several areas relevant to regenerative medicine including the use of stimuli-responsive materials, 4 dimensional biofabrication, inducible pluripotent stem cells, control of stem cell fate using chemical and physical factors, minimal access delivery, and information-communication technology. In this short perspective, recent advances are discussed with a focus on a recent report on the use of mechanical stretching of nanoparticle-laden stem cells by using external magnetic field to induce defined cardiac line differentiation. Although more and more tools are becoming available for engineering tissue models tissues and the range of potential applications is expanding, there is still much work to be done before it is proved to work with human cells, form tissues and ultimately achieve application in the clinic. PMID- 29485572 TI - Review of "Why Do General Surgeons Decide to Retire? A Population-Level Survey" by Poushay HM, Kagedan DJ, Hallet J, Conn LG, Beyfuss K, Nadler A, Ahmed N, Wright FC in Ann Surg 267: e4-e5, 2018. PMID- 29485571 TI - Is Coincidental Rhinosinusitis a Predisposing Factor for Postoperative Central Nervous System Infection After Endoscopic Endonasal Transsphenoidal Surgery? AB - BACKGROUND: To investigate the effect of rhinosinusitis in patients who undergo surgery via the endoscopic endonasal transsphenoidal approach (EETSA). METHODS: The authors retrospectively reviewed the medical records of patients who underwent surgery via the EETSA between February 2009 and November 2016. In total, 505 patients were included in the study. Preoperative paranasal sinus computed tomography, sellar magnetic resonance imaging, and nasal endoscopy were performed for all the patients. RESULTS: Fifteen patients without sphenoid sinusitis underwent surgery with the concomitant transsphenoidal approach and functional endoscopic sinus surgery, and showed no central nervous system (CNS) complication. During surgery via the EETSA, the presence of rhinosinusitis did not significantly affect the incidence of postoperative CNS infection (P = 0.051), except for sphenoid sinusitis (P = 0.003). Conversely, the incidence of postoperative CNS infection was not related significantly to the Lund-Mackay score or tumor size. The risk of CNS infection was 12.151-fold higher in patients with sphenoid sinusitis (95% confidence interval, 3.153-46.827; P <= 0.001). CONCLUSION: Surgery via the EETSA and functional endoscopic sinus surgery can be safely performed together in most patients with rhinosinusitis. However, sphenoid sinus infection appears to be a predisposing factor for postoperative CNS infection. Therefore, a separate surgical procedure for sphenoid lesions should be considered in these patients before the use of the EETSA. PMID- 29485573 TI - Skull Base Metastasis From Occult Renal Cell Carcinoma. AB - Skull base metastases are extremely rare. The authors report a case of a 65-year old man who presented with a headache and diplopia secondary to a skull base metastasis from occult renal cell carcinoma. Since there were no other systemic metastases, radical nephrectomy and radiotherapy of the unresectable skull base location were performed. He subsequently received immunotherapy with sunitinib, everolimus, and sorafenib with local and systemic control of the disease after 53 months from surgery. When metastasis is unresectable radical nephrectomy and radiotherapy aimed at the metastasis may be of benefit improving quality of life. Immunotherapy may provide alternative treatment strategies improving the outcomes of patients affected by this rare pathology with historically poor prognosis. PMID- 29485574 TI - Locally Aggressive Fibrous Dysplasia Mimicking Malign Calvarial Lesion. AB - Fibrous dysplasia is an unusual benign bone tumor. It is divided into 3 groups as monostotic, polyostotic, and craniofacial form. The authors reported an unusual patient with fibrous dysplasia with an aggressive radiologic appearance. PMID- 29485575 TI - Surgical Treatment for Extracapsular Condylar Fractures of the Mandible. AB - BACKGROUND: Condylar fractures are considered the most controversial mandibular fractures, regarding both the diagnosis and the treatment. With the increase in surgical indications for handling this type of fracture, it is important to discuss about the advantages and disadvantages of the several surgical approaches available. This article describes the surgical details and postoperative results of the mini-retromandibular transparotid approach for treating extracapsular condylar fractures of the mandible. METHODS: In a 1-year period, 16 patients affected by extracapsular condylar fractures with surgical indication were treated with the mini-retromandibular transparotid approach. All the surgeries were executed by the same surgeon. Preoperative and postoperative details of each patient were analyzed. RESULTS: In the postoperatory, only 2 patients had purulent drainage in the associated fractures area and only 1 patient had paresis of the buccal branch of the facial nerve. No scar issues concerning the surgical wound were observed and reintervention was not necessary in any of the patients. CONCLUSION: The mini-retromandibular transparotid approach offers advantages and should be included as an option for the open treatment of extracapsular condylar fractures of the mandible. PMID- 29485576 TI - Long-Term Patient-Reported Outcomes following Free Flap Lower Extremity Reconstruction for Traumatic Injuries. AB - BACKGROUND: Reconstruction of severe lower extremity injuries using free flaps has become a reliable approach. Knowledge of long-term surgical outcomes, limb function, and quality of life is limited. METHODS: Two hundred thirty-nine patients undergoing a free flap reconstruction of an open lower extremity fracture between 1993 and 2014 were divided into three groups and studied, as follows: group 1, early free flap reconstruction within 6 weeks; group 2, delayed reconstruction after 6 weeks; and group 3, delayed reconstruction with osteomyelitis. Patient-reported outcomes were assessed with the 36-Item Short Form Health Survey and the Lower Extremity Functional Scale. Independent variables predicting outcomes were identified using multivariate analyses. RESULTS: Patients in group 3 significantly more often experienced delayed union. Questionnaires were completed by 108 patients (mean follow-up, 9.7 years). The 36 Item Short-Form Health Survey physical component scores were significantly lower in all three groups compared with Dutch norms, as was the mental health score in group 3. There were no significant differences in quality of life and lower limb function among the three groups. Chronic pain was an independent predictor for decreased quality of life and limb function in groups 1 and 2, as was delayed union for decreased limb function in group 3. CONCLUSIONS: After free flap reconstruction of severe lower extremity injuries, all patient groups showed significantly lower quality of life compared to the Dutch population; however, there were no significant differences between the groups. Predictors for poorer quality of life and limb function were chronic pain and delayed union. PMID- 29485577 TI - Routine Pathologic Evaluation of Plastic Surgery Specimens: Are We Wasting Time and Money? AB - BACKGROUND: Recent health care changes have encouraged efforts to decrease costs. In plastic surgery, an area of potential cost savings includes appropriate use of pathologic examination. Specimens are frequently sent because of hospital policy, insurance request, or habit, even when clinically unnecessary. This is an area where evidence-based guidelines are lacking and significant cost-savings can be achieved. METHODS: All specimen submitted for pathologic examination at two hospitals between January and December of 2015 were queried for tissue expanders, breast implants, fat, skin, abdominal pannus, implant capsule, hardware, rib, bone, cartilage, scar, and keloid. Specimens not related to plastic surgery procedures were excluded. Pathologic diagnosis and cost data were obtained. RESULTS: A total of 759 specimens were identified. Of these, 161 were sent with a specific request for gross examination only. There were no clinically significant findings in any of the specimens. There was one incidental finding of a seborrheic keratosis on breast skin. The total amount billed in 2015 was $430,095. CONCLUSIONS: The infrequency of clinically significant pathologic examination results does not support routine pathologic examination of all plastic surgery specimens. Instead, the authors justify select submission only when there is clinical suspicion or medical history that warrants evaluation. By eliminating unnecessary histologic or macroscopic examination, significant cost savings may be achieved. PMID- 29485578 TI - Inconsistency in Automated Reports of Scientific Productivity and Impact in Academic Plastic Surgery. AB - BACKGROUND: Currently, no consensus metric for measuring academic productivity within plastic surgery exists. The h-index is widely used, as it captures both the quantity and quality of an individual's contribution. However, discrepancies in online reporting make accurate h-index calculation challenging. This study highlights inconsistencies within plastic surgery by assessing differences in reporting of the h-index and other measures of academic productivity across online scientific databases. METHODS: Plastic surgery faculty at institutions with Accreditation Council for Graduate Medical Education-accredited residency programs were identified and searched across four databases: Web of Science, Scopus, Google Scholar, and the National Library of Medicine (PubMed). The total number of publications, citations, and h-index were recorded for each author and analyzed using a Mann-Whitney test. RESULTS: Seven hundred twenty-two faculty members were included in this study. Reporting of publications was highest in Google Scholar and lowest in Web of Science. Because of incomplete information (PubMed) and underuse (Google Scholar), h-index could be assessed only between Web of Science and Scopus, where the average discrepancy in citations and h-index was 722 and 7.0 per author, respectively. Discrepancies were more significant among faculty members holding a Ph.D. degree, higher academic rank, or belonging to the male gender. CONCLUSIONS: Inconsistencies between online scientific databases profoundly affect plastic surgeons. Given the importance placed on metrics such as the h-index, it is imperative that the plastic surgery community push for solutions that ensure more reliable, transparent, and cohesive reporting of academic productivity. PMID- 29485579 TI - Predictors, Classification, and Management of Umbilical Complications in DIEP Flap Breast Reconstruction. PMID- 29485580 TI - Reply: Predictors, Classification, and Management of Umbilical Complications in DIEP Flap Breast Reconstruction. PMID- 29485581 TI - Extended Transconjunctival Lower Eyelid Blepharoplasty with Release of the Tear Trough Ligament and Fat Redistribution. PMID- 29485582 TI - Reply: Extended Transconjunctival Lower Eyelid Blepharoplasty with Release of the Tear Trough Ligament and Fat Redistribution. PMID- 29485583 TI - Extended Transconjunctival Lower Eyelid Blepharoplasty with Release of the Tear Trough Ligament and Fat Redistribution. PMID- 29485584 TI - Reply: Extended Transconjunctival Lower Eyelid Blepharoplasty with Release of the Tear Trough Ligament and Fat Redistribution. PMID- 29485585 TI - Extended Transconjunctival Lower Eyelid Blepharoplasty with Release of the Tear Trough Ligament and Fat Redistribution. PMID- 29485586 TI - Reply: Extended Transconjunctival Lower Eyelid Blepharoplasty with Release of the Tear Trough Ligament and Fat Redistribution. PMID- 29485587 TI - The Six-Step Lower Blepharoplasty: Using Fractionated Fat to Enhance Blending of the Lid-Cheek Junction. PMID- 29485588 TI - Facial Nerve Supply to the Orbicularis Oculi around the Lower Eyelid: Anatomy and Its Clinical Implications. PMID- 29485589 TI - Reply: Facial Nerve Supply to the Orbicularis Oculi around the Lower Eyelid: Anatomy and Its Clinical Implications. PMID- 29485590 TI - Comparison of Steroid and Botulinum Toxin Type A Monotherapy with Combination Therapy for Treating Human Hypertrophic Scars in an Animal Model. PMID- 29485591 TI - Reply: Comparison of Steroid and Botulinum Toxin Type A Monotherapy with Combination Therapy for Treating Human Hypertrophic Scars in an Animal Model. PMID- 29485592 TI - Outpatient Circumferential Lower Body Lift: Is the Lipo-Body Lift an Ideal Method? PMID- 29485593 TI - Reply: Safety of Outpatient Circumferential Body Lift: Evidence from 42 Consecutive Cases. PMID- 29485594 TI - Autologous Fat Transfer for Thumb Carpometacarpal Joint Osteoarthritis: A Prospective Study. PMID- 29485595 TI - Reply: Autologous Fat Transfer for Thumb Carpometacarpal Joint Osteoarthritis: A Prospective Study. PMID- 29485596 TI - Predictors of Autologous Free Fat Graft Retention in the Management of Craniofacial Contour Deformities. PMID- 29485597 TI - An Appraisal of the Cephalic Index in Sagittal Craniosynostosis, and the Unseen Third Dimension. PMID- 29485598 TI - Reply: An Appraisal of the Cephalic Index in Sagittal Craniosynostosis, and the Unseen Third Dimension. PMID- 29485599 TI - The Efficacy of Perforator Flaps in the Treatment of Chronic Osteomyelitis. PMID- 29485600 TI - Reply: The Efficacy of Perforator Flaps in the Treatment of Chronic Osteomyelitis. PMID- 29485601 TI - Business Education for Plastic Surgeons: A Systematic Review, Development, and Implementation of a Business Principles Curriculum in a Residency Program. PMID- 29485602 TI - Reply: Business Education for Plastic Surgeons: A Systematic Review, Development, and Implementation of a Business Principles Curriculum in a Residency Program. PMID- 29485603 TI - Population Health Implications of Medical Tourism. PMID- 29485604 TI - Reply: Population Health Implications of Medical Tourism. PMID- 29485605 TI - The Safety of Early Adjuvant Internal Mammary Lymph Node Irradiation following Mastectomy and Immediate Autologous Reconstruction. PMID- 29485606 TI - Vascularized Jejunal Mesenteric Lymph Node Transfer for Lymphedema: A Novel Approach. PMID- 29485607 TI - Negative-Pressure Wound Therapy as a Skin Graft Bolster in Lesions of the Glans Penis: The Lotus Petal Technique. PMID- 29485608 TI - Change of Title: Microarrays Becomes High-Throughput. AB - MDPI's journal Microarrays released its first volume in 2012. Since then, the journal has published 129 articles on the topic of microarrays, including their applications, analysis and new developments. [...]. PMID- 29485609 TI - Oral Health: The Need for Both Conventional Microbial and Molecular Characterization. AB - This study aims to consider the microbial distribution in oral disease, as well as gene analysis and expression, in elucidating: 1, the fundamental underpinnings of oral disease, and 2, the potential relationship between oral diseases and systemic health. A key focus is identifying the microbiota associated with oral disease manifestations characterized by both conventional microbiological and molecular methods. Variations in the observed microbial populations characterized by conventional and molecular approaches have been identified for caries, periodontitis, peri-implantitis, and stomatitis. The discovery of therapeutic approaches for oral disease will require comprehensive microbial and genomic analysis. This study evaluated the current state of the relevant microbial and genomic information for several prevalent oral diseases. PMID- 29485610 TI - High-Throughput Methods to Detect Long Non-Coding RNAs. AB - Increasing evidence suggests that the numbers of long non-coding RNAs (lncRNAs) are more than those of protein-coding genes in various organisms. Although the detection methods for lncRNAs are being increasingly established, there are advantages and disadvantages that exist for each method. In this opinion article, I highlight the differences between microarrays and RNA sequencing (RNA-seq) for the detection of lncRNAs. Compared to RNA-seq, microarrays are limited to the known sequences. However, the detection method as well as data analysis workflow is more established, which makes it easier to analyze the data for bench scientists without extensive knowledge about computer programming. In order to highlight the usage of microarrays over RNA-seq for the detection of lncRNAs, we are organizing a special issue for High-Throughput called "Microarrays in Non Coding RNAs Profiling", which will include the specific usages of microarrays for lncRNAs. PMID- 29485611 TI - Small RNAs in Circulating Exosomes of Cancer Patients: A Minireview. AB - Extracellular vesicles (EVs) secreted from many cell types play important roles in intercellular communication, both as paracrine and endocrine factors, as they can circulate in biological fluids, including plasma. Amid EVs, exosomes are actively secreted vesicles that contain proteins, lipids, soluble factors, and nucleic acids, including microRNAs (miRNAs) and other classes of small RNAs (sRNA). miRNAs are prominent post-transcriptional regulators of gene expression and epigenetic silencers of transcription. We concisely review the roles of miRNAs in cell-fate determination and development and their regulatory activity on almost all the processes and pathways controlling tumor formation and progression. Next, we consider the evidence linking exosomes to tumor progression, particularly to the setting-up of permissive pre-metastatic niches. The study of exosomes in patients with different survival and therapy response can inform on the possible correlations between exosomal cargo and disease features. Moreover, the exploration of circulating exosomes as possible sources of non-invasive biomarkers could give new implements for anti-cancer therapy and metastasis prevention. Since the characterization of sRNAs in exosomes of cancer patients sparks opportunities to better understand their roles in cancer, we briefly present current experimental and computational protocols for sRNAs analysis in circulating exosomes by RNA-seq. PMID- 29485612 TI - Gradient Material Strategies for Hydrogel Optimization in Tissue Engineering Applications. AB - Although a number of combinatorial/high-throughput approaches have been developed for biomaterial hydrogel optimization, a gradient sample approach is particularly well suited to identify hydrogel property thresholds that alter cellular behavior in response to interacting with the hydrogel due to reduced variation in material preparation and the ability to screen biological response over a range instead of discrete samples each containing only one condition. This review highlights recent work on cell-hydrogel interactions using a gradient material sample approach. Fabrication strategies for composition, material and mechanical property, and bioactive signaling gradient hydrogels that can be used to examine cell-hydrogel interactions will be discussed. The effects of gradients in hydrogel samples on cellular adhesion, migration, proliferation, and differentiation will then be examined, providing an assessment of the current state of the field and the potential of wider use of the gradient sample approach to accelerate our understanding of matrices on cellular behavior. PMID- 29485613 TI - Could Proteomics Become a Future Useful Tool to Shed Light on the Mechanisms of Rare Neurodegenerative Disorders? AB - Very often the clinical features of rare neurodegenerative disorders overlap with those of other, more common clinical disturbances. As a consequence, not only the true incidence of these disorders is underestimated, but many patients also experience a significant delay before a definitive diagnosis. Under this scenario, it appears clear that any accurate tool producing information about the pathological mechanisms of these disorders would offer a novel context for their precise identification by strongly enhancing the interpretation of symptoms. With the advent of proteomics, detection and identification of proteins in different organs/tissues, aimed at understanding whether they represent an attractive tool for monitoring alterations in these districts, has become an area of increasing interest. The aim of this report is to provide an overview of the most recent applications of proteomics as a new strategy for identifying biomarkers with a clinical utility for the investigation of rare neurodegenerative disorders. PMID- 29485615 TI - Early Probe and Drug Discovery in Academia: A Minireview. AB - Drug discovery encompasses processes ranging from target selection and validation to the selection of a development candidate. While comprehensive drug discovery work flows are implemented predominantly in the big pharma domain, early discovery focus in academia serves to identify probe molecules that can serve as tools to study targets or pathways. Despite differences in the ultimate goals of the private and academic sectors, the same basic principles define the best practices in early discovery research. A successful early discovery program is built on strong target definition and validation using a diverse set of biochemical and cell-based assays with functional relevance to the biological system being studied. The chemicals identified as hits undergo extensive scaffold optimization and are characterized for their target specificity and off-target effects in in vitro and in animal models. While the active compounds from screening campaigns pass through highly stringent chemical and Absorption, Distribution, Metabolism, and Excretion (ADME) filters for lead identification, the probe discovery involves limited medicinal chemistry optimization. The goal of probe discovery is identification of a compound with sub-uM activity and reasonable selectivity in the context of the target being studied. The compounds identified from probe discovery can also serve as starting scaffolds for lead optimization studies. PMID- 29485617 TI - Applying Expression Profile Similarity for Discovery of Patient-Specific Functional Mutations. AB - The progress of cancer genome sequencing projects yields unprecedented information of mutations for numerous patients. However, the complexity of mutation profiles of cancer patients hinders the further understanding to mechanisms of oncogenesis. One basic question is how to find mutations with functional impacts. In this work, we introduce a computational method to predict functional somatic mutations of each patient by integrating mutation recurrence with expression profile similarity. With this method, the functional mutations are determined by checking the mutation enrichment among a group of patients with similar expression profiles. We applied this method to three cancer types and identified the functional mutations. Comparison of the predictions for three cancer types suggested that most of the functional mutations were cancer-type specific with one exception to p53. By checking predicted results, we found that our method effectively filtered non-functional mutations resulting from large protein sizes. In addition, this method can also perform functional annotation to each patient to describe their association with signalling pathways or biological processes. In breast cancer, we predicted "cell adhesion" and other terms to be significantly associated with oncogenesis. PMID- 29485616 TI - Whole-Transcriptome Sequencing: a Powerful Tool for Vascular Tissue Engineering and Endothelial Mechanobiology. AB - Among applicable high-throughput techniques in cardiovascular biology, whole transcriptome sequencing is of particular use. By utilizing RNA that is isolated from virtually all cells and tissues, the entire transcriptome can be evaluated. In comparison with other high-throughput approaches, RNA sequencing is characterized by a relatively low-cost and large data output, which permits a comprehensive analysis of spatiotemporal variation in the gene expression profile. Both shear stress and cyclic strain exert hemodynamic force upon the arterial endothelium and are considered to be crucial determinants of endothelial physiology. Laminar blood flow results in a high shear stress that promotes atheroresistant endothelial phenotype, while a turbulent, oscillatory flow yields a pathologically low shear stress that disturbs endothelial homeostasis, making respective arterial segments prone to atherosclerosis. Severe atherosclerosis significantly impairs blood supply to the organs and frequently requires bypass surgery or an arterial replacement surgery that requires tissue-engineered vascular grafts. To provide insight into patterns of gene expression in endothelial cells in native or bioartificial arteries under different biomechanical conditions, this article discusses applications of whole transcriptome sequencing in endothelial mechanobiology and vascular tissue engineering. PMID- 29485618 TI - Parallels between Postpartum Disorders in Humans and Preweaning Piglet Mortality in Sows. AB - Pregnancy and parturition in all mammals is accompanied with physical, psychological, social, and hormonal shifts that impact the mother physically and psychologically. Pre-weaning piglet mortality continues to be a major welfare and economic issue in U.S. swine production, running at 12-15% with crushing by the sow the major cause. Much research has focused on farrowing environment design, yet the fact that little progress has been made emphasizes that psychosocial factors may impact rates of postpartum disorders (PPD). There is a mismatch between evolved adaptations and contemporary psychosocial and management practices. Many factors associated with the development of PPD in humans are mirrored in sows that perform piglet crushing. These factors include poor mental welfare (anxiety, difficulty coping with stress), a lack of experience, a lack of social support, and individual differences in their sensitivity to hormone concentrations. Understanding what strategies are effective in preventing PPD in humans may have welfare and production benefits for sows-and sows may be a possible model for better understanding PPD in humans. PMID- 29485619 TI - Resveratrol and Pterostilbene Exhibit Anticancer Properties Involving the Downregulation of HPV Oncoprotein E6 in Cervical Cancer Cells. AB - Cervical cancer is one of the most common cancers in women living in developing countries. Due to a lack of affordable effective therapy, research into alternative anticancer compounds with low toxicity such as dietary polyphenols has continued. Our aim is to determine whether two structurally similar plant polyphenols, resveratrol and pterostilbene, exhibit anticancer and anti-HPV (Human papillomavirus) activity against cervical cancer cells. To determine anticancer activity, extensive in vitro analyses were performed. Anti-HPV activity, through measuring E6 protein levels, subsequent downstream p53 effects, and caspase-3 activation, were studied to understand a possible mechanism of action. Both polyphenols are effective agents in targeting cervical cancer cells, having low IC50 values in the uM range. They decrease clonogenic survival, reduce cell migration, arrest cells at the S-phase, and reduce the number of mitotic cells. These findings were significant, with pterostilbene often being more effective than resveratrol. Resveratrol and to a greater extent pterostilbene downregulates the HPV oncoprotein E6, induces caspase-3 activation, and upregulates p53 protein levels. Results point to a mechanism that may involve the downregulation of the HPV E6 oncoprotein, activation of apoptotic pathways, and re-establishment of functional p53 protein, with pterostilbene showing greater efficacy than resveratrol. PMID- 29485620 TI - The Effect of Annealing Treatment and Atom Layer Deposition to Au/Pt Nanoparticles-Decorated TiO2 Nanorods as Photocatalysts. AB - The wide band gap of TiO2 hinders the utilization of visible light in high performance photocatalysis. Herein, vertically aligned Ti nanopillar arrays (NPAs) were grown by the glancing angle deposition method (GLAD) and then thermally oxidized into TiO2 NPAs. The metallic nanoparticles (NPs) were fabricated by successive ion layer adsorption and reaction (SILAR) method. And we covered ultrathin TiO2 layer on Au/Pt NPs decorated NPA using atomic layer deposition (ALD) method and did annealing process in the end. The photoelectrochemical (PEC) performance and dye degradation have been studied. We find the dye degradation efficiency of best combination reaches up to 1.5 times higher than that of original Au/Pt-TiO2 sample under visible light irradiation. The TiO2 ALD layer effectively protects the nanostructure from corrosion and helps the transmission of electrons to the electrolyte. By controlling the annealing temperature we could achieve a matched band gap due to change in noble metal particle size. Our work demonstrates that rational design of composite nanostructures enhances the usage of broader wavelength range light and optimizes photocatalytic degradation of organic pollutants in practical applications. PMID- 29485621 TI - Interoperable and accessible census and survey data from IPUMS. AB - The first version of the Integrated Public Use Microdata Series (IPUMS) was released to users in 1993, and since that time IPUMS has come to stand for interoperable and accessible census and survey data. Initially created to harmonize U.S. census microdata over time, IPUMS now includes microdata from the U.S. and international censuses and from surveys on health, employment, and other topics. IPUMS also provides geo-spatial data, aggregate population data, and environmental data. IPUMS supports ten data products, each disseminating an integrated data collection with a set of tools that make complex data easy to find, access, and use. Key features are record-level integration to create interoperable datasets, user-friendly interfaces, and comprehensive metadata and documentation. The IPUMS philosophy aligns closely with the FAIR principles of findability, accessibility, interoperability, and re-usability. IPUMS data have catalyzed knowledge generation across a wide range of social science and other disciplines, as evidenced by the large volume of publications and other products created by the vast IPUMS user community. PMID- 29485622 TI - ImmPort, toward repurposing of open access immunological assay data for translational and clinical research. AB - Immunology researchers are beginning to explore the possibilities of reproducibility, reuse and secondary analyses of immunology data. Open-access datasets are being applied in the validation of the methods used in the original studies, leveraging studies for meta-analysis, or generating new hypotheses. To promote these goals, the ImmPort data repository was created for the broader research community to explore the wide spectrum of clinical and basic research data and associated findings. The ImmPort ecosystem consists of four components Private Data, Shared Data, Data Analysis, and Resources-for data archiving, dissemination, analyses, and reuse. To date, more than 300 studies have been made freely available through the Shared Data portal (www.immport.org/immport-open), which allows research data to be repurposed to accelerate the translation of new insights into discoveries. PMID- 29485623 TI - High-quality science requires high-quality open data infrastructure. AB - Resources for data management, discovery and (re)use are numerous and diverse, and more specifically we need data resources that enable the FAIR principles1 of Findability, Accessibility, Interoperability and Reusability of data. PMID- 29485624 TI - A new, short-recorded photoplethysmogram dataset for blood pressure monitoring in China. AB - Open clinical trial data provide a valuable opportunity for researchers worldwide to assess new hypotheses, validate published results, and collaborate for scientific advances in medical research. Here, we present a health dataset for the non-invasive detection of cardiovascular disease (CVD), containing 657 data segments from 219 subjects. The dataset covers an age range of 20-89 years and records of diseases including hypertension and diabetes. Data acquisition was carried out under the control of standard experimental conditions and specifications. This dataset can be used to carry out the study of photoplethysmograph (PPG) signal quality evaluation and to explore the intrinsic relationship between the PPG waveform and cardiovascular disease to discover and evaluate latent characteristic information contained in PPG signals. These data can also be used to study early and noninvasive screening of common CVD such as hypertension and other related CVD diseases such as diabetes. PMID- 29485625 TI - Datasets2Tools, repository and search engine for bioinformatics datasets, tools and canned analyses. AB - Biomedical data repositories such as the Gene Expression Omnibus (GEO) enable the search and discovery of relevant biomedical digital data objects. Similarly, resources such as OMICtools, index bioinformatics tools that can extract knowledge from these digital data objects. However, systematic access to pre generated 'canned' analyses applied by bioinformatics tools to biomedical digital data objects is currently not available. Datasets2Tools is a repository indexing 31,473 canned bioinformatics analyses applied to 6,431 datasets. The Datasets2Tools repository also contains the indexing of 4,901 published bioinformatics software tools, and all the analyzed datasets. Datasets2Tools enables users to rapidly find datasets, tools, and canned analyses through an intuitive web interface, a Google Chrome extension, and an API. Furthermore, Datasets2Tools provides a platform for contributing canned analyses, datasets, and tools, as well as evaluating these digital objects according to their compliance with the findable, accessible, interoperable, and reusable (FAIR) principles. By incorporating community engagement, Datasets2Tools promotes sharing of digital resources to stimulate the extraction of knowledge from biomedical research data. Datasets2Tools is freely available from: http://amp.pharm.mssm.edu/datasets2tools. PMID- 29485626 TI - An open repository for single-cell reconstructions of the brain forest. AB - NeuroMorpho.Org was launched in 2006 to provide unhindered access to any and all digital tracings of neuronal morphology that researchers were willing to share freely upon request. Today this database is the largest public inventory of cellular reconstructions in neuroscience with a content of over 80,000 neurons and glia from a representative diversity of animal species, anatomical regions, and experimental methods. Datasets continuously contributed by hundreds of laboratories worldwide are centrally curated, converted into a common non proprietary format, morphometrically quantified, and annotated with comprehensive metadata. Users download digital reconstructions for a variety of scientific applications including visualization, classification, analysis, and simulations. With more than 1,000 peer-reviewed publications describing data stored in or utilizing data retrieved from NeuroMorpho.Org, this ever-growing repository can already be considered a mature resource for neuroscience. PMID- 29485627 TI - A multi-year data set on aerosol-cloud-precipitation-meteorology interactions for marine stratocumulus clouds. AB - Airborne measurements of meteorological, aerosol, and stratocumulus cloud properties have been harmonized from six field campaigns during July-August months between 2005 and 2016 off the California coast. A consistent set of core instruments was deployed on the Center for Interdisciplinary Remotely-Piloted Aircraft Studies Twin Otter for 113 flight days, amounting to 514 flight hours. A unique aspect of the compiled data set is detailed measurements of aerosol microphysical properties (size distribution, composition, bioaerosol detection, hygroscopicity, optical), cloud water composition, and different sampling inlets to distinguish between clear air aerosol, interstitial in-cloud aerosol, and droplet residual particles in cloud. Measurements and data analysis follow documented methods for quality assurance. The data set is suitable for studies associated with aerosol-cloud-precipitation-meteorology-radiation interactions, especially owing to sharp aerosol perturbations from ship traffic and biomass burning. The data set can be used for model initialization and synergistic application with meteorological models and remote sensing data to improve understanding of the very interactions that comprise the largest uncertainty in the effect of anthropogenic emissions on radiative forcing. PMID- 29485628 TI - Holocene geochemical footprint from Semi-arid alpine wetlands in southern Spain. AB - Here we provide the geochemical dataset that our research group has collected after 10 years of investigation in the Sierra Nevada National Park in southern Spain. These data come from Holocene sedimentary records from four alpine sites (ranging from ~2500 to ~3000 masl): two peatlands and two shallow lakes. Different kinds of organic and inorganic analyses have been conducted. The organic matter in the bulk sediment was characterised using elemental measurements and isotope-ratio mass spectrometry (EA-IRMS). Leaf waxes in the sediment were investigated by means of chromatography with flame-ionization detection and mass spectrometry (GC-FID, GC-MS). Major, minor and trace elements of the sediments were analysed with atomic absorption (AAS), inductively coupled plasma mass spectrometry (ICP-MS), as well as X-ray scanning fluorescence. These data can be reused by environmental researchers and soil and land managers of the Sierra Nevada National Park and similar regions to identify the effect of natural climate change, overprinted by human impact, as well as to project new management policies in similar protected areas. PMID- 29485629 TI - Osmoregulatory adaptations during lactation: Thirst, arginine vasopressin and plasma osmolality responses. AB - Pregnancy and lactation are accompanied by an increase in circulating blood volume secondary to a 10 mOsmol/kgH20 decrease in plasma osmolality, decrease in the osmotic threshold for thirst and arginine vasopressin (AVP) release, prolactin-induced AVP, oxytocin and aldosterone release, as well as increased water intake and retention. The increased blood volume as a result of increased thirst; drinking and fluid retention could be beneficial for milk production and secretion during lactation. Furthermore, AVP can directly initiate milk ejection similar to oxytocin by interacting with both vasopressin and oxytocin receptors located in myoepithelial cells of the mammary gland. This review explores how osmotic equilibrium is maintained during lactation through changes in thirst, AVP release and plasma osmolality; and highlights the potential role of AVP in milk secretion. PMID- 29485630 TI - Differential Kolaviron Attenuated Contractile Responses to Agonists on Isolated Rabbit Aorta in Na+-K+ Pump Blockade. AB - The mechanism of kolaviron-induced vascular smooth muscles (VSMs) responses has not been fullycharacterised. The present study investigated the effect and mode of action of kolaviron a biflavanoid-complex and majorcomponent of Garcinia Kola fraction on differential contractile responses to agonists-[phenylephrine (PHE) and histamine(HIST)] on VSMs of rabbit isolated aortic rings in K+-free physiological salt solution (KFPSS). Cumulative concentrationresponses to PHE and HIST were examined on 2 mm ring segments of the thoracic aortae which were suspended in 20 mlorgan baths containing physiological salt solution (PSS) for measurement of isometric contractions, at 370C and pH 7.4. Themedium was bubbled with 95% O2, 5% CO2, and rings were given an initial load of 1g. Cumulative contractile responses tothe agonists were studied in normal PSS (control) and following 30 minutes exposure to K+-free PSS and/or 800ug/mLkolaviron. Contractile responses were expressed as percentage of 80 mM K+ contractions in normal PSS. Maximalcontractions (Emax) induced by PHE and HIST compared with high K+ contraction in the various preparations weredifferentially altered following exposure to K+-free or 800ug/mL kolaviron in both intact (+E) and endotheliumdenuded (-E) rings. Based on the efficacy (Emax) and potency (EC50) values for the dose-response curves of the agonists, it isconcluded that enhanced differential contractile responses elicited by agonists in K+-free PSS were significantly attenuatedby kolaviron concentration-dependently. This observation probably suggests the existence of another pathway of kolavironmode of action in vascular smooth muscle reactivity. PMID- 29485631 TI - A Comparison of Surface Infrared with Rectal Thermometry in Dogs. AB - Accurate determination of temperature is crucial in the diagnosis of febrile conditions. Although fewer techniques have proven as useful and reliable a predictor of core body temperature as the rectal thermometry, the process of obtaining the rectal temperature could be stressful in dogs. The infrared thermometry is a noncontact device used for measuring body temperature, with advantages which include speed, convenience, and reduced stress to the animals and reduced occupational risks to the animal handler. Therefore, there is the need to assess the consistency and agreement between non-contact infrared thermometry and traditional rectal thermometry in body temperature estimation. This study compared and assessed the sensitivity of non-contact infrared thermometer used on the forehead and nasal regions respectively with that of a rectal thermometer in dogs for body temperature estimation. One hundred and thirty (130) dogs presented for veterinary attention at the Veterinary Teaching Hospital (VTH), University of Ibadan, Nigeria were enrolled in this study during August to September 2014, irrespective of sex, age, breed or health status. Temperatures of dogs presented at the clinic were obtained using both multiple non-contact infrared thermometric measures obtained in the nasal and frontal head regions; and by rectal temperature. A multivariate cross-matrix analysis was used to assess the difference in measurements between the rectal thermometry and non contact infrared thermometry. Descriptive statistics was used to compare variation and trend regularity of the nasal and fore-head infrared thermometry. A logistic regression of the difference in measurements was computed at 95% confidence interval and P<0.05. The mean difference revealed that the rectal temperature was 5.330C higher than the non-contact infrared forehead-based temperature and 7.570C higher than nasal-based temperature measurements respectively. The Bland-Altman (B-A) plot showed that the 95% limits of agreement between the frontal and nasal obtained infrared laser thermometry methods. Temperature measure obtained using non-contact infrared thermometry (forehead and nasal region of the head) was poor in consistency and agreement compared to rectal thermometry. Usefulness of non-contact forehead infrared thermometry in routine clinical practice as a close estimate of core body temperature depends on accurate calibration and therefore not recommended. PMID- 29485632 TI - Effects of Lipopolysaccharide and High Saline Intake on Blood Pressure, Angiogenic Factors and Liver Enzymes of Pregnant Rats. AB - This study investigated the effect of high salt water intake and lipopolysaccharide injection as probable rat models of preeclampsia during pregnancy. Thirty-three female Sprague-Dawley rats weighing between 150-170g were divided into 4 groups of the control (normal saline), high salt water intake (1.8% NaCl from days 13-18 of pregnancy), lipopolysaccharide group (40 ug/kg b.w. ip injection from day 16-18 of pregnancy) and high salt water (1.8% NaCl) and lipopolysaccharide injection (40 ug/kg b.w i.p. from days 16-18 of pregnancy). Urine samples were collected on day 18 of pregnancy and the animals were sacrificed on day 19 of pregnancy for blood pressure parameters, angiogenic and liver enzyme assays. The systolic, diastolic and mean arterial blood pressure of pregnant rats on high saline intake increased significantly when compared with control. Fetal weight was decreased while VEGF levels were increased in this group and no difference was found in the protein and liver enzyme levels. Decreased fetal weight was also observed in HS + lip group accompanied with an increase in PIGF, and VEGF levels with no change in blood pressure, protein and liver enzymes. Similar result was found in the Lipopolysaccharide alone group but with additional changes such as increase in VEGFR-1 levels and protein levels. Both high salt and lipopolysaccharide presents preeclampsia symptoms but the absence of protein in the urine in high salt water intake group as well as the inability of lipopolysaccharide to increase blood pressure suggest that both substances might not be ideal for preeclampsia research in rats. PMID- 29485633 TI - Effects of Fermented Ginger Rhizome (Zingiber officinale) and Fenu Greek (Trigonella foenum-graceum) Supplements on Oxidative stress and Lipid Peroxidation Biomarkers in Poloxamer-407 Induced -Hyperlipidemic Wistar Rats. AB - This research was aimed at investigating the Effects of Fermented Ginger Rhizome (Zingiber officinale) and Fenu Greek (Trigonella foenum-graceum) on Oxidative stress and Lipid Peroxidation Biomarkers in Poloxamer 407Induced-Hyperlipidemic Wistar Rats. Hyperlipidaemia was induced with poloxamer P407 (1.5 g/kg b.w. i.p.) The Animals were grouped into six of five animals each group. Group 1 normal control, Group 2 served as the hyperlipidemic control, Group 3 administered 0.26 g/kg cholestyramine, Group 4 fed on Fenugreek 25% supplement. Group 5 fed on 25% fermented ginger supplement, while group 6 were fed on 25% ginger and fenu greek combined respectively. All treatments were given for a period of four week. Serum antioxidant activities such as catalase (CAT), glutathione peroxidase (GPx), Superoxide dismutase (SOD) and Malondialdehyde were evaluated. As regards to the catalase activity there was a significant decrease in the groups' fed on 25% fenugreek and 25% fermented ginger supplements respectively. However, co-fed with both supplements significantly increase the catalase activity as compared with the hyperlipidaemic control untreated. Comparism with the positive control cholestyramine, there was also a significant increase. Also in relation to the SOD activity there was a significant increase in the activity as compared with the hyperlipidemic control. Furthermore, the Gpx activity there was a significant increase in the as compared with the hyperlipidemic control. oxidative stress biomarker activities SOD) there was significant increase (p<0.05) when compared with hyperlipidemic control. There was a significant (p<0.05) decrease in the Malondialdehyde levels in the groups fed with the supplement when compared with hyperlipidemic control. In conclusion supplements of Fenugreek and Ginger improved antioxidant status and reduced Malondialdehyde in Poloxamer-407 Induced-Hyperlipidemic Wistar Rats. PMID- 29485634 TI - Melatonin modulates neuronal mitochondria function during normal ageing in mice. AB - Mitochondrial dysfunction has been shown to be associated with normal ageing and may account for age-related vulnerability to disease. The increasing number of old people worldwide has created the need to find effective therapeutic agents to reduce the incidence of age-related disease. In the current report, we carried out an assessment of mitochondrial function in established young, middle-aged and old synaptosomal mitochondria bearing cybrids without or with melatonin treatment. The cybrids were generated by transferring isolated mitochondria from synaptosomes of brain cortical cells in mice to rho-zero mtDNA-less cells. In galactose media, a selective media that tests a cells ability to produce ATP through the electron transport chain and oxidative phosphorylation, 500uM melatonin (N-acetyl-5-methoxytryptamine) raised cell viability in young and middle-aged cybrids (P<0.05) and a concentration of 1mM raised cell viability in the old cybrids (P<0.05). The mitochondrial membrane potential (MMP) was lowered in the young cybrids (P<0.05) treated with melatonin, but it was raised in the middle-aged and old cybrids (P<0.05) with melatonin treatment. The levels of reactive oxygen species were significantly lower in the melatonin treated middle aged and old cybrids compared with controls (P<0.05). Furthermore, ATP measurements showed no significant increase in the young cybrids (P>0.05), but increased significantly in the middle-aged and old cybrids (P<0.05) with melatonin treatment. Light and fluorescence microscopy showed observable structural damage and cell death in the middle-aged and old cybrids without melatonin treatment. The results suggest that melatonin may be a potent therapeutic intervention during age-related neuronal mitochondrial dysfunction. PMID- 29485635 TI - Skull Typology and Morphometrics of the Nigerian Local Dog (Canis lupus familiaris). AB - Understanding skull anatomy and morphometry is crucial to the diagnosis and treatment of some osteology disorders. This study investigated the morphometry and skull typology of the skull of the Nigerian local dog as a skull prototype for the dolichocephalic breed of dogs. A total of sixteen adult dogs (7 males, 9 females), of about 2 years were used. A total of 20 parameters were measured on each skull, and two indices (cephalic and orbital) calculated. The males had higher values for nine parameters (two of which were calculated indices), including the maximum width of the skull, length of the mandibular symphysis, height of the tympanic bulla and height of the external auditory opening, although no statistically significant difference was observed (p > 0.05). Statistically significant difference was observed in only one parameter, the length of the parietal bone (p = 0.0505), with the female value (3.775 +/- 0.388 cm) being higher than the male (3.4 +/- 0.179 cm). Cephalic and orbital indices (52.69 +/- 4.677 % and 80.87 +/- 7.218 % respectively) were higher in males (54.13 +/- 1.616 % and 81.57 +/- 4.295 % respectively) than in females (51.24 +/- 6.434 % and 80.35 +/- 9.102 % respectively), although no statistically significant difference was observed (p = 0.6905 and 0.9483 respectively). Results obtained from this study will provide baseline data on dolichocephalic skull measurements and also find application in archaeology, veterinary forensic medicine and applied anatomy. PMID- 29485636 TI - Glucose Tolerance in Non-Diabetic Adult Subjects of an Urban West-African Population. AB - The present study was carried out to determine glucose tolerance and insulin sensitivity in adult subjects of a west African population. 103 subjects recruited in the town of Cotonou were included in the study. After anthropometric measurement, they were subjected to an oral glucose tolerance test (OGTT). Serum glucose and insulin levels were determined throughout the OGTT. Homeostatic model of assessment of insulin resistance (HOMA-IR), MATSUDA insulin sensitivity index (MATSUDA-ISI) and insulinogenic index (IGI) have been determined to evaluate insulin sensitivity and beta cells function. Normal glucose tolerance (NGT), isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT) and combined glucose intolerance (CGI) were observed in respectively 53.40%, 1.94%, 35.92% and 8.74% of subjects. The prevalence of IFG and or IGT (IFG/IGT) was higher in obese subjects (66.67%) than in subjects with normal BMI (41.17%). Fasting hyperinsulinemia was observed in 82% of subjects. Mean values of HOMA-IR were not significantly different in NGT (6.86 +/- 0.7) and in IFG/IGT subjects (7.47 +/- 0.57). In contrast to HOMA-IR, mean value of Matsuda-ISI was significantly lower in IFG/IGT than in NGT subjects (1.47 +/- 0.1 versus 1.96 +/- 0.13, p<0.01). Matsuda-ISI values were also significantly lower in obese subjects (1.33 +/- 0.12) than in subjects with normal BMI (1.93 +/- 0.13). The mean insulinogenic index value in IFG/IGT subjects (42.5 +/- 4.36) was not significantly different of that in NGT subjects (50.3 +/- 5.21). These data show that the glucose tolerance disorders observed in subjects of the present study are more related to a decrease in insulin sensitivity than to an alteration of the beta cells function. PMID- 29485637 TI - Influence of Tramadol on Anaesthetic Indices and Physiological Parameters of Epidural Lignocaine in West African Dwarf Sheep Undergoing Laparo-Ovariectomy. AB - The influence of tramadol on the anaesthetic indices and physiological parameters of epidural injection of lignocaine was evaluated in West African Dwarf (WAD) sheep undergoing laparo-ovariectomy. Ten female sheep weighing (16.2 +/- 1.3 kg) were randomly allocated into anaesthesia with epidural injection of lignocaine (4mg/kg) (LIG), or lignocaine (2mg/kg) and tramadol (2mg/kg) (LIG-TRA). Following anaesthesia, they were aseptically prepared and subjected to laparo-ovariectomy. Behavioural changes were noted as they occur, and onset of drug action (OAN) (time between epidural injection and loss of pedal reflex), duration of analgesia (DAN) (time between disappearance and reappearance of pedal reflex) were determined. Also, duration of recumbency (DRC) (time between loss of righting reflex and returns to sternal recumbency) and recovery time (RCT) (time between re-appearance of pedal reflex and when the animal was able to stand without ataxia) were determined. Rectal temperatures (RT), respiratory rates (RR) and heart rates (HR) were determined every ten minutes for two hours. Results were expressed as mean +/- standard error of mean. Anaesthetic indices were compared with Student's t-test, while physiological parameters were compared with analysis of variance (ANOVA) for repeated measures. In this study, one sheep anaesthetized with LIG-TRA had bloat while none in sheep anaesthetized with LIG had bloat. The OAN was significantly (p < 0.05) shorter in LIG-TRA (1.4 +/- 0.5 mins) than with LIG (4.4 +/- 2.8 mins). Although DAN and DRC were longer in LIG-TRA (133 +/- 19.5 mins, 192.6 +/- 43.6 mins) than LIG (119.4 +/- 52.5 mins; 166.2 +/- 30.6 mins) respectively, values were not statistically significant (p = 0.863). In addition, RCT was longer in LIG-TRA (56.0 +/- 48.6 mins) than LIG (34.0 +/- 20.6 mins). The RT, RR and HR did not differ significantly (p > 0.05) between LIG-TRA and LIG, and as well as throughout the duration of study. It was therefore concluded that tramadol did not appear to improve the anaesthetic indices of epidural lignocaine injection in sheep but increased the duration of recumbency with the tendency to cause bloat. PMID- 29485638 TI - Potential link between Complement 5a Receptor and mood disorders in mouse exposed to experimental malaria in utero. AB - In Africa, a large number of pregnancies are exposed to Plasmodium falciparum infection. The in-utero environment extremely influences childhood neurodevelopment and behaviour. The complement 5a receptor (C5aR) is linked to several disease conditions. However, the influence of Plasmodium berghei during pregnancy on maternal complement 5a receptor and subsequently on fetal behaviour is unknown. Pregnant mice were intra-peritoneally inoculated on gestational day 13 with 1.02x105 infected red blood cells (iRBCs). iRBCs used in this experiment were gotten by in vivo passage of P. berghei in mice when the level of iRBCs have gotten to about 10-20%. A section of pregnant mice (both test and control groups) were earmarked to give birth and their offspring monitored up to postnatal day 42 when depression-like behaviour was evaluated using tail suspension test model. The other pregnant mice were subjected to cardiac puncture on gestational day 19 for C5a receptor estimation using Elisa assay. Results showed that pregnant mice infected with P. berghei had elevated C5a receptor compared with uninfected pregnant females. It was also shown that P. berghei-exposed offspring presented a depressive-like behaviour compared to unexposed controls. It may be concluded from this study, that complement 5a receptor demonstrates a pathogenic role in signaling and its possible role in mediating depression linked to Plasmodium berghei exposure in utero. PMID- 29485639 TI - Effects of Salmon Calcitonin and Omega - 3 Fatty Acids on Glucoregulatory Indices, Lipid Profile and Antioxidant Markers in Experimental Knee Osteoarthritis in Wistar Rats. AB - It has been opined that a combined therapeutic approach should be considered in the optimal management ofosteoarthritis (OA). Therefore, the study investigated the effects of salmon calcitonin (Sct) and/or omega-3 fatty acids (N-3), relative to diclofenac sodium (DF) on selected biochemical parameters in induced osteoarthritic rats. Forty (40) adultmale Wistar rats were used for this study. The rats were divided into 8 groups (n=5), viz: Group 1-Normal control; Group 2 OA control; Group 3-OA+N-3 (200 mg/kg, p.o.); Group 4-OA + low dose of Sct (Sct.Lw-2.5 IU/kg, i.m.); Group 5-OA +high dose of SCT (Sct.Hi-5.0 IU/kg, i.m.); Group 6-OA+N-3+Sct.Lw; Group 7-OA+N-3+Sct.Hi; and, Group 8-OA+DF (1mg/kg, p.o.). Osteoarthritis was induced with 4 mg of sodium monoiodoacetate in 40 ul of saline. The solution was injectedintra-articularly into the left knee joint space of anaesthetised (sodium pentobarbital - 40 mg/kg, i.p.) rats. Nine (9) daysafterwards, treatments started, and they lasted for 28 days. The results showed that Sct has hypocalcaemic, hypocortisolism,and anti-dyslipidaemic effects. It significantly inhibited nitric oxide (NO) production and insulin release. Like Sct, N-3 havehypocortisolism and anti-dyslipidaemic actions. Nevertheless, they caused significant increases in hepatic glycogen contentand plasma levels of calcium ion, insulin and NO. Although DF was also observed to stimulate insulin release and NOsynthesis, it significantly increased plasma level of LDL-c, but significantly decreased HDL-C. In conclusion, N-3 annul theundesirable effect of Sct, presenting it as a better anti-arthritic drug. Moreover, the combined administration of bothpharmacological agents proffer preferable therapeutic benefits in OA condition relative the single or DF therapy. PMID- 29485640 TI - Immunolocalization And Distribution Pattern of Estrogen (ERalpha and ERbeta) and Progesterone (PR) Receptors along the Excurrent Duct of Male Greater Cane Rat (Thryonomys swinderianus). AB - The excurrent duct, which plays vital roles in the reproductive biology of all male mammals, shows some structural variations among different species. Some hormones such as testosterone, estrogen and progesterone, through their different receptors, have been known to be involved in the normal functioning of the excurrent duct. Here we evaluated the presence, localization and patterns of distribution of three hormone receptors, estrogen alpha (ERalpha), estrogen beta (ERbeta) receptors and progesterone receptors (PR) along the excurrent duct of sexually matured male greater cane rats. Immunohistochemistry revealed presence of ERalpha in epididymal stroma but not epithelium, selective ERbeta staining in narrow & apical cells as well as unique presence of PR in caudal epididymis, which to the best of our knowledge, is the first report on the cellular localization of progesterone receptor in the cauda epididymis. The result suggests the possible involvement of not only estrogen but also progesterone in the modulation of epididymal function in greater cane rat. PMID- 29485641 TI - Anthropometric Indices and Serum Micronutrient Status of Helminth - Infected School Children from Semi-Urban Communities in Southwestern Nigeria. AB - Adequate nutrition is essential for normal growth of children but helminth infection is proposed to cause nutritional deficiencies. This study was carried out to assess the nutritional status of helminth infected school aged children in semi-urban communities of South-West Nigeria. Two hundred children from primary schools in Akinyele Local Government of Oyo State, Nigeria participated in the study. Anthropometric measurements were analyzed using the WHO AnthroPlus software. Kato Katz method was used to detect ova of helminths in the stool while serum levels of iron, zinc, selenium, ferritin, transferrin, vitamin A, vitamin C and haptoglobin were measured using High Performance Liquid Chromatography and Atomic Absorption Spectophotometry as appropriate. 60 (30%) of the children had intestinal helminth infection with Ascaris lumbricoides (23.0%) as most prevalent, followed by hookworm (2.5%) and Trichuris trichuria (0.5%). Stunting was more prevalent than thinness or underweight among the study population especially the female children. There were significantly reduced serum levels of zinc and vitamin A and significantly increased serum levels of transferrin and selenium in helminth-infected children compared with helminth-uninfected children. This study established the need for regular deworming of school age children and supplementing diets of school children in rural communities with vitamin A and zinc. PMID- 29485642 TI - Modulatory Role of Rutin Supplement on Open Space Forced Swim Test Murine Model of Depression. AB - Flavonoids have been demonstrated to possess an anti-depressant effect and less adverse effects than tricyclic anti-depressants. For this reason, flavonoids in natural products have attracted growing attention. Rutin is a glycoside flavonoid which belongs to an important class of flavonoids, abundantly found in plants, such as buckwheat seeds, asparagus, red pepper, apples, citrus fruits and leaves of many herbs such as rosemary, dandelion or sage, and black and green tea. It is a vital nutritional component of food stuff. This study aimed at investigating the antidepressant potential of the rutin supplement on Swiss albino mice. For assessment of antidepressant activity, Open Space Forced Swim Test (OSFST), Tail Suspension Test (TST), Open-Field Test (OFT) and Novel Object Recognition Test (NORT) were used. Twenty-five Swiss albino mice were used for the study and divided into five groups. Group I received 10 mg/kg distilled water, group II received fluoxetine 20 mg/kg while group III, IV and V received rutin (30 mg/kg, 60 mg/kg and 120 mg/kg respectively) for sixteen days. The administration of the rutin supplement for sixteen days produced a reduction of immobility time in the TST (at 30 mg/kg, 60 mg/kg and 120 mg/kg), p<0.05. Likewise, a statistically significant difference was observed in line crossing in OFT, p<0.05. However, no significant effect was observed in percentage novel object preference in NORT. This study revealed that oral administration of rutin has an antidepressant potential in a dose dependent manner in OSFST mouse model of depression. PMID- 29485643 TI - Ionoregulatory Disruption and Acetylcholinesterase Activity in Aluminium Toxicity: Effects of Vitamins C and E. AB - To investigate the effects of vitamin C and E on electrolyte profile and the activity of acetylcholinesterase (AChE) in Aluminium (Al) chloride exposed rats, thirty-six male rats were used for this study. The animals were randomly grouped into six (n=6); group I (Control) was given normal saline. Group II (Al only) was exposed to 20mg/kg body weight (BW) of Al. Groups III (Vitamin C only) and IV (Vitamin E only) were administered 200mg/kg BW of vitamin C and vitamin E respectively. Groups V (Al + Vit C) and VI (Al + Vit E) were exposed to 20mg/kg Al and were treated with 200mg/kg vitamin C and vitamin E respectively. Al exposure resulted in a significant (P<0.05) increase in plasma calcium and erythrocyte magnesium concentrations compared with control. The erythrocyte sodium concentration of group treated with Al alone was significantly (P<0.05) higher by 2.01folds than the control group. While the two vitamins were unable to correct the disruption in calcium homeostasis, they ameliorated the intracellular levels of sodium and magnesium ions. A reduction in the activity of AChE (1378.90+/-130.02U/L)was observed in erythrocyte of the group exposed to Al when compared to the control (1968.80+/-283.72U/L). Treatment with vitamins C and E further inhibited erythrocyte AChE activity by 34% and 39% respectively compared to a 30% inhibition by Al only. Positive associations were observed between erythrocyte magnesium and blood sodium, and plasma calcium and erythrocyte sodium levels. Negative associations were however observed between plasma AChE activity and erythrocyte sodium and magnesium levels. In conclusion, vitamins C and E ameliorated ionoregulatory disruptions caused by sub-acute aluminium on only erythrocyte sodium and magnesium levels but not on plasma calcium level and erythrocyte acetylcholinesterase activity. PMID- 29485644 TI - Serum Troponin I levels among hypertensive Military Service Personnel at a Military Health Facility in Abuja, Nigeria. AB - Hypertension constitutes one of the major metabolic disease in Nigeria especially among military personnel and their families. Myocardial infarction and other cardiovascular diseases may occur in this group of patient due to uncontrolled or poorly controlled hypertension. The objective of this study was to determine serum cardiac Troponin I (cTnI), levels in hypertensive Nigerian Military service personnel attending clinic in a military Health facility. We measured the serum levels of cTnI in 126 hypertensive subjects [76 males (19-73 years) and 50 females (26-77years)] and 82 normotensive controls [41 males (19-60years) and 41 females (18-53years)] using Latex Enhanced Immunoturbidimetry technique. The data were compared between test and control group using Students't-test. Serum cTnI was detected in the sample of 95(75.4%) subjects and was not detected in 31 (24.6%) subjects. Nine subjects (2.38%) had cTnI levels within the normal range(0.00-0.01ng/mL), 85 (67.5%) subjects had significantly higher (p<0.001) cTnI levels (0.100 +/- 0.091 ng/ml; CL: 0.02 - 0.47ng/mL), while one (0.8%) subject had a cTnI value of 1.09 ng/mL. Nine (10.98%) control subjects had detectable cTnI levels (0.01ng/mL) while 73(89.02%) controls had a 0.00 ng/mL cTnI level. There was no significance difference in cTnI levels when subjects on chemotherapy were compared with newly diagnosed subjects (P = 0.0694). This study revealed that cTnI was detectable in the serum of majority of the study participants which may suggest sub-clinical cardiac necrosis. There may be risk of developing adverse cardiovascular disorders and the need for appropriate intensive management is emphasized. PMID- 29485645 TI - Correlation of Serum Estradiol and Duration of Anastrazole Therapy with Treatment Related Adverse Effects Among Postmenopausal Breast Cancer Women: A Cross sectional Study. AB - Although anastrozole (Anas) plays a key role in the management of endocrine sensitive post-menopausal (PM) breast cancer (BC), there is much variability in its efficacy and tolerability. Anas-associated musculoskeletal symptoms (MS) and other adverse reactions, such as hot flashes (HF) and vaginal dryness/dyspareunia (VDD), are common and can affect the quality of life of BC patients, even sometimes leading to treatment withdrawal. The aim of this study was to determine the clinical and demographic factors associated with these adverse events. This is a cross-sectional study in estrogen receptor (ER) positive PM women (n = 92) with stages I to III BC receiving Anas. Multivariate analyses were performed to investigate the factors associated with Anas-induced adverse effects such as MS, HF and VDD. A serum estradiol concentration was undetectable (< 36.7 pmol/L) in 68.1% of patients but was detectable within a normal range (>36.7-88.1 pmol/L) in the other 31.9% of patients, and this group was found to have a lower odds of having at least one adverse effect (AE) compared to those with undetectable levels [adjusted odds ratio (AOR) 0.12, 95% confidence interval (CI) 0.02 to 0.64, p = 0.013]. Women with grades II and III tumors and a family history of BC had a higher odds of AE (grade II: AOR 12.22, CI 1.48 to 100.80, p = 0.020; grade III: AOR 12.95, CI 1.25 to 134.33, p = 0.032) and VDD (AOR 5.99, CI 1.30 to 27.52, p = 0.021), respectively. Patients who received Anas treatment for more than one year had a higher odds of VDD (one to three years: AOR 34.57, CI 3.86, 309.50, p = 0.002; more than 3 years: AOR 27.90, CI 2.21 to 351.84, p = 0.010). Advanced age also lowered the odds of HF (AOR 0.90, CI 0.83 to 1.00, p = 0.049). In conclusion, patients' hormonal environments and durations of Anas treatment may play a role in developing Anas-induced adverse effects. PMID- 29485646 TI - Transforming hemithioindigo from a two-way to a one-way molecular photoswitch by isolation in the gas phase. AB - Hemithioindigo compounds are attractive two-way molecular photoswitches combining stilbene and thioindigo parts connected by a C-C double bond. In solution, these photoswitches have been well studied. This study presents the investigation of a hemithioindigo derivative in the gas phase. Visible absorption spectra, measured by standard (visPD) and helium-tagging visible photodissociation (He-visPD) techniques were used to unravel absorption characteristics at the level of isolated molecules at 3 Kelvin. Comparison between the Z and E isomers shows a quite distinctive behavior upon visible light absorption. The Z isomer readily undergoes Z -> E conversion in the gas phase, as evidenced by the changes in the helium-tagging infrared photodissociation (He-IRPD) spectra. Surprisingly, visible light excitation of the E isomer does not lead to efficient E -> Z isomerization unlike in solution. Instead, the ions relax back to their ground state. Influencing the microenvironment of the E isomer by complexation with the highly polar betaine zwitterion resulted in absorption changes, albeit without activating the photoswitching process. Hence, isolation in the gas phase transforms hemithioindigo into a one-way molecular photoswitch. Furthermore, the combination of He-visPD and IRPD spectroscopies proved to be an excellent method for studying photochemical processes such as the double-bond isomerization in the gas phase. PMID- 29485647 TI - Direct formation of Au(iii) acetyl, alkoxyl and alkynyl functionalities via halide free tricationic Au(iii) precursors. AB - A novel synthetic approach for the synthesis of gold(iii) acetato, alkoxolato and alkynyl complexes was developed via the reactivity of gold(iii) trications containing the N,N-chelating ligand 2,2'-bipyridine and N,N,N-chelating ligand terpyridine through direct reactions with the protic precursors. This protocol avoids the gold(iii) chloride bond activation pathway commonly employed to access these functionalities. For example exposure of [LAu(iii)L']OTf3 (L = N,N,N terpyridine, L' = 4-DMAP) to RH (R = OCH3, OAc, Ph-[triple bond, length as m dash]) results in the facile formation of the corresponding functionalised gold(iii) complexes [LAu(iii)R]OTf2. PMID- 29485648 TI - Six uranyl-organic frameworks with naphthalene-dicarboxylic acid and bipyridyl based spacers: syntheses, structures, and properties. AB - A new series of uranium coordination polymers have been hydrothermally synthesized by using 1,4-naphthalene dicarboxylic acid (H2NDC), namely, (H3O)2[(UO2)2(NDC)3].H2O (1), (H2-bpp)[(UO2)2(NDC)3].EtOH.5H2O (2), (H2 bpe)2/2[(UO2)2(NDC)3].EtOH (3), (H2-bpp)[(UO2)2(NDC)3].5H2O (4), (H2 bpp)[(UO2)(HNDC)(NDC)]2.2H2O (5), and (H2-bpy)[(UO2)(NDC)2] (6) [bpp = 1,3-di(4 pyridyl) propane, bpe = 4,4'-vinylenedipyridine, bpy = 4,4'-bipyridine]. Single crystal X-ray diffraction demonstrates that complex 1 represents the uranyl organic polycatenated framework derived from a simple two-dimensional honeycomb grid network structure via a H2NDC linker. Complexes 2-4 contain the dinuclear motifs of the two UO7 pentagonal and one UO8 hexagonal bipyramids which are linked by NDC2- anions creating a (UO2)4(NDC)2 unit, and further extend to a 2D layer through NDC2- anions. Complex 5 displays a 1D zigzag double chain structure, in which the carboxylate groups of the NDC2- anions adopt a chelate mode and further extends to a 2D framework via hydrogen bonds. The 1D structure of complex 6 is similar to the zigzag chain of complex 5. In addition, powder X ray diffraction, elemental analysis, IR, thermal stability and luminescence properties of all complexes have also been investigated in this paper. The photocatalytic properties of the six complexes for the degradation of tetracycline hydrochloride (TC) under UV irradiation have been examined. Moreover, density functional theory (DFT) calculations were carried out to explore the electronic structural and bonding properties of the uranyl complexes 1-6. PMID- 29485649 TI - Twist-bend nematic phase in biphenylethane-based copolyethers. AB - The main-chain liquid crystal (LC) copolyethers in which the nematic-nematic phase transition was first experimentally observed were revisited and re characterised. Grazing incidence X-ray scattering revealed that the low-T nematic (Ntb) phase could be highly aligned by shearing, more so than in previously studied bent LC dimers. This was evidenced by a four-point wide-angle X-ray scattering pattern, which originates from convolution of two tilt distributions. Through intensity simulation the orientational order parameter associated with each of the distributions, as well as the conical angle of the Ntb phase, was calculated. Information regarding the polymer chain conformation was obtained using polarised infrared spectroscopy. The findings suggest the average conformation of the chains is a helix, and that the bend angle between mesogenic units is inversely related to temperature. All experimental evidence, including a jump in birefringence at the Ntb-nematic (N) phase transition, shows that copolyether samples mirror the behaviour of bent LC dimers over the transition. This confirms that the low-T nematic phase in copolyethers is indeed the same as that in LC dimers, now known to be the Ntb. The unusual broadening of transition peaks in complex heat capacity, obtained by modulated DSC experiments, is discussed. PMID- 29485650 TI - Tailoring the structures and photonic properties of low-dimensional organic materials by crystal engineering. AB - Low-dimensional organic materials have given rise to tremendous interest in optoelectronic applications, owing to their controllable photonic properties. However, the controlled-synthesis approaches for organic nano-/micro architectures are very difficult to attain, because the weak interaction (van der Waals force) between the organic molecules cannot dominate the kinetic process of crystal growth. We report a simple method, which involves selective adhesion to the organic crystal plane by hydrogen-bonding interaction for modulating the crystal growth process, which leads either to the self-assembly of one organic molecule into two-dimensional (2D) microsheets with an obvious asymmetric light propagation or one-dimensional (1D) microrods with low propagation loss. The method of tailoring the structures and photonic properties for fabricating different micro-structures would provide enlightenment for the development of tailor-made mini-sized devices for photonic integrated circuits. PMID- 29485651 TI - Electron microscopy of polyoxometalate ions on graphene by electrospray ion beam deposition. AB - Aberration-corrected high-resolution transmission electron microscopy (AC-HRTEM) has enabled atomically resolved imaging of molecules adsorbed on low-dimensional materials like carbon nanotubes, graphene oxide and few-layer-graphene. However, conventional methods for depositing molecules onto such supports lack selectivity and specificity. Here, we describe the chemically selective preparation and deposition of molecules-like polyoxometalate (POM) anions [PW12O40]3- using electrospray ion-beam deposition (ES-IBD) along with high-resolution TEM imaging. This approach provides access to sub-monolayer coatings of intact molecules on freestanding graphene, which enables their atomically resolved ex situ characterization by low-voltage AC-HRTEM. The capability to tune the deposition parameters in either soft or reactive landing mode, combined with the well defined high-vacuum deposition conditions, renders the ES-IBD based method advantageous over alternative methods such as drop-casting. Furthermore, it might be expanded towards depositing and imaging large and nonvolatile molecules with complex structures. PMID- 29485652 TI - Support effects on adsorption and catalytic activation of O2 in single atom iron catalysts with graphene-based substrates. AB - The adsorption and catalytic activation of O2 on single atom iron catalysts with graphene-based substrates were investigated systematically by density functional theory calculation. It is found that the support effects of graphene-based substrates have a significant influence on the stability of the single atom catalysts, the adsorption configuration, the electron transfer mechanism, the adsorption energy and the energy barrier. The differences in the stable adsorption configuration of O2 on single atom iron catalysts with different graphene-based substrates can be well understood by the symmetrical matching principle based on frontier molecular orbital analysis. There are two different mechanisms of electron transfer, in which the Fe atom acts as the electron donor in single vacancy graphene-based substrates while the Fe atom mainly acts as the bridge for electron transfer in double vacancy graphene-based substrates. The Fermi softness and work function are good descriptors of the adsorption energy and they can well reveal the relationship between electronic structure and adsorption energy. This single atom iron catalyst with single vacancy graphene modified by three nitrogen atoms is a promising non-noble metal single atom catalyst in the adsorption and catalytic oxidation of O2. Furthermore, the findings can lay the foundation for the further study of graphene-based support effects and provide a guideline for the development and design of new non-noble metal single atom catalysts. PMID- 29485653 TI - Two pure MOF-photocatalysts readily prepared for the degradation of methylene blue dye under visible light. AB - Two 3D metal-organic frameworks (MOFs) with different structures, [Cu(4,4' bipy)Cl]n (1) and [Co(4,4'-bipy).(HCOO)2]n (2), were synthesized by means of a hydrothermal method using a typical ligand (4,4'-bipyridine), and characterized by elemental analyses, thermal analyses and single crystal X-ray diffraction. As MOF materials, the two complexes showed active performance for the photodegradation of methylene blue (MB) dye under visible light. MB degradation over the two MOF-based photocatalysts follows first-order kinetics. The addition of an H2O2 electron acceptor can markedly enhance the photocatalytic MB degradation performance via a ligand-to-metal charge transfer mechanism, especially in complex 1. Complex 1 is better than complex 2 in MB photodegradation performance under the same conditions. Moreover, complex 1 showed a stable activity for MB degradation after four consecutive usages. Owing to the advantages of the visible light response, stable structure, low cost and high yield, these MOF-based photocatalysts will facilitate new efforts in environmental purification. PMID- 29485654 TI - Gut : liver : brain axis: the microbial challenge in the hepatic encephalopathy. AB - Hepatic encephalopathy (HE) is a debilitating neuropsychiatric condition often associated with acute liver failure or cirrhosis. Advanced liver diseases are characterized by a leaky gut and systemic inflammation. There is strong evidence that the pathogenesis of HE is linked to a dysbiotic gut microbiota and to harmful microbial by-products, such as ammonia, indoles, oxindoles and endotoxins. Increased concentrations of these toxic metabolites together with the inability of the diseased liver to clear such products is thought to play an important patho-ethiological role. Current first line clinical treatments target microbiota dysbiosis by decreasing the counts of pathogenic bacteria, blood endotoxemia and ammonia levels. This review will focus on the role of the gut microbiota and its metabolism in HE and advanced cirrhosis. It will critically assess data from different clinical trials measuring the efficacy of the prebiotic lactulose, the probiotic VSL#3 and the antibiotic rifaximin in treating HE and advanced cirrhosis, through gut microbiota modulation. Additionally data from Randomised Controlled Trials using pre-, pro- and synbiotic will be also considered by reporting meta-analysis studies. The large amount of existing data showed that HE is a clear example of how an altered gut microbiota homeostasis can influence and impact on physiological functions outside the intestine, with implication for host health at the systems level. Nevertheless, a strong effort should be made to increase the information on gut microbiota ecology and its metabolic function in liver diseases and HE. PMID- 29485656 TI - Hydrogen bonding and dominant conformations of hydrated sugar analogue complexes using tetrahydrofurfuryl alcohol as the model sugar molecule. AB - Water molecules, which serve as both hydrogen bond donors and acceptors, have been found to influence the conformational landscape of gas-phase phenyl-beta-d glucopyranoside. Herein, tetrahydrofurfuryl alcohol (THFA), a sugar-like molecule without chromophores (e.g. phenyl-substitution), was used as the model sugar molecule for exploring the behaviour of water molecules on the conformational landscape of a pentose sugar such as deoxyribose. We used mass selected infrared vacuum ultraviolet (IR-VUV) (118 nm) spectroscopy to investigate the hydrated neutral THFA and its complex cation in a supersonic jet. High level density functional theory (DFT) calculations were performed to ascertain the experimental results. The results revealed that the water molecule tends to insert into the twisted conformer at a position where two stronger intermolecular hydrogen bonds were formed by breaking the weak intramolecular interactions. We found that the twisted conformer of the hydrated neutral THFA complex is more stable than the envelope conformation, while the latter is more stable for the THFA molecule. However, the conformational landscape of the hydrated THFA complex cation did not significantly change on microsolvation with water molecules. These results indicated that the dominant structural landscape of the hydrated cationic complex is the twisted configuration with a trans-hydroxymethyl group. This finding provides valuable insight into the microsolvation of gas-phase sugar molecules. PMID- 29485657 TI - Pyrolysis of cyano-bridged hetero-metallic aerogels: a general route to immobilize Sn-M (M = Fe, Ni) alloys within a carbon matrix for stable and fast lithium storage. AB - The practical application of Sn-M (M = Fe, Ni, Co, and Cu) alloys, a promising anodic category for lithium-ion batteries, is hindered primarily by their huge volume change upon cycling. Immobilization of Sn-M alloys within carbon matrices has proven to be effective to improve their cycling stability, but the traditional pyrolysis of separate Sn, M, and C precursors often leads to uneven distribution of the three components in Sn-M-C ternary anodes. Herein, we report a facile and general aerogel-derived pyrolysis route to realize homogeneous embedding of uniformly-sized Sn-M alloy nanocrystals, within a nanoporous carbon matrix, using cyano-bridged hetero-metallic (Sn-M) aerogels hybridized with carbon sources as precursors. Using the optimized citric acid (CA) as a carbon source, the formations of nanoporous Sn-Fe@C and Sn-Ni@C networks have been illustrated as examples through pyrolyzing CA/Sn-Fe and CA/Sn-Ni aerogels, respectively. By virtue of their compositional/structural superiorities toward lithium storage, the as-prepared Sn-Fe@C and Sn-Ni@C networks manifest higher capacities, enhanced cycling stability, and improved rate capability compared to the Sn-M-C composites and carbon samples derived from bare aerogels and CA precursors, respectively. Specifically, the Sn-Fe@C network manifests a high reversible capacity of 441.6 mA h g-1 after 100 cycles at 100 mA g-1 and an average capacity of 438.6 mA h g-1 at 1 A g-1. This work shows a new guideline for designing highly-uniform Sn-M-C, Sb-M-C, and Bi-M-C ternary anodes for boosting energy storage. PMID- 29485655 TI - Hypoxia activates enhanced invasive potential and endogenous hyaluronic acid production by glioblastoma cells. AB - Glioblastoma (GBM) is the most common, aggressive, and deadly form of adult brain cancer, and is associated with a short survival rate (median 12-15 months, 5+ year less than 5%). The complex tumor microenvironment includes matrix transitions at the tumor margin, such as gradations in hyaluronic acid (HA). In addition, metabolic stress induced by decreased oxygen content across the tumor may contribute to tumor progression. However, cross-talk between matrix composition and metabolic stress remains unclear. In this study, we fabricated an in vitro brain memetic HA-decorated gelatin hydrogel platform incorporating variable oxygen concentrations to mimic intra-tumoral hypoxia. We observed that EGFR status (wildtype vs. a constitutively active EGFRvIII mutant) of U87 GBM cells affected proliferation and metabolic activity in response to hypoxia and matrix-bound HA. The use of an invasion assay revealed that invasion was significantly enhanced in both cell types under hypoxia. Moreover, we observed compensatory secretion of soluble HA in cases of enhanced GBM cell invasion, consistent with our previous findings using other GBM cell lines. Interestingly, U87 GBM cells adapted to hypoxia by shifting toward a more anaerobic metabolic state, a mechanism that may contribute to GBM cell invasion. Collectively, these data demonstrate that the use of a three-dimensional hydrogel provides a robust method to study the impact of matrix composition and metabolic challenges on GBM cell invasion, a key factor contributing to the most common, aggressive, and deadly form of adult brain cancer. PMID- 29485658 TI - The osteoimmunomodulatory property of a barrier collagen membrane and its manipulation via coating nanometer-sized bioactive glass to improve guided bone regeneration. AB - A barrier membrane is a major component of guided bone regeneration (GBR), which is traditionally viewed as a physical barrier. Due to its "foreign body" nature, the implantation of a barrier membrane would inevitably modulate immune response and subsequently affect bone dynamics, which has long been neglected. To bridge this knowledge gap, we investigated the osteoimmunomodulatory effects of barrier collagen membranes. It is found that barrier collagen membranes elicit significant effects on modulating the osteoimmune response of macrophages, by upregulating the expression of pro-inflammatory cytokines (TNFalpha, IL-1beta, IL 6, and IL-18) and osteogenic factors (BMP2/6, WNT10b, OSM). The modulated osteoimmune environment was beneficial for the osteogenic differentiation of BMSCs, due to the activation of BMP, canonical WNT/beta-catenin, and OSM signalling pathways. The membrane-mediated osteoimmunomodulation was further modulated to show whether osteogenesis could be enhanced via manipulating the membrane-mediated osteoimmunomodulation. The membrane-mediated osteoimmune response was successfully tuned through coating the collagen membranes with nanometer-sized bioactive glass Ca2ZnSi2O7 by pulsed laser deposition, which is indicated from the change in the expression profile of inflammatory cytokines and the upregulated expression of osteogenic factors. The modulated osteoimmune environment enhanced the osteogenic differentiation of BMSCs, suggesting that collagen membranes with nanometer-sized Ca2ZnSi2O7 coating can be promising for GBR applications. These results collectively imply that barrier membranes are bioactive barriers with an osteoimmunomodulatory effect and not just physical barriers. New generation barrier membranes should be designed with a favourable osteoimmunomodulatory property. PMID- 29485659 TI - Density functional theory studies on the solvent effects in Al(H2O)63+ water exchange reactions: the number and arrangement of outer-sphere water molecules. AB - Density functional theory (DFT) calculations combined with cluster models are performed at the B3LYP/6-311+G(d,p) level for investigating the solvent effects in Al(H2O)63+ water-exchange reactions. A "One-by-one" method is proposed to obtain the most representative number and arrangement of explicit H2Os in the second hydration sphere. First, all the possible ways to locate one explicit H2O in second sphere (Nm' = 1) based on the gas phase structure (Nm' = 0) are examined, and the optimal pathway (with the lowest energy barrier) for Nm' = 1 is determined. Next, more explicit H2Os are added one by one until the inner-sphere is fully hydrogen bonded. Finally, the optimal pathways with Nm' = 0-7 are obtained. The structural and energetic parameters as well as the lifetimes of the transition states are compared with the results obtained with the "Independent minimum" method and the "Independent-average" method, and all three methods show that the pathway with Nm' = 6 may be representative. Our results give a new idea for finding the representative pathway for water-exchange reactions in other hydrated metal ion systems. PMID- 29485660 TI - The effects of surface bioactivity and sustained-release of genistein from a mesoporous magnesium-calcium-silicate/PK composite stimulating cell responses in vitro, and promoting osteogenesis and enhancing osseointegration in vivo. AB - The surface of a mesoporous magnesium-calcium-silicate (m MCS)/polyetheretherketone (PK) composite (MPC) was modified by sand blasting, and genistein (GS) was loaded inside the nanopores of the m-MCS on the modified MPC (MPCm) surface. The results showed that compared with MPC, the surface roughness and hydrophilcity of MPCm obviously improved with more m-MCS exposed on its surface. Moreover, no obvious differences in surface roughness and hydrophilcity were found between MPCm and GS loaded MPCm (MPCm-Ge), and both of them possessed an improved apatite mineralization ability in simulated body fluid solution (SBF) compared with MPC, indicating excellent surface bioactivity. Moreover, the MPCm obviously stimulated the adhesion, proliferation, differentiation and gene expressions of MC3T3-E1 cells compared with MPC, and the sustained-release of GS from the MPCm-Ge surface further significantly promoted the cell proliferation, differentiation and gene expression. According to the Micro-CT, histological and SEM analysis, the results demonstrated that the MPCm obviously improved osteogenesis and enhanced osseointegration in vivo compared with MPC, and the release of GS from the MPCm-Ge surface further significantly improved osteogenesis and enhanced osseointegration. In summary, the significant promotion of cell responses in vitro, and the improvements of osteogenesis and the enhancement of osseointegration in vivo were attributed to the effects of surface bioactivity and GS sustained-release from the MPCm-Ge surface. Therefore, MPCm-Ge would be a potential candidate for orthopedic and dental applications. PMID- 29485661 TI - Colloidal lithography-based fabrication of highly-ordered nanofluidic channels with an ultra-high surface-to-volume ratio. AB - This article shows a new strategy for the fabrication of nanofluidics based on nanoscale gaps in nanopillar arrays. Silicon nanopillar arrays are prepared in a designed position by combining conventional photolithography with colloidal lithography. The nanogaps between the pillars are used as nanochannels for the connection of two polydimethylsiloxane-based microchannels in microfluidics. The gap between neighbouring nanopillars can be accurately controlled by changing the size of initial colloidal spheres and by an etching process, which further determines the dimensions of the nanochannels. At a low ionic strength, the surface charge-governed ion transportation shows that the nanochannels possess the same electrokinetic properties as typical nanofluidics. Benefiting from the advantage of photolithography, large-area nanochannel arrays can be prepared in a parallel manner. Due to the perm-selectivity of the nanochannels, the nanofluidic chips can be used to preconcentrate low concentration samples. The large-area ordered nanostructures preserve their high-throughput property and large surface to-volume ratio, which shows their great potential in the development of nanofluidics and their applications, such as in the separation of small molecules, energy conversion, etc. PMID- 29485662 TI - Recent progress in the development of near-infrared organic photothermal and photodynamic nanotherapeutics. AB - Phototherapies including photothermal therapy (PTT) and photodynamic therapy (PDT) have gained considerable attention due to their high tumor ablation efficiency, excellent spatial resolution and minimal side effects on normal tissue. In contrast to inorganic nanoparticles, near-infrared (NIR) absorbing organic nanoparticles bypass the issue of metal-ion induced toxicity and thus are generally considered to be more biocompatible. Moreover, with the guidance of different kinds of imaging methods, the efficacy of cancer phototherapy based on organic nanoparticles has shown to be optimizable. In this review, we summarize the synthesis and application of NIR-absorbing organic nanoparticles as phototherapeutic nanoagents for cancer phototherapy. The chemistry, optical properties and therapeutic efficacies of organic nanoparticles are firstly described. Their phototherapy applications are then surveyed in terms of therapeutic modalities, which include PTT, PDT and PTT/PDT combined therapy. Finally, the present challenges and potential of imaging guided PTT/PDT are discussed. PMID- 29485664 TI - ? PMID- 29485665 TI - ? PMID- 29485666 TI - ? PMID- 29485663 TI - Recommendation on test readiness criteria for new approach methods in toxicology: Exemplified for developmental neurotoxicity. AB - Multiple non-animal-based test methods have never been formally validated. In order to use such new approach methods (NAMs) in a regulatory context, criteria to define their readiness are necessary. The field of developmental neurotoxicity (DNT) testing is used to exemplify the application of readiness criteria. The costs and number of untested chemicals are overwhelming for in vivo DNT testing. Thus, there is a need for inexpensive, high-throughput NAMs, to obtain initial information on potential hazards, and to allow prioritization for further testing. A background on the regulatory and scientific status of DNT testing is provided showing different types of test readiness levels, depending on the intended use of data from NAMs. Readiness criteria, compiled during a stakeholder workshop, uniting scientists from academia, industry and regulatory authorities are presented. An important step beyond the listing of criteria, was the suggestion for a preliminary scoring scheme. On this basis a (semi)-quantitative analysis process was assembled on test readiness of 17 NAMs with respect to various uses (e.g. prioritization/screening, risk assessment). The scoring results suggest that several assays are currently at high readiness levels. Therefore, suggestions are made on how DNT NAMs may be assembled into an integrated approach to testing and assessment (IATA). In parallel, the testing state in these assays was compiled for more than 1000 compounds. Finally, a vision is presented on how further NAM development may be guided by knowledge of signaling pathways necessary for brain development, DNT pathophysiology, and relevant adverse outcome pathways (AOP). PMID- 29485667 TI - ? PMID- 29485668 TI - ? PMID- 29485669 TI - ? PMID- 29485670 TI - ? PMID- 29485671 TI - ? PMID- 29485672 TI - ? PMID- 29485674 TI - ? AB - Patients had several suggestions on how to improve healthcare meetings in order to create safer care An open question "Do you have suggestions on how to improve meetings between patients and healthcare professionals in order to create safer care?" was incorporated into a questionnaire survey to 2673 patients in Sweden. The survey addressed patient participation for safer care. The open question was answered by 591 respondents. Content analysis was used to analyze the responses. The proposed suggestions concerned both the individual level (healthcare staff's competence and trust in the patient) and the system level (forms of communication, planning and structure, and time and staffing). The study findings show that there are many ways to improve meetings in healthcare of potential relevance for patient safety. Further research is needed to develop, apply and evaluate interventions based on patient suggestions. PMID- 29485673 TI - The syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL) AB - The syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL) is a self-limited disorder with an unknown pathogenesis, characterized by one or more transient episodes of severe headache accompanied with neurologic deficits, and lymphocytic pleocytosis in the cerebrospinal fluid (CSF). Despite being uncommon and benign it is important for clinicians to identify and differentiate HaNDL from other potentially fatal neurologic disorders. We present six HaNDL patients from our institution. All had a relatively typical course with repeated migraine-like headaches accompanied by various transient neurologic deficits and a mean CSF lymphocytic pleocytosis of 178 cells/mm3. Most of the patients were disorientated during the attacks, which has been described previously. When neurofilament light in CSF was measured, there was a substantial increase of this marker which normalized after several months, suggesting certain nerve damage. PMID- 29485675 TI - POSTPARTUM BONDING DIFFICULTIES AND ADULT ATTACHMENT STYLES: THE MEDIATING ROLE OF POSTPARTUM DEPRESSION AND CHILDBIRTH-RELATED PTSD. AB - Despite decades of research demonstrating the role of adult attachment styles and early mother-infant bonding in parenting behaviors and maternal mental health, these constructs have seldom been studied together. The present study aimed to investigate the relationship between attachment styles and specific bonding difficulties of mothers. In addition, as postpartum depression and childbirth related posttraumatic stress symptoms have been associated with both constructs, we explored their possible mediation effect. One hundred fourteen mothers, 4 to 12 weeks' postpartum, completed a demographic questionnaire, the Adult Attachment Style Questionnaire (M. Mikulincer, V. Florian, & A. Tolmacz, 1990), the Postpartum Bonding Questionnaire (L.F. Brockington, C. Fraser, & D. Wilson, 2006), the Modified Perinatal Posttraumatic Stress Disorder Questionnaire (J.L. Callahan, S.E. Borja, & M.T. Hynan, 2006), and the Edinburgh Postnatal Depression Scale (J.L. Cox, G. Chapman, D. Murray, & P. Jones, 1996), using an online survey system. As predicted, insecure attachment styles were associated with bonding difficulties wherein anxious/ambivalent attachment was associated with greater infant-focused anxiety, mediated by postpartum depression but not childbirth related PTSD symptoms. In contrast, greater avoidant attachment style was associated with greater rejection and anger, mediated by childbirth-related posttraumatic stress disorder (PTSD), but not depression symptoms. The current study confirmed the association of different attachment styles with bonding as well as the mediating roles of childbirth-related PTSD and postpartum depression symptoms. Future psychological interventions may utilize such evidence to target interventions for bonding disorders in accordance with individual differences. PMID- 29485677 TI - Sex differences in heart failure. AB - Heart failure (HF) numbers continue to grow in the United States and approximately 50% of patients living with HF are women. For the provider, it is critical to understand the role that gender plays in recognition, diagnosis, and management. The purpose of this literature review is to highlight the prevalence of heart failure in women and discuss gender variations in epidemiology, symptoms, pharmacology, and treatment as well as examine the representation of women in clinical trials. PMID- 29485676 TI - A Randomized Trial of a Personalized Feedback Intervention for Nonstudent Emerging Adult At-Risk Drinkers. AB - BACKGROUND: Emerging adulthood is a period of heightened vulnerability for problematic alcohol use. Considerable research has been devoted to reducing alcohol risks in college student populations, although far less effort has focused on their noncollege-attending peers. Research targeting nonstudent emerging adults is critical as this group is at risk of experiencing alcohol related harms. Consequently, the main objective of the present randomized study was to examine the preliminary efficacy of a brief personalized feedback intervention (PFI) tailored for nonstudent at-risk drinkers. We also examined the influence of gender on intervention outcomes. Finally, we explored participant acceptability of the intervention. METHODS: Participants were 164 (65.9% men) emerging adults (M age = 21.98, SD = 2.02) recruited from the community. They were randomly assigned to either a 50-minute, in-person PFI or an assessment-only control group and were assessed over 9 months postintervention. RESULTS: Results showed that for short-term change (1 month), the PFI condition reduced drinking significantly more than controls. For longer-term change (1 to 9 months), both conditions continued to show gradual decline in consumption. The groups did not differ in alcohol-related problems, and the intervention was equally effective for both women and men. Regarding acceptability, participants were extremely satisfied with the intervention, perceived the information to be personally relevant, and thought it provided them a new way of looking at their own drinking. CONCLUSIONS: Overall, the present research advanced knowledge regarding an understudied and at-risk group of drinkers. This is among one of the first randomized studies to evaluate a brief intervention tailored to the needs of nonstudent emerging adults based on prior formative research with this group. Our data support PFI as a promising intervention approach for nonstudent drinkers in the community. Ultimately, this line of research aims to reduce alcohol-related health disparities associated with inequities in education. PMID- 29485678 TI - Transcatheter aortic valve replacement in women. AB - This review examines the treatment options for women with severe aortic stenosis. It is known that female sex is associated with poorer outcomes after surgical aortic valve replacement. With the introduction and adoption of transcatheter aortic valve replacement as an alternative to surgical aortic valve replacement, there are emerging data about the potential impact of female sex-specific characteristics on clinical outcomes after transcatheter aortic valve replacement. These data provide an insight into female-specific aspects of the treatment of aortic stenosis. The data can help guide patient selection, choice of intervention method, and evaluation of risk to help improve long-term follow up of patients with aortic stenosis. PMID- 29485679 TI - Development of the TeamOBS-PPH - targeting clinical performance in postpartum hemorrhage. AB - INTRODUCTION: This study aimed to develop a valid and reliable TeamOBS-PPH tool for assessing clinical performance in the management of postpartum hemorrhage (PPH). The tool was evaluated using video-recordings of teams managing PPH in both real-life and simulated settings. MATERIAL AND METHODS: A Delphi panel consisting of 12 obstetricians from the UK, Norway, Sweden, Iceland, and Denmark achieved consensus on (i) the elements to include in the assessment tool, (ii) the weighting of each element, and (iii) the final tool. The validity and reliability were evaluated according to Cook and Beckman. (Level 1) Four raters scored four video-recordings of in situ simulations of PPH. (Level 2) Two raters scored 85 video-recordings of real-life teams managing patients with PPH >=1000 mL in two Danish hospitals. (Level 3) Two raters scored 15 video-recordings of in situ simulations of PPH from a US hospital. RESULTS: The tool was designed with scores from 0 to 100. (Level 1) Teams of novices had a median score of 54 (95% CI 48-60), whereas experienced teams had a median score of 75 (95% CI 71-79; p < 0.001). (Level 2) The intra-rater [intra-class correlation (ICC) = 0.96] and inter-rater (ICC = 0.83) agreements for real-life PPH were strong. The tool was applicable in all cases: atony, retained placenta, and lacerations. (Level 3) The tool was easily adapted to in situ simulation settings in the USA (ICC = 0.86). CONCLUSION: The TeamOBS-PPH tool appears to be valid and reliable for assessing clinical performance in real-life and simulated settings. The tool will be shared as the free TeamOBS App. PMID- 29485680 TI - CAREGIVER'S DEPRESSIVE SYMPTOMS AND YOUNG CHILDREN'S SOCIOEMOTIONAL DEVELOPMENT DELAYS: A CROSS-SECTIONAL STUDY IN POOR RURAL AREAS OF CHINA. AB - Poverty and its associated factors put people at risk for depression. The aims of this study were to describe the prevalence of depressive symptoms (DS) of primary caregivers and socioemotional development (SED) delays of young children in poor rural areas of China, and to explore the association between them. Cross sectional data of 2,664 children aged 3 to 35 months and their primary caregivers were used for analysis. Characteristics of the child, caregiver, and family were collected through face-to-face caregiver interviews. DS were assessed by the Zung Self-Rating Depression Scale (W.W. Zung, 1965, as cited in World Health Organization, ), and SED was evaluated by the Ages and Stage Questionnaires: Social-Emotional (J. Squires, D. Bricker, & L. Potter, 1997). The chi2 test, stratification analysis, and logistic regression analyses were used to explore the association. Among the caregivers, 40.3% (95% confidence interval [CI] [38.4, 42.1]), reported DS. Caregivers who were male, older and ethnic minorities as well as had a low level of education, a low family income, or more children were more likely to have DS. Of the children, 24.4% (95% CI [22.8, 26.0]) were recognized with SED delays. Older children displayed more delays than did younger children, but no significant differences between males and females were found. SED delays were significantly associated with mother outmigrating, male caregivers, older age, ethnic minorities, and low education or families with a single parent, low-income, and having more children. Caregivers having DS, odds ratio (OR) = 2.40, 95% CI [1.99, 2.88], was a significant predictor of increased odds of SED delays; other factors were single-parent family, OR = 1.99, 95% CI [1.37, 2.89], inadequate care, OR = 1.69, 95% CI [1.30, 2.21], physical punishment, OR = 1.61, 95% CI [1.33, 1.95], ethnic minorities, OR = 1.41, 95% CI [1.17, 1.71], and child age in months, OR = 1.03, 95% CI [1.02, 1.04], according to the logistic regression analysis. DS are prevalent among caregivers with young children in poor rural areas. Interventions to improve the mental health of caregivers and their parenting behaviors are needed to improve children's SED. PMID- 29485681 TI - Eicosanoids in the gastrointestinal tract. AB - Eicosanoids play important roles in modulating inflammation throughout the body. The gastrointestinal (GI) tract, in part because of its intimate relationship with the gut microbiota, is in a constant state of low-grade inflammation. Eicosanoids like PGs, lipoxins and leukotrienes play essential roles in maintenance of mucosal integrity. On the other hand, in some circumstances, these mediators can become major drivers of inflammatory processes when the lining of the GI tract is breached. Drugs such as nonsteroidal anti-inflammatories, by altering the production of various eicosanoids, can dramatically impact the ability of the GI tract to respond appropriately to injury. Disorders such as inflammatory bowel disease appear to be driven in part by altered production of eicosanoids. Several classes of drugs have been developed that target eicosanoids. PMID- 29485682 TI - MATERNAL DEPRESSION AND THE DEVELOPMENT OF EXECUTIVE FUNCTION AND BEHAVIOR PROBLEMS IN HEAD START: INDIRECT EFFECTS THROUGH PARENTING. AB - The present study used a large, nationally representative sample of Head Start children (N=3,349) from the Family and Child Experiences Survey of 2009 (FACES) to examine associations among maternal depression (measured when children were ~36 months old) and children's executive function (EF) and behavior problems (measured when children were ~48 months old). Preliminary analyses revealed that 36% of mothers in the sample had clinically significant levels of depressive symptoms. Furthermore, a path analysis with demographic controls showed a mediation effect that was significant and quite specific; mother-reported warmth (and not mother-child reading) mediated the path between maternal depression, children's EF, and behavior problems. Findings provide empirical support for a family process model in which warm, sensitive parenting supports children's emerging self-regulation and reduces the likelihood of early onset behavior problems in families in which children are exposed to maternal depression. PMID- 29485683 TI - Sunscreen habits and skin cancer rates in patients with vitiligo in Australia. PMID- 29485684 TI - Regulatory Perspectives in Pharmacometric Models of Osteoporosis. AB - Osteoporosis is a disorder of the bones in which they are weakened to the extent that they become more prone to fracture. There are various forms of osteoporosis: some of them are induced by drugs, and others occur as a chronic progressive disorder as an individual gets older. As the median age of the population rises across the world, the chronic form of the bone disease is drawing attention as an important worldwide health issue. Developing new treatments for osteoporosis and comparing them with existing treatments are complicated processes due to current acceptance by regulatory authorities of bone mineral density (BMD) and fracture risk as clinical end points, which require clinical trials to be large, prolonged, and expensive to determine clinically significant impacts in BMD and fracture risk. Moreover, changes in BMD and fracture risk are not always correlated, with some clinical trials showing BMD improvement without a reduction in fractures. More recently, bone turnover markers specific to bone formation and resorption have been recognized that reflect bone physiology at a cellular level. These bone turnover markers change faster than BMD and fracture risk, and mathematically linking the biomarkers via a computational model to BMD and/or fracture risk may help in predicting BMD and fracture risk changes over time during the progression of a disease or when under treatment. Here, we discuss important concepts of bone physiology, osteoporosis, treatment options, mathematical modeling of osteoporosis, and the use of these models by the pharmaceutical industry and the Food and Drug Administration. PMID- 29485685 TI - Change in alcohol and tobacco consumption after a diagnosis of head and neck cancer: Findings from Head and Neck 5000. AB - BACKGROUND: Tobacco and alcohol consumption are risk factors for developing head and neck cancer, and continuation postdiagnosis can adversely affect prognosis. We explored changes to these behaviors after a head and neck cancer diagnosis. METHODS: Demographic and clinical data were collected from 973 people newly diagnosed with oral cavity, oropharyngeal, or laryngeal cancer. Tobacco and alcohol consumption were additionally collected 4 and 12 months later. RESULTS: The prevalence of high alcohol consumption reduced from 54.3% at diagnosis to 41.4% at 12 months, and smoking reduced from 21.0% to 11.7%. Changes in behavior were dynamic, for example, 44% of smokers at 12 months were not smoking at diagnosis or 4 months. Several factors were associated with alcohol consumption, whereas only tumor site and comorbidities were associated with smoking. CONCLUSION: A diagnosis of head and neck cancer can result in important changes in alcohol consumption and smoking prevalence. However, these changes are dynamic in the first year after diagnosis. PMID- 29485686 TI - Hyphal induction under the condition without inoculation in Candida albicans is triggered by Brg1-mediated removal of NRG1 inhibition. AB - Candida albicans can switch between yeast and hyphae growth forms, which is critical for its pathogenesis. Diluting from saturated cells into fresh medium at 37 degrees C is routinely used to induce hyphae, which depends on the cAMP-PKA pathway-activated transcriptional down-regulation of NRG1 and degradation of Nrg1 protein triggered by inoculation. It is reported that N-acetylglucosamine (GlcNAc), serum or neutral pH could stimulate filamentation in log phase cells, whereas how C. albicans develops hyphae without inoculation remains unknown. Here, we show that NRG1 down-regulation is necessary for hyphal growth under this condition. Instead of cAMP-PKA pathway, GlcNAc sensor Ngs1 is responsible for the down-regulation of NRG1 upon GlcNAc induction in log phase cells through its N acetyltransferase activity. From a genetic screen, Brg1 is found to be essential for hyphal development without inoculation. Ngs1 binds to BRG1 promoter to induce its expression in GlcNAc. Importantly, constitutively expressed BRG1 induces NRG1 down-regulation even in the absence of GlcNAc or Ngs1. Serum or neutral pH induced filamentation in log phase cells is also through Brg1-mediated NRG1 down regulation. Our study provides a molecular mechanism for how C. albicans forms hyphae in different cell states. This flexibility may facilitate C. albicans to adapt varied host environment during infection. PMID- 29485687 TI - DEVELOPMENT OF THE PARENT-CHILD PLAY SCALE FOR USE IN CHILDREN WITH FEEDING DISORDERS. AB - The Parent-Child Play Scale was developed as a scale that complements the Parent Child Feeding Scale, created by I. Chatoor et al. (1997), to evaluate mother infant/toddler interactions in two different caregiving contexts of a young child's everyday life, specifically play and feeding. This Play Scale can be used with infants and toddlers ranging in age from 1 month to 3 years and provides reliable global ratings of mother-child interactions during 10 min of videotaped free-play in a laboratory setting. The scale consists of 32 mother and infant/toddler interactive behaviors which are rated by trained observers from videotaped observations. Four subscales are derived: Dyadic Reciprocity, Maternal Unresponsiveness to Infant's/Toddler's Cues, Dyadic Conflict, and Maternal Intrusiveness. Construct validity and interrater and test-retest reliability of the Play Scale have been demonstrated. This Play Scale discriminates between children with and without feeding disorders as well as between children with different subtypes of feeding disorders as defined by the Diagnostic Classification of Mental Health and Developmental Disorders of Infancy and Early Childhood, Revised (DC:0-3R) (Feeding Disorder of State Regulation, Feeding Disorder of Caregiver-Infant Reciprocity, and Infantile Anorexia). It can be used for research or clinical practice in the diagnosis and treatment of early feeding problems, to assess the pervasiveness of mother-infant/toddler difficulties and to monitor changes following therapy. PMID- 29485688 TI - Do you know your guidelines? Diagnosis and management of cutaneous head and neck melanoma. AB - The following article is the next installment of the series "Do You Know Your Guidelines?" presented by the Education Committee of the American Head and Neck Society. Guidelines for the prevention, diagnosis, workup, and management of cutaneous melanoma are reviewed in an evidence-based fashion. PMID- 29485689 TI - Effect of atopic skin stressors on natural moisturizing factors and cytokines in healthy adult epidermis. AB - BACKGROUND: Epidermal deficiency of filaggrin, and the derived natural moisturizing factors (NMFs), is associated with increased risk of atopic dermatitis (AD). While filaggrin gene mutations cause filaggrin deficiency, there is limited insight into the causative environmental factors. OBJECTIVES: To explore the effect of selected exogenous skin stressors on NMF and skin cytokine levels in healthy adult epidermis. METHODS: Forty healthy volunteers (aged 18-49 years) were exposed to hard, soft and chlorinated water, 0.5% sodium lauryl sulfate, house dust mite, cat allergen, staphylococcal enterotoxin B (SEB), cooling and histamine. Participants were tape-stripped and biophysiological measurements performed. NMF was determined after 24 and 48 h, whereas skin cytokines were measured after 24 h for selected exposures. RESULTS: At 24 h, a significant decrease in NMFs was observed for soft (0.51 +/- 0.19 g m-2 h-1 ) and hard water (0.61 +/- 0.32 g m-2 h-1 ) compared with occlusion alone (0.71 +/- 0.18 g m-2 h-1 ). Hard water led to increased levels of interleukin (IL)-4, interferon (IFN)-gamma and IL-10. Exposure to house dust mite and SEB led to a significant decrease in NMFs after 24 h (0.77 +/- 0.28 and 0.80 +/- 0.28 g m-2 h 1 , respectively) compared with occlusion alone (1.00 +/- 0.42 g m-2 h-1 ). House dust mite led to an increase in IFN-gamma, IL-2 and IL-4 vs. the nonoccluded control site. CONCLUSIONS: Based on experimental exposure to selected atopic skin stressors, we conclude that NMFs levels are decreased along with increased secretion of various skin cytokines in healthy individuals. Our data highlight environmental factors that might play a role in AD pathophysiology. PMID- 29485690 TI - New polymyxin derivatives that display improved efficacy in animal infection models as compared to polymyxin B and colistin. AB - Polymyxin B and colistin (polymyxin E) are bactericidal pentacationic lipopeptides that act specifically on Gram-negative bacteria, first by disrupting their outermost permeability barrier, the outer membrane (OM), and then damaging the cytoplasmic membrane. The discovery of both polymyxin B and colistin was published independently by three laboratories as early as in 1947. They were subsequently used in intravenous therapy. Unfortunately, they also exhibit significant and dose-limiting nephrotoxicity. Therefore, polymyxins were reserved as agents of last-line defense. The emergence of extremely multiresistant strains has now forced clinicians to reinstate polymyxins in the therapy of severe infections. However, the current dosage regimens lead to insufficient drug concentrations in serum and clinicians have been advised to use larger doses, which further increases the risk of nephrotoxicity. Very recently, the interest in developing better tolerated and more effective polymyxins has grown. This review focuses on describing four development programs that have yielded novel derivatives that are more effective than the old polymyxins in animal infection models. Compounds from three programs are superior to the old polymyxins in the rodent lung infection model with Acinetobacter baumannii and/or Pseudomonas aeruginosa. One of them is also more effective than polymyxin B in A. baumannii mouse thigh infection. The fourth program includes compounds that are approximately tenfold more effective in Escherichia coli murine pyelonephritis than polymyxin B. PMID- 29485691 TI - Unique fluid-fluid level ultrasonic appearance in subacute placenta abruption with massive subchorionic hematoma. PMID- 29485692 TI - CD64 on monocytes and granulocytes in severe acute bronchiolitis: Pilot study on its usefulness as a bacterial infection biomarker. AB - The CD64 receptor has been described as a biomarker of bacterial infection. We speculated that CD64 surface expression on monocytes and granulocytes of children with severe acute bronchiolitis (SAB) could be altered in cases of probable bacterial infection (PBI) determined using classical biomarkers (procalcitonin and C-reactive protein, leukocyte count, and radiographic findings). A prospective observational pilot study was conducted from October 2015 to February 2016 in children admitted for pediatric critical care. A blood sample was taken in the first 24 hours of admission, and CD64 was measured by flow cytometry. The values obtained were analyzed and correlated with traditional biomarkers of PBI. Thirty-two children were included; a correlation was found between CD64 expression and the PBI criteria. CD64 surface expression was higher in children with PBI (area under the receiver operating characteristic curve of 0.73; P = 0.042) and the percentage of CD64+ granulocytes was higher in children with PBI. This is the first study to describe CD64 surface expression on monocytes and granulocytes in SAB, finding CD64 values to be higher in children with PBI. Larger clinical studies are needed to elucidate the real accuracy of CD64 as a biomarker of bacterial infection. PMID- 29485693 TI - Bat and bee pollination in Psittacanthus mistletoes, a genus regarded as exclusively hummingbird-pollinated. PMID- 29485694 TI - Lipophilicity evaluation of some thiazolyl-1,3,4-oxadiazole derivatives with antifungal activity. AB - The chromatographic behavior of a series of thiazolyl-1,3,4-oxadiazoles with antifungal activity was studied by reverse-phase thin-layer chromatography (RP TLC). The lipophilicity parameters derived from RP-TLC were correlated with the data derived from liquid-chromatography mass-spectrometry. Good linear relationships were observed between the chromatographic lipophilicity parameters and the theoretical lipophilicity descriptors (logP) generated by various computer software and internet modules. Principal component analysis, applied on the experimental chromatographic lipophilicity indices and the theoretically calculated logP, enabled us to obtain a lipophilicity chart for better vizualization of the similarities and differences of the investigated compounds, which were grouped by k-means clustering in two congeneric classes. PMID- 29485696 TI - The Bordetella bronchiseptica nic locus encodes a nicotinic acid degradation pathway and the 6-hydroxynicotinate-responsive regulator BpsR. AB - The classical Bordetella species use amino acids as carbon sources and can catabolize organic acids and tricarboxylic acid cycle intermediates. They are also auxotrophic for nicotinamide adenine dinucleotide (NAD) pathway precursors such as nicotinic acid. Bordetellae have a putative nicotinate catabolism gene locus highly similar to that characterized in Pseudomonas putida KT2440. This study determined the distribution of the nic genes among Bordetella species and analyzed the regulation of this nicotinic acid degradation system. Transcription of the Bordetella bronchiseptica nicC gene was repressed by the NicR ortholog, BpsR, previously shown to regulate extracellular polysaccharide synthesis genes. nicC expression was derepressed by nicotinic acid or by the first product of the degradation pathway, 6-hydroxynicotinic acid, which was shown to be the inducer. Results using mutants with either a hyperactivated pathway or an inactivated pathway showed a marked effect on growth on nicotinic acid that indicated this degradation pathway influences NAD biosynthesis. Pathway dysregulation also affected Bordetella BvgAS-mediated virulence gene regulation, demonstrating that fluctuation of intracellular nicotinic acid pools impacts Bvg phase transition responses. PMID- 29485695 TI - A colourimetric evaluation of the effect of bacterial contamination on teeth stained with blood in vitro: Evaluation of the efficacy of two different bleaching regimes. AB - BACKGROUND: Tooth discolouration could occur due to bacterial contamination in traumatized teeth. Hydrogen peroxide is the commonly used bleaching agent. However, due to concerns over safety, alternative bleaching regimes such as sodium perborate (S) and thiourea-hydrogen peroxide (T) have been investigated. METHODS: Apices resected and pulp extirpated 99 premolars were divided into two groups. Group 1 and 2 was injected with blood and blood/bacteria, stored anaerobically for 35 days. The two groups were treated by bleaching with water, S or T. Teeth were rebleached after 7 days. Colourimetric evaluation was assessed using digital imaging, CasMatch standardization and CIE L*a*b colour system preoperatively, 35 days of staining and 7 and 14 of bleaching. A linear mixed model with fixed effects of time, group and bleach was used to examine colour difference. RESULTS: Blood-stained teeth were significantly redder and darker on day 35 compared with blood/bacteria-stained teeth. After bleaching, blood-stained teeth retained significant redness compared with blood/bacteria-stained teeth using either S or T. T produced a significantly whiter shade in both the groups after 14 days. CONCLUSIONS: Blood-stained teeth were significantly darker and red compared with blood/bacteria-stained teeth. T bleaching regime was more effective than S. PMID- 29485697 TI - Cerebrospinal fluid gammadelta T cell frequency is age-related: a case-control study of 435 children with inflammatory and non-inflammatory neurological disorders. AB - Studies of cerebrospinal fluid (CSF) gammadelta T cells in children are limited, due especially to the lack of control data. In adults, gamma/delta T cells (TCR gammadelta) residing in the intrathecal space are sometimes involved in neuroinflammation. To evaluate the possible role of gammadelta T cells in paediatric neuroinflammation, we immunophenotyped cerebrospinal fluid (CSF) and blood lymphocytes using flow cytometry in a case-control study of 100 children with non-inflammatory neurological disorders (NIND), 312 with opsoclonus myoclonus (OMS) and 23 with other inflammatory neurological disorders (OIND). In NIND, the negative correlation between CSF gammadelta T cell frequency and patient age was striking: median frequency of 27% in infants and 3.3% in teens. Interindividual variations were largest in the youngest. There was no gender effect. In all OMS, after correcting for age, only a small effect of OMS severity remained. Measurement of markers for gammadelta T cell activation [human leucocyte antigen D-related (HLA-DR)], maturation (CD45RA, CD45RO) or intracellular cytokine staining [interleukin (IL)-4, interferon (IFN)-gamma] failed to discriminate OMS and NIND groups. Of seven OMS immunotherapies/combinations, none altered the frequency of total CSF gammadelta T cells or subsets significantly. In OIND, the CSF gammadelta T cell frequency was < 10% for single samples of other paraneoplastic disorders [anti-neuronal nuclear antibody (ANNA)-1, PCA-1, teratoma-associated syndrome], cerebellar ataxia (post-infectious, ataxia-telangiectasia), acute disseminated encephalomyelitis, neuroborreliosis and encephalitis. This study provides new insights into CSF gammadelta T cells in the paediatric population. Although their role in CSF remains elusive, the negative age correlation, resistance to immunotherapy and our age cut-off references for NIND are important findings for the design of future paediatric studies. PMID- 29485698 TI - Solution structure and dynamics of Xanthomonas albilineans Cas2 provide mechanistic insight on nuclease activity. PMID- 29485699 TI - Cardiac release of urocortin precedes the occurrence of irreversible myocardial damage in the rat heart exposed to ischemia/reperfusion injury. AB - Richard A. Knight, Carol Chen-Scarabelli, Zhaokan Yuan, Roy B. McCauley, J. Di Rezze, Gabriele M. Scarabelli, Paul A. Townsend, David Latchman, Louis Saravolatz, Giuseppe Faggian, Alessandro Mazzucco, Hardial S. Chowdrey, Anastasis Stephanou, Tiziano M. Scarabelli First published: 22 February 2008 FEBS Letters, Volume 582, Issue 6, Pages 984-990 DOI: 10.1016/j.febslet.2008.02.035 The above article from FEBS Letters, published online on February 22, 2008 in Wiley Online Library (http://wileyonlinelibrary.com), has been withdrawn by agreement between the authors, the Journal Managing Editor Felix Wieland, and John Wiley & Sons Ltd., on behalf of the Federation of European Biochemical Societies. The retraction has been agreed following an initial investigation from the University College London that found clear signs of manipulation in Figures 1, 3, and 5. A subsequent investigation by the journal's Editorial Office with the assistance of an image integrity analyst corroborated these findings. PMID- 29485700 TI - The N terminus of cGAS de-oligomerizes the cGAS:DNA complex and lifts the DNA size restriction of core-cGAS activity. PMID- 29485701 TI - Brain alpha-amylase: a novel energy regulator important in Alzheimer disease? AB - Reduced glucose metabolism and formation of polyglucosan bodies (PGB) are, beside amyloid beta plaques and neurofibrillary tangles, well-known pathological findings associated with Alzheimer's disease (AD). Since both glucose availability and PGB are regulated by enzymatic degradation of glycogen, we hypothesize that dysfunctional glycogen degradation is a critical event in AD progression. We therefore investigated whether alpha (alpha)-amylase, an enzyme known to efficiently degrade polysaccharides in the gastrointestinal tract, is expressed in the hippocampal CA1/subiculum and if the expression is altered in AD patients. Using immunohistochemical staining techniques, we show the presence of the alpha-amylase isotypes AMY1A and AMY2A in neuronal dendritic spines, pericytes and astrocytes. Moreover, AD patients showed reduced gene expression of alpha-amylase, but conversely increased protein levels of alpha-amylase as well as increased activity of the enzyme compared with non-demented controls. Lastly, we observed increased, albeit not significant, load of periodic acid-Schiff positive PGB in the brain of AD patients, which correlated with increased alpha amylase activity. These findings show that alpha-amylase is expressed and active in the human brain, and suggest the enzyme to be affected, alternatively play a role, in the neurodegenerative Alzheimer's disease pathology. PMID- 29485702 TI - Mutational analysis of TAF6 revealed the essential requirement of the histone fold domain and the HEAT repeat domain for transcriptional activation. AB - TAF6, bearing the histone H4-like histone-fold domain (HFD), is a subunit of the core TAF module in TFIID and SAGA transcriptional regulatory complexes. We isolated and characterized several yeast TAF6 mutants bearing amino acid substitutions in the HFD, the middle region or the HEAT repeat domain. The TAF6 mutants were highly defective for transcriptional activation by the Gcn4 and Gal4 activators. CHIP assays showed that the TAF6-HFD and the TAF6-HEAT domain mutations independently abrogated the promoter occupancy of TFIID and SAGA complex in vivo. We employed genetic and biochemical assays to identify the relative contributions of the TAF6 HFD and HEAT domains. First, the temperature sensitive phenotype of the HEAT domain mutant was suppressed by overexpression of the core TAF subunits TAF9 and TAF12, as well as TBP. The HFD mutant defect, however, was suppressed by TAF5 but not by TAF9, TAF12 or TBP. Second, the HEAT mutant but not the HFD mutant was defective for growth in the presence of transcription elongation inhibitors. Third, coimmunoprecipitation assays using yeast cell extracts indicated that the specific TAF6 HEAT domain residues are critical for the interaction of core TAF subunits with the SAGA complex but not with TFIID. The specific HFD residues in TAF6, although required for heterodimerization between TAF6 and TAF9 recombinant proteins, were dispensable for association of the core TAF subunits with TFIID and SAGA in yeast cell extracts. Taken together, the results of our studies have uncovered the non overlapping requirement of the evolutionarily conserved HEAT domain and the HFD in TAF6 for transcriptional activation. PMID- 29485703 TI - Chemometrics comparison of gas chromatography with mass spectrometry and comprehensive two-dimensional gas chromatography with time-of-flight mass spectrometry Daphnia magna metabolic profiles exposed to salinity. AB - The performances of gas chromatography with mass spectrometry and of comprehensive two-dimensional gas chromatography with time-of-flight mass spectrometry are examined through the comparison of Daphnia magna metabolic profiles. Gas chromatography with mass spectrometry and comprehensive two dimensional gas chromatography with mass spectrometry were used to compare the concentration changes of metabolites under saline conditions. In this regard, a chemometric strategy based on wavelet compression and multivariate curve resolution-alternating least squares is used to compare the performances of gas chromatography with mass spectrometry and comprehensive two-dimensional gas chromatography with time-of-flight mass spectrometry for the untargeted metabolic profiling of Daphnia magna in control and salinity-exposed samples. Examination of the results confirmed the outperformance of comprehensive two-dimensional gas chromatography with time-of-flight mass spectrometry over gas chromatography with mass spectrometry for the detection of metabolites in D. magna samples. The peak areas of multivariate curve resolution-alternating least squares resolved elution profiles in every sample analyzed by comprehensive two-dimensional gas chromatography with time-of-flight mass spectrometry were arranged in a new data matrix that was then modeled by partial least squares discriminant analysis. The control and salt-exposed daphnids samples were discriminated and the most relevant metabolites were estimated using variable importance in projection and selectivity ratio values. Salinity de-regulated 18 metabolites from metabolic pathways involved in protein translation, transmembrane cell transport, carbon metabolism, secondary metabolism, glycolysis, and osmoregulation. PMID- 29485704 TI - Improved labelling for consumers with food allergy. PMID- 29485706 TI - Electromyographic characterisation of abdominal wall trigger points developed after caesarean section and response to local anaesthesia: an observational study. AB - OBJECTIVE: This study examines the electromyography pattern of abdominal trigger points developed after a caesarean section, and the association between clinical response and local anaesthetic injection. DESIGN: Prospective cohort study. SETTING: A tertiary university hospital. POPULATION: Twenty-nine women with chronic pelvic pain associated with trigger points after a caesarean section were included in the study. METHODS: Participants received needle electromyography before treatment, then underwent a treatment protocol consisting of trigger-point injection of 2 ml of 1% lidocaine. The protocol was repeated once a week for 4 weeks. The clinical responses of the patients were compared 1 week after and 3 months after treatment. The clinical trial is registered with the Brazilian Clinical Trials Registry (REBEC) under RBR-42c6gz (www.ensaiosclinicos.gov.br/rg/RBR-42c6gz/). MAIN OUTCOME MEASURES: Needle electromyography and algometry results and pain reduction. RESULTS: Fifteen patients had abnormal electromyography findings; 14 had normal findings. The rates of response 1 week and 3 months after treatment within the abnormal electromyography group were 95 and 87%, respectively. In the normal group, the rate was 38% both 1 week after and 3 months after treatment. CONCLUSIONS: Trigger points developed after caesarean section, even without clinical symptoms or signs of neuralgia, may originate from neuropathies. Electromyographic abnormalities were associated with pain remission after anaesthesia injection; normal electromyography findings were associated with undiagnosed causes of pain, such as adhesions. TWEETABLE ABSTRACT: Trigger points developed after caesarean section are neuropathies, even in the absence of classical neuralgia. PMID- 29485708 TI - Salivary cortisone and cortisol following synacthen, a future replacement for serum cortisol? Commentary to: Use of Salivary Cortisol and cortisone in the high and low dose synacthen test. PMID- 29485707 TI - Overexpression of Tpl2 is linked to imatinib resistance and activation of MEK-ERK and NF-kappaB pathways in a model of chronic myeloid leukemia. AB - The introduction of tyrosine kinase inhibitors (TKI) has transformed chronic myeloid leukemia (CML) into a chronic disease with long-term survival exceeding 85%. However, resistance of CML stem cells to TKI may contribute to the 50% relapse rate observed after TKI discontinuation in molecular remission. We previously described a model of resistance to imatinib mesylate (IM), in which K562 cells cultured in high concentrations of imatinib mesylate showed reduced Bcr-Abl1 protein and activity levels while maintaining proliferative potential. Using quantitative phosphoproteomic analysis of these IM-resistant cells, we have now identified significant upregulation of tumor progression locus (Tpl2), also known as cancer Osaka thyroid (COT1) kinase or Map3k8. Overexpression of Tpl2 in IM-resistant cells was accompanied by elevated activities of Src family kinases (SFKs) and NF-kappaB, MEK-ERK signaling. CD34+ cells isolated from the bone marrow of patients with CML and exposed to IMin vitro showed increased MAP3K8 transcript levels. Dasatinib (SFK inhibitor), U0126 (MEK inhibitor), and PS-1145 (IkappaB kinase (IKK) inhibitor) used in combination resulted in elimination of 65% of IM-resistant cells and reduction in the colony-forming capacity of CML CD34+ cells in methylcellulose assays by 80%. In addition, CML CD34+ cells cultured with the combination of inhibitors showed reduced MAP3K8 transcript levels. Overall, our data indicate that elevated Tpl2 protein and transcript levels are associated with resistance to IM and that combined inhibition of SFK, MEK, and NF-kappaB signaling attenuates the survival of IM-resistant CML cells and CML CD34+ cells. Therefore, combination of SFK, MEK, and NF-kappaB inhibitors may offer a new therapeutic approach to overcome TKI resistance in CML patients. PMID- 29485709 TI - HIV risks and needs related to the Sustainable Development Goals among female sex workers who were commercially sexually exploited as children in Lesotho. AB - INTRODUCTION: Sustainable Development Goals (SDGs) about gender equality; decent work; and peace, justice, and strong institutions include a focus on eradicating trafficking and sexual exploitation of and violence against women and children. In Lesotho, 86% of women have experienced gender-based violence. In addition, overall HIV prevalence is among the highest globally, and higher among adolescent girls than boys. Moreover, nearly three quarters of female sex workers (FSW) are estimated to be living with HIV in Lesotho. In this context, sexually exploited children may be particularly vulnerable to violence and HIV acquisition risks. This study's objective is to examine the prevalence and correlates of experiencing sexual exploitation as a child among FSW in Lesotho. METHODS: FSW (>=18 years) recruited through respondent-driven sampling in Maseru and Maputsoe from February to September 2014 completed HIV and syphilis testing and an interviewer-administered survey, including a question about the age at which they started providing sex for money. This study examined correlates of experiencing sexual exploitation as a child (<18 years) through multivariable logistic regression analyses for each city, controlling for current age. RESULTS: Across both cities, 20.0% (142/710) of participants were sexually exploited as children. Among them, 65.5% (93/142) tested positive for HIV and 31.0% (44/142) for syphilis, which was similar to those who started selling sex as adults, after adjusting for current age. Participants who experienced child sexual exploitation were more likely to have been forced to have sex before age 18 than those who started selling sex as adults (Maseru-adjusted odds ratio (aOR): 3.52, 95% Confidence Interval (CI): 1.61 to 7.66, p = 0.002; Maputsoe-aOR: 4.39, 95% CI: 1.22 to 15.75, p = 0.023). In Maseru, participants who were sexually exploited as children were more likely to avoid carrying condoms to prevent trouble with police (aOR: 3.18, 95% CI: 1.50 to 6.75, p = 0.003). CONCLUSIONS: Risk determinants for HIV and violence among sexually exploited children can be studied retrospectively through research with adult FSW. Further research working directly with sexually exploited children will improve understanding of their needs. Preventing commercial sexual exploitation of children and addressing the social and healthcare needs of those who are exploited are necessary to fully achieve SDGs 5, 8 and 16 and an AIDS-Free Generation. PMID- 29485710 TI - The ramifications of recent health policy actions for cardiovascular care of women: Progress, threats, and opportunities. AB - Women's health and well-being are shaped by a combination of healthcare policies that impact the type of health insurance coverage they benefit from, as well as access to preventive, screening, and treatment services. Furthermore, more distal policies, such as those that pertain to housing, education, and employment, as well as social determinants of health, such as issues of socioeconomic status and women's status in society, also impact their cardiac health. Before the passage of the Affordable Care Act in 2010, women were at greater risk of facing barriers to coverage, reflecting gender rating and the higher likelihood of the existence of preexisting health conditions such as a previous pregnancy. The ACA made substantial progress in responding to women's health needs by expanding the numbers of low-income groups eligible for Medicaid (for the 32 states and Washington, DC that expanded the program) and other subsidized healthcare, as well as access to preventive health services. Although health reform efforts to eliminate the ACA failed in 2016, the administration and Congress are using a variety of channels, including the new Tax Cuts and Job Act, to implement policies such as the elimination of the individual insurance mandate, as well as the elimination of premium subsidies, that will likely impact women differentially, potentially undoing the progress that has been achieved over the past decade. PMID- 29485711 TI - Trends in liver transplantation for hepatitis C in a country with reduced access to direct-acting antiviral agents. AB - BACKGROUND: Hepatitis C virus (HCV)-related cirrhosis is a leading indication for liver transplantation (LT) worldwide. Access to effective HCV treatment is inequitable globally. We aimed to analyze whether the introduction of effective HCV treatment caused an impact in LT trends in a middle-income country. METHODS: Cross-sectional analysis of all adult patients who were listed/received a LT in Argentina for HCV, alcohol-related liver disease (ALD), or autoimmune hepatitis/primary biliary cirrhosis (AIH/PBC) from 2007 to 2017. Joinpoint regression analysis was used to identify changes in the cumulative incidence rates in waiting list (WL) registration, WL mortality, and LT. RESULTS: Liver transplantation WL for HCV increased significantly between 2007 and 2014, with an annual percentage change (APC) +7.8%, P = .01, followed by a downward slope from 2014 to 2017 with an APC -9.8%, P = .1. There were no significant changes in WL mortality. LT trends remained stable. LT for HCV without MELD exception points for HCC decreased (APC -6.6%, P = .01), whereas LT for HCV with HCC exception points increased (APC +11.1, P = .01) during the study period. CONCLUSION: Waiting list and LT for HCV without HCC decreased, whereas LT for HCV and HCC increased; this may be related to selective antiviral treatment access for patients with advanced fibrosis. PMID- 29485713 TI - Active site alanine preceding catalytic cysteine determines unique substrate specificity in bacterial CoA-acylating prenal dehydrogenase. AB - In detoxification and fermentation processes, acylating dehydrogenases catalyze the reversible oxidation of aldehydes to their corresponding acyl-CoA esters. Here, we characterize an enzyme from Aquincola tertiaricarbonis L108 responsible for prenal (3-methyl-2-butenal) to 3-methylcrotonyl-CoA oxidation. Enzyme kinetics demonstrate a preference for C5 substrates not yet observed in aldehyde dehydrogenases. Compared to acetaldehyde and acetyl-CoA, conversion of valeraldehyde and valeryl-CoA is > 100- and 8-fold more efficient, respectively. Enzyme variants with A254I, A254P, and A254G mutations indicate that active site Ala preceding the catalytic C255 is crucial for this unique specificity. These results shed new light on evolutionary adaptation of aldehyde dehydrogenases toward xenobiotics and structure-guided design of highly specific enzymes for production of biofuels, such as linear or iso-branched butanols and pentanols. PMID- 29485712 TI - Antinociceptive effect of two novel transient receptor potential melastatin 8 antagonists in acute and chronic pain models in rat. AB - BACKGROUND AND PURPOSE: Transient receptor potential (TRP) channels are a superfamily of non-selective cation permeable channels involved in peripheral sensory signalling. Animal studies have shown that several TRPs are important players in pain modulation. Among them, the TRP melastatin 8 (TRPM8) has elicited more interest for its controversial role in nociception. This channel, expressed by a subpopulation of sensory neurons in dorsal root ganglia (DRG) and trigeminal ganglia (TG), is activated by cold temperatures and cooling agents. In experimental neuropathic pain models, an up-regulation of this receptor in DRG and TG has been observed, suggesting a key role for TRPM8 in the development and maintenance of pain. Consistent with this hypothesis, TRPM8 knockout mice are less responsive to pain stimuli. EXPERIMENTAL APPROACH: In this study, the therapeutic potential and efficacy of two novel TRPM8 antagonists, DFL23693 and DFL23448, were tested. KEY RESULTS: Two potent and selective TRPM8 antagonists with distinct pharmacokinetic profiles, DFL23693 and DFL23448, have been fully characterized in vitro. In vivo studies in well-established models, namely, the wet-dog shaking test and changes in body temperature, confirmed their ability to block the TRPM8 channel. Finally, TRPM8 blockage resulted in a significant antinociceptive effect in formalin-induced orofacial pain and in chronic constriction injury-induced neuropathic pain, confirming an important role for this channel in pain perception. CONCLUSION AND IMPLICATIONS: Our findings, in agreement with previous literature, encourage further studies for a better comprehension of the therapeutic potential of TRPM8 blockers as novel agents for pain management. PMID- 29485715 TI - Case law update. PMID- 29485716 TI - Self-Sorting of Metal-Organic Polymeric Assemblies in Gels: Selective Templation and Catalysis of Homodimers. AB - The development of generic strategy is essential for the construction of higher order supramolecular assemblies from the mixture of molecular components. Such higher order aggregations are possible through a self-sorting phenomenon, which is not well-explored in gel materials. Here, first examples of self-sorting in the coordination polymer (CP) based gels have been explored using three and four component systems. The self-sorting phenomenon has been monitored through a [2+2] photochemical reaction in the gel state and characterized by 1 H NMR, diffuse reflectance spectroscopy (DRS) and single crystal XRD analyses. Furthermore, AgI was shown to act as a supramolecular catalyst for the [2+2] photochemical reaction in gels. PMID- 29485714 TI - The effectiveness and cost-effectiveness of community-based support for adolescents receiving antiretroviral treatment: an operational research study in South Africa. AB - INTRODUCTION: Adolescents and youth receiving antiretroviral treatment (ART) in sub-Saharan Africa have high attrition and inadequate ART outcomes, and evaluations of interventions improving ART outcomes amongst adolescents are very limited. Sustainable Development Goal (SDG) target 3c is to substantially increase the health workforce in developing countries. We measured the effectiveness and cost-effectiveness of community-based support (CBS) provided by lay health workers for adolescents and youth receiving ART in South Africa. METHODS: A retrospective cohort study including adolescents and youth who initiated ART at 47 facilities. Previously unemployed CBS-workers provided home based ART-related education, psychosocial support, symptom screening for opportunistic infections and support to access government grants. Outcomes were compared between participants who received CBS plus standard clinic-based care versus participants who received standard care only. Cumulative incidences of all cause mortality and loss to follow-up (LTFU), adherence measured using medication possession ratios (MPRs), CD4 count slope, and virological suppression were analysed using multivariable Cox, competing-risks regression, generalized estimating equations and mixed-effects models over five years of ART. An expenditure approach was used to determine the incremental cost of CBS to usual care from a provider perspective. Incremental cost-effectiveness ratios were calculated as annual cost per patient-loss (through death or LTFU) averted. RESULTS: Amongst 6706 participants included, 2100 (31.3%) received CBS. Participants who received CBS had reduced mortality, adjusted hazard ratio (aHR) = 0.52 (95% CI: 0.37 to 0.73; p < 0.0001). Cumulative LTFU was 40% lower amongst participants receiving CBS (29.9%) compared to participants without CBS (38.9%), aHR = 0.60 (95% CI: 0.51 to 0.71); p < 0.0001). The effectiveness of CBS in reducing attrition ranged from 42.2% after one year to 35.9% after five years. Virological suppression was similar after three years, but after five years 18.8% CBS participants versus 37.2% non-CBS participants failed to achieve viral suppression, adjusted odds ratio = 0.24 (95% CI: 0.06 to 1.03). There were no significant differences in MPR or CD4 slope. The cost of CBS was US$49.5/patient/year. The incremental cost per patient-loss averted was US$600 and US$776 after one and two years, respectively. CONCLUSIONS: CBS for adolescents and youth receiving ART was associated with substantially reduced patient attrition, and is a low-cost intervention with reasonable cost effectiveness that can aid progress towards several health, economic and equality related SDG targets. PMID- 29485717 TI - Setting the top 10 research priorities to improve the health of people with Type 2 diabetes: a Diabetes UK-James Lind Alliance Priority Setting Partnership. AB - AIMS: To describe processes and outcomes of a priority setting partnership to identify the 'top 10 research priorities' in Type 2 diabetes, involving people living with the condition, their carers, and healthcare professionals. METHODS: We followed the four-step James Lind Alliance Priority Setting Partnership process which involved: gathering uncertainties using a questionnaire survey distributed to 70 000 people living with Type 2 diabetes and their carers, and healthcare professionals; organizing the uncertainties; interim priority setting by resampling of participants with a second survey; and final priority setting in an independent group of participants, using the nominal group technique. At each step the steering group closely monitored and guided the process. RESULTS: In the first survey, 8227 uncertainties were proposed by 2587 participants, of whom 18% were from black, Asian and minority ethnic groups. Uncertainties were formatted and collated into 114 indicative questions. A total of 1506 people contributed to a second survey, generating a shortlist of 24 questions equally weighted to the contributions of people living with diabetes and their carers and those of healthcare professionals. In the final step the 'top 10 research priorities' were selected, including questions on cure and reversal, risk identification and prevention, and self-management approaches in Type 2 diabetes. CONCLUSION: Systematic and transparent methodology was used to identify research priorities in a large and genuine partnership of people with lived and professional experience of Type 2 diabetes. The top 10 questions represent consensus areas of research priority to guide future research, deliver responsive and strategic allocation of research resources, and improve the future health and well-being of people living with, and at risk of, Type 2 diabetes. PMID- 29485718 TI - Punishment and the potential for negative reinforcement with histamine injection. AB - The present study examined punishment of responding with histamine injection, and its potential to generate avoidance of punishment. Sprague-Dawley rats were trained under concurrent schedules in which responses on one lever (the punishment lever) produced food under a variable-interval schedule, and under some conditions intermittent injections of histamine, which suppressed behavior. Responses on a second (avoidance) lever prevented histamine injections scheduled on the punishment lever. After stabilization of punished responding, a variable interval 15-s schedule of cancellation of histamine (avoidance) was added for responding on the second/avoidance lever, without subsequent acquisition of responding on that lever. Progressive decreases in the length of the punishment variable-interval schedule increased suppression on the punishment lever without increases in response rates on the avoidance lever. Exchanging contingencies on the levers ensured that response rates on the avoidance lever were sufficiently high to decrease the histamine injection frequency; nonetheless response rates on the avoidance lever decreased over subsequent sessions. Under no condition was responding maintained on the avoidance lever despite continued punishing effectiveness of histamine throughout. The present results suggest that avoidance conditioning is not a necessary condition for effective punishment, and confirm the importance of empirical rather than presumed categorization of behavioral effects of stimulus events. PMID- 29485719 TI - Women as leaders in cardiovascular medicine. AB - Cardiology remains a specialty that is dominated by men. Even though half of all medical students and over 40% of internal medicine residents are women, the number of women in the field of cardiology remains low. The reasons for the persistent lack of increase in cardiology trainees are not well understood and are likely multifactorial. Despite this under-representation, women cardiologists are increasingly visible in leadership roles, including those in research science, health systems administration, professional societies, and clinical practice. This review will highlight the various leadership roles and paths taken on by prominent women in the practice of cardiovascular medicine. PMID- 29485720 TI - Placenta accreta spectrum: a need for more research on its aetiopathogenesis. PMID- 29485721 TI - Elevated RTP801 promotes cell proliferation in non-small cell lung cancer. AB - Lung cancer, particularly non-small cell lung cancer (NSCLC), is one of main causes of mortality in cancer patients worldwide. It is necessary to seek effective biomarkers to improve diagnostic and therapeutic efficacies in human NSCLC. RTP801 is a stress-response protein that can be induced by many types of cellular stress such as hypoxia and DNA damage, produces different biological effects depending on cell type and context. Up to now, there is no direct evidence showing the expression and involvement of RTP801 in human NSCLC. Here, we found that the expression of RTP801 significantly increased in NSCLC tissues compared with that in normal lung and the level of RTP801 in peripheral blood of NSCLC patients was higher than that of healthy persons. Further study showed that knockdown of RTP801 induced by lentivirus encoded RTP801-shRNA markedly inhibited the proliferation of A549 and SW900 cells. Moreover, the inhibitor of PI3K significantly decreased the expression of RTP801 mRNA and protein and, at the same time, inhibited the proliferation of A549 and SW900 cells. Taken together, our study provides the novel and direct evidence that there is a close relationship between RTP801 and human NSCLC, and RTP801 can promote the proliferation of NSCLC cells which is regulated by PI3K signaling pathway, suggesting that RTP801 could be a potential biomarker for diagnosis and therapeutic target of human NSCLC. (c) 2018 IUBMB Life, 70(4):310-319, 2018. PMID- 29485722 TI - In vitro assessment of the effect of acidemia on coagulation in dogs. AB - OBJECTIVE: Minimal data are available assessing the effect of acidemia on coagulation in dogs. The objective of this study was to assess the effect of in vitro acidification of canine blood on coagulation as measured via thromboelastography (TEG) and traditional tests of coagulation. We hypothesized that worsening acidemia would lead to progressive impairment on coagulation. DESIGN: Prospective study. SETTING: University teaching hospital. ANIMALS: Six client-owned dogs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Blood was collected into 3.2% sodium citrate vacutainer tubes. The pH of blood was adjusted from baseline using hydrochloric acid to create weak acidemia and strong acidemia. Coagulation was assessed using TEG, prothrombin time, and activated partial thromboplastin time. Kruskal-Wallis tests with Dunn's post hoc comparison tests were used to compare groups. Strong acidemia samples were significantly more acidic than baseline based on pH (P < 0.0005), HCO3- (P < 0.0062), pCO2 (P < 0.0001), and base excess (P < 0.0001). Using TEG, in vitro acidification of blood caused significant, progressive impairment of maximum amplitude (P = 0.0282) and alpha angle (P = 0.0312). Acidification of blood had no significant effect on prothrombin time (P = 0.345) or activated partial thromboplastin time (P = 0.944). CONCLUSIONS: In vitro acidification of canine whole blood results in hypocoagulability as measured by some TEG variables. PMID- 29485723 TI - Temporal and external validation of a prediction model for adverse outcomes among inpatients with diabetes. AB - AIM: To temporally and externally validate our previously developed prediction model, which used data from University Hospitals Birmingham to identify inpatients with diabetes at high risk of adverse outcome (mortality or excessive length of stay), in order to demonstrate its applicability to other hospital populations within the UK. METHODS: Temporal validation was performed using data from University Hospitals Birmingham and external validation was performed using data from both the Heart of England NHS Foundation Trust and Ipswich Hospital. All adult inpatients with diabetes were included. Variables included in the model were age, gender, ethnicity, admission type, intensive therapy unit admission, insulin therapy, albumin, sodium, potassium, haemoglobin, C-reactive protein, estimated GFR and neutrophil count. Adverse outcome was defined as excessive length of stay or death. RESULTS: Model discrimination in the temporal and external validation datasets was good. In temporal validation using data from University Hospitals Birmingham, the area under the curve was 0.797 (95% CI 0.785 0.810), sensitivity was 70% (95% CI 67-72) and specificity was 75% (95% CI 74 76). In external validation using data from Heart of England NHS Foundation Trust, the area under the curve was 0.758 (95% CI 0.747-0.768), sensitivity was 73% (95% CI 71-74) and specificity was 66% (95% CI 65-67). In external validation using data from Ipswich, the area under the curve was 0.736 (95% CI 0.711-0.761), sensitivity was 63% (95% CI 59-68) and specificity was 69% (95% CI 67-72). These results were similar to those for the internally validated model derived from University Hospitals Birmingham. CONCLUSIONS: The prediction model to identify patients with diabetes at high risk of developing an adverse event while in hospital performed well in temporal and external validation. The externally validated prediction model is a novel tool that can be used to improve care pathways for inpatients with diabetes. Further research to assess clinical utility is needed. PMID- 29485724 TI - Inequality in outcomes for adolescents living with perinatally acquired HIV in sub-Saharan Africa: a Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) Cohort Collaboration analysis. AB - INTRODUCTION: Eighty percent of adolescents living with perinatally and behaviourally acquired HIV live in sub-Saharan Africa (SSA), a continent with marked economic inequality. As part of our global project describing adolescents living with perinatally acquired HIV (APH), we aimed to assess whether inequality in outcomes exists by country income group (CIG) for APH within SSA. METHODS: Through the CIPHER cohort collaboration, individual retrospective data from 7 networks and 25 countries in SSA were included. APH were included if they entered care at age <10 years (as a proxy for perinatally acquired HIV) and had follow-up at age >10 years. World Bank CIG classification for median year of first visit was used. Cumulative incidence of mortality, transfer-out and loss-to-follow-up was calculated by competing risks analysis. Mortality was compared across CIG by Cox proportional hazards models. RESULTS: A total of 30,296 APH were included; 50.9% were female and 75.7% were resident in low-income countries (LIC). Median [interquartile range (IQR)] age at antiretroviral therapy (ART) start was 8.1 [6.3; 9.5], 7.8 [6.2; 9.3] and 7.3 [5.2; 8.9] years in LIC, lower-middle income countries (LMIC) and upper-middle income countries (UMIC) respectively. Median age at last follow-up was 12.1 [10.9; 13.8] years, with no difference between CIG. Cumulative incidence (95% CI) for mortality between age 10 and 15 years was lowest in UMIC (1.1% (0.8; 1.4)) compared to LIC (3.5% (3.1; 3.8)) and LMIC (3.9% (2.7; 5.4)). Loss-to-follow-up was highest in UMIC (14.0% (12.9; 15.3)) compared to LIC (13.1% (12.4; 13.8)) and LMIC (8.3% (6.3; 10.6)). Adjusted mortality hazard ratios (95% CI) for APH in LIC and LMIC in reference to UMIC were 2.50 (1.85; 3.37) and 2.96 (1.90; 4.61) respectively, with little difference when restricted only to APH who ever received ART. In adjusted analyses mortality was similar for male and female APH. CONCLUSIONS: Results highlight probable inequality in mortality according to CIG in SSA even when ART was received. These findings highlight that without attention towards SDG 10 (to reduce inequality within and among countries), progress towards ensuring healthy lives and promoting wellbeing for all at all ages (SDG 3) will be hampered for APH in LIC and LMIC. PMID- 29485725 TI - Climate change accelerates local disease extinction rates in a long-term wild host-pathogen association. AB - Pathogens are a significant component of all plant communities. In recent years, the potential for existing and emerging pathogens of agricultural crops to cause increased yield losses as a consequence of changing climatic patterns has raised considerable concern. In contrast, the response of naturally occurring, endemic pathogens to a warming climate has received little attention. Here, we report on the impact of a signature variable of global climate change - increasing temperature - on the long-term epidemiology of a natural host-pathogen association involving the rust pathogen Triphragmium ulmariae and its host plant Filipendula ulmaria. In a host-pathogen metapopulation involving approximately 230 host populations growing on an archipelago of islands in the Gulf of Bothnia we assessed changes in host population size and pathogen epidemiological measures over a 25-year period. We show how the incidence of disease and its severity declines over that period and most importantly demonstrate a positive association between a long-term trend of increasing extinction rates in individual pathogen populations of the metapopulation and increasing temperature. Our results are highly suggestive that changing climatic patterns, particularly mean monthly growing season (April-November) temperature, are markedly influencing the epidemiology of plant disease in this host-pathogen association. Given the important role plant pathogens have in shaping the structure of communities, changes in the epidemiology of pathogens have potentially far-reaching impacts on ecological and evolutionary processes. For these reasons, it is essential to increase understanding of pathogen epidemiology, its response to warming, and to invoke these responses in forecasts for the future. PMID- 29485726 TI - Supine positioning for the subscapular system of flaps: A pictorial essay. AB - BACKGROUND: This pictorial essay demonstrates a modification to the positioning, prepping, and draping technique for the subscapular system of flaps allowing the patient to be placed supine and without the need for a second assistant during the harvest or closure. METHODS AND RESULTS: We performed a literature review focusing on the positioning of the patient during the harvest of the subscapular system of flaps. A supine modification harvest prepping, draping, and position is then described in pictorial essay format. The technique is made possible with the use of a Mayo stand to position the arm. DISCUSSION: A literature review demonstrates limited description of nonlateral decubitus position harvest of the scapular flap. A novel positioning technique is described in pictorial essay format to demonstrate the ease and feasibility without the need for a second assistant during the case, an important goal in the era of limited resident duty hours. PMID- 29485727 TI - Shortening the decade-long gap between adult and paediatric drug formulations: a new framework based on the HIV experience in low- and middle-income countries. AB - INTRODUCTION: Despite the coordinated efforts by several stakeholders to speed up access to HIV treatment for children, development of optimal paediatric formulations still lags 8 to 10 years behind that of adults, due mainly to lack of market incentives and technical complexities in manufacturing. The small and fragmented paediatric market also hinders launch and uptake of new formulations. Moreover, the problems affecting HIV similarly affect other disease areas where development and introduction of optimal paediatric formulations is even slower. Therefore, accelerating processes for developing and commercializing optimal paediatric drug formulations for HIV and other disease areas is urgently needed. DISCUSSION: The Global Accelerator for Paediatric Formulations (GAP-f) is an innovative collaborative model that will accelerate availability of optimized treatment options for infectious diseases, such as HIV, tuberculosis and viral hepatitis, affecting children in low- and middle-income countries (LMICs). It builds on the HIV experience and existing efforts in paediatric drug development, formalizing collaboration between normative bodies, research networks, regulatory agencies, industry, supply and procurement organizations and funding bodies. Upstream, the GAP-f will coordinate technical support to companies to design and study optimal paediatric formulations, harmonize efforts with regulators and incentivize manufacturers to conduct formulation development. Downstream, the GAP f will reinforce coordinated procurement and communication with suppliers. The GAP-f will be implemented in a three-stage process: (1) development of a strategic framework and promotion of key regulatory efficiencies; (2) testing of feasibility and results, building on the work of existing platforms such as the Paediatric HIV Treatment Initiative (PHTI) including innovative approaches to incentivize generic development and (3) launch as a fully functioning structure. CONCLUSIONS: GAP-f is a key partnership example enhancing North-South and international cooperation on and access to science and technology and capacity building, responding to Sustainable Development Goal (SDG) 17.6 (technology) and 17.9. (capacity-building). By promoting access to the most needed paediatric formulations for HIV and high-burden infectious diseases in low-and middle-income countries, GAP-f will support achievement of SDG 3.2 (infant mortality), 3.3 (end of AIDS and combat other communicable diseases) and 3.8 (access to essential medicines), and be an essential component of meeting the global Start Free, Stay Free, AIDS Free super-fast-track targets. PMID- 29485728 TI - Children, HIV, emergencies and Sustainable Development Goals: roadblocks ahead and possible solutions. PMID- 29485729 TI - EARLY REGULATION IN CHILDREN WHO ARE LATER DIAGNOSED WITH AUTISM SPECTRUM DISORDER. A LONGITUDINAL STUDY WITHIN THE DANISH NATIONAL BIRTH COHORT. AB - Studies have shown that children later diagnosed with autism spectrum disorders (ASD) in their first years of life might show symptoms in main developmental areas and that these signs might be sensed by the parents. The present study investigated in a large birth cohort if children later diagnosed with ASD had deviations at 6 and 18 months in areas such as the ability to self-regulate emotions, feeding, and sleeping. The study was based on prospective information collected from 76,322 mothers who participated in the Danish National Birth Cohort. When the children reached an average age of 11 years, 973 children with ASD and a control group of 300 children with intellectual disability (IDnoASD) were identified via Danish health registries. Associations were found between short periods of breast-feeding and the children later diagnosed with ASD and IDnoASD as well as associations at 18 months to deviations in regulation of emotions and activity. The similarities in these associations emphasize how difficult it is to distinguish between diagnoses early in life. PMID- 29485731 TI - Systematic review and meta-analysis of single-dose and non-single-dose methotrexate protocols in the treatment of ectopic pregnancy. AB - BACKGROUND: It remains unclear which methotrexate protocol for the treatment of ectopic pregnancy has a higher success rate or a higher adverse effect rate. OBJECTIVE: To compare the treatment success rates and adverse effect rates of single-dose and non-single-dose (two-dose and multi-dose) methotrexate protocols in the treatment of ectopic pregnancy. SEARCH STRATEGY: Various databases including Medline, Embase, and the Cochrane Central Register of Controlled Trials were searched on July 1, 2017, using search terms including "methotrexate" and "pregnancy." SELECTION CRITERIA: Randomized controlled trials comparing different methotrexate protocols for the treatment of ectopic pregnancy were included. DATA COLLECTION AND ANALYSIS: Relative risks (RRs) and 95% confidence intervals (CIs) were calculated to compare treatment success rates and adverse effect rates. MAIN RESULTS: The single-dose and non-single-dose protocols had similar success rates (RR 1.00, 95% CI 0.96-1.04; 11 trials, 1121 patients, I2 =18%). The non-single dose protocols had a higher adverse effect rate than did the single-dose protocol (RR 0.73, 95% CI 0.59-0.91; nine trials, 934 patients, I2 =0%). CONCLUSIONS: The single-dose methotrexate protocol was the optimal protocol for the medical treatment of ectopic pregnancy. PMID- 29485732 TI - Warming weakens facilitative interactions between decomposers and detritivores, and modifies freshwater ecosystem functioning. AB - Warming is among the major drivers of changes in biotic interactions and, in turn, ecosystem functioning. The decomposition process occurs in a chain of facilitative interactions between detritivores and microorganisms. It remains unclear, however, what effect warming may have on the interrelations between detritivores and microorganisms, and the consequences for the functioning of natural freshwater ecosystems. To address these gaps, we performed a field experiment using tank bromeliads and their associated aquatic fauna. We manipulated the presence of bacteria and detritivorous macroinvertebrates (control, "bacteria," and "bacteria + macroinvertebrates") under ambient and warming scenarios, and analyzed the effects on the microorganisms and ecosystem functioning (detritus mass loss, colored dissolved organic matter, and nitrogen flux). We applied antibiotic solution to eliminate or reduce bacteria from control bromeliads. After 60 days incubation, bacterial density was higher in the presence than in the absence of macroinvertebrates. In the absence of macroinvertebrates, temperature did not influence bacterial density. However, in the presence of macroinvertebrates, bacterial density decreased by 54% with warming. The magnitude of the effects of organisms on ecosystem functioning was higher in the combined presence of bacteria and macroinvertebrates. However, warming reduced the overall positive effects of detritivores on bacterial density, which in turn, cascaded down to ecosystem functioning by decreasing decomposition and nitrogen flux. These results show the existence of facilitative mechanisms between bacteria and detritivores in the decomposition process, which might collapse due to warming. Detritivores seem to contribute to nutrient cycling as they facilitate bacterial populations, probably by increasing nutrient input (feces) in the ecosystem. However, increased temperature mitigated these beneficial effects. Our results add to a growing research body that shows that warming can affect the structure of aquatic communities, and highlight the importance of considering the interactive effects between facilitation and climatic drivers on the functioning of freshwater ecosystems. PMID- 29485730 TI - Biologically active quinoline and quinazoline alkaloids part II. AB - To follow-up on our prior Part I review, this Part II review summarizes and provides updated literature on novel quinoline and quinazoline alkaloids isolated during the period of 2009-2016, together with the biological activity and the mechanisms of action of these classes of natural products. Over 200 molecules with a broad range of biological activities, including antitumor, antiparasitic and insecticidal, antibacterial and antifungal, cardioprotective, antiviral, anti inflammatory, hepatoprotective, antioxidant, anti-asthma, antitussive, and other activities, are discussed. This survey should provide new clues or possibilities for the discovery of new and better drugs from the original naturally occurring quinoline and quinazoline alkaloids. PMID- 29485733 TI - Globular adiponectin acts as a melanogenic signal in human epidermal melanocytes. AB - BACKGROUND: Adiponectin is an adipocyte-derived cytokine that circulates as a full-length protein and a fragment containing the globular domain of adiponectin (gAd). A recent study has reported the antimelanogenic effects of full-length adiponectin. OBJECTIVES: To examine the involvement of gAd in melanogenesis and its mechanisms of action. METHODS: The effects of gAd on melanogenesis and its mechanisms of action were investigated in human epidermal melanocytes and reconstructed epidermis, including melanin content, cellular tyrosinase activity, cyclic adenosine monophosphate (cAMP) production and protein kinase A (PKA) activity, expression and phosphorylation of signalling molecules. RESULTS: Exogenous gAd increased melanin content, and the mRNA levels of microphthalmia associated transcription factor (MITF) and its downstream genes TRP1, but not TRP2, were increased by gAd. However, cAMP production and PKA activity were not affected by gAd. Moreover, attempts to elucidate the underlying mechanism behind the gAd-mediated effect revealed that gAd could regulate melanogenesis by upregulating MITF through phosphorylation of the cAMP response element-binding protein (CREB). In addition, upregulation of MITF was mediated by activation of adenosine monophosphate-activated protein kinase (AMPK)-p38 mitogen-activated protein kinase (MAPK) signalling. Taken together, these findings indicate that promotion of melanogenesis by gAd occurs through increased expression of MITF, which is mediated by activation of the AMPK-p38 MAPK-CREB pathway. CONCLUSIONS: These findings suggest that gAd contributes to epidermal homeostasis via its effect on melanocyte biology, and products of adipose tissue could affect epidermal biology. PMID- 29485735 TI - Equity of child and adolescent treatment, continuity of care and mortality, according to age and gender among enrollees in a large HIV programme in Tanzania. AB - INTRODUCTION: Global scale up of anti-retroviral therapy (ART) has led to expansion of HIV treatment and prevention across sub-Saharan Africa. However, age and gender-specific disparities persist leading to failures in fulfillment of Sustainability Development Goals, including SDG3 (achieving healthy lives and wellbeing for all, at all ages) and SDG5 (gender equality). We assessed ART initiation and adherence, loss to follow-up, all-cause death and early death, according to SDG3 and SDG5 indicators among a cohort of HIV-infected children and adolescents enrolled in care in Dar-es-Salaam, Tanzania METHODS: SDG3 indicators included young (<5 years) and older paediatric children (5 to <10 years), early adolescent (10 to <15 years) and late adolescent (15 to <20 years) age group divisions and the SDG5 indicator was gender. Associations of age group and gender with ART initiation, loss to follow-up and all-cause death, were analysed using Cox proportional hazards regression and with adherence, using generalized estimating equations (GEE) with the Poisson distribution. Associations of age group and gender with early death were analysed, using log-Poisson regression with empirical variance. RESULTS: A total of 18,315 enrollees with at least one clinic visit were included in this cohort study. Of these 7238 (40%) were young paediatric , 4169 (23%) older paediatric, 2922 (16%) early adolescent and 3986 (22%) late adolescent patients at enrolment. Just over half of paediatric and early adolescents and around four fifths of the late adolescents were female. Young paediatric patients were at greater risk of early death, being almost twice as likely to die within 90 days. Males were at greater risk of early death once initiated on ART (HR 1.35, 95% CI 1.09, 1.66)), while females in late adolescence were at greatest risk of late death (HR 2.44 [1.60, 3.74] <0.01). Late adolescents demonstrated greater non-engagement in care (RR 1.21 (95% CI 1.16, 1.26)). Among both males and females, early paediatric and late adolescent groups experienced significantly greater loss to follow-up. CONCLUSION: These findings highlight equity concerns critical to the fulfillment of SDG3 and SDG5 within services for children and adolescents living with HIV in sub-Saharan Africa. Young paediatric and late adolescent age groups were at increased risk of late diagnosis, early death, delayed treatment initiation and loss of continuity of care. Males were more likely to die earlier. Special attention to SDG3 and SDG5 disparities for children and adolescents living with HIV will be critical for fulfillment of the 2030 SDG agenda. PMID- 29485734 TI - T-cell egress from the thymus: Should I stay or should I go? AB - T-cells bearing the alphabetaTCR play a vital role in defending the host against foreign pathogens and malignant transformation of self. Importantly, T-cells are required to remain tolerant to the host's own cells and tissues in order to prevent self-reactive responses that can lead to autoimmune disease. T-cells achieve the capacity for self/nonself discrimination by undergoing a highly selective and rigorous developmental program during their maturation in the thymus. This organ is unique in its ability to support a program of T-cell development that ensures the establishment of a functionally diverse alphabetaTCR repertoire within the peripheral T-cell pool. The thymus achieves this by virtue of specialized stromal microenvironments that contain heterogeneous cell types, whose organization and function underpins their ability to educate, support, and screen different thymocyte subsets through various stages of development. These stages range from the entry of early T-cell progenitors into the thymus, through to the positive and negative selection of the alphabetaTCR repertoire. The importance of the thymus medulla as a site for T-cell tolerance and the exit of newly generated T-cells into the periphery is well established. In this review, we summarize current knowledge on the developmental pathways that take place during alphabetaT-cell development in the thymus. In addition, we focus on the mechanisms that regulate thymic egress and contribute to the seeding of peripheral tissues with newly selected self-tolerant alphabetaT-cells. PMID- 29485736 TI - A Cytidine Phosphoramidite with Protected Nitroxide Spin Label: Synthesis of a Full-Length TAR RNA and Investigation by In-Line Probing and EPR Spectroscopy. AB - EPR studies on RNA are complicated by three major obstacles related to the chemical nature of nitroxide spin labels: Decomposition while oligonucleotides are chemically synthesized, further decay during enzymatic strand ligation, and undetected changes in conformational equilibria due to the steric demand of the label. Herein possible solutions for all three problems are presented: A 2 nitrobenzyloxymethyl protective group for nitroxides that is stable under all conditions of chemical RNA synthesis and can be removed photochemically. By careful selection of ligation sites and splint oligonucleotides, high yields were achieved in the assembly of a full-length HIV-1 TAR RNA labeled with two protected nitroxide groups. PELDOR measurements on spin-labeled TAR in the absence and presence of arginine amide indicated arrest of interhelical motions on ligand binding. Finally, even minor changes in conformation due to the presence of spin labels are detected with high sensitivity by in-line probing. PMID- 29485737 TI - Hypertension in pregnancy: Taking cues from pathophysiology for clinical practice. AB - Pregnancy-related hypertension (PHTN) syndromes are a frequent and potentially deadly complication of pregnancy, while also negatively impacting the lifelong health of the mother and child. PHTN appears in women likely to develop hypertension later in life, with the stress of pregnancy unmasking a subclinical hypertensive phenotype. However, distinguishing between PHTN and chronic hypertension is essential for optimal management. Preeclampsia (PE) is linked to potentially severe outcomes and lacks effective treatments due to poorly understood mechanisms. Inadequate remodeling of spiral uterine arteries (SUAs), the cornerstone of PE pathophysiology, leads to hypoperfusion of the developing placenta. In normal pregnancies, extravillous trophoblast (EVT) cells assume an invasive phenotype and invade SUAs, transforming them into large conduits. Decidual natural killer cells play an essential role, mediating materno-fetal immune tolerance, inducing early SUA remodeling and regulating EVT invasiveness. Notch signaling is important in EVT phenotypic switch and is dysregulated in PE. The hypoxic placenta releases antiangiogenic and proinflammatory factors that converge upon maternal endothelium, inducing endothelial dysfunction, hypertension, and organ damage. Hypoxia-inducible factor 1-alpha is upstream of such molecules, whereas endothelin-1 is a major effector. We also describe important genetic links and evidence of incomplete materno-fetal immune tolerance, with PE patients presenting with autoantibodies, lower Treg , and higher Th 17 cells. Thus, PE manifestations arise as a consequence of mal placentation or/and because of a predisposition of the maternal vascular bed to excessively react to pathogenic molecules. From this pathophysiological basis, we provide current and propose future therapeutic directions for PE. PMID- 29485738 TI - Curcumin suppressed the prostate cancer by inhibiting JNK pathways via epigenetic regulation. AB - Curcumin is a component of turmeric and is isolated from the rhizomes of the plant Curcuma longa. Curcumin was reported to have therapeutic effects on prostate cancer. Yet the molecular mechanism of curcumin remains unclear. In this study, mouse prostate cancer xenograft model was established and subjected to curcumin treatment. GST-c-Jun pull down kinase assays were performed to study the phospho-c-Jun level. Cell Counting Kit-8 assay kit was utilized to detect the cell viability. Immunoblotting and qRT-PCR were performed for target gene expression analysis. Curcumin inhibited growth of prostate cancer in vivo as well as promoted apoptosis of LNCaP cells in vitro. Curcumin inhibited JNK pathway and repressed H3K4me3 in LNCaP cells. Combined use of curcumin and JQ-1 inhibited the prostate cancer efficiently. In conclusion, curcumin inhibits JNK pathway and plays a role in epigenetic regulation of prostate cancer cells by repressing H3K4me3. PMID- 29485739 TI - Sustainable Survival for adolescents living with HIV: do SDG-aligned provisions reduce potential mortality risk? AB - INTRODUCTION: The Sustainable Development Goals (SDGs) present a groundbreaking global development agenda to protect the most vulnerable. Adolescents living with HIV in Sub-Saharan Africa continue to experience extreme health vulnerabilities, but we know little about the impacts of SDG-aligned provisions on their health. This study tests associations of provisions aligned with five SDGs with potential mortality risks. METHODS: Clinical and interview data were gathered from N = 1060 adolescents living with HIV in rural and urban South Africa in 2014 to 2015. All ART-initiated adolescents from 53 government health facilities were identified, and traced in their communities to include those defaulting and lost-to-follow up. Potential mortality risk was assessed as either: viral suppression failure (1000+ copies/ml) using patient file records, or adolescent self-report of diagnosed but untreated tuberculosis or symptomatic pulmonary tuberculosis. SDG aligned provisions were measured through adolescent interviews. Provisions aligned with SDGs 1&2 (no poverty and zero hunger) were operationalized as access to basic necessities, social protection and food security; An SDG 3-aligned provision (ensure healthy lives) was having a healthy primary caregiver; An SDG 8 aligned provision (employment for all) was employment of a household member; An SDG 16-aligned provision (protection from violence) was protection from physical, sexual or emotional abuse. Research partners included the South African national government, UNICEF and Pediatric and Adolescent Treatment for Africa. RESULTS: 20.8% of adolescents living with HIV had potential mortality risk - i.e. viral suppression failure, symptomatic untreated TB, or both. All SDG-aligned provisions were significantly associated with reduced potential mortality risk: SDG 1&2 (OR 0.599 CI 0.361 to 0.994); SDG 3 (OR 0.577 CI 0.411 to 0.808); SDG 8 (OR 0.602 CI 0.440 to 0.823) and SDG 16 (OR 0.686 CI 0.505 to 0.933). Access to multiple SDG-aligned provisions showed a strongly graded reduction in potential mortality risk: Among adolescents living with HIV, potential mortality risk was 38.5% with access to no SDG-aligned provisions, and 9.3% with access to all four. CONCLUSIONS: SDG-aligned provisions across a range of SDGs were associated with reduced potential mortality risk among adolescents living with HIV. Access to multiple provisions has the potential to substantially improve survival, suggesting the value of connecting and combining SDGs in our response to paediatric and adolescent HIV. PMID- 29485741 TI - Initiation of Term Newborn Skin-to-Skin Contact in the Operating Room Following Scheduled Cesarean Section: A DNP Capstone Project. AB - This column shares the best evidence-based strategies and innovative ideas on how to facilitate the learning and implementation of EBP principles and processes by clinicians as well as nursing and interprofessional students. Guidelines for submission are available at https://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1741-6787. PMID- 29485740 TI - Discovery of Molidustat (BAY 85-3934): A Small-Molecule Oral HIF-Prolyl Hydroxylase (HIF-PH) Inhibitor for the Treatment of Renal Anemia. AB - Small-molecule inhibitors of hypoxia-inducible factor prolyl hydroxylases (HIF PHs) are currently under clinical development as novel treatment options for chronic kidney disease (CKD) associated anemia. Inhibition of HIF-PH mimics hypoxia and leads to increased erythropoietin (EPO) expression and subsequently increased erythropoiesis. Herein we describe the discovery, synthesis, structure activity relationship (SAR), and proposed binding mode of novel 2,4-diheteroaryl 1,2-dihydro-3H-pyrazol-3-ones as orally bioavailable HIF-PH inhibitors for the treatment of anemia. High-throughput screening of our corporate compound library identified BAY-908 as a promising hit. The lead optimization program then resulted in the identification of molidustat (BAY 85-3934), a novel small molecule oral HIF-PH inhibitor. Molidustat is currently being investigated in clinical phase III trials as molidustat sodium for the treatment of anemia in patients with CKD. PMID- 29485742 TI - Universal Scaling of Intrinsic Resistivity in Two-Dimensional Metallic Borophene. AB - Two-dimensional boron sheets (borophenes) have been successfully synthesized in experiments and are expected to exhibit intriguing transport properties. A comprehensive first-principles study is reported of the intrinsic electrical resistivity of emerging borophene structures. The resistivity is highly dependent on different polymorphs and electron densities of borophene. Interestingly, a universal behavior of the intrinsic resistivity is well-described using the Bloch Gruneisen model. In contrast to graphene and conventional metals, the intrinsic resistivity of borophenes can be easily tuned by adjusting carrier densities, while the Bloch-Gruneisen temperature is nearly fixed at 100 K. This work suggests that monolayer boron can serve as intriguing platform for realizing tunable two-dimensional electronic devices. PMID- 29485743 TI - A large aggregation of self-fragmenting mushroom corals in the Arabian/Persian Gulf. PMID- 29485744 TI - Evolution or extinction? Paediatric and adolescent HIV responses in the Agenda 2030 era. PMID- 29485745 TI - Insecticide toxicity associated with detoxification enzymes and genes related to transcription of cuticular melanization among color morphs of Asian citrus psyllid. AB - The Asian citrus psyllid (Diaphorina citri Kuwayama) is known to exhibit abdominal color polymorphisms. In the current study, susceptibility to four insecticides was compared among orange/yellow, blue/green and gray/brown color morphs of field collected D. citri. The LD50 values and 95% fiducial limits were quantified for each insecticide and color morph combination and ranged between 0.10 ng/MUL (0.06-0.10) and 6.16 ng/MUL (3.30-12.50). Second, we measured the detoxification enzyme activity levels of orange/yellow, blue/green and gray/brown color morphs for cytochrome P450, glutathione S-transferase, and general esterase. The mean P450 activity (equivalent units) was significantly lower in gray/brown (0.152 +/- 0.006) and blue/green morphs (0.149 +/- 0.005) than in the orange/yellow morphs (0.179 +/- 0.008). GST activity (MUmol/min/mg protein) was significantly lower in the orange/yellow morph (299.70 +/-1.24) than gray/brown (350.86 +/- 1.19) and blue/green (412.25 +/- 1.37) morphs. The mean EST activity (MUmol/min/mg protein) was significantly higher in blue/green (416.72 +/- 5.12) and gray/brown morphs (362.19 +/- 4.69) than in the orange/yellow morphs (282.56 +/- 2.93). Additionally, we analyzed the relative expression of assortment genes involved in cuticular melanization and basal immunity. The transcripts of Dopa Decarboxylase and Tyrosine Hydroxylase were expressed higher in blue/green and gray/brown than orange/yellow morphs. The transcription results paralleled the susceptibility of D. citri to organophosphate, neonicotinoid and pyrethroid insecticides. GST and EST activity may also be correlated with low levels of insecticide susceptibility. Cuticular melanization could be a factor for the development of resistance to insecticides among different color morphs. PMID- 29485747 TI - Designing Homogeneous Bromine Redox Catalysis for Selective Aliphatic C-H Bond Functionalization. AB - The potential of homogeneous oxidation catalysis employing bromine has remained largely unexplored. We herein show that the combination of a tetraalkylammonium bromide and meta-chloroperbenzoic acid offers a unique catalyst system for the convenient and selective oxidation of saturated C(sp3 )-H bonds upon photochemical initiation with day light. This approach enables remote, intramolecular, position-selective C-H amination as demonstrated for 20 different examples. For the first time, an N-halogenated intermediate was isolated as the active catalyst state in a catalytic Hofmann-Loffler reaction. In addition, an expeditious one-pot synthesis of N-sulfonyl oxaziridines from N-sulfonamides was developed and exemplified for 15 transformations. These pioneering examples provide a change in paradigm for molecular catalysis with bromine. PMID- 29485746 TI - Conditional cash transfers and the reduction in partner violence for young women: an investigation of causal pathways using evidence from a randomized experiment in South Africa (HPTN 068). AB - INTRODUCTION: Evidence has shown that the experience of violence by a partner has important influences on women's risk of HIV acquisition. Using a randomized experiment in northeast South Africa, we found that a conditional cash transfer (CCT) targeted to poor girls in high school reduced the risk of physical intimate partner violence (IPV) in the past 12 months by 34%. The purpose of this analysis is to understand the pathways through which the CCT affects IPV. METHODS: HPTN 068 was a phase 3, randomized controlled trial in rural Mpumalanga province, South Africa. Eligible young women (aged 13-20) and their parents or guardians were randomly assigned (1:1) to either receive a monthly cash transfer conditional on monthly high school attendance or no cash transfer. Between 2011 and 2015, participants (N = 2,448) were interviewed at baseline, then at annual follow-up visits at 12, 24 and 36 months. The total effect of the CCT on IPV was estimated using a GEE log-binomial regression model. We then estimated controlled direct effects to examine mediation of direct effects through intermediate pathways. Mediators include sexual partnership measures, the sexual relationship power scale, and household consumption measures. RESULTS: We found evidence that the CCT works in part through delaying sexual debut or reducing the number of sexual partners. The intervention interacts with these mediators leading to larger reductions in IPV risk compared to the total effect of the CCT on any physical IPV [RR 0.66, CI(95%):0.59-0.74]. The largest reductions are seen when we estimate the controlled direct effect under no sexual debut [RR 0.57, CI(95%):0.48-0.65] or under no sexual partner in the last 12 months [RR 0.53, CI(95%):0.46-0.60]. CONCLUSIONS: Results indicate that a CCT for high school girls has protective effects on their experience of IPV and that the effect is due in part to girls choosing not to engage in sexual partnerships, thereby reducing the opportunity for IPV. As a lower exposure to IPV and safer sexual behaviours also protect against HIV acquisition, this study adds to the growing body of evidence on how cash transfers may reduce young women's HIV risk. PMID- 29485748 TI - HIV and AIDS among adolescents who use drugs: opportunities for drug policy reform within the sustainable development agenda. AB - INTRODUCTION: The international community's commitment to halve by 2015 the HIV transmission among people who inject drugs has not only been largely missed, instead new HIV infections have increased by 30%. Moreover, drug injection remains one of the drivers of new HIV infections due to punitive responses and lack of harm reduction resourcing. In the midst of this situation, adolescents are a forgotten component of the global response to illegal drugs and their link with HIV infection. The Sustainable Development Goals (SDGs) present an opportunity to achieve the global objective of ending AIDS among adolescents who use drugs, by addressing the structural vulnerabilities they face be they economic, social, criminal, health-related or environmental. DISCUSSION: The implementation of the SDGs presents an opportunity to address the horizontal nature of drug policy and to efficiently address the drugs-adolescents-HIV risk nexus. Adolescent-focused drug policies are linked to goals 1, 3, 4, 10, 16 and 17. Goals 3 and 16 are the most relevant; the targets of the latter link to the criminalization of drug use and punitive policy environments and their impact on adolescents' health and HIV transmission risks. Moreover, it presents an opportunity to include adolescent needs that are missing in the three drug control conventions (1961, 1971 and 1988), and link them with the provisions of the Convention on the Rights of the Child (1989). Finally, the six principles to deliver on sustainable development are also an opportunity to divert adolescents who use drugs away from criminalization and punitive environments in which their vulnerability to HIV is greater. CONCLUSIONS: Addressing HIV among adolescents who use drugs is an extremely complex policy issue depending on different sets of binding and non-binding commitments, interventions and stakeholders. The complexity requires a horizontal response provided by the SDGs framework, starting with the collection of disaggregated data on this specific subgroup. Ending AIDS among adolescents who use drugs requires the implementation of national drugs and HIV plans based on the multi-sectoral approach and the transformative nature of the SDGs, to provide a comprehensive response to the epidemic among this key affected subgroup. PMID- 29485749 TI - Ending AIDS by 2030: the importance of an interlinked approach and meaningful youth leadership. AB - INTRODUCTION: This commentary by authors from the Adolescent HIV Treatment Coalition calls for action to improve advocacy and service delivery for young people by leveraging the interlinkages between HIV and the broader development agenda. The 2030 Agenda for Sustainable Development includes target 3.3 on ending the AIDS epidemic by 2030, and along with the 2016 Political Declaration on HIV and AIDS, this has led to a global renewal of political commitment to the HIV response. However, young people are still being left behind, and to provide an equitable and sustainable response to HIV we must ensure that we are meeting the needs of the 3.9 million young people living with HIV, and the millions more at risk. DISCUSSION: While HIV has its own target within the 2030 Agenda, efforts to end AIDS are inextricable from other goals and targets, such as on poverty eradication, education, gender equality and peace. To tackle HIV we must work beyond target 3.3 and provide a comprehensive response that addresses the underlying structural inequalities that impact adolescents and young people, ensuring that we enable the meaningful engagement of youth and adolescents as partners and leaders of sustainable development and the HIV response. Finally, it is necessary to collect better disaggregated data and evidence on the HIV epidemic among adolescents, as well as on best practices for supporting them. CONCLUSIONS: Ending the AIDS epidemic among adolescents and young people (aged 10 to 24) by 2030 is possible. However, it requires an integrated, multi-sectoral response to HIV which pays attention to the social determinants that put adolescents at risk and fuel the epidemic. Positioning efforts to end AIDS among young people within the broader 2030 Agenda and building youth leadership will contribute to building a more healthy, equitable and sustainable society for all. PMID- 29485750 TI - A challenge-response endoscopic sinus surgery specific checklist as an add-on to standard surgical checklist: an evaluation of potential safety and quality improvement issues. AB - BACKGROUND: The goal of this study was to develop and evaluate the impact of an aviation-style challenge and response sinus surgery-specific checklist on potential safety and equipment issues during sinus surgery at a tertiary academic health center. The secondary goal was to assess the potential impact of use of the checklist on surgical times during, before, and after surgery. This initiative is designed to be utilized in conjunction with the "standard" World Health Organization (WHO) surgical checklist. Although endoscopic sinus surgery is generally considered a safe procedure, avoidable complications and potential safety concerns continue to occur. The WHO surgical checklist does not directly address certain surgery-specific issues, which may be of particular relevance for endoscopic sinus surgery. METHODS: This prospective observational pilot study monitored compliance with and compared the occurrence of safety and equipment issues before and after implementation of the checklist. Forty-seven consecutive endoscopic surgeries were audited; the first 8 without the checklist and the following 39 with the checklist. The checklist was compiled by evaluating the patient journey, utilizing the available literature, expert consensus, and finally reevaluation with audit type cases. The final checklist was developed with all relevant stakeholders involved in a Delphi method. RESULTS: Implementing this specific surgical checklist in 39 cases at our institution, allowed us to identify and rectify 35 separate instances of potentially unsafe, improper or inefficient preoperative setup. These incidents included issues with labeling of topical vasoconstrictor or injectable anesthetics (3, 7.7%) and availability, function and/or position of video monitors (2, 5.1%), endoscope (6, 15.4%), microdebrider (6, 15.4%), bipolar cautery (6, 15.4%), and suctions (12, 30.8%). CONCLUSION: The design and integration of this checklist for endoscopic sinus surgery, has helped improve efficiency and patient safety in the operating room setting. PMID- 29485751 TI - Identifying Best Practice for Healthcare Providers Caring for Autistic Children Perioperatively. AB - This column shares the best evidence-based strategies and innovative ideas on how to facilitate the learning and implementation of EBP principles and processes by clinicians as well as nursing and interprofessional students. Guidelines for submission are available at https://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1741-6787. PMID- 29485752 TI - Development of consensus on models of care in adults with intestinal failure using a modified Delphi approach. AB - BACKGROUND AND AIM: The aims of this study were to establish consensus on service delivery models for management of Type III intestinal failure (IF) and home parenteral nutrition (HPN) within the Australian health-care system and to identify barriers and enablers in moving towards this ideal model. METHODS: A modified Delphi methodology was utilized to survey experts working in Type III IF HPN. The panel comprised physicians, dietitians, nurses, and pharmacists from 18 of the 20 adult Type III IF HPN centres across Australia. The study consisted of two rounds of email administered questionnaires developed around four key areas of health service delivery: access to services, clinical care, service guidance, and models of care. Open-ended responses were evaluated via an inductive thematic approach to identify areas of consensus. Experts reviewed the final report to consolidate consensus and validity. RESULTS: There was >80% consensus that an ideal team should consist of a physician, nurse, dietitian, pharmacist, and access to psychological support. Consensus supported the need for updated guidelines (75%) and a hub and spoke model of care (82%). However, further consultation is required in order to establish consensus around the use of HPN in the palliative oncology setting (69%). CONCLUSIONS: This consensus provides a framework within which health professionals, managers, policy-makers, and consumer groups can move towards optimal management for Type III IF HPN patients. Advocacy and a review of service delivery across Australia are now required to facilitate the ideal model of care identified. PMID- 29485753 TI - A novel Meloidogyne graminicola effector, MgMO237, interacts with multiple host defence-related proteins to manipulate plant basal immunity and promote parasitism. AB - Plant-parasitic nematodes can secrete effector proteins into the host tissue to facilitate their parasitism. In this study, we report a novel effector protein, MgMO237, from Meloidogyne graminicola, which is exclusively expressed within the dorsal oesophageal gland cell and markedly up-regulated in parasitic third /fourth-stage juveniles of M. graminicola. Transient expression of MgMO237 in protoplasts from rice roots showed that MgMO237 was localized in the cytoplasm and nucleus of the host cells. Rice plants overexpressing MgMO237 showed an increased susceptibility to M. graminicola. In contrast, rice plants expressing RNA interference vectors targeting MgMO237 showed an increased resistance to M. graminicola. In addition, yeast two-hybrid and co-immunoprecipitation assays showed that MgMO237 interacted specifically with three rice endogenous proteins, i.e. 1,3-beta-glucan synthase component (OsGSC), cysteine-rich repeat secretory protein 55 (OsCRRSP55) and pathogenesis-related BetvI family protein (OsBetvI), which are all related to host defences. Moreover, MgMO237 can suppress host defence responses, including the expression of host defence-related genes, cell wall callose deposition and the burst of reactive oxygen species. These results demonstrate that the effector MgMO237 probably promotes the parasitism of M. graminicola by interacting with multiple host defence-related proteins and suppressing plant basal immunity in the later parasitic stages of nematodes. PMID- 29485755 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 10/2018. PMID- 29485754 TI - Management of long-lasting phantosmia: a systematic review. AB - BACKGROUND: Interest in the pathophysiology and management of phantom smells has increased rapidly over the last decade. A PubMed search for the term "phantosmia" demonstrated a near-doubling of articles published on phantosmia within the past 7 years. We aimed to systematically review the literature on the management of phantosmia. METHODS: The PubMed, EMBASE, and Cochrane databases were searched for articles published since January 1990, using terms combined with pertinent Boolean search operators. We included articles evaluating management of phantosmia written in the English language, with original data and a minimum of 6 months of follow-up, on at least 2 patients and with well-defined and measurable outcomes. RESULTS: A total of 2151 unique titles were returned upon the initial search. Of these, 146 abstracts were examined, yielding 7 articles meeting the inclusion criteria. All articles were predominantly level 4 evidence. One prospective level 3 study was included. The studies included a total of 96 patients, with follow-up ranging from 6 months to 11 years. Endpoints were primarily based on subjective patient responses. Management options included observation and medical and surgical therapy. Olfactory mucosa excision was the only surgical intervention studied, with short-term symptomatic improvement in 10 of 11 patients. Forty-one patients were treated medically, which included antipsychotic, antimigraine, and antiseizure medications, transcranial stimulation, and topical cocaine application. CONCLUSION: Despite increasing interest in the treatment of phantosmia and reports of successful therapies, there remains a paucity of data and lack of consensus regarding optimal management of this difficult condition. PMID- 29485756 TI - Corrigendum: Visible-Light-Driven Hydrogen Evolution Using Planarized Conjugated Polymer Photocatalysts. PMID- 29485757 TI - A Preview of Selected Articles in This Issue. PMID- 29485758 TI - Inferior In Vivo Osteogenesis and Superior Angiogenesis of Human Adipose-Derived Stem Cells Compared with Bone Marrow-Derived Stem Cells Cultured in Xeno-Free Conditions. PMID- 29485760 TI - Erratum. PMID- 29485761 TI - Erratum. PMID- 29485759 TI - Adaptation of global land use and management intensity to changes in climate and atmospheric carbon dioxide. AB - Land use contributes to environmental change, but is also influenced by such changes. Climate and atmospheric carbon dioxide (CO2 ) levels' changes alter agricultural crop productivity, plant water requirements and irrigation water availability. The global food system needs to respond and adapt to these changes, for example, by altering agricultural practices, including the crop types or intensity of management, or shifting cultivated areas within and between countries. As impacts and associated adaptation responses are spatially specific, understanding the land use adaptation to environmental changes requires crop productivity representations that capture spatial variations. The impact of variation in management practices, including fertiliser and irrigation rates, also needs to be considered. To date, models of global land use have selected agricultural expansion or intensification levels using relatively aggregate spatial representations, typically at a regional level, that are not able to characterise the details of these spatially differentiated responses. Here, we show results from a novel global modelling approach using more detailed biophysically derived yield responses to inputs with greater spatial specificity than previously possible. The approach couples a dynamic global vegetative model (LPJ-GUESS) with a new land use and food system model (PLUMv2), with results benchmarked against historical land use change from 1970. Land use outcomes to 2100 were explored, suggesting that increased intensity of climate forcing reduces the inputs required for food production, due to the fertilisation and enhanced water use efficiency effects of elevated atmospheric CO2 concentrations, but requiring substantial shifts in the global and local patterns of production. The results suggest that adaptation in the global agriculture and food system has substantial capacity to diminish the negative impacts and gain greater benefits from positive outcomes of climate change. Consequently, agricultural expansion and intensification may be lower than found in previous studies where spatial details and processes consideration were more constrained. PMID- 29485762 TI - Diagnosis and endoscopic endonasal management of nontraumatic pseudoaneurysms of the cranial base. AB - BACKGROUND: Nontraumatic pseudoaneurysms of the cranial base are rare and present unique diagnostic and treatment dilemmas compared with both true aneurysms and pseudoaneurysms outside of the cranial base. There is a dearth of knowledge regarding the management of these complicated lesions. METHODS: Nontraumatic pseudoaneurysms of the cranial base internal carotid artery (ICA) were retrospectively identified at the University of Pittsburgh Medical Center through a key word search of cranial base cases from 2010 to 2017. RESULTS: Three cases were identified, demonstrating pseudoaneurysms of the cavernous and petrous ICA. Each patient underwent diagnostic work-up with computed tomography, magnetic resonance imaging, and angiography, followed by endovascular occlusion and endoscopic endonasal surgery, which resulted in relief of presenting complaints and ablation of the pseudoaneurysm. CONCLUSION: Symptomatic cranial base pseudoaneurysms should undergo treatment to obliterate the aneurysm and relieve the mass effect. First, formal angiography is necessary for accurate diagnosis and treatment planning. Next, endovascular occlusion is performed, with a preference for coiling or endoluminal reconstruction with a flow diverter. Last, endoscopic intervention follows in cases where: (1) decompression of vital structures is indicated; (2) diagnosis of the pseudoaneurysm cannot be definitively confirmed with angiography; or (3) the etiology of the confirmed pseudoaneurysm requires further investigation. PMID- 29485763 TI - Assessing the combined effects of resurgence and reinstatement in children diagnosed with autism spectrum disorder. AB - Resurgence and reinstatement are laboratory models of relapse following treatments for problem behavior that arrange alternative sources of reinforcement, such as differential reinforcement of alternative behavior and noncontingent reinforcement. Resurgence models the elimination or reduction of reinforcers during treatment and reinstatement models the re-presentation of reinforcers previously maintaining problem behavior. The present study examined individual and combined effects of resurgence and reinstatement in a translational model of treatment relapse with three children diagnosed with Autism Spectrum Disorder. We first reinforced and then extinguished an arbitrary response while providing access to a preferred toy to model a version of noncontingent reinforcement with extinction. In the following phases, we examined resurgence by removing the toy, reinstatement by presenting the training reinforcer response-independently, and a combination of resurgence and reinstatement. Overall, relapse of target responding reliably exceeded functionally similar responses never reinforced in the experimental situation. Most importantly, relapse tended to be greater when combining resurgence and reinstatement than when assessing either alone. These findings support previous studies showing that combinations of operations can increase treatment relapse. This translational model arranging simulated problem behavior with arbitrary tasks provides a platform from which to thoroughly and systematically assess methods for understanding and improving behavioral treatments. PMID- 29485764 TI - The stuff that dreams are made of: HIV-positive adolescents' aspirations for development. AB - BACKGROUND: The Sustainable Development Goals (SDGs) commit to strengthening collaborations between governments and civil society. Adolescents are among the key target populations for global development initiatives, but research studies and programmes rarely include their direct perspectives on how to promote health and wellbeing. This article explores how both the methods and the findings of participatory research provide insights into adolescents' aspirations across the domains of health and social development. It investigates how adolescents conceive of health and social services as interconnected, and how this reflects the multisectoral objectives of the SDGs. METHODS: This research was conducted within a longitudinal, mixed-methods study of HIV-positive adolescents (n = 80 qualitative participants, n = 1060 quantitative interviews). Between November 2013 and February 2014, a participatory exercise - the "dream clinic" - was piloted with 25 adolescents in South Africa's Eastern Cape. Key themes were identified based on the insights shared by participants, and through visual and thematic analysis. These findings were explored through a second participatory exercise, "Yummy or crummy? You are the Mzantsi Wakho masterchef !," conducted in January 2016. Findings are described in relation to emerging quantitative results. RESULTS: Mixed methods explored associations between access to food, medicines, clean water and sanitation in HIV-positive adolescents' aspirations for development. The exercises produced practicable recommendations for innovations in development, based on associations between healthcare, food security, clean water and sanitation, while illustrating the value of partnership and collaboration (the objective of SDG17). Findings capture strong interlinkages between SDGs 2, 3 and 6 - confirming the importance of specific SDGs for HIV positive adolescents. Study results informed the objectives of South Africa's National and Adolescent and Youth Health Policy (2017). CONCLUSIONS: Participatory research may be used to leverage the perspectives and experiences of adolescents. The methods described here provide potential for co-design and implementation of developmental initiatives to fulfil the ambitious mandate of the SDGs. They may also create new opportunities to strengthen the engagement of adolescents in policy and programming. PMID- 29485765 TI - Hybrid approach to thoracic aortic aneurysm: The Lupiae technique. AB - Aortic diseases, especially when the entire aorta is involved, are often challenging to treat since they frequently require invasive interventions. Minimally invasive hybrid treatment of such pathologies is proving to be a valid option for complex cases (for example, dilation involving the entire aorta) and is improving postoperative outcomes. It consists of a minimally invasive opening stage, where ascending aorta and aortic arch replacement and epiaortic vessel rerouting is performed using a multibranched graft equipped with a radiopaque marker. This is followed by an endovascular stage, where the remaining diseased aorta is covered with an endoprosthesis. This procedure has been described as Lupiae technique and the results seem encouraging. In this tutorial, we give a practical overview of this technique, describing the treatment of a particular condition called mega-aorta syndrome type 1, which is the dilation of the aorta up to celiac trunk. PMID- 29485766 TI - Transapical neo-chord implantation. AB - The neo-chord procedure was introduced to facilitate chordal replacement for mitral valve repair using a transapical beating heart off-pump approach. This tutorial describes the concept, the technique, the operative approach, and the procedure in a step-by-step manner. PMID- 29485767 TI - Mitral valve repair and aortic valve replacement with sutureless prosthesis implantation through a right minithoracotomy. AB - Little experience exists in minimally invasive treatment of double-valve disease. In this report, we present a minimally invasive approach for mitral and aortic valve disease through a minithoracotomy in the 3rd intercostal space with a sutureless aortic prosthesis implantation. PMID- 29485768 TI - Retrograde administration of cardioplegia. AB - The use of retrograde cardioplegia is a safe, effective and widespread method for myocardial protection in a broad range of cardiac procedures. Retrograde cardioplegia may be delivered retrograde alone or, most frequently, in combination with an antegrade way of delivery. However, the degree of myocardial protection provided by retrograde cardioplegia may vary due to anatomic differences or for other reasons. PMID- 29485769 TI - Conventional open harvesting of the great saphenous vein as a conduit for coronary artery bypass grafting. AB - This short tutorial video summarizes the surgical technique for conventional open harvesting of the great saphenous vein as a conduit for coronary artery bypass grafting. PMID- 29485770 TI - Left ventricular apical aneurysm resection in hypertrophic cardiomyopathy. AB - Apical aneurysms are outpouchings of the left ventricular apex that are relatively common in patients with apical hypertrophic cardiomyopathy or hypertrophic cardiomyopathy with midventricular obstruction. Apical aneurysms have been associated with ventricular tachycardia and sudden cardiac death, but surgical resection may reduce the risks of these complications. In this tutorial, we describe resection of a left ventricular apical aneurysm in a patient with hypertrophic cardiomyopathy and midventricular obstruction. PMID- 29485771 TI - Single-stage repair of double outlet right ventricle with subpulmonic ventricular septal defect (Taussig-Bing anomaly). AB - Double outlet right ventricle with subpulmonic ventricular septal defect is a very rare form of congenital heart disease. Surgical correction involves closure of the ventricular septal defect with baffling of blood flow from the left ventricle to the pulmonic valve and arterial switch of the usually side-by-side great arteries. In this tutorial, we present our surgical technique for single stage repair of this complex anomaly. PMID- 29485772 TI - Minimally invasive redo-aortic valve replacement. AB - Bioprosthetic aortic valves have been used with increasing frequency over the past two decades, often in relatively young patients who may eventually require aortic valve re-operations due to degeneration of the bioprosthesis. Growing experience with minimally invasive aortic valve replacement has prompted surgeons to use minimally invasive approaches also with redo operations for replacement of the aortic valve. This tutorial describes the operative steps for a minimally invasive redo replacement of the aortic valve through an upper ministernotomy. We demonstrate the surgical access, initiation of cardiopulmonary bypass, venting, and cardioplegia strategies. Special situations, such as how to approach patent coronary grafts, the small aortic annulus, and the use of sutureless or rapid deployment valves are demonstrated and discussed. The tutorial shows that minimally invasive redo aortic valve replacement is a safe, effective, and reproducible procedure. PMID- 29485773 TI - Lung resections combined with vena cava replacement. AB - Resection and reconstruction of the superior vena cava in patients with lung cancer is still considered a surgical challenge; the numerous problems related to patient selection, the choice of the most appropriate surgical strategy and technique, the most suitable material for replacement, and the number of potential complications definitively show an impact on short-term outcome and long-term prognosis. However, with the appropriate indications and surgical technique, a clear benefit has been documented in a select group of patients with lung cancer. PMID- 29485774 TI - Transapical approach to optimize left ventricular resynchronization in patients with dilated cardiomyopathy. AB - An alternative to coronary sinus implantation for a left ventricular pacing lead is frequently needed for cardiac resynchronization therapy. We have developed a transapical approach to implant an endocardial pacing lead that will reach the most delayed segment of the left ventricle. This method is easily combined with other transapical heart surgeries. After some technological improvement, our technique should offer easier access and better results than other currently available implantation methods. PMID- 29485775 TI - Modified reimplantation of bicuspid aortic valve. AB - We present a modified bicuspid aortic valve reimplantation operation using a unique technique of second line, continuous suturing during implantation of the aortic valve scallop to the prosthesis that mimics stentless, minicylinder implantation. The feasibility of bicuspid aortic valve repair with associated aortic root management has been demonstrated. However, this repair seems to be less durable than tricuspid aortic valve repair, and this may be partly because of the connective tissue disorders that are an inherent feature of bicuspid aortic valve disease. Annular progressive dilatation as a consequence of annuloaortic ectasia may also affect long-term stability of a repair and the modified reimplantation technique presented here has been developed to address issues of annular stabilization as well. PMID- 29485776 TI - Poison gas and thefirst World War: key role ofpharmacists. AB - Poison gas has been the subject of attention from the French army (Grand Quartier General). The 22sd of April 1915, General Joffre decided that the General Direction for Health Service was in charge of the protection of troops against what he called "this new mode of terror, disease, and death". Actions are been launched to found ways for the protection means and to obtain for the army at least equivalent weapons. Pharmacists will have a leading role thanks to their knowledge in chemistry. Research laboratories were working in two areas: individual protection and production of aggressive agents. Paul Lebeau, Gabriel Bertrand, Alexandre Degrez, Charles Moureu were among many others very committed to fight and remains at the top and to react quickly to ennemy's attacks. At the end of the war, Paul Lebeau received the Legion d'Honneur medal for his contribution to war. The school of pharmacy was recognized as faculty of pharmacy, by a decree of May 14th, 1920. The knowledge that were obtained during this period will be used for the second World War, but the chemical weapon was not much used, as opposed to more recent usage in Vietnam, Irak and Syria. PMID- 29485777 TI - The copy of the Essays of Jean Rey, used by Bayen and Gobet, at the BIU Sante, pole Pharmacie. AB - The copy of the innovative book written by Jean Rey in 1630, entitied : The Essays on the reasons why the weight of stain and lead increased when they were burnt, which is nowadays kept in the BIU Sante, pole Pharmacie, proved to be the authentic copy which had been used by Pierre Bayer when he rediscovered Jean Rey's Works. It was also the same copy that Gobey used when he real- ized his new edition of the Essays in 1777. This copy first belonged to M. de Villars from La Rochelle, and then was acquired by M. de Villiers, who accepted to lend it to Bayen. The probes for this identification were detailed in the article. PMID- 29485778 TI - A century of Pharmaceutical and professorial presidency at the <> (1911-2011). AB - The society was created in 1911 at the Ecole supirieure de pharmacie of Nancy by professor Julien Godfrin wno was the chairman of the school and wno becamed its first president. But Godfrin died in 1913. The second president was Auguste Sartory who was extremely active in spite of the war but who leaved Nancy at its end to be named as a professor at the new school of pharmacy in Strasbourg. Four presidents followed each other during these years after Sartory: Pierre Seyot, Emile Steimetz, Pierre Lectard and Frangois Mortier. All of them were pharmacists and professors. During this century, the society was always associated to the school and to the faculty for the teaching of mycology to pharmacy students and other lovers. PMID- 29485779 TI - Chemist in chief Charles Laubert - Charles Laubert (1762-1834]. AB - Charles Laubert (1762-1834) was one of the french pharmacists of imperial army. He participates in the war in Italy, then he becomes a president of the government of the junta of Parthenopean republic (1799). During the Spanish war (1808-1811) chemist in chief in his laboratory, he focuses his research about isolation quinine of quinquina. Chemist in chief of famous army (1812-1814), he contributes to Russian war, Berezina passage with many difficulties and Sax war. He finds the pharmacist Jacob there. After the death of Parmentier, Laubert succeeds as general inspector of the Health service (1814-1816). PMID- 29485780 TI - Apothecaries and their clients in the State of Burgundy. AB - In 1477, the State of Burgundy from Charles the Bold comprised the Low Countries (including large parts of present-day Belgium, the Netherlands, Luxembourg and northern France) as well as the duchy of Burgundy and the counties of Nevers and Burgundy. From 44 towns in the State of Burgundy, their apothecaries have been identified and based on studies on the population in European mediaeval towns, the number of inhabitants per apothecary (= the client-potential) could be established for the years 1400, 1440, 1480, 1520, 1560 and 1600. A distinction among small towns, medium sized and big towns has been made. In towns with less than 2500 inhabitants usually just one apothecary is present. Because of the limited number of potential clients - between 1000 and 2000 - it concerns often a town-apothecary (partly) paid by the magistrate and with additional privileges or a monopolized position. In towns with 5000-25000 inhabitants we see for the 16th century a tendency of a diminishing number of potential clients in time: this forms a strong indication for a growing degree of competition between the apothecaries in the bigger towns. A client-potential of 3500-4000 or higher allowed the apothecary in the territory of Burgundy to be commercially successful in the 15th and 16th century. The clients of the apothecary in this territory consisted of the three classes of the "Ancien Regime" with bishops, abbots, hospitals, churches, Seigniors, Counts, Dukes, courts of the crowned nobility, town magistrates, town garrisons, citizens, plague patients and the poor of the town. PMID- 29485781 TI - Henri Bocquillon-Limousin (1856-1917). AB - A pharmacist facinated by materia medica Henri Bocquillon-Limousin (1856-1917) get married with the daughter of Stanislas Limousin in 1885. After being graduated from pharmacy high school of Paris, he joined the laboratory of Jungfleisch. Afterwards, he briefly worked in the municipal laboratory of Paris and then he turned to a pharmacy activity. He took up the pharmacy of his father in law in 1887. His research was mainly directed to materia medica and valorization of colonial medicinal plants. Thanks to a well expanded network of associates, he managed to obtain an important collection of medicinal plants which is actually preserved in "Francois Tillequin museum - Collections of materia medica" in the faculty of pharmacy of Paris. H. Bocquillon-Limousin is also well known for his numerous editions of Formulaire des medicaments nouveaux and his books in the field of material medica. PMID- 29485782 TI - The apothecaries of the IIe de Ia Cite in Paris in the 17th century. AB - This article studies the location of the apothecaries living in the lie de Ia Cit~ between 1580 and the middle of the 7th century. In 1637, twelve apothecaries were living along the main commercial streets - Rue de La Juiverie, Rue de La Lanterne and Rue de La Calandre. Their biographies are studied. PMID- 29485783 TI - [In process]. PMID- 29485784 TI - [In process]. PMID- 29485785 TI - Vitamin D Status in Renal Transplant recipients is not Associated with Erectile Dysfunction. AB - Erectile dysfunction (ED) is a highly prevalent disorder among renal transplant recipients. Vitamin D deficiency (VDD) has been associated with several ED risk factors but only recently directly linked to ED. We conducted a study to investigate whether vitamin D serum levels were associated with the presence and severity of ED in 40 male patients that underwent deceased donor kidney transplantation (TX) from 2001 to 2013. Blood samples were collected on two seasonally distinct occasions and 25(OH)D concentration was assessed by radioimmunoassay. A 5-item version of the International Index of Erectile Function (IIEF-5) was used for ED evaluation and group stratification. We found comparable rates of ED (75%) and VDD (42.5%-62.5%) as in previously published studies. Serum levels of 25(OH)D did not differ between patients with and those without ED on both measurements (p=0.656 and p=0.914, respectively), or when comparing different ED severity groups. Duration of renal replacement therapy before TX and graft duration until analysis were longer in patients with ED (p=0.022 and p=0.05, respectively), but with the results being nonsignificant on logistic regression. In conclusion, we found no association of 25(OH)D concentration with the presence and severity of ED in renal transplant recipients. So far, there are no similar published data. PMID- 29485786 TI - QuantiFERON-TB Gold In-Tube Test in the Diagnosis of Latent Tuberculosis Infection in Arthritis Patients Treated with Tumor Necrosis Factor Antagonists. AB - The aim of this study was to investigate the role of the QuantiFERON-TB Gold In Tube test (QFT-GIT) in detecting latent tuberculosis in immunocompromised patients before introducing tumor necrosis factor (TNF-alpha) antagonists. The study included 300 subjects of similar age. The study group comprised of 150 QuantiFERON (QFT) positive subjects with rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis and psoriatic arthritis, while control group comprised of 150 QFT negative respondents with the same diseases. Exhaustive medical history was documented for all patients. Screening tests were performed including QFT-GIT, tuberculin skin test (TST), chest radiography and detection of Mycobacterium tuberculosisin sputum culture 2 times. A positive QFT GIT test result, regardless of TST result, was considered as an indication for latent tuberculosis infection (LTBI) treatment. Results of this study showed good correlation between the conclusive results of QFT-GIT and TST. All study group patients had normal clinical findings, normal radiologic findings and negative results of sputum microbiological analysis during the course of prophylaxis and after its completion and during the course of biological therapy. Conversion of positive QFT-GIT test to negative was observed in 4% of study group patients, while QFT negative respondents remained negative. There was a statistically significant positive correlation between QFTGIT, TST results and patient age, smoking habit and contact with tuberculosis. Study results showed that along with good clinical evaluation and detailed medical history, it is important to conduct testing in order to avoid disease progression or unnecessary isoniazid prophylaxis. PMID- 29485787 TI - Correlation Between Occurrence and Deterioration of Respiratory Diseases and Air Pollution Within the Legally Permissible Limits. AB - The aim of the study was to investigate the unknown effect of air pollutants on the occurrence or deterioration of respiratory diseases in the area with a humid continental climate. This retrospective study included 5868 patients with respiratory symptomatology (upper respiratory tract infection (URTI), pneumonia, acute bronchitis, chronic obstructive pulmonary disease (COPD), and asthma) admitted to emergency department (ED). The number of patients, values of meteorological parameters (mean daily values of air temperature pressure and relative humidity) and concentrations of air pollution particles (<=10 MUm (PM10), ozone (O3) and nitrogen dioxide (NO2)) were collected during a two-year ( July 2008 - June 2010) period. There were 1839 (31.3%), 1712 (29.2%), 1313 (22.4%), 614 (10.5%) and 390 (6.6%) patients with pneumonia, COPD, URTI, acute bronchitis and asthma, respectively. The mean daily concentrations of NO2 (25.9 (1.7-89.7) MUg/m3), O3 (47.1 (4.7-135.4) MUg/m3) and PM10 particles (25.7 (4.6 146.6) MUg/m3) were below the legally defined thresholds. Among other results, the occurrence of respiratory diseases showed positive Spearman's correlation with the values of air humidity (days 0-3, r=0.15 to 0.19), PM10(days 0-3, r=0.10 to 0.13) and NO2 concentrations (day 0, r=0.11), and negative correlation with the values of air temperature (days 0-3, r=-0.36 to -0.34), pressure (day 0, r= 0.10) and O3 concentrations (days 0-3, r=-0.21 to -0.22) (p<0.05 all). In conclusion, the occurrence of respiratory diseases showed correlation with weather conditions and air pollutants despite the legally permitted values in the region with a humid continental climate. PMID- 29485788 TI - Psychosocial Determinants of Satisfaction with Hospital Care in Adult Patients Suffering from Advanced Cancer. AB - In this observational study, direct and indirect (moderator and mediator) relationships between sociodemographic (age, gender, life partner, education level, income and length of treatment) and psychological (Hospital Anxiety and Depression Scale, HADS) variables and satisfaction with hospital care (EORTC INPATSAT32) in adult (advanced cancer) patients were investigated. Study sample consisted of 75 hospitalized advanced cancer patients recruited at the Zagreb University Hospital Centre and Sestre milosrdnice University Hospital Centre in 2015. Statistically significant negative correlations were found between HADS and elementary school education level, as well as with all satisfaction variables (satisfaction with physicians, nurses and organization). Moderate to high and statistically significant positive correlations were found between elementary school level and all satisfaction variables. Gender and level of education appeared as significant moderator variables in the relationship between HADS and satisfaction with nurse care. There were no significant mediator effects of sociodemographic variables on the correlation between HADS and satisfaction with care. Male participants who were more disturbed emotionally were more satisfied with nurses. Participants with elementary and high school levels of education and lower scores on HADS were more satisfied with nurses, while participants with university level of education had higher HADS scores and lower level of satisfaction with nurses. PMID- 29485789 TI - Comparison of Optic Nerve Head Morphology in Patients with Primary Open Angle Glaucoma and Non-Arteritic Anterior Ischemic Optic Neuropathy. AB - The aim of this study was to assess damage to retinal ganglion cells (RGC) and morphology of the optic nerve head (ONH) in patients with primary open angle glaucoma (POAG) and non-arteritic anterior ischemic optic neuropathy (NAION). The study included three groups of patients, as follows: 40 eyes with POAG, 40 eyes with NAION and 40 eyes with refraction anomaly. All patients underwent standard automated perimetry and analysis of ONH topography by using confocal scanning laser ophthalmoscopy (CSLO)-HRT II. Visual field defects such as decreased retinal sensitivity prevailed in the eyes with POAG, whereas in the eyes with NAION they were mostly manifested as concentrically narrowed visual field and quadrant excesses. Topographic ONH alterations, examined by HRT II, showed the same number of sectors to be affected in the eyes with POAG and NAION. A larger number of sectors in the upper part of ONH were affected in the eyes with NAION. Optic disc morphology differed significantly between the eyes with POAG and NAION by a higher rate of neuroretinal rim thinning and higher mean cup depth in the POAG group. PMID- 29485790 TI - Analgesic Effect - Comparison of Paracetamol Administered Intermittently and Through Patient-Controlled Analgesia Pump after Lumbar Discectomy: a Prospective Clinical Study. AB - Lumbar discectomy is the most common surgical treatment for intervertebral disc extrusion. Postoperative pain is a common clinical problem that greatly affects the length of hospitalization, functional status and patient quality of life. Th e aim of this study was to compare the postoperative analgesic effi cacy of paracetamol administered intermittently and through patient-controlled analgesia (PCA) pump following single level lumbar discectomy. Patients who underwent elective lumbar discectomy of intervertebral disc extrusion at the L4-L5 level diagnosed by magnetic resonance of the lumbosacral spine were included in the study. Pain was assessed at regular intervals for 48 hours through a shortened version of McGill pain questionnaire translated in the Croatian language. When pain was monitored as a summarized variable for each measurement, PCA group significantly stood up after 24 hours with better perception of pain compared to the intermittent group (c2-test, p<0.05). Adequate pain relief is an important aspect of postoperative care in spinal surgery patients. Postoperative use of paracetamol through PCA pump achieved better pain control and pain management versuspostoperative use of intermittent paracetamol analgesia after lumbar discectomy. PMID- 29485791 TI - Thoracic Epidural Versus Intravenous Patient-Controlled Analgesia after Open Colorectal Cancer Surgery. AB - The aim of the study was to compare thoracic epidural analgesia (TEA) and intravenous patient-controlled analgesia (IV-PCA) after open colorectal cancer surgery. This prospective study included sixty patients scheduled for elective open colorectal surgery and randomized to either postoperative IV-PCA with morphine (n=30) or TEA with a mixture of levobupivacaine, fentanyl and adrenaline (n=30). Th e primary outcome was return of bowel function. The secondary outcome was quality of postoperative analgesia at rest, on coughing and during mobilization. Intermediate outcomes included patient satisfaction, time out of bed, rate of side effects and postoperative complications, and time of discharge. Recovery of postoperative ileus occurred sooner (p<0.001) and resumption of dietary intake was achieved earlier (p<0.001) in TEA group. Intensity of pain during the first 3 postoperative days was significantly lower at rest, on coughing and during mobilization (p<0.001), and mobilization was much more effi cient (p<0.005) in TEA than in IV-PCA group. Satisfaction scores were better in TEA group (p<0.001). Nausea, sedation and postoperative delirium occurred less frequently in TEA group (p<0.05, p<0.001 and p<0.05, respectively). TEA demonstrated significantly better effectiveness than IV-PCA after open colorectal cancer surgery and had a positive impact on bowel function, dietary intake, patient satisfaction and early mobilization. The results of this study demonstrated the importance of implementation of TEA as a preferred method for postoperative pain control after major open colorectal surgery. PMID- 29485792 TI - Herpes Group Viruses: a Seroprevalence Study in Hemodialysis Patients. AB - Herpes group viruses (herpes simplex virus, HSV; varicella-zoster virus, VZV; cytomegalovirus, CMV; and Epstein-Barr virus, EBV) remain an important cause of morbidity in immunocompromised persons. The aim of the study was to analyze the prevalence of HSV-1, HSV-2, VZV, CMV and EBV in patients undergoing hemodialysis. During a three-year period (2013-2015), 152 consecutive serum samples from hemodialysis patients and 150 healthy subjects (control group) were tested for the presence of IgM/IgG antibodies to herpes group viruses. Serologic tests were performed using a commercial enzyme-linked immunosorbent assay (ELISA) or enzyme linked immunofluorescent assay (ELFA). Hemodialysis patients showed significantly higher CMV IgG seropositivity compared to controls (88.2% vs. 78.7%, p=0.011). In addition, seroprevalence rates of HSV-1 and VZV were higher in hemodialysis patients; however, these differences did not reach statistical significance (85.5% vs. 80.0%, p=0.054 and 99.3% vs. 96.0%, p=0.051, respectively). The prevalence of HSV-2 and EBV was similar in both groups (12.5% vs. 12.7%, p=0.137 and 98.0% vs. 95.3%, p=0.113, respectively). There was no difference in IgG seropositivity according to gender and place of residence. Logistic regression showed that older age was a significant predictor for CMV and EBV IgG seropositivity (increase in age by one year: CMV OR=1.055; 95%CI=1.030-1.080 and EBV OR=1.075, 95%CI=1.023-1.130). PMID- 29485793 TI - Multiple Myeloma with Advanced Bone Disease and Low Tumor Burden - Different Clinical Presentation but Similar Outcome after Bortezomib-Based Therapy and Radiotherapy. AB - There is a small but well recognized group of patients with multiple myeloma (MM), characterized by multiple bone lesions and low tumor burden, the so-called macrofocal form of MM (MF-MM). The aim of the study was to analyze the incidence, clinical manifestation, therapeutic outcome and prognosis of patients with MF-MM treated with bortezomib-based therapy and radiotherapy, in comparison to classic MM. There were 148 MM patients treated with bortezomibbased regimens, with 15 (10.1%) of them meeting the criteria for MF-MM. Comparative analysis involved disease- and therapy-related variables and markers of bone metabolism in MF-MM and classic MM groups. Event-free survival (EFS) and median survival (MS) were analyzed. Patients in MF-MM and classic MM groups had similar mean age and sex distribution. Patients with MF-MM had advanced myeloma bone disease (MBD), significantly lower clonal plasma cell infiltration in bone marrow, and lower paraprotein level. These patients were predominantly in an early International Staging System stage, showed non-secretory and light-chain variants, and significant association with extramedullary plasmacytomas. EFS was 20 months in MF-MM group versus 13 months in classic MM group (nonsignificant difference). MS was 42 months in both MF-MM and classic MM groups. MF-MM presents with imbalance of the minimal tumor burden and massive bone involvement. Along with advanced skeletal manifestations, these patients showed features of preserved bone marrow and no end-organ damages. Following bortezomib-based therapy and radiotherapy, the EFS and MS did not differ between MF-MM and classic MM groups. PMID- 29485794 TI - Chronic Obstructive Pulmonary Disease and Heart Failure: Closer than Close. AB - Chronic obstructive pulmonary disease (COPD) and heart failure (HF) both are global epidemics with substantial burden on morbidity and mortality. They present major challenges to healthcare providers and often coexsist. Multiple interactions exist between these conditions. COPD is often responsible for delayed diagnosis of HF and vice versa, since both conditions have similar symptoms such as dyspnea and poor exercise tolerance based on the skeletal myopathic response rather than the primary organ failure. Patients with COPD also have an increased risk of developing HF and higher hospitalization and death rates compared with HF patients without COPD. Echocardiography and pulmonary function tests along with natriuretic peptides should be performed and carefully interpreted. Diagnostic assessment of both conditions present in the same patient is often difficult, but therapeutic approach is also often non-adherent to current guidelines. For example, patients with coexisting COPD and HF receive beta-blockers at disappointingly low rates below 20%. Closer collaboration between cardiologists and pulmonologists is required for better identification and management of concurrent COPD and HF. PMID- 29485795 TI - Drug-Induced Photosensitivity - a Continuing Diagnostic Challenge. AB - When taking different drugs, their possible side effects on the skin should be considered, including skin reactions connected to photosensitivity. This photosensitivity caused by drugs can appear as phototoxic reactions (which occur more often) or photoallergic reactions (which occur less often and include allergic mechanisms). The following drugs stand out as medications with a high photosensitivity potential: nonsteroidal anti-inflammatory drugs (NSAIDs), cardiovascular drugs (such as amiodarone), phenothiazines (especially chlorpromazine), retinoids, antibiotics (sulfonamides, tetracyclines, especially demeclocycline and quinolones), etc. In recent years, photosensitive reactions to newer drugs have appeared, e.g., targeted anticancer therapies such as BRAF kinase inhibitors (vemurafenib, dabrafenib), EGFR inhibitors, VEGFR inhibitors, MEK inhibitors, Bcr-Abl tyrosine kinase inhibitors, etc. In patients taking drugs over a longer period of time (e.g., NSAIDs, cardiovascular drugs, etc.), a particular problem arises when an unrecognized drug-induced photosensitivity on the skin manifests in summer months. When taking patient histories, the physician/dermatovenereologist should bear in mind that any drug the patient is currently taking may be the cause of skin reactions. Therefore, patients who use potentially photosensitive drugs and treatments on a long term basis should be warned of the possibility of these side effects on their skin and advised to avoid direct exposure to sunlight and to use adequate photoprotection. If patients carefully protect themselves from the sun, it is often not necessary to stop treatments that include photosensitive drugs. If such reactions appear, anti inflammatory and antiallergic therapies should be introduced. PMID- 29485796 TI - Evaluation of the Head Multislice Computed Tomography Scan in Emergency Department. AB - The aim of the study was to examine the prevalence of head injuries, acute stroke and brain tumors obtained from computed tomography (CT) scans in the emergency department (ED) during a one-year period. We also assessed the potential effect of seasons on the occurrence of stroke, head trauma and tumors found on CT scans, expressed in monthly intervals. This retrospective review included all patients that underwent emergency head CT from the hospital database. A total of 3888 head CT examinations were performed in adult patients presenting to ED and 1424 CT scans had at least one pathologic finding meeting diagnostic criteria for the study. Of the total number of CT scans analyzed, acute stroke was identified in 552 (14.19%), head trauma in 660 (16.97%), and brain tumor in 212 (5.45%) patients. Head trauma was more commonly found in males (n=465, 70.45%) than in females (n=195, 29.54%). Acute stroke was slightly more common in males than in females. Brain tumors were more frequently found in female patients. There were monthly variations in the number of head injuries and acute stroke diagnosed during the study period. Men and elderly patients were found to account for the greatest number of traumatic head injuries and therefore are at the highest risk of possible brain injury. PMID- 29485797 TI - Healthy Settings in Hospital - How to Prevent Burnout Syndrome in Nurses: Literature Review. AB - Healthy settings involve a holistic and multidisciplinary method that integrates actions towards risk factors. In hospital settings, a high level of stress can lead to depression, anxiety, decreased job satisfaction and lower loyalty to the organization. Burnout syndrome can be defined as physical, psychological and emotional exhaustion, depersonalization, and low sense of personal accomplishment. The aim of this literature review was to make systematic literature analysis to provide scientific evidence for the consequences of constant exposure to high levels of stress and for the methods to be used to prevent burnout syndrome among health care workers. The Medline database was searched to identify relevant studies and articles published during the last 15 years. The key words used in this survey were burnout syndrome, prevention, nurses, and healthy settings. The 6 eligible studies were included in literature review. Evidence showed nurses to be exposed to stress and to have symptoms of burnout syndrome. As a result of burnout syndrome, chronic fatigue and reduced working capacity occur, thus raising the risk of adverse events. In conclusion, the occurrence of burnout syndrome is a major problem for hospitals and healthcare system. Action plan for hospital burnout syndrome prevention would greatly reduce the incidence and improve the quality of health care. PMID- 29485798 TI - Quality of Life in Mothers of Children with Cerebral Palsy. AB - The aim of the study was to investigate whether there is difference in the quality of life between mothers of children with cerebral palsy and mothers of healthy children, as well as whether the quality of life in mothers of children with cerebral palsy depends on their level of education, child's mobility and child's functional status. A total of 141 mothers participated in the research. Mothers were divided into two groups, 71 mothers of children with cerebral palsy and 70 mothers of healthy children from the Tuzla Canton (Bosnia and Herzegovina). A multidimensional questionnaire PedsQLTM 2.0 Family Impact Mode was used for assessment of the impact of pediatric chronic health condition on the mothers' functioning. Th e level of functional disability of the child was measured by the Gross Motor Function Classification System (GMFCS levels I-V) scale. Mothers of children with cerebral palsy had poorer quality of life than mothers of healthy children in all investigated domains. In relation to mobility of the child, the quality of life was worse in mothers whose children did not move in the area of social functioning in comparison to mothers whose children had the ability to move independently. A statistically significant negative correlation existed between functional status of a child measured with GMFCS and social functioning of mothers, mothers' daily activities, parental functioning, family functioning, and overall quality of life of mothers. PMID- 29485799 TI - Development of Respiratory Allergies, Asthma and Allergic Rhinits in Children with Atopic Dermatitis. AB - Children with atopic dermatitis (AD) usually develop symptoms when they reach the age of 6-7 years, but the risk of developing respiratory allergies, asthma and allergic rhinitis (AR) remains high. In most children with AD, the development of asthma and AR is associated with sensitization to food allergens and/or aeroallergens, while only a small percentage missed atopic diathesis. In about 35% of children with AD, food allergy is the provoking cause, and 60% of infants who had AD in the first 3 months of life were sensitized against aeroallergens by the age of 5. The aim of the study was to follow development of asthma and AR and to assess the most significant risk factors for developing respiratory allergy. A total of 114 children with AD were followed up for five years. At annual visits, the severity of disease, total immunoglobulin E (IgE) antibody values, skin prick tests, specific IgE antibodies to food allergens and aeroallergens, and absolute eosinophil count were assessed. Information on the family history of atopy and AD, feeding patterns during infancy, data on sensitivity to food allergens and/or aeroallergens, and on the occurrence of bronchial obstruction and nose symptoms were obtained. Asthma developed in 36 children, median age 7.7 years; 33 children had symptoms of AR, and 13 children with AD had both diseases associated; 38 children had sensitivity to food, of which 24 developed asthma and 13 AR; asthma developed in 18/23 children with sensitivity to aeroallergens, and almost an equal number of children developed AR. The increased absolute eosinophil count and specific IgE to aeroallergens and food allergens were the best asthma predictors, while AR predictors were family history and early onset of AD. In conclusion, children with AD are at a significant risk of developing respiratory allergies, and those with the increased absolute eosinophil count, positive specific IgE to aeroallergens and food allergens, heredity of AD, and early onset of AD are at the highest risk. Identification of risk factors will enable us to improve the treatments of AD in order to reduce the severity of disease and prevent manifestation of respiratory allergy. PMID- 29485800 TI - Laparoscopic Treatment of Morgagni Hernia: Report of Three Cases. AB - We report on three cases of diaphragmatic (Morgagni) hernia with different clinical presentation. It is important to consider the possibility of this rare but potentially very dangerous condition in patients with respiratory problems and pain in the upper abdomen. Before laparoscopy, two different approaches were used in diaphragmatic hernia operations (abdominal and thoracic approach). Laparoscopy has brought significant changes in the treatment of diaphragmatic hernia. It is important to stress that laparoscopic diaphragmatic surgical therapy uses stronger mesh than the mesh used to repair an inguinal hernia. PMID- 29485801 TI - Primary Oral Mucosal Melanomas - Two Case Reports and Comprehensive Literature Review. AB - Oral melanoma (OM) occurs from activated or genetically altered epidermal melanocytes. There is no scientific evidence that OM can be linked to physical, chemical and thermal irritation, or to other risk factors of the oral cavity. According to fi gures from various countries, OM accounts for 0.2% to 7.5% ( Japan) of all cases of melanoma of the skin and mucous membrane. The male to female ratio of OM is 2:1. About 80% of OMs are located in the mucosa of the palate and maxillary gingiva. This paper presents two cases of oral mucosal melanoma of the upper and lower lips in women aged 62 and 59 years. Diagnosis, differential diagnosis and therapy are reported. PMID- 29485802 TI - Tolosa-Hunt Syndrome - Case Report. AB - This case report presents a patient diagnosed with Tolosa-Hunt syndrome (THS) after an extensive neuro-diagnostic and neuroimaging evaluation. Diagnostic work up included thorough physical and neurological examination, complete laboratory serum assessments, neuroendocrine and immunohistochemistry analysis, cerebrospinal fluid analysis, neurophysiology assessment, ophthalmologist examination and neuroimaging. Th e most important diagnostic tool in deriving the diagnosis of THS was neuroimaging evaluation that included baseline and follow-up cranial contrast enhanced magnetic resonance imaging (MRI). Baseline cranial contrast enhanced MRI detected a nonspecific inflammatory granulomatous lesion in the right cavernous sinus extending basally towards the right trigeminal cave (Meckel's cave) and anteriorly towards the apex of the right orbit. Systemic intravenous high-dose corticosteroid therapy was administered for 3 consecutive days and then tapered down to lower oral steroid doses. Following therapy, the patient experienced complete regression of symptoms. Follow-up cranial contrast enhanced MRI showed significant regression of inflammatory lesion in the area of right cavernous sinus, thus verifying the efficacy of the treatment applied. This paper shows that an extensive diagnostic schedule for THS must be conducted prior to therapeutic treatment, for the possibility of alternative diagnosis. Patients suspected of having THS require careful evaluation, appropriate treatment, and follow-up. PMID- 29485803 TI - Extensive Deep Venous Thrombosis in a Young Male Patient as the First Manifestation of a Rare Venous Anomaly - Inferior Vena Cava Duplication: Case Report. AB - Although venous thromboembolism (VTE) including deep venous thrombosis (DVT) and pulmonary embolism is a major health problem in the world, it is an infrequent disease among young people. It is always mandatory to look at the underlying conditions for VTE, and in young patients, inherited prothrombotic factors should also be evaluated, especially in case of unprovoked VTE. Anomalies of inferior vena cava (IVC) are very rare in the general population. In this case report we describe rare occurrence of extensive DVT in a young male patient with rare anomaly of IVC - duplication of IVC - as a predisposition factor for DVT. Physicians need to be reminded of the IVC anomalies that should be considered in young patients with idiopathic DVT of lower extremity, which may require extended anticoagulant treatment. PMID- 29485804 TI - What is the Right Therapeutic Approach to Biliary Choledochal Cyst? AB - We report a case of biliary cyst type II which, independently of its a priori benign nature, caused numerous complications such as recurrent cholangitis and pancreatitis, as well as subsequent hepatic fibrosis and the potential danger of choledochocele perforation. Although they are benign, biliary/choledochal cysts can cause numerous disorders such as cholestasis, leading to cholangitis and pancreatitis and biliary sepsis, and due to chronic inflammation of the biliary system even cholangiocarcinogenesis. Our findings showed that sometimes this type of biliary cyst (according to the available literature the rarest and most benign type), as well as type I cyst, should undergo timely radical excision. In our patient, timely choledochocele resection would have certainly contributed to the reduction of subsequent complications, as well as to obviating repeated invasive diagnostic and surgical procedures. PMID- 29485806 TI - Suburethral Leiomyoma. PMID- 29485805 TI - Re: Aortoduodenal Fistula Three Years After Aortobifemoral Bypass: Case Report and Literature Review. PMID- 29485807 TI - Central nervous system abnormalities and psychomotor retardation in a girl with a 15.4-MB deletion of 14q12->q21.2 and a 550-KB deletion of 18p11.23: microarray delineation of an unbalanced chromosome rearrangement and a literature review. AB - This paper describes the presence of a 15.4 Mb deletion of 14q12->q21.2 and a 550 KB deletion of 18p11.23 in a patient with an apparently balanced translocation between chromosomes 14 and 18 [t( 14; 18) (ql2; pi 11)]. The patient had developmental delay, truncal hypotonia, hyperreflexia and spasticity of the lower extremities, prominent forehead, fullness of the periorbital region, hypertelorism, upslanted palpebral fissures, systagmus, a depressed nasal bridge, down-turned conrners of the mouth, a prominent philtrum, thin upper lip, pointed chin, and deep palmar creases. Cranial MRI revealed agenesis of the corpus callosum, diffuse cerebral atrophy, and enlargement of the third and lateral ventricles. Here, we review and compare published cases with proximal 14q deletions to establish a genotype-phenotype correlation according to the deleted regions involving the 14q12, 14q13, 14q21, and 14q22q23. We also examined the literature to find cases with deleted regions overlapping the deletion in our patient to establish a clinical spectrum in proximal 14q deletions. PMID- 29485808 TI - Distal 13q monosomy and neural tube defects. AB - We present a fetus with typical manifestations of distal monosomy 13q (oligodactyly, heart defect, anal atresia, hypoplastic kidneys) and der( 13)t( 1 ; 13)(q42;q21)pat. He also had exencephaly which at this developmental stage is an embryological precursor of anencephaly. Detailed analysis of neural tube defects (NTD) in publications about distal monosomy 13q showed that most defects affect cranial aspect of the neural tube (anencephaly, exencephaly, encephaloceles) with a relative small proportion of spina bifida. There are strong evidences that the gene(s) responsible for the origin of NTD in distal monosomy 13q has to be located within 13q33q34 segments. However, our analysis showed that NTD are much more common for the patients (fetuses) having larger deletions (with breakpoints at 13q22 or more proximal). These data suggest that the 13q22 segment includes a regulatory element somehow controlling function of the "distal" NTD-related gene(s). PMID- 29485809 TI - A Deletion Mutation of the Connexin 26 (Gjb2) Gene in a Turkish Patient with Vohwinkel Syndrome . AB - Vohwinkel syndrome (VS), also known as keratoderma hereditaria mutilans, is a rare keratinization genetic disorder characterized by palmoplantar keratoderma, skeletal dysmorphisms and varying degrees of sensorineural deafness. Its mode of inheritance is autosomal-dominant, with mutations in loricrin and connexin 26 (GJB2) genes that manifest during infancy and boceme more evident during adulthood. We herein report a case of VS in a 23-year-old female exhibiting sensorineural hearing loss, palmar keratoderma and homozygous deletion mutation delE120 (c.358-360delGAG) in the GJB2 gene. VS, is a rare genetic disorder, should be considered in patients with palmoplantar keratoderma and hearing loss and should be investigated connexin 26 (GJB2) gene mutation. PMID- 29485810 TI - Rising Stars of HIT Leadership. PMID- 29485811 TI - The 2016 HMT salary survey: A snapshot of the HIT labor force. PMID- 29485813 TI - Connecting the continuum--and beyond: Sharing health information between providers should be everyone's priority. PMID- 29485812 TI - Mitochondrial Neurogastrointestinal Encephalopathy: Clinical, Biochemical and Molecular Study in Three Egyptian Patients. AB - Background: Mitochondrial Neurogastrointestinal Encephalopathy syndrome is a rare autosomal recessive disorder. The disease is caused by mutations in the thymidine phosphorylase gene. This article reports the clinical, biochemical and molecular findings in three Egyptian patients with Mitochondrial Neurogastrointestinal Encephalopathy sundrome from two different pedigrees. Subjects and Methods: The three patients were subjected to thorough neurologic examination. Brain Magtnetic Resonance Imaging. Histochemical and biochemical assay of the mitochondrial respiratory chain complexes in muscle homogenate was performed (1/3). Thymidine Phosphorylase enzyme activity was performed in 2/3 patients and Thymidine Phosphorylase gene sequencing was done (2/3) to confirm the diagnosis. Results: All patients presented with symptoms of severe gastrointestinal dysmotility with progressive cachexia, neuropathy, sensory neural hearing loss, asymptomatic leukoencephalopathy. Histochemical analysis of themuscle biopsy revealed deficient cytochrome C oxidase and mitochrondrial respiratory chain enzyme assay revealed isolated complex 1 deficiency (1/3). Thymidine Phosphorylase enzyme activity revealed complete absence of enzyme activity in 2/3 patients. Direct sequencing of Thymidine Phosphorylase gene revealed c.3371 A>C homozygous mutation. Molecular screening of both families revealed heterozygous mutation in both parents and 4 siblings. Conclusions: Mitochondrial Neurogastrointestinal Encephalopathy syndrome is a rare mitochondrial disorder with an important diagnostic delay. In case of pathogenic mutations in Thymidine Phosphorylase gene in the family, carrier testing and prenatal diagmosis of at risk members is recommended for early detection. The possibility of new therapeutic options makes it necessary to diagnose the disease in an early state. PMID- 29485814 TI - Why digitization is changing the way healthcare providers share data. PMID- 29485815 TI - Provider communications in a risk-based world. PMID- 29485816 TI - Three disaster recovery mistakes and how to avoid them. PMID- 29485817 TI - You've been breached! Now what? PMID- 29485819 TI - Nine steps to better disaster recovery planning. PMID- 29485820 TI - Being prepared in the age of HIPAA audits. PMID- 29485821 TI - The dread of data sharing: Why does sharing health information remain a struggle? PMID- 29485822 TI - Can the cloud really offer better service at a lower cost? PMID- 29485823 TI - How ACOs can better manage two-sided risk. PMID- 29485824 TI - Annular Pancreas, Severe Tracheomalacia and Bronchomalacia in a Preterm Boy with Vacterl Association. AB - VACTERL association includes vertebral anomalies, anal atresia, cardiac defects, tracheao-esophageal fistula, renal anomalies, and limb abnormalities. It is defined by the presence of at least three of these congenital malformations. The incidence has been estimated to be 1/10.000-1/40.000 live births. We report on a preterm infant with VACTERL presentin with respiratory complicatons due to the presence of severe tracheomalacia and bronchomalacia. He also had an annular pancreas. PMID- 29485825 TI - A Rare Case of Hanhart Syndrome with Mild Developmental Delay. AB - Hanhart Syndrome (OMIM 103300) is an extremely rare syndrome with some congenital malformations. It is characterized by hypoglossia, adactylia/hypodactylia, peromelia of arms and/or legs and micrognathia. The severity of the symptoms can differ from patient to patient. Some affected individuals may have only a part of these clinical features. In this case report, we want to present a Turkish girl with hypoglossia, micrognathia and peromelia who was diagnosed according to the clinical and radiographic findings. PMID- 29485826 TI - The clinical spectrum of a rare chromosomal abnormality: Isochromosome 18p. AB - Isochromosome 18p is a rare chromosomal disorder that occurs with a frequency of approximately one in every 180,000 live births, and affects both genders equally. MOst cases result from a de novo formation. In the literature, there are currently only a small number of reports that describe the phenotypic and clinical features of Isochromosome 18p. In this article, we report six cases that displayed the phenotypic and clinical features of Isochromosome 18p, and which were subsequently confirmed by conventional karyotyping and fluorescence in situ hybridization. We also discuss the clinical features of these patients in the context of the cases previously reported in the literature. PMID- 29485827 TI - Ultrasonographic and Cytogenetic Issues in Prenatal Diagnosis of Pallister Killian Syndrome. PMID- 29485828 TI - Penile Plexiform Neurofibroma in a Patient with Neurofibromatosis I. PMID- 29485829 TI - A Newborn with Down Syndrome, Developing Hydrops Fetalis Due to Transient Myeloproliferative Disorder and Liver Hamartoma. PMID- 29485830 TI - Sick and Tired of Being Sick and Tired: Putting an End to Separate and Unequal Health Care in the United States 50 Years After the Civil Rights Act of 1964. PMID- 29485831 TI - Concomitance of Goldenhar Syndrome with Congenital Alopecia Areata. PMID- 29485832 TI - Transmembrane Activator and Caml Interactor (Taci) Haploinsufficiency in B-Cell Dysfunction in a Patient with Smith-Magenis Syndrome. PMID- 29485833 TI - A Novel Mutation of the Gaa Gene in a Patient with Early-Onset Pompe Disease Lacking a Disease-Specific Pathology. PMID- 29485834 TI - Basal Cell Nevus (Gorlin) Syndrome with a Novel Heterozygous Deletion Frameshift Mutation (C.959delc, P.val322 Phe Fsx2) in the Ptch1 Gene Associated with Epiretinal Membrane, Odontogenic Keratocysts and without Skin Lesions and Falx Cerebri Calcification. PMID- 29485835 TI - Dyskeratosis Congenita: A Case Report. PMID- 29485836 TI - A Boy with Short Stature, Unusual Findings and Low Percentage of 45,x(4%) / 46,xy(96%) Mosaicism. PMID- 29485837 TI - Distal trisomy 10q due to maternal insertional translocation (15;10): A case report and review of literature. PMID- 29485838 TI - Kept in Mind Infantile Neuroaxonal Dystrophy. PMID- 29485839 TI - The "Golden Rules" for Eliminating Disparities: Title VI, Medicare, and the Implementation of the Affordable Care Act. AB - Addressing health care disparities rarely focuses on how the "gold" (meaning the federal dollars flowing into the nation's health system) has, at different times, both widened and narrowed health care disparities. This paper describes (1) the early attempts to use the power of the federal purse to address disparities that led to the enactment of Title VI of the 1964 Civil Rights Act; (2) how Title VI, as applied in the implementation of Medicare, reduced disparities; and (3) the lessons that this story offers for similar opportunities in the implementation of the Affordable Care Act (ACA). Reducing disparities with the implementation of the ACA will require (1) rekindling the spirit of the grass roots movement that captured the Title VI enforcement process with the implementation of Medicare; (2) exposing adversaries through data disclosure and taking advantage of the "invisible army" that supports these goals; (3) using the power of both the economic and ethical versions of the Golden Rule; and (4) creating the political insulation and urgency necessary to reduce health care disparities. PMID- 29485840 TI - Toward a Structural Theory of Implicit Racial and Ethnic Bias in Health Care. PMID- 29485841 TI - Race and Rationing. PMID- 29485842 TI - Understanding and Addressing the Common Roots of Racial Health Disparities: The Case of Cardiovascular Disease and HIV/AIDS in African Americans. PMID- 29485843 TI - Pathogenic Compound Heterozygous Mutations in a Mexican Mestizo Patient with Niemann-Pick Disease Type B. AB - Niemann-Pick disease (NPD) type B is a lysosomal storage disorder caused by a deficiency of acid sphingomyelinase (ASM). We report the clinical follow-up of a 16-year-old Mexican mestizo woman with a NPD type B phenotype who presented hepatosplenomegaly, persitstenly low high-density lipoprotein (HDL) cholesterol and thrombocytopenia, without central nervous system involvement. After of a dengue fever episode with severe anemia and pancytopenia, leading to a bone marrow study n which foamy histiocytes were noticed and diagnosis of NiemannPick disease was suspected; and confirmed by biochemical and molecular tests. The missense c.1343 A>G (p.Tyr448Cys, formerly Y446C) and c. 1426C>T (p.Arg476Trp, formerly R474W) mutations in the SMPD1 gene were identified. These mutations have never been reported in the Mexican population. Since the c.1343 A>G (Y446C) mutation has been previously reported in a Japanese patient with NPD type A, we suggest an attenuator effect of c.1426C>T (R474W) allele (previously associated with the NPD type B phenotype). In conclusion, this is the first description of the concomitant occurrence of Y446C and R476W mutations in a Mexican patient with NPD type B, showing the importance of increased awareness and availability of specialized diagnostic tests in the diagnosis of rare inherited metabolic diseases. PMID- 29485844 TI - Biologic Drugs, Biosimilars, and Barriers to Entry. AB - Biologic drugs represent an important new category of drugs in the effort to improve health outcomes in this country. Yet, thesecutting-edge drugs are often cost prohibitive, preventing access for many Americans. Recognizing the need for more affordable, genericsubstitutes for biologic drugs-or biosimilars-Congress recently created a biosimilars approval pathway that would enable thesecheaper biologic drugs to obtain FDA approval and reach patients more quickly. Unfortunately, original biologics manufacturers havesought to extend their current monopoly profits by erecting various legal and regulatory barriers to entry. Their legal maneuvers takemany forms, from delaying approval of safe biosimilars to abrogating previous commitments to international drug-naming protocols, andeven circumventing Congressional intent for biosimilar substitution. Regrettably, these policies reduce competition in the market forbiologic drugs, impede drug innovation, increase drug costs, and limit patient access to these important medications. This article exploresthe conflict between biologics and biosimilars, and the consequences that barriers to biosimilar entry in this market will create. PMID- 29485846 TI - Why the Medical Malpractice Crisis Persists Even When Malpractice Insurance Premiums Fall. PMID- 29485847 TI - Designing Recognition Molecules and Tailoring Functional Surfaces for In Vivo Monitoring of Small Molecules in the Brain. AB - The in vivo analysis of chemical signals in brain extracellular fluid (ECF) using implanted electrochemical biosensors is a vital way to study brain functions and brain activity mapping. This approach offers excellent spatial (10-200 MUm) and temporal (approximately second) resolution and the major advantage of long-term stability. By implantation of a microelectrode in a specific brain region, changes in the concentration of a variety of ECF chemical species can be monitored through applying a suitable electrical signal and, typically, recording the resulting Faradaic current. However, the high performance requirements for in vivo biosensors greatly limit our understanding of the roles that biomolecules play in the brain. Since a large number of biological species, including reactive oxygen species (ROS), metal ions, amino acids, and proteins, coexist in the brain and interact with each other, developing in vivo biosensors with high selectivity is a great challenge. Meanwhile, it is difficult to quantitatively determine target molecules in the brain because of the variation in the distinct environments for monitoring biomolecules in vitro and in vivo. Thus, there are large errors in the quantification of concentrations in the brain using calibration curves obtained in artificial cerebrospinal fluid (aCSF). More importantly, to gain a full understanding of the physiological and pathological processes in the brain, the development of novel approaches for the simultaneous determination of multiple species in vivo is urgently needed. This Account provides insight into the basic design principles and criteria required to convert chemical/electrochemical reactions into electric signals, while satisfying the increasing requirements, including high selectivity, sensitivity, and accuracy, for the in vivo analysis of biomolecules in the brain. Recent developments in designing various functional surfaces, such as self-assembled monolayers, gold nanostructures, and nanostructured semiconductors for facilitating electron transfer from specific enzymes, including superoxide dismutase (SOD), and further application to an O2*- biosensor are summarized. This Account also aims to highlight the design principles for the selective biosensing of Cu2+ and pH in the brain through the rational design and synthesis of specific recognition molecules. Additionally, electrochemical ratiometric biosensors with current signal output have been constructed to correct the effect of distinct environments in a timely manner, thus greatly improving the accuracy of the determination of Cu2+ in the live brain. This method of using a built-in element has been extended to biosensors with the potential signal output for in vivo pH analysis. More importantly, the new concept of both current and potential signal outputs provides an avenue to simultaneously determine dual species in the brain. The extension of the design principles and developed strategy demonstrated in this Account to other biomolecules, which may be closely correlated to the biological processes of brain events, is promising. The final section of this Account outlines potential future directions in tailoring functional surfaces and designing recognition molecules based on recent advances in molecular science, nanoscience and nanotechnology, and biological chemistry for the design of advanced devices with multiple target species to map the molecular imaging of the brain. There are still opportunities to engineer surfaces that improve on this approach by constructing implantable, multifunctional nanodevices that promise to combine the benefits of multiple sensing and therapeutic modules. PMID- 29485848 TI - Subcutaneous Nanodisc Vaccination with Neoantigens for Combination Cancer Immunotherapy. AB - While cancer immunotherapy provides new exciting treatment options for patients, there is an urgent need for new strategies that can synergize with immune checkpoint blockers and boost the patient response rates. We have developed a personalized vaccine nanodisc platform based on synthetic high-density lipoproteins for co-delivery of immunostimulatory agents and tumor antigens, including tumor-specific neoantigens. Here we examined the route of delivery, safety profiles, and therapeutic efficacy of nanodisc vaccination against established tumors. We report that nanodiscs administered via the subcutaneous (SC) or intramuscular (IM) routes were well tolerated in mice without any signs of toxicity. The SC route significantly enhanced nanoparticle delivery to draining lymph nodes, improved nanodisc uptake by antigen-presenting cells, and generated 7-fold higher frequency of neoantigen-specific T cells, compared with the IM route. Importantly, when mice bearing advanced B16F10 melanoma tumors were treated with nanodiscs plus anti-PD-1 and anti-CTLA-4 IgG therapy, the combination immunotherapy exerted potent antitumor efficacy, leading to eradication of established tumors in ~60% of animals. These results demonstrate nanodiscs customized with patient-specific tumor neoepitopes as a safe and powerful vaccine platform for immunotherapy against advanced cancer. PMID- 29485849 TI - Intestinal Mucin Induces More Endocytosis but Less Transcytosis of Nanoparticles across Enterocytes by Triggering Nanoclustering and Strengthening the Retrograde Pathway. AB - Mucus, which is secreted by the goblet cells of enterocytes, constitutes the first obstacle encountered for the intestinal absorption of nanomedicines. For decades, mucus has simply been regarded as a physical barrier that hinders the permeation and absorption of drugs, because of its high viscosity and reticular structure, whereas the interaction of mucus ingredients with nanomedicines is usually neglected. It is unclear whether glycoproteins, as the main components of mucus, interact with nanomedicines. We also do not know how the potential interaction affects the subsequent transportation of nanomedicines through the intestinal epithelium. In this study, mucin as the key element of mucus was investigated to characterize the interaction of nanomedicines with mucus. PEG modified gold nanoparticles (PGNPs) were fabricated as model nanoparticles. Mucin was found to adhere to the nanoparticle surface to form a corona structure and induce the clustering of PGNPs by joining particles together, demonstrating the interaction between mucin and PGNPs. In addition, two intestinal epithelia, Caco 2 (non- mucus secretion) and HT-29 (high mucus secretion), were compared to evaluate the influence of mucin on the cellular interaction of PGNPs. Amazingly, mucin altered the trafficking characteristic of PGNPs in intestinal epithelium. Both in vitro and in vivo investigations demonstrated more nanoparticles being internalized by cells due to the mucin coverage. However, mucin induced a significant reduction in the transcytosis of PGNPs across epithelial monolayers. The mechanism exploration further revealed that the "more endocytosis but less transcytosis (MELT)" effect was mainly attributed to the strengthened retrograde pathway in which more PGNPs were transported to Golgi apparatus and exocytosed back to the apical but not the basolateral side of the epithelial monolayers. The "MELT" effect endowed mucin with duality in the nanoparticle transportation. Therefore, the rational regulation based on the "MELT" effect will provide new insight into overcoming the mucus obstacle as a barrier and enhancing the oral absorption rate of nanomedicines. PMID- 29485850 TI - Self-Assembled Polystyrene Beads for Templated Covalent Functionalization of Graphitic Substrates Using Diazonium Chemistry. AB - A network of self-assembled polystyrene beads was employed as a lithographic mask during covalent functionalization reactions on graphitic surfaces to create nanocorrals for confined molecular self-assembly studies. The beads were initially assembled into hexagonal arrays at the air-liquid interface and then transferred to the substrate surface. Subsequent electrochemical grafting reactions involving aryl diazonium molecules created covalently bound molecular units that were localized in the void space between the nanospheres. Removal of the bead template exposed hexagonally arranged circular nanocorrals separated by regions of chemisorbed molecules. Small molecule self-assembly was then investigated inside the resultant nanocorrals using scanning tunneling microscopy to highlight localized confinement effects. Overall, this work illustrates the utility of self-assembly principles to transcend length scale gaps in the development of hierarchically patterned molecular materials. PMID- 29485851 TI - Structurally Controlled Large-Area 10 nm Pitch Graphene Nanomesh by Focused Helium Ion Beam Milling. AB - Graphene nanomesh (GNM) is formed by patterning graphene with nanometer-scale pores separated by narrow necks. GNMs are of interest due to their potential semiconducting characteristics when quantum confinement in the necks leads to an energy gap opening. GNMs also have potential for use in phonon control and water filtration. Furthermore, physical phenomena, such as spin qubit, are predicted at pitches below 10 nm fabricated with precise structural control. Current GNM patterning techniques suffer from either large dimensions or a lack of structural control. This work establishes reliable GNM patterning with a sub-10 nm pitch and an < 4 nm pore diameter by the direct helium ion beam milling of suspended monolayer graphene. Due to the simplicity of the method, no postpatterning processing is required. Electrical transport measurements reveal an effective energy gap opening of up to ~450 meV. The reported technique combines the highest resolution with structural control and opens a path toward GNM-based, room temperature semiconducting applications. PMID- 29485852 TI - Functionally Biased D2R Antagonists: Targeting the beta-Arrestin Pathway to Improve Antipsychotic Treatment. AB - Schizophrenia is a severe neuropsychiatric disease that lacks completely effective and safe therapies. As a polygenic disorder, genetic studies have only started to shed light on its complex etiology. To date, the positive symptoms of schizophrenia are well-managed by antipsychotic drugs, which primarily target the dopamine D2 receptor (D2R). However, these antipsychotics are often accompanied by severe side effects, including motoric symptoms. At D2R, antipsychotic drugs antagonize both G-protein dependent (Galphai/o) signaling and G-protein independent (beta-arrestin) signaling. However, the relevant contributions of the distinct D2R signaling pathways to antipsychotic efficacy and on-target side effects (motoric) are still incompletely understood. Recent evidence from mouse genetic and pharmacological studies point to beta-arrestin signaling as the major driver of antipsychotic efficacy and suggest that a beta-arrestin biased D2R antagonist could achieve an additional level of selectivity at D2R, increasing the therapeutic index of next generation antipsychotics. Here, we characterize BRD5814, a highly brain penetrant beta-arrestin biased D2R antagonist. BRD5814 demonstrated good target engagement via PET imaging, achieving efficacy in an amphetamine-induced hyperlocomotion mouse model with strongly reduced motoric side effects in a rotarod performance test. This proof of concept study opens the possibility for the development of a new generation of pathway selective antipsychotics at D2R with reduced side effect profiles for the treatment of schizophrenia. PMID- 29485853 TI - Detection and Manipulation of Charge States for Double-Decker DyPc2 Molecules on Ultrathin CuO Films. AB - Charge states of lanthanide double-decker phthalocyanines complexes significantly influence their geometrical structures and magnetic properties. In this study, the charge states of single DyPc2 molecules on an ultrathin CuO film were detected by scanning tunneling microscopy and spectroscopy in magnetic fields. Four types of adsorptions of DyPc2 molecules on CuO were experimentally observed. Without applying voltages, two of them were positively charged with the other two at the neutral state. By controlling the sample bias, two types of neutral molecules can be switched to the positively and negatively charged states, respectively. This manipulation was not realized for the DyPc2 cations. A way to precisely detect the molecular charge states with and without current is beneficial for the development of molecular electronics. PMID- 29485854 TI - Toward Understanding in Vivo Sequestration of Nanoparticles at the Molecular Level. AB - A longstanding and widely accepted bottleneck in the targeted delivery of intravenously injected nanoparticles lies in their clearance by macrophages in the liver and spleen. In this Perspective, we call for deeper understanding of the critical role of endothelial cells in the sequestration of nanoparticles in vivo. In this issue of ACS Nano, Campbell et al. used a combination of real-time imaging and genome-editing methods to demonstrate that stabilin-2 is an important receptor for removing anionic liposomes from blood circulation in a zebrafish model. Such mechanistic insights at the molecular level will provide a more holistic picture of the in vivo sequestration of administered nanoparticles beyond the cellular level and pose valuable design considerations for redistributing nanoparticles in vivo. PMID- 29485855 TI - Molecular Umbrellas Modulate the Selective Toxicity of Polyene Macrolide Antifungals. AB - Antifungal polyene macrolide antibiotics Amphotericin B (AmB) and Nystatin (NYS) were conjugated through the omega-amino acid linkers with diwalled "molecular umbrellas" composed of spermidine-linked deoxycholic or cholic acids. The presence of "umbrella" substituents modulated biological properties of the antibiotics, especially their selective toxicity. Some of the AmB-umbrella conjugates demonstrated antifungal in vitro activity comparable to that of the mother antibiotic but diminished mammalian toxicity, especially the hemolytic activity. In contrast, antifungal in vitro activity of NYS-umbrella conjugates was strongly reduced and all these conjugates demonstrated poorer than NYS selective toxicity. No correlation between the aggregation state and hemolytic activity of the novel conjugates was found. PMID- 29485856 TI - SWATHtoMRM: Development of High-Coverage Targeted Metabolomics Method Using SWATH Technology for Biomarker Discovery. AB - The complexity of metabolome presents a great analytical challenge for quantitative metabolite profiling, and restricts the application of metabolomics in biomarker discovery. Targeted metabolomics using multiple-reaction monitoring (MRM) technique has excellent capability for quantitative analysis, but suffers from the limited metabolite coverage. To address this challenge, we developed a new strategy, namely, SWATHtoMRM, which utilizes the broad coverage of SWATH-MS technology to develop high-coverage targeted metabolomics method. Specifically, SWATH-MS technique was first utilized to untargeted profile one pooled biological sample and to acquire the MS2 spectra for all metabolites. Then, SWATHtoMRM was used to extract the large-scale MRM transitions for targeted analysis with coverage as high as 1000-2000 metabolites. Then, we demonstrated the advantages of SWATHtoMRM method in quantitative analysis such as coverage, reproducibility, sensitivity, and dynamic range. Finally, we applied our SWATHtoMRM approach to discover potential metabolite biomarkers for colorectal cancer (CRC) diagnosis. A high-coverage targeted metabolomics method with 1303 metabolites in one injection was developed to profile colorectal cancer tissues from CRC patients. A total of 20 potential metabolite biomarkers were discovered and validated for CRC diagnosis. In plasma samples from CRC patients, 17 out of 20 potential biomarkers were further validated to be associated with tumor resection, which may have a great potential in assessing the prognosis of CRC patients after tumor resection. Together, the SWATHtoMRM strategy provides a new way to develop high-coverage targeted metabolomics method, and facilitates the application of targeted metabolomics in disease biomarker discovery. The SWATHtoMRM program is freely available on the Internet ( http://www.zhulab.cn/software.php ). PMID- 29485858 TI - Elegant Face-Down Liquid-Space-Restricted Deposition of CsPbBr3 Films for Efficient Carbon-Based All-Inorganic Planar Perovskite Solar Cells. AB - It is a great challenge to obtain the uniform films of bromide-rich perovskites such as CsPbBr3 in the two-step sequential solution process (two-step method), which was mainly due to the decomposition of the precursor films in solution. Herein, we demonstrated a novel and elegant face-down liquid-space-restricted deposition to inhibit the decomposition and fabricate high-quality CsPbBr3 perovskite films. This method is highly reproducible, and the surface of the films was smooth and uniform with an average grain size of 860 nm. As a consequence, the planar perovskite solar cells (PSCs) without the hole-transport layer based on CsPbBr3 and carbon electrodes exhibit enhanced power conversion efficiency (PCE) along with high open circuit voltage ( VOC). The champion device has achieved a PCE of 5.86% with a VOC of 1.34 V, which to our knowledge is the highest performing CsPbBr3 PSC in planar structure. Our results suggest an efficient and low-cost route to fabricate the high-quality planar all-inorganic PSCs. PMID- 29485859 TI - Stepwise Hydrogen Atom and Proton Transfers in Dioxygen Reduction by Aryl-Alcohol Oxidase. AB - The mechanism of dioxygen reduction by the flavoenzyme aryl-alcohol oxidase was investigated with kinetic isotope, viscosity, and pL (pH/pD) effects in rapid kinetics experiments by stopped-flow spectrophotometry of the oxidative half reaction of the enzyme. Double mixing of the enzyme in a stopped-flow spectrophotometer with [alpha-2H2]- p-methoxybenzyl alcohol and oxygen at varying aging times established a slow rate constant of 0.0023 s-1 for the wash-out of the D atom from the N5 atom of the reduced flavin. Thus, the deuterated substrate could be used to probe the cleavage of the N-H bond of the reduced flavin in the oxidative half-reaction. A significant and pH-independent substrate kinetic isotope effect (KIE) of 1.5 between pH 5.0 and 8.0 demonstrated that H transfer is partially limiting the oxidative half-reaction of the enzyme; a negligible solvent KIE of 1.0 between pD 5.0 and 8.0 proved a fast H+ transfer reaction that does not contribute to determining the flavin oxidation rates. Thus, a mechanism for dioxygen reduction in which the H atom originating from the reduced flavin and a H+ from a solvent exchangeable site are transferred in separate kinetic steps is proposed. The spectroscopic and kinetic data presented also showed a lack of stabilization of transient flavin intermediates. The substantial differences in the mechanistic details of O2 reduction by aryl-alcohol oxidase with respect to other alcohol oxidases like choline oxidase, pyranose 2-oxidase, and glucose oxidase further demonstrate the high level of versatility of the flavin cofactor in flavoenzymes. PMID- 29485857 TI - Structural and Kinetic Studies of the Potent Inhibition of Metallo-beta lactamases by 6-Phosphonomethylpyridine-2-carboxylates. AB - There are currently no clinically available inhibitors of metallo-beta-lactamases (MBLs), enzymes that hydrolyze beta-lactam antibiotics and confer resistance to Gram-negative bacteria. Here we present 6-phosphonomethylpyridine-2-carboxylates (PMPCs) as potent inhibitors of subclass B1 (IMP-1, VIM-2, and NDM-1) and B3 (L1) MBLs. Inhibition followed a competitive, slow-binding model without an isomerization step (IC50 values of 0.3-7.2 MUM; Ki values of 0.03-1.5 MUM). Minimum inhibitory concentration assays demonstrated potentiation of beta-lactam (Meropenem) activity against MBL-producing bacteria, including clinical isolates, at concentrations at which eukaryotic cells remain viable. Crystal structures revealed unprecedented modes of binding of inhibitor to B1 (IMP-1) and B3 (L1) MBLs. In IMP-1, binding does not replace the nucleophilic hydroxide, and the PMPC carboxylate and pyridine nitrogen interact closely (2.3 and 2.7 A, respectively) with the Zn2 ion of the binuclear metal site. The phosphonate group makes limited interactions but is 2.6 A from the nucleophilic hydroxide. Furthermore, the presence of a water molecule interacting with the PMPC phosphonate and pyridine N C2 pi-bond, as well as the nucleophilic hydroxide, suggests that the PMPC binds to the MBL active site as its hydrate. Binding is markedly different in L1, with the phosphonate displacing both Zn2, forming a monozinc enzyme, and the nucleophilic hydroxide, while also making multiple interactions with the protein main chain and Zn1. The carboxylate and pyridine nitrogen interact with Ser221 and -223, respectively (3 A distance). The potency, low toxicity, cellular activity, and amenability to further modification of PMPCs indicate these and similar phosphonate compounds can be further considered for future MBL inhibitor development. PMID- 29485861 TI - Bisphosphonate-Linked TrkB Agonist: Cochlea-Targeted Delivery of a Neurotrophic Agent as a Strategy for the Treatment of Hearing Loss. AB - Hearing loss affects more than two-thirds of the elderly population, and more than 17% of all adults in the U.S. Sensorineural hearing loss related to noise exposure or aging is associated with loss of inner ear sensory hair cells (HCs), cochlear spiral ganglion neurons (SGNs), and ribbon synapses between HCs and SGNs, stimulating intense interest in therapies to regenerate synaptic function. 7,8-Dihydroxyflavone (DHF) is a selective and potent agonist of tropomyosin receptor kinase B (TrkB) and protects the neuron from apoptosis. Despite evidence that TrkB agonists can promote survival of SGNs, local delivery of drugs such as DHF to the inner ear remains a challenge. We previously demonstrated in an animal model that a fluorescently labeled bisphosphonate, 6-FAM-Zol, administered to the round window membrane penetrated the membrane and diffused throughout the cochlea. Given their affinity for bone mineral, including cochlear bone, bisphosphonates offer an intriguing modality for targeted delivery of neurotrophic agents to the SGNs to promote survival, neurite outgrowth, and, potentially, regeneration of synapses between HCs and SGNs. The design and synthesis of a bisphosphonate conjugate of DHF (Ris-DHF) is presented, with a preliminary evaluation of its neurotrophic activity. Ris-DHF increases neurite outgrowth in vitro, maintains this ability after binding to hydroxyapatite, and regenerates synapses in kainic acid-damaged cochlear organ of Corti explants dissected in vitro with attached SGNs. The results suggest that bisphosphonate TrkB agonist conjugates have promise as a novel approach to targeted delivery of drugs to treat sensorineural hearing loss. PMID- 29485860 TI - A "Seleno Effect" Differentiates the Roles of Redox Active Cysteine Residues in Plasmodium falciparum Thioredoxin Reductase. AB - Here, we introduce the concept of the "seleno effect" in the study of oxidoreductases that catalyze thiol/disulfide exchange reactions. In these reactions, selenium can replace sulfur as a nucleophile, electrophile, or leaving group, and the resulting change in rate (the seleno effect) is defined as kS/ kSe. In solution, selenium accelerates the rate of thiol/disulfide exchange regardless of its chemical role (e.g., nucleophile or electrophile). Here we show that this is not the case for enzyme catalyzed reactions and that the magnitude of the seleno effect can differentiate the role of each sulfur atom of a disulfide bond between that of an electrophile or leaving group. We used selenium for sulfur substitution to study the thiol/disulfide exchange step that occurs between the N-terminal redox center and the C-terminal disulfide-containing beta hairpin motif of Plasmodium falciparum thioredoxin reductase (PfTrxR), which has the sequence Gly-Cys535-Gly-Gly-Gly-Lys-Cys540-Gly. We assayed a truncated PfTrxR enzyme missing this C-terminal tail for disulfide-reductase activity using synthetic peptide substrates in which either Cys535 or Cys540 was replaced with selenocysteine (Sec). The results show that substitution of Cys535 with Sec resulted in a nearly 9-fold decrease in the rate of reduction, while substitution of Cys540 resulted in a 1.5-fold increase in the rate of reduction. We also produced full-length, semisynthetic enzymes in which Sec replaced either of these two Cys residues and observed similar results using E. coli thioredoxin as the substrate. In this assay, the observed seleno effect ( kS/ kSe) for the C535U mutant was 7.4, and that for the C540U mutant was 0.2. PMID- 29485862 TI - Substituted versus Naked Thiourea Ligand Containing Pseudotetrahedral Cobalt(II) Complexes: A Comparative Study on Its Magnetization Relaxation Dynamics Phenomenon. AB - A series of mononuclear tetrahedral cobalt(II) complexes with the general molecular formula [Co(L1)2X2] [where L1 = tetramethylthiourea ([(CH3)2N]2C?S) and X = Cl (1), Br (2), and I (3)] were isolated, and their structures were characterized by single-crystal X-ray diffraction. The experimental direct current magnetic data are excellently reproduced by fitting both chiM T( T) and M( H) simultaneously using the spin Hamiltonian (SH) parameters D1 = -18.1 cm-1 and g1,iso = 2.26, D2 = -16.4 cm-1 and g2,iso = 2.33, and D3 = -22 cm-1 and g3,iso = 2.4 for 1-3, respectively, and the sign of D was unambiguously confirmed from X-band electron paramagnetic resonance measurements. The effective energy barrier extracted for the magnetically diluted complexes 1-3 (10%) is larger than the barrier observed for the pure samples and implies a nonzero contribution of dipolar interaction to the magnetization relaxation dynamics. The SH parameters extracted for the three complexes drastically differ from their respective parent complexes that possess the general molecular formula [Co(L)2X2] [where L = thiourea [(NH2)2C?S] and X = Cl (1a), Br (2a), and I (3a)], which is rationalized by detailed ab initio calculations. An exhaustive theoretical study reveals that both the ground and excited states are not pure but rather multideterminental in nature (1-3). Noticeably, the substitution of L by L1 induces structural distortion in 1-3 on the level of the secondary coordination sphere compared to 1a-3a. This distortion leads to an overall reduction in | E/ D| of 1-3 compared to 1a-3a. This may be one of the reasons for the origin of the slower relaxation times of 1-3 compared to 1a-3a. PMID- 29485863 TI - Hydrogen and Halogen Bonding in Cyclic FH(4- n):FCl n Complexes, for n = 0-4. AB - Ab initio MP2/aug'-cc-pVTZ calculations have been carried out to investigate the six unique cyclic quaternary complexes FH:FH:FH:FH, FH:FH:FH:FCl, FH:FH:FCl:FCl, FH:FCl:FH:FCl, FH:FCl:FCl:FCl, and FCl:FCl:FCl:FCl stabilized by F-H...F hydrogen bonds and F-Cl...F halogen bonds. The binding energies of these complexes decrease as the number of FH molecules decreases, and therefore as the number of hydrogen bonds decreases, indicating that hydrogen bonds are primarily responsible for stabilities. Nonadditivities of binding energies are synergistic for complexes with 4, 3, and 2 FH molecules, but antagonistic for those with 1 and 0 FH molecules. In addition to depending on changes in F-F, F-H, and F-Cl distances, complex binding energies are also influenced by two sets of angular parameters. These include the external F-F-F angles which must sum to 360 degrees in these cyclic structures, and the internal H-F-F angles for hydrogen bonds and F-Cl-F angles for halogen bonds, which measure the deviation from linearity of these bonds. Transition structures present the barriers to converting an equilibrium structure to an equivalent equilibrium structure on the potential surfaces. These barriers increase as the number of FH molecules decreases. EOM CCSD spin-spin coupling constants 2h J(F-F) across hydrogen bonds in complexes tend to increase with decreasing F-F distance. They increase dramatically in transition structures, but show no dependence on the F-F distance. The one-bond coupling constants 1h J(F-H) are relatively small and negative in complexes, increase dramatically, and are positive in transition structures. 1 J(F-H) values are greatest for the covalent F-H bond. Coupling constants 1x J(F-Cl) across halogen bonds are relatively small and positive in complexes, and increase dramatically in transition structures. The largest values of 1 J(F-Cl) are found for covalent bonds. PMID- 29485864 TI - Discovery of 7-Oxo-2,4,5,7-tetrahydro-6 H-pyrazolo[3,4- c]pyridine Derivatives as Potent, Orally Available, and Brain-Penetrating Receptor Interacting Protein 1 (RIP1) Kinase Inhibitors: Analysis of Structure-Kinetic Relationships. AB - We report the discovery of 7-oxo-2,4,5,7-tetrahydro-6 H-pyrazolo[3,4- c]pyridine derivatives as a novel class of receptor interacting protein 1 (RIP1) kinase inhibitors. On the basis of the overlay study between HTS hit 10 and GSK2982772 (6) in RIP1 kinase, we designed and synthesized a novel class of RIP1 kinase inhibitor 11 possessing moderate RIP1 kinase inhibitory activity and P-gp mediated efflux. The optimization of the core structure and the exploration of appropriate substituents utilizing SBDD approach led to the discovery of 22, a highly potent, orally available, and brain-penetrating RIP1 kinase inhibitor with excellent PK profiles. Compound 22 significantly suppressed necroptotic cell death both in mouse and human cells. Oral administration of 22 (10 mg/kg, bid) attenuated disease progression in the mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Moreover, analysis of structure-kinetic relationship (SKR) for our novel chemical series was also discussed. PMID- 29485865 TI - Substrate-Directed Catalytic Selective Chemical Reactions. AB - The development of highly efficient reactions at only the desired position is one of the most important subjects in organic chemistry. Most of the reactions in current organic chemistry are reagent- or catalyst-controlled reactions, and the regio- and stereoselectivity of the reactions are determined by the inherent nature of the reagent or catalyst. In sharp contrast, substrate-directed reaction determines the selectivity of the reactions by the functional group on the substrate and can strictly distinguish sterically and electronically similar multiple reaction sites in the substrate. In this Perspective, three topics of substrate-directed reaction are mainly reviewed: (1) directing group-assisted epoxidation of alkenes, (2) ring-opening reactions of epoxides by various nucleophiles, and (3) catalytic peptide synthesis. Our newly developed synthetic methods with new ligands including hydroxamic acid derived ligands realized not only highly efficient reactions but also pinpointed reactions at the expected position, demonstrating the substrate-directed reaction as a powerful method to achieve the desired regio- and stereoselective functionalization of molecules from different viewpoints of reagent- or catalyst-controlled reactions. PMID- 29485867 TI - Multiscale Coarse-Graining with Effective Polarizabilities: A Fully Bottom-Up Approach. AB - Coarse-grain (CG) models offer a way to estimate the behavior of larger systems, for longer times than possible in fine-grain calculations by eliminating fine detail. For most atomistic models this often involves eliminating electrostatic interactions, yet, in many calculations, the dielectric properties of a material may be too important to ignore. In this work, we expand upon a previous CG representation which preserves the instantaneous center of mass (CoM), charge, and dipole of clusters of atoms by representing them with charged dimers. We then derive a formal mapping of the microscopic coordinates onto the CG representation allowing for a fully bottom-up construction of the CG force field that statistically matches the CoM, and first two terms of the multipole expansion. In the method presented here, unlike any previous bottom-up mappings, the atomistic particles are fractionally mapped to both sites in the dimer representation. Despite this difference, we show that the corresponding coordinate transformation augmented with a dipole moment mapping can be constructed as a canonical transformation and hence can derive correct ensemble statistics in the associated force mapping. The method is tested on nitromethane at a submolecular resolution, where the nitro group is represented through a charged dimer while the methyl group is a standard CoM projection, next we test a lower resolution of nitromethane where the entire molecule is represented as a single dimer. At the high resolution we showed the method can be mixed with standard CoM projections, and give rise to intramolecular interactions. After nitromethane, we test the method at a supramolecular level using an aggressive scheme of 10 water molecules to one CG dimer. We find in all cases the CoM-CoM radial distribution functions are well matched, and the dipole distributions are matched. For the submolecular nitromethane we find the model is transferable to simulations with external fields, and with the single-dimer nitromethane, we see the dipole-dipole correlation function is matched, but we find the frequency dependent dielectric constant significantly deviates indicating enhanced kinetics as commonly seen in CG molecular dynamics. Lastly, for water we see some discrepancy in the dipole dipole correlation function that stems from the pairwise decomposition of forces rather than the mapping method presented here. PMID- 29485866 TI - O-GlcNAc Transferase Recognizes Protein Substrates Using an Asparagine Ladder in the Tetratricopeptide Repeat (TPR) Superhelix. AB - The essential mammalian enzyme O-GlcNAc Transferase (OGT) is uniquely responsible for transferring N-acetylglucosamine to over a thousand nuclear and cytoplasmic proteins, yet there is no known consensus sequence and it remains unclear how OGT recognizes its substrates. To address this question, we developed a protein microarray assay that chemoenzymatically labels de novo sites of glycosylation with biotin, allowing us to simultaneously assess OGT activity across >6000 human proteins. With this assay we examined the contribution to substrate selection of a conserved asparagine ladder within the lumen of OGT's superhelical tetratricopeptide repeat (TPR) domain. When five asparagines were mutated, OGT retained significant activity against short peptides, but showed limited limited glycosylation of protein substrates on the microarray. O-GlcNAcylation of protein substrates in cell extracts was also greatly attenuated. We conclude that OGT recognizes the majority of its substrates by binding them to the asparagine ladder in the TPR lumen proximal to the catalytic domain. PMID- 29485868 TI - Bridging the Gap between Pentacene and Perfluoropentacene: Synthesis and Characterization of 2,3,9,10-Tetrafluoropentacene in the Neutral, Cationic, and Dicationic States. AB - The thermal and photochemical syntheses of 2,3,9,10-tetrafluoropentacene (F4PEN) from 6,13-etheno bridged precursors were investigated computationally and experimentally. A computational study of the retro-Diels-Alder reaction to give 2,3,9,10-tetrasubstituted pentacenes and pyridazine revealed a linear correlation between barrier height and substituent constant (sigmap) indicative of an electronic effect that could diminish the yield of electron-poor 2,3,9,10 tetrasubstituted pentacenes in this reaction. The photochemical route from the corresponding bridged alpha-diketone yields F4PEN, which was characterized photophysically, electrochemically, and structurally. The compound crystallizes in a herringbone motif with quite short intermolecular F-F contacts that are, however, only very weakly bonding according to computations. The electrochemical and photophysical data show that the HOMO-LUMO gap of F4PEN is increased compared to that of PEN. This is due to an increase of the oxidation potential of F4PEN by 0.18 V in combination with an essentially unchanged reduction potential. The radical cation and dication of F4PEN could be generated in oxidizing solvents and characterized by optical spectroscopy and ESR or NMR, respectively. Both charged F4PEN species persist for days in solution. PMID- 29485869 TI - Adhesive and Stimulus-Responsive Polydopamine-Coated Graphene Oxide System for Pesticide-Loss Control. AB - Pesticide carrier systems are highly desirable in achieving the effective utilization of pesticides and reduction of their loss. In order to increase utilization and enhance pesticide adhesion to harmful targets, adhesive and stimulus-responsive nanocomposites were prepared using graphene oxide (GO) and polydopamine (PDA). The results demonstrated that graphene oxide with a layer of PDA had a high hymexazol-loading capacity. The release curve of hymexazol from the nanocomposite showed that the release was NIR-laser-dependent and pH dependent. The adhesion-performance investigation demonstrated that Hy-GO@PDA exhibited greater hymexazol persistence than a hymexazol solution after a simulated-rainwash experiment, and it also left more hymexazol residue than a hymexazol solution with a surfactant under high concentrations. Finally, the bioactivity of the prepared hymexazol-loaded nanocomposite was measured against Fusarium oxysporum f. sp. cucumebrium Owen, and it showed an inhibition activity similar to that of the hymexazol solution. All of these revealed that GO with a PDA layer could serve as pesticide carrier to solve low-utilization and wash-off problems, especially for water-soluble pesticides. PMID- 29485870 TI - Trans Lipid Library: Synthesis of Docosahexaenoic Acid (DHA) Monotrans Isomers and Regioisomer Identification in DHA-Containing Supplements. AB - Docosahexaenoic acid (DHA) is a semiessential polyunsaturated fatty acid (PUFA) for eukaryotic cells that is found in natural sources such as fish and algal oils and widely used as an ingredient for omega-3 containing foods or supplements. DHA effects are connected to its natural structure with six cis double bonds, but geometrical monotrans isomers can be formed during distillation or deodorization processes, as an unwanted event that alters molecular characteristics and annihilates health benefits. The characterization of the six monotrans DHA regioisomers is an open issue to address for analytical, biological, and nutraceutical applications. Here we report the preparation, separation, and first identification of each isomer by a dual approach consisting of the following: (i) the direct thiyl radical-catalyzed isomerization of cis-DHA methyl ester and (ii) the two-step synthesis from cis-DHA methyl ester via monoepoxides as intermediates, which are separated and identified by nuclear magnetic resonance spectroscopy, followed by elimination for the unequivocal assignment of the double bond position. This monotrans DHA isomer library with NMR and GC analytical characterization was also used to examine the products of thiyl radical-catalyzed isomerization of a fish oil sample and to evaluate the trans isomer content in omega-3 containing supplements commercially available in Italy and Spain. PMID- 29485871 TI - Mechanistic Investigation of Oxidative Decarboxylation Catalyzed by Two Iron(II)- and 2-Oxoglutarate-Dependent Enzymes. AB - Two non-heme iron enzymes, IsnB and AmbI3, catalyze a novel decarboxylation assisted olefination to produce indole vinyl isonitrile, an important building block for many natural products. Compared to other reactions catalyzed by this enzyme family, decarboxylation-assisted olefination represents an attractive biosynthetic route and a mechanistically unexplored pathway in constructing a C?C bond. Using mechanistic probes, transient state kinetics, reactive intermediate trapping, spectroscopic characterizations, and product analysis, we propose that both IsnB and AmbI3 initiate stereoselective olefination via a benzylic C-H bond activation by an Fe(IV)-oxo intermediate, and the reaction likely proceeds through a radical- or carbocation-induced decarboxylation to complete C?C bond installation. PMID- 29485872 TI - Sterically Induced Ligand Framework Distortion Effects on Catalytic Cyclic Ester Polymerizations. AB - Aluminum alkoxide complexes supported by salen ligands [salen = N, N' bis(salicylaldimine)-2-methylpropane-1,2-diamine or N, N'-bis(salicylaldimine) 2,2-dimethylpropane-1,3-diamine] with o-adamantyl substituents have been synthesized and investigated for the polymerization of epsilon-caprolactone. Geometric analysis of the catalysts used for the reaction reveals the metal coordination geometries to be intermediate between square-pyramidal and trigonal bipyramidal. A detailed kinetic study accompanied by density functional theory modeling of key mechanistic steps of the reaction suggest that, in addition to the length of the backbone linker, the o-aryl substituents have a significant impact on the catalyst's reactivity. Bulky ortho substituents favorably distort the precatalyst geometry and thereby foster the achievement of the rate-limiting transition-state geometry at low energetic cost, thus accelerating the reaction. PMID- 29485873 TI - PdIV Species Mediation in PdII-Catalyzed Direct Alkylation of Arenes with Oxiranes: A DFT Study. AB - The reaction mechanisms of Pd(OAc)2-catalyzed dehydrogenative alkylation of 2 phenylpyridine with oxirane were investigated using DFT calculations. The most plausible reaction pathway was confirmed as a PdII/IV/II catalytic cycle consisting of four processes: C-H activation, ring-opening oxidative addition of oxirane, reductive elimination, and recovery of the catalyst. According to the B2PLYP/DGDZVP computational data, the oxidative addition of oxirane for converting PdII to PdIV was assigned to be the rate-determining step with a free energy barrier of 28.1 kcal.mol-1. For comparison, we also studied the alternative PdII-only pathway without a change of oxidation state and found that it was hindered kinetically by a high free-energy barrier of 75.1 kcal.mol-1 occurring for the ring-opening migratory insertion of oxirane. In addition, the small-ring strain of oxirane should be responsible for the feasible C-O bond cleavage and subsequent PdII -> PdIV conversion, because the designed four-, five , and six-membered-ring reagents did not display such an oxidative addition reactivity. Lastly, an extended reactivity order among oxirane, PhI, PhBr, and PhCl toward oxidative addition onto PdII to form PdIV was proposed in this article based on the computed kinetic parameters. PMID- 29485874 TI - Creation of a Novel Class of Potent and Selective MutT Homologue 1 (MTH1) Inhibitors Using Fragment-Based Screening and Structure-Based Drug Design. AB - Recent literature has both suggested and questioned MTH1 as a novel cancer target. BAY-707 was just published as a target validation small molecule probe for assessing the effects of pharmacological inhibition of MTH1 on tumor cell survival, both in vitro and in vivo. (1) In this report, we describe the medicinal chemistry program creating BAY-707, where fragment-based methods were used to develop a series of highly potent and selective MTH1 inhibitors. Using structure-based drug design and rational medicinal chemistry approaches, the potency was increased over 10,000 times from the fragment starting point while maintaining high ligand efficiency and drug-like properties. PMID- 29485875 TI - Discovery of Novel Adenosine Receptor Antagonists through a Combined Structure- and Ligand-Based Approach Followed by Molecular Dynamics Investigation of Ligand Binding Mode. AB - An intense effort is made by pharmaceutical and academic research laboratories to identify and develop selective antagonists for each adenosine receptor (AR) subtype as potential clinical candidates for "soft" treatment of various diseases. Crystal structures of subtypes A2A and A1ARs offer exciting opportunities for structure-based drug design. In the first part of the present work, Maybridge HitFinder library of 14400 compounds was utilized to apply a combination of structure-based against the crystal structure of A2AAR and ligand based methodologies. The docking poses were rescored by CHARMM energy minimization and calculation of the desolvation energy using Poisson-Boltzmann equation electrostatics. Out of the eight selected and tested compounds, five were found positive hits (63% success). Although the project was initially focused on targeting A2AAR, the identified antagonists exhibited low micromolar or micromolar affinity against A2A/A3, ARs, or A3AR, respectively. Based on these results, 19 compounds characterized by novel chemotypes were purchased and tested. Sixteen of them were identified as AR antagonists with affinity toward combinations of the AR family isoforms (A2A/A3, A1/A3, A1/A2A/A3, and A3). The second part of this work involves the performance of hundreds of molecular dynamics (MD) simulations of complexes between the ARs and a total of 27 ligands to resolve the binding interactions of the active compounds, which were not achieved by docking calculations alone. This computational work allowed the prediction of stable and unstable complexes which agree with the experimental results of potent and inactive compounds, respectively. Of particular interest is that the 2-amino-thiophene-3-carboxamides, 3-acylamino-5-aryl-thiophene-2 carboxamides, and carbonyloxycarboximidamide derivatives were found to be selective and possess a micromolar to low micromolar affinity for the A3 receptor. PMID- 29485876 TI - Thermal, Mutual, and Self-Diffusivities of Binary Liquid Mixtures Consisting of Gases Dissolved in n-Alkanes at Infinite Dilution. AB - In the present study, dynamic light scattering (DLS) experiments and molecular dynamics (MD) simulations were used for the investigation of the molecular diffusion in binary mixtures of liquids with dissolved gases at macroscopic thermodynamic equilibrium. Model systems based on the n-alkane n-hexane or n decane with dissolved hydrogen, helium, nitrogen, or carbon monoxide were studied at temperatures between 303 and 423 K and at gas mole fractions below 0.06. With DLS, the relaxation behavior of microscopic equilibrium fluctuations in concentration and temperature is analyzed to determine simultaneously mutual and thermal diffusivity in an absolute way. The present measurements document that even for mole gas fractions of 0.007 and Lewis numbers close to 1, reliable mutual diffusivities with an average expanded uncertainty ( k = 2) of 13% can be obtained. By use of suitable molecular models for the mixture components, the self-diffusion coefficient of the gases was determined by MD simulations with an averaged expanded uncertainty ( k = 2) of 7%. The DLS experiments showed that the thermal diffusivity of the studied systems is not affected by the dissolved gas and agrees with the reference data for the pure n-alkanes. In agreement with theory, mutual diffusivities and self-diffusivities were found to be equal mostly within combined uncertainties at conditions approaching infinite dilution of the gas. Our DLS and MD results, representing the first available data for the present systems, reveal distinctly larger mass diffusivities for mixtures containing hydrogen or helium compared to mixtures containing nitrogen or carbon monoxide. On the basis of the broad range of mass diffusivities of the studied gas-liquid systems covering about 2 orders of magnitude from about 10-9 to 10-7 m2.s-1, effects of the solvent and solute properties on the temperature-dependent mass diffusivities are discussed. This contributed to the development of a simple semiempirical correlation for the mass diffusivity of the studied gases dissolved in n-alkanes of varying chain length at infinite dilution as a function of temperature. The generalized expression requiring only information on the kinematic viscosity and molar mass of the pure solvent as well as the molar mass and acentric factor of the solute represents the database from this work and further literature with an absolute average deviation of about 11%. PMID- 29485877 TI - Gas Hydrate Formation Probability Distributions: The Effect of Shear and Comparisons with Nucleation Theory. AB - Gas hydrate formation is a stochastic phenomenon of considerable significance for any risk-based approach to flow assurance in the oil and gas industry. In principle, well-established results from nucleation theory offer the prospect of predictive models for hydrate formation probability in industrial production systems. In practice, however, heuristics are relied on when estimating formation risk for a given flowline subcooling or when quantifying kinetic hydrate inhibitor (KHI) performance. Here, we present statistically significant measurements of formation probability distributions for natural gas hydrate systems under shear, which are quantitatively compared with theoretical predictions. Distributions with over 100 points were generated using low-mass, Peltier-cooled pressure cells, cycled in temperature between 40 and -5 degrees C at up to 2 K.min-1 and analyzed with robust algorithms that automatically identify hydrate formation and initial growth rates from dynamic pressure data. The application of shear had a significant influence on the measured distributions: at 700 rpm mass-transfer limitations were minimal, as demonstrated by the kinetic growth rates observed. The formation probability distributions measured at this shear rate had mean subcoolings consistent with theoretical predictions and steel-hydrate-water contact angles of 14-26 degrees . However, the experimental distributions were substantially wider than predicted, suggesting that phenomena acting on macroscopic length scales are responsible for much of the observed stochastic formation. Performance tests of a KHI provided new insights into how such chemicals can reduce the risk of hydrate blockage in flowlines. Our data demonstrate that the KHI not only reduces the probability of formation (by both shifting and sharpening the distribution) but also reduces hydrate growth rates by a factor of 2. PMID- 29485878 TI - Isoselenocyanates versus Isothiocyanates and Isocyanates. AB - Alkyl and aryl isoselenocyanates are well known intermediates in the synthesis of various organoselenium compounds, but the knowledge of the physicochemical properties of simple unsaturated derivatives is still fragmentary. Vinyl-, 2 propenyl-, and cyclopropyl isoselenocyanates have been prepared by reaction of selenium in powder with the corresponding isocyanides. The isoselenocyanates of this series, with a variable distance between the N?C?Se group and the unsaturated or pseudounsaturated group, have been studied by UV-photoelectron spectroscopy and quantum-chemical calculations. For each of these three isoselenocyanates, the exploration of conformers and geometrical optimization always converge toward only one local minimum. The vinyl and cyclopropyl derivatives are characterized by similar order of magnitude of interactions between the NCSe group and the substituent, while for allylic compound two noninteracting moieties should be considered. The same conclusions were obtained for vinylic and cyclopropylic sulfur and oxygen derivatives. Thus the type and extent of interactions between the N?C?X (X = O, S, Se) group and an unsaturated (vinyl, allyl, or cyclopropyl) moiety are now clarified. PMID- 29485879 TI - Ferroelectric Nematic and Ferrielectric Smectic Mesophases in an Achiral Bent Core Azo Compound. AB - Here, we report the observation of ferroelectric nematic and ferrielectric smectic mesophases in an achiral bent-core azo compound consisting of nonsymmetrical molecules with a lateral fluoro substitution on one of the wings. These mesophases are enantiotropic in nature with fairly low transition temperatures and wide mesophase ranges. The liquid crystalline properties of this compound are investigated using polarizing optical microscope, differential scanning calorimeter, X-ray diffraction, and electro-optical studies. As revealed by X-ray diffraction measurements, the nematic mesophase is composed of skewed cybotactic clusters and, in the smectic mesophase, the molecules are tilted with respect to the layer normal. The polar order in these mesophases was confirmed by the electro-optical switching and dielectric spectroscopy measurements. The dielectric study in the nematic mesophase shows a single relaxation process at low frequency ( f < 1 kHz) measured in the range 10 Hz to 5 MHz, which is attributed to the collective motion of the molecules within cybotactic clusters. The formation of local polar order in these clusters leads to a ferroelectric like polar switching in the nematic mesophase. Of particular interest is the fact that the smectic phase exhibits a field induced ferrielectric state, which can be exploited for designing of the potential optical devices due to multistate switching. PMID- 29485880 TI - Measuring the Electronic Structure of Nanocrystal Thin Films Using Energy Resolved Electrochemical Impedance Spectroscopy. AB - Use of nanocrystal thin films as active layers in optoelectronic devices requires tailoring of their electronic band structure. Here, we demonstrate energy resolved electrochemical impedance spectroscopy (ER-EIS) as a method to quantify the electronic structure in nanocrystal thin films. This technique is particularly well-suited for nanocrystal-based thin films as it allows for in situ assessment of electronic structure during solution-based deposition of the thin film. Using well-studied lead sulfide nanocrystals as an example, we show that ER-EIS can be used to probe the energy position and number density of defect or dopant states as well as the modification of energy levels in nanocrystal solids that results through the exchange of surface ligands. This work highlights that ER-EIS is a sensitive and fast method to measure the electronic structure of nanocrystal thin films and enables their optimization in optoelectronic devices. PMID- 29485881 TI - A Computational Study of the Reactivity of 3,5-(Oxo/Thioxo) Derivatives of 2,7 Dimethyl-1,2,4-Triazepines. Keto-Enol Tautomerization and Potential for Hydrogen Storage. AB - The G4 level of theory was used to evaluate the acidity of a series of triazepines, that is, 3-thioxo-5-oxo-, 5-thioxo-3-oxo-, 3,5-dioxo-, and 3,5 dithioxo- derivatives of 2,7-dimethyl-[1,2,4]-triazepine. The ability of their available nitrogen lone pair to form a dative bond with BH3 was also studied to highlight the resulting changes in acidity and to understand the behavior of the complexes formed. The effect of the substitution of sulfur by oxygen on the stability of the complex and the activation barrier of dehydrogenation was also evaluated. The formation of these triazepine:BH3 complexes, accompanied by the loss of H2 molecular hydrogen, is a strongly exothermic process. With one triazepine the pathway for H2 elimination from [triazepine]-BH3 is characterized by a small energy barrier ranging from 11 to 23 kJ/mol. The second H2 elimination is relatively more energetic than the first one (~27 kJ/mol). Because of the steric hindrance associated with the addition of two molecules of triazepine (triazepine)2-BH2, the third dehydrogenation step is relatively less favorable than the two preceding steps, particularly in the case of the 3,5-dithio- derivative. The potential energy surface associated with the dehydrogenation reaction of all triazepine derivatives was explored. The thermodynamic favorability reported in this study could allow triazepine-borane to be used as a material for H2 storage applications. PMID- 29485882 TI - Probing the Surface Tension of Ionic Liquids Using the Langmuir Principle. AB - At 298 K, the surface tension of ionic liquids (ILs) of the 1-alkyl-3 methylimidazolium bis(trifluoromethylsulfonyl)imide series, [C nC1Im][NTf2], ranges from around 35 mN.m-1 for [C2C1Im][NTf2] to just below 30 mN.m-1 for [C12C1Im][NTf2]. However, the decrease rate along the series is not constant: a large decrease from [C2C1Im][NTf2] to [C8C1Im][NTf2] is followed by almost constant values from [C8C1Im][NTf2] to [C12C1Im][NTf2]. Such behavior is hard to interpret from a molecular point of view without suitable information about the free-surface structure of the different ILs. In this work, we have successfully used the Langmuir principle in combination with structural data obtained from angle-resolved X-ray photoelectron spectroscopy experiments and molecular dynamics simulations, to predict the correct surface tension trend along the IL series. The concepts unveiled for this particular homologous IL family can be easily extended to other systems. PMID- 29485883 TI - Enhanced Delivery of Galanin Conjugates to the Brain through Bioengineering of the Anti-Transferrin Receptor Antibody OX26. AB - The blood-brain barrier (BBB) is a formidable obstacle for brain delivery of therapeutic antibodies. However, antibodies against the transferrin receptor (TfR), enriched in brain endothelial cells, have been developed as delivery carriers of therapeutic cargoes into the brain via a receptor-mediated transcytosis pathway. In vitro and in vivo studies demonstrated that either a low affinity or monovalent binding of these antibodies to the TfR improves their release on the abluminal side of the BBB and target engagement in brain parenchyma. However, these studies have been performed with mouse-selective TfR antibodies that recognize different TfR epitopes and have varied binding characteristics. In this study, we evaluated serum pharmacokinetics and brain and CSF exposure of the rat TfR-binding antibody OX26 affinity variants, having KDs of 5 nM, 76 nM, 108 nM, and 174 nM, all binding the same epitope in bivalent format. Pharmacodynamic responses were tested in the Hargreaves chronic pain model after conjugation of OX26 affinity variants with the analgesic and antiepileptic peptide, galanin. OX26 variants with affinities of 76 nM and 108 nM showed enhanced brain and cerebrospinal fluid (CSF) exposure and higher potency in the Hargreaves model, compared to a 5 nM affinity variant; lowering affinity to 174 nM resulted in prolonged serum pharmacokinetics, but reduced brain and CSF exposure. The study demonstrates that binding affinity optimization of TfR binding antibodies could improve their brain and CSF exposure even in the absence of monovalent TfR engagement. PMID- 29485884 TI - Plasmon-Assisted Selective and Super-Resolving Excitation of Individual Quantum Emitters on a Metal Nanowire. AB - Hybrid systems composed of multiple quantum emitters coupled with plasmonic waveguides are promising building blocks for future integrated quantum nanophotonic circuits. The techniques that can super-resolve and selectively excite contiguous quantum emitters in a diffraction-limited area are of great importance for studying the plasmon-mediated interaction between quantum emitters and manipulating the single plasmon generation and propagation in plasmonic circuits. Here we show that multiple quantum dots coupled with a silver nanowire can be controllably excited by tuning the interference field of surface plasmons on the nanowire. Because of the period of the interference pattern is much smaller than the diffraction limit, we demonstrate the selective excitation of two quantum dots separated by a distance as short as 100 nm. We also numerically demonstrate a new kind of super-resolution imaging method that combines the tunable surface plasmon interference pattern on the NW with the structured illumination microscopy technique. Our work provides a novel high-resolution optical excitation and imaging method for the coupled systems of multiple quantum emitters and plasmonic waveguides, which adds a new tool for studying and manipulating single quantum emitters and single plasmons for quantum plasmonic circuitry applications. PMID- 29485885 TI - A Metalens with a Near-Unity Numerical Aperture. AB - The numerical aperture (NA) of a lens determines its ability to focus light and its resolving capability. Having a large NA is a very desirable quality for applications requiring small light-matter interaction volumes or large angular collections. Traditionally, a large NA lens based on light refraction requires precision bulk optics that ends up being expensive and is thus also a specialty item. In contrast, metasurfaces allow the lens designer to circumvent those issues producing high-NA lenses in an ultraflat fashion. However, so far, these have been limited to numerical apertures on the same order of magnitude as traditional optical components, with experimentally reported NA values of <0.9. Here we demonstrate, both numerically and experimentally, a new approach that results in a diffraction-limited flat lens with a near-unity numerical aperture (NA > 0.99) and subwavelength thickness (~lambda/3), operating with unpolarized light at 715 nm. To demonstrate its imaging capability, the designed lens is applied in a confocal configuration to map color centers in subdiffractive diamond nanocrystals. This work, based on diffractive elements that can efficiently bend light at angles as large as 82 degrees , represents a step beyond traditional optical elements and existing flat optics, circumventing the efficiency drop associated with the standard, phase mapping approach. PMID- 29485886 TI - Characterization of Robust and Free-Standing 2D-Nanomembranes of UV-Polymerized Diacetylene Lipids. AB - Free-standing lipid membranes are promising as artificial functional membrane systems for application in separation, filtration, and nanopore sensing. To improve the mechanical properties of lipid membranes, UV-polymerized lipids have been introduced. We investigated free-standing as well as substrate-supported monolayers of 1-palmitoyl-2-(10,12-tricosadiynoyl)- sn-glycero-3 phosphoethanolamine (PTPE) and 1,2-bis(10,12-tricosadiynoyl)- sn-glycero-3 phosphocholine (DiynePC) and characterized them with respect to their structure, morphology, and stability. Using helium ion microscopy (HIM), we were able to visualize the integrity of the lipid 2D-nanomembranes spanning micrometer-sized voids under high-vacuum conditions. Atomic force microscopy (AFM) investigations under ambient conditions revealed formation of intact and robust pore-spanning 2D nanomembranes up to 8 * 2 MUm2 in size. Analysis by attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) verified a distinct reduction of signal at 2143 cm-1 from diacetylene groups in the 2D-nanomembranes after UV polymerization. Further high-resolution AFM investigations of unpolymerized lipid monolayers revealed a well-ordered two-dimensional network, when deposited on highly oriented pyrolytic graphite (HOPG). These structures were inhibited for polymerized adlayers. Structural models for the molecular arrangement of the adlayers are proposed and discussed. PMID- 29485887 TI - CVD Graphene/Ni Interface Evolution in Sulfuric Electrolyte. AB - Systems comprising single and multilayer graphene deposited on metals and immersed in acid environments have been investigated, with the aim of elucidating the mechanisms involved, for instance, in hydrogen production or metal protection from corrosion. In this work, a relevant system, namely chemical vapor deposited (CVD) multilayer graphene/Ni (MLGr/Ni), is studied when immersed in a diluted sulfuric electrolyte. The MLGr/Ni electrochemical and morphological properties are studied in situ and interpreted in light of the highly oriented pyrolytic graphite (HOPG) electrode behavior, when immersed in the same electrolyte. Following this interpretative framework, the dominant role of the Ni substrate in hydrogen production is clarified. PMID- 29485888 TI - Personalized Medicine in Nasal Delivery: The Use of Patient-Specific Administration Parameters To Improve Nasal Drug Targeting Using 3D-Printed Nasal Replica Casts. AB - Effective targeting of nasal spray deposition could improve local, systemic, and CNS drug delivery; however, this has proven to be difficult due to the anatomical features of the nasal cavity, including the nasal valve and turbinate structures. Furthermore, nasal cavity geometries and dimensions vary between individuals based on differences in their age, gender, and ethnicity. The effect of patient specific administration parameters was evaluated for their ability to overcome the barriers of targeted nasal drug delivery. The nasal spray deposition was evaluated in 10 3D-printed nasal cavity replicas developed based on the CT-scans of five pediatric and five adult subjects. Cromolyn sodium nasal solution, USP, modified with varying concentrations of hypromellose was utilized as a model nasal spray to evaluate the deposition pattern from formulations producing a variety of plume angles. A central composite design of experiments was implemented using the formulation with the narrowest plume angle to determine the patient-specific angle for targeting the turbinate region in each individual. The use of the patient-specific angle with this formulation significantly increased the turbinate deposition efficiency compared to that found for all subjects using an administration angle of 30 degrees , around 90% compared to about 73%. Generally, we found turbinate deposition increased with decreases in the administration angle. Deposition to the upper regions of the replica was poor with any formulation or administration angle tested. Effective turbinate targeting of nasal sprays can be accomplished with the use of patient-specific administration parameters in individuals. Further research is required to see if these parameters can be device-controlled for patients and if other regions can be effectively targeted with other nasal devices. PMID- 29485889 TI - Microfluidic Assembly To Synthesize Dual Enzyme/Oxidation-Responsive Polyester Based Nanoparticulates with Controlled Sizes for Drug Delivery. AB - Controlling the size and narrow size distribution of polymer-based nanocarriers for targeted drug delivery is an important parameter that significantly influences their colloidal stability, biodistribution, and targeting ability. Herein, we report a high-throughput microfluidic process to fabricate colloidally stable aqueous nanoparticulate colloids with tunable sizes at 50-150 nm and narrow size distribution. The nanoparticulates are designed with different molecular weight polyesters having both ester bonds (responsive to esterase) and sulfide linkages (to oxidative reaction) on the backbones, thus exhibiting dual esterase/oxidation responses, causing the destabilization of the nanoparticulates to lead to the controlled release of encapsulated therapeutics. The systematic investigation on both microfluidic and formulation parameters enables to control their properties as allowing for decreasing nanoparticulate sizes as well as improving colloidal stability and cytotoxicity. Further to such control over smaller size and narrow size distribution, dual stimuli-responsive degradation and excellent cellular uptake could suggest that the microfluidic nanoparticulates stabilized with polymeric stabilizers could offer the versatility toward dual smart drug delivery exhibiting enhanced release kinetics. PMID- 29485890 TI - Update: Malaria, U.S. Armed Forces, 2017. AB - Malaria infection remains an important health threat to U.S. service members who are located in endemic areas because of long-term duty assignments, participation in shorter-term contingency operations, or personal travel. In 2017, a total of 32 service members were diagnosed with or reported to have malaria, which is the lowest number of cases in any given year during the 10-year surveillance period. The relatively low numbers of cases during 2012-2017 mainly reflect decreases in cases acquired in Afghanistan, a reduction due largely to the progressive withdrawal of U.S. forces from that country. The percentage of cases of malaria caused by unspecified malaria species (53.1%; n=17) in 2017 was the highest during any given year of the surveillance period. The percentages of cases caused by Plasmodium vivax (15.6%; n=5), P. falciparum (25.0%; n=8), and by P. malariae (6.3%, n=2) remained similar to those of the preceding 4 years, although the numbers of cases decreased. Malaria was diagnosed at or reported from 19 different medical facilities in the U.S., Afghanistan, Qatar, Germany, Djibouti, Japan, and Korea. Providers of medical care to military members should be knowledgeable of, and vigilant for, clinical manifestations of malaria outside of endemic areas. PMID- 29485891 TI - Surveillance for vector-borne diseases among active and reserve component service members, U.S. Armed Forces, 2010-2016. AB - This report summarizes available health record information about the occurrence of vector-borne infectious diseases among members of the U.S. Armed Forces during a recent 7-year surveillance period. Information about confirmed, possible, and suspected cases was obtained from electronic reports of reportable medical events (RMEs) and records of diagnoses documented during hospitalizations and outpatient healthcare encounters. Lyme disease and malaria were the most common diagnoses among confirmed and possible cases. Diagnoses of chikungunya and Zika were elevated in the years following their respective entries into the Western Hemisphere. Large numbers of diagnoses of arboviral diseases were recorded in the category of suspected cases, but the overwhelming majority were associated with coding errors and tentative diagnoses not subsequently confirmed. For many confirmed cases, documentation could not be found in healthcare databases for positive laboratory tests that would be the basis for confirmation. Discussion covers the limitations of the available data and the importance to surveillance of RMEs, confirmatory laboratory tests, and accurate recording of diagnoses and their codes. PMID- 29485892 TI - Diagnostic evaluation of military blood donors screening positive for Trypanosoma cruzi infection. AB - Routine blood donor screening for Trypanosoma cruzi, the causative parasitic agent of Chagas disease, began in the U.S. in 2007. Results of follow-up testing and evaluation after a positive screen have not been studied in the armed forces. Among first-time donors at the Joint Base San Antonio- Lackland Blood Donor Center between January 2014 and December 2016 (N=43,402), a total of 23 (0.05%) screened positive for T. cruzi. This descriptive study highlights demographic and follow-up information for all 22 active duty service members who screened positive; a non-active duty member was excluded due to unavailability of clinical records. Members who screened positive received 13 different combinations of confirmatory testing (mean: 2.7 tests per person). In select cases, clinical evaluation included electrocardiogram (n=15) and 30-second rhythm strip (n=5). Two patients met criteria for Chagas disease; 11 patients were considered negative; and nine patients were indeterminate. Among a small cohort of active duty service members who screened positive for T. cruzi infection on blood donation, diagnostic evaluation varied considerably. Opportunities exist to decrease heterogeneity of clinical workup and improve evaluation of persons who screen positive. PMID- 29485895 TI - Unusual Milk Colors. PMID- 29485893 TI - Use of imaging for pre- and post-operative characterisation of ventral hernia: systematic review. AB - OBJECTIVE: Complex ventral hernia (CVH) repair is performed increasingly, exacerbated by the obesity epidemic. Imaging can characterise hernia morphology and diagnose recurrence. By systematic review we investigated the extent to which studies employ imaging. METHODS: The PubMed database was searched for studies of ventral hernia repair from January 1995 to March 2016. Hernias of all size were eligible. Independent reviewers screened articles and extracted data from selected studies related to study design, use of pre- and post-operative hernia imaging and the proportion of subjects imaged. The review was registered: PROSPERO CRD42016043071. RESULTS: 15,771 records were identified initially. 174 full-texts were examined and 158 ultimately included in the systematic review [31 randomised controlled trials (RCTs); 32 cohort studies; 95 retrospective cohort studies]. 31,874 subjects were reported overall. Only 19 (12%) studies employed pre-operative imaging for hernia characterisation and 46 (29%) post-operatively [equating to 511 (2%) of all pre-operative subjects and 1123 (4%) post operative]. Furthermore, most studies employing imaging did not do so in all subjects: Just 6 (4%) of the 158 studies used imaging in all subjects pre operatively and just 4 (3%) post-operatively, i.e. imaging was usually applied to a proportion of patients only. Moreover, the exact proportion was frequently not specified. Studies using imaging frequently stated that "imaging", "radiography" or "radiology" was used but did not specify the modality precisely nor the proportion of subjects imaged. CONCLUSION: Despite the ability to characterise ventral hernia morphology and recurrence with precision, most indexed studies do not employ imaging. Where imaging is used, data are often reported incompletely. Advances in knowledge: (1) This systematic review is the first to focus on the use of imaging in surgical studies of ventral hernia repair. (2) Studies of ventral hernia repair rarely use imaging, either to characterise hernias pre operatively or to diagnose recurrence, despite the latter being the primary outcome of most studies. (3) Failure to use imaging will result in incomplete hernia characterisation and underestimate recurrence rates in studies of surgical repair. PMID- 29485894 TI - Environmental Concerns for Children with Asthma on the Navajo Nation. AB - RATIONALE: Navajo children living on the reservation have high rates of asthma prevalence and severity. Environmental influences may contribute to asthma on the Navajo Nation and are inadequately understood. OBJECTIVES: We performed a comprehensive, integrative literature review to determine the environmental factors that may contribute to increased asthma prevalence and severity among Navajo children living on the reservation. METHODS: A systematic search was conducted in four databases regarding the environmental risk factors for asthma in Navajo children living on the reservation. Relevant studies between 1990 and 2017 were examined. Nonexperimental literature was also integrated into the review to describe the environmental injustices that have historically, disproportionately, and systematically affected the Navajo people, thus contributing to respiratory disparities among Navajo children. RESULTS: Eight studies met inclusion criteria for systematic review; however, limited research regarding environmental risk factors specific to asthma and Navajo children living on the reservation was identified. Our integrative review indicated both indoor and outdoor environmental risk factors commonly found on the Navajo reservation appear to be important determinants of asthma. CONCLUSIONS: Future research should examine indoor and outdoor air pollution from wood-burning stoves and cook stoves, coal combustion, tobacco and traditional ceremonial smoke, diesel exhaust exposure from long bus rides, indoor allergens, ambient pollutants, and regional dusts. Comprehensive mitigation efforts created in partnership with the Navajo Nation are necessary to address less-recognized risk factors as well as the common risk factors known to contribute to increased childhood asthma prevalence and severity. PMID- 29485896 TI - Multimodal Approaches in Integrative Health: Whole Persons, Whole Practices, Whole SystemsAn Invitation to Submit to JACM's Special Issue. PMID- 29485900 TI - Social Media Use and Happiness in Adults with Autism Spectrum Disorder. AB - Social media (SM) use by adults with autism spectrum disorder (ASD) is not well understood. Co-occurring mental health concerns, such as depression, are common for adults with ASD. The current investigation explored the relationship between SM use and happiness in a population of adults with self-disclosed ASD. Of the 84 percent of the sample who used SM, those who used Facebook, the most popular site, were happier than those who did not. The same relationship did not exist for the second most popular site, Twitter. Happiness and SM use showed a quadratic relationship: Happiness and SM use increased together until they reached a point where happiness fell off. SM use by adults with ASD, specifically Facebook use in moderation, may enhance well-being and may be a protective factor against secondary mental health concerns common in this population. PMID- 29485899 TI - The breadth of the diaphragm: updates in embryogenesis and role of imaging. AB - The diaphragm is an unique skeletal muscle separating the thoracic and abdominal cavities with a primary function of enabling respiration. When abnormal, whether by congenital or acquired means, the consequences for patients can be severe. Abnormalities that affect the diaphragm are often first detected on chest radiographs as an alteration in position or shape. Cross-sectional imaging studies, primarily CT and occasionally MRI, can depict structural defects, intrinsic and adjacent pathology in greater detail. Fluoroscopy is the primary radiologic means of evaluating diaphragmatic motion, though MRI and ultrasound also are capable of this function. This review provides an update on diaphragm embryogenesis and discusses current imaging of various abnormalities, including the emerging role of three-dimensional printing in planning surgical repair of diaphragmatic derangements. PMID- 29485901 TI - Association between Emphysema and Chronic Obstructive Pulmonary Disease Outcomes in the COPDGene and SPIROMICS Cohorts: A Post Hoc Analysis of Two Clinical Trials. PMID- 29485902 TI - NF-kappaB directly regulates beta-arrestin-1 expression and forms a negative feedback circuit in TNF-alpha-induced cell death. AB - beta-Arrestins (beta-arrestin-1 and -2) are multifunctional proteins that play important roles in the regulation of inflammation and cell survival that need to be tightly controlled; however, the mechanism that underlies their gene expression is largely unclear. Here, we demonstrate that beta-arrestin-1 is a transcriptional target of NF-kappaB. mRNA and protein levels of beta-arrestin-1 were up-regulated by NF-kappaB inducers. Inhibition of NF-kappaB prevented the up regulation of beta-arrestin-1 mRNA, whereas activation of NF-kappaB led to increased beta-arrestin-1 expression. beta-Arrestin-1 promoter activity was consistently enhanced upon NF-kappaB activation as a result of the presence of a highly conserved kappaB site. beta-Arrestin-1, in turn, suppressed the transcriptional activity of NF-kappaB by interfering with the interaction between p65 and p50. beta-Arrestin-1-deficient mice displayed reduced TNF-alpha-induced cell death and increased expression of antiapoptotic genes. Reintroduction of beta-arrestin-1, but not its mutant, which is unable to interfere with the p65 p50 interaction, into beta-arrestin-deficient mouse embryonic fibroblasts partially restored sensitivity to TNF-alpha-induced cell death. These findings reveal NF-kappaB and beta-arrestin-1 to be key components of a negative feedback circuit that is necessary to regulate cell death.-Li, J., Guo, A., Wang, Q., Li, Y., Zhao, J., Lu, J., Pei, G. NF-kappaB directly regulates beta-arrestin-1 expression and forms a negative feedback circuit in TNF-alpha-induced cell death. PMID- 29485904 TI - Corrigendum. AB - Smith-Greenaway, Emily. 2017. "Community Context and Child Health: A Human Capital Perspective." Journal of Health and Social Behavior 58(3):307-21. (Original DOI: 10.1177/0022146517718897). PMID- 29485903 TI - Metabolic and molecular framework for the enhancement of endurance by intermittent food deprivation. AB - Evolutionary considerations suggest that the body has been optimized to perform at a high level in the food-deprived state when fatty acids and their ketone metabolites are a major fuel source for muscle cells. Because controlled food deprivation in laboratory animals and intermittent energy restriction in humans is a potent physiologic stimulus for ketosis, we designed a study to determine the impact of intermittent food deprivation during endurance training on performance and to elucidate the underlying cellular and molecular mechanisms. Male mice were randomly assigned to either ad libitum feeding or alternate-day food deprivation (ADF) groups, and half of the mice in each diet group were trained daily on a treadmill for 1 mo. A run to exhaustion endurance test performed at the end of the training period revealed superior performance in the mice maintained on ADF during training compared to mice fed ad libitum during training. Maximal O2 consumption was increased similarly by treadmill training in mice on ADF or ad libitum diets, whereas respiratory exchange ratio was reduced in ADF mice on food-deprivation days and during running. Analyses of gene expression in liver and soleus tissues, and metabolomics analysis of blood suggest that the metabolic switch invoked by ADF and potentiated by exercise strongly modulates molecular pathways involved in mitochondrial biogenesis, metabolism, and cellular plasticity. Our findings demonstrate that ADF engages metabolic and cellular signaling pathways that result in increased metabolic efficiency and endurance capacity.-Marosi, K., Moehl, K., Navas-Enamorado, I., Mitchell, S. J., Zhang, Y., Lehrmann, E., Aon, M. A., Cortassa, S., Becker, K. G., Mattson, M. P. Metabolic and molecular framework for the enhancement of endurance by intermittent food deprivation. PMID- 29485905 TI - Infant Exposure to Methylphenidate and Duloxetine During Lactation. AB - BACKGROUND: Duloxetine and methylphenidate are commonly prescribed for the management of depression and attention-deficit/hyperactivity disorder (ADHD), respectively. However, little information is available concerning their safety during lactation. The purpose of this case series was to provide additional information to the medical literature concerning infant exposure to methylphenidate and duloxetine through breast milk. METHOD: Bioanalytical method (liquid chromatography coupled to mass spectrometry) was developed and validated before its use to determine the concentrations of both medications in breast milk samples. CASES: Case 1: A 30-year-old woman with depression and ADHD took duloxetine 90 mg daily and methylphenidate 36 mg daily during pregnancy and breastfeeding. The newborn was found to have a congenital pulmonary airway malformation. The breastfeeding status was nonexclusive. At week 4 postpartum, the concentration found in the milk was 32.8 ng/mL of duloxetine and 7.9 ng/mL of methylphenidate (estimated relative infant dose [RID] of 0.3% and 0.2%, respectively). Case 2: A 41-year-old women with depression took duloxetine 60 mg daily during pregnancy and lactation. She gave birth to a healthy child. The breastfeeding status was nonexclusive. Cord to maternal plasma concentration ratio was 0.4. At day 6 postpartum, the concentration of duloxetine was 23.6 ng/mL in the foremilk and 14.3 ng/mL in the hindmilk (RID of 0.4% and 0.2%, respectively). At week 6 postpartum, the concentration was 25.2 ng/mL in the foremilk and 29.3 ng/mL in the hindmilk (RID of 0.4% and 0.4%, respectively). CONCLUSION: In accordance with previously published data, this case series suggests a minimal exposure to duloxetine and methylphenidate through breast milk. Thus, these drugs are likely compatible with lactation. However, large cohort studies are necessary to evaluate their long-term impact on the exposed infants. PMID- 29485907 TI - Fluid Overload in Acute Asthma Exacerbation and Clinical Outcomes. Is There an Association? PMID- 29485906 TI - The value of multi ultra high-b-value DWI in grading cerebral astrocytomas and its association with aquaporin-4. AB - OBJECTIVE: To investigate the value of multi-ultrahigh-b-value diffusion-weighted imaging (UHBV-DWI) in differentiating high-grade astrocytomas (HGAs) from low grade astrocytomas (LGAs), analyze its association with aquaporin (AQP) expression. METHODS: 40 astrocytomas divided into LGAs (N = 15) and HGAs (N = 25) were studied. Apparent diffusion coefficient (ADC) and UHBV-ADC values in solid parts and peritumoral edema were compared between LGAs and HGAs groups by the t test. Using receiver operating characteristic curves to identify the better parameter. Using real time polymerase chain reaction to assess AQP messenger ribonucleic acid (mRNA). Using spearman correlation analysis to assess the correlation of AQP mRNA with each parameter. RESULTS: ADC values in solid parts of HGAs were significantly lower than LGAs (p = 0.02), while UHBV-ADC values of HGAs were significantly higher than LGAs (p < 0.01). Area under the curve (AUC) of UHBV-ADC (0.810) was larger than ADC (0.713), and the area under the curve of UHBV-ADC was significantly higher than that of ADC (p = 0.041). AQP4 mRNA was significantly higher in HGAs than that in LGAs (p < 0.01); there was less AQP9 mRNA and no AQP1 mRNA in LGAs and HGAs groups (p > 0.05); ADC value showed a negative correlation with AQP4 mRNA (r = -0.357; p = 0.024). UHBV-ADC value positively correlated with the AQP4 mRNA (r = 0.646; p < 0.01). CONCLUSION: UHBV DWI allowed for a more accurate grading of cerebral astrocytoma than DWI, and UHBV-ADC value may be related with the AQP4 mRNA levels. UHBV-DWI could be of value in the assessment of astrocytoma. Advances in knowledge: UHBV-DWI generated by multi UHBV could have particular value for astrocytoma grading, and the level of AQP4 mRNA might be potentially linked to the change of UHBV-DWI parameter, and we might find the exact reason for the difference of UHBV-ADC between the LGAs and HGAs. PMID- 29485908 TI - Phosphodiesterase-5 Inhibitor Therapy for Pulmonary Hypertension in the United States. Actual versus Recommended Use. AB - RATIONALE: Care of patients with pulmonary hypertension is complex. Although pulmonary vasodilators are effective for Group 1 pulmonary hypertension, clinical guidelines and the Choosing Wisely Campaign recommend against routine use for Groups 2 and 3 pulmonary hypertension (the most common types of pulmonary hypertension) because of a lack of benefit, potential for harm, and high cost ($10,000-$13,000 per patient per year treated). Little is known about how these medications are used in practice. OBJECTIVES: To determine national patterns of phosphodiesterase-5 inhibitor prescribing for pulmonary hypertension in the Veterans Health Administration. METHODS: Retrospective analysis of Veterans prescribed phosphodiesterase-5 inhibitor for pulmonary hypertension between 2005 and 2012 at any Veterans Health Administration site. Patients were identified by presence of an International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code for pulmonary hypertension and one or more outpatient prescriptions for daily phosphodiesterase-5 inhibitor therapy. We developed and validated, using gold-standard chart abstraction, an International Classification of Diseases, Ninth Revision, Clinical Modification-based algorithm to assign pulmonary hypertension group. Our primary outcome was the proportion of patients who received potentially inappropriate phosphodiesterase-5 inhibitor, as determined by guideline recommendations (Group 1 pulmonary hypertension: appropriate; Groups 2/3: potentially inappropriate; Groups 4/5: uncertain value), among all patients prescribed phosphodiesterase-5 inhibitor for pulmonary hypertension. Secondary outcomes included proportion of treated patients who received guideline-recommended right heart catheterization. RESULTS: Among 108,777 Veterans with pulmonary hypertension, 2,790 (2.6% [95% confidence interval, 2.5-2.7%]) received daily phosphodiesterase-5 inhibitor therapy. Among treated patients, 541 (19.4% [95% confidence interval, 18.0-20.9%]) received appropriate treatment, 1,711 (61.3% [95% confidence interval, 59.5-63.1%]) potentially inappropriate treatment, and 358 (12.8% [95% confidence interval, 11.6-14.1%]) treatment of uncertain value. The number of potentially inappropriately treated patients per year increased substantially over the study period (53 in 2005, 748 in 2012). On the basis of chart abstraction in a randomly selected subset of patients treated with phosphodiesterase-5 inhibitor, half (110 of 230, 47.8% [95% confidence interval, 41.3-54.5%]) had documented right heart catheterization to confirm presence or type of pulmonary hypertension. After factoring presence of and data from right heart catheterization into our treatment appropriateness algorithm, only 11.7% (95% confidence interval, 8.0 16.8%) received clearly appropriate treatment. CONCLUSIONS: Most Veterans with pulmonary hypertension do not receive phosphodiesterase-5 inhibitor therapy. However, among treated Veterans, almost two-thirds of phosphodiesterase-5 inhibitor prescriptions are inconsistent with pulmonary hypertension guidelines, exposing patients to potential harm and creating a financial burden on the healthcare system. Further study is warranted to clarify the effects of these prescription patterns on pulmonary hypertension outcomes. PMID- 29485910 TI - Re: "Academy of Breastfeeding Medicine's 2017 Position Statement on Informal Breast Milk Sharing for the Term Healthy Infant" by Sriraman NK, et al. (Breastfeed Med 2018;13(1):2-4). PMID- 29485909 TI - The Hispanic Paradox: Socioeconomic Factors and Race/Ethnicity in Breastfeeding Outcomes. AB - BACKGROUND: Breastfeeding has multiple benefits for both mother and infant. Previous studies have shown that Hispanic/Latina women have higher rates of breastfeeding and better health outcomes than non-Hispanic black (NHB) women of similar socioeconomic status. Our primary objective was to explore the association of race/ethnicity with breastfeeding rates and the impact of socioeconomic factors on initiation and continuation of breastfeeding. MATERIALS AND METHODS: We performed a hypothesis-generating secondary analysis of a prospective cohort study of perinatal mental health in a diverse sample of 213 mothers. Twenty-eight participants self-identified as non-Hispanic white, 43 as NHB, and 142 as Hispanic/Latina. We examined bivariate relationships and performed logistic regression analysis for a series of maternal, infant, and psychosocial factors to examine their individual effect on the breastfeeding and race/ethnicity relationship odds ratio (OR). RESULTS: Hispanic/Latina women were more likely to initiate exclusive breastfeeding at delivery compared with NHB women (OR 2.4, 95% confidence interval: 1.2-4.9, p = 0.01). Adjustment for maternal, infant, and psychosocial factors measured did not statistically significantly attenuate the OR for initiation of breastfeeding between NHB and Hispanic/Latina women. Women with a history of sexual abuse were also more likely to initiate exclusive breastfeeding (67%) compared with women without a sexual abuse history (54%, p < 0.05). CONCLUSIONS: In this low socioeconomic status cohort study, Hispanic/Latina women had higher proportions of any amount of breastfeeding compared with their NHB counterparts. This difference was not attenuated by any of the maternal, infant, or psychosocial factors examined, although our secondary analysis of this prospective cohort was limited by the available covariates in the parent study. PMID- 29485911 TI - Leadership Primer for Current and Aspiring Pulmonary, Critical Care, and Sleep Medicine Academic Division Chiefs. AB - An academic medical career traditionally revolves around patient care, teaching, and scholarly projects. Thus, when an opportunity for a leadership role arises, such as division chief, the new leader is often unprepared with little or no formal leadership training. In this focused review, academic leaders of the Association of Pulmonary, Critical Care, and Sleep Division Directors describe several leadership concepts adapted from the business sector and apply their years of experience to aid new division chiefs with their first day on the job. The first 90 days are highlighted to include achieving early wins; performing a division-wide Strengths, Weaknesses, Opportunities, Threats analysis; establishing division rapport; redefining the division infrastructure; avoiding conflicts; and managing the relationship with the department chair. The five levels of leadership applicable to academic medicine are discussed: position, permission, production, people, and pinnacle. Finally, emotional intelligence and behavior styles crucial to leadership success are reviewed. PMID- 29485912 TI - Alcohol policy and fatal alcohol-related crashes in Finland 2000-2016. AB - OBJECTIVE: The purpose of this study was to explore the relationship between annual alcohol consumption per capita/alcohol price index and the number of alcohol-related fatal motor vehicle accidents (AFMVAs). We were particularly interested in whether a tax reduction in 2004 increased the number of alcohol related accidents. METHOD: The data consisted of all fatal motor vehicle accidents (FMVAs) during the years 2000-2016 obtained from a database maintained by the Finnish Crash Data Institute (OTI). The data included all fatally injured drivers. We compared the OTI data to official statistics on annual alcohol consumption and the alcohol price index. RESULTS: There were 3,447 fatally injured drivers, of which 25% (n = 869) were intoxicated (blood alcohol concentration [BAC] >= 0.05%). After the reduction of the alcohol tax in 2004, the alcohol consumption rose 12.4% from 2003 to 2005 and AFMVAs rose 38%. There was a strong correlation (r = 0.7000, P < .018) between the recorded consumption of alcohol and the number of AFMVAs. There was a strong negative correlation between AFMVAs and the combined (retail + restaurant sales) alcohol price index (r = -0.7863, P = .0005). A linear mixed-effects model showed that a 1-L increase in total alcohol consumption per capita per year increases AFMVAs by 10.6 and a one-unit increase in the price index decreases AFMVAs by 1.8 per year. CONCLUSIONS: The correlation between alcohol consumption and alcohol-related crashes should be considered when making political decisions regarding alcohol price and availability. Any further liberalization of the alcohol policy would likely lead to an increase in alcohol-related fatal motor vehicle accidents. Similar consequences are likely to occur with drugs. Alcohol price policy is an effective way to improve road safety, but other measures taken to prevent FMVAs also seem to reduce the prevalence of AFMVAs. PMID- 29485913 TI - An update on radiation therapy in head and neck cancers. AB - INTRODUCTION: Technological and technical improvements allowed for significant advances in the field of radiation therapy (RT) of head and neck cancer (HNC). Several organ-sparing strategies have been investigated with the objective to decrease acute and long-term adverse effects and, subsequently, to assure a better quality of life in patients affected by HNC. In this context, intensity modulated irradiation and the use of multimodality-imaging could help clinicians to obtain a rapid dose fall off towards surrounding healthy tissues and a better delineation of targets volumes and organs at risk. Areas covered: A literature review was performed with the aim to offer an update on radiation therapy in HNC. Expert commentary: During these last years, radiation oncologists have observed a continuous changing regarding radiation treatment for HNC. The adoption of intensity-modulated RT (IMRT) and the use of multimodality-imaging for tumor volume definition and organs at risk or delineation have improved the clinical outcomes of HNC patients. In the future, a better integration of functional imaging for target volume delineation as well as adaptive delivery strategies will allow to further personalize radiation oncology in HNC. Furthermore, the latest breakthrough technologies, such as magnetic resonance imaging (MRI)-linacs and heavy particles technologies have a great potential to improve treatment related quality of life in HNC. Future studies are needed to demonstrate the clinical advantages of these new RT technologies in HNC. PMID- 29485914 TI - Streptozotocin-Induced Autophagy Reduces Intracellular Insulin in Insulinoma INS 1E Cells. AB - Streptozotocin (STZ), a glucose analog, induces diabetes in experimental animals by inducing preferential cytotoxicity in pancreatic beta cells. We investigated whether STZ reduced the production of intracellular insulin through autophagy in insulinoma INS-1E cells. Typically, 2 mM STZ treatment for 24 h significantly decreased cell survival. STZ treatment led to significant decrease in phospho-AMP activated protein kinase (p-AMPK) level; reduction in levels of phospho-protein kinase R-like endoplasmic reticulum kinase (PERK) and inositol-requiring enzyme 1alpha (IRE1alpha); significant reduction in levels of p85alpha, p110, phospho serine and threonine kinase/protein kinase B (p-Akt/PKB) (Ser473), phospho extracellular-regulated kinase (p-ERK), and phospho-mammalian target of rapamycin (p-mTOR); increase in levels of Cu/Zn-superoxide dismutase (SOD), Mn-SOD, and catalase; decrease in B-cell lymphoma 2 (Bcl-2) expression; increase in Bcl-2 associated X protein (Bax) expression; increase in levels of microtubule associated protein 1 light chain 3 (LC3) and Beclin 1; and reduction in production of intracellular insulin. These results suggest that insulin synthesis during STZ treatment involves autophagy in INS-1E cells and, subsequently, results in a decrease in intracellular production of insulin. PMID- 29485915 TI - Relation between serum cystatin C level and brachial-ankle pulse wave velocity in Chinese general population. AB - BACKGROUND: The purpose of the study is to evaluate whether serum cystatin C level is associated with arterial stiffness independent of other risk factors in Chinese general population. HYPOTHESIS: Cystatin C is a predictable marker of arterial stiffness in Chinese general population. METHODS: Subjects are 748 persons (mean age, 38.8years) who attended a health checkup in Beijing, China. We measured brachial-ankle PWV (baPWV) by using an automatic oscillometric method, and the concentration of serum cystatin C was quantified. RESULTS: The level of baPWV showed a significantly positive correlation with BMI, SBP, DBP, TG, TC, cystatin C (r = 0.251, p < 0.001), and a negative correlation with HDL-C. And when adjustment for age, BMI, and cigarette smoking, these correlations remain significantly. CONCLUSION: Arterial stiffness increases with an increase in serum cystatin C level in Chinese general population with normal renal function. PMID- 29485916 TI - S100A7 Regulates Ovarian Cancer Cell Metastasis and Chemoresistance Through MAPK Signaling and Is Targeted by miR-330-5p. AB - Epithelial ovarian cancer (EOC) is the most common cause of gynecological cancer associated death. The high mortality rate is largely due to early stage metastasis and posttreatment recurrence. Identifying crucial regulators of EOC cells as well as ways to target them promises to improve the disease's prognosis. The S100 calcium-binding protein A7 (S100A7) has been shown to promote cell proliferation, migration, invasion, and tumor metastasis. In this study, we have investigated the role that S100A7 plays in regulating EOC cells. We have also identified the microRNA protein miR-330-5p, a known suppressor of oncogenesis and chemoresistance, as an inhibitor of S100A7 activity. We employed both fresh EOC tissue specimens as well as EOC cell lines Caov3 and SKOV3. S100A7 levels were analyzed using quantitative real-time polymerase chain reaction, western blot, and immunohistochemistry. siRNA was used to knockdown S100A7. Cell proliferation, colony formation, and Transwell migration and invasion assays were performed on EOC cell lines with and without cisplatin treatment. TargetScan was used to identify miR-330-5p as a regulator of S100A7. Luciferase reporter plasmids were constructed with either the wild-type or mutant S100A7 3'UTR to determine the effect of miR-330-5p on S100A7. S100A7 was significantly overexpressed in human EOC tissue specimens and EOC cell lines Caov3 and SKOV3. Knocking down S100A7 reduced EOC cell proliferation, migration, and invasion. Furthermore, S100A7 knockdown cells demonstrated increased sensitivity to the chemotherapeutic cisplatin. Finally, miR-330-5p was shown to target the S100A7 3'UTR and to reduce EOC cell growth by inhibiting S100A7 expression. As a regulator of EOC cell proliferation, metastasis, and chemoresistance, S100A7 represents a potential prognostic biomarker for EOC as well as a treatment target. Because miR-330-5p functions as an inhibitor of EOC cell growth and S100A7 expression, it promises to improve EOC outcomes. Further research into the clinical significance of both S100A7 and miR-300-5p is warranted. PMID- 29485917 TI - Detection of KIT Genotype in Pigs by TaqMan MGB Real-Time Quantitative Polymerase Chain Reaction. AB - The dominant white phenotype in domestic pigs is caused by two mutations in the KIT gene: a 450 kb duplication containing the entire KIT gene together with flanking sequences and one splice mutation with a G:A substitution in intron 17. The purpose of this study was to establish a simple, rapid method to determine KIT genotype in pigs. First, to detect KIT copy number variation (CNV), primers for exon 2 of the KIT gene, along with a TaqMan minor groove binder (MGB) probe, were designed. The single-copy gene, estrogen receptor (ESR), was used as an internal control. A real-time fluorescence-based quantitative PCR (FQ-PCR) protocol was developed to accurately detect KIT CNVs. Second, to detect the splice mutation ratio of the G:A substitution in intron 17, a 175 bp region, including the target mutation, was amplified from genomic DNA. Based on the sequence of the resulting amplified fragment, an MGB probe set was designed to detect the ratio of splice mutation to normal using FQ-PCR. A series of parallel amplification curves with the same internal distances were obtained using gradually diluted DNA as templates. The CT values among dilutions were significantly different (p < 0.001) and the coefficients of variation from each dilution were low (from 0.13% to 0.26%). The amplification efficiencies for KIT and ESR were approximately equal, indicating ESR was an appropriate control gene. Furthermore, use of the MGB probe set resulted in detection of the target mutation at a high resolution and stability; standard curves illustrated that the amplification efficiencies of KIT1 (G) and KIT2 (A) were approximately equal (98.8% and 97.2%). In conclusion, a simple, rapid method, with high specificity and stability, for the detection of the KIT genotype in pigs was established using TaqMan MGB probe real-time quantitative PCR. PMID- 29485918 TI - Trajectories and Early Determinants of Circulating CC16 from Birth to Age 32 Years. PMID- 29485919 TI - Regional Socioeconomic Inequalities in Physical Activity and Sedentary Behavior Among Brazilian Adolescents. AB - BACKGROUND: This study aims to describe the regional prevalence and patterns of physical activity (PA) and sedentary behavior among Brazilian adolescents. METHODS: Data from the Brazilian Scholar Health Survey, a nationally representative survey of ninth-grade adolescents [mean age: 14.29 y (14.27 14.29)] conducted in 2015 (n = 101,445), were used. Outcomes were television viewing, sitting time (ST), total PA, and active traveling collected via self administered questionnaire. Information on frequency of physical education classes and type of school was collected from the school's director. Frequencies with 95% confidence intervals were used to determine the prevalence and patterns of outcomes. RESULTS: Higher prevalence of PA (>=300 min/wk) and ST (>4 h/d) was found in Midwest (PA = 38.0%; ST = 44.5%), South (PA = 37.6%; ST = 50.1%), and Southeast (PA = 36.1%; ST = 49.3%) compared with Northeast (PA = 29.7%; ST = 36.9%) and North (PA = 34.4%; ST = 34.8%) regions of Brazil. ST was higher among adolescents from private schools (51.5%) than public schools (42.9%), whereas active traveling was greater among students of public schools than private schools (62.0% vs 34.4%). Most inequalities in outcomes between capital and interior cities were in the poorest regions. CONCLUSIONS: The results indicate that national plans targeting regional inequalities are needed to improve PA and to reduce sedentary behavior among Brazilian adolescents. PMID- 29485920 TI - Age-Related Differences in Functional Hamstring/Quadriceps Ratio Following Soccer Exercise in Female Youth Players: An Injury Risk Factor. AB - PURPOSE: Fatigue negatively alters dynamic knee control, and the functional hamstring/quadriceps ratio (H/QFUNC) plays an important role in stabilizing the joint. The aim of this study was to investigate the influence of soccer-specific exercise on H/QFUNC in under (U) 13-, U15-, and U17-year-old female soccer players. METHODS: A total of 36 female players performed concentric and eccentric actions of the hamstrings at 60 degrees , 120 degrees , and 180 degrees /s before and after an age group-specific field-based soccer protocol. H/QFUNC was determined in the first 30 degrees of knee flexion. RESULTS: Significant angle * velocity (P = .001) and time * angle (P = .033) interaction effects were found indicating a lower H/QFUNC with increased movement velocity at 0 degrees -10 degrees as opposed to greater knee flexion angles. Fatigue-related effects were only evident near full knee extension. Probabilistic inferences indicated that changes in H/QFUNC were generally unclear in U13s, likely detrimental in U15s, and very likely beneficial in U17s. CONCLUSIONS: Altered muscular control following soccer-specific exercise is age dependent with players' 1-year post peak height velocity at greatest risk of injury. Injury prevention and screening need to be age and maturation appropriate, should consider the effects of fatigue, and include movements near full extension. PMID- 29485922 TI - Loss of VPS9b enhances vps9a-2 phenotypes. AB - Plant innate immunity enables plants to defend themselves against infectious pathogens. While membrane trafficking and release of exosomes are considered vital for correct execution of innate immunity, the mechanisms behind remain elusive. Recently, we have shown that VPS9a, the general guanine-nucleotide exchange factor activating Rab5 GTPases, is required for both pre- and post invasive immunity against powdery mildew fungi in Arabidopsis thaliana. Yet, the Arabidopsis genome contains a close homologue of VPS9a, which potentially plays specific roles in innate immunity. Here we show that this gene, VPS9b, while weakly expressed, contributes to regulating development and disease resistance, which is predominantly regulated by VPS9a. Based on these observations, we suggest that VPS9b has no specialized functionality, but rather is becoming a non expressed pseudogene. PMID- 29485921 TI - When monoclonal antibodies are not monospecific: Hybridomas frequently express additional functional variable regions. AB - Monoclonal antibodies are commonly assumed to be monospecific, but anecdotal studies have reported genetic diversity in antibody heavy chain and light chain genes found within individual hybridomas. As the prevalence of such diversity has never been explored, we analyzed 185 random hybridomas, in a large multicenter dataset. The hybridomas analyzed were not biased towards those with cloning difficulties or known to have additional chains. Of the hybridomas we evaluated, 126 (68.1%) contained no additional productive chains, while the remaining 59 (31.9%) contained one or more additional productive heavy or light chains. The expression of additional chains degraded properties of the antibodies, including specificity, binding signal and/or signal-to-noise ratio, as determined by enzyme linked immunosorbent assay and immunohistochemistry. The most abundant mRNA transcripts found in a hybridoma cell line did not necessarily encode the antibody chains providing the correct specificity. Consequently, when cloning antibody genes, functional validation of all possible VH and VL combinations is required to identify those with the highest affinity and lowest cross-reactivity. These findings, reflecting the current state of hybridomas used in research, reiterate the importance of using sequence-defined recombinant antibodies for research or diagnostic use. PMID- 29485923 TI - Effect of different rootstocks on the leaf metabolite profile of 'Sugar Belle' mandarin hybrid. AB - Currently, citrus greening is threatening the citrus industry worldwide. So far, there is no effective cure for this destructive disease and management mainly depends on the control of Diaphorina citri vector using insecticides. Although the use of different rootstocks could increase citrus scions' tolerance to biotic and abiotic stresses, little work has been conducted to investigate the effect of rootstocks on citrus tolerance to citrus greening pathogen. In this study, we investigated the effect of rootstock on the metabolite profile of 'Sugar Belle' mandarin hybrid using gas-chromatography mass spectrometry (GC-MS). The principle component analysis showed that the metabolite profiles of the 'Sugar Belle' mandarin hybrid on the three selected rootstocks were different from each other. These results indicated that rootstocks could affect the primary and secondary metabolites of citrus scions, and consequently could affect scion tolerance to pathogens. PMID- 29485924 TI - The Influence of Life Events and Psychological Stress on Objectively Measured Physical Activity: A 12-Month Longitudinal Study. AB - BACKGROUND: This study examined how life event occurrences and stressfulness influence objectively measured light through vigorous physical activity (PA) among young adults. METHODS: Every 3 months over a 12-month period, 404 healthy young adults completed questionnaires on the occurrence and stress of 16 life events and wore an accelerometer for 10 days. RESULTS: A modest positive relationship was seen between cumulative life event occurrences [between effect: beta = 22.2 (9.7) min/d, P = .02] and cumulative stress [between effect: beta = 7.6 (2.9) min/d, P = .01] with light through vigorous PA among men. When considering events individually, job change, starting a first job, beginning a mortgage, and changes in a relationship influenced men's PA. For women, mortgage, starting a first job, job change, and engagement had significant associations. Life event stressfulness influenced PA in women more than in men. For men, stress from changes in a relationship or job positively influenced PA. Stress of a mortgage, quitting a job, changing jobs or a first job influenced women's PA. CONCLUSION: Considering each life event individually was more informative than the summation of life events or summation of stress. Specific life events substantially altered PA, and this change varied by gender, direction of association, and PA intensity and duration. PMID- 29485927 TI - Patient-Centered Outcomes and Resuscitation Fluids. PMID- 29485928 TI - Segregating the Distinct Effects of Sedentary Behavior and Physical Activity on Older Adults' Cardiovascular Structure and Function: Part 1-Linear Regression Analysis Approach. AB - BACKGROUND: Physical behavior [PB, physical activity (PA), and sedentary behavior (SB)] can adjust cardiovascular mortality risk in older adults. The aim of this study was to predict cardiovascular parameters (CVPs) using 21 parameters of PB. METHODS: Participants [n = 93, 73.8 (6.23) y] wore a thigh-mounted accelerometer for 7 days. Phenotype of the carotid, brachial, and popliteal arteries was conducted using ultrasound. RESULTS: Sedentary behavior was associated with one of the 19 CVPs. Standing and light-intensity PA was associated with 3 and 1 CVP, respectively. Our prediction model suggested that an hourly increase in light intensity PA would be negatively associated with popliteal intima-media thickness [0.09 mm (95% confidence interval, 0.15 to 0.03)]. sMVPA [moderate-vigorous PA (MVPA), accumulated in bouts <10 min] was associated with 1 CVP. 10MVPA (MVPA accumulated in bouts >=10 min) had no associations. W50% had associations with 3 CVP. SB%, alpha, true mean PA bout, daily sum of PA bout time, and total week 10MVPA each were associated with 2 CVP. CONCLUSIONS: Patterns of PB are more robust predictors of CVP than PB (hours per day). The prediction that popliteal intima-media thickness would be negatively associated with increased standing and light-intensity PA engagement suggests that older adults could obtain health benefits without MVPA engagement. PMID- 29485926 TI - Balanced Crystalloids versus Saline in Noncritically Ill Adults. AB - BACKGROUND: Comparative clinical effects of balanced crystalloids and saline are uncertain, particularly in noncritically ill patients cared for outside an intensive care unit (ICU). METHODS: We conducted a single-center, pragmatic, multiple-crossover trial comparing balanced crystalloids (lactated Ringer's solution or Plasma-Lyte A) with saline among adults who were treated with intravenous crystalloids in the emergency department and were subsequently hospitalized outside an ICU. The type of crystalloid that was administered in the emergency department was assigned to each patient on the basis of calendar month, with the entire emergency department crossing over between balanced crystalloids and saline monthly during the 16-month trial. The primary outcome was hospital free days (days alive after discharge before day 28). Secondary outcomes included major adverse kidney events within 30 days - a composite of death from any cause, new renal-replacement therapy, or persistent renal dysfunction (defined as an elevation of the creatinine level to >=200% of baseline) - all censored at hospital discharge or 30 days, whichever occurred first. RESULTS: A total of 13,347 patients were enrolled, with a median crystalloid volume administered in the emergency department of 1079 ml and 88.3% of the patients exclusively receiving the assigned crystalloid. The number of hospital-free days did not differ between the balanced-crystalloids and saline groups (median, 25 days in each group; adjusted odds ratio with balanced crystalloids, 0.98; 95% confidence interval [CI], 0.92 to 1.04; P=0.41). Balanced crystalloids resulted in a lower incidence of major adverse kidney events within 30 days than saline (4.7% vs. 5.6%; adjusted odds ratio, 0.82; 95% CI, 0.70 to 0.95; P=0.01). CONCLUSIONS: Among noncritically ill adults treated with intravenous fluids in the emergency department, there was no difference in hospital-free days between treatment with balanced crystalloids and treatment with saline. (Funded by the Vanderbilt Institute for Clinical and Translational Research and others; SALT-ED ClinicalTrials.gov number, NCT02614040 .). PMID- 29485925 TI - Balanced Crystalloids versus Saline in Critically Ill Adults. AB - BACKGROUND: Both balanced crystalloids and saline are used for intravenous fluid administration in critically ill adults, but it is not known which results in better clinical outcomes. METHODS: In a pragmatic, cluster-randomized, multiple crossover trial conducted in five intensive care units at an academic center, we assigned 15,802 adults to receive saline (0.9% sodium chloride) or balanced crystalloids (lactated Ringer's solution or Plasma-Lyte A) according to the randomization of the unit to which they were admitted. The primary outcome was a major adverse kidney event within 30 days - a composite of death from any cause, new renal-replacement therapy, or persistent renal dysfunction (defined as an elevation of the creatinine level to >=200% of baseline) - all censored at hospital discharge or 30 days, whichever occurred first. RESULTS: Among the 7942 patients in the balanced-crystalloids group, 1139 (14.3%) had a major adverse kidney event, as compared with 1211 of 7860 patients (15.4%) in the saline group (marginal odds ratio, 0.91; 95% confidence interval [CI], 0.84 to 0.99; conditional odds ratio, 0.90; 95% CI, 0.82 to 0.99; P=0.04). In-hospital mortality at 30 days was 10.3% in the balanced-crystalloids group and 11.1% in the saline group (P=0.06). The incidence of new renal-replacement therapy was 2.5% and 2.9%, respectively (P=0.08), and the incidence of persistent renal dysfunction was 6.4% and 6.6%, respectively (P=0.60). CONCLUSIONS: Among critically ill adults, the use of balanced crystalloids for intravenous fluid administration resulted in a lower rate of the composite outcome of death from any cause, new renal-replacement therapy, or persistent renal dysfunction than the use of saline. (Funded by the Vanderbilt Institute for Clinical and Translational Research and others; SMART-MED and SMART-SURG ClinicalTrials.gov numbers, NCT02444988 and NCT02547779 .). PMID- 29485929 TI - Ventilatory Responses During Submaximal Exercise in Children With Prader-Willi Syndrome. AB - PURPOSE: Prader-Willi syndrome (PWS) is a genetic neurobehavioral disorder presenting hypothalamic dysfunction and adiposity. At rest, PWS exhibits hypoventilation with hypercapnia. We characterized ventilatory responses in children with PWS during exercise. METHODS: Participants were children aged 7-12 years with PWS (n = 8) and without PWS with normal weight (NW; n = 9, body mass index <= 85th percentile) or obesity (n = 9, body mass index >= 95th percentile). Participants completed three 5-minute ambulatory bouts at 3.2, 4.0, and 4.8 km/h. Oxygen uptake, carbon dioxide output, ventilation, breathing frequency, and tidal volume were recorded. RESULTS: PWS had slightly higher oxygen uptake (L/min) at 3.2 km/h [0.65 (0.46-1.01) vs 0.49 (0.34-0.83)] and at 4.8 km/h [0.89 (0.62-1.20) vs 0.63 (0.45-0.97)] than NW. PWS had higher ventilation (L/min) at 3.2 km/h [16.2 (13.0-26.5) vs 11.5 (8.4-17.5)], at 4.0 km/h [16.4 (13.9-27.9) vs 12.7 (10.3-19.5)], and at 4.8 km/h [19.7 (17.4-31.8) vs 15.2 (9.5-21.6)] than NW. PWS had greater breathing frequency (breaths/min) at 3.2 km/h [38 (29-53) vs 29 (22 35)], at 4.0 km/h [39 (29-58) vs 29 (23-39)], and at 4.8 km/h [39 (33-58) vs 32 (23-42)], but similar tidal volume and ventilation/carbon dioxide output to NW. CONCLUSION: PWS did not show impaired ventilatory responses to exercise. Hyperventilation in PWS may relate to excessive neural stimulation and metabolic cost. PMID- 29485930 TI - The Final Verdict: Chemotherapy Benefits Estrogen Receptor-Negative Isolated Local Recurrence. PMID- 29485931 TI - Associations Between Parent-Perceived Neighborhood Safety and Encouragement and Child Outdoor Physical Activity Among Low-Income Children. AB - BACKGROUND: A growing body of research has examined the relationship between perceived neighborhood safety and parental encouragement for child physical activity (PA), yet these potential predictors have not been studied together to predict child outdoor PA. The purpose of this study is to examine these predictors and parent- and child-reported child outdoor PA. METHODS: The Texas Childhood Obesity Research Demonstration study collected data from fifth-grade students attending 31 elementary schools across Austin and Houston and their parents (N = 748 parent-child dyads). Mixed-effects linear and logistic regressions stratified by gender and adjusted for sociodemographic covariates assessed associations among parental-perceived neighborhood safety, parental encouragement for child's outdoor PA, and parent- and child-reported child's outdoor PA. RESULTS: Parental-perceived neighborhood safety was significantly associated with encouraging outdoor PA (P = .01) and child-reported child's outdoor PA in boys, but not in girls. Significant associations were found between parental encouragement and child-reported outdoor PA for girls (P < .05) and parent-reported outdoor PA (P < .01) for boys and girls. CONCLUSIONS: Parent encouragement of PA and neighborhood safety are potential predictors of child outdoor PA and could be targeted in youth PA interventions. PMID- 29485932 TI - Do we have scientific evidence about the effect of hypoxaemia on cognitive outcome in adult patients with severe acute respiratory failure? PMID- 29485933 TI - Acute Effect of Intermittent Exercise and Action-Based Video Game Breaks on Math Performance in Preadolescent Children. AB - PURPOSE: The purpose of this study was to compare the acute effects of video game breaks and intermittent exercise breaks, performed at varying intensities, on math performance in preadolescent children. METHODS: A total of 39 children (18 males and 21 females; aged 7-11 y) completed 4 experimental conditions in random order: 8 hours of sitting interrupted with 20 two-minute low-, moderate-, or high intensity exercise breaks or 20 two-minute sedentary computer game breaks. The intensity of exercise breaks for the low-, moderate-, and high-intensity conditions corresponded with 25%, 50%, and 75% of heart rate reserve, respectively. Math performance was assessed 3 times throughout each condition day using a 90-second math test consisting of 40 single-digit addition and subtraction questions. RESULTS: There were no significant differences in percent change in math scores (correct answers out of attempted) by condition [low: -1.3 (0.8), moderate: 0.1 (1.3), high: -1.8 (0.7), and computer: -2.5 (0.8); P > .05]. There were significant differences in percent change in math scores over the course of the condition days with lower math scores reported at end-of-day test compared with midday test [-2.4 (0.5) vs -0.4 (0.3); P = .01]. There were no significant condition * time, time * age, condition * age, or condition * time * age interactions (all Ps > .05). CONCLUSION: Action-based video game and exercise breaks elicit the same level of math performance in children; however, time of day may impact this relationship. These findings may have important implications for instructional time in elementary classrooms. PMID- 29485934 TI - Differentiation of vascular elements in haustoria of Cuscuta japonica. AB - Parasitic plants establish vascular-conducting cells in an intrusive organ called haustorium. In haustoria of a stem parasitic plant, Cuscuta japonica, the presence of cells expressing cell-type-specific genes of phloem companion cell, phloem sieve element, procambial cell and xylem vessel has recently been demonstrated. Differentiation of these vascular cells is regulated in a manner similar to that in conventional vascular tissues. However, the initiation of procambial cells occurs concomitantly with the differentiation of vascular conducting cells. The differentiation process of phloem also differed from that of conventional vascular tissues because enucleation of sieve elements appeared to be impeded. These results collectively imply that the vascular differentiation process in haustoria of parasitic plants may be different from that in conventional vascular tissues. PMID- 29485935 TI - The Use of a Wheelchair Propulsion Field Test to Determine Peak Heart Rate in Children and Adolescents With Myelomeningocele. AB - PURPOSE: We analyzed the evolution and pattern of heart rate (HR) during the 12 minute wheelchair propulsion field test (WPFT) and compared the peak HR (HRpeak) from the WPFT to the HRpeak obtained in the progressive cardiopulmonary exercise test on arm cranking ergometer (ACT). We aimed to determine if the field test detects the HRpeak consistently and could be used in clinical practice. METHODS: Eleven wheelchair-using children and adolescents with myelomeningocele (aged 8-15 y) performed a maximal ACT and a 12-minute WPFT. HR was recorded continuously at rest, during each minute of the tests, and at recovery. Mixed analysis of variance was used to compare the variables at rest and peak. Bland-Altman plot and Lin's concordance correlation coefficient were used to show agreement between the tests. RESULTS: During minute 2 of the WPFT, participants reached 73%-96% of the HRpeak values recorded in the ACT. From minutes 4 to 12, participants reached HRpeak values ranging 86%-109% of the values recorded in the ACT. There is agreement between the ACT and the WPFT tests. CONCLUSION: WPFT with minimal duration of 4 minutes may be an alternative tool to obtain HRpeak in children and adolescents with myelomeningocele. PMID- 29485936 TI - Whole Sequences and Characteristics of mcr-1-Harboring Plasmids of Escherichia coli Strains Isolated from Livestock in South Korea. AB - Of 11 mcr-1-harboring plasmids previously identified from livestock in Korea, we performed whole plasmid sequencing on 3 plasmids and determined the genetic structure surrounding mcr-1 for all 11 plasmids. Transconjugation frequencies were measured for all mcr-1-harboring plasmids and competitive growth experiments were performed to investigate the fitness cost of each plasmid. Although they belong to different clones, the mcr-1-harboring plasmids, pEC006 and pEC019, were highly similar to the first identified mcr-1-carrying Incl2-type plasmid, pHNSHP45. Another IncX4-type plasmid, pEC111, had completely different structure from these plasmids, but was similar to pMCR1-IncX4. A nearly identical 11.3 kb mcr-1 region (nikB-ISApl1-mcr-1-pap2-topB) was shared by all mcr-1-harboring plasmids except pEC111. The transfer rate of mcr-1-harboring plasmids was highly variable (10-11 to 10-3) and was not related to plasmid structure. Competitive growth experiments revealed that the fitness of all three transconjugants with mcr-1-harboring plasmids increased compared with that of the recipient strain, Escherichia coli J53. The mcr-1-harboring plasmids may have been repeatedly introduced into bacterial isolates since the initial introduction of the mcr-1 positive strain from other countries into South Korea. Transferability and reduced burden to the host of mcr-1-harboring plasmid may lead to the proliferation of colistin-resistant isolates in the future. Therefore, continuous monitoring is necessary. PMID- 29485937 TI - Relationship Among Changes in Sedentary Time, Physical Activity, and Body Mass Index in Young Schoolchildren: A 3-Year Longitudinal Study. AB - PURPOSES: To examine the association between sedentary time (ST) and light physical activity (LPA), moderate- to vigorous-intensity physical activity (MVPA), and body mass index (BMI), and to track these behaviors over a 3-year follow-up in young schoolchildren. METHODS: The final sample was 64 children (female: n = 36 or 56.3%), enrolled in schools in Porto, Portugal. Height and mass of children were measured by standard methods, and BMI was then calculated. ST, LPA, and MVPA were measured by accelerometer. Changes (Delta) and relative changes (Delta%) between 2009/2010 and 2012/2013 of ST, LPA, MVPA, and BMI were computed. Multiple linear regression analyses were fit to predict Delta%ST (outcome variable), by Delta%LPA, Delta%MVPA, and Delta%BMI (exposure variables). RESULTS: ST increased and LPA decreased significantly for whole sample (both Ps < .05). No statistically significant difference was found for MVPA over time. There were no differences for DeltaST, DeltaLPA, DeltaMVPA, and DeltaBMI between boys and girls. The Delta%LPA and Delta%MVPA were negatively associated with Delta%ST, whereas Delta%BMI was positively associated. Tracking coefficients varied from moderate to strong. CONCLUSIONS: Time spent in ST increases due to displacement of time in LPA. This reinforces public health measures and suggests the need for interventions focusing on offsetting the decline ST and increasing MVPA during childhood. PMID- 29485938 TI - Erratum: Lakes et al (2017). AB - In the article by Lakes KD, Abdullah MM, Youssef J, et al. Assessing parent perceptions of physical activity in families of toddlers with neurodevelopmental disorders: The Parent Perceptions of Physical Activity Scale (PPPAS), Pediatr Exerc Sci. 2017; 29: 396-407, https://doi.org/10.1123/pes.2016-0213 , an author's name was incorrectly listed. Shlomit Aizik should have been listed as Shlomit Radom-Aizik. The online version of this article has been corrected. We apologize for this error. PMID- 29485939 TI - Circulation of Highly Drug-Resistant Clostridium difficile Ribotypes 027 and 001 in Two Tertiary-Care Hospitals in Mexico. AB - OBJECTIVE: To assess drug susceptibility and characterize Clostridium difficile ribotypes in isolates from two tertiary-care hospitals in Mexico. METHODS: Isolates were evaluated for genotyping, antimicrobial susceptibility testing and detection of mutations associated with drug resistance. PCR ribotyping was performed using a combination of gel-based and capillary electrophoresis-based approaches. RESULTS: MIC50 and MIC90 were >=128 mg/L for ciprofloxacin, erythromycin, clindamycin, and rifampicin. There was no reduced susceptibility to metronidazole or tetracycline; however, reduced susceptibility to vancomycin (>=4 mg/L) and fidaxomicin (>=2 mg/L) was detected in 50 (40.3%) and 4 (3.2%) isolates, respectively. Furthermore, the rpoB Arg505Lys mutation was more frequently detected in isolates with high minimum inhibitory concentration (MIC) to rifampicin (>=32 mg/L) (OR = 52.5; 95% CI = 5.17-532.6; p < 0.000). Of the 124 C. difficile isolates recovered, 84 (66.7%) were of ribotype 027, 18 (14.5%) of ribotype 001, and the remainder were other ribotypes (353, 255, 220, 208, 176, 106, 076, 020, 019, 017, 014, 012, 003, and 002). CONCLUSION: Ribotypes 027 and 001 were the most frequent C. difficile isolates recovered in this study, and demonstrated higher MICs. Furthermore, we found four isolates with reduced susceptibility to fidaxomicin, raising a concern since this drug is currently unavailable in Mexican Hospitals. PMID- 29485940 TI - Surveillance of Intrauterine Opioid Exposures Using Electronic Health Records. AB - The objective was to use population-based electronic health records for surveillance of intrauterine exposures to substances of abuse, including opioids, and to monitor changes in exposure rates over time. This retrospective, descriptive analysis utilized geocoded neonatal physician billing records representing intrauterine exposures to substances of abuse detected through universal maternal drug testing. Census tract-level exposure rates were identified among the newborn population of Hamilton County, Ohio between 2014 and 2016. Among 27,896 newborns, the authors detected an intrauterine opioid exposure rate of 37.9 per 1000 infants, with 10.5 per 1000 experiencing severe opioid withdrawal (neonatal abstinence syndrome). Individual data were mapped to 222 US census tracts. Tract-level opioid exposure rates ranged from 0.0 to 607.1 (median: 32.9) per 1000 live births. Secondary use of electronic health record data has potential to aid in intrauterine opioid exposure and other public health surveillance efforts without disrupting clinical workflows or placing an additional burden on limited resources. Surveillance of intrauterine opioid exposures may inform stakeholders and enable targeting of interventions and prevention strategies toward the highest risk populations. PMID- 29485941 TI - Quadriceps Strength Deficit at 6 Months After ACL Reconstruction Does Not Predict Return to Preinjury Sports Level. AB - BACKGROUND: There is a lack of literature-based objective criteria for return to sport after anterior cruciate ligament (ACL) injury. Establishing such objective criteria is crucial to improving return to sport after ACL reconstruction (ACLR). HYPOTHESES: Patients who return to their preinjury level of sport will have higher isokinetic, postural stability, and drop vertical jump test scores 6 months after surgery and greater patient satisfaction compared with those who did not. Additionally, quadriceps strength deficit cutoff values of 80% and 90% would differentiate patients who returned to preinjury sports level from those who did not. STUDY DESIGN: Cohort study. LEVEL OF EVIDENCE: Level 3. METHODS: A retrospective search was conducted to identify all patients who underwent ACLR and completed isokinetic evaluation, postural stability analysis, and drop vertical jump testing at 6 months postoperatively. Patients were asked to complete 3 questionnaires at a minimum 1 year after surgery. Chi-square and logistic regression analyses were used for categorical dependent variables, while the Student t test, Pearson correlation, or analyses of variance with Bonferroni post hoc testing were used for continuous dependent variables. A post hoc power analysis was completed. Based on the results regarding correlations between return to preinjury level and all other variables, effect sizes from 0.24 to 3.03 were calculated. With these effect sizes, an alpha of 0.05 and sample size of 58, a power ranging from 0.15 to 0.94 was calculated. RESULTS: The rates of return to preinjury level and to any sports activity were 53.4% and 84.4%. Those who were able to return to their preinjury level of sport (n = 33) showed significantly higher Lysholm (91.6 +/- 9.7 vs 76.7 +/- 15.4) and International Knee Documentation Committee (IKDC) (83.6 +/- 10.6 vs 69.8 +/- 14.6) values compared with those who were unable to return to their preinjury level of sport (n = 25) ( P < 0.001). No significant differences were found for the clinical evaluations between those who were and those who were not able to return at the same level for the clinical evaluations (isokinetic evaluation, postural stability, drop vertical jump test) ( P > 0.05). No significant differences were found when comparing quadriceps strength deficit with cutoff values of 80% and 90% for return to preinjury activity level (Tegner), Lysholm, and IKDC scores. CONCLUSION: Quadriceps strength deficit, regardless of cutoff value (80% or 90%), at 6 months after ACLR does not predict return to preinjury level of sport. Patients who returned to sport at their preinjury level were more satisfied with their reconstruction compared with those who did not. CLINICAL RELEVANCE: Quadriceps strength deficit is not a reliable predictor of return to sports, and therefore it should not be used as the single criterion in such evaluations. PMID- 29485942 TI - First Evidence of Vertical Infection of Dengue Virus 2 in Aedes aegypti Mosquitoes from Sinaloa, Mexico. AB - Fourteen pools of Aedes aegypti larvae collected within the urban area of Culiacan, Sinaloa, were analyzed by RT-PCR. The results demonstrate, for the first time, the vertical infection of serotype-2 dengue virus (DENV-2) in Sinaloa, Mexico, suggesting that Ae. aegypti acts as a natural reservoir of DENV 2 in this region. PMID- 29485943 TI - Contested Paradigm in Raising Zebrafish (Danio rerio). AB - The current body of work on rearing larval/juvenile zebrafish is based on (1) utilization of freshwater and (2) diurnal light/dark cycle, (3) provision of live feed at modest density, and (4) culture in high visibility environment. We challenged these rearing approaches by maintaining zebrafish under constant light for 46-48 days (days postfertilization [dpf]), while securing continuous feeding in high turbidity and saline (1.8-2.1 parts per thousand) environment for the experiment's duration, allowing 24 h feeding/growth of fish from first exogenous feeding to maturation. There was no evidence of negative effects on zebrafish larvae behavior, growth, survival, and life cycle duration at constant illumination when food was continuously available. Zebrafish were stocked at high initial density (100 larvae/L) in a static system and fed high densities of rotifers (Brachionus plicatilis) (200-400/mL) from 6 to 12 dpf. Fish density was then reduced by 50% and two diet treatments, live rotifers or brine shrimp (Artemia) nauplii (10/mL), followed. Fish were reared on these two diets until first maturation. Performance of adult zebrafish fed live rotifer followed by Artemia nauplii diet was the highest recorded in the literature after 42 dpf, 250 +/- 29 (males) and 430 +/- 5 mg (females). Use of these rearing conditions, during the entire life cycle, until reproduction, resulted in the shortest ever recorded generation time (from egg to egg) of 43-45 dpf and fertilization rate (1 dpf) of 80.3%-94%. PMID- 29485944 TI - The Effects of Viral Infection on Lymphocyte Metabolism: A New Perspective on Disease Characterization. AB - Over the past decade, metabolic dysfunction has been re-examined as an area of interest in a variety of atopic, malignant, and autoimmune conditions. The unique immune and, specifically, lymphocyte metabolic dysfunctions in disease are starting to be more clearly classified. Exploring the lymphocyte metabolic profiles of these diseases in the current literature, we characterize these diseases into two distinct metabolic groups. The influence of viral infection on immune metabolic dysfunction is explored. During an acute or chronic infection, there is a varied rapid shift in nutrients available to immune cells. This article explores the effect of these changes in nutrient availability and the resulting outcome on immune cell function. From this, a new hypothesis is proposed that these two groups of conditions, characterized by two unique immune profiles, are caused by either acute or chronic viral infections. The physiology behind this is explored, which proposes a new step between a healthy immune system and that of disease, in a unique working model. PMID- 29485945 TI - Seeing What You Feel: Affect Drives Visual Perception of Structurally Neutral Faces. AB - Affective realism, the phenomenon whereby affect is integrated into an individual's experience of the world, is a normal consequence of how the brain processes sensory information from the external world in the context of sensations from the body. In the present investigation, we provided compelling empirical evidence that affective realism involves changes in visual perception (i.e., affect changes how participants see neutral stimuli). In two studies, we used an interocular suppression technique, continuous flash suppression, to present affective images outside of participants' conscious awareness. We demonstrated that seen neutral faces are perceived as more smiling when paired with unseen affectively positive stimuli. Study 2 also demonstrated that seen neutral faces are perceived as more scowling when paired with unseen affectively negative stimuli. These findings have implications for real-world situations and challenge beliefs that affect is a distinct psychological phenomenon that can be separated from cognition and perception. PMID- 29485946 TI - Implementation of a Proactive Pilot Health Plan-Driven Opioid Tapering Program to Decrease Chronic Opioid Use for Conditions of the Back and Spine in a Medicaid Population. AB - BACKGROUND: In 2016, the Oregon Health Authority and the Health Evidence Review Commission implemented guidance for Oregon Medicaid members who were taking opioids for chronic pain related to conditions of the back and spine. This guidance required that an individualized taper plan be developed and initiated by January 1, 2017, and a discontinuation date for all chronic opioid therapy of January 1, 2018. PROGRAM DESCRIPTION: This program evaluated the effect of a proactive and voluntary health plan-driven opioid tapering program on morphine equivalent daily dose (MEDD) before the implementation of governmental guidance. Two mailings were sent to the providers of the targeted members with a variety of resources to facilitate an opioid taper. Pharmacy claims were analyzed to measure member opioid use, in the form of MEDD, after the provider outreach to be compared with their MEDDs before the outreach. OBSERVATIONS: A total of 113 members met the study inclusion criteria for the second provider outreach. Of the 19 members' providers who submitted responses via fax to the health plan in response to this outreach, 6 indicated they would initiate taper plans. Of the 6 members with taper plans, 5 had decreases in MEDD (3.6%, 4.5%, 42.9%, 45.5%, and 46.1%) after the 3-month data collection period, while the sixth member had no change in MEDD. Of the 113 members, 16 members (14.2%) had a decrease in MEDD; 23 members (20.4%) had no change in MEDD; and 72 members (63.7%) had an increase in MEDD. IMPLICATIONS: This study demonstrated that when a physician agrees to enroll patients in a health-plan driven clinical program it may result in decreased opioid use as referenced by MEDD. However, the results also showed the progressive nature of opioid use in this population. While these initial taper results were promising, a larger sample size and longer follow-up duration are needed to validate long-term adherence to an opioid tapering program and confirm that these results are attributable to the program and not other factors. DISCLOSURES: This study was sponsored by Moda Health. Patel is employed by Moda Health; Page and Saliba were employed by Moda Health during this project; and Traver was employed by Moda Health during part of this project. Page is now employed by Oregon State University (during the writing of this manuscript) to support the College of Pharmacy's contract with the Oregon Health Authority to provide professional pharmacist support for the Oregon Medicaid program. All other authors have nothing to disclose. Study concept and design were contributed by Page and Traver, who also collected the data. Data interpretation was performed by Page and Patel. The manuscript was written by Page and revised by Page, Patel, and Saliba. PMID- 29485947 TI - Differences in Medicaid Antipsychotic Medication Measures Among Children with SSI, Foster Care, and Income-Based Aid. AB - BACKGROUND: Concerns about antipsychotic prescribing for children, particularly those enrolled in Medicaid and with Supplemental Security Income (SSI), continue despite recent calls for selective use within established guidelines. OBJECTIVES: To (a) examine the application of 6 quality measures for antipsychotic medication prescribing in children and adolescents receiving Medicaid and (b) understand distinctive patterns across eligibility categories in order to inform ongoing quality management efforts to support judicious antipsychotic use. METHODS: Using data for 10 states from the 2008 Medicaid Analytic Extract (MAX), a cross sectional assessment of 144,200 Medicaid beneficiaries aged < 21 years who received antipsychotics was conducted to calculate the prevalence of 6 quality measures for antipsychotic medication management, which were developed in 2012 2014 by the National Collaborative for Innovation in Quality Measurement. These measures addressed antipsychotic polypharmacy, higher-than-recommended doses of antipsychotics, use of psychosocial services before antipsychotic initiation, follow-up after initiation, baseline metabolic screening, and ongoing metabolic monitoring. RESULTS: Compared with children eligble for income-based Medicaid, children receiving SSI and in foster care were twice as likely to receive higher than-recommended doses of antipsychotics (adjusted odds ratio [AOR] = 2.4, 95% CI = 2.3-2.6; AOR = 2.5, 95% CI = 2.4-2.6, respectively) and multiple concurrent antipsychotic medications (AOR = 2.2, 95% CI = 2.0-2.4; AOR = 2.2, 95% CI = 2.0 2.4, respectively). However, children receiving SSI and in foster care were more likely to have appropriate management, including psychosocial visits before initiating antipsychotic treatment and ongoing metabolic monitoring. While children in foster care were more likely to experience baseline metabolic screening, SSI children were no more likely than children eligible for income based aid to receive baseline screening. CONCLUSIONS: While indicators of overuse were more common in SSI and foster care groups, access to follow-up, metabolic monitoring, and psychosocial services was somewhat better for these children. However, substantial quality shortfalls existed for all groups, particularly metabolic screening and monitoring. Renewed efforts are needed to improve antipsychotic medication management for all children. DISCLOSURES: This project was supported by grant number U18HS020503 from the Agency for Healthcare Research and Quality (AHRQ) and Centers for Medicare & Medicaid Services (CMS). Additional support for Rutgers-based participants was provided from AHRQ grants R18 HS019937 and U19HS021112, as well as the New York State Office of Mental Health. The content of this study is solely the responsibility of the authors and does not necessarily represent the official views of AHRQ, CMS, or the New York State Office of Mental Health. Finnerty has been the principle investigator on research grants/contracts from Bristol Myers Squibb and Sunovion, but her time on these projects is fully supported by the New York State Office of Mental Health. Scholle, Byron, and Morden work for the National Committee for Quality Assurance, a not-for-profit organization that develops and maintains quality measures. Neese Todd was at Rutgers University at the time of this study and is now employed by the National Committee for Quality Assurance. The other authors have no financial relationships relevant to this article to disclose. Study concept and design were contributed by Finnerty, Neese-Todd, and Crystal, assisted by Scholle, Leckman Westin, Horowitz, and Hoagwood. Scholle, Byron, Morden, and Hoagwood collected the data, and data interpretation was performed by Pritam, Bilder, Leckman Westin, and Finnerty, with assistance from Scholle, Byron, Crystal, Kealey, and Neese-Todd. The manuscript was written by Leckman-Westin, Kealey, and Horowitz and revised by Layman, Crystal, Leckman-Westin, Finnerty, Scholle, Neese-Todd, and Horowitz, along with the other authors. PMID- 29485948 TI - Prospective Service Use and Health Care Costs of Medicaid Beneficiaries with Treatment-Resistant Depression. AB - BACKGROUND: Although the clinical and health economic characteristics of commercially insured adults with treatment-resistant depression (TRD) have been well characterized, little is known about TRD in the Medicaid population. OBJECTIVE: To describe clinical and health economic characteristics of adult Medicaid beneficiaries with TRD. METHODS: Retrospective longitudinal cohort analyses were performed with Truven Health MarketScan Medicaid Database (2008 2014), focusing on adults with major depressive disorder (MDD) following an index antidepressant prescription. TRD was operationally defined as starting a third treatment regimen after 2 adequate regimens of antidepressants or augmentation therapy within 12 months of an index antidepressant prescription. Among patients with and without TRD, percentages with inpatient admissions, emergency department visits, and outpatient visits (all cause, mental health related, and depression related) were determined. Logistic regression models were used to examine associations between TRD status and use of inpatient, outpatient, and emergency services. Separate analyses were performed for the first and second year after the index antidepressant prescription. RESULTS: Approximately one quarter (25.9%) of pharmacologically treated adults with MDD met criteria for TRD. In relation to MDD patients without TRD, patients with TRD were proportionately more likely to be older, male, and white. Compared with MDD patients without TRD, patients with TRD were also significantly more likely to receive inpatient care for any cause (31.0% vs. 21.6%; P < 0.001), a mental health-related reason (12.7% vs. 7.6%; P < 0.001), or depression (10.1% vs. 6.1%; P < 0.001) during the first year following their index antidepressant prescription. Over the second follow-up year, patients with TRD continued to be more likely than patients without TRD to receive inpatient care for any reason (26.7% vs. 19.5%; P < 0.001), a mental health related reason (5.6% vs. 2.7%; P < 0.001), and depression (3.7% vs. 1.7%; P < 0.001). The mean health care costs of patients with TRD were also significantly higher than the costs of patients without TRD during the first year ($18,982 [SD +/- $35,276] vs. $11,642 [SD +/- $29,203]) and second year ($17,997 [SD +/- $34,146] vs. $10,325 [SD +/- $28,224]) following the index antidepressant prescription. CONCLUSIONS: In the U.S. Medicaid program, adults with TRD have substantially and persistently higher health care costs than their counterparts who do not meet criteria for TRD. The service use and health care cost patterns of patients with TRD in the Medicaid program highlight challenges of developing interventions and care coordination strategies to meet their complex clinical needs. DISCLOSURES: This project was sponsored by Janssen Scientific Affairs. Olfson received a grant from Janssen Scientific Affairs through Columbia University Medical Center. Amos and Benson are employees of Janssen Scientific Affairs. Marcus was paid by Janssen Scientific Affairs to provide consulting support for this study and reports fees from Sunovion Pharmaceuticals and Alkermes outside of this study. McRae was a fellow affiliated with Janssen Scientific Affairs during the development of this research and manuscript. Study concept and design were contributed by Amos, Olfson, Marcus, Benson, and McRae. Data analysis was performed by all the authors. The manuscript was primarily written by Olfson, along with the other authors, and revised by McRae, Benson, Amos, Marcus, and Olfson. A different data cut from the same database was presented previously at the 2017 Annual Meeting of the International Society for Pharmacoeconomics and Outcomes Research; May 20-24, 2017; Boston, MA; and the 2017 AcademyHealth Annual Research Meeting; June 25-27, 2017; New Orleans, LA. PMID- 29485949 TI - Use of Prescription Assistance Programs After the Affordable Health Care Act. AB - BACKGROUND: Insurance coverage in the United States seems to be in a state of unrest. The 2010 passage of the Patient Protection and Affordable Health Care Act (ACA) extended health insurance coverage to roughly 32 million people. An increase in the number of people with health insurance benefits raised the question of whether prescription assistance programs (PAPs) would still be used after ACA implementation. OBJECTIVE: To evaluate the use of PAPs following the implementation of the ACA insurance mandate. METHODS: Health insurance was not required by the ACA until January 2014, so we retrospectively examined the use of drug company-sponsored PAPs before and after the ACA implementation. Since each PAP had its own qualifying criteria, any person who used a PAP through the assistance of NeedyMeds and its PAPTracker between the years of 2011 and 2016 were included for analysis. Data were pulled by NeedyMeds from the PAPTracker software, which produces completed PAP applications from drug manufacturer forms for PAPs. The number of PAP orders, number of unique patient orders, and annual patient prescription savings were assessed. RESULTS: Between 2011 and 2013, there was an average of 4.2 annual PAP orders per patient; however, annual PAP orders decreased to 3.1 per patient between 2014 and 2016 (P < 0.001). PAP orders declined by an average of 3.0% per month between 2014 and 2016 (P < 0.001), and average prescription savings per order increased from $870.40 before the ACA to $1,086.40 after ACA implementation (P = 0.0024). Patients saved an average of over $3,000 on prescriptions annually with the use of PAPs after the ACA mandate. CONCLUSIONS: Although health care reform is inevitable, our study showed that PAPs remain important to help cover prescription drug costs for eligible patients, even with invariable changes to health insurance, including a health insurance requirement. While the ACA may have been an important step forward in extending health insurance coverage to millions, PAPs are still used to help U.S. patients obtain their medications at no cost or very low cost. These programs will most likely remain relevant until other approaches are taken to help alleviate the effects of increasing drug prices in the United States. DISCLOSURES: No outside funding supported this research. The authors have no relevant financial or nonfinancial relationships to disclose. Study concept and design were contributed by Khan, Lerchenfeldt, and Karabon. Khan collected the data, and all authors participated in data analysis. The manuscript was primarily written by Lerchenfeldt, along with Khan and Karabon, and revised by Lerchenfeldt, along with Karabon and Khan. PMID- 29485950 TI - Estimating the Direct Costs of Outpatient Opioid Prescriptions: A Retrospective Analysis of Data from the Rhode Island Prescription Drug Monitoring Program. AB - BACKGROUND: Overuse and misuse of prescription opioids is associated with increased morbidity and mortality and places a significant cost burden on health systems. OBJECTIVE: To estimate annual statewide spending for prescription opioids in Rhode Island. METHODS: A cross-sectional study of opioids dispensed from retail pharmacies using data from the Rhode Island Prescription Drug Monitoring Program (PDMP) was performed. The study sample consisted of 651,227 opioid prescriptions dispensed to 197,062 patients between January 1, 2015, and December 31, 2015. The mean, median, and total cost of opioid use was estimated using prescription dispensings and patients as units of analysis. A generalized linear model with gamma distribution with an identity link function, and separately with a log link function, was used to estimate the absolute and relative differences in per-patient annual adjusted average opioid prescription cost, respectively, by potential predictors. RESULTS: The estimated 2015 annual expenditure for opioid prescriptions in Rhode Island was $44,271,827. The average and median costs of an opioid prescription were $67.98 (SD $210.91) and $21.08 (quartile 1 to quartile 3 = $7.65-$47.51), respectively. Prescriptions for branded opioid products accounted for $17,380,279.05, which was approximately 39.3% of overall spending, although only 6% of all opioids dispensed were for branded drugs. On average, patients aged 45-54 years and 55-64 years had overall adjusted spending for opioids that were 1.53 (95% CI = 1.49-1.57) and 1.75 (95% CI = 1.71-1.80) times higher than patients aged 65 years and older, respectively. Per patient Medicaid and Medicare average annual spending for opioid prescriptions were 1.19 (95% CI = 1.16-1.22) and 2.01 (95% CI = 1.96-2.06) times higher than commercial insurance spending, respectively. Annual opioid prescription spending was 2.01 (95% CI = 1.98-2.04) and 1.50 (95% CI = 1.45-1.55) times higher among patients who also had at least 1 dispensing of a benzodiazepine or sympathomimetic stimulant, respectively. Average total spending for prescription opioids per patient increased with the average daily dosage: from 3-fold for patients using 50-90 morphine milligrams equivalent (MME) daily to 22-fold for those receiving 90 or more MME daily compared with those receiving less than 50 MME daily. CONCLUSIONS: This study provides the first estimate of the statewide direct cost burden of prescription opioid use using PDMP data and standardized pricing benchmarks. Total annual cost increased with age up to 65 years, mean daily dose, and concurrent use of benzodiazepines or stimulants. Commercial insurance bore the majority of the cost of prescription opioid use, but cost per patient was highest among Medicare beneficiaries. In addition to reducing harms associated with opioid overuse and misuse, substantial cost savings could be realized by reducing unnecessary opioid use, especially among middle-aged adults. DISCLOSURES: This study was funded by the Rhode Island Department of Health. Aroke and Kogut report grants from the Rhode Island Department of Health during this study. Kogut is partially supported by Institutional Development Award Number U54GM115677 from the National Institute of General Medical Sciences of the National Institutes of Health, which funds Advance Clinical and Translational Research (Advance-CTR). Koziol reports grants from the Centers for Disease Control and Prevention during this study. The other authors have nothing to disclose. The content of this study is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Study concept and design were contributed by Koziol, Ragosta, and Kogut, along with Aroke. Koziol, Ragosta, Aroke, and Kogut collected the data, and data interpretation was performed by Aroke, Buchanan, Wen, and Kogut. The manuscript was primarily written by Aroke, along with Buchanan and Kogut, and revised by Aroke, Buchanan, Wen, and Kogut. PMID- 29485951 TI - Predicting Acute Exacerbations in Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: With increasing health care costs that have outpaced those of other industries, payers of health care are moving from a fee-for-service payment model to one in which reimbursement is tied to outcomes. Chronic obstructive pulmonary disease (COPD) is a disease where this payment model has been implemented by some payers, and COPD exacerbations are a quality metric that is used. Under an outcomes-based payment model, it is important for health systems to be able to identify patients at risk for poor outcomes so that they can target interventions to improve outcomes. OBJECTIVE: To develop and evaluate predictive models that could be used to identify patients at high risk for COPD exacerbations. METHODS: This study was retrospective and observational and included COPD patients treated with a bronchodilator-based combination therapy. We used health insurance claims data to obtain demographics, enrollment information, comorbidities, medication use, and health care resource utilization for each patient over a 6-month baseline period. Exacerbations were examined over a 6-month outcome period and included inpatient (primary discharge diagnosis for COPD), outpatient, and emergency department (outpatient/emergency department visits with a COPD diagnosis plus an acute prescription for an antibiotic or corticosteroid within 5 days) exacerbations. The cohort was split into training (75%) and validation (25%) sets. Within the training cohort, stepwise logistic regression models were created to evaluate risk of exacerbations based on factors measured during the baseline period. Models were evaluated using sensitivity, specificity, and positive and negative predictive values. The base model included all confounding or effect modifier covariates. Several other models were explored using different sets of observations and variables to determine the best predictive model. RESULTS: There were 478,772 patients included in the analytic sample, of which 40.5% had exacerbations during the outcome period. Patients with exacerbations had slightly more comorbidities, medication use, and health care resource utilization compared with patients without exacerbations. In the base model, sensitivity was 41.6% and specificity was 85.5%. Positive and negative predictive values were 66.2% and 68.2%, respectively. Other models that were evaluated resulted in similar test characteristics as the base model. CONCLUSIONS: In this study, we were not able to predict COPD exacerbations with a high level of accuracy using health insurance claims data from COPD patients treated with bronchodilator-based combination therapy. Future studies should be done to explore predictive models for exacerbations. DISCLOSURES: No outside funding supported this study. Samp is now employed by, and owns stock in, AbbVie. The other authors have nothing to disclose. Study concept and design were contributed by Joo and Pickard, along with the other authors. Samp and Lee performed the data analysis, with assistance from the other authors. Samp wrote the manuscript, which was revised by Schumock and Calip, along with the other authors. PMID- 29485952 TI - The Effect of Opioid Use and Mental Illness on Chronic Disease Medication Adherence in Superutilizers. AB - BACKGROUND: Nonadherence to essential chronic medications has been identified as a potential driver of high health care costs in superutilizers of inpatient services. Few studies, however, have documented the levels of nonadherence and factors associated with nonadherence in this high-cost, vulnerable population. OBJECTIVE: To examine the factors associated with nonadherence to essential chronic medications, with special emphasis on mental illness and use of opioid medications. METHODS: This study was a retrospective panel analysis of 2-year baseline data for Medicare Part D beneficiaries eligible for the SafeMed care transitions program in Memphis, Tennessee, from February 2013 to December 2014. The 2-year baseline data for each patient were divided into four, 6-month patient periods. The study included Medicare superutilizers (defined as patients with >= 3 hospitalizations or >= 2 hospitalizations with >= 2 emergency visits in 6 months) with continuous Part D coverage who had filled at least 1 drug class used to treat hypertension, diabetes mellitus, congestive heart failure, coronary artery disease, or chronic lung disease. The outcome included medication nonadherence assessed using proportion of days covered (PDC), with PDC < 80% defined as nonadherent, and the main exposure variables included mental illness (defined as a diagnosis of depression or anxiety or >= 1 anxiolytic or antidepressant fill) and opioid medication fills assessed in each 6-month period. Pooled observations from the four 6-month periods were used for multivariable analyses using the patient periods as the unit of analysis. A random effects model with robust standard errors and a binary distribution were used to examine associations between independent variables (time invariant and time variant factors) and medication nonadherence. The model included lagged effects of time variant factors measured in each period. RESULTS: Overall nonadherence to essential chronic medications ranged from 39.3% to 58.4%, with the highest for chronic lung disease medications (49.1%-64.4%). Factors associated with nonadherence included >= 4 opioid medication fills in the previous 6-month period (adjusted odds ratio [OR] = 1.90, 95% CI = 1.32-2.73); age 22-44 and 45-64 years vs. >= 65 years (OR = 3.57, 95% CI = 2.07-6.16, and OR = 2.07, 95% CI = 1.49 2.88); and a higher number of unique prescribers (OR = 1.10, 95% CI = 1.04-1.17). Factors protecting against nonadherence included higher number of unique medications filled (OR = 0.95, 95% CI = 0.92-0.98) and >= 1 physician office visit in the previous 6-month period (OR = 0.66, 95% CI = 0.46-0.94). CONCLUSIONS: This study demonstrated that high levels of opioid medication use are significantly associated with essential chronic disease medication nonadherence among superutilizers. Other risk factors for nonadherence were aged < 65 years, low-income status, and a higher number of unique prescribers. Factors protecting against nonadherence were physician office visits and filling higher number of medications. Medication management interventions targeting superutilizers should focus on supporting chronic disease medication adherence. DISCLOSURES: This project was supported by Funding Opportunity Number 1C1CMS331067-01-00 from the Centers for Medicare & Medicaid Services, Center for Medicare and Medicaid Innovation. Support was also provided by the Pharmaceutical Research and Manufacturers of America Foundation. The content of this study is solely the responsibility of the authors. The authors declare no relevant conflicts of interest or financial relationships. Study concept and design were contributed by Surbhi, Bailey, and Graetz. Surbhi and Wan collected the data, and data interpretation was performed primarily by Surbhi, along with Graetz, Bailey, and Gatwood. The manuscript was primarily written by Surbhi, with assistance from Bailey and Graetz, and revised by Bailey, Graetz, Gatwood, and Surbhi. This study was presented as a poster at the Academy Health Annual Research Meeting in Boston, Massachusetts, on June 26-28, 2016. PMID- 29485953 TI - The Association Between Patient Sociodemographic Characteristics and Generic Drug Use: A Systematic Review and Meta-analysis. AB - BACKGROUND: Generic drugs are bioequivalent and cost-effective alternatives to brand drugs. In 2014, $254 billion was saved because of the use of generic drugs in the United States. OBJECTIVE: To critically assess evidence on the association between patient characteristics and generic drug use in order to inform the development of educational outreach for improving generic drug use among patients. METHODS: We systematically searched the literature between January 2005 and December 2016 using PubMed, Web of Science, Ovid MEDLINE, Google Scholar, and EBSCO IPA-MEDLINE for potentially relevant studies. The titles and abstracts of identified articles were assessed independently by 2 reviewers. Titles and abstracts that were not written in English, were published before 2005, were not empirical, did not contain sociodemographic data, or were not policy or methodologically relevant to generic drug use were excluded. Data were pooled in a meta-analysis using the RStudio software to assess the association of patient related factors with generic drug use. RESULTS: Our searches resulted in 11 articles on patient-level factors, and 6 of these articles had sufficient information to conduct meta-analyses in the domains of patients' gender, age, race/ethnicity, and income. Quantitative analysis indicated that no differences in generic drug use existed between subgroups of patients defined by gender, age, or race/ethnicity. However, patients with lower income (i.e., < 200% federal poverty level [FPL]) were more likely to use generic drugs than those with higher income (>= 200% FPL; pooled OR = 1.32, 95% CI = 1.15-1.52). Heterogeneity was high (I 2 > 75%) for all analyses but income. CONCLUSIONS: Patients with lower income were more likely to use generic drugs, whereas evidence was heterogeneous regarding an association between generic drug use and gender, age, or race/ethnicity. Educational outreach targeting patients with higher incomes to understand their perspectives in generic drugs may help improve generic drug use within that population. DISCLOSURES: Funding for this study was made possible, in part, by the U.S. Food and Drug Administration through grant U01FD005486. Hansen has provided expert testimony for Daiichi Sankyo. No other authors have declared a potential conflict of interest. Views expressed in written materials or publications and by speakers do not necessarily reflect the official policies of the U.S. Department of Health and Human Services, nor does any mention of trade names, commercial practices, or organization imply endorsement by the U.S. government. Study concept and design were contributed by Howard, Harris, Kiptanui, Hansen, and Qian. Frank, Mishuk, Howard, Harris, and Kiptanui collected the data, and data interpretation was performed by Mishuk and Hansen, along with Qian, Harris, and Kiptanui. The manuscript was written and revised primarily by Mishuk, along with Qian and Hansen. PMID- 29485954 TI - Differences in All-Cause Health Care Utilization and Costs in a Type 2 Diabetes Mellitus Population with and Without a History of Cardiovascular Disease. AB - BACKGROUND: Multiple studies have reported that type 2 diabetes mellitus (T2DM) is a major risk factor for cardiovascular diseases (CVD), and presence of T2DM and CVD increases risk of death. There is growing interest in examining the effects of antidiabetic treatments on the reduction of cardiovascular events in T2DM adults with a history of CVD and thus at higher risk of cardiovascular events. OBJECTIVE: To estimate the incremental all-cause health care utilization and costs among adults with T2DM and a history of CVD compared with adults without a history of CVD, using a national linked electronic medical records (EMR) and claims database. METHODS: Adults aged >= 18 years with evidence of at least 1 T2DM-related diagnosis code or antidiabetic medication (date of earliest occurrence was defined as the index date) in calendar year 2012 were identified. The population was divided into 2 cohorts (with and without a history of CVD) and followed until the end of their enrollment coverage, death, or 12 months, whichever came first. Multivariable generalized linear models were used to assess differences in health care utilization and per patient per month (PPPM) total costs (plan- and patient-paid amount for health care services) between the 2 groups during the post-index year, while adjusting for an a priori list of demographic and clinical characteristics. RESULTS: A total of 138,018 adults with T2DM was identified, of which 16,547 (12%) had a history of CVD. The unadjusted resource utilization (outpatient: 27.5 vs. 17.8; emergency room [ER]: 0.8 vs. 0.4; inpatient: 0.4 vs. 0.2 days; and total unique drug prescriptions: 10.1 vs. 8.3) and PPPM total health care costs ($2,655.1 vs. $1,435.0) were significantly higher in T2DM adults with a history of CVD versus T2DM adults without a history of CVD. The adjusted models revealed that T2DM adults with a history of CVD had a 31% higher number of ER visits (rate ratio [RR] = 1.31, 95% CI = 1.25-1.37); 27% more inpatient visits (RR = 1.27, 95% CI = 1.21-1.34); 15% longer mean inpatient length of stay (RR = 1.15, 95% CI = 1.06-1.25); and 11% more outpatient visits (RR = 1.11, 95% CI = 1.09-1.13) compared with T2DM adults without a history of CVD. Furthermore, the difference in total PPPM health care cost was found to be 16% ($200) higher in adults with a history of CVD (RR = 1.16, 95% CI = 1.13 1.19). PPPM costs associated with outpatient and ER visits were approximately 21% and 19% higher among adults with a history of CVD, respectively (P < 0.0001), while costs for inpatient visits were similar between the 2 groups. In addition, a subgroup analysis revealed that adjusted differences in PPPM total cost was larger in the younger age group (56% higher cost in those aged < 45 years) and diminished in the older age group (only 2% higher in those aged >= 65 years). CONCLUSIONS: Study findings showed that resource utilization and costs remains significantly higher in T2DM patients with a history of CVD compared with patients without a history of CVD even after controlling for significant patient comorbid and demographic characteristics. Also, younger age groups had higher differences in outcomes compared with older age groups. This study underscores the importance of cost-effective interventions that may reduce economic burden in this T2DM population with a history of CVD. DISCLOSURES: This study was funded by Boehringer Ingelheim. At the time of this study, Mehta and Mountford were employed by IQVIA, which received funding from Boehringer Ingelheim to conduct this study. Mountford is employed by Allergan, which has no connection with this study. Ghosh, Sander, and Kuti are employed by Boehringer Ingelheim. Study concept and design were contributed by Mountford, Mehta, and Ghosh, along with Sander and Kuti. Mountford and Mehta collected the data, and data interpretation was performed by all the authors. The manuscript was written by Sander and Kuti, along with the other authors, and revised by Mehta and Gosh, along with the other authors. PMID- 29485955 TI - Case Report: Surgical Treatment of Two Asymptomatic Myxomas at Two Atypical Locations. AB - Atypical presentation of myxomas in the two cases described here arise from the fact that both patients were asymptomatic and both showed unexpected echocardiographic findings. Asymptomatic presentation is very rare, and occurs in only about 10% of individuals. Atrial myxomas discovered on incidental echocardiography is also a rare phenomenon, as seen in our cases. Early diagnosis and timely surgical treatment allow these patients to live a completely asymptomatic life. PMID- 29485956 TI - Proximal Aortic Surgery: Upper "J" or Conventional Sternotomy? AB - BACKGROUND: While minimally invasive procedures are being used in cardiac surgery, experience with minimally invasive proximal aortic surgery has been limited to certain centers. METHODS: Between January 2010 and March 2015, 54 patients with an upper "J" hemi-sternotomy and 75 patients with a conventional sternotomy due to proximal aortic pathology were included in this study. Forty five patients from the "J" hemi-sternotomy group were matched with 45 patients from the conventional sternotomy group with respect to age, sex, ejection fraction, diabetes, hypertension, smoking history and operative type. Perioperative variables were in-hospital mortality, surgery for revision, amount of blood loss, requirement for blood transfusion, cardiopulmonary bypass (CPB), aortic cross-clamp and unilateral cerebral protection times, duration of ventilation, and length of intensive care unit (ICU) and total hospital stay. RESULTS: Patients were between 21-76 years with a mean age of 58.14 +/- 11.06 years; 73.3% (n = 66) were male and 26.7% (n = 24) were female. Of all the cases included, 36.7% (n = 33) had isolated ascending aortic replacement, 41.1% (n = 37) had concomitant aortic valve replacement and ascending aortic replacement, and 22.2% (n = 20) had a Bentall procedure. Statistically, the amount of bleeding (P = .026), length of ventilation (P = .001), ICU (P = .001) and total hospital stay (P = .004) in the "J" hemi-sternotomy group were all found to be significantly lower than those in the conventional group. CONCLUSIONS: Minimally invasive techniques like an upper "J" hemi-sternotomy can be safely performed without prolonging the aortic clamp time, and with less blood loss, less ventilatory support, and shorter ICU and total hospital stays when compared to conventional methods. PMID- 29485957 TI - Impact of Major Pulmonary Resections on Right Ventricular Function: Early Postoperative Changes. AB - BACKGROUND: Right ventricular (RV) dysfunction after pulmonary resection in the early postoperative period is documented by reduced RV ejection fraction and increased RV end-diastolic volume index. Supraventricular arrhythmia, particularly atrial fibrillation, is common after pulmonary resection. RV assessment can be done by non-invasive methods and/or invasive approaches such as right cardiac catheterization. Incorporation of a rapid response thermistor to pulmonary artery catheter permits continuous measurements of cardiac output, right ventricular ejection fraction, and right ventricular end-diastolic volume. It can also be used for right atrial and right ventricular pacing, and for measuring right-sided pressures, including pulmonary capillary wedge pressure. METHODS: This study included 178 patients who underwent major pulmonary resections, 36 who underwent pneumonectomy assigned as group (I) and 142 who underwent lobectomy assigned as group (II). The study was conducted at the cardiothoracic surgery department of Benha University hospital in Egypt; patients enrolled were operated on from February 2012 to February 2016. A rapid response thermistor pulmonary artery catheter was inserted via the right internal jugular vein. Preoperatively the following was recorded: central venous pressure, mean pulmonary artery pressure, pulmonary capillary wedge pressure, cardiac output, right ventricular ejection fraction and volumes. The same parameters were collected in fixed time intervals after 3 hours, 6 hours, 12 hours, 24 hours, and 48 hours postoperatively. RESULTS: For group (I): There were no statistically significant changes between the preoperative and postoperative records in the central venous pressure and mean arterial pressure; there were no statistically significant changes in the preoperative and 12, 24, and 48 hour postoperative records for cardiac index; 3 and 6 hours postoperative showed significant changes. There were statistically significant changes between the preoperative and postoperative records for heart rate, mean pulmonary artery pressure, pulmonary capillary wedge pressure, pulmonary vascular resistance, right ventricular ejection fraction and right ventricular end diastolic volume index, in all postoperative records. For group (II): There were no statistically significant changes between the preoperative and all postoperative records for the central venous pressure, mean arterial pressure and cardiac index. There were statistically significant changes between the preoperative and postoperative records for heart rate, mean pulmonary artery pressure, pulmonary capillary wedge pressure, pulmonary vascular resistance, right ventricular ejection fraction and right ventricular end diastolic volume index in all postoperative records. There were statistically significant changes between the two groups in all postoperative records for heart rate, mean pulmonary artery pressure, pulmonary capillary wedge pressure, pulmonary vascular resistance, right ventricular ejection fraction and right ventricular end diastolic volume index. CONCLUSION: There is right ventricular dysfunction early after major pulmonary resection caused by increased right ventricular afterload. This dysfunction is more present in pneumonectomy than in lobectomy. Heart rate, mean pulmonary artery pressure, pulmonary capillary wedge pressure, pulmonary vascular resistance, right ventricular ejection fraction, and right ventricular end diastolic volume index are significantly affected by pulmonary resection. PMID- 29485958 TI - Identifying the Risk Factor and Prevention of Limb Ischemia in Extracorporeal Membrane Oxygenation with Femoral Artery Cannulation. AB - OBJECTIVE: Application of extracorporeal membrane oxygenation (ECMO) for life support has been widely used in various fields of resuscitation. When the common femoral artery (CFA) is used during cannulation for ECMO support in adults, it is often complicated by limb ischemia. Placement of distal perfusion catheter (DPC) can reduce the incidence of limb ischemia and increases the likelihood of limb preservation, but selection criteria is uncertain. METHODS: This is a retrospective study. Data was reviewed for patients in one medical center who were supported by venoarterial extracorporeal membrane oxygenation (VA-ECMO) via CFA cannulation percutaneously between January 2008 and June 2014. Two groups were divided into no-ischemia and ischemic limb. Age, sex, height, weight, body surface area (BSA), cannula size, femoral artery diameter, comorbidity, acute physiology and chronic health evaluation (APACHE) II score, vasoactive-inotropic score (VIS) and mortality rate were analyzed. Doppler was used by measuring the distal pulsation in the dorsalis pedis and posterior tibial artery to select the patients. A DPC was prophylactically inserted percutaneously into the superficial femoral artery for antegrade flow to the extremity in the patients who met selection criteria. RESULTS: 139 (43.6%) patients were included in the study and limb ischemia occurred in 46 (33%) of 139. There was a significant difference between the no-ischemia group and the ischemia group in age (55.5 +/- 14.2 versus 63.2 +/- 13.2; P < .001), common femoral artery diameter (0.82 +/- 0.14 versus 0.63 +/- 0.17; P < .001 ), known peripheral artery occlusive disease (9% versus 24%; P < .001) and VIS (12.1 +/- 8.1 versus 15.8 +/- 10.1; P < .001). Mortality rate was higher in the ischemia group (46% versus 26% ; P < .001). 11 patients who met the selection criteria had a DPC prophylactically inserted and no ischemia limb occurred. CONCLUSION: Smaller common femoral artery diameter (<=6.3 cm); known peripheral arterial occlusive disease; higher VIS (>=15.8); absence of distal pulsation pre-cannulation or immediately after post-cannulation or 4 hrs later have higher risk of limb ischemia when CFA cannulation is used for VA-ECMO. Due to this, the mortality and morbidity rate increases when limb ischemia occurs. A DPC should be prophylactically inserted in high-risk patients who meet selection criteria. PMID- 29485959 TI - A Case Report of Penicillin-Tolerant Streptococcus mitis Endocarditis Chang-Hua Chen, MD, MSc, PhD. AB - There is no clear relationship between the serum inhibition test and clinical outcome for Streptococcus mitis (S. mitis) endocarditis. We report an 84-year-old male with endocarditis caused by penicillin-tolerant S. mitis. The results for the serum inhibitory test (SIT) and serum bactericidal test (SBT) showed a trough level of SIT = 1:256 and SBT = 1:4 and a peak level of SIT >= 1:1024 and SBT = 1:16. In addition, the SIT/SBT ratio was 64 at peak level and more than 64 at trough level, which is compatible with penicillin-tolerant S. mitis. Following a 42-day high-dose penicillin treatment (24 M IU/day, via a continuous drip), the patient made a good recovery. In vitro inhibitory and bactericidal test results were not a valid predictor of medical treatment failure. Physicians need to continue to evaluate the surgical indications when treating patients with S. mitis endocarditis. PMID- 29485960 TI - Use of an On-X Prosthetic Valve In A 42-Year Old Female With Antiphospholipid Syndrome. AB - Antiphospholipid syndrome is a rare autoimmune disease with a hypercoagulable state causing vascular thrombosis. We present the case of a 42-year old female who underwent mitral valve replacement with a mechanical valve 15 months ago. The postoperative course was uneventful, and echocardiography performed 14 months postoperatively showed good valve function. The patient developed sudden dyspnea 15 months postoperatively and was referred to our hospital. Echocardiography revealed mitral stenosis with stuck leaflets. Emergent re-mitral valve replacement was successfully performed using an On-X valve (On-X Life Technologies, Austin, TX, USA). The patient tested positive for antiphospholipid antibodies. Antiphospholipid syndrome should be considered when valve dysfunction occurs suddenly in relatively young female patients. The On-X valve may be considered as a therapeutic option in patients with antiphospholipid syndrome because of its low anticoagulation intensity. PMID- 29485961 TI - Cerebral Function and Perfusion during Cardiopulmonary Bypass: A Plea for a Multimodal Monitoring Approach. AB - BACKGROUND: Postoperative neurological injury still represents a major cause of morbidity after cardiac surgery. Our objective was to compare the limits as well as advantages of routine monitoring tools for the detection of cerebral function and perfusion deficits during cardiopulmonary bypass in a daily clinical setting. METHODS: Adult patients undergoing elective cardiac surgery with use of cardiopulmonary bypass were included. Patients received monitoring comprising Bispectral Index (BIS), Near Infrared Spectroscopy (NIRS) and assessment of middle cerebral artery flow velocity (MCAV) using transcranial Doppler (TCD) sonography. Measurements were taken after anesthesia induction (at baseline) and every 10 minutes during aortic cross-clamping. Relative deviation from baseline values was calculated. Values were compared with predefined, generally accepted threshold values identifying patients at risk for cerebral functional and perfusion deficits. RESULTS: 30 consecutive patients were included into data analysis. Compared to NIRS as well as BIS monitoring, there was a wide interindividual variability in relative MCAV values for the whole cohort (median 0.9, range 0.39-2.19). Out of 229 measurements in total, 82 BIS but only 30 NIRS and 12 TCD values were lying outside predefined limits. TCD monitoring identified two patients with disturbed cerebral autoregulation, while NIRS remained unremarkable. The latter was significantly associated with systemic hemoglobin levels. Finally, patients with relative MCAV values >1.0 had a higher risk of developing postoperative delirium. CONCLUSION: Our findings reveal inherent technical limitations of each individual monitoring component, such as high interindividual variability (TCD), low spatial resolution (NIRS), or interaction with anesthetics (BIS). We therefore argue for a multimodal neuromonitoring that combines several qualities. Such approach would help reducing these limitations while individual components complement each other, thus providing more patient safety during cardiac surgery. Furthermore, such an approach would be easily applicable in a routine clinical setting. PMID- 29485962 TI - Validation of EuroSCORE II in Chinese Patients Undergoing Coronary Artery Bypass Surgery. AB - BACKGROUND: Comparisons between the EuroSCORE and EuroSCORE II in the patient populations for coronary artery bypass grafting are limited. The aim of the study was to compare the use of the EuroSCORE and EuroSCORE II as risk model for predicting in-hospital mortality in Chinese patients undergoing coronary artery bypass grafting (CABG). METHODS: Patients (n = 1598) with complete records of baseline and operative data were retrospectively collected from computerized records. The expected mortality rate for logistic EuroSCORE and EuroSCORE II was determined. Performance of the logistic EuroSCORE and EuroSCORE II model was assessed by comparing the observed and expected in-hospital mortality. The area under the receiver operating characteristics curve (AUC) values were calculated for these models to compare predictive power. RESULTS: Observed in-hospital overall mortality rate was 3.19%. The logistic EuroSCORE model (Hosmer-Lemeshow: P < .05, O/E = 0.73) over-predicted mortality (4.39%) and the EuroSCORE II model showed good calibration and discriminative capacity (area 0.762) in predicting in hospital mortality (Hosmer-Lemeshow: P = .191, O/E = 1.24). CONCLUSION: EuroSCORE II model reduces the overestimation of the calculated risk by logistic EuroSCORE in this population. EuroSCORE II risk model may be suitable in patients undergoing coronary artery bypass surgery in China. PMID- 29485963 TI - Carcinoid Heart Disease: Early Outcomes after Surgical Valve Replacement in Nine Patients. AB - AIM: To describe the early outcomes of carcinoid patients undergoing surgical heart valve replacement. METHODS: In a retrospective study, records of patients with symptomatic carcinoid heart disease referred for valve surgery between 2012 and 2016 were reviewed. The perioperative and early postoperative outcomes were analyzed. RESULTS: Nine patients, with a mean age of 61 years (range 55-70 years) underwent cardiac surgery for carcinoid syndrome. 3 patients had quadruple valve replacement, 5 had tricuspid and pulmonary valves changed, while one had tricuspid, pulmonary, and aortic valves replaced. Right-sided valves were replaced with biological valves in 8 patients and a mechanical valve in 1 patient. Left-sided valves were replaced with a mechanical valve in 2 patients and with a biological valve in 1 patient. Mean postoperative follow-up was 24 months (range 6-50 months, median 16 months). All patients had a good left ventricle except one, in whom it was mildly impaired. The right ventricle was severely dilated in 4 patients, moderately in 2, and mildly in 3. One patient died of heart failure 10 days postoperatively. Functional improvement was noted in all survivors, and they were in New York Heart Association class I at last follow up. CONCLUSION: Although carcinoid syndrome is a rare and progressive disease, valve replacement in symptomatic patients is a reasonable option with survival benefit, low early postoperative mortality, without valve-related complications, and with functional improvement. Cardiac assessment is required in all patients with carcinoid disease from the earliest time of medical treatment to improve patients' result. PMID- 29485964 TI - Expression of Rho Kinase and Its Mechanism in the Left Atrial Appendage in Patients with Atrial Fibrillation. AB - AIM: To study the expression of Rho kinase (Rho associated coil forming protein kinase-1, ROCK-1) and its substrate myosin phosphatase target subunit 1 (myosin phosphatase target subunit-1, MYPT-1), connexin 40 (Cx40) and connexin 43 (Cx43) in the left atrial appendage of patients with atrial fibrillation, and explore the role of ROCK signaling pathway in patients with atrial fibrillation and its underlying mechanism. Methods: 40 patients undergoing open heart surgery were divided into two groups; atrial fibrillation group (AF group) and sinus rhythm group (SR group). About 100 mg of left atrial appendage tissue was taken during surgery and quickly frozen in liquid nitrogen. Immunohistochemistry and western blot were performed to evaluate the expression and location of ROCK-1, MYPT-1, Cx40 and Cx43 in the left atrial appendage tissue. Results: The results indicated that the expression of ROCK-1, MYPT-1, and Cx40 in the left atrial appendage in patients with atrial fibrillation was significantly upregulated (P < .01), the difference in the two groups was statistically significant, and ROCK-1, Cx40, and MYPT-1 expression in the AF group were higher than those in sinus rhythm group; there was a weakly positive expression of Cx43 protein in the AF group and sinus rhythm group, the difference was not statistically significant, and ROCK-1 and MYPT-1 expression showed a significant positive correlation (r = 0.968, P < .05), MYPT 1 and Cx40 protein expression was also positively correlated (r = 0.983, P < .05). Evidence in the left atrial appendage tissue of patients with atrial fibrillation showed that some proteins in Rho/ROCK pathway were upregulated, and MYPT-1 and Cx40 protein expression in AF group were significantly higher than that of SR group, which was also positively correlated; Cx43 showed a weak positive expression in both the SR group and AF group, which indicates that Rho kinase may induce expression of Cx40 by phosphorylation of MYPT-1; Cx43 may not be involved, suggesting that Rho kinase signaling pathway may activate and play an important role in the pathogenesis of atrial fibrillation lesions. PMID- 29485965 TI - Temporary Epicardial Pacing After Valve Replacement: Incidence And Predictors. AB - Temporary pacemaker wires are usually inserted in patients after valve replacement and may be beneficial for optimizing myocardial function in patients that develop postoperative hemodynamically significant arrhythmias [Elmi 2002]. Indications for temporary cardiac pacing (TCP) are atrial, ventricular or atrioventricular pacing for bradyarrhythmias and for management of both atrial and ventricular tachyarrhythmias [De Belder 1990; Liebold 1998].Pacemaker wires have two ends - one end has a small needle, which is passed into the myocardial surface, then is cut off. The needles may be coiled or clipped for better fixation. On the other end, the larger needle is used to penetrate the body wall, to pass the wire through to the body surface. There is debate about the ideal site for wire insertion, with agreement that the most common site of insertion is in the right ventricle [Hurle 2002]. The complications of PMWs include: bleeding, tamponade, arrhythmias, and even retention with its serious hazards [Kapoor 2011; Smith 2013]. During removal of PMWs, there may be atrial or ventricular lacerations which lead to bleeding and to developing tamponade. This may prolong the hospital stay of patients, especially patients on anticoagulant medications. This study was done on patients who received pacing wires during cardiac surgery. The purpose of the study was to predict risk factors that could lead to cardiac pacing after valve surgery. PMID- 29485966 TI - Evaluation of P wave Dispersion and Tissue Doppler Imaging for Predicting Paroxysmal Atrial Fibrillation in Patients with Hypertension. AB - BACKGROUND: There are no previous studies dealing with paroxysmal atrial fibrillation (AF) and hypertension using electrocardiogram and tissue doppler imaging (TDI). The aim of this study was to investigate and identify the predictive indicators for paroxysmal AF in hypertensive patients using P wave dispersion (Pd) and TDI. METHODS: Patients with hypertension were enrolled. Patients with paroxysmal AF were classified as the PAF group, and patients without a history of paroxysmal AF were classified as the NAF group. The clinical data, P wave indicators and TDI indicators were collected and compared between the two groups. RESULTS: A total of 120 patients were enrolled into the study with 40 cases in the PAF group and 80 cases in the NAF group. Compared with NAF group, Pd, maximum P wave duration (Pmax), left ventricular end-diastolic dimension (LVEDd) and left atrial dimension (LAD) were significantly longer (P < .05) in the PAF group. PAL, PAI, PAR, LR, LI and IR were significantly longer (P < .05) in the PAF group than in the NAF group. As for ROC analysis, Pd and PAL had the greatest area under the curve. The best diagnostic value of Pd and PAL was 40ms and 78ms, respectively. The combination of Pd >=40ms with Pmax >= 110ms showed higher specificity and positive predictive value but decreased sensitivity and negative predictive value for paroxysmal AF. CONCLUSIONS: The PAF group had significantly longer atrial electromechanical time and higher Pd compared with NAF group. The combination of Pd and TDI may be helpful to predict the onset of paroxysmal AF in patients with hypertension. PMID- 29485967 TI - Report of the Third Heart Surgery Forum Scientific Sessions: Zagreb, Croatia December 6-8, 2017: Conference Highlights. AB - The Heart Surgery Forum is an online community dedicated to topics related to all aspects of cardiothoracic surgery. It consists of an informative website (www.hsforum.com), a traditional indexed journal both in print and online, and an email-based "list-serv" for discussion of surgical cases and techniques. The email list-serv, "OpenHeart-L" (The Forum) is composed of surgeons and allied specialties (perfusion, anesthesia, nursing). Dr. Mark Levinson (USA) started The Forum originally in 1995. He also served as the first Editor-in-Chief of the print journal for many years. Coinciding with the popularity of The Forum, and the desire by many members to meet in person, the First Heart Surgery Forum Conference (#1 HSF) was held in Savudrija, Istria, Croatia in 2010. The overwhelming success of this meeting, in terms of attendance and scientific content, resulted in #2 HSF being held in Split, Croatia in 2014. Recently, the #3 HSF meeting was held in Zagreb, Croatia on December 6-8th, 2017. This report highlights the scientific events of this meeting, and more importantly aims to inspire greater involvement by the international cardiothoracic community. Substantial increasing attendance was seen at each subsequent meeting, not only in terms of the number of participants and lectures, but also in the number of countries represented. PMID- 29485968 TI - Reoperative Cardiac Surgery: Part I - Preoperative Planning. AB - While reoperative cardiac surgery has become safer in recent years, it is still more difficult and dangerous than a primary operation. In a recent review of the Cleveland Clinic's experience, 7% of the patients undergoing cardiac reoperations had major intraoperative adverse events (IAEs). In that report, if an IAE occurred, there was a 5% mortality and a 19% incidence of myocardial infarction (MI), stroke, or death [Roselli 2011]. Those are sobering statistics, particularly when reported by one of the busiest cardiac surgical services in the world. The take-home message is that reoperative cardiac surgery is riskier than primary cardiac operations and that there are strategies that should be employed at each juncture to lower the risks of a reoperation.However, many of these strategies and recommendations have been more implicit than explicit. In fact, surprisingly little has been written about reoperative cardiac surgery. Thus, it seems appropriate to collect some of the lessons, adages, tricks, and tools that might make reoperations a click safer. PMID- 29485969 TI - Margaret Bruce. PMID- 29485970 TI - Reply to: Effect of female genital cutting performed by health care professionals on labor complications in Egyptian women: methodological concerns. PMID- 29485971 TI - Evaluation of Lavandula stoechas L. subsp. stoechas L., Mentha spicata L. subsp. spicata L. essential oils and their main components against sinusitis pathogens. PMID- 29485972 TI - Exploring the situational motivation of medical specialists: a qualitative study. AB - Objectives: The aim was to obtain insight into the factors in the work environment that motivate or demotivate a medical specialist during his/her working day. Methods: A qualitative ethnographic design was used, and a constructivist approach was adopted with the Self-Determination theory of motivation as a framework. Six medical specialists from VU University Medical Center in the Netherlands, recruited through convenience, snowball, and purposive sampling, were shadowed for one day each. Data were transcribed and open-coded. Themes were finalized through discussion and consensus. Results: Sixty hours of observation data identified motivating and demotivating factors categorized into four themes that are important for specialists' motivation. Informational technology issues are demotivating factors. Working with colleagues can be both a motivating and demotivating factor, e.g., filling in for each other through feelings of relatedness was motivating. Being in control of one's planning through feelings of autonomy was motivating. Furthermore, patient care and teaching, especially in combination, stimulated specialists' motivation. Regarding the design of the study, we found that situational motivation is indeed observable. Conclusions: The basic psychological needs autonomy, competence, and relatedness are important for specialists' motivation. Investing in a more motivating, open, transparent, and basic-needs- supportive work environment for medical specialists is necessary. Keywords: Continuing professional development, motivation, medical specialists, self-determination theory, qualitative research. PMID- 29485973 TI - Self-adjuvanting nanoemulsion targeting dendritic cell receptor Clec9A enables antigen-specific immunotherapy. AB - Non-antigen-specific stimulatory cancer immunotherapies are commonly complicated by off-target effects. Antigen-specific immunotherapy, combining viral tumor antigen or personalized neoepitopes with immune targeting, offers a solution. However, the lack of flexible systems targeting tumor antigens to cross presenting dendritic cells (DCs) limits clinical development. Although antigen anti-Clec9A mAb conjugates target cross-presenting DCs, adjuvant must be codelivered for cytotoxic T lymphocyte (CTL) induction. We functionalized tailored nanoemulsions encapsulating tumor antigens to target Clec9A (Clec9A TNE). Clec9A-TNE encapsulating OVA antigen targeted and activated cross presenting DCs without additional adjuvant, promoting antigen-specific CD4+ and CD8+ T cell proliferation and CTL and antibody responses. OVA-Clec9A-TNE-induced DC activation required CD4 and CD8 epitopes, CD40, and IFN-alpha. Clec9A-TNE encapsulating HPV E6/E7 significantly suppressed HPV-associated tumor growth, while E6/E7-CpG did not. Clec9A-TNE loaded with pooled B16-F10 melanoma neoepitopes induced epitope-specific CD4+ and CD8+ T cell responses, permitting selection of immunogenic neoepitopes. Clec9A-TNE encapsulating 6 neoepitopes significantly suppressed B16-F10 melanoma growth in a CD4+ T cell-dependent manner. Thus, cross-presenting DCs targeted with antigen-Clec9A-TNE stimulate therapeutically effective tumor-specific immunity, dependent on T cell help. PMID- 29485975 TI - Benralizumab (Fasenra) for severe eosinophilic asthma. PMID- 29485974 TI - Redirection to the bone marrow improves T cell persistence and antitumor functions. AB - A key predictor for the success of gene-modified T cell therapies for cancer is the persistence of transferred cells in the patient. The propensity of less differentiated memory T cells to expand and survive efficiently has therefore made them attractive candidates for clinical application. We hypothesized that redirecting T cells to specialized niches in the BM that support memory differentiation would confer increased therapeutic efficacy. We show that overexpression of chemokine receptor CXCR4 in CD8+ T cells (TCXCR4) enhanced their migration toward vascular-associated CXCL12+ cells in the BM and increased their local engraftment. Increased access of TCXCR4 to the BM microenvironment induced IL-15-dependent homeostatic expansion and promoted the differentiation of memory precursor-like cells with low expression of programmed death-1, resistance to apoptosis, and a heightened capacity to generate polyfunctional cytokine producing effector cells. Following transfer to lymphoma-bearing mice, TCXCR4 showed a greater capacity for effector expansion and better tumor protection, the latter being independent of changes in trafficking to the tumor bed or local out competition of regulatory T cells. Thus, redirected homing of T cells to the BM confers increased memory differentiation and antitumor immunity, suggesting an innovative solution to increase the persistence and functions of therapeutic T cells. PMID- 29485976 TI - Once-monthly subcutaneous buprenorphine (Sublocade) for opioid use disorder. PMID- 29485977 TI - Odactra--sublingual immunotherapy for house dust mite-induced allergic rhinitis. PMID- 29485978 TI - Haegarda--a subcutaneous C1 esterase inhibitor for prevention of hereditary angioedema. PMID- 29485979 TI - Hydrogen Sulfide Attenuates Hypertensive Inflammation via Regulating Connexin Expression in Spontaneously Hypertensive Rats. AB - BACKGROUND Hydrogen sulfide (H2S) has anti-inflammatory and anti-hypertensive effects, and connexins (Cxs) are involved in regulation of immune homeostasis. In this study, we explored whether exogenous H2S prevents hypertensive inflammation by regulating Cxs expression of T lymphocytes in spontaneously hypertensive rats (SHR). MATERIAL AND METHODS We treated SHR with sodium hydrosulfide (NaHS) for 9 weeks. Vehicle-treated Wistar-Kyoto rats (WKYs) were used as a control. The arterial pressure was monitored by the tail-cuff method, and vascular function in basilar arteries was examined by pressure myography. Hematoxylin and eosin staining was used to show vascular remodeling and renal injury. The percentage of T cell subtypes in peripheral blood, surface expressions of Cx40/Cx43 on T cell subtypes, and serum cytokines level were determined by flow cytometry or ELISA. Expression of Cx40/Cx43 proteins in peripheral blood lymphocytes was analyzed by Western blot. RESULTS Chronic NaHS treatment significantly attenuated blood pressure elevation, and inhibited inflammation of target organs, vascular remodeling, and renal injury in SHR. Exogenous NaHS also improved vascular function by attenuating KCl-stimulated vasoconstrictor response in basilar arteries of SHR. In addition, chronic NaHS administration significantly suppressed inflammation of peripheral blood in SHR, as evidenced by the decreased serum levels of IL-2, IL-6, and CD4/CD8 ratio and the increased IL-10 level and percentage of regulatory T cells. NaHS treatment decreased hypertension-induced Cx40/Cx43 expressions in T lymphocytes from SHR. CONCLUSIONS Our data demonstrate that H2S reduces hypertensive inflammation, at least partly due to regulation of T cell subsets balance by Cx40/Cx43 expressions inhibition. PMID- 29485981 TI - Systemic immune-inflammation index in germ-cell tumours: search for a biological prognostic biomarker. AB - This corrects the article DOI: 10.1038/bjc.2017.85. PMID- 29485980 TI - Systemic immune-inflammation index in germ-cell tumours. AB - BACKGROUND: We evaluated systemic immune-inflammation index (SII) and its association with patient outcome in germ-cell tumours (GCTs). METHODS: Two independent cohorts of patients were analysed; the discovery set (n=171) from a single institution and the validation set (n=181) previously included in a study evaluating PD-L1 in GCTs. The SII was calculated using platelet (P), neutrophil (N) and lymphocyte (L) counts before chemotherapy and correlated with survival using regression analyses and Kaplan-Meier method. RESULTS: In the discovery cohort, the SII was associated with poor risk clinical features. Patients with low SII had significantly longer progression-free survival (HR=0.22, 95% CI 0.12 0.41, P<0.001) and overall survival (OS) (HR=0.16, 95% CI 0.08-0.32, P<0.001) compared to high SII. This index was independent of International Germ Cell Cancer Collaborative Group criteria in multivariable Cox regression analysis for OS and was validated in an independent cohort. When combining PD-L1 expression on tumour infiltrating lymphocytes (TILs) and SII, we identified three distinctive prognostic groups. CONCLUSIONS: High SII was associated with poor outcome in GCTs. Combination of PD-L1 positive TILs and SII could further refine prognosis in GCTs. PMID- 29485982 TI - Systemic inflammatory markers have independent prognostic value in patients with metastatic testicular germ cell tumours undergoing first-line chemotherapy. AB - BACKGROUND: The prognostic utility of systemic inflammatory markers has so far not been investigated in patients with metastatic testicular germ cell tumours (GCTs). METHODS: International Germ Cell Cancer Cooperative Group (IGCCCG) risk groups and blood-based systemic inflammatory markers (haemoglobin, leukocytes, platelets (P), neutrophils (N), lymphocytes (L), C-reactive protein (CRP) and albumin) of 146 patients undergoing first-line chemotherapy for GCT were retrieved. In addition, N to L ratio (NLR), P to L ratio and the systemic immune inflammation index (SII=N * P/L) were calculated. The prognostic ability of these markers for overall survival (OS) were assessed using regression analyses and Kaplan-Meier curves with log-rank tests. RESULTS: In univariate Cox regression, low haemoglobin and albumin as well as high leukocytes, N, NLR, SII and CRP were associated with a shorter OS. In multivariable Cox regression analyses, high leukocyte (hazard ratio (HR) 1.274 (95% confidence interval (CI) 1.057-1.535); P=0.011) and N count (1.470 (1.092-1.980); P=0.011), higher NLR (84.5 (2.2 3193.4); P=0.017) and SII (12.15 (1.17-126.26); P=0.037) remained independent prognostic predictors for OS besides the IGCCCG risk groups. CONCLUSIONS: Systemic inflammatory markers might have prognostic utility for patients with metastatic GCT. The planned IGCCCG update could be an opportunity to test these markers in a larger data set. PMID- 29485984 TI - Preventing cholera outbreaks through early targeted interventions. AB - In a Perspective, Lorenz von Seidlein and Jacqueline L. Deen discuss the implications of Andrew Azman and colleagues' accompanying study for management of cholera outbreaks. PMID- 29485983 TI - Beyond fitness tracking: The use of consumer-grade wearable data from normal volunteers in cardiovascular and lipidomics research. AB - The use of consumer-grade wearables for purposes beyond fitness tracking has not been comprehensively explored. We generated and analyzed multidimensional data from 233 normal volunteers, integrating wearable data, lifestyle questionnaires, cardiac imaging, sphingolipid profiling, and multiple clinical-grade cardiovascular and metabolic disease markers. We show that subjects can be stratified into distinct clusters based on daily activity patterns and that these clusters are marked by distinct demographic and behavioral patterns. While resting heart rates (RHRs) performed better than step counts in being associated with cardiovascular and metabolic disease markers, step counts identified relationships between physical activity and cardiac remodeling, suggesting that wearable data may play a role in reducing overdiagnosis of cardiac hypertrophy or dilatation in active individuals. Wearable-derived activity levels can be used to identify known and novel activity-modulated sphingolipids that are in turn associated with insulin sensitivity. Our findings demonstrate the potential for wearables in biomedical research and personalized health. PMID- 29485985 TI - Prevalence of sexually transmitted infections among young people in South Africa: A nested survey in a health and demographic surveillance site. AB - BACKGROUND: Sexually transmitted infections (STIs) and bacterial vaginosis (BV) are associated with increased transmission of HIV, and poor reproductive and sexual health. The burden of STIs/BV among young people is unknown in many high HIV prevalence settings. We conducted an acceptability, feasibility, and prevalence study of home-based sampling for STIs/BV among young men and women aged 15-24 years old in a health and demographic surveillance site (HDSS) in rural KwaZulu-Natal, South Africa. METHODS AND FINDINGS: A total of 1,342 young people, stratified by age (15-19 and 20-24 years) and sex were selected from the HDSS sampling frame; 1,171/1,342 (87%) individuals had >=1 attempted home visit between 4 October 2016 and 31 January 2017, of whom 790 (67%) were successfully contacted. Among the 645 who were contacted and eligible, 447 (69%) enrolled. Consenting/assenting participants were interviewed, and blood, self-collected urine (men), and vaginal swabs (women) were tested for herpes simplex virus type 2 (HSV-2), chlamydia, gonorrhoea, syphilis, trichomoniasis, and BV. Both men and women reported that sample collection was easy. Participants disagreed that sampling was painful; more than half of the participants disagreed that they felt anxious or embarrassed. The weighted prevalence of STIs/BV among men and women, respectively, was 5.3% and 11.2% for chlamydia, 1.5% and 1.8% for gonorrhoea, 0% and 0.4% for active syphilis, 0.6% and 4.6% for trichomoniasis, 16.8% and 28.7% for HSV-2, and 42.1% for BV (women only). Of the women with >=1 curable STI, 75% reported no symptoms. Factors associated with STIs/BV included having older age, being female, and not being in school or working. Among those who participated in the 2016 HIV serosurvey, the prevalence of HIV was 5.6% among men and 19% among women. Feasibility was impacted by the short study duration and the difficulty finding men at home. CONCLUSIONS: A high prevalence of STIs/BV was found in this rural setting with high HIV prevalence in South Africa. Most STIs and HIV infections were asymptomatic and would not have been identified or treated under national syndromic management guidelines. A nested STI/BV survey within a HDSS proved acceptable and feasible. This is a proof of concept for population-based STI surveillance in low- and middle-income countries that could be utilised in the evaluation of STI/HIV prevention and control programmes. PMID- 29485987 TI - The potential impact of case-area targeted interventions in response to cholera outbreaks: A modeling study. AB - BACKGROUND: Cholera prevention and control interventions targeted to neighbors of cholera cases (case-area targeted interventions [CATIs]), including improved water, sanitation, and hygiene, oral cholera vaccine (OCV), and prophylactic antibiotics, may be able to efficiently avert cholera cases and deaths while saving scarce resources during epidemics. Efforts to quickly target interventions to neighbors of cases have been made in recent outbreaks, but little empirical evidence related to the effectiveness, efficiency, or ideal design of this approach exists. Here, we aim to provide practical guidance on how CATIs might be used by exploring key determinants of intervention impact, including the mix of interventions, "ring" size, and timing, in simulated cholera epidemics fit to data from an urban cholera epidemic in Africa. METHODS AND FINDINGS: We developed a micro-simulation model and calibrated it to both the epidemic curve and the small-scale spatiotemporal clustering pattern of case households from a large 2011 cholera outbreak in N'Djamena, Chad (4,352 reported cases over 232 days), and explored the potential impact of CATIs in simulated epidemics. CATIs were implemented with realistic logistical delays after cases presented for care using different combinations of prophylactic antibiotics, OCV, and/or point-of-use water treatment (POUWT) starting at different points during the epidemics and targeting rings of various radii around incident case households. Our findings suggest that CATIs shorten the duration of epidemics and are more resource efficient than mass campaigns. OCV was predicted to be the most effective single intervention, followed by POUWT and antibiotics. CATIs with OCV started early in an epidemic focusing on a 100-m radius around case households were estimated to shorten epidemics by 68% (IQR 62% to 72%), with an 81% (IQR 69% to 87%) reduction in cases compared to uncontrolled epidemics. These same targeted interventions with OCV led to a 44-fold (IQR 27 to 78) reduction in the number of people needed to target to avert a single case of cholera, compared to mass campaigns in high cholera-risk neighborhoods. The optimal radius to target around incident case households differed by intervention type, with antibiotics having an optimal radius of 30 m to 45 m compared to 70 m to 100 m for OCV and POUWT. Adding POUWT or antibiotics to OCV provided only marginal impact and efficiency improvements. Starting CATIs early in an epidemic with OCV and POUWT targeting those within 100 m of an incident case household reduced epidemic durations by 70% (IQR 65% to 75%) and the number of cases by 82% (IQR 71% to 88%) compared to uncontrolled epidemics. CATIs used late in epidemics, even after the peak, were estimated to avert relatively few cases but substantially reduced the number of epidemic days (e.g., by 28% [IQR 15% to 45%] for OCV in a 100-m radius). While this study is based on a rigorous, data-driven approach, the relatively high uncertainty about the ways in which POUWT and antibiotic interventions reduce cholera risk, as well as the heterogeneity in outbreak dynamics from place to place, limits the precision and generalizability of our quantitative estimates. CONCLUSIONS: In this study, we found that CATIs using OCV, antibiotics, and water treatment interventions at an appropriate radius around cases could be an effective and efficient way to fight cholera epidemics. They can provide a complementary and efficient approach to mass intervention campaigns and may prove particularly useful during the initial phase of an outbreak, when there are few cases and few available resources, or in order to shorten the often protracted tails of cholera epidemics. PMID- 29485986 TI - Prevalence of sexually transmitted infections and bacterial vaginosis among women in sub-Saharan Africa: An individual participant data meta-analysis of 18 HIV prevention studies. AB - BACKGROUND: Estimates of sexually transmitted infection (STI) prevalence are essential for efforts to prevent and control STIs. Few large STI prevalence studies exist, especially for low- and middle-income countries (LMICs). Our primary objective was to estimate the prevalence of chlamydia, gonorrhea, trichomoniasis, syphilis, herpes simplex virus type 2 (HSV-2), and bacterial vaginosis (BV) among women in sub-Saharan Africa by age, region, and population type. METHODS AND FINDINGS: We analyzed individual-level data from 18 HIV prevention studies (cohort studies and randomized controlled trials; conducted during 1993-2011), representing >37,000 women, that tested participants for >=1 selected STIs or BV at baseline. We used a 2-stage meta-analysis to combine data. After calculating the proportion of participants with each infection and standard error by study, we used a random-effects model to obtain a summary mean prevalence of each infection and 95% confidence interval (CI) across ages, regions, and population types. Despite substantial study heterogeneity for some STIs/populations, several patterns emerged. Across the three primary region/population groups (South Africa community-based, Southern/Eastern Africa community-based, and Eastern Africa higher-risk), prevalence was higher among 15 24-year-old than 25-49-year-old women for all STIs except HSV-2. In general, higher-risk populations had greater prevalence of gonorrhea and syphilis than clinic/community-based populations. For chlamydia, prevalence among 15-24-year olds was 10.3% (95% CI: 7.4%, 14.1%; I2 = 75.7%) among women specifically recruited from higher-risk settings for HIV in Eastern Africa and was 15.1% (95% CI: 12.7%, 17.8%; I2 = 82.3%) in South African clinic/community-based populations. Among clinic/community-based populations, prevalence was generally greater in South Africa than in Southern/Eastern Africa for most STIs; for gonorrhea, prevalence among 15-24-year-olds was 4.6% (95% CI: 3.3%, 6.4%; I2 = 82.8%) in South Africa and was 1.7% (95% CI: 1.2%, 2.6%; I2 = 55.2%) in Southern/Eastern Africa. Across the three primary region/population groups, HSV-2 and BV prevalence was high among 25-49-year-olds (ranging from 70% to 83% and 33% to 44%, respectively). The main study limitation is that the data are not from random samples of the target populations. CONCLUSIONS: Combining data from 18 HIV prevention studies, our findings highlight important features of STI/BV epidemiology among sub-Saharan African women. This methodology can be used where routine STI surveillance is limited and offers a new approach to obtaining critical information on STI and BV prevalence in LMICs. PMID- 29485989 TI - The more the merrier? Increasing group size may be detrimental to decision-making performance in nominal groups. AB - Demonstrability-the extent to which group members can recognize a correct solution to a problem-has a significant effect on group performance. However, the interplay between group size, demonstrability and performance is not well understood. This paper addresses these gaps by studying the joint effect of two factors-the difficulty of solving a problem and the difficulty of verifying the correctness of a solution-on the ability of groups of varying sizes to converge to correct solutions. Our empirical investigations use problem instances from different computational complexity classes, NP-Complete (NPC) and PSPACE-complete (PSC), that exhibit similar solution difficulty but differ in verification difficulty. Our study focuses on nominal groups to isolate the effect of problem complexity on performance. We show that NPC problems have higher demonstrability than PSC problems: participants were significantly more likely to recognize correct and incorrect solutions for NPC problems than for PSC problems. We further show that increasing the group size can actually decrease group performance for some problems of low demonstrability. We analytically derive the boundary that distinguishes these problems from others for which group performance monotonically improves with group size. These findings increase our understanding of the mechanisms that underlie group problem-solving processes, and can inform the design of systems and processes that would better facilitate collective decision-making. PMID- 29485990 TI - Intrusion detection system using Online Sequence Extreme Learning Machine (OS ELM) in advanced metering infrastructure of smart grid. AB - Advanced Metering Infrastructure (AMI) realizes a two-way communication of electricity data through by interconnecting with a computer network as the core component of the smart grid. Meanwhile, it brings many new security threats and the traditional intrusion detection method can't satisfy the security requirements of AMI. In this paper, an intrusion detection system based on Online Sequence Extreme Learning Machine (OS-ELM) is established, which is used to detecting the attack in AMI and carrying out the comparative analysis with other algorithms. Simulation results show that, compared with other intrusion detection methods, intrusion detection method based on OS-ELM is more superior in detection speed and accuracy. PMID- 29485988 TI - Effectiveness of integrated care including therapeutic assertive community treatment in severe schizophrenia-spectrum and bipolar I disorders: Four-year follow-up of the ACCESS II study. AB - : The ACCESS-model offers integrated care including assertive community treatment to patients with psychotic disorders. ACCESS proved more effective compared to standard care (ACCESS-I study) and was successfully implemented into clinical routine (ACCESS-II study). In this article, we report the 4-year outcomes of the ACCESS-II study. Between May 2007 and December 2013, 115 patients received continuous ACCESS-care. We hypothesized that the low 2-year disengagement and hospitalization rates and significant improvements in psychopathology, functioning, and quality of life could be sustained over 4 years. Over 4 years, only 10 patients disengaged from ACCESS. Another 23 left for practical reasons and were successfully transferred to other services. Hospitalization rates remained low (13.0% in year 3; 9.1% in year 4). Involuntary admissions decreased from 35% in the 2 years prior to ACCESS to 8% over 4 years in ACCESS. Outpatient contacts remained stably high at 2.0-2.4 per week. We detected significant improvements in psychopathology (effect size d = 0.79), illness severity (d = 1.29), level of functioning (d = 0.77), quality of life (d = 0.47) and stably high client satisfaction (d = 0.02) over 4 years. Most positive effects were observed within the first 2 years with the exception of illness severity, which further improved from year 2 to 4. Within continuous intensive 4-year ACCESS care, sustained improvements in psychopathology, functioning, quality of life, low service disengagement and re-hospitalization rates, as well as low rates of involuntary treatment, were observed in contrast to other studies, which reported a decline in these parameters once a specific treatment model was stopped. Yet, stronger evidence to prove these results is required. TRIAL REGISTRATION: Clinical Trial Registration Number: NCT01888627. PMID- 29485991 TI - The dead and the dying - a difficult part of EMS transport: A Swiss cross sectional study. AB - OBJECTIVE: Most deaths occur in the pre-hospital setting, whereas mortality in the emergency department (ED) is low (<1%). However, our clinical impression is that some patients are being transported to hospital in devastating conditions with no likelihood of survival, but demanding extensive hospital resources. The decision on whether to transport a dying person to hospital or not is a difficult task for emergency medical services (EMS) personnel. As there is little epidemiological data about these patients, this paper aims to describe this special population. METHODS: Retrospective cross-sectional study on adult patients transported by ground ambulance to the ED of a Swiss university hospital, who died during their stay in the ED between January 2008 and December 2012. Data was collected on the basis of ambulance report forms and discharge summaries of the ED. RESULTS: One hundred and sixty-one patients were analysed. Most deaths were due to cardiovascular diseases (43%). Only 9% of patients died of trauma. The median age was 70 years (IQR 56-81 years) and 70% (n = 112) were men. Trauma patients were significantly younger (median age 55 years, p<0.001). The overall mortality rate was 0.9% for all patients transported by EMS to the ED. About one third of all patients received cardiopulmonary resuscitation (CPR) from bystanders (n = 53). The most common electrocardiogram (ECG) findings were asystole (n = 57) and pulseless electrical activity (n = 91). Fifty percent (n = 64) of the resuscitated patients were defibrillated. Three quarters (n = 115, 72%) of all patients were intubated on site. The mechanical chest compression device LucasTM2 was mainly used in cases of cardiovascular or uncertain cause of death and did not reduce the operating time on site. CONCLUSION: The low ED mortality rate of 0.9% shows that only a few dying patients are transported to hospital. However, transport to hospital has to be carefully evaluated, especially for elderly patients with asystole or PEA due to medical conditions. The low CPR rate from bystanders demonstrates that public CPR training should be promoted further. The use of LucasTM2 did not reduce the operating time on site. For further investigations, comparison with survivors would be needed. PMID- 29485992 TI - Revealing how an adenylate cyclase toxin uses bait and switch tactics in its activation. AB - Dissecting how bacterial pathogens escape immune destruction and cause respiratory infections in humans is a work in progress. One tactic employed by microbes is to use bacterial adenylate cyclase toxins (ACTs) to disarm immune cells and disrupt cellular signaling in host cells, which facilitates the infection process. Several clinically significant pathogens, such as Bacillus anthracis and Bordetella pertussis, have ACTs that are stimulated by an activator protein in human cells. Research has shown that these bacterial ACTs have evolved distinct ways of controlling their activities, but our understanding of how the B. pertussis ACT does this is limited. In a recent study, O'Brien and colleagues provide new and exciting evidence demonstrating that the regulation of B. pertussis ACT involves conformational switching between flexible and rigid states, which is triggered upon binding the host activator protein. This study increases our knowledge of how bacterial ACTs are unique enzymes, representing a potentially novel class of drug targets that may open new pathways to combat reemerging infectious diseases. PMID- 29485993 TI - Assessment of data transformations for model-based clustering of RNA-Seq data. AB - Quality control, global biases, normalization, and analysis methods for RNA-Seq data are quite different than those for microarray-based studies. The assumption of normality is reasonable for microarray based gene expression data; however, RNA-Seq data tend to follow an over-dispersed Poisson or negative binomial distribution. Little research has been done to assess how data transformations impact Gaussian model-based clustering with respect to clustering performance and accuracy in estimating the correct number of clusters in RNA-Seq data. In this article, we investigate Gaussian model-based clustering performance and accuracy in estimating the correct number of clusters by applying four data transformations (i.e., naive, logarithmic, Blom, and variance stabilizing transformation) to simulated RNA-Seq data. To do so, an extensive simulation study was carried out in which the scenarios varied in terms of: how genes were selected to be included in the clustering analyses, size of the clusters, and number of clusters. Following the application of the different transformations to the simulated data, Gaussian model-based clustering was carried out. To assess clustering performance for each of the data transformations, the adjusted rand index, clustering error rate, and concordance index were utilized. As expected, our results showed that clustering performance was gained in scenarios where data transformations were applied to make the data appear "more" Gaussian in distribution. PMID- 29485994 TI - Bonobo and chimpanzee gestures overlap extensively in meaning. AB - Cross-species comparison of great ape gesturing has so far been limited to the physical form of gestures in the repertoire, without questioning whether gestures share the same meanings. Researchers have recently catalogued the meanings of chimpanzee gestures, but little is known about the gesture meanings of our other closest living relative, the bonobo. The bonobo gestural repertoire overlaps by approximately 90% with that of the chimpanzee, but such overlap might not extend to meanings. Here, we first determine the meanings of bonobo gestures by analysing the outcomes of gesturing that apparently satisfy the signaller. Around half of bonobo gestures have a single meaning, while half are more ambiguous. Moreover, all but 1 gesture type have distinct meanings, achieving a different distribution of intended meanings to the average distribution for all gesture types. We then employ a randomisation procedure in a novel way to test the likelihood that the observed between-species overlap in the assignment of meanings to gestures would arise by chance under a set of different constraints. We compare a matrix of the meanings of bonobo gestures with a matrix for those of chimpanzees against 10,000 randomised iterations of matrices constrained to the original data at 4 different levels. We find that the similarity between the 2 species is much greater than would be expected by chance. Bonobos and chimpanzees share not only the physical form of the gestures but also many gesture meanings. PMID- 29485995 TI - Genetic programming based models in plant tissue culture: An addendum to traditional statistical approach. AB - In this paper, we compared the efficacy of observation based modeling approach using a genetic algorithm with the regular statistical analysis as an alternative methodology in plant research. Preliminary experimental data on in vitro rooting was taken for this study with an aim to understand the effect of charcoal and naphthalene acetic acid (NAA) on successful rooting and also to optimize the two variables for maximum result. Observation-based modelling, as well as traditional approach, could identify NAA as a critical factor in rooting of the plantlets under the experimental conditions employed. Symbolic regression analysis using the software deployed here optimised the treatments studied and was successful in identifying the complex non-linear interaction among the variables, with minimalistic preliminary data. The presence of charcoal in the culture medium has a significant impact on root generation by reducing basal callus mass formation. Such an approach is advantageous for establishing in vitro culture protocols as these models will have significant potential for saving time and expenditure in plant tissue culture laboratories, and it further reduces the need for specialised background. PMID- 29485996 TI - Characterization of knockin mice at the Rosa26, Tac1 and Plekhg1 loci generated by homologous recombination in oocytes. AB - Design and engineering of complex knockin mice has revolutionized the in vivo manipulation of genetically defined cells. Recently development of the bacterial clustered regularly interspersed short palindromic repeats (CRISPR) associated protein 9 (Cas9) system for single site cleavage of mammalian genomes has opened the way for rapid generation of knockin mice by targeting homology directed repair to selected cleavage sites. We used this approach to generate new lines of mice that will be useful for a variety of aspects of neuroscience research. These lines have been bred to homozygosity and details of the expression and function of the transgenes are reported. Two lines target the Rosa26-locus and have been engineered to allow Cre-dependent expression of the avian tva receptor, and Cre dependent expression of a cell surface targeted spaghetti-monster carrying many copies of the "ollas-tag". Another line expresses red fluorescent protein and tva in Tac1-positive neurons; the fourth line targets FlpO expression to Plekhg1 expressing neurons, providing a powerful approach to modify gene expression in thalamic excitatory neurons. PMID- 29485997 TI - Update of thermotolerant genes essential for survival at a critical high temperature in Escherichia coli. AB - Previous screening of a single-gene knockout library consisting of 3,908 disrupted-mutant strains allowed us to identify 51 thermotolerant genes that are essential for survival at a critical high temperature (CHT) in Escherichia coli [Murata M, Fujimoto H, Nishimura K, Charoensuk K, Nagamitsu H, Raina S, Kosaka T, Oshima T, Ogasawara N, Yamada M (2011) PLoS ONE 6: e20063]. In this study, we identified another 21 thermotolerant genes. E. coli thus has 72 thermotolerant genes in total. The genes are classified into 8 groups: genes for energy metabolism, outer membrane organization, DNA double-strand break repair, tRNA modification, protein quality control, translation control, cell division and transporters. This classification and physiological analysis indicate the existence of fundamental strategies for survival at a CHT, which seems to exclude most of the heat shock responses. PMID- 29485998 TI - Identification and characterization of highly versatile peptide-vectors that bind non-competitively to the low-density lipoprotein receptor for in vivo targeting and delivery of small molecules and protein cargos. AB - Insufficient membrane penetration of drugs, in particular biotherapeutics and/or low target specificity remain a major drawback in their efficacy. We propose here the rational characterization and optimization of peptides to be developed as vectors that target cells expressing specific receptors involved in endocytosis or transcytosis. Among receptors involved in receptor-mediated transport is the LDL receptor. Screening complex phage-displayed peptide libraries on the human LDLR (hLDLR) stably expressed in cell lines led to the characterization of a family of cyclic and linear peptides that specifically bind the hLDLR. The VH411 lead cyclic peptide allowed endocytosis of payloads such as the S-Tag peptide or antibodies into cells expressing the hLDLR. Size reduction and chemical optimization of this lead peptide-vector led to improved receptor affinity. The optimized peptide-vectors were successfully conjugated to cargos of different nature and size including small organic molecules, siRNAs, peptides or a protein moiety such as an Fc fragment. We show that in all cases, the peptide-vectors retain their binding affinity to the hLDLR and potential for endocytosis. Following i.v. administration in wild type or ldlr-/- mice, an Fc fragment chemically conjugated or fused in C-terminal to peptide-vectors showed significant biodistribution in LDLR-enriched organs. We have thus developed highly versatile peptide-vectors endowed with good affinity for the LDLR as a target receptor. These peptide-vectors have the potential to be further developed for efficient transport of therapeutic or imaging agents into cells -including pathological cells-or organs that express the LDLR. PMID- 29485999 TI - High-density genetic mapping of a major QTL for resistance to multiple races of loose smut in a tetraploid wheat cross. AB - Loose smut, caused by Ustilago tritici (Pers.) Rostr., is a systemic disease of tetraploid durum wheat (Triticum turgidum L.). Loose smut can be economically controlled by growing resistant varieties, making it important to find and deploy new sources of resistance. Blackbird, a variety of T. turgidum L. subsp. carthlicum (Nevski) A. Love & D. Love, carries a high level of resistance to loose smut. Blackbird was crossed with the loose smut susceptible durum cultivar Strongfield to produce a doubled haploid (DH) mapping population. The parents and progenies were inoculated with U. tritici races T26, T32 and T33 individually and as a mixture at Swift Current, Canada in 2011 and 2012 and loose smut incidence (LSI) was assessed. Genotyping of the DH population and parents using an Infinium iSelect 90K single nucleotide polymorphism (SNP) array identified 12,952 polymorphic SNPs. The SNPs and 426 SSRs (previously genotyped in the same population) were mapped to 16 linkage groups spanning 3008.4 cM at an average inter-marker space of 0.2 cM in a high-density genetic map. Composite interval mapping analysis revealed three significant quantitative trait loci (QTL) for loose smut resistance on chromosomes 3A, 6B and 7A. The loose smut resistance QTL on 6B (QUt.spa-6B.2) and 7A (QUt.spa-7A.2) were derived from Blackbird. Strongfield contributed the minor QTL on 3A (QUt.spa-3A.2). The resistance on 6B was a stable major QTL effective against all individual races and the mixture of the three races; it explained up to 74% of the phenotypic variation. This study is the first attempt in durum wheat to identify and map loose smut resistance QTL using a high-density genetic map. The QTL QUt.spa-6B.2 would be an effective source for breeding resistance to multiple races of the loose smut pathogen because it provides near-complete broad resistance to the predominant virulence on the Canadian prairies. PMID- 29486000 TI - Effects of physical exercise programs on cognitive function in Parkinson's disease patients: A systematic review of randomized controlled trials of the last 10 years. AB - BACKGROUND: Given the relative importance of cognitive impairment, there was considerable interest in identifying the cognitive profile of PD patients, in order to ensure specific and appropriate therapeutic interventions. PURPOSE: To determine the effects of physical exercise programs on cognitive function in PD patients, compared with the control group. DATA SOURCES: Medline, Cochrane, Scopus, PEDro and Web of Science (last searched in September 2016). STUDY SELECTION: Randomized clinical trials examining the effects of physical exercise programs and cognitive function in PD patients. Nine studies fulfilled the selection criteria and were included in this review. DATA EXTRACTION: Characteristics of the publication, characteristics of the participants, test used for cognitive screening, cognitive domain assessed, tools used to assess cognitive function, characteristics of the experimental intervention, characteristics of the control group, mean results and standard deviation of function cognitive. The PEDro score was used to evaluate methodological quality. DATA SYNTHESIS: Most eligible studies showed good methodological quality based on the PEDro scale. Studies have shown that adapted tango for PD patients, cognitive training combined with motor training, and treadmill training promote the preservation or improvement of cognitive function in PD patients. LIMITATIONS: The diversity of cognitive tests used to assess cognitive function and the high heterogeneity identified between the physical exercise programs. CONCLUSIONS: Physical exercise programs promote positive and significant effects on global cognitive function, processing speed, sustained attention and mental flexibility in PD patients, at a mild to moderate stage for patients with a 6-year clinical diagnosis of PD. However, treadmill training performed 3 times a week for about 60 minutes and for a period of 24 weeks produced larger improvements in cognition. PMID- 29486001 TI - Comparison of NREM sleep and intravenous sedation through local information processing and whole brain network to explore the mechanism of general anesthesia. AB - BACKGROUND: The mechanism of general anesthesia (GA) has been explored for hundreds of years, but unclear. Previous studies indicated a possible correlation between NREM sleep and GA. The purpose of this study is to compare them by in vivo human brain function to probe the neuromechanism of consciousness, so as to find out a clue to GA mechanism. METHODS: 24 healthy participants were equally assigned to sleep or propofol sedation group by sleeping ability. EEG and Ramsay Sedation Scale were applied to determine sleep stage and sedation depth respectively. Resting-state functional magnetic resonance imaging (RS-fMRI) was acquired at each status. Regional homogeneity (ReHo) and seed-based whole brain functional connectivity maps (WB-FC maps) were compared. RESULTS: During sleep, ReHo primarily weakened on frontal lobe (especially preoptic area), but strengthened on brainstem. While during sedation, ReHo changed in various brain areas, including cingulate, precuneus, thalamus and cerebellum. Cingulate, fusiform and insula were concomitance of sleep and sedation. Comparing to sleep, FCs between the cortex and subcortical centers (centralized in cerebellum) were significantly attenuated under sedation. As sedation deepening, cerebellum-based FC maps were diminished, while thalamus- and brainstem-based FC maps were increased. CONCLUSION: There're huge distinctions in human brain function between sleep and GA. Sleep mainly rely on brainstem and frontal lobe function, while sedation is prone to affect widespread functional network. The most significant differences exist in the precuneus and cingulate, which may play important roles in mechanisms of inducing unconciousness by anesthetics. TRIAL REGISTRATION: Institutional Review Board (IRB) ChiCTR-IOC-15007454. PMID- 29486002 TI - Validation of the Spanish version of the Edinburgh Feeding Evaluation in Dementia Scale for older people with dementia. AB - AIMS: To adapt the Edinburgh Feeding Evaluation in Dementia Scale (EdFED) for use in a Spanish-speaking population and to assess its validity and reliability in patients with dementia. METHOD: A cross-sectional study was carried out in two stages: 1. Cross-cultural adaptation (translation, back-translation, review by committee of experts, pilot test and weighting of results); 2. Clinimetric validation comprising interobserver reliability assessment, test-retest reliability and internal consistency. To determine construct validity, confirmatory factorial analysis and principal components analysis were performed by oblique rotations. Criteria validity was analysed using the Pearson correlation (p<0.05) with the BMI, MNA and analytical values of albumin, transferrin, cholesterol, absolute lymphocytes and total proteins. Data collection was carried out for six months in 2016 in nursing homes and Alzheimer's day centers in the province of Malaga (Spain), at nine centers, with 262 patients (aged over 60 years and presenting feeding difficulties), 20 nurses, 20 professional caregivers and 103 family caregivers. RESULTS: A version of EdFED culturally adapted to Spanish was obtained. The sample presented the following characteristics: 76.3% women, mean age 82.3 years (SD: 7.9); MNA 18.73 (SD: 4.44); BMI 23.99 (SD: 4.72); serum albumin 3.79 mg/dl (SD: 0.36). A Cronbach's alpha of 0.88 was obtained, with an inter-item global correlation of 0.43 and a homogeneity index ranging from 0.42 to 0.73. The exploratory factor analysis reproduced the three-factor model identified by the original authors, explaining 62.32% of the total variance. The criterion validity showed a good inverse correlation with MNA and a moderate one with albumin, total proteins, transferrin and BMI. DISCUSSION: The Spanish version of EdFED is reliable and valid for use in elderly people with dementia. The most appropriate for our environment is the three-factor model, which maintains the original factors, with a slight redistribution of the items. PMID- 29486003 TI - Clinical spectrum and risk factors associated with asymptomatic erosive esophagitis as determined by Los Angeles classification: A cross-sectional study. AB - BACKGROUND: Gastro esophageal reflux disease (GERD) is a chronic and recurrent disease, and it varies in regions. However, to date, there are no reports available on clinical features and the risk factors for the asymptomatic reflux esophagitis in Nepalese adults. METHODS: Data were gathered from 142 erosive patients who had undergone endoscopy at Bir Hospital, Kathmandu. Los Angeles classification was used to grade the severity of the disease. Patients were interviewed to find out the presence of various reflux symptoms. RESULTS: Based on the Los Angeles classification, the severity of the disease assessed was; grade A 31.8% (31/142), grade B 39.4% (56/142), grade C 33.8% (48/142), and grade D 4.9% (7/142). One hundred and twenty six (88.7%) subjects had reflux symptoms. Prevalence of asymptomatic esophagitis was 16(11.3%). Age was independently linked to asymptomatic esophagitis (P<0.05), and the odd of being asymptomatic appeared lower in younger adults (P<0.05; OR: 0.118; CI: 0.014-.994). CONCLUSION: A low prevalence of asymptomatic reflux esophagitis (RE) was seen. Most subjects experienced mild to moderate RE. Age remained an independent factor associated with reflux esophagitis, and the odds of being asymptomatic was lower in younger age. PMID- 29486005 TI - Setbacks in Alzheimer research demand new strategies, not surrender. AB - In this month's editorial, the PLOS Medicine Editors discuss the challenges of addressing a growing population with Alzheimer disease and dementia amidst disappointing news from the pharmaceutical industry. PMID- 29486004 TI - Temporal mechanically-induced signaling events in bone and dorsal root ganglion neurons after in vivo bone loading. AB - Mechanical signals play an integral role in the regulation of bone mass and functional adaptation to bone loading. The osteocyte has long been considered the principle mechanosensory cell type in bone, although recent evidence suggests the sensory nervous system may play a role in mechanosensing. The specific signaling pathways responsible for functional adaptation of the skeleton through modeling and remodeling are not clearly defined. In vitro studies suggest involvement of intracellular signaling through mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), and mammalian target of rapamycin (mTOR). However, anabolic signaling responses to bone loading using a whole animal in vivo model have not been studied in detail. Therefore, we examined mechanically-induced signaling events at five time points from 0 to 24 hours after loading using the rat in vivo ulna end-loading model. Western blot analysis of bone for MAPK's, PI3K/Akt, and mTOR signaling, and quantitative reverse transcription polymerase chain reaction (qRT-PCR) to estimate gene expression of calcitonin gene-related protein alpha (CGRP-alpha), brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), c-jun, and c-fos in dorsal root ganglion (DRG) of the brachial intumescence were performed. There was a significant increase in signaling through MAPK's including extracellular signal related kinase (ERK) and c-Jun N-terminal kinase (JNK) in loaded limbs at 15 minutes after mechanical loading. Ulna loading did not significantly influence expression of the genes of interest in DRG neurons. Bone signaling and DRG gene expression from the loaded and contralateral limbs was correlated (SR>0.40, P<0.05). However, bone signaling did not correlate with expression of the genes of interest in DRG neurons. These results suggest that signaling through the MAPK pathway may be involved in load-induced bone formation in vivo. Further characterization of the molecular events involved in regulation of bone adaptation is needed to understand the timing and impact of loading events, and the contribution of the neuronal signaling to functional adaptation of bone. PMID- 29486006 TI - Sexual dysfunctions in MS in relation to neuropsychiatric aspects and its psychological treatment: A scoping review. AB - OBJECTIVE: Sexual dysfunction in multiple sclerosis (MS) is a significant, but often underestimated and overlooked suffering. Interventions to treat sexual dysfunction in MS are rare. The relation between sexual dysfunction in MS and psychological as well as neuropsychological aspects is evident. However, this field of research remains markedly underdeveloped in this severe chronic illness. The aim of this scoping review is to describe the relevant knowledge in this area and to identify psychological interventions to treat sexual dysfunctions in MS. METHODS: A scoping review was conducted to answer the following questions: (1) Which psychological and neuropsychological factors impact on sexual dysfunction in MS and vice versa? (2) What kind of psychological interventions aiming to improve sexual dysfunctions in MS are available? A comprehensive search and review of MEDLINE, PsycINFO, and CINAHL was completed by using a recent methodological framework for scoping reviews. RESULTS: 23 publications covering a total of 13,259 people with MS and 532 healthy controls were identified. Sexual dysfunction was found to be very common in MS and there is an obvious relation to psychological disorders as e.g. depression and anxiety and also to psychological aspects as partner relationship and quality of life. The relation between sexual dysfunction in MS and neuropsychological impairment has only rarely been studied and no clear results were found. Only two studies were identified, assessing the effectiveness of psychological intervention studies on sexual dysfunction in people with MS, and a third study presenting a secondary analysis of a study targeting depression. All three studies reported significant improvements in sexual dysfunction as well as partly in psychological variables. CONCLUSIONS: There is a pressing need for the development and adequate evaluation of psychological interventions for sexual dysfunctions in MS. In addition, sexual dysfunction and its impact on psychological wellbeing should be more focussed in clinical care. REGISTRATION: This review is registered with PROSPERO; Registration number: CRD42016033066. PMID- 29486007 TI - A field-based indicator for determining the likelihood of Ixodes scapularis establishment at sites in Ontario, Canada. AB - The emergence of the vector Ixodes scapularis in Ontario, Canada poses a significant public health risk. Both passive and active surveillance approaches have been employed by public health professionals (i.e., government employees) to monitor for the range expansion of this tick. Field surveillance using drag sampling for questing ticks is a recognized and effective method to identify reproducing tick populations. The degree of effort (i.e., number of visits per site) can enhance the sensitivity and specificity of surveillance, but increased effort conflicts with the cost to public health for field surveillance. Here we developed an indicator to determine the likelihood of I. scapularis establishment based on field sampling results. Field data from two established populations of I. scapularis in Ontario were incorporated with previous analyses of surveillance data to create the indicator, which is in the form of a scoring system. The life stage(s) collected, overall abundance and past surveillance findings from a site are all considered and a level is assigned for the likelihood of I. scapularis establishment based on current field sampling results. The likelihood levels are non-zero (i.e., no I. scapularis detected, but risk still present due to adventitious ticks), low, medium or high, and recommendations for future surveillance and public health measures are provided. The indicator was validated against field sampling results from five other established sites in the province and correctly categorized all five areas as high likelihood of establishment. The indicator was also applied to field sampling results from 36 sites of unknown status that were visited twice during the period of 2014-2016. There was substantial agreement of levels between measurements, as calculated using a weighted kappa. The indicator can assist public health professionals with the interpretation of field sampling results and direct their efforts for ongoing surveillance and public health interventions for I. scapularis-borne diseases, including Lyme disease. PMID- 29486008 TI - Effects of blood glucose level on 18F-FDG uptake for PET/CT in normal organs: A systematic review. AB - PURPOSE: To perform a systematic review of the effect of blood glucose levels on 2-Deoxy-2-[18F]fluoro-D-glucose (18F-FDG) uptake in normal organs. METHODS: We searched the MEDLINE, EMBASE and Cochrane databases through 22 April 2017 to identify all relevant studies using the keywords "PET/CT" (positron emission tomography/computed tomography), "standardized uptake value" (SUV), "glycemia," and "normal." Analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations. Maximum and mean SUVs and glycemia were the main parameters analyzed. To objectively measure the magnitude of the association between glycemia and 18F-FDG uptake in different organs, we calculated the effect size (ES) and the coefficient of determination (R2) whenever possible. RESULTS: The literature search yielded 225 results, and 14 articles met the inclusion criteria; studies included a total of 2714 (range, 51 557) participants. The brain SUV was related significantly and inversely to glycemia (ES = 1.26; R2 0.16-0.58). Although the liver and mediastinal blood pool were significantly affected by glycemia, the magnitudes of these associations were small (ES = 0.24-0.59, R2 = 0.01-0.08) and negligible (R2 = 0.02), respectively. Lung, bone marrow, tumor, spleen, fat, bowel, and stomach 18F-FDG uptakes were not influenced by glycemia. Individual factors other than glycemia can also affect 18F-FDG uptake in different organs, and body mass index appears to be the most important of these factors. CONCLUSION: The impact of glycemia on SUVs in most organs is either negligible or too small to be clinically significant. The brain SUV was the only value largely affected by glycemia. PMID- 29486009 TI - Precision (repeatability and reproducibility) of ocular parameters obtained by the Tomey OA-2000 biometer compared to the IOLMaster in healthy eyes. AB - PURPOSE: To assess the precision (repeatability and reproducibility) of ocular parameters measured by the Tomey OA-2000 biometer, and to compare them with those measured by the IOLMaster. METHODS: In this prospective study, the right eyes of 108 healthy subjects were included. Three consecutive scans were obtained by 2 observers using the Tomey OA-2000, and in the same session one observer used the IOLMaster (version 5.4.4.0006) for the measurements. About 1 week later, 3 scans were obtained by one observer using the Tomey OA-2000. The axial length (AL), central corneal thickness (CCT), anterior chamber depth (ACD), lens thickness (LT), keratometer readings, pupil diameter (PD) and corneal diameter (CD) values measured by the Tomey OA-2000 and IOLMaster were analyzed. The coefficient of variation (CoV), intraclass correlation coefficient (ICC), within subject standard deviation (Sw) and 2.77Sw were calculated to assess the repeatability and reproducibility. The paired t test and Bland-Altman plots were used to analyze the differences and agreements of parameters measured by the two devices, respectively. RESULTS: Intraobserver repeatability, and interobserver and intersession reproducibility of the AL, CCT, ACD, LT, Kf, Ks, Km, PD and CD values measured by the Tomey OA-2000 biometer showed a CoV of less than 1% except that for PD, and an ICC of more than 0.97 except that for PD and CD. The AL, Kf, Ks, Km and CD values measured by the Tomey OA-2000 were 0.058 +/- 0.094 mm, 0.088+/- 0.150 diopters (D), 0.163 +/- 0.170 D, 0.127 +/- 0.117 D and 0.171 +/- 0.217 mm lower than those measured by the IOLMaster, respectively (all Ps < 0.05). However, the ACD values from the two devices were comparable (P = 0.169). The 95% linite of agreement (LoA) of the AL, ACD, CD and all keratometer readings were no more than 0.24 mm, 0.14 mm 0.60 mm and 0.5 D, respectively. CONCLUSION: Except for the PD and CD, the ocular parameters measured by the Tomey OA-2000 were highly repeatable and reproducible. Except for the CD value, there was good agreement of ocular parameters measured by the Tomey OA-2000 and the IOLMaster in healthy eyes. PMID- 29486010 TI - The cellular uptake of angiogenin, an angiogenic and neurotrophic factor is through multiple pathways and largely dynamin independent. AB - Angiogenin (ANG), a member of the RNase superfamily (also known as RNase 5) has neurotrophic, neuroprotective and angiogenic activities. Recently it has also been shown to be important in stem cell homeostasis. Mutations in ANG are associated with neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS) and Fronto-temporal dementia (FTD). ANG is a secreted protein which is taken up by cells and translocated to the nucleus. However, the import pathway/s through which ANG is taken up is/are still largely unclear. We have characterised the uptake of ANG in neuronal, astrocytic and microglial cell lines as well as primary neurons and astrocytes using pharmacological agents as well as dominant negative dynamin and Rab5 to perturb uptake and intracellular trafficking. We find that uptake of ANG is largely clathrin/dynamin independent and microtubule depolymerisation has a marginal effect. Perturbation of membrane ruffling and macropinocytosis significantly inhibited ANG uptake suggesting an uptake mechanism similar to RNase A. Our findings shed light on why mutations which do not overtly affect RNase activity but cause impaired localization are associated with neurodegenerative disease. PMID- 29486011 TI - Comparison of two cannulation methods for assessment of intracavernosal pressure in a rat model. AB - Intracavernous pressure (ICP) measurement is a well-established technique for assessing the erectile function, which was performed by cannulating either crus or shaft of the penis. However, there are no studies concerning the experimental performance of the two cannulation sites yet. The aim of this study was to compare the measuring outcomes using two different cannulation sites. To validate the capacity of our study, both normal and the castration-induced erectile dysfunction rat models were conducted. Fifty adult male Sprague-Dawley rats were randomized equally into two groups: an intact group and a castration group. Five rats from each group firstly underwent different stimulation parameters to detect the optimal erectile responses. The residual rats in each group were further assigned into two subgroups (n = 10 per subgroup) according to two different cannulation sites (crus or shaft of the corpus cavernosum). The ICP values were compared between groups after different interventions. The optimal parameters for mean maximum ICP were recorded at 2.5V and a frequency of 15 Hz. The rats under the two different cannulation sites tended to show similar ICP values in both the intact and the castration groups. However, the success rate in monitoring ICP was significantly higher in the groups cannulating into the shaft of the penis compared to the crus (100% vs. 70%; P = 0.02). Our data suggested that the method of cannulation into the penile shaft could serve as a better alternative for the ICP measurement in rats. PMID- 29486012 TI - A decision tree model for predicting mediastinal lymph node metastasis in non small cell lung cancer with F-18 FDG PET/CT. AB - We aimed to develop a decision tree model to improve diagnostic performance of positron emission tomography/computed tomography (PET/CT) to detect metastatic lymph nodes (LN) in non-small cell lung cancer (NSCLC). 115 patients with NSCLC were included in this study. The training dataset included 66 patients. A decision tree model was developed with 9 variables, and validated with 49 patients: short and long diameters of LNs, ratio of short and long diameters, maximum standardized uptake value (SUVmax) of LN, mean hounsfield unit, ratio of LN SUVmax and ascending aorta SUVmax (LN/AA), and ratio of LN SUVmax and superior vena cava SUVmax. A total of 301 LNs of 115 patients were evaluated in this study. Nodular calcification was applied as the initial imaging parameter, and LN SUVmax (>=3.95) was assessed as the second. LN/AA (>=2.92) was required to high LN SUVmax. Sensitivity was 50% for training dataset, and 40% for validation dataset. However, specificity was 99.28% for training dataset, and 96.23% for validation dataset. In conclusion, we have developed a new decision tree model for interpreting mediastinal LNs. All LNs with nodular calcification were benign, and LNs with high LN SUVmax and high LN/AA were metastatic Further studies are needed to incorporate subjective parameters and pathologic evaluations into a decision tree model to improve the test performance of PET/CT. PMID- 29486013 TI - Gabapentin Approvals, Off-Label Use, and Lessons for Postmarketing Evaluation Efforts. PMID- 29486014 TI - Airway Management During Out-of-Hospital Cardiac Arrest. PMID- 29486015 TI - Gabapentin for Chronic Neuropathic Pain. AB - Clinical Question: Is gabapentin associated with pain relief in people with chronic neuropathic pain? Bottom Line: Oral gabapentin (1200-3600 mg/d for 4-12 weeks) for patients with moderate or severe neuropathic pain from postherpetic neuralgia (PHN) or painful diabetic neuropathy (PDN) is associated with pain reduction of at least 50% in 14% to 17% more patients than placebo. PMID- 29486016 TI - Guidelines for Adult Stroke Rehabilitation and Recovery. PMID- 29486017 TI - Plant-Chemical Shows Promise for Pain Relief. PMID- 29486018 TI - Iodine Deficiency May Impair Fertility. PMID- 29486019 TI - Accelerating Clinical Gene Editing. PMID- 29486021 TI - The Good and Bad News of Health Care Employment. PMID- 29486022 TI - Food Inspection and Food Control. PMID- 29486023 TI - Trends in Red Blood Cell, Plasma, and Platelet Transfusions in the United States, 1993-2014. PMID- 29486024 TI - The Evidence for Cognitive Behavioral Therapy. PMID- 29486025 TI - Drug Interactions With Non-Vitamin K Oral Anticoagulants. PMID- 29486026 TI - Drug Interactions With Non-Vitamin K Oral Anticoagulants. PMID- 29486027 TI - The Evidence for Cognitive Behavioral Therapy. PMID- 29486028 TI - Drug Interactions With Non-Vitamin K Oral Anticoagulants. PMID- 29486029 TI - Drug Interactions With Non-Vitamin K Oral Anticoagulants. PMID- 29486030 TI - Drug Interactions With Non-Vitamin K Oral Anticoagulants. PMID- 29486031 TI - Drug Interactions With Non-Vitamin K Oral Anticoagulants-Reply. PMID- 29486033 TI - A Two-Dose Hepatitis B Vaccine for Adults (Heplisav-B). PMID- 29486032 TI - The Evidence for Cognitive Behavioral Therapy-Reply. PMID- 29486034 TI - Breastfeeding Rates Improved With Financial Reward. PMID- 29486036 TI - High-Intensity Exercise Safe in De Novo Parkinson Disease. PMID- 29486035 TI - Air Pollution May Limit Health Benefits of Walking. PMID- 29486037 TI - Internet-Accessed STI Test Complements Face-to-Face Services. PMID- 29486038 TI - Stem Cell Transplantation Improves Scleroderma Outcomes. PMID- 29486039 TI - Effect of Bag-Mask Ventilation vs Endotracheal Intubation During Cardiopulmonary Resuscitation on Neurological Outcome After Out-of-Hospital Cardiorespiratory Arrest: A Randomized Clinical Trial. AB - Importance: Bag-mask ventilation (BMV) is a less complex technique than endotracheal intubation (ETI) for airway management during the advanced cardiac life support phase of cardiopulmonary resuscitation of patients with out-of hospital cardiorespiratory arrest. It has been reported as superior in terms of survival. Objectives: To assess noninferiority of BMV vs ETI for advanced airway management with regard to survival with favorable neurological function at day 28. Design, Settings, and Participants: Multicenter randomized clinical trial comparing BMV with ETI in 2043 patients with out-of-hospital cardiorespiratory arrest in France and Belgium. Enrollment occurred from March 9, 2015, to January 2, 2017, and follow-up ended January 26, 2017. Intervention: Participants were randomized to initial airway management with BMV (n = 1020) or ETI (n = 1023). Main Outcomes and Measures: The primary outcome was favorable neurological outcome at 28 days defined as cerebral performance category 1 or 2. A noninferiority margin of 1% was chosen. Secondary end points included rate of survival to hospital admission, rate of survival at day 28, rate of return of spontaneous circulation, and ETI and BMV difficulty or failure. Results: Among 2043 patients who were randomized (mean age, 64.7 years; 665 women [32%]), 2040 (99.8%) completed the trial. In the intention-to-treat population, favorable functional survival at day 28 was 44 of 1018 patients (4.3%) in the BMV group and 43 of 1022 patients (4.2%) in the ETI group (difference, 0.11% [1-sided 97.5% CI, -1.64% to infinity]; P for noninferiority = .11). Survival to hospital admission (294/1018 [28.9%] in the BMV group vs 333/1022 [32.6%] in the ETI group; difference, -3.7% [95% CI, -7.7% to 0.3%]) and global survival at day 28 (55/1018 [5.4%] in the BMV group vs 54/1022 [5.3%] in the ETI group; difference, 0.1% [95% CI, -1.8% to 2.1%]) were not significantly different. Complications included difficult airway management (186/1027 [18.1%] in the BMV group vs 134/996 [13.4%] in the ETI group; difference, 4.7% [95% CI, 1.5% to 7.9%]; P = .004), failure (69/1028 [6.7%] in the BMV group vs 21/996 [2.1%] in the ETI group; difference, 4.6% [95% CI, 2.8% to 6.4%]; P < .001), and regurgitation of gastric content (156/1027 [15.2%] in the BMV group vs 75/999 [7.5%] in the ETI group; difference, 7.7% [95% CI, 4.9% to 10.4%]; P < .001). Conclusions and Relevance: Among patients with out-of-hospital cardiorespiratory arrest, the use of BMV compared with ETI failed to demonstrate noninferiority or inferiority for survival with favorable 28-day neurological function, an inconclusive result. A determination of equivalence or superiority between these techniques requires further research. Trial Registration: clinicaltrials.gov Identifier: NCT02327026. PMID- 29486040 TI - Association of Varicose Veins With Incident Venous Thromboembolism and Peripheral Artery Disease. AB - Importance: Varicose veins are common but rarely associated with serious health risks. Deep venous thrombosis (DVT), pulmonary embolism (PE), and peripheral artery disease (PAD) are also vascular diseases but associated with serious systemic effects. Little is known about the association between varicose veins and the incidence of other vascular diseases including DVT, PE, and PAD. Objective: To investigate whether varicose veins are associated with an increased risk of DVT, PE, or PAD. Design, Setting, and Participants: A retrospective cohort study using claims data from Taiwan's National Health Insurance program. Patients aged 20 years and older with varicose veins were enrolled from January 1, 2001-December 31, 2013, and a control group of patients without varicose veins were matched by propensity score. Patients previously diagnosed with DVT, PE, or PAD were excluded. Follow-up ended December 31, 2014. Exposures: Presence of varicose veins. Main Outcomes and Measures: Incidence rates of DVT, PE, and PAD were assessed in people with and without varicose veins. Cox proportional hazards models were used to estimate relative hazards, with the control group as reference. Results: There were 212 984 patients in the varicose veins group (mean [SD] age, 54.5 [16.0] years; 69.3% women) and 212 984 in the control group (mean [SD] age, 54.3 [15.6] years; 70.3% women). The median follow-up duration was 7.5 years for DVT, 7.8 years for PE, and 7.3 years for PAD for patients with varicose veins, and for the control group, follow-up duration was 7.6 years for DVT, 7.7 years for PE, and 7.4 years for PAD. The varicose veins group had higher incidence rates than the control group for DVT (6.55 vs 1.23 per 1000 person years [10 360 vs 1980 cases]; absolute risk difference [ARD], 5.32 [95% CI, 5.18 5.46]), for PE (0.48 for the varicose veins group vs 0.28 for the control group per 1000 person-years [793 vs 451 cases]; ARD, 0.20 [95% CI, 0.16-0.24]), and for PAD (10.73 for the varicose veins group vs 6.22 for the control group per 1000 person-years [16 615 vs 9709 cases]; ARD, 4.51 [95% CI, 4.31-4.71]). The hazard ratios for the varicose veins group compared with the control group were 5.30 (95% CI, 5.05-5.56) for DVT, 1.73 (95% CI, 1.54-1.94) for PE, and 1.72 (95% CI, 1.68-1.77) for PAD. Conclusions and Relevance: Among adults diagnosed with varicose veins, there was a significantly increased risk of incident DVT; the findings for PE and PAD are less clear due to the potential for confounding. Whether the association between varicose veins and DVT is causal or represents a common set of risk factors requires further research. PMID- 29486045 TI - Women's Use of ADHD Drugs Skyrockets. PMID- 29486043 TI - Please, Doc, Take It All This Time. PMID- 29486046 TI - Hepatitis B Recommendations Updated. PMID- 29486041 TI - Effect of Meropenem-Vaborbactam vs Piperacillin-Tazobactam on Clinical Cure or Improvement and Microbial Eradication in Complicated Urinary Tract Infection: The TANGO I Randomized Clinical Trial. AB - Importance: Meropenem-vaborbactam is a combination carbapenem/beta-lactamase inhibitor and a potential treatment for severe drug-resistant gram-negative infections. Objective: To evaluate efficacy and adverse events of meropenem vaborbactam in complicated urinary tract infection (UTI), including acute pyelonephritis. Design, Setting, and Participants: Phase 3, multicenter, multinational, randomized clinical trial (TANGO I) conducted November 2014 to April 2016 and enrolling patients (>=18 years) with complicated UTI, stratified by infection type and geographic region. Interventions: Eligible patients were randomized 1:1 to receive meropenem-vaborbactam (2g/2g over 3 hours; n = 274) or piperacillin-tazobactam (4g/0.5g over 30 minutes; n = 276) every 8 hours. After 15 or more doses, patients could be switched to oral levofloxacin if they met prespecified criteria for improvement, to complete 10 days of total treatment. Main Outcomes and Measures: Primary end point for FDA criteria was overall success (clinical cure or improvement and microbial eradication composite) at end of intravenous treatment in the microbiologic modified intent-to-treat (ITT) population. Primary end point for European Medicines Agency (EMA) criteria was microbial eradication at test-of-cure visit in the microbiologic modified ITT and microbiologic evaluable populations. Prespecified noninferiority margin was -15%. Because the protocol prespecified superiority testing in the event of noninferiority, 2-sided 95% CIs were calculated. Results: Among 550 patients randomized, 545 received study drug (mean age, 52.8 years; 361 [66.2%] women; 374 [68.6%] in the microbiologic modified ITT population; 347 [63.7%] in the microbiologic evaluable population; 508 [93.2%] completed the trial). For the FDA primary end point, overall success occurred in 189 of 192 (98.4%) with meropenem vaborbactam vs 171 of 182 (94.0%) with piperacillin-tazobactam (difference, 4.5% [95% CI, 0.7% to 9.1%]; P < .001 for noninferiority). For the EMA primary end point, microbial eradication in the microbiologic modified ITT population occurred in 128 of 192 (66.7%) with meropenem-vaborbactam vs 105 of 182 (57.7%) with piperacillin-tazobactam (difference, 9.0% [95% CI, -0.9% to 18.7%]; P < .001 for noninferiority); microbial eradication in the microbiologic evaluable population occurred in 118 of 178 (66.3%) vs 102 of 169 (60.4%) (difference, 5.9% [95% CI, -4.2% to 16.0%]; P < .001 for noninferiority). Adverse events were reported in 106 of 272 (39.0%) with meropenem-vaborbactam vs 97 of 273 (35.5%) with piperacillin-tazobactam. Conclusions and Relevance: Among patients with complicated UTI, including acute pyelonephritis and growth of a baseline pathogen, meropenem-vaborbactam vs piperacillin-tazobactam resulted in a composite outcome of complete resolution or improvement of symptoms along with microbial eradication that met the noninferiority criterion. Further research is needed to understand the spectrum of patients in whom meropenem-vaborbactam offers a clinical advantage. Trial Registration: clinicaltrials.gov Identifier: NCT02166476. PMID- 29486047 TI - Challenges and emergent solutions for LC-MS/MS based untargeted metabolomics in diseases. AB - In the past decade, advances in liquid chromatography-mass spectrometry (LC-MS) have revolutionized untargeted metabolomics analyses. By mining metabolomes more deeply, researchers are now primed to uncover key metabolites and their associations with diseases. The employment of untargeted metabolomics has led to new biomarker discoveries and a better mechanistic understanding of diseases with applications in precision medicine. However, many major pertinent challenges remain. First, compound identification has been poor, and left an overwhelming number of unidentified peaks. Second, partial, incomplete metabolomes persist due to factors such as limitations in mass spectrometry data acquisition speeds, wide range of metabolites concentrations, and cellular/tissue/temporal-specific expression changes that confound our understanding of metabolite perturbations. Third, to contextualize metabolites in pathways and biology is difficult because many metabolites partake in multiple pathways, have yet to be described species specificity, or possess unannotated or more-complex functions that are not easily characterized through metabolomics analyses. From a translational perspective, information related to novel metabolite biomarkers, metabolic pathways, and drug targets might be sparser than they should be. Thankfully, significant progress has been made and novel solutions are emerging, achieved through sustained academic and industrial community efforts in terms of hardware, computational, and experimental approaches. Given the rapidly growing utility of metabolomics, this review will offer new perspectives, increase awareness of the major challenges in LC-MS metabolomics that will significantly benefit the metabolomics community and also the broader the biomedical community metabolomics aspire to serve. PMID- 29486048 TI - Prostaglandin E1 for maintaining ductal patency in neonates with ductal-dependent cardiac lesions. AB - BACKGROUND: Prostaglandin E1 (PGE1) is used to keep the ductus arteriosus patent and can be life-saving in neonates with ductal-dependent cardiac lesions. PGE1 is used to promote mixing of pulmonary and systemic blood flow or improve pulmonary or systemic circulations, prior to balloon atrial septostomy or surgery. PGE1 therapy may cause several short-term and long-term adverse effects. The efficacy and safety of PGE1 in neonates with ductal-dependent cardiac lesions has not been systematically reviewed. OBJECTIVES: To determine the efficacy and safety of both short-term (< 120 hours) and long-term (>=120 hours) PGE1 therapy in maintaining patency of the ductus arteriosus and decreasing mortality in ductal-dependent cardiac lesions. SEARCH METHODS: We searched the literature in October 2017, using the search strategy recommended by Cochrane Neonatal. We searched electronic databases (CENTRAL (in the Cochrane Library), MEDLINE, CINAHL, Embase); abstracts of the Pediatric Academic Societies; websites for registered trials at www.clinicaltrials.gov and www.controlled-trials.com; and in the reference list of identified articles. SELECTION CRITERIA: Randomized or quasi randomized trials using PGE1 at any dose or duration to maintain ductal patency in term or late preterm (>= 34 weeks' gestation) infants with ductal-dependent cardiac lesions and which reported effectiveness and safety in the short term or long term. DATA COLLECTION AND ANALYSIS: We followed the standard Cochrane methods for conducting a systematic review. Two review authors (SA and MP) independently assessed the titles and abstracts of studies identified by the search strategy to determine eligibility for inclusion. We obtained the full-text version if eligibility could not be done reliably by title and abstract. We resolved any differences by discussion. We designed electronic forms for trial inclusion/exclusion, data extraction, and for requesting additional published information from authors of the original reports. MAIN RESULTS: Our search did not identify any completed or ongoing trials that met our inclusion criteria. AUTHORS' CONCLUSIONS: There is insufficient evidence from randomized controlled trials to determine the safety and efficacy of PGE1 in neonates with ductal dependent cardiac lesions. Evidence from observational trials have informed clinical practice on the use of PGE, which is now considered the standard of care for ductal-dependent cardiac lesions. It is unlikely that randomized controlled studies will be performed for this indication but comparative efficacy of newer formulations of PGE1, different doses of PGE1 and studies comparing PGE with PDA stents or other measures to keep the ductus open may be ethical and necessary. PMID- 29486051 TI - Immune class regulation as an integrated response of factors related to host, stimulus and context. PMID- 29486050 TI - Adipokines and inflammation: is it a question of weight? AB - Obesity has reached epidemic proportions in the Western society and is increasing in the developing world. It is considered as one of the major contributors to the global burden of disability and chronic diseases, including autoimmune, inflammatory and degenerative diseases. Research conducted on obesity and its complications over the last two decades has transformed the outdated concept of white adipose tissue (WAT) merely serving as an energy depot. WAT is now recognized as an active and inflammatory organ capable of producing a wide variety of factors known as adipokines. These molecules participate through endocrine, paracrine, autocrine or juxtacrine crosstalk mechanisms in a great variety of physiological or pathophysiological processes, regulating food intake, insulin sensitivity, immunity and inflammation. Although initially restricted to metabolic activities (regulation of glucose and lipid metabolism), adipokines currently represent a new family of proteins that can be considered key players in the complex network of soluble mediators involved in the pathophysiology of immune/inflammatory diseases. However, the complexity of the adipokine network in the pathogenesis and progression of inflammatory diseases has posed, since the beginning, the important question of whether it may be possible to target the mechanism(s) by which adipokines contribute to disease selectively without suppressing their physiological functions. Here, we explore in depth the most recent findings concerning the involvement of adipokines in inflammation and immune responses, in particular in rheumatic, inflammatory and degenerative diseases. We also highlight several possible strategies for therapeutic development and propose that adipokines and their signalling pathways may represent innovative therapeutic strategies for inflammatory disorders. PMID- 29486052 TI - Endodontic applications of 3D printing. AB - Computer-aided design (CAD) and computer-aided manufacturing (CAM) technologies can leverage cone beam computed tomography data for production of objects used in surgical and nonsurgical endodontics and in educational settings. The aim of this article was to review all current applications of 3D printing in endodontics and to speculate upon future directions for research and clinical use within the specialty. A literature search of PubMed, Ovid and Scopus was conducted using the following terms: stereolithography, 3D printing, computer aided rapid prototyping, surgical guide, guided endodontic surgery, guided endodontic access, additive manufacturing, rapid prototyping, autotransplantation rapid prototyping, CAD, CAM. Inclusion criteria were articles in the English language documenting endodontic applications of 3D printing. Fifty-one articles met inclusion criteria and were utilized. The endodontic literature on 3D printing is generally limited to case reports and pre-clinical studies. Documented solutions to endodontic challenges include: guided access with pulp canal obliteration, applications in autotransplantation, pre-surgical planning and educational modelling and accurate location of osteotomy perforation sites. Acquisition of technical expertise and equipment within endodontic practices present formidable obstacles to widespread deployment within the endodontic specialty. As knowledge advances, endodontic postgraduate programmes should consider implementing 3D printing into their curriculums. Future research directions should include clinical outcomes assessments of treatments employing 3D printed objects. PMID- 29486049 TI - Pathomechanisms of TDP-43 in neurodegeneration. AB - Neurodegeneration, a term that refers to the progressive loss of structure and function of neurons, is a feature of many neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). There is no cure or treatment available that can prevent or reverse neurodegenerative conditions. The causes of neurodegeneration in these diseases remain largely unknown; yet, an extremely small proportion of these devastating diseases are associated with genetic mutations in proteins involved in a wide range of cellular pathways and processes. Over the past decade, it has become increasingly clear that the most notable neurodegenerative diseases, such as ALS, FTLD, and AD, share a common prominent pathological feature known as TAR DNA binding protein 43 (TDP-43) proteinopathy, which is usually characterized by the presence of aberrant phosphorylation, ubiquitination, cleavage and/or nuclear depletion of TDP-43 in neurons and glial cells. The role of TDP-43 as a neurotoxicity trigger has been well documented in different in vitro and in vivo experimental models. As such, the investigation of TDP-43 pathomechanisms in various major neurodegenerative diseases is on the rise. Here, after a discussion of stages of TDP-43 proteinopathy during disease progression in various major neurodegenerative diseases, we review previous and most recent studies about the potential pathomechanisms with a particular emphasis on ALS, FTLD, and AD, and discuss the possibility of targeting TDP-43 as a common therapeutic approach to treat neurodegenerative diseases. PMID- 29486053 TI - A two-state model for the kinetics of competitive radioligand binding. AB - BACKGROUND AND PURPOSE: Ligand-receptor binding kinetics is receiving increasing attention in the drug research community. The Motulsky and Mahan model, a one state model, offers a method for measuring the binding kinetics of an unlabelled ligand, with the assumption that the labelled ligand has no preference while binding to distinct states or conformations of a drug target. As such, the one state model is not applicable if the radioligand displays biphasic binding kinetics to the receptor. EXPERIMENTAL APPROACH: We extended the Motulsky and Mahan model to a two-state model, in which the kinetics of the unlabelled competitor binding to different receptor states (R1 and R2 ) can be measured. With this extended model, we determined the binding kinetics of unlabelled N-5' ethylcarboxamidoadenosine (NECA), a representative agonist for the adenosine A1 receptor. Subsequently, an application of the model was exemplified by measuring the binding kinetics of other A1 receptor ligands. In addition, limitations of the model were investigated as well. KEY RESULTS: The kinetic rate constants of unlabelled NECA were comparable with the results of kinetic radioligand binding assays in which [3 H]-NECA was used. The model was further validated by good correlation between simulated results and the experimental data. CONCLUSION: The two-state model is sufficient to analyse the binding kinetics of an unlabelled ligand, when a radioligand shows biphasic association characteristics. We expect this two-state model to have general applicability for other targets as well. PMID- 29486054 TI - Sensitivity of chickpea and faba bean to root-zone hypoxia, elevated ethylene, and carbon dioxide. AB - During soil waterlogging, plants experience O2 deficits, elevated ethylene, and high CO2 in the root-zone. The effects on chickpea (Cicer arietinum L.) and faba bean (Vicia faba L.) of ethylene (2 MUL L-1 ), CO2 (2-20% v/v) or deoxygenated stagnant solution were evaluated. Ethylene and high CO2 reduced root growth of both species, but O2 deficiency had the most damaging effect and especially so for chickpea. Chickpea suffered root tip death when in deoxygenated stagnant solution. High CO2 inhibited root respiration and reduced growth, whereas sugars accumulated in root tips, of both species. Gas-filled porosity of the basal portion of the primary root of faba bean (23%, v/v) was greater than for chickpea (10%), and internal O2 movement was more prominent in faba bean when in an O2 free medium. Ethylene treatment increased the porosity of roots. The damaging effects of low O2 , such as death of root tips, resulted in poor recovery of root growth upon reaeration. In conclusion, ethylene and high CO2 partially inhibited root extension in both species, but low O2 in deoxygenated stagnant solution had the most damaging effect, even causing death of root tips in chickpea, which was more sensitive to the low O2 condition than faba bean. PMID- 29486055 TI - Silencing barley cystatins HvCPI-2 and HvCPI-4 specifically modifies leaf responses to drought stress. AB - Protein breakdown and mobilization are some of the major metabolic features associated with abiotic stresses, essential for nutrient recycling and plant survival. Genetic manipulation of protease and/or protease inhibitors may contribute to modulate proteolytic processes and plant responses. The expression analysis of the whole cystatin family, inhibitors of C1A cysteine proteases, after water deprivation in barley leaves highlighted the involvement of Icy-2 and Icy-4 cystatin genes. Artificial microRNA lines independently silencing the two drought-induced cystatins were generated to assess their function in planta. Phenotype alterations at the final stages of the plant life cycle are represented by the stay-green phenotype of silenced cystatin 2 lines. Besides, the enhanced tolerance to drought and differential responses to water deprivation at the initial growing stages are observed. The mutual compensating expression of Icy-2 and Icy-4 genes in the silencing lines pointed to their cooperative role. Proteolytic patterns by silencing these cystatins were concomitant with modifications in the expression of potential target proteases, in particular, HvPap-1, HvPap-12, and HvPap-16 C1A proteases. Metabolomics analysis lines also revealed specific modifications in the accumulation of several metabolites. These findings support the use of plants with altered proteolytic regulation in crop improvement in the face of climate change. PMID- 29486056 TI - Defining the ionic mechanisms of optogenetic control of vascular tone by channelrhodopsin-2. AB - BACKGROUND AND PURPOSE: Optogenetic control of electromechanical coupling in vascular smooth muscle cells (VSMCs) is emerging as a powerful research tool with potential applications in drug discovery and therapeutics. However, the precise ionic mechanisms involved in this control remain unclear. EXPERIMENTAL APPROACH: Cell imaging, patch-clamp electrophysiology and muscle tension recordings were used to define these mechanisms over a wide range of light stimulations. KEY RESULTS: Transgenic mice expressing a channelrhodopsin-2 variant [ChR2(H134R)] selectively in VSMCs were generated. Isolated VSMCs obtained from these mice demonstrated blue light-induced depolarizing whole-cell currents. Fine control of artery tone was attained by varying the intensity of the light stimulus. This arterial response was sufficient to overcome the endogenous, melanopsin-mediated, light-evoked, arterial relaxation observed in the presence of contractile agonists. Ca2+ entry through voltage-gated Ca2+ channels, and opening of plasmalemmal depolarizing channels (TMEM16A and TRPM) and intracellular IP3 receptors were involved in the ChR2(H134R)-dependent arterial response to blue light at intensities lower than ~0.1 mW.mm-2 . Light stimuli of greater intensity evoked a significant Ca2+ influx directly through ChR2(H134R) and produced marked intracellular alkalinization of VSMCs. CONCLUSIONS AND IMPLICATIONS: We identified the range of light intensity allowing optical control of arterial tone, primarily by means of endogenous channels and without substantial alteration to intracellular pH. Within this range, mice expressing ChR2(H134R) in VSMCs are a powerful experimental model for achieving accurate and tuneable optical voltage-clamp of VSMCs and finely graded control of arterial tone, offering new approaches to the discovery of vasorelaxant drugs. PMID- 29486057 TI - Niclosamide inhibits vascular smooth muscle cell proliferation and migration and attenuates neointimal hyperplasia in injured rat carotid arteries. AB - BACKGROUND AND PURPOSE: The anti-helminthic drug niclosamide regulates multiple cellular signals including STAT3, AMP-activated protein kinase (AMPK), Akt, Wnt/beta-catenin and mitochondrial uncoupling which are involved in neointimal hyperplasia. Here we have examined the effects of niclosamide on vascular smooth muscle cell proliferation, migration and neointimal hyperplasia and assessed the potential mechanisms. EXPERIMENTAL APPROACH: Cell migration was measured by using wound-induced migration assay and Boyden chamber assay. Protein levels were measured by using Western blot technique. Neointimal hyperplasia in vivo was induced in rats by balloon injury to the carotid artery. KEY RESULTS: Niclosamide treatment inhibited serum-induced (15% FBS) and PDGF-BB-induced proliferation and migration of vascular smooth muscle cells (A10 cells). Niclosamide showed no cytotoxicity at anti-proliferative concentrations, but induced cell apoptosis at higher concentrations. Niclosamide treatment inhibited serum-induced (15% FBS) and PDGF-BB-induced STAT3 activation (increased protein levels of p-STAT3 at Tyr705 ) but activated AMPK, in A10 cells. Niclosamide exerted no significant effects on beta-catenin expression and the activities of ERK1/2 and Akt in A10 cells. Injection (i.p.) of soluble pegylated niclosamide (PEG5000-niclosamide) (equivalent to niclosamide 25 mg.kg-1 ) attenuated neointimal hyperplasia following balloon-injury in rat carotid arteries in vivo. CONCLUSIONS AND IMPLICATIONS: Niclosamide inhibited vascular smooth muscle cell proliferation and migration and attenuated neointimal hyperplasia in balloon-injured rat carotid arteries through a mechanism involving inhibition of STAT3. PMID- 29486059 TI - Communicating Zika Risk: Using Metaphor to Increase Perceived Risk Susceptibility. AB - Effectively communicating the risks associated with emerging zoonotic diseases remains an important challenge. Drawing on research into the psychological effects of metaphoric framing, we explore the conditions under which exposure to the "nation as a body" metaphor influences perceived risk susceptibility, behavioral intentions, and policy support in the context of Zika virus. In a between-subjects experiment, 354 U.S. adults were randomly assigned to one of four experimental conditions as part of a 2 (severity message: high vs. low) * 2 (U.S. framing: metaphoric vs. literal) design. Results revealed an interaction effect such that metaphoric (vs. literal) framing increased perceived risk susceptibility in the high-severity condition only. Further analyses revealed that perceived risk susceptibility and negative affect mediated the path between the two-way interaction and policy support and behavioral intentions regarding Zika prevention. Overall, these findings complement prior work on the influence of metaphoric framing on risk perceptions, while offering practical insights for risk communicators seeking to communicate about Zika and other zoonotic diseases. PMID- 29486058 TI - Antinociceptive effects of novel histamine H3 and H4 receptor antagonists and their influence on morphine analgesia of neuropathic pain in the mouse. AB - BACKGROUND AND PURPOSE: The histaminergic system is a promising target for the development of new analgesics, as histamine H3 and H4 receptors are expressed in regions concerned with nociceptive transmission. Here we have determined the analgesic effects of new H3 and H4 receptor antagonists in naive and neuropathic mice. EXPERIMENTAL APPROACH: We used chronic constriction injury (CCI) to the sciatic nerve in mice to model neuropathy. Effects of a new H3 receptor antagonist, E-162(1-(5-(naphthalen-1-yloxy)pentyl)piperidine) and H4 receptor antagonist, TR-7(4-(4-chlorophenyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2 amine) were assessed on mechanical (von Frey) and thermal (cold plate, tail flick) stimuli in mice with and without CCI (7 days after injury). Effects of these antagonists on morphine analgesia were also evaluated, along with the possible participation of H1 receptors in their effects. We analysed the compounds in binding and functional cAMP assays at the H3 and H4 receptors and determined metabolic stability. KEY RESULTS: E-162 and TR-7 attenuated nociceptive responses and profound morphine analgesia in males with CCI. These antagonists showed analgesia in naive mice (tail flick test) and produced prolonged analgesia in neuropathic females. E-162-induced analgesia was reversed by pyrilamine, an H1 receptor antagonist. E-162 bound potently to H3 receptors (Ki = 55 nM) and inhibited cAMP accumulation (IC50 = 165 nM). TR-7 showed lower affinity for H4 receptors (Ki = 203 nM) and IC50 of 512 nM. CONCLUSIONS AND IMPLICATIONS: We describe a therapeutic use for new H3 (E-162) and H4 receptor (TR-7) antagonists in neuropathy. Targeting H3 and H4 receptors enhanced morphine analgesia, consistent with multimodal pain therapy. PMID- 29486060 TI - Prevention of liver cancer with new curative hepatitis C antivirals: Real-world challenges. PMID- 29486061 TI - Hepatitis C: When high drug prices preclude patient benefit. PMID- 29486062 TI - Factors associated with equine shedding of multi-drug-resistant Salmonella enterica and its impact on health outcomes. AB - BACKGROUND: Salmonella enterica is an important cause of healthcare-associated infections in veterinary hospitals - with outbreaks of multi-drug resistant (MDR) Salmonella among equine cases resulting in high case fatality rates and substantial financial cost. OBJECTIVES: Study objectives were to 1) investigate factors associated with shedding of MDR-Salmonella enterica and 2) evaluate the effect shedding may have on health outcomes of previously hospitalised horses and their stablemates. STUDY DESIGN: Retrospective case-control study with prospective cohort study. METHODS: Analysis of medical records (N = 373; 94 culture positive, 279 culture negative) was undertaken to determine factors associated with shedding of MDR-Salmonella. Additionally, a follow-up study was conducted to assess long-term outcomes associated with shedding among previously hospitalised horses and their stablemates. Data regarding exposures of interest were collected retrospectively from medical records. Information on long-term outcomes was obtained by phone interview of owners. Multivariable regression techniques were used to investigate factors associated with shedding and subsequent health outcomes. RESULTS: Horses experiencing diarrhoea during hospitalisation were more likely to shed Salmonella (OR 1.88; 95% CI 1.02, 3.45) compared with horses without diarrhoea, but isolates tended to be susceptible strains. Antimicrobial therapy during hospitalisation was not associated with shedding or recovery of MDR strains. Shedding did not increase long-term risk for non-survival, colic or abnormal faeces after hospital discharge; nor increase risk for hospitalisation or occurrence of abnormal faeces in stablemates. MAIN LIMITATIONS: Data collection was reliant upon the quality of medical records and owner recall, which may have led to information bias. The study population was derived from central Kentucky and may differ from horse populations in other regions. CONCLUSIONS AND CLINICAL IMPORTANCE: In general, Salmonella shedding was not associated with decreased average survival times or impacts to health of stablemates, perhaps due to owner implemented biosecurity precautions. Regardless, recently hospitalised horses should be segregated after discharge, in addition to employing rigorous hygiene practices. The Summary is available in Spanish - see Supporting Information. PMID- 29486063 TI - Combining Rome III criteria with alarm symptoms provides high specificity but low sensitivity for functional gastrointestinal disorders in children. AB - AIM: This study aimed to validate the Rome III criteria and alarm symptoms with regard to their ability to discriminate between organic and functional diagnoses in children with gastrointestinal complaints. METHODS: We recruited 258 children aged four years to 17 years who consulted a paediatrician in secondary or tertiary care in Stockholm from January 2013 to May 2014 due to gastrointestinal complaints. A symptom questionnaire based on the official Questionnaire on Pediatric Gastrointestinal Symptoms Rome III, including questions on alarm symptoms, was used. A diagnostic review of their medical records was also carried out. RESULTS: The reference diagnoses were organic (16%), pain-predominant functional gastrointestinal disorders (54%) and other functional diseases (30%). When the reported symptoms that fulfilled the Rome III criteria for pain predominant functional gastrointestinal disorders were combined with an absence of alarm symptoms, they had a high specificity (0.90) for a functional diagnosis, but a low sensitivity (0.15). Alarm symptoms were equally common in patients with organic (83%) and functional diseases (80%, p = 0.66). CONCLUSIONS: Combining the Rome III criteria and an absence of alarm symptoms from patient questionnaires had high specificity but low sensitivity when diagnosing pain-predominant functional gastrointestinal disorders in children seeking medical care for gastrointestinal complaints. PMID- 29486064 TI - Evolution from one autoimmune disorder to another. Epitope spreading? PMID- 29486065 TI - The state of testosterone therapy since the FDA's 2015 labelling changes: Indications and cardiovascular risk. AB - OBJECTIVE: A label change in testosterone (T) products in March 2015 followed a highly publicized FDA advisory committee meeting in September 2014. Changes included a warning of possible increased cardiovascular (CV) risks and restriction of indicated populations to younger men with a limited set of known aetiologies of testosterone deficiency (TD). These changes greatly impacted clinical practice and public perception of T therapy (TTh). Our aim was to review these changes in the light of subsequently published studies. DESIGN: We identified 23 studies through June 2017, including 12 clinical trials and 11 observational studies. The Testosterone Trials included 790 men aged 65 years and older with TD without known aetiology, assigned to 1-year T gel or placebo. RESULTS: Demonstrated benefits of T included sexual activity and desire, physical activity and mood. There were 9 major adverse CV events (MACE) in the T arm and 16 in the placebo arm. No study reported increased MACE with TTh. A 3-year RCT showed no difference in carotid atherosclerosis. Several large observational studies reported reduced CV events with TTh, including one showing progressively reduced CV and mortality risk with greater duration of TTh. Men whose serum T normalized with TTh had reduced risk of MI and death compared with men whose T levels failed to normalize. CONCLUSION: We conclude that existing evidence fails to support increased CV risk with TTh; on the contrary, there is evidence suggestive of real-world CV benefits. Finally, existing evidence provides benefits of TTh in older men without known aetiology for T deficiency. PMID- 29486066 TI - Spectroscopy of Ethylenedione and Ethynediolide: A Reinvestigation. AB - In an effort to characterize the electronic states of ethylenedione, OCCO, photoelectron-photofragment coincidence (PPC) spectroscopy was applied to measure anions at m/z 56 and 57 using a pulsed discharge of glyoxal vapor and N2 O. PPC measurements at a photon energy of 3.20 eV yield photoelectron spectra in coincidence with either neutral photofragments or stable neutral products. The measurements showed that primarily stable neutral products were formed, with photoelectron spectra consistent with the oxyallyl diradical, C3 H4 O, and acetone enolate radical, C3 H5 O. The spectra were also found to have features nearly identical to those reported for OCCO and HOCCO by Sanov and co-workers. The stability of the neutral products, as well as an examination of spectra reported for the oxyallyl anion and acetone enolate show that the previous assignments of OCCO and HOCCO are in error, and are instead attributed here to the oxyallyl diradical, C3 H4 O, and the acetone enolate radical, C3 H5 O. PMID- 29486067 TI - The fine anatomy of the perivascular compartment in the human brain: relevance to dilated perivascular spaces in cerebral amyloid angiopathy. PMID- 29486068 TI - Age-based norm-reference values for the Child Oral and Motor Proficiency Scale. AB - AIM: To determine reference values for the Child Oral and Motor Proficiency Scale (ChOMPS) based on healthy, typically developing and typically eating children between six months and seven years old. METHODS: Parents of children six months to seven years old (n = 1057) completed the 63-item ChOMPS. Median, range, 5th and 10th percentiles were calculated for scores on the four subscales of the ChOMPS as well as the total score in each of 11 age groups. RESULTS: Age-based norm-reference values are reported. By 24 months, 95% of children could perform all skills in the Basic Movement Patterns subscale. By four years, more than 95% of children could perform all of the skills in the Fundamental Oral-Motor Skills subscale. The Oral-Motor Coordination and Complex Movement Patterns skills developed later. By five years, 90% of children could perform all Oral-Motor Coordination skills. In six to seven year olds, 95% received a score of 44 of 46 on the Complex Movement Patterns subscale, indicating that some typical children had not established all of these complex skills by seven years. CONCLUSION: The ChOMPS is the first valid and reliable parent-report measure of eating, drinking and related skills that has age-based norm-reference values for use in clinical practice and research. PMID- 29486069 TI - The Gold(I)-Mediated Domino Reaction to Fused Diphenyl Phosphoniumfluorenes: Mechanistic Consequences for Gold-Catalyzed Hydroarylations and Application in Solar Cells. AB - A domino sequence, involving a phosphinoauration and a gold-catalyzed 6-endo-dig cyclization step, was developed. Starting from modular and simple-to-prepare phosphadiynes, pi-extended phosphoniumfluorenes were synthesized. The mechanistic proposal was supported by kinetic measurements and by the trapping of key intermediates. These led to important conclusions for the gold-catalyzed hydroarylation mechanism. Cyclic voltammetry (CV) and UV/Vis spectroscopy measurements indicated interesting properties for materials science. The phosphoniumfluorene structure was tested as a hole-blocking layer in perovskite solar cells of inverted architecture. Devices with the phosphoniumfluorene exhibited an efficiency of 14.2 %, which was much higher than that of devices without (10.7 %). PMID- 29486071 TI - Guideline Quick View: Product Selection. PMID- 29486072 TI - Laparoscopic Roux-en-Y gastric bypass. PMID- 29486070 TI - Expression and activity profiling of the steroidogenic enzymes of glucocorticoid biosynthesis and the fdx1 co-factors in zebrafish. AB - The spatial and temporal expression of steroidogenic genes in zebrafish has not been fully characterised. Because zebrafish are increasingly employed in endocrine and stress research, a better characterisation of steroidogenic pathways is required to target specific steps in the biosynthetic pathways. In the present study, we have systematically defined the temporal and spatial expression of steroidogenic enzymes involved in glucocorticoid biosynthesis (cyp21a2, cyp11c1, cyp11a1, cyp11a2, cyp17a1, cyp17a2, hsd3b1, hsd3b2), as well as the mitochondrial electron-providing ferredoxin co-factors (fdx1, fdx1b), during zebrafish development. Our studies showed an early expression of all these genes during embryogenesis. In larvae, expression of cyp11a2, cyp11c1, cyp17a2, cyp21a2, hsd3b1 and fdx1b can be detected in the interrenal gland, which is the zebrafish counterpart of the mammalian adrenal gland, whereas the fdx1 transcript is mainly found in the digestive system. Gene expression studies using quantitative reverse transcriptase-PCR and whole-mount in situ hybridisation in the adult zebrafish brain revealed a wide expression of these genes throughout the encephalon, including neurogenic regions. Using ultra-high-performance liquid chromatography tandem mass spectrometry, we were able to demonstrate the presence of the glucocorticoid cortisol in the adult zebrafish brain. Moreover, we demonstrate de novo biosynthesis of cortisol and the neurosteroid tetrahydrodeoxycorticosterone in the adult zebrafish brain from radiolabelled pregnenolone. Taken together, the present study comprises a comprehensive characterisation of the steroidogenic genes and the fdx co-factors facilitating glucocorticoid biosynthesis in zebrafish. Furthermore, we provide additional evidence of de novo neurosteroid biosynthesising in the brain of adult zebrafish facilitated by enzymes involved in glucocorticoid biosynthesis. Our study provides a valuable source for establishing the zebrafish as a translational model with respect to understanding the roles of the genes for glucocorticoid biosynthesis and fdx co-factors during embryonic development and stress, as well as in brain homeostasis and function. PMID- 29486073 TI - Creutzfeldt-Jakob Disease: Considerations for Perioperative Care: 2.2 www.aornjournal.org/content/cme. PMID- 29486076 TI - Avoiding errors when preparing medications in the perioperative setting. PMID- 29486075 TI - An Interprofessional Learning Experience for Health Professions Students. PMID- 29486079 TI - Back to Basics: Orthopedic Positioning: 2.2 www.aornjournal.org/content/cme. PMID- 29486077 TI - Embracing Action: Passing the Torch, Reviewing the Year. PMID- 29486080 TI - A Nurse's Story of Veracity. PMID- 29486081 TI - Did You Know? PMID- 29486082 TI - Use of a Novel Memory Aid to Educate Perioperative Team Members on Proper Patient Positioning Technique. AB - Interdisciplinary collaboration is key to safe surgical positioning. Although the surgical procedure dictates the patient's position, surgeons, anesthesia care providers, intraoperative nurses, and ancillary staff members must work together to achieve the goal of safe positioning. Correct patient positioning includes the provision of adequate access to the surgical site for the surgeon and surgical assistants. Surgical positions may put the patient at risk of injury. Understanding human anatomy, including the nerves commonly affected by each surgical position, can help the surgical team prevent accidental and irreversible patient injury. A lack of knowledge of proper positioning practices can result in serious patient injury, such as permanent paralysis, blindness, tissue necrosis, burns, bone fracture, and even death. This article reviews surgical positioning and introduces a learning module that involves the use of mnemonics as memory aids for perioperative team members who are learning proper positioning techniques. PMID- 29486083 TI - Educational Opportunities. PMID- 29486084 TI - Medication safety resources provide key information on error prevention. PMID- 29486087 TI - Evidence appraisal of Kim C, Park SS, Dhotar HS, Perruccio AV, Zywiel MG, Davey JR. Topical tranexamic acid reduces transfusion rates in simultaneous bilateral total knee arthroplasty: a retrospective case series. Can J Surg. 2017;60(5):311 315. PMID- 29486085 TI - Surgical Fire Safety: An Ambulatory Surgical Center Quality Improvement Project. AB - Surgical team members use fire risk assessment tools to determine the risk of a surgical fire occurring and facilitate communication to reduce risk. The purposes of this quality improvement project were to improve knowledge and awareness of surgical fire risk and increase practitioners' use of a fire risk assessment tool during the surgical safety communication process. We recruited a purposive sample of participants that included all surgical team members of a metropolitan ambulatory surgical center. We based the educational intervention on published evidence and findings of a preintervention knowledge, attitude, and practice (KAP) survey. We assessed knowledge, current practice, and practice intent using a 10-item pretest and posttest, and used a follow-up posttest to assess knowledge retention and practice change. The findings suggest that a brief educational intervention regarding fire risk assessment contributes to improving staff member knowledge and use of prevention strategies. PMID- 29486089 TI - Falling Between the Cracks in the Software. PMID- 29486088 TI - Safety considerations for laser surgery of the airway. PMID- 29486090 TI - Understanding Value as a Key Concept in Sustaining the Perioperative Nursing Workforce. AB - Perioperative nursing is faced with a staffing crisis attributed in part to minimal numbers of newly graduated nurses choosing a career in this specialty. This article analyzes and applies the concept of value to explore how to maintain an adequate perioperative nursing workforce; recruit newly graduated nurses; and encourage career professional, nurse educator, and student collaboration to generate meaningful value for perioperative nursing. This analysis revealed that value co-creation for perioperative nursing could lead to newly graduated nurses increasingly choosing perioperative nursing as a career, and enjoying satisfying perioperative nursing careers while providing high-quality patient care. PMID- 29486091 TI - Clinical Issues-March 2018: 1.8 www.aornjournal.org/content/cme. PMID- 29486092 TI - Mannose-Decorated Multicomponent Supramolecular Polymers Trigger Effective Uptake into Antigen-Presenting Cells. AB - A modular route to prepare functional self-assembling dendritic peptide amphiphiles decorated with mannosides, to effectively target antigen-presenting cells, such as macrophages, is reported. The monomeric building blocks were equipped with tetra(ethylene glycol)s (TEGs) or labeled with a Cy3 fluorescent probe. Experiments on the uptake of the multifunctional supramolecular particles into murine macrophages (Mphis) were monitored by confocal microscopy and fluorescence-activated cell sorting. Mannose-decorated supramolecular polymers trigger a significantly higher cellular uptake and distribution, relative to TEG carrying bare polymers. No cytotoxicity or negative impact on cytokine production of the treated Mphis was observed, which emphasized their biocompatibility. The modular nature of the multicomponent supramolecular polymer coassembly protocol is a promising platform to develop fully synthetic multifunctional vaccines, for example, in cancer immunotherapy. PMID- 29486094 TI - Impact of myosteatosis on skeletal muscle volume loss in patients with chronic liver disease. AB - BACKGROUND AND AIM: Severe muscle volume loss is a recognized negative prognostic factor in patients with chronic liver disease. However, the effect of skeletal muscle fat deposition, referred to as myosteatosis on muscle volume loss remains unclear. The aim of this study was to investigate the relationships between myosteatosis and skeletal muscle volume loss. METHODS: We enrolled 362 patients with chronic liver disease (186 men, 176 women; mean age 68.4 +/- 10.0 years, 94 with cirrhosis) who underwent liver biopsy and computed tomography scanning between January 2013 and February 2017. A transverse computed tomography image of each scan at the third lumbar vertebra was used to evaluate skeletal muscle tissues. RESULTS: Prevalence of skeletal muscle volume loss and myosteatosis were 36% and 82%, respectively. Of those with skeletal muscle volume loss, 93% have concomitant myosteatosis. Univariate analysis revealed that higher age, female, lower body mass index (BMI), higher serum albumin, lower alanine aminotransferase (ALT), lower gamma-glutamyl transpeptidase, lower total bilirubin, lower alpha fetoprotein, lower skeletal muscle attenuation, and liver steatosis were significantly associated with skeletal muscle volume loss. Multivariate logistic regression analysis confirmed that lower BMI (odds ratio [OR] 5.26, 95% confidence interval [CI], 3.21-8.54; P < 0.001), presence of myosteatosis (OR, 2.82; 95% CI, 1.26-6.30; P < 0.001), lower ALT (OR, 2.04; 95% CI, 1.18-3.52; P = 0.010), and female (OR, 1.71; 95% CI, 1.04-2.28; P = 0.034) were significant independent factors associated with skeletal volume loss. CONCLUSIONS: Myosteatosis, low BMI, low ALT, and female are associated with skeletal muscle volume loss in patients with chronic liver disease. PMID- 29486093 TI - Depression is associated with dimensional and categorical effects on white matter pathways. AB - BACKGROUND: Diffusion tensor imaging (DTI) studies report reduced fractional anisotropy (FA) in major depressive disorder (MDD). However, whether FA covaries with key depressive symptoms, such as anhedonia, is unclear. METHODS: Magnetic resonance imaging data were acquired from 38 unmedicated adults with MDD and 52 healthy controls. DTI metrics were extracted from regions of interest that have consistently shown reduced FA in MDD. Analyses focused first on identifying group differences, and then determining whether reduced FA in depressed adults was related to individual differences in anhedonia and depressive severity. To establish specificity to depression, these analyses controlled for symptoms of anxiety. RESULTS: Relative to controls, depressed adults showed reduced FA in the genu of the corpus callosum, the anterior limb of the internal capsule (ALIC), the cingulum bundle near the anterior cingulate cortex, and the uncinate fasciculus (UF). In the depressed group, anhedonia negatively correlated with FA in the genu, cingulum, and UF, but positively correlated with radial diffusivity (RD)-a metric previously linked to demyelination-in the genu and ALIC. Depressive severity positively correlated with RD in the ALIC. These relationships remained significant after accounting for anxiety. CONCLUSION: Anhedonia was positively correlated with reduced FA and increased RD in white matter pathways that connect regions critical for value coding, representing stimulus-reward associations, and guiding value-based action selection. Thus, a cardinal symptom of MDD-anhedonia was lawfully related to abnormalities in reward network connectivity. PMID- 29486095 TI - Clinical and functional outcomes of cannabis use among individuals with anxiety disorders: A 3-year population-based longitudinal study. AB - BACKGROUND: Cannabis use has been reported to negatively affect the course and outcome of various psychiatric disorders, yet little is known on its effect on rates of remission from anxiety disorders and associated clinical and functional outcomes. METHODS: In this study, data were drawn from Waves 1 and 2 of the National Epidemiologic survey on Alcohol and Related Conditions, focusing on individuals who qualified for a diagnosis of any anxiety disorder (social anxiety, panic disorder, generalized anxiety disorder, and specific phobias) at Wave 1 (N = 3,723). Cannabis users and individuals with cannabis use disorders (CUDs) throughout a 4-year period were compared to nonusers in rates of remission, suicidality, general functioning, and quality of life at Wave 2, while controlling for baseline confounders. RESULTS: Although rates of remission decreased with level of cannabis use, this was not maintained in adjusted models. Aside from specific outcomes (individuals with CUDs were significantly more prone to report breaking up from a romantic relationship; adjusted odds ratio [AOR] = 3.85, 95% confidence interval [CI] = 1.66-8.97) and repeatedly quitting school (AOR = 6.02, 95% CI = 2.65-13.66)), following adjustment no additional differences were found in outcome measures. CONCLUSIONS: These findings add to previous reports suggesting that poorer outcome of anxiety disorders among cannabis users may be attributed mainly to differences in baseline factors and not cannabis use. PMID- 29486097 TI - Immediate effects on adult drinkers of exposure to alcohol harm reduction advertisements with and without drinking guideline messages: experimental study. AB - AIMS: To compare the immediate effects on drinkers of television advertisements focusing upon short- versus long-term harms with and without low-risk drinking guidelines. DESIGN: Between-participants on-line experiment, with random assignment to view: (a) alcohol product advertisements (ALC control); (b) advertisements unrelated to alcohol (NON-ALC control); (c) advertisements featuring short-term harms (STH) of alcohol; (d) advertisements featuring STH plus a STH guideline (STH+G); (e) advertisements featuring long-term harms (LTH); or (f) advertisements featuring LTH plus a LTH guideline (LTH+G). SETTING: Australia, 2016. PARTICIPANTS: A total of 3718 drinkers aged 18-64 years (48.5% male). MEASUREMENTS: Post-exposure likelihood that participants provided a correct estimate of drinking levels associated with short- and long-term harms; post-exposure intentions to avoid alcohol or reduce consumption. FINDINGS: After exposure to STH+G or LTH+G advertisements, participants were more likely to estimate correctly rather than overestimate drinking levels associated with harm, compared with those exposed to STH (P < 0.001) and LTH advertisements without guidelines, respectively (P = 0.019) and ALC control (STH+G, P < 0.001; LTH+G, P < 0.001) and NON-ALC control conditions (STH+G, P < 0.001; LTH+G, P = 0.011). Drinkers exposed to STH conditions were more likely to intend to reduce next-week alcohol consumption than those exposed to ALC control (both P < 0.001) and NON ALC control conditions (STH, P = 0.001; STH+G, P < 0.001); a similar pattern was observed for intentions to avoid alcohol. Drinkers exposed to LTH conditions were also more likely than drinkers exposed to ALC or NON-ALC controls to intend to avoid and reduce alcohol in the next week. Additionally, drinkers exposed to LTH+G were more likely to intend to reduce drinking than those exposed to LTH advertisements without guidelines (P = 0.022). Response patterns for low- and high-risk drinkers by condition were similar. CONCLUSIONS: Alcohol harm television advertisements increase intentions to reduce alcohol consumption among both low- and high-risk drinkers. The addition of low-risk drinking guidelines can enhance these effects for advertisements featuring long-term harms and improve estimates of both short- and long-term harmful drinking levels. PMID- 29486096 TI - Prospective association of depression and phobic anxiety with changes in telomere lengths over 11 years. AB - BACKGROUND: Although depression and anxiety have been associated with shorter telomeres in cross-sectional studies, the data regarding the prospective relations of depression and anxiety to accelerated telomere length shortening are limited and findings are mixed. We prospectively examined relations of baseline depression and phobic anxiety to subsequent 11-year change in relative leukocyte telomere lengths (LTLs). METHODS: We selected 1,250 women from a subcohort of the Nurses' Health Study who provided blood specimens at both blood collections (1989 1990 and 2000-2001). Depression was defined by self-reported regular antidepressant use or presence of severe depressive symptoms; anxiety symptoms were assessed using the Crown-Crisp Experiential Index. Using quantitative real time polymerase chain reaction assay, LTLs were measured as the copy number ratio of telomere repeat to a single control gene. Changes in LTLs were defined in three ways: absolute change, symmetrized percent change, and decile shift. RESULTS: Overall, there were no statistically significant associations of depression or phobic anxiety to subsequent 11-year LTL shortening, despite a point estimates in the direction of greater telomere shortening among participants with versus without depression, across all three metrics of telomere change. The strongest predictor of LTL change was baseline telomere length, and regression-to-the-mean was observed. CONCLUSION: Baseline depression and phobic anxiety were not significantly associated with 11-year attrition in LTLs among 1,250 mid-life and older women. However, a suggestion of depression and greater subsequent LTL attrition, while not statistically significant, may warrant further inquiry, particularly in prospective studies with larger sample sizes and broader windows of the lifespan. PMID- 29486098 TI - Benzylic Fluorination of Aza-Heterocycles Induced by Single-Electron Transfer to Selectfluor. AB - A selective and mild method for the benzylic fluorination of aromatic azaheterocycles with Selectfluor is described. These reactions take place by a previously unreported mechanism, in which electron transfer from the heterocyclic substrate to the electrophilic fluorinating agent Selectfluor eventually yields a benzylic radical, thus leading to the desired C-F bond formation. This mechanism enables high intra- and intermolecular selectivity for aza-heterocycles over other benzylic components with similar C-H bond-dissociation energies. PMID- 29486099 TI - The Pre-exponential Factor in Electrochemistry. AB - Like many branches of science, not to mention culture in general, electrochemistry has a number of recurring topics: Areas of research that are popular for a certain time, then fade away as their possibilities seem to have been exhausted, only to return decades later as progress in experimental or theoretical techniques offer new possibilities for their investigation. A prime example are fuel cells, which have undergone five such cycles, but here we discuss a general concept of kinetics-the pre-exponential factor of a rate constant-which has undergone two such cycles. The first cycle was in the 1950 1980s, when the methods of electrochemical kinetics were developed, and the interpretation was based on transition-state theory. The second was triggered by the re-discovery of Kramers theory for reactions in condensed phases. This Minireview will show that the time has come for a third cycle based on recent progress in electrocatalysis. PMID- 29486100 TI - Diversifying Cross-Coupling Strategies, Catalysts and Monomers for the Controlled Synthesis of Conjugated Polymers. AB - Chain-growth polymerization of aromatic building blocks (termed catalyst-transfer polycondensation or CTP) has emerged as a powerful method for the controlled synthesis of conjugated polymers. CTP affords semiconducting materials with predictable molecular weights, relatively narrow molar mass distributions and tailored backbone compositions (e.g. blocks, gradients, stars). Homogeneous catalysis utilizing transition metals has played a critical role in the rise of this field and this Minireview is designed to highlight some of the catalysts employed for these polycondensations. Some descriptions of the metal and ancillary ligands are included, along with which catalysts have been used for different aromatic monomers. Cross-coupling strategies are discussed briefly for ease of use. Finally, some potential future directions are described for further evolution of this exciting area. PMID- 29486101 TI - One-step Access to Resorcinsalens-Solvent-Dependent Synthesis, Tautomerism, Self sorting and Supramolecular Architectures of Chiral Polyimine Analogues of Resorcinarene. AB - Substituted 2,4- and 4,6-dihydroxyisophthalaldehydes were condensed with optically pure and racemic trans-1,2-diaminocyclohexane to form resorcinarene like polyimine macrocycles (resorcinsalens), the structure and stoichiometry of which were controlled by the choice of the reaction medium. Particularly, the cyclocondensation reactions were driven by the solubility, tautomerization, or by social self-sorting. The resorcinsalens crystallized as inclusion compounds, in which the guest molecules were situated either in channels or in voids. In the highly hydrated crystals of one of the [2+2] macrocycles and chloroform-solvated crystals of a [4+4] product the channels were interconnected, as in zeolites, enabling possible migration of loosely bound solvent molecules in three dimensions. The association mode depended on the structural modification of the host molecule and the type of included solvent molecule(s). PMID- 29486102 TI - The effect of increased NaCl intake on rat brain endogenous MU-opioid receptor signalling. AB - Numerous studies demonstrate the significant role of central beta-endorphin and its receptor, the MU-opioid receptor (MOR), in sodium intake regulation. The present study aimed to investigate the possible relationship between chronic high NaCl intake and brain endogenous MOR functioning. We examined whether short-term (4 days) obligatory salt intake (2% NaCl solution) in rats induces changes in MOR mRNA expression, G-protein activity and MOR binding capacity in brain regions involved in salt intake regulation. Plasma osmolality and electrolyte concentrations after sodium overload and the initial and final body weight of the animals were also examined. After 4 days of obligatory hypertonic sodium chloride intake, there was clearly no difference in MOR mRNA expression and G-protein activity in the median preoptic nucleus (MnPO). In the brainstem, MOR binding capacity also remained unaltered, although the maximal efficacy of MOR G-protein significantly increased. Finally, no significant alterations were observed in plasma osmolality and electrolyte concentrations. Interestingly, animals that received sodium gained significantly less weight than control animals. In conclusion, we found no significant alterations in the MnPO and brainstem in the number of available cell surface MORs or de novo syntheses of MOR after hypertonic sodium intake. The increased MOR G-protein activity following acute sodium overconsumption may participate in the maintenance of normal blood pressure levels and/or in enhancing sodium taste aversion and sodium overload induced anorexia. PMID- 29486103 TI - Screening test for direct oral anticoagulants with the dilute Russell viper venom time. AB - OBJECTIVES: To evaluate the dilute Russell viper venom time (DRVVT) for the detection of direct-acting oral anticoagulants (DOACs) and to investigate the effect of DOACS on coagulation assays. METHODS: Patients with DOACs and controls had plasma levels determined by an anti-Xa assay and dilute thrombin clotting time (TCT). Levels were correlated with the DRVVT as well as TCT, prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, protein C, protein S and antithrombin levels. The utility of the DRVVT for detecting clinically significant levels of DOACs was evaluated. RESULTS: There were 44 samples from patients taking dabigatran, 83 with rivaroxaban, 18 with apixaban and 55 controls. The PT and APTT failed to detect clinically significant doses of anticoagulants adequately. The TCT was increased in patients taking dabigatran and normal in controls and patients on FXa inhibitors. There was a linear correlation with all DOAC levels and the DRVVT, with moderate precision, but it showed high sensitivity (95%) and specificity (90%) for clinically significant DOAC levels. CONCLUSION: The DRVVT detects clinically significant levels of DOACs and, in conjunction with the TCT, may be used as a screen for the presence and type of DOAC. PMID- 29486104 TI - HOW TO FOLLOW THE MONEY IN THE BEHAVIORAL HEALTHCARE MARKET: INVESTORS HAVE A VISION OF FUTURE TRANSFORMATION, AND YOU SHOULD TOO. PMID- 29486105 TI - Take action on the year's emerging trends to sustain your vision and strengthen your bottom line. PMID- 29486106 TI - 6 QUESTIONS TO ASK BEFORE SELLING YOUR TREATMENT CENTER. PMID- 29486107 TI - EXAMINE THE TRENDS IN ACCREDITATION: A TREATMENT CENTERS EXPAND THEIR SCOPE, MORE WILL BE DEMANDED OF THEM. PMID- 29486108 TI - HOW TO ADD MEDICATION-ASSISTED TREATMENT SERVICES; PREPARE FOR STAFFING AND EDUCATION NEEDS BEFORE LAUNCHING MAT AT YOUR FACILITY. PMID- 29486109 TI - TBI AND PTSD SYMPTOMS APPEAR SIMILAR BUT CLINICAL TREATMENTS MUST DIFFER: SOME TREATMENT CAN DO MORE HARM THAN GOOD WHEN PROPER DIAGNOSIS IS NOT MADE. PMID- 29486110 TI - BETTY FORD CENTER: WEST LOS ANGELES, CALIFORNIA. PMID- 29486111 TI - Modification of the Wolf Method and Evaluation for Molecular Simulation of Vapor Liquid Equilibria. AB - A modification of the Wolf method [ Wolf et al. J. Chem. Phys. 1999 , 110 , 8254 8282 ], a spherically truncated pairwise summation to evaluate electrostatic interactions efficiently, is proposed. This method achieves better results for the energy, and the approach is used for determining phase equilibria in the grand canonical ensemble. To assess optimal parameters for the Wolf summation we propose a simple iterative approach using the Ewald summation as a reference. We show that phase equilibrium properties for pure components as well as mixtures can be calculated accurately using the Wolf summation. Our study considers molecular fluids with partial charges but without net charge. PMID- 29486112 TI - Phase Transitions in Small Isotropic Bicelles. AB - Isotropic phospholipid bicelles are one of the most prospective membrane mimetics for the structural studies of membrane proteins in solution. Recent works provided an almost full set of data regarding the properties of isotropic bicelles; however, one major aspect of their behavior is still under consideration: the possible mixing between the lipid and detergent in the bilayer area. This problem may be resolved by studying the lipid phase transitions in bicelle particles. In the present work, we investigate two effects: phase transitions of bilayer lipids and temperature-induced growth of isotropic bicelles using the NMR spectroscopy. We propose an approach to study the phase transitions in isotropic bicelles based on the properties of 31P NMR spectra of bilayer-forming lipids. We show that phase transitions in small bicelles are "fractional", particles with the liquid-crystalline and gel bilayers coexist in solution at certain temperatures. We study the effects of lipid fatty chain type and demonstrate that the behavior of various lipids in bilayers is reproduced in the isotropic bicelles. We show that the temperature-induced growth of isotropic bicelles is not related directly to the phase transition but is the result of the reversible fusion of bicelle particles. In accordance with our data, rim detergents also have an impact on phase transitions: detergents that resist the temperature-induced growth provide the narrowest and most expressed transitions at higher temperatures. We demonstrate clearly that phase transitions take place even in the smallest bicelles that are applicable for structural studies of membrane proteins by solution NMR spectroscopy. This last finding, together with other data draws a thick line under the long-lasting argument about the relevance of small isotropic bicelles. We show with certainty that the small bicelles can reproduce the most fundamental property of lipid membranes: the ability to undergo phase transition. PMID- 29486113 TI - PMes3-Promoted Ruthenium-Catalyzed Meta C-H Nitration of 6-Arylpurines. AB - To address the challenge of meta nitration of 6-arylpurine substrates, a versatile ruthenium catalyzed meta C-H nitration is developed. The use of a sterically hindered phosphine ligand is crucial for the catalytic efficiency, and a broad class of 6-arylpurines and nucleosides were found suitable for this process providing corresponding exclusively meta nitrated products in good yields. PMID- 29486114 TI - Transgenerational DNA Methylation Changes in Daphnia magna Exposed to Chronic gamma Irradiation. AB - Our aim was to investigate epigenetic changes in Daphnia magna after a 25-day chronic external gamma irradiation (generation F0 exposed to 6.5 MUGy.h-1 or 41.3 mGy.h-1) and their potential inheritance by subsequent recovering generations, namely, F2 (exposed as germline cells in F1 embryos) and F3 (the first truly unexposed generation). Effects on survival, growth, and reproduction were observed and DNA was extracted for whole-genome bisulfite sequencing in all generations. Results showed effects on reproduction in F0 but no effect in the subsequent generations F1, F2, and F3. In contrast, we observed significant methylation changes at specific CpG positions in every generation independent of dose rate, with a majority of hypomethylation. Some of these changes were shared between dose rates and between generations. Associated gene functions included gene families and genes that were previously shown to play roles during exposure to ionizing radiation. Common methylation changes detected between generations F2 and F3 clearly showed that epigenetic modifications can be transmitted to unexposed generations, most likely through the germline, with potential implications for environmental risk. PMID- 29486115 TI - Superbase-Catalyzed anti-Markovnikov Alcohol Addition Reactions to Aryl Alkenes. AB - The organic superbase P4- t-Bu catalyzes the direct anti-Markovnikov addition of alcohols to aryl alkenes to access valuable beta-phenethyl ethers. A diverse substrate scope of aryl alkenes and alcohols is demonstrated, including heterocyclic systems and unprotected aminoalcohols. Mechanistic studies reveal that the reaction is under equilibrium control and extensive comparisons to common inorganic bases indicate that the broad reaction scope is uniquely enabled through the use of the organic superbase. PMID- 29486116 TI - Self-Assembly of Partially Alkylated Dextran- graft-poly[(2-dimethylamino)ethyl methacrylate] Copolymer Facilitating Hydrophobic/Hydrophilic Drug Delivery and Improving Conetwork Hydrogel Properties. AB - Key issues of injectable hydrogels are incapability of loading hydrophobic drugs due to insolubility of drugs in aqueous prepolymer solution as well as in hydrogel matrix, and high water swelling, which leads to poor mechanical and bioadhesive properties. Herein, we report that self-assembly of partially long chain alkylated dextran- graft-poly[(2-dimethylamino)ethyl methacrylate] copolymer in aqueous solution could encapsulate pyrene, a hydrophobic probe, griseofulvin, a hydrophobic antifungal drug, and ornidazole, a hydrophilic antibiotic. Addition of activated chloride terminated poly(ethylene glycol) (PEG) into the guest molecules loaded copolymer solution produced an injectable dextran graft-poly[(2-dimethylamino)ethyl methacrylate]-linked-PEG conetwork hydrogel. The alkylated hydrogels exhibited zero order release kinetics and were mechanically tough (50-54 kPa storage modulus) and bioadhesive (8-9 kPa). The roles of alkyl chains and dextran on the drug loading-release behavior, degradation behavior, gelation time, and the mechanical property of the hydrogels have been studied in details. Additionally, DNA hybrid composite hydrogel was formed owing to the cationic nature of the prepolymer solution and the hydrogel. Controlled alkylation of a prepolymer thus highlights the potential to induce and enhance the hydrogel property. PMID- 29486117 TI - Highly Effective and Low-Cost MicroRNA Detection with CRISPR-Cas9. AB - MicroRNAs have been reported as related to multiple diseases and have potential applications in diagnosis and therapeutics. However, detection of miRNAs remains improvable, given their complexity, high cost, and low sensitivity as of currently. In this study, we attempt to build a novel platform that detects miRNAs at low cost and high efficacy. This detection system contains isothermal amplification, detecting and reporting process based on rolling circle amplification, CRISPR-Cas9, and split-horseradish peroxidase techniques. It is able to detect trace amount of miRNAs from samples with mere single-base specificity. Moreover, we demonstrated that such scheme can effectively detect target miRNAs in clinical serum samples and significantly distinguish patients of non-small cell lung cancer from healthy volunteers by detecting the previously reported biomarker: circulating let-7a. As the first to use CRISPR-Cas9 in miRNA detection, this method is a promising approach capable of being applied in screening, diagnosing, and prognosticating of multiple diseases. PMID- 29486118 TI - Positively Charged Polyprodrug Amphiphiles with Enhanced Drug Loading and Reactive Oxygen Species-Responsive Release Ability for Traceable Synergistic Therapy. AB - Due to the vast differences in chemical properties among small molecule drugs, nucleotide drugs, and superparamagnetic iron oxide nanocubes (SPIONs), such as charge and hydrophobicity, entrapment of these within a single carrier for traceable synergistic therapy has been proven difficult. Herein, we synthesize positively charged polyprodrug amphiphiles. The hydrophobic polyprodrug unit of the amphiphiles is positively charged, which can simultaneously load hydrophobic SPIONs and absorb negative let-7b antisense oligonucleotide to construct traceable co-delivery nanoparticles (NPs). This characteristic avoids the use of inert materials and enhances drug loading of the traceable NPs. The traceable NPs can achieve controlled release of drugs to reduce the differentiation of exogenous neural stem cells (NSCs) and enhance their secretion of brain-derived neurotrophic factor (BDNF) synergistically. Exogenous NSCs treated with the NPs significantly rescue the memory deficits in 2xTg-AD mice. In addition, the transplantation site and migration of exogenous NSCs can be traced using the SPIONs with high r2 value for magnetic resonance imaging. Therefore, traceable NPs self-assembled from the positively charged polyprodrug amphiphiles may have the potential to open up a new avenue for treatment of Alzheimer's disease (AD), as well as other neurodegenerative disorders. PMID- 29486119 TI - Comparative Phosphoproteomic Analysis of the Developing Seeds in Two Indica Rice ( Oryza sativa L.) Cultivars with Different Starch Quality. AB - Protein phosphorylation plays important roles in regulation of various molecular events such as plant growth and seed development. However, its involvement in starch biosynthesis is less understood. Here, a comparative phosphoproteomic analysis of two indica rice cultivars during grain development was performed. A total of 2079 and 2434 phosphopeptides from 1273 and 1442 phosphoproteins were identified, covering 2441 and 2808 phosphosites in indica rice 9311 and Guangluai4 (GLA4), respectively. Comparative analysis identified 303 differentially phosphorylated peptides, and 120 and 258 specifically phosphorylated peptides in 9311 and GLA4, respectively. Phosphopeptides in starch biosynthesis related enzymes such as AGPase, SSIIa, SSIIIa, BEI, BEIIb, PUL, and Pho1were identified. GLA4 and 9311 had different amylose content, pasting viscosities, and gelatinization temperature, suggesting subtle difference in starch biosynthesis and regulation between GLA4 and 9311. Our study will give added impetus to further understanding the regulatory mechanism of starch biosynthesis at the phosphorylation level. PMID- 29486120 TI - Coarse-Grained Modeling of the Interplay between Secondary Structure Propensities and Protein Fold Assembly. AB - We recently developed a new coarse-grained model of protein structure and dynamics [ Dawid et al. J. Chem. Theory Comput. 2017 , 13 ( 11 ), 5766 - 5779 ]. The model assumed a single bead representation of amino acid residues, where positions of such united residues were defined by centers of mass of four amino acid fragments. Replica exchange Monte Carlo sampling of the model chains provided good pictures of modeled structures and their dynamics. In its generic form the statistical knowledge-based force field of the model has been dedicated for single-domain globular proteins. Sequence-specific interactions are defined by three-letter secondary structure data. In the present work we demonstrate that different assignments and/or predictions of secondary structures are usually sufficient for enforcing cooperative formation of native-like folds of SURPASS chains for the majority of single-domain globular proteins. Simulations of native like structure assembly for a representative set of globular proteins have shown that the accuracy of secondary structure data is usually not crucial for model performance, although some specific errors can strongly distort the obtained three-dimensional structures. PMID- 29486121 TI - Reaction Electronic Flux Perspective on the Mechanism of the Zimmerman Di-pi methane Rearrangement. AB - The reaction electronic flux (REF) offers a powerful tool in the analysis of reaction mechanisms. Noteworthy, the relationship between aromaticity and REF can eventually reveal subtle electronic events associated with reactivity in aromatic systems. In this work, this relationship was studied for the triplet Zimmerman di pi-methane rearrangement. The aromaticity loss and gain taking place during the reaction is well acquainted by the REF, thus shedding light on the electronic nature of reactions involving dibenzobarrelenes. PMID- 29486122 TI - Confocal-Raman Microscopy Characterization of Supported Phospholipid Bilayers Deposited on the Interior Surfaces of Chromatographic Silica. AB - A common approach to exploring the structure and dynamics of biological membranes is through the deposition of model lipid bilayers on planar supports by Langmuir trough or vesicle-fusion methods. Planar-supported lipid bilayers have been shown to exhibit structure and properties similar to those of lipid-vesicle membranes and are suitable for biosensing applications. Investigations using these planar membrane models are limited to high-sensitivity methods capable of detecting a small population of molecules at the interface between a planar support and aqueous solution. In this work, we present evidence that supported-lipid bilayers can be deposited by vesicle fusion onto the interior surfaces throughout the wide pore network of chromatographic silica particles. The thickness of a 1,2 dimyristoyl- sn-glycero-3-phosphocholine (DMPC) film and headgroup spacing are consistent with a single bilayer of DMPC deposited onto the pore surfaces. The high specific surface area of these materials generates phospholipid concentrations easily detected by confocal-Raman microscopy within an individual particle, which allows the structure of these supported bilayers to be investigated. Raman spectra of porous-silica-supported DMPC bilayers are equivalent to spectra of DMPC vesicle membranes, both above and below their melting phase transitions, suggesting comparable phospholipid organization and bilayer structure. These porous-silica-supported model membranes could share benefits that planar-supported lipid bilayers bring to biosensing applications, but in a material that overcomes the limited surface area of a planar support. To test this concept, the potential of these porous-silica-supported lipid bilayers as high-surface-area platforms for label-free Raman-scattering-based protein biosensing is demonstrated with detection of concanavalin A selectively binding to a lipid-immobilized mannose target. PMID- 29486123 TI - Automated Planning Enables Complex Protocols on Liquid-Handling Robots. AB - Robotic automation in synthetic biology is especially relevant for liquid handling to facilitate complex experiments. However, research tasks that are not highly standardized are still rarely automated in practice. Two main reasons for this are the substantial investments required to translate molecular biological protocols into robot programs, and the fact that the resulting programs are often too specific to be easily reused and shared. Recent developments of standardized protocols and dedicated programming languages for liquid-handling operations addressed some aspects of ease-of-use and portability of protocols. However, either they focus on simplicity, at the expense of enabling complex protocols, or they entail detailed programming, with corresponding skills and efforts required from the users. To reconcile these trade-offs, we developed Roboliq, a software system that uses artificial intelligence (AI) methods to integrate (i) generic formal, yet intuitive, protocol descriptions, (ii) complete, but usually hidden, programming capabilities, and (iii) user-system interactions to automatically generate executable, optimized robot programs. Roboliq also enables high-level specifications of complex tasks with conditional execution. To demonstrate the system's benefits for experiments that are difficult to perform manually because of their complexity, duration, or time-critical nature, we present three proof-of principle applications for the reproducible, quantitative characterization of GFP variants. PMID- 29486124 TI - Life Cycle Assessment of Neodymium-Iron-Boron Magnet-to-Magnet Recycling for Electric Vehicle Motors. AB - Neodymium-iron-boron (NdFeB) magnets offer the strongest magnetic field per unit volume, and thus, are widely used in clean energy applications such as electric vehicle motors. However, rare earth elements (REEs), which are the key materials for creating NdFeB magnets, have been subject to significant supply uncertainty in the past decade. NdFeB magnet-to-magnet recycling has recently emerged as a promising strategy to mitigate this supply risk. This paper assesses the environmental footprint of NdFeB magnet-to-magnet recycling by directly measuring the environmental inputs and outputs from relevant industries and compares the results with production from "virgin" materials, using life cycle assessments. It was found that magnet-to-magnet recycling lowers environmental impacts by 64-96%, depending on the specific impact categories under investigation. With magnet-to magnet recycling, key processes that contribute 77-95% of the total impacts were identified to be (1) hydrogen mixing and milling (13-52%), (2) sintering and annealing (6-24%), and (3) electroplating (6-75%). The inputs from industrial sphere that play key roles in creating these impacts were electricity (24-93% of the total impact) and nickel (5-75%) for coating. Therefore, alternative energy sources such as wind and hydroelectric power are suggested to further reduce the overall environmental footprint of NdFeB magnet-to-magnet recycling. PMID- 29486125 TI - Automatic Selection of an Active Space for Calculating Electronic Excitation Spectra by MS-CASPT2 or MC-PDFT. AB - Multireference methods such as multistate complete active space second-order perturbation theory (MS-CASPT2) and multiconfiguration pair-density functional theory (MC-PDFT) can be very accurate, but they have the disadvantage that they are not black-box methods, and finding a good active space for the reference wave function often requires nonsystematic procedures based on intimate knowledge of the system under study. In this paper, we propose a scheme called the ABC scheme, which is a three-step calculation using three parameters, for automatic selection (without looking at the orbitals and without using any knowledge of the specific system at hand) of the active space (including both the size of the active space and the orbitals in the active space) for MS-CASPT2 or MC-PDFT calculations, and we report tests of the scheme on the first five excitation energies for a set of ten doublet radicals. The results show that the ABC scheme is very successful for both MS-CASPT2 and MC-PDFT for all ten systems considered here. PMID- 29486126 TI - Fast Magic-Angle-Spinning 19F Spin Exchange NMR for Determining Nanometer 19F-19F Distances in Proteins and Pharmaceutical Compounds. AB - Internuclear distances measured using NMR provide crucial constraints of three dimensional structures but are often restricted to about 5 A due to the weakness of nuclear-spin dipolar couplings. For studying macromolecular assemblies in biology and materials science, distance constraints beyond 1 nm will be extremely valuable. Here we present an extensive and quantitative analysis of the feasibility of 19F spin exchange NMR for precise and robust measurements of interatomic distances up to 1.6 nm at a magnetic field of 14.1 T, under 20-40 kHz magic-angle spinning (MAS). The measured distances are comparable to those achievable from paramagnetic relaxation enhancement but have higher precision, which is better than +/-1 A for short distances and +/-2 A for long distances. For 19F spins with the same isotropic chemical shift but different anisotropic chemical shifts, intermediate MAS frequencies of 15-25 kHz without 1H irradiation accelerate spin exchange. For spectrally resolved 19F-19F spin exchange, 1H-19F dipolar recoupling significantly speeds up 19F-19F spin exchange. On the basis of data from five fluorinated synthetic, pharmaceutical, and biological compounds, we obtained two general curves for spin exchange between CF groups and between CF3 and CF groups. These curves allow 19F-19F distances to be extracted from the measured spin exchange rates after taking into account 19F chemical shifts. These results demonstrate the robustness of 19F spin exchange NMR for distance measurements in a wide range of biological and chemical systems. PMID- 29486127 TI - Iodine-Catalyzed Diazenylation with Arylhydrazine Hydrochlorides in Air. AB - A mild approach to diazenylation of active methylene compounds and N-heterocyclic compounds with arylhydrazine hydrochlorides in the presence of iodine under basic aerobic conditions was developed. The reaction could be executed either under heating or in the presence of blue LED light, though the latter condition was found to be relatively efficient. Presumably, the aryldiazene produced by oxidation of arylhydrazine hydrochloride acts as a nitrogen scavenger of the radical intermediate generated from the active methylene compound in the presence of iodine to produce the diazo compounds. The scope and limitations of the protocol are presented. PMID- 29486128 TI - Hydration Promoted by a Methylene Group: A Volumetric Study on Alkynes in Water. AB - Hydrocarbons including a methylene group are generally considered a hydrophobic building block, in the sense that the density of their hydration water is lower than that of bulk water. However, is the methylene group always hydrophobic? In this study, we experimentally determined the partial molar volume of a methylene group in water as 14.01 +/- 0.46 cm3 mol-1 for 1-alkyne, 9.83 +/- 0.35 cm3 mol-1 for 2-alkyne, and 11.39 +/- 0.55 cm3 mol-1 for 3-alkyne. These values are all unusually small compared to the ~16 cm3 mol-1 for model compounds from the literature. The subsequent volumetric analysis on the basis of the Kirkwood-Buff parameter indicates that the hydration water is enriched by the addition of a methylene group for 2-alkyne, while it is depleted for the reported model compounds that contain hydrophilic functional groups, 1-alkyne, and 3-alkyne. Our findings suggest that the triple bonded carbons in 2-alkyne that reduce hydration water act as a hydrophobic group in 2-alkyne. Thus, the methylene group should be called "hydrophilic" in this case because it actually recovers the hydration water when placed next to more hydrophobic groups. Therefore, we conclude that the hydrophobicity of a methylene group varies depending on its hydration environment due to other functional groups in the solute. PMID- 29486129 TI - Pyrimidine nucleotide synthesis in the emerging pathogen Pseudomonas monteilii. AB - Regulation of pyrimidine biosynthesis by pyrimidines in the emerging, opportunistic human pathogen Pseudomonas monteilii ATCC 700476 was evident. When wild-type cells were grown on succinate in the presence of uracil or orotic acid, the activities of all 5 pyrimidine biosynthetic enzymes were depressed while the activities of 3 of the enzymes decreased in glucose-grown cells supplemented with uracil or orotic acid compared with unsupplemented cells. Pyrimidine limitation of succinate- or glucose-grown pyrimidine auxotrophic cells lacking orotate phosphoribosyltransferase activity resulted in more than a doubling of the pyrimidine biosynthetic enzyme activities relative to their activities in uracil grown cells. Independent of carbon source, pyrimidine-limited cells of the pyrimidine auxotrophic cells deficient for dihydroorotase activity generally resulted in a slight elevation or depression of the pyrimidine biosynthetic enzyme activities compared with their activities in cells grown under saturating uracil conditions. Aspartate transcarbamoylase activity in P. monteilii was regulated at the enzyme activity level, since the enzyme was strongly inhibited by CTP, UMP, GMP, GDP, ADP, and UTP. In summary, the regulation of pyrimidine biosynthesis in P. monteilii could be used to control its growth or to differentiate it biochemically from other related species of Pseudomonas. PMID- 29486130 TI - Treatment of acute exacerbations of interstitial lung disease. AB - INTRODUCTION: Interstitial lung diseases (ILD) include a broad range of diffuse parenchymal lung disorders of known and unknown etiologies. Patients with ILD can experience acute exacerbations (AE) which are associated with extremely high morbidity and mortality. Little is known about the etiology of AEs, and whether inciting triggers (such as infection) result in an aberrant inflammatory response in a predisposed host. Areas covered: The majority of data regarding AE-ILD comes from the idiopathic pulmonary fibrosis (IPF) population and is extrapolated to other forms of ILD. For the purposes of this review we have summarized the current literature regarding AE of IPF, and when available have included data from AE of other ILDs. Expert commentary: Therapeutic options for AE are limited without definitive treatments available, and the prognosis is often poor. Treatment is mainly based on correcting hypoxemia, looking for reversible etiologies of respiratory decline, and palliation of symptoms. Overall little is known about the pathogenesis of ILDs and AE-ILD, more research is needed in hopes of identifying better treatment options. PMID- 29486131 TI - Agrimonia eupatoria L. (Agrimony) Extract Alters Liver Health in Subjects with Elevated Alanine Transaminase Levels: A Controlled, Randomized, and Double-Blind Trial. AB - Agrimonia eupatoria L. has been shown to protect against liver injury due to its lipid lowering and antioxidant activities. The aim of this research was to evaluate the effect of A. eupatoria L. aqueous extract (AEE) on 80 subjects with elevated alanine transaminase (ALT) levels in a randomized, double-blind, placebo controlled, 8-week study. This trial was conducted between January 2013 and July 2013 at the Oriental Medical Hospital (Jecheon) of Semyung University. The trial included subjects aged 20 years or older who were diagnosed with mildly to moderately elevated ALT levels (between 45 and 135 IU/L). Subjects received two capsules of placebo or AEE twice a day for 8 weeks. Adverse events were recorded. Eighty subjects were randomized to placebo or AEE groups who had similar baseline characteristics. During the 8 weeks of treatment, 11 subjects were excluded from the analysis for protocol violation or consent withdrawal; efficacy of treatment was, therefore, evaluated in 69 subjects (placebo = 35, AEE = 34). The AEE group showed a significant reduction in ALT and serum triglyceride (TG) at 8 weeks compared with the placebo group (ALT P = .044, TG P = .020). Significant group and time interactions were found in ALT (P = .038), aspartate aminotransferase (P = .040), and TG (P = .010). Alkaline phosphatase, total bilirubin, and gamma glutamyl transferase levels were not different between the two groups. There were no reported severe adverse events during this study, and total protein, albumin, blood urea nitrogen, creatine, and total cholesterol levels were normal in both groups. AEE consumption was safe and generally well tolerated without severe adverse events. PMID- 29486132 TI - The Role of Neuropilin-1-FYN Interaction in Odontoblast Differentiation of Dental Pulp Stem Cells. AB - Abnormal odontoblast differentiation of dental pulp stem cells (DPSCs) caused by inflammation is closely related to the development of dental caries. Neuropilin-1 (NRP1) is one of the members of neuropilin family. It can combine with disparate ligands involved in regulating cell differentiation. FYN belongs to the protein tyrosine kinase family, which has been implicated in the control of cell growth, and the effect can be further strengthened by inflammatory factors. In our studies, we verified that NRP1 can form complexes with FYN and have the correlation changes in odontoblast differentiation of DPSCs. Therefore, we surmise that in the progress of dental caries, NRP1 interacts with FYN, by expanding inflammation and inhibition of odontoblast differentiation of DPSCs through nuclear factor kappa B (NF-kappaB) signaling pathway. In this subject, we first investigated the expression and interaction of NRP1 and FYN in DPSCs. And then, we researched the effect of this complex controlling downstream signal pathway in normal or inflammation stimulated DPSCs. Finally, we analyzed the relationship between this role and odontoblast differentiation of DPSCs. This research will provide the molecular mechanism of inflammation factors of dental caries through activating NF-kappaB signal regulating odontoblast differentiation in DPSCs for finding new potential drug targets for the clinical treatment of dental caries. PMID- 29486133 TI - Acute endurance exercise increases Vegfa mRNA expression in adipose tissue of rats during the early stages of weight gain. AB - The aim of this study was to determine the effects of acute exercise on key factors regulating angiogenesis in adipose tissue. Adipose tissue Vegf-a messenger RNA expression was upregulated immediately after acute exercise (p < 0.05) in rats consuming a high-fat diet, but was lower after exercise (p < 0.05) in rats consuming a low-fat diet. Our working hypothesis is that acute exercise augments angiogenic signaling under conditions when adipose tissue is expanding, and with repeated exercise sessions these signals can accrue to enhance vascularization. PMID- 29486134 TI - A Case of Aluminum Casting in the Nasal Cavity and the Paranasal Sinus. PMID- 29486135 TI - Transcriptional Regulation of TCF/LEF and PPARgamma by Daidzein and Genistein in 3T3-L1 Preadipocytes. AB - Adipogenesis is central to adipose tissue plasticity and lipid homeostasis. Regulation of adipogenic signaling by phytoestrogens has been implicated as a potential therapeutic strategy for obesity-related disease. However, it remains unclear how these compounds directly impact transcriptional control of adipogenesis. As such, the focus of this study was to determine how daidzein and genistein effect transcriptional activation of peroxisome proliferator-activated receptor gamma (PPARgamma) and TCF/LEF in 3T3-L1 preadipocytes. We also measured the effect of estrogen receptor (ER) knockdown on expression of preadipocyte (i.e., Pref1) and adipocyte (i.e., Fabp4) markers in cells treated with varying concentrations of daidzein or genistein (i.e., 10-4, 10-7, and 10-10). Our findings showed that activation of TCF/LEF was induced by daidzein and genistein in undifferentiated and differentiated 3T3-L1 preadipocytes. Conversely, PPARgamma reporter activity was inhibited by genistein, which corresponded with a reduction in cell diameter of differentiated preadipocytes. Daidzein increased cell diameter, as well as reduced Pref1 abundance in undifferentiated cells. Although small, there was a significant reduction in Pref1 and Fabp4 abundance in undifferentiated cells with ERalpha and ERbeta knockdown. However, reduced abundance of ER subtypes exhibited no significant effect on phytoestrogen treatment. Collectively, our findings show phytoestrogens distinctly regulate adipogenic transcription factors and thus, may have implications for adipose dysfunction and obesity-related disease. PMID- 29486136 TI - Non-traumatic neurological injury and hepatitis E infection. PMID- 29486137 TI - Characteristics of Children Prescribed Antipsychotics: Analysis of Routinely Collected Data. AB - OBJECTIVE: Antipsychotics are licensed for psychosis and are also prescribed for behavior control. This study aims to examine characteristics and outcomes of children prescribed antipsychotics. METHODS: A cohort study using general practice and hospital records linked with education records for 1,488,936 children living in Wales between 1999 and 2015. The characteristics of the children who were prescribed antipsychotics are presented using descriptive statistics and outcomes such as respiratory illness, diabetes, and injury were analyzed using multilevel logistic regression and the prior event rate ratio (PERR). RESULTS: Children with intellectual difficulty/autism were more likely to be prescribed antipsychotics (2.8% have been prescribed an antipsychotic [75% with autism] compared with 0.15% of children without intellectual difficulty). Those with intellectual disabilities/autism were prescribed antipsychotics at a younger age and for a longer period. Antipsychotic use was associated with a higher rate of respiratory illness for all (PERR of hospital admission: 1.55 [95% CI: 1.51-1.598] or increase in rate of 2 per 100 per year in those treated), and for those with intellectual difficulty/autism, there was a higher rate of injury and hospitalized depression. However, among those without intellectual difficulty/autism, there were lower rates of depression (PERR: 0.55 [95% CI: 0.51 0.59]). CONCLUSIONS: This work shows real-world use of antipsychotics and provides information on the rate of possible adverse events in children treated. Antipsychotics are predominantly used for those with intellectual difficulty/autism rather than those with a psychotic diagnosis. There is evidence that rates of respiratory disease, epilepsy, and diabetes are also higher postantipsychotic use for all. In those with intellectual difficulty/autism, hospital-admitted depression and injury are higher postantipsychotic use. The use of antipsychotics for behavioral management is likely to have increased cost implications to the healthcare system. PMID- 29486138 TI - Nrf2 deletion from adipocytes, but not hepatocytes, potentiates systemic metabolic dysfunction after long-term high-fat diet-induced obesity in mice. AB - Nuclear factor erythroid 2-related factor 2 (Nrf2) is a canonical regulator of cytoprotective gene expression, but evidence of its cross talk with other pathways, including metabolic ones, is ever increasing. Pharmacologic or systemic genetic activation of the Nrf2 pathway partially protects from obesity in mice and ameliorates fasting hyperglycemia in mice and humans. However, systemic Nrf2 deletion also protects from diet-induced obesity and insulin resistance in mice. To further investigate the effect of the disruption of Nrf2 on obesity in a tissue-specific manner, we focused on adipocytes and hepatocytes with targeted deletion of Nrf2. To this end, mice with cell-specific deletion of Nrf2 in adipocytes (ANKO) or hepatocytes (HeNKO) were fed a high-fat diet (HFD) for 6 mo and showed similar increases in body weight and body fat content. ANKO mice showed a partially deteriorated glucose tolerance, higher fasting glucose levels, and higher levels of cholesterol and nonesterified fatty acids compared with their Control counterparts. The HeNKO mice, though, had lower insulin levels and trended toward improved insulin sensitivity without having any difference in liver triglyceride accumulation. This study compared for the first time two conditional Nrf2 knockout models in adipocytes and in hepatocytes during HFD induced obesity. None of these models could completely recapitulate the unexpected protection against obesity observed in the whole body Nrf2 knockout mice, but this study points out the differential roles that Nrf2 may play, beyond cytoprotection, in different target tissues and rather suggests systemic activation of the Nrf2 pathway as an effective means of prevention and treatment of obesity and type 2 diabetes. PMID- 29486139 TI - Microbiota and metabolism: what's new in 2018? AB - The concept that the gut microbiota plays a broadly important role in health and disease in general, and metabolic health in particular, is now well established. However, many of the underlying mechanisms remain poorly understood while approaches to reliably manipulate the microbiota to promote health have not yet been clearly defined. Nonetheless, progress in these areas is steadily accelerating. Herein, we review select areas of progress that have been made in the last year that should hasten the era in which the microbiota can be therapeutically manipulated to promote metabolic health. PMID- 29486140 TI - Severe hypoglycemia-induced sudden death is mediated by both cardiac arrhythmias and seizures. AB - We previously demonstrated that insulin-induced severe hypoglycemia-associated sudden death is largely mediated by fatal cardiac arrhythmias. In the current study, a pharmacological approach was taken to explore the potential contribution of hypoglycemic seizures and the sympathoadrenergic system in mediating severe hypoglycemia-associated sudden death. Adult Sprague-Dawley rats were randomized into one of four treatment groups: 1) saline (SAL), 2) anti-arrhythmic (beta1 blocker atenolol), 3) antiseizure (levetiracetam), and 4) combination antiarrhythmic and antiseizure (beta1 Blocker+Levetiracetam). All rats underwent hyperinsulinemic severe hypoglycemic clamps for 3.5 h. When administered individually during severe hypoglycemia, beta1 blocker reduced 2nd and 3rd degree heart block by 7.7- and 1.6-fold, respectively, and levetiracetam reduced seizures 2.7-fold, but mortality in these groups did not decrease. However, it was combined treatment with both beta1 blocker and levetiracetam that remarkably reduced seizures and completely prevented respiratory arrest, while also eliminating 2nd and 3rd degree heart block, leading to 100% survival. These novel findings demonstrate that, in mediating sudden death, hypoglycemia elicits two distinct pathways (seizure-associated respiratory arrest and arrhythmia associated cardiac arrest), and therefore, prevention of both seizures and cardiac arrhythmias is necessary to prevent severe hypoglycemia-induced mortality. PMID- 29486141 TI - CD317 Signature in Head and Neck Cancer Indicates Poor Prognosis. AB - Targeted therapy using monoclonal antibodies (mAbs) has emerged as a widely used form of immunotherapy in head and neck squamous cell carcinoma (HNSCC). Membrane associated glycoprotein CD317 has been preferentially overexpressed by multiple myeloma cells, and its humanized mAb has been previously used in clinical trials. However, overexpression of CD317 in HNSCC and its correlation with tumor immunity is still uncertain. Here, the immunoreactivity of CD317 was detected in human HNSCC tissue microarrays, which contained 43 oral mucosa samples, 48 dysplasia samples, and 165 primary HNSCC. We found that CD317 expression was up-regulated in HNSCC tumor cells, and the CD317 expression level was independent of the histological grade, tumor size, and lymph node metastasis. Moreover, Kaplan-Meier survival curve analysis showed that patients with high expression of CD317 had a poor prognosis compared with patients with low expression. Furthermore, CD317 overexpression in HNSCC was correlated with immune checkpoint molecules PD-L1, B7 H3, and B7-H4 and tumor-associated macrophage markers (CD68 and CD163). We also observed that CD317 was overexpressed in immunocompetent mouse HNSCC tissue compared with normal tissue. Taken together, our findings demonstrate that CD317 overexpression indicates poor prognosis and is correlated with immune-related components in this patient cohort. CD317 may serve as a potential target for effective immunotherapy of HNSCC. PMID- 29486142 TI - Antiepileptic Drug Titration and Related Health Care Resource Use and Costs. AB - BACKGROUND: Unexpected breakthrough seizures resulting from suboptimal antiepileptic drug (AED) dosing during the titration period, as well as adverse events resulting from rapid AED titration, may influence the titration schedule and significantly increase health care resource use (HRU) and health care costs. OBJECTIVE: To assess the relationship between AEDs, HRU, and costs during AED titration and maintenance. METHODS: Practicing neurologists were recruited from a nationwide panel to provide up to 3 patient records each for this retrospective medical chart review. Patients with epilepsy who were aged >= 18 years and had initiated an AED between January 1, 2014, and January 1, 2016, were followed for 6 months from AED initiation. Titration duration was the time from AED initiation to the beginning of treatment maintenance as determined by the physician. Outcomes were epilepsy-specific HRU (hospitalizations, emergency department visits, outpatient visits, physician referral, laboratory testing/diagnostic imaging, and phone calls) and related costs that occurred during the titration or maintenance treatment periods. RESULTS: Of 811 patients, 156, 128, 125, 120, 114, 107, and 61 initiated the following AEDs: levetiracetam, lamotrigine, lacosamide, valproate, topiramate, carbamazepine, and phenytoin, respectively. Most patients (619/803 [77.1%] with complete AED data) received monotherapy. Baseline characteristics were similar across AEDs (mean [SD] age, 36.6 [14.4] years; 59.0% male). Kaplan-Meier estimates of titration duration ranged from 3.3 weeks (phenytoin) to 8.1 weeks (lamotrigine). From titration to maintenance, the overall incidence of HRU per person-month decreased 54.5%-89.3% for each HRU measure except outpatient visits (24.6% decrease). Total epilepsy-related costs decreased from $80.48 to $42.77 per person-month, or 46.9% from titration to maintenance. CONCLUSIONS: AED titration periods had higher HRU rates and costs than AED maintenance, suggesting that use of AEDs with shorter titration requirements reduces health care costs, although disease severity may also factor into overall cost. DISCLOSURES: UCB Pharma sponsored this study and reviewed the manuscript. Fishman and Kalilani are employees of UCB Pharma. Wild was an employee of UCB Pharma at the time this analysis was conducted. Song and Swallow are employees of Analysis Group, which received funding from UCB Pharma. PMID- 29486143 TI - Locating People Diagnosed With HIV for Public Health Action: Utility of HIV Case Surveillance and Other Data Sources. AB - INTRODUCTION: Human immunodeficiency virus (HIV) case surveillance and other health care databases are increasingly being used for public health action, which has the potential to optimize the health outcomes of people living with HIV (PLWH). However, often PLWH cannot be located based on the contact information available in these data sources. We assessed the accuracy of contact information for PLWH in HIV case surveillance and additional data sources and whether time since diagnosis was associated with accurate contact information in HIV case surveillance and successful contact. MATERIALS AND METHODS: The Case Surveillance Based Sampling (CSBS) project was a pilot HIV surveillance system that selected a random population-based sample of people diagnosed with HIV from HIV case surveillance registries in 5 state and metropolitan areas. From November 2012 through June 2014, CSBS staff members attempted to locate and interview 1800 sampled people and used 22 data sources to search for contact information. RESULTS: Among 1063 contacted PLWH, HIV case surveillance data provided accurate telephone number, address, or HIV care facility information for 239 (22%), 412 (39%), and 827 (78%) sampled people, respectively. CSBS staff members used additional data sources, such as support services and commercial people-search databases, to locate and contact PLWH with insufficient contact information in HIV case surveillance. PLWH diagnosed <1 year ago were more likely to have accurate contact information in HIV case surveillance than were PLWH diagnosed >=1 year ago ( P = .002), and the benefit from using additional data sources was greater for PLWH with more longstanding HIV infection ( P < .001). PRACTICE IMPLICATIONS: When HIV case surveillance cannot provide accurate contact information, health departments can prioritize searching additional data sources, especially for people with more longstanding HIV infection. PMID- 29486144 TI - Evaluation of the Sensitivity of the Flow Through Assay for detection of White Spot Syndrome Virus (WSSV) using a cocktail of monoclonal antibodies. AB - A panel of four monoclonal antibodies (C-05, C-14, C-38 and C-56) specific to VP28 of White spot syndrome virus (WSSV) were evaluated individually and in cocktail to increase sensitivity of the Flow Through Assay (FTA) for detection of the virus. Recombinant VP28 and semi purified WSSV was used as antigen for evaluation. Out of the total 11 cocktails and four individual of MAbs, 2 MAb cocktails C-05 + C-56 and C-14 + C-56 exhibited highest sensitivity in the FTA. The two MAb cocktail were 100 times more sensitive than 1-step PCR and nearly equivalent to 2-step PCR for the detection of WSSV. The detection limit of WSSV by MAb cocktail increased by two fold compared to the single MAb C-05 currently being used in (FTA). PMID- 29486145 TI - Testing and reporting antineutrophil cytoplasmic antibodies (ANCA) in treated vasculitis and non-vasculitic disease. AB - Testing for antineutrophil cytoplasmic antibodies (ANCA) is performed to diagnose or exclude small vessel vasculitis, and, in treated patients, to monitor disease activity. However testing is also undertaken to assist with the diagnosis of other autoimmune diseases and some infections. Most laboratories use the same assays for all sera regardless of the testing indications. The International Consensus Statement on ANCA Testing and Reporting recommended screening for ANCA by indirect immunofluorescence (IIF) and confirming IIF-positive sera in antigen specific ELISAs for both proteinase 3 (PR3) and myeloperoxidase (MPO). These guidelines have been reviewed after many refinements of the assays, and the development of new testing methodologies. However the advances have focused largely on improving the diagnostic accuracy in new-onset vasculitis, and not on more accurately monitoring disease activity, nor increasing the diagnostic sensitivity for non-vasculitic conditions. The recently-revised guidelines for ANCA testing indicate that where new onset vasculitis is suspected, sera should be examined for both PR3- and MPO-ANCA using any highly sensitive and specific assay, rather than IIF. They further state that where sera are negative in one assay but the suspicion of vasculitis is high, that testing should be repeated using a different assay. The guidelines do not provide recommendations for treated vasculitis or non-vasculitic disease. However for a routine diagnostic laboratory where sera are tested for many different indications, or where the reasons are not known, IIF screening followed by confirmation of IIF-positive sera in antigen-specific assays remains a highly sensitive, specific and convenient method for detecting ANCA in "all-comers". PMID- 29486146 TI - Identification and functional characterization of two Secretogranin II genes in orange-spotted grouper (Epinephelus coioides). AB - Secretoneurin (SN) is an important stimulator of pituitary luteinizing hormone (LH) synthesis and secretion in goldfish. It is unknown whether this neuropeptide performs the same role in other fish species. In this study, the full-length cDNAs encoding Secretogranin IIa (SgIIa) and b (SgIIb) were cloned from the brain of orange-spotted grouper. Sequence analysis showed that a 34-amino acid SN peptide (SNa) is present in SgIIa proprotein, and a 33-amino acid SN peptide (SNb) is present in SgIIb proprotein. The two SN peptides share a low degree of similarity but contain the signature YTPQ-X-LA-X7-EL sequence. Real-time PCR showed that two SgII genes are mainly expressed in the brain and pituitary. During ovarian development, the expression levels of two SgII genes in the hypothalamus and pituitary were significantly reduced at the stage when the ovary contained full-grown oocytes. The biological functions of the two SN peptides were further investigated in vitro and in vivo. Both SN peptides could significantly elevate the mRNA levels of Gonadotropin-Releasing Hormone 1 (GnRH1) and 3 (GnRH3) in the hypothalamic fragments and upregulated the expression of Follicle-Stimulating Hormone beta (FSHb) and Luteinizing Hormone beta (LHb) in the pituitary cells. The stimulatory effects on the expression of GnRHs and Gonadotropins were also observed after intraperitoneal injection of SN peptides. Our study indicated that the SgII/SN system has stimulatory effects on the reproductive axis of orange-spotted grouper. PMID- 29486147 TI - URAT1 and GLUT9 mutations in Spanish patients with renal hypouricemia. AB - BACKGROUND: Renal hypouricemia (RHUC), a rare inherited disorder characterized by impaired uric acid (UA) reabsorption in the proximal tubule, is caused by mutations in SLC22A12 or SLC2A9. Most mutations have been identified in Japanese patients, and only a few have been detected in Europeans. METHODS: We report clinical, biochemical and genetics findings of fourteen Spanish patients, six Caucasians and eight of Roma ethnia, diagnosed with idiopathic RHUC. Two of the patients presented exercise-induced acute renal failure and another one had several episodes of nephrolithiasis and four of them had progressive deterioration of renal function, while the rest were asymptomatic. RESULTS: Molecular analysis revealed SLC22A12 mutations in ten of the patients, and SLC2A9 mutations in the other four. A new heterozygous SLC22A12 missense mutation, c.1427C>A (p.A476D), was identified in two affected members of the same family. The rest of the patients presented homozygous, heterozygous or compound heterozygous mutations that have been previously identified in patients with RHUC; SLC22A12 p.T467M and p.L415_G417del, and SLC2A9 p.T125M. Expression studies in Xenopus oocytes revealed that c.1427C>A reduced UA transport but did not alter the location of URAT1 protein on the plasma membrane. CONCLUSIONS: The biochemical and clinical features of our patients together with the genetic analysis results confirmed the diagnosis of RHUC. This is the first report describing SLC22A12 and SLC2A9 mutations in Spanish patients. PMID- 29486149 TI - The sand dollar sign: a reliable EUS image to identify the excluded stomach during EUS-guided gastrogastrostomy. PMID- 29486148 TI - Glycomics meets artificial intelligence - Potential of glycan analysis for identification of seropositive and seronegative rheumatoid arthritis patients revealed. AB - In this study, one hundred serum samples from healthy people and patients with rheumatoid arthritis (RA) were analyzed. Standard immunoassays for detection of 10 different RA markers and analysis of glycan markers on antibodies in 10 different assay formats with several lectins were applied for each serum sample. A dataset containing 2000 data points was data mined using artificial neural networks (ANN). We identified key RA markers, which can discriminate between healthy people and seropositive RA patients (serum containing autoantibodies) with accuracy of 83.3%. Combination of RA markers with glycan analysis provided much better discrimination accuracy of 92.5%. Immunoassays completely failed to identify seronegative RA patients (serum not containing autoantibodies), while glycan analysis correctly identified 43.8% of these patients. Further, we revealed other critical parameters for successful glycan analysis such as type of a sample, format of analysis and orientation of captured antibodies for glycan analysis. PMID- 29486152 TI - Editorial Comment. PMID- 29486150 TI - Novel fused oxazepino-indoles (FOIs) attenuate liver carcinogenesis via IL 6/JAK2/STAT3 signaling blockade as evidenced through data-based mathematical modeling. AB - AIMS: To potentiate the well-documented tumor protecting ability of paullones, literatures demand for rational modifications in paullone ring structure and exploration of a precise mechanism underlying their antitumor effects. Thus, recently we synthesized novel paullone-like scaffold, 5H-benzo [2, 3][1,4]oxazepino[5,6-b]indoles, where compounds 13a and 14a attenuated the growth of liver cancer specific Hep-G2 cells in vitro and formed stable binding complex with IL-6. Henceforth, we hypothesized that this action is probably due to the blockade of IL-6 mediated JAK2/STAT3 signaling cascade. MAIN METHODS: A preclinical study was conducted using NDEA-induced HCC rat model by oral administration of FOIs at 10 mg/kg dose for 15 days. The molecular insights were confirmed through ELISA, qRT-PCR, western blot analyses. The study was further confirmed by data-based mathematical modeling using the quantitative data obtained from western blot analysis. 1H NMR based metabolomics study was also performed to unveil metabolite discriminations among various studied groups. KEY FINDINGS: We identified that the HCC condition was produced due to the IL-6 induced activation of JAK2 and STAT3 which, in turn, was due to enhanced phosphorylation of JAK2 and STAT3. The treatment with FOIs led to the significant blockade of the IL-6 mediated JAK2/STAT3 signaling pathway. Besides, FOIs showed their potential ability in restoring perturbed metabolites linked to HCC. In particular, the anticancer efficacy of compound 13a was comparable or somewhat better than marketed chemotherapeutics, 5-flurouracil. SIGNIFICANCE: These findings altogether opened up possibilities of developing fused oxazepino-indoles (FOIs) as new candidate molecule for plausible alternative of paullones to treat liver cancer. PMID- 29486153 TI - A long range distal enhancer controls temporal fine-tuning of PAX6 expression in neuronal precursors. AB - Proper embryonic development relies on a tight control of spatial and temporal gene expression profiles in a highly regulated manner. One good example is the ON/OFF switching of the transcription factor PAX6 that governs important steps of neurogenesis. In the neural tube PAX6 expression is initiated in neural progenitors through the positive action of retinoic acid signaling and downregulated in neuronal precursors by the bHLH transcription factor NEUROG2. How these two regulatory inputs are integrated at the molecular level to properly fine tune temporal PAX6 expression is not known. In this study we identified and characterized a 940-bp long distal cis-regulatory module (CRM), located far away from the PAX6 transcription unit and which conveys positive input from RA signaling pathway and indirect repressive signal(s) from NEUROG2. These opposing regulatory signals are integrated through HOMZ, a 94 bp core region within E940 which is evolutionarily conserved in distant organisms such as the zebrafish. We show that within HOMZ, NEUROG2 and RA exert their opposite temporal activities through a short 60 bp region containing a functional RA-responsive element (RARE). We propose a model in which retinoic acid receptors (RARs) and NEUROG2 repressive target(s) compete on the same DNA motif to fine tune temporal PAX6 expression during the course of spinal neurogenesis. PMID- 29486154 TI - Protein Linkers Provide Limits on the Domain Interactions in the ABC Importer GlnPQ and Determine the Rate of Transport. AB - GlnPQ is an ATP-binding cassette importer with a unique domain organization and intricate transport behavior. The protein has two extracytoplamic substrate binding domains (SBDs) per membrane subunit, each with different specificity for amino acids and different spacing to the translocator domain. We determined the effect of the length and structure of the linkers, which connect the SBDs to each other and to the membrane-embedded translocator domain, on the transport by GlnPQ. We reveal that varying the linker length impacts transport in a dual manner that depends on the conformational dynamics of the SBD. Varying the linker length not only changes the time for the SBD to find the translocator (docking) but also changes the probability to release the substrate again, thus altering the transport efficiency. On the basis of the experimental data and mathematical modeling, we calculate the docking efficiency as function of linker length and lifetime of the closed conformation. Importantly, not only linker length but also features in the sequence are important for efficient delivery of substrate from SBD to the translocator. We show that the linkers provide a platform for SBD docking and are not merely flexible structures. PMID- 29486155 TI - Persistent Extracellular Signal-Regulated Kinase Activation by the Histamine H4 Receptor in Spinal Neurons Underlies Chronic Itch. AB - Transient extracellular signal-regulated kinase (ERK) activation in the spinal cord triggers histamine-induced acute itch. However, whether persistent ERK activation plays an important role in chronic itch development remains unclear. This study investigated the role of spinal ERK activation in chronic itch. The results showed that repetitive DNFB painting on the nape of mice evoked not only initial scratching but also sustained, spontaneous scratching. In addition, DNFB induced itching rather than nociception, as demonstrated using a cheek model. Furthermore, ERK was persistently activated in the spinal cord of DNFB-treated mice, and the intrathecal inhibition of phosphorylation of ERK suppressed both spontaneous itching and ERK activation. ERK activation was observed in neurons but not in glia cells during chronic itch development. Finally, DNFB-induced spontaneous itching behavior and ERK activation were largely inhibited by the histamine H4 receptor antagonist JNJ7777120 but not by the H1 receptor antagonist chlorpheniramine. Our results indicate that persistent ERK activation via the histamine H4 receptor in spinal neurons underlies DNFB-induced chronic itch. PMID- 29486157 TI - Abnormalities of the serotonergic system in diacylglycerol kinase delta-deficient mouse brain. AB - We previously reported that brain-specific diacylglycerol kinase (DGK) delta knockout (KO) mice showed obsessive-compulsive disorder (OCD)-like behaviors, which were alleviated by a serotonin (5-HT) transporter (SERT) inhibitor. However, the molecular mechanisms causing the OCD-like abnormal behaviors remain unclear. In the present study, we found that DGKdelta deficiency increased SERT protein levels in the mouse cerebral cortex. Moreover, DGKdelta interacted and co localized with SERT. Furthermore, DGKdelta-KO decreased tryptophan hydroxylase-2 expression and increased monoamine oxidase-A expression. Indeed, the amount of 5 HT in the cerebral cortex was significantly decreased in DGKdelta-KO mice. These data strongly suggest that OCD-like behaviors in the DGKdelta-KO mice are caused by comprehensive and composite serotonergic hypofunction. PMID- 29486156 TI - Nonmuscle myosin IIA and IIB differentially contribute to intrinsic and directed migration of human embryonic lung fibroblasts. AB - Nonmuscle myosin II (NMII) plays an essential role in directional cell migration. In this study, we investigated the roles of NMII isoforms (NMIIA and NMIIB) in the migration of human embryonic lung fibroblasts, which exhibit directionally persistent migration in an intrinsic manner. NMIIA-knockdown (KD) cells migrated unsteadily, but their direction of migration was approximately maintained. By contrast, NMIIB-KD cells occasionally reversed their direction of migration. Lamellipodium-like protrusions formed in the posterior region of NMIIB-KD cells prior to reversal of the migration direction. Moreover, NMIIB KD led to elongation of the posterior region in migrating cells, probably due to the lack of load-bearing stress fibers in this area. These results suggest that NMIIA plays a role in steering migration by maintaining stable protrusions in the anterior region, whereas NMIIB plays a role in maintenance of front-rear polarity by preventing aberrant protrusion formation in the posterior region. These distinct functions of NMIIA and NMIIB might promote intrinsic and directed migration of normal human fibroblasts. PMID- 29486158 TI - Crystal structure of heat shock protein 15 (Hsp15) from Vibrio cholerae: Novel mode of trimerization and nucleic acid binding properties. AB - Vibrio cholerae, experiences a highly hostile environment at human intestine which trigger the induction of various heat shock genes. VcHsp15, the hslR gene product of V. cholerae O395 is a highly up regulated protein which targets erroneously dislodged 50S subunit upon heat shock that carries a tRNA attached to the abortive nascent polypeptide chain, and recycle it for another round of translation. In this study we report the crystal structure of VcHsp15 at 2.33 A. Although the structure of VcHsp15 share very similar fold to E. Coli Hsp15 their oligomerization properties are quite different. While EcHsp15 is a monomer, VcHsp15 exhibit a novel trimeric form both in crystal structure and in solution. The putative alphaL motif of VcHsp15 shares a strikingly similar fold with several RNA binding proteins like ribosomal protein S4 and threonyl-tRNA synthetase. Curiously, their alphaL motif display a comparable surface charge, albeit extremely low sequence identity, indicating that this motif serves as a basic module to bind RNA. PMID- 29486159 TI - Solution conformation of a cohesin module and its scaffoldin linker from a prototypical cellulosome. AB - Bacterial cellulases are drawing increased attention as a means to obtain plentiful chemical feedstocks and fuels from renewable lignocellulosic biomass sources. Certain bacteria deploy a large extracellular multi-protein complex, called the cellulosome, to degrade cellulose. Scaffoldin, a key non-catalytic cellulosome component, is a large protein containing a cellulose-specific carbohydrate-binding module and several cohesin modules which bind and organize the hydrolytic enzymes. Despite the importance of the structure and protein/protein interactions of the cohesin module in the cellulosome, its structure in solution has remained unknown to date. Here, we report the backbone 1H, 13C and 15N NMR assignments of the Cohesin module 5 from the highly stable and active cellulosome from Clostridium thermocellum. These data reveal that this module adopts a tightly packed, well folded and rigid structure in solution. Furthermore, since in scaffoldin, the cohesin modules are connected by linkers we have also characterized the conformation of a representative linker segment using NMR spectroscopy. Analysis of its chemical shift values revealed that this linker is rather stiff and tends to adopt extended conformations. This suggests that the scaffoldin linkers act to minimize interactions between cohesin modules. These results pave the way towards solution studies on cohesin/dockerin's fascinating dual-binding mode. PMID- 29486160 TI - Biochemical and functional insights on the triheme cytochrome PpcA from Geobacter metallireducens. AB - G. metallireducens bacterium has highly versatile respiratory pathways that provide the microorganism an enormous potential for many biotechnological applications. However, little is known about the structural and functional properties of its electron transfer components. In this work, the periplasmic cytochrome PpcA from G. metallireducens was studied in detail for the first time using complementary biophysical techniques, including UV-visible, CD and NMR spectroscopy. The results obtained showed that PpcA contains three low-spin c type heme groups with His-His axial coordination, a feature also observed for its homologue in G. sulfurreducens. However, despite the high sequence homology between the two cytochromes, important structural and functional differences were observed. The comparative analysis of the backbone, side chain and heme substituents NMR signals revealed differences in the relative orientation of the hemes I and III. In addition, redox titrations followed by visible spectroscopy showed that the redox potential values for PpcA from G. metallireducens (-78 and 93 mV at pH 7 and 8, respectively) are considerably less negative. Overall, this study provides biochemical and biophysical data of a key cytochrome from G. metallireducens, paving the way to understand the extracellular electron transfer mechanisms in these bacteria. PMID- 29486161 TI - Anti-angiogenic effect of phospholipases A2 from Scorpio maurus venom glands on Human Umbilical Vein Endothelial Cells. AB - In a previous study, we purified Sm-PLGV an heterodimeric phospholipase A2, from the venom glands of the Tunisian scorpion Scorpio maurus. This enzyme contains a Long chain, a penta-peptide insertion, which is cut out during the maturation process, followed by a short chain. A disulfide bridge links the two chains. Three recombinant forms of this enzyme were produced in Escherichia coli: rPLA2(+5) with a penta-peptide insert, rPLA2(-5) without the penta-peptide, and the Long chain alone without the short one. In the present study, we showed that Sm-PLGV, rPLA2(+5) and rPLA2(-5) displayed more potent anti-angiogenic activity in vitro than the recombinant Long chain and the short one obtained by chemical synthesis. These phospholipases A2 inhibited in a dose-dependent manner adhesion, migration and invasion of Human Umbilical Vein Endothelial Cells. Using MatrigelTM, we demonstrated that Sm-PLGV, rPLA2(+5) and rPLA2(-5) significantly inhibited tubulogensesis. We also showed a clear dissociation between the anti angiogenic effect of Sm-PLGV and its catalytic activity. PMID- 29486163 TI - Toxicity of cosmetic preservatives on human ocular surface and adnexal cells. AB - Cosmetic products, such as mascara, eye shadow, eyeliner and eye makeup remover are used extensively to highlight the eyes or clean the eyelids, and typically contain preservatives to prevent microbial growth. These preservatives include benzalkonium chloride (BAK) and formaldehyde (FA)-releasing preservatives. We hypothesize that these preservatives, at concentrations (BAK = 1 mg/ml; FA = 0.74 mg/ml) approved for consumer use, are toxic to human ocular surface and adnexal cells. Accordingly, we tested the influence of BAK and FA on the morphology, survival, and proliferation and signaling ability of immortalized human meibomian gland (iHMGECs), corneal (iHCECs) and conjunctival (iHConjECs) epithelial cells. iHMGECs, iHCECs and iHConjECs were cultured with different concentrations of BAK (5 MUg/ml to 0.005 MUg/ml) or FA (1 mg/ml to 1 MUg/ml) under basal, proliferating or differentiating conditions up to 7 days. We used low BAK levels, because we found that 0.5 mg/ml and 50 MUg/ml BAK killed iHMGECs within 1 day after a 15 min exposure. Experimental procedures included analyses of cell appearance, cell number, and neutral lipid content (LipidTox), lysosome accumulation (LysoTracker) and AKT signaling in all 3 cell types. Our results demonstrate that BAK and FA cause dose-dependent changes in the morphology, survival, proliferation and AKT signaling of iHMGECs, iHCECs and iHConjECs. Many of the concentrations tested induced cell atrophy, poor adherence, decreased proliferation and death, after 5 days of exposure. Cellular signaling, as indicated by AKT phosphorylation after 15 (FA) or 30 (BAK) minutes of treatment, was also reduced in a dose-dependent fashion in all 3 cell types, irrespective of whether cells had been cultured under proliferating or differentiating conditions. Our results support our hypothesis and demonstrate that the cosmetic preservatives, BAK and FA, exert many toxic effects on cells of the ocular surface and adnexa. PMID- 29486162 TI - Analysis of 14-3-3 isoforms expressed in photoreceptors. AB - The 14-3-3 family of proteins has undergone considerable expansion in higher eukaryotes with humans and mice expressing seven isoforms (beta, epsilon, eta, gamma, theta, zeta, and sigma) from seven distinct genes (YWHAB, YWAHE, YWHAH, YWHAG, YWHAQ, YWHAZ, and SFN). Growing evidence indicates that while highly conserved, these isoforms are not entirely functionally redundant as they exhibit unique tissue expression profiles, subcellular localization, and biochemical functions. A key limitation in our understanding of 14-3-3 biology lies in our limited knowledge of cell-type specific 14-3-3 expression. Here we provide a characterization of 14-3-3 expression in whole retina and isolated rod photoreceptors using reverse-transcriptase digital droplet PCR. We find that all 14-3-3 genes with the exception of SFN are expressed in mouse retina with YWHAQ and YWHAE being the most highly expressed. Rod photoreceptors are enriched in YWHAE (14-3-3 epsilon). Immunohistochemistry revealed that 14-3-3 epsilon and 14 3-3 zeta exhibit unique distributions in photoreceptors with 14-3-3 epsilon restricted to the inner segment and 14-3-3 zeta localized to the outer segment. Our data demonstrates that, in the retina, 14-3-3 isoforms likely serve specific functions as they exhibit unique expression levels and cell-type specificity. As such, future investigations into 14-3-3 function in rod photoreceptors should be centered on 14-3-3 epsilon and 14-3-3 zeta, depending on the subcellular region of question. PMID- 29486164 TI - Stimulation of the adenosine A3 receptor, not the A1 or A2 receptors, promote neurite outgrowth of retinal ganglion cells. AB - Among candidate neuroprotective agents, adenosine is thought to be a possible treatment for central nervous system disorders. Adenosine elicits biological effects through four G protein-coupled receptors (A1, A2A, A2B, and A3). The A2A and A2B receptors stimulate adenylyl cyclase (AC) and increase cyclic adenosine monophosphate (cAMP) levels, whereas A1 and A3 receptors inhibit AC and decrease cAMP levels. Several studies have investigated the effects of adenosine receptors (AdoRs) in glaucoma, because modulation of A1, A2A, or A3 receptor regulates intraocular pressure. In addition, AdoR-related phenomena may induce neuroprotective effects in retinal neurons. Notably, A1, A2A, and A3 receptor agonists reportedly inhibit retinal ganglion cell (RGC) death in in vitro and in vivo glaucoma models. However, there is limited knowledge of the effects of AdoR activation on neurite outgrowth or the regeneration of RGCs. In this report, we described the role of an AdoR subtype in neurite outgrowth and RGC axonal regeneration. The distribution of AdoRs in the retina was evaluated by immunohistochemical analysis. Using primary cultured rat RGCs in vitro and an optic nerve crush model in vivo, neurite elongation was evaluated after stimulation by the following AdoR agonists: CHA, an A1 receptor agonist; CGS21680, an A2A receptor agonist; BAY60-6583, an A2B receptor agonist; and 2-Cl IB-MECA, an A3 receptor agonist. To determine the mechanism of neurite promotion, the candidate molecules of signal transduction associated with the neurite elongation of AdoRs were evaluated by enzyme-linked immunosorbent assay (ELISA) and Western blot analysis, respectively. All four AdoRs (A1, A2A, A2B, and A3) were present in the inner retinal layers. Among the agonists for AdoR, only 2-Cl IB-MECA significantly promoted neurite outgrowth in primary cultured RGCs. Signaling pathway analyses showed that 2-Cl-IB-MECA caused upregulated phosphorylation of Akt in cultured RGCs. Additionally, LY294002, an inhibitor of Akt, suppressed the neurite-promoting effects of the A3 receptor agonist in RGCs. Moreover, 2-Cl-IB-MECA increased the number of regenerating axons in the optic nerve crush model. Taken together, these data indicate that activation of the A3 receptor, not the A1 or A2 receptors, promotes in vitro and in vivo neurite outgrowth during the regeneration of rat RGCs, which is caused by the activation of an Akt-dependent signaling pathway. Therefore, AdoR activation may be a promising candidate for the development of novel regenerative modalities for glaucoma and other optic neuropathies. PMID- 29486165 TI - MITF acts as an anti-oxidant transcription factor to regulate mitochondrial biogenesis and redox signaling in retinal pigment epithelial cells. AB - There is increasing evidence that the mechanisms protecting the retinal pigment epithelium (RPE) against oxidative stress are important for preventing retinal degenerative diseases. Little, however, is known about these mechanisms. Here we show that MITF, a transcription factor responsible for RPE development and function, regulates redox signaling by acting through PGC1alpha, a master regulator of mitochondrial biogenesis. Mitf deficiency in mice leads to significantly higher levels of reactive oxygen species (ROS) in both RPE and retina, suggesting that Mitf dysfunction might lead to oxidative damage in the RPE and, by extension, in the retina. Furthermore, overexpression of MITF in the human RPE cell line ARPE-19 indicates that MITF up-regulates antioxidant gene expression and mitochondrial biogenesis by regulating PGC1alpha and protects cells against oxidative stress. Our findings provide new insights into understanding the redox function of MITF in RPE cells and its potential contribution to prevention of RPE-associated retinal degenerations. PMID- 29486166 TI - Adiponectin attenuates neuronal apoptosis induced by hypoxia-ischemia via the activation of AdipoR1/APPL1/LKB1/AMPK pathway in neonatal rats. AB - Adiponectin is an important adipocyte-derived plasma protein that has beneficial effects on cardio- and cerebrovascular diseases. A low level of plasma Adiponectin is associated with increased mortality post ischemic stroke; however, little is known about the causal role of Adiponectin as well as its molecular mechanisms in neonatal hypoxia ischemia (HI). In the present study, ten-day-old rat pups were subjected to right common carotid artery ligation followed by 2.5 h hypoxia. Recombinant human Adiponectin (rh-Adiponectin) was administered intranasally 1 h post HI. Adiponectin Receptor 1 (AdipoR1) siRNA, APPL1 siRNA, LKB1 siRNA were administered through intracerebroventricular injection 48 h before HI. Brain infarct area measurement, neurological function test, western blot, Fluoro Jade C (FJC), TUNEL, and immunofluorescence staining were conducted. Results revealed that endogenous Adiponectin, AdipoR1 and APPL1 were increased in a time dependent manner after HI. Administration of rh-Adiponectin reduced brain infarct area, neuronal apoptosis, brain atrophy and improved neurological function at 24 h and 4 weeks post HI. Furthermore, rh-Adiponectin treatment increased Adiponectin, AdipoR1, APPL1, cytosolic LKB1, p-AMPK expression levels and thereby attenuated apoptosis as shown by the decreased expression of the pro apoptotic marker, Cleaved Caspase 3 (C-Cas3), as well as the number of FJC and TUNEL positively stained neurons. AdipoR1, APPL1 and LKB1 siRNAs abolished the anti-apoptotic effects of rh-Adiponectin at 24 h after HI. Collectively, the data provided evidence that intranasal administration of rh-Adiponectin attenuated neuronal apoptosis at least in part via activating AdipoR1/APPL1/LKB1/AMPK signaling pathway. Adiponectin could represent a therapeutic target for treatment of neonatal hypoxic ischemic encephalopathy. PMID- 29486168 TI - Pleiotropic activity of systemically delivered angiogenin in the SOD1G93A mouse model. AB - Loss-of-function mutations in the angiogenin (ANG) gene have been identified in familial and sporadic ALS patients. Previous work from our group identified human ANG (huANG) to protect motoneurons in vitro, and provided proof-of-concept that daily intraperitoneal (i.p.) huANG injections post-symptom onset increased lifespan and delayed disease progression in SOD1G93A mice. huANG's mechanism of action remains less well understood. Here, we implemented a preclinical in vivo design to validate our previous results, provide pharmacokinetic and protein distribution data after systemic administration, and explore potential pleiotropic activities of huANG in vivo. SOD1G93A mice (n = 45) and non transgenic controls (n = 31) were sex- age- and litter-matched according to the 2010 European ALS/MND group guidelines, and treated with huANG (1 MUg, i.p., 3 times/week) or vehicle from 90 days on. huANG treatment increased survival and delayed motor dysfunction as assessed by rotarod in SOD1G93A mice. Increased huANG serum levels were detectable 2 and 24 h after i.p. injection equally in transgenic and non-transgenic mice. Exogenous huANG localized to spinal cord astrocytes, supporting a glia-mediated, paracrine mechanism of action; uptake into endothelial cells was also observed. 1 MUg huANG or vehicle were administered from 90 to 115 days of age for histological analysis. Vehicle treated SOD1G93A mice showed decreased motoneuron numbers and vascular length per ventral horn area, while huANG treatment resulted in improved vascular network maintenance and motoneuron survival. Our data suggest huANG represents a new class of pleiotropic ALS therapeutic that acts on the spinal cord vasculature and glia to delay motoneuron degeneration and disease progression. PMID- 29486167 TI - AMPA receptor GluA1 Ser831 phosphorylation is critical for nitroglycerin-induced migraine-like pain. AB - Migraine is the third most common disease worldwide; however, the mechanisms underlying migraine headache are still not fully understood. Previous studies have demonstrated that alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor phosphorylation plays an important role in central sensitization of pain transmission. In the present study, we observed that AMPA receptor GluA1 Ser831 phosphorylation was enhanced in the spinal trigeminal nucleus caudalis (Sp5C) after intraperitoneal injection of nitroglycerin (NTG). The NTG injection induced acute migraine-like pain including photophobia and mechanical hypersensitivity as reported previously. Interestingly, targeted mutation of GluA1 Ser831 site to prevent phosphorylation significantly inhibited NTG-induced migraine-like pain. Moreover, NTG incubation caused a robust Ca2+ influx in cultured brainstem neurons, which was dramatically inhibited by GluA1 S831A (serine at the 831 site of GluA1 is mutated to alanine) phospho-deficient mutation, and treatment with 1-naphthyl acetyl spermine (NASPM), a selective Ca2+ permeable AMPA receptor channel blocker, dose-dependently blocked the NTG-evoked increase of Ca2+ influx in the cultured neurons. We further found that intra-Sp5C injection of NASPM significantly inhibited NTG-produced mechanical hypersensitivity. These results suggest that AMPA receptor phosphorylation at the Ser831 site in the Sp5C is critical for NTG-induced migraine-like pain. PMID- 29486169 TI - Defining the number of bouts and oxygen uptake during the "Tabata protocol" performed at different intensities. AB - It is usually reported that the Tabata protocol (TP) is performed with eight bouts of 20:10 intervals at a load equivalent to 170% of i V O2max. However, the feasibility of accumulating 160 s of work at 170% i V O2max has been questioned. This article tested the intensity that would allow the performance of the original TP on a cycle ergometer, and measured the highest value of oxygen consumption (V O2) obtained during the TP and the time spent above 90% of the maximal oxygen uptake (V O2max) during the TP performed at different intensities. Thirteen young active males (25.9 +/- 5.5 years, 67.9 +/- 9.2 kg, 1.70 +/- 0.06 m, 23.6 +/- 3.1 kg.m-2) participated in the study. Participants performed a graded exertion test (GXT) on a cycle ergometer to obtain maximum oxygen consumption (V O2max) and the intensity associated with V O2max (i V O2max). V O2, maximal heart rate (HRmax), and number of bouts performed were evaluated during the TP performed at 115%, 130%, and 170% of i V O2max. V O2max, HRmax, and iV O2max were 51.8 +/- 8.0 mL.kg-1.min-1, 186 +/- 10 bpm, and 204 +/- 26 W, respectively. The number of bouts performed at 115% (7 +/- 1 bouts) was higher than at 130% (5 +/- 1 bouts) and 170% (4 +/- 1 bouts) (p < .0001). The highest V O2 achieved at 115%, 130%, and 170% of iV O2max was 54.2 +/- 7.9 mL.kg-1.min-1, 52.5 +/- 8.1 mL.kg-1.min-1, and 49.6 +/- 7.5 mL.kg-1.min-1, respectively. Non significant difference was found between the highest V O2 achieved at different intensities, however qualitative magnitude-inference indicate a likely small effect between 115% and 170% of iV O2max. Time spent above 90% of the V O2max during the TP at 115% (50 +/- 48 s) was higher than 170% (23 +/- 21 s; p < 0.044) with a probably small effect. In conclusion, our data suggest that the adequate intensity to perform a similar number of bouts in the original TP is lower than previously proposed, and equivalent to 115% of the iV O2max. In addition, intensities between 115 and 130% of the iV O2max should be used to raise the time spent above 90% VO2max. PMID- 29486171 TI - Sex differences and the role of acute stress in the open-field tower maze. AB - Many studies provide evidence that differences in spatial learning exist between males and females. However, it is necessary to consider non-mnemonic factors that may influence these findings. The present experiment investigated acquisition, retention, and the effects of stress on response- and place-learning in male and female rats. Rats were trained in an open-field tower maze. Procedures were used to minimize stress in the rats, and their ability to solve place- or response learning in the maze was determined by analyzing a response variable (i.e., first choice correct response) that was not influenced by general locomotor activity. The results revealed that male and female rats acquire place- and response learning at the same rate even though females moved significantly faster in the maze. However, females showed better retrieval of place-, but not response learning compared to male rats. This effect appeared to be enhanced when the rats were tested immediately following an acute restraint stress. Furthermore, both female and male rats that were exposed to acute restraint stress showed less impairment than controls when subsequently tested in a novel situation. These findings have clinical implications that a mild physiological stress response can make one more cognitively resistant to adversities later in life. PMID- 29486172 TI - Validation of a urine circulating cathodic antigen cassette test for detection of Schistosoma haematobiumin uMkhanyakude district of South Africa. AB - Circulating cathodic antigen (CCA) tests for schistosomiasis are fast and less complicated allowing making them good candidates for routine qualitative screening for schistosomiasis at point of care. The urine-CCA has been evaluated for detection of S. mansoni with promising results. Its specificity and consistency in detecting S. haematobium infection in different endemic regions has been variable. This study validated a rapid urine-CCA cassette test for qualitative detection of S. haematobium infection in an S. haematobium endemic area with low S. mansoni prevalence. Microscopic examination for the standard urine filtration technique was used to validate the commercially available urine CCA cassette test (rapid medical diagnostics (r)). The validation was done in a sample of primary school pupils (n = 420) aged 10-15 years in schools in the Jozini Municipality, KZN. There was a relationship between infection intensity and a positive urine-CCA test. Using the urine filtration method as the gold standard, the prevalence for S. haematobium was 40%, the accuracy of the CCA kit was 54.8%, sensitivity was 68.1% while the specificity was 45.8%. The positive predictive value was 45.82% while the negative predictive value was 68.05%. Both the urine filtration and the urine-CCA methods detected heavy (>=50 eggs/10 mL urine) and light infections at statistically significant levels. The overall accuracy, sensitivity and specificity of the urine-CCA cassette test were low. The urine-CCA cassette test performed much better for heavy infections than low infections (p < 0.05) implying that the kit may not be suitable for low endemic areas. PMID- 29486173 TI - Soil-transmitted helminth infections and intestinal and systemic inflammation in schoolchildren. PMID- 29486170 TI - Timing of eating in adults across the weight spectrum: Metabolic factors and potential circadian mechanisms. AB - Timing of eating is recognized as a significant contributor to body weight regulation. Disruption of sleep-wake cycles from a predominantly diurnal (daytime) to a delayed (evening) lifestyle leads to altered circadian rhythms and metabolic dysfunction. This article reviews current evidence for timed and delayed eating in individuals of normal weight and those with overweight or obesity: although some findings indicate a benefit of eating earlier in the daytime on weight and/or metabolic outcomes, results have not been uniformly consistent, and more rigorous and longer-duration studies are needed. We also review potential circadian mechanisms underlying the metabolic- and weight related changes resulting from timed and delayed eating. Further identification of such mechanisms using deep phenotyping is required to determine targets for medical interventions for obesity and for prevention of metabolic syndrome and diabetes, and to inform clinical guidelines regarding eating schedules for management of weight and metabolic disease. PMID- 29486174 TI - Antibody responses to P. falciparum Apical Membrane Antigen 1(AMA-1) in relation to haemoglobin S (HbS), HbC, G6PD and ABO blood groups among Fulani and Masaleit living in Western Sudan. AB - Fulani and Masaleit are two sympatric ethnic groups in western Sudan who are characterised by marked differences in susceptibility to Plasmodium falciparum malaria. It has been demonstrated that Glucose-6-phosphate dehydrogenase (G6PD) deficiency and Sickle cell trait HbAS carriers are protected from the most severe forms of malaria. This study aimed to investigate a set of specific IgG subclasses against P. falciparum Apical Membrane Antigen 1 (AMA-1 3D7), haemoglobin variants and (G6PD) in association with malaria susceptibility among Fulani ethnic group compared to sympatric ethnic group living in Western Sudan. A total of 124 children aged 5-9 years from each tribe living in an area of hyper endemic P. falciparum unstable malaria transmission were recruited and genotyped for the haemoglobin (Hb) genes, (G6PD) and (ABO) blood groups. Furthermore, the level of plasma IgG antibody subclasses against P. falciparum antigen (AMA-1) were measured using enzyme linked immunosorbent assays (ELISA). Higher levels of anti-malarial IgG1, IgG2 and IgG3 but not IgG4 antibody were found in Fulani when compared to Masaleit. Individuals carrying the HbCC phenotype were significantly associated with higher levels of IgG1 and IgG2. Furthermore, individuals having the HbAS phenotype were associated with higher levels of specific IgG2 and IgG4 antibodies. In addition, patients with G6PD A/A genotype were associated with higher levels of specific IgG2 antibody compared with those carrying the A/G and G/G genotypes. The results indicate that the Fulani ethnic group show lower frequency of HbAS, HbSS and HbAC compared to the Masaleit ethnic group. The inter ethnic analysis shows no statistically significant difference in G6PD genotypes (P value = 0.791). However, the intra-ethnic analysis indicates that both ethnic groups have less A/A genotypes and (A) allele frequency of G6PD compared to G/G genotypes, while the HbSA genotype was associated with higher levels of IgG2 (AMA 1) and IgG4 antibodies. In addition, patients carrying the G6PD A/A genotype were associated with higher levels of specific IgG2 antibody compared with those carrying the A/G and G/G genotypes. The present results revealed that the Fulani ethnic group has statistically significantly lower frequency of abnormal haemoglobin resistant to malaria infection compared to the Masaleit ethnic group. PMID- 29486175 TI - Degree of calcification and cyst activity in hepatic cystic echinococcosis in humans. AB - To evaluate the relationship between cyst activity and calcification degree in cystic echinococcosis (CE) in humans, 99 hepatic cysts at successive stages of involution, surgically excised from 72 Sardinian patients, have been analyzed. Cysts were classified into 4 groups according to calcification extent: CALC 0 (no calcification); CALC 1 (scattered punctate calcifications); CALC 2 (large coarse segmental/partial calcifications); CALC 3 (complete or nearly complete circumferential ring of calcification up to thick wall of osseous consistency/calcified content of cyst). In addition the possible correlation with antibody response has been explored analyzing IgG1, IgG4 and IgE produced against somatic PSCAg. Results showed that calcification is not restricted to the inactive WHO cyst types CE4 and CE5, but occurs to a varying extent in all morphotypes of metacestode, from active classic unilocular or multivesicular cysts to the more complicated and highly degenerate stages, where cyst wall appears massively calcified. Prevalence of calcification increases with progression of cyst degenerative process, but is not synonymous with parasite inactivity and can be misleading as signs of calcification may coexist with still metabolically active cysts. On the contrary, detection of entirely firmly solidified content seems a reliable indication of cyst inactivity. IgG4 is the dominant isotype associated particularly with the evolutive phase. Positive rates and OD levels, higher in active vs inactive stages, are stable or increase slightly in weakly and moderately calcified cysts (CALC 1/CALC 2), compared to non-calcified ones (CALC 0), strongly decreasing in highly calcified forms (CALC 3). In conclusion, evaluation of calcification extent may be pertinent for staging CE, and immunological tests, particularly for IgG4, and IgE may help to better define cyst activity. PMID- 29486177 TI - Self-Expandable Stentless Valve Versus Rigid Stented Valve: The Matter of the Right Comparison. PMID- 29486176 TI - Ultrasonographic investigation of cholangiocarcinoma in Lao PDR. AB - Opisthorchis viverrini is a group 1 carcinogen that causes cholangiocarcinoma (CCA). Although opisthorchiasis is known to be severely endemic to several areas along the Mekong River in Lao PDR, the CCA status of residents of this region is still under investigation. In this study, we analyzed the results of abdominal ultrasonography (US) performed on 6113 residents in 9 provinces (Vientiane Municipality, Savannakhet, Phongsaly, Khammouane, Saravane, Champasak, Vientiane, Xieng Khuouang, and Luang Prabang provinces) of Lao PDR from 2007 to 2011. Overall, 51 cases (0.83%) were detected with suspected CCA. The CCA rates in Vientiane Municipality and in Savannakhet and Khammouane provinces were 1.45%, 1.58%, and 1.09%, respectively. However, in the other 6 provinces, the rate of CCA averaged only 0.26%. In the 3 provinces with higher rates of CCA, bile duct dilatation (grade >= 2) was also significantly more prevalent (P < 0.0001). These results are concordant with previous reports showing a higher endemicity of opisthorchiasis in Vientiane Municipality and in Savannakhet and Khammouane provinces. PMID- 29486178 TI - Robotic Endoscopic Airway Challenge: REACH Assessment. AB - PURPOSE: Bronchoscopy for peripheral pulmonary lesions continues to present challenges to clinicians. One potential limitation may be the inability to advance conventional bronchoscopes into close proximity of peripheral lesions before biopsy. This study was performed to assess the reach of a robotic endoscopic system within human cadaveric lungs compared with conventional thin bronchoscopes. DESCRIPTION: All segmental bronchi (RB1 to 10, LB1 to 10) were accessed in two human cadavers using a conventional thin bronchoscope and robotic endoscope of identical outer diameter. Bronchus generation count and insertion depth measured by electromagnetic navigation and external fluoroscopy were recorded. EVALUATION: The robotic endoscope was advanced beyond the conventional thin bronchoscope in all segments, particularly in bronchi with increased angulation such as RB1 (mean generation count 8 versus 3.5, respectively) and LB1+2 (mean generation count 8 versus 4.5). CONCLUSIONS: The robotic endoscopic system was advanced beyond a conventional thin bronchoscope with identical outer diameter into the periphery of human cadaveric lungs. Improved reach within the lung periphery may address some limitations with contemporary bronchoscopic approaches for peripheral lesion biopsy. PMID- 29486179 TI - Epidermal Growth Factor Receptor Mutation as a Risk Factor for Recurrence in Lung Adenocarcinoma. AB - BACKGROUND: The presence of epidermal growth factor receptor (EGFR) mutations is an established prognostic factor for patients with advanced lung adenocarcinoma. Here, we examined whether EGFR mutation status is a prognostic factor for patients who had undergone surgery. METHODS: Clinicopathologic data from 1,463 patients who underwent complete surgical resection for lung adenocarcinoma between 2005 and 2012 were collected. Differences in postoperative recurrence free survival and overall survival according to EGFR mutation status were evaluated. RESULTS: Of 835 eligible patients, the numbers of patients with wild type EGFR (WT), exon 19 deletion (Ex19), and exon 21 L858R (Ex21) were 426, 175, and 234, respectively. Patients with Ex19 had a significantly higher incidence of extrathoracic recurrence than patients with Ex21 (p = 0.004). The 5-year recurrence-free survival rates for patients with WT, Ex19, and Ex21 were 63.0%, 67.5%, and 78.2%, respectively. The Ex21 group had a significantly longer recurrence-free survival than the WT group (p < 0.001) and the Ex19 group (p = 0.016). The 5-year overall survival for patients with WT, Ex19, and Ex21 were 76.9%, 86.5%, and 87.5%, respectively. Patients with Ex19 and Ex21 had a significantly longer overall survival than patients with WT (Ex19, p = 0.009; Ex21, p < 0.001). Multivariate analysis for recurrence-free survival showed that Ex19 was significantly associated with a worse prognosis than Ex21 (p = 0.019). CONCLUSIONS: Patients with Ex19 had significantly shorter recurrence-free survival and had extrathoracic recurrence more frequently than patients with Ex21 among patients with resected lung adenocarcinoma, implying that Ex19 could be a worse prognostic factor. PMID- 29486180 TI - Primary Salivary Type Lung Cancers in the National Cancer Database. AB - BACKGROUND: Primary salivary type lung cancers such as adenoid cystic carcinoma (ACC) and mucoepidermoid carcinoma (MEC) are uncommon primary lung tumors that, given their rarity, remain incompletely understood. This study aimed to characterize the management and outcomes associated with these less common pulmonary malignancies. METHODS: Patients in the National Cancer Database diagnosed with primary lung and bronchial (not tracheal) MEC and ACC between 2004 and 2014 were identified. Adjusted mortality risk of surgically managed patients was evaluated in multivariable Cox proportional hazards regression models. RESULTS: In all, 699 MEC patients and 424 ACC patients were identified. The MEC tumors were smaller (mean size 3.1 cm versus 3.8 cm, p < 0.001), less likely to have lymph node metastases (16% versus 38%, p < 0.001), and less likely to undergo pneumonectomy (9% versus 39%, p < 0.001) compared with ACC. Adjusted Cox models of the surgically managed subset of MEC patients identified high tumor grade (hazard ratio [HR] 3.0, 95% confidence interval [CI]: 1.31 to 7.1, p = 0.01), tumor size greater than 4 cm (HR 6.7, 95% CI: 2.0 to 22.0, p = 0.01), and wedge resection (HR 3.7, 95% CI: 1.1 to 12.0, p = 0.03) to be associated with increased risk of death. For ACC patients, incomplete tumor resection, R1 versus R0 (HR 4.0, 95% CI: 1.5 to 10.6, p = 0.006), and distant metastases (HR 12.6, 95% CI: 2.5 to 64.4, p = 0.002) were associated with increased mortality. CONCLUSIONS: Pulmonary MEC and ACC appear to have distinct physical and oncologic attributes in the National Cancer Database. Although the overall prognosis appears to be favorable, there are subsets of primary salivary type lung cancers with increased mortality risk, and efforts should be made to completely resect these tumors. PMID- 29486181 TI - Successful Bronchial Replacement Using a Thoracodorsal Artery Perforator Flap. AB - Pneumonectomy is known to be associated with a high rate of morbidity and mortality and may be contraindicated in patients with altered lung function. Sleeve lobectomy is a treatment option, but it may be technically impossible in cases of large bronchial involvement. Here, we describe a patient with impaired lung function and right upper lobe lung cancer that involved the intermediate bronchial trunk. The patient was treated successfully with a right upper sleeve lobectomy and bronchial replacement with the use of a thoracodorsal artery perforator flap and a temporary endostent. Clinical outcomes were favorable, and no recurrence has been observed in the 4 years since the operation. PMID- 29486182 TI - Phytol suppresses melanogenesis through proteasomal degradation of MITF via the ROS-ERK signaling pathway. AB - Phytol (3,7,11,15-tetramethyl-2-hexadecen-1-ol) is an acyclic monounsaturated diterpene alcohol generated from chlorophyll metabolism that exerts anti inflammatory, antithrombotic, antimicrobial, and antitumor effects. However, the effect of phytol on melanogenesis and the underlying molecular mechanisms of its inhibition remain unknown. Here, we found that phytol suppressed alpha-melanocyte stimulating hormone-induced melanogenesis in B16F10 murine melanoma cells without any toxic effects. Phytol significantly attenuated melanin production by reducing the expression of tyrosinase and tyrosinase related protein 1. Treatment with phytol inhibited the expression of microphthalmia-associated transcription factor (MITF) by phosphorylating extracellular signal-regulated protein kinase (ERK). The ERK inhibitor PD98059 restored MITF expression and prevented the anti melanogenic effect of phytol. We found that the ERK inhibitor coincidently abrogated MITF ubiquitination and degradation, suggesting that the ERK pathway is involved in phytol-induced ubiquitination of MITF. Furthermore, our data show that reactive oxygen species (ROS) production was increased in cells treated with phytol. Consistently, a ROS scavenger inhibited ERK phosphorylation and restored MITF degradation. Accordingly, the intermediary role of ROS was confirmed in phytol-induced MITF degradation. Taken together, these results demonstrate that phytol stimulates ROS production and modulates ERK-mediated proteasomal degradation of MITF in B16F10 murine melanoma cells. These findings suggest that phytol may have potential to be utilized as a whitening agent in cosmetics and as a therapy for skin hyperpigmentation. PMID- 29486183 TI - Nrf-2 transcriptionally activates P21Cip/WAF1 and promotes A549 cell survival against oxidative stress induced by H2O2. AB - Cancer cells possess elevated ROS coupled with increased levels of antioxidant enzymes which render them resistant against cytotoxic chemotherapies. Therefore, an understanding of the interaction between key molecules involved in stress adaptive mechanisms is important to innovate strategies against cancer cell chemoresistance. Here, the lung adenocarcinoma cell line A549 with constitutively expressed Nrf2 was found to be more tolerant to H2O2 (0.1, 0.2, 0.5 and 1 mM) than normal lung cell line L132 or p53 null lung cancer cell line H1299. Maximum cytoprotection was observed at 0.2 mM H2O2 accompanied by a significant increase in p21, Nrf2 and antioxidant enzymes in A549 cells. The increased p21 expression was independent of p53 but dependent on Nrf2 as evident from qPCR, Western blotting and dual luciferase assays after silencing Nrf-2 and p53 genes. Highly conserved Nrf-2 binding sites were identified in p21 promoter by bioinformatics and homology modeling which was further confirmed by ChIP and reporter assay. PMID- 29486184 TI - Coralyne, a protoberberine alkaloid, causes robust photosenstization of cancer cells through ATR-p38 MAPK-BAX and JAK2-STAT1-BAX pathways. AB - Photodynamic therapy (PDT) provides an effective cancer treatment option but it requires sufficient cellular oxygen concentration to exert its photosensitizing effects. Due to hypoxic nature of most tumors, widespread clinical application of PDT is restricted and warrants development of photosensitizers which can kill cancer cells in ROS independent manner. Previously, we reported significant enhancement of the anti-cancer property of coralyne in presence of ultraviolet-A (UVA) light exposure against several human carcinoma cell lines. This study aimed at unravelling molecular cascades of events in CUVA treatment (coralyne and UVA light)-mediated photosensitization of human skin cancer. The CUVA-treatment caused robust apoptosis of A431 cancer cells, primarily through mitochondrial and lysosomal dysfunctions. Silencing of BAX conferred a significant protection against CUVA-induced apoptosis. Both lysosomal proteases and caspase-8 activation contributed to BID cleavage. Further, our results revealed that a dual signaling axis e.g., ATR-p38 MAPK and JAK2-STAT1 pathways functioned upstream of BAX activation in apoptosis response. Moreover, transient silencing of ATR and pharmacological inhibition of p38-MAPK or JAK2 significantly abolished the effect of CUVA treatment induced BAX expression and cell death, linking the extrinsic and intrinsic pathways with the observed cell death. Our data suggest that coralyne, which is known topoisomerase-I inhibitor, may be an attractive agent for photo-chemotherapeutic treatment of human skin cancers. PMID- 29486185 TI - Use of a model for A1c formation to estimate average glucose operative between short-interval measurements of %A1c. AB - BACKGROUND: Estimated average glucose (AG) is generally reported along with hemoglobin A1c measurements according to a standard calculation. Given a normal red blood cell lifetime of 120 days, serial A1c measurements at intervals <120 days are not completely independent. For short interval measurements, a change in AG (DeltaAG) necessarily underestimates the change in average glucose operative during the interval (DeltaG). We use a model for kinetics of HbA1c to evaluate the theoretical relationship between DeltaAG and DeltaG for HbA1c measurements made at intervals between 0 and 120 days. METHODS: From any given starting point for A1c, step changes in G were simulated using model calculations to determine the extent to which A1c could change as a function of the interval of exposure. Values for DeltaAG were compared to the operative DeltaG as a function of the interval between A1c measurements. RESULTS: Results of model simulations are a single graph for relationship of DeltaAG to DeltaG as a function of the interval between A1c measurements. DeltaAG for (15, 30, 45, 60, 76, and 90) day intervals underestimated operative DeltaG by (73, 51, 34, 21, 11, and 5)%, respectively. CONCLUSIONS: Model calculations predict the relationship between changes in estimated average glucose to changes in operative glucose for serial A1c measurements made at intervals <120 days. Given that serial measurements of A1c made at short intervals are not uncommon in practice, physicians may find this information to be useful. PMID- 29486186 TI - Clinical usefulness of Glycated Albumin in the diagnosis of diabetes: Results from an Italian study. AB - OBJECTIVES: Glycated Albumin (GA) has been proposed as a screening marker for diabetes in Asian countries in the last years. Nevertheless, few studies have been conducted in Caucasian population. The aim of this study is to evaluate the clinical usefulness of GA in diabetes diagnosis in Caucasian asymptomatic subjects considered at risk of diabetes based on medical history and Fasting Plasma Glucose (FPG). DESIGN AND METHODS: Three hundred and thirty-four Caucasian subjects having one or more risk factor for diabetes, and/or FPG ranging from 5.6 mmol/L to 6.9 mmol/L with no symptoms for diabetes were enrolled in this study. Plasma GA was measured by an enzymatic method (quantILab Glycated Albumin) on ILab Taurus instrument (Instrumentation Laboratory - A Werfen Company). RESULTS: GA median levels were 13.2% (IQR:12.2-14.4). Eighteen subjects (5.4%) were classified as diabetics based on their HbA1c. According to the ROC curve analysis, GA identified subjects with diabetes with a sensitivity of 72.2% (95% CI: 46.5-90.3) and a specificity of 71.8% (95% CI: 66.5-76.7) (AUC: 0.80; 95% CI: 0.75-0.84; P < 0.0001) at the cut-off of 14%. The cut-off of 13.5% was associated to a higher sensitivity 88.9% (95%CI: 65.3-98.6) and a specificity of 60.4% (95%CI, 54.8-65.9). CONCLUSIONS: This study confirms the clinical usefulness of GA for the diagnosis of diabetes in Caucasian subjects at risk for diabetes. More studies are required to clarify the role of GA in relation to the other diagnostic criteria for diabetes. PMID- 29486187 TI - Reflex and reflective testing strategies for early detection of pituitary dysfunction. AB - OBJECTIVE: The clinical presentation of pituitary dysfunction is typically variable and may often be insidious, resulting in delayed diagnosis by up to decades. The complexity of presentation and difficulty in pattern recognition of first line hormone tests result in challenges in early diagnosis of this condition. The aim of this study was to determine the impact of reflective testing and interpretive commenting on the early detection and management of such cases from primary care. METHODS: Prospective audit over 12 months in which first line pituitary target organ hormones were identified via a reflex algorithm in the laboratory information system. Selected tests were reviewed by a laboratory clinician and decision made on reflective testing and interpretive commenting based on available clinical information and previous result trends. Patients who had a laboratory intervention were followed up to determine the clinical outcome. RESULTS: Out of 1099 patients identified, additional testing was made for 214. Interpretative comments were subsequently added to reports of 196 patients, 48 (25%) of whom were referred to endocrinology and 35 (73%) of these were directly related to the laboratory intervention. Eleven other patients had outcomes related to the intervention. Pituitary related conditions (insufficiency and/or adenoma) were found in 29 patients, 24 of which were identified as a result of laboratory intervention. CONCLUSIONS: This study highlights the clinical value of laboratory intervention in aiding early detection of pituitary dysfunction and may avoid the disease burden of delayed management. PMID- 29486188 TI - A Role for Ploidy in Heart Regeneration. AB - There is mounting circumstantial evidence that ploidy, a cell's relative DNA content, is in part responsible for the differential cardiac regenerative capacity observed between regenerative and non-regenerative organisms. In this issue of Developmental Cell, Gonzalez-Rosa et al. (2018) provide direct evidence that polyploid cardiomyocytes have reduced proliferative and regenerative potential. PMID- 29486189 TI - A Fat Lot of Good for Wound Healing. AB - The insect's fat body combines metabolic and immunological functions. In this issue of Developmental Cell, Franz et al. (2018) show that in Drosophila, cells of the fat body are not static, but can actively "swim" toward sites of epithelial injury, where they physically clog the wound and locally secrete antimicrobial peptides. PMID- 29486190 TI - Organizing Complex Tissue Architecture by Pushing and Pulling Cell Contacts. AB - Changes to cell shape and interaction drive animal tissue morphogenesis. Reporting now in Developmental Cell, Del Signore et al. (2018) describe active lengthening of cell-cell contacts by Arp2/3-based actin networks. Through cycles of contact lengthening and shortening, the developing Drosophila eye passes through various multicellular configurations to achieve its complex architecture. PMID- 29486191 TI - Ultraviolet Rays Light Up Transcriptional Networks Regulating Plant Growth. AB - Light and hormones tightly regulate plant growth and development by both synergistic and antagonistic actions. In the current issue of Developmental Cell, Liang et al. (2018) uncover how the UV-B photoreceptor UVR8 mediates inhibition of plant growth via direct interactions with key transcriptional regulators of brassinosteroid signaling. PMID- 29486192 TI - Dynamic Encoding in the Notch Pathway. AB - A small number of signaling pathways are used ubiquitously throughout development. How can enough information be carried through such a small number of channels? Reporting in Cell, Nandagopal et al. (2018) reveal how different Notch ligands can regulate different targets through the same receptor using differences in signaling dynamics. PMID- 29486193 TI - A Tribute to Ben Barres: Remembrances from Barres Lab Members. PMID- 29486194 TI - Cellular Stress Associated with Aneuploidy. AB - Aneuploidy, chromosome stoichiometry that deviates from exact multiples of the haploid compliment of an organism, exists in eukaryotic microbes, several normal human tissues, and the majority of solid tumors. Here, we review the current understanding about the cellular stress states that may result from aneuploidy. The topics of aneuploidy-induced proteotoxic, metabolic, replication, and mitotic stress are assessed in the context of the gene dosage imbalance observed in aneuploid cells. We also highlight emerging findings related to the downstream effects of aneuploidy-induced cellular stress on the immune surveillance against aneuploid cells. PMID- 29486197 TI - Cell Extrusion: A Stress-Responsive Force for Good or Evil in Epithelial Homeostasis. PMID- 29486195 TI - Myocardial Polyploidization Creates a Barrier to Heart Regeneration in Zebrafish. AB - Correlative evidence suggests that polyploidization of heart muscle, which occurs naturally in post-natal mammals, creates a barrier to heart regeneration. Here, we move beyond a correlation by demonstrating that experimental polyploidization of zebrafish cardiomyocytes is sufficient to suppress their proliferative potential during regeneration. Initially, we determined that zebrafish myocardium becomes susceptible to polyploidization upon transient cytokinesis inhibition mediated by dominant-negative Ect2. Using a transgenic strategy, we generated adult animals containing mosaic hearts composed of differentially labeled diploid and polyploid-enriched cardiomyocyte populations. Diploid cardiomyocytes outcompeted their polyploid neighbors in producing regenerated heart muscle. Moreover, hearts composed of equivalent proportions of diploid and polyploid cardiomyocytes failed to regenerate altogether, demonstrating that a critical percentage of diploid cardiomyocytes is required to achieve heart regeneration. Our data identify cardiomyocyte polyploidization as a barrier to heart regeneration and suggest that mobilizing rare diploid cardiomyocytes in the human heart will improve its regenerative capacity. PMID- 29486196 TI - Fat Body Cells Are Motile and Actively Migrate to Wounds to Drive Repair and Prevent Infection. AB - Adipocytes have many functions in various tissues beyond energy storage, including regulating metabolism, growth, and immunity. However, little is known about their role in wound healing. Here we use live imaging of fat body cells, the equivalent of vertebrate adipocytes in Drosophila, to investigate their potential behaviors and functions following skin wounding. We find that pupal fat body cells are not immotile, as previously presumed, but actively migrate to wounds using an unusual adhesion-independent, actomyosin-driven, peristaltic mode of motility. Once at the wound, fat body cells collaborate with hemocytes, Drosophila macrophages, to clear the wound of cell debris; they also tightly seal the epithelial wound gap and locally release antimicrobial peptides to fight wound infection. Thus, fat body cells are motile cells, enabling them to migrate to wounds to undertake several local functions needed to drive wound repair and prevent infections. PMID- 29486198 TI - Endoscopic Full Thickness Resection. AB - Recent advances in minimally invasive endoscopic approaches have pushed the boundaries of well-established resection techniques for therapeutic and diagnostic applications. Endoscopic full thickness resection techniques are a key development in the management of challenging epithelial and subepithelial lesions that are not amenable to conventional endoscopic resection methods and previously required a surgical approach. Endoscopic full thickness biopsy represents a paradigm shift in tissue acquisition and will enhance our understanding of the pathophysiology, and guide therapy, of gastrointestinal neuromuscular diseases, as well as other inflammatory and neoplastic conditions. This review highlights current tools and techniques available for endoscopic full thickness resection and biopsy, as well as outcomes from such interventions. PMID- 29486200 TI - Endoscopic Submucosal Dissection: Indications and Application in Western Endoscopy Practice. AB - Endoscopic submucosal dissection was developed in Japan, early in this century, to provide a minimally invasive yet curative treatment for the large numbers of patients with early gastric cancer identified by the national screening program. Previously, the majority of these patients were treated surgically at substantial cost and with significant risk of short- and long-term morbidity. En-bloc excision of these early cancers, most with a limited risk of nodal metastasis, allowed complete staging of the tumor, stratification of the subsequent therapeutic approach, and potential cure. This transformative innovation changed the nature of endoscopic treatment for superficial mucosal neoplasia and, ultimately, for the first time allowed endoscopists to assert that the early cancer had been definitively cured. Subsequently, Western endoscopists have increasingly embraced the therapeutic possibilities offered by endoscopic submucosal dissection, but with some justifiable scientific caution. Here we provide an evidence-based critical appraisal of the role of endoscopic submucosal dissection in advanced endoscopic tissue resection. PMID- 29486199 TI - Loss of Chromatin-Remodeling Proteins and/or CDKN2A Associates With Metastasis of Pancreatic Neuroendocrine Tumors and Reduced Patient Survival Times. AB - Despite prognostic grading and staging systems, it is a challenge to predict outcomes for patients with pancreatic neuroendocrine tumors (PanNETs). Sequencing studies of PanNETs have identified alterations in death domain-associated protein (DAXX) and alpha-thalassemia/mental retardation X-linked chromatin remodeler (ATRX). In tumors, mutations in DAXX or ATRX and corresponding loss of protein expression correlate with shorter times of disease-free survival and disease specific survival of patients. However, DAXX or ATRX proteins were lost in only 50% of distant metastases analyzed. We performed whole-exome sequencing analyses of 20 distant metastases from 20 patients with a single nonsyndrome, nonfunctional PanNET. We found distant metastases contained alterations in multiple endocrine neoplasia type 1 (MEN1) (n = 8), ATRX (n = 5), DAXX (n = 5), TSC2 (n = 3), and DEP domain containing 5 (DEPDC5) (n = 3). We found copy number loss of cyclin dependent kinase inhibitor 2A (CDKN2A) in 15 metastases (75%) and alterations in genes that regulate chromatin remodeling, including set domain containing 2 (SETD2) (n = 4), AT-rich interaction domain 1A (ARID1A) (n = 2), chromodomain helicase DNA binding protein 8 (CHD8) (n = 2), and DNA methyl transferase 1 (DNMT1) (n = 2). In a separate analysis of 347 primary PanNETs, we found loss or deletion of DAXX and ATRX, disruption of SETD2 function (based on loss of H3 lysine 36 trimethylation), loss of ARID1A expression or deletions in CDKN2A in 81% of primary PanNETs with distant metastases. Among patients with loss or deletion of at least 1 of these proteins or genes, 39% survived disease free for 5 years and 44% had disease-specific survival times of 10 years. Among patients without any of these alterations, 98% survived disease-free for 5 years and 95% had disease-specific survival times of 10 years. Therefore, primary PanNETs with loss of DAXX, ATRX, H3 lysine 36 trimethylation, ARID1A, and/or CDKN2A associate with shorter survival times of patients. Our findings indicate that alterations in chromatin-remodeling genes and CDKN2A contribute to metastasis of PanNETs. PMID- 29486201 TI - Kinetic operational models of agonism for G-protein-coupled receptors. AB - The application of kinetics to research and therapeutic development of G-protein coupled receptors has become increasingly valuable. Pharmacological models provide the foundation of pharmacology, providing concepts and measurable parameters such as efficacy and potency that have underlain decades of successful drug discovery. Currently there are few pharmacological models that incorporate kinetic activity in such a way as to yield experimentally-accessible drug parameters. In this study, a kinetic model of pharmacological response was developed that provides a kinetic descriptor of efficacy (the transduction rate constant, ktau) and allows measurement of receptor-ligand binding kinetics from functional data. The model assumes: (1) receptor interacts with a precursor of the response ("Transduction potential") and converts it to the response. (2) The response can decay. Familiar response vs time plots emerge, depending on whether transduction potential is depleted and/or response decays. These are the straight line, the "association" exponential curve, and the rise-and-fall curve. Convenient, familiar methods are described for measuring the model parameters and files are provided for the curve-fitting program Prism (GraphPad Software) that can be used as a guide. The efficacy parameter ktau is straightforward to measure and accounts for receptor reserve; all that is required is measurement of response over time at a maximally-stimulating concentration of agonist. The modular nature of the model framework allows it to be extended. Here this is done to incorporate antagonist-receptor binding kinetics and slow agonist-receptor equilibration. In principle, the modular framework can incorporate other cellular processes, such as receptor desensitization. The kinetic response model described here can be applied to measure kinetic pharmacological parameters than can be used to advance the understanding of GPCR pharmacology and optimize new and improved therapeutics. PMID- 29486202 TI - An electrochemical immunosensor based on poly p-phenylenediamine and graphene nanocomposite for detection of neuron-specific enolase via electrochemically amplified detection. AB - In this work, a label-free electrochemical immunosensor was constructed on the base of poly p-phenylenediamine (PPD) and GR nanocomposite (PPD-GR). Screen printed electrodes modified with PPD-GR nanocomposite and applied to advance enzyme-free and label free electrochemical immunosensor for detection of protein biomarker neuron-specific enolase (NSE). It was found that the PPD-GR nanocomposite exhibits excellent electrocatalytic activity towards ascorbic acid (AA) oxidation as analytical signal based on EC' mechanism. Due to the excellent electrocatalytic activity of PPD-GR nanocomposite, determination of NSE antigen was based on its obstruction to the electrocatalytic oxidation of AA after binding to the surface of electrode through interaction with the anti-NSE. The proposed immunosensor exhibited a wide linear range of 1.0-1000 ng mL-1, with a low detection limit of 0.3 ng mL-1. Furthermore, the proposed immunosensor were successfully used for the determination of NSE antigen in human serum samples. PMID- 29486203 TI - A method for the extraction of the endogenous tryptic peptides (peptidome) from human EDTA plasma. AB - The proteins identified from endogenous peptides agreed between serum versus plasma, and tryptic versus non-tryptic peptides, when collected by C18 alone and analyzed by liquid chromatography electrospray ionization and tandem mass spectrometry (LC-ESI-MS/MS) including amyloids, apolipoproteins, haptoglobin, complements, fibrinogens, hemopexin, antitrypsin and alpha 2 macroglobulin. Precipitation of polypeptides from plasma in 9 vol of 100% organic solvent followed by stepwise extraction of the insoluble pellet with an increasing fraction of water identified thousands of proteins. A Coomassie-blue protein binding assay, and tricine SDS-PAGE, showed that Acetonitrile-Water (AH) resulted in a greater relative enrichment of low molecular weight plasma polypeptides than Acetonitrile-Methanol Water (AMH). A total of 905,386 MS/MS spectra greater than ~10,000 (E4) counts were correlated by X!TANDEM to a federated human protein library of 153,124 different protein sequences that resulted in 58,223 fully tryptic peptides from 3463 Gene Symbols of which 1880 had >= 5 independent peptides (p <= 0.00001). The results were filtered and organized in an SQL database for analysis using the generic R statistical analysis system. Cellular proteins including secreted and exosome proteins, signaling factors, nucleic acid binding proteins, metabolic enzymes and uncharacterized factors were observed with a significant enrichment of expected protein-protein interactions by STRING analysis. PMID- 29486204 TI - Multi-laboratory analysis of the variability of shipped samples for proteomics following non-cooled international transport. AB - Transporting biological samples such as cells or tissues is complicated by the need to maintain integrity and minimise modification and degradation, but this is economically costly as the samples must be shipped in a frozen state. This multi laboratory study investigated sample variability introduced by non-cooled transport of dried peptide samples for proteomic analysis using mass spectrometry. Human cancer cell tryptic lysates were proteolysed and dried in Australia and shipped by air to Europe and China. Samples were measured using label free mass spectrometry on similar LC-MS systems at all three sites. Preparation and analysis of the specimens in this manner resulted in only minor differences in protein identification and showed high quantitative reproducibility amongst the participating laboratories. We examined any impact on peptide chemical modification and report no discrepancies compared to the starting, non-shipped sample. We conclude that transport of non-cooled, dried peptides has negligible effect on sample integrity for downstream LC-MS analysis and therefore represents a cost-effective option to facilitate international proteomic collaborations. Data is available via ProteomeXchange with identifier PXD008160. PMID- 29486205 TI - Microparticle-based platform for point-of-care immunoassays. AB - There is a need for quantitative and sensitive, yet simple point-of-care immunoassays. We have developed a point-of-care microparticle-based immunoassay platform which combines the performance of a microtiter well-based assay with the usability of a rapid assay. The platform contained a separate reaction and detection chambers and microparticles for the solid-phase. Photoluminescent up converting nanoparticles (UCNPs) were used as labels. The platform was tested with a cardiac troponin I assay, and a limit of detection of 19.7 ng/L was obtained. This study demonstrates the feasibility of developing point-of-care assays on the new platform for various analytes of interests. PMID- 29486206 TI - Real-time multiparameter study of mitochondrial functions: Instrumental and analytical approaches. AB - In modern biomedical science, a descriptive study is no longer the major focus of many fields. More researchers are now seeking approaches that will help them obtain maximum information from a single sample or model, which will allow them to make more detailed conclusions than previously about mechanisms that underlie certain phenomena. Clearly, simultaneous measurement of multiple parameters will provide more useful information compared to that which can be assessed through parallel studies with multiple single-parameter measurements. Mitochondria are actively involved in the regulation of a number of biochemical processes that are vitally important for normal cell functioning. Dysregulation of cell metabolism occurs under multiple pathological conditions. While changes in mitochondrial and cellular functioning are related to each other, understanding of the details of most mechanisms underlying these relationships are still unknown. It would be appropriate to have an instrument that will help to uncover sequences of events and temporal links among the parameters that involve functional mitochondrial and cellular integration. The current review is focused on the analysis of these technological limitations, and, based on the combined approach, provides hypothetical suggestion on how possibly to create such an instrument. PMID- 29486208 TI - Meat in the post-truth era: Mass media discourses on health and disease in the attention economy. AB - The debate on meat's role in health and disease is a rowdy and dissonant one. This study uses the health section of the online version of The Daily Mail as a case study to carry out a quantitative and qualitative reflection on the related discourses in mass media during the first fifteen years of the 21st century. This period ranged from the fall-out of the bovine spongiform encephalopathy (BSE) crisis and its associated food safety anxieties, over the Atkins diet-craze in 2003 and the avian flu episode in 2007, to the highly influential publication of the report on colon cancer by the International Agency for Research on Cancer (IARC) in 2015. A variety of conflicting news items was discernible, whereby moments of crisis, depicting the potential hazards of meat eating, seemed to generate reassuring counter-reactions stressing the benefits of meat as a rich source of nutrients. In contrast, when the popularity of meat-rich diets was on the rise due to diets stressing the role of protein in weight control, several warnings were issued. Meat's long-standing and semiotic connotations of vitality, strength, and fertility were either confirmed, rejected or inverted. Often this was achieved through scientification or medicalisation, with references to nutritional studies. The holistic role of meat within human diets and health was thus mostly reduced to a focus on specific food components and isolated biological mechanisms. The narratives were often histrionic and displayed serious contradictions. Since several interests were at play, involving a variety of input from dieticians, (health) authorities, the food industry, vegan or vegetarian movements, and celebrities, the overall discourse was highly heterogeneous. PMID- 29486207 TI - nAChRs-ERK1/2-Egr-1 signaling participates in the developmental toxicity of nicotine by epigenetically down-regulating placental 11beta-HSD2. AB - Impaired placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) activity which inactivates maternal glucocorticoids is associated with poor fetal growth and a higher risk of chronic diseases in adulthood. This study aimed to elucidate the epigenetically regulatory mechanism of nicotine on placental 11beta HSD2 expression. Pregnant Wistar rats were administered 1.0 mg/kg nicotine subcutaneously twice a day from gestational day 9 to 20. The results showed that prenatal nicotine exposure increased corticosterone levels in the placenta and fetal serum, disrupted placental morphology and endocrine function, and reduced fetal bodyweight. Meanwhile, histone modification abnormalities (decreased acetylation and increased di-methylation of histone 3 Lysine 9) on the HSD11B2 promoter and lower-expression of 11beta-HSD2 were observed. Furthermore, the expression of nicotinic acetylcholine receptor (nAChR) alpha4/beta2, the phosphorylation of extracellular regulated kinase 1/2 (ERK1/2) and Ets-like protein-1 (Elk-1), and the expression of early growth response-1 (Egr-1) were increased in the nicotine groups. In human BeWo cells, nicotine decreased 11beta HSD2 expression, increased nAChRalpha9 expression, and activated ERK1/2/Elk-1/Egr 1 signaling in the concentration (0.1-10 MUM)-dependent manner. Antagonism of nAChRs, inhibition of ERK1/2 and Egr-1 knockdown by siRNA were able to block/abrogate the effects of nicotine on histone modification and expression of 11beta-HSD2. Taken together, nicotine can impair placental structure and function, and induce fetal developmental toxicity. The underlying mechanism involves histone modifications and down-regulation of 11beta-HSD2 through nAChRs/ERK1/2/Elk-1/Egr-1 signaling, which increases active glucocorticoids levels in the placenta and fetus, and eventually inhibits the fetal development. PMID- 29486209 TI - Probing recalcitrant problems in polyclad evolution and systematics with novel mitochondrial genome resources. AB - For their apparent morphological simplicity, the Platyhelminthes or "flatworms" are a diverse clade found in a broad range of habitats. Their body plans have however made them difficult to robustly classify. Molecular evidence is only beginning to uncover the true evolutionary history of this clade. Here we present nine novel mitochondrial genomes from the still undersampled orders Polycladida and Rhabdocoela, assembled from short Illumina reads. In particular we present for the first time in the literature the mitochondrial sequence of a Rhabdocoel, Bothromesostoma personatum (Typhloplanidae, Mesostominae). The novel mitochondrial genomes examined generally contained the 36 genes expected in the Platyhelminthes, with all possessing 12 of the 13 protein-coding genes normally found in metazoan mitochondrial genomes (ATP8 being absent from all Platyhelminth mtDNA sequenced to date), along with two ribosomal RNA genes. The majority presented possess 22 transfer RNA genes, and a single tRNA gene was absent from two of the nine assembled genomes. By comparison of mitochondrial gene order and phylogenetic analysis of the protein coding and ribosomal RNA genes contained within these sequences with those of previously sequenced species we are able to gain a firm molecular phylogeny for the inter-relationships within this clade. Our phylogenetic reconstructions, using both nucleotide and amino acid sequences under several models and both Bayesian and Maximum Likelihood methods, strongly support the monophyly of Polycladida, and the monophyly of Acotylea and Cotylea within that clade. They also allow us to speculate on the early emergence of Macrostomida, the monophyly of a "Turbellarian-like" clade, the placement of Rhabditophora, and that of Platyhelminthes relative to the Lophotrochozoa (=Spiralia). The data presented here therefore represent a significant advance in our understanding of platyhelminth phylogeny, and will form the basis of a range of future research in the still-disputed classifications within this taxon. PMID- 29486210 TI - Whole genome sequencing of pairwise human subjects reveals DNA mutations specific to developmental dysplasia of the hip. AB - Developmental dysplasia of the hip (DDH) is a common congenital malformation characterized by mismatch in shape between the femoral head and acetabulum, and leads to hip dysplasia. To date, the pathogenesis of DDH is poorly understood and may involve multiple factors, including genetic predisposition. However, comprehensive genetic analysis has not been applied to investigate a genetic component of DDH. In the present study, 10 pairs of healthy fathers and DDH daughters were enrolled to identify genetic hallmarks of DDH using high throughput whole genome sequencing. The DDH-specific DNA mutations were found in each patient. Overall 1344 genes contained DDH-specific mutations. Functional enrichment analysis showed that these genes played important roles in the cytoskeleton, microtubule cytoskeleton, sarcoplasm and microtubule associated complex. These functions affected osteoblast and osteoclast development. Therefore, we proposed that the DDH-specific mutations might affect bone development, and caused DDH. Our pairwise high throughput sequencing results comprehensively delineated genetic hallmarks of DDH. Further research into the biological impact of these mutations may inform the development of DDH diagnostic tools and allow neonatal gene screening. PMID- 29486211 TI - Compatibility and entry exclusion of IncA and IncC plasmids revisited: IncA and IncC plasmids are compatible. AB - In an early study, IncA and IncC plasmids that were reported to be compatible were grouped as the "A-C complex" based on similarities and on strong entry exclusion. However, recently, the term IncA/C has been used frequently to describe plasmids belonging to both of these two groups. Granted that the supporting data was not included in the original reports and that the consensus iteron sequences have since been shown to be essentially identical, we have addressed the question again. The original IncA plasmid, RA1, and the IncC plasmid pRMH760, were introduced into the same cell by transformation, and were found to be maintained stably for over 100 generations in the absence of selection for either plasmid, i.e. they were compatible. We conclude that use of the term IncA/C for this important plasmid group is indeed incorrect and it causes unnecessary confusion. Granted the importance of IncC plasmids in the spread of antibiotic resistance genes, we recommend that use of the misleading terms IncA/C, IncA/C1 and IncA/C2 should cease. In addition, RA1 and pRMH760 were shown to each completely prevent entry of the other via conjugative transfer into the cell they reside in. PMID- 29486212 TI - Poor interrater reliability of hidradenitis suppurativa phenotypes. PMID- 29486213 TI - Predication of different stages of Alzheimer's disease using neighborhood component analysis and ensemble decision tree. AB - BACKGROUND: There is a spectrum of the progression from healthy control (HC) to mild cognitive impairment (MCI) without conversion to Alzheimer's disease (AD), to MCI with conversion to AD (cMCI), and to AD. This study aims to predict the different disease stages using brain structural information provided by magnetic resonance imaging (MRI) data. NEW METHOD: The neighborhood component analysis (NCA) is applied to select most powerful features for prediction. The ensemble decision tree classifier is built to predict which group the subject belongs to. The best features and model parameters are determined by cross validation of the training data. RESULTS: Our results show that 16 out of a total of 429 features were selected by NCA using 240 training subjects, including MMSE score and structural measures in memory-related regions. The boosting tree model with NCA features can achieve prediction accuracy of 56.25% on 160 test subjects. COMPARISON WITH EXISTING METHOD(S): Principal component analysis (PCA) and sequential feature selection (SFS) are used for feature selection, while support vector machine (SVM) is used for classification. The boosting tree model with NCA features outperforms all other combinations of feature selection and classification methods. CONCLUSIONS: The results suggest that NCA be a better feature selection strategy than PCA and SFS for the data used in this study. Ensemble tree classifier with boosting is more powerful than SVM to predict the subject group. However, more advanced feature selection and classification methods or additional measures besides structural MRI may be needed to improve the prediction performance. PMID- 29486214 TI - Automatic procedures for the synthesis of difficult peptides using oxyma as activating reagent: A comparative study on the use of bases and on different deprotection and agitation conditions. AB - Solid-Phase Peptide Synthesis (SPPS) is a rapid and efficient methodology for the chemical synthesis of peptides and small proteins. However, the assembly of peptide sequences classified as "difficult" poses severe synthetic problems in SPPS for the occurrence of extensive aggregation of growing peptide chains which often leads to synthesis failure. In this framework, we have investigated the impact of different synthetic procedures on the yield and final purity of three well-known "difficult peptides" prepared using oxyma as additive for the coupling steps. In particular, we have comparatively investigated the use of piperidine and morpholine/DBU as deprotection reagents, the addition of DIPEA, collidine and N-methylmorpholine as bases to the coupling reagent. Moreover, the effect of different agitation modalities during the acylation reactions has been investigated. Data obtained represent a step forward in optimizing strategies for the synthesis of "difficult peptides". PMID- 29486215 TI - Hand hygiene and compliance behaviours are the under-appreciated human factors pivotal to reducing hospital-acquired infections. PMID- 29486216 TI - Interoception sensitivity in the parental brain during the first months of parenting modulates children's somatic symptoms six years later: The role of oxytocin. AB - Interoception, the perception and interpretation of one's own bodily signals, is a key aspect of human caregiving that impacts infant health and well-being across life. Interoception relies on limbic structures, mainly the amygdala, and the agranular visceromotor cortex, particularly the anterior insula (AI), that integrate with the oxytocin (OT) system to support interoceptive sensitivity. Here, we used functional magnetic resonance imaging (fMRI) to examine whether interoception sensitivity in the parent's brain during the first months of parenting combines with sensitive parenting and OT-system functionality to predict children's somatic symptoms six years later. We followed 45 primary caregiving first-time mothers and fathers and their infants across the first six years of parenting. In infancy (Time 1), parents' brain response to infant stimuli was imaged, salivary OT measured, and parent-infant interactions coded for parent sensitivity. In preschool (Time 2), parent and child's OT and parent sensitivity were measured again. At six years (Time 3), parents reported on children's somatic symptoms. Greater activation of the parent's AI bilaterally when his/her child was an infant predicted lower child somatic problems at six years. Parent sensitivity partially mediated the links between parental AI activation and child somatic symptoms. In addition, greater parental bilateral amygdala activity predicted higher child OT levels at 3 years and parental OT moderated the relations between preschoolers' OT and later somatic symptoms. Our findings chart two independent cross-generational pathways from interoception sensitivity in the parent's brain and child somatization. The first defines an evolutionary-ancient path including the amygdala and the OT system that support mammalian attention to arousal modulations in response to social cues; the second, via the AI, implicates higher-order interoceptive representations of bodily responses and affective states that underpins human embodiment. PMID- 29486217 TI - Parental hospital-treated somatic illnesses during offspring's childhood associated with later offspring use of psychotropic medication during childhood to young adult - The 1987 Finnish Birth Cohort study. AB - This study aimed to systematically examine whether parental hospital-treated somatic illnesses, diagnosed during an offspring's childhood (1987-1995), are associated with later use of psychotropic medication (1996-2012) by the offspring. If so, which parental somatic illnesses, in particular, increase the likelihood for later use of psychotropic medication among the offspring. The 1987 Finnish Birth Cohort study yields longitudinal nationwide follow-up data that include a complete census of children born in a single year. A total 58,551 offspring are included in this study and, of these 57,752 had a known father. Offspring who had used psychotropic medication between the ages of 9 and 24 years, more often had parents who had experienced a greater number of somatic illnesses when their child was aged under 9, compared to offspring without any use of psychotropic medication. The specific parental somatic illnesses early in life, for example disorders of female tract (OR 1.12, 95%CI 1.01-1.23), pregnancy with abortive outcome (1.18, 1.09-1.28), paternal acute infections (1.20, 1.05 1.38), and paternal symptoms, signs, and ill-defined conditions (1.21, 1.03 1.42), were found to be associated with psychotropic medication treatment using parental-related determinants; death, education, receipt of social assistance and psychiatric inpatient care as covariates. This suggests that these specific parental somatic illnesses can affect psychological well-being of the offspring. Preventive actions and support for the child, should be provided in situations where a parent with a somatic illness has limited ability to care for and rear their child. PMID- 29486218 TI - Cadmium exposure exacerbates hyperlipidemia in cholesterol-overloaded hepatocytes via autophagy dysregulation. AB - Metabolic factors are the major risk of non-alcoholic fatty liver disease, although other factors may contribute steatosis. Cadmium exposure produces histopathological and molecular changes in liver, which are consistent with steatosis. In the present study, we describe the effect of low cadmium acute treatment on hepatocytes obtained from mice fed with a high cholesterol diet. Our data suggest that hepatocytes with cholesterol overload promote an adaptive response against cadmium-induced acute toxicity by up-regulating anti-apoptotic proteins, managing ROS overproduction, increasing GSH synthesis and MT-II content to avoid protein oxidation. Cadmium treatment increases lipid content in cholesterol-fed mice hepatocytes because of an impaired autophagy process. Our data suggest an essential function of macroautophagy in the regulation of lipid storage induced by Cd on hepatocytes, that implies that alterations in this pathway may be a mechanism that aggravates hepatic steatosis. PMID- 29486219 TI - Environmentally relevant manganese overexposure alters neural cell morphology and differentiation in vitro. AB - Manganese (Mn) is a trace metal and micronutrient that is necessary for neurological function. Because of its ability to cross the blood brain barrier, excessive amounts of Mn are neurotoxic and can lead to a neurological disorder, manganism. Environmental overexposure to Mn correlates with impaired cognitive development in children. Though symptoms of manganism and overexposure are well defined, the changes in cellular mechanisms underlying these symptoms are not fully understood. We used cultured adult neural stem cells (NSCs) from young adult rats as an accessible model to investigate the effect of Mn on cellular mechanisms underlying neural differentiation. Concentrations of Mn below current EPA limits caused a dose- and time-dependent collapse of neurites and restructuring of cellular morphology. This effect was confirmed in B35 neuroblastoma cells. These findings indicate that Mn alters cytoskeleton dynamics during differentiation. In addition, Mn overexposure caused downregulation of DCX, a neuronal migration marker, and GFAP, a neural stem cell and astrocyte marker, in NSCs. We conclude that environmentally relevant concentrations of Mn impair cytoskeletal structure and morphology, and may impair differentiation in NSCs. These effects of Mn overexposure on brain cell function could underlie manganism and neurocognitive and developmental defects associated with environmental Mn overexposure. PMID- 29486220 TI - SIRT1 suppresses high glucose and palmitate-induced osteoclast differentiation via deacetylating p66Shc. AB - Findings concerning the role of diabetes mellitus (DM) in osteoclast differentiation are contradictory in vivo and in vitro. Sirtuin 1 (SIRT1) can inhibit RANKL-induced osteoclastogenesis and deacetylate p66Shc suppress its phosphorylation in high glucose (HG)-stimulated human umbilical vein endothelial cells. This study aimed to investigate the role and mechanism of SIRT1 in DM related osteoclast differentiation. Osteoclast precursors were cultured with HG and palmitate (PA), with or without resveratrol/sirtinol. TRAP staining was used to evaluate osteoclast formation. The expression of SIRT1, RANK, RANKL, OPG, NFATc1, TRAP, c-fos, p66Shc, phospho-p66Shc (S36), phospho-NF-kappaBp65 (p-p65), and IkappaB was determined by real-time PCR or western blotting. Lysine acetylation of p66Shc was assayed by immunoprecipitation. Reactive oxygen species (ROS) production was analyzed by DCFH-DA fluorescence. p66Shc siRNA and PDTC were used to confirm the mechanism of SIRT1 in osteoclastogenesis. We found HG and PA enhanced osteoclast differentiation, decreased SIRT1 and OPG expression, and increased levels of RANK, RANKL, NFATc1, TRAP, and c-fos. Upregulation of SIRT1 by resveratrol inhibited HG- and PA-induced osteoclast differentiation, whereas sirtinol further enhanced it. Resveratrol suppressed lysine acetylation and S36 phosphorylation of p66Shc, ROS production, and NF-kappaB activation induced by HG and PA, while sirtinol boosted these processes. p66Shc siRNA abrogated HG- and PA induced ROS production and NF-kappaB activation. In addition, p66Shc siRNA and PDTC greatly suppressed the expression of RANK and RANKL induced by HG and PA. In conclusion, this study confirms the role of DM in osteoclast differentiation in vitro. SIRT1 suppresses HG- and PA-induced osteoclast differentiation via p66Shc/ROS/NF-kappaB signaling. PMID- 29486221 TI - Endogenous H2S resists mitochondria-mediated apoptosis in the adrenal glands via ATP5A1 S-sulfhydration in male mice. AB - In a previous study, we showed that endogenous hydrogen sulfide (H2S) plays a key role in the maintenance of intact adrenal cortex function via the protection of mitochondrial function during endoxemia. We further investigated whether mitochondria-mediated apoptosis is involved in H2S protection of adrenal function. LPS treatment resulted in mitochondria-mediated apoptosis in the adrenal glands of male mice, and these effects were prevented by the H2S donor GYY4137. In the model of Y1 cells, the LPS-induced mitochondria-mediated apoptosis and blunt response to ACTH were rescued by GYY4137. The H2S-generating enzyme cystathionine-beta-synthase (CBS) knockout heterozygous (CBS+/-) mice showed mitochondria-mediated apoptosis in the adrenal gland and adrenal insufficiency. GYY4137 treatment restored adrenal function and eliminated mitochondria-mediated apoptosis. Maleimide assay combined with mass spectrometry analysis showed that a number of proteins in mitochondria were S-sulfhydrated in the adrenal gland. ATP5A1 was further confirmed as S-sulfhydrated using a modified biotin switch assay. The level of S-sulfhydrated ATP5A1 was decreased in the adrenal gland of endotoxemic and CBS+/- mice, which was restored by GYY4137. ATP5A1 was identified as sulfhydrated at cysteine 244 by H2S. Overexpression of the cysteine 244 mutant ATP5A1 in Y1 cells resulted in a loss of LPS-induced mitochondria-mediated apoptosis and GYY4137 restoration of LPS-induced hyporesponsiveness to ACTH. Collectively, the present study revealed that decreased H2S generation leads to mitochondrial-mediated apoptosis in the adrenal cortex and a blunt response to ACTH. S-sulfhydration of ATP5A1 at cysteine 244 is an important molecular mechanism by which H2S maintains mitochondrial function and steroidogenesis in the adrenal glands. PMID- 29486223 TI - Exposure of human neurons to silver nanoparticles induces similar pattern of ABC transporters gene expression as differentiation: Study on proliferating and post mitotic LUHMES cells. AB - The Lund human mesencephalic (LUHMES) cell line originated from mesencephalon of 8-week human foetus is a renowned in vitro model of human dopaminergic neurons. After differentiation the cells exhibit dopaminergic and neuronal characteristics of biochemically and morphologically mature dopamine-like neurons. In this study we analysed expression of 42 genes from ABC transporter superfamily in both proliferating cells and differentiated neurons after treatment with silver nanoparticles. ABC transporter superfamily is especially known due to the involvement in multidrug resistance phenomenon, but also involvement in transport through blood-brain barrier. Our results indicate that in neurons silver nanoparticles mainly attenuate transporters responsible for maintaining asymmetry of cellular membrane and homeostasis of lipids and cholesterol. Our results revealed also that proliferating foetal brain cells are by far more susceptible to silver nanoparticles than differentiated neurons. PMID- 29486224 TI - Fairness, fast and slow: A review of dual process models of fairness. AB - Fairness, the notion that people deserve or have rights to certain resources or kinds of treatment, is a fundamental dimension of moral cognition. Drawing on recent evidence from economics, psychology, and neuroscience, we ask whether self interest is always intuitive, requiring self-control to override with reasoning based fairness concerns, or whether fairness itself can be intuitive. While we find strong support for rejecting the notion that self-interest is always intuitive, the literature has reached conflicting conclusions about the neurocognitive systems underpinning fairness. We propose that this disagreement can largely be resolved in light of an extended Social Heuristics Hypothesis. Divergent findings may be attributed to the interpretation of behavioral effects of ego depletion or neurostimulation, reverse inference from brain activity to the underlying psychological process, and insensitivity to social context and inter-individual differences. To better dissect the neurobiological basis of fairness, we outline how future research should embrace cross-disciplinary methods that combine psychological manipulations with neuroimaging, and that can probe inter-individual, and cultural heterogeneities. PMID- 29486222 TI - Naltrexone alters alcohol self-administration behaviors and hypothalamic pituitary-adrenal axis activity in a sex-dependent manner in rats. AB - BACKGROUND: The mu-opioid antagonist, naltrexone (NTX), is a FDA-approved treatment for alcohol use disorder (AUD); however, the data on whether it differentially affects males vs. females are mixed. NTX increases hypothalamic pituitary-adrenal (HPA) axis activity that associates with subjective responses to alcohol and craving in individuals with AUD. The present study tested for sex differences in the ability of NTX to decrease appetitive and consummatory behaviors in rats in operant alcohol self-administration. Because the opioid system and HPA axis are sexually dimorphic, we examined NTX's effect on adrenocorticotropic hormone (ACTH) and corticosterone (CORT) levels. METHODS: Male and female Sprague-Dawley rats (n's = 6-8) were trained to lever press for alcohol (10% v/v) under a fixed-ratio 2 schedule of reinforcement. NTX doses (0, 0.1-10 mg/kg) were assessed in tests conducted under a progressive ratio schedule of reinforcement. Separate groups of alcohol and water drinking rats (n's = 8) were used to assess NTX's (10 mg/kg) effects on HPA axis hormones. RESULTS: NTX decreased consummatory behaviors for alcohol in a dose-related manner, but not appetitive behaviors in males. In females, NTX decreased appetitive behaviors for alcohol in a dose-dependent manner, but only decreased consummatory behaviors at the highest (10 mg/kg) NTX dose. NTX increased ACTH levels in alcohol drinking females in diestrus, but not in other groups. However, NTX increased CORT levels for longer durations in alcohol drinking males relative to alcohol drinking females in diestrus. CONCLUSIONS: Our findings suggest that NTX selectively reduces consummatory behaviors for alcohol in males and appetitive behaviors in females, while also showing differential sex effects on HPA hormones. PMID- 29486225 TI - Comparison of a newly developed binary typing with ribotyping and multilocus sequence typing methods for Clostridium difficile. AB - Clostridium difficile is the causative pathogen for antibiotic-related nosocomial diarrhea. For epidemiological study and identification of virulent clones, a new binary typing method was developed for C. difficile in this study. The usefulness of this newly developed optimized 10-loci binary typing method was compared with two widely used methods ribotyping and multilocus sequence typing (MLST) in 189 C. difficile samples. The binary typing, ribotyping and MLST typed the samples into 53 binary types (BTs), 26 ribotypes (RTs), and 33 MLST sequence types (STs), respectively. The typing ability of the binary method was better than that of either ribotyping or MLST expressed in Simpson Index (SI) at 0.937, 0.892 and 0.859, respectively. The ease of testing, portability and cost-effectiveness of the new binary typing would make it a useful typing alternative for outbreak investigations within healthcare facilities and epidemiological research. PMID- 29486226 TI - Detection of different classes of carbapenemases: Adaptation and assessment of a phenotypic method applied to Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii, and proposal of a new algorithm. AB - A new phenotypic method for detecting carbapenemases has been adapted (assembling of two MAST(r) kits, including one that contains faropenem to which a temocillin disk has been added) then assessed using 101 bacterial strains (Enterobacteriaceae with assays on Pseudomonas aeruginosa and Acinetobacter baumannii) including 62 which produce genetically identified carbapenemases. Concerning Carbapenemase-Producing Enterobacteriaceae (CPE), there is 100% sensitivity for Klebsiella pneumoniae carbapenemase (KPC, Ambler class A) and OXA 48 (Ambler class D), and 91% for metallo-beta-lactamase (MBL, Ambler class B), with a 97% sensitivity for all carbapenemases, with a specificity of 100%. The test is also efficient for detecting Pseudomonas aeruginosa carbapenemases (sensitivity between 82 and 100% and 100% specificity). The major innovation is the combined use of faropenem and temocillin for reliable detection (excellent performance with 100% sensitivity and specificity) of OXA-48. This study has led to the development of a new algorithm to detect the different classes of carbapenemases, for first-line diagnosis, by combining this modified MAST(r) test with immunochromatographic methods and molecular biology techniques. PMID- 29486227 TI - Influence of working memory and executive function on stair ascent and descent in young and older adults. AB - This study assessed the influence of attention division, working memory and executive function on stair ascent and descent in young and older adults. Twenty young (25.5 +/- 2.1 yrs) and 20 older adults (68.4 +/- 5.4 yrs) ascended and descended a 3-step staircase with no simultaneous cognitive task (single-motor task) or while performing a cognitive task (dual-task condition). The cognitive task involved either 1) recalling a word list of the subject's word-span minus 2 words (SPAN-2) to assess the attention division effect, 2) a word list of subject's word-span (SPAN-O) to assess the working memory effect, or 3) recalling in alphabetical order, a word list of the subject's word-span (SPAN-A) to assess the executive function effect. Word-span corresponds to the longest string of words that can be recalled correctly. The duration of ascent and descent of stairs was used to assess the cognitive-motor interaction. Stair ascent and descent duration did not differ between age groups for the single-motor task, and was similar between single-motor task and SPAN-2 in both groups (p > 0.05). In contrast, stair ascent and descent duration increased with SPAN-O compared with SPAN-2 for both groups (p < 0.01). Stair ascent (p = 0.017) and descent (p = 0.008) were longer in SPAN-A than SPAN-O only in older adults. Healthy aging was not associated with a decrease in the capacity to perform motor-cognitive dual tasks that involved ascending and descending of stairs when the cognitive task only required working memory. However, the decrease in dual-task performance involving executive functioning may reflect a subclinical cognitive decline in healthy older adults. PMID- 29486229 TI - Epigenome analysis links gene regulatory elements in group 2 innate lymphocytes to asthma susceptibility. AB - BACKGROUND: Group 2 innate lymphoid cells (ILC2s) are major producers of the cytokines driving allergic asthma, and increased ILC2 numbers have been detected in blood and sputum of asthmatic patients. Asthma susceptibility has a strong genetic component, but the underlying mechanisms and whether asthma genetics affect ILC2 biology remain unclear. OBJECTIVE: We sought to study the ILC2 transcriptome and epigenome during airway inflammation (AI) to couple these to genes and genetic variants associated with asthma pathogenesis. METHODS: Mice harboring a reporter for the key ILC2 transcription factor GATA-3 were subjected to IL-33-driven AI, and ILC2s were isolated from bronchoalveolar lavage fluid and mediastinal lymph nodes. Human ILC2s were purified from peripheral blood and activated in vitro. We used RNA sequencing, genome-wide identification of histone 3 lysine-4 dimethylation-marked chromatin, and computational approaches to study the ILC2 transcriptome and epigenome. RESULTS: Activated ILC2s in mice displayed a tissue-specific gene expression signature that emerged from remarkably similar epigenomes. We identified superenhancers implicated in controlling ILC2 identity and asthma-associated genes. More than 300 asthma-associated genetic polymorphisms identified in genome-wide association studies localized to H3K4Me2+ gene regulatory elements in ILC2s. A refined set of candidate causal asthma associated variants was uniquely enriched in ILC2, but not TH2 cell, regulatory regions. CONCLUSIONS: ILC2s in AI use a flexible epigenome that couples adaptation to new microenvironments with functional plasticity. Importantly, we reveal strong correlations between gene regulatory mechanisms in ILC2s and the genetic basis of asthma, supporting a pathogenic role for ILC2s in patients with allergic asthma. PMID- 29486228 TI - Long term rapamycin treatment improves mitochondrial DNA quality in aging mice. AB - Age-induced mitochondrial DNA deletion mutations may underlie cell loss and tissue aging. Rapamycin extends mouse lifespan and modulates mitochondrial quality control. We hypothesized that reduced deletion mutation abundance may contribute to rapamycin's life extension effects. To test this hypothesis, genetically heterogeneous male and female mice were treated with rapamycin, compounded in chow at 14 or 42 ppm, from 9 months to 22 months of age. Mice under a 40% dietary restriction were included as a control known to protect mtDNA quality. To determine if chronic rapamycin treatment affects mitochondrial DNA quality, we assayed mtDNA deletion frequency and electron transport chain deficient fiber abundances in mouse quadriceps muscle. At 42 ppm rapamycin, we observed a 57% decrease in deletion frequency, a 2.8-fold decrease in ETC deficient fibers, and a 3.4-fold increase in the number of mice without electron transport chain deficient fibers. We observed a similar trend with the 14 ppm dose. DR significantly decreased ETC deficient fiber abundances with a trend toward lower mtDNA deletion frequency. The effects of rapamycin treatment on mitochondrial DNA quality were greatest in females at the highest dose. Rapamycin treatment at 14 ppm did not affect muscle mass or function. Dietary restriction also reduced deletion frequency and ETC deficient fibers. These data support the concept that the lifespan extending effects of rapamycin treatment result from enhanced mitochondrial DNA quality. PMID- 29486230 TI - Endovascular Iliocaval Stent Reconstruction for Iliocaval Thrombosis: A Multi Institutional International Practice Pattern Survey. AB - BACKGROUND: Limited guidelines for the treatment and management of acute and chronic iliocaval thrombosis are published in the literature. The purpose of this report is to present global iliocaval stent reconstruction practices by interventionalists. METHODS: A 45-question survey focusing on iliocaval stent reconstruction evaluation was distributed through the Open Forum and Venous Disease Service Line of the Society of Interventional Radiology Connect website from June 20, 2017 until September 7, 2017 and the Cardiovascular and Interventional Radiological Society of Europe electronic newsletter on August 11, 2017. RESULTS: One hundred seven complete responses were received from interventional radiologists in the United States, 2 from South America, and 2 from Central America. 92.5% performed iliocaval reconstruction, and 79.8% performed the procedure for both acute and chronic iliocaval thrombosis. 82.8% completed a standardized physician assessment tool, and 91.9% obtained computed tomography (CT) venography before the procedure. 64.6% used intravascular ultrasound to guide reconstruction. 41.4% found blunt recanalization successful for >75% of patients. 63.6% used sharp recanalization for <25% of patients. 97.0% and 90.9% used uncovered and self-expanding stents, respectively. Wallstents were used most commonly. Most common stent diameters were 24-mm in the inferior vena cava, 14-mm in the common iliac vein, and 12-mm in the external iliac vein. 48.5% and 21.2% prescribed 2 and 3 anticoagulants after stent placement, respectively. 62.6% found iliocaval reconstruction provided symptomatic clinical improvement for iliocaval thrombosis in >75% of patients. 72.7% estimated their 1-year primary stent patency to be >75%. CONCLUSIONS: Iliocaval reconstruction is performed by many interventionalists; however, there are global inconsistencies in practices, suggesting a need for further research and guideline development. PMID- 29486231 TI - Recent Trends in Publications of US and European Directors in Vascular Surgery. AB - BACKGROUND: We hypothesized that there may be significant differences between academic productivity of the vascular training programs in the United States (US) and Europe. In an effort to explore this theory, we reviewed the number of vascular publications listed in PubMed from 2010 to 2015 for US and European directors in vascular surgery. METHODS: The list of program directors from the Association of Program Directors in Vascular Surgery (APDVS) and the European Union of Medical Specialists (EUMS) were queried for the names of the directors of vascular surgical training programs at the end of 2015. PubMed listed 5,474 citations published from 2010 to 2015. Three thousand five hundred sixty-one were from Europe while 1,912 were from the US. UK and German programs did not list their directors' names in the EUMS website and were thus not included in the European data. RESULTS: The average number of citations in PubMed per program director was 2.36 per year. In Europe, each of the 273 program directors averaged 2.17 publications per year, whereas each of the 114 US program directors averaged 2.80 publications per year (P = 0.37). Journal of Vascular Surgery (JVS) publications made up 24.0% (12.7% in Europe and 45.0% in the US). In the US, the top third produced 69% of the publications and 77% of the JVS publications, whereas in Europe, the top third produced 87% of the publications and 98% of the JVS publications. In the US, 5 program directors (4.4%) had no publications and 21 (18.4%) had no JVS publications. In Europe, 82 program directors (30.0%) had no publications, whereas 180 (65.9%) had no JVS publications. Abstracts were categorized by topic for comparison. CONCLUSIONS: In both Europe and the US, the top third produced more than two-thirds of the publications, with the disparity being even more pronounced in Europe where the top third produced almost 90% of the total publications. Comparing the topics of the publications from Europe and the US, it was found that the US program directors published a great deal more on Endovenous Lower Extremity, Open Lower Extremity, Education, thoracic endovascular aortic repair, Open Carotid, and Endo Venous, whereas their European counterparts published more in the areas of Vascular Medicine, Replies, and Not Vascular. PMID- 29486232 TI - Immunization with intestinal microbiota-derived Staphylococcus aureus and Escherichia coli reduces bacteria-specific recolonization of the intestinal tract. AB - A wide array of microorganisms colonizes distinctive anatomical regions of animals, being the intestine the one that harbors the most abundant and complex microbiota. Phylogenetic analyses indicate that it is composed mainly of bacteria, and that Bacterioidetes and Firmicutes are the most represented phyla (>90% of the total eubacteria) in mice and humans. Intestinal microbiota plays an important role in host physiology, contributing to digestion, epithelial cells metabolism, stimulation of intestinal immune responses, and protection against intestinal pathogens. Changes in its composition may affect intestinal homeostasis, a condition known as dysbiosis, which may lead to non-specific inflammation and disease. The aim of this work was to analyze the effect that a bacteria-specific systemic immune response would have on the intestinal re colonization by that particular bacterium. Bacteria were isolated and identified from the feces of Balb/c mice, bacterial cell-free extracts were used to immunize the same mice from which bacteria came from. Concurrently with immunization, mice were subjected to a previously described antibiotic-based protocol to eliminate most of their intestinal bacteria. Serum IgG and feces IgA, specific for the immunizing bacteria were determined. After antibiotic treatment was suspended, specific bacteria were orally administered, in an attempt to specifically re colonize the intestine. Results showed that parenteral immunization with gut derived bacteria elicited the production of both anti-bacterial IgG and IgA, and that immunization reduces bacteria specific recolonization of the gut. These findings support the idea that the systemic immune response may, at least in part, determine the bacterial composition of the gut. PMID- 29486234 TI - Detached and distracted: ERP correlates of altered attentional function in depersonalisation. AB - Depersonalisation (DP) is a psychological condition marked by feelings of disembodiment. In everyday life, it is frequently associated with concentration problems. The present study used visual event-related potentials (ERPs) in a Posner-type spatial cueing task with valid, invalid and spatially neutral cues to delineate the potential neurophysiological correlates of these concentration problems. Altered attentional functioning at early, sensory stages was found in DP patients but not in anxiety- and depression-matched psychosomatic patients without DP. Specifically, DP was associated with decreased suppression of stimuli at unattended locations, shown as absent processing costs for invalidly versus neutrally cued stimuli over P1 (135-150 ms). Attentional benefits at N1, and all attentional effects at later, cognitive processing stages (P2-N2, P3) were similar in both groups. We propose that this insufficient early suppression of unattended stimuli may result from atypical sensory gain control in DP. PMID- 29486233 TI - Polymyxin B and fosfomycin thwart KPC-producing Klebsiella pneumoniae in the hollow-fibre infection model. AB - Polymyxin B (PMB) and fosfomycin are two 'old' antibiotics that consistently maintain activity against Klebsiella pneumoniae carbapenemase (KPC)-producing organisms based on in vitro susceptibility testing. However, the use of each antibiotic in monotherapy has been associated with high rates of treatment failure. Therefore, the objective of this study was to investigate the combinatorial pharmacodynamics of PMB and fosfomycin against KPC-producing K. pneumoniae (KPC-Kp). PMB front-loading (3.33 mg/kg for one dose, followed by 1.43 mg/kg every 12 h starting 12 h later) and burst (5.53 mg/kg for one dose, with no subsequent doses) simulated dosing regimens were explored in combination with fosfomycin (4 g every 8 h) against KPC-2-producing K. pneumoniae ST258 in a hollow-fibre infection model over 120 h. Population analysis profiles were used to track the temporal PMB and fosfomycin resistance profiles. Against isolate KPC Kp 9A (PMB MIC = 0.5 mg/L; fosfomycin MIC <= 8 mg/L), monotherapies resulted in >3 log10 CFU/mL killing within 3 h but re-growth and proliferation of resistant subpopulations within 48 h. PMB combinations with fosfomycin demonstrated rapid bacterial killing (>6 log10 CFU/mL reductions) while preventing propagation of PMB and fosfomycin resistance. Against isolate KPC-Kp 24A with a higher fosfomycin MIC (polymyxin B MIC = 0.5 mg/L; fosfomycin MIC = 32 mg/L), a PMB burst and fosfomycin combination caused a >6 log10 CFU/mL reduction within 1 h, although bacterial re-growth occurred with the amplification of fosfomycin resistant subpopulations. PMB in combination with fosfomycin may provide a practicable treatment strategy against KPC-Kp and warrants further investigation. PMID- 29486235 TI - Frightened by the perpetrator's voice: Startle responsivity and cognitive processing predict earwitness speaker identification. AB - This study was inspired by the case of a robbery victim who was startled and reminded of the crime upon hearing a stranger's voice, while not clearly recognizing the speaker. To investigate whether specific voices can modulate startle reactions and thereby predict speaker identification, we presented an audio hijack scenario to 84 participants and afterwards asked them to identify the perpetrator among neutral and negative speech fragments, while measuring flash-evoked eye-blink startle responses. Furthermore, we addressed data-driven cognitive processing during the audio scenario as a potential moderator in voice discrimination. Negative speech and the perpetrator's voice led to potentiated startle. Enhanced startle was positively associated with voice discrimination, but only in neutral speech fragments. In negative fragments, this association was weakened as a function of self-reported levels of data-driven processing during encoding. Thus, startle responses can generally predict accurate voice recognition, but speech emotionality and cognitive processing moderate this relationship. PMID- 29486236 TI - Unconventional protein secretion triggered by nutrient starvation. AB - It is usually assumed that eukaryotic cells secrete only proteins that contain a signal sequence for Sec61 mediated translocation into the lumen of endoplasmic reticulum (ER). Surprisingly however, many proteins, such as superoxide dismutase (SOD)1, acyl-CoA binding protein (Acb1), interleukin 1beta, fibroblast growth factor 2 and the adipokine Unpaired2, to name a few, are secreted even though they lack a signal sequence. The discovery that these proteins are secreted has presented a new challenge and we describe here a common pathway by which SOD1 and Acb1 are specifically secreted upon nutrient starvation. Their secretion follows a type III unconventional pathway, requiring the exposure of a di-acidic motif, which we propose promotes their capture into a membrane compartment called CUPS (compartment for unconventional protein secretion). We suggest that CUPS, composed of membranes derived from the Golgi apparatus and endosomes, serves as a major sorting station prior to release of SOD1 and Acb1 into the extracellular space. The trafficking of these signal sequence lacking proteins therefore has functional similarities to conventional protein secretion in that they rely on membrane bounded compartments for their sorting and transport, but bypass the need of Sec61 for translocating into the ER and COPII and COPI for their intracellular transfers. This review is part of a Special Issue of SCDB on "unconventional protein secretion" edited by Walter Nickel and Catherine Rabouille. PMID- 29486237 TI - Evolution of Trichobaris (Curculionidae) in relation to host plants: Geometric morphometrics, phylogeny and phylogeography. AB - The family Curculionidae (Coleoptera), the "true" weevils, have diversified tightly linked to the evolution of flowering plants. Here, we aim to assess diversification at a lower taxonomic level. We analyze the evolution of the genus Trichobaris in association with their host plants. Trichobaris comprises eight to thirteen species; their larvae feed inside the fruits of Datura spp. or inside the stem of wild and cultivated species of Solanaceae, such as potato, tobacco and tomato. We ask the following questions: (1) does the rostrum of Trichobaris species evolve according to the plant tissue used to oviposit, i.e., shorter rostrum to dig in stems and longer to dig in fruits? and (2) does Trichobaris diversify mainly in relation to the use of Datura species? For the first question, we estimated the phylogeny of Trichobaris based on four gene sequences (nuclear 18S and 28S rRNA genes and mitochondrial 16S rRNA and COI genes). Then, we carried out morphogeometric analyses of the Trichobaris species using 75 landmarks. For the second question, we calibrated a COI haplotype phylogeny using a constant rate of divergence to infer the diversification time of Trichobaris species, and we traced the host plant species on the haplotype network. We performed an ancestral state reconstruction analysis to infer recent colonization events and conserved associations with host plant species. We found that ancestral species in the Trichobaris phylogeny use the stem of Solanum plants for oviposition and display weak sexual dimorphism of rostrum size, whereas other, more recent species of Trichobaris display sexual dimorphism in rostrum size and use the fruits of Datura species, and a possible reversion to use the stem of Solanaceae was detected in one Trichobaris species. The use of Datura species by Trichobaris species is widely distributed on haplotype networks and restricted to Trichobaris species that originated ca. 5 +/- 1.5 Ma. Given that the origin of Trichobaris is estimated to be ca. 6 +/- 1.5 Ma, it is likely that Datura has played a role in its diversification. PMID- 29486238 TI - Perspectives of a most pestilent past. PMID- 29486240 TI - Under-diagnosis of rickettsial disease in clinical practice: A systematic review. AB - BACKGROUND: Rickettsial diseases present as acute febrile illnesses, sometimes with inoculation eschars. METHODS: We performed a systematic review of studies published between 1997 and 2017 to assess the underestimation of non-eschar rickettsial disease (NERD) relative to eschar rickettsial disease (ERD), as a cause of acute fever in patients with rickettsial diseases that commonly present with eschar(s): scrub typhus (ST), Mediterranean spotted fever (MSF), and African tick-bite fever. We compared ERD/NERD ratios according to study design: 'complete approach' studies, with testing performed in all patients with 'unspecified febrile illness'; versus 'clinical judgement' studies, with testing performed if patients presented with specific symptoms. RESULTS: In 'complete approach' studies, ERD/NERD ratios were significantly lower, suggesting a considerable under-diagnosis of NERD in 'clinical judgement' studies. Based on these results, we estimate that the diagnosis of rickettsial disease was missed in 66.5% of patients with ST, and in 57.9% of patients with MSF. CONCLUSIONS: Study design influences the reported eschar rates in ST and MSF significantly. NERD is likely to be a vastly underdiagnosed entity, and clinicians should consider and test for the disease more often. PROSPERO REGISTRATION NUMBER: CRD 42016053348. PMID- 29486239 TI - A detailed cell-free transcription-translation-based assay to decipher CRISPR protospacer-adjacent motifs. AB - The RNA-guided nucleases derived from the CRISPR-Cas systems in bacteria and archaea have found numerous applications in biotechnology, including genome editing, imaging, and gene regulation. However, the discovery of novel Cas nucleases has outpaced their characterization and subsequent exploitation. A key step in characterizing Cas nucleases is determining which protospacer-adjacent motif (PAM) sequences they recognize. Here, we report advances to an in vitro method based on an E. coli cell-free transcription-translation system (TXTL) to rapidly elucidate PAMs recognized by Cas nucleases. The method obviates the need for cloning Cas nucleases or gRNAs, does not require the purification of protein or RNA, and can be performed in less than a day. To advance our previously published method, we incorporated an internal GFP cleavage control to assess the extent of library cleavage as well as Sanger sequencing of the cleaved library to assess PAM depletion prior to next-generation sequencing. We also detail the methods needed to construct all relevant DNA constructs, and how to troubleshoot the assay. We finally demonstrate the technique by determining PAM sequences recognized by the Neisseria meningitidis Cas9, revealing subtle sequence requirements of this highly specific PAM. The overall method offers a rapid means to identify PAMs recognized by diverse CRISPR nucleases, with the potential to greatly accelerate our ability to characterize and harness novel CRISPR nucleases across their many uses. PMID- 29486241 TI - Clinical outcomes and satisfaction with a pharmacist-managed travel clinic in Alberta, Canada. AB - BACKGROUND: In Alberta, Canada, authorized pharmacists may prescribe medications and vaccines and administer injections. Some have implemented travel clinics to meet the growing demand for pre-travel consultations. As a new service, the outcomes of independent pharmacist-performed pre-travel consultations is unknown. METHODS: Chart review and post-travel surveys were performed among a convenience sample of patients presenting to a pharmacist-managed travel clinic for consultation. Data collected included patients' travel plans, recommendations for vaccines and other prescription and non-prescription drugs and adherence to these recommendations, satisfaction with the service, and health issues experienced during travel. RESULTS: 103 patients participated in the study. The overwhelming majority (79%) of recommended vaccinations were administered in clinic. The post travel questionnaire was completed by 76% of patients, with 94% of these reporting being satisfied or very satisfied with the care received. Health issues during travel were infrequent, with gastrointestinal illness most common. Of those patients who experienced any health issue during their trip, 93% felt adequately prepared to manage the condition. CONCLUSIONS: This study reports positive patient satisfaction and health status while travelling following a pharmacist-performed pre-travel consultation including authorization to prescribe and to administer vaccines. These results support the continued expansion of pharmacists' scope in this area. PMID- 29486242 TI - Utility of CBCT for the measurement of palatal bone thickness. AB - INTRODUCTION: The palate is an alternative anchoring site for orthodontic implants. Adequate bone at mini-implant placement site can influence the success or failure of anchorage. Hence, it is imperative to measure the thickness of the palatal bone. MATERIALS AND METHODS: CBCT scans of 30 subjects in the age range of 12 to 28 years were retrospectively analyzed with the objective of measuring the palatal bone thickness. Thirty sites were identified on each CBCT scan with incisive foramen as a landmark and measurements were obtained anteroposteriorly as well as mediolaterally, using Carestream 3D imaging software. The data collected was analyzed using one-way ANOVA. RESULTS: Statistical analysis revealed higher palatal bone thickness at the median and paramedian regions of anterior palate, 4mm and 8mm distal to incisive foramen. CONCLUSION: CBCT is an ideal modality for measuring palatal bone thickness and can be utilized for locating the ideal site for placement of orthodontic mini-implants. PMID- 29486243 TI - MadMax meeting in Paris, 8th February 2018. PMID- 29486244 TI - Surgery for lung tumors in the elderly: A retrospective cohort study on the influence of advanced age (over 80 years) on the development of complications by using a multivariate risk model. AB - BACKGROUND: The prevalence of lung cancer and other tumors is increasing among the elderly people. The purpose of this study was to examine the influence of advanced age (80 + years) on the immediate perioperative outcome as well as to define potential risk factors that may lead to increasing morbidity and mortality after lung resections. METHODS: A retrospective cohort analysis of the data from an electronic database of 208 elderly patients (165 patients >=70 years, 45 patients >=80 years) undergoing pulmonary anatomical resection for lung tumors during January 2013-December 2016 was conducted. The patients were initially observed and then divided into two groups: septuagenarians and octogenarians. The risk of developing postoperative complications in association with the numerous observed factors, which appeared significant in univariate tests, was assessed using univariate and multivariate logistic regression analyses to construct a risk model that assesses the highest chance of developing complications. Readmission rate and mortality within 90 days were recorded. RESULTS: There were 140 men and 68 women with the mean age of 76 +/- 4 years. A total of 15 pneumonectomies (7.2%), 11 bilobectomies (5.3%), 27 segmentectomies (13%), and 155 lobectomies (74.5%) were performed through 84 thoracotomies (40.4%) and 124 video-assisted thoracoscopic surgery (VATS) procedures (59.6%). Ninety-one patients (44%) exhibited at least one of 113 postoperative complications. There were four deaths (1.9%). Readmission rate was 12%, and 90-day mortality was 5.3%. There was no difference in postoperative morbidity among the groups according to their age (RR = 0.95; p = 78). According to multivariate logistic regression, adjusted Charlson Comorbidity Index>=11, FEV1<=0.72, DLCO<=0.57, male gender, and nonsegmentectomies appeared to be strong predictors for the development of complications. CONCLUSIONS: In this cohort, age more than 80 years was not found to be significant for the development of complications, when compared to the septuagenarians. Female gender, better lung function (FEV1>72%, DLCO>57%), less comorbidities (ACCI<11), and segmentectomy type of lung resection were associated with improved outcomes. PMID- 29486245 TI - Organellar transcriptome sequencing reveals mitochondrial localization of nuclear encoded transcripts. AB - Mitochondria are organelles involved in a variety of biological functions in the cell, apart from their principal role in generation of ATP, the cellular currency of energy. The mitochondria, in spite of being compact organelles, are capable of performing complex biological functions largely because of the ability to exchange proteins, RNA, chemical metabolites and other biomolecules between cellular compartments. A close network of biomolecular interactions are known to modulate the crosstalk between the mitochondria and the nuclear genome. Apart from the small repertoire of genes encoded by the mitochondrial genome, it is now known that the functionality of the organelle is highly reliant on a number of proteins encoded by the nuclear genome, which localize to the mitochondria. With exceptions to a few anecdotal examples, the transcripts that have the potential to localize to the mitochondria have been poorly studied. We used a deep sequencing approach to identify transcripts encoded by the nuclear genome which localize to the mitoplast in a zebrafish model. We prioritized 292 candidate transcripts of nuclear origin that are potentially localized to the mitochondrial matrix. We experimentally demonstrated that the transcript encoding the nuclear encoded ribosomal protein 11 (Rpl11) localizes to the mitochondria. This study represents a comprehensive analysis of the mitochondrial localization of nuclear encoded transcripts. Our analysis has provided insights into a new layer of biomolecular pathways modulating mitochondrial-nuclear cross-talk. This provides a starting point towards understanding the role of nuclear encoded transcripts that localize to mitochondria and their influence on mitochondrial function. PMID- 29486246 TI - The DNA methylation status of MyoD and IGF-I genes are correlated with muscle growth during different developmental stages of Japanese flounder (Paralichthys olivaceus). AB - Many genes related to muscle growth modulate myoblast proliferation and differentiation and promote muscle hypertrophy. MyoD is a myogenic determinant that contributes to myoblast determination, and insulin-like growth factor 1 (IGF I) interacts with MyoD to regulate muscle hypertrophy and muscle mass. In this study, we aimed to assess DNA methylation and mRNA expression patterns of MyoD and IGF-I during different developmental stages of Japanese flounder, and to examine the relationship between MyoD and IGF-I gene. DNA and RNA were extracted from muscles, and DNA methylation of MyoD and IGF-I promoter and exons was detected by bisulfite sequencing. The relative expression of MyoD and IGF-I was measured by quantitative polymerase chain reaction. IGF-I was measured by radioimmunoassay. Interestingly, the lowest expression of MyoD and IGF-I emerged at larva stage, and the mRNA expression was negatively associated with methylation. We hypothesized that many skeletal muscle were required to complete metamorphosis; thus, the expression levels of MyoD and IGF-I genes increased from larva stage and then decreased. The relative expression levels of MyoD and IGF-I exhibited similar patterns, suggesting that MyoD and IGF-I regulated muscle growth through combined effects. Changes in the concentrations of IGF-I hormone were similar to those of IGF-I gene expression. Our results the mechanism through which MyoD and IGF-I regulate muscle development and demonstrated that MyoD interacted with IGF-I to regulate muscle growth during different developmental stages. PMID- 29486247 TI - Nanomaterial bio-activation and macromolecules functionalization: The search for reliable protocols. AB - The possibility of successfully applying nanomaterials such as biosensors or nanoparticles in diagnostics and therapy is critically dependent on the capacity to optimize their target recognition selectivity and their ability to be delivered minimizing off-side accumulation. Biological macromolecules possess the necessary specificity and for this reason have been often coupled to nanomaterials. However, such process is not straightforward because it often induces structural alterations of the involved macromolecules, in most of the cases proteins or antibodies the functions of which can be hampered when single amino acids are modified. Several strategies have been proposed to rationalize the methodology of macromolecule functionalization with reactive groups and tags that should improve the nanomaterial bio-activation in terms of final yields, process simplicity and reproducibility, and cost-efficiency. This review will describe the features of both chemical and enzymatic reactions exploited to activate polypeptide residues as well as some of the strategies suitable for preparing recombinant proteins fused to tags directly accessible for nanomaterial modification. PMID- 29486248 TI - Recombinant protein of the first two ectodomains of cadherin 23 from erl mice shows impairment in Ca2+-dependent proteolysis protection. AB - The erl mouse is a mouse model of nonsyndromic autosomal recessive deafness (DFNB12) on the C57BL/6J background. This project was carried out to express the first two ectodomains of cadherin 23 (CDH23 EC1+2) of erl mice in Escherichia coli and identify the Ca2+-binding ability of the recombinant protein. DNA sequences of CDH23 EC1+2 from wild type and erl mice were synthesized and cloned into pBV220 plasmids. Recombinant plasmids were transformed into Escherichia coli and expression of CDH23 EC1+2 was induced by increasing the temperature from 30 degrees C to 42 degrees C. The proteins were analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and antigenicity of proteins was identified by Western Blotting. Inclusion bodies were denatured in 8 M urea, purified by ion-exchange and gel filtration chromatography and refolded with dialysis in buffer containing 0.1% sarkosyl. The Ca2+-binding ability of CDH23 EC1+2 was determined by Ca2+-dependent proteolysis protection. The results showed that the sizes and sequences of inserts in recombinant plasmids were consistent with expectation and that the recombinant proteins were found mainly in the form of inclusion bodies which maintain antigenicity. After refolding, the secondary structures of recombinant proteins were measured by circular dichroism (CD) spectra. Moreover, CDH23 EC1+2 from the erl mice showed less Ca2+-dependent proteolysis protection comparing with that of the wild type control. We therefore concluded that impairment of Ca2+-dependent protein interaction was likely involved in the progressive hearing loss in erl mice. The results may aid in understanding the mechanism of hearing loss in DFNB12. PMID- 29486249 TI - Exploring applications of crowdsourcing to cryo-EM. AB - Extraction of particles from cryo-electron microscopy (cryo-EM) micrographs is a crucial step in processing single-particle datasets. Although algorithms have been developed for automatic particle picking, these algorithms generally rely on two-dimensional templates for particle identification, which may exhibit biases that can propagate artifacts through the reconstruction pipeline. Manual picking is viewed as a gold-standard solution for particle selection, but it is too time consuming to perform on data sets of thousands of images. In recent years, crowdsourcing has proven effective at leveraging the open web to manually curate datasets. In particular, citizen science projects such as Galaxy Zoo have shown the power of appealing to users' scientific interests to process enormous amounts of data. To this end, we explored the possible applications of crowdsourcing in cryo-EM particle picking, presenting a variety of novel experiments including the production of a fully annotated particle set from untrained citizen scientists. We show the possibilities and limitations of crowdsourcing particle selection tasks, and explore further options for crowdsourcing cryo-EM data processing. PMID- 29486250 TI - Tripeptides derived from reactive centre loop of potato type II protease inhibitors preferentially inhibit midgut proteases of Helicoverpa armigera. AB - Potato type II protease inhibitors (Pin-II PIs) impede the growth of lepidopteran insects by inhibiting serine protease-like enzymes in the larval gut. The three amino acid reactive centre loop (RCL) of these proteinaceous inhibitors is crucial for protease binding and is conserved across the Pin-II family. However, the molecular mechanism and inhibitory potential of the RCL tripeptides in isolation of the native protein has remained elusive. In this study, six peptides corresponding to the RCLs of the predominant Pin-II PIs were identified, synthesized and evaluated for in vitro and in vivo inhibitory activity against serine proteases of the polyphagous insect, Helicoverpa armigera. RCL peptides with sequences PRN, PRY and TRE were found to be potent inhibitors that adversely affected the growth and development of H. armigera. The binding mechanism and differential affinity of the RCL peptides with serine proteases was delineated by crystal structures of complexes of the RCL peptides with trypsin. Residues P1 and P2 of the inhibitors play a crucial role in the interaction and specificity of these inhibitors. Important features of RCL peptides like higher inhibition of insect proteases, enhanced efficacy at alkaline gut pH, longer retention and high stability in insect gut make them suitable molecules for the development of sustainable pest management strategies for crop protection. PMID- 29486251 TI - Disseminated abscesses due to Mycoplasma faucium in a patient with activated PI3Kdelta syndrome type 2. PMID- 29486252 TI - Is a little atrial fibrillation still too much? PMID- 29486254 TI - Sex differences in attachment styles. AB - Sex differences in attachment styles have been found in adulthood, emerge as early as middle childhood, and can be sizable when described at the appropriate level of analysis. However, they have received relatively little attention in mainstream attachment research. Here I review the evidence of sex differences in attachment, including what is currently known about developmental patterns and cross-cultural variation. I summarize existing evolutionary models of sex differences, and discuss evidence for a role of prenatal and postnatal sex hormones. I highlight current theoretical and empirical gaps in the literature, and call for more integrative research on this fascinating topic. PMID- 29486253 TI - Biologics Delay Progression of Crohn's Disease, but Not Early Surgery, in Children. AB - BACKGROUND & AIMS: Up to 30% of patients with Crohn's disease (CD) require surgery within the first 5 years from diagnosis. We investigated the recent risk of bowel surgery in an inception cohort of pediatric patients with CD and whether early use of biologics (tumor necrosis factor antagonists) alters later disease course. METHODS: We collected data from the Pediatric Inflammatory Bowel Disease Collaborative Research Group registry on 1442 children (age, <=16 y) diagnosed with CD from January 2002 through December 2014. Data were collected at diagnosis, 30 days following diagnosis, and then quarterly and during hospitalizations for up to 12 years. Our primary aim was to determine the 10-year risk for surgery in children with CD. Our secondary aim was to determine whether early use of biologics (<3 mo of diagnosis) affected risk of disease progression. RESULTS: The 10-year risk of first bowel surgery was 26%. The 5-year risk of bowel surgery did not change from 2002 through 2014, and remained between 13% and 14%. Most surgeries occurred within 3 years from diagnosis. The only predictor of surgery was disease behavior at diagnosis. CD with inflammatory behavior had the lowest risk of surgery compared to stricturing disease, penetrating disease, or both. We associated slowing of disease progression to stricturing or penetrating disease (but not surgery) with early use of biologics, but this effect only became evident after 5 years of disease. Our results indicate that biologics slow disease progression over time (hazard ratio, 0.85; 95% CI, 0.76-0.95). CONCLUSIONS: In an analysis of data from a registry of pediatric patients with CD, we found that among those with significant and progressing disease at or shortly after presentation, early surgery is difficult to prevent, even with early use of biologics. Early use of biologics (<3 mo of diagnosis) can delay later disease progression to stricturing and/or penetrating disease, but this affect could become evident only years after initial management decisions are made. PMID- 29486255 TI - Evolved to be connected: the dynamics of attachment and sex over the course of romantic relationships. AB - Sexual urges and emotional attachments are not always connected. Still, joint operation of the sexual and the attachment systems is typical of romantic relationships. Hence, within this context, the two systems mutually influence each other and operate together to affect relationship well-being. In this article, we review evidence indicating that sex promotes enduring bonds between partners and provide an overview of the contribution of attachment processes to understanding the sex-relationship linkage. We then present a model delineating the functional significance of sex in relationship development. We conclude by suggesting future directions for studying the dual potential of sex for either deepening attachment to a current valued partner or promoting a new relationship when the existing relationship has become less rewarding. PMID- 29486256 TI - Novel insights into freshwater hydrocarbon-rich sediments using metatranscriptomics: Opening the black box. AB - Baseline biogeochemical surveys of natural environments is an often overlooked field of environmental studies. Too often research begins once contamination has occurred, with a knowledge gap as to how the affected area behaved prior to outside (often anthropogenic) influences. These baseline characterizations can provide insight into proposed bioremediation strategies crucial in cleaning up chemical spill sites or heavily mined regions. Hence, this study was conducted to survey the in-situ microbial activity within freshwater hydrocarbon-rich environments cutting through the McMurray formation - the geologic strata constituting the oil sands. We are the first to report in-situ functional variations among these freshwater microbial ecosystems using metatranscriptomics, providing insight into the in-situ gene expression within these naturally hydrocarbon-rich sites. Key genes involved in energy metabolism (nitrogen, sulfur and methane) and hydrocarbon degradation, including transcripts relating to the observed expression of methane oxidation are reported. This information provides better linkages between hydrocarbon impacted environments, closing knowledge gaps for optimizing not only oil sands mine reclamation but also enhancing microbial reclamation strategies in various freshwater environments. These finding can also be applied to existing contaminated environments, in need of efficient reclamation efforts. PMID- 29486257 TI - Estrogenic activity and contributing compounds in stagnant water bodies with massive occurrence of phytoplankton. AB - Stagnant water bodies have generally received little attention regarding the presence of endocrine disruptive compounds, although they can integrate diverse pollutants from multiple different sources. Many compounds of anthropogenic as well as natural origin can contribute to the overall estrogenicity of surface waters and some of them can exhibit adverse effects on aquatic biota even in very low concentrations. This study focused on freshwater ponds and reservoirs affected by water blooms and determined the estrogenic activity of water by in vitro bioassay as well as concentrations of several important groups of estrogenic compounds (estrogenic hormones, alkylphenols, and phytoestrogens) by LC-MS/MS analyses. Estrogenic hormones were found at concentrations up to 7.1 ng.L-1, similarly to flavonoids, whose concentrations did not exceed 12.5 ng.L-1. Among alkylphenols, only bisphenol A and 4-tert-octylphenol were detected in levels reaching 100 ng.L-1 at maximum. Estrogenic activity of water samples varied from below the quantification limit to 1.95 ng.L-1. There does not seem to be any general causal link of the massive phytoplankton occurrence with the estrogenicity of water or concentration of phytoestrogens, since they showed no direct relationship with the phytoplankton abundance or composition across sites. The contribution of the analysed compounds to the estrogenic activity was calculated in three scenarios. In minimum scenario, just the compounds above quantification limit (LOQ) were taken into account and for most samples, only minor part (<6%) of the biological activity could be explained. In the mean and maximum scenarios, we included also compounds below LOQ into the calculations at the level of LOQ/2 and LOQ, respectively. In these cases, a considerable part of the estrogenic activity could be attributed to the possible presence of steroid estrogens below LOQ. However, for the samples with estrogenic activity greater than 1 ng.L-1, more than 50% of the estrogenic activity remained unexplained even in the maximum scenario. Probably other compounds or possible interactions between individual substances cause the estrogenic activity in these types of water bodies and in this case, the results of LC-MS/MS analyses cannot sufficiently predict the biological effects. A complex approach including bioassays is needed when assessing the estrogenicity of these types of surface waters. PMID- 29486258 TI - Chitosan hydrochloride/hyaluronic acid nanoparticles coated by mPEG as long circulating nanocarriers for systemic delivery of mitoxantrone. AB - The purpose of this study was to prepare and investigate long circulating polyelectrolyte nanoparticles (PENPs) based on hydrochloride chitosan (HCS) and hyaluronic acid (HA) coated by methoxy poly(ethylene glycol) (mPEG). Mitoxantrone hydrochloride (MTO) was selected as a model drug. TEM showed that MTO-loaded PENPs (MTO-PENPs) were spherical but MTO-loaded PENPs coated by mPEG (MTO-mPEG PENPs) had a slightly rough morphology with an average hydrodynamic diameter around 200-240nm. The EE of MTO-mPEG-PENPs and MTO-PENPs were 99.02% and 98.33%, respectively. DSC thermograms showed MTO existed at the molecular level inside the MTO-mPEG-PENPs. Drug release studies revealed MTO-mPEG-PENPs offered better control over the release of drug than uncoated counterparts. Observations of the pharmacokinetic study reveal that MTO-mPEG-PENPs exhibited significant prolongation in blood circulation of drug compared to MTO-PENPs and MTO solution in rats after intravenous administration. The MRT of MTO increased from 117.83min (MTO solutions) and 162.34min (MTO-PENPs) to 344.42min (MTO-mPEG-PENPs). The AUC of MTO in MTO-mPEG-PENPs increased 2.52-fold and 3.41-fold compared to MTO-PENPs and MTO solution, respectively. In conclusion, mPEG coated PENPs based on HCS/HA could present a workable strategy for long-circulating systemic delivery of drugs. PMID- 29486260 TI - Effect of germination on composition profiling and antioxidant activity of the polysaccharide-protein conjugate in black soybean [Glycinemax (L.) Merr.]. AB - Black soybeans are commonly consumed as health foods and used in traditional Chinese medicine, but they are rarely cultivated as edible sprouts. During germination, the composition of seeds undergoes distinct changes that cause variations in bioactivities. In this study, the water-soluble black soybean polysaccharide (BSPS) was isolated from sprouts harvested at two-day intervals during the first week of seedling growth. The chromatographic profiles of the BSPS in ungerminated seeds showed fraction 1 (F1, about 64kDa) and fraction 2 (F2, <1kDa) that degraded during germination. The polysaccharide in F1 fraction of ungerminated seeds was covalently associated with the protein and mainly contained arabinose, galactose, glucose, and galacturonic acid at various levels during germination. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3 ethylbenzthiazoline-6-sulphonic acid) (ABTS) scavenging activities and the reducing power of F1 were highest on the seventh day of germination. The phenolic and flavonoid content significantly increased after the fifth day of germination, suggesting that these ingredients also contributed to the antioxidant activities. During long-term germination, the polysaccharide-protein conjugate in the F1 fraction with enhanced antioxidant activities is regarded as a potential natural antioxidant for the development of functional foods. PMID- 29486259 TI - Synthesis and characterization of cellulose and hydroxyapatite-carbon electrode composite for trace plumbum ions detection and its validation in blood serum. AB - A novel synthesis and characterization of cellulose, hydroxyapatite and chemically-modified carbon electrode (Cellulose-HAp-CME) composite was reported for the analysis of trace Pb(II) ions detection and its validation in blood serum. The Field Emission Scanning Electron Microscopy (FESEM) analyses showed that the composite retained the orderly porous structure but with scattered particle size agglomeration. The Fourier Transform Infrared Spectroscopy (FTIR) spectra suggested the presence of functional groups associated with the bending and stretching of carbon bonds and intermolecular H-bonding. X-ray Diffraction (XRD) analyses further elucidated that the crystallite size could have influenced the properties of the electrode. Based on Thermo-gravimetric Analysis (TGA/DTG), the composites showed thermal stability with more than 60% residual content at 700 degrees C. The sensor was successfully developed for trace Pb(II) ions detection in complex medium such as blood serum, in the physiologically relevant range of 10-60ppb, with resulting Limit of Detection (LOD) of 0.11+/-0.36ppb and Limit of Quantification (LOQ) of 0.36+/-0.36ppb. The newly fabricated electrode could be advantageous as a sensing platform with favourable electrochemical characteristics for robust, in situ and rapid environmental and clinical analyses of heavy metal ions. PMID- 29486261 TI - Starch hydrogels: The influence of the amylose content and gelatinization method. AB - Gelatinization and retrogradation, influenced by amylose and amylopectin ratio, are important characteristics for starch hydrogels elaboration. The objective of this study was to evaluate the influence of amylose content and the gelatinization method on the physicochemical characteristics of native and cross linked rice starch hydrogels. The native and cross-linked starches were gelatinized with heating or alkaline solution, added polyvinyl alcohol, frozen and then freeze-dried. The cross-linked starch had a low final viscosity (101.38 RVU), which made the heat-induced gelatinized hydrogel readily disintegrated in water. However, modified starch hydrogels obtained by alkaline-induced gelatinization resulted in a more rigid structure than the native starch hydrogels. In addition, the starch sample with high amylose content had lower water absorption (322.2%) due to the greater stiffness of the hydrogel structure that resisted swelling. The alkaline-gelatinization resulted in stiffer hydrogels with lower water absorption (322.2 to 534.8%), while the heat-gelatinized behaved as a superabsorbent (658.7 to 1068.5%). The variability of the hydrogels properties of this study can enable a range of applications due to different amylose contents and gelatinization methods. PMID- 29486262 TI - Dual targeting system by supramolecular complex of folate-conjugated methyl-beta cyclodextrin with adamantane-grafted hyaluronic acid for the treatment of colorectal cancer. AB - In our previous study, we demonstrated that folate-appended methyl-beta cyclodextrin (FA-M-beta-CyD) was a promising antitumor agent for the treatment of folate receptor-alpha (FR-alpha)-expressing tumors. In the present study, to enhance the antitumor effect of FA-M-beta-CyD against FR-alpha- and CD44 expressing colorectal cancer cells, we synthesized a dual targeting supramolecular complex composed of FA-M-beta-CyD and adamantane-grafted hyaluronic acid (Ad-HA). The supramolecular complex of Ad-HA/FA-M-beta-CyD showed higher cytotoxic activity in HCT116 cells (FR-alpha (+), CD44 (+)), a human colon cancer cell line, than FA-M-beta-CyD alone. In addition, the cytotoxic activity of Ad-HA/FA-M-beta-CyD was significantly impaired by the addition of FA and HA, as inhibitors of FR-alpha and CD44, respectively. Furthermore, tetramethylrhodamine isothiocyanate (TRITC)-labeled FA-M-beta-CyD was efficiently internalized into HCT116 cells through supramolecular complexation with Ad-HA, compared to that of TRITC-FA-M-beta-CyD alone. Additionally, Ad-HA/FA-M-beta-CyD induced mitophagy in HCT116 cells. These results suggest that Ad-HA/FA-M-beta-CyD targeted HCT116 cells, as well as induced mitophagy-mediated cell death. Notably, an intravenous injection of the Ad-HA/FA-M-beta-CyD complex in a mouse model of colorectal cancer significantly ameliorated the growth of tumor polyps. Collectively, these results suggest that Ad-HA/FA-M-beta-CyD has antiproliferation effects in tumors, based on the dual targeting activity. PMID- 29486263 TI - Improvement of stability and reusability of alpha-amylase immobilized on naringin functionalized magnetic nanoparticles: A robust nanobiocatalyst. AB - Enzyme immobilized on magnetic nanoparticles (MNPs) can be used as efficient recoverable biocatalysts under strong magnetic responses. In the present work, alpha-amylase was immobilized onto naringin functionalized MNPs via ionic interactions. For this purpose, the MNPs were functionalized with naringin, as a biocompatible flavonoid. The morphology, structure, and properties of functionalized MNPs and the immobilization of alpha-amylase on synthesized nanocomposite were characterized through different analytical tools including TGA, VSM, FTIR, SEM-EDX and TEM. Furthermore, the optimum conditions of temperature, pH, reaction time and enzyme concentration for immobilization process were investigated. The results showed that the optimal conditions for immobilization of alpha-amylase onto synthesized nanocarrier occurred at pH6.5 and 55 degrees C. The reusability experiments revealed high activity maintenance of immobilized alpha-amylase even after 10 reaction cycles. Moreover, the storage stability of immobilized enzyme improved via immobilization in comparison with free one and it maintained 60% of its initial activity after 6weeks storage at 4 degrees C. The improvements in enzyme catalytic properties via immobilization made this nanobiocatalyst as a good candidate in bio-industrial applications. Furthermore, the synthesized nanocomposite would have the potential for practical applications in other and binary enzyme immobilization. PMID- 29486264 TI - Adsorption removal of tartrazine by chitosan/polyaniline composite: Kinetics and equilibrium studies. AB - The present work focused on the performance of chitosan/polyaniline (Cht-PANI) composite for removing tartrazine dye from aqueous solutions. The adsorbent was characterized using SEM, XRD, FTIR, and TGA/DTA techniques. The effects of pH, initial dye concentration, contact time, and temperature on azo dye removal were studied. The kinetics and isotherm of tartrazine removal follow pseudo-second order kinetics and the Freundlich isotherm, respectively. The Langmiur isotherm model exhibted a maximum adsorption capacity of 584.0 mg/g. The thermodynamic parameters were calculated and the negative values of DeltaG degrees and positive value of DeltaH degrees indicate that the adsorption processes are spontaneous and endothermic in nature. In addition, the resulting adsorbent reusability was demonstrated over four cycles, indicating that the Cht-PANI is a very promising adsorbent for removal of toxic pollutants from aqueous solutions. PMID- 29486265 TI - Design of cellulose ether-based macromolecular prodrugs of ciprofloxacin for extended release and enhanced bioavailability. AB - The present study reveals the syntheses of hydroxypropylcellulose-(HPC) and hydroxyethylcellulose-(HEC) based macromolecular prodrugs (MPDs) of ciprofloxacin (CIP) using homogeneous reaction methodology. Covalently loaded drug content (DC) of each prodrug was quantified using UV-Vis spectrophotometry to determine degree of substitution (DS). HPC-ciprofloxacin (HPC-CIP) conjugates showed DS of CIP in the range 0.87-1.15 whereas HEC-ciprofloxacin (HEC-CIP) conjugates showed DS range 0.51-0.75. Transmission electron microscopy revealed that HPC-CIP conjugate 2 and HEC-CIP conjugate 6 self-assembled into nanoparticles of 150-300 and 180 250nm, respectively. Size exclusion chromatography revealed HPC-CIP conjugate 2 and HEC-CIP conjugate 6 as monodisperse systems. In vitro drug release studies indicated 15 and 43% CIP release from HPC-CIP conjugate 2 after 6h in simulated gastric and simulated intestinal fluids (SGF and SIF), respectively. HEC-CIP conjugate 6 showed 16% and 46% release after 6h in SGF and SIF, respectively. HPC CIP conjugate 2 and HEC-CIP conjugate 6 exhibited half-lives of 10.87 and 11.71h, respectively with area under the curve values of 164 and 175hMUgmL-1, respectively, indicating enhanced bioavailability and improved pharmacokinetic profiles in animal model. Equal antibacterial activities to that of unmodified CIP confirmed their competitive efficacies. Cytotoxicity studies supported their non-toxic nature and biocompatibility. PMID- 29486266 TI - Social modulation of risky decision-making in rats (Rattus norvegicus) and tufted capuchin monkeys (Sapajus spp.). AB - Both human and non-human animals frequently deal with risky decisions in a social environment. Nevertheless, the influence of the social context on decision-making has been scarcely investigated. Here, we evaluated for the first time whether the presence of a conspecific influences risk preferences in rats and in tufted capuchin monkeys. Subjects received a series of choices between a constant, safe option and a variable, risky option, both alone (Alone condition) and when paired with a conspecific (Paired condition). The average payoff of the risky option was always lower than that of the safe option. Overall, the two species differed in their attitude towards risk: whereas rats were indifferent between options, capuchins exhibited a preference for the safe option. In both species, risk preferences changed in the Paired condition compared to the Alone condition, although in an opposite way. Whereas rats increased their risk preferences over time when paired with a conspecific, capuchins chose the risky option less in the Paired condition than in the Alone condition. Moreover, whereas anxiety-like behaviours decreased across sessions in rats, these behaviours where more represented in the Paired condition than in the Alone condition in capuchins. Thus, our findings extends to two distantly-related non-human species the evidence, so far available for human beings, that a decrease in anxiety corresponds to an increase in risk preferences, and vice versa. This suggests that the modulation of risk preferences by social influences observed in rats and capuchin monkeys may rely on a common, evolutionarily ancient, mechanism. PMID- 29486267 TI - The distressed (Type D) personality factor of social inhibition, but not negative affectivity, enhances eyeblink conditioning. AB - Recent work has focused on a learning diathesis model in which specific personality factors such as behavioral inhibition (BI) may influence associative learning and in turn increase risk for the development of anxiety disorders. We have found in a series of studies that individuals self-reporting high levels of BI exhibit enhanced acquisition of conditioned eyeblinks. In the study reported here, hypotheses were extended to include distressed (Type D) personality which has been found to be related to BI. Type D personality is measured with the DS-14 scale which includes two subscales measuring negative affectivity (NA) and social inhibition (SI). We hypothesized that SI, which is similar to BI, would result in enhanced acquisition while the effect of NA is unclear. Eighty nine participants completed personality inventories including the Adult Measure of Behavioral Inhibition (AMBI) and DS-14. All participants received 60 acquisition trials with a 500 ms, 1000 Hz, tone CS and a co-terminating 50 ms, 5 psi corneal airpuff US. Participants received either 100% CS-US paired trials or a schedule of partial reinforcement where 50% US alone trials were intermixed into CS-US training. Acquisition of CRs did not differ between the two training protocols. Whereas BI was significantly related to Type D, SI, and NA, only BI and SI individuals exhibited enhanced acquisition of conditioned eyeblinks as compared to non inhibited individuals. Personality factors now including social inhibition can be used to identify individuals who express enhanced associative learning which lends further support to a learning diathesis model of anxiety disorders. PMID- 29486268 TI - Effects of n-3 polyunsaturated fatty acid supplementation on cognitive functions, electrocortical activity and neurogenesis in a non-human primate, the grey mouse lemur (Microcebus murinus). AB - Among environmental factors that may affect on brain function, some nutrients and particularly n-3 polyunsaturated fatty acids (n-3 PUFA) are required for optimal brain development. Their effects on cognitive functions, however, are still unclear, and studies in humans and rodents have yielded contradictory results. We used a non-human primate model, the grey mouse lemur, phylogenetically close to human. The aim of this study was to demonstrate the impact of n-3 PUFA supplementation on cognitive functions, neuronal activity and neurogenesis. Two groups of animals whose diet was supplemented with either fish oil (rich in n-3 PUFA) or olive oil as a control. These two groups were subjected to a visual discrimination task and to a test of anxiety in the open-field. In parallel, cortical activity was measured with telemetric ECoG recordings. Finally, adult neurogenesis was investigated ex vivo by means of immunohistochemistry. Animals supplemented with fish oil exhibited better visual discrimination performance and tended to have lower anxiety levels. Furthermore, supplementation increased the power of alpha, beta and gamma frequency bands in the EEG, which are related to various aspects of memory and decision-making. This study also provides the first evidence of the existence of adult neurogenesis process in a prosimian primate. Notably, lemurs supplemented with n-3 PUFAs for 21 months exhibited a higher number of newly born neurons in brain areas related to memory and emotions, compared to control animals. Altogether, these results point to long-term positive effects of dietary n-3 PUFAs on various functions of the primate brain. Further studies will be needed to determine a formal causal link between behavioral improvement and creation of new neurons. PMID- 29486269 TI - Older adults reveal enhanced task-related beta power decreases during a force modulation task. AB - Older adults (OA) compared to young adults (YA) reveal deteriorated fine motor control. However, it remains unknown whether this age difference is reflected on the central level, i.e., in electrophysiological correlates such as EEG task related power (TRPow) in alpha (8-13 Hz) or beta band (13-30 Hz). Furthermore, we were interested in the association between age and alpha/beta power at rest as a potential determinant for TRPow changes. Twenty-five YA (19-29 years) and 45 OA (67-83 years) performed a force modulation (FM) task requiring to match a sinusoidal target force by exerting an isometric force with thumb and index finger. EEG was measured at rest and during FM task. YA outperformed OA in the FM task. For alpha, OA demonstrated less frontal power at rest than YA. For beta, OA revealed more power than YA in frontal, central, and parietal areas at rest. TRPow results depended on whether analyses were controlled for power at rest. When analyses were controlled, OA showed higher TRPow decreases than YA in beta in parietal and occipital areas during FM performance. TRPow decreases for beta were stronger in the contralateral than in the ipsilateral frontal hemisphere in OA than in YA. Decreases in TRPow indicate increased cortical activity to accomplish the FM task. Our findings suggest higher parietal and occipital processing demands while performing the FM task in OA than in YA. This study further confirmed the importance of controlling for EEG power at rest when investigating TRPow during motor performance to account for interindividual variability. PMID- 29486270 TI - Mechanism-informed read-across assessment of skin sensitizers based on SkinSensDB. AB - Integrative testing strategies using adverse outcome pathway (AOP)-based alternative assays for assessing skin sensitizers show the potential for replacing animal testing. However, the application of alternative assays for a large number of chemicals is still time-consuming and expensive. In order to facilitate the assessment of skin sensitizers based on integrative testing strategies, a mechanism-informed read-across assessment method was proposed and evaluated using data from SkinSensDB. First, the prediction performance of two integrated testing strategy models was evaluated giving the highest area under the receiver operating characteristic curve (AUC) values of 0.928 and 0.837 for predicting human and LLNA data, respectively. The proposed read-across prediction method achieves AUC values of 0.957 and 0.802 for predicting human and LLNA data, respectively, with interpretable activation statuses of AOP events. As data grows, a better prediction performance is expected. A user-friendly tool has been constructed and integrated into SkinSensDB that is publicly accessible at http://cwtung.kmu.edu.tw/skinsensdb. PMID- 29486271 TI - Survival of Escherichia coli harboring nucleic acid-hydrolyzing 3D8 scFv during RNA virus infection. AB - Previously, Escherichia coli harboring the codon-optimized 3D8scFv gene (E. coli 3D8scFv) was developed as a feed additive for use in preventing norovirus infection. Here, we evaluated whether the 3D8scFv gene affects the colonization of E coli when E. coli 3D8scFv passes through the mouse gastrointestinal tract. To determine the colonization ability of E. coli 3D8scFv, E. coli cells with or without the 3D8scFv gene were fed to mice. Total DNA was extracted from the animals' stools, stomach, small intestine and colon. All samples were amplified using 3D8scFv gene-specific primer sets. E. coli 3D8scFv begins to be excreted 1 h after feeding and that all E. coli 3D8scFv cells were excreted between 12 and 24 h after the last feeding of the cells. The previously measured gastrointestinal transit time of the mice was between 8 h and 22 h. The results of this study therefore show that E. coli 3D8scFv cannot colonize the gastrointestinal tracts of mice. In addition, if the purified 3D8 scFv protein is used as a feed additive, any associated E. coli 3D8scFv bacteria will not colonize the gastrointestinal tracts of the livestock. Thus, this feed additive meets the safety assessment criteria for the commercial use of bacteria. PMID- 29486272 TI - Weight of contribution of in vitro chromosomal aberration assay for evaluation of pesticides: Experience of risk assessment at the Food Safety Commission of Japan. AB - Due to the course of registration of pesticides in Japan, the Food Safety Commission (FSC) has the responsibility to make a risk assessment of residual pesticides and related chemicals through foods. Among the set of safety evaluations for pesticides, genotoxicity assay data are mandatory. The standard test battery for this evaluation consists of a bacterial gene mutation assay, in vitro mammalian chromosomal aberrations and/or other chromosome damage assay, and in vivo rodent micronucleus assay. These assay outcomes are used for mechanistic consideration of carcinogenicity, if any. As a rule, if a certain substance is carcinogenic and the mechanism of it includes genotoxicity, the FSC might decide it is not possible to establish the acceptable daily intake of that pesticide. Therefore, the information about genotoxicity is critical for potentially carcinogenic chemicals, whether the applied substance will be adopted and permitted for use or not as pesticides. It is important to assess fairly, carefully, and transparently, but feasible, rapid, and efficient assessment also should be taken into account. Therefore, needless to say, the assay(s) should have the sensitivity to detect potent mutagens. It is also important to be aware that the required data set should be consisted of reliable assays without certain assay(s) that give(s) false positive information or offer less of a contribution for the safety assessment. PMID- 29486273 TI - Isolation, identification and characterization of the bioluminescent bacteria isolated from the blue swimmer crab Portunus pelagicus along Thondi Coast and virulence studies at high temperatures. AB - The current study was conducted to isolate the marine bioluminescent bacteria from the blue swimmer crab Portunus pelagicus along the Thondi Coast. Morphological, biochemical and molecular characterization techniques including 16S rRNA gene sequencing and phylogenetic analyses confirmed that the isolated strain was Vibrio harveyi. Experiments were further carried out at different temperatures and various time intervals and the results revealed a significant effects of high temperature and extended time duration on elimination of V. harveyi. Hence, high temperature treatments could facilitate the suppression of V. harveyi from sea food and thereby, preventing food borne infections during human consumption. PMID- 29486274 TI - Review on emergence of drug-resistant tuberculosis (MDR & XDR-TB) and its molecular diagnosis in Ethiopia. AB - Tuberculosis (TB) remains a major global health problem and ranks as the second leading cause of death among deaths caused by infectious diseases worldwide. Although the availability of short-course regimens as first-line anti tuberculosis drugs, the emergence of drug-resistant Mycobacterium tuberculosis strains pose a major challenge to the prevention and control efforts of national tuberculosis programs (NTPs). M. tuberculosis changes its cellular environment with the mechanisms that have been evolved since prehistoric times. The interactions between the bacteria and the host environment have been studied well. However, the studies at molecular level began to emerge recently including expression profiling of micro RNA (miRNA) and literature survey revealed that researchers find more information about their regulatory role in biological processes including immune response to infectious agents like mycobacteria. In developing countries, including Ethiopia, the burden of tuberculosis and or drug resistance profile of M. tuberculosis remains largely unexplored, mainly due to lack of quality controlled second-line laboratory tests and also lack of knowledge on molecular diagnostics. This review describes the disease etiology, pathogenesis, epidemiology, molecular mechanism and advanced molecular diagnostics for precision MDR-TB diagnosis. PMID- 29486275 TI - Effectiveness of root-bark extract from Salvadora persica against the growth of certain molecularly identified pathogenic bacteria. AB - The acetone extract from root-bark of Salvadora persica L. (Salvadoraceae), is assayed for its antibacterial activity against some bacterial pathogens. By GC/MS analysis, the main chemical components of the acetone extract were found to be benzylisothiocyanate (39.4%), and benzyl nitrile (benzeneacetonitrile) (37.9%). According the extract concentrations used, the measured inhibition zones observed were between from 13.6 to 18.6 mm, 15.3-23 mm, 13.3-18.3 mm, 13.3-18.3 mm, and 12.3-19 mm, against the isolated plant bacterial pathogens namely Agrobacterium tumefaciens, Pectobacterium atrosepticum, Enterobacter cloacae, Dickeya solani and Ralstonia solanacearum, respectively, whilst it was between 8 and 12 mm, 8 9.6 mm, 8-11.6 mm, and 8-10.3 mm against Bacillus subtilis, Sarcina lutea, Escherichia coli and Staphylococcus aureus, respectively. The minimum inhibitory concentration values of the extract were between 16 and 32 MUg/mL against the growth of plant bacterial, and from 1000 to 2000 MUg/mL against the growth of the human bacteria. In conclusion, the acetone extract of root-bark of S. persica showed strong antibacterial activity against the plant pathogens and some activity against the human pathogens were reported. The results suggested that using the acetone extract from root-bark of S. persica as bioactive agent against the growth of the studied plant bacterial pathogens. PMID- 29486276 TI - Phytochemical investigation and biological activities of Echium arenarium (Guss) extracts. AB - The present work was developed to evaluate the in vitro antioxidant, antibacterial, antileishmanial and cytotoxic activities of Echium arenarium (Guss) extracts, and to analyze their phytochemical composition. The highest content of total phenolic compounds was obtained in the ethyl acetate extract which showed the best DPPH scavenging activity and beta-carotene bleaching inhibition (IC50 = 1.1 and 9.94 MUg/mL respectively). It also exhibited the highest antibacterial activity against Gram-positive bacteria (L. monocytogenes; S. aureus; MRSA, E. faecalis and B. cereus) and antileishmanial activity against L. major (IC50 = 13.91 +/- 0.43 MUg/mL) and L. infantum (IC50 = 9.91 +/- 0.15 MUg/mL). Moreover, the active extract exhibited potent antiamastigote activity (IC50 = 22.48 +/- 0.14 MUg/mL and 18.59 +/- 0.09 MUg/mL against L. major and L. infantum respectively). Cytotoxicity studies revealed low toxicity against Raw 264.7 macrophage cell line (IC50 = 145.80 +/- 0.84 MUg/mL, SI < 10). Luteolin-7-O glucoside was identified as the major flavonoid component by RP-HPLC analysis. In conclusion, Echium arenarium (Guss) extract was characterized by a wide range of biological activities and could be used as a potential natural anti-infectious drug. PMID- 29486277 TI - Complete genomic analysis of multidrug-resistance Pseudomonas aeruginosa Guangzhou-Pae617, the host of megaplasmid pBM413. AB - OBJECTIVES: We previously described the novel qnrVC6 and blaIMP-45 carrying megaplasmid pBM413. This study aimed to investigate the complete genome of multidrug-resistance P. aeruginosa Guangzhou-Pae617, a clinical isolate from the sputum of a patient who was suffering from respiratory disease in Guangzhou, China. METHODS: The genome was sequenced using Illumina Hiseq 2500 and PacBio RS II sequencers and assembled de novo using HGAP. The genome was automatically and manually annotated. RESULTS: The genome of P. aeruginosa Guangzhou-Pae617 is 6,430,493 bp containing 5881 predicted genes with an average G + C content of 66.43%. The genome showed high similarity to two new sequenced P. aeruginosa strains isolated from New York, USA. From the whole genome sequence, we identified a type IV pilin, two large prophages, 15 antibiotic resistant genes, 5 genes involved in the "Infectious diseases" pathways, and 335 virulence factors. CONCLUSIONS: The antibiotic resistance and virulence factors in the genome of P. aeruginosa strain Guangzhou-Pae617 were identified by complete genomic analysis. It contributes to further study on antibiotic resistance mechanism and clinical control of P. aeruginosa. PMID- 29486278 TI - A systematic review on the rhizome of Ligusticum chuanxiong Hort. (Chuanxiong). AB - Chuanxiong Rhizome (called Chuanxiong, CX in Chinese), the dried rhizome of Ligusticum chuanxiong Hort, is an extremely common traditional edible-medicinal herb. As a widely used ethnomedicine in Asia including China, Japan and Korea, CX possesses ideal therapeutic effect on cardiovascular and cerebrovascular diseases, and is also used as a major ingredient in soups for regular consumption to benefit health. Based on the traditional perception, amounts of investigations on different aspects have been done for CX in the past decades. However, no literature systematic review about these achievements have been compiled. Herein, the aim of this review is to present the up-to-date information on the ethnobotany, ethnopharmacological uses, phytochemicals, pharmacological activities, toxicology of this plant to identify their therapeutic potential and directs future research opportunities. So far, about 174 compounds has been isolated and identified from CX, in which phthalides and alkaloids would be the main bioactive ingredients for its pharmacological properties, such as anti cerebral ischemia, anti-myocardial ischemia, blood vessel protection, anti thrombotic, anti-hypertensive, anti-atherosclerosis, anti-spasmodic, anti inflammatory, anti-cancer, anti-oxidant, and anti-asthma effects. Even so, due to the incomplete standardized planting, unstable herbal quality, and outdated preparation techniques, the industrial progress of CX is still less developed. PMID- 29486280 TI - Regression discontinuity was a valid design for dichotomous outcomes in three randomized trials. AB - OBJECTIVE: Regression discontinuity (RD) is a quasi-experimental design that may provide valid estimates of treatment effects in case of continuous outcomes. We aimed to evaluate validity and precision in the RD design for dichotomous outcomes. STUDY DESIGN AND SETTING: We performed validation studies in three large randomized controlled trials (RCTs) (Corticosteroid Randomization After Significant Head injury [CRASH], the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries [GUSTO], and PROspective Study of Pravastatin in elderly individuals at risk of vascular disease [PROSPER]). To mimic the RD design, we selected patients above and below a cutoff (e.g., age 75 years) randomized to treatment and control, respectively. Adjusted logistic regression models using restricted cubic splines (RCS) and polynomials and local logistic regression models estimated the odds ratio (OR) for treatment, with 95% confidence intervals (CIs) to indicate precision. RESULTS: In CRASH, treatment increased mortality with OR 1.22 [95% CI 1.06-1.40] in the RCT. The RD estimates were 1.42 (0.94-2.16) and 1.13 (0.90-1.40) with RCS adjustment and local regression, respectively. In GUSTO, treatment reduced mortality (OR 0.83 [0.72-0.95]), with more extreme estimates in the RD analysis (OR 0.57 [0.35; 0.92] and 0.67 [0.51; 0.86]). In PROSPER, similar RCT and RD estimates were found, again with less precision in RD designs. CONCLUSION: We conclude that the RD design provides similar but substantially less precise treatment effect estimates compared with an RCT, with local regression being the preferred method of analysis. PMID- 29486279 TI - Validation of the antihyperglycaemic and hepatoprotective activity of the flavonoid rich fraction of Brachychiton rupestris using in vivo experimental models and molecular modelling. AB - Oxidative stress leads to many disorders as diabetes mellitus and liver diseases. This study evaluates the antihyperglycemic and hepatoprotective activities of Brachychiton rupestris (Malvaceae). The antihyperglycemic activity of the total methanol extract of B. rupestris leaves (BRT) and its ethyl acetate fraction (BRE) was evaluated using streptozotocin induced diabetic rats. The hepatoprotective activity was assessed using carbon-tetrachloride induced hepatotoxicity. Oral administration of 50 mg/kg b.wt (body weight) of BRT and BRE to Streptozotocin -diabetic rats caused a notable decrease in serum glucose by 39.38 and 42.09% with 35.62 and 15.44% increase in serum insulin, respectively, compared with Streptozotocin-diabetic rats. Oral administration of BRT and BRE to carbon-tetrachloride -treated rats (50 mg/kg b.wt) resulted in reduction in serum aspartate transaminase (AST) (28.88 and 27.2%, respectively) and alanine transaminase (ALT) (8 and 13.56%) levels, respectively. They also ameliorated oxidative stress in both models as evidenced from oxidative stress markers. Liquid chromatography coupled with electrospray ionization mass spectrometry (LC ESI-MS) analysis of the most active fraction (BRE) identified nine compounds including flavonoids and phenolic acids. Molecular modelling of the identified compounds was performed on human pancreatic alpha-amylase (HPA) and human alpha glucosidase (HAG) using Discovery Studio 2.5. Quercetin-3-O-(6"-O-alpha-l rhamnopyranosyl)-beta-D-glucoside showed the greatest affinity towards both HPA and HAG. Thus, this study provided scientific evidence on the antihyperglycemic and hepatoprotective activities of Brachychiton rupestris. PMID- 29486281 TI - Increasing the efficiency of clinical trials in neurodegenerative disorders using group sequential trial designs. AB - OBJECTIVES: Clinical trials in neurodegenerative disorders are facing high futility rates and rising development costs. We aim to review and exemplify the value of group sequential trial designs (i.e., designs with one or more prospectively planned interim analyses) within the field of amyotrophic lateral sclerosis. STUDY DESIGN AND SETTING: We reviewed the literature to identify sequentially conducted trials. Subsequently, we reanalyzed the dexpramipexole trial (EMPOWER), a classically designed and conducted trial involving 942 participants, by sequentially monitoring the functional questionnaire and survival endpoint. Finally, we simulated the performance of the sequential methodology under different treatment effects. RESULTS: Only six (12%) randomized, placebo-controlled trials incorporated stopping rules for both futility and superiority. Despite its high enrollment rate, sequential reanalysis of the EMPOWER study reduced the total trial duration with 140 days (23.4%, 95% confidence interval [CI] 13.2-34.4%), the number of follow-ups with 2,688 visits (23.6%, 95% CI 11.3-38.6%), and the total drug exposure time with 73,377 days (20.6%, 95% CI 9.8-35.9%). The functional questionnaire considerably increased the heterogeneity in the test statistics, which may negatively affect sequential monitoring. CONCLUSION: Group sequential trials can result in important reductions in the trial duration, which could make clinical trials more ethical by reducing the patients' exposure to noneffective treatments or by limiting their time on placebo. PMID- 29486282 TI - Novel role of apatinib as a multi-target RTK inhibitor in the direct suppression of hepatocellular carcinoma cells. AB - Although apatinib has been demonstrated with potential antitumor activity in multiple solid tumors, the underlying mechanism of apatinib for the treatment of hepatocellular carcinoma (HCC) remains unclear. In the present study, we explored if there are any direct suppression effects of apatinib on HCC cells and its relevant targets. We investigated the effect of apatinib on viability of five HCC cell lines and an intrahepatic cholangiocarcinoma cell line, and colony formation, apoptosis and migration of representative HCC cells in vitro; and HCC progression in a xenograft mouse model. Using a phospho-receptor tyrosine kinase pathway array with 49 different tyrosine kinases, we screened and verified the tyrosine kinase targets involved in apatinib response. Apatinib treatment significantly inhibited HCC cell viability, proliferation, colony formation, and migration, and enhanced cell apoptosis in a concentration-dependent manner (p < 0.05). Furthermore, apatinib showed a favorable anti-tumor growth effect (71% of inhibition ratio, p < 0.05) in an established human HCC xenograft mice model with good safety. RTK pathway arrays and western blots analysis demonstrated that apatinib significantly downregulated the phosphorylation levels of several tyrosine kinase receptors, particularly PDGFR-alpha and IGF-IR, and inhibited Akt phosphorylation. These data suggest that the apatinib may have a direct anti-HCC effect as a direct multi-target RTK inhibitor of HCC cells and a promising potentiality in HCC clinical therapies. PMID- 29486283 TI - Musashi-1 promotes chemoresistant granule formation by PKR/eIF2alpha signalling cascade in refractory glioblastoma. AB - Musashi-1 (MSI1), one of the RNA-binding proteins, is abundantly found not only in neural stem cells but also in several cancer tissues and has been reported to act as a positive regulator of cancer progression. Growing evidence indicates that PKR and eIF2alpha play pivotal roles in the stimulation of stress granule formation as well as in the subsequent translation modulation in response to stressful conditions; however, little is known about whether MSI1 is involved in this PKR/eIF2alpha cancer stem cell-enhancing machinery. In this study, we demonstrated that MSI1 promotes human glioblastoma multiforme (GBM) stem cells and enhances chemoresistance when exposed to sublethal stress. The overexpression of MSI1 leads to a protective effect in mitigating drug-induced cell death, thus facilitating the formation of chemoresistant stress granules (SGs) in response to arsenic trioxide (ATO) treatment. SG components, such as PKR and eIF2alpha, were dominantly activated and assembled, while ATO was engaged. The activated PKR and eIF2alpha contribute to the downstream enhancement of stem cell genes, thereby promoting the progression of GBM. The silencing of MSI1 or PKR both obviously withdrew the phenomena. Taken together, our findings indicate that MSI1 plays a leading role in stress granule formation that grants cancer stem cell properties and chemoresistant stress granules in GBM, in response to stressful conditions via the PKR/eIF2alpha signalling cascade. PMID- 29486284 TI - Herpud1 impacts insulin-dependent glucose uptake in skeletal muscle cells by controlling the Ca2+-calcineurin-Akt axis. AB - Skeletal muscle plays a central role in insulin-controlled glucose homeostasis. The molecular mechanisms related to insulin resistance in this tissue are incompletely understood. Herpud1 is an endoplasmic reticulum membrane protein that maintains intracellular Ca2+ homeostasis under stress conditions. It has recently been reported that Herpud1-knockout mice display intolerance to a glucose load without showing altered insulin secretion. The functions of Herpud1 in skeletal muscle also remain unknown. Based on these findings, we propose that Herpud1 is necessary for insulin-dependent glucose disposal in skeletal muscle. Here we show that Herpud1 silencing decreased insulin-dependent glucose uptake, GLUT4 translocation to the plasma membrane, and Akt Ser473 phosphorylation in cultured L6 myotubes. A decrease in insulin-induced Akt Ser473 phosphorylation was observed in soleus but not in extensor digitorum longus muscle samples from Herpud1-knockout mice. Herpud1 knockdown increased the IP3R-dependent cytosolic Ca2+ response and the activity of Ca2+-dependent serine/threonine phosphatase calcineurin in L6 cells. Calcineurin decreased insulin-dependent Akt phosphorylation and glucose uptake. Moreover, calcineurin inhibition restored the insulin response in Herpud1-depleted L6 cells. Based on these findings, we conclude that Herpud1 is necessary for adequate insulin-induced glucose uptake due to its role in Ca2+/calcineurin regulation in L6 myotubes. PMID- 29486285 TI - Dual-effect liposomes with increased antitumor effects against 67-kDa laminin receptor-overexpressing tumor cells. AB - This study sought to evaluate the antitumor effects of and elucidate the mechanisms underlying (-)-epigallocatechin-3-O-gallate (EGCG) and polyethyleneglycol (PEG)-modified liposomes. EGCG functions as a target ligand of the 67-kDa laminin receptor (67LR), which is expressed on high-grade tumor cells. An EGCG derivative was synthesized for binding to the end of PEG. Doxorubicin (DOX)-loaded EGCG-PEG-modified liposome (EPL) significantly decreased tumor size in mice bearing high 67LR-high-expressing tumors. Caspase-3 activity, which indicates induction of apoptosis, was also elevated only in the EPL group. The importance of PEG for the antitumor effects of EGCG was noted, as soluble EGCG did not accumulate at a sufficient concentration to exert an apoptotic effect. Moreover, EPL significantly increased caspase-8 activity, suggesting that EPL induced apoptosis occurred due to caspase-8 activity induced following the binding of EGCG to 67LR as a cell-death ligand. In conclusion, EPL appear to have superior antitumor activity against high 67LR-expressing tumor cells, as the liposomes had dual effects, namely antitumor effects due to the loaded DOX and apoptosis induced by the bound EGCG. PMID- 29486287 TI - Impact of formulation pH on physicochemical protein characteristics at the liquid air interface. AB - Both, formulation parameters and the presence of liquid-air interfaces are known to affect the aggregation of protein drugs. In this study, the impact of pH on the liquid-air interfacial behavior of three proteins, a polyclonal and two monoclonal antibodies (IgG, mAB1 and mAB2) was investigated using different surface sensitive methods. Equilibrium surface pressure values revealed only a minor impact of pH. Infrared Reflectance Absorbance Spectroscopy (IRRAS) proved not only the presence of the proteins at the interface but also showed that the secondary structure was not considerably affected by the adsorption to the interface independent of pH between pH 3 and 9. Additionally, the physical resistance of the film as determined by the interfacial compressibility in a Langmuir trough was not affected by pH. Compression of the interfacial film caused the formation of telescoped areas which were no longer present after decompression at all pH values as investigated by underwater Atomic Force Microscopy (AFM). Brewster Angle Microscopy (BAM) showed some slight changes in the film reflectivity depending on pH, indicating changes in the interfacial film thickness. IRRAS experiments at different angles of incidence as well as section analysis of AFM images proved not only that the film thickness increased upon compression, but also that the interfacial film is thinner at pH 4 than at pH 9. Continuous compression and decompression of the protein film resulted in particle formation with increasing numbers of particles at higher pH value as detected by Light Obscuration (LO) and Micro-Flow Imaging (MFI). The use of different surface sensitive methods provides expedient information on how liquid-air interfacial events are affected by formulation pH. These findings enable a better understanding of not only the events and processes happening at the interface but can also be directly linked to the interface-related formation of particles. PMID- 29486286 TI - Manufacturing and ambient stability of shelf freeze dried bacteriophage powder formulations. AB - The severity of multidrug resistance to antibiotics has urged development of alternative treatment approaches, including bacteriophage therapy. Given the complexity of the bacteriophage structure, formulation and stability are primary concerns. Our present work optimized process and formulations of phage powder manufacturing and investigated the stability of lyophilized bacteriophage powders under ambient storage. The model phage M13 was formulated with trehalose, mannitol, sucrose and PEG6000 and lyophilized in different conditions. Bacteriophage viability was examined by titering and was considered as the assessment of phage stability. Less titer loss of trehalose and sucrose formulations were observed compared to mannitol and PEG groups both immediately after lyophilization and upon long term storage. When evaluating lyophilization conditions, an additional 1 log titer was preserved by reduction of product drying stress. Trehalose was stabilized in the amorphous state whereas mannitol stayed in crystalline state in lyophilized powders. Increased moisture content was demonstrated to have a positive impact on viability of phage after lyophilization and upon storage. Overall, 2% trehalose or sucrose (w/v) can sufficiently stabilize phage during lyophilization process and storage in ambient conditions. There is a positive correlation between residual water and stability of phage. These collective findings highlight the potential of long-term, ambient storage of bacteriophage towards their successful use in diverse healthcare settings. PMID- 29486288 TI - The level of 24-hydroxycholesteryl esters decreases in plasma of patients with Parkinson's disease. AB - 24-hydroxycholesterol (24OH-C) is synthesized almost exclusively in neurons. This oxysterol is mostly present as ester form in both cerebrospinal fluid and plasma. The enzyme lecithin-cholesterol acyltransferase esterifies 24OH-C in the brain, and the level of 24OH-C esters in cerebrospinal fluid was found to be correlated with the level of 24OH-C esters in plasma. Decreased levels of 24OH-C esters levels were previously found in Alzheimer's disease and Amyotrophic Lateral Sclerosis. This finding was attributed to the inhibitory effect of oxidative stress on lecithin-cholesterol acyltransferase activity in neurodegenerative conditions. Data reported here show that the plasma level of 24OH-C esters is decreased also in Parkinson's disease. ROC analysis identified 69.0% of 24OH-C esterification as the threshold (AUC = 0.98) discriminating patients (N = 19) from healthy subjects (N = 19) with 100% specificity vs controls, 89.5% sensitivity, 94.7% accuracy, and 100% precision. The level of 24OH-C esters was not correlated with UPDRS I or UPDRS III when evaluated at the time of blood sampling. By contrast, it was negatively correlated with UPDRS I (r = -0.4984, p = 0.0299) after one year of follow up. Therefore, this level might represent a novel biomarker of neurodegeneration in Parkinson's disease. The biomarker level is here proposed as a measure to evaluate the severity of disease, as well as to monitor the progression of this pathology. PMID- 29486289 TI - Influence of prenatal pre-exposure to an odor on intake behavior of an aversive solution in newborn rats. AB - Early pre- or postnatal sensory experiences significantly influence flavor preference and food intake, and can induce liking for innately unpalatable flavors. Previous work found that newborn rats stimulated with an odor experienced shortly after birth exhibited heightened intake and seeking towards an artificial nipple containing quinine. This result suggests that odors made familiar trough early postnatal pre-exposure can shift the motivational value of unconditional stimuli. The objective of the current study was to assess the effect of an odor (lemon) experienced in-utero on the first intake responses towards an artificial nipple supplying quinine. The hypothesis, which was corroborated, was that stimulation with the olfactory stimulus experienced in utero would increase the newborn's intake and grasp responses to the artificial nipple containing quinine. Exposure to the odor that had been pre-exposed in utero increased quinine intake and seeking (i.e., latency to grasp and total time in contact with the nipple, as well as number of and mean duration of nipple grasps) in 3-h-old pups. These results replicate those previously found with postnatal odor pre-exposure, and extend the phase for pre-exposure to the prenatal stage. PMID- 29486290 TI - Functional ectopic neural lobe increases GAP-43 expression via PI3K/AKT pathways to alleviate central diabetes insipidus after pituitary stalk lesion in rats. AB - Central diabetes insipidus can occur after hypothalamic-hypophyseal tract injury. This injury is linked with a deficit in circulating vasopressin and oxytocin, which are produced in the supraoptic nuclei and the hypothalamic paraventricular nuclei. Previous studies indicate that an ectopic neural lobe forms after pituitary stalk lesion in rats, and while the relationship between an ectopic neural lobe and CDI outcomes is unclear, the underlying mechanisms are also unknown. Here, we report that two different CDI characteristics are shown in rats that underwent pituitary stalk electric lesion and are defined by two different groups classified as the recovery group and the no-recovery group. Rats showed an enlarged functional ectopic neural lobe at the lesion site with a low CDI index. Moreover, growth associated protein-43, p-PI3K and p-AKT were up-regulated in the unmyelinated fibers of the ectopic neural lobe. Our findings suggest that the enlarged structure formed a functional ectopic neural lobe after the pituitary stalk lesion, and its regeneration might influence the CDI outcome. This regeneration might be due to an increase in GAP-43 expression through the PI3K/AKT pathway. PMID- 29486291 TI - Primary low-grade fibromyxoid sarcoma of the breast: a rare case report with immunohistochemical and fluorescence in situ hybridization detection. AB - Low-grade fibromyxoid sarcoma (LGFMS) is a rare tumor with a bland histologic appearance but malignant biological behavior. Primary LGFMS of the breast has not been described in the English-language literature. Here, we report a 58-year-old Chinese female patient who presented with a painless mass in the right breast for more than 30 years. The tumor consists of spindle cells resembling fibroblasts and includes 2 kinds of morphologic change, which are alternating collagenized hypocellular zone and cell-rich myxoid area. There are more arcades of curvilinear blood vessels. The spindle cells are not heteromorphic, and mitotic figures are scarce. Immunostaining shows that tumor cells are positive for vimentin, mucin4, CD99, and Bcl-2, but negative for smooth muscle actin, desmin, S100, CD34, ALK, and myogenin. FUS gene rearrangement is positively detected by fluorescence in situ hybridization. The patient has been followed up for 59 months and is in a favorable condition. This rare location of LGFMS should be noted. PMID- 29486292 TI - Expression profiles of stemness genes in gastrointestinal stromal tumor. AB - Gastrointestinal stromal tumor (GIST) is believed to originate from intestinal cells of Cajal or their stem cell precursors, and expresses stemness-related markers, such as CD117, CD34, DOG1 and nestin. To further characterize phenotypic features of GISTs, we examined expression profiles of a panel of stemness genes in GISTs, by analyzing existing gene expression profiling datasets. Our results showed that mRNA levels of B-lymphoma moloney murine leukaemia virus insertion region-1 (BMI1), kruppel-like factor 4 (KLF4), sal-like protein 4 (SALL4) and telomerase reverse transcriptase (TERT) were significantly unregulated in GISTs. Subsequently, protein expression of BMI1 and TERT was identified in GIST specimens by immunohistochemistry. Especially, we found that high expression of nuclear BMI1 was associated with large tumor size (P = .0239), high mitotic count (P < .01), high Ki-67 index (P = .0357), advanced National Institute of Health (NIH) criteria (P = .0025) and advanced World Health Organization (WHO) classification (P < .01) in GISTs. Functional and pathway enrichment analysis showed that most of BMI1's coexpressed genes were involved in tumor growth related process, such as regulation of cell cycle and proliferation. Furthermore, we confirmed RAS oncogene family (RAB18) and limb development membrane protein 1 (LMBR1) genes as novel targets for BMI1 in GIST cells. These results provide valuable information for the expression profiles of stemness genes in GISTs, and identified nuclear BMI1 as an important marker of GIST cell proliferation and progression. PMID- 29486293 TI - Familial PDGFRA-mutation syndrome: somatic and gastrointestinal phenotype. AB - Germline activating platelet-derived growth factor receptor alpha (PDGFRA) mutations have been described in four families. All the index patients have presented with multiple mesenchymal tumors of the gastrointestinal tract. We identified a fifth family with four first-degree relatives that harbor a PDGFRA exon 18 (D846V) germline mutation. The affected kindred have a unique phenotype including coarse facies and skin, broad hands and feet, and previously undescribed premature tooth loss. While the index patient presented with multiple small bowel inflammatory fibroid polyps (IFPs) and has a gastric gastrointestinal stromal tumor (GIST), no tumors have yet been identified in other family members. We describe the pathology, genetics, the incomplete penetrance and variable expressivity of the familial PDGFRA-mutation syndrome referencing the mouse knock in Pdgfra model. We speculate on the role of the telocyte, a recently described CD34, PDGFRA+ stromal cell, in the development of inflammatory fibroid polyps and the somatic phenotype. PMID- 29486294 TI - Mitochondrial DNA variants modulate genetic susceptibility to Parkinson's disease in Han Chinese. AB - It is well recognized that mitochondrial dysfunction is involved in the pathogenesis of Parkinson's disease (PD). The mtDNA displacement loop (D-loop) region is known to accumulate structural alterations and mutations. To understand how mtDNA variants contribute to the susceptibility to sporadic PD in Chinese, a total of 500 PD patients and 505 controls were recruited from East China, and their D-loop regions were sequenced. A total of 389 variants were detected out of the 1005 subjects. There were 91 variants with frequencies >1%, which included 88 single nucleotide polymorphisms (SNPs), 2 deletions and 1 insertion. Amongst, 6 SNPs were significantly associated with sporadic PD. Specifically, the SNPs 151T/C, 189G/A, 16086C/T and 16271C/T contributed to increased susceptibility, while 318C/T and 16134T/C were associated with reduced risk for PD. Further analyses of mtDNA haplogroups and their risk for PD occurrence showed that subjects carrying haplogroup A5 were susceptible while haplogroup B5 carriers were more resistant to the disease. In summary, our study for the first time systematically analyzed mtDNA variants by sequencing the D-loop region in a Chinese population to understand their associations with PD. These results demonstrate that mtDNA variants modulate risk for sporadic PD. PMID- 29486295 TI - Parkinson's disease genetic risk in a midbrain neuronal cell line. AB - In genome-wide association studies of complex diseases, many risk polymorphisms are found to lie in non-coding DNA and likely confer risk through allele dependent differences in gene regulatory elements. However, because distal regulatory elements can alter gene expression at various distances on linear DNA, the identity of relevant genes is unknown for most risk loci. In Parkinson's disease, at least some genetic risk is likely intrinsic to a neuronal subpopulation of cells in the brain regions affected. In order to compare neuron relevant methods of pairing risk polymorphisms to target genes as well as to further characterize a single-cell model of a neurodegenerative disease, we used the portionally-dopaminergic, neuronal, mesencephalic-derived cell line LUHMES to dissect differentiation-specific mechanisms of gene expression. We compared genome-wide gene expression in undifferentiated and differentiated cells with genome-wide histone H3K27ac and CTCF-bound regions. Whereas promoters and CTCF binding were largely consistent between differentiated and undifferentiated cells, enhancers were mostly unique. We matched the differentiation-specific appearance or disappearance of enhancers with changes in gene expression and identified 22,057 enhancers paired with 6388 differentially expressed genes by proximity. These enhancers are enriched with at least 13 transcription factor response elements, driving a cluster of genes involved in neurogenesis. We show that differentiated LUHMES cells, but not undifferentiated cells, show enrichment for PD-risk SNPs. Candidate genes for these loci are largely unrelated, though a subset is linked to synaptic vesicle cycling and transport, implying that PD related disruption of these pathways is intrinsic to dopaminergic neurons. PMID- 29486296 TI - Abnormal hippocampal theta and gamma hypersynchrony produces network and spike timing disturbances in the Fmr1-KO mouse model of Fragile X syndrome. AB - Neuronal networks can synchronize their activity through excitatory and inhibitory connections, which is conducive to synaptic plasticity. This synchronization is reflected in rhythmic fluctuations of the extracellular field. In the hippocampus, theta and gamma band LFP oscillations are a hallmark of the processing of spatial information and memory. Fragile X syndrome (FXS) is an intellectual disability and the most common genetic cause of autism spectrum disorder (Belmonte and Bourgeron, 2006). Here, we investigated how neuronal network synchronization in the mouse hippocampus is compromised by the Fmr1 mutation that causes FXS (Santos et al., 2014), relating recently observed single cell level impairments (Arbab et al., 2017) to neuronal network aberrations. We implanted tetrodes in hippocampus of freely moving Fmr1-KO and littermate wildtype (WT) mice (Mientjes et al., 2006), to record spike trains from multiple, isolated neurons as well as LFPs in a spatial exploration paradigm. Compared to wild type mice, Fmr1-KO mice displayed greater power of hippocampal theta oscillations, and higher coherence in the slow gamma band. Additionally, spike trains of Fmr1-KO interneurons show decreased spike-count correlations and they are hypersynchronized with theta and slow gamma oscillations. The hypersynchronization of Fmr1-KO oscillations and spike timing reflects functional deficits in local networks. This network hypersynchronization pathologically decreases the heterogeneity of spike-LFP phase coupling, compromising information processing within the hippocampal circuit. These findings may reflect a pathophysiological mechanism explaining cognitive impairments in FXS and autism, in which there is anomalous processing of social and environmental cues and associated deficits in memory and cognition. PMID- 29486297 TI - Muscle microRNA signatures as biomarkers of disease progression in amyotrophic lateral sclerosis. AB - ALS is a fatal neurodegenerative disorder of motor neurons leading to progressive atrophy and weakness of muscles. Some of the earliest pathophysiological changes occur at the level of skeletal muscle and the neuromuscular junction. We previously identified distinct mRNA patterns, including members of the Smad and TGF-beta family, that emerge in muscle tissue at the earliest (pre-clinical) stages. These patterns track disease progression in the mutant SOD1 mouse and are present in human ALS muscle. Because miRNAs play a direct regulatory role in mRNA expression, we hypothesized in this study that there would be distinct miRNA patterns in ALS muscle appearing in early stages that could track disease progression. We performed next-generation miRNA sequencing on muscle samples from G93A SOD1 mice at early (pre-clinical) and late (symptomatic) stages, and identified distinct miRNA patterns at both stages with some overlap. An Ingenuity Pathway Analysis predicted effects on a number of pathways relevant to ALS including TGF-beta signaling, axon guidance signaling, and mitochondrial function. A subset of miRNAs was validated in the G93A SOD1 mouse at four stages of disease, and several appeared to track disease progression, including miR-206. We assessed these miRNAs in a large cohort of human ALS and disease control samples and found that some had similar changes but were not specific for ALS. Surprisingly, miR-206 levels did not change overall compared to normal controls, but did correlate with changes in strength of the muscle biopsied. In summary, we identified distinct miRNA patterns in ALS muscle that reflected disease stage which could potentially be used as biomarkers of disease activity. PMID- 29486298 TI - In vivo imaging of early signs of dopaminergic neuronal death in an animal model of Parkinson's disease. AB - The Parkinson's disease (PD) evolves over an extended period of time with the onset occurring long before clinical signs begin to manifest. Characterization of the molecular events underlying the PD onset is instrumental for the development of diagnostic markers and preventive treatments, progress in this field is hindered by technical limitations. We applied an imaging approach to demonstrate the activation of Nrf2 transcription factor as a hallmark of neurodegeneration in neurotoxin-driven models of PD. In dopaminergic SK-N-BE neuroblastoma cells, Nrf2 activation was detected in cells committed to die as proven by time lapse microscopy; in the substantia nigra pars compacta area of the mouse brain, the Nrf2 activation preceded dopaminergic neurodegeneration as demonstrated by in vivo and ex vivo optical imaging, a finding confirmed by co-localization experiments carried out by immunohistochemistry. Collectively, our results identify the Nrf2 signaling as an early marker of neurodegeneration, anticipating dopaminergic neurodegeneration and motor deficits. PMID- 29486299 TI - Phase-amplitude coupling and epileptogenesis in an animal model of mesial temporal lobe epilepsy. AB - Polyrhythmic coupling of oscillatory components in electrophysiological signals results from the interactions between neuronal sub-populations within and between cell assemblies. Since the mechanisms underlying epileptic disorders should affect such interactions, abnormal level of cross-frequency coupling is expected to provide a signal marker of epileptogenesis. We measured phase-amplitude coupling (PAC), a form of cross-frequency coupling between neural oscillations, in a rodent model of mesial temporal lobe epilepsy. Sprague-Dawley rats (n = 4, 250-300 g) were injected with pilocarpine (380 mg/kg, i.p) to induce a status epilepticus (SE) that was stopped after 1 h with diazepam (5 mg/kg, s.c.) and ketamine (50 mg/kg, s.c.). Control animals (n = 6) did not receive any injection or treatment. Three days after SE, all animals were implanted with bipolar electrodes in the hippocampal CA3 subfield, entorhinal cortex, dentate gyrus and subiculum. Continuous video/EEG recordings were performed 24/7 at a sampling rate of 2 kHz, over 15 consecutive days. Pilocarpine-treated animals showed interictal spikes (5.25 (+/-2.5) per minute) and seizures (n = 32) that appeared 7 (+/-0.8) days after SE. We found that CA3 was the seizure onset zone in most epileptic animals, with stronger ongoing PAC coupling between seizures than in controls (Kruskal-Wallis test: chi2 (1,36) = 46.3, Bonferroni corrected, p < 0.001). Strong PAC in CA3 occurred between the phase of slow-wave oscillations (<1 Hz) and the amplitude of faster rhythms (50-180 Hz), with the strongest bouts of high frequency activity occurring preferentially on the ascending phase of the slow wave. We also identified that cross-frequency coupling in CA3 (rho = 0.44, p < 0.001) and subiculum (rho = 0.41, p < 0.001) was positively correlated with the daily number of seizures. Overall, our study demonstrates that cross-frequency coupling may represent a signal marker in epilepsy and suggests that this methodology could be transferred to clinical scalp MEG and EEG recordings. PMID- 29486301 TI - Haplogroup J mitogenomes are the most sensitive to the pesticide rotenone: Relevance for human diseases. AB - There is growing evidence that the sequence variation of mitochondrial DNA (mtDNA), which clusters in population- and/or geographic-specific haplogroups, may result in functional effects that, in turn, become relevant in disease predisposition or protection, interaction with environmental factors and ultimately in modulating longevity. To unravel functional differences between mtDNA haplogroups we here employed transmitochondrial cytoplasmic hybrid cells (cybrids) grown in galactose medium, a culture condition that forces oxidative phosphorylation, and in the presence of rotenone, the classic inhibitor of respiratory Complex I. Under this experimental paradigm we assessed functional parameters such as cell viability and respiration, ATP synthesis, reactive oxygen species production and mtDNA copy number. Our analyses show that haplogroup J1, which is common in western Eurasian populations, is the most sensitive to rotenone, whereas K1 mitogenomes orchestrate the best compensation, possibly because of the haplogroup-specific missense variants impinging on Complex I function. Remarkably, haplogroups J1 and K1 fit the genetic associations previously established with Leber's hereditary optic neuropathy (LHON) for J1, as a penetrance enhancer, and with Parkinson's disease (PD) for K1, as a protective background. Our findings provide functional evidences supporting previous well established genetic associations of specific haplogroups with two neurodegenerative pathologies, LHON and PD. Our experimental paradigm is instrumental to highlighting the subtle functional differences characterizing mtDNA haplogroups, which will be increasingly needed to dissect the role of mtDNA genetic variation in health, disease and longevity. PMID- 29486300 TI - Vascular tight junction disruption and angiogenesis in spontaneously hypertensive rat with neuroinflammatory white matter injury. AB - Vascular cognitive impairment is a major cause of dementia caused by chronic hypoxia, producing progressive damage to white matter (WM) secondary to blood brain barrier (BBB) opening and vascular dysfunction. Tight junction proteins (TJPs), which maintain BBB integrity, are lost in acute ischemia. Although angiogenesis is critical for neurovascular remodeling, less is known about its role in chronic hypoxia. To study the impact of TJP degradation and angiogenesis during pathological progression of WM damage, we used the spontaneously hypertensive/stroke prone rats with unilateral carotid artery occlusion and Japanese permissive diet to model WM damage. MRI and IgG immunostaining showed regions with BBB damage, which corresponded with decreased endothelial TJPs, claudin-5, occludin, and ZO-1. Affected WM had increased expression of angiogenic factors, Ki67, NG2, VEGF-A, and MMP-3 in vascular endothelial cells and pericytes. To facilitate the study of angiogenesis, we treated rats with minocycline to block BBB disruption, reduce WM lesion size, and extend survival. Minocycline-treated rats showed increased VEGF-A protein, TJP formation, and oligodendrocyte proliferation. We propose that chronic hypoxia disrupts TJPs, increasing vascular permeability, and initiating angiogenesis in WM. Minocycline facilitated WM repair by reducing BBB damage and enhancing expression of TJPs and angiogenesis, ultimately preserving oligodendrocytes. PMID- 29486302 TI - Brain targeting of resveratrol by nasal administration of chitosan-coated lipid microparticles. AB - Lipid microparticles (LMs) uncoated or coated with chitosan and containing the neuroprotective polyphenol resveratrol were developed for its targeting to the brain via nasal administration. The lipid microparticles loaded with resveratrol (LMs-Res) were produced by melt emulsification, using stearic acid as lipid material and phosphatidylcholine as the surfactant. The chitosan coated particles LMs-Res-Ch (1.75% w/v chitosan solution) and LMs-Res-Ch-plus (8.75% w/v chitosan solution) were prepared by adding a chitosan solution to the formed particles. The mean diameter of the particles were 68.5 +/- 3.1 MUm, 76.3 +/- 5.2 MUm and 84.5 +/- 8.1 MUm for LMs-Res, LMs-Res-Ch and LMs-Res-Ch-plus respectively, suitable for nasal delivery. Chitosan coating changed the particle surface charge from a negative zeta potential value (-12.7 +/- 2.1 mV) for the uncoated particles to a higher positive values respectively, 24.0 +/- 4.7 and 44.6 +/- 3.1 mV for the chitosan coated LM-Res-Ch and LM-Res-Ch-plus. Permeation studies across human NCM460 cell monolayers demonstrated that their transepithelial electrical resistance (TEER) values were not modified in the presence of free resveratrol, unloaded LMs, loaded LMs-Res or LMs-Res-Ch. On the other hand, the TEER values decreased from 150 +/- 7 to 41 +/- 3 Omega cm2 in the presence of LMs Res-Ch-plus, which corresponded to a significant increase in the apparent permeability (Papp) of resveratrol from 518 +/- 8 * 10-4 cm/min to 750 +/- 98 * 10-4 cm/min. In vivo studies demonstrated that no resveratrol was detected in the rat cerebrospinal fluid (CSF) after an intravenous infusion of the polyphenol. Conversely, the nasal delivery of resveratrol in a chitosan suspension or encapsulated in uncoated LMs-Res dispersed in water achieved the uptake of resveratrol in the CSF with Cmax after 60 min of 1.30 +/- 0.30 MUg/ml and 0.79 +/ 0.15 MUg/ml, respectively. However, a dramatic increase in the levels of resveratrol reaching the CSF was attained by the administration of an aqueous suspension of LMs-Res-Ch-plus with a Cmax after 60 min of 9.7 +/- 1.9 MUg/ml. This marked increase in the CSF bioavailability was achieved without any distribution in the systemic circulation, demonstrating a direct and specific nose to brain delivery. PMID- 29486303 TI - Effect of storage temperature on the stability of spray dried bacteriophage powders. AB - This study aimed to assess the robustness of using a spray drying approach and formulation design in producing inhalable phage powders. Two types of Pseudomonas phages, PEV2 (Podovirus) and PEV40 (Myovirus) in two formulations containing different amounts of trehalose (70% and 60%) and leucine (30% and 40%) were studied. Most of the surface of the produced powders was found to be covered in crystalline leucine. The powders were stored at 4 degrees C and 20 degrees C under vacuum. The phage stability and in vitro aerosol performance of the phage powders were examined on the day of production and after 1, 3 and 12 months of storage. A minor titer loss during production was observed for both phages (0.2 0.8 log10 pfu/ml). The storage stability of the produced phage powders was found to be phage and formulation dependent. No further reduction in titer occurred for PEV2 powders stored at 4 degrees C across the study. The formulation containing 30% leucine maintained the viability of PEV2 at 20 degrees C, while the formulation containing 40% leucine gradually lost titer over time with a storage reduction of ~0.9 log10 pfu/ml measured after 12 months. In comparison, the PEV40 phage powders generally had a ~ 0.5 log10 pfu/ml loss upon storage regardless of temperature. When aerosolized, the total in vitro lung doses of PEV2 were of the order of 107 pfu, except the formulation containing 40% leucine stored at 20 degrees C which had a lower lung dose. The PEV40 powders also had lung doses of 106-107 pfu. The results demonstrate that spray dried Myoviridae and Podoviridae phage in a simple formulation of leucine and trehalose can be successfully stored for one year at 4 degrees C and 20 degrees C with vacuum packaging. PMID- 29486305 TI - Studying allergic inflammation and spirometry over menstrual cycles in well controlled asthmatic women: Changes in progesterone and estradiol affect neither FENO levels nor lung function. AB - It has been reported that female sex hormones influence on allergic inflammation and ventilation parameters in asthma but conclusions drawn by different researchers are divergent. The aim of our study was to assess the impact of progesterone (Pg) and estradiol (E) on the dynamics of allergic inflammation and spirometry test results in regularly menstruating women with stable allergic asthma. 13 women (28 days menstrual cycle), aged 18-45, taking no hormonal contraceptives, with mild and moderate asthma, without reported exacerbations at the near-ovulation and/or menstruation time, were monitored during two consecutive menstrual cycles. They had 4 visits per cycle (the first day of menstruation was assumed to be day 1 of the cycle; visits were carried out on days: 3-4, 10-11, 13-14 and 23-24). At each visit asthma symptoms, asthma control test (ACT) results, asthma treatment, fractioned nitric oxide (FENO) levels, spirometry test results, Pg and E, levels were analyzed. As a result of the study, no essential variability in FENO values and ventilation parameters' values in the course of menstruation cycle were observed. Negative correlation between FENO values and Pg concentrations was demonstrated (r = 0.27), but no correlation between FENO values and E levels was shown. No relationship between the ACT values and ventilation parameters and the levels of the sex hormones under investigation was detected. We conclude that changing levels of estradiol and progesterone (regardless of the negative correlation of progesterone and FENO values) affect neither the dynamics of allergic inflammation nor pulmonary function in women with stable allergic mild/moderate asthma. PMID- 29486304 TI - Development of a portable mini-generator to safely produce nitric oxide for the treatment of infants with pulmonary hypertension. AB - OBJECTIVES: To test the safety of a novel miniaturized device that produces nitric oxide (NO) from air by pulsed electrical discharge, and to demonstrate that the generated NO can be used to vasodilate the pulmonary vasculature in rabbits with chemically-induced pulmonary hypertension. STUDY DESIGN: A miniature NO (mini-NO) generator was tested for its ability to produce therapeutic levels (20-80 parts per million (ppm)) of NO, while removing potentially toxic gases and metal particles. We studied healthy 6-month-old New Zealand rabbits weighing 3.4 +/- 0.4 kg (mean +/- SD, n = 8). Pulmonary hypertension was induced by chemically increasing right ventricular systolic pressure to 28-30 mmHg. The mini-NO generator was placed near the endotracheal tube. Production of NO was triggered by a pediatric airway flowmeter during the first 0.5 s of inspiration. RESULTS: In rabbits with acute pulmonary hypertension, the mini-NO generator produced sufficient NO to induce pulmonary vasodilation. Potentially toxic nitrogen dioxide (NO2) and ozone (O3) were removed by the Ca(OH)2 scavenger. Metallic particles, released from the electrodes by the electric plasma, were removed by a 0.22 MUm filter. While producing 40 ppm NO, the mini-NO generator was cooled by a flow of air (70 ml/min) and the external temperature of the housing did not exceed 31 degrees C. CONCLUSIONS: The mini-NO generator safely produced therapeutic levels of NO from air. The mini-NO generator is an effective and economical approach to producing NO for treating neonatal pulmonary hypertension and will increase the accessibility and therapeutic uses of life-saving NO therapy worldwide. PMID- 29486306 TI - Altered levels of exhaled nitric oxide in rheumatoid arthritis. AB - BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disorder characterized by bone and joint destruction, but other organ systems can also be involved. Recent studies have suggested that the disease may start in the lungs. Exhaled nitric oxide (FENO) is a marker of inflammation. The aims of the study were to compare the NO parameters between subjects with RA and healthy control subjects, and to examine whether the NO parameters correlated with lung function and disease activity in the subjects with RA. METHODS: Subjects with RA (n = 35) were recruited during their regular outpatient visits to the rheumatology department. The nitric oxide (NO) parameters: alveolar NO concentration (CANO), airway compartment diffusing capacity of NO (DawNO), and tissue concentration of NO in the airway wall (CawNO), were algorithmically estimated. Healthy subjects (n = 35) matched by age, gender and height were used as controls. Data are given in median, (quartile 25, 75). Wilcoxon Matched Pairs test was used for group comparisons. Mann-Whitney U test was used to make comparisons between any two groups and for pairwise comparisons. Correlations were tested with Spearman rank order correlation. RESULTS: CANO was significantly lower in the RA subjects compared with healthy subjects; 1.1 (0.5, 1.8) ppb versus 2.4 (2.0, 3.0) ppb, (p < 0.001). CawNO was significantly lower in the RA subjects with 51 (22, 87) ppb versus 120 (76, 162) ppb in the control group. DawNO was significantly higher at 25 (15, 36) mL/s in the RA group versus the control group's 7.7 (5.3, 10.7) mL/s. CONCLUSIONS: There are significant differences between subjects with RA and matched healthy control subjects regarding the exhaled NO parameters. It is unclear if this can be explained by the pathogenesis of RA, consequences of long term disease, and/or due to drug treatment. PMID- 29486307 TI - Medical and Surgical Treatment of Endemic Mycotic Spinal Osteomyelitis. PMID- 29486308 TI - The Ponticulus Posticus as Risk Factor for Screw Insertion into the First Cervical Lateral Mass. AB - BACKGROUND: Awareness of the osseous anomaly of ponticulus posticus (PP) is crucial in avoiding vertebral artery (VA) injuries during C1 instrumentation. The aim of this study was to investigate PP and its relationship with the VA with three-dimensional computed tomography angiography. METHODS: PP and the VA were investigated as intraoperative landmarks. The intersection of the VA to the posterior arch of C1 and the medial line and the posterior arch and VA curve around lateral masses were measured as intraoperative references. RESULTS: PP was identified in 14.3% of samples. The anomaly was more common in women and on the right side. Of cases, 48.2% had PP bilaterally. In PP cases, the VA had variable courses through C2 before it passed under its bony bridges on the posterior arch of C1. Mean distances were found at the intersection of the VA to the posterior arch of C1 and the medial line to be larger and the posterior arch of C1 and the VA curve around lateral masses to be narrower than normal cases. Dual computed tomography scan data from C1 with PP were used to create three-dimensional patient-specific life-sized cervical spine models. Models revealed how the bone bridge affected the VA. The feasibility (>4 mm) of a safe lateral mass screw fixation was not influenced by PP anomalies. CONCLUSIONS: The presence of the PP loop can limit space available for placement of the screw through the bony elements of C1. Standard screw techniques are contraindicated owing to the unacceptable high risk of VA injury. PMID- 29486309 TI - Improve the Accuracy of Neurosurgery Studies: Join the STROBE Initiative. PMID- 29486310 TI - Safety and Efficacy of Endovascular Treatment of Previously Clipped Aneurysms: A Systematic Review and Meta-Analysis. AB - BACKGROUND/OBJECTIVE: The safety and efficacy of endovascular treatment of previously clipped aneurysms have not been well-established. We conducted a systematic review of the literature to evaluate the outcomes of endovascular treatment of previously clipped aneurysms. METHODS: A systematic search of MEDLINE, Embase, Scopus, and the Web of Science was performed for studies published until October 2017. We included studies with >=2 patients that described endovascular treatment of previously clipped aneurysms. A random effects meta-analysis was used to pool the following outcomes: technical success, aneurysm occlusion/recurrence/rebleed, ischemic/thrombotic/thromboembolic events, neurologic/procedure-related morbidity/mortality, and favorable neurologic outcomes. We performed subgroup analyses by aneurysm rupture status on presentation to the endovascular procedure, treatment timing, and by aneurysm location (anterior vs. posterior circulation). RESULTS: In total, 27 studies with 271 patients were included. Overall complete occlusion was 76.1% (95% confidence interval [CI] 0.676-0.836) and technical success was 97.9% (95% CI 0.958-0.993). Combined procedure-related morbidity/mortality was 4.5% (95% CI 0.024-0.073). There were no statistically significant differences in any of the safety and efficacy outcomes by aneurysm location. Overall long-term favorable neurologic outcome was 78.5% (95% CI 0.732-0.834). All included studies are retrospective. CONCLUSIONS: Our meta-analysis demonstrated that endovascular treatment is acceptably safe and effective. It is important to point out that the complication rate of treatment of these aneurysms is not negligible. These findings should be considered when deciding the best therapeutic strategy. Our findings may suggest that endovascular treatment of previously clipped aneurysms should only be considered in circumstances in which conservative management seems to be unsafe. PMID- 29486311 TI - Microvascular Decompression and Arachnoid Cyst Fenestration for Treatment of Medulla Oblongata Compression Caused by Arachnoid Cyst-Vascular Loop Complex. AB - BACKGROUND: Vascular compression of neural structures has long been established as an etiology for dysfunction of multiple cranial nerves. Classically, as is the case of trigeminal neuralgia, vascular compression by an offending artery and sometimes vein-exerting pressure at the root entry zone of the trigeminal nerve can lead to the characteristic pain syndrome. CASE DESCRIPTION: In these cases, microvascular decompression is an effective, durable surgical intervention to relieve the neuralgia. In this report, we present a unique case of a patient with direct compression of the medulla oblongata by an arachnoid cyst and associated vascular loops. CONCLUSION: Confirming our suspected pathophysiology of this case, we noted resolution of the patient's symptoms following fenestration of cyst and microvascular decompression. PMID- 29486312 TI - Feasibility of Clinician-Facilitated Three-Dimensional Printing of Synthetic Cranioplasty Flaps. AB - BACKGROUND: Integration of three-dimensional (3D) printing and stereolithography into clinical practice is in its nascence, and concepts may be esoteric to the practicing neurosurgeon. Currently, creation of 3D printed implants involves recruitment of offsite third parties. We explored a range of 3D scanning and stereolithographic techniques to create patient-specific synthetic implants using an onsite, clinician-facilitated approach. METHODS: We simulated bilateral craniectomies in a single cadaveric specimen. We devised 3 methods of creating stereolithographically viable virtual models from removed bone. First, we used preoperative and postoperative computed tomography scanner-derived bony window models from which the flap was extracted. Second, we used an entry-level 3D light scanner to scan and render models of the individual bone pieces. Third, we used an arm-mounted, 3D laser scanner to create virtual models using a real-time approach. RESULTS: Flaps were printed from the computed tomography scanner and laser scanner models only in a ultraviolet-cured polymer. The light scanner did not produce suitable virtual models for printing. The computed tomography scanner derived models required extensive postfabrication modification to fit the existing defects. The laser scanner models assumed good fit within the defects without any modification. CONCLUSIONS: The methods presented varying levels of complexity in acquisition and model rendering. Each technique required hardware at varying in price points from $0 to approximately $100,000. The laser scanner models produced the best quality parts, which had near-perfect fit with the original defects. Potential neurosurgical applications of this technology are discussed. PMID- 29486313 TI - Full Endoscopic Vascular Decompression in Trigeminal Neuralgia: Experience of 230 Patients. AB - BACKGROUND: Although most surgeons are using endoscopy as an adjunct to microscopy in microvascular decompression, a full endoscopic technique is less commonly performed. The present study is aimed to evaluate results of 230 patients of endoscopic vascular decompression. METHODS: A retrospective study was carried out in a tertiary care hospital. Patients with typical neuralgia, with or without preoperatively detected vascular compression, were advised to undergo vascular decompression. RESULTS: Maxillary and mandibular division were involved in 116 and 93 patients, respectively. Superior cerebellar (n = 174) artery was most common vascular conflict followed by anterior inferior cerebellar artery (n = 96). Tortuous basilar artery and small veins were possible causes of neuralgia in 1 and 2 patients, respectively. Single- and double-vessel conflict were observed in 173 and 50 patients, respectively. The compressing vessel was placed anterior to the trigeminal nerve in 39 patients. An arterial loop was in contact with the nerve, producing grooving, and displacing the nerve in 215, 35, and 21 patients, respectively. Complete, satisfactory, and no relief of pain were observed in 204 (88.7%), 11 (5.8%), and 15 (6.5%) patients, respectively. Recurrence was observed in 25 patients at an average follow-up of 60 months. Temporary complications included trigeminal dysesthesia, vertigo, facial paresis, CSF leak, and reduced hearing in 9, 8, 8, 7, and 3 patients, respectively. CONCLUSION: Endoscopic vascular decompression is a safe and efficient alternative technique to endoscopic assisted microvascular decompression provided surgeon is experienced in endoscopic surgery. It is helpful in identification of all offending vessels including the double vessel, and anterior compression without brain and nerve retraction. PMID- 29486314 TI - Growth Potential of Subdural Hematomas Under Clinical Observation: Which Subdural Hematomas Tend to Grow and Why They Do. AB - OBJECTIVE: To study the prognoses of patients with subdural hematoma (SDH) who were not operated on at the time of the first diagnosis and the causes of enlarged hematomas in some patients during the follow-up period. MATERIALS AND METHODS: The records, service files, and radiologic examination results of the patients with diagnoses of SDH were reviewed. The SDH patients were recorded under 5 different categories: acute SDH (ASDH), subacute SDH (SSDH), chronic SDH (CSDH), acute component with chronic SDH (A-CSDH), and subacute component with chronic SDH (S-CSDH). The symptoms, clinical findings, and progression in the patients were correlated with radiologic examinations. RESULTS: A total of 291 patients received diagnoses of SDHs: 80 patients with acute, 29 patients with subacute, and 163 patients with chronic hematoma. Thirty-five patients had diagnoses of SDH with a combination of different components. It was determined that in the follow-up period, patients with A-CSDH showed the greatest increase in hematoma size over time and required surgical intervention the most often. CONCLUSION: SDHs reveal different prognoses in different age groups. Multicomponent SDHs are within the group that shows the greatest increase in size in the follow-up period. SDHs and CSDHs cause recurrent hemorrhages by sustaining the tension on the bridging veins. The greater the hematoma volume, the greater the growth potential of the hematoma tends to be. CSDHs that do not manifest changes in volume for a long time can be monitored without surgical intervention as long as the clinical picture remains stable. PMID- 29486315 TI - Chordomas of the Skull Base, Mobile Spine, and Sacrum: An Epidemiologic Investigation of Presentation, Treatment, and Survival. AB - BACKGROUND: Chordomas are rare primary bone tumors that arise from the axial skeleton. Our objective was to analyze trends in radiation and surgery over time and determine location-based survival predictors for chordomas of the skull base, mobile spine, and sacrum. METHODS: A retrospective cohort study of the SEER (Surveillance Epidemiology and End Results) database from 1973 to 2013 was conducted. All patients had histologically confirmed chordomas. The principal outcome measure was overall survival (OS). RESULTS: The cohort included 1616 patients: skull base (664), mobile spine (444), and sacrum (508). Skull base tumors presented earliest in life (47.4 years) and sacral tumors presented latest (62.7 years). Rates of radiation remained stable for skull base and mobile spine tumors but declined for sacral tumors (P = 0.006). Rates of surgical resection remained stable for skull base and sacral tumors but declined for mobile spine tumors (P = 0.046). Skull base chordomas had the longest median survival (162 months) compared with mobile spine (94 months) and sacral tumors (87 months). Being married was independently associated with improved OS for skull base tumors (hazard ratio, 0.73; 95% confidence interval, 0.53-0.99; P = 0.044). Surgical resection was independently associated with improved OS for sacral chordomas (hazard ratio, 0.48; 95% confidence interval, 0.34-0.69; P < 0.001). CONCLUSIONS: Surgical resection for mobile spine chordomas and radiation for sacral chordomas decreased over time. Patients with skull base tumors survived longer than did patients with mobile spine and sacral chordomas, and surgical resection was associated with improved survival in sacral chordomas only. Understanding the behavior of these tumors can help cranial and spinal surgeons improve treatment in this patient population. PMID- 29486316 TI - Microsurgical Decompression of the Cochlear Nerve to Treat Disabling Tinnitus via an Endoscope-Assisted Retrosigmoid Approach: The Padua Experience. AB - BACKGROUND: The use of surgical cochlear nerve decompression is controversial. This study aimed at investigating the safety and validity of microsurgical decompression via an endoscope-assisted retrosigmoid approach to treat tinnitus in patients with neurovascular compression of the cochlear nerve. CASE DESCRIPTION: Three patients with disabling tinnitus resulting from a loop in the internal auditory canal were evaluated with magnetic resonance imaging and tests of pure tone auditory, tinnitus, and auditory brain response (ABR) to identify the features of the cochlear nerve involvement. We observed a loop with a caliber greater than 0.8 mm in all patients. Patients were treated via an endoscope assisted retrosigmoid microsurgical decompression. After surgery, none of the patients reported short-term or long-term complications. After surgery, tinnitus resolved immediately in 2 patients, whereas in the other patient symptoms persisted although they improved; in all patients, hearing was preserved and ABR improved. CONCLUSION: Microsurgical decompression via endoscope-assisted retrosigmoid approach is a promising, safe, and valid procedure for treating tinnitus caused by cochlear nerve compression. This procedure should be considered in patients with disabling tinnitus who have altered ABR and a loop that has a caliber greater than 0.8 mm and is in contact with the cochlear nerve. PMID- 29486317 TI - Lumbosacral Intraspinal Paraganglioma: Clinicopathologic and Computed Tomography/Magnetic Resonance Imaging Features of 13 Cases. AB - OBJECTIVE: To retrospectively review the clinicopathologic features and computed tomography (CT) and magnetic resonance imaging (MRI) findings of lumbosacral intraspinal paragangliomas (PGLs). METHODS: Thirteen patients with surgically and pathologically confirmed lumbosacral intraspinal PGLs were enrolled. Their clinicopathologic data and imaging findings were retrospectively reviewed. RESULTS: Ten male and 3 female patients with a median age of 43 years (range, 36 74 years) were included. CT or MRI showed a well-defined (n = 13), oval (n = 10), or striated (n = 3) mass with heterogeneous (n = 6) or homogeneous density/signal intensity (n = 7). The lesions appeared isointense (n = 13) and mildly hyperintense (n = 13) on T1-weighted and T2-weighted MRI, respectively. On enhanced CT/MRI, markedly heterogeneous (n = 6) and homogeneous (n = 7) enhancement patterns were observed. The tadpole sign was observed in 9 cases. Systolic and diastolic blood pressure were higher before than after surgery (PSBP = 0.002 and PDBP = 0.001). Both systolic and diastolic blood pressure were reduced to normal after surgery. No recurrence or metastatic disease was found during the follow-up period. CONCLUSIONS: Lumbosacral intraspinal PGLs should be considered when a mass appears as well defined or oval, and when a striated solitary homogeneous or heterogeneous mass is characterized by a tadpolelike appearance with a marked enhancement pattern. The fluctuation of blood pressure before and after surgery is an interesting clinical feature of lumbosacral intraspinal PGLs. PMID- 29486319 TI - Tour around the globe: The case of invasive tapeworm Atractolytocestus huronensis (Cestoda: Caryophyllidea), a parasite of common carp. AB - The monozoic tapeworm Atractolytocestus huronensis Anthony, 1958 (Cestoda: Caryophyllidea), an intestinal parasite of the common carp, is characterized by its invasive character and potential to colonize new territories. It was initially described from North America and has also been found in several European countries. The most recent findings of A. huronensis originated from China and South Africa; however, no data on genetic relationships of these populations were available. The current study provides the first molecular characterisation of A. huronensis from South Africa and China using a partial sequence of mitochondrial cytochrome c oxidase subunit 1 (cox1) and a complete ribosomal ITS2 spacer. Ribosomal and mitochondrial data were applied for phylogenetic analyses in order to assess the genetic interrelationships among global A. huronensis populations. Divergent intragenomic copies of ribosomal ITS2 were detected in all analysed specimens; the structure and frequency of the ITS2 variants of tapeworms from China and South Africa corresponded with the data on ITS2 paralogues observed previously in A. huronensis from Slovakia, the United States and the United Kingdom. The phylogenetic analysis of cox1 indicated that A. huronensis exist in two slightly differentiated clusters; one cluster was supported by all phylogenetic approaches (NJ, ML, BI) and was represented by samples from China, the USA and the UK. A second cluster was represented by tapeworms from continental Europe (Slovakia, Hungary, Romania, Croatia) and South Africa. Haplotype network analysis revealed that the highest population diversity occurs in China. The results provide useful pilot information about the interrelationships of A. huronensis on four continents and indicate that China, or the eastern Palaearctic, served as the original source population for the global expansion of this invasive tapeworm. Data on the origin and distribution of the common carp, the only specific host of A. huronensis, are also discussed. PMID- 29486320 TI - The bilingual language network: Differential involvement of anterior cingulate, basal ganglia and prefrontal cortex in preparation, monitoring, and execution. AB - Research on the neural bases of bilingual language control has largely overlooked the role of preparatory processes, which are central to cognitive control. Additionally, little is known about how the processes involved in global language selection may differ from those involved in the selection of words and morpho syntactic rules for manipulating them. These processes were examined separately in an fMRI experiment, with an emphasis on understanding how and when general cognitive control regions become activated. Results of region-of-interest analyses on 23 early Spanish-English bilinguals showed that the anterior cingulate cortex (ACC) was primarily engaged during the language preparation phase of the task, whereas the left prefrontal (DLPFC) and pre-supplementary motor areas showed increasing activation from preparation to execution. Activation in the basal ganglia (BG), left middle temporal lobe, and right precentral cortical regions did not significantly differ throughout the task. These results suggest that three core cognitive control regions, the ACC, DLPFC, and BG, which have been previously implicated in bilingual language control, engage in distinct neurocognitive processes. Specifically, the results are consistent with the view that the BG "keep track" of the target language in use throughout various levels of language selection, that the ACC is particularly important for top-down target language preparation, and that the left prefrontal cortex is increasingly involved in selection processes from preparation through task execution. PMID- 29486318 TI - Targeting IkappaappaB kinases for cancer therapy. AB - The inhibitory kappa B kinases (IKKs) and IKK related kinases are crucial regulators of the pro-inflammatory transcription factor, nuclear factor kappa B (NF-kappaB). The dysregulation in the activities of these kinases has been reported in several cancer types. These kinases are known to regulate survival, proliferation, invasion, angiogenesis, and metastasis of cancer cells. Thus, IKK and IKK related kinases have emerged as an attractive target for the development of cancer therapeutics. Several IKK inhibitors have been developed, few of which have advanced to the clinic. These inhibitors target IKK either directly or indirectly by modulating the activities of other signaling molecules. Some inhibitors suppress IKK activity by disrupting the protein-protein interaction in the IKK complex. The inhibition of IKK has also been shown to enhance the efficacy of conventional chemotherapeutic agents. Because IKK and NF-kappaB are the key components of innate immunity, suppressing IKK is associated with the risk of immune suppression. Furthermore, IKK inhibitors may hit other signaling molecules and thus may produce off-target effects. Recent studies suggest that multiple cytoplasmic and nuclear proteins distinct from NF-kappaB and inhibitory kappaB are also substrates of IKK. In this review, we discuss the utility of IKK inhibitors for cancer therapy. The limitations associated with the intervention of IKK are also discussed. PMID- 29486321 TI - Oxytocin attenuates trust as a subset of more general reinforcement learning, with altered reward circuit functional connectivity in males. AB - Oxytocin (OT) is an endogenous neuropeptide that, while originally thought to promote trust, has more recently been found to be context-dependent. Here we extend experimental paradigms previously restricted to de novo decision-to-trust, to a more realistic environment in which social relationships evolve in response to iterative feedback over twenty interactions. In a randomized, double blind, placebo-controlled within-subject/crossover experiment of human adult males, we investigated the effects of a single dose of intranasal OT (40 IU) on Bayesian expectation updating and reinforcement learning within a social context, with associated brain circuit dynamics. Subjects participated in a neuroeconomic task (Iterative Trust Game) designed to probe iterative social learning while their brains were scanned using ultra-high field (7T) fMRI. We modeled each subject's behavior using Bayesian updating of belief-states ("willingness to trust") as well as canonical measures of reinforcement learning (learning rate, inverse temperature). Behavioral trajectories were then used as regressors within fMRI activation and connectivity analyses to identify corresponding brain network functionality affected by OT. Behaviorally, OT reduced feedback learning, without bias with respect to positive versus negative reward. Neurobiologically, reduced learning under OT was associated with muted communication between three key nodes within the reward circuit: the orbitofrontal cortex, amygdala, and lateral (limbic) habenula. Our data suggest that OT, rather than inspiring feelings of generosity, instead attenuates the brain's encoding of prediction error and therefore its ability to modulate pre-existing beliefs. This effect may underlie OT's putative role in promoting what has typically been reported as 'unjustified trust' in the face of information that suggests likely betrayal, while also resolving apparent contradictions with regard to OT's context-dependent behavioral effects. PMID- 29486322 TI - Exploring the origins of EEG motion artefacts during simultaneous fMRI acquisition: Implications for motion artefact correction. AB - Motion artefacts (MAs) are induced within EEG data collected simultaneously with fMRI when the subject's head rotates relative to the magnetic field. The effects of these artefacts have generally been ameliorated by removing periods of data during which large artefact voltages appear in the EEG traces. However, even when combined with other standard post-processing methods, this strategy does not remove smaller MAs which can dominate the neuronal signals of interest. A number of methods are therefore being developed to characterise the MA by measuring reference signals and then using these in artefact correction. These methods generally assume that the head and EEG cap, plus any attached sensors, form a rigid body which can be characterised by a standard set of six motion parameters. Here we investigate the motion of the head/EEG cap system to provide a better understanding of MAs. We focus on the reference layer artefact subtraction (RLAS) approach, as this allows measurement of a separate reference signal for each electrode that is being used to measure brain activity. Through a series of experiments on phantoms and subjects, we find that movement of the EEG cap relative to the phantom and skin on the forehead is relatively small and that this non-rigid body movement does not appear to cause considerable discrepancy in artefacts between the scalp and reference signals. However, differences in the amplitude of these signals is observed which may be due to differences in geometry of the system from which the reference signals are measured compared with the brain signals. In addition, we find that there is non-rigid body movement of the skull and skin which produces an additional MA component for a head shake, which is not present for a head nod. This results in a large discrepancy in the amplitude and temporal profile of the MA measured on the scalp and reference layer, reducing the efficacy of MA correction based on the reference signals. Together our data suggest that the efficacy of the correction of MA using any reference-based system is likely to differ for different types of head movement with head shake being the hardest to correct. This provides new information to inform the development of hardware and post-processing methods for removing MAs from EEG data acquired simultaneously with fMRI data. PMID- 29486325 TI - Consistency and similarity of MEG- and fMRI-signal time courses during movie viewing. AB - Movie viewing allows human perception and cognition to be studied in complex, real-life-like situations in a brain-imaging laboratory. Previous studies with functional magnetic resonance imaging (fMRI) and with magneto- and electroencephalography (MEG and EEG) have demonstrated consistent temporal dynamics of brain activity across movie viewers. However, little is known about the similarities and differences of fMRI and MEG or EEG dynamics during such naturalistic situations. We thus compared MEG and fMRI responses to the same 15 min black-and-white movie in the same eight subjects who watched the movie twice during both MEG and fMRI recordings. We analyzed intra- and intersubject voxel wise correlations within each imaging modality as well as the correlation of the MEG envelopes and fMRI signals. The fMRI signals showed voxel-wise within- and between-subjects correlations up to r = 0.66 and r = 0.37, respectively, whereas these correlations were clearly weaker for the envelopes of band-pass filtered (7 frequency bands below 100 Hz) MEG signals (within-subjects correlation r < 0.14 and between-subjects r < 0.05). Direct MEG-fMRI voxel-wise correlations were unreliable. Notably, applying a spatial-filtering approach to the MEG data uncovered consistent canonical variates that showed considerably stronger (up to r = 0.25) between-subjects correlations than the univariate voxel-wise analysis. Furthermore, the envelopes of the time courses of these variates up to about 10 Hz showed association with fMRI signals in a general linear model. Similarities between envelopes of MEG canonical variates and fMRI voxel time-courses were seen mostly in occipital, but also in temporal and frontal brain regions, whereas intra- and intersubject correlations for MEG and fMRI separately were strongest only in the occipital areas. In contrast to the conventional univariate analysis, the spatial-filtering approach was able to uncover associations between the MEG envelopes and fMRI time courses, shedding light on the similarities of hemodynamic and electromagnetic brain activities during movie viewing. PMID- 29486323 TI - The impact of in-scanner head motion on structural connectivity derived from diffusion MRI. AB - Multiple studies have shown that data quality is a critical confound in the construction of brain networks derived from functional MRI. This problem is particularly relevant for studies of human brain development where important variables (such as participant age) are correlated with data quality. Nevertheless, the impact of head motion on estimates of structural connectivity derived from diffusion tractography methods remains poorly characterized. Here, we evaluated the impact of in-scanner head motion on structural connectivity using a sample of 949 participants (ages 8-23 years old) who passed a rigorous quality assessment protocol for diffusion magnetic resonance imaging (dMRI) acquired as part of the Philadelphia Neurodevelopmental Cohort. Structural brain networks were constructed for each participant using both deterministic and probabilistic tractography. We hypothesized that subtle variation in head motion would systematically bias estimates of structural connectivity and confound developmental inference, as observed in previous studies of functional connectivity. Even following quality assurance and retrospective correction for head motion, eddy currents, and field distortions, in-scanner head motion significantly impacted the strength of structural connectivity in a consistency- and length-dependent manner. Specifically, increased head motion was associated with reduced estimates of structural connectivity for network edges with high inter-subject consistency, which included both short- and long-range connections. In contrast, motion inflated estimates of structural connectivity for low consistency network edges that were primarily shorter-range. Finally, we demonstrate that age-related differences in head motion can both inflate and obscure developmental inferences on structural connectivity. Taken together, these data delineate the systematic impact of head motion on structural connectivity, and provide a critical context for identifying motion-related confounds in studies of structural brain network development. PMID- 29486326 TI - Distribution of gonadotropin-inhibitory hormone (GnIH) in male Luchuan piglets. AB - Gonadotropin inhibitory hormone (GnIH) has emerged as a novel hypothalamic neuropeptide that actively inhibits gonadotropin release in birds and mammals. Recent evidence indicates that GnIH not only acts as a key neurohormone that controls vertebrate reproduction but is also involved in stress response, food intake, and aggressive and sexual behaviors, suggesting a broad physiological role for this neuropeptide. To elucidate its multiple sites of action and potential functions, studying the detailed distribution of GnIH in different organs, except for the hypothalamus-pituitary-ovary/testis axis, is necessary. Therefore, in the present study, in different central nervous system (CNS) and peripheral organs of male Luchuan piglets, the distribution of GnIH was systemically determined using immunohistochemistry, and the expression of GnIH mRNA was investigated using semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). Our results demonstrate that GnIH immune reactive (GnIH ir) neurons were widely distributed in the pig CNS, but the number and size of the GnIH-ir neurons varied and exhibited morphological diversity. In the peripheral organs, GnIH immunoreactive cells were observed in the respiratory tract, alimentary tract, endocrine organs, genitourinary tract and lymphatic organs. GnIH mRNA was highly expressed in the CNS, with the highest expression in the hypothalamus. In the peripheral organs, high GnIH mRNA levels were detected in the testis, while no GnIH expression was observed in the liver, lungs and heart et al. These results demonstrated that GnIH might play an important role in modulating a variety of physiological functions and provided the morphological data for further study of GnIH in pigs. PMID- 29486324 TI - Socioeconomic disparities in academic achievement: A multi-modal investigation of neural mechanisms in children and adolescents. AB - Growing evidence suggests that childhood socioeconomic status (SES) influences neural development, which may contribute to the well-documented SES-related disparities in academic achievement. However, the particular aspects of SES that impact neural structure and function are not well understood. Here, we investigate associations of childhood SES and a potential mechanism-degree of cognitive stimulation in the home environment-with cortical structure, white matter microstructure, and neural function during a working memory (WM) task across development. Analyses included 53 youths (age 6-19 years). Higher SES as reflected in the income-to-needs ratio was associated with higher parent-reported achievement, WM performance, and cognitive stimulation in the home environment. Although SES was not significantly associated with cortical thickness, children raised in more cognitively stimulating environments had thicker cortex in the frontoparietal network and cognitive stimulation mediated the assocation between SES and cortical thickness in the frontoparietal network. Higher family SES was associated with white matter microstructure and neural activation in the frontoparietal network during a WM task, including greater fractional anisotropy (FA) in the right and left superior longitudinal fasciculi (SLF), and greater BOLD activation in multiple regions of the prefrontal cortex during WM encoding and maintenance. Greater FA and activation in these regions was associated higher parent-reported achievement. Together, cognitive stimulation, WM performance, FA in the SLF, and prefrontal activation during WM encoding and maintenance significantly mediated the association between SES and parent-reported achievement. These findings highlight potential neural, cognitive, and environmental mechanisms linking SES with academic achievement and suggest that enhancing cognitive stimulation in the home environment might be one effective strategy for reducing SES-related disparities in academic outcomes. PMID- 29486328 TI - Modeling of ultra-small lipid nanoparticle surface charge for targeting glioblastoma. AB - Surface modification of ultra-small nanostructured lipid carriers (usNLC) via introduction of a positive charge is hypothesized to prompt site-specific drug delivery for glioblastoma multiforme (GBM) treatment. A more effective interaction with negatively charged lipid bilayers, including the blood-brain barrier (BBB), will facilitate the nanoparticle access to the brain. For this purpose, usNLC with a particle size of 43.82 +/- 0.03 nm and a polydispersity index of 0.224 were developed following a Quality by Design approach. Monomeric and gemini surfactants, either with conventional headgroups or serine-based ones, were tested for the surface modification, and the respective safety and efficacy to target GBM evaluated. A comprehensive in silico-in vitro approach is also provided based on molecular dynamics simulations and cytotoxicity studies. Overall, monomeric serine-derived surfactants displayed the best performance, considering altogether particle size, zeta potential, cytotoxic profile and cell uptake. Although conventional surfactants were able to produce usNLC with suitable physicochemical properties and cell uptake, their use is discouraged due to their high cytotoxicity. This study suggests that monomeric serine-derived surfactants are promising agents for developing nanosystems aiming at brain drug delivery. PMID- 29486327 TI - FTO promotes SREBP1c maturation and enhances CIDEC transcription during lipid accumulation in HepG2 cells. AB - The fat mass and obesity-associated (FTO) gene is tightly related to body weight and fat mass, and plays a pivotal role in regulating lipid accumulation in hepatocytes. However, the mechanisms underlying its function are poorly understood. Sterol regulatory element binding protein-1c (SREBP1c) is a transcription factor that regulates lipogenesis. Cell death-inducing DFFA (DNA fragmentation factor-alpha)-like effector c (CIDEC) plays a crucial role in lipid droplets (LDs) size controlling and lipid accumulation. In this report, we first observed that FTO overexpression in HepG2 cells resulted in an increase of lipogenesis and up-regulation of SREBP1c and CIDEC, two key regulatory factors in lipogenesis. In contrast, FTO knockdown in HepG2 cells resulted in a decrease of lipogenesis and down-regulation of SREBP1c and CIDEC expression. Moreover, SREBP1c knockdown resulted in a decrease of lipogenesis in HepG2 cells with FTO overexpression. In addition, FTO demethylation defect mutant presented less transcription of the key genes, and less nuclear translocation and maturation of SREBP1c. Further investigation demonstrated that overexpression of SREBP1c in HepG2 cells also promoted high CIDEC expression. Luciferase reporter assays showed that SREBP1c significantly stimulated CIDEC gene promoter activity. Finally, CIDEC knockdown reduced SREBP1c-induced lipogenesis. In conclusion, our studies suggest that FTO increased the lipid accumulation in hepatocytes by increasing nuclear translocation of SREBP1c and SREBP1c maturation, thus improving the transcriptional activity of LD-associated protein CIDEC. Our studies may provide new mechanistic insight into nonalcoholic fatty liver disease (NAFLD) mediated by FTO. PMID- 29486329 TI - Risk of alcohol use disorder among South African university students: The role of drinking motives. PMID- 29486330 TI - Competitive long-term health insurance. AB - I study the interplay among competition, contractual commitment, income risk, and saving and borrowing in insuring consumers against both short-term healthcare expenses and longer-term changes in health status. Examining different combinations of firms' ability to commit to long-term contracts, consumers' access to credit markets, and the availability of termination fees helps to highlight sources of inefficiency. PMID- 29486331 TI - Employment, job skills and occupational mobility of cancer survivors. AB - Previous studies find significant negative effects of cancer on employment, with stronger effects for less-educated workers. We investigate whether the effect of cancer varies by skill requirement in the pre-cancer occupation, whether such heterogeneity can explain educational gradients, and whether cancer is associated with changes in job characteristics for cancer survivors who remain employed four years after the diagnosis. We combine Danish administrative registers with detailed skill requirement data and use individuals without cancer as a control group. Our main findings are the following: the negative effect of cancer on employment is stronger if the pre-cancer occupation requires high levels of manual skills or low levels of cognitive skills; the educational gradient diminishes substantially if we allow the effects of cancer to also depend on pre cancer skill requirements; and cancer is not associated with occupational mobility, indicating potential for policies that reduce labour market frictions for cancer survivors. PMID- 29486332 TI - Optimization of a single insertion electrode array for the creation of clinically relevant ablations using high-frequency irreversible electroporation. AB - High-frequency irreversible electroporation (H-FIRE) is an emerging ablation modality, delivering rapid bursts of bipolar microsecond-duration electrical pulses to non-thermally ablate tissue including tumors. With advantages over current electroporation techniques including mitigation of muscle stimulation and reduced susceptibility to heterogeneous tissue properties, H-FIRE may produce more uniform and predictable ablations and can potentially be delivered with a single applicator device. However, the resulting ablations tend to be smaller than those provided with equivalent energy monopolar pulse protocols. Here, we develop numerical simulations that demonstrate the potential for clinically relevant ablations with H-FIRE delivered via a single insertion technique comprised of an expandable array and a distally placed grounding pad. Based on existing in vivo data and new in vitro results, delivery of H-FIRE with a clinical IRE single electrode probe (1 cm long) is predicted to produce a 2.2 cm3 ablation while an optimized eight tine array produces a 3.2 cm3 ablation when the same H-FIRE bursts are delivered (5000 V). We demonstrate that alternative pulse protocols can be used to increase ablation volumes with this optimized array and these results indicate that in vivo investigation of a single insertion array and grounding pad are warranted. PMID- 29486333 TI - Investigation of insulin resistance in the popularly used four rat models of type 2 diabetes. AB - Animal models are widely used to develop drugs for treating diabetes mellitus (DM). Insulin resistance (IR) is one of the main problems in type-2 DM (T2DM). Streptozotocin (STZ) is used to damage pancreatic cells for induction of DM. Many rat models were applied in research as T2DM. However, the degree of IR in each model is unknown. In the present study, IR and insulin signaling were compared in four models of type 2 diabetes: rats fed a fructose-rich chow for 8 weeks, rats feed high-fat chow for 4 weeks followed by injection with streptozotocin (35 mg/kg, i.p.), rats injected with a single low dose streptozotocin (45 mg/kg, i.p.), and rats injected with a single dose of nicotinamide followed by a single high dose of streptozotocin (60 mg/kg, i.p.). Values from these determinations in diabetic rats showing the order that insulin resistance is most marked in rats received fructose-rich chow followed by high-fat diet before STZ injection induced model (HFD/STZ rats), and rats injected with low dose of STZ but it is less marked in rats induced by nicotinamide and STZ. Additionally, insulin secretion was reduced in three rat models except the rats receiving fructose-rich chow. Western blots also showed the same changes in phosphorylation of IRS-1 or Akt using soleus muscle from each model. The obtained data suggest a lack of pronounced IR in the rats with acute diabetes induced by nicotinamide and STZ while IR is markedly identified in rats fed fructose-rich chow. However, the increase of plasma glucose levels in fructose-rich chow-fed rats was not so significant as other groups. Therefore, HFD/STZ rats is an appropriate and stable animal model which is analogous to the human T2DM through a combination of high fat diet with multiple low-dose STZ injections. PMID- 29486334 TI - Caffeic acid phenethyl ester rescued streptozotocin-induced memory loss through PI3-kinase dependent pathway. AB - The present study was undertaken to elucidate the role of PI3-kinase signaling in memory enhancing potential of caffeic acid phenethyl ester (CAPE) against cognitive defects in rats after centrally administered streptozotocin as a model of Alzheimer's disease. The Morris water maze and elevated plus maze paradigms showed profound loss of memory in adult Wistar rats (180-200 g) injected with streptozotocin (3 mg/kg) bilaterally (STZ-ICV) on day 1 and 3. Intraperitoneal administration of CAPE (6 mg/kg, i.p., 28 days) attenuated STZ-ICV triggered memory loss in rats. Treatment with PI3-kinase inhibitor (wortmannin, 5 MUg/rat, ICV) or NOS blocker (L-NAME, 20 mg/kg, i.p., 28 days) interfered with memory restorative function of CAPE in STZ treated rats. In biochemical analysis markers of oxidative stress (TBARS, GSH, SOD, CAT), nitrite, AChE, TNF-alpha, eNOS and NFkappaB were measured in brain of rats on day 28. Interestingly, L-Arginine (100 mg/kg, i.p., 28 days) group exhibited moderate (p > 0.05) decline in memory functions. The brain oxidative stress, TNF-alpha, AChE activity and NFkappaB levels were elevated, and eNOS level was lowered by STZ-ICV treatment. Administration of CAPE lowered oxidative stress, AChE, nitrite and TNF-alpha levels in brain of rats. The eNOS level was enhanced and NFkappaB level was decreased by CAPE in STZ treated rats. Wortmannin injection elevated the brain oxidative stress, AChE activity and TNF-alpha levels, and decreased the nitrite, eNOS and NFkappaB level. Rise of brain oxidative stress parameters, AChE activity, TNF-alpha, eNOS and NFkappaB levels, and decline in brain nitrite content was observed in L-NAME treated group. L-Arginine administration showed modest effects (p > 0.05) on oxidative stress parameters. Brain nitrite content was enhanced although eNOS, NFkappaB levels, and AChE activity was decimated by L Arginine treatment. It can be concluded that PI3-kinase mediated nitric oxide facilitation is an essential feature of CAPE action in STZ-ICV treated rats. PMID- 29486335 TI - Crocin attenuates cyclophosphamide induced testicular toxicity by preserving glutathione redox system. AB - Chemotherapy induced testicular toxicity is an emerging reason for azoospermia and impotency in males. Cyclophosphamide (CP) is a widely used chemotherapeutic agent to manage neoplastic and non-neoplastic autoimmune diseases. Testicular toxicity along with bladder and hepatotoxicity are its widely reported adverse effects. Crocin (CR) is the digentiobiosyl ester of crocetin, found in the fruits of gardenia (Gardenia jasminoides E.) and dried stigmas of saffron (Crocus sativus L.) possess antioxidant, anti-depressant, anti-tumor and aphrodisiac properties. In the light of these reports, the present study aimed to investigate protective effect of CR administration (10 mg/kg and 20 mg/kg per day for eight weeks) on CP induced (15 mg/kg per week for eight weeks) testicular toxicity in male Sprague dawley rats by analysing the Glutathione redox cycle, Sperm quality, spermatogenic and steroidogenesis hormonal axis, caspase 3 activity and histological investigations. Administration of CR preserved the glutathione redox cycle, sperm quality, hormonal mediators associated with sperm production. It also decreased testicular apoptosis as evident from the reduction of caspase 3 activity. These biochemical findings were well reflected on the histo pathological investigation. Conclusively, the results of this study indicate that administration of CR can dose dependently attenuate the toxic effects of CP on testis. PMID- 29486336 TI - The anticonvulsant effect of a polysaccharide-rich extract from Genipa americana leaves is mediated by GABA receptor. AB - BACKGROUND: This study aimed to chemically characterize a polysaccharide-rich extract (PRE) obtained from Genipa americana leaves and evaluate its neuroprotective effect in the brain morphology and oxidative markers using mice behavioral models. METHODS: Dry powder (5 g) of G. americana leaves were submitted to depigmentation in methanol. PRE was obtained by extraction in NaOH and precipitation with absolute ethanol and characterized by infrared spectroscopy (FTIR) and nuclear magnetic resonance (1H and 13C NMR). Swiss mice (25-35 g) received saline (0.9% NaCl) or PRE (1-27 mg/kg) by intraperitoneal (i.p.) route, 30 min before evaluation in behavioral models (open field, elevated plus maze, sleeping time, tail suspension, forced swimming, seizures induced by pentylenetetrazole-PTZ). Animal's brain were dissected and analyzed for histological alterations and oxidative stress. RESULTS: FTIR spectrum showed bands around 3417 cm-1 and 2928 cm-1, relative to the vibrational stretching of OH and CH, respectively. 1H NMR spectrum revealed signals at delta 3.85 (methoxyl groups) and delta 2.4 (acetyl) ppm. 13C NMR spectrum revealed signals at delta 108.0 and delta 61.5 ppm, corresponding to C1 and C5 of alpha-L-arabinofuranosyl residues. PRE presented central inhibitory effect, increasing the latency for PTZ induced seizures by 63% (9 mg/kg) and 55% (27 mg/kg), and the latency to death by 73% (9 mg/kg) and 72% (27 mg/kg). Both effects were reversed by the association with flumazenil. CONCLUSIONS: PRE, containing a heteropolysaccharide, presents antioxidant and anticonvulsant effect in the model of PTZ-induced seizures via gamma-aminobutyric acid (GABA), decreasing the number of hippocampal black neurons. PMID- 29486337 TI - Antioxidant and anti-inflammatory activities of alpha lipoic acid protect against indomethacin-induced gastric ulcer in rats. AB - Little is known about the role of tumor necrosis factor-alpha (TNF-alpha), plasminogen activator inhibitor-1 (PAI-1), and inducible nitric oxide synthase (iNOS) in the gastric ulcer and the effect of alpha lipoic acid (ALA) in their modulation. Hence, this experimental study was designed to assess the possible protective effect of ALA against indomethacin (IND)-induced gastric ulcer in rats, as well as to determine the possible underlying mechanisms with a special focus on TNF-alpha, PAI-1, and iNOS. Adult male rats (n = 28) were divided into four equal groups: the control group received distilled water, the vehicle group received 0.5% carboxymethylcellulose, the ulcer group received a single oral dose of IND (50 mg/kg) and the ALA-treated group received ALA (100 mg/kg) orally for 3 days before ulcer induction. Four hours after IND administration, all rats were sacrificed. The ulcer index, and gastric tissue homogenate contents of total antioxidant capacity (TAC), malondialdehyde (MDA), TNF-alpha, and PAI-1 were evaluated. Immunohistochemical evaluation of iNOS protein expression and histopathological examination of gastric tissue were investigated. The results revealed that ALA pretreatment significantly decreased the ulcer index, the gastric levels of MDA, TNF-alpha, PAI-1, and iNOS protein expression while increased the gastric levels of TAC as well as improved the histopathological appearance of gastric tissues. In conclusion, ALA ameliorated the IND-induced gastric ulceration. This could be attributed to its antioxidant and anti inflammatory activities via suppression of TNF-alpha-induced elevation of both PAI-1 level and iNOS expression in the gastric tissue. PMID- 29486339 TI - Low cocaine- and amphetamine-regulated transcript (CART) peptide levels in human cerebrospinal fluid of major depressive disorder (MDD) patients. AB - BACKGROUND: Cocaine- and amphetamine-regulated transcript (CART) peptide is a candidate neuropeptide as a biomarker for major depressive disorder (MDD) because of its effects on emotion and distribution covering brain areas involved in the pathophysiology of MDD symptoms. However, it is unknown whether CART peptide levels are altered in the cerebrospinal fluid (CSF) of patients with MDD patients and are correlated with MDD symptoms. METHODS: Subjects were 24 patients with MDD and 25 healthy controls matched for age, gender and ethnicity (Japanese). We measured CSF CART levels by a commercially available immunoassay kit and analyzed the relationships of the levels with antidepressant dose and symptoms assessed with the 21 item Hamilton Depression Rating Scale (HAMD-21). RESULTS: CSF CART levels were significantly decreased in the patients than in the controls (p < 0.05). In MDD patient group, the CART levels had a negative correlation with antidepressant dose (imipramine-equivalent dose) (rho = -0.55, p < 0.01) and significantly decreased in antidepressant-treated group (AD-treated group) compared to controls (p < 0.05). CSF CART levels showed significant negative correlations with psychomotor retardation, somatic anxiety, and general somatic symptoms (all p < 0.05) and a positive correlation with obsessive and compulsive symptoms (p < 0.05). LIMITATIONS: In our analysis, all classes of antidepressants were combined together and the effects of medication use in a longitudinal manner did not confirm. CONCLUSIONS: We report for the first time that CSF CART peptide levels are reduced in patients with MDD compared with healthy controls. The CART levels showed negative correlations with antidepressant dose and some symptoms, supporting the possibility that CART peptide is involved in the development of depressive symptoms. PMID- 29486338 TI - Palmitoylethanolamide as adjunctive therapy in major depressive disorder: A double-blind, randomized and placebo-controlled trial. AB - BACKGROUND: Experimental studies provide evidence for antidepressant effects of Palmitoylethanolamide (PEA) in animal models of depression. We aimed to evaluate the efficacy and tolerability of PEA add-on therapy in treatment of patients with major depressive disorder (MDD). METHODS: In a randomized double-blind, and placebo-controlled study, 58 patients with MDD (DSM-5) and Hamilton Depression Rating Scale (HAM-D) score >= 19 were randomized to receive either 600 mg twice daily Palmitoylethanolamide or placebo in addition to citalopram for six weeks. Patients were assessed using the HAM-D scale at baseline and weeks 2, 4, and 6. RESULTS: Fifty-four individuals completed the trial. At week 2, patients in the PEA group demonstrated significantly greater reduction in HAM-D scores compared to the placebo group (8.30 +/- 2.41 vs. 5.81 +/- 3.57, P = .004). The PEA group also demonstrated significantly greater improvement in depressive symptoms [F (3, 156) = 3.35, P = .021] compared to the placebo group throughout the trial period. The patients in the PEA group experienced more response rate (>= 50% reduction in the HAM-D score) than the placebo group (100% vs. 74% respectively, P = .01) at the end of the trial. Baseline parameters and frequency of side effects were not significantly different between the two groups. LIMITATIONS: The population size in this study was small and the follow-up period was relatively short. CONCLUSIONS: Palmitoylethanolamide adjunctive therapy to citalopram can effectively improve symptoms of patients (predominantly male gender) with major depressive disorder. PEA showed rapid-onset antidepressant effects which need further investigation. PMID- 29486340 TI - Investigating the iatrogenic effects of repeated suicidal ideation screening on suicidal and depression symptoms: A staggered sequential study. AB - BACKGROUND: Research suggests that screening for suicidality does not have iatrogenic effects; however, less is known regarding the impact of repeatedly screening for suicidal ideation among individuals with varying levels of exposure to these screenings. This staggered sequential study evaluated whether suicidal ideation severity increases with repeated screening for suicidal ideation and depression symptoms. METHODS: Undergraduates (N = 207) were recruited at one of four time points (baseline [n = 37], 1 month later [n = 61], 4 months later [n = 55], and 12 months later [n = 54]) to complete the self-report Beck Depression Inventory (BDI). Participants completed the BDI at the time point at which they were recruited and all subsequent study time points. Non-parametric tests were employed to compare suicidal ideation severity (BDI Item 9) and depression symptom severity (BDI total score): (1) within each group across time points and (2) within each time point across groups. RESULTS: Suicidal ideation severity did not significantly differ within any group across time points, and for two groups, depression symptom severity decreased over time. For analyses between groups, suicidal ideation and depression symptom scores were, at times, significantly lower during subsequent BDI completion time points. LIMITATIONS: This study utilized a relatively small sample size and participants of low clinical severity. CONCLUSIONS: Findings align with prior research indicating that suicidality screening is not iatrogenic. This study also expanded upon previous studies by leveraging a staggered sequential design to compare suicidal ideation and depression symptom severity among individuals with varying exposure to suicidal ideation screenings. PMID- 29486341 TI - Predicting central line-associated bloodstream infections and mortality using supervised machine learning. AB - PURPOSE: The purpose of this study was to compare machine learning techniques for predicting central line-associated bloodstream infection (CLABSI). MATERIALS AND METHODS: The Multiparameter Intelligent Monitoring in Intensive Care III database was queried for all ICU admissions. The variables included six different severities of illness scores calculated on the first day of ICU admission with their components and comorbidities. The outcomes of interest were in-hospital mortality, central line placement, and CLABSI. Predictive models were created for these outcomes using classifiers with different algorithms: logistic regression, gradient boosted trees, and deep learning. RESULTS: There were 57,786 total hospital admissions and the mortality rate was 10.1%. There were 38.4% patients with a central line and the rate of CLABSI was 1.5%. The classifiers using deep learning performed with the highest AUC for mortality, 0.885+/-0.010 (p<0.01) and central line placement, 0.816+/-0.006 (p<0.01). The classifier using logistic regression for predicting CLABSI performed with an AUC of 0.722+/-0.048 (p<0.01). CONCLUSIONS: This study demonstrates models for identifying patients who will develop CLABSI. Early identification of these patients has implications for quality, cost, and outcome improvements. PMID- 29486342 TI - Spatio-temporal variation of trematode parasites community in Cerastoderma edule cockles from Ria de Aveiro (Portugal). AB - Cerastoderma edule (edible cockle) is among the most exploited bivalves in Europe playing an important socio-economic role. Cockles live in estuaries and lagoons where their population is controlled by several environmental factors including parasitism. Parasites represent an important part of the world known biodiversity but are often neglected. Trematodes are the most prevalent macroparasites of cockles being able to exert an impact both at the individual and population levels. Therefore, it is of prime relevance to recognize and understand the parasite-host system dynamics in order to better predict potential conservation threats to bivalve populations and to maximize the success of stock and disease episodes management. Cockle monitoring was conducted in 2012 and 2016, in six and eight stations, respectively, at the Ria de Aveiro coastal lagoon, Portugal. Cockles were sampled in one single occasion in 2012 and seasonally in 2016. The tested hypothesis is that the trematode community in cockles was spatially and seasonally heterogeneous but stable over time. The main result showed that despite a relative homogeneity of the parasite community structure in cockles, the among-years heterogeneity of trematode communities was higher than among stations and among-seasons heterogeneity rejecting the postulated hypothesis. Results demonstrated that trematode communities from the Ria de Aveiro are characterized by low abundance, which resulted in a spatial and seasonal trematode homogeneity (despite an overall channel difference and a slight downstream-upstream gradient). The interannual analysis showed a worrisome loss of trematode diversity and prevalence which consequently indicates an important loss of overall diversity and/or environmental conditions reflecting the negative effects of global change (mean temperature rise and overharvesting, among others). The present study highlighted the importance of trematodes in characterising their associated environment and respective biodiversity which might be helpful to assess ecosystem ecological status and to identify threatened areas. PMID- 29486344 TI - Spatiotemporal analysis of PM2.5 and pancreatic cancer mortality in China. AB - BACKGROUND: Previous studies have reported that the development of pancreatic cancer (PC) may be associated with environment pollution. But the relationship between ambient air pollution and PC remains unclear. OBJECTIVES: This study aimed to examine the association between PC mortality and exposure of fine particular matter. METHODS: We used PC mortality data from 103 continuous points in national Disease Surveillance Point system from 1991 to 2009 in China. The annual concentrations of PM2.5 at 0.1 degrees * 0.1 degrees spatial resolution for each points were estimated based on the context of the Global Burden of Disease Study 2015. A spatial age-period-cohort model was used to examine the relative risks of PC mortality associated with PM exposure, after adjusting gender, urban/rural status, spatial variation as well as age, period and cohort effect. RESULTS: The relative risks of PC mortality related to 10 MUg/m3 increase of PM2.5 were 1.16 (95% confidence interval (CI): 1.13, 1.20) for all the population, 1.08 (1.05,1.13) for those aged 40-64 years, 1.21 (1.17,1.25) for those aged 65-84 years, 1.14 (1.10,1.18) for the male, 1.19 (1.14,1.24) for the female, 1.23 (1.16,1.30) for the urban population and 1.29 (1.22, 1.37) for the rural population. CONCLUSIONS: Ambient PM2.5 may raise the risk of mortality from PC, especially in older population. Pollution control policy should be further strengthened to reduce the health damages. PMID- 29486343 TI - A cross-sectional study of general cognitive abilities among Uruguayan school children with low-level arsenic exposure, potential effect modification by methylation capacity and dietary folate. AB - BACKGROUND: Few studies have evaluated the association between low-level arsenic (As) exposure and cognitive performance among children. OBJECTIVES: In this cross sectional study, we assessed the association between low-level As exposure and cognitive performance among 5-8 year-old children in Montevideo, and tested effect modification by As methylation capacity and children's dietary folate intake. METHODS: We measured total urinary As (UAs) concentrations and the proportion of monomethylarsonic acid (MMA) in the urine of 328 children. Seven subtests of the standardized Woodcock-Munoz cognitive battery were used to assess cognitive performance, from which, the general intellectual abilities (GIA) score was derived. Total folate intake was estimated from two 24-h dietary recalls. Linear regression analyses were performed. Effect modification was assessed by stratifying at the median %MMA value and tertiles of total folate intake calculated as micrograms (ug) of dietary folate equivalents (dfe). RESULTS: The median UAs was 11.9 ug/l (range = 1.4-93.9), mean folate intake was 337.4 (SD = 123.3) ug dfe, and median %MMA was 9.42 (range = 2.6-24.8). There was no association between UAs and cognitive abilities, and no consistent effect modification by %MMA. UAs was associated inversely with concept formation, and positively with cognitive efficiency and numbers reversed subtest in the lowest folate intake tertile; UAs was also positively associated with sound integration in the second tertile and concept formation in the highest tertile of folate intake. There was no consistent pattern of effect modification by %MMA or folate intake. CONCLUSION: There was no association between low-level As exposure and general cognitive abilities. PMID- 29486345 TI - Sources of household air pollution: The association with lung function and respiratory symptoms in middle-aged adult. AB - INTRODUCTION: The objective of the present study was to investigate the relationship between sources of household air pollution, respiratory symptoms and lung function. METHODS: 3039 adults aged from 40 to 65 participated in the 2011 2013 ELISABET cross-sectional survey in northern France. Lung function was measured using spirometry. During a structured interview, respiratory symptoms, household fuels, exposure to moulds, and use of ventilation were recorded on a questionnaire. RESULTS: The self-reported presence of mould in at least two rooms (not including the bathroom and the kitchen) was associated with a 2.5% lower predicted forced expiratory volume in 1 s (95% confidence interval, -4.7 to 0.29; p-trend <0.05) and a higher risk of wheezing (p-trend < 0.001). Visible condensation was associated with wheezing (p < .05) and chronic cough (p < .05). There were no significant associations with the type of household fuel or inadequate ventilation/aeration. Similar results were found when the analyses were restricted to participants without known respiratory disease. CONCLUSION: Our results suggest that the presence of mould (known to be associated with more severe asthma symptoms) could also have an impact on respiratory symptoms and lung function in the general population and in populations without known respiratory disease. PMID- 29486346 TI - Educational attainment for youth who were maltreated in adolescence: Investigating the influence of maltreatment type and foster care placement. AB - Decades of research have consistently shown a link between foster care and low rates of high school completion. Despite the overwhelming knowledge surrounding this association, it remains unclear whether the low rates of high school completion are due to placement in foster care or the maltreatment and other contextual factors that foster care youth have experienced. This study examined the extent to which (a) maltreatment type and (b) foster care placement were associated with the educational attainment of 337 maltreated adolescents. Logistic regression analyses were conducted using two waves of data and the ACR dataset of the National Survey of Child and Adolescent Well-Being (NSCAW). After controlling for academic risk factors related to the adolescents (age, race, and gender), their family (household poverty and parental education), and their environment (community environment), neither maltreatment type nor foster care placement status were associated with subsequent high school completion. Overall, only 58% of the maltreated adolescents reported completing their education. That is about 15% less than the national average at the time data were collected for this study. Results, overall, suggest a need for educational supports and interventions for youth who experience maltreatment during their adolescent years, regardless of maltreatment type and foster care placement. PMID- 29486347 TI - Profiles and behavioral consequences of child abuse among adolescent girls and boys from Barbados and Grenada. AB - The current study used latent class analysis to uncover groups of youths with specific abuse (physical, emotional, and sexual) profiles in and outside the family, and identify how membership in each abuse group is associated with behavioral outcomes. Data were collected among a sample of male (n = 662; Mage = 13.02 years) and female (n = 689; Mage = 12.95 years) children and adolescents (9 17 years old) from Barbados and Grenada. Self-report surveys were completed by participants in school settings. Three latent classes of child abuse were distinguished among boys, including 'low abuse' (39.2% of the sample), 'physical and emotional abuse high outside/medium in the family' (43.2%), and 'high overall abuse' (17.6%). Among girls, four unique classes were recovered: 'low abuse' (40.7%), 'high physical and emotional abuse outside the family' (7.6%), 'high emotional and moderate physical abuse' (33.9%), and 'high overall abuse' (17.8%). Compared with members of low abuse groups, youths who reported having experienced high/moderate levels of various forms of violence, including those who were abused in multiple ways and across the two settings ('high overall abuse'), were significantly more likely to engage in violent and hostile behavior. Abused and non-abused youths did not differ on non-violent conflict resolution skills. The significance of present findings for future research and practice is discussed. PMID- 29486348 TI - Pilot randomized controlled trial of Tuning Relationships with Music: Intervention for parents with a trauma history and their adolescent. AB - : For parents who have experienced childhood interpersonal trauma, the challenges of parenting an adolescent may trigger memories of abuse, intensifying conflict, resulting in negative cycles of relating and poorer responsiveness to emotions when parenting. This study examined whether Tuning Relationships with Music, a dyadic therapy for parents and adolescents, increased responsive parent adolescent interactions and parent emotion coaching whilst reducing conflict and adolescent mental health difficulties. Twenty-six parent-adolescent dyads were recruited if parents had a trauma history and the dyad were currently having high levels of conflict. Dyads were randomly allocated into intervention or wait-list control and completed questionnaires and observation assessments at baseline and 4-month post-baseline follow-up. Those allocated to the intervention condition participated in 8 sessions of Tuning Relationships with Music. TRIAL REGISTRATION: ANZCTR: 12615000814572. Parents and adolescents reported significant reductions in conflict. Parents in the intervention condition were observed to significantly improve their nonverbal communication, emotional responsiveness and non-reactivity toward their adolescent. Although parents reported they were less dismissive and punitive, and more encouraging of their adolescent's emotions, and both parents and adolescents reported improvements in the adolescent's mental health, these were not statistically significant. Findings suggest Tuning Relationships with Music may assist parents with a history of childhood interpersonal trauma and their adolescent to reduce conflict and increase responsive ways of relating that may positively impact the young person's mental health. Future trials with a larger sample are warranted. PMID- 29486349 TI - Predicting running away in girls who are victims of commercial sexual exploitation. AB - Youth that are victims of commercial sexual exploitation of children (CSEC) have a host of clinical problems and often run away from home, residential care, and treatment, which complicates and limits treatment effectiveness. No research to date has attempted to predict running away in CSEC victims. The present study aimed to 1) characterize a clinically referred sample of girls who were victims of CSEC and compare them to other high-risk girls (i.e., girls who also have a history of trauma and running away, but deny CSEC); and 2) examine the utility of using the Youth Level of Service/Case Management Inventory (YLS/CMI) to predict future running away. Data were collected from de-identified charts of 80 girls (mean age = 15.38, SD = 1.3, 37.9% White, 52.5% CSEC victims) who were referred for psychological assessment by the Department of Child Services. Girls in the CSEC group were more likely to have experienced sexual abuse (chi2 = 6.85, p = .009), an STI (chi2 = 6.45, p = .01), a post-traumatic stress disorder diagnosis (chi2 = 11.84, p = .001), and a substance use disorder diagnosis (chi2 = 11.32, p = .001) than high-risk girls. Moderated regression results indicated that YLS/CMI scores significantly predicted future running away among the CSEC group (beta = 0.23, SE = .06, p = .02), but not the high-risk group (beta = -.008, SE = .11, p =.90). The YLS/CMI shows initial promise for predicting future running away in girls who are CSEC victims. Predicting running away can help identify those at risk for and prevent running away and improve treatment outcomes. We hope current findings stimulate future work in this area. PMID- 29486350 TI - Identification and characterization of a type I interferon induced by cyprinid herpesvirus 2 infection in crucian carp Carassius auratus gibelio. AB - Crucian carp (Carassius auratus gibelio) is a popular food fish in Asia, and cyprinid herpesvirus 2 (CyHV-2) is the only known viral pathogen for crucian carp. Type I interferon genes are induced up on host cell recognition of viral nucleic acids and well recognized for their crucial roles in providing local or systemic protection against the viruses in various organisms. In a transcriptome analysis to uncover differentially expressed genes in crucian carp in response to CyHV-2 challenge, a partial interferon transcript was identified to be significantly up-regulated in the kidney of infected fish, which was named as crucian carp IFNc (ccIFNc). The complete ORF of ccIFNc was further determined by RACE technique, which spanned over 546 bp and encoded a polypeptide containing 182 amino acids. Phylogenetic analysis revealed that ccIFNc clustered with known type I IFN genes from other aquatic organisms. Quantitative RT-PCR analysis demonstrated that ccIFNc was constitutively expressed in all investigated tissues with a comparably higher expression level in spleen, gill, kidney, and muscle. Following challenge with CyHV-2, the transcriptional levels of ccIFNc were dramatically up-regulated in all of the tested tissues, especially in the spleen and gill with increased folds of 436 and 158, respectively. The intramuscular (i.m.) injection of a eukaryotic expression plasmid encoding ccIFNc (pEGFP-cIFNc) resulted in increased ccIFNc expression and reduced the mortality after the CyHV 2 challenge significantly. In summary, our data suggested that the ccIFNc belongs to the type I interferon family with a potential role in countering CyHV-2 infection in crucian carp. PMID- 29486351 TI - Molecular characterization of complement component 3 (C3) in Mytilus coruscus improves our understanding of bivalve complement system. AB - Complement component 3 (C3) plays a central role in the complement system whose activation is essential for all the important functions performed by this system. Here, a novel C3 gene, termed Mc-C3, was identified from thick shell mussel (Mytilus coruscus). The deduced Mc-C3 protein possessed the characteristic structure features present in its homologs and contained the A2M_N_2, ANATO, A2M, A2M_comp, A2M_recep, and C345C domains, as well as the C3 convertase cleavage site, thioester motif, and conserved Cys, His, and Glu residues. Mc-C3 gene constitutively expressed in all examined tissues and predominantly expressed in immune-related tissues such as gills, hemocytes and hepatopancreas. After stimulation with lipopolysaccharide or Cu2+, the expression of Mc-C3 was significantly induced in gills. Further luciferase reporter assays showed the ability for activation of NF-kappaB signaling transduction of Mc-C3a. Taken together, these results show that C3 may play an essential role in the immune defense of M. coruscus. The present data therefore provide a more detailed insight into the functional activities of the bivalve complement system. PMID- 29486352 TI - Histological and transcriptomic responses of two immune organs, the spleen and head kidney, in Nile tilapia (Oreochromis niloticus) to long-term hypersaline stress. AB - Hyperosmotic stress can adversely affect fish immunity, but little is known about the histological and transcriptomic responses of immune organs in fish in a hyperosmotic environment. This study evaluated the effects of long-term hypersaline conditions (160/00) on the growth, histology and transcriptomics of the two main immune organs, the spleen and head kidney, in Nile tilapia Oreochromis niloticus relative to those reared in freshwater for eight weeks. No differences in weight gain and specific growth rate were found between fish reared under these two salinities. Hyperosmotic stress induced a congestive or enlarged spleen. Platelet- and coagulation-related gene expression was significantly decreased in tilapia at 160/00. The red cell distribution width and value of the mean corpuscular hemoglobin were significantly greater in fish at 160/00 salinity than in control fish in freshwater. A large volume of melano macrophages in the spleen and pigment deposition in both the spleen and head kidney were observed in the histological sections in fish at 160/00 salinity. Transmission electron microscopic results showed abnormal macrophages with deposition granules in the spleen and head kidney and more neutrophils in the head kidney of fish at 160/00 than in control fish. In total, 772 and 502 genes were annotated for significantly different expression in the spleen and head kidney, respectively, and corresponded to five and one significantly changed immune system pathways, respectively. The complement pathway in the spleen was significantly down-regulated at 160/00. This study indicates that long-term exposure of Nile tilapia to a hyperosmotic environment can induce splenomegaly, reduce coagulation function, enhance phagocytic activity and down-regulate the complement pathway in the spleen. The spleen is a more sensitive organ for immune responses to chronic ambient salinity stress than the head kidney in Nile tilapia. PMID- 29486353 TI - Clinical and histological evaluation of the efficacy of antimicrobial photodynamic therapy used in addition to antibiotic therapy in pericoronitis treatment. AB - BACKGROUND: Although antimicrobial efficacy of photodynamic therapy has been studied several times, there is no study investigating its efficacy on pericoronitis. This study aimed to determine whether antimicrobial photodynamic therapy combined with antibiotic therapy is clinically and histologically superior to antibiotic therapy alone in pericoronitis treatment. METHODS: Patients (n = 40) with pericoronitis were divided into two groups (20 patients for each) to receive either antibiotic + indocyanine green + 810 nm wavelength diode laser (antimicrobial photodynamic therapy group) or antibiotic alone. Initial biopsy samples were obtained from the affected tissue of the patients at their first presentation to the clinic before any intervention. The second biopsy samples were obtained on the 3rd day of treatment in both groups from the tissue part not biopsied before; tooth extraction was then performed. All tissue samples were histologically examined to assess inflammatory cell response. Patients' pain (using Visual Analogue Scale) and lymphadenopathy (presence or absence) were clinically evaluated in the first 3 days and on the 7th day of treatment. RESULTS: In the antimicrobial photodynamic therapy group, 100% improvement was achieved regarding pain and lymphadenopathy at the end of the 7th day. Comparison of the inflammatory cell scores of the 2nd biopsy samples between the antibiotic alone and antimicrobial photodynamic therapy groups revealed a significant difference in favor of antimicrobial photodynamic therapy group. CONCLUSIONS: Antimicrobial photodynamic therapy combined with antibiotic therapy for pericoronitis treatment was found to be more successful as compared with the antibiotic therapy alone regarding clinical and histological outcomes. PMID- 29486354 TI - An in vivo evaluation of microbial diversity before and after the photo-activated disinfection in primary endodontic infections: Traditional phenotypic and molecular approaches. AB - BACKGROUND: It is essential to identify the root canal microbial diversity and count. This is due to the polymicrobial nature of the primary endodontic infection that is associated with the microbial diversity and increased resistance to the antimicrobial agents. Photo-activated disinfection (PAD), also known as antimicrobial photodynamic therapy, is a new promising non-antibiotic approach, studied to prevent microbial resistance and treatment failure. MATERIALS AND METHODS: In this study, we investigated the effect of PAD on reduction of microbial diversity and count, related with primary endodontic infections. Microbial specimens were collected before PAD from patients infected with the primary endodontic infection. PAD with toluidine blue O (TBO), in combination with diode laser, was performed on infected root canals. Resampling was carried out on the root canal after PAD, and microorganisms were identified by classical microbiological tests using biochemical and analytical profile index (API (r) 20A) assays and nucleic acid approaches. RESULTS: From the 36 subjects studied before TBO-PAD, 187 cultivable isolates from 14 different genera and 19 various microbial species were retrieved. Of the bacterial isolates, 45.4% were strict anaerobes including Veillonella parvula, Porphyromonas gingivalis, Propionibacterium acnes, Lactobacillus acidophilus, Campylobacter rectus, and Slackia exigua, in order of their frequency; 45.4% were facultative anaerobes; and 9.2% were microaerophilic bacteria (Aggregatibacter actinomycetemcomitans). This in vivo study revealed significant decrease in the microbial diversity and count of the infected root canal after TBO-PAD (P < 0.05); whereas P. gingivalis strains, the most resistance microorganisms, were recovered in 34% of the samples after TBO-mediated PAD (P > 0.05). CONCLUSIONS: TBO-mediated PAD is an effective in exhibiting efficient antimicrobial activity due to the substantial reduction of the microbial diversity and count in the primary endodontic infections. PMID- 29486355 TI - Efficacy of Er Cr: YSGG laser therapy at different frequency and power levels on bond integrity of composite to bleached enamel. AB - The aim was to evaluate the influence of Er, Cr: YSGG laser therapy at different pulse frequency and power levels on the bond strength and microleakage of bleached enamel. One hundred samples were bleached using in-office whitening agent. Bleached samples were divided into six subgroups, four subgroups was based on laser application parameters (pulse frequency 50 and 30 Hz; Power 4.5 & 6 W) one subgroup was treated with bleach (B) and the other was control (no bleaching, no laser application). All specimens including control were etched with 37% phosphoric acid and composite build-ups were performed. Ten specimens from all the groups (B: Bleach only, L1: 50 Hz-4.5 W, L2: 50 Hz-6 W, L3: 30 Hz-4.5 W, L4:50 Hz-6W & C: Control) were assessed for shear bond strength and microleakage scores. Ten samples from all groups were immersed in 2% methylene blue for 24 h and assessed under a digital microscope for microleakage. The lowest mean bond strength was achieved in bleached group (9.49 +/- 0.95) and maximum bond strength was observed in control group (33.97 +/- 0.86). The highest mean microleakage score was found in bleached specimens (group B) (630.32 +/- 156.58) and the lowest in controls (group C) (36.66 +/- 27.33). Among assessed laser frequency and power combinations, 4.5 W and 30 Hz frequency showed maximum adhesive bond integrity (high bond strength and low microleakage) for bleached enamel samples. PMID- 29486356 TI - Rezafungin (CD101), a next-generation echinocandin: A systematic literature review and assessment of possible place in therapy. AB - OBJECTIVES: Rezafungin (CD101) is a novel echinocandin currently under development. The purpose of this study was to perform a systematic literature review of published evidence on rezafungin and an antimicrobial stewardship audit of real-world use of echinocandins to determine areas of unmet medical needs and potential places in therapy for rezafungin. METHODS: The systematic literature review identified 8 peer-reviewed manuscripts and 19 separate abstracts. A stewardship audit was performed on hospitalised patients receiving echinocandins to better understand potential future areas of use for rezafungin. RESULTS: Rezafungin is a cyclic hexapeptide with a lipophilic tail derived from anidulafungin, with a choline moiety at the C5 ornithine position resulting in increased in vitro and in vivo stability compared with other echinocandins. Microbiological data showed similar susceptibility and resistance development between rezafungin and other echinocandins. Rezafungin has a long half-life (80h) and a favourable safety profile that allows for high doses (up to 400mg) given once weekly. A phase 2 study is ongoing. The antimicrobial stewardship audit of echinocandin identified several areas of possible use for rezafungin, including patients receiving daily echinocandins for >7 days, patients who remained in the hospital to complete a full course of daily echinocandin therapy, and patients who required an echinocandin scheduled via an infusion clinic after discharge. CONCLUSION: Rezafungin is a novel echinocandin currently in phase 2 studies, differentiated by a long half-life that allows once-weekly dosing and a safety profile that allows higher doses. Several potential areas of use for rezafungin were identified. PMID- 29486357 TI - Antimicrobial susceptibility testing of Finnish Bordetella pertussis isolates collected during 2006-2017. AB - OBJECTIVES: Macrolides, such as azithromycin and erythromycin, are first-line drugs for the (prophylactic) treatment of pertussis. This study aimed to screen for macrolide-, quinolone- or trimethoprim/sulfamethoxazole (SXT)-resistant strains among Finnish Bordetella pertussis isolates. METHODS: Antimicrobial susceptibility testing was performed on 148 B. pertussis strains isolated during 2006-2017. Isolates were analysed by allele-specific PCR for detection of the macrolide resistance-associated mutation A2047G in the 23S rRNA gene. The gyrA gene was sequenced for detection of the A260G mutation associated with quinolone resistance. For phenotyping, a random selection was made by selecting every third isolate (n=50) to determine the minimum inhibitory concentrations (MICs) for erythromycin and azithromycin by Etest and the inhibition zone size for nalidixic acid (NAL) and SXT by single disk diffusion assay. RESULTS: Neither the macrolide resistance-associated mutation A2047G nor the quinolone resistance-associated mutation A260G was detected in any of the B. pertussis isolates. MICs of azithromycin and erythromycin ranged between 0.016-0.19MUg/mL and 0.016 0.25MUg/mL, respectively. The size of the inhibition zone surrounding the NAL disk ranged between 22-27mm in diameter. The inhibition zone surrounding the SXT disk ranged between 24-37mm in diameter. No isolates resistant to any of the tested antimicrobials were identified. CONCLUSIONS: The allele-specific PCR is a simple and useful tool for screening B. pertussis resistance to macrolides. All Finnish isolates tested were susceptible to macrolides, quinolones and SXT. PMID- 29486358 TI - Antifungal susceptibility testing results of New Zealand yeast isolates, 2001 2015: Impact of recent CLSI breakpoints and epidemiological cut-off values for Candida and other yeast species. AB - OBJECTIVES: We reviewed the antifungal susceptibility testing results of local yeast isolates (2001-2015) to record the impact of recently updated interpretive criteria and epidemiological cut-off values (ECVs) for yeast species. METHODS: Susceptibility testing was performed using Sensititre(r) YeastOne(r). The results were interpreted following CLSI criteria or YeastOne-derived ECVs. RESULTS: A total of 2345 isolates were tested; 62.0% were from sterile body sites or tissue. Application of new CLSI interpretative criteria for fluconazole increased the proportion of non-susceptible isolates of Candida parapsilosis, Candida tropicalis and Candida glabrata (P<=0.03 for all species). For voriconazole, the greatest increase was for C. tropicalis (P<0.0001). Application of new CLSI interpretive criteria for caspofungin increased the proportion of non-susceptible isolates for C. glabrata and Pichia kudriavzevii (P<0.0001 for both). The new amphotericin ECV (<=2mg/L) did not reveal any non-wild-type (non-WT) isolates in the five species covered. YeastOne itraconazole ECVs detected 2%, 5% and 6% non WT isolates for P. kudriavzevii, C. tropicalis and C. glabrata, respectively. No itraconazole non-WT isolates of Clavispora lusitaniae were detected. CONCLUSIONS: Whilst most results are similar to other large surveys of fungal susceptibility, the new CLSI interpretive criteria significantly altered the proportion of non susceptible isolates to fluconazole, voriconazole and caspofungin for several Candida spp. Application of CLSI and YeastOne-derived ECVs revealed the presence of a low proportion of non-WT isolates for many species. The results serve as a baseline to monitor the susceptibility of Candida and other yeast species in New Zealand over time. PMID- 29486359 TI - Variation pattern of terrestrial antibiotic resistances and bacterial communities in seawater/freshwater mixed microcosms. AB - The ocean is the final place where pollutants generated by human activities are deposited. As a result, the long-range transport of the ocean can facilitate the diffusion of terrestrial contaminants, including ARGs. However, to our knowledge, little research has been devoted to discussing the content change of terrestrial ARGs and the reason for the change in coastal area. This study established various microcosms, in which seawater and freshwater were mixed at different ratio to simulate the environmental conditions of different regions in coastal areas. Four ARGs were quantified, and 16S pyrosequencing was conducted. The results showed that the terrestrial ARGs influenced the concentration of the corresponding ARGs in coastal areas, and the content change pattern of each ARG was distinct. The influence of salinity on the ARG content was limited in most cases. Moreover, most dominant bacteria from freshwater had significant positive correlation (p < 0.05) with selected ARGs, except for blaTEM. The dominant bacteria in freshwater diminished dramatically in microcosms with a high proportion of seawater. Freshwater may have a strong impact on the bacteria composition of seawater, and the materials from freshwater may prompt the growth of some bacteria (include potential hosts of ARGs) in coastal area. PMID- 29486360 TI - Impact of natural organic matter in water on in vitro bioactivity assays. AB - Surface water can be contaminated with pollutants from multiple sources and contain a vast number of various chemicals. In vitro bioassays are valuable tools to assess the total bioactivity of micropollutants in water samples. Besides anthropogenic chemicals, natural organic matter (NOM) is ubiquitous in water, which also may have an impact on the bioactivity in water samples. In the present study we investigated concentration-dependent effects of Nordic Aquatic fulvic acid (NA-FA) and Nordic reservoir NOM (NR-NOM) on bioactivity measured by a panel of luciferase reporter gene assays. The assays included measurements of both induction of activities and inhibition of induced activation on aryl hydrocarbon receptor (AhR), androgen receptor (AR), estrogen receptor (ER), peroxisome proliferator-activated receptor alpha, and on the nuclear factor (erythroid derived 2)-like 2 (Nrf2) activity as a marker of oxidative stress. At non cytotoxic concentrations both NA-FA and NR-NOM induced AhR activity, inhibited AR activity with and without the known inducer dihydrotestosterone, inhibited Nrf2 activity, and NR-NOM induced ER activity. The results indicate that the presence of NOM in water samples may lead to false positive results for AhR activity and false positive results for AR and Nrf2 activity, when assessing inhibition of induced bioactivities from anthropogenic substances. We have demonstrated that NA FA and NR-NOM have an impact on in vitro bioactivities and conclude that the impact of NOM in water should be considered in the evaluation of results from bioactivity assays. PMID- 29486361 TI - Effect of nano zero-valent iron application on As, Cd, Pb, and Zn availability in the rhizosphere of metal(loid) contaminated soils. AB - Characterisation of geochemical transformations and processes in soils with special focus on the rhizosphere is crucial for assessing metal(loid) bioavailability to plants during in situ immobilisation and phytostabilisation. In this study, the effects of nano zero-valent iron (nZVI) were investigated in terms of the immobilisation of As, Zn, Pb and Cd in two soil types and their potential uptake by plants using rhizobox experiments. Such system allowed monitoring the behaviour of trace elements in rooted and bulk soil compartments separately. Sunflower (Helianthus annuus L.) and ryegrass (Lolium perenne L.) were tested for As-rich (15.9 g As kg-1) and Zn-rich (4.1 g Zn kg-1) soil samples, respectively. The application of nZVI effectively lowered the uptake of all target risk elements into plant tissues. Efficient immobilisation of As was determined in the As-soil without a significant difference between plant and bulk soil compartments. Similarly, a significant decrease was determined for CaCl2 available fractions of Zn, Pb and Cd in nZVI-treated Zn-soil. The behaviour of As corresponded to changes in Eh, while Zn and Cd showed to be mainly pH-dependent. However, despite the observed stabilisation effect of nZVI, high amounts of As and Zn still remained available for plants. Furthermore, the accumulation of the target risk elements in roots and the overall effect of nZVI transformations in the rhizosphere were verified and visualised by SEM/EDS. The following immobilising mechanisms were suggested: (i) sorption onto both existing and newly formed Fe (hydr)oxides, (ii) formation of secondary Fe-As phases, and (iii) sorption onto Mn (hydr)oxides. PMID- 29486362 TI - Postural control deficits in people with Multiple Sclerosis: A systematic review and meta-analysis. AB - BACKGROUND: Multiple sclerosis (MS) is a neurological condition that can affect the postural stability of the individual and predispose falls in this population. METHODS: A systematic literature search identified case-control studies investigating differences in postural control across a diversity of task conditions, with the exception of gait, between people with MS and healthy controls. Meta-analysis was conducted where a variable was presented by four or more studies. RESULTS: Forty-three studies of people with a mean Expanded Disability Status Scale (EDSS) of 1.0 to 6.0 were included. Seven conditions of assessment and 105 individual measurement variables relating to postural control were included. Quiet stance was the only condition (11 studies) possessing sufficient data to contribute to meta-analysis in terms of centre of pressure path length (SMD = 1.04, 95% CI {0.86-1.22}, p < 0.001), medio-lateral velocity (SMD = 1.35, 95% CI {0.77-1.92}, p < 0.001) and 95% confidence ellipse (SMD = 0.83 95% CI {0.59-1.08}, p < 0.001). RESULTS: indicate that regardless of task complexity or sensory condition, people with MS display considerable deficits in postural control in comparison to healthy controls. CONCLUSIONS: The large number of variables and lack of standardisation of reporting makes data synthesis challenging, however, people with MS display considerable deficits in postural control compared to healthy controls regardless of task condition or complexity. PMID- 29486363 TI - Single leg squat ratings by clinicians are reliable and predict excessive hip internal rotation moment. AB - BACKGROUND: Single leg squats are commonly used subjective assessments of general biomechanical function, injury risk, as a predictor for recovery and as an outcome measure of rehabilitation. While 3D motion capture is a useful tool for elite sports performance and research it is impractical for routine clinical use. RESEARCH QUESTION: This cross-sectional study aims to: assess reliability and validity of clinicians' subjective ratings of single leg squats compared to 3D motion capture, and to identify whether performance predicts joint moments. METHODS: 22 healthy military volunteers were simultaneously recorded on video and 3D motion capture performing single leg squats. Videos were reviewed twice by 5 physiotherapists rating performance on a 0-5 scale assessing squat depth, hip adduction, pelvic obliquity, pelvic tilt and trunk flexion summated into a composite score. RESULTS: Hip adduction and trunk flexion exhibited moderate to substantial inter- and intra-rater reliability (range kappa = 0.408-0.699) other individual criteria were mostly fair (kappa <= 0.4). Composite scores for inter rater reliability were ICC(1,1) = 0.419 and ICC(1,kappa) = 0.783 and intra-rater reliability were ICC(1,1) = 0.672 and kappa(w) = 0.526. Validity against 3D kinematics was poor with only 6/75 individually rated criteria reaching kappa > 0.40. Correlation was found between composite scores and hip internal rotation moment (rs = 0.571, p = 0.009). SIGNIFICANCE: Repeated use of single leg squats by a single practitioner is supported. Comparisons between clinicians are unreliable but improved by average measures from multiple raters. Heterogeneous reliability across scoring components suggests a qualitative description of the criteria scored is less ambiguous than using composite scores in a clinical setting. Composite scores may be more useful for analysis at a population level. Poor validity against kinematic data suggests clinicians use additional information upon which they find agreement such as estimating kinetics. Correlation between hip internal rotation moment and subjective ratings may be such an example of clinicians trying to identify excessive abnormal loading. PMID- 29486364 TI - Gluteal tendinopathy and hip osteoarthritis: Different pathologies, different hip biomechanics. AB - BACKGROUND: Gluteal tendinopathy (GT) and hip osteoarthritis (OA) are the most common causes of hip pain and associated disability in older adults. Pain and altered walking biomechanics are common to both conditions. This study aimed to compare three-dimensional walking biomechanics between individuals with unilateral, symptomatic GT and HOA. METHODS: Sixty individuals with symptomatic unilateral GT confirmed by magnetic-resonance-imaging and 73 individuals with symptomatic unilateral HOA (Kellgren-Lawrence Grade >= 2) underwent three dimensional gait analysis. Maximum and minimum values of the external sagittal hip moment, the first peak, second peak and mid-stance minimum of the hip adduction moment (HAM), sagittal plane hip excursion and hip joint angles, pelvic obliquity and trunk lean, at the three HAM time points during stance phase of walking were compared between groups. RESULTS: Compared to individuals with HOA, those with GT exhibited a greater hip peak extension moment (P < 0.001) and greater HAM throughout the stance phase of walking (P = 0.01-P < 0.001), greater hip adduction (P < 0.001) and internal rotation (P < 0.01-P < 0.001) angles and lower hip flexion angles and excursion (P = 0.02 - P < 0.001). Individuals with HOA exhibited a greater forward trunk lean (P <= 0.001) throughout stance, and greater ipsilateral trunk lean in the frontal plane (P < 0.001) than those with GT. CONCLUSION: Despite presence of pain in both conditions, hip kinematics and kinetics differ between individuals with symptomatic unilateral GT and those with symptomatic unilateral HOA. These condition-specific impairments may be targets for optimization of management of HOA and GT. PMID- 29486365 TI - Importance of common TLR2 genetic variants on clinical phenotypes and risk in tuberculosis disease in a Western Chinese population. AB - OBJECTIVES: Abundant studies have suggested that TLR2 genetic variants involve in susceptibility to TB infection. We tried to verified the hypothesis that TLR2 genetic loci effect on the susceptibility to TB in the Western Chinese population. METHODS: A total 1109 individuals (634 TB patients and 475 healthy controls) were genotyped for rs3804099, rs3804100 and rs76112010 by using a custom-by-design 2x48-Plex SNP scan TM Kit. The statistical analysis between candidate 3 SNPs and risk and phenotypes of TB were conducted in this study. Significant SNPs were further interrogated in relation to TB susceptibility to TB infection and clinical phenotypes. RESULTS: None of the three genetic loci (rs3804099, rs3804100 and rs76112010) showed statistically significant differences between all TB cases and healthy controls in genotype, allele frequencies and genetic models (all p > 0.05). Statistical comparisons of retreatment TB cases and healthy controls or primary cases revealed that rs3804099 was significantly associated with the increased risk of developing TB in Western Chinese population. For genotypes frequencies, the subgroups of retreatment TB group versus healthy control group analysis and retreatment TB group versus primary TB group analysis results showed the p = 0.041 and p = 0.002 respectively. For recessive model, the subgroup of retreatment TB group versus healthy control group and retreatment TB group versus primary TB group analyses showed the p = 0.028 and P = 0.002 after Bonferroni correction respectively. Furthermore, analysis of the genotypes of rs76112010 in relation to clinical phenotypes of active TB using the dominant model demonstrated that it was strongly correlated with different hematological parameters (Erythrocyte P = 0.043, Hemoglobin P = 0.047, Hematocrit P = 0.027). CONCLUSION: Our study presented the significant associations of rs3804099 with TB susceptibility in the retreatment TB subgroup analysis. Our study proposed that common TLR2 genetic variants may influence TB development and disease phenotypes in Western Chinese population. PMID- 29486366 TI - Mini-review on CRISPR-Cas9 and its potential applications to help controlling neglected tropical diseases caused by Trypanosomatidae. AB - The CRISPR-Cas system, which was originally identified as a prokaryotic defense mechanism, is increasingly being used for the functional study of genes. This technology, which is simple, inexpensive and efficient, has aroused a lot of enthusiasm in the scientific community since its discovery, and every month many publications emanate from very different communities reporting on the use of CRISPR-Cas9. Currently, there are no vaccines to control neglected tropical diseases (NTDs) caused by Trypanosomatidae, particularly Human African Trypanosomiasis (HAT) and Animal African Trypanosomoses (AAT), and treatments are cumbersome and sometimes not effective enough. CRISPR-Cas9 has the potential to functionally analyze new target molecules that could be used for therapeutic and vaccine purposes. In this review, after briefly describing CRIPSR-Cas9 history and how it works, different applications on diseases, especially on parasitic diseases, are reviewed. We then focus the review on the use of CRISPR-Cas9 editing on Trypanosomatidae parasites, the causative agents of NTDs, which are still a terrible burden for human populations in tropical regions, and their vectors. PMID- 29486368 TI - Bone toughness at the molecular scale: A model for fracture toughness using crosslinked osteopontin on synthetic and biogenic mineral substrates. AB - The most prominent structural components in bone are collagen and mineral. However, bone additionally contains a substantial amount of noncollagenous proteins (most notably of the SIBLING protein family), some of which may act as cohesive/adhesive "binders" for the composite hybrid collagen/mineral scaffolding, whether in the bulk phase of bone, or at its interfaces. One such noncollagenous protein - osteopontin (OPN) - appears to be critical to the deformability and fracture toughness of bone. In the present study, we used a reconstructed synthetic mineral-OPN-mineral interface, and a biogenic (natural tooth dentin) mineral/collagen-OPN-mineral/collagen interface, to measure the fracture toughness of OPN on mineralized substrates. We used this system to test the hypothesis that OPN crosslinking by the enzyme tissue transglutaminase 2 (TG2) that is found in bone enhances interfacial adhesion to increase the fracture toughness of bone. For this, we prepared double-cantilever beam substrates of synthetic pure hydroxyapatite mineral, and of narwhal dentin, and directly apposed them to one another under different intervening OPN/crosslinking conditions, and fracture toughness was tested using a miniaturized loading stage. The work-of-fracture of the OPN interface was measured for different OPN formulations (monomer vs. polymer), crosslinking states, and substrate composition. Noncrosslinked OPN provided negligible adhesion on pure hydroxyapatite, whereas OPN crosslinking (by the chemical crosslinker glutaraldehyde, and TG2 enzyme) provided strong interfacial adhesion for both hydroxyapatite and dentin using monomeric and polymeric OPN. Pre-coating of the substrate beams with monomeric OPN further improved the adhesive performance of the samples, likely by allowing effective binding of this nascent OPN form to mineral/matrix components, with this pre-attachment providing a protein layer for additional crosslinking between the substrates. PMID- 29486367 TI - Comparison of the effect of daily versus bolus dose maternal vitamin D3 supplementation on the 24,25-dihydroxyvitamin D3 to 25-hydroxyvitamin D3 ratio. AB - OBJECTIVE: Supplementing lactating mothers with high doses of vitamin D3 can adequately meet vitamin D requirements of the breastfed infant. We compared the effect of bolus versus daily vitamin D3 dosing in lactating mothers on vitamin D3 catabolism. We hypothesized that catabolism of 25(OH)D3 to 24,25(OH)2D3 would be greater in the bolus than in the daily dose group. DESIGN, SETTING AND PATIENTS: Randomized controlled trial (clinicaltrials.govNCT01240265) in 40 lactating women. INTERVENTIONS: Subjects were randomized to receive vitamin D3 orally, either a single dose of 150,000IU or 5000IU daily for 28days. Vitamin D metabolites were measured in serum and breast milk at baseline, 1, 3, 7, 14 and 28days. MAIN OUTCOME MEASURE: Temporal changes in the serum 24,25(OH)2D3/25(OH)D3 ratio. RESULTS: The concentration of serum 24,25(OH)2D3 was directly related to that of 25(OH)D in both groups (r2=0.63; p<0.001). The mean (+/-SD) 24,25(OH)2D3/25(OH)D3 ratio remained lower at all time points than baseline values in the daily dose group (0.093+/-0.024, 0.084+/-0.025, 0.083+/-0.024, 0.080+/-0.020, 0.081+/-0.023, 0.083+/-0.018 at baseline, 1, 3, 7, 14, and 28days, respectively). In the single dose group, the increase in 24,25(OH)2D3 lagged behind that of 25(OH)D, but the 24,25(OH)2D3/25(OH)D3 values (0.098+/-0.032, 0.067+/-0.019, 0.081+/-0.017, 0.092+/-0.024, 0.103+/-0.020, 0.106+/-0.024, respectively) exceeded baseline values at 14 and 28days and were greater than the daily dose group at 14 and 28days (p=0.003). The 24,25(OH)2D3/25(OH)D3 ratio remained in the normal range with both dosing regimens. Greater breast milk vitamin D3 values in the single dose group were inversely associated with the 24,25(OH)2D3/25(OH)D3 ratio (r2=0.14, p<0.001), but not with daily dosing. CONCLUSIONS: After a 14-day lag, a single high dose of vitamin D led to greater production of 24,25(OH)2D3, presumably via induction of the 24-hydroxylase enzyme (CYP24A1), relative to the 25(OH)D3 value than did daily vitamin D supplementation, and this effect persisted for at least 28days after vitamin D administration. A daily dose of vitamin D may have more lasting effectiveness in increasing 25(OH)D3 with lesser diversion of 25(OH)D3 to 24,25(OH)2D3 than does larger bolus dosing. PMID- 29486369 TI - Discovery and optimization of 2-thio-5-amino substituted benzoquinones as potent anticancer agents. AB - Based on our discovered novel lead compound 1 through phenotypic drug discovery (PDD) approaches, systematic structural optimization was performed. A series of 2 allylthio-5-amino substituted benzoquinones were synthesized and evaluated for their in-vitro anticancer activities against human prostate cancer cell line PC3. The compound 7a was found inhibit the growth of PC3 with an IC50 of 0.22 MUM, which is over 20-fold improvement compared to lead compound 1. It is noteworthy that compound 7a also showed potent anti-proliferation activity toward a panel of cancer cells with relatively less cytotoxicity to nonmalignant cell, as well as good water solubility. PMID- 29486370 TI - Pre-sleep arousal can be associated with efficient processing of sleep-related information. AB - BACKGROUND AND OBJECTIVES: Cognitive bias to sleep-related information is thought to be a core feature of sleep disturbances. The bias may enhance pre-sleep arousal, such as excessive worry about sleeplessness, which prevents people from initiating normal sleep onset. The present study focused on (a) attention bias toward sleep-related stimuli and (b) difficulty in updating working memory for sleep-related stimuli as two possible mechanisms underlying pre-sleep cognitive arousal. METHOD: Participants (n = 61, a community sample) completed a dot-probe task (with sleep-related and matched control word stimuli) and a 1-back and 2 back task (with sleep-related and non-sleep-related pictorial stimuli). RESULTS: For the dot-probe task, the results showed no significant association between pre sleep cognitive arousal and sleep-related attention bias. However, the results of the 2-back task suggest that pre-sleep arousal is associated with decreased interference by sleep-related stimuli in maintaining non-sleep-related information. That is, individuals with higher levels of pre-sleep arousal are more efficient at processing sleep-related materials. LIMITATIONS: The non clinical nature of the sample may limit the clinical implications of the findings. CONCLUSIONS: Although the current results cannot be explained by the extant cognitive theories of insomnia, we offer an alternative explanation based on the idea of worry as mental habit: mental processes that occur frequently (e.g., repetitive thoughts about sleep) require less cognitive resource. Therefore, sleep-related information may be processed easily without consuming much cognitive effort. PMID- 29486371 TI - Testing a novelty-based extinction procedure for the reduction of conditioned avoidance. AB - BACKGROUND AND OBJECTIVES: Excessive avoidance towards non-dangerous cues is a key diagnostic criterion across anxiety-related disorders. Despite current therapies being successful in reducing such avoidance, relapse rates remain high. Based on recent findings, according to which learned fear responses were reduced after the presentation of the fear stimulus with a novel-neutral event (novel based extinction), we tested whether novel-based extinction could diminish conditioned avoidance. METHODS: Forty-six participants completed a Pavlovian acquisition procedure during which two pictures of a spider were presented, one of which (CS+) was always followed by a shock (US), while the other (CS-) was never followed by a US. Next, participants learned that they could avoid the shock by pressing a computer button. An extinction and response procedure followed. During this phase, the control group was presented with both CSs that were not followed by the US. The experimental group encountered both CSs, but the CS+ was followed by a neutral event (i.e., presentation of a tone). Return of avoidance (i.e., button presses) and fear (i.e., US-expectancies and fear ratings) towards both CSs was tested after three unexpected presentations of the US. RESULTS: Similar levels of return of avoidance and explicit fear were found for both groups. LIMITATIONS: We collected no physiological measures of fear and we assessed only the short-term effects of our manipulation. CONCLUSIONS: Our results do not support the hypothesis that novelty-based extinction reduces avoidance responses. This study can serve as a first exploration of novelty-based extinction for reducing avoidance and explicit measures of fear. PMID- 29486372 TI - Digit ratio (2D:4D) and behavioral symptoms in primary-school aged boys. AB - The second-to-forth digit length ratio (2D:4D) is considered to be a biomarker for intrauterine androgen levels. It is associated with adult and child mental health problems, primarily with behavioral symptoms and predominantly in males. Using a cross-sectional design, we examined whether 2D:4D was associated with conduct disorder (CD) symptoms in 138 primary-school aged children (54% boys, Mage = 7.70 years) and considered child sex as a moderating factor. Children's digit lengths were measured from hand scans and mothers rated the behavioral/emotional symptoms of their child. The regression analyses revealed that 2D:4D ratios were associated with behavioral symptoms in boys (beta = 0.260, p = 0.026), but not in girls (beta = -0.040, p = 0.762). Child emotional symptoms, analyzed as a control, were not significantly correlated with 2D:4D. In conclusion, prenatal brain hyperandrogenization - operationalized by the 2D:4D biomarker - could result in behavioral symptoms in boys at early school age, reflecting one predictor for early onset CD. Our data support the use of 2D:4D as a marker of prenatal androgen exposure. PMID- 29486373 TI - mGlu receptors as potential targets for novel antidepressants. AB - Ever since the discovery of the rapid and sustained antidepressant effect of ketamine, a non-competitive N-methyl-d-aspartate receptor antagonist, agents acting on the glutamatergic system have been explored for their potential as novel antidepressants. Among the glutamategic system, metabotropic glutamate (mGlu) receptors, which play important roles in regulating glutamate transmission, have recently gained much attention as potential targets for the development of novel antidepressants. Of these, the antidepressant effects of agents acting on the mGlu2/3 receptor and mGlu5 receptor have been well characterized in several animal models. Moreover, the synaptic and neural mechanisms underlying the antidepressant actions of mGlu2/3 receptor and mGlu5 receptor antagonists have been elucidated, in comparison with those of ketamine. In contrast, the roles of the group III mGlu receptors, including mGlu4 and mGlu7, in depression remain to be investigated further by using selective ligands for each receptor. PMID- 29486375 TI - Aspartic acid functionalized PEGylated MSN@GO hybrid as an effective and sustainable nano-system for in-vitro drug delivery. AB - PURPOSE: In this research, aspartic acid functionalized PEGylated mesoporous silica nanoparticlesgraphene oxide nanohybrid (As-PEGylated-MSN@GO) prepared as a pH-responsive drug carrier for the curcumin delivery. For better camouflage during blood circulation, poly(ethylene glycol) was decorated on the surface of MSN@GO nanohybrid. MATERIALS AND METHODS: The nanocarrier was characterized by using X-ray powder diffraction (XRD), dynamic light scattering (DLS), UV-vis spectroscopy, thermal gravimetry analysis (TGA), FT-IR, SEM and TEM. RESULTS: The size of modified MSN@GO was around 75.8 nm and 24% wt. of curcumin was loaded on the final nanohybrid. pHdecrement from 7.4 to 5.8 the release medium led to increase the cumulative amount of drug release from 54% to 98%. CONCLUSIONS: As functionalized MSN@GO had no cytotoxicity against human breast adenocarcinoma (MCF-7) and human mammary epithelial (MCF10A) as cancerous and normal cell lines, respectively. Whereas curcuminloaded nanohybrid showed excellent killing capability against MCF-7 cells. PMID- 29486374 TI - The therapeutic potential of metabotropic glutamate receptor modulation for schizophrenia. AB - Accumulating evidence suggests that a dysregulation of the glutamatergic system exists in the brains of schizophrenia patients. The metabotropic glutamate (mGlu) receptors are being investigated as novel drug targets for this disease, and have shown promise in both preclinical and clinical studies. Activation of mGlu5 receptors may be efficacious for several symptom domains (positive, negative, and cognitive) and the potential for targeting mGlu5 receptors has been bolstered by recent research on mitigating toxicity profiles associated with mGlu5 activation. Additionally, genetic profiling of schizophrenia patients suggests that genes encoding for mGlu1 and mGlu3 receptors are altered, prompting preclinical studies that have demonstrated potential antipsychotic and cognitive enhancing effects of agents that activate mGlu1 and mGlu3 receptors, respectively. Development of subtype-specific drugs for the mGlu receptors, such as allosteric modulators, could provide a path forward for more efficacious and tolerable therapeutics for schizophrenia. PMID- 29486376 TI - Markers of anaphylaxis - a systematic review. AB - Anaphylaxis is defined as severe, life-threatening, systemic or general, immediate reaction of hypersensitivity, with repeatable symptoms caused by the dose of stimulus which is well tolerated by healthy persons. The proper diagnosis, immediate treatment and differential diagnosis are crucial for saving patient's life. However, anaphylaxis is relatively frequently misdiagnosed or confused with other clinical entities. Thus, there is a continuous need for identifying detectable markers improving the proper diagnosis of anaphylaxis. Here we presented currently known markers of anaphylaxis and discussed in more detail the most clinically valuable ones: tryptase, platelet activacting factor (PAF), PAF-acethylhydrolase, histamine and its metabolites. PMID- 29486377 TI - Questioning the automaticity of audiovisual correspondences. AB - An audiovisual correspondence (AVC) refers to an observer's seemingly arbitrary yet consistent matching of sensory features across the two modalities; for example, between an auditory pitch and visual size. Research on AVCs has frequently used a speeded classification procedure in which participants are asked to rapidly classify an image when it is either accompanied by a congruent or an incongruent sound (or vice versa). When, as is typically the case, classification is faster in the presence of a congruent stimulus, researchers have inferred that the AVC is automatic and bottom-up. Such an inference is incomplete because the procedure does not show that the AVC is not subject to top down influences. To remedy this problem, we devised a procedure that allows us to assess the degree of "bottom-up-ness" and "top-down-ness" in the processing of an AVC. We did this in studies of AVCs between pitch and five visual features: size, height, spatial frequency, brightness, and angularity. We find that all the AVCs we studied involve both bottom-up and top-down processing, thus undermining the prevalent generalization that AVCs are automatic. PMID- 29486378 TI - Spatialization in working memory is related to literacy and reading direction: Culture "literarily" directs our thoughts. AB - The ability to maintain arbitrary sequences of items in the mind contributes to major cognitive faculties, such as language, reasoning, and episodic memory. Previous research suggests that serial order working memory is grounded in the brain's spatial attention system. In the present study, we show that the spatially defined mental organization of novel item sequences is related to literacy and varies as a function of reading/writing direction. Specifically, three groups (left-to-right Western readers, right-to-left Arabic readers, and Arabic-speaking illiterates) were asked to memorize random (and non-spatial) sequences of color patches and determine whether a subsequent probe was part of the memorized sequence (e.g., press left key) or not (e.g., press right key). The results showed that Western readers mentally organized the sequences from left to right, Arabic readers spontaneously used the opposite direction, and Arabic speaking illiterates showed no systematic spatial organization. This finding suggests that cultural conventions shape one of the most "fluid" aspects of human cognition, namely, the spontaneous mental organization of novel non-spatial information. PMID- 29486379 TI - Interaction between frailty and nutritional status on mortality and long-term hospitalization in older Koreans: A retrospective analysis of data from the 2008 Survey on Health and Welfare Status of the Elderly in Korea. AB - OBJECTIVES: Although it is well known that nutritional deficiency influences frailty, and both nutritional status and frailty are closely related to mortality and morbidity in older people, there are no studies concerning this interaction. In this study, we evaluated whether the interaction of frailty and nutritional deficiency is additive and/or multiplicative. METHODS: We analyzed data from 8907 individuals (>=65 years old) who took part in the 2008 Survey on Health and Welfare Status of the Elderly in Korea. We used the Cardiovascular Health Study (CHS) frailty index and the DETERMINE checklist for assessment of frailty and nutritional status, respectively. We conducted Cox regression analysis for the outcomes 'mortality' and 'mortality and long-term hospitalization risk.' RESULTS: In the multivariate analysis for main effect model on 'mortality', the hazard ratios (HRs) of frail, high nutritional risk were 2.63 (95% CI 1.76-3.93), 1.04 (95% CI 0.78-1.38), respectively, and on 'mortality and long-term hospitalization risk' those values were 2.56 (95% CI 1.72-3.80), 1.18 (95% CI 0.88-1.58), respectively. In interaction effect model, multiplicative interaction existed between frailty and nutritional status (p < 0.001). Participants with frail X high nutritional risk had much higher HRs for 'mortality' (4.14, 95% CI 2.43 7.07) and 'mortality and long-term hospitalization risk' (4.60, 95% CI 2.74 7.72). CONCLUSION: We found that frailty and nutritional status have a multiplicative effect on adverse outcomes in community-dwelling older adults. Nutritional status assessment in older people is important because nutritional supplementation can potentially improve both nutritional status and frailty. PMID- 29486380 TI - Salient object detection based on multi-scale contrast. AB - Due to the development of deep learning networks, a salient object detection based on deep learning networks, which are used to extract the features, has made a great breakthrough compared to the traditional methods. At present, the salient object detection mainly relies on very deep convolutional network, which is used to extract the features. In deep learning networks, an dramatic increase of network depth may cause more training errors instead. In this paper, we use the residual network to increase network depth and to mitigate the errors caused by depth increase simultaneously. Inspired by image simplification, we use color and texture features to obtain simplified image with multiple scales by means of region assimilation on the basis of super-pixels in order to reduce the complexity of images and to improve the accuracy of salient target detection. We refine the feature on pixel level by the multi-scale feature correction method to avoid the feature error when the image is simplified at the above-mentioned region level. The final full connection layer not only integrates features of multi-scale and multi-level but also works as classifier of salient targets. The experimental results show that proposed model achieves better results than other salient object detection models based on original deep learning networks. PMID- 29486381 TI - Manifold regularized matrix completion for multi-label learning with ADMM. AB - Multi-label learning is a common machine learning problem arising from numerous real-world applications in diverse fields, e.g, natural language processing, bioinformatics, information retrieval and so on. Among various multi-label learning methods, the matrix completion approach has been regarded as a promising approach to transductive multi-label learning. By constructing a joint matrix comprising the feature matrix and the label matrix, the missing labels of test samples are regarded as missing values of the joint matrix. With the low-rank assumption of the constructed joint matrix, the missing labels can be recovered by minimizing its rank. Despite its success, most matrix completion based approaches ignore the smoothness assumption of unlabeled data, i.e., neighboring instances should also share a similar set of labels. Thus they may under exploit the intrinsic structures of data. In addition, the matrix completion problem can be less efficient. To this end, we propose to efficiently solve the multi-label learning problem as an enhanced matrix completion model with manifold regularization, where the graph Laplacian is used to ensure the label smoothness over it. To speed up the convergence of our model, we develop an efficient iterative algorithm, which solves the resulted nuclear norm minimization problem with the alternating direction method of multipliers (ADMM). Experiments on both synthetic and real-world data have shown the promising results of the proposed approach. PMID- 29486382 TI - Dynamic interactions between sulfidated zerovalent iron and dissolved oxygen: Mechanistic insights for enhanced chromate removal. AB - Recent research on contaminant removal by zerovalent iron (ZVI) has evolved from investigating simple model systems to systems that encompass increased dimensions of complexity. Sulfidation and aerobic conditions are two of the most broadly relevant complications. Combining these two, this study investigated the dynamic interactions between sulfidated microscale ZVI and dissolved O2, for removal of Cr(VI), a model contaminant for metals and metalloids. The results show that the coupling of sulfidation and oxygenation significantly improves Cr removal, which is attributed to enhanced Fe(II) production that resulted from accelerated corrosion of Fe(0). The Cr(VI) removal rate increased with increasing O2 saturation from 0% to 100% but showed a bimodal dependence on the S/Fe ratio. At the optimal S/Fe ratio, the ZVI exhibits a highly porous surface morphology, which, according to prior literature on sulfur induced corrosion, promotes corrosion. In addition, a novel time series correlation was developed between aqueous Fe(II) and Cr(VI) based on data collected in the presence and absence of 1,10-phenanthroline, to probe for changes of reductants during the reaction time course. The analysis indicated that Fe(0) was responsible for the initial small amount of Cr(VI) removal, which then transitioned to a phase controlled by surface Fe(II). The slopes of the time series correlations during the latter phase of the reaction vary with experimental conditions but are mostly much higher than the theoretical stoichiometric ratio between Cr(VI) and Fe(II) (i.e., 0.33), indicating that Fe(II) regeneration contributes significantly to Cr removal. PMID- 29486383 TI - Mixed stereotype content and attitudes toward students with special educational needs and their inclusion in regular schools in Luxembourg. AB - BACKGROUND: Students with special educational needs (SEN) remain one of the most socially excluded and vulnerable groups. To this extent, negative attitudes and stereotypes may impede their inclusion. Theoretical frameworks have suggested that stereotypes and attitudes elicit differential expectations and judgments, which in turn affect (social) behaviors. AIMS: In this study, we aimed to investigate the stereotypes and implicit attitudes held by a sample of Luxemburgish adults toward students with learning difficulties and challenging behavior. We also explored the adults' explicit attitudes towards inclusion. METHOD AND PROCEDURES: Participants (N = 103) completed an evaluative priming task and rated students on the stereotype dimensions of warmth and competence. In addition, they completed the German version of The Opinions Relative to Integration of Students with Disabilities questionnaire and provided demographic information. OUTCOMES AND RESULTS: Results showed differential stereotype content with respect to students with learning difficulties and challenging behavior. Results further indicated that participants' implicit attitudes toward both challenging behavior and learning difficulties were negative. By contrast, participants expressed positive attitudes towards inclusion. CONCLUSIONS AND IMPLICATIONS: The results of the current study contribute to the understanding of why some people accept, whereas others reject students with SEN. Understanding prevalent stereotypes and attitudes can inform the development of targeted interventions to promote and facilitate the social inclusion of students with SEN. PMID- 29486384 TI - Sexuality in the lives of people with intellectual disabilities: A meta ethnographic synthesis of qualitative studies. AB - BACKGROUND: The normalisation movement calls for more recognition of the sexual rights of people with intellectual disabilities to challenge classically paradoxical cultural beliefs: 'hypersexual' versus 'asexual'. AIMS: This meta ethnographic qualitative synthesis aimed to explore the voices of people with intellectual disabilities in regards to their experiences and perceptions of sexuality using a Coordinated Management of Meaning framework to derive new conceptual understandings of how their sexuality exists within multiple contexts. METHODS AND PROCEDURES: A systematic literature search and quality assessment yielded 16 studies that met the inclusion criteria and were synthesised following the method of meta-ethnography. OUTCOMES AND RESULTS: Four core themes were identified; 'Sociocultural Norms'; 'Under Others Power'; 'Sexual Identity' and 'Sexual Experience'. CONCLUSIONS AND IMPLICATIONS: Application of the hierarchical Coordinated Management of Meaning model suggested caregivers contextual beliefs about people with intellectual disabilities' sexuality inhibited or facilitated positive expressions of sexuality over and above individual needs and desires. Rights-based cultural messages provided the only context that led to positive sexuality outcomes and research that explores sexuality within this context is much needed. The Coordinated Management of Meaning model identified by this research may act as a framework to support the reflective-practice of caregivers. PMID- 29486385 TI - Standardization of rubella immunoassays. AB - Currently, rubella and congenital rubella has been eliminated or is becoming a rare disease in many countries that have implemented effective vaccination programs. In most of these countries, it is recommended and of major importance to screen childbearing age women in order to identify susceptible women and offer them vaccination before pregnancy or after delivery. Immunity to rubella virus (RV) is commonly determined by measuring rubella-specific IgG (RV-IgG). However, looking at literature, it is obvious that standardization of RV-IgG assays is not effective, with different levels of International Units per milliliter (IU/mL) reported for a same sample, and consequently different interpretations of the result. This situation leads to misinterpretation of results, sometimes causing adverse clinical outcomes. This article aimed to review several factors, such as the introduction of large-scale vaccination programs and changes in epidemiology of RV infection, along with the development of new technologies that have complicated appreciation of the immune status of patients. However, there is currently no evidence that these factors may be of any influence on rubella resurgence. PMID- 29486386 TI - Long-term stability of CMV DNA in human breast milk. AB - BACKGROUND: Human cytomegalovirus (CMV) is the leading cause of intrauterine and perinatal viral infection. The most common route of CMV transmission in newborns is through breastmilk and this can lead to infant morbidity and mortality. Breast milk that has been frozen for an extended period may need to be tested for CMV DNA to determine the source of infection. It has been a challenge for clinical laboratories to ensure the stability of CMV DNA in frozen breast milk for accurate viral load measurement. OBJECTIVES: To evaluate the stability of CMV DNA in breast milk by testing quantitative viral loads over a 28-day period for breast milk stored at 4 degrees C and a 90-day period for breast milk stored at 20 degrees C. STUDY DESIGN: Baseline viral loads were determined on day 0 and the samples stored at 4 degrees C underwent extraction and amplification at four time points, up to 28 days. The samples stored at -20 degrees C underwent extraction and amplification at five time points up to 90 days. Log10 values were calculated and t-test, Pearson's coefficient, and concordance correlation coefficient were calculated. RESULTS: There was no statistically significant difference between the time points by t-test, and correlation coefficients showed greater than 90% concordance for days 0 and 28 as well as days 0 and 90 at both storage temperatures tested. CONCLUSIONS: The concentration of CMV DNA in breast milk was stable for 28 days at 4 degrees C and 90 days at -20 degrees C as the concentrations did not differ significantly from the baseline viral loads. PMID- 29486387 TI - Modulation of calcium and potassium permeation in plant TPC channels. AB - Plant two-pore channels (TPCs) are non-selective cation channels permeable both to monovalent potassium and divalent calcium. We previously developed a technique that allowed the simultaneous determination of the fluxes of these two ions across the channel by a combined use of patch-clamp and fluorescence. In this paper we studied how potassium and calcium fluxes were influenced by modification of cytosolic concentrations of K+ and Ca2+. A decrease in cytosolic calcium from 2 to 0.5 mM led to a shift of the activation curve of about +60 mV; although at positive potentials currents were very similar, calcium ion permeation was significantly reduced and the ratio between the total and calcium-mediated current increased about two-fold. Upon removal of cytosolic potassium, in the presence of 2 mM cytosolic calcium, the voltage-dependent activation curve was not modified but a dramatic reduction of the currents at positive voltages was apparent. However, calcium permeation did not change significantly in this condition. This work demonstrated that the electrophysiological measurements alone were not capable to predict the extent of the flow of different ions through cation channels. The parallel use of calcium detection by fluorescent dyes proved to be a valuable tool for the correct quantification of the permeation mechanisms in non-selective ion channels. PMID- 29486388 TI - The effect of prenatal education classes on the birth expectations of Spanish women. AB - BACKGROUND: Maternity care has focused on lowering maternal and neonatal morbidity, though women's beliefs and expectations of care have been set aside. Women face childbirth with preconceived expectations, some of which could be expressed on their birth plan. The latter could beinfluenced by health professionals through prenatal education classes, though this has not been measured before. Antenatal classes have been argued against,since no resulting improvement in childbirth experience has been demonstrated, though some advantages may be seen: they favour communication and give time for expressing maternal expectations and beliefs. The present study evaluates the influence of prenatal educational classes led by midwives upon women birth preferences. METHODS: A multicentre, observational, prospective study was carried out, measuring variables in pregnant women attending prenatal educational classes in different health centres within the health districts in Valencia (Spain) over the period January-October 2012. Birth plan preferences were compared prior to and upon completion of the classes. RESULTS: A total of 212 eligible pregnant women (78.3% nulliparous) with an average age of 31.39+/-4.0 years consented to participate in the study. There were significant differences in birth plan preferences prior to and upon completion of the prenatal classes. Three items showed an increase between the initial session and the end of the intervention: the ability to push spontaneously, episiotomy avoidance, and early breastfeeding. An adjusted general linear model was used to compare pre-post results in relation to sociodemographic and obstetric variables. DISCUSSION: The changes in birth plans could suggest that prenatal educational classes exert an influence upon maternal birth preferences. PMID- 29486389 TI - Quantum molecular modeling of hepatitis C virus inhibition through non-structural protein 5B polymerase receptor binding of C5-arylidene rhodanines. AB - We have carried out high-level quantum chemical computations followed by molecular docking studies on a set of 17C5-arylidene rhodanine isomers to provide insights into the binding modes with different reported binding pockets of the nonstructural protein 5B (NS5B) polymerase that contribute to the hepatitis C virus (HCV) inhibition. We optimized the multi-target profile of the selected rhodanine analogs to investigate potential non-nucleotide inhibitors (NNIs) by quantum chemical optimization of the 18 isomers followed by docking with quantum chemically optimized structures of each isomer with NS5B polymerase at multiple binding pockets. The binding affinities of the PP-I, PP-II and TP-II pockets of NS5B polymerase were analyzed for all the 17 isomers of 2-[(5Z)-5-(2,4 dichlorobenzylidene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]-3-phenylpropanoic acid. On the basis of binding propensity at the different pockets and inhibitor constants, we ranked these isomers as potential candidates for the HCV inhibition. We have identified four isomers as promising NNIs of NS5B polymerase with comparable binding and inhibition to the standard (1,3) dichloro substituted isomer that exhibits in vitro activity and several other isomers as candidates in a "multi-targeted drug" approach. PMID- 29486390 TI - Markovian encoding models in human splice site recognition using SVM. AB - Splice site recognition is among the most significant and challenging tasks in bioinformatics due to its key role in gene annotation. Effective prediction of splice site requires nucleotide encoding methods that reveal the characteristics of DNA sequences to provide appropriate features to serve as input of machine learning classifiers. Markovian models are the most influential encoding methods that highly used for pattern recognition in biological data. However, a direct performance comparison of these methods in splice site domain has not been assessed yet. This study compares various Markovian encoding models for splice site prediction utilizing support vector machine, as the most outstanding learning method in the domain, and conducts a new precise evaluation of Markovian approaches that corrects this limitation. Moreover, a novel sequence encoding approach based on third order Markov model (MM3) is proposed. The experimental results show that the proposed method, namely MM3-SVM, performs significantly better than thirteen best known state-of-the-art algorithms, while tested on HS3D dataset considering several performance criteria. Further, it achieved higher prediction accuracy than several well-known tools like NNsplice, MEM, MM1, WMM, and GeneID, using an independent test set of 50 genes. We also developed MMSVM, a web tool to predict splice sites in any human sequence using the proposed approach. The MMSVM web server can be assessed at https://pashaei.shinyapps.io/mmsvm. PMID- 29486391 TI - Bridging intracellular scales by mechanistic computational models. AB - The impact of intracellular spatial organization beyond classical compartments on processes such as cell signaling is increasingly recognized. A quantitative, mechanistic understanding of cellular systems therefore needs to account for different scales in at least three coordinates: time, molecular abundances, and space. Mechanistic mathematical models may span all these scales, but corresponding multi-scale models need to resolve mechanistic details on small scales while maintaining computational tractability for larger ones. This typically results in models that combine different levels of description: from a microscopic representation of chemical reactions up to continuum dynamics in space and time. We highlight recent progress in bridging these model classes and outline current challenges in multi-scale models such as active transport and dynamic geometries. PMID- 29486393 TI - Stress-buffering effects of volunteering on salivary cortisol: Results from a daily diary study. AB - Based on the theoretical foundations of the caregiving system model, which holds that prosocial behavior can be conceptualized in relation to a neurobiological stress-buffering mechanism, we addressed the question of whether daily volunteering yields buffering effects in terms of suppressing a neuroendocrine response (i.e., salivary cortisol) to daily stressors. We used daily diary data from the second wave of the National Study of Daily Experiences (NSDE II), which is part of the Midlife in the United States study (MIDUS II), a nationally representative survey of middle-aged and older adults. Analyzing a sample of volunteers (N = 340), we tested the buffering role of daily volunteer work for the same day stressors-salivary cortisol response relationship (person-day observations, N = 1,042). Findings from multilevel models indicated that the relationship between daily stressors and cortisol output was attenuated on days when volunteering was performed compared to days volunteering was not performed. Our findings are suggestive of a unique, but unobserved, neurobiological mechanism underlying the link between volunteering and better health. Volunteer programs designed to help others in need may be considered as an intervention strategy for individuals living under stressful conditions. PMID- 29486394 TI - Negative body talk measures for Asian, Latina(o), and White women and men: Measurement equivalence and associations with ethnic-racial identity. AB - Negative body talk measures have been developed with predominantly White, female samples. We tested measurement invariance (equivalence) of two available negative body talk scales for Asian, Latina(o), and White college women and men in the U.S. In Study 1 (n = 1501 women; n = 1436 men), multiple group confirmatory factor analyses indicated scalar (strong) invariance across groups for the Negative Body Talk (Engeln-Maddox, Salk, & Miller, 2012) and Male Body Talk (Sladek, Engeln, & Miller, 2014) scales, suggesting these measures can be used to test mean group differences. Ethnic group comparisons adjusting for body mass index (BMI) showed similarities overall; few differences that emerged had small effect sizes. In Study 2 (n = 227 women; n = 141 men), greater ethnic-racial identity resolution was associated with less frequent negative body talk for Latina and Asian women but more frequent muscularity-focused negative body talk for Asian men, adjusting for BMI. PMID- 29486392 TI - Recent developments in intracellular protein delivery. AB - Protein therapeutics based on transcription factors, gene editing enzymes, signaling proteins and protein antigens, have the potential to provide cures for a wide number of untreatable diseases, but cannot be developed into therapeutics due to challenges in delivering them into the cytoplasm. There is therefore great interest in developing strategies that can enable proteins to enter the cytoplasm of cells. In this review article we will discuss recent progress in intracellular protein therapeutics, which are focused on the following four classes of therapeutics, Firstly, vaccine development, secondly, transcription factor therapies, thirdly, gene editing and finally, cancer therapeutics. These exciting new advances raise the prospect of developing cures for several un-treatable diseases. PMID- 29486395 TI - Targeted gene expression analyses and immunohistology suggest a pro-proliferative state in tricuspid aortic valve-, and senescence and viral infections in bicuspid aortic valve-associated thoracic aortic aneurysms. AB - BACKGROUND AND AIMS: Despite the potential life-threatening consequences of thoracic aortic aneurysms (TAAs), the pathogenesis of these diseases is still poorly understood. While some aspects of TAA formation have been elucidated, the role of vascular smooth muscle cells (SMCs) in both bicuspid aortic valve (BAV) associated and degenerative tricuspid aortic valve (TAV)-associated TAAs has not yet been fully unravelled. Thus, this work was aimed at uncovering processes in SMC biology that may contribute to TAA formation. METHODS: Using isolated SMCs and tissue samples from TAAs linked to BAV syndrome, TAV-associated degenerative TAAs and control aortas, we performed targeted mRNA expression profile analyses and conducted immunohistological analyses on aortic wall tissue sections. RESULTS: While SMC expression profiles and tissue analyses in TAV-TAAs clearly point toward a pro-proliferative state of the aortic media SMCs, BAV-TAA SMCs and tissue provide evidence for DNA damage, DNA damage response signalling as well as profound TLR-3 signalling. CONCLUSIONS: The data presented in this study emphasizes the importance of SMCs in TAA development. Furthermore, our results provide evidence that the state of SMCs in the BAV-TAA (senescent) and TAV-TAA (pro-proliferative) differs significantly. For the first time, we also present findings that may argue for the occurrence of a viral infection in BAV-TAA SMCs. PMID- 29486396 TI - Conversion to brivaracetam monotherapy for the treatment of patients with focal seizures: Two double-blind, randomized, multicenter, historical control, Phase III studies. AB - Brivaracetam (BRV), a selective, high-affinity ligand for synaptic vesicle protein 2A, is a new antiepileptic drug (AED) approved for monotherapy (in the USA) and adjunctive treatment of focal (partial-onset) seizures in adults, at a dose range of 50-200 mg/day taken in two equal doses, with a recommended starting dose of 100 mg/day. Two Phase III, randomized, double-blind, multicenter, historical-controlled, conversion-to-monotherapy studies (N01276, NCT00698581; N01306, NCT00699283) were conducted to evaluate the efficacy, safety, and tolerability of conversion to BRV 50 mg/day monotherapy in adults with uncontrolled focal seizures. Patients aged 16-75 years, with 2-40 focal seizures per 4 weeks during an 8-week baseline, and on stable doses of 1-2 AEDs were enrolled. Patients were randomized to BRV 50 or 100 mg/day (3:1) in two equal doses without titration. The treatment period comprised 1-week BRV add-on, 8-week baseline AED tapering, and 8-week BRV monotherapy periods. Primary efficacy endpoint was Kaplan-Meier estimate of the cumulative exit rate due to pre-defined exit criteria at Day 112 (50 mg/day, efficacy population). The upper 95% confidence interval (CI) was compared with the historical control threshold (0.722). Safety and tolerability assessments included treatment-emergent adverse events (TEAEs; intent-to-treat population). After randomization of 150 patients (N01276: 88; N01306: 62), both studies were terminated due to the confounding effects of a higher-than-expected discontinuation rate. For BRV 50 mg/day, >=1 exit criterion was met by 26/67 (38.8%) patients (study N01276) and 18/45 (40.0%) patients (study N01306). In both studies, the cumulative exit rate was lower than the historical control threshold (N01276: 0.487, 95% CI 0.347, 0.626; N01306: 0.474, 95% CI 0.310, 0.638). However, with maximum 10% censoring due to early withdrawal (sensitivity analysis), cumulative exit rates were above historical control (N01276: 0.652, 95% CI 0.532, 0.772; N01306: 0.704, 95% CI 0.563, 0.844). Overall incidence of TEAEs was 110/150, 73.3% (treatment period); 78/147, 53.1% (baseline AED tapering period); 41/84, 48.8% (BRV monotherapy period). In conclusion, BRV 50 mg/day monotherapy demonstrated an exit rate lower than historical control. Results should be interpreted with caution as, following termination of both studies, patient numbers were too low to evaluate the efficacy of BRV monotherapy. These are the first published safety and tolerability data for BRV monotherapy. Monotherapy was well tolerated, with a relatively low incidence of TEAEs, though this should be interpreted with the caveat that the majority of common TEAEs were likely to have occurred earlier in the course of treatment with BRV. No new safety concerns were identified, supporting the favorable safety profile of BRV observed in adjunctive studies. PMID- 29486397 TI - The developmental emergence of direct reciprocity and its influence on prosocial behavior. AB - Humans are a remarkably cooperative species, and one behavior thought to play an important role is that of reciprocal altruism. By ensuring that the immediate costs associated with performing a prosocial action will be recouped in the long run, reciprocal interactions support the emergence and maintenance of group-level cooperation. Existing developmental research suggests that a tendency toward selective prosocial behavior and an understanding of direct reciprocal interactions emerge in early childhood, but much less is known about the interplay between these two behaviors. In this paper, I review the existing literature supporting the notion that reciprocity mediates early prosocial tendencies and suggest that a greater understanding of the psychological mechanisms underlying reciprocity is needed. Finally, I propose two social cognitive capacities related to prospection that I believe may help to shed light on the psychology of strategic reciprocal interactions and their role in prosocial behavior more broadly. PMID- 29486398 TI - Laparoscopic treatment in Type IV Giant Paraesophagic Hernia and intestinal occlusion a case report. AB - INTRODUCTION: A Giant Hiatal Paraesophageal Hernia (GPEH) is a Hiatal Hernia (HH) that includes more than 30% of the stomach in the thorax. The gold standard form of repair today is the laparoscopic abdominal approach in elective scenarios. Laparoscopic HH repair advantages include, less postoperative pain, small incisions, reduced postoperative respiratory complications are reduced, shorter hospital stay. The objective of this paper is to describe a patient undergoing with upper intestinal obstruction and a GPEH Type IV, approached laparoscopically. CASE PRESENTATION: We received a female patient 59 years old, she came with symptoms abdominal pain, emesis of intestinal characteristics and obstipation, with an evolution of 5 days. She also referred dyspnea; she went to another institution where made a CAT scan finding a GPEH. We decided to realize the procedure laparoscopically. We follow the principal objectives, reducing the hernia, dissecting al de hernia sac excision, Hiatal reparation with no mesh, and Nissen type fundoplication without Collis Gastroplasty. The patient stayed for seven days for surveillance and when the leukocyte and LDH went to a regular rate patient was discharged. With no complications with normal intestinal function and nearly no pain. DISCUSSION: We present a GPEH case associated with upper intestinal obstruction, with clinical findings that suggested ischemia. The approach of the treatment was abdominal laparoscopy. CONCLUSION: In elective patients Laparoscopy is superior than abdominal approach. Randomized trials comparing laparoscopic versus open approach are needed to conclude that laparoscopic approach is superior to open approach, in potentially GPEH complicated patients. PMID- 29486399 TI - Generation of induced pluripotent stem cell line, CSSi004-A (2962), from a patient diagnosed with Huntington's disease at the presymptomatic stage. AB - Huntington's disease (HD) is an incurable, autosomal dominant, hereditary neurodegenerative disorder that typically manifests itself in midlife. This pathology is linked to the deregulation of multiple, as yet unknown, cellular processes starting before HD onset. A human iPS cell line was generated from skin fibroblasts of a subject at the presymptomatic life stage, carrying a polyglutamine expansion in HTT gene codifying Huntingtin protein. The iPSC line contained the expected CAG expansion, expressed the expected pluripotency markers, displayed in vivo differentiation potential to the three germ layers and had a normal karyotype. PMID- 29486400 TI - Generation of a transgene-free induced pluripotent stem cells line (UNIPDi002-A) from oral mucosa epithelial stem cells carrying the R304Q mutation in TP63 gene. AB - Transgene free UNIPDi002-A-human induced pluripotent stem cell (hiPSC) line was generated by Sendai Virus Vectors reprogramming from human oral mucosal epithelial stem cells (hOMESCs) of a patient affected by ectrodactyly-ectodermal dysplasia-clefting (EEC)-syndrome, carrying a mutation in exon 8 of the TP63 gene (R304Q). The UNIPDi002-A-hiPSC line retained the mutation of the parental R304Q hOMESCs and displayed a normal karyotype. No residual expression of transgenes nor Sendai virus vector sequences were detected in the line at passage 8. UNIPDi002-A-hiPSC expressed a panel of pluripotency-associated markers and could form embryoid bodies expressing markers belonging to the three germ layers ectoderm, endoderm and mesoderm. PMID- 29486401 TI - In the eye of the beholder: Evaluative context modulates mind-wandering. AB - We present novel evidence that mind-wandering rates during a reading task are influenced by experimental context. In Experiment 1, participants read a series of passages and we measured their frequency of mind-wandering and their subjective evaluations of passage difficulty/interest. Section length was manipulated, such that some passages were presented in short sections and others were presented in long sections. Importantly, participants were randomly assigned to complete either a within-subject version of the experiment (in which they read some short-section passages and some long-section passages) or a between-subjects design (in which they only read either short-section or long-section passages). We found that the within-subject design yielded significant effects of section length on mind-wandering and on subjective passage evaluations, whereas the between-subjects design yielded null effects. This pattern of results was replicated in Experiment 2. These results provide compelling evidence that mind wandering rates can be influenced by the experimental design. We conclude that mind-wandering is not only driven by the objective demands of the task, but also by subjective evaluations of those task properties, which are influenced by the context in which the task is evaluated (i.e., the "evaluative context"). PMID- 29486402 TI - Clinical epidemiology of long-term suicide risk in a nationwide population-based cohort study in South Korea. AB - We investigated the effects of a large range of clinical factors on the long-term risk of suicide in the general population of South Korea. We analyzed the National Health Insurance Service-National Sample Cohort (NHIS-NSC) database in South Korea. A total of 300,232 individuals were followed for up to 12 years. We obtained information on demographic variables (age and sex), lifestyle variables (cigarette smoking, alcohol drinking and exercise), psychiatric and physical disorders, laboratory examination results and physical examination findings. We conducted a competing risk survival analysis to estimate the risk of completed suicide. 725 individuals (241/100,000) died by suicide in the follow-up period. After Bonferroni correction, we found a significant suicide risk associated with 6 variables: Parkinson's disease, depressive disorder, obsessive-compulsive disorder (inverted association), elevated serum aspartate aminotransferase levels, male gender and age. Before Bonferroni correction, variables such as cigarette smoking, heavy alcohol drinking, psychotic disorder, other psychiatric disorder, benzodiazepine use and higher fasting glucose showed some significant association. In addition, body mass index and height were inversely related to completed suicide before Bonferroni correction. However, only the 6 variables listed above were robust predictors of suicide in the fully adjusted analyses with multiple test correction. Common medical conditions had no clear influence on suicide. Diverse clinical factors influenced the long-term risk of completed suicide in this general population sample. Comprehensive assessment of these risk factors will facilitate more focused suicide surveillance measures. PMID- 29486403 TI - Trauma related guilt cognitions partially mediate the relationship between PTSD symptom severity and functioning among returning combat veterans. AB - Trauma related guilt, a distressing emotion associated with negative cognitions regarding one's actions or inaction during a traumatic event, is common among individuals with posttraumatic stress disorder (PTSD). We hypothesized that trauma related guilt cognitions would partially explain the relationship between PTSD symptom severity and functioning. The sample consisted of 254 combat veterans or active duty military personnel who served in Operation Enduring Freedom, Operation Iraqi Freedom or Operation New Dawn (OEF/OIF/OND) who consented to participate in a larger PTSD treatment study. Results revealed a significant relationship between PTSD severity and guilt cognitions (standardized beta = 0.40), as well as PTSD and overall functioning (beta = 0.49). Guilt cognitions (beta's = 0.13 to 0.32) were significantly associated with nearly all domains of functioning, including overall functioning (beta = 0.27), and partially explained the relationship between PTSD and functioning. This study lends support to the addition of guilt as a symptom of PTSD in the DSM-5 as it contributes significantly to functional impairment even when accounting for other symptoms of PTSD, although co-occurring mental health problems may also contribute to functional impairments associated with PTSD. Future studies are needed to investigate whether reductions in traumatic guilt are related to improved functional outcomes in PTSD treatments. PMID- 29486404 TI - Genome-wide scan of depressive symptomatology in two representative cohorts in the United States and the United Kingdom. AB - Unlike the diagnosed Major Depressive Disorder, depressive symptomatology in the general population has received less attention in genome-wide association scan (GWAS) studies. Here we report a GWAS study on depressive symptomatology using a discovery-replication design and the following approaches: To improve the robustness of the phenotypic measure, we used longitudinal data and calculated mean scores for at least 3 observations for each individual. To maximize replicability, we used nearly identical genotyping platforms and identically constructed phenotypic measures in both the Discovery and Replication samples. We report one genome-wide significant hit; rs58682566 in the EPG5 gene was associated (p = 3.25E-08) with the mean of the depression symptom in the Discovery sample, without confirmation in the Replication sample. We also report 4 hits exceeding the genome-wide suggestive significance level with nominal replications. Rs11774887, rs4147527 and rs1379328, close to the SAMD12 gene, were associated with the mean depression symptom score (P-values in Discovery sample: 4.58E-06, 7.65E-06 and 7.66E-06; Replication sample: 0.049, 0.029 and 0.030, respectively). Rs13250896, located in an intergenic region, was associated with the mean score of the three somatic items of the depression symptoms score (p = 3.31E-07 and 0.042 for the Discovery and Replication samples). These results were not supported by evidence in the literature. We conclude that despite the strengths of our approach, using robust phenotypic measures and samples that maximize replicability potential, this study does not provide compelling evidence of a single genetic variant's significant role in depressive symptomatology. PMID- 29486405 TI - Changes in nursing education in Hong Kong - Progressive or regressive? PMID- 29486406 TI - Modification of zeolite 4A for use as an adsorbent for glyphosate and as an antibacterial agent for water. AB - The aim of this work was to design a low cost adsorbent for efficient and selective removal of glyphosate from water at neutral pH conditions. For this purpose, zeolite 4A, a locally abundant and cheap mineral material, was ion exchanged with Cu2+ to produce Cu-zeolite 4A. The FTIR results revealed that the modification has no important effect on chemical structure of zeolite 4A. After modification, highly crystalline zeolite 4A was converted to amorphous Cu-zeolite 4A according to XRD studies. The SEM images showed spherical-like particles with porous surfaces for Cu-zeolite 4A compared to cubic particles with smooth surfaces for zeolite 4A. Adsorption equilibrium data were well fitted with non linear forms of Langmuir, Freundlich and Temkin isotherms. The maximum adsorption capacity for Cu-zeolite 4A was calculated to be 112.7 mg g-1 based on the Langmuir model. The adsorption of glyphosate by the modified adsorbent had fast kinetics fitted both pseudo-first-order and pseudo-second-order models. A mechanism based on chemical adsorption was proposed for the removal process. The modified adsorbent had a good selectivity to glyphosate over natural waters common cations and anions. It also showed desired regeneration ability as an important feature for practical uses. The potential use of the developed material as antibacterial agent for water disinfection filters was also investigated by MIC method. Relatively strong antibacterial activity was observed for Cu-zeolite 4A against Gram-positive and Gram-negative model bacteria while zeolite 4A had no antibacterial properties. No release of Cu2+ to aqueous solutions was detected as unique feature of the developed material. PMID- 29486407 TI - Feedforward neural network model estimating pollutant removal process within mesophilic upflow anaerobic sludge blanket bioreactor treating industrial starch processing wastewater. AB - In this a, three-layered feedforward-backpropagation artificial neural network (BPANN) model was developed and employed to evaluate COD removal an upflow anaerobic sludge blanket (UASB) reactor treating industrial starch processing wastewater. At the end of UASB operation, microbial community characterization revealed satisfactory composition of microbes whereas morphology depicted rod shaped archaea. pH, COD, NH4+, VFA, OLR and biogas yield were selected by principal component analysis and used as input variables. Whilst tangent sigmoid function (tansig) and linear function (purelin) were assigned as activation functions at the hidden-layer and output-layer, respectively, optimum BPANN architecture was achieved with Levenberg-Marquardt algorithm (trainlm) after eleven training algorithms had been tested. Based on performance indicators such the mean squared errors, fractional variance, index of agreement and coefficient of determination (R2), the BPANN model demonstrated significant performance with R2 reaching 87%. The study revealed that, control and optimization of an anaerobic digestion process with BPANN model was feasible. PMID- 29486408 TI - Impact of cationic substances on biofilm formation from sieved fine particles of anaerobic granular sludge at high salinity. AB - This study investigated early stages of biofilm formation from sieved fine particles of anaerobic granules in the presence of various cationic substances using a quartz crystal sensor to improve biofilm formation in the anaerobic treatment of saline wastewater. The biomass attached on the sensor was greatly increased with Ca within the low range (8-16 mM), which was not affected by 50 mM of Na. However, the positive effect of 16 mM of Ca was strongly reduced in the co presence of Ca and Na when Na concentrations were in the range from 25 to 150 mM because Ca may compete with Na for the limited binding sites in biofilm. The addition of cationic polymer at 150 mM of Na increased biomass adhesion by several folds at only 10-80 mg/L compared to the addition of 16 mM of Ca. Moreover, no methanogenic inhibition was presented below the polymer content of 20 mg/L. PMID- 29486409 TI - Characterization of Enterococcus faecalis JF85 and Enterococcus faecium Y83 isolated from Tibetan yak (Bos grunniens) for ensiling Pennisetum sinese. AB - Two bacteria strains with cellulolytic potential isolated from Tibetan yak (Bos grunniens) rumen were identified as Enterococcus faecalis (JF85) and Enterococcus faecium (Y83). Isolates grow well within a range of temperature 15 to 55 degrees C and pH 3.0-7.0, respectively. Two strains were inoculated with or without Lactobacillus plantarum (Lp) to Pennisetum sinese silage for 90 days. All inoculants increased lactic acid content, decreased pH and lignocellulose contents compared with silage without additives (control). The lowest pH, highest lactic acid and largest reduction in lignocellulose contents were observed in JF85+Lp and Y83+Lp silages. Isolates alone or in combination with Lp significantly increased WSC, mono- and disaccharides contents as compared to the control. Combined addition efficiently improved enzymatic hydrolysis of Pennisetum sinese silage, indicated by higher glucose yield and cellulose convertibility. Pennisetum sinese ensiled with combined additives is a suitable storage and pretreatment method prior to sugars production from energy crop. PMID- 29486410 TI - Effect of light on the kinetics and equilibrium of the textile dye (Reactive Red 120) adsorption by Helianthus annuus hairy roots. AB - The study demonstrates for the first time that light influences the adsorption equilibrium and kinetics of a dye by root culture system. The azo dye (Reactive Red 120) adsorption by the hairy roots of H. annuus followed a pseudo first-order kinetic model and the adsorption equilibrium parameters were best estimated using Langmuir isotherm. The maximum dye adsorption capacity of the roots increased 6 fold, from 0.26 mg g-1 under complete dark conditions to 1.51 mg g-1 under 16/8 h light/dark photoperiod. Similarly, adsorption rate of the dye and removal (%) also increased in the presence of light, irrespective of the initial concentration of the dye (20-110 mg L-1). The degradation of the azo dye upon adsorption by the hairy roots of H. annuus was also confirmed. In addition, a strategy for simultaneous dye removal and increased alpha-tocopherol (industrially relevant) production by H. annuus hairy root cultures has been proposed and demonstrated. PMID- 29486411 TI - Engineering of artificial microbial consortia of Ralstonia eutropha and Bacillus subtilis for poly(3-hydroxybutyrate-co-3-hydroxyvalerate) copolymer production from sugarcane sugar without precursor feeding. AB - Ralstonia eutropha is a well-known microbe reported for polyhydroxyalkonate (PHA) production, and unable to utilize sucrose as carbon source. Two strains, Ralstonia eutropha H16 and Ralstonia eutropha 5119 were co-cultured with sucrose hydrolyzing microbes (Bacillus subtilis and Bacillus amyloliquefaciens) for PHA production. Co-culture of B. subtilis:R. eutropha 5119 (BS:RE5) resulted in best PHA production (45% w/w dcw). Optimization of the PHA production process components through response surface resulted in sucrose: NH4Cl:B. subtilis: R. eutropha (3.0:0.17:0.10:0.190). Along with the hydrolysis of sucrose, B. subtilis also ferments sugars into organic acid (propionic acid), which acts as a precursor for HV monomer unit. Microbial consortia of BS:RE5 when cultured in optimized media led to the production of poly(3-hydroxybutyrate-co-3 hydroxyvalerate) (P(3HB-co-3HV) with 66% w/w of dcw having 16 mol% HV fraction. This co-culture strategy overcomes the need for metabolic engineering of R. eutropha for sucrose utilization, and addition of precursor for copolymer production. PMID- 29486412 TI - Estimation of residential radon exposure and definition of Radon Priority Areas based on expected lung cancer incidence. AB - Radon is a naturally occurring gas, classified as a Class 1 human carcinogen, being the second most significant cause of lung cancer after tobacco smoking. A robust spatial definition of radon distribution in the built environment is therefore essential for understanding the relationship between radon exposure and its adverse health effects on the general population. Using Ireland as a case study, we present a methodology to estimate an average indoor radon concentration and calculate the expected radon-related lung cancer incidence. We use this approach to define Radon Priority Areas at the administrative level of Electoral Divisions (EDs). Geostatistical methods were applied to a data set of almost 32,000 indoor radon measurements, sampled in Ireland between 1992 and 2013. Average indoor radon concentrations by ED range from 21 to 338 Bq m-3, corresponding to an effective dose ranging from 0.8 to 13.3 mSv y-1 respectively. Radon-related lung cancer incidence by ED was calculated using a dose-effect model giving between 15 and 239 cases per million people per year, depending on the ED. Based on these calculations, together with the population density, we estimate that of the approximately 2,300 lung cancer cases currently diagnosed in Ireland annually, about 280 may be directly linked to radon exposure. This figure does not account for the synergistic effect of radon exposure with other factors (e.g. tobacco smoking), so likely represents a minimum estimate. Our approach spatially defines areas with the expected highest incidence of radon-related lung cancer, even though indoor radon concentrations for these areas may be moderate or low. We therefore recommend that both indoor radon concentration and population density by small area are considered when establishing national radon action plans. PMID- 29486413 TI - Ladies first: Female and male adult height in Switzerland, 1770-1930. AB - When investigating the well-being of a society, the living conditions of females are of special importance, not only due to the immediate impact for those directly involved, but also because of the potential intergenerational effects. Studying the dimorphism in the mean height helps to depict variation in the basic biological sex difference due to gender-related factors that potentially determine net nutrition. To expand knowledge of diachronic development in Swiss well-being conditions we investigate changes in the height of adult females born 1770-1930, and compare the series with data on contemporary males from the same sources: We employ a sample of N = 21'028 women and N = 21'329 men from passport , convict-, maternity hospital-, and voluntary World War II army auxiliary records. The secular height trend is found both in males, from the 1870s/1880s, and in females starting with the 1840s/1850s birth cohorts. During the decades under study, mean height increased from 157 cm to 164 cm in female and 167 cm to 172 cm in male passport applicants, 154 cm to 159 cm in female and 167 cm to 169 cm in male convicts, 159 cm to 163 cm in female auxiliaries, and 155 cm to 159 cm in females giving birth in the maternity hospital of Basel. Because females seem to have started the secular trend in height earlier than their male contemporaries, the height dimorphism decreased during the second half of the 19th century. Differences between socio-economic status (SES) and data sources are found in both females and males: Women with low SES were significantly shorter than those of the other SES groups in all sources (on average 1.40 cm, p values between 0.00 and 0.03). In men we found individuals of upper SES to be significantly taller (on average 1.96 cm, p-value = 0.00-0.10). Concerning differences between the sources, overall, passport applicants were the tallest for men as well as women; in females the individuals measured at the maternity hospital and in prison were the shortest. The variances across the datasets highlight the importance of considering different sources to depict average living conditions. Noteworthy is the finding that the diverse sources under study all show the same trajectory of increasing mean height over the course of the 19th century. In the long run, the improving net nutritional status of Swiss females may have been one of the contributors behind the general rise in well being of the country's population from the later 19th century onwards. PMID- 29486414 TI - Neural synchronization: Average strength vs. temporal patterning. PMID- 29486415 TI - Factors related to the continuation of aripiprazole once-monthly treatment at 1 year. PMID- 29486417 TI - The co-occurrence of autistic traits and borderline personality disorder traits is associated to increased suicidal ideation in nonclinical young adults. AB - BACKGROUND: The co-occurrence of Autism Spectrum Disorder (ASD) and Borderline Personality Disorder (BPD) is not rare and has been linked to increased suicidality. Despite this significant comorbidity between ASD and BPD, no study had examined the co-occurrence of autistic traits and borderline personality disorder traits in the general population. The aim of the present study was to examine the co-occurrence of autistic and borderline traits in a non-clinical sample of young adults and its influence on the levels of suicidal ideation and depressive symptomatology. PROCEDURES: Participants were 474 college students who completed self-report questionnaires. Data were analysed using correlation and cluster analyses. MAIN FINDINGS: Borderline personality traits and autistic traits were weakly correlated. However, cluster analysis yielded four groups: a low traits group, a borderline traits group, an autistic traits group, and a group characterized by high levels of both traits. Cluster analysis revealed that autistic and borderline traits can co-occur in a significant proportion of young adults. The high autistic and borderline traits group constituted 17% of the total sample and had higher level of suicidal ideation than the borderline traits group, despite similar levels of depressive symptoms. CONCLUSION: This result suggests that the higher suicidality observed in patients with comorbid ASD and BPD may extent to non-clinical individuals with high levels of co-occurrent autistic and borderline traits. PMID- 29486416 TI - Silica nanoparticles with Tb(III)-centered luminescence decorated by Ag0 as efficient cellular contrast agent with anticancer effect. AB - The present work introduces composite luminescent nanoparticles (Ag0-Tb3+-SNs), where ultra-small nanosilver (4 +/- 2 nm) is deposited onto amino-modified silica nanoparticles (35+/-6 nm) doped by green luminescent Tb(III) complexes. Ag0-Tb3+ SNs are able to image cancer (Hep-2) cells in confocal microscopy measurements due to efficient cell internalization, which is confirmed by TEM images of the Hep-2 cells exposed by Ag0-Tb3+-SNs. Comparative analysis of the cytotoxicity of normal fibroblasts (DK-4) and cancer cells (Hep-2) incubated with various concentrations of Ag0-Tb3+-SNs revealed the concentration range where the toxic effect on the cancer cells is significant, while it is insignificant towards the nonmalignant fibroblasts cells. The obtained results reveal Ag0-Tb3+-SNs as good cellular contrast agent able to induce the cancer cells death, which makes them promising theranostic in cancer diagnostics and therapy. PMID- 29486418 TI - Correlation of vapor phase infrared spectra and regioisomeric structure in synthetic cannabinoids. AB - The twelve 1-n-pentyl-2-, 3-, 4-, 5-, 6- and 7-(1- and 2-naphthoyl)-indoles each have the same substituents attached to the indole ring, identical elemental composition (C24H23NO) yielding identical nominal and accurate masses. These twelve isomers cover all possible positions of carbonyl bridge substitution for both indole (positons 2-7) and naphthalene rings (positions 1 and 2). Regioisomeric compounds can represent significant challenges for mass based analytical methods however, infrared spectroscopy is a powerful tool for the identification of positional isomers in organic compounds. The vapor phase infrared spectra of these twelve uniquely similar compounds were evaluated in GC IR experiments. These spectra show the bridge position on the indole ring is a dominating influence over the carbonyl absorption frequency observed for these compounds. Substitution on the pyrrole moiety of the indole ring yields the lowest CO frequency values for position 2 and 3 giving a narrow range from 1656 to 1654cm-1. Carbonyl absorption frequencies are higher when the naphthoyl group is attached to the benzene portion of the indole ring yielding absorption values from 1674 to 1671cm-1. The aliphatic stretching bands in the 2900cm-1 region yield a consistent triplet pattern because the N-alkyl substituent tail group remains unchanged for all twelve regioisomers. The asymmetric CH2 stretch is the most intense of these three bands. Changes in positional bonding for both the indole and naphthalene ring systems results in unique patterns within the 700 wavenumber out-of-plane region and these absorption bands are different for all 12 regioisomers. PMID- 29486419 TI - Cross-sectional cause of death comparisons for stimulant and opioid mortality in San Francisco, 2005-2015. AB - BACKGROUND: Opioids and stimulants (e.g., cocaine or methamphetamine/amphetamine [MAMP]) are major contributors to acute substance toxicity deaths. Causes of stimulant death have received little attention. We sought to characterize and compare causes of death and significant contributing conditions among persons who died from acute opioid, cocaine, or MAMP toxicity. METHODS: We identified all opioid, cocaine, or MAMP deaths in San Francisco from 2005 to 2015 through the California Electronic Death Reporting System. Multivariable logistic regression analyses were used to estimate associations between acute substance toxicity deaths (opioid versus stimulant; cocaine versus MAMP), additional reported causes of death, and significant contributing conditions most often linked to opioid and stimulant use. RESULTS: From 2005-2015, there were 1252 opioid deaths and 749 stimulant deaths. Cocaine accounted for most stimulant deaths. Decedents with cardiac or cerebral hemorrhage deaths had higher adjusted odds of death due to acute stimulant toxicity versus acute opioid toxicity (aOR = 4.79, 95%CI = 2.88 7.96, p < 0.01; aOR = 58.58, 95%CI = 21.06-162.91, p < 0.01, respectively); no statistically significant associations were found for cocaine compared to MAMP deaths. Significant contributing cardiac conditions were associated with higher adjusted odds of stimulant compared to opioid (aOR = 1.46, 95%CI = 1.19-1.79, p < 0.01) and cocaine compared to MAMP death (aOR = 1.66, 95%CI = 1.13-2.45, p = .01). CONCLUSIONS: Stimulant compared to opioid deaths tended to involve cardiac or cerebrovascular causes of death, and cocaine deaths were more likely than MAMP deaths to involve significant contributing cardiac conditions. Mounting evidence suggests that stimulant use be considered a cardio/cerebrovascular risk factor and clinical care be adjusted to address this heightened risk. PMID- 29486420 TI - Trends in incidence of neonatal abstinence syndrome in Canada and associated healthcare resource utilization. AB - BACKGROUND: Neonatal abstinence syndrome (NAS) is a collection of symptoms that occurs primarily due to antenatal opioid exposure. National data on incidence, hospital resource utilization, and demographic features of NAS have not been previously described for Canada. METHODS: Secondary analysis was performed with data from hospitals in all Canadian provinces and territories, excluding Quebec. Infants with NAS were identified by searching for ICD-10-CA code P96.1 in the Canadian Institute for Health Information's discharge abstract database. We examined incidence, hospital beds occupied per day, length of stay (fiscal 2003 2014), hospital costs, and demographic features (due to data availability, limited to fiscal 2010-2014). RESULTS: The incidence of NAS in Canada tripled between 2003 and 2014 (1.8-5.4 per 1000 live births), with an average annual increase of 0.33 cases per 1000 live births (95% CI 0.31, 0.34). Provincial incidence in 2014 ranged from 2.7 (Alberta) to 9.7 (New Brunswick) per 1000 live births. Between 2010 and 2014 total and mean per-patient costs rose from $15.7 to $26.9 million CAD and $14,629 to $17,367 CAD, respectively, with substantial inter-provincial variation in expenditure. Mean length of stay was 14.4 days in 2003 and 14.8 days in 2014, and beds occupied per day rose from 19.7 in 2003 to 69.4 in 2014. CONCLUSIONS: The incidence of NAS is increasing in Canada with associated rise in healthcare resource utilization. Inter-provincial variability in incidence and resource utilization underscores the need to further explore best practices for cost-effective prevention and management of NAS. PMID- 29486422 TI - Antioxidant treatment in peripheral artery disease: the rationale is there, but what about clinical results? AB - Peripheral arterial disease is a major cause of morbidity and disability and has been consistently associated with an adverse overall prognosis. Oxidative stress has been linked to vascular disease, with several suggested pathogenetic mechanisms, leading to various insults of the arterial wall and, ultimately, to atherothrombotic disease. Considering that the pathophysiological background is quite compelling, attenuation of oxidative processes by means of various substances with antioxidant properties has been conceived as a promising therapeutic target. However, clinical results have been mostly disappointing and 'antioxidant' therapies are still far from being integrated into treatment algorithms for vascular disease. PMID- 29486421 TI - Fentanyl and heroin contained in seized illicit drugs and overdose-related deaths in British Columbia, Canada: An observational analysis. AB - BACKGROUND: Due to the alarming rise in opioid-related overdose deaths, a public health emergency was declared in British Columbia (BC). In this study, we examined the relationship between illicit fentanyl and heroin found in seized drugs and illicit overdose deaths in BC. METHODS: An observational cross sectional survey was conducted using BC data from Health Canada's Drug Analysis Service, which analyzes drug samples seized by law enforcement agencies, and non intentional illicit overdoses from the BC Coroner's Service, from 2000 to 2016. Initial scatter plots and subsequent multivariate regression analysis were performed to describe the potential relationship between seized illicit fentanyl samples and overdose deaths and to determine if this differed from seized heroin and overdose deaths. Fentanyl samples were analyzed for other drug content. RESULTS: Fentanyl is increasingly being found combined with other opioid and non opioid illicit drugs. Strong positive relationships were found between the number of seized fentanyl samples and total overdose deaths (R2 = 0.97) as well as between seized fentanyl and fentanyl-detected overdose deaths (R2 = 0.99). A positive association was found between the number of seized heroin samples and total overdose deaths (R2 = 0.78). CONCLUSION: This research contributes to the expanding body of evidence implicating illicit fentanyl use (often combined with heroin or other substances) in overdose deaths in BC. Policy makers and healthcare providers are urged to implement drug treatment and harm reduction strategies for people at risk of overdose associated with current trends in illicit opioid use. PMID- 29486423 TI - Improving the test-retest and inter-rater reliability for stretch reflex measurements using an isokinetic device in stroke patients with mild to moderate elbow spasticity. AB - The conventional tools to measure spasticity exhibited insufficient test-retest or inter-rater reliability. Therefore, the spasticity measurement using an isokinetic device has been proposed to improve these reliabilities of the angle of catch (AoC) measurements; however, this proposal has not been investigated in a standardized manner. In this study, the comparison of the AoC measurement was performed using two modes (isokinetic and manual motion) to investigate whether the standardized isokinetic motion could increase the reliabilities. Motion consistency was calculated using a newly developed index. To analyze the effect of the motion standardization, AoC were estimated using EMG data for both modes, and to compare the measurement reliability, AoC for isokinetic mode was estimated using both EMG and torque data. Although the test-retest reliability for manual motion was excellent, the use of isokinetic motion improved it to the level of extremely excellent. Intraclass correlation coefficient (ICC) for the inter-rater reliability of manual motion was 0.788, which was near the lower limit of the excellent. Isokinetic motion improved it to the ICC of 0.890 and 0.931 based on the EMG and torque, respectively. These improvements in reliabilities reduced the measurement errors, sample size, and need for the same rater in clinical trials. PMID- 29486424 TI - Altered trunk muscle recruitment patterns during lifting in individuals in remission from recurrent low back pain. AB - Changes in the recruitment pattern of trunk muscles may contribute to the development of recurrent or chronic symptoms in people with low back pain (LBP). However, the recruitment pattern of trunk muscles during lifting tasks associated with a high risk of LBP has not been clearly determined in recurrent LBP. The present study aimed to investigate potential differences in trunk muscles recruitment patterns between individuals with recurrent LBP and asymptomatic individuals during lifting. The subjects were 25 individuals with recurrent LBP and 20 asymptomatic individuals. Electromyography (EMG) was used to measure onset time, EMG amplitude, overall activity of abdominal muscles, and overall activity of back muscles during a lifting task. The onsets of the transversus abdominis/internal abdominal oblique and multifidus were delayed in the recurrent LBP group despite remission from symptoms. Additionally, the EMG amplitudes of the erector spinae, as well as the overall activity of abdominal muscles or back muscles, were greater in the recurrent LBP group. No differences in EMG amplitude of the external oblique, transversus abdominis/internal abdominal oblique, and multifidus were found between the groups. Our findings indicate the presence of an altered trunk muscle recruitment pattern in individuals with recurrent LBP during lifting. PMID- 29486425 TI - Integrative whole-brain neuroscience in larval zebrafish. AB - Due to their small size and transparency, zebrafish larvae are amenable to a range of fluorescence microscopy techniques. With the development of sensitive genetically encoded calcium indicators, this has extended to the whole-brain imaging of neural activity with cellular resolution. This technique has been used to study brain-wide population dynamics accompanying sensory processing and sensorimotor transformations, and has spurred the development of innovative closed-loop behavioral paradigms in which stimulus-response relationships can be studied. More recently, microscopes have been developed that allow whole-brain calcium imaging in freely swimming and behaving larvae. In this review, we highlight the technologies underlying whole-brain functional imaging in zebrafish, provide examples of the sensory and motor processes that have been studied with this technique, and discuss the need to merge data from whole-brain functional imaging studies with neurochemical and anatomical information to develop holistic models of functional neural circuits. PMID- 29486426 TI - The effects of stakeholder involvement on perceptions of an evaluation's credibility. AB - This article presents a study of the effects of stakeholder involvement on perceptions of an evaluation's credibility. Crowdsourced members of the public and a group of educational administrators read a description of a hypothetical program and two evaluations of the program: one conducted by a researcher and one conducted by program staff (i.e. program stakeholders). Study participants were randomly assigned versions of the scenario with different levels of stakeholder credibility and types of findings. Results showed that both samples perceived the researcher's evaluation findings to be more credible than the program staff's, but that this difference was significantly reduced when the program staff were described to be highly credible. The article concludes with implications for theory and research on evaluation dissemination and stakeholder involvement. PMID- 29486427 TI - Pharmacogenetics and target identification in diabetes. AB - In diabetes, pharmacogenetics can be used both to identify patient subgroups who will have most benefit and/or least harm from a particularly treatment, and to gain insights into the molecular mechanisms of drug action and disease aetiology. There is increasing evidence that genetic variation alters response to diabetes treatments-both in terms of glycaemic response and side effects. This can be seen with dramatic impact on clinical care, in patients with genetic forms of diabetes such as Maturity Onset Diabetes of the Young caused by HNF1A mutations, and Neonatal diabetes due to activating mutations in ABCC8 or KCNJ11. Beyond monogenic diabetes, pharmacogenetic variants have yet to impact on clinical practice, yet the effect sizes (e.g. for metformin intolerance and OCT1 variants; or for metformin action and SLC2A2 variants) are potentially of clinical utility, especially if the genotype is already known at the point of prescribing. Over the next few years, increasing cohort sizes and linkage at scale to electronic medical records will provide considerable potential for stratification and novel target identification in diabetes. PMID- 29486428 TI - Effects of manipulated auditory information on local dynamic gait stability. AB - Auditory information affects sensorimotor control of gait. Noise or active noise cancelling alters the perception of movement related sounds and, probably, gait stability. The aim of the current study was to evaluate the effects of noise cancelling on gait stability. Twenty-five healthy older subjects (70 +/- 6 years) were included into a randomized cross-over study. Gait stability (largest Lyapunov exponent) in normal overground walking was determined for the following hearing conditions: no manipulation and active noise cancelling. To assess differences between the two hearing conditions (no manipulation vs. active noise cancelling), Student's repeated measures t-test was used. The results indicate an improvement of gait stability when using active noise cancelling compared to normal hearing. In conclusion, our results indicate that auditory information might not be needed for a stable gait in elderly. PMID- 29486429 TI - Region-specific modulation of tendon reflex along human rectus femoris muscle. AB - INTRODUCTION: We investigated regional differences in amplitude modulation of the spinal reflex along the human rectus femoris (RF) muscle to test the hypothesis that this muscle is regionally regulated at the spinal cord or a higher level. METHODS: Surface electromyography was conducted at six different sites along the RF muscle during the conditioned patellar tendon reflex in eight healthy young men. RESULTS: A significant difference in the reflex amplitude among the channels was observed during 20% of the maximal voluntary contraction (MVC) and there was a significant difference in normalized reflex amplitude between 10 and 20% of the MVC at most proximal channel (p < 0.05), but not at the other channels (p > 0.05), during knee flexion of the ipsilateral leg. DISCUSSION: From the results in the present study, we infer that the amplitude modulation of the tendon reflex within the RF muscle is regionally regulated, and that this regulation is dependent on the performed tasks. PMID- 29486430 TI - Non-lamellar lyotropic liquid crystalline nanoparticles enhance the antibacterial effects of rifampicin against Staphylococcus aureus. AB - The fight against infection in an era of emerging antibiotic resistant bacteria is one of the grandest scientific challenges facing society today. Nano-carriers show great promise in improving the antibacterial activity of antibiotics as they are able to enhance their solubility, provide sustained release and reduce toxic side effects via specifically targeting infection sites. Here, we investigate the antibacterial effect of two lipidic nano-carriers that contain the poorly soluble antibiotic rifampicin in their bilayers. One nanoparticle is assembled solely from the lipid monoolein, thus is neutral at physiological pH and the other contains a mixture of monoolein and the cationic lipid N-[1-(2,3 Dioleoyloxy)propyl]-N,N,N-trimethylammonium methyl-sulfate (DOTAP), thus is positively charged. Our results show that rifampicin-loaded nanoparticles reduce the minimum inhibitory concentration against Staphylococcus aureus compared to rifampicin alone, however this reduction was most pronounced for the positively charged nanoparticles. Fluorescent microscopy revealed binding of all nanoparticles to the bacteria and enhanced binding was observed for the charged nanoparticles. This suggests that the cationic lipids promote electrostatic interactions with the negatively charged bacterial membrane. Forster resonance energy transfer demonstrated that the cationic charged nanoparticles were able to fuse with bacterial membranes whilst atomic force microscopy and transmission electron microscopy revealed structural damage to the bacterial membranes caused by the nanoparticles. Significantly, we identified a concentration window in which the nanoparticles exhibited antibacterial activity while not affecting HeLa and CHO cell viability. This ability to improve the efficacy of antibiotics without affecting their eukaryotic cytotoxicity is of significant importance for future development of nanomedicine based strategies to combat infections. PMID- 29486431 TI - Carbohydrate gel beads as model probes for quantifying non-ionic and ionic contributions behind the swelling of delignified plant fibers. AB - Macroscopic beads of water-based gels consisting of uncharged and partially charged beta-(1,4)-d-glucan polymers were developed to be used as a novel model material for studying the water induced swelling of the delignified plant fiber walls. The gel beads were prepared by drop-wise precipitation of solutions of dissolving grade fibers carboxymethylated to different degrees. The internal structure was analyzed using Solid State Cross-Polarization Magic Angle Spinning Carbon-13 Nuclear Magnetic Resonance and Small Angle X-ray Scattering showing that the internal structure could be considered a homogeneous, non-crystalline and molecularly dispersed polymer network. When beads with different charge densities were equilibrated with aqueous solutions of different ionic strengths and/or pH, the change in water uptake followed the trends expected for weak polyelectrolyte gels and the trends found for cellulose-rich fibers. When dried and subsequently immersed in water the beads also showed an irreversible loss of swelling depending on the charge and type of counter-ion which is commonly also found for cellulose-rich fibers. Taken all these results together it is clear that the model cellulose-based beads constitute an excellent tool for studying the fundamentals of swelling of cellulose rich plant fibers, aiding in the elucidation of the different molecular and supramolecular contributions to the swelling. PMID- 29486432 TI - An all-water-based system for robust superhydrophobic surfaces. AB - Superhydrophobic surfaces with micro-/nanohierarchical structures are mechanically weak. Generally, organic solvents are used to dissolve or disperse organic adhesives and modifiers to enhance the mechanical strength of superhydrophobic surfaces. In this work, an all-water-based spraying solution is developed for the preparation of robust superhydrophobic surfaces, which contains ZnO nanoparticles, aluminum phosphate as an inorganic adhesive, and polytetrafluoroethylene with low surface energy. The all-water-based system is appreciated for low price and less pollution. Importantly, the prepared superhydrophobic surfaces are durable enough against various harsh conditions (such as UV irradiation for 12 h, pH values from 1 to 13, and temperatures from 10 to 300 degrees C for 12 h) and physical damages (including sandpaper abrasion and sand impact tests for 50 cycles). In addition, the obtained interfacial materials show promise for practical applications such as anti-icing and oil water separation. PMID- 29486433 TI - The impact of witnessing other people's trauma: The resilience and coping strategies of members of the Faculty of Forensic and Legal Medicine. AB - INTRODUCTION: The coping strategies, resilience and psychological distress of members of the Faculty of Forensic and Legal Medicine (FFLM) were measured in an attempt to establish how they are affected by, and accommodate potentially traumatic encounters with patients. Belief in a just world was also measured as it was deemed to be a mediating factor in the psychological distress exhibited in the medical practitioners who participated in this study. METHODS: 120 members of the FFLM (65 females, 54 males and 1 undisclosed) volunteered to complete an online survey. Data was collected using Survey Monkey. Participants filled out the Personal Belief in a Just World Scale and General Belief in a Just World Scale, as well as the Connor-Davidson Resilience Scale 25, the COPE and the Brief Symptom Inventory. RESULTS: A multiple regression with stepwise entry was carried out. Personal belief in a just world, coping strategies and resilience were all identified as having a significant relationship with psychological distress. CONCLUSIONS: Although this is only a preliminary study into this phenomenon, findings suggest the personal belief in a just world, coping strategies and resilience are useful predictors of psychological distress amongst forensic medical practitioners. However they did not predict the majority of the variance and as such, more detailed investigations are needed to identify which other factors are important in order to design interventions and support for members of the Faculty of Forensic and Legal Medicine and other forensic medical practitioners. PMID- 29486434 TI - "The devil's in the detail": Release of an expanded, enhanced and dynamically revised forensic STR Sequence Guide. AB - The STR sequence template file published in 2016 as part of the considerations from the DNA Commission of the International Society for Forensic Genetics on minimal STR sequence nomenclature requirements, has been comprehensively revised and audited using the latest GRCh38 genome assembly. The list of forensic STRs characterized was expanded by including supplementary autosomal, X- and Y chromosome microsatellites in less common use for routine DNA profiling, but some likely to be adopted in future massively parallel sequencing (MPS) STR panels. We outline several aspects of sequence alignment and annotation that required care and attention to detail when comparing sequences to GRCh37 and GRCh38 assemblies, as well as the necessary matching of MPS-based allele descriptions to previously established repeat region structures described in initial sequencing studies of the less well known forensic STRs. The revised sequence guide is now available in a dynamically updated FTP format from the STRidER website with a date-stamped change log to allow users to explore their own MPS data with the most up-to-date forensic STR sequence information compiled in a simple guide. PMID- 29486435 TI - Influence of land cover on riverine dissolved organic carbon concentrations and export in the Three Rivers Headwater Region of the Qinghai-Tibetan Plateau. AB - The Qinghai-Tibetan plateau (QTP) stores a large amount of soil organic carbon and is the headwater region for several large rivers in Asia. Therefore, it is important to understand the influence of environmental factors on river water quality and the dissolved organic carbon (DOC) export in this region. We examined the water physico-chemical characteristics, DOC concentrations and export rates of 7 rivers under typical land cover types in the Three Rivers Headwater Region during August 2016. The results showed that the highest DOC concentrations were recorded in the rivers within the catchment of alpine wet meadow and meadow. These same rivers had the lowest total suspended solids (TSS) concentrations. The rivers within steppe and desert had the lowest DOC concentrations and highest TSS concentrations. The discharge rates and catchment areas were negatively correlated with DOC concentrations. The SUVA254 values were significantly negatively correlated with DOC concentrations. The results suggest that the vegetation degradation, which may represent permafrost degradation, can lead to a decrease in DOC concentration, but increasing DOC export and soil erosion. In addition, some of the exported DOC will rapidly decompose in the river, and therefore affect the regional carbon cycle, as well as the water quality in the source water of many large Asian rivers. PMID- 29486436 TI - Anaerobic digestion of orange peel in a semi-continuous pilot plant: An environmentally sound way of citrus waste management in agro-ecosystems. AB - The management of residues of citrus processing involves economic and environmental problems. In particular, the uncontrolled disposal of citrus processing waste near production sites can have heavy impacts on air, soil, surface water bodies and groundwater. Anaerobic digestion has been proposed as a viable alternative for citrus waste valorisation, if some problems, linked to the biochemical processes, are overcome. Although many experimental tests have studied the inhibitory effects of the high essential oil content of orange peel on biomethanisation processes, fewer experiences have been carried out in continuous or semi-continuous pilot digesters, more similar to the full-scale biogas plants, using real orange peel. This study has evaluated the methane production through anaerobic digestion of industrial orange peel using a pilot plant (84L) with semi-continuous feeding at increasing Organic Loading Rates (OLR) and essential oil (EO) supply rates (EOsr) until the complete process inhibition. Under mesophilic conditions, the highest daily specific methane yield was achieved at OLR of 1.0gTVSL-1 d-1 and EOsr of 47.6mgL-1d-1. Partial inhibition of the anaerobic digestion was detected at OLR and EOsr of 1.98gTVSL 1d-1 and 88.1mgL-1 d-1, respectively and the process irreversibly stopped when OLR and EOsr reached 2.5gTVS L-1 d-1 and 111.2mgL-1 d-1, respectively. Under thermophilic conditions, the cumulative methane production (0.12LgTVS-1) was about 25% of that under mesophilic conditions (0.46LgTVS-1). The thermophilic digestion was completely inhibited at lower OLR (1.98gTVSL-1 d-1) and EOsr (88.1mgL-1 d-1) compared to mesophilic conditions. This study confirmed the suitability of anaerobic digestion of orange peel for biomethane production (provided that the right management of the process is set), in view of an environmentally sound way of agricultural residues management in agro-ecosystems. PMID- 29486437 TI - Chemical characterisation and source identification of atmospheric aerosols in the Snowy Mountains, south-eastern Australia. AB - Characterisation of atmospheric aerosols is of major importance for: climate, the hydrological cycle, human health and policymaking, biogeochemical and palaeo climatological studies. In this study, the chemical composition and source apportionment of PM2.5 (particulate matter with aerodynamic diameters less than 2.5MUm) at Yarrangobilly, in the Snowy Mountains, SE Australia are examined and quantified. A new aerosol monitoring network was deployed in June 2013 and aerosol samples collected during the period July 2013 to July 2017 were analysed for 22 trace elements and black carbon by ion beam analysis techniques. Positive matrix factorisation and back trajectory analysis and trajectory clustering methods were employed for source apportionment and to isolate source areas and air mass travel pathways, respectively. This study identified the mean atmospheric PM2.5 mass concentration for the study period was (3.3+/-2.5)MUgm-3. It is shown that automobile (44.9+/-0.8)%, secondary sulfate (21.4+/-0.9)%, smoke (12.3+/-0.6)%, soil (11.3+/-0.5)% and aged sea salt (10.1+/-0.4)% were the five PM2.5 source types, each with its own distinctive trends. The automobile and smoke sources were ascribed to a significant local influence from the road network and bushfire and hazard reduction burns, respectively. Long-range transport are the dominant sources for secondary sulfate from coal-fired power stations, windblown soil from the inland saline regions of the Lake Eyre and Murray-Darling Basins, and aged sea salt from the Southern Ocean to the remote alpine study site. The impact of recent climate change was recognised, as elevated smoke and windblown soil events correlated with drought and El Nino periods. Finally, the overall implications including potential aerosol derived proxies for interpreting palaeo-archives are discussed. To our knowledge, this is the first long-term detailed temporal and spatial characterisation of PM2.5 aerosols for the region and provides a crucial dataset for a range of multidisciplinary research. PMID- 29486438 TI - Multi-scale assessments of droughts: A case study in Xinjiang, China. AB - Understanding the multi-scale variation of drought is essentially important in drought assessment. Now, a comprehensive assessment is still lacking on the meteorological, ecological and hydrological drought perspectives. In order to better investigate multi-scale droughts, we carried out a comprehensive analysis of their long-term variation based on the two drought indices and observation data in Xinjiang, China, from 1961 to 2015. The two indices are the Standardized Precipitation Index (SPI) and the Standardized Precipitation Evapotranspiration Index (SPEI). The results show that the SPI and SPEI are highly consistent for most stations and time scales in Xinjiang. Based on multi-scale and considered evaporative demand, the SPEI from 1961 to 2015 showed a wetting trend followed by a drying trend (as of 1997), giving an overall slight drying trend (-0.0122+/ 0.0043 per year) for the 54-year period. We assessed the sensitivity of the two drought indices to precipitation (P) and potential evapotranspiration (PET) and found that the SPEI shows different sensitivity to P and PET. In arid regions characterized by high PET, drought severity is mostly determined by changes in PET. The intensified warming and diminished precipitation in Xinjiang that have been observed over the past two decades have resulted in SPEI-drought severity. These changes also amplify the risk of ecological drought. However, the hydrological drought was highly complex and not entirely comparable to the SPEI and SPI droughts. Hydrological records indicate that runoff in most rivers in the Tianshan Mountains has increased, whereas runoff in the Kunlun Mountains is either stable or has slightly decreased over the past 20years. A moderately high and statistically significant correlation between the runoff anomaly and the SPEI and SPI was revealed for four major rivers in the region. This implies that the accelerated river runoff in Xinjiang is a function of both precipitation and increasing glacier melt. PMID- 29486439 TI - Exposure risk of local residents to copper near the largest flash copper smelter in China. AB - Copper (Cu) smelting released large amounts of Cu and contaminated the environment. However, few studies have investigated the Cu exposure risks for people located near Cu smelters. In this study, atmospheric bulk deposition, food from local families, drinking water and biological samples (hair and urine) were collected in three villages near the largest flash Cu smelter in China. The objective of the current study was to investigate how non-ferrous metals smelting affect the human health. Total atmospheric Cu depositions (56-767MUgm-2yr-1) were one or two orders of magnitude greater than that of unpolluted rural areas. The Cu concentrations in locally grown vegetables and dietary chronic daily intake (CDI) of local residents showed a consistently decreasing trend with atmospheric Cu depositions. Dietary intake of vegetables and rice were the two major pathways of total CDI, which accounted for >93% totally. The Cu exposure showed higher potential non-carcinogenic risk to human health of local residents, especially children living around the Cu smelter through food consumptions. Health impact monitoring data revealed that mean Cu concentrations in hair and urine samples were ranged from 5.13 to 28.85mgkg-1 and 19.90 to 54.61MUgL-1 in the three villages, respectively. Significant correlation between hair Cu concentrations and the CDI of Cu indicated food ingestion had adverse effects on the health of the local residents. The result suggested that nonferrous metal smelter should be away from residential area and locally produced crops became unsuitable for consumption. Therefore, effective measures on Cu pollution management and control in the surrounding area should be formulated and implemented. PMID- 29486440 TI - Biological groundwater denitrification systems: Lab-scale trials aimed at nitrous oxide production and emission assessment. AB - Bio-trenches are a sustainable option for treating nitrate contamination in groundwater. However, a possible side effect of this technology is the production of nitrous oxide, a greenhouse gas that can be found both dissolved in the liquid effluent as well as emitted as off gas. The aim of this study was to analyze NO3- removal and N2O production in lab-scale column trials. The column contained olive nut as organic carbon media. The experimental study was divided into three phases (I, II and III) each characterized by different inlet NO3- concentrations (30, 50, 75mgNO3-NL-1 respectively). Sampling ports deployed along the length of the column allowed to observe the denitrification process as well as the formation and consumption of intermediate products, such as nitrite (NO2-) and nitrous oxide (N2O). In particular, it was observed that N2O production represent only a small fraction of removed NO3- during Phase I and II, both for dissolved (0.007%) and emitted (0.003%) phase, and it was recorded a high denitrification efficiency, over 99%. Nevertheless, significantly higher values were recorded for Phase 3 concerning emitted phase (0.018%). This fact is due to increased inlet concentration which resulted in a carbon limitation and in a consequent decrease in denitrification efficiency (76%). PMID- 29486441 TI - Analyzing the carbon mitigation potential of tradable green certificates based on a TGC-FFSRO model: A case study in the Beijing-Tianjin-Hebei region, China. AB - Contradictions of increasing carbon mitigation pressure and electricity demand have been aggravated significantly. A heavy emphasis is placed on analyzing the carbon mitigation potential of electric energy systems via tradable green certificates (TGC). This study proposes a tradable green certificate (TGC) fractional fuzzy stochastic robust optimization (FFSRO) model through integrating fuzzy possibilistic, two-stage stochastic and stochastic robust programming techniques into a linear fractional programming framework. The framework can address uncertainties expressed as stochastic and fuzzy sets, and effectively deal with issues of multi-objective tradeoffs between the economy and environment. The proposed model is applied to the major economic center of China, the Beijing-Tianjin-Hebei region. The generated results of proposed model indicate that a TGC mechanism is a cost-effective pathway to cope with carbon reduction and support the sustainable development pathway of electric energy systems. In detail, it can: (i) effectively promote renewable power development and reduce fossil fuel use; (ii) lead to higher CO2 mitigation potential than non TGC mechanism; and (iii) greatly alleviate financial pressure on the government to provide renewable energy subsidies. The TGC-FFSRO model can provide a scientific basis for making related management decisions of electric energy systems. PMID- 29486442 TI - Reutilization of the expired tetracycline for lithium ion battery anode. AB - Waste antibiotics into the natural environment are the large challenges to the environmental protection and the human health, and the unreasonable disposal of the expired antibiotics is a major pollution source. Herein, to achieve the innocent treatment and the resource recovery, the expired tetracycline was tried to be reutilized as the electrode active material in lithium ion battery (LIB) for the first time. The micro-structure and element component of the expired tetracycline were characterized by scanning electron microscope (SEM), energy dispersive X-ray spectroscopy (EDX), X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FTIR). Furthermore, the corresponding electrochemical performances were also investigated by galvanostatic charge/discharge and cyclic voltammetry (CV). To be satisfactory, the expired tetracycline-based electrode delivered the initial specific discharge capacity of 371.6mAh/g and the reversible specific capacity of 304.1mAh/g after 200cycles. The decent results will not only offer an effective strategy to recycle the expired tetracycline, but also shed a new light on the cyclic economy and the sustainable development. PMID- 29486443 TI - SWAT-MODSIM-PSO optimization of multi-crop planning in the Karkheh River Basin, Iran, under the impacts of climate change. AB - Agriculture is one of the environmental/economic sectors that may adversely be affected by climate change, especially, in already nowadays water-scarce regions, like the Middle East. One way to cope with future changes in absolute as well as seasonal (irrigation) water amounts can be the adaptation of the agricultural crop pattern in a region, i.e. by planting crops which still provide high yields and so economic benefits to farmers under such varying climate conditions. To do this properly, the whole cascade starting from climate change, effects on hydrology and surface water availability, subsequent effects on crop yield, agricultural areas available, and, finally, economic value of a multi-crop cultivation pattern must be known. To that avail, a complex coupled simulation optimization tool SWAT-LINGO-MODSIM-PSO (SLMP) has been developed here and used to find the future optimum cultivation area of crops for the maximization of the economic benefits in five irrigation-fed agricultural plains in the south of the Karkheh River Basin (KRB) southwest Iran. Starting with the SWAT distributed hydrological model, the KR-streamflow as well as the inflow into the Karkheh reservoir, as the major storage of irrigation water, is calibrated and validated, based on 1985-2004 observed discharge data. In the subsequent step, the SWAT predicted streamflow is fed into the MODSIM river basin Decision Support System to simulate and optimize the water allocation between different water users (agricultural, environmental, municipal and industrial) under standard operating policy (SOP) rules. The final step is the maximization of the economic benefit in the five agricultural plains through constrained PSO (particle swarm optimization) by adjusting the cultivation areas (decision variables) of different crops (wheat, barley, maize and "others"), taking into account their specific prizes and optimal crop yields under water deficiency, with the latter computed in the LINGO-sub-optimization module embedded in the SLMP-tool. For the optimization of the agricultural benefits in the KRB in the near future (2038 2060), quantile-mapping (QM) bias-corrected downscaled predictors for daily precipitation and temperatures of the HadGEM2-ES GCM-model under RCP4.5- and RCP8.5-emission scenarios are used as climate drivers in the streamflow- and crop yield simulations of the SWAT-model, leading to corresponding changes in the final outcome (economic benefit) of the SLMP-tool. In fact, whereas for the historical period (1985-2004) a total annual benefit of 94.2 million US$ for all multi-crop areas in KRB is computed, there is a decrease to 88.3 million US$ and 72.1 million US$ for RCP4.5 and RCP8.5, respectively, in the near future (2038 2060) prediction period. In fact, this future income decrease is due to a substantial shift from cultivation areas devoted nowadays to high-price wheat and barley in the winter season to low-price maize-covered areas in the future summers, owing to a future seasonal change of SWAT-predicted irrigation water available, i.e. less in the winter and more in the summer. PMID- 29486444 TI - Derivation of avian dermal LD50 values for dermal exposure models using in vitro percutaneous absorption of [14C]-atrazine through rat, mallard, and northern bobwhite full thickness skin. AB - Understanding dermal exposure is important for higher-tier avian ecological risk assessments. However, dermal exposure and toxicity are often unknown for avifauna. The US EPA's Terrestrial Investigation Model (TIM) uses a method to estimate avian dermal LD50 values (and ultimately dermal exposure) that frequently results in unusually high dermal exposure and low dermal LD50 estimates. This is primarily a result of using organophosphate and carbamate toxicity data to develop the oral-dermal relationship. An estimated dermal LD50 is necessary to generate a dermal route equivalency factor that normalizes potency relative to oral toxicity within the dermal pathway dose equation. In this study, atrazine dermal absorption experiments were conducted with mallard, northern bobwhite, and rat skin. These data were used to derive an avian-mammal dermal route equivalency factor for atrazine and introduce a new approach for estimating dermal LD50 values and ultimately predicting exposure via the TIM dermal pathway. Compared to the default TIM method, this new approach yielded TIM output with lower mean total dose, lower dermal fraction of total dose, greater oral fraction of total dose, and reduced model predicted mortality for atrazine. In addition, the new approach was compared with other methods for estimating avian dermal LD50 values such as those proposed for use with mammalian data and physico-chemical properties and a triazine-specific oral-dermal equation using mammalian LD50 data. The three alternative approaches resulted in output similar to one another and different from the default TIM methods. These results indicate that a dermal route equivalency factor derived from empirical data provides a higher avian dermal LD50 estimate that is consistent with other methods. In addition, the use of this dermal route equivalency factor results in greatly reduced modeled atrazine risk to birds than previously reported in US EPA risk assessments using TIM. PMID- 29486445 TI - Effect of propionamide on the growth of Microcystis flos-aquae colonies and the underlying physiological mechanisms. AB - Reducing the formation and growth of Microcystis colonies is an important prerequisite for the effective prevention and treatment of cyanobacterial blooms. Microcystis flos-aquae colonies was selected to investigate the potential of propionamide for use in controlling cyanobacterial blooms. Propionamide, one of the major allelochemicals in the root exudates of E. crassipes, was tested using different concentrations (0, 0.2, 1, and 2mgL-1) and dosing methods (one-time addition, semi-continuous addition, and continuous addition) to assess its effect on the growth of M. flos-aquae colonies. The results showed that in the presence of different concentrations of propionamide, the growth of M. flos-aquae colonies followed a logistic growth model, with a higher degree of fit at lower propionamide concentrations. With the semi-continuous addition of 2mgL-1 propionamide, the growth of M. flos-aquae colonies was markedly inhibited; the relative inhibition ratio of algal cells reached >90% at day 7 of co-culture, and the colonial form gradually disintegrated, transforming mainly into unicellular and bicellular forms and small colonies (average diameter<50MUm). Following the semi-continuous addition of 2mgL-1 propionamide, the exopolysaccharide content, the chlorophyll-a concentration, and the maximum photochemical efficiency of photosystem II (Fv/Fm) trended downward in M. flos-aquae colonies, whereas the relative expression of the microcystin (MC) biosynthetic genes, mcyA and mcyH, was upregulated overall. Importantly, the synthesis of intracellular microcystin LR (MC-LR) was decreased after an initial increase, and the extracellular MC-LR concentration did not differ significantly from that in the control group (p>0.05). Moreover, an acute toxicity test showed that 2mgL-1 propionamide was generally non-toxic to Daphnia magna. In conclusion, appropriate use of propionamide could effectively control the expansion of M. flos-aquae colonies without potential risks to the ecological safety of aquatic environments; therefore, propionamide can actually be used to regulate cyanobacterial blooms in natural waters. PMID- 29486447 TI - Optimizing the conditions for hydrothermal liquefaction of barley straw for bio crude oil production using response surface methodology. AB - The present paper examines the conversion of barley straw to bio-crude oil (BO) via hydrothermal liquefaction. Response surface methodology based on central composite design was utilized to optimize the conditions of four independent variables including reaction temperature (factor X1, 260-340 degrees C), reaction time (factor X2, 5-25min), catalyst dosage (factor X3, 2-18%) and biomass/water ratio (factor X4, 9-21%) for BO yield. It was found that reaction temperature, catalyst dosage and biomass/water ratio had more remarkable influence than reaction time on BO yield by analysis of variance. The predicted BO yield by the second order polynomial model was in good agreement with experimental results. A maximum BO yield of 38.72wt% was obtained at 304.8 degrees C, 15.5min, 11.7% potassium carbonate as catalyst and 18% biomass (based on water). GC/MS analysis revealed that the major BO components were phenols and their derivatives, acids, aromatic hydrocarbon, ketones, N-contained compounds and alcohols, which makes it a promising material in the applications of either bio-fuel or as a phenol substitute in bio-phenolic resins. PMID- 29486446 TI - Near-infrared spectroscopy (NIRS) as a tool to monitor exhaust air from poultry operations. AB - Intensive poultry operation systems emit a considerable volume of inorganic and organic matter in the surrounding environment. Monitoring cleaning properties of exhaust air cleaning systems and to detect small but significant changes in emission characteristics during a fattening cycle is important for both emission and fattening process control. In the present study, we evaluated the potential of near-infrared spectroscopy (NIRS) combined with chemometric techniques as a monitoring tool of exhaust air from poultry operation systems. To generate a high quality data set for evaluation, the exhaust air of two poultry houses was sampled by applying state-of-the-art filter sampling protocols. The two stables were identical except for one crucial difference, the presence or absence of an exhaust air cleaning system. In total, twenty-one exhaust air samples were collected at the two sites to monitor spectral differences caused by the cleaning device, and to follow changes in exhaust air characteristics during a fattening period. The total dust load was analyzed by gravimetric determination and included as a response variable in multivariate data analysis. The filter samples were directly measured with NIR spectroscopy. Principal component analysis (PCA), linear discriminant analysis (LDA), and factor analysis (FA) were effective in classifying the NIR exhaust air spectra according to fattening day and origin. The results indicate that the dust load and the composition of exhaust air (inorganic or organic matter) substantially influence the NIR spectral patterns. In conclusion, NIR spectroscopy as a tool is a promising and very rapid way to detect differences between exhaust air samples based on still not clearly defined circumstances triggered during a fattening period and the availability of an exhaust air cleaning system. PMID- 29486448 TI - Predicting risk of trace element pollution from municipal roads using site specific soil samples and remotely sensed data. AB - Studies of environmental processes exhibit spatial variation within data sets. The ability to derive predictions of risk from field data is a critical path forward in understanding the data and applying the information to land and resource management. Thanks to recent advances in predictive modeling, open source software, and computing, the power to do this is within grasp. This article provides an example of how we predicted relative trace element pollution risk from roads across a region by combining site specific trace element data in soils with regional land cover and planning information in a predictive model framework. In the Kenai Peninsula of Alaska, we sampled 36 sites (191 soil samples) adjacent to roads for trace elements. We then combined this site specific data with freely-available land cover and urban planning data to derive a predictive model of landscape scale environmental risk. We used six different model algorithms to analyze the dataset, comparing these in terms of their predictive abilities and the variables identified as important. Based on comparable predictive abilities (mean R2 from 30 to 35% and mean root mean square error from 65 to 68%), we averaged all six model outputs to predict relative levels of trace element deposition in soils-given the road surface, traffic volume, sample distance from the road, land cover category, and impervious surface percentage. Mapped predictions of environmental risk from toxic trace element pollution can show land managers and transportation planners where to prioritize road renewal or maintenance by each road segment's relative environmental and human health risk. PMID- 29486449 TI - In vitro characterization of 3D printed scaffolds aimed at bone tissue regeneration. AB - The incidence of fractures and bone-related diseases like osteoporosis has been increasing due to aging of the world's population. Up to now, grafts and titanium implants have been the principal therapeutic approaches used for bone repair/regeneration. However, these types of treatment have several shortcomings, like limited availability, risk of donor-to-recipient infection and tissue morbidity. To overcome these handicaps, new 3D templates, capable of replicating the features of the native tissue, are currently being developed by researchers from the area of tissue engineering. These 3D constructs are able to provide a temporary matrix on which host cells can adhere, proliferate and differentiate. Herein, 3D cylindrical scaffolds were designed to mimic the natural architecture of hollow bones, and to allow nutrient exchange and bone neovascularization. 3D scaffolds were produced with tricalcium phosphate (TCP)/alginic acid (AA) using a Fab@home 3D printer. Furthermore, graphene oxide (GO) was incorporated into the structure of some scaffolds to further enhance their mechanical properties. The results revealed that the scaffolds incorporating GO displayed greater porosity, without impairing their mechanical properties. These scaffolds also presented a controlled swelling profile, enhanced biomineralization capacity and were able to increase the Alkaline Phosphatase (ALP) activity. Such characteristics make TCP/AA scaffolds functionalized with GO promising 3D constructs for bone tissue engineering applications. PMID- 29486450 TI - In-growth metal organic framework/synthetic hybrids as antimicrobial fabrics and its toxicity. AB - Bio-active synthetic fabrics based on polyester (PET) and Nylon were manufactured by in-situ formation of Cu-BTC metal organic framework (MOF). In-growth of Cu-BTC within fabrics was accomplished in one pot simple process. The scanning microscope, X-ray diffraction and infrared spectra were all confirmed the formation of Cu-BTC within fabrics structure and reflected the role of fabrics' building unit in the Cu-BTC preparation. The estimated contents of materials onto fabrics were ranged in 97.14-127.33 mg MOF/g fabric and 30.59-40.10 mg Cu/g fabric. After embracing with Cu-BTC, color of fabrics was transformed to greenish blue. The so-produced Cu-BTC/fabric hybrids were exhibited good biological activities against three different microbial pathogens (E. coli, S. aureus and C. albicans). The minimal inhibitory concentrations from the residual Cu-BTC powder were 65-70, 60-64 and 62-67 mg/mL, for S. aureus, E. coli and C. albicans pathogens, respectively, which were similar to that reported for commercial Cu BTC. Moreover, no toxicity was observably detected for the released Cu-BTC from fabrics against brine shrimp at 10 mg/mL. These results revealed that, the in growth of Cu-BTC resulted in production of biocidal synthetic fabrics without any ecotoxic effects at the as-used Cu-BTC content. PMID- 29486451 TI - Limits in measurements of contact lens surface profile using atomic force microscopy. AB - In the paper the results of AFM surface profile measurements of seven new long wear contact lenses (CL) available in Poland are presented. Calculated statistical roughness parameters are shown, namely standard deviation (RMS), mean roughness, maximum difference between peak and valley, skewness, and kurtosis. It is demonstrated that CLs manufactured using recent methods, such as two-stage polimerisation or extending silicon chains exhibit small RMS, less than 10 nm, in comparison with older generation CLs which maintains RMS on the level of tens of nanometers. Then, a comparison of results obtained using a typical silicon tip and a silicon tip covered with alkylsilane is also demonstrated. As a result, roughness parameters, such as RMS, are higher for the case of alkylsilane-coated tip than for a typical silicon tip, 8.39 +/- 0.16 nm vs. 6.22 +/- 0.9 nm, which leads to the conclusion that the proper choice of the tip material significantly influences the outcome of the experiment. Finally, the reliability and limits of such measurements are discussed. PMID- 29486452 TI - Polyelectrolyte complex nanoparticles based on chitosan and methoxy poly(ethylene glycol) methacrylate-co-poly(methylacrylic acid) for oral delivery of ibuprofen. AB - In this study, the copolymer of methoxy poly(ethylene glycol) methacrylate-co poly(methylacrylic acid) [poly(mPEGMA-co-MAA)] was synthesized via radical polymerization. Based on this copolymer, novel chitosan-modified poly(mPEGMA-co MAA) nanoparticles (CS/NPs) were developed to improve the bio-availability of ibuprofen (IBU). Fourier transform infrared spectroscopy (FTIR) and 1H nuclear magnetic resonance (1H NMR) spectra were used to confirm the synthesis of the copolymers. The morphology of CS/NPs was investigated with transmission electron microscopy (TEM). Thermogravimetric analysis (TGA) was used to reveal the thermodynamic properties of the CS/NPs. The cytotoxicity of CS/NPs was assessed by the cell viability of 293T cells. FTIR and 1H NMR spectra confirmed the synthesis of the novel copolymer. TEM photographs showed that the CS/NPs had a core-shell structure. High cell viability indicated that the CS/NPs were nontoxic. The in vitro release profiles suggested that the CS/NPs released IBU in pH 7.4 buffer in a continuous manner. Furthermore, the IBU-CS/NPs showed a long antifebrile effect. Animal experiments showed that the IBU-CS/NPs had obvious antifebrile effects. Therefore, CS/NPs could reduce the dosing frequency of IBU, and improve its bio-availability. PMID- 29486453 TI - Two-year cortical trajectories are abnormal in children and adolescents with prenatal alcohol exposure. AB - OBJECTIVES: Cortical abnormalities in prenatal alcohol exposure (PAE) are known, including in gyrification (LGI), thickness (CT), volume (CV), and surface area (CS). This study provides longitudinal and developmental context to the PAE cortical development literature. EXPERIMENTAL DESIGN: Included: 58 children with PAE and 52 controls, ages 6-17 at enrollment, from four Collaborative Initiative on FASD (CIFASD) sites. Participants underwent a formal evaluation of physical anomalies and dysmorphic facial features associated with PAE. MRI data were collected on three platforms (Siemens, GE, and Philips) at four sites. Scans were spaced two years apart. Change in LGI, CT, CS, and CV were examined. PRINCIPAL OBSERVATIONS: Several significant regional age-by-diagnosis linear and quadratic interaction effects in LGI, CT, and CV were found, indicating atypical developmental trajectories in PAE. No significant correlations were observed between cortical measures and IQ. CONCLUSIONS: Regional differences were seen longitudinally in CT, CV, and LGI in those with PAE. The findings represent important insights into developmental trajectories and may have implications for the timing of assessments and interventions in this population. It is noteworthy that cortical metrics did not correlate with IQ, suggesting that more specific aspects of cognitive development may need to be explored to provide further context. PMID- 29486454 TI - VOC emissions and carbon balance of two bioenergy plantations in response to nitrogen fertilization: A comparison of Miscanthus and Salix. AB - Energy crops are an important renewable source for energy production in future. To ensure high yields of crops, N fertilization is a common practice. However, knowledge on environmental impacts of bioenergy plantations, particularly in systems involving trees, and the effects of N fertilization is scarce. We studied the emission of volatile organic compounds (VOC), which negatively affect the environment by contributing to tropospheric ozone and aerosols formation, from Miscanthus and willow plantations. Particularly, we aimed at quantifying the effect of N fertilization on VOC emission. For this purpose, we determined plant traits, photosynthetic gas exchange and VOC emission rates of the two systems as affected by N fertilization (0 and 80 kg ha-1 yr-1). Additionally, we used a modelling approach to simulate (i) the annual VOC emission rates as well as (ii) the OH. reactivity resulting from individual VOC emitted. Total VOC emissions from Salix was 1.5- and 2.5-fold higher compared to Miscanthus in non-fertilized and fertilized plantations, respectively. Isoprene was the dominating VOC in Salix (80-130 MUg g-1 DW h-1), whereas it was negligible in Miscanthus. We identified twenty-eight VOC compounds, which were released by Miscanthus with the green leaf volatile hexanal as well as dimethyl benzene, dihydrofuranone, phenol, and decanal as the dominant volatiles. The pattern of VOC released from this species clearly differed to the pattern emitted by Salix. OH. reactivity from VOC released by Salix was ca. 8-times higher than that of Miscanthus. N fertilization enhanced stand level VOC emissions, mainly by promoting the leaf area index and only marginally by enhancing the basal emission capacity of leaves. Considering the higher productivity of fertilized Miscanthus compared to Salix together with the considerably lower OH. reactivity per weight unit of biomass produced, qualified the C4-perennial grass Miscanthus as a superior source of future bioenergy production. PMID- 29486455 TI - Comparative toxicity of pristine graphene oxide and its carboxyl, imidazole or polyethylene glycol functionalized products to Daphnia magna: A two generation study. AB - To investigate the chronic toxicity of graphene oxide (GO) and its functionalized products (GO-carboxyl, GO-imidazole and GO-polyethylene glycol), a two-generation study was conducted using the aquatic model species Daphnia magna. Each generation of daphnids were exposed for 21 days to 1.0 mg L-1 graphene material, with body length, neonate number, time of first brood and the intrinsic rate of natural increase (r) assessed as endpoints. Chronic exposure to GO, GO-carboxyl, and GO-imidazole had no adverse effect on body length or offspring number in the daphnid F0 generation, however, this exposure paradigm led to significant growth or reproduction inhibition in the following generation. Meanwhile, GO was found to show the strongest inhibitory effect, sequentially followed by GO-carboxyl and GO-imidazole. With exposure to GO-polyethylene glycol, no significant effects on growth or reproduction were observed for both F0 and F1 generation daphnids. These results reveal that carboxyl, imidazole and polyethylene glycol functional attachments alleviate the bio-toxicity of GO, especially polyethylene glycol. The increased C/O atomic ratio present in GO-carboxyl, GO-imidazole and GO polyethylene glycol due to functionalization may mainly explain the reduced toxicity. PMID- 29486456 TI - Enhanced immobilization of U(VI) on Mucor circinelloides in presence of As(V): Batch and XAFS investigation. AB - The combined pollution of radionuclides and heavy metals has been given rise to widespread concern during uranium mining. The influence of As(V) on U(VI) immobilization by Mucor circinelloides (M. circinelloides) was investigated using batch experiments. The activity of antioxidative enzymes and concentrations of thiol compounds and organic acid in M. circinelloides increased to respond to different U(VI) and As(V) stress. The morphological structure of M. circinelloides changed obviously under U(VI) and As(V) stress by SEM and TEM analysis. The results of XANES and EXAFS analysis showed that U(VI) was mainly reduced to nano-uraninite (nano-UO2, 30.1%) in U400, while only 9.7% of nano-UO2 was observed in the presence of As(V) in U400-As400 due to the formation of uranyl arsenate precipitate (Trogerite, 48.6%). These observations will provide the fundamental data for fungal remediation of uranium and heavy metals in uranium-contaminated soils. PMID- 29486457 TI - Land-use type affects N2O production pathways in subtropical acidic soils. AB - The change in land-use from woodland to crop production leads to increased nitrous oxide (N2O) emissions. An understanding of the main N2O sources in soils under a particular land can be a useful tool in developing mitigation strategies. To better understand the effect of land-use on N2O emissions, soils were collected from 5 different land-uses in southeast China: shrub land (SB), eucalyptus plantation (ET), sweet potato farmland (SP), citrus orchard (CO) and vegetable growing farmland (VE). A stable isotope experiment was conducted incubating soils from the different land use types at 60% water holding capacity (WHC), using 15NH4NO3 and NH415NO3 to determine the dominant N2O production pathway for the different land-uses. The average N2O emission rates for VE, CO and SP were 5.30, 4.23 and 3.36 MUg N kg-1 dry soil d-1, greater than for SB and ET at 0.98 and 1.10 MUg N kg-1 dry soil d-1, respectively. N2O production was dominated by heterotrophic nitrification for SB and ET, accounting for 51 and 50% of N2O emissions, respectively. However, heterotrophic nitrification was negligible (<8%) in SP, CO and VE, where autotrophic nitrification was a primary driver of N2O production, accounting for 44, 45 and 66% for SP, CO and VE, respectively. Denitrification was also an important pathway of N2O production across all land-uses, accounting for 35, 35, 49, 52 and 32% for SB, ET, SP, CO and VE respectively. Average N2O emission rates via autotrophic nitrification, denitrification and heterotrophic nitrification increased significantly with gross nitrification rates, NO3- contents and C:N ratios respectively, indicating that these were important factors in the N2O production pathways for these soils. These results contribute to our understanding and ability to predict N2O emissions from different land-uses in subtropical acidic soils and in developing potential mitigation strategies. PMID- 29486458 TI - Leaching characteristic of toxic trace elements in soils amended by sewage sludge compost: A comparison of field and laboratory investigations. AB - A 3-years field test and laboratory leaching test have been conducted to assess the environmental impact of land application of sewage sludge compost in conjunction with wheat and rice crops. Considering the complexity and variability of field conditions, we compared the result of laboratory test with the field test to understand the accuracy and uncertainty associated with using the laboratory test to evaluate the field scenario. The laboratory test with cycling of compost additions and water percolation was a high time-efficient and feasible method to simulate the annually repeated additions of compost in the field application scenario. The results of laboratory test were congruent to the 3 years field test regarding the leaching characteristics and geochemical speciation of toxic trace elements. Both the laboratory and the field test showed that repeated additions of compost to soils can increase leaching concentrations of toxic trace elements at neutral to alkaline pH. Increased toxic trace elements leaching was caused by the increase of organic matter from compost application and organic matter dissolution at alkaline pH. Uncertainties of the laboratory test mainly included the negligibility of crop growth and the strongly reducing condition formed with continuous percolation procedure. PMID- 29486459 TI - The effect of combined photobiomodulation and curcumin on skin wound healing in type I diabetes in rats. AB - The purpose of the present scientific study was to analyze the effects of combined pulsed wave Photobiomodulation (PW PBM) and Curcumin on the microbial flora; in addition, the tensiometrical wounds properties for type one diabetes mellitus (TIDM) in an experimental animal model. TIDM induction was performed in thirty rats. In the entire animals, one full-thickness excision was implemented on their backs. Randomly, the divisions of rats into 5 groups took place. The primary group was considered as the control group and did not receive any treatment. The secondary group (placebo) received sesame oil by gastric gavage. The third group received PWPBM (890 nm, 80 Hz, 0.2 J/cm2). The fourth group received curcumin (40 mg/kg, which was dissolved in sesame oil) by gastric gavage. Eventually, the fifth group received PW PBM + curcumin. Precisely, on day 7, microbiological examinations, and on the 15th day microbiological and tensiometrical examinations were conducted. The data were analyzed by statistical tests. PW PBM, significantly exacerbated tensiometrical properties of the TIDM repairing wound. PW PBM, curcumin, and PWPBM + curcumin significantly decreased colony forming units compared to the control and the placebo groups indeed. It was remarkably attained that PW PBM significantly accelerated the process of wound healing in the STZ-induced TIDM. The PW PBM was statistically more compelling compared to the curcumin and PWPBM + curcumin. PW PBM, curcumin, and PWPBM + curcumin significantly decreased colony forming units compared to the control and placebo groups. PMID- 29486460 TI - Effect of carbon limitation on photosynthetic electron transport in Nannochloropsis oculata. AB - This study describes the impacts of inorganic carbon limitation on the photosynthetic efficiency and operation of photosynthetic electron transport pathways in the biofuel-candidate microalga Nannochloropsis oculata. Using a combination of highly-controlled cultivation setup (photobioreactor), variable chlorophyll a fluorescence and transient spectroscopy methods (electrochromic shift (ECS) and P700 redox kinetics), we showed that net photosynthesis and effective quantum yield of Photosystem II (PSII) decreased in N. oculata under carbon limitation. This was accompanied by a transient increase in total proton motive force and energy-dependent non-photochemical quenching as well as slightly elevated respiration. On the other hand, under carbon limitation the rapid increase in proton motive force (PMF, estimated from the total ECS signal) was also accompanied by reduced conductivity of ATP synthase to protons (estimated from the rate of ECS decay in dark after actinic illumination). This indicates that the slow operation of ATP synthase results in the transient build-up of PMF, which leads to the activation of fast energy dissipation mechanisms such as energy-dependent non-photochemical quenching. N. oculata also increased content of lipids under carbon limitation, which compensated for reduced NAPDH consumption during decreased CO2 fixation. The integrated knowledge of the underlying energetic regulation of photosynthetic processes attained with a combination of biophysical methods may be used to identify photo-physiological signatures of the onset of carbon limitation in microalgal cultivation systems, as well as to potentially identify microalgal strains that can better acclimate to carbon limitation. PMID- 29486461 TI - Kaolin particle film application stimulates photoassimilate synthesis and modifies the primary metabolome of grape leaves. AB - Water scarcity is associated with extreme temperatures and high irradiance, and significantly and increasingly affects grapevine yield and quality. In this context, the foliar application of kaolin, a chemically inert mineral that greatly reflects ultraviolet and infrared radiations, as well as, in part, photosynthetically active radiation, has recently been shown to decrease photoinhibition in mature leaves. Here, the influence of this particle film on grapevine leaf metabolome and carbohydrate metabolism was evaluated. Molecular mechanisms underlying photoassimilate synthesis, metabolism and transport capacity were assessed by targeted transcriptional analyses and enzymatic activity assays. Kaolin application increased sucrose concentration in leaves and sucrose transport/phloem loading capacity, as suggested by the stimulation of the transcription of sucrose transporters VvSUC12 and VvSUC27 in these source organs. While the biosynthesis of sucrose increased, as evidenced by higher sucrose content and sucrose phosphate synthase (SPS) activity in leaves, the concentration of transitory starch before the dark period remained unaltered, despite a higher total amylolytic activity in the leaves of kaolin-treated plants. Metabolomic analysis by GC-TOF-MS showed that the application of kaolin enhanced the amounts of simple sugars, including fructose, maltose, xylulose, xylose, sophorose, ribose and erythrose; sugars-phosphate, like mannose-6-Pi, hexose-6-Pi, glucose-6-Pi, glucose-1-Pi, glycerol-alpha-Pi and fructose-6-Pi; polyols, like xylitol, maltitol, lactitol, glycerol, galactinol and erythritol; organic acids and amino acids. PMID- 29486462 TI - Spatial distribution and sources of heavy metals in natural pasture soil around copper-molybdenum mine in Northeast China. AB - The characterization of the content and source of heavy metals are essential to assess the potential threat of metals to human health. The present study collected 140 topsoil samples around a Cu-Mo mine (Wunugetushan, China) and investigated the concentrations and spatial distribution pattern of Cr, Ni, Zn, Cu, Mo and Cd in soil using multivariate and geostatistical analytical methods. Results indicated that the average concentrations of six heavy metals, especially Cu and Mo, were obviously higher than the local background values. Correlation analysis and principal component analysis divided these metals into three groups, including Cr and Ni, Cu and Mo, Zn and Cd. Meanwhile, the spatial distribution maps of heavy metals indicated that Cr and Ni in soil were no notable anthropogenic inputs and mainly controlled by natural factors because their spatial maps exhibited non-point source contamination. The concentrations of Cu and Mo gradually decreased with distance away from the mine area, suggesting that human mining activities may be crucial in the spreading of contaminants. Soil contamination of Zn were associated with livestock manure produced from grazing. In addition, the environmental risk of heavy metal pollution was assessed by geo accumulation index. All the results revealed that the spatial distribution of heavy metals in soil were in agreement with the local human activities. Investigating and identifying the origin of heavy metals in pasture soil will lay the foundation for taking effective measures to preserve soil from the long-term accumulation of heavy metals. PMID- 29486464 TI - Chromosome Rearrangements Caused by Double Monosomy in Wheat-Barley Group-7 Substitution Lines. AB - Interspecific or introgressive hybridization is one of the driving forces in plant speciation, producing allopolyploids or diploids with rearranged genomes. The process of karyotype reshaping following homoploid interspecific hybridization has not been studied experimentally. Interspecific hybridization is widely used in plant breeding to increase genetic diversity and introgress new traits. Numerous introgression stocks were developed for hexaploid wheat Triticum aestivum L. (2n = 6x = 42, genome AABBDD). Double monosomic lines, containing one alien chromosome from the tertiary gene pool of wheat and one homoeologous wheat chromosome, represent a simplified model for studying chromosome rearrangements caused by interspecific hybridization. The pairing of a chromosome from the tertiary gene pool with a wheat homoeologue is restricted by the activity of the wheat Ph1 gene, thus, rearrangements caused by chromosome breakage followed by the fusion of the broken arms can be expected. We analyzed chromosome aberrations in 4 sets of lines that originated from double monosomics of barley (Hordeum vulgare L.) chromosome 7H and wheat group-7 chromosomes with dicentric or ring chromosomes. The dynamics of wheat-barley dicentric chromosomes during plant development was followed and an increased diversity of rearrangements was observed. Besides the targeted group-7 chromosomes, other wheat chromosomes were involved in rearrangements, as chromosomes broken in the centromeric region fused with other broken chromosomes. In some cells, multi-centric chromosomes were observed. The structure and dosage of the introgressed barley chromatin was changed. The transmission of the rearrangements to the progenies was analyzed. The observed aberrations emphasize the importance of cytogenetic screening in gene introgression projects. PMID- 29486466 TI - Activation of the ERK1/2-MAPK Signaling Pathway by Complement Serum in UV-POS Pretreated ARPE-19 Cells. AB - BACKGROUND: Retinal pigment epithelial (RPE) cells undergo functional changes upon complement stimulation, which play a role in the pathogenesis of age-related macular degeneration (AMD). These effects are in part enhanced by pretreating ARPE-19 cells with UV-irradiated photoreceptor outer segments (UV-POS) in vitro. The aim of this study was to investigate the effects of human complement serum (HCS) treatment on p44/42 mitogen-activated protein kinase (extracellular signal regulated kinase 1/2 [ERK1/2]) activation in ARPE-19 cells pretreated with UV POS. METHODS: UV-POS-pretreated ARPE-19 cells were stimulated with 5% HCS or heat inactivated HCS (HI-HCS) as a control. Pro tein expression of phosphorylated (activated) ERK1/2, total ERK1/2, Bax, and Bcl-2 was analyzed by Western blotting. Cell culture supernatants were analyzed for IL-6, IL-8, MCP-1, and VEGF by enzyme-linked immunosorbent assay (ELISA). Furthermore, extra- and intracellular reactive oxygen species (ROS) were determined. RESULTS: The amount of phosphorylated ERK1/2 was increased in UV-POS-pretreated ARPE-19 cells, especially in combination with HCS stimulation, compared to non-pretreated ARPE 19 cells incubated with HCS alone or HI-HCS. The same observation was made for Bax and Bcl-2 expression. Furthermore, an increase in extra- and intracellular ROS was detected in UV-POS-pretreated ARPE-19 cells. The ELISA data showed that the production of IL-6, IL-8, and MCP-1 tended to increase in response to HCS in both UV-POS-pretreated and non-pretreated ARPE-19 cells. CONCLUSIONS: Our data imply that ERK1/2 activation in ARPE-19 cells may represent a response mechanism to cellular and oxidative stress, associated with apoptosis-regulating factors such as Bax and Bcl-2, which might play a role in AMD, while ERK1/2 seems not to represent the crucial signaling pathway mediating the functional changes in RPE cells in response to complement stimulation. PMID- 29486465 TI - Chronic Prenatal Hypoxia Down-Regulated BK Channel Beta1 Subunits in Mesenteric Artery Smooth Muscle Cells of the Offspring. AB - BACKGROUND/AIMS: Chronic hypoxia in utero could impair vascular functions in the offspring, underlying mechanisms are unclear. This study investigated functional alteration in large-conductance Ca2+-activated K+ (BK) channels in offspring mesenteric arteries following prenatal hypoxia. METHODS: Pregnant rats were exposed to normoxic control (21% O2, Con) or hypoxic (10.5% O2, Hy) conditions from gestational day 5 to 21, their 7-month-old adult male offspring were tested for blood pressure, vascular BK channel functions and expression using patch clamp and wire myograh technique, western blotting, and qRT-PCR. RESULTS: Prenatal hypoxia increased pressor responses and vasoconstrictions to phenylephrine in the offspring. Whole-cell currents density of BK channels and amplitude of spontaneous transient outward currents (STOCs), not the frequency, were significantly reduced in Hy vascular myocytes. The sensitivity of BK channels to voltage, Ca2+, and tamoxifen were reduced in Hy myocytes, whereas the number of channels per patch and the single-channel conductance were unchanged. Prenatal hypoxia impaired NS1102- and tamoxifen-mediated relaxation in mesenteric arteries precontracted with phenylephrine in the presence of Nomega-nitro-L arginine methyl ester. The mRNA and protein expression of BK channel beta1, not the alpha-subunit, was decreased in Hy mesenteric arteries. CONCLUSIONS: Impaired BK channel beta1-subunits in vascular smooth muscle cells contributed to vascular dysfunction in the offspring exposed to prenatal hypoxia. PMID- 29486463 TI - Genetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer's Disease Sequencing Project. AB - BACKGROUND/AIMS: The Alzheimer's Disease Sequencing Project (ADSP) aims to identify novel genes influencing Alzheimer's disease (AD). Variants within genes known to cause dementias other than AD have previously been associated with AD risk. We describe evidence of co-segregation and associations between variants in dementia genes and clinically diagnosed AD within the ADSP. METHODS: We summarize the properties of known pathogenic variants within dementia genes, describe the co-segregation of variants annotated as "pathogenic" in ClinVar and new candidates observed in ADSP families, and test for associations between rare variants in dementia genes in the ADSP case-control study. The participants were clinically evaluated for AD, and they represent European, Caribbean Hispanic, and isolate Dutch populations. RESULTS/CONCLUSIONS: Pathogenic variants in dementia genes were predominantly rare and conserved coding changes. Pathogenic variants within ARSA, CSF1R, and GRN were observed, and candidate variants in GRN and CHMP2B were nominated in ADSP families. An independent case-control study provided evidence of an association between variants in TREM2, APOE, ARSA, CSF1R, PSEN1, and MAPT and risk of AD. Variants in genes which cause dementing disorders may influence the clinical diagnosis of AD in a small proportion of cases within the ADSP. PMID- 29486467 TI - Atypia of Undetermined Significance in Thyroid Fine-Needle Aspirations: Follow-Up and Outcome Experience in Newfoundland, Canada. AB - INTRODUCTION: The rates of atypia of undetermined significance (AUS) by fine needle aspiration (FNA) and malignant outcomes have been estimated at < 7% and 5 15%, respectively. Initial AUS diagnosis is followed up clinically with serial ultrasounds, repeat FNA, molecular testing, or direct surgery. We investigated the incidence, follow-up modalities, and final outcomes of AUS in Newfoundland. METHODS: All cases of AUS diagnosed at the Eastern Health Cytology Laboratory between 1 January 2010 and 31 December 2013 were identified. Electronic medical records were examined for follow-up modalities and final histologic diagnosis. The final outcomes were reported as benign, malignant, or undetermined. RESULTS: Out of 3,285 thyroid FNAs, 181 (5.5%) were AUS. Fifty-seven (31.5%) had repeat FNA diagnosed as benign (38.6%), AUS (29.8%), or suspicious/malignant (8.8%). Eighty-four (46.4%) had surgery after the first AUS diagnosis, 39 (46.4%) of which were malignant. Twenty-four patients (13.3%) were followed up by serial ultrasound only, 2 (1.1%) by molecular testing, and 1 (0.6%) died of unrelated disease. Thirteen (7.2%) had no follow-up record. Our malignancy rate (MR) was 29.8%. CONCLUSION: The MR in our population was higher than the rate proposed by The Bethesda System for Reporting Thyroid Cytopathology. Repeat FNA can reduce the rate of unnecessary surgeries, but practice guidelines should consider individual and institutional circumstances. The ratio MR:ADR (AUS diagnostic rate) may be a better indicator of performance. PMID- 29486468 TI - Shifting from Oral Contraceptives to Norethisterone Acetate, or Vice Versa, because of Drug Intolerance: Does the Change Benefit Women with Endometriosis? AB - BACKGROUND/AIMS: Oral contraceptives (OC) and norethisterone acetate (NETA) are among first-line medical therapies for symptomatic endometriosis, but their use is sometimes associated with intolerable side effects. We investigated whether shifting from low-dose OC to NETA (2.5 mg/day), or vice versa, improved tolerability. METHODS: Sixty-seven women willing to discontinue their treatment because of intolerable side effects despite good pain relief, were enrolled in a self-controlled study, and shifted from OC to NETA (n = 35) or from NETA to OC (n = 32). The main study outcome was satisfaction with treatment 12 months after the change. Tolerability, pain symptoms, health-related quality of life, psychological status, and sexual functioning were also evaluated. RESULTS: After treatment change, good tolerability was reported by 37% of participants who shifted to NETA, and by 52% of those who shifted to OC. At 12-month assessment, 51% of women intolerant to OC were satisfied with NETA, and 65% of those intolerant to NETA were satisfied with OC (intention-to-treat analysis). Other study variables did not vary substantially. CONCLUSIONS: In selected endometriosis patients, shifting from OC to NETA, or vice versa, because of side effects, improved tolerability. Better results were observed when substituting NETA with OC rather than the other way round. PMID- 29486469 TI - Enhanced Delignification of Lignocellulosic Biomass by Recombinant Fungus Phanerochaete chrysosporium Overexpressing Laccases and Peroxidases. AB - Ligninolytic enzyme production and lignin degradation are typically the rate limiting steps in the biofuel industry. To improve the efficiency of simultaneous bio-delignification and enzyme production, Phanerochaete chrysosporium was transformed by shock wave-induced acoustic cavitation to co-overexpress 3 peroxidases and 1 laccase and test it on the degradation of sugarcane bagasse and wheat bran. Lignin depolymerization was enhanced by up to 25% in the presence of recombinant fungi in comparison with the wild-type strain. Sugar release on lignocellulose was 2- to 6-fold higher by recombinant fungi as compared with the control. Wheat bran ostensibly stimulated the production of ligninolytic enzymes. The highest peroxidase activity from the recombinant strains was 2.6-fold higher, whereas the increase in laccase activity was 4-fold higher in comparison to the control. The improvement of lignin degradation was directly proportional to the highest peroxidase and laccase activity. Because various phenolic compounds released during lignocellulose degradation have proven to be toxic to cells and to inhibit enzyme activity, a significant reduction (over 40%) of the total phenolic content in the samples treated with recombinant strains was observed. To our knowledge, this is the first report that engineering P. chrysosporium enhances biodegradation of lignocellulosic biomass. PMID- 29486471 TI - TNFAIP3 mRNA Level Is Associated with Psychological Anxiety in Major Depressive Disorder. AB - BACKGROUND: Major depressive disorder has been shown to be associated with inflammation and the dysregulation of innate immune responses. Previously, we showed an inverse correlation between the severity of depression and level of TNFAIP3 mRNA expression. The present study further evaluated the association between TNFAIP3 mRNA expression level and symptoms of major depressive disorder (MDD) in 91 patients (20 men and 71 women). METHODS: The relationships between subscores on the 17-item Hamilton Depression Rating Scale (HAMD-17) and TNFAIP3 mRNA levels were assessed by multiple linear regression. RESULTS: Only psychological anxiety on the HAMD-17 correlated significantly with TNFAIP3 mRNA expression. Other symptoms, such as depressed mood, insomnia, work and activities, and suicide, were not associated with TNFAIP3 mRNA expression. CONCLUSION: These findings suggest a significant association between anxiety and TNFAIP3 mRNA levels in patients with MDD. PMID- 29486470 TI - Abnormal Downregulation of Caveolin-3 Mediates the Pro-Fibrotic Action of MicroRNA-22 in a Model of Myocardial Infarction. AB - BACKGROUND/AIMS: Cardiac fibrosis is an important cardiac remodeling event that can ultimately lead to the development of severe arrhythmia and heart failure. MicroRNAs (miRNAs) are involved in the pathogenesis of many cardiovascular diseases. Here, we aimed to investigate the effects of caveolin-3 (Cav3) on the pathogenesis of cardiac fibrosis and the underlying molecular mechanisms. METHODS: Cav3 expression was decreased in cardiac fibrosis in vivo and in vitro model. To investigate the role of Cav3 in cardiac fibrosis, we transfected cardiac fibroblasts (CFs) with the siRNA of Cav3 and Cav3-overexpressing plasmid. The collagen content and proliferation of CFs were detected by qRT-PCR, western blot, MTT, and immunofluorescence. A luciferase reporter gene assay and gain/loss of function were used to detect the relationship between miR-22 and Cav3. RESULTS: Cav3 depletion in CFs induced an increase in collagen content, cell proliferation, and phenotypic conversion of fibroblasts to myofibroblasts. Conversely, Cav3 overexpression in CFs was shown to inhibit angiotensin II mediated excessive collagen deposition through protein kinase C (PKC)epsilon inactivation. Cav3 was experimentally confirmed as a direct target of miR-22, containing two seed binding sites in its 3'-untranslated region, and miR-22 was demonstrated to be significantly upregulated in the ischemic border zone in mice after myocardial infarction and in neonatal rat CFs pretreated with angiotensin II. miR-22 overexpression increased CFs proliferation, and collagen and alpha smooth muscle actin levels in CFs, while the knockdown of endogenous miR-22 decreased CFs numbers. CONCLUSIONS: Our findings demonstrate that miR-22 accelerates cardiac fibrosis through the miR-22-Cav3-PKCepsilon pathway, which, therefore, may represent a new therapeutic target for treatment of excessive fibrosis-associated cardiac diseases. PMID- 29486472 TI - MicroRNA-214 Suppresses Ovarian Cancer by Targeting beta-Catenin. AB - BACKGROUND/AIMS: Ovarian cancer is one of the most common malignancies with a high rate of mortality in women. However, current therapies for ovarian cancer treatment are ineffective. Therefore, novel target identification is an urgent requisite. The present study aimed to investigate the role of microRNA-214 (miR 214) in ovarian cancer. METHODS: The expression of miR-214, beta-catenin, cyclin D1, c-myc, and TCF-1 at the transcriptional level was measured by real-time PCR, while that of beta-catenin, Cyclin D1, and c-Myc at the protein level were detected by western blot. Colony formation assay and transwell assay were used to explore the invasion ability of the cancer cells. Cell cycle was measured by flow cytometry. RESULTS: Real-time PCR showed that miR-214 expression in ovarian cancer cell lines was lower than that in the human normal ovarian epithelial cells, IOSE80. Furthermore, the low expression of miR-214 was correlated with high pathological grade. The rate of colony formation and invasion of miR-214 overexpression in SKOV-3 cells were weaker than that in control cells. Moreover, miR-214 overexpression led to the G0/G1 phase arrest. The expression of beta catenin, Cyclin D1, and c-Myc was suppressed by the overexpression of miR-214. CONCLUSION: These results suggested that miR-214 may serve as a tumor suppressor of ovarian cancer by targeting the beta-catenin pathway. PMID- 29486473 TI - ShenFu Preparation Protects AML12 Cells Against Palmitic Acid-Induced Injury Through Inhibition of Both JNK/Nox4 and JNK/NFkappaB Pathways. AB - BACKGROUND/AIMS: Nonalcoholic steatohepatitis includes steatosis along with liver inflammation, hepatocyte injury and fibrosis. In this study, we investigated the protective role and the potential mechanisms of a traditional Chinese medicine ShenFu (SF) preparation in an in vitro hepatic steatosis model. METHODS: In palmitic acid (PA)-induced murine hepatic AML12 cell injury, effects of SF preparation on cellular apoptosis and intracellular triglyceride (iTG) level were assessed using TUNEL and TG Colorimetric Assay. Reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) levels were measured using DCF and JC-1 assay. Cytokine levels were evaluated using ELISA assay. Immunoblot was used to compare the activation level of c-Jun N terminal kinase (JNK), NADPH oxidase (Nox4), and NFkappaB pathways. RESULTS: Addition of SF preparation prevented PA mediated increase of apoptosis and iTG as well as IL-8 and IL-6. In PA-treated cell, SF preparation reduced the level of Nox4 and ROS, while increasing the level of MMP and the expression of manganese superoxide dismutase (MnSOD) and catalase, indicating emendation of mitochondrial dysfunction. Nox4 inhibitor GKT137381 prevented PA-induced increase of ROS and apoptosis, while decreasing iTG slightly and not influencing the level of IL-8 and IL-6. SF preparation prevented PA-induced upregulation of phospho-JNK. JNK inhibitor SP600125 prevented PA-mediated increase of Nox4, IL-8, IL-6 and iTG. Nuclear translocation of NFkappaB/p65 was detected in PA-treated cells, which was prevented by SF preparation. An IkappaB degradation inhibitor, BAY11-7082, prevented PA-induced increase of IL-8 and IL-6 as well as iTG, whereas it only decreased ROS levels slightly and showed no influence on cellular apoptosis. CONCLUSION: SF preparation shows a beneficial role in prevention of hepatocyte injury by attenuating oxidative stress and cytokines production at least partially through inhibition of JNK/Nox4 and JNK/NFkappaB pathway, respectively. PMID- 29486475 TI - Hearing Preservation with the Slim Modiolar Electrode Nucleus CI532(r) Cochlear Implant: A Preliminary Experience. AB - As the indications for cochlear implant have expanded to include younger patients and individuals with greater degrees of residual hearing, increasing emphasis has been placed on atraumatic surgery and the preservation of the cochlear structure. Here, a descriptive prospective randomized study was performed. It was shown that residual hearing preservation is possible 12 months postoperatively with an atraumatic perimodiolar flexible electrode array CI532(r) (Cochlear Ltd, Sydney, Australia). Residual hearing preservation, considered as < 15 dB, was obtained in 70% of the cases. Better clinical outcomes and performance could be obtained compared with the previous perimodiolar CI512(r), but further research and a longer follow-up are necessary to verify the impact of outcomes. PMID- 29486474 TI - Characterizing the Tumor Suppressor Role of CEACAM1 in Multiple Myeloma. AB - BACKGROUND/AIMS: Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), also known as CD66a, is a member of the immunoglobulin (Ig) superfamily that belongs to the carcinoembryonic antigen (CEA) family which plays a dual role in cancer. Previous studies showed high expression of CEACAM1 in multiple myeloma (MM). The aim of this study was to investigate the biological consequences of CEACAM1 overexpression in MM. METHODS: pEGFP-N1-CEACAM1 and pcDNA3.1-CEACAM1 expression plasmids were transfected into U-266 and RPMI8266 cell lines . Effect of CEACAM1 overexpression on the proliferation of two cell lines were tested by the CCK8 assay. Cell cycle and Apoptotic changes after CEACAM1 transfection were examined with AnnexinV-FITC/PI by flow cytometry. Hochest staining assay was used to confirm the apoptotic changes. Caspase-3 activity was examined by Western blotting. The cell invasion and migration activity change after CEACAM1 transfection were performed by well chamber assays and a wound healing, respectively. MMP-2 and MMP-9 proteins expression were detected by Western blotting. Flow cytometry immunophenotyping was be evaluated on myeloma cells from bone marrow taken from 50 patients with symptomatic MM newly diagnosed. The correlations between CEACAM1 expression levels and the clinical features across all groups were investigated. RESULTS: CEACAM1 overexpression significantly suppressed MM cell proliferation, induced cell apoptosis, and inhibited cell invasion and migration possibly through activation of caspase-3 and downregulation of MMP-2 and MMP-9. CEACAM1 expression in patients with DS stage I was more frequent (61.5%) than those with DS stage II (21.1%) or III (22.2%). Furthermore, patients with beta2-microglobulin levels equal to or less than 3.5 mg/L had higher CEACAM1 expression than those with beta2-microglobulin levels greater than 3.5 mg/L. CONCLUSION: Our findings suggest that CEACAM1 may act as a tumor suppressor in MM. PMID- 29486476 TI - Voruciclib, a Potent CDK4/6 Inhibitor, Antagonizes ABCB1 and ABCG2-Mediated Multi Drug Resistance in Cancer Cells. AB - BACKGROUND/AIMS: The overexpression of ATP-Binding Cassette (ABC) transporters has known to be one of the major obstacles impeding the success of chemotherapy in drug resistant cancers. In this study, we evaluated voruciclib, a CDK 4/6 inhibitor, for its chemo-sensitizing activity in ABCB1- and ABCG2- overexpressing cells. METHODS: Cytotoxicity and reversal effect of voruciclib was determined by MTT assay. The intracellular accumulation and efflux of ABCB1 and ABCG2 substrates were measured by scintillation counter. The effects on expression and intracellular localization of ABCB1 and ABCG2 proteins were determined by Western blotting and immunofluorescence, respectively. Vanadate-sensitive ATPase assay was done to determine the effect of voruciclib on the ATPase activity of ABCB1 and ABCG2. Flow cytometric analysis was done to determine the effect of voruciclib on apoptosis of ABCB1 and ABCG2-overexpressing cells and docking analysis was done to determine the interaction of voruciclib with ABCB1 and ACBG2 protein. RESULTS: Voruciclib significantly potentiated the effect of paclitaxel and doxorubicin in ABCB1-overexpressing cells, as well as mitoxantrone and SN-38 in ABCG2-overexpressing cells. Voruciclib moderately sensitized ABCC10- overexpressing cells to paclitaxel, whereas it did not alter the cytotoxicity of substrates of ABCC1. Furthermore, voruciclib increased the intracellular accumulation and decreased the efflux of substrate anti-cancer drugs from ABCB1- or ABCG2-overexpressing cells. However, voruciclib did not alter the expression or the sub-cellular localization of ABCB1 or ABCG2. Voruciclib stimulated the ATPase activity of both ABCB1 and ABCG2 in a concentration-dependent manner. Lastly, voruciclib exhibited a drug-induced apoptotic effect in ABCB1- or ABCG2- overexpressing cells. CONCLUSION: Voruciclib is currently a phase I clinical trial drug. Our findings strongly support its potential use in combination with conventional anti-cancer drugs for cancer chemotherapy. PMID- 29486477 TI - Combined Inhibition of C5 and CD14 Attenuates Systemic Inflammation in a Piglet Model of Meconium Aspiration Syndrome. AB - BACKGROUND: Meconium aspiration syndrome (MAS) is a severe lung condition affecting newborns and it can lead to a systemic inflammatory response. We previously documented complement activation and cytokine release in a piglet MAS model. Additionally, we showed ex vivo that meconium-induced inflammation was dependent on complement and Toll-like receptors. OBJECTIVES: To assess the efficacy of the combined inhibition of complement (C5) and CD14 on systemic inflammation induced in a forceful piglet MAS model. METHODS: Thirty piglets were randomly allocated to a treatment group receiving the C5-inhibitor SOBI002 and anti-CD14 (n = 15) and a nontreated control group (n = 15). MAS was induced by intratracheal meconium instillation, and the piglets were observed for 5 h. Complement, cytokines, and myeloperoxidase (MPO) were measured by ELISA. RESULTS: SOBI002 ablated C5 activity and the formation of the terminal complement complex in vivo. The combined inhibition attenuated the inflammasome cytokines IL-1beta and IL-6 by 60 (p = 0.029) and 44% (p = 0.01), respectively, and also MPO activity in the bronchoalveolar fluid by 42% (p = 0.017). Ex vivo experiments in human blood revealed that the combined regimen attenuated meconium-induced MPO release by 64% (p = 0.008), but there was only a negligible effect with single inhibition, indicating a synergic cross-talk between the key molecules C5 and CD14. CONCLUSION: Combined inhibition of C5 and CD14 attenuates meconium-induced inflammation in vivo and this could become a future therapeutic regimen for MAS. PMID- 29486478 TI - Short-Term Effects of a Multimodal 3-Week Inpatient Pulmonary Rehabilitation Programme for Patients with Sarcoidosis: The ProKaSaRe Study. AB - BACKGROUND: Real-world data on the effects of a multicomponent pulmonary rehabilitation (PR) for patients with sarcoidosis are scarce. OBJECTIVE: To describe characteristics of patients with sarcoidosis referred for a 3-week inpatient PR, to assess the effects of PR on their quality of life (QoL) and clinical outcomes, and to investigate whether there are specific subgroups who particularly benefit from PR. METHODS: Using a prospective multicentre study design, data regarding 6-min walking distance (6MWD), QoL (Saint George's Respiratory Questionnaire, SGRQ), and the secondary outcomes of dyspnoea and psychological burden (fatigue, anxiety, and depression) were collected. RESULTS: We included 296 patients in the study (average age 49.1 +/- 9.7 years, 47% female, average vital capacity 3.5 +/- 1.0 L [87.0 +/- 20.6 predicted]). The 6MWD improved by the end of the rehabilitation by 39.8 m on average (p < 0.0001; standardised response mean, SRM = 0.61), SGRQ showed significant improvements in all 3 domains, and the total score (p < 0.001) improved by 5.69-8.28 points (SRM 0.46-0.62). For the secondary outcomes, significant improvement (p < 0.001) was seen for all measured parameters, e.g., dyspnoea (modified Medical Research Council Scale, mMRC), fatigue (Fatigue Assessment Scale [FAS]; SRM = -0.71), anxiety and depression (Hospital Anxiety and Depression Scale [HADS]; SRM -0.58/ 0.38), and generic QoL (measured by the SF-36 scales of physical and mental health; SRM 0.31/0.55). CONCLUSIONS: Our results provide the first documented evidence that PR is a promising complementary therapy option for sarcoidosis patients who remain subjectively symptomatic despite optimised outpatient medical treatment. PMID- 29486481 TI - IFP News. PMID- 29486480 TI - Improving Family Functioning to (Hopefully) Improve Treatment Efficacy of Borderline Personality Disorder: An Opportunity Not to Dismiss. AB - People having intimate relationships with persons suffering from borderline personality disorder (BPD) - for instance, members of their family - are likely to be involved in stormy, roller coaster relationships. Thus, they may feel overwhelmed by extreme, unpredictable feelings and situations, even when they do not suffer from any mental disorder or have no problems with mentalization. As a consequence of living with a BPD relative, family members often experience an emotional and financial burden, and may blame themselves for their relative's illness or for not being able to do more to help. This can lead to emotional pain including anxiety, guilt, anger, frustration, despair, and hopelessness. Available evidence suggests a possible usefulness of family interventions for relatives of BPD persons. Starting from these background considerations, a qualitative review of the published literature on family interventions for relatives of BPD persons was carried out. The main findings concerning specific contents and available effectiveness data of psychoeducational family interventions, family skills training, and mentalization-based family programs are reported, in the perspective of 3 family intervention scenarios: (a) taking care of the family of origin of the BPD person; (b) taking care of the new family that the BPD person has started; (c) helping the BPD person to be an effective parent. PMID- 29486479 TI - Use of Vitamin K Antagonists and Brain Morphological Changes in Older Adults: An Exposed/Unexposed Voxel-Based Morphometric Study. AB - BACKGROUND: Vitamin K antagonists (VKAs) are commonly used for their role in haemostasis by interfering with the vitamin K cycle. Since vitamin K also participates in brain physiology, this voxel-based morphometric study aimed to determine whether the duration of exposure to VKAs correlated with focal brain volume reduction in older adults. METHODS: In this exposed/unexposed (1: 2) study nested within the GAIT (Gait and Alzheimer Interactions Tracking) cohort, 18 participants exposed to VKA (mean age 75 +/- 5 years; 33.3% female; mean exposure 2,122 +/- 1,799 days) and 36 matched participants using no VKA (mean age 75 +/- 5 years; 33.3% female) underwent MRI scanning of the brain. Cortical grey and white matter volumes were automatically segmented using statistical parametric mapping. Age, gender, educational level, history of atrial fibrillation, type of MRI, and total intracranial volume were included as covariables. RESULTS: The duration of exposure to VKA correlated inversely across the whole brain with the subvolumes of two clusters in the grey matter (right frontal inferior operculum and right precuneus) and one cluster in the white matter (left middle frontal gyrus). In contrast, the grade of white matter hyperintensities did not differ according to the use of VKA. CONCLUSION: We found focal atrophies in older adults exposed to VKA. These findings provide new insights elucidating the effects of VKAs on brain health and function in older adults. PMID- 29486482 TI - CHK2 Promotes Anoikis and is Associated with the Progression of Papillary Thyroid Cancer. AB - BACKGROUND/AIMS: Cell cycle checkpoint kinase 2 (CHK2) performs essential cellular functions and might be associated with tumorigenesis and tumor progression. Here, we explored the function and molecular mechanisms of CHK2 in the progression of papillary thyroid cancer (PTC). METHODS: The expression levels of both total CHK2 and activated CHK2 (p-CHK2) in tissues from 100 PTC patients were detected and evaluated using immunohistochemistry. The roles of CHK2 on cell proliferation, invasion, migration, apoptosis and cancer stem cell (CSC) markers were investigated by CCK-8, Transwell, flow cytometry, western blot and ALDEFLOUR assay. PTC cells cultured in suspension conditions were assayed for anoikis. The anchorage-independent condition was further detected by soft agar colony formation assay. Furthermore, anoikis associated regulatory proteins were explored by western blot and verified by forced downregulation experiment, respectively. RESULTS: We found that the levels of both CHK2 and p-CHK2 were significantly upregulated in PTC cancer tissues compared with those in tumor adjacent tissues. The overexpression of p-CHK2 in primary tumor tissues was associated with tumor aggressiveness and metastatic potential. However, the levels of both CHK2 and p-CHK2 were decreased in metastatic lymph nodes. Our results showed that CHK2 upregulated the levels of CSC markers with no effect on cell proliferation, invasion and migration. Interestingly, we revealed a previously undescribed anoikis-promoting role for CHK2 in PTC. Specifically, the detachment of PTC cells from the extracellular matrix (ECM) triggers CHK2 degradation. Then, the forced downregulation of CHK2 rescued PTC cells from anoikis, but no effect was observed on the apoptosis of adherent PTC cells. Additionally, as a novel regulator of anoikis, CHK2 can induce cell death in a p53-independent manner via the regulation of PRAS40 activation. CONCLUSION: High expression levels of CHK2 and p-CHK2 were associated with the progression of PTC. Our results defined an unexpected role for CHK2 as a mediator of anoikis that functions through the regulation of PRAS40 activation, which may be associated with the survival of circulating tumor cells and metastatic behavior. PMID- 29486483 TI - Sports Behavior in Middle-Aged Individuals with Anomalous Coronary Artery from the Opposite Sinus of Valsalva. AB - OBJECTIVES: Recommendations regarding sports restriction are lacking for middle aged athletes with anomalous coronary arteries originating from the opposite sinus of Valsalva (ACAOS). METHODS: Sixty-three patients with ACAOS were subdivided into ACAOS with (n = 38) or without (n = 25) an interarterial course (IAC). Sports behavior, either competitive (COMP) or recreational (REC), was evaluated at the time of diagnosis and after a median follow-up of 4.2 years. RESULTS: Mean age was 56 +/- 11 years and 48 (76.2%) patients were engaged in sports. Three individuals (4.8%) were surgically corrected after diagnosis. Thirty-eight (60.3%) patients were aware of their diagnosis at follow-up and 12 (19.0%) were counseled by their physician about sports restrictions. Sports behavior at the time of diagnosis and at follow-up did not differ significantly, neither in patients engaged in COMP (17.5 vs. 12.7%, p = 0.619) nor those engaged in REC (58.7 vs. 61.9%, p = 0.856). Sport-related symptoms were not significantly different between ACAOS patients with and without IAC. No athlete had died at follow-up. CONCLUSIONS: The majority of middle-aged individuals with ACAOS were involved in sports activities at the time of diagnosis and at follow-up. Awareness and counseling about ACAOS diagnosis had no significant effect on sports behavior. IAC did not have an impact on sport-related symptoms, and outcomes were favorable in all athletes, regardless of surgical correction. PMID- 29486488 TI - Interpreting Mini-Mental State Examination Performance in Highly Proficient Bilingual Spanish-English and Asian Indian-English Speakers: Demographic Adjustments, Item Analyses, and Supplemental Measures. AB - Purpose: Performance on the Mini-Mental State Examination (MMSE), among the most widely used global screens of adult cognitive status, is affected by demographic variables including age, education, and ethnicity. This study extends prior research by examining the specific effects of bilingualism on MMSE performance. Method: Sixty independent community-dwelling monolingual and bilingual adults were recruited from eastern and western regions of the United States in this cross-sectional group study. Independent sample t tests were used to compare 2 bilingual groups (Spanish-English and Asian Indian-English) with matched monolingual speakers on the MMSE, demographically adjusted MMSE scores, MMSE item scores, and a nonverbal cognitive measure. Regression analyses were also performed to determine whether language proficiency predicted MMSE performance in both groups of bilingual speakers. Results: Group differences were evident on the MMSE, on demographically adjusted MMSE scores, and on a small subset of individual MMSE items. Scores on a standardized screen of language proficiency predicted a significant proportion of the variance in the MMSE scores of both bilingual groups. Conclusions: Bilingual speakers demonstrated distinct performance profiles on the MMSE. Results suggest that supplementing the MMSE with a language screen, administering a nonverbal measure, and/or evaluating item based patterns of performance may assist with test interpretation for this population. PMID- 29486490 TI - Vocalization Subsystem Responses to a Temporarily Induced Unilateral Vocal Fold Paralysis. AB - Purpose: The purpose of this study is to quantify the interactions of the 3 vocalization subsystems of respiration, phonation, and resonance before, during, and after a perturbation to the larynx (temporarily induced unilateral vocal fold paralysis) in 10 vocally healthy participants. Using dynamic systems theory as a guide, we hypothesized that data groupings would emerge revealing context dependent patterns in the relationships of variables representing the 3 vocalization subsystems. We also hypothesized that group data would mask important individual variability important to understanding the relationships among the vocalization subsystems. Method: A perturbation paradigm was used to obtain respiratory kinematic, aerodynamic, and acoustic formant measures from 10 healthy participants (8 women, 2 men) with normal voices. Group and individual data were analyzed to provide a multilevel analysis of the data. A 3-dimensional state space model was constructed to demonstrate the interactive relationships among the 3 subsystems before, during, and after perturbation. Results: During perturbation, group data revealed that lung volume initiations and terminations were lower, with longer respiratory excursions; airflow rates increased while subglottic pressures were maintained. Acoustic formant measures indicated that the spacing between the upper formants decreased (F3-F5), whereas the spacing between F1 and F2 increased. State space modeling revealed the changing directionality and interactions among the 3 subsystems. Conclusions: Group data alone masked important variability necessary to understand the unique relationships among the 3 subsystems. Multilevel analysis permitted a richer understanding of the individual differences in phonatory regulation and permitted subgroup analysis. Dynamic systems theory may be a useful heuristic to model the interactive relationships among vocalization subsystems. Supplemental Material: https://doi.org/10.23641/asha.5913532. PMID- 29486489 TI - Effect of On-Demand vs Routine Nebulization of Acetylcysteine With Salbutamol on Ventilator-Free Days in Intensive Care Unit Patients Receiving Invasive Ventilation: A Randomized Clinical Trial. AB - Importance: It remains uncertain whether nebulization of mucolytics with bronchodilators should be applied for clinical indication or preventively in intensive care unit (ICU) patients receiving invasive ventilation. Objective: To determine if a strategy that uses nebulization for clinical indication (on demand) is noninferior to one that uses preventive (routine) nebulization. Design, Setting, and Participants: Randomized clinical trial enrolling adult patients expected to need invasive ventilation for more than 24 hours at 7 ICUs in the Netherlands. Interventions: On-demand nebulization of acetylcysteine or salbutamol (based on strict clinical indications, n = 471) or routine nebulization of acetylcysteine with salbutamol (every 6 hours until end of invasive ventilation, n = 473). Main Outcomes and Measures: The primary outcome was the number of ventilator-free days at day 28, with a noninferiority margin for a difference between groups of -0.5 days. Secondary outcomes included length of stay, mortality rates, occurrence of pulmonary complications, and adverse events. Results: Nine hundred twenty-two patients (34% women; median age, 66 (interquartile range [IQR], 54-75 years) were enrolled and completed follow-up. At 28 days, patients in the on-demand group had a median 21 (IQR, 0-26) ventilator-free days, and patients in the routine group had a median 20 (IQR, 0 26) ventilator-free days (1-sided 95% CI, -0.00003 to infinity). There was no significant difference in length of stay or mortality, or in the proportion of patients developing pulmonary complications, between the 2 groups. Adverse events (13.8% vs 29.3%; difference, -15.5% [95% CI, -20.7% to -10.3%]; P < .001) were more frequent with routine nebulization and mainly related to tachyarrhythmia (12.5% vs 25.9%; difference, -13.4% [95% CI, -18.4% to -8.4%]; P < .001) and agitation (0.2% vs 4.3%; difference, -4.1% [95% CI, -5.9% to -2.2%]; P < .001). Conclusions and Relevance: Among ICU patients receiving invasive ventilation who were expected to not be extubated within 24 hours, on-demand compared with routine nebulization of acetylcysteine with salbutamol did not result in an inferior number of ventilator-free days. On-demand nebulization may be a reasonable alternative to routine nebulization. Trial Registration: clinicaltrials.gov Identifier: NCT02159196. PMID- 29486491 TI - Masked Repetition Priming Treatment for Anomia. AB - Purpose: Masked priming has been suggested as a way to directly target implicit lexical retrieval processes in aphasia. This study was designed to investigate repeated use of masked repetition priming to improve picture naming in individuals with anomia due to aphasia. Method: A single-subject, multiple baseline design was used across 6 people with aphasia. Training involved repeated exposure to pictures that were paired with masked identity primes or sham primes. Two semantic categories were trained in series for each participant. Analyses assessed treatment effects, generalization within and across semantic categories, and effects on broader language skills, immediately and 3 months after treatment. Results: Four of the 6 participants improved in naming trained items immediately after treatment. Improvements were generally greater for items that were presented in training with masked identity primes than items that were presented repeatedly during training with masked sham primes. Generalization within and across semantic categories was limited. Generalization to broader language skills was inconsistent. Conclusion: Masked repetition priming may improve naming for some individuals with anomia due to aphasia. A number of methodological and theoretical insights into further development of this treatment approach are discussed. PMID- 29486492 TI - Early Warning Systems for Hospitalized Pediatric Patients. PMID- 29486493 TI - Effect of a Pediatric Early Warning System on All-Cause Mortality in Hospitalized Pediatric Patients: The EPOCH Randomized Clinical Trial. AB - Importance: There is limited evidence that the use of severity of illness scores in pediatric patients can facilitate timely admission to the intensive care unit or improve patient outcomes. Objective: To determine the effect of the Bedside Paediatric Early Warning System (BedsidePEWS) on all-cause hospital mortality and late admission to the intensive care unit (ICU), cardiac arrest, and ICU resource use. Design, Setting, and Participants: A multicenter cluster randomized trial of 21 hospitals located in 7 countries (Belgium, Canada, England, Ireland, Italy, New Zealand, and the Netherlands) that provided inpatient pediatric care for infants (gestational age >=37 weeks) to teenagers (aged <=18 years). Participating hospitals had continuous physician staffing and subspecialized pediatric services. Patient enrollment began on February 28, 2011, and ended on June 21, 2015. Follow-up ended on July 19, 2015. Interventions: The BedsidePEWS intervention (10 hospitals) was compared with usual care (no severity of illness score; 11 hospitals). Main Outcomes and Measures: The primary outcome was all cause hospital mortality. The secondary outcome was a significant clinical deterioration event, which was defined as a composite outcome reflecting late ICU admission. Regression analyses accounted for hospital-level clustering and baseline rates. Results: Among 144 539 patient discharges at 21 randomized hospitals, there were 559 443 patient-days and 144 539 patients (100%) completed the trial. All-cause hospital mortality was 1.93 per 1000 patient discharges at hospitals with BedsidePEWS and 1.56 per 1000 patient discharges at hospitals with usual care (adjusted between-group rate difference, 0.01 [95% CI, -0.80 to 0.81 per 1000 patient discharges]; adjusted odds ratio, 1.01 [95% CI, 0.61 to 1.69]; P = .96). Significant clinical deterioration events occurred during 0.50 per 1000 patient-days at hospitals with BedsidePEWS vs 0.84 per 1000 patient-days at hospitals with usual care (adjusted between-group rate difference, -0.34 [95% CI, -0.73 to 0.05 per 1000 patient-days]; adjusted rate ratio, 0.77 [95% CI, 0.61 to 0.97]; P = .03). Conclusions and Relevance: Implementation of the Bedside Paediatric Early Warning System compared with usual care did not significantly decrease all-cause mortality among hospitalized pediatric patients. These findings do not support the use of this system to reduce mortality. Trial Registration: clinicaltrials.gov Identifier: NCT01260831. PMID- 29486495 TI - What Does a Cue Do? Comparing Phonological and Semantic Cues for Picture Naming in Aphasia. AB - Purpose: Impaired naming is one of the most common symptoms in aphasia, often treated with cued picture naming paradigms. It has been argued that semantic cues facilitate the reliable categorization of the picture, and phonological cues facilitate the retrieval of target phonology. To test these hypotheses, we compared the effectiveness of phonological and semantic cues in picture naming for a group of individuals with aphasia. To establish the locus of effective cueing, we also tested whether cue type interacted with lexical and image properties of the targets. Method: Individuals with aphasia (n = 10) were tested with a within-subject design. They named a large set of items (n = 175) 4 times. Each presentation of the items was accompanied by a different cueing condition (phonological, semantic, nonassociated word and tone). Item level variables for the targets (i.e., phoneme length, frequency, imageability, name agreement, and visual complexity) were used to test the interaction of cue type and item variables. Naming accuracy data were analyzed using generalized linear mixed effects models. Results: Phonological cues were more effective than semantic cues, improving accuracy across individuals. However, phonological cues did not interact with phonological or lexical aspects of the picture names (e.g., phoneme length, frequency). Instead, they interacted with properties of the picture itself (i.e., visual complexity), such that phonological cues improved naming accuracy for items with low visual complexity. Conclusions: The findings challenge the theoretical assumptions that phonological cues map to phonological processes. Instead, phonological information benefits the earliest stages of picture recognition, aiding the initial categorization of the target. The data help to explain why patterns of cueing are not consistent in aphasia; that is, it is not the case that phonological impairments always benefit from phonological cues and semantic impairments form semantic cues. A substantial amount of the literature in naming therapy focuses on picture naming paradigms. Therefore, the results are also critically important for rehabilitation, allowing for therapy development to be more rooted in the true mechanisms through which cues are processed. PMID- 29486494 TI - Language Assessment for Children With a Range of Neurodevelopmental Disorders Across Four Languages in South Africa. AB - Purpose: The purpose of this study is (a) to examine the applicability of a culturally and linguistically adapted measure to assess the receptive and expressive language skills of children with neurodevelopmental disorders (NDDs) in South Africa and then (b) to explore the contributions of 2 additional language measures. Method: In Part 1, 100 children with NDD who spoke Afrikaans, isiZulu, Setswana, or South African English were assessed on the culturally and linguistically adapted Mullen Scales of Early Learning (MSEL). Clinicians independently rated the children's language skills on a 3-point scale. In Part 2, the final 20 children to be recruited participated in a caregiver-led interaction, after which the caregiver completed a rating scale about their perceptions of their children's language. Results: Performance on the MSEL was consistent with clinician-rated child language skills. The 2 additional measures confirmed and enriched the description of the child's performance on the MSEL. Conclusions: The translated MSEL and the supplemental measures successfully characterize the language profiles and related skills in children with NDD in multilingual South Africa. Together, these assessment tools can serve a valuable function in guiding the choice of intervention and also may serve as a way to monitor progress. PMID- 29486496 TI - [The Overrated Impact of Inhaled Substances (LABA, LAMA, ICS) on Exacerbation Rates in COPD]. PMID- 29486497 TI - Physiological Approach to Sodium Supplementation in Preterm Infants. AB - OBJECTIVE: To implement and evaluate a clinical practice algorithm to identify preterm infants with sodium deficiency and guide sodium supplementation based on urine sodium concentrations. STUDY DESIGN: Urine sodium concentration was measured in infants born at 260/7 to 296/7 weeks' gestation at 2-week intervals. Sodium supplementation was based on the urine sodium algorithm. Growth and respiratory outcomes in this cohort were compared with a matched cohort cared for in our neonatal intensive care unit prior to algorithm implementation (2014-2015 cohort). RESULTS: Data were compared for 50 infants in the 2014-2015 cohort and 40 infants in the 2016 cohort. Urine sodium concentration met criteria for supplementation in 75% of the 2016 cohort infants within the first 4 weeks after birth. Average daily sodium intake was greater in the 2016 cohort compared with the 2014-2015 cohort (p < 0.05). Caloric, protein, and total fluid intakes were similar between cohorts. The change in weight Z-score between 2 and 8 weeks of age was significantly greater in the 2016 versus 2014-2015 cohort (0.32 +/- 0.05 vs. -0.01 +/- 0.08; p < 0.01). No impact on respiratory status at 28 days of age or 36 weeks of postmenstrual age was identified. CONCLUSION: Institution of a clinical practice algorithm to instruct clinicians on sodium supplementation in preterm infants may improve growth outcomes. PMID- 29486498 TI - [The use of E-Cigarettes in the German Population: Results of the Epidemiological Survey of Substance Abuse 2015]. AB - AIM: Estimates of e-cigarette consumption in Germany vary considerably. The use of e-cigarettes for tobacco cessation is critically discussed. Based on current data, the distribution of the consumption of e-cigarettes and their use in the adult general population of Germany will be presented. METHODS: The 2015 Epidemiological Survey of Substance Abuse, a nationwide survey of 18 to 64 year old people in Germany (n=9,204, response rate: 52,2%), was used as data basis. RESULTS: E-cigarettes were known to most of the respondents (85,3%, 43,5 Mio.), whereas only 2,9% (1,5 Mio.) used e-cigarettes in the last 30 days. Higher risk of consuming e-cigarettes was seen in younger people (OR=0,95, 95%-KI=(0,93; 0,97)), men (OR=1,45, 95%-KI=(1,02; 2,07)) and smokers (OR=12,53, 95%-KI=(8,71; 18,03)). About a third of smokers and ex-smokers of conventional cigarettes (36,6%) who consumed e-cigarettes used these for tobacco cessation of which one fifth (21,3%) was able to quit smoking. CONCLUSION: E-cigarette users seem to be more likely to be male, younger and smokers of conventional cigarettes. In addition to curiosity, the change in smoking behavior is an important motive for consumption. The results indicate that the use of e-cigarettes can contribute to tobacco cessation, the majority of users, however, continue to consume conventional and/or e-cigarettes. PMID- 29486499 TI - [Practicability and Efficiency of E-health Applications in Patient-Reported Outcomes: State of and Need for Research]. AB - AIMS: E-health-based technologies also play an increasing role in the collection of patient- reported outcomes (ePRO). However, it remains unclear how feasible and powerful e-health applications are in the collection of PRO. Therefore, it should be examined to what extent the requirements for the use of technology based PRO instruments has already been explored in order to allow its broad use in the "e-health world". Specifically, the research focus is on practicability, capability and technical implementation of ePRO. The design of the basic legal requirements for the conduct of PRO interviews and how the challenges of ePRO have already been harmonized here need to be examined.Methods Literature study: selective literature research in Pubmed as well as in the databases of DIMDI, G BA, FDA and EMA. RESULTS: Current scientific knowledge about hurdles, acceptance and usefulness in relation to sociodemografic factors, health status and technical skills as well as about technical implementation is low. The legal standards for ePRO are restricted only to the composition of the survey instrument and methodology quality criteria. There are no prerequisites for a broad use of ePRO, which is why therapeutic measures should not be based on them. CONCLUSION: The standards of the legislators must be specified and adapted to the requirements of ePRO. Because the design of the tool surface and the rate of usability can influence the response behavior of the patients, the focus should be on the reliability and validity of ePRO surveys in the context of their implementation in relation to the patients, disease, questionnaire and ePRO specific variables, which determine the response behavior, in order not to endanger the meaningfulness of PRO surveys. PMID- 29486500 TI - [Musical Inactivity - A Risk Factor? A Short Questionnaire to Assess Musical Activity (MusA)]. AB - BACKGROUND: There is only a limited number of studies on associations between musical activity and health issues. It seems that musical activity has physiological and psychological benefits, as well as effects on the mental capacity, but this has been studied only in a few clinical and epidemiological studies. One reason might be that no appropriate survey instrument assessing musical activity is available. AIM OF THE STUDY: Here we provide an overview of survey instruments that assess musicality and musical activity. One focus is the presentation of a newly developed German questionnaire (MusA), which assesses musical activity (active music making and music reception) and was specifically developed for the "German National Cohort", a German health study. METHOD: Through literature research, questionnaires were identified that assess musicality and / or musical activity. A new German questionnaire was developed from a panel of experts and tested in a small study (n=121, women and men age 18 70 years). RESULTS: In the literature research, 3 questionnaires were identified which focus on musicality and musical activity with different aspects (Gold-MSI, MUSE, MEQ). All 3 instruments may be characterized as large psychometric scales, which especially assess aspects of musicality in the English language. The Gold MSI is additionally available in German. None of the existing questionnaires covers musical activities in detail. A new short German questionnaire consisting of 9 questions with a maximum filling time of 3-5 min has been developed. CONCLUSION: There are few questionnaires available for assessing musicality and musical activity with different aspects. The newly developed MusA in the German language focuses on the assessment of musical activity and is intended to be used in larger, population-based as well as clinical studies, to examine music activities and listening to music as independent factors in connection with prevention and therapy of chronic diseases. PMID- 29486501 TI - [Diagnostic and therapeutic concepts for vesicovaginal and ureterovaginal fistulas]. PMID- 29486503 TI - Torcular Pseudomass. PMID- 29486504 TI - Impact of Hippotherapy on Gross Motor Function and Quality of Life in Children with Bilateral Cerebral Palsy: A Randomized Open-Label Crossover Study. AB - This study investigated the effect of hippotherapy on gross motor function (Gross Motor Function Measure [GMFM]-66, GMFM dimension E and D) and quality of life (Child Health Questionnaire [CHQ 28], KIDSCREEN-27 parental versions) in children with bilateral spastic cerebral palsy. Seventy-three children (age: 9.1 +/- 3.3 years; male = 44; GMFCS levels II = 27; III = 17; IV = 29) were randomized to an early (n = 35) or late (n = 38) treatment group. Data from 66 probands were available for further analysis. Probands received hippotherapy once to twice weekly during a period of 16 to 20 weeks (mean: 17 treatments) in a crossover approach. Whereas no significant changes were found for total GMFM scores and quality of life parameters, a significant increase in GMFM dimension E was found. Children terminating the study early showed lower mean psychosocial quality of life scores than children who completed the whole study (CHQ-28 "psychosocial dimension"; KIDSCREEN-27 "mood and emotional dimension"). Our data are in line with previous reports and suggest that hippotherapy shows distinct therapeutic strengths with regard to promoting upright stand and gait in children with cerebral palsy. Children with higher psychosocial burden of disease may need special support to get access to and benefit from intensified physiotherapy programs. PMID- 29486502 TI - Colon capsule versus computed tomography colonography for colorectal cancer screening in patients with positive fecal occult blood test who refuse colonoscopy: a randomized trial. AB - OBJECTIVE: Some patients (10 % - 32 %) with a positive guaiac fecal occult blood test (gFOBT) do not undergo the recommended colonoscopy. The aim of this study was to compare video capsule endoscopy (VCE) and computed tomography colonography (CTC) in terms of participation rate and detection outcomes when offered to patients with a positive gFOBT who did not undergo the recommended colonoscopy. METHODS: An invitation letter offering CTC or VCE was sent to selected patients after randomization. Acceptance of the proposed (or alternative) procedure and procedure results were recorded. Sample size was evaluated according to the hypothesis of a 13 % increase of participation with VCE. RESULTS: A total of 756 patients were targeted. Following the invitation letter, 5.0 % (19/378) of patients underwent the proposed VCE and 7.4 % (28/378) underwent CTC, (P = 0.18). Following the letter, 9.8 % (37/378) of patients in the VCE group underwent a diagnostic procedure (19 VCE, 1 CTC, 17 colonoscopy) vs. 10.8 % in the CTC group (41/378: 28 CTC, 13 colonoscopy; P = 0.55). There were more potentially neoplastic lesions diagnosed in the VCE group than in the CTC group (12/20 [60.0 %] vs. 8/28 [28.6 %]; P = 0.04). Thus, 15/20 noninvasive procedures in the VCE group (19 VCE, 1 CTC; 75.0 %) vs. 10/28 in the CTC group (35.7 %; P = 0.01) resulted in a recommendation of further colonoscopy, but only 10/25 patients actually underwent this proposed colonoscopy. CONCLUSION: Patients with a positive gFOBT result who do not undergo the recommended colonoscopy are difficult to recruit to the screening program and simply proposing an additional, less-invasive procedure, such as VCE or CTC, is not an effective strategy.ClinicalTrials.govNCT02558881TRIAL REGISTRATION: Randomized, controlled trial NCT02558881 at clinicaltrials.gov. PMID- 29486505 TI - Ceramic-on-Ceramic in Total Hip Replacement Revision. AB - BACKGROUND: The use of Ceramic-on-Ceramic (CoC) bearings in primary total hip arthroplasty (THA) is increasing and has been intensively analysed. This bearing plays a particularly relevant role in young, active patients and shows advantages over other bearings in biocompatibility, wear rate and lubrication properties. On the contrary, CoC bearings in revision THA are seldom used and scarcely analysed. The aim of this study is to systematically review the available literature on CoC bearings in revision THA. METHODS: A systematic research in the English literature was performed to identify all studies reporting results of THA revisions using ceramic-on-ceramic bearing. The initial search strategy revealed 555 articles for consideration. On the basis of eligibility criteria, 26 studies were included in this review. RESULTS: Twenty-six studies, accounting for 1846 procedures, were eligible and included in the review. No studies of Level I were identified. Eighteen studies reported on revisions of CoC implants for various reasons, performed either with CoC or different bearings. In 111 patients a CoC bearing was used for the revision. Six studies consistently reported outcome measures for CoC bearing THA revisions, so that a quantitative synthesis of the data was possible. The range of follow-up across the six studies varied between 2.1 and 19 years, with a cumulative avearage follow-up of 9.3 years. A good functional result was documented, with a cumulative weighted mean for postoperative Harris Hip Score (HHS) of 87 points. The rate of dislocation in this group was 3.45% and the risk of fracture of an alumina ceramic head was 0.35% (1 study). Squeaking was reported as complication of CoC bearing THA revisions in three studies, with a calculated incidence of 0.52%. CONCLUSION: Modern CoC bearings show advantages in preclinical and retrospective studies over other bearings also in revision cases and are therefore to be considered a promising alternative for this kind of operation. Reasonable indications for CoC bearing in revision THA are revisions for aseptic loosening or recurrent dislocation in young patients, fractures of ceramic components, large acetabular defects or in patients that are allergic to bone cement components. Nevertheless, prospectively designed or randomized studies are lacking and needed to confirm CoC as optimal solution for revision THA cases. PMID- 29486507 TI - ? PMID- 29486506 TI - [Performing a Structural Cranio-Maxilla-Facial Examination after Trauma]. PMID- 29486508 TI - [What Do Young Surgeons Want? Modern Requirements for Senior Surgeons]. AB - Due to the shortage of surgical specialists, the question arises as to what surgical residents want and how the fascination of general and visceral surgery may be highlighted. The surgical working group "Young Surgeons" (CAJC) of the German Society for General and Visceral Surgery (DGAV) has organised and subdivided the aspects of an attractive surgical workplace and provides solutions. On the one hand, there is the structured and transparent residency which includes a defined curriculum, assistance of sub-steps during surgery, residency dialogues held on a regular basis, logbooks, the possibility of training and simulation in the clinic as well as permission to participate in further education and training. This has to go hand in hand with a "livable surgery" that is characterised by the compatibility of family and work, better planning of the routine in the clinic, a positive feedback culture, work-life balance, new work (time) models and more time for teaching and research. For many of these aspects, the head of surgery has to be the central role model to initiate structural changes in the clinic, especially as many of these key points may be easily implemented. In this way, the attraction of surgery can be rapidly enhanced and a "livable surgery" may be lived. PMID- 29486509 TI - ? PMID- 29486510 TI - [Small Cell Lung Cancer]. AB - Small cell lung cancer accounts for roughly 14% of all lung cancers and is characterized by rapid progression, early distant metastasis and poor prognosis. Only a minority of patients presents with early stage disease upon initial diagnosis where surgical resection may be discussed. In addition, various treatment modalities demonstrate effectiveness including chemotherapy and radiotherapy. However, although most patients respond to platinum doublet chemotherapy, virtually all patients with metastatic disease eventually develop tumor progression for which there are limited treatment options. Novel therapeutic approaches such as immune checkpoint inhibitors or the antibody drug conjugate rovalpituzumab tesirine show promising results in early clinical trials and might broaden our treatment options in the future. PMID- 29486511 TI - Response to Lithium in Patients with Bipolar Disorder: What are Psychiatrists' Experiences and Practices Compared to Literature Review? AB - BACKGROUND: This study aims at characterizing French psychiatrists' opinions regarding definition criteria and factors associated with lithium prophylactic response in patients with bipolar disorders. METHODS: After a literature review, an online survey targeted French psychiatrists in 2016. RESULTS: Literature review showed inconsistencies in reported definition criteria and clinical predictors of lithium prophylactic response. A total of 104 psychiatrists, mostly working in hospitals, completed the survey. The inconsistencies regarding definition criteria and predictors of lithium response were confirmed. Five factors were commonly reported by psychiatrists as positively associated with successful response (family history of lithium response and of bipolar I disorder, and lithium efficacy in acute mood phases treatment) or with an unsuccessful response (rapid cycling and alcohol misuse). DISCUSSION: The divergence in psychiatrists' opinions surely plays a major role in the variability of lithium prescriptions among psychiatrists. Currently, the large variations in response definitions, and in study designs used to quantify each factor's effect, preclude synthesizing the findings. A standardization of response measures is needed to explore factors that influence the prophylactic lithium efficacy. PMID- 29486512 TI - DNA Methylation Profiling in a Neuroblastoma Cell Line Exposed to the Antipsychotic Perospirone. AB - INTRODUCTION: Accumulating evidence suggests the importance of epigenetic changes in the brain induced by antipsychotic drugs. However, due to the lack of systematic investigation, their effects on epigenetic status remain largely unclear. During the course of examining the epigenetic effects of antipsychotics, we here focused on perospirone, an atypical antipsychotic drug mainly used in Japan. METHODS: Genomic DNA was obtained from human neuroblastoma cells exposed to 2 different doses of perospirone. Comprehensive DNA methylation analysis was performed using the Infinium HumanMethylation450 BeadChip. RESULTS: Of about 470,000 probes, perospirone exposure changed DNA methylation at 4098 probes. These probes were enriched to genes for neural development. Probes showing hypermethylation were mainly found at gene body and intergenic regions, whereas those that showed hypomethylation were located near promoter regions. Additionally, DNA methylation changes were found in the probes for dopamine receptor 2 and serotonin receptor (HTR) 2A and HTR1A, which are the pharmacological targets of atypical antipsychotics. DISCUSSION: Our comprehensive DNA methylation analyses will contribute to a better understanding of detailed pharmacological actions of perospirone. PMID- 29486513 TI - Combination of Metformin and Lifestyle Intervention for Antipsychotic-Related Weight Gain: A Meta-Analysis of Randomized Controlled Trials. AB - INTRODUCTION: Weight gain is a common antipsychotic (AP)-related adverse drug reaction (ADR) that can increase the risk of cardiovascular diseases and premature mortality. This meta-analysis examined the efficacy and tolerability of combining metformin and lifestyle intervention for AP-related weight gain in schizophrenia. METHODS: Randomized controlled trials (RCTs) with meta-analyzable data were searched and retrieved by 2 independent investigators. RevMan software (version 5.3) was used to synthesize data, and to calculate the standardized or weighted mean differences and risk ratio with their 95% confidence intervals. RESULTS: Six RCTs (n=732) were included and meta-analyzed. The metformin and lifestyle combination (MLC) group had significant reduction in weight and body mass index compared with the metformin group, lifestyle group, and placebo group. There was less frequent weight gain of>=7% in the MLC group over placebo. No other group differences in ADRs, total psychopathology, and all-cause discontinuation were found. In terms of study quality, 5 RCTs were open-labelled, 1 RCT had low risk allocation concealment, and 3 RCTs specifically described randomization methods. CONCLUSION: Combining metformin and lifestyle intervention shows significant effect in reducing AP-related weight gain. Higher quality and larger RCTs are needed to confirm these findings.Review registration: CRD42017059198. PMID- 29486514 TI - Locally acting ACE-083 increases muscle volume in healthy volunteers. AB - INTRODUCTION: ACE-083 is a locally acting follistatin-based therapeutic that binds myostatin and other muscle regulators and has been shown to increase muscle mass and force in neuromuscular disease mouse models. This first-in-human study examined these effects. METHODS: In this phase 1, randomized, double-blind, placebo-controlled, dose-ranging study in healthy postmenopausal women, ACE-083 (50-200 mg) or placebo was administered unilaterally into rectus femoris (RF) or tibialis anterior (TA) muscles as 1 or 2 doses 3 weeks apart. RESULTS: Fifty eight postmenopausal women were enrolled, 42 ACE-083 and 16 placebo. No serious adverse events (AE), dose-limiting toxicities, or discontinuations resulting from AEs occurred. Maximum (mean +/- SD) increases in RF and TA muscle volume were 14.5% +/- 4.5% and 8.9% +/- 4.7%, respectively. No significant changes in mean muscle strength were observed. DISCUSSION: ACE-083 was well tolerated and resulted in significant targeted muscle growth. ACE-083 may have the potential to increase muscle mass in a wide range of neuromuscular disorders. Muscle Nerve 57: 921-926, 2018. PMID- 29486515 TI - Head-to-head comparison of 18 F-FP-CIT and 123 I-FP-CIT for dopamine transporter imaging in patients with Parkinson's disease: A preliminary study. AB - 123 I-FP-CIT and 18 F-FP-CIT are radiotracers which are widely used to diagnose Parkinson's disease (PD). However, to our knowledge, no studies to date have made head-to-head comparisons between 123 I-FP-CIT and 18 F-FP-CIT. Therefore, in this study, 123 I-FP-CIT SPECT/CT was compared with 18 F-FP-CIT PET/CT in the same cohort of subjects. Patients with PD and essential tremor (ET) underwent 123 I-FP CIT SPECT/CT and 18 F-FP-CIT PET/CT. Visual and semiquantitative analyses were conducted. The specific binding ratio (SBR) and putamen to caudate ratio (PCR) were compared between subjects who underwent 123 I-FP-CIT SPECT/CT and 18 F-FP CIT PET/CT. Visual analysis showed that the striatal uptake of both radiotracers was decreased in the PD group, whereas striatal uptake was intact in the ET group. The SBR between 123 I-FP-CIT SPECT/CT and 18 F-FP-CIT PET/CT showed a positive correlation (r = .78, p < .01). However, the mean SBRs on 18 F-FP-CIT PET/CT were higher than those on 123 I-FP-CIT SPECT/CT (2.19 +/- .87 and 1.22 +/- .49, respectively; p < .01). The PCRs in these two modalities were correlated with each other (r = .71, p < .01). The mean PCRs on 18 F-FP-CIT PET/CT were not significantly higher than those on 123 I-FP-CIT SPECT/CT (1.31 +/- .19 and 0.98 +/- .06, respectively; p = .06). These preliminary results indicate that the uptake of both 123 I-FP-CIT and 18 F-FP-CIT was decreased in the PD group when compared with the ET controls. Visual analyses using both methods did not affect the diagnostic accuracy in this study. However, semiquantitative analysis indicated a better contrast of 18 F-FP-CIT PET/CT relative to 123 I-FP-CIT SPECT/CT. PMID- 29486516 TI - Transient elastography is useful in diagnosing biliary atresia and predicting prognosis after hepatoportoenterostomy. AB - : We investigated the utility of transient elastography (TE) for diagnosing biliary atresia (BA) in cholestatic infants and predicting the outcome of BA. Forty-eight cholestatic infants (9-87 days of age) with direct bilirubin level >1 mg/dL were enrolled. Liver stiffness measurement (LSM) by TE was performed during the cholestasis workup, and 15 subjects were diagnosed as BA. We assessed liver histology using liver biopsies from 36 subjects and graded fibrosis status using the METAVIR score. BA infants had significantly higher LSM values and METAVIR scores than non-BA cholestatic infants. A receiver operating characteristic (ROC) curve analysis showed that an LSM >7.7 kPa was predictive of BA among cholestatic infants (sensitivity = 80%; specificity = 97%; area under the curve [AUC] = 85.3%; P = 0.0001). Cholestatic infants with an LSM >7.7 kPa were more likely to be diagnosed with BA (odds ratio [OR] = 128; P < 0.001). Very early measurement of LSM after hepatoportoenterostomy (HPE) is associated with occurrence of thrombocytopenia, splenomegaly, and esophageal varices 6 months post-HPE. Five of the BA subjects were awaiting or had received liver transplantation (LT), and they had a significantly higher LSM measured 1 week post-HPE than that in the other BA subjects (26.0 vs. 10.8 kPa; P = 0.006). A Cox proportional analysis demonstrated that the need for LT was significantly higher in BA subjects with LSM >16 kPa measured 1 week post-HPE than other BA subjects (hazard ratio [HR] = 10.16; P = 0.04). CONCLUSION: LSM assessment during the workup of cholestatic infants may facilitate the diagnosis of BA. LSM post-HPE may predict complications and the need for early LT in infants with BA. (Hepatology 2018). PMID- 29486517 TI - Glycogen storage disease type Ia: Adult presentation with microcytic anemia and liver adenomas. PMID- 29486518 TI - Multiple saccular aortic aneurysms following the arterial switch operation. AB - We report a 3-month-old male presenting with multiple aortic aneurysms arising de novo 2 months following the arterial switch operation. Successful repair of the aneurysms was performed under total circulatory arrest and at seven years follow up, the patient has no recurrence. PMID- 29486519 TI - Hepatic diagnostics in pregnancy: Biopsy, biomarkers, and beyond. PMID- 29486520 TI - Characterization of Athabasca lean oil sands and mixed surficial materials: Comparison of capillary electrophoresis/low-resolution mass spectrometry and high resolution mass spectrometry. AB - RATIONALE: Oil sands mining in Alberta, Canada, requires removal and stockpiling of considerable volumes of near-surface overburden material. This overburden includes lean oil sands (LOS) which cannot be processed economically but contain sparingly soluble petroleum hydrocarbons and naphthenic acids, which can leach into environmental waters. In order to measure and track the leaching of dissolved constituents and distinguish industrially derived organics from naturally occurring organics in local waters, practical methods were developed for characterizing multiple sources of contaminated water leakage. METHODS: Capillary electrophoresis/positive-ion electrospray ionization low-resolution time-of-flight mass spectrometry (CE/LRMS), high-resolution negative-ion electrospray ionization Orbitrap mass spectrometry (HRMS) and conventional gas chromatography/flame ionization detection (GC/FID) were used to characterize porewater samples collected from within Athabasca LOS and mixed surficial materials. GC/FID was used to measure total petroleum hydrocarbon and HRMS was used to measure total naphthenic acid fraction components (NAFCs). HRMS and CE/LRMS were used to characterize samples according to source. RESULTS: The amounts of total petroleum hydrocarbon in each sample as measured by GC/FID ranged from 0.1 to 15.1 mg/L while the amounts of NAFCs as measured by HRMS ranged from 5.3 to 82.3 mg/L. Factors analysis (FA) on HRMS data visually demonstrated clustering according to sample source and was correlated to molecular formula. LRMS coupled to capillary electrophoresis separation (CE/LRMS) provides important information on NAFC isomers by adding analyte migration time data to m/z and peak intensity. CONCLUSIONS: Differences in measured amounts of total petroleum hydrocarbons by GC/FID and NAFCs by HRMS indicate that the two methods provide complementary information about the nature of dissolved organic species in a soil or water leachate samples. NAFC molecule class Ox Sy is a possible tracer for LOS seepage. CE/LRMS provides complementary information and is a feasible and practical option for source evaluation of NAFCs in water. PMID- 29486521 TI - Burden of illness in patients with treatment refractory myasthenia gravis. AB - INTRODUCTION: This study assessed the clinical burden of refractory myasthenia gravis (MG), relative to nonrefractory MG. METHODS: Rates of myasthenic crises, exacerbations, inpatient hospitalizations, and emergency room (ER) visits over a 1-year period were measured for 403 refractory, 3,811 nonrefractory, and 403 non MG control patients from two administrative health plan databases. RESULTS: Compared with nonrefractory patients, a significantly greater percentage of refractory patients had at least one myasthenic crisis (21.3% vs. 6.1%; P < 0.001) and at least one exacerbation (71.2% vs. 32.4%; P < 0.001) over a 1-year period. Refractory patients were also significantly more likely to be hospitalized and/or have an ER visit than nonrefractory patients and non-MG controls (P < 0.001 for all). DISCUSSION: Refractory MG patients have significantly greater clinical burden and are more likely to utilize intensive healthcare resources than nonrefractory patients. Furthermore, refractory patients may be at greater risk of crises throughout the disease course than previous studies have suggested. Muscle Nerve, 2018. PMID- 29486522 TI - Vaporization and thermodynamics of ceramics based on the La2 O3 -Y2 O3 -HfO2 system studied by the high-temperature mass spectrometric method. AB - RATIONALE: Materials based on the La2 O3 -Y2 O3 -HfO2 system are promising for the production of highly refractory ceramics, e.g., thermal barrier coatings and molds for casting of elements of gas turbine engines. When these ceramics are synthesized or used at high temperatures, selective vaporization of components may take place, resulting in changes in the physicochemical properties of the materials. Consequently, development of materials based on the La2 O3 -Y2 O3 HfO2 system requires information on vaporization in this system as well as on its thermodynamics, without which prediction and modeling of their physicochemical properties are impossible. METHODS: Vaporization processes and thermodynamic properties in the La2 O3 -Y2 O3 -HfO2 system were studied by the high-temperature Knudsen effusion mass spectrometric method using a MS-1301 mass spectrometer. Electron ionization of vapor species was employed at an ionization energy of 25 eV. The samples under study and reference substances were vaporized from a tungsten twin effusion cell. RESULTS: At 2337 K the main vapor species over samples in the La2 O3 -Y2 O3 -HfO2 system were shown to be LaO, YO and O. The partial pressures of the vapor species mentioned and the La2 O3 and Y2 O3 activities in the samples were obtained at 2337 K. The Gibbs energies of mixing and excess Gibbs energies were found in the solid solution of this system. CONCLUSIONS: Vaporization of ceramics based on the La2 O3 -Y2 O3 -HfO2 system at 2337 K led to selective transition of La2 O3 and Y2 O3 to the gaseous phase, with the La2 O3 vaporization rate being higher than that of Y2 O3 . The directions of composition changes of samples due to their vaporization at 2337 K were determined. In the solid solution of this system negative deviations from ideal behavior were found. The ability to estimate the excess Gibbs energies in the solid solution of the La2 O3 -Y2 O3 -HfO2 system by the Kohler method was shown. PMID- 29486523 TI - Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism. AB - : Bile acids activate farnesoid X receptor (FXR) and G protein-coupled bile acid receptor-1 (aka Takeda G protein-coupled receptor-5 [TGR5]) to regulate bile acid metabolism and glucose and insulin sensitivity. FXR and TGR5 are coexpressed in the enteroendocrine L cells, but their roles in integrated regulation of metabolism are not completely understood. We reported recently that activation of FXR induces TGR5 to stimulate glucagon-like peptide-1 (GLP-1) secretion to improve insulin sensitivity and hepatic metabolism. In this study, we used the intestine-restricted FXR agonist fexaramine (FEX) to study the effect of activation of intestinal FXR on the gut microbiome, bile acid metabolism, and FXR and TGR5 signaling. The current study revealed that FEX markedly increased taurolithocholic acid, increased secretion of fibroblast growth factors 15 and 21 and GLP-1, improved insulin and glucose tolerance, and promoted white adipose tissue browning in mice. Analysis of 16S ribosomal RNA sequences of the gut microbiome identified the FEX-induced and lithocholic acid-producing bacteria Acetatifactor and Bacteroides. Antibiotic treatment completely reversed the FEX induced metabolic phenotypes and inhibited taurolithocholic acid synthesis, adipose tissue browning, and liver bile acid synthesis gene expression but further increased intestinal FXR target gene expression. FEX treatment effectively improved lipid profiles, increased GLP-1 secretion, improved glucose and insulin tolerance, and promoted adipose tissue browning, while antibiotic treatment reversed the beneficial metabolic effects of FEX in obese and diabetic mice. CONCLUSION: This study uncovered a mechanism in which activation of intestinal FXR shaped the gut microbiota to activate TGR5/GLP-1 signaling to improve hepatic glucose and insulin sensitivity and increase adipose tissue browning; the gut microbiota plays a critical role in bile acid metabolism and signaling to regulate metabolic homeostasis in health and disease. (Hepatology 2018). PMID- 29486524 TI - Labile iron pool as a parameter to monitor iron overload and oxidative stress status in beta-thalassemic erythrocytes. AB - BACKGROUND: Labile iron pool (LIP) is intracellular nonprotein bound iron that can generate oxygen radicals via the Fenton reaction resulting in oxidative cell damage. Therefore, quantitative measurement of LIP will be helpful for detecting and monitoring the toxic iron status in iron overloaded patients. This study demonstrated LIP level and its correlation to oxidative stress status in beta thalassemic erythrocytes. METHODS: LIP and reactive oxygen species (ROS) level, numbers of erythrocyte vesicles and apoptosis were assayed by flow cytometric methods in 30 blood samples from beta-thalassemia/hemoglobin E patients and 17 blood samples from healthy volunteers with normal hemoglobin type. RESULTS: beta thalassemic erythrocytes showed higher LIP level, defined as the difference in calcein fluorescent intensity of the cells treated with or without deferiprone, than normal erythrocytes (mean +/- 2SD as 62.39 +/- 39.58 versus 44.65 +/- 35.86, P = 0.003). The LIP level above 67, a cutoff value of LIP level obtained from receiver operating characteristic curve analysis, had a significant positive correlation with oxidative stress status for ROS level (r = 0.90, P < 0.001) and also the amount of erythrocyte vesicles (r = 0.79, P = 0.002). In contrast, the LIP level showed a significant negative correlation with the patients' hemoglobin level (r = -0.66, P = 0.028). CONCLUSIONS: The LIP assay is suggested as an alternative test to monitor the magnitude of iron overload and its consequent oxidative stress in beta-thalassemia. LIP level may also be used as a marker for therapeutic response to iron chelation treatment. (c) 2018 International Clinical Cytometry Society. PMID- 29486525 TI - A Quasi-3D compartmental multi-scale approach to detect and quantify diseased regional lung constriction using spirometry data. AB - Spirometry is a widely used pulmonary function test to detect the airflow limitations associated with various obstructive lung diseases, such as asthma, chronic obstructive pulmonary disease, and even obesity-related complications. These conditions arise due to the change in the airway resistance, alveolar compliance, and inductance values. Currently, zero-dimensional compartmental models are commonly used for calibrating these resistance, compliance, and inductance values, ie, solving the inverse spirometry problem. However, zero dimensional compartments cannot capture the flow physics or the spatial geometry effects, thereby generating a low fidelity prediction of the diseased lung. Computational fluid dynamics (CFD) models offer higher fidelity solutions but may be impractical for certain applications due to the duration of these simulations. Recently, a novel, fast-running, and robust Quasi-3D (Q3D) wire model for simulating the airflow in the human lung airway was developed by CFD Research Corporation. This Q3D method preserved the 3D spatial nature of the airways and was favorably validated against CFD solutions. In the present study, the Q3D compartmental multi-scale combination is further improved to predict regional lung constriction of diseased lungs using spirometry data. The Q3D mesh is resolved up to the eighth lung airway generation. The remainder of the airways and the alveoli sections are modeled using a compartmental approach. The Q3D geometry is then split into different spatial sections, and the resistance values in these regions are obtained using parameter inversion. Finally, the airway diameter values are then reduced to create the actual diseased lung model, corresponding to these resistance values. This diseased lung model can be used for patient-specific drug deposition predictions and the subsequent optimization of the orally inhaled drug products. PMID- 29486526 TI - Collision cross section (CCS) measurement by ion cyclotron resonance mass spectrometry with short-time Fourier transform. AB - RATIONALE: The collision cross section (CCS) is an important shape parameter which is often used in molecular structure investigation. In Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS), the CCS affects the ion signal damping shape due to the effect of ion-neutral collisions. It is potential to obtain ion CCS values from FTICR-MS with the help of a proper ion-collision model. METHODS: We have developed a rapid method to obtain the ion damping profile and CCS for mixtures by only one FTICR-MS measurement. The method utilizes short-time Fourier transform (STFT) to process FTICR-MS time domain signals. The STFT-processed result is a three-dimensional (3D) spectrum which has an additional time axis in addition to the conventional mass-to-charge ratio and intensity domains. The damping profile of each ion can be recognized from the 3D spectrum. RESULTS: After extracting the decay profile of a specified ion, all the three ion-neutral collision models were tested in curve fitting. The hard-sphere model was proven to be suitable for our experimental setup. A linear relationship was observed between the CCS value and hard-sphere model parameters. Therefore, the CCS values of all the peaks were obtained through the addition of internal model compounds and linear calibration. CONCLUSIONS: The proposed method was successfully applied to determine the CCSs of fatty acids and polyalanines in a petroleum gas oil matrix. This technique can be used for simultaneous measurement of cross sections for many ions in congested spectra. PMID- 29486527 TI - Thoracoscopic pleural biopsy improves yield of Xpert MTB/RIF for diagnosis of pleural tuberculosis. AB - BACKGROUND AND OBJECTIVE: Extrapulmonary tuberculosis (EPTB) accounts for ~15% of all TB patients, and TB pleural effusion is the second most common site of EPTB. The diagnosis of pleural TB is challenging due to the pauci-bacillary nature of the disease. Histopathology of thoracoscopically obtained pleural biopsy provides the highest diagnostic yield. The Xpert MTB/RIF assay (Xpert) is a PCR test that can identify both Mycobacterium tuberculosis (MTB) and rifampicin resistance. Currently, there is a lack of clarity regarding the value of Xpert on pleural tissue. We report our experience of using Xpert on thoracoscopic pleural biopsy samples. METHODS: We retrospectively reviewed the records of patients who underwent thoracoscopy in our institution over a 1-year period. Relevant clinical details; indications; and results of tests on pleural tissue and fluid, including histopathology, mycobacterial cultures and Xpert, were extracted. RESULTS: Of the 156 patients who underwent thoracoscopy, 73 (47%) had TB, 66 (42%) malignancy and 17 (11%) other conditions. Histopathology was diagnostic in all the 73 TB patients (100%). The yields of the microbiological tests against histopathology on thoracoscopic biopsy sample and pleural fluid were: pleural tissue Xpert 45%, pleural tissue culture 39%, pleural fluid culture 17% and pleural fluid Xpert 14%. Pleural tissue provided higher yields than fluid in both Xpert and culture (P < 0.05). Pleural tissue Xpert provided a higher yield than culture and substantially improved yield compared with closed pleural biopsy as we previously reported. CONCLUSION: Thoracoscopic pleural biopsy results in increased sensitivity on Xpert testing. PMID- 29486528 TI - Patient-specific simulation of guidewire deformation during transcatheter aortic valve implantation. AB - Transcatheter aortic valve implantation is a recent mini-invasive procedure to implant an aortic valve prosthesis. Prosthesis positioning in transcatheter aortic valve implantation appears as an important aspect for the success of the intervention. Accordingly, we developed a patient-specific finite element framework to predict the insertion of the stiff guidewire, used to position the aortic valve. We simulated the guidewire insertion for 2 patients based on their pre-operative CT scans. The model was designed to primarily predict the position and the angle of the guidewires in the aortic valve, and the results were successfully compared with intraoperative images. The present paper describes extensively the numerical model, which was solved by using the ANSYS software with an implicit resolution scheme, as well as the stabilization techniques which were used to overcome numerical instabilities. We performed sensitivity analysis on the properties of the guidewire (curvature angle, curvature radius, and stiffness) and the conditions of insertion (insertion force and orientation). We also explored the influence of the model parameters. The accuracy of the model was quantitatively evaluated as the distance and the angle difference between the simulated guidewires and the intraoperative ones. A good agreement was obtained between the model predictions and intraoperative views available for 2 patient cases. In conclusion, we showed that the shape of the guidewire in the aortic valve was mainly determined by the geometry of the patient's aorta and by the conditions of insertion (insertion force and orientation). PMID- 29486529 TI - Meta-analysis and transcriptome profiling reveal hub genes for soybean seed storage composition during seed development. AB - Soybean is an important crop providing edible oil and protein source. Soybean oil and protein contents are quantitatively inherited and significantly affected by environmental factors. In this study, meta-analysis was conducted based on soybean physical maps to integrate quantitative trait loci (QTLs) from multiple experiments in different environments. Meta-QTLs for seed oil, fatty acid composition, and protein were identified. Of them, 11 meta-QTLs were located on hot regions for both seed oil and protein. Next, we selected 4 chromosome segment substitution lines with different seed oil and protein contents to characterize their 3 years of phenotype selection in the field. Using strand-specific RNA sequencing analysis, we profile the time-course transcriptome patterns of soybean seeds at early maturity, middle maturity, and dry seed stages. Pairwise comparison and K-means clustering analysis revealed 7,482 differentially expressed genes and 45 expression patterns clusters. Weighted gene coexpression network analysis uncovered 46 modules of gene expression patterns. The 2 most significant coexpression networks were visualized, and 7 hub genes were identified that were involved in soybean oil and seed storage protein accumulation processes. Our results provided a transcriptome dataset for soybean seed development, and the candidate hub genes represent a foundation for further research. PMID- 29486530 TI - Quantification of volatile compounds released by roasted coffee by selected ion flow tube mass spectrometry. AB - RATIONALE: The major objective of this exploratory study was to implement selected ion flow tube mass spectrometry, SIFT-MS, as a method for the on-line quantification of the volatile organic compounds, VOCs, in the headspace of the ground roasted coffee. METHODS: The optimal precursor ions and characteristic analyte ions were selected for real-time SIFT-MS quantification of those VOCs that are the most abundant in the headspace or known to contribute to aroma. NO+ reagent ion reactions were exploited for most of the VOC analyses. VOC identifications were confirmed using gas chromatography/mass spectrometry, GC/MS, coupled with solid-phase microextraction, SPME. RESULTS: Thirty-one VOCs were quantified, including several alcohols, aldehydes, ketones, carboxylic acids, esters and some heterocyclic compounds. Variations in the concentrations of each VOC in the seven regional coffees were typically less than a factor of 2, yet concentrations patterns characteristic of the different regional coffees were revealed by heat map and principal component analyses. The coefficient of variation in the concentrations across the seven coffees was typically below 24% except for furfural, furan, methylfuran and guaiacol. CONCLUSIONS: The SIFT-MS analytical method can be used to quantify in real time the most important odoriferous VOCs in ground coffee headspace to sufficient precision to reveal some differences in concentration patterns for coffee produced in different countries. PMID- 29486531 TI - Establishment and identification of cell lines from type O blood Korean native pigs and their efficiency in supporting embryonic development via somatic cell nuclear transfer. AB - Due to their similarities with humans in anatomy, physiology, and genetics miniature pigs are becoming an attractive model for biomedical research. We aim to establish and evaluate blood type O cells derived from Korean native pig (KNP), a typical miniature pig breed in Korea. Ten cell lines derived from 8 KNP piglets and one adult female KNP (kidney and ear tissues) were established. To confirm the presence of blood type O, genomic DNA, fucosyltransferase (FUT) expression, and immunofluorescence staining were examined. Additionally, fluorescence-activated cell sorting and somatic cell nuclear transfer were performed to investigate the normality of the cell lines and to evaluate their effectiveness in embryo development. We found no significant bands corresponding to specific blood group A, and no increase in FUT expression in cell lines derived from piglets No. 1, No. 4, No. 5, No. 8, and the adult female KNP; moreover, they showed normal levels of expression of alpha 1,3 galactosyltransferase and cytidine monophosphate-N-acetylneuraminic acid hydroxylase. There was no significant difference in embryo development between skin and kidney fibroblasts derived from the blood type O KNPs. In conclusion, we successfully established blood type O KNP cell lines, which may serve as a useful model in xenotransplantation research. PMID- 29486532 TI - Ultrasonographic ovarian dynamic, plasma progesterone, and non-esterified fatty acids in lame postpartum dairy cows. AB - The objective of this study was to compare ovulation rate, number of large ovarian follicles, and concentrations of plasma progesterone (P4) and non esterified fatty acids (NEFA) between lame (n = 10) and non-lame (n = 10) lactating Holstein cows. The study was conducted in an organic dairy farm, and cows were evaluated by undertaking ultrasonography and blood sampling every 3 days from 30 days postpartum for a period of 34 days. Cows which became lame during the first 30 days postpartum experienced a lower ovulation rate determined by the presence of a corpus luteum (50% presence for lame cows and 100% for non lame cows, p <= 0.05). The number of large ovarian follicles in the ovaries was 5 for lame cows and 7 for non-lame cows (p = 0.09). Compared to non-lame cows, lame cows had significantly lower (p <= 0.05) concentrations of plasma P4. Furthermore, NEFA concentrations were lower (p <= 0.05) in lame cows than in non lame cows. It is concluded that lameness in postpartum dairy cows is associated with ovulation failure and lower concentrations of P4 and NEFA. PMID- 29486533 TI - Prevalence, toxin gene profile, antibiotic resistance, and molecular characterization of Clostridium perfringens from diarrheic and non-diarrheic dogs in Korea. AB - Clostridium perfringens causes diarrhea and other diseases in animals and humans. We investigated the prevalence, toxin gene profiles, and antibiotic resistance of C. perfringens isolated from diarrheic dogs (DD) and non-diarrheic dogs (ND) in two animal hospitals in Seoul, Korea. Fecal samples were collected from clinically DD (n = 49) and ND (n = 34). C. perfringens was isolated from 31 of 49 DD (63.3%) and 21 of 34 ND dogs (61.8%). All C. perfringens strains were positive for the alpha toxin gene, but not for the beta, epsilon, or iota toxin genes; therefore, all strains were identified as type A C. perfringens. All isolates were cpe-negative, whereas the beta2 toxin gene was identified in 83.9% and 61.9% of isolates from DD and ND, respectively. Most isolates were susceptible to ampicillin (94%), chloramphenicol (92%), metronidazole (100%), moxifloxacin (96%), and imipenem (100%). However, 25.0% and 21.2% of isolates were resistant to tetracycline and clindamycin, respectively. Molecular subtyping of the isolated strains was performed by using pulsed-field gel electrophoresis. Fifty two isolates were classified into 48 pulsotypes based on more than 90% similarity of banding patterns. No notable differences were observed among the isolates from DD and ND. PMID- 29486534 TI - Influence of bronchoalveolar lavage on thoracic radiography in the horse. AB - Bronchoalveolar lavage (BAL) and thoracic radiography are routinely performed diagnostic procedures. We hypothesized that BAL increases the interstitial opacity of caudoventral and caudodorsal thoracic radiographs. Fifty-three horses, including 8 clinic owned and 45 from a referral hospital population, were classified as healthy controls (n = 12), severe equine asthma (recurrent airway obstruction, n = 12) or mild-to-moderate equine asthma (inflammatory airway disease, n = 21) based on the results of a clinical scoring system. Eight were excluded due to different diagnoses and poor image quality. Four randomized thoracic radiographs of each horse were scored by two blinded observers, who were also asked to identify the image as obtained before or after a BAL procedure. In severe equine asthma, the chance (adjusted odds) of misinterpretation of the correct imaging time was approximately 5 times higher than in controls (odds ratio [OR] = 5.373, p = 0.028). The chance of misinterpretation was approximately 4 times lower in caudodorsal images than in caudoventral projections (OR = 0.241, p = 0.004). Identification of the correct imaging time was highly correlated with an increase in interstitial opacity (OR = 9.976, p < 0.0001). In conclusion, we recommend performing BAL after thoracic radiography to avoid possible misinterpretation. PMID- 29486535 TI - Phenotypic and genotypic analyses of an attenuated porcine reproductive and respiratory syndrome virus strain after serial passages in cultured porcine alveolar macrophages. AB - The porcine reproductive and respiratory syndrome virus (PRRSV) is a globally ubiquitous swine viral pathogen that causes major economic losses worldwide. We previously reported an over-attenuated phenotype of cell-adapted PRRSV strain CA 2-P100 in vivo. In the present study, CA-2-P100 was serially propagated in cultured porcine alveolar macrophage (PAM) cells for up to 20 passages to obtain the derivative strain CA-2-MP120. Animal inoculation studies revealed that both CA-2-P100 and CA-2-MP120 had decreased virulence, eliciting weight gains, body temperatures, and histopathologic lesions similar to those in the negative control group. However, compared to CA-2-P100 infection, CA-2-MP120 yielded consistently higher viremia kinetics and enhanced antibody responses in pigs. All pigs inoculated with CA-2-MP120 developed viremia and seroconverted to PRRSV. During 20 passages in PAM cells, CA-2-MP120 acquired 15 amino acid changes that were mostly distributed in nsp2 and minor structural protein-coding regions. Among these changes, 6 mutations represented reversions to the sequences of the reference CA-2 and parental CA-2-P20 strains. These genetic drifts may be hypothetical molecular markers associated with PRRSV macrophage tropism and virulence. Our results indicate that the PAM-passaged CA-2-MP120 strain is a potential candidate for developing a live, attenuated PRRSV vaccine. PMID- 29486536 TI - Non-invasive quantification of hepatic fat content in healthy dogs by using proton magnetic resonance spectroscopy and dual gradient echo magnetic resonance imaging. AB - The objective of the present study was to describe two non-invasive methods for fat quantification in normal canine liver by using magnetic resonance imaging (MRI) and spectroscopy. Eleven adult beagle dogs were anesthetized and underwent magnetic resonance examination of the cranial abdomen by performing morphologic, modified Dixon (mDixon) dual gradient echo sequence, and proton magnetic resonance spectroscopy (1H MRS) imaging. In addition, ultrasonographic liver examination was performed, fine-needle liver aspirates and liver biopsies were obtained, and hepatic triglyceride content was assayed. Ultrasonographic, cytologic, and histologic examination results were unremarkable in all cases. The median hepatic fat fraction calculated was 2.1% (range, 1.3%-5.5%) using mDixon, 0.3% (range, 0.1%-1.0%) using 1H MRS, and 1.6% (range 1.0%-2.5%) based on triglyceride content. The hepatic fat fractions calculated using mDixon and 1H MRS imaging were highly correlated to that based on triglyceride content. A weak correlation between mDixon and 1H MRS imaging was detected. The results show that hepatic fat content can be estimated using non-invasive techniques (mDixon or 1H MRS) in healthy dogs. Further studies are warranted to evaluate the use of these techniques in dogs with varying hepatic fat content and different hepatic disorders. PMID- 29486537 TI - Porcine intestinal lymphoid tissues synthesize estradiol. AB - Estradiol (17beta-estradiol) is synthesized primarily in the gonads of both sexes and regulates the development and function of reproductive organs. Recently, we reported that intestinal lymphocyte homeostasis is regulated by estradiol synthesized de novo in the endothelial cells of the high endothelial venules (HEVs) of mesenteric lymph nodes and Peyer's patches in mice. This observation prompted us to hypothesize that HEVs of intestinal lymphoid tissues are sites of estradiol synthesis across species. In this study, we examined whether estradiol is synthesized in the intestinal lymphoid tissues of adolescent piglets. Comparisons of estradiol levels in blood and tissue showed that estradiol concentrations in mesenteric lymph nodes and Peyer's patches were significantly higher than the level in serum. Reverse transcription polymerase chain reaction showed that porcine intestinal lymphoid tissues express mRNAs for steroidogenic enzymes (StAR, 17beta-Hsd,3beta-Hsd, Cyp17a1, and Cyp19a1), and immunohistochemical results in ilial tissue showed expression of aromatase (CYP19) in Peyer's patch-localized endothelial cells of HEVs. When mesenteric lymph node and Peyer's patch tissues were cultured in vitro, they produced estradiol. Taken together, the results indicate that mesenteric lymph nodes and Peyer's patches are sites of estradiol synthesis in adolescent piglets. PMID- 29486538 TI - Hepatobiliary diseases in buffalo (Bubalus bubalis): clinical, laboratory, and ultrasonographic findings. AB - This study describes ultrasonographic observations of five hepatobiliary diseases in buffalo (Bubalus bubalis). Fifty buffalo, including 20 clinically normal and 30 hepatobiliary diseased buffalo were enrolled in the study. Complete clinical, radiographic and ultrasonographic examinations and laboratory analyses were conducted. Focal parenchymal lesions including liver abscess (n = 12) and hepatic cyst (n = 6), diffuse parenchymal lesion (hepatobiliary cirrhosis, n = 5) and obstruction of hepatobiliary passages including cholestasis (n = 4), and hepatocholelithiasis (n = 3) were successfully imaged by ultrasonography. Hepatic abscess imaged as a hypoechoic to echogenic circumscribed mass of various diameters with a distinct echogenic capsule. Hepatic cyst imaged as a pear-shaped sac with a bright echogenic margin, anechoic content, and distal acoustic enhancement. In hepatobiliary fibrosis, the liver showed linear bands of increasing echogenicity with less distinct imaging of the portal vasculature. Cholestasis was imaged as dilatation of the gallbladder (GB) with wall thickening and homogeneous or heterogeneous contents. Hepatocholelithiasis imaged as an echoic structure within the hepatic parenchyma, or within and around the GB and bile duct, with more echogenicity of the hepatic parenchyma than normal. Ultrasonography can be an efficient rapid, noninvasive tool for screening of common hepatobiliary diseases in buffalo under field conditions. PMID- 29486539 TI - Changes in hoof kinetics and kinematics at walk in response to hoof trimming: pressure plate assessment. AB - Appropriate hoof preparation and symmetry are linked to the well-being of the horse. Previous studies have shown the efficacy of pressure plates (PPs) in delivering objective biomechanical analysis. We aimed to assess the effect of hoof trimming on hoof biomechanics using a PP. Nine clinically sound Arabian horses were walked across a PP while foot strike was recorded by a digital camera. Kinetic and kinematic parameters were recorded before and after trimming. Changes were considered significant when p < 0.05. Vertical force (p = 0.026) and contact pressure (p = 0.006) increased after trimming. Stance-phase duration (p = 0.006), swing-phase duration (p = 0.023), and gait-cycle duration (p = 0.007) decreased significantly post-trimming. The observed changes in kinetic and kinematic parameters were related to hoof trimming. The reported results underline the importance of farriery practice and its effect on hoof biomechanics, which should be considered by both farriers and veterinarians. PMID- 29486540 TI - Comparison of Treatment Outcomes for T3 Glottic Squamous Cell Carcinoma: A Meta Analysis. AB - OBJECTIVES: This study compared the survival outcomes, local control rate, and laryngeal preservation rate of various treatment strategies in the treatment of T3 squamous cell carcinoma of the glottis using proportional meta-analyses. METHODS: Twenty-five retrospective case-series studies were included in these analyses. Treatment strategies were classified as total laryngectomy (TL), open partial laryngectomy (PL), transoral laser microsurgery (TLM), chemo-radiation therapy (CRT), and radiation therapy (RT) alone. RESULTS: The overall survival rate and disease-specific survival rate among laryngeal preservation treatments did not differ from the overall survival rate of TL. However, the local control rate was lower with RT than TL and PL, and laryngeal preservation rates of TLM and CRT were higher than RT alone. CONCLUSION: Consideration of preservation of laryngeal function is necessary when treating T3 glottic squamous cell carcinoma. PL, TLM, and, CRT are considered more appropriate initial laryngeal preservation strategies if available. PMID- 29486541 TI - Efficacy of Tympanoplasty Without Mastoidectomy for Treating Chronic Otitis Media in Patients With Mastoid Cavity Opacification in Temporal Bone Computed Tomography Findings. AB - OBJECTIVES: Combined mastoidectomy is generally preferred to tympanoplasty alone when treating patients with chronic otitis media (COM), particularly when temporal bone computed tomography (TBCT) shows that the mastoid cavity contains opacification of soft tissue density. However, in cases with Eustachian tube dysfunction, a mastoid cavity volume may be a burden to its function. We hypothesized that tympanoplasty alone might be better than tympanoplasty combined with mastoidectomy because soft tissue in the mastoid cavity is a sequel to a protective physiological response. Thus, we explored the efficacy of tympanoplasty without mastoidectomy in COM patients exhibiting mastoid air cell opacification on TBCT. METHODS: Between 2010 and 2014, a total of 33 patients, diagnosed with COM and with evidence of mastoid cavity opacification on TBCT, underwent tympanoplasty without mastoidectomy. All ears had been dry for >=3 months before surgery. All procedures were performed by the same surgeon. We retrospectively analyzed the preoperative otoscopic findings, pre- and postoperative pure tone averages (PTAs; the mean of the values at 0.5, 1, 2, and 4 kHz), surgical procedures, and complications or recurrence. RESULTS: Of the 33 patients, 28 (84.8%) exhibited hearing improvement after surgery. The mean pre- and postoperative PTAs were 46.9+/-21.2 dB and 29.4+/-17.0 dB, respectively (P<0.001). The air-bone gap decreased from 25.7+/-10.7 dB to 10.3+/-8.7 dB (P<0.001). Thirty-two patients (97.0%) did not develop any COM recurrence or cholesteatoma; one patient developed attic retraction of the tympanic membrane. Other minor complications were transient otorrhea caused by myringitis (two cases) and a pinpoint perforation (one case). CONCLUSION: Tympanoplasty alone, i.e., without mastoidectomy, may adequately control COM, if it shows dry-up status for at least 3 months even though mastoid cavity opacification is detected in TBCT. PMID- 29486542 TI - Association of Body Mass Index with Suicide Behaviors, Perceived Stress, and Life Dissatisfaction in the Korean General Population. AB - OBJECTIVE: The purpose of the present study was to investigate the association between Body Mass Index, suicide, perceived stress, and life dissatisfaction in a general population sample of Korean adults. METHODS: A total of 6,022 nationally representative adults aged 18 to 74 were selected using a multistage cross sectional cluster sampling method. Questionnaires regarding suicide behaviors, perceived stress, and life satisfaction were completed by the participants. They also reported their heights and weights, which were used to calculate BMI. Psychiatric disorders were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, using the Korean version of the Composite International Diagnostic Interview. RESULTS: The results showed that being underweight was associated with higher risk for suicide ideation [odds ratio (OR), 1.6; 95% confidence interval (Cl), 1.18-2.05] and suicide attempt (OR, 2.0, 95% Cl, 1.23-3.31). Likewise, obesity also increased the risk of suicide ideation (OR, 1.3; 95% Cl, 1.11-1.56) although not suicide attempt. Furthermore, underweight individuals were more likely to report severe level of perceived stress (OR, 1.7; 95% Cl, 1.26-2.17) and life dissatisfaction (OR, 1.3; 95% Cl, 1.07-1.68). All of the results remained significant after adjusting for age, gender, education, and psychiatric illnesses. CONCLUSION: This study found that being underweight is a significant risk factor for suicide and poor subjective wellbeing in Korea. It suggests that BMI status may be an important modifiable factor for improving mental health in Korea. PMID- 29486543 TI - Clinical Utility of the Korean Version of the WHO Adult Attention Deficit/Hyperactivity Disorder Self-Report Scale Screener. AB - OBJECTIVE: The aim of this study was to compare the performance of the 18-item Korean version of the World Health Organization adult attention deficit/hyperactivity disorder self-report scale (ASRS) with the six-item ASRS Screener for predicting attention-deficit/hyperactivity disorder (ADHD) group. METHODS: The study sample included 51 adult patients with ADHD and 158 normal controls. All participants completed the ASRS and were interviewed individually using the Mini-International Neuropsychiatric Interview. Receiver operating characteristic (ROC) curves were used to compare the ASRS (ASRS-18) with the ASRS Screener (ASRS-6) in Korean samples. RESULTS: The ADHD group had higher ASRS and ASRS subscale scores than those of the control group. ROC curve analysis revealed the ASRS was more powerful to predict ADHD group than the ASRS Screener, but the ASRS Screener also had strong concordance with clinician diagnoses. CONCLUSION: This study shows that the 18-question ASRS outperforms the six-question ASRS Screener. However, the weighted Screener is also a valid and useful screening instrument both in epidemiological surveys and in clinical settings. PMID- 29486544 TI - Effects of Cognitive-Behavioral Therapy on Empathy in Patients with Chronic Pain. AB - OBJECTIVE: Cognitive-behavioral therapy (CBT) is effective in patients with chronic pain. However, the efficacy of CBT for impaired empathy has not been studied in this population. We investigated the effect of CBT on empathy in patients with chronic pain. METHODS: Patients with severe chronic pain were recruited. Empathy was assessed before and after CBT using the Interpersonal Reactivity Index (IRI). The patients underwent eight sessions over the course of 1 month conducted. Additional symptoms were assessed using the Short-Form McGill Pain Questionnaire (SF-MPQ), Beck Depression Inventory, Beck Anxiety Inventory, World Health Organization Quality of Life Scale Abbreviated Version, and the Scale for Suicide Ideation. RESULTS: A total of 26 participants were included. Pre-CBT pain severity assessed using the SF-MPQ was significantly correlated with the IRI-empathic concern subscale score (p=0.021), and the relationship remained significant after adjusting for sex, age, education level, and marital status. After CBT, the IRI-perspective-taking subscale scores (p=0.004) increased significantly and the IRI-personal distress subscale scores (p=0.013) decreased significantly in all participants. The SF-MPQ scores increased significantly (p=0.021). CONCLUSION: CBT improved empathy in patients with chronic pain independent of its effect on pain, suggesting that CBT is useful for improving interpersonal relationships in patients with chronic pain. PMID- 29486545 TI - The Alpha-2A Adrenergic Receptor Gene -1291C/G Single Nucleotide Polymorphism is Associated with the Efficacy of Methylphenidate in Treating Taiwanese Children and Adolescents with Attention-Deficit Hyperactivity Disorder. AB - OBJECTIVE: The therapeutic effect of methylphenidate (MPH) in treating attention deficit/hyperactivity disorder (ADHD) has been related to the alpha-2A adrenergic receptor (ADRA2A) gene -1291C/G single nucleotide polymorphism (SNP). We investigated the effect of MPH in treating Taiwanese children and adolescent with ADHD and its relation to the ADRA2A gene -1291C/G SNP. METHODS: The subjects with DSM-IV ADHD diagnosis underwent a titration period to find out the dose of MPH for maintenance treatment. After 4 weeks maintenance treatment, the effect of MPH was evaluated by the Swanson, Nolan and Pelham version IV total scores. The subjects with more than 25% score reduction were referred to responders and those with >=50% improvement were considered as better responders. The -1291C/G variant of the ADRA2A gene was identified by DNA sequencing and what relevance it has to the MPH response was examined by binary logistic regression analysis. RESULTS: Of the 59 subjects, 44 (74.6%) were responsive to MPH treatment and the responsiveness was not shown to be associated with the ADRA2A gene -1291C/G SNP. As the responsive subjects were categorized as moderate responders and better responders and subjected to statistical analysis, the GG homozygotes showed a greater chance to have a better response to MPH treatment than CC homozygotes (p=0.02), with an odds ratio of 32.14 (95% CI=1.64-627.80). CONCLUSION: The ADRA2A gene -1291C/G SNP is associated with the efficacy of MPH for the treatment of ADHD in Taiwanese children and adolescents. The responsive subjects bearing homozygous -1291G allele are more likely to have a better response to MPH treatment. PMID- 29486546 TI - Impaired White Matter Integrity and Social Cognition in High-Function Autism: Diffusion Tensor Imaging Study. AB - OBJECTIVE: It is known that many of the cognitive and social deficits associated with autism can arise from abnormal functional connectivity between brain networks. This aberrant functional connectivity in autism spectrum disorders (ASD) can be explained by impaired integrity of white matter tracts that link distant regions of the networks. METHODS: We investigated white matter in 9 children with high-function autism (HFA) compared to 13 typically developing controls using diffusion tensor imaging (DTI). The aim of this research is to provide supporting evidence for abnormalities in neural connectivity as an underlying pathophysiology of the main characteristics of ASD. RESULTS: We found impairment of neural connectivity, mainly in association fiber tracts as evidenced by decreased fractional anisotropy (FA), the index of white matter integrity, of these tracts. Among them, inferior fronto-occipital fasciculus (IFOF) had a significant relationship with ADI-R score. The inferior longitudinal fasciculus (ILF) and superior longitudinal fasciculus (SLF) also showed decreased FA. Decreased FA of ILF and SLF had negative correlations with scores of social interaction. CONCLUSION: These findings suggest that widespread abnormalities in association fiber tracts may contribute to both core and associated symptoms of ASD. PMID- 29486547 TI - Stress and Heart Rate Variability: A Meta-Analysis and Review of the Literature. AB - OBJECTIVE: Physical or mental imbalance caused by harmful stimuli can induce stress to maintain homeostasis. During chronic stress, the sympathetic nervous system is hyperactivated, causing physical, psychological, and behavioral abnormalities. At present, there is no accepted standard for stress evaluation. This review aimed to survey studies providing a rationale for selecting heart rate variability (HRV) as a psychological stress indicator. METHODS: Term searches in the Web of Science(r), National Library of Medicine (PubMed), and Google Scholar databases yielded 37 publications meeting our criteria. The inclusion criteria were involvement of human participants, HRV as an objective psychological stress measure, and measured HRV reactivity. RESULTS: In most studies, HRV variables changed in response to stress induced by various methods. The most frequently reported factor associated with variation in HRV variables was low parasympathetic activity, which is characterized by a decrease in the high-frequency band and an increase in the low-frequency band. Neuroimaging studies suggested that HRV may be linked to cortical regions (e.g., the ventromedial prefrontal cortex) that are involved in stressful situation appraisal. CONCLUSION: In conclusion, the current neurobiological evidence suggests that HRV is impacted by stress and supports its use for the objective assessment of psychological health and stress. PMID- 29486548 TI - Symptom Persistence after Iron Normalization in Women with Restless Legs Syndrome. AB - OBJECTIVE: The aim of this study was to determine the clinical course of restless legs syndrome (RLS) and potential risk factors for the persistence of RLS symptoms after iron normalization in women with RLS and low serum ferritin (<50 MUg/L). METHODS: We reviewed 39 women with RLS and iron deficiency, who achieved iron normalization after oral iron replacement for three months. Risk factors contributing to symptom persistence were estimated by logistic regression analyses. Remission was defined as no RLS symptoms for at least 6 months after the iron normalization. RESULTS: Over the observation period of 2.5+/-1.4 years, 15 patients reported no RLS symptom whereas 24 patients still complained of RLS symptoms. The remission rate of RLS with iron replacement was 38.5%. The relative risk of symptom persistence was increased by the duration of RLS symptoms (OR: 1.88, 95% CI: 1.01-3.49) or by the age at RLS diagnosis (OR: 1.25, 95% CI: 1.01 1.56). CONCLUSION: Almost two-third of RLS patients with iron deficiency showed persistence of the symptom even after iron normalization. Considering that longer duration of RLS symptoms and older age at RLS diagnosis were risk factors for symptom persistence, early intervention of iron deficiency in RLS is warranted. PMID- 29486549 TI - Association Between Vitamin D Insufficiency and Metabolic Syndrome in Patients With Psychotic Disorders. AB - OBJECTIVE: This study examined the association between vitamin D and metabolic syndrome in patients with psychotic disorders. METHODS: The study enrolled 302 community-dwelling patients with psychotic disorders. Sociodemographic and clinical characteristics, including blood pressure, physical activity, and dietary habit were gathered. Laboratory examinations included vitamin D, lipid profile, fasting plasma glucose, HbA1c, liver function, and renal function. Vitamin D insufficiency was defined as <20 ng/mL. Clinical characteristics associated with vitamin D insufficiency were identified. RESULTS: Among the 302 participants, 236 patients (78.1%) had a vitamin D insufficiency and 97 (32.1%) had metabolic syndrome. Vitamin D insufficiency was significantly associated with the presence of metabolic syndrome (p=0.006) and hypertension (p=0.017). Significant increases in triglycerides and alanine transaminase were observed in the group with a vitamin D insufficiency (p=0.002 and 0.011, respectively). After adjusting for physical activity and dietary habit scores, vitamin D insufficiency remained significantly associated with metabolic syndrome and hypertension. CONCLUSION: Vitamin D insufficiency was associated with metabolic syndrome and was particularly associated with high blood pressure, although the nature, direction and implications of this association are unclear. PMID- 29486550 TI - Can Residual Symptoms During Inter-Episode Period after Partial Remission in Bipolar I Disorder Have Cyclic Patterns with Specific Frequencies? AB - This case report aimed to describe cyclic patterns of residual mood symptoms in partially remitted bipolar I patient. In a 24-year-old woman with bipolar I disorder, residual mood symptoms measured by self-rated daily mood chart for 18 months were analyzed using wavelet analysis. A 146-day periodicity was prominent for the first 100 days after discharge. Between 100-200 days, 146-day periodicity was progressively diminished and 21- and 8-day periodicity was prominent. Between 200-516 days, 21-day periodicity was diminished and 85-day periodicity became prominent. This case suggest that bipolar patients might have cyclic residual symptoms with specific frequencies. PMID- 29486551 TI - A Comparative Study of Suicide Rates among 10-19-Year-Olds in 29 OECD Countries. AB - OBJECTIVE: This study had two main objectives: to compare current suicide rates in OECD countries among 10-19-year-olds and to identify patterns of suicide rates based on age, gender and time. Furthermore we investigated the main dimensions that contributed to the variation in child and adolescent suicide rates across countries. METHODS: We combined the WHO mortality data and the population data released by OECD to calculate the suicide rates in 29 OECD countries. A self organizing map (SOM), k-means clustering analysis, and multi-dimensional scaling were used to classify countries based on similarities in suicide rate structure and to identify the important dimensions accounting for differences among groups. RESULTS: We identified significant differences in suicide rates depending on age, sex, country, and time period. Late adolescence and male gender were universal risk factors for suicide, and we observed a general trend of declining suicide rates in OECD countries. The SOM analysis yielded eight types of countries. Most countries showed gender gaps in suicide rates of similar magnitudes; however, there were outliers in which the gender gap was particularly large or small. CONCLUSION: Significant variation exists with respect to suicide rates and their associated gender gaps in OECD countries. PMID- 29486552 TI - Social Security Is Fair to All Generations: Demystifying the Trust Fund, Solvency, and the Promise to Younger Americans. AB - The Social Security system has come under attack for having illegitimately transferred wealth from younger generations to the Baby Boomgeneration. This attack is unfounded, because it fails to understand how the system was altered in order to force the Baby Boomers to financetheir own benefits in retirement. Any challenges that Social Security now faces are not caused by the pay-as-you-go structure of the system but byBaby Boomers' other policy errors, especially the emergence of extreme economic inequality since 1980. Attempting to fix the wrong problem allbut guarantees a solution that will make matters worse. Generational justice and distributive justice go hand in hand. PMID- 29486553 TI - Interrogated with Intellectual Disabilities: The Risks of False Confession. AB - False confessions happen. At least 245 people have been exonerated from convictions in cases featuring confessions that were simply not true. Confessions offer a narrative that allows law enforcement, and society in general, to neatly resolve cases with apparent clarity and closure. And yet the pressures officers place on suspects to provide that closure weigh disproportionately on the vulnerable, including individuals with intellectual disabilities. These individuals are disadvantaged at every step of the custodial interrogation, and they face heightened risks of falsely confessing. Moreover, the principal judicial safeguards against false confessions--assessing a suspect's Miranda waiver and determining whether a confession was voluntarily given within the bounds of the Fourteenth Amendment's Due Process Clause--provide little protection for the innocent with intellectual disabilities. Few pieces of scholarship focus specifically on the heightened risks faced by individuals with intellectual disabilities throughout the process of police interrogation. This Note describes the various ways these individuals are disadvantaged. And it offers an additional data point illustrating the vulnerability of people with intellectual disabilities. This Note analyzes the 245 individuals (as of June 2, 2017) on the National Registry of Exonerations who have falsely confessed. Over one-quarter of them display indicia of intellectual disability. This percentage dwarfs the prevalence of people with intellectual disabilities in the general population and even exceeds most estimates of the proportion of the prison population suffering from intellectual disabilities. This Note concludes with several policy and doctrinal suggestions to better protect individuals with intellectual disabilities from the risks of false confession. PMID- 29486554 TI - Juice Test for Identification of Nonerosive Reflux Disease in Heartburn Patients. AB - Background/Aims: Evaluation of esophageal clearance by orange juice swallowing could be useful to identify different categories of gastroesophageal reflux disease. We determined whether a juice test at the beginning of esophageal pH monitoring can identify nonerosive reflux disease (NERD) among heartburn patients. Methods: Multiple swallows of orange juice (pH 3) were performed at the beginning of esophageal pH monitoring in 71 heartburn patients off acid suppressive therapy. The area between pH drop below 5 and recovery to 5 was calculated from pH tracings and named Delta5 (mmol?L-1?sec). Fifteen healthy subjects served to determine Delta5 cutoff (95th percentile). Patients were classified as NERD, non-NERD (a mix of reflux hypersensitivity, functional heartburn, and undetermined), and erosive disease depending on acid exposure, reflux symptom analysis, and upper endoscopy. Results: Delta5 cutoff in healthy subjects was 251 mmol.L-1?sec. Among 71 patients, 23 had NERD, 26 had non-NERD, and 22 had erosive disease. Compared to non-NERD, Delta5 was higher in both NERD (median [interquartile range]: 316 [213-472] vs 165 [105-225]; P < 0.01) and erosive disease (310 [169-625] vs 165 [105-225]; P < 0.01). An elevated Delta5 (> 251 mmol?L-1?sec) showed sensitivity of 74% and specificity of 81% for identification of NERD. Positive and negative likelihood ratios were 3.84 and 0.32 respectively, whereas test accuracy was 78%. Conclusions: A juice test with calculation of Delta5 helps in the identification of true NERD among heartburn patients with endoscopy-negative reflux disease. In these patients, an elevated Delta5 could make prolonged reflux testing unnecessary. PMID- 29486555 TI - Muscarinic M1 Receptor Modulation of Synaptic Plasticity in Nucleus Accumbens of Wild-Type and Fragile X Mice. AB - We investigated how metabotropic acetylcholine receptors control excitatory synaptic plasticity in the mouse nucleus accumbens core. Pharmacological and genetic approaches revealed that M1 mAChRs (muscarinic acetylcholine receptors) trigger multiple and interacting forms of synaptic plasticity. As previously described in the dorsal striatum, moderate pharmacological activation of M1 mAChR potentiated postsynaptic NMDARs. The M1-potentiation of NMDAR masked a previously unknown coincident TRPV1-mediated long-term depression (LTD). In addition, strong pharmacological activation of M1 mAChR induced canonical retrograde LTD, mediated by presynaptic CB1R. In the fmr1-/y mouse model of Fragile X, we found that CB1R but not TRPV1 M1-LTD was impaired. Finally, pharmacological blockade of the degradation of anandamide and 2-arachidonylglycerol, the two principal endocannabinoids restored fmr1-/y LTD to wild-type levels. These findings shed new light on the complex influence of acetylcholine on excitatory synapses in the nucleus accumbens core and identify new substrates of the synaptic deficits of Fragile X. PMID- 29486556 TI - Preparation and Properties of Asymmetric Synthetic Membranes Based on Lipid and Polymer Self-Assembly. AB - Cell membrane asymmetry is a common structural feature of all biological cells. Researchers have tried for decades to better study its formation and its function in membrane-regulated phenomena. In particular, there has been increasing interest in developing synthetic asymmetric membrane models in the laboratory, with the aim of studying basic physical chemistry properties that may be correlated to a relevant biological function. The present article aims to summarize the main presented approaches to prepare asymmetric membranes, which are most often made from lipids, polymers, or a combination of both. PMID- 29486557 TI - Dual Functions of Lip6 and Its Regulation of Lipid Metabolism in the Oleaginous Fungus Mucor circinelloides. AB - Although multiple roles of lipases have been reported in yeasts and microalgae, the functions of lipases have not been studied in oleaginous filamentous fungi. Lipase Lip6 has been reported in the oleaginous filamentous fungus Mucor circinelloides with the consensus lipase motif GXSXG and the typical acyltransferase motif of H-(X)4-D. To demonstrate that Lip6 might play dual roles as a lipase and an acyltransferase, we performed site-directed mutagenesis in the lipase motif and the acyltransferase motif of Lip6. Mutation in the lipase motif increased cell biomass by 12%-18% and promoted lipid accumulation by 9%-24%, while mutation in the acyltransferase motif induced lipid degradation. In vitro, purified Lip6 had a slight lipase activity but had a stronger phospholipid:DAG acyltransferase activity. Enzyme activity assays in vivo and phospholipid synthesis pathway analysis suggested that phosphatidyl serine and phosphatidyl ethanolamine can be the supplier of a fatty acyl moiety to form TAG in M. circinelloides. PMID- 29486558 TI - Inverse Design of Self-Assembling Frank-Kasper Phases and Insights Into Emergent Quasicrystals. AB - We discuss how a machine learning approach based on relative entropy optimization can be used as an inverse design strategy to discover isotropic pair interactions that self-assemble single- or multicomponent particle systems into Frank-Kasper phases. In doing so, we also gain insights into the self-assembly of quasicrystals. PMID- 29486559 TI - Binding Modes of Ligands Using Enhanced Sampling (BLUES): Rapid Decorrelation of Ligand Binding Modes via Nonequilibrium Candidate Monte Carlo. AB - Accurately predicting protein-ligand binding affinities and binding modes is a major goal in computational chemistry, but even the prediction of ligand binding modes in proteins poses major challenges. Here, we focus on solving the binding mode prediction problem for rigid fragments. That is, we focus on computing the dominant placement, conformation, and orientations of a relatively rigid, fragment-like ligand in a receptor, and the populations of the multiple binding modes which may be relevant. This problem is important in its own right, but is even more timely given the recent success of alchemical free energy calculations. Alchemical calculations are increasingly used to predict binding free energies of ligands to receptors. However, the accuracy of these calculations is dependent on proper sampling of the relevant ligand binding modes. Unfortunately, ligand binding modes may often be uncertain, hard to predict, and/or slow to interconvert on simulation time scales, so proper sampling with current techniques can require prohibitively long simulations. We need new methods which dramatically improve sampling of ligand binding modes. Here, we develop and apply a nonequilibrium candidate Monte Carlo (NCMC) method to improve sampling of ligand binding modes. In this technique, the ligand is rotated and subsequently allowed to relax in its new position through alchemical perturbation before accepting or rejecting the rotation and relaxation as a nonequilibrium Monte Carlo move. When applied to a T4 lysozyme model binding system, this NCMC method shows over 2 orders of magnitude improvement in binding mode sampling efficiency compared to a brute force molecular dynamics simulation. This is a first step toward applying this methodology to pharmaceutically relevant binding of fragments and, eventually, drug-like molecules. We are making this approach available via our new Binding modes of ligands using enhanced sampling (BLUES) package which is freely available on GitHub. PMID- 29486560 TI - Analyzing the Wave Nature of Hot Electrons with a Molecular Nanoprobe. AB - We report on a novel method, the molecular nanoprobe (MONA) technique, which allows us to measure the nanoscale quasiparticle transport between two arbitrary surface points. In these experiments, hot electrons are injected into the sample surface from the probe tip of a scanning tunneling microscope (STM) and detected by tautomerization switching events of a single deprotonated phthalocyanine (H2Pc) molecule. By making use of atom-by-atom-engineered interferometers on a Ag(111) surface, we demonstrate that the quantum-mechanical wave nature of hot electrons leads to characteristic oscillations of the molecule tautomerization probability. Two interferometers can be combined to build an energy-dependent selector, which allows it to selectively switch one out of two molecules without changing the position of the STM tip. The MONA technique is compared with conventional d I/d U measurements, where the injection and detection point of hot electrons is intrinsically tied to the same tip location. PMID- 29486561 TI - Theory of Sequence Effects in Amyloid Aggregation. AB - We present a simple model for the effect of amino acid sequences on amyloid fibril formation. Using the HP model we find the binding lifetimes of four simple sequences by solving the first passage time for the intermolecular H-bond reaction coordinate. We find that sequences with identical binding energies have widely varying binding times depending on where the aggregation prone amino acids are located in the sequence. In general, longer binding times occur when the aggregation prone amino acids are clustered in a single "hot spot". Similarly, binding times are shortened by clustering weakly bound residues. Both of these effects are explained by an increase in the multiplicity of unbinding trajectories that comes from adding weak binding residues. Our model predicts a transition from ordered to disordered fibrils as the concentration of monomers increases. We apply our model to Abeta, IAPP, and apomyoglobin using binding energy estimates derived from bioinformatics. We find that these sequences are highly selective of the in-register state. This selectivity arises from the having strongly bound segments of varying length and separation. PMID- 29486563 TI - Annual Editorial for Chemical Reviews. PMID- 29486562 TI - Polymer-Lipid Microparticles for Pulmonary Delivery. AB - Toward engineering approaches that are designed to optimize the particle size, morphology, and mucoadhesion behavior of the particulate component of inhaler formulations, this paper presents the preparation, physicochemical characterization, and preliminary in vitro evaluation of multicomponent polymer lipid systems that are based on "spray-drying engineered" alpha-lactose monohydrate microparticles. The formulations combine an active (budesonide) with a lung surfactant (dipalmitoylphosphatidylcholine) and with materials that are known for their desirable effects on morphology (polyvinyl alcohol), aerosolization (l-leucine), and mucoadhesion (chitosan). The effect of the composition of formulations on the morphology, distribution, and in vitro mucoadhesion profiles is presented along with "Calu-3 cell monolayers" data that indicate good cytocompatibility and also with simulated-lung-fluid data that are consistent with the therapeutically useful release of budesonide. PMID- 29486565 TI - Probing Liquid-Solid and Vapor-Liquid-Solid Interfaces of Hierarchical Surfaces Using High-Resolution Microscopy. AB - Liquid-solid (LS) and vapor-liquid-solid (VLS) interfaces are important for the fundamental understanding of how surface chemistry impacts industrial processes and applications. Superhydrophobic surfaces, from structural hierarchies, were fabricated by coating flat smooth surfaces with hollow glass microspheres. These surfaces are referred to as structural hierarchical-modified microsphere surfaces (SHiMMs). Two-phase LS and three-phase VLS interfaces of water droplets on SHiMMs, with an apparent static contact angle (aSCA) of ~160 degrees , were probed at microscale using environmental scanning electron microscopy (ESEM) and high-resolution optical microscopy (OM). Both ESEM and OM confirmed the presence of air pockets in 3-150 MUm range at the VLS triple-phase of the droplet peripheral contact line. The wetting characteristics of the LS interface in the interior of the water droplet were probed using energy-dispersive spectroscopy, which corroborated well with the VLS triple-phase observations, confirming the presence of both the microscale air pockets and fractional complete wetting of the SHiMMs. The superhydrophobic water droplets on the SHiMMs also exhibited relatively high adhesion to the SHiMMs-a tilt angle of 10 degrees -40 degrees was needed for detaching the droplets off the surfaces. Semiquantitative three phase contact-line analysis and experimental data indicated high-water aSCA, and large adhesion on the microscale-roughened SHiMMs is attributed to pinning of the probe liquid both at the triple VLS and interior LS interfaces. The control over microroughness and surface chemistry of the SHiMMs will allow tuning of both the static and dynamic liquid-surface interactions. PMID- 29486567 TI - Role of immune checkpoint inhibitors and novel immunotherapies in uveal melanoma. AB - Uveal melanoma (UM) is one of the rare malignancies, which can be lethal despite local treatment. Treatment options available now can control UM in early stages, but once it metastasized to distant organs especially liver, prognosis is poor. Immune checkpoint inhibitors (ICIs) are the new revolutionary treatment in management of metastatic cutaneous melanoma. UM and cutaneous melanoma are similar as both of them derived from melanocytes but in terms of mutational load and expression of antigens they are distinct. In most of clinical trials of melanoma, UM patients were excluded and up till now there are only few studies regarding role of ICIs in metastatic UM. Most of these studies showed poor outcome and low survival benefit. Currently, research is going on combinational therapies and novel immunotherapy options. Here in this article we will discuss results of studies regarding ICIs in UM, ongoing trials and new immunotherapeutic options of UM. PMID- 29486566 TI - Pancreaticoduodenectomy with en bloc vein resection for locally advanced pancreatic cancer: a case series without venous reconstruction. AB - Resection with clean margin (R0 resection) is associated with better survival in patients with pancreatic cancer. Over the last decade, advancements in preoperative chemotherapy and radiation therapy in pancreatic cancer have led to expansion of indications for surgical resection. Current guidelines define pancreatic cancer with unreconstructable vascular involvement as locally advanced, or surgically unresectable. We present our experience in managing patients with locally advanced pancreatic cancer with a very unique series of patients who achieved R0 resection despite "unresectable" vascular involvement. Additionally, we review current guidelines, the ability to predict venous resection by imaging, outcomes after venous resection and reconstruction, published patency rates of venous reconstructions, and potential future implications of this novel technique. PMID- 29486568 TI - Comprehensive clinical genetics care for patients with inherited colorectal cancer associated with Lynch syndrome: Western and Asian perspectives. AB - Lynch syndrome (LS) arises from germline mutations that lead to defective functioning of the DNA mismatch repair (MMR) system. It is the most common cause of inherited colorectal cancer (CRC), and predisposes individuals to significantly elevated risks for extracolonic cancers. A sensitive and accurate diagnostic approach will enable proactive management of the proband and at-risk relatives in order to minimize their cancer burden. Comprehensive clinical genetics care should include personalized and tailored multidisciplinary oncologic care, with consideration for the extent of surgical resection, the choice of systemic agents, and the use of radiation. Preventive strategies including lifelong multi-organ surveillance, testing of family members, prophylactic-intent surgery and chemoprevention should be considered. In this review, we aim to provide an update on the diagnostic approach to LS, and to summarize key components of comprehensive clinical genetics care, through an examination of existing data and guidelines from Asian and from Western perspectives. PMID- 29486569 TI - "Cor Occidere": a novel strategy of targeting the tumor core by radiosurgery in a radio- and chemo-resistant intracranial hemangiopericytoma. AB - Intracranial hemangiopericytomas (HPC) are chemotherapy- and radiotherapy (RT) resistant. Here, we report on a novel stereotactic radiosurgery (SRS) technique "Cor Occidere" (Latin), as a potential strategy of overcoming radioresistance of HPC. A 36-year old female presented to our clinic for consideration of a 3rd course of RT for her recurrent cavernous sinus HPC, following previous cranial RT at 13 and 5 years prior, and a failed 9 months trial of bevacizumab/temozolomide. The tumor-adjacent brain stem and carotid artery risked substantial damage given the cumulative RT doses to these organs. We therefore designed an SRS plan targeting only the tumor core with 16 Gy single-fraction. Despite underdosing the tumor margin, we achieved stable disease over 25 months, contrasting her responses to systemic therapies. Achieving tumor control despite a suboptimal treatment that utilized high dose ablation of the tumor core suggests novel biological mechanisms to overcome radioresistance of HPC. PMID- 29486570 TI - Sweet syndrome as the leading symptom in the diagnosis of gastric cancer. AB - Sweet syndrome is a neutrophilic infiltration of the papillary dermis, which may be associated with the presence of unknown malignancies, either haematological or solid tumours, in 1 out of 5 cases, being considered then as a paraneoplastic syndrome. We present the case of a male with a locally advanced gastric cancer whose final diagnosis was led by the prior debut of Sweet syndrome not explained by other causes. PMID- 29486571 TI - Internet gaming disorder in Lebanon: Relationships with age, sleep habits, and academic achievement. AB - Background and aims The latest (fifth) edition of the Diagnostic and Statistical Manual of Mental Disorders included Internet gaming disorder (IGD) as a disorder that needs further research among different general populations. In line with this recommendation, the primary objective of this was to explore the relationships between IGD, sleep habits, and academic achievement in Lebanese adolescents. Methods Lebanese high-school students (N = 524, 47.9% males) participated in a paper survey that included the Internet Gaming Disorder Test and demographic information. The sample's mean average age was 16.2 years (SD = 1.0). Results The pooled prevalence of IGD was 9.2% in the sample. A hierarchical multiple regression analysis demonstrated that IGD was associated with being younger, lesser sleep, and lower academic achievement. While more casual online gamers also played offline, all the gamers with IGD reported playing online only. Those with IGD slept significantly less hours per night (5 hr) compared with casual online gamers (7 hr). The school grade average of gamers with IGD was the lowest among all groups of gamers, and below the passing school grade average. Conclusions These findings shed light on sleep disturbances and poor academic achievement in relation to Lebanese adolescents identified with IGD. Students who are not performing well at schools should be monitored for their IGD when assessing the different factors behind their low academic performance. PMID- 29486572 TI - Age-related physical and psychological vulnerability as pathways to problem gambling in older adults. AB - Background To inform clinical treatment and preventative efforts, there is an important need to understand the pathways to late-life gambling disorder. Aims This study assesses the association between age-related physical health, social networks, and problem gambling in adults aged over 65 years and assesses the mediating role of affective disorders in this association. Methods The sample comprised 595 older adults (mean age: 74.4 years, range: 65-94 years; 77.1% female) who were interviewed using a structured questionnaire to assess physical frailty, geriatric pain, loneliness, geriatric depression, geriatric anxiety, and problem gambling. Results Pathway analysis demonstrated associations between these variables and gambling problems, providing a good fit for the data, but that critically these relationships were mediated by both anxiety and depression symptoms. Conclusions This study indicates that late-life problem gambling may develop as vulnerable individuals gamble to escape anxiety and depression consequent to deteriorating physical well-being and social support. When individuals develop late-life problem gambling, it is recommended that the treatment primarily focuses upon targeting and replacing avoidant coping approaches. PMID- 29486573 TI - Epidemiological situation of measles in Romania, Italy, and Hungary: On what threats should we focus nowadays? AB - Although the prevalence of wild-type measles virus infection has decreased by >90% in Europe, the disease is still not eliminated and has even reemerged with recurrent outbreaks in different countries, including Romania and Italy. Minor outbreaks of Romanian origin were reported from Hungary as well. In Romania, an outbreak has been ongoing since February 2016. As of October 2017, 9,670 measles cases and 35 deaths were registered in the country. The three most affected counties are located next to the Hungarian border. In Italy, until the end of August 2017, 4,477 cases were reported to the surveillance system. The outbreak affected most of the Italian administrative regions. Until October 2017, three minor measles outbreaks were also detected in Hungary. All of these outbreaks were derived from Romanian cases. Although in these countries, there are vaccination programs running, the spread of the disease raises the possibility of secondary vaccine failure. PMID- 29486574 TI - The "Three Amigos" lurking behind type 1 diabetes: Hygiene, gut microbiota and viruses. AB - Incidence of type 1 diabetes (T1D) is on the rise and yet, despite decades of research, the exact ethology of the disease still remains a mystery. The autoimmune reaction, which ultimately leads to the destruction of pancreatic beta cells, causing insulin deficiency and T1D, is a result of genetic susceptibility and environmental factors. Precisely, what are these environmental factors? Current popular opinion implies these pathogens, such as viruses, especially human enteroviruses, are a triggering factor. On the other hand, the hygiene hypotheses states in which the increase of autoimmune diseases, such as T1D, can, in fact, be explained by the decrease of infections, and infectious agents, more like viruses, actually serve as a defense mechanism, therefore, protect us from developing certain autoimmune diseases. Additionally, the relationship between the gut microbiota and autoimmune diseases is currently gaining increased interest including relative research now demonstrating how the guts immune system plays a crucial role in the development of autoimmune diseases. This literature review aims to evaluate these three popular suspects: Viral infections, hygiene and gut microbiota, in relation to their potential triggering effect on T1D and their close relationship to one another. PMID- 29486575 TI - Effect of endocrine disruptor phytoestrogens on the immune system: Present and future. AB - Endocrine disruptors (EDs) are bound by steroid receptors, have steroid-like effects, and by this, negatively influence hormone-regulated processes. Phytoestrogens, which are consumed in enormously high amount by man, are also EDs; however, in contrast to industrial or communal EDs, in some cases have beneficial effects. As immune cells have steroid (first of all, estrogen) nuclear and plasma membrane receptors, which bind phytostrogens (genistein, daidzein, etc.), the development, lifespan, and function of them are deeply influenced by phytoestrogens. They can provoke perinatal faulty hormonal imprinting with lifelong consequences. However, faulty imprinting can be developed not only perinatally but also in other critical periods of life, as weaning, adolescence, and even in continuously dividing cells (e.g., hemopoietic cells) during the whole life. This means that the phytoestrogens could cause direct - instant or long-lasting - steroid effects and durable imprinting effects. As the effect of hormonal imprinting is epigenetically inherited, the phytoestrogen's effects appear in the progeny generations, and the generationally repeated disruptor effects will be different from the present ones. This could also be manifested in the amount, type, and appearance of autoimmune diseases. The consumption of soy is enormously growing, and its immune effect is extended. As the immune system influences basic physiological processes, it seems likely that evolutionary alterations will be observed. In this case, some phytoestrogens will be needed for the normal life of man, as it happened in the case of vitamins A and D, which are already life-important exohormones. However, quantitatively or qualitatively enormous amount of phytoestrogens will cause pathological and epigenetically inherited alterations. PMID- 29486576 TI - Excision of thoracic vertebral chondrosarcoma after spinal decompression. AB - A 44-year-old man presented with an abnormal chest shadow. Computed tomography guided biopsy showed a chondral tumor of the thoracic vertebrae. Five years later, he developed a walking disorder, left leg numbness, and a vesicorectal disorder. Emergency orthopedic spinal decompression was performed. Eight months later, the residual tumor had become larger and was adjacent to the aorta. Prior to thoracotomy, an intraaortic stent was inserted. The 4th and 5th ribs were invaded by the tumor. The entire tumor and chest wall were excised with the aortic adventitia. The tumor was diagnosed as a low-grade chondrosarcoma of the thoracic vertebrae. PMID- 29486577 TI - Proteomic analysis identifies NPTX1 and HIP1R as potential targets of histone deacetylase-3-mediated neurodegeneration. AB - A defining feature of neurodegenerative diseases is the abnormal and excessive loss of neurons. One molecule that is particularly important in promoting neuronal death in a variety of cell culture and in vivo models of neurodegeneration is histone deacetylase-3 (HDAC3), a member of the histone deacetylase family of proteins. As a step towards understanding how HDAC3 promotes neuronal death, we conducted a proteomic screen aimed at identifying proteins that were regulated by HDAC3. HDAC3 was overexpressed in cultured rat cerebellar granule neurons (CGNs) and protein lysates were analyzed by mass spectrometry. Of over 3000 proteins identified in the screen, only 21 proteins displayed a significant alteration in expression. Of these, 12 proteins were downregulated whereas 9 proteins were upregulated. The altered expression of five of these proteins, TEX10, NPTX1, TFG, TSC1, and NFL, along with another protein that was downregulated in the proteomic screen, HIP1R, was confirmed using Western blots and commercially available antibodies. Because antibodies were not available for some of the proteins and since HDAC3 is a transcriptional regulator of gene expression, we conducted RT-PCR analysis to confirm expression changes. In separate analyses, we also included other proteins that are known to regulate neurodegeneration, including HDAC9, HSF1, huntingtin, GAPDH, FUS, and p65/RELA. Based on our proteomic screen and candidate protein approach, we identify three genes, Nptx1, Hip1r, and Hdac9, all known to regulate neurodegeneration that are robustly regulated by HDAC3. Given their suggested roles in regulating neuronal death, these genes are likely to be involved in regulating HDAC3-mediated neurotoxicity. Impact statement Neurodegenerative diseases are a major medical, social, and economic problem. Recent studies by several laboratories have indicated that histone deacetylase-3 (HDAC3) plays a key role in promoting neuronal death. But the downstream mediators of HDAC3 neurotoxicity have yet to be identified. We conducted a proteomic screen to identify HDAC3 targets the results of which have been described in this report. Briefly, we identify Nptx1, Hip1r, and Hdac9 as genes whose expression is altered by HDAC3. Investigating how these genes are involved in HDAC3 neurotoxicity could shed valuable insight into neurodegenerative disease and identify molecules that can be targeted to treat these devastating disorders. PMID- 29486578 TI - Scorpion inhibits epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most malignant diseases worldwide. The unfavorable clinical outcome and poor prognosis are due to high rates of recurrence and metastasis after treatments. Some scholars of traditional Chinese medicine suggested that endogenous wind-evil had played an important role in metastasis of malignant tumor. Therefore, the drug of dispelling wind-evil could be used to prevent cancer metastasis and improve the poor prognosis. So we wondered whether Scorpion, one of the most important wind calming drugs, has antitumor effect especially in epithelial-mesenchymal transition (EMT) and metastasis of HCC in this research. We found that Scorpion-medicated serum could inhibit proliferation, induce apoptosis, and decrease migration and invasion capacity of Hepa1-6 cells in vitro. Meanwhile, we observed that water decoction of Scorpion restrained tumor growth and metastasis in nude mouse of HCC metastasis models. Further experiments showed that Scorpion could suppress EMT, which is characterized by increased epithelial marker E-cadherin expression and decreased mesenchymal markers N-cadherin and Snail expression following Scorpion treatment both in vitro and in vivo. These results suggested that the Scorpion could inhibit Hepa1-6 cells' invasion and metastasis in part by reversing EMT and providing a possible potential approach for preventing HCC metastasis. Impact statement The unfavorable clinical outcome and poor prognosis of hepatocellular carcinoma (HCC) are due to high rates of recurrence and metastasis after treatments. Here we found Scorpion, one of the most important wind calming drugs, has antitumor effect. Scorpion-medicated serum inhibited the proliferation, induced apoptosis, and decreased migration and invasion capacity of Hepa1-6 cells in vitro. Water decoction of Scorpion restrained tumor growth and metastasis in nude mouse of HCC metastasis models. Further experiments showed that Scorpion could suppress EMT of HCC both in vitro and in vivo. Our results suggested that the Scorpion could inhibit Hepa1-6 cells' invasion and metastasis in part by reversing EMT and providing a possible potential approach for preventing HCC metastasis. PMID- 29486579 TI - Vital Signs as Predictor Factors of Intravenous Immunoglobulin Resistance in Patients With Kawasaki Disease. AB - Kawasaki disease (KD) is the most common cause of acquired heart disease in children. Intravenous immunoglobulin (IVIG) may significantly lower the frequency of coronary artery complications. However, some patients do not respond to initial therapy and are at higher risk of developing coronary artery lesion. A retrospective analysis of data from 419 KD patients was performed. The patients were divided into IVIG responders (n = 318) and IVIG nonresponders (n = 101). Multivariate logistic regression analysis revealed neutrophil percentage, albumin, aspartate aminotransferase, heart rate, and body temperature were independent predictors of IVIG resistance. We generated a predictive scoring system by assigning 1 point for the presence of these parameters (neutrophil >80%, albumin <3.4 g/dL, aspartate aminotransferase >100 IU/L, heart rate >146 bpm, and body temperature >38.8 degrees C). This scoring system had a sensitivity of 76.2% and specificity of 64.8%, and a positive predictive value of 40.1% and a negative predictive value of 89.4%. Vital signs may be helpful to detect KD patients with IVIG resistance. PMID- 29486580 TI - The contribution of CACNA1A, ATP1A2 and SCN1A mutations in hemiplegic migraine: A clinical and genetic study in Finnish migraine families. AB - Objective To study the position of hemiplegic migraine in the clinical spectrum of migraine with aura and to reveal the importance of CACNA1A, ATP1A2 and SCN1A in the development of hemiplegic migraine in Finnish migraine families. Methods The International Classification of Headache Disorders 3rd edition criteria were used to determine clinical characteristics and occurrence of hemiplegic migraine, based on detailed questionnaires, in a Finnish migraine family collection consisting of 9087 subjects. Involvement of CACNA1A, ATP1A2 and SCN1A was studied using whole exome sequencing data from 293 patients with hemiplegic migraine. Results Overall, hemiplegic migraine patients reported clinically more severe headache and aura episodes than non-hemiplegic migraine with aura patients. We identified two mutations, c.1816G>A (p.Ala606Thr) and c.1148G>A (p.Arg383His), in ATP1A2 and one mutation, c.1994C>T (p.Thr665Met) in CACNA1A. Conclusions The results highlight hemiplegic migraine as a clinically and genetically heterogeneous disease. Hemiplegic migraine patients do not form a clearly separate group with distinct symptoms, but rather have an extreme phenotype in the migraine with aura continuum. We have shown that mutations in CACNA1A, ATP1A2 and SCN1A are not the major cause of the disease in Finnish hemiplegic migraine patients, suggesting that there are additional genetic factors contributing to the phenotype. PMID- 29486581 TI - A Review of Military Health Research Using a Social-Ecological Framework. AB - OBJECTIVE: We aim to contextualize the growing body of research on the sequelae of military service in the wars in Afghanistan and Iraq. We employ a social ecological (SE) framework for the taxonomy of military health research and classify risk as arising from the individual, family, community, and the institutional levels. We intend for this review to inform enhanced health promotion efforts in military communities. DATA SOURCE: Articles reviewed were extracted from Web of Science, PubMed, and Scopus. INCLUSION AND EXCLUSION CRITERIA: Research focused on somatic and psychological sequelae of combat deployment published from 2001-the year the war in Afghanistan began-through the end of 2014. We excluded studies of non-US military personnel, other systematic reviews, meta-analyses, book chapters, and theoretical papers. DATA EXTRACTION: We examined and summarized the aims, participants, methods, study design, SE framework tier, risk factors, and health outcomes. DATA SYNTHESIS: Studies were categorized according to SE tier, whether they focused on somatic, behavioral, or psychological outcomes, and by risk factor. RESULTS: Of the 352 peer-reviewed papers, 84% focused on war's sequelae on the index military personnel, and 75% focused on mental or behavioral health outcomes-mostly on post-traumatic stress disorder. We find comparatively little research focusing on the family, community, or institutional tiers. CONCLUSIONS: We know relatively little about how family and community respond to the return of personnel from combat deployment; how family resources affect the health of returning military personnel; and how a war's persistence presents challenges for federal, state, and local agencies to meet military health-care needs. Such work is especially salient as US troops return home from war-particularly in communities where there are substantial military populations. PMID- 29486582 TI - Short Communication: Apoptotic Membrane Microparticles Quantified by Fluorescent Bead-Based Assay Are Elevated in HIV and SIV Infections. AB - Apoptotic membrane microparticles (MMPs) derived from dying cells of multiple cell origins are highly immunostimulatory and are indicative of global immune activation and cell death in a variety of diseases. In this study, we developed a flow cytometric bead assay to quantify annexin-V+ apoptotic (MMPs) in plasma from humans and rhesus macaques. With a combination of flow cytometry and pan fluorescent beads, MMPs were enumerated in plasma specimens by adding a constant ratio of beads to initial fluid volumes and then calculating MMP/mL based on MMP to-bead ratios. Using this straightforward assay, we found that circulating MMP quantifications were highly reproducible and similar in number between normal rhesus macaques and humans subjects. However, MMPs increased two- to threefold during HIV and simian immunodeficiency virus (SIV) infections and were positively associated with T cell immune activation. Collectively, we present a rapid bead based assay for both humans and macaque models to quantify MMPs that could be an instigator and predictor of immune activation, which is a primary source of HIV/SIV disease. PMID- 29486583 TI - Predictors of COPD in symptomatic smokers and ex-smokers seen in primary care. AB - Even in subjects at high risk of chronic obstructive pulmonary disease (COPD), the diagnosis is often missed due to lack of awareness of symptoms and risk factors. The objective of this study was to identify predictors of a diagnosis of COPD in symptomatic current and ex-smokers seen in a primary care setting. General practitioners ( n = 241) consecutively recruited subjects >= 35 years, with tobacco exposure, at least one respiratory symptom (i.e. cough, sputum, wheeze, dyspnoea and/or recurrent lower respiratory tract infections), and no previous diagnosis of obstructive airways disease. Information on age, smoking status, body mass index (BMI) and dyspnoea (Medical Research Council (MRC) dyspnoea scale) was obtained. Individuals with airway obstruction (i.e. forced expiratory volume in 1 second (FEV1)/forced vital capacity ratio (FVC) < 0.70) at initial spirometry had a diagnostic spirometry after administration of a bronchodilator. COPD was defined as the presence of symptoms, tobacco exposure and persistent airflow limitation. The most prevalent symptoms were cough (72%) and dyspnoea (48%). Of 3875 (50% females, mean age 57 years) subjects screened, 700 (18.1%) were diagnosed with COPD. Multivariate logistic regression analysis revealed that increasing age 50-59 years (OR 2.4, 95% CI 1.8-3.3), 60-69 years (OR 4.1, 95% CI 3.1-5.5), >=70 years (OR 5.7, 95% CI 4.2-7.8), BMI < 25 (OR 2.3, 95% CI 1.9-2.7), being current smoker (OR 1.2, 95% CI 1.01-1.5), self-reported dyspnoea (OR 1.7, 95% CI 1.4-2.0), wheeze (OR 1.9, 95% CI 1.5-2.3) and sputum (OR 1.4, 95% CI 1.1-1.7) were associated with a significantly higher risk of being diagnosed with COPD. No association was found between gender, cough and recurrent respiratory tract infections and a diagnosis of COPD. Among symptomatic smokers and ex-smokers seen in primary care, self-reported sputum production, wheeze, dyspnoea and low BMI identify a subgroup with a higher likelihood of COPD. PMID- 29486584 TI - Elevated circulating ghrelin in patients with COPD: A meta-analysis. AB - Ghrelin, an endogenous ligand for growth hormone secretagogue receptor, has been implicated in chronic obstructive pulmonary disease (COPD). Recently, several studies reported inconsistent levels of ghrelin in plasma/serum of COPD patients. This meta-analysis aims to determine the circulating level of ghrelin in COPD. Published case-control or cohort studies were retrieved from Pubmed and Embase databases. Pooled standardized mean difference (SMD) with 95% confidence interval (CI) was calculated in a random-effects model. Nine studies involving 515 subjects were included. Pooled effect size showed that circulating ghrelin levels were significantly enhanced in COPD patients compared with those in controls (SMD: 0.83, 95% CI: 0.04 to 1.62, p = 0.039). Noticeably, five studies stratified for body mass index in COPD group and we further found ghrelin levels were significantly higher in underweight COPD patients than those in normal weight cases (SMD: 1.52, 95% CI: 0.43 to 2.61, p = 0.006). However, no significant difference regarding ghrelin levels was indicated between normal weight COPD and controls (SMD: 0.64, 95% CI: -0.36 to 1.63, p = 0.210). In this meta-analysis, circulating level of ghrelin is significantly elevated in patients with COPD, especially in those underweight, indicating supplement with exogenous ghrelin could be a therapeutic choice for underweight COPD patients. PMID- 29486585 TI - Using Ethnography to Identify Barriers and Facilitators to Optimal Infant and Young Child Feeding in Rural Ghana: Implications for Programs. AB - BACKGROUND: Understanding the context of infant and young child feeding (IYCF) is recognized as essential for designing appropriate complementary feeding interventions. OBJECTIVE: Our objective was to study household IYCF behaviors in 2 districts in southern and northern Ghana to identify opportunities to improve existing nutrition programs. METHODS: We interviewed 80 caregivers of children aged 6 to 23 months using ethnographic methods, including free listing, guided discussions and cognitive mapping techniques, and 24-hour dietary recall. Descriptive statistics and thematic content analysis were used to analyze quantitative and qualitative data. RESULTS: In both settings, children's diets were predominantly maize based. Fish, the main animal source food, was consumed daily but in very small quantities. Milk was consumed by only a few children, in tea and porridge. Fruits were seldom consumed. Household food production did not meet requirements, and the markets were heavily relied on for staples and other key ingredients. Most caregivers demonstrated basic knowledge and understanding of key health and nutrition concepts. Barriers to optimal child feeding identified were lack of money to purchase the nutritious foods recommended for children, seasonal food insecurity, and some caregiver beliefs, practices, and nutrition knowledge gaps. Positive contextual features include caregiver recognition of the dietary needs of young children and commitment to provide foods to meet these needs. CONCLUSION: Our findings suggest that complementary feeding in these rural settings can be improved through reinforcement or modification of strategic components of local health and nutrition education in light of existing barriers and enablers to optimal IYCF. PMID- 29486586 TI - Single-Cell Transcriptomics of Human Oocytes: Environment-Driven Metabolic Competition and Compensatory Mechanisms During Oocyte Maturation. AB - AIMS: The mechanisms coordinating maturation with an environment-driven metabolic shift, a critical step in determining the developmental potential of human in vitro maturation (IVM) oocytes, remain to be elucidated. Here we explored the key genes regulating human oocyte maturation using single-cell RNA sequencing and illuminated the compensatory mechanism from a metabolic perspective by analyzing gene expression. RESULTS: Three key genes that encode CoA-related enzymes were screened from the RNA sequencing data. Two of them, ACAT1 and HADHA, were closely related to the regulation of substrate production in the Krebs cycle. Dysfunction of the Krebs cycle was induced by decreases in the activity of specific enzymes. Furthermore, the activator of these enzymes, the calcium concentration, was also decreased because of the failure of influx of exogenous calcium. Although release of endogenous calcium from the endoplasmic reticulum and mitochondria met the requirement for maturation, excessive release resulted in aneuploidy and developmental incompetence. High nicotinamide nucleotide transhydrogenase expression induced NADPH dehydrogenation to compensate for the NADH shortage resulting from the dysfunction of the Krebs cycle. Importantly, high NADP+ levels activated DPYD to enhance the repair of DNA double-strand breaks to maintain euploidy. INNOVATION: The present study shows for the first time that exposure to the in vitro environment can lead to the decline of energy metabolism in human oocytes during maturation but that a compensatory action maintains their developmental competence. CONCLUSION: In vitro maturation of human oocytes is mediated through a cascade of competing and compensatory actions driven by genes encoding enzymes. Antioxid. Redox Signal. 00, 000-000. PMID- 29486588 TI - The EXPERT vision of exercise training in cardiovascular disease patients: A routine, practical and reasonable technique. PMID- 29486587 TI - Do clinicians prescribe exercise similarly in patients with different cardiovascular diseases? Findings from the EAPC EXPERT working group survey. AB - Background Although disease-specific exercise guidelines for cardiovascular disease (CVD) are widely available, it remains uncertain whether these different exercise guidelines are integrated properly for patients with different CVDs. The aim of this study was to assess the inter-clinician variance in exercise prescription for patients with various CVDs and to compare these prescriptions with recommendations from the EXercise Prescription in Everyday practice and Rehabilitative Training (EXPERT) tool, a digital decision support system for integrated state-of-the-art exercise prescription in CVD. Design The study was a prospective observational survey. Methods Fifty-three CV rehabilitation clinicians from nine European countries were asked to prescribe exercise intensity (based on percentage of peak heart rate (HRpeak)), frequency, session duration, programme duration and exercise type (endurance or strength training) for the same five patients. Exercise prescriptions were compared between clinicians, and relationships with clinician characteristics were studied. In addition, these exercise prescriptions were compared with recommendations from the EXPERT tool. Results A large inter-clinician variance was found for prescribed exercise intensity (median (interquartile range (IQR)): 83 (13) % of HRpeak), frequency (median (IQR): 4 (2) days/week), session duration (median (IQR): 45 (18) min/session), programme duration (median (IQR): 12 (18) weeks), total exercise volume (median (IQR): 1215 (1961) peak-effort training hours) and prescription of strength training exercises (prescribed in 78% of all cases). Moreover, clinicians' exercise prescriptions were significantly different from those of the EXPERT tool ( p < 0.001). Conclusions This study reveals significant inter-clinician variance in exercise prescription for patients with different CVDs and disagreement with an integrated state-of-the-art system for exercise prescription, justifying the need for standardization efforts regarding integrated exercise prescription in CV rehabilitation. PMID- 29486589 TI - Autophagy Attenuates Angiotensin II-Induced Pulmonary Fibrosis by Inhibiting Redox Imbalance-Mediated NOD-Like Receptor Family Pyrin Domain Containing 3 Inflammasome Activation. AB - AIMS: The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which is activated by reactive oxygen species (ROS) and repressed by autophagy, has been identified as a novel agent of pulmonary fibrosis. Angiotensin II (AngII), the bioactive pro-oxidant in the renin-angiotensin system, aggravates lung fibrosis. However, the effect of AngII on NLRP3 inflammasome and autophagy in lung fibrosis remains unknown. This study investigates the potential link between AngII-induced autophagy in the regulation of NLRP3 inflammasome/IL-1beta axis in lung fibrosis. RESULTS: In vivo, autophagy and the NLRP3 inflammasome were activated in fibrotic patients and positively correlated with oxidation. Treatment with rapamycin promoted autophagy but inhibited oxidation, NLRP3 inflammasome, and lung fibrosis after bleomycin (BLM) infusion. The autophagy inhibitor 3-methyladenine reduced BLM-induced lung fibrosis and concurrently facilitated NLRP3 inflammasome activation and oxidation in fibroblasts. In vitro, AngII promoted intercellular ROS, hydrogen peroxide, and NADPH oxidase 4 (NOX4) protein levels and reduced the glutathione concentration, thereby leading to NLRP3 inflammasome activation and consequent collagen synthesis. AngII induced autophagy, while VAS2870, NOX4, small interfering RNA (siRNA), and compound C eliminated AngII-induced LC3B augmentation. Moreover, blocking autophagy with bafilomycin A1 or LC3B siRNA resulted in oxidant accumulation, NLRP3 inflammasome hyperactivation, and collagen deposition. Finally, AngII induced P62/SQSTM1, targeting ubiquitinated apoptosis-associated speck-like protein containing a CARD for degradation, thereby contributing to NLRP3 inflammasome inactivation. Innovation and Conclusion: Autophagy attenuates pulmonary fibrosis by regulating NLRP3 inflammasome activation induced by AngII-mediated ROS via redox balance modulation. Antioxid. Redox Signal. 00, 000-000. PMID- 29486590 TI - Pharmacological interventions for reducing pain related to immunization or intramuscular injection in children: A mixed treatment comparison network meta analysis of randomized controlled clinical trials. AB - Various interventions were observed to reduce pain following vaccination in children. This study is a network meta-analysis comparing pharmacological interventions. Electronic databases were searched for appropriate randomized controlled clinical trials comparing active pharmacological agents to reduce pain following vaccination or intramuscular injection in neonates, infants, or children. Pain score was the primary outcome measure. Random effects model was used for generating pooled estimates. A total of 23 studies were included in the network meta-analysis. Topical eutectic mixture of local anesthetics (EMLA) significantly reduced pain scores. Crying time was also observed to be lower with vapocoolant spray and 25% sucrose and glucose solutions. Quality of the evidence was observed to be either low or very low. Topical EMLA significantly reduce pain following intramuscular injections particularly vaccination. However, due to low grade quality of the evidence, more studies are obligatory. PMID- 29486591 TI - Information needs of parents of infants diagnosed with cystic fibrosis: Results of a pilot study. AB - This study investigated the information needs, priorities and information-seeking behaviours of parents of infants recently diagnosed with cystic fibrosis (CF) following newborn screening, by piloting the 'Care of Cystic Fibrosis Families Survey'. The questionnaires were posted to eligible parents ( n = 66) attending CF clinics in hospitals in two Australian states; reply-paid envelopes were provided for return of the questionnaires. Twenty-six were returned (response rate 39.4%). The most common questions to which parents required answers during their initial education period related to what CF is, how it is treated and how to care for their child. Parents preferred face-to-face consultations to deliver information, and yet all reported using the Internet to search for more information at some point during the education period. Many parents provided negative feedback about being given their child's CF diagnosis via telephone. The timing, content and method of information delivery can all affect the initial education experience. We can deliver education to better suit the information needs and priorities for education of parents of infants recently diagnosed with CF. The Care of Cystic Fibrosis Families Survey was successfully piloted and recommendations for amendments have been made for use in a larger study across Australia. PMID- 29486592 TI - Pyoderma Gangranosum-Like Blastomycosis. AB - Blastomyces dermatitidis is typically contracted through inhalation of the dimorphic conidia, resulting in pulmonary infection as well as extrapulmonary disease through hematogenous spread. Blastomycosis is considered one of the great mimickers in medicine, with verrucous cutaneous blastomycosis resembling skin malignancy and B dermatitidis pulmonary infections often confused with lung cancer. Cutaneous blastomycosis can also often mimic pyoderma gangrenosum and should be considered in the differential diagnosis in any suspected case. This case involves a cutaneous blastomycosis lesion of the leg that was initially diagnosed as squamous cell carcinoma, which was excised. Within a month, the atypical lesion recurred in the area and was unresponsive to antibiotic therapy, rapidly progressing in size and inflammation. We discuss the eventual diagnosis of this blastomycosis infection and the importance of ruling out cutaneous blastomycosis when managing pyoderma gangrenosum. PMID- 29486593 TI - Pemphigoid Gestationis: A Case Presentation. PMID- 29486594 TI - Properties of microparticles from a whey protein isolate/alginate emulsion gel. AB - Designing soft, palatable and nutritious texture-modified foods for the elderly is a challenge for food technologists. The aim of this work was to produce and characterize emulsion-gelled microparticles (EGM) made from whey protein isolate (WPI) and sodium alginate (NaAlg) that may be used to modify the rheology of liquid foods and as carriers of lipids and lipophilic nutrients and bioactives. Olive oil microdroplets became embedded in the WPI/NaAlg gel matrix in the form of an emulsion produced by ultrasound (US) or high-speed blending (HSB). Oil microdroplets were obtained by US and HSB, with an average equivalent diameter varying between 2.0-3.2 um and 4.5-6.7 um, respectively. Oil incorporation increased compression stress of bulk emulsion gels at small deformations compared to the no-oil microgel, but this effect was reversed at high strains. EGM were prepared by shear-induced size reduction. Rheological tests at 20 C and 40 C showed that US-EGM and HSB-EGM exhibited a predominant elastic behavior, with G' > G" throughout the frequency range. However, when HSB-EGM were heated at 60 C their rheological behavior changed to a more fluid-like condition, but not that of US-EGM. Consequently, EGM have the properties needed to improve food texture for people with masticatory/swallowing dysfunctions or needing special nutrition. PMID- 29486595 TI - Critical Roles of Carbon Monoxide and Nitric Oxide in Ca2+ Signaling for Insulin Secretion in Pancreatic Islets. AB - AIMS: Glucagon-like peptide-1 (GLP-1) increases intracellular Ca2+ concentrations, resulting in insulin secretion from pancreatic beta-cells through the sequential production of Ca2+ mobilizing messengers nicotinic acid adenine dinucleotide phosphate (NAADP) and cyclic ADP-ribose (cADPR). We previously found that NAADP activates the neuronal type of nitric oxide (NO) synthase (nNOS), the product of which, NO, activates guanylyl cyclase to produce cyclic guanosine monophosphate (cGMP), which, in turn, induces cADPR formation. Our aim was to explore the relationship between Ca2+ signals and gasotransmitters formation in insulin secretion in beta-cells upon GLP-1 stimulation. RESULTS: We show that NAADP-induced cGMP production by nNOS activation is dependent on carbon monoxide (CO) formation by heme oxygenase-2 (HO-2). Treatment with exogenous NO and CO amplifies cGMP formation, Ca2+ signal strength, and insulin secretion, whereas this signal is impeded when exposed to combined treatment with NO and CO. Furthermore, CO potentiates cGMP formation in a dose-dependent manner, but higher doses of CO inhibited cGMP formation. Our data with regard to zinc protoporphyrin, a HO inhibitor, and HO-2 knockdown, revealed that NO-induced cADPR formation and insulin secretion are dependent on HO-2. Consistent with this observation, the administration of NO or CO donors to type 2 diabetic mice improved glucose tolerance, but the same did not hold true when both were administered concurrently. INNOVATION: Our research reveals the role of two gas transmitters, CO and NO, for Ca2+ second messengers formation in pancreatic beta cells. CONCLUSION: These results demonstrate that CO, the downstream regulator of NO, plays a role in bridging the gap between the Ca2+ signaling messengers during insulin secretion in pancreatic beta-cells. Antioxid. Redox Signal. 00, 000-000. PMID- 29486596 TI - A comparative study of Gaussian and non-Gaussian diffusion models for differential diagnosis of prostate cancer with in-bore transrectal MR-guided biopsy as a pathological reference. AB - Background Although several studies have been reported on evaluating the performance of Gaussian and different non-Gaussian diffusion models on prostate cancer, few studies have been reported on the comparison of different models on differential diagnosis for prostate cancer. Purpose To compare the utility of various metrics derived from monoexponential model (MEM), biexponential model (BEM), stretched-exponential model (SEM) based diffusion-weighted imaging (DWI) and diffusion kurtosis imaging (DKI) in the differential diagnosis of prostate cancer. Material and Methods Thirty-three patients underwent magnetic resonance imaging (MRI) examination. Multi-b value and multi-direction DWIs were performed. In-bore MR-guided biopsy was performed. Apparent diffusion coefficient (ADC), pure molecular diffusion (ADCslow), pseudo-diffusion coefficient (ADCfast), perfusion fraction (f), water molecular diffusion heterogeneity index (alpha), distributed diffusion coefficient (DDC), non-Gaussian diffusion coefficient (MD), and mean kurtosis (MK) values were calculated and compared between cancerous and non-cancerous groups. Receiver operating characteristic (ROC) analysis was performed for all parameters and models. Results ADC, ADCslow, DDC, and MD values were significantly lower while MK value was significantly higher in prostate cancer than those of prostatitis and benign prostatic hyperplasia. ADC, ADCslow, DDC, MD, and MK could discriminate between tumor and non-tumorous lesions (area under the curve, 0.856, 0.835, 0.866, 0.918, and 0.937, respectively). MK was superior to ADC in the discrimination of prostate cancer. DKI was superior to MEM in the discrimination of prostate cancer. Conclusions Parameters derived from both Gaussian and non-Gaussian models could characterize prostate cancer. DKI may be advantageous than DWI for detection of prostate cancer. PMID- 29486597 TI - Physiological uptake of 18F-FDG in the vertebral bone marrow in healthy adults on PET/CT imaging. AB - BACKGROUND: 18F-fluorodeoxyglucose *Equal contributors. positron emission tomography/computed tomography (18F-FDG PET/CT) has proven to be a valuable imaging modality for the assessment of bone marrow condition. PURPOSE: To investigate the physiological uptake of 18F-FDG in the vertebral bone marrow in healthy adults on PET/CT imaging, and correlate the appearance with clinical factors including gender, body mass index, and age. MATERIAL AND METHODS: A total of 64 healthy individuals underwent PET/CT scan, and for each vertebral body, the mean and maximum standardized uptake value (SUVmean and SUVmax) were determined in the central slice of vertebral body on the transversal fused PET/CT image. For each individual, the FDG uptake of the four regions was obtained by averaging the SUVmean and SUVmax of the vertebrae in individual regions. RESULTS: The FDG uptake from thoracic to sacral vertebrae showed an upward trend first, then a downward trend, while that of cervical vertebrae was relatively stable. The SUVmax and SUVmean values of bone marrow in the old group (age >= 50 years) were significantly lower than those in the young group (age < 50 years) in all regions of the spine ( P < 0.05). FDG uptake of the whole spine showed significant negative correlation with age, and the strongest correlation was observed in lumbar spine (SUVmean: r = -0.364, P < 0.05; SUVmax: r = -0.344, P < 0.05). CONCLUSION: FDG uptake showed a tendency to increase first then decrease from thoracic to sacral vertebrae while the tendency was not obvious in cervical vertebrae. In addition, the glycolytic metabolism of all the four regions decreased with advancing age. PMID- 29486598 TI - A new imaging technology to reduce the radiation dose during uterine fibroid embolization. AB - BACKGROUND: Uterine fibroid embolization (UFE) is a minimally invasive imaging guided treatment using radiation exposure. PURPOSE: To compare the patients' radiation exposure during UFE before and after introduction of a new X-ray imaging platform. MATERIAL AND METHODS: Forty-one patients were enrolled in a prospective, comparative two-arm project before and after introduction of a new X ray imaging platform with reduced dose settings, i.e. novel real-time image processing techniques (AlluraClarity). Demographic, pre-interventional imaging, and procedural data, including dose area product (DAP) and estimated organ dose on the ovaries and uterus, were recorded and angiographic quality of overall procedure was assessed. RESULTS: There were no significant differences in demographic characteristics and preoperative fibroid and uterine volumes in the two groups. The new imaging platform led to a significant reduction in mean total DAP (102 vs. 438 Gy.cm2; P < 0.001), mean fluoroscopy DAP (32 vs. 138 Gy.cm2; P < 0.001), mean acquisition DAP (70 vs. 300 Gy.cm2; P < 0.001), and acquisition DAP estimated organ dose in ovaries (42 vs. 118 mGy; P < 0.001) and uterus (40 vs. 118 mGy, P < 0.001), without impairment of the procedure and angiographic image quality. CONCLUSION: A substantial 77% reduction of DAP values and 64% and 66% reduction in organ dose on ovaries and uterus, respectively, was demonstrated with the new imaging platform, while maintaining optimal imaging quality and efficacy. PMID- 29486599 TI - Chest pain CT in the Emergency Department: evaluating the coronary arteries even when not specifically asked for? AB - Background Computed tomography (CT) for excluding acute aortic syndrome (AAS) and pulmonary embolism (PE) simultaneously in patients with chest pain could be used to exclude coronary artery disease (CAD). Purpose To evaluate the frequency of further testing for CAD in patients receiving a CT in the emergency department (ED) for simultaneous evaluation for AAS and PE. Material and Methods This retrospective study was conducted over a three-year period including all patients with acute chest pain visiting our ED. All patients were included that received an electrocardiography (ECG)-gated CT of the entire chest enquiring simultaneously for AAS and PE. Those patients were followed up for 30 days after their initial ED visit whether they received further testing for CAD. Results Within the study period, a total of 157 patients with acute chest pain received a chest pain CT for simultaneous evaluation of both AAS and PE. Image quality was deemed sufficient to evaluate the coronary arteries in 80% of the patients. Thirty-seven patients (24%) underwent additional testing for CAD within 30 days of their ED visit, including catheter coronary angiography (n = 25), cardiac stress single-photon emission-CT (n = 6), and cardiac magnetic resonance imaging (MRI) (n = 6). Conclusion Of patients presenting to the ED with acute chest pain who received a chest pain CT for simultaneous evaluation of AAS and PE, 24% had further imaging for CAD within 30 days of the initial ED visit. Immediate evaluation of the coronary arteries as part of a chest pain CT should be considered here for not delaying diagnosis. PMID- 29486600 TI - Safety of humanized monoclonal antibodies against IL-5 in asthma: focus on reslizumab. AB - INTRODUCTION: Reslizumab, a humanized mAb against IL-5, reduces the number of eosinophils in the blood and lungs. Based on efficacy and safety data from pivotal RCTs, reslizumab had been approved for use as an add-on maintenance treatment of severe asthma with an eosinophilic phenotype in adults who have a history of exacerbations despite receiving their current asthma medicines. Areas covered: Current literature on reslizumab has been reviewed with a specific focus on its safety profile in the treatment of severe asthma. Expert opinion: Large pivotal and supportive trials reinforce the view that reslizumab is well tolerated, with an acceptable safety profile in patients exposed for longer than 2 years. However, no or few data concerning safety in special populations such as smokers, those with immune- and cellular senescence, patients with comorbidities and those receiving multi-drug treatments are available as yet. Furthermore, we need to fully elucidate some fundamental issues such as the risk of anaphylaxis and the long-term risk-benefit ratio of the impact of depletion of eosinophils and the potential risk of malignancies induced by a treatment with this anti-IL-5 agent. PMID- 29486601 TI - Balancing patient value and payer cost in hematologic malignancies: can it be done? PMID- 29486602 TI - Generation of insulin-producing cells from human induced pluripotent stem cells on PLLA/PVA nanofiber scaffold. AB - Pancreatic tissue engineering as a therapeutic option for restoring and maintenance of damaged pancreas function has a special focus to using synthetic Scaffolds. This study was designed to evaluate pancreatic differentiation of human induced pluripotent stem cells (hiPSCs) on poly-L-lactic acid and polyvinyl alcohol (PLLA/PVA) scaffolds as 3 D matrix. During differentiation process, morphology of cells gradually changed and iPSCs derived insulin producing cells (iPSCs-IPCs) formed spherical shaped cell aggregation that was the typical shape of islets of pancreas. The highly efficient differentiation of iPSCs into a relatively homogeneous population of IPCs was shown by immunostaining. Real-time reverse transcription polymerase chain reaction (RT-PCR) results demonstrated that iPSCs-IPCs expressed pancreas-specific transcription factors (Pdx1, insulin, glucagon and Ngn3). The expressions of these transcription factors in PLLA/PVA scaffold were significantly higher than 2 D groups. Furthermore, we showed that concentration of insulin and C-peptide in PLLA/PVA scaffold and/or 2 D culture in response to various concentrations of glucose increased but the difference between them were not significant. Altogether the current results demonstrated that PLLA/PVA scaffold could provide the microenvironment that promotes the pancreatic differentiation of iPSCs, up-regulate pancreatic-specific transcription factors and improved metabolic activity. PMID- 29486603 TI - Quality improvement strategies and tools: A comparative analysis between Italy and the United States. AB - Italian and American hospitals, in two different periods, have been urged by external circumstances to extensively redesign their quality improvement strategies. This paper, through the use of a survey administered to chief quality officers in both countries, aims to identify commonalities and differences between the two systems and to understand which approaches are effective in improving quality of care. In both countries chief quality officers report quality improvement has become a strategic priority, clinical governance approaches, and tools-such as disease-specific quality improvement projects and clinical pathways-are commonly used, and there is widespread awareness that clinical decision making must be supported by protocols and guidelines. Furthermore, the study clearly outlines the critical importance of adopting a system-wide approach to quality improvement. To this extent Italy seems lagging behind compared to US in fact: (i) responsibilities for different dimensions of quality are spread across different organizational units; (ii) quality improvement strategies do not typically involve administrative staff; and (iii) quality performance measures are not disseminated widely within the organization but are reported primarily to top management. On the other hand, in Italy chief quality officers perceive that the typical hospital organizational structure, which is based on clinical directories, allows better coordination between clinical specialties than in the United States. In both countries, the results of the study show that it is not the single methodology/model that makes the difference but how the different quality improvement strategies and tools interact to each other and how they are coherently embedded with the overall organizational strategy. PMID- 29486604 TI - Low Seroprevalence of Neutralizing Antibodies Targeting Two Clade F AAV in Humans. AB - To assess the therapeutic utility of AAVHSC15 and AAVHSC17, two recently described Clade F adeno-associated viruses, the seroprevalence of neutralizing antibodies to these AAVs was assessed in a representative human population and compared to that of AAV9. Neutralizing antibody levels were measured in 100 unique human sera of different races (34:33:33, Black:Caucasian:Hispanic) and sex (49% Female, 51% Male) collected within the United States. Fifty-six sera were tested in HuH7 cells and 44 sera were tested in 2V6.11 cells with vectors packaged with either a CMV-promoter upstream of LacZ or a CBA-promoter upstream of Firefly Luciferase, respectively. For AAVHSC15, AAVHSC17, and AAV9, 24/100 (24%), 21/100 (21%), and 17/100 (17%), respectively, of all sera tested were seropositive for neutralizing antibodies using 50% inhibition of cellular transduction at a 1/16 dilution of serum as cut-off for seropositivity. Only six percent of positive sera had titers of 1/150 to 1/340 indicating that the majority of positive sera were of low titer. Significant cross-reactivity of neutralizing antibodies across all three AAV serotypes was observed. These data show that approximately 80% of humans evaluated were seronegative for pre existing neutralizing antibodies to the AAV serotypes tested, suggesting that the vast majority of human subjects would be amenable to therapeutic intervention with Clade F AAVs. PMID- 29486605 TI - Relationship of Parental and Adolescents' Screen Time to Self-Rated Health: A Structural Equation Modeling. AB - AIM: To investigate the association of parental and adolescents' screen time with self-rated health and to examine the mediating effects of psychosocial factors (social relationships and distress) on this association. METHOD: A cross sectional study was conducted among 984 Brazilian adolescents (10- to 17-year olds). Self-rated health, screen time (adolescents and parental), and perception of social relationships and distress were evaluated through self-report questionnaires. Structural equation modeling was adopted to investigate the pathways of the relationship between adolescents' screen time and self-rated health. RESULTS: Adolescents' screen time was directly and negatively related to self-rated health only in boys ( r = -0.158, p = .015). In girls, screen time was related to self-rated health through distress ( r = -0.188, p = .007) and social relationships ( r = 0.176, p = .008). The models fit was adequate (chi2/ df <= 3.0, root mean square error of approximation <0.08, comparative fit index >0.90, and Tucker-Lewis Index >0.90). CONCLUSIONS: Higher screen time was associated with poor self-rated health in boys, while in girls, psychosocial factors mediated the adverse relationships between screen time and self-rated health. PMID- 29486606 TI - Emerging treatment options for uterine fibroids. AB - INTRODUCTION: Uterine fibroids (also known as leiomyomas or myomas) are the most common form of benign uterine tumors. Current management strategies involve mainly surgical interventions, but the choice of treatment is guided by patient age and desire to preserve fertility or avoid 'radical' surgery such as hysterectomy. Areas covered: There is growing evidence of the crucial role of progesterone pathways in the pathophysiology of uterine fibroids, leading to increasing use of selective progesterone receptor modulators (SPRMs) such as ulipristal acetate. We searched all published studies on medical management of fibroids with SPRMs. Expert opinion: The need for alternatives to surgical intervention is very real, especially for women seeking to preserve their fertility. These options now exist, with SPRMs proven to treat fibroid symptoms effectively. Gynecologists now have new tools in their armamentarium, opening up novel strategies for the management of uterine fibroids. PMID- 29486607 TI - Durvalumab in urothelial cancers. AB - INTRODUCTION: Urothelial bladder cancer is one of the most predominant malignancies worldwide with a poor prognosis when presented at an advanced or metastatic stage. Improving the therapeutic landscape in this setting has been an unmet medical need. Palliative cisplatin-based chemotherapy is currently the standard of care in first line therapies, but many patients are ineligible and few alternative therapies exist. Moreover second-line chemotherapy has minimal activity. Recently, immune-checkpoint inhibitors have shifted the therapeutic armamentarium of bladder cancer and it is now necessary to redesign the therapeutic paradigm. Areas covered: In this article, we focus on the development of durvalumab and provide an overview of the safety, activity, efficacy and future perspectives of this drug in urothelial carcinoma. Expert commentary: Durvalumab is a well-tolerated drug and demonstrated major and durable response in advanced bladder cancer. Combinations with durvalumab will probably emerge as promising therapeutic strategies for the treatment of urothelial carcinoma. Further research efforts are needed to identify predictive biomarkers of response to immune-oncology agents. PMID- 29486608 TI - Congenital central hypoventilation syndrome: diagnosis and management. AB - INTRODUCTION: Congenital central hypoventilation syndrome (CCHS) is a rare disorder defined by a failure in autonomic control of breathing secondary to mutations of the PHOX2B gene. Affected individuals demonstrate absent or diminished physiologic response to hypercapnia and hypoxia that is most severe during sleep as well as multi-system dysregulation of autonomic functions. Areas covered: In this review, we will discuss how evaluation of the disease-defining PHOX2B gene aids diagnosis and helps prognosticate disease severity, review disease physiology, describe clinical presentation and various aspects of autonomic nervous system dysregulation, review ventilatory strategies, and highlight current challenges in the care of these complex patients. Expert commentary: CCHS is a rare disorder that requires a high degree of vigilance. PHOX2B mutation is essential for diagnosis and also helps direct disease management. There is currently no pharmacologic treatment proven effective in improving disease-related hypoventilation and care is focused on providing adequate ventilatory support and managing autonomic dysfunction. PMID- 29486609 TI - Comparative study of the chemical profiling, antioxidant and antimicrobial activities of essential oils of different parts of Thymus willdenowii Boiss & Reut. AB - The analysis of Thymus willdenowii Boiss & Reut essential oils (TW EOs) shows 33 components accounting for (96.3-97.7%) of all identified. The main constituents of TW EOs were thymol (35.5-47.3%), p-cymene (13.9-23.8%), gamma-terpinene (8.9 20.3%). The antioxidant assays revealed that all TW EOs tested showed strong activities, the antimicrobial effect of TW EOs has been tested against isolated clinical strains of Proteus mirabilis (ATCC 35659), Escherichia coli (ATCC 25922), Candida albicans (ATCC 10231), Bacillus cereus (ATCC 10876), and Aspergillus brasilliensis (ATCC 16404). The antimicrobial test indicates that TW EOs show an inhibition effect against all the tested bacteria with a MIC of 6.9 to 27.6 MUg/mL-1. These results proving that the essential oils extracted from Thymus willdenowii Boiss & Reut may be a new potential source of natural antimicrobial applied in pharmaceutical and food industries. PMID- 29486610 TI - A Multicenter, Double-Blind, Phase III Clinical Trial to Evaluate the Efficacy and Safety of a Cell and Gene Therapy in Knee Osteoarthritis Patients. AB - OBJECTIVE: To test the clinical efficacy of TissueGene-C (TG-C), a cell and gene therapeutic for osteoarthritis consisting of non-transformed and transduced chondrocytes (3:1), retrovirally transduced to overexpress TGF-beta1. DESIGN: We randomly assigned 163 with knee osteoarthritis to receive intra-articular TG-C or placebo in Kellgren-Lawrence grade 3 patients for clinical trial. Primary efficacy measures included criteria for subjective assessment by International Knee Documentation Committee (IKDC) and pain severity by Visual Analog Scale (VAS) for 52 weeks. Secondary efficacy measures included IKDC and VAS at 26 and 39 weeks; pain, stiffness, and physical functions by the Western Ontario and McMaster Universities Arthritis Index (WOMAC); and pain, symptoms, daily activities, functions in sports and recreation, and quality of life by the Knee Injury and Osteoarthritis Outcome Score (KOOS), X ray, MRI, and soluble urine and blood biomarkers. RESULTS: TG-C was associated with statistically significant improvement over placebo in the total IKDC score and individual categories, and in the VAS score at 26, 39, and 52 weeks. WOMAC and KOOS scores also improved with TG-C over placebo. Patients treated with TG-C showed trends directed towards thicker cartilage and slower growing rates of subchondral bone surface area in the medial tibia, lateral tibia, lateral patella, and lateral patella femoral regions, although not statistically significant (P > 0.05). Serum CTX-I and urine CTX II levels showed lower over 1 year in TG-C than placebo treated patients with CTX-I level reaching statistical significance. These tendencies supported TG-C as holding a great potential for disease-modifying osteoarthritis drug. The most frequent adverse events in the TG-C group were peripheral edema (9%), arthralgia (8%), joint swelling (6%), and injection-site pain (5%). CONCLUSIONS: TG-C was associated with statistically significant improvements in functions and pain in patients with knee osteoarthritis. The unexpected adverse events were not observed. TRIAL REGISTRATION: clinicaltrials.gov NCT02072070 and CRiS: KCT0001112. PMID- 29486611 TI - Anti-elastase and anti-collagenase potential of Lactobacilli exopolysaccharides on human fibroblast. AB - Polysaccharides could be used as biodegradable and biocompatible polymers for scaffolds and carriers matrix. Numerous algal, fungi and herbal polysaccharides can attenuate degradation of skin matrix by the inhibition of elastase, collagenase and matrix metalloproteinases (MMPs). In this study, we investigate anti-elastase and anti-collagenase potential of Lactobacilli exopolysaccharides (LEPS) on normal human fibroblast. Among 60 Lactobacilli isolated from herbal plants and dairy products, selected LEPS showed high anti-collagenase (up to 100%), anti-elastase (up to 87%) and antioxidant activity (up to 60%). Most of them had no cytotoxicity effect on fibroblast, and some of them promote cell proliferation (up to 10%). In scratch assay, all the investigated EPSs stimulated wound healing process in fibroblast (up to 99%). MMP1, MMP2, MMP3, MMP9 and MMP10 were down-regulated significantly and TIMP1 and TIMP2 were up-regulated slightly in LEPS of B9-1 from L. casei with high anti-collagenase and anti-elastase activity; however, no meaningful alteration was observed in MMPs expression level for LEPS of P35 from L. plantarum with low anti-collagenase and anti-elastase activity. By consideration of high anti-collagenase, anti-elastase, antioxidant activity and wound healing of LEPS, they could be considered as good candidate of skin anti-aging agents for tissue engineering and skin regeneration scaffolds. PMID- 29486612 TI - Response to letter to the editor "Early amniotomy after dinoprostone insert used for the induction of labor". PMID- 29486613 TI - Magnesium isoglycyrrhizinate attenuates D-galactosamine/lipopolysaccharides induced acute liver injury of rat via regulation of the p38-MAPK and NF-kappaB signaling pathways. AB - CONTEXT: Acute hepatic failure involves in serious inflammatory responses and leads to a high mortality. Magnesium isoglycyrrhizinate (MgIG), a magnesium salt of 18-alpha glycyrrhizic acid (GA) stereoisomer, has been shown anti-inflammatory activity previously. OBJECTIVE: This study aimed to investigate the protective effects of MgIG, a hepatocyte protective agent, on D-galactosamine and lipopolysaccharide (D-GaIN/LPS)-induced acute liver injury in rats, and meanwhile explore the molecular mechanism. MATERIALS AND METHODS: Male Sprague-Dawley (SD) rats were injected with D-GaIN/LPS (800 mg/kgBW/10 MUg/kgBW) with or without administration of MgIG (225 mg/kg once 6 h after D-GaIN/LPS injection and MgIG 45 mg/kg twice in another 12 h, intraperitoneal injection). Rats were sacrificed 24 h after D-GaIN/LPS injection, the blood and liver samples were collected for future inflammation and hepatotoxicity analyses. RESULTS: MgIG significantly inhibited D-GaIN/LPS-induced inflammatory cytokines production and hepatotoxicity as indicated by both diagnostic indicators of liver damage [aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels] and histopathological analysis. Western blot analysis demonstrated that MgIG significantly decreased p38-mitogen activated protein kinase (MAPK) and nuclear factor kappa B (NF-kappaB) activation induced by D-GaIN/LPS. CONCLUSION: The results indicated that the protective effects of MgIG on D-GaIN/LPS-induced acute liver injury might be correlated with its capacity to regulate the p38-MAPK and NF-kappaB signaling pathways. PMID- 29486614 TI - Molecular mechanism of amygdalin action in vitro: review of the latest research. AB - Amygdalin, named as 'laetrile' and 'vitamin B-17' was initially supposed to be a safe drug for cancer treatment and was recognized by followers of natural medicine since it has been considered to be hydrolyzed only in cancer cells releasing toxic hydrogen cyanide (HCN), and thus destroying them. Unfortunately, current studies have shown that HCN is also released in normal cells, therefore it may not be safe for human organism. However, there have still been research works conducted on anti-cancer properties of this compound. In vitro experiments have shown induction of apoptosis by amygdalin as a result of increased expression of Bax protein and caspase-3 and reduced expression of antiapoptotic BcL-2protein. Amygdalin has also been shown to inhibit the adhesion of breast cancer cells, lung cancer cells and bladder cancer cells by decreased expression of integrin's, reduction of catenin levels and inhibition of the Akt-mTOR pathway, which may consequently lead to inhibition of metastases of cancer cells. It has also been revealed that amygdalin in renal cancer cells increased expression of p19 protein resulting in inhibition of cell transfer from G1-phase to S-phase, and thus inhibited cell proliferation. Other studies have indicated that amygdalin inhibits NF-kbeta and NLRP3 signaling pathways, and consequently has anti-inflammatory effect due to reducing the expression of proinflammatory cytokines such as pro-IL-1beta. Moreover, the effect of amygdalin on TGFbeta/CTGF pathway, anti-fibrous activity and expression of follistatin resulting in activation of muscle cells growth has been reported. This compound might be applicable in the treatment of various cancer cell types. PMID- 29486615 TI - First data on in vitro fertilization and blastocyst formation after intraovarian injection of calcium gluconate-activated autologous platelet rich plasma. AB - Platelets modulate clinically relevant yet incompletely understood tissue regeneration processes, and platelet rich plasma (PRP) has been previously used with some success in various non-reproductive medical contexts. Here, we extended PRP application to ovarian tissue with a view to document impact on ovarian reserve among women attending for infertility treatment. PRP was freshly isolated from patients (n= 4) with diminished ovarian reserve as determined by at least one prior IVF cycle canceled for poor follicular recruitment response or estimated by serum AMH and/or FSH, no menses for >=1 year. Immediately following substrate isolation and activation with calcium gluconate, approximately 5 mL of autologous PRP was injected into each ovary under direct transvaginal sonogram guidance. For each study subject, AMH, FSH, and serum estradiol data were recorded at two-week intervals post-PRP and compared to baseline (pre-PRP) values. In this pilot group, mean (+/-SD) patient age was 42 +/- 4 years with infertility duration reported as 60 +/- 25 months. Following this protocol of intraovarian PRP administration, increases in serum AMH (p = .17), decreases in FSH (p < .01), or both, were observed in all cases, sufficient to permit retrieval of 5.3 +/- 1.3 MII oocytes. IVF occurred 78 +/- 22 (range = 59-110) days after activated PRP injection, and results appeared independent of patient age, infertility duration, baseline platelet concentration or pretreatment antral follicle count. Each patient had at least one blastocyst suitable for cryopreservation. While autologous PRP has been successfully applied therapeutically to various tissues to accelerate healing and wound repair, this is the first description of direct injection of activated PRP into the human ovary of poor prognosis IVF patients. Evidence of improved ovarian function was noted in all who received intraovarian PRP, possibly as early as two months after treatment. Additional research is needed to clarify (and enhance) which PRP components are responsible for altered ovarian function, and to identify predictive characteristics for patients most likely to benefit from this intervention. PMID- 29486616 TI - Opportunities and challenges in drug discovery targeting metabotropic glutamate receptor 4. AB - INTRODUCTION: Until recently, metabotropic glutamate receptor 4 (mGlu4) has not received adequate attention in terms of drug targeting when compared to other members of the same mGlu receptor family, possibly because of the difficulties encountered in developing highly selective, either orthosteric or allosteric, ligands for this receptor. Areas covered: This review gives to discussion to the past and recent advances (between 2012-2017) in targeting the mGlu4 receptor for the treatment of disorders of the central nervous system (CNS) as well as immunological (neuroinflammation) and metabolic diseases (diabetes). Chemical structures, properties, and pharmacological properties discussed herein were retrieved from the scientific literature databases, PubMed and Google Scholar. Expert opinion: The fertile field of mGlu receptor positive allosteric modulators (PAMs) has recently led to the discovery of foliglurax, a highly selective mGlu4 receptor PAM with optimal bioavailability after oral administration and excellent brain distribution. However, further elucidation of the biological properties of the mGlu4 receptor, including expression and its signalling profile in distinct tissues and cells are still awaited in order to establish the mGlu4 receptor as a definite drug target in several CNS and non-CNS diseases. PMID- 29486617 TI - Selective apoptosis induction in cancer cells using folate-conjugated gold nanoparticles and controlling the laser irradiation conditions. AB - In this study, we explained in detail a targeted nano-photo-thermal therapy (NPTT) method to induce selective apoptosis in cancer cells. Folate-conjugated gold nanoparticles (F-AuNPs) were synthesized by tailoring the surface of AuNPs with folic acid to enhance the specificity of NPTT. KB cancer cells, as a folate receptor over-expressing cell line, and L929 normal cells with low level of folate receptors were incubated with the synthesized F-AuNPs and then irradiated with various laser intensities and exposure durations. Following various regimes of NPTT, we assessed the level of cell viability and the ratio of apoptosis/necrosis. No significant cytotoxicity was observed for both cell lines at concentrations up to 40 MUM of F-AuNPs. Moreover, no significant cell lethality occurred for various laser irradiation conditions. The viability of KB and L929 cells incubated with F-AuNPs (40 MUM; 6 h) and then irradiated by laser (1 W/cm2; 2 min) was 57 and 83%, respectively. It was also demonstrated that the majority of cancer cell death is related to apoptosis (41% apoptosis of 43% overall cell death). In this process of F-AuNPs based NPTT, it may be concluded that the main factor determining whether a cell dies due to apoptosis or necrosis depends on laser irradiation conditions. In this study, we explained in detail a targeted nano-photo-thermal therapy (NPTT) method to induce selective apoptosis in cancer cells. PMID- 29486618 TI - Involvement of IL-1beta and IL-6 in antiarrhythmic properties of atorvastatin in ouabain-induced arrhythmia in rats. AB - PURPOSE: Evidence show that statins possess wide beneficial cardioprotective and anti-inflammatory effects; therefore, in the present experiment, we investigated the antiarrhythmic properties of atorvastatin in ouabain-induced arrhythmia in isolated rat atria and the role of several inflammatory cytokines in this effect. MATERIALS AND METHODS: Male rats were pretreated with either of atorvastatin (10 mg/kg) or vehicle, orally once daily for 6 weeks. After induction of anesthesia, we isolated the atria and after incubation with ouabain, time of onset of arrhythmia and asystole as well as atrial beating rate and contractile force were recorded. We also measured the atrial levels of IL-1beta, IL-6, and TNF-alpha after the injection of ouabain to animals. RESULTS: Pretreatment with atorvastatin significantly delayed the onset of arrhythmia and asystole compared with vehicle-treated group (p < .01, p < .001, respectively). Incubation of ouabain boosted both atrial beating rate and contractile force in vehicle-treated group (p < .05), while these responses in atorvastatin-treated group were not significant (p > .05). Injection of ouabain elevated the atrial levels of IL 1beta, IL-6, and TNF-alpha, while pretreatment of animals with atorvastatin could reverse the ouabain-induced increase in atrial IL-1beta and IL-6 (p < .01 and p < .05, respectively). CONCLUSIONS: It is concluded that observed antiarrhythmic effects of atorvastatin might be attributed to modulation of some inflammatory cytokines, at least IL-1beta and IL-6. PMID- 29486619 TI - A novel in vivo adjuvant activity of kaempferol: enhanced Tbx-21, GATA-3 expression and peritoneal CD11c+MHCII+ dendritic cell infiltration. AB - OBJECTIVE: Kaempferol, a natural flavonol present in various traditional medicinal plants, is known to possess potent anti-inflammatory properties. This study was designed to study the adjuvant effect of kaempferol administration along with ovalbumin antigen (K + O) in balb/c mice. METHODS: Mice were immunized with kaempferol (100 and 50 mg/kg body weight) without or with ovalbumin (20 ug/mouse). After priming, booster was administered on day 21. Antigen specific IgG titers and its subtypes, on day 28, were estimated by indirect ELISA. Effect of kaempferol administration on CD11c+MHCII+ peritoneal dendritic cells was studied by flow cytometry. Expression levels of proteins Tbx21, GATA-3, BLIMP-1, Caspase-1 and Oct-2 were studied by western blotting. LPS activated IL-1beta production by peritoneal cells of immunized mice was estimated by sandwich ELISA. RESULTS: Ovalbumin specific IgG, IgG1 and IgG2a antibody titers in sera samples of K + O immunized mice increased significantly (p < .01) as compared to controls. The enhanced Th1 and Th2 immune response in K + O immunized mice was also supported by the increased expression of Tbx21 and GATA-3 transcription factors in splenocytes. This corroborated with increased BLIMP-1 and Oct-2 protein expression. Kaempferol increased the infiltration of peritoneal CD11c+MHCII+ dendritic cells but failed to enhance LPS activated IL-1beta by peritoneal macrophages and suppressed caspase-1 protein expression as compared to that in ovalbumin immunized mice. CONCLUSION: Present study strongly demonstrates the novel adjuvant activity of kaempferol in vivo and its potential as an immunostimulatory agent. PMID- 29486620 TI - Kinetic Analysis of Fingers During Aimed Throwing. AB - This study had two objectives: (a) revealing the difference in finger segments between the conventional and finger models during aimed throwing and (b) examining the central nervous system's timing control between the wrist torque and finger torque. Participants were seven baseball players. Finger kinetics was calculated by an inverse dynamics method. In the conventional model, wrist flexion torque was smaller than that in the finger model because of the error in ball position approximation. The maximal correlation coefficient between the wrist torque and finger torque was high (r = .85 +/- .10), and the time lag at maximal correlation coefficient was small (t = 0.36 +/- 3.02 ms). The small timing delay between the wrist torque and finger torque greatly influenced ball trajectory. We conclude that, to stabilize release timing, the central nervous system synchronized the wrist torque and finger torque by feed-forward adjustments. PMID- 29486622 TI - A novel functional crosstalk between DDR1 and the IGF axis and its relevance for breast cancer. AB - In the last decades increasing importance has been attributed to the Insulin/Insulin-like Growth Factor signaling (IIGFs) in cancer development, progression and resistance to therapy. In fact, IIGFs is often deregulated in cancer. In particular, the mitogenic insulin receptor isoform A (IR-A) and the insulin-like growth factor receptor (IGF-1R) are frequently overexpressed in cancer together with their cognate ligands IGF-1 and IGF-2. Recently, we identified discoidin domain receptor 1 (DDR1) as a new IR-A interacting protein. DDR1, a non-integrin collagen tyrosine kinase receptor, is overexpressed in several malignancies and plays a role in cancer progression and metastasis. Herein, we review recent findings indicating that DDR1 is as a novel modulator of IR and IGF-1R expression and function. DDR1 functionally interacts with IR and IGF-1R and enhances the biological actions of insulin, IGF-1 and IGF-2. Conversely, DDR1 is upregulated by IGF-1, IGF-2 and insulin through the PI3K/AKT/miR-199a-5p circuit. Furthermore, we discuss the role of the non canonical estrogen receptor GPER1 in the DDR1-IIGFs crosstalk. These data suggest a wider role of DDR1 as a regulator of cell response to hormones, growth factors, and signals coming from the extracellular matrix. PMID- 29486621 TI - Comorbidities and cardiovascular risk factors in an aged cohort of HIV-infected patients on antiretroviral treatment in a Spanish hospital in 2016. AB - OBJECTIVES: The increased survival of HIV-infected individuals has resulted in a premature aging of this population, with the consequent development of premature age-related comorbidities and risk factors. We aimed to describe the prevalence of age-related comorbidities and cardiovascular risk factors in older adults with HIV infection on antiretroviral therapy (ART). METHODS: A retrospective cross sectional study was undertaken in a cohort of HIV patients aged >=50 years on ART in September 2016 in Spain. The prevalence of comorbidities (liver cirrhosis, respiratory diseases, cancer, cardiovascular, diabetes, and kidney and bone disorders) and risk factors (smoking, dyslipidemia, and arterial hypertension) was captured. RESULTS: Among the 339 patients included in the study, any comorbidity was present in 52%, the most common being cirrhosis (19%), chronic lung disease (13%), and diabetes mellitus (11%). Over three quarters (78%) had any risk factor: dyslipidemia (55%) and smoking (44%). A higher prevalence of cardiovascular disease was seen in patients >=60 years in comparison to those aged 50-59 years (23% vs 8%, p = 0.001). Of all study patients, 44% took more than three drugs in addition to their ART, while 29% received no additional pharmacological interventions. CONCLUSIONS: Comorbidities and risk factors for chronic diseases are very common in HIV-infected patients aged >=50 years and increase with age, so they should be early considered in the clinical management of these patients. It is important to encourage healthy lifestyles to prevent comorbidities and to control risk factors. Concomitant treatments with ART should be carefully monitored to prevent drug interactions, adverse effects, and patient adherence failures. PMID- 29486623 TI - Diagnostic accuracy and interobserver agreement of contrast-enhanced ultrasound in the evaluation of residual lesions after treatment for malignant lymphoma and testicular cancer: a retrospective pilot study in 52 patients. AB - Value of contrast-enhanced-ultrasound (CEUS) in the evaluation of residual lesions (RL) after therapy in patients with malignant lymphomas (ML) and testicular cancer (TC) with regard to tumor activity. From May 2004-October 2010, in n = 52 patients with ML (n = 34) or TC (n = 18) and RL, B-mode-imaging and CEUS of the RL was performed. In CEUS, differentiation was made between high enhancement (HE), low-(LE) or no-enhancement (NE) of the RL after therapy. Data were retrospectively evaluated. A positive test result (HE) was found in n = 13 (25%); a negative test result (LE/NE) in n = 39 (75%) patients. Sensitivity was 72.7%, specificity 87.8%, positive likelihood-ratio 5.96, negative likelihood ratio 0.31. In the subgroup of ML a sensitivity of 80% and a specificity of 86.2% was reached. Active residual disease in ML and TC is associated with a marked enhancement, so CEUS might be helpful in the evaluation of RL, especially to exclude residual disease. PMID- 29486624 TI - Diagnosis of retinal detachments by a tele-ophthalmology screening program. AB - In 2015, a tele-ophthalmology program was undertaken at the Atlanta Veterans Affairs Medical Center to provide screening eye care for veterans in their primary care clinics. Though this program was developed as a screening tool, the availability of these services in primary care clinics has enabled triage of certain acute eye complaints. These case reports describe two patients who were diagnosed with retinal detachments through this program, although their primary care providers had triaged them as requiring non-urgent referrals to the eye clinic. Although many patients are seen for acute ocular complaints in primary care clinics and emergency departments, providers in such settings may lack the ability to adequately examine eyes and thus triage ocular complaints. These cases demonstrate the ability of tele-ophthalmology to assist in diagnosing urgent ocular conditions in primary care clinics. Though tele-ophthalmology has been accepted in some parts of the world, in the United States of America it remains widely underutilized. These cases highlight the ability of tele-ophthalmology to close the gap in acute eye care coverage that exists in the USA, most prominently in rural regions. PMID- 29486625 TI - Management of relapsed or refractory follicular lymphoma patients in daily practice - a French non-interventional study. PMID- 29486626 TI - Influence of diagnosis threat and illness cognitions on the cognitive performance of people with acquired brain injury. AB - Illness cognitions - cognitive representations of illness - have been found to influence health outcomes in chronic diseases: more adaptive illness cognitions generally lead to better outcomes. Concomitantly, diagnosis threat (DT) is a phenomenon whereby participants with acquired brain injury (ABI) underperform on neuropsychological tasks due to stereotype activation. This randomised study examined the impact of illness cognitions and DT on cognitive performance. People with ABI completed the Illness Cognitions Questionnaire and were then exposed to either a DT condition or a reduced DT condition (in which stereotype cues were reduced). They then completed memory and attentional tasks. Control participants performed only the tasks under one of the two conditions. Under the reduced DT condition, higher adaptive illness cognitions were associated with better memory and attentional performance. However, the DT condition diminished memory (but not attentional) performance in participants with a high level of adaptive illness cognitions, often leading to performance at the pathological level. This study confirms the detrimental impact of DT in people with ABI and highlights the necessity for clinicians to consider psychosocial influences when assessing and treating this population. PMID- 29486627 TI - Working Memory Task Influence in Postural Stability and Cognitive Function in Adolescents. AB - This paper describes a study on postural stability and cognitive function according to the difficulty increment of a working memory task (WMT) and age group in adolescents. One hundred and twenty-three participants (13-16 years) performed single and dual tasks in a bipedal standing position while barefoot. Four trials were conducted, consisting of single and dual tasks in three progressively difficult WMT conditions (i.e., 3-, 5-, and 7-digit sequences). Friedman's analysis of variance and Kruskal-Wallis tests were conducted to test the effect of the WMT and age group, respectively. Both the WMT and age were found to affect performance (p < .01). As the cognitive requirements increased, the adolescents were not able to maintain their performance in both balance and cognition, while postural control and cognition were found to evolve with age. PMID- 29486629 TI - Higher specialty training in genitourinary medicine: A curriculum competencies based approach. AB - Specialty trainees in genitourinary medicine (GUM) are required to attain competencies described in the GUM higher specialty training curriculum by the end of their training, but learning opportunities available may conflict with service delivery needs. In response to poor feedback on trainee satisfaction surveys, a four-year modular training programme was developed to achieve a curriculum competencies-based approach to training. We evaluated the clinical opportunities of the new programme to determine: (1) Whether opportunity cost of training to service delivery is justifiable; (2) Which competencies are inadequately addressed by direct clinical opportunities alone and (3) Trainee satisfaction. Local faculty and trainees assessed the 'usefulness' of the new modular programme to meet each curriculum competence. The annual General Medical Council (GMC) national training survey assessed trainee satisfaction. The clinical opportunities provided by the modular training programme were sufficiently useful for attaining many competencies. Trainee satisfaction as captured by the GMC survey improved from two reds pre- to nine greens post-intervention on a background of rising clinical activity in the department. The curriculum competencies-based approach to training offers an objective way to balance training with service provision and led to an improvement in GMC survey satisfaction. PMID- 29486628 TI - Genital Chlamydia trachomatis and Neisseria gonorrhoeae infections among women in sub-Saharan Africa: A structured review. AB - Chlamydia trachomatis and Neisseria gonorrhoeae constitute major public health problems among women, but the burden of infection in sub-Saharan Africa is poorly documented. We conducted a structured review of the prevalence and incidence of genital, oral and anal C. trachomatis and N. gonorrhoeae infection in women in sub-Saharan Africa. We searched Medline, EMBASE and Web of Science over a 10-year period for studies on epidemiology of genital, oral and anal chlamydial infection and gonorrhoea in women in all countries of sub-Saharan Africa. We assessed geographic and demographic differences in prevalence and incidence of infection; weighted mean prevalence estimates were calculated with a random-effect model. A total of 102 study results were included, with data available for 24/49 of sub Saharan countries. The weighted prevalence of chlamydial infection was lower among women in community-based studies (3.9%; 95% CI: 2.9-5.1%) than for women recruited at primary healthcare facilities (6.0%; 95% CI: 4.2-8.4%, p < 0.001); the same was observed for gonorrhoea (2.2%; 95% CI: 1.2-4.0% vs. 4.2%; 95% CI: 3.2-5.6%, p < 0.001). Prevalence of Chlamydia among sex workers was 5.5% (95% CI: 4.2-7.3%) and gonorrhoea 7.6% (95% CI: 5.4-11%). Seven studies reported on incidence which varied between 0.75-28 and 2.8-17 per 100 person-years-at-risk for chlamydial infection and gonorrhoea, respectively. Only two studies reported on anal infections and one on oral infection. This overview underscores the considerable incidence and prevalence of genital C. trachomatis and N. gonorrhoeae in women in different settings in sub-Saharan Africa. Better control strategies are warranted to reduce the burden of infection and to prevent long term complications of these infections. PMID- 29486630 TI - Diabetic ketoacidosis among pregnant and non-pregnant women: a comparison of morbidity and mortality. AB - PURPOSE: Diabetic ketoacidosis (DKA) is a critical diagnosis that can cause severe morbidity and mortality in the diabetic population. Although it is rare in pregnancy, the aim of this study is to compare DKA in pregnant women with age matched non-pregnant women to determine if outcomes are influenced by pregnancy. MATERIALS AND METHODS: A population-based age-matched retrospective cohort was carried out using data from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample from 1999 to 2013. Pregnant patients with DKA were age-matched with non-pregnant controls also admitted with DKA at a ratio of 1:10. Severe morbidities and mortality were compared among the two groups. Logistic regression was used to adjust for baseline characteristics and comorbidities. RESULTS: We identified 4661 cases of DKA in pregnancy during our study period, which were age-matched to 46,610 non-pregnant controls. Pregnant women with DKA were more likely to stay in hospital for >3 d (odds ratios (OR) 2.15, 95% CI 2.06 2.25) and had more associated renal failure (OR 2.86, 95% CI 1.76-4.55); however, they were less likely to require ventilation (OR 0.70, 95% CI 0.62-0.79), experience systemic inflammatory response syndrome (OR 0.53, 95% CI 0.38-0.73), or seizures (OR 0.49, 95% CI 0.42-0.57). Among pregnant women, rates of coma (0.04%) and death (0.17%, OR 0.23, 95% CI 0.14-0.39) were lower than previously reported and lower than non-pregnant women. CONCLUSION: Pregnant women with DKA are admitted to hospital for longer periods than non-pregnant controls and are at higher risk for renal failure but otherwise have better outcomes and less mortality than non-pregnant controls. PMID- 29486631 TI - Social medicine, feminism and the politics of population: From transnational knowledge networks to national social movements in Brazil and Mexico. AB - This article examines the role of national actors articulated with an explicitly counter-hegemonic transnational knowledge network (TKN) mobilising around social medicine in policy debates on population control and family planning. It focuses primarily on Brazil, using Mexico as a shadow case to highlight salient points of contrast. In doing so, it makes two contributions to larger debates about TKNs. First, it highlights the plural and contested nature of the knowledge production they enact, underscoring contestation around a global reproductive regime that consolidated around family planning. Second, it underscores how the position and relative influence of actors articulated with TKNs is shaped by political and institutional contexts at the national level, producing variable opportunities for the mobilisation of applied knowledge. Reflecting its advocates' embeddedness in larger opposition movements to authoritarian states, social medicine had a greater influence on these debates in Brazil, where synergies with a resurgent feminist movement reinforced a shared insistence on comprehensive women's healthcare and increased the salience of sterilisation abuse on the political agenda. PMID- 29486632 TI - Bilateral hyperkeratosis of the nipples and areolae with linear nevus: a rare case report and review of the literature. AB - Hyperkeratosis of the nipple and areola is an uncommon dermatosis without well defined etiology, which occurs mostly in young women and may only be a cosmetic problem. In 1938, Levy-Frankel classified this disease into three variants; type I involves hyperkeratosis with an epidermal nevus, and has rarely been reported. We report a case of a 23-year-old woman with long-term bilateral pigmentation and thickening of the nipples and areolae, accompanied with dark brown, flat lesions with a linear distribution on her left forearm. The verrucous plaques were asymptomatic and could be scratched off by the patient herself. Consequently, she did not seek medical care for more than ten years. The prevalence of this condition is likely underestimated because many affected individuals are not sufficiently motivated to seek medical attention. PMID- 29486633 TI - Loss of ARID1A Expression Correlates With Tumor Differentiation and Tumor Progression Stage in Pancreatic Ductal Adenocarcinoma. AB - Mutations in the AT-rich interactive domain 1A gene, which encodes a subunit of the Switch/Sucrose nonfermentable chromatin remodeling complex, can result in loss of protein expression and are associated with different cancers. Here, we used immunohistochemistry to investigate the significance of AT-rich interactive domain 1A loss in 73 pancreatic ductal adenocarcinoma cases with paired paracancerous normal pancreatic tissues. The relationship between levels of the AT-rich interactive domain 1A protein product, BAF250a, and clinicopathological parameters in the 73 pancreatic cancer specimens was also analyzed. We found that the expression of AT-rich interactive domain 1A in normal pancreatic tissue was higher than that in tumor tissue. Loss of AT-rich interactive domain 1A expression in pancreatic tumors was associated with tumor differentiation ( P = .002) and tumor stage ( P = .048). Meanwhile, BAF250a protein levels were not related to lymph node metastasis, distant metastasis, sex, or age and were not associated with survival. Transfection of the pancreatic cancer cell lines AsPC-1 and PANC-1 with small-interfering RNA specific for AT-rich interactive domain 1A resulted in elevated messenger RNA and protein expression levels of B-cell lymphoma-2 (Bcl-2), CyclinD1, and Kirsten rat sarcoma viral oncogene (KRAS). The AT-rich interactive domain 1A expression level in the cells was increased following microRNA-31 (miR-31) inhibitor transfection. Our data provide additional evidence that AT-rich interactive domain 1A might function as a tumor suppressor gene in pancreatic carcinogenesis. PMID- 29486634 TI - The Cultural Boundaries of Perspective-Taking: When and Why Perspective-Taking Reduces Stereotyping. AB - Research conducted in Western cultures indicates that perspective-taking is an effective social strategy for reducing stereotyping. The current article explores whether and why the effects of perspective-taking on stereotyping differ across cultures. Studies 1 and 2 established that perspective-taking reduces stereotyping in Western but not in East Asian cultures. Using a socioecological framework, Studies 2 and 3 found that relational mobility, that is, the extent to which individuals' social environments provide them opportunities to choose new relationships and terminate old ones, explained our effect: Perspective-taking was negatively associated with stereotyping in relationally mobile (Western) but not in relationally stable (East Asian) environments. Finally, Study 4 examined the proximal psychological mechanism underlying the socioecological effect: Individuals in relationally mobile environments are more motivated to develop new relationships than those in relationally stable environments. Subsequently, when this motivation is high, perspective-taking increases self-target group overlap, which then decreases stereotyping. PMID- 29486636 TI - Conservative laparoscopic management of adnexal torsion based on a 17-year follow up experience. AB - Laparoscopic unwinding of adnexal torsion has been proposed for decades. However, this technique is still controversial regarding the concern of thromboembolic events. We present two cases of conservative laparoscopic management of adnexal torsion. In the first case, a 16-year-old adolescent with serous cystadenoma was successfully managed by untwisting and cystectomy. We followed up this patient for 17 years with regular re-examinations in our hospital. To the best of our knowledge, this is the longest follow-up reported of this condition. In the second case, a 32-year-old infertile woman who received oocyte retrieval 3 days before being admitted to hospital was referred to hospital with right ovarian torsion. We treated her successfully based on our long-term follow-up experience, and she is now asymptomatic and in her 7th month of pregnancy. PMID- 29486637 TI - Comparison of the effectiveness of venous thromboembolism prophylaxis with enoxaparin between obese and non-obese patients. AB - Objective The purpose of this study is to compare the incidence of venous thromboembolism between obese and non-obese hospitalized patients who received United States Food and Drug Administration-approved prophylactic enoxaparin doses and to describe enoxaparin dosing strategies used in obese patients. Methods This was a retrospective cohort study including patients who were admitted to Parkview Regional Medical Center, Parkview Hospital, or Parkview Orthopedic Hospital between September 2011 and August 2012 and received at least one dose of enoxaparin 30 mg twice daily or enoxaparin 40 mg once daily for venous thromboembolism prophylaxis. Patients classified based on their body mass index into three groups, Group 1 (non-obese: body mass index < 25 kg/m2), Group 2 (overweight: body mass index >= 25 kg/m2 but < 30 kg/m2), and Group 3 (obese: body mass index >= 30 kg/m2). The primary endpoint was venous thromboembolism occurrence within 90 days, considering day 1 of hospitalization as day 1. Results Of the 428 patients included, 8 cases of venous thromboembolism (1.9%) were identified; 3 in the non-obese group, 2 in the overweight group, and 3 in the obese group, no statistically significant differences were found between the three groups, p = 0.81. When venous thromboembolism incidence was adjusted for age and sex, no statistically significant differences were found between overweight (OR = 0.685; 95% CI 0.115-4.095), obese (OR = 0.797; 95% CI 0.353 1.796), and combined overweight and obese (OR = 0.656; 95% CI 0.154-2.799) groups compared to patients with normal body weight. Conclusion This study did not find a statistically significant difference in venous thromboembolism incidence between obese, overweight, and non-obese hospitalized patients receiving approved enoxaparin prophylaxis doses. PMID- 29486635 TI - The predictive utility of the plant phylogeny in identifying sources of cardiovascular drugs. AB - CONTEXT: Cardiovascular disease (CVD) is the number one cause of death globally, responsible for over 17 million (31%) deaths in the world. Novel pharmacological interventions may be needed given the high prevalence of CVD. OBJECTIVE: In this study, we aimed to find potential new sources of cardiovascular (CV) drugs from phylogenetic and pharmacological analyses of plant species that have experimental and traditional CV applications in the literature. MATERIALS AND METHODS: We reconstructed the molecular phylogeny of these plant species and mapped their pharmacological mechanisms of action on the phylogeny. RESULTS: Out of 139 plant species in 71 plant families, seven plant families with 45 species emerged as phylogenetically important exhibiting common CV mechanisms of action within the family, as would be expected given their common ancestry: Apiaceae, Brassicaceae, Fabaceae, Lamiaceae, Malvaceae, Rosaceae and Zingiberaceae. Apiaceae and Brassicaceae promoted diuresis and hypotension; Fabaceae and Lamiaceae had anticoagulant/thrombolytic effects; Apiaceae and Zingiberaceae were calcium channel blockers. Moreover, Apiaceae, Lamiaceae, Malvaceae, Rosaceae and Zingiberaceae species were found to possess anti-atherosclerotic properties. DISCUSSION AND CONCLUSIONS: The phylogeny identified certain plant families with disproportionately more species, highlighting their importance as sources of natural products for CV drug discovery. Though there were some species that did not show the same mechanism within the family, the phylogeny predicts that these species may contain undiscovered phytochemistry, and potentially, the same bioactivity. Evolutionary pharmacology, as applied here, may guide and expedite our efforts in discovering sources of new CV drugs. PMID- 29486639 TI - Cilioretinal artery occlusion associated with cisplatin. AB - Introduction Cancer is an important risk factor for venous and arterial thromboembolic events. Treatment with chemotherapy was associated with a 6.5-fold increase in the risk of thromboembolic events. Here, we present a patient with cilioretinal artery emboli during cisplatin-based therapy. Case report A 54-year old male patient with a diagnosis of metastatic small cell carcinoma was under cisplatin-based regimen. He presented with visual disturbance. Retinal fluorescein angiography showed multiple plaques located in cilioretinal artery and cilioretinal artery occlusion. After excluding other potential etiological factors, patient was diagnosed with cilioretinal artery occlusion associated with cisplatin. Discussion In oncology practice, patients are prone to thromboembolic events due to primary disease, underlying comorbidities and treatment modalities. In addition to numerous toxicities, cisplatin is an important risk factor for thromboembolic events. Clinicians caring patients with a diagnosis of cancer should be aware of this rare complication of cisplatin-based therapies. PMID- 29486638 TI - Evaluating the use of appropriate anticoagulation with lenalidomide and pomalidomide in patients with multiple myeloma. AB - Background Lenalidomide and pomalidomide are two immunomodulatory medications with the potential to improve outcomes for patients with multiple myeloma; however, a black box warning for venous thromboembolism exists. Purpose The purpose of this study was to assess overall adherence to guideline recommendations for anticoagulation therapy with lenalidomide and pomalidomide in multiple myeloma patients. Methods This retrospective study at an ambulatory oncology clinic utilized chart reviews from the calendar years 2013-2016. The primary endpoint was prescription of appropriate anticoagulation upon initiation of therapy based on a list of predetermined risk factors. Secondary endpoints included incidence of deep venous thromboembolism, pulmonary embolism, myocardial infarction, stroke, and major bleed; initial anticoagulant prescribed; and whether or not anticoagulation was prescribed for another disease state. Results A total of 130 patients met inclusion criteria: 70.8% (n = 92) and 29.2% (n = 38) were prescribed lenalidomide and pomalidomide, respectively. A total risk score of two was most common (n = 54, 41.5%). Aspirin 81 mg oral tablet was prescribed most often (n = 53, 40.8%), followed by no anticoagulation (n = 30, 23.1%). Overall, 27 patients (20.8%) were prescribed anticoagulation in accordance with National Comprehensive Cancer Network guidelines. Incidence of deep venous thromboembolism was the most common adverse event (n = 4, 3.1%), followed by major bleed (n = 1, 0.8%). No reports of pulmonary embolism, myocardial infarction, or stroke were documented. Conclusions Overall, a disparity exists between appropriate prescribing of prophylactic anticoagulation and current practice guidelines. However, documentation of thromboembolic events was lower than recorded in previously published literature. PMID- 29486640 TI - The Level of Personality Organization and Revictimization in Lives of Child Sexual Abuse Survivors. AB - Previous research has documented that women who were sexually abused in childhood are also often victims of sexual abuse in adulthood. In the current study, we investigated the relationship between the phenomenon of sexual revictimization and personality organization (PO) conceptualized in accordance with the Otto Kernberg's theory. The central hypothesis was that women with borderline personality organization (BPO) and neurotic personality organization (NPO) differ in terms of the occurrence of revictimization and its features. We predicted that women with BPO would experience revictimization more often, and that it would be characterized by features determining its higher severity than in women with NPO. In our study, 119 Polish adult women completed measures of PO and experiences of sexual violence in childhood and adulthood. The results supported the predicted relationships. After controlling for participants' age, we showed that women with a close to borderline level of personality organization (cBPO) are at the greater risk of experiencing revictimization than those with NPO, in particular the revictimization involving penetration and by the previously known offender. Moreover, specific structural features related to BPO were found to have particular associations: Fear of Fusion (FF) was associated with the experience of revictimization; Identity Diffusion (ID), Primitive Defense Mechanism (PDM), FF, and Impaired Reality Testing (IRT) with penetration during revictimization; and PDM and IRT with revictimization by the previously known offender. Our findings suggest the importance of taking into account PO in estimating the risk of revictimization, as well as in therapy programs aimed at reducing this risk. PMID- 29486641 TI - ? PMID- 29486642 TI - ? PMID- 29486643 TI - ? PMID- 29486644 TI - ? PMID- 29486645 TI - ? PMID- 29486646 TI - ? PMID- 29486647 TI - ? PMID- 29486648 TI - ? PMID- 29486649 TI - ? PMID- 29486650 TI - ? PMID- 29486651 TI - ? PMID- 29486653 TI - Brain Activity on Observation of Another Person's Action: A Magnetoencephalographic Study. AB - Brain activity was recorded using a whole-head magnetoencephalography system followed by coherence analysis to assess neural connectivity in 10 healthy right handed adults to clarify differences in neural connectivity in brain regions during action observation from several perspectives. The subjects were instructed to observe and memorize or imitate the hand action from a first-person or second person visual perspective. The brain activity in coherence was modified among frontal and central, sensorimotor, and mirror neuron system-related regions based on the visual perspectives of finger movements. The regional activity in coherence changed similarly under the imitation and observation tasks compared with the condition of observing static hand figures. The information from different visual perspectives of body movements was processed in the frontal central regions related to sensorimotor processes and partially in mirror neuron system. PMID- 29486652 TI - Functional sequestration of microRNA-122 from Hepatitis C Virus by circular RNA sponges. AB - Circular RNAs (circRNAs) were recently described as a novel class of cellular RNAs. Two circRNAs were reported to function as molecular sponges, sequestering specific microRNAs, thereby de-repressing target mRNAs. Due to their elevated stability in comparison to linear RNA, circRNAs may be an interesting tool in molecular medicine and biology. In this study, we provide a proof-of-principle that circRNAs can be engineered as microRNA sponges. As a model system, we used the Hepatitis C Virus (HCV), which requires cellular microRNA-122 for its life cycle. We produced artificial circRNA sponges in vitro that efficiently sequester microRNA-122, thereby inhibiting viral protein production in an HCV cell culture system. These circRNAs are more stable than their linear counterparts, and localize both to the cytoplasm and to the nucleus, opening up a wide range of potential applications. PMID- 29486654 TI - Three-year follow-up and quality of life of endovenous radiofrequency ablation of the great saphenous vein with the ClosureFastTM procedure: Influence of BMI and CEAP class. AB - Purpose Endovascular ablation of the great saphenous vein has been proposed as a less invasive alternative to conventional ligation and stripping of varicose veins. Outcomes of patients treated with the radiofrequency ablation ClosureFastTM system over an eight-year period from a single-center were evaluated. Methods Three-year follow-up data included duplex ultrasound scan, complication rate, and questionnaires to assess patients' QOL, level of pain, and days off work. Results A total of 1080 consecutive patients (49.5 +/- 18.6 years, 72% female, mean body mass index: 25.44 +/- 4.1 kg m-2) underwent radiofrequency ablation for incompetent saphenous veins in a single institution. Occlusion of the great saphenous vein was obtained in 98.6% and 93.8% cases at the end of the procedures and within 36 months, respectively. Only three deep venous thromboses and minor complications occurred in this series throughout the first week from the procedure. A decrease of the external vein diameter, equal to 72.7% and 31.1% of the pretreatment diameter, was observed at 1 week and 36 months, respectively. The average Aberdeen Varicose Vein Questionnaire score improved from 18.06 +/- 9.47 before treatment to 11.56 +/- 10.23 at 12 months, with no significant differences in the subsequent follow-up. SF-36 QOL scores significantly improved after the procedure in all domains, while there were no changes over time. Patients reported a prompt return to normal daily activities (1.5 +/- 0.7 days) and work (3.1 +/- 1.9 days). Body mass index influenced QOL scores, while it did not affect great saphenous vein diameter reduction during the follow-up. On the contrary, Clinical Etiologic Anatomic Pathophysiologic class significantly influenced both great saphenous vein diameter reduction after the treatment and QOL scores within 36 months. Conclusion Results of this retrospective monocentric, large patients study suggest that radiofrequency ablation of the great saphenous vein may be a safe and efficient alternative to conventional surgery. PMID- 29486655 TI - Association of human platelet antigen polymorphisms with platelet count and mean platelet volume. AB - OBJECTIVES: Although recent genome-wide association studies have identified a number of single nucleotide polymorphisms associated with platelet count and mean platelet volume (MPV), it is unclear whether polymorphisms in the human platelet antigens (HPA) genes are associated with platelet count and MPV. The aim of this study was to determine the association of the HPA-2, -3, -5 and -15 polymorphisms with platelet count and MPV. METHODS: The HPA were genotyped by 5'-nuclease assay in 139 healthy Chinese Han individuals, while platelet count and MPV from the same samples were measured using an hematology cell analyzer. RESULTS: The platelet count was significantly lower in the individuals with the HPA-2aa genotype compared to those with HPA-2ab (P = 0.020), and significantly higher in individuals with HPA-5aa and HPA-15aa genotypes compared to those with HPA-5ab (P = 0.045) and HPA-15ab/bb (P = 0.032), respectively. On the other hand, platelet count of individuals with the HPA-3aa and HPA-3ab/bb genotypes did not differ significantly (P = 0.084). The MPV was significantly lower in individuals with HPA-5aa genotype compared to those with HPA-5ab (P = 0.001) but did not differ among the HPA-2, -3 and -15 genotypes. Furthermore, HPA-2, -5 and -15 polymorphisms were identified as independent factors for the platelet count and HPA-5 polymorphism was shown as an independent factor for MPV. CONCLUSIONS: This study demonstrates that HPA-2, -5 and -15 polymorphisms are associated with the platelet count while HPA-5 polymorphism is associated with MPV. This finding will further our understanding of the association of HPA polymorphisms with platelet related diseases. PMID- 29486656 TI - Aluminium in foodstuff and the influence of aluminium foil used for food preparation or short time storage. AB - Aluminium is an omnipresent part of everyday life. It is widely used in industry and furthermore in products like cosmetics, sun creams or it can be applied for instance as aluminium foil by consumers during food preparation in households. However, over the last decades the toxicity of aluminium for humans has been heavily discussed and is still not completely clarified. Therefore, food aluminium concentrations were investigated in different untreated foodstuff as well as a possible aluminium transfer from aluminium foil to food. The results show that untreated food is not significantly contaminated. Furthermore, short time contact to aluminium foil increases the food aluminium concentration only marginally. Nevertheless, as soon as the food is in contact to aluminium foil and at the same time in contact with metals (alloys) with a higher standard electrode potential than aluminium (-1.66 V) high aluminium contaminations were observed. PMID- 29486657 TI - Aflatoxins in sunflower seeds and unrefined sunflower oils from Singida, Tanzania. AB - A total of 61 samples comprising sunflower seeds (40) and unrefined sunflower oils (21) samples collected randomly from Singida, Tanzania were analysed by Reverse Phase-high performance liquid chromatography (RP-HPLC). 15% (6/40) of the seed samples were contaminated with aflatoxin B1 ranging from limit of detection (LOD) to 218 ng g-1 with three of them exceeding the European Commission/European Union (EC/EU) and Tanzania Bureau of Standards (TBS)/Tanzania Food and Drug Authority (TFDA) maximum limits of 2 ng g-1 for AFB1 in oilseeds. The levels of total aflatoxins (AFT) in seeds ranged from LOD to 243 ng g-1. Other aflatoxins, except AFG2, were also detected. For the unrefined sunflower oils, the levels of AFB1 ranged from LOD to 2.56 ng mL-1. About 80.9% (17/21) of the analysed oil samples contained AFB1 of which 17.65% (3/17) exceeded the EC/EU and TBS/TFDA maximum limits of 2 ng mL-1. Other aflatoxins were also detected in the oils. The measured levels indicate there is a need for food quality education among food processors. PMID- 29486658 TI - Polycyclic aromatic hydrocarbons in traditionally smoked meat products from the Baltic states. AB - A total of 77 traditionally smoked meat samples produced in Latvia, Lithuania, and Estonia were tested for the occurrence of four EU regulated polycyclic aromatic hydrocarbons (PAHs). Levels of PAHs exceeding the EU maximum levels for benzo[a]pyrene and for the sum of four PAHs (PAH4) were detected in 46% and 48% of the samples originating from Latvia. The detected BaP levels in smoked meats ranged from 0.05 to 166 MUg kg-1, while the PAH4 content ranged from 0.42 to 628 MUg kg-1. The mean dietary exposure to PAHs was estimated at the levels of 5.4 ng BaP/kg bw/day and 36 ng PAH4/kg bw/day. The margin of exposure (MOE) approach was utilised to assess the risks to Latvian consumers due to PAHs and the obtained MOEs were in a range of 7205-24,434, thus indicating a potential concern for consumer health for specific population groups. PMID- 29486659 TI - Reducing Commercial Truck Driver BMI Through Motivational Interviewing and Self Efficacy. AB - Obesity is recognized as a national and global health epidemic. Commercial truck drivers (CTDs) have a higher obesity rate and lower life expectancy compared with the general population. CTDs work sedentary jobs with long hours that pose barriers to healthy eating and regular exercise. An evidenced-based practice (EBP) change project that used motivational interviewing (MI) and education regarding diet and exercise over a 4-week period was found to have a positive impact on CTDs behavior. Results revealed an increase in aggregated self-efficacy for weight loss (14.8%, exceeding the benchmark of 11%). For aggregated body mass index (BMI), CTDs lost a mean of 0.65 kg/m2, over a 4-week period which was statistically significant at p = .0001. The results suggest a short-term MI intervention can be effective when implemented as a clinical standard for CTDs. PMID- 29486660 TI - Consistent Use of Assistive Devices for Patient Transfer Is Associated With Less Patient-Initiated Violence: Cross-Sectional Study Among Health Care Workers at General Hospitals. AB - This study investigated whether factors related to bodily contact between health care workers and patients were associated with patient-initiated violence. This cross-sectional study surveyed 496 Danish health care workers measuring patient initiated violence, use of assistive devices, body mass index, physical exertion, frequency of patient transfers, psychosocial work environment, gender, age, and seniority. Associations were modeled using logistic regression analyses using patient-initiated violence as the outcome. Twenty-five percent of the respondents had experienced physical or verbal violence during the past year. Infrequent use of assistive devices, high physical strain, and severe obesity all significantly increased the risk of physical violence (risk ratio [RR] = 1.18, RR = 1.18, and RR = 1.16, respectively), whereas only the lack of assistive device use significantly increased the risk of verbal violence (RR = 1.13 and RR = 1.08). Consistent use of assistive devices appears to reduce the risk of patient initiated violence. Managers should require the use of assistive devices when designing work processes for patient transfers. PMID- 29486661 TI - Clinical outcomes of myeloid/lymphoid neoplasms with fibroblast growth factor receptor-1 (FGFR1) rearrangement. AB - OBJECTIVE: Myeloid/lymphoid neoplasms with fibroblast growth factor receptor-1 (FGFR1) rearrangement are hematopoietic stem cell disorders with a poor prognosis, but no established standard therapy. METHODS: We experienced a patient with T-lymphoblastic lymphoma (LBL) associated with FGFR1 rearrangement who underwent cord blood transplantation, but died of pulmonary complication. We collected the clinical data of patients with FGFR1 rearrangement from the medical literature and analyzed 45 patients, including our patient. RESULTS: The primary diagnoses were myeloproliferative neoplasm (MPN) or myelodysplastic syndromes (MDS) in 14 and acute leukemia or LBL in 31. In MPN and MDS patients, the cumulative incidence of transformation to blast phase (BP) at 12 months was 46.2%. The 1-year overall survival (OS) from diagnosis in all cases was 43.1%. With regard to the impact of treatment response on survival, the achievement of complete response with a landmark at 2 months after diagnosis of BP was associated with a superior OS (40.0% vs. 26.0% P = 0.011 for 1-year OS from BP). Allogeneic hematopoietic stem cell transplantation (HSCT) was performed in 13 patients, and the 1-year OS from allogeneic HSCT was 61.5%. The hazard ratio for mortality was 0.34 (95% CI, 0.08-1.51, P = 0.15) for allogeneic HSCT treated as a time-dependent covariate, which suggests that allogeneic HSCT may confer a clinical benefit. CONCLUSION: The further accumulation of clinical data is needed to determine the optimal therapeutic approach for these neoplasms. PMID- 29486662 TI - Polycyclic aromatic hydrocarbons in teas using QuEChERS and HPLC-FLD. AB - Polycyclic aromatic hydrocarbons (PAHs) are food-processing contaminants considered to be carcinogenic and genotoxic. Due to its drying process stage, teas may be contaminated with PAHs. The aim of the study was to validate an analytical method involving QuEChERS and HPLC-FLD for the determination of PAH4 in teas and evaluate the contamination levels in 10 different types of teas from Brazil. Recoveries varied from 54% to 99% and relative standard deviations from 1% to 21%. Limits of detection and quantification were from 0.03 to 0.3 ug/kg and 0.1 to 0.5 ug/kg, respectively. Mate tea presented the highest PAH levels, with PAH4 varying from 194 to 1795 ug/kg; followed by black (1.8-186 ug/kg), white (24 119 ug/kg), and green teas (3.1-92 ug/kg). Teas with lowest PAH4 were strawberry, lemongrass, peppermint, and boldo. Only trace levels of PAHs were detected in tea infusions, so apparently it would not affect PAH intake by Brazilian population. PMID- 29486663 TI - Outcomes with frontline nilotinib treatment in Turkish patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase. AB - OBJECTIVES: Nilotinib is a BCR-ABL1 tyrosine kinase inhibitor approved for the treatment of patients with chronic myeloid leukemia in chronic phase (CML-CP). This study was the first prospective evaluation of the efficacy and safety of nilotinib in Turkish patients with newly diagnosed CML-CP. The primary endpoint of the study was the rate of major molecular response (MMR; BCR-ABL1 <= 0.1% on the International Scale [BCR-ABL1IS]) by 12 months. METHODS: Patients with newly diagnosed CML-CP were treated with nilotinib 300 mg twice daily. This analysis was based on the first 12 months of follow-up in a 24-month study. This study is registered with ClinicalTrials.gov (NCT01274351). RESULTS: Of 112 patients enrolled, 66.1% (80% CI, 59.7-72.0%) achieved MMR and 22.3% achieved a deep molecular response of MR4.5 (BCR-ABL1IS <=0.0032%) by 12 months. During the first year of treatment, one patient progressed to blast crisis and two patients died. Safety results were consistent with previous studies. Most adverse events (AEs) were grade 1/2. Most frequently reported nonhematologic AEs of any grade were elevations in bilirubin, alanine aminotransferase, and triglycerides. CONCLUSION: These results support the use of nilotinib 300 mg twice daily as a standard-of care treatment option for patients with newly diagnosed CML-CP with low and intermediate risk. PMID- 29486664 TI - A Pharmacy-Based Electronic Handoff Tool to Reduce Discharge Prescribing of Atypical Antipsychotics Initiated in the Intensive Care Unit: A Quality Improvement Initiative. AB - PURPOSE: To evaluate whether a pharmacist-initiated electronic handoff tool can reduce the overall, and potentially inappropriate, hospital discharge prescribing rate of atypical antipsychotics (AAP) initiated in AAP-naive critically ill adults. METHODS: This pre-post quality improvement study was initiated in 5 intensive care units (ICUs) at a large academic medical center. An electronic handoff tool (iVent) was utilized in the post-intervention period to enhance pharmacist communication at inpatient transitions of care. RESULTS: Of the 358 included patients, the proportion of hospital survivors with an AAP initiated in the ICU receiving a hospital discharge prescription was not different between the pre- and post-intervention period (28.6% vs 22.2%, P = .12). The proportion of ICU survivors with an AAP continued at the time of ICU transfer to the floor was reduced post-intervention (78.7% vs 66.7%, P = .012). Additionally, the overall proportion of a patient's hospitalization receiving an AAP was also reduced (50.4% vs 42.8%, P = .008). A multivariate logistic regression demonstrated thatutilization of the electronic handoff tool was not associated with a reduction in hospital discharge prescribing of an AAP (odds ratio [OR]: 0.97, 95% confidence interval [CI]: 0.57-1.65). CONCLUSIONS: A pharmacy-initiated electronic handoff tool may reduce the proportion of AAP-naive ICU survivors with an AAP continued at the time of ICU transfer. The handoff tool was not associated with a significant reduction in the discharge prescribing rates of AAPs for hospital survivors, but a clinically meaningful reduction was possibly achieved due to enhanced communication enabled by this tool. PMID- 29486665 TI - Mirtazapine-Induced Pancreatitis-A Case Report. AB - Acute pancreatitis has numerous etiologies, with the most common including gallstones, alcohol abuse, and medications such as angiotensin-converting enzyme (ACE) inhibitors, statins, and diuretics. Mirtazapine has been associated with increased serum cholesterol and serum triglyceride levels. However, few studies have reported dangerously elevated triglyceride levels resulting in acute pancreatitis. This report discusses a case of mirtazapine-induced pancreatitis in a 46-year-old African American female. The patient presented to the emergency department with pancreatitis, presumably alcohol-induced as with a prior admission, but she denied any recent alcohol use. Mirtazapine then became the suspected cause of her hypertriglyceridemia-induced pancreatitis and was discontinued. After discontinuing mirtazapine, and utilizing an insulin infusion, her triglyceride levels normalized and symptoms of pancreatitis resolved. Using the Naranjo Adverse Drug Reaction Probability Scale, a total score of 5 was calculated indicating a probable adverse drug reaction of acute pancreatitis from mirtazapine. PMID- 29486666 TI - Identifying Opportunities for Improvement in Safety and Efficacy of Community Pharmacy Immunization Programs. AB - OBJECTIVE: To identify opportunities to improve safe and effective immunization delivery in community pharmacies. METHODS: Pharmacy managers from chains in Michigan were interviewed about their company's immunizations programs. A survey regarding immunization training, quality assurance measures, pharmacist comfort level immunizing different patient populations, and resources used in practice was distributed to community pharmacists throughout Michigan. RESULTS: Most pharmacists (88.8%) confirmed they received American Pharmacists Association immunization training and felt they followed the guidelines outlined in that training course very well. No routine reassessment of immunization technique was reported. In a minority of respondents, some issues were identified: (1) not being up-to-date on cardiopulmonary resuscitation certification as required by state law (7.1%), (2) lack of awareness of location of emergency kit (4.2% for epinephrine, 13.5% for diphenhydramine), and (3) feeling uncomfortable immunizing children (51% for children <7 years). CONCLUSION: To address quality control issues identified in the survey, we recommend chain pharmacies incorporate credential checks into annual pharmacy training requirements. Pharmacists may benefit from immunization-related continuing education requirements. State pharmacy organizations may want to take the lead in developing the material to ensure that it is timely and abides by state and federal laws. PMID- 29486667 TI - Which Measures of Online Control Are Least Sensitive to Offline Processes? AB - A major challenge to the measurement of online control is the contamination by offline, planning-based processes. The current study examined the sensitivity of four measures of online control to offline changes in reaching performance induced by prism adaptation and terminal feedback. These measures included the squared Z scores (Z2) of correlations of limb position at 75% movement time versus movement end, variable error, time after peak velocity, and a frequency domain analysis (pPower). The results indicated that variable error and time after peak velocity were sensitive to the prism adaptation. Furthermore, only the Z2 values were biased by the terminal feedback. Ultimately, the current study has demonstrated the sensitivity of limb kinematic measures to offline control processes and that pPower analyses may yield the most suitable measure of online control. PMID- 29486668 TI - Partially threaded headless screw may benefit adequate interfragmentary compression and reduced driving torque for small bone fixation. AB - Headless compression screws (HCSs) are commonly used to fixate small bones and articular fractures. Understanding the biomechanical efficacy of different HCS designs can help surgeons make proper interfragmentary compression when a specific implant is chosen. HCSs with three different central shaft designs (unthreaded, fully threaded, and partially threaded) were studied: the Herbert Whipple, Mini-Acutrak 2, and headless reduction (HLR). Polyurethane foam blocks were machined with a simulated fracture gap of 0.5 mm and set onto a custom-made jig to simultaneously measure compression force and driving torque during screw insertion. The maximal achievable compression forces and driving torques recorded were 47.4 +/- 0.9 N and 145.11 +/- 1.65 N mm for the HLR, 50.98 +/- 1.29 N and 152.62 +/- 2.83 N mm for the Mini-Acutrak 2, and 19.33 +/- 1.0 N and 33.4 +/- 2.2 N mm for the Herbert-Whipple. Overall, the compression force of the Mini-Acutrak 2 and HLR increased with the torque. Unlike the other screws, the Herbert Whipple's driving torque increased while the compression force decreased after peak compression force was achieved. The partially threaded shaft design (HLR) demonstrated equivalent biomechanical advantage with the Mini-Acutrak 2 in interfragmentary compression. The HCSs with cone-shaped proximal ends (HLR and Mini-Acutrak 2) maintained their compression force during over-fastening, whereas the unthreaded central shaft of the Herbert-Whipple screw caused it to lose compression force. PMID- 29486669 TI - Ultrasonographic movement of the flexor pollicis longus tendon before and after removal of a volar plate for the distal radius fracture. AB - INTRODUCTION: The purpose of this study was to compare the movement of the flexor pollicis longus (FPL) tendon on the distal radius during wrist and finger motions before and after removal of a volar plate in patients with distal radius fractures using transverse ultrasound and to evaluate the kinematic effects on the FPL by the removal. METHODS: Twenty-five patients with distal radius fracture were evaluated quantitatively by transverse ultrasound using coordinates for the movement of the FPL on the distal radius during wrist and finger motions before and after the plate removal. RESULTS: At all wrist positions, during finger motion, the FPL moved significantly more palmarly away from the radius after plate removal compared to before. However, the FPL was still situated more dorsoulnarly compared with unaffected side. Moreover, the FPL moved significantly most dorsally both before and after removal at the wrist dorsal flexion position with finger flexion. CONCLUSIONS: These findings suggested that any adhesion between the FPL and the pronator quadratus (PQ) muscle was released by removing the plate and that the FPL would approach original tendon movement. Additionally, it is speculated that any remaining atrophy and fibrosis of the PQ may be the reason for more dorsoulnar location of the FPL in the affected side compared with the unaffected one. This ultrasound evaluation may be useful in further understanding the FPL kinematics on the distal radius, and in appropriate treatment of the distal radius fracture with plate fixation for preventing FPL rupture. PMID- 29486670 TI - Synovial fluid levels of TWEAK and matrix metalloproteinase 1 in patients with osteoarthritis, and associations with disease severity. AB - PURPOSE: This study assessed the levels of soluble tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and matrix metalloproteinase 1 (MMP-1) in the synovial fluid from osteoarthritic knees to determine their role as well as the relationship between these levels and the severity of osteoarthritis (OA). METHODS: Synovial fluid was obtained from 44 knees of 40 patients. The Kellgren Lawrence (KL) grade was measured using radiograph. The concentration of TWEAK and MMP-1 in the synovial fluid was assessed by enzyme-linked immunosorbent assay. The underlying inflammatory factors (erythrocyte sedimentation rate and C reactive protein) were also measured. We analyzed the correlation between the factors measured. In addition, the samples were subdivided into three groups according to OA severity using the KL grade, and the differences in TWEAK and MMP 1 levels between groups were analyzed. RESULTS: The TWEAK and MMP-1 levels in the synovial fluid showed a positive correlation with each other. The TWEAK and MMP-1 levels were compared between the three groups according to the KL grade, and the levels showed a significant difference. A post hoc test demonstrated that the group with advanced OA showed a lower concentration of both factors when compared to groups with early OA. CONCLUSION: The concentration of TWEAK and MMP-1 in the synovial fluid were relatively high in the early stage of OA, and the levels decreased as the OA progressed. PMID- 29486671 TI - Incomplete articular-side repair increase re-tear rate in full-thickness rotator cuff tears. AB - PURPOSE: This study compared the functional outcome and repair integrity of arthroscopic rotator cuff repair according to articular-side repair state in full thickness tears. METHODS: We prospectively enrolled 80 consecutive patients with full-thickness rotator cuff tears of 1.5-3.5 cm at the anterior to posterior dimension. These patients were divided into two groups according to intraoperative articular-side repair state during operation: complete and incomplete repair groups. Repair integrity was evaluated at 6 months after the operation by magnetic resonance image or ultrasonography. Clinical outcomes were evaluated at 1 year and 2 years postoperatively. Four outcome measures were used in this study: visual analog scale pain score, American Shoulder and Elbow Surgeons (ASES) score, the Shoulder Rating Scale of the University of California at Los Angeles (UCLA) score, and range of motion. RESULTS: At 2-year follow-up, the average UCLA, ASES, and constant score improved significantly to 32.46, 87.94, and 79.69, respectively, in the complete group and to 32.50, 87.65, and 78.92, respectively, in the incomplete group. The UCLA, ASES, and constant score improved in both groups postoperatively (all ps < 0.000); however, there was no significant difference between the two groups ( p = 0.960, 0.921, and 0.796, respectively). The re-tear rate was 13.7% in the shoulders that underwent complete repair and 33.3% in the shoulders that underwent incomplete repair; this difference was statistically significant ( p = 0.041). CONCLUSION: Regardless of the repair state of articular-side rotator cuff, the arthroscopic rotator cuff repair resulted in comparable functional outcomes between two groups at short term follow-up. However, patients who repaired articular-side rotator cuff incompletely revealed higher re-tear rate after operation than those who repaired completely. PMID- 29486672 TI - Reverse shoulder arthroplasty for the treatment of acute complex proximal humeral fractures: Influence of greater tuberosity healing on the functional outcomes. AB - PURPOSE: To investigate the influence of greater tuberosity healing on the functional outcomes of reverse shoulder arthroplasty (RSA) for the treatment of acute complex proximal humeral fractures (PHFs), and to investigate the influence of patient- and surgery-related factors in the healing of the greater tuberosity. METHODS: Retrospective study including 41 consecutive PHFs treated using RSA with minimum 2-year follow-up. In all the cases, tuberosities were reattached with a standardized technique. All the patients were assessed at the last follow-up with constant score. Body mass index, surgery delay, comorbidities, polyethylene size, glenosphere size, overhanging of glenosphere, and scapular notch were recorded, and their influence in final constant score and in greater tuberosity healing was analyzed. RESULTS: Mean final constant score was of 60.7 points (standard deviation (SD) = 9.9). Greater tuberosity healed in proper position in 68% of the cases. There were no significant differences in constant score between patients with (mean = 61; SD = 9.5) and without (mean = 61; SD = 11.3) the healing of greater tuberosity. All patients scored above 90 degrees in forward elevation. Scapular notch was reported in 14.6% of the cases. Age significantly affected the constant score ( p = 0.008). Comorbidities significantly interfered with greater tuberosity healing ( p = 0.03). There was one reoperation after dislocation. CONCLUSION: In spite of expecting good functional outcome with low complication rate after RSA for acute PHFs, the influence of greater tuberosity healing on shoulder function could not be demonstrated. The presence of comorbidities, but not age or gender, negatively influenced the healing of the greater tuberosity. PMID- 29486673 TI - Cellular Plasticity-Targeted Therapy in Head and Neck Cancers. AB - Head and neck cancer is one of the most frequent human malignancies worldwide, with a high rate of recurrence and metastasis. Head and neck squamous cell carcinoma (HNSCC) is cellularly and molecularly heterogeneous, with subsets of undifferentiated cancer cells exhibiting stem cell-like properties, called cancer stem cells (CSCs). Epithelial-mesenchymal transition, gene mutation, and epigenetic modification are associated with the formation of cellular plasticity of tumor cells in HNSCC, contributing to the acquisition of invasive, recurrent, and metastatic properties and therapeutic resistance. Tumor microenvironment (TME) plays a supportive role in the initiation, progression, and metastasis of head and neck cancer. Stromal fibroblasts, vasculature, immune cells, cytokines, and hypoxia constitute the main components of TME in HNSCC, which contributes not only to the acquisition of CSC properties but also to the recurrence and therapeutic resistance of the malignancies. In this review, we discuss the potential mechanisms underlying the development of cellular plasticity, especially the emergence of CSCs, in HNSCC. We also highlight recent studies implicating the complex interplays among TME components, plastic CSCs, tumorigenesis, recurrence, and therapeutic resistance of HNSCC. Finally, we summarize the treatment modalities of HNSCC and reinforce the novel concept of therapeutic targeting CSCs in HNSCC. PMID- 29486674 TI - Renal involvement in paroxysmal nocturnal hemoglobinuria: an update on clinical features, pathophysiology and treatment. AB - OBJECTIVES: The present review summarizes the available knowledge regarding acute and chronic kidney dysfunction in patients with paroxysmal nocturnal hemoglobinuria (PNH) focusing on its clinical features, pathophysiology and treatment. METHODS: A thorough PubMed search was performed using as main keywords: 'paroxysmal nocturnal hemoglobinuria', 'acute kidney injury', 'chronic kidney disease' and 'eculizumab'. RESULTS: PNH's etiopathogenesis is based on acquired mutations that lead to the reduction or absence of CD55 and CD59 complement regulators, which are responsible for some of the disease's major clinical features, like intravascular hemolysis, cytopenias and thrombosis. PNH is often underdiagnosed, mainly due to its occasional mild manifestations and to its ability to mimic other severe clinical conditions. Various mechanisms have been proposed for the kidney damage attributed to the release of cell-free heme and free iron, including inflammatory response, oxidative stress, nitric oxide depletion, renal ischemia, membrane damage and apoptosis. Eculizumab, a terminal complement inhibitor, provides a safe and effective treatment option, especially when it is initiated early in the presence of kidney damage. DISCUSSION: Kidney injury is a poorly investigated clinical feature of PNH that affects a significant portion of patients. Increased awareness is needed by physicians to recognize the early signs and symptoms of acute and chronic renal insufficiency, so as to initiate the necessary therapy. It is also important to re-evaluation of PNH-specific treatments during the course of the disease. CONCLUSION: Understanding the difficult but at the same time impressive mechanisms behind PNH remains a challenge for treating physicians. PMID- 29486675 TI - Popliteal Venous Aneurysm Presenting With Bilateral Pulmonary Thromboembolism. AB - A 12-year-old boy presenting with chest pain and dyspnea was found to have bilateral pulmonary thromboembolism (PTE) secondary to left popliteal venous aneurysm (PVA) with thrombus. He improved with thrombolytics, developed recurrent PTE, then underwent surgical repair of his PVA. The pathophysiology, diagnosis, and management of PVA are discussed. PMID- 29486676 TI - Complete Lower Extremity Revascularization via a Hybrid Procedure for Patients with Critical Limb Ischemia. AB - BACKGROUND: Complete revascularization, achieving inline flow to the foot through at least 1 patent tibioperoneal artery, is considered to be desirable for treating critical limb ischemia (CLI). Hybrid procedure, combined femoral endarterectomy and endovascular treatment, is commonly performed on patients with CLI because they often present with complicated lower extremity lesions involving the common femoral artery. This study aimed to investigate the efficacy of complete revascularization (CR) achieved by hybrid procedure on limb salvage in patients with CLI. METHODS: Between February 2010 and January 2016, 95 limbs (82 patients) were treated by lower extremity hybrid procedure; of these 95 procedures, 61 were for patients with CLI. We defined CR as achieving inline flow to the foot through at least 1 patent tibioperoneal artery. Complete revascularization was performed on 37 limbs, and incomplete revascularization (IR) was performed on 24 limbs. Specific variables, including patient age, male female ratio, Rutherford classification, preoperative and postoperative ankle brachial pressure indices (ABIs), follow-up duration (months), primary patency rate, assisted primary patency rate, secondary patency rate, and major amputation rate, were analyzed. RESULTS: The mean age was similar between the groups 67.2 years in the CR group and 70.7 years in the IR group ( P = .11). Limb ischemia severity was significantly higher in the CR group: 63% of the patients scored Rutherford 5 in the CR group, compared to 30% in the IR group ( P = .027). Mean postoperative ABI was significantly higher in the CR group (CR: 0.87, IR: 0.53; P = .0001). Major amputation rate was higher in the IR group (CR: 2.7%, IR: 13%; P = .29), and major amputation-free survival rate at 3 years after the index procedure was higher in the CR group (CR: 97%, IR: 81%; P = .054). CONCLUSION: Complete lower extremity revascularization was beneficial for patients with CLI, avoiding major amputation. PMID- 29486678 TI - Dental Radiography of the Horse. AB - This step-by-step article describes radiographic imaging of the horse's teeth and paranasal sinuses with standard radiographic equipment. Obtaining radiographs of the horse's skull that are of diagnostic quality can be challenging. The descriptions offered in this article can help practitioners become more comfortable with obtaining diagnostic images, which will improve recognition of radiographic signs of dental and paradental pathology. PMID- 29486679 TI - Cementation of Full Coverage Metal Crowns in Dogs. AB - This step-by-step article describes the technique for cementation of a full metal prosthodontic crown on the maxillary fourth premolar tooth of a dog using a common resin-based cement. PMID- 29486680 TI - Histopathologic Diagnoses From Biopsies of the Oral Cavity in 403 Dogs and 73 Cats. AB - This retrospective study documents the prevalence of various histopathological diagnoses within a practice specializing in veterinary dentistry and oral surgery. Histopathology results obtained from biopsies of oral lesions from 403 dogs and 73 cats were sorted and categorized. Lesions of inflammatory origin represented the most common histopathology result in cats (n = 37; 51%), followed by squamous cell carcinoma (n = 27; 37%). The most common histopathological diagnoses in dogs were malignant neoplasms (n = 151; 37%), followed by tumors of odontogenic origin (n = 138, 34%) and lesions of inflammatory origin (n = 114; 28%). The results of this study are representative of a private referral dentistry practice and are compared to other studies that assessed common oral neoplasia diagnoses in dogs and cats. Treatment options and prognoses of the most common canine and feline neoplasms are discussed. PMID- 29486681 TI - A Review of Dental Cements. AB - This review provides an in-depth comparison of advantages and disadvantages of different types of dental cements as they are used for cementing base metal alloy crowns in dogs. PMID- 29486682 TI - Successful Treatment of a Persistent Oroantral Fistula via Transbuccal and Transnasal Endoscopic Debridement in a Horse. AB - We report an unusual case of a young Quarter Horse with a large dental fracture fragment displaced into the maxillary sinus, leaving an oroantral communication that caused food impaction and metaplastic calcification in the sinus and facial deformation with cutaneous fistulation. Oral extraction of a remaining tooth fragment from its alveolus was succeeded by a maxillary sinusotomy for removal of the abnormal sinus contents. Since the oroantral fistula did not heal spontaneously following the placement of a silicone dental prosthesis, minimally invasive transbuccal and transnasal endoscopic approaches were used to encourage closure of the oroantral fistula by alveolar granulation. The clinical, diagnostic, and therapeutic features of this case may be helpful to clinicians when dealing with similar cases. PMID- 29486683 TI - New Challenges in 2018! PMID- 29486686 TI - A Modified Technique for Extraction Site Closure of the Maxillary Molars in a Dog. AB - Performing oral surgery in dogs can present unique challenges. Among those challenges are the varying size and anatomical shape of the oral cavity in veterinary patients. Very small dogs and brachycephalic breeds provide limited exposure to the caudal maxilla. With the addition of an endotracheal tube and tie, the operating window can be quite limited and difficult to visualize and instrument. The following is a simple yet effective step-by-step procedure of tension-free closure of maxillary molar extractions in the dog. PMID- 29486687 TI - Transposition of Mandibular Molars in a Dog. AB - Tooth transposition is a rare anomaly resulting in the interchanged position of 2 permanent teeth. Etiology of tooth transposition is unclear. In human dentistry, multiple influences are described, and there is strong evidence of a genetic basis. This is the first reported case of tooth transposition in a dog. PMID- 29486689 TI - Attention: Veterinary Technicians, Managers and Veterinarians. PMID- 29486691 TI - Relevant research from orthodontic journals. PMID- 29486692 TI - Programmed Aging of Mammals: Proof of Concept and Prospects of Biochemical Approaches for Anti-aging Therapy. AB - (i) In 2015-2017 we compared possible reasons for longevity of two mammalian highly social species, i.e. naked mole rats and humans. We proposed that in both cases longevity is a result of neoteny, prolongation of youth by deceleration of late ontogeny (Skulachev, V. P. (2015) Abst. 11th Conf. on Mitochondrial Physiology (MiP2015), Lucni Bouda, Czech Republic, pp. 64-66; Skulachev, V. P., Holtze, S., Vyssokikh, M. Y., Bakeeva, L. E., Skulachev, M. V., Markov, A. V., Hildebrandt, T. B., and Sadovnichii, V. A. (2017) Physiol. Rev., 97, 699-720). Both naked mole rats and humans strongly decreased the pressure of natural selection, although in two different manners. Naked mole rats preferred an "aristocratic" pathway when reproduction (and, hence, involvement in evolution) is monopolized by the queen and her several husbands. Huge number of subordinates who have no right to take part in reproduction and hence in evolution serves the small queen's family. Humans used an alternative, "democratic" pathway, namely technical progress facilitating adaptation to the changing environmental conditions. This pathway is open to all humankind. (ii) As a result, aging as a mechanism increasing evolvability by means of facilitation of natural selection became unnecessary for naked mole rats and humans due to strong attenuation of this selection. This is apparently why aging became a counterproductive atavism for these two species and was strongly shifted to late ages. This shift is direct evidence of the hypothesis that aging is programmed, being the last step of late ontogeny. (iii) Further deceleration of aging for humans by means of neoteny is unrealistic since the development of neoteny probably takes million years. (iv) However, if biological aging is a program, an alternative and much simpler way to avoid it seems possible. We mean inhibition of an essential step of this program. (v) At present, the most probable scheme of the aging program assumes that it is a mechanism of slow poisoning of an organism by reactive oxygen species produced by mitochondria. If this is the case, a mitochondria-targeted antioxidant might be an inhibitor of the aging program. During the last 12 years, such an antioxidant, namely SkQ1, was synthesized and studied in detail in our group. It consists of plastoquinone and decyltriphenylphosphonium (a penetrating cation responsible for electrophoretic accumulation of SkQ1 in mitochondria). It was shown that long-term treatment with SkQ1 increased the lifespan of plants, fungi, invertebrates, fish, and mammals. Moreover, SkQ1 is effective in the therapy of various age-related diseases. It was also shown that a single SkQ1 injection could save life in certain models of sudden death of animals. (vi) A tentative scheme is proposed considering aging as a process of chronic phenoptosis, which eventually results in initiation of acute phenoptosis and death. This scheme also suggests that under certain conditions chronic phenoptosis can be neutralized by an anti-aging program that is activated by food restriction regarded by an organism as a signal of starvation. As for acute phenoptosis, it is apparently controlled by receptors responsible for measuring key parameters of homeostasis. The first experimental indications have been already obtained indicating that both chronic and acute phenoptosis are suppressed by SkQ1. PMID- 29486693 TI - Evolvability, Population Benefit, and the Evolution of Programmed Aging in Mammals. AB - Programmed aging theories contend that evolved biological mechanisms purposely limit internally determined lifespans in mammals and are ultimately responsible for most instances of highly age-related diseases and conditions. Until recently, the existence of programmed aging mechanisms was considered theoretically impossible because it directly conflicted with Darwin's survival-of-the-fittest evolutionary mechanics concept as widely taught and generally understood. However, subsequent discoveries, especially in genetics, have exposed issues with some details of Darwin's theory that affect the mechanics of the evolution process and strongly suggest that programmed aging mechanisms in humans and other mammals can and did evolve, and more generally, that a trait that benefits a population can evolve even if, like senescence, it is adverse to individual members of the population. Evolvability theories contend that organisms can possess evolved design characteristics (traits) that affect their ability to evolve, and further, that a trait that increases a population's ability to evolve (increases evolvability) can be acquired and retained even if it is adverse in traditional individual fitness terms. Programmed aging theories based on evolvability contend that internally limiting lifespan in a species-specific manner creates an evolvability advantage that results in the evolution and retention of senescence. This issue is critical to medical research because the different theories lead to dramatically different concepts regarding the nature of biological mechanisms behind highly age-related diseases and conditions. PMID- 29486694 TI - Externally Regulated Programmed Aging and Effects of Population Stress on Mammal Lifespan. AB - Programmed (adaptive) aging refers to the idea that mammals, including humans and other complex organisms, have evolved mechanisms that purposely cause or allow senescence or otherwise internally limit their lifespans in order to obtain an evolutionary advantage. Until recently, programmed aging had been thought to be theoretically impossible because of the mechanics of the evolution process. However, there is now substantial theoretical and empirical support for the existence of programmed aging in mammals. Therefore, a comprehensive approach to medical research on aging and age-related diseases must consider programmed aging mechanisms and the detailed nature of such mechanisms is of major importance. Theories of externally regulated programmed aging suggest that in mammals and other complex organisms, genetically specified senescence mechanisms detect local or temporary external conditions that affect the optimal lifespan for a species population and can adjust the lifespans of individual members in response. This article describes why lifespan regulation in response to external conditions adds to the evolutionary advantage produced by programmed aging and why a specific externally regulated programmed aging mechanism provides the best match to empirical evidence on mammal senescence. PMID- 29486695 TI - Sex and Aging: A Comparison between Two Phenoptotic Phenomena. AB - Phenoptosis is a phenomenon that is genetically programmed and favored by natural selection, and that determines death or increased risk of death (fitness reduction) for the individual that manifests it. Aging, here defined as age related progressive mortality increase in the wild, if programmed and favored by natural selection, falls within the definition of phenoptosis. Sexual reproduction (sex), as for the involved individuals determines fitness reduction and, in some species, even certain death, also falls within the definition of phenoptosis. In this review, sex and aging are analyzed as phenoptotic phenomena, and the similarities between them are investigated. In particular, from a theoretical standpoint, the genes that cause and regulate these phenomena: (i) require analyses that consider both individual and supra-individual selection because they are harmful in terms of individual selection, but advantageous (that is, favored by natural selection) in particular conditions of supra-individual selection; (ii) determine a higher velocity of and greater opportunities for evolution and, therefore, greater evolutionary potential (evolvability); (iii) are advantageous under ecological conditions of K-selection and with finite populations; (iv) are disadvantageous (that is, not favored by natural selection) under ecological conditions of r-selection and with unlimited populations; (v) are not advantageous in all ecological conditions and, so, species that reproduce asexually or species that do not age are predicted and exist. PMID- 29486696 TI - Combining Life Extension Treatments: A Proposal for High-Throughput Testing in Rodents. AB - An experimental design is proposed for high-throughput testing of combined interventions that might increase life expectancy in rodents. There is a growing backlog of promising treatments that have never been tested in mammals, and known treatments have not been tested in combination. The dose-response curve is often nonlinear, as are the interactions among different therapies. Herein are proposed two experimental designs optimized for detecting high-value combinations. In Part I, numerical simulation is used to explore a protocol for testing different dosages of a single intervention. With reasonable and general biological assumptions about the dose-response curve, information is maximized when each animal receives a different dosage. In Part II, numerical simulation is used to explore a protocol for testing interactions among many combinations of treatments, once their individual dosages have been established. Combinations of three are identified as a sweet spot for statistics. To conserve resources, the protocol is designed to identify those outliers that lead to life extension greater than 50%, but not to offer detailed survival curves for any treatments. Every combination of three treatments from a universe of 15 total treatments is represented, with just three mice replicating each combination. Stepwise regression is used to infer information about the effects of individual treatments and all their pairwise interactions. Results are not quite as robust as for the dosage protocol in Part I, but if there is a combination that extends lifespan by more than 50%, it will be detected with 80% certainty. These two screening protocols offer the possibility of expediting the identification of treatment combinations that are most likely to have the largest effect, while controlling costs overall. PMID- 29486697 TI - On the Cause and Mechanism of Phenoptosis. AB - Based upon evolvability theory, phenotypes like aging that offer no apparent individual benefit may evolve nonetheless. Pursuant to that concept, the evolution of a hypothetical, genome-based aging program called phenoptosis was proposed. However, while aging may facilitate evolvability, it need not result from a program specifically selected for that purpose. Instead, it is possible that the potential for aging is conserved within the genome as a part of a beneficial program that orchestrates and integrates developmental transformation of the soma from conception to maturation. Because somatic remodeling is inherently unstable, its continued non-programmatic expression beyond young adulthood (developmental inertia) erodes internal order, initiating and exacerbating aging. Thus, aging may result paradoxically from post-maturational expression of the same programmatic function for somatic transformation that previously provided individual benefit. It did so by ensuring acquisition of reproductive competence, post-reproductive development of parents to nurture offspring and thereby, to guarantee species survival. In an attempt to identify genes capable of controlling developmental inertia, we sequenced DNA from a series of subjects displaying extreme neoteny, i.e. retention of youthful characteristics during adulthood. We hoped to identify mutations associated with delayed development and to compare each subject's biological and chronological ages. De novo mutations of coding-genes were found in all the subjects, but they could not be definitively identified as a cause of developmental delay. Nonetheless, genetic and epigenetic studies of neotenic subject's DNA are on going. We are attempting to determine if phenoptosis specifically evolved to cause aging, or rather if it exists as a cryptic component of the developmental program that expresses its lethal potential serendipitously and only after individual benefit is realized. PMID- 29486698 TI - Coefficient of Variation of Lifespan Across the Tree of Life: Is It a Signature of Programmed Aging? AB - Measurements of variation are of great importance for studying the stability of pathological phenomena and processes. For the biology of aging, it is very important not only to determine average mortality, but also to study its stability in time and the size of fluctuations that are indicated by the variation coefficient of lifespan (CVLS). It is believed that a relatively small (~20%) value of CVLS in humans, comparable to the coefficients of variation of other events programmed in ontogenesis (for example, menarche and menopause), indicates a relatively rigid determinism (N. S. Gavrilova et al. (2012) Biochemistry (Moscow), 77, 754-760). To assess the prevalence of this phenomenon, we studied the magnitude of CVLS, as well as the coefficients of skewness and kurtosis in diverse representatives of the animal kingdom using data provided by the Institute for Demographic Research (O. R. Jones et al. (2014) Nature, 505, 169-173). We found that, unlike humans and laboratory animals, in most examined species the values of CVLS are rather high, indicating heterogeneity of the lifespan in the cohorts studied. This is probably due to the large influence of background mortality, as well as the non-monotonicity of total mortality in the wild, especially at the earliest ages. One way to account for this influence is to "truncate" the data (removing the earliest and latest ages from consideration). To reveal the effect of this procedure, we proposed a new indicator, the stability coefficient of mortality dynamics, which indicates how quickly CVLS is reduced to values that characterize a relatively homogeneous population (33%) when the data are "truncated". Such indicators facilitate the use of the parameters of survival curves for analysis of the effects of geroprotectors, lifestyle, and other factors on lifespan, and for the quantification of relative contributions of genetic and environmental factors to the dynamics of aging in human and animal populations, including those living in the wild. PMID- 29486699 TI - Mitochondria-Targeted Antioxidant SkQ1 (10-(6' Plastoquinonyl)decyltriphenylphosphonium Bromide) Inhibits Mast Cell Degranulation in vivo and in vitro. AB - The therapeutic effect of mitochondria-targeted antioxidant 10-(6' plastoquinonyl)decyltriphenylphosphonium bromide (SkQ1) in experimental models of acute inflammation and wound repair has been shown earlier. It was suggested that the antiinflammatory activity of SkQ1 is related to its ability to suppress inflammatory activation of the vascular endothelium and neutrophil migration into tissues. Here, we demonstrated that SkQ1 inhibits activation of mast cells (MCs) followed by their degranulation and histamine release in vivo and in vitro. Intraperitoneal injections of SkQ1 in the mouse air-pouch model reduced the number of leukocytes in the air-pouch cavity and significantly decreased the histamine content in it, as well as suppressing MC degranulation in the air-pouch tissue. The direct effect of SkQ1 on MCs was studied in vitro in the rat basophilic leukemia RBL-2H3 cell line. SkQ1 inhibited induced degranulation of RBL-2H3 cells. These results suggest that mitochondrial reactive oxygen species are involved in the activation of MCs. It is known that MCs play a crucial role in regulation of vascular permeability by secreting histamine. Suppression of MC degranulation by SkQ1 might be a significant factor in the antiinflammatory activity of this mitochondria-targeted antioxidant. PMID- 29486700 TI - Spontaneous and Experimentally Induced Pathologies in the Naked Mole Rat (Heterocephalus glaber). AB - The naked mole rat (Heterocephalus glaber, Ruppell, 1842) is a unique eusocial rodent with unusually long lifespan. Therefore, the study of spontaneous and experimentally induced pathologies in these animals is one of the most important tasks of gerontology. Various infections, noninfectious pathologies (including age-dependent changes), and tumors have been described in the naked mole rat. The most frequent pathologies are traumas (bite wounds), purulent and septic complications of traumatic injuries, renal tubular calcinosis, chronic progressive nephropathy, hepatic hemosiderosis, testicular interstitial cell hyperplasia, calcinosis cutis, cardiomyopathy, and dysbiosis-related infectious lesions of the digestive system. However, the summarized data on pathology (including tumor incidence) and on the causes of mortality are insufficient. There are only few publications about the results of experiments where pathologies were induced in the naked mole rat. All these problems could be subjects for promising future studies without which adequate studies on mechanisms providing the long lifespan of the naked mole rat are impossible, as well as the elucidation of causes of tumor resistance of this species. PMID- 29486701 TI - Effects of Mitochondrial Antioxidant SkQ1 on Biochemical and Behavioral Parameters in a Parkinsonism Model in Mice. AB - According to one hypothesis, Parkinson's disease pathogenesis is largely caused by dopamine catabolism that is catalyzed on mitochondrial membranes by monoamine oxidase. Reactive oxygen species are formed as a byproduct of these reactions, which can lead to mitochondrial damage followed by cell degeneration and death. In this study, we investigated the effects of administration of the mitochondrial antioxidant SkQ1 on biochemical, immunohistochemical, and behavioral parameters in a Parkinson-like condition caused by protoxin MPTP injections in C57BL/6 mice. SkQ1 administration increased dopamine quantity and decreased signs of sensory motor deficiency as well as destruction of dopaminergic neurons in the substantia nigra and ventral tegmental area in mice with the Parkinson-like condition. PMID- 29486702 TI - Y-Box-Binding Protein 1 Stimulates Abasic Site Cleavage. AB - Apurinic/apyrimidinic (AP) sites are among the most frequent DNA lesions. The first step in the AP site repair involves the magnesium-dependent enzyme AP endonuclease 1 (APE1) that catalyzes hydrolytic cleavage of the DNA phosphodiester bond at the 5' side of the AP site, thereby generating a single strand DNA break flanked by the 3'-OH and 5'-deoxyribose phosphate (dRP) groups. Increased APE1 activity in cancer cells might correlate with tumor chemoresistance to DNA-damaging treatment. It has been previously shown that the multifunctional oncoprotein Y-box-binding protein 1 (YB-1) interacts with APE1 and inhibits APE1-catalyzed hydrolysis of AP sites in single-stranded DNAs. In this work, we demonstrated that YB-1 stabilizes the APE1 complex with double stranded DNAs containing the AP sites and stimulates cleavage of these AP sites at low magnesium concentrations. PMID- 29486703 TI - Heterologous Expression and Isolation of Influenza A Virus Nuclear Export Protein NEP. AB - Influenza A virus nuclear export protein NEP (NS2, 14.4 kDa) plays a key role in various steps of the virus life cycle. Highly purified protein preparations are required for structural and functional studies. In this study, we designed a series of Escherichia coli plasmid constructs for highly efficient expression of the NEP gene under control of the constitutive trp promoter. An efficient method for extraction of NEP from inclusion bodies based on dodecyl sulfate treatment was developed. Preparations of purified NEP with either N- or C-terminal (His)6 tag were obtained using Ni-NTA agarose affinity chromatography with yield of more than 20 mg per liter of culture. According to CD data, the secondary structure of the proteins matched that of natural NEP. A high propensity of NEP to aggregate over a wide range of conditions was observed. PMID- 29486704 TI - Metagenomics of Bolidophyceae in Plankton and Ice of the White Sea. AB - The molecular diversity of poorly studied algae of Bolidophyceae class was first estimated by Illumina sequencing of V4 region of 18S rRNA gene in ice, under-ice water and summer water of the subarctic White Sea. We used two clustering thresholds - 93 and 97% - and revealed 31 phylotypes of Bolidophyceae. Triparma pacifica and T. strigata were identified to species level. The association of individual phylotypes to certain biotopes (ice or plankton) and stages of seasonal succession (under ice or summer plankton) has been established. Some phylotypes are found in different biotopes and over a wide temperature range. Due to changing their genetic composition, Bolidophyceae are a constant component of the photoautotrophic plankton and ice communities. PMID- 29486705 TI - Bacterial Therapy and Mitochondrial Therapy. AB - Current methods for treatment of cellular and organ pathologies are extremely diverse and constantly evolving, going beyond the use of drugs, based on chemical interaction with biological targets to normalize the functions of the system. Because pharmacological approaches are often untenable, recent strategies in the therapy of different pathological conditions are of particular interest through introducing into the organism of some living system or its components, in particular, bacteria or isolated subcellular structures such as mitochondria. This review describes the most interesting and original examples of therapy using bacteria and mitochondria, which in perspective can dramatically change our views on the principles for the treatment of many diseases. Thus, we analyze such therapeutic effects from the perspective of the similarities between mitochondria and bacteria as the evolutionary ancestors of mitochondria. PMID- 29486706 TI - Concordance of gonorrhoea of the rectum, pharynx and urethra in same-sex male partnerships attending a sexual health service in Melbourne, Australia. AB - BACKGROUND: We aimed to describe anatomic site-specific concordance of gonococcal infections in partnerships of men who have sex with men (MSM). METHODS: We conducted a cross-sectional analysis of data from MSM partnerships attending Melbourne Sexual Health Centre between March 2011 and February 2015. Logistic regression models (random effect) were used to examine the association between gonococcal infections of the urethra, rectum and pharynx. Gonococci were detected by culture at all anatomic sites. RESULTS: The analysis included 495 partnerships. Of the men with urethral gonorrhoea, 33% (95% CI 18-52) had partners with pharyngeal gonorrhoea and 67% (95% CI 48-82) had partners with rectal gonorrhoea. The adjusted odds of having urethral gonorrhoea was 4.6 (95% CI 1.2-17.1) for a man whose partner had pharyngeal gonorrhoea, and 48.1 (95% CI 18.3-126.7) for a man whose partner had rectal gonorrhoea. Of the men with rectal gonorrhoea, 46% (95% CI 31-61) had a partner with urethral gonorrhoea and 23% (95% CI 12-37) had a partner with pharyngeal gonorrhoea. The adjusted odds of having rectal gonorrhoea was 63.9 (95% CI 24.7-165.6) for a man whose partner had urethral gonorrhoea. Of the men with pharyngeal gonorrhoea, 42% (95% CI 23-63) had a partner with rectal gonorrhoea and 23% (95% CI 9-44) had a partner with had a partner with pharyngeal gonorrhoea. The adjusted odds of having pharyngeal gonorrhoea was 8.9 (95% CI 3.2-24.6) for a man whose partner had rectal gonorrhoea. The crude odds of having pharyngeal gonorrhoea was 14.2 (95% CI 5.1 39.0) for a man whose partner had pharyngeal gonorrhoea. CONCLUSIONS: These data provide the first estimates of concordance of anatomic site-specific gonococcal infections in MSM partnerships, and confirm that urethral gonorrhoea is contracted from both rectal and pharyngeal sites, and suggest that gonococci transmit between the rectum and pharynx. However, due to use of culture rather than NAAT, our analysis was not adequately powered to assess pharynx-to-pharynx transmission of gonococci. PMID- 29486707 TI - Genomic analysis in patients with myxomatous mitral valve prolapse: current state of knowledge. AB - BACKGROUND: Myxomatous mitral valve prolapse is a common cardiac abnormality. Morbus Barlow is characterized by excess myxomatous leaflet tissue, bileaflet prolapse or billowing, chordae elongation and annular dilatation with or without calcification. Extensive myxoid degeneration with destruction of the normal three layered leaflet tissue architecture is observed histologically in such patients. Autosomal dominant inheritance with an age and sex-dependent expression has long been recognised. This review explores the current understanding of the genetics of bileaflet prolapse, with a focus on genetic analysis and the role for echocardiographical screening of the first degree relatives of affected patients. METHODS: Systematic literature searches were performed using PubMed and Embase up to September 2017. In Disse et al.'s study (study one) first degree relatives of 25 patients with Morbus Barlow who underwent mitral valve repair were screened for bileaflet valve prolapse. In Nesta et al.'s study one family with three living generations of 43 individuals with 9 confirmed cases of MVP was screened. Genotyping was performed in four families for 344 microsatellite markers from Chromosome 1 to 16. RESULTS: In study one, autosomal dominant inheritance was shown in four pedigrees. Genome-wide linkage analysis of the most informative pedigree (24 individuals, three generations) showed a significant linkage for markers mapping to chromosome 16p. Linkage to this locus was confirmed in a second family within the same study, but was excluded in the remaining two pedigrees. In study two an autosomal dominant locus was mapped to chromosome 13. 8 of the 9 individuals affected were found to suffer from bileaflet prolapse. CONCLUSIONS: Barlow's disease is a heritable trait but the genetic causes remain largely elusive. Ch16p11.2-p12.1 is the only locus proven to be associated with bileaflet prolapse. Locus 13.q31.3-q32.1 was shown to cause bileaflet as well as posterior leaflet prolapse. This review intends to make physicians aware of genetic causes of myxomatous mitral valve prolapse, thereby emphasising the importance of cardiological examination of first-degree relatives of patients with Morbus Barlow. Integrated and more comprehensive studies are needed for identification of genes involved in this heterogenic disease. Further genomic studies may facilitate more individualised and accurate risk assessment and may help to develop possible preventive stategies for patients in the future. PMID- 29486708 TI - Functional gastrointestinal diseases and psychological maladjustment, personality traits and quality of life. AB - BACKGROUND: Chronic abdominal pain is a common worldwide problem and known to be associated with psychological problems. This study evaluated the association between abdominal pain-predominant functional gastrointestinal disorders (AP FGIDs), psychological maladjustment and personality traits in adolescents. METHODS: Adolescents aged 13-18 years were recruited from 5 randomly selected schools in Ampara district of Sri Lanka. AP-FGIDs were diagnosed using Rome III criteria. Translated and validated Rome III questionnaire (Child report form), personality questionnaire (PAQ) and PedsQL (Pediatric Quality of Life) inventory were used in data collection. Written consent was obtained from a parent and assent was obtained from every child recruited. The questionnaire was distributed in an examination setting to ensure confidentiality and privacy. Research assistants were present during data collection to assist on any necessary clarifications. RESULTS: A total of 1697 subjects were recruited [males 779 (45.9%), mean age 15.1 years, SD 1.6 years]. AP-FGIDs were present in 202 (11.9%). Those with AP-FGIDs had significantly higher mean scores for all personality traits (hostility and aggression, negative self-esteem, emotional unresponsiveness, emotional instability and negative world view), except dependency. Affected children had lower scores for all 4 domains of HRQoL (physical, emotional, social and school functioning), compared to controls (p < 0.05). When the cut off value for Sri Lankan children (89) was used, 66.3% with AP-FGIDs and 48.2% controls had PAQ scores within that of psychological maladjustment (p < 0.001). When the international normative value of 105 was used, these percentages were 27.2% and 14.2% respectively (p < 0.0001). The scores obtained for PAQ negatively correlated with scores obtained for HRQoL (r = - 0.52, p < 0.0001). One hundred and seventeen adolescents with AP-FGIDs (57.9%) had sought healthcare for their symptoms. Healthcare consulters had higher PAQ and lower HRQoL scores (p < 0.05). CONCLUSIONS: Adolescents with AP-FGIDs have more psychological maladjustment and abnormal personality traits than healthy controls. Affected adolescents with higher psychological maladjustments have lower HRQoL. Greater psychological maladjustment and lower HRQoL are associated with healthcare seeking behaviour in adolescents with AP-FGIDs. PMID- 29486709 TI - Evidence for a centrosome-attracting body like structure in germ-soma segregation during early development, in the urochordate Oikopleura dioica. AB - BACKGROUND: Germ cell formation has been investigated in sessile forms of tunicates. This process involves the release of a subset of maternal transcripts from the centrosome-attracting body (CAB) in the progenitor cells of the germ line. When germ-soma segregation is completed, CAB structures are missing from the newly formed primordial germ cells (PGCs). In free-swimming tunicates, knowledge about germ cell formation is lacking. In this investigation, comparative gene expression and electron microscopy studies were used to address germ cell formation in Oikopleura dioica (O. dioica). RESULTS: We found that the RNA localization pattern of pumilio (pum1) is similar to the pattern described for a subset of maternal transcripts marking the posterior end of ascidian embryos. Transcripts marking the posterior end are called postplasmic or posterior-end mark (PEM) transcripts. We found no localization of vasa (vas) transcripts to any sub-region within the germ-line precursor cells. Expression of vas4 was detected in the newly formed PGCs. Electron microscopy studies confirmed the presence of structures with similar morphology to CAB. In the same cytoplasmic compartment, we also identified pum1 transcripts and an epitope recognized by an antibody to histone H3 phosphorylated on serine 28. CONCLUSIONS: Our findings support that a CAB-like structure participates in the segregation of maternal pum1 transcripts during germ-soma separation in O. dioica. PMID- 29486710 TI - Molecular characterization of mutations associated with resistance to second-line tuberculosis drug among multidrug-resistant tuberculosis patients from high prevalence tuberculosis city in Morocco. AB - BACKGROUND: The emergence of extensively drug-resistant tuberculosis (XDR-TB) has raised public health concern for global TB control. Although multi drug-resistant tuberculosis (MDR- TB) prevalence and associated genetic mutations in Morocco are well documented, scarce information on XDR TB is available. Hence, the evaluation of pre-XDR and XDR prevalence, as well as the mutation status of gyrA, gyrB, rrs, tlyA genes and eis promoter region, associated with resistance to second line drugs, is of great value for better management of M/XDR TB in Morocco. OBJECTIVES: To evaluate pre-XDR and XDR prevalence, as well as the mutation status of gyrA, gyrB, rrs, tlyA genes and eis promoter region, associated with resistance to second line drug resistance, in 703 clinical isolates from TB patients recruited in Casablanca, and to assess the usefulness of molecular tools in clinical laboratories for better management of M/XDR TB in Morocco. METHODS: Drug susceptibility testing (DST) was performed by the proportional method for first line drugs, and then the selected MDR isolates were tested for second line drugs (Ofloxacin, Kanamycin, Amikacin and Capreomycin). Along with DST, all samples were subjected to rpoB, katG and p-inhA mutation analysis by PCR and DNA sequencing. MDR isolates as well as 30 pan-susceptible strains were subjected to PCR and DNA sequencing of gyrA, gyrB, rrs, tlyA genes and eis promoter, associated with resistance to fluoroquinolones and injectable drugs. RESULTS: Among the 703 analysed strains, 12.8% were MDR; Ser531Leu and Ser315Thr being the most common recorded mutations within rpoB and katG genes associated with RIF and INH resistance respectively. Drug susceptibility testing for second line drugs showed that among the 90 MDR strains, 22.2% (20/90) were resistant to OFX, 2.22% (2/90) to KAN, 3.33% (3/90) to AMK and 1.11% (1/90) to CAP. Genotypic analysis revealed that 19 MDR strains harbored mutations in the gyrA gene; the most recorded mutation being Asp91Ala accounting for 47.6% (10/21), and 2 isolates harbored mutations in the promoter region of eis gene. No mutation was found in gyrB, rrs and tlyA genes. Moreover, none of the pan-susceptible isolates displayed mutations in targeted genes. CONCLUSION: Most of mutations associated with SLD resistance occurred in gyrA gene (codons 90-94) and eis promoter region. These findings highlight the impact of mutations in gyrA on the development of fluroquinolones resistance and provide the first estimates of the proportion of pre-XDR-TB among MDR-TB cases in Morocco. PMID- 29486712 TI - Acute coronary syndrome secondary to allergic coronary vasospasm (Kounis Syndrome): a case series, follow-up and literature review. AB - BACKGROUND: Kounis syndrome (KS) is the concurrence of acute coronary syndrome associated with mast-cell and platelet activation in the setting of hypersensitivity and allergic or anaphylactic insults. Many drugs and environmental exposures had been reported as inducers, but various inducers and the mechanism of KS remained unknown till now. The widely used traditional Chinese medicine (TCM) as a potential sensitizer were scarcely reported to induce allergic vasospasm due to the ignorance of the linkage between traditional medicine allergy and vasospasm. CASE PRESENTATION: We described 5 rare cases of KS including unreported triggers of TCM and abortion, reported the treatment strategy and 1~4 years' follow-up results, and tried to probe into the etiology of KS. Case 1 and case 2 for the first time reported acute ST-segment elevation myocardial infarction (STEMI) caused by Chinese herbs related allergic coronary vasospasm. Case 3 reported recurrent angina following allergen contact and wheezing, indicating the internal linkage of coronary vasospasm and allergic asthma. Case 4 described a childbearing-age woman suffered refractory ischemic chest pain due to coronary vasospasm in a special period of post-abortion, the attacks suddenly disappeared when her menopause recovered. Case 5 described an isolated episode of allergic coronary vasospasm under exposure of smoking and stress, which was successfully prevented by avoiding the exposures. CONCLUSION: Kounis syndrome is not rare but rarely recognized and under-diagnosed. It is necessary to recognize KS and various inducers, especially for the patients suffering refractory vasospastic cardiac attacks concentrating in special periods. Blood test of eosinophil might contribute to diagnose KS and anti allergic agents might be helpful for controlling KS attacks. PMID- 29486711 TI - lme4qtl: linear mixed models with flexible covariance structure for genetic studies of related individuals. AB - BACKGROUND: Quantitative trait locus (QTL) mapping in genetic data often involves analysis of correlated observations, which need to be accounted for to avoid false association signals. This is commonly performed by modeling such correlations as random effects in linear mixed models (LMMs). The R package lme4 is a well-established tool that implements major LMM features using sparse matrix methods; however, it is not fully adapted for QTL mapping association and linkage studies. In particular, two LMM features are lacking in the base version of lme4: the definition of random effects by custom covariance matrices; and parameter constraints, which are essential in advanced QTL models. Apart from applications in linkage studies of related individuals, such functionalities are of high interest for association studies in situations where multiple covariance matrices need to be modeled, a scenario not covered by many genome-wide association study (GWAS) software. RESULTS: To address the aforementioned limitations, we developed a new R package lme4qtl as an extension of lme4. First, lme4qtl contributes new models for genetic studies within a single tool integrated with lme4 and its companion packages. Second, lme4qtl offers a flexible framework for scenarios with multiple levels of relatedness and becomes efficient when covariance matrices are sparse. We showed the value of our package using real family-based data in the Genetic Analysis of Idiopathic Thrombophilia 2 (GAIT2) project. CONCLUSIONS: Our software lme4qtl enables QTL mapping models with a versatile structure of random effects and efficient computation for sparse covariances. lme4qtl is available at https://github.com/variani/lme4qtl . PMID- 29486713 TI - Gallbladder function predicts subsequent biliary complications in patients with common bile duct stones after endoscopic treatment? AB - BACKGROUND: In patients with common bile duct stones (CBDS) and intact gallbladder, further management for the gallbladder after the CBDS clearance is still controversial. The relationship between gallbladder motility and the biliary complications were seldom discussed. Our study is to predict the subsequent biliary complications by gallbladder function test using fatty meal sonography (FMS) in patients with CBDS who had been treated by endoscopic retrograde cholangiopancreatography (ERCP). METHODS: Patients with an intact gallbladder and CBDS after endoscopic clearance of bile duct were enrolled. Patients received a fatty meal sonography after liver function returned to normal. The fasting volume, residual volume, and gallbladder ejection fraction (GBEF) in FMS were measured. Relationships of patients' characteristics, gallbladder function and recurrent biliary complication were analyzed. RESULTS: From 2011 to 2014, 118 patients were enrolled; 86 patients had calculus gallbladders, and 32 patients had acalculous gallbladders. After a mean follow- up of 33 months, 23 patients had recurrent biliary complications. Among 86 patients with calculus gallbladder, 15 patients had spontaneous clearance of gallbladder stones; 14 patients received cholecystectomy due to acute cholecystitis or recurrent colic pain with smooth postoperative courses. In the follow up period, six patients died of non-biliary causes. The GBEF is significant reduced in most patients with a calculus gallbladder in spite of stone color. Calculus gallbladder, alcohol drinking and more than one sessions of initial endoscopic treatment were found to be the risk factors of recurrent biliary complication. CONCLUSIONS: Gallbladder motility function was poorer in patients with a calculus gallbladder, but it cannot predict the recurrent biliary complication. Since spontaneous clearance of gallbladder stone may occur, wait and see policy of gallbladder management after endoscopic treatment of CBDS is appropriate, but regular follow- up in those patients with risk factors for recurrence is necessary. PMID- 29486714 TI - Knowledge, attitude, and practice regarding dengue virus infection among inhabitants of Aceh, Indonesia: a cross-sectional study. AB - BACKGROUND: The Indonesian region of Aceh was the area most severely affected by the earthquake and tsunami of 26 December 2004. Department of Health data reveal an upward trend of dengue cases in Aceh since the events of the tsunami. Despite the increasing incidence of dengue in the region, there is limited understanding of dengue among the general population of Aceh. The aim of this study was to assess the knowledge, attitude, and practice (KAP) regarding dengue among the people of Aceh, Indonesia in order to design intervention strategies for an effective dengue prevention program. METHODS: A community-based cross-sectional study was conducted in Aceh between November 2014 and March 2015 with a total of 609 participants living in seven regencies and two municipalities. Information on the socio-demographic characteristics of participants and their KAP regarding dengue was collected using a pre-tested structured questionnaire. The KAP status (good vs. poor) of participants with different socio-demographic characteristics was compared using Chi Square-test, ANOVA or Fisher's exact test as appropriate. Logistic regression analysis was used to determine the predictors of each KAP domain. RESULTS: We found that 45% of participants had good knowledge regarding dengue and only 32% had good attitudes and good dengue preventive practices. There was a significant positive correlation between knowledge and attitudes, knowledge and practice, and attitudes and practice. In addition, people who had good knowledge were 2.7 times more likely to have good attitudes, and people who had good attitudes were 2.2 times more likely to have good practices regarding dengue. The level of education, occupation, marital status, monthly income, socioeconomic status (SES) and living in the city were associated with the knowledge level. Occupation, SES, and having experienced dengue fever were associated with attitudes. Education, occupation, SES and type of residence were associated with preventive practices. CONCLUSION: Our study suggests that dengue prevention programs are required to increase KAP levels regarding dengue in the communities of Aceh. PMID- 29486715 TI - A nested case-control study of predictors for tuberculosis recurrence in a large UK Centre. AB - BACKGROUND: Tuberculosis (TB) recurrence represents a challenge to control programs. In low incidence countries, the prevailing risk factors leading to recurrence are poorly characterised. METHODS: We conducted a nested case-control study using the Leicester TB service TBIT database. Cases were identified from database notifications between 1994 and 2014. Controls had one episode and were matched to cases on a ratio of two to one by the date of notification. Multiple imputation was used to account for missing data. Multivariate conditional logistic regression analysis was employed to identify clinical, sociodemographic and TB specific risk factors for recurrence. RESULTS: From a cohort of 4628 patients, 82 TB recurrences occurred (1.8%). Nineteen of 82 patients had paired isolates with MIRU-VNTR strain type profiles available, of which 84% were relapses and 16% reinfections. On multivariate analysis, smoking (OR 3.8; p = 0.04), grade 3/4 adverse drug reactions (OR 5.6; p = 0.02), ethnicity 'Indian subcontinent' (OR 8.5; p = <0.01), ethnicity 'other' (OR 31.2; p = 0.01) and receipt of immunosuppressants (OR 6.8; p = <0.01) were independent predictors of TB recurrence. CONCLUSIONS: Within this UK setting, the rate of TB recurrence was low, predominantly due to relapse. The identification of an elevated recurrence risk amongst the ethnic group contributing most cases to the national TB burden presents an opportunity to improve individual and population health. PMID- 29486716 TI - Characterization of hepatitis B and delta coinfection in Israel. AB - BACKGROUND: Characteristics of hepatitis B (HBV) and delta (HDV) coinfection in various geographical regions, including Israel, remain unclear. Here we studied HDV seroprevalence in Israel, assessed HDV/HBV viral loads, circulating genotypes and hepatitis delta antigen (HDAg) conservation. METHODS: Serological anti HDV IgG results from 8969 HBsAg positive individuals tested in 2010-2015 were retrospectively analyzed to determine HDV seroprevalence. In a cohort of HBV/HDV coinfected (n=58) and HBV monoinfected (n=27) patients, quantitative real-time PCR (qRT-PCR) and sequencing were performed to determine viral loads, genotypes and hepatitis delta antigen (HDAg) protein sequence. RESULTS: 6.5% (587/8969) of the HBsAg positive patients were positive for anti HDV antibodies. HDV viral load was >2 log copies/ml higher than HBV viral load in most of the coinfected patients with detectable HDV RNA (86%, 50/58). HDV genotype 1 was identified in all patients, most of whom did not express HBV. While 66.6% (4/6) of the HBV/HDV co-expressing patients carried HBV-D2 only 18.5% (5/27) of the HBV monoinfections had HBV-D2 (p=0.03). Higher genetic variability in the HDAg protein sequence was associated with higher HDV viral load. CONCLUSIONS: The overall significant prevalence of HDV (6.5%) mandates HDV RNA testing for all coinfected patients. Patients positive for HDV RNA (characterized by low HBV DNA blood levels) carried HDV genotype 1. Taken together, the significant HDV seroprevalence and the lack of effective anti-HDV therapy, necessitates strict clinical surveillance especially in patients with higher HDV viral loads and increased viral evolution. PMID- 29486717 TI - Splash M-knife versus Flush Knife BT in the technical outcomes of endoscopic submucosal dissection for early gastric cancer: a propensity score matching analysis. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) is a standard treatment for early gastric cancer. A new multi-functional ESD device was developed to achieve complete ESD with a single device. A metal plate attached to its distal sheath achieves better hemostasis during the procedure than the other needle-knife device, Flush Knife BT(r), that has been conventionally used. The aim of this study was to compare the technical outcomes of ESD for early gastric cancer using the Splash M-Knife(r) with those using the Flush Knife BT. METHODS: We conducted a retrospective review of the case records of 149 patients with early gastric cancer treated with ESD using the needle-type ESD knives between January 2012 and August 2016 at Kitakyushu Municipal Medical Center. Lesions treated with ESD using the Splash M-knife (ESD-M) and the Flush Knife BT (ESD-F) were compared. Multivariate analyses and propensity score matching were used to compensate for the differences in age, gender, underlying disease, antithrombotic drug use, lesion location, lesion position, macroscopic type, tumor size, presence of ulceration, operator level and types of electrosurgical unit used. The primary endpoint was the requirement to use hemostatic forceps in the two groups. The secondary endpoints of procedure time, en bloc and complete resection rates, and adverse events rates were evaluated for the two groups. RESULTS: There were 73 patients in the ESD-M group, and 76 patients in the ESD-F group. Propensity score matching analysis created 45 matched pairs. Adjusted comparisons between the two groups showed a significantly lower usage rate of hemostatic forceps in the ESD-M group than in the ESD-F group (6.7% vs 84.4%, p < 0.001). Treatment outcomes showed an en bloc resection rate of 100% in both groups; complete resection rate of 95.6% vs 100%, p = 0.49; median procedure time of 74.0 min vs 71.0 min, p = 0.90; post-procedure bleeding of 2.2% vs 2.2%, p = 1, in the ESD-M and ESD-F groups, respectively. There were no perforations in either group. CONCLUSIONS: ESD-M appeared to reduce the usage of hemostatic forceps during ESD for early gastric cancer without increasing the adverse effects. Thus, it may contribute to a reduction in the total ESD cost. PMID- 29486718 TI - Geranylgeranylacetone attenuates fibrogenic activity and induces apoptosis in cultured human hepatic stellate cells and reduces liver fibrosis in carbon tetrachloride-treated mice. AB - BACKGROUND: Geranylgeranylacetone (GGA), an anti-ulcer drug widely used in Japan, has attracted interest because of its various therapeutic effects. Therefore, we investigated the effects of GGA on human hepatic stellate cells (HSCs) in vitro and in a mouse model of liver fibrosis. METHODS: LX2, an immortalized human HSC line, was cultured and treated with GGA at concentrations up to 0.5 mM. After GGA treatment, changes in cellular morphology, apoptosis, and fibrosis-related gene expression were assessed. Male C57BL/6 J mouse model of carbon tetrachloride (CCl4)-induced liver fibrosis was treated with GGA. Liver fibrosis was evaluated using Sirius red staining and immunohistochemistry for alpha-smooth muscle actin (SMA). RESULTS: GGA decreased the density of LX2 and primary human hepatic stellate cells but not that of HepG2 cells (a human hepatoma cell line), which was employed as control. In addition, GGA decreased the expression of fibrogenic genes and increased that of C/EBP homologous protein (CHOP). It also induced endoplasmic reticulum (ER) stress and increased apoptosis. CHOP knockdown, however, failed to suppress the GGA-induced decrease in LX2 cell density, suggesting the involvement of additional molecules in ER stress-associated apoptosis. Expression of death receptor 5, mitogen-activated protein kinase, heat shock protein 70, and Akt, all of which affect the activity of stellate cells, was unchanged in relation to LX2 cell fibrogenic activity. In the mouse model of liver fibrosis, GGA decreased the extent of Sirius red staining and SMA expression. CONCLUSIONS: GGA attenuated fibrogenic activity and induced apoptosis in cultured human HSCs, and suppressed liver fibrosis in mice, suggesting its potential as an agent for treating liver fibrosis. PMID- 29486719 TI - The PhyR homolog RSP_1274 of Rhodobacter sphaeroides is involved in defense of membrane stress and has a moderate effect on RpoE (RSP_1092) activity. AB - BACKGROUND: A major role of the PhyR-NepR-sigma(EcfG) cascade in the general stress response was demonstrated for some bacterial species and considered as conserved in Alphaproteobacteria. The sigma(EcfG) factor activates its target genes in response to diverse stresses and NepR represents its anti-sigma factor. PhyR comprises a response regulator domain and a sigma factor domain and acts as anti-sigma factor antagonist. The facultative phototrophic alphaproteobacterium Rhodobacter sphaeroides harbours a PhyR homolog in the same genomic context as found in other members of this class. RESULTS: Our study reveals increased expression of the phyR gene in response to superoxide, singlet oxygen, and diamide and also an effect of PhyR on rpoE expression. RpoE has a central role in mounting the response to singlet oxygen in R. sphaeroides. Despite these findings a mutant lacking PhyR was not significantly impeded in resistance to oxidative stress, heat stress or osmotic stress. However a role of PhyR in membrane stress is demonstrated. CONCLUSION: These results support the view that the effect of the PhyR-NepR-sigma(EcfG) cascade on diverse stress responses varies among members of the Alphaproteobacteria. In the facultative phototroph Rhodobacter sphaeroides PhyR plays no major role in the general stress or the oxidative stress response but rather has a more specialized role in defense of membrane stress. PMID- 29486720 TI - Intrathecal morphine administration reduces postoperative pain and peripheral endocannabinoid levels in total knee arthroplasty patients: a randomized clinical trial. AB - BACKGROUND: The primary goal of this study was to determine whether administration of intrathecal morphine reduces postoperative pain. The secondary goal was to determine the effect of intrathecal morphine upon circulating levels of the weakly analgesic endocannabinoids, anandamide (AEA) and 2 arachidonoylglycerol (2-AG), and the related lipids palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). METHODS: Forty two total knee arthroplasty (TKA) patients were enrolled in a prospective, double-blinded, randomized study. The intervention consisted of intrathecal morphine (200 MUg) or placebo administered at the time of the spinal anesthesia. Postoperative pain was measured during the first 4 h after surgery while serum levels of AEA, 2-AG, PEA, OEA, and cortisol were measured at baseline and 4 h after surgery. RESULTS: Administration of intrathecal morphine reduced postoperative pain 4 h after TKA surgery compared to placebo (p = 0.005) and reduced postoperative systemic opioid consumption (p = 0.001). At baseline, intrathecal morphine led to a significant reduction in AEA, 2-AG, and OEA levels but did not affect PEA or cortisol levels. In patients administered intrathecal placebo, 2-AG levels were elevated 4 h after surgery; whereas patients receiving intrathecal morphine showed reductions in AEA, PEA, and OEA when compared to placebo. At 4 h after TKA surgery cortisol levels were significantly elevated in the placebo group and reduced in those receiving morphine. CONCLUSIONS: These results indicate that intrathecal morphine reduces postoperative pain in TKA patients. Furthermore, activation of central opioid receptors negatively modulates the endocannabinoid tone, suggesting that potent analgesics may reduce the stimulus for production of peripheral endocannabinoids. This study is the first to document the existence of rapid communication between the central opioid and peripheral endocannabinoid systems in humans. TRIAL REGISTRATION: This trial was registered retrospectively. TRIAL REGISTRY: NCT02620631 . Study to Examine Pain Relief With Supplemental Intrathecal Morphine in TKA Patients, NCT02620631 , 12/03/2015. PMID- 29486721 TI - Complete mitochondrial genomes of Nanorana taihangnica and N. yunnanensis (Anura: Dicroglossidae) with novel gene arrangements and phylogenetic relationship of Dicroglossidae. AB - BACKGROUND: Complete mitochondrial (mt) genomes have been used extensively to test hypotheses about microevolution and to study population structure, phylogeography, and phylogenetic relationships of Anura at various taxonomic levels. Large-scale mt genomic reorganizations have been observed among many fork tongued frogs (family Dicroglossidae). The relationships among Dicroglossidae and validation of the genus Feirana are still problematic. Hence, we sequenced the complete mt genomes of Nanorana taihangnica (=F. taihangnica) and N. yunnanensis as well as partial mt genomes of six Quasipaa species (dicroglossid taxa), two Odorrana and two Amolops species (Ranidae), and one Rhacophorus species (Rhacophoridae) in order to identify unknown mt gene rearrangements, to investigate the validity of the genus Feirana, and to test the phylogenetic relationship of Dicroglossidae. RESULTS: In the mt genome of N. taihangnica two trnM genes, two trnP genes and two control regions were found. In addition, the trnA, trnN, trnC, and trnQ genes were translocated from their typical positions. In the mt genome of N. yunnanensis, three control regions were found and eight genes (ND6, trnP, trnQ, trnA, trnN, trnC, trnY and trnS genes) in the L-stand were translocated from their typical position and grouped together. We also found intraspecific rearrangement of the mitochondrial genomes in N. taihangnica and Quasipaa boulengeri. In phylogenetic trees, the genus Feirana nested deeply within the clade of genus Nanorana, indicating that the genus Feirana may be a synonym to Nanorana. Ranidae as a sister clade to Dicroglossidae and the clade of (Ranidae + Dicroglossidae) as a sister clade to (Mantellidae + Rhacophoridae) were well supported in BI analysis but low bootstrap in ML analysis. CONCLUSIONS: We found that the gene arrangements of N. taihangnica and N. yunnanensis differed from other published dicroglossid mt genomes. The gene arrangements in N. taihangnica and N. yunnanensis could be explained by the Tandem Duplication and Random Loss (TDRL) and the Dimer-Mitogenome and Non-Random Loss (DMNR) models, respectively. The invalidation of the genus Feirana is supported in this study. PMID- 29486722 TI - Study protocol: rationale and design of the community-based prospective cohort study of kidney function and diabetes in rural New Mexico, the COMPASS study. AB - BACKGROUND: Rural areas in the state of New Mexico have been the "ground-zero" for the epidemic of diabetic Chronic Kidney Disease (CKD) in the United States. However, there is limited research about risk factors of diabetic CKD in this area and scarce data regarding the performance of emerging markers of renal filtration and epigenetic biomarkers of renal function and diabetes in this area with its unique ethnic/racial population. We designed the COMPASS study as a community-based program in rural New Mexico aiming to screen for CKD and to discover CKD-related translational biomarkers. METHODS/DESIGN: The study involves a prospective, longitudinal cohort design involving individuals living in rural New Mexico. Participants undergo a screening for kidney disease using markers of abnormal renal filtration (impaired glomerular filtration rate) or damage (albuminuria). Those found to have CKD on the basis of these tests or those at risk for CKD are enrolled in a prospective longitudinal cohort. We measure markers of renal function, insulin resistance and epigenetics (microRNAs) on patients. Individuals are invited to participate in interviews and focus groups in order to characterize their attitudes towards research and barriers or facilitators to participation in future research studies about kidney disease. DISCUSSION: This study will provide important data about the local epidemiology of kidney disease in a high-risk rural setting and the utility of emerging renal filtration markers (Beta 2 Microglobulin and Cystatin C), while generating data and methods for the analyses of microRNA biomarkers. The qualitative research subproject will identify factors associated with increased willingness to participate in future translational research projects. With its geographical focus, this study will address a critical disparity in kidney disease research, while generating novel epigenetic data that are relevant for future studies in the general population. PMID- 29486723 TI - Genomics of NSCLC patients both affirm PD-L1 expression and predict their clinical responses to anti-PD-1 immunotherapy. AB - BACKGROUND: Programmed Death Ligand 1 (PD-L1) is a co-stimulatory and immune checkpoint protein. PD-L1 expression in non-small cell lung cancers (NSCLC) is a hallmark of adaptive resistance and its expression is often used to predict the outcome of Programmed Death 1 (PD-1) and PD-L1 immunotherapy treatments. However, clinical benefits do not occur in all patients and new approaches are needed to assist in selecting patients for PD-1 or PD-L1 immunotherapies. Here, we hypothesized that patient tumor cell genomics influenced cell signaling and expression of PD-L1, chemokines, and immunosuppressive molecules and these profiles could be used to predict patient clinical responses. METHODS: We used a recent dataset from NSCLC patients treated with pembrolizumab. Deleterious gene mutational profiles in patient exomes were identified and annotated into a cancer network to create NSCLC patient-specific predictive computational simulation models. Validation checks were performed on the cancer network, simulation model predictions, and PD-1 match rates between patient-specific predicted and clinical responses. RESULTS: Expression profiles of these 24 chemokines and immunosuppressive molecules were used to identify patients who would or would not respond to PD-1 immunotherapy. PD-L1 expression alone was not sufficient to predict which patients would or would not respond to PD-1 immunotherapy. Adding chemokine and immunosuppressive molecule expression profiles allowed patient models to achieve a greater than 85.0% predictive correlation among predicted and reported patient clinical responses. CONCLUSIONS: Our results suggested that chemokine and immunosuppressive molecule expression profiles can be used to accurately predict clinical responses thus differentiating among patients who would and would not benefit from PD-1 or PD-L1 immunotherapies. PMID- 29486724 TI - A case of ureteral myeloid sarcoma post-renal transplantation. AB - BACKGROUND: Significant attention has been directed toward the high incidence of malignant tumours that occur post-transplantation. However, there are few reports of myeloid sarcomas (MSs) following renal transplantation. CASE PRESENTATION: This case report describes a 26-year-old male patient who presented with repeatedly high creatinine levels and hydronephrosis six months post-renal transplantation. Surgical pathology revealed ureteral MS; however, the tumour recurred following resection. Bone marrow biopsy indicated that the patient also had acute promyelocytic leukaemia. The tumour was treated with local radiotherapy, and the leukaemia was treated with systemic chemotherapy. The patient's conditions were satisfactory at the one-year follow-up. CONCLUSIONS: This report is the first to describe a ureteral MS post-renal transplantation. Our findings suggest that surgical resection combined with radiotherapy and chemotherapy can help control the status of patients with this condition. PMID- 29486725 TI - Immune checkpoint inhibitor (nivolumab)-associated kidney injury and the importance of recognizing concomitant medications known to cause acute tubulointerstitial nephritis: a case report. AB - BACKGROUND: Acute tubulointerstitial nephritis (ATIN) has been increasingly recognized as an important manifestation of kidney injury associated with the use of immune checkpoint inhibitors (anti-PD-1 and anti-CTLA-4). While the exact pathophysiology remains unknown, corticosteroids are the mainstay of management. CASE PRESENTATION: We describe a 67-year-old man with stage IV non-small-cell lung cancer who developed kidney injury during treatment with the anti-PD-1 antibody nivolumab. A kidney biopsy showed ATIN without granuloma formation. Considering their mechanism of action, immune checkpoint inhibitors can alter immunological tolerance to concomitant drugs that have been safely used for a long time. For more than 4 years before the initiation of nivolumab therapy, the patient had been receiving the proton pump inhibitor lansoprazole, known to cause drug-induced ATIN, without significant adverse events including kidney injury. He showed rapid improvement in kidney function in 3 days (creatinine decreased from 2.74 to 1.82 mg/dl) on discontinuation of lansoprazole. He then received 500 mg intravenous methylprednisolone for 3 days followed by 1 mg/kg/day oral prednisolone and his creatinine levels eventually stabilized around 1.7 mg/dl. Drug-induced lymphocyte stimulation test (DLST) for lansoprazole was positive. CONCLUSIONS: The rapid improvement of kidney function after discontinuation and DLST positivity indicate that lansoprazole contributed to the development of ATIN during nivolumab therapy. Considering the time course, it is plausible that nivolumab altered the long-lasting immunological tolerance against lansoprazole in this patient. To the best of our knowledge, this is the first case report of DLST positivity for a drug that had been used safely before the initiation of an immune checkpoint inhibitor. Although corticosteroid therapy is recommended, the recognition and discontinuation of concomitant drugs, especially those known to induce ATIN, is necessary for the management of kidney injury associated with anti-PD-1 therapy. PMID- 29486726 TI - Concurrent methicillin-resistant Staphylococcus aureus septicemia and pyomyositis in a patient with dengue hemorrhagic fever: a case report. AB - BACKGROUND: Concurrent presence of dengue hemorrhagic fever (DHF), tropical pyomyositis and septicemia due to methicillin-resistant Staphylococcus aureus (MRSA) in a previously healthy person has never been reported. These three conditions even individually are potentially fatal. "Here we describe a case of a patient contracting dengue and developing DHF along with concurrent pyomyositis likely to be due to MRSA, leading to MRSA septicemia with abscesses formed by MRSA". CASE PRESENTATION: A 44-year old previously healthy Sinhalese man presented on day 3 of the illness with fever, headache, arthralgia and myalgia and watery loose stools. His pulse rate was 76/min, blood pressure was 110/80 mmHg, while cardiovascular, respiratory and abdomen examination findings were unremarkable. The test for the dengue NS1 antigen was positive on the same day. We have diagnosed dengue and started managing him symptomatically as per the current national guidelines. The patient developed DHF with bilateral pleural effusion and ascitis. On the day 5 he developed severe myalgia, tenderness and non pitting edema of lower limbs especially in the thighs. His creatine kinase levels were high and an ultrasound scan confirmed myositis of both thighs. We suspected myositis due to dengue but investigated for possible simultaneous sepsis as well. On day 9 his blood culture became positive for MRSA. Considering the sensitivity of the bacteria intravenous vancomycin and ciprofloxacin was administered for 21 days. He developed a small abscess at the site of the first intravenous access and a large one above the ankle on the left. On day 12 the latter was drained and the pus culture yielded MRSA sensitive to the same antibiotics. The rapid test for dengue IgM was negative initially but later a positive MAC-ELISA test entrenched dengue infection. After improvement he was sent home on day 33 of the illness. He has developed two other abscesses in the proximity of the drained one and they were drained on day 57. The patient recovered. CONCLUSIONS: When dengue patients develop symptoms and signs of myositis, prompt investigations for pyomyositis and the treatment can save lives. PMID- 29486727 TI - Correction to: Palliative external beam radiotherapy for the treatment of tumor bleeding in inoperable advanced gastric cancer. AB - CORRECTION TO: BMC CANCER (2017) 17:541 DOI: 10.1186/S12885-017-3508-X: In the original version of this article [1], published on 12 August 2017, the affiliations and author contributor details were not correct. In this Correction the incorrect affiliations and author contributor details and correct affiliations and author contributor details are shown. PMID- 29486728 TI - Low-dose aspirin use and survival in colorectal cancer: results from a population based cohort study. AB - BACKGROUND: Aspirin has been proposed as a novel adjuvant agent in colorectal cancer (CRC). Six observational studies have reported CRC-specific survival outcomes in patients using aspirin after CRC diagnosis but the results from these studies have been conflicting. Using a population-based cohort design this study aimed to assess if low-dose aspirin use after diagnosis reduced CRC-specific mortality. METHODS: A cohort of 8391 patients with Dukes' A-C CRC (2009-2012) was identified from the Scottish Cancer Registry and linked to national prescribing and death records. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for CRC-specific mortality were calculated using time-dependent Cox regression. RESULTS: There were 1064 CRC-specific deaths after a median follow-up of 3.6 years. Post-diagnostic low-dose aspirin use was not associated with a reduction in CRC-specific mortality either before or after adjustment for confounders (adjusted HR = 1.17, 95% CI 1.00-1.36). In sensitivity analysis pre diagnostic low-dose aspirin was also not associated with reduced CRC-specific mortality (adjusted HR = 0.96, 95% CI 0.88-1.05). CONCLUSION: Low-dose aspirin use, either before or after diagnosis, did not prolong survival in this population-based CRC cohort. PMID- 29486729 TI - Phosphate stimulates myotube atrophy through autophagy activation: evidence of hyperphosphatemia contributing to skeletal muscle wasting in chronic kidney disease. AB - BACKGROUND: Accelerated muscle atrophy is associated with a three-fold increase in mortality in chronic kidney disease (CKD) patients. It is suggested that hyperphosphatemia might contribute to muscle wasting, but the underlying mechanisms remain unclear. Although evidence indicates that autophagy is involved in the maintenance of muscle homeostasis, it is not known if high phosphate levels can result in activation of autophagy, leading to muscle protein loss. METHODS: Immortalized rat L6 myotubes were exposed to a high concentration of phosphate, with or without autophagy inhibition. Myotube atrophy was examined by phase contrast microscopy. Autophagic activity was assessed by measuring the expression of microtubule-associated protein 1 light chain 3 (LC3) and p62 using quantitative real-time polymerase chain reaction and western blot. RESULTS: Phosphate induced cell atrophy in L6 myotubes in a dose- and time-dependent manner, and these responses were not associated with calcification or osteogenesis. Phosphate also dose- and time-dependently increased the LC3-II/LC3 I ratio. Inhibition of autophagy with wortmannin or knockdown of Atg5 significantly suppressed myotube atrophy caused by high phosphate concentration. CONCLUSIONS: High phosphate concentration induces muscle cell atrophy through the activation of autophagy. Targeting autophagy could be a therapeutic strategy for preventing muscle wasting caused by hyperphosphatemia. PMID- 29486730 TI - Centralising specialist cancer surgery services in England: survey of factors that matter to patients and carers and health professionals. AB - BACKGROUND: The centralisation of specialist cancer surgical services across London Cancer and Greater Manchester Cancer, England, may significantly change how patients experience care. These centres are changing specialist surgical pathways for several cancers including prostate, bladder, kidney, and oesophago gastric cancers, increasing the specialisation of centres and providing surgery in fewer hospitals. While there are potential benefits related to centralising services, changes of this kind are often controversial. The aim of this study was to identify factors related to the centralisation of specialist surgical services that are important to patients, carers and health care professionals. METHODS: This was a questionnaire-based study involving a convenience sample of patient and public involvement (PPI) and cancer health care professional (HCP) sub-groups in London and Greater Manchester (n = 186). Participants were asked to identify which of a list of factors potentially influenced by the centralisation of specialist cancer surgery were important to them and to rank these in order of importance. We ranked and shortlisted the most important factors. RESULTS: We obtained 52 responses (28% response rate). The factors across both groups rated most important were: highly trained staff; likelihood and severity of complications; waiting time for cancer surgery; and access to staff members from various disciplines with specialised skills in cancer. These factors were also ranked as being important separately by the PPI and HCP sub-groups. There was considerable heterogeneity in the relative ordering of factors within sub-groups and overall. CONCLUSIONS: This study examines and ranks factors important to patients and carers, and health care professionals in order to inform the implementation of centralisation of specialist cancer surgical services. The most important factors were similar in the two stakeholder sub-groups. Planners should consider the impact of reorganising services on these factors, and disseminate this information to patients, the public and health care professionals when deciding whether or not and how to centralise specialist cancer surgical services. PMID- 29486732 TI - Whole-genome scan reveals significant non-additive effects for sire conception rate in Holstein cattle. AB - BACKGROUND: Service sire has a considerable impact on reproductive success in dairy cattle. Most gene mapping studies for bull fertility have focused on additive effects, while non-additive effects have been largely ignored. The main goal of this study was to assess the relevance of non-additive effects on Sire Conception Rate (SCR) in Holstein dairy cattle. The analysis included 7.5 k Holstein bulls with both SCR records and 57.8 k single nucleotide polymorphism (SNP) markers spanning the entire genome. RESULTS: The importance of non-additive effects was evaluated using an efficient two-step mixed model-based approach. Four genomic regions located on chromosomes BTA8, BTA9, BTA13 and BTA17 showed marked dominance and/or recessive effects. Most of these regions harbor genes, such as ADAM28, DNAJA1, TBC1D20, SPO11, PIWIL3 and TMEM119, that are directly implicated in testis development, male germ line maintenance, and sperm maturation. CONCLUSIONS: This study provides further evidence for the relevance of non-additive effects in fitness-related traits, such as male fertility. In addition, these findings may point out new strategies for improving service sire fertility in dairy cattle via marker-assisted selection. PMID- 29486731 TI - Combined activity of COX-1 and COX-2 is increased in non-neoplastic colonic mucosa from colorectal neoplasia patients. AB - BACKGROUND: Cyclooxygenase (COX) activity is increased in endoscopic normal colonic mucosa from patients with colorectal neoplasia (CRN). COX-2 is thought to be the predominant COX isozyme involved in neoplasia. Meanwhile, relative contributions of COX-1 and COX-2 isoforms are unknown. Knowledge about their mutual activity in colonic mucosa is important for diagnostics and targeted therapy for CRN. The aim of this study was to assess the relative function, expression and localization of COX-1 and COX-2 enzymes in colonic non-neoplastic human mucosa and thereby to potentially reveal a mucosal disease predisposition for better treatment. METHODS: Biopsies were pinched from normal appearing colonic mucosa in patients undergoing endoscopy. Ussing chamber technique was applied for an indirect assessment of epithelial activity, RT-qPCR for expression and immunohistochemistry for localization of COX-1 and COX-2 enzymes in patients without (ctrls) and with a history of CRN (CRN-pts). RESULTS: Combined COX-1 and COX-2 activity was higher in CRN-pts, p = 0.036. COX-2 was primarily localized in absorptive cells, while COX-1 appeared to be restricted to nonenteroendocrine tuft cells of the colonic epithelium. CONCLUSIONS: In biopsies from endoscopic normal appearing colonic mucosa, combined activity of COX-1 and COX-2 enzymes is increased in CRN-pts compared with ctrls. This indicates that COX-1 and COX-2 together contribute to an increased proliferation process. Of note, in colonic epithelial cell lining, the COX-1 enzyme seems localized in tuft cells. PMID- 29486733 TI - Development and evaluation of a risk assessment tool to improve clinical triage accuracy for colonoscopic investigations. AB - BACKGROUND: Gastroenterology Departments at hospitals within Australia receive thousands of General Practitioner (GP)-referral letters for gastrointestinal investigations every month. Many of these requests are for colonoscopy. This study aims to evaluate the performance of the current symptoms-based triage system compared to a novel risk score using objective markers. METHODS: Patients with lower abdominal symptoms referred by their GPs and triaged by a Gastroenterology consultant to a colonoscopy consent clinic were recruited into the study. A risk assessment tool (RAT) was developed using objective data (clinical, demographic, pathology (stool test, FIT), standard blood tests and colonoscopy outcome). Colonoscopy and histology results were scored and then stratified as either significant bowel disease (SBD) or non-significant bowel disease (non-SBD). RESULTS: Of the 467 patients in our study, 45.1% were male, the mean age was 54.3 +/- 13.8 years and mean BMI was 27.8 +/- 6.2. Overall, 26% had SBD compared to 74% with non-SBD (42% of the cohort had a normal colonoscopy). Increasing severity of referral symptoms was related to a higher triage category, (rectal bleeding, P = 2.86*10-9; diarrhoea, P = 0.026; abdominal pain, P = 5.67*10-4). However, there was no significant difference in the prevalence of rectal bleeding (P = 0.991) or diarrhoea (P = 0.843) for SBD. Abdominal pain significantly reduced the risk of SBD (P = 0.0344, OR = 0.52, CI = 0.27-0.95). Conversely, the RAT had a very high specificity of 98% with PPV and NPV of SBD prediction, 74% and 77%, respectively. The RAT provided an odds ratio (OR) of 9.0, 95%CI 4.29-18.75, p = 2.32*10-11), higher than the FIT test (OR = 5.3, 95%CI 2.44-11.69, p = 4.88*10-6), blood score (OR = 2.8, 95%CI 1.72- 4.38, p = 1.47*10-5) or age (OR = 2.5, 95%CI 1.61-4.00, 5.12*10-5) independently. Notably, the ORs of these individual objective measures were higher than the current practice of symptoms-based triaging (OR = 1.4, 95%CI 0.88-2.11, p = 0.153). CONCLUSIONS: It is critical that individuals with high risk of having SBD are triaged to the appropriate category with the shortest wait time. Here we provide evidence that a combination of blood markers, demographic markers and the FIT test have a higher diagnostic accuracy for SBD than FIT alone. PMID- 29486734 TI - The association of diabetes mellitus and insulin treatment with expression of insulin-related proteins in breast tumors. AB - BACKGROUND: The insulin receptor (INSR) and the insulin growth factor 1 receptor (IGF1R) play important roles in the etiology of both diabetes mellitus and breast cancer. We aimed to evaluate the expression of hormone and insulin-related proteins within or related to the PI3K and MAPK pathway in breast tumors of women with or without diabetes mellitus, treated with or without insulin (analogues). METHODS: Immunohistochemistry was performed on tumor tissue of 312 women with invasive breast cancer, with or without pre-existing diabetes mellitus, diagnosed in 2000-2010, who were randomly selected from a Danish breast cancer cohort. Women with diabetes were 2:1 frequency matched by year of birth and age at breast cancer diagnosis to those without diabetes. Tumor Microarrays were successfully stained for p-ER, EGFR, p-ERK1/2, p-mTOR, and IGF1R, and scored by a breast pathologist. Associations of expression of these proteins with diabetes, insulin treatment (human insulin and insulin analogues) and other diabetes medication were evaluated by multivariable logistic regression adjusting for menopause and BMI; effect modification by menopausal status, BMI, and ER status was assessed using interactions terms. RESULTS: We found no significant differences in expression of any of the proteins in breast tumors of women with (n = 211) and without diabetes (n = 101). Among women with diabetes, insulin use (n = 53) was significantly associated with higher tumor protein expression of IGF1R (OR = 2.36; 95%CI:1.02-5.52; p = 0.04) and p-mTOR (OR = 2.35; 95%CI:1.13-4.88; p = 0.02), especially among women treated with insulin analogues. Menopause seemed to modified the association between insulin and IGF1R expression (p = 0.07); the difference in IGF1R expression was only observed in tumors of premenopausal women (OR = 5.10; 95%CI:1.36-19.14; p = 0.02). We found no associations between other types of diabetes medication, such as metformin, and protein expression of the five proteins evaluated. CONCLUSIONS: In our study, breast tumors of women with pre-existing diabetes did not show an altered expression of selected PI3K/MAPK pathway-related proteins. We observed an association between insulin treatment and increased p-mTOR and IGF1R expression of breast tumors, especially in premenopausal women. This observation, if confirmed, might be clinically relevant since the use of IGF1R and mTOR inhibitors are currently investigated in clinical trials. PMID- 29486735 TI - Positive expression of Midkine predicts early recurrence and poor prognosis of initially resectable combined hepatocellular cholangiocarcinoma. AB - BACKGROUND: Post-surgical prognosis is usually poor for combined hepatocellular cholangiocarcinoma (CHCC-CC), a rare primary liver cancer. Although midkine (MK) is a prognostic biomarker for several known cancers, it is not known whether it can be used as such in resectable CHCC-CC. This study examined whether MK expression can predict recurrence and survival in patients with resectable CHCC CC. METHODS: We retrospectively enrolled 52 patients with resectable CHCC-CC who had received curative hepatic resections. MK expression was assessed in post surgical immunohistochemical studies of specimens in paraffin blocks. Clinical outcomes were analyzed from medical records. RESULTS: Two-year disease-free and three-year overall survival rates were 42.1% and 44.6%. MK was expressed in 30 patients. Univariate analysis showed patients positively expressing MK had a significantly poorer 2-year disease free and three-year overall survival. Multivariate analysis found positive MK expression independently predicted recurrence. CONCLUSIONS: Positive expression of MK predicts poor prognosis in patients with resectable CHCC-CC. PMID- 29486736 TI - Stability of personality traits over a five-year period in Swedish patients with schizophrenia spectrum disorder and non-psychotic individuals: a study using the Swedish universities scales of personality. AB - BACKGROUND: Personality is considered as an important aspect in persons with psychotic disorders. Several studies have investigated personality in schizophrenia. However, no study has investigated stability of personality traits exceeding three years in patients with schizophrenia. This study aims to investigate the stability of personality traits over a five-year period among patients with schizophrenia and non-psychotic individuals and to evaluate case control differences. METHODS: Patients with psychotic disorders (n = 36) and non psychotic individuals (n = 76) completed Swedish universities Scales of Personality (SSP) at two occasions five years apart. SSP scores were analysed for effect of time and case-control differences by multiple analysis of covariance (MANCOVA) and within-subjects correlation. RESULTS: MANCOVA within-subjects analysis did not show any effect of time. Thus, SSP mean scale scores did not significantly vary during the five-year interval. Within subject correlations (Spearman) ranged 0.30-0.68 and 0.54-0.75 for the different SSP scales in patients and controls, respectively. Patients scored higher than controls in SSP scales Somatic Trait Anxiety, Psychic Trait Anxiety, Stress Susceptibility, Lack of Assertiveness, Detachment, Embitterment, and Mistrust. CONCLUSION: The stability of the SSP personality trait was reasonably high among patients with psychotic disorder, although lower than among non-psychotic individuals, which is in accordance with previous research. PMID- 29486737 TI - High HIV risk and syndemic burden regardless of referral source among MSM screening for a PrEP demonstration project in Toronto, Canada. AB - BACKGROUND: To maximize public health impact and cost-effectiveness, HIV pre exposure prophylaxis (PrEP) must reach individuals at high HIV risk. Referrals for PrEP can be self- or provider-initiated, but there are several challenges to both. We assessed whether HIV risk differed by referral source among gay, bisexual and other men who have sex (gbMSM) screening for an HIV PrEP demonstration project. METHODS: PREPARATORY-5 was an open-label PrEP demonstration project enrolling gbMSM at high risk of HIV acquisition in Toronto, Canada. Study eligibility criteria related to high risk was defined as scoring >=10 on the HIV Incidence Risk Index for MSM (HIRI-MSM) and engaging in at least 1 act of condomless receptive anal sex within the past 6 months. Recruitment was promoted through self-referrals (ads in a sexual networking app and gay newspaper/website) and provider-referrals (10 community-based organizations, CBOs). HIV risk score (HIRI-MSM) and syndemic health burden were measured among gbMSM screened for study participation and compared according to referral source. RESULTS: Between October 16 and December 30, 2014, online ads generated 1518 click-throughs and CBOs referred 115 individuals. Overall, 165 men inquired about the trial, of which 86 underwent screening. The majority of screened men were self-referrals (60.5%), scored >=10 on HIRI-MSM (96.5%), and reported condomless receptive anal sex in the past 6 months (74.2%). Self- and provider-referrals had similarly high HIV risk profiles, with a median (IQR) HIRI-MSM score of 26.0 (19.0-32.5) and 28.5 (20.0-34.0) (p = 0.3), and 75.0% and 73.5% reporting condomless receptive anal sex (p = 0.9), respectively. The overall burden of syndemic health problems was also high, with approximately one-third overall identified as having depressive symptoms (39.5%), alcohol-related problems (39.5%), multiple drug use (31.4%), or sexual compulsivity (31.4%). There were no significant differences in syndemic health problems by referral source. CONCLUSIONS: HIV risk and syndemic burden were high among gbMSM presenting for this PrEP demonstration project regardless of referral source. Self-referral may be a useful and efficient strategy for identifying individuals suitable for PrEP use. Online strategies and CBOs working in gay men's health may play important roles in connecting individuals at high HIV risk to PrEP services. TRIAL REGISTRATION: ClinicalTrials.gov NCT02149888 . Registered May 12th 2014. PMID- 29486738 TI - Compound A attenuates toll-like receptor 4-mediated paclitaxel resistance in breast cancer and melanoma through suppression of IL-8. AB - BACKGROUND: Paclitaxel (PTX) is a potent anti-cancer drug commonly used for the treatment of advanced breast cancer (BCA) and melanoma. Toll-like receptor 4 (TLR4) promotes the production of pro-inflammatory cytokines associated with cancer chemoresistance. This study aims to explore the effect of TLR4 in PTX resistance in triple-negative BCA and advanced melanoma and the effect of compound A (CpdA) to attenuate this resistance. METHODS: BCA and melanoma cell lines were checked for the response to PTX by cytotoxic assay. The response to PTX of TLR4-transient knockdown cells by siRNA transfection was evaluated compared to the control cells. Levels of pro-inflammatory cytokines, IL-6 and IL 8, and anti-apoptotic protein, XIAP were measured by real-time PCR whereas the secreted IL-8 was quantitated by ELISA in TLR4-transient knockdown cancer cells with or without CpdA treatment. The apoptotic cells after adding PTX alone or in combination with CpdA were detected by caspase-3/7 assay. RESULTS: PTX could markedly induce TLR4 expression in both MDA-MB-231 BCA and MDA-MB-435 melanoma cell lines having a basal level of TLR4 whereas no significant induction in TLR4 transient knockdown cells occurred. The siTLR4-treated BCA cells revealed more dead cells after PTX treatment than that of mock control cells. IL-6, IL-8 and XIAP showed increased expressions in PTX-treated cells and this over-production effect was inhibited in TLR4-transient knockdown cells. Apoptotic cells were detected higher when PTX and CpdA were combined than PTX treatment alone. Isobologram exhibited the synergistic effect of CpdA and PTX. CpdA could significantly decrease expressions of IL-6, XIAP and IL-8, as well as excreted IL 8 levels together with reduced cancer viability after PTX treatment. CONCLUSIONS: The acquired TLR4-mediated PTX resistance in BCA and melanoma is explained partly by the paracrine effect of IL-6 and IL-8 released into the tumor microenvironment and over-production of anti-apoptotic protein, XIAP, in BCA cells and importantly CpdA could reduce this effect and sensitize PTX-induced apoptosis in a synergistic manner. In conclusion, the possible impact of TLR4-dependent signaling pathway in PTX resistance in BCA and melanoma is proposed and using PTX in combination with CpdA may attenuate TLR4-mediated PTX resistance in the treatment of the patients. PMID- 29486739 TI - Smoking, leisure-time exercise and frequency of self-reported common cold among the general population in northeastern China: a cross-sectional study. AB - BACKGROUND: Physical activity (PA) and smoking have been reported to be associated with the duration and severity of common cold symptoms. However, few studies have addressed the associations between the frequency of leisure-time exercise, cigarette smoking status and the frequency of the common cold in a cold area. This study was designed to investigate these issues in northeastern China. METHODS: This cross-sectional study included individuals who participated in a regular health examination conducted in Jilin Province, China. Information on episodes of the common cold, the frequency of leisure-time exercise and cigarette smoking status in the past year were collected by self-administered health questionnaires. Ordinal logistic regression models were used to analyse the associations between the frequency of leisure-time exercise, cigarette smoking status and the retrospective frequency of common cold. RESULTS: A total of 1413 employees participated in the study, with an average age of 38.92 +/- 9.04 years and 44.4% of them were male. Of all participants, 80.8% reported having experienced the common cold in the past year. After adjustment, the risk of suffering from the common cold more than once (odds ratios (ORs), 1.59; 95% confidence interval (CI), 1.27-1.99) in passive smokers was 1.59 times as high as that in non-smokers. Nevertheless, the results of the adjusted analysis showed no statistically significant relation between current smoking and the frequency of the common cold. A high frequency of leisure-time exercise (>=3 days/week) was associated with a 26% reduced risk of having at least one episode of the common cold (OR, 0.74; 95% CI, 0.55-0.98) compared with a low frequency group (< 4 days/month). For current and passive smokers, the protective effect of a high frequency of leisure-time exercise appears not to be obvious (current smokers: OR, 0.68; 95% CI, 0.33-1.43; passive smokers: OR, 1.15; 95% CI, 0.69-1.93). CONCLUSION: Passive smoking was associated with a higher risk of having self reported common cold at least once, while a high frequency of leisure-time exercise was related to a lower risk of reporting more than one episode of the disease in Chinese. PMID- 29486740 TI - Nanog induced intermediate state in regulating stem cell differentiation and reprogramming. AB - BACKGROUND: Heterogeneous gene expressions of cells are widely observed in self renewing pluripotent stem cells, suggesting possible coexistence of multiple cellular states with distinct characteristics. Though the elements regulating cellular states have been identified, the underlying dynamic mechanisms and the significance of such cellular heterogeneity remain elusive. RESULTS: We present a gene regulatory network model to investigate the bimodal Nanog distribution in stem cells. Our model reveals a novel role of dynamic conversion between the cellular states of high and low Nanog levels. Model simulations demonstrate that the low-Nanog state benefits cell differentiation through serving as an intermediate state to reduce the barrier of transition. Interestingly, the existence of low-Nanog state dynamically slows down the reprogramming process, and additional Nanog activation is found to be essential to quickly attaining the fully reprogrammed cell state. CONCLUSIONS: Nanog has been recognized as a critical pluripotency gene in stem cell regulation. Our modeling results quantitatively show a dual role of Nanog during stem cell differentiation and reprogramming, and the importance of the intermediate state during cell state transitions. Our approach offers a general method for analyzing key regulatory factors controlling cell differentiation and reprogramming. PMID- 29486741 TI - Intensive home treatment for patients in acute psychiatric crisis situations: a multicentre randomized controlled trial. AB - BACKGROUND: Hospitalization is a common method to intensify care for patients experiencing a psychiatric crisis. A short-term, specialised, out-patient crisis intervention by a Crisis Resolution Team (CRT) in the Netherlands, called Intensive Home Treatment (IHT), is a viable intervention which may help reduce hospital admission days. However, research on the (cost-)effectiveness of alternatives to hospitalisation such as IHT are scarce. In the study presented in this protocol, IHT will be compared to care-as-usual (CAU) in a randomized controlled trial (RCT). CAU comprises low-intensity outpatient care and hospitalisation if necessary. In this RCT it is hypothesized that IHT will reduce inpatient days by 33% compared to CAU while safety and clinical outcomes will be non-inferior. Secondary hypotheses are that treatment satisfaction of patients and their relatives are expected to be higher in the IHT condition compared to CAU. METHODS: A 2-centre, 2-arm Zelen double consent RCT will be employed. Participants will be recruited in the Amsterdam area, the Netherlands. Clinical assessments will be carried out at baseline and at 6, 26 and 52 weeks post treatment allocation. The primary outcome measure is the number of admission days. Secondary outcomes include psychological well-being, safety and patients' and their relatives' treatment satisfaction. Alongside this RCT an economic evaluation will be carried out to assess the cost-effectiveness and cost-utility of IHT compared to CAU. DISCUSSION: RCTs on the effectiveness of crisis treatment in psychiatry are scarce and including patients in studies performed in acute psychiatric crisis care is a challenge due to the ethical and practical hurdles. The Zelen design may offer a feasible opportunity to carry out such an RCT. If our study finds that IHT is a safe and cost-effective alternative for CAU it may help support a further decrease of in-patient bed days and may foster the widespread implementation of IHT by mental health care organisations internationally. TRIAL REGISTRATION: The trial is registered in the Netherlands Trial Register as # NTR-6151 . Registered 23 November 2016. PMID- 29486742 TI - Parental separation and behaviours that influence the health of infants aged 28 to 32 months: a cross-sectional study. AB - BACKGROUND: In Western countries, many children are affected by the separation of their parents. The study's main objective was to analyse the parental behaviours potentially influential for preschool children's health by family structure (parents together or separated). METHODS: We conducted a cross-sectional study based on data collected from examinations as part of free preventive medical consultations in the French Community of Belgium. During the assessment of 30,769 infants aged 28 to 32 months, information was collected on the parents' use of tobacco, brushing of the infant's teeth, being monitored by a dentist, and receiving vision screening. The chi2 test was applied and the odds ratios were derived to compare the two groups of children (exposed/not exposed to parental separation). Multivariate logistic regression analyses were used to adjust the effect of exposure. RESULTS: Nearly one in ten (9.8%) did not live with both parents under the same roof. Taking into account the social and cultural environment and other potential confounders at our disposal, we found that in the event of parental separation, behaviours differ in comparison with situations where parents live together; the adjusted odds ratios (ORs) (95% confidence interval) for the infant's exposure to tobacco, absence of teeth brushing, lack of monitoring by a dentist and absence of visual screening, were respectively 1.7 (1.2-2.0), 1.1 (0.9-1.2), 1.3 (1.1-1.6), 1.2 (1.1-1.2), and 1.2 (1.1-1.4). CONCLUSIONS: This study confirms the suspicion that parental separation is an independent risk factor for parental behaviours that negatively influence the infant's health. If these results are confirmed, this it could affect the work of the family doctors and paediatricians, especially in terms of family support and information to parents. PMID- 29486745 TI - Cross-communication between Gi and Gs in a G-protein-coupled receptor heterotetramer guided by a receptor C-terminal domain. AB - BACKGROUND: G-protein-coupled receptor (GPCR) heteromeric complexes have distinct properties from homomeric GPCRs, giving rise to new receptor functionalities. Adenosine receptors (A1R or A2AR) can form A1R-A2AR heteromers (A1-A2AHet), and their activation leads to canonical G-protein-dependent (adenylate cyclase mediated) and -independent (beta-arrestin mediated) signaling. Adenosine has different affinities for A1R and A2AR, allowing the heteromeric receptor to detect its concentration by integrating the downstream Gi- and Gs-dependent signals. cAMP accumulation and beta-arrestin recruitment assays have shown that, within the complex, activation of A2AR impedes signaling via A1R. RESULTS: We examined the mechanism by which A1-A2AHet integrates Gi- and Gs-dependent signals. A1R blockade by A2AR in the A1-A2AHet is not observed in the absence of A2AR activation by agonists, in the absence of the C-terminal domain of A2AR, or in the presence of synthetic peptides that disrupt the heteromer interface of A1 A2AHet, indicating that signaling mediated by A1R and A2AR is controlled by both Gi and Gs proteins. CONCLUSIONS: We identified a new mechanism of signal transduction that implies a cross-communication between Gi and Gs proteins guided by the C-terminal tail of the A2AR. This mechanism provides the molecular basis for the operation of the A1-A2AHet as an adenosine concentration-sensing device that modulates the signals originating at both A1R and A2AR. PMID- 29486744 TI - Exome sequencing reveals a novel PLP1 mutation in a Moroccan family with connatal Pelizaeus-Merzbacher disease: a case report. AB - BACKGROUND: Epilepsy regroups a common and diverse set of chronic neurological disorders that are characterized by spontaneous, unprovoked, and recurrent epileptic seizures. Epilepsies have a highly heterogeneous background with a strong genetic contribution and various mode of inheritance. X-linked epilepsy usually manifests as part of a syndrome or epileptic encephalopathy. The variability of clinical manifestations of X-linked epilepsy may be attributed to several factors including the causal genetic mutation, making diagnosis, genetic counseling and treatment decisions difficult. We report the description of a Moroccan family referred to our genetic department with X-linked epileptic seizures as the only initial diagnosis. CASE PRESENTATION: Knowing the new contribution of Next-Generation Sequencing (NGS) for clinical investigation, and given the heterogeneity of this group of disorders we performed a Whole-Exome Sequencing (WES) analysis and co-segregation study in several members of this large family. We detected a novel pathogenic PLP1 missense mutation c.251C > A (p.Ala84Asp) allowing us to make a diagnosis of Pelizaeus-Merzbacher Disease for this family. CONCLUSION: This report extends the spectrum of PLP1 mutations and highlights the diagnostic utility of NGS to investigate this group of heterogeneous disorders. PMID- 29486743 TI - Men's reactions to receiving objective feedback on their weight, BMI and other health risk indicators. AB - BACKGROUND: Receiving information about one's weight, Body Mass Index (BMI) and other indicators of health risk may prompt behaviour change. This study investigated men's reactions to receiving information on indicators of health risk prior to taking part in a men-only weight management programme, Football Fans in Training (FFIT). It also investigated the extent to which the information was reported as influencing lifestyle change and having adverse consequences. METHODS: We undertook a qualitative, semi-structured, telephone interview study with 28 men who took part in FFIT. We sought to interview approximately equal numbers of men who had and had not lost 5% or more of their pre-programme body weight by the end of the 12-week programme. Data were analysed thematically utilising principles of framework analysis. RESULTS: Some men were apprehensive about receiving information which confirmed their overweight/obese status, particularly those less familiar with having similar information fed back to them. The professional football setting and the people present (including other men on the programme whom they perceived to be 'like them' and the fieldwork staff) were important factors in making the men feel comfortable in an otherwise potentially threatening situation. Men who achieved greater weight loss were more likely to report being motivated by this pre-programme feedback and to perceive themselves as responsible for their current weight and health status. However, for others the information only reaffirmed what they suspected about their relatively poor health status and was insufficient to prompt behaviour change. CONCLUSION: Undertaking measurements and receiving information on health risk indicators, such as weight or BMI, within the context of behaviour change programmes can enhance motivation for behaviour change when communicated in an empathic and non-stigmatising way, and therefore should be considered as an integral part of interventions. However, providing feedback on health risk may be insufficient to prompt behaviour change in some people and may be detrimental to those with poor body image and/or lacking personal agency to adopt lifestyle changes. It is therefore imperative that adequate support and opportunities are made available when information on weight and disease risk are fed back within research or other settings. PMID- 29486746 TI - Conjunctival repair after glaucoma drainage device exposure using collagen glycosaminoglycane matrices. AB - BACKGROUND: To report the results of the repair of conjunctival erosions resulting from glaucoma drainage device surgery using collagen-glycosaminoglycane matrices (CGM). METHODS: Case series of 8 patients who underwent revision surgery due to conjunctival defects with exposed tubes through necrosis of the overlying scleral flap and conjunctiva after Baerveldt drainage device surgery. The defects were repaired by lateral displacement of the tube towards the sclera, with a slice of a CGM as a patch, covered by adjacent conjunctiva. RESULT: Successful, lasting closure (follow-up of 12 to 42 months) of the conjunctival defects was achieved without any side-effects or complications in all eight cases. CONCLUSIONS: Erosion of the drainage tube, creating buttonholes in the conjunctiva after implantation of glaucoma drainage devices, is a potentially serious problem. It can be managed successfully using a biodegradable CGM as a patch. PMID- 29486747 TI - Pulmonary actinomycosis mimicking a lung metastasis from esophageal cancer; a case report. AB - BACKGROUND: Actinomycosis is a rare bacterial infection caused by Actinomyces. The symptom of actinomycosis is nonspecific and radiological images present as a slow-progressive mass lesion similarly to malignancies. Thus, it is difficult to distinguish pulmonary actinomycosis from malignancies. CASE PRESENTATION: A 74 year-old male who had esophageal cancer and a pulmonary mass that was positive for 18F-fluorodeoxyglucose positron emission tomography/computed tomography was initially diagnosed with esophageal cancer with a lung metastasis because he was asymptomatic. However, aspiration of pleural effusion revealed that the pulmonary lesion was actinomycosis. CONCLUSION: We present a case of pulmonary actinomycosis mimicking a lung metastasis from esophageal cancer. Diagnosis of asymptomatic pulmonary actinomycosis is difficult, and needle aspiration could be useful for a definitive diagnosis of pulmonary actinomycosis. PMID- 29486748 TI - Levonorgestrel-releasing intrauterine system for treatment of heavy menstrual bleeding in adolescents with Glanzmann's Thrombasthenia: illustrated case series. AB - BACKGROUND: Glanzmann's Thrombasthenia (GT) is an inherited genetic disorder caused by defects in the platelet membrane glycoproteins IIb/IIIA, and is associated with heavy menstrual bleeding (HMB). HMB is a common complication in female patients, and many adolescent girls with this disease have issues with HMB beginning at menarche. The available treatment modalities including anti fibrinolytics, nonsteroidal anti-inflammatory drugs (NSAIDs) and hormonal therapies though are effective, their associated side effects, limited efficacy and the poor compliance is a challenge in management of HMB. Levonorgestrel releasing intrauterine system (LNG-IUS) has been a potential alternative to overcome this challenge. The use of the LNG-IUS for the management of HMB in adolescents with GT is explored in this case series. CASE PRESENTATION: Two adolescents diagnosed with GT and received the LNG-IUS as treatment modality for management of HMB is discussed in this case series. CONCLUSIONS: For patients with poor compliance to oral hormonal therapies, the use of LNG-IUS is associated with a significant reduction of menstrual blood loss along with improved quality of life. These findings support the use of LNG-IUS to control adolescent GT related HMB. PMID- 29486749 TI - Modulation of human airway smooth muscle biology by human adipocytes. AB - BACKGROUND: Asthma and obesity, two growing epidemics worldwide, may share an underlying causal relationship. Airway hyperresponsiveness (AHR), a defining component of asthma, has been documented in both 'obese' animal models and non asthmatic obese individuals. However, there is a paucity of evidence that obesity derived factors directly affect human airway smooth muscles (ASM). METHODS: Experiments were designed with primary ASM and adipocytes isolated from the same human tissue explants (n = 6). The modulatory effects of human adipocytes extracted from subcutaneous (extrathoracic) and visceral (intrathoracic) depots, on ASM biology was examined with respect to proliferation, migration, contractility and pro-inflammatory cytokine synthesis. RESULTS: Adipocyte conditioned media as well as myocyte-adipocyte co-cultures failed to show any significant changes in the proliferative or migrational properties of the ASM. Adipocyte-conditioned media also had no effect on the contractility or relaxation of bovine tracheal muscle strips. In contrast, there was a moderate yet significant increase of IL-6 and eotaxin release by ASM incubated with adipocyte conditioned media (P = 0.0035 and P = 0.0067, vs. control, respectively), thereby further consolidating the altered inflammatory state reported for both diseases. CONCLUSION: We report, for the first time, that adipocytes from either subcutaneous or visceral depots can trigger an inflammatory state in the ASM, with negligible modulatory effects on hyperplasia, hypertrophy or contractile properties. PMID- 29486750 TI - Study protocol: a randomized controlled trial study on the effect of a game-based exercise training program on promoting physical fitness and mental health in children with autism spectrum disorder. AB - BACKGROUND: Suboptimal physical activity levels and tolerance, poor motor skills and poor physical health are demonstrated in children with Autism Spectrum Disorder (ASD). We speculate that social interaction and communication deficits in children with ASD are two major factors that hinder these children from actively participating in group physical activities. While previous studies have demonstrated that exercise intervention improves motor skills and behavioral outcomes in children with ASD, these programs tend to focus only on a single sport, which may not cater to the interests of different children with ASD. In this protocol, a game-based exercise training program designed by a multi disciplinary team (pediatrics, physical education and psychology) will be implemented by front-line healthcare providers trained following the train-the trainer (TTT) model and subjected to validation. METHOD: Using a randomized controlled trial design, the effectiveness of the game-based exercise program will be examined for 112 young children with ASD. These children were randomly assigned to two groups, which will be tested and trained in either one of the two arms of the waitlist conditions (control and intervention). The assessment of physical and psychological traits will be conducted at baseline (pre-test), at 16 weeks (post-treatment) and at 32-weeks (follow-up) of the program. DISCUSSION: Most of the interventions designed for ASD children target either their psychological traits or physical conditions, without bridging the two states. With the recognition of bidirectional relations between mental and physical health, the present game-based exercise program which includes multiple level of difficulties was developed to equip ASD children with the necessary skills for engaging in sustainable team sports or even professional sport training. The program, if effective, will provide an entertaining and engaging training for whole-person development among children with ASD. TRIAL REGISTRATION: This study is registered with the Chinese Clinical Trial Registry ( ChiCTR-IOR-17011898 ). Registered 6th July 2017. PMID- 29486751 TI - Stellate cells and mesenchymal stem cells in benign mammary stroma are associated with risk factors for breast cancer - an observational study. AB - BACKGROUND: It is not known whether stromal cells in benign breast tissue can mediate risk of breast cancer. We recently described aldehyde dehydrogenase 1 A1 (ALDH1) positive (+) cells in morphologically normal breast stroma of premenopausal women, and the data indicated that their distribution is associated with clinical risk factors for breast cancer. The aim of the present study was to define the identities of these cells using histologic and immunohistologic methods, and to investigate associations between those cells and hormonal and genetic risk factors in pre- and postmenopausal women. METHODS: Stroma of morphologically normal tissue was analyzed in samples from 101 well-characterized women whose breasts had been operated. Morphology and immunolabeling were applied to determine cell identities based on the putative stem cell markers ALDH1 and stage-specific embryonic antigen-3 (SSEA3), and immunophenotypes indicating mast cells or stellate cells. The results were compared with the patients' risk factors using regression analysis (two-tailed). RESULTS: ALDH1+ round/oval cells were associated with low parity in BRCA1/2 carriers (p = 0.022), while in non BRCA1/2-carriers they were negatively associated with nulliparity (p = 0.057). In premenopausal women ALDH1+ round/oval cells were associated with family history (p = 0.058). SSEA3+ round/oval cells were morphologically and immunohistologically consistent with multilineage stress-enduring (Muse) cells, and these cells were independently associated with the breast cancer risk factors low parity (p = 0.015), family history (p = 0.021), and hormone use after menopause (p = 0.032). ALDH1+ spindle-shaped/polygonal cells were immunohistologically consistent with stellate cells, and were negatively associated with family history of breast cancer (p = 0.001). CONCLUSION: This study identified novel stromal cell types in benign breast tissue that have a potential for stratifying women for breast cancer risk. PMID- 29486752 TI - Facing HIV infection and unintended pregnancy: Rakai, Uganda, 2001-2013. AB - BACKGROUND: Unintended pregnancy is a persistent and global issue with consequences for the health and well-being of mothers and babies. The aim of this paper is to examine unintended pregnancy over time in the context of substantial human immunodeficiency virus (HIV) prevalence and increasing access to anti-retro viral therapy (ART). METHOD: Data are from the Rakai Community Cohort Study (RCCS) - a cohort of communities with 10,000-12,000 adults, ages 15-49, in Rakai District, Uganda. We examined prevalence of current pregnancies over time, intended pregnancy, and unintended pregnancies (unwanted, mistimed, ambivalent). We then examined risk factors for the different categories of unintended pregnancy among women who were currently pregnant. The full sample included 32,205 observations over 13 years. RESULTS: The prevalence of mistimed pregnancy and unwanted pregnancy both decreased significantly over time (p < .001). The prevalence of current pregnancies and intended pregnancy showed no significant changes over the thirteen year period. The same overall pattern was found when only examining HIV positive women in the sample; however, the trends were not significant. Out of the 2820 current pregnancies reported, 54.4% were intended, 29.8% were mistimed, 13.2% were unwanted, and 2.5% were ambivalent. After controlling for other predictors, HIV status had no independent effect on mistimed pregnancy but had a significant effect on unwanted pregnancy (RRR = 2.44, 95% CI = 1.65-3.61, p < .001] and ambivalent pregnancy [RRR = 2.07; CI: 1.03 to 4.18, p = 0.041]. In 2004, after the introduction of ART, there was a decreased risk in unintended pregnancy [RR = 0.75; CI: 0.66 to 0.84, p < .001]. Women with a secondary education or higher also had a decreased risk in unintended pregnancy [RR = 0.70; CI: 0.70 to 0.92, p = 0.002]. DISCUSSION: HIV was an important predictor of unwanted pregnancy. Unintended pregnancy decreased in the sample over time which may be due to an increase in ART availability and rising levels of education. PMID- 29486753 TI - Evaluation of the effectiveness of a WHO-5A model based comprehensive tobacco control program among migrant workers in Guangdong, China: a pilot study. AB - BACKGROUND: As a vulnerable population in China, migrant workers have a higher smoking rate than the general population. This study aims to assess the effectiveness of a WHO-5A based comprehensive tobacco control program in workplaces aggregated with migrants. METHODS: Using a controlled before and after design, four purposely selected manufacturing factories were assigned to either intervention or control groups. Participants in the intervention arm received adapted 5A group counseling regularly supported by social-media and traditional health education approaches. The primary outcome was the change of smoking rate based on salivary cotinine concentration at three-month follow-up as compared to the control arm. Secondary outcomes were changes in smoking-related knowledge and attitudes assessed using questionnaires. Difference-in-differences approach (DID) and generalized estimating equations (GEE) models were used to conduct the effectiveness analysis. RESULTS: 149 and 166 workers were enrolled in the intervention and control arm respectively. The multiple imputed and adjusted GEE models demonstrated that, compared to those in the control arm, participants in the intervention arm had nearly 2.4 times odds of improving smoking-related knowledge (OR = 2.40, 95% CI = 1.32-4.36, P = 0.02) and three times the odds of improving smoking-related attitude (OR = 3.07, 95% CI = 1.28-7.41, P = 0.03). However, no significant difference was found regarding the change of smoking rate between the two arms (P > 0.05). The regression analysis showed that attendance at the 5A group counseling sections was an important determinant of stopping smoking or improving smoking-related knowledge and attitudes in the intervention group. CONCLUSIONS: This WHO-5A comprehensive intervention was effective in improving migrant workers' knowledge of smoking and anti-smoking attitudes. A large-scale, long-term trial is recommended to determine the effectiveness of this intervention. TRIAL REGISTRATION: ChiCTR-OPC-17011637 at Chinese Clinical Trial Registry. Retrospectively registered on 12th June 2017. PMID- 29486754 TI - Treating Diabetic Macular Oedema (DMO): real world UK clinical outcomes for the 0.19mg Fluocinolone Acetonide intravitreal implant (IluvienTM) at 2 years. AB - BACKGROUND: To compare visual function and structural improvements in pseudophakic eyes with diabetic macular oedema (DMO) treated with the 0.19mg Fluocinolone Acetonide (FAc) intravitreal implant (IluvienTM) in a 'real world' setting. METHODS: A single centre retrospective evaluation of patients with DMO unresponsive to conventional treatment treated with the FAc implant according to UK guidelines. Primary efficacy endpoint was best corrected visual acuity (BCVA); secondary endpoints included optical coherence tomography evaluations of the macula (a) central retinal and (b) peak macular thickness collected at annual time points. Primary safety endpoint was new rise in IOP >27mmHg or glaucoma surgery. Patients with <1 year follow-up were excluded. RESULTS: Twenty-nine eyes were included, with mean(SD) follow up of 792(270) days. Improvement in BCVA and reduction in macular oedema was noted at all timepoints. Mean improvement in BCVA from baseline was 6 ETDRS letters at year 1(n=29), 6.5L at year 2(n=22) and 11L at year 3(n=6). Mean central retinal thickness at baseline was 451 microns, 337 microns at year 1, 342 microns at year 2 and 314 microns at year 3. Two eyes required IOP-lowering drops post implant. Supplementary treatment for persistence or recurrence of DMO was necessary in 18 eyes over the total study period of 3 years with mean time to supplementary treatment being 12 months. CONCLUSIONS: Our evaluation of the 0.19mg FAc implant delivered in a real-world setting, provides additional evidence that it is effective and safe in the treatment of patients with DMO, and can provide sustained benefit for patients with previously refractory disease. PMID- 29486755 TI - Partial regression of large anterior scleral staphyloma secondary to rhinosporidiosis after corneoscleral graft - a case report. AB - BACKGROUND: Rhinosporidiosis is a rare chronic infection of the mucous membranes caused by the Rhinosporidium seeberi. Approximately 15% of cases of rhinosporidiosis are ocular, occurring mainly in the tarsal conjunctiva. There are only 11 cases of scleral melt with staphyloma formation associated with bulbar conjuctival oculosporidiosis and none of them was associated with partial regression of the scleral ectasia after a corneoscleral tectonic graft. CASE PRESENTATION: a 13-year-old girl with a progressively increasing black mass in the upper nasal part above the cornea of the left eye. The biomicroscopy revealed an oval, bluish mass measuring 10x10x5 mm with congestion of the overlying conjunctiva. Conjunctival biopsy showed sporoblasts of Rinosporidium seeberi. Treatment was conducted by conjunctival resection and tectonic corneoscleral graft (13x13mm) over the staphyloma. Within 1 year of follow-up the patient presented a partial staphyloma reduction, 9x9x2.5 mm, and the patch detached from the lesion. A novel surgical approach was done reducing the corneal patch and no recurrence was seen after 9 months. CONCLUSIONS: This case is one of the largest anterior scleral staphylomas secondary to rhinosporidiosis described in the literature. Scleral anterior staphyloma partial regression is an unusual outcome after a tectonic corneoscleral graft. Infection resolution and graft covering of thinned area contributed to scleral reepithelization. PMID- 29486756 TI - Failing to retain a new generation of doctors: qualitative insights from a high income country. AB - BACKGROUND: The failure of high-income countries, such as Ireland, to achieve a self-sufficient medical workforce has global implications, particularly for low income, source countries. In the past decade, Ireland has doubled the number of doctors it trains annually, but because of its failure to retain doctors, it remains heavily reliant on internationally trained doctors to staff its health system. To halve its dependence on internationally trained doctors by 2030, in line with World Health Organisation (WHO) recommendations, Ireland must become more adept at retaining doctors. METHOD: This paper presents findings from in depth interviews conducted with 50 early career doctors between May and July 2015. The paper explores the generational component of Ireland's failure to retain doctors and makes recommendations for retention policy and practice. RESULTS: Interviews revealed that a new generation of doctors differ from previous generations in several distinct ways. Their early experiences of training and practice have been in an over-stretched, under-staffed health system and this shapes their decision to remain in Ireland, or to leave. Perhaps as a result of the distinct challenges they have faced in an austerity-constrained health system and their awareness of the working conditions available globally, they challenge the traditional view of medicine as a vocation that should be prioritised before family and other commitments. A new generation of doctors have career options that are also strongly shaped by globalisation and by the opportunities presented by emigration. DISCUSSION: Understanding the medical workforce from a generational perspective requires that the health system address the issues of concern to a new generation of doctors, in terms of working conditions and training structures and also in terms of their desire for a more acceptable balance between work and life. This will be an important step towards future-proofing the medical workforce and is essential to achieving medical workforce self-sufficiency. PMID- 29486757 TI - Socioeconomic and environmental determinants of under-five mortality in Gamo Gofa Zone, Southern Ethiopia: a matched case control study. AB - BACKGROUND: Despite global declaration of the right to life as a fundamental human right and substantial progress in reducing childhood mortality, unacceptably high number of children still die before their fifth birthday every day. Different factors have been studied and implicated for under-five mortality with mixed results. Mortality studies in the current study sites were lacking. Therefore, this study examined environmental and socioeconomic determinants of under-five mortality. METHODS: The study applied a matched case control study design on 381 cases of children who died before their fifth birthday and 762 controls born within 1 month in the same locality as the cases. We conducted weighted conditional logistic regression to assess the association between selected factors and mortality status. RESULT: The odds of death was found to be significantly lower among children of mothers whose educational status was grade nine or above (Adjusted odds ratio (AOR) of 0.34(0.16-0.72)). The odds of death was significantly higher among children whose mothers' marital status were separated/divorced or widowed (AOR of 3.60(1.23-10.47)) and whose fathers were daily laborers (AOR of 2.34(1.29-4.23)). Presence of separate kitchen in the household for cooking was a proximate factor which was significantly associated with under-five mortality with AOR of 1.77(1.16-2.70). CONCLUSION: Socioeconomic factors like maternal education, husband occupation and marital status of the mother were shown to be significantly associated with under-five mortality. Hence, in order to enhance reduction in childhood mortality, investing on maternal education targeting those at risk groups is recommended. PMID- 29486758 TI - A stakeholder co-design approach for developing a community pharmacy service to enhance screening and management of atrial fibrillation. AB - BACKGROUND: Community pharmacies provide a suitable setting to promote self screening programs aimed at enhancing the early detection of atrial fibrillation (AF). Developing and implementing novel community pharmacy services (CPSs) is a complex and acknowledged challenge, which requires comprehensive planning and the participation of relevant stakeholders. Co-design processes are participatory research approaches that can enhance the development, evaluation and implementation of health services. The aim of this study was to co-design a pharmacist-led CPS aimed at enhancing self-monitoring/screening of AF. METHODS: A 3-step co-design process was conducted using qualitative methods: (1) interviews and focus group with potential service users (n = 8) to identify key needs and concerns; (2) focus group with a mixed group of stakeholders (n = 8) to generate a preliminary model of the service; and (3) focus group with community pharmacy owners and managers (n = 4) to explore the feasibility and appropriateness of the model. Data were analysed qualitatively to identify themes and intersections between themes. The JeMa2 model to conceptualize pharmacy-based health programs was used to build a theoretical model of the service. RESULTS: Stakeholders delineated: a clear target population (i.e., individuals >=65 years old, with hypertension, with or without previous AF or stroke); the components of the service (i.e., patient education; self-monitoring at home; results evaluation, referral and follow-up); and a set of circumstances that may influence the implementation of the service (e.g., quality of the service, competency of the pharmacist, inter-professional relationships, etc.). A number of strategies were recommended to enable implementation (e.g.,. endorsement by leading cardiovascular organizations, appropriate communication methods and channels between the pharmacy and the general medical practice settings, etc.). CONCLUSION: A novel and preliminary model of a CPS aimed at enhancing the management of AF was generated from this participatory process. This model can be used to inform decision making processes aimed at adopting and piloting of the service. It is expected the co-designed service has been adapted to suit existing needs of patients and current care practices, which, in turn, may increase the feasibility and acceptance of the service when it is implemented into a real setting. PMID- 29486759 TI - Acute intraparenchymal cerebral haemorrhage in an Iberian golden eagle - a case report. AB - BACKGROUND: In birds there are reports of intracranial lesions but not of the clinical, computed tomographic and histopathologic features of acute intraparenchymal cerebral haemorrhage in Iberian golden eagle. CASE PRESENTATION: The following report describes a case of a 30-year-old Iberian golden eagle (Aquila chrysaetos homeyeri) with no history of trauma, presented with acute opisthotonus, left head tilt and circling, anisocoria, positional nystagmus, and ataxia. The main differential diagnosis were hypovitaminosis B or E and intracranial disease due to trauma, infection, toxins or masses. A computed tomography (CT) of the head was performed with an 8-slices scanner and evidenced a hyperdense (63-65 HU) non-enhancing homogeneous well delineated round area in the midbrain, with 6 mm in its highest diameter. The attenuation values and the non-enhancing nature of the lesion strongly suggested the diagnosis of acute intraparenchymal haemorrhage, which was histologically confirmed after necropsy. CONCLUSIONS: In birds with a central neurological dysfunction, the diagnosis of acute brain haemorrhage should be considered when the CT evidences a non enhancing, homogeneous, well circumscribed hyperattenuated round area. PMID- 29486760 TI - Metabolic characterization of human aqueous humor in the cataract progression after pars plana vitrectomy. AB - BACKGROUND: While pars plana vitrectomy (PPV) has become the third most commonly performed surgery in the world, it can also induce multiple post complications easily. Among them, cataract progression is the most frequent one that can lead to blindness eventually. METHODS: To understand the underlying mechanisms of post PPV cataract progression, we performed comprehensive metabolic characterization of aqueous humor (AH) samples from 20 cataract patients (10 post PPV complication and 10 none PPV cataract) by a non-targeted metabolomic analysis using gas chromatography combined with time-of-flight mass spectrometer (GC/TOF MS). RESULTS: A total of 263 metabolites were identified and eight of them are determined to be significantly different (VIP >= 1 and p <= 0.05) between post PPV group and none PPV control group. The significantly changed metabolites included glutaric acid and pelargonic acid that play key roles in the regulation of oxidative stress and inflammatory responses. Furthermore, we constructed a metabolic regulatory network in each group based on metabolite-metabolite correlations, which reveals key metabolic pathways and regulatory elements including amino acids and lipids metabolisms that are related to cataract progression. CONCLUSIONS: Altogether, this work discovered some potential metabolite biomarkers for post PPV cataract diagnostics, as well as casted some novel insights into the underlying mechanisms of cataract progression after PPV. PMID- 29486761 TI - Impaired diversity of the lung microbiome predicts progression of idiopathic pulmonary fibrosis. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is the most frequent and severe form of idiopathic interstitial pneumonias. Although IPF has not been thought to be associated with bacterial communities, recent papers reported the possible role of microbiome composition in IPF. The roles of microbiomes in respiratory functions and as clinical biomarkers for IPF remain unknown. In this study, we aim to identify the relationship between the microbial environment in the lung and clinical findings. METHODS: Thirty-four subjects diagnosed with IPF were included in this analysis. The 16S rDNA was purified from bronchoalveolar lavage fluid obtained at the time of diagnosis and analyzed using next-generation sequencing techniques to characterize the bacterial communities. Furthermore, microbiomes from mice with bleomycin-induced lung fibrosis were analyzed. RESULTS: The most prevalent lung phyla were Firmicutes, Proteobacteria and Bacteroidetes. Decreased microbial diversity was found in patients with low forced vital capacity (FVC) and early mortality. Additionally, the diversity and relative abundance of Firmicutes, Streptococcaceae, and Veillonellaceae were significantly associated with FVC, 6-min walk distance, and serum surfactant protein D. Bleomycin-induced lung fibrosis resulted in decrease of diversity and alteration of microbiota in PCoA analysis. These results support the observations in human specimens. CONCLUSIONS: This study identified relationships between specific taxa in BALF and clinical findings, which were also supported by experiments in a mouse model. Our data suggest the possibility that loss of microbial diversity is associated with disease activities of IPF. PMID- 29486762 TI - Outcomes and costs of Ranibizumab and Aflibercept treatment in a health-service research context. AB - BACKGROUND: To compare anti-VEGF treatments for macular disease in terms of costs and clinical outcomes. METHODS: We identified patients suffering from macular disease and treated either with aflibercept, ranibizumab or both at the largest public eye clinic in Switzerland between January 1st and December 31st 2016 who were insured in one of the two participating health insurance companies. Clinical data were extracted from the electronic health record system. The health insurers provided the health claim costs for the ophthalmologic care and the total health care costs of each patient in the observation period. Using multivariate regression models, we assessed the monthly ophthalmologic and the monthly total costs of patients with no history of switching (ranibizumab vs. aflibercept), patients with a history of switching from ranibizumab to aflibercept, patients switching during the observation period and a miscellaneous group. We examined baseline differences in age, proportion of males, visual acuity (letters), central retinal thickness (CRT) and treatment history before entering the study. We investigated treatment intensity and compared the changes in letters and CRT. RESULTS: The analysis involved 488 eyes (361 patients), 182 on ranibizumab treatment, and 63 on aflibercept treatment, 160 eyes with a history of switching from ranibizumab to aflibercept, and 45 switchers during follow-up and 38 eyes of the miscellaneous group. Compared to ranibizumab, monthly costs of ophthalmologic treatment were slightly higher for aflibercept treatment + 175.0 CHF (95%CI: 1.5 CHF to 348.3 CHF; p = 0.048) as were the total monthly costs + 581.0 CHF (95%CI: 159.5 CHF to 1002.4 CHF; p = 0.007). Compared to ranibizumab, the monthly treatment intensity with aflibercept was similar (+ 0.057 injections/month (95%CI -0.023 to 0.137; p = 0.162), corresponding to a projected annual number of 5.4 injections for ranibizumab vs. 6.1 injections for aflibercept. During follow-up, visus dropped by 0.7 letters with ranibizumab and increased by 0.6 letters with aflibercept (p = 0.243). CRT dropped by - 14.9 MUm with ranibizumab and by - 19.5 MUm with aflibercept (p = 0.708). The monthly costs of all other groups examined were higher. CONCLUSION: These real-life data show that aflibercept treatment is equally expensive, and clinical outcomes between the two drugs are similar. PMID- 29486763 TI - A pragmatic controlled trial to prevent childhood obesity within a risk group at maternity and child health-care clinics: results up to six years of age (the VACOPP study). AB - BACKGROUND: Obesity in childhood appears often during the toddler years. The prenatal environment influences obesity risk. Maternal gestational diabetes, the child's diet, and physical activity in the first few years have an important role in subsequent weight gain. A study was conducted to evaluate effectiveness of a primary health-care lifestyle counselling intervention in prevention of childhood obesity up to 6 years of age. METHODS: The study was a controlled pragmatic trial to prevent childhood obesity and was implemented at maternity and child health care clinics. The participants (n = 185) were mothers at risk of gestational diabetes mellitus with their offspring born between 2008 and 2010. The prenatal intervention, started at the end of the first trimester of pregnancy, consisted of counselling on diet and physical activity by municipal health-care staff. The intervention continued at yearly appointments with a public health-nurse at child health-care clinics. The paper reports the offspring weight gain results for 2-6 years of age. Weight gain up to 6 years of age was assessed as BMI standard deviation scores (SDS) via a mixed-effect linear regression model. The proportion of children at 6 years with overweight/obesity was assessed as weight-for-height percentage and ISO-BMI. Priority was not given to power calculations, because of the study's pragmatic nature. RESULTS: One hundred forty seven children's (control n = 76/85% and intervention n = 71/56%) weight and height scores were available for analysis at 6 years of age. There was no significant difference in weight gain or overweight/obesity proportions between the groups at 6 years of age, but the proportion of children with obesity in both groups was high (assessed as ISO-BMI 9.9% and 11.8%) relative to prevalence in this age group in Finland. CONCLUSION: As the authors previously reported, the intervention-group mothers had lower prevalence of gestational diabetes mellitus, but a decrease in obesity incidence before school age among their offspring was not found. The authors believe that an effective intervention should start before conception, continuing during pregnancy and the postpartum period through the developmentally unique child's first years. TRIAL REGISTRATION: ClinicalTrials.gov NCT00970710 . Registered 1 September 2009. Retrospectively registered. PMID- 29486764 TI - Impaired type I interferon regulation in the blood transcriptome of recurrent asthma exacerbations. AB - BACKGROUND: Asthma exacerbations are an important cause of morbidity in asthma. Respiratory infections are often involved in asthma exacerbations in both children and adults. Some individuals with asthma have increased susceptibility to viral infections and as a result increased rates of asthma exacerbations. We sought to identify a transcriptomic signature in the blood associated with asthma exacerbations triggered by respiratory infections (AETRI) and determine its association with increased risk for asthma exacerbations. METHODS: We conducted a two-step study using publicly available, previously generated transcriptomic signatures in peripheral blood mononuclear cells (PBMCs) from asthmatics to identify novel markers of increased risk for asthma exacerbations. In the 1st step, we identified an in vitro PBMC signature in response to rhinovirus. In the 2nd step, we used the in vitro signature to filter PBMC transcripts in response to asthma exacerbations in an independent in vivo cohort. Three different subgroups were identified and studied in the in vivo cohort: 1. Single AETRI; 2. Multiple AETRIs; and 3. Single non-infectious asthma exacerbations. We performed pathway and network analyses in all independent comparisons. We also performed an immunologic gene set enrichment analysis (GSEA) of the comparison between single AETRI and non-infectious asthma exacerbations. RESULTS: The in vitro signature identified 4354 differentially expressed genes (DEGs) with a fold change (FC) >= 1.2, false discovery rate (FDR) < 0.05. Subsequent analyses filtered by this in vitro signature on an independent cohort of adult asthma identified 238 DEGs (FC>=1.1, FDR < 0.1) in subjects with a single AETRI and no DEGs in single non infectious asthma exacerbations. A comparison between the response in subjects with single and multiple AETRIs identified two discordant gene subsets. In the largest discordant subset (n = 63 genes) we identified an impaired type I interferon and STAT1 response in multiple AETRIs during the acute phase of the exacerbation and an upregulated STAT1 response at baseline. The STAT1 upregulation at baseline in subjects with multiple AETRIs was accompanied by upregulation of pro-inflammatory molecules including IL-15, interferon-stimulated genes (ISGs), several toll-like receptors 2, - 4, - 5 and - 8 and a triggering receptor expressed on myeloid cells 1 (TREM1) network. CONCLUSIONS: Subjects with asthma and multiple AETRIs display a pro-inflammatory signature at baseline, associated with elevated STAT, IL-15 and ISGs, and an impaired STAT1 response during acute asthma exacerbations. PMID- 29486765 TI - Xiangbin prescription for the recovery of gastrointestinal function after abdominal surgery (the XBPRS trial): study protocol for a randomized controlled trial. AB - BACKGROUND: Most patients who undergo abdominal surgery recover bowel movements within a week; however, some suffer prolonged intestinal paralysis or postoperative ileus (POI) leading to complications, such as infection and intestinal adhesions, which can extend hospitalization and increase readmission rates, and consequently increasing healthcare costs. Chinese medicine is effective for accelerating the recovery of gastrointestinal function after abdominal surgery. Xiangbin prescription (XBP) is the standard prescription for this purpose in our hospital; however, randomized controlled trials of it have not yet been conducted. METHODS/DESIGN: This double-blind, randomized controlled clinical trial aims to recruit patients who have undergone abdominal surgery and experienced postoperative dysmotility to evaluate the efficacy and safety of XBP for preventing POI and accelerating recovery. The research will tackle the common problem of slow recovery of gastrointestinal function after surgery. The participants will be patients who undergo laparoscopic radical resection of rectal carcinoma or laparoscopic panhysterectomy of a benign lesion. Primary outcome measures will be time to first flatus, defecation, normal bowel sounds, and liquid/semi-liquid/general diet. Good Clinical Practice (GCP) standards of efficacy and safety will also be evaluated, along with objective investigation of the mechanism of action of ghrelin. DISCUSSION: This pivotal trial will be a standardized, scientific, clinical trial designed to evaluate the use of XBP for the recovery of gastrointestinal function after surgery, and it will conform to international standards for clinical trials for the recognition of traditional Chinese medicine. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ID: ChiCTR TRC-14004156 . Registered on 3 January 2014. PMID- 29486766 TI - Molecular markers of resistance to amodiaquine plus sulfadoxine-pyrimethamine in an area with seasonal malaria chemoprevention in south central Niger. AB - BACKGROUND: In Niger, malaria transmission is markedly seasonal with most of the disease burden occurring in children during the rainy season. Seasonal malaria chemoprevention (SMC) with amodiaquine plus sulfadoxine-pyrimethamine (AQ + SP) is recommended in the country to be administered monthly just before and during the rainy season. Moreover, clinical decisions on use of SP for intermittent preventive treatment in pregnancy (IPTp) now depend upon the validated molecular markers for SP resistance in Plasmodium falciparum observed in the local parasite population. However, little is known about molecular markers of resistance for either SP or AQ in the south of Niger. To address this question, clinical samples which met clinical and biological criteria, were collected in Gabi, Madarounfa district, Maradi region, Niger in 2011-2012 (before SMC implementation). Molecular markers of resistance to pyrimethamine (pfdhfr), sulfadoxine (pfdhps) and amodiaquine (pfmdr1) were assessed by DNA sequencing. RESULTS: Prior to SMC implementation, the samples showed a high proportion of clinical samples that carried the pfdhfr 51I/59R/108N haplotype associated with resistance to pyrimethamine and pfdhps 436A/F/H and 437G mutations associated with reduced susceptibility to sulfadoxine. In contrast mutations in codons 581G, and 613S in the pfdhps gene, and in pfmdr1, 86Y, 184Y, 1042D and 1246Y associated with resistance to amodiaquine, were less frequently observed. Importantly, pfdhfr I164L and pfdhps K540E mutations shown to be the most clinically relevant markers for high level clinical resistance to SP were not detected in Gabi. CONCLUSIONS: Although parasites with genotypes associated with the highest levels of resistance to AQ + SP are not yet common in this setting, their importance for deployment of SMC and IPTp dictates that monitoring of these markers of resistance should accompany these interventions. This study also highlights the parasite heterogeneity within a small spatial area and the need to use caution when extrapolating results from surveys of molecular markers of resistance in a single site to inform regional policy decisions. PMID- 29486767 TI - HDP2: a ribosomal DNA (NTS-ETS) sequence as a target for species-specific molecular diagnosis of intestinal taeniasis in humans. AB - BACKGROUND: Taenia solium, T. asiatica and T. saginata tapeworms cause human taeniasis and are the origin of porcine and bovine cysticercosis. Furthermore, T. solium eggs can cause human cysticercosis, with neurocysticercosis being the most serious form of the disease. These helminth infections are neglected tropical diseases and are endemic in several countries in the Americas, Asia and Africa. As a result of globalization, migration in particular, the infections have been extending to non-endemic territories. Species-specific diagnosis of taeniasis is subject to drawbacks that could be resolved using molecular approaches. In the present study, conventional and real-time amplification protocols (cPCR and qPCR) based on the T. saginata HDP2 sequence were applied in the differential diagnosis of taeniasis (T. saginata, T. solium) in both fecal samples and proglottids expelled by patients. The HDP2 homolog in T. solium was cloned and characterized. RESULTS: Semi-nested cPCR and qPCR (Sn-HDP2 cPCR and Sn-HDP2 qPCR) amplified T. saginata and T. solium DNA, with an analytical sensitivity of 40 and 400 fg, respectively, and identically in both protocols. Eighteen taeniasis patients were diagnosed directly with T. saginata or T. solium, either from proglottids or fecal samples with/without eggs (detected using microscopy), based on the optimized Sn-HDP2 qPCR. After cloning, the T. solium HDP2 homolog sequence was confirmed to be a ribosomal sequence. The HDP2 fragment corresponded to a non transcribed sequence/external transcribed repeat (NTS/ETS) of ribosomal DNA. Compared with the T. saginata HDP2 homolog, the T solium HDP2 sequence lacked the first 900 nt at the 5' end and showed nucleotide substitutions and small deletions. CONCLUSIONS: Sn-HDP2 cPCR and Sn-HDP2 qPCR were set up for the diagnosis of human taeniasis, using proglottids and fecal samples from affected patients. The new Sn-HDP2 qPCR protocol was the best option, as it directly differentiated T. saginata from T. solium. The diagnosis of an imported T. solium taeniasis case and nine European T. saginata cases was relevant. Finally, the cloning and sequencing of the T. solium HDP2 fragment confirmed that HDP2 was part of a ribosomal unit. PMID- 29486768 TI - Cellular and behavioral effects of lipopolysaccharide treatment are dependent upon neurokinin-1 receptor activation. AB - BACKGROUND: Several psychiatric conditions are affected by neuroinflammation and neuroimmune activation. The transcription factor nuclear factor kappa light-chain enhancer of activated B cells (NFkB) plays a major role in inflammation and innate immunity. The neurokinin-1 receptor (NK1R) is the primary endogenous target of the neuroactive peptide substance P, and some data suggests that NK1R stimulation may influence NFkB activity. Both NK1R and NFkB have been shown to play a functional role in complex behaviors including stress responsivity, depression, and addiction. In this study, we test whether NFkB activity in the brain (stimulated by lipopolysaccharide administration) is dependent upon the NK1R. METHODS: Adult male Wistar rats were treated systemically with the NK1R antagonist L822429 followed by administration of systemic lipopolysaccharide (LPS, a strong activator of NFkB). Hippocampal extracts were used to assess expression of proinflammatory cytokines and NFkB-DNA-binding potential. For behavioral studies, rats were trained to consume 1% (w/v) sucrose solution in a continuous access two-bottle choice model. After establishment of baseline, animals were treated with L822429 and LPS and sucrose preference was measured 12 h post-treatment. RESULTS: Systemic LPS treatment causes a significant increase in proinflammatory cytokine expression and NFkB-DNA-binding activity within the hippocampus. These increases are attenuated by systemic pretreatment with the NK1R antagonist L822429. Systemic LPS treatment also led to the development of anhedonic-like behavior, evidenced by decreased sucrose intake in the sucrose preference test. This behavior was significantly attenuated by systemic pretreatment with the NK1R antagonist L822429. CONCLUSIONS: Systemic LPS treatment induced significant increases in NFkB activity, evidenced by increased NFkB-DNA binding and by increased proinflammatory cytokine expression in the hippocampus. LPS also induced anhedonic-like behavior. Both the molecular and behavioral effects of LPS treatment were significantly attenuated by systemic NK1R antagonism, suggesting that NK1R stimulation lies upstream of NFkB activation following systemic LPS administration and is at least in part responsible for NFkB activation. PMID- 29486769 TI - Association of chronic fatigue syndrome with premature telomere attrition. AB - BACKGROUND: Chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME), is a severely debilitating condition of unknown etiology. The symptoms and risk factors of ME/CFS share features of accelerated aging implicated in several diseases. Using telomere length as a marker, this study was performed to test the hypothesis that ME/CFS is associated with accelerated aging. METHODS: Participant (n = 639) data came from the follow-up time point of the Georgia CFS surveillance study. Using the 1994 CFS Research Case Definition with questionnaire-based subscale thresholds for fatigue, function, and symptoms, participants were classified into four illness groups: CFS if all criteria were met (n = 64), CFS-X if CFS with exclusionary conditions (n = 77), ISF (insufficient symptoms/fatigue) if only some criteria were met regardless of exclusionary conditions (n = 302), and NF (non-fatigued) if no criteria and no exclusionary conditions (n = 196). Relative telomere length (T/S ratio) was measured using DNA from whole blood and real-time PCR. General linear models were used to estimate the association of illness groups or T/S ratio with demographics, biological measures and covariates with significance set at p < 0.05. RESULTS: The mean T/S ratio differed significantly by illness group (p = 0.0017); the T/S ratios in CFS (0.90 +/- 0.03) and ISF (0.94 +/- 0.02) were each significantly lower than in NF (1.06 +/- 0.04). Differences in T/S ratio by illness groups remained significant after adjustment for covariates of age, sex, body mass index, waist-hip ratio, post-exertional malaise and education attainment. Telomere length was shorter by 635, 254 and 424 base pairs in CFS, CFS-X and ISF, respectively, compared to NF. This shorter telomere length translates to roughly 10.1-20.5, 4.0-8.2 and 6.6-13.7 years of additional aging in CFS, CFS-X and ISF compared to NF respectively. Further, stratified analyses based on age and sex demonstrated that the association of ME/CFS with short telomeres is largely moderated by female subjects < 45 years old. CONCLUSIONS: This study found a significant association of ME/CFS with premature telomere attrition that is largely moderated by female subjects < 45 years old. Our results indicate that ME/CFS could be included in the list of conditions associated with accelerated aging. Further work is needed to evaluate the functional significance of accelerated aging in ME/CFS. PMID- 29486770 TI - A novel DNA methylation panel accurately detects colorectal cancer independently of molecular pathway. AB - BACKGROUND: Colorectal cancer (CRC) is one of the most incident cancers, associated with significant morbidity and mortality, and usually classified into three main molecular pathways: chromosomal instability, microsatellite instability (MSI) and CpG island methylator phenotype (CIMP). Currently, available screening methods are either costly or of limited specificity, impairing global implementation. More cost-effective strategies, including DNA methylation-based tests, might prove advantageous. Although some are already available, its performance is suboptimal, entailing the need for better candidate biomarkers. Herein, we tested whether combined use of APC, IGF2, MGMT, RASSF1A, and SEPT9 promoter methylation might accurately detect CRC irrespective of molecular subtype. METHODS: Selected genes were validated using formalin-fixed paraffin-embedded tissues from 214 CRC and 50 non-malignant colorectal mucosae (CRN). Promoter methylation levels were assessed using real-time quantitative methylation-specific PCR. MSI and CIMP status were determined. Molecular data were correlated with standard clinicopathological features. Diagnostic and prognostic performances were evaluated by receiver operator characteristics curve and survival analyses, respectively. RESULTS: Except for IGF2, promoter methylation levels were significantly higher in CRC compared to CRN. A three-gene panel (MGMT, RASSF1A, SEPT9) identified malignancy with 96.6% sensitivity, 74.0% specificity and 91.5 positive predictive value (area under the curve: 0.97), independently of tumor location, stage, and molecular pathway. CONCLUSIONS: Combined promoter methylation analysis of MGMT/RASSF1A/SEPT9 displays a better performance than currently available epigenetic-based biomarkers for CRC, providing the basis for the development of a non-invasive assay to detect CRC irrespective of the molecular pathway. PMID- 29486771 TI - Mitochondrial damage and "plugging" of transport selectively in myelinated, small diameter axons are major early events in peripheral neuroinflammation. AB - BACKGROUND: Small-diameter, myelinated axons are selectively susceptible to dysfunction in several inflammatory PNS and CNS diseases, resulting in pain and degeneration, but the mechanism is not known. METHODS: We used in vivo confocal microscopy to compare the effects of inflammation in experimental autoimmune neuritis (EAN), a model of Guillain-Barre syndrome (GBS), on mitochondrial function and transport in large- and small-diameter axons. We have compared mitochondrial function and transport in vivo in (i) healthy axons, (ii) axons affected by experimental autoimmune neuritis, and (iii) axons in which mitochondria were focally damaged by laser induced photo-toxicity. RESULTS: Mitochondria affected by inflammation or laser damage became depolarized, fragmented, and immobile. Importantly, the loss of functional mitochondria was accompanied by an increase in the number of mitochondria transported towards, and into, the damaged area, perhaps compensating for loss of ATP and allowing buffering of the likely excessive Ca2+ concentration. In large-diameter axons, healthy mitochondria were found to move into the damaged area bypassing the dysfunctional mitochondria, re-populating the damaged segment of the axon. However, in small-diameter axons, the depolarized mitochondria appeared to "plug" the axon, obstructing, sometimes completely, the incoming (mainly anterograde) transport of mitochondria. Over time (~ 2 h), the transported, functional mitochondria accumulated at the obstruction, and the distal part of the small diameter axons became depleted of functional mitochondria. CONCLUSIONS: The data show that neuroinflammation, in common with photo-toxic damage, induces depolarization and fragmentation of axonal mitochondria, which remain immobile at the site of damage. The damaged, immobile mitochondria can "plug" myelinated, small-diameter axons so that successful mitochondrial transport is prevented, depleting the distal axon of functioning mitochondria. Our observations may explain the selective vulnerability of small-diameter axons to dysfunction and degeneration in a number of neurodegenerative and neuroinflammatory disorders. PMID- 29486772 TI - Probiotic fruit beverages with different polyphenol profiles attenuated early insulin response. AB - BACKGROUND: Consumption of polyphenol-rich fruits and vegetables may improve postprandial glucose and insulin levels and hence promote well-being. Previously it has been observed that consumption of bilberry decreases the postprandial insulin demand. The intention with the present study was to compare the impact of different supplements with various polyphenol profiles, on the postprandial glucose and insulin responses in healthy young adults. METHODS: In a randomized, controlled, crossover study the postprandial glycemic and insulin responses were observed in eleven healthy adults after intake of five different beverages containing bilberry (European blueberry), blackcurrant, beetroot, mango and rose hip, respectively; all drinks were enriched with the same composition of fermented oatmeal and probiotics. The control was a glucose drink. The profile and content of the polyphenols in the different beverages were determined by HPLC DAD analysis. The antioxidative capacity of the different beverages were measured by TEAC and DPPH assays. RESULTS: Beverages containing bilberry, blackcurrant, mango or rose hip significantly attenuated the early postprandial insulin response (0-90 min), but showed no effect on glucose response. Drinks with bilberry or rose hip reduced the insulin response from the very early phase (0-30 min), and had significantly lower insulin index compared with the control. The efficiency of the bilberry and rose hip to decrease early postprandial insulin responses correlated with higher phenolic contents. CONCLUSIONS: Supplements with bilberry, blackcurrant, mango or rose hip in the tested probiotic and oatmeal enriched beverage attenuated early-phase insulin response, but had no effect on the postprandial glycemic response. The improved ability of bilberry and rose hip to lower the very early phase of insulin response seems to be due to a higher phenolic content. TRIAL REGISTRATION: The study was retrospectively registered at ClinicalTrials.gov with number NCT03159065 . PMID- 29486773 TI - Quality of care in integrated community case management services in Bugoye, Uganda: a retrospective observational study. AB - BACKGROUND: Village health workers (VHWs) in five villages in Bugoye subcounty (Kasese District, Uganda) provide integrated community case management (iCCM) services, in which VHWs evaluate and treat malaria, pneumonia, and diarrhoea in children under 5 years of age. VHWs use a "Sick Child Job Aid" that guides them through the evaluation and treatment of these illnesses. A retrospective observational study was conducted to measure the quality of iCCM care provided by 23 VHWs in 5 villages in Bugoye subcounty over a 2-year period. METHODS: Patient characteristics and clinical services were summarized using existing aggregate programme data. Lot quality assurance sampling of individual patient records was used to estimate adherence to the iCCM algorithm, VHW-level quality (based on adherence to the iCCM protocol), and change over time in quality of care (using generalized estimating equations regression modelling). RESULTS: For each of 23 VHWs, 25 patient visits were randomly selected from a 2-year period after iCCM care initiation. In these visits, 97% (150) of patients with diarrhoea were treated with oral rehydration and zinc, 95% (216) of patients with pneumonia were treated with amoxicillin, and 94% (240) of patients with malaria were treated with artemisinin-based combination therapy or rectal artesunate. However, only 44% (44) of patients with a negative rapid test for malaria were appropriately referred to a health facility. Overall, 75% (434) of patients received all the correct evaluation and management steps. Only 9 (39%) of the 23 VHWs met the pre determined LQAS threshold for high-quality care over the 2-year observation period. Quality of care increased significantly in the first 6 months after initiation of iCCM services (p = 0.003), and then plateaued during months 7-24. CONCLUSIONS: Quality of care was high for uncomplicated malaria, pneumonia and diarrhoea. Overall quality of care was lower, in part because VHWs often did not follow the guidelines to refer patients with fever who tested negative for malaria. Quality of care appears to improve in the initial months after iCCM implementation, as VHWs gain initial experience in iCCM care. PMID- 29486774 TI - "They accept me, because I was one of them": formative qualitative research supporting the feasibility of peer-led outreach for people who use drugs in Dakar, Senegal. AB - BACKGROUND: Peer outreach harm reduction initiatives are being developed with and for people who use drugs in Dakar, Senegal. This is in response to growing injecting drug use across the West Africa region and linked emerging epidemics of HIV and hepatitis C. We undertook formative qualitative research to explore the feasibility and potential of peer outreach in this context and in particular how outreach could be linked to fostering community-level processes of change. METHODS: We undertook a total of 44 semi-structured qualitative interviews. Thirty-four interviews were with people who used drugs (comprised of 25 participants who had injected at least once in their life) and included 11 peer educators who delivered "awareness-raising" harm reduction activities. We also interviewed 10 service providers involved in the planning and monitoring of peer outreach initiatives. We used thematic analysis to identify key characteristics of how peer-led outreach is being delivered, beneficiary need, and the nature of the social networks in which the awareness-raising activities operate. RESULTS: Through interviews with peer educators, people who use drugs, and service providers, four main overlapping themes are identified as follows: peer educators as a bridge to responsibilization through awareness-raising activities, awareness raising activities as an enactment of recovery, awareness raising through social network diffusion, and the contexts and constraints of peer outreach engagement through awareness-raising activities. CONCLUSIONS: The study results suggest that peer education is on a trajectory to develop into a central role for harm reduction interventions in Dakar, Senegal. This research shows how peer education is bound in processes of responsibilization and self-change, which link to varying possibilities for risk reduction or recovery. For peer education to achieve a range of significant goals, broader structural and system changes should be implemented in the region. We caution that without such changes, awareness-raising activities and the role of peer educators may instead become part of state- and agency-sponsored processes of seeking to responsibilize individuals for health and harm reduction. PMID- 29486775 TI - Neural predictors of gait stability when walking freely in the real-world. AB - BACKGROUND: Gait impairments during real-world locomotion are common in neurological diseases. However, very little is currently known about the neural correlates of walking in the real world and on which regions of the brain are involved in regulating gait stability and performance. As a first step to understanding how neural control of gait may be impaired in neurological conditions such as Parkinson's disease, we investigated how regional brain activation might predict walking performance in the urban environment and whilst engaging with secondary tasks in healthy subjects. METHODS: We recorded gait characteristics including trunk acceleration and brain activation in 14 healthy young subjects whilst they walked around the university campus freely (single task), while conversing with the experimenter and while texting with their smartphone. Neural spectral power density (PSD) was evaluated in three brain regions of interest, namely the pre-frontal cortex (PFC) and bilateral posterior parietal cortex (right/left PPC). We hypothesized that specific regional neural activation would predict trunk acceleration data obtained during the different walking conditions. RESULTS: Vertical trunk acceleration was predicted by gait velocity and left PPC theta (4-7 Hz) band PSD in single-task walking (R-squared = 0.725, p = 0.001) and by gait velocity and left PPC alpha (8-12 Hz) band PSD in walking while conversing (R-squared = 0.727, p = 0.001). Medio-lateral trunk acceleration was predicted by left PPC beta (15-25 Hz) band PSD when walking while texting (R-squared = 0.434, p = 0.010). CONCLUSIONS: We suggest that the left PPC may be involved in the processes of sensorimotor integration and gait control during walking in real-world conditions. Frequency-specific coding was operative in different dual tasks and may be developed as biomarkers of gait deficits in neurological conditions during performance of these types of, now commonly undertaken, dual tasks. PMID- 29486776 TI - TLR4-mediated autophagic impairment contributes to neuropathic pain in chronic constriction injury mice. AB - Neuropathic pain is a complex, chronic pain state characterized by hyperalgesia, allodynia, and spontaneous pain. Accumulating evidence has indicated that the microglial Toll-like receptor 4 (TLR4) and autophagy are implicated in neurodegenerative diseases, but their relationship and role in neuropathic pain remain unclear. In this study, we examined TLR4 and its association with autophagic activity using a chronic constriction injury (CCI)-induced neuropathic pain model in wild-type (WT) and TLR4-knockout (KO) mice. The mice were assigned into four groups: WT-Contralateral (Contra), WT-Ipsilateral (Ipsi), TLR4 KO Contra, and TLR4 KO-Ipsi. Behavioral and mechanical allodynia tests and biochemical analysis of spinal cord tissue were conducted following CCI to the sciatic nerve. Compared with the Contra group, mechanical allodynia in both the WT- and TLR4 KO-Ipsi groups was significantly increased, and a marked decrease of allodynia was observed in the TLR4 KO-Ipsi group. Although glial cells were upregulated in the WT-Ipsi group, no significant change was observed in the TLR4 KO groups. Moreover, protein expression and immunoreactive cell regulation of autophagy (Beclin 1, p62) were significantly increased in the neurons, but not microglia, of WT-Ipsi group compared with the WT-Contra group. The level of PINK1, a marker for mitophagy was increased in the neurons of WT, but not in TLR4 KO mice. Together, these results show that TLR4-mediated p62 autophagic impairment plays an important role in the occurrence and development of neuropathic pain. And what is more, microglial TLR4-mediated microglial activation might be indirectly coupled to neuronal autophage. PMID- 29486777 TI - Weak sharing of genetic association signals in three lung cancer subtypes: evidence at the SNP, gene, regulation, and pathway levels. AB - BACKGROUND: There are two main types of lung cancer: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC has many subtypes, but the two most common are lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). These subtypes are mainly classified by physiological and pathological characteristics, although there is increasing evidence of genetic and molecular differences as well. Although some work has been done at the somatic level to explore the genetic and biological differences among subtypes, little work has been done that interrogates these differences at the germline level to characterize the unique and shared susceptibility genes for each subtype. METHODS: We used single-nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS) of European samples to interrogate the similarity of the subtypes at the SNP, gene, pathway, and regulatory levels. We expanded these genotyped SNPs to include all SNPs in linkage disequilibrium (LD) using data from the 1000 Genomes Project. We mapped these SNPs to several lung tissue expression quantitative trait loci (eQTL) and enhancer datasets to identify regulatory SNPs and their target genes. We used these genes to perform a biological pathway analysis for each subtype. RESULTS: We identified 8295, 8734, and 8361 SNPs with moderate association signals for LUAD, LUSC, and SCLC, respectively. Those SNPs had p < 1 * 10- 3 in the original GWAS or were within LD (r2 > 0.8, Europeans) to the genotyped SNPs. We identified 215, 320, and 172 disease-associated genes for LUAD, LUSC, and SCLC, respectively. Only five genes (CHRNA5, IDH3A, PSMA4, RP11 650 L12.2, and TBC1D2B) overlapped all subtypes. Furthermore, we observed only two pathways from the Kyoto Encyclopedia of Genes and Genomes shared by all subtypes. At the regulatory level, only three eQTL target genes and two enhancer target genes overlapped between all subtypes. CONCLUSIONS: Our results suggest that the three lung cancer subtypes do not share much genetic signal at the SNP, gene, pathway, or regulatory level, which differs from the common subtype classification based upon histology. However, three (CHRNA5, IDH3A, and PSMA4) of the five genes shared between the subtypes are well-known lung cancer genes that may act as general lung cancer genes regardless of subtype. PMID- 29486778 TI - A simulation study on the effects of neuronal ensemble properties on decoding algorithms for intracortical brain-machine interfaces. AB - BACKGROUND: Intracortical brain-machine interfaces (BMIs) harness movement information by sensing neuronal activities using chronic microelectrode implants to restore lost functions to patients with paralysis. However, neuronal signals often vary over time, even within a day, forcing one to rebuild a BMI every time they operate it. The term "rebuild" means overall procedures for operating a BMI, such as decoder selection, decoder training, and decoder testing. It gives rise to a practical issue of what decoder should be built for a given neuronal ensemble. This study aims to address it by exploring how decoders' performance varies with the neuronal properties. To extensively explore a range of neuronal properties, we conduct a simulation study. METHODS: Focusing on movement direction, we examine several basic neuronal properties, including the signal-to noise ratio of neurons, the proportion of well-tuned neurons, the uniformity of their preferred directions (PDs), and the non-stationarity of PDs. We investigate the performance of three popular BMI decoders: Kalman filter, optimal linear estimator, and population vector algorithm. RESULTS: Our simulation results showed that decoding performance of all the decoders was affected more by the proportion of well-tuned neurons that their uniformity. CONCLUSIONS: Our study suggests a simulated scenario of how to choose a decoder for intracortical BMIs in various neuronal conditions. PMID- 29486780 TI - Correction to: Clinical relevance of the tumor microenvironment and immune escape of oral squamous cell carcinoma. AB - The original version of this article [1], published on 5 April 2016, contains a mistake. In the 'Role of pH stabilisation' section, "intracellular pH" has been incorrectly abbreviated as "pHe". The correct abbreviation is "pHi". The affected sentence with the correct abbreviation is given below. PMID- 29486779 TI - Response criteria in solid tumors (PERCIST/RECIST) and SUVmax in early-stage non small cell lung cancer patients treated with stereotactic body radiotherapy. AB - BACKGROUND: The purpose of this study was to evaluate the prognostic impact of Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) and Response Evaluation Criteria in Solid Tumors (RECIST) and of pre- and post treatment maximum Standard Uptake Value (SUVmax) in regards to survival and tumor control for patients treated for early-stage non-small cell lung cancer (ES NSCLC) with stereotactic body radiotherapy (SBRT). METHODS: This is a retrospective review of patients with ES-NSCLC treated at our institution using SBRT. Lobar, locoregional, and distant failures were evaluated based on PERCIST/RECIST and clinical course. Univariate analysis of the Kaplan-Meier curves for overall survival (OS), progression free survival (PFS), lobar control (LC), locoregional control (LRC), and distant control (DC) was conducted using the log-rank test. Pre- and post-treatment SUVmax were evaluated using cutoffs of < 5 and >= 5, < 4 and >= 4, and < 3 and >= 3. ?SUVmax was also evaluated at various cutoffs. Cox regression analysis was conducted to evaluate survival outcomes based on age, gender, pre-treatment gross tumor volume (GTV), longest tumor dimension on imaging, and Charlson Comorbidity Index (CCI). RESULTS: This study included 95 patients (53 female, 42 male), median age 75. Lung SBRT was delivered in 3-5 fractions to a total of 48-60 Gy, with a BEDalpha/beta = 10Gy of at least 100 Gy. Median OS and PFS from the end of SBRT was 15.4 and 11.9 months, respectively. On univariate analysis, PERCIST/RECIST response correlated with PFS (p = 0.039), LC (p = 0.007), and LRC (p = 0.015) but not OS (p = 0.21) or DC (p = 0.94). Pre-treatment SUVmax and post-treatment SUVmax with cutoff values of < 5 and >= 5, < 4 and >= 4, and < 3 and >= 3 did not predict for OS, PFS, LC, LRC, or DC. ?SUVmax did not predict for OS, PFS, LC, LRC, or DC. On multivariate analysis, pre-treatment GTV >= 30 cm3 was significantly associated with worse survival outcomes when accounting for other confounding variables. CONCLUSIONS: PERCIST/RECIST response is associated with improved LC and PFS in patients treated for ES-NSCLC with SBRT. In contrast, pre- and post-treatment SUVmax is not predictive of disease control or survival. PMID- 29486781 TI - Vasoplegia treatments: the past, the present, and the future. AB - Vasoplegia is a ubiquitous phenomenon in all advanced shock states, including septic, cardiogenic, hemorrhagic, and anaphylactic shock. Its pathophysiology is complex, involving various mechanisms in vascular smooth muscle cells such as G protein-coupled receptor desensitization (adrenoceptors, vasopressin 1 receptors, angiotensin type 1 receptors), alteration of second messenger pathways, critical illness-related corticosteroid insufficiency, and increased production of nitric oxide. This review, based on a critical appraisal of the literature, discusses the main current treatments and future approaches. Our improved understanding of these mechanisms is progressively changing our therapeutic approach to vasoplegia from a standardized to a personalized multimodal treatment with the prescription of several vasopressors. While norepinephrine is confirmed as first line therapy for the treatment of vasoplegia, the latest Surviving Sepsis Campaign guidelines also consider that the best therapeutic management of vascular hyporesponsiveness to vasopressors could be a combination of multiple vasopressors, including norepinephrine and early prescription of vasopressin. This new approach is seemingly justified by the need to limit adrenoceptor desensitization as well as sympathetic overactivation given its subsequent deleterious impacts on hemodynamics and inflammation. Finally, based on new pathophysiological data, two potential drugs, selepressin and angiotensin II, are currently being evaluated. PMID- 29486782 TI - Improve dosimetric outcome in stage III non-small-cell lung cancer treatment using spot-scanning proton arc (SPArc) therapy. AB - BACKGROUND: To evaluate spot-scanning proton arc therapy (SPArc) and multi-field robust optimized intensity modulated proton therapy (RO-IMPT) in treating stage III non-small-cell lung cancer (NSCLC) patients. METHODS: Two groups of stage IIIA or IIIB NSCLC patients (group 1: eight patients with tumor motion less than 5 mm; group 2: six patients with tumor motion equal to or more than 5 mm) were re planned with SPArc and RO-IMPT. Both plans were generated using robust optimization to achieve an optimal coverage with 99% of internal target volume (ITV) receiving 66 Gy (RBE) in 33 fractions. The dosimetric results and plan robustness were compared for both groups. The interplay effect was evaluated based on the ITV coverage by single-fraction 4D dynamic dose. Total delivery time was simulated based on a full gantry rotation with energy-layer-switching-time (ELST) from 0.2 to 4 s. Statistical analysis was also evaluated via Wilcoxon signed rank test. RESULTS: Both SPArc and RO-IMPT plans achieved similar robust target volume coverage for all patients, while SPArc significantly reduced the doses to critical structures as well as the interplay effect. Specifically, compared to RO-IMPT, SPArc reduced the average integral dose by 7.4% (p = 0.001), V20, and mean lung dose by an average of 3.2% (p = 0.001) and 1.6 Gy (RBE) (p = 0.001), the max dose to cord by 4.6 Gy (RBE) (p = 0.04), and the mean dose to heart and esophagus by 0.7 Gy (RBE) (p = 0.01) and 1.7 Gy (RBE) (p = 0.003) respectively. The average total estimated delivery time was 160.1 s, 213.8 s, 303.4 s, 840.8 s based on ELST of 0.2 s, 0.5 s, 1 s, and 4 s for SPArc plans, compared with the respective values of 182.0 s (p = 0.001), 207.9 s (p = 0.22), 250.9 s (p = 0.001), 509.4 s (p = 0.001) for RO-IMPT plans. Hence, SPArc plans could be clinically feasible when using a shorter ELST. CONCLUSIONS: This study has indicated that SPArc could further improve the dosimetric results in patients with locally advanced stage NSCLC and potentially be implemented into routine clinical practice. PMID- 29486783 TI - Longitudinal stability of fibromyalgia symptom clusters. AB - BACKGROUND: Using self-report questionnaires of key fibromyalgia symptom domains (pain, fatigue, sleep disturbance, function, stiffness, dyscognition, depression, and anxiety), we previously identified four unique symptom clusters. The purpose of this study was to examine the stability of fibromyalgia symptom clusters between baseline and 2-year follow-up. METHODS: Women with a diagnosis of fibromyalgia completed the Brief Pain Inventory, Profile of Mood States, Medical Outcomes Study Sleep measure, Multidimensional Fatigue Inventory, Multiple Ability Self-Report Questionnaire, Revised Fibromyalgia Impact Questionnaire, and the 36-Item Short Form Survey Instrument at baseline. Follow-up measures were completed approximately 2 years later. The hierarchical agglomerative clustering algorithm previously developed was applied; agreement between baseline and follow up was assessed with the kappa statistic. RESULTS: Among 433 participants, the mean age was 56 (range 20-85) years. The median Revised Fibromyalgia Impact Questionnaire total score was 57 (range 8-96). More than half of participants (58%) remained in the same cluster at follow-up as at baseline, which represented moderate agreement between baseline and follow-up (kappa = 0.44, 95% confidence interval (CI) 0.37-0.50). Only two patients changed from high symptom intensity to low symptom intensity; similarly, only three moved from low to high. CONCLUSIONS: Fibromyalgia patients classified into four unique symptom clusters based on the key domains of pain, fatigue, sleep disturbance, function, stiffness, dyscognition, depression, and anxiety showed moderate stability in cluster assignment after 2 years. Few patients moved between the two extremes of severity, and it was slightly more common to move to a lower symptom level than to worsen. TRIAL REGISTRATION: Not applicable. PMID- 29486784 TI - Energy, nutrient and food content of snacks in French adults. AB - BACKGROUND: Snacking raises concern since it may lead to an additional energy intake and poor nutrient quality. A snacking occasion can be defined as any eating occasion apart from main meals, regardless of the amount or type of foods consumed. We described the frequency of snacking occasions according to daily timing in French adults, and compared them between each other, and with the main meals, in terms of energy intake, energy and nutrient density, and food content. METHODS: This cross-sectional analysis included 104,265 adults from the NutriNet Sante cohort. Food intake was estimated using 24-h records of weekdays. For each eating occasion, nutrient density and energy content and density were computed. RESULTS: After weighting, 47.6% of our sample were men and mean age was 45.6 (15.3). Overall, 68% of participants ate at least one snack during the reported record, mainly in the morning or afternoon. Overall snack had a lower nutrient density [22.8 (SD = 278.3)] than main meals [25.8 (36.9) to 30.0 (30.4)]; but higher energy density [222.2 (163.3) kcal/100 g] than meals [133.9 (57.3) to 175.9 (99.6) kcal/100 g]. Morning snack was the snacking occasion with the lowest energy density [211 kcal/100 g], the lowest energy intake [104.1 kcal] and the highest nutrient density [60.1]. Afternoon and evening snacks had the highest energy loads [192.4 kcal and 207.6 kcal], but low nutrient scores [16 and 13, respectively]. The main food groups contributing to energy intake from snacks were fatty-sweet and sugary foods, fruit, hot beverages, and bread. CONCLUSIONS: Our findings highlight the frequency of snacking and the varying nutritional quality of snacks over the day. The morning snack was shown to be healthier than afternoon and evening snacks. TRIAL REGISTRATION: This study was conducted according to guidelines laid down in the Declaration of Helsinki, and all procedures were approved by the Institutional Review Board of the French Institute for Health and Medical Research (IRB Inserm No. 0000388FWA00005831) and the French Data Protection Authority (Commission Nationale Informatique et Libertes No. 908450 and No. 909216). Electronic informed consent was obtained from all participants (Clinical Trial no. NCT03335644 ). PMID- 29486786 TI - Detection of IL10-producing B cell (B10) in adenoids of atopic children with adenoidal hypertrophy. PMID- 29486785 TI - Identification of candidate genes associated with fibromyalgia susceptibility in southern Spanish women: the al-Andalus project. AB - BACKGROUND: Candidate-gene studies on fibromyalgia susceptibility often include a small number of single nucleotide polymorphisms (SNPs), which is a limitation. Moreover, there is a paucity of evidence in Europe. Therefore, we compared genotype frequencies of candidate SNPs in a well-characterised sample of Spanish women with fibromyalgia and healthy non-fibromyalgia women. METHODS: A total of 314 women with a diagnosis of fibromyalgia (cases) and 112 non-fibromyalgia healthy (controls) women participated in this candidate-gene study. Buccal swabs were collected for DNA extraction. Using TaqManTM OpenArrayTM, we analysed 61 SNPs of 33 genes related to fibromyalgia susceptibility, symptoms, or potential mechanisms. RESULTS: We observed that the rs841 and rs1799971 GG genotype was more frequently observed in fibromyalgia than in controls (p = 0.04 and p = 0.02, respectively). The rs2097903 AT/TT genotypes were also more often present in the fibromyalgia participants than in their control peers (p = 0.04). There were no differences for the remaining SNPs. CONCLUSIONS: We identified, for the first time, associations of the rs841 (guanosine triphosphate cyclohydrolase 1 gene) and rs2097903 (catechol-O-methyltransferase gene) SNPs with higher risk of fibromyalgia susceptibility. We also confirmed that the rs1799971 SNP (opioid receptor MU1 gene) might confer genetic risk of fibromyalgia. We did not adjust for multiple comparisons, which would be too stringent and yield to non significant differences in the genotype frequencies between cases and controls. Our findings may be biologically meaningful and informative, and should be further investigated in other populations. Of particular interest is to replicate the present study in a larger independent sample to confirm or refute our findings. On the other hand, by including 61 SNPs of 33 candidate-genes with a strong rationale (they were previously investigated in relation to fibromyalgia susceptibility, symptoms or potential mechanisms), the present research is the most comprehensive candidate-gene study on fibromyalgia susceptibility to date. PMID- 29486787 TI - The correlation between raised body mass index and assisted reproductive treatment outcomes: a systematic review and meta-analysis of the evidence. AB - BACKGROUND: Public funding for fertility services within the United Kingdom is limited, and therefore, strict guidance exists regarding who can be offered treatment under the National Health Service (NHS). Body mass index (BMI) is a universal criteria adopted by both the public and private sector. This study addresses an important aspect of the impact of a raised BMI on fertility treatment outcomes. We standardise the analysis of the data by only including studies incorporating the WHO BMI criteria; the current reference point for clinicians and clinical commissioning groups in ascertaining which group of patients should receive treatment. This study is an update of the previous systematic review performed in 2010, with the inclusion of a larger number of cycles from central databases such as the Society for Assisted Reproductive Technology (SART). METHODS: An electronic literature search was conducted through the Cochrane, Medline and Embase libraries. Data extraction for each outcome measure was pooled and expressed as an odds ratio with 95% confidence intervals. Where clinical heterogeneity was evident, the random effects model was used to calculate the risk ratio and a fixed effects model was used for the remaining studies. A p value < 0.05 was considered statistically significant. RESULTS: A total of 49 studies have been identified and included in this systematic review. Overweight and obese (BMI >= 25 kg/m2) women have a statistically significant lower live birth rate (OR 0.81, 95% CI 0.74-0.89, p < 0.00001) following Assisted Reproductive Technology (ART) when comparisons are drawn to women with a normal BMI. An increase is also demonstrated in the number of miscarriages experienced by women with a BMI >= 30 kg/m2 (OR 1.52, 95% CI 1.28-1.81, p < 0.00001). CONCLUSION: Although this review concludes that a clear impact of BMI on ART outcomes is demonstrated, there remains questions as to the pathophysiology underlying these differences. This review supports the government's stringent criteria regarding BMI categories under which NHS funding is made available for ART, through a clear description of poor reproductive outcomes in women with a BMI >= 30 kg/m2. PMID- 29486788 TI - Quality of life in small-scaled homelike nursing homes: an 8-month controlled trial. AB - BACKGROUND: Quality of life is a clinical highly relevant outcome for residents with dementia. The question arises whether small scaled homelike facilities are associated with better quality of life than regular larger scale nursing homes do. METHODS: A sample of 145 residents living in a large scale care facility were followed over 8 months. Half of the sample (N = 77) subsequently moved to a small scaled facility. Quality of life aspects were measured with the QUALIDEM and GIP before and after relocation. RESULTS: We found a significant Group x Time interaction on measures of anxiety meaning that residents who moved to small scale units became less anxious than residents who stayed on the regular care large-scale units. No significant differences were found on other aspects of quality of life. CONCLUSIONS: This study demonstrates that residents who move from a large scale facility to a small scale environment can improve an aspect of quality of life by showing a reduction in anxiety. TRIAL REGISTRATION: Current Controlled Trials ISRCTN11151241 . registration date: 21-06-2017. Retrospectively registered. PMID- 29486789 TI - Blood-feeding, susceptibility to infection with Schmallenberg virus and phylogenetics of Culicoides (Diptera: Ceratopogonidae) from the United Kingdom. AB - BACKGROUND: Culicoides biting midges (Diptera: Ceratopogonidae) are responsible for the biological transmission of internationally important arboviruses of livestock. In 2011, a novel Orthobunyavirus was discovered in northern Europe causing congenital malformations and abortions in ruminants. From field studies, Culicoides were implicated in the transmission of this virus which was subsequently named Schmallenberg virus (SBV), but to date no assessment of susceptibility to infection of field populations under standardised laboratory conditions has been carried out. We assessed the influence of membrane type (chick skin, collagen, Parafilm M(r)) when offered in conjunction with an artificial blood-feeding system (Hemotek, UK) on field-collected Culicoides blood feeding rates. Susceptibility to infection with SBV following blood-feeding on an SBV-blood suspension provided via either (i) the Hemotek system or via (ii) a saturated cotton wool pledglet was then compared. Schmallenberg virus susceptibility was defined by RT-qPCR of RNA extractions of head homogenates and related to Culicoides species and haplotype identifications based on the DNA barcode region of the mitochondrial cytochrome c oxidase 1 (cox1) gene. RESULTS: Culicoides blood-feeding rates were low across all membrane types tested (7.5% chick skin, 0.0% for collagen, 4.4% Parafilm M(r), with 6029 female Culicoides being offered a blood meal in total). Susceptibility to infection with SBV through membrane blood-feeding (8 of 109 individuals tested) and pledglet blood feeding (1 of 94 individuals tested) was demonstrated for the Obsoletus complex, with both C. obsoletus (Meigen) and C. scoticus Downes & Kettle susceptible to infection with SBV through oral feeding. Potential evidence of cryptic species within UK populations was found for the Obsoletus complex in phylogenetic analyses of cox1 DNA barcodes of 74 individuals assessed from a single field site. CONCLUSIONS: Methods described in this study provide the means to blood feed Palaearctic Culicoides for vector competence studies and colonisation attempts. Susceptibility to SBV infection was 7.3% for membrane-fed members of the subgenus Avaritia and 1.1% for pledglet-fed. Both C. obsoletus and C. scoticus were confirmed as being susceptible to infection with SBV, with potential evidence of cryptic species within UK Obsoletus complex specimens, however the implications of cryptic diversity in the Obsoletus complex on arbovirus transmission remains unknown. PMID- 29486790 TI - Effect of an integrated intervention package of preventive chemotherapy, community-led total sanitation and health education on the prevalence of helminth and intestinal protozoa infections in Cote d'Ivoire. AB - BACKGROUND: Preventive chemotherapy with donated anthelminthic drugs is the cornerstone for the control of helminthiases. However, reinfection can occur rapidly in the absence of clean water and sanitation coupled with unhygienic behaviour. The purpose of this study was to assess the effect of an integrated package of interventions, consisting of preventive chemotherapy, community-led total sanitation (CLTS) and health education, on the prevalence of helminth and intestinal protozoa infections and on participants' knowledge, attitude, practice and beliefs (KAPB) towards these diseases including water, sanitation and hygiene (WASH). METHODS: A cross-sectional survey was carried out in nine communities of south-central Cote d'Ivoire to assess people's infection with helminths and intestinal protozoa and KAPB. Subsequently, interventions were targeted to five communities, while the remaining communities served as control. The intervention encouraged latrine construction and an evaluation was done 6-7 months later to determine open defecation status of the respective communities. Anthelminthic treatment was provided to all community members. A follow-up cross-sectional survey was conducted approximately one year later, using the same procedures. RESULTS: Overall, 810 people had complete baseline and follow-up data and were given anthelminthic treatment. The baseline prevalence of hookworm, Schistosoma haematobium, Trichuris trichiura, Schistosoma mansoni and Ascaris lumbricoides was 31.1%, 7.0%, 2.0%, 1.0% and 0.3%, respectively. Four of the five intervention communities were classified open-defecation free. For hookworm infection, we observed higher negative changes in terms of proportion of decrease (-0.10; 95% confidence interval (CI): - 0.16, -0.04) and higher egg reduction rate (64.9 vs 15.2%) when comparing intervention with control communities. For intestinal protozoa, prevalence reduction was higher in intervention compared to control communities (8.2 vs 2.6%) and WASH indicators and intervention outcomes associated with lower odds for infection at follow-up. The intervention significantly impacted on reported latrine use (before: 15.5%, after: 94.6%), open defecation in the community surroundings (before: 75.0%, after: 16.7%) and awareness for environmental contamination through open defecation (before: 20.4%, after: 52.2%). CONCLUSIONS: An integrated package of interventions consisting of preventive chemotherapy, health education and CLTS reduces the prevalence of helminth and intestinal protozoa infection. Additional studies in other social ecological settings are warranted to confirm our findings. PMID- 29486791 TI - Unequal distribution of health human resource in mainland China: what are the determinants from a comprehensive perspective? AB - BACKGROUND: The inequality of health human resource is a worldwide problem, and solving it also is one of the major goals of China's recent health system reform. Yet there is a huge disparity among cities in mainland China. The aim of this study is to analyze the distribution inequality of the health human resource in 322 prefecture-level cities of mainland China in 2014, and to reveal the facets and causes of the inequalities. METHODS: The data for this study were acquired from the provincial and municipal Health Statistics Yearbook (2014) and Statistical Yearbook (2014), the municipal National Economic Bulletin (2014), and the official websites of municipal governments, involving 322 prefecture-level cities. Meanwhile, Concentration Index was used to measure the magnitude of the unequal distribution of health human resource. A decomposition analysis was employed to quantify the contribution of each determinant to the total inequality. RESULTS: The overall concentration index of doctors and nurses in mainland China in 2014 was 0.1038 (95% CI = 0.0208, 0.1865) and 0.0785 (95% CI =0.0018, 0.1561). Decomposition of the concentration index revealed that economic status was the primary contributor (58.5% and 57%) to the inequality of doctors and nurses, followed by the Southwest China (19.1% and 18.6%), urbanization level (- 13.1% and - 12.8%), and revenue (8.0% and 7.8%). Party secretaries with Master degree (7.0%, 6.8%), mayors who were 60 years old or above (6.3%, 6.1%) also were proved to be a major contributor to the inequality of health human resource. CONCLUSIONS: There was inequality of health human resource distribution which was pro-rich in mainland China in 2014. Economic status of the cities accounted for most of the existing inequality, followed by the Southwest China, urbanization level, revenue, party secretaries with Master degree, and mayors who were 60 years old or above in respective importance. Besides, the party secretaries and mayors also had certain influence on the allocation of health human resource. The tough issue of HHR inequality should be addressed by comprehensive measures from a multidisciplinary perspective. PMID- 29486793 TI - Prevalence and determinants of comprehensive eye care in a group of patients with diabetes: a cross-sectional study in a sub-Saharan African setting. AB - OBJECTIVES: We aimed to investigate the determinants of comprehensive eye examination in diabetes patients. We conducted a cross-sectional study at the eye department of the Douala General Hospital. Adult patients with diabetes were consecutively interviewed on the history of their diabetes. Main outcomes were a first ever comprehensive eye examination including fundoscopy, and diagnosis-to fundoscopy time. RESULTS: 52 patients were included of whom 59.6% were males with a mean age of 55.9 +/- 10.9 years. 51.9% have had counselling on the risk of visual impairment and blindness due to diabetes, and 61.5% [95% CI 47-74.7] have had a comprehensive eye examination. Of those with a first ever fundoscopy, only 21.9% had the test performed within 1 year of diagnosis. Thus, after an average of 10 years of the diagnosis of diabetes, 13.5% (7/52) of patients have had a comprehensive eye examination within 1 year of diagnosis. Only dose with duration of diabetes of more than 10 years were 7-24 times more likely to have a comprehensive eye examination. In summary, patients with diabetes in this low income setting do not receive a comprehensive eye care as recommended. Most patients will get an eye examination at least 10 years after the diagnosis of diabetes. PMID- 29486794 TI - Exosomal long noncoding RNA HOTTIP as potential novel diagnostic and prognostic biomarker test for gastric cancer. AB - Long noncoding RNA HOTTIP plays important roles in the generation and progression of human cancers. Exosomes participate in cellular communication by transmitting moleculars between cells and are regarded as suitable candidates for non-invasive diagnosis. However, the existence of HOTTIP in the circulating exosomes and the potential roles of exosomal HOTTIP in gastric cancer (GC) was poorly understood. This study aims at investigating the clinical roles of exosomal HOTTIP in GC. Serum exosomal HOTTIP from 246 subjects (126 GC patients and 120 healthy people) were detected by reverse transcription real-time quantitative polymerase chain reaction (RT-qPCR). Our results showed that expression levels of exosomal HOTTIP were typically upregulated in GC than in normal control (P < 0.001). And its expression levels were significantly correlated with invasion depth (P = 0.0298) and TNM stage (P < 0.001). The AUC for exosomal HOTTIP was 0.827, which demonstrated a higher diagnostic capability than CEA, CA 19-9 and CA72-4 (AUC = 0.653, 0.685 and 0.639, respectively) (P < 0.001). The Kaplan-Meier analysis showed a correlation between increased exosomal HOTTIP levels and poor overall survival (OS) (logrank P < 0.001). And univariate and multivariate COX analysis revealed exosomal HOTTIP overexpression was an independent prognostic factor in GC patients (P = 0.027). These findings demonstrated that exosomal HOTTIP may be a potential biomarker for GC in diagnosis and prognosis. PMID- 29486792 TI - NSAID use and somatic exomic mutations in Barrett's esophagus. AB - BACKGROUND: Use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been shown to protect against tetraploidy, aneuploidy, and chromosomal alterations in the metaplastic condition Barrett's esophagus (BE) and to lower the incidence and mortality of esophageal adenocarcinoma (EA). The esophagus is exposed to both intrinsic and extrinsic mutagens resulting from gastric reflux, chronic inflammation, and exposure to environmental carcinogens such as those found in cigarettes. Here we test the hypothesis that NSAID use inhibits accumulation of point mutations/indels during somatic genomic evolution in BE. METHODS: Whole exome sequences were generated from 82 purified epithelial biopsies and paired blood samples from a cross-sectional study of 41 NSAID users and 41 non-users matched by sex, age, smoking, and continuous time using or not using NSAIDs. RESULTS: NSAID use reduced overall frequency of point mutations across the spectrum of mutation types, lowered the frequency of mutations even when adjusted for both TP53 mutation and smoking status, and decreased the prevalence of clones with high variant allele frequency. Never smokers who consistently used NSAIDs had fewer point mutations in signature 17, which is commonly found in EA. NSAID users had, on average, a 50% reduction in functional gene mutations in nine cancer-associated pathways and also had less diversity in pathway mutational burden compared to non-users. CONCLUSIONS: These results indicate NSAID use functions to limit overall mutations on which selection can act and supports a model in which specific mutant cell populations survive or expand better in the absence of NSAIDs. PMID- 29486795 TI - The first-in-class alkylating deacetylase inhibitor molecule tinostamustine shows antitumor effects and is synergistic with radiotherapy in preclinical models of glioblastoma. AB - BACKGROUND: The use of alkylating agents such as temozolomide in association with radiotherapy (RT) is the therapeutic standard of glioblastoma (GBM). This regimen modestly prolongs overall survival, also if, in light of the still dismal prognosis, further improvements are desperately needed, especially in the patients with O6-methylguanine-DNA-methyltransferase (MGMT) unmethylated tumors, in which the benefit of standard treatment is less. Tinostamustine (EDO-S101) is a first-in-class alkylating deacetylase inhibitor (AK-DACi) molecule that fuses the DNA damaging effect of bendamustine with the fully functional pan-histone deacetylase (HDAC) inhibitor, vorinostat, in a completely new chemical entity. METHODS: Tinostamustine has been tested in models of GBM by using 13 GBM cell lines and seven patient-derived GBM proliferating/stem cell lines in vitro. U87MG and U251MG (MGMT negative), as well as T98G (MGMT positive), were subcutaneously injected in nude mice, whereas luciferase positive U251MG cells and patient derived GBM stem cell line (CSCs-5) were evaluated the orthotopic intra-brain in vivo experiments. RESULTS: We demonstrated that tinostamustine possesses stronger antiproliferative and pro-apoptotic effects than those observed for vorinostat and bendamustine alone and similar to their combination and irrespective of MGMT expression. In addition, we observed a stronger radio-sensitization of single treatment and temozolomide used as control due to reduced expression and increased time of disappearance of gammaH2AX indicative of reduced signal and DNA repair. This was associated with higher caspase-3 activation and reduction of RT mediated autophagy. In vivo, tinostamustine increased time-to-progression (TTP) and this was additive/synergistic to RT. Tinostamustine had significant therapeutic activity with suppression of tumor growth and prolongation of DFS (disease-free survival) and OS (overall survival) in orthotopic intra-brain models that was superior to bendamustine, RT and temozolomide and showing stronger radio sensitivity. CONCLUSIONS: Our data suggest that tinostamustine deserves further investigation in patients with glioblastoma. PMID- 29486796 TI - Differential human gut microbiome assemblages during soil-transmitted helminth infections in Indonesia and Liberia. AB - BACKGROUND: The human intestine and its microbiota is the most common infection site for soil-transmitted helminths (STHs), which affect the well-being of ~ 1.5 billion people worldwide. The complex cross-kingdom interactions are not well understood. RESULTS: A cross-sectional analysis identified conserved microbial signatures positively or negatively associated with STH infections across Liberia and Indonesia, and longitudinal samples analysis from a double-blind randomized trial showed that the gut microbiota responds to deworming but does not transition closer to the uninfected state. The microbiomes of individuals able to self-clear the infection had more alike microbiome assemblages compared to individuals who remained infected. One bacterial taxon (Lachnospiracae) was negatively associated with infection in both countries, and 12 bacterial taxa were significantly associated with STH infection in both countries, including Olsenella (associated with reduced gut inflammation), which also significantly reduced in abundance following clearance of infection. Microbial community gene abundances were also affected by deworming. Functional categories identified as associated with STH infection included arachidonic acid metabolism; arachidonic acid is the precursor for pro-inflammatory leukotrienes that threaten helminth survival, and our findings suggest that some modulation of arachidonic acid activity in the STH-infected gut may occur through the increase of arachidonic acid metabolizing bacteria. CONCLUSIONS: For the first time, we identify specific members of the gut microbiome that discriminate between moderately/heavily STH infected and non-infected states across very diverse geographical regions using two different statistical methods. We also identify microbiome-encoded biological functions associated with the STH infections, which are associated potentially with STH survival strategies, and changes in the host environment. These results provide a novel insight of the cross-kingdom interactions in the human gut ecosystem by unlocking the microbiome assemblages at taxonomic, genetic, and functional levels so that advances towards key mechanistic studies can be made. PMID- 29486797 TI - A randomized, controlled trial evaluating the efficacy and safety of BTH1677 in combination with bevacizumab, carboplatin, and paclitaxel in first-line treatment of advanced non-small cell lung cancer. AB - BACKGROUND: BTH1677, a beta-glucan pathogen-associated molecular pattern molecule, drives an anti-cancer immune response in combination with oncology antibody therapies. This phase II study explored the efficacy, pharmacokinetics (PK), and safety of BTH1677 combined with bevacizumab/carboplatin/paclitaxel in patients with untreated advanced non-small cell lung cancer (NSCLC). METHODS: Patients were randomized to the BTH1677 arm (N = 61; intravenous [IV] BTH1677, 4 mg/kg, weekly; IV bevacizumab, 15 mg/kg, once each 3-week cycle [Q3W]; IV carboplatin, 6 mg/mL/min Calvert formula area-under-the-curve, Q3W; and IV paclitaxel, 200 mg/m2, Q3W) or Control arm (N = 31; bevacizumab/carboplatin/paclitaxel as above). Carboplatin/paclitaxel was discontinued after 4-6 cycles and patients who responded or remained stable received maintenance therapy with BTH1677/bevacizumab (BTH1677 arm) or bevacizumab (Control arm). Efficacy assessments, based on blinded central radiology review, included objective response rate (ORR; primary endpoint), disease control rate, duration of objective response, and progression-free survival. Overall survival and adverse events (AEs) were also assessed. RESULTS: ORR was higher in the BTH1677 vs Control arm but the difference between groups was not statistically significant (60.4% vs 43.5%; P = .2096). All other clinical endpoints also favored the BTH1677 arm but none statistically differed between arms. PK was consistent with previous studies. Although a higher incidence of Grade 3/4 AEs occurred in the BTH1677 vs Control arm (93.2% vs 66.7%), no unexpected AEs were observed. Serious AEs and discontinuations due to AEs were lower in the BTH1677 vs Control arm. CONCLUSIONS: Improvements in tumor assessments and survival were observed with BTH1677/bevacizumab/carboplatin/paclitaxel compared with control treatment in patients with advanced NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov registration ID: NCT00874107 . Registered 2 April 2009. First participant was enrolled on 29 September 2009. PMID- 29486798 TI - Mobility and increased risk of HIV acquisition in South Africa: a mixed-method systematic review protocol. AB - BACKGROUND: In South Africa (home of the largest HIV epidemic globally), there are high levels of mobility. While studies produced in the recent past provide useful perspectives to the mobility-HIV risk linkage, systematic analyses are needed for in-depth understanding of the complex dynamics between mobility and HIV risk. We plan to undertake an evidence-based review of existing literature connecting mobility and increased risky sexual behavior as well as risk of HIV acquisition in South Africa. METHODS/DESIGN: We will conduct a mixed-method systematic review of peer-reviewed studies published between 2000 and 2015. In particular, we will search for relevant South African studies from the following databases: MEDLINE, EMBASE, Web of Science, and J-STOR databases. Studies explicitly examining HIV and labor migration will be eligible for inclusion, while non-empirical work and other studies on key vulnerable populations such as commercial sex workers (CSW) and men who have sex with men (MSM) will be excluded. DISCUSSION: The proposed mixed-method systematic review will employ a three-phase sequential approach [i.e., (i) identifying relevant studies through data extraction (validated by use of Distiller-SR data management software), (ii) qualitative synthesis, and (iii) quantitative synthesis including meta-analysis data]. Recurrent ideas and conclusions from syntheses will be compiled into key themes and further processed into categories and sub-themes constituting the primary and secondary outcomes of this study. Synthesis of main findings from different studies examining the subject issue here may uncover important research gaps in this literature, laying a strong foundation for research and development of sustainable localized migrant-specific HIV prevention strategies in South Africa. SYSTEMATIC REVIEW REGISTRATION: Our protocol was registered with PROSPERO under registration number: CRD 42017055580. ( https://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42017055580 ). PMID- 29486799 TI - Radiation and PD-(L)1 treatment combinations: immune response and dose optimization via a predictive systems model. AB - BACKGROUND: Numerous oncology combination therapies involving modulators of the cancer immune cycle are being developed, yet quantitative simulation models predictive of outcome are lacking. We here present a model-based analysis of tumor size dynamics and immune markers, which integrates experimental data from multiple studies and provides a validated simulation framework predictive of biomarkers and anti-tumor response rates, for untested dosing sequences and schedules of combined radiation (RT) and anti PD-(L)1 therapies. METHODS: A quantitative systems pharmacology model, which includes key elements of the cancer immunity cycle and the tumor microenvironment, tumor growth, as well as dose-exposure-target modulation features, was developed to reproduce experimental data of CT26 tumor size dynamics upon administration of RT and/or a pharmacological IO treatment such as an anti-PD-L1 agent. Variability in individual tumor size dynamics was taken into account using a mixed-effects model at the level of tumor-infiltrating T cell influx. RESULTS: The model allowed for a detailed quantitative understanding of the synergistic kinetic effects underlying immune cell interactions as linked to tumor size modulation, under these treatments. The model showed that the ability of T cells to infiltrate tumor tissue is a primary determinant of variability in individual tumor size dynamics and tumor response. The model was further used as an in silico evaluation tool to quantitatively predict, prospectively, untested treatment combination schedules and sequences. We demonstrate that anti-PD-L1 administration prior to, or concurrently with RT reveal further synergistic effects, which, according to the model, may materialize due to more favorable dynamics between RT-induced immuno-modulation and reduced immuno-suppression of T cells through anti-PD-L1. CONCLUSIONS: This study provides quantitative mechanistic explanations of the links between RT and anti-tumor immune responses, and describes how optimized combinations and schedules of immunomodulation and radiation may tip the immune balance in favor of the host, sufficiently to lead to tumor shrinkage or rejection. PMID- 29486800 TI - MRI features of combined hepatocellular- cholangiocarcinoma versus mass forming intrahepatic cholangiocarcinoma. AB - BACKGROUND: Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare primary liver tumor, which has overlapping imaging features with mass forming intra-hepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC). Previous studies reported imaging features more closely resemble ICC and the aim of our study was to examine the differential MRI features of cHCC-CC and ICC with emphasis on enhancement pattern observations of gadolinium enhanced MRI. METHODS: Institutional review board approval with consent waiver was obtained for this retrospective bi-centric study. Thirty-three patients with pathologically proven cHCC-CC and thirty-eight patients with pathologically proven ICC, who had pre operative MRI, were identified. MRI images were analyzed for tumor location and size, T1 and T2 signal characteristics, the presence/absence of: cirrhosis, intra lesional fat, hemorrhage/hemosiderin, scar, capsular retraction, tumor thrombus, biliary dilatation, degree of arterial enhancement, enhancement pattern, pseudocapsule and washout. Associations between MRI features and tumor type were examined using the Fisher's exact and chi-square tests. RESULTS: Strong arterial phase enhancement and the presence of: washout, washout and progression, intra lesional fat and hemorrhage were all strongly associated with cHCC-CC (P < 0.001). While cHCC-CC had a varied enhancement pattern, the two most common enhancement patterns were peripheral persistent (n = 6) and heterogeneous hyperenhancement with washout (n = 6), compared to ICC where the most common enhancement patterns were peripheral hypoenhancement with progression (n = 18) followed by heterogeneous hypoenhancement with progression (n = 14) (P < 0.001). CONCLUSION: The cHCC-CC enhancement pattern seems to more closely resemble HCC with the degree of arterial hyperenhancement and the presence of washout being valuable in differentiating cHCC-CC from ICC. However the presence of washout and progression, in the same lesion or a predominantly peripheral /rim hyperenhancing mass were also seen as important features that should alert the radiologist to the possibility of a cHCC-CC. PMID- 29486801 TI - Mapping the global health employment market: an analysis of global health jobs. AB - BACKGROUND: The number of university global health training programs has grown in recent years. However, there is little research on the needs of the global health profession. We therefore set out to characterize the global health employment market by analyzing global health job vacancies. METHODS: We collected data from advertised, paid positions posted to web-based job boards, email listservs, and global health organization websites from November 2015 to May 2016. Data on requirements for education, language proficiency, technical expertise, physical location, and experience level were analyzed for all vacancies. Descriptive statistics were calculated for the aforementioned job characteristics. Associations between technical specialty area and requirements for non-English language proficiency and overseas experience were calculated using Chi-square statistics. A qualitative thematic analysis was performed on a subset of vacancies. RESULTS: We analyzed the data from 1007 global health job vacancies from 127 employers. Among private and non-profit sector vacancies, 40% (n = 354) were for technical or subject matter experts, 20% (n = 177) for program directors, and 16% (n = 139) for managers, compared to 9.8% (n = 87) for entry level and 13.6% (n = 120) for mid-level positions. The most common technical focus area was program or project management, followed by HIV/AIDS and quantitative analysis. Thematic analysis demonstrated a common emphasis on program operations, relations, design and planning, communication, and management. CONCLUSIONS: Our analysis shows a demand for candidates with several years of experience with global health programs, particularly program managers/directors and technical experts, with very few entry-level positions accessible to recent graduates of global health training programs. It is unlikely that global health training programs equip graduates to be competitive for the majority of positions that are currently available in this field. PMID- 29486802 TI - Sex composition and its impact on future childbearing: a longitudinal study from urban Uttar Pradesh. AB - BACKGROUND: The sex composition of existing children has been shown to influence childbearing decision-making and behaviors of women and couples. One aspect of this influence is the preference for sons. In India, where son preference is deeply entrenched, research has normally focused on rural areas using cross sectional data. However, urban areas in India are rapidly changing, with profound implications for childbearing patterns. Yet, evidence on the effect of the sex composition of current children on subsequent childbearing intentions and behavior in urban areas is scant. In this study, we analyze the impact of sex composition of children on subsequent (1) parity progression, (2) contraceptive use, and (3) desire for another child. METHODS: We analyze prospective data from women over a four year period in urban Uttar Pradesh using discrete-time event history logistic regression models to analyze parity progression from the first to second parity, second to third parity, and third to fourth parity. We also use logistic regression models to analyze contraceptive use and desire for another child. RESULTS: Relative to women with no daughters, women with no sons had significantly higher odds of progressing to the next birth (parity 1 - aOR: 1.31; CI: 1.04-1.66; parity 2 - aOR: 4.65; CI: 3.11-6.93; parity 3 - aOR:3.45; CI: 1.83 6.52), as well as reduced odds of using contraception (parity 2 - aOR:.58; CI: .44-.76; parity 3 - aOR: .58; CI: .35-.98). Relative to women with two or more sons, women with two or more daughters had significantly higher odds of wanting to have another child (parity 1 - aOR: 1.33; CI: 1.06-1.67; parity 2 - aOR: 3.96; CI: 2.45-6.41; parity 3-4.89; CI: 2.22-10.77). CONCLUSIONS: Our study demonstrates the pervasiveness of son preference in urban areas of Uttar Pradesh. We discuss these findings for future programmatic strategies to mitigate son preference in urban settings. PMID- 29486803 TI - Seroclearance of hepatitis B surface antigen following hepatitis E exacerbation on chronic hepatitis E and B dual infection in a renal transplant recipient: a case report. AB - BACKGROUND: Hepatitis E virus infection usually causes an acute and self resolving hepatitis. In areas where chronic hepatitis B virus infection is prevalent, acute hepatitis E virus superinfection on chronic hepatitis B virus infection occurs sporadically. In recent years, however, chronic hepatitis E virus infection has been recognized in patients under immunosuppressant therapy. To the best of our knowledge, cases involving patients with chronic hepatitis E virus and hepatitis B virus dual infection have never been reported. CASE PRESENTATION: A 47-year-old Taiwanese woman who was a renal transplant recipient with chronic hepatitis B virus infection was under immunosuppressant and antiviral treatment. An episode of hepatitis B exacerbation developed due to withdrawal of antiviral treatment against advice, but the flare subsided following antiviral re-treatments. However, an episode of hepatitis exacerbation developed following removal of the renal graft because of graft failure. During the hepatitis flare, she was still under successful antiviral suppression against hepatitis B virus, while her serum samples were positive for hepatitis E virus RNA. Following the hepatitis flare, seroclearance of hepatitis B virus surface antigen developed. From then on, she was under regular hemodialysis. Five years later, another episode of mild hepatitis exacerbation occurred again with positive serum hepatitis E virus RNA. Tracing back the longitudinal serum samples, serum hepatitis E virus RNA was persistently positive throughout the course. This patient was thus recognized to have chronic hepatitis E virus and hepatitis B virus dual infection with intermittent hepatitis E exacerbations. CONCLUSIONS: In areas where chronic hepatitis B virus infection is prevalent, chronic hepatitis E virus coinfection can occur in organ transplant recipients receiving immunosuppressant. Intermittent hepatitis E exacerbations may develop, interfering with the status of hepatitis B virus infection. PMID- 29486804 TI - Was Eysenck right after all? A reassessment of the effects of psychotherapy for adult depression. AB - AIMS: In the 1950s, Eysenck suggested that psychotherapies may not be effective at all. Twenty-five years later, the first meta-analysis of randomised controlled trials showed that the effects of psychotherapies were considerable and that Eysenck was wrong. However, since that time methods have become available to assess biases in meta-analyses. METHODS: We examined the influence of these biases on the effects of psychotherapies for adult depression, including risk of bias, publication bias and the exclusion of waiting list control groups. RESULTS: The unadjusted effect size of psychotherapies compared with control groups was g = 0.70 (limited to Western countries: g = 0.63), which corresponds to a number needed-to-treat of 4.18. Only 23% of the studies could be considered as a low risk of bias. When adjusting for several sources of bias, the effect size across all types of therapies dropped to g = 0.31. CONCLUSIONS: These results suggest that the effects of psychotherapy for depression are small, above the threshold that has been suggested as the minimal important difference in the treatment of depression, and Eysenck was probably wrong. However, this is still not certain because we could not adjust for all types of bias. Unadjusted meta-analyses of psychotherapies overestimate the effects considerably, and for several types of psychotherapy for adult depression, insufficient evidence is available that they are effective because too few low-risk studies were available, including problem solving therapy, interpersonal psychotherapy and behavioural activation. PMID- 29486805 TI - Association Between Healthcare-Associated Infection and Exposure to Hospital Roommates and Previous Bed Occupants with the Same Organism. AB - OBJECTIVETo quantify the association between having a prior bed occupant or roommate with a positive blood, respiratory, urine, or wound culture and subsequent infection with the same organism.DESIGNCase-control study.SETTINGThe study included 4 hospitals within an academically affiliated network in New York City, including a community hospital (221 beds), a pediatric acute-care hospital (283 beds), an adult tertiary-/quaternary-care hospital (647 beds), and a pediatric and adult tertiary-/quaternary-care hospital (914 beds).PATIENTSAll 761,426 inpatients discharged from 2006 to 2012 were eligible. Cases included all patients who developed a healthcare-associated infection (HAI) with Staphylococcus aureus, Acinetobacter baumannii, Streptococcus pneumoniae, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterococcus faecalis, or Enterococcus faecium. Controls were uninfected patients matched by fiscal quarter, hospital, and length of stay. For each bed occupied during the 3-5-day period prior to infection, microbiology results for assigned roommates and the patient who occupied the bed immediately prior to the case were collected. For controls, the day of infection of the matched case served as the reference point.RESULTSIn total, 10,289 HAIs were identified. In a multivariable analysis controlling for both exposures and patient characteristics, the odds of cases having been exposed to a prior bed occupant with the same organism were 5.83 times that of controls (95% confidence interval [CI], 3.62-9.39), and the odds of cases having been exposed to a roommate with the same organism were 4.82 times that of controls (95% CI, 3.67-6.34).CONCLUSIONInfected or colonized roommates and prior occupants do pose a risk, which may warrant enhanced terminal and intermittent cleaning measures.Infect Control Hosp Epidemiol 2018;39:541-546. PMID- 29486806 TI - Acute general hospital admissions in people with serious mental illness. AB - BACKGROUND: Serious mental illness (SMI, including schizophrenia, schizoaffective disorder, and bipolar disorder) is associated with worse general health. However, admissions to general hospitals have received little investigation. We sought to delineate frequencies of and causes for non-psychiatric hospital admissions in SMI and compare with the general population in the same area. METHODS: Records of 18 380 individuals with SMI aged ?20 years in southeast London were linked to hospitalisation data. Age- and gender-standardised admission ratios (SARs) were calculated by primary discharge diagnoses in the 10th edition of the World Health Organization International Classification of Diseases (ICD-10) codes, referencing geographic catchment data. RESULTS: Commonest discharge diagnosis categories in the SMI cohort were urinary conditions, digestive conditions, unclassified symptoms, neoplasms, and respiratory conditions. SARs were raised for most major categories, except neoplasms for a significantly lower risk. Hospitalisation risks were specifically higher for poisoning and external causes, injury, endocrine/metabolic conditions, haematological, neurological, dermatological, infectious and non-specific ('Z-code') causes. The five commonest specific ICD-10 diagnoses at discharge were 'chronic renal failure' (N18), a non-specific code (Z04), 'dental caries' (K02), 'other disorders of the urinary system' (N39), and 'pain in throat and chest' (R07), all of which were higher than expected (SARs ranging 1.57-6.66). CONCLUSION: A range of reasons for non-psychiatric hospitalisation in SMI is apparent, with self-harm, self-neglect and/or reduced healthcare access, and medically unexplained symptoms as potential underlying explanations. PMID- 29486807 TI - Mindfulness-based cognitive therapy v. treatment as usual in adults with ADHD: a multicentre, single-blind, randomised controlled trial. AB - BACKGROUND: There is a high need for evidence-based psychosocial treatments for adult attention-deficit hyperactivity disorder (ADHD) to offer alongside treatment as usual (TAU). Mindfulness-based cognitive therapy (MBCT) is a promising psychosocial treatment. This trial investigated the efficacy of MBCT + TAU v. TAU in reducing core symptoms in adults with ADHD. METHODS: A multicentre, single-blind, randomised controlled trial (ClinicalTrials.gov: NCT02463396). Participants were randomly assigned to MBCT + TAU (n = 60), an 8-weekly group therapy including meditation exercises, psychoeducation and group discussions, or TAU only (n = 60), which reflected usual treatment in the Netherlands and included pharmacotherapy and/or psychoeducation. Primary outcome was ADHD symptoms rated by blinded clinicians. Secondary outcomes included self-reported ADHD symptoms, executive functioning, mindfulness skills, self-compassion, positive mental health and general functioning. Outcomes were assessed at baseline, post-treatment, 3- and 6-month follow-up. Post-treatment effects at group and individual level, and follow-up effects were examined. RESULTS: In MBCT + TAU patients, a significant reduction of clinician-rated ADHD symptoms was found at post-treatment [M difference = -3.44 (-5.75, -1.11), p = 0.004, d = 0.41]. This effect was maintained until 6-month follow-up. More MBCT + TAU (27%) than TAU participants (4%) showed a ?30% reduction of ADHD symptoms (p = 0.001). MBCT + TAU patients compared with TAU patients also reported significant improvements in ADHD symptoms, mindfulness skills, self-compassion and positive mental health at post-treatment, which were maintained until 6-month follow-up. Although patients in MBCT + TAU compared with TAU reported no improvement in executive functioning at post-treatment, they did report improvement at 6-month follow-up. CONCLUSIONS: MBCT might be a valuable treatment option alongside TAU for adult ADHD aimed at alleviating symptoms. PMID- 29486808 TI - Bisphosphonate-induced osteonecrosis of the ear canal: our experience and a review of the literature. AB - BACKGROUND: Oesophageal disorders and osteonecrosis of the jaw are recognised complications of the commonly prescribed medication bisphosphonate. Despite these diagnoses being seen comparatively frequently within the ENT clinic, osteonecrosis of the external ear is a less well reported complication. METHODS: The current literature is reviewed and our experience with six cases of bisphosphonate-related ear canal osteonecrosis is presented. RESULTS: Six cases were identified as suffering from ear canal osteonecrosis as a result of bisphosphonate treatment. One of our cases suffered bilateral ear canal osteonecrosis after only 20 months of oral alendronic acid treatment. Management ranged from bisphosphonate cessation and topical treatment, to surgical debridement in the operating theatre. CONCLUSION: Bisphosphonate-related ear canal osteonecrosis is undoubtedly under-diagnosed. For such a commonly prescribed medication, the risks and side effects of bisphosphonate should be better known and long-term treatment should be avoided if possible. PMID- 29486810 TI - Resident Physician Knowledge of Urine Testing and Treatment Over Four Years. AB - We surveyed resident physicians at 2 academic medical centers regarding urinary testing and treatment as they progressed through training. Demographics and self reported confidence were compared to overall knowledge using clinical vignette based questions. Overall knowledge was 40% in 2011 and increased to 48%, 55%, and 63% in subsequent years (P<.001).Infect Control Hosp Epidemiol 2018;39:616-618. PMID- 29486809 TI - Lower limb exercise generates pulsatile flow into the pulmonary vascular bed in the setting of the Fontan circulation. AB - The absence of a subpulmonary ventricle in the Fontan circulation results in non pulsatile pulmonary blood flow. Lower limb exercise in this setting can generate pulsatile pulmonary blood flow. PMID- 29486811 TI - Dynamic networks of PTSD symptoms during conflict. AB - BACKGROUND: Conceptualizing posttraumatic stress disorder (PTSD) symptoms as a dynamic system of causal elements could provide valuable insights into the way that PTSD develops and is maintained in traumatized individuals. We present the first study to apply a multilevel network model to produce an exploratory empirical conceptualization of dynamic networks of PTSD symptoms, using data collected during a period of conflict. METHODS: Intensive longitudinal assessment data were collected during the Israel-Gaza War in July-August 2014. The final sample (n = 96) comprised a general population sample of Israeli adult civilians exposed to rocket fire. Participants completed twice-daily reports of PTSD symptoms via smartphone for 30 days. We used a multilevel vector auto-regression model to produce contemporaneous and temporal networks, and a partial correlation network model to obtain a between-subjects network. RESULTS: Multilevel network analysis found strong positive contemporaneous associations between hypervigilance and startle response, avoidance of thoughts and avoidance of reminders, and between flashbacks and emotional reactivity. The temporal network indicated the central role of startle response as a predictor of future PTSD symptomatology, together with restricted affect, blame, negative emotions, and avoidance of thoughts. There were some notable differences between the temporal and contemporaneous networks, including the presence of a number of negative associations, particularly from blame. The between-person network indicated flashbacks and emotional reactivity to be the most central symptoms. CONCLUSIONS: This study suggests various symptoms that could potentially be driving the development of PTSD. We discuss clinical implications such as identifying particular symptoms as targets for interventions. PMID- 29486812 TI - Rheumatism and chronic fatigue, the two facets of post-chikungunya disease: the TELECHIK cohort study on Reunion island. AB - Prolonged fatigue is increasingly reported among chikungunya virus (CHIKV) infected populations. We investigated the relationships between CHIKV exposure, long-lasting rheumatic musculoskeletal pain (LRMSP) and chronic fatigue. 1094 participants (512 CHIKV seropositive and 582 seronegative) of the TELECHIK population-based cohort were analysed considering the duration of the manifestations throughout an average 2-year follow-up. Weighted prevalence rates and prevalence ratios for LRMSP, idiopathic chronic fatigue (ICF), and chronic fatigue syndrome (CFS)-like illness, both latter syndromes adapted from Centers for Disease Control (CDC)-1994/Fukuda criteria, were compared. Population attributable fractions (PAF) were estimated to assess the contribution of CHIKV infection to each of the three phenotypes. Among 362 adult subjects who had reported either rheumatic pain or fatigue at the onset of the infection, weighted prevalence rates of LRMSP, ICF and CFS-like illness were respectively of 32.9%, 38.7% and 23.9%, and of 8.7%, 8.5% and 7.4% among initially asymptomatic peers (P < 0.01, respectively). Each of the three outcomes was highly attributable to chikungunya (PAF of 43.2%, 36.2% and 41.0%, respectively). In the sub-cohort of CHIKV-infected subjects, LRMSP, ICF and CFS-like illness, which overlapped in 70%, accounted for 53% of the chronic manifestations. In addition to rheumatic disease, chronic fatigue could be considered in caring for patients with chronic chikungunya disease. PMID- 29486814 TI - Stable-isotope analysis: a neglected tool for placing parasites in food webs. AB - Parasites are often overlooked in the construction of food webs, despite their ubiquitous presence in almost every type of ecosystem. Researchers who do recognize their importance often struggle to include parasites using classical food-web theory, mainly due to the parasites' multiple hosts and life stages. A novel approach using compound-specific stable-isotope analysis promises to provide considerable insight into the energetic exchanges of parasite and host, which may solve some of the issues inherent in incorporating parasites using a classical approach. Understanding the role of parasites within food webs, and tracing the associated biomass transfers, are crucial to constructing new models that will expand our knowledge of food webs. This mini-review focuses on stable isotope studies published in the past decade, and introduces compound-specific stable-isotope analysis as a powerful, but underutilized, newly developed tool that may answer many unresolved questions regarding the role of parasites in food webs. PMID- 29486813 TI - Prevalence and heritability of body dysmorphic symptoms in adolescents and young adults: a population-based nationwide twin study. AB - BACKGROUND: Body dysmorphic disorder (BDD) usually begins during adolescence but little is known about the prevalence, etiology, and patterns of comorbidity in this age group. We investigated the prevalence of BDD symptoms in adolescents and young adults. We also report on the relative importance of genetic and environmental influences on BDD symptoms, and the risk for co-existing psychopathology. METHODS: Prevalence of BDD symptoms was determined by a validated cut-off on the Dysmorphic Concerns Questionnaire (DCQ) in three population-based twin cohorts at ages 15 (n = 6968), 18 (n = 3738), and 20-28 (n = 4671). Heritability analysis was performed using univariate model-fitting for the DCQ. The risk for co-existing psychopathology was expressed as odds ratios (OR). RESULTS: The prevalence of clinically significant BDD symptoms was estimated to be between 1 and 2% in the different cohorts, with a significantly higher prevalence in females (1.3-3.3%) than in males (0.2-0.6%). The heritability of body dysmorphic concerns was estimated to be 49% (95% CI 38-54%) at age 15, 39% (95% CI 30-46) at age 18, and 37% (95% CI 29-42) at ages 20-28, with the remaining variance being due to non-shared environment. ORs for co existing neuropsychiatric and alcohol-related problems ranged from 2.3 to 13.2. CONCLUSIONS: Clinically significant BDD symptoms are relatively common in adolescence and young adulthood, particularly in females. The low occurrence of BDD symptoms in adolescent boys may indicate sex differences in age of onset and/or etiological mechanisms. BDD symptoms are moderately heritable in young people and associated with an increased risk for co-existing neuropsychiatric and alcohol-related problems. PMID- 29486815 TI - Implications of a school outbreak of multidrug-resistant tuberculosis in Northern China. AB - In this study, we identified a multidrug-resistant tuberculosis (MDR-TB) outbreak in a high school in northern China. The aim of this work was to describe TB transmission, drug resistance and treatment outcomes for this patient cluster. In January 2017, pulmonary TB was identified in a 17-year-old boy in northern China. Subsequently, a total of 11 TB cases were identified during 6-month follow-up of attendees of the same school. Of five students with latent TB infection (LTBI) receiving isoniazid preventive therapy (IPT), two pulmonary TB cases (40.0%) emerged in March and April, for an active case rate not significantly different from that of the non-IPT group (4/16, 25.0%, P = 0.598). All TB patients were first treated with a standardised first-line treatment regimen administered by the local TB hospital, with 11 of 12 active TB patients exhibiting poor treatment outcomes. Further data demonstrated that all nine patient isolates collected during this outbreak were MDR-TB and shared a common genotypic profile. In conclusion, our data demonstrate that diagnostic delay for the index MDR-TB case of this outbreak played a primary role in transmission of MDR-TB infection within a school setting. Importantly, IPT failed to prevent progression of MDR-TB from LTBI to active TB. PMID- 29486816 TI - Spontaneous regression of severe aortic coarctation in trisomy 18. AB - Spontaneous regression of severe aortic coarctation with ductus dependency has not been reported. We experienced a case of trisomy 18 with spontaneous regression of severe aortic coarctation complicated by ventricular septal defect and patent ductus arteriosus. The aortic isthmus diameter was 1.2 mm at birth. After 5 months, it increased to 4.5 mm, and the shape of the isthmus was fully normalised. PMID- 29486817 TI - Henry Darger and the Aronburg mystery. PMID- 29486818 TI - Predictors of retention in care in HIV-infected patients in a large hospital cohort in Italy. AB - Retention in care is a key feature of the cascade of continuum of care, playing an important role in achieving therapeutic success and being crucial for reduction of HIV transmission. The aim of this study was to evaluate the rate of retention in care in a large referral centre in the North of Italy and to identify predictors associated with failed retention. All new HIV-infected subjects were consecutive enrolled from 1 January 2008 to 31 December 2014. Demographics, immune-virological status, hepatitis co-infection and timing of initiation of combined antiretroviral therapy (cART) data were collected at baseline and at the time of last observation. Failed retention in care was defined as lack of laboratory data, clinical visits and drug dispensation for more than 6 months from the last visit. Cox regression analysis was used. Multivariate analysis of variables with P<0.05 in univariate analysis was performed. We enrolled 269 patients (mean age 46.1 years). Males were 197 (73%), Italian 219 (81%) with mean length of disease of 5.1 years. cART was prescribed for 257 patients (95%). The rate of retention in care was 78.4% and the rate of virological suppression was 75%. Predictors of being loss to follow-up were foreign origin (P = 0.048), CD4+ count <200/mmc (P = 0.001) and not being treated for HIV infection (P = 0.0004). Predictors of cART efficacy were shorter duration of HIV infection and baseline HIV-RNA <100 000 copies/ml. These findings underline the necessity to improve retention in care by identifying groups at increased risk of being loss to follow-up. Retention in care of vulnerable population is crucial to reach 90-90-90 UNAIDS endpoint. PMID- 29486819 TI - Ketamine as anaesthesia for ECT: is there room to improve a gold standard treatment? AB - One meta-analysis of ketamine anaesthesia for electroconvulsive therapy found no improvement of end-point antidepressant outcomes; another meta-analysis with a broader range of included trials found that ketamine improved both early and late outcomes. If ketamine anaesthesia is useful, researchers may need to look for benefits earlier during the treatment course. Declaration of interest None. PMID- 29486820 TI - Impact of cholinesterase inhibitors or memantine on survival in adults with Down syndrome and dementia: clinical cohort study. AB - BACKGROUND: There is little evidence to guide pharmacological treatment in adults with Down syndrome and Alzheimer's disease. Aims To investigate the effect of cholinesterase inhibitors or memantine on survival and function in adults with Down syndrome and Alzheimer's disease. METHOD: This was a naturalistic longitudinal follow-up of a clinical cohort of 310 people with Down syndrome diagnosed with Alzheimer's disease collected from specialist community services in England. RESULTS: Median survival time (5.59 years, 95% CI 4.67-6.67) for those on medication (n = 145, mainly cholinesterase inhibitors) was significantly greater than for those not prescribed medication (n = 165) (3.45 years, 95% CI 2.91-4.13, log-rank test P<0.001). Sequential assessments demonstrated an early effect in maintaining cognitive function. CONCLUSIONS: Cholinesterase inhibitors appear to offer benefit for people with Down syndrome and Alzheimer's disease that is comparable with sporadic Alzheimer's disease; a trial to test the effect of earlier treatment (prodromal Alzheimer's disease) in Down syndrome may be indicated. Declaration of interest A.S. has undertaken consulting for Ono Pharmaceuticals, outside the submitted work. Z.W. has received a consultancy fee and grant from GE Healthcare, outside the submitted work. PMID- 29486822 TI - Challenges and mental health needs of women in prison. AB - The world population of women and girls in prison is increasing. Evidence points to high rates of mental health problems. Approaches to these problems vary and include both psychiatric epidemiology and gender-sensitive understanding and intervention. Prison environments and women prisoners' needs are complex and demand gender-aware care in view of women's vulnerability and histories of trauma. Declaration of interest A.B. was a clinical director of the offender care services at Central and North West London National Health Service (NHS) Foundation Trust until August 2016, with responsibility for several women's prison healthcare services in London and the South East, and is currently clinical director of NHS England London Health in Justice Clinical Network, paid as a salary one day a week. PMID- 29486823 TI - Psychotic major depression: challenges in clinical practice and research. AB - Psychotic major depression is an under-researched and under-identified disorder. We highlight the major challenges both in clinical practice and in conducting research with people with this disorder. We also suggest which major issues need addressing to move treatment and knowledge of this disorder forward. Declaration of interest M.H. and A.H.Y. both report grants from the National Institute for Health Research (NIHR). PMID- 29486827 TI - Correspondence. PMID- 29486828 TI - Gender, power and mental illness. PMID- 29486829 TI - Influenza vaccine effectiveness in preventing hospitalisation of individuals 60 years of age and over with laboratory-confirmed influenza, Valencia Region, Spain, influenza season 2016/17. AB - IntroductionSeasonal influenza vaccination is widely recommended for people with risk factors, especially for people who are elderly. However, influenza vaccine effectiveness (IVE) varies year after year because of the variable antigenic composition of the circulating viruses and the vaccine composition. Methods: We summarise the results of IVE and the impact of previous vaccination among subjects 60 years of age and over in a multicentre prospective study in the Valencia Hospital Surveillance Network for the Study of Influenza and Respiratory Viruses Disease (VAHNSI) in Spain. We applied the test-negative design taking laboratory-confirmed influenza as outcome and vaccination status as exposure. Information about potential confounders was obtained from clinical registries or directly from patients. Results: Adjusted IVE was 19% (95% confidence interval (CI): -15 to 43). For patients vaccinated in the current season but not in the two previous seasons, effectiveness was 49% (95% CI: -20 to 78) and for patients vaccinated in the current and any of two previous seasons, effectiveness was 29% (95% CI: -3 to 52). For those patients not vaccinated in the current season but vaccinated in any of the two previous seasons, effectiveness was 53% (95% CI: 8 to 76). Conclusions: Our data show a low vaccine effectiveness for the 2016/17 influenza season. PMID- 29486830 TI - Interim estimate of influenza vaccine effectiveness in hospitalised children, Hong Kong, 2017/18. AB - We conducted a hospital-based test-negative study in Hong Kong to estimate influenza vaccine effectiveness (VE) for the winter of 2017/18. The interim analysis included data on 1,078 children admitted between 4 December 2017 and 31 January 2018 with febrile acute respiratory illness and tested for influenza. We estimated influenza VE at 66% (95% confidence interval (CI): 43-79) overall, and 65% (95% CI: 40-80) against influenza B, the dominant virus type (predominantly B/Yamagata). PMID- 29486833 TI - Antimicrobial sponge prepared by hydrophobically modified chitosan for bacteria removal. AB - Hydrophobically modified chitosan (HMCS) prepared by reacting chitosan with dodecyl aldehyde can generate very stable foam when dissolved in mild acidic condition under vigorous mechanical stirring. A durable and lightweight (density of 32 mg/ml) sponge was obtained by freeze-drying the stably formed HMCS foam. In addition to the cationic nature of chitosan, the grafted C12 alkyl chains were also able to help HMCS sponge for capturing E. coli cells (~4.0 * 108 cells/mg sponge) by intercalating into the outer membrane of E. coli cells. E. coli cells captured on HMCS sponge were found to be mostly dead and easily released into the bulk solution so that the active surface could be continuously regenerated for capturing and killing the rest of alive cells. In comparison with its counterpart (chitosan sponge), HMCS sponge maintained a higher operational stability for the removal of E. coli cells. After 5 repeated cells removal operation, the removal capacity of HMCS sponge could be regenerated back to >90% by thorough washing with ethanol. PMID- 29486834 TI - Mechanical reinforcement of gellan gum polyelectrolyte hydrogels by cationic polyurethane soft nanoparticles. AB - Novel mechanically reinforced nanocomposite hydrogels (NCHs) were developed based on methacrylated gellan gum (MGG) and cationic polyurethane nanoparticles (CPUNs) through a green chemical approach. A series of NCHs were synthesized by the incorporation of CPUNs with weight ratios of 0, 10, 30 and 50 w/w% into the MGG solution, with two different methacrylation degrees (1.2, 5.6%). The chemical structure, morphology, mechanical properties, stimuli-responsivity and cytotoxicity of synthesized NCHs were investigated. Analysis of the hydrogels mechanical testing demonstrated that the addition of CPUNs affords the significant increase in compressive properties. Meanwhile, the formulation of NCH containing the MGG with lower methacrylation degree and 30 w/w% CPUNs showed the highest mechanical properties. Furthermore, equilibrium swelling ratio of the hydrogels decreased by CPUNs addition. Finally, it is worth mentioning that NCHs showed no significant toxicity to human dermal fibroblast cells (HDFs) which idealize them as the suitable hydrogels for biomedical applications. PMID- 29486835 TI - Chemical structure of a partially 3-O-methylated mannofucogalactan from edible mushroom Grifola frondosa. AB - An unusual heteropolysaccharide was isolated from the fruiting bodies of the medicinal mushroom Grifola frondosa, via successive cold aqueous extraction, followed by fractionation through freeze-thawing, precipitation with Fehling solution and dialysis using a membrane with a size exclusion cut-off of 500 kDa. Its chemical structure was determined based on total acid hydrolysis, methylation analysis and NMR studies. The mannofucogalactan had a molar mass of 15.9 * 103 g mol-1, which was determinate by HPSEC-MALLS. This heteropolymer showed to have a main chain of (1 -> 6)-linked alpha-d-Galp partially substituted at O-2 by 3-O alpha-d-mannopyranosyl-alpha-l-fucopyranosyl groups and in a minor proportion with alpha-l-Fucp single-unit side chains. Moreover, the presence of 3-O-Me-Galp units could also be observed in the main chain of the G. frondosa mannofucogalactan. PMID- 29486836 TI - NMR study on the stabilization and chiral discrimination of sulforaphane enantiomers and analogues by cyclodextrins. AB - Sulforaphane (SFN), a phytochemical isolated from broccoli, is an important antitumoral compound with additional beneficial effect on other important diseases. However, the chemical instability of SFN has hampered its clinical use. In order to circumvent this problem, we report the first comparative study on the inclusion complexes of SFN and SFN homologues with different cyclodextrins by NMR spectroscopy. From this study it has been shown that alpha-CD is the most indicated cyclodextrin for the stabilization of SFN and SFN homologues, and that the highest affinity constant is that of the isothiocyanate obtained from the wasabi. Furthermore, the study of the inclusion complexes of alpha-CD and the non natural SFN and analogues with S absolute configuration at sulfur shows for the first time that alpha-CD is able to discriminate between the two enantiomers, with the natural R enantiomers forming the inclusion complexes with higher affinity. PMID- 29486831 TI - Efficiency of different control measures for preventing carbapenemase-producing enterobacteria and glycopeptide-resistant Enterococcus faecium outbreaks: a 6 year prospective study in a French multihospital institution, January 2010 to December 2015. AB - An infection control programme was implemented in a 21,000-bed multihospital institution for controlling the spread of carbapenemase-producing Enterobacteriaceae (CPE) and glycopeptide-resistant Enterococcus faecium (GRE), classified as 'emergent extensively drug-resistant bacteria' (eXDR) in France. We evaluated factors associated with outbreaks occurrence (n = 103), which followed 901 eXDR introductions (index case followed or not by secondary cases) from 2010 to 2015. In univariate analysis, knowing that patients had been hospitalised abroad, bacterial species (GRE vs CPE, as well as the CPE Klebsiella pneumoniae compared with the other Enterobacteriaceae species) and type of measures implemented within the first 2 days of hospitalisation were associated with outbreaks occurrence, but not the type of wards where carriers were hospitalised, nor the eXDR colonisation or infection status. In multivariate analysis, occurrence of outbreaks was significantly lower when contact precautions (odds ratio (OR): 0.34; 95% confidence interval (CI): 0.22-0.54) and even more when dedicated nursing staff (OR: 0.09; 95% CI: 0.02-0.39) were implemented around eXDR index cases within the first 2 days of hospitalisation (p < 10 - 3). GRE introductions were more frequently associated with occurrence of outbreaks than CPE (OR: 3.58; 95% CI: 2.32-5.51, p < 10 - 3). A sustained and coordinated strategy is efficient to limit the spread of eXDR at the scale of a large health institution. PMID- 29486837 TI - Exo-enzyme like degradation of a polysaccharide by an inorganic solid acid catalyst. AB - Inulin is a beta(1 -> 2) linked linear fructose polymer, the reducing end of which is capped by a glucose residue. Upon dissolution in aqueous HCl the polymer is statistically split. During the reaction progress the ratio of glucose to fructose increases and the concentration of sucrose, as an intermediate product, goes through a maximum. However, when the splitting is performed on a dealuminated faujasite zeolite, the ratio of glucose to fructose is constant and equal to the average degree of polymerization; sucrose does not appear as intermediate product. This behavior is explained by a sequential splitting starting from the end of the polymer (exo-mechanism). If the glucose or fructose end is preferred is unknown. Adsorption studies of the polymer fragments show that the polymer enters the pore mouth of the zeolite with a penetration depth limited to the length of maximal 3 saccharide units. The protons in that surface region are 4-5 times more catalytically active than those in HCl. PMID- 29486838 TI - Cellulose nanofiber board. AB - A cellulose nanofiber board (CNF-board) with a nominal thickness of 3 mm was fabricated without adhesive or additive. To provide comparison, a cellulose fiber board (CF-board) was also fabricated. A novel cold pre-press apparatus was made to dewater highly absorbent CNF gel prior to drying. A mild drying condition in the vacuum oven at 70 degrees C and 0.005 MPa was enough to provide the CNF board with a density of 1.3 g/cm3 thanks to its self-densification capability. Unlike the CF-board, the fabricated CNF-board had a high water-activated dimensional recovery ratio (averagely 96%) during the five cyclic wetting-drying process. The flexural and tensile strengths of CNF-board obtained were 162 MPa and 85 MPa, respectively. The corresponding values for CF-board were 28 MPa and 11 MPa, respectively. The specific flexural and tensile strengths of CNF-board obtained were higher than those of CF-board as well as some other traditional wood-based composites, polymers and structural ASTM A36 steel. PMID- 29486839 TI - Corrigendum to "Pyrolytic and kinetic characteristics of platycodon grandiflorum peel and its cellulose extract" [Carbohydr. Polym. 117 (6 march 2015) 644-649]. PMID- 29486840 TI - The isolation, structural characterization and anti-osteosarcoma activity of a water soluble polysaccharide from Agrimonia pilosa. AB - A homogenous polysaccharide (APP), with a molecular weight of 120 kDa, was isolated from the dried aerial parts of Agrimonia pilosa. Gas chromatography (GC) and GC-MS analysis revealed that APP has a backbone of 1,3-linked Glcp and 1,3, 6 linked Glcp, and branched with 1-linked Glcp terminal along the main chain in a relative ratio of 2:1:1. We investigated the response of human osteosarcoma U-2 OS cells to APP treatment. MTT result showed that APP significantly inhibited cell viability in a concentration dependent manner via induction of apoptotic death in U-2 OS cells, as determined by annexin V/propidium iodide (PI) staining. Western blot analysis also indicated that APP CRA increased in Bax/Bcl-2 ratios by up-regulating Bax expression and triggered the release of cytochrome c from mitochondria into the cytoplasm. Moreover, APP supplement induced the activation of caspase-3, and -9, but not caspase-8 in U-2 OS cells. Likewise, APP administration significantly suppressed tumor growth in BALB/C nude mice bearing U-2 OS xenograft tumors. All these results indicate that APP-induced apoptosis is associated with the activation of a caspase-3-mediated mitochondrial pathway. PMID- 29486841 TI - Transglutaminase-treated conjugation of sodium caseinate and corn fiber gum hydrolysate: Interfacial and dilatational properties. AB - This study compliments previous work where peroxidase was successfully used to crosslink corn fiber gum (CFG) with bovine serum albumin and improve CFG's emulsifying properties. Herein, an alternative type of enzyme, transglutaminase, was used to prepare conjugates of CFG and sodium caseinate. Additionally, the CFG was partially hydrolyzed by sulfuric acid and its crosslinking pattern with caseinate was evaluated. The interfacial crosslinking degree between caseinate and CFG increased after hydrolysis according to high performance size exclusion chromatography. The equilibrium interfacial tension of CFG hydrolysate-caseinate conjugate was lower than that of CFG-caseinate conjugate as the rearrangement rate of the CFG hydrolysate-caseinate conjugate was higher. The dilatational modulus of CFG hydrolysate decreased from that of CFG. PMID- 29486842 TI - Anatase titania coated CNTs and sodium lignin sulfonate doped chitosan proton exchange membrane for DMFC application. AB - Anatase titania coated CNTs (TCNTs) and sodium lignin sulfonate (SLS) were introduced to chitosan membrane to improve the conductivity based on extra proton transfer channels built by TCNTs and sulfonate groups supplied by SLS. Water uptake, mechanical properties, oxidation stability and methanol-rejecting property of composite membranes were characterized. The results show that TCNTs and SLS doped membranes have enhanced conductivity and the sample with 5% TCNTs and 2% SLS doped (CS/TCNT-5/SLS-2) achieved a conductivity of 0.0367 S cm-1 at room temperature and 0.0647 S cm-1 at 60 degrees C, which is much higher than pure chitosan membrane. Moreover, with TCNTs incorporation, the mechanical properties, oxidation stability and methanol-rejecting property also improved. Overall, selectivity of CS/TCNT-5/SLS-2 sample achieved 28.2 * 104 S s cm-3 which is much higher than 3.8 * 104 S s cm-3 of pure chitosan membrane. Thus, with enhanced properties, chitosan composite membrane could be promising as proton exchange membrane (PEM) in the use of direct methanol fuel cell (DMFC). PMID- 29486843 TI - Readily dispersible antimicrobial Ag-SiO2 Janus particles and their application on cellulosic fabric. AB - Silver-silica (Ag-SiO2) Janus particles with varying functionalities i.e. amine, thiol and epoxy on the exposed surface of SiO2 particles were synthesized and explored for their antimicrobial activity. Due to their easy dispersibility, Janus particles with silver nanoparticles (AgNPs) of diameter ~3 nm showed much lower minimum bactericidal concentration (MBC) as compared to conventional isotropic AgNPs powder having AgNPs of almost similar diameter. The isotropic AgNPs and functionalized Ag-SiO2 Janus particles were attached on cotton fabric using exhaustion method followed by curing. The treated fabrics were tested for their antimicrobial activity and wash durability. Ag-SiO2 Janus particles, due to the presence of various functionalities on one-half of their surface, could be attached to cellulosic substrates for imparting durable antimicrobial property. PMID- 29486844 TI - Novel biorenewable composite of wood polysaccharide and polylactic acid for three dimensional printing. AB - Hemicelluloses, the second most abundant polysaccharide right after cellulose, are in practice still treated as a side-stream in biomass processing industries. In the present study, we report an approach to use a wood-derived and side-stream biopolymer, spruce wood hemicellulose (galactoglucomannan, GGM) to partially replace the synthetic PLA as feedstock material in 3D printing. A solvent blending approach was developed to ensure the even distribution of the formed binary biocomposites. The blends of hemicellulose and PLA with varied ratio up to 25% of hemicellulose were extruded into filaments by hot melt extrusion. 3D scaffold prototypes were successfully printed from the composite filaments by fused deposition modeling 3D printing. Combining with 3D printing technique, the biocompatible and biodegradable feature of spruce wood hemicellulose into the composite scaffolds would potentially boost this new composite material in various biomedical applications such as tissue engineering and drug-eluting scaffolds. PMID- 29486845 TI - Flaxseed mucilage: A natural stabilizer in stirred yogurt. AB - Today, there is much interest in the use of natural ingredients in the food industry. Flaxseed mucilage (FSM) stands out for its health benefits and functional characteristics. The effect of FSM and its combination with carboxymethylcellulose (CMC) on quality properties of stirred yogurt were investigated. The addition of FSM and FSM + CMC to stirred yogurt increased the viscosity and decreased syneresis. Addition of FSM decreased the cohesiveness and increased the adhesiveness of the stirred yogurt, while its combination with CMC leads to decreased adhesiveness, increased cohesiveness and springiness. The gumminess and hardness of yogurt were reduced when supplemented with FSM and FSM + CMC. Sensory attributes were influenced by FSM and FSM + CMC; however, these were not deteriorated significantly during 21 days storage at 4 degrees C. FSM has the potential as a natural stabilizer to improve the texture of stirred yogurt. PMID- 29486846 TI - Agarose-based biomaterials for tissue engineering. AB - Agarose is a natural polysaccharide polymer having unique characteristics that give reason to consider it for tissue engineering applications. Special characteristics of agarose such as its excellent biocompatibility, thermo reversible gelation behavior and physiochemical features support its use as a biomaterial for cell growth and/or controlled/localized drug delivery. The resemblance of this natural carbohydrate polymer to the extracellular matrix results in attractive features that bring about a strong interest in its usage in the field. The scope of this review is to summarize the extensive researches addressing agarose-based biomaterials in order to provide an in-depth understanding of its tissue engineering-related applications. PMID- 29486847 TI - Development of active packaging material based on cellulose acetate butyrate/polyethylene glycol/aryl ammonium cation modified clay. AB - Active packaging is one of the interesting concepts in food industry which extend the shelf-life of the food products. The purpose of this work was to develop nontoxic antimicrobial nanocomposite films. Benzyltrimethylammonium chloride modified montmorillonite (BMMT) were used as nano-filler and the prepared BMMT was characterized using Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and thermogravimetric analysis. Polyethylene glycol (PEG) plasticized cellulose acetate butyrate (CAB) films with different ratios of PEG and CAB was prepared and it was found that the 20 wt% PEG in CAB matrix (CBP20) gave optimal results in terms of mechanical properties. BMMT was mixed with CBP20 in different proportions to prepare nanocomposites. 3 wt% BMMT loaded nanocomposite gave best in terms of the barrier and mechanical properties. The storage modulus, thermal stability, glass transition, and melting temperature of the nanocomposites increased with the loading of 1, 3, and 5 wt% of BMMT. Furthermore, these nanocomposites showed nontoxic and antimicrobial behavior. PMID- 29486848 TI - Engineering sodium alginate-based cross-linked beads with high removal ability of toxic metal ions and cationic dyes. AB - Sodium alginate (SA) beads with ultrahigh adsorption capacity were prepared via hydrogen bonds between SA and 2-acrylamido-2-methylpropa-1-propanesulfonic acid (AMPS), and the AMPS was then post-cross-linked to manufacture SA/PAMPS beads. The equilibrium adsorption capacities of methylene blue (MB) and Pb2+ for the SA/PAMPS10 beads were 2977 and 2042 mg/g, respectively. Although the SA beads exhibited higher equilibrium adsorption capacities of MB and Pb2+ than those of the SA/PAMPS10 beads, the SA/PAMPS10 beads had better mechanical property and higher stability. The pseudo-second-order kinetic model and the Langmuir isotherm described the adsorption processes of the SA/PAMPS10 beads for MB well. In addition, the SA/PAMPS10 beads could be reused with stable adsorption capacity for at least three cycles. The beads also had excellent performances on absorbing methylene violet and other heavy metal ions (Cu2+, Cd2+ and Ni2+). Therefore, the SA-based beads with high adsorption capacity might be good candidates for industrial pollutant treatments. PMID- 29486849 TI - Preparation of new GO-based slide ring hydrogel through a convenient one-pot approach as methylene blue absorbent. AB - Slide ring hydrogels (SRHG) with supramolecular structures are a new class of hydrogels that contrary to the traditional hydrogels comprise dynamic cross linking points. Herein, we reported on the fabrication of a new slide ring hydrogel through a very convenient one-pot approach. In this regard, isocyanate functionalized GO was synthesized and used as a stopper as well as cross-linker in the presence of a polypseudorotaxane of cyclodextrin threaded on poly(ethylene glycol) (PR). The surface of the resulting SRHG modified via graft polymerization with polyacrylamide (PAAm) and its application as a new type of absorbent for wastewater treatment was studied. Due to its porous structure and its high content of surface functional groups, the synthesized hydrogel was able to efficiently remove cationic dye methylene blue (MB) from wastewater in a short time. The maximum adsorption capacity of the resulting hydrogel was 92.3 mg/g which exhibited an almost 100% increment as compared to that of untreated GO. The adsorption mechanism of MB was also investigated. The kinetic data, obtained at the optimum pH 7, were fitted well with the pseudo-second-order model. Results from degradation and recycling experiments toward MB showed that the SRHG was stable and reusable. PMID- 29486850 TI - Remodeling of the cardiovascular circulation in fetuses of mothers with diabetes: A fetal computational model analysis. AB - AIMS: Myocardial structural and functional abnormalities are known to occur in fetuses of mothers with diabetes mellitus (FMDM). The main aim of this investigation was to explore the cardiovascular circulatory patterns in FMDM using a validated lumped computational model of the cardiovascular system. METHODS: This was a multi-institutional study involving FMDM compared to fetuses of maternal controls (FC). Fetal echocardiographic Doppler data from left and right ventricular outflow tracts, aortic isthmus, middle cerebral and umbilical arteries were fitted into a validated fetal circulation computational model to estimate patient-specific placental and vascular properties. Non-parametric comparisons were made between resistances, compliances and flows in the brain and placenta in FMDM and FC. RESULTS: Data from 23 FMDM and 31 FC were fitted into the model. In FMDM, compared to FC, placental relative resistance was lower (0.59 +/- 0.50 versus 0.91 +/- 0.41; p < .05) with higher brain relative resistance (2.36 +/- 1.65 versus 1.60 +/- 0.85; p < .05). Middle cerebral artery flow was lower in FMDM than FC (0.12 +/- 0.14 vs. 0.27 +/- 0.21 ml/min; p 0.04) with a lower cerebral-placental flow ratio. Combined stroke volume was lower in FMDM (3.65 +/- 2.05 ml) than FC (4.97 +/- 2.45 ml) (p 0.04). CONCLUSIONS: Blood flow is redistributed in FMDM to the placenta, away from the brain. This alteration may play a role in the postnatal health of these fetuses. PMID- 29486851 TI - Placental pathologic changes and perinatal outcomes in placenta previa. AB - INTRODUCTION: Placenta previa is a condition in which the placenta implants in the poorly vascularized lower uterine segment, which may result in inadequate uteroplacental perfusion, in turn, adversely affect the neonatal outcome. Abnormal placentation may also lead to severe postpartum hemorrhage as placenta separation proceeds. We aimed to evaluate the differences in placental histopathology and perinatal outcomes in pregnancies complicated with placenta previa and controls. METHOD: We undertook a retrospective case-control study of 93 pregnancies with placenta previa and 81 controls between 2011 and 2017. RESULTS: Gross findings of the placenta showed that the placentas in placenta previa had significantly higher mean large chorionic plate diameters (18.5 +/- 3.2 vs 17.5 +/- 2.6 cm, P = .0298), chorionic plate areas (218.4 +/- 62.9 cm2 vs 198.7 +/- 56.0 cm2, P = .0344), and marginal cord insertion (19.8% vs 8.6%, P = .0411) than control groups. Placental histopathological findings showed that placentas in placenta previa was significantly associated with maternal underperfusion, including villous infarction (50.5% vs 25.9%, P = .0009) and increased intervillous fibrin deposition (38.7% vs 7.4%, P < .0001). Also, women in the placenta previa group had a higher rate of abnormally invasive placenta and severe postpartum hemorrhage. However, placenta previa was not associated with the increased risk of neonatal mortality and morbidity. DISCUSSION: Abnormal placentation into the poorly vascularized lower uterine segment induces compensatory placental growth and increased surface area in response to reduced placental perfusion, which was consistent with the histopathological findings of coagulative necrosis of chorionic villi and fibrin deposition in the intervillous space. The morphological changes occurring in placenta previa may have important roles in maintaining adequate uteroplacental-fetal perfusion, which may prevent adverse neonatal outcomes. PMID- 29486852 TI - Soluble ST2, a preeclampsia-related cytokine receptor, is transported bi directionally across the placenta. AB - INTRODUCTION: We aimed to elucidate whether soluble ST2 (sST2), a preeclampsia (PE)-related cytokine, in the maternal or fetal circulation could be transported to the other circulatory system across the placenta. METHODS: A placental perfusion model in a closed system was established and optimized. HPLC was performed to determine the dynamics of antipyrine levels in the perfusate. Placentas (n = 18) collected from healthy controls and PE patients were perfused without additional treatment or with added sST2 in the maternal or fetal circulation. The concentration of sST2 in the perfusate samples was quantified by ELISA. RESULTS: Monitoring of the antipyrine levels were used as a quality control and showed each placenta established successfully. In the untreated group, sST2 could be produced by the placenta and enter into both the maternal and fetal circulations, and significantly higher levels were detected in the maternal circulation. In placentas perfused with additional sST2 in the maternal circulation, a similar trend was observed as for the untreated placentas. When sST2 was added to the fetal circulation, increased sST2 was detected in the maternal circulation. Compared with the healthy controls, significantly elevated sST2 in the maternal side of PE patients were detected. CONCLUSION: Soluble ST2 could be bi-directionally transported across placentas. It was an active process that maintained a higher level of sST2 in the maternal circulation. Furthermore, the significant increase of sST2 in the maternal blood of PE patients was due to an impaired placental barrier as a result of PE. PMID- 29486854 TI - Pregestational diabetes increases fetoplacental vascular resistance in rats. AB - INTRODUCTION: Diabetes is a well-known risk factor in pregnancy. Because maternal diabetes involves oxidative stress that is also induced by chronic hypoxia and can alter vascular function, we sought to determine the effects of chronic maternal hyperglycemia on the fetoplacental vasculature in rats and to compare it with the effects of chronic hypoxia. METHODS: Diabetes was induced in female rats by a streptozotocin injection at a neonatal age. When these animals reached adulthood, their hyperglycemia was confirmed and they were inseminated. Half of them were exposed to hypoxia (10% O2) for the last week before the delivery. One day before the expected date of delivery, one of their placentae was isolated and perfused. RESULTS: Fetoplacental vascular resistance was increased equally by experimental diabetes, chronic hypoxia, and their combination. Fetoplacental perfusion pressure-flow analysis suggested increased resistance in the small vessels in chronic hypoxia and in larger vessels in diabetes. Fetal plasma nitrotyrosine levels, measured as a marker of peroxynitrite (reaction product of superoxide and nitric oxide), mirrored the differences in fetoplacental resistance, suggesting a causative role. Fetoplacental vasoconstrictor reactivity to acute hypoxic stimuli was reduced similarly in all groups. Fasudil, a strong vasodilator agent, reduced fetoplacental vascular resistance similarly in all groups, suggesting that for the observed differences among the groups, the changes in vascular morphology were more important than variances in vascular tone. DISCUSSION: Maternal diabetes increases fetoplacental vascular resistance to a similar extent as chronic hypoxia. These stimuli are not additive. Changes in vascular tone are not responsible for these effects. PMID- 29486853 TI - Oxidative stress induces senescence and sterile inflammation in murine amniotic cavity. AB - OBJECTIVE: A physiologic increase of reactive oxygen species (ROS) is observed through pregnancy. ROS-induced damage to major cellular elements, specifically protein peroxidation, can lead to fetal and placental tissue senescence and inflammation often associated with normal parturition. The purpose of this study was to examine the effects of oxidative stress (OS) in inducing changes in proteins, senescence, and sterile inflammation in pregnant mice. METHODS: CD-1 mice (n = 5/group) on day 14 of gestation were subjected to minilaparotomy and the uterine horn between gestational sacs was injected with the following: saline (control), cigarette smoke extract (CSE) CSE diluted in saline and CSE + SB 203580 (SB) (a p38 mitogen-activated protein kinase (MAPK) inhibitor). Mice were sacrificed on day 18, and amniotic sacs, placentas and amniotic fluid (AF) were collected. Protein damage was evaluated by immunostaining for 3-Nitrotyrosine modified proteins (3-NT). Activation of prosenescence p38MAPK was evaluated by western blot. Senescence features, beta-galactosidase (SA-beta-Gal) and AF inflammatory cytokines were analyzed by immunostaining and multiplex luminex based immunoassays, respectively. The data were analyzed by ANOVA and Tukey's test, p < .05 was used for significance. RESULTS: Amniotic sac from CSE-treated animals showed significant protein peroxidation compared to control as indicated by 3-NT staining. CSE activated p38MAPK phosphorylation in amniotic sac but not in placenta. Membrane p38MAPK activation was reduced after treatment with SB. CSE increased fetal membrane senescence (staining for SA-beta-Gal) and increased AF concentrations of all evaluated cytokines. High inflammation correlated with pup loss and a decrease in placental weight. Treatment with p38MAPK inhibitor (SB) minimized damages, senescence and sterile inflammation. CONCLUSION: OS induction by cigarette smoke extract cause fetal tissue protein damage, p38MAPK activation, senescence and sterile inflammation in the amniotic cavity of mouse. Prevention of p38MAPK activation can be a novel approach to prevention of adverse pregnancy outcomes related to OS induced premature senescence. PMID- 29486855 TI - The placental component and neonatal outcome in singleton vs. twin pregnancies complicated by gestational diabetes mellitus. AB - OBJECTIVE: We aimed to compare placental histopathological lesions and neonatal outcome in singleton vs. twin pregnancies complicated by gestational diabetes mellitus (GDM). METHODS: Maternal characteristics, neonatal outcomes, and placental histopathology reports of pregnancies complicated by GDM, between 1/2008-10/2016, were reviewed. Results were compared between singletons (singleton group) and dichorionic-diamniotic twins (twin group). Placental lesions were classified as placental weight abnormalities, maternal and fetal vascular malperfusion lesions (MVM, FVM), inflammatory lesions, and lesions associated with chronic villitis. LGA was defined as birth-weight >=90th percentile. Composite adverse neonatal outcome was defined as one or more early neonatal complications. RESULTS: Compared with the twin group (n = 57), the singleton group (n = 228) was characterized by higher gestational-age (38.6 +/- 0.9 vs. 35.1 +/- 1.8 weeks, p < 0.001) and a higher rate of insulin treatment (32.9% vs. 17.5%, p = 0.023). Placentas from the singleton group were characterized by higher rates of MVM lesions (54.4% vs. 30.7%, p < 0.001), villitis of unknown etiology (VUE, 5.7% vs. 0.9%, p = 0.040), villous immaturity (10.1% vs. 0.9%, p = 0.001), and placental weight <10th percentile (16.7% vs. 8.8%, respectively, p = 0.049). Using multivariable regression analysis, MVM (aOR = 2.2, 95% CI = 1.6-4.1), VUE (aOR = 1.2, 95% CI = 1.1-2.1), villous immaturity (aOR = 2.3, 95% CI 1.8-7.6), and placental weight <10th percentile (aOR = 1.1, 95% CI = 1.02-1.6), were the only lesions associated with singleton pregnancies. Composite adverse neonatal outcome was more common in the twin group (54.3% vs. 14.0%, p < 0.001) and it was associated only with lower GA (aOR = 3.7, 95% CI 2.1 7.3). CONCLUSION: Higher rate of placental weight <10th percentile, MVM lesions, villous immaturity, and VUE characterize GDM singleton pregnancy as compared to twins GDM gestation, suggesting different placental alterations in the diabetic environment. PMID- 29486856 TI - ARHGEF11 affecting the placental insulin signaling pathway in fetal macrosomia of normal glucose tolerance pregnant women. AB - INTRODUCTION: Fetal macrosomia has confirmed be related to multiple labor complications and metabolism syndromes later in life. However, the mechanism of fetal macrosomia in normal glucose tolerance (NGT) and gestational diabetes mellitus (GDM) pregnant women is still obscure. This study aimed to investigate the mechanism of Rho guanine nucleotide exchange factor 11 (ARHGEF11) and the insulin signaling pathway in placenta affecting fetal overgrowth in NGT and GDM pregnant women. METHODS: Eighty-nine pregnant women with paired antepartum BMI were recruited and divided into four groups: NGT with normal birth weight (NGT-N, n = 30) or macrosomia (NGT-M, n = 22) and GDM with normal birth weight (GDM-N, n = 22) or macrosomia (GDM-M, n = 15). Placenta tissue was collected to examine the expression of ARHGEF11, ROCK1, the phosphorylation of Tyr612 IRS-1 (p-Y612), Ser307 IRS-1 (p-S307), PI3K, AKT, pAKT, GLUT4 and S6K. RESULTS: Gene expression of ARHGEF11, ROCK1, p-S307 and S6K in placenta was significantly increased in the NGT-M group (p < .05). The protein density of ARHGEF11 and ROCK1 was positively correlated with birth weight (p < .001) in the NGT groups. p-Y612, PI3K, pAKT and GLUT4 were significantly decreased in NGT-M, GDM-N and GDM-M group (p < .05). But there was no statistical difference between the two GDM groups. DISCUSSION: ARHGRF11 inhibited the insulin signaling pathway in placenta may participated in fetal macrosomia in NGT pregnant women. The insulin signaling pathway was suppressed in GDM placenta, but was not closely related to fetal macrosomia, indicated different mechanism in fetal overgrowth in NGT and GDM pregnant women. PMID- 29486857 TI - Defining Mechanisms of Transcranial Magnetic Stimulation as a Treatment for Depression Through Neuroimaging: Progress and Challenges. PMID- 29486858 TI - Linking Neuroimaging-Based Predictive Biomarkers and Mechanisms. PMID- 29486859 TI - Time-Varying Analyses of Imaging Data: Capturing the Role of Network Dynamics in Psychopathology. PMID- 29486860 TI - Too Much Is Still Not Enough, When Talking About Cortisol. PMID- 29486861 TI - The Wrong Kind of Connections: Cannabis Dependence and Subcortical Hyperconnectivity. PMID- 29486863 TI - Machine Learning for Precision Psychiatry: Opportunities and Challenges. AB - The nature of mental illness remains a conundrum. Traditional disease categories are increasingly suspected to misrepresent the causes underlying mental disturbance. Yet psychiatrists and investigators now have an unprecedented opportunity to benefit from complex patterns in brain, behavior, and genes using methods from machine learning (e.g., support vector machines, modern neural network algorithms, cross-validation procedures). Combining these analysis techniques with a wealth of data from consortia and repositories has the potential to advance a biologically grounded redefinition of major psychiatric disorders. Increasing evidence suggests that data-derived subgroups of psychiatric patients can better predict treatment outcomes than DSM/ICD diagnoses can. In a new era of evidence-based psychiatry tailored to single patients, objectively measurable endophenotypes could allow for early disease detection, individualized treatment selection, and dosage adjustment to reduce the burden of disease. This primer aims to introduce clinicians and researchers to the opportunities and challenges in bringing machine intelligence into psychiatric practice. PMID- 29486862 TI - Neuroimaging Mechanisms of Therapeutic Transcranial Magnetic Stimulation for Major Depressive Disorder. AB - Research into therapeutic transcranial magnetic stimulation (TMS) for major depression has dramatically increased in the last decade. Understanding the mechanism of action of TMS is crucial to improve efficacy and develop the next generation of therapeutic stimulation. Early imaging research provided initial data supportive of widely held assumptions about hypothesized inhibitory or excitatory consequences of stimulation. Early work also indicated that while TMS modulated brain activity under the stimulation site, effects at deeper regions, in particular, the subgenual anterior cingulate cortex, were associated with clinical improvement. Concordant with earlier findings, functional connectivity studies also demonstrated that clinical improvements were related to changes distal, rather than proximal, to the site of stimulation. Moreover, recent work suggests that TMS modulates and potentially normalizes functional relationships between neural networks. An important observation that emerged from this review is that similar patterns of connectivity changes are observed across studies regardless of TMS parameters. Though promising, we stress that these imaging findings must be evaluated cautiously given the widespread reliance on modest sample sizes and little implementation of statistical validation. Additional limitations included use of imaging before and after a course of TMS, which provided little insight into changes that might occur during the weeks of stimulation. Furthermore, as studies to date have focused on depression, it is unclear whether our observations were related to mechanisms of action of TMS for depression or represented broader patterns of functional brain changes associated with clinical improvement. PMID- 29486864 TI - Mnemonic Discrimination Deficits in First-Episode Psychosis and a Ketamine Model Suggests Dentate Gyrus Pathology Linked to N-Methyl-D-Aspartate Receptor Hypofunction. AB - BACKGROUND: Converging evidence from neuroimaging and postmortem studies suggests that hippocampal subfields are differentially affected in schizophrenia. Recent studies report dentate gyrus dysfunction in chronic schizophrenia, but the underlying mechanisms remain to be elucidated. Here we sought to examine if this deficit is already present in first-episode psychosis, and if N-methyl-D aspartate receptor hypofunction, a putative central pathophysiological mechanism in schizophrenia, experimentally induced by ketamine, would result in a similar abnormality. METHODS: We applied a mnemonic discrimination task selectively taxing pattern separation in two experiments: 1) a group of 23 first-episode psychosis patients and 23 matched healthy volunteers and 2) a group of 19 healthy volunteers before and during a ketamine challenge (0.27 mg/kg over 10 minutes, then 0.25 mg/kg/hour for 50 minutes, 0.01 mL/s). We calculated response bias corrected pattern separation and recognition scores. We also examined the relationships between task performance and symptom severity as well as ketamine levels. RESULTS: We report a deficit in pattern separation but not recognition performance in first-episode psychosis patients compared with healthy volunteers (p = .04) and in volunteers during the ketamine challenge compared with baseline (p = .003). Exploratory analyses revealed no correlation between task performance and Repeatable Battery for the Assessment of Neuropsychological Status total scores or positive symptoms in first-episode psychosis patients, or with ketamine serum levels. CONCLUSIONS: We observed a mnemonic discrimination deficit but intact recognition in both datasets. Our findings suggest a tentative mechanistic link between dentate gyrus dysfunction in first-episode psychosis and N-methyl-D aspartate receptor hypofunction. PMID- 29486865 TI - Motivational Deficits in Schizophrenia Are Associated With Reduced Differentiation Between Gain and Loss-Avoidance Feedback in the Striatum. AB - BACKGROUND: The current study was designed to test the hypothesis that motivational deficits in schizophrenia (SZ) are tied to a reduced ability to differentially signal gains and instances of loss-avoidance in the brain, leading to reduced ability to form adaptive representations of expected value. METHODS: We administered a reinforcement learning paradigm to 27 medicated SZ patients and 27 control subjects in which participants learned three probabilistic discriminations. In regions of interest in reward networks identified a priori, we examined contrasts between trial types with different expected values (e.g., expected gain-nonmonetary) and between outcomes with the same prediction error valence but different experienced values (e.g., gain-loss-avoidance outcome, miss loss outcome). RESULTS: Both whole-brain and region of interest analyses revealed that SZ patients showed reduced differentiation between gain and loss-avoidance outcomes in the dorsal anterior cingulate cortex and bilateral anterior insula. That is, SZ patients showed reduced contrasts between positive prediction errors of different objective values in these areas. In addition, we observed significant correlations between gain-loss-avoidance outcome contrasts in the ventral striatum and ratings for avolition/anhedonia and between expected gain nonmonetary contrasts in the ventral striatum and ventromedial prefrontal cortex. CONCLUSIONS: These results provide further evidence for intact prediction error signaling in medicated SZ patients, especially with regard to loss-avoidance. By contrast, components of frontostriatal circuits appear to show reduced sensitivity to the absolute valence of expected and experienced outcomes, suggesting a mechanism by which motivational deficits may emerge. PMID- 29486866 TI - Decoupling of Brain Temperature and Glutamate in Recent Onset of Schizophrenia: A 7T Proton Magnetic Resonance Spectroscopy Study. AB - BACKGROUND: Converging evidence suggests that cerebral metabolic and cellular homeostasis is altered in patients with recent onset of schizophrenia. As a possible marker of metabolic changes that might link to altered neurotransmission, we used proton magnetic resonance spectroscopy to estimate brain temperature, and we evaluated its relationship to a relevant metabolite, glutamate, within this study population. METHODS: Using proton magnetic resonance spectroscopy at 7T, 20 patients with recent onset (<=24 months after first psychotic symptoms) of schizophrenia and 20 healthy control subjects were studied. We measured levels of N-acetylaspartate and glutamate and estimated brain temperature in a noninvasive manner. RESULTS: Healthy control subjects showed a significant negative correlation between glutamate and brain temperature in the anterior cingulate cortex. In contrast, the physiological correlation between glutamate and brain temperature was lost in patients with recent onset of schizophrenia. CONCLUSIONS: This study supports the hypothesized disrupted relationship between brain metabolism and neurotransmission in patients with recent onset of schizophrenia. The findings include mechanistic implications that are to be followed up in both preclinical and clinical studies. PMID- 29486867 TI - Rostral Anterior Cingulate Cortex Morphology Predicts Treatment Response to Internet-Based Cognitive Behavioral Therapy for Depression. AB - BACKGROUND: Rostral and subgenual anterior cingulate cortex (rACC and sgACC) activity and, to a lesser extent, volume have been shown to predict depressive symptom improvement across different antidepressant treatments. This study extends prior work by examining whether rACC and/or sgACC morphology predicts treatment response to Internet-based cognitive behavioral therapy (iCBT) for major depressive disorder. This is the first study to examine neural predictors of response to iCBT. METHODS: Hierarchical linear modeling tested whether pretreatment rACC and sgACC volumes predicted depressive symptom improvement during a six-session (10-week) randomized clinical trial of iCBT (n = 35) versus a monitored attention control condition (n = 38). Analyses also tested whether pretreatment rACC and sgACC volumes differed between patients who achieved depression remission versus patients who did not remit. RESULTS: Larger pretreatment right rACC volume was a significant predictor of greater depressive symptom improvement in iCBT even when controlling for demographic (age, gender, race) and clinical (baseline depression, anhedonia, and anxiety) variables previously linked to treatment response. In addition, pretreatment right rACC volume was larger among patients receiving iCBT whose depression eventually remitted relative to patients who did not remit. Corresponding analyses in the monitored attention control group and for the sgACC were not significant. CONCLUSIONS: rACC volume before iCBT demonstrated incremental predictive validity beyond clinical and demographic variables previously found to predict symptom improvement. Such findings may help inform our understanding of the mediating anatomy of iCBT and, if replicated, may suggest neural targets to augment treatment response (e.g., via modulation of rACC function). PMID- 29486868 TI - Aberrant Time-Varying Cross-Network Interactions in Children With Attention Deficit/Hyperactivity Disorder and the Relation to Attention Deficits. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is thought to stem from aberrancies in large-scale cognitive control networks. However, the exact nature of aberrant brain circuit dynamics involving these control networks is poorly understood. Using a saliency-based triple-network model of cognitive control, we tested the hypothesis that dynamic cross-network interactions among the salience, central executive, and default mode networks are dysregulated in children with ADHD, and we investigated how these dysregulations contribute to inattention. METHODS: Using functional magnetic resonance imaging data from 140 children with ADHD and typically developing children from two cohorts (primary cohort = 80 children, replication cohort = 60 children) in a case-control design, we examined both time-averaged and dynamic time-varying cross-network interactions in each cohort separately. RESULTS: Time-averaged measures of salience network-centered cross-network interactions were significantly lower in children with ADHD compared with typically developing children and were correlated with severity of inattention symptoms. Children with ADHD displayed more variable dynamic cross-network interaction patterns, including less persistent brain states, significantly shorter mean lifetimes of brain states, and intermittently weaker cross-network interactions. Importantly, dynamic time varying measures of cross-network interactions were more strongly correlated with inattention symptoms than with time-averaged measures of functional connectivity. Crucially, we replicated these findings in the two independent cohorts of children with ADHD and typically developing children. CONCLUSIONS: Aberrancies in time-varying engagement of the salience network with the central executive network and default mode network are a robust and clinically relevant neurobiological signature of childhood ADHD symptoms. The triple-network neurocognitive model provides a novel, replicable, and parsimonious dynamical systems neuroscience framework for characterizing childhood ADHD and inattention. PMID- 29486869 TI - Neural Signaling of Cortisol, Childhood Emotional Abuse, and Depression-Related Memory Bias. AB - BACKGROUND: Cortisol has potent effects on learning and neuroplasticity, but little is known about its effects on negative memory biases in depression. Animal models show that aversive caregiving alters effects of glucocorticoids (primarily corticosterone in rodents and cortisol in primates) on learning and neuroplasticity into adulthood. METHODS: We investigated whether history of childhood emotional abuse (EA) moderated effects of cortisol administration (CORT) versus placebo on emotional memory formation in depression. Participants included 75 unmedicated women with varying levels of depression severity and/or EA history. In a double-blind crossover investigation, we used functional magnetic resonance imaging to measure effects of CORT (vs. placebo) on neural function during emotional memory formation. RESULTS: CORT eliminated the well known relationship between depression severity and negative memory bias, a finding explained by EA severity. For women with a history of severe EA, CORT reduced depression-related negative memory bias and normalized recall for pleasant stimuli. EA severity also moderated CORT effects on neural function: in women with history of severe EA, CORT increased activation in the supplementary motor area during viewing of unpleasant relative to pleasant pictures. Additionally, supplementary motor area activation predicted reduced negative bias for pictures encoded during CORT. CONCLUSIONS: These results suggest that increasing cortisol signaling may be neurocognitively beneficial in depressed women with a history of maltreatment. The findings corroborate prior research suggesting that presence or absence of adverse caregiving is etiologically important in depression. These findings suggest potential neurocognitive mechanisms of therapeutics targeting cortisol signaling, which show promise in treating affective disorders. PMID- 29486873 TI - Emerging viruses of zoonotic and veterinary importance. PMID- 29486870 TI - Subcortical Local Functional Hyperconnectivity in Cannabis Dependence. AB - BACKGROUND: Cannabis abuse (CA) has been associated with psychopathology, including negative emotionality and higher risk of psychosis, particularly with early age of initiation. However, the mechanisms underlying this association are poorly understood. Because aberrant dopamine signaling is implicated in cannabis associated psychopathology, we hypothesized that regular CA would be associated with altered resting-state functional connectivity in dopamine midbrain-striatal circuits. METHODS: We examined resting-state brain activity of subcortical regions in 441 young adults from the Human Connectome Project, including 30 subjects with CA meeting DSM-IV criteria for dependence and 30 control subjects matched on age, sex, education, body mass index, anxiety, depression, and alcohol and tobacco usage. RESULTS: Across all subjects, local functional connectivity density hubs in subcortical regions were most prominent in ventral striatum, hippocampus, amygdala, dorsal midbrain, and posterior-ventral brainstem. As hypothesized, subjects with CA showed markedly increased local functional connectivity density relative to control subjects, not only in ventral striatum (where nucleus accumbens is located) and midbrain (where substantia nigra and ventral tegmental nuclei are located) but also in brainstem and lateral thalamus. These effects were observed in the absence of significant differences in subcortical volumes and were most pronounced in individuals who began cannabis use earliest in life and who reported high levels of negative emotionality. CONCLUSIONS: Together, these findings suggest that chronic CA is associated with changes in resting-state brain function, particularly in dopaminergic nuclei implicated in psychosis but that are also critical for habit formation and reward processing. These results shed light on neurobiological differences that may be relevant to psychopathology associated with cannabis use. PMID- 29486871 TI - An Examination of Behavioral and Neuronal Effects of Comorbid Traumatic Brain Injury and Alcohol Use. AB - BACKGROUND: Chronic alcohol use disorders (AUDs) and traumatic brain injury (TBI) are highly comorbid and share commonly affected neuronal substrates (i.e., prefrontal cortex, limbic system, and cerebellum). However, no studies have examined how combined physical trauma and heavy drinking affect neurocircuitry relative to heavy drinking alone. METHODS: The current study investigated whether comorbid AUDs and mild or moderate TBI (AUDs+TBI) would negatively affect maladaptive drinking behaviors (n = 90 AUDs+TBI; n = 62 AUDs) as well as brain structure (i.e., increased atrophy; n = 62 AUDs+TBI; n = 44 AUDs) and function (i.e., activation during gustatory cue reactivity; n = 55 AUDs+TBI; n = 37 AUDs) relative to AUDs alone. RESULTS: Participants reported a much higher incidence of trauma (59.2%) compared with the general population. There were no differences in demographic and clinical measures between groups, suggesting that they were well matched. Although maladaptive drinking behaviors tended to be worse for the AUDs+TBI group, effect sizes were small and not statistically significant. Increased alcohol-cue reactivity was observed in bilateral anterior insula and orbitofrontal cortex, anterior cingulate cortex, medial prefrontal cortex, posterior cingulate cortex, dorsal striatum, thalamus, brainstem, and cerebellum across both groups relative to a carefully matched appetitive control. However, there were no significant differences in structural integrity or functional activation between AUDs+TBI and AUDs participants, even when controlling for AUD severity. CONCLUSIONS: Current results indicate that a combined history of mild or moderate TBI was not sufficient to alter drinking behaviors and/or underlying neurocircuitry at detectable levels relative to heavy drinking alone. Future studies should examine the potential long-term effects of combined alcohol and trauma on brain functioning. PMID- 29486874 TI - Goats singly heterozygous for PRNP S146 or K222 orally inoculated with classical scrapie at birth show no disease at ages well beyond 6 years. AB - Scrapie is a transmissible spongiform encephalopathy of sheep and goats, and scrapie eradication programs in many parts of the world rely on strong genetic resistance to classical scrapie in sheep. However, the utility of putative resistance alleles in goats has been a focus of research because goats can transmit scrapie to sheep and may serve as a scrapie reservoir. Prior work showed that disease-free survival time was significantly extended in orally inoculated goats singly heterozygous for prion amino acid substitutions S146 or K222, but average durations were only around 3 years post-inoculation. The aim of this study was to investigate whether extended survival would exceed 6 years, which represents the productive lifetimes of most commercial goats. While all control homozygotes were clinically affected by an average of <2 years, none of the NS146 or QK222 goats developed clinical scrapie or had PrPSc-positive rectal biopsies. Several NS146 and QK222 goats developed other conditions unrelated to scrapie, but tissue accumulation of PrPSc was not detected in any of these animals. The NS146 heterozygotes have remained disease-free for an average of 2734days (approximately 7.5 years), the longest duration of any classical scrapie challenge experiment with any genotype to date. The QK222 heterozygotes have remained disease-free for an average of 2450days (approximately 6.7 years), the longest reported average duration for QK222 goats challenged with classical scrapie. This research is ongoing, but the current results demonstrate S146 and K222 confer strong resistance to classical scrapie in goats. PMID- 29486875 TI - Domesticated animals as hosts of henipaviruses and filoviruses: A systematic review. AB - Bat-borne viruses carry undeniable risks to the health of human beings and animals, and there is growing recognition of the need for a 'One Health' approach to understand their frequently complex spill-over routes. While domesticated animals can play central roles in major spill-over events of zoonotic bat-borne viruses, for example during the pig-amplified Malaysian Nipah virus outbreak of 1998-1999, the extent of their potential to act as bridging or amplifying species for these viruses has not been characterised systematically. This review aims to compile current knowledge on the role of domesticated animals as hosts of two types of bat-borne viruses, henipaviruses and filoviruses. A systematic literature search of these virus-host interactions in domesticated animals identified 72 relevant studies, which were categorised by year, location, design and type of evidence generated. The review then focusses on Africa as a case study, comparing research efforts in domesticated animals and bats with the distributions of documented human cases. Major gaps remain in our knowledge of the potential ability of domesticated animals to contract or spread these zoonoses. Closing these gaps will be necessary to fully evaluate and mitigate spill-over risks of these viruses, especially with global agricultural intensification. PMID- 29486876 TI - Bias, limits of agreement, and percent errors between acceleromyography and mechanomyography in anesthetized dogs. AB - This study compared measurements of neuromuscular function with mechanomyography (MMG) and acceleromyography (AMG) in nine anesthetized dogs receiving 0.1mg/kg vecuronium intravenously. Train-of-four (TOF) stimulation was applied to each ulnar nerve every 15s. The resulting amplitude of the first twitch (T1) and the TOF ratio were measured with both monitors. The baseline TOF ratio (prior to vecuronium), onset time (time of injection to T1<5%), recovery index (time between T1 values of 25% and 75%) and duration of neuromuscular block (injection to TOF 0.9) were recorded. The MMG TOF ratios when the AMG first reached 0.7 (AMG 0.7) and 0.9 (AMG 0.9) during recovery were also recorded. Values were compared with paired tests and individual errors>25% between monitors were identified for each dog. Bias, limits of agreement (LOA) and percentage error (PE) between methods were calculated from Bland-Altman plots for T1 and TOF ratio for the complete data set, and for TOF>=0.7 during recovery. There were no statistical differences in baseline TOF ratio, onset, recovery index, duration, AMG 0.7 and AMG 0.9. Individual errors>25% were evident in onset, recovery index, AMG 0.7 and AMG 0.9. Overall, T1 and TOF ratio had a small bias, wide LOA and PE>100%. Percent error was reduced to 30% when TOF>=0.7 was analyzed. Although there were no statistical differences between MMG and AMG in any variable of interest, individual discrepancies, wide LOA and high PE suggest that these monitors should not be used interchangeably for serial measurements on the same animals. PMID- 29486877 TI - Use of transfer learning to detect diffuse degenerative hepatic diseases from ultrasound images in dogs: A methodological study. AB - The aim of this methodological study was to develop a deep convolutional neural network (DNN) to detect degenerative hepatic disease from ultrasound images of the liver in dogs and to compare the diagnostic accuracy of the newly developed DNN with that of serum biochemistry and cytology on the same samples, using histopathology as a standard. Dogs with suspected hepatic disease that had no prior history of neoplastic disease, no hepatic nodular pathology, no ascites and ultrasonography performed 24h prior to death were included in the study (n=52). Ultrasonography and serum biochemistry were performed as part of the routine clinical evaluation. On the basis of histopathology, dogs were categorised as 'normal' (n=8), or having 'vascular abnormalities'(n=8), or 'inflammatory'(n=0), 'neoplastic' (n=4) or 'degenerative'(n=32) disease; dogs with 'neoplastic' disease were excluded from further analysis. On cytological evaluation, dogs were categorised as 'normal' (n=11), or having 'inflammatory' (n=0), 'neoplastic' (n=4) or 'degenerative' (n=37) disease. Dogs were categorised as having 'degenerative' (n=32) or 'non-degenerative' (n=16) liver disease for analysis due to the limited sample size. The DNN was developed using a transfer learning methodology on a pre-trained neural network that was retrained and fine-tuned to our data set. The resultant DNN had a high diagnostic accuracy for degenerative liver disease (area under the curve 0.91; sensitivity 100%; specificity 82.8%). Cytology and serum biochemical markers (alanine transaminase and aspartate transaminase) had poor diagnostic accuracy in the detection of degenerative liver disease. The DNN outperformed all the other non-invasive diagnostic tests in the detection of degenerative liver disease. PMID- 29486879 TI - Clinical comparison of the effects of isoflurane or propofol anaesthesia on mean arterial blood pressure and ventilation in dogs undergoing orthopaedic surgery receiving epidural anaesthesia. AB - The aim of this study was to compare the effects on mean arterial pressure (MAP) and ventilation of propofol total IV anaesthesia (TIVA) and isoflurane as anaesthetic maintenance in healthy dogs undergoing orthopaedic surgery, with epidural anaesthesia. Dogs were premedicated IM with dexmedetomidine (4MUg/kg) and methadone (0.3mg/kg), induced with IV propofol (0.65-5mg/kg) and randomly assigned to be maintained with isoflurane (group I) or propofol (group P). Isoflurane end-tidal concentration (EtISO) and propofol infusion rate were adjusted during the surgery to maintain a suitable anaesthetic depth. All dogs received bupivacaine (1mg/kg) and morphine (0.1mg/kg) in the lumbosacral epidural space (total volume 0.2mL/kg). MAP was recorded every 5min during the procedure. Statistical analysis was performed using parametric (Student's t test) and nonparametric (Mann-Whitney U-test, chi-square) tests, as appropriate. Anaesthetic maintenance in groups I and P was accomplished by providing a mean EtISO of 1.12+/-0.15% and a mean propofol infusion rate of 15.0+/-4.7mg/kg/h, respectively. MAP was significantly higher in group P than in group I (92+/ 17mmHg versus 78+/-10mmHg; P=0.021). Eleven dogs in group P and two dogs in group I reached an EtCO2>7.3kPa, requiring mechanical ventilation (P=0.001). In combination with epidural anaesthesia, propofol TIVA improved MAP and is a suitable alternative to isoflurane in orthopaedic surgery of the hind limb in healthy dogs. Nevertheless, since it was associated with increased respiratory depression, mechanical ventilation should be available. PMID- 29486878 TI - African swine fever: A re-emerging viral disease threatening the global pig industry. AB - African swine fever (ASF) recently has spread beyond sub-Saharan Africa to the Trans-Caucasus region, parts of the Russian Federation and Eastern Europe. In this new epidemiological scenario, the disease has similarities, but also important differences, compared to the situation in Africa, including the substantial involvement of wild boar. A better understanding of this new situation will enable better control and prevent further spread of disease. In this article, these different scenarios are compared, and recent information on the pathogenesis of ASF virus strains, the immune response to infection and prospects for developing vaccines is presented. Knowledge gaps and the prospects for future control are discussed. PMID- 29486880 TI - Novel viruses in birds: Flying through the roof or is a cage needed? AB - Emerging viral diseases continue to have a major global impact on human beings and animals. To be able to take adequate measures in case of an outbreak of an emerging disease, rapid detection of the causative agent is a crucial first step. In this review, various aspects of virus discovery are discussed, with a special focus on recently discovered viruses in birds. Novel viruses with a potential major impact have been discovered in domestic and wild bird species in recent years using various virus discovery methods. Only a few studies report the detection of novel viruses in endangered bird species, although increased knowledge about viruses circulating in these species is important. Additional studies focusing on the exact role of a novel virus in disease and on the impact of a novel virus on bird populations are often lacking. Intensive collaboration between different disciplines is needed to obtain useful information about the role of these novel viruses. PMID- 29486881 TI - Lack of effect of a topical regenerative agent on re-epithelialization rate of canine spontaneous chronic corneal epithelial defects: A randomized, double masked, placebo-controlled study. AB - Spontaneous chronic corneal epithelial defects (SCCEDs) are characteristic ulcers in dogs that are refractory to healing. The aim of the study was to evaluate the use of a topical regenerative agent to promote healing of SCCEDs. Nineteen dogs (20 eyes) were randomized to receive either regenerative agent (10 eyes) or placebo (10 eyes) every 48h following corneal debridement, which was repeated 1 week later if the SCCED had not yet healed. The mean+/-standard deviation time to re-epithelialization was 17.3+/-12.8 days for the group treated with a topical regenerative agent and 19.3+/-11.7 days for the group treated with a placebo; the cumulative healing rates were not statistically different (P>0.650). A positive association was found between the initial size of the ulcer and the time to re epithelialization (r=0.555, P=0.011). Although well tolerated by dogs, there was no therapeutic advantage in using a topical regenerative agent for re epithelialization of SCCEDs. PMID- 29486884 TI - Where some things change, others don't. PMID- 29486882 TI - Ultrasonography, computed tomography and magnetic resonance imaging of the bovine metacarpo/metatarsophalangeal joint. AB - The aims of the present study were to describe the normal ultrasonographic, magnetic resonance imaging (MRI) and computed tomographic (CT) appearances of the bovine metacarpo/metatarsophalangeal (MCP/MTP) joints and to assess the normal cross-sectional dimensions of the superficial (SDFT) and deep (DDFT) digital flexor tendons. A systematic ultrasound examination was performed on the MCP/MTP joints of 22 healthy cattle and two bovine cadavers, and the cross-sectional dimensions of the SDFT and DDFT were recorded. The cadaveric MCP/MTP joints (n=8) were scanned using a 16-slice multi-detector CT scanner and a 1.5 Tesla MRI scanner, injected with green latex and sectioned into transverse (n=4), sagittal (n=2) and dorsal (n=2) slices. Ultrasonographic, CT and MRI images were correlated with corresponding findings in anatomical dissections for the distal aspects of the third and fourth metacarpal/metatarsal bones, proximal aspects of the proximal phalanges, proximal sesamoid bones, lateral, common and medial digital extensor tendons, SDFT, DDFT, axial and abaxial collateral ligaments, suspensory, palmar/plantar, interdigital intersesamoidean and interdigital phalangosesamoidean ligaments, and collateral, cruciate and short sesamoidean ligaments. The axial and collateral sesamoidean ligaments could not be evaluated by ultrasonography. The articular cartilage, and the short and cruciate sesamoidean ligaments, were not identified in CT images. The cross-sectional dimensions of the SDFT and DDFT differed significantly between the forelimbs and hind limbs (P<0.05); there were no significant differences between the contralateral limbs. The annotated ultrasonographic, CT and MRI images are intended as a normal reference that could be useful for interpretation of clinical disease in the bovine MCP/MTP joint. PMID- 29486883 TI - Photodynamic therapy and diagnosis: Principles and comparative aspects. AB - Photodynamic therapy (PDT) is an evolving method of treating superficial tumours that is non-invasive and carries minimal risk of toxicity. It combines tumour selective photosensitiser dyes, tissue oxygen and targeted illumination to generate cytotoxic reactive oxygen species (ROS) within the tumour. In addition to directly acting on tumour cells, PDT damages and restricts tumour microvasculature, and causes a local inflammatory response that stimulates an immune response against the tumour. Unlike surgery or radiotherapy, the surrounding extracellular matrix is unaffected by PDT; thus, tissue healing is excellent and PDT seldom causes scars. This, combined with the ease of light application, has made PDT a popular treatment for cancers and pre-cancerous conditions in human beings. Moreover, because photosensitiser dyes are fluorescent and selectively accumulate in tumour tissues, they can additionally be used to visualise and discriminate tumour from normal tissues, thereby improving the accuracy of tumour surgery. In veterinary practice, PDT has been used successfully for treatment of superficial squamous cell carcinomas of the feline nasal planum; urinary tract, urinary bladder and prostate neoplasia in dogs; and equine sarcoids. The purpose of this article is to provide a comparative review of the current literature on PDT in human and veterinary medicine, and to establish a basis for future development of PDT in veterinary medicine. PMID- 29486885 TI - Future challenges of stroke treatment. AB - Posterior circulation stroke accounts for approximately 20% of all ischaemic strokes. Acute basilar artery occlusion (BAO) is one of the most severe conditions, it is associated with death or major disability in more than three quarters of the cases, and its optimal management remains unestablished. Currently, the treatment is based primarily upon consensus, the clinical practice varies widely, and the actual benefit of mechanical thrombectomy has to be fully estimated. Although the recent years have profoundly revolutionized and improved the stroke care, many questions still remain unanswered and will represent the challenges of the next future. PMID- 29486886 TI - Mobile phase effects in reversed-phase and hydrophilic interaction liquid chromatography revisited. AB - Correct adjustment of the mobile phase is equally important as the selection of the appropriate column for the separation of polar compounds in LC. Both solvophobic and selective polar interactions control the retention in the Reversed Phase and Hydrophilic Interaction modes. The retention models describing the effects of the volume fraction of the strong eluent component in binary mobile phases on the sample retention factors apply in a limited mobile phase composition range. We introduced a three-parameter retention model, which provides improved prediction of retention over a broad mobile phase range, under isocratic and gradient elution conditions. The model does not imply any assumptions concerning either adsorption or partition distribution mechanism, but allows estimating retention in pure strong and in pure weak mobile phase components. The experimental retention data for phenolic acids and flavones on several core-shell columns with different types of stationary phases agree with the theory. Many polar columns with important structural hydrophobic moieties show dual retention mechanism, (Reversed Phase in water rich mobile phases and Hydrophilic Interaction at high acetonitrile concentrations). It is possible to select the mobile phase compositions in each of the two modes for separations of samples containing compounds largely differing in polarity. The three-parameter model describes the retention in each mode, with separately determined best-fit parameters. We applied the two-mode model to the retention data of sulfonamides and benzoic acid related compounds on a new polymethacrylate zwitterionic monolithic micro-column. PMID- 29486887 TI - Linear solvation energy relationship (LSER) characterization of the normal phase retention mechanism on hypercrosslinked polystyrenes. AB - Linear solvation energy relationships (LSERs) were applied to retention on hypercrosslinked polystyrene on silica (HC-Tol) to elucidate the type and relative importance of molecular interactions between model solutes and the HC Tol stationary phase. Classical amino phase and another hypercrosslinked phase (5 HGN) were used as reference columns. On both the HC-Tol and amino, polar interactions predominate and contribute to retention. Solute volume V has no impact on retention on the amino column, while V has a slightly negative influence on retention for the HC-Tol column. The differences in coefficient v between the amino and the HC-Tol columns might explain why the HC-Tol is capable of group-type separations. 5-HGN phase has smaller a and b values compared to HC Tol, which means that 5-HGN is not as basic or acidic in terms of hydrogen bonds as is HC-Tol. This suggests that the hydrogen bonding character of the HC-Tol phase arises from its silica substrate. PMID- 29486888 TI - Novel thoracoscopic navigation surgery for neonatal chylothorax using indocyanine green fluorescent lymphography. AB - BACKGROUND: Postoperative chylothorax after surgery for esophageal atresia/tracheoesophageal fistula (TEF) is a rare but serious complication, especially in neonates. This study aimed to identify the thoracic duct and ligate chylous leakage sites, using thoracoscopic navigation of an indocyanine-green (ICG)-based near-infrared (NIR) fluorescence imaging system. METHODS: From November 2014 to April 2017, thoracoscopic intraoperative ICG-NIR imaging was performed in 10 newborns (11 surgeries) with first TEF operation or with persistent postoperative chylothorax after TEF operation. NIR imaging was performed 1h after an inter-toe injection of ICG. Thoracoscopic ligations against the NIR-detected leakage sites were performed with sutures. RESULTS: The thoracic duct or lymphatic leakage was directly visualized in each patient. In 8 surgeries with first thoracoscopic TEF operation, one case had suspected minor chylous leakage without postoperative chylothorax. Another case with no chylous leakage at the first operation resulted in chylothorax at postoperative day 11. In three neonates with postoperative chylothorax, leakage points were detected near the ablation site of the azygos vein during the first operation. These points were properly ligated, and postoperative chylous leakage ceased with no adverse events. CONCLUSIONS: Thoracoscopic ICG-NIR imaging encourages the repair of refractory chylothorax and seems reliable. LEVEL OF EVIDENCE: IV. PMID- 29486889 TI - Battery ingestions in children: Variations in care and development of a clinical algorithm. AB - PURPOSE: To review current management and outcomes of ingested batteries and develop a clinical management algorithm. METHODS: Children <18years old who ingested a battery between 1/2011 and 9/2016 at two tertiary care children's hospitals were reviewed. Demographics, imaging, management and outcomes were analyzed using descriptive statistics, Chi-square and Wilcoxon Rank-sum tests. RESULTS: There were 180 battery ingestions. The median age was 3.9 (range 0.7-18) years, with 78 (43%) males. The most common symptoms were abdominal pain (17%) and nausea/vomiting (14%). Diagnosis was confirmed with plain radiographs in 170 (94%) patients. Locations on imaging were: stomach (37%), small bowel (24%), esophagus (18%), colon (11%), and non-specific location past the gastroesophageal junction (9%). Treatment was dictated by five different subspecialties including surgery (35%), gastroenterology (25%), emergency medicine (19%), primary care/emergency with a consulting service (13%), and otolaryngology (8%). All esophageal batteries (n=33) had an intervention. Interventions included fluoroscopic balloon extraction (6 attempted, 33% retrieval rate), rigid esophagoscopy (26 attempted, 96% retrieval rate), and EGD (6 attempted, 83% retrieval rate). For batteries distal to the gastroesophageal junction 16 (11%) patients had an intervention. Interventions included EGD (13 patients, 69% retrieval), colonoscopy (1 patient, successful retrieval), and abdominal surgery in two patients. CONCLUSION: Isolated batteries that pass the gastroesophageal junction rarely require intervention and can be managed conservatively. Given the variability in managing these patients, we developed an evidence based algorithm. LEVEL OF EVIDENCE: Level 2. STUDY TYPE: Retrospective Study. PMID- 29486890 TI - To create or pull from the shelf? PMID- 29486891 TI - Dynamic Changes of the Mitochondria in Psychiatric Illnesses: New Mechanistic Insights From Human Neuronal Models. AB - Mitochondria play a crucial role in neuronal function, especially in energy production, the generation of reactive oxygen species, and calcium signaling. Multiple lines of evidence have suggested the possible involvement of mitochondrial deficits in major psychiatric disorders, such as schizophrenia and bipolar disorder. This review will outline the current understanding of the physiological role of mitochondria and their dysfunction under pathological conditions, particularly in psychiatric disorders. The current knowledge about mitochondrial deficits in these disorders is somewhat limited because of the lack of effective methods to dissect dynamic changes in functional deficits that are directly associated with psychiatric conditions. Human neuronal cell model systems have been dramatically developed in recent years with the use of stem cell technology, and these systems may be key tools for overcoming this dilemma and improving our understanding of the dynamic changes in the mitochondrial deficits in patients with psychiatric disorders. We introduce recent discoveries from new experimental models and conclude the discussion by referring to future perspectives. We emphasize the significance of combining studies of human neuronal cell models with those of other experimental systems, including animal models. PMID- 29486892 TI - Value of PCR in sonication fluid for the diagnosis of orthopedic hardware associated infections: Has the molecular era arrived? AB - INTRODUCTION: Bone healing disturbance following fracture fixation represents a continuing challenge. We evaluated a novel fully automated polymerase chain reaction (PCR) assay using sonication fluid from retrieved orthopedic hardware to diagnose infection. PATIENTS AND METHODS: In this prospective diagnostic cohort study, explanted orthopedic hardware materials from consecutive patients were investigated by sonication and the resulting sonication fluid was analyzed by culture (standard procedure) and multiplex PCR (investigational procedure). Hardware-associated infection was defined as visible purulence, presence of a sinus tract, implant on view, inflammation in peri-implant tissue or positive culture. McNemar's chi-squared test was used to compare the performance of diagnostic tests. For the clinical performance all pathogens were considered, whereas for analytical performance only microorganisms were considered for which primers are included in the PCR assay. RESULTS: Among 51 patients, hardware associated infection was diagnosed in 38 cases (75%) and non-infectious causes in 13 patients (25%). The sensitivity for diagnosing infection was 66% for peri implant tissue culture, 84% for sonication fluid culture, 71% (clinical performance) and 77% (analytical performance) for sonication fluid PCR, the specificity of all tests was >90%. The analytical sensitivity of PCR was higher for gram-negative bacilli (100%), coagulase-negative staphylococci (89%) and Staphylococcus aureus (75%) than for Cutibacterium (formerly Propionibacterium) acnes (57%), enterococci (50%) and Candida spp. (25%). CONCLUSION: The performance of sonication fluid PCR for diagnosis of orthopedic hardware associated infection was comparable to culture tests. The additional advantage of PCR was short processing time (<5 h) and fully automated procedure. With further improvement of the performance, PCR has the potential to complement conventional cultures. PMID- 29486893 TI - Hinfinity control for time-delay systems with randomly occurring nonlinearities subject to sensor saturations, missing measurements and channel fadings. AB - The Hinfinity control problem for a class of time-delay systems with randomly occurring nonlinearities (RONs) is addressed in this paper. Sensor saturations, missing measurements and channel fadings are governed by random variables obeying the Bernoulli distributions. The measurement output is subject to both data missing and randomly occurring sensor saturations (ROSSs) described by sector nonlinearities as well as the channel fadings caused typically in wireless communication. The aim of the addressed problem is to design a full-order dynamic output-feedback controller such that the closed-loop system is exponentially mean square stable and satisfies the prescribed Hinfinity performance constraint. Sufficient conditions are presented by resorting to intensive stochastic analysis and matrix inequality techniques, which not only guarantee the existence of the desired controller for all possible time-delays, RONs, missing measurements and ROSSs but also lead to the explicit expressions of such controllers. Finally, a numerical example is given to demonstrate the applicability of the proposed control scheme. PMID- 29486894 TI - Asynchronous L1-gain control of uncertain switched positive linear systems with dwell time. AB - In this paper, dwell time (DT) stability, L1-gain performance analysis and asynchronous L1-gain controller design problems of uncertain switched positive linear systems (SPLSs) are investigated. Via a time-scheduled multiple linear co positive Lyapunov function (TSMLCLF) approach, convex sufficient conditions of DT stability and L1-gain performance of SPLSs with interval and polytopic uncertainties are presented. Furthermore, by utilizing the feature that the TSMLCLF keeps decreasing even if the controller is running asynchronously with the system, the asynchronous L1-gain controller design problem of SPLSs with interval and polytopic uncertainties is investigated. Convex sufficient conditions of the existence of time-varying asynchronous state-feedback controller which can ensure the closed-loop system's positivity, stability and L1 gain performance are established, and the controller gain matrices can be calculated instantaneously online. The obtained L1-gain in the paper is standard. All the results are presented in terms of linear programming. A practical example is provided to show the effectiveness of the results. PMID- 29486895 TI - E-cadherin mediated lateral interactions between neighbor cells necessary for collective migration. AB - Collective cell movement is critical in pathological processes such as wound healing and cancer invasion. It entails complex interactions between adjacent cells and between cells-extracellular matrices. Most studies measure the migration patterns and force propagation by placing cells on flat, patterned substrates. The cooperative behavior resulting from cell-cell interactions is not well understood. We have developed a multi-channel microfluidic device that has junctional protein E-cadherin coated onto the sidewalls of the channels that enables the cells' lateral interactions with their neighbors to be studied. Our study reveals that epithelial cells rely on lateral E-cadherin-based adhesions to maintain the cohesion of the group. Cells move faster in narrower channels, but the average velocity along the channels is reduced in E-cadherin coated channels versus non-adhesive channels. We have directly measured the forces in the cross linking protein, alpha-actinin, using FRET sensors during cell migration, and found that higher tension exists at the cell edges adjacent to the walls coated with E-cadherin, the implication being E-cadherin transmits the shear forces but does not provide a driving force for this migration. PMID- 29486896 TI - Effects of a single-session stance-slip perturbation training program on reducing risk of slip-related falls. AB - The purpose of this pilot study was to establish the efficacy and feasibility of a single-session treadmill-based stance-slip perturbation program on preventing slip-related falls while walking over the ground among young adults. Two groups (training vs. control) of healthy young participants were respectively exposed to a treadmill-based stance-slip perturbation training protocol and a placebo training protocol. Post training, both groups experienced an unexpected overground gait-slip. Our results indicated that 28.6% of individuals in the training group and 55.0% of controls fell when responding to the overground slip. In comparison with the control group, the training group exhibited better control over the compensatory step and dynamic stability at the instant immediately prior to recovery touchdown. The improved dynamic stability control in the training group likely resulted from the enhanced capability of harnessing the slip kinematics of the base of support. Dynamic stability did not display any significant group-associated difference at slipping foot touchdown and recovery foot liftoff. This implies that a stance-slip perturbation training protocol with eight slips may not provide enough and very task-specific incentive to the Central Nervous System to form the capability of sufficiently modifying regular gait pattern after an unexpected gait slip. However, given its ease of use, stance-perturbation could be a practical option to train individuals in clinical settings as a simple push or pull could exert a perturbation to a standing individual. The findings from this study provide information for developing future studies based on large-scale samples. PMID- 29486897 TI - Sensitivity, Specificity and Reliability of the RIPASA Score for Diagnosis of Acute Appendicitis in Relation to the Alvarado Score. AB - INTRODUCTION: In order to avoid delay in the diagnosis of acute appendicitis and reduce the margin of error, the use of scales has been used. The aim of this study was to compare the effectiveness of the Alvarado and RIPASA scores in the clinical diagnosis of acute appendicitis and to correlate with the histopathological results. METHODS: Prospective, longitudinal, analytical, comparative and observational study. Patients with abdominal pain syndrome suggestive of acute appendicitis and submitted to surgical intervention were included; the Alvarado and RIPASA scores were simultaneously applied. The pathology report was obtained and the efficacy of both scores for the diagnosis of acute appendicitis was compared. RESULTS: One hundred patients were included. It was shown that the RIPASA score demonstrated greater diagnostic accuracy compared to the Alvarado score, with sensitivity of 98,8% and specificity of 71,4% versus 90,7% and 64,3%, respectively. The RIPASA score showed an area under the curve of 0,88 and the Alvarado scale of 0,80. CONCLUSIONS: The RIPASA score is a more specific, convenient and accurate system than the Alvarado score for the Mexican population. PMID- 29486898 TI - Magnetocardiographic classification and non-invasive electro-anatomical imaging of outflow tract ventricular arrhythmias in recreational sport activity practitioners. AB - Ventricular arrhythmias (VAs) with left bundle-branch-block and inferior axis morphology (LBBB-IA), suggestive of outflow tract (OT) origin, are a challenge in sports medicine because they can be benign or expression of a silent cardiomyopathy. Non-invasive classification is essential to plan ablation strategy if required. We aimed to evaluating magnetocardiographic (MCG) discrimination of OT-VAs site of origin (SoO). MCG and ECG data of 26 sports activity practitioners, with OT-VAs were analyzed. OT-VAs-SoO was classified with discriminant analysis (DA) of 8 MCG parameters and with invasively-validated ECG algorithms. MCG inverse source-localization merged with magnetic resonance (CMR) provided three-dimensional electro-anatomical imaging (MCG 3D-EAI). ECG classification was univocal in 73%. MCG-DA differentiated right ventricular OT from aortic sinus cusp VAs, with 94.7% accuracy. MCG 3D-EAI confirmed OT-VAs-SoO in CMR images. In cases undergoing ablation, MCG 3D-EAI was confirmed by CARTO 3D EAI. MCG-DA improves non-invasive classification of OT-VAs-SoO. Further comparison with interventional results is required. PMID- 29486899 TI - Origins of the power of the low frequency heart rate variability bandwidth. AB - PURPOSE: We hypothesized that heart period (HP) variability in the low frequency (LF) band is due to transient fluctuations of about 10 s in HP sequences, associated with fluctuations in blood pressure. METHODS: 10 healthy subjects, mean age 36 y, had HP and blood pressure acquired for 10 min each. Nonrandom HP fluctuations (ripples) lasting 6.7-20 s were detected using time-scrambled surrogate sequences as controls. RESULTS: Ripples were 99 +/- 40 ms in amplitude, in concatenates 23.4 +/- 7.4 s long. They co-occurred with similar blood pressure ripples with amplitudes 5 +/- 5 mm Hg, correlating with them with r2 = 0.68 +/- 0.10, slope 23.9 +/- 10.8 ms/mm Hg, at an optimum lag of 2.16 +/- 0.63 beats. A second HP structure consisting of transient tachycardias of 140 +/- 53 ms lasting 15.1 +/- 6.1 occurred singly. Together the two structures contributed 84% +/- 8% of the total power in the LF band. CONCLUSION: The LF band is caused by two types of HP structures that occur at discrete times. PMID- 29486900 TI - Venous Thromboembolic Disease and Cancer: A Challenge for Clinicians. PMID- 29486901 TI - Corrigendum to "Slime mould: The fundamental mechanisms of biological cognition" [BioSystems 165 (2018) 57-70]. PMID- 29486902 TI - LncRNA MIAT facilitated BM-MSCs differentiation into endothelial cells and restored erectile dysfunction via targeting miR-200a in a rat model of erectile dysfunction. AB - BACKGROUND: Bone-marrow derived mesenchymal stem cells (BM-MSCs) implantation effectively restored rats' erectile dysfunction (ED). Long noncoding RNA (LncRNA) myocardial infarction-associated transcript (MIAT) has been reported to play an important role in regulating endothelial cells (ECs) function via vascular endothelial growth factor (VEGF) that induced BM-MSCs differentiation into ECs. However, the molecular functions and biological roles of lncRNA MIAT in ED remained unclear. METHODS: The rat model of ED was established. Quantitative real time PCR (qRT-PCR) and western blotting were used to detect the expression of lncRNA MIAT, von Willebrand factor (vWF), vascular endothelial cadherin (VE cadherin), endothelial NO synthase (eNOS) and VEGF following BM-MSCs transfection. Erectile function was evaluated by intra-cavernous pressure/mean artery pressure (ICP/MAP). Furthermore, RNA immunoprecipitation (RIP) assay and RNA pull down as well as luciferase reporter assay were carried out to examine the interaction among lncRNA MIAT, miR-200a and VEGF. RESULTS: BM-MSCs restored ED by upregulating lncRNA MIAT. LncRNA MIAT was upregulated in a time-dependent manner during BM-MSCs differentiation into ECs. LncRNA MIAT regulated VEGF via targeting miR-200a, thereby promoting BM-MSCs differentiation into ECs. LncRNA MIAT knockdown in vivo abolished the effect of BM-MSCs on ED. CONCLUSION: LncRNA MIAT promoted BM-MSCs differentiation into ECs and restored ED via miR-200a. PMID- 29486903 TI - Choroidal Microvasculature Dropout Is Associated with Progressive Retinal Nerve Fiber Layer Thinning in Glaucoma with Disc Hemorrhage. AB - OBJECTIVE: We used OCT angiography (OCT-A) to investigate parapapillary choroidal microvasculature dropout (MvD) in glaucomatous eyes with or without disc hemorrhage (DH), and the association with changes in retinal nerve fiber layer (RNFL) thickness. DESIGN: An observational case-control study. PARTICIPANTS: Eighty-two open-angle glaucoma (OAG) eyes with DH and 68 OAG eyes without DH that underwent at least 4 serial OCT examinations were included. METHODS: MvD was defined as complete loss of microvasculature within the choroidal layer of the parapapillary region, as revealed by standardized assessment of OCTA-derived density maps of the vessels of the optic nerve head. The circumferential extent of MvD was measured on OCT-A images. The RNFL thinning rate was calculated using a linear mixed model. Kaplan-Meier survival analysis and the log-rank test were used to compare the cumulative risk ratio of progression between groups stratified by DH and MvD. MAIN OUTCOME MEASURES: MvD detection rate, the extent of MvD as measured by the MvD angle, and RNFL thinning rate. RESULTS: MvD was found in 38 (46.3%) eyes with DH at the prior DH site, which was found in only 20 (29.4%) eyes without DH, which was significantly different between the 2 groups (P = 0.025). Patients with progressive glaucoma exhibited significantly more MvD than the stable patients in both DH and no-DH groups. There were statistically significant differences between groups subdivided by the presence of DH and MvD as assessed by Kaplan-Meier analysis (log-rank test, P < 0.001). The angle of MvD was significantly greater in eyes with recurrent DH compared with eyes with single DH. Presence of DH, recurrent DH, and presence of MvD were factors associated with progressive RNFL thinning. CONCLUSIONS: We found that MvD was frequent in progressive OAG eyes on the choroidal map of OCT-A, which was more frequently found at the prior DH locations in eyes with DH. This means that observing the presence of MvD using OCT-A may provide a biomarker for glaucoma progression, especially in eyes with DH. PMID- 29486904 TI - Importance of carbon dioxide in the critical patient: Implications at the cellular and clinical levels. AB - Important recent insights have emerged regarding the cellular and molecular role of carbon dioxide (CO2) and the effects of hypercapnia. The latter may have beneficial effects in patients with acute lung injury, affording reductions in pulmonary inflammation, lessened oxidative alveolar damage, and the regulation of innate immunity and host defenses by inhibiting the expression of inflammatory cytokines. However, other studies suggest that CO2 can have deleterious effects upon the lung, reducing alveolar wound repair in lung injury, decreasing the rate of reabsorption of alveolar fluid, and inhibiting alveolar cell proliferation. Clearly, hypercapnia has both beneficial and harmful consequences, and it is important to determine the net effect under specific conditions. The purpose of this review is to describe the immunological and physiological effects of carbon dioxide, considering their potential consequences in patients with acute respiratory failure. PMID- 29486905 TI - Alternative statistical methods and their application to research in intensive care setting. AB - In nested case-control studies, sampling of controls is usually done by density of incidence and pairing. With regard to the classic control cases studies, nested ones are more efficient, allow the calculation of the incidence of the disease and they have more internal validity due to the lower presence of bias. Competitive risks techniques can be used if we study different types of events and focus on the time and type of the first event. Recursive partitioning is a type of multivariate analysis whose purpose is the construction of classification algorithms, and it is especially useful when there are a large number of predictive variables with complex relationships with the event. PMID- 29486906 TI - Thermotherapy in calcaneal infection due to Prototheca wickerhamii. PMID- 29486907 TI - Timing of PROTein INtake and clinical outcomes of adult critically ill patients on prolonged mechanical VENTilation: The PROTINVENT retrospective study. AB - BACKGROUND & AIMS: Optimal protein intake during critical illness is unknown. Conflicting results on nutritional support during the first week of ICU stay have been published. We addressed timing of protein intake and outcomes in ICU patients requiring prolonged mechanical ventilation. METHODS: We retrospectively collected nutritional and clinical data on the first 7 days of ICU admission of adult critically ill patients, who were mechanically ventilated in our ICU for at least 7 days and admitted between January 1st 2011 and December 31st 2015. Based on recent literature, patients were divided into 3 protein intake categories, <0.8 g/kg/day, 0.8-1.2 g/kg/day and >1.2 g/kg/day. Our primary aim was to identify the optimum protein dose and timing related to the lowest 6 month mortality. Secondary endpoints were ventilation duration, need for renal replacement therapy (RRT), ICU length of stay (LOS) and mortality and hospital LOS and mortality. RESULTS: In total 455 patients met the inclusion criteria. We found a time-dependent association of protein intake and mortality; low protein intake (<0.8 g/kg/day) before day 3 and high protein intake (>0.8 g/kg/day) after day 3 was associated with lower 6-month mortality, adjusted HR 0.609; 95% CI 0.480-0.772, p < 0.001) compared to patients with overall high protein intake. Lowest 6-month mortality was found when increasing protein intake from <0.8 g/kg/day on day 1-2 to 0.8-1.2 g/kg/day on day 3-5 and >1.2 g/kg/day after day 5. Moreover, overall low protein intake was associated with the highest ICU, in hospital and 6-month mortality. No differences in ICU LOS, need for RRT or ventilation duration were found. CONCLUSIONS: Our data suggest that although overall low protein intake is associated with the highest mortality risk, high protein intake during the first 3-5 days of ICU stay is also associated with increased long-term mortality. Therefore, timing of high protein intake may be relevant for optimizing ICU, in-hospital and long-term mortality outcomes. PMID- 29486908 TI - Update of pathophysiology and management of diabetic kidney disease. AB - Diabetic kidney disease (DKD) is a major cause of morbidity and mortality in patients with diabetes mellitus and the leading cause of end-stage renal disease in the world. The most characteristic marker of DKD is albuminuria, which is associated with renal disease progression and cardiovascular events. Renal hemodynamics changes, oxidative stress, inflammation, hypoxia and overactive renin-angiotensin-aldosterone system (RAAS) are involved in the pathogenesis of DKD, and renal fibrosis plays the key role. Intensified multifactorial interventions, including RAAS blockades, blood pressure and glucose control, and quitting smoking, help to prevent DKD development and progression. In recent years, novel agents are applied for preventing DKD development and progression, including new types of glucose-lowering agents, pentoxifylline, vitamin D analog paricalcitol, pyridoxamine, ruboxistaurin, soludexide, Janus kinase inhibitors and nonsteroidal minerocorticoid receptor antagonists. In this review, recent large studies about DKD are also summarized. PMID- 29486909 TI - Midterm Survivorship and Patient Satisfaction of Robotic-Arm-Assisted Medial Unicompartmental Knee Arthroplasty: A Multicenter Study. AB - BACKGROUND: Studies have showed improved accuracy of lower leg alignment, precise component position, and soft-tissue balance with robotic-assisted unicompartmental knee arthroplasty (UKA). No studies, however, have assessed the effect on midterm survivorship. Therefore, the purpose of this prospective, multicenter study was to determine midtem survivorship, modes of failure, and satisfaction of robotic-assisted medial UKA. METHODS: A total of 473 consecutive patients (528 knees) underwent robotic-arm-assisted medial UKA surgery at 4 separate institutions between March 2009 and December 2011. All patients received a fixed-bearing, metal-backed onlay tibial component. Each patient was contacted at minimum 5-year follow-up and asked a series of questions to determine survival and satisfaction. Kaplan-Meier method was used to determine survivorship. RESULTS: Data were collected for 384 patients (432 knees) with a mean follow-up of 5.7 years (5.0-7.7). The follow-up rate was 81.2%. In total, 13 revisions were performed, of which 11 knees were converted to total knee arthroplasty and in 2 cases 1 UKA component was revised, resulting in 97% survivorship. The mean time to revision was 2.27 years. The most common failure mode was aseptic loosening (7/13). Fourteen reoperations were reported. Of all unrevised patients, 91% was either very satisfied or satisfied with their knee function. CONCLUSION: Robotic arm-assisted medial UKA showed high survivorship and satisfaction at midterm follow-up in this prospective, multicenter study. However, in spite of the robotic technique, early fixation failure remains the primary cause for revision with cemented implants. Comparative studies are necessary to confirm these findings and compare to conventional implanted UKA and total knee arthroplasty. PMID- 29486910 TI - Effects of Seating Load Magnitude on Incremental Cyclic Fretting Corrosion in 5 degrees 40' Mixed Alloy Modular Taper Junctions. AB - BACKGROUND: Mechanically assisted crevice corrosion of modular tapers continues to be a concern in total joint arthroplasties. A surgical factor that may affect taper fretting corrosion during cyclic loading is seating load magnitude. In this study, modular head-neck taper junctions were seated, capturing load displacement, over a range of axially oriented loads, and electrochemical and micromotion data were captured during short-term incremental cyclic fretting corrosion (ICFC) tests. The hypothesis is low seating loads result in greater motion and fretting corrosion in ICFC tests. The effect of assembly load on pull off force post-ICFC testing was also evaluated. METHODS: The study employed custom-built test fixtures which measured head-neck micromotion and an electrochemical chamber to monitor electrochemical reactions. Head-neck motion measurements were captured using 2 noncontact differential variable reluctance transducers mounted to the head. Seating experiments ranged from 1000 to 8000 N. RESULTS: Significant differences due to seating loads were reported in seating displacement, ICFC subsidence, and fretting current at 4000 N cyclic load. Seating load decreased but did not eliminate currents. Fretting onset load remained fixed (approximately 1200 N) for tapers seated above 2000 N. Fretting subsidence was negligible for seating loads of 4000 N or higher, and increased subsidence was observed below 4000 N. CONCLUSION: This short-term test method evaluated the acute performance of modular implants which were assembled under various loads and demonstrated the link between seating loads, fretting motions, and electrochemical reactions. While increased seating loads reduced fretting corrosion and taper subsidence, it did not prevent fretting corrosion even at 8 kN seating. PMID- 29486911 TI - Hydrogen and methane production in a two-stage anaerobic digestion system by co digestion of food waste, sewage sludge and glycerol. AB - In this study, hydrogen and methane production from co-digestion of food waste (FW), sewage sludge (SS) and raw glycerol (GL) was evaluated in a two-stage acidogenesis-methanogenesis anaerobic system under mesophilic conditions (35 degrees C). The effect of glycerol addition (1 and 3% v/v) as co-substrate was assessed in ternary mixtures (FW + SS + GL), with the concentration of all substrates kept at 10 g VS/L. Besides contributing to reduce the lag phase of the acidogenic bacterial culture, the presence of GL increased the hydrogen production in all tested conditions and the maximum hydrogen yield was obtained for the FW + SS + 3%GL mixture (179.3 mL H2/g VS). On the other hand, the highest methane production (342 mL CH4/g VS) was achieved in the test supplemented with 1% GL. At 3% GL, abrupt reductions in the biogas CH4 content and pH values resulting from instability in methanogenesis process were noticed over the experiment. By taking into account the hydrogen and methane production stages, the highest energy yield (i.e., 15.5 kJ/g VS) was obtained with the ternary mixture containing 1% GL. Overall, the results of this study demonstrate the feasibility of using glycerol as co-substrate to increase the H2 and CH4 production efficiency in a two-stage anaerobic co-digestion process, allowing simultaneous treatment of three residues (FW, SS and GL) and energy production. PMID- 29486912 TI - Perspectives on cavitation enhanced endothelial layer permeability. AB - Traditional drug delivery systems, where pharmaceutical agents are conveyed to the target tissue through the blood circulation, suffer of poor therapeutic efficiency and limited selectivity largely due to the low permeability of the highly specialised biological interface represented by the endothelial layer. Examples concern cancer therapeutics or degenerative disorders where drug delivery is inhibited by the blood-brain barrier (BBB). Microbubbles injected into the bloodstream undergo volume oscillations under localised ultrasound irradiation and possibly collapse near the site of interest, with no effect on the rest of the endothelium. The resulting mechanical action induces a transient increase of the inter-cellular spaces and facilitates drug extravasation. This approach, already pursed in in vivo animal models, is extremely expensive and time-consuming. On the other hand in vitro studies using different kinds of microfluidic networks are firmly established in the pharmaceutical industry for drug delivery testing. The combination of the in vitro approach with ultrasound used to control microbubbles oscillations is expected to provide crucial information for developing cavitation enhanced drug delivery protocols and for screening the properties of the biological interface in presence of healthy or diseased tissues. Purpose of the present review is providing the state of the art in this rapidly growing field where cavitation is exploited as a viable technology to transiently modify the permeability of the biological interface. After describing current in vivo studies, particular emphasis will be placed on illustrating characteristics of micro-devices, biological functionalisation, properties of the artificial endothelium and ultrasound irradiation techniques. PMID- 29486913 TI - High-efficient production of biobutanol by a novel Clostridium sp. strain WST with uncontrolled pH strategy. AB - A novel Clostridium sp. strain WST isolated from mangrove sediments demonstrated its unique characteristics of producing high titer of biobutanol from low concentration of substrates via anaerobic fermentation. The strain is able to convert glucose and galactose to high amount of biobutanol up to 16.62 and 12.11 g/L, respectively, and the yields of 0.54 and 0.55 g/g were determined to be much higher than those from the previous reports on Clostridial batch fermentation. Moreover, the inherent strong regulatory system of strain WST also prompts itself to perform the fermentation process without any requirement of pH control. In addition to tolerance of high butanol concentration and negligible production of by-products (e.g., ethanol or acids), this strain has immense potential for the sustainable industry-scale production of biobutanol. PMID- 29486914 TI - Flexibilization in controlling the use of clozapine: A great opportunity. PMID- 29486915 TI - Rescue of autophagy and lysosome defects in salivary glands of MRL/lpr mice by a therapeutic phosphopeptide. AB - Sjogren's syndrome is a multifactorial systemic autoimmune disorder characterized by lymphocytic infiltrates in exocrine organs. Patients present with sicca symptoms, such as extensive dry eyes and dry mouth, and parotid enlargement. Other serious complications include profound fatigue, chronic pain, major organ involvement, neuropathies and lymphomas. Current treatments only focus on relieving symptoms and do not target the origin of the disease, which is largely unknown. The question we addressed here was whether some defects exist in autophagy processes in Sjogren's syndrome and if they can be corrected or minimized using an appropriate mechanism-driven treatment targeting this central survival pathway. Using a recognized murine model of secondary Sjogren's syndrome, we identified molecular alterations of autophagy occurring in the salivary glands of MRL/lpr mice, and discovered that opposite (up- or down regulated) autophagy events can arise in distinct organs of the same mouse strain, here in lymphoid organs and salivary glands. We showed further that the therapeutic P140 peptide, known to directly act on chaperone-mediated autophagy, rescued MRL/lpr mice from cellular infiltration and autophagy defects occurring in salivary glands. Our findings provide a proof-of-concept that targeting autophagy might represent a promising therapeutic strategy for treating patients with Sjogren's syndrome. PMID- 29486916 TI - Survival Impact of CAPOX Versus FOLFOX in the Adjuvant Treatment of Stage III Colon Cancer. AB - BACKGROUND: Capecitabine and oxaliplatin (CAPOX) and folinic acid, fluorouracil, and oxaliplatin (FOLFOX) are both used in the adjuvant treatment of colon cancer, and while their efficacy is assumed to be similar, they have not been directly compared. We reviewed the toxicity profiles, relative dose intensity (RDI), and survival associated with these regimens across a multi-institutional cohort. PATIENTS AND METHODS: We identified 394 consecutively treated patients with stage III colon cancer who received an oxaliplatin-containing regimen. RDI was defined as the total dose received divided by the intended total dose if all cycles were received. RESULTS: FOLFOX was associated with increased mucositis (6.2% vs. 0.7%, P = .0069) and neutropenia (25.9% vs. 8.6%, P < .0001), while CAPOX was associated with increased dose-limiting toxicities (DLTs) (90.7% vs. 80.2%, P = .0055), diarrhea (31.8% vs. 9.0%, P < .0001), and hand-foot syndrome (19.9% vs. 2.1%, P < .0001). Higher median RDI of fluoropyrimidine (93.7% vs. 80.0%, P < .0001) and oxaliplatin (87.2% vs. 76.3%, P < .0001) was noted for patients receiving FOLFOX. Reducing the duration from 6 to 3 months would have prevented 28.7% of FOLFOX and 20.5% of CAPOX patients from ever experiencing a DLT (P = .0008). Overall survival did not differ by regimen (hazard ratio = 0.73; 95% confidence interval 0.45-1.22; P = .24). However, CAPOX was associated with improved disease-free survival (3-year disease-free survival 83.8% vs. 73.4%, P = .022), which remained significant in high-risk (T4 or N2) (P = .039) but not low risk patients (P = .19). CONCLUSION: CAPOX may be associated with improved disease-free survival despite greater toxicities and lower RDI. Reducing adjuvant chemotherapy duration to 3 months would prevent 26% of patients from ever experiencing a DLT. PMID- 29486917 TI - Systematic review of the clinical utility and validity of the Sendai and Fukuoka Consensus Guidelines for the management of intraductal papillary mucinous neoplasms of the pancreas. AB - BACKGROUND: This systematic review was performed to assess the clinical utility of the Sendai Consensus Guidelines (SCG) and Fukuoka Consensus Guidelines (FCG) for intraductal papillary mucinous neoplasm (IPMN). METHODS: A computerized search of PubMed was performed to identify all the studies which evaluated the SCG and FCG in surgically resected, histologically confirmed IPMNs. RESULTS: Ten studies evaluating the FCG, 8 evaluating the SCG and 4 evaluating both guidelines were included. In 14 studies evaluating the FCG, out of a total of 2498 neoplasms, 849 were malignant and 1649 were benign neoplasms. Pooled analysis showed that 751 of 1801 (42%) FCG+ve neoplasms were malignant and 599 neoplasms of 697 (86%) FCG-ve neoplasms were benign. PPV of the high risk and worrisome risk groups were 465/986 (47%) and 239/520 (46%) respectively. In 12 studies evaluating the SCG, 1234 neoplasms were analyzed of which 388 (31%) were malignant and 846 (69%) were benign. Pooled analysis demonstrated that 265 of 802 (33%) SCG+ve neoplasms were malignant and 238 of 266 SCG-ve (90%) neoplasms were benign. CONCLUSION: The FCG had a higher positive predictive value (PPV) compared to the SCG. However, the negative predictive value (NPV) of the FCG was slightly lower than that of the SCG. Malignant and even invasive IPMN may be missed according to both guidelines. PMID- 29486919 TI - [Follow-up protocol for newborns of birthweight less than 1500 g or less than 32 weeks gestation]. AB - The mortality of children with a birthweight of less than 1500g or with a gestational age of less than 32 weeks (<1500<32) has decreased significantly in the last 20 years or so. Given the higher risk of disability in these children, follow-up after hospital discharge is considered essential. In this document, the Follow-Up Group of the Spanish Society of Neonatology, in collaboration with the Spanish Society of Paediatric Primary Care, propose a follow-up protocol specific for the<1500<32, which has as its aim to standardise the activities and evaluations according to good practice criteria. PMID- 29486918 TI - Selective internal radiation therapy (SIRT) before partial hepatectomy or radiofrequency destruction for treatment of hepatocellular carcinoma in cirrhotic patients: a feasibility and safety pilot study. AB - BACKGROUND/PURPOSE: Preoperative selective internal radiation therapy (SIRT) may improve the results of partial hepatectomy (PH) or radiofrequency destruction (RF) for hepatocellular carcinoma (HCC) in patients with cirrhosis. The aim of this study was to evaluate the feasibility and safety of this combined approach. METHODS: Patients with cirrhosis and HCC selected for PH or RF were prospectively included and systematically proposed for preoperative SIRT. Feasibility and safety of SIRT and post-SIRT PH or RF were assessed. RESULTS: Thirty patients were included. SIRT was contraindicated in seven, due to lack of access to tumour artery or to hepato-pulmonary shunts. SIRT was performed in 23 patients without significant complications. Post-SIRT, surgery was refuted in seven patients, due to tumour progression or the patient's deteriorating condition. After surgery, major complications were observed in 2/16 patients (12.5%) and one patient died 52 days post-surgery. A major tumour pathological response was seen in most patients who underwent surgery after SIRT. CONCLUSIONS: On intention-to-treat basis, the overall feasibility of combining preoperative SIRT and surgery was limited. Preoperative SIRT did not increase expected operative morbidity, but post-SIRT, a third of patients were refuted for surgery. Accurate selection criteria and potential long-term oncological benefit of this approach remains to be determined. ClinicalTrials.gov NCT01686880. PMID- 29486920 TI - [What are the expectations of coordination and accompaniment of French patients with cancer towards their community pharmacist?] AB - PURPOSES: Analyze the relationship and expectations of cancer patients towards the community pharmacist in a pharmaceutical care coordination project. METHODS: In November 2014, a questionnaire was distributed to ambulatory patients of a university hospital specialized in oncology. Thirteen questions explored the consumption habits and the usage of the pharmacy (typology of consumers, use of goods and benefits consumed), and collected their expectations for pharmaceutical benefits in the context of the management of their cancer. RESULTS: One thousand two hundred and seventy two patients were included for a final response rate of 78%. Characteristics of the respondents: 64% were women, 63% lived in Ile-de France and 49% took cancer-related treatments (anticancer drugs, supportive care medications). More than 84% of respondents went to pharmacies at least once a month and 95% reported resorting to a single pharmacy. 36% to be ready to share their hospital discharge report with their pharmacist and 61% to have their hospitalization order sent to their "referral" pharmacy to anticipate treatments. Discussion Community pharmacists were perceived positively by the respondents. Patients were willing to share information and be accompanied by this health professional in their cancer care. Their expectations were first and foremost the management of drug-related iatrogenic effects with a report of adverse effects to the hospital, and validated solutions for their management. PMID- 29486922 TI - [Homeopathy in cancer patients: What does the "best" evidence tell us?] AB - Homeopathic medicines are used by many patients with cancer, usually alongside conventional treatment. A recent report by the European Academies' Science Advisory Council concluded that "that there are no robust and reproducible evidence that homeopathy is effective". This literature review aims to make the analysis of published controlled randomized trials involving homeopathic treatment in the field of oncology. PMID- 29486921 TI - [Dihydropyrimidine dehydrogenase (DPD) deficiency screening and securing of fluoropyrimidine-based chemotherapies: Update and recommendations of the French GPCO-Unicancer and RNPGx networks]. AB - Fluoropyrimidines (FU) are still the most prescribed anticancer drugs for the treatment of solid cancers. However, fluoropyrimidines cause severe toxicities in 10 to 40% of patients and toxic deaths in 0.2 to 0.8% of patients, resulting in a real public health problem. The main origin of FU-related toxicities is a deficiency of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme of 5-FU catabolism. DPD deficiency may be identified through pharmacogenetics testing including phenotyping (direct or indirect measurement of enzyme activity) or genotyping (detection of inactivating polymorphisms on the DPYD gene). Approximately 3 to 15% of patients exhibit a partial deficiency and 0.1 to 0.5% a complete DPD deficiency. Currently, there is no regulatory obligation for DPD deficiency screening in patients scheduled to receive a fluoropyrimidine-based chemotherapy. Based on the levels of evidence from the literature data and considering current French practices, the Group of Clinical Pharmacology in Oncology (GPCO)-UNICANCER and the French Network of Pharmacogenetics (RNPGx) recommend the following: (1) to screen DPD deficiency before initiating any chemotherapy containing 5-FU or capecitabine; (2) to perform DPD phenotyping by measuring plasma uracil (U) concentrations (possibly associated with dihydrouracil/U ratio), and DPYD genotyping (variants *2A, *13, p.D949V, HapB3); (3) to reduce the initial FU dose (first cycle) according to DPD status, if needed, and further, to consider increasing the dose at subsequent cycles according to treatment tolerance. In France, 17 public laboratories currently undertake routine screening of DPD deficiency. PMID- 29486924 TI - Application of apheresis science in Emergency Medicine. PMID- 29486923 TI - Cystic fibrosis epithelial cells are primed for apoptosis as a result of increased Fas (CD95). AB - BACKGROUND: Previous work suggests that apoptosis is dysfunctional in cystic fibrosis (CF) airways with conflicting results. We evaluated the relationship between dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) and apoptosis in CF airway epithelial cells. METHODS: Apoptosis and associated caspase activity were analysed in non-CF and CF tracheal and bronchial epithelial cell lines. RESULTS: Basal levels of apoptosis and activity of caspase-3 and caspase-8 were significantly increased in CF epithelial cells compared to controls, suggesting involvement of extrinsic apoptosis signalling, which is mediated by the activation of death receptors, such as Fas (CD95). Increased levels of Fas were observed in CF epithelial cells and bronchial brushings from CF patients compared to non-CF controls. Neutralisation of Fas significantly inhibited caspase-3 activity in CF epithelial cells compared to untreated cells. In addition, activation of Fas significantly increased caspase-3 activity and apoptosis in CF epithelial cells compared to control cells. CONCLUSIONS: Overall, these results suggest that CF airway epithelial cells are more sensitive to apoptosis via increased levels of Fas and subsequent activation of the Fas death receptor pathway, which may be associated with dysfunctional CFTR. PMID- 29486925 TI - Angiogenesis - a crucial step in breast cancer growth, progression and dissemination by Raman imaging. AB - Combined micro-Raman imaging and AFM imaging are efficient methods for analyzing human tissue due to their high spatial and spectral resolution as well as sensitivity to subtle chemical, structural and topographical changes. The aim of this study was to determine biochemical composition and mechanical topography around blood vessels in the tumor mass of human breast tissue. Significant alterations of the chemical composition and structural architecture around the blood vessel were found compared to the normal breast tissue. A pronounced increase of collagen-fibroblast-glycocalyx network, as well as enhanced lactic acid, and glycogen activity in patients affected by breast cancer were reported. PMID- 29486926 TI - World Health Organization and Its Initiative for Ear and Hearing Care. AB - The World Health Organization (WHO) addresses ear diseases and hearing loss through its program on prevention of deafness and hearing loss. Recently, the World Health Assembly called for action at global and national levels to tackle the rising prevalence and adverse impact of unaddressed hearing loss. Following a public health approach toward this issue, WHO is focusing on i) raising awareness among policymakers and civil society; and ii) providing technical support to countries for promoting hearing care. Meeting this challenge requires a coordinated global effort with all stakeholders working together to make ear and hearing care accessible to all. PMID- 29486927 TI - Beware of an allergic reaction in stented patients: Amoxicillin/clavulanic acid anaphylaxis associated with fatal Kounis syndrome and stent thrombosis. PMID- 29486928 TI - Opioids and methamphetamine: a tale of two crises. PMID- 29486929 TI - The hope for a new dawn for South Africa. PMID- 29486930 TI - A new approach to treating infection. PMID- 29486931 TI - Health and wellbeing of Indigenous adolescents in Australia. PMID- 29486932 TI - UK's role in global health research innovation. PMID- 29486933 TI - Introducing In Practice. PMID- 29486934 TI - Offline: The fact of faith. PMID- 29486935 TI - Debate over recreational cannabis use legalisation in Canada. PMID- 29486936 TI - Fall armyworm threatens food security in southern Africa. PMID- 29486937 TI - Lassa fever in Nigeria: the great unknown. PMID- 29486938 TI - The art of conversation. PMID- 29486939 TI - Poetry and emotion. PMID- 29486940 TI - Universal health coverage is needed to deliver NCD control. PMID- 29486941 TI - Women helping women prevent HIV in resource-limited settings. PMID- 29486942 TI - Glaucoma. PMID- 29486943 TI - Glaucoma - Authors' reply. PMID- 29486944 TI - [Greater omentum flap: Treatment of chronic wounds and seroma: About a case]. AB - INTRODUCTION: Cicatricial complications after abdominal or pelvic surgery are more frequent in obese patients. In this case, infection, seroma and delays in scarring can be extremely difficult to treat. The objective of this technical note is to present an original case of an obese patient operated nine years ago of a hysterectomy by laparotomy and chronically presenting a non-resolving septic seroma despite multiple surgical procedures whose healing could be obtained by a flap of greater omentum. SURGICAL TECHNIQUE: The ideal is to carry out this intervention in a double team with a digestive surgeon in case of intra-abdominal visceral or vascular wound during dissection. The greater omentum flap was raised in a conventional manner over the gastroepiploic artery. A sufficiently wide orifice should be left at the level of the abdominal aponeurosis in order to avoid any compression of the pedicle. Finally, the flap must be spread over the whole surface of the detachment and fixed to the anterior aponeurosis. CONCLUSION: Reliability and vascular and lymphatic richness make the greater omentum flap a very effective method in chronic wound cases associated with important seroma. The scarring obtained in the clinical case presented thus highlights the specific qualities of this flap. PMID- 29486945 TI - Safety implication of Salmonella based Brucella vaccine candidate in mice and in vitro human cell culture. AB - An anti-Brucella vaccine candidate comprising rough Salmonella vector delivering Brucella antigens was developed. This system provides a platform for live Brucella-free vaccine development as it can mimic active-intracellular infection of Brucella organism. Exploiting this phenomenon thus provides significant protection at a single dose and also re-assured the safety. To date, no human anti-Brucella vaccines are available, owing to the lack of safe and effective formulation. This study investigated the safety of the vaccine formulation in mice model and in vitro human cell cultures. The experiment was designed to determine the LD50 of the vaccine formulation. The vaccine formulation did not induce any mortality even when mice were administered at 8 * 109 CFU per oral or per subcutaneous (SC), which was 100-times more than the actual vaccine dose intended for mice model. In contrast, wild-type (WT) Salmonella positive control strain induced 100% mortality at 8 * 107 CFU per mice via oral or SC routes. Interaction of the vaccine with phagocytic (THP-1 derived macrophage) and non phagocytic (Caco-2) human cell lines as well as human PBMC was investigated. In in vitro experiments, inflammatory and pyretic cytokines TNF-alpha, and IL-1beta inductions were significantly lower in vaccine group as compared to WT group. Further, apoptosis, nitric oxide synthase and cytotoxicity inductions were comparable and not exacerbated, given that the strain is based on a rough bacterial vector that may have endotoxic lipid-A more readily exposed. These findings corroborated that the vaccine formulation is highly safe in mice model and is relatively mild in the induction of inflammatory cytokines and cellular changes in human cell lines. PMID- 29486946 TI - Generation, safety and immunogenicity of an Actinobacillus pleuropneumoniae quintuple deletion mutant SLW07 (DeltaapxICDeltaapxIICDeltaorf1DeltacpxARDeltaarcA). AB - We inactivated a virulence determinant, ArcA, in an Actinobacillus pleuropneumoniae quadruple deletion mutant SLW06 (DeltaapxICDeltaapxIICDeltaorf1DeltacpxAR, serovar 1), and a quintuple deletion mutant SLW07 was generated. SLW07 showed decreased adherence to and invasion of host cells, compared to its parent strain SLW06. SLW07 was more sensitive in RAW264.7 macrophage-mediated phagocytosis and clearance. SLW07 was less virulent in mice. An immunization assay indicated that both SLW07 and SLW06 preferentially stimulated T helper cell type 2 response in mice. Live vaccines induced the production of interleukin-6 and tumor necrosis factor-alpha by splenic lymphocytes. Furthermore, the protective immunity of SLW07 was not affected after ArcA mutation. Immunization with SLW07 could provide a complete protection following virulent A. pleuropneumoniae challenge in mice. Our results suggest that SLW07 is a promising live vaccine candidate, which is further attenuated from and shares similar protective efficacy with its quadruple deletion parent SLW06. PMID- 29486947 TI - [Assessment of clinical complications and their associated factors in hip fracture patients in an Acute Geriatric Orthopaedic Unit]. AB - INTRODUCTION: The incidence of clinical complications in hip fracture (HF) patients is high and variable due to their heterogeneous nature. The aim of the study was to assess the clinical complications and their associated factors in HF patients admitted to the Orthopaedic Geriatric Unit of a 283 bed University Hospital. An average of 200 HF patients is attended yearly. MATERIAL AND METHODS: A prospective, observational and analytical study was conducted on 383 consecutive patients admitted to the unit during the years 2013 and 2014. Clinical complications were defined according to recommendations supported by the AOTrauma Network (International Network of Traumatologists for the Study of Osteosynthesis). RESULTS: A total of 273 patients (71.28%) showed some clinical complication. The main ones were, delirium (55.4%), renal failure (15.4%), and cardiac complications (12.3%). An ASA III-IV score of OR = 1.962 (95% CI; 1.040 3.704, P=.038), lower Barthel index at discharge (b = -3.572, 95% CI -0.866 to 0.104, P=.01), the increase in pre-operative stay (OR = 1.165, 95% CI 1.050 1.294, P=.004) and an increased length of stay (b = 2.663, 95% CI 3.522-0.325; P<.001) were factors associated with clinical complications. CONCLUSIONS: Delirium, renal failure, and cardiac complications were the most frequent complications according the new recommendations. An ASA III-IV score, worse functional status at discharge, prolonged pre-operative period, and increased length of stay, were risk factors associated with clinical complications. Cardiac, pulmonary, and gastrointestinal complications were the main causes of mortality in the unit. PMID- 29486948 TI - [Assessment of the sense of coherence in the perceived burden and in the adherence to a psycho-educational program for informal caregivers of dependent persons]. AB - INTRODUCTION: The care of dependent persons is arduous, and requires time, energy, and physical effort on the part of caregivers. Personal characteristics, such as the sense of coherence (SOC), can influence the perceived burden and care giving. OBJECTIVE: To determine the impact of SOC on the perceived burden and to determine if these characteristics are associated with adherence to a psycho educational program for informal caregivers. MATERIAL AND METHOD: Prospective observational study of caregivers of dependent persons participating in the 'School of Caregivers', a psycho-educational program for family and paid caregivers. An analysis was made of the SOC-13 items and the results of the Zarit Burden Interview. The relationship between the SOC and the adherence to the program (>=50% sessions) was also analysed. RESULTS: The study included 96 participants, with 71.9% family carers. The higher burden was associated with a lower SOC meaningfulness factor (beta=-0.388; P=.002), and to be a relative vs. paid carer (beta=-0.300; P=.010). Just over half (52.1%) of carers completed 50% or more sessions, and in the case of the relatives, this adherence increased by higher SOC (OR: 1.1, P=.034), and lower burden (OR: 0.95, P=.032). The lack of adherence of paid caregivers was not associated with any of the analysed variables. CONCLUSIONS: The sense of coherence and mainly the meaning, is a characteristic to take into account for the adaptation of interventions in caregivers and provide them with greater equity working more on the people who need it the most (lower SOC and greater burden). PMID- 29486949 TI - Unprecedented sugar bridged bisindoles selective inhibiting glioma stem cells. AB - Unlike reported bisindoles linked by single bond directly, alstoniasidines A (1) and B (2), from Alstonia scholaris featuring unprecedented skeleton with two indole moieties bridged by a sugar, represented a novel bisindole type having strictosamide-glucopyranose-picraline scaffold. Both compounds exhibited selective cytotoxicity against human glioma stem cells (GSCs) and induced caspase 3 dependent extrinsic apoptosis by increasing the expression of interleukin 1 (IL 1), tumor necrosis factor (TNF-alpha), and the cleaved caspase-3, while damaged the unlimited proliferation and self-renewal capacity of GSCs. This finding might provide new type of leads for the selective killing of human glioma stem cells. PMID- 29486950 TI - pH-dependent production of himeic acid A and its non-enzymatic conversions to himeic acids B and C. AB - The fungus Aspergillus japonicus MF275 produces himeic acid A (1), containing a 4 pyrone ring, along with its congeners, himeic acids B (2) and C (3). During culture, 1 was gradually converted to 3, the corresponding 4-pyridone derivative. A study of the relationship between the culture pH and the fungal metabolites showed that a decrease from pH 6.5 to pH 2 is essential for production of 1, while a subsequent increase to pH 5 is necessary for production of 3. In addition, we revealed that 1 was non-enzymatically converted to 3 by the incorporation of an ammonium nitrogen atom in a pH 5 buffer, and that 1 was converted to 2 at a conversion ratio of 50% during incubation in MeOH for five days. PMID- 29486951 TI - Design, synthesis and biological evaluation of novel 7-azaspiro[3.5]nonane derivatives as GPR119 agonists. AB - The design and synthesis of a novel class of 7-azaspiro[3.5]nonane GPR119 agonists are described. In this series, optimization of the right piperidine N capping group (R2) and the left aryl group (R3) led to the identification of compound 54g as a potent GPR119 agonist. Compound 54g showed a desirable PK profile in Sprague-Dawley (SD) rats and a favorable glucose lowering effect in diabetic rats. PMID- 29486952 TI - A Rhodamine B-based fluorescent probe for imaging Cu2+ in maize roots. AB - A new Rhodamine B-based fluorescent probe (RBO) is successfully designed and synthesized, which is a higher selective and sensitive chemosensor for Cu2+ than other ions. Under physiological conditions (pH = 7.0), the non emission RBO displays a rapid fluorescence increase together with a color change after addition of Cu2+ and the detection limit is down to 28nM, which can clearly illustrate the distribution of Cu2+ with the help of laser scanning confocal microscope in plant tissues. Eventually, it confirmed that the Cu2+ accumulates mostly in the vascular cylinder and very less in the epidermal cells of maize roots, which is important to understand how the plants take up, transport and store in the Cu2+. PMID- 29486953 TI - Discovery of selective EGFR modulator to inhibit L858R/T790M double mutants bearing a N-9-Diphenyl-9H-purin-2-amine scaffold. AB - Based upon the modeling binding mode of marketed AZD9291 with T790M, a series of N-9-Diphenyl-9H-purin-2-amine derivatives were designed and synthesized with the purpose to overcome the drug resistance resulted from T790M/L858R double mutations. The most potent compound 23a showed excellent enzyme inhibitory activities and selectivity with nanomolar IC50 values for both the single T790M and double T790M/L858R mutant EGFRs, and was more than 8-fold selective for wild type EGFR. Compound 23a displayed strong antiproliferative activity against the H1975 non-small cell lung cancer (NSCLC) cells bearing T790M/L858R. And it was less potent against A549 (WT EGFR and k-Ras mutation) and HT-29 (non-special gene type) cells, showing a high safety index. PMID- 29486955 TI - What does the Managing Emotions branch of the MSCEIT add to the MATRICS consensus cognitive battery? AB - The Managing Emotions branch of the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT-ME) was included within the MATRICS Consensus Cognitive Battery (MCCB) as the measure of social cognition, although limited research has examined its associations with psychosocial functioning in people with schizophrenia or other severe mental illnesses. This secondary analysis with 107 participants examined what the MSCEIT-ME contributes to our understanding of functioning in this population, and whether it uniquely predicts psychosocial functioning after controlling for performance on the other MCCB tests and negative symptoms. Performance on the MSCEIT-ME was significantly correlated with all three MCCP factors (processing speed, attention/working memory, learning) within schizophrenia-schizoaffective disorder, bipolar disorder, and other mixed diagnoses groups. Better performance on MSCEIT-ME was associated with better psychosocial functioning on the Quality of Life Scale (QLS) in the schizophrenia schizoaffective disorder group, but not in the bipolar or other mixed diagnoses groups. In addition, in the schizophrenia-schizoaffective disorder group, after controlling for demographic characteristics in stepwise multiple regression analyses, MSCEIT-ME was the only significant predictor of the QLS total score and the QLS interpersonal relations and intrapsychic foundations subscales, with none of the MCCB factors entering any of the regression models. The MSCEIT-ME may reflect a unique aspect of social cognition that is related to impaired psychosocial functioning in schizophrenia and is not tapped by the other cognitive tests on the MCCB. Further research on the MSCEIT-ME could provide unique insights into the social functioning problems in schizophrenia. PMID- 29486954 TI - Discovery of 18beta-glycyrrhetinic acid conjugated aminobenzothiazole derivatives as Hsp90-Cdc37 interaction disruptors that inhibit cell migration and reverse drug resistance. AB - A series of 18beta-glycyrrhetinic acid (GA) conjugated aminobenzothiazole derivatives were designed, synthesized and evaluated for disruption activity of Hsp90-Cdc37 as well as the effects of in vitro cell migration. These compounds exhibited relatively good disruption activity against Hsp90-Cdc37 with IC50 values in low micromolar range. A docking study of the most active compound 11g revealed key interactions between 11g and Hsp90-Cdc37 complex in which the benzothiazole moiety and the amine chain group were important for improving activity. It is noteworthy that further antitumor activity screening revealed that some compounds exhibited better inhibitory activity than the commercial anticancer drug 5-FU and showed potent suppression activity against drug resistant cancer cells. In particular, compound 11 g appeared to be the most potent compound against the A549 cell line, at least partly, by inhibition of the activity of Hsp90 and apoptosis induction. The treatment of A549 cells with compound 11g resulted in inhibition of in vitro cell migration through wound healing assay and S phase of cell cycle arrested. In addition, 11g-induced apoptosis was significantly facilitated in A549 cells. Thus, we conclude that GA aminobenzothiazole derivatives may be the potential Hsp90-Cdc37 disruptors with the ability to suppress cells migration and reversed drug-resistant. PMID- 29486956 TI - Virtual reality therapy for refractory auditory verbal hallucinations in schizophrenia: A pilot clinical trial. AB - Schizophrenia is a chronic and severe mental illness that poses significant challenges. While many pharmacological and psychosocial interventions are available, many treatment-resistant schizophrenia patients continue to suffer from persistent psychotic symptoms, notably auditory verbal hallucinations (AVH), which are highly disabling. This unmet clinical need requires new innovative treatment options. Recently, a psychological therapy using computerized technology has shown large therapeutic effects on AVH severity by enabling patients to engage in a dialogue with a computerized representation of their voices. These very promising results have been extended by our team using immersive virtual reality (VR). Our study was a 7-week phase-II, randomized, partial cross-over trial. Nineteen schizophrenia patients with refractory AVH were recruited and randomly allocated to either VR-assisted therapy (VRT) or treatment-as-usual (TAU). The group allocated to TAU consisted of antipsychotic treatment and usual meetings with clinicians. The TAU group then received a delayed 7weeks of VRT. A follow-up was ensured 3months after the last VRT therapy session. Changes in psychiatric symptoms, before and after TAU or VRT, were assessed using a linear mixed-effects model. Our findings showed that VRT produced significant improvements in AVH severity, depressive symptoms and quality of life that lasted at the 3-month follow-up period. Consistent with previous research, our results suggest that VRT might be efficacious in reducing AVH related distress. The therapeutic effects of VRT on the distress associated with the voices were particularly prominent (d=1.2). VRT is a highly novel and promising intervention for refractory AVH in schizophrenia. PMID- 29486957 TI - Clinical and cognitive correlates of unsheltered status in homeless persons with psychotic disorders. AB - Homeless persons with psychosis are particularly susceptible to unsheltered homelessness, which includes living on the streets, in cars, and other places not meant for human habitation. Homeless persons with psychosis have distinct barriers to accessing care and comprise a high-need and hard-to-serve homeless subpopulation. Therefore, this study sought to understand unsheltered homelessness in persons with psychosis and its relationship to cognitive impairment, clinical symptoms, and community functioning, examined both categorically and dimensionally. This study included 76 homeless participants with a history of a psychotic diagnosis who were enrolled in a supported housing program but had not yet received housing. This study used two different housing stability thresholds (literally homeless at any point vs. literally homeless >20% of days) for comparing homeless Veterans with psychosis living in sheltered versus unsheltered situations on cognition, clinical symptoms, and community integration. Dimensional analyses also examined the relationship between percentage of days spent in unsheltered locations and cognition, clinical symptoms, and community integration. Sheltered and unsheltered Veterans with psychosis did not differ on clinical symptoms or community integration, but there was an inconsistent group difference on cognition depending on the threshold used for determining housing stability. In the unsheltered group, cognitive deficits in overall cognition, visual learning, and social cognition were related to more days spent in unsheltered locations. Rehabilitation efforts targeting specific cognitive deficits may be useful to facilitate greater access to care and successful interventions in this population. PMID- 29486958 TI - Whole genome sequencing of 91 multiplex schizophrenia families reveals increased burden of rare, exonic copy number variation in schizophrenia probands and genetic heterogeneity. AB - The importance of genomic copy number variants (CNVs) has long been recognized in the etiology of neurodevelopmental diseases. We report here the results from the CNV analysis of whole-genome sequences from 91 multiplex schizophrenia families. Employing four algorithms (CNVnator, Cn.mops, DELLY and LUMPY) to identify CNVs, we find 1231 rare deletions and 287 rare duplications in 300 individuals (77 with schizophrenia (SZ), 32 with schizoaffective disorder (SAD), 82 with another neuropsychiatric diagnosis and 109 unaffected). The size of the CNVs ranges from a few hundred base-pairs to about 1.3Mb. The total burden of CNVs does not differ significantly between affected (SZ and SAD) and unaffected individuals. Parent-to child transmission rate for rare CNVs affecting exonic regions is significantly higher for affected (SZ and SAD) probands as compared to their siblings, but rates for all CNVs is not. We observe heterogeneity between families in terms of genes involved in CNVs, and find several CNVs involving genes previously implicated in either schizophrenia or other neuropsychiatric disorders. PMID- 29486959 TI - Cardio-metabolic risk and its management in a cohort of clozapine-treated outpatients. AB - OBJECTIVE: To comprehensively assess cardio-metabolic risk factors and their management in a large sample of outpatients treated with clozapine. METHODS: Observational cross-sectional study of all clozapine users attending specialized clozapine monitoring outpatient clinics in three public hospitals in Sydney, Australia were approached to participate over the one-year period 01/10/2015 30/09/2016. Cardio-metabolic risk factors including metabolic syndrome, risk for future development of diabetes, smoking, physical activity, nutrition, and prescribed medications were assessed at face-to-face interview and through medical record review. Among patients who had cardio-metabolic risk factors, the proportion receiving appropriate management was assessed. RESULTS: Of 451 registered clozapine clinic attenders, 92.2% completed questionnaires and anthropometric measurements. 58.3% met criteria for metabolic syndrome. 79.6% were overweight or obese. 55.9% had blood pressure meeting metabolic syndrome criteria. 46.6% had elevated fasting blood glucose and 55.2% had elevated blood triglycerides. 43.6% were current smokers. Only 10% achieved recommended weekly physical activity levels. Unhealthy food categories were highly consumed. 32.1% were on additional antipsychotics. In the majority of individuals, cardio metabolic risk factors were untreated or under-treated. CONCLUSIONS: Clozapine use was associated with very high rates of cardiovascular and metabolic risk factors, which were frequently under-treated. Management of both physical and mental health should be prioritized. Polypharmacy should be rationalized. Future research should investigate the effectiveness of smoking cessation and lifestyle interventions in this high-risk population. PMID- 29486960 TI - Effects of short-term, high-frequency repetitive transcranial magnetic stimulation to bilateral dorsolateral prefrontal cortex on smoking behavior and cognition in patients with schizophrenia and non-psychiatric controls. AB - BACKGROUND: High rates of tobacco smoking and smoking cessation failure in schizophrenia may be related to prefrontal cortical dysfunction. Novel treatment options for tobacco use disorder are needed given the limited efficacy of current pharmacotherapies. Preliminary evidence suggests high-frequency repetitive transcranial magnetic stimulation (rTMS) to bilateral dorsolateral prefrontal cortex (DLPFC) may suppress tobacco craving in smokers with schizophrenia. The goal of this study was to determine effects of rTMS for tobacco craving and cognition using a short-term (3-day) human laboratory paradigm. METHODS: Bilateral active (20Hz) versus sham rTMS stimulation was administered in a counterbalanced, double-blind, cross-over design to thirteen smokers with schizophrenia and n=14 non-psychiatric smoking controls. Participants were studied at baseline (smoking satiated), after 16h of smoking abstinence, and after smoking reinstatement. Primary outcome measures included tobacco craving, withdrawal and cognition. RESULTS: Overnight abstinence produced a significant increase in tobacco craving and withdrawal, and impaired verbal memory and visuospatial working memory in both diagnostic groups; these effects were reversed with smoking reinstatement. However, active rTMS did not modify this pattern of results. Moreover, active versus sham rTMS had no significant effects on cognitive outcomes, and was not associated with significant adverse events. CONCLUSIONS: Our preliminary findings suggest that short-term rTMS administration may not be sufficient enough to modify cognition, craving, and withdrawal outcomes in smokers with schizophrenia (NCT00736710). Longer-term, controlled treatment studies examining effects of rTMS on smoking behaviors and cognition in schizophrenia are warranted. PMID- 29486961 TI - The intestinal complement system in inflammatory bowel disease: Shaping intestinal barrier function. AB - The complement system is part of innate sensor and effector systems such as the Toll-like receptors (TLRs). It recognizes and quickly systemically and/or locally respond to microbial-associated molecular patterns (MAMPs) with a tailored defense reaction. MAMP recognition by intestinal epithelial cells (IECs) and appropriate immune responses are of major importance for the maintenance of intestinal barrier function. Enterocytes highly express various complement components that are suggested to be pivotal for proper IEC function. Appropriate activation of the intestinal complement system seems to play an important role in the resolution of chronic intestinal inflammation, while over-activation and/or dysregulation may worsen intestinal inflammation. Mice deficient for single complement components suffer from enhanced intestinal inflammation mimicking the phenotype of patients with chronic inflammatory bowel disease (IBD) such as Crohn's disease (CD) or ulcerative colitis (UC). However, the mechanisms leading to complement expression in IECs seem to differ markedly between UC and CD patients. Hence, how IECs, intestinal bacteria and epithelial cell expressed complement components interact in the course of IBD still remains to be mostly elucidated to define potential unique patterns contributing to the distinct subtypes of intestinal inflammation observed in CD and UC. PMID- 29486962 TI - A case of low grade fibromyxoid sarcoma with dedifferentiation. PMID- 29486963 TI - Indolent T-lymphoblastic proliferation associated with low grade follicular dendritic cell sarcoma and Castleman disease. PMID- 29486964 TI - Comparison between Optical COherence tomography guidance and Angiography guidance in percutaneous coronary intervention (COCOA): Study protocol for a randomized controlled trial. AB - BACKGROUND: Optical coherence tomography (OCT) is increasingly used as an adjunct to coronary angiography for guiding percutaneous coronary intervention (PCI). The current consensus on PCI is that the large final stent area offers the best chance of a good late clinical outcome. Since OCT provides more accurate information about the coronary artery and implanted stents, OCT-guided stent implantation is expected to achieve greater stent expansion than angiography guidance alone. Therefore, we designed the COCOA (Comparison between Optical COherence tomography guidance and Angiography guidance in percutaneous coronary intervention) study to evaluate whether OCT-guided stent implantation would result in a minimum stent area greater than that achieved with angiography guidance alone. METHODS AND DESIGN: The COCOA study is a large-scale, multicenter, single country (Japan), prospective randomized controlled, open label, parallel group, superiority study comparing OCT-guided PCI with angiography-guided PCI. The eligible patients (n=550) are randomly allocated in a 1:1 ratio to receive either OCT-guided PCI or angiography-guided PCI. PCI is performed using the everolimus-eluting stent in accordance with certain criteria of OCT or angiography for optimal stent implantation. Following the stent optimization guided by OCT or angiography alone, OCT is performed in both groups. The primary endpoint is minimum stent area at post-PCI with allocated imaging guidance. CONCLUSION: When completed, the COCOA study will contribute to define the clinical value of the OCT guidance in PCI. PMID- 29486965 TI - Biosynthesis and in vitro enzymatic synthesis of the isoleucine conjugate of 12 oxo-phytodienoic acid from the isoleucine conjugate of alpha-linolenic acid. AB - The isoleucine conjugate of 12-oxo-phytodienoic acid (OPDA-Ile), a new member of the jasmonate family, was recently identified in Arabidopsis thaliana and might be a signaling molecule in plants. However, the biosynthesis and function of OPDA Ile remains elusive. This study reports an in vitro enzymatic method for synthesizing OPDA-Ile, which is catalyzed by reactions of lipoxygenase (LOX), allene oxide synthase (AOS), and allene oxide cyclase (AOC) using isoleucine conjugates of alpha -linolenic acid (LA-Ile) as the substrate. A. thaliana fed LA Ile exhibited a marked increase in the OPDA-Ile concentration. LA-Ile was also detected in A. thaliana. Furthermore, stable isotope labelled LA-Ile was incorporated into OPDA-Ile. Thus, OPDA-Ile is biosynthesized via the cyclization of LA-Ile in A. thaliana. PMID- 29486966 TI - Radiosynthesis and biological evaluation of 18F-labeled 4-anilinoquinazoline derivative (18F-FEA-Erlotinib) as a potential EGFR PET agent. AB - Epidermal growth factor receptor (EGFR) has gained significant attention as a therapeutic target. Several EGFR targeting drugs (Gefitinib and Erlotinib) have been approved by US Food and Drug Administration (FDA) and have received high approval in clinical treatment. Nevertheless, the curative effect of these medicines varied in many solid tumors because of the different levels of expression and mutations of EGFR. Therefore, several PET radiotracers have been developed for the selective treatment of responsive patients who undergo PET/CT imaging for tyrosine kinase inhibitor (TKI) therapy. In this study, a novel fluorine-18 labeled 4-anilinoquinazoline based PET tracer, 1N-(3-(1-(2-18F fluoroethyl)-1H-1,2,3-triazol-4-yl)phenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4 amine (18F-FEA-Erlotinib), was synthesized and biological evaluation was performed in vitro and in vivo. 18F-FEA-Erlotinib was achieved within 50min with over 88% radiochemical yield (decay corrected RCY), an average specific activity over 50GBq/MUmol, and over 99% radiochemical purity. In vitro stability study showed no decomposition of 18F-FEA-Erlotinib after incubated in PBS and FBS for 2h. Cellular uptake and efflux experiment results indicated the specific binding of 18F-FEA-Erlotinib to HCC827 cell line with EGFR exon 19 deletions. In vivo, Biodistribution studies revealed that 18F-FEA-Erlotinib exhibited rapid blood clearance both through hepatobiliary and renal excretion. The tumor uptake of 18F FEA-Erlotinib in HepG2, HCC827, and A431 tumor xenografts, with different EGFR expression and mutations, was visualized in PET images. Our results demonstrate the feasibility of using 18F-FEA-Erlotinib as a PET tracer for screening EGFR TKIs sensitive patients. PMID- 29486967 TI - Promiscuous (+)-gamma-lactamase activity of an amidase from nitrile hydratase pathway for efficient synthesis of carbocyclic nucleosides intermediate. AB - Based on bioinformatics analysis, the promiscuous (+)-gamma-lactamase activity of an amidase was identified in Rhodococcus erythropolis PR4 and found to be involved in the nitrile hydratase pathway. The amidase is highly enantioselective and can be used in the kinetic resolution of the Vince lactam. The known structure provides a rare insight into the catalytic mechanism of (+)-gamma lactamase with absolute chiral selectivity. This lactamase was cloned, purified, biochemically characterized, and demonstrated to be an ideal catalyst for the preparation of carbocyclic nucleosides of pharmaceutical interest. The chiral selectivity of this enzyme was investigated by molecular docking and site specific mutagenesis, which provides a foundation for further engineering of these versatile biocatalysts. PMID- 29486968 TI - In silico discovery of quinoxaline derivatives as novel LRP5/6-sclerostin interaction inhibitors. AB - The Wnt/beta-catenin signaling pathway is a key regulator of bone homeostasis. Sclerostin act as an extracellular inhibitor of canonical Wnt signaling through high-affinity binding to the Wnt co-receptor LRP5/6. Disruption of the interaction between LRP5/6 and sclerostin has been recognized as a therapeutic target for osteoporosis. We identified a quinoxaline moiety as a new small molecule inhibitor of the LRP5/6-sclerostin interaction through pharmacophore based virtual screening, docking simulations, and in vitro assays. Structure activity relationship studies and binding mode hypotheses were used to optimize the scaffold and yield the compound BMD4503-2, which recovered the downregulated activity of the Wnt/beta-catenin signaling pathway by competitive binding to the LRP5/6-sclerostin complex. Overall, this study showed that the optimized structure-based drug design was a promising approach for the development of small molecule inhibitors of the LRP5/6-sclerostin interaction. A novel scaffold offered considerable insights into the structural basis for binding to LRP5/6 and disruption of the sclerostin-mediated inhibition of Wnt signaling. PMID- 29486969 TI - Design and synthesis of 1,4-substituted 1H-1,2,3-triazolo-quinazolin-4(3H)-ones by Huisgen 1,3-dipolar cycloaddition with PI3Kgamma isoform selective activity. AB - A strategy for construction of medicinally important 1,4-substituted 1H-1,2,3 triazolo-quinazolin-4(3H)-ones has been devised and presented here. The compounds have been synthesized using one-pot multicomponent strategy under microwave assisted conditions. Triazolyl-quinazolinone based D-ring modified analogs are designed based on IC87114 scaffold, which is first known isoform selective inhibitor of PI3Kdelta. Herein, we identified two triazolyl-quinazolinone compounds (5a and 5l) based on same scaffold with PI3Kgamma specific inhibitory potential, the selectivity towards this isoform is well supported by in silico results, wherein, these compounds show better interaction and affinity and inhibitory activity for PI3Kgamma rather than PI3Kdelta. This repositioning of scaffold from PI3Kdelta to PI3Kgamma isoform can be very useful from medicinal chemistry and drug discovery perspective to unravel molecular interactions of this new scaffold in different cellular pathways. PMID- 29486970 TI - Bicyclo((aryl)methyl)benzamides as inhibitors of GlyT1. AB - A series of isoquinuclidine benzamides as glycine uptake inhibitors for the treatment of schizophrenia are described. Potency, lipophilicity, and intrinsic human microsomal clearance were parameters for optimization. Potency correlated with the nature of the ortho substituents of the benzamide ring, and reductions in lipophilicity could be achieved through heteroatom incorporation in the benzamide and pendant phenyl moieties. Improvements in human CLint were achieved through changes in ring size and the N-alkyl group of the isoquinuclidine itself, with des-alkyl derivatives (40-41, 44) demonstrating the most robust microsomal stability. Dimethylbenzamide 9 was tested in a mouse MK801 LMA assay and had a statistically significant attenuation of locomotor activity at 3 and 10 MUmol/kg compared to control. PMID- 29486971 TI - When should computed tomography angiography of pulmonary vessels be done in patients with low clinical probability of acute pulmonary embolism? AB - When the probability of pulmonary embolism is low, the decision to do a computed tomography angiography (CTA) of the pulmonary vessels is based on the D-dimer concentration. However, excessive dependence on this parameter can result in unnecessary imaging studies, inappropriate treatment, or an inappropriate increase in the estimated probability of venous thromboembolism developing. The main objective of this study was to determine when CTA of pulmonary vessels could be avoided in patients with low clinical probability of pulmonary embolism through an efficient literature search of studies published about this question. PMID- 29486972 TI - Amikacin and cefoperazone/sulbactam alone or in combination against carbapenem resistant Pseudomonas aeruginosa. AB - BACKGROUND: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) has become a major therapeutic problem worldwide. Combination therapy may be an alternative chemotherapeutic option. METHODS: Bioluminescent CRPA Xen5-D9 was developed in the present study. Minimum inhibitory concentration of amikacin (AMK) or cefoperazone/sulbactam (SCF) against CRPA Xen5-D9 was determined by microdilution method. CRPA Xen5-D9 was intraperitoneally injected to establish a mouse model of intraperitoneal infection. In vivo bioluminescence imaging was applied at 2 and 5 h after treatment to dynamically evaluate bactericidal effects of AMK alone or in combination with SCF. After 5 h of treatment, ex vivo bacterial colony counts from liver, kidney, spleen, lung, and blood were also determined. RESULTS: CRPA Xen5-D9 was AMK sensitive and SCF intermediate. In vivo imaging showed that AMK alone significantly decreased bioluminescent signals compared with the control, while signals from the SCF-alone group barely changed. Moreover, the AMK-SCF combination did not show greater bactericidal effect compared with AMK alone. Results of ex vivo bacterial counts confirmed that AMK alone significantly decreased the colony counts from different tissues. Although SCF also decreased the colony counts in liver, kidney, spleen, and lung compared with the control, the counts were still higher than those of the AMK-alone group. In addition, AMK SCF combination resulted in significantly lower numbers of colony-forming units in blood compared with individual antibiotics. CONCLUSIONS: AMK-SCF combination did not show better bactericidal effect on AMK-sensitive CRPA-caused infections compared with AMK alone. Although further studies are needed, these results suggest that this combination does not seem to be indicated for treatment of CRPA caused infections. PMID- 29486973 TI - Gastrointestinal tract and liver graft-versus-host disease in pediatric patients with hematopoietic progenitor cell transplantation at a tertiary care center in Mexico. AB - INTRODUCTION AND AIMS: Graft-versus-host disease (GVHD) is a common multisystemic complication of allogeneic hematopoietic cell transplantation. The most frequent presentations of graft-versus-host disease involve the skin, the gastrointestinal tract, and the liver. The aim of the present study was to know the frequency of gastrointestinal tract and liver GVHD and the characteristics of disease presentation in pediatric patients that underwent hematopoietic stem cell transplantation (HSCT) at a tertiary care hospital center in Mexico City. MATERIAL AND METHODS: A retrospective study was carried out, utilizing the case records of patients that underwent HSCT in 2015, to determine the frequency of GVHD in pediatric patients at a Mexican tertiary care hospital center. RESULTS: In 2015, 16 HSCT were performed, 11 of which were carried out in males (68%). Only 3 patients developed graft-versus-host disease (18.7%). One patient presented with skin and liver GVHD and 2 patients presented with gastrointestinal tract and liver GVHD, which was the most frequent type. CONCLUSIONS: HSCT is still an uncommon procedure in Mexico and there is a lower frequency of gastrointestinal tract and liver GVHD than that reported in other studies. Most certainly, there will be an increase in this type of patient and risk factors in the Mexican population must still be determined to help predict the onset of GVHD. PMID- 29486974 TI - Use of epidural clonidine for the management of analgesia in the opioid addicted parturient on buprenorphine maintenance therapy: an observational study. AB - OBJECTIVES: Management of labor analgesia and post-cesarean delivery pain is challenging in the patient taking buprenorphine as opioid addiction maintenance therapy. We observed whether substituting clonidine for fentanyl in an epidural solution would provide adequate analgesia for labor and after cesarean delivery. METHODS: We substituted our standard 2 ug/mL fentanyl in 0.0625% bupivacaine epidural solution with 2 ug/mL clonidine in 0.0625% bupivacaine, or 1.2 ug/mL clonidine in 0.1% bupivacaine, for labor and post-cesarean analgesia in parturients on buprenorphine therapy. All cesarean deliveries were performed with a combined spinal-epidural technique and the catheters maintained for immediate postoperative analgesia using an epidural infusion. Catheters were discontinued the next day and patients were then managed with other analgesics based on obstetric preference. We recorded pain scores during labor and in the immediate post-surgical period; and supplemental medications given after epidural catheter removal. RESULTS: Fourteen patients were included in the study, of whom seven presented in spontaneous labor and seven had elective cesarean delivery. All laboring patients achieved good analgesia, and five of seven avoided supplemental opioid use in the postpartum phase. Of the postsurgical patients, six of seven had pain scores less than 5/10 at epidural catheter removal and three of seven avoided supplemental opioids postoperatively. CONCLUSIONS: The combination of clonidine and bupivacaine appears effective in parturients on buprenorphine therapy for opioid addiction maintenance. As study numbers were small and several factors were not examined, further confirmatory research is needed, including to determine the ideal dose of epidural clonidine in this setting. PMID- 29486975 TI - [Implementation of models to ensure healthcare in rural areas: Development of a consultancy service]. AB - INTRODUCTION: The combination of an ageing population and unequal distribution of healthcare capacity between rural and urban regions requires the development of innovative healthcare models, especially in rural areas, thus increasing the need to involve community representatives. The aim of this study was to ascertain the need for support and advice among municipalities and family doctors planning and implementing regional projects to ensure the provision of healthcare, and to develop a support and consultancy service on that basis. METHODS: Using semi structured telephone interviews, 16 local representatives of the target groups (representatives from rural districts, mayors of rural municipalities and communities, doctors in private practice) were asked to identify the kind of support and advice they needed. The interviews were evaluated using the framework approach, a form of qualitative content analysis, and the results used to develop modules of a support and consultancy service. We discussed and finalized the concept during several workshops involving different representatives of the target groups (another 36 general practitioners, 19 mayors and representatives from rural districts). RESULTS: After taking into account the expressed need for advice and support, the developed consultancy service included the following modules: local situation/needs analysis, financial support options (e. g., grant application), concept/project development (including presentation of best practice examples), networks, assessment and evaluation, junior staff recruitment and introduction to other experts (for legal or IT-related advice, mediation, etc.). DISCUSSION: The study showed that local representatives have a substantial need for advice and support for which no nationwide consultancy service is yet available. Future practice tests should establish the extent to which local participants and projects can benefit from the consultancy service we have developed. PMID- 29486976 TI - Physicians' perspectives on implementing the prevention scheme "Physical Activity on Prescription": Results of a survey in Bavaria. AB - The prevention scheme called "Rezept fur Bewegung" (Physical Activity on Prescription, PAP) enables physicians to formally prescribe participation in health-oriented sports programs to their patients. The PAP scheme aims to strengthen the binding character of physicians' patient counselling for physical activity. The research objective was to investigate the physicians' awareness and their use of PAP as a prevention tool in patient counselling, as well as perceived barriers to implementation. A cross-sectional total population mail questionnaire survey was performed in two districts of Bavaria. 2,821 physicians in private practice were contacted; the response rate was 32.7 %. Descriptive data analysis of 923 questionnaires was carried out using SPSS. Only 26.4 % of the respondents (244/923) were familiar with the PAP scheme, and only 7.7 % (71/923) used PAP at least once a month when counselling their patients. Key barriers to implementation include lack of information on the prevention scheme, a limited choice of local matching sports programs and an unclear commitment of health insurances to reimburse patients for participation fees. Every third physician distrusts PAP to be an efficient way of improving physical activity in patients. To foster the implementation of PAP in the future, awareness-raising campaigns and an expansion of sports programs might be helpful. In order to strengthen the physicians' confidence in the effectiveness of preventive patient counselling on physical activity, existing research evidence needs to be spread among physicians. PMID- 29486977 TI - Panchgavya and cow products: A trail for the holy grail. AB - For millennia, cow has been central to Indian economy, life and culture. There are innumerable references-Vedic and subsequent to the sacred significance of cow. The benefits of cow have been described at length in relation to agriculture, environment, health, economy and spiritual progress. However, the socio-political issues surrounding cow as a sacred animal have raised acrimonious debates. In Ayurveda also, there is a long tradition of using cow products for positive health, pharmaceutical processes and in therapeutics. There have been quite a few studies on the activity, efficacy, safety and acceptability of Panchagavya and other cow products. Paradoxically, many cow products available in the market for human consumption require improved standardization and proper regulation. Integration of cowpathy (Govaidyak) in traditional Indian systems of medicine has been natural, based on their common dravyagunavigyan. But if its integration with conventional medicine is contemplated, we will need better understanding of the ingredients of cow products, their pharmacokinetics, pharmacodynamics and therapeutic ratio. A rational beginning can be made by data collection of experiential and anecdotal responses. A meticulous analysis of database of panchgavya and other cow products should look for temporal relationships, biological plausibility and translational potential before embarking on state-of-the-art experimental and clinical studies for selected indications. PMID- 29486978 TI - Guiding Mitotic Progression by Crosstalk between Post-translational Modifications. AB - Cell division is tightly regulated to disentangle copied chromosomes in an orderly manner and prevent loss of genome integrity. During mitosis, transcriptional activity is limited and post-translational modifications (PTMs) are responsible for functional protein regulation. Essential mitotic regulators, including polo-like kinase 1 (PLK1) and cyclin-dependent kinases (CDK), as well as the anaphase-promoting complex/cyclosome (APC/C), are members of the enzymatic machinery responsible for protein modification. Interestingly, communication between PTMs ensures the essential tight and timely control during all consecutive phases of mitosis. Here, we present an overview of current concepts and understanding of crosstalk between PTMs regulating mitotic progression. PMID- 29486979 TI - Unravelling the Mechanisms of RNA Helicase Regulation. AB - RNA helicases are critical regulators at the nexus of multiple pathways of RNA metabolism, and in the complex cellular environment, tight spatial and temporal regulation of their activity is essential. Dedicated protein cofactors play key roles in recruiting helicases to specific substrates and modulating their catalytic activity. Alongside individual RNA helicase cofactors, networks of cofactors containing evolutionarily conserved domains such as the G-patch and MIF4G domains highlight the potential for cross-regulation of different aspects of gene expression. Structural analyses of RNA helicase-cofactor complexes now provide insight into the diverse mechanisms by which cofactors can elicit specific and coordinated regulation of RNA helicase action. Furthermore, post translational modifications (PTMs) and long non-coding RNA (lncRNA) regulators have recently emerged as novel modes of RNA helicase regulation. PMID- 29486980 TI - Cross-cultural adaptation and measurement properties testing of the Iconographical Falls Efficacy Scale (Icon-FES). AB - BACKGROUND: The Iconographical Falls Efficacy Scale (Icon-FES) is an innovative tool to assess concern of falling that uses pictures as visual cues to provide more complete environmental contexts. Advantages of Icon-FES over previous scales include the addition of more demanding balance-related activities, ability to assess concern about falling in highly functioning older people, and its normal distribution. OBJECTIVE: To perform a cross-cultural adaptation and to assess the measurement properties of the 30-item and 10-item Icon-FES in a community dwelling Brazilian older population. METHODS: The cross-cultural adaptation followed the recommendations of international guidelines. We evaluated the measurement properties (i.e. internal consistency, test-retest reproducibility, standard error of the measurement, minimal detectable change, construct validity, ceiling/floor effect, data distribution and discriminative validity), in 100 community-dwelling people aged >=60 years. RESULTS: The 30-item and 10-item Icon FES-Brazil showed good internal consistency (alpha and omega >0.70) and excellent intra-rater reproducibility (ICC2,1=0.96 and 0.93, respectively). According to the standard error of the measurement and minimal detectable change, the magnitude of change needed to exceed the measurement error and variability were 7.2 and 3.4 points for the 30-item and 10-item Icon-FES, respectively. We observed an excellent correlation between both versions of the Icon-FES and Falls Efficacy Scale - International (rho=0.83, p<0.001 [30-item version]; 0.76, p<0.001 [10-item version]). Icon-FES versions showed normal distribution, no floor/ceiling effects and were able to discriminate between groups relating to fall risk factors. CONCLUSION: Icon-FES-Brazil is a semantically and linguistically appropriate tool with acceptable measurement properties to evaluate concern about falling among the community-dwelling older population. PMID- 29486981 TI - Elevated preoperative blood pressures in adult surgical patients are highly predictive of elevated home blood pressures. AB - Blood pressure (BP) measurement during the presurgical assessment has been suggested as a way to improve longitudinal detection and treatment of hypertension. The relationship between BP measured during this assessment and home blood pressure (HBP), a better indicator of hypertension, is unknown. The purpose of the present study was to determine the positive predictive value of presurgical BP for predicting elevated HBP. We prospectively enrolled 200 patients at a presurgical evaluation clinic with clinic blood pressures (CBPs) >=130/85 mm Hg, as measured using a previously validated automated upper-arm device (Welch Allyn Vital Sign Monitor 6000 Series), to undergo daily HBP monitoring (Omron Model BP742N) between the index clinic visit and their day of surgery. Elevated HBP was defined, per American Heart Association guidelines, as mean systolic HBP >=135 mm Hg or mean diastolic HBP >=85 mm Hg. Of the 200 participants, 188 (94%) returned their home blood pressure monitors with valid data. The median number of HBP recordings was 10 (interquartile range, 7-14). Presurgical CBP thresholds of 140/90, 150/95, and 160/100 mm Hg yielded positive predictive values (95% confidence interval) for elevated HBP of 84.1% (0.78 0.89), 87.5% (0.81-0.92), and 94.6% (0.87-0.99), respectively. In contrast, self reported BP control, antihypertensive treatment, availability of primary care, and preoperative pain scores demonstrated poor agreement with elevated HBP. Elevated preoperative CBP is highly predictive of longitudinally elevated HBP. BP measurement during presurgical assessment may provide a way to improve longitudinal detection and treatment of hypertension. PMID- 29486982 TI - Dietary Inflammatory Potential Score and Risk of Breast Cancer: Systematic Review and Meta-analysis. AB - Several studies have been conducted on the relationship between dietary inflammatory potential (DIP) and breast cancer. However, the findings are conflicting. This systematic review and meta-analysis summarizes the findings on the association between DIP and the risk of breast cancer. We used relevant keywords and searched online international electronic databases, including PubMed and NLM Gateway (for Medline), Institute for Scientific Information (ISI), and Scopus for articles published through February 2017. All cross-sectional, case control, and cohort studies were included in this meta-analysis. Meta-analysis was performed using the random effects meta-analysis method to address heterogeneity among studies. Findings were analyzed statistically. Nine studies were included in the present systematic review and meta-analysis. The total sample size of these studies was 296,102, and the number of participants varied from 1453 to 122,788. The random effects meta-analysis showed a positive and significant association between DIP and the risk of breast cancer (pooled odds ratio, 1.14; 95% confidence interval, 1.01-1.27). The pooled effect size was not statistically significant because of the type of studies, including cohort (pooled relative risk, 1.04; 95% confidence interval, 0.98-1.10) and case-control (pooled odds ratio, 1.63; 95% confidence interval, 0.89-2.37) studies. We found a significant and positive association between higher DIP score and risk of breast cancer. Modifying inflammatory characteristics of diet can substantially reduce the risk of breast cancer. PMID- 29486983 TI - Phase II Trial of Bevacizumab Plus Weekly Paclitaxel, Carboplatin, and Metronomic Cyclophosphamide With or Without Trastuzumab and Endocrine Therapy as Preoperative Treatment of Inflammatory Breast Cancer. AB - BACKGROUND: Inflammatory breast cancer (IBC) is a rare and highly aggressive disease. A neoadjuvant regimen with chemotherapy and an antiangiogenic strategy was investigated. PATIENTS AND METHODS: Patients with primary or recurrent IBC who were candidates for neoadjuvant treatment received weekly carboplatin and paclitaxel plus bevacizumab every 3 weeks and oral metronomic cyclophosphamide for 6 months. Trastuzumab was added for patients with HER2+ tumors and endocrine therapy was added for patients with estrogen receptor and/or progesterone receptor >= 10% tumors. Oral metronomic capecitabine and cyclophosphamide was continued for 6 months after surgery in those patients with a response. The primary efficacy endpoints were pathologic complete remission (pCR) and the objective response. RESULTS: From July 2010 to December 2013, 34 patients with IBC were included. The surrogate intrinsic tumor subtypes were as follows: luminal B-like (HER2-), 10 (29%); luminal B-like (HER2+), 8 (24%); HER2+ (nonluminal), 6 (18%); and triple negative, 10 (29%). An objective response was obtained in 30 patients (88%; 95% confidence interval, 73%-97%) and a pCR in 10 patients (29%; 95% confidence interval, 15%-48%). The proportion of pCR was significantly greater in the patients with HER2+ tumors (57%) than in patients with triple-negative (20%) or luminal B-like (HER2-) tumors (0%; P = .019). After a median follow-up of 4.4 years, the 5-year disease-free survival and overall survival was 58% and 72%, respectively. The achievement of pCR was associated with longer disease-free (P = .12) and overall (P = .029) survival. CONCLUSION: In patients with IBC, neoadjuvant treatment with the investigated regimen was successful and well tolerated. Further studies evaluating the potential benefit of an antiangiogenic strategy in this setting are awaited. PMID- 29486984 TI - Cardiac autonomic responses to nociceptive stimuli in patients with chronic disorders of consciousness. AB - OBJECTIVES: Patients with chronic disorders of consciousness (DOC) may show alterations of autonomic function; however, in this clinical population, no data are available on the specific effects of nociceptive stimuli on cardiac autonomic control. Thus, we aimed at investigating the effects of a noxious stimulation on heart rate variability (HRV) in a population of patients with chronic DOC, taking into account different states of consciousness (vegetative state/unresponsive wakefulness syndrome, VS/UWS and minimally conscious state, MCS). METHODS: We enrolled twenty-four DOC patients (VS/UWS, n = 12 and MCS, n = 12). ECG and respiration were recorded during baseline, immediately after the nociceptive stimulus and, finally, during the recovery period. Linear and nonlinear HRV measures were used to evaluate the cardiac autonomic control. RESULTS: In DOC patients, nonlinear HRV analysis showed that nociceptive stimuli are able to elicit a change of autonomic function characterized by an increased sympathetic and a reduced vagal modulation. A significant reduction of autonomic complexity has also been detected. More interestingly, VS/UWS patients showed a less complex dynamics compared to MCS patients. CONCLUSIONS: Cardiac autonomic responses are able to significantly differentiate the autonomic function between VS/UWS and MCS patients. SIGNIFICANCE: Nonlinear HRV analysis may represent a useful tool to characterize the cardiac autonomic responses to nociceptive stimuli in a chronic DOC population. PMID- 29486985 TI - Current use of Social Media in Neurosurgery in Spain. AB - OBJECTIVE: To analyze the current situation in Spain of the use of Social Media in Neurosurgery. MATERIALS AND METHODS: We made an observational transversal study between February and March 2017, with a systematic search of the Facebook, Twitter and Youtube accounts from public and private neurosurgical units, scientific societies, peer-reviewed publications and patients groups in relation with Neurosurgical pathologies. We rank them according their popularity. RESULTS: According of our search only 5 public neurosurgical services have social media accounts, being their popularity inferior to the private units accounts. In relation with the scientific societies and neurosurgical publications their presence in social media is marginal, even more in comparison to the accounts of other medical specialities. The popularity of associations of patients and supporting groups is high, especially among patients, finding there more information about their disease. CONCLUSIONS: The use in Spain of Social Media about Neurosurgery is low in comparison to other medical specialities. There is a huge field to improve the popularity of the accounts, making in them promotion of health and extend the diffusion of the scientific society and the peer-reviewed publication Neurocirugia. PMID- 29486986 TI - Sinusoidal hemangioma and intravascular papillary endothelial hyperplasia: Interrelated processes that share a histogenetic piecemeal angiogenic mechanism. AB - Sinusoidal hemangioma, characterized by interconnecting thin-walled vascular spaces, may present papillae/pseudo-papillae and zones that resemble intravascular papillary endothelial hyperplasia (IPEH). Our objectives are to explore the existence of zones in IPEH with sinusoidal hemangioma characteristics, the mechanism of papillary and septa formation in sinusoidal hemangioma and the comparison of this mechanism with that in IPEH. For these purposes, specimens of 4 cases of each entity were selected and studied by serial histologic sections and by immunochemistry and immunofluorescence procedures. The results showed a) zones with characteristics of sinusoidal hemangioma in IPEH cases, b) presence in both entities of papillae with a cover formed by a monolayer of CD34+ and CD31+ endothelial cells (ECs) and a core formed by either type I collagen and alphaSMA+ cells (presenting a pericyte/smooth muscle cell aspect) or thrombotic components, and c) a similar piecemeal angiogenic mechanism in papillary formation, including sprouting of intimal ECs toward the vessel wall itself or intravascular thrombi, formation of vascular loops that encircle and separate vessel wall or thrombus components, and parietal or thrombotic papillae development. The major differences between both entities were the number, arrangement and substrate of papillae: myriad, densely grouped, parietal and thrombotic papillae in IPEH, and a linear arrangement of predominant parietal papillae in sinusoidal hemangioma, originating septa (segmentation). In conclusion, sinusoidal hemangioma and IPEH are interrelated processes, which share morphologic findings and a piecemeal angiogenic mechanism, combining sprouting and intussusceptive angiogenesis, and leading to papillary formation and vessel segmentation. PMID- 29486987 TI - Multivessel vs. culprit-only revascularization in patients with non-ST-elevation acute coronary syndromes and multivessel coronary disease. AB - INTRODUCTION: There have been no prospective randomized trials that enable the best strategy and timing to be determined for revascularization in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) and multivessel coronary artery disease (CAD). OBJECTIVES: To compare short- and long-term adverse events following multivessel vs. culprit-only revascularization in patients with NSTE-ACS and multivessel CAD. METHODS: This was a retrospective observational study that included all patients diagnosed with NSTE-ACS and multivessel CAD who underwent percutaneous coronary intervention (PCI) between January 2010 and June 2013 (n=232). After exclusion of patients with previous coronary artery bypass grafting (n=30), a multivessel revascularization strategy was adopted in 35.1% of patients (n=71); in the others (n=131, 64.9%), only the culprit artery was revascularized. After propensity score matching (PSM), two groups of 66 patients were obtained, matched according to revascularization strategy. RESULTS: During follow-up (1543+/-545 days), after PSM, patients undergoing multivessel revascularization had lower rates of reinfarction (4.5% vs. 16.7%; log-rank p=0.018), unplanned revascularization (6.1% vs. 16.7%; log rank p=0.048), unplanned PCI (3.0% vs. 13.6%; log-rank p=0.023) and the combined endpoint of death, reinfarction and unplanned revascularization (16.7 vs. 31.8%; log-rank p=0.046). CONCLUSIONS: In real-world patients presenting with NSTE-ACS and multivessel CAD, a multivessel revascularization strategy was associated with lower rates of reinfarction, unplanned revascularization and unplanned PCI, as well as a reduction in the combined endpoint of death, reinfarction and unplanned revascularization. PMID- 29486989 TI - The authors responds on comparing Macintosh and Miller Laryngoscopes during Pediatric Resuscitation". PMID- 29486988 TI - Non-invasive assessment of coronary artery geometry using coronary CTA. AB - AIM: To assess the association of coronary artery geometry with the severity of coronary artery disease (CAD). METHODS: 73 asymptomatic individuals at increased risk of CAD due to peripheral vascular disease (18 women, mean age 63.5 +/- 8.2 years) underwent coronary computed tomography angiography (coronary CTA) using first generation dual-source CT. Curvature and tortuosity of the coronary arteries were quantified using semi-automatically generated centerlines. Measurements were performed for individual segments and for the entire artery. Coronary segments were labeled according to the presence of significant stenosis, defined as >70% luminal narrowing, and the presence of plaque. Comparisons were made by segment and by artery, using linear mixed models. RESULTS: Overall, median curvature and tortuosity were, respectively, 0.094 [0.071; 0.120] and 1.080 [1.040; 1.120] on a per-segment level, and 0.096 [0.078; 0.118] and 1.175 [1.090; 1.420] on a per-artery level. Curvature was associated with significant stenosis at a per-segment (p < 0.001) and per-artery level (p = 0.002). Curvature was 16.7% higher for segments with stenosis, and 13.8% higher for arteries with stenosis. Tortuosity was associated with significant stenosis only at the per segment level (p = 0.002). Curvature was related to the presence of plaque at the per-segment (p < 0.001) and per-artery level (p < 0.001), tortuosity was only related to plaque at the per-segment level (p < 0.001). CONCLUSION: Coronary artery geometry as derived from coronary CTA is related to the presence of plaque and significant stenosis. PMID- 29486990 TI - Concomitant external and internal hemorrhage: Challenges to managing patients with open pelvic fracture. AB - INTRODUCTION: Managing patients with open pelvic fractures continues to be challenging and requires a multidisciplinary approach. In this study, we examined the characteristics of patients with open pelvic fractures and strategies for managing such patients. MATERIALS AND METHODS: The records of patients with open pelvic fractures from January 2010 to August 2016 were retrospectively reviewed. Emergency surgery was performed to control hemorrhaging in patients with an active external hemorrhage. Transcatheter arterial embolization (TAE) was used for definitive hemostasis. The relation between cause of death and timing of death was examined. We also compared the characteristics of surviving and non surviving patients. Furthermore, patients who received both surgery and post operative TAE were analyzed in detail. RESULTS: In total, 42 patients with open pelvic fractures were enrolled in the study. The overall mortality rate among patients with open pelvic fractures was 26.2%. Patients whose deaths were related to hemorrhaging and associated injuries died significantly earlier than patients whose deaths were related to sepsis and multiple organ failure (1.3days vs. 12.3days, p<0.001). Sixteen patients (38.1%) received TAE for hemostasis, and their systolic blood pressure (SBP) improved significantly following TAE (from 88.4mmHg to 111.6mmHg, p<0.05). In the patients who received both surgery and post-operative TAE (n=8), the SBP increased significantly after surgery (from 58.8mmHg to 81.1mmHg, p<0.05). Similarly, the patients' SBP after TAE was significantly higher than their post-operative SBP (110.5mmHg vs. 81.1mmHg, p<0.05). CONCLUSION: Active external hemorrhaging was initially controlled when managing patients with open pelvic fractures; however, most patients also required TAE for definitive hemorrhage control. Early TAE should be considered due to the high probability of concomitant internal and external hemorrhage. Close observation and further infection control are important following the hemostatic procedure. PMID- 29486991 TI - Characteristics of African American women at high-risk for ovarian cancer in the southeast: Results from a Gynecologic Cancer Risk Assessment Clinic. AB - OBJECTIVES: Describe patient characteristics in African American (AA) women seen for gynecologic cancer related genetic counseling at a large southeastern comprehensive cancer center. METHODS: We reviewed an IRB approved, prospective observational cohort of patients from a Gynecologic Cancer Risk Assessment Clinic. Data evaluated included personal cancer history, family history, frequency of genetic testing, frequency/type of genetic mutations, and frequency of surgical intervention. Standard statistical statistics were utilized. RESULTS: 1227 patients were evaluated from 2003 to 2015, of which 95 (7.7%) were AA. Sixteen patients had a personal history of ovarian cancer. 21 women (22%) underwent genetic counseling only; subsequent genetic testing was not recommended based on absence of risk factors. Of the seventy-four AA patients in whom genetic testing was recommended, sixty-six (69.5%) completed testing. Of women tested, 37 (56%) had abnormal results. Eight and 14 patients had pathogenic variants in BRCA1 and BRCA2, respectively. Two were found to have pathogenic PALB2 variants; one had a pathogenic ATM variant and one constitutional MLH1 epimutation case was identified. Eleven had BRCA variants of uncertain significance. Of the patients with abnormal testing, six of 22 women with pathogenic BRCA variants underwent risk-reducing salpingo-oophorectomy (RRSO). CONCLUSIONS: Our study demonstrates that in a region where AAs represent 27% of the population, the proportion of AA patients referred to a Gynecologic Cancer Risk Assessment Clinic remains low. Pathogenic variant and variant of uncertain significance rates were high in patients tested, likely representing a selection bias of high-risk patients. Endeavors should continue to identify minorities at risk for ovarian cancer and institute measures to provide thorough genetic counseling and testing. PMID- 29486992 TI - Combined ASRGL1 and p53 immunohistochemistry as an independent predictor of survival in endometrioid endometrial carcinoma. AB - OBJECTIVE: In clinical practise, prognostication of endometrial cancer is based on clinicopathological risk factors. The use of immunohistochemistry-based markers as prognostic tools is generally not recommended and a systematic analysis of their utility as a panel is lacking. We evaluated whether an immunohistochemical marker panel could reliably assess endometrioid endometrial cancer (EEC) outcome independent of clinicopathological information. METHODS: A cohort of 306 EEC specimens was profiled using tissue microarray (TMA). Cost- and time-efficient immunohistochemical analysis of well-established tissue biomarkers (ER, PR, HER2, Ki-67, MLH1 and p53) and two new biomarkers (L1CAM and ASRGL1) was carried out. Statistical modelling with embedded variable selection was applied on the staining results to identify minimal prognostic panels with maximal prognostic accuracy without compromising generalizability. RESULTS: A panel including p53 and ASRGL1 immunohistochemistry was identified as the most accurate predictor of relapse-free and disease-specific survival. Within this panel, patients were allocated into high- (5.9%), intermediate- (29.5%) and low- (64.6%) risk groups where high-risk patients had a 30-fold risk (P<0.001) of dying of EEC compared to the low-risk group. CONCLUSIONS: P53 and ASRGL1 immunoprofiling stratifies EEC patients into three risk groups with significantly different outcomes. This simple and easily applicable panel could provide a useful tool in EEC risk stratification and guiding the allocation of treatment modalities. PMID- 29486993 TI - Modeling treatment outcomes for patients with advanced ovarian cancer: Projected benefits of a test to optimize treatment selection. AB - OBJECTIVE: For patients with advanced stage epithelial ovarian cancer (EOC), substantial emphasis has been placed on diagnostic tests that can discern which of two treatment options - primary cytoreductive surgery (PCS) or neoadjuvant chemotherapy followed by interval cytoreductive surgery (NACT+ICS) - optimizes patient-level outcomes. Our goal was to project potential life expectancy (LE) gains that could be achieved by use of such a test. METHODS: We developed a microsimulation model to project LE for patients with stage IIIC EOC. We compared: a "standard-of-care" strategy, in which patients were triaged to PCS vs. NACT+ICS based on current clinical practice; and a "test" strategy, in which patients were triaged based on results of a hypothetical test. We identified those test performance characteristics for which the test strategy outperformed the standard-of-care strategy, from a LE standpoint. Effects of parameter uncertainty were evaluated in sensitivity analysis. RESULTS: Even with a perfect test, the LE gain was modest (LE with test vs. standard-of-care strategy=67.6 vs. 66.4months; LE gain=1.2months). In order to outperform the standard-of-care, the test had to have a high probability of correctly identifying "resectable" patients at PCS (i.e. those for whom complete or optimal cytoreduction would be possible); this test property was more important than correct triage of unresectable patients to NACT+ICS. Results were sensitive to the proportion of patients whose underlying disease was resectable at PCS. CONCLUSION: Diagnostic tests that are designed to triage patients with advanced stage EOC will likely have only a modest effect on LE. PMID- 29486994 TI - The efficacy of telehealth delivered educational approaches for patients with chronic diseases: A systematic review. AB - OBJECTIVE: The virtual delivery of patient education and other forms of telehealth have been proposed as alternatives to providing needed care for patients with chronic diseases. The purpose of this systematic review was to compare the efficacy of virtual education delivery on patient outcomes compared with usual care. METHODS: The review examined citations from 3 databases, MEDLINE, CINAHL, and EMBASE using the search words telehealth, chronic disease, patient education, and related concepts. From 2447 records published between 2006 and 2017, 16 high to moderate quality studies were selected for review. Eligible papers compared virtual education to usual care using designs allowing for assessment of causality. RESULTS: Telehealth modalities included the web, telephone, videoconference, and television delivered to patients with diabetes, chronic obstructive pulmonary disease, irritable bowel syndrome and heart failure. In 11 of 16 studies, virtually delivered interventions significantly improved outcomes compared to control conditions. In the remaining 5 studies, virtual education showed comparable outcomes to the control conditions. CONCLUSIONS: Findings demonstrated that virtual education delivered to patients with chronic diseases was comparable, or more effective, than usual care. RESEARCH IMPLICATIONS: Despite its benefits, there is potential for further research into the individual components which improve effectiveness of virtually delivered interventions. PMID- 29486996 TI - Impact of age on the selection of nuclear cardiology stress protocols: The INCAPS (IAEA nuclear cardiology protocols) study. AB - BACKGROUND: There is growing concern about radiation exposure from nuclear myocardial perfusion imaging (MPI), particularly among younger patients who are more prone to develop untoward effects of ionizing radiation, and hence US and European professional society guidelines recommend age as a consideration in weighing radiation risk from MPI. We aimed to determine how patient radiation doses from MPI vary across age groups in a large contemporary international cohort. METHODS: Data were collected as part of a global cross-sectional study of centers performing MPI coordinated by the International Atomic Energy Agency (IAEA). Sites provided information on each MPI study completed during a single week in March-April 2013. We compared across age groups laboratory adherence to pre-specified radiation-related best practices, radiation effective dose (ED; a whole-body measure reflecting the amount of radiation to each organ and its relative sensitivity to radiation's deleterious effects), and the proportion of patients with ED <= 9 mSv, a target level specified in guidelines. RESULTS: Among 7911 patients undergoing MPI in 308 laboratories in 65 countries, mean ED was 10.0 +/- 4.5 mSv with slightly higher exposure among younger age groups (trend p value < 0.001). There was no difference in the proportion of patients with ED <= 9 mSv across age groups, or in adherence to best practices based on the median age of patients in a laboratory. CONCLUSIONS: In contemporary nuclear cardiology practice, the age of the patient appears not to impact protocol selection and radiation dose, contrary to professional society guidelines. PMID- 29486995 TI - Relation between total shock energy and mortality in patients with implantable cardioverter-defibrillator. AB - BACKGROUND: Implantable Cardioverter-Defibrillator (ICD) shocks have been associated with mortality. However, no study has examined the relation between total shock energy and mortality. The aim of this study is to assess the association of total shock energy with mortality, and to determine the patients who are at risk of this association. METHODS: Data from 316 consecutive patients who underwent initial ICD implantation in our hospital between 2000 and 2011 were retrospectively studied. We collected shock energy for 3 years from the ICD implantation, and determined the relation of shock energy on mortality after adjusting confounding factors. RESULTS: Eighty-seven ICD recipients experienced shock(s) within 3 years from ICD implantation and 43 patients had died during the follow-up. The amount of shock energy was significantly associated with all-cause death [adjusted hazard ratio (HR) 1.26 (per 100 joule increase), p < 0.01] and tended to be associated with cardiac death (adjusted HR 1.30, p = 0.08). The survival rate of patients with high shock energy accumulation (>=182 joule) was lower (p < 0.05), as compared to low shock energy accumulation (<182 joule), likewise to no shock. Besides, the relation between high shock energy accumulation and all-cause death was remarkable in the patients with low left ventricular ejection fraction (LVEF <=40%) or atrial fibrillation (AF). CONCLUSIONS: Increase of shock energy was related to mortality in ICD recipients. This relation was evident in patients with low LVEF or AF. PMID- 29486997 TI - ST2 as a predictor of late ventricular remodeling after myocardial infarction. AB - Out of 163 STEMI patients, 33 presented left ventricular remodeling (LVR) as assessed by multiple cardiac magnetic resonance (CMR) scans. LVR patients were identified as EarlyLVR (LVR occurring between baseline and 3 months) or LateLVR (LVR occurring between 3 months and one year), and matched to non-remodeler patients in term of age, gender, anterior infarction, baseline LV ejection fraction and infarct size. ST2 and NT-proBNP were measured at baseline and 3 months. Systolic wall stress (SWS) was calculated by CMR. At baseline, mean levels of ST2, NT-proBNP and SWS were 67.1 +/- 54.1 ng/mL, 1529 +/- 1702 ng/L and 17.9 +/- 7.1 103 N.m-2, respectively, and did not differ among the groups. At 3 months, EarlyLVR patients presented significant higher ST2, NT-proBNP and SWS (31.6 +/- 12.7 ng/mL, 1142 +/- 1069 ng/L, 25.5 +/- 9.7 103 N.m-2), compared to the corresponding non-remodelers (20.5 +/- 8.6 ng/mL, 397 +/- 273 ng/L, 18 +/- 7.3 103 N.m-2; with p = 0.017, 0.040, and 0.036, respectively). LateLVR patients presented higher ST2 at 3 months than their non-remodelers (33.6 +/- 15.9 versus 23.66 +/- 8.7 ng/mL, p = 0.046), while NT-proBNP and SWS were not different between groups at both timepoints. PMID- 29486998 TI - Age at menopause, extent of coronary artery disease and outcome among postmenopausal women with acute coronary syndromes. AB - BACKGROUND: Early menopause has been associated with increased cardiovascular mortality, but prospective studies investigating outcomes of postmenopausal women with acute coronary syndromes (ACS) in relation to menopausal age are lacking. METHODS: We analyzed the 1-year outcome of 373 women with acute myocardial infarction enrolled in the Ladies ACS study. All patients underwent coronary angiography, with corelab analysis. Menopause questionnaires were administered during admission. Menopausal age below the median of the study population (50 years) was defined as "early menopause". The composite 1-year outcome included all-cause mortality, recurrent myocardial infarction and stroke. RESULTS: The mean age at index ACS was 73 years (IQR 65-83) for women with early menopause, and 74 (IQR 65-80) for those with late menopause. Patients with early menopause had more prevalent chronic kidney disease (12.8% vs 5.9%, p = 0.03), whereas there were no differences in all other clinical characteristics, extent of coronary disease at angiography (as assessed by Gensini and SYNTAX scores), as well as interventional treatments. Within 1 year, women with late menopause had significantly better outcome as compared with those with early menopause (6.5% vs 15.3%, p = 0.007). At logistic regression analysis, late menopause was independently associated with better outcome (OR 0.28; 95% CI 0.12-0.67; p = 0.004). With each year's delay in the menopause the adjusted risk decreased by 12% (OR 0.88, 0.77-0.99, p = 0.040). CONCLUSION: Despite comparable clinical and angiographic characteristics, women with late menopausal age experience better outcomes after an ACS as compared with those with early menopause. PMID- 29486999 TI - Prospective evaluation of Globus pallidus internus deep brain stimulation in Huntington's disease. AB - INTRODUCTION: Pharmacological treatment of chorea in Huntington's disease (HD) is often limited by poor efficacy or side effects. Pallidal deep brain stimulation (DBS) has been considered in these patients but experience is so far limited. METHODS: We prospectively evaluated the effects of bilateral DBS of the Globus pallidus internus (GPi) over one year in six severely affected HD patients with treatment refractory chorea in an advanced stage of the disease. Primary endpoint of the study was improvement in chorea. Additionally, we evaluated the effects of GPi DBS on the motor part of the Unified Huntington's Disease Rating Scale (UHDRS), bradykinesia, dystonia, functional impairment, psychiatric and cognitive symptoms. Side effects were systematically assessed. RESULTS: The chorea subscore was significantly reduced postoperatively (-47% six months, -40% twelve months postoperatively). The UHDRS total motor score was significantly reduced at six months postoperatively (- 17%) but the effect was not sustained twelve months after the operation (- 5%). Pallidal DBS did not improve other motor symptoms or functional impairment. There was no effect on psychiatric symptoms or cognition. A number of side effects were noted, especially spasticity in three of the patients. CONCLUSIONS: Pallidal DBS is a treatment option for HD patients with severe pharmacologically refractory chorea. Further studies are needed to define optimal candidates for this procedure. PMID- 29487000 TI - Glucocerebrosidase gene variants are accumulated in idiopathic REM sleep behavior disorder. AB - INTRODUCTION: Glucocerebrosidase (GBA) gene variants are associated with the development of the Lewy body disorders (LBD) Parkinson disease (PD) and dementia with Lewy bodies (DLB). Idiopathic REM sleep behavior disorder (IRBD) represents prodromal LBD in most instances. We investigated whether GBA variants are overrepresented in IRBD and if their presence shortens the time to conversion to clinically-defined LBD. METHODS: All GBA coding exons from 69 polysomnography confirmed IRBD patients and 84 matched controls were sequenced by the Sanger method. RESULTS: Seven missense variants (E326K, L444P, A446T, A318G, R329C, T369M, N370S) were identified in eight (11.6%) IRBD patients and in one (1.2%) control (P = 0.026). After a mean follow-up of 8.9 +/- 3.8 years from IRBD diagnosis, five subjects with GBA variants developed LBD (3 DLB and 2 PD) and three remained disease-free. The risk of developing a LBD was similar in IRBD subjects with GBA variants than in those without variants (log rank test, p = 0.935). CONCLUSIONS: In IRBD, GBA variants are 1) more frequent when compared to controls, 2) associated with impending PD and DLB but 3) not indicative of a short-term risk for LBD after IRBD diagnosis. IRBD patients carrying GBA variants could be studied with disease-modifying interventions aiming to restore the GBA metabolic pathway. PMID- 29487001 TI - The Influence of Segond Fracture on Outcomes After Anterior Cruciate Ligament Reconstruction. AB - PURPOSE: To determine the prevalence of Segond fractures using computed tomography (CT) and to investigate the effects of Segond fractures on the outcomes of primary anterior cruciate ligament (ACL) reconstruction for isolated ACL injuries. METHODS: Between January 2010 and July 2015, we retrospectively evaluated 383 patients who underwent primary ACL reconstruction, who underwent CT scans immediately after surgery, and who were available at 2 years of follow-up. The absence or presence of a Segond fracture was confirmed using CT. The following parameters were evaluated in all patients at the 2-year follow-up visit: clinical scores (International Knee Documentation Committee subjective score, Lysholm score, and Tegner activity score) and knee joint stability (anterior drawer test, Lachman test, pivot-shift test, and side-to-side difference in anterior tibial translation on Telos stress radiographs). RESULTS: Among 383 patients with primary ACL tears, a Segond fracture was confirmed in 8.9% (n = 34) using 3-dimensional CT. We placed 349 patients into the group with ACL tears without Segond fractures (group A) and the other 34 into the group with ACL tears with Segond fractures (group B). Between the 2 groups, there were no significant differences in the postoperative International Knee Documentation Committee subjective score (P = .97), Lysholm score (P = .17), or Tegner activity score (P = .95). No significant differences in the anterior drawer test (P = .28), Lachman test (P = .45), pivot-shift test (P = .14), and side-to-side difference in anterior tibial translation on Telos stress radiographs (P = .93) between the 2 groups were found preoperatively and postoperatively. CONCLUSIONS: The presence of a Segond fracture did not affect knee joint stability in patients with ACL tears. Moreover, the 2 groups did not show significant differences in clinical scores or knee joint stability after undergoing ACL reconstruction. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 29487002 TI - Overexpression of YAP1 in EGFR mutant lung adenocarcinoma prior to tyrosine kinase inhibitor therapy is associated with poor survival. AB - EGFR tyrosine kinase inhibitor (EGFR TKI) is approved as first-line treatment for advanced-stage EGFR mutant lung adenocarcinoma (LADC). Yes-associated protein 1 (YAP1), a main effector of the Hippo pathway, is associated with adverse prognosis and disruption of EGFR TKI modulation of non-small cell lung cancer. In this study, we demonstrated a prognostic role of YAP1 in EGFR mutant LADC and efficacy of EGFR TKI therapy. A total of 63 patients, including 41 with paired lung cancer specimens before and after EGFR TKI therapy and 22 with non-paired lung cancer specimens prior to EGFR TKI, were enrolled for examination. Expression of YAP1 protein was evaluated using immunohistochemistry. Fifteen paired cases (36.6%) with high nuclear YAP1 expression were detected in the pre EGFR TKI LADC group and 21 paired cases (52.5%) after treatment with EGFR TKI. Nuclear YAP1 expression was significantly upregulated after EGFR TKI therapy (P = .002). Fifteen paired cases with high nuclear YAP1 expression before EGFR TKI LADCs showed poorer overall survival (OS) (P = .023) and progression-free survival (PFS) (P = .041). Among the 63 patients under study, those with high nuclear YAP1 expression before EGFR TKI showed shorter OS (P = .038) and PFS (P < .001). High nuclear YAP1 expression in cases with acquired EGFR exon 20 T790 M mutant LADCs showed poorer OS (P < .001). We demonstrated that YAP1 burden before clinical application of EGFR TKI plays a crucial role in prognosis of EGFR mutant LADC treated using EGFR TKI. PMID- 29487003 TI - SATB2 is a supportive marker for the differentiation of a primary mucinous tumor of the ovary and an ovarian metastasis of a low-grade appendiceal mucinous neoplasm (LAMN): A series of seven cases. AB - The differentiation between a primary mucinous ovarian neoplasm and an extra ovarian metastasis in the ovary is often challenging in the histopathologic practice. Among various ovarian metastases from the gastro-intestinal tract the low-grade appendiceal mucinous neoplasm (LAMN) is an important differential diagnosis to consider particularly in case of pseudomyxoma peritonei. A newly recognized marker in the routine diagnostic of a mucinous neoplasm in the ovary is SATB2 (Special AT-rich sequence-binding protein 2). The expression of SATB2 is, within cells of epithelial lineages, mainly restricted to the lower gastro intestinal tract, indicating colorectal or appendiceal cancer origin. We report seven cases of LAMN, which clinically became apparent due to ovarian metastases in context of pseudomyxoma peritonei or at least small foci of peritoneal tumor spread. An immunohistochemical marker-panel including SATB2, CDX2, CK20, CK7, PAX8, ER and PR revealed a strong expression of SATB2 in all seven cases. On the contrary SATB2-negativity could be demonstrated in the 40 cases of mucinous borderline tumors and primary mucinous carcinomas of the ovary. The histopathologic tentative diagnosis of an ovarian metastasis of LAMN could be confirmed in the findings of the Appendix in six of seven cases. This report supports SATB2 as an additional diagnostic marker for the diagnosis of an ovarian manifestation of LAMN. PMID- 29487004 TI - High-expressed CKS2 is associated with hepatocellular carcinoma cell proliferation through down-regulating PTEN. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is a product of cumulative genetic, epigenetic, somatic, and endocrine aberrations. Identifying the differentially expressed genes (DEGs) in HCC is of critical importance for diagnosis and treatment. The purpose of the present study was to screen the key genes associated with hepatocellular carcinoma and to investigate the functions underlying hepatocellular carcinoma progression. MATERIALS AND METHODS: The gene expression profile of GSE64041, GSE40367 and GSE60502, including 100 specimens from HCC patients and 92 specimens from normal liver controls, was downloaded from the GEO database. DEGs were screened using the online analysis tool from the GCBI website and validated by Q-PCR and Kaplan-Meier survival analysis. After knockdown by siRNA in HepG2/C3A and Bel7402 HCC cells, the CCK-8 assay and colony formation assay were used to measure the clonogenic capacity of the tumor cells. Western blotting assay was used to measure the expression of PTEN. RESULTS: Five up-regulated genes were identified as overlapping genes associated with tumor cell activation. Upon validation by Q-PCR and Kaplan-Meier survival analysis, CKS2 was selected for further study. Although the results of CCK-8 did not show a significant difference, the colony formation assay results indicated that the silencing of CKS2 significantly inhibited cancer cell proliferation. Further study found that CKS2 knockdown induced PTEN up-regulation and may associate with P53 pathway activation. CONCLUSION: These findings indicated that CKS2 play a role in tumor activation and serve as a useful potential target for the treatment of HCC. PMID- 29487005 TI - Downregulation of SETD8 by miR-382 is involved in glioma progression. AB - BACKGROUND: SETD8 (named PR-SET7 or KMT5a) has been reported to regulate various biological processes including carcinogenesis. However, the role of SETD8 in glioma progression has not been investigated. METHOD: qPCR and western blot were used to detect the expression levels of miR-382 and SETD8. MTT and wound healing assay used to detect the cell proliferation and migratory capability. A predicted target of miR-382 (SETD8) was first validated using a luciferase assay. RESULTS: In this study, we found that SETD8 expression was evidently upregulated in glioma tissues and glioma cells, compared with the adjacent normal tissues and normal human astrocytes (NHA). Next, we showed that SETD8 evidently induced cell proliferation and migration in vitro and in vivo. In addition,dual-luciferase assays revealed that miR-382 directly regulates oncogenic SETD8 expression in U87 and U251 cells. Finally a statistically significant inverse correlation of miR 382 and SETD8 expression was observed in 30 glioma patients. CONCLUSION: These data indicated that oncogenic SETD8 was regulated by miR-382 and involved glioma progression, revealing new therapeutic targets for glioma cancer. PMID- 29487006 TI - The diagnostic and prognostic significance of long noncoding RNAs expression in thyroid cancer: A systematic review and meta-analysis. AB - OBJECTIVE: Thyroid cancer (TC) is the most common malignant endocrine-related cancer with an increasing trend worldwide. Therefore, it's in urgent need to find new markers for prognosis and diagnosis. Many long noncoding RNAs (lncRNAs) have been reported to be aberrantly expressed in TC, and may serve as biomarkers. Therefore, we performed this meta-analysis to systematically summarize the relationship between lncRNA expressions and TC. METHODS: Sources from PubMed, Embase and Web of Science were searched. A total of 16 eligible studies including 15 on clinicopahology, 5 on prognosis and 6 on diagnosis were enrolled in our meta-analysis. Revman5.3 and Stata11.0 Software were used to conduct the meta analysis. RESULTS: For diagnostic value, lncRNAs could discriminate between TC and the normal, and yield a high overall sensitivity and specificity (0.80, 95% CI: 0.75-0.84; 0.80, 95% CI: 0.70-0.87). Meanwhile, their sensitivity and specificity were 0.74 (95% CI: 0.59-0.85) and 0.81 (95% CI: 0.73-0.88) respectively, when used to differentiate patients with lymph node metastasis (LNM) from without LNM. The summary receiver operator characteristic curve (sROC) showed that lncRNAs could be considered as valuable diagnostic markers for distinguishing TC patients from the normal (AUC = 0.84) and TC patients with LNM from TC patients without LNM (AUC = 0.85). CONCLUSIONS: In summary, our meta analysis suggested that lncRNAs could function as potential diagnostic markers for TC and predict the LNM. In addition, the systematic review elaborated that lncRNAs might be as prognostic indicators in TC. PMID- 29487007 TI - MiR-21-5p, miR-34a, and human telomerase RNA component as surrogate markers for cervical cancer progression. AB - OBJECTIVE: This study aimed to demonstrate the predictive value of miR-21-5p, miR 34a, and human telomerase RNA component (hTERC) in cervical cancer (CC) development and evaluated their potential possibility for future clinical applications. METHODS: Specimens were collected from the normal cervix, cervical intraepithelial neoplasia (CIN) I, CIN II/III, cervical squamous cell carcinoma. Cytological evaluations and histopathologic examinations were conducted in all subjects, along with the assessment of human papillomavirus (HPV) DNA. The expression levels of the miR-21-5p and miR-34a were detected by RT-PCR. hTERC amplification was detected by dual-color interphase fluorescence in situ hybridization (FISH). Then miRNA, hTERC expressions were compared with the cytological and histologic examination. RESULTS: Compared to that in the benign samples, the expression of miR-21-5p and miR-34a in abnormal samples was significantly upregulated and downregulated, gradually corresponding to the severity of cervical lesions (P < 0.05). There was a trend toward an increasing amplification of hTERC with the increasing severity of cervical lesions. miR-21 5p and miR-34a expression, and hTERC amplification were more specific than HPV positivity in differentiating low-grade cervical disorders from high-grade ones (P < 0.05). CONCLUSIONS: MiR-21-5p upregulation, miR-34a downregulation, and hTERC amplification were associated with the aggressive progression of CC, which suggests that miR-21-5p, miR-34a and hTERC might serve as surrogate markers for CC progression and potential molecular targets for blockage of the development of CC. PMID- 29487008 TI - Tumor budding and poorly-differentiated cluster in prognostication in Stage II colon cancer. AB - Comparison between tumor budding (TB) and poorly-differentiated clusters (PDC) for prognostication in Stage II colon cancer was not extensively studied in literature. In this retrospective study, we assessed TB (according to the consensus statement in 2016) and PDC in 135 Stage II colon adenocarcinoma resection specimens. Counting of TB and PDC was performed on H&E slides. High grade TB (Bd3 (>=10 tumor buds in 0.785 mm2)) and high-grade PDC (Grade 3 (>=10)) were found in 20% and 17% of cases respectively. High-grade TB was associated with pT4 (p = 0.008) and presence of lymphovascular invasion (p = 0.001). There was correlation between TB and PDC grades (p < 0.001), in which both grades were the same or one grade apart in majority of the cases (95%). Both TB and PDC correlated with 5-year disease-specific survival (DSS) and overall survival (OS) (DSS for TB: 89% (Bd1); 73% (Bd2); 52% (Bd3), p = 0.001) (DSS for PDC: 88% (Grade 1); 72% (Grade 2); 61% (Grade 3), p = 0.021). Survival curves of Stage II colon cancer could be further stratified by TB and PDC (log-rank tests: TB p < 0.001; PDC p = 0.009). Combining TB and PDC grades into single grading system (high grade: Bd3 + G2, Bd2 + G3, Bd3 + G3; low-grade: other combinations) was found to have strong correlation with both 5-year DSS and OS (both p < 0.001). Our study has confirmed TB and PDC as independent prognostic factors in Stage II colon cancer, and might help selecting high-risk patients for adjuvant chemotherapy. PMID- 29487010 TI - Small round cell myofibroblastoma of the oral cavity: A tumor mimicking embryonal rhabdomyosarcoma. PMID- 29487009 TI - An immunohistochemical panel consisting of EZH2, C-KIT, and CD205 is useful for distinguishing thymic squamous cell carcinoma from type B3 thymoma. AB - Type B3 thymoma and thymic squamous cell carcinoma (SqCC) often cause a diagnostic problem due to their histological similarities. The aim of this study is to identify EZH2 as a novel and powerful biomarker that can effectively distinguish thymic SqCC from type B3 thymoma, and find optimal combinations among 11 markers. A total of 53 patients, comprising 26 with type B3 thymoma and 27 with thymic SqCC, were allocated to the discovery or validation cohorts, and immunohistochemical staining was performed and analyzed. The expression level of each marker was scored, and receiver-operator characteristic curve analysis was performed to evaluate their diagnostic accuracies. This analysis identified EZH2, C-KIT, and CD205 as useful markers for distinguishing thymic SqCC, and a combined panel approach using them further improved diagnostic accuracy in both the discovery and validation cohorts. In the combined cohorts analysis, EZH2 was the single best marker with 88.9% sensitivity and 100% specificity [area under the curve (AUC) = 0.967]. The sensitivity and specificity were 85.2% and 100% (AUC = 0.962) for C-KIT, and 100% and 73.1% (AUC = 0.844) for CD205. The combined panel had the highest sensitivity and specificity at 96.3% and 100%, which was significantly or marginally higher than those of EZH2, C-KIT, and CD205 alone (P = 0.071, 0.034, and 0.005, respectively). The present findings indicate that EZH2 is useful as a novel diagnostic marker for distinguishing thymic SqCC and that the panel approach can be used as an effective differential diagnostic tool in daily practice. PMID- 29487011 TI - Analysis of the proliferative activity in lung adenocarcinomas with specific driver mutations. AB - In the last decade it became evident that many lung adenocarcinomas (ADC) harbor key genetic alterations such as KRAS, EGFR or BRAF mutations as well as rearrangements of ROS1 or ALK that drive these tumors. In the present study we investigated whether different driver mutations of ADC result in different proliferation rates, which might have clinical impact, including resistance to therapy, recurrence and prognosis. We analyzed the proliferation index (PI) on full slides of surgically resected ADC (n = 230) with known genetic aberrations by means of immunohistochemistry and subsequent digital image analysis and correlated the results with clinicopathological variables including overall (OS) and disease free survival (DFS). We did not observe significant differences in OS or DFS regarding the KRAS or EGFR mutational status (P = 0.56). However, KRAS mutated ADC showed an increased PI compared to EGFR mutated ADC, and ADC with ALK translocations (P < 0.01). Subgroup analysis of EGFR mutated ADC showed a higher PI for tumors harboring a mutation in exon 18 and 20, compared to tumors with a mutation in exon 19 or 21. A PI of 11.5% was the best possible prognostic stratificator for OS (P = 0.01 in KRAS mutated and P < 0.01 in EGFR mutated ADC). In conclusion, the PI differs significantly among ADC with distinct driver mutations. This might explain the varying indications for a prognostic relevance of the PI observed in prior studies. Our study provides a basis for the establishment of a reliable and clinically meaningful PI threshold. PMID- 29487012 TI - [Editorial]. PMID- 29487014 TI - Clinical trials in ophthalmology, do we do what we must? PMID- 29487013 TI - AG490, a JAK2-specific inhibitor, downregulates the expression and activity of organic anion transporter-3. AB - Human organic anion transporter-3 (hOAT3) is richly expressed in the kidney, where it plays critical roles in the secretion of clinically important drugs, including anti-viral therapeutics, anti-cancer drugs, antibiotics, antihypertensives, and anti-inflammatories. In the current study, we examined the role of AG490, a specific inhibitor of the Janus tyrosine kinase 2 (JAK2), in hOAT3 transport activity in the kidney COS-7 cells. AG490 induced a time- and concentration-dependent inhibition of hOAT3-mediated uptake of estrone sulfate, a prototypical substrate for the transporter. The inhibitory effect of AG490 correlated with a reduced expression of hOAT3 at the cell surface. Our lab previously demonstrated that Nedd4-2, a ubiquitin ligase, down regulates OAT expression and transport activity by enhancing OAT ubiquitination, which leads to an internalization of OAT from cell surface to intracellular compartments and subsequent degradation. In the current study, we showed that treatment of hOAT3 expressing cells with AG490 resulted in an enhanced hOAT3 ubiquitination and degradation, which was accompanied by a strengthened association of Nedd4-2 with hOAT3 and a reduction in Nedd4-2 phosphorylation. SiRNA knockdown of endogenous Nedd4-2 abrogated the effects of AG490 on hOAT3. In summary, our study demonstrated that AG490 regulates hOAT3 expression and transport activity through the modulation of Nedd4-2. PMID- 29487016 TI - [Small-fiber neuropathies: A cause of great concern for dermatologists]. PMID- 29487015 TI - [Allergological investigations in fixed pigmented erythema. Method recommended by the FISARD (drug eruptions) group of the French Dermatology Society]. PMID- 29487017 TI - [Clinical and evolutionary characteristics of a child with aquagenic keratoderma: A retrospective study of 12 patients]. AB - INTRODUCTION: Aquagenic keratoderma (AK) is a rare condition characterized by wrinkled and edematous appearance of the skin of the hands occurring within minutes of immersion in water. Other than in a setting of cystic fibrosis, AK has rarely been reported in children, with only 13 clinical cases on record. Many clinicians are unfamiliar with AK and have fears relating to the association with cystic fibrosis The aim of this study is to describe the characteristics and to discuss management of the disease. METHODS: Retrospective, multicentre study, including children aged under 16 years presenting AK. RESULTS: 12 children were included. KA started at a mean age of 9.25 years (range: 20 months to 15 years). Clinical appearance and mode of onset were classical, with the palms being more severely affected than the soles. Pruritus or pain were reported in six cases. The median impact on daily life was 1.5/10. Some of the children underwent investigations: two had a negative sweat test, three had molecular analysis of the gene CFTR: one was negative and two had a heterozygote mutation. The course of the disease was variable: eight stabilizations, two exacerbations, one cure and one improvement. DISCUSSION: This is the first series on childhood KA. Clinical characteristics were similar to those seen in adults. Impact was moderate and the disease course was variable. Systematic medical check-up for cystic fibrosis does not appear warranted in children since to date, cystic fibrosis has not been diagnosed in any patients presenting AK alone. CONCLUSION: AK is rare in children and should not cause erroneous concern, and improvement can occur. PMID- 29487018 TI - [Dermoscopic features of onychomatricoma]. PMID- 29487019 TI - [Corynebacterium-associated skin infections]. PMID- 29487020 TI - [Factors associated with the severity of acute ocular involvement in Stevens Johnson syndrome and toxic epidermal necrolysis in sub-Saharan Africa]. AB - AIM: The purpose of this study was to identify risk factors associated with the severity of acute ocular involvement in Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) in sub-Saharan Africa. PATIENTS AND METHOD: A retrospective study was carried out at the dermatology department in collaboration with the ophthalmology department for SJS/TEN patients between January 2000 and December 2016 in Lome (Togo). The severity of acute ocular involvement was evaluated using the Power classification, and the drug eruption score was assessed using de Bastuji-Garin classification. RESULTS: A total of 107 cases of SJS/TEN (84 cases of SJS, 20 cases of TEN and 3 cases of overlap syndrome) were analyzed. There were 71 women and 36 men, with an average age of 32.3+/-12.5 years (range: 5 to 75 years). Sulfonamides (37.4%) were the most commonly used drugs followed by nevirapine (22.4%). HIV serology was positive in 46 (58.2%) of the 79 patients tested. A total of 54 (50.5%) patients had acute ocular involvement, which was mild in 29.9% of patients, moderate in 13.1% and severe in 7.5%. In multivariate analysis, exposure to sulfadoxine was the sole factor associated with moderate or severe acute ocular involvement in SJS/TEN (adjusted odds ratio=3.3; 95% CI=[1.1; 10.2]). CONCLUSION: Exposure to sulfadoxine was identified in our study as a risk factor associated with the severity of acute ocular involvement in SJS/TEN. Multicenter studies should be conducted in sub-Saharan Africa to confirm this associated risk factor. PMID- 29487021 TI - Reply: Lymph stasis promotes tumor growth. AB - Our study suggested that surgical damage of the lymphatic system promotes tumor progression via impaired immune response. However, as pointed out by Valerio et al, lymph stasis is likely to induce immune stasis, resulting in not only enhanced tumor growth but also tumor generation. Although mechanisms of the tumor generation may not only include impaired immune response but also other factors induced by lymph stasis, we should avoid unnecessary lymphatic disruption in any surgeries and carefully consider the flap design to minimalize lymphatic disruption even in cases with benign tumors. PMID- 29487022 TI - Methylation of PD-1 Promoter Gene as New Prognostic Marker for IDH Mutant Low Grade Glioma? PMID- 29487023 TI - Patient-Reported Sexual Aid Utilization and Efficacy After Radiation Therapy for Localized Prostate Cancer. AB - PURPOSE: To report sexual health-related quality of life outcomes and utilization and efficacy of sexual aids in a contemporary cohort of patients treated for localized prostate cancer. PATIENTS AND METHODS: Between 2008 and 2013, 471 consecutive men with localized prostate cancer were treated on 2 institutional protocols (NCT01766492, NCT01618851) or on a prospective institutional registry with patient-reported health-related quality of life. All patients were treated with ultra-hypofractionated radiation therapy. Erectile function (EF) was defined as "firm enough for intercourse" with or without aids per Expanded Prostate Cancer Index Composite-26 (n = 222 at baseline); results apply to this cohort unless specifically noted. Sexual aid utilization and efficacy were patient reported. Multivariable analysis of EF was performed. RESULTS: Median follow-up was 60 months, median age was 67 years, and 70% had intermediate- or high-risk disease per National Comprehensive Cancer Network guidelines. At 24 and 60 months, questionnaire response rates were 86% and 67%, and EF was retained in 53% and 41%, respectively. Baseline sexual aid utilization was 37% (n = 82) and was associated with lower 24-month EF preservation on multivariable analysis (adjusted odds ratio 0.49, 95% confidence interval 0.26-0.92). By 60 months, 70% of men had tried aids. Of those who found aids helpful at baseline, 84% to 89% reported continued benefit at 24 to 60 months. Among aid-naive patients, efficacy was 80% with first-time use within 12 months and 70% more than 12 months after radiation therapy (P = .02). Among men who developed erectile dysfunction but found sexual aids helpful, 25% were not current users at 60 months. CONCLUSIONS: One-third of men used sexual aids at baseline, which doubled by 5 years after radiation therapy. Self-reported efficacy was high and sustained. Despite significant declines in EF, a number of men reported helpfulness of aids but were not active users. Future study is required to understand drivers of aid utilization to optimize posttreatment sexual function. PMID- 29487024 TI - Phase 1 Study of Accelerated Hypofractionated Radiation Therapy With Concurrent Chemotherapy for Stage III Non-Small Cell Lung Cancer: CALGB 31102 (Alliance). AB - PURPOSE: To investigate the safety of accelerated hypofractionated radiation therapy (AHRT) with concurrent chemotherapy (CT) for inoperable stage III non small cell lung cancer (NSCLC). PATIENTS AND METHODS: The primary objectives were to define the maximally tolerable course of accelerated radiation therapy and to describe toxicities of therapy. Total radiation therapy remained at 60 Gy. The number of once-daily fractions in each successive cohort was reduced as follows: cohort 1, 60 Gy in 27 fractions; cohort 2, 60 Gy in 24 fractions; cohort 3, 60 Gy in 22 fractions; and cohort 4, 60 Gy in 20 fractions. Concurrent treatment consisted of weekly carboplatin area under the curve (AUC) 2 and paclitaxel 45 mg/m2. Consolidation treatment consisted of carboplatin AUC 6 and paclitaxel 200 mg/m2 every weeks * 2 cycles. Maximum tolerated dose: Of 6 patients/cohort, <=2 patients experienced grade >=3 toxicity, and <=1 patient experienced grade >=4 toxicity. RESULTS: 22 patients were accrued; of those, 21 patients were evaluable between July 2012 and May 2014. Grade 5 toxicity occurred in 3 patients: 1 patient in cohort 2 (hemoptysis), 2 patients in cohort 3 (hemoptysis, pneumonitis). The maximum tolerated dose (MTD) was defined by cohort 2 (60 Gy in 2.5 Gy/fraction). Time to grade 5 toxicity was 9 months, 6 months, and 9 months after the start of treatment. The median follow-up time was 23.0 months (range, 7.6-30.6 months) in living patients, the median overall survival was 19.3 months (95% confidence interval [CI] 9.3-34.0 months), and the median progression-free survival was 12.2 months (95% CI 6.1-22.5 months). CONCLUSIONS: Only modest hypofractionation was achievable as a result of long-term toxicities. Nevertheless, the MTD of 60 Gy given at 2.5 Gy/fraction allows completion of RT in 20% fewer treatments than conventional therapy. Further investigation of AHRT may help to better define the therapeutic index. PMID- 29487025 TI - Use of Radiation Therapy Within the Last Year of Life Among Cancer Patients. AB - PURPOSE: We examined radiation therapy (RT) use within the last year of life (LYOL). As palliative RT (PRT) has been well studied in patients with >=6-week life expectancies, we hypothesized that PRT use would be constant over the LYOL, except for the last 30 days, when use would decline given lack of prospective data supporting it. MATERIALS AND METHODS: At a single institution, 870 cancer patients died between October 2, 2014, and September 30, 2015, and had >=3 evaluation and management visits within the LYOL. Claims and RT data were extracted and linked. Over the LYOL, we evaluated RT use by intent (curative vs palliative) and indications. RESULTS: Within the LYOL, one-third of patients underwent RT in the last 365 days of life to 444 sites, which decreased to 24.3% and 8.5% in the last 180 and 30 days of life, respectively. Patients who received any RT in the last 365 days of life were younger at death and had a higher proportion of lung, sarcoma, and transplant disease groups. One-quarter of sites were irradiated with curative intent, which remained constant over the LYOL. In contrast, PRT was used at a supralinear rate, in which treatment of bone metastases and use of single-fraction PRT increased closer to death. CONCLUSIONS: PRT appears to be disproportionately used closer to death, with an increasing proportion of irradiated sites being bone metastases. This may be secondary to increased symptoms from advanced cancer toward the end of life. As patients with very poor prognoses (eg, within 30 days of death) are generally not included in RT clinical trials, further studies are warranted to assess whether PRT for bone metastases at the end of life is efficacious. PMID- 29487026 TI - Is radical surgery always curative in pancreatic neuroendocrine tumors? A cure model survival analysis. AB - BACKGROUND: Adjuvant therapy after curative surgery for sporadic pancreatic neuroendocrine tumor (pNETs) is not currently recommended, assuming that all patients could be cured by a radical resection. The aim of our study is to establish how many and which kind of patients remained uncured after radical resection of pNET. METHODS: Retrospective study involving 143 resected sporadic pNETs. The survival analysis was carried out using the cure model, describing the cure fraction and the excess of risk recurrence. Multivariate analyses were made in order to evaluate the non negligible effect of demographics, clinical and pathological factors on survival parameters. The results were reported as percentages, fractions, ORs and HRs with 95% confidence interval (95 CI %). RESULTS: The cure fraction and the excess of hazard rate of the whole population were 57.1% (37.4-74.6, 95% CI) and 0.06 (0.03-0.07, 95% CI), respectively. Two independent factors were related to the cure fraction: TNM stage (OR 0.27 +/- 0.17; P = 0.002) and grading (OR 0.11 +/- 0.18; P = 0.004). Considering the excess of hazard rate, only two independent factors were related to an increased risk of recurrence: TNM stage (HR 3.49 +/- 1.12; P = 0.004) and grading (HR 4.93 +/- 1.82; P < 0.001). CONCLUSION: The radical surgery has a high probability of cure in stages I-II or in grading 1 while, in stages III-IV or in grading 3 tumors, surgery alone failed to achieve a "cure". A multimodal treatment should be employed in order to avoid a recurrence of the disease. PMID- 29487027 TI - Childhood Obesity: Influential Factors and Interventions. PMID- 29487028 TI - Should Multiple Vessels be Recanalised for Tissue Loss Irrespective of Pedal Anatomy and Angiosome? PMID- 29487029 TI - Distinguishing Clinical Versus Pathological Syndromes in "Nutcracker" Nosology. PMID- 29487031 TI - New drugs and perspectives for new anti-tuberculosis regimens. AB - Tuberculosis (TB) is the ninth cause of global death, more than any other infectious disease. With growing drug resistance the epidemic remains and will require significant attention and investment for the elimination of this disease to occur. With susceptible TB treatment not changing over the last four decades and the advent of drug resistance, new drugs and regimens are required. Recently, through greater collaboration and research networks some progress with significant advances has taken place, not withstanding the comparatively low amount of resources invested. Of late the availability of the new drugs bedaquiline, delamanid and repurposed drugs linezolid, clofazimine and carbapenems are being used more frequently in drug-resistant TB regimens. The WHO shorter multidrug-resistant tuberculosis regimen promises to reach more patients and treat them more quickly and more cheaply. With this new enthusiasm and hope we this review gives an update on the new drugs and perspectives for the treatment of drug-susceptible and drug-resistant tuberculosis. PMID- 29487030 TI - Infant fMRI: A Model System for Cognitive Neuroscience. AB - Our understanding of the typical human brain has benefitted greatly from studying different kinds of brains and their associated behavioral repertoires, including animal models and neuropsychological patients. This same comparative perspective can be applied to early development - the environment, behavior, and brains of infants provide a model system for understanding how the mature brain works. This approach requires noninvasive methods for measuring brain function in awake, behaving infants. fMRI is becoming increasingly viable for this purpose, with the unique ability to precisely measure the entire brain, including both cortical and subcortical structures. Here we discuss potential lessons from infant fMRI for several domains of adult cognition and consider the challenges of conducting such research and how they might be mitigated. PMID- 29487032 TI - Bacteria isolated from companion animals in Japan (2014-2016) by blood culture. AB - We aimed to identify microorganisms isolated by blood culture (BC) from companion animals and to determine antimicrobial resistance of these isolates during 2014 2016 at veterinary laboratory, in comparison with those during 2010-2013, in Japan. Clinical data (animal species, visiting animals/hospitalized animals, and others except for disease type and clinical course including history of antimicrobial agent use) on ill animals at veterinary clinics or hospitals were obtained. We retrospectively analyzed animal-origin BC results extracted from the database in 2014-2016 and those obtained in 2010-2013. BC-positive samples were from most of dogs (n = 174 in 2014-2016 and n = 86 in 2010-2013). Escherichia coli (n = 50, 25.1%) and Staphylococcus intermedius group (SIG) bacteria (n = 23, 11.6%) were most prevalent in 2014-2016, while the percentages of E. coli (n = 22, 25.3%) and SIG (n = 9, 10.3%) in 2010-2013 were similar to those in 2014 2016. Percentages of extended-spectrum beta-lactamase (ESBL)-producing E. coli and methicillin-resistant staphylococci (MRS) rate of SIG bacteria isolated in 2014-2016 were 28.0% and 69.6% (vs. 22.7% and 44.4% in 2010-2013), respectively. Fourteen ESBL-producing E. coli in 2014-2016 were isolated from 7 visiting animals and 7 hospitalized ones, whereas the sixteen MRS of SIG were from 7 visiting animals and 9 hospitalized ones. Our observations support the prevalent microorganisms isolated by BC and their antimicrobial resistance patterns for two study periods. PMID- 29487033 TI - Nasal diphtheria (chronic carriage) caused by nontoxigenic Corynebacterium diphtheriae. AB - Toxigenic strains of Corynebacterium diphtheriae cause the majority of respiratory diphtheria cases. However, nontoxigenic strains of C. diphtheriae can also cause diseases, and have become increasingly common. Infection that is limited to the anterior nares (nasal diphtheria) is a well-described but rare condition, even for toxigenic C. diphtheriae. We report a case involving chronic carriage of nasal diphtheria caused by nontoxigenic C. diphtheriae, as well as a review of other reported nontoxigenic C. diphtheriae cases in Japan. Mild or asymptomatic nasal diphtheria involving nontoxigenic strains, which can be the source of transmission, may be underrecognized. Our case highlights the importance of awareness regarding nontoxigenic diphtheria among clinicians, especially in the era of improved diphtheria vaccination coverage. PMID- 29487034 TI - Isolates and antibiotic susceptibilities of endogenous bacterial endophthalmitis: A retrospective multicenter study in Japan. AB - Endogenous bacterial endophthalmitis, also called metastatic endophthalmitis, is a rare bacterial endophthalmitis derived from distant infectious foci via the bloodstream. This infection can potentially cause not only severe visual disturbance, but also loss of the eyeball or death, as most patients are immunocompromised. This retrospective Japanese multicenter study analyzed 32 eyes in 25 definitive cases. Twelve patients (48.0%) had diabetes mellitus. Typical ocular findings were vitreous haze (87.5%), cells in the anterior chambers (62.5%) and retinal infiltrates (50.0%). Elevated body temperature (64.0%), high serum C-reactive protein (96.0%) and leukocytosis (52.0%) were also frequently observed. Culture positivity rates for intraocular fluid were higher in the vitreous (62.5%) versus aqueous humor (28.6%). High positivity rates were also observed for blood (57.1%) and central venous catheters (100%). The most common pathogen was Staphylococcus aureus (10 cases), including methicillin-resistant S. aureus (4 cases). The next most common pathogen was Klebsiella pneumoniae (7 cases), which was highly associated with liver abscess. Compared to a previous 1991 national multicenter study, there has been a fourfold increase in the ratio of S. aureus. Antibiotic susceptibility tests revealed that all Gram-positives were susceptible to vancomycin and all Gram-negatives were susceptible to third generation cephalosporins, imipenem/cilastatin, gentamycin and levofloxacin. Prognostic factors influencing poor visual outcome included poor initial visual acuity (p < 0.01), K. pneumoniae (p = 0.027) and gram-negative bacteria (p = 0.014) as the causative bacteria. Intravitreal antibiotic injection in combination with vancomycin and ceftazidime may be applicable for use as part of the standard treatment regimen for EBE. PMID- 29487036 TI - An experimental and computational study of the inferior vena cava hemodynamics under respiratory-induced collapse of the infrarenal IVC. AB - Inferior vena cava (IVC) filters have been used for over five decades as an alternative to anticoagulation therapy in the treatment of venous thromboembolic disease. However, complications associated with IVC filters remain common. Though many studies have investigated blood flow in the IVC, the effects of respiration induced IVC collapse have not been evaluated. Our hypothesis is that IVC collapse may have an influence on IVC filter performance. Therefore, we herein investigate the hemodynamics in uncollapsed and collapsed IVC configurations using in vitro flow experiments and computational simulations. Particle image velocimetry (PIV) is used to measure the hemodynamics in an idealized, compliant model of the human IVC made of silicone rubber. Flow is studied under uncollapsed and collapsed scenarios, with the minor diameter of the IVC reduced by 30% in the collapsed state. Both rest and exercise flow conditions are investigated, corresponding to suprarenal flow rates of 2 lpm and 5.5 lpm, respectively. Finite element analysis simulations are carried out in a computational model of the undeformed, idealized IVC to reproduce the 30% collapse configuration and an additional 50% collapse configuration. Computational fluid dynamics (CFD) simulations are then performed to predict the flow in the uncollapsed and collapsed scenarios, and CFD results are compared to the experimental data. The results show that the collapsed states generate a higher velocity jet at the iliac junction that propagates farther into the lumen of the vena cava in comparison to the jet generated in the uncollapsed state. Moreover, 50% collapse of the IVC causes a shift of the jet away from the IVC wall and towards the center of the vena cava lumen. The area of maximum wall shear stress occurs where the jet impacts the wall and is larger in the collapsed scenarios. Secondary flow is also more complex in the collapsed scenarios. Interestingly, this study demonstrates that a small variation in the flow rate distribution between the right and left iliac veins induces significant variations in the flow characteristics. We speculate that asymmetries in the flow may generate unbalanced forces on the IVC wall and on placed IVC filters that could promote filter tilting and migration, although this requires further investigation. If unbalanced forces are present in vivo, the forces should be considered when determining the optimal placement positions and geometric features for IVC filters. Therefore, these findings motivate further investigation of the in vivo hemodynamics in the infrarenal IVC. PMID- 29487035 TI - Clinical effectiveness of four neuraminidase inhibitors (oseltamivir, zanamivir, laninamivir, and peramivir) for children with influenza A and B in the 2014-2015 to 2016-2017 influenza seasons in Japan. AB - The clinical effectiveness of four neuraminidase inhibitors (NAIs) (oseltamivir, zanamivir, laninamivir, and peramivir) for children aged 0 months to 18 years with influenza A and B were investigated in the 2014-2015 to 2016-2017 influenza seasons in Japan. A total of 1207 patients (747 with influenza A and 460 with influenza B) were enrolled. The Cox proportional-hazards model using all of the patients showed that the duration of fever after administration of the first dose of the NAI was shorter in older patients (hazard ratio = 1.06 per 1 year of age, p < 0.001) and that the duration of fever after administration of the first dose of the NAI was shorter in patients with influenza A infection than in patients with influenza B infection (hazard ratio = 2.21, p < 0.001). A logistic regression model showed that the number of biphasic fever episodes was 2.99-times greater for influenza B-infected patients than for influenza A-infected patients (p < 0.001). The number of biphasic fever episodes in influenza A- or B-infected patients aged 0-4 years was 2.89-times greater than that in patients aged 10-18 years (p = 0.010), and the number of episodes in influenza A- or B-infected patients aged 5-9 years was 2.13-times greater than that in patients aged 10-18 years (p = 0.012). PMID- 29487037 TI - A computational framework for simultaneous estimation of muscle and joint contact forces and body motion using optimization and surrogate modeling. AB - Concurrent estimation of muscle activations, joint contact forces, and joint kinematics by means of gradient-based optimization of musculoskeletal models is hindered by computationally expensive and non-smooth joint contact and muscle wrapping algorithms. We present a framework that simultaneously speeds up computation and removes sources of non-smoothness from muscle force optimizations using a combination of parallelization and surrogate modeling, with special emphasis on a novel method for modeling joint contact as a surrogate model of a static analysis. The approach allows one to efficiently introduce elastic joint contact models within static and dynamic optimizations of human motion. We demonstrate the approach by performing two optimizations, one static and one dynamic, using a pelvis-leg musculoskeletal model undergoing a gait cycle. We observed convergence on the order of seconds for a static optimization time frame and on the order of minutes for an entire dynamic optimization. The presented framework may facilitate model-based efforts to predict how planned surgical or rehabilitation interventions will affect post-treatment joint and muscle function. PMID- 29487038 TI - A flow-leak correction algorithm for pneumotachographic work-of-breathing measurement during high-flow nasal cannula oxygen therapy. AB - Measuring work of breathing (WOB) is an intricate task during high-flow nasal cannula (HFNC) therapy because the continuous unidirectional flow toward the patient makes pneumotachography technically difficult to use. We implemented a new method for measuring WOB based on a differential pneumotachography (DP) system, equipped with one pneumotachograph inserted in the HFNC circuit and another connected to a monitoring facemask, combined with a leak correction algorithm (LCA) that corrects flow measurement errors arising from leakage around the monitoring facemask. To test this system, we used a mechanical lung model that provided data to compare LCA-corrected respiratory flow, volume and time values with effective values obtained with a third pneumotachograph used instead of the LCA to measure mask flow leaks directly. Effective and corrected volume and time data showed high agreement (Bland-Altman plots) even at the highest leak. Studies on two healthy adult volunteers confirmed that corrected respiratory flow combined with esophageal pressure measurements can accurately determine WOB (relative error < 1%). We conclude that during HFNC therapy, a DP system combined with a facemask and an algorithm that corrects errors due to flow leakages allows pneumotachography to measure reliably the respiratory flow and volume data needed for calculating WOB. PMID- 29487039 TI - Could ZnT8 antibodies replace ICA, GAD, IA2 and insulin antibodies in the diagnosis of type 1 diabetes? AB - BACKGROUND: The zinc transporter 8 (ZnT8) is an islet beta-cell secretory granule membrane protein coded by the SLC30A8 gene, identified as a novel autoantigen in human type 1 diabetes (T1D). As no data of ZnT8ab in Algerian patients have been reported, we aim to evaluate the prevalence of ZnT8ab in young Algerians with T1D and determine whether ZnT8ab could be a better diagnostic tool to replace the other conventional autoantibodies detected in patients with type 1 diabetes. For this purpose, we evaluated the prevalence of islets cells antibodies (ICA), glutamic acid decarboxylase (GAD), islet antigen type 2 (IA2), insulin (IA) autoantibodies (ab) and for the first time in Algeria, the zinc transporter 8 (ZnT8) in young Algerian patients with type 1 diabetes. PATIENTS AND METHODS: In our cross-sectional study, 160 patients between 1 and 35 years old, diagnosed with type 1 diabetes were enrolled. ICAab was analyzed by indirect immunofluorescence (IIF), GADab, IA2ab, IAab and ZnT8ab were analyzed by ELISA, fasting blood glucose was performed by enzymatic method (glucose-oxidase) and HbA1c by turbid metric method. RESULTS: Our cohort was composed with 74 males and 86 females (OR=1.16); the mean of age was 14.09 [1-35] years old and the median diabetes duration was 4.10 [1-18] years. Our cohort had a mean of HbA1c of 9.22 [5.40-15]%, the mean of birth weight was 3360.52 [2200-4800]g; the mean of BMI was 19.30 [16.04-22.46]kg/m2. Out of 160 patients, 44 (27.5%) were under mother breastfeeding and 116/160 (72.5%) were under artificial feeding. One antibody, at least, was found in 94.38% and the ZnT8ab was significantly more positive in females (70.3%) than in males (10.7%) (***P=8.033*10-15). The concentration of ZnT8ab was higher in females than in males (females=122.25UI/mL versus males=51.38UI/mL; *P=0.03); ICAab, GADab and ZnT8ab were more present in patients with consanguineous parents (***P=0.0002, *P=0.019 and *P=0.03; respectively) CONCLUSION: Our study on ZnT8ab in T1D is the first in the Maghreb region and we observed a prevalence of 46.25%. The positivity of ZnT8ab enabled us to classify in T1DA 50% of diabetics with obvious T1D phenotype and negative routine autoantibodies, thus ZnT8ab is a good tool for differential diagnosis of type 1 diabetes. According to our results, a simultaneous analysis for ZnT8 and IA2 autoantibodies can be a better and efficient diagnosis of type 1A diabetes from the beginning of the disease. PMID- 29487040 TI - Feasibility of a Mobile Phone App to Support Recovery From Addiction in China: Secondary Analysis of a Pilot Study. AB - BACKGROUND: Mobile health technologies have been found to improve the self management of chronic diseases. However, there is limited research regarding their feasibility in supporting recovery from substance use disorders (SUDs) in China. OBJECTIVE: The objective of this study was to examine the feasibility of a mobile phone-based ecological momentary assessment (EMA) app by testing the concordance of drug use assessed by the EMA, urine testing, and a life experience timeline (LET) assessment. METHODS: A total of 75 participants dependent on heroin or amphetamine-type stimulant (ATS) in Shanghai were recruited to participate in a 4-week pilot study. Of the participants, 50 (67% [50/75]) were randomly assigned to the experimental group and 25 (33% [25/75]) were assigned to the control group. The experimental group used mobile health (mHealth) based EMA technology to assess their daily drug use in natural environments and received 2 short health messages each day, whereas the control group only received 2 short health messages each day from the app. Urine tests and LET assessments were conducted each week and a post-intervention survey was administered to both groups. The correlations among the EMA, the LET assessment, and the urine test were investigated. RESULTS: The mean age of the participants was 41.6 (SD 8.0) years, and 71% (53/75) were male. During the 4 weeks of observation, 690 daily EMA survey data were recorded, with a response rate of 49.29% (690/1400). With respect to drug use, the percent of agreement between the EMA and the LET was 66.7%, 79.2%, 72.4%, and 85.8%, respectively, for each of the 4 weeks, whereas the percent of agreement between the EMA and the urine test was 51.2%, 65.1%, 61.9%, and 71.5%, respectively. The post-intervention survey indicated that 46% (32/70) of the participants preferred face-to-face interviews rather than the mHealth app. CONCLUSIONS: This study demonstrated poor agreement between the EMA data and the LET and found that the acceptance of mHealth among individuals with SUDs in China was not positive. Hence, greater efforts are needed to improve the feasibility of mHealth in China. PMID- 29487041 TI - Why Clinicians Don't Report Adverse Drug Events: Qualitative Study. AB - BACKGROUND: Adverse drug events are unintended and harmful events related to medications. Adverse drug events are important for patient care, quality improvement, drug safety research, and postmarketing surveillance, but they are vastly underreported. OBJECTIVE: Our objectives were to identify barriers to adverse drug event documentation and factors contributing to underreporting. METHODS: This qualitative study was conducted in 1 ambulatory center, and the emergency departments and inpatient wards of 3 acute care hospitals in British Columbia between March 2014 and December 2016. We completed workplace observations and focus groups with general practitioners, hospitalists, emergency physicians, and hospital and community pharmacists. We analyzed field notes by coding and iteratively analyzing our data to identify emerging concepts, generate thematic and event summaries, and create workflow diagrams. Clinicians validated emerging concepts by applying them to cases from their clinical practice. RESULTS: We completed 238 hours of observations during which clinicians investigated 65 suspect adverse drug events. The observed events were often complex and diagnosed over time, requiring the input of multiple providers. Providers documented adverse drug events in charts to support continuity of care but never reported them to external agencies. Providers faced time constraints, and reporting would have required duplication of documentation. CONCLUSIONS: Existing reporting systems are not suited to capture the complex nature of adverse drug events or adapted to workflow and are simply not used by frontline clinicians. Systems that are integrated into electronic medical records, make use of existing data to avoid duplication of documentation, and generate alerts to improve safety may address the shortcomings of existing systems and generate robust adverse drug event data as a by-product of safer care. PMID- 29487042 TI - Therapist-Assisted Rehabilitation of Visual Function and Hemianopia after Brain Injury: Intervention Study on the Effect of the Neuro Vision Technology Rehabilitation Program. AB - BACKGROUND: Serious and often lasting vision impairments affect 30% to 35% of people following stroke. Vision may be considered the most important sense in humans, and even smaller permanent injuries can drastically reduce quality of life. Restoration of visual field impairments occur only to a small extent during the first month after brain damage, and therefore the time window for spontaneous improvements is limited. One month after brain injury causing visual impairment, patients usually will experience chronically impaired vision and the need for compensatory vision rehabilitation is substantial. OBJECTIVE: The purpose of this study is to investigate whether rehabilitation with Neuro Vision Technology will result in a significant and lasting improvement in functional capacity in persons with chronic visual impairments after brain injury. Improving eyesight is expected to increase both physical and mental functioning, thus improving the quality of life. METHODS: This is a prospective open label trial in which participants with chronic visual field impairments are examined before and after the intervention. Participants typically suffer from stroke or traumatic brain injury and will be recruited from hospitals and The Institute for the Blind and Partially Sighted. Treatment is based on Neuro Vision Technology, which is a supervised training course, where participants are trained in compensatory techniques using specially designed equipment. Through the Neuro Vision Technology procedure, the vision problems of each individual are carefully investigated, and personal data is used to organize individual training sessions. Cognitive face-to-face assessments and self-assessed questionnaires about both life and vision quality are also applied before and after the training. RESULTS: Funding was provided in June 2017. Results are expected to be available in 2020. Sample size is calculated to 23 participants. Due to age, difficulty in transport, and the time-consuming intervention, up to 25% dropouts are expected; thus, we aim to include at least 29 participants. CONCLUSIONS: This investigation will evaluate the effects of Neuro Vision Technology therapy on compensatory vision rehabilitation. Additionally, quality of life and cognitive improvements associated to increased quality of life will be explored. TRIAL REGISTRATION: ClinicalTrials.gov NCT03160131; https://clinicaltrials.gov/ct2/show/NCT03160131 (Archived by WebCite at http://www.webcitation.org/6x3f5HnCv). PMID- 29487043 TI - Increasing Reasoning Awareness: Video Analysis of Students' Two-Party Virtual Patient Interactions. AB - BACKGROUND: Collaborative reasoning occurs in clinical practice but is rarely developed during education. The computerized virtual patient (VP) cases allow for a stepwise exploration of cases and thus stimulate active learning. Peer settings during VP sessions are believed to have benefits in terms of reasoning but have received scant attention in the literature. OBJECTIVE: The objective of this study was to thoroughly investigate interactions during medical students' clinical reasoning in two-party VP settings. METHODS: An in-depth exploration of students' interactions in dyad settings of VP sessions was performed. For this purpose, two prerecorded VP sessions lasting 1 hour each were observed, transcribed in full, and analyzed. The transcriptions were analyzed using thematic analysis, and short clips from the videos were selected for subsequent analysis in relation to clinical reasoning and clinical aspects. RESULTS: Four categories of interactions were identified: (1) task-related dialogue, in which students negotiated a shared understanding of the task and strategies for information gathering; (2) case-related insights and perspectives were gained, and the students consolidated and applied preexisting biomedical knowledge into a clinical setting; (3) clinical reasoning interactions were made explicit. In these, hypotheses were followed up and clinical examples were used. The researchers observed interactions not only between students and the VP but also (4) interactions with other resources, such as textbooks. The interactions are discussed in relation to theories of clinical reasoning and peer learning. CONCLUSIONS: The dyad VP setting is conducive to activities that promote analytic clinical reasoning. In this setting, components such as peer interaction, access to different resources, and reduced time constraints provided a productive situation in which the students pursued different lines of reasoning. PMID- 29487044 TI - A Mobile Health Platform for Clinical Monitoring in Early Psychosis: Implementation in Community-Based Outpatient Early Psychosis Care. AB - BACKGROUND: A growing body of literature indicates that smartphone technology is a feasible add-on tool in the treatment of individuals with early psychosis (EP) . However, most studies to date have been conducted independent of outpatient care or in a research clinic setting, often with financial incentives to maintain user adherence to the technology. Feasibility of dissemination and implementation of smartphone technology into community mental health centers (CMHCs) has yet to be tested, and whether young adults with EP will use this technology for long periods of time without incentive is unknown. Furthermore, although EP individuals willingly adopt smartphone technology as part of their treatment, it remains unclear whether providers are amenable to integrating smartphone technology into treatment protocols. OBJECTIVE: This study aimed to establish the feasibility of implementing a smartphone app and affiliated Web-based dashboard in 4 community outpatient EP clinics in Northern California. METHODS: EP individuals in 4 clinics downloaded an app on their smartphone and responded to daily surveys regarding mood and symptoms for up to 5 months. Treatment providers at the affiliated clinics viewed survey responses on a secure Web-based dashboard in sessions with their clients and between appointments. EP clients and treatment providers filled out satisfaction surveys at study end regarding usability of the app. RESULTS: Sixty-one EP clients and 20 treatment providers enrolled in the study for up to 5 months. Forty-one EP clients completed the study, and all treatment providers remained in the study for their duration in the clinic. Survey completion for all 61 EP clients was moderate: 40% and 39% for daily and weekly surveys, respectively. Completion rates were slightly higher in the participants who completed the study: 44% and 41% for daily and weekly surveys, respectively. Twenty-seven of 41 (66%) EP clients who completed the study and 11 of 13 (85%) treatment providers who responded to satisfaction surveys reported they would continue to use the app as part of treatment services. Six (15%; 6/41) clients and 3 providers (23%; 3/13) stated that technological glitches impeded their engagement with the platform. CONCLUSIONS: EP clients and treatment providers in community-based outpatient clinics are responsive to integrating smartphone technology into treatment services. There were logistical and technical challenges associated with enrolling individuals in CMHCs. To be most effective, implementing smartphone technology in CMHC EP care necessitates adequate technical staff and support for utilization of the platform. PMID- 29487045 TI - Feasibility of Virtual Tablet-Based Group Exercise Among Older Adults in Siberia: Findings From Two Pilot Trials. AB - BACKGROUND: Regular physical activity has a positive effect on physical health, well-being, and life satisfaction of older adults. However, engaging in regular physical activity can be challenging for the elderly population because of reduced mobility, low motivation, or lack of the proper infrastructures in their communities. OBJECTIVE: The objective of this paper was to study the feasibility of home-based online group training-under different group cohesion settings-and its effects on adherence and well-being among Russian older adults. We focused particularly on the technology usability and usage and on the adherence to the training (in light of premeasures of social support, enjoyment of physical activity, and leg muscle strength). As a secondary objective, we also explored the effects of the technology-supported intervention on subjective well-being and loneliness. METHODS: Two pilot trials were carried out exploring two different group cohesion settings (weak cohesion and strong cohesion) in the period from 2015 to 2016 in Tomsk, Russian Federation. A total of 44 older adults (59-83 years) participated in the two pilots and followed a strength and balance training program (Otago) for 8 weeks with the help of a tablet-based virtual gym app. Participants in each pilot were assigned to an interaction condition, representing the online group exercising, and an individual condition, representing a home-based individual training. Both conditions featured persuasion strategies but differed in the ability to socialize and train together. RESULTS: Both interaction and individual groups reported a high usability of the technology. Trainees showed a high level of technology acceptance and, particularly, a high score in intention to future use (4.2-5.0 on a 5-point Likert scale). Private texting (short service message [SMS]) was used more than public texting, and the strong cohesion condition resulted in more messages per user. Joint participations to training sessions (copresence) were higher for the social group with higher cohesion. The overall adherence to the training was 74% (SD 27%). Higher levels of social support at baseline were associated with higher adherence in the low cohesion condition (F1,18=5.23, P=.03), whereas in the high cohesion, such association was not found. Overall improvement in the satisfaction with life score was observed between pre and post measures (F1,31=5.85, P=.02), but no decrease in loneliness. CONCLUSIONS: Online group exercising was proven feasible among healthy independently living older adults in Russia. The pilots suggest that a physical training performed in a virtual environment positively affect the life satisfaction of the trainees, but it does not provide support for a decrease in loneliness. High cohesion groups are preferable for group exercising, especially to mitigate effects of low social support on adherence. Further research in motivating group interactions in training settings is needed. PMID- 29487046 TI - A Novel Approach for Fully Automated, Personalized Health Coaching for Adults with Prediabetes: Pilot Clinical Trial. AB - BACKGROUND: Prediabetes is a high-risk state for the future development of type 2 diabetes, which may be prevented through physical activity (PA), adherence to a healthy diet, and weight loss. Mobile health (mHealth) technology is a practical and cost-effective method of delivering diabetes prevention programs in a real world setting. Sweetch (Sweetch Health, Ltd) is a fully automated, personalized mHealth platform designed to promote adherence to PA and weight reduction in people with prediabetes. OBJECTIVE: The objective of this pilot study was to calibrate the Sweetch app and determine the feasibility, acceptability, safety, and effectiveness of the Sweetch app in combination with a digital body weight scale (DBWS) in adults with prediabetes. METHODS: This was a 3-month prospective, single-arm, observational study of adults with a diagnosis of prediabetes and body mass index (BMI) between 24 kg/m2 and 40 kg/m2. Feasibility was assessed by study retention. Acceptability of the mobile platform and DBWS were evaluated using validated questionnaires. Effectiveness measures included change in PA, weight, BMI, glycated hemoglobin (HbA1c), and fasting blood glucose from baseline to 3-month visit. The significance of changes in outcome measures was evaluated using paired t test or Wilcoxon matched pairs test. RESULTS: The study retention rate was 47 out of 55 (86%) participants. There was a high degree of acceptability of the Sweetch app, with a median (interquartile range [IQR]) score of 78% (73%-80%) out of 100% on the validated System Usability Scale. Satisfaction regarding the DBWS was also high, with median (IQR) score of 93% (83%-100%). PA increased by 2.8 metabolic equivalent of task (MET)-hours per week (SD 6.8; P=.02), with mean weight loss of 1.6 kg (SD 2.5; P<.001) from baseline. The median change in A1c was -0.1% (IQR -0.2% to 0.1%; P=.04), with no significant change in fasting blood glucose (-1 mg/dL; P=.59). There were no adverse events reported. CONCLUSIONS: The Sweetch mobile intervention program is a safe and effective method of increasing PA and reducing weight and HbA1c in adults with prediabetes. If sustained over a longer period, this intervention would be expected to reduce diabetes risk in this population. TRIAL REGISTRATION: ClincialTrials.gov NCT02896010; https://clinicaltrials.gov/ct2/show/NCT02896010 (Archived by WebCite at http://www.webcitation.org/6xJYxrgse). PMID- 29487047 TI - Potential Application of Digitally Linked Tuberculosis Diagnostics for Real-Time Surveillance of Drug-Resistant Tuberculosis Transmission: Validation and Analysis of Test Results. AB - BACKGROUND: Tuberculosis (TB) is the highest-mortality infectious disease in the world and the main cause of death related to antimicrobial resistance, yet its surveillance is still paper-based. Rifampicin-resistant TB (RR-TB) is an urgent public health crisis. The World Health Organization has, since 2010, endorsed a series of rapid diagnostic tests (RDTs) that enable rapid detection of drug resistant strains and produce large volumes of data. In parallel, most high burden countries have adopted connectivity solutions that allow linking of diagnostics, real-time capture, and shared repository of these test results. However, these connected diagnostics and readily available test results are not used to their full capacity, as we have yet to capitalize on fully understanding the relationship between test results and specific rpoB mutations to elucidate its potential application to real-time surveillance. OBJECTIVE: We aimed to validate and analyze RDT data in detail, and propose the potential use of connected diagnostics and associated test results for real-time evaluation of RR TB transmission. METHODS: We selected 107 RR-TB strains harboring 34 unique rpoB mutations, including 30 within the rifampicin resistance-determining region (RRDR), from the Belgian Coordinated Collections of Microorganisms, Antwerp, Belgium. We subjected these strains to Xpert MTB/RIF, GenoType MTBDRplus v2.0, and Genoscholar NTM + MDRTB II, the results of which were validated against the strains' available rpoB gene sequences. We determined the reproducibility of the results, analyzed and visualized the probe reactions, and proposed these for potential use in evaluating transmission. RESULTS: The RDT probe reactions detected most RRDR mutations tested, although we found a few critical discrepancies between observed results and manufacturers' claims. Based on published frequencies of probe reactions and RRDR mutations, we found specific probe reactions with high potential use in transmission studies: Xpert MTB/RIF probes A, Bdelayed, C, and Edelayed; Genotype MTBDRplus v2.0 WT2, WT5, and WT6; and Genoscholar NTM + MDRTB II S1 and S3. Inspection of probe reactions of disputed mutations may potentially resolve discordance between genotypic and phenotypic test results. CONCLUSIONS: We propose a novel approach for potential real-time detection of RR-TB transmission through fully using digitally linked TB diagnostics and shared repository of test results. To our knowledge, this is the first pragmatic and scalable work in response to the consensus of world-renowned TB experts in 2016 on the potential of diagnostic connectivity to accelerate efforts to eliminate TB. This is evidenced by the ability of our proposed approach to facilitate comparison of probe reactions between different RDTs used in the same setting. Integrating this proposed approach as a plug-in module to a connectivity platform will increase usefulness of connected TB diagnostics for RR TB outbreak detection through real-time investigation of suspected RR-TB transmission cases based on epidemiologic linking. PMID- 29487048 TI - Satisfaction with NHS hits new low. PMID- 29487050 TI - Government proposal could make vaccination programmes harder to approve. PMID- 29487051 TI - Paediatric critical care: from fragmentation via centralisation to integration. PMID- 29487052 TI - One in five GP prescriptions for antibiotics is inappropriate. PMID- 29487049 TI - Clinical course of untreated cervical intraepithelial neoplasia grade 2 under active surveillance: systematic review and meta-analysis. AB - OBJECTIVE: To estimate the regression, persistence, and progression of untreated cervical intraepithelial neoplasia grade 2 (CIN2) lesions managed conservatively as well as compliance with follow-up protocols. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) from 1 January 1973 to 20 August 2016. ELIGIBILITY CRITERIA: Studies reporting on outcomes of histologically confirmed CIN2 in non-pregnant women, managed conservatively for three or more months. DATA SYNTHESIS: Two reviewers extracted data and assessed risk of bias. Random effects model was used to calculate pooled proportions for each outcome, and heterogeneity was assessed using I2 statistics. MAIN OUTCOME MEASURES: Rates of regression, persistence, or progression of CIN2 and default rates at different follow-up time points (3, 6, 12, 24, 36, and 60 months). RESULTS: 36 studies that included 3160 women were identified (seven randomised trials, 16 prospective cohorts, and 13 retrospective cohorts; 50% of the studies were at low risk of bias). At 24 months, the pooled rates were 50% (11 studies, 819/1470 women, 95% confidence interval 43% to 57%; I2=77%) for regression, 32% (eight studies, 334/1257 women, 23% to 42%; I2=82%) for persistence, and 18% (nine studies, 282/1445 women, 11% to 27%; I2=90%) for progression. In a subgroup analysis including 1069 women aged less than 30 years, the rates were 60% (four studies, 638/1069 women, 57% to 63%; I2=0%), 23% (two studies, 226/938 women, 20% to 26%; I2=97%), and 11% (three studies, 163/1033 women, 5% to 19%; I2=67%), respectively. The rate of non-compliance (at six to 24 months of follow-up) in prospective studies was around 10%. CONCLUSIONS: Most CIN2 lesions, particularly in young women (<30 years), regress spontaneously. Active surveillance, rather than immediate intervention, is therefore justified, especially among young women who are likely to adhere to monitoring. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2014: CRD42014014406. PMID- 29487053 TI - NIH Offers Funding for Genome-Editing Projects. AB - The NIH is launching a new funding program for genome-editing technologies. The agency will award $190 million for projects including new delivery methods for genome editors, new editing technologies, and preclinical models to test their safety. PMID- 29487054 TI - Lutetium Lu 177 Dotatate Approved by FDA. AB - The FDA recently approved the radiopharmaceutical lutetium Lu 177 dotatate to treat patients with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. The approval was based on results of the phase III NETTER 1 trial. PMID- 29487055 TI - A Resource for Managing Immunotherapy Side Effects. AB - Checkpoint inhibitors, now approved to treat several cancer types, can cause patients to develop side effects unlike those caused by targeted agents and chemotherapies. Recently released guidelines provide clinicians with detailed descriptions of possible side effects and recommendations for managing them. PMID- 29487056 TI - Non-opioid analgesia is as effective as opioid management in acute pain and supports a change in prescribing practice to help address the 'opioid epidemic'. PMID- 29487057 TI - Human herpesvirus 6 viremia affects T-cell reconstitution after allogeneic hematopoietic stem cell transplantation. AB - Human herpesvirus 6 (HHV6) viremia is a common cause of morbidity following allogeneic hematopoietic cell transplantation (HCT). We previously associated T cell reconstitution with HHV6 viremia. Here, we investigated whether HHV6 viremia affects T-cell reconstitution after HCT in a time-dependent retrospective analysis. We included 273 pediatric patients (0.1-22.7 years; median follow-up, 58 months) receiving a first HCT between 2004 and 2014. HHV6 was screened weekly in plasma via polymerase chain reaction and occurred in 79 patients (29%) at a median time of 19 days after transplant. Main outcome of interest was immune reconstitution (IR) (CD3/CD4/CD8 T cells), measured biweekly until 12 weeks and monthly thereafter. Cox proportional-hazard models were used with IR and HHV6 as time-dependent variables in multivariate analysis with serotherapy in conditioning, graft source, graft-versus-host disease, age, and other viruses (Epstein-Barr virus, cytomegalovirus, and adenovirus) as covariates. Only patients with very high HHV6 viremia (>105 copies/mL) showed hampered CD4+ (hazard ratio [HR], 0.913; 95% confidence interval [CI], 0.892-0.934; P < .001) and CD8+ (HR, 0.912; 95% CI, 0.891-0.933; P < .001) reconstitution in comparison with patients without HHV6, from ~6 months after HCT. Especially naive CD4+ IR was affected (P = .028) but not effector memory CD4+ IR (P = .33). Interestingly, T-cell reconstitution was improved in patients treated with antivirals (HR, 1.572; 95% CI, 1.463-1.690; P < .001). These findings suggest that HHV6 viremia affects late but not early T-cell reconstitution. PMID- 29487058 TI - Reduced red blood cell deformability in Plasmodium knowlesi malaria. AB - The simian parasite Plasmodium knowlesi can cause severe and fatal human malaria. However, little is known about the pathogenesis of this disease. In falciparum malaria, reduced red blood cell deformability (RBC-D) contributes to microvascular obstruction and impaired organ perfusion. In P knowlesi infection, impaired microcirculatory flow has been observed in Macaca mulatta (rhesus macaques), unnatural hosts who develop severe and fatal disease. However, RBC-D has not been measured in human infection or in the natural host M fascicularis (long-tailed macaques). Using ektacytometry, we measured RBC-D in adults with severe and non-severe knowlesi and falciparum malaria and in healthy controls. In addition, we used micropipette aspiration to determine the relative stiffness of infected RBCs (iRBCs) and uninfected RBCs (uRBCs) in P knowlesi-infected humans and M fascicularis Ektacytometry demonstrated that RBC-D overall was reduced in human knowlesi malaria in proportion to disease severity, and in severe knowlesi malaria, it was comparable to that of severe falciparum malaria. RBC-D correlated inversely with parasitemia and lactate in knowlesi malaria and HRP2 in falciparum malaria, and it correlated with hemoglobin nadir in knowlesi malaria. Micropipette aspiration confirmed that in humans, P knowlesi infection increased stiffness of both iRBCs and uRBCs, with the latter mostly the result of echinocytosis. In contrast, in the natural host M fascicularis, echinocyte formation was not observed, and the RBC-D of uRBCs was unaffected. In unnatural primate hosts of P knowlesi, including humans, reduced deformability of iRBCs and uRBCs may represent a key pathogenic mechanism leading to microvascular accumulation, impaired organ perfusion, and anemia. PMID- 29487059 TI - Midostaurin: its odyssey from discovery to approval for treating acute myeloid leukemia and advanced systemic mastocytosis. AB - Midostaurin was a prototype kinase inhibitor, originally developed as a protein kinase C inhibitor and subsequently as an angiogenesis inhibitor, based on its inhibition of vascular endothelial growth factor receptor. Despite promising preclinical data, early clinical trials in multiple diseases showed only modest efficacy. In 1996, the relatively frequent occurrence of fms-like tyrosine kinase 3 (FLT3) activating mutations in acute myeloid leukemia (AML) was first recognized. Several years later, midostaurin was discovered to be a potent inhibitor of the FLT3 tyrosine kinase and to have activity against mutant forms of KIT proto-oncogene receptor tyrosine kinase, which drive advanced systemic mastocytosis (SM). Through a series of collaborations between industry and academia, midostaurin in combination with standard chemotherapy was evaluated in the Cancer and Leukemia Group B 10603/RATIFY study, a large, phase 3, randomized, placebo-controlled trial in patients with newly diagnosed FLT3-mutated AML. This was the first study to show significant improvements in overall survival and event-free survival with the addition of a targeted therapy to standard chemotherapy in this population. Around the same time, durable responses were also observed in other trials of midostaurin in patients with advanced SM. Collectively, these clinical data led to the approval of midostaurin by the US Food and Drug Administration and the European Medicines Agency for both newly diagnosed FLT3-mutated AML and advanced SM. PMID- 29487060 TI - Eltrombopag for use in children with immune thrombocytopenia. AB - Eltrombopag is currently the only US Food and Drug Administration-approved thrombopoietin receptor agonist for the treatment of chronic immune thrombocytopenia (ITP) in children. This oral, once-per-day therapy has shown favorable efficacy and adverse effect profiles in children. Two multicenter, double-blind, placebo controlled clinical trials (PETIT [Efficacy and Safety Study of Eltrombopag in Pediatric Patients With Thrombocytopenia From Chronic Idiopathic Thrombocytopenic Purpura (ITP)] and PETIT2 [Study of a New Medication for Childhood Chronic Immune Thrombocytopenia (ITP), a Blood Disorder of Low Platelet Counts That Can Lead to Bruising Easily, Bleeding Gums, and/or Bleeding Inside the Body]) demonstrated efficacy in raising platelet counts, reducing bleeding, and reducing the need for concomitant ITP therapies with relatively few adverse effects. The most commonly reported drug-related adverse effects include headache, nausea, and hepatobiliary laboratory abnormalities. Long-term safety data in children are limited, and studies in adults have not revealed a clinically significant increased incidence of thrombosis, marrow fibrosis, or cataract formation. Eltrombopag has also been approved for treating refractory severe aplastic anemia (AA) and has potential for expanded use in ITP and severe AA as well as in other conditions associated with thrombocytopenia. PMID- 29487061 TI - BMA responds to articles on assisted dying. PMID- 29487062 TI - Anti-inflammatory and autonomic effects of electroacupuncture in a rat model of diet-induced obesity. AB - OBJECTIVE: To study the effect of electroacupuncture (EA) on the cholinergic anti inflammatory pathway (CAP) by measurement of vagal activity in rats with high-fat diet (HFD)-induced obesity. METHODS: Diet-induced obesity (DIO) was induced in 30 rats by feeding them a HFD for 12 weeks. A further 10 rats fed normal food comprised the lean diet (LD) control group. DIO rats were further subdivided into three groups that received a HFD only (HFD group, n=10), a HFD plus electroacupuncture (HFD+EA group, n=10) or a HFD plus minimal acupuncture (HFD+MA group, n=10). EA and MA treatments were continued for 8 weeks. Heart rate variability (HRV) was used to measure the function of the autonomic nervous system before and after treatment. ELISA was used to determine acetylcholine (ACh) and tumour necrosis factor (TNF)-alpha levels in the serum. Real-time PCR was used to assess the mRNA expression of alpha7-subtype nicotinic acetylcholine cholinergic receptors (alpha7nAChRs) and TNF-alpha in the mesenteric white adipose tissues (MWAT). RESULTS: EA but not MA significantly reduced rats' bodyweight. No difference was found in the low frequency (LF), high frequency (HF) and the balance between LF and HF (LF/HF) components of HRV before treatment. After the EA intervention, HF was elevated and LF/HF was reduced in the HFD+EA group comparedwith the HFD group. TNF-alpha in the serum and MWAT were increased in the HFD group, but were reduced in the HFD+EA group. Furthermore, EA promoted expression of alpha7nAChRs and ACh in the MWAT. There was no difference between the HFD and HFD+MA groups for any indices. CONCLUSIONS: EA enhanced vagal activity, promoted ACh release and activated alpha7nAChRs in the MWAT, leading to inhibition of proinflammatory cytokine production. PMID- 29487064 TI - Sixty seconds on . . . OxyContin. PMID- 29487066 TI - "Frictionless trade" of drugs must continue after Brexit, warn European organisations. PMID- 29487065 TI - No way out: when RNA elements promote nuclear retention. PMID- 29487067 TI - Myosin 1f is specifically required for neutrophil migration in 3D environments during acute inflammation. AB - Neutrophil extravasation and interstitial migration are important steps during the recruitment of neutrophils to sites of inflammation. In the present study, we addressed the functional importance of the unconventional class I myosin 1f (Myo1f) for neutrophil trafficking during acute inflammation. In contrast to leukocyte rolling and adhesion, the genetic absence of Myo1f severely compromised neutrophil extravasation into the inflamed mouse cremaster tissue when compared with Myo1f+/+ mice as studied by intravital microscopy. Similar results were obtained in experimental models of acute peritonitis and acute lung injury. In contrast to 2-dimensional migration, which occurred independently of Myo1f, Myo1f was indispensable for neutrophil migration in 3-dimensional (3D) environments, that is, transmigration and migration in collagen networks as it regulated squeezing and dynamic deformation of the neutrophil nucleus during migration through physical barriers. Thus, we provide evidence for an important role of Myo1f in neutrophil trafficking during inflammation by specifically regulating neutrophil extravasation and migration in 3D environments. PMID- 29487063 TI - Age trends in 30 day hospital readmissions: US national retrospective analysis. AB - OBJECTIVE: To assess trends in and risk factors for readmission to hospital across the age continuum. DESIGN: Retrospective analysis. SETTING AND PARTICIPANTS: 31 729 762 index hospital admissions for all conditions in 2013 from the US Agency for Healthcare Research and Quality Nationwide Readmissions Database. MAIN OUTCOME MEASURE: 30 day, all cause, unplanned hospital readmissions. Odds of readmission were compared by patients' age in one year epochs with logistic regression, accounting for sex, payer, length of stay, discharge disposition, number of chronic conditions, reason for and severity of admission, and data clustering by hospital. The middle (45 years) of the age range (0-90+ years) was selected as the age reference group. RESULTS: The 30 day unplanned readmission rate following all US index admissions was 11.6% (n=3 678 018). Referenced by patients aged 45 years, the adjusted odds ratio for readmission increased between ages 16 and 20 years (from 0.70 (95% confidence interval 0.68 to 0.71) to 1.04 (1.02 to 1.06)), remained elevated between ages 21 and 44 years (range 1.02 (1.00 to 1.03) to 1.12 (1.10 to 1.14)), steadily decreased between ages 46 and 64 years (range 1.02 (1.00 to 1.04) to 0.91 (0.90 to 0.93)), and decreased abruptly at age 65 years (0.78 (0.77 to 0.79)), after which the odds remained relatively constant with advancing age. Across all ages, multiple chronic conditions were associated with the highest adjusted odds of readmission (for example, 3.67 (3.64 to 3.69) for six or more versus no chronic conditions). Among children, young adults, and middle aged adults, mental health was one of the most common reasons for index admissions that had high adjusted readmission rates (>=75th centile). CONCLUSIONS: The likelihood of readmission was elevated for children transitioning to adulthood, children and younger adults with mental health disorders, and patients of all ages with multiple chronic conditions. Further attention to the measurement and causes of readmission and opportunities for its reduction in these groups is warranted. PMID- 29487068 TI - Identification of novel recurrent CPSF6-RARG fusions in acute myeloid leukemia resembling acute promyelocytic leukemia. PMID- 29487069 TI - The interplay of leukemia cells and the bone marrow microenvironment. AB - The interplay of cancer cells and surrounding stroma is critical in disease progression. This is particularly evident in hematological malignancies that infiltrate the bone marrow and peripheral lymphoid organs. Despite clear evidence for the existence of these interactions, the precise repercussions on the growth of leukemic cells are poorly understood. Recent development of novel imaging technology and preclinical disease models has advanced our comprehension of leukemia-microenvironment crosstalk and has potential implications for development of novel treatment options. PMID- 29487070 TI - Minimal residual hairy cell leukemia eradication with moxetumomab pasudotox: phase 1 results and long-term follow-up. AB - Anti-CD22 moxetumomab pasudotox achieved 46% complete remissions (CRs) in previously reported phase 1 testing in relapsed/refractory hairy cell leukemia (HCL; n = 28). The importance of minimal residual disease (MRD) after CR in HCL is unknown. A 21-patient extension cohort received 50 ug/kg every other day for 3 doses in 4-week cycles. These patients plus 12 previously reported at this upper dose level received 143 cycles without dose-limiting toxicity. The combined 33 patient cohort achieved 64% CR and 88% overall response rates, with median CR duration of 42.4 months. Of 32 50-ug/kg patients evaluable for MRD by bone marrow aspirate flow cytometry (most stringent assessment), median CR duration was 13.5 (4.9-42.4) months in 9 MRD-positive CRs vs 42.1 (24.0-69.2) months in 11 MRD negative CRs (P < .001). Among MRD-negative CRs, 10 patients had ongoing CR, 9 without MRD, at end of study. To our knowledge, moxetumomab pasudotox is the only nonchemotherapy regimen that can eliminate MRD in a significant percentage of HCL patients, to enhance CR duration. Repeated dosing, despite early neutralizing antibodies, increased active drug levels without detectable toxicity from immunogenicity. The activity and safety profiles of moxetumomab pasudotox support ongoing phase 3 testing in HCL. This trial was registered at www.clinicaltrials.gov as #NCT00586924. PMID- 29487071 TI - Disentangling the determinants of interest and willingness-to-pay for breast cancer susceptibility testing in the general population: a cross-sectional Web based survey among women of Quebec (Canada). AB - OBJECTIVES: To identify common and specific individual factors that favour or impede women's interest in and willingness-to-pay (WTP) for breast cancer susceptibility testing (BCST) and to identify the most impactful factors on both outcome measures. DESIGN AND METHODS: This study used a self-administered cross sectional Web-based questionnaire that included hypothetical scenarios about the availability of a new genetic test for breast cancer. PARTICIPANTS: French speaking women of the general population of Quebec (Canada), aged between 35 and 69 years, were identified from a Web-based panel (2410 met the selection criteria, 1160 were reached and 1031 completed the survey). MEASURES: The outcomes are the level of interest in and the range of WTP for BCST. Three categories of individual factors identified in the literature were used as potential explanatory factors, that is, demographic, clinical and psychosocial. RESULTS: Descriptive statistics indicated that the vast majority of sampled women are interested in BCST (90%). Among those, more than half of them are willing-to pay for such a test (57%). The regression models pointed out several factors associated with both outcomes (eg, age, income, family history, locus of control powerful others) and marginal effects were used to highlight the most impactful factors for each outcome. CONCLUSION: The results of this study provide a proxy of the readiness of women of the general population to use and to pay for BCST. They also offer insights for developing inclusive and specific strategies to foster informed decision-making and guide the services offered by health organisations corresponding to women's preferences and needs. PMID- 29487072 TI - Can obesity and physical activity predict outcomes of elective knee or hip surgery due to osteoarthritis? A meta-analysis of cohort studies. AB - OBJECTIVE: The aim of this study was to systematically review the literature to identify whether obesity or the regular practice of physical activity are predictors of clinical outcomes in patients undergoing elective hip and knee arthroplasty due to osteoarthritis. DESIGN: Systematic review and meta-analysis. DATA SOURCE AND ELIGIBILITY CRITERIA: A systematic search was performed on the Medline, CINAHL, EMBASE and Web of Science electronic databases. Longitudinal cohort studies were included in the review. To be included, studies needed to have assessed the association between obesity or physical activity participation measured at baseline and clinical outcomes (ie, pain, disability and adverse events) following hip or knee arthroplasty. DATA EXTRACTION: Two independent reviewers extracted data on pain, disability, quality of life, obesity, physical activity and any postsurgical complications. RESULTS: 62 full papers were included in this systematic review. From these, 31 were included in the meta analyses. Our meta-analysis showed that compared to obese participants, non-obese participants report less pain at both short term (standardised mean difference (SMD) -0.43; 95% CI -0.67 to -0.19; P<0.001) and long term post-surgery (SMD 0.36; 95% CI -0.47 to -0.24; P<0.001), as well as less disability at long term post-surgery (SMD -0.32; 95% CI -0.36 to -0.28; P<0.001). They also report fewer postsurgical complications at short term (OR 0.48; 95% CI 0.25 to 0.91; P<0.001) and long term (OR 0.55; 95% CI 0.41 to 0.74; P<0.001) along with less postsurgical infections after hip arthroplasty (OR 0.33; 95% CI 0.18 to 0.59; P<0.001), and knee arthroplasty (OR 0.42; 95% CI 0.23 to 0.78; P=0.006). CONCLUSIONS: Presurgical obesity is associated with worse clinical outcomes of hip or knee arthroplasty in terms of pain, disability and complications in patients with osteoarthritis. No impact of physical activity participation has been observed. PROSPERO REGISTRATION NUMBER: CRD42016032711. PMID- 29487073 TI - Electroacupuncture for poststroke spasticity (EAPSS): protocol for a randomised controlled trial. AB - INTRODUCTION: Spasticity is a common complication of stroke. Current therapies for poststroke spasticity (PSS) have been reported to be associated with high costs, lack of long-term benefit and unwanted adverse events (AEs). Electroacupuncture (EA) has been used for PSS, however, its efficacy and safety is yet to be confirmed by high-quality clinical studies. This study is designed to evaluate the add-on effects and safety profile of EA when used in combination with usual care (UC). METHODS AND ANALYSIS: This study is a parallel group randomised controlled trial. A total of 136 participants will be included and randomly assigned to either the treatment group (EA plus UC) or the control group (UC alone). Prior to the main trial, a pilot study involving 30 participants will be conducted to assess the feasibility of the trial protocol. EA will be administered by registered acupuncturists for 20min to 30 min, three times per week for 4 weeks. The primary outcome measure (Modified Ashworth Scale) and secondary outcome measures (Fugl-Meyer Assessment and Barthel Index) will be evaluated at baseline, the end of treatment (week 4) and the end of follow-up (week 8). AEs will be monitored, recorded and reported, and their causality will be explored. ETHICS AND DISSEMINATION: Ethics approval was obtained from the ethics committees of Guangdong Provincial Hospital of Chinese Medicine and RMIT University in December 2016. The results will be disseminated in a peer-reviewed journal, and PhD theses and might be presented at international conferences. TRIAL REGISTRATION NUMBER: ChiCTR-IOR-16010283; Pre-results. PMID- 29487074 TI - Multiple barriers to participation for people with psychosocial disability in Dehradun district, North India: a cross-sectional study. AB - OBJECTIVES: This study used a population-based cross-sectional survey to describe the prevalence of psychosocial disability and unmet need for access to services in North India. SETTING: This study was conducted in Dehradun district, Uttarakhand, in 2014. PARTICIPANTS: A population-based sample of 2441 people over the age of 18 years. PRIMARY OUTCOME MEASURES: The Rapid Assessment of Disability survey tool identified people with disability and used an adapted version of the Kessler scale to identify those with psychosocial disability. It additionally collected information on socioeconomic variables, access to community services and barriers to participation. Prevalence of psychosocial disability and unmet needs and descriptions of barriers to services were calculated, and multivariable logistic regression was used to assess associations between risk factors and psychosocial disability. RESULTS: Prevalence of psychosocial disability was 4.8% and 75% of participants with psychological distress also reported comorbid functional impairments. Adjusted ORs for depression of more than two were found for people who were unschooled, unemployed and of moderate or poor socioeconomic status. The unmet need for access to services was significantly higher in every domain for people with psychosocial disability and was more than 25% in the areas of employment, health service access and community consultation. People with psychosocial disability encountered greater barriers in each domain compared with controls. CONCLUSIONS: People who are poor, uneducated and unemployed are two to four times more likely to have psychosocial disability in Dehradun district. They face unmet needs in accessing community services and perceive negative social attitudes, lack of physical accessibility and lack of information as barriers limiting their participation. Social policy must increase access to education and reduce poverty but additionally ensure action is taken in all community services to increase information, physical accessibility and social inclusion of people with psychosocial and other forms of disability. PMID- 29487075 TI - Seeking the balance between caregiving in dementia, family and employment: study protocol for a mixed methods study in Northern Germany. AB - INTRODUCTION: The debate on reconciliation between childcare and working has to be expanded to caregiving for the elderly, since the importance of informal caregiving will increase in the future due to populations' ageing and women's increasing labour force participation. Informal caregivers who are caring for the rising number of persons with dementia (PwD) are often female and subjected to high caregiving requirements. These are added to further demands emerging from their family and work life. How affected caregivers seek to balance those requirements depends on, inter alia, their own characteristics and the informal caregiving network to whom they relate. Both aspects were not yet considered in previous studies. This mixed methods study thus aims to explore the reconciliation between caregiving in dementia, family and employment by including different members of caregiving networks of home-dwelling PwD and by considering their personal characteristics. METHODS AND ANALYSIS: By purposive sampling, we include at least five caregiving networks of home-dwelling PwD; each of them consisting of at least three informal caregivers living in Northern Germany. Narrative interviews of participants will be recorded, transcribed verbatim and interpreted according to the Documentary Method (QUAL). By completing standardised questionnaires, participants will provide sociodemographic and psychographic data concerning themselves and the networks from whom they arise (quan). This supplemental, descriptive information will give further background to the themes and types emerging from the interviews. Hence, the quan-data enrich the QUAL-data by exploring the narratives of participants in the light of their personal and network-related characteristics. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Ethics Committee of the German Society of Nursing Sciences. Study results will be disseminated through conference presentations and publications in peer-reviewed journals. TRIAL REGISTRATION NUMBER: DRKS00012929. PMID- 29487076 TI - Reliability of wireless monitoring using a wearable patch sensor in high-risk surgical patients at a step-down unit in the Netherlands: a clinical validation study. AB - BACKGROUND AND OBJECTIVES: Intermittent vital signs measurements are the current standard on hospital wards, typically recorded once every 8 hours. Early signs of deterioration may therefore be missed. Recent innovations have resulted in 'wearable' sensors, which may capture patient deterioration at an earlier stage. The objective of this study was to determine whether a wireless 'patch' sensor is able to reliably measure respiratory and heart rate continuously in high-risk surgical patients. The secondary objective was to explore the potential of the wireless sensor to serve as a safety monitor. DESIGN: In an observational methods comparisons study, patients were measured with both the wireless sensor and bedside routine standard for at least 24 hours. SETTING: University teaching hospital, single centre. PARTICIPANTS: Twenty-five postoperative surgical patients admitted to a step-down unit. OUTCOME MEASURES: Primary outcome measures were limits of agreement and bias of heart rate and respiratory rate. Secondary outcome measures were sensor reliability, defined as time until first occurrence of data loss. RESULTS: 1568 hours of vital signs data were analysed. Bias and 95% limits of agreement for heart rate were -1.1 (-8.8 to 6.5) beats per minute. For respiration rate, bias was -2.3 breaths per minute with wide limits of agreement (-15.8 to 11.2 breaths per minute). Median filtering over a 15 min period improved limits of agreement of both respiration and heart rate. 63% of the measurements were performed without data loss greater than 2 min. Overall data loss was limited (6% of time). CONCLUSIONS: The wireless sensor is capable of accurately measuring heart rate, but accuracy for respiratory rate was outside acceptable limits. Remote monitoring has the potential to contribute to early recognition of physiological decline in high-risk patients. Future studies should focus on the ability to detect patient deterioration on low care environments and at home after discharge. PMID- 29487078 TI - Risk Factors for Incident Diabetic Polyneuropathy in a Cohort With Screen Detected Type 2 Diabetes Followed for 13 Years: ADDITION-Denmark. AB - OBJECTIVE: To study incident diabetic polyneuropathy (DPN) prospectively during the first 13 years after a screening-based diagnosis of type 2 diabetes and determine the associated risk factors for the development of DPN. RESEARCH DESIGN AND METHODS: We assessed DPN longitudinally in the Danish arm of the Anglo-Danish Dutch study of Intensive Treatment of Diabetes in Primary Care (ADDITION) using the Michigan Neuropathy Screening Instrument questionnaire (MNSIQ), defining DPN with scores >=4. Risk factors present at the diabetes diagnosis associated with the risk of incident DPN were estimated using Cox proportional hazard models adjusted for trial randomization group, sex, and age. RESULTS: Of the total cohort of 1,533 people, 1,445 completed the MNSIQ at baseline and 189 (13.1%) had DPN at baseline. The remaining 1,256 without DPN entered this study (median age 60.8 years [interquartile range 55.6; 65.6], 59% of whom were men). The cumulative incidence of DPN was 10% during 13 years of diabetes. Age (hazard ratio [HR] 1.03 [95% CI 1.00; 1.07]) (unit = 1 year), weight (HR 1.09 [95% CI 1.03; 1.16]) (unit = 5 kg), waist circumference (HR 1.14 [95% CI 1.05; 1.24]) (unit = 5 cm), BMI (HR 1.14 [95% CI 1.06; 1.23]) (unit = 2 kg/m2), log2 methylglyoxal (HR 1.45 [95% CI 1.12; 1.89]) (unit = doubling), HDL cholesterol (HR 0.82 [95% CI 0.69; 0.99]) (unit = 0.25 mmol/L), and LDL cholesterol (HR 0.92 [95% CI 0.86; 0.98]) (unit = 0.25 mmol/L) at baseline were significantly associated with the risk of incident DPN. CONCLUSIONS: This study provides further epidemiological evidence for obesity as a risk factor for DPN. Moreover, low HDL cholesterol levels and higher levels of methylglyoxal, a marker of dicarbonyl stress, are identified as risk factors for the development of DPN. PMID- 29487079 TI - Effect of Food Order on Ghrelin Suppression. PMID- 29487080 TI - Treatment or surveillance for CIN2? PMID- 29487077 TI - Improving cardiometabolic and mental health in women with gestational diabetes mellitus and their offspring: study protocol for MySweetHeart Trial, a randomised controlled trial. AB - INTRODUCTION: Gestational diabetes mellitus (GDM) carries prenatal and perinatal risk for the mother and her offspring as well as longer-term risks for both the mother (obesity, diabetes, cardiovascular disease) and her child (obesity, type 2 diabetes). Compared with women without GDM, women with GDM are twice as likely to develop perinatal or postpartum depression. Lifestyle interventions for GDM are generally limited to physical activity and/or nutrition, often focus separately on the mother or the child and take place either during or after pregnancy, while their results are inconsistent. To increase efficacy of intervention, the multifactorial origins of GDM and the tight link between mental and metabolic as well as maternal and child health need to be heeded. This calls for an interdisciplinary transgenerational approach starting in, but continuing beyond pregnancy. METHODS AND ANALYSIS: This randomised controlled trial will assess the effect of a multidimensional interdisciplinary lifestyle and psychosocial intervention aimed at improving the metabolic and mental health of 200 women with GDM and their offspring. Women with GDM at 24-32 weeks gestational age who understand French or English, and their offspring and partners can participate. The intervention components will be delivered on top of usual care during pregnancy and the first year postpartum. Metabolic and mental health outcomes will be measured at 24-32 weeks of pregnancy, shortly after birth and at 6-8 weeks and 1 year after childbirth. Data will be analysed using intention-to-treat analyses. The MySweetHeart Trial is linked to the MySweetHeart Cohort (clinicaltrials.gov/ct2/show/NCT02872974). ETHICS AND DISSEMINATION: We will disseminate the findings through regional, national and international conferences and through peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02890693; Pre results. PMID- 29487081 TI - David Oliver: What might Health Education England's workforce strategy mean for doctors? PMID- 29487083 TI - Drugs for Insomnia beyond Benzodiazepines: Pharmacology, Clinical Applications, and Discovery. AB - Although the GABAergic benzodiazepines (BZDs) and Z-drugs (zolpidem, zopiclone, and zaleplon) are FDA-approved for insomnia disorders with a strong evidence base, they have many side effects, including cognitive impairment, tolerance, rebound insomnia upon discontinuation, car accidents/falls, abuse, and dependence liability. Consequently, the clinical use of off-label drugs and novel drugs that do not target the GABAergic system is increasing. The purpose of this review is to analyze the neurobiological and clinical evidence of pharmacological treatments of insomnia, excluding the BZDs and Z-drugs. We analyzed the melatonergic agonist drugs, agomelatine, prolonged-release melatonin, ramelteon, and tasimelteon; the dual orexin receptor antagonist suvorexant; the modulators of the alpha2delta subunit of voltage-sensitive calcium channels, gabapentin and pregabalin; the H1 antagonist, low-dose doxepin; and the histamine and serotonin receptor antagonists, amitriptyline, mirtazapine, trazodone, olanzapine, and quetiapine. The pharmacology and mechanism of action of these treatments and the evidence-base for the use of these drugs in clinical practice is outlined along with novel pipelines. There is evidence to recommend suvorexant and low-dose doxepin for sleep maintenance insomnia; there is also sufficient evidence to recommend ramelteon for sleep onset insomnia. Although there is limited evidence for the use of the quetiapine, trazodone, mirtazapine, amitriptyline, pregabalin, gabapentin, agomelatine, and olanzapine as treatments for insomnia disorder, these drugs may improve sleep while successfully treating comorbid disorders, with a different side effect profile than the BZDs and Z-drugs. The unique mechanism of action of each drug allows for a more personalized and targeted medical management of insomnia. PMID- 29487084 TI - Biomarkers for In Vivo Assessment of Transporter Function. AB - Drug-drug interactions are a major concern not only during clinical practice, but also in drug development. Due to limitations of in vitro-in vivo predictions of transporter-mediated drug-drug interactions, multiple clinical Phase I drug-drug interaction studies may become necessary for a new molecular entity to assess potential drug interaction liabilities. This is a resource-intensive process and exposes study participants, who frequently are healthy volunteers without benefit from study treatment, to the potential risks of a new drug in development. Therefore, there is currently a major interest in new approaches for better prediction of transporter-mediated drug-drug interactions. In particular, researchers in the field attempt to identify endogenous compounds as biomarkers for transporter function, such as hexadecanedioate, tetradecanedioate, coproporphyrins I and III, or glycochenodeoxycholate sulfate for hepatic uptake via organic anion transporting polypeptide 1B or N1-methylnicotinamide for multidrug and toxin extrusion protein-mediated renal secretion. We summarize in this review the currently proposed biomarkers and potential limitations of the substances identified to date. Moreover, we suggest criteria based on current experiences, which may be used to assess the suitability of a biomarker for transporter function. Finally, further alternatives and supplemental approaches to classic drug-drug interaction studies are discussed. PMID- 29487082 TI - Peripherally derived T regulatory and gammadelta T cells have opposing roles in the pathogenesis of intractable pediatric epilepsy. AB - The pathophysiology of drug-resistant pediatric epilepsy is unknown. Flow cytometric analysis of inflammatory leukocytes in resected brain tissues from 29 pediatric patients with genetic (focal cortical dysplasia) or acquired (encephalomalacia) epilepsy demonstrated significant brain infiltration of blood borne inflammatory myeloid cells and memory CD4+ and CD8+ T cells. Significantly, proinflammatory (IL-17- and GM-CSF-producing) gammadelta T cells were concentrated in epileptogenic lesions, and their numbers positively correlated with disease severity. Conversely, numbers of regulatory T (T reg) cells inversely correlated with disease severity. Correspondingly, using the kainic acid model of status epilepticus, we show ameliorated seizure activity in both gammadelta T cell- and IL-17RA-deficient mice and in recipients of T reg cells, whereas T reg cell depletion heightened seizure severity. Moreover, both IL-17 and GM-CSF induced neuronal hyperexcitability in brain slice cultures. These studies support a major pathological role for peripherally derived innate and adaptive proinflammatory immune responses in the pathogenesis of intractable epilepsy and suggest testing of immunomodulatory therapies. PMID- 29487086 TI - Personalized medicine and proper dosage: Over- and undertreatment of chronic diseases endanger patients' health and strain public health systems. PMID- 29487087 TI - Etiology and Resource Use of Fever of Unknown Origin in Hospitalized Children. AB - BACKGROUND: Fever of unknown origin (FUO) is a well-known pediatric presentation. The primary studies determining the causes of prolonged fever in children were performed 4 decades ago, before major advances in laboratory and diagnostic testing. Given that the distribution of diagnosed causes of adult FUO has changed in recent decades, we hypothesized that the etiology of FUO in children has concordantly changed and also may be impacted by a definition that includes a shorter required duration of fever. METHODS: A single-center, retrospective review of patients 6 months to 18 years of age admitted to the North Carolina Children's Hospital from January 1, 2002, to December 21, 2012, with an International Classification of Diseases, Ninth Revision diagnosis of fever, a documented fever duration >7 days before admission, and a previous physician evaluation of each patient's illness. RESULTS: A total of 1164 patients were identified, and of these, 102 met our inclusion criteria for FUO. Etiologic categories included "infectious" (42 out of 102 patients), "autoimmune" (28 out of 102 patients), "oncologic" (18 out of 102 patients), and "other" or "unknown" (14 out of 102 patients). Several clinical factors were statistically and significantly different between etiologic categories, including fever length, laboratory values, imaging performed, length of stay, and hospital costs. CONCLUSIONS: Unlike adult studies, the categorical distribution of diagnoses for pediatric FUO has marginally shifted compared to previously reported pediatric studies. Patients hospitalized with FUO undergo prolonged hospital stays and have high hospital costs. Additional study is needed to improve the recognition, treatment, and expense of diagnosis of prolonged fever in children. PMID- 29487085 TI - The deubiquitinating enzyme USP20 stabilizes ULK1 and promotes autophagy initiation. AB - Autophagy begins with the formation of autophagosomes, a process that depends on the activity of the serine/threonine kinase ULK1 (hATG1). Although earlier studies indicated that ULK1 activity is regulated by dynamic polyubiquitination, the deubiquitinase involved in the regulation of ULK1 remained unknown. In this study, we demonstrate that ubiquitin-specific protease 20 (USP20) acts as a positive regulator of autophagy initiation through stabilizing ULK1. At basal state, USP20 binds to and stabilizes ULK1 by removing the ubiquitin moiety, thereby interfering with the lysosomal degradation of ULK1. The stabilization of basal ULK1 protein levels is required for the initiation of starvation-induced autophagy, since the depletion of USP20 by RNA interference inhibits LC3 puncta formation, a marker of autophagic flux. At later stages of autophagy, USP20 dissociates from ULK1, resulting in enhanced ULK1 degradation and apoptosis. Taken together, our findings provide the first evidence that USP20 plays a crucial role in autophagy initiation by maintaining the basal expression level of ULK1. PMID- 29487089 TI - Off we go into the wild blue yonder: preflight hypoxic testing in patients with congenital heart disease. PMID- 29487088 TI - Reconstitution and functional characterization of ion channels from nanodiscs in lipid bilayers. AB - Recent studies have shown that membrane proteins can be efficiently synthesized in vitro before spontaneously inserting into soluble nanoscale lipid bilayers called nanodiscs (NDs). In this paper, we present experimental details that allow a combination of in vitro translation of ion channels into commercially available NDs followed by their direct reconstitution from these nanobilayers into standard bilayer setups for electrophysiological characterization. We present data showing that two model K+ channels, Kcv and KcsA, as well as a recently discovered dual topology F- channel, Fluc, can be reliably reconstituted from different types of NDs into bilayers without contamination from the in vitro translation cocktail. The functional properties of Kcv and KcsA were characterized electrophysiologically and exhibited sensitivity to the lipid composition of the target DPhPC bilayer, suggesting that the channel proteins were fully exposed to the target membrane and were no longer surrounded by the lipid/protein scaffold. The single-channel properties of the three tested channels are compatible with studies from recordings of the same proteins in other expression systems. Altogether, the data show that synthesis of ion channels into NDs and their subsequent reconstitution into conventional bilayers provide a fast and reliable method for functional analysis of ion channels. PMID- 29487090 TI - Research on infection prevention bundles: hidden risk of bias? PMID- 29487091 TI - Cholesteryl ester transfer protein and its inhibitors. AB - Most of the cholesterol in plasma is in an esterified form that is generated in potentially cardioprotective HDLs. Cholesteryl ester transfer protein (CETP) mediates bidirectional transfers of cholesteryl esters (CEs) and triglycerides (TGs) between plasma lipoproteins. Because CE originates in HDLs and TG enters the plasma as a component of VLDLs, activity of CETP results in a net mass transfer of CE from HDLs to VLDLs and LDLs, and of TG from VLDLs to LDLs and HDLs. As inhibition of CETP activity increases the concentration of HDL cholesterol and decreases the concentration of VLDL- and LDL-cholesterol, it has the potential to reduce atherosclerotic CVD. This has led to the development of anti-CETP neutralizing monoclonal antibodies, vaccines, and antisense oligonucleotides. Small molecule inhibitors of CETP have also been developed and four of them have been studied in large scale cardiovascular clinical outcome trials. This review describes the structure of CETP and its mechanism of action. Details of its regulation and nonlipid transporting functions are discussed, and the results of the large scale clinical outcome trials of small molecule CETP inhibitors are summarized. PMID- 29487092 TI - Clinical Trial End Points for Hemodialysis Vascular Access: Background, Rationale, and Definitions. PMID- 29487093 TI - Management of Osteoporosis in CKD. AB - CKD mineral and bone disease is a common complication of kidney disease, and it affects the majority of patients with moderate to severe CKD. Recently, prospective studies have shown that measurement of bone mineral density by dual energy x-ray absorptiometry predicts incident fracture, providing nephrologists the ability to risk classify patients for skeletal fragility and targeted antifracture strategies for the first time. Furthermore, an expanding body of literature and anecdotal evidence suggest that pharmacologic agents used to treat osteoporosis in the general population can be safely used in patients with CKD. This review highlights the effects of the Kidney Disease Improving Global Outcomes updates on the management of CKD-associated osteoporosis, discusses recent investigations on the effects of antiosteoporotic agents in patients with CKD, and provides an overview of novel antiosteoporosis agents and the potential challenges related to their use in CKD. PMID- 29487095 TI - The Influence of Different Mouthpieces on Impulse Oscillometry Results. AB - BACKGROUND: Impulse oscillometry is a method of airway assessment and diagnosis that provides data on lung mechanics. In the literature, studies have used different types of mouthpieces or did not describe the model used for the tests. We sought to compare the 3 most commonly described mouthpieces in terms of test results, comfort, and subject preference. METHODS: Thirty-nine healthy volunteers were evaluated with spirometry and impulse oscillometry, assessing the resistance at 5 Hz and 20 Hz (R5 and R20, respectively), reactance at 5 Hz (X5), reactance area, and resonant frequency. A filter heat exchanger with a circular mouthpiece (B1), a filter heat exchanger with an oval mouthpiece (B2), and a filter heat exchanger with a circular mouthpiece coupled with a free-flow piece (B3) were compared using an acceptability and tolerance scale, and subjects noted their preference. RESULTS: Statistical analysis showed differences between all the mouthpieces and the predicted values for R5, R20, and X5. The mouthpiece comparison showed differences in R5 between a filter heat exchanger with an oval mouthpiece (B2) and a circular mouthpiece coupled with a free-flow piece (B3) (P = .007); resonant frequency between a filter heat exchanger with a circular mouthpiece (B1) and a filter heat exchanger with an oval mouthpiece (B2) (P = .004) and between a filter heat exchanger with a circular mouthpiece (B1) and a circular mouthpiece coupled with a free-flow piece (B3) (P = .003); and reactance area between a filter heat exchanger with a circular mouthpiece (B1) and a circular mouthpiece coupled with a free-flow piece (B3) (P = .01). In the subjective evaluation, acceptability and tolerance differences were found in the ease of carrying out the evaluation, and no difference was found with regard to the degree of discomfort. Ten subjects preferred a filter heat exchanger with a circular mouthpiece (B1), 15 preferred a filter heat exchanger with an oval mouthpiece (B2), and 14 preferred a circular mouthpiece coupled with a free-flow piece (B3). CONCLUSIONS: A circular mouthpiece coupled with a free-flow piece (B3) appeared to be the most suitable mouthpiece for the impulse oscillometry tests. It assured smaller impedance values for the respiratory system, and subjects expressed the most confidence in using this mouthpiece. PMID- 29487094 TI - Minimizing Asynchronies in Mechanical Ventilation: Current and Future Trends. AB - Patient-ventilator asynchrony exists when the phases of breath delivered by the ventilator do not match those of the patient. Asynchronies occur throughout mechanical ventilation and negatively affect patient comfort, duration of mechanical ventilation, length of ICU stays, and mortality. Identifying asynchronies requires careful attention to patients and their ventilator waveforms. This review discusses the different types of asynchronies, how they are generated, and their impact on patient comfort and outcome. Moreover, it discusses practical approaches for detecting, correcting, and preventing asynchronies. Current evidence suggests that the best approach to managing asynchronies is by adjusting ventilator settings. Proportional modes improve patient-ventilator coupling, resulting in greater comfort and less dyspnea, but not in improved outcomes with respect to the duration of mechanical ventilation, delirium, or cognitive impairment. Advanced computational technologies will allow smart alerts, and models based on time series of asynchronies will be able to predict and prevent asynchronies, making it possible to tailor mechanical ventilation to meet each patient's needs throughout the course of mechanical ventilation. PMID- 29487096 TI - 'Barely a scratch': Capnocytophaga canimorsus causing prosthetic hip joint infection following a dog scratch. AB - Capnocytophaga canimorsus is a commensal organism commonly found in the oral cavity of cats and dogs. Infections with this organism are rare and can affect both immunocompetent and immunocompromised individuals. The authors present a case of Ccanimorsus causing indolent prosthetic hip joint infection in a healthy 66-year-old woman following a history of being scratched by her pet dog. The patient had an atypical history of chronic, low-grade infection which is unusual, as this organism is more frequently associated with acute presentations and fulminant sepsis. This patient was treated successfully with a two-stage exchange of her hip prosthesis and broad-spectrum antibiotics.C. canimorsus is a very rare cause of prosthetic joint infection but an important pathogen to consider, particularly in culture-negative joint infections and a history of animal exposure. PMID- 29487097 TI - Primary spontaneous pneumothorax in conjunction with Marfan syndrome. AB - A 25-year-old man with a history of Marfan syndrome, asthma and smoking presented with worsening dyspnoea and right-sided chest pain worsened with deep breathing after a fall 2 days prior. Diagnostic imaging revealed a spontaneous right-sided pneumothorax due to ruptured subpleural bullae in the apex of the right lung. Smaller subpleural bullae were also noted in the apex of the left lung. A chest tube was placed to reduce the right pneumothorax successfully. PMID- 29487098 TI - Ruptured hepatocellular carcinoma disguising as heterotopic pregnancy. AB - The incidence of hepatocellular carcinoma (HCC) in pregnancy is rare but is typically aggressive, with a 1-year survival rate of 23%. One of the complications of HCC is spontaneous rupture, resulting in haemoperitoneum. A 36 year-old pregnant Chinese immigrant who was positive for hepatitis B virus and in her first trimester presented to the emergency department of Wyong Hospital, Hamlyn Terrace, New South Wales, Australia, with severe epigastric and right upper quadrant pain and haemodynamic instability. Spontaneous rupture of a heterotopic pregnancy was initially suspected. However, histopathological staining of the lesions excised during surgery revealed HCC. To our knowledge, this is the first case of spontaneous rupture of HCC with haemoperitoneum during pregnancy in Australia. As developed countries receive global migrants, similar cases may be seen in the future. Epidemiological studies suggest that immigrants from China and Vietnam have the highest incidence of chronic hepatitis B virus carrier status. PMID- 29487099 TI - Obstructive uropathy from complete bladder and bilateral ureteral incarceration within an inguinal hernia. AB - A 59-year-old man with a medical history of hypertension, gout and obesity presented to the hospital with a chief complaint of worsening scrotal oedema. The patient endorsed associated symptoms of decreased force of stream on urination, stranguria and hesitancy with slight dysuria. Physical exam showed an effaced umbilicus and phallus with a hidden scrotum estimated to be 30*20*30 cm in size. Imaging and lab findings led to a diagnosis of total bladder herniation within an incarcerated right inguinal hernia. Surgical repair of the inguinal hernia and replacement of the bladder and ureters led to a resolution of urinary symptoms with no evidence of vesicoureteral reflux or urinary retention. PMID- 29487100 TI - The man that lost (part of) his mind. AB - An 84-year-old man presented to the emergency department following recurrent falls over several weeks and onset of new left-sided weakness. CT of the brain revealed a large air cavity (pneumatocoele) in the right frontal lobe thought to be secondary to an ethmoidal osteoma communicating through the cribriform plate allowing air to be forced into the skull under pressure. Subsequent MRI confirmed these findings and also revealed a small focal area of acute infarction in the adjacent corpus callosum. The patient had a prolonged hospital stay, declined neurosurgical intervention and was discharged home on secondary stroke prevention. PMID- 29487101 TI - Persistent wrist monarthritis: down to the bone. AB - A minority of osteoid osteomas are found to be juxta-articular and within the small bones of the wrist. We present a 30-year-old man diagnosed with an osteoid osteoma of the lunate bone, presenting with 3 years of left wrist pain, swelling and reduced range of motion. Given the patient's background and laboratory testing, consideration was given to both inflammatory and infectious causes and the diagnosis was delayed, requiring repeat interval imaging and assisted by multiple imaging modalities. Management by surgical excision led to resolution of pain and swelling. In cases of a prolonged isolated monarthritis, juxta-articular osteoid osteoma should be considered in the differential. PMID- 29487102 TI - Teriparatide-induced atrial tachycardia. AB - We present the case of a patient who presented with worsening chest pain and tachycardia. We were able to monitor her remotely through her pacemaker. She had been started on the injectable medication teriparatide (Forteo) and since then she had an increase in her symptoms. She was found to have intermittent atrial tachycardia with 1:1 conduction and occasional atrioventricular block transiently, coinciding with her injection of teriparatide. This specific associated arrhythmia has yet to be described. PMID- 29487103 TI - Should catheter-directed thrombolysis be the standard of care for pregnancy related iliofemoral deep vein thrombosis? AB - A 33-year-old, 8-week pregnant woman presented with mottling, pain and swelling of her left leg. Ultrasound Doppler scan revealed a large left iliofemoral deep vein thrombosis and the patient was diagnosed with phlegmasia cerulea dolens. After 24 hours of treatment with unfractionated heparin, there were minimal improvements in her symptoms. Catheter-directed thrombolysis was performed, following multidisciplinary consultation with the patient. An underlying May Thurner lesion was identified and successfully stented. Radiation exposure to the fetus was minimised with the use of intravenous ultrasound and very low-dose fluoroscopy. Total radiation exposure to the fetus is 1.38 mGy, which is equivalent to 8 months of background radiation exposure. No immediate complication occurred and patient's symptoms completely resolved. On further follow-up, her iliofemoral veins remained patent with good flow and there were no recurrence of symptoms. A healthy infant was successfully delivered at 40 weeks gestation. PMID- 29487105 TI - Cytokinin signaling in plant development. AB - The phytohormone cytokinin plays diverse roles in plant development, influencing many agriculturally important processes, including growth, nutrient responses and the response to biotic and abiotic stresses. Cytokinin levels in plants are regulated by biosynthesis and inactivation pathways. Cytokinins are perceived by membrane-localized histidine-kinase receptors and are transduced through a His Asp phosphorelay to activate a family of transcription factors in the nucleus. Here, and in the accompanying poster, we summarize the current understanding of cytokinin metabolism, transport and signaling, and discuss how this phytohormone regulates changes in gene expression to mediate its pleiotropic effects. PMID- 29487104 TI - Prp8 positioning of U5 snRNA is linked to 5' splice site recognition. AB - Prp8 is an essential protein that regulates spliceosome assembly and conformation during pre-mRNA splicing. Recent cryo-EM structures of the spliceosome model Prp8 as a scaffold for the spliceosome's catalytic U snRNA components. Using a new amino acid probing strategy, we identified a dynamic region in human Prp8 that is positioned to stabilize the pre-mRNA in the spliceosome active site through interactions with U5 snRNA. Mutagenesis of the identified Prp8 residues in yeast indicates a role in 5' splice site recognition. Genetic interactions with spliceosome proteins Isy1, which buttresses the intron branch point, and Snu114, a regulatory GTPase that directly contacts Prp8, further corroborate a role for the same Prp8 residues in substrate positioning and activation. Together the data suggest that adjustments in interactions between Prp8 and U5 snRNA help establish proper positioning of the pre-mRNA into the active site to enhance 5' splice site fidelity. PMID- 29487106 TI - An interview with Yka Helariutta. AB - Yrjo (Yka) Helariutta is a group leader at The Institute of Biotechnology in the University of Helsinki and at the Sainsbury Laboratory in the University of Cambridge. Recently appointed an editor at Development, his lab works on vascular development in plants and trees. We met Yka in his Cambridge office to hear how a childhood passion for collecting led him to plant science, what Arabidopsis can tell us about trees and vice versa, and why he thinks there are many different ways of being successful in science. PMID- 29487107 TI - In vivo three-dimensional tracking of sperm behaviors in the mouse oviduct. AB - Mammalian sperm evolutionarily acquired complex mechanisms to regulate their behaviors, which are thought to be crucial in navigating through the female reproductive tract toward fertilization. However, all current knowledge of this process is largely extrapolated from in vitro and ex vivo studies, because in vivo analysis of sperm in their native fertilization environment has not been possible. Here, we report a functional optical coherence tomography approach that allows, for the first time, in vivo three-dimensional tracking of sperm behaviors in the mouse oviduct. Motile sperm are identified with their intrinsic dynamic characteristics. Sperm trajectories are reconstructed in three dimensions with a ~5 um spatial resolution, allowing for quantitative analysis of the sperm velocity and location relative to the oviduct. Using this method, we found different behavior patterns, including sperm collection by the oviduct epithelium, spatial dependence of sperm velocity, and sperm grouping and separation as the first in vivo evidence of sperm cooperation in the ampulla, the site of fertilization. This approach opens new avenues to study sperm-oviduct interactions in vivo toward a more complete understanding of fertility and reproductive disorders. PMID- 29487108 TI - Microtubule organization in presynaptic boutons relies on the formin DAAM. AB - Regulation of the cytoskeleton is fundamental to the development and function of synaptic terminals, such as neuromuscular junctions. Despite the identification of numerous proteins that regulate synaptic actin and microtubule dynamics, the mechanisms of cytoskeletal control during terminal arbor formation have remained largely elusive. Here, we show that DAAM, a member of the formin family of cytoskeleton organizing factors, is an important presynaptic regulator of neuromuscular junction development in Drosophila We demonstrate that the actin filament assembly activity of DAAM plays a negligible role in terminal formation; rather, DAAM is necessary for synaptic microtubule organization. Genetic interaction studies consistently link DAAM with the Wg/Ank2/Futsch module of microtubule regulation and bouton formation. Finally, we provide evidence that DAAM is tightly associated with the synaptic active zone scaffold, and electrophysiological data point to a role in the modulation of synaptic vesicle release. Based on these results, we propose that DAAM is an important cytoskeletal effector element of the Wg/Ank2 pathway involved in the determination of basic synaptic structures, and, additionally, that DAAM may couple the active zone scaffold to the presynaptic cytoskeleton. PMID- 29487109 TI - Centrosomal protein Dzip1l binds Cby, promotes ciliary bud formation, and acts redundantly with Bromi to regulate ciliogenesis in the mouse. AB - The primary cilium is a microtubule-based organelle required for Hedgehog (Hh) signaling and consists of a basal body, a ciliary axoneme and a compartment between the first two structures, called the transition zone (TZ). The TZ serves as a gatekeeper to control protein composition in cilia, but less is known about its role in ciliary bud formation. Here, we show that centrosomal protein Dzip1l is required for Hh signaling between Smoothened and Sufu. Dzip1l colocalizes with basal body appendage proteins and Rpgrip1l, a TZ protein. Loss of Dzip1l results in reduced ciliogenesis and dysmorphic cilia in vivo Dzip1l interacts with, and acts upstream of, Cby, an appendage protein, in ciliogenesis. Dzip1l also has overlapping functions with Bromi (Tbc1d32) in ciliogenesis, cilia morphogenesis and neural tube patterning. Loss of Dzip1l arrests ciliogenesis at the stage of ciliary bud formation from the TZ. Consistent with this, Dzip1l mutant cells fail to remove the capping protein Cp110 (Ccp110) from the distal end of mother centrioles and to recruit Rpgrip1l to the TZ. Therefore, Dzip1l promotes ciliary bud formation and is required for the integrity of the TZ. PMID- 29487110 TI - Farnesoid X Receptor Agonists Obeticholic Acid and Chenodeoxycholic Acid Increase Bile Acid Efflux in Sandwich-Cultured Human Hepatocytes: Functional Evidence and Mechanisms. AB - The farnesoid X receptor (FXR) is a nuclear receptor that regulates genes involved in bile acid homeostasis. FXR agonists, obeticholic acid (OCA) and chenodeoxycholic acid (CDCA), increase mRNA expression of efflux transporters in sandwich-cultured human hepatocytes (SCHH). This study evaluated the effects of OCA and CDCA treatment on the uptake, basolateral efflux, and biliary excretion of a model bile acid, taurocholate (TCA), in SCHH. In addition, changes in the protein expression of TCA uptake and efflux transporters were investigated. SCHH were treated with 1 uM OCA, 100 uM CDCA, or vehicle control for 72 hours followed by quantification of deuterated TCA uptake and efflux over time in Ca2+ containing and Ca2+-free conditions (n = 3 donors). A mechanistic pharmacokinetic model was fit to the TCA mass-time data to obtain estimates for total uptake clearance (CLUptake), total intrinsic basolateral efflux clearance (CLint,BL), and total intrinsic biliary clearance (CLint,Bile). Modeling results revealed that FXR agonists significantly increased CLint,BL by >6-fold and significantly increased CLint,Bile by 2-fold, with minimal effect on CLUptake Immunoblotting showed that protein levels of the basolateral transporter subunits organic solute transporter alpha and beta (OSTalpha and OSTbeta) in FXR agonist-treated SCHH were significantly induced by >2.5- and 10-fold, respectively. FXR agonist mediated changes in the expression of other TCA transporters in SCHH were modest. In conclusion, this is the first report demonstrating that OCA and CDCA increased TCA efflux in SCHH, which contributed to reduced intracellular TCA concentrations. Increased basolateral efflux of TCA was consistent with increased OSTalpha/beta protein expression in OCA- and CDCA-treated SCHH. PMID- 29487111 TI - Prognostic Value of Early Postoperative Troponin T in Patients Undergoing Coronary Artery Bypass Grafting. AB - BACKGROUND: Cardiac troponin T (cTnT) is elevated after coronary artery bypass grafting surgery. The aim of this study was to determine the association between cTnT elevations between 6 and 12 hours after coronary artery bypass grafting and in-hospital outcome. METHODS AND RESULTS: We prospectively studied 1722 patients undergoing isolated coronary artery bypass grafting. We assessed the association between conventional cTnT (749 patients) and high-sensitivity cTnT (hs-cTnT; 973 patients) 6 to 12 hours postoperatively with in-hospital major adverse cardiac or cerebrovascular events (MACCE), a composite of all-cause death, myocardial infarction, or stroke. The prespecified secondary outcome was a safety composite of MACCE, resuscitation, intensive care unit readmission or admission >=48 hours, inotrope or vasopressor use >=24 hours, or new-onset renal insufficiency. Among patients with a conventional cTnT measurement, 92 experienced a MACCE (12%) and 146 experienced a safety composite event (19%). Likewise, for hs-cTnT, 114 experienced a MACCE (12%) and 153 experienced a safety composite event (16%). Compared with cTnT <=200 ng/L, each 200-ng/L increment in cTnT was associated with a monotonous increase in the odds of MACCE and the safety composite outcome. Conventional and hs-cTnT demonstrated moderate discrimination for MACCE (areas under the fitted receiver operating characteristics curve, 0.72 and 0.77 for conventional and hs-cTnT, respectively) and the safety composite outcome (areas under the fitted receiver operating characteristics curve, 0.66 and 0.74 for conventional and hs-cTnT, respectively) and resulted in improved prognostic performance when added to the EuroSCORE. At a cutoff of 800 ng/L, conventional and hs-cTnT provided clinically relevant power to rule in MACCE and the safety composite outcome. CONCLUSIONS: cTnT levels assessed between 6 and 12 hours after coronary artery bypass grafting identify patients at increased risk of MACCE or other complications. PMID- 29487112 TI - Cardiac Rehabilitation Protects Against the Expansion of Abdominal Aortic Aneurysm. AB - BACKGROUND: Virtually no reports on the effects of exercise in patients with a small abdominal aortic aneurysm (AAA) exist. METHODS AND RESULTS: We conducted a retrospective cohort study on 1515 patients with a small AAA before surgery at 2 high-volume hospitals in Tokyo, Japan, from April 2004 to September 2015. A carefully modified cardiac rehabilitation program without excessive blood pressure elevation during exercise was prescribed to 50 patients with an AAA. Using propensity score matching, mortality and clinical outcomes, including AAA expansion rate, were compared between 2 groups: rehabilitation group and nonrehabilitation group. The background characteristics of the rehabilitation group (n=49) and the nonrehabilitation group (n=163) were almost identical. The risk for AAA repair was much lower in the rehabilitation group after matching (before matching: hazard ratio, 0.43; 95% confidence interval, 0.25-0.72; P=0.001; and after matching: hazard ratio, 0.19; 95% confidence interval, 0.07 0.50; P<0.001). AAA expansion rate was slower in the rehabilitation group (before matching: rehabilitation versus nonrehabilitation group, 2.3+/-3.7 versus 3.8+/ 3.4 mm/y [P=0.008]; after matching: rehabilitation versus nonrehabilitation group, 2.1+/-3.0 versus 4.5+/-4.0 mm/y [P<0.001]). Elevation of blood pressure during exercise was positively correlated with AAA expansion rate after the rehabilitation program (r=0.569, P<0.001). CONCLUSIONS: Cardiac rehabilitation protects against the expansion of small AAAs and mitigates the risk associated with AAA repair, possibly because of the decreased elevation of blood pressure during exercise. CLINICAL TRIAL REGISTRATION: URL: upload.umin.ac.jp. Unique identifier: UMIN000028237. PMID- 29487113 TI - Panorama Public: A Public Repository for Quantitative Data Sets Processed in Skyline. AB - To address the growing need for a centralized, community resource of published results processed with Skyline, and to provide reviewers and readers immediate visual access to the data behind published conclusions, we present Panorama Public (https://panoramaweb.org/public.url), a repository of Skyline documents supporting published results. Panorama Public is built on Panorama, an open source data management system for mass spectrometry data processed with the Skyline targeted mass spectrometry environment. The Panorama web application facilitates viewing, sharing, and disseminating results contained in Skyline documents via a web-browser. Skyline users can easily upload their documents to a Panorama server and allow other researchers to explore uploaded results in the Panorama web-interface through a variety of familiar summary graphs as well as annotated views of the chromatographic peaks processed with Skyline. This makes Panorama ideal for sharing targeted, quantitative results contained in Skyline documents with collaborators, reviewers, and the larger proteomics community. The Panorama Public repository employs the full data visualization capabilities of Panorama which facilitates sharing results with reviewers during manuscript review. PMID- 29487114 TI - Erratum. Engineering Glucose Responsiveness Into Insulin. Diabetes 2018;67:299 308. PMID- 29487116 TI - Implementing post-trial access plans for HIV prevention research. AB - Ethics guidance increasingly recognises that researchers and sponsors have obligations to consider provisions for post-trial access (PTA) to interventions that are found to be beneficial in research. Yet, there is little information regarding whether and how such plans can actually be implemented. Understanding practical experiences of developing and implementing these plans is critical to both optimising their implementation and informing conceptual work related to PTA. This viewpoint is informed by experiences with developing and implementing PTA plans for six large-scale multicentre HIV prevention trials supported by the HIV Prevention Trials Network. These experiences suggest that planning and implementing PTA often involve challenges of planning under uncertainty and confronting practical barriers to accessing healthcare systems. Even in relatively favourable circumstances where a tested intervention medication is approved and available in the local healthcare system, system-level barriers can threaten the viability of PTA plans. The aggregate experience across these HIV prevention trials suggests that simply referring participants to local healthcare systems for PTA will not necessarily result in continued access to beneficial interventions for trial participants. Serious commitments to PTA will require additional efforts to learn from future approaches, measuring the success of PTA plans with dedicated follow-up and further developing normative guidance to help research stakeholders navigate the complex practical challenges of realising PTA. PMID- 29487117 TI - Dignity and equality in healthcare. AB - This paper critically examines Barclay's conception of dignity proposed in her 'Dignitarian Medical Ethics'. According to Barclay, a subject S enjoys dignity if and only if S is reliably treated as having equal social status. I argue that Barclay's view faces a number of practical and theoretical problems. First, it is not obvious that failing to treat someone as a social equal is incompatible with respecting her dignity. Second, it is not always clear what treating someone as a social equal amounts to in practice. To be more compelling, her conception of dignity needs to be supplemented with a more principled and substantive account of the content of equal treatment. PMID- 29487118 TI - Truthful nudging. PMID- 29487115 TI - Fibroblast Growth Factor 21 Protects Photoreceptor Function in Type 1 Diabetic Mice. AB - Retinal neuronal abnormalities occur before vascular changes in diabetic retinopathy. Accumulating experimental evidence suggests that neurons control vascular pathology in diabetic and other neovascular retinal diseases. Therefore, normalizing neuronal activity in diabetes may prevent vascular pathology. We investigated whether fibroblast growth factor 21 (FGF21) prevented retinal neuronal dysfunction in insulin-deficient diabetic mice. We found that in diabetic neural retina, photoreceptor rather than inner retinal function was most affected and administration of the long-acting FGF21 analog PF-05231023 restored the retinal neuronal functional deficits detected by electroretinography. PF 05231023 administration protected against diabetes-induced disorganization of photoreceptor segments seen in retinal cross section with immunohistochemistry and attenuated the reduction in the thickness of photoreceptor segments measured by optical coherence tomography. PF-05231023, independent of its downstream metabolic modulator adiponectin, reduced inflammatory marker interleukin-1beta (IL-1beta) mRNA levels. PF-05231023 activated the AKT-nuclear factor erythroid 2 related factor 2 pathway and reduced IL-1beta expression in stressed photoreceptors. PF-05231023 administration did not change retinal expression of vascular endothelial growth factor A, suggesting a novel therapeutic approach for the prevention of early diabetic retinopathy by protecting photoreceptor function in diabetes. PMID- 29487119 TI - 3'-Phosphoadenosine 5'-Phosphate Accumulation Delays the Circadian System. AB - The circadian system optimizes cellular responses to stress, but the signaling pathways that convey the metabolic consequences of stress into this molecular timekeeping mechanism remain unclear. Redox regulation of the SAL1 phosphatase during abiotic stress initiates a signaling pathway from chloroplast to nucleus by regulating the accumulation of a metabolite, 3'-phosphoadenosine 5'-phosphate (PAP). Consequently, PAP accumulates in response to redox stress and inhibits the activity of exoribonucleases (XRNs) in the nucleus and cytosol. We demonstrated that osmotic stress induces a lengthening of circadian period and that genetically inducing the SAL1-PAP-XRN pathway in plants lacking either SAL1 or XRNs similarly delays the circadian system. Exogenous application of PAP was also sufficient to extend circadian period. Thus, SAL1-PAP-XRN signaling likely regulates circadian rhythms in response to redox stress. Our findings exemplify how two central processes in plants, molecular timekeeping and responses to abiotic stress, can be interlinked to regulate gene expression. PMID- 29487122 TI - The Sync/deSync Model: How a Synchronized Hippocampus and a Desynchronized Neocortex Code Memories. AB - Neural oscillations are important for memory formation in the brain. The desynchronization of alpha (10 Hz) oscillations in the neocortex has been shown to predict successful memory encoding and retrieval. However, when engaging in learning, it has been found that the hippocampus synchronizes in theta (4 Hz) oscillations, and that learning is dependent on the phase of theta. This inconsistency as to whether synchronization is "good" for memory formation leads to confusion over which oscillations we should expect to see and where during learning paradigm experiments. This paper seeks to respond to this inconsistency by presenting a neural network model of how a well functioning learning system could exhibit both of these phenomena, i.e., desynchronization of alpha and synchronization of theta during successful memory encoding.We present a spiking neural network (the Sync/deSync model) of the neocortical and hippocampal system. The simulated hippocampus learns through an adapted spike-time dependent plasticity rule, in which weight change is modulated by the phase of an extrinsically generated theta oscillation. Additionally, a global passive weight decay is incorporated, which is also modulated by theta phase. In this way, the Sync/deSync model exhibits theta phase-dependent long-term potentiation and long term depression. We simulated a learning paradigm experiment and compared the oscillatory dynamics of our model with those observed in single-cell and scalp EEG studies of the medial temporal lobe. Our Sync/deSync model suggests that both the desynchronization of neocortical alpha and the synchronization of hippocampal theta are necessary for successful memory encoding and retrieval.SIGNIFICANCE STATEMENT A fundamental question is the role of rhythmic activation of neurons, i.e., how and why their firing oscillates between high and low rates. A particularly important question is how oscillatory dynamics between the neocortex and hippocampus support memory formation. We present a spiking neural-network model of such memory formation, with the central ideas that (1) in neocortex, neurons need to break out of an alpha oscillation to represent a stimulus (i.e., alpha desynchronizes), whereas (2) in hippocampus, the firing of neurons at theta facilitates formation of memories (i.e., theta synchronizes). Accordingly, successful memory formation is marked by reduced neocortical alpha and increased hippocampal theta. This pattern has been observed experimentally and gives our model its name-the Sync/deSync model. PMID- 29487120 TI - Monitoring Polysaccharide Dynamics in the Plant Cell Wall. PMID- 29487121 TI - Transcriptional Roadmap to Seasonal Variation in Wood Formation of Norway Spruce. AB - Seasonal cues influence several aspects of the secondary growth of tree stems, including cambial activity, wood chemistry, and transition to latewood formation. We investigated seasonal changes in cambial activity, secondary cell wall formation, and tracheid cell death in woody tissues of Norway spruce (Picea abies) throughout one seasonal cycle. RNA sequencing was performed simultaneously in both the xylem and cambium/phloem tissues of the stem. Principal component analysis revealed gradual shifts in the transcriptomes that followed a chronological order throughout the season. A notable remodeling of the transcriptome was observed in the winter, with many genes having maximal expression during the coldest months of the year. A highly coexpressed set of monolignol biosynthesis genes showed high expression during the period of secondary cell wall formation as well as a second peak in midwinter. This midwinter peak in expression did not trigger lignin deposition, as determined by pyrolysis-gas chromatography/mass spectrometry. Coexpression consensus network analyses suggested the involvement of transcription factors belonging to the ASYMMETRIC LEAVES2/LATERAL ORGAN BOUNDARIES and MYELOBLASTOSIS-HOMEOBOX families in the seasonal control of secondary cell wall formation of tracheids. Interestingly, the lifetime of the latewood tracheids stretched beyond the winter dormancy period, correlating with a lack of cell death-related gene expression. Our transcriptomic analyses combined with phylogenetic and microscopic analyses also identified the cellulose and lignin biosynthetic genes and putative regulators for latewood formation and tracheid cell death in Norway spruce, providing a toolbox for further physiological and functional assays of these important phase transitions. PMID- 29487123 TI - Role of Rostral Fastigial Neurons in Encoding a Body-Centered Representation of Translation in Three Dimensions. AB - Many daily behaviors rely critically on estimates of our body motion. Such estimates must be computed by combining neck proprioceptive signals with vestibular signals that have been transformed from a head- to a body-centered reference frame. Recent studies showed that deep cerebellar neurons in the rostral fastigial nucleus (rFN) reflect these computations, but whether they explicitly encode estimates of body motion remains unclear. A key limitation in addressing this question is that, to date, cell tuning properties have only been characterized for a restricted set of motions across head-re-body orientations in the horizontal plane. Here we examined, for the first time, how 3D spatiotemporal tuning for translational motion varies with head-re-body orientation in both horizontal and vertical planes in the rFN of male macaques. While vestibular coding was profoundly influenced by head-re-body position in both planes, neurons typically reflected at most a partial transformation. However, their tuning shifts were not random but followed the specific spatial trajectories predicted for a 3D transformation. We show that these properties facilitate the linear decoding of fully body-centered motion representations in 3D with a broad range of temporal characteristics from small groups of 5-7 cells. These results demonstrate that the vestibular reference frame transformation required to compute body motion is indeed encoded by cerebellar neurons. We propose that maintaining partially transformed rFN responses with different spatiotemporal properties facilitates the creation of downstream body motion representations with a range of dynamic characteristics, consistent with the functional requirements for tasks such as postural control and reaching.SIGNIFICANCE STATEMENT Estimates of body motion are essential for many daily activities. Vestibular signals are important contributors to such estimates but must be transformed from a head- to a body-centered reference frame. Here, we provide the first direct demonstration that the cerebellum computes this transformation fully in 3D. We show that the output of these computations is reflected in the tuning properties of deep cerebellar rostral fastigial nucleus neurons in a specific distributed fashion that facilitates the efficient creation of body-centered translation estimates with a broad range of temporal properties (i.e., from acceleration to position). These findings support an important role for the rostral fastigial nucleus as a source of body translation estimates functionally relevant for behaviors ranging from postural control to perception. PMID- 29487124 TI - Long-Term Neuroinflammation Induced by Influenza A Virus Infection and the Impact on Hippocampal Neuron Morphology and Function. AB - Acute influenza infection has been reported to be associated with neurological symptoms. However, the long-term consequences of an infection with neurotropic and non-neurotropic influenza A virus (IAV) variants for the CNS remain elusive. We can show that spine loss in the hippocampus after infection with neurotropic H7N7 (rSC35M) and non-neurotropic H3N2 (maHK68) in female C57BL/6 mice persists well beyond the acute phase of the disease. Although spine number was significantly reduced at 30 d postinfection (dpi) with H7N7 or H3N2, full recovery could only be observed much later at 120 dpi. Infection with H1N1 virus, which was shown previously to affect spine number and hippocampus-dependent learning acutely, had no significant long-term effects. Spine loss was associated with an increase in the number of activated microglia, reduced long-term potentiation in the hippocampus, and impairment in spatial memory formation, indicating that IAV-associated inflammation induced functional and structural alterations in hippocampal networks. Transcriptome analyses revealed regulation of many inflammatory and neuron- and glia-specific genes in H3N2- and H7N7 infected mice at day 18 and in H7N7-infected mice at day 30 pi that related to the structural and functional alterations. Our data provide evidence that neuroinflammation induced by neurotropic H7N7 and infection of the lung with a non-neurotropic H3N2 IAV result in long-term impairments in the CNS. IAV infection in humans may therefore not only lead to short-term responses in infected organs, but may also trigger neuroinflammation and associated chronic alterations in the CNS.SIGNIFICANCE STATEMENT In the acute phase of influenza infection, neuroinflammation can lead to alterations in hippocampal neuronal morphology and cognitive deficits. The results of this study now also provide evidence that neuroinflammation induced by influenza A virus (IAV) infection can induce longer-lasting, virus-specific alterations in neuronal connectivity that are still detectable 1 month after infection and are associated with impairments in spatial memory formation. IAV infection in humans may therefore not only lead to short-term responses in infected organs, but may also trigger neuroinflammation and associated chronic alterations in the CNS. PMID- 29487125 TI - Testing the Efficacy of Single-Cell Stimulation in Biasing Presubicular Head Direction Activity. AB - To support navigation, the firing of head direction (HD) neurons must be tightly anchored to the external space. Indeed, inputs from external landmarks can rapidly reset the preferred direction of HD cells. Landmark stimuli have often been simulated as excitatory inputs from "visual cells" (encoding landmark information) to the HD attractor network; when excitatory visual inputs are sufficiently strong, preferred directions switch abruptly to the landmark location. In the present work, we tested whether mimicking such inputs via juxtacellular stimulation would be sufficient for shifting the tuning of individual presubicular HD cells recorded in passively rotated male rats. We recorded 81 HD cells in a cue-rich environment, and evoked spikes trains outside of their preferred direction (distance range, 11-178 degrees ). We found that HD tuning was remarkably resistant to activity manipulations. Even strong stimulations, which induced seconds-long spike trains, failed to induce a detectable shift in directional tuning. HD tuning curves before and after stimulation remained highly correlated, indicating that postsynaptic activation alone is insufficient for modifying HD output. Our data are thus consistent with the predicted stability of an HD attractor network when anchored to external landmarks. A small spiking bias at the stimulus direction could only be observed in a visually deprived environment in which both average firing rates and directional tuning were markedly reduced. Based on this evidence, we speculate that, when attractor dynamics become unstable (e.g., under disorientation), the output of HD neurons could be more efficiently controlled by strong biasing stimuli.SIGNIFICANCE STATEMENT The activity of head direction (HD) cells is thought to provide the mammalian brain with an internal sense of direction. To support navigation, the firing of HD neurons must be anchored to external landmarks, a process thought to be supported by associative plasticity within the HD system. Here, we investigated these plasticity mechanisms by juxtacellular stimulation of single HD neurons in vivo in awake rats. We found that HD coding is strongly resistant to external manipulations of spiking activity. Only in a visually deprived environment was juxtacellular stimulation able to induce a small activity bias in single presubicular neurons. We propose that juxtacellular stimulation can bias HD tuning only when competing anchoring inputs are reduced or not available. PMID- 29487126 TI - The Integration of Functional Brain Activity from Adolescence to Adulthood. AB - Age-related changes in human functional neuroanatomy are poorly understood. This is partly due to the limits of interpretation of standard fMRI. These limits relate to age-related variation in noise levels in data from different subjects, and the common use of standard adult brain parcellations for developmental studies. Here we used an emerging MRI approach called multiecho (ME)-fMRI to characterize functional brain changes with age. ME-fMRI acquires blood oxygenation level-dependent (BOLD) signals while also quantifying susceptibility weighted transverse relaxation time (T2*) signal decay. This approach newly enables reliable detection of BOLD signal components at the subject level as opposed to solely at the group-average level. In turn, it supports more robust characterization of the variability in functional brain organization across individuals. We hypothesized that BOLD components in the resting state are not stable with age, and would decrease in number from adolescence to adulthood. This runs counter to the current assumptions in neurodevelopmental analyses of brain connectivity that the number of BOLD signal components is a random effect. From resting-state ME-fMRI of 51 healthy subjects of both sexes, between 8.3 and 46.2 years of age, we found a highly significant (r = -0.55, p ? 0.001) exponential decrease in the number of BOLD components with age. The number of BOLD components were halved from adolescence to the fifth decade of life, stabilizing in middle adulthood. The regions driving this change were dorsolateral prefrontal cortices, parietal cortex, and cerebellum. The functional network of these regions centered on the cerebellum. We conclude that an age-related decrease in BOLD component number concurs with the hypothesis of neurodevelopmental integration of functional brain activity. We show evidence that the cerebellum may play a key role in this process.SIGNIFICANCE STATEMENT Human brain development is ongoing from childhood to at least 30 years of age. Functional MRI (fMRI) is key for characterizing changes in brain function that accompany development. However, developmental fMRI studies have relied on reference maps of adult brain organization in the analysis of data from younger subjects. This approach may limit the characterization of functional activity patterns that are particular to children and adolescents. Here we used an emerging fMRI approach called multi echo fMRI that is not susceptible to such biases when analyzing the variation in functional brain organization over development. We hypothesized an integration of the components of brain activity over development, and found that the number of components decreases exponentially, halving from 8 to 35 years of age. The brain regions most affected underlie executive function and coordination. In summary, we show major changes in the organization and integration of functional networks over development into adulthood, with both methodological and neurobiological implications for future lifespan and disease studies on brain connectivity. PMID- 29487128 TI - Task Division within the Prefrontal Cortex: Distinct Neuron Populations Selectively Control Different Aspects of Aggressive Behavior via the Hypothalamus. AB - An important question in behavioral neurobiology is how particular neuron populations and pathways mediate the overall roles of brain structures. Here we investigated this issue by studying the medial prefrontal cortex (mPFC), an established locus of inhibitory control of aggression. We established in male rats that dominantly distinct mPFC neuron populations project to and produce dense fiber networks with glutamate release sites in the mediobasal hypothalamus (MBH) and lateral hypothalamus (LH; i.e., two executory centers of species specific and violent bites, respectively). Optogenetic stimulation of mPFC terminals in MBH distinctively increased bite counts in resident/intruder conflicts, whereas the stimulation of similar terminals in LH specifically resulted in violent bites. No other behaviors were affected by stimulations. These findings show that the mPFC controls aggressiveness by behaviorally dedicated neuron populations and pathways, the roles of which may be opposite to those observed in experiments where the role of the whole mPFC (or of its major parts) has been investigated. Overall, our findings suggest that the mPFC organizes into working units that fulfill specific aspects of its wide-ranging roles.SIGNIFICANCE STATEMENT Aggression control is associated with many cognitive and emotional aspects processed by the prefrontal cortex (PFC). However, how the prefrontal cortex influences quantitative and qualitative aspects of aggressive behavior remains unclear. We demonstrated that dominantly distinct PFC neuron populations project to the mediobasal hypothalamus (MBH) and the lateral hypothalamus (LH; i.e., two executory centers of species-specific and violent bites, respectively). Stimulation of mPFC fibers in MBH distinctively increased bite counts during fighting, whereas stimulation of similar terminals in LH specifically resulted in violent bites. Overall, our results suggest a direct prefrontal control over the hypothalamus, which is involved in the modulation of quantitative and qualitative aspects of aggressive behavior through distinct prefrontohypothalamic projections. PMID- 29487127 TI - Maternal Immune Activation During the Third Trimester Is Associated with Neonatal Functional Connectivity of the Salience Network and Fetal to Toddler Behavior. AB - Prenatal maternal immune activation (MIA) is associated with altered brain development and risk of psychiatric disorders in offspring. Translational human studies of MIA are few in number. Alterations of the salience network have been implicated in the pathogenesis of the same psychiatric disorders associated with MIA. If MIA is pathogenic, then associated abnormalities in the salience network should be detectable in neonates immediately after birth. We tested the hypothesis that third trimester MIA of adolescent women who are at risk for high stress and inflammation is associated with the strength of functional connectivity in the salience network of their neonate. Thirty-six women underwent blood draws to measure interleukin-6 (IL-6) and C-reactive protein (CRP) and electrocardiograms to measure fetal heart rate variability (FHRV) at 34-37 weeks gestation. Resting-state imaging data were acquired in the infants at 40-44 weeks postmenstrual age (PMA). Functional connectivity was measured from seeds placed in the anterior cingulate cortex and insula. Measures of cognitive development were obtained at 14 months PMA using the Bayley Scales of Infant and Toddler Development-Third Edition (BSID-III). Both sexes were studied. Regions in which the strength of the salience network correlated with maternal IL-6 or CRP levels included the medial prefrontal cortex, temporoparietal junction, and basal ganglia. Maternal CRP level correlated inversely with FHRV acquired at the same gestational age. Maternal CRP and IL-6 levels correlated positively with measures of cognitive development on the BSID-III. These results suggest that MIA is associated with short- and long-term influences on offspring brain and behavior.SIGNIFICANCE STATEMENT Preclinical studies in rodents and nonhuman primates and epidemiological studies in humans suggest that maternal immune activation (MIA) alters the development of brain circuitry and associated behaviors, placing offspring at risk for psychiatric illness. Consistent with preclinical findings, we show that maternal third trimester interleukin-6 and C reactive protein levels are associated with neonatal functional connectivity and with both fetal and toddler behavior. MIA-related functional connectivity was localized to the salience, default mode, and frontoparietal networks, which have been implicated in the pathogenesis of psychiatric disorders. Our results suggest that MIA alters functional connectivity in the neonatal brain, that those alterations have consequences for cognition, and that these findings may provide pathogenetic links between preclinical and epidemiological studies associating MIA with psychiatric risk in offspring. PMID- 29487129 TI - Biomarkers of platinum resistance in ovarian cancer: what can we use to improve treatment. AB - Ovarian cancer has poor survival rates due to a combination of diagnosis at advanced disease stages and disease recurrence as a result of platinum chemotherapy resistance. High-grade serous ovarian cancer (HGSOC), the most common ovarian cancer subtype, is conventionally treated with surgery and paclitaxel/carboplatin combination chemotherapy. Initial response rates are 60 80%, but eventually the majority of patients become platinum-resistant with subsequent relapses. Extensive research on individual biomarkers of platinum resistance has revealed many potential targets for the development new treatments. While this is ongoing, there are also epigenetic, DNA repair, genome and immune changes characterised in platinum-resistant HGSOC that can be targeted with current therapies. This review discusses biomarkers of platinum chemotherapy resistance in ovarian cancer with a focus on biomarkers that are targetable with alternative treatment combinations to those currently used. After decades of research focused on elucidating the biological cause of platinum resistance, future research needs to focus on using this knowledge to overcome resistance for patients with ovarian cancer. PMID- 29487130 TI - Mass spectrometric evidence for neuropeptide-amidating enzymes in Caenorhabditis elegans. AB - Neuropeptides constitute a vast and functionally diverse family of neurochemical signaling molecules and are widely involved in the regulation of various physiological processes. The nematode Caenorhabditis elegans is well-suited for the study of neuropeptide biochemistry and function, as neuropeptide biosynthesis enzymes are not essential for C. elegans viability. This permits the study of neuropeptide biosynthesis in mutants lacking certain neuropeptide-processing enzymes. Mass spectrometry has been used to study the effects of proprotein convertase and carboxypeptidase mutations on proteolytic processing of neuropeptide precursors and on the peptidome in C. elegans However, the enzymes required for the last step in the production of many bioactive peptides, the carboxyl-terminal amidation reaction, have not been characterized in this manner. Here, we describe three genes that encode homologs of neuropeptide amidation enzymes in C. elegans and used tandem LC-MS to compare neuropeptides in WT animals with those in newly generated mutants for these putative amidation enzymes. We report that mutants lacking both a functional peptidylglycine alpha hydroxylating monooxygenase and a peptidylglycine alpha-amidating monooxygenase had a severely altered neuropeptide profile and also a decreased number of offspring. Interestingly, single mutants of the amidation enzymes still expressed some fully processed amidated neuropeptides, indicating the existence of a redundant amidation mechanism in C. elegans All MS data are available via ProteomeXchange with the identifier PXD008942. In summary, the key steps in neuropeptide processing in C. elegans seem to be executed by redundant enzymes, and loss of these enzymes severely affects brood size, supporting the need of amidated peptides for C. elegans reproduction. PMID- 29487131 TI - Oxysterol-binding protein homologs mediate sterol transport from the endoplasmic reticulum to mitochondria in yeast. AB - Sterols are present in eukaryotic membranes and significantly affect membrane fluidity, permeability, and microdomain formation. They are synthesized in the endoplasmic reticulum (ER) and transported to other organelles and the plasma membrane. Sterols play important roles in the biogenesis and maintenance of mitochondrial membranes. However, the mechanisms underlying ER-to-mitochondrion sterol transport remain to be identified. Here, using purified yeast membrane fractions enriched in ER and mitochondria, we show that the oxysterol-binding protein homologs encoded by the OSH genes in the yeast Saccharomyces cerevisiae mediate sterol transport from the ER to mitochondria. Combined depletion of all seven Osh proteins impaired sterol transport from the ER to mitochondria in vitro; however, sterol transport was recovered at different levels upon adding one of the Osh proteins. Of note, the sterol content in the mitochondrial fraction was significantly decreased in vivo after Osh4 inactivation in a genetic background in which all the other OSH genes were deleted. We also found that Osh5 Osh7 bind cholesterol in vitro We propose a model in which Osh proteins share a common function to transport sterols between membranes, with varying contributions by these proteins, depending on the target membranes. In summary, we have developed an in vitro system to examine intracellular sterol transport and provide evidence for involvement of Osh proteins in sterol transport from the ER to mitochondria in yeast. PMID- 29487132 TI - The dopamine D2 receptor can directly recruit and activate GRK2 without G protein activation. AB - The dopamine D2 receptor (D2R) is a G protein-coupled receptor (GPCR) that is critical for many central nervous system functions. The D2R carries out these functions by signaling through two transducers: G proteins and beta-arrestins (betaarrs). Selectively engaging either the G protein or betaarr pathway may be a way to improve drugs targeting GPCRs. The current model of GPCR signal transduction posits a chain of events where G protein activation ultimately leads to betaarr recruitment. GPCR kinases (GRKs), which are regulated by G proteins and whose kinase action facilitates betaarr recruitment, bridge these pathways. Therefore, betaarr recruitment appears to be intimately tied to G protein activation via GRKs. Here we sought to understand how GRK2 action at the D2R would be disrupted when G protein activation is eliminated and the effect of this on betaarr recruitment. We used two recently developed biased D2R mutants that can preferentially interact either with G proteins or betaarrs as well as a betaarr-biased D2R ligand, UNC9994. With these functionally selective tools, we investigated the mechanism whereby the betaarr-preferring D2R achieves betaarr pathway activation in the complete absence of G protein activation. We describe how direct, G protein-independent recruitment of GRK2 drives interactions at the betaarr-preferring D2R and also contributes to betaarr recruitment at the WT D2R. Additionally, we found an additive interaction between the betaarr-preferring D2R mutant and UNC9994. These results reveal that the D2R can directly recruit GRK2 without G protein activation and that this mechanism may have relevance to achieving betaarr-biased signaling. PMID- 29487133 TI - In silico and crystallographic studies identify key structural features of biliverdin IXbeta reductase inhibitors having nanomolar potency. AB - Heme cytotoxicity is minimized by a two-step catabolic reaction that generates biliverdin (BV) and bilirubin (BR) tetrapyrroles. The second step is regulated by two non-redundant biliverdin reductases (IXalpha (BLVRA) and IXbeta (BLVRB)), which retain isomeric specificity and NAD(P)H-dependent redox coupling linked to BR's antioxidant function. Defective BLVRB enzymatic activity with antioxidant mishandling has been implicated in metabolic consequences of hematopoietic lineage fate and enhanced platelet counts in humans. We now outline an integrated platform of in silico and crystallographic studies for the identification of an initial class of compounds inhibiting BLVRB with potencies in the nanomolar range. We found that the most potent BLVRB inhibitors contain a tricyclic hydrocarbon core structure similar to the isoalloxazine ring of flavin mononucleotide and that both xanthene- and acridine-based compounds inhibit BLVRB's flavin and dichlorophenolindophenol (DCPIP) reductase functions. Crystallographic studies of ternary complexes with BLVRB-NADP+-xanthene-based compounds confirmed inhibitor binding adjacent to the cofactor nicotinamide and interactions with the Ser-111 side chain. This residue previously has been identified as critical for maintaining the enzymatic active site and cellular reductase functions in hematopoietic cells. Both acridine- and xanthene-based compounds caused selective and concentration-dependent loss of redox coupling in BLVRB-overexpressing promyelocytic HL-60 cells. These results provide promising chemical scaffolds for the development of enhanced BLVRB inhibitors and identify chemical probes to better dissect the role of biliverdins, alternative substrates, and BLVRB function in physiologically relevant cellular contexts. PMID- 29487134 TI - The N-terminal domain of a tick evasin is critical for chemokine binding and neutralization and confers specific binding activity to other evasins. AB - Tick chemokine-binding proteins (evasins) are an emerging class of biologicals that target multiple chemokines and show anti-inflammatory activities in preclinical disease models. Using yeast surface display, we identified a CCL8 binding evasin, P672, from the tick Rhipicephalus pulchellus We found that P672 binds CCL8 and eight other CC-class chemokines with a Kd < 10 nm and four other CC chemokines with a Kd between 10 and 100 nm and neutralizes CCL3, CCL3L1, and CCL8 with an IC50 < 10 nm The CC chemokine-binding profile was distinct from that of evasin 1 (EVA1), which does not bind CCL8. We also show that P672's binding activity can be markedly modulated by the location of a StrepII-His purification tag. Combining native MS and bottom-up proteomics, we further demonstrated that P672 is glycosylated and forms a 1:1 complex with CCL8, disrupting CCL8 homodimerization. Homology modeling of P672 using the crystal structure of the EVA1 and CCL3 complex as template suggested that 44 N-terminal residues of P672 form most of the contacts with CCL8. Replacing the 29 N-terminal residues of EVA1 with the 44 N-terminal residues of P672 enabled this hybrid evasin to bind and neutralize CCL8, indicating that the CCL8-binding properties of P672 reside, in part, in its N-terminal residues. This study shows that the function of certain tick evasins can be manipulated simply by adding a tag. We conclude that homology modeling helps identify regions with transportable chemokine-binding functions within evasins, which can be used to construct hybrid evasins with altered properties. PMID- 29487135 TI - Hypoxanthine is a checkpoint stress metabolite in colonic epithelial energy modulation and barrier function. AB - Intestinal epithelial cells form a selectively permeable barrier to protect colon tissues from luminal microbiota and antigens and to mediate nutrient, fluid, and waste flux in the intestinal tract. Dysregulation of the epithelial cell barrier coincides with profound shifts in metabolic energy, especially in the colon, which exists in an energetically depleting state of physiological hypoxia. However, studies that systematically examine energy flux and adenylate metabolism during intestinal epithelial barrier development and restoration after disruption are lacking. Here, to delineate barrier-related energy flux, we developed an HPLC based profiling method to track changes in energy flux and adenylate metabolites during barrier development and restoration. Cultured epithelia exhibited pooling of phosphocreatine and maintained ATP during barrier development. EDTA-induced epithelial barrier disruption revealed that hypoxanthine levels correlated with barrier resistance. Further studies uncovered that hypoxanthine supplementation improves barrier function and wound healing and that hypoxanthine appears to do so by increasing intracellular ATP, which improved cytoskeletal G- to F-actin polymerization. Hypoxanthine supplementation increased the adenylate energy charge in the murine colon, indicating potential to regulate adenylate energy charge-mediated metabolism in intestinal epithelial cells. Moreover, experiments in a murine colitis model disclosed that hypoxanthine loss during active inflammation correlates with markers of disease severity. In summary, our results indicate that hypoxanthine modulates energy metabolism in intestinal epithelial cells and is critical for intestinal barrier function. PMID- 29487136 TI - A Damage Sensor Associated with the Cuticle Coordinates Three Core Environmental Stress Responses in Caenorhabditis elegans. AB - Extracellular matrix barriers and inducible cytoprotective genes form successive lines of defense against chemical and microbial environmental stressors. The barrier in nematodes is a collagenous extracellular matrix called the cuticle. In Caenorhabditis elegans, disruption of some cuticle collagen genes activates osmolyte and antimicrobial response genes. Physical damage to the epidermis also activates antimicrobial responses. Here, we assayed the effect of knocking down genes required for cuticle and epidermal integrity on diverse cellular stress responses. We found that disruption of specific bands of collagen, called annular furrows, coactivates detoxification, hyperosmotic, and antimicrobial response genes, but not other stress responses. Disruption of other cuticle structures and epidermal integrity does not have the same effect. Several transcription factors act downstream of furrow loss. SKN-1/Nrf and ELT-3/GATA are required for detoxification, SKN-1/Nrf is partially required for the osmolyte response, and STA-2/Stat and ELT-3/GATA for antimicrobial gene expression. Our results are consistent with a cuticle-associated damage sensor that coordinates detoxification, hyperosmotic, and antimicrobial responses through overlapping, but distinct, downstream signaling. PMID- 29487138 TI - Accounting for Errors in Low Coverage High-Throughput Sequencing Data When Constructing Genetic Maps Using Biparental Outcrossed Populations. AB - Next-generation sequencing is an efficient method that allows for substantially more markers than previous technologies, providing opportunities for building high-density genetic linkage maps, which facilitate the development of nonmodel species' genomic assemblies and the investigation of their genes. However, constructing genetic maps using data generated via high-throughput sequencing technology (e.g., genotyping-by-sequencing) is complicated by the presence of sequencing errors and genotyping errors resulting from missing parental alleles due to low sequencing depth. If unaccounted for, these errors lead to inflated genetic maps. In addition, map construction in many species is performed using full-sibling family populations derived from the outcrossing of two individuals, where unknown parental phase and varying segregation types further complicate construction. We present a new methodology for modeling low coverage sequencing data in the construction of genetic linkage maps using full-sibling populations of diploid species, implemented in a package called GUSMap. Our model is based on the Lander-Green hidden Markov model but extended to account for errors present in sequencing data. We were able to obtain accurate estimates of the recombination fractions and overall map distance using GUSMap, while most existing mapping packages produced inflated genetic maps in the presence of errors. Our results demonstrate the feasibility of using low coverage sequencing data to produce genetic maps without requiring extensive filtering of potentially erroneous genotypes, provided that the associated errors are correctly accounted for in the model. PMID- 29487137 TI - Seven-Up Is a Novel Regulator of Insulin Signaling. AB - Insulin resistance is associated with obesity, cardiovascular disease, non alcoholic fatty liver disease, and type 2 diabetes. These complications are exacerbated by a high-calorie diet, which we used to model type 2 diabetes in Drosophila melanogaster Our studies focused on the fat body, an adipose- and liver-like tissue that stores fat and maintains circulating glucose. A gene regulatory network was constructed to predict potential regulators of insulin signaling in this tissue. Genomic characterization of fat bodies suggested a central role for the transcription factor Seven-up (Svp). Here, we describe a new role for Svp as a positive regulator of insulin signaling. Tissue-specific loss of-function showed that Svp is required in the fat body to promote glucose clearance, lipid turnover, and insulin signaling. Svp appears to promote insulin signaling, at least in part, by inhibiting ecdysone signaling. Svp also impairs the immune response possibly via inhibition of antimicrobial peptide expression in the fat body. Taken together, these studies show that gene regulatory networks can help identify positive regulators of insulin signaling and metabolic homeostasis using the Drosophila fat body. PMID- 29487139 TI - Proteomic Biomarkers for Incident Aortic Stenosis Requiring Valvular Replacement. AB - BACKGROUND: Aortic valve stenosis (AS) is the most common indication for cardiac valve surgery; untreated AS is linked to high mortality. The etiological background of AS is unknown. Previous human studies were typically based on case control studies. Biomarkers identified in prospective studies could lead to novel mechanistic insights. METHODS: Within a large population survey with blood samples obtained at baseline, 334 patients were identified who later underwent surgery for AS (median age [interquartile range], 59.9 [10.4] years at survey and 68.3 [12.7] at surgery; 48% female). For each case, 2 matched referents were allocated. Plasma was analyzed with the multiplex proximity extension assay for screening of 92 cardiovascular candidate proteins. Conditional logistic regression models were used to assess associations between each protein and AS, with correction for multiple testing. A separate set of 106 additional cases with 212 matched referents was used in a validation study. RESULTS: Six proteins (growth differentiation factor 15, galectin-4, von Willebrand factor, interleukin 17 receptor A, transferrin receptor protein 1, and proprotein convertase subtilisin/kexin type 9) were associated with case status in the discovery cohort; odds ratios ranged from 1.25 to 1.37 per SD increase in the protein signal. Adjusting the multivariable models for classical cardiovascular risk factors at baseline yielded similar results. Subanalyses of case-referent triplets (n=133) who showed no visible coronary artery disease at the time of surgery in the index person supported associations between AS and growth differentiation factor 15 (odds ratio, 1.40; 95% confidence interval, 1.10-1.78) and galectin-4 (odds ratio, 1.27; 95% confidence interval, 1.02-1.59), but these associations were attenuated after excluding individuals who donated blood samples within 5 years before surgery. In triplets (n=201), which included index individuals with concurrent coronary artery disease at the time of surgery, all 6 proteins were robustly associated with case status in all sensitivity analyses. In the validation study, the association of all but 1 (interleukin 17 receptor A) of these proteins were replicated in patients with AS with concurrent coronary artery disease but not in patients with AS without coronary artery disease. CONCLUSIONS: We provide evidence that 5 proteins were altered years before AS surgery and that the associations seem to be driven by concurrent atherosclerotic disease. PMID- 29487141 TI - Olfaction, experience and neural mechanisms underlying mosquito host preference. AB - Mosquitoes are best known for their proclivity towards biting humans and transmitting bloodborne pathogens, but there are over 3500 species, including both blood-feeding and non-blood-feeding taxa. The diversity of host preference in mosquitoes is exemplified by the feeding habits of mosquitoes in the genus Malaya that feed on ant regurgitation or those from the genus Uranotaenia that favor amphibian hosts. Host preference is also by no means static, but is characterized by behavioral plasticity that allows mosquitoes to switch hosts when their preferred host is unavailable and by learning host cues associated with positive or negative experiences. Here we review the diverse range of host preference behaviors across the family Culicidae, which includes all mosquitoes, and how adaptations in neural circuitry might affect changes in preference both within the life history of a mosquito and across evolutionary time-scales. PMID- 29487140 TI - Bone Morphogenetic Protein 9 Reduces Cardiac Fibrosis and Improves Cardiac Function in Heart Failure. AB - Background -Heart failure is a growing cause of morbidity and mortality worldwide. Transforming growth factor beta (TGF-beta1) promotes cardiac fibrosis, but also activates counter-regulatory pathways that serve to regulate TGF-beta1 activity in heart failure. Bone morphogenetic protein 9 (BMP9) is a member of the TGFbeta family of cytokines and signals via the downstream effector protein Smad1. Endoglin is a TGFbeta co-receptor that promotes TGF-beta1 signaling via Smad3 and binds BMP9 with high affinity. We hypothesized that BMP9 limits cardiac fibrosis by activating Smad1 and attenuating Smad3 and further that neutralizing endoglin activity promotes BMP9 activity. Methods -We examined BMP9 expression and signaling in human cardiac fibroblasts and human subjects with heart failure. We utilized the thoracic aortic constriction (TAC) induced model of heart failure to evaluate the functional effect of BMP9 signaling on cardiac remodeling. Results -BMP9 expression is increased in the circulation and left ventricle (LV) of human subjects with heart failure and is expressed by cardiac fibroblasts. Next, we observed that BMP9 attenuates Type I collagen synthesis in human cardiac fibroblasts using recombinant human BMP9 and an siRNA approach. In BMP9-/- mice subjected to TAC, loss of BMP9 activity promotes cardiac fibrosis, impairs LV function, and increases LV levels of phosphorylated Smad3 (pSmad3), not pSmad1. In contrast, treatment of wild-type mice subjected to TAC with recombinant BMP9 limits progression of cardiac fibrosis, improves LV function, enhances myocardial capillary density, and increases LV levels of pSmad1, not pSmad3 compared to vehicle treated controls. Since endoglin binds BMP9 with high affinity, we explored the effect of reduced endoglin activity on BMP9 activity. Neutralizing endoglin activity in human cardiac fibroblasts or in wild-type mice subjected to TAC induced heart failure limits collagen production, increases BMP9 protein levels, and increases levels of pSmad1, not pSmad3. Conclusions -Our results identify a novel functional role for BMP9 as an endogenous inhibitor of cardiac fibrosis due to LV pressure overload and further show that treatment with either recombinant BMP9 or disruption of endoglin activity promotes BMP9 activity and limits cardiac fibrosis in heart failure, thereby providing potentially novel therapeutic approaches for patients with heart failure. PMID- 29487142 TI - A Decade in the MIST: Learnings from Investigations of Drug Metabolites in Drug Development under the "Metabolites in Safety Testing" Regulatory Guidance. AB - Since the introduction of metabolites in safety testing (MIST) guidance by the Food and Drug Administration in 2008, major changes have occurred in the experimental methods for the identification and quantification of metabolites, ways to evaluate coverage of metabolites, and the timing of critical clinical and nonclinical studies to generate this information. In this cross-industry review, we discuss how the increased focus on human drug metabolites and their potential contribution to safety and drug-drug interactions has influenced the approaches taken by industry for the identification and quantitation of human drug metabolites. Before the MIST guidance was issued, the method of choice for generating comprehensive metabolite profile was radio chromatography. The MIST guidance increased the focus on human drug metabolites and their potential contribution to safety and drug-drug interactions and led to changes in the practices of drug metabolism scientists. In addition, the guidance suggested that human metabolism studies should also be accelerated, which has led to more frequent determination of human metabolite profiles from multiple ascending-dose clinical studies. Generating a comprehensive and quantitative profile of human metabolites has become a more urgent task. Together with technological advances, these events have led to a general shift of focus toward earlier human metabolism studies using high-resolution mass spectrometry and to a reduction in animal radiolabel absorption/distribution/metabolism/excretion studies. The changes induced by the MIST guidance are highlighted by six case studies included herein, reflecting different stages of implementation of the MIST guidance within the pharmaceutical industry. PMID- 29487143 TI - The Evolution of Science in a Latin-American Country: Genetics and Genomics in Brazil. AB - This article begins with a brief overview of the history of Brazil and that of Brazilian science, from the European discovery of the country in 1500 up to the early 21st century. The history of the fields of genetics and genomics, from the 1930s, is then first examined from the focal point of the lives and publications of the three persons who are generally considered to be the founders of genetics in Brazil (C. A. Krug, F. G. Brieger, and A. Dreyfus), and then by 12 other researchers up to 1999. The area of molecular genetics and genomics from 2000 to present is then described. Despite the problems of underdevelopment and the periodical political and economic crises that have affected life in Brazil, the fields of genetics and genomics in Brazil can be regarded as having developed at an appropriate pace, and have contributed in several major ways to world science. PMID- 29487144 TI - How Surrogate and Chemical Genetics in Model Organisms Can Suggest Therapies for Human Genetic Diseases. AB - Genetic diseases are both inherited and acquired. Many genetic diseases fall under the paradigm of orphan diseases, a disease found in < 1 in 2000 persons. With rapid and cost-effective genome sequencing becoming the norm, many causal mutations for genetic diseases are being rapidly determined. In this regard, model organisms are playing an important role in validating if specific mutations identified in patients drive the observed phenotype. An emerging challenge for model organism researchers is the application of genetic and chemical genetic platforms to discover drug targets and drugs/drug-like molecules for potential treatment options for patients with genetic disease. This review provides an overview of how model organisms have contributed to our understanding of genetic disease, with a focus on the roles of yeast and zebrafish in gene discovery and the identification of compounds that could potentially treat human genetic diseases. PMID- 29487145 TI - RNA Interference (RNAi) Screening in Drosophila. AB - In the last decade, RNA interference (RNAi), a cellular mechanism that uses RNA guided degradation of messenger RNA transcripts, has had an important impact on identifying and characterizing gene function. First discovered in Caenorhabditis elegans, RNAi can be used to silence the expression of genes through introduction of exogenous double-stranded RNA into cells. In Drosophila, RNAi has been applied in cultured cells or in vivo to perturb the function of single genes or to systematically probe gene function on a genome-wide scale. In this review, we will describe the use of RNAi to study gene function in Drosophila with a particular focus on high-throughput screening methods applied in cultured cells. We will discuss available reagent libraries and cell lines, methodological approaches for cell-based assays, and computational methods for the analysis of high-throughput screens. Furthermore, we will review the generation and use of genome-scale RNAi libraries for tissue-specific knockdown analysis in vivo and discuss the differences and similarities with the use of genome-engineering methods such as CRISPR/Cas9 for functional analysis. PMID- 29487149 TI - Revisiting the Role of the Male-Specific Lethal Complex in the Sex Determination Decision of Drosophila. PMID- 29487148 TI - Regulation of Circadian Behavior by Astroglial MicroRNAs in Drosophila. AB - We describe a genome-wide microRNA (miRNA)-based screen to identify brain glial cell functions required for circadian behavior. To identify glial miRNAs that regulate circadian rhythmicity, we employed a collection of "miR-sponges" to inhibit miRNA function in a glia-specific manner. Our initial screen identified 20 glial miRNAs that regulate circadian behavior. We studied two miRNAs, miR-263b and miR-274, in detail and found that both function in adult astrocytes to regulate behavior. Astrocyte-specific inhibition of miR-263b or miR-274 in adults acutely impairs circadian locomotor activity rhythms with no effect on glial or clock neuronal cell viability. To identify potential RNA targets of miR-263b and miR-274, we screened 35 predicted miRNA targets, employing RNA interference-based approaches. Glial knockdown of two putative miR-274 targets, CG4328 and MESK2, resulted in significantly decreased rhythmicity. Homology of the miR-274 targets to mammalian counterparts suggests mechanisms that might be relevant for the glial regulation of rhythmicity. PMID- 29487151 TI - Detection and direction discrimination of single vortex rings by harbour seals (Phoca vitulina). AB - Harbour seals possess highly sensitive vibrissae that enable them to track hydrodynamic trails left behind by a swimming fish. Most of these trails contain vortex rings as a main hydrodynamic component. They may reveal information about their generator as the trails differ depending on the fish species, the fish's body shape, size and swimming style. In addition, fish generate single vortex rings in diverse natural situations. In this study, the ability of blindfolded stationary harbour seals to detect and analyse single vortex rings regarding directional information has been investigated. In three different behavioural experiments, the animals were trained to respond to single artificially generated vortex rings. The results show that harbour seals are able to respond to a variety of different vortex rings upon vibrissal stimulation. The investigation of the minimum hydrodynamically perceivable angle revealed that it is at least as small as 5.7 deg, which was the smallest adjustable angle. Moreover, harbour seals are capable of analysing the travel direction of a vortex ring perceived by the mystacial vibrissae irrespective of whether the vibrissae were stimulated ipsilaterally or contralaterally. In situations in which no complex hydrodynamic trail is available, it is advantageous for a hunting seal to be able to extract information from a single vortex ring. PMID- 29487146 TI - Female Meiosis: Synapsis, Recombination, and Segregation in Drosophila melanogaster. AB - A century of genetic studies of the meiotic process in Drosophila melanogaster females has been greatly augmented by both modern molecular biology and major advances in cytology. These approaches, and the findings they have allowed, are the subject of this review. Specifically, these efforts have revealed that meiotic pairing in Drosophila females is not an extension of somatic pairing, but rather occurs by a poorly understood process during premeiotic mitoses. This process of meiotic pairing requires the function of several components of the synaptonemal complex (SC). When fully assembled, the SC also plays a critical role in maintaining homolog synapsis and in facilitating the maturation of double strand breaks (DSBs) into mature crossover (CO) events. Considerable progress has been made in elucidating not only the structure, function, and assembly of the SC, but also the proteins that facilitate the formation and repair of DSBs into both COs and noncrossovers (NCOs). The events that control the decision to mature a DSB as either a CO or an NCO, as well as determining which of the two CO pathways (class I or class II) might be employed, are also being characterized by genetic and genomic approaches. These advances allow a reconsideration of meiotic phenomena such as interference and the centromere effect, which were previously described only by genetic studies. In delineating the mechanisms by which the oocyte controls the number and position of COs, it becomes possible to understand the role of CO position in ensuring the proper orientation of homologs on the first meiotic spindle. Studies of bivalent orientation have occurred in the context of numerous investigations into the assembly, structure, and function of the first meiotic spindle. Additionally, studies have examined the mechanisms ensuring the segregation of chromosomes that have failed to undergo crossing over. PMID- 29487153 TI - Emptying and refilling of slime glands in Atlantic (Myxine glutinosa) and Pacific (Eptatretus stoutii) hagfishes. AB - Hagfishes are known for their unique defensive slime, which they use to ward off gill-breathing predators. Although much is known about the slime cells (gland thread cells and gland mucous cells), little is known about how long slime gland refilling takes, or how slime composition changes with refilling or repeated stimulation of the same gland. Slime glands can be individually electrostimulated to release slime, and this technique was used to measure slime gland refilling times for Atlantic and Pacific hagfish. The amount of exudate produced, the composition of the exudate and the morphometrics of slime cells were analyzed during refilling, and as a function of stimulation number when full glands were stimulated in rapid succession. Complete refilling of slime glands for both species took 3-4 weeks, with Pacific hagfish achieving faster absolute rates of exudate recovery than Atlantic hagfish. We found significant changes in the composition of the exudate and in the morphometrics of slime cells from Pacific hagfish during refilling. Over successive stimulations of full Pacific hagfish glands, multiple boluses of exudate were released, with exudate composition, but not thread cell morphometrics, changing significantly. Finally, histological examination of slime glands revealed slime cells retained in glands after exhaustion. Discrepancies in the volume of cells released suggest that mechanisms other than contraction of the gland musculature alone may be involved in exudate ejection. Our results provide a first look at the process and timing of slime gland refilling in hagfishes, and raise new questions about how refilling is achieved at the cellular level. PMID- 29487152 TI - Acid-base regulation in the air-breathing swamp eel (Monopterus albus) at different temperatures. AB - Vertebrates reduce arterial blood pH (pHa) when body temperature increases. In water breathers, this response occurs primarily by reducing plasma HCO3- levels with small changes in the partial pressure of CO2 (PCO2 ). In contrast, air breathers mediate the decrease in pHa by increasing arterial PCO2 (PaCO2 ) at constant plasma HCO3- by reducing lung ventilation relative to metabolic CO2 production. Much less is known about bimodal breathers, which utilize both water and air. Here, we characterized the influence of temperature on arterial acid base balance and intracellular pH (pHi) in the bimodal-breathing swamp eel, Monopterus albus This teleost uses the buccopharyngeal cavity for gas exchange and has very reduced gills. When exposed to ecologically relevant temperatures (20, 25, 30 and 35 degrees C) for 24 and 48 h, pHa decreased by -0.025 pH units (U) degrees C-1 in association with an increase in PaCO2 , but without changes in plasma [HCO3-]. pHi was also reduced with increased temperature. The slope of pHi of liver and muscle was -0.014 and -0.019 U degrees C-1, while the heart muscle showed a smaller reduction (-0.008 U degrees C-1). When exposed to hypercapnia (7 or 14 mmHg) at either 25 or 35 degrees C, M. albus elevated plasma [HCO3-] and therefore seemed to defend the new pHa set-point, demonstrating an adjusted control of acid-base balance with temperature. Overall, the effects of temperature on acid-base balance in M. albus resemble those in air-breathing amniotes, and we discuss the possibility that this pattern of acid-base balance results from a progressive transition in CO2 excretion from water to air as temperature rises. PMID- 29487154 TI - Kinematics of swimming of the manta ray: three-dimensional analysis of open-water maneuverability. AB - For aquatic animals, turning maneuvers represent a locomotor activity that may not be confined to a single coordinate plane, making analysis difficult, particularly in the field. To measure turning performance in a three-dimensional space for the manta ray (Mobula birostris), a large open-water swimmer, scaled stereo video recordings were collected. Movements of the cephalic lobes, eye and tail base were tracked to obtain three-dimensional coordinates. A mathematical analysis was performed on the coordinate data to calculate the turning rate and curvature (1/turning radius) as a function of time by numerically estimating the derivative of manta trajectories through three-dimensional space. Principal component analysis was used to project the three-dimensional trajectory onto the two-dimensional turn. Smoothing splines were applied to these turns. These are flexible models that minimize a cost function with a parameter controlling the balance between data fidelity and regularity of the derivative. Data for 30 sequences of rays performing slow, steady turns showed the highest 20% of values for the turning rate and smallest 20% of turn radii were 42.65+/-16.66 deg s-1 and 2.05+/-1.26 m, respectively. Such turning maneuvers fall within the range of performance exhibited by swimmers with rigid bodies. PMID- 29487147 TI - Sexual Dimorphism and Sex Differences in Caenorhabditis elegans Neuronal Development and Behavior. AB - As fundamental features of nearly all animal species, sexual dimorphisms and sex differences have particular relevance for the development and function of the nervous system. The unique advantages of the nematode Caenorhabditis elegans have allowed the neurobiology of sex to be studied at unprecedented scale, linking ultrastructure, molecular genetics, cell biology, development, neural circuit function, and behavior. Sex differences in the C. elegans nervous system encompass prominent anatomical dimorphisms as well as differences in physiology and connectivity. The influence of sex on behavior is just as diverse, with biological sex programming innate sex-specific behaviors and modifying many other aspects of neural circuit function. The study of these differences has provided important insights into mechanisms of neurogenesis, cell fate specification, and differentiation; synaptogenesis and connectivity; principles of circuit function, plasticity, and behavior; social communication; and many other areas of modern neurobiology. PMID- 29487155 TI - Three-dimensional analysis of the fast-start escape response of the least killifish, Heterandria formosa. AB - Fish make C-starts to evade predator strikes. Double-bend (DB) C-starts consist of three stages: Stage 1, in which the fish rapidly bends into a C-shape; Stage 2, in which the fish bends in the opposite direction; and a variable Stage 3. In single-bend (SB) C-starts, the fish immediately straightens after Stage 1. Despite fish moving in three-dimensional (3D) space, fast-start responses of adult fish have mainly been studied in a horizontal plane. Using automated 3D tracking of multi-camera high-speed video sequences, we show that both SB and DB fast-starts by adult female least killifish (Heterandria formosa) often contain a significant vertical velocity component, and large changes in pitch (DB up to 43 deg) and roll (DB up to 77 deg) angles. Upwards and downwards elevation changes are correlated with changes in pitch angle of the head; movement in the horizontal plane is correlated with changes in yaw angle of the head. With respect to the stimulus, escape heading correlates with the elevation of the fish at the onset of motion. Irrespective of the initial orientation, fish can escape in any horizontal direction. In many cases, the centre of mass barely accelerates during Stage 1. However, it does accelerate in the final direction of the escape in other instances, indicating that Stage 1 can serve a propulsive role in addition to its preparatory role for Stage 2. Our findings highlight the importance of large-scale 3D analyses of fast-start manoeuvres of adult fish in uncovering the versatility of fish escape repertoire. PMID- 29487156 TI - The membrane pacemaker hypothesis: novel tests during the ontogeny of endothermy. AB - The 'membrane pacemaker' hypothesis proposes a biochemical explanation for among species variation in resting metabolism, based on the positive correlation between membrane docosahexaenoic acid (DHA) and metabolic rate. We tested this hypothesis using a novel model, altricial red-winged blackbird nestlings, predicting that the proportion of DHA in muscle and liver membranes should increase with the increasing metabolic rate of the nestling as it develops endothermy. We also used a dietary manipulation, supplementing the natural diet with fish oil (high DHA) or sunflower oil (high linoleic acid) to alter membrane composition and then assessed metabolic rate. In support of the membrane pacemaker hypothesis, DHA proportions increased in membranes from pectoralis muscle, muscle mitochondria and liver during post-hatch development. By contrast, elevated dietary DHA had no effect on resting metabolic rate, despite causing significant changes to membrane lipid composition. During cold challenges, higher metabolic rates were achieved by birds that had lower DHA and higher linoleic acid in membrane phospholipids. Given the mixed support for this hypothesis, we conclude that correlations between membrane DHA and metabolic rate are likely spurious, and should be attributed to a still-unidentified confounding variable. PMID- 29487157 TI - Differences in stress and disease resilience related to emergence time for first feeding in farmed rainbow trout (Oncorhynchus mykiss). AB - Salmonid individuals show a relatively high variability in the time required to abandon the gravel nest where they hatch, the so-called 'emergence time'. Different behavioral and physiological traits have been shown to be associated with emergence time in wild salmonids. In general, early- and late-emerging fish have traits resembling those of proactive and reactive stress coping styles, respectively. Proactive fish are considered to be more resilient to stress and probably to disease, so it was hypothesized that fish with different emergence times have different abilities to resist repeated episodes of stress without suffering deleterious effects on their welfare or health status. In this study, rainbow trout eyed eggs were hatched and larvae were fractionated according to their emergence time (early fraction: first 20% of fish to emerge; intermediate fraction: mid 20%; late fraction: last 20%). When the fish were 4 months old, they were exposed to a daily repeated stress protocol for 15 days. The next day, both naive and repeatedly stressed fish were exposed to an acute stress challenge. Different plasma (cortisol, glucose, lactate) as well as CNS (serotonergic activity) stress markers were assessed to evaluate the stress resilience of the different groups. Furthermore, an intraperitoneal infection challenge with Flavobacterium psychrophilum was carried out to assess disease resilience. Altogether, the results showed that fish from different fractions displayed differences in activation of the hypothalamus-pituitary-inter-renal axis, indicating a higher stress resilience in the fish with early emergence times. However, those differences were not reflected in the ability of the different fractions to grow and perform well in terms of growth, or in the ability to overcome infection with bacteria, which was similar for all the emergence fractions. This suggests that discriminating fish according to emergence time would probably have little effect in improving the performance and the welfare of farmed fish. PMID- 29487158 TI - Miniaturisation decreases visual navigational competence in ants. AB - Evolution of a smaller body size in a given lineage, called miniaturisation, is commonly observed in many animals including ants. It affects various morphological features and is hypothesised to result in inferior behavioural capabilities, possibly owing to smaller sensory organs. To test this hypothesis, we studied whether reduced spatial resolution of compound eyes influences obstacle detection or obstacle avoidance in five different species of ants. We trained all ant species to travel to a sugar feeder. During their return journeys, we placed an obstacle close to the nest entrance. We found that ants with higher spatial resolution exited the corridor - the area between the two ends of the obstacle - on average 10 cm earlier, suggesting they detected the obstacle earlier in their path. Ants with the lowest spatial resolution changed their viewing directions only when they were close to the obstacle. We discuss the effects of miniaturisation on visual navigational competence in ants. PMID- 29487159 TI - Molecular and functional characterization of the Gulf toadfish serotonin transporter SLC6A4. AB - The serotonin transporter (SERT) functions in the uptake of the neurotransmitter serotonin (5-HT) from the extracellular milieu and is the molecular target of the selective serotonin re-uptake inhibitors (SSRIs), a common group of anti depressants. The current study comprehensively assesses the sequence, tissue distribution, transport kinetics and physiological function of a teleost SERT. The 2022 bp toadfish SERT sequence encodes a protein of 673 amino acids, which shows 83% similarity to zebrafish SERT and groups with SERT of other teleosts in phylogenetic analysis. SERT mRNA is ubiquitous in tissues and is expressed at high levels in the heart and, within the brain, in the cerebellum. SERT cRNA expressed in Xenopus laevis oocytes demonstrates a Km value of 2.08+/-0.45 MUmol l-1, similar to previously reported Km values for zebrafish and human SERT. Acute systemic blockade of SERT by intraperitoneal administration of the SSRI fluoxetine (FLX) produces a dose-dependent increase in plasma 5-HT, indicating effective inhibition of 5-HT uptake from the circulation. As teleosts lack platelets, which are important 5-HT sequestration sites in mammals, the FLX induced increase in plasma 5-HT suggests that toadfish tissues may normally be responsible for maintaining low 5-HT concentrations in the bloodstream. PMID- 29487160 TI - The effect of air resistance on the jump performance of a small parasitoid wasp, Anagyrus pseudococci (Encyrtidae). AB - The distance a small insect moves through the air during a jump is limited by the launch velocity at take-off and by air resistance. The launch velocity is limited by the length of the jumping legs and the maximum power that the jump apparatus can provide for pushing against the ground. The effect of air resistance is determined by the insect mass-to-area ratio. Both limitations are highly dependent on body size, making high jumps a challenge for smaller insects. We studied both effects in the tiny Encyrtid wasp Anagyrus pseudococci. Males are smaller than females (mean body length 1.2 and 1.8 mm, respectively), but both sexes take off in a powerful jump. Using high-speed cameras, we analyzed the relationship between take-off kinematics and distance traveled through the air. We show that the velocity, acceleration and mass-specific power when leaving the ground places A. pseudococci among the most prominent jumpers of the insect world. However, the absolute distance moved through the air is modest compared with other jumping insects, as a result of air resistance acting on the small body. A biomechanical model suggests that air resistance reduces the jump distance of these insects by 49% compared with jumping in the absence of air resistance. The effect of air resistance is more pronounced in the smaller males, resulting in a segregation of the jumping performance between sexes. The limiting effect of air resistance is inversely proportional to body mass, seriously constraining jumping as a form of moving through the air in these and other small insects. PMID- 29487161 TI - HSP90 regulates larval settlement of the bryozoan Bugula neritina through the nitric oxide pathway. AB - The larvae of many sessile marine invertebrates go through a settlement process, during which planktonic larvae attach to a substrate and metamorphose into sessile juveniles. Larval attachment and metamorphosis (herein defined as 'settlement') are complex processes mediated by many signalling pathways. Nitric oxide (NO) signalling is one of the pathways that inhibits larval settlement in marine invertebrates across different phyla. NO is synthesized by NO synthase (NOS), which is a client of the molecular chaperone heat shock protein 90 (HSP90). In the present study, we provide evidence that NO, a gaseous messenger, regulates larval settlement of Bugula neritina By using pharmacological bioassays and western blotting, we demonstrated that NO inhibits larval settlement of B. neritina and that NO signals occur mainly in the sensory organ of swimming larvae. The settlement rate of B. neritina larvae decreased after heat shock treatment. Inhibition of HSP90 induced larval settlement, and attenuated the inhibition of NO donors during larval settlement. In addition, the expression level of both HSP90 and NOS declined upon settlement. These results demonstrate that HSP90 regulates the larval settlement of B. neritina by interacting with the NO pathway. PMID- 29487162 TI - High activity before breeding improves reproductive performance by enhancing mitochondrial function and biogenesis. AB - Understanding of physiological responses of organisms is typically based on data collected during an isolated event. Although many fundamental insights have been gained from these studies, evaluating the response to a single event ignores the fact that each individual has experienced a unique set of events throughout its life that may have altered its physiology. The idea that prior experiences can influence subsequent performance is known as a carry-over effect. Carry-over effects may explain much of the variation in performance found among individuals. For example, high physical activity has been shown to improve mitochondrial respiratory function and biogenesis and reduce oxidative stress, and has been linked to improved health and longevity. In this study, we asked whether the bioenergetic differences between active and inactive individuals carry over to impact performance in a subsequent reproductive event and alter a female's reproductive outcome. Female mice that had access to a running wheel for a month before mating gave birth to a larger litter and weaned a heavier litter, indicating that high physical activity had a positive carry-over effect to reproduction. Mice that ran also displayed higher mitochondrial respiration and biogenesis with no changes in endogenous antioxidant enzymes. These results provide a mechanistic framework for how the conditions that animals experience before breeding can impact reproductive outcomes. PMID- 29487163 TI - Characteristics of Children 2 to 5 Years of Age With Severe Obesity. AB - BACKGROUND AND OBJECTIVES: As a distinct group, 2- to 5-year-olds with severe obesity (SO) have not been extensively described. As a part of the Expert Exchange Workgroup on Childhood Obesity, nationally-representative data were examined to better characterize children with SO. METHODS: Children ages 2 to 5 (N = 7028) from NHANES (1999-2014) were classified as having normal weight, overweight, obesity, or SO (BMI >=120% of 95th percentile). Sociodemographics, birth characteristics, screen time, total energy, and Healthy Eating Index 2010 scores were evaluated. Multinomial logistic and linear regressions were conducted, with normal weight as the referent. RESULTS: The prevalence of SO was 2.1%. Children with SO had higher (unadjusted) odds of being a racial and/or ethnic minority (African American: odds ratio [OR]: 1.7; Hispanic: OR: 2.3). They were from households with lower educational attainment (OR: 2.4), that were single-parent headed (OR: 2.0), and that were in poverty (OR: 2.1). Having never been breastfed was associated with increased odds of obesity (OR: 1.5) and higher odds of SO (OR: 1.9). Odds of >4 hours of screen time were 1.5 and 2.0 for children with obesity and SO. Energy intake and Healthy Eating Index 2010 scores were not significantly different in children with SO. CONCLUSIONS: Children ages 2 to 5 with SO appear to be more likely to be of a racial and/or ethnic minority and have greater disparities in social determinants of health than their peers and are more than twice as likely to engage in double the recommended screen time limit. PMID- 29487164 TI - The Current Pediatric Telehealth Landscape. AB - The growth and evolution of telehealth are opening new avenues for efficient, effective, and affordable pediatric health care services in the United States and around the world. However, there remain several barriers to the integration of telehealth into current practice. Establishing the necessary technical, administrative, and operational infrastructure can be challenging, and there is a relative lack of rigorous research data to demonstrate that telehealth is indeed delivering on its promise. That being said, a knowledge of the current state of pediatric telehealth can overcome many of these barriers, and programs are beginning to collaborate through a new pediatric telehealth research network called Supporting Pediatric Research on Outcomes and Utilization of Telehealth (SPROUT). In this report, we provide an update on the landscape of pediatric telehealth and summarize the findings of a recent SPROUT study in which researchers assessed pediatric telehealth programs across the United States. There were >50 programs representing 30 states that provided data on their implementation barriers, staffing resources, operational processes, technology, and funding sources to establish a base understanding of pediatric telehealth infrastructure on a national level. Moving forward, the database created from the SPROUT study will also serve as a foundation on which multicenter studies will be developed and facilitated in an ongoing effort to firmly establish the value of telehealth in pediatric health care. PMID- 29487165 TI - Phosphatase of regenerating liver maintains cellular magnesium homeostasis. AB - Phosphatase of regenerating liver (PRL) is highly expressed in malignant cancers and promotes cancer progression. Recent studies have suggested its functional relationship with Mg2+, but the importance and molecular details of this relationship remain unknown. Here, we report that PRL expression is regulated by Mg2+ and PRL protects cells from apoptosis under Mg2+-depleted conditions. When cultured cells were subjected to Mg2+ depletion, endogenous PRL protein levels increased significantly. siRNA-mediated knockdown of endogenous PRL did not significantly affect cell proliferation under normal culture conditions, but it increased cell death after Mg2+ depletion. Imaging analyses with a fluorescent probe for Mg2+ showed that PRL knockdown severely reduced intracellular Mg2+ levels, indicating a role for PRL in maintaining intracellular Mg2+ We also examined the mechanism of augmented expression of PRL proteins and found that PRL mRNA transcription was stimulated by Mg2+ depletion. A series of analyses revealed the activation and the crucial importance of signal transducer and activator of transcription 1 in this process. Collectively, these results implicate PRL in maintaining cellular Mg2+ homeostasis. PMID- 29487166 TI - Dynamic changes in Sox2 spatio-temporal expression promote the second cell fate decision through Fgf4/Fgfr2 signaling in preimplantation mouse embryos. AB - Oct4 and Sox2 regulate the expression of target genes such as Nanog, Fgf4, and Utf1, by binding to their respective regulatory motifs. Their functional cooperation is reflected in their ability to heterodimerize on adjacent cis regulatory motifs, the composite Sox/Oct motif. Given that Oct4 and Sox2 regulate many developmental genes, a quantitative analysis of their synergistic action on different Sox/Oct motifs would yield valuable insights into the mechanisms of early embryonic development. In the present study, we measured binding affinities of Oct4 and Sox2 to different Sox/Oct motifs using fluorescence correlation spectroscopy. We found that the synergistic binding interaction is driven mainly by the level of Sox2 in the case of the Fgf4 Sox/Oct motif. Taking into account Sox2 expression levels fluctuate more than Oct4, our finding provides an explanation on how Sox2 controls the segregation of the epiblast and primitive endoderm populations within the inner cell mass of the developing rodent blastocyst. PMID- 29487167 TI - Neurofilament light chain and tau concentrations are markedly increased in the serum of patients with sporadic Creutzfeldt-Jakob disease, and tau correlates with rate of disease progression. AB - OBJECTIVES: A blood-based biomarker of neuronal damage in sporadic Creutzfeldt Jakob disease (sCJD) will be extremely valuable for both clinical practice and research aiming to develop effective therapies. METHODS: We used an ultrasensitive immunoassay to measure two candidate biomarkers, tau and neurofilament light (NfL), in serum from patients with sCJD and healthy controls. We tested longitudinal sample sets from six patients to investigate changes over time, and examined correlations with rate of disease progression and associations with known phenotype modifiers. RESULTS: Serum concentrations of both tau and NfL were increased in patients with sCJD. NfL distinguished patients from controls with 100% sensitivity and 100% specificity. Tau did so with 91% sensitivity and 83% specificity. Both tau and NfL appeared to increase over time in individual patients, particularly in those with several samples tested late in their disease. Tau, but not NfL, was positively correlated with rate of disease progression, and was particularly increased in patients homozygous for methionine at codon 129 of PRNP. CONCLUSIONS: These findings independently replicate other recent studies using similar methods and offer novel insights. They show clear promise for these blood-based biomarkers in prion disease. Future work should aim to fully establish their potential roles for monitoring disease progression and response to therapies. PMID- 29487168 TI - Successful long-term therapy with flecainide in a family with paramyotonia congenita. PMID- 29487169 TI - Predictors of symptomatic intracranial haemorrhage in patients with an ischaemic stroke with neurological deterioration after intravenous thrombolysis. AB - OBJECTIVES: Early neurological deterioration prompting urgent brain imaging occurs in nearly 15% of patients with ischaemic stroke receiving intravenous tissue plasminogen activator (tPA). We aim to determine risk factors associated with symptomatic intracranial haemorrhage (sICH) in patients with ischaemic stroke undergoing emergent brain imaging for early neurological deterioration after receiving tPA. METHODS: We abstracted data from our prospective stroke database and included all patients receiving tPA for ischaemic stroke between 1 March 2015 and 1 March 2017. We then identified patients with neurological deterioration who underwent urgent brain imaging prior to their per-protocol surveillance imaging and divided patients into two groups: those with and without sICH. We compared baseline demographics, clinical variables, in-hospital treatments and functional outcomes at 90 days between the two groups. RESULTS: We identified 511 patients who received tPA, of whom 108 (21.1%) had an emergent brain CT. Of these patients, 17.5% (19/108) had sICH; 21.3% (23/108) of emergent scans occurred while tPA was infusing, though only 4.3% of these scans (1/23) revealed sICH. On multivariable analyses, the only predictor of sICH was a change in level of consciousness (OR 6.62, 95% CI 1.64 to 26.70, P=0.008). CONCLUSION: Change in level of consciousness is associated with sICH among patients undergoing emergent brain imaging after receiving tPA. In this group of patients, preparation of tPA reversal agents while awaiting brain imaging may reduce reversal times. Future studies are needed to study the cost-effectiveness of this approach. PMID- 29487171 TI - Mycoplasma genitalium: an important sexually transmitted infection comes into focus. PMID- 29487170 TI - Prevalence and type distribution of human papillomavirus (HPV) in Malaysian women with and without cervical cancer: an updated estimate. AB - Information on the prevalence and type distribution of human papillomavirus (HPV) among Malaysian women is currently limited. The present study therefore aimed to provide an updated estimate on the prevalence and type distribution of HPV among Malaysian women with and without cervical cancer. Total DNA was isolated from the cervical cell specimens of 185 histopathologically confirmed cervical cancer patients and 209 cancer-free healthy females who were tested negative in a recent Pap test. Viral-specific DNA was subsequently amplified with biotinylated primers and hybridized to HPV type-specific probes via a proprietary "flow-through hybridization" process for determination of HPV genotype. It was demonstrated that 83.2% of the cervical cancer patients and none (0.0%) of the cancer-free females were positive for HPV infection. Among HPV-positive subjects, 14 different viral genotypes were observed, namely HPV16, 18, 31, 33, 35, 45, 52, 53, 58, 66/68, 73, 81, 82, and 84/26. A total of 91.6% of the HPV-positive subjects had single-type HPV infections and the remaining 8.4% were simultaneously infected by two HPV genotypes. The most common HPV infections found were HPV16 (35.7%), HPV18 (26.0%), HPV58 (9.1%), and HPV33 (7.1%) single type infections, followed by HPV16 + HPV18 co-infections (5.2%). The study has successfully provided an updated estimate on the prevalence and type distribution of HPV among Malaysian women with and without cervical cancer. These findings could contribute valuable information for appraisal of the impact and cost effectiveness of prophylactic HPV vaccines in the Malaysian population. PMID- 29487173 TI - Communicating with our patients for shared decision making. PMID- 29487172 TI - Does HIV pre-exposure prophylaxis use lead to a higher incidence of sexually transmitted infections? A case-crossover study of men who have sex with men in Los Angeles, California. AB - BACKGROUND: Pre-exposure prophylaxis (PrEP) is an effective method for reducing HIV incidence among at-risk populations. However, concerns exist over the potential for an increase in STIs following PrEP initiation. The objective of this study is to compare the STI incidence before and after PrEP initiation within subjects among a cohort of men who have sex with men in Los Angeles, California. METHODS: The present study used data from patients who initiated PrEP services at the Los Angeles LGBT Center between October 2015 and October 2016 (n=275). A generalised linear mixed model was used with a case-crossover design to determine if there was a significant difference in STIs within subjects 365 days before (before-PrEP period) and 365 days after PrEP initiation (after-PrEP period). RESULTS: In a generalised linear mixed model, there were no significant differences in urethral gonorrhoea (P=0.95), rectal gonorrhoea (P=0.33), pharyngeal gonorrhoea (P=0.65) or urethral chlamydia (P=0.71) between periods. There were modest increases in rectal chlamydia (rate ratio (RR) 1.83; 95% CI 1.13 to 2.98; P=0.01) and syphilis diagnoses (RR 2.97; 95% CI 1.23 to 7.18; P=0.02). CONCLUSIONS: There were significant increases in rectal chlamydia and syphilis diagnoses when comparing the periods directly before and after PrEP initiation. However, only 28% of individuals had an increase in STIs between periods. Although risk compensation appears to be present for a segment of PrEP users, the majority of individuals either maintain or decrease their sexual risk following PrEP initiation. PMID- 29487174 TI - Correction: Habitual chocolate consumption and risk of cardiovascular disease among healthy men and women. PMID- 29487175 TI - Connexin hemichannels mediate glutathione transport and protect lens fiber cells from oxidative stress. AB - Elevated oxidized stress contributes to lens cataracts, and gap junctions play important roles in maintaining lens transparency. As well as forming gap junctions, connexin (Cx) proteins also form hemichannels. Here, we report a new mechanism whereby hemichannels mediate transport of reductant glutathione into lens fiber cells and protect cells against oxidative stress. We found that Cx50 (also known as GJA8) hemichannels opened in response to H2O2 in lens fiber cells but that transport through the channels was inhibited by two dominant-negative mutants in Cx50, Cx50P88S, which inhibits transport through both gap junctions and hemichannels, and Cx50H156N, which only inhibits transport through hemichannels and not gap junctions. Treatment with H2O2 increased the number of fiber cells undergoing apoptosis, and this increase was augmented with dominant negative mutants that disrupted both hemichannels formed from Cx46 (also known as GJA3) and Cx50, while Cx50E48K, which only impairs gap junctions, did not have such an effect. Moreover, hemichannels mediate uptake of glutathione, and this uptake protected lens fiber cells against oxidative stress, while hemichannels with impaired transport had less protective benefit from glutathione. Taken together, these results show that oxidative stress activates connexin hemichannels in the lens fiber cells and that hemichannels likely protect lens cell against oxidative damage through transporting extracellular reductants. PMID- 29487176 TI - Aplip1, the Drosophila homolog of JIP1, regulates myonuclear positioning and muscle stability. AB - During muscle development, myonuclei undergo a complex set of movements that result in evenly spaced nuclei throughout the muscle cell. In Drosophila, two separate pools of Kinesin and Dynein work in synchrony to drive this process. However, how these two pools are specified is not known. Here, we investigate the role of Aplip1 (the Drosophila homolog of JIP1, JIP1 is also known as MAPK8IP1), a known regulator of both Kinesin and Dynein, in myonuclear positioning. Aplip1 localizes to the myotendinous junction and has genetically separable roles in myonuclear positioning and muscle stability. In Aplip1 mutant embryos, there was an increase in the percentage of embryos that had both missing and collapsed muscles. Via a separate mechanism, we demonstrate that Aplip1 regulates both the final position of and the dynamic movements of myonuclei. Aplip1 genetically interacts with both Raps (also known as Pins) and Kinesin to position myonuclei. Furthermore, Dynein and Kinesin localization are disrupted in Aplip1 mutants suggesting that Aplip1-dependent nuclear positioning requires Dynein and Kinesin. Taken together, these data are consistent with Aplip1 having a function in the regulation of Dynein- and Kinesin-mediated pulling of nuclei from the muscle end.This article has an associated First Person interview with the first author of the paper. PMID- 29487177 TI - Parallel assembly of actin and tropomyosin, but not myosin II, during de novo actin filament formation in live mice. AB - Many actin filaments in animal cells are co-polymers of actin and tropomyosin. In many cases, non-muscle myosin II associates with these co-polymers to establish a contractile network. However, the temporal relationship of these three proteins in the de novo assembly of actin filaments is not known. Intravital subcellular microscopy of secretory granule exocytosis allows the visualisation and quantification of the formation of an actin scaffold in real time, with the added advantage that it occurs in a living mammal under physiological conditions. We used this model system to investigate the de novo assembly of actin, tropomyosin Tpm3.1 (a short isoform of TPM3) and myosin IIA (the form of non-muscle myosin II with its heavy chain encoded by Myh9) on secretory granules in mouse salivary glands. Blocking actin polymerization with cytochalasin D revealed that Tpm3.1 assembly is dependent on actin assembly. We used time-lapse imaging to determine the timing of the appearance of the actin filament reporter LifeAct-RFP and of Tpm3.1-mNeonGreen on secretory granules in LifeAct-RFP transgenic, Tpm3.1 mNeonGreen and myosin IIA-GFP (GFP-tagged MYH9) knock-in mice. Our findings are consistent with the addition of tropomyosin to actin filaments shortly after the initiation of actin filament nucleation, followed by myosin IIA recruitment. PMID- 29487178 TI - Ki-67 and condensins support the integrity of mitotic chromosomes through distinct mechanisms. AB - Although condensins play essential roles in mitotic chromosome assembly, Ki-67 (also known as MKI67), a protein localizing to the periphery of mitotic chromosomes, had also been shown to make a contribution to the process. To examine their respective roles, we generated a set of HCT116-based cell lines expressing Ki-67 and/or condensin subunits that were fused with an auxin inducible degron for their conditional degradation. Both the localization and the dynamic behavior of Ki-67 on mitotic chromosomes were not largely affected upon depletion of condensin subunits, and vice versa. When both Ki-67 and SMC2 (a core subunit of condensins) were depleted, ball-like chromosome clusters with no sign of discernible thread-like structures were observed. This severe defective phenotype was distinct from that observed in cells depleted of either Ki-67 or SMC2 alone. Our results show that Ki-67 and condensins, which localize to the external surface and the central axis of mitotic chromosomes, respectively, have independent yet cooperative functions in supporting the structural integrity of mitotic chromosomes. PMID- 29487180 TI - A model suite of green algae within the Scenedesmaceae for investigating contrasting desiccation tolerance and morphology. AB - Microscopic green algae inhabiting desert microbiotic crusts are remarkably diverse phylogenetically, and many desert lineages have independently evolved from aquatic ancestors. Here we worked with five desert and aquatic species within the family Scenedesmaceae to examine mechanisms that underlie desiccation tolerance and release of unicellular versus multicellular progeny. Live cell staining and time-lapse confocal imaging coupled with transmission electron microscopy established that the desert and aquatic species all divide by multiple (rather than binary) fission, although progeny were unicellular in three species and multicellular (joined in a sheet-like coenobium) in two. During division, Golgi complexes were localized near nuclei, and all species exhibited dynamic rotation of the daughter cell mass within the mother cell wall at cytokinesis. Differential desiccation tolerance across the five species, assessed from photosynthetic efficiency during desiccation/rehydration cycles, was accompanied by differential accumulation of intracellular reactive oxygen species (ROS) detected using a dye sensitive to intracellular ROS. Further comparative investigation will aim to understand the genetic, ultrastructural and physiological characteristics supporting unicellular versus multicellular coenobial morphology, and the ability of representatives in the Scenedesmaceae to colonize ecologically diverse, even extreme, habitats. PMID- 29487179 TI - Epidermal growth factor receptor and integrins control force-dependent vinculin recruitment to E-cadherin junctions. AB - This study reports novel findings that link E-cadherin (also known as CDH1) mediated force-transduction signaling to vinculin targeting to intercellular junctions via epidermal growth factor receptor (EGFR) and integrins. These results build on previous findings that demonstrated that mechanically perturbed E-cadherin receptors activate phosphoinositide 3-kinase and downstream integrins in an EGFR-dependent manner. Results of this study show that this EGFR-mediated kinase cascade controls the force-dependent recruitment of vinculin to stressed E cadherin complexes - a key early signature of cadherin-based mechanotransduction. Vinculin targeting requires its phosphorylation at tyrosine 822 by Abl family kinases (hereafter Abl), but the origin of force-dependent Abl activation had not been identified. We now present evidence that integrin activation, which is downstream of EGFR signaling, controls Abl activation, thus linking E-cadherin to Abl through a mechanosensitive signaling network. These findings place EGFR and integrins at the center of a positive-feedback loop, through which force activated E-cadherin signals regulate vinculin recruitment to cadherin complexes in response to increased intercellular tension.This article has an associated First Person interview with the first author of the paper. PMID- 29487182 TI - The cytoskeleton regulates symmetry transitions in moving amoeboid cells. AB - Symmetry and symmetry breaking are essential in biology. Symmetry comes in different forms: rotational symmetry, mirror symmetry and alternating right-left symmetry (for example, gliding reflection symmetry). Especially the transitions between the different symmetry forms are important because they specify crucial points in cell biology, including gastrulation in development, formation of the cleavage furrow in cell division, or the front in cell polarity. However, the mechanisms of these symmetry transitions are not well understood. Here, we have investigated the fundamental properties of symmetry and symmetry transitions of the cytoskeleton during cell movement. Our data show that the dynamic shape changes of amoeboid cells are far from random, but are the consequence of refined symmetries and symmetry changes that are orchestrated by small G-proteins and the cytoskeleton, with local stimulation by F-actin and Scar, and local inhibition by IQGAP2 and myosin. PMID- 29487181 TI - Puf3 participates in ribosomal biogenesis in malaria parasites. AB - In this study, we characterized the Puf family gene member Puf3 in the malaria parasites Plasmodium falciparum and Plasmodium yoelii Secondary structure prediction suggested that the RNA-binding domains of the Puf3 proteins consisted of 11 pumilio repeats that were similar to those in the human Puf-A (also known as PUM3) and Saccharomyces cerevisiae Puf6 proteins, which are involved in ribosome biogenesis. Neither P. falciparum (Pf)Puf3 nor P. yoelii (Py)Puf3 could be genetically disrupted, suggesting they may be essential for the intraerythrocytic developmental cycle. Cellular fractionation of PfPuf3 in the asexual stages revealed preferential partitioning to the nuclear fraction, consistent with nuclear localization of PfPuf3::GFP and PyPuf3::GFP as detected by immunofluorescence. Furthermore, PfPuf3 colocalized with the nucleolar marker PfNop1, demonstrating that PfPuf3 is a nucleolar protein in the asexual stages. We found, however, that PyPuf3 changed its localization from being nucleolar to being present in cytosolic puncta in the mosquito and liver stages, which may reflect alternative functions in these stages. Affinity purification of molecules that associated with a PTP-tagged variant of PfPuf3 revealed 31 proteins associated with the 60S ribosome, and an enrichment of 28S rRNA and internal transcribed spacer 2 sequences. Taken together, these results suggest an essential function for PfPuf3 in ribosomal biogenesis. PMID- 29487183 TI - A Metagenome-Wide Association Study and Arrayed Mutant Library Confirm Acetobacter Lipopolysaccharide Genes Are Necessary for Association with Drosophila melanogaster. AB - A metagenome wide association (MGWA) study of bacterial host association determinants in Drosophila predicted that LPS biosynthesis genes are significantly associated with host colonization. We were unable to create site directed mutants for each of the predicted genes in Acetobacter, so we created an arrayed transposon insertion library using Acetobacter fabarum DsW_054 isolated from Drosophila Creation of the A. fabarum DsW_054 gene knock-out library was performed by combinatorial mapping and Illumina sequencing of random transposon insertion mutants. Transposon insertion locations for 6,418 mutants were successfully mapped, including hits within 63% of annotated genes in the A. fabarum DsW_054 genome. For 45/45 members of the library, insertion sites were verified by arbitrary PCR and Sanger sequencing. Mutants with insertions in four different LPS biosynthesis genes were selected from the library to validate the MGWA predictions. Insertion mutations in two genes biosynthetically upstream of Lipid-A formation, lpxC and lpxB, show significant differences in host association, whereas mutations in two genes encoding LPS biosynthesis functions downstream of Lipid-A biosynthesis had no effect. These results suggest an impact of bacterial cell surface molecules on the bacterial capacity for host association. Also, the transposon insertion mutant library will be a useful resource for ongoing research on the genetic basis for Acetobacter traits. PMID- 29487184 TI - A Genomic Reference Panel for Drosophila serrata. AB - Here we describe a collection of re-sequenced inbred lines of Drosophila serrata, sampled from a natural population situated deep within the species endemic distribution in Brisbane, Australia. D. serrata is a member of the speciose montium group whose members inhabit much of south east Asia and has been well studied for aspects of climatic adaptation, sexual selection, sexual dimorphism, and mate recognition. We sequenced 110 lines that were inbred via 17-20 generations of full-sib mating at an average coverage of 23.5x with paired-end Illumina reads. 15,228,692 biallelic SNPs passed quality control after being called using the Joint Genotyper for Inbred Lines (JGIL). Inbreeding was highly effective and the average levels of residual heterozygosity (0.86%) were well below theoretical expectations. As expected, linkage disequilibrium decayed rapidly, with r2 dropping below 0.1 within 100 base pairs. With the exception of four closely related pairs of lines which may have been due to technical errors, there was no statistical support for population substructure. Consistent with other endemic populations of other Drosophila species, preliminary population genetic analyses revealed high nucleotide diversity and, on average, negative Tajima's D values. A preliminary GWAS was performed on a cuticular hydrocarbon trait, 2-Me-C28 revealing 4 SNPs passing Bonferroni significance residing in or near genes. One gene Cht9 may be involved in the transport of CHCs from the site of production (oenocytes) to the cuticle. Our panel will facilitate broader population genomic and quantitative genetic studies of this species and serve as an important complement to existing D. melanogaster panels that can be used to test for the conservation of genetic architectures across the Drosophila genus. PMID- 29487185 TI - Transcriptome Analysis of Litsea cubeba Floral Buds Reveals the Role of Hormones and Transcription Factors in the Differentiation Process. AB - BACKGROUND: Litsea cubeba (Lour.) Pers. is an important economic plant that is rich in valuable essential oil. The essential oil is often used as a raw material for perfumes, food additives, insecticides and bacteriostats. Most of the essential oil is contained in the fruit, and the quantity and quality of fruit are dependent on the flowers. To explore the molecular mechanism of floral bud differentiation, high-throughput RNA sequencing was used to detect differences in the gene expression of L. cubeba female and male floral buds at three differentiation stages. RESULTS: This study obtained 160.88 Gbp of clean data that were assembled into 100,072 unigenes, and a total of 38,658 unigenes were annotated. A total of 27,521 simple sequence repeats (SSRs) were identified after scanning the assembled transcriptome, and the mono-nucleotide repeats were predominant, followed by di-nucleotide and tri-nucleotide repeats. A total of 12,559 differentially expressed genes (DEGs) were detected from the female (F) and male (M) floral bud comparisons. The gene ontology (GO) databases revealed that these DEGs were primarily contained in "metabolic processes", "cellular processes", and "single-organism processes". The Kyoto Encyclopedia of Genes and Genomes (KEGG) databases suggested that the DEGs belonged to "plant hormone signal transduction" and accounted for a relatively large portion in all of these comparisons. We analyzed the expression level of plant hormone-related genes and detected the contents of several relevant plant hormones in different stages. The results revealed that the dynamic changes in each hormone content were almost consistent with the expression levels of relevant genes. The transcription factors selected from the DEGs were analyzed. Most DEGs of MADS-box were upregulated and most DEGs of bZIP were downregulated. The expression trends of the DEGs were nearly identical in female and male floral buds, and qRT-PCR analysis revealed consistency with the transcriptome data. CONCLUSIONS: We sequenced and assembled a high-quality L. cubeba floral bud transcriptome, and the data appeared to be well replicated (n = 3) over three developmental time points during flower development. Our study explored the changes in the contents of several plant hormones during floral bud differentiation using biochemical and molecular biology techniques, and the changes in expression levels of several flower development related transcription factors. These results revealed the role of these factors (i.e., hormones and transcription factors) and may advance our understanding of their functions in flower development in L. cubeba. PMID- 29487186 TI - The End of a 60-year Riddle: Identification and Genomic Characterization of an Iridovirus, the Causative Agent of White Fat Cell Disease in Zooplankton. AB - The planktonic freshwater crustacean of the genus Daphnia are a model system for biomedical research and, in particular, invertebrate-parasite interactions. Up until now, no virus has been characterized for this system. Here we report the discovery of an iridovirus as the causative agent of White Fat Cell Disease (WFCD) in Daphnia WFCD is a highly virulent disease of Daphnia that can easily be cultured under laboratory conditions. Although it has been studied from sites across Eurasia for more than 60 years, its causative agent had not been described, nor had an iridovirus been connected to WFCD before now. Here we find that an iridovirus-the Daphnia iridescent virus 1 (DIV-1)-is the causative agent of WFCD. DIV-1 has a genome sequence of about 288 kbp, with 39% G+C content and encodes 367 predicted open reading frames. DIV-1 clusters together with other invertebrate iridoviruses but has by far the largest genome among all sequenced iridoviruses. Comparative genomics reveal that DIV-1 has apparently recently lost a substantial number of unique genes but has also gained genes by horizontal gene transfer from its crustacean host. DIV-1 represents the first invertebrate iridovirus that encodes proteins to purportedly cap RNA, and it contains unique genes for a DnaJ-like protein, a membrane glycoprotein and protein of the immunoglobulin superfamily, which may mediate host-pathogen interactions and pathogenicity. Our findings end a 60-year search for the causative agent of WFCD and add to our knowledge of iridovirus genomics and invertebrate-virus interactions. PMID- 29487187 TI - Genetic Interactions Between BOB1 and Multiple 26S Proteasome Subunits Suggest a Role for Proteostasis in Regulating Arabidopsis Development. AB - Protein folding and degradation are both required for protein quality control, an essential cellular activity that underlies normal growth and development. We investigated how BOB1, an Arabidopsis thaliana small heat shock protein, maintains normal plant development. bob1 mutants exhibit organ polarity defects and have expanded domains of KNOX gene expression. Some of these phenotypes are ecotype specific suggesting that other genes function to modify them. Using a genetic approach we identified an interaction between BOB1 and FIL, a gene required for abaxial organ identity. We also performed an EMS enhancer screen using the bob1-3 allele to identify pathways that are sensitized by a loss of BOB1 function. This screen identified genetic, but not physical, interactions between BOB1 and the proteasome subunit RPT2a Two other proteasome subunits, RPN1a and RPN8a, also interact genetically with BOB1 Both BOB1 and the BOB1 interacting proteasome subunits had previously been shown to interact genetically with the transcriptional enhancers AS1 and AS2, genes known to regulate both organ polarity and KNOX gene expression. Our results suggest a model in which BOB1 mediated protein folding and proteasome mediated protein degradation form a functional proteostasis module required for ensuring normal plant development. PMID- 29487188 TI - A Genetic Screen Identifies PRP18a, a Putative Second Step Splicing Factor Important for Alternative Splicing and a Normal Phenotype in Arabidopsis thaliana. AB - Splicing of pre-mRNA involves two consecutive trans-esterification steps that take place in the spliceosome, a large dynamic ribonucleoprotein complex situated in the nucleus. In addition to core spliceosomal proteins, each catalytic step requires step-specific factors. Although the Arabidopsis thaliana genome encodes around 430 predicted splicing factors, functional information about these proteins is limited. In a forward genetic screen based on an alternatively spliced GFP reporter gene in Arabidopsis thaliana, we identified a mutant impaired in putative step II factor PRP18a, which has not yet been investigated for its role in pre-mRNA splicing in plants. Step II entails cleavage at the 3' splice site accompanied by ligation of the 5' and 3' exons and intron removal. In the prp18 mutant, splicing of a U2-type intron with non-canonical AT-AC splice sites in GFP pre-mRNA is reduced while splicing of a canonical GT-AG intron is enhanced, resulting in decreased levels of translatable GFP mRNA and GFP protein. These findings suggest that wild-type PRP18a may in some cases promote splicing at weak, non-canonical splice sites. Analysis of genome-wide changes in alternative splicing in the prp18a mutant identified numerous cases of intron retention and a preponderance of altered 3' splice sites, suggesting an influence of PRP18a on 3' splice site selection. The prp18a mutant featured short roots on synthetic medium and small siliques, illustrating that wild-type PRP18a function is needed for a normal phenotype. Our study expands knowledge of plant splicing factors and provides foundational information and resources for further functional studies of PRP18 proteins in plants. PMID- 29487189 TI - Integrated in vivo multiomics analysis identifies p21-activated kinase signaling as a driver of colitis. AB - Inflammatory bowel disease (IBD) is a chronic disorder of the gastrointestinal tract that has limited treatment options. To gain insight into the pathogenesis of chronic colonic inflammation (colitis), we performed a multiomics analysis that integrated RNA microarray, total protein mass spectrometry (MS), and phosphoprotein MS measurements from a mouse model of the disease. Because we collected all three types of data from individual samples, we tracked information flow from RNA to protein to phosphoprotein and identified signaling molecules that were coordinately or discordantly regulated and pathways that had complex regulation in vivo. For example, the genes encoding acute-phase proteins were expressed in the liver, but the proteins were detected by MS in the colon during inflammation. We also ascertained the types of data that best described particular facets of chronic inflammation. Using gene set enrichment analysis and trans-omics coexpression network analysis, we found that each data set provided a distinct viewpoint on the molecular pathogenesis of colitis. Combining human transcriptomic data with the mouse multiomics data implicated increased p21 activated kinase (Pak) signaling as a driver of colitis. Chemical inhibition of Pak1 and Pak2 with FRAX597 suppressed active colitis in mice. These studies provide translational insights into the mechanisms contributing to colitis and identify Pak as a potential therapeutic target in IBD. PMID- 29487191 TI - Wdpcp promotes epicardial EMT and epicardium-derived cell migration to facilitate coronary artery remodeling. AB - During coronary vasculature development, endothelial cells enclose the embryonic heart to form the primitive coronary plexus. This structure is remodeled upon recruitment of epicardial cells that may undergo epithelial-mesenchymal transition (EMT) to enable migration and that give rise to smooth muscle cells. In mice expressing a loss-of-function mutant form of Wdpcp, a gene involved in ciliogenesis, the enclosure of the surface of the heart by the subepicardial coronary plexus was accelerated because of enhanced chemotactic responses to Shh. Coronary arteries, but not coronary veins in Wdpcp mutant mice, showed reduced smooth muscle cell coverage. In addition, Wdpcp mutant hearts had reduced expression of EMT and mesenchymal markers and had fewer epicardium-derived cells (EPDCs) that showed impaired migration. Epicardium-specific deletion of Wdpcp recapitulated the coronary artery defect of the Wdpcp mutant. Thus, Wdpcp promotes epithelial EMT and EPDC migration, processes that are required for remodeling of the coronary primitive plexus. The Wdpcp mutant mice will be a useful tool to dissect the molecular mechanisms that govern the remodeling of the primitive plexus during coronary development. PMID- 29487190 TI - Convergence of Wnt, growth factor, and heterotrimeric G protein signals on the guanine nucleotide exchange factor Daple. AB - Cellular proliferation, differentiation, and morphogenesis are shaped by multiple signaling cascades, and their dysregulation plays an integral role in cancer progression. Three cascades that contribute to oncogenic potential are those mediated by Wnt proteins and the receptor Frizzled (FZD), growth factor receptor tyrosine kinases (RTKs), and heterotrimeric G proteins and associated GPCRs. Daple is a guanine nucleotide exchange factor (GEF) for the G protein Galphai Daple also binds to FZD and the Wnt/FZD mediator Dishevelled (Dvl), and it enhances beta-catenin-independent Wnt signaling in response to Wnt5a-FZD7 signaling. We identified Daple as a substrate of multiple RTKs and non-RTKs and, hence, as a point of convergence for the three cascades. We found that phosphorylation near the Dvl-binding motif in Daple by both RTKs and non-RTKs caused Daple/Dvl complex dissociation and augmented the ability of Daple to bind to and activate Galphai, which potentiated beta-catenin-independent Wnt signals and stimulated epithelial-mesenchymal transition (EMT) similarly to Wnt5a/FZD7 signaling. Although Daple acts as a tumor suppressor in the healthy colon, the concurrent increased abundance of Daple and epidermal growth factor receptor (EGFR) in colorectal tumors was associated with poor patient prognosis. Thus, the Daple-dependent activation of Galphai and the Daple-dependent enhancement of beta catenin-independent Wnt signals are not only stimulated by Wnt5a/FZD7 to suppress tumorigenesis but also hijacked by growth factor-activated RTKs to enhance tumor progression. These findings identify a cross-talk paradigm among growth factor RTKs, heterotrimeric G proteins, and the Wnt/FZD pathway in cancer. PMID- 29487192 TI - Association of interleukin-10 gene single nucleotide polymorphisms with rheumatoid arthritis in a Chinese population. AB - PURPOSE OF THE STUDY: Increasing numbers of studies show that interleukin (IL)-10 plays a key role in the pathogenesis of autoimmune diseases including rheumatoid arthritis (RA) and acts as an immunomodulatory cytokine. The purpose of the present study was to analyse the relationship between gene single nucleotide polymorphisms (SNPs) in the IL-10 gene and RA susceptibility. STUDY DESIGN: We genotyped three SNPs (rs1800890, rs3024495, rs3024505) of the IL-10 gene in a Chinese population of 354 RA patients and 367 controls. Genotyping was conducted using TaqMan SNP genotyping assays. Plasma IL-10 levels were measured by ELISA. RESULTS: The A allele of the rs1800890 variant was significantly related to decreased risk for RA compared with the T allele (A vs T: OR 0.580, 95% CI 0.345 to 0.975, P=0.038). No significant association between the genotype distribution of these SNPs and RA susceptibility was detected. The genotype effect of the dominant model was also evaluated, but no statistical difference was found. Further analysis in RA patients demonstrated that none of these SNPs were associated with rheumatoid factor (RF) or anti-citrullinated protein antibody (anti-CCP). In addition, no significant differences in plasma IL-10 levels were observed among RA patients with different genotypes. CONCLUSIONS: The IL-10 rs1800890 variant might contribute to RA susceptibility in the Chinese population. Replication studies in different ethnic groups are required to further examine the critical role of IL-10 gene variation in the pathogenesis of RA. PMID- 29487194 TI - Equipoise dumbbell. PMID- 29487193 TI - Comparison of a pressure-sensing sheath and radial arterial line for intraoperative blood pressure monitoring in neurointerventional procedures. AB - PURPOSE: The efficiency of neuroendovascular procedures may partly depend on the time devoted to placement of a radial arterial line (RAL) for intraoperative blood pressure monitoring. An alternative approach is to use a pressure-sensing sheath (PSS) that serves to provide invasive blood pressure monitoring without requiring a separate procedure for placement. We compared the use of a RAL versus PSS and assessed procedure time, anesthetist and patient satisfaction, and cost. METHODS: We performed a single-center, prospective, blockwise, comparative trial of procedure start time using traditional RAL placement versus the EndoPhys PSS for invasive blood pressure monitoring. Endpoints included time from room arrival to groin puncture, patient and anesthetist satisfaction ratings, and costs associated with RAL placement. RESULTS: Twenty patients were enrolled in the PSS+RAL arm and 20 in the PSS-alone arm. Mean time from arrival in the room until groin puncture was 61.9+/-14.0 min in the RAL group and 51.2+/-10.8 min in the PSS-alone group (P=0.01; difference=10.7 min). Patients in the PSS-alone group reported less pain than those in the RAL group. Furthermore, anesthetists reported accurate blood pressure in the PSS group. The average cost estimate of RAL placement was US$774.70, with a range of US$743 to US$1171. CONCLUSIONS: Placement of a RAL at the start of the neuroendovascular procedures resulted in increased delays to procedure start time and more patient-reported pain compared with the PSS, which may offer a more efficient means of blood pressure monitoring for neurointerventional procedures. CLINICAL TRIAL REGISTRATION: NCT03239847. PMID- 29487195 TI - Non-photosynthetic plastids as hosts for metabolic engineering. AB - Using plants as hosts for production of complex, high-value compounds and therapeutic proteins has gained increasing momentum over the past decade. Recent advances in metabolic engineering techniques using synthetic biology have set the stage for production yields to become economically attractive, but more refined design strategies are required to increase product yields without compromising development and growth of the host system. The ability of plant cells to differentiate into various tissues in combination with a high level of cellular compartmentalization represents so far the most unexploited plant-specific resource. Plant cells contain organelles called plastids that retain their own genome, harbour unique biosynthetic pathways and differentiate into distinct plastid types upon environmental and developmental cues. Chloroplasts, the plastid type hosting the photosynthetic processes in green tissues, have proven to be suitable for high yield protein and bio-compound production. Unfortunately, chloroplast manipulation often affects photosynthetic efficiency and therefore plant fitness. In this respect, plastids of non-photosynthetic tissues, which have focused metabolisms for synthesis and storage of particular classes of compounds, might prove more suitable for engineering the production and storage of non-native metabolites without affecting plant fitness. This review provides the current state of knowledge on the molecular mechanisms involved in plastid differentiation and focuses on non-photosynthetic plastids as alternative biotechnological platforms for metabolic engineering. PMID- 29487196 TI - Structural components involved in plastid protein import. AB - Import of preproteins into chloroplasts is an essential process, requiring two major multisubunit protein complexes that are embedded in the outer and inner chloroplast envelope membrane. Both the translocon of the outer chloroplast membrane (Toc), as well as the translocon of the inner chloroplast membrane (Tic) have been studied intensively with respect to their individual subunit compositions, functions and regulations. Recent advances in crystallography have increased our understanding of the operation of these proteins in terms of their interactions and regulation by conformational switching. Several subdomains of components of the Toc translocon have been studied at the structural level, among them the polypeptide transport-associated (POTRA) domain of the channel protein Toc75 and the GTPase domain of Toc34. In this review, we summarize and discuss the insight that has been gained from these structural analyses. In addition, we present the crystal structure of the Toc64 tetratrico-peptide repeat (TPR) domain in complex with the C-terminal domains of the heat-shock proteins (Hsp) Hsp90 and Hsp70. PMID- 29487197 TI - Cardiac-specific inducible overexpression of human plasma membrane Ca2+ ATPase 4b is cardioprotective and improves survival in mice following ischemic injury. AB - Background: Heart failure (HF) is associated with reduced expression of plasma membrane Ca2+-ATPase 4 (PMCA4). Cardiac-specific overexpression of human PMCA4b in mice inhibited nNOS activity and reduced cardiac hypertrophy by inhibiting calcineurin. Here we examine temporally regulated cardiac-specific overexpression of hPMCA4b in mouse models of myocardial ischemia reperfusion injury (IRI) ex vivo, and HF following experimental myocardial infarction (MI) in vivoMethods and results: Doxycycline-regulated cardiomyocyte-specific overexpression and activity of hPMCA4b produced adaptive changes in expression levels of Ca2+-regulatory genes, and induced hypertrophy without significant differences in Ca2+ transients or diastolic Ca2+ concentrations. Total cardiac NOS and nNOS-specific activities were reduced in mice with cardiac overexpression of hPMCA4b while nNOS, eNOS and iNOS protein levels did not differ. hMPCA4b-overexpressing mice also exhibited elevated systolic blood pressure vs. controls, with increased contractility and lusitropy in vivo In isolated hearts undergoing IRI, hPMCA4b overexpression was cardioprotective. NO donor-treated hearts overexpressing hPMCA4b showed reduced LVDP and larger infarct size versus vehicle-treated hearts undergoing IRI, demonstrating that the cardioprotective benefits of hPMCA4b-repressed nNOS are lost by restoring NO availability. Finally, both pre-existing and post-MI induction of hPMCA4b overexpression reduced infarct expansion and improved survival from HF.Conclusions: Cardiac PMCA4b regulates nNOS activity, cardiac mass and contractility, such that PMCA4b overexpression preserves cardiac function following IRI, heightens cardiac performance and limits infarct progression, cardiac hypertrophy and HF, even when induced late post-MI. These data identify PMCA4b as a novel therapeutic target for IRI and HF. PMID- 29487198 TI - Retraction for Melillo et al., "Critical Role of the HMGI(Y) Proteins in Adipocytic Cell Growth and Differentiation". PMID- 29487199 TI - Targeting the SUMO Pathway Primes All-trans Retinoic Acid-Induced Differentiation of Nonpromyelocytic Acute Myeloid Leukemias. AB - Differentiation therapies using all-trans retinoic acid (ATRA) are highly efficient at treating acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia (AML). However, their efficacy, if any, is limited in the case of non-APL AML. We report here that inhibition of SUMOylation, a posttranslational modification related to ubiquitination, restores the prodifferentiation and antiproliferative activities of retinoids in non-APL AML. Controlled inhibition of SUMOylation with the pharmacologic inhibitors 2-D08 or anacardic acid, or via overexpression of SENP deSUMOylases, enhanced the ATRA induced expression of key genes involved in differentiation, proliferation, and apoptosis in non-APL AML cells. This activated ATRA-induced terminal myeloid differentiation and reduced cell proliferation and viability, including in AML cells resistant to chemotherapeutic drugs. Conversely, enhancement of SUMOylation via overexpression of the SUMO-conjugating enzyme Ubc9 dampened expression of ATRA-responsive genes and prevented differentiation. Thus, inhibition of the SUMO pathway is a promising strategy to sensitize patients with non-APL AML to retinoids and improve the treatment of this poor-prognosis cancer.Significance: SUMOylation silences key ATRA-responsive genes in nonpromyelocytic acute myeloid leukemias. Cancer Res; 78(10); 2601-13. (c)2018 AACR. PMID- 29487200 TI - Interleukin-30/IL27p28 Shapes Prostate Cancer Stem-like Cell Behavior and Is Critical for Tumor Onset and Metastasization. AB - Prostate cancer stem-like cells (PCSLC) are believed to be responsible for prostate cancer onset and metastasis. Autocrine and microenvironmental signals dictate PCSLC behavior and patient outcome. In prostate cancer patients, IL30/IL27p28 has been linked with tumor progression, but the mechanisms underlying this link remain mostly elusive. Here, we asked whether IL30 may favor prostate cancer progression by conditioning PCSLCs and assessed the value of blocking IL30 to suppress tumor growth. IL30 was produced by PCSLCs in human and murine prostatic intraepithelial neoplasia and displayed significant autocrine and paracrine effects. PCSLC-derived IL30 supported PCSLC viability, self-renewal and tumorigenicity, expression of inflammatory mediators and growth factors, tumor immune evasion, and regulated chemokine and chemokine receptor genes, primarily via STAT1/STAT3 signaling. IL30 overproduction by PCSLCs promoted tumor onset and development associated with increased proliferation, vascularization, and myeloid cell recruitment. Furthermore, it promoted PCSLC dissemination to lymph nodes and bone marrow by upregulating the CXCR5/CXCL13 axis, and drove metastasis to lungs through the CXCR4/CXCL12 axis. These mechanisms were drastically hindered by IL30 knockdown or knockout in PCSLCs. Collectively, these results mark IL30 as a key driver of PCSLC behavior. Targeting IL30 signaling may be a potential therapeutic strategy against prostate cancer progression and recurrence.Significance: IL30 plays an important role in regulating prostate cancer stem-like cell behavior and metastatic potential, therefore targeting this cytokine could hamper prostate cancer progression or recurrence. Cancer Res; 78(10); 2654-68. (c)2018 AACR. PMID- 29487201 TI - Heterochromatin Protein 1alpha Mediates Development and Aggressiveness of Neuroendocrine Prostate Cancer. AB - Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer arising mostly from adenocarcinoma via neuroendocrine transdifferentiation following androgen deprivation therapy. Mechanisms contributing to both NEPC development and its aggressiveness remain elusive. In light of the fact that hyperchromatic nuclei are a distinguishing histopathologic feature of NEPC, we utilized transcriptomic analyses of our patient-derived xenograft (PDX) models, multiple clinical cohorts, and genetically engineered mouse models to identify 36 heterochromatin-related genes that are significantly enriched in NEPC. Longitudinal analysis using our unique, first-in-field PDX model of adenocarcinoma-to-NEPC transdifferentiation revealed that, among those 36 heterochromatin-related genes, heterochromatin protein 1alpha (HP1alpha) expression increased early and steadily during NEPC development and remained elevated in the developed NEPC tumor. Its elevated expression was further confirmed in multiple PDX and clinical NEPC samples. HP1alpha knockdown in the NCI-H660 NEPC cell line inhibited proliferation, ablated colony formation, and induced apoptotic cell death, ultimately leading to tumor growth arrest. Its ectopic expression significantly promoted NE transdifferentiation in adenocarcinoma cells subjected to androgen deprivation treatment. Mechanistically, HP1alpha reduced expression of androgen receptor and RE1 silencing transcription factor and enriched the repressive trimethylated histone H3 at Lys9 mark on their respective gene promoters. These observations indicate a novel mechanism underlying NEPC development mediated by abnormally expressed heterochromatin genes, with HP1alpha as an early functional mediator and a potential therapeutic target for NEPC prevention and management.Significance: Heterochromatin proteins play a fundamental role in NEPC, illuminating new therapeutic targets for this aggressive disease. Cancer Res; 78(10); 2691-704. (c)2018 AACR. PMID- 29487202 TI - Opinion: How to bring science and technology expertise to state governments. PMID- 29487204 TI - Metabolic reprogramming in type 2 diabetes and the development of breast cancer. AB - A wealth of epidemiological data has found that patients with type 2 diabetes have a greater risk of developing breast cancer. The molecular mechanisms underpinning this relationship are yet to be elucidated; however, this review examines the available evidence suggesting that the metabolic abnormalities observed in type 2 diabetes can predispose to the development of breast cancer. Alterations in substrate availability and the hormonal milieu, particularly hyperinsulinemia, not only create a favorable metabolic environment for tumorigenesis, but also induce metabolic reprogramming events that are required for the transformation of breast cancer cells. In addition, the dysfunction and hypoxia of adipose tissue surrounding the breast cancer niche is another putative link that will be discussed. Finally, the mechanisms by which breast cancer cells evade checkpoints associated with nutrient overload will be examined. Experimentally validating these potential links will be important for prediction and treatment of breast cancer in patients with type 2 diabetes. PMID- 29487205 TI - Effect of ageing on the calibration of ballistic gelatin. AB - PURPOSE: Ballistic gelatin is commonly used as a validated surrogate for soft tissue during terminal ballistic testing. However, the effect of a delay between production and testing of a gelatin mould remains unknown. The aim of this study was to determine any potential effects of ageing on ballistic gelatin. METHODS: Depth of penetration (DoP) of 4.5 mm spherical fragment simulating projectiles was ascertained using mixtures of 10%, 11.25% and 20% Type A 250 Bloom ballistic gelatin. Testing was performed daily for 5 days using velocities between 75 and 210 m/s. DoP at day 5 was statistically compared with day 1, and net mass change was recorded daily. RESULTS: No significant difference was found for DoP observed with time in any of the samples (P>0.05). Spearman correlation was excellent in all moulds. The moulds with known standard calibrations remained in calibration throughout the study period. Mass loss of less than 1% was noted in all samples. CONCLUSION: Mass loss was the only quantifiable measure of changes in the blocks with time, but did not correlate with any changes in DoP. This may provide reassurance when undertaking such testing that an inadvertent delay will not significantly alter the penetration properties of the mould. Future research is recommended to determine any potential effect on the mechanical properties of gelatin at higher velocity impacts and whether the calibration corresponds to an adequate simulation under such conditions. PMID- 29487206 TI - Summary of latest NHS England Emergency Preparedness Resilience and Response (EPRR) guidance. AB - The National Health Service (NHS) England Emergency Preparedness, Resilience and Response Framework exists to provide a structure by which NHS England and NHS funded bodies prepare for and respond to a range of emergencies. This framework exists to ensure that in emergencies the NHS retains the capability to deliver appropriate care to patients. Rather than dealing with individual scenarios, the framework aims to maintain the adaptability and capacity to deal with a variety of emergencies, their consequences and guide recovery plans. This paper summarises this guidance and elucidates the reasoning and mechanisms by which this care will be facilitated and delivered. PMID- 29487207 TI - How many patients could benefit from REBOA in prehospital care? A retrospective study of patients rescued by the doctors of the Paris fire brigade. AB - INTRODUCTION: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a technique to control haemorrhage by placing a retrograde catheter in an artery and inflating a balloon at its tip. This retrospective study aimed to evaluate the proportion of injured people who could potentially have benefited from this technique prior to hospitalisation, including on the scene or during transport. METHODS: A retrospective analysis was conducted of all patients with trauma registered in the Paris Fire Brigade emergency medical system between 1 January and 31 December 2014. Inclusion criteria included all patients over 18 years of age with bleeding of supposedly abdominal and/or pelvic and/or junctional origin, uncontrolled haemorrhagic shock or cardiac arrest with attempted resuscitation. RESULTS: During this study period, a total of 1159 patients with trauma (3.2%) would have been eligible to undergo REBOA. Death on scene rate was 83.8% (n=31) and six patients had a beating heart when they arrived at the hospital. Ten out of the 37 patients had spontaneous circulatory activity. Among them, four people died on the scene or during transport. Thirty six out of 37 patients were intubated, one benefited from the use of a haemostatic dressing and one benefited from a tourniquet. CONCLUSIONS: REBOA can be seen as an effective non-surgical solution to ensure complete haemostasis during the prehospital setting. When comparing the high mortality rate following haemorrhage with the REBOA's rare side effects, the risk-benefit balance is positive. Given that 3% of all patients with trauma based on this study would have been eligible for REBOA, we believe that this intervention should be available in the prehospital setting. The results of this study will be used: educational models for REBOA balloon placement using training manikins, with an ultimate aim to undertake a prospective feasibility study in the prehospital setting. PMID- 29487208 TI - Lamellipodium is a myosin-independent mechanosensor. AB - The ability of adherent cells to sense changes in the mechanical properties of their extracellular environments is critical to numerous aspects of their physiology. It has been well documented that cell attachment and spreading are sensitive to substrate stiffness. Here, we demonstrate that this behavior is actually biphasic, with a transition that occurs around a Young's modulus of ~7 kPa. Furthermore, we demonstrate that, contrary to established assumptions, this property is independent of myosin II activity. Rather, we find that cell spreading on soft substrates is inhibited due to reduced myosin-II independent nascent adhesion formation within the lamellipodium. Cells on soft substrates display normal leading-edge protrusion activity, but these protrusions are not stabilized due to impaired adhesion assembly. Enhancing integrin-ECM affinity through addition of Mn2+ recovers nascent adhesion assembly and cell spreading on soft substrates. Using a computational model to simulate nascent adhesion assembly, we find that biophysical properties of the integrin-ECM bond are optimized to stabilize interactions above a threshold matrix stiffness that is consistent with the experimental observations. Together, these results suggest that myosin II-independent forces in the lamellipodium are responsible for mechanosensation by regulating new adhesion assembly, which, in turn, directly controls cell spreading. This myosin II-independent mechanism of substrate stiffness sensing could potentially regulate a number of other stiffness sensitive processes. PMID- 29487209 TI - Human Ska complex and Ndc80 complex interact to form a load-bearing assembly that strengthens kinetochore-microtubule attachments. AB - Accurate segregation of chromosomes relies on the force-bearing capabilities of the kinetochore to robustly attach chromosomes to dynamic microtubule tips. The human Ska complex and Ndc80 complex are outer-kinetochore components that bind microtubules and are required to fully stabilize kinetochore-microtubule attachments in vivo. While purified Ska complex tracks with disassembling microtubule tips, it remains unclear whether the Ska complex-microtubule interaction is sufficiently strong to make a significant contribution to kinetochore-microtubule coupling. Alternatively, Ska complex might affect kinetochore coupling indirectly, through recruitment of phosphoregulatory factors. Using optical tweezers, we show that the Ska complex itself bears load on microtubule tips, strengthens Ndc80 complex-based tip attachments, and increases the switching dynamics of the attached microtubule tips. Cross-linking mass spectrometry suggests the Ska complex directly binds Ndc80 complex through interactions between the Ska3 unstructured C-terminal region and the coiled-coil regions of each Ndc80 complex subunit. Deletion of the Ska complex microtubule binding domain or the Ska3 C terminus prevents Ska complex from strengthening Ndc80 complex-based attachments. Together, our results indicate that the Ska complex can directly strengthen the kinetochore-microtubule interface and regulate microtubule tip dynamics by forming an additional connection between the Ndc80 complex and the microtubule. PMID- 29487210 TI - Monitoring ligand-dependent assembly of receptor ternary complexes in live cells by BRETFect. AB - There is currently an unmet need for versatile techniques to monitor the assembly and dynamics of ternary complexes in live cells. Here we describe bioluminescence resonance energy transfer with fluorescence enhancement by combined transfer (BRETFect), a high-throughput technique that enables robust spectrometric detection of ternary protein complexes based on increased energy transfer from a luciferase to a fluorescent acceptor in the presence of a fluorescent intermediate. Its unique donor-intermediate-acceptor relay system is designed so that the acceptor can receive energy either directly from the donor or indirectly via the intermediate in a combined transfer, taking advantage of the entire luciferase emission spectrum. BRETFect was used to study the ligand-dependent cofactor interaction properties of the estrogen receptors ERalpha and ERbeta, which form homo- or heterodimers whose distinctive regulatory properties are difficult to dissect using traditional methods. BRETFect uncovered the relative capacities of hetero- vs. homodimers to recruit receptor-specific cofactors and regulatory proteins, and to interact with common cofactors in the presence of receptor-specific ligands. BRETFect was also used to follow the assembly of ternary complexes between the V2R vasopressin receptor and two different intracellular effectors, illustrating its use for dissection of ternary protein protein interactions engaged by G protein-coupled receptors. Our results indicate that BRETFect represents a powerful and versatile technique to monitor the dynamics of ternary interactions within multimeric complexes in live cells. PMID- 29487211 TI - Structural basis of transcriptional stalling and bypass of abasic DNA lesion by RNA polymerase II. AB - Abasic sites are among the most abundant DNA lesions and interfere with DNA replication and transcription, but the mechanism of their action on transcription remains unknown. Here we applied a combined structural and biochemical approach for a comprehensive investigation of how RNA polymerase II (Pol II) processes an abasic site, leading to slow bypass of lesion. Encounter of Pol II with an abasic site involves two consecutive slow steps: insertion of adenine opposite a noninstructive abasic site (the A-rule), followed by extension of the 3'-rAMP with the next cognate nucleotide. Further studies provided structural insights into the A-rule: ATP is slowly incorporated into RNA in the absence of template guidance. Our structure revealed that ATP is bound to the Pol II active site, whereas the abasic site is located at an intermediate state above the Bridge Helix, a conserved structural motif that is cirtical for Pol II activity. The next extension step occurs in a template-dependent manner where a cognate substrate is incorporated, despite at a much slower rate compared with nondamaged template. During the extension step, neither the cognate substrate nor the template base is located at the canonical position, providing a structural explanation as to why this step is as slow as the insertion step. Taken together, our studies provide a comprehensive understanding of Pol II stalling and bypass of the abasic site in the DNA template. PMID- 29487213 TI - Transparency in authors' contributions and responsibilities to promote integrity in scientific publication. AB - In keeping with the growing movement in scientific publishing toward transparency in data and methods, we propose changes to journal authorship policies and procedures to provide insight into which author is responsible for which contributions, better assurance that the list is complete, and clearly articulated standards to justify earning authorship credit. To accomplish these goals, we recommend that journals adopt common and transparent standards for authorship, outline responsibilities for corresponding authors, adopt the Contributor Roles Taxonomy (CRediT) (docs.casrai.org/CRediT) methodology for attributing contributions, include this information in article metadata, and require authors to use the ORCID persistent digital identifier (https://orcid.org). Additionally, we recommend that universities and research institutions articulate expectations about author roles and responsibilities to provide a point of common understanding for discussion of authorship across research teams. Furthermore, we propose that funding agencies adopt the ORCID identifier and accept the CRediT taxonomy. We encourage scientific societies to further authorship transparency by signing on to these recommendations and promoting them through their meetings and publications programs. PMID- 29487212 TI - Target selectivity of septal cholinergic neurons in the medial and lateral entorhinal cortex. AB - The entorhinal cortex (EC) plays a pivotal role in processing and conveying spatial information to the hippocampus. It has long been known that EC neurons are modulated by cholinergic input from the medial septum. However, little is known as to how synaptic release of acetylcholine affects the different cell types in EC. Here we combined optogenetics and patch-clamp recordings to study the effect of cholinergic axon stimulation on distinct neurons in EC. We found dense cholinergic innervations that terminate in layer I and II (LI and LII). Light-activated stimulation of septal cholinergic projections revealed differential responses in excitatory and inhibitory neurons in LI and LII of both medial and lateral EC. We observed depolarizing responses mediated by nicotinic and muscarinic receptors primarily in putative serotonin receptor (p5HT3R) expressing interneurons. Hyperpolarizing muscarinic receptor-mediated responses were found predominantly in excitatory cells. Additionally, some excitatory as well as a higher fraction of inhibitory neurons received mono- and/or polysynaptic GABAergic inputs, revealing that medial septum cholinergic neurons have the capacity to corelease GABA alongside acetylcholine. Notably, the synaptic effects of acetylcholine were similar in neurons of both medial and lateral EC. Taken together, our findings demonstrate that EC activity may be differentially modulated via the activation or the suppression of distinct subsets of LI and LII neurons by the septal cholinergic system. PMID- 29487214 TI - Role of a single noncoding nucleotide in the evolution of an epidemic African clade of Salmonella. AB - Salmonella enterica serovar Typhimurium ST313 is a relatively newly emerged sequence type that is causing a devastating epidemic of bloodstream infections across sub-Saharan Africa. Analysis of hundreds of Salmonella genomes has revealed that ST313 is closely related to the ST19 group of S Typhimurium that cause gastroenteritis across the world. The core genomes of ST313 and ST19 vary by only ~1,000 SNPs. We hypothesized that the phenotypic differences that distinguish African Salmonella from ST19 are caused by certain SNPs that directly modulate the transcription of virulence genes. Here we identified 3,597 transcriptional start sites of the ST313 strain D23580, and searched for a gene expression signature linked to pathogenesis of Salmonella We identified a SNP in the promoter of the pgtE gene that caused high expression of the PgtE virulence factor in African S. Typhimurium, increased the degradation of the factor B component of human complement, contributed to serum resistance, and modulated virulence in the chicken infection model. We propose that high levels of PgtE expression by African S Typhimurium ST313 promote bacterial survival and dissemination during human infection. Our finding of a functional role for an extragenic SNP shows that approaches used to deduce the evolution of virulence in bacterial pathogens should include a focus on noncoding regions of the genome. PMID- 29487215 TI - Phosphorylation-dependent activation of the cell wall synthase PBP2a in Streptococcus pneumoniae by MacP. AB - Most bacterial cells are surrounded by an essential cell wall composed of the net like heteropolymer peptidoglycan (PG). Growth and division of bacteria are intimately linked to the expansion of the PG meshwork and the construction of a cell wall septum that separates the nascent daughter cells. Class A penicillin binding proteins (aPBPs) are a major family of PG synthases that build the wall matrix. Given their central role in cell wall assembly and importance as drug targets, surprisingly little is known about how the activity of aPBPs is controlled to properly coordinate cell growth and division. Here, we report the identification of MacP (SPD_0876) as a membrane-anchored cofactor of PBP2a, an aPBP synthase of the Gram-positive pathogen Streptococcus pneumoniae We show that MacP localizes to the division site of S. pneumoniae, forms a complex with PBP2a, and is required for the in vivo activity of the synthase. Importantly, MacP was also found to be a substrate for the kinase StkP, a global cell cycle regulator. Although StkP has been implicated in controlling the balance between the elongation and septation modes of cell wall synthesis, none of its substrates are known to modulate PG synthetic activity. Here we show that a phosphoablative substitution in MacP that blocks StkP-mediated phosphorylation prevents PBP2a activity without affecting the MacP-PBP2a interaction. Our results thus reveal a direct connection between PG synthase function and the control of cell morphogenesis by the StkP regulatory network. PMID- 29487216 TI - Identification of a highly neurotoxic alpha-synuclein species inducing mitochondrial damage and mitophagy in Parkinson's disease. AB - Exposure of cultured primary neurons to preformed alpha-synuclein fibrils (PFFs) leads to the recruitment of endogenous alpha-synuclein and its templated conversion into fibrillar phosphorylated alpha-synuclein (palpha-synF) aggregates resembling those involved in Parkinson's disease (PD) pathogenesis. Palpha-synF was described previously as inclusions morphologically similar to Lewy bodies and Lewy neurites in PD patients. We discovered the existence of a conformationally distinct, nonfibrillar, phosphorylated alpha-syn species that we named "palpha syn*." We uniquely describe the existence of palpha-syn* in PFF-seeded primary neurons, mice brains, and PD patients' brains. Through immunofluorescence and pharmacological manipulation we showed that palpha-syn* results from incomplete autophagic degradation of palpha-synF. Palpha-synF was decorated with autophagic markers, but palpha-syn* was not. Western blots revealed that palpha-syn* was N- and C-terminally trimmed, resulting in a 12.5-kDa fragment and a SDS-resistant dimer. After lysosomal release, palpha-syn* aggregates associated with mitochondria, inducing mitochondrial membrane depolarization, cytochrome C release, and mitochondrial fragmentation visualized by confocal and stimulated emission depletion nanoscopy. Palpha-syn* recruited phosphorylated acetyl-CoA carboxylase 1 (ACC1) with which it remarkably colocalized. ACC1 phosphorylation indicates low ATP levels, AMPK activation, and oxidative stress and induces mitochondrial fragmentation via reduced lipoylation. Palpha-syn* also colocalized with BiP, a master regulator of the unfolded protein response and a resident protein of mitochondria-associated endoplasmic reticulum membranes that are sites of mitochondrial fission and mitophagy. Palpha-syn* aggregates were found in Parkin-positive mitophagic vacuoles and imaged by electron microscopy. Collectively, we showed that palpha-syn* induces mitochondrial toxicity and fission, energetic stress, and mitophagy, implicating palpha-syn* as a key neurotoxic alpha-syn species and a therapeutic target. PMID- 29487217 TI - Reply to Pierret and Lacombe: Global controls on maximum rooting depths remain important. PMID- 29487218 TI - Hydrologic regulation of plant rooting depth: Breakthrough or observational conundrum? PMID- 29487219 TI - A Phase II Trial of Selinexor, an Oral Selective Inhibitor of Nuclear Export Compound, in Abiraterone- and/or Enzalutamide-Refractory Metastatic Castration Resistant Prostate Cancer. AB - LESSONS LEARNED: In abiraterone- and/or enzalutamide-refractory metastatic castration-resistant prostate cancer (mCRPC) patients, selinexor led to prostate specific antigen and/or radiographic responses in a subset of patients, indicating clinical activity in this indication.Despite twice-a-week dosing and maximal symptomatic management, selinexor was associated with significant anorexia, nausea, and fatigue in mCRPC patients refractory to second-generation anti-androgen therapies, limiting further clinical development in this patient population.This study highlights the challenge of primary endpoint selection for phase II studies in the post-abiraterone and/or post-enzalutamide mCRPC space. BACKGROUND: Selinexor is a first-in-class selective inhibitor of nuclear export compound that specifically inhibits the nuclear export protein Exportin-1 (XPO 1), leading to nuclear accumulation of tumor suppressor proteins. METHODS: This phase II study evaluated the efficacy and tolerability of selinexor in patients with metastatic castration-resistant prostate cancer (mCRPC) refractory to abiraterone and/or enzalutamide. RESULTS: Fourteen patients were enrolled. Selinexor was initially administered at 65 mg/m2 twice a week (days 1 and 3) and was subsequently reduced to 60 mg flat dose twice a week (days 1 and 3), 3 weeks on, 1 week off, to improve tolerability. The median treatment duration was 13 weeks. At a median follow-up of 4 months, two patients (14%) had >=50% prostate specific antigen (PSA) decline, and seven patients (50%) had any PSA decline. Of eight patients with measurable disease at baseline, two (25%) had a partial response and four (50%) had stable disease as their best radiographic response. Five patients (36%) experienced serious adverse events (SAEs; all unrelated to selinexor), and five patients (36%) experienced treatment-related grade 3-4 AEs. The most common drug-related adverse events (AEs) of any severity were anorexia, nausea, weight loss, fatigue, and thrombocytopenia. Three patients (21%) came off study for unacceptable tolerability. CONCLUSION: Selinexor demonstrated clinical activity and poor tolerability in mCRPC patients refractory to second-line anti androgenic agents. PMID- 29487220 TI - Effect of Concomitant pH-Elevating Medications with Pazopanib on Progression-Free Survival and Overall Survival in Patients with Metastatic Renal Cell Carcinoma. AB - BACKGROUND: Pazopanib is an oral tyrosine-kinase inhibitor that is approved by the U.S. Food and Drug Administration for treatment of metastatic renal cell carcinoma (mRCC). Pharmacokinetic data have shown that concomitant administration of pazopanib and esomeprazole, a proton pump inhibitor (PPI), leads to decreased area under the curve and thus decreased exposure of pazopanib by 40%. Despite the pharmacokinetic data published to date, the clinical significance and impact on patient outcomes resulting from decreased pazopanib exposure remains unknown. MATERIALS AND METHODS: In this retrospective, observational, cohort study, 90 patients with mRCC who either received pazopanib in combination with a PPI or histamine 2 receptor antagonist (H2RA; concurrent PPI/H2RA group) or who did not take concurrent pH-elevating medications (no PPI/H2RA group) were compared to determine if there was an impact on progression-free survival (PFS), the primary endpoint, and secondary endpoints, overall survival (OS) and safety. RESULTS: The differences between the PFS of 9.0 months and OS of 28.0 months for the concomitant PPI/H2RA group versus 11.0 months and 30.1 months, respectively, for the no PPI/H2RA group were not statistically significant. Rates of adverse events were similar between the concomitant PPI/H2RA and no PPI/H2RA groups. CONCLUSION: Concomitant PPI or H2RA usage was not shown to be associated with a reduction in PFS or OS for patients receiving pazopanib for mRCC, with a similar toxicity profile in each group. Based on the results of this retrospective cohort study and the palliative nature of the treatment of patients with mRCC, clinicians should consider allowing patients to remain on concomitant pazopanib and acid reducing therapy. IMPLICATIONS FOR PRACTICE: Pazopanib is a preferred category one first-line treatment for predominant clear cell metastatic renal cell carcinoma (mRCC). However, because of an aging demographic, coupled with patients with mRCC presenting with multiple comorbidities, including symptomatic dyspepsia or gastroesophageal reflux disease, patients are commonly required to take pazopanib concomitantly with a proton pump inhibitor (PPI) or a histamine 2 receptor antagonist (H2RA). Despite earlier pharmacokinetic reports suggesting that an alkaline pH may result in poorer absorption, this institutional retrospective study found no effect on clinical outcomes. These data suggest that concurrent treatment of mRCC with pazopanib and a PPI or H2RA may be safe in everyday practice. PMID- 29487222 TI - Meeting Kristoff. PMID- 29487221 TI - A Phase II Study of Tumor Ablation in Patients with Metastatic Sarcoma Stable on Chemotherapy. AB - LESSONS LEARNED: Ablation therapy appears to be a reasonably safe and effective approach to obtain a significant treatment-free interval for a subset of patients with limited sites of metastatic disease for which systemic control can be obtained with six cycles of chemotherapy. BACKGROUND: Metastatic sarcoma often becomes resistant to treatment by chemotherapy. There is sometimes prolonged stable disease from active chemotherapy that provides a window of opportunity for an intervention to prolong disease-free survival. MATERIALS AND METHODS: We performed a phase II study in patients with metastatic sarcoma who had been stable on six cycles of chemotherapy who then received ablation therapy to their residual disease. Histologies captured in this study included leiomyosarcoma, malignant peripheral nerve sheath tumor, pleiomorphic rhabdomyosarcoma, and myxoid liposarcoma. Sites ablated included lung metastases and retroperitoneal metastatic deposits. In this study, up to three lesions were ablated in any given interventional radiology session. After ablation, patients were not treated with any further therapy but were followed by surveillance imaging to determine progression-free rate (PFR). RESULTS: Although terminated early because of slow accrual, this study demonstrated a 3-month PFR of 75% for this cohort of eight patients treated with ablation performed after completion of six cycles of chemotherapy with stable disease. Median progression-free survival (PFS) was 19.74 months, and the median overall survival (OS) was not reached. CONCLUSION: Our data are the first prospective study to suggest that ablation therapy in selected patients who are stable on chemotherapy can provide a significant progression-free interval off therapy and warrants further study in a randomized trial. PMID- 29487223 TI - A Randomized Phase II Study of Metformin plus Paclitaxel/Carboplatin/Bevacizumab in Patients with Chemotherapy-Naive Advanced or Metastatic Nonsquamous Non-Small Cell Lung Cancer. AB - BACKGROUND: In the absence of a targeted oncogenic driver mutation or high programmed death-ligand 1 expression, systemic therapy with platinum-based doublet chemotherapy with or without bevacizumab has been the standard treatment in advanced or metastatic non-small cell lung cancer (NSCLC). Metformin has been shown to have antitumor effects via a variety of insulin-dependent and insulin independent mechanisms and to be potentially synergistic with chemotherapy. MATERIALS AND METHODS: This open-label single-center phase II study (NCT01578551) enrolled patients with chemotherapy-naive advanced or metastatic nonsquamous NSCLC and randomized them (3:1) to receive carboplatin, paclitaxel, and bevacizumab with (Arm A) or without (Arm B) concurrent metformin for four to six cycles followed by maintenance therapy with bevacizumab +/- metformin continued until disease progression, intolerable toxicity, or study withdrawal. The primary outcome was 1-year progression free survival (PFS). Secondary outcomes included overall survival, response to therapy, and toxicity. RESULTS: A total of 25 patients were enrolled from August 2012 to April 2015, of whom 24 received at least one cycle of therapy administration. The study was stopped early due to slow accrual and changes in standard first-line therapy of advanced NSCLC. The 1 year PFS on Arm A (n = 18) was 47% (95% confidence interval [CI]: 25%-88%), which exceeded the historical control 1-year PFS of 15%. Median overall survival of patients treated on Arm A was 15.9 months (95% CI: 8.4-not available [NA]) and 13.9 months (95% CI: 12.7-NA) on Arm B. There were no significant differences in toxicity between the study arms. CONCLUSION: To the authors' knowledge, this is the first study to show a significant benefit in PFS with the use of metformin in this patient population and is a signal of efficacy for metformin in advanced NSCLC. IMPLICATIONS FOR PRACTICE: The anticancer effects of metformin continue to be elucidated. To the authors' knowledge, this is the first trial in nondiabetic advanced non-small cell lung cancer patients to show a significant change in outcome with the addition of metformin to standard first-line chemotherapy. Well tolerated and widely available, metformin is a drug that should be considered for further study in the lung cancer treatment landscape. PMID- 29487224 TI - Second-Line Treatment Landscape for Renal Cell Carcinoma: A Comprehensive Review. AB - : The management of advanced clear-cell renal cell carcinoma has steadily improved over the past decade with the introduction of antiangiogenic and targeted therapies. Recently, three new therapies have been approved for use as second-line options that further advance the treatment armamentarium: nivolumab, a monoclonal antibody targeting the programmed cell death receptor; cabozantinib, a small-molecule tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptor (VEGFR), MET, and AXL; and lenvatinib, a small-molecule TKI of VEGF and fibroblast growth factor receptors that is used in combination with everolimus, an inhibitor of the mechanistic target of rapamycin. Together, these and previously approved second-line treatments offer clinicians the ability to better individualize treatment for patients after progression on first-line VEGFR targeted therapies. In this comprehensive review, we discuss the efficacy and safety results from the pivotal trials of these newly approved therapies, including the quality of study design, the level of evidence, subgroup analyses, and how these data can help to guide clinicians to select the most appropriate second-line therapy for their patients. IMPLICATIONS FOR PRACTICE: This review article provides the reader with a comprehensive overview of current treatment options for patients with advanced clear-cell renal cell carcinoma (RCC) whose disease has progressed after their first therapy. As many patients with RCC experience disease progression with initial treatments, effective second-line therapies are critical. Nivolumab, cabozantinib, and lenvatinib plus everolimus have recently been approved as second-line treatments. The new agents discussed in this review increase the therapeutic options available and provide physicians with opportunities to individualize treatments for their patients, with a view to improving disease control and survival outcomes. PMID- 29487226 TI - Emerging Perspectives on mTOR Inhibitor-Associated Pneumonitis in Breast Cancer. AB - : Substantial improvements in the early detection and treatment of breast cancer have led to improvements in survival, but breast cancer remains a significant cause of morbidity and mortality in women. In 2012, the mammalian target of rapamycin (mTOR) inhibitor everolimus was approved by the U.S. Food and Drug Administration for the treatment of advanced breast cancer in patients resistant to endocrine therapy. Although everolimus is generally well tolerated, mTOR inhibitor-associated pneumonitis is one of the most common adverse drug events leading to treatment discontinuation. To date, the underlying pathophysiology of this toxicity is unclear, and this uncertainty may hinder the optimization of management strategies. However, experiences from breast cancer and renal cell carcinoma clinical trials indicate that mTOR inhibitor-associated pneumonitis can be effectively managed by early detection, accurate diagnosis, and prompt intervention that generally involves everolimus dose reductions, interruptions, or discontinuation. Management can be achieved by a multidisciplinary approach that involves the collaborative efforts of nurses, oncologists, radiologists, infectious disease specialists, pulmonologists, clinical pharmacists, and pathologists. Comprehensive education must be provided to all health care professionals involved in managing patients receiving everolimus therapy. Although general recommendations on the management of mTOR inhibitor-associated pneumonitis have been published, there is a lack of consensus on the optimal management of this potentially serious complication. This article provides an overview of mTOR inhibitor-associated pneumonitis, with a focus on the detection, accurate diagnosis, and optimal management of this class-related complication of mTOR inhibitor therapy. IMPLICATIONS FOR PRACTICE: This article summarizes the pathogenesis, clinical presentation, incidence, detection, and optimal management of everolimus-related noninfectious pneumonitis in breast cancer. In particular, this article provides a detailed overview of the important aspects of the detection, accurate diagnosis, and appropriate management of mammalian target of rapamycin inhibitor-associated pneumonitis. In addition, this article emphasizes that effective management of this adverse drug event in patients with breast cancer will require a multidisciplinary approach and collaboration among various health care professionals. PMID- 29487225 TI - Next-Generation Sequencing of Circulating Tumor DNA Reveals Frequent Alterations in Advanced Hepatocellular Carcinoma. AB - BACKGROUND: Because imaging has a high sensitivity to diagnose hepatocellular carcinoma (HCC) and tissue biopsies carry risks such as bleeding, the latter are often not performed in HCC. Blood-derived circulating tumor DNA (ctDNA) analysis can identify somatic alterations, but its utility has not been characterized in HCC. MATERIALS AND METHODS: We evaluated 14 patients with advanced HCC (digital ctDNA sequencing [68 genes]). Mutant relative to wild-type allele fraction was calculated. RESULTS: All patients (100%) had somatic alterations (median = 3 alterations/patient [range, 1-8]); median mutant allele fraction, 0.29% (range, 0.1%-37.77%). Mutations were identified in several genes: TP53 (57% of patients), CTNNB1 (29%), PTEN (7%), CDKN2A (7%), ARID1A (7%), and MET (7%); amplifications, in CDK6 (14%), EGFR (14%), MYC (14%), BRAF (7%), RAF1 (7%), FGFR1 (7%), CCNE1 (7%), PIK3CA (7%), and ERBB2/HER2 (7%). Eleven patients (79%) had >=1 theoretically actionable alteration. No two patients had identical genomic portfolios, suggesting the need for customized treatment. A patient with a CDKN2A inactivating and a CTNNB1-activating mutation received matched treatment: palbociclib (CDK4/6 inhibitor) and celecoxib (COX-2/Wnt inhibitor); des-gamma carboxy prothrombin level decreased by 84% at 2 months (1,410 to 242 ng/mL [normal: <=7.4 ng/mL]; alpha fetoprotein [AFP] low at baseline). A patient with a PTEN-inactivating and a MET-activating mutation (an effect suggested by in silico molecular dynamic simulations) received sirolimus (mechanistic target of rapamycin inhibitor) and cabozantinib (MET inhibitor); AFP declined by 63% (8,320 to 3,045 ng/mL [normal: 0-15 ng/mL]). CONCLUSION: ctDNA derived from noninvasive blood tests can provide exploitable genomic profiles in patients with HCC. IMPLICATIONS FOR PRACTICE: This study reports that blood-derived circulating tumor DNA can provide therapeutically exploitable genomic profiles in hepatocellular cancer, a malignancy that is known to be difficult to biopsy. PMID- 29487227 TI - Nesprin-1/2: roles in nuclear envelope organisation, myogenesis and muscle disease. AB - Nesprins (nuclear envelope spectrin repeat proteins) are multi-isomeric scaffolding proteins. Nesprin-1 and -2 are highly expressed in skeletal and cardiac muscles and together with SUN (Sad1p/UNC84) domain-containing proteins form the LInker of Nucleoskeleton and Cytoskeleton (LINC) complex at the nuclear envelope in association with lamin A/C and emerin. Mutations in nesprin-1/2 have been found in patients with autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD) as well as dilated cardiomyopathy (DCM). Several lines of evidence indicate that compromised LINC complex function is the critical step leading to muscle disease. Here, we review recent advances in our understanding of the functions of nesprin-1/2 in the LINC complex and mechanistic insights into how mutations in nesprin-1/2 lead to nesprin-related muscle diseases, in particular DCM and EDMD. PMID- 29487228 TI - Structure of the plant photosystem I. AB - Plant photosystem I (PSI) is one of the most intricate membrane complexes in nature. It comprises two complexes, a reaction center and light-harvesting complex (LHC), which together form the PSI-LHC supercomplex. The crystal structure of plant PSI was solved with two distinct crystal forms. The first, crystallized at pH 6.5, exhibited P21 symmetry; the second, crystallized at pH 8.5, exhibited P212121 symmetry. The surfaces involved in binding plastocyanin and ferredoxin are identical in both forms. The crystal structure at 2.6 A resolution revealed 16 subunits, 45 transmembrane helices, and 232 prosthetic groups, including 143 chlorophyll a, 13 chlorophyll b, 27 beta-carotene, 7 lutein, 2 xanthophyll, 1 zeaxanthin, 20 monogalactosyl diglyceride, 7 phosphatidyl diglyceride, 5 digalactosyl diglyceride, 2 calcium ions, 2 phylloquinone, and 3 iron sulfur clusters. The model reveals detailed interactions, providing mechanisms for excitation energy transfer and its modulation in one of nature's most efficient photochemical machine. PMID- 29487229 TI - The fumarylacetoacetate hydrolase (FAH) superfamily of enzymes: multifunctional enzymes from microbes to mitochondria. AB - Prokaryotic and eukaryotic fumarylacetoacetate hydrolase (FAH) superfamily members, sharing conserved regions that form the so-called FAH-domain, catalyze a remarkable variety of reactions. These enzymes are essential in the metabolic pathways to degrade aromatic compounds in prokaryotes and eukaryotes. It appears that prokaryotic FAH superfamily members evolved mainly to allow microbes to generate energy and useful metabolites from complex carbon sources. We review recent findings, indicating that both prokaryotic and eukaryotic members of the FAH superfamily also display oxaloacetate decarboxylase (ODx) activity. The identification of human FAH domain-containing protein 1 as mitochondrial ODx regulating mitochondrial function supports the new concept that, during evolution, eukaryotic FAH superfamily members have acquired important regulatory functions beyond catabolism of complex carbon sources. Molecular studies on the evolution and function of FAH superfamily members are expected to provide new mechanistic insights in their physiological roles. PMID- 29487230 TI - Mouse and Human Monoclonal Antibodies Protect against Infection by Multiple Genotypes of Japanese Encephalitis Virus. AB - Japanese encephalitis virus (JEV) remains a leading cause of viral encephalitis worldwide. Although JEV-specific antibodies have been described, an assessment of their ability to neutralize multiple genotypes of JEV has been limited. Here, we describe the development of a panel of mouse and human neutralizing monoclonal antibodies (MAbs) that inhibit infection in cell culture of four different JEV genotypes tested. Mechanism-of-action studies showed that many of these MAbs inhibited infection at a postattachment step, including blockade of virus fusion. Mapping studies using site-directed mutagenesis and hydrogen-deuterium exchange with mass spectrometry revealed that the lateral ridge on domain III of the envelope protein was a primary recognition epitope for our panel of strongly neutralizing MAbs. Therapeutic studies in mice demonstrated protection against lethality caused by genotype I and III strains when MAbs were administered as a single dose even 5 days after infection. This information may inform the development of vaccines and therapeutic antibodies as emerging strains and genotypic shifts become more prevalent.IMPORTANCE Although Japanese encephalitis virus (JEV) is a vaccine-preventable cause of viral encephalitis, the inactivated and live attenuated platforms available are derived from strains belonging to a single genotype (GIII) due to its historical prevalence in areas of JEV epidemics. Related to this, studies with vaccines and antibodies have focused on assessing the in vitro and in vivo protective responses to homologous or heterologous GIII strains. An epidemiological shift in JEV genotype distribution warrants the induction of broadly neutralizing antibody responses that inhibit infection of multiple JEV genotypes. Here, we generated a panel of mouse and human neutralizing monoclonal antibodies and evaluated their inhibitory activity, epitope location, and capacity for protection against multiple JEV genotypes in mice. PMID- 29487231 TI - Widespread Distribution and Functional Specificity of the Copper Importer CcoA: Distinct Cu Uptake Routes for Bacterial Cytochrome c Oxidases. AB - Cytochrome c oxidases are members of the heme-copper oxidase superfamily. These enzymes have different subunits, cofactors, and primary electron acceptors, yet they all contain identical heme-copper (CuB) binuclear centers within their catalytic subunits. The uptake and delivery pathways of the CuB atom incorporated into this active site, where oxygen is reduced to water, are not well understood. Our previous work with the facultative phototrophic bacterium Rhodobacter capsulatus indicated that the copper atom needed for the CuB site of cbb3-type cytochrome c oxidase (cbb3-Cox) is imported to the cytoplasm by a major facilitator superfamily-type transporter, CcoA. In this study, a comparative genomic analysis of CcoA orthologs in alphaproteobacterial genomes showed that CcoA is widespread among organisms and frequently co-occurs with cytochrome c oxidases. To define the specificity of CcoA activity, we investigated its function in Rhodobacter sphaeroides, a close relative of R. capsulatus that contains both cbb3- and aa3-Cox. Phenotypic, genetic, and biochemical characterization of mutants lacking CcoA showed that in its absence, or even in the presence of its bypass suppressors, only the production of cbb3-Cox and not that of aa3-Cox was affected. We therefore concluded that CcoA is dedicated solely to cbb3-Cox biogenesis, establishing that distinct copper uptake systems provide the CuB atoms to the catalytic sites of these two similar cytochrome c oxidases. These findings illustrate the large variety of strategies that organisms employ to ensure homeostasis and fine control of copper trafficking and delivery to the target cuproproteins under different physiological conditions.IMPORTANCE The cbb3- and aa3-type cytochrome c oxidases belong to the widespread heme-copper oxidase superfamily. They are membrane-integral cuproproteins that catalyze oxygen reduction to water under hypoxic and normoxic growth conditions. These enzymes diverge in terms of subunit and cofactor composition, yet they all share a conserved heme-copper binuclear site within their catalytic subunit. In this study, we show that the copper atoms of the catalytic center of two similar cytochrome c oxidases from this superfamily are provided by different copper uptake systems during their biogenesis. This finding illustrates different strategies by which organisms fine-tune the trafficking of copper, which is an essential but toxic micronutrient. PMID- 29487232 TI - Mmf1p Couples Amino Acid Metabolism to Mitochondrial DNA Maintenance in Saccharomyces cerevisiae. AB - A variety of metabolic deficiencies and human diseases arise from the disruption of mitochondrial enzymes and/or loss of mitochondrial DNA. Mounting evidence shows that eukaryotes have conserved enzymes that prevent the accumulation of reactive metabolites that cause stress inside the mitochondrion. 2-Aminoacrylate is a reactive enamine generated by pyridoxal 5'-phosphate-dependent alpha,beta eliminases as an obligatory intermediate in the breakdown of serine. In prokaryotes, members of the broadly conserved RidA family (PF14588) prevent metabolic stress by deaminating 2-aminoacrylate to pyruvate. Here, we demonstrate that unmanaged 2-aminoacrylate accumulation in Saccharomyces cerevisiae mitochondria causes transient metabolic stress and the irreversible loss of mitochondrial DNA. The RidA family protein Mmf1p deaminates 2-aminoacrylate, preempting metabolic stress and loss of the mitochondrial genome. Disruption of the mitochondrial pyridoxal 5'-phosphate-dependent serine dehydratases (Ilv1p and Cha1p) prevents 2-aminoacrylate formation, avoiding stress in the absence of Mmf1p. Furthermore, chelation of iron in the growth medium improves maintenance of the mitochondrial genome in yeast challenged with 2-aminoacrylate, suggesting that 2-aminoacrylate-dependent loss of mitochondrial DNA is influenced by disruption of iron homeostasis. Taken together, the data indicate that Mmf1p indirectly contributes to mitochondrial DNA maintenance by preventing 2 aminoacrylate stress derived from mitochondrial amino acid metabolism.IMPORTANCE Deleterious reactive metabolites are produced as a consequence of many intracellular biochemical transformations. Importantly, reactive metabolites that appear short-lived in vitro have the potential to persist within intracellular environments, leading to pervasive cell damage and diminished fitness. To overcome metabolite damage, organisms utilize enzymatic reactive-metabolite defense systems to rid the cell of deleterious metabolites. In this report, we describe the importance of the RidA/YER057c/UK114 enamine/imine deaminase family in preventing 2-aminoacrylate stress in yeast. Saccharomyces cerevisiae lacking the enamine/imine deaminase Mmf1p was shown to experience pleiotropic growth defects and fails to maintain its mitochondrial genome. Our results provide the first line of evidence that uncontrolled 2-aminoacrylate stress derived from mitochondrial serine metabolism can negatively impact mitochondrial DNA maintenance in eukaryotes. PMID- 29487233 TI - Phosphotyrosine-Mediated Regulation of Enterohemorrhagic Escherichia coli Virulence. AB - Enteric pathogens with low infectious doses rely on the ability to orchestrate the expression of virulence and metabolism-associated genes in response to environmental cues for successful infection. Accordingly, the human pathogen enterohemorrhagic Escherichia coli (EHEC) employs a complex multifaceted regulatory network to link the expression of type III secretion system (T3SS) components to nutrient availability. While phosphorylation of histidine and aspartate residues on two-component system response regulators is recognized as an integral part of bacterial signaling, the involvement of phosphotyrosine mediated control is minimally explored in Gram-negative pathogens. Our recent phosphotyrosine profiling study of E. coli identified 342 phosphorylated proteins, indicating that phosphotyrosine modifications in bacteria are more prevalent than previously anticipated. The present study demonstrates that tyrosine phosphorylation of a metabolite-responsive LacI/GalR family regulator, Cra, negatively affects T3SS expression under glycolytic conditions that are typical for the colonic lumen environment where production of the T3SS is unnecessary. Our data suggest that Cra phosphorylation affects T3SS expression by modulating the expression of ler, which encodes the major activator of EHEC virulence gene expression. Phosphorylation of the Cra Y47 residue diminishes DNA binding to fine-tune the expression of virulence-associated genes, including those of the locus of enterocyte effacement pathogenicity island that encode the T3SS, and thereby negatively affects the formation of attaching and effacing lesions. Our data indicate that tyrosine phosphorylation provides an additional mechanism to control the DNA binding of Cra and other LacI/GalR family regulators, including LacI and PurR. This study describes an initial effort to unravel the role of global phosphotyrosine signaling in the control of EHEC virulence potential.IMPORTANCE Enterohemorrhagic Escherichia coli (EHEC) causes outbreaks of hemorrhagic colitis and the potentially fatal hemolytic-uremic syndrome. Successful host colonization by EHEC relies on the ability to coordinate the expression of virulence factors in response to environmental cues. A complex network that integrates environmental signals at multiple regulatory levels tightly controls virulence gene expression. We demonstrate that EHEC utilizes a previously uncharacterized phosphotyrosine signaling pathway through Cra to fine-tune the expression of virulence-associated genes to effectively control T3SS production. This study demonstrates that tyrosine phosphorylation negatively affects the DNA-binding capacity of Cra, which affects the expression of genes related to virulence and metabolism. We demonstrate for the first time that phosphotyrosine-mediated control affects global transcription in EHEC. Our data provide insight into a hitherto unexplored regulatory level of the global network controlling EHEC virulence gene expression. PMID- 29487235 TI - Invasion of the Brain by Listeria monocytogenes Is Mediated by InlF and Host Cell Vimentin. AB - Listeria monocytogenes is a facultative intracellular bacterial pathogen that is frequently associated with food-borne infection. Of particular concern is the ability of L. monocytogenes to breach the blood-brain barrier, leading to life threatening meningitis and encephalitis. The mechanisms used by bacterial pathogens to infect the brain are not fully understood. Here we show that L. monocytogenes is able to utilize vimentin for invasion of host cells. Vimentin is a type III intermediate filament protein within the cytosol but is also expressed on the host cell surface. We found that L. monocytogenes interaction with surface localized vimentin promoted bacterial uptake. Furthermore, in the absence of vimentin, L. monocytogenes colonization of the brain was severely compromised in mice. The L. monocytogenes virulence factor InlF was found to bind vimentin and was necessary for optimal bacterial colonization of the brain. These studies reveal a novel receptor-ligand interaction that enhances infection of the brain by L. monocytogenes and highlights the importance of surface vimentin in host pathogen interactions.IMPORTANCEListeria monocytogenes is an intracellular bacterial pathogen that is capable of invading numerous host cells during infection. L. monocytogenes can cross the blood-brain barrier, leading to life threatening meningitis. Here we show that an L. monocytogenes surface protein, InlF, is necessary for optimal colonization of the brain in mice. Furthermore, in the absence of vimentin, a cytosolic intermediate filament protein that is also present on the surface of brain endothelial cells, colonization of the brain was significantly impaired. We further show that InlF binds vimentin to mediate invasion of host cells. This work identifies InlF as a bacterial surface protein with specific relevance for infection of the brain and underscores the significance of host cell surface vimentin interactions in microbial pathogenesis. PMID- 29487234 TI - Calcium-Dependent Protein Kinase 5 Is Required for Release of Egress-Specific Organelles in Plasmodium falciparum. AB - The human malaria parasite Plasmodium falciparum requires efficient egress out of an infected red blood cell for pathogenesis. This egress event is highly coordinated and is mediated by several signaling proteins, including the plant like Pfalciparum calcium-dependent protein kinase 5 (PfCDPK5). Knockdown of PfCDPK5 results in an egress block where parasites are trapped inside their host cells. The mechanism of this PfCDPK5-dependent block, however, remains unknown. Here, we show that PfCDPK5 colocalizes with a specialized set of parasite organelles known as micronemes and is required for their discharge, implicating failure of this step as the cause of the egress defect in PfCDPK5-deficient parasites. Furthermore, we show that PfCDPK5 cooperates with the Pfalciparum cGMP dependent kinase (PfPKG) to fully activate the protease cascade critical for parasite egress. The PfCDPK5-dependent arrest can be overcome by hyperactivation of PfPKG or by physical disruption of the arrested parasite, and we show that both treatments facilitate the release of the micronemes required for egress. Our results define the molecular mechanism of PfCDPK5 function and elucidate the complex signaling pathway of parasite egress.IMPORTANCE The signs and symptoms of clinical malaria result from the replication of parasites in human blood. Efficient egress of the malaria parasite Plasmodium falciparum out of an infected red blood cell is critical for pathogenesis. The Pfalciparum calcium-dependent protein kinase 5 (PfCDPK5) is essential for parasite egress. Following PfCDPK5 knockdown, parasites remain trapped inside their host cell and do not egress, but the mechanism for this block remains unknown. We show that PfCDPK5 colocalizes with parasite organelles known as micronemes. We demonstrate that PfCDPK5 is critical for the discharge of these micronemes and that failure of this step is the molecular mechanism of the parasite egress arrest. We also show that hyperactivation of the cGMP-dependent kinase PKG can overcome this arrest. Our data suggest that small molecules that inhibit the egress signaling pathway could be effective antimalarial therapeutics. PMID- 29487236 TI - Role of the Antigen Capture Pathway in the Induction of a Neutralizing Antibody Response to Anthrax Protective Antigen. AB - Toxin neutralizing antibodies represent the major mode of protective immunity against a number of toxin-mediated bacterial diseases, including anthrax; however, the cellular mechanisms that lead to optimal neutralizing antibody responses remain ill defined. Here we show that the cellular binding pathway of anthrax protective antigen (PA), the binding component of anthrax toxin, determines the toxin neutralizing antibody response to this antigen. PA, which binds cellular receptors and efficiently enters antigen-presenting cells by receptor-mediated endocytosis, was found to elicit robust anti-PA IgG and toxin neutralizing antibody responses. In contrast, a receptor binding-deficient mutant of PA, which does not bind receptors and only inefficiently enters antigen presenting cells by macropinocytosis, elicited very poor antibody responses. A chimeric protein consisting of the receptor binding-deficient PA mutant tethered to the binding subunit of cholera toxin, which efficiently enters cells using the cholera toxin receptor rather than the PA receptor, elicited an anti-PA IgG antibody response similar to that elicited by wild-type PA; however, the chimeric protein elicited a poor toxin neutralizing antibody response. Taken together, our results demonstrate that the antigen capture pathway can dictate the magnitudes of the total IgG and toxin neutralizing antibody responses to PA as well as the ratio of the two responses.IMPORTANCE Neutralizing antibodies provide protection against a number of toxin-mediated bacterial diseases by inhibiting toxin action. Therefore, many bacterial vaccines are designed to induce a toxin neutralizing antibody response. We have used protective antigen (PA), the binding component of anthrax toxin, as a model antigen to investigate immune mechanisms important for the induction of robust toxin neutralizing antibody responses. We found that the pathway used by antigen-presenting cells to capture PA dictates the robustness of the neutralizing antibody response to this antigen. These results provide new insights into immune mechanisms that play an important role in the induction of toxin neutralizing antibody responses and may be useful in the design of new vaccines against toxin-mediated bacterial diseases. PMID- 29487237 TI - Salmonella Reprograms Nucleotide Metabolism in Its Adaptation to Nitrosative Stress. AB - The adaptations that protect pathogenic microorganisms against the cytotoxicity of nitric oxide (NO) engendered in the immune response are incompletely understood. We show here that salmonellae experiencing nitrosative stress suffer dramatic losses of the nucleoside triphosphates ATP, GTP, CTP, and UTP while simultaneously generating a massive burst of the alarmone nucleotide guanosine tetraphosphate. RelA proteins associated with ribosomes overwhelmingly synthesize guanosine tetraphosphate in response to NO as a feedback mechanism to transient branched-chain amino acid auxotrophies. Guanosine tetraphosphate activates the transcription of valine biosynthetic genes, thereby reestablishing branched-chain amino acid biosynthesis that enables the translation of the NO-consuming flavohemoglobin Hmp. Guanosine tetraphosphate synthesized by RelA protects salmonellae from the metabolic stress inflicted by reactive nitrogen species generated in the mammalian host response. This research illustrates the importance of nucleotide metabolism in the adaptation of salmonellae to the nutritional stress imposed by NO released in the innate host response.IMPORTANCE Nitric oxide triggers dramatic drops in nucleoside triphosphates, the building blocks that power DNA replication; RNA transcription; translation; cell division; and the biosynthesis of fatty acids, lipopolysaccharide, and peptidoglycan. Concomitantly, this diatomic gas stimulates a burst of guanosine tetraphosphate. Global changes in nucleotide metabolism may contribute to the potent bacteriostatic activity of nitric oxide. In addition to inhibiting numerous growth-dependent processes, guanosine tetraphosphate positively regulates the transcription of branched-chain amino acid biosynthesis genes, thereby facilitating the translation of antinitrosative defenses that mediate recovery from nitrosative stress. PMID- 29487238 TI - Gene Flow between Divergent Cereal- and Grass-Specific Lineages of the Rice Blast Fungus Magnaporthe oryzae. AB - Delineating species and epidemic lineages in fungal plant pathogens is critical to our understanding of disease emergence and the structure of fungal biodiversity and also informs international regulatory decisions. Pyricularia oryzae (syn. Magnaporthe oryzae) is a multihost pathogen that infects multiple grasses and cereals, is responsible for the most damaging rice disease (rice blast), and is of growing concern due to the recent introduction of wheat blast to Bangladesh from South America. However, the genetic structure and evolutionary history of M. oryzae, including the possible existence of cryptic phylogenetic species, remain poorly defined. Here, we use whole-genome sequence information for 76 M. oryzae isolates sampled from 12 grass and cereal genera to infer the population structure of M. oryzae and to reassess the species status of wheat infecting populations of the fungus. Species recognition based on genealogical concordance, using published data or extracting previously used loci from genome assemblies, failed to confirm a prior assignment of wheat blast isolates to a new species (Pyricularia graminis-tritici). Inference of population subdivisions revealed multiple divergent lineages within M. oryzae, each preferentially associated with one host genus, suggesting incipient speciation following host shift or host range expansion. Analyses of gene flow, taking into account the possibility of incomplete lineage sorting, revealed that genetic exchanges have contributed to the makeup of multiple lineages within M. oryzae These findings provide greater understanding of the ecoevolutionary factors that underlie the diversification of M. oryzae and highlight the practicality of genomic data for epidemiological surveillance in this important multihost pathogen.IMPORTANCE Infection of novel hosts is a major route for disease emergence by pathogenic microorganisms. Understanding the evolutionary history of multihost pathogens is therefore important to better predict the likely spread and emergence of new diseases. Magnaporthe oryzae is a multihost fungus that causes serious cereal diseases, including the devastating rice blast disease and wheat blast, a cause of growing concern due to its recent spread from South America to Asia. Using whole-genome analysis of 76 fungal strains from different hosts, we have documented the divergence of M. oryzae into numerous lineages, each infecting a limited number of host species. Our analyses provide evidence that interlineage gene flow has contributed to the genetic makeup of multiple M. oryzae lineages within the same species. Plant health surveillance is therefore warranted to safeguard against disease emergence in regions where multiple lineages of the fungus are in contact with one another. PMID- 29487239 TI - Structural Basis for DNA Recognition by the Two-Component Response Regulator RcsB. AB - RcsB is a highly conserved transcription regulator of the Rcs phosphorelay system, a complex two-component signal transduction system (N. Majdalani and S. Gottesman, Annu Rev Microbiol 59:379-405, 2005; A. J. Wolfe, Curr Opin Microbiol 13:204-209, 2010, https://doi.org/10.1016/j.mib.2010.01.002; D. J. Clarke, Future Microbiol 5:1173-1184, 2010, https://doi.org/10.2217/fmb.10.83). RcsB plays an important role in virulence and pathogenicity in human hosts by regulating biofilm formation. RcsB can regulate transcription alone or together with its auxiliary transcription regulators by forming heterodimers. This complexity allows RcsB to regulate transcription of more than 600 bacterial genes in response to different stresses (D. Wang et al., Mol Plant Microbe Interact 25:6 17, 2012, https://doi.org/10.1094/MPMI-08-11-0207). Despite increasing knowledge of RcsB importance, molecular mechanisms that drive the ability of RcsB to control transcription of a large number of genes remain unclear. Here, we present crystal structures of unphosphorylated RcsB in complex with the consensus DNA binding sequence of 22-mer (DNA22) and 18-mer (DNA18) of the flhDC operon from Escherichia coli determined at 3.15- and 3.37-A resolution, respectively. The results of our structural analysis combined with the results of in vitro binding assays provide valuable insights to the protein regulatory mechanism, demonstrate how RcsB recognizes target DNA sequences, and reveal a unique oligomeric state that allows RcsB to form homo- and heterodimers. This information will help us understand the complex mechanisms of transcriptional regulation by RcsB in bacteria.IMPORTANCE RcsB is a well-studied two-component response regulator of the Rcs phosphorelay system, conserved within the family Enterobacteriaceae, which includes many pathogens. It is a global regulator, controlling more than 5% of bacterial genes associated with capsule biosynthesis, flagellar biogenesis, cell wall biosynthesis, antibiotic resistance, biofilm formation, and virulence in pathogens. Knowledge of RcsB structure represents a unique opportunity to explore mechanisms that regulate the Rcs phosphorelay system and its role in the family Enterobacteriaceae. PMID- 29487240 TI - Coiled-Coil Antagonism Regulates Activity of Venus Flytrap-Domain-Containing Sensor Kinases of the BvgS Family. AB - Bordetella pertussis controls the expression of its virulence regulon through the two-component system BvgAS. BvgS is a prototype for a family of multidomain sensor kinases. In BvgS, helical linkers connect periplasmic Venus flytrap (VFT) perception domains to a cytoplasmic Per-Arnt-Sim (PAS) domain and the PAS domain to the dimerization/histidine phosphotransfer (DHp) domain of the kinase. The two linkers can adopt coiled-coil structures but cannot do so simultaneously. The first linker forms a coiled coil in the kinase mode and the second in the phosphatase mode, with the other linker in both cases showing an increase in dynamic behavior. The intervening PAS domain changes its quaternary structure between the two modes. In BvgS homologues without a PAS domain, a helical "X" linker directly connects the VFT and DHp domains. Here, we used BvgS as a platform to characterize regulation in members of the PAS-less subfamily. BvgS chimeras of homologues with natural X linkers displayed various regulation phenotypes. We identified two distinct coiled-coil registers in the N- and C terminal portions of the X linkers. Stable coil formation in the C-terminal moiety determines the phosphatase mode, similarly to BvgS; in contrast, coil formation in the N-terminal moiety along the other register leads to the kinase mode. Thus, antagonism between two registers in the VFT-DHp linker forms the basis for activity regulation in the absence of the PAS domain. The N and C moieties of the X linker play roles similar to those played by the two independent linkers in sensor kinases with a PAS domain, providing a unified mechanism of regulation for the entire family.IMPORTANCE The whooping cough agent Bordetella pertussis uses the BvgAS sensory transduction two-component system to regulate production of its virulence factors. BvgS serves as a model for a large family of multidomain bacterial sensor kinases. B. pertussis is virulent when BvgS functions as a kinase and avirulent when it switches to phosphatase activity in response to modulating signals. Understanding the molecular regulation of those proteins might lead to new antibacterial strategies. Here, we show that the linker regions between the perception and the enzymatic domains shift between distinct states of conformation in an alternating manner in response to signals and that their antagonistic changes control sensor kinase activity. These linker regions and mechanistic principles appear to be conserved among BvgS homologues, irrespective of the presence or absence of an intervening domain between the perception and the enzymatic domains. This work has thus uncovered general molecular mechanisms that regulate activity of sensor kinases in the BvgS family. PMID- 29487242 TI - Pneumonia bugs and determinants of their occurrence. PMID- 29487241 TI - Tracking Electron Uptake from a Cathode into Shewanella Cells: Implications for Energy Acquisition from Solid-Substrate Electron Donors. AB - While typically investigated as a microorganism capable of extracellular electron transfer to minerals or anodes, Shewanella oneidensis MR-1 can also facilitate electron flow from a cathode to terminal electron acceptors, such as fumarate or oxygen, thereby providing a model system for a process that has significant environmental and technological implications. This work demonstrates that cathodic electrons enter the electron transport chain of S. oneidensis when oxygen is used as the terminal electron acceptor. The effect of electron transport chain inhibitors suggested that a proton gradient is generated during cathode oxidation, consistent with the higher cellular ATP levels measured in cathode-respiring cells than in controls. Cathode oxidation also correlated with an increase in the cellular redox (NADH/FMNH2) pool determined with a bioluminescence assay, a proton uncoupler, and a mutant of proton-pumping NADH oxidase complex I. This work suggested that the generation of NADH/FMNH2 under cathodic conditions was linked to reverse electron flow mediated by complex I. A decrease in cathodic electron uptake was observed in various mutant strains, including those lacking the extracellular electron transfer components necessary for anodic-current generation. While no cell growth was observed under these conditions, here we show that cathode oxidation is linked to cellular energy acquisition, resulting in a quantifiable reduction in the cellular decay rate. This work highlights a potential mechanism for cell survival and/or persistence on cathodes, which might extend to environments where growth and division are severely limited.IMPORTANCE The majority of our knowledge of the physiology of extracellular electron transfer derives from studies of electrons moving to the exterior of the cell. The physiological mechanisms and/or consequences of the reverse processes are largely uncharacterized. This report demonstrates that when coupled to oxygen reduction, electrode oxidation can result in cellular energy acquisition. This respiratory process has potentially important implications for how microorganisms persist in energy-limited environments, such as reduced sediments under changing redox conditions. From an applied perspective, this work has important implications for microbially catalyzed processes on electrodes, particularly with regard to understanding models of cellular conversion of electrons from cathodes to microbially synthesized products. PMID- 29487243 TI - A survey of flexible bronchoscopy practices in India: The Indian bronchoscopy survey (2017). AB - Background: There is a lack of contemporaneous data on the practices of flexible bronchoscopy in India. Aim: The aim of the study was to study the prevalent practices of flexible bronchoscopy across India. Methods: The "Indian Bronchoscopy Survey" was a 98-question, online survey structured into the following sections: general information, patient preparation and monitoring, sedation and topical anesthesia, procedural/technical aspects, and bronchoscope disinfection/staff protection. Results: Responses from 669 bronchoscopists (mean age: 40.2 years, 91.8% adult pulmonologists) were available for analysis. Approximately, 70,000 flexible bronchoscopy examinations had been performed over the preceding year. A majority (59%) of bronchoscopists were performing bronchoscopy without sedation. A large number (45%) of bronchoscopists had learned the procedure outside of their fellowship training. About 55% used anticholinergic premedication either as a routine or occasionally. Nebulized lignocaine was being used by 72%, while 24% utilized transtracheal administration of lignocaine. The most commonly (75%) used concentration of lignocaine was 2%. Midazolam with or without fentanyl was the preferred agent for intravenous sedation. The use of video bronchoscope was common (80.8%). The most common (94%) route for performing bronchoscopy was nasal. Conventional transbronchial needle aspiration (TBNA) was being performed by 74%, while 92% and 78% performed endobronchial and transbronchial lung biopsy, respectively. Therapeutic airway interventions (stents, electrocautery, cryotherapy, and others) were being performed by 30%, while endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) and rigid bronchoscopy were performed by 27% and 19.5%, respectively. Conclusion: There is a wide national variation in the practices of performing flexible bronchoscopy. However, there has been a considerable improvement in bronchoscopy practices compared to previous national surveys. PMID- 29487244 TI - Microbial etiology in hospitalized North Indian adults with community-acquired pneumonia. AB - Background: There is a paucity of literature regarding the microbial etiology of community-acquired pneumonia (CAP) in India. The current study was aimed to study the microbial etiology of hospitalized adults with CAP. Methods: The study was conducted in a 700-bedded North Indian hospital. Consecutive adults admitted with CAP over a period of 2 years from 2013 to 2015 were recruited for the study, and apart from clinical evaluation underwent various microbiological studies in the form of blood culture, sputum culture, urinary antigen for pneumococcus and Legionella, serology for Mycoplasma and Chlamydia and real-time reverse transcriptase polymerase chain reaction for influenza viruses. Radiographic studies were performed in all patients and repeated as required. The patients were treated with standard antibiotic/antiviral therapy and outcomes were recorded. Results: A total of 225 patients (median age: 59 years) were enrolled. Streptococcus pneumoniae was the most common organism found (30.5%), followed by Legionella pneumophila (17.5%), influenza viruses (15.4%), Mycoplasma pneumoniae (7.2%), Chlamydia pneumonia (5.5%), Mycobacterium tuberculosis (4.8%), Klebsiella pneumoniae (4.8%), methicillin-resistant Staphylococcus aureus (3.5%), Pseudomonas aeruginosa (3.1%), methicillin-sensitive S. aureus (1.7%), and Acinetobacter sp. (0.8%) with 4% of patients having multiple pathogens etiologies. High Pneumonia Severity Index score correlated with the severity and outcome of the CAP but was not predictive of any definite etiological pathogen. In-hospital mortality was 8%. Conclusion: Streptococcus pneumoniae, Legionella, and influenza constitute the most common etiological agents for north Indian adults with CAP requiring hospitalization. Appropriate antibiotic therapy and preventive strategies such as influenza and pneumococcal vaccination need to be considered in appropriate groups. PMID- 29487245 TI - Etiology of community acquired pneumonia among children in India with special reference to atypical pathogens. AB - Objectives: The aim is to identify the etiology of community acquired pneumonia in children with special reference to atypical bacteria and viruses. Materials and Methods: A total of 94 pneumonia children were enrolled in the study. Sixty seven did not have an etiological diagnosis by conventional culture. These children were subjected to immunofluorescence assay by Pneumoslide IgM. Results: Ninety-four children were evaluated for etiology by conventional culture. Twenty seven of them had the bacteriological diagnosis. Rest 67 were further analyzed for causative organism using Pneumoslide immunofluorescence test. Among this group, 38 (56.7%) had etiological diagnosis. Atypical bacteria were identified in 23 cases, most common being Mycoplasma pneumoniae and which was more common between 5 months and 2 years of age. Viruses were identified in 19 cases, and the most common virus was Respiratory syncytial virus. Mixed pathogens were identified in five children., M. pneumoniae was the common offending agent. Conclusions: Atypical bacteria and viruses play an important role as etiological agents in pneumonia in children. Pneumoslide IgM is useful for rapid detection of atypical bacteria and viruses. PMID- 29487246 TI - Computed tomography of solitary fibrous tumor of the pleura abutting the mediastinum: A diagnostic challenge. AB - Background: Solitary fibrous tumor of the pleura (SFTP) arising from the mediastinal pleura may be confused with primary mediastinal tumors. We studied the computerized tomographic (CT) findings of patients with SFTP that could suggest a diagnosis of SFTP. Materials and Methods: At our hospital from January 1995 to June 2012, 39 patients with histologically confirmed SFTP were surgically treated; seven of them abutting the mediastinal pleura. The study group included seven patients aged between 53 and 81 years. Baseline CT scans were retrospectively reviewed to identify radiological findings suggestive of SFTP including: (1) smooth and sharply delineated contours; (2) obtuse, acute, or tapering angles between the lesion and the mediastinum depending on the size; (3) homogeneous soft-tissue attenuation; (4) "geographic pattern" due to the contemporary presence of large vessels, necrosis, and calcifications; (5) displacement of the lung parenchyma; (6) presence of a cleavage plane; and (7) absence of lymphadenopathy or pleural methastasis. Results: All tumors formed acute angles with the pleura. Six out of the seven presented smoothly tapering margins, three had a "geographic pattern" of attenuation and displaced the anterior junction line; one showed an outside junction line development. Four cases had a clear pleural origin. Conclusions: The possibility of SFTP should be taken into account when a mass abuts the mediastinum projecting inside the thoracic cavity in the presence of an intense and "geographical pattern" of enhancement without lymphoadenopathy or pleural metastasis. These findings assume greater significance in the presence of discrepancy between the size of the lesion and the clinical presentation. PMID- 29487247 TI - Body plethysmography in chronic obstructive pulmonary disease patients: A cross sectional study. AB - Background: Chronic obstructive pulmonary disease (COPD) is the fourth most common cause of death in the world, for which smoking is a common cause. It is preferable to diagnose COPD at an earlier stage and to assess its progression so that mortality and morbidity of the disease could be reduced. Hence, we conducted this study to assess parameters of body plethysmography in Indian population where the data are lacking and to assess whether the use of body plethysmography can detect COPD earlier. Subjects and Methods: The study was approved by the Ethics Committee at B. J Government Medical College, Pune. In this comparative randomized cross-sectional study, healthy control subjects (CN), smokers without COPD diagnosis (SM) who were smoking for more than 5 pack-years and smokers with COPD who were further classified depending upon GOLD criteria as mild COPD (C1), moderate COPD (C2), and severe COPD (C3) (n = 30 each group) were considered. All the participants were males who gave written informed consent. Subject underwent routine spirometry (FEV1, FVC, FEV1/FVC, PEFR, and FEF25-75%) along with body plethysmography where sGaweff, sGawtot, residual volume (RV), total lung capacity (TLC), and inspiratory capacity (IC) were recorded. Statistical Analysis: The differences in lung function were compared between healthy controls and smokers and also between the three groups of COPD severity (GOLD guidelines) employing univariate analysis of variance and Bonferroni's post hoc test. Results: Spirometry could not differentiate between smokers without COPD and healthy controls. However, three parameters on body plethysmography (IC, sGawtot, and sGaweff) were sensitive enough to detect differences between smokers without COPD and healthy controls. Conclusion: Using body plethysmography, the vexed question troubling the clinician, which of the smokers progress to COPD and who do not before they develop irreversible changes can perhaps be answered if further large scale multicenter studies and long-term follow-up studies confirm the findings in this study. PMID- 29487248 TI - Association of pediatric obstructive sleep apnea with poor academic performance: A school-based study from India. AB - Background: Pediatric obstructive sleep apnea (OSA) is a highly prevalent but often neglected disorder. There is paucity of reports on the prevalence of pediatric OSA from India. This study was done to estimate the prevalence of OSA in school children aged 5-10 years and its association with academic performance. Methodology: This school-based cross-sectional epidemiological study was conducted from July 2015 to November 2015. A questionnaire seeking information on sociodemographic variables, school performance, sleeping pattern, and a validated 22-item pediatrics sleep-related breathing disorder (SRBD) scale was distributed to 1820 pupils in three primary schools. The prevalence of OSA (defined as SRBD score >33%) was reported as proportion and its 95% confidence interval (CI). Results: We received 1520 questionnaires out of 1820 distributed and of which 1346 were complete and were analyzed. The prevalence of OSA among children in our study was 9.6% (95% CI: 8.1%-11.7%). On multivariate analysis, working mother (adjusted odds ratio [OR]: 1.8; 95% CI: 1.2-2.7), sleep bruxism (adjusted OR: 1.7; 95% CI: 1.1-2.6), and sleep talking (adjusted OR: 3.0; 95% CI: 1.9-4.7) were found to be independently associated with OSA. Students with positive SRBD were more prone to nocturnal enuresis (NE) (OR 3.48; 95% CI 2.27-5.26) and poor academic performance in all subjects. Conclusion: OSA is highly prevalent (9.6%) in Indian children. OSA is associated with NE and poor academic performance in all subjects. This study found association of maternal occupation and OSA which needs to be confirmed in larger studies. PMID- 29487249 TI - Predictors of asthma-chronic obstructive pulmonary disease overlap syndrome in patients with chronic obstructive pulmonary disease from a tertiary care center in India. AB - Background: There is dearth of literature on asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS) in India. The aim was to compare clinical characteristics between patients with ACOS and non-ACOS COPD and to identify clinical predictors of ACOS in patients with COPD. Methods: We conducted a retrospective study by reviewing data collected from patients performing spirometry at our hospital. Those with postbronchodilator FEV1/FVC <70% were included in the study. Among them, those with significant reversibility (change in FEV1or FVC by 12% and 200 ml postbronchodilator) were diagnosed with ACOS and the rest were considered to have non-ACOS COPD. Data on the 2 groups were compared and statistical analysis was performed. Results: Out of a total of 324 patients, 100 of them had postbronchodilator FEV1/FVC <70%. Of them, 45 and 55 were diagnosed with ACOS and non-ACOS COPD, respectively. Patients with ACOS had significantly higher postbronchodilator FVC volumes and FVC % predicted values (P < 0.05), had higher reported wheeze (P = 0.02) and ankle edema (P < 0.05), were more likely to be smokers (P = 0.01) with lower smoking index (P = 0.03), and had frequent (>=2) ER visits (P = 0.04). However, very frequent (>=3 per year) hospital admissions (P < 0.01) with higher rates of invasive mechanical ventilation (P = 0.02), and pulmonary hypertension diagnosed by two-dimensional echocardiography (P < 0.01) were significantly higher in the non-ACOS group. The two groups did not differ with respect to history of atopy, family history of wheeze, compliance to inhaler therapy, or blood absolute eosinophil counts. Conclusion: Our study highlights how the ACOS phenotype may clinically differ from their counterparts elsewhere, making it a clinical challenge to identify them in India. PMID- 29487250 TI - Management of lower respiratory tract infection in outpatient settings: Focus on clarithromycin. AB - Lower respiratory tract infection (LRTI) is a broad terminology which includes acute bronchitis, pneumonia, acute exacerbations of chronic obstructive pulmonary disease/chronic bronchitis (AECB), and acute exacerbation of bronchiectasis. Acute LRTIs (ALRTIs) are one of the common clinical problems in community and hospital settings. Management of community-acquired pneumonia (CAP) and AECB may pose challenges because of diagnostic difficulty in differentiating infections caused by typical and atypical microorganisms and rising rates of antimicrobial resistance. Beta-lactam antibiotics, macrolides, and fluoroquinolones are routinely prescribed medicines for the management of ALRTIs. Macrolides are time tested and effective agents for the treatment of LRTIs. Clarithromycin, a macrolide, offers several benefits in the management of ALRTIs. In this article, we discuss the management approach of LRTIs with focus on clarithromycin in the management of mild-to-moderate LRTIs (CAP and AECB), i.e., in outpatient settings. PMID- 29487252 TI - Pulmonary lymphangioleiomyomatosis presenting as spontaneous pneumothorax treated with sirolimus - A case report. AB - Spontaneous pneumothorax is a very common medical emergency. Patients are often treated without treating the underlying cause. Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease. Until recently, diagnosis of LAM was a challenge with nearly 100% mortality in 10 years, but better understanding of the disease through research and better radiological techniques and newer drugs such as sirolimus has improved the survival in such patients. We are presenting a rare case of LAM presenting as a secondary spontaneous pneumothorax treated with sirolimus. PMID- 29487251 TI - Clinical significance and epidemiological evolution of epitrochlear lymphadenopathy in pre- and post-highly active antiretroviral therapy era: A systematic review of the literature. AB - Epitrochlear lymphadenopathy is believed to be associated with distinct etiologies, however the evidence for the same is lacking. We systematically reviewed the reported causes of an enlarged epitrochlear lymph node and compared them over different time periods. Epitrochlear lymphadenopathy was encountered in a wide range of diseases, and we found no association with any particular disease. PMID- 29487253 TI - Paclitaxel-induced dermal hypersensitivity lesions: 2-deoxy-2-[18F]fluoro-D glucose positron emission tomography/computed tomography. AB - Paclitaxel is frequently used for the treatment of patients with nonsmall cell lung cancer. Hypersensitivity reactions (HSRs) have been one of the toxicities observed with administration of paclitaxel. Here, we presented a case of a 49 year-old man with a history of right lung mass proven by biopsy to be a nonsmall cell lung cancer (squamous cell carcinoma) who developed HSR during therapy. In addition to the hypermetabolic primary malignancy, a positron emission tomography/computed tomography (PET/CT) scan showed multiple hypermetabolic skin lesions at several parts of the body. These cutaneous lesions were resolved in the restaging PET/CT scan performed after completion of the six cycles of chemotherapy. This is the first documented case of comparative PET/CT findings of a paclitaxel-induced hypersensitivity. PMID- 29487254 TI - Histological transformation of adenocarcinoma to small cell carcinoma lung as a rare mechanism of resistance to epidermal growth factor receptor-tyrosine kinase inhibitors: Report of a case with review of literature. AB - A subset of non-small cell lung carcinoma (NSCC) harbor active mutations of epidermal growth factor receptor (EGFR). In these, EGFR tyrosine kinase inhibitors (EGFR-TKIs) are recommended as the first-line treatment. Though drug resistance is inevitable, histological transformation to small cell lung carcinoma (SCLC) is a rare mechanism for acquired resistance. Here we report one such rare case of histological transformation of pulmonary adenocarcinoma to small cell lung carcinoma in 46 year old male treated with Gefitinib. PMID- 29487255 TI - Pulmonary artery leiomyosarcoma: A clinical dilemma. AB - Leiomyosarcomas are rare neoplasms of the smooth muscles. Primary pulmonary leiomyosarcomas, which constitute approximately 0.2%-0.5% of all primary lung malignancies, are extremely rare and highly lethal. They may originate from the smooth muscle cells of the bronchial wall, the blood vessels, or the pulmonary interstitium, and their rare occurrence, localization, and nonspecific clinical symptoms mean that correct diagnosis and proper management are often delayed. Here, we report a rapidly growing primary pulmonary leiomyosarcoma, which invaded the right atrium, vena cava superior, mediastinum, right hilar area, and left pulmonary artery within 4 months. On histopathology, a transthoracic needle biopsy of the mass confirmed leiomyosarcoma, and delayed presentation meant that there was a local spread to the neighboring structures at the time of diagnosis. PMID- 29487256 TI - Pyrosequencing to resolve discrepant Xpert MTB/RIF and Mycobacterial Growth Indicator Tube 960. AB - Delayed diagnosis of drug resistance has been a major obstacle to proper management and control of drug-resistant tuberculosis (TB). Expanded access to rapid molecular diagnostics such as Xpert MTB/RIF has been helpful, but has generated confusion about how to interpret genotype-phenotype discordance. Optimal management is not clearly defined for patients with rifampin resistance by Xpert MTB/RIF but rifampin susceptibility by phenotypic testing. To resolve this discrepancy, we performed pyrosequencing of discordant isolates identified at a reference laboratory over a 6-month period. We present here strategies to address genotype-phenotype discordance using sequencing. PMID- 29487257 TI - A 45-year-old man presenting with chest pain. PMID- 29487258 TI - A rare clinical case presenting as right lower zone shadow. PMID- 29487259 TI - Pulmonary adenocarcinoma presenting with symptoms of ectopic adrenocorticotropic hormone production. PMID- 29487260 TI - Spontaneous rupture of hepatocellular carcinoma with tumor embolism in pulmonary arteries. PMID- 29487261 TI - Surgical management of endobronchial hamartoma. PMID- 29487262 TI - Solitary pulmonary nodule: Increasing diagnosis and accuracy of biopsy by biparametric MR imaging. PMID- 29487263 TI - Barriers to building an effective workforce for respiratory research in India: A survey of American Thoracic Society Methods in Epidemiologic, Clinical, and Operations Research India 2017 participants. PMID- 29487264 TI - Intrathoracic liposarcoma: Case report with emphasis to histogenesis and site of origin classification problems. PMID- 29487265 TI - Tracheoesophageal fistula diagnosis during open tracheostomy. PMID- 29487266 TI - Paediatric ureterolithotripsy: Tips and tricks - Experience at a single center. AB - Background: Paediatric stone disease is very common in certain regions of India. Traditionally, the endourology for the stones even in paediatric age group is managed by adult urologist and paediatric surgeons tend to do open surgeries. The nonavailability of paediatric size equipments and lack of training at the teaching and tertiary care paediatric surgical centers in India are factors due to which there is continued apathy of paediatric surgeons to endourology. The aim of this study was to discuss the feasibility of paediatric ureterolithotripsy for successful procedure. We introduced the paediatric ureterolithotripsy as per the predecided indications of stone size up to 15 mm in paediatric ureterolithiasis at a tertiary care center in rural set up. Subjects and Methods:: Patients up to 18 years of age presenting with ureterolithiasis and not responding to conservative treatment or who needed endourological intervention were included in the study. Results:: Thirty-one patients underwent uretero lithotripsy (URSL) for ureteric calculus with more than 95% clearance rate. Conclusions:: Single-stage paediatric ureterolithotripsy is quite feasible and effective in achieving the stone clearance in paediatric ureterolithiasis. PMID- 29487267 TI - Is the plastibell of any haemostatic value after 24 h? AB - Background: The Plastibell is the most popular circumcision method among mothers in our city. Haemorrhage is its major problem. At our centre, we have recorded many circumcision problems resulting from prolonged retention of the Plastibell ring and this study, therefore, sought to explore the ways of reducing complications resulting from prolonged retention of the ring. Patients and Methods: This was a prospective study, in which a total of sixty consecutive male neonates were recruited with all undergoing circumcision using the Plastibell device. Thirty patients were assigned to the subject group, in whom the Plastibell ring was removed by the investigator at 24 h while the other thirty constituted the control group whose Plastibell rings were allowed to fall off on their own. The patients selected were aged between 7 and 28 days. Results: Overall, 4 (6.6%) of the sixty neonatal circumcisions in this study were complicated by haemorrhage. There was minor bleeding in 3 (10%) of the thirty subjects and 1 (3.3%) of the thirty controls. There was no statistically significant difference between the groups (P = 0.3006). One patient each from the subject and control groups bled following slipped ligature a few hours after Plastibell circumcision. The other two patients in the subject group bled following the removal of the Plastibell ring at 24 h. All the bleeding episodes were effectively controlled within 5 min by firm digital pressure only administered through a piece of dry, sterile gauze. Conclusion: Post-circumcision haemorrhage was not significantly different between circumcised babies whose Plastibell rings were removed at 24 h and those in whom it was left to fall off on its own. PMID- 29487268 TI - Delayed primary end-to-end anastomosis for traumatic long segment urethral stricture and its short-term outcomes. AB - Background:: The purpose of this study is to evaluate the aetiology of posterior urethral stricture in children and analysis of results after delayed primary repair with extensive distal urethral mobilisation. Materials and Methods: This was a retrospective study carried out in a tertiary care centre from January 2009 to December 2013. Results:: Eight children with median age 7.5 years (range 4-11 years), underwent delayed anastomotic urethroplasty: Six through perineal and two through combined perineal and transpubic approach. All the eight children had long-segment >2 cm stricture: Three posterior and five anterior urethral stricture. On a mean follow-up period of 33 months (range 24-48 m), all were passing urine with good flow and stream. Conclusion:: End-to-end anastomosis in post-traumatic long segment posterior urethral stricture between prostatic and penile urethra in children is possible by perineal or combined perineal and transpubic approach with good results without any urethral replacement. PMID- 29487269 TI - Chronic recurrent vomiting associated with primary gastric volvulus in infant: A case report and review of literature. AB - Gastric volvulus is an uncommon entity found in the paediatric population. We are reporting a case of chronic gastric volvulus presented to us with the complaints of recurrent vomiting after each feed. The vomiting was projectile, nonbilious, and the content was milk. The patient was evaluated by clinical and radiological means in the form of the X-ray abdomen, ultrasound abdomen, upper gastrointestinal (GI) contrast study, and computed tomography scan of the abdomen. The upper GI contrast study was suggestive of gastric volvulus. The patient was operated and gastropexy was done. There was lax gastrocolic ligament with increased distance between stomach and transverse colon without any obvious gastric volvulus. Postsurgery, the patient was symptom-free. PMID- 29487270 TI - Successful reconstruction of congenital perineal skin defect using gluteal-fold bilobed perforator flap. AB - Perineovaginorectal defect usually requires surgical repair; however, direct closure often leads to dehiscence. We present two patients with a congenital perineal skin defect who were successfully treated using a gluteal-fold bilobed perforator flap. This flap facilitates esthetic restoration and a more natural perineovaginorectal appearance, using only a one-stage procedure. This technique may be a favorable option for perineal and genital repair. PMID- 29487271 TI - Pre-exposure and Post-exposure prophylaxis for dog bites. PMID- 29487272 TI - Erratum: Transanal protrusion of intussusception in children. AB - [This corrects the article DOI: 10.4103/0189-6725.137331]. PMID- 29487273 TI - A Novel Tetrameric Assembly Configuration in VV2_1132, a LysR-Type Transcriptional Regulator in Vibrio vulnificus. AB - LysR-type transcriptional regulators (LTTRs) contain an N-terminal DNA binding domain (DBD) and a C-terminal regulatory domain (RD). Typically, LTTRs function as homotetramers. VV2_1132 was identified in Vibrio vulnificus as an LTTR that is a homologue of HypT (also known as YjiE or QseD) in Escherichia coli. In this study, we determined the crystal structure of full-length VV2_1132 at a resolution of 2.2 A, thereby revealing a novel combination of the domains in the tetrameric assembly. Only one DBD dimer in the tetramer can bind to DNA, because the DNA binding motifs of the other DBD dimer are completely buried in the tetrameric assembly. Structural and functional analyses of VV2_1132 suggest that it might not perform the same role as E. coli HypT, indicating that further study is required to elucidate the function of this gene in V. vulnificus. The unique structure of VV2_1132 extends our knowledge of LTTR function and mechanisms of action. PMID- 29487274 TI - Evolution and Design Principles of the Diverse Chloroplast Transit Peptides. AB - Chloroplasts are present in organisms belonging to the kingdom Plantae. These organelles are thought to have originated from photosynthetic cyanobacteria through endosymbiosis. During endosymbiosis, most cyanobacterial genes were transferred to the host nucleus. Therefore, most chloroplast proteins became encoded in the nuclear genome and must return to the chloroplast after translation. The N-terminal cleavable transit peptide (TP) is necessary and sufficient for the import of nucleus-encoded interior chloroplast proteins. Over the past decade, extensive research on the TP has revealed many important characteristic features of TPs. These studies have also shed light on the question of how the many diverse TPs could have evolved to target specific proteins to the chloroplast. In this review, we summarize the characteristic features of TPs. We also highlight recent advances in our understanding of TP evolution and provide future perspectives about this important research area. PMID- 29487275 TI - Identification of the Regulatory Region Responsible for Vascular Tissue-Specific Expression in the Rice Hd3a Promoter. AB - Flowering time is determined by florigens. These genes include, Heading date 3a (Hd3a) and Rice FT 1 (RFT1) in rice, which are specifically expressed in the vascular tissues of leaves at the floral transition stage. To study the cis regulatory elements present in the promoter region of Hd3a, we generated transgenic plants carrying the 1.75-kb promoter fragment of Hd3a that was fused to the beta-glucuronidase (GUS) reporter gene. Plants expressing this construct conferred a vascular cell-specific expression pattern for the reporter gene. However, GUS was expressed in leaves at all developmental stages, including the early seedling stage when Hd3a was not detected. Furthermore, the reporter was expressed in roots at all stages. This suggests that the 1.75-kb region lackings cis-elements that regulate leaf-specific expression at the appropriate developmental stages. Deletion analyses of the promoter region indicated that regulatory elements determining vascular cell-specific expression are present in the 200-bp region between -245 bp and -45 bp from the transcription initiation site. By transforming the Hd3a-GUS construct to rice cultivar 'Taichung 65' which is defective in Ehd1, we observed that Ehd1 is the major regulatory element that controls Hd3a promoter activity. PMID- 29487276 TI - Transcriptional Repression of High-Mobility Group Box 2 by p21 in Radiation Induced Senescence. AB - High mobility group box 2 (HMGB2) is an abundant, chromatin-associated, non histone protein involved in transcription, chromatin remodeling, and recombination. Recently, the HMGB2 gene was found to be significantly downregulated during senescence and shown to regulate the expression of senescent associated secretory proteins. Here, we demonstrate that HMGB2 transcription is repressed by p21 during radiation-induced senescence through the ATM-p53-p21 DNA damage signaling cascade. The loss of p21 abolished the downregulation of HMGB2 caused by ionizing radiation, and the conditional induction of p21 was sufficient to repress the transcription of HMGB2. We also showed that the p21 protein binds to the HMGB2 promoter region, leading to sequestration of RNA polymerase and transcription factors E2F1, Sp1, and p300. In contrast, NF-Y, a CCAAT box-binding protein complex, is required for the expression of HMGB2, but NF-Y binding to the HMGB2 promoter was unaffected by either radiation or p21 induction. A proximity ligation assay results confirmed that the chromosome binding of E2F1 and Sp1 was inhibited by p21 induction. As HMGB2 have been shown to regulate premature senescence by IR, targeting the p21-mediated repression of HMGB2 could be a strategy to overcome the detrimental effects of radiation-induced senescence. PMID- 29487277 TI - AtMyb56 Regulates Anthocyanin Levels via the Modulation of AtGPT2 Expression in Response to Sucrose in Arabidopsis. AB - Sucrose is a crucial compound for the growth and development of plants, and the regulation of multiple genes depends on the amount of soluble sugars present. Sucrose acts as a signaling molecule that regulates a proton-sucrose symporter, with its sensor being the sucrose transporter. Flavonoid and anthocyanin biosynthesis are regulated by sucrose, and sucrose signaling can affect flavonoid and anthocyanin accumulation. In the present study, we found a Myb transcription factor affecting accumulation of anthocyanin. AtMyb56 showed an increase in its expression in response to sucrose treatment. Under normal conditions, anthocyanin accumulation was similar between Col-0 (wild type) and atmyb56 mutant seedlings; however, under sucrose treatment, the level of anthocyanin accumulation was lower in the atmyb56 mutant plants than in Col-0 plants. Preliminary microarray analysis led to the investigation of the expression of one candidate gene, AtGPT2, in the atmyb56 mutant. The phosphate translocator, which is a plastidial phosphate antiporter family, catalyzes the import of glucose-6-phosphate (G-6-P) into the chloroplast. AtGPT2 gene expression was altered in atmyb56 seedlings in a sucrose-dependent manner in response to circadian cycle. Furthermore, the lack of AtMyb56 resulted in altered accumulation of maltose in a sucrose-dependent manner. Therefore, the sucrose responsive AtMyb56 regulates AtGPT2 gene expression in a sucrose-dependent manner to modulate maltose and anthocyanin accumulations in response to the circadian cycle. PMID- 29487278 TI - Post-Transcriptional Control of Tropoelastin in Aortic Smooth Muscle Cells Affects Aortic Dissection Onset. AB - Aortic dissection (AD) is a catastrophic disease with high mortality and morbidity, characterized with fragmentation of elastin and loss of smooth muscle cells. Although AD has been largely attributable to polymorphisms defect in the elastin-coding gene, tropoelastin (TE), other undermined factors also appear to play roles in AD onset. Here, we investigated the effects of post-transcriptional control of TE by microRNAs (miRNAs) on elastin levels in aortic smooth muscle cells (ASMC). We found that miR-144-3p is a miRNA that targets TE mRNA in both human and mouse. Bioinformatics analyses and dual luciferase reporter assay showed that miR-144-3p inhibited protein translation of TE, through binding to the 3'-UTR of the TE mRNA. Interestingly, higher miR-144-3p levels and lower TE were detected in the ASMC obtained from AD patients, compared to those from non AD controls. In a mouse model for human AD, infusion of adeno-associated viruses (serotype 6) carrying antisense for miR-144-3p (as-miR-144-3p) under CAG promoter significantly reduced the incidence and severity of AD, seemingly through enhancement of TE levels in ASMC. Thus, our data suggest an essential role of miR 144-3p on the pathogenesis of AD. PMID- 29487279 TI - Diffuse Alveolar Hemorrhage without Extrapulmonary Manifestations: A Rare Presentation of Lupus. AB - BACKGROUND Diffuse alveolar hemorrhage (DAH) is a life-threatening disorder resulting in hemorrhage into the lungs due to a variety of reasons. The underlying etiology for DAH is broadly divided into immune and non-immune mediated causes. Rheumatological disorders account for a small number of cases. Although hemoptysis is one of the alarming symptoms of DAH, it is absent in a third of the cases. Diagnosis often requires a conglomerate of history, clinical, and laboratory investigation and radiological studies. CASE REPORT We describe a case of a 31-year-old female who had an atypical presentation of systemic lupus erythematosus (SLE) with primary lung involvement/DAH and no other organ involvement. CONCLUSIONS This case report illustrates the importance of awareness and early recognition of the complication that can prevent mortality. PMID- 29487280 TI - Reduction of Abeta Generation by Schisandrin B through Restraining Beta-Secretase 1 Transcription and Translation. AB - BACKGROUND Beta-secretase 1 (BACE1) is a rate-limiting enzyme in the generation of amyloid beta peptides, which are associated with Alzheimer's disease (AD). It has been reported that Schisandrin B could improve cognitive functions in animal models of AD, but the underlying mechanisms are not completely understood. MATERIAL AND METHODS In this research, in order to investigate the effects of Schisandrin B on amyloid-beta (Abeta) metabolism and its mechanisms, amyloid precursor protein (APP) and its proteolytic products were determined by enzyme linked immunosorbent assay (ELISA), western blotting, and RT-PCR after incubation of N2a/Swe cells with Schisandrin B. RESULTS The results indicated that Schisandrin B can significantly reduce the level of secretion of Abeta40 and Abeta42 secreted in N2a/Swe cells. Additionally, there was nonsignificant change in APP level after Schisandrin B treatment. Treatment of Schisandrin B dramatically reduced the mRNA and protein expression levels of BACE1. Moreover, Schisandrin B treatment resulted in a reduction of protein level of sAPPbeta, an APP fragment cleavage by BACE1. CONCLUSIONS These results suggest that Schisandrin B inhibits the transcription and translation of BACE1, suppresses the activity of BACE1, and ultimately attenuates Abeta generation, which provides a novel mechanism for the regulation of Abeta metabolism by Schisandrin B. PMID- 29487281 TI - Tailed giant Tupanvirus possesses the most complete translational apparatus of the known virosphere. AB - Here we report the discovery of two Tupanvirus strains, the longest tailed Mimiviridae members isolated in amoebae. Their genomes are 1.44-1.51 Mb linear double-strand DNA coding for 1276-1425 predicted proteins. Tupanviruses share the same ancestors with mimivirus lineages and these giant viruses present the largest translational apparatus within the known virosphere, with up to 70 tRNA, 20 aaRS, 11 factors for all translation steps, and factors related to tRNA/mRNA maturation and ribosome protein modification. Moreover, two sequences with significant similarity to intronic regions of 18 S rRNA genes are encoded by the tupanviruses and highly expressed. In this translation-associated gene set, only the ribosome is lacking. At high multiplicity of infections, tupanvirus is also cytotoxic and causes a severe shutdown of ribosomal RNA and a progressive degradation of the nucleus in host and non-host cells. The analysis of tupanviruses constitutes a new step toward understanding the evolution of giant viruses. PMID- 29487282 TI - G-protein betagamma subunits determine grain size through interaction with MADS domain transcription factors in rice. AB - The simultaneous improvement of grain quality and yield of cereal crops is a major challenge for modern agriculture. Here we show that a rice grain yield quantitative trait locus qLGY3 encodes a MADS-domain transcription factor OsMADS1, which acts as a key downstream effector of G-protein betagamma dimers. The presence of an alternatively spliced protein OsMADS1lgy3 is shown to be associated with formation of long and slender grains, resulting in increases in both grain quality and yield potential of rice. The Ggamma subunits GS3 and DEP1 interact directly with the conserved keratin-like domain of MADS transcription factors, function as cofactors to enhance OsMADS1 transcriptional activity and promote the co-operative transactivation of common target genes, thereby regulating grain size and shape. We also demonstrate that combining OsMADS1 lgy3 allele with high-yield-associated dep1-1 and gs3 alleles represents an effective strategy for simultaneously improving both the productivity and end-use quality of rice. PMID- 29487283 TI - Glucose metabolism and NRF2 coordinate the antioxidant response in melanoma resistant to MAPK inhibitors. AB - Targeted therapies as BRAF and MEK inhibitor combination have been approved as first-line treatment for BRAF-mutant melanoma. However, disease progression occurs in most of the patients within few months of therapy. Metabolic adaptations have been described in the context of acquired resistance to BRAF inhibitors (BRAFi). BRAFi-resistant melanomas are characterized by an increase of mitochondrial oxidative phosphorylation and are more prone to cell death induced by mitochondrial-targeting drugs. BRAFi-resistant melanomas also exhibit an enhancement of oxidative stress due to mitochondrial oxygen consumption increase. To understand the mechanisms responsible for survival of BRAFi-resistant melanoma cells in the context of oxidative stress, we have established a preclinical murine model that accurately recapitulates in vivo the acquisition of resistance to MAPK inhibitors including several BRAF or MEK inhibitors alone and in combination. Using mice model and melanoma cell lines generated from mice tumors, we have confirmed that the acquisition of resistance is associated with an increase in mitochondrial oxidative phosphorylation as well as the importance of glutamine metabolism. Moreover, we have demonstrated that BRAFi-resistant melanoma can adapt mitochondrial metabolism to support glucose-derived glutamate synthesis leading to increase in glutathione content. Besides, BRAFi-resistant melanoma exhibits a strong activation of NRF-2 pathway leading to increase in the pentose phosphate pathway, which is involved in the regeneration of reduced glutathione, and to increase in xCT expression, a component of the xc-amino acid transporter essential for the uptake of cystine required for intracellular glutathione synthesis. All these metabolic modifications sustain glutathione level and contribute to the intracellular redox balance to allow survival of BRAFi-resistant melanoma cells. PMID- 29487284 TI - Opponent control of behavioral reinforcement by inhibitory and excitatory projections from the ventral pallidum. AB - The ventral pallidum (VP) lies at the interface between sensory, motor, and cognitive processing-with a particular role in mounting behavioral responses to rewards. Though the VP is predominantly GABAergic, glutamate neurons were recently identified, though their relative abundances and respective roles are unknown. Here, we show that VP glutamate neurons are concentrated in the rostral ventromedial VP and project to qualitatively similar targets as do VP GABA neurons. At the functional level, we used optogenetics to show that activity in VP GABA neurons can drive positive reinforcement, particularly through projections to the ventral tegmental area (VTA). On the other hand, activation of VP glutamate neurons leads to behavioral avoidance, particularly through projections to the lateral habenula. These findings highlight cell-type and projection-target specific roles for VP neurons in behavioral reinforcement, dysregulation of which could contribute to the emergence of negative symptoms associated with drug addiction and other neuropsychiatric disease. PMID- 29487285 TI - NAD+ analog reveals PARP-1 substrate-blocking mechanism and allosteric communication from catalytic center to DNA-binding domains. AB - PARP-1 cleaves NAD+ and transfers the resulting ADP-ribose moiety onto target proteins and onto subsequent polymers of ADP-ribose. An allosteric network connects PARP-1 multi-domain detection of DNA damage to catalytic domain structural changes that relieve catalytic autoinhibition; however, the mechanism of autoinhibition is undefined. Here, we show using the non-hydrolyzable NAD+ analog benzamide adenine dinucleotide (BAD) that PARP-1 autoinhibition results from a selective block on NAD+ binding. Following DNA damage detection, BAD binding to the catalytic domain leads to changes in PARP-1 dynamics at distant DNA-binding surfaces, resulting in increased affinity for DNA damage, and providing direct evidence of reverse allostery. Our findings reveal a two-step mechanism to activate and to then stabilize PARP-1 on a DNA break, indicate that PARP-1 allostery influences persistence on DNA damage, and have important implications for PARP inhibitors that engage the NAD+ binding site. PMID- 29487286 TI - Multi-indicator sustainability assessment of global food systems. AB - Food systems are at the heart of at least 12 of the 17 Sustainable Development Goals (SDGs). The wide scope of the SDGs call for holistic approaches that integrate previously "siloed" food sustainability assessments. Here we present a first global-scale analysis quantifying the status of national food system performance of 156 countries, employing 25 sustainability indicators across 7 domains as follows: nutrition, environment, food affordability and availability, sociocultural well-being, resilience, food safety, and waste. The results show that different countries have widely varying patterns of performance with unique priorities for improvement. High-income nations score well on most indicators, but poorly on environmental, food waste, and health-sensitive nutrient-intake indicators. Transitioning from animal foods toward plant-based foods would improve indicator scores for most countries. Our nation-specific quantitative results can help policy-makers to set improvement targets on specific areas and adopt new practices, while keeping track of the other aspects of sustainability. PMID- 29487287 TI - On the relative motions of long-lived Pacific mantle plumes. AB - Mantle plumes upwelling beneath moving tectonic plates generate age-progressive chains of volcanos (hotspot chains) used to reconstruct plate motion. However, these hotspots appear to move relative to each other, implying that plumes are not laterally fixed. The lack of age constraints on long-lived, coeval hotspot chains hinders attempts to reconstruct plate motion and quantify relative plume motions. Here we provide 40Ar/39Ar ages for a newly identified long-lived mantle plume, which formed the Rurutu hotspot chain. By comparing the inter-hotspot distances between three Pacific hotspots, we show that Hawaii is unique in its strong, rapid southward motion from 60 to 50 Myrs ago, consistent with paleomagnetic observations. Conversely, the Rurutu and Louisville chains show little motion. Current geodynamic plume motion models can reproduce the first order motions for these plumes, but only when each plume is rooted in the lowermost mantle. PMID- 29487288 TI - Attosecond recorder of the polarization state of light. AB - High harmonic generation in multi-color laser fields opens the opportunity of generating isolated attosecond pulses with high ellipticity. Such pulses hold the potential for time-resolving chiral electronic, magnetization, and spin dynamics at their natural timescale. However, this potential cannot be realized without characterizing the exact polarization state of light on the attosecond timescale. Here we propose and numerically demonstrate a complete solution of this problem. Our solution exploits the extrinsic two-dimensional chirality induced in an atom interacting with the chiral attosecond pulse and a linearly polarized infrared probe. The resulting asymmetry in the photoelectron spectra allows to reconstruct the complete polarization state of the attosecond pulse, including its possible time dependence. The challenging problem of distinguishing circularly polarized, partially polarized, or unpolarized pulses in the extreme ultraviolet range is also resolved. We expect this approach to become the core ingredient for attosecond measurements of chiral-sensitive processes in gas and condensed phase. PMID- 29487289 TI - Meta- and cross-species analyses of insulin resistance based on gene expression datasets in human white adipose tissues. AB - Ample evidence indicates that insulin resistance (IR) is closely related to white adipose tissue (WAT), but the underlying mechanisms of IR pathogenesis are still unclear. Using 352 microarray datasets from seven independent studies, we identified a meta-signature which comprised of 1,413 genes. Our meta-signature was also enriched in overall WAT in in vitro and in vivo IR models. Only 12 core enrichment genes were consistently enriched across all IR models. Among the meta signature, we identified a drug signature made up of 211 genes with expression levels that were co-regulated by thiazolidinediones and metformin using cross species analysis. To confirm the clinical relevance of our drug signature, we found that the expression levels of 195 genes in the drug signature were significantly correlated with both homeostasis model assessment 2-IR score and body mass index. Finally, 18 genes from the drug signature were identified by protein-protein interaction network cluster. Four core enrichment genes were included in 18 genes and the expression levels of selected 8 genes were validated by quantitative PCR. These findings suggest that our signatures provide a robust set of genetic markers which can be used to provide a starting point for developing potential therapeutic targets in improving IR in WAT. PMID- 29487290 TI - Src-mediated regulation of the PI3K pathway in advanced papillary and anaplastic thyroid cancer. AB - Advanced stages of papillary and anaplastic thyroid cancer continue to be plagued by a dismal prognosis, which is a result of limited effective therapies for these cancers. Due to the high proportion of thyroid cancers harboring mutations in the MAPK pathway, the MAPK pathway has become a focal point for therapeutic intervention in thyroid cancer. Unfortunately, unlike melanoma, a similar responsiveness to MAPK pathway inhibition has yet to be observed in thyroid cancer patients. To address this issue, we have focused on targeting the non receptor tyrosine kinase, Src, and we and others have demonstrated that targeting Src results in inhibition of growth, invasion, and migration both in vitro and in vivo, which can be enhanced through the combined inhibition of Src and the MAPK pathway. Therefore, we examined the efficacy of the combination therapy across a panel of thyroid cancer cell lines representing common oncogenic drivers (BRAF, RAS, and PIK3CA). Interestingly, combined inhibition of Src and the MAPK pathway overcomes intrinsic dasatinib resistance in cell lines where both the MAPK and PI3K pathways are inhibited, which we show is likely due to the regulation of the PI3K pathway by Src in these responsive cells. Interestingly, we have mapped downstream phosphorylation of rpS6 as a key biomarker of response, and cells that maintain rpS6 phosphorylation likely represent drug tolerant persisters. Altogether, the combined inhibition of Src and the MAPK pathway holds great promise for improving the overall survival of advanced thyroid cancer patients with BRAF and RAS mutations, and activation of the PI3K pathway and rpS6 phosphorylation represent important biomarkers of response for patients treated with this therapy. PMID- 29487291 TI - Evidence that DNA polymerase delta contributes to initiating leading strand DNA replication in Saccharomyces cerevisiae. AB - To investigate nuclear DNA replication enzymology in vivo, we have studied Saccharomyces cerevisiae strains containing a pol2-16 mutation that inactivates the catalytic activities of DNA polymerase epsilon (Pol epsilon). Although pol2 16 mutants survive, they present very tiny spore colonies, increased doubling time, larger than normal cells, aberrant nuclei, and rapid acquisition of suppressor mutations. These phenotypes reveal a severe growth defect that is distinct from that of strains that lack only Pol epsilon proofreading (pol2-4), consistent with the idea that Pol epsilon is the major leading-strand polymerase used for unstressed DNA replication. Ribonucleotides are incorporated into the pol2-16 genome in patterns consistent with leading-strand replication by Pol delta when Pol epsilon is absent. More importantly, ribonucleotide distributions at replication origins suggest that in strains encoding all three replicases, Pol delta contributes to initiation of leading-strand replication. We describe two possible models. PMID- 29487292 TI - Reactive gaseous mercury is generated from chloralkali factories resulting in extreme concentrations of mercury in hair of workers. AB - Occupational exposure of chloralkali workers to highly concentrated mercury (Hg) vapour has been linked to an increased risk of renal dysfunction and behavioural changes. It is generally believed that these workers are exposed to elemental Hg, which is used in abundance during the production process however, the lack in analytical techniques that would allow for identification of gaseous Hg species poses a challenge, which needs to be addressed in order to reach a consensus. Here, we present the results from simulated exposure studies, which provide sound evidence of higher adsorption rate of HgCl2 than Hg0 and its irreversible bonding on the surface of hair. We found that chloralkali workers were exposed to HgCl2, which accumulated in extremely high concentrations on the hair surface, more than 1,000 times higher than expected from unexposed subjects and was positively correlated with Hg levels in the finger- and toenails. PMID- 29487293 TI - Impact of weight changes on the incidence of diabetes mellitus: a Korean nationwide cohort study. AB - Obesity is a well-known risk factor for type 2 diabetes, but few data exist on the association between weight changes and diabetes risk in non-obese subjects. This study aimed to investigate the effect of weight changes on the incidence of type 2 diabetes in Korea, using 51,405 non-diabetic subjects. Individuals who developed type 2 diabetes were more likely to be older and male, to have high body mass index (BMI), blood pressure, fasting blood glucose, and total cholesterol, to be current smokers and frequent drinkers, to be hypertensive and hyperlipidemic, and to have a family history of diabetes, compared to those without type 2 diabetes. Compared with the consistently non-obese group, there was a higher hazard ratio for incident diabetes (95% confidence interval) in subjects becoming obese [1.49 (1.26-1.77)] and remaining obese [2.56 (2.34-2.81)] after adjustment for confounding factors. Decreased BMI was significantly associated with lower risks for incident diabetes and the trends were more evident in the non-obese group. However, overall there was no significant association of increased BMI with incident diabetes. In conclusion, weight loss was significantly associated with lower risk for diabetes both in non-obese and obese Koreans, but particularly in the non-obese. PMID- 29487294 TI - Creating a 3D microbial and chemical snapshot of a human habitat. AB - One of the goals of forensic science is to identify individuals and their lifestyle by analyzing the trace signatures left behind in built environments. Here, microbiome and metabolomic methods were used to see how its occupants used an office and to also gain insights into the lifestyle characteristics such as diet, medications, and personal care products of the occupants. 3D molecular cartography, a molecular visualization technology, was used in combination with mass spectrometry and microbial inventories to highlight human-environmental interactions. Molecular signatures were correlated with the individuals as well as their interactions with this indoor environment. There are person-specific chemical and microbial signatures associated with this environment that directly relate who had touched objects such as computers, computer mice, cell phones, desk phone, table or desks. By combining molecular and microbial investigation forensic strategies, this study offers novel insights to investigators who value the reconstructing of human lifestyle and characterization of human environmental interaction. PMID- 29487295 TI - Evidences for a New Role of miR-214 in Chondrogenesis. AB - miR-214 is known to play a role in mammalian skeletal development through inhibition of osteogenesis and stimulation of osteoclastogenesis, but data regarding other vertebrates, as well as a possible role in chondrogenesis, remain unknown. Here, we show that miR-214 expression is detected in bone and cartilage of zebrafish skeleton, and is downregulated during murine ATDC5 chondrocyte differentiation. Additionally, we observed a conservation of the transcriptional regulation of miR-214 primary transcript Dnm3os in vertebrates, being regulated by Ets1 in ATDC5 chondrogenic cells. Moreover, overexpression of miR-214 in vitro and in vivo mitigated chondrocyte differentiation probably by targeting activating transcription factor 4 (Atf4). Indeed, miR-214 overexpression in vivo hampered cranial cartilage formation of zebrafish and coincided with downregulation of atf4 and of the key chondrogenic players sox9 and col2a1. We show that miR-214 overexpression exerts a negative role in chondrogenesis by impacting on chondrocyte differentiation possibly through conserved mechanisms. PMID- 29487296 TI - Solid-phase synthesis of protein-polymers on reversible immobilization supports. AB - Facile automated biomacromolecule synthesis is at the heart of blending synthetic and biologic worlds. Full access to abiotic/biotic synthetic diversity first occurred when chemistry was developed to grow nucleic acids and peptides from reversibly immobilized precursors. Protein-polymer conjugates, however, have always been synthesized in solution in multi-step, multi-day processes that couple innovative chemistry with challenging purification. Here we report the generation of protein-polymer hybrids synthesized by protein-ATRP on reversible immobilization supports (PARIS). We utilized modified agarose beads to covalently and reversibly couple to proteins in amino-specific reactions. We then modified reversibly immobilized proteins with protein-reactive ATRP initiators and, after ATRP, we released and analyzed the protein polymers. The activity and stability of PARIS-synthesized and solution-synthesized conjugates demonstrated that PARIS was an effective, rapid, and simple method to generate protein-polymer conjugates. Automation of PARIS significantly reduced synthesis/purification timelines, thereby opening a path to changing how to generate protein-polymer conjugates. PMID- 29487297 TI - Structure, computational and biochemical analysis of PcCel45A endoglucanase from Phanerochaete chrysosporium and catalytic mechanisms of GH45 subfamily C members. AB - The glycoside hydrolase family 45 (GH45) of carbohydrate modifying enzymes is mostly comprised of beta-1,4-endoglucanases. Significant diversity between the GH45 members has prompted the division of this family into three subfamilies: A, B and C, which may differ in terms of the mechanism, general architecture, substrate binding and cleavage. Here, we use a combination of X-ray crystallography, bioinformatics, enzymatic assays, molecular dynamics simulations and site-directed mutagenesis experiments to characterize the structure, substrate binding and enzymatic specificity of the GH45 subfamily C endoglucanase from Phanerochaete chrysosporium (PcCel45A). We investigated the role played by different residues in the binding of the enzyme to cellulose oligomers of different lengths and examined the structural characteristics and dynamics of PcCel45A that make subfamily C so dissimilar to other members of the GH45 family. Due to the structural similarity shared between PcCel45A and domain I of expansins, comparative analysis of their substrate binding was also carried out. Our bioinformatics sequence analyses revealed that the hydrolysis mechanisms in GH45 subfamily C is not restricted to use of the imidic asparagine as a general base in the "Newton's cradle" catalytic mechanism recently proposed for this subfamily. PMID- 29487298 TI - Symmetry between repulsive and attractive interactions in driven-dissipative Bose Hubbard systems. AB - The driven-dissipative Bose-Hubbard model can be experimentally realized with either negative or positive onsite detunings, inter-site hopping energies, and onsite interaction energies. Here we use one-dimensional matrix product density operators to perform a fully quantum investigation of the dependence of the non equilibrium steady states of this model on the signs of these parameters. Due to a symmetry in the Lindblad master equation, we find that simultaneously changing the sign of the interaction energies, hopping energies, and chemical potentials leaves the local boson number distribution and inter-site number correlations invariant, and the steady-state complex conjugated. This shows that all driven dissipative phenomena of interacting bosons described by the Lindblad master equation, such as "fermionization" and "superbunching", can equivalently occur with attractive or repulsive interactions. PMID- 29487299 TI - Differential modulation of the auditory steady state response and inhibitory gating by chloral hydrate anesthesia. AB - Auditory steady state response (ASSR) and inhibitory gating (IG) are electrophysiological examinations commonly used to evaluate the sensory and cognitive functions of the brain. In some clinic examinations and animal experiments, general anesthesia is necessary to conduct electrophysiological recordings. However, the effects of anesthesia on ASSR and IG remain unclear. For this reason, we recorded local field potentials though electrodes implanted in different brain areas of rats: the auditory cortex (AC), hippocampus (HC), amygdala (AMY), and prefrontal cortex (PFC), and compared the characteristics of ASSR and IG under anesthetized and conscious conditions. We found that ASSR signals were the strongest in the AC, and decreased sequentially in the HP, AMY, and PFC. Chloral hydrate anesthesia significantly reduced the power and phase locking of ASSR in the AC, HP, and AMY. In contrast, the extent of IG in the AC was weakest and it increased sequentially in the HP, AMY, and PFC. Anesthesia had less effect on the extent of IG. Our results suggest that ASSR and IG may originate from different neural circuits and that IG is more resistant to general anesthesia and therefore better suited to examining the functioning of non auditory brain regions. PMID- 29487300 TI - Rational Design, Synthesis and Biological Evaluation of Pyrimidine-4,6-diamine derivatives as Type-II inhibitors of FLT3 Selective Against c-KIT. AB - FMS-like Tyrosine Kinase 3 (FLT3) is a clinically validated target for acute myeloid leukemia (AML). Inhibitors targeting FLT3 have been evaluated in clinical studies and have exhibited potential to treat FLT3-driven AML. A frequent, clinical limitation is FLT3 selectivity, as concomitant inhibition of FLT3 and c KIT is thought to cause dose-limiting myelosuppression. Through a rational design approach, novel FLT3 inhibitors were synthesized employing a pyridine/pyrimidine warhead. The most potent compound identified from the studies is compound 13a, which exhibited an IC50 value of 13.9 +/- 6.5 nM against the FLT3 kinase with high selectivity over c-KIT. Mechanism of action studies suggested that 13a is a Type-II kinase inhibitor, which was also supported through computer aided drug discovery (CADD) efforts. Cell-based assays identified that 13a was potent on a variety of FLT3-driven cell lines with clinical relevance. We report herein the discovery and therapeutic evaluation of 4,6-diamino pyrimidine-based Type-II FLT3 inhibitors, which can serve as a FLT3-selective scaffold for further clinical development. PMID- 29487301 TI - Hydrodynamic Choreographies of Microswimmers. AB - We unveil orbital topologies of two nearby swimming microorganisms using an artificial microswimmer, called Quadroar. Depending on the initial conditions of the microswimmers, we find diverse families of attractors including dynamical equilibria, bound orbits, braids, and pursuit-evasion games. We also observe a hydrodynamic slingshot effect: a system of two hydrodynamically interacting swimmers moving along braids can advance in space faster than non-interacting swimmers that have the same actuation parameters and initial conditions as the interacting ones. Our findings suggest the existence of complex collective behaviors of microswimmers, from equilibrium to rapidly streaming states. PMID- 29487302 TI - Anisotropic N-Graphene-diffused Co3O4 nanocrystals with dense upper-zone top-on plane exposure facets as effective ORR electrocatalysts. AB - We provide strong evidence of the effectiveness of homogenously self-propelled particle-in-particle diffusion, interaction and growth protocol. This technique was used for one-pot synthesis of novel nitrogen-graphene oxide (N-GO)/Co3O4 nanocrystals with cuboid rectangular prism-shaped nanorods (NRs) along {110} plane and truncated polyhedrons with densely-exposed, multi-facet sites along {311} and {111} planes. These hierarchal nanocrystals create electrode catalyst patterns with vast-range accessibility to active Co2+ sites, a vascular system for the transport and retention of captured O2 molecule interiorly, and low adsorption energy and dense electron configuration surfaces during the oxygen reduction reaction (ORR). The superior electrocatalytic ORR activity of the N GO/Co3O4 polyhedron nanocrystals in terms of electrochemical selectivity, durability and stability compared with NRs or commercial Pt/C catalysts confirms the synergetic contribution of multi-functional, dense-exposed, and actively topographic facets of polyhedrons to significantly activate the catalytic nature of the catalyst. Our findings show real evidence, for the first time that not only the large number of catalytically active Co2+ cations at the top surface layer but also the dense location of active Co2+ sites on the upper-zone top-on plane exposure, and the electron density configuration and distribution around the Co2+ sites were important for effective ORR. PMID- 29487304 TI - Small-Angle Twist Grain Boundaries as Sinks for Point Defects. AB - It is known that grain boundaries (GBs) provide sinks for defects induced into a solid by irradiation. At the same time radiation can change the atomic structure and chemistry of GBs, which in turn impacts the ability of GBs to continue absorbing defects. Although a number of studies have been reported for tilt GBs acting as defect sinks, the questions of how twist GBs evolve to absorb non equilibrium concentrations of defects and whether GBs saturate as defect sinks for typical irradiation conditions have remained largely unanswered. Here, we used a combination of molecular dynamics and grand canonical Monte Carlo simulations to determine how twist GBs accommodate point defects. We used SiC and {001} and {111} twist GBs as model systems. We found that diffusion of defects along GBs in this material is slow and for most experimentally relevant conditions point defects will accumulate at twist GBs, driving structural and chemical evolution of these interfaces. During irradiation, screw dislocations within GB planes absorb interstitials by developing mixed dislocation segments that climb. Formation of mixed dislocations occurs either by nucleation of interstitial loops or by faulting/unfaulting of stacking faults. Both types of twist GBs can accommodate a high density of interstitials without losing the crystalline structure, irrespectively of the interstitial flux. PMID- 29487303 TI - Differential effects of real versus hypothetical monetary reward magnitude on risk-taking behavior and brain activity. AB - Human decisions are more easily affected by a larger amount of money than a smaller one. Although numerous studies have used hypothetical money as incentives to motivate human behavior, the validity of hypothetical versus real monetary rewards remains controversial. In the present study, we used event-related potential (ERP) with the balloon analogue risk task to investigate how magnitudes of real and hypothetical monetary rewards modulate risk-taking behavior and feedback-related negativity (FRN). Behavioral data showed that participants were more risk averse after negative feedback with increased magnitude of real monetary rewards, while no behavior differences were observed between large and small hypothetical monetary rewards. Similarly, ERP data showed a larger FRN in response to negative feedback during risk taking with large compared to small real monetary rewards, while no FRN differences were observed between large and small hypothetical monetary rewards. Moreover, FRN amplitude differences correlated with risk-taking behavior changes from small to large real monetary rewards, while such correlation was not observed for hypothetical monetary rewards. These findings suggest that the magnitudes of real and hypothetical monetary rewards have differential effects on risk-taking behavior and brain activity. Real and hypothetical money incentives may have different validity for modulating human decisions. PMID- 29487305 TI - Chaihulonggumulitang Shows Psycho-cardiology Therapeutic Effects on Acute Myocardial Infarction by Enhancing Bone Marrow Mesenchymal Stem Cells Mobilization. AB - Ischemic myocardium initiates the mobilization and homing of bone marrow mesenchymal stem cells (BM-MSCs) to promote myocardial regeneration after acute myocardial infarction (AMI). Inflammation caused by necrotic cardiomyocytes induce major pathological changes (cardiac remodeling and myocardial apoptosis) as well as anxiety disorder. This process may be inhibited by the differentiation and paracrine effects of BM-MSCs. However, the spontaneous mobilization of BMSCs is insufficient to prevent this effect. Given the anti-inflammatory effects of BM MSCs, ventricular remodeling and anxiety following AMI, methods focused on enhancing BMSCs mobilization are promising. BFG is a classical traditional Chinese prescription medicine and has been proved effective in treating AMI and reducing anxiety, but the potential mechanism of its function remains unknown. In the present study, we explored the effects of Chaihulonggumulitang (BFG) on AMI and anxiety in vivo and in vitro. We also tested its effects in promoting BMSCs mobilization and alleviating inflammation. Our data showed that the classical Chinese prescription BFG promoted BM-MSCs mobilization, inhibited inflammatory response, and improved heart damage and anxiety developed from AMI. Thus, we provided an underlying mechanism of BFG function in psycho-cardiology conditions such as AMI. PMID- 29487306 TI - Prediction of Postnatal Growth Failure among Very Low Birth Weight Infants. AB - Postnatal growth failure (PGF) in preterm infants remains an important clinical issue. In this study, we analysed the incidence of PGF among very low birth weight (VLBW) infants and evaluated the risk factors for PGF based on the data of 2799 VLBW infants obtained from the Korean Neonatal Network database from 2013 to 2014. PGF was defined as a decrease in weight Z score between birth and discharge of more than -1.28 using the Fenton growth charts. Risk factors were evaluated in relation to birth weight for gestational age, namely small (SGA) or appropriate (AGA) for gestational age, using propensity score matching used for between-group differences. The overall incidence of PGF was 45.5%, with a rate of 68.9% in the SGA group and 36.2% in the AGA group. PGF was negatively correlated with gestation and birth weight; additionally, PGF was associated with a higher incidence of co-morbidities. Predictors of PGF in the SGA group were respiratory distress syndrome and days to attain 100 mL/kg of enteral feeding. The only predictor of PGF in the AGA group was days to attain 100 mL/kg of enteral feeding. Early initiation and aggressive progression of enteral nutrition may decrease the incidence of PGF. PMID- 29487307 TI - Multi-objective Optimization for Materials Discovery via Adaptive Design. AB - Guiding experiments to find materials with targeted properties is a crucial aspect of materials discovery and design, and typically multiple properties, which often compete, are involved. In the case of two properties, new compounds are sought that will provide improvement to existing data points lying on the Pareto front (PF) in as few experiments or calculations as possible. Here we address this problem by using the concept and methods of optimal learning to determine their suitability and performance on three materials data sets; an experimental data set of over 100 shape memory alloys, a data set of 223 M2AX phases obtained from density functional theory calculations, and a computational data set of 704 piezoelectric compounds. We show that the Maximin and Centroid design strategies, based on value of information criteria, are more efficient in determining points on the PF from the data than random selection, pure exploitation of the surrogate model prediction or pure exploration by maximum uncertainty from the learning model. Although the datasets varied in size and source, the Maximin algorithm showed superior performance across all the data sets, particularly when the accuracy of the machine learning model fits were not high, emphasizing that the design appears to be quite forgiving of relatively poor surrogate models. PMID- 29487308 TI - Potential effects of ultraviolet radiation reduction on tundra nitrous oxide and methane fluxes in maritime Antarctica. AB - Stratospheric ozone has begun to recover in Antarctica since the implementation of the Montreal Protocol. However, the effects of ultraviolet (UV) radiation on tundra greenhouse gas fluxes are rarely reported for Polar Regions. In the present study, tundra N2O and CH4 fluxes were measured under the simulated reduction of UV radiation in maritime Antarctica over the last three-year summers. Significantly enhanced N2O and CH4 emissions occurred at tundra sites under the simulated reduction of UV radiation. Compared with the ambient normal UV level, a 20% reduction in UV radiation increased tundra emissions by an average of 8 MUg N2O m-2 h-1 and 93 MUg CH4 m-2 h-1, whereas a 50% reduction in UV radiation increased their emissions by an average of 17 MUg N2O m-2 h-1 and 128 MUg CH4 m-2 h-1. No statistically significant correlation (P > 0.05) was found between N2O and CH4 fluxes and soil temperature, soil moisture, total carbon, total nitrogen, NO3--N and NH4+-N contents. Our results confirmed that UV radiation intensity is an important factor affecting tundra N2O and CH4 fluxes in maritime Antarctica. Exclusion of the effects of reduced UV radiation might underestimate their budgets in Polar Regions with the recovery of stratospheric ozone. PMID- 29487309 TI - Sunlight-driven eco-friendly smart curtain based on infrared responsive graphene oxide-polymer photoactuators. AB - Photomechanical actuation is the conversion of light energy into mechanical energy through some smart materials. Infrared-responsive smart materials have become an emerging field of research due to easy availability and eco-friendly nature of their stimulus in the form of sunlight, which contains about 50% of near-infrared(nIR) making these materials useful at macro-scale photoactuator applications. Here, we demonstrate fabrication of highly versatile nIR triggered photoactuators based on graphene oxide/polycarbonate bilayers that offers fast, low-cost fabrication, large deflection, reversible actuation and wavelength selective response. The photoactuators are realized by vacuum filtration of graphene oxide/water dispersion through polycarbonate membrane resulting graphene oxide/polymer bilayer structure. The photoactuation response was measured in the form of deflection from equilibrium position as a result of infrared-irradiation. The deflection is caused by the generated thermal stress at the interface of bilayers due to mismatch of thermal expansion coefficient as a results of nIR absorption by graphene oxide and subsequent temperature rise. A maximum deflection of 12 mm (circular-shaped structure with diameter 28 mm) with corresponding bending curvature of 0.33 cm-1 was shown by this photoactuator for illumination intensity of 106 mW/cm2. Few applications of these photoactuators such as sunlight-driven smart curtain, infrared actuated curtain and self-folding box are also demonstrated. PMID- 29487310 TI - Immunologic targeting of CD30 eliminates tumourigenic human pluripotent stem cells, allowing safer clinical application of hiPSC-based cell therapy. AB - Induced pluripotent stem cells (iPSCs) are promising candidate cells for cardiomyogenesis in the failing heart. However, teratoma/tumour formation originating from undifferentiated iPSCs contaminating the graft is a critical concern for clinical application. Here, we hypothesized that brentuximab vedotin, which targets CD30, induces apoptosis in tumourigenic cells, thus increasing the safety of iPSC therapy for heart failure. Flow cytometry analysis identified consistent expression of CD30 in undifferentiated human iPSCs. Addition of brentuximab vedotin in vitro for 72 h efficiently induced cell death in human iPSCs, associated with a significant increase in G2/M phase cells. Brentuximab vedotin significantly reduced Lin28 expression in cardiomyogenically differentiated human iPSCs. Transplantation of human iPSC-derived cardiomyocytes (CMs) without treatment into NOG mice consistently induced teratoma/tumour formation, with a substantial number of Ki-67-positive cells in the graft at 4 months post-transplant, whereas iPSC-derived CMs treated with brentuximab vedotin prior to the transplantation did not show teratoma/tumour formation, which was associated with absence of Ki-67-positive cells in the graft over the same period. These findings suggest that in vitro treatment with brentuximab vedotin, targeting the CD30-positive iPSC fraction, reduced tumourigenicity in human iPSC derived CMs, potentially providing enhanced safety for iPSC-based cardiomyogenesis therapy in clinical scenarios. PMID- 29487311 TI - Biological methane production under putative Enceladus-like conditions. AB - The detection of silica-rich dust particles, as an indication for ongoing hydrothermal activity, and the presence of water and organic molecules in the plume of Enceladus, have made Saturn's icy moon a hot spot in the search for potential extraterrestrial life. Methanogenic archaea are among the organisms that could potentially thrive under the predicted conditions on Enceladus, considering that both molecular hydrogen (H2) and methane (CH4) have been detected in the plume. Here we show that a methanogenic archaeon, Methanothermococcus okinawensis, can produce CH4 under physicochemical conditions extrapolated for Enceladus. Up to 72% carbon dioxide to CH4 conversion is reached at 50 bar in the presence of potential inhibitors. Furthermore, kinetic and thermodynamic computations of low-temperature serpentinization indicate that there may be sufficient H2 gas production to serve as a substrate for CH4 production on Enceladus. We conclude that some of the CH4 detected in the plume of Enceladus might, in principle, be produced by methanogens. PMID- 29487312 TI - Frequency multiplexing for quasi-deterministic heralded single-photon sources. AB - Parametric single-photon sources are well suited for large-scale quantum networks due to their potential for photonic integration. Active multiplexing of photons can overcome the intrinsically probabilistic nature of these sources, resulting in near-deterministic operation. However, previous implementations using spatial and temporal multiplexing scale unfavorably due to rapidly increasing switching losses. Here, we break this limitation via frequency multiplexing in which switching losses remain fixed irrespective of the number of multiplexed modes. We use low-noise optical frequency conversion for efficient frequency switching and demonstrate multiplexing of three modes. We achieve a generation rate of 4.6 * 104 photons per second with an ultra-low g(2)(0) = 0.07 indicating high single photon purity. Our scalable, all-fiber multiplexing system has a total loss of just 1.3 dB, such that the 4.8 dB multiplexing enhancement markedly overcomes switching loss. Our approach offers a promising path to creating a deterministic photon source on an integrated chip-based platform. PMID- 29487313 TI - Body size influences energetic and osmoregulatory costs in frogs infected with Batrachochytrium dendrobatidis. AB - Sloughing maintains the skins integrity and critical functionality in amphibians. Given the behavioural, morphological and osmoregulatory changes that accompany sloughing, this process is likely to be physiologically costly. Chytridiomycosis, a cutaneous disease of amphibians caused by the fungus Batrachochytrium dendrobatidis (Bd), disrupts skin function and increases sloughing rates. Moreover, mortality rates from chytridiomycosis are significantly higher in juveniles and so we hypothesised that smaller individuals maybe more susceptible to chytridiomycosis because of allometric scaling effects on the energetic and osmoregulatory costs of sloughing. We measured in-vivo cutaneous ion loss rates and whole animal metabolic rate (MR) of Green tree frogs, Litoria caerulea, over a range of body sizes both infected and uninfected frogs during sloughing. Infected animals had a greater rate of ion loss and mass-specific MR during non sloughing periods but there were no additional effects of sloughing on either of these parameters. There were also significant interactions with body size and Bd load indicating that smaller animals with higher Bd loads have greater rates of ion loss and higher energetic demands. Our results shed light on why smaller Bd infected anurans often exhibit greater physiological disruption than larger individuals. PMID- 29487314 TI - Synergistic effect of mutagenesis and truncation to improve a polyesterase from Clostridium botulinum for polyester hydrolysis. AB - The activity of the esterase (Cbotu_EstA) from Clostridium botulinum on the polyester poly(ethylene terephthalate) (PET) was improved by concomitant engineering of two different domains. On the one hand, the zinc-binding domain present in Cbotu_EstA was subjected to site-directed mutagenesis. On the other hand, a specific domain consisting of 71 amino acids at the N-terminus of the enzyme was deleted. Interestingly, a combination of substitution of residues present in the zinc-binding domain (e.g. S199A) synergistically increased the activity of the enzyme on PET seven fold when combined to the truncation of 71 amino acids at the N-terminus of the enzyme only. Overall, when compared to the native enzyme, the combination of truncation and substitutions in the zinc binding domain lead to a 50-fold activity improvement. Moreover, analysis of the kinetic parameters of the Cbotu_EstA variants indicated a clear shift of activity from water soluble (i.e. para-nitrophenyl butyrate) to insoluble polymeric substrates. These results evidently show that the interaction with non-natural polymeric substrates provides targets for enzyme engineering. PMID- 29487315 TI - Allergic tendencies are associated with larger gray matter volumes. AB - Allergic tendencies are associated with important cognitive and physiological factors, such as intelligence and mathematical abilities. Allergies are widely prevalent, especially in modern life, and the reason for its association with important cognitive variables is an intriguing scientific question. However, despite the unique characteristics of cognitive correlates of allergy, the anatomical correlates of allergy remain unknown. The aim of this study was to identify the associations between regional gray matter volume (rGMV) and allergic tendencies in young adults. In a study cohort of 1,219 healthy, educated young adults, we identified a positive correlation between total allergic tendency and rGMV in large anatomical clusters that mainly encompassed the dorsal part of the cerebral neocortex, right anterior insula, and cerebellum. Furthermore,both mean rGMV of the entire part of these clusters and total allergenic tendency showed a significant positive correlation with spatial ability. These results suggest the link among allergic tendencies, larger rGMV, and the better spatial ability in healthy, educated young adults. PMID- 29487316 TI - Relaxation dynamics of generalized scale-free polymer networks. AB - We focus on treelike generalized scale-free polymer networks, whose geometries depend on a parameter, gamma, that controls their connectivity and on two modularity parameters: the minimum allowed degree, K min , and the maximum allowed degree, K max . We monitor the influence of these parameters on the static and dynamic properties of the achieved generalized scale-free polymer networks. The relaxation dynamics is studied in the framework of generalized Gaussian structures model by employing the Rouse-type approach. The dynamical quantities on which we focus are the average monomer displacement under external forces and the mechanical relaxation moduli (storage and loss modulus), while for the static and structure properties of these networks we concentrate on the eigenvalue spectrum, diameter, and degree correlations. Depending on the values of network's parameters we were able to switch between distinct hyperbranched structures: networks with more linearlike segments or with a predominant star or dendrimerlike topology. We have observed a stronger influence on K min than on K max . In the intermediate time (frequency) domain, all physical quantities obey power-laws for polymer networks with gamma = 2.5 and K min = 2 and we prove additionally that for networks with gamma >= 2.5 new regions with constant slope emerge by a proper choice of K min . Remarkably, we show that for certain values of the parameter set one may obtain self-similar networks. PMID- 29487317 TI - Proximity effects across oxide-interfaces of superconductor-insulator-ferromagnet hybrid heterostructure. AB - A case study of electron tunneling or charge-transfer-driven orbital ordering in superconductor (SC)-ferromagnet (FM) interfaces has been conducted in heteroepitaxial YBa2Cu3O7(YBCO)/La0.67Sr0.33MnO3(LSMO) multilayers interleaved with and without an insulating SrTiO3(STO) layer between YBCO and LSMO. X-ray magnetic circular dichroism experiments revealed anti-parallel alignment of Mn magnetic moments and induced Cu magnetic moments in a YBCO/LSMO multilayer. As compared to an isolated LSMO layer, the YBCO/LSMO multilayer displayed a (50%) weaker Mn magnetic signal, which is related to the usual proximity effect. It was a surprise that a similar proximity effect was also observed in a YBCO/STO/LSMO multilayer, however, the Mn signal was reduced by 20%. This reduced magnetic moment of Mn was further verified by depth sensitive polarized neutron reflectivity. Electron energy loss spectroscopy experiment showed the evidence of Ti magnetic polarization at the interfaces of the YBCO/STO/LSMO multilayer. This crossover magnetization is due to a transfer of interface electrons that migrate from Ti(4+)-delta to Mn at the STO/LSMO interface and to Cu2+ at the STO/YBCO interface, with hybridization via O 2p orbitals. So charge-transfer driven orbital ordering is the mechanism responsible for the observed proximity effect and Mn-Cu anti-parallel coupling in YBCO/STO/LSMO. This work provides an effective pathway in understanding the aspect of long range proximity effect and consequent orbital degeneracy parameter in magnetic coupling. PMID- 29487318 TI - A G-protein pathway determines grain size in rice. AB - Manipulating grain size is an effective strategy for increasing cereal yields. Here we identify a pathway composed of five subunits of the heterotrimeric G proteins that regulate grain length in rice. The Gbeta protein is essential for plant survival and growth. Galpha provides a foundation for grain size expansion. Three Ggamma proteins, DEP1, GGC2 and GS3, antagonistically regulate grain size. DEP1 and GGC2, individually or in combination, increase grain length when in complex with Gbeta. GS3, having no effect on grain size by itself, reduces grain length by competitively interacting with Gbeta. By combining different G-protein variants, we can decrease grain length by up to 35% or increase it by up to 19%, which leads to over 40% decreasing to 28% increasing of grain weight. The wide existence of such a conserved system among angiosperms suggests a possible general predictable approach to manipulating grain/organ sizes. PMID- 29487320 TI - Characteristics of pulsed runoff-erosion events under typical rainstorms in a small watershed on the Loess Plateau of China. AB - The pulsed events of rainstorm erosion on the Loess Plateau are well-known, but little information is available concerning the characteristics of superficial soil erosion processes caused by heavy rainstorms at the watershed scale. This study statistically evaluated characteristics of pulsed runoff-erosion events based on 17 observed rainstorms from 1997-2010 in a small loess watershed on the Loess Plateau of China. Results show that: 1) Rainfall is the fundamental driving force of soil erosion on hillslopes, but the correlations of rainfall-runoff and rainfall-sediment in different rainstorms are often scattered due to infiltration excess runoff and soil conservation measures. 2) Relationships between runoff and sediment for each rainstorm event can be regressed by linear, power, logarithmic and exponential functions. Cluster Analysis is helpful in classifying runoff erosion events and formulating soil conservation strategies for rainstorm erosion. 3) Response characteristics of sediment yield are different in different levels of pulsed runoff-erosion events. Affected by rainfall intensity and duration, large changes may occur in the interactions between flow and sediment for different flood events. Results provide new insights into runoff-erosion processes and will assist soil conservation planning in the loess hilly region. PMID- 29487319 TI - Magnetic Resonance Imaging of Atherosclerotic Plaque at Clinically Relevant Field Strengths (1T) by Targeting the Integrin alpha4beta1. AB - Inflammation drives the degradation of atherosclerotic plaque, yet there are no non-invasive techniques available for imaging overall inflammation in atherosclerotic plaques, especially in the coronary arteries. To address this, we have developed a clinically relevant system to image overall inflammatory cell burden in plaque. Here, we describe a targeted contrast agent (THI0567-targeted liposomal-Gd) that is suitable for magnetic resonance (MR) imaging and binds with high affinity and selectivity to the integrin alpha4beta1(very late antigen-4, VLA-4), a key integrin involved in recruiting inflammatory cells to atherosclerotic plaques. This liposomal contrast agent has a high T1 relaxivity (~2 * 105 mM-1s-1 on a particle basis) resulting in the ability to image liposomes at a clinically relevant MR field strength. We were able to visualize atherosclerotic plaques in various regions of the aorta in atherosclerosis-prone ApoE-/- mice on a 1 Tesla small animal MRI scanner. These enhanced signals corresponded to the accumulation of monocyte/macrophages in the subendothelial layer of atherosclerotic plaques in vivo, whereas non-targeted liposomal nanoparticles did not demonstrate comparable signal enhancement. An inflammatory cell-targeted method that has the specificity and sensitivity to measure the inflammatory burden of a plaque could be used to noninvasively identify patients at risk of an acute ischemic event. PMID- 29487321 TI - Foot strength and stiffness are related to footwear use in a comparison of minimally- vs. conventionally-shod populations. AB - The longitudinal arch (LA) helps stiffen the foot during walking, but many people in developed countries suffer from flat foot, a condition characterized by reduced LA stiffness that can impair gait. Studies have found this condition is rare in people who are habitually barefoot or wear minimal shoes compared to people who wear conventional modern shoes, but the basis for this difference remains unknown. Here we test the hypothesis that the use of shoes with features that restrict foot motion (e.g. arch supports, toe boxes) is associated with weaker foot muscles and reduced foot stiffness. We collected data from minimally shod men from northwestern Mexico and men from urban/suburban areas in the United States who wear 'conventional' shoes. We measured dynamic LA stiffness during walking using kinematic and kinetic data, and the cross-sectional areas of three intrinsic foot muscles using ultrasound. Compared to conventionally-shod individuals, minimally-shod individuals had higher and stiffer LAs, and larger abductor hallucis and abductor digiti minimi muscles. Additionally, abductor hallucis size was positively associated with LA stiffness during walking. Our results suggest that use of conventional modern shoes is associated with weaker intrinsic foot muscles that may predispose individuals to reduced foot stiffness and potentially flat foot. PMID- 29487322 TI - Fast, sensitive method for trisaccharide biomarker detection in mucopolysaccharidosis type 1. AB - Certain recessively inherited diseases result from an enzyme deficiency within lysosomes. In mucopolysaccharidoses (MPS), a defect in glycosaminoglycan (GAG) degradation leads to GAG accumulation followed by progressive organ and multiple system dysfunctions. Current methods of GAG analysis used to diagnose and monitor the diseases lack sensitivity and throughput. Here we report a LC-MS method with accurate metabolite mass analysis for identifying and quantifying biomarkers for MPS type I without the need for extensive sample preparation. The method revealed 225 LC-MS features that were >1000-fold enriched in urine, plasma and tissue extracts from untreated MPS I mice compared to MPS I mice treated with iduronidase to correct the disorder. Levels of several trisaccharides were elevated >10000-fold. To validate the clinical relevance of our method, we confirmed the presence of these biomarkers in urine, plasma and cerebrospinal fluid from MPS I patients and assessed changes in their levels after treatment. PMID- 29487323 TI - Analysis of strain distribution, migratory potential, and invasion history of fall armyworm populations in northern Sub-Saharan Africa. AB - Fall armyworm (Spodoptera frugiperda J.E. Smith) is a noctuid moth pest endemic throughout the Western Hemisphere that has recently become widespread in sub Saharan Africa. There is a strong expectation of significant damage to African maize crop yield and a high likelihood of further dispersal, putting the rest of the Eastern Hemisphere at risk. Specimens from multiple locations in six countries spanning the northern portion of the infested region were analyzed for genetic markers. The similarity of haplotypes between the African collections was consistent with a common origin, but significant differences in the relative frequency of the haplotypes indicated limitations in migration. The mitochondrial marker frequently used to identify two host strains appears to be compromised, making uncertain previous reports that both strains are present in Africa. This more extensive study confirmed initial indications based on Togo populations that Florida and the Greater Antilles are the likely source of at least a subset of the African infestation and further suggest an entry point in western Africa. The origin of a second subgroup is less clear as it was rarely found in the collections and has a haplotype that has not yet been observed in the Western Hemisphere. PMID- 29487325 TI - Physics of the mechanical toy Gee-Haw Whammy Diddle. AB - Gee-Haw Whammy Diddle is a seemingly simple mechanical toy consisting of a wooden stick and a second stick that is made up of a series of notches with a propeller at its end. When the wooden stick is pulled over the notches, the propeller starts to rotate. Despite its simplicity, physical principles governing the motion of the stick and the propeller are rather complicated and interesting. Here we provide a thorough analysis of the system and parameters influencing the motion. We show that contrary to the results published on this topic so far, neither elliptic motion of the stick nor frequency synchronization is needed for starting a stable motion of the propeller. PMID- 29487324 TI - Human protective response induced by meningococcus B vaccine is mediated by the synergy of multiple bactericidal epitopes. AB - 4CMenB is the first broad coverage vaccine for the prevention of invasive meningococcal disease caused by serogroup B strains. To gain a comprehensive picture of the antibody response induced upon 4CMenB vaccination and to obtain relevant translational information directly from human studies, we have isolated a panel of human monoclonal antibodies from adult vaccinees. Based on the Ig-gene sequence of the variable region, 37 antigen-specific monoclonal antibodies were identified and produced as recombinant Fab fragments, and a subset also produced as full length recombinant IgG1 and functionally characterized. We found that the monoclonal antibodies were cross-reactive against different antigen variants and recognized multiple epitopes on each of the antigens. Interestingly, synergy between antibodies targeting different epitopes enhanced the potency of the bactericidal response. This work represents the first extensive characterization of monoclonal antibodies generated in humans upon 4CMenB immunization and contributes to further unraveling the immunological and functional properties of the vaccine antigens. Moreover, understanding the mechanistic nature of protection induced by vaccination paves the way to more rational vaccine design and implementation. PMID- 29487326 TI - Potential use of superparamagnetic iron oxide nanoparticles for in vitro and in vivo bioimaging of human myoblasts. AB - Myocardial infarction (MI) is one of the most frequent causes of death in industrialized countries. Stem cells therapy seems to be very promising for regenerative medicine. Skeletal myoblasts transplantation into postinfarction scar has been shown to be effective in the failing heart but shows limitations such, e.g. cell retention and survival. We synthesized and investigated superparamagnetic iron oxide nanoparticles (SPIONs) as an agent for direct cell labeling, which can be used for stem cells imaging. High quality, monodisperse and biocompatible DMSA-coated SPIONs were obtained with thermal decomposition and subsequent ligand exchange reaction. SPIONs' presence within myoblasts was confirmed by Prussian Blue staining and inductively coupled plasma mass spectrometry (ICP-MS). SPIONs' influence on tested cells was studied by their proliferation, ageing, differentiation potential and ROS production. Cytotoxicity of obtained nanoparticles and myoblast associated apoptosis were also tested, as well as iron-related and coating-related genes expression. We examined SPIONs' impact on overexpression of two pro-angiogenic factors introduced via myoblast electroporation method. Proposed SPION-labeling was sufficient to visualize firefly luciferase-modified and SPION-labeled cells with magnetic resonance imaging (MRI) combined with bioluminescence imaging (BLI) in vivo. The obtained results demonstrated a limited SPIONs' influence on treated skeletal myoblasts, not interfering with basic cell functions. PMID- 29487327 TI - Molecular detection of colistin resistance genes (mcr-1, mcr-2 and mcr-3) in nasal/oropharyngeal and anal/cloacal swabs from pigs and poultry. AB - Antimicrobial resistance against colistin has emerged worldwide and is threatening the efficacy of colistin treatment of multi-resistant Gram-negative bacteria. In this study, PCRs were used to detect mcr genes (mcr-1, mcr-2, mcr-3) in 213 anal and 1,339 nasal swabs from pigs (n = 1,454) in nine provinces of China, and 1,696 cloacal and 1,647 oropharyngeal samples from poultry (n = 1,836) at live-bird markets in 24 provinces. The mcr-1 prevalences in pigs (79.2%) and geese (71.7%) were significantly higher than in chickens (31.8%), ducks (34.6%) and pigeons (13.1%). The mcr-2 prevalence in pigs was 56.3%, significantly higher than in chickens (5.5%), ducks (2.3%), geese (5.5%) and pigeons (0%). The mcr-3 prevalences in pigs (18.7%), ducks (13.8%) and geese (11.9%) were significantly higher than in chickens (5.2%) and pigeons (5.1%). In total, 173 pigs and three chickens were positive for all three mcr genes. The prevalences of the mcr were significantly higher in nasal/oropharyngeal swabs than in the anal /cloacal swabs. Phylogenetic studies identified 33 new mcr-2 variants and 12 new mcr-3 variants. This study demonstrates high prevalences of mcr in pigs and poultry in China, and indicates there is need for more thorough surveillance and control programs to prevent further selection of colistin resistance. PMID- 29487328 TI - In vitro Evaluation of Porous borosilicate, borophosphate and phosphate Bioactive Glasses Scaffolds fabricated using Foaming Agent for Bone Regeneration. AB - In this work, glasses within the borosilicate borophosphate and phosphate family were sintered into 3D porous scaffolds using 60 and 70 vol. % NH4(HCO3) as a foaming agent. All scaffolds produced remained amorphous; apart from one third of the glasses which crystallized. All produced scaffolds had porosity >50% and interconnected pores in the range of 250-570 um; as evidenced by uCT. The in vitro dissolution of the scaffolds in SBF and changes in compression were assessed as a function of immersion time. The pH of the solution containing the borosilicate scaffolds increased due to the typical non-congruent dissolution of this glass family. Borophosphate and phosphate scaffolds induced a decrease in pH upon dissolution attributed to the congruent dissolution of those materials and the large release of phosphate within the media. As prepared, scaffolds showed compressive strength of 1.29 +/- 0.21, 1.56 +/- 0.63, 3.63 +/- 0.69 MPa for the borosilicate, borophosphate and phosphate samples sintered with 60 vol. % NH4 (HCO3), respectively. Evidence of hydroxyapatite precipitation on the borosilicate glass scaffolds was shown by SEM/EDS, XRD and ICP-OES analysis. The borophosphate scaffolds remained stable upon dissolution. The phosphate scaffolds were fully crystallized, leading to very large release of phosphate in the media. PMID- 29487329 TI - AGO1 may influence the prognosis of hepatocellular carcinoma through TGF-beta pathway. AB - AGO1 is a major component of RNA-induced silencing complexes and plays a crucial role in solid tumors. The aim of our study was to investigate AGO1 functions in hepatocellular carcinoma (HCC). Using small interfering RNA, AGO1 functions were investigated in HCCLM3 cell lines. Cell proliferation, immigration, and invasion significantly decreased after AGO1 depletion using MTT, wound-healing, and transwell assay. The associated proteins in the epithelial-mesenchymal transition (EMT) and the activation of its signal pathways were measured using western blot. After AGO1 depleted, increased E-cadherin and decreased N-cadherin, Vimentin, Snail, and Zeb1 were founded. In its upstream pathway, the phosphorylation of ERK1/2(Thr202/Tyr204), Smad2(S425/250/255), and Smad4 were significantly inhibited. Meanwhile, inhibitor of ERK1/2(LY3214996) significantly inhibited the growth and migration of the AGO1 cells. The nuclear importing of Smad4 was blocked and furthermore, the transcription of Snail was also influenced for the decrease of combination between Smad4 and the promotor region of Snail. After Snail was overexpressed, the invasion of HCCLM3 cells was significantly rescued. Immunohistochemistry in tissue microarrays consisting of 200 HCC patients was used to analyze the associations between AGO1 expression and prognosis. Intratumoral AGO1 expression was an independent risk factor for overall survival (P = 0.008) and recurrence-free survival (P < 0.001). In conclusion, AGO1 may promote HCC metastasis through TGF-beta pathway, and AGO1 may be a reliable prognostic factor in HCC. PMID- 29487330 TI - Internal Motion Estimation by Internal-external Motion Modeling for Lung Cancer Radiotherapy. AB - The aim of this study is to develop an internal-external correlation model for internal motion estimation for lung cancer radiotherapy. Deformation vector fields that characterize the internal-external motion are obtained by respectively registering the internal organ meshes and external surface meshes from the 4DCT images via a recently developed local topology preserved non-rigid point matching algorithm. A composite matrix is constructed by combing the estimated internal phasic DVFs with external phasic and directional DVFs. Principle component analysis is then applied to the composite matrix to extract principal motion characteristics, and generate model parameters to correlate the internal-external motion. The proposed model is evaluated on a 4D NURBS-based cardiac-torso (NCAT) synthetic phantom and 4DCT images from five lung cancer patients. For tumor tracking, the center of mass errors of the tracked tumor are 0.8(+/-0.5)mm/0.8(+/-0.4)mm for synthetic data, and 1.3(+/-1.0)mm/1.2(+/-1.2)mm for patient data in the intra-fraction/inter-fraction tracking, respectively. For lung tracking, the percent errors of the tracked contours are 0.06(+/ 0.02)/0.07(+/-0.03) for synthetic data, and 0.06(+/-0.02)/0.06(+/-0.02) for patient data in the intra-fraction/inter-fraction tracking, respectively. The extensive validations have demonstrated the effectiveness and reliability of the proposed model in motion tracking for both the tumor and the lung in lung cancer radiotherapy. PMID- 29487332 TI - Electrofusion of single cells in picoliter droplets. AB - We present a microfluidic chip that enables electrofusion of cells in microdroplets, with exchange of nuclear components. It is shown, to our knowledge for the first time, electrofusion of two HL60 cells, inside a microdroplet. This is the crucial intermediate step for controlled hybridoma formation where a B cell is electrofused with a myeloma cell. We use a microfluidic device consisting of a microchannel structure in PDMS bonded to a glass substrate through which droplets with two differently stained HL60 cells are transported. An array of six recessed platinum electrode pairs is used for electrofusion. When applying six voltage pulses of 2-3 V, the membrane electrical field is about 1 MV/cm for 1 ms. This results in electrofusion of these cells with a fusion yield of around 5%. The operation with individual cell pairs, the appreciable efficiency and the potential to operate in high-throughput (up to 500 cells sec-1) makes the microdroplet fusion technology a promising platform for cell electrofusion, which has the potential to compete with the conventional methods. Besides, this platform is not restricted to cell fusion but is also applicable to various other cell-based assays such as single cell analysis and differentiation assays. PMID- 29487333 TI - Improving RNAi in the Brown Marmorated Stink Bug: Identification of target genes and reference genes for RT-qPCR. AB - The brown marmorated stink bug (BMSB) is native to Asia and recently invaded the USA. RNA interference (RNAi) is a gene silencing mechanism in which the introduction of double-stranded RNA (dsRNA) inhibits gene function by degrading target mRNA. In dsRNA stability assays, the dsRNases present in the hemolymph and salivary gland secretions of BMSB showed lower activity than those in the hemolymph of Heliothis virescens. We evaluated six housekeeping genes (18S rRNA, EF1-alpha, Actin, Ubiquitin, 60S RP and beta-Tubulin) across dsRNA treatments (injection and feeding) in nymphs and adults of BMSB and identified 18S rRNA and 60S RP as the best genes to use as a reference in reverse-transcriptase quantitative PCR (RT-qPCR). Homologs of 13 genes that were shown to function as effective RNAi targets in other insects were identified and evaluated by injecting dsRNA targeting these homologs into BMSB adults. Five out of 13 dsRNAs tested caused more than 70% mortality by seven days after injection of dsRNA. Feeding dsRNA targeting five of these genes (IAP, ATPase, SNF7, GPCR, and PPI) to nymphs caused more than 70% mortality by three of the five dsRNAs tested. These data suggest that feeding dsRNA causes target gene knockdown and mortality in BMSB. PMID- 29487331 TI - Regulation of neuroblast proliferation by surface glia in the Drosophila larval brain. AB - Despite the importance of precisely regulating stem cell division, the molecular basis for this control is still elusive. Here, we show that surface glia in the developing Drosophila brain play essential roles in regulating the proliferation of neural stem cells, neuroblasts (NBs). We found that two classes of extracellular factors, Dally-like (Dlp), a heparan sulfate proteoglycan, and Glass bottom boat (Gbb), a BMP homologue, are required for proper NB proliferation. Interestingly, Dlp expressed in perineural glia (PG), the most outer layer of the surface glia, is responsible for NB proliferation. Consistent with this finding, functional ablation of PG using a dominant-negative form of dynamin showed that PG has an instructive role in regulating NB proliferation. Gbb acts not only as an autocrine proliferation factor in NBs but also as a paracrine survival signal in the PG. We propose that bidirectional communication between NBs and glia through TGF-beta signaling influences mutual development of these two cell types. We also discuss the possibility that PG and NBs communicate via direct membrane contact or transcytotic transport of membrane components. Thus, our study shows that the surface glia acts not only as a simple structural insulator but also a dynamic regulator of brain development. PMID- 29487334 TI - Nano-scale mechanisms explain the stiffening and strengthening of ligament tissue with increasing strain rate. AB - Ligament failure is a major societal burden causing disability and pain. Failure is caused by trauma at high loading rates. At the macroscopic level increasing strain rates cause an increase in failure stress and modulus, but the mechanism for this strain rate dependency is not known. Here we investigate the nano scale mechanical property changes of human ligament using mechanical testing combined with synchrotron X-ray diffraction. With increasing strain rate, we observe a significant increase in fibril modulus and a reduction of fibril to tissue strain ratio, revealing that tissue-level stiffening is mainly due to the stiffening of collagen fibrils. Further, we show that the reduction in fibril deformation at higher strain rates is due to reduced molecular strain and fibrillar gaps, and is associated with rapid disruption of matrix-fibril bonding. This reduction in number of interfibrillar cross-links explains the changes in fibril strain; this is verified through computational modelling. PMID- 29487335 TI - Gender bias in clinicians' pathologization of atypical sexuality: a randomized controlled trial with mental health professionals. AB - The psychiatric classification of "normal" versus disordered sexual behavior has been a subject of some dispute. Although atypical sexual interests have been viewed traditionally as typically male, epidemiological data indicate its presence in both genders. We examined how gender and sexual orientation influence whether or not atypical sexual behavior is classified as a mental disorder. Mental health professionals (N = 546) were presented with five case vignettes where subjects exhibit paraphilic behaviors; one case with psychotic symptoms served as the control condition. For each vignette we randomly changed the described subject's gender (male/female), sexual orientation (homosexual/heterosexual), and presented diagnostic criteria (fulfilled/ambiguous). Female subjects were significantly less pathologized and overall more stigmatized in terms of exhibitionistic, frotteuristic, sexual sadistic and pedophilic behavior. On the other hand, female sexual behavior that fulfilled diagnostic criteria for masochistic disorder was more pathologized. Our results demonstrate that nosologically irrelevant factors, which may be related to different sexual norms for men and women, affect clinicians' decisions regarding atypical sexuality. PMID- 29487337 TI - Homoarginine and inhibition of human arginase activity: kinetic characterization and biological relevance. AB - The inhibition of arginase, resulting in higher arginine (ARG) availability for nitric oxide synthesis, may account for the putative protective effect of homoarginine (HOMOARG) against atherosclerosis and cardiovascular disease. However, uncertainty exists regarding the significance of HOMOARG-induced arginase inhibition in vivo. A novel UPLC-MS method, measuring the conversion of ARG to ornithine (ORN), was developed to determine arginase 1 and arginase 2 inhibition by HOMOARG, lysine (LYS), proline (PRO), agmatine (AG), asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and NG-Monomethyl-L arginine (L-NMMA). Plasma HOMOARG, ARG and ORN concentrations were further measured in 50 healthy older adults >65 years (27 males and 23 females). HOMOARG inhibited arginase 1 with IC50 and Ki values of 8.14 +/- 0.52 mM and 6.1 +/- 0.50 mM, and arginase 2 with IC50 and Ki values of 2.52 +/- 0.01 mM and 1.73 +/- 0.10 mM, respectively. Both arginase isoforms retained 90% activity vs. control when physiological HOMOARG concentrations (1-10 uM) were used. In partial correlation analysis, plasma HOMOARG was not associated with ARG (P = 0.38) or ARG/ORN ratio (P = 0.73) in older adults. Our results suggest that arginase inhibition is unlikely to play a significant role in the reported cardio-protective effects of HOMOARG. PMID- 29487336 TI - Enhanced synaptic plasticity and spatial memory in female but not male FLRT2 haplodeficient mice. AB - The Fibronectin Leucine-Rich Transmembrane protein 2 (FLRT2) has been implicated in several hormone -and sex-dependent physiological and pathological processes (including chondrogenesis, menarche and breast cancer); is known to regulate developmental synapses formation, and is expressed in the hippocampus, a brain structure central for learning and memory. However, the role of FLRT2 in the adult hippocampus and its relevance in sex-dependent brain functions remains unknown. We here used adult single-allele FLRT2 knockout (FLRT2+/-) mice and behavioral, electrophysiological, and molecular/biological assays to examine the effects of FLRT2 haplodeficiency on synaptic plasticity and hippocampus-dependent learning and memory. Female and male FLRT2+/- mice presented morphological features (including body masses, brain shapes/weights, and brain macroscopic cytoarchitectonic organization), indistinguishable from their wild type counterparts. However, in vivo examinations unveiled enhanced hippocampus dependent spatial memory recall in female FLRT2+/- animals, concomitant with augmented hippocampal synaptic plasticity and decreased levels of the glutamate transporter EAAT2 and beta estrogen receptors. In contrast, male FLRT2+/- animals exhibited deficient memory recall and decreased alpha estrogen receptor levels. These observations propose that FLRT2 can regulate memory functions in the adulthood in a sex-specific manner and might thus contribute to further research on the mechanisms linking sexual dimorphism and cognition. PMID- 29487338 TI - Lysine methyltransferase SMYD2 promotes triple negative breast cancer progression. AB - We identified SMYD2, a SMYD (SET and MYND domain) family protein with lysine methyltransferase activity, as a novel breast cancer oncogene. SMYD2 was expressed at significantly higher levels in breast cancer cell lines and in breast tumor tissues. Silencing of SMYD2 by RNAi in triple-negative breast cancer (TNBC) cell lines or inhibition of SMYD2 with its specific inhibitor, AZ505, significantly reduced tumor growth in vivo. SMYD2 executes this activity via methylation and activation of its novel non-histone substrates, including STAT3 and the p65 subunit of NF-kappaB, leading to increased TNBC cell proliferation and survival. There are cross-talk and synergistic effects among SMYD2, STAT3, and NF-kappaB in TNBC cells, in that STAT3 can contribute to the modification of NF-kappaB p65 subunit post-translationally by recruitment of SMYD2, whereas the p65 subunit of NF-kappaB can also contribute to the modification of STAT3 post translationally by recruitment of SMYD2, leading to methylation and activation of STAT3 and p65 in these cells. The expression of SMYD2 can be upregulated by IL-6 STAT3 and TNFalpha-NF-kappaB signaling, which integrates epigenetic regulation to inflammation in TNBC development. In addition, we have identified a novel SMYD2 transcriptional target gene, PTPN13, which links SMYD2 to other known breast cancer associated signaling pathways, including ERK, mTOR, and Akt signaling via PTPN13 mediated phosphorylation. PMID- 29487339 TI - Ablation of Bax and Bak protects skeletal muscle against pressure-induced injury. AB - Pressure-induced injury (PI), such as a pressure ulcer, in patients with limited mobility is a healthcare issue worldwide. PI is an injury to skin and its underlying tissue such as skeletal muscle. Muscle compression, composed of mechanical deformation of muscle and external load, leads to localized ischemia and subsequent unloading reperfusion and, hence, a pressure ulcer in bed-bound patients. Although the gross factors involved in PI have been identified, little is known about the exact disease mechanism or its links to apoptosis, autophagy and inflammation. Here, we report that PI is mediated by intrinsic apoptosis and exacerbated by autophagy. Conditional ablation of Bax and Bak activates the Akt mTOR pathway and Bnip3-mediated mitophagy and preserves mitochondrial contents in compressed muscle. Moreover, we find that the presence/absence of Bax and Bak alters the roles and functions of autophagy in PI. Our results suggest that manipulating apoptosis and autophagy are potential therapeutic targets for treatment and prevention of PI. PMID- 29487340 TI - Nonmonotonic particle-size-dependence of magnetoelectric coupling in strained nanosized particles of BiFeO3. AB - Using high resolution powder x-ray and neutron diffraction experiments, we determined the off-centered displacement of the ions within a unit cell and magnetoelectric coupling in nanoscale BiFeO3 (~20-200 nm). We found that both the off-centered displacement of the ions and magnetoelectric coupling exhibit nonmonotonic variation with particle size. They increase as the particle size reduces from bulk and reach maximum around 30 nm. With further decrease in particle size, they decrease precipitously. The magnetoelectric coupling is determined by the anomaly in off-centering of ions around the magnetic transition temperature (T N ). The ions, in fact, exhibit large anomalous displacement around the T N which is analyzed using group theoretical approach. It underlies the nonmonotonic particle-size-dependence of off-centre displacement of ions and magnetoelectric coupling. The nonmonotonic variation of magnetoelectric coupling with particle size is further verified by direct electrical measurement of remanent ferroelectric hysteresis loops at room temperature under zero and ~20 kOe magnetic field. Competition between enhanced lattice strain and compressive pressure appears to be causing the nonmonotonic particle-size-dependence of off centre displacement while coupling between piezo and magnetostriction leads to nonmonotonicity in the variation of magnetoelectric coupling. PMID- 29487341 TI - Phylogeny and evolution of Mullerian mimicry in aposematic Dilophotes: evidence for advergence and size-constraints in evolution of mimetic sexual dimorphism. AB - Multiple patterns and intraspecific polymorphism should not persist in mutualistic Mullerian systems due to purifying and frequency-dependent selection, but they are commonly identified in nature. We analysed molecular phylogeny and reconstructed dispersal history of 58 species of Dilophotes (Coleoptera: Lycidae) in Asia. Dilophotes colonized the Great Sundas and Malay Peninsula where they joined extensive mimetic communities of net-winged beetles. We identified the brightly bi-coloured males and females which adverged on five occasions to different autochthonous models. This is the first described case of Mullerian sexual dimorphism based on sex-specific body size. We propose that the constraint, i.e. the conservative sexual size dimorphism, forced the unprofitable prey to such complex adaptation in a multi-pattern environment. Although mimetic sexual dimorphism has frequently evolved in Dilophotes, a single pattern has been maintained by both sexes in multiple closely related, sympatrically occurring species. Some patterns may be suboptimal because they are rare, crudely resemble co-mimics, or are newly evolved, but they persist in Mullerian communities for a long time. We assume that failure to closely resemble the most common model can increase the diversity of large Mullerian communities and produce mimetic dimorphism. PMID- 29487342 TI - Bonding dissimilar polymer networks in various manufacturing processes. AB - Recently developed devices mimic neuromuscular and neurosensory systems by integrating hydrogels and hydrophobic elastomers. While different methods are developed to bond hydrogels with hydrophobic elastomers, it remains a challenge to coat and print various hydrogels and elastomers of arbitrary shapes, in arbitrary sequences, with strong adhesion. Here we report an approach to meet this challenge. We mix silane coupling agents into the precursors of the networks, and tune the kinetics such that, when the networks form, the coupling agents incorporate into the polymer chains, but do not condensate. After a manufacturing step, the coupling agents condensate, add crosslinks inside the networks, and form bonds between the networks. This approach enables independent bonding and manufacturing. We formulate oxygen-tolerant hydrogel resins for spinning, printing, and coating in the open air. We find that thin elastomer coatings enable hydrogels to sustain high temperatures without boiling. PMID- 29487343 TI - Effective gamma-ray sterilization and characterization of conductive polypyrrole biomaterials. AB - Conductive polymers, including polypyrrole (PPy), have been extensively explored to fabricate electrically conductive biomaterials for bioelectrodes and tissue engineering scaffolds. For their in vivo uses, a sterilization method without severe impairment of original material properties and performance is necessary. Gamma-ray radiation has been commonly applied for sterilization of medical products because of its simple and uniform sterilization without heat generation. Herein we describe the first study on gamma-ray sterilization of PPy bioelectrodes and its effects on their characteristics. We irradiated PPy bioelectrodes with different doses (0-75 kGy) of gamma-rays. Gamma-ray irradiation of the PPy (gamma-PPy) increased the oxygenation and hydrophilicity of the surfaces. Interestingly, gamma-ray irradiation did not alter the electrical impedances and conductivities of the PPy substrates. Additionally, gamma-PPy prepared with various dopants (e.g., para-toluene sulfonate, polystyrene sulfonate, and chlorine) showed the electrochemical properties similar to the non-irradiated control. Gamma-ray irradiation at doses of >=15 kGy was required for effective sterilization as evidenced by complete eradication of gram positive and negative bacteria. gamma-PPy substrates also showed cytocompatibility similar to untreated control PPy, indicating no substantial alteration of cytocompatibility. In conclusion, gamma ray sterilization is a viable method of sterilization of conducting polymer-based biomaterials for biomedical applications. PMID- 29487344 TI - A metabolomics study of Qiliqiangxin in a rat model of heart failure: a reverse pharmacology approach. AB - The Chinese medicine Qiliqiangxin (QL) has been shown to have a protective role in heart failure. Here, we explore the underlying working mechanism of the key therapeutic component in QL using a rat model of heart failure. Heart failure after myocardial infarction was induced surgically and confirmed using echocardiography; a separate group of rats underwent sham surgery. The rats with heart failure were randomly assigned to receive QL, the angiotensin-converting enzyme inhibitor benazepril, or placebo groups. Blood samples were collected from the rats at four time points for up to 8 weeks and used for biochemical analysis and mass spectrometry-based metabolomics profiling. In total, we measured nine well-known biochemical parameters of heart failure and 147 metabolites. In the rats with heart failure, QL significantly improved these biochemical parameters and metabolomics profiles, significantly increasing the cardioprotective parameter angiopoietin-like 4 and significantly lowering inflammation-related oxylipins and lysophosphatidic acids compared to benazepril. Mechanistically, QL may improve outcome in heart failure by controlling inflammatory process and cardiac hypertrophy. Clinical studies should be designed in order to investigate these putative mechanisms in patients. PMID- 29487345 TI - Author Correction: Establishment of patient derived xenografts as functional testing of lung cancer aggressiveness. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29487346 TI - Galectin-1 enhances TNFalpha-induced inflammatory responses in Sertoli cells through activation of MAPK signalling. AB - Galectin-1 (Gal-1) is a pleiotropic lectin involved in the modulation of immune responses. Using a model of rat experimental autoimmune orchitis (EAO), we investigated the role of Gal-1 in testicular inflammation. EAO is characterized by leukocytic infiltrates in the interstitium, damage of spermatogenesis and production of inflammatory mediators like TNFalpha and MCP1 causing infertility. In normal rat testis Gal-1 was mainly expressed in Sertoli cells and germ cells. In the inflamed testis, Gal-1 expression was significantly downregulated most likely due to germ cell loss. Analyses of lectin binding and expression of glucosaminyl- and sialyltransferases indicated that the glycan composition on the cell surface of Sertoli and peritubular cells becomes less favourable for Gal-1 binding under inflammatory conditions. In primary Sertoli cells Gal-1 expression was found to be upregulated after TNFalpha challenge. Pretreatment with Gal-1 synergistically and specifically enhanced TNFalpha-induced expression of MCP1, IL 1alpha, IL-6 and TNFalpha in Sertoli cells. Combined stimulation of Sertoli cells with Gal-1 and TNFalpha enhanced the phosphorylation of MAP kinases as compared to TNFalpha or Gal-1 alone. Taken together, our data show that Gal-1 modulates inflammatory responses in Sertoli cells by enhancing the pro-inflammatory activity of TNFalpha via stimulation of MAPK signalling. PMID- 29487347 TI - Xiexin Tang improves the symptom of type 2 diabetic rats by modulation of the gut microbiota. AB - Type 2 diabetes mellitus (T2DM), a chronic metabolic disease which severely impairs peoples' quality of life, currently attracted worldwide concerns. There are growing evidences that gut microbiota can exert a great impact on the development of T2DM. Xiexin Tang (XXT), a traditional Chinese medicine prescription, has been clinically used to treat diabetes for thousands of years. However, few researches are investigated on the modulation of gut microbiota community by XXT which will be very helpful to unravel how it works. In this study, bacterial communities were analyzed based on high-throughput 16S rRNA gene sequencing. Results indicated that XXT could notably shape the gut microbiota. T2DM rats treated with XXT exhibited obvious changes in the composition of the gut microbiota, especially for some short chain fatty acids producing and anti inflammatory bacteria such as Adlercreutzia, Alloprevotella, Barnesiella, [Eubacterium] Ventriosum group, Blautia, Lachnospiraceae UCG-001, Papillibacter and Prevotellaceae NK3B31 group. Additionally, XXT could also significantly ameliorate hyperglycemia, lipid metabolism dysfunction and inflammation in T2DM rats. Moreover, the correlation analysis illustrated that the key microbiota had a close relationship with the T2DM related indexes. The results probably provided useful information for further investigation on its active mechanism and clinical application. PMID- 29487348 TI - mRNA m6A plays opposite role in regulating UCP2 and PNPLA2 protein expression in adipocytes. AB - BACKGROUND/OBJECTIVE: N6-methyladenosine (m6A) modification of mRNA plays an important role in regulating adipogenesis. However, its underlying mechanism remains largely unknown. SUBJECTS/METHODS: Using Jinhua and Landrace pigs as fat and lean models, we presented a comprehensive transcriptome-wide m6A profiling in adipose tissues from these two pig breeds. Two differentially methylated genes were selected to explore the mechanisms of m6A-mediated regulation of gene function. RESULTS: The ratio of m6A/A in the layer of backfat (LB) was significantly higher in Landrace than that in Jinhua. Transcriptome-wide m6A profiling revealed that m6A modification on mRNA occurs in the conserved sequence motif of RRACH and that the pig transcriptome contains 0.53-0.91 peak per actively expressed transcript. The relative density of m6A peaks in the 3'UTR were higher than in 5'UTR. Genes with common m6A peaks from both Landrace (L-LB) and Jinhua (J-LB) were enriched in RNA splicing and cellular lipid metabolic process. The unique m6A peak genes (UMGs) from L-LB were mainly enriched in the extracellular matrix (ECM) and collagen catabolic process, whereas the UMGs from J-LB are mainly involved in RNA splicing, etc. Lipid metabolism processes were not significantly enriched in the UMGs from L-LB or J-LB. Uncoupling protein-2 (UCP2) and patatin-like phospholipase domain containing 2 (PNPLA2) were two of the UMGs in L-LB. Synonymous mutations (MUT) were conducted to reduce m6A level of UCP2 and PNPLA2 mRNAs. Adipogenesis test showed that UCP2-MUT further inhibited adipogenesis, while PNPLA2-MUT promoted lipid accumulation compared with UCP2-WT and PNPLA2-WT, respectively. Further study showed m6A negatively mediates UCP2 protein expression and positively mediates PNPLA2 protein expression. m6A modification affects the translation of PNPLA2 most likely through YTHDF1, whereas UCP2 is likely neither the target of YTHDF2 nor the target of YTHDF1. CONCLUSION: Our data demonstrated a conserved and yet dynamically regulated m6A methylome in pig transcriptomes and provided an important resource for studying the function of m6A epitranscriptomic modification in obesity development. PMID- 29487349 TI - Progeny of old parents have increased social space in Drosophila melanogaster. AB - We report the effects of aging and parental age in Drosophila melanogaster on two types of responses to social cues: the choice of preferred social spacing in an undisturbed group and the response to the Drosophila stress odorant (dSO) emitted by stressed flies. The patterns of changes during aging were notably different for these two social responses. Flies were initially closer in space and then became further apart. However, the pattern of change in response to dSO followed a more typical decline in performance, similarly to changes in locomotion. Interestingly, the increased social space of old parents, as well as their reduced performance in avoiding dSO, was passed on to their progeny, such that young adults adopted the behavioural characteristic of their old parents. While the response to social cues was inherited, the changes in locomotion were not. We were able to scale the changes in the social space of parents and their progeny by accelerating or decelerating the physiological process of aging by increasing temperatures and exposure to oxidative stress, or via caloric restriction, respectively. Finally, when we aged only one parent, only the male progeny of old fathers and the progeny of very old mothers were more distant. PMID- 29487350 TI - Winging it: maternal perspectives and experiences of breastfeeding newborns with complex congenital surgical anomalies. AB - OBJECTIVE: To describe the experience of breastfeeding (inclusive of breast milk expression/pumping, provision of breast milk via devices, and at-breastfeeding) among mothers of newborns with complex congenital surgical anomalies and the contexts under which pro-breastfeeding behaviors and attitudes are facilitated or compromised. STUDY DESIGN: We used qualitative description to analyze 23 interviews conducted with 15 mothers of newborns undergoing surgery for gastrointestinal, cardiac, or neural tube defects. RESULTS: Breastfeeding experiences were characterized by naivety regarding the importance and rationale for exclusive breast milk feedings and best practices to facilitate milk supply maintenance and transition to at-breast feeds. Maternal breastfeeding views and behaviors were impacted by indeterminate prenatal plans to breastfeed/provide breast milk, limited prior breastfeeding exposure and knowledge, and gaps in postnatal lactation support. CONCLUSION: Future research should investigate methods to improve exclusive breast milk feeding and facilitate transitions to at breast feeds among mothers of newborns with surgical congenital anomalies, with consideration of identified barriers. PMID- 29487352 TI - The tango of ROS and p53 in tissue stem cells. PMID- 29487351 TI - Predicting the need for home gavage or g-tube feeds in asphyxiated neonates treated with therapeutic hypothermia. AB - BACKGROUND: Asphyxiated infants treated with therapeutic cooling can have persistent oral feeding difficulty because of involvement of neural pathways in the brainstem, cortex, and basal ganglia. The goal is to predict the composite adverse outcome of death or persistent oral feeding difficulty using precooling/cooling attributes, and the severity and distribution of hypoxic ischemic lesions, especially brainstem lesions on post-cooling brain magnetic resonance imaging (MRI). METHODS: Retrospective review of 86 asphyxiated infants cooled from January 2006 to August 2014. Persistent feeding difficulty was defined as needing feeding support (gastrostomy tube (g-tube) or home gavage feeds) after discharge. Clinical and laboratory risk factors, and the brain MRI abnormalities including the presence of brainstem lesions were compared between infants with and without adverse outcome using univariate analysis. Significant variables were then analyzed in a stepwise logistic regression (LR) model. RESULTS: Infants with adverse outcome (n = 31, 4 died pre-discharge) had longer hospital stay (26 days, interquartile range (IQR) 19-43 vs. 13 days, IQR 9-20; p < 0.01) and reached goal enteral feeds (oral/gavage) later (11 days vs. 8 days, p < 0.01) compared to 55 infants discharged on full oral feeds. The former infants were more likely to have cord pH <= 7.15, severely abnormal neurological examination, bleeding diathesis, continued need for ventilation, and positive MRI findings including brainstem lesions. In LR analysis, brainstem lesions on MRI (p = 0.00, odds ratio 19, 95% confidence interval 4-85) was independently associated with the adverse outcome. CONCLUSIONS: Brainstem involvement on post-cooling brain MRI was predictive of adverse outcome. Early identification of these infants may facilitate discussion of home feeding plans between clinicians and parents earlier, thereby potentially reducing the length of hospital stay. PMID- 29487353 TI - Nrf3 promotes UV-induced keratinocyte apoptosis through suppression of cell adhesion. AB - The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of the cellular stress response, but the biological functions of the related Nrf3 protein are largely unknown. Here we demonstrate a novel pro apoptotic function of Nrf3 in mouse and human keratinocytes. In response to UV irradiation, Nrf3-deficient keratinocytes were protected from apoptosis in vitro and in vivo. The protective function was also seen under oxidative or hyperosmotic stress conditions, but not when apoptosis was induced by disruption of cell-matrix interactions. Mechanistically, we show that Nrf3-deficient keratinocytes exhibit stronger cell-cell and cell-matrix adhesion, which correlates with higher cell surface integrin levels and enhanced activation of focal adhesion kinase. Nrf3-deficient cells also formed more and larger focal adhesions and exhibited a higher motility. These results suggest that the strong expression of Nrf3 in basal keratinocytes promotes their elimination in response to DNA damage-inducing agents, thereby preventing accumulation of mutated stem and transit amplifying cells in the epidermis. PMID- 29487354 TI - miRNA profiling of small intestinal neuroendocrine tumors defines novel molecular subtypes and identifies miR-375 as a biomarker of patient survival. AB - The aim of this study was to define the miRNA profile of small intestinal neuroendocrine tumors and to search for novel molecular subgroups and prognostic biomarkers. miRNA profiling was conducted on 42 tumors from 37 patients who underwent surgery for small intestinal neuroendocrine tumors. Unsupervised hierarchical clustering analysis of miRNA profiles identified two groups of tumor metastases, denoted cluster M1 and M2. The smaller cluster M1 was associated with shorter overall survival and contained tumors with higher grade (WHO grade G2/3) and multiple chromosomal gains including gain of chromosome 14. Tumors of cluster M1 had elevated expression of miR-1246 and miR-663a, and reduced levels of miR 488-3p. Pathway analysis predicted Wnt signaling to be the most significantly altered signaling pathway between clusters M1 and M2. Analysis of miRNA expression in relation to tumor proliferation rate showed significant alterations including downregulation of miR-137 and miR-204-5p in tumors with Ki67 index above 3%. Similarly, tumor progression was associated with significant alterations in miRNA expression, e.g. higher expression of miR-95 and miR-210, and lower expression of miR-378a-3p in metastases. Pathway analysis predicted Wnt signaling to be altered during tumor progression, which was supported by decreased nuclear translocation of beta-catenin in metastases. Survival analysis revealed that downregulation of miR-375 was associated with shorter overall survival. We performed in situ hybridization on biopsies from an independent cohort of small intestinal neuroendocrine tumors using tissue microarrays. Expression of miR-375 was found in 578/635 (91%) biopsies and survival analysis confirmed that there was a correlation between downregulation of miR-375 in tumor metastases and shorter patient survival. We conclude that miRNA profiling defines novel molecular subgroups of metastatic small intestinal neuroendocrine tumors and identifies miRNAs associated with tumor proliferation rate and progression. miR-375 is highly expressed in small intestinal neuroendocrine tumors and may be used as a prognostic biomarker. PMID- 29487355 TI - Pancreatic alpha cells in diabetic rats express active GLP-1 receptor: Endosomal co-localization of GLP-1/GLP-1R complex functioning through intra-islet paracrine mechanism. AB - Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion from pancreatic beta cells and suppresses glucagon secretion from alpha cells. It remains controversial, however, whether GLP-1 receptor (GLP-1R) is expressed in mature alpha cells. In this study, unlike previous studies using non-diabetic animals, we demonstrated using diabetic model rats and confocal laser scanning microscopy that the GLP-1/GLP-1R complex was located in the endosome of diabetic islets. In addition, we showed that GLP-1 and GLP-1R co-localized with various endosomal markers and adenylate cyclase in the alpha cells of diabetic rats. Diabetic rats had endosomal signaling pathway but normal rats had classical signaling pathway for activated GLP-1R. Furthermore, we performed pancreatic perfusion to assess the functional activity of GLP-1R when stimulated by exendin-4 (EX4). In a pancreas perfusion study, EX4 significantly stimulated glucagon secretion in diabetic rats but not normal rats. However, such glucagon secretion was immediately suppressed, probably due to concomitantly secreted insulin. The GLP 1/GLP-1R complex appears to function through an intra-islet paracrine mechanism in diabetic conditions which could explain, at least in part, the mechanism of paradoxical hyperglucagonaemia in type 2 diabetes. PMID- 29487356 TI - Enteropathogenic E. coli effectors EspF and Map independently disrupt tight junctions through distinct mechanisms involving transcriptional and post transcriptional regulation. AB - Enteropathogenic E. coli infection is characterized by rapid onset of diarrhea but the underlying mechanisms are not well defined. EPEC targets the tight junctions which selectively regulate the permeability of charged and uncharged molecules. Cooperative actions of the EPEC effectors EspF and Map have been reported to mediate tight junction disruption. To analyze the individual contributions of EspF and Map, we generated in vitro models where EspF and Map, derived from the EPEC strain E2348/69, were constitutively expressed in epithelial cells. Here we report that tight junction disruption by EspF and Map is caused by the inhibition of the junctional recruitment of proteins during tight junction assembly. Constitutive expression of EspF and Map depleted the levels of tight junction proteins. EspF down-regulated the transcript levels of claudin-1, occludin and ZO-1, while Map down-regulated only claudin-1 transcripts. Both effectors also caused lysosomal degradation of existing tight junction proteins. We also identified a novel interaction of Map with non-muscle myosin II. Consistent with earlier studies, EspF was found to interact with ZO-1 while actin was the common interacting partner for both effectors. Our data provides evidence for the distinct roles of Map and EspF in tight junction disruption through non-synergistic functions. PMID- 29487357 TI - Repurposing the anthelmintic drug niclosamide to combat Helicobacter pylori. AB - There is an urgent need to discover novel antimicrobial therapies. Drug repurposing can reduce the time and cost risk associated with drug development. We report the inhibitory effects of anthelmintic drugs (niclosamide, oxyclozanide, closantel, rafoxanide) against Helicobacter pylori strain 60190 and pursued further characterization of niclosamide against H. pylori. The MIC of niclosamide against H. pylori was 0.25 MUg/mL. Niclosamide was stable in acidic pH and demonstrated partial synergy with metronidazole and proton pump inhibitors, such as omeprazole and pantoprazole. Niclosamide administration at 1 * MIC concentration, eliminated 3-log10 CFU of H. pylori adhesion/invasion to AGS cells. Interestingly, no resistance developed even after exposure of H. pylori bacteria to niclosamide for 30 days. The cytotoxic assay demonstrated that niclosamide is not hemolytic and has an IC50 of 4 MUg/mL in hepatic and gastric cell lines. Niclosamide administration decreased transmembrane pH as determined by DiSC3(5) assay indicating that the mechanism of action of the anti-H. pylori activity of niclosamide was the disruption of H. pylori proton motive force. Niclosamide was effective in the Galleria mellonella-H. pylori infection model (p = 0.0001) and it can be develop further to combat H. pylori infection. However, results need to be confirmed with other H. pylori and clinical strains. PMID- 29487358 TI - PV1, a novel Plasmodium falciparum merozoite dense granule protein, interacts with exported protein in infected erythrocytes. AB - Upon invasion, Plasmodium falciparum exports hundreds of proteins across its surrounding parasitophorous vacuole membrane (PVM) to remodel the infected erythrocyte. Although this phenomenon is crucial for the parasite growth and virulence, elucidation of precise steps in the export pathway is still required. A translocon protein complex, PTEX, is the only known pathway that mediates passage of exported proteins across the PVM. P. falciparum Parasitophorous Vacuolar protein 1 (PfPV1), a previously reported parasitophorous vacuole (PV) protein, is considered essential for parasite growth. In this study, we characterized PfPV1 as a novel merozoite dense granule protein. Structured illumination microscopy (SIM) analyses demonstrated that PfPV1 partially co localized with EXP2, suggesting the protein could be a PTEX accessory molecule. Furthermore, PfPV1 and exported protein PTP5 co-immunoprecipitated with anti PfPV1 antibody. Surface plasmon resonance (SPR) confirmed the proteins' direct interaction. Additionally, we identified a PfPV1 High-affinity Region (PHR) at the C-terminal side of PTP5 where PfPV1 dominantly bound. SIM analysis demonstrated an export arrest of PTP5DeltaPHR, a PTP5 mutant lacking PHR, suggesting PHR is essential for PTP5 export to the infected erythrocyte cytosol. The overall results suggest that PfPV1, a novel dense granule protein, plays an important role in protein export at PV. PMID- 29487359 TI - Fabrication and Characterization of a Magnetic Drilling Actuator for Navigation in a Three-dimensional Phantom Vascular Network. AB - Intravascular microrobots have emerged as a promising tool for vascular diseases. They can be wirelessly and precisely manipulated with a high degree of freedom. Previous studies have evaluated their drilling performance and locomotion, and showed the feasibility of using microrobots for biomedical applications in two dimensional space. However, it is critical to validate micro-drillers in a three dimensional (3D) environment because gravity plays an important role in a 3D environment and significantly affects the performance of the micro-drillers in vascular networks. In this work, we fabricated magnetic drilling actuators (MDAs) and characterized their locomotion and drilling performance in vascular network mimicking fluidic channels. The MDAs were precisely manipulated in the fluidic channel network in both horizontal and vertical planes, selecting and moving through the desired path via the junctions of multiple channels. The MDAs also accurately navigated an artificial thrombosis in an artificial 3D vascular network and successfully drilled through it. The results obtained here confirmed the precise manipulation and drilling performance of the developed MDAs in 3D. We think that the MDAs presented in this paper have great potential as intravascular drillers for precise thrombus treatment. PMID- 29487360 TI - Sugar based N,N'-didodecyl-N,N'digluconamideethylenediamine gemini surfactant as corrosion inhibitor for mild steel in 3.5% NaCl solution-effect of synergistic KI additive. AB - The inhibitory behaviour of non-ionic sugar based N,N'-didodecyl-N,N' digluconamideethylenediamine gemini surfactant, designated as Glu(12)-2-Glu(12) on mild steel (MS) corrosion in 3.5% NaCl at 30-60 degrees C was explored using weight loss, PDP, EIS and SEM/EDAX/AFM techniques. The compound inhibited the corrosion of mild steel in 3.5% NaCl and the extent of inhibition was dependent on concentration and temperature. The inhibiting action of Glu(12)-2-Glu(12) is synergistically enhanced on addition of potassium iodide (KI) at all concentrations and temperatures. The inhibiting formulation comprising of 2.5 * 10-3 mM of Glu(12)-2-Glu(12) and 10 mM of KI exhibits an inhibition efficiency of 96.9% at 60 degrees C. Quantum chemical calculations and MD simulation were applied to analyze the experimental data and elucidate the adsorption behaviour and inhibition mechanism of inhibitors. MD simulation showed a nearly parallel or flat disposition for Glu(12)-2-Glu(12) molecules on the MS surface providing larger blocking area to prevent the metal surface from corrosion. PMID- 29487361 TI - Multicenter cohort-study of 15326 cases analyzing patient satisfaction and perioperative pain management: general, regional and combination anesthesia in knee arthroplasty. AB - Numbers of knee replacement surgeries have been rising over the past years. After having ameliorated operation techniques and material, pain management and anesthetic methods have come into focus. All 15326 patients included had undergone primary knee arthroplasty within this multicenter cohort-study, conducted in 46 orthopedic departments. Parameters were evaluated on first postoperative day. Primary outcome values were pain levels (activity, minimum and maximum pain, and pain management satisfaction). Pain medication necessity was analyzed. Parameters were compared between the types of anesthesia used: general, regional and combination anesthesia. Pain scores and pain management satisfaction were significantly better in the groups of either spinal or peripheral anesthesia combined with general anesthesia (p < 0.001, respectively). Patients who received the combination of general and spinal anesthesia were associated with the lowest need for opioids (p < 0.001). The use of a combined general and spinal anesthesia as well as using a combination of general and peripheral anesthesia in knee arthroplasty was associated with a highly significant advantage to other anesthetic techniques regarding perioperative pain management in daily clinical practice, but maybe below clinical relevance. Furthermore they were associated with positive tendency considering side effects and subjective well-being parameters. PMID- 29487363 TI - The lattice of trumping majorization for 4D probability vectors and 2D catalysts. AB - The transformation of an initial bipartite pure state into a target one by means of local operations and classical communication and entangled-assisted by a catalyst defines a partial order between probability vectors. This partial order, so-called trumping majorization, is based on tensor products and the majorization relation. Here, we aim to study order properties of trumping majorization. We show that the trumping majorization partial order is indeed a lattice for four dimensional probability vectors and two dimensional catalysts. In addition, we show that the subadditivity and supermodularity of the Shannon entropy on the majorization lattice are inherited by the trumping majorization lattice. Finally, we provide a suitable definition of distance for four dimensional probability vectors. PMID- 29487362 TI - Chiral DOTA chelators as an improved platform for biomedical imaging and therapy applications. AB - Despite established clinical utilisation, there is an increasing need for safer, more inert gadolinium-based contrast agents, and for chelators that react rapidly with radiometals. Here we report the syntheses of a series of chiral DOTA chelators and their corresponding metal complexes and reveal properties that transcend the parent DOTA compound. We incorporated symmetrical chiral substituents around the tetraaza ring, imparting enhanced rigidity to the DOTA cavity, enabling control over the range of stereoisomers of the lanthanide complexes. The Gd chiral DOTA complexes are shown to be orders of magnitude more inert to Gd release than [GdDOTA]-. These compounds also exhibit very-fast water exchange rates in an optimal range for high field imaging. Radiolabeling studies with (Cu-64/Lu-177) also demonstrate faster labelling properties. These chiral DOTA chelators are alternative general platforms for the development of stable, high relaxivity contrast agents, and for radiometal complexes used for imaging and/or therapy. PMID- 29487364 TI - Exotic complexes in one-dimensional Bose-Einstein condensates with spin-orbit coupling. AB - By means of the F-expansion method and intensive numerical simulations, the existence of three families of nonlinear matter waves including Jacobi elliptic functions, solitons, and triangular periodic functions, is demonstrated for spin orbit coupled Bose-Einstein condensates with a linear potential. In addition, several complexes are obtained by taking two distinct solutions of each family or two distinct families. These solutions sustain different types of two-body interactions in the condensate that can be repulsive, attractive, or attractive and repulsive. Whereas the spin-orbit coupling destabilized these nonlinear matter waves, the linear potential leads to a stabilization. The numerical results are in excellent agreement with our analytical findings and it can be expected that the proposed robust solutions should be observable for experimentally relevant conditions. PMID- 29487366 TI - Publisher Correction: Parallel genome reduction in symbionts descended from closely related free-living bacteria. AB - The Supplementary Information file originally published with this Article was missing Supplementary Figs 1-7. This has now been corrected. PMID- 29487365 TI - Language continuity despite population replacement in Remote Oceania. AB - Recent genomic analyses show that the earliest peoples reaching Remote Oceania associated with Austronesian-speaking Lapita culture-were almost completely East Asian, without detectable Papuan ancestry. However, Papuan-related genetic ancestry is found across present-day Pacific populations, indicating that peoples from Near Oceania have played a significant, but largely unknown, ancestral role. Here, new genome-wide data from 19 ancient South Pacific individuals provide direct evidence of a so-far undescribed Papuan expansion into Remote Oceania starting ~2,500 yr BP, far earlier than previously estimated and supporting a model from historical linguistics. New genome-wide data from 27 contemporary ni Vanuatu demonstrate a subsequent and almost complete replacement of Lapita Austronesian by Near Oceanian ancestry. Despite this massive demographic change, incoming Papuan languages did not replace Austronesian languages. Population replacement with language continuity is extremely rare-if not unprecedented-in human history. Our analyses show that rather than one large-scale event, the process was incremental and complex, with repeated migrations and sex-biased admixture with peoples from the Bismarck Archipelago. PMID- 29487368 TI - Nonlinear radiation effect on MHD Carreau nanofluid flow over a radially stretching surface with zero mass flux at the surface. AB - A mathematical model is envisaged to study the axisymmetric steady magnetohydrodynamic (MHD) Carreau nanofluid flow under the influence of nonlinear thermal radiation and chemical reaction past a radially stretched surface. Impact of heat generation/absorption with newly introduced zero mass flux condition of nanoparticles at the sheet is an added feature towards novelty of the problem. Further, for nanofluid the most recently organized model namely Buongiorno's model is assumed that comprises the effects thermophoresis and Brownian motion. Utilizing suitable self-similar transformations, the set of partial differential equations with high nonlinearity are converted into a dimensionless system of ordinary differential equations. Set of these transmuted equations are numerically solved by MATLAB built-in function bvp4c. Impact of germane parameters on all involved profiles are plotted to examine the heat and mass transfer characteristics. This study reveals that the temperature distribution is an escalating function of the heat generation and nonlinear radiation parameters. Also, it is noted that the incrementing values of chemical reaction parameter lowers the nanoparticles concentration profile. A comparison of the present investigation with already published explorations in limiting case is also added to authenticate the presented results; hence reliable results are being presented. PMID- 29487367 TI - Influenza A viruses alter the stability and antiviral contribution of host E3 ubiquitin ligase Mdm2 during the time-course of infection. AB - The interplay between influenza A viruses (IAV) and the p53 pathway has been reported in several studies, highlighting the antiviral contribution of p53. Here, we investigated the impact of IAV on the E3-ubiquitin ligase Mdm2, a major regulator of p53, and observed that IAV targets Mdm2, notably via its non structural protein (NS1), therefore altering Mdm2 stability, p53/Mdm2 interaction and regulatory loop during the time-course of infection. This study also highlights a new antiviral facet of Mdm2 possibly increasing the list of its many p53-independent functions. Altogether, our work contributes to better understand the mechanisms underlining the complex interactions between IAV and the p53 pathway, for which both NS1 and Mdm2 arise as key players. PMID- 29487369 TI - FoxP3 isoforms and PD-1 expression by T regulatory cells in multiple sclerosis. AB - Forkhead box P3 (FoxP3)+ regulatory T cells (Treg) are powerful mediators of immune regulation and immune homeostasis. In humans, Tregs are a heterogeneous population expressing surface markers which define phenotypically and functionally distinct subsets. Moreover, it is now clear that intracellular staining for FoxP3 does not unequivocally identify "true" suppressor cells, since several FoxP3 isoforms exist, and different reagents for FoxP3 detection are available. Here, we propose a strategy to identify potentially functional and suppressive Treg cells in an autoimmune disease like multiple sclerosis, and we suggest that in patients affected by this disease these cells are both reduced in number and functionally exhausted. PMID- 29487370 TI - Unlimited sucrose consumption during adolescence generates a depressive-like phenotype in adulthood. AB - Depression is highly prevalent worldwide, but its etiology is not fully understood. An overlooked possible contributor to the epidemic of depression is feeding styles, particularly at early age when the brain is intensely changing. We have previously reported that unlimited sucrose consumption during adolescence leads to enduring changes in brain reward function. Here, we tested the hypothesis that sucrose consumption during adolescence would lead to a 'depressive-like' phenotype. Adolescent male rats were given unlimited access to 5% sucrose in their home cages from postnatal day 30 to postnatal day 46 and their emotional behavior was subsequently examined at adulthood. Sucrose consumption during adolescence caused anhedonia, decreased motivation for saccharin, increased immobility in the forced swim test and exacerbated anxiety like behavior. Additionally, sucrose consumption during adolescence decreased cell proliferation in the hippocampus in adulthood. Chronic treatment with imipramine (10 mg/kg) normalized behavior and restored cell proliferation in the hippocampus of adult rats with a history of sucrose consumption during adolescence. A similar sucrose consumption starting at adulthood only increases immobility in the forced swim test, suggesting that sucrose intake affects also adults' behavior but to a lesser degree. Overall, our findings reveal an unsuspected protracted effect of sucrose consumption on behavior and suggest that unlimited sucrose consumption during critical periods of brain development may play an important role in the etiology of reward-related disorders such as depression. PMID- 29487371 TI - Organocatalyzed chemoselective ring-opening polymerizations. AB - A novel metal-free and protecting-group-free synthesis method to prepare telechelic thiol-functionalized polyesters is developed by employing organocatalysis. A scope of Bronsted acids, including trifluoromethanesulfonic acid (1), HCl.Et2O (2), diphenyl phosphate (3), gamma-resorcylic acid (4) and methanesulfonic acid (5), are evaluated to promote ring-opening polymerization of epsilon-caprolactone with unprotected 6-mercapto-1-hexanol as the multifunctional initiator. Among them, diphenyl phosphate (3) exhibits great chemoselectivity and efficiency, which allows for simply synthesis of thiol-terminated poly(epsilon caprolactone) with near-quantitative thiol fidelity, full monomer conversion, controlled molecular weight and narrow polydispersity. Kinetic study confirms living/controlled nature of the organocatalyzed chemoselective polymerizations. Density functional theory calculation illustrates that the chemoselectivity of diphenyl phosphate (3) is attributed to the stronger bifunctional activation of monomer and initiator/chain-end as well as the lower energy in hydroxyl pathway than thiol one. Moreover, series of tailor-made telechelic thiol-terminated poly(delta-valerolactone) and block copolymers are efficiently generated under mild conditions. PMID- 29487372 TI - Evaluation of Polygenic Determinants of Non-Alcoholic Fatty Liver Disease (NAFLD) By a Candidate Genes Resequencing Strategy. AB - NAFLD is a polygenic condition but the individual and cumulative contribution of identified genes remains to be established. To get additional insight into the genetic architecture of NAFLD, GWAS-identified GCKR, PPP1R3B, NCAN, LYPLAL1 and TM6SF2 genes were resequenced by next generation sequencing in a cohort of 218 NAFLD subjects and 227 controls, where PNPLA3 rs738409 and MBOAT7 rs641738 genotypes were also obtained. A total of 168 sequence variants were detected and 47 were annotated as functional. When all functional variants within each gene were considered, only those in TM6SF2 accumulate in NAFLD subjects compared to controls (P = 0.04). Among individual variants, rs1260326 in GCKR and rs641738 in MBOAT7 (recessive), rs58542926 in TM6SF2 and rs738409 in PNPLA3 (dominant) emerged as associated to NAFLD, with PNPLA3 rs738409 being the strongest predictor (OR 3.12, 95% CI, 1.8-5.5, P < 0.001). A 4-SNPs weighted genetic risk score value >0.28 was associated with a 3-fold increased risk of NAFLD. Interestingly, rs61756425 in PPP1R3B and rs641738 in MBOAT7 genes were predictors of NAFLD severity. Overall, TM6SF2, GCKR, PNPLA3 and MBOAT7 were confirmed to be associated with NAFLD and a score based on these genes was highly predictive of this condition. In addition, PPP1R3B and MBOAT7 might influence NAFLD severity. PMID- 29487373 TI - Spatial Organization of the Gastrointestinal Microbiota in Urban Canada Geese. AB - Recent reviews identified the reliance on fecal or cloacal samples as a significant limitation hindering our understanding of the avian gastrointestinal (gut) microbiota and its function. We investigated the microbiota of the esophagus, duodenum, cecum, and colon of a wild urban population of Canada goose (Branta canadensis). From a population sample of 30 individuals, we sequenced the V4 region of the 16S SSU rRNA on an Illumina MiSeq and obtained 8,628,751 sequences with a median of 76,529 per sample. These sequences were assigned to 420 bacterial OTUs and a single archaeon. Firmicutes, Proteobacteria, and Bacteroidetes accounted for 90% of all sequences. Microbiotas from the four gut regions differed significantly in their richness, composition, and variability among individuals. Microbial communities of the esophagus were the most distinctive whereas those of the colon were the least distinctive, reflecting the physical downstream mixing of regional microbiotas. The downstream mixing of regional microbiotas was also responsible for the majority of observed co occurrence patterns among microbial families. Our results indicate that fecal and cloacal samples inadequately represent the complex patterns of richness, composition, and variability of the gut microbiota and obscure patterns of co occurrence of microbial lineages. PMID- 29487374 TI - Trial by trial dependencies in multisensory perception and their correlates in dynamic brain activity. AB - A well-known effect in multisensory perception is that congruent information received by different senses usually leads to faster and more accurate responses. Less well understood are trial-by-trial interactions, whereby the multisensory composition of stimuli experienced during previous trials shapes performance during a subsequent trial. We here exploit the analogy of multisensory paradigms with classical flanker tasks to investigate the neural correlates underlying trial-by-trial interactions of multisensory congruency. Studying an audio-visual motion task, we demonstrate that congruency benefits for accuracy and reaction times are reduced following an audio-visual incongruent compared to a congruent preceding trial. Using single trial analysis of motion-sensitive EEG components we then localize current-trial and serial interaction effects within distinct brain regions: while the multisensory congruency experienced during the current trial influences the encoding of task-relevant information in sensory-specific brain regions, the serial interaction arises from task-relevant processes within the inferior frontal lobe. These results highlight parallels between multisensory paradigms and classical flanker tasks and demonstrate a role of amodal association cortices in shaping perception based on the history of multisensory congruency. PMID- 29487375 TI - Enhanced intracellular delivery via coordinated acoustically driven shear mechanoporation and electrophoretic insertion. AB - Delivery of large and structurally complex target molecules into cells is vital to the emerging areas of cellular modification and molecular therapy. Inadequacy of prevailing in vivo (viral) and in vitro (liposomal) gene transfer methods for delivery of proteins and a growing diversity of synthetic nanomaterials has encouraged development of alternative physical approaches. Efficacy of injury/diffusion-based delivery via shear mechanoporation is largely insensitive to cell type and target molecule; however, enhanced flexibility is typically accompanied by reduced gene transfer effectiveness. We detail a method to improve transfection efficiency through coordinated mechanical disruption of the cell membrane and electrophoretic insertion of DNA to the cell interior. An array of micromachined nozzles focuses ultrasonic pressure waves, creating a high-shear environment that promotes transient pore formation in membranes of transmitted cells. Acoustic Shear Poration (ASP) allows passive cytoplasmic delivery of small to large nongene macromolecules into established and primary cells at greater than 75% efficiency. Addition of an electrophoretic action enables active transport of target DNA molecules to substantially augment transfection efficiency of passive mechanoporation/diffusive delivery without affecting viability. This two-stage poration/insertion method preserves the compelling flexibility of shear-based delivery, yet substantially enhances capabilities for active transport and transfection of plasmid DNA. PMID- 29487376 TI - The most basal ankylosaurine dinosaur from the Albian-Cenomanian of China, with implications for the evolution of the tail club. AB - The tail club knob is a highly specialized structure thought to characterize a subgroup of the ankylosaurine ankylosaurians, and the oldest documented tail club knob in the fossil record occurred in the Campanian ankylosaurine Pinacosaurus. Here we report a new ankylosaurid Jinyunpelta sinensis, gen. et sp. nov., from the Albian-Cenomanian Liangtoutang Formation, Jinyun County, Zhejiang, China. This is the first definitive and the best preserved ankylosaurid dinosaur ever found in southern China. Jinyunpelta possesses unique cranial features differs from other ankylosaurs including two paranasal apertures level with and posterior to the external naris, a triangular fossa on the anterodorsal edge of the maxilla, an antorbital fossa in the junction between the maxilla, lacrimal and jugal, and an anterior process of the prearticular that lies ventral to the splenial. Our phylogenetic analysis suggests Jinyunpelta as the most basal ankylosaurine dinosaur. Jinyunpelta has a tail club with interlocking caudal vertebrae and a well-developed tail club knob, it represents the oldest and the most basal ankylosaurian known to have a well-developed tail club knob. The new discovery thus demonstrates that a large and highly modified tail club evolved at the base of the ankylosaurine ankylosaurs at least about 100 million years ago. PMID- 29487377 TI - A validation and extended description of the Lund taxonomy for urothelial carcinoma using the TCGA cohort. AB - Global gene expression analysis has been a major tool for urothelial carcinoma subtype discovery. This approach has revealed extensive complexity both in intrinsic features of the tumor cells and in the microenvironment. However, global gene expression cannot distinguish between gene expression signals originating from the tumor cells proper and from normal cells in the biopsy. Here, we use a large cohort of advanced urothelial carcinomas for which both gene expression data and extensive immunohistochemistry are available to create a supervised mRNA expression centroid classifier. This classifier identifies the major Lund taxonomy tumor cell phenotypes as defined by IHC. We apply this classifier to the independent TCGA dataset and show excellent associations between identified subtypes and genomic features. We validate a progressed version of Urothelial-like A (UroA-Prog) that shows FGFR3 mutations and CDKN2A deletions, and we show that the variant Urothelial-like C is almost devoid of FGFR3 mutations. We show that Genomically Unstable tumors are very distinct from Urothelial-like tumors at the genomic level, and that tumors classified as Basal/SCC-like all complied with the established definition for Basal/SCC-like tumors. We identify the Mesenchymal-like and Small-cell/Neuroendocrine-like subtypes, and demonstrate that patients with UroB and Sc/NE-like tumors show the worst overall survival. PMID- 29487378 TI - Environmental and anthropogenic factors affecting the increasing occurrence of shark-human interactions around a fast-developing Indian Ocean island. AB - Understanding the environmental drivers of interactions between predators and humans is critical for public safety and management purposes. In the marine environment, this issue is exemplified by shark-human interactions. The annual shark bite incidence rate (SBIR) in La Reunion (Indian Ocean) is among the highest in the world (up to 1 event per 24,000 hours of surfing) and has experienced a 23-fold increase over the 2005-2016 period. Since 1988, 86% of shark bite events on ocean-users involved surfers off the leeward coast, where 96% of surfing activities took place. We modeled the SBIR as a function of environmental variables, including benthic substrate, sea temperature and period of day. The SBIR peaked in winter, during the afternoon and dramatically increased on coral substrate since the mid-2000s. Seasonal patterns of increasing SBIR followed similar fluctuations of large coastal shark occurrences (particularly the bull shark Carcharhinus leucas), consistent with the hypothesis that higher shark presence may result in an increasing likelihood of shark bite events. Potential contributing factors and adaptation of ocean-users to the increasing shark bite hazard are discussed. This interdisciplinary research contributes to a better understanding of shark-human interactions. The modeling method is relevant for wildlife hazard management in general. PMID- 29487379 TI - Controlled Synthesis of ZrO2 Nanoparticles with Tailored Size, Morphology and Crystal Phases via Organic/Inorganic Hybrid Films. AB - In this investigation, well defined mesoporous zirconia nanoparticles (ZrO2 NPs) with cubic, tetragonal or monoclinic pure phase were synthesized via thermal recovery (in air) from chitosan (CS)- or polyvinyl alcohol (PVA)-ZrOx hybrid films, prepared using sol-gel processing. This facile preparative method was found to lead to an almost quantitative recovery of the ZrOx content of the film in the form of ZrO2 NPs. Impacts of the thermal recovery temperature (450, 800 and 1100 degrees C) and polymer type (natural bio-waste CS or synthetic PVA) used in fabricating the organic/inorganic hybrid films on bulk and surface characteristics of the recovered NPs were probed by means of X-ray diffractometry and photoelectron spectroscopy, FT-IR and Laser Raman spectroscopy, transmission electron and atomic force microscopy, and N2 sorptiometry. Results obtained showed that the method applied facilates control over the size (6-30 nm) and shape (from loose cubes to agglomerates) of the recovered NPs and, hence, the bulk crystalline phase composition and the surface area (144-52 m2/g) and mesopore size (23-10 nm) and volume (0.31-0.11 cm3/g) of the resulting zirconias. PMID- 29487380 TI - Rearrangement of Actin Microfilaments in the Development of Olfactory Receptor Cells in Fish. AB - At present, it remains poorly understood how the olfactory neuron migrates through the thick neuroepithelium during its maturation from a stem cell and how it develops a specific sensitivity to environmental odorants after maturation. We investigated the cytochemical features associated with the development of olfactory cells before and after the incorporation of dendrites into the surface of the olfactory epithelium. Using cytochemical staining for the actin cytoskeleton and other cell components, we found that immature neurons acquire a streamlined shape that resembles a "hot-dog" during their migration: a dense layer of actin microfilaments forms beneath the surface membrane of the growing dendrite, and the bulk of the nuclear material moves inside this layer. We have found that when the cell makes contact with its environment, the dendritic terminal develops a wide actin layer, inside which a pore is formed. It is assumed that the functional receptors of odorants generate across this pore the first intracellular signal from environmental water-soluble odorants. These data illustrate the important role of the cytoskeleton in the differentiation of olfactory cells. PMID- 29487381 TI - mGluR5 antagonism inhibits cocaine reinforcement and relapse by elevation of extracellular glutamate in the nucleus accumbens via a CB1 receptor mechanism. AB - Metabotropic glutamate receptor 5 (mGluR5) antagonism inhibits cocaine self administration and reinstatement of drug-seeking behavior. However, the cellular and molecular mechanisms underlying this action are poorly understood. Here we report a presynaptic glutamate/cannabinoid mechanism that may underlie this action. Systemic or intra-nucleus accumbens (NAc) administration of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) dose-dependently reduced cocaine (and sucrose) self-administration and cocaine-induced reinstatement of drug-seeking behavior. The reduction in cocaine-taking and cocaine-seeking was associated with a reduction in cocaine-enhanced extracellular glutamate, but not cocaine-enhanced extracellular dopamine (DA) in the NAc. MPEP alone, when administered systemically or locally into the NAc, elevated extracellular glutamate, but not DA. Similarly, the cannabinoid CB1 receptor antagonist, rimonabant, elevated NAc glutamate, not DA. mGluR5s were found mainly in striatal medium-spiny neurons, not in astrocytes, and MPEP-enhanced extracellular glutamate was blocked by a NAc CB1 receptor antagonist or N-type Ca++ channel blocker, suggesting that a retrograde endocannabinoid-signaling mechanism underlies MPEP-induced glutamate release. This interpretation was further supported by our findings that genetic deletion of CB1 receptors in CB1-knockout mice blocked both MPEP-enhanced extracellular glutamate and MPEP-induced reductions in cocaine self-administration. Together, these results indicate that the therapeutic anti-cocaine effects of mGluR5 antagonists are mediated by elevation of extracellular glutamate in the NAc via an endocannabinoid-CB1 receptor disinhibition mechanism. PMID- 29487382 TI - Antibodies to a strain-specific citrullinated Epstein-Barr virus peptide diagnoses rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease. Anti citrullinated protein antibodies (ACPA) are crucial for the serological diagnosis of RA, where Epstein-Barr virus (EBV) has been suggested to be an environmental agent in triggering the onset of the disease. This study aimed to analyse antibody reactivity to citrullinated EBV nuclear antigen-2 (EBNA-2) peptides from three different EBV strains (B95-8, GD1 and AG876) using streptavidin capture enzyme-linked immunosorbent assay. One peptide, only found in a single strain (AG876), obtained a sensitivity and specificity of 77% and 95%, respectively and showed high sequence similarity to the filaggrin peptide originally used for ACPA detection. Comparison of antibody reactivity to commercial assays found that the citrullinated peptide was as effective in detecting ACPA as highly sensitive and specific commercial assays. The data presented demonstrate that the citrullinated EBNA-2 peptide indeed is recognised specifically by RA sera and that the single peptide is able to compete with assays containing multiple peptides. Furthermore, it could be hypothesized that RA may be caused by (a) specific strain(s) of EBV. PMID- 29487383 TI - De novo transcriptome analysis and gene expression profiling of an oleaginous microalga Scenedesmus acutus TISTR8540 during nitrogen deprivation-induced lipid accumulation. AB - Nitrogen deprivation (-N) has been used as a technique to promote lipid accumulation in various microalgae. Scenedesmus acutus is a promising oleaginous green microalga that can be cultivated in organic wastewater for biodiesel production. Nevertheless, the molecular mechanisms controlling S. acutus lipid accumulation in response to -N remain unidentified. Physiological study determined that -N reduced cell growth and photosynthetic pigments. On the other hand, it promoted carbohydrate and neutral lipid accumulation. To find the mechanisms underlying lipid accumulation, we performed de novo transcriptome profiling of the non-model S. acutus in response to -N. The transcriptome analysis revealed that glycolysis and starch degradation were up-regulated; on the contrary, gluconeogenesis, photosynthesis, triacylglycerol (TAG) degradation and starch synthesis were down-regulated by -N. Under -N, the carbon flux was shifted toward fatty acid and TAG synthesis, and the down regulation of TAG lipase genes may contribute to TAG accumulation. A comparative analysis of the -N transcriptomes of oleaginous microalgae identified that the down-regulation of multiple lipase genes was a specific mechanism found only in the -N transcriptome of S. acutus. Our study unraveled the mechanisms controlling -N-induced lipid accumulation in S. acutus, and provided new perspectives for the genetic manipulation of biodiesel-producing microalgae. PMID- 29487384 TI - Continental-scale animal tracking reveals functional movement classes across marine taxa. AB - Acoustic telemetry is a principle tool for observing aquatic animals, but coverage over large spatial scales remains a challenge. To resolve this, Australia has implemented the Integrated Marine Observing System's Animal Tracking Facility which comprises a continental-scale hydrophone array and coordinated data repository. This national acoustic network connects localized projects, enabling simultaneous monitoring of multiple species over scales ranging from 100 s of meters to 1000 s of kilometers. There is a need to evaluate the utility of this national network in monitoring animal movement ecology, and to identify the spatial scales that the network effectively operates over. Cluster analyses assessed movements and residency of 2181 individuals from 92 species, and identified four functional movement classes apparent only through aggregating data across the entire national network. These functional movement classes described movement metrics of individuals rather than species, and highlighted the plasticity of movement patterns across and within populations and species. Network analyses assessed the utility and redundancy of each component of the national network, revealing multiple spatial scales of connectivity influenced by the geographic positioning of acoustic receivers. We demonstrate the significance of this nationally coordinated network of receivers to better reveal intra-specific differences in movement profiles and discuss implications for effective management. PMID- 29487385 TI - Histone deacetylase (HDAC) inhibitor ACY241 enhances anti-tumor activities of antigen-specific central memory cytotoxic T lymphocytes against multiple myeloma and solid tumors. AB - Histone deacetylases (HDAC) are therapeutic targets in multiple cancers. ACY241, an HDAC6 selective inhibitor, has shown anti-multiple myeloma (MM) activity in combination with immunomodulatory drugs and proteasome inhibitors. Here we show ACY241 significantly reduces the frequency of CD138+ MM cells, CD4+CD25+FoxP3+ regulatory T cells, and HLA-DRLow/-CD11b+CD33+ myeloid-derived suppressor cells; and decreases expression of PD1/PD-L1 on CD8+ T cells and of immune checkpoints in bone marrow cells from myeloma patients. ACY241 increased B7 (CD80, CD86) and MHC (Class I, Class II) expression on tumor and dendritic cells. We further evaluated the effect of ACY241 on antigen-specific cytotoxic T lymphocytes (CTL) generated with heteroclitic XBP1unspliced184-192 (YISPWILAV) and XBP1spliced367 375 (YLFPQLISV) peptides. ACY241 induces co-stimulatory (CD28, 41BB, CD40L, OX40) and activation (CD38) molecule expression in a dose- and time-dependent manner, and anti-tumor activities, evidenced by increased perforin/CD107a expression, IFN gamma/IL-2/TNF-alpha production, and antigen-specific central memory CTL. These effects of ACY241 on antigen-specific memory T cells were associated with activation of downstream AKT/mTOR/p65 pathways and upregulation of transcription regulators including Bcl-6, Eomes, HIF-1 and T-bet. These studies therefore demonstrate mechanisms whereby ACY241 augments immune response, providing the rationale for its use, alone and in combination, to restore host anti-tumor immunity and improve patient outcome. PMID- 29487386 TI - Hypomethylating agents in combination with immune checkpoint inhibitors in acute myeloid leukemia and myelodysplastic syndromes. AB - Immune checkpoint inhibitors, as single-agent therapy, have shown modest clinical efficacy in the treatment of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). As has been successfully shown in other less immunogenic hematologic malignancies, rationally designed combination approaches may be more effective than single-agent checkpoint inhibitors, and may be the approach to pursue in AML/MDS. Hypomethylating agents (HMAs) such as azacitidine, while enhancing anti-tumor immune response, concurrently dampen immune response by upregulating inhibitory immune checkpoint molecule expression. Immune checkpoint molecule upregulation may be an important mechanism of azacitidine resistance. These findings have resulted in multiple clinical trials combining HMAs with immune checkpoint blockade. Clinical trial data have shown encouraging response rates and durable responses without resorting to stem cell transplant. In this review, we discuss preclinical data supporting the use of these agents in combination, and focus on clinical and correlative data emerging from numerous clinical trials investigating HMA-immune checkpoint inhibitor combinations in AML/MDS. PMID- 29487388 TI - Fiona Marshall. PMID- 29487389 TI - Cancer: Targeting the ubiquitin pathway. PMID- 29487390 TI - Alzheimer disease: Identification of blood-based biomarkers. PMID- 29487387 TI - Drugging the lncRNA MALAT1 via LNA gapmeR ASO inhibits gene expression of proteasome subunits and triggers anti-multiple myeloma activity. AB - The biological role and therapeutic potential of long non-coding RNAs (lncRNAs) in multiple myeloma (MM) are still to be investigated. Here, we studied the functional significance and the druggability of the oncogenic lncRNA MALAT1 in MM. Targeting MALAT1 by novel LNA-gapmeR antisense oligonucleotide antagonized MM cell proliferation and triggered apoptosis both in vitro and in vivo in a murine xenograft model of human MM. Of note, antagonism of MALAT1 downmodulated the two major transcriptional activators of proteasome subunit genes, namely NRF1 and NRF2, and resulted in reduced trypsin, chymotrypsin and caspase-like proteasome activities and in accumulation of polyubiquitinated proteins. NRF1 and NRF2 decrease upon MALAT1 targeting was due to transcriptional activation of their negative regulator KEAP1, and resulted in reduced expression of anti-oxidant genes and increased ROS levels. In turn, NRF1 promoted MALAT1 expression thus establishing a positive feedback loop. Our findings demonstrate a crucial role of MALAT1 in the regulation of the proteasome machinery, and provide proof-of concept that its targeting is a novel powerful option for the treatment of MM. PMID- 29487392 TI - Alnylam prepares to land first RNAi drug approval. PMID- 29487391 TI - Cardiovascular disease: Inhalation therapy for heart failure. PMID- 29487393 TI - Immunotherapy: Direct shot. PMID- 29487394 TI - Antibacterials: Synthetic peptides eradicate resistant infections. PMID- 29487395 TI - Autophagy: Mitochondria encaged. PMID- 29487396 TI - Corrigendum: Anderson localization and Mott insulator phase in the time domain. AB - This corrects the article DOI: 10.1038/srep10787. PMID- 29487397 TI - Contemporary approach to predict early biochemical recurrence after radical prostatectomy: update of the Walz nomogram. AB - BACKGROUND: Early biochemical recurrence (eBCR) after radical prostatectomy (RP) heralds poor oncological outcomes and may be prevented with adjuvant radiation (aRT). METHODS: We developed a contemporary eBCR nomogram in 13 797 RP patients from Hamburg (2005-2016) and externally validated it in 5952 RP patients from Vienna. Receiver operating characteristics-derived area under the curve (AUC), Heagerty's C-index, and decision curve analysis (DCA) were used to quantify model accuracy and to compare the current tool with the Walz nomogram, the online Memorial Sloan Kettering Cancer Center (MSKCC) nomogram and the post-surgical Cancer of the Prostate Risk Assesment (CAPRA-S). RESULTS: The eBCR nomogram relies on independent BCR predictors at 12 and 24 months after RP: preoperative PSA, pathological Gleason Score, tumor stage, lymph node, and surgical margin status. It achieved 81% accuracy at both time points in external validation. Additionally, the current nomogram yielded best calibration, optimal DCA results, and highest rates of avoided aRT in cutoff analyses, compared to the Walz nomogram, the MSKCC nomogram, and the CAPRA-S score. CONCLUSIONS: The updated eBCR nomogram is easily applicable, highly accurate, and may allow avoiding immediate aRT in a large proportion of patients with few concomitant missed eBCR instances. It compares favorably to similar tools. PMID- 29487398 TI - Fosfomycin vs. quinolone-based antibiotic prophylaxis for transrectal ultrasound guided biopsy of the prostate: a systematic review and meta-analysis. AB - BACKGROUND: Infection-related complications secondary to quinolone resistance have been on the rise following transrectal ultrasound-guided biopsy of the prostate (TRUSBP). The aim of this review was to compare the efficacy of fosfomycin with quinolone-based antibiotic prophylaxis for TRUSBP. METHODS: A systematic review in line with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) and Cochrane guidelines was conducted. All studies comparing fosfomycin vs. non-fosfomycin antimicrobial prophylaxis for TRUSBP were considered. The main outcomes were number of urinary tract infections (UTIs) (overall, afebrile, febrile, and urosepsis) and fluoroqinolone resistance. Secondary outcomes were positive urine and blood cultures, and adverse effects of drugs. RESULTS: Five studies comparing fosfomycin and non-fosfomycin antimicrobials were included in the review. In all, 1447 and 1665 patients were included in the fosfomycin and non-fosfomycin cohorts, respectively. The systematic review report significantly lower UTIs in the fosfomycin cohort (M-H, Fixed, 95% CI), 0.20 (0.13, 0.30), p < 0.00001. Urine cultures from patients given fosfomycin showed significantly lower resistance rates (M-H, Fixed, 95% CI) 0.27 (0.15, 0.50), p < 0.0001. The adverse effect profile between the two cohorts were similar (M-H, Fixed, 95% CI) 1.13 (0.51, 2.50), p = 0.33. On Grade Pro evaluation, overall UTI, afebrile UTI, febrile UTI, and urosepsis were rates as moderate, low, very low, and moderate quality evidence, respectively. Positive blood and urine culture were rated as moderate and very low-quality evidence, respectively. Fluoroquinolone resistance was rated as low-quality evidence. Adverse effects was rated as very low-quality evidence. CONCLUSIONS: This review suggests that fosfomycin has significantly lower septic complications with an equivalent side effect profile in comparison with quinolone-based prophylaxis regimen for TRUSBP. There is an urgent need for appropriate antibiotic stewardship and it is paramount that studies with robust methodology are developed to establish the role of fosfomycin over existing antibiotic regimens for TRUSBP. PMID- 29487400 TI - Genetics for your whole life. PMID- 29487399 TI - Publisher Correction: Embryonic defects induced by maternal obesity in mice derive from Stella insufficiency in oocytes. AB - In the version of this article originally published, the positions of Wenjie Shu and Qiang Wang in the author list were reversed and incorrect images were displayed in the HTML for Supplementary Figs. 1-12. The errors have been corrected in the HTML and PDF versions of the article. PMID- 29487401 TI - Are immunotherapies for Huntington's disease a realistic option? AB - There is compelling evidence that the pathophysiology of many neurodegenerative diseases includes dysregulation of the immune system, with some elements that precede disease onset. However, if these alterations are prominent, why have clinical trials targeting this system failed to translate into long-lasting meaningful benefits for patients? This review focuses on Huntington's disease, a genetic disorder marked by notable cerebral and peripheral inflammation. We summarize ongoing and completed clinical trials that have involved pharmacological approaches to inhibit various components of the immune system and their pre-clinical correlates. We then discuss new putative treatment strategies using more targeted immunotherapies such as vaccination and intrabodies and how these may offer new hope in the treatment of Huntington's disease as well as other neurodegenerative diseases. PMID- 29487402 TI - Ketamine has distinct electrophysiological and behavioral effects in depressed and healthy subjects. AB - Ketamine's mechanism of action was assessed using gamma power from magnetoencephalography (MEG) as a proxy measure for homeostatic balance in 35 unmedicated subjects with major depressive disorder (MDD) and 25 healthy controls enrolled in a double-blind, placebo-controlled, randomized cross-over trial of 0.5 mg/kg ketamine. MDD subjects showed significant improvements in depressive symptoms, and healthy control subjects exhibited modest but significant increases in depressive symptoms for up to 1 day after ketamine administration. Both groups showed increased resting gamma power following ketamine. In MDD subjects, gamma power was not associated with the magnitude of the antidepressant effect. However, baseline gamma power was found to moderate the relationship between post ketamine gamma power and antidepressant response; specifically, higher post ketamine gamma power was associated with better response in MDD subjects with lower baseline gamma, with an inverted relationship in MDD subjects with higher baseline gamma. This relationship was observed in multiple regions involved in networks hypothesized to be involved in the pathophysiology of MDD. This finding suggests biological subtypes based on the direction of homeostatic dysregulation and has important implications for inferring ketamine's mechanism of action from studies of healthy controls alone. PMID- 29487403 TI - Use of an Alzheimer's disease polygenic risk score to identify mild cognitive impairment in adults in their 50s. AB - Early identification of younger, non-demented adults at elevated risk for Alzheimer's disease (AD) is crucial because the pathological process begins decades before dementia onset. Toward that end, we showed that an AD polygenic risk score (PRS) could identify mild cognitive impairment (MCI) in adults who were only in their 50s. Participants were 1176 white, non-Hispanic community dwelling men of European ancestry in the Vietnam Era Twin Study of Aging (VETSA): 7% with amnestic MCI (aMCI); 4% with non-amnestic MCI (naMCI). Mean age was 56 years, with 89% <60 years old. Diagnosis was based on the Jak-Bondi actuarial/neuropsychological approach. We tested six P-value thresholds (0.05 0.50) for single nucleotide polymorphisms included in the ADPRS. After controlling for non-independence of twins and non-MCI factors that can affect cognition, higher PRSs were associated with significantly greater odds of having aMCI than being cognitively normal (odds ratios (ORs) = 1.36-1.43 for thresholds P < 0.20-0.50). The highest OR for the upper vs. lower quartile of the ADPRS distribution was 3.22. ORs remained significant after accounting for APOE-related SNPs from the ADPRS or directly genotyped APOE. Diabetes was associated with significantly increased odds of having naMCI (ORs = 3.10-3.41 for thresholds P < 0.05-0.50), consistent with naMCI having more vascular/inflammation components than aMCI. Analysis of sensitivity, specificity, and negative and positive predictive values supported some potential of ADPRSs for selecting participants in clinical trials aimed at early intervention. With participants 15+ years younger than most MCI samples, these findings are promising with regard to efforts to more effectively treat or slow AD progression. PMID- 29487405 TI - Synchrony and social connection in immersive Virtual Reality. AB - Synchronising movements in time with others can have significant positive effects on affiliative attitudes and behaviors. To explore the generalizability of synchrony effects, and to eliminate confounds of suggestion, competence and shared intention typical of standard laboratory and field experiments, we used an Immersive Virtual Reality (VR) environment. Participants, represented as virtual humans, took part in a joint movement activity with two other programmed virtual humans. The timings of the co-participant characters' movements were covertly manipulated to achieve synchrony or non-synchrony with the focal participant. Participants in the synchrony condition reported significantly greater social closeness to their virtual co-participants than those in the non-synchrony condition. Results indicate that synchrony in joint action causes positive social effects and that these effects are robust in a VR setting. The research can potentially inform the development of VR interventions for social and psychological wellbeing. PMID- 29487404 TI - Role and regulation of growth plate vascularization during coupling with osteogenesis in tibial dyschondroplasia of chickens. AB - Tibial dyschondroplasia (TD) is the most-prevalent leg disorder in fast-growing chickens; it is intractable and characterized by abnormal endochondral bone formation of proximal tibial growth-plates (TGPs). Previous studies have shown that bone is a highly vascularized tissue dependent on the coordinated coupling between angiogenesis and osteogenesis, but the underlying mechanisms of bone formation and bone remodeling are poorly defined in TD chickens. Here, we observed that inhibition of vasculogenesis and angiogenesis remarkably impaired vascular invasion in the hypertrophic chondrocyte zone of the TGPs, resulting in the massive death of chondrocytes due to a shortage of blood vessels and nutrients. Moreover, the balance of the OPG (osteoprotegerin)/RANKL (receptor activator of nuclear factor-kB ligand) system is also severely disrupted during the osteogenesis process while coupling with angiogenesis, both of which eventually lead to abnormal endochondral bone formation in TD chickens. Thus, the process of vascular formation in endochondral bone appears to initiate the pathological changes in TD, and improvement of this process during coupling with osteogenesis may be a potential therapeutic approach to treat this intractable disease. PMID- 29487406 TI - High strength films from oriented, hydrogen-bonded "graphamid" 2D polymer molecular ensembles. AB - The linear polymer poly(p-phenylene terephthalamide), better known by its tradename Kevlar, is an icon of modern materials science due to its remarkable strength, stiffness, and environmental resistance. Here, we propose a new two dimensional (2D) polymer, "graphamid", that closely resembles Kevlar in chemical structure, but is mechanically advantaged by virtue of its 2D structure. Using atomistic calculations, we show that graphamid comprises covalently-bonded sheets bridged by a high population of strong intermolecular hydrogen bonds. Molecular and micromechanical calculations predict that these strong intermolecular interactions allow stiff, high strength (6-8 GPa), and tough films from ensembles of finite graphamid molecules. In contrast, traditional 2D materials like graphene have weak intermolecular interactions, leading to ensembles of low strength (0.1-0.5 GPa) and brittle fracture behavior. These results suggest that hydrogen-bonded 2D polymers like graphamid would be transformative in enabling scalable, lightweight, high performance polymer films of unprecedented mechanical performance. PMID- 29487407 TI - Association between Depression and More Aggressive Inflammatory Bowel Disease. PMID- 29487408 TI - C. difficile and celiac disease: the "difficile" to tell association. PMID- 29487409 TI - Who is wrong? Responses to Kwo et al. PMID- 29487410 TI - When and how to use magnetic resonance elastography for patients with liver disease in clinical practice. PMID- 29487411 TI - Office management of hemorrhoids. PMID- 29487412 TI - The characteristics and predictors of postpartum hepatitis flares in women with chronic hepatitis B. AB - INTRODUCTION: We aimed to characterize postpartum disease flares among treatment naive mothers with chronic hepatitis B (CHB). CHB mothers were enrolled and compared with non-infected mothers in terms of postpartum alanine aminotransferase (ALT) abnormalities. METHODS: Demographic, virological, and biochemical parameters were collected up to postpartum week 16, with flares and exacerbations defined as ALT levels 5-10 and >10 times the upper limit of normal, respectively. Outcome assessments included ALT flares or exacerbation and their predictive parameters. RESULTS: Among 4236 patients enrolled, 869 and 3367 had no infection (group A) and had CHB (group B), respectively. Infected mothers were further stratified into two subgroups by the presence (B1, n = 1928) or absence (B2, n = 1439) of detectable serum levels of hepatitis B virus (HBV) DNA (lowest level of quantitation, 100 IU/mL). A significantly higher frequency of abnormal ALT levels was observed in group B vs. group A (28.27 vs. 20.37%, p < 0.001). ALT events mainly occurred in group B1 (flares, 115/1928, 5.96%; exacerbations, 57/1928, 2.96%). The ALT levels had a bimodal pattern, with peaks at postpartum weeks 3-4 and 9-12. On multivariate analysis, elevated ALT levels and detectable levels of HBV DNA at delivery were independent risk factors for postpartum disease flares. Further subgroup analysis in group B1 demonstrated that a cut-off HBV DNA level of 5 log10 IU/mL at delivery predicted ALT events (positive predictive value, 14.4%; negative predictive value, 98.2%). CONCLUSIONS: Postpartum ALT level elevation is common in CHB patients. ALT flares or exacerbations are mainly observed in mothers with elevated ALT or HBV DNA levels >=5 log10 IU/mL at delivery. PMID- 29487413 TI - Patterns and predictors of repeat fecal immunochemical and occult blood test screening in four large health care systems in the United States. AB - OBJECTIVES: Effectiveness of fecal occult blood test (FOBT) for colorectal cancer (CRC) screening depends on annual testing, but little is known about patterns of repeat stool-based screening within different settings. Our study's objective was to characterize screening patterns and identify factors associated with repeat screening among patients who completed an index guaiac FOBT (gFOBT) or fecal immunochemical test (FIT). METHODS: We performed a multi-center retrospective cohort study among people who completed a FOBT between January 2010 and December 2011 to characterize repeat screening patterns over the subsequent 3 years. We studied at 4 large health care delivery systems in the United States. Logistic regression analyses were used to identify factors associated with repeat screening patterns. We included individuals aged 50-71 years who completed an index FOBT and had at least 3 years of follow-up. We excluded people with a history of CRC, colonoscopy within 10 years or flexible sigmoidoscopy within 5 years before the index test, or positive index stool test. Consistent screening was defined as repeat FOBT within every 15 months and inconsistent screening as repeat testing at least once during follow-up but less than consistent screening. RESULTS: Among 959,857 eligible patients who completed an index FIT or gFOBT, 344,103 had three years of follow-up and met inclusion criteria. Of these, 46.6% had consistent screening, 43.4% inconsistent screening, and 10% had no repeat screening during follow-up. Screening patterns varied substantially across healthcare systems, with consistent screening proportions ranging from 1 to 54.3% and no repeat screening proportions ranging from 6.9 to 42.8%. Higher consistent screening proportions were observed in health systems with screening outreach and in-reach programs, whereas the safety-net health system, which uses opportunistic clinic-based screening, had the lowest consistent screening. Consistent screening increased with older age but was less common among racial/ethnic minorities and patients with more comorbidities. CONCLUSIONS: Adherence with annual FOBT screening is highly variable across healthcare delivery systems. Settings with more organized screening programs performed better than those with opportunistic screening, but evidence-based interventions are needed to improve CRC screening adherence in all settings. PMID- 29487414 TI - Parallel graded attention in reading: A pupillometric study. AB - There are roughly two lines of theory to account for recent evidence that word processing is influenced by adjacent orthographic information. One line assumes that multiple words can be processed simultaneously through a parallel graded distribution of visuo-spatial attention. The other line assumes that attention is strictly directed to single words, but that letter detectors are connected to both foveal and parafoveal feature detectors, as such driving parafoveal-foveal integrative effects. Putting these two accounts to the test, we build on recent research showing that the pupil responds to the brightness of covertly attended (i.e., without looking) locations in the visual field. Experiment 1 showed that foveal target word processing was facilitated by related parafoveal flanking words when these were positioned to the left and right of the target, but not when these were positioned above and below the target. Perfectly in line with this asymmetry, in Experiment 2 we found that the pupil size was contingent with the brightness of the locations of horizontally but not vertically aligned flankers, indicating that attentional resources were allocated to those words involved in the parafoveal-on-foveal effect. We conclude that orthographic parafoveal-on-foveal effects are driven by parallel graded attention. PMID- 29487415 TI - Genetic diseases and information to relatives: practical and ethical issues for professionals after introduction of a legal framework in France. AB - Health professionals have a role to play in assisting patients to communicate genetic information to their relatives. In France, a specific unique legal framework has been implemented concerning this issue. We questioned professionals about their practice and how it has evolved in this new frame. The French law has opted to lay responsibility for disclosure on the person concerned by a positive test result, without totally excluding some responsibility on the part of the professionals involved, in the information to be disclosed and in the transmission of the information if a patient refuses to do it themselves (indirect disclosure). We designed and validated an online survey to be sent out to healthcare professionals to explore their practice and how they went about implementing the legal provisions. We also sought to determine how healthcare professionals dealt with a patient's refusal to disclose information to their relatives, and whether the legal framework was helpful. We carried out a statistical analysis of the responses to questionnaires to interpret the results by professional category, field of medicine and genetic disorder. The results show that professionals agreed on the relevance of disclosure to relatives. However, they show a range of practices and varying representations of the genetic issue in the framework of disclosure to relatives according to their medical field, their role in the health system and their own interpretations. They indicated a lack of resources, raised some ethical issues and put forward some arguments against contacting relatives themselves. PMID- 29487416 TI - RD-Connect, NeurOmics and EURenOmics: collaborative European initiative for rare diseases. AB - Although individually uncommon, rare diseases (RDs) collectively affect 6-8% of the population. The unmet need of the rare disease community was recognized by the European Commission which in 2012 funded three flagship projects, RD-Connect, NeurOmics, and EURenOmics, to help move the field forward with the ambition of advancing -omics research and data sharing at their core in line with the goals of IRDiRC (International Rare Disease Research Consortium). NeurOmics and EURenOmics generate -omics data and improve diagnosis and therapy in rare renal and neurological diseases, with RD-Connect developing an infrastructure to facilitate the sharing, systematic integration and analysis of these data. Here, we summarize the achievements of these three projects, their impact on the RD community and their vision for the future. We also report from the Joint Outreach Day organized by the three projects on the 3rd of May 2017 in Berlin. The workshop stimulated an open, multi-stakeholder discussion on the challenges of the rare diseases, and highlighted the cross-project cooperation and the common goal: the use of innovative genomic technologies in rare disease research. PMID- 29487417 TI - Clinical utility gene card: for pseudoxanthoma elasticum. PMID- 29487418 TI - HIF1alpha drives chemokine factor pro-tumoral signaling pathways in acute myeloid leukemia. AB - Approximately 80% of patients diagnosed with acute myeloid leukemia (AML) die as a consequence of failure to eradicate the tumor from the bone marrow microenvironment. We have recently shown that stroma-derived interleukin-8 (IL-8) promotes AML growth and survival in the bone marrow in response to AML-derived macrophage migration inhibitory factor (MIF). In the present study we show that high constitutive expression of MIF in AML blasts in the bone marrow is hypoxia driven and, through knockdown of MIF, HIF1alpha and HIF2alpha, establish that hypoxia supports AML tumor proliferation through HIF1alpha signaling. In vivo targeting of leukemic cell HIF1alpha inhibits AML proliferation in the tumor microenvironment through transcriptional regulation of MIF, but inhibition of HIF2alpha had no measurable effect on AML blast survival. Functionally, targeted inhibition of MIF in vivo improves survival in models of AML. Here we present a mechanism linking HIF1alpha to a pro-tumoral chemokine factor signaling pathway and in doing so, we establish a potential strategy to target AML. PMID- 29487420 TI - Colorectal cancer: Evading the immune response in metastasis. PMID- 29487421 TI - Viral hepatitis: A new model for HBV infection of primary human hepatocytes. PMID- 29487419 TI - Functional screening of FGFR4-driven tumorigenesis identifies PI3K/mTOR inhibition as a therapeutic strategy in rhabdomyosarcoma. AB - Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma and outcomes have stagnated, highlighting a need for novel therapies. Genomic analysis of RMS has revealed that alterations in the receptor tyrosine kinase (RTK)/RAS/PI3K axis are common and that FGFR4 is frequently mutated or overexpressed. Although FGFR4 is a potentially druggable receptor tyrosine kinase, its functions in RMS are undefined. This study tested FGFR4-activating mutations and overexpression for the ability to generate RMS in mice. Murine tumor models were subsequently used to discover potential therapeutic targets and to test a dual PI3K/mTOR inhibitor in a preclinical setting. Specifically, we provide the first mechanistic evidence of differential potency in the most common human RMS mutations, V550E or N535K, compared to FGFR4wt overexpression as murine myoblasts expressing FGFR4V550E undergo higher rates of cellular transformation, engraftment into mice, and rapidly form sarcomas that highly resemble human RMS. Murine tumor cells overexpressing FGFR4V550E were tested in an in vitro dose response drug screen along with human RMS cell lines. Compounds were grouped by target class, and potency was determined using average percentage of area under the dose-response curve (AUC). RMS cells were highly sensitive to PI3K/mTOR inhibitors, in particular, GSK2126458 (omipalisib) was a potent inhibitor of FGFR4V550E tumor-derived cell and human RMS cell viability. FGFR4V550E overexpressing myoblasts and tumor cells had low nanomolar GSK2126458 EC50 values. Mass cytometry using mouse and human RMS cell lines validated GSK2126458 specificity at single-cell resolution, decreasing the abundance of phosphorylated Akt as well as decreasing phosphorylation of the downstream mTOR effectors 4ebp1, Eif4e, and S6. Moreover, PI3K/mTOR inhibition also robustly decreased the growth of RMS tumors in vivo. Thus, by developing a preclinical platform for testing novel therapies, we identified PI3K/mTOR inhibition as a promising new therapy for this devastating pediatric cancer. PMID- 29487423 TI - Liver cancer: Lenvatinib non-inferior to sorafenib for hepatocellular carcinoma. PMID- 29487422 TI - Surgery: Describing the global burden of infection after gastrointestinal surgery. PMID- 29487424 TI - Therapy: FMT: the rules of engraftment. PMID- 29487425 TI - Potential functional bakery products as delivery systems for prebiotics and probiotics health enhancers. AB - Several health benefits have been associated to probiotics and prebiotics, most of these are involved in the regulation of the host's gut microbiome. Their incorporation to diverse food products has been done to develop potential functional foods. In the case of bakery products, their incorporation has been seen to improve several technological parameters such as volume, specific volume, texture along with sensorial parameters such as flavor and aroma. Scientific literature in this topic has been divided in three main research branches: nutrition, physical quality and sensory analyzes, however, studies rarely cover all of them. Due to the harsh thermal stress during baking, sourdough technology along with microencapsulation of probiotics, has been studied as an alternative to enhance its nutritional values and increase cell viability, though in few occasions. The potential functional baked goods have maintained acceptable physical characteristics and sensorial acceptability, while in some cases an improvement is seen due to the effect of probiotics and prebiotics. The results obtained from several studies done, have shown the viability of developing functional bakery products by applying prebiotics or probiotics. This could be used as an encouragement for more research to be done in this topic. PMID- 29487426 TI - Influences of cold atmospheric plasma on microbial safety, physicochemical and sensorial qualities of meat products. AB - Meat and meat products can be contaminated with pathogenic microorganisms, which cause serious health problems and economic loss. Recently, numerous novel non thermal technologies have been developed to respond to growing consumer demand for high quality and safe meat products. Cold atmospheric plasma (CAP) is a novel and emerging non-thermal technology, showing great potential for applications in the food industry. This review presents recent advances on the developments and applications of CAP in meat products, including generation and microbial inactivation effects of CAP as well as its influences on physicochemical qualities and sensory attributes of meat products. Furthermore, the safety assessment of CAP-treated meat products and challenges in industrial application of CAP are also discussed. PMID- 29487427 TI - Animal fat replacement by vegetable oils in formulations of breads with flour mixes. AB - The improvement of fatty acids (FA) profile of bread made with bovine fat (BF) and a mixture of flours completely replacing fat with canola oil (CO), or olive oil (OO) was evaluated. Technological and sensory characteristics and overall acceptability of the fortified breads were also studied. The results showed a decrease in saturated FA and a relative increase in monounsaturated and polyunsaturated FA compared to bread made with BF. Regarding CO, this caused the higher increase in n3 FA. This effect was maximized in bread made from the mixture of wheat flour (WF) + flaxseed flour (FF) + soybean flour (SF). OO caused a rise of n9 and n6 FA, mainly in bread made with WF + FF + wheat bran (WB). The breads with WF + FF + SF + CO and WF + FF + WB + OO presented higher specific volume, softer crumb and colour similar to those from base formulations. Furthermore, they had a very good sensory acceptance. PMID- 29487428 TI - Effect of pH and pulsed electric field process parameters on the aflatoxin reduction in model system using response surface methodology: Effect of pH and PEF on Aflatoxin Reduction. AB - The presence of aflatoxin, a carcinogenic and toxigenic secondary metabolite produced by Aspergillus species, in food matrix has been a major worldwide problem for years now. Food processing methods such as roasting, extrusion, etc. have been employed for effective destruction of aflatoxins, which are known for their thermo-stable nature. The high temperature treatment, adversely affects the nutritive and other quality attributes of the food, leading to the necessity of application of non-thermal processing techniques such as ultrasonication, gamma irradiation, high pressure processing, pulsed electric field (PEF), etc. The present study was focused on analysing the efficacy of the PEF process in the reduction of the toxin content, which was subsequently quantified using HPLC. The process parameters of different pH model system (potato dextrose agar) artificially spiked with aflatoxin mix standard was optimized using the response surface methodology. The optimization of PEF process effects on the responses aflatoxin B1 and total aflatoxin reduction (%) by pH (4-10), pulse width (10-26 us) and output voltage (20-65%), fitted 2FI model and quadratic model respectively. The response surface plots obtained for the processes were of saddle point type, with the absence of minimum or maximum response at the centre point. The implemented numerical optimization showed that the predicted and actual values were similar, proving the adequacy of the fitted models and also proved the possible application of PEF in toxin reduction. PMID- 29487429 TI - Evaluation of variability and environmental stability of grain quality and agronomic parameters of pigmented rice (O. sativa L.). AB - Eleven pigmented rice genotypes were evaluated to estimate genetic parameters, heritability and association. The results indicated that, genotypic variation was high among the lines. The distinct seasonal effect on plant performance for antioxidant capacity, anthocyanin, flavonoids, head rice recovery and test weights was also observed. Wet season favoured the crop performance in all genotypes as compared to drought conditions. The differential accumulation of different quality traits such as AOA, anthocyanin content, flavonoids content, etc showed high heritability, which would be transfer to high yeilding popular rice cultivars through conventional or geneticaly modification techniques. The line Mamihunger was chosen as donor of the high-quality rice grain and Annapurna for high yield. Further, Mamihunger are foreseen to be good in nutritional quality and industry use. PMID- 29487430 TI - Physical properties and estimated glycemic index of protein-enriched sorghum based chips. AB - Sorghum is a gluten-free grain and more attention has been given to the nutritional properties and recently its usage as a wheat replacement in food products. In the present work, protein-enriched sorghum based snack chips, prepared from sorghum meal with soy protein isolates and soy flour to meet the final protein content of 35.7%, were produced. The effect of varying baking powder (1.5-2.5%), dough sheet thickness (0.7-1.7 mm), and baking time (6-12 min) on the physical properties of the snack chips was investigated using a central composite design of response surface methodology. Under baking temperature of 160 degrees C, with baking powder added, the water activity and puffiness of chips significantly increased. Baking time was the most significant factor for all the parameters detected except for puffiness. The optimized conditions of preparing protein-enriched sorghum chips were baking powder 2.5%, dough sheet thickness 0.7 mm, and baking time 7.66 min. The estimated glycemic index (eGI) of the protein enriched sorghum chips (eGI = 59.8) was significantly lower than soybean-free sorghum chips. The gluten-free protein-enriched sorghum chips developed could be considered as protein rich with lower intermediate-glycemic index classified healthy snacks and potential commercialization. PMID- 29487431 TI - Surface modification of nanosatrch using nano silver: a potential antibacterial for food package coating. AB - Starch nanocrystal was prepared using weak sulfuric acid hydrolysis at 40 degrees C. Transmission electron micrographs of dilute suspensions of starch nanocrystals showed round particles with a diameter ranging from 20 to 40 nm. SEM of freeze dried samples showed separated particles between 40 and 100 nm and confirmed production of starch nano particles. XRD patterns obtained for the prepared nanostarch and raw starch sample showed no special pattern of crystallinity for starch sample. Extracted nanostarch showed pattern of crystallinity with the peaks at Bragg angles (2theta) at about 15 degrees and 23 degrees , and a doublet at 17 degrees and 18 degrees . The crystalline structure of prepared sample was A-type. FTIR spectra confirmed the particles oxidation. Nano silver particle was precipitated on the starch nano particle. UV spectra confirmed the presence of silver particle on the starch particles. Inhibitions tests of nanostarch bearing nano silver on three types of bacteria was investigated. The inhibition test results were 25 ug/mL for S. aureus, and S. typhi, and 12.5 ug/mL for E. coli. PMID- 29487432 TI - Effect of extrusion process on the functional properties of high amylose corn starch edible films and its application in mango (Mangifera indica L.) cv. Tommy Atkins. AB - Starch is an attractive raw material as ingredient for edible film manufacture because of its low cost, abundant availability, renewability, and biodegradability. Nevertheless, starch based films exhibit several disadvantages such as brittleness and poor mechanical and barrier properties, which restrict its application for food packaging. The use of the extrusion technology as a pretreatment of the casting technique to change the starch structure in order to obtain edible films, may constitute an alternative to generate coatings with good functional properties and maintain longer the postharvest quality and shelf life of fruits. For this reason, the objective of this study was to optimize the conditions of an extrusion process to obtain a formulation of modified starch to elaborate edible films with good functional properties using the casting technique and assess the effect during the storage when applied on a model fruit. The best conditions of the extrusion process and concentration of plasticizers were obtained using response surface methodology. From optimization study, it was found that appropriate conditions to obtain starch edible films with the best mechanical and barrier properties were an extrusion temperature of 100 degrees C and a screw speed of 120 rpm, while the glycerol content was 16.73%. Also, once applied in fruit, the loss of quality attributes was diminished. PMID- 29487433 TI - Increase of content and bioactivity of total phenolic compounds from spent coffee grounds through solid state fermentation by Bacillus clausii. AB - Spent coffee grounds are waste material generated during coffee beverage preparation. This by-product disposal causes a negative environmental impact, in addition to the loss of a rich source of nutrients and bioactive compounds. A rotating central composition design was used to determine the optimal conditions for the bioactivity of phenolic compounds obtained after the solid state fermentation of spent coffee grounds by Bacillus clausii. To achieve this, temperature and fermentation time were varied according to the experimental design and the total phenolic and flavonoid content, antioxidant activity and antimicrobial activity were determined. Surface response methodology showed that optimum bioprocessing conditions were a temperature of 37 degrees C and a fermentation time of 39 h. Under these conditions, total phenolic and flavonoid contents increased by 36 and 13%, respectively, in fermented extracts as compared to non-fermented. In addition, the antioxidant activity was increased by 15% and higher antimicrobial activity was observed against Gram positive and negative bacteria. These data demonstrated that bioprocessing optimization of spent coffee grounds using the surface response methodology was an important tool to improve phenolic extraction, which could be used as an antioxidant and antimicrobial agents incorporated into different types of food products. PMID- 29487434 TI - Antibacterial activity and mode of action of totarol against Staphylococcus aureus in carrot juice. AB - Food contaminated with pathogenic bacteria such as Staphylococcus aureus (S. aureus), represents a serious health risk to human beings. Totarol is an antibacterial novel phenolic diterpenes. In present study, the antibacterial activity of totarol against S. aureus was investigated in a food system. The antibacterial activity of totarol was determined by measuring the zones of inhibition and minimum inhibitory concentrations (MICs). The MICs for S. aureus strains were in the range of 2-4 MUg/ml. The probable antibacterial mechanism of totarol was the alteration in cell membranes integrity and permeability, which leading to the leakage of cellular materials. The electric conductivity showed a time- and dose-dependent increasing manner, and we utilized totarol to induce the production of cytoplasmic beta-galactosidase in S. aureus. Scanning electron microscopy and transmission electron microscopy analysis further confirmed that S. aureus cell membranes were damaged by totarol. The time-kill assay and detection of the kinetics of S. aureus deactivation in situ indicated that totarol has good preservative activities in a food model. Totarol successfully inhibited S. aureus development in carrot juice, at room temperature (25 degrees C) and in refrigerator (4 degrees C) respectively. Our works provided not only additional evidences in support of totarol being regarded as a natural antibacterial food preservative but also fundamental understanding on the mode of antibacterial action. It is necessary to consider that totarol will become a promising antibacterial additive for food preservative. PMID- 29487435 TI - Thermodynamic sorption analysis and glass transition temperature of faba bean (Vicia faba L.) protein. AB - Freeze-dried faba bean (Vicia faba L.) protein adsorption isotherms were determined at 25, 35 and 40 degrees C and fitted with the Guggenheim-Anderson-de Boer model. The pore radius of protein was in the range of 0.87-6.44 nm, so that they were considered as micropores and mesopores. The minimum integral entropy ranged between 4.33 and 4.44 kg H2O/100 kg d.s., was regarded as the point of maximum of stability. The glass transition temperature of the protein equilibrated at the different conditions of storage was determined, showing that the protein remained in glassy state for all cases. The protein showed compact and rigid structures, evidenced by microscopy analysis. PMID- 29487436 TI - Nutritional quality of different grades of adult male chinese mitten crab, Eriocheir sinensis. AB - This study mainly investigated the composition of adult male Chinese mitten crab (Eriocheir sinensis) from four grades/sizes (Grade I: 200-249 g; Grade II: 175 199 g; Grade III: 150-174 g; Grade IV: <= 150 g). The results showed that the grade III crabs had the largest gonadsomatic index (GSI), which was significantly higher than the grade I and grade II crabs, no significant difference was found with the grade IV crab. Significant differences in moisture and total lipid contents were observed among various edible parts from different grades of male Eriocheir sinensis. In particular, grade II crabs had the highest total lipid and dry matter content for hepatopancreas. A balanced amino acids composition and a high essential amino acids score (EAAS) were found in the muscle and gonads of grade III crabs. The levels of poly-unsaturated fatty acids (PUFA), n-3 PUFA, n-6 PUFA and docosahexaenoic acid (DHA) in the hepatopancreas, as well as the contents of PUFA, highly-unsaturated fatty acids (HUFA), n-3 PUFA, arachidonic acid (ARA), and eicosapentaenoic acid (EPA) in the gonads were significantly increased in the grade II crabs. Taken together, it can generally be concluded that adult male Eriocheir sinensis of 150-200 g (Grade II-III) weight have the highest nutritional quality even though they are not the largest crabs. PMID- 29487437 TI - Determination of the microbial flora in traditional Izmir Tulum cheeses by Denaturing Gradient Gel Electrophoresis. AB - In this study, it was aimed to determine microbial flora members in three traditional Tulum cheeses (C1, C2 and C3) produced in different villages and settlement areas in Izmir, Turkey. For this purpose, culture depended and 16S rRNA based culture independent methods were used. According to the results of culture depended method, Lactococcus spp., Enterococcus spp., Staphylococcus spp., Lactobacillus spp., Pediococcus spp. and yeast-mold were detected in all samples at different levels. In order to determine and identify both of the culturable and non-culturable microorganisms, denaturing gradient gel electrophoresis (DGGE) method was used. DGGE results have shown that there were eight different dominant microorganisms (Streptococcus thermophilus, Lactococcus lactis subs. lactis, Streptococcus infantarius subs. infantarius, Lactobacillus gallinarum, Streptococcus equinus, Enterococcus faecalis, Enterococcus faecium, Lactococcus garvieae) in three regionally cheese samples. Further more, total bacterial loads were monitored with real-time PCR (qPCR) method. According to the results, 3.5 * 108, 3.8 * 108, 8.4 * 108 copy number of DNA was detected in C1, C2 and C3 cheese samples, respectively. This study is the first description for the dynamics of microbial composition of Izmir Tulum cheese after the production and brining processes. PMID- 29487438 TI - Improving the quality of matured coconut (Cocos nucifera Linn.) water by low alcoholic fermentation with Saccharomyces cerevisiae: antioxidant and volatile profiles. AB - Matured coconut water (MCW) is a by-product in the coconut milk industry that is usually discarded due to its unpleasant flavor. In this study, low-alcohol coconut water (LACW) was fermented with Saccharomyces cerevisiae to improve the quality of MCW. Volatile components and nonvolatile flavor-related elements were estimated to compare the qualities of the MCW and LACW. Besides measuring the kinetic changes, the levels of fructose, glucose, sucrose and ethanol contents were also determined. The results of the organic acid assays showed that tartaric, pyruvic and succinic acids were the primary organic acids present in LACW and increased significantly with fermentation. The resulting volatile composition assay indicated that esters, alcohols and fatty acids were significantly influenced by fermentation and yeast strains. Moreover, 1,1 diphenyl-2-picrylhydrazyl (DPPH), 2,2'-azinobis-(3-ethylbenzothiazoline-6 sulfonic acid) (ABTS), cupric ion reducing antioxidant capacity and ferric reducing antioxidant power values increased significantly throughout the process, correlating with the enhancement of total phenolic content. PMID- 29487439 TI - Optimization of ultrasound-assisted extraction (UAE) of phenolic compounds from olive cake. AB - The use of ultrasound in ultrasound-assisted extraction (UAE) is one of the main applications of this technology in food industry. This study aimed to optimize UAE conditions for olive cake extract (OCE) through response surface methodology (RSM). The optimal UAE conditions were obtained with extraction temperature of 56 degrees C, extraction time of 3 min, duty cycle of 0.6 s, and solid to solvent ratio of 3.6%. At the optimum conditions, the total phenolic compounds (TPC) content and antioxidant activity (AA) were measured 4.04 mg/g and 68.9%, respectively. The linear term of temperature had the most effect on TPC content and AA of OCE prepared by UAE. Protocatechuic acid and cinnamic acid were characterized as the highest (19.5%) and lowest (1.6%) phenolic compound measured in OCE extracted by UAE. This research revealed that UAE is an effective method to extract phenolic compounds from olive cake. RSM successfully optimized UAE conditions for OCE. PMID- 29487440 TI - Effect of high hydrostatic pressure on background microflora and furan formation in fruit puree based baby foods. AB - The baby foods industry is currently seeking technologies to pasteurize products without formation of processing contaminants such as furan. This work demonstrates the applicability of high hydrostatic pressure (HHP) as a non thermal decontamination intervention for fruit puree based baby foods. HHP processing was evaluated at 200, 300, and 400 MPa pressures, for 5, 10 and 15 min of treatment times at 25, 35 and 45 degrees C. HHP application at 400 MPa, 45 degrees C for 15 min ensured complete inactivation (about 6 log10) of total mesophilic aerophiles, as well as yeasts and molds. No furan was detected in HHP processed products. Thus, the key advantage of HHP over thermal processing is the ability to achieve commercially acceptable microbiological inactivation while avoiding the formation of processing contaminants such as furan. PMID- 29487441 TI - Antioxidant activity, fatty acids characterization and oxidative stability of Gouda cheese fortified with mango (Mangifera indica L.) kernel fat. AB - Effect of mango kernel fat (MKF) on antioxidant characteristics and lipolysis of Gouda cheese was investigated. Milk fat (3.5%) was partially replaced with MKF i.e. 5, 10, 15 and 20% concentrations (T1, T2, T3 and T4). Cheese prepared from 100% milk fat served as control. Cheese samples were ripened for 90 days at 6 +/- 1 degrees C and analysed at 0, 45 and 90 days of ripening. Total phenolic contents of control, T1, T2, T3 and T4 were 14 +/- 0.35, 129 +/- 0.75, 188 +/- 2.52, 267 +/- 10.61 and 391 +/- 8.46 mg GAE/g. Total flavonoid content of control, T1, T2, T3 and T4 were 0.22 +/- 0.03, 1.47 +/- 0.09, 3.62 +/- 0.15, 5.88 +/- 0.35, 8.29 +/- 0.63 mg quercetin equivalent/ml. DPPH free radical scavenging activity of control and experimental samples increased throughout the ripening period. DPPH free radicals scavenging activity of 90 days old control, T1, T2, T3 and T4 were 16.38 +/- 0.0.26e, 30.47 +/- 0.64d, 68.62 +/- 0.91c, 73.29 +/- 0.85b, 92.61 +/- 1.44a %. HPLC characterization revealed the existence of mangiferin, caffeic acid, catechin, quercetin and chlorogenic acid in MKF fortified Gouda cheese. Fortification of MKF increased the concentration of C18:1, C18:2 and C18:3 in cheese. The concentration of C18:1, C18:2 and C18:3 in control were 24.55 +/- 0.95, 1.76 +/- 0.09 and 0.31 +/- 0.02%. While, the concentration of C18:1, C18:2 and C18:3 in T4 were 30.11 +/- 1.34, 2.79 +/- 2.79 and 0.92 +/- 0.11%. MKF fortified Gouda cheese had better oxidative stability and sensory characteristics. These results evidenced that antioxidant capacity, unsaturated fatty acids and oxidative stability of Gouda cheese can be improved with MKF. PMID- 29487442 TI - Kinetic modelling of non-enzymatic browning and changes of physio-chemical parameters of peach juice during storage. AB - Kinetics of non-enzymatic browning and loss of free amino acids during different storage temperature (4, 25, 37 degrees C) were investigated. Changes of browning degree (A420), color parameters, Vitamin C (Vc), free amino acids and 5 hydroxymethylfurfural (5-HMF) were analyzed to evaluate the non-enzymatic browning reactions, which were significantly affected by storage temperature. The lower temperature (4 degrees C) decreased the loss of Vc and the generation of 5 HMF, but induce the highest loss of serine. At the end of storage, loss of serine, alanine and aspartic acid were mainly lost. Results showed that zero order kinetic model (R2 > 0.859), the first-order model (R2 > 0.926) and the combined kinetic model (R2 > 0.916) were the most appropriate to describe the changes of a* and b* values, the degradation of Vc and the changes of A420, L* and 5-HMF during different storage temperatures. These kinetic models can be applied for predicting and minimizing the non-enzymatic browning of fresh peach juice during storage. PMID- 29487443 TI - Antioxidant capacity and amino acid profile of millet bran wine and the synergistic interaction between major polyphenols. AB - Millet bran, the by-product of millet processing industry, contains an abundance of phytochemicals, especially polyphenols. The main objective of this study was brewing antioxidant wine from millet bran, as well as the nutritional evaluation. The total polyphenol content of wine samples was determined by Folin-Ciocalteu colorimetric method, and the antioxidant capacity was evaluated by DPPH radical scavenging capacity, Trolox equivalent antioxidant capacity (TEAC), and ferric reducing antioxidant power (FRAP). Results showed that millet bran wine (MBW) contained as much as six times of total polyphenols compared with millet wine (MW), and performed considerably stronger antioxidant activity in DPPH, TEAC and FRAP assays. More than sixfold of total amino acids (AA) were found in MBW than in MW. Moreover, the indispensable AA and functional AA were also abundant in MBW. The major polyphenol compounds in MBW were identified using HPLC, including vanillic acid, syringic acid (SA), p-coumaric acid (CA) and ferulic acid (FA). They exhibited synergism in the antioxidant assays, especially the combinations of SA and CA, SA and FA. This study not only provides evidence for MBW as a nutraceutical with antioxidant activity, but also opens new avenues in the area of making comprehensive utilization of agricultural by-products. PMID- 29487445 TI - Chlorophyll extraction from suji leaf (Pleomele angustifolia Roxb.) with ZnCl2 stabilizer. AB - Suji (Pleomele angustifolia Roxb.) leaves are a prominent source of chlorophyll and well-known for their ability to produce green color for food ingredients. However, chlorophyll is suspectible to color degradation at high temperature. Color degradation occurred because porphyrin loses magnesium in its ring and it can be avoided by adding zinc. The aim of this work was to investigate the combined effect of independent variables on chlorophyll extraction process using ZnCl2 as a stabilizer. Suji leaves were blanched with boiling water for 2 min, Zn chlorophyll synthesis was done by varying concentration of ZnCl2, Zn-chlorophyll extraction with ethanol, and UV-Vis spectrophotometry analysis of the final extracted solutions. A full three-level factorial design under response surface methodology was used to obtain the optimum condition of extraction process. The experimental data were analyzed by analysis of variance and fitted with second order polynomial equation. The coefficient of determination (R2) was found to be 81.99%. The optimum operating conditions were obtained at pH 7, ZnCl2 concentration of 700 ppm and temperature of 85 degrees C with desirability value of 1.0000. At the optimum conditions, the total chlorophyll content (TCC) was found to be 47.2975 mg/100 g fresh weight. PMID- 29487444 TI - Plastein reaction enhanced bile-acid binding capacity of soybean protein hydrolysates and whey protein hydrolysates. AB - Plastein reaction is a modification reaction that can improve the functional properties of protein hydrolysate. The product of the reaction is a thixotropic aggregation of peptides. This study investigated the formation condition of soybean-whey plastein and bile acid binding capacity of plastein. Soy protein and whey protein were hydrolyzed by pepsin. The mixture (1:1, w/w) of two hydrolysates was modified by pepsin again. After the reaction, the decrease in free amino groups and the turbidity of the modified hydrolysate were measured to obtain appropriate reaction condition. Results showed that the concentration of hydrolysates 40% (w/v), enzyme ratio of 2.0 KU/g protein, pH 5.0, 37 degrees C, reaction time of 3.0 h respectively, were showed maximum changes in protein hydrolysates. Tricine SDS-PAGE analysis under denaturing conditions revealed that whey protein was more sensitive to pepsin and yielded different polypeptides (PPs) of molecular weight ranged from 3.5-17 kDa. However, a high molecular weight PP was completely hydrolyzed while PPs of 14.2-26 kDa were partially digested after pepsin treatment. Native page analysis further revealed the presence of a high-molecular weight PP in crude and purified plastein product. The bile acid binding capacity was improved by the plastein reaction. The amount of binding sodium deoxycholate, sodium taurocholate, and sodium cholate were 0.75, 2.0 and 1.87 MUmol/100 mg respectively. PMID- 29487446 TI - Influence of ultrasound pretreatment on enzymolysis kinetics and thermodynamics of sodium hydroxide extracted proteins from tea residue. AB - The effect of ultrasound pretreatment using Single Frequency Counter Current Ultrasound (SFCCU) on the enzymolysis of tea residue protein (TRP) extracted with sodium hydroxide was investigated. The concentration of TRP hydrolysate, enzymolysis kinetics and thermodynamic parameters after SFCCU pretreatment were determined and compared with traditional enzymolysis. The results indicated that both ultrasound assisted and traditional enzymolysis conformed to first-order kinetics within the limits of the studied parameters. Temperature and sonication had affirmative effect on the enzymolysis of TRP with temperature yielding greater impact. Michaelis constant (KM ) in ultrasonic pretreated enzymolysis decreased by 32.7% over the traditional enzymolysis. The highest polypeptide concentration of 24.12 mg ml-1 was obtained with the lowest energy requirement at improved conditions of 50 g L-1 of TRP, alcalase concentration of 2000 U g-1, time of 10 min and temperature of 50 degrees C for the ultrasonic treated enzymolysis. The values of reaction rate constant (k) for TRP enzymolysis increased by 78, 40, 82 and 60% at 20, 30, 40 and 50 degrees C, respectively. The thermodynamic properties comprising activation energy (Ea), change in enthalpy (?H) and entropy (?S) were reduced by ultrasound pretreatment whereas Gibbs free energy (?G) was increased. PMID- 29487447 TI - Thermal stability and haemolytic effects of depolymerized guar gum derivatives. AB - The purpose of current study was to purify and partially depolymerize guar gum by beta-mannanase, HCl, Ba(OH)2 actions and subjected to inspect compositional, thermogravimetric analysis (TGA) and haemolytic activity. Chemical composition revealed mannose and galactose ratio remained un-altered even after process of purification and hydrolysis. TGA thermograms affirmed initial and final decomposition temperature in various zones. Major decomposition stages apparently revealed partially hydrolyzed guar gum (PHGG) exhibited better heat stable properties having more zones of degradation than crude one. Furthermore, all guar fractions (2.5-250 mg/mL) were subjected to haemolysis to evaluate toxic effects during process of hydrolysis. The crude and hydrolyzed guar galactomannans exhibited minor haemolytic activity (1.9 +/- 0.03-7.24 +/- 0.02%) when compared to 0.1% Triton-X 100 (100% haemolysis) showing no toxic effects to human RBC's. Conclusively, hydrolyzed guar-galactomannans are safe and can be used in food products with improved heat stability. PMID- 29487448 TI - Elucidating potential utilization of Portuguese common bean varieties in rice based processed foods. AB - The present study was aimed at studying the physico-chemical and functional properties of 31 Portuguese common bean varieties. In addition, the whole bean flours (WBF) and starch isolates (SI) of three representative bean varieties and their rice: bean blends (70:30; 50:50) were assessed for amylose content, thermal and pasting properties in view of supplementation in rice based processed foods. Bean varieties showed significant differences in protein content (20.78-27.10%), fat content (1.16-2.18%), hydration capacity (95.90-149.30%), unhydrated seeds (4.00-40.00%), gamma tocopherol (3.20-98.05 mg/100 g fat), delta tocopherol (0.06 4.72 mg/100 g fat) and pasting behavior. Amylose content of WBF (11.4-20.2%) was significantly lower than rice flour (23.51%) whereas SI of beans (40.00-47.26%) had significantly higher amylose content than SI of rice (28.13%). DSC results showed that WBF (11.4-20.2 degrees C) had significantly broader and lower gelatinization temperature range (?Tr) than corresponding SI (20.9-23.1 degrees C). WBF had significantly lower pasting viscosity due to low starch content and compositional matrix effect as compared to SI. Setback viscosities of WBF and rice: bean blends was lower than rice flour. Low setback viscosities of rice:bean blends may be used to prevent syneresis and stabilizing the quality of frozen foods in rice based processed foods. PMID- 29487449 TI - Chemical acetylation of nixtamalized maize flour and structural, rheological and physicochemical properties of flour, dough and tortillas. AB - Nixtamalized maize tortilla is a basic food for the Mexican population. It has high energy due to high starch, which may be modified to decrease its bioavailability and to produce changes in the characteristics of flours. For this research, nixtamalized maize flour was prepared and subjected to an acetylation chemical process, with and without prior hydrolysis. Raw maize flour, traditionally nixtamalized maize flour, acetylated-nixtamalized maize flour (AF) and acetylated-hydrolyzed nixtamalized maize flour (AHF) were prepared and evaluated. These flours were used for dough and tortilla preparation and analyzed for degree of substitution (DS), physicochemical properties, structure, thermal, rheological, morphological and texture properties. FTIR spectra and DS showed the presence of acetyl groups. AHF showed the highest value for water absorption index. The resistant starch increased 0.27 and 0.42% for AF and AHF samples. The gelatinization enthalpy (?Hg) for AF was greater than other flours. AF tortillas showed better characteristics than the traditional ones and their consumption was recommended since showed better RS. PMID- 29487450 TI - Quality of pomegranate pomace as affected by drying method. AB - During the industrial manufacturing of pomegranate juice, large amounts of pomace are produced. The aim of this work was to find the effective method to dry pomegranate pomace to open new commercial applications for this co-product. The effects of three drying methods: (i) convective drying (CD) at 50, 60, and 70 degrees C; (ii) vacuum microwave drying (VMD) at 240, 360, and 480 W, and (iii) a combined method (CPD-VMFD); convective pre-drying (60 degrees C) followed by vacuum microwave finish drying (360 W), on drying kinetics and quality of PomP (pomegranate pomace obtained after preparing pomegranate juice by squeezing only arils) were evaluated. The shortest treatments were VMD at 240 and 360 W (52 and 33 min, respectively); besides, these treatments led to interesting values of the green-red coordinate, a*, (12.2 and 4.1, respectively), total phenolic content (4.0 and 4.1 mg eq gallic acid g-1 dry weight, respectively), and antioxidant activity (30.8 and 29.0 umol g-1 dry weight, respectively). On the other hand, this study demonstrated that this co-product is a rich source of punicic acid (average value = 66.4%), being a good opportunity for the pharmaceutical and nutraceutical industries. Moreover, no significant changes in the fatty acid profile was observed as affected by the drying treatments, and no off-flavors were generated by any of the drying methods. PMID- 29487451 TI - Ultrasound-assisted extraction, characterization, and antioxidant activity in vitro and in vivo of polysaccharides from Chestnut rose (Rosa roxburghii tratt) fruit. AB - In this study, the response surface methodology was utilized to determine optimum conditions for extracting the polysaccharides from Rosa roxburghii Tratt fruit (RRTPs) using ultrasonic-assisted extraction, and the characterization and antioxidant activities of the RRTPs were discussed. RRTPs yield was 6.59 +/- 1.34%, which was well consistent with the predicted value of 6.716%, under the following optimum conditions: ratio of water to raw material 40.18 mL/g, extraction temperature 78.8 degrees C, ultrasonic power 148 W, and extraction time 32.8 min. The monosaccharide composition analysis indicated that RRTPs were composed of mannose (Man), rhamnose (Rha), glucuronic acid (GlcA), galacturonic acid (GalA), glucose (Glc), galactose (Gal), arabinose (Ara) and xylose (Xyl). The molecular weight distribution analysis showed that RRTPs had four main components with molecular weights of 332.56, 183.96, 11.92 and 5.95 kDa, respectively. In vitro antioxidant studies revealed RRTPs exhibited significant antioxidant potential on hydroxyl, superoxide and DPPH radicals. In addition, antioxidant assays in vivo demonstrated that RRTPs can significantly increase the superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) activities, and total antioxidant capacity (TAOC) to some extent, as well as decrease the level of malondialdehyde (MDA) in both serum and liver of d-Gal aging-induced mice. These data suggested that RRTPs could be a potential candidate of natural antioxidants for applications in functional food, pharmaceuticals or cosmetic industries. In summary, this work provided an effective method for the exploitation and utilization of value-added R. roxburghii Tratt fruit which would be useful to fully utilize this resource. PMID- 29487452 TI - Olive oil aromatization with saffron by liquid-liquid extraction. AB - A new aromatization method for olive oils with saffron aqueous extracts rich in safranal has been developed using liquid-liquid extraction. Four flavoured olive oils were obtained (SO1-SO4). SO1 showed the highest safranal concentration (145.89 mg L-1), followed by SO2 (79.33 mg L-1), SO3 (0.30 mg L-1) and SO4 (0.01 mg L-1). Although flavouring originated a decrease in the quality parameters and the oxidative stability of the oils, even after 7 months of storage, at room and refrigeration temperatures, the oil parameters evaluated were still comparable to those of extra virgin olive oil. Flavored olive oils with less safranal (SO3, SO4) are preferred by consumers. PMID- 29487453 TI - Crystallization of low saturated lipid blends of palm and canola oils with sorbitan monostearate and fully hydrogenated palm oil. AB - Several scientific investigations have focused on providing new strategies for supporting the development of low saturated and zero trans lipid materials, as healthier fat alternatives for food application. This work evaluated the consistency, crystallization behavior, microstructure and polymorphism of six blends composed of palm and canola oils at different concentrations (100:0, 80:20, 60:40, 40:60, 20:80 and 0:100, in w/w%) added with 5.0% of fully hydrogenated palm oil (FHPO) or with a mixture of 2.5% of FHPO and 2.5% of sorbitan monostearate (SMS). The results were compared with the non-structured blends (standard samples). Through microstructure images, the formation of a more homogeneous and denser packed crystal network was observed for samples added with both crystallization modifiers (FHPO/SMS) compared to the corresponding standard samples, after stabilization at 25 degrees C during 3 h. In particular, enhanced crystallization modifications were observed for the 40:60 blend, in which the crystal form beta' emerged after the addition of FHPO/SMS. Moreover, the 40:60 blend structured with FHPO/SMS showed increased consistency (from 30 to 658 gF/cm2) and induced onset crystallization in a higher temperature (from 13.1 to 23.9 degrees C) compared with the non-structured one, due to the specific crystallization effects provided by both added structurants. PMID- 29487454 TI - Effect of calcium and salicylic acid on quality retention in relation to antioxidative enzymes in radish stored under refrigerated conditions. AB - Effect of post harvest treatments with calcium chloride (CaCl2) and salicylic acid (SA) on physiological and biochemical parameters in relation to activities of antioxidative enzymes were investigated in radish. Radish of variety Punjab Safed Mooli 2 was harvested, washed and treated with CaCl2 (1, 1.5 and 2%) or SA (1, 1.5 and 2 mM). Treated as well as untreated radish were placed in open trays and stored under refrigerated (5 +/- 1 degrees C, 90% RH) conditions for 42 days. Treatment of radish with CaCl2 and SA slowed down changes in physiological weight, colour, total soluble solids, ascorbic acid, titrable acidity, total phenolics and antioxidant activity. Treated samples exhibited higher enhancement in activities of antioxidant enzymes viz. catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GR), peroxidase (POD), dehydroascorbate reductase (DHAR) and monodehydro-ascorbate reductase (MDHAR) than untreated samples. However SA was found to be more effective in slowing down the metabolic activities of radish as compared to CaCl2 treatment. Among all the treatments, 1.5 mM SA maintained the quality parameters to greater extent probably by reducing the oxidative stress to larger extent due to highest activities of antioxidative enzymes and can be used to enhance the shelf life of radish during refrigerated storage. PMID- 29487455 TI - Evaluation of the efficacy of nisin-loaded chitosan nanoparticles against foodborne pathogens in orange juice. AB - The current study aimed to fabricate nisin-loaded chitosan (N-CS) nanoparticles through ionic interactions between positive amino groups of chitosan and negatively charged tripolyphosphate ions in the presence of nisin and to evaluate their efficacy against foodborne pathogens in orange juice. The synthesized nanoparticles were sphere-shaped and homogenous with an average size of 64.34 +/- 2.1 and 147.93 +/- 2.9 for chitosan and N-CS nanoparticles, respectively. The encapsulation efficiency of nisin into nanoparticles was 67.32 +/- 0.63%. Both chitosan and N-CS nanoparticles showed greater stability, as indicated by a higher zeta potential value of + 49.3 and + 33.4 mV, respectively. The in vitro antibacterial activities of chitosan and N-CS nanoparticles were investigated against the Gram-positive bacteria Staphylococcus aureus and Listeria monocytogenes and the Gram-negative bacteria Escherichia coli O157:H7 and Salmonella Typhimurium. N-CS nanoparticles showed higher activity compared with chitosan nanoparticles. The highest reduction of microorganisms was recorded for S. aureus of 3.82 log CFU/ml and L. monocytogenes of 3.61 log CFU/ml. The antimicrobial activity of N-CS nanoparticles in orange juice for 48 h revealed higher activity compared with the control against all the tested strains. The highest microbial reduction was recorded for N-CS nanoparticles against S. aureus with a 3.84 log CFU/ml reduction. L. monocytogenes and E. coli 0157:H7 were reduced by 3.54 and 3.44 log CFU/ml, respectively. The results showed high potential for the N-CS nanoparticles to be used as potent antibacterial agents in food and other related areas. PMID- 29487456 TI - Bioactive compounds and antioxidant activities of some cereal milling by products. AB - The present study was performed to evaluate the phytochemicals profiles of some cereal milling by-products such as wheat (bran, germ and shorts), rice (bran, germ and husk) and corn (bran, germ and germ meal) to assess their potentiality as bioactive compounds sources. Distilled water, ethanol, methanol, and acetone separately were used as solvents for the extraction of phytochemicals compounds. The antioxidant activity (AOA), total phenolics content (TPC), and total flavonoids content (TFC) of the extracts were investigated using various in vitro assays. The results showed that tannins content was ranged from 113.4 to 389.5 (mg/100 g sample).The study revealed that TPC and TFC of cereal by-products extracts were significantly different for various solvents. TPC content varied from 366.1 to 1924.9 mg/100 g and TFC content varied from 139.3 to 681.6 mg/100 g. High carotenoids content was observed for corn germ meal and minimum for wheat bran. Distilled water, ethanol and methanol extracts showed significantly different antioxidant activity. Significant variations were observed with regard to AOA of different cereal by-products by using various solvents. The ethanol and methanol were observed to be the best solvents to extract phenolic compounds and antioxidant activity, while acetone extract showed less efficiency. Also, the cereal milling by-products were rich in bioactive compounds and could be used as a value added products. PMID- 29487457 TI - Thermodynamic compatibility and interactions between Speckled Sugar bean protein and xanthan gum for production of multilayer O/W emulsion. AB - Thermodynamic compatibility and probable interactions between Speckled Sugar been protein (SSBP) and xanthan gum for production of multilayer O/W emulsion (30% oil) were investigated. Different interactions were observed between SSBP and xanthan at different pH (3-7) including electrostatic interactions and hydrogen bonding. These interactions were predominant at pH 3. When low xanthan gum concentration (0.1%) was used, phase separation and complex coacervation observed at this pH (negative effect of interactions). However, at pH 5, only 0.1% xanthan was enough to drastically reduce non-dissolved protein and its precipitation which normally occurs at this pH. In addition, incompatibility or segregative phase behavior which normally occurs when protein and polysaccharide have same charges was not observed (positive effects of interactions). Protein-gum interactions influenced emulsion properties (zeta potential, particle size, PDI, rheology, emulsion capacity, heat stability and creaming rate). Interactions had considerable influence on emulsion shelf life and produced completely stable emulsions at all pH values. Results confirmed that SSBP-xanthan gum mixture has a high potential for production of multilayer emulsions. PMID- 29487458 TI - LC-ESI-Q-TOF-MS/MS profiling and antioxidant activity of phenolics from L. Sativum seedcake. AB - Lepidium sativum is widely used as a culinary and medicinal herb and is claimed to cure many diseases. In this study, an attempt was made to investigate the biochemical composition and functional properties of L. sativum ethanolic extract. The extract contained a total phenolic content of 11.03 +/- 0.75 (mg GAE/g dw plant material) and a flavonoid content of 4.79 +/- 0.24 (mg QE/100 g dw plant material). Further, the extract was characterized by LC-ESI-Q-TOF-MS/MS profiling and the results showed that the ethanolic fraction contains many important phenolics such as Kaempferol, Coumaroylquinic acid, p-Coumaroyl glycolic acid, Caffeic acid. The identified compounds are known for their biological properties and therefore, the functional properties of the extract as a whole were also studied. The extract showed significant antioxidant activity (IC50 values) 162.4 +/- 2.3, 35.29 +/- 1.02, 187.12 +/- 3.4 and 119.32 +/- 1.5 MUg/ml in terms of DPPH, ABTS, Superoxide scavenging activity and metal chelating property respectively. Further, the extract showed IC50 values, 73.72 +/- 1.23 and 121.78 +/- 1.03 MUg/ml in HRBC membrane stabilization ability and protein denaturation inhibition capacity respectively, which in turn is a measure of its anti-inflammatory activity. The results of the study are promising and serve basis for further investigation into the plant and possible consideration for use in nutraceuticals and functional foods. PMID- 29487459 TI - Multiple-sip temporal dominance of sensations associated with acceptance test: a study on special beers. AB - In this study, we proposed the use of a multiple-sip temporal dominance of sensations (TDS) test alongside with an acceptance test over repeated consumption for the analysis of special beers, with the aim of contributing to a deeper understanding of consumer behavior regarding temporal descriptions and sensory acceptance. Consumers of special beers sequentially evaluated six sips of a particular type of beer by TDS analysis and an acceptance test was performed for each sip. Four different kinds of specialty beers were evaluated [Bohemian Pilsner (BP), Witbier (WB), Belgian Strong Ale Dubbel (BD), and Russian Imperial Stout (RS)]. In general, the descriptive profile of beers varied temporally, i.e., there was an increased dominance of bitterness and a decreased dominance of fruity, floral, toffee, and coffee attributes. Concurrently, a reduction in sensory acceptance with an increased number of sips, especially the last sip, was observed in two kinds of beers that possessed a strong flavor, BD and RS. BP and WB presented smooth attributes and low notable characteristics, which could have contributed to the maintenance of the acceptance grades as the number of sips increased. The combination of TDS and acceptance over repeated sips can be useful for obtaining detailed descriptions of products that are closer to real time consumption by consumers, and thus aids in ensuring good product performance once released. The information obtained can also help product development scientists to fine-tune product formulations and ensure acceptability. PMID- 29487460 TI - Non-destructive and rapid evaluation of aflatoxins in brown rice by using near infrared and mid-infrared spectroscopic techniques. AB - The applicability of near-infrared (NIR) and mid-infrared (MIR) spectroscopy combined with chemometrics was explored in this study to develop rapid, low-cost and non-destructive spectroscopic methods for classification and quantification of aflatoxins in brown rice. A total of 132 brown rice samples within the aflatoxin concentration range of 0-2435.8 MUg/kg were prepared by artificially inoculated with A. flavus and A. parasiticus strains of fungus. For the classification of samples at varying levels of aflatoxin B1, the linear discriminant analysis model obtained correct classification rate of 96.9 and 90.6% for NIR and MIR spectroscopy, respectively. For the simultaneous determination of aflatoxins B1, B2, G1, G2 and the total aflatoxins, partial least squares regression also showed good predictive accuracy for both NIR (rv = 0.936-0.973, RPD = 2.5-4.0) and MIR spectroscopy (rv = 0.922-0.970, RPD = 2.5 4.0). The overall results indicated that the two spectroscopic techniques offered the feasibility to be used as alternative tools for rapid detection of various aflatoxin contaminations in grain. PMID- 29487461 TI - Flavor characteristics and chemical compositions of oolong tea processed using different semi-fermentation times. AB - Flavor characteristics and chemical compositions of Tieguanyin oolong tea processed using different semi-fermentation times were investigated. Six flavor attributes of the teas, namely, astringency, bitterness, umami, sweet aftertaste, floral flavor, and green fruity flavor, were analysed. With extended semi fermentation time, the taste intensity of sweet aftertaste increased, and the aroma intensity of floral and green fruity flavors increased, while the intensities of astringency, bitterness, and umami showed no clear trend. With increasing semi-fermentation time, the concentrations of gallated catechins, myricetin-rhamnose, quercetin-rutinoside, myricetin, and theanine greatly decreased, while those of total theaflavins, vitexin-rhamnose, kaempferol galactose, kaempferol-rutinoside, vitexin, quercetin, and kaempferol increased significantly. The intensity of bitter taste was positively correlated with the concentrations of total catechins and gallated catechins. The intensity of astringent taste strongly correlated with the flavonoid concentrations, and that of sweet aftertaste positively correlated with the concentrations of (-) epigallocatechin and (-)-epicatechin. However, dose-over-threshold analysis revealed that catechins, theaflavin, flavonol glycosides, and caffeine are the main taste-active compounds contributing to the taste of Tieguanyin oolong tea. The concentrations of total volatiles and most of the esters increased markedly with the semi-fermentation time, while the concentrations of low aldehydes showed a significant decrease. The flavor index was consistent with the intensity of floral aroma, increasing from 0.59 (12 h) to 0.84 (24 h) and then decreasing to 0.63 (32 h). Results of this work suggest that the flavor change is mainly due to the variation of taste-active and aroma-active compounds in oolong tea. PMID- 29487462 TI - Quantification and varietal variation of low molecular weight glutenin subunits (LMW-GS) using size exclusion chromatography. AB - Crude glutenin of four commercial wheat varieties viz. C 306, HI 977, HW 2004 and PBW 550 of diverse origin and breadmaking quality were fractionated by size exclusion chromatography into three fractions of decreasing molecular weights. The relative quantity of peak II, containing LMW-GS specifically, varied considerably among the varieties as reflected from their discrete SEC profiles. The area % of peak II, containing protein of interest, was maximal for C 306 (22.08%) followed by PBW 550 (15.86%). The least proportion of LMW-GS were recovered from variety HW 2004 (9.68%). As the concentration of the sample extract injected to the column increased, the resolution of the peak declined in association with the slight shifting of retention time to the higher values. The best results were obtained for variety C 306 at 100 mg protein concentration with 3 M urea buffer. Consequently, the optimized conditions for purification of LMW GS in appreciable amounts using SEC were established. PMID- 29487464 TI - Modelling of rheological behaviour of guava, pomelo and soursop juice concentrates via shear rate-temperature-concentration superpositioning. AB - The steady-state flow test was conducted on pink-fleshed guava, pink-fleshed pomelo and soursop juice concentrates using a rheometer to understand its rheological behaviour. The power law model was used and a master-curve was created using the shear rate-temperature-concentration superposition technique to predict rheological properties from a wide range of temperatures and concentrations. All three juice concentrates undergo a double horizontal shift whilst the pink-fleshed guava required an additional vertical shift. The final equations show shear-thinning behaviour of pink-fleshed guava, pink-fleshed pomelo and soursop with flow behaviour index of 0.2217, 0.7507 and 0.6347, respectively. The final master-curve predicts shear stress at wide range of shear rates, i.e. between 10-2 and 106 s-1 for the pink-fleshed guava, 100 and 106 s-1 for the pink-fleshed pomelo and 100 and 107 s-1 for the soursop. The results provide useful information and effective technique to predict fruit juice concentrates behaviour affected by heat changes during processing. PMID- 29487465 TI - Infectious Diseases Continued to be the World's Core Challenge. PMID- 29487463 TI - The effect of extrusion screw-speed on the water extractability and molecular weight distribution of arabinoxylans from defatted rice bran. AB - Arabinoxylans (AXs) are major dietary fibre in cereals. Recently, AXs have attracted a great deal of attention because of their biological activities. These activities have been suggested to be related to the content of low molecular weight (Mw) AXs, in particular those with Mw below 32 kDa. Rice bran is a rich source of AXs. However, water extraction of AXs is difficult and often gives low yield. Extrusion processing has been used to increase the solubility of cereal dietary fibre. The aim of this research was to study the effect of extrusion screw-speeds (80 and 160) rpm on the extraction yield and Mw of water extractable AXs from rice bran. It was found that the extraction of AXs increased significantly with an increase in screw speed and was accompanied by a significant decrease in the Mw of AXs from extruded rice bran. The percentage of very low molecular weight AXs (0.79-1.58 kDa) significantly increased with increasing screw speed. PMID- 29487467 TI - Empiric Treatment of Acute Meningitis Syndrome in a Resource-Limited Setting: Clinical Outcomes and Predictors of Survival or Death. AB - Background: Bacterial meningitis is a significant cause of morbidity and mortality in the developing world. However, limited research has focused on the diagnosis and management of meningitis in resource-limited settings. Methods: We designed a prospective case series of children admitted to a large, academic referral hospital with acute meningitis syndrome. Data were collected on age, time of presentation, prior antibiotics, cerebrospinal fluid (CSF) parameters, antibiotic and steroid prescription, and clinical outcome. Results: Data on 99 patients were collected and analyzed. Most of the patients were males, n=69 (70%), and were from a rural area, n=83 (84%). Incomplete vaccination was common, n=36 (36%) and many have evidence of malnutrition, n=25 (38%). Most patients, n=64 (72%), had received antibiotics prior to admission with a mean duration of symptoms of 4.9 days prior to admission. The CSF white blood cell (WBC) count was higher in those who had not received prior antibiotics though it was elevated in both groups. The CSF WBC count was not associated with survival; malnutrition and length of symptoms prior to admission were both associated with decreased survival. Conclusions: While use of antibiotics prior to obtaining CSF in patients with acute meningitis syndrome may decrease their CSF WBC count, it is not clinically significant. Many patients had a significant delay in presentation that had an effect on survival, This is a potentially modifiable risk factor despite the resourcelimited setting. PMID- 29487466 TI - Magnitude of Helicobacter pylori among Dyspeptic Patients Attending at University of Gondar Hospital, Gondar, Northwest Ethiopia. AB - Background: Helicobacter pylori (H.pylori) infection is predominantly acquired in childhood from family members. The infection can cause dypepepsia, chronic and acute gastritis and gastric cancer. Dyspepsia is the most common illness in the Ethiopian population visiting outpatient department of health facilities, and it has also been associated with H.pylori infection. The aim of this study was to assess the magnitude of H.pylori and its associated factors among dyspeptic patients who visited University of Gondar Hospital Outpatient Department. Materials and Methods: An institutional-based cross-sectional study was conducted on 354 dyspeptic patients. A systematic random sampling technique was employed to select study participants. Data were collected by using structured questionnaire via face-to-face interview. H.pylori infection was diagnosed using stool antigen test method. The data were entered into Epi info version 3.5.3 and transferred to Statistical Package for Social Sciences version 20. Both Bivariable and multivariable binary logistic regression analyses were performed to see the effect of independent variables on the dependent variable. Result: Of the total study participants, 201(56.8%), 195(55.1%) and 182(51.4%) were married, urban residents and females, respectively. The overall magnitude of H.pylori infection was 37.6%. In bivariable logistic regression analysis, sex and marital status were significantly associated with H.pylori infection, but in multivariable logistic regression analysis only marital status was significantly associated with H.pylori infection. Conclusion: The magnitude of H.pylori infection is high indicating that it is a public health problem in the study to area. According to this study, none of the variables were significantly associated with H.pylori infection. Hence, effective preventive, control and screening strategies need to be designed to reduce the burden of the disease. PMID- 29487468 TI - Prevalence of Selected Sexually Transmitted Infection (STI) and Associated Factors among Symptomatic Patients Attending Gondar Town Hospitals and Health Centers. AB - Background: Sexually transmitted infection (STI) is a major global cause of acute illness, infertility, long-term disability and death, with serious medical and psychological consequences to millions of men, women and infants. Moreover, in Ethiopia, epidemiological studies on STI among STI clinic clients are limited. Therefore, the aim of this study was to determine the prevalence and associated risk factors of sexually transmitted infection (STI). Methods: A cross sectional study was conducted between April and August 2014 among STI clinic clients in Gondar Town hospitals and health centers. One hundred twenty study participants who fulfill the criteria were included. Different laboratory methods and techniques were applied to identify the possible microorganisms. Data were entered and analyzed using SPSS version 20. Logistic regression was used to determine risk factors for STI and P values < 0.05 was considered statistically significant. Results: The overall laboratory test confirmed that STIs prevalence was 74.1% with 32.5% being Candida spp., 30% T. palladium, 20.8% N. gonorrhoeae and 14.2% T. vaginalis. Two or more organisms were isolated in 20% of the study subjects. Risk factors for STI had knowledge about STI and alcohol consumption. Conclusion: The prevalence of N. gonorrhoeae, T. pallidum, T. vaginalis, and Candida spp. in the study area was high. It needs health education programs, promotes condom utilization and more comprehensive community based STI studies. PMID- 29487469 TI - Knowledge, Risk Perception and Practice Regarding Tuberculosis Transmission among Long Distance Bus Drivers in Addis Ababa, Ethiopia: A Cross Sectional Study. AB - Background: Window opening during bus transportation is recommended as a tuberculosis prevention strategy.Yet, drivers are affected by lack knowledge and risk perception of passengers and assistants. Boosting knowledge of and notifying the high risk of tuberculosis transmission for every passenger could be too costly. However, strategies targeting bus drivers as key agents unlike targeting all passengers might be less costly for window opening. Method: Data were collected from November 18/2014 to December 21/2014 in inter-region bus stations of Addis Ababa using cross sectional study design. Samples of 306 participants were selected using simple random sampling, and data were collected through face to-face interview. Data were entered into Epi-data version 3.1 andanalyzed using IBM SPSS version 21. Result: From a sample of 306 bus drivers, 303 were interviewed. Nine in ten and nearly half of participants believed in the need for opening all windows and avoiding overcrowding of passengers as TB preventive measures respectively. Few bus drivers (7.3%) believed that bus drivers and their assistants could be at risk of tuberculosis. The majority (85.7%) of bus drivers opened side window the whole day without precondition. Hearing tuberculosis related information from radio was a promoting factor for tuberculosis preventive measures among bus drivers. Conclusion: Tuberculosis preventive practices and knowledge of bus drivers seempositive (opportunities), despite their low risk perception (challenge). Using the opportunity, further empowering bus drivers to persuade passengers and assistants to open all the rest of the windows is needed. PMID- 29487470 TI - The Use of First Line Highly Active Anti-Retroviral Therapy (HAART) is Not Associated with Qtc Prolongation in HIV Patients. AB - Background: HAART has improved survival of HIV patients. Its contribution to the development of new cardiovascular abnormalities has generated much interest. This study aimed at determining the prevalence of QTc prolongation among HIV patients and determining the influence if any of the use of HAART on the QTc and on the risk of having QTc prolongation. Materials and Methods: One hundred and fifty HIV positive subjects comprising 76 HIV positive subjects on HAART (Group A), 74 who were HAART- naive (Group B), and 150 age and sex-matched healthy controls (Group C) were studied. All subjects had electrocardiography, and QTc duration was calculated. Results: Mean QTc was significantly different among the three groups (P <0.001), highest in Group B > Group A > Group C. Frequency of QTc prolongation was highest in Group B (32%)>, Group A (17.3%)> Group C (4.7%) (P<0.001). Mean QTc was significantly longer among patients with CD4 count <200 cells/mm3 than among those with >200 cells/mm3 0.445 +/- 0.03secs vs 0.421 +/- 0.03secs (P<0.001). QTc prolongation was commoner among individuals with CD4 count <200 cells/mm3 50% vs 20.5% (P<0.001). On binary logistic regression, none of the HAART medications used by our patients was predictive of the occurrence of QTc prolongation. Conclusion: The QTc is longer, and QTc prolongation occurs more frequently in HAART-naive HIV patients than patients on HAART and healthy controls. None of the HAART medications used by our patients was predictive of the development of QTc prolongation. PMID- 29487471 TI - Nurturing the Continuum of HIV Testing, Treatment and Prevention Matrix Cascade in Reducing HIV Transmission. AB - Background: Despite the shift in antiretroviral therapy (ARVs) eligibility cascade from CD4 <= 200 to CD4 <= 350 to CD4 <= 500 mm3, HIV related morbidity and mortality continue to escalate annually, as do HIV infections. The new paradigm of treatment for all HIV positives individual irrespective of CD4 count may significantly reduce HIV and related illnesses. The author assumes that all HIV infected partners should be eligible for HIV treatment and care, irrespective of CD4 count. A second assumption is that high risk HIV negative partners have free access to continuum of HIV pre-exposure prophylaxis (PrEP), post exposure prophylaxis (PEP) and other prevention packages. Methods: A literature review search was used to extract evidence-based ARVs-HIV treatment and prevention interventions among HIV positives and high risk partners respectively. Only articles published in English and indexed in journal nuclei were used for the study. The information was used to nurture understanding of HIV treatment and prevention approaches as well as HIV incidence multiplier effect among HIV serodiscordant partners. The imputed HIV incident reference was assumed at 1.2 per 100 person-years (2). This was based on the imputation that retention in care, adherence and other predetermined factors are functions of an effective health care delivery system. Result: The model showed a reduced HIV transmission from 1.2 per 100 person-years to 1.032 per 100 person-years in 6 months. The average threshold period of HIV suppressed partners on ARVs to an undetectable level. The combined multiplier protective-effect probability of transmitting HIV from HIV positive partners on ARVs-suppressed viremic load to HIV negative partners on PrEP/PEP-prevention was detected at 86. Conclusion: The model showed a significant reduction in HIV incidence. Placing serodiscordant sexual partners in HIV treatment and prevention plays a significant role in reducing and controlling HIV infection. Therefore, the policy of enrolling all HIV positives irrespective of CD4 count on ARVs and high risk partners on prevention if adopted and sustained may underpin reduction and control of HIV genotype and HIV related morbidity, mortality and opportunistic infections. PMID- 29487473 TI - Establishment of Immunohematological Reference Values among HIV Sero-negative Pregnant Women at St. Paul's Hospital Millennium Medical College (SPHMMC), Addis Ababa, Ethiopia. AB - Background: Normal pregnancy is characterized by profound changes in almost every organ and system. Immunohematological parameters are important in clinical practice for the assessment of health and disease. Therefore, this study was aimed to establish immunohematological reference range among HIV sero-negative pregnant women. Methods: A cross-sectional study was conducted among HIV sero negative pregnant women at St. Paul's Hospital Millennium Medical College (SPHMMC), Addis Ababa, Ethiopia, from 20/1-30/6/ 2016. Whole blood was collected and immunological and hematological parameters were measured following the standard procedure. Data were entered in to Epi Info version 3.5, checked for completeness and exported to SPSS version 20 software for analysis. The mean +/- SD and 95% Confidence Interval (95% CI) values were calculated for different immunohematological parameters. Results: A total of 400 women with mean age +/-SD (27.3 +/-4.7) ranging from 18-40 years were enrolled. The mean +/- SD reference value of white blood cells count with 95% CI was 8.3 +/-2.3 (8.1-8.6) *109 cells/L and for CD4+, CD8+, and CD4 to CD8 ratio cells absolute count with 95% CI were 906 +/-404 (867-946), 698+/- 378 (662-736) cell/ul, and 1.5+/-0.9 (1.4-1.6), respectively.The mean +/- SD reference values for red blood cells count with 95% CI was 4.5+/-0.5(4.4-4.5) 1012/L, for hemoglobin 14+/-7.2(13.3-14.7) gm/dl, and for hematocrite was 39.5+/- 4(39-39.9). Conclusions: These values were lower than the one from developed countries but not lower than the one from other African studies. It suggests the need for further large study. PMID- 29487472 TI - Assessment of Reliability of Greulich and Pyle (GP) Method for Determination of Age of Children at Debre Markos Referral Hospital, East Gojjam Zone. AB - Background: Greulich and Pyle standards are the most widely used age estimation standards all over the world. The applicability of the Greulich and Pyle standards to populations which differ from their reference population is often questioned. This study aimed to assess the reliability of Greulich and Pyle (GP) method for determination of age of children at Debre Markos Referral Hospital, East Gojjam Zone, Ethiopia. Subjects and Methods: Hospital based cross sectional study design was applied to children who came to Debre Markos Referral Hospital from May to October 2015 and fulfilled the inclusion criteria of the study. The data was analyzed using SPSS version 20 and medcalc version 15 softwares. Significance was set at alpha = 0.05. Results: A total of 108 radiographs were analyzed. Chronological age in most of the children was under estimated. The mean under-estimation was 11.8 months in the female sample and 8.7 months in the male sample. Greulich and Pyle method became inapplicable for the sample at 16 years for females and 16.5 years for males and later. Delay in skeletal maturation was observed in both sexes, but the females in the sample matured earlier than the males. Conclusion: The findings of this study suggest against the applicability of GP atlas which were not directly applicable to an East Gojjam Zone population. Large scale studies should be planned and nationwide guideline, and atlas which can easily be used throughout the country should be developed. PMID- 29487474 TI - Health Economic Evaluation of Home and Hospital-Based Care in T2D Patients on Insulin Therapy. AB - Background: Type 2 Diabetes is a main concern of public health in contemporary world with remarkable mortality, delayed complications and health costs. Governments are obliged to improve the quality of health care and consider appropriate strategies to reduce the costs. An alternative strategy for hospital services is care at home. Therefore, this study was aimed to evaluate the cost effectiveness of home-based and hospital-based diabetes care. Methods: A quasi experimental, pre-test and post-test design was conducted in Northwest Iran. Sixty subjects who were eligible insulin-treatment type 2 diabetes mellitus were randomly assigned into two equal groups to receive home-based or conventional hospital-based care. Data on glycosylated hemoglobin (HbA1c), hypoglycemia episodes, time needed to achieve glycemic control level, diabetes treatment satisfaction, diabetes knowledge and costs during three months were collected. Results: The cost of home-based care in insulin therapy diabetes was 61% less compared with the hospital-based methods. The former strategy was cost-effective in terms of reduction in HbA1C and the time needed to achieve glycemic control. The patients in home care group were more satisfied and knowledgeable. Conclusions: The care at home approach for type 2 diabetic patients can be introduced and supported as a cost-effective care method in the country. PMID- 29487475 TI - Health Care Managers' Perspectives on the Sources of Evidence in Evidence-Based Hospital Management: A Qualitative Study in Iran. AB - Background: Evidence-based management (EBMgt) has been developed as a management framework for improving the quality of management decisions. To use that, we need to identify the source of evidence in decision-making. Therefore, the purpose of this study was to identify the sources of evidence in managing hospitals. Methods: Qualitative methods were used to explore the sources of evidence and to identify hospital managers' attitudes towards evidence-based management. A series of semi-structured interviews (n=48), with a purposive sample of 48 participants, were conducted in 2016. Also, four focus group discussions (FGDs) were conducted with health managers and specialists in the field of management. A questionnaire was used for collection of demographic characteristics and managers' perspectives. Results: Six main themes emerged from the interviews including: scientific and research evidence, facts and information of hospital, political social development plans, managers' professional expertise and ethical-moral evidence. Also, the results showed that the majority of participants believed to use the evidence-based hospital management (95.83%). Conclusions: Our study suggested that a full evidence-based hospital manager someone who is using all the sources of evidence for making hospital decisions. Using hexagon of evidence sources, managers can identify the best available evidence for hospital decisions and to make the best decision in the process of evidence-based decision making. PMID- 29487476 TI - Awareness and Knowledge of the Sustainable Development Goals in a University Community in Southwestern Nigeria. AB - Background: The Sustainable Development Goals (SDGs) is a globally accepted developmental agenda, and it is expected that everyone everywhere in the world would be aware, knowledgeable and be willing to contribute to its attainment. This study aims to assess the level of awareness, knowledge of, and attitudes towards the SDGs among members of a university community. Methods: A cross sectional survey was conducted on 450 students and staff of Osun State University, Southwestern Nigeria, selected from three of its six multi-campuses via multi-stage sampling. Data were collected by means of semi-structured questionnaire. Data were analysed using SPSS version 20.0. Results: The mean age for the respondents was 26(10.2) years. Only 43% of the respondents were aware of the SDGs and only 4.2% had good knowledge of the SDGs. However, 56.3% had positive attitude towards it. More respondents with good knowledge of the SDGs were either acadenic staff or those have been enlightened via personal study of the SDGs or through other means. Similarly having a positive attitude was associated with being an academic staff/ high level of education as well as belonging to the middle age group. (p<0.05). Conclusion: The awareness of and attitudes towards the SDGs was just fair. However, the level of knowledge was abysmally low, and this has serious negative implications for SDGs attainment. Pertinent individual and population-level methods of enlightening people about the SDGs must be put in place in educational settings; curricular changes are imperative. PMID- 29487478 TI - Rainfall and Development of Zika Virus. PMID- 29487477 TI - Frontal Lobe Tuberculoma: A Clinical and Imaging Challenge. AB - Background: Pediatric nervous system tuberculomas are usually infra-tentorial and multiple. A frontal lobe location is rare. Case Details: We report a 10 year-old boy who presented with a chronic headache and episodes of loss of consciousness. He had no signs of primary pulmonary tuberculosis and a diagnosis of frontal tuberculoma was made upon a post-operative biopsy. He improved following treatment with anti-tubercular drugs. Conclusion: Tuberculosis should be considered in children with a chronic headache or focal neurologic deficit and a supra-tentorial intracranial mass in endemic countries like Ethiopia. PMID- 29487479 TI - Islet Autoantibody Detection by Electrochemiluminescence (ECL) Assay. PMID- 29487481 TI - The role of MMP-1 and FGFR4-R388 gene polymorphisms in pituitary adenoma. AB - Background: The pathogenesis of pituitary adenoma (PA) is complex and poorly understood. It is thought that PA has a multifactorial aetiology; genetic factors also have an impact on PA development. Since MMP1 and FGFR4 genes play an important role in tumour growth, differentiation and progression, we decided to determine if the frequency of the genotypes of MMP-1 and FGFR4-R388 polymorphisms influence the development of PA. Materials and methods: The study enrolled n = 100 patients with PA and n = 200 healthy controls (reference group). The genotyping tests of MMP-1 and FGFR4-R388 were carried out using the real-time polymerase chain reaction (PCR) method. Results: The polymorphism in the MMP-1 gene 1G/1G genotype was more frequent in the group of invasive PA than in the control group: 28.6% vs. 16.5%, p = 0.044. The 1G/2G genotype was more frequent in females of the control group compared to PA group females: 50.3% vs. 30.8%, p = 0.011. The polymorphism in the MMP-1 gene 1G/1G genotype was more frequent in the active PA group than in the control group: 28.4% vs. 16.5%, p = 0.044. FGFR4 R388 did not play any predominant role in PA development. Conclusion: The MMP-1 gene 1G/1G may play a role in invasive and active PA development. PMID- 29487482 TI - Respiratory syncytial virus infection in a selected sample of infants hospitalized for lower respiratory tract infection in Lithuania and Estonia. AB - Background: The study presents data on a sample of children under one year of age hospitalized with lower respiratory tract infections (LRTIs) in Lithuania and Estonia. Subjects and methods: This large, retrospective, cross-sectional, observational epidemiologic survey was conducted in 12 countries in Central and Eastern Europe. Eligible subjects were under one year of age, hospitalized for LRTIs, for whom RDT (Rapid Diagnostic Test) was performed. Physicians completed questionnaires at discharge or on the first check-up visit after hospitalization. To test for RSV, the immunochromatographic method was used in Lithuania, and immunofluorescense or the PCR methods were applied in Estonia. Results: In two countries, 482 patients fulfilling the definition of a LRTI case (i.e., children below one year of age hospitalized with a diagnosis of bronchiolitis and/or pneumonia) were enrolled during two consecutive RSV seasons. Bronchiolitis was the most common diagnosis (84%). In Lithuania and Estonia, 36.6% and 83.3% of cases were conscious at admission. RSV was confirmed in 87.3% and 54.2% of tested LRTI cases in Estonia and Lithuania, respectively. Intensive care unit hospitalization was required for 9.1% of LRTI cases in Lithuania and for 3.1% of cases in Estonia. Supplemental oxygen was required for 23.2% and 31.6% in cases in Lithuania and Estonia, respectively. In Lithuania, complete recovery at discharge was assessed for 35.8% of LRTI cases and improvement in 62.2% of cases. In Estonia, all LRTI cases were improved at discharge and there were no complete recoveries. Conclusion: RSV was prevalent among children hospitalized for LRTI in Lithuania and Estonia; bronchiolitis was the most common diagnosis in hospitalized patients. PMID- 29487480 TI - Modulation of Tryptophan and Serotonin Metabolism as a Biochemical Basis of the Behavioral Effects of Use and Withdrawal of Androgenic-Anabolic Steroids and Other Image- and Performance-Enhancing Agents. AB - Modulation of tryptophan (Trp) metabolism may underpin the behavioral effects of androgenic-anabolic steroids (AAS) and associated image and performance enhancers. Euphoria, arousal, and decreased anxiety observed with moderate use and exercise may involve enhanced cerebral serotonin synthesis and function by increased release of albumin-bound Trp and estrogen-mediated liver Trp 2,3 dioxygenase (TDO) inhibition and enhancement of serotonin function. Aggression, anxiety, depression, personality disorders, and psychosis, observed on withdrawal of AAS or with use of large doses, can be caused by decreased serotonin synthesis due to TDO induction on withdrawal, excess Trp inhibiting the 2 enzymes of serotonin synthesis, and increased cerebral levels of neuroactive kynurenines. Exercise and excessive protein and branched-chain amino acid intakes may aggravate the effects of large AAS dosage. The hypothesis is testable in humans and experimental animals by measuring parameters of Trp metabolism and disposition and related metabolic processes. PMID- 29487485 TI - David M. Gourlay, MD, FACS, FAAP. PMID- 29487483 TI - Survival of children treated for Ewing sarcoma in Lithuania: a single centre experience. AB - Introduction: Ewing sarcoma (ES) is a rare and aggressive malignant neoplasm that mostly affects children and adolescents. Recent studies reported a gap of 20% in childhood cancer survival rates between the Northern/Western and the Eastern European countries. We aimed to analyse the survival of patients treated for ES at our institution, to evaluate its correspondence to current survival rates in the expert centres, and to assess changes in treatment outcomes over time. Materials and methods: A retrospective single-centre study was performed. Children under 18 years of age, diagnosed and treated for Ewing sarcoma/PNET at our institution from 2000 to 2014 were included. To assess the hypothesized improvement of treatment outcomes over time, a comparative analysis of two time periods - 2000-2007 and 2008-2014 - was carried out. Five-year overall survival (OS5y) and disease-free survival (DFS5y) were chosen as primary study end-points. Clinical and laboratory data were retrieved from patient records. Results: In total, 40 patients were included in the study: 24 (60%) males and 16 (40%) females. Twenty-eight children (70%) presented with local and 12 (30%) with primary metastatic disease. Over the analysed time frame, improvement in treatment outcomes was observed: DFS5y improved from 46% in 2000-2007 to 61% in 2008-2014 (p = 0.27), whereas OS5y changed minimally from 62% in 2000-2007 to 65% in 2008-2014. Increase in DFS5y was more prominent for localized disease -from 50% in 2000-2007 to 74% in 2008-2014 (p = 0.14). Prognosis of initial metastatic disease remained poor with DFS5y: 25% in 2000-2007 and 38% in 2008-2014. Patients' median follow-up was 12.3 years (the range from 8.1 to 15.6) and 3.9 years (the range from 1.1 to 8.0) in the first and second study groups, respectively. Conclusions: OS5y of the entire patient cohort did not change considerably over time and remained slightly inferior compared to the best reported survival rates. There was an evident trend for improvement of DFS5y in localized disease. Survival of children with primary metastases remained poor despite slight increase in DFS5y. Implementation of international clinical trials, consolidation of multidisciplinary approach, patients' concentration and widening of research activities could be beneficial for the treatment of children in the future. PMID- 29487484 TI - Relationships between pulmonary function test parameters and quantitative computed tomography measurements of emphysema in subjects with chronic obstructive pulmonary disease. AB - Objective: CT is able to precisely define the pathological process in COPD. There are a number of previous articles discussing the distribution of emphysema and its connection with pulmonary function tests. However, the results obtained by the researchers are not identical. Purpose: To assess relationships between emphysema and pulmonary function test parameters in COPD patients. Materials and methods: Fifty-nine patients diagnosed to have COPD underwent chest CT examinations and pulmonary function tests.For the quantitative assessment, percentages of low attenuation volume LAV 950 HU (%) of a both lungs, the right lung, the left lung, and each lobe were obtained. Quantitative CT measurements were compared with forced expiratory volume in 1 s (FEV1), the ratio of FEV1 to forced vital capacity (FEV1/FVC), the diffusing capacity for carbon monoxide (DLco) and total lung capacity (TLC). Results: Except for the right middle lobe and the right upper lobe, respectively, all the quantitative CT measurements showed weak to moderate negative correlations with diffusing capacity (DLco) (r = -0.35 to -0.61, p < 0.05) and weak positive correlations with TLC (r = 0.34 to 0.44, p < 0.05). Group analysis indicated that LAV-950 HU (%) values of both lungs, right lung, left lung, and each lobe, except for right middle lobe, were increased in patients with GOLD stages 3 and 4 of COPD compared to GOLD stages 1 and 2 (p < 0.05). Conclusion: CT measurements of emphysema are significantly related to pulmonary function tests results, particularly DLco. PMID- 29487486 TI - Pediatric and Congenital Colorectal Diseases in the Adult Patient. PMID- 29487487 TI - Hirschsprung Disease beyond Infancy. AB - Hirschsprung disease (HD) is a common cause of neonatal intestinal obstruction in which a variable segment of the distal intestinal tract lacks the normal enteric nervous system elements. Affected individuals present with varying degrees of obstructive symptoms, but today most patients are diagnosed within the first several months of life owing to the well-recognized symptoms and the ease of making the diagnosis by way of the bedside suction rectal biopsy. Thus, for the adult general or colorectal surgeon, the vast majority of patients who present for evaluation will have already undergone surgical treatment within the first year of life by a pediatric surgeon. Despite several safe operative interventions to treat patients with HD, the long-term results are far from perfect. These patients may reach adult life with ongoing defecation disorders that require a systematic evaluation by a multidisciplinary group that should be led by a surgeon with a thorough knowledge of HD operations and the potential problems. The evaluation of these patients will form the basis for the majority of this review-however, some patients manage to escape diagnosis beyond the infant and childhood period-and a section herein will briefly address the case of an older patient who is suspected of having HD. PMID- 29487488 TI - Anorectal Malformations. AB - Anorectal malformation are common congenital problems occurring in 1 in 5,000 births and have a spectrum of anatomical presentations, requiring individualized treatments for the newborn, sophisticated approaches to the definitive reconstruction, and management of long-term treatments and outcomes. Associated anomalies related to the cardiac, renal, gynecologic, orthopedic, spinal, and sacral systems impact care and prognosis. Long-term results are good provided there is an accurate anatomical reconstruction and a focus on maximizing of functional results. PMID- 29487489 TI - Medical and Surgical Management of Pediatric Ulcerative Colitis. AB - Inflammatory bowel disease (IBD) describes a spectrum of idiopathic, lifelong, and progressive intestinal inflammatory conditions that includes Crohn's disease, ulcerative colitis, and indeterminate colitis. A worldwide increase in the incidence of IBD has been observed. In comparison to adults, IBD occurring during childhood and adolescence has several unique clinical characteristics and surgical management issues. In this article, we provide an overview contrasting these important differences. PMID- 29487490 TI - Pediatric Crohn's Disease. AB - The incidence of Crohn's disease in the pediatric population is increasing. While pediatric patients with Crohn's disease exhibit many of the characteristics of older patients, there are important differences in the clinical presentation and course of disease that can impact the clinical decisions made during treatment. The majority of children are diagnosed in the early teen years, but subgroups of very early onset and infantile Crohn's present much earlier and have a unique clinical course. Treatment paradigms follow the traditional laddered approach, but growth and development represent special considerations that must be given to pediatric-specific complications of the treatment and disease. Surgical intervention is an important component of Crohn's management and is often employed to allow improved nutritional intake or decrease reliance on medical treatments that compromise growth. PMID- 29487491 TI - Surgical Management of Idiopathic Constipation in Pediatric Patients. AB - Constipation is a common childhood problem, but an anatomic or physiologic cause is identified in fewer than 5% of children. By definition, idiopathic constipation is a diagnosis of exclusion. Careful clinical evaluation and thoughtful use of imaging and other testing can help exclude specific causes of constipation and guide therapy. Medical management with laxatives is effective for the majority of constipated children. For those patients unresponsive to medications, however, several surgical options can be employed, including anal procedures, antegrade colonic enemas, colorectal resection, and intestinal diversion. Judicious use of these procedures in properly selected patients and based on appropriate preoperative testing can lead to excellent outcomes. This review summarizes the surgical options available for managing refractory constipation in children and provides guidance on how to choose the best procedure for a given patient. PMID- 29487492 TI - Chronic Intestinal Pseudo-obstruction. AB - Chronic intestinal pseudo-obstruction (CIP) is defined by either continuous or intermittent symptoms of bowel obstruction in the absence of fixed lumen excluding lesion. CIP includes a heterogeneous group of disorders which result either from diseases affecting the enteric neurons and smooth muscle lining or those involving the autonomic innervation of the bowel. Symptoms associated with CIP are nonspecific, which can sometimes contribute to the delay in recognizing the condition and making the correct diagnosis. The diagnostic workup should include imaging and manometry studies and, occasionally, full-thickness bowel biopsies for histopathological examination may be required. Multidisciplinary team approach for the management of these patients is recommended, and the team members should include a gastroenterologist, surgeon, chronic pain specialist, clinical nutritionist, and a psychologist. The treatment goals should include optimizing the nutritional status and preventing or delaying the development of intestinal failure. The majority of the patients require enteral or parenteral nutrition support, and chronic pain is a common and distressing symptom. Small bowel transplantation may be required if patients develop liver complications due to parenteral nutrition, have difficult central line access, or have poor quality of life and worsening pain despite aggressive medical management. PMID- 29487493 TI - Pediatric Rectal Prolapse. AB - Rectal prolapse is a common and self-limiting condition in infancy and early childhood. Most cases respond to conservative management. Patients younger than 4 years with an associated condition have a better prognosis. Patients older than 4 years require surgery more often than younger children. Multiple operative and procedural approaches to rectal prolapse exist with variable recurrence rates and without a clearly superior operation. These include sclerotherapy, Thiersch's anal cerclage, Ekehorn's rectopexy, laparoscopic suture rectopexy, and posterior sagittal rectopexy. PMID- 29487494 TI - Anorectal Complaints: Hemorrhoids, Fissures, Abscesses, Fistulae. AB - Anorectal complaints are not uncommon in pediatric care, but the etiology and management can differ significantly from adults. Age is an important factor when considering etiology and management, distinguishing between infants, children, and adolescents. For all ages, malignancy is rarely a consideration, but a thorough examination of infants and children typically requires deep sedation or general anesthesia. Very little primary literature or evidence exists to guide care; so there are many opportunities for careful study to enhance our understanding beyond personal experience and historical practice patterns. PMID- 29487495 TI - Meconium Ileus. AB - Cystic fibrosis is one of the most common inheritable traits in Caucasians. Meconium ileus and its potential complications are the most likely reasons that these patients will need surgical care. Surgical intervention is usually needed in the neonatal period but may also be required later in life. This article discusses the various ways cystic fibrosis can affect the gastrointestinal tract. Both the operative and nonoperative management of complicated and uncomplicated meconium ileus are discussed in the neonatal period as well as long-term issues, such as distal intestinal obstructive syndrome, fibrosing colonopathy, and rectal prolapse, all of which may be seen in older children and adults. PMID- 29487496 TI - Enteric Duplication. AB - Enteric duplications have been described throughout the entire gastrointestinal tract. The usual perinatal presentation is an abdominal mass. Duplications associated with the foregut have associated respiratory symptoms, whereas duplications in the midgut and hindgut can present with obstructive symptoms, perforation, nausea, emesis, hemorrhage, or be asymptomatic, and identified as an incidental finding. These are differentiated from other cystic lesions by the presence of a normal gastrointestinal mucosal epithelium. Enteric duplications are located on the mesenteric side of the native structures and are often singular with tubular or cystic characteristics. Management of enteric duplications often requires operative intervention with preservation of the native blood supply and intestine. These procedures are usually very well tolerated with low morbidity. PMID- 29487498 TI - Neurophysiological and Behavioral Differences between Older and Younger Adults When Processing Violations of Tonal Structure in Music. AB - Aging is associated with decline in both cognitive and auditory abilities. However, evidence suggests that music perception is relatively spared, despite relying on auditory and cognitive abilities that tend to decline with age. It is therefore likely that older adults engage compensatory mechanisms which should be evident in the underlying functional neurophysiology related to processing music. In other words, the perception of musical structure would be similar or enhanced in older compared to younger adults, while the underlying functional neurophysiology would be different. The present study aimed to compare the electrophysiological brain responses of younger and older adults to melodic incongruities during a passive and active listening task. Older and younger adults had a similar ability to detect an out-of-tune incongruity (i.e., non chromatic), while the amplitudes of the ERAN and P600 were reduced in older adults compared to younger adults. On the other hand, out-of-key incongruities (i.e., non-diatonic), were better detected by older adults compared to younger adults, while the ERAN and P600 were comparable between the two age groups. This pattern of results indicates that perception of tonal structure is preserved in older adults, despite age-related neurophysiological changes in how melodic violations are processed. PMID- 29487497 TI - Current Approaches to Pediatric Polyposis Syndromes. AB - Colorectal adenomatous polyposis syndromes encompass a diverse group of disorders with varying modes of inheritance and penetrance. Children may present with overt disease or within screening programs for families at high risk. We provide an overview of the array of pediatric polyposis syndromes, current screening recommendations, and surgical indications and technical considerations. Optimal disease management for these pediatric patients is still evolving and has implications for screening, surveillance, pediatric surgical management, and transition of care gastroenterologic neoplasia physicians and surgeons. PMID- 29487499 TI - Clustering-Constrained ICA for Ballistocardiogram Artifacts Removal in Simultaneous EEG-fMRI. AB - Combination of electroencephalogram (EEG) recording and functional magnetic resonance imaging (fMRI) plays a potential role in neuroimaging due to its high spatial and temporal resolution. However, EEG is easily influenced by ballistocardiogram (BCG) artifacts and may cause false identification of the related EEG features, such as epileptic spikes. There are many related methods to remove them, however, they do not consider the time-varying features of BCG artifacts. In this paper, a novel method using clustering algorithm to catch the BCG artifacts' features and together with the constrained ICA (ccICA) is proposed to remove the BCG artifacts. We first applied this method to the simulated data, which was constructed by adding the BCG artifacts to the EEG signal obtained from the conventional environment. Then, our method was tested to demonstrate the effectiveness during EEG and fMRI experiments on 10 healthy subjects. In simulated data analysis, the value of error in signal amplitude (Er) computed by ccICA method was lower than those from other methods including AAS, OBS, and cICA (p < 0.005). In vivo data analysis, the Improvement of Normalized Power Spectrum (INPS) calculated by ccICA method in all electrodes was much higher than AAS, OBS, and cICA methods (p < 0.005). We also used other evaluation index (e.g., power analysis) to compare our method with other traditional methods. In conclusion, our novel method successfully and effectively removed BCG artifacts in both simulated and vivo EEG data tests, showing the potentials of removing artifacts in EEG-fMRI applications. PMID- 29487500 TI - The Effects of 10 Hz Transcranial Alternating Current Stimulation on Audiovisual Task Switching. AB - Neural oscillations in the alpha band (7-13 Hz) are commonly associated with disengagement of visual attention. However, recent studies have also associated alpha with processes of attentional control and stability. We addressed this issue in previous experiments by delivering transcranial alternating current stimulation at 10 Hz over posterior cortex during visual tasks (alpha tACS). As this stimulation can induce reliable increases in EEG alpha power, and given that performance on each of our visual tasks was negatively associated with alpha power, we assumed that alpha tACS would reliably impair visual performance. However, alpha tACS was instead found to prevent both deteriorations and improvements in visual performance that otherwise occurred during sham & 50 Hz tACS. Alpha tACS therefore appeared to exert a stabilizing effect on visual attention. This hypothesis was tested in the current, pre-registered experiment by delivering alpha tACS during a task that required rapid switching of attention between motion, color, and auditory subtasks. We assumed that, if alpha tACS stabilizes visual attention, this stimulation should make it harder for people to switch between visual tasks, but should have little influence on transitions between auditory and visual subtasks. However, in contrast to this prediction, we observed no evidence of impairments in visuovisual vs. audiovisual switching during alpha vs. control tACS. Instead, we observed a trend-level reduction in visuoauditory switching accuracy during alpha tACS. Post-hoc analyses showed no effects of alpha tACS in response time variability, diffusion model parameters, or on performance of repeat trials. EEG analyses also showed no effects of alpha tACS on endogenous or stimulus-evoked alpha power. We discuss possible explanations for these results, as well as their broader implications for current efforts to study the roles of neural oscillations in cognition using tACS. PMID- 29487502 TI - Netrin-1 Promotes Synaptic Formation and Axonal Regeneration via JNK1/c-Jun Pathway after the Middle Cerebral Artery Occlusion. AB - As a secreted axon guidance molecule, Netrin-1 has been documented to be a neuroprotective factor, which can reduce infarct volume, promote angiogenesis and anti-apoptosis after stroke in rodents. However, its role in axonal regeneration and synaptic formation after cerebral ischemic injury, and the related underlying mechanisms remain blurred. In this study, we used Adeno-associated vectors carrying Netrin-1 gene (AAV-NT-1) to up-regulate the expression level of Netrin-1 in rats' brain after middle cerebral artery occlusion (MCAO). We found that the up-regulated level of Netrin-1 and its receptor DCC promoted axonal regeneration and synaptic formation; the overexpression of Netrin-1 activated the JNK1 signaling pathway; these effects were partially reduced when JNK1 signaling pathway was inhibited by SP600125 (JNK specific inhibitor). Taken together, these findings suggest that Netrin-1 can facilitate the synaptic formation and axonal regeneration via the JNK1 signaling pathway after cerebral ischemia, thus promoting the recovery of neural functions. PMID- 29487501 TI - A Review of Oxytocin and Arginine-Vasopressin Receptors and Their Modulation of Autism Spectrum Disorder. AB - Oxytocin (OXT) and arginine-vasopressin (AVP) play a key regulatory part in social and affiliative behaviors; two aspects highly compromised in Autism Spectrum Disorder (ASD). Furthermore, variants in the adjacent oxytocin vasopressin gene regions have been found to be associated with ASD diagnosis and endophenotypes. This review focuses mainly on common OXTr single nucleotide polymorphisms (SNPs), AVPR1a microsatellites and AVPR1b polymorphisms in relation to the development of autism. Although these genes did not surface in genome-wide association studies, evidence supports the hypothesis that these receptors and their polymorphisms are widely involved in the regulation of social behavior, and in modulating neural and physiological pathways contributing to the etiology of ASD. With a specific focus on variants considered to be among the most prevalent in the development of ASD, these issues will be discussed in-depth and suggestions to approach inconsistencies in the present literature will be provided. Translational implications and future directions are deliberated from a short-term and a forward-looking perspective. While the scientific community has made significant progress in enhancing our understanding of ASD, more research is required for the ontology of this disorder to be fully elucidated. By supplementing information related to genetics, highlighting the differences across male and female sexes, this review provides a wider view of the current state of knowledge of OXTr and AVPr mechanisms of functioning, eventually addressing future research in the identification of further risk factors, to build new strategies for early interventions. PMID- 29487503 TI - Electrophysiological and Morphological Characterization of Chrna2 Cells in the Subiculum and CA1 of the Hippocampus: An Optogenetic Investigation. AB - The nicotinic acetylcholine receptor alpha2 subunit (Chrna2) is a specific marker for oriens lacunosum-moleculare (OLM) interneurons in the dorsal CA1 region of the hippocampus. It was recently shown using a Chrna2-cre mice line that OLM interneurons can modulate entorhinal cortex and CA3 inputs and may therefore have an important role in gating, encoding, and recall of memory. In this study, we have used a combination of electrophysiology and optogenetics using Chrna2-cre mice to determine the role of Chrna2 interneurons in the subiculum area, the main output region of the hippocampus. We aimed to assess the similarities between Chrna2 subiculum and CA1 neurons in terms of the expression of interneuron markers, their membrane properties, and their inhibitory input to pyramidal neurons. We found that subiculum and CA1 dorsal Chrna2 cells similarly expressed the marker somatostatin and had comparable membrane and firing properties. The somas of Chrna2 cells in both regions were found in the deepest layer with axons projecting superficially. However, subiculum Chrna2 cells displayed more extensive projections with dendrites which occupied a significantly larger area than in CA1. The post-synaptic responses elicited by Chrna2 cells in pyramidal cells of both regions revealed comparable inhibitory responses elicited by GABAA receptors and, interestingly, GABAB receptor mediated components. This study provides the first in-depth characterization of Chrna2 cells in the subiculum, and suggests that subiculum and CA1 Chrna2 cells are generally similar and may play comparable roles in both sub-regions. PMID- 29487505 TI - The Mouse Superior Colliculus: An Emerging Model for Studying Circuit Formation and Function. AB - The superior colliculus (SC) is a midbrain area where visual, auditory and somatosensory information are integrated to initiate motor commands. The SC plays a central role in visual information processing in the mouse; it receives projections from 85% to 90% of the retinal ganglion cells (RGCs). While the mouse SC has been a long-standing model used to study retinotopic map formation, a number of technological advances in mouse molecular genetic techniques, large scale physiological recordings and SC-dependent visual behavioral assays have made the mouse an even more ideal model to understand the relationship between circuitry and behavior. PMID- 29487506 TI - High-Throughput Automatic Training System for Odor-Based Learned Behaviors in Head-Fixed Mice. AB - Understanding neuronal mechanisms of learned behaviors requires efficient behavioral assays. We designed a high-throughput automatic training system (HATS) for olfactory behaviors in head-fixed mice. The hardware and software were constructed to enable automatic training with minimal human intervention. The integrated system was composed of customized 3D-printing supporting components, an odor-delivery unit with fast response, Arduino based hardware-controlling and data-acquisition unit. Furthermore, the customized software was designed to enable automatic training in all training phases, including lick-teaching, shaping and learning. Using HATS, we trained mice to perform delayed non-match to sample (DNMS), delayed paired association (DPA), Go/No-go (GNG), and GNG reversal tasks. These tasks probed cognitive functions including sensory discrimination, working memory, decision making and cognitive flexibility. Mice reached stable levels of performance within several days in the tasks. HATS enabled an experimenter to train eight mice simultaneously, therefore greatly enhanced the experimental efficiency. Combined with causal perturbation and activity recording techniques, HATS can greatly facilitate our understanding of the neural-circuitry mechanisms underlying learned behaviors. PMID- 29487504 TI - Potential Mechanisms Underlying Centralized Pain and Emerging Therapeutic Interventions. AB - Centralized pain syndromes are associated with changes within the central nervous system that amplify peripheral input and/or generate the perception of pain in the absence of a noxious stimulus. Examples of idiopathic functional disorders that are often categorized as centralized pain syndromes include fibromyalgia, chronic pelvic pain syndromes, migraine, and temporomandibular disorder. Patients often suffer from widespread pain, associated with more than one specific syndrome, and report fatigue, mood and sleep disturbances, and poor quality of life. The high degree of symptom comorbidity and a lack of definitive underlying etiology make these syndromes notoriously difficult to treat. The main purpose of this review article is to discuss potential mechanisms of centrally-driven pain amplification and how they may contribute to increased comorbidity, poorer pain outcomes, and decreased quality of life in patients diagnosed with centralized pain syndromes, as well as discuss emerging non-pharmacological therapies that improve symptomology associated with these syndromes. Abnormal regulation and output of the hypothalamic-pituitary-adrenal (HPA) axis is commonly associated with centralized pain disorders. The HPA axis is the primary stress response system and its activation results in downstream production of cortisol and a dampening of the immune response. Patients with centralized pain syndromes often present with hyper- or hypocortisolism and evidence of altered downstream signaling from the HPA axis including increased Mast cell (MC) infiltration and activation, which can lead to sensitization of nearby nociceptive afferents. Increased peripheral input via nociceptor activation can lead to "hyperalgesic priming" and/or "wind-up" and eventually to central sensitization through long term potentiation in the central nervous system. Other evidence of central modifications has been observed through brain imaging studies of functional connectivity and magnetic resonance spectroscopy and are shown to contribute to the widespreadness of pain and poor mood in patients with fibromyalgia and chronic urological pain. Non-pharmacological therapeutics, including exercise and cognitive behavioral therapy (CBT), have shown great promise in treating symptoms of centralized pain. PMID- 29487507 TI - Putative Adult Neurogenesis in Old World Parrots: The Congo African Grey Parrot (Psittacus erithacus) and Timneh Grey Parrot (Psittacus timneh). AB - In the current study, we examined for the first time, the potential for adult neurogenesis throughout the brain of the Congo African grey parrot (Psittacus erithacus) and Timneh grey parrot (Psittacus timneh) using immunohistochemistry for the endogenous markers proliferating cell nuclear antigen (PCNA), which labels proliferating cells, and doublecortin (DCX), which stains immature and migrating neurons. A similar distribution of PCNA and DCX immunoreactivity was found throughout the brain of the Congo African grey and Timneh grey parrots, but minor differences were also observed. In both species of parrots, PCNA and DCX immunoreactivity was observed in the olfactory bulbs, subventricular zone of the lateral wall of the lateral ventricle, telencephalic subdivisions of the pallium and subpallium, diencephalon, mesencephalon and the rhombencephalon. The olfactory bulb and telencephalic subdivisions exhibited a higher density of both PCNA and DCX immunoreactive cells than any other brain region. DCX immunoreactive staining was stronger in the telencephalon than in the subtelencephalic structures. There was evidence of proliferative hot spots in the dorsal and ventral poles of the lateral ventricle in the Congo African grey parrots at rostral levels, whereas only the dorsal accumulation of proliferating cells was observed in the Timneh grey parrot. In most pallial regions the density of PCNA and DCX stained cells increased from rostral to caudal levels with the densest staining in the nidopallium caudolaterale (NCL). The widespread distribution of PCNA and DCX in the brains of both parrot species suggest the importance of adult neurogenesis and neuronal plasticity during learning and adaptation to external environmental variations. PMID- 29487509 TI - Enduring Effects of Paternal Deprivation in California Mice (Peromyscus californicus): Behavioral Dysfunction and Sex-Dependent Alterations in Hippocampal New Cell Survival. AB - Early-life experiences with caregivers can significantly affect offspring development in human and non-human animals. While much of our knowledge of parent offspring relationships stem from mother-offspring interactions, increasing evidence suggests interactions with the father are equally as important and can prevent social, behavioral, and neurological impairments that may appear early in life and have enduring consequences in adulthood. In the present study, we utilized the monogamous and biparental California mouse (Peromyscus californicus). California mouse fathers provide extensive offspring care and are essential for offspring survival. Non-sibling virgin male and female mice were randomly assigned to one of two experimental groups following the birth of their first litter: (1) biparental care: mate pairs remained with their offspring until weaning; or (2) paternal deprivation (PD): paternal males were permanently removed from their home cage on postnatal day (PND) 1. We assessed neonatal mortality rates, body weight, survival of adult born cells in the dentate gyrus of the hippocampus, and anxiety-like and passive stress-coping behaviors in male and female young adult offspring. While all biparentally-reared mice survived to weaning, PD resulted in a ~35% reduction in survival of offspring. Despite this reduction in survival to weaning, biparentally-reared and PD mice did not differ in body weight at weaning or into young adulthood. A sex-dependent effect of PD was observed on new cell survival in the dentate gyrus of the hippocampus, such that PD reduced cell survival in female, but not male, mice. While PD did not alter classic measures of anxiety-like behavior during the elevated plus maze task, exploratory behavior was reduced in PD mice. This observation was irrespective of sex. Additionally, PD increased some passive stress-coping behaviors (i.e., percent time spent immobile) during the forced swim task-an effect that was also not sex-dependent. Together, these findings demonstrate that, in a species where paternal care is not only important for offspring survival, PD can also contribute to altered structural and functional neuroplasticity of the hippocampus. The mechanisms contributing to the observed sex-dependent alterations in new cell survival in the dentate gyrus should be further investigated. PMID- 29487510 TI - Facts and Misconceptions about 2D:4D, Social and Risk Preferences. AB - We study how the ratio between the length of the second and fourth digit (2D:4D) correlates with choices in social and risk preferences elicitation tasks by building a large dataset from five experimental projects with more than 800 subjects. Our results confirm the recent literature that downplays the link between 2D:4D and many domains of economic interest, such as social and risk preferences. As for the former, we find that social preferences are significantly lower when 2D:4D is above the median value only for subjects with low cognitive ability. As for the latter, we find that a high 2D:4D is not correlated with the frequency of subjects' risky choices. PMID- 29487511 TI - Functional MRI of Handwriting Tasks: A Study of Healthy Young Adults Interacting with a Novel Touch-Sensitive Tablet. AB - Handwriting is a complex human activity that engages a blend of cognitive and visual motor skills. Current understanding of the neural correlates of handwriting has largely come from lesion studies of patients with impaired handwriting. Task-based fMRI studies would be useful to supplement this work. To address concerns over ecological validity, previously we developed a fMRI compatible, computerized tablet system for writing and drawing including visual feedback of hand position and an augmented reality display. The purpose of the present work is to use the tablet system in proof-of-concept to characterize brain activity associated with clinically relevant handwriting tasks, originally developed to characterize handwriting impairments in Alzheimer's disease patients. As a prelude to undertaking fMRI studies of patients, imaging was performed of twelve young healthy subjects who copied sentences, phone numbers, and grocery lists using the fMRI-compatible tablet. Activation maps for all handwriting tasks consisted of a distributed network of regions in reasonable agreement with previous studies of handwriting performance. In addition, differences in brain activity were observed between the test subcomponents consistent with different demands of neural processing for successful task performance, as identified by investigating three quantitative behavioral metrics (writing speed, stylus contact force and stylus in air time). This study provides baseline behavioral and brain activity results for fMRI studies that adopt this handwriting test to characterize patients with brain impairments. PMID- 29487512 TI - The Effect of Transcranial Direct Current Stimulation on Jaw Motor Function Is Task Dependent: Speech, Syllable Repetition and Chewing. AB - Motor cortex transcranial direct current stimulation (tDCS) has been shown to enhance motor learning in healthy adults as well as various neurological conditions. However, there has been limited data on whether tDCS enhances jaw motor performance during different oral behaviors such as speech, maximum syllable repetition, and chewing. Because the effects of anodal and cathodal stimulation are known to be dependent on task demands, we hypothesized that tDCS would have a distinct effect on the jaw motor performance during these disparate oral behaviors. Ten healthy adults completed speech, maximum syllable repetition, and chewing tasks as their jaw movements were recorded using 3D optical motion capture during sham, anodal, and cathodal tDCS. Our findings showed that compared to the sham condition, jaw displacements during speech and syllable repetition were smaller during anodal stimulation, but larger during cathodal stimulation for syllable repetition and chewing indicating improved performance during anodal tDCS. On the other hand, there were no effects of anodal tDCS during chewing. These results confirm our hypotheses that: (1) tDCS induces a significant effect on jaw motor function; (2) its effects are polarity dependent; and (3) its effects are dependent on the task demands on jaw motor function. These findings support future studies exploring the effects of tDCS on persons with oral sensorimotor impairments and the development of therapeutic protocols. PMID- 29487513 TI - Corrigendum: A Quantitative Electroencephalography Study on Cochlear Implant Induced Cortical Changes in Single-Sided Deafness with Tinnitus. AB - [This corrects the article on p. 210 in vol. 11, PMID: 28572760.]. PMID- 29487508 TI - To Do or Not to Do: Dopamine, Affordability and the Economics of Opportunity. AB - Five years ago, we introduced the thrift hypothesis of dopamine (DA), suggesting that the primary role of DA in adaptive behavior is regulating behavioral energy expenditure to match the prevailing economic conditions of the environment. Here we elaborate that hypothesis with several new ideas. First, we introduce the concept of affordability, suggesting that costs must necessarily be evaluated with respect to the availability of resources to the organism, which computes a value not only for the potential reward opportunity, but also the value of resources expended. Placing both costs and benefits within the context of the larger economy in which the animal is functioning requires consideration of the different timescales against which to compute resource availability, or average reward rate. Appropriate windows of computation for tracking resources requires corresponding neural substrates that operate on these different timescales. In discussing temporal patterns of DA signaling, we focus on a neglected form of DA plasticity and adaptation, changes in the physical substrate of the DA system itself, such as up- and down-regulation of receptors or release probability. We argue that changes in the DA substrate itself fundamentally alter its computational function, which we propose mediates adaptations to longer temporal horizons and economic conditions. In developing our hypothesis, we focus on DA D2 receptors (D2R), arguing that D2R implements a form of "cost control" in response to the environmental economy, serving as the "brain's comptroller". We propose that the balance between the direct and indirect pathway, regulated by relative expression of D1 and D2 DA receptors, implements affordability. Finally, as we review data, we discuss limitations in current approaches that impede fully investigating the proposed hypothesis and highlight alternative, more semi naturalistic strategies more conducive to neuroeconomic investigations on the role of DA in adaptive behavior. PMID- 29487514 TI - Rapid Improvement in Visual Selective Attention Related to Action Video Gaming Experience. AB - A central issue in cognitive science is understanding how learning induces cognitive and neural plasticity, which helps illuminate the biological basis of learning. Research in the past few decades showed that action video gaming (AVG) offered new, important perspectives on learning-related cognitive and neural plasticity. However, it is still unclear whether cognitive and neural plasticity is observable after a brief AVG session. Using behavioral and electrophysiological measures, this study examined the plasticity of visual selective attention (VSA) associated with a 1 h AVG session. Both AVG experts and non-experts participated in this study. Their VSA was assessed prior to and after the AVG session. Within-group comparisons on the participants' performance before and after the AVG session showed improvements in response time in both groups and modulations of electrophysiological measures in the non-experts. Furthermore, between-group comparisons showed that the experts had superior VSA, relative to the non-experts, prior to the AVG session. These findings suggested an association between the plasticity of VSA and AVG. Most importantly, this study showed that the plasticity of VSA was observable after even a 1 h AVG session. PMID- 29487515 TI - Modulation of EMG-EMG Coherence in a Choice Stepping Task. AB - The voluntary step execution task is a popular measure for identifying fall risks among elderly individuals in the community setting because most falls have been reported to occur during movement. However, the neurophysiological functions during this movement are not entirely understood. Here, we used electromyography (EMG) to explore the relationship between EMG-EMG coherence, which reflects common oscillatory drive to motoneurons, and motor performance associated with stepping tasks: simple reaction time (SRT) and choice reaction time (CRT) tasks. Ten healthy elderly adults participated in the study. Participants took a single step forward in response to a visual imperative stimulus. EMG-EMG coherence was analyzed for 1000 ms before the presentation of the stimulus (stationary standing position) from proximal and distal tibialis anterior (TA) and soleus (SOL) muscles. The main result showed that all paired EMG-EMG coherences in the alpha and beta frequency bands were greater in the SRT than the CRT task. This finding suggests that the common oscillatory drive to the motoneurons during the SRT task occurred prior to taking a step, whereas the lower value of corticospinal activity during the CRT task prior to taking a step may indicate an involvement of inhibitory activity, which is consistent with observations from our previous study (Watanabe et al., 2016). Furthermore, the beta band coherence in intramuscular TA tended to positively correlate with the number of performance errors that are associated with fall risks in the CRT task, suggesting that a reduction in the inhibitory activity may result in a decrease of stepping performance. These findings could advance the understanding of the neurophysiological features of postural adjustments in elderly individuals. PMID- 29487516 TI - Perceived Gaze Direction Modulates Neural Processing of Prosocial Decision Making. AB - Gaze direction is a common social cue implying potential interpersonal interaction. However, little is known about the neural processing of social decision making influenced by perceived gaze direction. Here, we employed functional magnetic resonance imaging (fMRI) method to investigate 27 females when they were engaging in an economic exchange game task during which photos of direct or averted eye gaze were shown. We found that, when averted but not direct gaze was presented, prosocial vs. selfish choices were associated with stronger activations in the right superior temporal gyrus (STG) as well as larger functional couplings between right STG and the posterior cingulate cortex (PCC). Moreover, stronger activations in right STG was associated with quicker actions for making prosocial choice accompanied with averted gaze. The findings suggest that, when the cue implying social contact is absent, the processing of understanding others' intention and the relationship between self and others is more involved for making prosocial than selfish decisions. These findings could advance our understanding of the roles of subtle cues in influencing prosocial decision making, as well as shedding lights on deficient social cue processing and functioning among individuals with autism spectrum disorder (ASD). PMID- 29487517 TI - MAO-A Phenotype Effects Response Sensitivity and the Parietal Old/New Effect during Recognition Memory. AB - A critical problem for developing personalized treatment plans for cognitive disruptions is the lack of understanding how individual differences influence cognition. Recognition memory is one cognitive ability that varies from person to person and that variation may be related to different genetic phenotypes. One gene that may impact recognition memory is the monoamine oxidase A gene (MAO-A), which influences the transcription rate of MAO-A. Examination of how MAO-A phenotypes impact behavioral and event-related potentials (ERPs) correlates of recognition memory may help explain individual differences in recognition memory performance. Therefore, the current study uses electroencephalography (EEG) in combination with genetic phenotyping of the MAO-A gene to determine how well characterized ERP components of recognition memory, the early frontal old/new effect, left parietal old/new effect, late frontal old/new effect, and the late posterior negativity (LPN) are impacted by MAO-A phenotype during item and source memory. Our results show that individuals with the MAO-A phenotype leading to increased transcription have lower response sensitivity during both item and source memory. Additionally, during item memory the left parietal old/new effect is not present due to increased ERP amplitude for correct rejections. The results suggest that MAO-A phenotype changes EEG correlates of recognition memory and influences how well individuals differentiate between old and new items. PMID- 29487518 TI - Mind the Gap: The Effects of Temporal and Spatial Separation in Localization of Dual Touches on the Hand. AB - In this study, we aimed to relate the findings from two predominantly separate streams of literature, one reporting on the localization of single touches on the skin, and the other on the distance perception of dual touches. Participants were touched with two points, delivered either simultaneously or separated by a short delay to various locations on their left hand dorsum. They then indicated on a size-matched hand silhouette the perceived locations of tactile stimuli. We quantified the deviations between the actual stimulus grid and the corresponding perceptual map which was constructed from the perceived tactile locations, and we calculated the precision of tactile localization (i.e., the variability across localization attempts). The evidence showed that the dual touches, akin to single touch stimulations, were mislocalized distally and that their variable localization error was reduced near joints, particularly near knuckles. However, contrary to single-touch localization literature, we observed for the dual touches to be mislocalized towards the ulnar side of the hand, particularly when they were presented sequentially. Further, the touches presented in a sequential order were slightly "repelled" from each other and their perceived distance increased, while the simultaneous tactile pairs were localized closer to each other and their distance was compressed. Whereas the sequential touches may have been localized with reference to the body, the compression of tactile perceptual space for simultaneous touches was related in the previous literature to signal summation and inhibition and the low-level factors, including the innervation density and properties of receptive fields (RFs) of somatosensory neurons. PMID- 29487519 TI - Financial Incentives Differentially Regulate Neural Processing of Positive and Negative Emotions during Value-Based Decision-Making. AB - Emotional and economic incentives often conflict in decision environments. To make economically desirable decisions then, deliberative neural processes must be engaged to regulate automatic emotional reactions. In this functional magnetic resonance imaging (fMRI) study, we evaluated how fixed wage (FW) incentives and performance-based (PB) financial incentives, in which pay is proportional to outcome, differentially regulate positive and negative emotional reactions to hypothetical colleagues that conflicted with the economics of available alternatives. Neural activity from FW to PB incentive contexts decreased for positive emotional stimuli but increased for negative stimuli in middle temporal, insula, and medial prefrontal regions. In addition, PB incentives further induced greater responses to negative than positive emotional decisions in the frontal and anterior cingulate regions involved in emotion regulation. Greater response to positive than negative emotional features in these regions also correlated with lower frequencies of economically desirable choices. Our findings suggest that whereas positive emotion regulation involves a reduction of responses in valence representation regions, negative emotion regulation additionally engages brain regions for deliberative processing and signaling of incongruous events. PMID- 29487520 TI - Comparing Gait with Multiple Physical Asymmetries Using Consolidated Metrics. AB - Physical changes such as leg length discrepancy, the addition of a mass at the distal end of the leg, the use of a prosthetic, and stroke frequently result in an asymmetric gait. This paper presents a metric that can potentially serve as a benchmark to categorize and differentiate between multiple asymmetric bipedal gaits. The combined gait asymmetry metric (CGAM) is based on modified Mahalanobis distances, and it utilizes the asymmetries of gait parameters obtained from motion capture and force data recorded during human walking. The gait parameters that were used in this analysis represent spatio-temporal, kinematic, and kinetic parameters. This form of a consolidated metric will help researchers identify overall gait asymmetry by showing them if the overall gait symmetry is improving and avoid the case where one parameter's symmetry is improving while another is getting worse. The CGAM metric successfully served as a measure for overall symmetry with eleven different gait parameters and successfully showed differences among gait with multiple physical asymmetries. The results showed that mass at the distal end had a larger magnitude on overall gait asymmetry compared to leg length discrepancy. It also showed that the combined effects are varied based on the cancelation effect between gait parameters. The metric was also successful in delineating the differences of prosthetic gait and able-bodied gait at three different walking velocities. PMID- 29487521 TI - The Abnormal Functional Connectivity between the Hypothalamus and the Temporal Gyrus Underlying Depression in Alzheimer's Disease Patients. AB - Hypothalamic communication with the rest of the brain is critical for accomplishing a wide variety of physiological and psychological functions, including the maintenance of neuroendocrine circadian rhythms and the management of affective processes. Evidence has shown that major depressive disorder (MDD) patients exhibit increased functioning of the hypothalamic-pituitary-adrenal (HPA) axis. Neurofibrillary tangles are also found in the hypothalamus of Alzheimer's disease (AD) patients, and AD patients exhibit abnormal changes in the HPA. However, little is known of how the hypothalamus interacts with other brain regions in AD patients with depression (D-AD). Functional connectivity (FC) analysis explores the connectivity between brain regions that share functional properties. Here, we used resting-state (rs) magnetic resonance imaging (MRI) technology and the FC method to measure hypothalamic connectivity across the whole brain in 22 D-AD patients and 21 non-depressed AD patients (nD-AD). Our results showed that D-AD patients had reduced FC among the hypothalamus, the right middle temporal gyrus (MTG) and the right superior temporal gyrus (STG) compared with the FC of nD-AD patients, suggesting that the abnormal FC between the hypothalamus and the temporal lobe may play a key role in the pathophysiology of depression in AD patients. PMID- 29487522 TI - Chronic MK-801 Application in Adolescence and Early Adulthood: A Spatial Working Memory Deficit in Adult Long-Evans Rats But No Changes in the Hippocampal NMDA Receptor Subunits. AB - The role of NMDA receptors in learning, memory and hippocampal function has long been recognized. Post-mortem studies have indicated that the expression or subunit composition of the NMDA glutamate receptor subtype might be related to the impaired cognitive functions found in schizophrenia patients. NMDA receptor antagonists have been used to develop animal models of this disorder. There is accumulating evidence showing that not only the acute but also the chronic application of NMDA receptor antagonists may induce schizophrenia-like alterations in behavior and brain functions. However, limited evidence is available regarding the consequences of NMDA receptor blockage during periods of adolescence and early adulthood. This study tested the hypothesis that a 2-week treatment of male Long-Evans and Wistar rats with dizocilpine (MK-801; 0.5 mg/kg daily) starting at postnatal days (PD) 30 and 60 would cause a long-term cognitive deficit and changes in the levels of NMDA receptor subunits. The working memory version of the Morris water maze (MWM) and active place avoidance with reversal on a rotating arena (Carousel) requiring cognitive coordination and flexibility probed cognitive functions and an elevated-plus maze (EPM) was used to measure anxiety-like behavior. The western blot method was used to determine changes in NMDA receptor subunit levels in the hippocampus. Our results showed no significant changes in behaviors in Wistar rats. Slightly elevated anxiety-like behavior was observed in the EPM in Long-Evans rats with the onset of treatment on PD 30. Furthermore, Long-Evans rats treated from PD 60 displayed impaired working memory in the MWM. There were; however, no significant changes in the levels of NMDA receptor subunits because of MK-801 administration. These findings suggest that a 2-week treatment starting on PD 60 in Long-Evans rats leads to long-term changes in working memory, but this deficit is not paralleled by changes in NMDA receptor subunits. These results support the face validity, but not construct validity of this model. We suggest that chronic treatment of adolescent and adult rats does not constitute a plausible animal model of schizophrenia. PMID- 29487523 TI - Facile Fabrication of Reduction-Responsive Supramolecular Nanoassemblies for Co delivery of Doxorubicin and Sorafenib toward Hepatoma Cells. AB - Combination of doxorubicin with sorafenib (SF) was reported to be a promising strategy for treating hepatocellular carcinoma (HCC). In this study, we designed a reduction-responsive supramolecular nanosystem based on poly (ethylene glycol) beta-cyclodextrin (PEG-CD) and a disulfide-containing adamantine-terminated doxorubicin prodrug (AD) for efficient co-delivery of doxorubicin and sorafenib. PEG-CD/AD supramolecular amphiphiles were formed through host-guest interaction between cyclodextrin and adamantine moieties, and then self-assembled into regular spherical nanoparticles with a uniform size of 166.4 nm. Flow cytometry analysis and confocal laser scanning microscopy images showed that PEG-CD/AD nanoparticles could be successfully taken up by HepG2 cells and then released doxorubicin into the cell nuclei. Moreover, sorafenib could be facilely encapsulated into the hydrophobic cores to form PEG-CD/AD/SF nanoparticles with a slightly larger size of 186.2 nm. PEG-CD/AD/SF nanoparticles sequentially released sorafenib and doxorubicin in a reduction-response manner. In vitro cytotoxicity assay showed that PEG-CD/AD/SF nanoparticles had an approximately 4.7-fold decrease in the IC50 value compared to that of PEG-CD/AD and SF physical mixtures, indicating stronger inhibitory effect against HepG2 cells by co-loading these two drugs. In summary, this novel supramolecular nanosystem provided a simple strategy to co-deliver doxorubicin and sorafenib toward hepatoma cells, which showed promising potential for treatment of HCC. PMID- 29487524 TI - Free Total Rhubarb Anthraquinones Protect Intestinal Injury via Regulation of the Intestinal Immune Response in a Rat Model of Severe Acute Pancreatitis. AB - Intestinal mucosal immune barrier dysfunction plays a key role in the pathogenesis of severe acute pancreatitis (SAP). Rhubarb is a commonly used traditional Chinese medicine as a laxative in China. It markedly protects pancreatic acinar cells from trypsin-induced injury in rats. Free total rhubarb anthraquinones (FTRAs) isolated and extracted from rhubarb display the beneficial effects of antibacteria, anti-inflammation, antivirus, and anticancer. The principal aim of the present study was to investigate the effects of FTRAs on the protection of intestinal injury and modification of the intestinal barrier function through regulation of intestinal immune function in rats with SAP. We established a rat model of SAP by injecting 3.5% sodium taurocholate (STC, 350 mg/kg) into the biliopancreatic duct via retrograde injection and treated the rats with FTRAs (36 or 72 mg/kg) or normal saline (control) immediately and 12 h after STC injection. Then, we evaluated the protective effect of FTRAs on intestinal injury by pathological analysis and determined the levels of endotoxin (ET), interleukin 1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), nitric oxide (NO), myeloperoxidase (MPO), capillary permeability, nucleotide binding oligomerization domain-like receptors 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD domain (ASC), casepase-1, secretary immunoglobulin A (SIgA), regulatory T cells (Tregs), and the ratio of Th1/Th2 in the blood and/or small intestinal tissues or mesenteric lymph node (MLN) cells. Moreover, the chemical profile of FTRAs was analyzed by HPLC-UV chromatogram. The results showed that FTRAs significantly protected intestinal damage and decreased the levels of ET, IL-1beta, TNF-alpha, and NO in the blood and TNF-alpha, IL 1beta, and protein extravasation in the intestinal tissues in SAP rats. Furthermore, FTRAs significantly decreased the expressions of NLRP3, ASC, and caspase-1, the number of Tregs and the ratio of Th1/Th2, while significantly increased the expression of SIgA in the intestinal tissues and/or MLN cells in SAP rats. Our results indicate that FTRAs could protect intestinal injury and improve intestinal mucosal barrier function through regulating immune function of SAP rats. Therefore, FTRAs may have the potential to be developed as the novel agent for the treatment of SAP clinically. PMID- 29487526 TI - Silencing of Long Non-coding RNA MIAT Sensitizes Lung Cancer Cells to Gefitinib by Epigenetically Regulating miR-34a. AB - Long non-coding RNA (lncRNA) myocardial infarction associated transcript (MIAT) was recently identified as oncogene in several cancers. However, the role of MIAT on acquired resistance in lung cancer and the underlying mechanisms remain unclear. Here, we showed that the expression of MIAT in lung cancer tissues was upregulated compared with adjacent tissues. LncRNA MIAT expression was associated with tumor size, lymph node metastasis, distant metastasis and TNM stage. Univariate analysis and multivariate analysis revealed that the lncRNA MIAT to be an independent factor for predicating the prognosis of lung cancer patients. Low lncRNA MIAT have longer overall survival time and progression-free survival time than patients with high lncRNA MIAT expression. Moreover, the knockdown of MIAT significantly sensitized PC9 and gefitinib-resistant PC9 cells to gefitinib in vitro and in vivo, and increased the expression of miR-34a and inactivated PI3K/Akt signaling. MIAT interacted with miR-34a and epigenetically controlled the miR-34a expression by hyper-methylating its promotor. Taken together, our findings demonstrated that knockdown of MIAT by siRNA enhances lung cancer cells to gefitinib through the PI3K/Akt signaling pathway by epigenetically regulating miR-34a. Thus, MIAT may be a useful prognostic marker and therapeutic target for lung cancer patients. PMID- 29487525 TI - Alcohol-Mediated Organ Damages: Heart and Brain. AB - Alcohol is one of the most commonly abused substances in the United States. Chronic consumption of ethanol has been responsible for numerous chronic diseases and conditions globally. The underlying mechanism of liver injury has been studied in depth, however, far fewer studies have examined other organs especially the heart and the central nervous system (CNS). The authors conducted a narrative review on the relationship of alcohol with heart disease and dementia. With that in mind, a complex relationship between inflammation and cardiovascular disease and dementia has been long proposed but inflammatory biomarkers have gained more attention lately. In this review we examine some of the consequences of the altered cytokine regulation that occurs in alcoholics in organs other than the liver. The article reviews the potential role of inflammatory markers such as TNF-alpha in predicting dementia and/or cardiovascular disease. It was found that TNF-alpha could promote and accelerate local inflammation and damage through autocrine/paracrine mechanisms. Unraveling the mechanisms linking chronic alcohol consumption with proinflammatory cytokine production and subsequent inflammatory signaling pathways activation in the heart and CNS, is essential to improve our understanding of the disease and hopefully facilitate the development of new remedies. PMID- 29487527 TI - RhoA/ROCK Signaling Pathway Mediates Shuanghuanglian Injection-Induced Pseudo allergic Reactions. AB - Background: Shuanghuanglian injection (SHLI) is a famous Chinese medicine used as an intravenous preparation for the treatment of acute respiratory tract infections. In the recent years, the immediate hypersensitivity reactions induced by SHLI have attracted broad attention. However, the mechanism involved in these reactions has not yet been elucidated. The present study aims to explore the characteristics of the immediate hypersensitivity reactions induced by SHLI and deciphers the role of the RhoA/ROCK signaling pathway in these reactions. Methods: SHLI-immunized mice or naive mice were intravenously injected (i.v.) with SHLI (600 mg/kg) once, and vascular leakage in the ears was evaluated. Passive cutaneous anaphylaxis test was conducted using sera collected from SHLI immunized mice. Naive mice were administered (i.v.) with a single dose of 150, 300, or 600 mg/kg of SHLI, and vascular leakage, histamine release, and histopathological alterations in the ears, lungs, and intestines were tested. In vitro, human umbilical vein endothelial cell (HUVEC) monolayer was incubated with SHLI (0.05, 0.1, or 0.15 mg/mL), and the changes in endothelial permeability and cytoskeleton were observed. Western blot analysis was performed and ROCK inhibitor was employed to investigate the contribution of the RhoA/ROCK signaling pathway in SHLI-induced hypersensitivity reactions, both in HUVECs and in mice. Results: Our results indicate that SHLI was able to cause immediate dose dependent vascular leakage, edema, and exudates in the ears, lungs, and intestines, and histamine release in mice. These were pseudo-allergic reactions, as SHLI-specific IgE was not elicited during sensitization. In addition, SHLI induced reorganization of actin cytoskeleton and disrupted the endothelial barrier. The administration of SHLI directly activated the RhoA/ROCK signaling pathway both in HUVECs and in the ears, lungs, and intestines of mice. Fasudil hydrochloride, a ROCK inhibitor, ameliorated the SHLI-induced hypersensitivity reactions in both endothelial cells and mice indicating its protective effect. SHLI-induced pseudo-allergic reactions were mediated by the activation of the RhoA/ROCK signaling pathway. Conclusion: This study presents a novel mechanism of SHLI-induced immediate hypersensitivity reactions and suggests a potential therapeutic strategy to prevent the associated adverse reactions. PMID- 29487528 TI - Toxicity Assessment of Wild Mushrooms from the Western Ghats, India: An in Vitro and Sub-Acute in Vivo Study. AB - Background: Poisoning by different kinds of toxic mushrooms is unfortunately becoming an increasingly important medical problem, evident from the growing number of reports worldwide since the 1950s. Mycetism being a health concern, deserves scientific attention. In this perspective, the present study aims to assess the potential effects of ingesting the selected wild mushrooms from regions of the Western Ghats, India. Methods: The preliminary cytotoxicity of the selected mushrooms was studied in vitro on the intestinal NCM460 and the Chang's liver cell lines on the basis of cell viability. Further, the hepatotoxicity was assessed by measuring biologically relevant endpoints such as membrane integrity, mitochondrial stress and oxidative status. A 28 day sub-acute toxicity study was carried out by orally administering the mushroom extracts to mice at 250 and 500 mg/kg body weight. The hematological and serum analysis as well as histological examinations were carried out to evaluate their in vivo toxicity. GC-MS analysis of the mushrooms facilitated the identification of their volatile chemical profile. Result: The in vitro intestinal cytotoxicity exhibited by these wild mushrooms in comparison to the edible mushroom indicated their potential gastrointestinal toxicity. The pathological findings in small intestine on exposure to Chlorophyllum molybdites and Agaricus endoxanthus also validates the speculations about their intestinal toxicity. The toxic insult to the hepatocytes due to Amanita angustilamellata, Entoloma crassum, and Clarkeinda trachodes was predictive of the observed in vivo hepatotoxicity which was also accompanied by renal toxicity at the higher dose of 500 mg/kg bwt. Conclusion: The potential toxicity exhibited by these representative mushrooms from the wild warrants caution about their consumption. The present work could also have broader implications for global mycetism. PMID- 29487529 TI - Nanoliposome-Encapsulated Brinzolamide-hydropropyl-beta-cyclodextrin Inclusion Complex: A Potential Therapeutic Ocular Drug-Delivery System. AB - Novel ocular drug delivery systems (NODDSs) remain to be explored to overcome the anatomical and physiological barriers of the eyes. This study was to encapsulate brinzolamide (BRZ)-hydropropyl-beta-cyclodextrin (HP-beta-CD) inclusion complex (HP-beta-CD/BRZ) into nanoliposomes and investigate its potential as one of NODDS to improve BRZ local glaucomatous therapeutic effect. HP-beta-CD/BRZ was firstly prepared to enhance the solubility of poorly water-soluble BRZ. The HP-beta CD/BRZ loaded nanoliposomes (BCL) were subsequently constructed by thin-film dispersion method. After the optimization of the ratio of BRZ to HP-beta-CD, the optimal BCL showed an average size of 82.29 +/- 6.20 nm, zeta potential of -3.57 +/- 0.46 mV and entrapment efficiency (EE) of 92.50 +/- 2.10% with nearly spherical in shape. The X-ray diffraction (XRD) confirmed the formation of HP beta-CD/BRZ and BCL. The in vitro release study of BCL was evaluated using the dialysis technique, and BCL showed moderate sustained release. BCL (1 mg/mL BRZ) showed a 9.36-fold increase in the apparent permeability coefficient and had a sustained and enhanced intraocular pressure reduction efficacy when compared with the commercially available formulation (BRZ-Sus) (10 mg/mL BRZ). In conclusion, BCL might have a promising future as a NODDS for glaucoma treatment. PMID- 29487530 TI - Scutellarin Increases Cisplatin-Induced Apoptosis and Autophagy to Overcome Cisplatin Resistance in Non-small Cell Lung Cancer via ERK/p53 and c-met/AKT Signaling Pathways. AB - Cisplatin, as the first-line anti-tumor agent, is widely used for treatment of a variety of malignancies including non-small cell lung cancer (NSCLC). However, the acquired resistance has been a major obstacle for the clinical application. Scutellarin is a active flavone extracted from Erigeron breviscapus Hand-Mazz that has been shown to exhibit anticancer activities on various types of tumors. Here, we reported that scutellarin was capable of sensitizing A549/DDP cells to cisplatin by enhancing apoptosis and autophagy. Mechanistic analyses indicated that cisplatin-induced caspase-3-dependent apoptosis was elevated in the presence of scutellarin through activating extracellular signal-regulated kinases (ERK) mediated p53 pathway. Furthermore, scutellarin also promoted cisplatin-induced cytotoxic autophagy, downregulated expression of p-AKT and c-met. Deficiency of c met reduced p-AKT level, and inhibition of p-AKT or c-met improved autophagy in A549/DDP cells. Interestingly, loss of autophagy attenuated the synergism of this combination. In vivo, the co-treatment of cisplatin and scutellarin notably reduced the tumor size when compared with cisplatin treatment alone. Notably, scutellarin significantly reduced the toxicity generated by cisplatin in tumor bearing mice. This study identifies the unique role of scutellarin in reversing cisplatin resistance through apoptosis and autophagy, and suggests that combined cisplatin and scutellarin might be a novel therapeutic strategy for patients with NSCLC. PMID- 29487531 TI - The Association of Unfavorable Traffic Events and Cannabis Usage: A Meta Analysis. AB - Background: In the last years were published many epidemiological articles aiming to link driving under the influence of cannabis (DUIC) with the risk of various unfavorable traffic events (UTEs), with sometimes contradictory results. Aim: The primary objective of this study was to analyze whether there is a significant association between DUIC and UTEs. Materials and Methods: We used two meta analytical methods to assess the statistical significance of the effect size: random-effects model and inverse variance heterogeneity model. Results: Twenty four studies were included in the meta-analysis. We obtained significant increases in the effect size for DUIC tested through blood analysis, with an odds ratio (OR) of 2.27 and a confidence interval (CI) between 1.36 and 3.80; death as an outcome, with an OR of 1.56 and a CI between 1.16 and 2.09; and case-control as the type of study, with an OR of 1.99 and a CI between 1.05 and 3.80. Publication bias was very high. Conclusion: Our analysis suggests that the overall effect size for DUIC on UTEs is not statistically significant, but there are significant differences obtained through subgroup analysis. This result might be caused by either methodological flaws (which are often encountered in articles on this topic), the indiscriminate employment of the term "cannabis use," or an actual absence of an adverse effect. When a driver is found, in traffic, with a positive reaction suggesting cannabis use, the result should be corroborated by either objective data regarding marijuana usage (like blood analyses, with clear cut-off values), or a clinical assessment of the impairment, before establishing his/her fitness to drive. PMID- 29487532 TI - Roles of Perivascular Adipose Tissue in the Pathogenesis of Atherosclerosis. AB - Traditionally, it is believed that white adipose tissues serve as energy storage, heat insulation, and mechanical cushion, whereas non-shivering thermogenesis occurs in brown adipose tissue. Recent evidence revealed that adipose tissue secretes many types of cytokines, called as adipocytokines, which modulate glucose metabolism, lipid profile, appetite, fibrinolysis, blood pressure, and inflammation. Most of the arteries are surrounded by perivascular adipose tissue (PVAT). PVAT has been thought to be simply a structurally supportive tissue for vasculature. However, recent studies showed that PVAT influences vasodilation and vasocontraction, suggesting that PVAT regulates vascular tone and diameter. Adipocytokines secreted from PVAT appear to have direct access to the adjacent arterial wall by diffusion or via vasa vasorum. In fact, PVAT around atherosclerotic lesions and mechanically-injured arteries displayed inflammatory cytokine profiles, suggesting that PVAT functions to promote vascular lesion formation. Many clinical studies revealed that increased accumulation of epicardial adipose tissue (EAT), which surrounds coronary arteries, is associated with coronary artery disease. In this review article, we will summarize recent findings about potential roles of PVAT in the pathogenesis of atherosclerosis, particularly focusing on a series of basic and clinical studies from our laboratory. PMID- 29487533 TI - Sub-cellular Electrical Heterogeneity Revealed by Loose Patch Recording Reflects Differential Localization of Sarcolemmal Ion Channels in Intact Rat Hearts. AB - The cardiac action potential (AP) is commonly recoded as an integral signal from isolated myocytes or ensembles of myocytes (with intracellular microelectrodes and extracellular macroelectrodes, respectively). These signals, however, do not provide a direct measure of activity of ion channels and transporters located in two major compartments of a cardiac myocyte: surface sarcolemma and the T-tubule system, which differentially contribute to impulse propagation and excitation contraction (EC) coupling. In the present study we investigated electrical properties of myocytes within perfused intact rat heart employing loose patch recording with narrow-tip (2 MUm diameter) extracellular electrodes. Using this approach, we demonstrated two distinct types of electric signals with distinct waveforms (single peak and multi-peak AP; AP1 and AP2, respectively) during intrinsic pacemaker activity. These two types of waveforms depend on the position of the electrode tip on the myocyte surface. Such heterogeneity of electrical signals was lost when electrodes of larger pipette diameter were used (5 or 10 MUm), which indicates that the electric signal was assessed from a region of <5 MUm. Importantly, both pharmacological and mathematical simulation based on transverse (T)-tubular distribution suggested that while the AP1 and the initial peak of AP2 are predominantly attributable to the fast, inward Na+ current in myocyte's surface sarcolemma, the late components of AP2 are likely representative of currents associated with L-type Ca2+ channel and Na+/Ca2+ exchanger (NCX) currents which are predominantly located in T-tubules. Thus, loose patch recording with narrow-tip pipette provides a valuable tool for studying cardiac electric activity on the subcellular level in the intact heart. PMID- 29487534 TI - Discovery of a Sweet Spot on the Foot with a Smart Wearable Soccer Boot Sensor That Maximizes the Chances of Scoring a Curved Kick in Soccer. AB - This paper provides the evidence of a sweet spot on the boot/foot as well as the method for detecting it with a wearable pressure sensitive device. This study confirmed the hypothesized existence of sweet and dead spots on a soccer boot or foot when kicking a ball. For a stationary curved kick, kicking the ball at the sweet spot maximized the probability of scoring a goal (58-86%), whereas having the impact point at the dead zone minimized the probability (11-22%). The sweet spot was found based on hypothesized favorable parameter ranges (center of pressure in x/y-directions and/or peak impact force) and the dead zone based on hypothesized unfavorable parameter ranges. The sweet spot was rather concentrated, independent of which parameter combination was used (two- or three parameter combination), whereas the dead zone, located 21 mm from the sweet spot, was more widespread. PMID- 29487535 TI - Acute Effects of Exercise Mode on Arterial Stiffness and Wave Reflection in Healthy Young Adults: A Systematic Review and Meta-Analysis. AB - Background: This systematic review and meta-analysis quantified the effect of acute exercise mode on arterial stiffness and wave reflection measures including carotid-femoral pulse wave velocity (cf-PWV), augmentation index (AIx), and heart rate corrected AIx (AIx75). Methods: Using standardized terms, database searches from inception until 2017 identified 45 studies. Eligible studies included acute aerobic and/or resistance exercise in healthy adults, pre- and post-intervention measurements or change values, and described their study design. Data from included studies were analyzed and reported in accordance with the Cochrane Handbook for Systematic Reviews of Interventions and PRISMA guidelines. Meta analytical data were reported via forest plots using absolute differences with 95% confidence intervals with the random effects model accounting for between study heterogeneity. Reporting bias was assessed via funnel plots and, individual studies were evaluated for bias using the Cochrane Collaboration's tool for assessing risk of bias. A modified PEDro Scale was applied to appraise methodological concerns inherent to included studies. Results: Acute aerobic exercise failed to change cf-PWV (mean difference: 0.00 ms-1 [95% confidence interval: -0.11, 0.11], p = 0.96), significantly reduced AIx (-4.54% [-7.05, 2.04], p = 0.0004) and significantly increased AIx75 (3.58% [0.56, 6.61], p = 0.02). Contrastingly, acute resistance exercise significantly increased cf-PWV (0.42 ms-1 [0.17, 0.66], p = 0.0008), did not change AIx (1.63% [-3.83, 7.09], p = 0.56), and significantly increased AIx75 (15.02% [8.71, 21.33], p < 0.00001). Significant heterogeneity was evident within all comparisons except cf-PWV following resistance exercise, and several methodological concerns including low applicability of exercise protocols and lack of control intervention were identified. Conclusions: Distinct arterial stiffness and wave reflection responses were identified following acute exercise with overall increases in both cf-PWV and AIx75 following resistance exercise potentially arising fromcardiovascular and non-cardiovascular factors that likely differ from those following aerobic exercise. Future studies should address identified methodological limitations to enhance interpretation and applicability of arterial stiffness and wave reflection indices to exercise and health. PMID- 29487536 TI - Cocaine Directly Impairs Memory Extinction and Alters Brain DNA Methylation Dynamics in Honey Bees. AB - Drug addiction is a chronic relapsing behavioral disorder. The high relapse rate has often been attributed to the perseverance of drug-associated memories due to high incentive salience of stimuli learnt under the influence of drugs. Drug addiction has also been interpreted as a memory disorder since drug associated memories are unusually enduring and some drugs, such as cocaine, interfere with neuroepigenetic machinery known to be involved in memory processing. Here we used the honey bee (an established invertebrate model for epigenomics and behavioral studies) to examine whether or not cocaine affects memory processing independently of its effect on incentive salience. Using the proboscis extension reflex training paradigm we found that cocaine strongly impairs consolidation of extinction memory. Based on correlation between the observed effect of cocaine on learning and expression of epigenetic processes, we propose that cocaine interferes with memory processing independently of incentive salience by directly altering DNA methylation dynamics. Our findings emphasize the impact of cocaine on memory systems, with relevance for understanding how cocaine can have such an enduring impact on behavior. PMID- 29487537 TI - Treatment of Human Urinary Kallidinogenase Combined with Maixuekang Capsule Promotes Good Functional Outcome in Ischemic Stroke. AB - Aims: To evaluate the clinical efficacy of Human Urinary Kallidinogenase (HUK) and Maixuekang capsule in the treatment of acute ischemic stroke (AIS) patients. Methods: In this study, from January 2016 to July 2016, 60 patients with acute ischemic stroke were enrolled and 56 patients with complete information of whom 21 patients received HUK+ basic treatment (HUK group), 16 patients received HUK+ Maixuekang capsule + basic treatment (HUK+ Maixuekang group), 19 patients received basic treatment (control group). 0.15 PNA unit of HUK injection plus 100 ml saline in intravenous infusion was performed in the HUK group and HUK+ Maixuekang group, with once a day for 14 consecutive days. 0.75 g Maixuekang capsules were taken in HUK+ Maixuekang group, with three times a day for 14 consecutive days. The National Institutes of Health Stroke Scale (NIHSS) scores in three groups were analyzed 7 days after treatment. The modified Rankin Scale (mRS) scores in three groups were analyzed 12 month after the treatment. Results: No difference was found in the NIHSS scores, age, gender, and comorbidities between three groups before treatment (p > 0.05). Seven days after treatment, the NIHSS scores in the HUK group and HUK+ Maixuekang group were significantly decreased than before (p HUK = 0.001, p HUK+Maixuekang < 0.001), and lower than that in the control group (p HUK = 0.032; p HUK+Maixuekang < 0.001). Twelve months after treatment, good functional outcome rate (12 month mRS score <= 2) in the HUK group and HUK+ Maixuekang group was significantly higher than that in the control group (p HUK = 0.049, p HUK+Maixuekang = 0.032). Conclusion: The treatment of HUK or HUK combined with Maixuekang capsule can effectively improve the neurological function and promote long-term recovery for AIS patients. PMID- 29487538 TI - Expression of Neuropeptide F Gene and Its Regulation of Feeding Behavior in the Pea Aphid, Acyrthosiphon pisum. AB - Neuropeptide F (NPF) signaling systems are widespread and highly evolutionarily conserved from vertebrates to invertebrates. In fact, NPF has been identified in many insect species and plays regulatory roles in diverse physiological processes, such as feeding, learning, reproduction and stress responses. NPF operates by interacting with the NPF receptor (NPFR). Here, we characterized and determined the presumed role of NPF signaling in the wingless parthenogenetic pea aphid, Acyrthosiphon pisum. Quantitative real-time reverse transcription-PCR (qRT PCR) revealed that the expression levels of both NPF and NPFR transcripts varied across developmental stages, which implies that the NPF signaling system might participate in the developmental regulation of aphid physiological processes or behaviors. The NPF transcript was mainly detected in the head but not in the gut, whereas the NPFR transcript was mainly detected in both the gut and head. In addition, the NPF transcript levels were markedly up-regulated in starved aphids compared with satiated aphids, and the transcript levels recovered after re feeding. In contrast, the NPFR transcript levels remained stable in starved and re-fed aphids. Furthermore, RNAi knockdown by the injection of NPF dsRNA into wingless adult aphids significantly reduced their food intake. Further analysis of the modification of aphid feeding behavior on broad bean plants using electrical penetration graphs (EPGs) revealed that both the probing time and the total duration of phloem activity decreased significantly in the NPF treatment group. These results indicated a lower appetite for food after NPF knockdown, which could explain the reduction in aphid food intake. NPF silencing was also shown to reduce reproduction but not survival in aphids. Overall, the results of these experiments suggest that NPF plays an important role in regulation of feeding in A. pisum. PMID- 29487539 TI - Impact of Air Exposure on Vasotocinergic and Isotocinergic Systems in Gilthead Sea Bream (Sparus aurata): New Insights on Fish Stress Response. AB - The hypothalamus-pituitary-interrenal (HPI) and hypothalamus-sympathetic chromaffin cell (HSC) axes are involved in the regulation of the stress response in teleost. In this regard, the activation of a complex network of endocrine players is needed, including corticotrophin-releasing hormone (Crh), Crh binding protein (Crhbp), proopiomelanocortin (Pomc), thyrotropin-releasing hormone (Trh), arginine vasotocin (Avt), and isotocin (It) to finally produce pleiotropic functions. We aimed to investigate, using the gilthead sea bream (Sparus aurata) as a biological model, the transcriptomic response of different endocrine factors (crh, crhbp, pomcs, trh), neuropeptides (avt and it), and their specific receptors (avtrv1a, avtrv2, and itr) in four important target tissues (hypothalamus, pituitary, kidney and liver), after an acute stress situation. We also investigated several stress hormones (catecholamines and cortisol). The stress condition was induced by air exposure for 3 min, and hormonal, metabolic and transcriptomic parameters were analyzed in a time course response (15 and 30 min, and 1, 2, 4, and 8 h post-stress) in a total of 64 fish (n = 8 fish per experimental group; p = 0.05; statistical power = 95%). Our results showed that plasma noradrenaline, adrenaline and cortisol values increased few minutes after stress exposure. At hypothalamic and hypophyseal levels, acute stress affected mRNA expression of all measured precursors and hormonal factors, as well as their receptors (avtrs and itr), showing the activation, at central level, of HPI, HSC, and Avt/It axes in the acute stress response. In addition, stress response also affected mRNA levels of avtrs and itr in the head kidney, as well as the steroidogenic acute regulatory protein (star) and tyrosine hydroxylase (th) expression, suggesting their participation in the HPI and HSC axes activation. Moreover, the pattern of changes in hepatic avtrs and itr gene expression also highlights an important role of vasotocinergic and isotocinergic pathways in liver metabolic organization after acute stress events. Our results demonstrate, both at transcriptional and circulating levels of several hormones, the existence of a complex activation of different endocrine pathways in S. aurata related to the stress pathways, where vasotocinergic and isotocinergic systems can also be considered key players of the acute stress response orchestration. PMID- 29487540 TI - Neurally Released GABA Acts via GABAC Receptors to Modulate Ca2+ Transients Evoked by Trains of Synaptic Inputs, but Not Responses Evoked by Single Stimuli, in Myenteric Neurons of Mouse Ileum. AB - gamma-Aminobutyric Acid (GABA) and its receptors, GABAA,B,C, are expressed in several locations along the gastrointestinal tract. Nevertheless, a role for GABA in enteric synaptic transmission remains elusive. In this study, we characterized the expression and function of GABA in the myenteric plexus of the mouse ileum. About 8% of all myenteric neurons were found to be GABA-immunoreactive (GABA+) including some Calretinin+ and some neuronal nitric oxide synthase (nNOS+) neurons. We used Wnt1-Cre;R26R-GCaMP3 mice, which express a genetically encoded fluorescent calcium indicator in all enteric neurons and glia. Exogenous GABA increased the intracellular calcium concentration, [Ca2+]i of some myenteric neurons including many that did not express GABA or nNOS (the majority), some GABA+, Calretinin+ or Neurofilament-M (NFM)+ but rarely nNOS+ neurons. GABA+ terminals contacted a significantly larger proportion of the cell body surface area of Calretinin+ neurons than of nNOS+ neurons. Numbers of neurons with GABA induced [Ca2+]i transients were reduced by GABAA,B,C and nicotinic receptor blockade. Electrical stimulation of interganglionic fiber tracts was used to examine possible effects of endogenous GABA release. [Ca2+]i transients evoked by single pulses were unaffected by specific antagonists for each of the 3 GABA receptor subtypes. [Ca2+]i transients evoked by 20 pulse trains were significantly amplified by GABAC receptor blockade. These data suggest that GABAA and GABAB receptors are not involved in synaptic transmission, but suggest a novel role for GABAC receptors in modulating slow synaptic transmission, as indicated by changes in [Ca2+]i transients, within the ENS. PMID- 29487541 TI - Adrenergic Blockade Bi-directionally and Asymmetrically Alters Functional Brain Heart Communication and Prolongs Electrical Activities of the Brain and Heart during Asphyxic Cardiac Arrest. AB - Sudden cardiac arrest is a leading cause of death in the United States. The neurophysiological mechanism underlying sudden death is not well understood. Previously we have shown that the brain is highly stimulated in dying animals and that asphyxia-induced death could be delayed by blocking the intact brain-heart neuronal connection. These studies suggest that the autonomic nervous system plays an important role in mediating sudden cardiac arrest. In this study, we tested the effectiveness of phentolamine and atenolol, individually or combined, in prolonging functionality of the vital organs in CO2-mediated asphyxic cardiac arrest model. Rats received either saline, phentolamine, atenolol, or phentolamine plus atenolol, 30 min before the onset of asphyxia. Electrocardiogram (ECG) and electroencephalogram (EEG) signals were simultaneously collected from each rat during the entire process and investigated for cardiac and brain functions using a battery of analytic tools. We found that adrenergic blockade significantly suppressed the initial decline of cardiac output, prolonged electrical activities of both brain and heart, asymmetrically altered functional connectivity within the brain, and altered, bi-directionally and asymmetrically, functional, and effective connectivity between the brain and heart. The protective effects of adrenergic blockers paralleled the suppression of brain and heart connectivity, especially in the right hemisphere associated with central regulation of sympathetic function. Collectively, our results demonstrate that blockade of brain-heart connection via alpha- and beta adrenergic blockers significantly prolonged the detectable activities of both the heart and the brain in asphyxic rat. The beneficial effects of combined alpha and beta blockers may help extend the survival of cardiac arrest patients. PMID- 29487542 TI - Cognition As a Therapeutic Target in the Suicidal Patient Approach. AB - The current considerations about completed suicides and suicide attempts in different cultures call the attention of professionals to this serious public health problem. Integrative approaches have shown that the confluence of multiple biological and social factors modulate various psychopathologies and dysfunctional behaviors, such as suicidal behavior. Considering the level of intermediate analysis, personality traits and cognitive functioning are also of great importance for understanding the suicide phenomenon. About cognitive factors, we can group them into cognitive schemas of reality interpretation and underlying cognitive processes. On the other hand, different types of primary cognitive alterations are related to suicidal behavior, especially those resulting from changes in frontostriatal circuits. Among such cognitive mechanisms can be highlighted the attentional bias for environmental cues related to suicide, impulsive behavior, verbal fluency deficits, non-adaptive decision making, and reduced planning skills. Attentional bias consists in the effect of thoughts and emotions, frequently not conscious, about the perception of environmental stimuli. Suicidal ideation and hopelessness can make the patient unable to find alternative solutions to their problems other than suicide, biasing their attention to environmental cues related to such behavior. Recent research efforts are directed to assess the possible use of attention bias as a therapeutic target in patients presenting suicide behavior. The relationship between impulsivity and suicide has been largely investigated over the last decades, and there is still controversy about the theme. Although there is strong evidence linking impulsivity to suicide attempts. Effective interventions address to reduce impulsivity in clinical populations at higher risk for suicide could help in the prevention. Deficits in problem-solving ability also seem to be distorted in patients who attempt suicide. Understanding cognitive changes in patients who attempt suicide open an important perspective in the approach of patients with mental disorders. Identifying cognitive deficits in these patients, along with personality traits, depressive symptoms, and suicidal cognitive schemas may indicate to the psychiatrist the need for emergency care. Behavioral and cognitive interventions have been associated with reductions in suicide ideation, as well as suicide attempts in different populations. PMID- 29487543 TI - Variation of Functional Neurological Symptoms and Emotion Regulation with Time. AB - Introduction: The present study addressed the variation of emotion regulation in the context of functional neurological symptom disorder (FNSD) by examining changes of functional neurological symptoms (FNS), general psychological strain, alexithymia, emotion regulation strategies, and cortical correlates of emotion regulation in the context of a standard inpatient treatment program. Methods and materials: Self-report data on FNS, general psychological strain, alexithymia, emotion regulation strategies, and cortical correlates of an experimentally induced emotion regulation task (participants either passively watched unpleasant and neutral pictures or regulated their emotional response to unpleasant pictures using pre-trained reappraisal, while an electroencephalogram was recorded) were compared between 19 patients with FNSD and 19 healthy comparison participants (HC) before and after a 4-week standard treatment protocol that included a combination of (individual and group) psychotherapies and functional treatments (such as physiotherapy) or a 4-week interval in HC, respectively. Results: General psychological strain did not decrease significantly in FNSD patients. Changes in emotion regulation in FNSD patients were constrained to an increase in self-reported use of cognitive reappraisal strategies. Subjective symptom intensity in FNSD patients varied with alexithymia pretreatment, but did not decrease significantly. Cortical activity in the time and frequency-domain distinguished passive watching of neutral and unpleasant pictures and regulating emotional responses upon unpleasant pictures from passively watching them without difference between groups and/or time. Discussion: Over the investigated time interval, augmented habitual cognitive emotion regulation suggests an alleviation of emotion processing deficits, but no significant symptom decrease. More controlled and prolonged treatment studies would be needed to determine whether and how a specific contribution of treatment-related changes of emotion regulation and FNS might be inferred. PMID- 29487545 TI - Processing Speed Mediates the Longitudinal Association between ADHD Symptoms and Preadolescent Peer Problems. AB - We investigated the relation between dimensional aspects of inattention and hyperactivity-impulsivity in childhood and peer problems 4 years later, as well as the potential mediating effects of intellectual function. The sample included 127 children (32 with attention-deficit/hyperactivity disorder). Symptoms of inattention and hyperactivity-impulsivity were assessed via parent and teacher reports on Swanson Nolan and Pelham-IV questionnaire. Peer problems were assessed by parent reports on the Strengths and Difficulties Questionnaire, and children's intellectual functioning by the third edition of the Wechsler Intelligence Scale for Children. Linear regressions showed a significant effect of inattention on future peer problems, partially mediated by slow processing speed. These effects remained significant when ADHD status was covaried. Findings highlight the importance of processing speed in explaining the predictive relation between childhood inattention and later peer problems. Inattention and processing speed in early childhood are potentially malleable factors influencing adolescent social functioning. PMID- 29487544 TI - Are Drinking Motives Universal? Characteristics of Motive Types in Alcohol Dependent Men from Two Diverse Populations. AB - Background and Aims: Since alcohol use disorders are among the most prevalent and destructive mental disorders, it is critical to address factors contributing to their development and maintenance. Drinking motives are relevant driving factors for consumption. Identifying groups of drinkers with similar motivations may help to specialize intervention components and make treatment more effective and efficient. We aimed to identify and describe distinct motive types of drinkers in dependent males from two diverse cultures (Uganda and Germany) and to explore potential differences and similarities in addiction-related measures. Moreover, we investigated specific links between motive types and childhood maltreatment, traumatic experiences, and symptoms of comorbid psychopathologies. Methods: To determine distinct drinking motive types, we conducted latent class analyses concerning drinking motives (Drinking Motive Scale) in samples of treatment seeking alcohol-dependent men (N = 75). Subsequently we compared the identified motive types concerning their alcohol consumption and alcohol-related symptoms (Alcohol Use Disorders Identification Test), history of childhood maltreatment (Childhood Trauma Questionnaire), trauma exposure (Violence, War and Abduction Exposure Scale), psychopathology (Posttraumatic Stress Diagnostic Scale, Depression-section of the Hopkins Symptom Checklist, and Brief Symptom Inventory) and deficits in emotion regulation (Difficulties in Emotion Regulation Scale). Results: We found two congruent drinking motive types in both contexts. Reward oriented drinking motives like the generation of positive feelings and enhancing performance were endorsed almost equally by both motive types, whereas high relief motive endorsement characterized one group, but not the other. The relief motive type drank to overcome aversive feelings, withdrawal, and daily hassles and was characterized by higher adversity in general. Emotional maltreatment in childhood and psychopathological symptoms were reported to a significantly greater extent by relief drinkers (effect sizes of comparisons ranging from r = 0.25 to r = 0.48). However, the motive types did not differ significantly on alcohol consumption or alcohol-related symptoms and traumatic experiences apart from childhood maltreatment. Conclusion: The chronology of addiction development and patterns of drinking motivation seem to be similar across cultures, i.e., that motive targeting interventions might be applicable cross-culturally. Addressing comorbid symptomatology should be a key treatment component for relief drinkers, whereas finding alternatives for the creation of positive feelings and ways to counteract boredom and inactivity should be a general treatment element. PMID- 29487546 TI - The Progressive Approach to EMDR Group Therapy for Complex Trauma and Dissociation: A Case-Control Study. AB - Eye Movement Desensitization and Reprocessing is a psychotherapeutic approach with recognized efficiency in treating post-traumatic stress disorder (PTSD), which is being used and studied in other psychiatric diagnoses partially based on adverse and traumatic life experiences. Nevertheless, there is not enough empirical evidence at the moment to support its usefulness in a diagnosis other than PTSD. It is commonly accepted that the use of EMDR in severely traumatized patients requires an extended stabilization phase. Some authors have proposed integrating both the theory of structural dissociation of the personality and the adaptive information processing model guiding EMDR therapy. One of these proposals is the Progressive Approach. Some of these EMDR procedures will be evaluated in a group therapy format, integrating them along with emotional regulation, dissociation, and trauma-oriented psychoeducational interventions. Patients presenting a history of severe traumatization, mostly early severe and interpersonal trauma, combined with additional significant traumatizing events in adulthood were included. In order to discriminate the specific effect of EMDR procedures, two types of groups were compared: TAU (treatment as usual: psychoeducational intervention only) vs. TAU+EMDR (the same psychoeducational intervention plus EMDR specific procedures). In pre-post comparison, more variables presented positive changes in the group including EMDR procedures. In the TAU+EMDR group, 4 of the 5 measured variables presented significant and positive changes: general health (GHQ), general satisfaction (Schwartz), subjective well-being, and therapy session usefulness assessment. On the contrary, only 2 of the 5 variables in the TAU group showed statistically significant changes: general health (GHQ), and general satisfaction (Schwartz). Regarding post-test inter-group comparison, improvement in subjective well-being was related to belonging to the group that included EMDR procedures, with differences between TAU and TAU+EMDR groups being statistically significant [chi2(1) = 14.226; p < 0.0001]. In the TAU+EMDR group there was not one patient who got worse or did not improve; 100% experienced some improvement. In the TAU group, 70.6% referred some improvement, and 29.4% said to have gotten worse or not improved. PMID- 29487547 TI - Designing a Summer Transition Program for Incoming and Current College Students on the Autism Spectrum: A Participatory Approach. AB - Students with Autism Spectrum Disorder (ASD) face unique challenges transitioning from high school to college and receive insufficient support to help them navigate this transition. Through a participatory collaboration with incoming and current autistic college students, we developed, implemented, and evaluated two intensive week-long summer programs to help autistic students transition into and succeed in college. This process included: (1) developing an initial summer transition program curriculum guided by recommendations from autistic college students in our ongoing mentorship program, (2) conducting an initial feasibility assessment of the curriculum [Summer Transition Program 1 (STP1)], (3) revising our initial curriculum, guided by feedback from autistic students, to develop a curriculum manual, and (4) pilot-testing the manualized curriculum through a quasi-experimental pre-test/post-test assessment of a second summer program [Summer Transition Program 2 (STP2)]. In STP2, two autistic college students assumed a leadership role and acted as "mentors" and ten incoming and current autistic college students participated in the program as "mentees." Results from the STP2 pilot-test suggested benefits of participatory transition programming for fostering self-advocacy and social skills among mentees. Autistic and non autistic mentors (but not mentees) described practicing advanced forms of self advocacy, specifically leadership, through their mentorship roles. Autistic and non-autistic mentors also described shared (e.g., empathy) and unique (an intuitive understanding of autism vs. an intuitive understanding of social interaction) skills that they contributed to the program. This research provides preliminary support for the feasibility and utility of a participatory approach in which autistic college students are integral to the development and implementation of programming to help less experienced autistic students develop the self-advocacy skills they will need to succeed in college. PMID- 29487549 TI - Relations of Dispositions toward Ridicule and Histrionic Self-Presentation with Quantitative and Qualitative Humor Creation Abilities. AB - Previous research has shown that humor and self-presentation are linked in several ways. With regard to individual differences, it turned out that gelotophilia (the joy of being laughed at) and katagelasticism (the joy of laughing at others) are substantially associated with the histrionic self presentation style that is characterized by performing explicit As-If-behaviors (e.g., irony, parodying others) in everyday interactions. By contrast, gelotophobia (the fear of being laughed at) shows a negative correlation with histrionic self-presentation. In order to further contribute to the nomological network, we have explored whether the three dispositions toward ridicule and laughter as well as histrionic self-presentation are related to humor creation abilities. In doing so, we have assessed the four constructs in a study with 337 participants that also completed the Cartoon Punch line Production Test (CPPT, Kohler and Ruch, 1993, unpublished). In the CPPT, subjects were asked to generate as many funny punch lines as possible for six caption-removed cartoons. The created punch lines were then analyzed with regard to quantitative (e.g., number of punch lines) and qualitative (e.g., wittiness of the punch lines and overall wittiness of the person as evaluated by three independent raters) humor creation abilities. Results show that both gelotophilia and histrionic self-presentation were positively correlated with quantitative and qualitative humor creation abilities. By contrast, gelotophobia showed slightly negative and katagelasticism no associations with the assessed humor creation abilities. These findings especially apply to the subgroup of participants that created punch lines for each of the six cartoons and partly replicate and extend the results of a previous study by Ruch et al. (2009). Altogether, the results of our study show that individual differences in humor-related traits are associated with the quantity and quality of humorous punch lines. It is argued that behavior-related or performative humor creation tasks should be considered in addition to the CPPT in order to open up new avenues that can cross-fertilize research on individual differences in humor and self-presentation. PMID- 29487548 TI - Comparison of Eye Movement Desensitization Reprocessing and Cognitive Behavioral Therapy as Adjunctive Treatments for Recurrent Depression: The European Depression EMDR Network (EDEN) Randomized Controlled Trial. AB - : Background: Treatment of recurrent depressive disorders is currently only moderately successful. Increasing evidence suggests a significant relationship between adverse childhood experiences and recurrent depressive disorders, suggesting that trauma-based interventions could be useful for these patients. Objectives: To investigate the efficacy of Eye Movement Desensitization and Reprocessing therapy (EMDR) in addition to antidepressant medication (ADM) in treating recurrent depression. Design: A non-inferiority, single-blind, randomized clinical controlled trial comparing EMDR or CBT as adjunctive treatments to ADM. Randomization was carried out by a central computer system. Allocation was carried out by a study coordinator in each center. Setting: Two psychiatric services, one in Italy and one in Spain. Participants: Eighty-two patients were randomized with a 1:1 ratio to the EMDR group (n = 40) or CBT group (n = 42). Sixty-six patients, 31 in the EMDR group and 35 in the CBT group, were included in the completers analysis. Intervention: 15 +/- 3 individual sessions of EMDR or CBT, both in addition to ADM. Participants were followed up at 6 months. Main outcome measure: Rate of depressive symptoms remission in both groups, as measured by a BDI-II score <13. Results: Sixty-six patients were analyzed as completers (31 EMDR vs. 35 CBT). No significant difference between the two groups was found either at the end of the interventions (71% EMDR vs. 48.7% CBT) or at the 6-month follow-up (54.8% EMDR vs. 42.9% CBT). A RM-ANOVA on BDI-II scores showed similar reductions over time in both groups [F(6,59) = 22.501, p < 0.001] and a significant interaction effect between time and group [F(6,59) = 3.357, p = 0.006], with lower BDI-II scores in the EMDR group at T1 [mean difference = -7.309 (95% CI [-12.811, -1.806]), p = 0.010]. The RM-ANOVA on secondary outcome measures showed similar improvement over time in both groups [F(14,51) = 8.202, p < 0.001], with no significant differences between groups [F(614,51) = 0.642, p = 0.817]. Conclusion: Although these results can be considered preliminary only, this study suggests that EMDR could be a viable and effective treatment for reducing depressive symptoms and improving the quality of life of patients with recurrent depression. TRIAL REGISTRATION: ISRCTN09958202. PMID- 29487550 TI - Majority Group Members' Negative Reactions to Future Demographic Shifts Depend on the Perceived Legitimacy of Their Status: Findings from the United States and Portugal. AB - Using concepts from social identity theory (Tajfel and Turner, 1979), we examined whether racial/ethnic majority group members' reactions to future demographic shifts is a function of the degree to which they perceive their ingroup's higher status in society to be legitimate. In two studies, participants who varied in the degree to which they perceived their group's status to be legitimate were either exposed to real projections for 2060 (i.e., large decline in proportion of population that is the "majority" group), or fake projections for 2060-that resembled current figures (i.e., small decline). In Study 1, White Americans who perceived their status to be highly legitimate expressed greater intergroup threat, and negative feelings (anger and fear) toward minorities after exposure to projections with a large decline in the relative size of the White American population. In contrast, demographic shift condition had no effect on intergroup threat and negative feelings toward minorities among White Americans who perceived their status to be relatively illegitimate; negative feelings and threat remained low across both conditions. Similarly, in Study 2, ethnic Portuguese people in Portugal exposed to projections in which there was a large decline in the relative size of the ethnic Portuguese population experienced more intergroup threat and expressed a greater desire to engage in anti-immigration behaviors. The effect of demographic shift condition on intergroup threat and anti-immigration behaviors was stronger among ethnic Portuguese who perceived their status to be legitimate compared to ethnic Portuguese people who perceived their status to be relatively illegitimate. These results highlight that across different cultural contexts, majority group members' beliefs about the legitimacy of intergroup relations can affect their reactions to the prospect of increased diversity. PMID- 29487551 TI - The Self-esteem Stability Scale (SESS) for Cross-Sectional Direct Assessment of Self-esteem Stability. AB - Self-esteem stability describes fluctuations in the level of self-esteem experienced by individuals over a brief period of time. In recent decades, self esteem stability has repeatedly been shown to be an important variable affecting psychological functioning. However, measures of self-esteem stability are few and lacking in validity. In this paper, we present the Self-Esteem Stability Scale (SESS), a unidimensional and very brief scale to directly assess self-esteem stability. In four studies (total N = 826), we describe the development of the SESS and present evidence for its validity with respect to individual outcomes (life satisfaction, neuroticism, and vulnerable narcissism) and dyadic outcomes (relationship satisfaction in self- and partner ratings) through direct comparisons with existing measures. The new SESS proved to be a stronger predictor than the existing scales and had incremental validity over and above self-esteem level. The results also showed that all cross-sectional measures of self-esteem stability were only moderately associated with variability in self esteem levels assessed longitudinally with multiple administrations of the Rosenberg Self-Esteem Scale. We discuss this validity issue, arguing that direct and indirect assessment approaches measure relevant, yet different aspects of self-esteem stability. PMID- 29487552 TI - The Wellbeing of Italian Peacekeeper Military: Psychological Resources, Quality of Life and Internalizing Symptoms. AB - Working as a peacekeeper is associated with the exposure to acute and/or catastrophic events and chronic stressors. Hence, the meager literature about peacekeepers' wellbeing has mainly analyzed Post-Traumatic Stress Disorder (PTSD). This study aims to deep the analysis of the wellbeing of peacekeepers military. Based on the few studies on this population, we hypothesized that Italian peacekeeper military officers and enlisted men (n = 167; 103 males, 6 females, 58 missing) exhibit lower levels of internalizing symptoms (i.e., PTSD, depression, general anxiety, obsessions, and somatization) as compared to a control group (n = 60; 32 males, 28 females). Moreover, we hypothesized that peacekeepers have higher levels of psychological resources (i.e., self-efficacy, self-esteem, social support) and quality of life (i.e., higher life satisfaction and lower general stress). We compared the groups by means of MANOVAs on the subscales of the Psychological Treatment Inventory (PTI; Gori et al., 2015). We found that Italian peacekeepers have lower internalizing symptoms and higher levels of self-efficacy and self-esteem than the control group; however, no statistically significant differences were observed on perceived social support. Finally, peacekeepers have a higher quality of life: scores reflect higher life satisfaction and lower distress than the control group. This study is in line with previous literature supporting the claim that Italian peacekeeper military officers have sufficient psychological resources for coping with the stressful situations implied in peacekeeping missions. Future studies should deepen the analysis of the military's psychological characteristics by comparing war veterans and peacekeeper military. PMID- 29487553 TI - Multiple Realities and Hybrid Objects: A Creative Approach of Schizophrenic Delusion. AB - Delusion is usually considered in DSM 5 as a false belief based on incorrect inference about external reality, but the issue of delusion raises crucial concerns, especially that of a possible (or absent) continuity between delusional and normal experiences, and the understanding of delusional experience. In the present study, we first aim to consider delusion from a perspectivist angle, according to the Multiple Reality Theory (MRT). In this model inherited from Alfred Schutz and recently addressed by Gallagher, we are not confronting one reality only, but several (such as the reality of everyday life, of imaginary life, of work, of delusion, etc.). In other terms, the MRT states that our own experience is not drawing its meaning from one reality identified as the outer reality but rather from a multiplicity of realities, each with their own logic and style. Two clinical cases illustrate how the Multiple Realities Theory (MRT) may help address the reality of delusion. Everyday reality and the reality of delusion may be articulated under a few conditions, such as compossibility [i.e., Double Book-Keeping (DBK), in Bleulerian terms] or flexibility. There are indeed possible bridges between them. Possible links with neuroscience or psychoanalysis are evoked. As the subject is confronting different realities, so do the objects among and toward which a subject is evolving. We call such objects Hybrid Objects (HO) due to their multiple belonging. They can operate as shifters, i.e., as some functional operators letting one switch from one reality to another. In the final section, we will emphasize how delusion flexibility, as a dynamic interaction between Multiple Realities, may offer psychotherapeutic possibilities within some reality shared with others, entailing relocation of the present subjects in regained access to some flexibility via Multiple Realities and perspectivism. PMID- 29487554 TI - Looking at My Own Face: Visual Processing Strategies in Self-Other Face Recognition. AB - We live in an age of 'selfies.' Yet, how we look at our own faces has seldom been systematically investigated. In this study we test if the visual processing of the highly familiar self-face is different from other faces, using psychophysics and eye-tracking. This paradigm also enabled us to test the association between the psychophysical properties of self-face representation and visual processing strategies involved in self-face recognition. Thirty-three adults performed a self-face recognition task from a series of self-other face morphs with simultaneous eye-tracking. Participants were found to look longer at the lower part of the face for self-face compared to other-face. Participants with a more distinct self-face representation, as indexed by a steeper slope of the psychometric response curve for self-face recognition, were found to look longer at upper part of the faces identified as 'self' vs. those identified as 'other'. This result indicates that self-face representation can influence where we look when we process our own vs. others' faces. We also investigated the association of autism-related traits with self-face processing metrics since autism has previously been associated with atypical self-processing. The study did not find any self-face specific association with autistic traits, suggesting that autism related features may be related to self-processing in a domain specific manner. PMID- 29487555 TI - The Interplay between Gaze Following, Emotion Recognition, and Empathy across Adolescence; a Pubertal Dip in Performance? AB - During puberty a dip in face recognition is often observed, possibly caused by heightened levels of gonadal hormones which in turn affects the re-organization of relevant cortical circuitry. In the current study we investigated whether a pubertal dip could be observed in three other abilities related to social information processing: gaze following, emotion recognition from the eyes, and empathizing abilities. Across these abilities we further explored whether these measurements revealed sex differences as another way to understand how gonadal hormones affect processing of social information. Results show that across adolescence, there are improvements in emotion recognition from the eyes and in empathizing abilities. These improvements did not show a dip, but are more plateau-like. The gaze cueing effect did not change over adolescence. We only observed sex differences in empathizing abilities, with girls showing higher scores than boys. Based on these results it appears that gonadal hormones are not exerting a unified influence on higher levels of social information processing. Further research should also explore changes in (visual) information processing around puberty onset to find a more fitted explanation for changes in social behavior across adolescence. PMID- 29487556 TI - Long-Term Pain Treatment Did Not Improve Sleep in Nursing Home Patients with Comorbid Dementia and Depression: A 13-Week Randomized Placebo-Controlled Trial. AB - Objective: Previous research indicates that pain treatment may improve sleep among nursing home patients. We aimed to investigate the long-term effect of pain treatment on 24-h sleep patterns in patients with comorbid depression and dementia. Design: A 13-week, multicenter, parallel-group, double-blind, placebo controlled randomized clinical trial conducted between August 2014 and September 2016. Setting: Long-term patients from 47 nursing homes in Norway. Participants: We included 106 patients with comorbid dementia and depression according to the Mini Mental Status Examination (MMSE) and the Cornell Scale for Depression in Dementia (CSDD).Intervention: Patients who were not using analgesics were randomized to receive either paracetamol (3 g/day) or placebo tablets. Those who already received pain treatment were randomized to buprenorphine transdermal system (maximum 10 MUg/h/7 days) or placebo transdermal patches. Measurements: Sleep was assessed continuously for 7 days by actigraphy, at baseline and in week 13. Total sleep time (TST), sleep efficiency (SE), sleep onset latency (SOL), wake after sleep onset (WASO), early morning awakening (EMA), and number of wake bouts (NoW) were evaluated. In addition, daytime total sleep time (DTS) was estimated. Pain was assessed with Mobilization-Observation-Behavior-Intensity Dementia-2 Pain Scale (MOBID-2). Results: The linear mixed model analyses for TST, SE, SOL, WASO, EMA, NoW and DTS showed no statistically significant differences between patients who received active pain treatment and those who received placebo. Post hoc subgroup analyses showed that there were no statistically significant differences between active treatment and placebo from baseline to week 13 in patients who were in pain (MOBID-2 >= 3) at baseline, or in patients who had poor sleep (defined as SE < 85%) at baseline. Patients who received active buprenorphine showed an increase in TST and SE compared to those who received active paracetamol. Conclusion: The main analyses showed that long term pain treatment did not improve sleep as measured with actigraphy. Compared to paracetamol, TST and SE increased among patients who received buprenorphine. This could indicate that some patients had beneficial effects from the most potent pain treatment. However, based on the present findings, long-term pain treatment is not recommended as a strategy to improve sleep. Clinical Trial https://clinicaltrials.gov/ct2/show/NCT02267057. PMID- 29487557 TI - Women's Job Search Competence: A Question of Motivation, Behavior, or Gender. AB - We examined motivation and behaviors in women's active job search in Spain and the gender gap in this process. The current crisis in Spain and the increase in the number of unemployed people have revealed new inequalities that particularly affect women's employability, especially the most vulnerable women. This paper addresses two exploratory studies: the first study analyzes gender differences in the active job search using a sample of 236 Spanish participants; the second study explores the heterogeneity and diversity of unemployed women in a sample of 235 Spanish women. To analyze the active job search, the respondents were invited to write open-ended responses to questions about their job search behaviors and complete some questionnaires about their motivation for their active job search. The content analysis and quantitative results showed no significant differences in motivational attributes, but there were significant gender differences in the job search behavior (e.g., geographical mobility). Moreover, the results showed heterogeneity in unemployed women by educational level and family responsibilities. The asynchronies observed in a neoliberal context reveal the reproduction of social roles, social-labor vulnerability, and a gender gap. Thus, women's behavior is an interface between employment and family work, but not their motivations or aspirations. Our results can have positive implications for labor gender equality by identifying indicators of effectiveness in training programs for women's job search, and it can contribute to designing intervention empowerment policies for women. PMID- 29487558 TI - The Bamberg Trucking Game: A Paradigm for Assessing the Detection of Win-Win Solutions in a Potential Conflict Scenario. AB - In win-win solutions, all parties benefit more from the solution than they would if they each pursued their own individual goals. Such solutions are beneficial at individual and collective levels and thus represent optimal solutions. Win-win solutions are desirable but often difficult to find. To allow the study of individual differences and situational factors that help or hinder the detection of win-win solutions, we created a paradigm that fills a gap in the repertoire of psychological instruments used to assess collaboration, cooperation, negotiation, and prosocial behavior. The new paradigm differs from previous ones in two aspects: (a) In existing paradigms that focus on social motivation, possible strategies are evident, whereas we focused here on the question of whether people can detect the solution and thus disentangle ability from motivation, (b) Paradigms that focus on cooperation typically entail a risk associated with the partner's defection, whereas cooperation in our paradigm is not associated with risk. We adjusted the Trucking Game-a method for assessing bargaining-to include a situation in which two parties can help each other achieve their respective goals and thus benefit over and above the pursuit of individual goals or compromising. We tested scenario-based and interaction-based versions with samples of 154 and 112 participants, respectively. Almost one third of the participants or dyads found the win-win solution. General mental abilities were not related to detecting the win-win solution in either version. The paradigm provides a way to extend research on cooperation and conflict and can thus be useful for research and training. PMID- 29487559 TI - Five-Year-Olds' and Adults' Use of Paralinguistic Cues to Overcome Referential Uncertainty. AB - An eye-tracking methodology was used to explore adults' and children's use of two utterance-based cues to overcome referential uncertainty in real time. Participants were first introduced to two characters with distinct color preferences. These characters then produced fluent ("Look! Look at the blicket.") or disfluent ("Look! Look at thee, uh, blicket.") instructions referring to novel objects in a display containing both talker-preferred and talker-dispreferred colored items. Adults (Expt 1, n = 24) directed a greater proportion of looks to talker-preferred objects during the initial portion of the utterance ("Look! Look at..."), reflecting the use of indexical cues for talker identity. However, they immediately reduced consideration of an object bearing the talker's preferred color when the talker was disfluent, suggesting they infer disfluency would be more likely as a talker describes dispreferred objects. Like adults, 5-year-olds (Expt 2, n = 27) directed more attention to talker-preferred objects during the initial portion of the utterance. Children's initial predictions, however, were not modulated when disfluency was encountered. Together, these results demonstrate that adults, but not 5-year-olds, can act on information from two talker-produced cues within an utterance, talker preference, and speech disfluencies, to establish reference. PMID- 29487560 TI - The Differential Effects of Repetitive Magnetic Stimulation in an In Vitro Neuronal Model of Ischemia/Reperfusion Injury. AB - Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive therapy that has been implicated in treatment of serious neurological disorders. However, the neurobiological mechanisms underlying the effects of rTMS remain unclear. Therefore, this study examined the differential effects of repetitive magnetic stimulation (rMS) in an in vitro neuronal model of ischemia/reperfusion (I/R) injury, depending on low and high frequency. Neuro-2a cells were differentiated with retinoic acid and established for in vitro neuronal model of I/R injury under a subsequent 3 h of oxygen and glucose deprivation/reoxygenation (OGD/R) condition. After the I/R injury, the differentiated neuronal cells were stimulated with rMS on day 1 and randomly divided into three groups: OGD/R+sham, OGD/R+low-frequency, and OGD/R+high-frequency groups. High-frequency rMS increases cell proliferation through activation of extracellular signal-regulated kinases and AKT-signaling pathway and inhibits apoptosis in OGD/R-injured cells. Furthermore, high-frequency rMS increases Ca2+-calmodulin-dependent protein kinase II (CaMKII)-cAMP-response element binding protein (CREB) signaling pathway, further leading to alternation of brain-derived neurotrophic factor expression and synaptic plasticity in OGD/R injured cells. These results verified the neurobiological mechanisms of frequency-dependent rMS in I/R injury-treated neuronal cells. These mechanisms will help develop more powerful and credible rTMS stimulation treatment protocols. PMID- 29487561 TI - A Case-Control Study Investigating Simulated Driving Errors in Ischemic Stroke and Subarachnoid Hemorrhage. AB - Background: Stroke can affect a variety of cognitive, perceptual, and motor abilities that are important for safe driving. Results of studies assessing post stroke driving ability are quite variable in the areas and degree of driving impairment among patients. This highlights the need to consider clinical characteristics, including stroke subtype, when assessing driving performance. Methods: We compared the simulated driving performance of 30 chronic stroke patients (>3 months), including 15 patients with ischemic stroke (IS) and 15 patients with subarachnoid hemorrhage (SAH), and 20 age-matched controls. A preliminary analysis was performed, subdividing IS patients into right (n = 8) and left (n = 6) hemispheric lesions and SAH patients into middle cerebral artery (MCA, n = 5) and anterior communicating artery (n = 6) territory. A secondary analysis was conducted to investigate the cognitive correlates of driving. Results: Nine patients (30%) exhibited impaired simulated driving performance, including four patients with IS (26.7%) and five patients with SAH (33.3%). Both patients with IS (2.3 vs. 0.3, U = 76, p < 0.05) and SAH (1.5 vs. 0.3, U = 45, p < 0.001) exhibited difficulty with lane maintenance (% distance out of lane) compared to controls. In addition, patients with IS exhibited difficulty with speed maintenance (% distance over speed limit; 8.9 vs. 4.1, U = 81, p < 0.05), whereas SAH patients exhibited difficulty with turning performance (total turning errors; 5.4 vs. 1.6, U = 39.5, p < 0.001). The Trail Making Test (TMT) and Useful Field of View test were significantly associated with lane maintenance among patients with IS (rs > 0.6, p < 0.05). No cognitive tests showed utility among patients with SAH. Conclusion: Both IS and SAH exhibited difficulty with lane maintenance. Patients with IS additionally exhibited difficulty with speed maintenance, whereas SAH patients exhibited difficulty with turning performance. Current results support the importance of differentiating between stroke subtypes and considering other important clinical characteristics (e.g., side of lesion, vascular territory) when assessing driving performance and reinforce the importance of physicians discussing driving safety with patients after stroke. PMID- 29487562 TI - Aripiprazole Selectively Reduces Motor Tics in a Young Animal Model for Tourette's Syndrome and Comorbid Attention Deficit and Hyperactivity Disorder. AB - Tourette's syndrome (TS) is a neurodevelopmental disorder characterized primarily by motor and vocal tics. Comorbidities such as attention deficit and hyperactivity disorder (ADHD) are observed in over 50% of TS patients. We applied aripiprazole in a juvenile rat model that displays motor tics and hyperactivity. We additionally assessed the amount of ultrasonic vocalizations (USVs) as an indicator for the presence of vocal tics and evaluated the changes in the striatal neurometabolism using in vivo proton magnetic resonance spectroscopy (1H MRS) at 11.7T. Thirty-one juvenile spontaneously hypertensive rats (SHRs) underwent bicuculline striatal microinjection and treatment with either aripiprazole or vehicle. Control groups were sham operated and sham injected. Behavior, USVs, and striatal neurochemical profile were analyzed at early, middle, and late adolescence (postnatal days 35 to 50). Bicuculline microinjections in the dorsolateral striatum induced motor tics in SHR juvenile rats. Acute aripiprazole administration selectively reduced both tic frequency and latency, whereas stereotypies, USVs, and hyperactivity remained unaltered. The striatal neurochemical profile was only moderately altered after tic induction and was not affected by systemic drug treatment. When applied to a young rat model that provides high degrees of construct, face, and predictive validity for TS and comorbid ADHD, aripiprazole selectively reduces motor tics, revealing that tics and stereotypies are distinct phenomena in line with clinical treatment of patients. Finally, our 1H-MRS results suggest a critical revision of the striatal role in the hypothesized cortico-striatal dysregulation in TS pathophysiology. PMID- 29487563 TI - Responsivity of Periaqueductal Gray Connectivity Is Related to Headache Frequency in Episodic Migraine. AB - Migraineurs show hypersensitivity to sensory stimuli at various stages throughout the migraine cycle. A number of putative processes have been implicated including a dysfunction in the descending pain modulatory system in which the periaqueductal gray (PAG) is considered to play a crucial role. Recurring migraine attacks could progressively perturb this system, lowering the threshold for future attacks, and contribute to disease chronification. Here, we investigated PAG connectivity with other brain regions during a noxious thermal stimulus to determine changes in migraineurs, and associations with migraine frequency. 21 episodic migraine patients and 22 matched controls were included in the study. During functional MRI, a thermode was placed on the subjects' temple delivering noxious and non-noxious heat stimuli. A psychophysiological interaction (PPI) analysis was carried out to examine pain-induced connectivity of the PAG with other brain regions. The PPI analysis showed increased PAG connectivity with the S1 face representation area and the supplementary motor area, an area involved with pain expectancy, in patients with higher frequency of migraine attacks. PAG connectivity with regions involved with the descending pain modulatory system (i.e., prefrontal cortex) was decreased in the migraineurs versus healthy individuals. Our results suggest that high frequency migraineurs may have diminished resistance to cephalic pain and a less efficient inhibitory pain modulatory response to external stressor (i.e., noxious heat). The findings support the notion that in migraine there is less effective pain modulation (viz., decreased pain inhibition or increased pain facilitation), potentially contributing to increased occurrence of attacks/chronification of migraine. PMID- 29487564 TI - The Effect of a Simulated Commercial Flight Environment with Hypoxia and Low Humidity on Clotting, Platelet, and Endothelial Function in Participants with Type 2 Diabetes - A Cross-over Study. AB - Aims: To determine if clotting, platelet, and endothelial function were affected by simulated short-haul commercial air flight conditions (SF) in participants with type 2 diabetes (T2DM) compared to controls. Methods: 10 participants with T2DM (7 females, 3 males) and 10 controls (3 females, 7 males) completed the study. Participants were randomized to either spend 2 h in an environmental chamber at sea level conditions (temperature: 23 degrees C, oxygen concentration 21%, humidity 45%), or subject to a simulated 2-h simulated flight (SF: temperature: 23 degrees C, oxygen concentration 15%, humidity 15%), and crossed over 7 days later. Main outcome measures: clot formation and clot lysis parameters, functional platelet activation markers, and endothelial function measured by reactive hyperemia index (RHI) by EndoPAT and serum microparticles. Results: Comparing baseline with SF conditions, clot maximal absorption was increased in controls (0.375 +/- 0.05 vs. 0.39 +/- 0.05, p < 0.05) and participants with T2DM (0.378 +/- 0.089 vs. 0.397 +/- 0.089, p < 0.01), while increased basal platelet activation for both fibrinogen binding and P-selectin expression (p < 0.05) was seen in participants with T2DM. Parameters of clot formation and clot lysis, stimulated platelet function (stimulated platelet response to ADP and sensitivity to prostacyclin), and endothelial function were unchanged. Conclusion: While SF resulted in the potential of denser clot formation with enhanced basal platelet activation in T2DM, the dynamic clotting, platelet, and endothelial markers were not affected, suggesting that short-haul commercial flying adds no additional hazard for venous thromboembolism for participants with T2DM compared to controls. PMID- 29487565 TI - Luteinizing Hormone and Testosterone Levels during Acute Phase of Severe Traumatic Brain Injury: Prognostic Implications for Adult Male Patients. AB - Traumatic brain injury (TBI) is a worldwide core public health problem affecting mostly young male subjects. An alarming increase in incidence has turned TBI into a leading cause of morbidity and mortality in young adults as well as a tremendous resource burden on the health and welfare sector. Hormone dysfunction is highly prevalent during the acute phase of severe TBI. In particular, investigation of the luteinizing hormone (LH) and testosterone levels during the acute phase of severe TBI in male has identified a high incidence of low testosterone levels in male patients (36.5-100%) but the prognostic significance of which remains controversial. Two independent studies showed that normal or elevated levels of LH levels earlier during hospitalization are significantly associated with higher mortality/morbidity. The association between LH levels and prognosis was independent of other predictive variables such as neuroimaging, admission Glasgow coma scale, and pupillary reaction. The possible mechanisms underlying this association and further research directions in this field are discussed. Overall, current data suggest that LH levels during the acute phase of TBI might contribute to accurate prognostication and further prospective multicentric studies are required to develop more sophisticated predictive models incorporating biomarkers such as LH in the quest for accurate outcome prediction following TBI. Moreover, the potential therapeutic benefits of modulating LH during the acute phase of TBI warrant investigation. PMID- 29487566 TI - Islet Cell Associated Autoantibodies and C-Peptide Levels in Patients with Diabetes and Symptoms of Gastroparesis. AB - Introduction: Individuals with diabetes are at increased risk for complications, including gastroparesis. Type 1 diabetes mellitus (T1DM) is an autoimmune disorder resulting in decreased beta-cell function. Glutamic acid decarboxylase 65 antibody (GADA) is the most commonly used test to assess autoimmunity while C peptide level is used to assess beta-cell function. Patients with type 2 diabetes mellitus (T2DM), who are GADA positive, are labeled latent autoimmune diabetes in adults (LADA). Objective: To characterize patients with T1 and T2DM who have symptoms of gastroparesis using GADA and C-peptide levels and to look for association with the presence of gastroparesis and its symptom severity. Design: 113 T1DM and 90 T2DM patients with symptoms suggestive of gastroparesis were studied. Symptom severity was assessed using Gastroparesis Cardinal Symptom Index (GCSI). Serum samples were analyzed for GADA and C-peptide. Results: Delayed gastric emptying was present in 91 (81%) of T1DM and 60 (67%) of T2DM patients (p = 0.04). GADA was present in 13% of T2DM subjects [10% in delayed gastric emptying and 20% in normal gastric emptying (p = 0.2)]. Gastric retention and GCSI scores were mostly similar in GADA positive and negative T2DM patients. GADA was present in 45% of T1DM subjects [46% in delayed gastric emptying and 41% in normal gastric emptying (p = 0.81)]. Low C-peptide levels were seen in 79% T1DM patients and 8% T2DM. All seven T2DM patients with low C-peptide were taking insulin compared to 52% of T2DM with normal C-peptide. Conclusion: GADA was present in 13% while low C-peptide was seen in 8% of our T2DM patients with symptoms of gastroparesis. Neither did correlate with degree of delayed gastric emptying or symptom severity. ClinicalTrialsgov Identifier: NCT01696747. PMID- 29487567 TI - Regulatory Architecture of the LbetaT2 Gonadotrope Cell Underlying the Response to Gonadotropin-Releasing Hormone. AB - The LbetaT2 mouse pituitary cell line has many characteristics of a mature gonadotrope and is a widely used model system for studying the developmental processes and the response to gonadotropin-releasing hormone (GnRH). The global epigenetic landscape, which contributes to cell-specific gene regulatory mechanisms, and the single-cell transcriptome response variation of LbetaT2 cells have not been previously investigated. Here, we integrate the transcriptome and genome-wide chromatin accessibility state of LbetaT2 cells during GnRH stimulation. In addition, we examine cell-to-cell variability in the transcriptional response to GnRH using Gel bead-in-Emulsion Drop-seq technology. Analysis of a bulk RNA-seq data set obtained 45 min after exposure to either GnRH or vehicle identified 112 transcripts that were regulated >4-fold by GnRH (FDR < 0.05). The top regulated transcripts constitute, as determined by Bayesian massive public data integration analysis, a human pituitary-relevant coordinated gene program. Chromatin accessibility [assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq)] data sets generated from GnRH-treated LbetaT2 cells identified more than 58,000 open chromatin regions, some containing notches consistent with bound transcription factor footprints. The study of the most prominent open regions showed that 75% were in transcriptionally active promoters or introns, supporting their involvement in active transcription. Lhb, Cga, and Egr1 showed significantly open chromatin over their promoters. While Fshb was closed over its promoter, several discrete significantly open regions were found at -40 to -90 kb, which may represent novel upstream enhancers. Chromatin accessibility determined by ATAC-seq was associated with high levels of gene expression determined by RNA-seq. We obtained high-quality single-cell Gel bead-in-Emulsion Drop-seq transcriptome data, with an average of >4,000 expressed genes/cell, from 1,992 vehicle- and 1,889 GnRH-treated cells. While the individual cell expression patterns showed high cell-to-cell variation, representing both biological and measurement variation, the average expression patterns correlated well with bulk RNA-seq data. Computational assignment of each cell to its precise cell cycle phase showed that the response to GnRH was unaffected by cell cycle. To our knowledge, this study represents the first genome-wide epigenetic and single-cell transcriptomic characterization of this important gonadotrope model. The data have been deposited publicly and should provide a resource for hypothesis generation and further study. PMID- 29487569 TI - Effects of Transport Duration and Environmental Conditions in Winter or Summer on the Concentrations of Insulin-Like Growth Factors and Insulin-Like Growth Factor Binding Proteins in the Plasma of Market-Weight Pigs. AB - In previous work using market-weight pigs, we had demonstrated that insulin-like growth factors (IGFs) and insulin-like growth factor binding proteins (IGFBPs) are regulated during shipment characterized by changing conditions of stress due to loading or unloading, transportation, lairage, and slaughter. In addition, we found in a previous study that IGFBP-2 concentrations were lower in pigs transported for longer periods of time. Therefore, we performed a more detailed study on the effects of transport duration and season on the plasma concentrations of IGFs and IGFBPs in adult pigs. For the study, exsanguination blood was collected from 240 market-weight barrows that were transported for 6, 12, or 18 h in January or July. IGF-I and -II were detected using commercial ELISAs whereas IGFBPs were quantified by quantitative Western ligand blotting. In addition, established markers of stress and metabolism were studied in the animals. The results show that plasma concentrations of IGFBP-3 were significantly reduced after 18 h of transport compared to shorter transport durations (6 and 12 h; p < 0.05). The concentrations of IGF-I in plasma were higher (p < 0.001) in pigs transported 12 h compared to shorter or longer durations. Season influenced plasma concentrations of IGFBP-3 and IGF-II (p < 0.05 and p < 0.01, respectively). Neither transport duration nor differential environmental conditions of winter or summer had an effect on glucocorticoids, albumin, triglycerides, or glucose concentrations (p > 0.05). However, low density lipoprotein concentrations decreased after 18 h compared to 6 h of transport (p < 0.05), whereas high-density lipoprotein concentrations were higher (p < 0.05) in pigs transported for 12 or 18 h compared to those transported for only 6 h. Our findings indicate differential regulation of IGF-compounds in response to longer transport duration or seasonal changes and support current evidence of IGFs and IGFBPs as innovative animal-based indicators of psycho social or metabolic stress in pigs. PMID- 29487571 TI - Molecular Survey of Viral and Bacterial Causes of Childhood Diarrhea in Khartoum State, Sudan. AB - Diarrheal disease is a major public health problem for children in developing countries. Knowledge of etiology that causes diarrheal illness is essential to implement public health measures to prevent and control this disease. Published studies regarding the situation of childhood diarrhea in Sudan is scanty. This study aims to investigate viral and bacterial etiology and related clinical and epidemiological factors in children with acute diarrhea in Khartoum State, Sudan. A total of 437 fecal samples were collected from hospitalized children <5 years old with acute diarrhea, viral and bacterial pathogens were investigated by using two-tube multiplex RT-PCR. The genotypes of adenovirus and bocavirus were determined by sequencing. Viral diarrhea was identified in 79 cases (62 single and 17 co-infections) (18%), and bacterial diarrhea in 49 cases (37 single and 12 co-infections) (11.2%). Mixed infections in both groups totaled 19 samples (4.3%) with more than one pathogen, they were viral co-infections (n = 7, 36.8%) bacterial co-infections (n = 2, 10.5%) and viral bacterial co-infection (n = 10, 52.6%). Rotavirus (10.2%) was predominantly detected, followed by norovirus G2 (4.0%), adenovirus (1.6%), bocavirus (1%), and norovirus G1 (0.9%). Infection with astrovirus was not detected in this study. The Shigella -Enteroinvasive E.coli (EIEC) (8.9%) was the predominantly found bacterial pathogen, followed by Vibrio parahaemolyticus (0.9%), enterohaemorrhagic E.coli (EHEC) Enteropathogenic E. coli (EPEC) (0.6%) and Salmonella enteritidis (0.6%). V. cholerae, Yersinia enterocolitica and Campylobacter jejuni were not detected in this study. The phylogenetic tree identified adenovirus belonged to genotype 41 and bocavirus belonged to two different clades within human bocavirus 1. Our findings represent the first report that adenovirus 41 is a cause of diarrhea in Sudan and that human bocavirus 1 is the principal bocavirus strain circulating in Sudan. In conclusion, this is the first comprehensive report to elaborate the pathogen spectrum associated with childhood diarrhea in Khartoum State, Sudan. The results obtained in the present study highlighted the current epidemic situation, the diverse pathogens related to childhood diarrhea, and the importance and the urgency of taking appropriate intervention measures in Khartoum State, Sudan. PMID- 29487570 TI - c-di-GMP Regulates Various Phenotypes and Insecticidal Activity of Gram-Positive Bacillus thuringiensis. AB - C-di-GMP has been well investigated to play significant roles in the physiology of many Gram-negative bacteria. However, its effect on Gram-positive bacteria is less known. In order to more understand the c-di-GMP functions in Gram-positive bacteria, we have carried out a detailed study on the c-di-GMP-metabolizing enzymes and their physiological functions in Bacillus thuringiensis, a Gram positive entomopathogenic bacterium that has been applied as an insecticide successfully. We performed a systematic study on the ten putative c-di-GMP synthesizing enzyme diguanylate cyclases (DGCs) and c-di-GMP-degrading enzyme phosphodiesterases (PDEs) in B. thuringiensis BMB171, and artificially elevated the intracellular c-di-GMP level in BMB171 by deleting one or more pde genes. We found increasing level of intracellular c-di-GMP exhibits similar activities as those in Gram-negative bacteria, including altered activities in cell motility, biofilm formation, and cell-cell aggregation. Unexpectedly, we additionally found a novel function exhibited by the increasing level of c-di-GMP to promote the insecticidal activity of this bacterium against Helicoverpa armigera. Through whole-genome transcriptome profile analyses, we found that 4.3% of the B. thuringiensis genes were differentially transcribed when c-di-GMP level was increased, and 77.3% of such gene products are involved in some regulatory pathways not reported in other bacteria to date. In summary, our study represents the first comprehensive report on the c-di-GMP-metabolizing enzymes, their effects on phenotypes, and the transcriptome mediated by c-di-GMP in an important Gram-positive bacterium. PMID- 29487572 TI - Western Indian Rural Gut Microbial Diversity in Extreme Prakriti Endo-Phenotypes Reveals Signature Microbes. AB - Heterogeneity amidst healthy individuals at genomic level is being widely acknowledged. This, in turn, is modulated by differential response to environmental cues and treatment regimens, necessitating the need for stratified/personalized therapy. We intend to understand the molecular determinants of Ayurvedic way (ancient Indian system of medicine) of endo phenotyping individuals into distinct constitution types termed "Prakriti," which forms the basis of personalized treatment. In this study, we explored and analyzed the healthy human gut microbiome structure within three predominant Prakriti groups from a genetically homogenous cohort to discover differentially abundant taxa, using 16S rRNA gene based microbial community profiling. We found Bacteroidetes and Firmicutes as major gut microbial components in varying composition, albeit with similar trend across Prakriti. Multiple species of the core microbiome showed differential abundance within Prakriti types, with gender specific signature taxons. Our study reveals that despite overall uniform composition of gut microbial community, healthy individuals belonging to different Prakriti groups have enrichment of specific bacteria. It highlights the importance of Prakriti based endo-phenotypes to explain the variability amongst healthy individuals in gut microbial flora that have important consequences for an individual's health, disease and treatment. PMID- 29487568 TI - The Growth Hormone Receptor: Mechanism of Receptor Activation, Cell Signaling, and Physiological Aspects. AB - The growth hormone receptor (GHR), although most well known for regulating growth, has many other important biological functions including regulating metabolism and controlling physiological processes related to the hepatobiliary, cardiovascular, renal, gastrointestinal, and reproductive systems. In addition, growth hormone signaling is an important regulator of aging and plays a significant role in cancer development. Growth hormone activates the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway, and recent studies have provided a new understanding of the mechanism of JAK2 activation by growth hormone binding to its receptor. JAK2 activation is required for growth hormone-mediated activation of STAT1, STAT3, and STAT5, and the negative regulation of JAK-STAT signaling comprises an important step in the control of this signaling pathway. The GHR also activates the Src family kinase signaling pathway independent of JAK2. This review covers the molecular mechanisms of GHR activation and signal transduction as well as the physiological consequences of growth hormone signaling. PMID- 29487573 TI - Secretome Analysis from the Ectomycorrhizal Ascomycete Cenococcum geophilum. AB - Cenococcum geophilum is an ectomycorrhizal fungus with global distribution in numerous habitats and associates with a large range of host species including gymnosperm and angiosperm trees. Moreover, C. geophilum is the unique ectomycorrhizal species within the clade Dothideomycetes, the largest class of Ascomycetes containing predominantly saprotrophic and many devastating phytopathogenic fungi. Recent studies highlight that mycorrhizal fungi, as pathogenic ones, use effectors in form of Small Secreted Proteins (SSPs) as molecular keys to promote symbiosis. In order to better understand the biotic interaction of C. geophilum with its host plants, the goal of this work was to characterize mycorrhiza-induced small-secreted proteins (MiSSPs) that potentially play a role in the ectomycorrhiza formation and functioning of this ecologically very important species. We combined different approaches such as gene expression profiling, genome localization and conservation of MiSSP genes in different C. geophilum strains and closely related species as well as protein subcellular localization studies of potential targets of MiSSPs in interacting plants using in tobacco leaf cells. Gene expression analyses of C. geophilum interacting with Pinus sylvestris (pine) and Populus tremula * Populus alba (poplar) showed that similar sets of genes coding for secreted proteins were up-regulated and only few were specific to each host. Whereas pine induced more carbohydrate active enzymes (CAZymes), the interaction with poplar induced the expression of specific SSPs. We identified a set of 22 MiSSPs, which are located in both, gene-rich, repeat poor or gene-sparse, repeat-rich regions of the C. geophilum genome, a genome showing a bipartite architecture as seen for some pathogens but not yet for an ectomycorrhizal fungus. Genome re-sequencing data of 15 C. geophilum strains and two close relatives Glonium stellatum and Lepidopterella palustris were used to study sequence conservation of MiSSP-encoding genes. The 22 MiSSPs showed a high presence-absence polymorphism among the studied C. geophilum strains suggesting an evolution through gene gain/gene loss. Finally, we showed that six CgMiSSPs target four distinct sub-cellular compartments such as endoplasmic reticulum, plasma membrane, cytosol and tonoplast. Overall, this work presents a comprehensive analysis of secreted proteins and MiSSPs in different genetic level of C. geophilum opening a valuable resource to future functional analysis. PMID- 29487574 TI - Versatile Antagonistic Activities of Soil-Borne Bacillus spp. and Pseudomonas spp. against Phytophthora infestans and Other Potato Pathogens. AB - The world potato is facing major economic losses due to disease pressure and environmental concerns regarding pesticides use. This work aims at addressing these two issues by isolating indigenous bacteria that can be integrated into pest management strategies. More than 2,800 strains of Bacillus-like and Pseudomonas-like were isolated from several soils and substrates associated with potato agro-systems in Belgium. Screenings for antagonistic activities against the potato pathogens Alternaria solani, Fusarium solani (BCCM-MUCL 5492), Pectobacterium carotovorum (ATCC 15713), Phytophthora infestans (CRA-W10022) and Rhizoctonia solani (BCCM-MUCL 51929) were performed, allowing the selection of 52 Bacillus spp. and eight Pseudomonas spp. displaying growth inhibition of at least 50% under in vitro conditions, particularly against P. infestans. All 60 bacterial isolates were identified based on 16S rRNA gene sequencing and further characterized for the production of potential bio-active secondary metabolites. The antagonistic activities displayed by the selected strains indicated that versatile metabolites can be produced by the strains. For instance, the detection of genes involved bacilysin biosynthesis was correlated with the strong antagonism of Bacillus pumilus strains toward P. infestans, whereas the production of both bio-surfactants and siderophores might explain the high antagonistic activities against late blight. Greenhouse assays with potato plants were performed with the most effective strains (seven Bacillus spp. and four Pseudomonas spp.) in order to evaluate their in vivo antagonistic effect against P. infestans. Based on these results, four strains (Bacillus amyloliquefaciens 17A-B3, Bacillus subtilis 30B-B6, Pseudomonas brenneri 43R-P1 and Pseudomonas protegens 44R-P8) were retained for further evaluation of their protection index against P. infestans in a pilot field trial. Interestingly, B. subtilis 30B-B6 was shown to significantly decrease late blight severity throughout the crop season. Overall, this study showed that antagonistic indigenous soil bacteria can offer an alternative to the indiscriminate use of pesticide in potato agro systems. PMID- 29487575 TI - Long-Term Warming Shifts the Composition of Bacterial Communities in the Phyllosphere of Galium album in a Permanent Grassland Field-Experiment. AB - Global warming is currently a much discussed topic with as yet largely unexplored consequences for agro-ecosystems. Little is known about the warming effect on the bacterial microbiota inhabiting the plant surface (phyllosphere), which can have a strong impact on plant growth and health, as well as on plant diseases and colonization by human pathogens. The aim of this study was to investigate the effect of moderate surface warming on the diversity and composition of the bacterial leaf microbiota of the herbaceous plant Galium album. Leaves were collected from four control and four surface warmed (+2 degrees C) plots located at the field site of the Environmental Monitoring and Climate Impact Research Station Linden in Germany over a 6-year period. Warming had no effect on the concentration of total number of cells attached to the leaf surface as counted by Sybr Green I staining after detachment, but changes in the diversity and phylogenetic composition of the bacterial leaf microbiota analyzed by bacterial 16S rRNA gene Illumina amplicon sequencing were observed. The bacterial phyllosphere microbiota were dominated by Proteobacteria, Bacteroidetes, and Actinobacteria. Warming caused a significant higher relative abundance of members of the Gammaproteobacteria, Actinobacteria, and Firmicutes, and a lower relative abundance of members of the Alphaproteobacteria and Bacteroidetes. Plant beneficial bacteria like Sphingomonas spp. and Rhizobium spp. occurred in significantly lower relative abundance in leaf samples of warmed plots. In contrast, several members of the Enterobacteriaceae, especially Enterobacter and Erwinia, and other potential plant or human pathogenic genera such as Acinetobacter and insect-associated Buchnera and Wolbachia spp. occurred in higher relative abundances in the phyllosphere samples from warmed plots. This study showed for the first time the long-term impact of moderate (+2 degrees C) surface warming on the phyllosphere microbiota on plants. A reduction of beneficial bacteria and an enhancement of potential pathogenic bacteria in the phyllosphere of plants may indicate that this aspect of the ecosystem which has been largely neglected up till now, can be a potential risk for pathogen transmission in agro-ecosystems in the near future. PMID- 29487576 TI - Determination of Lipophilic Marine Biotoxins in Mussels Harvested from the Adriatic Sea by LC-MS/MS. AB - Lipophilic marine biotoxins include okadaic acid, pectenotoxin, yessotoxin and azaspiracid groups. The consumption of contaminated molluscs can lead to acute food poisoning syndromes depending on the exposure level. Regulatory limits have been set by Regulation (European Community, 2004a) No 853/2004 and LC-MS/MS is used as the official analytical method according to Regulation (European Community, 2011) No 15/2011. In this study specimens of mussels (Mytilus galloprovincialis) were collected along the coasts of the central Adriatic Sea during the years 2015-2017 and analyzed by the European harmonized Standard Operating Procedure. The method was validated for linearity, specificity, repeatability and reproducibility and it revealed able to be used for the detection of the lipophilic marine biotoxins. Levels of okadaic acid, pectenotoxin, yessotoxin and its analogs were detected at different concentrations in 148 (37%) out of a total of 400 samples, always below the maximum limits, except for 11 (4.3%) of them that were non-compliant because they exceeded the regulatory limit. Moreover, some samples were exposed to a multi toxin mixture with regards to okadaic acid, yessotoxin and 1-Homo yessotoxin. Following these results, the aquaculture farms from which the non-compliant samples derived were closed until the analytical data of two consecutive samplings returned favorable. Besides the potential risk of consumption of mussels contaminated by lipophilic marine biotoxins, these marine organisms can be considered as bio-indicators of the contamination status of the marine ecosystem. PMID- 29487577 TI - Staphylococcus aureus Complex in the Straw-Colored Fruit Bat (Eidolon helvum) in Nigeria. AB - Bats are economically important animals and serve as food sources in some African regions. They can be colonized with the Staphylococcus aureus complex, which includes Staphylococcus schweitzeri and Staphylococcus argenteus. Fecal carriage of S. aureus complex in the straw-colored fruit bat (Eidolon helvum) has been described. However, data on their transmission and adaptation in animals and humans are limited. The aim of this study was to investigate the population structure of the S. aureus complex in E. helvum and to assess the geographical spread of S. aureus complex among other animals and humans. Fecal samples were collected from E. helvum in Obafemi Awolowo University, Ile-Ife, Nigeria. The isolates were characterized by antimicrobial susceptibility testing, spa typing and multilocus sequence typing (MLST). Isolates were screened for the presence of lukS/lukF-PV and the immune evasion cluster (scn, sak, chp) which is frequently found in isolates adapted to the human host. A Neighbor-Joining tree was constructed using the concatenated sequences of the seven MLST genes. A total of 250 fecal samples were collected and 53 isolates were included in the final analysis. They were identified as S. aureus (n = 28), S. schweitzeri (n = 11) and S. argenteus (n = 14). Only one S. aureus was resistant to penicillin and another isolate was intermediately susceptible to tetracycline. The scn, sak, and chp gene were not detected. Species-specific MLST clonal complexes (CC) were detected for S. aureus (CC1725), S. argenteus (CC3960, CC3961), and S. schweitzeri (CC2463). STs of S. schweitzeri from this study were similar to STs from bats in Nigeria (ST2464) and Gabon (ST1700) or from monkey in Cote d'Ivoire (ST2058, ST2072). This suggests host adaptation of certain clones to wildlife mammals with a wide geographical spread in Africa. In conclusion, there is evidence of fecal carriage of members of S. aureus complex in E. helvum. S. schweitzeri from bats in Nigeria are closely related to those from bats and monkeys in West and Central Africa suggesting a cross-species transmission and wide geographical distribution. The low antimicrobial resistance rates and the absence of the immune evasion cluster suggests a limited exposure of these isolates to humans. PMID- 29487580 TI - Highly Sensitive Colorimetric Biosensor for Staphylococcal Enterotoxin B by a Label-Free Aptamer and Gold Nanoparticles. AB - A simple, sensitive and selective colorimetric biosensor for the detection of Staphylococcal enterotoxin B (SEB) was developed using SEB-binding aptamer (SEB2) as recognition element and unmodified gold nanoparticles (AuNPs) as colorimetric probes. The assay is based on color change from red to purple due to conformational change of aptamer in the presence of SEB, and the phenomenon of salt-induced AuNPs aggregation which could be monitored by naked eye or UV-vis spectrometer. Results showed that the AuNPs can effectively differentiate the SEB induced conformational change of the aptamer in the presence of a given high salt concentration. A linear response in the range of 50 MUg/mL to 0.5 ng/mL of SEB concentration was obtained. The assay was highly specific to SEB as compared to other related toxins. The limit of detection (LOD) of SEB achieved within few minutes was 50 ng/mL visually and spectrometric method improved it to 0.5 ng/mL. Robustness of the assay was tested in artificially spiked milk samples and cross checked using in house developed sandwich ELISA (IgY as capturing and SEB specific monoclonal as revealing antibody) and PCR. This colorimetric assay could be a suitable alternative over existing methods during biological emergencies due to its simplicity, sensitive and cost effectiveness. PMID- 29487579 TI - HERVs New Role in Cancer: From Accused Perpetrators to Cheerful Protectors. AB - Initial indications that retroviruses are connected to neoplastic transformation were seen more than a century ago. This concept has also been tested for endogenized retroviruses (ERVs) that are abundantly expressed in many transformed cells. In healthy cells, ERV expression is commonly prevented by DNA methylation and other epigenetic control mechanisms. ERVs are remnants of former exogenous forms that invaded the germ line of the host and have since been vertically transmitted. Several examples of ERV-induced genomic recombination events and dysregulation of cellular genes that contribute to tumor formation have been well documented. Moreover, evidence is accumulating that certain ERV proteins have oncogenic properties. In contrast to these implications for supporting cancer induction, a recent string of papers has described favorable outcomes of increasing human ERV (HERV) RNA and DNA abundance by treatment of cancer cells with methyltransferase inhibitors. Analogous to an infecting agent, the ERV derived nucleic acids are sensed in the cytoplasm and activate innate immune responses that drive the tumor cell into apoptosis. This "viral mimicry" induced by epigenetic drugs might offer novel therapeutic approaches to help target cancer cells that are normally difficult to treat using standard chemotherapy. In this review, we discuss both the detrimental and the new beneficial role of HERV reactivation in terms of its implications for cancer. PMID- 29487581 TI - Bioenergetic Controls on Microbial Ecophysiology in Marine Sediments. AB - Marine sediments constitute one of the most energy-limited habitats on Earth, in which microorganisms persist over extraordinarily long timescales with very slow metabolisms. This habitat provides an ideal environment in which to study the energetic limits of life. However, the bioenergetic factors that can determine whether microorganisms will grow, lie dormant, or die, as well as the selective environmental pressures that determine energetic trade-offs between growth and maintenance activities, are not well understood. Numerical models will be pivotal in addressing these knowledge gaps. However, models rarely account for the variable physiological states of microorganisms and their demand for energy. Here, we review established modeling constructs for microbial growth rate, yield, maintenance, and physiological state, and then provide a new model that incorporates all of these factors. We discuss this new model in context with its future application to the marine subsurface. Understanding the factors that regulate cell death, physiological state changes, and the provenance of maintenance energy (i.e., endogenous versus exogenous metabolism), is crucial to the design of this model. Further, measurements of growth rate, growth yield, and basal metabolic activity will enable bioenergetic parameters to be better constrained. Last, biomass and biogeochemical rate measurements will enable model simulations to be validated. The insight provided from the development and application of new microbial modeling tools for marine sediments will undoubtedly advance the understanding of the minimum power required to support life, and the ecophysiological strategies that organisms utilize to cope under extreme energy limitation for extended periods of time. PMID- 29487582 TI - Soil Bacterial Community Was Changed after Brassicaceous Seed Meal Application for Suppression of Fusarium Wilt on Pepper. AB - Application of Brassicaceous seed meal (BSM) is a promising biologically based disease-control practice but BSM could directly and indirectly also affect the non-target bacterial communities, including the beneficial populations. Understanding the bacterial response to BSM at the community level is of great significance for directing plant disease management through the manipulation of resident bacterial communities. Fusarium wilt is a devastating disease on pepper. However, little is known about the response of bacterial communities, especially the rhizosphere bacterial community, to BSM application to soil heavily infested with Fusarium wilt pathogen and cropped with peppers. In this study, a 25-day microcosm incubation of a natural Fusarium wilt pathogen-infested soil supplemented with three BSMs, i.e., Camelina sativa 'Crantz' (CAME), Brassica juncea 'Pacific Gold' (PG), and a mixture of PG and Sinapis alba cv. 'IdaGold' (IG) (PG+IG, 1:1 ratio), was performed. Then, a further 35-day pot experiment was established with pepper plants growing in the BSM treated soils. The changes in the bacterial community in the soil after 25 days of incubation and changes in the rhizosphere after an additional 35 days of pepper growth were investigated by 454 pyrosequencing technique. The results show that the application of PG and PG+IG reduced the disease index by 100% and 72.8%, respectively, after 35 days of pepper growth, while the application of CAME did not have an evident suppressive effect. All BSM treatments altered the bacterial community structure and decreased the bacterial richness and diversity after 25 days of incubation, although this effect was weakened after an additional 35 days of pepper growth. At the phylum/class and the genus levels, the changes in specific bacterial populations resulting from the PG and PG+IG treatments, especially the significant increase in Actinobacteria-affiliated Streptomyces and an unclassified genus and the significant decrease in Chloroflexi, were suspected to be one of the microbial mechanisms involved in PG-containing BSM-induced disease suppression. This study is helpful for our understanding of the mechanisms that lead to contrasting plant disease severity after the addition of different BSMs. PMID- 29487578 TI - Distribution of the Most Prevalent Spa Types among Clinical Isolates of Methicillin-Resistant and -Susceptible Staphylococcus aureus around the World: A Review. AB - Background:Staphylococcus aureus, a leading cause of community-acquired and nosocomial infections, remains a major health problem worldwide. Molecular typing methods, such as spa typing, are vital for the control and, when typing can be made more timely, prevention of S. aureus spread around healthcare settings. The current study aims to review the literature to report the most common clinical spa types around the world, which is important for epidemiological surveys and nosocomial infection control policies. Methods: A search via PubMed, Google Scholar, Web of Science, Embase, the Cochrane library, and Scopus was conducted for original articles reporting the most prevalent spa types among S. aureus isolates. The search terms were "Staphylococcus aureus, spa typing." Results: The most prevalent spa types were t032, t008 and t002 in Europe; t037 and t002 in Asia; t008, t002, and t242 in America; t037, t084, and t064 in Africa; and t020 in Australia. In Europe, all the isolates related to spa type t032 were MRSA. In addition, spa type t037 in Africa and t037and t437 in Australia also consisted exclusively of MRSA isolates. Given the fact that more than 95% of the papers we studied originated in the past decade there was no option to study the dynamics of regional clone emergence. Conclusion: This review documents the presence of the most prevalent spa types in countries, continents and worldwide and shows big local differences in clonal distribution. PMID- 29487583 TI - Functional Genomics and Phylogenetic Evidence Suggest Genus-Wide Cobalamin Production by the Globally Distributed Marine Nitrogen Fixer Trichodesmium. AB - Only select prokaryotes can biosynthesize vitamin B12 (i.e., cobalamins), but these organic co-enzymes are required by all microbial life and can be vanishingly scarce across extensive ocean biomes. Although global ocean genome data suggest cyanobacteria to be a major euphotic source of cobalamins, recent studies have highlighted that >95% of cyanobacteria can only produce a cobalamin analog, pseudo-B12, due to the absence of the BluB protein that synthesizes the alpha ligand 5,6-dimethylbenzimidizole (DMB) required to biosynthesize cobalamins. Pseudo-B12 is substantially less bioavailable to eukaryotic algae, as only certain taxa can intracellularly remodel it to one of the cobalamins. Here we present phylogenetic, metagenomic, transcriptomic, proteomic, and chemical analyses providing multiple lines of evidence that the nitrogen-fixing cyanobacterium Trichodesmium transcribes and translates the biosynthetic, cobalamin-requiring BluB enzyme. Phylogenetic evidence suggests that the Trichodesmium DMB biosynthesis gene, bluB, is of ancient origin, which could have aided in its ecological differentiation from other nitrogen-fixing cyanobacteria. Additionally, orthologue analyses reveal two genes encoding iron-dependent B12 biosynthetic enzymes (cbiX and isiB), suggesting that iron availability may be linked not only to new nitrogen supplies from nitrogen fixation, but also to B12 inputs by Trichodesmium. These analyses suggest that Trichodesmium contains the genus-wide genomic potential for a previously unrecognized role as a source of cobalamins, which may prove to considerably impact marine biogeochemical cycles. PMID- 29487584 TI - Altered Fermentation Performances, Growth, and Metabolic Footprints Reveal Competition for Nutrients between Yeast Species Inoculated in Synthetic Grape Juice-Like Medium. AB - The sequential inoculation of non-Saccharomyces yeasts and Saccharomyces cerevisiae in grape juice is becoming an increasingly popular practice to diversify wine styles and/or to obtain more complex wines with a peculiar microbial footprint. One of the main interactions is competition for nutrients, especially nitrogen sources, that directly impacts not only fermentation performance but also the production of aroma compounds. In order to better understand the interactions taking place between non-Saccharomyces yeasts and S. cerevisiae during alcoholic fermentation, sequential inoculations of three yeast species (Pichia burtonii, Kluyveromyces marxianus, Zygoascus meyerae) with S. cerevisiae were performed individually in a synthetic medium. Different species dependent interactions were evidenced. Indeed, the three sequential inoculations resulted in three different behaviors in terms of growth. P. burtonii and Z. meyerae declined after the inoculation of S. cerevisiae which promptly outcompeted the other two species. However, while the presence of P. burtonii did not impact the fermentation kinetics of S. cerevisiae, that of Z. meyerae rendered the overall kinetics very slow and with no clear exponential phase. K. marxianus and S. cerevisiae both declined and became undetectable before fermentation completion. The results also demonstrated that yeasts differed in their preference for nitrogen sources. Unlike Z. meyerae and P. burtonii, K. marxianus appeared to be a competitor for S. cerevisiae (as evidenced by the uptake of ammonium and amino acids), thereby explaining the resulting stuck fermentation. Nevertheless, the results suggested that competition for other nutrients (probably vitamins) occurred during the sequential inoculation of Z. meyerae with S. cerevisiae. The metabolic footprint of the non-Saccharomyces yeasts determined after 48 h of fermentation remained until the end of fermentation and combined with that of S. cerevisiae. For instance, fermentations performed with K. marxianus were characterized by the formation of phenylethanol and phenylethyl acetate, while those performed with P. burtonii or Z. meyerae displayed higher production of isoamyl alcohol and ethyl esters. When considering sequential inoculation of yeasts, the nutritional requirements of the yeasts used should be carefully considered and adjusted accordingly. Finally, our chemical data suggests that the organoleptic properties of the wine are altered in a species specific manner. PMID- 29487585 TI - Identification and Characterization of T5-Like Bacteriophages Representing Two Novel Subgroups from Food Products. AB - During recent years, interest in the use of bacteriophages as biocontrol agents against foodborne pathogens has increased, particularly for members of the family Enterobacteriaceae, with pathogenic Escherichia coli, Shigella, and Salmonella strains among them. Here, we report the isolation and characterisation of 12 novel T5-like bacteriophages from confiscated food samples. All bacterophages effectively lysed E. coli K-12 strains and were able to infect pathogenic E. coli strains representing enterohaemorrhagic (EHEC), enteropathogenic (EPEC), enterotoxigenic (ETEC), and enteroinvasive (EIEC) pathotypes, Shigella dysenteriae, S. sonnei strains, as well as multidrug-resistant (MDR) E. coli and multiple strains representing different Salmonella enterica serovars. All the bacteriophages exhibited Siphoviridae morphology. Whole genome sequencing of the novel T5-like bacteriophages showed that they represent two distinct groups, with the genome-based grouping correlating to the different host spectra. As these bacteriophages are of food origin, their stability and lack of any virulence genes, as well as their broad and mutually complementary host spectrum makes these new T5-like bacteriophages valuable candidates for use as biocontrol agents against foodborne pathogenic enterobacteria. PMID- 29487586 TI - Autophagy in Negative-Strand RNA Virus Infection. AB - Autophagy is a homoeostatic process by which cytoplasmic material is targeted for degradation by the cell. Viruses have learned to manipulate the autophagic pathway to ensure their own replication and survival. Although much progress has been achieved in dissecting the interplay between viruses and cellular autophagic machinery, it is not well understood how the cellular autophagic pathway is utilized by viruses and manipulated to their own advantage. In this review, we briefly introduce autophagy, viral xenophagy and the interaction among autophagy, virus and immune response, then focus on the interplay between NS-RNA viruses and autophagy during virus infection. We have selected some exemplary NS-RNA viruses and will describe how these NS-RNA viruses regulate autophagy and the role of autophagy in NS-RNA viral replication and in immune responses to virus infection. We also review recent advances in understanding how NS-RNA viral proteins perturb autophagy and how autophagy-related proteins contribute to NS-RNA virus replication, pathogenesis and antiviral immunity. PMID- 29487587 TI - The Initiation Factors eIF2, eIF2A, eIF2D, eIF4A, and eIF4G Are Not Involved in Translation Driven by Hepatitis C Virus IRES in Human Cells. AB - Animal viruses have evolved a variety of strategies to ensure the efficient translation of their mRNAs. One such strategy is the use of internal ribosome entry site (IRES) elements, which circumvent the requirement for some eukaryotic initiation factors (eIFs). Much effort has been directed to unravel the precise mechanism of translation initiation by hepatitis C virus (HCV) mRNA. In the present study, we examined the involvement of several eIFs in HCV IRES-driven translation in human cells in a comparative analysis with mRNAs bearing the encephalomyocarditis virus or the Cricket paralysis virus IRES element. Consistent with previous findings, several inhibitors of eIF2 activity, including sodium arsenite, thapsigargin, tunicamycin, and salubrinal, had no inhibitory effect on the translation of an mRNA bearing the HCV IRES, and all induced the phosphorylation of eIF2alpha. In addition, hippuristanol and pateamine A, two known inhibitors of eIF4A, failed to block HCV IRES-directed translation. To test the release of nuclear proteins to the cytoplasm and to analyze the formation of stress granules, the location of the nuclear protein TIA1 was tested by immunocytochemistry. Both arsenite and pateamine A could efficiently induce the formation of stress granules containing TIA1 and eIF4G, whereas eIF3 and eIF2 failed to localize to these cytoplasmic bodies. The finding of eIF4A and eIF4G in stress granules suggests that they do not participate in mRNA translation. Human HAP1 cells depleted for eIF2A, eIF2D, or both factors, were able to synthesize luciferase from an mRNA bearing the HCV IRES even when eIF2alpha was phosphorylated. Overall, these results demonstrate that neither eIF2A nor eIF2D does not participate in the translation directed by HCV IRES. We conclude that eIF2, eIF4A, eIF2A, and eIF2D do not participate in the initiation of translation of HCV mRNA. PMID- 29487588 TI - Flagellar Basal Body Structural Proteins FlhB, FliM, and FliY Are Required for Flagellar-Associated Protein Expression in Listeria monocytogenes. AB - Listeria monocytogenes is a food-associated bacterium that is responsible for food-related illnesses worldwide. In the L. monocytogenes EGD-e genome, FlhB, FliM, and FliY (encoded by lmo0679, lmo0699, and lmo0700, respectively) are annotated as putative flagella biosynthesis factors, but their functions remain unknown. To explore whether FlhB, FliM, and FliY are involved in Listeria flagella synthesis, we constructed flhB, fliM, fliY, and other flagellar-related gene deletion mutants using a homologous recombination strategy. Then, we analyzed the motility, flagella synthesis, and protein expression of these mutant strains. Motility and flagella synthesis were completely abolished in the absence of flhB, fliM, or fliY. These impaired phenotypes were fully restored in the complemented strains CDeltaflhB, CDeltafliM, and CDeltafliY. The transcriptional levels of flagellar-related genes, including flaA, fliM, fliY, lmo0695, lmo0698, fliI, and fliS, were downregulated markedly in the absence of flhB, fliM, or fliY. Deletion of flhB resulted in the complete abolishment of FlaA expression, while it decreased FliM and FliY expression. The expression of FlaA was abolished completely in the absence of fliM or fliY. No significant changes were found in the expression of FlhF and two flagella synthesis regulatory factors, MogR and GmaR. We demonstrate for the first time that FlhB, FliM, and FliY not only mediate Listeria motility, but also are involved in regulating flagella synthesis. This study provides novel insights that increase our understanding of the roles played by FlhB, FliM, and FliY in the flagellar type III secretion system in L. monocytogenes. PMID- 29487589 TI - Elevated HERV-K Expression in Soft Tissue Sarcoma Is Associated with Worsened Relapse-Free Survival. AB - A wide variety of endogenous retroviral sequences has been demonstrated in the human genome so far, divided into several different families according to the sequence homology to viral strains. While increased expression of human endogenous retrovirus (HERV) elements has already been linked to unfavorable prognosis in hepatocellular carcinoma, breast cancer, and ovarian carcinoma yet less is known about the impact of the expression of different HERV elements on sarcomagenesis in general as well as the outcome of soft tissue sarcoma (STS) patients. Therefore, in this study the association between expression of HERV-K and HERV-F and the clinicopathological characteristics in a cohort of STSs as well as the patients' prognosis was evaluated. HERV-K and HERV-F expression was assessed by quantitative real-time PCR in 120 patient specimens. HERV-K and HERV F expression was significantly correlated (rS = 0.5; p = 6.4 * 10-9; Spearman's rank bivariate correlation). Also, tumor diameter exhibited a significant negative association to HERV-K and HERV-F expression. Levels of several hypoxia related RNAs like HIF-1alpha and miR-210 showed a significant positive correlation with both HERV-K and HERV-F expression. Although in survival analyses no impact of HERV expression on disease-specific survival could be detected, patients with elevated HERV-K expression had a significantly shorter relapse-free survival (p = 0.014, log-rank analysis). In conclusion, we provide evidence for the first time that the increased expression of HERV-K in tumors is associated with STS patients' prognosis. PMID- 29487590 TI - QseC Mediates Osmotic Stress Resistance and Biofilm Formation in Haemophilus parasuis. AB - Haemophilus parasuis is known as a commensal organism discovered in the upper respiratory tract of swine where the pathogenic bacteria survive in various adverse environmental stress. QseC, a histidine protein kinase of the two component regulatory systems CheY/QseC, is involved in the environmental adaptation in bacteria. To investigate the role of QseC in coping with the adverse environment stresses and survive in the host, we constructed a qseC mutant of H. parasuis serovar 13 strain (DeltaqseC), MY1902. In this study, we found that QseC was involved in stress tolerance of H. parasuis, by the DeltaqseC exhibited a decreased resistance to osmotic pressure, oxidative stress, and heat shock. Moreover, the DeltaqseC weakened the ability to take up iron and biofilm formation. We also found that the QseC participate in sensing the epinephrine in environment to regulate the density of H. parasuis. PMID- 29487591 TI - FibroChip, a Functional DNA Microarray to Monitor Cellulolytic and Hemicellulolytic Activities of Rumen Microbiota. AB - Ruminants fulfill their energy needs for growth primarily through microbial breakdown of plant biomass in the rumen. Several biotic and abiotic factors influence the efficiency of fiber degradation, which can ultimately impact animal productivity and health. To provide more insight into mechanisms involved in the modulation of fibrolytic activity, a functional DNA microarray targeting genes encoding key enzymes involved in cellulose and hemicellulose degradation by rumen microbiota was designed. Eight carbohydrate-active enzyme (CAZyme) families (GH5, GH9, GH10, GH11, GH43, GH48, CE1, and CE6) were selected which represented 392 genes from bacteria, protozoa, and fungi. The DNA microarray, designated as FibroChip, was validated using targets of increasing complexity and demonstrated sensitivity and specificity. In addition, FibroChip was evaluated for its explorative and semi-quantitative potential. Differential expression of CAZyme genes was evidenced in the rumen bacterium Fibrobacter succinogenes S85 grown on wheat straw or cellobiose. FibroChip was used to identify the expressed CAZyme genes from the targeted families in the rumen of a cow fed a mixed diet based on grass silage. Among expressed genes, those encoding GH43, GH5, and GH10 families were the most represented. Most of the F. succinogenes genes detected by the FibroChip were also detected following RNA-seq analysis of RNA transcripts obtained from the rumen fluid sample. Use of the FibroChip also indicated that transcripts of fiber degrading enzymes derived from eukaryotes (protozoa and anaerobic fungi) represented a significant proportion of the total microbial mRNA pool. FibroChip represents a reliable and high-throughput tool that enables researchers to monitor active members of fiber degradation in the rumen. PMID- 29487592 TI - Diversity Generator Mechanisms Are Essential Components of Biological Systems: The Two Queen Hypothesis. AB - Diversity is widely known to fuel adaptation and evolutionary processes and increase robustness at the population, species and ecosystem levels. The Neo Darwinian paradigm proposes that the diversity of biological entities is the consequence of genetic changes arising spontaneously and randomly, without regard for their usefulness. However, a growing body of evidence demonstrates that the evolutionary process has shaped mechanisms, such as horizontal gene transfer mechanisms, meiosis and the adaptive immune system, which has resulted in the regulated generation of diversity among populations. Though their origins are unrelated, these diversity generator (DG) mechanisms share common functional properties. They (i) contribute to the great unpredictability of the composition and/or behavior of biological systems, (ii) favor robustness and collectivism among populations and (iii) operate mainly by manipulating the systems that control the interaction of living beings with their environment. The definition proposed here for DGs is based on these properties and can be used to identify them according to function. Interestingly, prokaryotic DGs appear to be mainly reactive, as they generate diversity in response to environmental stress. They are involved in the widely described Red Queen/arms race/Cairnsian dynamic. The emergence of multicellular organisms harboring K selection traits (longer reproductive life cycle and smaller population size) has led to the acquisition of a new class of DGs that act anticipatively to stress pressures and generate a distinct dynamic called the "White Queen" here. The existence of DGs leads to the view of evolution as a more "intelligent" and Lamarckian-like process. Their repeated selection during evolution could be a neglected example of convergent evolution and suggests that some parts of the evolutionary process are tightly constrained by ecological factors, such as the population size, the generation time and the intensity of selective pressure. The ubiquity of DGs also suggests that regulated auto-generation of diversity is a fundamental property of life. PMID- 29487593 TI - Transglycosylated Starch Modulates the Gut Microbiome and Expression of Genes Related to Lipid Synthesis in Liver and Adipose Tissue of Pigs. AB - Dietary inclusion of resistant starches can promote host health through modulation of the gastrointestinal microbiota, short-chain fatty acid (SCFA) profiles, and lipid metabolism. This study investigated the impact of a transglycosylated cornstarch (TGS) on gastric, ileal, cecal, proximal-colonic, and mid-colonic bacterial community profiles and fermentation metabolites using a growing pig model. It additionally evaluated the effect of TGS on the expression of host genes related to glucose and SCFA absorption, incretins, and satiety in the gut as well as host genes related to lipid metabolism in hepatic and adipose tissue. Sixteen growing pigs (4 months of age) were fed either a TGS or control (CON) diet for 11 days. Bacterial profiles were determined via Illumina MiSeq sequencing of the V3-5 region of the 16S rRNA gene, whereas SCFA and gene expression were measured using gas chromatography and reverse transcription quantitative PCR. Megasphaera, which was increased at all gut sites, began to benefit from TGS feeding in gastric digesta, likely through cross-feeding with other microbes, such as Lactobacillus. Shifts in the bacterial profiles from dietary TGS consumption in the cecum, proximal colon, and mid colon were similar. Relative abundances of Ruminococcus and unclassified Ruminococcaceae genus were lower, whereas that of unclassified Veillonellaceae genus was higher in TGS- compared to CON-fed pigs (p < 0.05). TGS consumption also increased (p < 0.05) concentrations of SCFA, especially propionate, and lactate in the distal hindgut compared to the CON diet which might have up-regulated GLP1 expression in the cecum (p < 0.05) and mid colon compared to the control diet (p < 0.10). TGS-fed pigs showed increased hepatic and decreased adipocyte expression of genes for lipid synthesis (FASN, SREBP1, and ACACA) compared to CON-fed pigs, which may be related to postprandial portal nutrient flow and reduced systemic insulin signaling. Overall, our data show that TGS consumption may affect gastrointestinal bacterial signaling, caused by changes in gut bacterial profiles and the action of propionate, and host lipid metabolism. PMID- 29487594 TI - Beta-Defensin 2 and 3 Promote Bacterial Clearance of Pseudomonas aeruginosa by Inhibiting Macrophage Autophagy through Downregulation of Early Growth Response Gene-1 and c-FOS. AB - Beta-defensins 2 and 3 (BD2 and BD3) are inducible peptides present at the sites of infection, and they are well characterized for their antimicrobial activities and immune-regulatory functions. However, no study has thoroughly investigated their immunomodulatory effects on macrophage-mediated immune responses against Pseudomonas aeruginosa (PA). Here, we use THP-1 and RAW264.7 cell lines and demonstrate that BD2 and BD3 suppressed macrophage autophagy but enhanced the engulfment of PA and Zymosan bioparticles as well as the formation of phagolysosomes, using immunofluorescence staining and confocal microscopy. Plate count assay showed that macrophage-mediated phagocytosis and intracellular killing of PA were promoted by BD2 and BD3. Furthermore, microarray and real-time PCR showed that the expression of two genes, early growth response gene-1 (EGR1) and c-FOS, was attenuated by BD2 and BD3. Western blot revealed that BD2 and BD3 inhibited the expression and nuclear translocation of EGR1 and c-FOS. Knockdown of EGR1 and c-FOS by siRNA transfection suppressed macrophage autophagy before and after PA infection; while overexpression of these two transcription factors enhanced autophagy but reversed the role of BD2 and BD3 on macrophage-mediated PA eradication. Together, these results demonstrate a novel immune defense activity of BD2 and BD3, which promotes clearance of PA by inhibiting macrophage autophagy through downregulation of EGR1 and c-FOS. PMID- 29487595 TI - From CD4-Based Initiation to Treating All HIV-Infected Adults Immediately: An Evidence-Based Meta-analysis. AB - Background: The World Health Organization (WHO) Consolidated antiretroviral therapy (ART) guidelines set the CD4+ T-cell counts threshold to 500 cells/mm3 in 2013, and 2015 guidelines recommend treating all HIV-infected adults regardless of their CD4+ T-cell counts. To inform the decision-making around ART guidelines for people living with HIV, we systematically reviewed the literature to estimate differences in clinical benefits between individuals starting treatment with baseline CD4+ T-cell counts >=500 cells/mm3 (early initiation) as compared to <500 cells/mm3 (deferred initiation). Methods: We systematically searched the electronic databases and abstracts for randomized controlled trials (RCT) and observational studies. Outcomes were mortality, AIDS progression, AIDS or death, immunologic recovery, and virologic suppression. We pooled data across studies and performed analyses of effect sizes. Results: We identified 13 studies comparing early and deferred treatment. The pooled risk ratio (RR) of mortality of 11 observational studies was 0.90 (95% CI 0.82-0.99), with moderate heterogeneity (I2 = 53%). The pooled RR for progression to AIDS from two observational studies was 0.77 (95% CI 0.47-1.24). Five observational studies found a pooled RR of death or AIDS of 0.94 (95% CI 0.93-0.95). For the outcome of immunologic recovery, defined as CD4+ T-cell counts reaching at least 800 cells/mm3 after ART, one observational study found early initiation of ART had an HR (hazard ratio) of 2.39 (95% CI 1.93-2.96). The pooled RR of viral suppression (a viral load <50 copies/ml) after 9 months from one cohort was 1.04 (95% CI 0.99 1.09). Conclusion: Mortality risk and risk for AIDS appear to be reduced among people living with HIV with early initiation of ART, based on current WHO guidelines, as compared to those with deferred initiation of ART (<500 cells/mm3). PMID- 29487596 TI - C-Type Lectin Receptor (CLR)-Fc Fusion Proteins As Tools to Screen for Novel CLR/Bacteria Interactions: An Exemplary Study on Preselected Campylobacter jejuni Isolates. AB - C-type lectin receptors (CLRs) are carbohydrate-binding receptors that recognize their ligands often in a Ca2+-dependent manner. Upon ligand binding, myeloid CLRs in innate immunity trigger or inhibit a variety of signaling pathways, thus initiating or modulating effector functions such as cytokine production, phagocytosis, and antigen presentation. CLRs bind to various pathogens, including viruses, fungi, parasites, and bacteria. The bacterium Campylobacter jejuni (C. jejuni) is a very frequent Gram-negative zoonotic pathogen of humans, causing severe intestinal symptoms. Interestingly, C. jejuni expresses several glycosylated surface structures, for example, the capsular polysaccharide (CPS), lipooligosaccharide (LOS), and envelope proteins. This "Methods" paper describes applications of CLR-Fc fusion proteins to screen for yet unknown CLR/bacteria interactions using C. jejuni as an example. ELISA-based detection of CLR/bacteria interactions allows a first prescreening that is further confirmed by flow cytometry-based binding analysis and visualized using confocal microscopy. By applying these methods, we identified Dectin-1 as a novel CLR recognizing two selected C. jejuni isolates with different LOS and CPS genotypes. In conclusion, the here-described applications of CLR-Fc fusion proteins represent useful methods to screen for and identify novel CLR/bacteria interactions. PMID- 29487597 TI - Loss of Rictor in Monocyte/Macrophages Suppresses Their Proliferation and Viability Reducing Atherosclerosis in LDLR Null Mice. AB - Background: Rictor is an essential component of mammalian target of rapamycin (mTOR) complex 2 (mTORC2), a conserved serine/threonine kinase that may play a role in cell proliferation, survival and innate or adaptive immune responses. Genetic loss of Rictor inactivates mTORC2, which directly activates Akt S473 phosphorylation and promotes pro-survival cell signaling and proliferation. Methods and results: To study the role of mTORC2 signaling in monocytes and macrophages, we generated mice with myeloid lineage-specific Rictor deletion (MRictor-/-). These MRictor-/- mice exhibited dramatic reductions of white blood cells, B-cells, T-cells, and monocytes but had similar levels of neutrophils compared to control Rictor flox-flox (Rictorfl/fl) mice. MRictor-/- bone marrow monocytes and peritoneal macrophages expressed reduced levels of mTORC2 signaling and decreased Akt S473 phosphorylation, and they displayed significantly less proliferation than control Rictorfl/fl cells. In addition, blood monocytes and peritoneal macrophages isolated from MRictor-/- mice were significantly more sensitive to pro-apoptotic stimuli. In response to LPS, MRictor-/- macrophages exhibited the M1 phenotype with higher levels of pro-inflammatory gene expression and lower levels of Il10 gene expression than control Rictorfl/fl cells. Further suppression of LPS-stimulated Akt signaling with a low dose of an Akt inhibitor, increased inflammatory gene expression in macrophages, but genetic inactivation of Raptor reversed this rise, indicating that mTORC1 mediates this increase of inflammatory gene expression. Next, to elucidate whether mTORC2 has an impact on atherosclerosis in vivo, female and male Ldlr null mice were reconstituted with bone marrow from MRictor-/- or Rictorfl/fl mice. After 10 weeks of the Western diet, there were no differences between the recipients of the same gender in body weight, blood glucose or plasma lipid levels. However, both female and male MRictor-/- -> Ldlr-/- mice developed smaller atherosclerotic lesions in the distal and proximal aorta. These lesions contained less macrophage area and more apoptosis than lesions of control Rictorfl/fl -> Ldlr-/- mice. Thus, loss of Rictor and, consequently, mTORC2 significantly compromised monocyte/macrophage survival, and this markedly diminished early atherosclerosis in Ldlr-/- mice. Conclusion: Our results demonstrate that mTORC2 is a key signaling regulator of macrophage survival and its depletion suppresses early atherosclerosis. PMID- 29487598 TI - Macrophages in the Human Cochlea: Saviors or Predators-A Study Using Super Resolution Immunohistochemistry. AB - The human inner ear, which is segregated by a blood/labyrinth barrier, contains resident macrophages [CD163, ionized calcium-binding adaptor molecule 1 (IBA1)-, and CD68-positive cells] within the connective tissue, neurons, and supporting cells. In the lateral wall of the cochlea, these cells frequently lie close to blood vessels as perivascular macrophages. Macrophages are also shown to be recruited from blood-borne monocytes to damaged and dying hair cells induced by noise, ototoxic drugs, aging, and diphtheria toxin-induced hair cell degeneration. Precise monitoring may be crucial to avoid self-targeting. Macrophage biology has recently shown that populations of resident tissue macrophages may be fundamentally different from circulating macrophages. We removed uniquely preserved human cochleae during surgery for treating petroclival meningioma compressing the brain stem, after ethical consent. Molecular and cellular characterization using immunofluorescence with antibodies against IBA1, TUJ1, CX3CL1, and type IV collagen, and super-resolution structured illumination microscopy (SR-SIM) were made together with transmission electron microscopy. The super-resolution microscopy disclosed remarkable phenotypic variants of IBA1 cells closely associated with the spiral ganglion cells. Monitoring cells adhered to neurons with "synapse-like" specializations and protrusions. Active macrophages migrated occasionally nearby damaged hair cells. Results suggest that the human auditory nerve is under the surveillance and possible neurotrophic stimulation of a well-developed resident macrophage system. It may be alleviated by the non-myelinated nerve soma partly explaining why, in contrary to most mammals, the human's auditory nerve is conserved following deafferentiation. It makes cochlear implantation possible, for the advantage of the profoundly deaf. The IBA1 cells may serve additional purposes such as immune modulation, waste disposal, and nerve regeneration. Their role in future stem cell-based therapy needs further exploration. PMID- 29487599 TI - Dectin-1-Syk-CARD9 Signaling Pathway in TB Immunity. AB - One of the first steps toward mounting an effective immune response to Mycobacterium tuberculosis (Mtb) is recognition of the pathogen through pattern recognition receptors (PRRs) expressed by innate immune cells. Activation of the PRR Dectin-1 by an unknown mycobacterial ligand triggers an intracellular signaling cascade involving numerous proteins, including spleen tyrosine kinase, protein kinase C-delta, and caspase recruitment domain family member 9, some of which have been shown to influence host immune response to TB infection. Here, we review the role of Dectin-1 signaling pathway in anti-mycobacterial immunity and discuss its contribution in the control of Mtb infection, and potential applications in TB vaccine adjuvanticity. PMID- 29487600 TI - Allergen and Epitope Targets of Mouse-Specific T Cell Responses in Allergy and Asthma. AB - Mouse allergy has become increasingly common, mainly affecting laboratory workers and inner-city households. To date, only one major allergen, namely Mus m 1, has been described. We sought to identify T cell targets in mouse allergic patients. PBMC from allergic donors were expanded with either murine urine or epithelial extract and subsequently screened for cytokine production (IL-5 and IFNgamma) in response to overlapping peptides spanning the entire Mus m 1 sequence, peptides from various Mus m 1 isoforms [major urinary proteins (MUPs)], peptides from mouse orthologs of known allergens from other mammalian species and peptides from proteins identified by immunoproteomic analysis of IgE/IgG immunoblots of mouse urine and epithelial extracts. This approach let to the identification of 106 non redundant T cell epitopes derived from 35 antigens. Three major T cell-activating regions were defined in Mus m 1 alone. Moreover, our data show that immunodominant epitopes were largely shared between Mus m 1 and other MUPs even from different species, suggesting that sequence conservation in different allergens is a determinant for immunodominance. We further identified several novel mouse T cell antigens based on their homology to known mammalian allergens. Analysis of cohort-specific T cell responses revealed that rhinitis and asthmatic patients recognized different epitope repertoires. Epitopes defined herein can be formulated into an epitope "megapool" used to diagnose mouse allergy and study mouse-specific T cell responses directly ex vivo. This analysis of T cell epitopes provides a good basis for future studies to increase our understanding of the immunopathology associated with MO-allergy and asthma. PMID- 29487601 TI - Serum Levels of Migration Inhibitory Factor (MIF) and In Situ Expression of MIF and Its Receptor CD74 in Lepromatous Leprosy Patients: A Preliminary Report. AB - Leprosy is a chronic disease caused by Mycobacterium leprae that affects the skin and peripheral nerves. It may present as one of two distinct poles: the self limiting tuberculoid leprosy and the highly infectious lepromatous leprosy (LL) characterized by M. leprae-specific absence of cellular immune response. The pro inflammatory cytokine macrophage migration inhibitory factor (MIF) enhance the bactericide activities of macrophages after interaction with its receptor, CD74. Importantly, MIF also possesses chemoattractant properties, and it is a key factor in situ for the activation of macrophages and in blood to promote leukocytes migration. MIF-mediated activation of macrophages is a key process for the elimination of pathogens such as Mycobacterium tuberculosis; however, its participation for the clearance of M. leprae is unclear. The aim of this study was to evaluate the serum levels of MIF as well as MIF and CD74 expression in skin lesions of LL and compare it with healthy skin (HSk) taken from subjects attending to dermatological consult. Samples of serum and skin biopsies were taken from 39 LL patients and compared with 36 serum samples of healthy subjects (HS) and 10 biopsies of HSk. Serum samples were analyzed by ELISA and skin biopsies by immunohistochemistry (IHC). IHC smears were observed in 12 100* microscopic fields, in which percentage of stained cells and staining intensity were evaluated. Both variables were used to calculate a semi-quantitative expression score that ranged from 0 to 3+. We found no differences in MIF levels between LL patients and HS in sera. In addition, MIF was observed in over 75% of cells with high intensity in the skin of patients and HSk. Although we found no differences in MIF expression between the groups, a CD74 score statistically higher was found in LL skin than HSk (p < 0.001); this was the result of a higher percentage of cells positive for CD74 (p < 0.001). As a conclusion, we found that CD74-positive cells are intensely recruited to the skin with LL lesions. In this manner, MIF signaling may be enhanced in the skin of LL patients due to increased expression of its receptor, but further studies are required. PMID- 29487602 TI - Clinical Grade Regulatory CD4+ T Cells (Tregs): Moving Toward Cellular-Based Immunomodulatory Therapies. AB - Regulatory T cells (Tregs) are CD4+ T cells that are key players of immune tolerance. They are powerful suppressor cells, able to impact the function of numerous immune cells, including key effectors of inflammation such as effector T cells. For this reason, Tregs are an ideal candidate for the development of cell therapy approaches to modulate immune responses. Treg therapy has shown promising results so far, providing key knowledge on the conditions in which these cells can provide protection and demonstrating that they could be an alternative to current pharmacological immunosuppressive therapies. However, a more comprehensive understanding of their characteristics, isolation, activation, and expansion is needed to be able design cost effective therapies. Here, we review the practicalities of making Tregs a viable cell therapy, in particular, discussing the challenges faced in isolating and manufacturing Tregs and defining what are the most appropriate applications for this new therapy. PMID- 29487605 TI - Aquatic Plant Diversity in Italy: Distribution, Drivers and Strategic Conservation Actions. AB - Italy is recognized as one of the prominent hot spot areas for plant diversity at regional and global scale, hosting a rich range of ecosystems and habitat types. This is especially true considering aquatic habitats, which represent a major portion of the total water surfaces in the Mediterranean region. Nevertheless, only a scant attention was paid to clarify the species richness of aquatic plant and its contribution to the total diversity at the country scale, despite such plants are seriously threatened at multiple scales. This paper provided the first comprehensive inventory of aquatic plants at the whole country scale, collecting data on species' distribution, trends, and explanatory determinants of species richness. We confirmed the key contribution of Italy to the regional and global aquatic plant diversity with a total of 279 species recorded since 2005, equal to the 88.5%, 55.9% and ~10% of the richness estimated at European/Mediterranean, Palearctic and global scale, respectively. Ten species are considered extinct in the wild [among which Aldrovanda vesiculosa L., Caldesia parnassifolia (Bassi ex L.) Parl., Helosciadium repens (Jacq.) W.J.D. Koch, and Pilularia globulifera L.], four were doubt [among which Luronium natans (L.) Raf., Utricularia intermedia Hayne, and U. ochroleuca R.W. Hartman.], and eight were erroneously reported in the past, among which Isoetes lacustris L., Myosotis rehsteineri Wartm., and Ranunculus aquatilis L. Only 18 species - mainly helophytes (14) - were present in all the 20 Italian regions, whereas hydrophytes showed most scanty regional frequencies. Temperature, latitude, area and water resources availability are the main drivers of aquatic plant spatial arrangement and diversity. Furthermore, the number of inhabitants per km2 well described the number of "lost species" since 2000. The findings of the present survey call for an urgent elaboration of large-scale strategies to ensure the survival of aquatic plants, stressing on multiple functions played by aquatic plants in supporting national economy and human well-being. In this context, Italy can play a fundamental role guaranteeing temporary refuge for projected or expected species migrations along latitude and longitude gradients. Besides, in hyper-exploited landscapes man-made water bodies can further enhance the achievement of minimum conservation targets. PMID- 29487604 TI - Identification and Fine-Mapping of a Major Maize Leaf Width QTL in a Re-sequenced Large Recombinant Inbred Lines Population. AB - Leaf width (LW) influences canopy architecture of population-cultured maize and can thus contribute to density breeding. In previous studies, almost all maize LW related mutants have extreme effect on leaf development or accompanied unfavorable phenotypes. In addition, the identification of quantitative trait loci (QTLs) has been resolution-limited, with cloning and fine-mapping rarely performed. Here, we constructed a bin map for 670 recombinant inbred lines (RILs) using ~1.2 billion 100-bp re-sequencing reads. QTL analysis of the LW trait directly narrowed the major effect QTL, qLW4, to a ~270-kb interval. A fine mapping population and near-isogenic lines (NILs) were quickly constructed using a key RIL harboring heterozygous genotypes across the qLW4 region. A recombinant derived progeny testing strategy was subsequently used to further fine-map qLW4 to a 55-kb interval. Examination of NILs revealed that qLW4 has a completely dominant effect on LW, with no additional effect on leaf length. Candidate gene analysis suggested that this locus may be a novel LW controlling allele in maize. Our findings demonstrate the advantage of large-population high-density bin mapping, and suggest a strategy for efficiently fine-mapping or even cloning of QTLs. These results should also be helpful for further dissection of the genetic mechanism of LW variation, and benefit maize density breeding. PMID- 29487603 TI - The Aryl Hydrocarbon Receptor and Tumor Immunity. AB - The aryl hydrocarbon receptor (AhR) is an important cytosolic, ligand-dependent transcription factor. Emerging evidence suggests the promoting role of the AhR in the initiation, promotion, progression, invasion, and metastasis of cancer cells. Studies on various tumor types and tumor cell lines have shown high AhR expression, suggesting that AhR is activated constitutively in tumors and facilitates their growth. Interestingly, immune evasion has been recognized as an emerging hallmark feature of cancer. A connection between the AhR and immune system has been recognized, which has been suggested as an immunosuppressive effector on different types of immune cells. Certain cancers can escape immune recognition via AhR signaling pathways. This review discusses the role of the AhR in tumor immunity and its potential mechanism of action in the tumor microenvironment. PMID- 29487606 TI - The Role of Herbivory in Structuring Tropical Seagrass Ecosystem Service Delivery. AB - Seagrass meadows support key ecosystem services, via provision of food directly for herbivores, and indirectly to their predators. The importance of herbivores in seagrass meadows has been well-documented, but the links between food webs and ecosystem services in seagrass meadows have not previously been made explicit. Herbivores interact with ecosystem services - including carbon sequestration, cultural values, and coastal protection. Interactions can be positive or negative and depend on a range of factors including the herbivore identity and the grazing type and intensity. There can be unintended consequences from management actions based on a poor understanding of trade-offs that occur with complex seagrass herbivore interactions. Tropical seagrass meadows support a diversity of grazers spanning the meso-, macro-, and megaherbivore scales. We present a conceptual model to describe how multiple ecosystem services are influenced by herbivore pressure in tropical seagrass meadows. Our model suggests that a balanced ecosystem, incorporating both seagrass and herbivore diversity, is likely to sustain the broadest range of ecosystem services. Our framework suggests the pathway to achieve desired ecosystem services outcomes requires knowledge on four key areas: (1) how size classes of herbivores interact to structure seagrass; (2) desired community and management values; (3) seagrass responses to top-down and bottom-up controls; (4) the pathway from intermediate to final ecosystem services and human benefits. We suggest research should be directed to these areas. Herbivory is a major structuring influence in tropical seagrass systems and needs to be considered for effective management of these critical habitats and their services. PMID- 29487607 TI - Uptake and Transformation of Methylated and Inorganic Antimony in Plants. AB - Used as a hardening agent in lead bullets, antimony (Sb) has become a major contaminant in shooting range soils of some countries including Switzerland. Soil contamination by Sb is also an environmental problem in countries with Sb-mining activities such as China and Bolivia. Because of its toxicity and relatively high mobility, there is concern over the risk of Sb transfer from contaminated soils into plants, and thus into the food chain. In particular there is very little information on the environmental behavior of methylated antimony, which can be produced by microbial biomethylation of inorganic Sb in contaminated soils. Using a new extraction and high-performance liquid chromatography inductively coupled plasma mass spectrometry (HPLC-ICP-MS) method, we investigated antimony speciation in roots and shoots of wheat, fescue, rye, and ryegrass plants exposed to trimethyl antimony(V) (TMSb), antimonite (Sb(III)), and antimonate (Sb(V)) in hydroponics. The total root Sb concentrations followed the order Sb(III) treatment > Sb(V) treatment > TMSb treatment, except for fescue. Shoot Sb concentrations, however, did not differ among the three treatments. In the Sb(V) treatment small quantities of TMSb were found in the roots, whereas no TMSb was detected in the roots of Sb(III)-treated plants. In contrast, similar concentrations of TMSb were found in the shoots in both inorganic Sb treatments. The results indicate that biomethylation of Sb may occur in plants. In the TMSb treatment TMSb was the major Sb species, but the two inorganic Sb species were also found both in shoots and roots along with some unknown Sb species, suggesting that also TMSb demethylation may occur within plant tissues. The results furthermore indicate that methylated Sb is more mobile in plants than inorganic Sb species. Knowledge about this is important in risk assessments of Sb contaminated sites, as methylation may render Sb more toxic than inorganic Sb, as it is known for arsenic (As). PMID- 29487608 TI - Co-expression of P173S Mutant Rice EPSPS and igrA Genes Results in Higher Glyphosate Tolerance in Transgenic Rice. AB - Weeds and their devastating effects have been a great threat since the start of agriculture. They compete with crop plants in the field and negatively influence the crop yield quality and quantity along with survival of the plants. Glyphosate is an important broad-spectrum systemic herbicide which has been widely used to combat various weed problems since last two decades. It is very effective even at low concentrations, and possesses low environmental toxicity and soil residual activity. However, the residual concentration of glyphosate inside the plant has been of major concern as it severely affects the important metabolic pathways, and results in poor plant growth and grain yield. In this study, we compared the glyphosate tolerance efficiency of two different transgenic groups over expressing proline/173/serine (P173S) rice EPSPS glyphosate tolerant mutant gene (OsmEPSPS) alone and in combination with the glyphosate detoxifying encoding igrA gene, recently characterized from Pseudomonas. The molecular analysis of all transgenic plant lines showed a stable integration of transgenes and their active expression in foliar tissues. The physiological analysis of glyphosate treated transgenic lines at seed germination and vegetative stages showed a significant difference in glyphosate tolerance between the two transgenic groups. The transgenic plants with OsmEPSPS and igrA genes, representing dual glyphosate tolerance mechanisms, showed an improved root-shoot growth, physiology, overall phenotype and higher level of glyphosate tolerance compared to the OsmEPSPS transgenic plants. This study highlights the advantage of igrA led detoxification mechanism as a crucial component of glyphosate tolerance strategy in combination with glyphosate tolerant OsmEPSPS gene, which offered a better option to tackle in vivo glyphosate accumulation and imparted more robust glyphosate tolerance in rice transgenic plants. PMID- 29487609 TI - Internal and External Dispersal of Plants by Animals: An Aquatic Perspective on Alien Interference. AB - Many alien plants use animal vectors for dispersal of their diaspores (zoochory). If alien plants interact with native disperser animals, this can interfere with animal-mediated dispersal of native diaspores. Interference by alien species is known for frugivorous animals dispersing fruits of terrestrial plants by ingestion, transport and egestion (endozoochory). However, less attention has been paid to possible interference of alien plants with dispersal of diaspores via external attachment (ectozoochory, epizoochory or exozoochory), interference in aquatic ecosystems, or positive effects of alien plants on dispersal of native plants. This literature study addresses the following hypotheses: (1) alien plants may interfere with both internal and external animal-mediated dispersal of native diaspores; (2) interference also occurs in aquatic ecosystems; (3) interference of alien plants can have both negative and positive effects on native plants. The studied literature revealed that alien species can comprise large proportions of both internally and externally transported diaspores. Because animals have limited space for ingested and adhering diaspores, alien species affect both internal and external transport of native diaspores. Alien plant species also form large proportions of all dispersed diaspores in aquatic systems and interfere with dispersal of native aquatic plants. Alien interference can be either negative (e.g., through competition with native plants) or positive (e.g., increased abundance of native dispersers, changed disperser behavior or attracting additional disperser species). I propose many future research directions, because understanding whether alien plant species disrupt or facilitate animal-mediated dispersal of native plants is crucial for targeted conservation of invaded (aquatic) plant communities. PMID- 29487611 TI - Accumulation of N and P in the Legume Lespedeza davurica in Controlled Mixtures with the Grass Bothriochloa ischaemum under Varying Water and Fertilization Conditions. AB - Water and fertilizers affect the nitrogen (N) and phosphorus (P) acquisition and allocation among organs in dominant species in natural vegetation on the semiarid Loess Plateau. This study aimed to clarify the N and P accumulation and N:P ratio at organ and plant level of a local legume species mixed with a grass species under varying water and fertilizer supplies, and thus to fully understand the requirements and balance of nutrient elements in response to growth conditions change of native species. The N and P concentration in the organ (leaf, stem, and root) and plant level of Lespedeza davurica (C3 legume), were examined when intercropped with Bothriochloa ischaemum (C4 grass). The two species were grown outdoors in pots under 80, 60, and 40% of soil water field capacity (FC), -NP, +N, +P, and +NP supply and the grass:legume mixture ratios of 2:10, 4:8, 6:6, 8:4, 10:2, and 12:0. The three set of treatments were under a randomized complete block design. Intercropping with B. ischaemum did not affect N concentrations in leaf, stem and root of L. davurica, but reduced P concentration in each organ under P fertilization. Only leaf N concentration in L. davurica showed decreasing trend as soil water content decreased under all fertilization and mixture proportion treatments. Stems had the lowest, while roots had the highest N and P concentration. As the mixture proportion of L. davurica decreased under P fertilization, P concentration in leaf and root also decreased. The N concentration in L. davurica at the whole plant level was 11.1-17.2%. P fertilization improved P concentration, while decreased N:P ratio in L. davurica. The N:P ratios were less than 14.0 under +P and +NP treatments. Our results implied that exogenous N and P fertilizer application may change the N:P stoichiometry and influence the balance between nutrients and organs of native dominant species in natural grassland, and P element should be paid more attention when considering rehabilitating degraded grassland via fertilization application in semiarid Loess Plateau region. PMID- 29487612 TI - The Effect of Storage Condition and Duration on the Deterioration of Primed Rice Seeds. AB - Seed priming is a successful practice to improve crop establishment under adverse environment. However, reduced longevity of primed rice (Oryza sativa L.) seeds during storage limited the adoption of this technique. Present study investigated the effect of temperature, relative air humidity (RH) and oxygen on the longevity of primed rice seeds in a range of 60 days storage. In addition, the biochemical and morphological mechanisms associated with deterioration of primed seeds during storage were explored. Three types of priming treated rice seeds and one non primed control were stored under (1) low temperature-vacuum (LT-V), (2) room temperature-vacuum (RT-V), (3) room temperature-aerobic-low RH (RT-A-LH) and (4) room temperature-aerobic- high RH (RT-A-HH) for 0, 15, 30, 45, and 60 days. The results showed that storage of seeds under different conditions for 15-60 days did not influence the longevity of non-primed rice seeds. Meanwhile, the viability of primed rice seeds did not reduce when stored under LT-V, RT-V, and RT-A-LH, but was significantly reduced under RT-A-HH. Under vacuum condition, the increases of storage temperature (30 degrees C) did not reduce the longevity of primed seeds. Likewise, the oxygen did not influence the longevity of primed rice seeds stored under low RH. Nevertheless, increase of RH significantly reduced the viability of primed seeds stored for 15-60 days. Reduced starch metabolism, the consumption of starch reserves in rice endosperms, the accumulation of malondialdehyde and the decreases of antioxidant enzyme activities might be associated with the deterioration of primed rice seeds during storage. In conclusion, storage of primed seeds under high RH condition beyond 15 days is deteriorative for germination and growth of rice. The primed rice seeds are recommended to store at vacuum or low RH or low temperature condition to ensure good crop establishment. PMID- 29487610 TI - Different Modes of Gene Duplication Show Divergent Evolutionary Patterns and Contribute Differently to the Expansion of Gene Families Involved in Important Fruit Traits in Pear (Pyrus bretschneideri). AB - Pear is an important fruit crop of the Rosaceae family and has experienced two rounds of ancient whole-genome duplications (WGDs). However, whether different types of gene duplications evolved differently after duplication remains unclear in the pear genome. In this study, we identified the different modes of gene duplication in pear. Duplicate genes derived from WGD, tandem, proximal, retrotransposed, DNA-based transposed or dispersed duplications differ in genomic distribution, gene features, selection pressure, expression divergence, regulatory divergence and biological roles. Widespread sequence, expression and regulatory divergence have occurred between duplicate genes over the 30-45 million years of evolution after the recent genome duplication in pear. The retrotransposed genes show relatively higher expression and regulatory divergence than other gene duplication modes. In contrast, WGD genes underwent a slower sequence divergence and may be influenced by abundant gene conversion events. Moreover, the different classes of duplicate genes exhibited biased functional roles. We also investigated the evolution and expansion patterns of the gene families involved in sugar and organic acid metabolism pathways, which are closely related to the fruit quality and taste in pear. Single-gene duplications largely account for the extensive expansion of gene families involved in the sorbitol metabolism pathway in pear. Gene family expansion was also detected in the sucrose metabolism pathway and tricarboxylic acid cycle pathways. Thus, this study provides insights into the evolutionary fates of duplicated genes. PMID- 29487613 TI - Digital Twins in Health Care: Ethical Implications of an Emerging Engineering Paradigm. AB - Personalized medicine uses fine grained information on individual persons, to pinpoint deviations from the normal. 'Digital Twins' in engineering provide a conceptual framework to analyze these emerging data-driven health care practices, as well as their conceptual and ethical implications for therapy, preventative care and human enhancement. Digital Twins stand for a specific engineering paradigm, where individual physical artifacts are paired with digital models that dynamically reflects the status of those artifacts. When applied to persons, Digital Twins are an emerging technology that builds on in silico representations of an individual that dynamically reflect molecular status, physiological status and life style over time. We use Digital Twins as the hypothesis that one would be in the possession of very detailed bio-physical and lifestyle information of a person over time. This perspective redefines the concept of 'normality' or 'health,' as a set of patterns that are regular for a particular individual, against the backdrop of patterns observed in the population. This perspective also will impact what is considered therapy and what is enhancement, as can be illustrated with the cases of the 'asymptomatic ill' and life extension via anti aging medicine. These changes are the consequence of how meaning is derived, in case measurement data is available. Moral distinctions namely may be based on patterns found in these data and the meanings that are grafted on these patterns. Ethical and societal implications of Digital Twins are explored. Digital Twins imply a data-driven approach to health care. This approach has the potential to deliver significant societal benefits, and can function as a social equalizer, by allowing for effective equalizing enhancement interventions. It can as well though be a driver for inequality, given the fact that a Digital Twin might not be an accessible technology for everyone, and given the fact that patterns identified across a population of Digital Twins can lead to segmentation and discrimination. This duality calls for governance as this emerging technology matures, including measures that ensure transparency of data usage and derived benefits, and data privacy. PMID- 29487615 TI - Genetic Parameter Estimates for Metabolizing Two Common Pharmaceuticals in Swine. AB - In livestock, the regulation of drugs used to treat livestock has received increased attention and it is currently unknown how much of the phenotypic variation in drug metabolism is due to the genetics of an animal. Therefore, the objective of the study was to determine the amount of phenotypic variation in fenbendazole and flunixin meglumine drug metabolism due to genetics. The population consisted of crossbred female and castrated male nursery pigs (n = 198) that were sired by boars represented by four breeds. The animals were spread across nine batches. Drugs were administered intravenously and blood collected a minimum of 10 times over a 48 h period. Genetic parameters for the parent drug and metabolite concentration within each drug were estimated based on pharmacokinetics (PK) parameters or concentrations across time utilizing a random regression model. The PK parameters were estimated using a non-compartmental analysis. The PK model included fixed effects of sex and breed of sire along with random sire and batch effects. The random regression model utilized Legendre polynomials and included a fixed population concentration curve, sex, and breed of sire effects along with a random sire deviation from the population curve and batch effect. The sire effect included the intercept for all models except for the fenbendazole metabolite (i.e., intercept and slope). The mean heritability across PK parameters for the fenbendazole and flunixin meglumine parent drug (metabolite) was 0.15 (0.18) and 0.31 (0.40), respectively. For the parent drug (metabolite), the mean heritability across time was 0.27 (0.60) and 0.14 (0.44) for fenbendazole and flunixin meglumine, respectively. The errors surrounding the heritability estimates for the random regression model were smaller compared to estimates obtained from PK parameters. Across both the PK and plasma drug concentration across model, a moderate heritability was estimated. The model that utilized the plasma drug concentration across time resulted in estimates with a smaller standard error compared to models that utilized PK parameters. The current study found a low to moderate proportion of the phenotypic variation in metabolizing fenbendazole and flunixin meglumine that was explained by genetics in the current study. PMID- 29487614 TI - RNA-Seq Reveals Extensive Transcriptional Response to Heat Stress in the Stony Coral Galaxea fascicularis. AB - Galaxea fascicularis, a stony coral belonging to family Oculinidae, is widely distributed in Red Sea, the Gulf of Aden and large areas of the Indo-Pacific oceans. So far there is a lack of gene expression knowledge concerning this massive coral. In the present study, G. fascicularis was subjected to heat stress at 32.0 +/- 0.5 degrees C in the lab, we found that the density of symbiotic zooxanthellae decreased significantly; meanwhile apparent bleaching and tissue lysing were observed at 10 h and 18 h after heat stress. The transcriptome responses were investigated in the stony coral G. fascicularis during heat bleaching using RNA-seq. A total of 42,028 coral genes were assembled from over 439 million reads. Gene expressions were compared at 10 and 18 h after heat stress. The significantly upregulated genes found in the Control_10h vs. Heat_10h comparison, presented mainly in GO terms related with DNA integration and unfolded protein response; and for the Control_18h vs. Heat_18h comparison, the GO terms include DNA integration. In addition, comparison between groups of Control_10h vs. Heat_10h and Control_18h vs. Heat_18h revealed that 125 genes were significantly upregulated in common between the two groups, whereas 21 genes were significantly downregulated in common, all these differentially expressed genes were found to be involved in stress response, DNA integration and unfolded protein response. Taken together, our results suggest that high temperature could activate the stress response at the early stage, and subsequently induce the bleaching and lysing through DNA integration and unfolded protein response, which are able to disrupt the balance of coral-zooxanthella symbiosis in the stony coral G. fascicularis. PMID- 29487616 TI - Identification of Two Novel LAMA2 Mutations in a Chinese Patient with Congenital Muscular Dystrophy. AB - Merosin-deficient CMD type 1A (MDC1A), caused by mutations of laminin subunit alpha 2 (LAMA2), is a predominant subtype of congenital muscular dystrophy (CMD). Herein, we described a Chinese patient with MDC1A who was admitted to hospital 17 days after birth because of marasmus and feeding difficulties. Mutations were identified by targeted capture and next generation sequencing (NGS) and further confirmed by Sanger sequencing. Paternity was confirmed by short tandem repeat analysis. Physical examination showed malnutrition, poor suck and appendicular hypotonia. Her serum CK levels were 2483 and 1962 U/L at 2 and 4 months of age, respectively. Brain magnetic resonance imaging performed at 1 month of age presented hyperintensity on T2-weighted images, T1-weighted images in parietal and occipital lobes, and diffusion-weighted image (DWI) as well as hypointensity on fluid attenuated inversion recovery (FLAIR) image; however, the cerebellum and corpus arenaceum were normal. At 7 months of age, delayed developmental milestones were observed, and she failed to turn her body over and raise her head up. A point mutation (c.1782+2T > G) and a frameshift duplication (c.8217dupT) in the LAMA2 gene were identified by targeted capture and NGS and further confirmed by Sanger sequencing. Moreover, genotyping with multiple short tandem repeat markers confirmed paternity to demonstrate that the point mutation is de novo. The frameshift duplication (c.8217dupT), inherited from her mother, was predicted to cause a substitution of Pro (P) to Ser (S) at the 2740th amino-acid residue and generate a prematurely truncated protein. The in silico analysis suggests that the mutation (c.1782+2T > G) may lead to aberrant splicing of LAMA2. Our case further confirms the heterogeneous clinical spectrum of MDC1A and presents two novel LAMA2 mutations to expand the mutation spectrum of MDC1A. PMID- 29487618 TI - Chemical Composition and Porosity Characteristics of Various Calcium Silicate Based Endodontic Cements. AB - Chemical composition and porosity characteristics of calcium silicate-based endodontic cements are important determinants of their clinical performance. Therefore, the aim of this study was to investigate the chemical composition and porosity characteristics of various calcium silicate-based endodontic cements: MTA-angelus, Bioaggregate, Biodentine, Micromega MTA, Ortho MTA, and ProRoot MTA. The specific surface area, pore volume, and pore diameter were measured by the porosimetry analysis of N2 adsorption/desorption isotherms. Chemical composition and powder analysis by scanning electron microscope (SEM) and energy dispersive spectroscopy (EDS) were also carried out on these endodontic cements. Biodentine and MTA-angelus showed the smallest pore volume and pore diameter, respectively. Specific surface area was the largest in MTA-angelus. SEM and EDS analysis showed that Bioaggregate and Biodentine contained homogenous, round and small particles, which did not contain bismuth oxide. PMID- 29487617 TI - The Druggable Pocketome of Corynebacterium diphtheriae: A New Approach for in silico Putative Druggable Targets. AB - Diphtheria is an acute and highly infectious disease, previously regarded as endemic in nature but vaccine-preventable, is caused by Corynebacterium diphtheriae (Cd). In this work, we used an in silico approach along the 13 complete genome sequences of C. diphtheriae followed by a computational assessment of structural information of the binding sites to characterize the "pocketome druggability." To this end, we first computed the "modelome" (3D structures of a complete genome) of a randomly selected reference strain Cd NCTC13129; that had 13,763 open reading frames (ORFs) and resulted in 1,253 (~9%) structure models. The amino acid sequences of these modeled structures were compared with the remaining 12 genomes and consequently, 438 conserved protein sequences were obtained. The RCSB-PDB database was consulted to check the template structures for these conserved proteins and as a result, 401 adequate 3D models were obtained. We subsequently predicted the protein pockets for the obtained set of models and kept only the conserved pockets that had highly druggable (HD) values (137 across all strains). Later, an off-target host homology analyses was performed considering the human proteome using NCBI database. Furthermore, the gene essentiality analysis was carried out that gave a final set of 10-conserved targets possessing highly druggable protein pockets. To check the target identification robustness of the pipeline used in this work, we crosschecked the final target list with another in-house target identification approach for C. diphtheriae thereby obtaining three common targets, these were; hisE-phosphoribosyl-ATP pyrophosphatase, glpX-fructose 1,6-bisphosphatase II, and rpsH-30S ribosomal protein S8. Our predicted results suggest that the in silico approach used could potentially aid in experimental polypharmacological target determination in C. diphtheriae and other pathogens, thereby, might complement the existing and new drug-discovery pipelines. PMID- 29487619 TI - Deep Learning for Computer Vision: A Brief Review. AB - Over the last years deep learning methods have been shown to outperform previous state-of-the-art machine learning techniques in several fields, with computer vision being one of the most prominent cases. This review paper provides a brief overview of some of the most significant deep learning schemes used in computer vision problems, that is, Convolutional Neural Networks, Deep Boltzmann Machines and Deep Belief Networks, and Stacked Denoising Autoencoders. A brief account of their history, structure, advantages, and limitations is given, followed by a description of their applications in various computer vision tasks, such as object detection, face recognition, action and activity recognition, and human pose estimation. Finally, a brief overview is given of future directions in designing deep learning schemes for computer vision problems and the challenges involved therein. PMID- 29487620 TI - Retroperitoneal Lymph Node Dissection as Primary Treatment for Metastatic Seminoma. AB - Reducing the long-term morbidity in testicular cancer survivors represents a major area of interest. External beam radiation therapy and systemic chemotherapy are established treatments for seminoma; however, they are associated with late toxicities such as cardiovascular disease, insulin resistance, and secondary malignancy. Retroperitoneal lymph node dissection (RPLND) is a standard treatment for nonseminomatous germ cell tumors (NSGCT) that has minimal long-term morbidity. Given the efficacy of RPLND in management of NSGCT, interest has developed in this surgery as a front-line treatment for seminoma with isolated lymph node metastasis to the retroperitoneum. Four retrospective studies have shown promising results when surgery is performed for seminomas with low-volume retroperitoneal metastases. To better determine if RPLND can be recommended as a primary treatment option, two prospective clinical trials (SEMS and PRIMETEST) are underway. This review will examine the literature, discuss the benefits/limitations of RPLND, and compare the methodologies of the two ongoing clinical trials. PMID- 29487621 TI - A Green and Efficient Method for the Preconcentration and Determination of Gallic Acid, Bergenin, Quercitrin, and Embelin from Ardisia japonica Using Nononic Surfactant Genapol X-080 as the Extraction Solvent. AB - A simple cloud point preconcentration method was developed and validated for the determination of gallic acid, bergenin, quercitrin, and embelin in Ardisia japonica by high-performance liquid chromatography (HPLC) using ultrasonic assisted micellar extraction. Nonionic surfactant Genapol X-080 was selected as the extraction solvent. The effects of various experimental conditions such as the type and concentration of surfactant and salt, temperature, and solution pH on the extraction of these components were studied to optimize the conditions of Ardisia japonica. The solution was incubated in a thermostatic water bath at 60 degrees C for 10 min, and 35% NaH2PO4 (w/v) was added to the solution to promote the phase separation and increase the preconcentration factor. The intraday and interday precision (RSD) were both below 5.0% and the limits of detection (LOD) for the analytes were between 10 and 20 ng.mL-1. The proposed method provides a simple, efficient, and organic solvent-free method to analyze gallic acid, bergenin, quercitrin, and embelin for the quality control of Ardisia japonica. PMID- 29487622 TI - Multivariate Analysis of Fruit Antioxidant Activities of Blackberry Treated with 1-Methylcyclopropene or Vacuum Precooling. AB - Effects of 1-methylcyclopropene (1-MCP) and vacuum precooling on quality and antioxidant properties of blackberries (Rubus spp.) were evaluated using one-way analysis of variance, principal component analysis (PCA), partial least squares (PLS), and path analysis. Results showed that the activities of antioxidant enzymes were enhanced by both 1-MCP treatment and vacuum precooling. PCA could discriminate 1-MCP treated fruit and the vacuum precooled fruit and showed that the radical-scavenging activities in vacuum precooled fruit were higher than those in 1-MCP treated fruit. The scores of PCA showed that H2O2 content was the most important variables of blackberry fruit. PLSR results showed that peroxidase (POD) activity negatively correlated with H2O2 content. The results of path coefficient analysis indicated that glutathione (GSH) also had an indirect effect on H2O2 content. PMID- 29487623 TI - Age and Unplanned Postoperative Visits Predict Outcome after Septoplasty: A National Swedish Register Study. AB - Objective: To study predictors of symptom relief six months after septoplasty using data from the Swedish National Septoplasty Register. Participants: This is a retrospective register study of adult patients undergoing septoplasty in Sweden in 2003-2012. Outcome: Relief of nasal symptoms was analysed in relation to age, gender, size of hospital performing the surgery, addition of turbinoplasty, and unplanned postoperative visits to the hospital due to pain, bleeding, or infection. Results: In all, 76% of the patients (n = 5,865) rated their symptoms as "almost gone" or "gone" six months after septoplasty. With every 10-year increase in the age of the patients, the OR was 1.19, 95% CI 1.15-1.23, for a better result and 1.54, 95% CI 1.38-1.71, if the septoplasty was performed at a county hospital versus a university hospital. If there was no unplanned postoperative visit due to pain, bleeding, or infection, the OR for a better result was 1.6, 95% CI 1.39-1.85. Conclusion: In this large national cohort of septoplasties, most of the patients felt that their symptoms had gone or almost gone six months after septoplasty. Higher age, surgery at smaller hospitals, and no unplanned visits to the hospital postoperatively predicted a better outcome. PMID- 29487624 TI - Patient Satisfaction and Associated Factors among Clients Admitted to Obstetrics and Gynecology Wards of Public Hospitals in Mekelle Town, Ethiopia: An Institution-Based Cross-Sectional Study. AB - Background: To improve the quality of services, satisfying patients is the primary goal of the Ethiopian reform programme. Objectives: To assess patient satisfaction and associated factors among clients admitted to obstetrics and gynecology wards of public hospitals in Mekelle town. Method: Institution-based cross-sectional study design was conducted on 413 participants using systematic sampling methods. Data were collected from March 9 to May 8, 2016, using structured questionnaires. Data were entered and cleaned in Epidata 3.1 and analysed using SPSS V20 with binary logistic regression model. Result. The observed satisfaction rate was 79.7% at 95% CI (75.8%, 83.6%). Clients were dissatisfied towards well-describing side effects of medication, informing what the medication is used for before prescribing and administering, cleanness of toilet and washroom, and access to drinking water, latrine, and hand-washing facility. Respondents live in rural area, stayed < 4 days, admitted for the first time, admitted in Mekelle General Hospital, and who reported their feeling on ways privacy was assured were more likely satisfied than their counterparts. Conclusions: The observed satisfaction rate is high. So, policymakers, Regional Health Bureau, hospital managers, caregivers, and researchers should plan and work together to keep track of patient satisfaction. Areas patients are dissatisfied should also improve. PMID- 29487625 TI - Laparoscopic Management of Adhesions Developed after Peritoneal Nonclosure in Primary Cesarean Section Delivery. AB - Objective: The aim of the current study was to laparoscopically investigate the effects of peritoneal nonclosure on the sites, types, and degrees of adhesions developed after primary caesarean section (CS) in women complaining of secondary infertility after first CS delivery. Study Design: This was a cross-sectional study, where 250 women suffering from secondary infertility after their first CS had been recruited. They had been classified into group I (n = 89), where both the visceral and parietal peritoneum had been left opened; group II (n = 75), where only the parietal peritoneum had been closed; and group III (n = 86), where both peritoneal layers had been closed. Laparoscopy had been used to classify those adhesions according to the location, severity, and their adverse impact on the reproductive capacity. Results: Both adnexal and nonadnexal adhesions had been found significantly higher in group I, while adnexal types of adhesions were significantly higher after nonclosure of the visceral peritoneum in group II. Laparoscopic tubal surgery performed included tubo-ovariolysis, fimbrioplasty, and neosalpingostomy. Pregnancy rate was found correlating with the adnexal adhesion location and score. Conclusion: Nonclosure of the peritoneum in CS is associated with more adhesion formation, which might adversely affect the future women reproduction. PMID- 29487626 TI - Geometric Modeling of Cellular Materials for Additive Manufacturing in Biomedical Field: A Review. AB - Advances in additive manufacturing technologies facilitate the fabrication of cellular materials that have tailored functional characteristics. The application of solid freeform fabrication techniques is especially exploited in designing scaffolds for tissue engineering. In this review, firstly, a classification of cellular materials from a geometric point of view is proposed; then, the main approaches on geometric modeling of cellular materials are discussed. Finally, an investigation on porous scaffolds fabricated by additive manufacturing technologies is pointed out. Perspectives in geometric modeling of scaffolds for tissue engineering are also proposed. PMID- 29487627 TI - The role of early colonoscopy in patients presenting with acute lower gastrointestinal bleeding: a systematic review and meta-analysis. AB - Objective: The use of early colonoscopy in the management of acute lower gastrointestinal bleeding (LGIB) is controversial, with disparate evidence. We aim to formally characterize the utility of early colonoscopy (within 24 h) in managing acute LGIB. Design: A systematic literature search to August 2016 identified fully published and abstracts of randomized controlled trials (RCTs) and observational studies assessing early colonoscopy in acute LGIB. Single-arm studies were also included to define incidence. Primary outcomes were overall rebleeding rates and time to rebleeding. Secondary outcomes included mortality, surgery, length of stay (LOS), definite cause of bleeding and adverse events (AEs). Odds ratios (OR) and weighted mean differences (WMD) were calculated. Results: Of 897 citations, 10 single-arm, 9 observational studies, and 2 RCTS were included (25,781 patients). Rebleeding was no different between patients undergoing early colonoscopy and controls (seven studies, OR = 0.89, 95% CI 0.49 1.62), or RCT data only (OR = 1.00, 95% CI 0.52-1.62). Early colonoscopy detected more definitive sources of bleeding (OR = 4.12, 95% CI 2.00-8.49), and was associated with shorter LOS colonoscopy (WMD = -1.52, 95% CI -2.54 to -0.50 days). No other differences were noted between early and late colonoscopy. AEs occurred in 4.0%, (95% CI 2.9%; 5.4%) of early colonoscopies. Included studies were of low quality, with significant heterogeneity for some outcomes. Conclusion: Early colonoscopy in acute LGIB does not decrease rebleeding, mortality or need for surgery, but is associated with increased detection of definitive sources of bleeding, shorter LOS, with low complication incidence. However, the quality of evidence is low, highlighting the need for additional high-level studies. PMID- 29487628 TI - Low serum zinc levels predict presence of depression symptoms, but not overall disease outcome, regardless of ATG16L1 genotype in Crohn's disease patients. AB - Background: Zinc deficiency (ZD) in Crohn's disease (CD) is considered a frequent finding and may exacerbate CD activity. ZD is associated with depression in non CD patients. We aimed to assess the prevalence of ZD in CD patients in clinical remission, its association with mood disturbances and to analyze a potential impact on future disease course. Methods: Zinc levels from CD patients in clinical remission at baseline and an uncomplicated disease course within the next 3 years (n = 47) were compared with those from patients developing complications (n = 50). Baseline symptoms of depression and anxiety were measured with the Hospital Anxiety and Depression scale. Results: Mean zinc level in the 97 patients (40.4 +/- 15.7 years, 44.3% males) was 18.0 +/- 4.7 MUmol/l. While no ZD (<11 MUmol/l) was observed, we found low zinc levels (<15.1 MUmol/l) in 28 patients (28.9%). Males had higher zinc levels compared with females (19.4 +/- 5.7 versus 16.8 +/- 3.3, p = 0.006). Patients with low zinc levels more often reported depression symptoms compared with patients with higher levels (27.3 versus 9.4%, p = 0.047). In a multivariate analysis, zinc levels were an independent negative predictor for depression symptoms [odds ratio (OR) 0.727, 95% confidence interval (CI) 0.532-0.993, p = 0.045]. Zinc levels of patients with a complicated disease course were not different from those of patients without (17.7 +/- 4.3 versus 18.3 +/- 5.1, n.s.). Baseline zinc levels did not predict disease outcome regardless of ATG16L1 genotype. Conclusion: Low-normal zinc levels were an independent predictor for the presence of depression symptoms in CD patients. Zinc levels at baseline did not predict a complicated disease course, neither in CD patients overall, nor ATG16L1T300A carriers. PMID- 29487629 TI - Portable Ultraviolet Light Surface-Disinfecting Devices for Prevention of Hospital-Acquired Infections: A Health Technology Assessment. AB - Background: Hospital-acquired infections (HAIs) are infections that patients contract while in the hospital that were neither present nor developing at the time of admission. In Canada an estimated 10% of adults with short-term hospitalization have HAIs. According to 2003 Canadian data, between 4% and 6% of these patients die from these infections. The most common HAIs in Ontario are caused by Clostridium difficile. The standard method of reducing and preventing these infections is decontamination of patient rooms through manual cleaning and disinfection. Several portable no-touch ultraviolet (UV) light systems have been proposed to supplement current hospital cleaning and disinfecting practices. Methods: We searched for studies published from inception of UV disinfection technology to January 23, 2017. We compared portable UV surface-disinfecting devices used together with standard hospital room cleaning and disinfecting versus standard hospital cleaning and disinfecting alone. The primary outcome was HAI from C. difficile. Other outcomes were combined HAIs, colonization (i.e., carrying an infectious agent without exhibiting disease symptoms), and the HAI associated mortality rate. We used Grading of Recommendations Assessment, Development, and Evaluation (GRADE) to rate the quality of evidence of included studies. We also performed a 5-year budget impact analysis from the hospital's perspective. This assessment was limited to portable devices and did not examine wall mounted devices, which are used in some hospitals. Results: The database search for the clinical review yielded 10 peer-reviewed publications that met eligibility criteria. Three studies focused on mercury UV-C-based technology, seven on pulsed xenon UV technology. Findings were either inconsistent or produced very low-quality evidence using the GRADE rating system. The intervention was effective in reducing the rate of the composite outcome of HAIs (combined) and colonization (but quality of evidence was low). For the review of economic studies, 152 peer-reviewed publications were identified and screened. No studies met the inclusion criteria. Under the assumption that two devices would be purchased per hospital, we estimated the 5-year budget impact of $586,023 for devices that use the pulsed xenon technology and of $634,255 for devices that use the mercury technology. Conclusions: We are unable to make a firm conclusion about the effectiveness of this technology on HAIs given the very low to low quality of evidence. The budget impact estimates are sensitive to assumptions made about the number of UV disinfecting devices purchased per hospital, frequency of daytime use, and staff time required per use. PMID- 29487630 TI - Fibromatosis of the breast mimicking cancer: A case report. AB - Breast fibromatosis, also referred to as desmoid tumor or aggressive fibromatosis, is a very rare, locally aggressive disease that does not metastasize. Bilateral lesions are extremely rare and are found in only 4% of patients with breast fibromatosis. Tumor recurrence following surgery occurs in 18%-29% of patients, most often within the first 2 years after surgery. In this report, we discuss a case of breast fibromatosis, mimicking a breast carcinoma both clinically and radiologically, that presented clinically with dimpling of the skin of the left breast in a 31-year-old woman. The patient relapsed a few months after surgery, with a multicentric and bilateral disease. PMID- 29487631 TI - Diagnosis and imaging characteristics of a juvenile fibroadenoma in a 2-year-old patient: a case report. AB - Fibroadenomas are abundantly reported in the literature with several papers documenting the natural progression and clinical outcomes of thousands of cases. Juvenile fibroadenomas (also called cellular fibroadenomas) are frequently characterized by rapid growth, often described as 5-10 cm in size. They constitute approximately 7%-8% of fibroadenomas. They often measure greater than 5 cm. Pathologically, they show similar features to fibroadenomas but can resemble phyllodes. There have been few documented cases of breast masses in early childhood. Furthermore, there are scant radiology publications focused on the imaging features of juvenile fibroadenomas in patients younger than 5 years old. Our patient presented at 2 years of age with a unilateral right breast mass. Two ultrasound examinations were completed over a period of 5 months, and a magnetic resonance imaging was performed prior to surgical intervention. Eventual surgical excision yielded a final pathologic diagnosis of juvenile fibroadenoma. In this report, we will discuss the imaging and pathology of juvenile fibroadenomas, and we will address important differential considerations both from a pathologic and radiologic standpoint. PMID- 29487632 TI - Right upper pulmonary vein metastasis from hepatocarcinoma. AB - Metastatic tumor involvement of the heart is uncommon but may occur with all types of primary neoplasms. We report the case of a 51-year-old male who developed a massive mass involving the upper right pulmonary vein. The tumor was removed and the final pathology report disclosed metastatic hepatocellular carcinoma. Hepatocellular carcinoma affecting the pulmonary veins is a very rare condition. PMID- 29487633 TI - Case report: Pulmonary sequestration in an adult. AB - Pulmonary sequestration is a rare congenital malformation that is uncommonly diagnosed during adulthood. Pulmonary sequestrations can manifest with variable presentations. It can remain asymptomatic or present with more severe symptoms such as hemoptysis and recurrent pneumonia. Diagnosis can be confirmed with computed tomography angiogram or angiography. Treatment with embolization of the afferent artery and surgical removal of the pulmonary sequestration generally has good outcomes. We report a case of a 43-year-old man who presented with recurrent pneumonia and left-sided back pain and was eventually diagnosed with pulmonary sequestration. PMID- 29487634 TI - Massive hemoptysis due to multiple bronchial artery aneurysms and multiple aneurysmal dilations: A case report. AB - Bronchial artery aneurysm (BAA) is a rare but potentially life-threatening clinical entity. Patients with multiple BAAs and multiple aneurysmal dilations are even rarer. In this case report, we will investigate a case of multiple BAAs and multiple aneurysmal dilations arising from 2 right bronchial artery branches presenting with hemoptysis. The patient was successfully treated with transcatheter arterial embolization. We should be vigilant for the possibility of BAA when encountering patients presenting with hemoptysis. Transcatheter arterial embolization is safe and effective to solve this condition. PMID- 29487635 TI - Hypoplastic superficial femoral artery combined with connection of the deep femoral artery to the popliteal artery. AB - The most common anatomical variation of the superficial femoral artery (SFA) is hypoplasia or aplasia associated with a persistent sciatic artery. We report a case exhibiting SFA hypoplasia combined with connection of the deep femoral artery (DFA) to the popliteal artery (in other words, the DFA became the popliteal artery). A 41-year-old man was admitted with a crush injury of the left foot. Computed tomography angiography revealed an SFA branched off the anteromedial side of the common femoral artery and exhibited severe hypoplasia and the DFA branched off the posterolateral side of the CFA and continued to become the popliteal artery. PMID- 29487636 TI - Ceftriaxone-associated pancreatitis captured on serial computed tomography scans. AB - A 74-year-old man was treated with ceftriaxone for 5 days and subsequently experienced epigastric pain. Computed tomography (CT) was performed 7 and 3 days before epigastralgia. Although the first CT image revealed no radiographic signs in his biliary system, the second CT image revealed dense radiopaque material in the gallbladder lumen. The third CT image, taken at symptom onset, showed high density in the common bile duct and enlargement of the pancreatic head. This is a very rare case of pseudolithiasis involving the common bile duct, as captured on a series of CT images. PMID- 29487637 TI - Hibernoma in the clavicular fossa: A case report and literature review. AB - A hibernoma is a benign soft tissue tumor consisting of brown adipose tissue. The tumors are mostly located in the thigh, back, and shoulder region. They are rarely found in the supraclavicular fossa. We report a 39-year-old woman who presented with a painless, slow-growing mass on the left supraclavicular fossa for nearly 15 years. Magnetic resonance imaging (MRI) showed an inhomogeneous round mass with a slightly hyperintense signal on fat-suppression T2-weighted imaging that compressed the adjacent tissues and subclavian vessels. Computed tomography angiography indicated a rich blood flow signal. Postoperative histology confirmed the diagnosis of a hibernating tumor. Although comprehensive imaging is important in the determination of tumor for the size, location, and nature, computed tomography angiography provides clear indication of the vascularity of the tumor, which provides vital clinicopathologic data for surgeons. PMID- 29487638 TI - Complicated jejunal diverticulitis with unusual presentation. AB - Jejunal diverticulosis is usually an asymptomatic condition characterized by herniation of mucosa through sites of weakening on the mesenteric border of the jejunum, leading to variable number of discrete outpouchings from the bowel. They are usually discovered incidentally on imaging or surgery done for some other reason. Complications such as diverticulitis with perforation and bowel obstruction and life-threatening gastrointestinal bleeding are rare. Our review highlights the correlation between radiological and surgical findings in 2 different cases of complicated jejunal diverticulitis. Both of the cases were successfully managed surgically. PMID- 29487639 TI - Complete dorsal pancreatic agenesis and unilateral renal agenesis. AB - Dorsal pancreatic agenesis is a very rare congenital anomaly. Unilateral renal agenesis, on the other hand, is a relatively common congenital anomaly, although its etiology is not fully understood. Renal and pancreatic embryologic development appears to be nonrelated. We report a case of a 34-year-old man who was referred to our hospital for evaluation of cholestasis and microalbuminuria. Ultrasound and magnetic resonance imaging examinations showed empty right renal fossa and absence of the pancreatic neck, body, and tail. Our case report is the second case of a dorsal pancreatic agenesis and unilateral renal agenesis in a young male patient. PMID- 29487640 TI - Pancreatocolonic fistulization secondary to pancreatic adenocarcinoma presenting as unexplained halitosis. AB - Pancreatic cancer is often detected in late stages, which contributes to its grim prognosis. Although the manifestations of pancreatic cancer most often include nonspecific gastrointestinal complaints, we report a case with the sole initial complaint of halitosis and subsequent diagnostic workup demonstrating a pancreatic mass with secondary pancreatocolonic fistulization. The etiologies of and the radiological findings pertaining to halitosis, the presenting symptoms and imaging studies relevant to the diagnosis of pancreatic cancer, and the imaging and clinical findings of pancreatic fistulization are discussed. PMID- 29487641 TI - Laparoscopic adjustable gastric band erosion with intragastric band migration: A rare but serious complication. AB - Although laparoscopic adjustable gastric banding is considered the most minimally invasive surgical technique for the treatment of morbid obesity, the procedure has a reported overall complication rate of up to 26%. Among the various complications, gastric band erosion with intragastric band migration is the most worrisome because of the risk of subsequent obstruction, peritonitis, and sepsis. Therefore, prompt and accurate diagnosis is crucial during imaging evaluation of these patients in the late postoperative setting. In this article, we report a case of a 47-year-old woman with a gastric band that had eroded into the gastric wall with intragastric migration demonstrating classic findings on fluoroscopic and computed tomography imaging. PMID- 29487642 TI - MRI of acquired Brown syndrome: a report of two cases. AB - Brown syndrome is characterized by upward gaze impairment while the eye is in adduction. It is caused by abnormalities involving the superior oblique tendon trochlea complex. Imaging can help confirm the diagnosis, shed light on its etiology, and determine the best course of treatment. However, reports of magnetic resonance imaging findings of acquired Brown syndrome are scarce in the literature. Here, we describe magnetic resonance imaging features of 2 cases of acquired Brown syndrome. PMID- 29487643 TI - C2 segmental type of vertebral artery on the unfused side of partially occipitalized atlas. AB - Patients with craniovertebral junction anomalies are more likely to undergo craniovertebral junction procedures because of neurologic complications. Vertebral arteries (VAs) are more prone to injury in these cases because of an often anomalous course, with potentially disabling or grave sequel. In our patient with partially occipitalized atlas, CT angiogram revealed that 1 of the VAs passed through the bony canal in the occipitalized and/or fused bone, whereas the VA on unfused side was also unexpectedly anomalous and of C2 segmental type. To the best of our knowledge, such anomaly has never been reported in studies of patients with occipitalized atlas in the literature. PMID- 29487644 TI - Case report: Diffuse metastatic infiltration of the thyroid by esophageal adenocarcinoma mimicking non-neoplastic thyroid disease. AB - We report a patient who suffered from esophageal cancer that metastasized to the thyroid. There are only a handful of cases of esophageal cancer with metastases to the thyroid reported in the literature. To our knowledge, this is the first with a diffusely infiltrative pattern (the others were focal masses/nodules). This diffusely infiltrative pattern of metastatic disease is important for radiologists to be aware of because it is particularly difficult to detect and is not characteristically neoplastic by pattern. A diffuse parenchymal abnormality that is bilaterally symmetric is more commonly associated with non-neoplastic diffuse thyroid disease, such as autoimmune thyroid diseases (eg, Graves' disease). As such, in addition to the more common non-neoplastic differential diagnoses associated with diffuse thyroid disease, a diffuse thyroid parenchymal abnormality in a patient with a history of esophageal carcinoma should raise the question of diffuse metastatic infiltration. PMID- 29487645 TI - Bilateral coronoid hyperplasia causing painless limitation of mandibular movement. AB - The coronoid process is a beaklike process in the ramus of the mandible. Coronoid process hyperplasia (CPH) is a rare possible cause of reduced mouth opening. An overgrown process interferes with mandibular rotation and lateral excursion and hence leads to restricted mouth opening (RMO). Although some factors are suggested, etiology of CPH is not completely known. Prescription of suitable radiography is necessary for an accurate diagnosis. This article reports a 30 year-old man with bilateral CPH and progressive RMO since childhood. This disorder affected his oral hygiene and quality of life. With the help of different types of radiography, CPH was diagnosed and coronoidectomy was the only treatment option. The patient showed normal jaw movements after the surgery and postoperative physiotherapy. General dentists have an important role in noticing RMO and referring the patients to maxillofacial radiologists. Although it is a rare phenomenon, general dentists need to keep CPH in mind as a possible cause. Panoramic imaging accompanied by computed tomography or cone beam computed tomography is the best imaging option in such cases. PMID- 29487646 TI - Multiple unerupted and supernumerary teeth in a patient with cleidocranial dysplasia. AB - Cleidocranial dysplasia is an extremely rare familial disorder characterized by partial or complete absence of clavicles, characteristic craniofacial deformities, and the presence of numerous supernumerary and unerupted teeth. Here, the author reviews the striking radiographic findings of cleidocranial dysplasia in a 16-year-old adolescent boy who presented with delayed teeth eruption. PMID- 29487648 TI - Application of cone-beam computed tomography angiography in a uterine fibroid embolization procedure: A case report. AB - One of the main causes of failure in uterine fibroid embolization procedures is incomplete infarction of the fibroid due to alternate vascular supply to the fibroid which was not identified by the operator. Cone-beam computed tomography angiography was used in this case to avoid nontarget embolization via a uterine artery, as well as identify incomplete embolization of the fibroid. This prompted a search for variant vascular supply to the fibroid, which was found to be originating from the right ovarian artery. Therefore, the use of cone-beam computed tomography angiography led to a successful outcome, which otherwise may not have been achieved. PMID- 29487647 TI - Balloon occlusion technique with ethylene vinyl alcohol for the treatment of a pediatric pulmonary artery mycotic aneurysm. AB - Mycotic aneurysms, which may occur anywhere in the body, may be prone to spontaneous rupture. Antibiotic therapy combined with surgical debridement without or with revascularization has been described as potential treatment options. This report describes a combined balloon occlusion technique with the injection of ethylene-vinyl alcohol copolymer for the treatment of a mycotic aneurysm of the pulmonary artery secondary to infective endocarditis. Similar techniques have been described in the cerebral circulation and may obviate concerns for coil erosion, non-target embolization, or superinfection. PMID- 29487649 TI - Anomalous adrenal vein anatomy complicating the evaluation of primary hyperaldosteronism. AB - Adrenal vein development in utero occurs concurrently with the development of the inferior vena cava, the renal veins, and the gonadal veins. The embryologic formation of these veins involves communication of various venous systems. Although the left adrenal-renal vein complex is most commonly described as a shared emptying of the left adrenal vein and the left inferior phrenic vein into the left renal vein, there have been reports of numerous anatomic variations of this complex. In this report, we present a case of a rare variant of the left adrenal vein, in which the left adrenal vein empties into the left gonadal vein, which takes an atypical course superolateral to the left kidney. PMID- 29487650 TI - Ekosonic Endovascular System (EKOS) in a trauma patient with intracranial bleed, recent major surgery, and massive pulmonary embolus: A case report. AB - Pulmonary embolism is a life-threatening condition treated with anticoagulation and systemic thrombolysis when appropriate. In patients with contraindications to thrombolysis, catheter-directed thrombolysis may be considered. Here, we present a patient with massive pulmonary embolus and 3 contraindications to systemic thrombolysis who was successfully treated with pharmacomechanical thrombolysis using the Ekosonic Endovascular System. PMID- 29487651 TI - Nutcracker syndrome in adolescent with perineal pain: An interesting case of an adolescent with perineal pain due to pelvic congestion from nutcracker syndrome with relief after balloon venoplasty and sclerotherapy. AB - Nutcracker phenomenon is the descriptor for a patient's anatomy whenever the left renal vein becomes compressed between the abdominal aorta and the superior mesenteric artery. Nutcracker syndrome is the terminology used when the nutcracker phenomenon is accompanied by symptoms including pain (abdominal, flank, pelvic), hematuria, and orthostatic proteinuria. Diagnosis can be made with Doppler ultrasound, venography, computed tomography, or magnetic resonance imaging. This case demonstrates some of the typical findings of nutcracker syndrome. The limited clinical features and interesting imaging findings, in addition to the young age of the patient, make this a notable case. PMID- 29487652 TI - Percutaneous rendezvous technique for the management of a bile duct injury. AB - The rendezvous technique typically involves combined efforts of interventional radiology, endoscopy, and surgery. It can be done solely percutaneously, whereby the interventionalist gains desired access to one point in the body by approaching it from two different access sites. We present the case of a woman who underwent cholecystectomy complicated by a bile duct injury. A percutaneous rendezvous procedure enabled placement of an internal-external drain from the intrahepatic ducts through the biloma and distal common bile duct and into the duodenum. Thus, a percutaneous rendezvous technique is feasible for managing a bile duct injury when endoscopic retrograde cholangio-pancreatography or percutaneous transhepatic cholangiogram alone has been unsuccessful. PMID- 29487653 TI - Ultrasound-guided percutaneous periarterial thrombin injection for paracentesis related hemoperitoneum. AB - Paracentesis is a common procedure used in the diagnostic evaluation of peritoneal fluid as well as the therapeutic removal of high-volume ascites. Although generally regarded as a safe procedure, complications may arise from arterial injury, including hematomas and pseudoaneurysms. Transcatheter embolization and surgery are first-line interventions for injuries refractory to conservative management. We present a case where a patient failed conventional therapies for hemoperitoneum following a paracentesis which resolved after thrombin injection into the subcutaneous tissues, a novel use for thrombin. Using a linear 12-3 MHz transducer, approximately 3000-3500 U of thrombin was injected through connecting tubing and a 25-gauge needle by the interventional radiologist into the subcutaneous tissues around the origin of the arterial hemorrhage. The bleeding ceased and the patient's hemoglobin and hemodynamics stabilized. PMID- 29487654 TI - Successful carotid thrombus aspiration, middle cerebral mechanical thrombectomy, and axillary artery clot disruption attempt in a patient with acute ischemic stroke and critical upper limb ischemia. AB - Acute thrombotic occlusions of the large vessels, such as internal carotid artery, arms and legs arteries, and intracranial vessels, frequently require multiple techniques such as selective thrombolysis, manual aspiration, and stent retrievers for mechanical thrombectomy with combination of the mentioned techniques. Because of the massive thrombotic burden associated with these conditions, the response to systemic intravenous thrombolysis is poor. We present a case of a successful massive thrombi aspiration in a single attempt using an 8Fr guide catheter with aspiration syringe, subsequent ipsilateral middle cerebral artery mechanical thrombectomy, and axillary artery clot disruption attempt in a patient with acute ischemic stroke, right arm critical ischemia, and persistent atrial fibrillation. PMID- 29487655 TI - Hindgut gastropancreatic neuroendocrine carcinoma mimicking hydatid disease. AB - Primary neuroendocrine tumors of the colon are usually very rare and difficult to spot on a nonfunctional imaging. Metastatic lesions are mostly hypervascular, with only a small percentage appearing as cystic or hypovascular lesions. We present a case of a 34-year-old Hispanic female with a history of dull aching upper abdominal pain lasting for a few months. Initial abdominal ultrasound revealed multiple cystic lesions replacing the hepatic parenchyma concerning for a hydatid disease. Liver biopsy was obtained due to negative serology for hydatid disease, which surprisingly revealed a metastatic neuroendocrine tumor of unknown etiology. The primary disease was depicted within the sigmoid colon on a whole body Octreotide single-photon emission computed tomography-computed tomography done following the biopsy. PMID- 29487656 TI - Talar insufficiency fracture complicating ankle cheilectomy. AB - Ankle cheilectomy as surgical treatment for anterior ankle impingement has high rates of procedural success and low rates of complications when performed before the onset of significant osteoarthritis. We present 3 patients who developed insufficiency fractures of the talar neck following cheilectomy for anterior ankle impingement. Due to the high risk of avascular necrosis associated with displaced talar neck fractures, the recognition of talar insufficiency fractures by the radiologist can aid in the timely diagnosis and initiation of intervention. Because radiographic findings of stress fractures often require weeks to manifest, maintaining a high index of suspicion in the postcheilectomy setting allows the radiologist to suggest appropriate further imaging when appropriate. PMID- 29487657 TI - Post-traumatic osteochondroma of the distal femur. AB - Osteochondroma are the most common benign primary bone tumor. They are bony outgrowths surrounded by a characteristic cartilaginous cap, most commonly arising from the long bones. They are most often asymptomatic, usually discovered as incidental findings before the third or fourth decade of life. Although the exact pathogenesis is not fully established, there have been reports of these tumors arising after incidents such as fractures, trauma, radiation, and stem cell transplants. There have been only a few cases describing the development of osteochondroma after traumatic events. This report presents a documented case of an osteochondroma arising at the site of a previous femoral fracture, 10 years after the initial trauma. PMID- 29487658 TI - Compartment syndrome of the hand: A case report and review of literature. AB - Elevation of pressure within tightly bound myofascial compartments has detrimental consequences if not treated promptly, leading to a loss of circulation, ischemia, myonecrosis, nerve damage, and limb loss. They are commonly seen in the distal upper and lower extremities; however, compartment syndrome of the hand is rarely encountered and prompt recognition can prevent permanent damage and tissue loss. This case study presents a complicated case of compartment syndrome of the hand and discusses the interrelationship between compartment syndrome and rhabdomyolysis. An emphasis is placed on pathophysiology of this relationship to allow a better understanding of the imaging features as well as early clinical recognition of compartment syndrome. Magnetic resonance imaging findings are specifically discussed as it remains the best imaging tool to evaluate the extent of the damage and surgical planning. PMID- 29487659 TI - Progressive retraction of a fractured os peroneum suggesting repetitive injury to the peroneus longus tendon. AB - The os peroneum is an accessory ossicle within the peroneus longus tendon. Prior reports have discussed fracture of the os peroneum with associated tears of the peroneus longus tendon. When the ossicle fractures, there can be varying degrees of retraction of the tendon, which can be diagnosed by malposition of the ossicle or the ossicle fragments. We report a case of a man with recurrent eversion ankle injuries with progressive retraction of a fractured os peroneum, implying injuries to the superior and inferior peroneal retinacula and the peroneus longus tendon. PMID- 29487660 TI - Apparent diffusion coefficient and arterial spin labeling perfusion of conventional chondrosarcoma in the parafalcine region: a case report. AB - Intracranial chondrosarcoma is a very rare malignant tumor of the central nervous system, and is difficult to preoperatively distinguish from other tumors using conventional imaging techniques. Here, we report the case of a 24-year-old woman who presented with mild headache due to chondrosarcoma in the frontal lobe. Preoperative conventional images showed findings typical of an oligodendroglial tumor. However, high apparent diffusion coefficient (ADC) value and extreme hypoperfusion on arterial spin labeling (ASL) were inconsistent with oligodendroglial tumor characteristics. The tumor was completely removed using a standard surgical procedure. Histologic diagnosis was a conventional (classic) chondrosarcoma. High ADC and hypoperfusion on ASL represented low cellularity and low vascularity within conventional chondrosarcoma, respectively. We discuss the utility of ADC and ASL for the preoperative diagnosis of conventional chondrosarcoma. PMID- 29487661 TI - Tension pneumocephalus mimicking septic shock: a case report. AB - Tension pneumocephalus can lead to rapid neurologic deterioration. We report for the first time its association with aseptic systemic inflammatory response syndrome mimicking septic shock and the efficacy of prompt neurosurgical intervention and critical care support in treating this condition. A 64-year-old man underwent 2-stage olfactory groove meningioma resection. The patient developed altered mental status and gait instability on postoperative day 6. Imaging showed significant pneumocephalus. The patient subsequently developed worsening mental status, respiratory failure, and profound shock requiring multiple vasopressors. Bedside needle decompression, identification and repair of the cranial fossa defect, and critical care support led to improved mental status and reversal of shock and multiorgan dysfunction. Thorough evaluation revealed no evidence of an underlying infection. In this case, tension pneumocephalus incited an aseptic systemic inflammatory response syndrome mimicking septic shock. Prompt neurosurgical correction of pneumocephalus and critical care support not only improved neurologic status, but also reversed shock. Such a complication indicates the importance of close monitoring of patients with progressive pneumocephalus. PMID- 29487662 TI - Pineal gliosarcoma in a 5-year-old girl. AB - The purpose of this paper is to report a rare case of a pediatric pineal gliosarcoma. Gliomas on the pineal region are uncommon, representing 0.4%-1% of all brain tumors. Furthermore, pediatric gliosarcomas are a very rare entity. We present a case of a 5-year-old girl, with a history of headache, vomiting, diplopia, and gait disturbances. A pineal tumor was found with pathology results consistent with a gliosarcoma. A total of 25 cases of pediatric gliosarcomas have been reported, none of them in pineal topography. Only 3 gliosarcomas were found in the pineal region, but these were found in adults. To our knowledge, this is the first pediatric pineal gliosarcoma reported in the literature. PMID- 29487663 TI - Occipital intraosseous dermoid cyst with restricted diffusion on magnetic resonance imaging in a child. AB - A 4-year-old girl presented repeatedly with a complicated occipital mass, which was erroneously treated as a pyogenic granuloma. Imaging performed before a planned surgical resection detected an underlying intraoccipital dermoid with a sinus tract to the skin surface and extension into the posterior fossa. This case highlights the value of high-resolution computed tomography imaging for depiction of anatomic details and the value of magnetic resonance imaging for differential diagnosis and surgical management. A comprehensive literature review of intraosseous dermoid cyst and detailed discussion of the differential diagnoses are provided. PMID- 29487664 TI - Progression of tumefactive demyelinating lesion in a child demonstrated with MRI. AB - Tumefactive demyelinating lesions (TDLs) are atypical presentations of various demyelinating diseases. They can mimic brain tumors in their clinical and radiological features and usually respond favorably to corticosteroid therapy. We report a case of a 17-year-old girl with a single TDL suddenly increasing in size even under steroid therapy. She underwent very strict follow-up examinations with conventional magnetic resonance and diffusion-weighted imaging, perfusion weighted imaging, proton-magnetic resonance spectroscopy. The behavior of the lesion during the different follow-up sessions posed a diagnostic challenge as it expanded its size during the final examination, in stark contrast to what we forecast. Diagnosis of TDL was initially hypothesized, but the aggressive behavior of the lesion required biopsy. PMID- 29487665 TI - Ipilimumab-induced hypophysitis involving the optic tracts and tuber cinereum evaluated using 3D fluid-attenuated inversion recovery. AB - Ipilimumab, a human monoclonal antibody against cytotoxic T-lymphocyte antigen 4, was approved by the U.S. FDA (Food and Drug Administration) in 2011 for the treatment of unresectable or metastatic malignant melanoma. Occurrence of hypophysitis, an immune-related adverse event due to ipilimumab use, has been frequently reported. We report a case of ipilimumab-induced hypophysitis involving the optic tracts and tuber cinereum, identified using 3D fluid attenuated inversion recovery. PMID- 29487666 TI - Lacrimal gland uptake on F-18 florbetapir amyloid positron emission tomography scan. AB - In 2012, the Food and Drug Administration (FDA) approved the use of F-18 florbetapir to estimate beta-amyloid neuritic plaque density when indicated. A normal scan will show increased radiotracer uptake in the white matter. Mild uptake in salivary glands, skin, muscles, and bones is considered normal. Being a new and infrequently performed study, familiarity with normal biodistribution and variants is important. We hereby present 2 cases with F-18 florbetapir uptake in lacrimal glands. Patients had no symptoms or known systemic conditions to explain this uptake. We speculate that lacrimal gland uptake of F-18 florbetapir could represent a normal variant. PMID- 29487667 TI - A case of primary squamous cell carcinoma of the gallbladder with local invasion of the liver and peritoneum, and metastasis to the omentum. AB - Primary squamous cell carcinoma of the gallbladder is a rare entity that comprises approximately 1%-3% of all primary gallbladder cancers. We report the case of a 37-year-old woman who was diagnosed with a locally invasive squamous cell carcinoma of the gallbladder. Surgical pathology revealed a predominantly squamous cell carcinoma composition of the tumor with a few microscopic foci of adenocarcinoma (<1% of tumor). We discuss pertinent clinical features, risk factors, and imaging characteristics to prompt early diagnosis and treatment, which will ultimately lead to improved patient outcomes. PMID- 29487669 TI - Spinal cord astrocytoma: a unique presentation of abdominal pain. AB - A previously healthy male presented at age 5 years with recurrent abdominal pain that occurred diffusely. The pain was severe enough to cause episodic screaming, especially at night with spontaneous resolution. The patient was initially treated for constipation but when motor symptoms began to develop, imaging revealed the cause of his pain to be a spinal cord mass. The tumor was treated with steroids, and biopsy confirmed a grade II spinal cord astrocytoma. We describe this unusual presentation of a pediatric spinal cord astrocytoma and review the literature. PMID- 29487668 TI - Fetal and placental anatomy visualized with cinematic rendering from volumetric CT data. AB - Avoiding unnecessary radiation exposure in children, including fetuses or embryos, is of paramount importance. However, emergent clinical situations will arise that necessitate the use of ionizing radiation-based modalities, such as computed tomography (CT), in this patient population. In such circumstances, the use of advanced visualization methods may provide optimum diagnostic utility. We present the case of a pregnant patient with Loeys-Dietz syndrome who was evaluated with CT angiography to rule out an acute aortic syndrome. The CT data from the fetus and placenta were reconstructed using the new cinematic rendering technique that allows for photorealistic display. The potential advantages of cinematic rendering relative to traditional volume rendering are discussed. PMID- 29487670 TI - Arterial tortuosity syndrome: An extremely rare disease presenting as a mimic of pulmonary sling. AB - Pulmonary sling is the anatomic variant defined by the aberrant origin of the left pulmonary artery from the right pulmonary artery. This patient presented with a mimic of pulmonary sling as a result of an extremely rare condition, arterial tortuosity syndrome (ATS). The patient was first diagnosed with pulmonary sling on prenatal echocardiogram performed by cardiology. Computed tomography angiography of the chest obtained at birth to evaluate respiratory depression demonstrated ATS. The early detection of ATS has been demonstrated to improve patient outcome. This case provides an overview of the typical imaging features of ATS to aid radiologists in making this uncommon diagnosis. PMID- 29487671 TI - A 10-Year Prospective Study of Implant-Based Breast Augmentation and Reconstruction. AB - Objective: Observational studies are essential for ensuring patient safety, decreasing complications, and developing better surgical techniques and implants. The primary objective of this study is to demonstrate the safety and efficacy of Sebbin breast implants in both augmentation and reconstruction cohorts. Methods: This prospective, multicenter, observational 10-year study conducted in France included 205 patients (385 implants) who underwent breast augmentation (n = 166) or reconstruction (n = 39) with Sebbin round silicone gel implants. Data on patient demographics, surgical details, and complications were collected. Results: Median patient age was 39 years; 20.5% of patients were smokers. The augmentation cohort included 166 patients (81.0%); the reconstruction cohort, 39 patients (19.0%). Median implant volume was 280 ml; 91.2% of implants were textured, and 8.8% were smooth. Average patient follow-up was 63 months. The most frequent surgical approach in the Augmentation Cohort was periareolar (72.4%), with 45.5% submuscular and 51.5% subglandular placements. All patients received antibiotic prophylaxis, and postoperative antibiotic therapy was given to 39.5% of patients (average 4.8 days). Drainage was performed in 59.5% of patients (average 2.9 days). Of the reconstruction cohort, 64.1% had preoperative radiotherapy. Nine patients had Baker III/IV capsular contracture (3 bilateral; 4 had a history of radiotherapy) and 7 patients had implant rupture; 41 patients underwent explantation. No cases of double capsule, late seroma, or anaplastic large cell lymphoma occurred. Conclusions: This study found an excellent safety profile and very low capsular contracture rate with breast augmentation and reconstruction using Sebbin round silicone gel implants. PMID- 29487672 TI - Efficacy of a Self-timed Trial of Laparoscopic Surgical Training Using a Dry Box. AB - Objective: This study evaluated the self-timed trial training for laparoscopic suturing. Methods: The set task involved grasping the suture, aligning the needle with a needle holder, passing the suture, making 3 knots, holding the 2 tails of the suture with one grasper, and cutting them. Trainees were given an instruction for suturing and reducing their suturing time. The same instruction was given 3 months later. Suturing times for the first and second trials and the last trial after the second instruction of the 9 trainees were measured. Results: Their mean suturing times were statistically significantly shorter after instruction (before instruction: 276.7 +/- 43.4 seconds, after instruction: 177.4 +/- 46.1 seconds; P = .0035). Four trainees were trained twice during the second instruction. Their suturing times were shorter than those of the other trainees, and the standard deviation decreased (120.5 +/- 21.2 seconds, P = .017). Conclusion: A self-timed trial training for laparoscopic suturing using a dry box makes training interesting and motivates trainees. PMID- 29487673 TI - Cutaneous Pyoderma Gangrenosum of the Hand. PMID- 29487674 TI - Left Ventricular Systolic Function Assessed by Global Longitudinal Strain is Impaired in Atrial Fibrillation Compared to Sinus Rhythm. AB - Background: Atrial fibrillation (AF) is the most common aberrant cardiac arrhythmia. Many AF patients present with symptoms of dyspnea and fatigue, but have normal left ventricular ejection fraction (LVEF). Purpose: To determine the reproducibility of measurements of global longitudinal strain (GLS) and strain rate in patients with AF and examine if the arrhythmia is associated with abnormal LV strain and strain rate independent of age, sex, heart rate, LVEF and LV mass. We hypothesized that AF independently reduces ventricular systolic performance. Methods: The study was conducted as a retrospective analysis of images from 150 randomly selected patients with AF compared to an equal number of subjects with sinus rhythm (SR) matched for age, sex, heart rate, LVEF and LV mass. Half of the patients had normal LVEF (LVEF > 50%) and half had reduced LVEF (LVEF < 50%). GLS and strain rate were measured in each group, as were quantitative LV volumes and standard systolic and diastolic parameters. Results: GLS was significantly impaired in patients with AF compared to subjects with SR, both in the overall population (-12.25 +/- 4.1% vs. -16.13 +/- 4.7%, p<0.0001), in patients with normal LVEF (-14.41 +/- 3.9% vs. -19.42 +/- 3.1%, p<0.0001) and in patients with reduced LVEF (-10.10 +/- 3.1% vs. -12.85 +/- 3.5%, p<0.0001).Linear regression and Bland Altman analyses demonstrated good intraobserver and interobserver agreement for measurements of GLS and strain rate parameters even in patients with AF. PMID- 29487675 TI - Tumor Or Thrombus? The Role Of Cardiac Magnetic Resonance Imaging In Differentiating Left Atrial Mass In a Transplanted Heart: A Case Report. AB - An unknown mass in the left atrium can be challenging to differentiate, especially after previous heart transplant. A precise diagnosis is clinically crucial because of the therapeutic implications. CMR is a useful, non-invasive tool to distinguish intra-cardiac lesions, thereby enabling clinicians to initiate adequate therapy. PMID- 29487677 TI - Beating-heart Thoracoscopic Left Atrial Appendage Exclusion in a Patient with Left atrial Thrombus. AB - Stroke remains a major complication of atrial fibrillation and third leading cause of death in Western Countries. [1] While Coumadin and novel oral anticoagulants have been efficient in reducing the stoke risk in patients with atrial fibrillation; there is a subset of patients who are not candidates for anticoagulation.[2] The management of these patients is clinical challenge.We describe a patient with history of permanent atrial fibrillation with contra indication to anticoagulation presenting with and left atrial thrombus. She was treated with novel generation of epicardial left atrial appendage exclusion device. PMID- 29487676 TI - Complications of Atrial Fibrillation Cryoablation. AB - Catheter ablation either by using radiofrequency or cryo energy in symptomatic patients with atrial fibrillation (AF) has shown to be effective as compared to anti-arrhythmic drugs. However, all the techniques used during AF ablation are not free of complication. There are several well-known peri-procedural complications in which operators should be informed of the possible risks, cautious during the procedure and able to manage them when occurred. Herein, we aimed to review possible complications of AF cryoablation. PMID- 29487678 TI - Reversal Agents in the Era of NOACs. AB - The incidence and prevalence of atrial fibrillation (AF) is expected to more than double between 2010 and 2030. Accordingly, the use of non-vitamin K oral anticoagulant (NOAC) agents for thromboembolic stroke prevention is anticipated to increase. The development of effective and safe antidotes is needed to address the unmet need for rapid anticoagulation reversal. The immediate role for these novel antidotes is for reversal of NOAC activity in life threatening bleeding and urgent surgical intervention. In addition, reversal agents may play an important role in simplifying bridging protocols in the peri-procedural period for catheter ablation of AF and elective surgery. Currently, novel reversal agents are either decoy drug receptors or small molecule non-specific anticoagulant activity inhibitors. These agents are at various stages of FDA investigation and approval, with emerging prospective data for safety and efficacy. The purpose of this review is to outline the currently developed NOAC molecular antagonists, their potential clinical roles and future directions. PMID- 29487679 TI - Left Atrial Strain Predicts Pro-Thrombotic State in Patients with Non-Valvular Atrial Fibrillation. AB - Background and Purpose: Atrial fibrillation (AF) has a high prevalence in the population and it is responsible for up to the 25% of the strokes in elderly people. The aim of our study was to assess the correlations of left atrial (LA) functional parameter, global peak atrial longitudinal strain (PALS), derived from speckle tracking echocardiography (STE), with transesophageal echocardiography (TEE) findings in patients with persistent AF undergoing TEE before electrical cardioversion or ablation procedures. Methods: 79 patients (58 males, 21 females) with persistent AF waiting for cardioversion were included in the study. The patients underwent conventional two-dimensional (2D) and 2D speckle tracking echocardiogram. PALS were measured in all subjects. Patients were divided into two groups according to the presence of reduced LA appendage (LAA) emptying velocity (<25 cm/s) and/or thrombus in the LAA at TEE examination. Results: Patients with reduced LAA emptying velocity and/or thrombus at TEE examination showed a significantly higher LA volume and increased E/E' ratio. 4-chamber, 2 chamber and global PALS were significantly lower in patients with reduced LAA emptying velocity and/or thrombus (6.8 +/- 2.0% vs. 27.5 +/- 5.4%, P < 0.0001; 8.6 +/- 3.5% vs. 29.4 +/- 7.1%, P < 0.0001; 7.9 +/- 3.2% vs. 28.5 +/- 6.1%, P <0.0001, respectively). Among all variables analyzed, global PALS demonstrated the highest diagnostic accuracy (AUC of 0.92) and, with a cut-off value less than 8.1%, good sensitivity and specificity of 87% and 94%, respectively, to predict LAA thrombus and/or reduced LAA emptying velocity. PMID- 29487680 TI - Left Atrial Appendage Occlusion with Amplatzer Cardiac Plug and Amplatzer Amulet: a Clinical Trials Update. AB - It has been over a decade since dedicated Amplatzer devices have been used for left atrial appendage occlusion (LAAO) in patients with atrial fibrillation. The first was the Amplatzer Cardiac Plug (ACP) that is now replaced in most countries by the Amplatzer Amulet device. Most of the clinical data for ACP come from the ACP multicenter registry that included 1047 patients from 22 sites, whereas the largest to date report on the Amplatzer Amulet is a recently published prospective multicenter study in 1088 patients from 64 sites. Two important randomized clinical trials the Amulet IDE trial and the STROKECLOSE trial are currently enrolling patients and expected to provide more data on LAAO with Amplatzer Amulet in the near future. PMID- 29487681 TI - Surgical epicardial left atrial appendage closure:A true alternative. AB - Left atrial appendage closure was originally described by Madden in 1949 who was the first to perform appendix amputation. This was a very invasive procedure with poor outcome, but preformed for stroke prevention. Much later, it was James Cox whom described the Cox-Maze procedure, which included multiple incisions to create a maze like pathway for the electrical impulse to go undisturbed from the sinus node down to the atrio-ventricular node. Since then cardiac surgeons stopped focusing on the left atrial appendage and went on about seemingly more important things. Only with the advent of catheter based options for stand alone left atrial appendage closure did the interest in the field light up again. PMID- 29487683 TI - Successful Denovo Implantation And Explanation Of An Old Malfunctioning Micratm Leadless Pacemaker. AB - An unknown mass in the left atrium can be challenging to differentiate, especially after previous heart transplant. A precise diagnosis is clinically crucial because of the therapeutic implications. CMR is a useful, non-invasive tool to distinguish intra-cardiac lesions, thereby enabling clinicians to initiate adequate therapy. PMID- 29487682 TI - Reduced P-wave Voltage in Lead I is Associated with Development of Atrial Fibrillation in Patients with Coronary Artery Disease. AB - Background: Reduced P-wave voltage in lead 1 (PVL1) has been associated with atrial fibrillation (AF) recurrence.This study sought to determine the association between reduced PVL1 and AF in the NSTEMI population and the correlation between reduced PVL1 and interatrial block (IAB)/coronary artery disease (CAD). Methods: Data were recorded for clinical, echocardiographic, angiographic, electrocardiographic and outcome variables. Patients were followed for a minimum of one year. Chi-square tests, independent samples t-tests and one way ANOVA were used for the analysis, which was done using IBM SPSSResults:: A total of 322 consecutive patients were included in the analysis. Patients with new-onset AF had a significantly lower PVL1 (0.085 +/- 0.030mV vs. 0.103 +/- 0.037mV; p=0.007). There was a significant difference in mean PVL1 between those with no IAB, partial IAB and advanced IAB (p = <0.001). Those with any type of IAB had a significantly lower mean PVL1 than those without (0.094 +/- 0.032 mV vs. 0.106 +/- 0.038 mV; p=0.005). Patients who developed AF had a significantly longer P-wave duration (126 +/- 20ms vs. 119 +/- 17ms; p=0.022). Patients with IAB were more likely to develop new-onset AF (15.4% versus 7.5%, p=0.025). There were significant co-linear associations between reduced PVL1 and IAB (p=0.005); reduced PVL1 and diffuse CAD (p=0.031) and IAB and diffuse CAD (p=0.022). PMID- 29487684 TI - Electrocardiogram (ECG) for the Prediction of Incident Atrial Fibrillation: An Overview. AB - Electrocardiograms (ECGs) have been employed to medically evaluate participants in population-based studies, and ECG-derived predictors have been reported for incident atrial fibrillation (AF). Here, we reviewed the status of ECG in predicting new-onset AF. We surveyed population-based studies and revealed ECG variables to be risk factors for incident AF. When available, the predictive values of each ECG risk marker were calculated. Both the atrium-related and ventricle-related ECG variables were risk factors for incident AF, with significant hazard risks (HRs) even after multivariate adjustments. The risk factors included P-wave indices (maximum P-wave duration, its dispersion or variation and P-wave morphology) and premature atrial contractions (PACs) or runs. In addition, left ventricular hypertrophy (LVH), ST-T abnormalities, intraventricular conduction delay, QTc interval and premature ventricular contractions (PVCs) or runs were a risk of incident AF. An HR of greater than 2.0 was observed in the upper 5th percentile of the P-wave durations, P-wave durations greater than 130 ms, P-wave morpholyg, PACs (PVCs) or runs, LVH, QTc and left anterior fascicular blocks. The sensitivity , specificity and the positive and negative predictive values were 3.6-53.8%, 61.7-97.9%, 2.9-61.7% and 77.4-97.7%, respectively. ECG variables are risk factors for incident AF. The correlation between the ECG-derived AF predictors, especially P-wave indices, and underlying diseases and the effects of the reversal of the ECG-derived predictors on incident AF by treatment of comorbidities require further study. PMID- 29487685 TI - Management of Stroke risk in atrial fibrillation patients with bleeding on Oral Anticoagulation Therapy-Role of Left Atrial Appendage Closure, Octreotide and more. AB - Background: Bleeding complications especially gastrointestinal bleeding remains a major challenge associated with oral anticoagulation therapy (OAT) and often leads clinicians to withdraw oral anticoagulation therapy (OAT) . This exposes patients to risk of stroke and systemic thromboembolism (STE). Novel oral anticoagulants (NOACs) have proved no better when it comes to bleeding events and in fact studies have shown that overall NOACs are associated with higher incidence of gastrointestinal (GI) bleeding compared to warfarin . Objectives: In this review, we describe the difficulties encountered in managing OAT in patients with bleeding and strategies to maneuver around these bleeding complications particularly gastrointestinal bleeding secondary to arteriovenous malformations (AVM) and other vascular abnormalities. Findings: Left atrial appendage closure (LAAC) has emerged as a very elegant and promising tool for stroke prevention in non-valvular atrial fibrillation (AF) patients who are intolerant to OAT. But the need for OAT post procedure for a brief period is becoming a major hurdle for clinicians to pursue in this direction in patients with recurrent gastrointestinal bleeds. And in majority of cases, recurrent or refractory gastrointestinal bleeds are usually secondary to arteriovenous malformations/angiodysplasias (AVM/AD). We suggest that the problem has to be approached by decreasing or eliminating the acute bleeding risk and closing the LAA in the long term, to enable the patients to come off of OAT and minimize the risk of recurrent bleeding. PMID- 29487686 TI - Safety and Efficacy of Inpatient Initiation of Dofetilide versus Sotalol for atrial fibrillation. AB - Background: We sought to investigate and compare the safety and efficacy of two commonly used antiarrhythmic drugs, Dofetilide (DF) and Sotalol (SL), during inpatient drug initiation in patients with symptomatic atrial fibrillation (AF). Methods: We performed a single center retrospective study of consecutive patients, admitted for initiation of either DF or SL, for AF between 2012 and 2015. Rates of successful cardioversion, QT interval prolongation, adverse events and drug discontinuations were calculated and compared. A two-tailed p value less than 0.05 was considered statistically significant. Results: Of 378 patients, 298 (78.8%) received DF and 80 (21.2%) SL, mean age was 64 +/- 11 years, 90% were Caucasians and 66% were males. Among the patients who remained in AF upon admission (DF: 215/298 (72%) vs. SL: 48/80 (60%)), no significant differences were noted in pharmacological cardioversion rates (DF: 125/215(58%) vs. SL: 30/48 (62.5%); p = 0.58). Baseline QTc was similar between the groups, with higher dose dependent QTc prolongation with DF (472.25+/- 31.3 vs. 458+/- 27.03; p = 0.008). There were no significant differences in the rates of adverse events such as bradycardia (7.4% vs. 11.3%; p = 0.26), Torsades de pointes (1.3% vs. 1.2%; p = 1.00), and drug discontinuation (9.0% vs. 5.0%; p = 0.47) between the two groups. PMID- 29487687 TI - Possible mechanism underlying the association between height and vascular remodeling in elderly Japanese men. AB - Height is reported to be inversely associated with cardiovascular disease. And platelets play an important role in vascular remodeling by supporting CD34 positive cells. To clarify the association between height and platelet, we conducted a cross-sectional study of 219 elderly Japanese men. Since hemoglobin concentration is influenced by vascular remodeling activity, an analysis stratified by hemoglobin level was performed. An inverse association was seen between height and platelet count in subjects with a high hemoglobin concentration (>= 14.5 g/dL), but not in subjects with a low hemoglobin concentration (< 14.5 g/dL). The standardized parameter estimates (beta) were beta = -0.22, p = 0.019 for subjects with high hemoglobin, and beta = -0.01, p = 0.931 for subjects with low hemoglobin. We also found a positive association between platelets and carotid intima media thickness (CIMT) and circulating CD34 positive cells in subjects with high hemoglobin (partial correlation coefficient (r) = 0.21, p = 0.037 and r = 0.40, p =< 0.001), but not in subjects with low hemoglobin (r = 0.04, p = 0.710 and r = 0.06, p = 0.544). In subjects with a high hemoglobin concentration, platelets were inversely associated with height, and positively associated with CIMT and circulating CD34-positive cells. These results indicate that subjects with a short stature activate vascular remodeling to a much greater extent than subjects with a tall stature. PMID- 29487688 TI - Fabry disease and multiple sclerosis misdiagnosis: the role of family history and neurological signs. AB - Fabry disease (FD) is an X-linked inherited lysosomal storage disorder caused by alpha galactosidase A (alpha-gal A) deficiency. Central nervous system involvement and chronic white matter lesions are observed in both FD and multiple sclerosis (MS), which can confound the differential diagnosis. We analyzed the GLA gene, which encodes alpha-gal A, in 86 patients with clinical and neuroradiological findings consistent with MS to determine whether they had FD. We identified four women initially diagnosed with MS who had GLA mutations associated with FD. Our results indicate that family history besides neurological findings should be evaluated in patients with an uncertain diagnosis of MS. Also the involvement of organs outside the central nervous system can support the FD diagnosis. PMID- 29487689 TI - CDK1 and PLK1 coordinate the disassembly and reassembly of the nuclear envelope in vertebrate mitosis. AB - Micronuclei (MN) arise from chromosomes or fragments that fail to be incorporated into the primary nucleus after cell division. These structures are a major source of genetic instability caused by DNA repair and replication defects coupled to aberrant Nuclear Envelope (NE). These problems ultimately lead to a spectrum of chromosome rearrangements called chromothripsis, a phenomenon that is a hallmark of several cancers. Despite its importance, the molecular mechanism at the origin of this instability is still not understood. Here we show that lagging chromatin, although it can efficiently assemble Lamin A/C, always fails to recruit Nuclear Pore Complexes (NPCs) proteins and that Polo-Like Kinase (PLK1) negatively regulates NPC assembly. We also provide evidence for the requirement of PLK1 activity for the disassembly of NPCs, but not Lamina A/C, at mitotic entry. Altogether this study reveals the existence of independent regulatory pathways for Lamin A/C and NPC reorganization during mitosis where Lamin A/C targeting to the chromatin is controlled by CDK1 activity (a clock-based model) while the NPC loading is also spatially monitored by PLK1. PMID- 29487690 TI - Temozolomide combined with irinotecan regresses a cisplatinum-resistant relapsed osteosarcoma in a patient-derived orthotopic xenograft (PDOX) precision-oncology mouse model. AB - Relapsed osteosarcoma is a recalcitrant tumor. A patient's cisplatinum (CDDP) resistant relapsed osteosarcoma lung metastasis was previously established orthotopically in the distal femur of mice to establish a patient-derived orthotopic xenograft (PDOX) model. In the present study, the PDOX models were randomized into the following groups when tumor volume reached 100 mm3: G1, control without treatment; G2, CDDP (6 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks); gemcitabine (GEM) (100 mg/kg, i.p., weekly, for 2 weeks) combined with docetaxel (DOC) (20 mg/kg, i.p., once); temozolomide (TEM) (25 mg/kg, p.o., daily, for 2 weeks) combined with irinotecan (IRN) (4 mg/kg i.p., daily for 2 weeks). Tumor size and body weight were measured with calipers and a digital balance twice a week. After 2 weeks, all treatments significantly inhibited tumor growth except CDDP compared to the untreated control: CDDP: p = 0.093; GEM+DOC: p = 0.0002, TEM+IRN: p < 0.0001. TEM combined with IRN was significantly more effective than either CDDP (p = 0.0001) or GEM combined with DOC (p = 0.0003) and significantly regressed the tumor volume compared to day 0 (p = 0.003). Thus the PDOX model precisely identified the combination of TEM-IRN that could regress the CDDP-resistant relapsed metastatic osteosarcoma PDOX. PMID- 29487691 TI - T-lymphokine-activated killer cell-originated protein kinase (TOPK) as a prognostic factor and a potential therapeutic target in glioma. AB - TOPK is overexpressed in various types of cancer and associated with poor outcomes in different types of cancer. In this study, we first found that the expression of T-lymphokine-activated killer cell-originated protein kinase (TOPK) was significantly higher in Grade III or Grade IV than that in Grade II in glioma (P = 0.007 and P < 0.001, respectively). Expression of TOPK was positively correlated with Ki67 (P < 0.001). Knockdown of TOPK significantly inhibited cell growth, colony formation and increased sensitivities to temozolomide (TMZ) in U 87 MG or U-251 cells, while TOPK overexpression promoted cell growth and colony formation in Hs 683 or A-172 cells. Glioma patients expressing high levels of TOPK have poor survival compared with those expressing low levels of TOPK in high grade or low-grade gliomas (hazard ratio = 0.2995; 95% CI, 0.1262 to 0.7108; P = 0.0063 and hazard ratio = 0.1509; 95% CI, 0.05928 to 0.3842; P < 0.0001, respectively). The level of TOPK was low in TMZ-sensitive patients compared with TMZ-resistant patients (P = 0.0056). In TMZ-resistant population, patients expressing high TOPK have two months' shorter survival time than those expressing low TOPK. Our findings demonstrated that TOPK might represent as a promising prognostic and predictive factor and potential therapeutic target for glioma. PMID- 29487692 TI - Use of deep neural network ensembles to identify embryonic-fetal transition markers: repression of COX7A1 in embryonic and cancer cells. AB - Here we present the application of deep neural network (DNN) ensembles trained on transcriptomic data to identify the novel markers associated with the mammalian embryonic-fetal transition (EFT). Molecular markers of this process could provide important insights into regulatory mechanisms of normal development, epimorphic tissue regeneration and cancer. Subsequent analysis of the most significant genes behind the DNNs classifier on an independent dataset of adult-derived and human embryonic stem cell (hESC)-derived progenitor cell lines led to the identification of COX7A1 gene as a potential EFT marker. COX7A1, encoding a cytochrome C oxidase subunit, was up-regulated in post-EFT murine and human cells including adult stem cells, but was not expressed in pre-EFT pluripotent embryonic stem cells or their in vitro-derived progeny. COX7A1 expression level was observed to be undetectable or low in multiple sarcoma and carcinoma cell lines as compared to normal controls. The knockout of the gene in mice led to a marked glycolytic shift reminiscent of the Warburg effect that occurs in cancer cells. The DNN approach facilitated the elucidation of a potentially new biomarker of cancer and pre-EFT cells, the embryo-onco phenotype, which may potentially be used as a target for controlling the embryonic-fetal transition. PMID- 29487693 TI - Uncovering genetic and non-genetic biomarkers specific for exudative age-related macular degeneration: significant association of twelve variants. AB - Age-related Macular Degeneration (AMD) represents one of the most sight threatening diseases in developed countries that substantially impacts the patients' lifestyle by compromising everyday activities, such as reading and driving. In this context, understanding the prevalence, burden, and population specific risk/protective factors of AMD is essential for adequate health care planning and provision. Our work aimed to characterize exudative AMD in Italian population and to identify the susceptibility/protective factors (genetic variants, age, sex, smoking and dietary habits) which are specific for the onset of disease. Our study involved a cohort of 1976 subjects, including 976 patients affected with exudative AMD and 1000 control subjects. In particular, the sample cohort has been subjected to a large genotyping analysis of 20 genetic variants which are known to be associated with AMD among European and Asiatic populations. This analysis revealed that 8 genetic variants (CFH, ARMS2, IL-8, TIMP3, SLC16A8, RAD51B, VEGFA and COL8A1) were significantly associated with AMD susceptibility. Successively, we performed a multivariate analysis, considering both genetic and non-genetic data available for our sample cohort. The multivariate analysis showed that age, smoking, dietary habits and sex, together with the genetic variants, were significantly associated with AMD in our population. Altogether, these data represent a starting point for the set-up of adequate preventive and personalized strategies aimed to decrease the burden of disease and improve the patients' quality of life. PMID- 29487694 TI - Ependymomas overexpress chemoresistance and DNA repair-related proteins. AB - Background: After surgery and radiation, treatment options for ependymoma are few making recurrence a challenging issue. Specifically, the efficacy of chemotherapy at recurrence is limited. We performed molecular profiling on a cohort of ependymoma cases in order to uncover therapeutic targets and to elucidate the molecular mechanisms contributing to treatment resistance. Results: This ependymoma cohort showed minimal alterations in gene amplifications and mutations but had high expression rates of DNA synthesis and repair enzymes such as RRM1 (47%), ERCC1 (48%), TOPO1 (62%) and class III beta-tublin (TUBB3) (57%), which are also all associated with chemoresistance. This cohort also had high expression rates of transporter proteins that mediate multi-drug resistance including BCRP (71%) and MRP1 (43%). Subgroup analyses showed that cranial ependymomas expressed the DNA synthesis enzyme TS significantly more frequently than spinal lesions did (57% versus 15%; p = 0.0328) and that increased TS expression was correlated with increased tumor grade (p = 0.0009). High-grade lesions were also significantly associated with elevated expression of TOP2A (p = 0.0092) and TUBB3 (p = 0.0157). Materials and Methods: We reviewed the characteristics of 41 ependymomas (21 cranial, 20 spinal; 8 grade I, 11 grade II, 22 grade III) that underwent multiplatform profiling with immunohistochemistry, next-generation sequencing, and in situ hybridization. Conclusions: Ependymomas are enriched with proteins involved in chemoresistance and in DNA synthesis and repair, which is consistent with the meager clinical effectiveness of conventional systemic therapy in ependymoma. Adjuvant therapies that combine conventional chemotherapy with the inhibition of chemoresistance-related proteins may represent a novel treatment paradigm for this difficult disease. PMID- 29487695 TI - Rapid detection of BRCA1/2 recurrent mutations in Chinese breast and ovarian cancer patients with multiplex SNaPshot genotyping panels. AB - BRCA1/2 mutations are significant risk factors for hereditary breast and ovarian cancer (HBOC), its mutation frequency in HBOC of Chinese ethnicity is around 9%, in which nearly half are recurrent mutations. In Hong Kong and China, genetic testing and counseling are not as common as in the West. To reduce the barrier of testing, a multiplex SNaPshot genotyping panel that targeted 25 Chinese BRCA1/2 mutation hotspots was developed, and its feasibility was evaluated in a local cohort of 441 breast and 155 ovarian cancer patients. For those who tested negative, they were then subjected to full-gene testing with next-generation sequencing (NGS). BRCA mutation prevalence in this cohort was 8.05% and the yield of the recurrent panel was 3.52%, identifying over 40% of the mutation carriers. Moreover, from 79 Chinese breast cancer cases recruited overseas, 2 recurrent mutations and one novel BRCA2 mutation were detected by the panel and NGS respectively. The developed genotyping panel showed to be an easy-to-perform and more affordable testing tool that can provide important contributions to improve the healthcare of Chinese women with cancer as well as family members that harbor high risk mutations for HBOC. PMID- 29487696 TI - The evolutionary pattern of mutations in glioblastoma reveals therapy-mediated selection. AB - Glioblastoma presents as a heterogeneous disease with poor prognosis despite the use of multimodal therapy. Analysis of genomic DNA changes between initial diagnosis and recurrence in response to standard treatment protocols would enhance understanding of disease progression and better inform new treatment strategies. A cohort of 21 patients with primary glioblastoma were examined between diagnosis and first recurrence. This study presented a rare opportunity to characterize molecular alterations in tumors observed in three patients who received no therapeutic intervention, other than surgery, offering a unique control. We focused this study by comparing the dynamic mutation profiles between the primary tumors and their matched recurrent counterparts. Molecular profiling of tumors was performed using multiplexed targeted deep sequencing of 409 well characterized cancer-associated genes, achieving a mean read depth of 1272 x. Three levels of evidence suggested an evolutionary pattern consistent with a response to therapy-mediated selection pressures exists in treated patients: 1) variant burden was reduced in recurrent tumors, 2) neutral evolutionary dynamics apparent in untreated tumors shifted toward a non-neutral mode of evolution in treated patients at recurrence, and 3) the recurrent tumor of one patient displayed an increased mutation rate attributable to a temozolomide-associated hypermutator phenotype. Our observations suggest that current treatment modalities are likely to fail in achieving long term remission with the majority of relapse samples containing distinct mutations when compared to primary diagnostic samples. PMID- 29487697 TI - DPYD and UGT1A1 genotyping to predict adverse events during first-line FOLFIRI or FOLFOXIRI plus bevacizumab in metastatic colorectal cancer. AB - Our study addresses the issue of the clinical reliability of three candidate DPYD and one UGT single nucleotide polymorphisms in predicting 5-fluorouracil- and irinotecan-related adverse events. To this purpose, we took advantage of a large cohort of metastatic colorectal cancer patients treated with first-line 5 fluorouracil- and irinotecan-based chemotherapy regimens (i.e., FOLFIRI or FOLFOXIRI) plus bevacizumab in the randomized clinical trial TRIBE by GONO (clinicaltrials.gov: NCT00719797), in which adverse events were carefully and prospectively collected at each treatment cycle. Here we show that patients bearing DPYD c.1905+1G/A and c.2846A/T genotypes, together with UGT1A1*28 variant carriers, have an increased risk of experiencing clinically relevant toxicities, including hematological AEs and stomatitis. No carrier of the DPYD c.1679T>G minor allele was identified. Present results support the preemptive screening of mentioned DPYD and UGT1A1 variants to identify patients at risk of clinically relevant 5-fluoruracil- and irinotecan-related AEs, in order to improve treatments' safety through a "genotype-guided" approach. PMID- 29487698 TI - Genetic and metabolic comparison of orthotopic and heterotopic patient-derived pancreatic-cancer xenografts to the original patient tumors. AB - Tumors from 25 patients with pancreatic cancer were used to establish two patient derived xenograft (PDX) models: orthotopic PDX (PDOX) and heterotopic (subcutaneous) PDX (PDHX). We compared gene expression by immunohistochemistry, single-nucleotide polymorphism (SNP), DNA methylation, and metabolite levels. The 4 cases, of the total of 13 in which simultaneous PDHX & PDOX models were established, were randomly selected. The molecular-genetic characteristics of the patient's tumor were well maintained in the two PDX models. SNP analysis demonstrated that both groups were more than 90% identical to the original patient's tumor, and there was little difference between the two models. DNA methylation of most genes was similar among the two models and the original patients tumor, but some gene sets were hypermethylated the in PDOX model and hypomethylated in the PDHX model. Most of the metabolites had a similar pattern to those of the original patient tumor in both PDX tumor models, but some metabolites were more prominent in the PDOX and PDHX models. This is the first simultaneous molecular-genetic and metabolite comparison of patient tumors and their tumors established in PDOX and PDHX models. The results indicate high fidelity of these critical properties of the patient tumors in the two models. PMID- 29487699 TI - Molecular imaging of Toll-like receptor 4 detects ischemia-reperfusion injury during intussusception. AB - We investigated the expression of Toll-like receptor 4 (TLR4) in the acute phase of intestinal I/R injury during intussusception and evaluated whether anti-TLR4 antibody-conjugated lead sulfide quantum dots (TLR4-PbS QDs) could be used to detect and monitor the injury. We first established a mouse model of I/R injury during intussusception. TLR-PbS QDs were then intravenously administered to intestinal I/R injured mice and visualized using whole-body fluorescence imaging in the second near-infrared window (NIR-II). Immunohistochemical analysis of intestinal tissue from the mice revealed that TLR4 expression was higher in the I/R injury group than the control and TAK-242 groups (5.189 +/- 2.482, 1.186 +/- 1.171, and 2.400 +/- 0.857, respectively, P < 0.05). NIR-II fluorescence intensity was also higher in the I/R injury group than in the control and TAK-242 groups (86.415 +/- 10.955, 38.975 +/- 8.619, and 71.977 +/- 3.838, respectively; P < 0.05). Thus, anti-TLR4-PbS QDs bound to TLR4 on the cell membranes of intestinal epithelial cells with high specificity in vitro and in vivo. These results indicate that TLR4 promotes intestinal I/R injury during intussusception and that the injury can be noninvasively imaged using TLR4-PbS QDs. PMID- 29487700 TI - Increased high mobility group A 2 expression promotes transition of cervical intraepithelial neoplasm into cervical cancer. AB - Integration of the high risk human papillomavirus (HR-HPV) genome into host chromatin is an important step in cervical carcinogenesis. We identified HR-HPV integration sites within the human genome through detection of integrated papillomavirus sequences-PCR and assessed the role of high mobility group A 2 (HMGA2) in cervical carcinogenesis in clinical samples and cell lines. HPV integration sites were analyzed in 40 cervical cancer samples, while copy number variation and protein expression were assessed in 19 normal cervixes, 49 cervical intraepithelial neoplasia (CIN), and 52 cervical cancer samples. Overall, 25 HR HPV integrating loci were detected in 24 cervical samples; HMGA2 was the only recurring integration site. Both HPV copy number and HMGA2 protein expression were higher in cervical cancer than CIN samples. Area under the curve (AUC) values for HMGA2 expression and HPV copy number were 0.910 (95% CI: 0.844-0.976) and 0.848 (95% CI: 0.772-0.923), respectively. Expression of Bcl-2 and Caspase 3 can indicate the cell proliferation and apoptosis. Transfection of HMGA2 siRNA decreased HMGA2 mRNA and protein expression, Bcl-2 expression, inhibited cell proliferation, and increased Caspase 3 expression and apoptosis in SiHa, CaSki and S12 cervical cancer cells. HMGA2 overexpression had the opposite effects. These results suggest that elevated HMGA2 expression is associated with transformation of CIN into cervical cancer and that HMGA2 might be a useful biomarker for assessing the risk of cervical lesion progression. PMID- 29487701 TI - Antitumor activity of HPA3P through RIPK3-dependent regulated necrotic cell death in colon cancer. AB - The antimicrobial peptide HPA3 shows anticancer activity in gastric cancer and leukaemia. However, how HPA3 exerts its anticancer activity, as well as whether it also exhibits activity in other cancers, remains unknown. Therefore, the aim of this study was to evaluate the anticancer activity of HPA3 and its analogues in colon cancer and to elucidate the mechanisms responsible for this activity. HPA3P decreased cell viability, whereas HPA3 and HPA3P2 did not decrease cell viability in colon cancer cells compared with control cells. This reduction in cell viability occurred through necrosis, a conclusion supported by our observation of the release of cellular contents, our intracellular PI staining results, and our observation of the release of HMGB1. Moreover, RIPK3 inhibition blocks the reduction of cell viability by HPA3P. Consistent with this finding, we found that knocking down RIPK3 and MLKL, key necroptosis proteins, attenuates the reductions in cell viability induced by HPA3P. Furthermore, HPA3P can improve the anticancer activity of chemotherapeutic agents and exhibits anticancer activity in other cancer cells. These results suggest that HPA3P may have potential as an anticancer agent in the treatment of colon cancer. PMID- 29487702 TI - C-Kit receptor and tryptase expressing mast cells correlate with angiogenesis in breast cancer patients. AB - C-Kit protein is a transmembrane tyrosine kinase (TK) receptor (c-KitR-TK), which is predominantly expressed on mast cells (MCs) playing a role in tumor angiogenesis. It could be also expressed on epithelial breast cancer cells (EBCCs), but no data have been published regarding the correlation between mast cells positive to c-KitR (MCs-c-KitR), EBCCs positive to c-KitR (EBCCs-c-KitR), BC angiogenesis in terms of microvessel density (MVD) and the main clinic pathological features. This study aims to evaluate the above parameters and their correlations in a series of selected 121 female early BC patients. It has been found a strong correlation between MVD and MCDPT, and MCs-c-KitR, MVD and MCs density positive to tryptase (MCDPT), and MCs-c-KitR and MCDPT by Pearson correlation. These data suggest an involvement of both MCDPT and MCs-c-KitR in BC tumor angiogenesis. Furthermore, BC tissue expressing c-KitR could be a putative predictive factor to c-KitR-TK inhibitors. In this way, selected patients with higher MCs-c-KitR could be candidate to receive c-KitR-TK inhibitors (e.g. masitinib, sunitinib) or tryptase inhibitors (e.g. nafamostat mesilate, gabexate mesilate). PMID- 29487703 TI - Network analysis of microRNAs, genes and their regulation in diffuse and follicular B-cell lymphomas. AB - MicroRNAs (miRs) are short non-coding regulatory RNAs that control gene expression at the post-transcriptional level and play an important role in cancer development and progression, acting either as oncogenes or as tumor suppressors. Identification of aberrantly expressed miRs in patients with hematological malignancies as compared to healthy individuals has suggested that these molecules may serve as novel clinical diagnostic and prognostic biomarkers. We conducted a systematic literature review of articles published between 2007 and 2017 and re-analyzed experimentally-validated human miR expression signatures in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) from various biological sources (tumor tissue, peripheral blood, bone marrow and cell lines). A unique miR expression pattern was observed for each disease. Compared to healthy individuals, 61 miRs were aberrantly expressed in DLBCL and 85 in FL; 20 30% of aberrantly expressed miRs overlapped between the two lymphoma subtypes. Analysis of integrative positive and negative miRNA-mRNA relationships using the Ingenuity Pathway Analysis (IPA) system revealed 970 miR-mRNA pairs for DLBCL and 90 for FL. Through gene ontology analysis, we found potential regulatory pathways that are deregulated in DLBCL and FL due to improper expression of miR target genes. By comparing the expression level of the aberrantly expressed miRs in DLBCL to their expression levels in other malignancies, we identified seven miRs that are aberrantly expressed in DLBCL tumor tissues (miR-15a, miR-16, miR-17, miR-106, miR-21, miR-155 and miR-34a-5p). This specific expression pattern may be a potential diagnostic tool for DLBCL. PMID- 29487704 TI - The effectiveness of PD-1 inhibitors in non-small cell lung cancer (NSCLC) patients of different ages. AB - Background: Immunosenescence, the age-related decline of immunity, affects the immune responses of non-small cell lung cancer (NSCLC) patients. Through immune responses, programmed death-1 (PD-1) inhibitors exert their antitumor robustness. In different ages of NSCLC patients, especially the older patients, the effectiveness of PD-1 inhibitors remains unclear. It is still controversial whether pembrolizumab or nivolumab should be used in treating NSCLC patients. Results: 2,192 NSCLC patients from four phase III RCTs were included. PD-1 inhibitors significantly prolonged the OS in both younger group (<65-year-age) (HR: 0.64, 95% CI: 0.54-0.75, P = 0.000) and older group (>=65-year-age) (HR: 0.68, 95% CI: 0.54-0.81, P = 0.001) than chemotherapy. Among patients aged over 75, no significantly longer OS was observed (HR: 1.02, 95% CI: 0.35-1.69, P = 0.971) than controls. In the older group (>=65-year-age), HR of OS favors nivolumab rather than pembrolizumab. Conclusions: Among patients aged over 75, no significantly prolonged overall survival was observed compared with chemotherapy. In comparison with pembrolizumab, nivolumab was associated with better OS in older NSCLC patients (>=65-year-age), and better PFS in all NSCLC patients. Older patients, especially those aged over 75, should be paid more attention to in the future clinical trials, guidelines, and clinical practice. Methods: The authors included clinical trials testing PD-1 inhibitors (nivolumab and pembrolizumab) compared with chemotherapies in older and younger patients. The authors used the hazard ratio (HR) and 95% confidence interval (CI) of overall survival (OS) and progression-free survival (PFS). PMID- 29487705 TI - Mutations in DNA repair genes are associated with increased neo-antigen load and activated T cell infiltration in lung adenocarcinoma. AB - Mutations in DNA repair genes lead to increased genomic instability and mutation frequency. These mutations represent potential biomarkers for cancer immunotherapy efficacy, as high tumor mutational burden has been associated with increased neo-antigens and tumor infiltrating lymphocytes. While mismatch repair mutations have successfully predicted response to anti-PD-1 therapy in colorectal and other cancers, they have not yet been tested for lung cancer, and few have investigated genes from other DNA repair pathways. We utilized TCGA samples to comprehensively immunophenotype lung tumors and analyze the links between DNA repair mutations, neo-antigen and total mutational burden, and tumor immune infiltration. Overall, 73% of lung tumors contained infiltration by at least one T cell subset, with high mutational burden tumors containing significantly increased infiltration by activated CD4 and CD8 T cells. Further, mutations in mismatch repair genes, homologous recombination genes, or POLE accurately predicted increased tumor mutational burden, neo-antigen load, and T cell infiltration. Finally, neo-antigen load correlated with expression of M1 polarized macrophage genes, PD-1, PD-L1, IFNgamma, GZMB, and FASLG, among other immune-related genes. Overall, after defining the immune infiltrate in lung tumors, we demonstrate the potential value of utilizing gene mutations from multiple DNA repair pathways as biomarkers for lung cancer immunotherapy. PMID- 29487706 TI - Clinical, prognostic, and therapeutic significance of heat shock protein 27 in bladder cancer. AB - Heat shock protein 27 (HSP27) is highly expressed in many cancers, and its prognostic and predictive value has been reported. HSP27 knockdown using siRNA or OGX-427 (an anti-sense oligonucleotide sequence targeting HSP27) is reported to have anti-cancer effects and to enhance chemosensitivity of cancer cells to chemotherapeutic agents. However, conflicting results have been reported regarding the clinical significance of HSP27 in bladder cancer (BC). Furthermore, long-term suppression of HSP27 has not been investigated in BC. In this study, we investigated the association between HSP27 expression and BC characteristics in 132 BC patient samples, as well as its prognostic value to determine the potential of HSP27 as a clinical biomarker. Additionally, we applied five different shRNAs targeting HSP27 in three invasive BC cell lines to analyze the long-term knockdown effects of HSP27. Our study revealed a significant association between HSP27 expression and adverse pathological characteristics such as high-stage and -grade BC. However, HSP27 expression was not associated with clinical outcomes such as tumor recurrence, progression, and patient survival. Interestingly, although our shRNAs had obvious knockdown effects on HSP27 in BC cells, we did not find consistent effects on apoptosis of BC cells or chemotherapeutic sensitivity of BC cells to cisplatin. Therefore, although HSP27 may be a predictor of adverse pathological characteristics in BC, its role as a prognostic biomarker and therapeutic target seems to be limited. PMID- 29487707 TI - Intrahepatic cholangiocarcinoma in the setting of HBV-related cirrhosis: Differentiation with hepatocellular carcinoma by using Intravoxel incoherent motion diffusion-weighted MR imaging. AB - Accurate preoperative differentiation of intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) in the setting of cirrhotic liver is of great clinical significance because the treatment and prognosis of these entities differ markedly. Through a retrospectively research, we sought to determine the diagnostic performances of intravoxel incoherent motion (IVIM) and diffusion weighted imaging (DWI) parameters in the differentiating of ICC and HCC. According to the results, we found that apparent diffusion coefficient (ADC) derived from mono-exponential model and true ADC (ADCslow) derived from bi exponential model can be used to distinguish the ICC and HCC, and ADCslowentailed the higher diagnostic performance than ADC. However, pseudo-ADC (ADCfast) and perfusion fraction (f) can not be used to differentiate ICC and HCC. These results suggested that IVIM and DWI parameters can be useful in differentiating ICC and HCC and might be helpful in selecting the treatment plan and predicting prognosis. PMID- 29487708 TI - A metabolomic study on early detection of steroid-induced avascular necrosis of the femoral head. AB - The early and accurate diagnosis of steroid-induced avascular necrosis of the femoral head (SANFH) is appealing considering its irreversible progression and serious consequence for the patients. The purpose of this study was to investigate the metabolic change of SANFH for its early detection. Two stages were designed in this study, namely discovery and verification. Except the biochemical index anomaly and the accidental death, 30 adult healthy adult Japanese white rabbits were used for screening out the potential metabolites in discovery experiment and 13 rabbits were used in verification experiment. The femoral heads were assessed with magnetic resonance imaging and transmission electron microscopy. The metabolomic profiling of serum samples were analysis by UHPLC-MS/MS. Metabolomic cluster analysis enable us to differentiate the rabbits without and with injection of the glucocorticoid in 1 week even when there is no obvious abnormal symptom in behaviors or imaging diagnosis. The majority of differential metabolites were identified as phospholipids which were observed significant change after injection of glucocorticoid in 1, 2, 3 weeks. And the results obtained in verification experiment of 6 weeks showed that these differential metabolites exhibited consistent trends in late progression with that in early-stage. At the end of 6 weeks the damage of SANFH could be verified by pathological imaging. Therefore the finding of serum metabolite profile links to the progression of SANFH and provides the potential of early detection of SANFH. PMID- 29487709 TI - SIRT1 increases cardiomyocyte binucleation in the heart development. AB - SIRT1 regulates cell senescence. We investigated a novel role of SIRT1 in the regulation of cardiomyocyte terminal differentiation in the developing heart. Retinoic acid (RA)-induced binucleation of H9c2 cells was associated with increased SIRT1 expression. Inhibition of SIRT1 activity or expression significantly decreased RA-induced binucleation. SIRT1 expression was minimal in the fetal heart and significantly upregulated in the hearts of postnatal day 7 (P7) rat pups. In contrast, heart-specific miR-133a expression was high in the fetal heart but significantly reduced in P7 pup hearts. The miR-133a promoter contains a canonical HRE element and hypoxia upregulated miR-133a gene expression in the heart. SIRT1 mRNA 3'UTR has miR-133a binding sequences and miR-133a and hypoxia suppressed SIRT1 expression in cardiomyocytes. Of importance, inhibition of SIRT1 significantly reduced binucleated cardiomyocytes in the hearts of P7 pups. Taken together, the present study reveals a novel role of SIRT1 and its regulation by miR-133a in cardiomyocyte terminal differentiation of the developing heart, and suggests a potential therapeutic strategy that may impact cardiac function later in life. PMID- 29487710 TI - The "bad" cholesterol can predict abnormal apolipoprotein B levels in a large unselected outpatient cohort. AB - Background: The significant association between total cholesterol (TC), non-high density lipoprotein cholesterol (non-HDL), and low-density lipoprotein cholesterol (LDL) has been shown to be associated with Apolipoprotein B (Apo B). The objective of this study was to assess whether abnormal levels of TC, non-HDL and LDL can be used as predictors of abnormal serum Apo B levels. Results: TC (r = 0.752), non-HDL (r = 0.799), and LDL(r = 0.817) were significantly positively correlated with Apo B. Areas under the curve of TC, non-HDL, and LDL for predicting abnormal Apo B (>1.10 g/L) were 0.906, 0.918, and 0.928, respectively. The optimal thresholds of prediction of abnormal Apo B were 5.13 mmol/L for TC, 4.23 mmol/L for non-HDL, and 3.34 mmol/L for LDL. At these optimal thresholds of TC, non-HDL and LDL, less than 1.13%, 1.67%, and 0.62% of tests with abnormal Apo B results would have been missed, but approximately 69.4%, 79.7%, and 73.2% of the performed Apo B tests could have been eliminated, respectively. Conclusions: Apo B levels of unselected outpatients need be not tested (especially when LDL < 3.34 mmol/L, non-HDL < 4.23 mmol/L, and/or TC < 5.13 mmol/L). It will result in 69% reduction in number of ordered Apo B tests. LDL was significantly better than the TC and non-HDL for predicting abnormal Apo B indicating that Apo B needn't tested when LDL level is normal. Methods: We retrospectively analyzed results of TC, HDL, LDL, and Apo B in a large cohort of unselected outpatients (n = 5486) in Shuyang People's Hospital, Shuyang, China. Non-HDL was calculated by deducting HDL from TC. Correlations between TC, non-HDL, LDL, and Apo B were analyzed by using Spearman's rho approach. Receiver operating characteristics curve analysis was used to evaluate the predictive value of TC, non-HDL, and LDL for abnormal Apo B. PMID- 29487711 TI - Identification of BAG3 target proteins in anaplastic thyroid cancer cells by proteomic analysis. AB - BAG3 protein is an apoptosis inhibitor and is highly expressed in Anaplastic Thyroid Cancer. We investigated the entire set of proteins modulated by BAG3 silencing in the human anaplastic thyroid 8505C cancer cells by using the Stable Isotope Labeling by Amino acids in Cell culture strategy combined with mass spectrometry analysis. By this approach we identified 37 up-regulated and 54 down regulated proteins in BAG3-silenced cells. Many of these proteins are reportedly involved in tumor progression, invasiveness and resistance to therapies. We focused our attention on an oncogenic protein, CAV1, and a tumor suppressor protein, SERPINB2, that had not previously been reported to be modulated by BAG3. Their expression levels in BAG3-silenced cells were confirmed by qRT-PCR and western blot analyses, disclosing two novel targets of BAG3 pro-tumor activity. We also examined the dataset of proteins obtained by the quantitative proteomics analysis using two tools, Downstream Effect Analysis and Upstream Regulator Analysis of the Ingenuity Pathways Analysis software. Our analyses confirm the association of the proteome profile observed in BAG3-silenced cells with an increase in cell survival and a decrease in cell proliferation and invasion, and highlight the possible involvement of four tumor suppressor miRNAs and TP53/63 proteins in BAG3 activity. PMID- 29487712 TI - Inhibition of mTORC1/C2 signaling improves anti-leukemia efficacy of JAK/STAT blockade in CRLF2 rearranged and/or JAK driven Philadelphia chromosome-like acute B-cell lymphoblastic leukemia. AB - Patients with cytokine receptor-like factor 2 rearranged (CRLF2-re) subgroup Philadelphia chromosome-like B-cell acute lymphoblastic leukemia (Ph-like B-ALL) have a high relapse rate and poor clinical outcomes. CRFL2-re Ph-like B-ALL is characterized by heightened activation of multiple signaling pathways, including the JAK/STAT and PI3K/AKT/mTOR pathways. We hypothesized that the combined inhibition by JAK2 and mTOR inhibitors would induce an additive antileukemia effect in CRLF2-re Ph-like B-ALL. In this study, we tested the antileukemia efficacy of the type I JAK inhibitor ruxolitinib and type II JAK inhibitor NVP BBT594 (hereafter abbreviated BBT594) [1] alone and combined with allosteric mTOR inhibitor rapamycin and a second generation ATP-competitive mTOR kinase inhibitor AZD2014. We found that BBT594/AZD2014 combination produced robust anti-leukemic effects in Ph-like cell lines in vitro and in patient-derived xenograft (PDX) cells cultured ex vivo. JAK2/mTOR inhibition arrested the cell cycle and reduced cell survival to a greater extent in Ph-like B-ALL cells with CRLF2-re and JAK2 mutation. Synergistic cell killing was associated with the greater inhibition of JAK2 phosphorylation by BBT594 than by ruxolitinib and the greater inhibition of AKT and 4E-BP1 phosphorylation by AZD2014 than by rapamycin. In vivo, BBT594/AZD2014 co-treatment was most efficacious in reducing spleen size in three Ph-like PDX models, and markedly depleted bone marrow and spleen ALL cells in an ATF7IP-JAK2 fusion PDX. In summary, combined inhibition of JAK/STAT and mTOR pathways by next-generation inhibitors had promising antileukemia efficacy in preclinical models of CRFL2-re Ph-like B-ALL. PMID- 29487713 TI - MMTV-NeuT/ATTAC mice: a new model for studying the stromal tumor microenvironment. AB - One of the central challenges in cancer prevention is the identification of factors in the tumor microenvironment (TME) that increase susceptibility to tumorigenesis. One such factor is stromal fibrosis, a histopathologic negative prognostic criterion for invasive breast cancer. Since the stromal composition of the breast is largely adipose and fibroblast tissue, it is important to understand how alterations in these tissues affect cancer progression. To address this question, a novel transgenic animal model was developed by crossing MMTV NeuT mice containing a constitutively active ErbB2 gene into the FAT-ATTAC (fat apoptosis through targeted activation of caspase 8) background, which expresses an inducible caspase 8 fusion protein targeted to mammary adipose tissue. Upon caspase 8 activation, lipoatrophy of the mammary gland results in stromal fibrosis and acceleration of mammary tumor development with an increase in tumor multiplicity. Fibrosis was accompanied by an increase in collagen deposition, alpha-smooth muscle actin and CD31 expression in the tumor stroma as well as an increase in PD-L1-positive tumor cells, and infiltration by regulatory T cells, myeloid-derived suppressor cells and tumor-associated macrophages. Gene expression and signal transduction profiling indicated upregulation of pathways associated with cytokine signaling, inflammation and proliferation. This model should be useful for evaluating new therapies that target desmoplasia in the TME associated with invasive cancer. PMID- 29487714 TI - Ribavirin as a potential therapeutic for atypical teratoid/rhabdoid tumors. AB - Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive, malignant tumors and are the most common malignant brain tumor in children under 6 months of age. Currently, there is no standard treatment for AT/RT. Recent studies have reported potential anti-tumoral properties of ribavirin, a guanosine analog and anti-viral molecule approved by the Food and Drug Administration for treatment of hepatitis C. We previously demonstrated that ribavirin inhibited glioma cell growth in vitro and in vivo. Based on these results and the fact that no pre-clinical model of ribavirin in AT/RT exists, we decided to investigate the effect of ribavirin on several human AT/RT cell lines (BT12, BT16, and BT37) both in vitro and in vivo. We provide evidence that ribavirin has a significant impact on AT/RT cell growth and increases cell cycle arrest and cell death, potentially through modulation of the eIF4E and/or EZH2 pathways. Interestingly, using scratch wound and transwell Boyden chamber assays, we observed that ribavirin also impairs AT/RT cell migration, invasion, and adhesion. Finally, we demonstrate that ribavirin significantly improves the survival of mice orthotopically implanted with BT12 cells. Our work establishes that ribavirin is effective against AT/RT by decreasing tumoral cell growth and dissemination and could represent a new therapeutic option for children with this deadly disease. PMID- 29487715 TI - Biophysical studies and NMR structure of YAP2 WW domain - LATS1 PPxY motif complexes reveal the basis of their interaction. AB - YES-associated protein (YAP) is a major effector protein of the Hippo tumor suppressor pathway, and is phosphorylated by the serine/threonine kinase LATS. Their binding is mediated by the interaction between WW domains of YAP and PPxY motifs of LATS. Their isoforms, YAP2 and LATS1 contain two WW domains and two PPxY motifs respectively. Here, we report the study of the interaction of these domains both in vitro and in human cell lines, to better understand the mechanism of their binding. We show that there is a reciprocal binding preference of YAP2 WW1 with LATS1-PPxY2, and YAP2-WW2 with LATS1-PPxY1. We solved the NMR structures of these complexes and identified several conserved residues that play a critical role in binding. We further created a YAP2 mutant by swapping the WW domains, and found that YAP2 phosphorylation at S127 by LATS1 is not affected by the spatial configuration of its WW domains. This is likely because the region between the PPxY motifs of LATS1 is unstructured, even upon binding with its partner. Based on our observations, we propose possible models for the interaction between YAP2 and LATS1. PMID- 29487716 TI - The prognostic value of HPV combined p16 status in patients with anal squamous cell carcinoma: a meta-analysis. AB - Human papillomavirus (HPV) DNA and p16 expression have been identified to be related to the progression of anal squamous cell carcinoma (ASCC). However, the prognostic relevance of combined detection, particularly HPV-/p16+ and HPV+/p16- signatures, is unknown. A meta-analysis of epidemiologic studies was therefore conducted to address this issue. Data were collected from studies comparing overall survival (OS) and disease-free survival (DFS) / disease-specific survival (DSS) / relapse-free survival (RFS) / progression-free survival (PFS) in ASCC patients with HPV and p16 status. The electronic databases of MEDLINE and EMBASE were searched from their inception till 31 May 2017. Study-specific risk estimates were pooled using a fixed-effects model for OS and DFS/DSS/RFS/PFS. Four studies involving a total of 398 ASCC cases were included in this meta analysis. The pooled results showed that HPV+/p16+ cancers were significantly associated with improved OS (HR = 0.30, 95% CI: 0.17-0.51) and DFS/DSS/RFS/PFS (HR = 0.23, 95% CI: 0.14-0.36). However, patients with HPV-/p16+ or HPV+/p16- do not have a comparably good prognosis compared with HPV+/p16+ patients. The meta analysis indicated that concomitant detection of HPV-DNA and p16 expression may be of prognostic or therapeutic utility in the evaluation of factors contributing to ASCC. Testing tumor specimens for HPV-DNA and p16 expression might indirectly affect treatment decisions. PMID- 29487717 TI - Meta-analysis of the effects of ischemic postconditioning on structural pathology in ST-segment elevation acute myocardial infarction. AB - In this meta-analysis, we assessed cardiac magnetic resonance imaging data to determine the effects of local and remote ischemic postconditioning (LPoC and RPoC, respectively) on structural pathology in ST-segmentel elevation acute myocardial infarction (STEMI). We searched the Pubmed, Embase and Cochrane Library databases up to May 2017 and included 12 randomized controlled trials (10 LPoC and 2 RPoC)containing 1069 study subjects with thrombolysis in myocardial infarction flow grade 0~1. Weighed mean difference (WMD), standardized mean difference (SMD), and odds ratio (OR) were used for the pooled analysis. Random effect model was used for the potential clinical inconsistency. LPoC and RPoC increased the myocardial salvage index (n = 5; weighted mean difference (WMD) = 5.52; P = 0.005; I2 = 76.0%), and decreased myocardial edema (n = 7; WMD = -3.35; P = 0.0009; I2 = 18.0%). However, LPoC and RPoC did not reduce the final infarct size (n = 10; WMD = -1.01; P > 0.05; I2 = 68.0%), left ventricular volume (n = 10; standardized mean difference = 0.23; P > 0.05; I2 = 93.0%), the incidence of microvascular obstruction (n = 6; OR = 0.99; P > 0.05; I2 = 0.0%) or the extent of microvascular obstruction (n = 3; WMD = -0.09; P > 0.05; I2 = 6.0%). This meta analysis shows that LPoC and/or RPoC improves myocardial salvage and decreases myocardial edema in STEMI patients without affecting final infarct size, left ventricular volume or microvascular obstruction. PMID- 29487718 TI - Meta-analysis of the prognostic value of long non-coding RNA AFAP1-AS1 for cancer patients in China. AB - LncRNA actin filament-associated protein 1 antisense RNA 1 (AFAP1-AS1) is often dysregulated in cancer. We performed this meta-analysis to clarify the usefulness of AFAP1-AS1 as a prognostic marker in malignant tumors. The PubMed, Medline, OVID, Cochrane Library, and Web of Science databases were searched from inception to Augest 7, 2017. Sixteen studies with a total of 1,386 patients were included in the study. The pooled hazard ratio (HR) suggested high AFAP1-AS1 expression correlated with poor overall survival (OS) (HR = 1.98, 95% confidence interval (CI): 1.71-2.28), disease-free survival (DFS) (HR = 1.54, 95% CI: 1.22-1.95), and progression-free survival (PFS) (HR = 2.17, 95% CI:1.64-2.88) in cancer patients, without obvious heterogeneity. High AFAP1-AS1 expression also correlated with larger tumor size (odds ratio (OR) = 2.04, 95% CI: 1.54-2.72), advanced tumor stage (OR=2.35, 95% CI: 1.70-3.26), poor histological grade (OR =1.39, 95% CI: 1.02-1.90), lymph node metastasis (OR = 2.71, 95% CI: 1.98-3.72) and distant metastasis (OR = 2.96, 95% CI: 2.03-4.32). Thus high AFAP1-AS1 expression is predictive of poor OS, DFS, PFS, lymph node metastasis, distant metastasis, histological grade, larger tumor size and tumor stage, which suggests high AFAP1 AS1 expression may serve as a novel biomarker of poor prognosis in cancer. PMID- 29487719 TI - Prognostic role of tumor-infiltrating CD57-positive lymphocytes in solid tumors: a meta-analysis. AB - The prognostic role of tumor-infiltrating CD57-positive lymphocytes (CD57+ lymphocytes) in human solid tumors remains controversial. Herein, we conducted a meta-analysis including 26 published studies with 7656 patients identified from PubMed and EBSCO to assess the prognostic impact of tumor-infiltrating CD57+ lymphocytes in human solid tumors. We found that CD57+ lymphocyte infiltration significantly improved overall survival (OS) including 1 - year, 3 - year and 5 - year survival, and disease - free survival (DFS) in all types of solid tumors. In stratified analyses, CD57+ lymphocyte infiltration was significantly associated with better OS in hepatocellular, esophageal, head and neck carcinoma, non-small cell lung cancer, 5 - year survival in colorectal cancer, and 3 - year and 5 - year survival in gastric cancer, but not with 1 - year survival in gastric cancer, or 1 - year or 3 - year survival in colorectal cancer. In addition, high density of intratumoral CD57+ lymphocytes was significantly inversely correlated with lymph node metastasis and TNM stage of solid tumor. In conclusion, CD57+ lymphocyte infiltration leads to a favorable clinical outcome in solid tumors, implicating that it is a useful biomarker for prognosis and adoptive immunotherapy based on these cells may be a promising choice for treatment. PMID- 29487720 TI - Efficacy and safety of targeting VEGFR drugs in treatment for advanced or metastatic gastric cancer: a systemic review and meta-analysis. AB - The value of targeting VEGFR (vascular endothelial growth factor receptor) drugs has demonstrated encouraging anti-cancer activity in advanced solid tumors within current clinical trials. This study aimed to serve as the first systemic review to assess their safety and efficacy according to biochemical characteristics of targeting VEGFR drugs in gastric cancer. We analyzed eight clinical trials on targeting VEGFR drugs in gastric cancer. Results showed that targeting VEGFR drugs significantly improved overall survival (OS) [Hazard Ratio (HR) 0.69, 95% confidence interval (CI) (0.55, 0.83), P < 0.001], progression free survival (PFS) [HR 0.50, 95% CI (0.34, 0.66), P < 0.001], disease control rate (DCR) [Odds Ratio (OR) 3.83, 95% CI (2.39, 6.15), P < 0.001] and significantly decreased the progressive disease rate(PDR)[OR 0.45, 95% CI (0.34, 0.59), P < 0.001], but not objective response rate (ORR) [OR 1.46, 95% CI (0.93, 2.29), P = 0.098]. Further subgroup revealed that VEGFR antibody (VEGFR-Ab) drugs were superior to VEGFR tyrosine kinase inhibitor (VEGFR-TKI) drugs in terms of the OS, PFS and PDR. To determine the toxic effect of targeting VEGFR drugs, the relative risk of adverse events (grade >= 3) of special interest(AESIs) were estimated. Most of these were predictable and manageable. Furthermore, less AESIs were observed in the VEGFR-Ab than the VEGFR-TKI drugs. In conclusion, VEGFR drugs were effective targeted therapy in advanced or metastatic gastric cancer, and its toxicity is within a controllable range. VEGFR-Ab drugs were more effective than VEGFR-TKI drugs in terms of the OS, PFS and PDR of gastric cancer patients with little toxicity. PMID- 29487721 TI - Clinicopathological characteristics and survival outcomes in adenosquamous carcinoma of the lung: a population-based study from the SEER database. AB - Adenosquamous carcinoma (ASC) of the lung is an unusual histology type in non small-cell lung cancers. Due to its rarity, the clinicopathological characteristics and survival outcomes of the lung ASC are incompletely understood. We used the Surveillance, Epidemiology, and End Results (SEER) database to enroll 203,208 eligible patients, including 4,245 ASC, 124,253 adenocarcinoma (ADC) and 74,710 squamous cell carcinoma (SCC) patients. To date, this is the largest cohort in a study for ASC of the lung. With regard to age, sex, race, year of diagnosis, tumor size and SEER stage, ASC was intermediate between ADC and SCC. However, compared with ADC and SCC patients, ASC patients presented with a higher tumor grade and lower prevalence of nodal metastasis. More ASC patients underwent surgery and a lower proportion underwent radiation treatment and chemotherapy. Kaplan-Meier analysis showed that ASC patients had a better prognosis than ADC and SCC patients, but stratified analysis showed that the prognosis of ASC patients was worse than that of ADC and SCC patients in surgery and non-surgery subgroup. Multivariate analysis further confirmed that the ASC histology type was a risk factor for poor prognosis with respect to ADC and SCC. Using the propensity score matching to 1:1 match ASC with ADC or SCC, we found that ASC patients had worse survival than ADC and SCC patients. Subgroup analysis further demonstrated that ASC was a more aggressive histology type with a worse prognosis. These results provided a deep understanding of ASC, which contributed to better clinical diagnosis and treatment. PMID- 29487722 TI - Prognostic role of the primary tumour site in patients with operable small intestine and gastrointestinal stromal tumours: a large population-based analysis. AB - The postoperative recurrence risk of gastrointestinal stromal tumour (GIST) should be estimated when considering adjuvant systemic therapy. Previous studies in the literature have suggested that small intestinal GISTs are more aggressive than gastric GISTs. We assessed the prognostic role of the primary tumour site in patients with operable GIST to compare the outcomes of gastric and small intestinal GISTs over a decade of treatment. The Surveillance, Epidemiology, and End Results (SEER) database was queried for cases of gastric and small intestinal GISTs between 2004 and 2014 using the GIST-specific histology code (ICD-O-3 code 8936), and only patients with tissues sampled by surgical resection were selected for this study. Cancer-specific survival (CSS) and overall survival (OS) were compared between small intestinal and gastric GISTs using Cox regression analyses. GISTs were located in the stomach (n = 2594, 65%), duodenum (n = 228, 6%), and jejunum/ileum (n = 1176, 29%). The OS and CSS of patients with GISTs in the duodenum and jejunum/ileum were similar to those of patients with gastric GISTs in Cox regression analyses, except for the CSS of patients with tumour sizes 2.1-5 cm in diameter and <= 5 mitoses per 50 HPFs (HR 1.657; 95% CI 1.062 2.587, p = 0.026). Tumours sizes 2.1-5 cm in diameter and > 5 mitoses per 50 HPFs (HR 4.627; 95% CI 1.035-20.67, p = 0.045) in jejunal/ileal GIST locations had significantly worse CSS than did those in gastric GIST locations. In this large nationwide study, the primary tumour site was not an independent prognostic factor in patients with operable small intestinal and gastric GISTs. PMID- 29487723 TI - A randomized phase II study of pelareorep and docetaxel or docetaxel alone in men with metastatic castration resistant prostate cancer: CCTG study IND 209. AB - Background: Pelareorep is an oncolytic virus with activity in many cancers including prostate. It has in vitro synergism with microtubule-targeted agents. We undertook a clinical trial evaluating pelareorep in mCRPC patients receiving docetaxel. Patients and Methods: In this randomized, open-label phase II study, patients received docetaxel 75mg/m2 on day 1 of a 21-day cycle and prednisone 5mg twice daily, in combination with pelareorep (arm A) or alone (arm B). The primary endpoint was 12 weeks lack of disease progression rate (LPD). Results: Eighty five pts were randomized. Median age was 69, ECOG performance status was 0/1/2 in 31%/66%/3% of patients. Bone/regional lymph node/liver metastases were present in 98%/24%/6%. The median prognostic score was slightly higher in Arm A (144 vs. 129 p= 0.005). Adverse events were as expected but more prevalent in arm A. The 12 week LPD rate was 61% and 52.4% in arms A/B (p=0.51). Median survival was 19.1 on Arm A and 21.1 months on Arm B (HR 1.83; 95% CI 0.96 to 3.52; p=0.06). No survival benefit of pelareorep was found. Conclusion: Pelareorep with docetaxel was tolerable with comparable LPD in both arms but response and survival were inferior and so this combination does not merit further study. PMID- 29487724 TI - FOXC1, the new player in the cancer sandbox. AB - In recent years, rapidly accumulating evidence implicates forkhead box C1 (FOXC1) in cancer, especially in studies of basal-like breast cancer (BLBC). Other studies have followed suit, demonstrating that FOXC1 is not only a major player in this breast cancer subtype, but also in hepatocellular carcinoma (HCC), endometrial cancer, Hodgkin's lymphoma (HL), and non-Hodgkin's lymphoma (NHL). The FOXC1 gene encodes a transcription factor that is crucial to mesodermal, neural crest, and ocular development, and mutations found in FOXC1 have been found to cause dominantly inherited Axenfeld-Rieger Syndrome (ARS). Interestingly, while FOXC1 missense mutations that are associated with ARS usually reduce gene activity, increased FOXC1 function now appears to be often linked to more aggressive cancer phenotypes in BLBC, HCC, HL, and NHL. This review discusses not only the role of FOXC1 in cancer cell progression, proliferation, differentiation, and metastasis, but also the underlying mechanisms of how FOXC1 can contribute to aggressive cancer phenotypes. PMID- 29487726 TI - Complete response in a patient with liver metastases from breast cancer employing hepatic arterial infusion 5-fluorouracil based chemotherapy plus systemic nab paclitaxel. AB - About half of patients with metastatic breast cancer (mBC) have unresectable liver metastases (LMs) or liver-predominant disease (LPD). Unfortunately systemic chemotherapy has limited tumor response due to LMs are supplied by hepatic artery. Hepatic intra-arterial (HAI) have antitumor activity in pretreated patients with LMs. Here we report the case of a 55-year-old woman affected by BCLPD and heavily pretreated. LMs responded to treatment based on HAI with 5 fluorouracil and nab-paclitaxel systemic chemotherapy, and they completely disappeared on a CT-scan. We conclude that this combination chemotherapy is safe and may be very useful for the treatment of patients with BCLPD. Therefore, this combination should be evaluated in a large study. PMID- 29487725 TI - microRNA involvement in the onset and progression of Barrett's esophagus: a systematic review. AB - Esophageal adenocarcinoma (EAC) is a highly aggressive malignancy that develops from Barrett's esophagus (BE), an intestinal metaplasia of the distal esophagus. microRNAs (miRNAs), short non-coding regulatory RNAs, are frequently dysregulated in BE and are thought to play key roles in the onset of BE and its progression to EAC. miRNAs thus have potential diagnostic and prognostic value and are increasingly being used as cancer biomarkers. This review summarizes the current literature related to miRNAs that are dysregulated in BE within the context of Hedgehog, Notch, MAPK, NF kappa-B, Wnt and epithelial-mesenchymal transition (EMT) signaling which are thought to drive BE onset and progression. This comprehensive analysis of miRNAs and their associated signaling in the regulation of BE provides an overview of vital discoveries in this field and highlights gaps in our understanding of BE pathophysiology that warrant further investigation. PMID- 29487727 TI - Red blood cell distribution width in heart failure: A narrative review. AB - The red blood cell distribution width (RDW) is a simple, rapid, inexpensive and straightforward hematological parameter, reflecting the degree of anisocytosis in vivo. The currently available scientific evidence suggests that RDW assessment not only predicts the risk of adverse outcomes (cardiovascular and all-cause mortality, hospitalization for acute decompensation or worsened left ventricular function) in patients with acute and chronic heart failure (HF), but is also a significant and independent predictor of developing HF in patients free of this condition. Regarding the biological interplay between impaired hematopoiesis and cardiac dysfunction, many of the different conditions associated with increased heterogeneity of erythrocyte volume (i.e., ageing, inflammation, oxidative stress, nutritional deficiencies and impaired renal function), may be concomitantly present in patients with HF, whilst anisocytosis may also directly contribute to the development and worsening of HF. In conclusion, the longitudinal assessment of RDW changes over time may be considered an efficient measure to help predicting the risk of both development and progression of HF. PMID- 29487728 TI - The high prevalence of Mycobacterium tuberculosis Beijing strain at an early age and extra-pulmonary tuberculosis cases. AB - Background and Objectives: Tuberculosis (TB) is still responsible for a wide range of deaths worldwide. Beijing genotype is one of the most important and virulent strains in Mycobacterium tuberculosis. This study was designed for determination Beijing genotypes of M. tuberculosis in Golestan province, north of Iran. Materials and Methods: In the current descriptive study, 238 clinical MTB isolates, obtained from patients with pulmonary and extra-pulmonary TB in north of Iran, were evaluated. Oligonucleotide primers for the Beijing and non-Beijing genotypes and specific probes for their detection by a real-time PCR method were employed. In addition, an association between the Beijing genotype and possible clinical and demographic factors was evaluated. Results: The method revealed that 33 cases (13.9%) were the Beijing lineage and 205 (86.1%) the non-Beijing genotype. The mean age of patients infected with the Beijing and non-Beijing strains was 37.27 +/- 18.3 and 51 +/- 21.2 years, respectively; the difference was statistically significant (P = 0.001). In addition, the prevalence of the Beijing strain decreased with age. Patients with a TB infection caused by the Beijing genotype were also more vulnerable to treatment failure. Based on the origin of the samples, the Beijing genotype was more often observed in extra pulmonary samples compared with Pulmonary ones (P = 0.001). Conclusion: The Beijing genotype of MTB is prevalent in our region especially among young people which could indicate the risk of further expansion in the future. PMID- 29487729 TI - Prevalence of Acinetobacter baumannii bacteremia in intensive care units of Ibn Rochd University Hospital, Casablanca. AB - Background and Objectives: Acinetobacter baumannii bacteremia are grave because of the multi-resistance of the organism to antibiotics. This study aimed to determine the prevalence of A. baumannii isolated from blood cultures and to describe their antibiotic resistance patterns. Materials and Methods: A retrospective longitudinal study was conducted on blood cultures between 2010 and 2014 from all Ibn Rochd University Hospital intensive care units; it was based on the exploitation of microbiology laboratory database (duplicates were excluded). Isolation and identification of A. baumannii were performed according to standard techniques of bacteriology and susceptibility testing as recommended by the CLSI. PCR was used to detect beta-Lactamase genes, blaOXA-51, blaOXA-23. Results: Among the 4232 samples received at the laboratory, 2402 (56.8%) were positive. Negative coagulase Staphylococcus was isolated in 21.6% of cases followed by A. baumannii (9.2%), and K. pneumoniae (9.1%). A. baumannii strains were resistant to most antibiotics tested: imipenem (75.7%), ceftazidim (85.4%), cefotaxim (98.6%), gentamicin (78.1%), amikacin (63.5%) and ciprofloxacin (88.2%). All A. baumannii strains, resistant to carbapenem, tested were positive for blaOXA-51 genes and 87.5% expressed the blaOXA-23 genes. Conclusion: A. baumannii was the second germ frequently isolated from blood cultures in intensive care units. It was multi resistant to antibiotics. The strengthening of hospital hygiene measures and surveillance of antibiotic resistance is needed to limit the spread of germs and to optimize the management of antibiotics. PMID- 29487730 TI - Fibrinogen and mucin binding activity of EF0737, a novel protein of Enterococcus faecalis. AB - Background and Objectives: Enterococcus faecalis is the leading cause of several human infections. This opportunist pathogen expresses surface components that have various functions in the infection process including bacterial adhesion, lytic activity, and induction of host immune responses. EF0737, a novel cell wall associated protein, may play an important role in pathogenesis of E. faecalis, based on our experiments. This study was conducted to clone and express EF0737 and demonstrate its interaction with biotinylated plasma proteins and patients' sera. Materials and Methods: The full length of ef0737 gene was cloned in pTZ57R/T cloning vector and subcloned in pET21a expression vector. Recombinant protein expressed in Escherichia coli Origami (DE3) was confirmed by western blot technique, using anti-His tagged monoclonal antibodies, and was then purified. Interaction of the recombinant protein with plasma proteins and patients' sera were examined by western blot. Results: The ef0737 gene was successfully cloned and expressed in E. coli Origami host. Binding activity was observed between the purified EF0737 recombinant protein and fibrinogen and mucin among other plasma proteins. Moreover, reaction was also observed between the purified product and sera obtained from patients diagnosed with E. faecalis infection. Conclusion: The observed reactions between EF0737 and fibrinogen, mucin and patients' sera suggest that EF0737 may play important role in pathogenesis of infections caused by E. faecalis. However, more comprehensive characterization of this novel protein may provide better understanding of host pathogen interaction. PMID- 29487731 TI - Evidence of heat-resistant microorganisms with a special emphasis on filamentous Actinomycetes in hyper-arid soils of Gandom Beryan area, Lut Desert, Iran. AB - Background and Objectives: In the present study, the Lut Desert, Iran was chosen as one of the hottest places in the world (with the recorded temperature of 70.7 degrees C during 2003-2009) to find out whether any heat-resistant microorganisms were present in the soil. Materials and Methods: The samples were collected from surface and depth of three identified places of Gandom Beryan in the Lut Desert. Chemical analysis and enumeration of the total bacteria, yeasts and molds were performed. Four selective culture media were employed to isolate the filamentous actinomycetes. The suspected colonies were further confirmed using PCR assay. Then the culture cell-free-supernatants (CFS) of isolates were used to investigate their antimicrobial activity against Staphylococcus aureus, Bacillus cereus, Salmonella Typhimurium and Escherichia coli. Results: Chemical analysis of the samples included moisture (0.2-0.9%), ash (85-91%), organic materials (8.3 14.4%), pH (7.59-9.40) and electrical conductivity (380-2000 MUS/cm). The number of isolated bacteria and molds varied from 0-20 to 0-40 CFU/g, respectively. Number of Actinomycetes isolated from the soil samples were between 0-12.2 CFU/g. Nine isolated colonies were identified as filamentous Actinomycetes. To determine the possibility of antimicrobial peptides, the CFS (cell-free supernatant) was firstly neutralized by NaOH and catalase. The results showed that none of the CFS of the isolates was effective against E. coli, S. Typhimurium and S. aureus, while the maximum inhibitory effect was investigated on B. cereus, which was 33.1%+/-1.19% (mean +/- SD). Conclusion: The results of the current study imply the presence of rare heat-resistant microorganisms in the soil of Gandom Beryan which may be further used to find out more about the function of natural bioactive compounds. Actinomycetes, as extremophile microorganisms, have shown the greatest genomic and metabolic diversity, as such the discovery of the novel Actinomycetes as a source of secondary metabolites is essential. PMID- 29487732 TI - Isolation and identification of Komagataeibacter xylinus from Iranian traditional vinegars and molecular analyses. AB - Background and Objectives: Acetic acid bacteria (AAB) are one of the major interests of researchers. Traditional vinegars are suitable sources of AAB because they are not undergone industrial process like filtering and adding preservatives. Komagataeibacter xylinus as a member of AAB is known as the main cellulose producer among other bacteria. The purpose of the current study was to isolate the bacteria from traditional vinegars and its molecular analyses. Materials and Methods: Vinegar samples were collected. Well-organized bacteriological tests were carried out to differentiate isolated bacteria from other cellulose producers and to identify K. xylinus. NaOH treatment and Calcofluor white staining were used for detecting cellulose. Chromosomal DNA of each strain was extracted via three methods of boiling, phenol-chloroform and sonication. Molecular analyses were performed on the basis of 16S rRNA sequences and cellulose synthase catalytic subunit gene (bcsA) for further confirmation. Phylogenetic tree was constructed for more characterization. Two housekeeping genes were studied including phenylalanyl-tRNA synthase alpha subunit (pheS) and RNA polymerase alpha subunit (rpoA). Results: Of the 97 samples, 43 K. xylinus strains were isolated. They were identified via bacteriological and molecular techniques. 16S rDNA sequence showed 99% similarity with registered sequences of the bacteria. Biodiversity of the genome confirmed by analyzing bcsA, pheS and rpoA genes. Conclusion: K. xylinus can be isolated from traditional vinegars. Screening tests ought to include the classical methods and molecular techniques. Different molecular techniques and more genomic research should be developed to expand our knowledge for distinguishing isolated bacteria especially in the fields of AAB. PMID- 29487733 TI - Antagonistic activities of some probiotic lactobacilli culture supernatant on Serratia marcescens swarming motility and antibiotic resistance. AB - Background and Objectives: Serratia marcescens, a potentially pathogenic bacterium, benefits from its swarming motility and resistance to antibiotic as two important virulence factors. Inappropriate use of antibiotics often results in drug resistance phenomenon in bacterial population. Use of probiotic bacteria has been recommended as partial replacement. In this study, we investigated the effects of some lactobacilli culture supernatant on swarming, motility and antibiotic resistance of S. marcescens. Materials and Methods: Antimicrobial activity of lactobacilli supernatant and susceptibility testing carried out on S. marcescens isolates. Pretreatment effect of lactobacilli culture supernatant on antibiotic - resistance pattern in S. marcescens was determined by comparison of the MIC of bacteria before and after the treatment. Results: Our results showed that pretreatment with L. acidophilus ATCC 4356 supernatant can affect the resistance of Serratia strains against ceftriaxone, but it had no effect on the resistance to other antibiotics. Furthermore, culture supernatant of lactobacilli with concentrations greater than 2%, had an effect on the swarming ability of S. marcescens ATCC 13880 and inhibited it. Conclusion: Probiotic bacteria and their metabolites have the ability to inhibit virulence factors such as antibiotic resistance and swarming motility and can be used as alternatives to antibiotics. PMID- 29487734 TI - Natural overproduction of catalase by Kocuria sp. ASB 107: extraction and semi purification. AB - Background and Objectives: Because of importance of catalase in various industries, efforts have been made to find more suitable bacterial sources for catalase production. Kocuria is one of well-known catalase-producing genus. This is the first report about a new catalase-overproducing bacterial strain, Kocuria sp. ASB 107. Materials and Methods: Kocuria sp. ASB 107 had been isolated from Abe-Siah Spring in Ramsar in our previous report. The bacterial biomass freezed, thawed and then lysed by three different operations separately: ultrasound, lysing buffer and enzymatic digestion. The crude extract was subjected to ammonium sulfate precipitation (40 and 60% saturation). Quality and quantity of the semi-purification was checked by electrophoresis and measuring specific activity, respectively. Results: Kocuria sp. ASB 107 can be lysed by a freeze thaw stage followed by lysozyme digestion and not by lysing buffer and not by ultrasound. Surprisingly specific activity of catalase in crude extract from Kocuria sp. ASB 107 was measured to be 195, 370 U/mg protein which is too much higher than other bacterial strains. The bacterium showed a relatively long growth curve about 40 hours. Semi-purification using ammonium sulfate precipitation was led in an increased specific activity up to about 7*106 U/mg protein implying more than 3.6-fold purification. Conclusion: We have showed natural catalase-overproducing ability of Kocuria sp. ASB 107. Yield and purity of catalase from Kocuria sp. ASB 107 showed great potential in industrial application suggesting the strain as good source for mass production of catalase for treatment of H2O2-containing wastewater in comparison to other bacterial sources. PMID- 29487735 TI - Antifungal susceptibility patterns of colonized Candida species isolates from immunocompromised pediatric patients in five university hospitals. AB - Background and Objectives: Colonization of Candida species is common in pediatric patients admitted to hematology-oncology wards. The aim of this study was to identify colonized Candida species and their susceptibility patterns in hematologic pediatric patients. Materials and Methods: Samples were collected from mouth, nose, urine and stool of the patients admitted to five university hospitals and cultured on sabouraud dextrose agar. The isolates were identified by API 20 C AUX system and their susceptibility patterns were evaluated by CLSI M27-A3 and S4. Results: From 650 patients, 320 (49.2%) were colonized with 387 Candida species. Candida albicans was the most prevalent isolated species, followed by Candida glabrata, Candida tropicalis, Candida famata, Candida kefyr and Candida kuresi. The epidemiological cut off value (ECV) for all Candida species to amphotericin B was <=0.25 MUg except C. krusei (4 MUg). The resistance rate to fluconazole in this study in C. albicans was 4.9% with ECV 8 MUg/ml, followed by C. tropicalis 8.8% with ECV 0.5 MUg/ml. Voriconazole and posaconazole were effective antifungal agents for all Candida isolates. The ECV of C. albicans, Candida parapsilosis, C. tropicalis, C. glabrata and C. krusei for itraconazole were 0.5, 0.25, 0.5, 1 and 2 MUg, respectively. The resistant and intermediate rates of Candida species to caspofungin in this study were 2.9%, 5.9%, 18.8%, 47.9%, 0.0% and 16.7% in C. tropicalis, C. glabrata and C. parapsilosis respectively. Conclusion: C. albicans was the most prevalent species in pediatric colonized patients. New azole agents like voriconazole and posaconazole are effective against non-albicans Candida species. Increase in intermediate species is alarming to future emerging resistant species. PMID- 29487736 TI - Assessment and comparison of the pathogenicity of Sheeppox Virus strains isolated in Morocco. AB - Background and Objectives: Sheeppox virus causes systemic disease in sheep that is often associated with high morbidity and mortality. Protection against sheep pox is mainly based on medical prophylaxis, vaccination being the only way. In Morocco, and up to now, there is no available information about local challenge strain to use for controlling the efficiency of vaccines produced against sheep pox. Hence, the objective of the present study was to evaluate and compare the pathogenicity of seven Sheeppox virus (SPVs) isolates from 1993-1995 in Morocco. Materials and Methods: These seven SPV isolates have undergone various tests to evaluate their pathogenicity: Passages and titration on cell culture, Experimental inoculation on sheep, Virus-neutralization, In vivo titration and viral re-isolation by real-time PCR assay. Results: All infected lambs showed severe clinical signs, while most of them have been reproduced on 5 dpi and persisted until 21 dpi. The lambs infected by Oj1P4, Oj2P4 and BerP5 appeared lethargic, reluctant to move compared to those infected by other isolates. The results also revealed that all isolates were able to induce serological response. Virus isolation from infected organs and blood and amplification of the viral DNA by real-time PCR proved the presence of the virus in tissues and blood of infected lambs. These Moroccan SPVs demonstrated that the three isolates Oj1P4, Oj2P4 and BerP5 have a high pathogenicity; especially the BerP5 isolate which has an important infectious titer. Conclusion: These results demonstrate that the Berkane isolate is the most pathogenic of the tested isolates and it can be an excellent challenge strain for the control of the efficiency of vaccines against sheep pox produced in Morocco. PMID- 29487737 TI - Recent approaches in whole cell pneumococcal vaccine development: a review study. AB - Despite the availability of relatively effective vaccines, Streptococcus pneumoniae still causes widespread morbidity and mortality. Current vaccines contain free polysaccharides or protein-polysaccharide conjugates, but do not induce protection against serotypes that are not included in the vaccines. Therefore, developing alternative vaccines is of high priority and importance. Several investigators have identified protective antigens common to pneumococci of many or all serotypes. Malley et al. in their study, have recommended unencapsulated whole cells, as an alternative vaccine, a number of such antigens unoccluded by capsule were presented in a native configuration in 2001. This review aimed at presenting this candidate of pneumococcal vaccine and results in an animal model. PMID- 29487738 TI - A multi-tool recipe to identify regions of protein-DNA binding and their influence on associated gene expression. AB - One commonly performed bioinformatics task is to infer functional regulation of transcription factors by observing differential expression under a knockout, and integrating DNA binding information of that transcription factor. However, until now, this this task has required dedicated bioinformatics support to perform the necessary data integration. GenomeSpace provides a protocol, or "recipe", and a user interface with inter-operating software tools to identifying protein occupancies along the genome from a ChIP-seq experiment and associated differentially regulated genes from an RNA-Seq experiment. By integrating RNA-Seq and ChIP-seq analyses, a user is easily able to associate differing expression phenotypes with changing epigenetic landscapes. PMID- 29487739 TI - Multi-species consumer jams and the fall of guarded corals to crown-of-thorns seastar outbreaks. AB - Outbreaks of predatory crown-of-thorns seastars (COTS) can devastate coral reef ecosystems, yet some corals possess mutualistic guardian crabs that defend against COTS attacks. However, guarded corals do not always survive COTS outbreaks, with the ecological mechanisms sealing the fate of these corals during COTS infestations remaining unknown. In August 2008 in Moorea (17.539 degrees S, 149.830 degrees W), French Polynesia, an unusually dense multi-species aggregation of predators was observed feeding upon guarded corals following widespread coral decline due to COTS predation. Concurrent assaults from these amplified, mixed-species predator guilds likely overwhelm mutualistic crab defense, ultimately leading to the fall of guarded corals. Our observations indicate that guarded corals can sustain devastating COTS attacks for an extended duration, but eventually concede to intensifying assaults from diverse predators that aggregate in high numbers as alternative prey decays. The fall of guarded corals is therefore suggested to be ultimately driven by an indirect trophic cascade that leads to amplified attacks from diverse starving predators following prey decline, rather than COTS assaults alone. PMID- 29487740 TI - Tuition reduction is the key factor determining tax burden of graduate students under the Tax Cuts and Job Act. AB - BACKGROUND: The proposed Tax Cuts and Jobs Act (H.R.1) has stirred significant public debate on the future of American economics. While supporters of the plan have championed it as a necessity for economic revitalization, detractors have pointed out areas of serious concern, particularly for low- and middle-income Americans. One particularly alarming facet of the plan is the radical change to education finance programs and taxation of students in higher education. Methods: By analyzing actual income and tuition of a public and a private university student, as well as the 'average' graduate student, we investigated the effect of both the House and Senate versions of H.R. 1 on taxation of students of various family structures. Results: Our findings indicate that taxable tuition would be the greatest contributor to graduate student tax burden across all four categories of filing status. However, when tuition reduction is upheld or a student is on sustaining fees rather than full tuition, graduate students would realize decreases in taxation. CONCLUSIONS: Overall, we conclude that removal of tuition reduction would result in enormous tax burdens for graduate students and their families and that these effects are dependent not only on the status of the student in their degree program but also on their tuition and stipend, and therefore the institution they attend. PMID- 29487741 TI - Associative memory cells and their working principle in the brain. AB - The acquisition, integration and storage of exogenous associated signals are termed as associative learning and memory. The consequences and processes of associative thinking and logical reasoning based on these stored exogenous signals can be memorized as endogenous signals, which are essential for decision making, intention, and planning. Associative memory cells recruited in these primary and secondary associative memories are presumably the foundation for the brain to fulfill cognition events and emotional reactions in life, though the plasticity of synaptic connectivity and neuronal activity has been believed to be involved in learning and memory. Current reports indicate that associative memory cells are recruited by their mutual synapse innervations among co-activated brain regions to fulfill the integration, storage and retrieval of associated signals. The activation of these associative memory cells initiates information recall in the mind, and the successful activation of their downstream neurons endorses memory presentations through behaviors and emotion reactions. In this review, we aim to draw a comprehensive diagram for associative memory cells, working principle and modulation, as well as propose their roles in cognition, emotion and behaviors. PMID- 29487743 TI - Mullerian duct cyst treated with template-guided transperineal aspiration: a case report and review of the literature. AB - Template-guided transperineal aspiration is a minimally invasive treatment option for patients with Mullerian duct cysts. The precise targeting provided by the brachytherapy template grid enables specific targeting, quick recovery and resolution of symptoms without complications. PMID- 29487744 TI - Combined caesarean section and open reduction internal fixation for the treatment of an acetabular fracture in late pregnancy. AB - In this case, we opted for dual surgery combining caesarean section and internal fixation of acetabular fracture in late pregnancy, which allowed safe foetal delivery, fracture repair and early ambulation of the mother. In similar cases, this method could be potentially considered in the armamentarium of treatment options, aiming to facilitating prompt motherhood input and early hospital discharge, as well as minimising the risk of post-traumatic arthritis of the hip. PMID- 29487745 TI - A qualitative study of the perspectives of key stakeholders on the delivery of clinical academic training in the East Midlands. AB - Objective: Major changes in the design and delivery of clinical academic training in the United Kingdom have occurred yet there has been little exploration of the perceptions of integrated clinic academic trainees or educators. We obtained the views of a range of key stakeholders involved in clinical academic training in the East Midlands. Design: A qualitative study with inductive iterative thematic content analysis of findings from trainee surveys and facilitated focus groups. Setting: The East Midlands School of Clinical Academic Training. Participants: Integrated Clinical Academic Trainees, clinical and academic educators involved in clinical academic training. Main outcome measures: The experience, opinions and beliefs of key stakeholders about barriers and enablers in the delivery of clinical academic training. Results: We identified key themes many shared by both trainees and educators. These highlighted issues in the systems and process of the integrated academic pathways, career pathways, supervision and support, the assessment process and the balance between clinical and academic training. Conclusions: Our findings help inform the future development of integrated academic training programmes. PMID- 29487742 TI - The interplay between immunity and aging in Drosophila. AB - Here, we provide a brief review of the mechanistic connections between immunity and aging-a fundamental biological relationship that remains poorly understood-by considering two intertwined questions: how does aging affect immunity, and how does immunity affect aging? On the one hand, aging contributes to the deterioration of immune function and predisposes the organism to infections ("immuno-senescence"). On the other hand, excessive activation of the immune system can accelerate degenerative processes, cause inflammation and immunopathology, and thus promote aging ("inflammaging"). Interestingly, several recent lines of evidence support the hypothesis that restrained or curbed immune activity at old age (that is, optimized age-dependent immune homeostasis) might actually improve realized immune function and thereby promote longevity. We focus mainly on insights from Drosophila, a powerful genetic model system in which both immunity and aging have been extensively studied, and conclude by outlining several unresolved questions in the field. PMID- 29487746 TI - Impact of Exercise Counseling on Physical Function in Chronic Kidney Disease: An Observational Study. AB - Background: Individuals with chronic kidney disease (CKD) have low levels of physical activity and physical function. Although guidelines endorse exercise counseling for individuals with CKD, it is not yet part of routine care. Objective: We investigated the effect of attending a real-life exercise counseling clinic (ECC) on physical function in individuals with CKD. Design: Retrospective analysis of prospectively collected observational data with quasi experimental design. Setting and Participants: Patients with all stages of CKD registered in a large provincial renal program were eligible. The exposed cohort who attended the ECC between January 1, 2011, and March 15, 2014, included 214 individuals. The control cohort included 292 individuals enrolled in an observational study investigating longitudinal change in frailty during the same time period. Predictor/Factor: Attendance at an ECC. Outcomes and Measurements: Change in physical function as measured by Short Physical Performance Battery (SPPB) score, physical activity level (Human Activity Profile [HAP]/Physical Activity Scale for the Elderly [PASE]), and health-related quality of life (HRQOL; EQ5D/VAS) over 1 year. Results: Eighty-seven individuals in the ECC cohort and 125 participants in the control cohort completed 1-year follow-up. Baseline median SPPB score was 10 (interquartile range [IQR]: 9-12) and 9 (IQR: 7 11) in the ECC and control cohorts, respectively (P < .01). At 1 year, SPPB scores were 10 (IQR: 8-12) and 9 (IQR: 6-11) in the ECC and control cohorts, respectively (P = .04). Mean change in SPPB over 1 year was not significantly different between groups: -0.33 (95% confidence interval [CI]: -0.81 to 0.15) in ECC and -0.22 (95% CI: -0.61 to 0.17) in control (P = .72). There was no significant difference in the proportion of individuals in each cohort with an increase/decrease in SPPB score over time. There was no significant change in physical activity or HRQOL over time between groups. Limitations: Quasi experimental design, low rate of follow-up attendance. Conclusions: In this pragmatic study, exercise counseling had no significant effect on change in SPPB score, suggesting that a single exercise counseling session alone is inadequate to improve physical function in CKD. PMID- 29487747 TI - Extranodal non-B, non-T-cell lymphoma with bilateral tympanic bulla involvement in a cat. AB - Case summary: A 9-year-old spayed female domestic shorthair cat with clinical signs suggestive of chronic recurrent otitis media and recent seizures was presented with multifocal nervous system disease, including bilateral central and/or peripheral vestibular, cerebellar and forebrain deficits. Prior to presentation, there was inadequate improvement after 6 weeks of treatment for bilateral middle ear effusion from which a highly susceptible Staphylococcus species was cultured. This was followed by the development of seizures. Results of a complete blood count and serum chemistry were unremarkable, and a previous feline leukemia virus/feline immunodeficiency virus ELISA was negative. The cat was hospitalized overnight and had multiple seizures. The following morning the cat's mentation worsened, and the cat lost ventilatory drive after induction for anesthesia in preparation for MRI. A brain herniation event was suspected, and the cat was euthanized prior to further diagnostics. On post-mortem examination both tympanic bullae were filled with a soft, tan-colored material. Histologically, this material was composed of neoplastic lymphocytes. In addition, neoplastic lymphocytes were found in the leptomeninges, brain parenchyma, submandibular lymph nodes and pancreas. The neoplastic lymphocytes were negative for both B- and T-lymphocyte immunohistochemical markers and PCR for antigen receptor rearrangements failed to amplify target DNA, indicating non B, non-T-cell lymphoma. Relevance and novel information: To our knowledge, this is the first report of lymphoma with confirmed bilateral tympanic bulla involvement in the human and veterinary literature. Neoplasia should be considered in cases of middle-ear effusion that do not improve adequately with appropriate antimicrobial therapy. PMID- 29487748 TI - Factors associated with pericolic fat stranding of colon cancer on computed tomography colonography. AB - Background: Pericolic fat stranding on computed tomography (CT) scans has been an important feature for staging colon cancer. However, the factors associated with pericolic fat stranding have not been elucidated to date. Purpose: To determine factors associated with pericolic fat stranding of colon cancer on CT colonography (CTC). Material and Methods: Overall, 150 patients with 155 colon cancer lesions were retrospectively assessed by two radiologists for pericolic fat stranding on CTC. Circumferential proportion of the tumor (CPtumor; <50%, 50 75%, and >=75%), longitudinal length, depth of invasion (<=T2, T3, T4), lymph node and distant metastasis, and lymphovascular invasion were recorded. Univariate and multivariate logistic regression analyses were performed between pericolic fat stranding and each factor. Multi-group comparisons were performed for the CPtumor and depth of invasion. Results: Pericolic fat stranding was identified in 57 lesions (36.8%). Univariate analysis revealed significant associations of pericolic fat stranding with all factors (P < 0.027), except for lymph node metastasis (P = 0.087). Multi-group comparisons revealed that pericolic fat stranding was more frequent with increasing CPtumor (P < 0.001); however, no significant differences were observed beyond subserosal infiltration (P = 0.225). Logistic regression analysis revealed the CPtumor (<75% vs. >=75%; P = 0.008, <50% vs. 50-75%; P = 0.047) and longitudinal length (P = 0.001) as explainable variables. Conclusion: Pericolic fat stranding identified on CT images of colon cancer is demonstrated more frequently with increasing circumferential proportion of the tumor and longitudinal length. PMID- 29487749 TI - Assessment of Salivary Adipokines Resistin, Visfatin, and Ghrelin as Type 2 Diabetes Mellitus Biomarkers. AB - Type 2 diabetes mellitus (T2DM) is emerging as a metabolic epidemic worldwide. Pathologically, dysregulation of many biological pathways precedes hyperglycemia and the clinical diagnosis of T2DM. Changing trajectories along the process of T2DM development necessitates frequent measurement of biomarkers for early identification of at-risk individuals and successful prevention. Increase in circulating inflammatory adipokines has been suggested as predictive of T2DM. Human saliva is an easily accessible biospecimen amenable for painless frequent collection and possesses nearly 50% of serum proteome. In this study, we measured the adipokines resistin, visfatin, TNF-alpha, and ghrelin as markers for T2DM in unstimulated whole saliva (UWS) using specific assay kits. Resistin and visfatin concentrations were significantly higher in T2DM saliva. Although the concentration of acylated or unacylated ghrelin was lower in diabetic saliva, the decrease was not significant. Since resistin and visfatin are biomarkers integral to T2DM pathology, their salivary assessments may receive clinical acceptance. PMID- 29487750 TI - Transcatheter Aortic Valve Implantation in a Nonagenarian with Aortic Aneurysm: Futility or Utility? AB - Transcatheter aortic valve implantation (TAVI) has emerged as the standard of care for older patients with symptomatic severe aortic stenosis (AS) at high or excessive operative risk. There remain patients that are of such considerable risk that even TAVI can be futile. Such patients present ethical conundrums for institutional heart teams. Herein we present a case of a 90-year-old female patient with symptomatic severe AS and significant comorbidities including diffuse peripheral vascular disease and a large ascending aortic aneurysm. Would TAVI be utile or futile in this patient? PMID- 29487751 TI - Alveolar Ridge Preservation Using a Novel Synthetic Grafting Material: A Case with Two-Year Follow-Up. AB - This case report highlights the use of a novel in situ hardening synthetic (alloplastic), resorbable, bone grafting material composed of beta tricalcium phosphate and calcium sulfate, for alveolar ridge preservation. A 35-year-old female patient was referred by her general dentist for extraction of the mandibular right first molar and rehabilitation of the site with a dental implant. The nonrestorable tooth was "atraumatically" extracted without raising a flap, and the socket was immediately grafted with the synthetic biomaterial and covered with a hemostatic fleece. No membrane was used, and the site was left uncovered without obtaining primary closure, in order to heal by secondary intention. After 12 weeks, the architecture of the ridge was preserved, and clinical observation revealed excellent soft tissue healing without loss of attached gingiva. At reentry for placement of the implant, a bone core biopsy was obtained, and primary implant stability was measured by final seating torque and resonance frequency analysis. Histological analysis revealed pronounced bone regeneration while high levels of primary implant stability were recorded. The implant was successfully loaded 12 weeks after placement. Clinical and radiological follow-up examination at two years revealed stable and successful results regarding biological, functional, and esthetic parameters. PMID- 29487752 TI - Thyroid Storm Triggered by Strangulation in a Patient with Undiagnosed Graves' Disease. AB - Thyroid storm is the life-threatening end-organ manifestation of severe thyrotoxicosis. If left untreated, thyroid storm may cause acute heart failure, multiorgan dysfunction, and death. A high degree of suspicion is necessary to make the diagnosis and start antithyroid medications to decrease mortality. Thyroid storm is generally seen in patients with Graves' disease but should also be suspected in patients with fever, tachycardia, altered mental status, and risk factors including local trauma to the neck, such as strangulation. Based on our review, we report the first case of thyroid storm after strangulation as the presentation of previously undiagnosed Graves' disease. PMID- 29487753 TI - Acquired Elliptocytosis as a Manifestation of Myelodysplastic Syndrome Associated with Deletion of Chromosome 20q. AB - Elliptocytosis is commonly seen as a hereditary condition. We present a case of myelodysplastic syndrome (MDS) del(q20) variant with concomitant acquired elliptocytosis. A 73-year-old male with a history of prostate cancer presented to the hospital for evaluation of bleeding gums. Initial evaluation showed Hgb of 9.3 gm/dl, hematocrit of 28%, platelet count of 36,000 K/cmm, and WBC of 1.8 K/cmm with an ANC of 0.8 K/cmm. A slightly elevated bilirubin of 1.2 mg/dl spurred a hemolytic workup. Peripheral smear showed frequent elliptocytes, teardrop cells, schistocytes, and occasional spherocytes. Bone marrow biopsy did not show significant fibrosis to explain the elliptocytosis. Cytogenetics showed 20q deletion, and later, he was started on therapy for intermediate risk MDS. Bone marrow biopsy after completion of 6 cycles showed complete cytogenetic remission with significant improvement in elliptocytosis. Elliptocytosis in the setting of MDS has rarely been reported, and association with 20q deletion is even rarer. Animal studies have shown that haploinsufficiency of L3MBTL1 contributes to some (20q-) myeloproliferative neoplasms and myelodysplastic syndromes by affecting erythroid differentiation. Our case report raises interesting questions: Does MDS with rarely reported elliptocytosis indicate a disease process that is different from the usual 20q deletion? Is haploinsufficiency of L3MBTL1 responsible for this manifestation? PMID- 29487754 TI - Modified Descemet's Stripping Automated Endothelial Keratoplasty: The Use of Ophthalmic Viscoelastic Devices in Hypotonic Eyes That Had Undergone Glaucoma Filtering Surgeries. AB - Purpose: Descemet's stripping automated endothelial keratoplasty (DSAEK) is more difficult in hypotonic eyes with filtering bleb, due to the difficulties in elevating the intraocular pressure (IOP). We report a new method that uses ophthalmic viscoelastic devices (OVDs) to achieve good graft adhesion. Case Presentation: We performed modified DSAEK surgery on 2 eyes of 2 patients, who had previously undergone a trabeculectomy. Both eyes had functioning filtering blebs; the IOP was lower than 10 mmHg without medication. After the graft was inserted into the anterior chamber, the conjunctiva was penetrated, apart from the bleb, using a 30 G needle, and Healon V(r) was injected into the bleb until the encapsulated space was filled completely. Air was subsequently injected into the anterior chamber to promote the graft attachment to the back surface of the cornea. The IOP was elevated above 40 mmHg in both eyes 1 h after surgery and then decreased to less than 30 mmHg over the subsequent 3 h period. The implanted graft showed good adhesion and no dislocation. Conclusions: Our novel DSAEK procedure that adds one step of OVD injection into the filtering bleb may be useful for hypotonic eyes that had undergone filtering surgeries. PMID- 29487755 TI - Suprasellar Ganglioglioma: Expanding the Differential Diagnosis. AB - This case study describes a young man with symptoms suggestive of the presence of a space-occupying lesion within the cranial cavity. Imaging studies confirmed a lesion in the suprasellar region and surgical intervention to remove the tumor yielded an unexpected diagnosis. Neuroimaging characteristics and histopathology including immunohistochemistry are described. Gangliogliomas are uncommon CNS neoplasms and are most commonly found in the temporal and frontal lobes of young, male adults. They are rarely seen in the suprasellar region and only a handful of cases have been reported to date. The differential diagnoses associated with these suprasellar region lesions can be dependent on the age of the patient and neuroimaging characteristics. The present report highlights the importance of histopathological examination and the need to consider a wide range of diagnostic entities in the differential diagnosis of lesions in this topographic distribution, including rarely encountered tumors such as gangliogliomas. PMID- 29487756 TI - Liver Transplant for Unusually Large Polycystic Liver Disease: Challenges and Pitfalls. AB - Patients with polycystic liver disease are described in the literature as both recipient and donor for liver transplant. Due to well-preserved liver function, it is often difficult for these patients to receive an organ. Livers of these patients are often large and heavier than a normal organ. We describe two cases who had exceedingly large livers, weighing 14 and 19 kg. To the best of our knowledge and search, these are some of the heaviest explanted livers, and one of the patients incidentally received a liver from a donor with ADPKD. The aim of this report is to discuss the challenges and pitfalls of evaluating and listing, technical aspect of the transplant, possibility of transplanting a liver from a donor with a genetic cystic disease to a cystic disease recipient, and the related literature with some highlights on the facts from UNOS/OPTN data. PMID- 29487757 TI - Integrating HIV, hepatitis B and syphilis screening and treatment through the Maternal, Newborn and Child Health platform to reach global elimination targets. AB - Every year, an estimated 180 000 babies in the Western Pacific Region are infected by hepatitis B, 13 000 by syphilis and 1400 by HIV through mother-to child transmission. (1) These infections can be largely prevented by antenatal screening, treatment and timely vaccination for newborns. Despite challenges in controlling each disease, major achievements have been made. National immunization programmes have reduced the regional hepatitis B prevalence from over 8% in 1990 to 0.93% among children born in 2012. In addition, HIV testing and treatment have helped keep the regional prevalence of HIV infections at 0.1%. In contrast, the number of maternal syphilis cases is still high in the Western Pacific Region, with an estimated 45 million cases in 2012. Elimination of mother to-child transmission of these infections cannot be achieved through vertically applied programming and require using and augmenting to the shared Maternal, Newborn and Child Health platform to coordinate, integrate and enable cost efficiencies for these elimination efforts. The Regional Framework for Triple Elimination of Mother-to-Child Transmission of HIV, Hepatitis B and Syphilis in Asia and the Pacific 2018-2030 offers such a coordinated approach towards achieving the triple elimination of mother-to-child transmission of HIV, hepatitis B and syphilis and provides guidance for decision-makers, managers and health professionals working in programmes addressing maternal, newborn and child health, HIV, hepatitis, sexually transmitted infections and immunization. PMID- 29487758 TI - Community-associated methicillin-resistant Staphylococcus aureus infections in Aboriginal children attending hospital emergency departments in a regional area of New South Wales, Australia: a seven-year descriptive study. AB - Objective: Community-associated methicillin-resistant Staphylococcus aureus (CA MRSA) can cause bacterial skin infections that are common problems for Aboriginal children in New South Wales (NSW). MRSA is not notifiable in NSW and surveillance data describing incidence and prevalence are not routinely collected. The study aims to describe the epidemiology of CA-MRSA in Aboriginal children in the Hunter New England Local Health District (HNELHD). Methods: We linked data from Pathology North Laboratory Management System (AUSLAB) and the HNELHD patient administration system from 33 hospital emergency departments. Data from 2008-2014 for CA-MRSA isolates were extracted. Demographic characteristics included age, gender, Aboriginality, rurality and seasonality. Results: Of the 1222 individuals in this study, 408 (33.4%) were Aboriginal people. Aboriginal people were younger with 45.8% aged less than 10 years compared to 25.9% of non-Aboriginal people. Most isolates came from Aboriginal people who attended the regional Tamworth Hospital (193/511 isolates from 149 people). A larger proportion of Aboriginal people, compared to non-Aboriginal people, resided in outer regional (64.9% vs 37.2%) or remote/very remote areas (2.5% vs 0.5%). Most infections occurred in summer and early autumn. For Aboriginal patients, there was a downward trend through autumn, continuing through winter and spring. Discussion: Aboriginal people at HNELHD emergency departments appear to represent a greater proportion of people with skin infections with CA-MRSA than non-Aboriginal people. CA-MRSA is not notifiable in NSW; however, pathology and hospital data are available and can provide valuable indicative data to health districts for planning and policy development. PMID- 29487759 TI - Pulmonary tuberculosis and non-recent immigrants in Japan - some issues for post entry interventions. AB - Foreign-born persons are considered one of the high-risk populations for tuberculosis (TB), and numerous studies have discussed the potential role of pre entry TB screening for immigrants. However, rates of TB disease among immigrants can remain high several years after entry. In Japan, approximately 50% of TB among foreign-born persons occurs among those who have entered Japan more than five years before being diagnosed, i.e. non-recent immigrants. However, little attention has been paid so far to the issue of TB control among the non-recent immigrants. A detailed analysis of the Japan Tuberculosis Surveillance data was therefore conducted to describe the characteristics of TB among non-recent immigrants and discuss policy implications in terms of post-entry interventions in Japan. The main findings were as follows: 1) the proportion of pulmonary TB cases aged 65 years and older was higher among non-recent than recent immigrants (9.8% vs 1.2%); 2) the proportion of those with social risk factors including homelessness and and being on social welfare assistance was higher among non recent than recent immigrants; and 3) the proportion of those detected via routine screening at school or workplace was significantly lower among non-recent immigrants aged between 25 and 64 than among recent immigrants in the same age group (15.4% vs 28.7%). Our results suggested the need to increase the opportunities for and simultaneously improve the take-up rate of community-based screening for non-recent immigrants. PMID- 29487760 TI - Trends in adult chlamydia and gonorrhoea prevalence, incidence and urethral discharge case reporting in Mongolia from 1995 to 2016 - estimates using the Spectrum-STI model. AB - Objective: To estimate Mongolia's prevalence and incidence trends of gonorrhoea and chlamydia in women and men 15-49 years old to inform control of STIs and HIV, a national health sector priority. Methods: We applied the Spectrum-STI estimation model, fitting data from two national population surveys (2001 and 2008) and from routine gonorrhoea screening of pregnant women in antenatal care (1997 to 2016) adjusted for diagnostic test performance, male/female differences and missing high-risk populations. Prevalence and incidence estimates were then used to assess completeness of national case reporting. Results: Gonorrhoea prevalence was estimated at 3.3% (95% confidence interval, 1.6-3.9%) in women and 2.9% (1.6-4.1%) in men in 2016; chlamydia prevalence levels were 19.5% (17.3 21.9%) and 15.6% (10.0-21.2%), respectively. Corresponding new incident cases in women and men in 2016 totalled 60 334 (36 147 to 121 933) and 76 893 (35 639 to 254 913) for gonorrhoea and 131 306 (84 232 to 254 316) and 148 162 (71 885 to 462 588) for chlamydia. Gonorrhoea and chlamydia prevalence declined by an estimated 33% and 11%, respectively from 2001 to 2016.Comparing numbers of symptomatic and treated cases estimated by Spectrum with gonorrhoea case reports suggests that 15% of symptomatic treated gonorrhoea cases were reported in 2016; only a minority of chlamydia episodes were reported as male urethral discharge cases. Discussion: Gonorrhoea and chlamydia prevalence are estimated to have declined in Mongolia during the early 2000s, possibly associated with syndromic management in primary care facilities and improving treatment coverage since 2001 and scale up of HIV/STI prevention interventions since 2003. However, prevalence remains high with most gonorrhoea and chlamydia cases not treated or recorded in the public health system. PMID- 29487761 TI - Acute cholangitis - an update. AB - Acute cholangitis is bacterial infection of the extra-hepatic biliary system. As it is caused by gallstones blocking the common bile duct in most of the cases, its prevalence is greater in ethnicities with high prevalence of gallstones. Biliary obstruction of any cause is the main predisposing factor. Diagnosis is established by the presence of clinical features, laboratory results and imaging studies. The treatment modalities include administration of intravenous fluid, antibiotics, and drainage of the bile duct. The outcome is good if the treatment is started early, otherwise it could be grave. PMID- 29487762 TI - Emergency resection surgery for colorectal cancer: Patterns of recurrent disease and survival. AB - AIM: To evaluate prognostic pathological factors associated with early metachronous disease and adverse long-term survival in these patients. METHODS: Clinical and histological features were analysed retrospectively over an eight year period for prognostic impact on recurrent disease and overall survival in patients undergoing curative resection of a primary colorectal cancer. RESULTS: A total of 266 patients underwent curative surgery during the study period. The median age of the study cohort was 68 year (range 26 to 91) with a follow-up of 7.9 years (range 4.6 to 12.6). Resection was undertaken electively in 225 (84.6%) patients and emergency resection in 35 (13.2%). Data on timing of surgery was missing in 6 patients. Recurrence was noted in 67 (25.2%) during the study period and was predominantly early within 3 years (82.1%) and involved hepatic metastasis in 73.1%. Emergency resection (OR = 3.60, P = 0.001), T4 stage (OR = 4.33, P < 0.001) and lymphovascular invasion (LVI) (OR = 2.37, P = 0.032) were associated with higher risk of recurrent disease. Emergency resection, T4 disease and a high lymph node ratio (LNR) were strong independent predictors of adverse long-term survival. CONCLUSION: Emergency surgery is associated with adverse disease free and long-term survival. T4 disease, LVI and LNR provide strong independent predictive value of long-term outcome and can inform surveillance strategies to improve outcomes. PMID- 29487763 TI - Abundance of Enterobacteriaceae in the colon mucosa in diverticular disease. AB - AIM: To compare gut bacterial diversity and amount of Enterobacteriaceae in colonic mucosa between patients with and without diverticular disease (DD). METHODS: Patients in a stable clinical condition with planned elective colonoscopy were included. Blood samples and colon mucosa biopsies were collected at the colonoscopy. Study questionnaires including questions about gastrointestinal symptoms were completed by the patients and physicians. DNA from mucosa samples was isolated and the amount of Enterobacteriaceae was estimated using PCR assay. Terminal restriction fragment length polymorphism was applied to assess microbial diversity. Diversity was estimated by calculations of richness (number of terminal restriction fragments) and Shannon-Wiener and Simpson's indices. RESULTS: A total of 51 patients were included, 16 patients with DD [68 (62-76) years] and 35 controls [62 (40-74) years] without any diverticula. Patients with DD had significantly higher levels of Enterobacteriaceae than those without DD (P = 0.043), and there was an inverse relationship between the amount of Enterobacteriaceae and the Simpson's index (rs = -0.361, P = 0.033) and the Shannon-Wiener index (rs = -0.299, P = 0.081). The Simpson's index (P = 0.383), Shannon-Wiener index (P = 0.401) or number of restrictions fragments (P = 0.776) did not differ between DD and controls. The majority of patients experienced gastrointestinal symptoms, and 22 patients (43.1%) fulfilled the criteria for irritable bowel syndrome, with no difference between the groups (P = 0.212). Demography, socioeconomic status, lifestyle habits, inflammatory biomarkers, or symptoms were not related to the amount of Enterobacteriaceae or bacterial diversity. CONCLUSION: Patients with DD had higher amount of Enterobacteriaceae in the colon mucosa compared to patients without diverticula. PMID- 29487764 TI - Liver cirrhosis-effect on QT interval and cardiac autonomic nervous system activity. AB - AIM: To examine the impact of liver cirrhosis on QT interval and cardiac autonomic neuropathy (CAN). METHODS: A total of 51 patients with cirrhosis and 51 controls were examined. Standard 12-lead electrocardiogram recordings were obtained and QT as well as corrected QT interval (QTc) and their dispersions (dQT, dQTc) were measured and calculated using a computer-based program. The diagnosis of CAN was based upon the battery of the tests proposed by Ewing and Clarke and the consensus statements of the American Diabetes Association. CAN was diagnosed when two out of the four classical Ewing tests were abnormal. RESULTS: QT, QTc and their dispersions were significantly longer (P < 0.01) in patients with cirrhosis than in controls. No significant differences in QT interval were found among the subgroups according to the etiology of cirrhosis. Multivariate regression analysis after controlling for age, gender and duration of cirrhosis demonstrated significant association between QT and presence of diabetes mellitus [standardized regression coefficient (beta) = 0.45, P = 0.02] and treatment with diuretics (beta = 0.55, P = 0.03), but not with the Child-Pugh score (P = 0.54). Prevalence of CAN was common (54.9%) among patients with cirrhosis and its severity was associated with the Child-Pugh score (r = 0.33, P = 0.02). Moreover, patients with decompensated cirrhosis had more severe CAN that those with compensated cirrhosis (P = 0.03). No significant association was found between severity of CAN and QT interval duration. CONCLUSION: Patients with cirrhosis have QT prolongation. Treatment with diuretics is associated with longer QT. CAN is common in patients with cirrhosis and its severity is associated with severity of the disease. PMID- 29487765 TI - Coil Now, Pipe Later: Two-stage Treatment for Acute Intracranial Aneurysm Rupture. AB - The two main treatment modalities of acute intracranial aneurysm rupture are endovascular embolization and surgical clipping, each with its own benefits and risks. Endovascular treatment is associated with better outcomes compared to surgical clipping, but is also associated with high recurrence rates. We present the case of a patient with an acutely ruptured intracranial aneurysm, who subsequently underwent partial endovascular coiling acutely, and later underwent flow diversion therapy with the Pipeline Embolization Device. We also review the literature on this topic for further recommendations on treatment options of acute intracranial aneurysm rupture. PMID- 29487766 TI - Case Report of Extended Survival and Quality of Life in a Melanoma Patient with Multiple Brain Metastases and Review of Literature. AB - Long-term survival for melanoma patients with multiple brain metastases is rare. A review of the literature reveals only three reported melanoma patients with multiple brain metastases who survived more than 10 years. We present a patient who is recurrence-free 11 years after the diagnosis of three brain metastases. Her treatment consisted of cytokine (interferon and interleukin-2) and chemotherapy nine months prior to developing brain and soft tissue metastases, which were treated with stereotactic radiosurgery and stereotactic ablative radiotherapy, respectively, followed by six months of chemotherapy. Notably, she has not received any treatment for over 10 years, never underwent craniotomy or whole brain radiation therapy, currently has a perfect score on the functional assessment of cancer therapy for brain (FACT-Br) quality of life (QoL) scale, and runs marathons. This treatment course is consistent with emerging literature on the abscopal effect (radiation-induced immune response). Clinical trials are needed to better understand and harness the abscopal effect in order to optimally integrate targeted drug and radiation therapies. PMID- 29487767 TI - Ultrasound-based Techniques as Alternative Treatments for Chronic Wounds: A Comprehensive Review of Clinical Applications. AB - Ultrasound (US) waves have been recently developed for the treatment of different chronic wounds with promising therapeutic outcomes. However, the clinical efficacy of these techniques is still not fully understood and standard guidelines on dose ranges and possible side effects should be determined. This paper aims to comprehensively review the recent advances in US techniques for chronic wound treatment, their therapeutic efficacies, and clinical considerations and challenges. The databases of PubMed (1985-2017), EMBASE (1985 2017), Web of Sciences (1985-2017), Cochrane central library (1990-2017), and Google Scholar (1980-2017) were searched using the set terms. The obtained results were screened for the title and abstract by two authors and the relevant papers were reviewed for further details. Preclinical and clinical studies have shown strong evidence on the therapeutic efficiency of US in chronic wounds. The main limitation on developing clinical standard protocols of US for treatment of wounds is the lack of definite dose-response for each wound. However, spatial average temporal average is the main parameter for defining US dosage in wound treatment. The range of 0.5 to 3 W/cm2 is a range of dose exerting significant therapeutic outcomes and minimum adverse effects. Low-frequency US waves can accelerate the healing speed of open wounds as well as deep-tissue injuries. In addition, US waves show promising therapeutic efficacy for chronic wounds. To develop clinical US protocol for each wound type, further in vitro and in vivo preclinical and clinical trials are needed to reach an exact dose-response for each wound type. PMID- 29487768 TI - Suprasellar Germinoma Presenting with Slipped Capital Femoral Epiphysis: Case Report. AB - Slipped capital femoral epiphysis (SCFE) is a fracture that results from displacement of the proximal femoral epiphysis from the femoral neck. SCFE can be caused by various endocrinopathies that lead to bone weakening in both adult and pediatric patients. We report a rare case of suprasellar germinoma presenting with SCFE in an 11-year-old female patient. The findings of this case further support the need to consider pituitary lesions as the underlying cause of endocrine deficiences leading to SCFE. PMID- 29487769 TI - Local Anesthetic Systemic Toxicity Complicating Thyroid Biopsy. AB - The overdiagnosis of thyroid malignancies may be contributing to the increased incidence of these cancers with a relatively stable mortality rate. We present the case of a man with known malignancies, who underwent biopsy of a suspicious thyroid nodule. This procedure was complicated by local anesthetic systemic toxicity (LAST). It is important to address goals of diagnostic testing and treatment with patients, particularly if further evaluation is unlikely to change management or outcomes. PMID- 29487770 TI - Point of Care Ultrasound Diagnosis of Upper Gastrointestinal Bleeding. AB - A 28-year-old male was brought to the emergency department by the Emergency medical services (EMS) after being found unconscious and unresponsive. Upon arrival, he was hypotensive, intubated with a Glasgow Coma Scale (GCS) 3T, without the signs of trauma or the evidence of bleeding. A focused assessment with sonography in trauma (FAST), point-of-care ultrasound (POCUS) was performed, obscuring part of the spleen from the distended stomach, which was filled with the heterogeneous contents, with the internal movement being identified. This was found to be blood after orogastric (OG) tube was placed for suction. The bedside endoscopy confirmed active variceal bleeding. This case illustrates the potential utility of the ultrasound in detecting the upper gastrointestinal bleeding. PMID- 29487771 TI - Machine-Specific Magnetic Resonance Imaging Quality Control Procedures for Stereotactic Radiosurgery Treatment Planning. AB - Purpose Magnetic resonance (MR) images are necessary for accurate contouring of intracranial targets, determination of gross target volume and evaluation of organs at risk during stereotactic radiosurgery (SRS) treatment planning procedures. Many centers use magnetic resonance imaging (MRI) simulators or regular diagnostic MRI machines for SRS treatment planning; while both types of machine require two stages of quality control (QC), both machine- and patient specific, before use for SRS, no accepted guidelines for such QC currently exist. This article describes appropriate machine-specific QC procedures for SRS applications. Methods and materials We describe the adaptation of American College of Radiology (ACR)-recommended QC tests using an ACR MRI phantom for SRS treatment planning. In addition, commercial Quasar MRID3D and Quasar GRID3D phantoms were used to evaluate the effects of static magnetic field (B0) inhomogeneity, gradient nonlinearity, and a Leksell G frame (SRS frame) and its accessories on geometrical distortion in MR images. Results QC procedures found in-plane distortions (Maximum = 3.5 mm, Mean = 0.91 mm, Standard deviation = 0.67 mm, >2.5 mm (%) = 2) in X-direction (Maximum = 2.51 mm, Mean = 0.52 mm, Standard deviation = 0.39 mm, > 2.5 mm (%) = 0) and in Y-direction (Maximum = 13. 1 mm , Mean = 2.38 mm, Standard deviation = 2.45 mm, > 2.5 mm (%) = 34) in Z-direction and < 1 mm distortion at a head-sized region of interest. MR images acquired using a Leksell G frame and localization devices showed a mean absolute deviation of 2.3 mm from isocenter. The results of modified ACR tests were all within recommended limits, and baseline measurements have been defined for regular weekly QC tests. Conclusions With appropriate QC procedures in place, it is possible to routinely obtain clinically useful MR images suitable for SRS treatment planning purposes. MRI examination for SRS planning can benefit from the improved localization and planning possible with the superior image quality and soft tissue contrast achieved under optimal conditions. PMID- 29487772 TI - An Oblique Columellar Artery Variant. AB - A variant of the columellar artery (CoA), also known as the nasal septal branch of the superior labial artery of the facial artery, and its unusual direct anastomosis with the right infraorbital artery were identified in a cadaveric dissection. Numerous variants and distribution patterns of the CoA have been described in the literature. However, an oblique and a third CoA variant that anastomoses with the contralateral infraorbital artery has never been reported or depicted. We highlight the significance of a preprocedural vascular examination of the perioral region for optimal functional and esthetic outcome by presenting this unique case. This CoA variant should be known by surgeons performing invasive surgical techniques in the columellar region. PMID- 29487773 TI - ABO Blood Group and Endometrial Carcinoma: A Preliminary Single-Center Experience from Saudi Arabia. AB - INTRODUCTION: Inherited ABO blood groups have been shown to play possible contributions in the pathogenesis of various gynecologic and non-gynecologic carcinomas. With regard to gynecologic carcinomas, there is a confined number of studies that explored the relationship between ABO blood group and endometrial carcinoma (EC) in the PubMed-indexed literature. To the best of our knowledge, no such study has ever been conducted in Saudi Arabia. OBJECTIVES: Our study has two objectives: (I) to determine the prevalence of ABO blood groups among Saudi patients with EC, and (II) to explore the relationship between ABO blood group and several clinico-pathological prognostic parameters (namely: menopausal status [age], body mass index [BMI], tumor grade, FIGO [Federation Internationale de Gynecologie et d'Obstetrique] stage and recurrence) in Saudi patients with EC. MATERIALS AND METHODS: A retrospective cross-sectional study from 01-January-2010 to 31-July-2014 was conducted at King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia - a referral tertiary healthcare institute. One hundred and fourteen patients (n=114) were included in the study. Clinico pathological data were extrapolated from medical records, and their association with ABO blood groups were evaluated. Categorical data were presented as number of cases (n) and percentages (%). Two-tailed Chi-square test was used for univariate analysis. For all purposes, p values <0.05 were regarded as statistically significant. RESULTS: The mean age and BMI were 59.5 +/- 10.8 years (range: 31 - 90) and 36.6 +/- 8.6 kg/m2 (range: 17 - 60), respectively. The vast majority of patients were post-menopausal (86%), had BMI >28 kg/m2 (84.2%), diagnosed with early FIGO stage I-II (76.3%) and developed no recurrence (86.8%). The frequencies of ABO blood group types A, B, AB, and O were 28.1%, 12.3%, 3.5% and 56.1%, respectively. When ABO blood groups were analyzed as four different types (A, B, AB and O), O-type was the most common ABO blood group in pre- and post-menopausal EC patients (43.8% and 58.2%, respectively; p=0.14). There were no statistically significant correlations between ABO blood groups and all the examined clinico-pathological factors. Moreover, when ABO blood groups were analyzed as two different types (O and non-O), similar results were obtained; no statistically significant correlations were found between ABO blood groups and all the examined clinico-pathological factors. CONCLUSIONS: O-type was the most prevalent ABO blood group among Saudi Arabian patients with EC, and our finding was different from the existing literature, probably highlighting an ethnic related variance. Furthermore, no statistically significant correlations were identified between ABO blood groups and all the examined clinico-pathological factors. Also, routine ABO blood group may emerge as a clinically accessible, beneficial and economical biomarker for a possible EC vulnerability. A large sized case-control study is needed to withdraw solid conclusions. PMID- 29487774 TI - Invasive Streptococcus Pneumoniae Infection Causing Cardioembolic Stroke: A Clinical Proximity to Austrian Syndrome. AB - Streptococcus pneumoniae (S. pneumoniae) is a significant human bacterial pathogen and the major cause of pneumonia. In the post-antibiotic era, S. pneumoniae endocarditis is rare but carries a high risk of central nervous system (CNS) involvement. We present a case of invasive S. pneumoniae infection, which led to a cardioembolic stroke in a young man from septic emboli. Diagnosing a disseminated S. pneumoniae infection at an early stage is crucial and may improve patient outcomes. PMID- 29487775 TI - An efficient protocol for in vitro direct shoot organogenesis of Sesamum indicum L. using cotyledon as explant. AB - Establishment of a suitable regeneration protocol is a pre-requisite to carry out transformation study in Sesamum indicum L. (sesame). In this paper, different parameters of regeneration were standardised to develop an efficient protocol for in vitro plant regeneration via direct adventitious shoot organogenesis using de embryonated cotyledons of sesame as explants. Among the various treatments of MS medium supplemented with 6-benzylaminopurine, thidiazuron and indole-3-acetic acid, maximum regeneration frequency (25.93 +/- 2.21%) was obtained in BTI 4 medium (MS supplemented with 33.33 uM BAP with 2.85 uM IAA) within 6 weeks of culture. Regeneration frequency increased further (50.37 +/- 2.49%) by fortifying BTI 4 with 29.43 uM silver nitrate (AG 3 medium). Pre-culture of cotyledon explants in AB 3 medium (AG 3 supplemented with 3.78 uM abscisic acid) for 14 days followed by sub-culture in AG 3 medium further improved the regeneration frequency (68.15 +/- 2.68%). The highest rate of shoot regeneration (94.82 +/- 1.34%) was obtained by pre-culturing 4-day-old cotyledon in a vertical position in AB 3 medium for 14 days and sub-culturing in AG 3 medium for 4 weeks. Regenerated shoots proliferated in MS medium supplemented with 4.44 MUM BAP and 1.44 MUM gibberelic acid (GA3). The highest frequency (65.33 +/- 3.78%) of root induction was achieved by culturing the elongated shoots in MS medium supplemented with 2.69 MUM alpha-naphthalene acetic acid (NAA) for 6 weeks. Rooted plants were acclimatised in soilrite and transferred to soil after 6-8 weeks. The rate of acclimatisation of plants was 76%. PMID- 29487776 TI - Complete Genome Sequence of Zucchini Yellow Mosaic Virus Strain Kurdistan, Iran. AB - The complete genome sequence of Zucchini yellow mosaic virus strain Kurdistan (ZYMV-Kurdistan) infecting squash from Iran was determined from 13 overlapping fragments. Excluding the poly (A) tail, ZYMV-Kurdistan genome consisted of 9593 nucleotides (nt), with 138 and 211 nt at the 5' and 3' non-translated regions, respectively. It contained two open-reading frames (ORFs), the large ORF encoding a polyprotein of 3080 amino acids (aa) and the small overlapping ORF encoding a P3N-PIPO protein of 74 aa. This isolate had six unique aa differences compared to other ZYMV isolates and shared 79.6-98.8% identities with other ZYMV genome sequences at the nt level and 90.1-99% identities at the aa level. A phylogenetic tree of ZYMV complete genomic sequences showed that Iranian and Central European isolates are closely related and form a phylogenetically homogenous group. All values in the ratio of substitution rates at non-synonymous and synonymous sites (dN/dS) were below 1, suggestive of strong negative selection forces during ZYMV protein history. This is the first report of complete genome sequence information of the most prevalent virus in the west of Iran. This study helps our understanding of the genetic diversity of ZYMV isolates infecting cucurbit plants in Iran, virus evolution and epidemiology and can assist in designing better diagnostic tools. PMID- 29487777 TI - A simplified and efficient Agrobacterium tumefaciens electroporation method. AB - Agrobacterium tumefaciens is a widely used microbial tool in plant molecular biology to transfer DNA into plant cells and produce, e.g., stable or transient transformants or induce gene silencing. In our study, we present a simplified version of electrocompetent cell preparation that is not only time and cost efficient, but it requires minimal handling of bacterial cells. Liquid cultures are normally used to prepare competent Agrobacterium cells. To overcome the difficulties of working with liquid cultures, we propose suspending bacterial cells directly from overnight agar plate cultures. In addition, we optimized several parameters to simplify the procedure and maximize the number of transformants (e.g., Agrobacterium strains, number of washing steps, amount of required plasmid DNA, electroporation parameters, type of incubation media, or incubation time). This optimized, simple, and fast protocol has proved to be efficient enough to obtain transformed colonies with low amounts (as little as 1 ng) of plasmid DNA. In addition, it also enabled us to introduce ligated plasmids directly into Agrobacterium omitting the E. coli transformation step and accelerating the cloning procedure further. PMID- 29487779 TI - Late presentation of Pneumocystis jirovecii pneumonia after renal transplant: A case report. AB - The highest risk of opportunistic infections is from 1 to 6 months post transplant. We report a rare case of Pneumocystis jirovecii pneumonia in a renal transplant recipient only on maintenance immunosuppression eleven years after transplant without concomitant CMV infection or recent episodes of graft rejection. PMID- 29487778 TI - Fundamentals and commercial aspects of nanobiosensors in point-of-care clinical diagnostics. AB - Among various problems faced by mankind, health-related concerns are prevailing since long which are commonly found in the form of infectious diseases and different metabolic disorders. The clinical cure and management of such abnormalities are greatly dependent on the availability of their diagnoses. The conventional diagnostics used for such purposes are extremely powerful; however, most of these are limited by time-consuming protocols and require higher volume of test sample, etc. A new evolving technology called "biosensor" in this context shows an enormous potential for an alternative diagnostic device, which constantly compliments the conventional diagnoses. In this review, we have summarized different kinds of biosensors and their fundamental understanding with various state-of-the-art examples. A critical examination of different types of biosensing mechanisms is also reported highlighting the advantages of electrochemical biosensors for its great potentials in next-generation commercially viable modules. In recent years, a number of nanomaterials are extensively used to enhance not only the performance of biosensing mechanism, but also obtain robust, cheap, and fabrication-friendly durable mechanism. Herein, we have summarized the importance of nanomaterials in biosensing mechanism, their syntheses as well as characterization techniques. Subsequently, we have discussed the probe fabrication processes along with various techniques for assessing its analytical performances and potentials for commercial viability. PMID- 29487780 TI - Simultaneous Bilateral Hip Arthroscopy. AB - Many patients are afflicted with painful conditions affecting both hips, most commonly femoroacetabular impingement. Some patients prefer the advantage of undergoing a single surgical procedure and anesthetic followed by a single postoperative rehabilitation program. We present a Technical Note on single-stage bilateral hip arthroscopy. This Technical Note reports on key steps enabling safe and efficient performance of bilateral arthroscopic acetabuloplasty, labral refixation, femoroplasty, and dynamic testing while limiting traction times and facilitating rapid transition to the second hip arthroscopic surgery. Enabling factors include supine positioning with bilateral mobile leg spars, rapid surgical and hip traction times, and postoperative rehabilitation with immediate weight bearing as tolerated. A rationale for deciding which hip should undergo arthroscopy first is also offered. Concurrent bilateral hip arthroscopy is a viable option for select patients and experienced surgical teams, enabling potentially expedited recovery and return to work or sport with inherent cost savings. PMID- 29487781 TI - Anatomic Repair of Posteromedial Meniscocapsular Separation Using an All-Inside Technique. AB - Separation of the posteromedial meniscocapsular junction (PMC) is a unique injury seen in patients with disruption of the anterior cruciate ligament. PMC tears may go unrecognized despite preoperative magnetic resonance imaging and diagnostic arthroscopy of the medial compartment. Unrepaired lesions may lead to persistent laxity of the knee after anterior cruciate ligament reconstruction. Inside-out repair techniques risk iatrogenic injury to the articular cartilage during needle passage and require dissection of the posteromedial knee for suture retrieval. Previous all-inside techniques have required specialized implants and repaired PMC lesions with direct visualization of the tear. The presented all-inside technique is an easily reproducible, cost-effective means to anatomically repair separation of the PMC. The technique provides the surgeon direct visualization and full arthroscopic access to the lesion, making repair technically easy and efficient. PMID- 29487782 TI - Primary Repair of the Medial Collateral Ligament With Internal Bracing. AB - The medial collateral ligament (MCL) is commonly injured in the setting of anterior cruciate ligament (ACL) injuries. Because the MCL has better healing capacity than the ACL, the general perception is that MCL injuries can be treated conservatively. Treating these injuries conservatively, however, can lead to residual valgus laxity. Furthermore, it delays time to surgery, which prevents acute treatment of concomitant ACL injuries using primary repair or acute reconstruction. Several treatment methods for MCL injuries have been proposed, including primary repair, augmented repair with autograft tissue, or primary reconstruction. In this surgical technique article, we present the technique of acute primary MCL repair with internal bracing with 2 limited incisions. With this technique, early surgical intervention is possible, and early rehabilitation is safe because of the internal bracing. Advantages include fast recovery, avoidance of muscle atrophy because of early mobilization, prevention of residual valgus instability, and maintenance of proprioception. PMID- 29487783 TI - Arthroscopic Lysis of Adhesions for Treatment of Post-traumatic Arthrofibrosis of the Knee Joint. AB - Normal knee range of motion varies slightly between individuals and measures approximately 0 degrees to -5 degrees of extension to 140 degrees of flexion. A full arc of motion is required for normal gait and knee function. Loss of normal joint range of motion may occur after a traumatic knee injury and may contribute to increased pain, lower functional outcome scores, and decreased patient satisfaction. Although multiple factors may contribute to the development of motion loss, the occurrence of intra-articular scar tissue adhesions, or post traumatic arthrofibrosis, may limit the patient's knee motion in the early postoperative period. Once motion loss has been identified, it can be a challenging complication to manage. Arthroscopic lysis of adhesions with manipulation under anesthesia is a reliable surgical technique that can improve range of motion in patients with knee stiffness due to post-traumatic arthrofibrosis. PMID- 29487784 TI - Pectoralis Major Muscle Transfer With the Sternal Head and Hamstring Autograft for Scapular Winging. AB - Medial scapular winging is often due to dysfunction of the serratus anterior muscle as a result of injury to the long thoracic nerve. Impairment of the serratus anterior muscle may cause uncoordinated scapulohumeral rhythm during shoulder elevation and subsequent subscapular or shoulder pain, subacromial impingement, and glenohumeral joint instability. Although long thoracic nerve injury typically resolves in 12 to 18 months after a physical therapy regimen, surgical intervention is indicated in patients who fail conservative management. Both direct and indirect pectoralis major tendon transfer techniques have been described in the literature as surgical options for these patients. Indirect transfer of the pectoralis major and augmentation with either allograft or autograft has been shown to successfully restore scapular functioning and glenohumeral stability. We describe a technique that uses hamstring autograft to augment a pectoralis major transfer with the sternal head to correct medial scapular winging due to dysfunction of the long thoracic nerve and serratus anterior muscle atrophy. PMID- 29487785 TI - Post-intubation tracheobronchomalacia in a young adult: A rare case report. AB - Tracheobronchomalacia (TBM) is characterized by weakness of cartilaginous supporting structures of tracheal and bronchial walls, resulting in central airway obstruction. It is a rare condition that can occur after prolonged intubation. Here, we report a 26-year-old, alcoholic male who had TBM, mild subglottic, and severe tracheal stenosis following 2 weeks of intubation. Subglottic and tracheal stenosis can occur after extubation but TBM is uncommon. The exact mechanism is still unknown but post-intubation TBM is a life threatening condition with high morbidity and mortality if left untreated. Early detection and timely management can improve the outcome of patients. PMID- 29487786 TI - Successful osimertinib rechallenge after osimertinib-induced pneumonitis in a patient with lung adenocarcinoma. AB - Pneumonitis is a serious adverse event of EGFR-TKI treatment. Although several cases of EGFR-TKI rechallenge after EGFR-TKI-induced pneumonitis have been reported, little is known about post-pneumonitis osimertinib rechallenge. We describe a 69-year-old never-smoking Japanese woman with postoperative recurrent lung adenocarcinoma retreated with osimertinib after osimertinib-induced pneumonitis. Although osimertinib rechallenge must be carefully chosen based on risk/benefit analysis, osimertinib rechallenge after osimertinib-induced pneumonitis may be an option, with limited alternative therapeutic options. PMID- 29487787 TI - Lung abscess caused by Streptococcus pneumoniae serotype 6B. AB - Lung abscess has been considered to be a rare complication of pneumococcal infection, and most cases are reported to be Streptococcus pneumoniae serotype 3. A 67-year-old man presented with fever and was diagnosed to have lung abscess caused by S. pneumoniae serotype 6B. The minimal inhibitory concentration (MIC) of penicillin for the isolate was 1 MUg/mL. He was treated with high-dose intravenous sulbactam/ampicillin as definitive therapy based on susceptibility testing for S. pneumoniae and recovered successfully without surgical intervention. S. pneumoniae serotype 6B can cause lung abscess. PMID- 29487788 TI - Should hut lung be called domestically acquired particulate lung disease or domestically acquired pneumoconiosis? AB - Indoor air pollution appears to be a major environmental and public health hazard for large numbers of the underdeveloped world's population. A detailed environmental history is important for making diagnosis in most individuals from foreign rural settings with nonspecific respiratory symptoms. In this report, we describe an illustrative case of domestically acquired particulate lung disease (DAPLD) or "hut lung" in a 65-year-old Sudanese male who immigrated to the United States in 1986. He presented with symptoms of chronic productive cough and dyspnea. Imaging and pathology from transbronchial cryo biopsy revealed anthracosis consistent with DAPLD. This case demonstrates persistence of physiologic, radiographic, and histopathologic abnormalities years after removal from exposure. To the best of our knowledge, this is the first case of DAPLD reported from Sudan. PMID- 29487789 TI - Thoracic herniation secondary to pleural effusion. AB - We present the case of a 61-year-old gentleman with history of stage IV esophageal cancer presented to the emergency department with the complaints of dyspnea on exertion and cough of 1-month duration. Patient had undergone resection of distal esophagus 4 years' prior this admission. Chest radiograph revealed a large right pleural effusion and, a computed tomography scan of the chest revealed a portion of the effusion herniating between the ribs in the right hemithorax. Thoracentesis was performed with improvement in patient's dyspnea and overall condition. Patient was doing better and asymptomatic on his 3-month follow-up. Inadequate closure after surgical procedure can lead to presentation of a lung herniation. This can appear immediately after or many years later. Video-assisted thoracoscopy has been attributed to post-operative presentation of thoracic hernias when compared to more extensive operative procedures. PMID- 29487790 TI - A case of cocaine-induced eosinophilic pneumonia: Case report and review of the literature. AB - Cocaine is a commonly abused recreational drug in the United States. An adult man developed non-specific pleuritic chest pain, pharyngitis and odynophagia after inhaling cocaine. Initial laboratory results revealed eosinophilia. Bronchoalveolar lavage also showed eosinophilia in the lavage fluid. These findings suggested the diagnosis of eosinophilic pneumonia. Chest imaging revealed scattered bilateral opacities and interstitial infiltrates. After initiation of systemic corticosteroids, the patient reported symptomatic resolution and radiographic clearance was achieved at 2 months follow up. PMID- 29487791 TI - Altered functional connectivity differs in stroke survivors with impaired touch sensation following left and right hemisphere lesions. AB - One in two survivors experience impairment in touch sensation after stroke. The nature of this impairment is likely associated with changes associated with the functional somatosensory network of the brain; however few studies have examined this. In particular, the impact of lesioned hemisphere has not been investigated. We examined resting state functional connectivity in 28 stroke survivors, 14 with left hemisphere and 14 with right hemisphere lesion, and 14 healthy controls. Contra-lesional hands showed significantly decreased touch discrimination. Whole brain functional connectivity (FC) data was extracted from four seed regions, i.e. primary (S1) and secondary (S2) somatosensory cortices in both hemispheres. Whole brain FC maps and Laterality Indices (LI) were calculated for subgroups. Inter-hemispheric FC was greater in healthy controls compared to the combined stroke cohort from the left S1 seed and bilateral S2 seeds. The left lesion subgroup showed decreased FC, relative to controls, from left ipsi-lesional S1 to contra-lesional S1 and to distributed temporal, occipital and parietal regions. In comparison, the right lesion group showed decreased connectivity from contra lesional left S1 and bilateral S2 to ipsi-lesional parietal operculum (S2), and to occipital and temporal regions. The right lesion group also showed increased intra-hemispheric FC from ipsi-lesional right S1 to inferior parietal regions compared to controls. In comparison to the left lesion group, those with right lesion showed greater intra-hemispheric connectivity from left S1 to left parietal and occipital regions and from right S1 to right angular and parietal regions. Laterality Indices were significantly greater for stroke subgroups relative to matched controls for contra-lesional S1 (left lesion group) and contra-lesional S2 (both groups). We provide evidence of altered functional connectivity within the somatosensory network, across both hemispheres, and to other networks in stroke survivors with impaired touch sensation. Hemisphere of lesion was associated with different patterns of altered functional connectivity within the somatosensory network and with related function was associated with different patterns of altered functional connectivity within the somatosensory network and with related functional networks. PMID- 29487792 TI - No evidence for systematic white matter correlates of dyslexia and dyscalculia. AB - Learning disabilities such as dyslexia, dyscalculia and their comorbid manifestation are prevalent, affecting as much as 15% of the population. Structural neuroimaging studies have indicated that these disorders can be related to differences in white matter integrity, although findings remain disparate. In this study, we used a unique design composed of individuals with dyslexia, dyscalculia, both disorders and controls, to systematically explore differences in fractional anisotropy across groups using diffusion tensor imaging. Specifically, we focused on the corona radiata and the arcuate fasciculus, two tracts associated with reading and mathematics in a number of previous studies. Using Bayesian hypothesis testing, we show that the present data favor the null model of no differences between groups for these particular tracts-a finding that seems to go against the current view but might be representative of the disparities within this field of research. Together, these findings suggest that structural differences associated with dyslexia and dyscalculia might not be as reliable as previously thought, with potential ramifications in terms of remediation. PMID- 29487793 TI - Differences in atypical resting-state effective connectivity distinguish autism from schizophrenia. AB - Autism and schizophrenia share overlapping genetic etiology, common changes in brain structure and common cognitive deficits. A number of studies using resting state fMRI have shown that machine learning algorithms can distinguish between healthy controls and individuals diagnosed with either autism spectrum disorder or schizophrenia. However, it has not yet been determined whether machine learning algorithms can be used to distinguish between the two disorders. Using a linear support vector machine, we identify features that are most diagnostic for each disorder and successfully use them to classify an independent cohort of subjects. We find both common and divergent connectivity differences largely in the default mode network as well as in salience, and motor networks. Using divergent connectivity differences, we are able to distinguish autistic subjects from those with schizophrenia. Understanding the common and divergent connectivity changes associated with these disorders may provide a framework for understanding their shared cognitive deficits. PMID- 29487794 TI - Cortical thickness and subcortical brain volumes in professional rugby league players. AB - Purpose: The purpose of this study was to examine cortical thickness and subcortical volumes in professional rugby players with an extensive history of concussions compared to control subjects. Method: Participants included 24 active and former professional rugby league players [Age M(SD) = 33.3(6.3); Range = 21 44] with an extensive history of concussion and 18 age- and education-matched controls with no history of neurotrauma or participation in contact sports. Participants underwent T1-weighted imaging and completed a neuropsychological battery, including two tests of memory. Whole brain cortical thickness analysis and structural volume analysis was performed using FreeSurfer version 6.0. Results: Professional rugby league players reported greater alcohol consumption (p < .001) and had significantly worse delayed recall of a visually complex design (p = .04). They did not differ from controls on other clinical outcome measures. There were no differences in cortical thickness between the groups. Professional players had smaller whole brain (p = .003), bilateral hippocampi (ps = .03), and left amygdala volumes (p = .01) compared to healthy controls. Within the players group, there were significant associations between greater alcohol use and smaller bilateral hippocampi and left amygdala volumes. There were no associations between structural volumes and history of concussions or memory performance. Conclusions: The literature examining cortical thickness in athletes with a history of multiple concussions is mixed. We did not observe differences in cortical thickness in professional rugby league players compared to controls. However, smaller subcortical volumes were found in players that were, in part, associated with greater alcohol consumption. PMID- 29487795 TI - Deficits of entropy modulation in schizophrenia are predicted by functional connectivity strength in the theta band and structural clustering. AB - Spectral entropy (SE) allows comparing task-related modulation of electroencephalogram (EEG) between patients and controls, i.e. spectral changes of the EEG associated to task performance. A SE modulation deficit has been replicated in different schizophrenia samples. To investigate the underpinnings of SE modulation deficits in schizophrenia, we applied graph-theory to EEG recordings during a P300 task and fractional anisotropy (FA) data from diffusion tensor imaging in 48 patients (23 first episodes) and 87 healthy controls. Functional connectivity was assessed from phase-locking values among sensors in the theta band, and structural connectivity was based on FA values for the tracts connecting pairs of regions. From those data, averaged clustering coefficient (CLC), characteristic path-length (PL) and connectivity strength (CS, also known as density) were calculated for both functional and structural networks. The corresponding functional modulation values were calculated as the difference in SE and CLC, PL and CS between the pre-stimulus and response windows during the task. The results revealed a higher functional CS in the pre-stimulus window in patients, predictive of smaller modulation of SE in this group. The amount of increase in theta CS from pre-stimulus to response related to SE modulation in patients and controls. Structural CLC was associated with SE modulation in the patients. SE modulation was predictive of negative symptoms, whereas CLC and PL modulation was associated with cognitive performance in the patients. These results support that a hyperactive functional connectivity and/or structural connective deficits in the patients hamper the dynamical modulation of connectivity underlying cognition. PMID- 29487796 TI - Alcohol intake and brain white matter in middle aged men: Microscopic and macroscopic differences. AB - Heavy alcohol consumption is associated with deleterious changes in the brain but associations of moderate alcohol intake are not well understood. We examined the association of alcohol consumption with brain white matter health in 377 middle aged men (56-66 years old; mean 61.8 +/- 2.6 years) who were participants in the Vietnam Era Twin Study of Aging (VETSA). T1-, T2-, proton density-, and diffusion weighted magnetic resonance images were obtained. Diffusion measures were quantified from 12 major white matter tracts. Global white matter lesion (WML) burden was also quantified. Mixed effects linear models examined differences in diffusivity and WMLs by amount of alcohol intake. Analyses adjusted for numerous demographic, health, and lifestyle variables. An inverted-U association was found between alcohol intake and fractional anisotropy (FA) in several tracts, including the inferior-frontal-occipital fasciculus, uncinate fasciculus, superior longitudinal fasciculus, the forceps minor and the anterior thalamic radiations. In these tracts, FA increased with increasing alcohol intake, peaking with moderate alcohol intake (9-28 drinks in 14 days), and declining with heavier intake. Associations remained significant after exclusion of individuals with diabetes or hypertension. There was a U-shaped association in WML burden with highest burden among never drinkers and heavy drinkers (>28 drinks in 14 days). This association was no longer significant after exclusion of individuals with hypertension, since WML burden among heavy drinkers no longer differed from that of other drinkers. This suggests that hypertension related to heavy alcohol intake may contribute to WML burden observed among heavy drinkers. Together, these correlational results suggest that among middle-aged men, moderate drinking may be associated with metrics of better white matter health, particularly microstructural measures, whereas drinking beyond recommended guidelines may be associated with both microstructural and macrostructural white matter damage. PMID- 29487797 TI - Disruption to functional networks in neonates with perinatal brain injury predicts motor skills at 8 months. AB - Objective: Functional connectivity magnetic resonance imaging (fcMRI) of neonates with perinatal brain injury could improve prediction of motor impairment before symptoms manifest, and establish how early brain organization relates to subsequent development. This cohort study is the first to describe and quantitatively assess functional brain networks and their relation to later motor skills in neonates with a diverse range of perinatal brain injuries. Methods: Infants (n = 65, included in final analyses: n = 53) were recruited from the neonatal intensive care unit (NICU) and were stratified based on their age at birth (premature vs. term), and on whether neuropathology was diagnosed from structural MRI. Functional brain networks and a measure of disruption to functional connectivity were obtained from 14 min of fcMRI acquired during natural sleep at term-equivalent age. Results: Disruption to connectivity of the somatomotor and frontoparietal executive networks predicted motor impairment at 4 and 8 months. This disruption in functional connectivity was not found to be driven by differences between clinical groups, or by any of the specific measures we captured to describe the clinical course. Conclusion: fcMRI was predictive over and above other clinical measures available at discharge from the NICU, including structural MRI. Motor learning was affected by disruption to somatomotor networks, but also frontoparietal executive networks, which supports the functional importance of these networks in early development. Disruption to these two networks might be best addressed by distinct intervention strategies. PMID- 29487798 TI - Defining SNAP by cross-sectional and longitudinal definitions of neurodegeneration. AB - Introduction: Suspected non-Alzheimer's pathophysiology (SNAP) is a biomarker driven designation that represents a heterogeneous group in terms of etiology and prognosis. SNAP has only been identified by cross-sectional neurodegeneration measures, whereas longitudinal measures might better reflect "active" neurodegeneration and might be more tightly linked to prognosis. We compare neurodegeneration defined by cross-sectional 'hippocampal volume' only (SNAP/L-) versus both cross-sectional and longitudinal 'hippocampal atrophy rate' (SNAP/L+) and investigate how these definitions impact prevalence and the clinical and biomarker profile of SNAP in Mild Cognitive Impairment (MCI). Methods: 276 MCI patients from ADNI-GO/2 were designated amyloid "positive" (A+) or "negative" (A ) based on their florbetapir scan and neurodegeneration 'positive' or 'negative' based on cross-sectional hippocampal volume and longitudinal hippocampal atrophy rate. Results: 74.1% of all SNAP participants defined by the cross-sectional definition of neurodegeneration also met the longitudinal definition of neurodegeneration, whereas 25.9% did not. SNAP/L+ displayed larger white matter hyperintensity volume, a higher conversion rate to dementia over 5 years and a steeper decline on cognitive tasks compared to SNAP/L- and the A- CN group. SNAP/L- had more abnormal values on neuroimaging markers and worse performance on cognitive tasks than the A- CN group, but did not show a difference in dementia conversion rate or longitudinal cognition. Discussion: Using a longitudinal definition of neurodegeneration in addition to a cross-sectional one identifies SNAP participants with significant cognitive decline and a worse clinical prognosis for which cerebrovascular disease may be an important driver. PMID- 29487799 TI - Parasite prevalence, infection intensity and richness in an endangered population, the Atlantic-Gaspesie caribou. AB - The Atlantic-Gaspesie caribou (Rangifer tarandus caribou) population is a small isolated relict herd considered endangered according to the Canadian Species at Risk Act (SARA). This population has low recruitment and survival rates but the potential role of parasites on individual fitness is unknown. In this context, we explored the parasite status of this population with the aim of 1) assessing the occurrence and intensity of parasite infections and the spatial, temporal and individual variations, 2) quantifying parasite richness and investigating factors such as sex and host body condition that may be associated with this variable and 3) evaluating the effects of parasite infections on survival in the Atlantic Gaspesie caribou population. We examined fecal samples from 32 animals captured in 2013-2014 for eggs, oocysts and larvae of parasites and detected 7 parasite species: dorsal-spined larvae protostrongylids, presumably Parelaphostrongylus andersoni based on PCR identification of a subset, Nematodirus odocoilei and other unidentified Strongyles, Trichuris sp., Capillaria sp., Moniezia sp. and Eimeria sp. For each caribou, mean parasite species richness was 1.8 +/- 1.1 (SD). Sex, body condition, year and capture location did not explain parasite prevalence, intensity of infection or richness except for intensity of infection of Capillaria sp. that was positively influenced by body condition. Parasites did not influence survival although mortality was higher for males than for females. We suggest that the relatively low and common gastrointestinal and protostrongylid parasite infections will not be a short-term threat leading to extinction. PMID- 29487800 TI - Biocatalytic production of adipic acid from glucose using engineered Saccharomyces cerevisiae. AB - Adipic acid is an important industrial chemical used in the synthesis of nylon 6,6. The commercial synthesis of adipic acid uses petroleum-derived benzene and releases significant quantities of greenhouse gases. Biocatalytic production of adipic acid from renewable feedstocks could potentially reduce the environmental damage and eliminate the need for fossil fuel precursors. Recently, we have demonstrated the first enzymatic hydrogenation of muconic acid to adipic acid using microbial enoate reductases (ERs) - complex iron-sulfur and flavin containing enzymes. In this work, we successfully expressed the Bacillus coagulans ER in a Saccharomyces cerevisiae strain producing muconic acid and developed a three-stage fermentation process enabling the synthesis of adipic acid from glucose. The ability to express active ERs and significant acid tolerance of S. cerevisiae highlight the applicability of the developed yeast strain for the biocatalytic production of adipic acid from renewable feedstocks. PMID- 29487801 TI - Urothelial carcinoma with sarcomatous variant of the bladder following radiotherapy for cervical cancer: A case report. PMID- 29487803 TI - An optimized method using peptide arrays for the identification of in vitro substrates of lysine methyltransferase enzymes. AB - While a number of post-translational modifications (PTM), such as phosphorylation and ubiquitination, have been extensively studied, lysine methylation is emerging as an important PTM with implications in a growing number of diverse cellular processes. To date, there are approximately 5000 identified methylation sites on non-histone proteins, and as the methyllysine proteome expands it becomes important to identify the lysine methyltransferase enzymes responsible for each methylation event. The use of peptide SPOT methylation assay has proven to be a useful in the identification and validation of novel substrates for lysine methyltransferase enzymes as it uses a weak beta emitter coupled with fluorography to detect methylation events. The method described in this paper provides improvements to the typical protocol for this assay, as a highly sensitive tritium assay can be developed with less radioactivity than previously described. This protocol provides an inexpensive alternative to weak beta signal enhancer sprays and washes for use in lysine methylation peptide SPOT arrays, and a simple open-source method for array quantification. PMID- 29487802 TI - Protective role of Emblica officinalis hydro-ethanolic leaf extract in cisplatin induced nephrotoxicity in Rats. AB - Nephrotoxicity is a major limiting factor in cisplatin treatment. In the present study hydro-ethanolic leaf extract of Emblica officinalis was investigated for its protective role in cisplatin induced nephrotoxicity. The experiment was designed for 14 days and male Wistar rats were divided into 9 groups (n = 5). Group 1 served as control (with no treatment), group 2 served as a vehicle control and received 0.9% NaCl intraperitoneally (i.p.) on 11th day of the treatment, group 3 received a single dose of cisplatin on 11th day (12 mg/kg body weight, i.p.), group 4-6 received leaf extract only (100 mg/kg, 200 mg/kg and 400 mg/kg body weight, respectively) throughout the treatment, group 7-9 received leaf extract (100 mg/kg, 200 mg/kg and 400 mg/kg body weight, respectively) throughout the treatment and single dose of cisplatin on the 11th day of the leaf extract treatment. At the end of the experiment (i.e. on 14th day) blood samples were collected from all the groups and were sacrificed to study renal functional parameters. Treatment with above doses of E. officinalis leaf extract significantly (p <= 0.05) attenuates renal damage by decreasing serum creatinine and blood urea nitrogen (BUN), enhanced the activities of Catalase, SOD, GPx, GR and decreased the renal MDA level compared with the cisplatin treatment group. Furthermore the oral administration of Amla leaf extract improves histological damage and morphological changes in RBCs. Our results suggest that, leaf extract of E. officinalis may ameliorate renal damage caused by cisplatin. PMID- 29487804 TI - Role of vasoactive intestinal peptide in Aspergillus fumigatus-infected cornea. AB - AIM: To investigate the anti-inflammatory role of vasoactive intestinal peptide (VIP) in Aspergillus fumigatus (A. fumigatus) ketatitis. METHODS: Expression of VIP was tested by polymerase chain reaction (PCR) in C57BL/6 and BALB/c normal and A. fumigatus infected corneas. C57BL/6 mice were pretreated with recombinant (r) VIP, while BALB/c mice were pretreated with VIP antagonist, and then infected with A. fumigatus. Clinical score was recorded. Expression of pro- and anti inflammatory cytokines, toll-like receptor 4 (TLR4), lectin-like oxidized low density lipoprotein receptor 1 (LOX-1), and neutrophil infiltration were tested by PCR, enzyme-linked immunosorbent assay (ELISA), and myeloperoxidase (MPO) assay. RESULTS: VIP mRNA expression in BALB/c cornea was higher than C57BL/6 cornea at 1 and 3d post infection (p.i.). rVIP treatment of C57BL/6 mice showed alleviated disease and down-regulated expression of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), while IL-10 expression was up regulated. Neutrophil infiltration and TLR4, IL-17 expression were decreased after rVIP treatment, while LOX-1 expression was up-regulated in C57BL/6. VIP antagonist pretreatment showed increased disease and higher IL-1beta, TNF-alpha, TLR4, IL-17 and MPO levels, while IL-10 and LOX-1 levels were down-regulated in BALB/c mice. CONCLUSION: rVIP alleviate disease response of C57BL/6 mice. VIP antagonist resulted in worsened disease of BALB/c mice. VIP proposed anti inflammatory role in A. fumigatus keratitis. PMID- 29487805 TI - Anti-fibrotic effect of rosmarinic acid on inhibition of pterygium epithelial cells. AB - AIM: To investigate the anti-fibrosis effect of rosmarinic acid (RA) in pterygium epithelial cells (PECs) to determine if RA is a potent agent for treating pterygium. METHODS: The PECs (1*104 cells/mL) were treated with 100 umol/L of RA for 1, 3 and 6h. After RA treatment, the cell viability was determined by staining with acridine orange/DAPI and analysis via a NucleoCounter NC-3000. The protein expression levels of type I collagen, transforming growth factor beta-1 (TGF-beta1), TGF-beta type II receptor (TGF-betaRII), p-Smad1/5, p-Smad2, p Smad3, and Smad4 of the cell lysates were measured by Western blot analysis. RESULTS: The cell viability of PECs was significantly decreased after RA treatment (P<0.01). As the result, RA reduced the protein expression of type I collagen and TGF-beta1 of PECs. Additionally, RA also inhibited TGF-beta1/Smad signaling by decreasing the protein expressions of TGF-betaRII, p-Smad1/5, p Smad2, p-Smad3, and Smad4. CONCLUSION: This study demonstrate that RA could inhibit fibrosis of PECs by down-regulating type I collagen expression and TGF beta1/Smad signaling. Therefore, RA is a potent therapeutic agent for the treatment of pterygium. PMID- 29487806 TI - Age-related pro-inflammatory and pro-angiogenic changes in human aqueous humor. AB - AIM: To reveal age-related aqueous cytokine changes in human aqueous humor. METHODS: Aqueous humor was collected from 12 young children (3-6.5 years old) and 71 healthy adults (22-106 years old) with cataract but without other systemic or ocular disorders. Levels of 22 cytokines, chemokines and vascular endothelial growth factor (VEGF) were measured and analyzed. RESULTS: The following proteins showed significant increase from childhood to adult: interferon-gamma (IFN gamma), interleukin (IL)-13, IL-6, IL-12(p70), IL-10, CCL2, CCL3, CCL4, CXCL8, CXCL9, CXCL10, IFN-alpha2 and VEGF (all P<0.05). IFN-gamma, IL-13, IL-12(p70), IL 10, CCL3, CXCL9 and VEGF also showed moderate strength age-related increase in the adult group (r>0.5). The strength of correlation between aging and CCL4 were fair (r=0.398). The concentrations of IL-2, IL-4, IL-5, IL-1beta and TNF-alpha were low in both groups. CONCLUSION: From childhood to adult, the immunological milieu of the anterior chamber become more pro-inflammatory and pro-angiogenic. Such changes may represent the parainflammation state of the human eye. PMID- 29487807 TI - miR-211 promotes lens epithelial cells apoptosis by targeting silent mating-type information regulation 2 homolog 1 in age-related cataracts. AB - AIM: To detect the expression of miR-211 in age-related cataract tissue, explore the effects of miR-211 on lens epithelial cell proliferation and apoptosis, and identify its target gene. METHODS: This study used real-time quantitative polymerase chain reaction (RT-qPCR) to measure the expression of miR-211 and its predicted target gene [silent mating-type information regulation 2 homolog 1 (SIRT1)] in 46 anterior lens capsules collected from age-related cataract patients. Human lens epithelial cell line (SRA01/04) cells were transfected with either miR-211 mimics, mimic controls, miR-211 inhibitors or inhibitor controls, 72h after transfection, miRNA and protein expression of SIRT1 were measured using RT-qPCR and Western blotting; then cells were exposed to 200 umol/L H2O2 for 1h, whereupon cell viability was measured by MTS assay, caspase-3 assay was performed. Dual luciferase reporter assay was performed to verify the relationship between miR-211 of SIRT1. RESULTS: Compared to the control group, expression of miR-211 was significantly increased (P<0.001), the miRNA and protein expression of SIRT1 were significantly decreased (P<0.001) in the anterior lens capsules of patients with age-related cataracts. Relative to the control group, SIRT1 miRNA and protein levels in the miR-211 mimic group were significantly reduced, cell proliferation activity significantly decreased, and caspase-3 activity was significantly increased (P<0.001). In the miR-211 inhibitor group, SIRT1 miRNA and protein expression were significantly increased, cell proliferation activity significantly increased, and caspase-3 activity was significantly decreased (P<0.001). A dual luciferase reporter assay confirmed that SIRT1 is a direct target of miR-211. CONCLUSION: miR-211 is highly expressed in the anterior lens capsules of patients with age-related cataracts. By negatively regulating the expression of SIRT1, miR-211 promotes lens epithelial cell apoptosis and inhibits lens epithelial cell proliferation. PMID- 29487808 TI - Effect of the Notch signaling pathway on retinal ganglion cells and its neuroprotection in rats with acute ocular hypertension. AB - AIM: To explore the effect of the Notch signaling pathway on retinal ganglion cells (RGCs) and optic nerve in rats with acute ocular hypertension (OH). METHODS: Totally 48 Sprague-Dawley (SD) rats were included, among which 36 rats were selected to establish acute OH models. OH rats received a single intravitreal injection of 2 uL phosphate buffered solution (PBS) and another group of OH rats received a single intravitreal injection of 10 umol/L gamma secretase inhibitor (DAPT). Quantitative real-time polymerase chain reaction (qPCR) and Western blot assay were adopted to determine the mRNA level of Notch and the protein levels of Notch, Bcl-2, Bax, caspase-3, and growth-associated protein 43 (GAP-43). The RGC apoptosis conditions were assessed by TUNEL staining. RESULTS: The OH rats and PBS-injected rats had increased expression levels of Notch1, Bax, caspase-3, and GAP-43, decreased expression levels of Bcl 2, and increased RGC apoptosis, with severer macular edema and RGCs more loosely aligned, when compared with the normal rats. The DAPT-treated rats displayed increased expression levels of Notch1, Bax, caspase-3, and GAP-43, decreased expression levels of Bcl-2, and increased RGC apoptosis, in comparison with the OH rats and PBS-injected rats. RGCs were hardly observed and macular edema became severe in the DAPT-treated rat. CONCLUSION: The Notch signaling pathway may suppress the apoptosis of retinal ganglion cells and enhances the regeneration of the damaged optic nerves in rats with acute OH. PMID- 29487809 TI - Monocyte chemoattractant protein 1 and fractalkine play opposite roles in angiogenesis via recruitment of different macrophage subtypes. AB - AIM: To explore the interaction between macrophages and chemokines [monocyte chemoattractant protein 1 (MCP-1/CCL2) and fractalkine/CX3CL1] and the effects of their interaction on neovascularization. METHODS: Human peripheral blood mononuclear cells, donated by healthy volunteers, were separated and cultured in RPMI-1640 medium containing 10% fetal bovine serum, then induced into macrophages by stimulation with 30 ug/L granulocyte macrophage-colony stimulating factor (GM CSF). The expression of CCR2 and/or CX3CR1 in the macrophages was examined using flow cytometry. Macrophages were then stimulated with recombinant human CCL2 (rh CCL2) or recombinant human CX3CL1 (rh-CX3CL1). The expression of angiogenesis related genes, including VEGF-A, THBS-1 and ADAMTS-1 were examined using real time quantitative polymerase chain reaction (PCR). Supernatants from stimulated macrophages were used in an assay of human retinal endothelial cell (HREC) proliferation. Finally, stimulated macrophages were co-cultured with HREC in a migration assay. RESULTS: The expression rate of CCR2 in macrophages stimulated by GM-CSF was 42%+/-1.9%. The expression rate of CX3CR1 was 71%+/-3.3%. Compared with vehicle-treated groups, gene expression of VEGF-A in the macrophages was greater in 150 mg/L CCL2-treated groups (P<0.05), while expression of THBS-1 and ADAMTS-1 was significantly lower (P<0.05). By contrast, compared with vehicle treated groups, expression of VEGF-A in 150 mg/L CX3CL1-treated groups was significantly lower (P<0.05), while expression of THBS-1 and ADAMTS-1 was greater (P<0.05). Supernatants from CCL2 treated macrophages promoted proliferation of HREC (P<0.05), while supernatants from CX3CL1-treated macrophages inhibited the proliferation of HREC (P<0.05). HREC migration increased when co-cultured with CCL2-treated macrophages, but decreased with CX3CL1-treated macrophages (P<0.05). CONCLUSION: CCL2 and CX3CL1 exert different effects in regulation of macrophage in expression of angiogenesis-related factors, including VEGF-A, THBS-1 and ADAMTS-1. Our findings suggest that CCL2 and CX3CL1 may be candidate proteins for further exploration of novel targets for treatment of ocular neovascularization. PMID- 29487810 TI - Modified ulcer debridement in the treatment of the superficial fungal infection of the cornea. AB - AIM: To evaluate the efficacy of modified corneal ulcer debridement in superficial fungal keratitis unresponsive to medications. METHODS: A total of 209 patients (209 eyes) with fungal keratitis, involving no more than 50% of the stromal depth and not responding to antifungal agents for 2wk, were recruited in this retrospective, noncomparative study. The patients were treated with modified corneal ulcer debridement. All visible corneal infiltrates were removed under an operating microscope to obtain a clean stromal bed and smooth incised edges. Antifungal drugs were used immediately after surgery. Healing time of the ulcers was recorded. Fungal recurrence, visual acuity, corneal thickness and risk factors for treatment failure were monitored. RESULTS: The follow-up was 13.6+/ 5.8mo. The corneal ulcers healed in 195 of 209 eyes (93.3%), with a mean healing time of 8.4+/-6.8d. The other 14 eyes were further treated by penetrating keratoplasty (PK) (1 eye), anterior lamellar keratoplasty (LK) (7 eyes), conjunctival flap covering (4 eyes) or amniotic membrane transplantation (2 eyes). The best corrected visual acuity (BCVA) was >=20/70 in 80.3% of the eyes, >=20/40 in 56.9% of the eyes, and >=20/25 in 27.3% of the eyes. The corneas at the lesions became thinner, but all in the safe range. No fungal recurrence or corneal ectasis developed during the follow-up. The risk of treatment failure was higher in patients with preoperative hypopyon (P=0.036) and ever using steroid (P=0.025). CONCLUSION: Modified surgical debridement is a simple and effective method for the treatment of superficial fungal infection of the cornea, with improved visual acuity and no recurrence. Such an intervention in time can rapidly control fungal infection and largely shorten corneal ulcer healing time. PMID- 29487811 TI - Evaluation of the safety and efficacy of therapeutic bandage contact lenses on post-cataract surgery patients. AB - AIM: To evaluate the safety of therapeutic bandage contact lens for post-cataract surgery patients and to illustrate its efficacy on post-operative comfort and tear-film stability. METHODS: A total of 40 participants were recruited and randomly divided into two groups. Group one was instructed to wear bandage contact lenses for a week and use antibiotic eye drops for a month since the first day after surgery. Group two received sub-conjunctival injection of tobramycin and was asked to wear eye pads on the first day after surgery and then were instructed to use antibiotic eye drops as the first group did. Ocular surface disease index (OSDI) questionnaire, slit-lamp microscope examination of tear break-up time (TBUT), corneal fluorescein score (CFS), tear meniscus height (TMH) together with anterior segment optical coherence tomography (AS-OCT) and corneal topography were evaluated preoperatively and postoperatively. RESULTS: The subjective feeling (P=0.004), TBUT (P<0.001) and TMH (P=0.02) post-surgery had improved in patients who used bandage contact lenses compared with those who did not at 1wk post-surgery. Until three month postoperatively, the comfort degree (P=0.004) and TMH (P=0.01) of group two were still worse than group one. Moreover, TBUT (P<0.001) and CFS (P=0.004) of the group with eye pads got worse than the results before, whereas the group with bandage contact lenses recovered to normal. None of these patients had infections or other complications. CONCLUSION: Wearing therapeutic bandage contact lens after cataract surgery, compared with traditional eye-pads, is a safe method to improve tear-film stability and reduce post-operative discomfort without hindering corneal incision recovery. PMID- 29487812 TI - Comparison of two Nd:YAG laser posterior capsulotomy: cruciate pattern vs circular pattern with vitreous strand cutting. AB - AIM: To investigate the effects and safety of neodymium: yttrium-aluminium-garnet (Nd:YAG) laser posterior capsulotomy with vitreous strand cutting. METHODS: A total of 40 eyes of 37 patients with symptomatic posterior capsular opacity (PCO) were included in this prospective randomized study and were randomly subjected to either cruciate pattern or round pattern Nd:YAG posterior capsulotomy with vitreous strand cutting (modified round pattern). The best corrected visual acuity (BCVA), intraocular pressure (IOP), refractive error, endothelial cell count (ECC), anterior segment parameters, including anterior chamber depth (ACD) and anterior chamber angle (ACA) were measured before and 1mo after the laser posterior capsulotomy. RESULTS: In both groups, the BCVA improved significantly (P<0.001 for the modified round pattern group, P=0.001 for the cruciate pattern group); the IOP and ECC did not significantly change. The ACD significantly decreased (P<0.001 for both) and the ACA significantly increased (P=0.001 for the modified round pattern group and P=0.034 for the cruciate group). The extent of changes in these parameters was not significantly different between the groups. CONCLUSION: Modified round pattern Nd:YAG laser posterior capsulotomy is an effective and safe method for the treatment of PCO. This method significantly changes the ACD and ACA, but the change in refraction is not significant. Modified round pattern Nd:YAG laser posterior capsulotomy can be considered a good alternative procedure in patients with symptomatic PCO. PMID- 29487813 TI - Managing high risk glaucoma with the Ahmed valve implant: 20 years of experience. AB - AIM: To estimate the efficacy and safety of the Ahmed implant in patients with high risk for failure after glaucoma surgery. METHODS: In 342 eyes of 342 patients with refractory glaucoma, even with application of medical treatment, the Ahmed valve was introduced for intraocular pressure (IOP) control, in the period of the last 20y. The nature of glaucoma was neovascular in 162 eyes, pseudophakic or aphakic in 49 eyes, inflammatory in 29 eyes and non working previous antiglaucomatic surgical interventions in 102 eyes. RESULTS: Follow-up ranged from 18 to 120mo with a mean follow-up of 63.2mo. IOP before the operation decreased from 31.6+/-10.4 mm Hg to 18.3+/-5.4 mm Hg (no systemic treatment) at the end of follow up period. When we compared the IOP values before the operation using ANOVA showed statistically significant difference (P<0.001). The success rate was 85.2% during the first semester, 76.8% at 12mo and 50.3% at the end of follow up period (18 to 120mo after implantation). Success rate was 25.7% in neovascular glaucoma, 63.2% in aphakic glaucoma and 73.8% in non working previous antiglaucomatic surgical interventions. Complications due to the implant were: serous choroidal detachment in 14.8%, blockage of the tube in 2.8%, malposition of the tube in 4.9%, suprachoroidal hemorrhage in 2.1%, cataract progression in 39.6% (phakic eyes), shallow anterior chamber in 9.2%, hyphaema in 28.9%, exposure of valve in 2.6%, exposure of tube in 9.3%, hypotony in 4.9% and conjunctival fibrosis in 41.5%. CONCLUSION: Despite the fact that Ahmed valve implant had suchlike results as other implants concerning the IOP control, complications rate due to hypotony or over filtration in the first days after the intervention are not that frequent as with other valve implants. PMID- 29487814 TI - Functional evaluation of the filtering bleb by ultrasound biomicroscopy after trabeculectomy with mitomycin C. AB - AIM: To study the role of ultrasound biomicroscopy (UBM) in the assessment of the bleb function after trabeculectomy with mitomycin C (MMC). METHODS: This was a cross-sectional study including all cases had undergone trabeculectomy with MMC 0.2 mg/mL for 3min. Participants were recruited from the follow-up cases at Department of Ophthalmology, Tanta University in the period from August 2015 to August 2016. Full history taking and ophthalmological examination were performed. Intraocular pressure (IOP) was measured using Goldmann applanation tonometry and the history of prescribed postoperative antiglaucoma medications was recorded. Accordingly, the trabeculectomy blebs were divided clinically into successful blebs when the IOP post-operative was <=18 mm Hg without medications. Scanning examination of the filtering bleb using UBM examination was performed at the period from 2 to 36mo after trabeculectomy (13.6+/-9.7mo). RESULTS: This study included 33 trabeculectomy filtering blebs of 25 patients (9 males and 16 females). The mean age of patients was 53.2+/-14.2y (range 25-71y). We had 20 eyes with complete success, 9 eyes with qualified success, and 4 eyes with failure after trabeculectomy with MMC. The blebs were classified into successful blebs (IOP <=18 mm Hg without antiglaucoma medications), others were classified into qualified successful and failed blebs. There was a significant correlation between certain UBM findings (intra-bleb reflectivity, draining sub-scleral tract, bleb height, and intrableb fluid cysts) and cases with different grades of clinical functional success (P<0.01). CONCLUSION: UBM is an objective tool in the functional assessment of the post-trabeculectomy filtering bleb through a significant correlation between certain UBM parameters and the different grades of clinical functional success. PMID- 29487815 TI - Trabeculectomy with Ologen implant versus mitomycin C in congenital glaucoma secondary to Sturge Weber Syndrome. AB - AIM: To compare the efficacy and safety of collagen matrix implant [Ologen (OLO) implant] versus mitomycin C (MMC) with subscleral trabeculectomy (SST) for the surgical treatment of congenital glaucoma (CG) in Sturge-Weber Syndrome (SWS). METHODS: A prospective comparative randomized study of 20 eyes of 16 patients with CG associated with SWS was divided into two groups. The first group (MMC Group) included 10 eyes that were subjected to SST with MMC. The second group (OLO Group) included 10 eyes that were subjected to trabeculectomy with a collagen matrix implant (OLO implant). Postoperative evaluation included intraocular pressure (IOP) level, bleb evaluation, complications, and the need for further medication or surgical intervention. RESULTS: The mean preoperative IOP was 29+/-3.16 mm Hg in MMC and 29.8+/-3.08 mm Hg in OLO eyes. Mean 12-month percentage reduction in IOP was significant in both groups (57.9% and 56.3%). At the end of the 12 postoperative follow-up month, in the MMC Group, 80% of eyes achieved the complete success, 20% of eyes had qualified success with no failed surgery in comparison to OLO Group which 70% of eyes achieved the complete success, 20% of eyes had qualified success with 10% failed surgery. In terms of complications, the MMC Group had a higher rate of complications than the OLO Group in the form of thin polycystic bleb in 6 eyes (60%), blebitis in only one eye (10%) treated with topical antibiotics, shallow anterior chamber in two eyes (20%). CONCLUSION: This study proves that the use of a collagen matrix implant yields equally effective results as MMC when combined with trabeculectomy for the treatment of CG in SWS. Furthermore, OLO implantation is safe and has low incidences of complications. PMID- 29487816 TI - Correlation between macular ganglion cell-inner plexiform layer thickness and visual acuity after resolution of the macular edema secondary to central retinal vein occlusion. AB - AIM: To examine the thickness of the ganglion cell-inner plexiform layer (GCIPL) in eyes with resolved macular edema (ME) in non-ischemic central retinal vein occlusion (CRVO), applying spectral-domain optical coherence tomography (SD-OCT), and its relationship with visual acuity. METHODS: The retrospective observational case-control study included 30 eyes of non-ischemic CRVO patients with resolved ME (ME eyes) after treatment, and 30 eyes of non-ischemic CRVO patients without ME (non-ME eyes). The macular GCIPL thickness, peripapillary retinal nerve fiber layer (pRNFL) thickness and central macular thickness (CMT) were measured on a SD OCT scan. Linear regression analyses were performed to determine the correlation between the thickness of each and the visual acuity (VA). RESULTS: No significant difference in average GCIPL thickness, mean pRNFL thickness and CMT were observed between ME group and non-ME group (P=0.296, 0.183, 0.846). But, minimum GCIPL thickness was reduced in ME eyes compared with non-ME eyes (P=0.022). Final VA significantly correlated with the minimum GCIPL thickness in ME eyes (r=-0.482, P=0.007), whereas no correlation was found with average GCIPL thickness, average pRNFL thickness and mean CMT. CONCLUSION: Minimum GCIPL thickness is reduced in ME eyes compared with non-ME eyes, and correlated with the VA in non-ischemic CRVO. These results propose that inner retinal damage occurring in patients with ME secondary to non-ischemic CRVO may lead to permanent visual defect after treatment. PMID- 29487817 TI - Paediatric retinal detachment: aetiology, characteristics and outcomes. AB - AIM: To provide contemporary data on the aetiology, clinical features and outcomes of paediatric retinal detachment. METHODS: A retrospective review of all those under 16y who underwent surgical repair for retinal detachment at a single centre between the years 2008 and 2015 inclusive was performed. In each case the cause of retinal detachment, the type of detachment, the presence or absence of macular involvement, the number and form of reparative surgeries undertaken, and the surgical outcome achieved was recorded. RESULTS: Twenty-eight eyes of 24 patients, 15 (62.5%) of whom were male and 9 (37.5%) of whom were female, their mean age being 11.6y and range 2-16y developed retinal detachment over the eight year period studied. Trauma featured in the development of retinal detachment in 14 (50.0%) cases. Retinal detachment was associated with other ocular and/or systemic conditions in 11 (39.3%) cases. A mean of 3.0 procedures with a range of 1-9 procedures per patient were undertaken in the management of retinal detachment. Complex vitrectomy combined with scleral buckling or complex vitrectomy alone were those most frequently performed. Mean postoperative visual acuity was 1.2 logMAR with range 0.0-3.0 logMAR. In 22 of 26 (84.6%) cases which underwent surgical repair the retina was attached at last follow-up. CONCLUSION: Aggressive management of paediatric retinal detachment including re-operation increases the likelihood of anatomical success. In cases where the retinal detachment can be repaired by an external approach alone there is a more favourable visual outcome. PMID- 29487818 TI - Real-life experience of ranibizumab therapy for neovascular age-related macular degeneration from Turkey. AB - AIM: To report the real-life experience and clinical results of intravitreal ranibizumab injections to neovascular age-related macular degeneration (nAMD) in a single institution in Turkey. METHODS: A total of 101 eyes of 89 patients with nAMD treated with intravitreal ranibizumab injection, followed up for at least 24mo between 2009 and June 2014, which were evaluated retrospectively. A pro re nata (PRN) treatment protocol was performed after the patients had received three, monthly loading injections. Best corrected visual acuity (BCVA) and central macular thickness measurements were evaluated at baseline and 3, 6, 12, 18, and 24mo. Number of injections and visits were also recorded. RESULTS: Of the 89 patients, 34 (38.2%) were male and 55 (61.8%) were female and the mean age was 74.0+/-9.5 (52-91)y. The mean follow-up period was 24.82+/-4.4 (24-29)mo. Mean number of visits was 8.4+/-1.12 (7-12) in the first year and 6.6+/-1.33 (4-12) in the second year. The mean number of injections was 5.8+/-1.6 (3-10) and 4.2+/-2.2 (0-9) in the first and second year, respectively. The mean BCVA was 59+/-15.8 letters at baseline by the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. The mean BCVA at 3, 12, and 24mo was 70.3+/-15.9, 67.9+/-14.3 and 67.3+/ 16.9 letters, respectively. Improvement in visual acuity for each of the visits from baseline was found to be statistically significant (P<0.01). Visual acuity in 9 eyes at month 3, 7 eyes at month 12, and 13 eyes at month 24 did not change. The mean central macular thickness (CMT) was 437.99+/-164.78 um at baseline. The mean CMT was 348.05+/-138.47 um, 349.27+/-139.79 um, and 344.13+/-146.30 um at months 3, 12, and 24, respectively. The decrease in CMT for each of the visits from baseline was found to be statistically significant (P<0.01). CONCLUSION: Anatomical and functional achievement are obtained in our study, but the mean number of injections and visits are found to be lower than the findings reported in randomized controlled clinical trials in the literature. However, the mean number of injections and visits in our study are compatible with the findings reported in real-life experience studies in the literature. PMID- 29487819 TI - Comparison of peripapillary retinal nerve fiber layer thickness between myopia severity groups and controls. AB - AIM: To compare the peripapillary retinal nerve fiber layer (RNFL) thickness measured via optical coherence tomography (OCT) between different groups of myopia severity and controls. METHODS: This was a prospective cross-sectional study. All subjects underwent a full ophthalmic examination, refraction, visual field analysis and A-scan biometry. Myopic patients were classified as low myopia (LM) [spherical equivalent (SE) from greater than -0.5 D, up to -3.0 D], moderate myopia (MM; SE greater than -3.0 D, up to -6.0 D) and high myopia (HM; SE greater than -6.0 D). The control group consisted of emmetropic (EM) patients (SE from +0.5 D to -0.5 D). A Zeiss Cirrus HD-OCT machine was used to measure the peripapillary RNFL thickness of both eyes of each subject. The mean peripapillary RNFL thickness between groups was compared using both analysis of variance and analysis of covariance. RESULTS: A total of 403 eyes of 403 subjects were included in this study. The mean age was 31.48+/-10.23y. There were 180 (44.7%) eyes with EM, 124 (30.8%) with LM, 73 (18.1%) with MM and 26 (6.5%) with HM. All groups of myopia severity had a thinner average RNFL than the EM group, but after controlling for gender, age, and axial eye length, only the HM group differed significantly from the EM group (P=0.017). Likewise, the superior, inferior and nasal RNFL was thinner in all myopia groups compared to controls, but after controlling for confounders, only the inferior quadrant RNFL was significantly thinner in the HM group, when compared to the EM group (P=0.017). CONCLUSION: The average and inferior quadrant RNFL is thinner in highly myopic eyes compared to emmetropic eyes. Refractive status must be taken into consideration when interpreting the OCT of myopic patients, as RNFL thickness varies with the degree of myopia. PMID- 29487820 TI - Meta-analysis of the efficacy and safety of combined surgery in the management of eyes with coexisting cataract and open angle glaucoma. AB - AIM: To conduct a systematic review and quantitative Meta-analysis of the efficacy and safety of combined surgery for the eyes with coexisting cataract and open angle glaucoma. METHODS: We performed a systematic search of the related literature in the Cochrane Library, PubMed, EMBASE, Web of Science databases, CNKI, CBM and Wan Fang databases, with no limitations on language or publication date. The primary efficacy estimate was identified by weighted mean difference of the percentage of intraocular pressure reduction (IOPR%) from baseline to end point, the percentage of number of glaucoma medications reduction from pre- to post-operation, and the secondary efficacy evaluations were performed by odds ratio (OR) and 95% confidence interval (CI) for complete and qualified success rate. Besides, ORs were applied to assess the tolerability of adverse incidents. Meta-analyses of fixed or random effect models were performed using RevMan software 5.2 to gather the consequences. Heterogeneity was evaluated by Chi2 test and the I2 measure. RESULTS: Ten studies enrolling 3108 patients were included. The combined consequences indicated that both glaucoma and combined cataract and glaucoma surgery significantly decreased IOP. For deep sclerectomy vs deep sclerectomy plus phacoemulsification and canaloplasty vs phaco-canaloplasty, the differences in IOPR% were not all statistically significant while trabeculotomy was detected to gain a quantitatively greater IOPR% compared with trabeculotomy plus phacoemulsification. Furthermore, there was no statistical significance in the complete and qualified success rate, and the rates of adverse incidents for trabeculotomy vs trabeculotomy plus phacoemulsification. CONCLUSION: Compared with trabeculotomy plus phacoemulsification, trabeculectomy alone is more effective in lowering IOP and the number of glaucoma medications, while the two surgeries can not demonstrate statistical differences in the complete success rate, qualified success rate, or incidence of adverse incidents. PMID- 29487821 TI - Effects of lipid-lowering agents on diabetic retinopathy: a Meta-analysis and systematic review. AB - AIM: To clarify this controversy and to provide evidence for application of lipid lowering agents in treatment of diabetic retinopathy (DR). METHODS: We searched the databases of PubMed, Embase and Cochrane Library Central Register of Controlled Trials (CENTRAL) and abstracts from main annual meetings up to January 1, 2017. Google scholar and ClinicalTrials.gov were also searched for unpublished relevant studies. We included randomized controlled trials (RCTs) that studied lipid-lowering agents in type 1 or type 2 diabetes in this Meta-analysis. The primary endpoint was the progression of DR, and the secondary endpoints included vision loss, development of diabetic macular edema (DME) and aggravation of hard exudates. The pooled odds ratios (OR) with corresponding 95% confidence intervals (95%CIs) were calculated. RESULTS: After systemic and manual literature search by two independent investigators, we included 8 RCTs from 7 published articles with 13 454 participants in this Meta-analysis. The results revealed that lipid lowering drugs were associated with reduced risk in DR progression [OR=0.77 (95%CI: 0.62, 0.96), P=0.02]. Lipid-lowering agents might have protective effect on DME compared to placebo, although the difference was not statistically significant [OR=0.60 (95%CI: 0.34, 1.08), P=0.09]. However, no significant differences in the worsening of vision acuity [OR=0.96 (95%CI: 0.81,1.14), P=0.64] and hard exudates [OR=0.50 (95%CI:0.15, 1.74), P=0.28] were found between the lipid-lowering drugs and the placebo groups. CONCLUSION: In DR patients, lipid-lowering agents show a protective effect on DR progression and might be associated with reduced risk in the development of DME. However, lipid-lowering agents have no effects on vision loss and hard exudates aggravation. Further clinical trials in larger scale are required to confirm the conclusion of this study and thus justify the use of intensive control lipids with anti-lipid agents at the early stages of DR. PMID- 29487822 TI - Association between endogenous cortisol level and the risk of central serous chorioretinopathy: a Meta-analysis. AB - AIM: To assess the association between endogenous cortisol level and the risk of central serous chorioretinopathy (CSC). METHODS: Case-control studies were systematically searched on PubMed, Embase, Cochrane, China National Knowledge Infrastructure (CNKI) for publishes between January 1990 and July 2017 to assess the association between endogenous cortisol level and CSC. The main endpoints were serum cortisol level at 8 a.m. and 24-hour urine 17-hydroxysteroids level. We assessed pooled data using a random-effects model. RESULTS: Of 86 identified studies, 5 were eligible included in our analysis. The 5 studies included a total of 315 participants, of whom 187 had CSC. Statistically significant association was observed between serum cortisol level (summary SMD=0.77, 95%CI=0.55-0.99), 24 hour urine 17-hydroxysteroids level (summary SMD=0.95, 95%CI=0.61-1.30), and the risk of CSC. CONCLUSION: Endogenous cortisol level is associated with an increased risk of CSC. Combined treatment targeting the serum cortisol level at 8 a.m. and 24-hour urine 17-hydroxysteroids level can be a potential preventive strategy for individuals who are at risk of CSC and therapeutic strategy for patients with CSC. PMID- 29487823 TI - Gender differences in adolescent dry eye disease: a health problem in girls. AB - AIM: To evaluate the signs and symptoms of dry eye disease (DED) in adolescents. METHODS: This was a cross-sectional, case-control study and outpatients aged 10 to 19y were recruited from six eye clinics of various practices and locations in Japan, and 253 non-DED subjects and 70 DED patients were enrolled. Participants were examined for DED-related signs. Patients were also interviewed to ascertain the presence or absence of six common DED-related symptoms: dryness, irritation, pain, eye fatigue, blurring, and photophobia. Main outcome measures were differences in signs and symptoms of dry eye disease between boys and girls. RESULTS: Of the 323 adolescents recruited, 70 (21.7%) were diagnosed with DED. Significant differences between the non-DED and DED groups were found for short tear break-up time (BUT; <=5s; P=0.000) and superficial punctate keratopathy (SPK; staining score >=3; P=0.000). Late adolescent girls reported fewer symptoms than late adolescent boys, although their DED-related signs were worse compared to other groups. The prevalence and severity of DED were similar in the Tokyo area compared with suburban and local areas but myopic errors were worse. CONCLUSION: We find that adolescents reported symptoms of DED similar to those found in adults, and the majority have short BUT-type DED. The prevalence and severity of DED in late adolescent girls is comparable with adults. Adolescents with DED are underserved and we believe that DED is a hidden but potentially serious health problem for this age group. PMID- 29487824 TI - Diagnosis related group grouping study of senile cataract patients based on E CHAID algorithm. AB - AIM: To figure out the contributed factors of the hospitalization expenses of senile cataract patients (HECP) and build up an area-specified senile cataract diagnosis related group (DRG) of Shanghai thereby formulating the reference range of HECP and providing scientific basis for the fair use and supervision of the health care insurance fund. METHODS: The data was collected from the first page of the medical records of 22 097 hospitalized patients from tertiary hospitals in Shanghai from 2010 to 2012 whose major diagnosis were senile cataract. Firstly, we analyzed the influence factors of HECP using univariate and multivariate analysis. DRG grouping was conducted according to the exhaustive Chi-squared automatic interaction detector (E-CHAID) model, using HECP as target variable. Finally we evaluated the grouping results using non-parametric test such as Kruskal-Wallis H test, RIV, CV, etc. RESULTS: The 6 DRGs were established as well as criterion of HECP, using age, sex, type of surgery and whether complications/comorbidities occurred as the key variables of classification node of senile cataract cases. CONCLUSION: The grouping of senile cataract cases based on E-CHAID algorithm is reasonable. And the criterion of HECP based on DRG can provide a feasible way of management in the fair use and supervision of medical insurance fund. PMID- 29487825 TI - A systematic review of teleophthalmological studies in Europe. AB - A systematic review of the recent literature regarding a series of ocular diseases involved in European telemedicine projects was performed based on the PubMed, Google Scholar and Springer databases in June 2017. Literature review returned 44 eligible studies; among them, emergency ophthalmology, diabetic retinopathy, glaucoma, age-related macular disease, cataract and retinopathy of prematurity. The majority of studies indicate teleophthalmology as a valid, reliable and cost-efficient method for care-provision in ophthalmology patients which delivers comparable outcomes to the traditional examination methods. PMID- 29487826 TI - Effect of Qingguang'an II on expressions of OX42 protein and IL-1beta mRNA of retinal microglia cells of rats with chronic high intraocular pressure. AB - The study investigated the effects of Qingguang'an II (a Chinese medicinal preparation) on expressions of OX42 protein and interleukin-1beta (IL-1beta) mRNA of retinal microglia cells of rats with chronic high intraocular pressure (IOP). SD rats were randomly divided into 6 groups, that were: A: blank group; B: model group; C: Qingguang'an II low dose group; D: Qingguang'an II medium dose group; E: Qingguang'an II high dose group; F: Yimaikang disket (a Chinese medicinal preparation) group. Experimental rats in B, C, D, E, F groups were established the model of chronic high IOP by cauterizing of superficial scleral vein. Tissues of eyes were obtained after intragastric administration for 2 and 4wk. At the time-point of 2wk, OX42 protein and IL-1beta mRNA in group B were statistically expressed in higher level comparing with other groups (P<0.05). Moreover, at the time-point of 4wk, OX42 protein and IL-1beta mRNA in groups C, D and E were statistically expressed in lower level comparing with group F (P<0.05). Besides, OX42 protein and IL-1beta mRNA in groups C and D were statistically expressed in higher level comparing with group E (P<0.05). OX42 protein and IL-1beta mRNA in groups C and D were expressed in similar level (P>0.05). The study indicated that, in the protection of optic nerve of rats with chronic high IOP, the high dose of Qingguang'an II at the time-point of 4wk was the better choice. PMID- 29487827 TI - Mechanism of delayed conduction of fellow eyes in patients with optic neuritis. AB - To test the hypothesis that latency delay in the fellow eyes of optic neuritis (ON) patients and to compensate for delayed transmission of visual information, latency change of multi-focal visual evoked potential (mfVEP) traces in fellow eyes of 15 ON patients were analyzed. Patients with low risk (LR) for developing multiple sclerosis (MS) were examined separately from MS patients to isolate effect of cortical plasticity from potential pathological changes in disseminated disease. The small increase in latency in fellow eyes of LR group was statistically not significant. In MS patients, the latency was significantly delayed (P<0.02). The magnitude of the latency change in the fellow eyes did not correlate with the severity of latency delay in the affected eyes (R2<0.02, P=0.3). The differences between ON patients with and without MS, reported here, suggest that the presence of disseminated disease plays critical role in latency delay of the fellow eye. PMID- 29487828 TI - Long term outcomes for patients treated with half-fluence photodynamic therapy for chronic central serous chorioretinopathy: a case series. AB - A case series was used to evaluate the efficacy of half-fluence photodynamic therapy (PDT) for chronic central serous chorioretinopathy (CSCR). Patients were treated with standard-dose verteporfin and half-fluence PDT. Totally 13 eyes from 11 patients were included. The mean patient age was 52.0y. There was a mean reduction in central retinal thickness of 107.0 microns. Totally 7/13 eyes (53.8%) achieved resolution of subretinal fluid (SRF) on optical coherence tomography (OCT) scan after 1 treatment with PDT. Four eyes had further treatment with PDT; of these 1 eye achieved resolution of SRF. Seven of the 13 eyes (53.8%) achieved an improvement of more than 5 ETDRS letters. One patient experienced acute macula oedema 1d post PDT treatment. These results support the hypothesis that half-fluence PDT can have a positive effect in chronic CSCR for a gain in visual acuity and reduction in sub-retinal fluid. Acute macula oedema is a rare but potential adverse effect of half-fluence PDT. PMID- 29487829 TI - A new application of capsulorhexis forceps in phacoemulsification: capsulorhexis forceps-assisted prechop technique. PMID- 29487830 TI - Visual impairment with possible macular changes after a high dose of sildenafil in a healthy young woman. PMID- 29487831 TI - Anterior proliferative vitreoretinopathy in a patient with Coats disease. PMID- 29487832 TI - Root canal irrigants influence the hydrophobicity and adherence of Staphylococcus epidermidis to root canal dentin: an in vitro study. AB - Objectives: To determine the effect of root canal irrigants on the hydrophobicity and adherence of Staphylococcus epidermidis (S. epidermidis) to root canal dentin in vitro. Materials and Methods: Root dentin blocks (n = 60) were randomly divided into 4 groups based on the irrigation regimen: group 1, saline; group 2, 5.25% sodium hypochlorite (NaOCl); group 3, 5.25% NaOCl followed by 17% ethylenediaminetetraacetic acid (EDTA); group 4, same as group 3 followed by 2% chlorhexidine (CHX). The hydrophobicity of S. epidermidis to root dentin was calculated by cell surface hydrophobicity while the adherence was observed by fluorescence microscopy, and bacteria were quantified using ImageJ software (National Institutes of Health). Statistical analysis of the data was done using Kruskal-Wallis test and Mann-Whitney U test (p = 0.05). Results: The hydrophobicity and adherence of S. epidermidis to dentin were significantly increased after irrigating with group 3 (NaOCl-EDTA) (p < 0.05), whereas in group 4 (NaOCl-EDTA-CHX) both hydrophobicity and adherence were significantly reduced (p < 0.05). Conclusions: The adherence of S. epidermidis to dentin was influenced differently by root canal irrigants. Final irrigation with CHX reduces the bacterial adherence and may impact biofilm formation. PMID- 29487833 TI - Influence of size and insertion depth of irrigation needle on debris extrusion and sealer penetration. AB - Objectives: To determine the effect of size and insertion depth of irrigation needle on the amount of apical extruded debris and the amount of penetration depth of sealer using a confocal laser scanning microscope (CLSM). Materials and Methods: Twenty maxillary premolars were assigned to 2 groups (n = 10), according to the size of needle tip, 28 G or 30 G. Buccal roots of samples were irrigated with respective needle type inserted 1 mm short of the working length (WL), while palatal roots were irrigated with respective needle type inserted 3 mm short of the WL. Prepared teeth were removed from the pre-weighed Eppendorf tubes. Canals were filled with F3 gutta-percha cone and rhodamine B dye-labeled AH 26 sealer. Teeth were transversally sectioned at 1 and 3 mm levels from the apex and observed under a CLSM. Eppendorf tubes were incubated to evaporate the irrigant and were weighed again. The difference between pre- and post-weights was calculated, and statistical evaluation was performed. Results: Inserting needles closer to the apex and using needles with wider diameters were associated with significantly more debris extrusion (p < 0.05). The position of needles and level of sections had statistically significant effects on sealer penetration depth (p < 0.05 for both). Conclusions: Following preparation, inserting narrower needles compatible with the final apical diameter of the prepared root canal at 3 mm short of WL during final irrigation might prevent debris extrusion and improve sealer penetration in the apical third. PMID- 29487835 TI - Statistical notes for clinical researchers: covariance and correlation. PMID- 29487834 TI - Root canal volume change and transportation by Vortex Blue, ProTaper Next, and ProTaper Universal in curved root canals. AB - Objectives: The aim of this study was to compare root canal volume change and canal transportation by Vortex Blue (VB; Dentsply Tulsa Dental Specialties), ProTaper Next (PTN; Dentsply Maillefer), and ProTaper Universal (PTU; Dentsply Maillefer) nickel-titanium rotary files in curved root canals. Materials and Methods: Thirty canals with 20 degrees -45 degrees of curvature from extracted human molars were used. Root canal instrumentation was performed with VB, PTN, and PTU files up to #30.06, X3, and F3, respectively. Changes in root canal volume before and after the instrumentation, and the amount and direction of canal transportation at 1, 3, and 5 mm from the root apex were measured by using micro-computed tomography. Data of canal volume change were statistically analyzed using one-way analysis of variance and Tukey test, while data of amount and direction of transportation were analyzed using Kruskal-Wallis and Mann Whitney U test. Results: There were no significant differences among 3 groups in terms of canal volume change (p > 0.05). For the amount of transportation, PTN showed significantly less transportation than PTU at 3 mm level (p = 0.005). VB files showed no significant difference in canal transportation at all 3 levels with either PTN or PTU files. Also, VB files showed unique inward transportation tendency in the apical area. Conclusions: Other than PTN produced less amount of transportation than PTU at 3 mm level, all 3 file systems showed similar level of canal volume change and transportation, and VB file system could prepare the curved canals without significant shaping errors. PMID- 29487837 TI - Appreciations to peer reviewers in 2017: contributions to the journal, Restorative Dentistry & Endodontics. PMID- 29487836 TI - Micro-computed tomographic evaluation of canal retreatments performed by undergraduate students using different techniques. AB - Objectives: This study evaluated the amount of remaining root canal filling materials after retreatment procedures performed by undergraduate students using manual, rotary, and reciprocating techniques through micro-computed tomographic analysis. The incidence of instrument fracture and the instrumentation time were also evaluated. Materials and Methods: Thirty maxillary single rooted teeth were prepared with Reciproc R25 files and filled with gutta-percha and AH Plus sealer by the continuous wave of condensation technique. Then, the specimens were assigned to 3 groups (n = 10), according to the retreatment technique used: manual, rotary, and reciprocating groups, which used K-file, Mtwo retreatment file, and Reciproc file, respectively. Retreatments were performed by undergraduate students. The sample was scanned after root canal filling and retreatment procedures, and the images of the canals were examined to quantify the amount of remaining filling material. The incidence of instrument fracture and the instrumentation time were recorded. Results: Remaining filling material was observed in all specimens regardless of the technique used. The mean volume of remaining material was significantly lower in the Reciproc group than in the manual K-file and Mtwo retreatment groups (p < 0.05). The time required to achieve a satisfactory removal of canal filling material and refinement was significantly lower in the Mtwo retreatment and Reciproc groups (p < 0.05) when compared to the manual K-file group. No instrument fracture was observed in any of the groups. Conclusions: Reciproc was the most effective instrument in the removal of canal fillings after retreatments performed by undergraduate students. PMID- 29487838 TI - Comparison of bond strengths of ceramic brackets bonded to zirconia surfaces using different zirconia primers and a universal adhesive. AB - Objectives: The aim of this study is to compare the shear bond strengths of ceramic brackets bonded to zirconia surfaces using different zirconia primers and universal adhesive. Materials and Methods: Fifty zirconia blocks (15 * 15 * 10 mm, Zpex, Tosoh Corporation) were polished with 1,000 grit sand paper and air abraded with 50 um Al2O3 for 10 seconds (40 psi). They were divided into 5 groups: control (CO), Metal/Zirconia primer (MZ, Ivoclar Vivadent), Z-PRIME Plus (ZP, Bisco), Zirconia Liner (ZL, Sun Medical), and Scotchbond Universal adhesive (SU, 3M ESPE). Transbond XT Primer (used for CO, MZ, ZP, and ZL) and Transbond XT Paste was used for bracket bonding (Gemini clear ceramic brackets, 3M Unitek). After 24 hours at 37 degrees C storage, specimens underwent 2,000 thermocycles, and then, shear bond strengths were measured (1 mm/min). An adhesive remnant index (ARI) score was calculated. The data were analyzed using one-way analysis of variance and the Bonferroni test (p = 0.05). Results: Surface treatment with primers resulted in increased shear bond strength. The SU group showed the highest shear bond strength followed by the ZP, ZL, MZ, and CO groups, in that order. The median ARI scores were as follows: CO = 0, MZ = 0, ZP = 0, ZL = 0, and SU = 3 (p < 0.05). Conclusions: Within this experiment, zirconia primer can increase the shear bond strength of bracket bonding. The highest shear bond strength is observed in SU group, even when no primer is used. PMID- 29487839 TI - A simple technique for impression taking of teeth and functionally generated paths. AB - The objective of this case report is to introduce a simple technique for simultaneously taking a closed-mouth impression and functionally generated path (FGP) for a full coverage crown restoration. A monolithic zirconia crown was the restoration of choice. An alginate impression of the abutment tooth was taken to fabricate a custom-made closed-mouth impression tray covering the abutment tooth and the adjacent teeth. The tray had an FGP table and an abutment tray in cameo and intaglio surfaces, respectively. The impression was taken with silicone impression material after adjusting the abutment tray and inscribing the FGP using self-curing acrylic resins. Plaster casts were made from the impression, and a zirconia crown was fabricated. The crown was cemented to the abutment tooth with minimal adjustments. This simple technique resulted in a well-fitting crown that accounted for mandibular movements. Using the custom closed-mouth impression tray incorporating an FGP table simultaneously aids in fabricating an accurately fitting restoration that incorporates harmonious mandibular movements using a single impression capture. PMID- 29487840 TI - The effect of root canal preparation on the surface roughness of WaveOne and WaveOne Gold files: atomic force microscopy study. AB - Objectives: To examine the surface topography of intact WaveOne (WO; Dentsply Sirona Endodontics) and WaveOne Gold (WOG; Dentsply Sirona Endodontics) nickel titanium rotary files and to evaluate the presence of alterations to the surface topography after root canal preparations of severely curved root canals in molar teeth. Materials and Methods: Forty-eight severely curved canals of extracted molar teeth were divided into 2 groups (n = 24/each group). In group 1, the canals were prepared using WO and in group 2, the canals were prepared using WOG files. After the preparation of 3 root canals, instruments were subjected to atomic force microscopy analysis. Average roughness and root mean square values were chosen to investigate the surface features of endodontic files. The data was analyzed using one-way analysis of variance and post hoc Tamhane's tests at 5% significant level. Results: The surface roughness values of WO and WOG files significantly changed after use in root canals (p < 0.05). The used WOG files exhibited higher surface roughness change when compared with the used WO files (p < 0.05). Conclusions: Using WO and WOG Primary files in 3 root canals affected the surface topography of the files. After being used in root canals, the WOG files showed a higher level of surface porosity value than the WO files. PMID- 29487842 TI - Plugger temperature of cordless heat carriers according to the time elapsed. AB - Objective: The purpose of this study was to measure the temperature of the plugger tip of 3 cordless heat carriers set at 200 degrees C. Materials and Methods: Pluggers of the same taper (0.06, 0.08, 0.10) and similar tip sizes (sizes of 50 and 55) from 3 cordless heat carriers, namely SuperEndo-alpha2 (B & L Biotech), Friendo (DXM), and Dia-Pen (Diadent), were used and an electric heat carrier, System B (SybronEndo), was used as the control. The plugger tips were covered with customized copper sleeves, heated for 10 seconds, and the temperature was recorded with a computerized measurement system attached to a K type thermometer at room temperature (n = 10). The data were analyzed with 2-way analysis of variance at a 5% level of significance. Results: The peak temperature of the plugger tips was significantly affected by the plugger taper and by the heat carrier brand (p < 0.05). The peak temperature of the plugger tips was between 177 degrees C and 325 degrees C. The temperature peaked at 207 degrees C 231 degrees C for the 0.06 taper pluggers, 195 degrees C-313 degrees C for the 0.08 taper pluggers, and 177 degrees C-325 degrees C for the 0.10 taper pluggers. Only 5 of the 12 plugger tips showed a temperature of 200 degrees C +/- 10 degrees C. The time required to reach the highest temperature or 200 degrees C +/ 10 degrees C was at least 4 seconds. Conclusion: When using cordless heat carriers, clinicians should pay attention to the temperature setting and to the activation time needed to reach the intended temperature of the pluggers. PMID- 29487841 TI - Mineral content analysis of root canal dentin using laser-induced breakdown spectroscopy. AB - Objectives: This study aimed to introduce the use of laser-induced breakdown spectroscopy (LIBS) for evaluation of the mineral content of root canal dentin, and to assess whether a correlation exists between LIBS and scanning electron microscopy/energy dispersive spectroscopy (SEM/EDS) methods by comparing the effects of irrigation solutions on the mineral content change of root canal dentin. Materials and Methods: Forty teeth with a single root canal were decoronated and longitudinally sectioned to expose the canals. The root halves were divided into 4 groups (n = 10) according to the solution applied: group NaOCl, 5.25% sodium hypochlorite (NaOCl) for 1 hour; group EDTA, 17% ethylenediaminetetraacetic acid (EDTA) for 2 minutes; group NaOCl+EDTA, 5.25% NaOCl for 1 hour and 17% EDTA for 2 minutes; a control group. Each root half belonging to the same root was evaluated for mineral content with either LIBS or SEM/EDS methods. The data were analyzed statistically. Results: In groups NaOCl and NaOCl+EDTA, the calcium (Ca)/phosphorus (P) ratio decreased while the sodium (Na) level increased compared with the other groups (p < 0.05). The magnesium (Mg) level changes were not significant among the groups. A significant positive correlation was found between the results of LIBS and SEM/EDS analyses (r = 0.84, p < 0.001). Conclusions: Treatment with NaOCl for 1 hour altered the mineral content of dentin, while EDTA application for 2 minutes had no effect on the elemental composition. The LIBS method proved to be reliable while providing data for the elemental composition of root canal dentin. PMID- 29487843 TI - Management of dental erosion induced by gastro-esophageal reflux disorder with direct composite veneering aided by a flexible splint matrix. AB - Dental erosion is frequently overlooked in clinical practice. The management of erosion-induced damage to the dentition is often delayed, such that extensive occlusal rehabilitation is required. These cases can be diagnosed by a careful clinical examination and a thorough review of the patient's medical history and/or lifestyle habits. This case report presents the diagnosis, categorization, and management of a case of gastro-esophageal reflux disease-induced palatal erosion of the maxillary teeth. The early management of such cases is of utmost importance to delay or prevent the progression of damage both to the dentition and to occlusal stability. Non-invasive adhesively bonded restorations aid in achieving this goal. PMID- 29487844 TI - Managing Bardet-Biedl Syndrome-Now and in the Future. AB - Bardet-Biedl syndrome is a rare autosomal recessive multisystem disorder caused by defects in genes encoding for proteins that localize to the primary cilium/basal body complex. Twenty-one disease-causing genes have been identified to date. It is one of the most well-studied conditions in the family of diseases caused by defective cilia collectively known as ciliopathies. In this review, we provide an update on diagnostic developments, clinical features, and progress in the management of Bardet-Biedl syndrome. Advances in diagnostic technologies including exome and whole genome sequencing are expanding the spectrum of patients who are diagnosed with Bardet-Biedl syndrome and increasing the number of cases with diagnostic uncertainty. As a result of the diagnostic developments, a small number of patients with only one or two clinical features of Bardet-Biedl syndrome are being diagnosed. Our understanding of the syndrome-associated renal disease has evolved and is reviewed here. Novel interventions are developing at a rapid pace and are explored in this review including genetic therapeutics such as gene therapy, exon skipping therapy, nonsense suppression therapy, and gene editing. Other non-genetic therapies such as gene repurposing, targeted therapies, and non-pharmacological interventions are also discussed. PMID- 29487845 TI - Measles Vaccination Supports Millennium Development Goal 4: Increasing Coverage and Increasing Child Survival in Northern Ghana, 1996-2012. AB - Background: Measles vaccine (MV) administered as the last vaccine after the third dose of diphtheria-tetanus-pertussis (DTP) may be associated with better child survival unrelated to prevention of measles infection. Other studies have shown that MV administered after DTP was more beneficial and was associated with lower mortality compared with DTP administered after MV or DTP administered simultaneously with MV. We compared the difference in mortality between measles vaccinated after DTP3 and measles-unvaccinated children in Navrongo, Ghana. Methods: This was a follow-up study involving annual cohort of children aged 9-23 months from 1996 to 2012. We assessed survival in relation to the measles vaccination status within the first 12 months from interview date and until 5 years of age using Cox proportional hazards models. Results: In all, 38,333 children were included in the study. The proportion of children vaccinated with MV-after-DTP3 increased from 45% in 1996 to 95% in 2012. The adjusted hazard ratio (HR) for measles unvaccinated compared with MV-after-DTP3 vaccinated children was 1.38 (1.15-1.66) in the first 12 months after assessment of vaccination status and 1.22 (1.05-1.41) with follow-up to 5 years of age. The national immunization days campaigns with oral polio vaccine or MV might have reduced the effect of being MV-after-DTP3 vaccinated vs MV-unvaccinated. For 12 months of follow-up, the HR before a campaign for MV-unvaccinated children was 1.63 (1.23-2.17) compared to those who received MV-after-DTP3. After the campaign, the HR reduced to 1.23 (0.97-1.54). Stratifying the analysis by sex, measles-unvaccinated boys had a HR of 1.69 (1.33-2.61) compared to measles unvaccinated girls who had a HR 1.06 (0.79-1.40) during 1-year follow-up. In 1989, only 7% of children in the area had received MV-after-DTP3; the increase in MV-after-DTP3 coverage from 1989 to 2012 may have lowered mortality rate among children aged 9 months to 3 years by 24%. Conclusion: Though an observational study, our findings suggest that measles vaccination, administered in the recommended sequence, is associated with improved child survival and may have contributed importantly to the mortality decline toward the achievement of Millennium Development Goal 4. PMID- 29487846 TI - Expression and Immunogenicity of M2e Peptide of Avian Influenza Virus H5N1 Fused to Ricin Toxin B Chain Produced in Duckweed Plants. AB - The amino acid sequence of the extracellular domain of the virus-encoded M2 matrix protein (peptide M2e) is conserved among all subtypes of influenza A strains, enabling the development of a broad-range vaccine against them. We expressed M2e from avian influenza virus A/chicken/Kurgan/5/2005 (H5N1) in nuclear-transformed duckweed plants for further development of an avian influenza vaccine. The 30-amino acid N-terminal fragment of M2, including M2e (denoted M130), was selected for expression. The M2e DNA sequence fused in-frame to the 3' end of ricin toxin B chain (RTB) was cloned under control of the CaMV 35S promoter into pBI121. The resulting plasmid was used for duckweed transformation, and 23 independent transgenic duckweed lines were obtained. Asialofetuin-binding ELISA of protein samples from the transgenic plants using polyclonal anti-RTB antibodies confirmed the expression of the RTB-M130 fusion protein in 20 lines. Quantitative ELISA of crude protein extracts from these lines showed RTB-M130 accumulation ranging from 0.25-2.5 MUg/g fresh weight (0.0006-0.01% of total soluble protein). Affinity chromatography with immobilized asialofetuin and western blot analysis of protein samples from the transgenic plants showed expression of fusion protein RTB-M130 in the aggregate form with a molecular mass of about 70 kDa. Mice were immunized orally with a preparation of total soluble protein from transgenic plants, receiving four doses of 7 MUg duckweed-derived RTB-M130 each, with no additional adjuvant. Specific IgG against M2e was detected in immunized mice, and the endpoint titer of nti-M2e IgG was 1,024. It was confirmed that oral immunization with RTB-M130 induces production of specific antibodies against peptide M2e, one of the most conserved antigens of the influenza virus. These results may provide further information for the development of a duckweed-based expression system to produce a broad-range edible vaccine against avian influenza. PMID- 29487847 TI - Lipase-Catalyzed Synthesis of Sugar Esters in Honey and Agave Syrup. AB - Honey and agave syrup are high quality natural products and consist of more than 80% sugars. They are used as sweeteners, and are ingredients of cosmetics or medical ointments. Furthermore, both have low water content, are often liquid at room temperature and resemble some known sugar-based deep eutectic solvents (DES). Since it has been shown that it is possible to synthesize sugar esters in these DESs, in the current work honey or, as vegan alternative, agave syrup are used simultaneously as solvent and substrate for the enzymatic sugar ester production. For this purpose, important characteristics of the herein used honey and agave syrup were determined and compared with other available types. Subsequently, an enzymatic transesterification of four fatty acid vinyl esters was accomplished in ordinary honey and agave syrup. Notwithstanding of the high water content for transesterification reactions of the solvent, the successful sugar ester formation was proved by thin-layer chromatography (TLC) and compared to a sugar ester which was synthesized in a conventional DES. For a clear verification of the sugar esters, mass determinations by ESI-Q-ToF experiments and a NMR analysis were done. These environmentally friendly produced sugar esters have the potential to be used in cosmetics or pharmaceuticals, or to enhance their effectiveness. PMID- 29487848 TI - Implantation of Neural Probes in the Brain Elicits Oxidative Stress. AB - Clinical implantation of intracortical microelectrodes has been hindered, at least in part, by the perpetual inflammatory response occurring after device implantation. The neuroinflammatory response observed after device implantation has been correlated to oxidative stress that occurs due to neurological injury and disease. However, there has yet to be a definitive link of oxidative stress to intracortical microelectrode implantation. Thus, the objective of this study is to give direct evidence of oxidative stress following intracortical microelectrode implantation. This study also aims to identify potential molecular targets to attenuate oxidative stress observed postimplantation. Here, we implanted adult rats with silicon non-functional microelectrode probes for 4 weeks and compared the oxidative stress response to no surgery controls through postmortem gene expression analysis and qualitative histological observation of oxidative stress markers. Gene expression analysis results at 4 weeks postimplantation indicated that EH domain-containing 2, prion protein gene (Prnp), and Stearoyl-Coenzyme A desaturase 1 (Scd1) were all significantly higher for animals implanted with intracortical microelectrode probes compared to no surgery control animals. To the contrary, NADPH oxidase activator 1 (Noxa1) relative gene expression was significantly lower for implanted animals compared to no surgery control animals. Histological observation of oxidative stress showed an increased expression of oxidized proteins, lipids, and nucleic acids concentrated around the implant site. Collectively, our results reveal there is a presence of oxidative stress following intracortical microelectrode implantation compared to no surgery controls. Further investigation targeting these specific oxidative stress linked genes could be beneficial to understanding potential mechanisms and downstream therapeutics that can be utilized to reduce oxidative stress-mediated damage following microelectrode implantation. PMID- 29487849 TI - PRDM14 Is a Unique Epigenetic Regulator Stabilizing Transcriptional Networks for Pluripotency. AB - PR-domain containing protein 14 (PRDM14) is a site-specific DNA-binding protein and is required for establishment of pluripotency in embryonic stem cells (ESCs) and primordial germ cells (PGCs) in mice. DNA methylation status is regulated by the balance between de novo methylation and passive/active demethylation, and global DNA hypomethylation is closely associated with cellular pluripotency and totipotency. PRDM14 ensures hypomethylation in mouse ESCs and PGCs through two distinct layers, transcriptional repression of the DNA methyltransferases Dnmt3a/b/l and active demethylation by recruitment of TET proteins. However, the function of PRDM14 remains unclear in other species including humans. Hence, here we focus on the unique characteristics of mouse PRDM14 in the epigenetic regulation of pluripotent cells and primordial germ cells. In addition, we discuss the expression regulation and function of PRDM14 in other species compared with those in mice. PMID- 29487850 TI - Regulating NETosis: Increasing pH Promotes NADPH Oxidase-Dependent NETosis. AB - Neutrophils migrating from the blood (pH 7.35-7.45) into the surrounding tissues encounter changes in extracellular pH (pHe) conditions. Upon activation of NADPH oxidase 2 (Nox), neutrophils generate large amounts of H+ ions reducing the intracellular pH (pHi). Nevertheless, how extracellular pH regulates neutrophil extracellular trap (NET) formation (NETosis) is not clearly established. We hypothesized that increasing pH increases Nox-mediated production of reactive oxygen species (ROS) and neutrophil protease activity, stimulating NETosis. Here, we found that raising pHe (ranging from 6.6 to 7.8; every 0.2 units) increased pHi of both activated and resting neutrophils within 10-20 min (Seminaphtharhodafluor dual fluorescence measurements). Since Nox activity generates H+ ions, pHi is lower in neutrophils that are activated compared to resting. We also found that higher pH stimulated Nox-dependent ROS production (R123 generation; flow cytometry, plate reader assay, and imaging) during spontaneous and phorbol myristate acetate-induced NETosis (Sytox Green assays, immunoconfocal microscopy, and quantifying NETs). In neutrophils that are activated and not resting, higher pH stimulated histone H4 cleavage (Western blots) and NETosis. Raising pH increased Escherichia coli lipopolysaccharide-, Pseudomonas aeruginosa (Gram-negative)-, and Staphylococcus aureus (Gram positive)-induced NETosis. Thus, higher pHe promoted Nox-dependent ROS production, protease activity, and NETosis; lower pH has the opposite effect. These studies provided mechanistic steps of pHe-mediated regulation of Nox dependent NETosis. Raising pH either by sodium bicarbonate or Tris base (clinically known as Tris hydroxymethyl aminomethane, tromethamine, or THAM) increases NETosis. Each Tris molecule can bind 3H+ ions, whereas each bicarbonate HCO3- ion binds 1H+ ion. Therefore, the amount of Tris solution required to cause the same increase in pH level is less than that of equimolar bicarbonate solution. For that reason, regulating NETosis by pH with specific buffers such as THAM could be more effective than bicarbonate in managing NET-related diseases. PMID- 29487852 TI - Focus on the Role of D-serine and D-amino Acid Oxidase in Amyotrophic Lateral Sclerosis/Motor Neuron Disease (ALS). AB - We have investigated a pathogenic mutation in D-amino acid oxidase (DAO), DAOR199W, associated with familial Amyotrophic Lateral Sclerosis (ALS) that impairs D-serine metabolism and causes protein aggregation, autophagy and cell death in motor neuron cell lines. These features are consistent with the pathogenic processes occurring in ALS but most importantly, we have demonstrated that activation of the formation of ubiquitinated protein inclusions, increased autophagosome production and apoptotic cell death caused by the mutation in cell lines are attenuated by 5,7-dichlorokynurenic acid (DCKA), a selective inhibitor of the glycine/D-serine binding site of the NMDA receptor. D-serine is an essential co-agonist at this glutamate receptor. This data provides insight into potential upstream mechanisms that involve the action of D-serine at the NMDA receptor and might contribute to neurodegeneration. This is highly relevant to sporadic ALS (SALS), familial ALS, as well as ALS models, where elevated levels of D-serine have been reported and hence has broader clinical therapeutic implications. In order to investigate this further, we have generated a transgenic line expressing the pathogenic mutation, in order to determine whether mice expressing DAOR199W develop a motor phenotype and whether crossing the SOD1G93A model of ALS with mice expressing DAOR199W affects disease progression. We found that heterozygous expression of DAOR199W led to a significant loss of spinal cord motor neurons at 14 months, which is similar to that found in homozygous mice expressing DAOG181R. We hypothesize that DAO has potential for development as a therapeutic agent in ALS. PMID- 29487851 TI - Candida Biofilms: Threats, Challenges, and Promising Strategies. AB - Candida species are fungal pathogens known for their ability to cause superficial and systemic infections in the human host. These pathogens are able to persist inside the host due to the development of pathogenicity and multidrug resistance traits, often leading to the failure of therapeutic strategies. One specific feature of Candida species pathogenicity is their ability to form biofilms, which protects them from external factors such as host immune system defenses and antifungal drugs. This review focuses on the current threats and challenges when dealing with biofilms formed by Candida albicans, Candida glabrata, Candida tropicalis, and Candida parapsilosis, highlighting the differences between the four species. Biofilm characteristics depend on the ability of each species to produce extracellular polymeric substances (EPS) and display dimorphic growth, but also on the biofilm substratum, carbon source availability and other factors. Additionally, the transcriptional control over processes like adhesion, biofilm formation, filamentation, and EPS production displays great complexity and diversity within pathogenic yeasts of the Candida genus. These differences not only have implications in the persistence of colonization and infections but also on antifungal resistance typically found in Candida biofilm cells, potentiated by EPS, that functions as a barrier to drug diffusion, and by the overexpression of drug resistance transporters. The ability to interact with different species in in vivo Candida biofilms is also a key factor to consider when dealing with this problem. Despite many challenges, the most promising strategies that are currently available or under development to limit biofilm formation or to eradicate mature biofilms are discussed. PMID- 29487853 TI - Positive Charges on the Surface of Thaumatin Are Crucial for the Multi-Point Interaction with the Sweet Receptor. AB - Thaumatin, an intensely sweet-tasting protein, elicits sweet taste with a threshold of only 50 nM. Previous studies from our laboratory suggested that the complex model between the T1R2-T1R3 sweet receptor and thaumatin depends critically on the complementarity of electrostatic potentials. In order to further validate this model, we focused on three lysine residues (Lys78, Lys106, and Lys137), which were expected to be part of the interaction sites. Three thaumatin mutants (K78A, K106A, and K137A) were prepared and their threshold values of sweetness were examined. The results showed that the sweetness of K106A was reduced by about three times and those of K78A and K137A were reduced by about five times when compared to wild-type thaumatin. The three-dimensional structures of these mutants were also determined by X-ray crystallographic analyses at atomic resolutions. The overall structures of mutant proteins were similar to that of wild-type but the electrostatic potentials around the mutated sites became more negative. Since the three lysine residues are located in 20-40 A apart each other on the surface of thaumatin molecule, these results suggest the positive charges on the surface of thaumatin play a crucial role in the interaction with the sweet receptor, and are consistent with a large surface is required for interaction with the sweet receptor, as proposed by the multipoint interaction model named wedge model. PMID- 29487854 TI - Re-sensitizing Multidrug Resistant Bacteria to Antibiotics by Targeting Bacterial Response Regulators: Characterization and Comparison of Interactions between 2 Aminoimidazoles and the Response Regulators BfmR from Acinetobacter baumannii and QseB from Francisella spp. AB - 2-aminoimidazole (2-AI) compounds inhibit the formation of bacterial biofilms, disperse preformed biofilms, and re-sensitize multidrug resistant bacteria to antibiotics. 2-AIs have previously been shown to interact with bacterial response regulators, but the mechanism of interaction is still unknown. Response regulators are one part of two-component systems (TCS). TCSs allow cells to respond to changes in their environment, and are used to trigger quorum sensing, virulence factors, and antibiotic resistance. Drugs that target the TCS signaling process can inhibit pathogenic behavior, making this a potent new therapeutic approach that has not yet been fully exploited. We previously laid the groundwork for the interaction of the Acinetobacter baumannii response regulator BfmR with an early 2-AI derivative. Here, we further investigate the response regulator/2 AI interaction and look at a wider library of 2-AI compounds. By combining molecular modeling with biochemical and cellular studies, we expand on a potential mechanism for interaction between response regulators and 2-AIs. We also establish that Francisella tularensis/novicida, encoding for only three known response regulators, can be a model system to study the interaction between 2-AIs and response regulators. We show that knowledge gained from studying Francisella can be applied to the more complex A. baumannii system, which contains over 50 response regulators. Understanding the impact of 2-AIs on response regulators and their mechanism of interaction will lead to the development of more potent compounds that will serve as adjuvant therapies to broad-range antibiotics. PMID- 29487857 TI - Airborne Detection of H5N8 Highly Pathogenic Avian Influenza Virus Genome in Poultry Farms, France. AB - In southwestern France, during the winter of 2016-2017, the rapid spread of highly pathogenic avian influenza H5N8 outbreaks despite the implementation of routine control measures, raised the question about the potential role of airborne transmission in viral spread. As a first step to investigate the plausibility of that transmission, air samples were collected inside, outside and downwind from infected duck and chicken facilities. H5 avian influenza virus RNA was detected in all samples collected inside poultry houses, at external exhaust fans and at 5 m distance from poultry houses. For three of the five flocks studied, in the sample collected at 50-110 m distance, viral genomic RNA was detected. The measured viral air concentrations ranged between 4.3 and 6.4 log10 RNA copies per m3, and their geometric mean decreased from external exhaust fans to the downwind measurement point. These findings are in accordance with the possibility of airborne transmission and question the procedures for outbreak depopulation. PMID- 29487856 TI - Effect of Feeding Bacillus subtilis Spores to Broilers Challenged with Salmonella enterica serovar Heidelberg Brazilian Strain UFPR1 on Performance, Immune Response, and Gut Health. AB - Salmonellosis is a poultry industry and public health concern worldwide. Recently, Salmonella enterica serovar Heidelberg (SH) has been reported in broilers in Brazil. The effect of feeding a blend of three strains of Bacillus subtilis (PRO) was studied in broilers orally challenged (107 CFU/chick) or not with a SH isolated in south of Brazil (UFPR1 strain). Twelve male Cobb 500 broilers per pen were randomly assigned to six treatments in a 3 * 2 factorial experiment where PRO was added at 0, 250, or 500 g/ton of broiler feed and fed to either SH-challenged (SH Control, SH + PRO 250, and SH + PRO 500) or non challenged birds (Control, PRO 250, and PRO 500). Broiler performance, histologic alterations in intestinal morphology, Salmonella quantification and immune cells counts in liver (macrophages, T CD4+ and T CD8+) were analyzed. Changes in the intestinal microbiota of broilers were also studied by metagenomics for Control, SH Control, SH + PRO 250, and SH + PRO 500 only. Feeding PRO at 250 or 500 g/ton reduced SH counts and incidence in liver and cecum at 21 days of age. It was observed that PRO groups increased the macrophage mobilization to the liver in SH challenged birds (P < 0.05) but reduced these cells in the liver of non challenged birds, showing an interesting immune cell dynamics effect. PRO at 250 g/ton did not affect gut histology, but improved animal performance (P < 0.05) while PRO at 500/ton did not affect animal performance but increased histologic alteration related to activation of the defense response in the ileum in SH challenged birds compared to control birds (P < 0.05). SH + PRO 500 group presented a more diverse cecal microbiota (Shannon-Wiener index; P < 0.05) compared to Control and SH Control groups; while SH + PRO 250 had greater ileal richness (JackkNife index) compared to Control (P < 0.05). PRO was effective in reducing Salmonella colonization in liver and cecum when fed at 250 or 500 g/ton to broilers inoculated with SH strain UFPR1. PRO promotes positive alterations in performance (at 250 g/ton), immune modulatory effect in the gastrointestinal tract, SH reduction, and intestinal microbiota modulation. PMID- 29487855 TI - Transplantation of Hearts Donated after Circulatory Death. AB - Cardiac transplantation has become limited by a critical shortage of suitable organs from brain-dead donors. Reports describing the successful clinical transplantation of hearts donated after circulatory death (DCD) have recently emerged. Hearts from DCD donors suffer significant ischemic injury prior to organ procurement; therefore, the traditional approach to the transplantation of hearts from brain-dead donors is not applicable to the DCD context. Advances in our understanding of ischemic post-conditioning have facilitated the development of DCD heart resuscitation strategies that can be used to minimize ischemia reperfusion injury at the time of organ procurement. The availability of a clinically approved ex situ heart perfusion device now allows DCD heart preservation in a normothermic beating state and minimizes exposure to incremental cold ischemia. This technology also facilitates assessments of organ viability to be undertaken prior to transplantation, thereby minimizing the risk of primary graft dysfunction. The application of a tailored approach to DCD heart transplantation that focuses on organ resuscitation at the time of procurement, ex situ preservation, and pre-transplant assessments of organ viability has facilitated the successful clinical application of DCD heart transplantation. The transplantation of hearts from DCD donors is now a clinical reality. Investigating ways to optimize the resuscitation, preservation, evaluation, and long-term outcomes is vital to ensure a broader application of DCD heart transplantation in the future. PMID- 29487858 TI - Noise Sensitivities in Dogs: An Exploration of Signs in Dogs with and without Musculoskeletal Pain Using Qualitative Content Analysis. AB - Noise sensitivity is a common behaviour problem in dogs. In humans, there is a well-established relationship between painful conditions and the development of fear-related avoidance responses. Whilst it is likely that a relationship exists between noise sensitivity and pain in dogs, this does not appear to have been investigated. The aim of this study was to explore the signs of noise sensitivity in dogs with and without musculoskeletal pain by comparing case histories using qualitative content analysis. Data were extracted from the clinical records of 20 cases of dogs presenting with noise sensitivity seen by clinical animal behaviourists at the University of Lincoln, composed of 2 groups-10 "clinical cases" with pain and 10 "control cases" without pain. Loud noises as a trigger of noise sensitivity were a common theme in both groups but ubiquitous among "clinical cases." In "clinical cases" (i.e., those where pain was identified), the age of onset of the noise sensitivity was on average nearly 4 years later than "control cases." In addition, strong themes emerged relating to widespread generalisation to associated environments and avoidance of other dogs in the "clinical cases," which did not appear in the "control cases." "Clinical cases" responded well to treatment once the involvement of pain had been identified. Veterinarians and behaviourists should carefully assess dogs with noise sensitivities for pain-related problems especially if presenting with these characteristics. PMID- 29487860 TI - Leishmania guyanensis parasites block the activation of the inflammasome by inhibiting maturation of IL-1beta. AB - The various symptomatic outcomes of cutaneous leishmaniasis relates to the type and potency of its underlying inflammatory responses. Presence of the cytoplasmic Leishmania RNA virus-1 (LRV1) within Leishmania guyanensis, worsens lesional inflammation and parasite burden, as the viral dsRNA genome acts as a potent innate immunogen stimulating Toll-Like-Receptor-3 (TLR3). Here we investigated other innate pattern recognition receptors capable of reacting to dsRNA and potentially contributing to LRV1-mediated inflammatory pathology. We included the cytoplasmic dsRNA sensors, namely, the RIG-like receptors (RLRs) and the inflammasome-dependent and -independent Nod-like-receptors (NLRs). Our study found no role for RLRs or inflammasome-dependent NLRs in the pathology of L. guyanensis infection irrespective of its LRV1-status. Further, neither LRV1 bearing L. guyanensis (LgyLRV1+) nor LRV1-negative L. guyanensis (LgyLRV1-) activated the inflammasome in vitro. Interestingly, similarly to L. donovani, L. guyanensis infection induced the up-regulation of the A20 protein, known to be involved in the evasion of inflammasome activation. Moreover, we observed that LgyLRV1+ promoted the transcription of inflammasome-independent NLRC2 (also called NOD2) and NLRC5. However, only NLRC2 showed some contribution to LRV1 dependent pathology. These data confirmed that the endosomal TLR3 pathway is the dominant route of LRV1-dependent signalling, thus excluding the cytosolic and inflammasome pathways. We postulate that avoidance of the inflammasome pathways is likely an important mechanism of virulence in Leishmania infection irrespective of the LRV1-status. PMID- 29487861 TI - A versatile plasmid system for reconstitution and analysis of mammalian ubiquitination cascades in yeast. AB - Ubiquitination is a posttranslational protein modification that regulates most aspects of cellular life. The sheer number of ubiquitination enzymes that are present in a mammalian cell, over 700 in total, has thus far hampered the analysis of distinct protein ubiquitination cascades in a cellular context. To overcome this complexity we have developed a versatile vector system that allows the reconstitution of specific ubiquitination cascades in the model eukaryote Saccharomyces cerevisae (baker's yeast). The vector system consists of 32 modular yeast shuttle plasmids allowing inducible or constitutive expression of up to four proteins of interest in a single cell. To demonstrate the validity of the system, we show that co-expression in yeast of the mammalian HECT type E3 ubiquitin ligase E6AP (E6-Associated Protein) and a model substrate faithfully recapitulates E6AP-dependent substrate ubiquitination and degradation. In addition, we show that the endogenous sumoylation pathway of S. cerevisiae can specifically sumoylate mouse PML (Promyelocytic leukemia protein). In conclusion, the yeast vector system described in this paper provides a versatile tool to study complex post-translational modifications in a cellular setting. PMID- 29487859 TI - pH homeostasis links the nutrient sensing PKA/TORC1/Sch9 menage-a-trois to stress tolerance and longevity. AB - The plasma membrane H+-ATPase Pma1 and the vacuolar V-ATPase act in close harmony to tightly control pH homeostasis, which is essential for a vast number of physiological processes. As these main two regulators of pH are responsive to the nutritional status of the cell, it seems evident that pH homeostasis acts in conjunction with nutrient-induced signalling pathways. Indeed, both PKA and the TORC1-Sch9 axis influence the proton pumping activity of the V-ATPase and possibly also of Pma1. In addition, it recently became clear that the proton acts as a second messenger to signal glucose availability via the V-ATPase to PKA and TORC1-Sch9. Given the prominent role of nutrient signalling in longevity, it is not surprising that pH homeostasis has been linked to ageing and longevity as well. A first indication is provided by acetic acid, whose uptake by the cell induces toxicity and affects longevity. Secondly, vacuolar acidity has been linked to autophagic processes, including mitophagy. In agreement with this, a decline in vacuolar acidity was shown to induce mitochondrial dysfunction and shorten lifespan. In addition, the asymmetric inheritance of Pma1 has been associated with replicative ageing and this again links to repercussions on vacuolar pH. Taken together, accumulating evidence indicates that pH homeostasis plays a prominent role in the determination of ageing and longevity, thereby providing new perspectives and avenues to explore the underlying molecular mechanisms. PMID- 29487862 TI - A novel system to monitor mitochondrial translation in yeast. AB - The mitochondrial genome is responsible for the production of a handful of polypeptides that are core subunits of the membrane-bound oxidative phosphorylation system. Until now the mechanistic studies of mitochondrial protein synthesis inside cells have been conducted with inhibition of cytoplasmic protein synthesis to reduce the background of nuclear gene expression with the undesired consequence of major disturbances of cellular signaling cascades. Here we have generated a system that allows direct monitoring of mitochondrial translation in unperturbed cells. A recoded gene for superfolder GFP was inserted into the yeast (Saccharomyces cerevisiae) mitochondrial genome and enabled the detection of translation through fluorescence microscopy and flow cytometry in functional mitochondria. This novel tool allows the investigation of the function and regulation of mitochondrial translation during stress signaling, aging and mitochondrial biogenesis. PMID- 29487863 TI - Multitarget Effects of Danqi Pill on Global Gene Expression Changes in Myocardial Ischemia. AB - Danqi pill (DQP) is a widely prescribed traditional Chinese medicine (TCM) in the treatment of cardiovascular diseases. The objective of this study is to systematically characterize altered gene expression pattern induced by myocardial ischemia (MI) in a rat model and to investigate the effects of DQP on global gene expression. Global mRNA expression was measured. Differentially expressed genes among the sham group, model group, and DQP group were analyzed. The gene ontology enrichment analysis and pathway analysis of differentially expressed genes were carried out. We quantified 10,813 genes. Compared with the sham group, expressions of 339 genes were upregulated and 177 genes were downregulated in the model group. The upregulated genes were enriched in extracellular matrix organization, response to wounding, and defense response pathways. Downregulated genes were enriched in fatty acid metabolism, pyruvate metabolism, PPAR signaling pathways, and so forth. This indicated that energy metabolic disorders occurred in rats with MI. In the DQP group, expressions of genes in the altered pathways were regulated back towards normal levels. DQP reversed expression of 313 of the 516 differentially expressed genes in the model group. This study provides insight into the multitarget mechanism of TCM in the treatment of complex diseases. PMID- 29487864 TI - Influence of Adalimumab on the Expression Profile of Genes Associated with the Histaminergic System in the Skin Fibroblasts In Vitro. AB - Objective: The aim of this study was to evaluate the influence of adalimumab on expression profile of genes associated with the histaminergic system in Normal Human Dermal Fibroblast (NHDF) cells stimulated with 8.00 MUg/ml of adalimumab and the identification of miRNAs regulating these genes' expression. Methods: NHDFs were cultured with or without the presence of adalimumab for 2, 8, and 24 hours. The expression profile of genes and miRNA were determined with the use of microarray technology. Results: Among 22283 ID mRNA, 65 are associated with the histaminergic system. It can be observed that 15 mRNAs differentiate NHDFs cultures with adalimumab form control. The analysis of miRNAs showed that, among 1105 ID miRNA, 20 miRNAs are differentiating in cells treated with adalimumab for 2 hours, 9 miRNA after 8 hours, and only 3 miRNAs after 24 hours. Conclusion: It was also determined that miRNAs play certain role in the regulation of the expression of genes associated with the histaminergic system. The results of this study confirmed the possibility of using both genes associated with this system as well as miRNAs regulating their expression, as complementary molecular markers of sensitivity to the adalimumab treatment. PMID- 29487865 TI - Hospital Epidemiology of Methicillin-Resistant Staphylococcus aureus in a Tertiary Care Hospital in Moshi, Tanzania, as Determined by Whole Genome Sequencing. AB - Objective: To determine molecular epidemiology of methicillin-resistant S. aureus in Tanzania using whole genome sequencing. Methods: DNA from 33 Staphylococcus species was recovered from subcultured archived Staphylococcus isolates. Whole genome sequencing was performed on Illumina Miseq using paired-end 2 * 250 bp protocol. Raw sequence data were analyzed using online tools. Results: Full susceptibility to vancomycin and chloramphenicol was observed. Thirteen isolates (43.3%) resisted cefoxitin and other antimicrobials tested. Multilocus sequence typing revealed 13 different sequence types among the 30 S. aureus isolates, with ST-8 (n = seven, 23%) being the most common. Gene detection in S. aureus stains were as follows: mecA, 10 (33.3%); pvl, 5 (16.7%); tst, 2 (6.7%). The SNP difference among the six Tanzanian ST-8 MRSA isolates ranged from 24 to 196 SNPs and from 16 to 446 SNPs when using the USA300_FPR3757 or the USA500_2395 as a reference, respectively. The mutation rate was 1.38 * 10-11 SNPs/site/year or 1.4 * 10-6 SNPs/site/year as estimated by USA300_FPR3757 or the USA500_2395, respectively. Conclusion: S. aureus isolates causing infections in hospitalized patients in Moshi are highly diverse and epidemiologically unrelated. Temporal phylogenetic analysis provided better resolution on transmission and introduction of MRSA and it may be important to include this in future routines. PMID- 29487866 TI - Deletion of NAD(P)H Oxidase 2 Prevents Angiotensin II-Induced Skeletal Muscle Atrophy. AB - Skeletal muscle atrophy is induced by an imbalance between protein synthesis and degradation. Our previous studies reported that angiotensin II (AII) directly induced muscle atrophy in mice. This study investigated the role of NAD(P)H oxidase 2 (Nox2) activation by AII in the induction of skeletal muscle atrophy. For 4 weeks, either saline (vehicle: V) or AII (1000 ng kg-1 min-1) was infused into male wild-type (WT) and Nox2 knockout (KO) mice via osmotic minipumps. Experiments were performed in the following 4 groups: WT + V, KO + V, WT + AII, and KO + AII. Body weight, muscle weight, and myocyte cross-sectional area were significantly decreased in WT + AII compared to WT + V mice, and these changes were not observed in KO + AII mice. Akt phosphorylation of Ser473 and p70S6K of Thr389 was decreased, gene expression levels of MuRF-1 and atrogin-1 were increased in WT + AII compared to WT + V, and these changes were significantly attenuated in KO + AII mice. The deletion of Nox2 prevented AII-induced skeletal muscle atrophy via improving the balance between protein synthesis and degradation. Therefore, Nox2 may be a therapeutic target for AII-induced skeletal muscle atrophy. PMID- 29487867 TI - Reduction of Pulmonary Air Leaks with a Combination of Polyglycolic Acid Sheet and Alginate Gel in Rats. AB - Postoperative air leaks remain a major cause of morbidity after lung resection. This study evaluated the effect of a combination of polyglycolic acid (PGA) sheet and alginate gel on pulmonary air leaks in rats. Four pulmonary sealing materials were evaluated in lung injury: fibrin glue, combination of PGA sheet and fibrin glue, alginate gel, and combination of PGA sheet and alginate gel. With the airway pressure maintained at 20 cmH2O, a 2 mm deep puncture wound was created on the lung surface using a needle. Lowering the airway pressure to 5 cmH2O, each sealing material was applied. The lowest airway pressure that broke the seal was measured. The seal-breaking pressure in each experimental group was fibrin, 10.4 +/- 6.8 cmH2O; PGA + fibrin, 13.5 +/- 6.5 cmH2O; alginate gel, 10.3 +/- 4.9 cmH2O; and PGA + alginate, 35.8 +/- 11.9 cmH2O, respectively. The seal-breaking pressure was significantly greater in the PGA + alginate gel group than in the other groups (p < 0.01). There were no significant differences among the other three groups. Alginate gel combined with a PGA sheet is a promising alternative to fibrin glue as a safe and low-cost material for air leak prevention in pulmonary surgery. PMID- 29487868 TI - The Reliability and Validity of a Modified Squat Test to Predict Cardiopulmonary Fitness in Healthy Older Men. AB - Background: Shortcomings are noted in currently available cardiopulmonary field tests for the older adult and thus relevant research is still ongoing. Purpose: The purpose of this study was to investigate the reliability and validity of a modified squat test and to establish a regression model for predicting aerobic fitness in the older adult. Methods: Twenty-five healthy men aged 60 to 75 years completed this study. Each subject performed two modified squat tests with a prototype testing equipment and a maximal exercise test to determine maximal oxygen consumption. Recovery heart rates (HR) (0~30, 60~90, and 120~150 seconds) were measured following the modified squat tests. The fitness indexes included the sum of recovery HR, recovery HR index, age-adjusted recovery HR index, and immediate HR. Results: The results revealed that the age-adjusted recovery HR index fitness had the highest intraclass correlation coefficients (ICC) of 0.9 and Pearson's correlation coefficients of 0.71, which suggested the modified squat test can reasonably assess cardiopulmonary fitness for the older adult. The regression equation for estimating aerobic power was [Formula: see text] = 16.781 + 16.732 * (age-adjusted recovery HR index) + 0.02467 * (physical activity level). Conclusion: The modified squat test is a valid and reliable field test and thus can be an option to assess the cardiopulmonary fitness level of healthy older men in clinics or communities. PMID- 29487869 TI - Comparison of the Effectiveness of Whole Body Vibration in Stroke Patients: A Meta-Analysis. AB - Objectives: The goals of this study were to assess the effectiveness of WBV (whole body vibration) training through an analysis of effect sizes, identify advantages of WBV training, and suggest other effective treatment methods. Methods: Four databases, namely, EMBASE, PubMed, EBSCO, and Web of Science, were used to collect articles on vibration. Keywords such as "vibration" and "stroke" were used in the search for published articles. Consequently, eleven studies were selected in the second screening using meta-analyses. Results: The total effect size of patients with dementia in the studies was 0.25, which was small. The effect size of spasticity was the greatest at 1.24 (high), followed by metabolism at 0.99 (high), balance, muscle strength, gait, and circulation in the decreasing order of effect size. Conclusions: The effect sizes for muscle strength and balance and gait function, all of which play an important role in performance of daily activities, were small. In contrast, effect sizes for bone metabolism and spasticity were moderate. This suggests that WBV training may provide a safe, alternative treatment method for improving the symptoms of stroke in patients. PMID- 29487870 TI - The Assessment of the Integrated Antioxidant System of the Body in the Course of Radon Therapy: A Pilot Study. AB - Introduction: The sources of Reactive Oxidative Species (ROS) in the organism are the respiratory processes occurring in cells catalyzed by different enzymes. Operation of ROS is balanced by antioxidants, the compounds; although present in low concentrations, they significantly inhibit the degree of oxidation of particular molecules. The Aim of the Study: The aim of this study was to assess the changes in the integrated antioxidant system under the influence of radon therapy in osteoarthritis patients. Material and Methods: Observation included 35 patients suffering from degenerative joints and disc disease (mean age 56.5 years) undergoing radon water therapy and control group that consisted of 15 osteoarthritis patients (mean age 54.2) without contact with radon water. Before therapy and after 18 days of treatment, serum total antioxidant status (TAS) was assessed with the use of standard colorimetric assay. Results: In the study group, we observed trends to increase TAS concentration, whereas, in the control group, TAS concentration was decreasing. Conclusions: (1) Radon waters treatment influenced the level of TAS of osteoarthritis patients treated with the radon water. (2) The change in TAS concentrations in the study group may be the result of low doses of ionizing radiation, but further studies on larger patient's groups are demanded. This study is registered with number NCT03274128. PMID- 29487871 TI - Serum Soluble Vascular Cell Adhesion Molecule-1 Overexpression Is a Disease Marker in Patients with First-Time Diagnosed Antinuclear Antibodies: A Prospective, Observational Pilot Study. AB - Objective: Antinuclear antibodies (ANA) serve as screening tests for connective tissue diseases but have low specificity. In this pilot study, we aimed to identify patients with first-time positive ANA and musculoskeletal complaints and correlate serum soluble vascular adhesion molecules as biomarkers. Methods: Prospective, observational study with 100 ANA-positive patients, comparing them to age- and gender-matched healthy controls (HC, n = 75), was conducted. Serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), endothelial leukocyte adhesion molecule-1 (sELAM-1), and vascular cell adhesion molecule-1 (sVCAM-1) were measured. A subgroup of patients with systemic sclerosis (SSc) treated with immunosuppressants was followed over 10 months. Results: Patients belonged to three main entities: rheumatoid arthritis (RA, n = 32), collagen diseases (CD, n = 56) also including systemic sclerosis (SSc, n = 11), and other autoimmune diseases (n = 12). sICAM-1 was similar among groups. sELAM-1 was elevated by 1.9-fold in only in SSc. sVCAM-1 was elevated by 3.1-fold in RA and by 3.3-fold in CD and in other autoimmune diseases by 3.4-fold. Seven SSc patients with immunosuppression had a 2.7-fold increased sVCAM-1 at baseline and reached the levels of healthy controls after 5 months, while CRP, ESR, and clinical parameters remained unchanged. Conclusion: Our study suggests that sVCAM 1 is a disease marker independent of standard serum parameters in several rheumatic diseases. This study is registered with EU PAS Register number: EUPAS22154. PMID- 29487872 TI - A Simplified Ultrasound Comet Tail Grading Scoring to Assess Pulmonary Congestion in Patients with Heart Failure. AB - Ultrasound lung comets (ULCs) are a nonionizing bedside approach to assess extravascular lung water. We evaluated a protocol for grading ULC score to estimate pulmonary congestion in heart failure patients and investigated clinical and echocardiographic correlates of the ULC score. Ninety-three patients with congestive heart failure, admitted to the emergency department, underwent pulmonary ultrasound and echocardiography. A ULC score was obtained by summing the ULC scores of 7 zones of anterolateral chest scans. The results of ULC score were compared with echocardiographic results, the New York Heart Association (NYHA) functional classification, radiologic score, and N-terminal pro-b-type natriuretic peptide (NT-proBNP). Positive linear correlations were found between the 7-zone ULC score and the following: E/e', systolic pulmonary artery pressure, severity of mitral regurgitation, left ventricular global longitudinal strain, NYHA functional classification, radiologic score, and NT-proBNP. However, there was no significant correlation between ULC score and left ventricular ejection fraction, left ventricle diameter, left ventricular volume, or left atrial volume. A multivariate analysis identified the E/e', systolic pulmonary artery pressure, and radiologic score as the only independent variables associated with ULC score increase. The simplified 7-zone ULC score is a rapid and noninvasive method to assess lung congestion. Diastolic rather than systolic performance may be the most important determinant of the degree of lung congestion in patients with heart failure. PMID- 29487873 TI - Ultrasound in Prenatal Diagnostics and Its Impact on the Epidemiology of Spina Bifida in a National Cohort from Denmark with a Comparison to Sweden. AB - Objectives: The aim of this study was to assess the incidence, the prenatal detection rate by ultrasound, and the pregnancy outcome of spina bifida (SB) in Denmark (DK) in 2008-2015 and to compare results to national data from Sweden. Methods: Data were retrieved from the Danish Fetal Medicine Database, which includes International Classification of Diseases- (ICD-) 10 codes for pre- or postnatally diagnoses and pregnancy outcome. Missing data were obtained from the National Patient Register. Livebirth data with myelomeningocele (MMC) in Sweden were obtained from different databases. Results: There were 234 cases with SB in DK in 2008-2015. The incidence of SB was 4.9 : 10,000; 89% were detected with ultrasound prior to week 22; 90% of these pregnancies were terminated (ToP); 91% were isolated malformations of which 11% showed abnormal karyotype. The incidence of newborns with MMC was 1.3 : 10,000 in Sweden. Conclusions: Ultrasound screening has a major impact on the epidemiology of SB. The prenatal detection rate of SB was high, and most SB cases were isolated and had a normal karyotype. Among women with a prenatal fetal diagnosis of SB, 90% chose to have ToP. The incidence of newborns with SB was higher in Sweden than in DK. PMID- 29487875 TI - Motion correction for infant functional near-infrared spectroscopy with an application to live interaction data. AB - Correcting for motion is an important consideration in infant functional near infrared spectroscopy studies. We tested the performance of conventional motion correction methods and compared probe motion and data quality metrics for data collected at different infant ages (5, 7, and 12 months) and during different methods of stimulus presentation (video versus live). While 5-month-olds had slower maximum head speed than 7- or 12-month-olds, data quality metrics and hemodynamic response recovery errors were similar across ages. Data quality was also similar between video and live stimulus presentation. Motion correction algorithms, such as wavelet filtering and targeted principal component analysis, performed well for infant data using infant-specific parameters, and parameters may be used without fine-tuning for infant age or method of stimulus presentation. We recommend using wavelet filtering with [Formula: see text]; however, a range of parameters seemed acceptable. We do not recommend using trial rejection alone, because it did not improve hemodynamic response recovery as compared to no correction at all. Data quality metrics calculated from uncorrected data were associated with hemodynamic response recovery error, indicating that full simulation studies may not be necessary to assess motion correction performance. PMID- 29487874 TI - Epidemiological Profile and Risk Factors for Acquiring HBV and/or HCV in HIV Infected Population Groups in Nepal. AB - HBV and HCV infections are widespread among the HIV-infected individuals in Nepal. The goals of this study were to investigate the epidemiological profile and risk factors for acquiring HBV and/or HCV coinfection in disadvantaged HIV positive population groups in Nepal. We conducted a retrospective study on blood samples from HIV-positive patients from the National Public Health Laboratory at Kathmandu to assay for HBsAg, HBeAg, and anti-HCV antibodies, HIV viral load, and CD4+ T cell count. Among 579 subjects, the prevalence of HIV-HBV, HIV-HCV, and HIV-HBV-HCV coinfections was 3.62%, 2.93%, and 0.34%, respectively. Multivariate regression analysis indicated that spouses of HIV-positive migrant labourers were at significant risk for coinfection with HBV infection, and an age of >40 years in HIV-infected individuals was identified as a significant risk factor for HCV coinfection. Overall our study indicates that disadvantaged population groups such as intravenous drug users, migrant workers and their spouses, female sex workers, and men who have sex with HIV-infected men are at a high and persistent risk of acquiring viral hepatitis. We conclude that Nepalese HIV patients should receive HBV and HCV diagnostic screening on a regular basis. PMID- 29487876 TI - Designing a large field-of-view two-photon microscope using optical invariant analysis. AB - Conventional two-photon microscopy (TPM) is capable of imaging neural dynamics with subcellular resolution, but it is limited to a field-of-view (FOV) diameter [Formula: see text]. Although there has been recent progress in extending the FOV in TPM, a principled design approach for developing large FOV TPM (LF-TPM) with off-the-shelf components has yet to be established. Therefore, we present a design strategy that depends on analyzing the optical invariant of commercially available objectives, relay lenses, mirror scanners, and emission collection systems in isolation. Components are then selected to maximize the space bandwidth product of the integrated microscope. In comparison with other LF-TPM systems, our strategy simplifies the sequence of design decisions and is applicable to extending the FOV in any microscope with an optical relay. The microscope we constructed with this design approach can image [Formula: see text] lateral and [Formula: see text] axial resolution over a 7-mm diameter FOV, which is a 100-fold increase in FOV compared with conventional TPM. As a demonstration of the potential that LF-TPM has on understanding the microarchitecture of the mouse brain across interhemispheric regions, we performed in vivo imaging of both the cerebral vasculature and microglia cell bodies over the mouse cortex. PMID- 29487877 TI - Influence of CT acquisition and reconstruction parameters on radiomic feature reproducibility. AB - High-dimensional imaging features extracted from diagnostic imaging, called radiomics, are increasingly reported for diagnosis, prognosis, and response to therapy. Establishing the sensitivity of radiomic features to variation in scan protocols is necessary because acquisition and reconstruction parameters can vary widely across and within institutions. Our objective was to assess the reproducibility of radiomic features derived from computed tomography (CT) images by varying tube current (mA), noise index, and reconstruction [adaptive statistical iterative reconstruction (ASiR)], parameters increasingly varied by institutions seeking to reduce radiation dose in their patients. We extracted radiomic features from CT images of a uniform water phantom, anthropomorphic phantom, and a human scan. Scans were acquired from the phantoms with six tube currents (50, 100, 200, 300, 400, and 500 mA) and five noise index levels (12, 14, 16, 18, and 20), respectively. Scans of the phantoms and patient were reconstructed from 0% ASiR (i.e., filtered back projection) to 100% ASiR in increments of 10%. Two hundred and forty-eight well-known radiomic features were extracted from all scans. The concordance correlation coefficient was used to assess agreement of features. Our analysis suggests that image acquisition parameters (tube current, noise index) as well as the reconstruction technique strongly influence radiomic feature reproducibility and demonstrate a subset of reproducible features potentially usable in clinical practice. PMID- 29487878 TI - Pulmonary lobe separation in expiration chest CT scans based on subject-specific priors derived from inspiration scans. AB - Segmentation of pulmonary lobes in inspiration and expiration chest CT scan pairs is an important prerequisite for lobe-based quantitative disease assessment. Conventional methods process each CT scan independently, resulting typically in lower segmentation performance at expiration compared to inspiration. To address this issue, we present an approach, which utilizes CT scans at both respiratory states. It consists of two main parts: a base method that processes a single CT scan and an extended method that utilizes the segmentation result obtained on the inspiration scan as a subject-specific prior for segmentation of the expiration scan. We evaluated the methods on a diverse set of 40 CT scan pairs. In addition, we compare the performance of our method to a registration-based approach. On inspiration scans, the base method achieved an average distance error of 0.59, 0.64, and 0.91 mm for the left oblique, right oblique, and right horizontal fissures, respectively, when compared with expert-based reference tracings. On expiration scans, the base method's errors were 1.54, 3.24, and 3.34 mm, respectively. In comparison, utilizing proposed subject-specific priors for segmentation of expiration scans allowed decreasing average distance errors to 0.82, 0.79, and 1.04 mm, which represents a significant improvement ([Formula: see text]) compared with all other methods investigated. PMID- 29487879 TI - Improved approach to quantitative cardiac volumetrics using automatic thresholding and manual trimming: a cardiovascular MRI study. AB - To establish the clinical validity and accuracy of automatic thresholding and manual trimming (ATMT) by comparing the method with the conventional contouring method for in vivo cardiac volume measurements. CMR was performed on 40 subjects (30 patients and 10 controls) using steady-state free precession cine sequences with slices oriented in the short-axis and acquired contiguously from base to apex. Left ventricular (LV) volumes, end-diastolic volume, end-systolic volume, and stroke volume (SV) were obtained with ATMT and with the conventional contouring method. Additionally, SV was measured independently using CMR phase velocity mapping (PVM) of the aorta for validation. Three methods of calculating SV were compared by applying Bland-Altman analysis. The Bland-Altman standard deviation of variation (SD) and offset bias for LV SV for the three sets of data were: ATMT-PVM (7.65, [Formula: see text]), ATMT-contours (7.85, [Formula: see text]), and contour-PVM (11.01, 4.97), respectively. Equating the observed range to the error contribution of each approach, the error magnitude of ATMT:PVM:contours was in the ratio 1:2.4:2.5. Use of ATMT for measuring ventricular volumes accommodates trabeculae and papillary structures more intuitively than contemporary contouring methods. This results in lower variation when analyzing cardiac structure and function and consequently improved accuracy in assessing chamber volumes. PMID- 29487880 TI - Performance analysis of a computer-aided detection system for lung nodules in CT at different slice thicknesses. AB - We study the performance of a computer-aided detection (CAD) system for lung nodules in computed tomography (CT) as a function of slice thickness. In addition, we propose and compare three different training methodologies for utilizing nonhomogeneous thickness training data (i.e., composed of cases with different slice thicknesses). These methods are (1) aggregate training using the entire suite of data at their native thickness, (2) homogeneous subset training that uses only the subset of training data that matches each testing case, and (3) resampling all training and testing cases to a common thickness. We believe this study has important implications for how CT is acquired, processed, and stored. We make use of 192 CT cases acquired at a thickness of 1.25 mm and 283 cases at 2.5 mm. These data are from the publicly available Lung Nodule Analysis 2016 dataset. In our study, CAD performance at 2.5 mm is comparable with that at 1.25 mm and is much better than at higher thicknesses. Also, resampling all training and testing cases to 2.5 mm provides the best performance among the three training methods compared in terms of accuracy, memory consumption, and computational time. PMID- 29487881 TI - Preoperative measurement of cutaneous melanoma and nevi thickness with photoacoustic imaging. AB - Photoacoustic imaging (PAI) is an emerging biomedical imaging technology, which can potentially be used in the clinic to preoperatively measure melanoma thickness and guide biopsy depth and sample location. We recruited 27 patients with pigmented cutaneous lesions suspicious for melanoma to test the feasibility of a handheld linear-array photoacoustic probe in imaging lesion architecture and measuring tumor depth. The probe was assessed in terms of measurement accuracy, image quality, and ease of application. Photoacoustic scans included single wavelength, spectral unmixing, and three-dimensional (3-D) scans. The photoacoustically measured lesion thickness gave a high correlation with the histological thickness measured from resected surgical samples ([Formula: see text], [Formula: see text] for melanomas, [Formula: see text], [Formula: see text] for nevi). Thickness measurements were possible for 23 of 26 cases for nevi and all (6) cases for melanoma. Our results show that handheld, linear-array PAI is highly reliable in measuring cutaneous lesion thickness in vivo, and can potentially be used to inform biopsy procedure and improve patient management. PMID- 29487882 TI - Virtual fluoroscopy for intraoperative C-arm positioning and radiation dose reduction. AB - Positioning of an intraoperative C-arm to achieve clear visualization of a particular anatomical feature often involves repeated fluoroscopic views, which cost time and radiation exposure to both the patient and surgical staff. A system for virtual fluoroscopy (called FluoroSim) that could dramatically reduce time- and dose-spent "fluoro-hunting" by leveraging preoperative computed tomography (CT), encoded readout of C-arm gantry position, and automatic 3D-2D image registration has been developed. The method is consistent with existing surgical workflow and does not require additional tracking equipment. Real-time virtual fluoroscopy was achieved via mechanical encoding of the C-arm motion, C-arm geometric calibration, and patient registration using a single radiograph. The accuracy, time, and radiation dose associated with C-arm positioning were measured for FluoroSim in comparison with conventional methods. Five radiology technologists were tasked with acquiring six standard pelvic views pertinent to sacro-illiac, anterior-inferior iliac spine, and superior-ramus screw placement in an anthropomorphic pelvis phantom using conventional and FluoroSim approaches. The positioning accuracy, exposure time, number of exposures, and total time for each trial were recorded, and radiation dose was characterized in terms of entrance skin dose and in-room scatter. The geometric accuracy of FluoroSim was measured to be [Formula: see text]. There was no significant difference ([Formula: see text]) observed in the accuracy or total elapsed time for C-arm positioning. However, the total fluoroscopy time required to achieve the desired view decreased by 4.1 s ([Formula: see text] for conventional, compared with [Formula: see text] for FluoroSim, [Formula: see text]), and the total number of exposures reduced by 4.0 ([Formula: see text] for conventional, compared with [Formula: see text] for FluoroSim, [Formula: see text]). These reductions amounted to a 50% to 78% decrease in patient entrance skin dose and a 55% to 70% reduction in in-room scatter. FluoroSim was found to reduce the radiation exposure required in C-arm positioning without diminishing positioning time or accuracy, providing a potentially valuable tool to assist technologists and surgeons. PMID- 29487883 TI - Family of boundary overlap metrics for the evaluation of medical image segmentation. AB - All medical image segmentation algorithms need to be validated and compared, yet no evaluation framework is widely accepted within the imaging community. None of the evaluation metrics that are popular in the literature are consistent in the way they rank segmentation results: they tend to be sensitive to one or another type of segmentation error (size, location, and shape) but no single metric covers all error types. We introduce a family of metrics, with hybrid characteristics. These metrics quantify the similarity or difference of segmented regions by considering their average overlap in fixed-size neighborhoods of points on the boundaries of those regions. Our metrics are more sensitive to combinations of segmentation error types than other metrics in the existing literature. We compare the metric performance on collections of segmentation results sourced from carefully compiled two-dimensional synthetic data and three dimensional medical images. We show that our metrics: (1) penalize errors successfully, especially those around region boundaries; (2) give a low similarity score when existing metrics disagree, thus avoiding overly inflated scores; and (3) score segmentation results over a wider range of values. We analyze a representative metric from this family and the effect of its free parameter on error sensitivity and running time. PMID- 29487884 TI - Ex-vivo study in nephroureterectomy specimens defining the role of 3-D upper urinary tract visualization using optical coherence tomography and endoluminal ultrasound. AB - Minimal invasive endoscopic treatment for upper urinary tract urothelial carcinoma (UUT-UC) is advocated in patients with low-risk disease and limited tumor volume. Diagnostic ureterorenoscopy combined with biopsy is the diagnostic standard. This study aims to evaluate two alternative diagnostic techniques for UUT-UC: optical coherence tomography (OCT) and endoluminal ultrasound (ELUS). Following nephroureterectomy, OCT, ELUS, and computed tomography (CT) were performed of the complete nephroureterectomy specimen. Visualization software (AMIRA(r)) was used for reconstruction and coregistration of CT, OCT, and ELUS. Finally, CT was used to obtain exact probe localization. Coregistered OCT and ELUS datasets were compared with histology. Coregistration with three-dimensional CT makes exact data matching possible in this ex-vivo setting to compare histology with OCT and ELUS. In OCT images of normal-appearing renal pelvis and ureter, urothelium, lamina propria, and muscularis were visible. With ELUS, all anatomical layers of the ureter could be distinguished, besides the urothelial layer. ELUS identified suspect lesions, although exact staging and differentiation between noninvasive and invasive lesions were not possible. OCT provides high-resolution imaging of normal ureter and ureter lesions. ELUS, however, is of limited value as it cannot differentiate between noninvasive and invasive tumors. PMID- 29487885 TI - Feasibility of photoacoustic-guided teleoperated hysterectomies. AB - Hysterectomies (i.e., surgical removal of the uterus) are the prevailing solution to treat medical conditions such as uterine cancer, endometriosis, and uterine prolapse. One complication of hysterectomies is accidental injury to the ureters located within millimeters of the uterine arteries that are severed and cauterized to hinder blood flow and enable full uterus removal. This work explores the feasibility of using photoacoustic imaging to visualize the uterine arteries (and potentially the ureter) when this imaging method is uniquely combined with a da Vinci(r) surgical robot that enables teleoperated hysterectomies. We developed a specialized light delivery system to surround a da Vinci(r) curved scissor tool, and an ultrasound probe was placed externally, representing a transvaginal approach, to receive the acoustic signals. Photoacoustic images were acquired while sweeping the tool across our custom 3-D uterine vessel model covered in ex vivo bovine tissue that was placed between the 3-D model and the fiber, as well as between the ultrasound probe and the 3-D model. Four tool orientations were explored, and the robot kinematics were used to provide tool position and orientation information simultaneously with each photoacoustic image acquisition. The optimal tool orientation produced images with contrast [Formula: see text] and background signal-to-noise ratios (SNRs) [Formula: see text], indicating minimal acoustic clutter from the tool tip. We achieved similar contrast and SNR measurements with four unique wrist orientations explored with the scissor tool in open and closed configurations. Results indicate that photoacoustic imaging is a promising approach to enable visualization of the uterine arteries to guide hysterectomies (and other gynecological surgeries). These results are additionally applicable to other da Vinci(r) surgeries and other surgical instruments with similar tip geometry. PMID- 29487886 TI - Signal dropout correction-based ultrasound segmentation for diastolic mitral valve modeling. AB - Three-dimensional ultrasound segmentation of mitral valve (MV) at diastole is helpful for duplicating geometry and pathology in a patient-specific dynamic phantom. The major challenge is the signal dropout at leaflet regions in transesophageal echocardiography image data. Conventional segmentation approaches suffer from missing sonographic data leading to inaccurate MV modeling at leaflet regions. This paper proposes a signal dropout correction-based ultrasound segmentation method for diastolic MV modeling. The proposed method combines signal dropout correction, image fusion, continuous max-flow segmentation, and active contour segmentation techniques. The signal dropout correction approach is developed to recover the missing segmentation information. Once the signal dropout regions of TEE image data are recovered, the MV model can be accurately duplicated. Compared with other methods in current literature, the proposed algorithm exhibits lower computational cost. The experimental results show that the proposed algorithm gives competitive results for diastolic MV modeling compared with conventional segmentation algorithms, evaluated in terms of accuracy and efficiency. PMID- 29487887 TI - Design and validation of an open-source library of dynamic reference frames for research and education in optical tracking. AB - Dynamic reference frames (DRFs) are a common component of modern surgical tracking systems; however, the limited number of commercially available DRFs poses a constraint in developing systems, especially for research and education. This work presents the design and validation of a large, open-source library of DRFs compatible with passive, single-face tracking systems, such as Polaris stereoscopic infrared trackers (NDI, Waterloo, Ontario). An algorithm was developed to create new DRF designs consistent with intra- and intertool design constraints and convert to computer-aided design (CAD) files suitable for three dimensional printing. A library of 10 such groups, each with 6 to 10 DRFs, was produced and tracking performance was validated in comparison to a standard commercially available reference, including pivot calibration, fiducial registration error (FRE), and target registration error (TRE). Pivot tests showed calibration error [Formula: see text], indistinguishable from the reference. FRE was [Formula: see text], and TRE in a CT head phantom was [Formula: see text], both equivalent to the reference. The library of DRFs offers a useful resource for surgical navigation research and could be extended to other tracking systems and alternative design constraints. PMID- 29487888 TI - Follow the light: projector-based augmented reality intracorporeal system for laparoscopic surgery. AB - A projector-based augmented reality intracorporeal system (PARIS) is presented that includes a miniature tracked projector, tracked marker, and laparoscopic ultrasound (LUS) transducer. PARIS was developed to improve the efficacy and safety of laparoscopic partial nephrectomy (LPN). In particular, it has been demonstrated to effectively assist in the identification of tumor boundaries during surgery and to improve the surgeon's understanding of the underlying anatomy. PARIS achieves this by displaying the orthographic projection of the cancerous tumor on the kidney's surface. The performance of PARIS was evaluated in a user study with two surgeons who performed 32 simulated robot-assisted partial nephrectomies. They performed 16 simulated partial nephrectomies with PARIS for guidance and 16 simulated partial nephrectomies with only an LUS transducer for guidance. With PARIS, there was a significant reduction [30% ([Formula: see text])] in the amount of healthy tissue excised and a trend toward a more accurate dissection around the tumor and more negative margins. The combined point tracking and reprojection root-mean-square error of PARIS was 0.8 mm. PARIS' proven ability to improve key metrics of LPN surgery and qualitative feedback from surgeons about PARIS supports the hypothesis that it is an effective surgical navigation tool. PMID- 29487889 TI - Probabilistic visual and electromagnetic data fusion for robust drift-free sequential mosaicking: application to fetoscopy. AB - The most effective treatment for twin-to-twin transfusion syndrome is laser photocoagulation of the shared vascular anastomoses in the placenta. Vascular connections are extremely challenging to locate due to their caliber and the reduced field-of-view of the fetoscope. Therefore, mosaicking techniques are beneficial to expand the scene, facilitate navigation, and allow vessel photocoagulation decision-making. Local vision-based mosaicking algorithms inherently drift over time due to the use of pairwise transformations. We propose the use of an electromagnetic tracker (EMT) sensor mounted at the tip of the fetoscope to obtain camera pose measurements, which we incorporate into a probabilistic framework with frame-to-frame visual information to achieve globally consistent sequential mosaics. We parametrize the problem in terms of plane and camera poses constrained by EMT measurements to enforce global consistency while leveraging pairwise image relationships in a sequential fashion through the use of local bundle adjustment. We show that our approach is drift free and performs similarly to state-of-the-art global alignment techniques like bundle adjustment albeit with much less computational burden. Additionally, we propose a version of bundle adjustment that uses EMT information. We demonstrate the robustness to EMT noise and loss of visual information and evaluate mosaics for synthetic, phantom-based and ex vivo datasets. PMID- 29487890 TI - Method validation of a set of 12 GEM(r) PremierTM 4000 blood gas analyzers for point-of-care testing in a university teaching hospital. AB - Background: Blood gas analyzers are o0.ften integrated into point-of-care testing provisions. International standards (ISO 22870 and 15189) as adapted to French COFRAC regulations make accreditation of point-ofta-care testintag obligatory. We installed and assessed 12 GEM PREMIER 4000 analyzers for pH, pCO2, pO2, Na+, K+, Cl-, Ca2+, lactate, hemoglobin and oxyhemoglobin (O2Hb) at Clermont-Ferrand Hospital. These instruments were distributed across 11 care sites in the hospital. Methods: Precision was studied at two control levels for each parameter. Comparisons between GEM analyzers were performed (on 30 samples) for pH, pCO2, pO2, Na+, K+, Cl-, Ca2+, lactate, hemoglobin and O2Hb; and between GEM analyzers and the central laboratory for Na+, K+, Cl-, Ca2+ and hemoglobin (on 30 50 samples). Uncertainty in measurement (UM) was evaluated with an approach using reproducibility and accuracy data. Results: The coefficients of variation (CVs) were in line with recommendations, except for the repeatability CV for pO2. All CVs were below 4%. All comparisons complied with recommendations. Uncertainties of measurement were also validated. Conclusion: Our results met standard requirements and the 12 analyzers were assessed as suitable for point-of-care testing in services of academic medical centers, as exemplified at Clermont Ferrand hospital. PMID- 29487891 TI - Enzymatic measurement of ether phospholipids in human plasma after hydrolysis of plasma with phospholipase A1. AB - Objectives: Ethanolamine ether phospholipids (ePE) and choline ether phospholipid (ePC) are present in human serum or plasma. Decreases in ether phospholipids (plasmalogens) in serum (plasma) have been reported in several diseases such as Alzheimer's disease, Parkinson's disease, metabolic syndrome, schizophrenia. Therefore, need for assay of ether phospholipids in plasma may increase in the future. Nowadays, measurement of the ether phospholipids in human plasma seem to depend on tandem mass spectrometry (LC/MS/MS), but a system for LC/MS/MS is too expensive for most of ordinary clinical laboratories, moreover, use and maintenance of the system are time consuming. Design and methods: Phospholipase A1 (PLA1) hydrolyzes ester (acyl) bond at the sn-1 position of glycerophospholipids, but it does not act on ether bond at the sn-1 position. We confirmed by a HPLC method that treatment of plasma with PLA1 causes complete disappearance of all diacyl phospholipids, but ether phospholipids remain intact. On the basis of these observations, we developed an enzymatic assay method for ePE and ePC in human plasma by use of a fluorescence plate reader. Results: The amount of ePE in human plasma measured by the enzymatic method was well correlated to that by LC/ESI-MS method (R2 > 0.94), but the correlation of ePC between the two methods was bit poorer (R2 > 0.77) than that of ePE. Conclusion: The enzymatic method may be applied to assay of ether phospholipids (ePE and ePC) not only in human plasma but also to assay of ePE and ePC in the other tissues. PMID- 29487892 TI - Predicting human clinical trial responses in mice. AB - Preclinical modeling of human Phase II oncology trials by traditional methods has failed to be highly predictive. Here, we comment on our data showing that much better prediction of clinical trial results can be achieved using a broad-based patient-derived xenograft (PDX) panel. PMID- 29487893 TI - UBASH3B-mediated silencing of the mitotic checkpoint: Therapeutic perspectives in cancer. AB - Defects in mitosis can lead to aneuploidy, which is a common feature of human cancers. Spindle Assembly Checkpoint (SAC) controls fidelity of chromosome segregation in mitosis to prevent aneuploidy. The ubiquitin receptor protein Ubiquitin Associated and SH3 Domain Containing B (UBASH3B) was recently found to control SAC silencing and faithful chromosome segregation by relocalizing Aurora B kinase to the mitotic microtubules. Accordingly, loss and gain of function of UBASH3B have strong effects on mitotic progression. Downregulation of UBASH3B prevents SAC satisfaction leading to inhibition of chromosome segregation, mitotic arrest, and cell death. In contrast, increased cellular levels of UBASH3B trigger premature and uncontrolled chromosome segregation. Interestingly, elevated levels of UBASH3B were found in aggressive tumors. Therefore, we raised the question whether the oncogenic potential of UBASH3B is linked to its role in chromosome segregation. Here we show that in cancer cells expressing high levels of UBASH3B and SAC proteins, downregulation of UBASH3B, can further potentiate SAC response inducing mitotic arrest and cell death. Moreover, data mining approaches identified a correlation between mRNA levels of UBASH3B and SAC components in a set of primary patient tumors including kidney and liver carcinomas. Thus, inhibition of UBASH3B may offer an attractive therapeutic perspective for cancers. PMID- 29487894 TI - Autophagy and mitophagy in hepatocarcinogenesis. AB - Autophagy is required for benign hepatic tumors to progress into malignant hepatocellular carcinoma. In our recent studies, we found that autophagy, or more specifically mitophagy, was required to suppress TP53 and induce the expression of the transcription factor NANOG to maintain hepatic cancer stem cells and promote hepatocarcinogenesis. PMID- 29487895 TI - MHC-I genotype drives early immune selection of oncogenic mutations. AB - MHC-I exposes the intracellular contents to immune cells for surveillance of cellular health. Due to high genomic variation, individuals' immune systems differ in their ability to expose and eliminate cancer-causing mutations. These personalized immune blind spots create specific oncogenic mutation predispositions within patients and influence their prevalence across populations. PMID- 29487896 TI - A path from melanocyte stem cells to cutaneous melanoma illuminated by UVB. AB - The relationship between melanocyte stem cells (MCSCs) and melanoma has been unclear. We recently demonstrated that melanoma-prone MCSCs are able to initiate cutaneous melanoma following stem cell activation through ultraviolet-B (UVB) exposure or natural stem cell cycling. Conversely, MCSC quiescence is sufficient to suppress tumorigenesis. This provides new insight into the role of environmental factors in tumor initiation from adult stem cells. PMID- 29487898 TI - Corrigendum. AB - [This corrects the article DOI: 10.1080/23723556.2017.1285385.]. PMID- 29487897 TI - Cellular quiescence: How TGFbeta protects cancer cells from chemotherapy. AB - Using a functional proliferation reporter we identified quiescent tumor propagating cancer cells (TPCs) in intact squamous cell carcinomas, and found that TGFbeta signaling controls their reversible entry into a growth arrested state, which protects TPCs from chemotherapy. TPCs with compromised TGFbeta/Smad signaling can't enter quiescence and subsequently die from chemotherapy. PMID- 29487899 TI - Convolutional neural network for earthquake detection and location. AB - The recent evolution of induced seismicity in Central United States calls for exhaustive catalogs to improve seismic hazard assessment. Over the last decades, the volume of seismic data has increased exponentially, creating a need for efficient algorithms to reliably detect and locate earthquakes. Today's most elaborate methods scan through the plethora of continuous seismic records, searching for repeating seismic signals. We leverage the recent advances in artificial intelligence and present ConvNetQuake, a highly scalable convolutional neural network for earthquake detection and location from a single waveform. We apply our technique to study the induced seismicity in Oklahoma, USA. We detect more than 17 times more earthquakes than previously cataloged by the Oklahoma Geological Survey. Our algorithm is orders of magnitude faster than established methods. PMID- 29487900 TI - Dipole-like electrostatic asymmetry of gold nanorods. AB - The symmetry of metallic nanocolloids, typically envisaged as simple geometrical shapes, is rarely questioned. However, the symmetry considerations are so essential for understanding their electronic structure, optical properties, and biological effects that it is important to reexamine these foundational assumptions for nanocolloids. Gold nanorods (AuNRs) are generally presumed to have nearly perfect geometry of a cylinder and therefore are centrosymmetric. We show that AuNRs, in fact, have a built-in electrostatic potential gradient on their surface and behave as noncentrosymmetric particles. The electrostatic potential gradient of 0.11 to 0.07 V/nm along the long axes of nanorods is observed by off-axis electron holography. Kelvin probe microscopy, secondary electron imaging, energy-filtered transmission electron microscopy, and plasmon mapping reveal that the axial asymmetry is associated with a consistently unequal number of cetyltrimethylammonium bromide moieties capping the two ends of the AuNRs. Electrostatic field maps simulated for the AuNR surface reproduce the holography images. The dipole-like surface potential gradient explains previously puzzling discrepancies in nonlinear optical effects originating from the noncentrosymmetric nature of AuNRs. Similar considerations of symmetry breaking are applicable to other nanoscale structures for which the property-governing symmetry of the organic shell may differ from the apparent symmetry of inorganic core observed in standard electron microscopy images. PMID- 29487901 TI - Remnants of Eoarchean continental crust derived from a subducted proto-arc. AB - Eoarchean [3.6 to 4.0 billion years ago (Ga)] tonalite-trondhjemite-granodiorite (TTG) is the major component of Earth's oldest remnant continental crust, thereby holding the key to understanding how continental crust originated and when plate tectonics started in the early Earth. TTGs are mostly generated by partial melting of hydrated mafic rocks at different depths, but whether this requires subduction remains enigmatic. Recent studies show that most Archean TTGs formed at relatively low pressures (<=1.5 GPa) and do not require subduction. We report a suite of newly discovered Eoarchean tonalitic gneisses dated at ~3.7 Ga from the Tarim Craton, northwestern China. These rocks are probably the oldest high pressure TTGs so far documented worldwide. Thermodynamic and trace element modeling demonstrates that the parent magma may have been generated by water fluxed partial melting of moderately enriched arc-like basalts at 1.8 to 1.9 GPa and 800 degrees to 830 degrees C, indicating an apparent geothermal gradient (400 degrees to 450 degrees C GPa-1) typical for hot subduction zones. They also locally record geochemical evidence for magma interaction with a mantle wedge. Accordingly, we propose that these high-pressure TTGs were generated by partial melting of a subducted proto-arc during arc accretion. Our model implies that modern-style plate tectonics was operative, at least locally, at ~3.7 Ga and was responsible for generating some of the oldest continental nuclei. PMID- 29487902 TI - Systematic deficiency of aftershocks in areas of high coseismic slip for large subduction zone earthquakes. AB - Fault slip during plate boundary earthquakes releases a portion of the shear stress accumulated due to frictional resistance to relative plate motions. Investigation of 101 large [moment magnitude (Mw) >= 7] subduction zone plate boundary mainshocks with consistently determined coseismic slip distributions establishes that 15 to 55% of all master event-relocated aftershocks with Mw >= 5.2 are located within the slip regions of the mainshock ruptures and few are located in peak slip regions, allowing for uncertainty in the slip models. For the preferred models, cumulative deficiency of aftershocks within the central three-quarters of the scaled slip regions ranges from 15 to 45%, increasing with the total number of observed aftershocks. The spatial gradients of the mainshock coseismic slip concentrate residual shear stress near the slip zone margins and increase stress outside the slip zone, driving both interplate and intraplate aftershock occurrence near the periphery of the mainshock slip. The shear stress reduction in large-slip regions during the mainshock is generally sufficient to preclude further significant rupture during the aftershock sequence, consistent with large-slip areas relocking and not rupturing again for a substantial time. PMID- 29487903 TI - Atomic-like high-harmonic generation from two-dimensional materials. AB - The generation of high-order harmonics from atomic and molecular gases enables the production of high-energy photons and ultrashort isolated pulses. Obtaining efficiently similar photon energy from solid-state systems could lead, for instance, to more compact extreme ultraviolet and soft x-ray sources. We demonstrate from ab initio simulations that it is possible to generate high-order harmonics from free-standing monolayer materials, with an energy cutoff similar to that of atomic and molecular gases. In the limit in which electrons are driven by the pump laser perpendicularly to the monolayer, they behave qualitatively the same as the electrons responsible for high-harmonic generation (HHG) in atoms, where their trajectories are described by the widely used semiclassical model, and exhibit real-space trajectories similar to those of the atomic case. Despite the similarities, the first and last steps of the well-established three-step model for atomic HHG are remarkably different in the two-dimensional materials from gases. Moreover, we show that the electron-electron interaction plays an important role in harmonic generation from monolayer materials because of strong local-field effects, which modify how the material is ionized. The recombination of the accelerated electron wave packet is also found to be modified because of the infinite extension of the material in the monolayer plane, thus leading to a more favorable wavelength scaling of the harmonic yield than in atomic HHG. Our results establish a novel and efficient way of generating high-order harmonics based on a solid-state device, with an energy cutoff and a more favorable wavelength scaling of the harmonic yield similar to those of atomic and molecular gases. Two-dimensional materials offer a unique platform where both bulk and atomic HHG can be investigated, depending on the angle of incidence. Devices based on two-dimensional materials can extend the limit of existing sources. PMID- 29487904 TI - Real-time observation of conformational switching in single conjugated polymer chains. AB - Conjugated polymers (CPs) are an important class of organic semiconductors that combine novel optoelectronic properties with simple processing from organic solvents. It is important to study CP conformation in solution to understand the physics of these materials and because it affects the properties of solution processed films. Single-molecule techniques are unique in their ability to extract information on a chain-to-chain basis; however, in the context of CPs, technical challenges have limited their general application to host matrices or semiliquid environments that constrain the conformational dynamics of the polymer. We introduce a conceptually different methodology that enables measurements in organic solvents using the single-end anchoring of polymer chains to avoid diffusion while preserving polymer flexibility. We explore the effect of organic solvents and show that, in addition to chain-to-chain conformational heterogeneity, collapsed and extended polymer segments can coexist within the same chain. The technique enables real-time solvent-exchange measurements, which show that anchored CP chains respond to sudden changes in solvent conditions on a subsecond time scale. Our results give an unprecedented glimpse into the mechanism of solvent-induced reorganization of CPs and can be expected to lead to a new range of techniques to investigate and conformationally manipulate CPs. PMID- 29487905 TI - Functional odor classification through a medicinal chemistry approach. AB - Crucial for any hypothesis about odor coding is the classification and prediction of sensory qualities in chemical compounds. The relationship between perceptual quality and molecular structure has occupied olfactory scientists throughout the 20th century, but details of the mechanism remain elusive. Odor molecules are typically organic compounds of low molecular weight that may be aliphatic or aromatic, may be saturated or unsaturated, and may have diverse functional polar groups. However, many molecules conforming to these characteristics are odorless. One approach recently used to solve this problem was to apply machine learning strategies to a large set of odors and human classifiers in an attempt to find common and unique chemical features that would predict a chemical's odor. We use an alternative method that relies more on the biological responses of olfactory sensory neurons and then applies the principles of medicinal chemistry, a technique widely used in drug discovery. We demonstrate the effectiveness of this strategy through a classification for esters, an important odorant for the creation of flavor in wine. Our findings indicate that computational approaches that do not account for biological responses will be plagued by both false positives and false negatives and fail to provide meaningful mechanistic data. However, the two approaches used in tandem could resolve many of the paradoxes in odor perception. PMID- 29487906 TI - Liquid gating elastomeric porous system with dynamically controllable gas/liquid transport. AB - The development of membrane technology is central to fields ranging from resource harvesting to medicine, but the existing designs are unable to handle the complex sorting of multiphase substances required for many systems. Especially, the dynamic multiphase transport and separation under a steady-state applied pressure have great benefits for membrane science, but have not been realized at present. Moreover, the incorporation of precisely dynamic control with avoidance of contamination of membranes remains elusive. We show a versatile strategy for creating elastomeric microporous membrane-based systems that can finely control and dynamically modulate the sorting of a wide range of gases and liquids under a steady-state applied pressure, nearly eliminate fouling, and can be easily applied over many size scales, pressures, and environments. Experiments and theoretical calculation demonstrate the stability of our system and the tunability of the critical pressure. Dynamic transport of gas and liquid can be achieved through our gating interfacial design and the controllable pores' deformation without changing the applied pressure. Therefore, we believe that this system will bring new opportunities for many applications, such as gas involved chemical reactions, fuel cells, multiphase separation, multiphase flow, multiphase microreactors, colloidal particle synthesis, and sizing nano/microparticles. PMID- 29487907 TI - Pre-Quaternary decoupling between Asian aridification and high dust accumulation rates. AB - Theories of late Cenozoic climate cooling assume that central Asian aridification and high dust accumulation rates in the Chinese Loess Plateau and the North Pacific Ocean are genetically related. On the basis of detailed sediment provenance analysis, we show that high dust accumulation rates in the Chinese Loess Plateau and the North Pacific Ocean during the late Miocene-Pliocene were mainly caused by increased erosion in the Qilian Mountains and low-elevation eastern Asia areas, driven by the effects of East Asian summer monsoon intensification. We conclude that precipitation-driven erosion increased dust input to the North Pacific Ocean and may have played a pivotal role in late Cenozoic climate cooling. PMID- 29487908 TI - Fractal universality in near-threshold magnetic lanthanide dimers. AB - Ergodic quantum systems are often quite alike, whereas nonergodic, fractal systems are unique and display characteristic properties. We explore one of these fractal systems, weakly bound dysprosium lanthanide molecules, in an external magnetic field. As recently shown, colliding ultracold magnetic dysprosium atoms display a soft chaotic behavior with a small degree of disorder. We broaden this classification by investigating the generalized inverse participation ratio and fractal dimensions for large sets of molecular wave functions. Our exact close coupling simulations reveal a dynamic phase transition from partially localized states to totally delocalized states and universality in its distribution by increasing the magnetic field strength to only a hundred Gauss (or 10 mT). Finally, we prove the existence of nonergodic delocalized phase in the system and explain the violation of ergodicity by strong coupling between near-threshold molecular states and the nearby continuum. PMID- 29487909 TI - Spin chirality induced skew scattering and anomalous Hall effect in chiral magnets. AB - Noncoplanar magnetic orders in magnetic metals give rise to an anomalous Hall effect of unconventional origin, which, by the spin Berry phase effect, is known as the topological Hall effect. This effect is pronounced in the low-temperature limit, where the fluctuation of spins is suppressed. In contrast, we here discuss that the fluctuating but locally correlated spins close to the phase boundary give rise to another anomalous Hall effect, that with the opposite sign to the topological Hall effect. Using the Born approximation, we show that the anomalous Hall effect is attributed to the skew scattering induced by the local correlation of spins. The relation of the scalar spin chirality to the skew scattering amplitude is given, and the explicit formula for the Hall conductivity is derived using a semiclassical Boltzmann transport theory. Our theory potentially accounts for the sign change of the anomalous Hall effect observed in chiral magnets in the vicinity of the phase boundary. PMID- 29487910 TI - Ultrafast selective transport of alkali metal ions in metal organic frameworks with subnanometer pores. AB - Porous membranes with ultrafast ion permeation and high ion selectivity are highly desirable for efficient mineral separation, water purification, and energy conversion, but it is still a huge challenge to efficiently separate monatomic ions of the same valence and similar sizes using synthetic membranes. We report metal organic framework (MOF) membranes, including ZIF-8 and UiO-66 membranes with uniform subnanometer pores consisting of angstrom-sized windows and nanometer-sized cavities for ultrafast selective transport of alkali metal ions. The angstrom-sized windows acted as ion selectivity filters for selection of alkali metal ions, whereas the nanometer-sized cavities functioned as ion conductive pores for ultrafast ion transport. The ZIF-8 and UiO-66 membranes showed a LiCl/RbCl selectivity of ~4.6 and ~1.8, respectively, which are much greater than the LiCl/RbCl selectivity of 0.6 to 0.8 measured in traditional porous membranes. Molecular dynamics simulations suggested that ultrafast and selective ion transport in ZIF-8 was associated with partial dehydration effects. This study reveals ultrafast and selective transport of monovalent ions in subnanometer MOF pores and opens up a new avenue to develop unique MOF platforms for efficient ion separations in the future. PMID- 29487911 TI - The force-dependent mechanism of DnaK-mediated mechanical folding. AB - It is well established that chaperones modulate the protein folding free-energy landscape. However, the molecular determinants underlying chaperone-mediated mechanical folding remain largely elusive, primarily because the force-extended unfolded conformation fundamentally differs from that characterized in biochemistry experiments. We use single-molecule force-clamp spectroscopy, combined with molecular dynamics simulations, to study the effect that the Hsp70 system has on the mechanical folding of three mechanically stiff model proteins. Our results demonstrate that, when working independently, DnaJ (Hsp40) and DnaK (Hsp70) work as holdases, blocking refolding by binding to distinct substrate conformations. Whereas DnaK binds to molten globule-like forms, DnaJ recognizes a cryptic sequence in the extended state in an unanticipated force-dependent manner. By contrast, the synergetic coupling of the Hsp70 system exhibits a marked foldase behavior. Our results offer unprecedented molecular and kinetic insights into the mechanisms by which mechanical force finely regulates chaperone binding, directly affecting protein elasticity. PMID- 29487912 TI - Rehealable, fully recyclable, and malleable electronic skin enabled by dynamic covalent thermoset nanocomposite. AB - Electronic skin (e-skin) mimicking functionalities and mechanical properties of natural skin can find broad applications. We report the first dynamic covalent thermoset-based e-skin, which is connected through robust covalent bonds, rendering the resulting devices good chemical and thermal stability at service condition. By doping the dynamic covalent thermoset with conductive silver nanoparticles, we demonstrate a robust yet rehealable, fully recyclable, and malleable e-skin. Tactile, temperature, flow, and humidity sensing capabilities are realized. The e-skin can be rehealed when it is damaged and can be fully recycled at room temperature, which has rarely, if at all, been demonstrated for e-skin. After rehealing or recycling, the e-skin regains mechanical and electrical properties comparable to the original e-skin. In addition, malleability enables the e-skin to permanently conform to complex, curved surfaces without introducing excessive interfacial stresses. These properties of the e-skin yield an economical and eco-friendly technology that can find broad applications in robotics, prosthetics, health care, and human-computer interface. PMID- 29487913 TI - Metasurface optics for full-color computational imaging. AB - Conventional imaging systems comprise large and expensive optical components that successively mitigate aberrations. Metasurface optics offers a route to miniaturize imaging systems by replacing bulky components with flat and compact implementations. The diffractive nature of these devices, however, induces severe chromatic aberrations, and current multiwavelength and narrowband achromatic metasurfaces cannot support full visible spectrum imaging (400 to 700 nm). We combine principles of both computational imaging and metasurface optics to build a system with a single metalens of numerical aperture ~0.45, which generates in focus images under white light illumination. Our metalens exhibits a spectrally invariant point spread function that enables computational reconstruction of captured images with a single digital filter. This work connects computational imaging and metasurface optics and demonstrates the capabilities of combining these disciplines by simultaneously reducing aberrations and downsizing imaging systems using simpler optics. PMID- 29487914 TI - Direct single-molecule dynamic detection of chemical reactions. AB - Single-molecule detection can reveal time trajectories and reaction pathways of individual intermediates/transition states in chemical reactions and biological processes, which is of fundamental importance to elucidate their intrinsic mechanisms. We present a reliable, label-free single-molecule approach that allows us to directly explore the dynamic process of basic chemical reactions at the single-event level by using stable graphene-molecule single-molecule junctions. These junctions are constructed by covalently connecting a single molecule with a 9-fluorenone center to nanogapped graphene electrodes. For the first time, real-time single-molecule electrical measurements unambiguously show reproducible large-amplitude two-level fluctuations that are highly dependent on solvent environments in a nucleophilic addition reaction of hydroxylamine to a carbonyl group. Both theoretical simulations and ensemble experiments prove that this observation originates from the reversible transition between the reactant and a new intermediate state within a time scale of a few microseconds. These investigations open up a new route that is able to be immediately applied to probe fast single-molecule physics or biophysics with high time resolution, making an important contribution to broad fields beyond reaction chemistry. PMID- 29487916 TI - Transplantation of schistosome sporocysts between host snails: A video guide. AB - Schistosomiasis is an important parasitic disease, touching roughly 200 million people worldwide. The causative agents are different Schistosoma species. Schistosomes have a complex life cycle, with a freshwater snail as intermediate host. After infection, sporocysts develop inside the snail host and give rise to human dwelling larvae. We present here a detailed step-by-step video instruction in English, French, Spanish and Portuguese that shows how these sporocysts can be manipulated and transferred from one snail to another. This procedure provides a technical basis for different types of ex vivo modifications, such as those used in functional genomics studies. PMID- 29487917 TI - A dinitro-functionalized metal-organic framework featuring visual and fluorogenic sensing of H2S in living cells, human blood plasma and environmental samples. AB - Here, we describe a new dinitro-functionalized Zr(iv) MOF (MOF = metal-organic framework) having a UiO-66 (UiO = University of Oslo) framework topology called UiO-66-(NO2)2 (1). It shows fluorescence turn-on behavior towards H2S in simulated biological medium (HEPES buffer, pH = 7.4). By employing solvothermal conditions, 1 was successfully synthesized by reacting ZrCl4, H2BDC-(NO2)2 [H2BDC (NO2)2 = 2,5-dinitro-1,4-benzenedicarboxylic acid] ligand and benzoic acid with a molar ratio of 1 : 1 : 10 in DMF (DMF = N,N-dimethylformamide) at 130 degrees C for 24 h. The material was characterized by infrared spectroscopy, X-ray powder diffraction (XRPD) and thermogravimetric (TG) analyses. The compound not only displays highly sensitive fluorometric sensing of H2S but also exhibits a visually detectable colorimetric change towards H2S in daylight. Moreover, the high selectivity of 1' towards H2S is retained even when several other biologically intrusive species co-exist in the sensing medium. The limit of detection (LOD) of the compound is 14.14 MUM which lies in the range of the H2S concentration found in biological systems. Fluorescence microscopy studies on J774A.1 cells revealed the efficacy of the probe for imaging H2S in living cells. Moreover, this material can detect H2S in human blood plasma (HBP) and monitor the sulfide concentration in real water samples. All these features clearly demonstrate that the material has huge potential for highly selective sensing of both extracellular and intracellular H2S. PMID- 29487915 TI - Skin-interfaced systems for sweat collection and analytics. AB - Recent interdisciplinary advances in materials, mechanics, and microsystem designs for biocompatible electronics, soft microfluidics, and electrochemical biosensors establish the foundations for emerging classes of thin, skin interfaced platforms capable of capturing, storing, and performing quantitative, spatiotemporal measurements of sweat chemistry, instantaneous local sweat rate, and total sweat loss. This review summarizes scientific and technical progress in this area and highlights the implications in real time and ambulatory modes of deployment during physical activities across a broad range of contexts in clinical health, physiology research, fitness/wellness, and athletic performance. PMID- 29487924 TI - A macrocyclic silver polycarbene complex based on 1,2,4-triazole units: synthesis and postsynthetic modification. AB - Facile synthesis and postsynthetic modification of a rectangular 1,2,4-triazole based NHC macrocycle have been developed. The silver complex [Ag2(1)2](BF4)2 is derived from the corresponding triazole salt H2-1(BF4)2 upon reaction with Ag2O. The structure of the metallocyclic Ag-NHC complex [Ag2(1)2](BF4)2 was determined by single-crystal X-ray diffraction analysis. The metal-carbene template undergoes photodimerisation of its terminal cinnamic esters (UV irradiation, lambda = 365 nm) and generates a macrocyclic tetra (NHC) ligand. The desired tetra-1,2,4-triazole macrocycle was isolated in good yield by eliminating the metal ions from the photodimerisation product. All complexes were fully characterized by multinuclear NMR measurements (1H, 13C{1H}, COSY, HSQC and HMBC) and ESI mass spectroscopy. PMID- 29487925 TI - Efficient and robust photocatalysts based on {P2W18} modified by an Ag complex. AB - Two novel Wells-Dawson polyoxometalate-based compounds, (H2bimb)2[{Ag1.5(bimb)1.5}(P2W18O62)] (1), (H2bimb)2[Ag(bimb)]0.5[Ag(eim)2]0.5[P2W18O62].H3O (2) (bimb = 1,4-bis(imidazole-l yl)butane, eim = ethyl(imidazole)), have been synthesized under hydrothermal conditions and characterized by IR, thermogravimetric, XRD and single-crystal X ray diffraction analyses. In compound 1, two "U"-type bimb ligands are connected together viapi interactions of Ag-C to form a ring unit. The ring unit alternately links with the "Z"-type bimb via an Ag-N bond to form an infinite Z shaped {Ag4(bimb)3}n chain. The adjacent two {P2W18} clusters bonded to two Ag1 ions on two adjacent Z-shaped chains to form an inorganic dimer linker, which further joins the Z-shaped chains together, resulting in unique organic-inorganic alternating 2-D layers. Adjacent 2D layers are further aggregated together via Ag O bonds between the Dawson cluster and the Z-type chain on different layers to yield a 3-D network with a new topology {103}2{10}{4.102}4{42.104}2. In compound 2, the eim ligand was synthesized in situ from bimb, which acts as a small molecular ligand to alter the structure and adjust the catalytic activity of compound 2. Each Ag2 connects with the bimb ligand to form a linear {Ag(bimb)} chain. Adjacent chains are bonded together via the bimb ligand to generate a supermolecule 2-D layer, in which a Dawson dimer cluster as a guest molecule is embedded in both sides of the layer through supermolecule interactions. Such 2-D layers are further supported by Ag(eim)2 units leading to 3D supermolecule nets. In addition, the compounds exhibit excellent electrocatalytic behavior and better photocatalytic degradation capability for typical dyes than other Wells-Dawson POMs. PMID- 29487926 TI - Correction: Prediction of topological property in TlPBr2 monolayer with appreciable Rashba effect. AB - Correction for 'Prediction of topological property in TlPBr2 monolayer with appreciable Rashba effect' by Min Yuan et al., Phys. Chem. Chem. Phys., 2018, 20, 4308-4316. PMID- 29487929 TI - C5-Regioselective C-H fluorination of 8-aminoquinoline amides and sulfonamides with Selectfluor under metal-free conditions. AB - A novel and efficient regioselective C-H fluorination of 8-aminoquinoline amides and sulfonamides at the C5 position was achieved. Using Selectfluor as a "F" reagent and HOAc as an additive, the reaction proceeds smoothly via a radical pathway. This method features metal-free conditions, a broad substrate scope and operational simplicity. PMID- 29487930 TI - Flow-induced dissolution of femtoliter surface droplet arrays. AB - The dissolution of liquid nanodroplets is a crucial step in many applied processes, such as separation and dispersion in the food industry, crystal formation of pharmaceutical products, concentrating and analysis in medical diagnosis, and drug delivery in aerosols. In this work, using both experiments and numerical simulations, we quantitatively study the dissolution dynamics of femtoliter surface droplets in a highly ordered array under a uniform flow. Our results show that the dissolution of femtoliter droplets strongly depends on their spatial positions relative to the flow direction, drop-to-drop spacing in the array, and the imposed flow rate. In some particular cases, the droplet at the edge of the array can dissolve about 30% faster than the ones located near the centre. The dissolution rate of the droplet increases by 60% as the inter droplet spacing is increased from 2.5 MUm to 20 MUm. Moreover, the droplets close to the front of the flow commence to shrink earlier than those droplets in the center of the array. The average dissolution rate is faster for the faster flow. As a result, the dissolution time (Ti) decreases with the Reynolds number (Re) of the flow as Ti ? Re-3/4. The experimental results are in good agreement with the numerical simulations where the advection-diffusion equation for the concentration field is solved and the concentration gradient on the surface of the drop is computed. The findings suggest potential approaches to manipulate nanodroplet sizes in droplet arrays simply by dissolution controlled by an external flow. The obtained droplets with varying curvatures may serve as templates for generating multifocal microlenses in one array. PMID- 29487931 TI - Molecules for security measures: from keypad locks to advanced communication protocols. AB - The idea of using molecules in the context of information security has sparked the interest of researchers from many scientific disciplines. This is clearly manifested in the diversity of the molecular platforms and the analytical techniques used for this purpose, some of which we highlight in this Tutorial Review. Moreover, those molecular systems can be used to emulate a broad spectrum of security measures. For a long time, molecular keypad locks enjoyed a clear preference and the review starts off with a description of how these devices developed. In the last few years, however, the field has evolved into something larger. Examples include more complex authentication protocols (multi-factor authentication and one-time passwords), the recognition of erroneous procedures in data transmission (parity devices), as well as steganographic and cryptographic protection. PMID- 29487932 TI - A wafer-scale 1 nm Ni(OH)2 nanosheet with superior electrocatalytic activity for the oxygen evolution reaction. AB - A wafer-scale 1.4 nm ultrathin Ni(OH)2 nanosheet was synthesized by ionic layer epitaxy. This free-standing Ni(OH)2 nanosheet was directly used to catalyze the oxygen evolution reaction (OER). At a current density of 10 mA cm-2, the overpotential reached 295 mV (vs. RHE) in Fe-rich 1 M NaOH. This 1.4 nm Ni(OH)2 nanosheet showed a very high turnover frequency of 5.47 s-1 and a mass activity of more than 2 * 104 A g-1 at an overpotential of 300 mV. Such a high electrocatalytic mass activity of the Ni(OH)2 nanosheet was more than 2 orders of magnitude higher than those of typical OER catalysts. The capability of producing wafer-scale nanometer-thick nanosheets offers a promising strategy to improve the mass efficiency of electrochemical catalysts, which is particularly valuable for preserving rare and precious catalyst materials. PMID- 29487933 TI - Synthesis, structural characterization and NMR studies of group 10 metal complexes with macrocyclic amine N-heterocyclic carbene ligands. AB - A series of Ni(ii), Pd(ii) and Pt(ii) complexes [ML][PF6]2 [L = L1, M = Ni (1), Pd (2), Pt (3); L = L2, M = Ni (4), Pd (5), Pt (6)] and [Pt(L2)(acac)] (7) have been prepared by the reactions of two tetradentate macrocyclic amine-NHC ligand precursors, [H2L1][PF6]2 and [H2L2][PF6]2, with Ni(OAc)2.4H2O, Pd(OAc)2 and Pt(acac)2 in the presence of NaOAc. Complex 7 is isolated along with 6 from the same reaction between [H2L2][PF6]2 and Pt(acac)2. There are two atropisomers in 1 3 and two achiral conformers in 4-6. The crystal structures of 1-3 and one conformer of 4-6 (4a-6a) have been determined by single-crystal X-ray diffraction studies. The metal ion is found to reside in the cavity of the macrocyclic ring and adopts a square-planar configuration. Detailed NMR studies including variable temperature NMR spectroscopy reveal a dynamic interconverting process between two atropisomers of 1-3 in the solutions via a ring twisting mechanism. Two conformers in the equilibrated solution of 4-6, probably arising from the orientation of two amine N-H bonds with respect to the coordination plane, exchange slowly. Time-dependent 1H NMR spectra show that one conformer (4a-6a) in solution converts into the other (4b-6b) via the inversion of the nitrogen atom. PMID- 29487934 TI - Bulk polymer nanocomposites with preparation protocol governed nanostructure: the origin and properties of aggregates and polymer bound clusters. AB - Polymer nanocomposites (PNCs) hold great promise as future lightweight functional materials processable by additive manufacturing technologies. However, their rapid deployment is hindered by their performance depending strongly on the nanoparticle (NP) spatial organization. Therefore, the ability to control nanoparticle dispersion in the process of PNC preparation is a crucial prerequisite for utilizing their potential in functional composites. We report on the bulk processing technique of tailored NP spatial organization in a model glass forming polymer matrix controlled by structural and kinetic variables of the preparation protocol. Namely, we studied the impact of solvent on the NP arrangement, which was already known as a tuning parameter of the solid-state structure. We emphasized the qualitative differences between "poorly dispersed" NP arrays, which, by combination of rheological assessment and structural analysis (TEM, USAXS), we identified as chain bound clusters and aggregates of either thermodynamic or kinetical origin. They are characterized by substantially distinct formation kinetics and mismatched properties compared to each other and individually dispersed NPs. We quantitatively linked all the currently observed types of NP dispersion with their rheological properties during the solution blending step and the amount of polymer adsorption and depletion attraction. We propose the ratio of NP-polymer and NP-solvent enthalpy of adsorption as a parameter capable of the quantitative prediction of NP arrangement in systems similar to our current model PNC. Finally, we bring forth the comparison of glass transition temperatures to further demonstrate the importance of NP spatial organization in PNCs. PMID- 29487938 TI - Defect formation dynamics in curved elastic surface crystals. AB - Topological defects shape the material and transport properties of physical systems. Examples range from vortex lines in quantum superfluids, defect-mediated buckling of graphene, and grain boundaries in ferromagnets and colloidal crystals, to domain structures formed in the early universe. The Kibble-Zurek (KZ) mechanism describes the topological defect formation in continuous non equilibrium phase transitions with a constant finite quench rate. Universal KZ scaling laws have been verified experimentally and numerically for second-order transitions in planar Euclidean geometries, but their validity for non-thermal transitions in curved and topologically nontrivial systems still poses open questions. Here, we use recent experimentally confirmed theory to investigate topological defect formation in curved elastic surface crystals formed by stress quenching a bilayer material. For both spherical and toroidal crystals, we find that the defect densities follow KZ-type power laws. Moreover, the nucleation sequences agree with recent experimental observations for spherical colloidal crystals. Our results suggest that curved elastic bilayers provide an experimentally accessible macroscopic system to study universal properties of non thermal phase transitions in non-planar geometries. PMID- 29487936 TI - Multi-heteroatom doped carbon coated Na3V2(PO4)3 derived from ionic liquids. AB - Multi-heteroatom (N, S and F) doped carbon coated Na3V2(PO4)3 (labeled as NVP/C ILs) derived from an ionic liquid 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([EMIM]TF2N) has been successfully fabricated. The as-prepared Na3V2(PO4)3 particles are well dispersed and closely coated with a multi-heteroatom (N, S and F) doped carbon layer. As a cathode for sodium-ion batteries, the NVP/C-ILs electrode exhibits high reversible specific capacity (117.5 mA h g-1 at 1C), superior rate performance (93.4 mA h g-1 at 10C) and excellent cycling stability (~95% capacity retention ratio at 10C over 1000 cycles). The impressive electrochemical performance of NVP/C-ILs can be attributed to effectively conductive networks for electrons and Na+ ions induced by a joint effect of N, S and F doping on carbon. The use of multi-heteroatom doped carbon coated Na3V2(PO4)3 provides a facile and effective strategy for the fabrication of high performance electrode materials with low intrinsic electrical conductivity. PMID- 29487939 TI - Nano-graphene oxide-manganese dioxide nanocomposites for overcoming tumor hypoxia and enhancing cancer radioisotope therapy. AB - While radiotherapy (RT) is commonly used in clinics for cancer treatment, the therapeutic efficiency is not satisfactory owing to the existence of the hypoxic tumor microenvironment which seriously affects the efficiency of RT. Herein, we design polyethylene glycol (PEG)-modified reduced nano-graphene oxide-manganese dioxide (rGO-MnO2-PEG) nanocomposites to trigger oxygen generation from H2O2 to reduce the tumor hypoxic microenvironments. We use the radioisotope, 131I labeled rGO-MnO2-PEG nanocomposites as therapeutic agents for in vivo tumor radioisotope therapy (RIT), achieving excellent tumor killing and further enhancing the therapeutic efficiency of RIT. More importantly, the dissolution of MnO2 under acidic conditions and the redox process during the catalytic pathway of H2O2 decomposition in the cellular microenvironment direct to the production of an enormous amount of Mn2+ which has been used as a contrast agent for magnetic resonance imaging (MRI). Our proposed work provides a strategy to trigger oxygen formation via an internal stimulus to enhance imaging-guided RIT efficiency. PMID- 29487940 TI - Shift work schedule and night work load: Effects on body mass index - a four-year longitudinal study. AB - Objectives The aim of this study was to investigate changes in body mass index (BMI) between different work schedules and different average number of yearly night shifts over a four-year follow-up period. Methods A prospective study of Norwegian nurses (N=2965) with different work schedules was conducted: day only, two-shift rotation (day and evening shifts), three-shift rotation (day, evening and night shifts), night only, those who changed towards night shifts, and those who changed away from schedules containing night shifts. Paired student's t-tests were used to evaluate within subgroup changes in BMI. Multiple linear regression analysis was used to evaluate between groups effects on BMI when adjusting for BMI at baseline, sex, age, marital status, children living at home, and years since graduation. The same regression model was used to evaluate the effect of average number of yearly night shifts on BMI change. Results We found that night workers [mean difference (MD) 1.30 (95% CI 0.70-1.90)], two shift workers [MD 0.48 (95% CI 0.20-0.75)], three shift workers [MD 0.46 (95% CI 0.30-0.62)], and those who changed work schedule away from [MD 0.57 (95% CI 0.17-0.84)] or towards night work [MD 0.63 (95% CI 0.20-1.05)] all had significant BMI gain (P<0.01) during the follow-up period. However, day workers had a non-significant BMI gain. Using adjusted multiple linear regressions, we found that night workers had significantly larger BMI gain compared to day workers [B=0.89 (95% CI 0.06-1.72), P<0.05]. We did not find any significant association between average number of yearly night shifts and BMI change using our multiple linear regression model. Conclusions After adjusting for possible confounders, we found that BMI increased significantly more among night workers compared to day workers. PMID- 29487941 TI - Capacity-building in clinical skills of rehabilitation workforce in low- and middle-income countries. AB - OBJECTIVE: Despite the prevalence of disability in low-and middle-income countries, the clinical skills of the rehabilitation workforce are not well described. We report health professionals' perspectives on clinical skills in austere settings and identify context-specific gaps in workforce capacity. METHODS: A cross-sectional pilot survey (Pakistan, Morocco, Nigeria, Malaysia) of health professionals' working in rehabilitation in hospital and community settings. A situational-analysis survey captured assessment of clinical skills required in various rehabilitation settings. Responses were coded in a line-by line process, and linked to categories in domains of the International Classification of Functioning, Disability and Health (ICF). RESULTS: Respondents (n = 532) from Pakistan 248, Nigeria 159, Morocco 93 and Malaysia 32 included the following: physiotherapists (52.8%), nurses (8.8%), speech (5.3%) and occupational therapists (8.5%), rehabilitation physicians (3.8%), other doctors (5.5%) and prosthetist/orthotists (1.5%). The 10 commonly used clinical skills reported were prescription of: physical activity, medications, transfer techniques, daily-living activities, patient/carer education, diagnosis/screening, behaviour/cognitive interventions, comprehensive patient care, referrals, assessments and collaboration. There was significant overlap in skills listed irrespective of profession. Most responses linked with ICF categories in activities/participation and personal factors. CONCLUSION: The core skills identified reflect general rehabilitation practice and a task-shifting approach, to address shortages of health workers in low-and middle-income countries. PMID- 29487942 TI - Assessing of imagined and real expanded Timed Up and Go tests in patients with chronic stroke: A case-control study. AB - OBJECTIVE: To assess temporal congruence (the difference in performance-time and time to imagine) between the sub-tasks of the Expanded Timed Up and Go (ETUG) and imagined ETUG (iETUG) tests in patients with hemiparesis following unilateral hemispheric stroke, and to compare the results with those for with healthy subjects. DESIGN: Case-controlled study. Subject/patients: Twenty patients with chronic stroke and 20 healthy subjects. METHODS: TUG, ETUG and iETUG test performance times were recorded for all participants. Temporal congruence was calculated with the following formula: (ETUG-iETUG)/[(ETUG+iETUG)/2]*100. RESULTS: Patients' performances were slower than those of healthy subjects for all 5 sub-tasks of the TUG, ETUG and iETUG tests. However, there was no significant difference in temporal congruence between healthy subjects and patients. Intragroup analysis showed significant differences between the executed and the imagined conditions for both groups for the "walking", "turn around" and "sitting" phases (healthy subjects p = 0.01, p = 0.03, p = 0.03, and patients p = 0.01, p = 0.003, p = 0.003, respectively). CONCLUSION: Temporal congruence was similar for healthy subjects and patients for all sub-tasks of the ETUG test. Moreover, temporal congruence was reduced for the same sub-tasks of the ETUG test in patients and healthy subjects. This suggests that the motor imagery involved the same cerebral structures in both groups, probably including the cerebellum, since it was intact in all patients. PMID- 29487943 TI - Rasch analysis of the UK Functional Assessment Measure in patients with complex disability after stroke. AB - OBJECTIVES: To determine whether the UK Functional Assessment Measure (UK FIM+FAM) fits the Rasch model in stroke patients with complex disability and, if so, to derive a conversion table of Rasch-transformed interval level scores. METHODS: The sample included a UK multicentre cohort of 1,318 patients admitted for specialist rehabilitation following a stroke. Rasch analysis was conducted for the 30-item scale including 3 domains of items measuring physical, communication and psychosocial functions. The fit of items to the Rasch model was examined using 3 different analytical approaches referred to as "pathways". RESULTS: The best fit was achieved in the pathway where responses from motor, communication and psychosocial domains were summarized into 3 super-items and where some items were split because of differential item functioning (DIF) relative to left and right hemisphere location (chi2 (10) = 14.48, p = 0.15). Re scoring of items showing disordered thresholds did not significantly improve the overall model fit. CONCLUSION: The UK FIM+FAM with domain super-items satisfies expectations of the unidimensional Rasch model without the need for re-scoring. A conversion table was produced to convert the total scale scores into interval level data based on person estimates of the Rasch model. The clinical benefits of interval-transformed scores require further evaluation. PMID- 29487944 TI - Overexpression of Amyloid Precursor Protein Promotes the Onset of Seborrhoeic Keratosis and is Related to Skin Ageing. AB - Seborrhoeic keratosis (SK) is an age-related skin disease. Amyloid precursor protein (APP) plays an important role in the pathogenesis of age-related Alzheimer's disease. The aim of this study was to elucidate the expression characteristics of APP in SK tissues (n = 50), and explore whether the production of APP is related to the onset of SK and skin ageing, including ultraviolet (UV) induced ageing, as observed in normal skin (n = 79). The results of immunohistochemistry, Western blotting and quantitative real-time PCR showed that APP and its downstream products (i.e. amyloid-beta42) were more highly expressed in SK than in paired adjacent normal skin tissues. In contrast, the expression of its key secretase (i.e. beta-secretase1) was generally low. Furthermore, APP expression was higher in UV-exposed than non-exposed skin sites, and expression in the older age group (61-85 years) was greater than that in the younger age group (41-60 years) in SK tissues (p<0.05). APP expression correlated positively with age in epidermis (p<0.05), but not in dermis. These findings suggest that overexpression of APP may promote the onset of SK and is a marker of skin ageing and UV damage. Further research will elucidate whether therapeutic mitigation of increased levels of APP in the skin might delay the onset of SK and skin ageing. PMID- 29487945 TI - Duration of Psoriatic Skin Disease as Risk Factor for Subsequent Onset of Psoriatic Arthritis. AB - It is unclear whether psoriasis is a progressive disease that requires early aggressive intervention. This population-based study identified patients with psoriasis and psoriatic arthritis (PsA). Survival analysis and Kaplan-Meier life table techniques were used. The study comprised 10,011 psoriasis patients (severe n = 4,618), and 1,269 patients also had PsA. Incidence of PsA increased with duration of cutaneous symptoms (p = 0.0001). Psoriasis diagnosed before age 20 or 30 years, respectively, suggested a lower risk of PsA than psoriasis diagnosed after age 50 years, yet age at first cutaneous symptoms did not predict development of PsA. No clear association with disease severity was found. PsA incidence appeared stable with longer duration of psoriasis, but further data are needed to firmly establish the relationship with age of psoriasis onset. PMID- 29487946 TI - Nanostring Analysis of Skin Biopsies from Patients with Henoch-Schonlein Purpura Reveals Genes Associated with Pathology and Heterogeneity in the Disease Process. PMID- 29487947 TI - Simultaneous Induction of Benign Condyloma and High-grade Anal Dysplasia Induced by Low-risk Human Papillomavirus Type 42. PMID- 29487948 TI - Economic evaluation of a bio-psycho-social intervention for comorbid disorders in a traumatized population in post-war Kosovo. AB - OBJECTIVE: Post-hoc economic evaluation of a bio-psycho-social intervention in post-war Kosovo from a societal perspective. DESIGN: Cost-effectiveness analysis, cost-utility analysis, and partial cost-benefit analysis using data from a randomized controlled trial. PATIENTS: Thirty-four torture/war victims with comorbid conditions enrolled in 2012-2013. METHODS: Participants were randomly assigned to an "intervention" and a "waiting-list" group. Changes in mental, emotional and physical health and functional impairment were assessed before and after treatment, along with increase in labour income as a proxy for productivity gain. The cost of an extra unit of effectiveness and an additional quality adjusted life year were calculated. RESULTS: The total cost per participant was ?1,322 including, or ?1,019 excluding, research costs. Wide variations in costs of changes in mental, emotional and physical effectiveness were demonstrated. Multidisciplinary intervention resulted in functional improvement at a cost of ?10,508 per quality-adjusted life year gained. With a mean monthly income increase to ?133 (18%) after intervention, the intervention cost per participant would be equal to the total increase in monthly income after 4-5 years, assuming the increased level is maintained. CONCLUSION: Socio-economic benefit associated with quality-adjusted life year gain is shown, although the cost of an additional quality-adjusted life year is above the World Health Organization cost effectiveness threshold. PMID- 29487949 TI - [Watchful waiting and active surveillance of small renal masses]. AB - The incidence of small renal masses <=4 cm is increasing due to the widespread use of cross-sectional imaging. The majority of these represent indolent forms, but the risk for developing metastases is reported in up to 6% of patients. Particularly in old and comorbid patients surgery might be harmful overtreatment. Thus, there is an increasing demand to establish oncologically safe active surveillance protocols. Radiographic or biopsy-based biological markers to appropriately designate candidates for active surveillance are currently the focus of research. PMID- 29487951 TI - [Content of a weekly morbidity and mortality conference in visceral surgery]. AB - BACKGROUND: Morbidity and mortality (M&M) conferences are essential instruments for quality improvement in surgical departments; however, publications concerning the detailed contents of M&M conferences are rare and have not been published in the German language. OBJECTIVE: Detailed analysis of the content of a weekly M&M conference in a department of general and visceral surgery. MATERIAL AND METHODS: Data from a weekly M&M conference were prospectively collected. Epidemiological data, diagnosis, type of surgery, morbidity, postoperative course and mortality were documented for each patient. Type (surgical vs. medicinal) and severity (I-V according to Clavien-Dindo classification) of complications were analyzed. RESULTS: From 1 January 2010 to 31 December 2014 a total of 761 out of 11,470 patients with a mean age of 62.2 (15.9) years were discussed in the M&M conferences. Of the M&M patients 39.4% were female, 88.9% showed surgical complications while 28.9% were diagnosed with a medical complication and 91 patients (12.0%) died. Complications were classified as Clavien-Dindo I: 27.9%, II: 10.5%, III: 37.7%, IV: 12% and V: 12.0%. Most surgical complications were classified as Clavien-Dindo I (30.0%) and Clavien-Dindo III (40.9%), medical complications were most often classified as Clavien-Dindo IV (29.6%) and V (34.6%). Wound healing impairment (41%), pulmonary complications (16.6%), anastomotic leakage (15.6%), septic (8.9%) and cardiac (8.0%) complications were discussed most often. Cardiac, pulmonary and septic complications were the main cause of morbidity in deceased patients. CONCLUSION: The M&M conferences display a morbidity profile of each surgical department. Depending on the speciality and focus of a surgical department, the content of the M&M conferences will vary. Detailed knowledge about the content of M&M conferences enable specific measures to be taken to improve quality and patient safety. PMID- 29487950 TI - Exchange of genetic material: a new paradigm in bone cell communications. AB - An emerging concept in intercellular communication in mammals is that communication can be mediated by exchange of genetic material, mainly in the form of RNAs. In this review, we discuss recent studies that describe the trafficking of genetic material with a focus on bone cell communication. Three major carriers are discussed: gap junctions, protein-binding complexes, and genetic material exchange mediated by extracellular vesicles. While protein-level exchange has been well documented, no review has summarized the novel paradigm of cell-to-cell communication by genetic information exchange in bone tissues or its biological relevance in terms of bone homeostasis and bone-related diseases. The purpose of this review is to promote further understanding of this novel discovery regarding bone cell communication and provide references for further investigations. PMID- 29487954 TI - [Full relaxation: magic bullet or marketing gag?] PMID- 29487953 TI - FAM13A and POM121C are candidate genes for fasting insulin: functional follow-up analysis of a genome-wide association study. AB - AIMS/HYPOTHESIS: By genome-wide association meta-analysis, 17 genetic loci associated with fasting serum insulin (FSI), a marker of systemic insulin resistance, have been identified. To define potential culprit genes in these loci, in a cross-sectional study we analysed white adipose tissue (WAT) expression of 120 genes in these loci in relation to systemic and adipose tissue variables, and functionally evaluated genes demonstrating genotype-specific expression in WAT (eQTLs). METHODS: Abdominal subcutaneous adipose tissue biopsies were obtained from 114 women. Basal lipolytic activity was measured as glycerol release from adipose tissue explants. Adipocytes were isolated and insulin-stimulated incorporation of radiolabelled glucose into lipids was used to quantify adipocyte insulin sensitivity. Small interfering RNA-mediated knockout in human mesenchymal stem cells was used for functional evaluation of genes. RESULTS: Adipose expression of 48 of the studied candidate genes associated significantly with FSI, whereas expression of 24, 17 and 2 genes, respectively, associated with adipocyte insulin sensitivity, lipolysis and/or WAT morphology (i.e. fat cell size relative to total body fat mass). Four genetic loci contained eQTLs. In one chromosome 4 locus (rs3822072), the FSI-increasing allele associated with lower FAM13A expression and FAM13A expression associated with a beneficial metabolic profile including decreased WAT lipolysis (regression coefficient, R = -0.50, p = 5.6 * 10-7). Knockdown of FAM13A increased lipolysis by ~1.5-fold and the expression of LIPE (encoding hormone-sensitive lipase, a rate-limiting enzyme in lipolysis). At the chromosome 7 locus (rs1167800), the FSI-increasing allele associated with lower POM121C expression. Consistent with an insulin-sensitising function, POM121C expression associated with systemic insulin sensitivity (R = -0.22, p = 2.0 * 10-2), adipocyte insulin sensitivity (R = 0.28, p = 3.4 * 10-3) and adipose hyperplasia (R = -0.29, p = 2.6 * 10-2). POM121C knockdown decreased expression of all adipocyte-specific markers by 25 50%, suggesting that POM121C is necessary for adipogenesis. CONCLUSIONS/INTERPRETATION: Gene expression and adipocyte functional studies support the notion that FAM13A and POM121C control adipocyte lipolysis and adipogenesis, respectively, and might thereby be involved in genetic control of systemic insulin sensitivity. PMID- 29487955 TI - [Holistic treatment of humans in internal medicine]. PMID- 29487956 TI - Trace Metals Bioavailability Approach in Intertidal Estuarine Sediments and Bioaccumulation in Associated Nereidid Polychaetes. AB - Polychaetes that inhabit the sediments of estuaries are important prey to many species all around the world. Laeonereis acuta is a deposit feeder living in estuaries along the Atlantic coast of South America. Ragworms accumulate metals from the sediment, and represent a means of entry of sediment contaminants into the trophic network. The concentrations of Zn, Pb, Cu, Cr and Cd were determined in polychaetes and sediments (total and extractable) from six estuarine beaches of Rio de la Plata. The associations between total and extractable concentrations in sediment and accumulated concentrations in L. acuta were analyzed. Sediments extracted by weak acid digestion appear to be a good proxy model of bioavailable metal fractions in the sediment. The association between metals in sediment and polychaetes denotes the role of L. acuta as an important link in metal trophic transfer from sediments to potential fish and bird predators of the worm. PMID- 29487957 TI - Treatment of proximal phalanx fractures: transarticular pinning the metacarpophalangeal joint or cross pinning from the base of the proximal phalanx a prospective study. AB - INTRODUCTION: For extraarticular proximal phalanx fractures, two methods are employed, transarticular fixation in which the metacarpophalangeal joint is crossed and the extraarticular method in which the pins are introduced through the base of the proximal Phalanx. MATERIALS AND METHODS: This study was a prospective one on patients with proximal phalanx transverse or short oblique fractures. In one of the groups we used parallel pins from metacarpal head through MCP joint to proximal phalanx. In the second, we used two cross pins from proximal phalanx the base of the proximal phalanx to fix the fracture. We evaluated metacarpophalangeal, proximal and distal interphalangeal joints active range of motion and how long it took the patient to resume their daily activities and work without difficulty, as well as post-operative complications such as wound infection, malunion, and nonunion in 3 and 6 months follow-up. RESULTS: Ultimately, 61 people entered the study, 29 in the parallel pins and 31 in the cross pins group. There was no significant difference between the two groups, but the improvement in all of the joints range of motion showed a statistically significant difference (P < 0.0001) from the 3 to 6 months follow-up. The final range of motion showed an inverse correlation with age of the patient (P < 0.05). Most of the patients were in the excellent grade of range of motion class and no serious complication was observed in any of them. CONCLUSION: The results of treatment in proximal phalangeal fractures with both methods were comparable and so the surgeon may select each based on the experience and training. PMID- 29487958 TI - Use of Chemical Indicators and Bioassays in Bottom Sediment Ecological Risk Assessment. AB - This study is was designed to assess the ecological risk associated with chemical pollution caused by heavy metals and PAHs on the basis of their ecotoxicological properties in sediments collected from the Rzeszow dam reservoir (Poland). The sediment samples were collected from three sampling stations: S1-inlet, backwater station, S2-middle of reservoir, S3 outlet, near the dam. The sediments' toxicity was evaluated using a battery of bioassays (Phytotoxkit, Phytotestkit, Ostracodtoxkit F, and Microtox). The highest content of metals (120.5 mg Zn; 22.65 mg Pb; 8.20 mg Cd ? kg-1 dw) and all PAHs (?9361 MUg ? kg-1 dw) in sediments was found at station S1. The lowest content of metals (86.72 mg Zn; 18.07 mg Cu; 17.20 mg Pb; 3.62 mg Cu; 28.78 mg Ni; 30.52 mg Cr ? kg-1 dw) and PAHs (?4390 MUg ? kg-1 dw) was found in the sediment from station S2. The ecological risk assessment of the six metals and eight PAHs revealed a high potential toxicity in sediments from stations S1 (PECq = 0.69) and S3 (PECq = 0.56) and a low potential toxicity in sediments from station S2 (PECq = 0.38). The studies also showed the actual toxicity of sediments for the test organisms. The sediment pore water was least toxic compared to the whole sediment: solid phases > whole sediment > pore water. The most sensitive organism for metals and PAHs in bottom sediments was Lepidium sativum, and in pore water-Sorghum saccharatum. The concentration of metals and PAHs in bottom sediments generally did not affect the toxicity for other organisms. Clay content and organic C content are likely to be important factors, which control heavy metal and PAH concentrations in the sediments. Data analysis by PCA found the same origin of metals as well as PAHs-mainly anthropogenic sources. The obtained information demonstrated the need to integrate ecotoxicological and chemical methods for an appropriate ecological risk assessment. PMID- 29487959 TI - Clinical pharmacology in Stockholm 50 years-report from the jubilee symposium. PMID- 29487960 TI - [Topical therapy for atopic eczema]. AB - Atopic eczema is a chronic recurrent inflammatory skin disease characterized by intensive pruritus and a high burden of disease. Based on a genetically determined skin barrier dysfunction, xerosis cutis and a tendency towards microbial skin infections are the leading clinical features. Mild and moderate disease manifestations are common, and usually treated with topical agents only. Treatment concepts are usually based on a combination of (i) topical basic therapy consisting of skin cleansing and barrier stabilizing emollients and (ii) topical anti-inflammatory therapy of visible skin lesions with topical corticosteroids and topical calcineurin inhibitors. Proactive therapy of the commonly affected and usually relapsing areas of skin is an important therapeutic option for long-term maintenance treatment of moderate to severe disease. Patients should be actively involved in planning of treatment, which should be adapted to individual patient factors such as age, involved body areas, type of skin lesions, as well as seasonal and climatic factors. New promising treatment options including topical phosphodiesterase inhibitors and topical Janus kinase inhibitors are currently being evaluated in clinical trials and may become a future treatment option for atopic eczema. This review article summarizes the current topical treatment options and new perspectives in the topical therapy of atopic eczema. PMID- 29487961 TI - [Increased revenues from secondary diagnoses : A comparison from dermatology, ophthalmology, and infectious diseases]. AB - BACKGROUND: Hospital revenues generated by diagnosis-related groups (DRGs) are in part dependent on the coding of secondary diagnoses. Therefore, more and more hospitals trust specialized coders with this task, thereby relieving doctors from time-consuming administrative burdens and establishing a highly professionalized coding environment. However, it is vastly unknown if the revenues generated by the coders do indeed exceed their incurred costs. METHODS: Coding data from the departments of dermatology, ophthalmology, and infectious diseases from Rostock University Hospital from 2007-2016 were analyzed for the effects of secondary diagnoses on the resulting DRG, i. e., hospital charges. RESULTS: Ophthalmological case were highly resistant to the addition of secondary diagnoses. In contrast, adding secondary diagnoses to cases from infectious diseases resulted in 15% higher revenues. Although dermatological and infectious cases share the same sensitivity to secondary diagnoses, higher revenues could only rarely be realized in dermatology, probably owing to a younger, less multimorbid patient population. CONCLUSION: Except for ophthalmology, trusting specialized coders with clinical coding generates additional revenues through the coding of secondary diagnoses which exceed the costs for employing these coders. PMID- 29487962 TI - [Quality of dermatological case reports in German-speaking journals : The Case Reporting (CARE) Guideline]. PMID- 29487963 TI - [Foot and ankle tumours : Part I: overview of incidence, diagnosis and staging of pedal tumours]. AB - CLINICAL ISSUE: Foot and ankle tumours are rare. Part I of this paper provides a survey about tumour distribution regarding age and location of benign and malignant bone and soft tissue tumours. STANDARD RADIOLOGICAL METHODS: All diagnostic radiological procedures are used for the diagnostic work-up of pedal tumours, in particular plain radiography, MRI, and ultrasonography. METHODICAL INNOVATIONS: Dual-energy CT proves to be a valuable (differential) diagnostic tool in identifying urate dihydrate crystals. PERFORMANCE: There are no reliable numbers available on accuracy of the aforementioned diagnostic procedures regarding tumour detection and identification. This is particularly true for soft tissue tumours which are small and well-defined, thus requiring histological clarification. ACHIEVEMENTS: To evaluate pedal tumours correctly and reasonably, a full range of radiological diagnostics should be employed. Neither plain radiography alone nor a stand-alone MRI examination-depending on the tumour site are sufficient to characterize such tumours including staging. PRACTICAL RECOMMENDATIONS: Plain radiography remains the first-choice imaging modality. Ultrasonography is superior to reliably detect and identify ganglion cysts. MRI, however, continues to remain the upmost diagnostic modality of choice for evaluating foot and ankle tumours. CT possesses unchallanged diagnostic power to assess osseous changes. Bone scintigraphy (including SPECT-CT) and FDG-PET imaging are used when multifocal distribution or metastatic disease are suspected or to detect avidity of the pedal lesions, respectively. PMID- 29487964 TI - [Use of antiepileptic drugs during breastfeeding : What do we tell the mother?] AB - BACKGROUND: Knowledge about the passage of various antiepileptic drugs into breast milk and its consequences for the infant is limited. Faced with this uncertainty, breastfeeding is often discouraged for these patients. The aim of this study was to comprehensively review the available data regarding antiepileptic drugs during breastfeeding, to compare these data with information provided by the summary of product characteristics (SmPCs), and to provide recommendations for the use of these drugs in breastfeeding women. MATERIAL AND METHODS: We performed a systematic literature review on breastfeeding data for 23 antiepileptic drugs. A breastfeeding compatibility score was developed and validated. The estimated score based on the literature review was compared with the estimated score based on recommendations provided by the SmPCs. RESULTS: We identified 75 articles containing exposure and safety data for 15 antiepileptic agents during breastfeeding. The comparison between the score values based on the literature review and on the SmPCs revealed a very low degree of concordance (weighted kappa: 0.08). CONCLUSION: Phenobarbital, primidone, carbamazepine, valproate and levetiracetam are probably compatible with breastfeeding. Treatment with phenytoin, ethosuximide, clonazepam, oxcarbazepine, vigabatrin, topiramate, gabapentin, pregabalin, lamotrigine and zonisamide can be authorized during breastfeeding, provided breastfed infants are carefully monitored for side effects. Since data on the use of mesuximide, clobazam, rufinamide, felbamate, lacosamide, sultiame, perampanel and retigabine are insufficient to adequately assess the risk for breastfed infants, use in breastfeeding women is in principle not recommended and should be carefully evaluated on a case by case basis. In practice, a risk-benefit analysis should be performed for each mother under antiepileptic treatment wishing to breastfeed her child, so that individual risk factors can adequately be taken into account when counseling the patient. PMID- 29487965 TI - Increased risk of symptomatic upper-extremity venous thrombosis with multiple peripherally inserted central catheter insertions in pediatric patients. AB - BACKGROUND: Peripherally inserted central catheters (PICCs) are associated with superficial and deep venous thrombosis of the arm. OBJECTIVE: The purpose of this study was to analyze the sequelae of repeated upper limb PICC insertions in children, in terms of the frequency of upper limb thrombosis in this patient group. MATERIALS AND METHODS: The study population included all children who underwent their first successful arm PICC insertion between January 2010 and December 2015. We included subsequent ipsilateral arm PICCs in the analysis. Patients were followed until March 2016 or until any alternative central venous line insertion. For each PICC insertion, we collected demographic variables and line characteristics. We correlated all symptomatic deep and superficial thromboses of the arm with the PICC database. RESULTS: Applying inclusion and exclusion criteria, 2,180 PICCs remained for analysis. We identified first, second, third and fourth PICC insertions in the same arm in 1,955, 181, 38 and 6 patients, respectively. In total there were 57 upper body deep symptomatic thrombotic events. An increasing odds ratio was seen with higher numbers of PICC insertions, which was significant when comparing the first with the third and fourth PICC insertions in the same arm (odds ratio [OR] 6.00, 95% confidence interval [CI] 2.25-16.04, P=0.0004). Double-lumen PICCs were associated with a significantly higher risk of thrombosis than single lumen (OR 2.77, 95% CI 1.72 4.47, P=0.0003). CONCLUSION: Repetitive PICC insertions in the same arm are associated with an increased risk of symptomatic thrombosis. Double-lumen PICCs are associated with a higher risk of thrombosis compared to single-lumen lines. PMID- 29487966 TI - Mechanisms of antifreeze proteins investigated via the site-directed spin labeling technique. AB - The site-directed spin labeling (SDSL) technique was used to examine the antifreeze mechanisms of type-I antifreeze proteins (AFPs). The effects on the growth of seed ice crystals by the spin-label groups attached to different side chains of the AFPs were observed, and the states of water molecules surrounding the spin-label groups were probed via analyses of variable-temperature (VT) dependent electron paramagnetic resonance (EPR) spectra. The first set of experiments revealed the antifreeze activities of the spin-labeled AFPs at the microscopic level, while the second set of experiments displayed those at the molecular level. The experimental results confirmed the putative ice-binding surface (IBS) of type-I AFPs. The VT EPR spectra indicate that type-I AFPs can inhibit the nucleation of seed ice crystals down to ~ - 20 degrees C in their aqueous solutions. Thus, the present authors believe that AFPs protect organisms from freezing damage in two ways: (1) inhibiting the nucleation of seed ice crystals, and (2) hindering the growth of seed ice crystals once they have formed. The first mechanism should play a more significant role in protecting against freezing damage among organisms living in cold environments. The VT EPR spectra also revealed that liquid-like water molecules existed around the spin labeled non-ice-binding side chains of the AFPs frozen within the ice matrices, and ice surrounding the spin-label groups melted at subzero temperatures during the heating process. This manuscript concludes with the proposed model of antifreeze mechanisms of AFPs based on the experimental results. PMID- 29487967 TI - Visual mismatch negativity is unaffected by top-down prediction of the timing of deviant events. AB - Visual mismatch negativity (VMMN) is an event-related brain potential component that is automatically elicited by infrequent (deviant) stimuli that are inserted among frequent (standard) stimuli (i.e., an oddball sequence). Although the elicitation of VMMN is basically determined in a stimulus-driven manner, it can be modulated by top-down control. In a previous study using a "patterned" oddball sequence, where deviant (D) stimuli were regularly inserted among standard (S) stimuli (i.e., repetitions of an SSSSD pattern), VMMN was largely reduced when participants noticed the SSSSD pattern and actively predicted both the identity and timing of the deviant stimuli compared to when they did not notice the SSSSD pattern and did not form such active prediction. The present study further investigated whether or not active prediction of only the timing of deviant stimuli is sufficient for the reduction of VMMN. With the patterned oddball sequence with one deviant (here, deviant stimuli were fixed throughout the block), VMMN was reduced when the participants noticed the SSSSD pattern and actively predicted both the identity and timing of deviant stimuli (i.e., replication of the previous finding). In contrast, with the patterned oddball sequence with two deviants (deviant stimuli were randomly varied between two possibilities), VMMN was not significantly reduced when the participants noticed the SSSSD pattern and actively predicted only the timing of deviant stimuli. These results suggest that active prediction of only the timing of deviant stimuli is not sufficient to reduce VMMN. PMID- 29487969 TI - Giant fibroepithelial polyp of the thigh and retroperitoneal fibromatosis in a young woman: a rare case. AB - We present a case of 20-year-old woman who presented with a large pedunculated skin covered mass lesion arising from the left thigh, measuring 40 * 25 cm, with no history of pain or skin ulceration and a feeling of a lump with dragging pain in the left side of the abdomen for about 7 years. Subsequently, ultrasound, contrast-enhanced computed tomography, and magnetic resonance imaging of abdomen and left thigh region were carried out. The lesion was broad-based toward the left upper thigh with a central core of interspersed fat supplied by branches of the superficial and deep femoral arteries. Another lesion was seen in the left retroperitoneum anterior to the psoas muscle in a left paravertebral location encasing the left common iliac vessels extending into the left pelvic cavity and inguinal region inferiorly. The lesion showed dense post-acoustic shadowing on ultrasound, mild enhancement on contrast-enhanced computed tomography, and appeared hypointense on T1- and T2-weighted images. A left thigh lesion was excised, whereas incisional biopsy was done for the left retroperitoneal lesion. The diagnosis of a giant fibroepithelial polyp arising from the left thigh and left retroperitoneal fibromatosis was made. This is the first report of such a giant fibroepithelial polyp arising from the thigh with associated retroperitoneal fibromatosis. PMID- 29487968 TI - Principles of ultrasound elastography. AB - Tissue stiffness has long been known to be a biomarker of tissue pathology. Ultrasound elastography measures tissue mechanical properties by monitoring the response of tissue to acoustic energy. Different elastographic techniques have been applied to many different tissues and diseases. Depending on the pathology, patient-based factors, and ultrasound operator-based factors, these techniques vary in accuracy and reliability. In this review, we discuss the physical principles of ultrasound elastography, discuss differences between different ultrasound elastographic techniques, and review the advantages and disadvantages of these techniques in clinical practice. PMID- 29487970 TI - Hemi-pelvic slope is correlated with the acetabular depth in adults-a radiological study. AB - OBJECTIVE: The purpose of this study was to determine if there is an anatomic relationship between pelvic geometry and acetabular depth. MATERIALS AND METHODS: One hundred and fifty-one anteroposterior pelvic radiographs (157 hip joints) were selected and analyzed in a retrospective fashion. Six parameters, including iliac offset, ischial offset, acetabular offset, pelvic height, center-edge (CE) angle of Wiberg, and acetabular index (AI) angle of Tonnis were measured for each of the hip joints. Based on the defined variables, three formulas (formulas 1, 2, and 3) were calculated to represent the hemi-pelvis slope. RESULTS: There was a strong relationship between the hemi-pelvis slope and probability of acetabular dysplasia. Wider upper pelvis was associated with deeper acetabulum and wider lower pelvis was associated with dysplastic acetabulum. CONCLUSIONS: Pelvic anatomic dimensions and the relationship between them are strongly correlated with hip dysplasia indices. Dysplastic hips tend to be found in pelvises with lower slope (low width of the upper pelvis at the level of iliac crest and high width of the lower part at the level of ischium). PMID- 29487974 TI - [Prevalence of dementia of insured persons with and without German citizenship : A study based on statuatory health insurance data]. AB - BACKGROUND: Elderly people with a non-German background are a fast growing population in Germany. OBJECTIVES: Is administrative prevalence of dementia and uptake of nursing-home care similar in the German and non-German insured? MATERIALS AND METHODS: Based on routine data, administrative prevalence rates for dementia were calculated for 2013 from a full census of data from one large sickness fund. Patients with dementia (PWD) were identified via ICD-10 codes (F00; F01; F03; F05; G30). RESULTS: Administrative prevalence of dementia was 2.67% in the study population; 3.06% in Germans, and 0.96% in non-Germans (p value <0.001). Age and sex adjusted prevalence was comparable in the insured with and without German citizenship, except in women aged 80-84 (17.2 vs. 15.4) and for men in the age groups 80-84 (16.5 vs. 14.2), 85-89 years (23.4 vs. 21.5), and above 90 years of age (32.3 vs. 26.3). Standardized to the population of all investigated insured, 31.4% of all Germans with dementia had no longterm care entitlement vs. 35.5% of all patients without German citizenship. Of German patients, 55.1% were institutionalized vs. 39.5% of all patients without German citizenship. CONCLUSIONS: There was a higher prevalence of dementia in the very old insured without German citizenship compared to those with German citizenship, especially in men. Non-Germans showed lower uptake of nursing home care compared to Germans. Additionally, Germans had slightly higher nursing care entitlements. It should be investigated further how much of the difference is due to underdiagnosis, cultural differences, or lack of adequate diagnostic work-up. PMID- 29487975 TI - [Assessing incident cardiovascular and metabolic diseases in epidemiological cohort studies in Germany]. AB - BACKGROUND: Cardiovascular and metabolic diseases are a major cause of mortality and loss of quality of life in Germany. Research into risk factors of these diseases requires large population-based cohort studies. Complete and accurate assessment of the incidence of cardiovascular and metabolic diseases is a key element for valid interpretation of the results from such studies. OBJECTIVE: Our aim was to identify population-based cohort studies with incidence of cardiovascular and metabolic diseases in Germany and to summarize their methods for assessment and classification of disease endpoints, including myocardial infarction, type 2 diabetes, stroke, heart failure, and arterial hypertension. METHODS: Within the framework of a workshop, representatives of the ascertained population-based cohort studies in Germany with incidence of cardiovascular or metabolic diseases were invited to present and to systematically provide information on their methods of endpoint identification. RESULTS: We identified eight studies from different regions in Germany with a total of 100,571 participants, aged 18-83 years at baseline. Self-reporting by study participants is the major source for further inquiries to assess disease endpoints in these studies. Most studies use additional data sources to verify the incidence of diseases, such as documents provided by the treating physician or hospital. CONCLUSIONS: Our results highlight the central role of self-reporting and the efforts associated with identification and verification of disease endpoints in cohort studies. They also provide a basis for future population-based studies that aim for standardized assessment of the incidence of cardiovascular and metabolic diseases. PMID- 29487976 TI - [Healthcare expenditures and the role of demografic change : An analysis of statutory health insurance data]. AB - The development of healthcare expenditures and the impact of demographic change are the subject of a controversial debate. Yearly healthcare expenditures have more than doubled between 1992 and 2015 and are often justified by the aging demographic. The majority of expenses are paid by the statutory health insurance (SHI). The aim of the current study was to evaluate the contribution of the demographic change to increasing total per capita expenditures in the SHI as well as to analyze the development and the impact in individual areas of spending.We calculated average per capita expenditures from 2004 to 2015 based on data from the German Federal (Social) Insurance Office. Information on the age distribution in SHI was derived from official statistics of the Federal Ministry of Health. To determine the impact of demographic change on per capita expenditures, age distribution was standardized based on 2004 data. Additionally, the impact of inflation and other factors was determined.The results show an increase in per capita expenditures from ?1722 in 2004 to ?2656 in 2015 (+54.2%). Assuming a constant age distribution at the 2004 level, average per capita expenditures would have increased by 44.9%. The relative share of demographic change is only 17.3%; 32.2% could be explained by inflation and 50.5% are based on other factors. We observed large differences in the increase for the individual areas of spending, which can partly be explained by the impact of demographic change.This analysis illustrates that the demographic change is not the frequently claimed cost driver in healthcare. Other factors have a substantially greater impact on healthcare expenditures. PMID- 29487977 TI - Biological tumour volumes of gliomas in early and standard 20-40 min 18F-FET PET images differ according to IDH mutation status. AB - PURPOSE: For the clinical evaluation of O-(2-18F-fluoroethyl)-L-tyrosine (18F FET) PET images, the use of standard summation images obtained 20-40 min after injection is recommended. However, early summation images obtained 5-15 min after injection have been reported to allow better differentiation between low-grade glioma (LGG) and high-grade glioma (HGG) by capturing the early 18F-FET uptake peak specific for HGG. We compared early and standard summation images with regard to delineation of the PET-derived biological tumour volume (BTV) in correlation with the molecular genetic profile according the updated 2016 WHO classification. METHODS: The analysis included 245 patients with newly diagnosed, histologically verified glioma and a positive 18F-FET PET scan prior to any further treatment. BTVs were delineated during the early 5-15 min and standard 20 40 min time frames using a threshold of 1.6 * background activity and were compared intraindividually. Volume differences between early and late summation images of >20% were considered significant and were correlated with WHO grade and the molecular genetic profile (IDH mutation and 1p/19q codeletion status). RESULTS: In 52.2% of the patients (128/245), a significant difference in BTV of >20% between early and standard summation images was found. While 44.3% of WHO grade II gliomas (31 of 70) showed a significantly smaller BTV in the early summation images, 35.0% of WHO grade III gliomas (28/80) and 37.9% of WHO grade IV gliomas (36/95) had a significantly larger BTVs. Among IDH-wildtype gliomas, an even higher portion (44.4%, 67/151) showed significantly larger BTVs in the early summation images, which was observed in 5.3% (5/94) of IDH-mutant gliomas only: most of the latter had significantly smaller BTVs in the early summation images, i.e. 51.2% of IDH-mutant gliomas without 1p/19q codeletion (21/41) and 39.6% with 1p/19q codeletion (21/53). CONCLUSION: BTVs delineated in early and standard summation images differed significantly in more than half of gliomas. While the standard summation images seem appropriate for delineation of LGG as well as IDH-mutant gliomas, a remarkably high percentage of HGG and, particularly, IDH-wildtype gliomas were depicted with significantly larger volumes in early summation images. This finding might be of interest for optimization of treatment planning (e.g. radiotherapy) in accordance with the individual IDH mutation status. PMID- 29487978 TI - Defective HLA class I antigen processing machinery in cancer. AB - Malignant transformation of cells is frequently associated with defective HLA class I antigen processing machinery (APM) component expression. This abnormality may have functional relevance, since it may have a negative impact on tumor cell recognition by cognate T cells. Furthermore, HLA class I APM abnormalities appear to have clinical significance, since they are associated with poor prognosis in several malignant diseases and may play a role in the resistance to immune checkpoint inhibitor-based immunotherapy. In this paper, we have reviewed the literature describing abnormalities in HLA class I APM component expression in many types of cancer. These abnormalities have been reported in all types of cancer analyzed with a frequency ranging between a minimum of 35.8% in renal cancer and a maximum of 87.9% in thyroid cancer for HLA class I heavy chains. In addition, we have described the molecular mechanisms underlying defects in HLA class I APM component expression and function by malignant cells. Lastly, we have discussed the clinical significance of HLA class I APM component abnormalities in malignant tumors. PMID- 29487979 TI - The multi-receptor inhibitor axitinib reverses tumor-induced immunosuppression and potentiates treatment with immune-modulatory antibodies in preclinical murine models. AB - Cancer immunotherapies have significantly improved the prognosis of cancer patients. Despite the clinical success of targeting inhibitory checkpoint receptors, including PD-1 and/or CTLA-4 on T cells, only a minority of patients derive benefit from these therapies. New strategies to improve cancer immunotherapy are therefore needed. Combination therapy of checkpoint inhibitors with targeted agents has promisingly shown to increase the efficacy of immunotherapy. Here, we analyzed the immunomodulatory effects of the multi receptor tyrosine kinase inhibitor axitinib and its efficacy in combination with immunotherapies. In different syngeneic murine tumor models, axitinib showed therapeutic efficacy that was not only mediated by VEGF-VEGFR inhibition, but also through the induction of anti-cancer immunity. Mechanistically, a significant reduction of immune-suppressive cells, including a decrease of tumor promoting mast cells and tumor-associated macrophages was observed upon axitinib treatment. Inhibition of mast cells by axitinib as well as their experimental depletion led to reduced tumor growth. Of note, treatment with axitinib led to an improved T cell response, while the latter was pivotal for the therapeutic efficacy. Combination with immune checkpoint inhibitors anti-PD-1 and anti-TIM-3 and/or agonistic engagement of the activating receptor CD137 resulted in a synergistic therapeutic efficacy. This demonstrates non-redundant immune activation induced by axitinib via modulation of myeloid and mast cells. These findings provide important mechanistic insights into axitinib-mediated anti cancer immunity and provide rationale for clinical combinations of axitinib with different immunotherapeutic modalities. PMID- 29487980 TI - Ipilimumab in metastatic melanoma patients with pre-existing autoimmune disorders. AB - BACKGROUND: Ipilimumab and programmed death (PD) 1-antibodies are effective treatment options in metastatic melanoma. The safety and efficacy of ipilimumab in patients with pre-existing autoimmune disorders (AD) has only been evaluated in a selected number of patients. METHODS: We performed a retrospective analysis in 14 German skin cancer centers for patients with metastatic melanoma and pre existing AD treated with ipilimumab. RESULTS: 41 patients with 44 pre-existing AD were treated with ipilimumab (thyroiditis n = 15, rheumatoid n = 11, dermatologic n = 10, Crohn's disease/ulcerative colitis n = 3, neurological n = 2, sarcoidosis n = 2, pancreatitis n = 1). 3 out of 41 patients had two AD, 11 patients required immunosuppressants at the time of induction of ipilimumab. 12 patients (29.2%) experienced a flare of their pre-existing AD, mainly patients with rheumatoid or dermatologic diseases. Additional immune-related adverse events (irAEs) occurred in 12 patients (29.2%). In 23 patients (56%) neither a change of their AD nor additional irAEs were observed. Objective responses were seen in five patients (one complete remission, four partial remissions, 12.1%). CONCLUSION: This is the largest series of patients with pre-existing AD and treatment with ipilimumab reported. Flares of pre-existing AD were observed but manageable. Response rates and occurrence of new irAEs were comparable to previous trials. Thus, in this patient subgroup, ipilimumab can be a treatment option after a thorough discussion of pros and cons and taking severity and activity of the preexisting AD into account. PMID- 29487981 TI - The relationship between maternal and child bone density in Nigerian children with and without nutritional rickets. AB - : We found a positive relationship between bone density in Nigerian children with and without rickets and that of their mothers. After treatment, children with rickets had greater bone density than children without rickets, indicating that children genetically programmed to have greater bone density may have a higher risk of rickets. INTRODUCTION: To determine the relationship between bone density in children with and without rickets and that of their mothers METHODS: Using an unmatched case-control design, forearm areal bone mineral density (aBMD) was measured in 52 and 135 Nigerian children with and without rickets and their mothers, respectively. We performed multivariate linear regression analyses to assess the relationship between maternal and child aBMD Z-scores. RESULTS: Forearm aBMD Z-scores in children were associated with maternal aBMD Z-scores at metaphyseal (effect estimate 0.23; 95% CI 0.08 to 0.37) and diaphyseal (effect estimate 0.16; 0.01 to 0.30) sites, after adjustment for rickets in the child, child's age and sex, height-for-age Z-score, and weight-for-age Z-score. In the adjusted model, rickets was inversely associated with child's aBMD Z-score at the diaphyseal site only (- 0.45, - 0.65 to - 0.24). The positive relationship between maternal and child aBMD Z-scores was marginally greater in children with rickets (slope 0.56, r = 0.47) than without rickets (slope 0.19, r = 0.20) at the diaphyseal site only (P = 0.06 for interaction) but not at the metaphyseal site (slopes 0.35 and 0.30, respectively, P = 0.48). After treatment with calcium for 6 months, metaphyseal aBMD Z-scores were greater in children with treated rickets (effect estimate 0.26; 95% CI 0.02 to 0.49) than in those without rickets. CONCLUSION: In Nigerian children with and without rickets, forearm aBMD Z-scores were positively associated with maternal aBMD Z-scores. Active rickets in the child marginally modified the relationship at the diaphyseal site only. After treatment, children with rickets had greater metaphyseal aBMD Z-scores than children without rickets. PMID- 29487982 TI - [Metastatic breast cancer in the spine : Molecular predictors for choosing adequate treatment strategies]. AB - Breast cancer is the most common malignancy affecting women and the spinal column is most likely affected by metastases. Modern oncologic treatment options have significantly prolonged survival times in the last decade. Therefore, treatment of vertebral metastases has been of special interest in spine surgery. Different scores are described to evaluate prognosis and to choose correct treatment strategies, which however only differentiate tumor entities and not specific tumor phenotypes. Breast cancer has been classified into five intrinsic subtypes with different survival rates since the turn of the millennium. The aim of this review was to describe molecular predictors of breast cancer malignancy and to better estimate expected survival times and invasiveness of therapies with regard to spinal metastases. PMID- 29487983 TI - Distribution characteristics of bone cement used for unilateral puncture percutaneous vertebroplasty in multiple planes. AB - OBJECTIVE: To study the distribution of bone cement in unilateral puncture percutaneous vertebroplasty (PVP). MATERIAL AND METHODS: A total of 64 patients with osteoporotic vertebral compression fractures (OVCF) who underwent unilateral PVP were included in this study. The vertebral body was longitudinally divided into four equal parts. The intermediate layer between each part was representative of the part and there were four layers in total. Each layer was divided into 4 regions a, b, c, and d by the crossed lines at the center of the vertebral body. Region c was the first half of the puncture side and region d was the second half of the puncture side. Region a was the first half of the opposite side, and b was the second half of the opposite side. Bone cement filling areas in the four layers and the four regions of each layer were compared. RESULTS: There were significant differences in visual analogue scale (VAS) scores before and after surgery (P < 0.05). Variance analysis indicated that the bone cement filling ratio of the region b in each layer was significantly lower than the other three regions, and that the bone cement filling ratio of region a was equal to that of the region d. CONCLUSION: Unilateral puncture PVP can reduce VAS scores, and plays a role in reducing pain. The bone cement showed a regular distribution. PMID- 29487984 TI - [Complications in the treatment of adult spinal deformities]. PMID- 29487986 TI - Selecting optimal feast-to-famine ratio for a new polyhydroxyalkanoate (PHA) production system fed by valerate-dominant sludge hydrolysate. AB - The feast-to-famine ratio (F/F) represents the extent of selective pressure during polyhydroxyalkanoate (PHA) culture selection. This study evaluated the effects of F/F on a new PHA production system by an enriched culture with valerate-dominant sludge hydrolysate and selected the optimal F/F. After the original F/F 1/3 was modified to 1/1, 1/2, 1/4, and 1/5, F/F did not affect their lengths of feast phase, but affected their biomass growth behaviors during the famine phase and PHA-producing abilities. The optimal F/F was 1/2, and compared with 1/3, it increased the maximal PHA content and the fraction of 3 hydroxyvalerate (3HV) and 3-hydroxy-2-methylvalerate (3H2MV) monomers, with higher productivity and better polymer properties. Although F/F 1/2 impaired the advantage of the dominant genus Delftia, it improved the PHA production rate while decreased biomass growth rate, meanwhile enhancing the utilization and conversion of valerate. These findings indicate that in contrast to previous studies using acetate-dominant substrate for PHA production, the new system fed by valerate-dominant substrate can adopt a higher F/F. PMID- 29487985 TI - [Risk factors for the development of rotator cuff tears in individuals with paraplegia : A cross-sectional study]. AB - QUESTION: Shoulder pain and rotator cuff tears are highly prevalent among wheelchair dependent individuals with paraplegia. The purpose of this study was to identify potential risk factors associated with the development of rotator cuff tears in this population. METHODS: A total of 217 wheelchair dependent individuals with paraplegia were included in this cross-sectional study (level of evidence III). The mean age of this population was 47.9 years and the mean duration of wheelchair dependence was 24.1 years. Each individual was asked to complete a questionnaire designed to identify risk factors for rotator cuff tears and underwent a standardized clinical examination with the documentation of the Constant-Murley shoulder outcome score and magnetic resonance imaging (MRI) of both shoulder joints. RESULTS: MRI analysis revealed at least one rotator cuff tear in 93 patients (43%). Multiple logistic regression analysis identified the following factors to be associated with the presence of rotator cuff tear: patient age, duration of spinal cord injury/wheelchair dependence, gender, and wheelchair athletic activity. Neither BMI nor the level of spinal cord injury was found to pose a risk factor in the population studied. With respect to patient age, the risk of developing a rotator cuff tear increased by 11% per annum. In terms of duration of spinal cord injury, the analysis revealed a 6% increased risk per year of wheelchair dependence (OR = 1.06). Females had a 2.6-fold higher risk of developing rotator cuff tears than males and wheelchair sport activity increased the risk 2.3-fold. DISCUSSION: There is a high prevalence of rotator cuff tears in wheel-chair dependent persons with paraplegia. Risk factors such as age, gender, duration of paraplegia, and wheel chair sport activity seem to play an important role in the development of rotator cuff tears. PMID- 29487987 TI - Current challenges and future directions for bacterial self-healing concrete. AB - Microbially induced calcium carbonate precipitation (MICP) has been widely explored and applied in the field of environmental engineering over the last decade. Calcium carbonate is naturally precipitated as a byproduct of various microbial metabolic activities. This biological process was brought into practical use to restore construction materials, strengthen and remediate soil, and sequester carbon. MICP has also been extensively examined for applications in self-healing concrete. Biogenic crack repair helps mitigate the high maintenance costs of concrete in an eco-friendly manner. In this process, calcium carbonate precipitation (CCP)-capable bacteria and nutrients are embedded inside the concrete. These bacteria are expected to increase the durability of the concrete by precipitating calcium carbonate in situ to heal cracks that develop in the concrete. However, several challenges exist with respect to embedding such bacteria; harsh conditions in concrete matrices are unsuitable for bacterial life, including high alkalinity (pH up to 13), high temperatures during manufacturing processes, and limited oxygen supply. Additionally, many biological factors, including the optimum conditions for MICP, the molecular mechanisms involved in MICP, the specific microorganisms suitable for application in concrete, the survival characteristics of the microorganisms embedded in concrete, and the amount of MICP in concrete, remain unclear. In this paper, metabolic pathways that result in conditions favorable for calcium carbonate precipitation, current and potential applications in concrete, and the remaining biological challenges are reviewed. PMID- 29487988 TI - Biofilms Developed on Dental Implant Titanium Surfaces with Different Roughness: Comparison Between In Vitro and In Vivo Studies. AB - Microbial biofilms developed on dental implants play a major role in perimplantitis' pathogenesis. Many studies have indicated that surface roughness is the main feature favoring biofilm development in vitro, but its actual influence in vivo has still to be confirmed. In this study, the amount of biofilm formed on differently treated titanium surfaces, showing distinct roughness, has been examined both in vivo and in vitro by Confocal Laser Scanning Microscopy. In vitro studies availed of biofilm developed by Pseudomonas aeruginosa or by salivary bacteria from volunteer donors. In vivo biofilm production was obtained by exposing titanium discs to the oral cavity of healthy volunteers. In vitro experiments showed that P. aeruginosa and, to a lesser extent, salivary bacteria produce more biomass and develop thicker biofilms on laser-treated and sandblasted titanium surfaces with respect to machined ones. In vivo experiments confirmed that bacterial colonization starts on sites of surface unevenness, but failed to disclose biomass differences among biofilms formed on surfaces with different roughness. Our study revealed that biofilm developed in vitro is more easily influenced by surface features than biofilm formed by complex communities in the mouth, where the cooperation of a variety of bacterial species and the presence of a wide range of nutrients and conditions allow bacteria to optimize substrate colonization. Therefore, quantitative differences observed in vitro among surfaces with different characteristics may not be predictive of different colonization rates in vivo. PMID- 29487989 TI - Baculovirus-Encoded MicroRNAs: A Brief Overview and Future Prospects. AB - MicroRNAs (miRNAs) are a class of non-coding RNAs with ~22 nucleotides, which are able to regulate various biological processes, including the viral life cycle and host-pathogen interactions. Long primary transcripts (pri-miRNAs) are initially transcribed in nucleus, and subsequently processed by Dicer in cytoplasm to generate mature miRNAs. Baculoviruses consist of large, enveloped, insect pathogenic viruses with a double-stranded circular DNA genome. Recent studies suggest that baculoviruses encode some miRNAs to manipulate expression regulation of host genes, whereas host modulate viral gene expression via miRNAs to limit viral infection. In the review, we will focus on the biogenesis and functions of miRNAs and the interactions between baculoviruses, insect, and miRNAs. It will be helpful to delve into the related mechanisms of BmNPV-encoded miRNAs that contribute to infection and pathogenesis. PMID- 29487990 TI - Three-in-one protocol reduces mortality of patients with haemodynamically unstable pelvic fractures-a five year multi-centred review in Hong Kong. AB - PURPOSE: The mortality rate in patients with haemodynamically unstable pelvic fractures is as high as 40-60%. Despite the new advances in trauma care which are in phase in trauma centres in Hong Kong, the management of haemodynamically unstable pelvic fracture is still heterogeneous. The aim of this study is to review the results of management of haemodynamically unstable pelvic fracture patients in Hong Kong over a five year period. METHODS: This is a retrospective multi-centred cohort study of patients with haemodynamic and mechanically unstable pelvic fractures from 1 January 2010 to 31 December 2014. The primary outcome investigated is mortality of patients (including overall, 30-day, 7-day and 24-hour mortalities). RESULTS: Implementation of three-in-one pelvic damage control protocol was identified to be a significant independent predictive factor for overall, 30-day, seven-day and 24-hour mortalities. The overall in-hospital and 30-day mortality rates for patients managed with three-in-one protocol was 12.5%, while it was 11% for seven day mortality and 6% for 24 hour mortality. There were no significant differences in demographic characteristics, physiological measurements, types of pelvic fracture, severity and mechanism of injury between patients managed with or without three-in-one protocol. CONCLUSIONS: Implementation of the multidisciplinary three-in-one pelvic damage control protocol reduces mortality and therefore should be highly recommended. The results are convincing as it has eliminated the limitations of our previous single-centred trial. PMID- 29487991 TI - Effect of pioglitazone on cardiometabolic profiles and safety in patients with type 2 diabetes undergoing percutaneous coronary artery intervention: a prospective, multicenter, randomized trial. AB - Pioglitazone has superior antiatherosclerotic effects compared with other classes of antidiabetic agents, and there is substantial evidence that pioglitazone improves cardiovascular (CV) outcomes. However, there is also a potential risk of worsening heart failure (HF). Therefore, it is clinically important to determine whether pioglitazone is safe in patients with type 2 diabetes mellitus (T2DM) who require treatment for secondary prevention of CV disease, since they have an intrinsically higher risk of HF. This prospective, multicenter, open-label, randomized study investigated the effects of pioglitazone on cardiometabolic profiles and CV safety in T2DM patients undergoing elective percutaneous coronary intervention (PCI) using bare-metal stents or first-generation drug-eluting stents. A total of 94 eligible patients were randomly assigned to either a pioglitazone or conventional (control) group, and pioglitazone was started the day before PCI. Cardiometabolic profiles were evaluated before PCI and at primary follow-up coronary angiography (5-8 months). Pioglitazone treatment reduced HbA1c levels to a similar degree as conventional treatment (pioglitazone group 6.5 to 6.0%, P < 0.01; control group 6.5 to 5.9%, P < 0.001), without body weight gain. Levels of high-molecular weight adiponectin increased more in the pioglitazone group than the control group (P < 0.001), and the changes were irrespective of baseline glycemic control. Furthermore, pioglitazone significantly reduced plasma levels of natriuretic peptides and preserved cardiac systolic and diastolic function (assessed by echocardiography) without incident hospitalization for worsening HF. The incidence of clinical adverse events was also comparable between the groups. These results indicate that pioglitazone treatment before and after elective PCI may be tolerable and clinically safe and may improve cardiometabolic profiles in T2DM patients. PMID- 29487992 TI - Outcomes and complications of surgery in patients with intermediate-risk neuroblastoma: experience from an Indian tertiary Cancer Centre. AB - PURPOSE: The treatment of intermediate risk (IR) neuroblastoma has evolved with the focus now on reducing the drugs, dosage, and duration of chemotherapy. The aim of this study is to present the outcomes of treatment and the complications of surgery in patients with IR neuroblastoma treated at a tertiary cancer center in India. METHODS: All eligible patients with IR neuroblastoma treated between April 2005 and August 2016 were identified. The presence and number of image defined risk factors (IDRF) before and after neoadjuvant chemotherapy were retrospectively analyzed as were the extent of surgery, complications, and outcomes. RESULTS: Of 282 neuroblastoma patients treated during the study period, 54 had IR neuroblastoma. Complete excision was achieved in 25 patients. There were 26 surgical complications in 22 patients with a similar incidence in patients with complete (n = 13) or incomplete (n = 13) resection (p = 0.78). After a median follow-up of 47 months, the 4-year overall and event-free survival was 91.5% and 75%, respectively. There was no difference in survival between patients who underwent complete resection versus those with incomplete resection (p = 0.9). CONCLUSION: Outcomes of IR neuroblastoma are favorable. The extent of resection does not affect the survival and complications can occur even when the resection is incomplete. PMID- 29487993 TI - Ablative dual-phase Erbium:YAG laser treatment of atrophy-related vaginal symptoms in post-menopausal breast cancer survivors omitting hormonal treatment. AB - PURPOSE: First evaluation of dual-phase vaginal Er:YAG laser to omit hormonal treatment for atrophy-related symptoms in post-menopausal breast cancer survivors following prolapse surgery. METHODS: Patients with a history of breast cancer at the time of surgery for pelvic organ prolapse were offered non-hormonal vaginal Er:YAG laser treatment when complaining of atrophy-related genitourinary syndrome of menopause. A single 10-min course of dual-phase protocol of pulsed Er:YAG laser (2940 nm, fractional ablative and thermal mode, fluence according to tissue thickness). Follow-up included subjective satisfaction, vaginal pH, vaginal health index (VHI), and complications after 6 weeks. RESULTS: A total of 16 breast cancer survivors (age 71 years, SD 7) had been seeking treatment for pelvic floor symptoms related to vaginal atrophy at follow-up visits after prolapse surgery. All ablative vaginal Er:YAG laser outpatient procedures were successfully completed, all patients returned to daily activities without a need for analgetic medication. Evaluation was performed after 8.3 (SD 2.5) weeks. Pre laser VHI scored 16 (SD 4.6) and post-laser VHI 20 (SD 3) with p = 0.01. Patients were satisfied in 94% (n = 15) regarding symptom relief. CONCLUSIONS: Breast cancer survivors with atrophy-related complaints after pelvic floor surgery may benefit from vaginal application of this innovative dual protocol of Er:YAG laser technology as a non-hormonal treatment approach. PMID- 29487994 TI - Age differences in the association between stressful work and sickness absence among full-time employed workers: evidence from the German socio-economic panel. AB - PURPOSE: We aim to extend current knowledge on associations between stressful work and sickness absence, first, by studying associations between ERI and sickness absence among full-time employees from various occupations, and second, by investigating if associations vary by age. METHODS: We use data from four waves of the German socio-economic panel (GSOEP), collected among men and women between 2006 and 2012, with 9418 observations. Stressful work is measured with a short form of the ERI questionnaire. We investigate an imbalance between effort and reward (ER ratio) as well as the two main components ("high effort" and "low reward"). Sickness absence is measured by self-reported number of sickness days (assessed the following year). After descriptive analyses, we estimate a series of multivariable regressions, including tests for interactions between age and work stress. RESULTS: Each of the three indicators of stressful work is related to higher number of sickness days, with except of "high effort" in case of men. Findings remain significant after adjusting for social position (income, education and occupational class) and health. In addition, for both men and women, associations were slightly higher among older workers, though interactions did not reach statistical significance. CONCLUSION: Our findings support that stressful work is linked to sickness absence across a wide spectrum of jobs with varying incomes and educational levels, and also that associations are slightly more pronounced among older workers. PMID- 29487995 TI - Treatment of atrial fibrillation in patients with enhanced sympathetic tone by pulmonary vein isolation or pulmonary vein isolation and renal artery denervation: clinical background and study design : The ASAF trial: ablation of sympathetic atrial fibrillation. AB - BACKGROUND: Hypertension is an important, modifiable risk factor for the development of atrial fibrillation (AF). Even after pulmonary vein isolation (PVI), 20-40% experience recurrent AF. Animal studies have shown that renal denervation (RDN) reduces AF inducibility. One clinical study with important limitations suggested that RDN additional to PVI could reduce recurrent AF. OBJECTIVE: The goal of this multicenter randomized controlled study is to investigate whether RDN added to PVI reduces AF recurrence. METHODS: The main end point is the time until first AF recurrence according to EHRA guidelines after a blanking period of 3 months. Assuming a 12-month accrual period and 12 months of follow-up, a power of 0.80, a two-sided alpha of 0.05 and an expected drop-out of 10% per group, 69 patients per group are required. We plan to randomize a total of 138 hypertensive patients with AF and signs of sympathetic overdrive in a 1:1 fashion. Patients should use at least two antihypertensive drugs. Sympathetic overdrive includes obesity, exercise-induced excessive blood pressure (BP) increase, significant white coat hypertension, hospital admission or fever induced AF, tachycardia induced AF and diabetes mellitus. The interventional group will undergo PVI + RDN and the control group will undergo PVI. RESULTS: Patients will have follow-up for 1 year, and continuous loop monitoring is advocated. CONCLUSION: This randomized, controlled study will elucidate if RDN on top of PVI reduces AF recurrence. PMID- 29487997 TI - Reduced anaerobic and aerobic performance in children with primary ciliary dyskinesia. AB - : Primary ciliary dyskinesia (PCD) restricts lifestyle and increases morbidity. The aim of the study was to investigate anaerobic and aerobic performance in children with PCD and their healthy counterparts. Thirty-one children with PCD and 29 age- and sex-matched healthy subjects were studied. Pulmonary function, hand grip strength (HGS), quadriceps strength (QMS), physical activity, anaerobic capacity (muscle power sprint test), and aerobic performance (modified shuttle walk test (MSWT)) were determined. Pulmonary function, HGS, QMS, mean anaerobic power (MAP), and MSWT distance in PCD were significantly lower than those of healthy subjects (p < 0.05). In PCD, the MAP was significantly correlated with age, FEV1, and the mean kcal for 3 days (p < 0.05), and age was its independent predictor (p < 0.05). The MSWT distance was significantly related to gender and weight (p < 0.05), and gender was selected as its independent predictor (p < 0.05). In healthy controls, the MAP was significantly associated with age, gender, FVC, FEV1, HGS, QMS, and the mean kcal for three days (p < 0.05). The MSWT distance was significantly related to weight and body mass index in healthy group (p < 0.05). CONCLUSION: Anaerobic and aerobic performance is impaired in PCD from the early stages. Age determines anaerobic performance. Gender is the determinant of aerobic performance. Whether skeletal muscle characteristics and sex-related changes in body composition affect anaerobic and aerobic capacity in PCD children warrants further study. What is Known: * Exercise performance is determined by anaerobic and aerobic power. * Few studies have shown that PCD patients have lower aerobic performance which is associated with impaired lung function. What is New: * The present research indicated that both anaerobic and aerobic exercise capacity determined using field testing is impaired in PCD from the early stages. * Anaerobic capacity was found to be independently associated with age in PCD. Higher aerobic performance is independently associated with male gender. PMID- 29487996 TI - Genetic variation in sensitivity to estrogens and breast cancer risk. AB - Breast cancer risk is intimately intertwined with exposure to estrogens. While more than 160 breast cancer risk loci have been identified in humans, genetic interactions with estrogen exposure remain to be established. Strains of rodents exhibit striking differences in their responses to endogenous ovarian estrogens (primarily 17beta-estradiol). Similar genetic variation has been observed for synthetic estrogen agonists (ethinyl estradiol) and environmental chemicals that mimic the actions of estrogens (xenoestrogens). This review of literature highlights the extent of variation in responses to estrogens among strains of rodents and compiles the genetic loci underlying pathogenic effects of excessive estrogen signaling. Genetic linkage studies have identified a total of the 35 quantitative trait loci (QTL) affecting responses to 17beta-estradiol or diethylstilbestrol in five different tissues. However, the QTL appear to act in a tissue-specific manner with 9 QTL affecting the incidence or latency of mammary tumors induced by 17beta-estradiol or diethylstilbestrol. Mammary gland development during puberty is also exquisitely sensitive to the actions of endogenous estrogens. Analysis of mammary ductal growth and branching in 43 strains of inbred mice identified 20 QTL. Regions in the human genome orthologous to the mammary development QTL harbor loci associated with breast cancer risk or mammographic density. The data demonstrate extensive genetic variation in regulation of estrogen signaling in rodent mammary tissues that alters susceptibility to tumors. Genetic variants in these pathways may identify a subset of women who are especially sensitive to either endogenous estrogens or environmental xenoestrogens and render them at increased risk of breast cancer. PMID- 29487999 TI - Complication of AQUAfilling(r) Gel Injection for Breast Augmentation: Case Report of One Case and Review of Literature. AB - INTRODUCTION: Augmentation mammoplasty is one of the most popular aesthetic operations in the world. In Korea, one of the fillers used for breast augmentation is AQUAfilling(r) gel (Biomedica. spol, s,r,o, Czech Republic). AQUAfilling(r) gel is a hydrophilic gel composed of 98% sodium chloride solution (0.9%) and 2% cation copolyamide. METHODS: This is a case report describing a patient that suffered complications after AQUAfilling(r) gel injection for breast augmentation. RESULTS: A 32-year-old female patient was referred to our plastic surgery department with a chief complaint of repeated wound dehiscence and fluid discharge involving both breasts. She was treated via surgical intervention for removal of necrotic infected tissue and filler, as well as massive irrigation three times. After the third surgery, there were no complications, including infection or dehiscence, during a 1-year follow-up period. CONCLUSIONS: Although AQUAfilling(r) gel is easy to inject and is natural looking, once a complication occurs, treatment is difficult. Also, there are concerns regarding toxicity of the gel material and its influence on surrounding tissues. Hence, sufficient evidences of long-term safety must be accumulated and proved, until which time the aesthetic use of the unapproved filler must be restricted. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29487998 TI - Hyperthyrotropinemia in newly diagnosed cystic fibrosis patients with pancreatic insufficiency reversed by enzyme therapy. AB - : Patients with cystic fibrosis (CF) commonly present with an elevated TSH concentration, suggesting subclinical hypothyroidism. Its relation to concomitant pancreatic insufficiency and its natural course upon initiation of enzyme replacement have not been adequately studied. Herein, we investigated the thyroid function in newly diagnosed infants with CF and monitored the course of thyroid function response to pancreatic enzyme substitution treatment. Fourteen, newly diagnosed infants with CF and pancreatic insufficiency, were followed every 6-8 weeks for 6 months ensuing onset of pancreatic enzyme substitution therapy. All infants had normal TSH values on neonatal screening. Ten out of 14 (71%) had hyperthyrotropinemia and normal freeT4 values at presentation. No patient received thyroxine. Upon follow-up, after 6 months, TSH values normalized in 90% of infants with CF and hyperthyrotropinemia. Serum selenium levels were negatively correlated with TSH levels. CONCLUSION: Mild TSH elevation is a frequent finding in newly diagnosed cystic fibrosis patients with pancreatic insufficiency during infancy. TSH elevation resolves in most cases after initiation of enzyme substitution and improvement of nutritional status without any substitutive therapy with thyroxine. What is Known: * Newly diagnosed infants with cystic fibrosis often present with a state of hyperthyrotropinemia suggesting subclinical hypothyroidism. What is New: * Pancreatic enzyme substitution and improvement of nutrition restores normal TSH levels without the need of thyroxine therapy. PMID- 29488001 TI - ATP-binding cassette (ABC) transporters in caprine preantral follicles: gene and protein expression. AB - The multidrug resistance proteins ABCB1, ABCC2 and ABCG2 are an energy-dependent efflux pump that functions in systemic detoxification processes. Physiologically expressed in a variety of tissues, most abundantly in the liver and intestinal epithelia, placenta, blood-brain barrier and various stem cells, until now, these pumps were not identified in goat ovarian tissue. Therefore, the aim of this study is to analyze ABCB1, ABCC2, and ABCG2 mRNA and protein expression in goat preantral follicles. Fragments (3 * 3 * 1 mm) from five pairs of ovary (n = 10) obtained from five goat were collected and immediately submitted to qPCR, Western blot, and immunofluorescence assay for mRNA detection and identification and localization of the ABC transporters, respectively. mRNA for ABCB1, ABCC2, and ABCG2 and the presence of their proteins were observed on ovarian tissue samples. Positive marks were observed for the three transport proteins in all follicular categories studied. However, the marks were primarily localized in the oocyte of primordial, transition and primary follicle categories. In conclusion, goat ovarian tissue expresses mRNA for the ABCB1, ABCC2 and ABCG2 transporters and the expression of these proteins in the preantral follicles is a follicle-dependent stage. PMID- 29488000 TI - Bilateral activation of STAT3 by phosphorylation at the tyrosine-705 (Y705) and serine-727 (S727) positions and its nuclear translocation in primary sensory neurons following unilateral sciatic nerve injury. AB - Unilateral sciatic nerve compression (SNC) or complete sciatic nerve transection (CSNT), both varying degrees of nerve injury, induced activation of STAT3 bilaterally in the dorsal root ganglia (DRG) neurons of lumbar (L4-L5) as well as cervical (C6-C8) spinal cord segments. STAT3 activation was by phosphorylation at the tyrosine-705 (Y705) and serine-727 (S727) positions and was followed by their nuclear translocation. This is the first evidence of STAT3(S727) activation together with the well-known activation of STAT3(Y705) in primary sensory neurons upon peripheral nerve injury. Bilateral activation of STAT3 in DRG neurons of spinal segments anatomically both associated as well as non-associated with the injured nerve indicates diffusion of STAT3 activation inducers along the spinal cord. Increased levels of IL-6 protein in the CSF following nerve injury as well as activation and nuclear translocation of STAT3 in DRG after intrathecal injection of IL-6 shows that this cytokine, released into the subarachnoid space can penetrate the DRG to activate STAT3. Previous results on increased bilateral IL-6 synthesis and the present manifestation of STAT3 activation in remote DRG following unilateral sciatic nerve injury may reflect a systemic reaction of the DRG neurons to nerve injury. PMID- 29488002 TI - Expression and regulation of M-type K+ channel in PC12 cells and rat adrenal medullary cells. AB - M-type K+ channels contribute to the resting membrane potential in the sympathetic ganglion neurons of various animals, whereas their expression in adrenal medullary (AM) cells has been controversial. The present experiment aims to explore the expression of M channels comprising the KCNQ2 subunit in the rat AM cell and its immortalized cell line PC12 cells at the protein level and how its expression in PC12 cells is regulated. The KCNQ2 isoform was recognized in homogenates of PC12 cells but not the rat adrenal medullae by immunoblotting and KCNQ2-like immunoreactivity (IR) was detected in PC12 cells but not in rat AM cells. When the PC12 cells were maintained in a dexamethasone-containing medium, KCNQ2-like IR in the cells was suppressed, whereas the removal of fetal bovine serum from the culture medium for 1 day resulted in an increase in KCNQ2-like IR. A similar enhancement occurred when PC12 cells were cultured under conditions where glucocorticoid receptor (GR) and/or mineralocorticoid receptor (MR) activities were suppressed. These morphological findings were confirmed in functional analysis. The cells cultured in the presence of an inhibitor of either GR or MR exhibited larger amplitudes of Ca2+ signal in response to an M channel inhibitor than did the cells in its absence, whereas the resting Ca2+ level in the former was lower than that in the latter. These results indicate that the M channel is not expressed in rat AM cells and this absence of expression may be ascribed to the suppression by glucocorticoid activity. PMID- 29488003 TI - Can an Emergency Department Observation Unit Reduce Hospital Admissions for COPD Exacerbation? AB - Studies on observation unit (OU) use to avoid a hospital admission from the emergency department (ED) have found variable effects on health care resource utilization, and these effects have not been studied in acute exacerbation of chronic obstruction pulmonary disease (AECOPD). We retrospectively collected data for all AECOPD-related ED visits (age > 40) to an urban, academic medical center between February 2013 and April 2017. We examined the total proportion of visits admitted to the hospital before and after availability of an OU and the proportion of visits discharged directly from the ED using segmented regression analysis. There was a 12.8% reduction in hospital admissions after OU availability (79.6 vs. 66.8%, p = 0.0049) without a change in the proportion discharged directly from the ED (p = 0.65). The availability of an OU can decrease hospital AECOPD admissions without affecting the number of patients discharged directly from the ED. PMID- 29488004 TI - [The activating GNAS mutation : A survey of fibrous dysplasia, its associated syndromes, and other skeletal and extraskeletal lesions]. AB - Fibrous dysplasia of bone is a connatal but not hereditary disease with monostotic or polyostotic manifestations and may be associated either with the extraskeletal disease McCune-Albright syndrome or with myxoma of the skeletal muscle, termed Mazabraud syndrome.The confirmation of recurrent chromosomal aberrations may lead to the conclusion that fibrous dysplasia is a neoplasia rather than a dysplastic skeletal disease.The primary cause of all forms of the described diseases is the activating GNAS mutation, which is detectable in almost all lesions. Research into the impact of this mutation has increased the understanding of these up to now solely descriptively defined diseases and also allowed easier discrimination of various fibro-osseous skeletal lesions. Current insights suggest that this mutation may also play a pivotal role in other extraskeletal neoplasias. PMID- 29488005 TI - Professor Emeritus, Dr. Med. Mirko Tos. PMID- 29488006 TI - Olfactory cleft evaluation: a predictor for olfactory function in smell-impaired patients? AB - OBJECTIVE: In this study, we introduce an extension of previous work by Soler et al. (Int Forum Allergy Rhinol 6(3):293-298, 2016) on a modified endoscopic scoring system of the Lund-Kennedy Score (focusing on the olfactory cleft) to evaluate its correlation with the olfactory function in patients with various smell disorders. STUDY DESIGN: A prospective cohort study. METHODS: Two-hundred and eighty-eight participants were included and categorized in five groups according to the cause of their olfactory disorder: (0) control, (1) idiopathic, (2) sino-nasal, (3) postinfectious and (4) post traumatic olfactory loss. Olfaction was evaluated using the "Sniffin' Sticks" test. The classical Lund Kennedy scoring and a new olfactory cleft specific Lund-Kennedy scoring (OC-LK) were performed to evaluate mucosal changes. RESULTS: Significantly higher OC-LK scores on both sides were found in smell-impaired patients as compared to normosmic controls. When comparing the 4 groups, a significant difference of the OC-LK score were present between the sino-nasal and all other groups. Most importantly, significant negative correlations with strong effects were shown in the sino-nasal group between the OC-LK score and odor discrimination and odor identification. However, no such correlation emerged between the classical LK score and smell function. CONCLUSION: Olfactory cleft evaluation using the OC-LK score correlates with the olfactory function in patients with sino-nasal smell disorder. This diagnostic tool may reflect the underlying pathophysiological mechanism of sino-nasal smell loss, and therefore, should complement olfactory diagnostics in patients with sino-nasal smell disorder. PMID- 29488008 TI - Assessing the potential impact of limited public health resources on the spread and control of typhoid. AB - Typhoid fever is a systemic infection caused by Salmonella Typhi and occurs predominantly in association with poor sanitation and lack of clean drinking water. Despite recent progress in water and sanitation coverage, the disease remains a substantial public health problem in many developing countries. A mathematical model for the spread of typhoid has been formulated using non linear ordinary differential equations. The model includes a special treatment function to assess the effects of limited treatment resources on the spread of typhoid. It is shown that the model has multiple equilibria and using the center manifold theory, the model exhibits the phenomenon of backward bifurcation whose implications are discussed. The results suggest the need for comprehensive and accessible treatment facilities to curtail typhoid infection. PMID- 29488007 TI - Tinnitus and temporary hearing loss result in differential noise-induced spatial reorganization of brain activity. AB - Loud noise frequently results in hyperacusis or hearing loss (i.e., increased or decreased sensitivity to sound). These conditions are often accompanied by tinnitus (ringing in the ears) and changes in spontaneous neuronal activity (SNA). The ability to differentiate the contributions of hyperacusis and hearing loss to neural correlates of tinnitus has yet to be achieved. Towards this purpose, we used a combination of behavior, electrophysiology, and imaging tools to investigate two models of noise-induced tinnitus (either with temporary hearing loss or with permanent hearing loss). Manganese (Mn2+) uptake was used as a measure of calcium channel function and as an index of SNA. Manganese uptake was examined in vivo with manganese-enhanced magnetic resonance imaging (MEMRI) in key auditory brain regions implicated in tinnitus. Following acoustic trauma, MEMRI, the SNA index, showed evidence of spatially dependent rearrangement of Mn2+ uptake within specific brain nuclei (i.e., reorganization). Reorganization of Mn2+ uptake in the superior olivary complex and cochlear nucleus was dependent upon tinnitus status. However, reorganization of Mn2+ uptake in the inferior colliculus was dependent upon hearing sensitivity. Furthermore, following permanent hearing loss, reduced Mn2+ uptake was observed. Overall, by combining testing for hearing sensitivity, tinnitus, and SNA, our data move forward the possibility of discriminating the contributions of hyperacusis and hearing loss to tinnitus. PMID- 29488009 TI - Innovating undergraduate pathology education through public engagement. AB - The trends in modern undergraduate medical education focus on a patient-centred approach through problem-based learning over the traditional modular curriculum. Integrating pathology into this style of learning has resulted in the dilution of core scientific principles which may have contributed to reduced understanding and interest in the subject. We aim to innovate pathology education by utilising National Pathology Week which is organised by the Royal College of Pathologists to develop the public engagement model which empowers students to learn pathology by teaching the public. Through this model, we hope to generate a greater interest in pathology at both undergraduate and postgraduate stages of education. We obtained funding from the Royal College of Pathologists to organise National Pathology Week at Exeter Medical School and the Royal Devon & Exeter Hospital. We involved 125 undergraduate student volunteers from health-related courses. We designed a curriculum aiming to educate both students and public on current topics such as cancer screening programmes, antibiotic resistance, diagnosis of inflammatory bowel disease and the role of pathologists. We hosted 15 pathologists, biomedical scientists and microbiologists to engage with students, share experiences and offer an insight into their careers. Through this project, we interacted with over 500 members of the public and 150 school students. The medical student volunteers developed a range of skills including competent use of microscopes to visualise pathology slides, effective communication with lay audiences to teach pathology and understanding of the clinical application of pathology. We believe the public engagement model of teaching undergraduate students has the potential to develop a greater interest in pathology whilst benefitting the wider community. PMID- 29488010 TI - The urinary phenolic acid profile varies between younger and older adults after a polyphenol-rich meal despite limited differences in in vitro colonic catabolism. AB - PURPOSE: To investigate whether age influences colonic polyphenol metabolism. METHODS: Healthy participants, younger (n = 8; 23-43 years) and older (n = 13; 51 76 years), followed a 3-day low-polyphenol diet (LPD) and a 3-day high-polyphenol diet (HPD). Urinary phenolic acids (PA), short chain fatty acids (SCFA), pH and gas were monitored, alongside selected colonic bacteria. Human faecal in vitro fermentations of rutin with or without raftiline were used to evaluate the gut microbiota capacity in a subset of both groups. RESULTS: Total urinary PA were higher in the older group after HPD compared to the younger group (1.5-fold; p = 0.04), with no difference between groups in terms of a change between diets (Delta high-low diet). While 17 PA were detected in all younger participants after HPD, a narrower range (n = 8 to 16 PA) was detected in most (n = 9/13) older participants, with lower level of benzoic acid (19-fold; p = 0.03), vanillic acid (4.5-fold; p = 0.04) but higher hippuric acid (2.7-fold; p = 0.03). Faecal SCFA concentration did not change after HPD within group, with similar differential excretion (Delta high-low diet) between groups. There were no differences between groups for faecal pH, total, faecal bacteria including Flavonifractor plautii, bifidobacteria, and bacteroides. In human in vitro faecal fermentations, seven PAs were detected in both groups after 24 h of rutin fermentation, with no quantitative and modest qualitative differences between groups. Total SCFA in faecal fermentation did not differ between groups, except for butyric acid (twofold higher in the older group; p = 0.009) when rutin was fermented with raftiline over 24 h. CONCLUSIONS: Urinary phenolic acids were less diverse in older participants despite limited difference in functional capacity of in vitro faecal fermentations. PMID- 29488011 TI - Factors Contributing to the Decline of Traditional Practices in Communities from the Gwallek-Kedar area, Kailash Sacred Landscape, Nepal. AB - Traditional knowledge and practices are increasingly recognized in the resource conservation and management practices, however are declining in many parts of the world including Nepal. Studies on the inventory of traditional knowledge are available, albeit limited, and empirical analysis of factors contributing to the decline of traditional knowledge are negligible in Nepal. We thus initiated this study in the Nepal part of the Kailash Sacred Landscape to (i) document traditional knowledge and practices on agriculture, forest-based herbal remedy, and genetic resource conservation; and (ii) identify factors contributing to the decline of traditional practices in the communities. Data was collected during September-December 2015 through key informant interviews, focus group discussions, and households survey. The household survey data was used in binary logistic regression analysis to identify factors contributing to the decline of six key traditional practices. The study documented 56 types of traditional practices. The regressions showed that the age of the respondent, distance to the nearest forest, distance to the nearest motorable road, family members' ill health, and seasonal migration of the household members for jobs significantly influencing to the decline of the particular traditional practices, however, their effects vary within a practice and among the practices. The use of modern medicine, increasing road linkages, decreasing trend of plant resource availability, and agriculture intensification are responsible for the decline of the particular traditional practices. We recommend to recognize their significance in the governing socio-ecological systems and to link the traditional and scientific knowledge systems through policy formulations. PMID- 29488012 TI - System productivity alters predator sorting of a size-structured mixed prey community. AB - Predator-prey interactions are often size-structured and focused on smaller vulnerable size classes. Predators are also predicted to sort prey communities according to relative vulnerabilities. Increased system productivity and juvenile growth may benefit some species more than others, making relative vulnerability non-static and growth-mediated. We hypothesized that increased system productivity would weaken juvenile-stage predation generally, and potentially shift the community sorting effects of a predator. Using replicated wetland mesocosms we quantified the effects of a generalist size-specific crayfish predator (Procambarus fallax) on juveniles of two species of apple snails (Pomacea spp.) under two levels of system productivity (low vs. high). After 6 weeks of exposure, we quantified predator and productivity effects on snail survival, biomass, and composition of the assemblage. Crayfish depressed the final density and biomass of snails, and sorted the assemblage, selectively favoring survival of the native P. paludosa over the intrinsically more vulnerable invasive P. maculata. Both snails grew faster at higher productivity, but growth differentially increased survival of the invasive snail in the presence of crayfish and weakened the sorting effect. The native P. paludosa hatches at a larger less vulnerable size than the invasive P. maculata, but higher productivity reduced the relative advantage of P. paludosa. Our results are inconsistent with predictions about the sorting effects of predators across productivity gradients, because the more vulnerable prey dominated at low productivity. Our findings highlight that the relative vulnerabilities of prey to a common predator are not always fixed, but can be growth-mediated. PMID- 29488013 TI - Candidate genes for cooperation and aggression in the social wasp Polistes dominula. AB - Cooperation and aggression are ubiquitous in social groups, and the genetic mechanisms underlying these behaviours are of great interest for understanding how social group formation is regulated and how it evolves. In this study, we used a candidate gene approach to investigate the patterns of expression of key genes for cooperation and aggression in the brain of a primitively eusocial wasp, Polistes dominula, during colony founding, when multiple foundresses can join the same nest and establish subtle hierarchies of dominance. We used a comparative approach to select candidate genes for cooperation and aggression looking at two previously published studies on global gene expression in wasps and ants. We tested the expression of these genes in P. dominula wasps that were either displaying aggressive behaviour (dominant and single foundresses) or cooperation (subordinate foundresses and workers) towards nestmates. One gene in particular, the egg yolk protein vitellogenin, known for its reproductive role in insects, displayed patterns of expression that strongly matched wasp social rank. We characterize the genomic context of vitellogenin by building a head co-expression gene network for P. dominula, and we discuss a potential role for vitellogenin as a mediator of social interactions in wasps. PMID- 29488014 TI - Tyraminergic modulation of agonistic outcomes in crayfish. AB - Octopamine, a biogenic amine, modulates various behaviors, ranging from locomotion and aggression to learning and memory in invertebrates. Several studies recently demonstrated that tyramine, the biological precursor of octopamine, also affects behaviors independent of octopamine. Here we investigated the involvement of tyramine in agonistic interaction of the male crayfish Procambarus clarkii. When male crayfish fight, larger animals (3-7% difference in body length) are more likely to win. By contrast, direct injection of tyramine or octopamine counteracted the physical advantage of larger animals. Tyramine or octopamine-injected naive large animals were mostly beaten by untreated smaller naive animals. This pharmacological effect was similar to the loser effect in which subordinate larger animals are frequently beaten by smaller animals. Furthermore, loser effects were partly eliminated by either injection of epinastine, an octopamine blocker, or yohimbine, a tyramine blocker, and significantly diminished by injection of a mixture of both blockers. We also observed that tyramine levels in the subesophageal ganglion were remarkably increased in subordinate crayfish after losing a fight. These results suggest that tyramine modulates aggressive levels of crayfish and contributes to the loser effect in parallel with octopamine. PMID- 29488015 TI - The POU5F1 gene expression in colorectal cancer: a novel prognostic marker. AB - PURPOSE: The POU5F1 gene, which encodes the POU domain, class 5, transcription factor 1 (also known as Oct-4), is expressed in embryonic stem cells where it regulates pluripotency and proliferation. Few studies have examined the expression and significance of POU5F1 in cancer tissues. The aim of this study was to clarify its significance in colorectal cancer (CRC). METHODS: The study included 95 patients who underwent surgery for CRC from 2009 to 2011. The correlations between the POU5F1 gene expression and the clinical parameters were assessed in these patients. The serum TP53 expression levels were also examined by an enzyme-linked immunosorbent assay. RESULTS: Patients with a high POU5F1 expression were significantly more likely to have a poor prognosis than those with a low expression. In contrast, patients with a low POU5F1 expression had a better disease-free survival after curative surgical resection than those with a high expression (P = 0.007). Multivariate analyses showed that the POU5F1 expression (P = 0.003) and lymph node metastasis (P < 0.001) were significantly correlated with the disease-free survival. The prognosis was significantly related to the serum TP53 levels, according to the POU5F1 expression. CONCLUSION: The POU5F1 expression was suggested to be a prognostic factor in patients with CRC. PMID- 29488016 TI - An Update on Systemic Sclerosis-Associated Pulmonary Arterial Hypertension: a Review of the Current Literature. AB - PURPOSE OF REVIEW: This review will summarize the most current literature on the clinical impact, epidemiology, risk factors, screening recommendations, predictors of outcomes, and treatment options in patients with pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc). RECENT FINDINGS: PAH continues to be a major cause of morbidity and mortality in SSc. Many risk factors and predictors of outcomes have been identified in patients with SSc including clinical, hemodynamic, and laboratory parameters. Screening for PAH in SSc patients is important and screening algorithms have been developed. Despite many available treatment options for PAH, prognosis remains poor. Awareness of risk factors, early detection, and up-front combination treatment are important considerations in SSc-PAH and may lead to improved outcomes. Further research to develop better biomarkers and therapies is needed to continue to improve survival and outcomes in patients with SSc-PAH. PMID- 29488017 TI - Network analysis of drug-related problems in hospitalized patients with hematologic malignancies. AB - PURPOSE: Network analysis was conducted to systematically analyze the relationship between causative drugs and types of drug-related problems (DRPs) in hospitalized patients with hematologic malignancies. METHODS: A total of 1187 DRPs identified in hematology wards between 2013 and 2015 were analyzed. DRPs were classified into 11 sub-domains for problems and 35 sub-domains for causes according to Pharmaceutical Care Network Europe classification. Causative drugs were classified by Anatomical Therapeutic Chemical code. Network analytic tool was used to represent the relationship between drugs, causes, and problems. In degree centrality (CD-in) was calculated to identify major causes of DRPs. RESULTS: The following drugs accounted for more than 5% of DRP, including antibacterials (J01, 26.5%), drugs for acid-related disorders (A02, 11.5%), antiemetics (A04, 9.7%), antifungals (J02, 8.8%), and antineoplastic agents (L01, 7.0%). Inappropriate combinations (C1.3, CD-in of 161) of drugs for acid-related disorders, antifungals, and antineoplastic agents were major causes of DRPs and induced non-optimal effects of drug treatment (P1.2). Inappropriate dose adjustments (C3.6, CD-in of 151) of antibacterials lowered effects (P1.2) and increased side effects (P2.1). Missing necessary synergistic or preventive drugs, especially antiemetics, (C1.8, CD-in of 54) resulted in untreated indication (P1.4). CONCLUSIONS: DRPs were mainly related to medications for supportive care. More attention should be paid to interactions of drugs used for acid-related disorders, dose adjustment of antibacterials, and omission of antiemetics in hospitalized patients with hematologic malignancy. PMID- 29488018 TI - Incidence and risk factors of medical complications and direct medical costs after osteoporotic fracture among patients in China. AB - : We analyzed the incidence of medical complications after osteoporotic fractures and estimated its risk factors and cost impacts. Osteoporotic fractures can result in lots of serious medical complications, which is associated with patients' baseline characteristics such as patients' disease history and significantly increased patients' direct medical costs. PURPOSE: The purpose of the study is to investigate the incidence and identify the risk factors of medical complications after osteoporotic fracture, and quantify patients' economic burden. METHODS: Data were obtained from the Tianjin Urban Employee Basic Medical Insurance database (2009-2014). Patients aged >= 50 years, had >= 1 diagnoses of hip or vertebral fracture between 2010 and 2012, and continuously enrolled from 12 months before to 24 months after the first identified fracture were included. The incidence of medical complications was estimated within 12 months before and after fracture. Direct medical costs were measured and compared between patients with at least one medical complication and without any medical complications. Logistic regression was applied to identify risk factors for any medical complications. RESULTS: Three thousand seven hundred nineteen patients were identified; 45.0% had hip fracture, and 56.2% had vertebral fracture. After osteoporotic fracture, the accumulative incidence of the most common medical complications including constipation (25.6%, RR 1.38 [1.28, 1.48]), stroke (25.2%, 1.16 [1.09, 1.24]), pneumonia (17.0%, 1.55 [1.40, 1.73]), urinary tract infection (16.3%, 1.23 [1.12, 1.36]), and arrhythmia (11.8%, 1.39 [1.23, 1.56]) was significantly higher than that before fracture. Advanced age; male sex; retirement status; diagnosis of hypertension, chronic heart disease, cerebrovascular disease, hemiplegia, or Parkinson's disease; and higher direct medical costs at baseline were significant predictors of complications. The all cause direct medical cost during 24-month follow-up was $5665. Medical complications significantly increased patients' direct medical costs. CONCLUSIONS: Osteoporotic fractures led to amount of medical complications, which significantly increased patients' economic burden. Complications correlate to various factors such as patients' disease history. PMID- 29488019 TI - Nonlinear mechanical behaviors of a nanoparticle monolayer at the air-water interface. AB - Nanoparticle can adsorb at the air-water interface and gives rise to the special interfacial mechanical properties. With the influence of external stimulus, the adsorption state of the particles may be changed and in turn the mechanical properties of the particle layer. In this work, we study the mechanical properties of a monolayer of silica nanoparticles deposited in the Langmuir trough. The area of the monolayer was varied sinusoidally by two oscillating barriers and the surface pressure was monitored by two orthogonal Wilhelmy plates. It has been found that the surface pressure of the particle layer exhibits a significant anisotropic effect. At the early stage of the oscillation, the surface pressure versus time is sinusoidal. However, with the increase of the oscillation time, the response of the particle layer significantly deviates the sinusoidal function, which implies that the response becomes nonlinear caused by a long-term oscillation. The fast Fourier Transformation (FFT) of the surface pressure data shows that the non-sinusoidal response is composed of several fundamental frequency responses. We eventually obtained the time variation of the compression modulus E and shear modulus G . A possible mechanism was proposed to account for the mechanical properties change and the nonlinear behavior of the particle monolayer. PMID- 29488020 TI - Effect of ventilation rate on air cleanliness and energy consumption in operation rooms at rest. AB - The interrelationships between ventilation rate, indoor air quality, and energy consumption in operation rooms at rest are yet to be understood. We investigate the effect of ventilation rate on indoor air quality indices and energy consumption in ORs at rest. The study investigates the air temperature, relative humidity, concentrations of carbon dioxide, particulate matter (PM), and airborne bacteria at different ventilation rates in operation rooms at rest of a medical center. The energy consumption and cost analysis of the heating, ventilating, and air conditioning (HVAC) system in the operation rooms at rest were also evaluated for all ventilation rates. No air-conditioned operation rooms had very highest PM and airborne bacterial concentrations in the operation areas. The bacterial concentration in the operation areas with 6-30 air changes per hour (ACH) was below the suggested level set by the United Kingdom (UK) for an empty operation room. A 70% of reduction in annual energy cost by reducing the ventilation rate from 30 to 6 ACH was found in the operation rooms at rest. Maintenance of operation rooms at ventilation rate of 6 ACH could save considerable amounts of energy and achieve the goal of air cleanliness. PMID- 29488021 TI - Correction to: Recommendations for the Development and Validation of Neutralizing Antibody Assays in Support of Biosimilar Assessment. AB - In the published article, the author B. Babbitt was cited as affiliation 9, but should have been cited as affiliation 2. In addition, there are 2 errors in the affiliations. The correct affiliations are shown in this erratum. PMID- 29488022 TI - Taribavirin and 5-Fluorouracil-Loaded Pegylated-Lipid Nanoparticle Synthesis, p38 Docking, and Antiproliferative Effects on MCF-7 Breast Cancer. AB - PURPOSE: Breast cancer is the second most common cause of mortality in women in the United States. Targeted delivery of antitumor breast cancer drugs as a drug delivery strategy may allow direct delivery into the tumor. Currently, chemotherapy is one of the principle strategies for cancer treatment, but it can have toxic side effects. Nanotechnology attempts to resolve these challenges by loading drugs in nanoparticles, such as solid lipid nanoparticles (SLN). In response to the breast cancer drug 5-fluorouracil (5-FU), p38MAPK signaling has been investigated since the 1990s. Ribavirin, a nucleotide derivative, inhibits p38MAPK in infected hepatocytes. A ribavirin prodrug, taribavirin (TBV), was recently synthesized to concentrate in the liver and have minimal concentration in red blood cells. METHODS: In this study, TBV and 5-FU-pegylated SLNs were prepared and characterized. The in vitro cytotoxicity was evaluated against MCF-7 breast cancer cells. Using molecular docking experiments, 5-FU and TBV were docked on p38MAPK protein. RESULTS: The TBV nanoformulation had the highest cytotoxic effects, achieving IC50 = 0.690 MUM after 24 h, compared with free TBV, which also achieved a good cytotoxic effect (IC50 = 0.756 MUM). However, there was a detectable cytotoxic effect and an undetectable IC50 of 5-FU nanoparticles and free 5-FU on MCF-7 cells. CONCLUSIONS: The effect of TBV nanoparticles on MCF 7 cells may be due to its inhibitory effect against p38MAPK protein, where it fits inside the active pocket site of the p38 protein molecular surface, with a minimum binding affinity of -5.5 kcal/mol (rmsd of 1.07), and it formed strong hydrogen bonds with amino acids ASP'168, ILE'166, HIS'148, and ILE'147. Further studies are warranted to investigate the mechanistic details of the proposed approach. PMID- 29488023 TI - Flagellated microswimmers: Hydrodynamics in thin liquid films. AB - The hydrodynamics of a flagellated microswimmer moving in thin films is discussed. The fully resolved hydrodynamics is exploited by solving the Stokes equations for the actual geometry of the swimmer. Two different interfaces are used to confine the swimmer: a bottom solid wall and a top air-liquid interface, as appropriate for a thin film. The swimmer follows curved clockwise trajectories that can converge towards an asymptotically stable circular path or can result in a collision with one of the two interfaces. A bias towards the air-liquid interface emerges. Slight changes in the swimmer geometry and film thickness strongly affect the resulting dynamics suggesting that a very reach phenomenology occurs in the presence of confinement. Under specific conditions, the swimmer follows a "crown-like" path. Implications for the motion of bacteria close to an air bubble moving in a microchannel are discussed. PMID- 29488024 TI - Evolution through cold and deep waters: the molecular phylogeny of the Lithodidae (Crustacea: Decapoda). AB - The objectives of this work are to use gene sequence data to assess the hypothesis that the Lithodinae arose from ancestors with uncalcified abdomens in shallow waters of the North-East Pacific, investigate the monophyly and interrelationships of genera within the Lithodinae and to estimate the scale and minimum number of biogeographic transitions from the shallow environment to the deep sea and vice versa. To do this, phylogenetic analysis from three mitochondrial and three nuclear markers was conducted using minimum evolution, maximum likelihood and Bayesian methods. The Lithodinae as defined to include North Pacific genus Cryptolithodes may be paraphyletic, with the Hapalogastrinae and Cryptolithodes as sister taxa. This implies that the soft-bodied abdomen of the Hapalogastrinae might not be plesiomorphic for the Lithodidae. Paralomis, Lopholithodes, Phyllolithodes, Lithodes and Neolithodes share a common ancestor, from which the North Pacific Hapalogastrinae did not descend. Lithodid ancestors are likely to have had a north Pacific, shallow water distribution and to have had planktotrophic larvae. North Pacific genus Paralithodes is paraphyletic; P. brevipes is the most basal member of the genus (as sampled) while P. camtschaticus and P. platypus are more closely related to the genera Lithodes and Neolithodes. Genera Lithodes, Neolithodes and Paralomis (as sampled) are monophyletic if Glyptolithodes is included within Paralomis. Lopholithodes is closely related to, but not included within, the Paralomis genus. Paralomis is divided into at least two major lineages: one containing South Atlantic, West African, and Indian Ocean species, and the other containing Pacific and South American species. Several species of Paralomis do not resolve consistently with any other groups sampled, implying a complex and possibly rapid global evolution early in the history of the genus. Relationships within the Lithodes genus vary between analytical methods, suggesting that conclusions may not be stable. Consistently, however, Indian Ocean and Pacific forms-L. murrayi, L. longispina and L. nintokuae form a group separated from Atlantic species such as L. santolla, L. confundens, L. maja and L. ferox. PMID- 29488025 TI - Positive end-expiratory pressure-induced increase in external jugular venous pressure does not predict fluid responsiveness in laparoscopic prostatectomy. AB - BACKGROUND: Dynamic change in central venous pressure (CVP) was associated with fluid responsiveness. External jugular venous pressure (EJVP) may reliably estimate CVP and have the advantages of being less invasive. We investigated whether increase in EJVP induced by positive end-expiratory pressure (PEEP) could be a reliable predictor of fluid responsiveness in patients undergoing robot assisted laparoscopic prostatectomy (RALP). METHODS: Fifty patients who underwent RALP with steep Trendelenburg position were enrolled. PEEP of 10 cmH2O was applied for 5 min and then 300 ml of colloid was administered. EJVP, stroke volume variation (SVV), and cardiac index calculated by pulse contour method were measured before and after the PEEP challenge and colloid administration. Increase in cardiac index > 10% was used to define the fluid responsiveness. RESULTS: Twenty-six patients were fluid responders. Neither the increase in EJVP after the initial PEEP nor SVV was significantly different between responders and non responders. They were not significantly correlated with an increase in cardiac index. The areas under the receiver operating characteristic curve (AUC) of these two variables were not significantly greater than 0.5. However, a post hoc analysis revealed that AUC of a decrease in EJVP after removal of PEEP was significantly greater than 0.50. CONCLUSION: Our study results suggested that SVV and increase in EJVP after applying PEEP were not accurate predictors of fluid responsiveness during RALP. Further studies are required to find an adequate preload index in robot-assisted urologic surgery with steep Trendelenburg position. PMID- 29488026 TI - Does local factors alter discharge times after surgery? PMID- 29488027 TI - Ultrasound versus fiberscope-guided tracheal intubation. PMID- 29488028 TI - In reply. PMID- 29488029 TI - Incidence of psychiatric disorders among accompanied and unaccompanied asylum seeking children in Denmark: a nation-wide register-based cohort study. AB - One in four asylum applicants in Europe are children, and 23% of whom are unaccompanied and may be at increased risk of mental illness. This study contributes to the limited evidence base by comparing the incidence of psychiatric disorders among unaccompanied and accompanied refugee children. We linked a cohort of refugee children who obtained right of residency in Denmark between 01 January 1993 and 31 December 2010 to the Danish Psychiatric Central Register, and calculated incidence rates per 100,000 person years and incidence rate ratios of overall psychiatric disorder, psychotic disorders, affective disorders, and neurotic disorders for accompanied and unaccompanied minors using Poisson regression. We adjusted the analyses for sex, age at residency, and age at arrival (aIRR). Stratified analyses were conducted by nationality. Unaccompanied minors had significantly higher rates of any psychiatric disorder (aIRR: 1.38, 95% CI 1.14-1.68) and neurotic disorders (aIRR: 1.67, 95% CI 1.32 2.13) than accompanied minors. Among children from Afghanistan, unaccompanied minors had significantly higher rates of any psychiatric disorder (aIRR: 2.23, 95% CI 1.26-3.93) and neurotic disorders (aIRR: 3.50, 95% CI 1.72-7.11). Among children from Iraq, unaccompanied minors had higher rates of any psychiatric disorder (aIRR: 2.02, 95% CI 1.18-3.45), affective disorders (aIRR: 6.04, 95% CI 2.17-16.8), and neurotic disorders (aIRR: 3.04, 95% CI 1.62-5.70). Unaccompanied children were found to experience a higher incidence of any psychiatric disorder and neurotic disorders. Strategies are needed to address the specific mental health and social needs of unaccompanied minors. PMID- 29488030 TI - Labeling of DOTA-conjugated HPMA-based polymers with trivalent metallic radionuclides for molecular imaging. AB - BACKGROUND: In this work, the in vitro and in vivo stabilities and the pharmacology of HPMA-made homopolymers were studied by means of radiometal labeled derivatives. Aiming to identify the fewer amount and the optimal DOTA linker structure that provides quantitative labeling yields, diverse DOTA-linker systems were conjugated in different amounts to HPMA homopolymers to coordinate trivalent radiometals Me(III)* = gallium-68, scandium-44, and lutetium-177. RESULTS: Short linkers and as low as 1.6% DOTA were enough to obtain labeling yields > 90%. Alkoxy linkers generally exhibited lower labeling yields than alkane analogues despite of similar chain length and DOTA incorporation rate. High stability of the radiolabel in all examined solutions was observed for all conjugates. Labeling with scandium-44 allowed for in vivo PET imaging and ex vivo measurements of organ distribution for up to 24 h. CONCLUSIONS: This study confirms the principle applicability of DOTA-HPMA conjugates for labeling with different trivalent metallic radionuclides allowing for diagnosis and therapy. PMID- 29488031 TI - Effects of mitral chordae tendineae on the flow in the left heart ventricle. AB - In this paper a computational model for the ventricular flow with a mitral valve and modeled chordae tendineae is presented. The results are compared with an analogous case in which the chordae are not included and their presence is replaced by kinematic boundary conditions. The problem is studied using direct numerical simulation of the Navier-Stokes equations, two-way coupled with a structural solver for the ventricle and mitral valve dynamics. An experimental validation of the model is performed by a comparison of the results with a companion dedicated experiment. It is found that the inclusion of the chordae tendineae makes the model self-consistent thus avoiding the use of ad hoc kinematic constraints to mimic their effect. In this way it is possible to simulate the correct system dynamics without user-defined parameters. More in detail, the results have shown that the mitral valve dynamics can be described also without chordae with the help of ad hoc kinematic constrains, whereas the changes produced in the intra-ventricular flow need the explicit consideration of the chordae in the model. On the other hand, the computational load increases owing to the presence of additional structures that, being thin filaments, are also demanding for the spatial resolution requirements. Since the presence of the chordae tendineae produces only specific differences in the overall flow structure, we conclude that their explicit modeling should be limited to those cases in which their presence is unavoidable. PMID- 29488032 TI - Contemporary Antiplatelet Pharmacotherapy in the Management of Acute Coronary Syndromes. AB - PURPOSE OF REVIEW: Antiplatelet therapies are pivotal treatments in the management of acute coronary syndrome (ACS) with or without revascularization. In recent years, the use of P2Y12 antagonists prior to catheterization, so-called pretreatment, has been questioned, particularly in patients who may be at higher bleeding risks. The purpose of this review was to evaluate the current literature on contemporary and novel antiplatelet therapy in the pretreatment and treatment of ACS. RECENT FINDINGS: The P2Y12 receptor antagonists are associated with substantial reductions in morbidity and mortality for all types of ACS but only clopidogrel and ticagrelor have sufficient evidence for use in the pretreatment setting. The data regarding prasugrel support the use in patients undergoing percutaneous intervention (PCI). The glycoprotein IIa/IIIb antagonists are the most optimal for use in high-risk ACS as an adjuvant therapy during and after PCI. In summary, although all P2Y12 antagonists have morbidity- and mortality reducing effects in ACS, only clopidogrel and ticagrelor have sufficient evidence in the pretreatment setting. Newer antiplatelet therapies, most notably the protease-activated receptor 1 antagonists, are evolving and promising but are associated with greater bleeding risks. PMID- 29488033 TI - Accelerating Therapeutic Development through Innovative Trial Design in Colorectal Cancer. AB - OPINION STATEMENT: Current trial design is challenged by the advancement of technologies that have enabled deeper understanding of the molecular drivers of colorectal cancer (CRC). The speed of trial testing and the ability to test larger volumes of promising novel agents in the face of smaller populations identified by molecular profiling are challenges posed to clinical studies. Master protocols that utilize umbrella designs are equipped to deal with potential biomarker and matched treatments simultaneously. Although complex in nature, they increase trial efficiency by utilizing shared screening platforms, test multiple treatments together, and simplify regulatory submission and reporting under a common protocol. Emerging technologies such as circulating tumor DNA (ctDNA) may help speed up adjuvant trials. These studies have been traditionally slow to complete due to low event rates and the high numbers needed to recruit. ctDNA used as a surrogate for minimal residual disease (MRD) and as an early marker of relapse may help counter some of these factors that deter innovation in this setting. Finally, in the era of precision medicine, surgery should not be forgotten as the only potentially curative option to date in metastatic disease. Five-year overall survival following resection of liver metastasis exceeds what can be achieved with chemotherapy alone in selected cases. Surgical advances have lowered morbidity and allow for greater resection volumes and repeated interventions. Although historically challenging, a well designed randomized surgical intervention trial would greatly facilitate moving single-institution guidelines reported by case series into wider clinical practice. PMID- 29488034 TI - Relative proportions of E. coli and Enterococcus spp. may be a good indicator of potential health risks associated with the use of roof harvested rainwater stored in tanks. AB - A total of 285 water samples were collected from 71 roof harvested rainwater tanks from four villages in different provinces over a two-year (2013-2014) period during the early (October to December) and late (January to March) rainy season. Water quality was evaluated based on Escherichia coli, faecal coliforms and Enterococcus spp. prevalence using the IDEXX Quanti-Tray quantification system. Real-Time PCR was used to analyse a subset of 168 samples for the presence of Shigella spp., Salmonella spp. and E. coli virulence genes (stx1, stx2 and eaeA). Escherichia coli were detected in 44.1% of the samples, Enterococcus spp. in 57.9% and faecal coliforms in 95.7%. The most prevalent E. coli concentrations in harvested rainwater were observed in 29.1% of samples and 22.5% for Enterococcus spp. and, were within 1-10 cfu/100 ml and 10-100 cfu/100 ml, respectively, whereas those for faecal coliforms (36.6%) were within 100-1000 cfu/100 ml. On average 16.8% of the samples had neither E. coli nor Enterococcus spp. detected, while 33.9% had only Enterococcus spp. and 23.7% had only E. coli. E. coli and Enterococcus spp. were detected together in 25.5% of the samples. Evaluation of samples for potential pathogenic bacteria showed all tested samples to be negative for the Shigella spp. ipaH gene, while five tested positive for Salmonella ipaB gene. None of the samples tested positive for the stx1 and stx2 genes, and only two tested positive for the eaeA gene. These findings are potentially useful in the development of a simplified risk assessment strategy based on the concentrations of indicator bacteria. PMID- 29488035 TI - [Voluntary stopping eating and drinking (VSED) : A position paper of the Austrian Palliative Society]. AB - In some cases terminally ill patients fear of prolonged dying and suffering can manifest itself in the voluntary refusal of food and fluids, aiming to accelerate the dying process. This represents a considerable area of conflict, because of the ethical responsibility to not aid a person's death but also to respect a patients autonomy.There is a clear separation between an assisted suicide and following a patient's wishes. Not to accept the voluntary refusal of FVNF would have to be considered as forced treatment of patients while they are capable of self-determination.Several symptoms associated with or caused by voluntary refusal of food and fluids do require palliative care. It is important to be aware, that caring for dying patients refusing food and fluids and accepting their choice is not synonymous with assisted suicide. Rather is it part of medical and nursing care for patients during their dying-process.An interprofessional working group of the Austrian Palliative Society (OPG) intends to shed light on the legal, ethical, medical and nursing related aspects concerning this subject of growing public and professional interest. PMID- 29488036 TI - Cholesterol metabolism-physiological regulation and pathophysiological deregulation by the endoplasmic reticulum. AB - Cholesterol is an essential lipid for mammalian cells and its homeostasis is tightly regulated. Disturbance of cellular cholesterol homeostasis is linked to atherosclerosis and cardiovascular diseases. A central role in the sensing and regulation of cholesterol homeostasis is attributed to the endoplasmic reticulum (ER). This organelle harbours inactive transcription factors, which sense ER cholesterol levels and initiate transcriptional responses after activation and translocation into the nucleus. Thereupon, these responses enable adaption to high or low cellular cholesterol levels. Besides the abovementioned canonical functions, ER stress-induced by metabolic burden-and the resulting unfolded protein response influence cholesterol metabolism relevant to metabolic disorders. This review summarizes basic as well as recent knowledge on the role of the ER in terms of regulation of cholesterol metabolism. PMID- 29488038 TI - Shame and Depressive Symptoms: Self-compassion and Contingent Self-worth as Mediators? AB - Research has identified the experience of shame as a relevant predictor of depressive symptoms. Building upon resilience theory, this is the first study to investigate if self-compassion and/or contingent self-worth (i.e., family support and God's love) mediate the link between shame and depressive symptoms. Participants were 109 African Americans, within the age range of 18 and 64, who sought service following a suicide attempt from a public hospital that serves mostly low-income patients. Findings suggest that shame was related to depressive symptoms through self-compassion but not through contingent self-worth, underscoring the significant role that self-compassion plays in ameliorating the aggravating effect of shame on depressive symptoms. Results highlight the value of incorporating self-compassion training into interventions for suicidal African Americans in an effort to reduce the impact of shame on their depressive symptoms and ultimately their suicidal behavior and as a result enhance their capacity for resilience. PMID- 29488037 TI - Severe Intestinal Inflammation in the Small Intestine of Mice Induced by Controllable Deletion of Claudin-7. AB - BACKGROUND: As a potential tumor suppressor gene, Claudin-7 (Cldn7), which is a component of tight junctions, may play an important role in colorectal cancer occurrence and development. AIMS: To generate a knockout mouse model of inducible conditional Cldn7 in the intestine and analyze the phenotype of the mice after induction with tamoxifen. METHODS: We constructed Cldn7-flox transgenic mice and crossed them with Villin-CreERT2 mice. The Cldn7 inducible conditional knockout mice appeared normal and were well developed at birth. We induced Cldn7 gene deletion by injecting different dosages of tamoxifen into the mice and then conducted a further phenotypic analysis. RESULTS: After induction for 5 days in succession at a dose of 200 ul tamoxifen in sunflower oil at 10 mg/ml per mouse every time, the mice appeared dehydrated, had a lower temperature, and displayed inactivity or death. The results of hematoxylin-eosin staining showed that the intestines of the Cldn7 inducible conditional knockout mice had severe intestinal defects that included epithelial cell sloughing, necrosis, inflammation and hyperplasia. Owing to the death of ICKO mice, we adjusted the dose of tamoxifen to a dose of 100 ul in sunflower oil at 10 mg/ml per mouse (aged more than 8 weeks old) every 4 days. And we could induce atypical hyperplasia and adenoma in the intestine. Immunofluorescent staining indicated that the intestinal epithelial structure was destroyed. Electron microscopy experimental analysis indicated that the intercellular gap along the basolateral membrane of Cldn7 inducible conditional knockout mice in the intestine was increased and that contact between the cells and matrix was loosened. CONCLUSIONS: We generated a model of intestinal Cldn7 inducible conditional knockout mice. Intestinal Cldn7 deletion induced by tamoxifen initiated inflammation and hyperplasia in mice. PMID- 29488040 TI - Did You Listen to the Beat? Auditory Steady-State Responses in the Human Electroencephalogram at 4 and 7 Hz Modulation Rates Reflect Selective Attention. AB - The acoustic envelope of human speech correlates with the syllabic rate (4-8 Hz) and carries important information for intelligibility, which is typically compromised in multi-talker, noisy environments. In order to better understand the dynamics of selective auditory attention to low frequency modulated sound sources, we conducted a two-stream auditory steady-state response (ASSR) selective attention electroencephalogram (EEG) study. The two streams consisted of 4 and 7 Hz amplitude and frequency modulated sounds presented from the left and right side. One of two streams had to be attended while the other had to be ignored. The attended stream always contained a target, allowing for the behavioral confirmation of the attention manipulation. EEG ASSR power analysis revealed a significant increase in 7 Hz power for the attend compared to the ignore conditions. There was no significant difference in 4 Hz power when the 4 Hz stream had to be attended compared to when it had to be ignored. This lack of 4 Hz attention modulation could be explained by a distracting effect of a third frequency at 3 Hz (beat frequency) perceivable when the 4 and 7 Hz streams are presented simultaneously. Taken together our results show that low frequency modulations at syllabic rate are modulated by selective spatial attention. Whether attention effects act as enhancement of the attended stream or suppression of to be ignored stream may depend on how well auditory streams can be segregated. PMID- 29488039 TI - Identification of Floral Volatiles and Pollinator Responses in Kiwifruit Cultivars, Actinidia chinensis var. chinensis. AB - Volatiles emitted from unpollinated in situ flowers were collected from two male cultivars, 'M33', 'M91', and one female cultivar 'Zesy002' (Gold3) of kiwifruit (Actinidia chinensis var. chinensis). The samples were found to contain 48 compounds across the three cultivars with terpenes and straight chain alkenes dominating the headspace. Electrophysiological responses of honey bees (Apis mellifera) and bumble bees (Bombus terrestris) to the headspace of the kiwifruit flowers were recorded. Honey bees consistently responded to 11 floral volatiles from Gold3 pistillate flowers while bumble bees consistently responded to only five compounds from the pistillate flowers. Nonanal, 2-phenylethanol, 4 oxoisophorone and (3E,6E)-alpha-farnesene from pistillate flowers elicited responses from both bee species. Overall, honey bees were more sensitive to the straight chain hydrocarbons of the kiwifruit flowers than the bumble bees, which represented one of the main differences between the responses of the two bee species. The floral volatiles from staminate flowers of the male cultivars 'M33' and 'M91' varied greatly from those of the pistillate flowers of the female cultivar Gold3, with most of the bee active compounds significantly different from those in the Gold3 flower headspace. The total floral emissions of 'M33' flowers were significantly less than those of the Gold3 flowers, while the total floral emissions of the 'M91' flowers were significantly greater than those of the Gold3 flowers. PMID- 29488042 TI - Characterization of hypertrophic cardiomyopathy according to global, regional, and multi-layer longitudinal strain analysis, and prediction of sudden cardiac death. AB - To evaluate the severity of hypertrophic cardiomyopathy (HCM) according to global, regional, and multi-layer longitudinal strain (LS) analysis using speckle tracking echocardiography. From February 2007 to November 2014, we prospectively evaluated 375 consecutive HCM patients referred to our specialized cardiomyopathy center. Demographics, clinical, and rest and exercise echocardiographic parameters were collected according to a completely standardized protocol. Global, regional, and multilayer strain analyses were performed. Correlations between LS and other characteristics were evaluated, and we assessed their prognostic value to predict sudden cardiac death (SCD) or appropriate implantable cardioverter defibrillator (ICD) shocks during follow-up, using Cox proportional hazards analyses. We finally included 217 patients (50.1 +/- 15.6 years, 67% male) but only 179 (82%) had LS analysis of sufficient quality. An inverse relation was observed between the mean basal left ventricular (LV) LS and diastolic parameters [E/Ea (r = - 0.30) and left atrium indexed volume (r = - 0.23)], as well as between the resting LV outflow-tract maximal gradient (r = - 0.26) or during peak exercise (r = - 0.20). Mean LS in the LV hypertrophic area was particularly related with maximal wall thickness (r = - 0.47) and transmural global LS with the degree of myocardial fibrosis in cardiac magnetic resonance (r = - 0.32). During a median follow-up of 2.8 +/- 1.5 years, mean transmural LS in the hypertrophic area was predictor of SCD and appropriate ICD shock (10 events/179 patients, hazard ratio = 0.83 [95% CI 0.72-0.95], p = 0.01). Basal LS and hypertrophic area LS are valuable parameters to evaluate HCM severity. Mean hypertrophic area LS particularly seems predictive of SCD occurrence and appropriate ICD shocks. PMID- 29488043 TI - Evaluation of Kawasaki's disease-associated coronary artery aneurysms with 3D CT cinematic rendering. AB - Kawasaki's disease (KD) is a vasculitis that predominantly affects children and can lead to the development of coronary artery aneurysms. These aneurysms can subsequently thrombose and occlude, which may lead to chest pain and other signs and symptoms of acute coronary syndrome in young patients. Coronary CT angiography, including 3D visualization techniques, is a common modality used in the follow-up of KD patients. In this series of three patients, we present the typical coronary artery imaging findings that can appear in these patients, with an emphasis on the use of the novel 3D technique of cinematic rendering (CR). CR utilizes a different lighting model than other 3D methods and is able to produce highly-detailed, photorealistic images. The potential advantages of CR images in understanding the complex mediastinal vascular anatomy and the relationships of coronary artery aneurysms to other anatomic structures are emphasized. PMID- 29488044 TI - Magnetic resonance imaging (MRI) induced 'hypoxia artifacts' on pulse oximetry: how reliable are MRI compatible monitoring devices? AB - Distinguishing a monitoring artifact requires expertise and adeptness. This can be practically challenging during the course of an anesthetic. We report a case, wherein we experienced episodes of aberrant pulse-oximeter values suggestive of desaturation with normal waveforms, occurring during a particular sequence of magnetic resonance imaging (MRI) performed under general anesthesia, which in fact was an artifact induced by the 3 T MRI during the diffusion tensor imaging sequence. PMID- 29488045 TI - Bladder pressure monitoring and CO2 gas-related adverse events during per-oral endoscopic myotomy. AB - Per-oral endoscopic myotomy (POEM) is a minimally invasive treatment for esophageal achalasia. However, POEM has the potential risk of inducing carbon dioxide (CO2) gas-related adverse events, such as pneumoperitoneum, pneumomediastinum, and pneumothorax. The aim of this study was to evaluate the usability of bladder pressure monitoring as an index of CO2 gas-related pneumoperitoneum. The monitoring of bladder pressure and lung compliance and the incidence of iatrogenic pneumoperitoneum were retrospectively studied in 20 patients who underwent POEM between June 2013 and March 2015. The bladder pressure was measured using a Foley catheter. Abdominal distention was found in nine patients. The bladder pressure was significantly higher in the nine patients with the distention findings compared with patients without distention [7 (6-9) mmHg vs. 1 (0-2) mmHg; P < 0.05]; however, the decrease in dynamic lung compliance was not significantly different compared with patients without distention [- 7 (- 9.3 to - 5.1) vs. - 5 (- 10.2 to - 1.3) ml/cmH2O; P = 0.62]. Based on postoperative changes on CT scans; the following were the observations: pneumomediastinum (55%), minor pneumothorax (5%), pleural effusion (45%), atelectasis (15%), pneumoperitoneum (85%), and subcutaneous emphysema (15%). No significant clinical status was found among the patients postoperatively. Bladder pressure monitoring might be useful for detecting pneumoperitoneum during POEM. PMID- 29488046 TI - Chemosensory cues of predators and competitors influence search for refuge in fruit by the coconut mite Aceria guerreronis. AB - Organisms are adapted to recognize environmental cues that can provide information about predation risk or competition. Non-vagrant eriophyoid mites mainly avoid predation by using habitats that are difficult for predators to access (galls or confined spaces in plants) such as the meristematic region of the coconut fruit, which is inhabited by the phytophagous mites Aceria guerreronis and Steneotarsonemus concavuscutum. The objective of this study was to investigate the response of A. guerreronis to cues from the predators Neoseiulus baraki and Amblyseius largoensis in coconut fruits, cues from conspecifics (A. guerreronis injured) and cues from the phytophage S. concavuscutum. The test was carried out through the release of about 300 A. guerreronis on coconut fruits previously treated with cues from predators, conspecific or heterospecific phytophagous. We also observed the walking behaviour of A. guerreronis exposed to the same chemical cues using a video tracking system. The infestation of fruits by A. guerreronis was greater in the presence of predator cues and reduced in the presence of S. concavuscutum cues, but cues from injured conspecifics did not interfere in the infestation process. In addition, the cues also altered the walking parameters of A. guerreronis: it walked more in response to cues from predators and the heterospecific phytophage. Aceria guerreronis spent more time in activity in the treatments with clues than in the control treatment. These results suggest that A. guerreronis recognizes cues from predators and competitors and modifies its behaviour to increase its fitness. PMID- 29488047 TI - Urological sequelae of desmoids associated with familial adenomatous polyposis. AB - The aim of this retrospective cohort study was to review urological complication rates arising from familial adenomatous polyposis associated desmoid tumours and their management. All patients over a 35-year period were identified from a prospectively maintained polyposis registry database and had an intra-abdominal desmoid tumour. Those without ureteric complications (n = 118, group A) were compared to those that developed ureteric obstruction (n = 40, group B) for demographics, treatment interventions and survival outcomes. 158 (56% female) patients were identified. Median age at diagnosis was 31 years and desmoids typically occurred 3.6 years after colectomy for familial adenomatous polyposis. Ureteric obstruction secondary to tumour growth occurred in 25% of cases. There was no significant difference in gender distribution or overall age at desmoid diagnosis between the two groups. In group B, the median age at desmoid diagnosis was significantly younger in women compared to men (25 and 43 years, respectively) (p = 0.01). Thirty-eight percent of patients already had ureteric obstruction at desmoid diagnosis, the remainder occurred after 48.6 months, but 20 years in two cases. Seventy-three percent (29/40) had ureteric stenting, a long-term requirement for most. Permanent renal injury occurred in six cases but survival between the two groups was not significantly different. Ureteric obstruction occurs frequently in patients with familial adenomatous polyposis and an intra-abdominal desmoid tumour. Those most at risk are the young following colectomy. Clinicians should actively survey the renal tract at regular intervals after a diagnosis of an intra-abdominal desmoid tumour as complications can arise insidiously, at any stage. PMID- 29488048 TI - Pharmacokinetic analysis of metronomic capecitabine in refractory metastatic colorectal cancer patients. AB - The aim of the present study was to assess the pharmacokinetics (PK) of metronomic capecitabine and its metabolites in a population of refractory metastatic colorectal cancer (mCRC) patients. Thirty-four patients (M/F, 22/12) with a diagnosis of mCRC received capecitabine 800 mg p.o. twice a day and cyclophosphamide 50 mg/day p.o. Blood samples were collected at baseline, 15 min, 30 min, 1 h, 1.5 h, 2 h, 3 h and 5 h at day 1 after capecitabine administration. Plasma concentrations of capecitabine and its metabolites were measured by high performance liquid chromatography and the main PK parameters were calculated. Maximum plasma concentrations (Cmax) of capecitabine (11.51 +/- 9.73 MUg/ml) occurred at 0.5 h, whereas the Cmax of 5'-deoxy-5-fluorocytidine (5'-DFCR; 2.45 +/- 2.93 MUg/ml), 5'-deoxy-5-fluorouridine (5'-DFUR; 6.43 +/- 8.2 MUg/ml), and 5 fluorouracil (5-FU; 0.24 +/- 0.16 MUg/ml) were found at 1 h, 1.5 h and 1 h, respectively. Capecitabine, 5'-DFCR, 5'-DFUR and 5-FU AUCs at day 1 were 21.30 +/ 10.78, 5.2 +/- 4.6, 19.59 +/- 3.83 and 0.66 +/- 0.77 hxMUg/ml, respectively. In conclusion, low doses of capecitabine were rapidly absorbed and extensively metabolized, achieving measurable plasma concentrations in a heavily pretreated population of patients. PMID- 29488049 TI - Mulberries in the urine: a tell-tale sign of Fabry disease. AB - Fabry disease is a treatable progressive illness of inborn error causing eventual multiple organ dysfunction in advanced untreated cases. We report on a classic Fabry child patient presenting with urinary mulberry cells and bodies without renal involvement. This report emphasizes the usefulness of urinary microscopic findings in the early diagnosis of Fabry disease. PMID- 29488050 TI - I Wanna Play Too: Factors Related to Changes in Social Behavior for Children With and Without Autism Spectrum Disorder After Implementation of a Structured Outdoor Play Curriculum. AB - Children with autism spectrum disorder (ASD) have difficulties interacting with same-aged peers during unstructured play (e.g., on the playground). Thirty-five toddler and preschool children with and without ASD participated in a structured 15-min outdoor play curriculum. The intervention, the Buddy Game, used familiar songs, movement, and games to promote peer social interaction. A 2 * 3 ANOVA assessed changes in overall targeted social behaviors during baseline, the Buddy Game, and generalization to free-pay. Multiple regression analyses examined factors related to increases in social interactions. Predictors were ASD status of child and age of child. Results indicated the Buddy Game increased overall social interactions and that social interactions were influenced more by ASD status than age. Implications for practitioners are highlighted. PMID- 29488051 TI - Scripted and Unscripted Science Lessons for Children with Autism and Intellectual Disability. AB - Both scripted lessons and unscripted task analyzed lessons have been used effectively to teach science content to students with intellectual disability and autism spectrum disorder. This study evaluated the efficacy, efficiency, and teacher preference of scripted and unscripted task analyzed lesson plans from an elementary science curriculum designed for students with intellectual disability and autism spectrum disorder by evaluating both lesson formats for (a) student outcomes on a science comprehension assessment, (b) sessions to criterion, and (c) average duration of lessons. Findings propose both lesson types were equally effective, but unscripted task analyzed versions may be more efficient and were preferred by teachers to scripted lessons. Implications, limitations, and suggestions for future research are also discussed. PMID- 29488052 TI - Integrating Behavioral Health and Primary Care Services for People with Serious Mental Illness: A Qualitative Systems Analysis of Integration in New York. AB - People with co-occurring behavioral and physical conditions receive poorer care through traditional health care services. One solution has been to integrate behavioral and physical care services. This study assesses efforts to integrate behavioral health and primary care services in New York. Semi-structured interviews were conducted with 52 professionals in either group or individual settings. We aimed to identify factors which facilitate or hinder integration for people with serious mental illness and how these factors inter-relate. Content analysis identified structural, process, organizational ("internal") and contextual ("external") themes that were relevant to integration of care. Network analysis delineated the interactions between these. We show that effective integration does not advance along a single continuum from minimally to fully integrated care but along several, parallel pathways reliant upon consequential factors that aid or hinder one another. PMID- 29488054 TI - The Evolution of Tumour Composition During Fractionated Radiotherapy: Implications for Outcome. AB - Current protocols for delivering radiotherapy are based primarily on tumour stage and nodal and metastases status, even though it is well known that tumours and their microenvironments are highly heterogeneous. It is well established that the local oxygen tension plays an important role in radiation-induced cell death, with hypoxic tumour regions responding poorly to irradiation. Therefore, to improve radiation response, it is important to understand more fully the spatiotemporal distribution of oxygen within a growing tumour before and during fractionated radiation. To this end, we have extended a spatially resolved mathematical model of tumour growth, first proposed by Greenspan (Stud Appl Math 51:317-340, 1972), to investigate the effects of oxygen heterogeneity on radiation-induced cell death. In more detail, cell death due to radiation at each location in the tumour, as determined by the well-known linear-quadratic model, is assumed also to depend on the local oxygen concentration. The oxygen concentration is governed by a reaction-diffusion equation that is coupled to an integro-differential equation that determines the size of the assumed spherically symmetric tumour. We combine numerical and analytical techniques to investigate radiation response of tumours with different intratumoral oxygen distribution profiles. Model simulations reveal a rapid transient increase in hypoxia upon regrowth of the tumour spheroid post-irradiation. We investigate the response to different radiation fractionation schedules and identify a tumour-specific relationship between inter-fraction time and dose per fraction to achieve cure. The rich dynamics exhibited by the model suggest that spatial heterogeneity may be important for predicting tumour response to radiotherapy for clinical applications. PMID- 29488053 TI - miR-140-5p/miR-149 Affects Chondrocyte Proliferation, Apoptosis, and Autophagy by Targeting FUT1 in Osteoarthritis. AB - Osteoarthritis (OA), the most prevalent chronic and degenerative joint disease, is characterized by articular cartilage degradation and chondrocyte injury. Increased cell apoptosis and defective cell autophagy in chondrocytes are a feature of degenerative cartilage. MicroRNAs (miRNAs) have been identified as potential regulators of OA. This study aimed to determine the potential role of miR-140-5p and miR-149 in apoptosis, autophagy, and proliferation in human primary chondrocytes and investigate the underlying mechanism. We revealed the differential expressional profiles of miR-140-5p/149 and fucosyltransferase 1 (FUT1) in the articular cartilage tissues of OA patients and normal people and validated FUT1 was a direct target of miR-140-5p/149. The overexpression of miR 140-5p/149 inhibited apoptosis and promoted proliferation and autophagy of human primary chondrocytes via downregulating FUT1. On the contrary, the downregulation of miR-140-5p/149 inhibited chondrocyte proliferation and autophagy, whereas the effect was reversed by FUT1 knockdown. Taken together, our data suggested that miR-140-5p and miR-149 could mediate the development of OA, which was regulated by FUT1. miR-140-5p/miR-149/FUT1 axis might serve as a predictive biomarker and a potential therapeutic target in OA treatment. PMID- 29488055 TI - The evolutionary origin of chordate segmentation: revisiting the enterocoel theory. AB - One of the definitive characteristics of chordates (cephalochordates, vertebrates) is the somites, which are a series of paraxial mesodermal blocks exhibiting segmentation. The presence of somites in the basal chordate amphioxus and in vertebrates, but not in tunicates (the sister group of vertebrates), suggests that the tunicates lost the somites secondarily. Somites are patterned from anterior to posterior during embryogenesis. How such a segmental pattern evolved from deuterostome ancestors is mysterious. The classic enterocoel theory claims that chordate mesoderm evolved from the ancestral deuterostome mesoderm that organizes the trimeric body parts seen in extant hemichordates. Recent progress in molecular embryology has been tremendous, which has enabled us to test this classic theory. In this review, the history of the study on the evolution of the chordate mesoderm is summarized. This is followed by a review of the current understanding of genetic mapping on anterior/posterior (A/P) mesodermal patterning between chordates (cephalochordates, vertebrates) and a direct developing hemichordate (Saccoglossus kowalevskii). Finally, a possible scenario about the evolution of the chordate mesoderm from deuterostome ancestors is discussed. PMID- 29488056 TI - Effect of achieving sustained virological response before hepatitis C virus related hepatocellular carcinoma occurrence on survival and recurrence after curative surgical microwave ablation. AB - BACKGROUND AND AIM: The effects of achieving sustained virological response (SVR) on recurrence and survival after curative treatment in patients with hepatitis virus C (HCV)-related hepatocellular carcinoma (HCC) is unclear. This study examined the influence of SVR achievement by interferon therapy before HCC occurrence on recurrence and survival. METHODS: This retrospective study included 518 patients who underwent surgical microwave ablation for initial HCV-related HCC between January 2001 and December 2015. Thirty-four patients had achieved SVR (SVR group) and 484 patients had not (control group). Clinical characteristics and long-term outcomes were compared between the two groups. RESULTS: Overall survival rates at 5 and 10 years after curative ablation were 95.8 and 80.4% in the SVR group, and 50.7 and 23.4% in the control, respectively (p < 0.0001). Recurrence-free survival rates at 5 and 10 years were 68.7 and 26.4% in the SVR group, and 24.5 and 7.8% in the control group, respectively (p < 0.0001). Multivariate analyses revealed that achieving SVR as an independent prognostic factor for both overall and recurrence-free survival. In the SVR group, the 5 year recurrence-free survival rates for patients with an interval of 5 years or fewer (n = 24) vs. more than 5 years (n = 10) between achieving SVR and curative ablation were 58.7 and 88.9%, respectively (p = 0.03). CONCLUSIONS: Achieving SVR before HCC occurrence allowed a favorable clinical outcome after curative ablation in HCV-related HCC patients. Patients with HCC that occurred more than 5 years after achieving SVR had longer recurrence-free survival. PMID- 29488057 TI - Patent foramen ovale, paradoxical embolism and fatal coronary obstruction. AB - A 75-year-old woman was admitted to the emergency room with chest pain and vomiting. An electrocardiogram and laboratory results were suggestive for myocardial infarction of the posterior cardiac wall. Echocardiography was indicative of aortic dissection, and a CT scan of the thoracic arteries showed a massive pulmonary thromboembolism and thrombotic occlusion of the right coronary artery (RCA). The woman died shortly after admission. Autopsy confirmed the presence of thromboemboli in the right pulmonary artery and its lobar branches. Also, the anterior aortic sinus was filled with a 9 cm long thromboembolus that extended into the RCA, making it dilated and completely occluded. Another 3.5 cm long thromboembolus extended from the beginning of the left subclavian artery. A patent foramen ovale (PFO) was present. On the posterior wall of the left ventricle, there was an area suggestive of myocardial infarction, and histopathological examination confirmed that it was 24-48 hours old. The coronary circulation was "co-dominant". The sources of thrombotic masses were the deep veins of the lower limbs. The cause of death was myocardial infarction, caused by RCA occlusion with thromboembolus originating from the deep veins of the left lower leg after paradoxical embolism via PFO. This case illustrates that although deep venous thrombosis, pulmonary thromboembolism, and PFO are not rare findings at autopsy, their combination could be a relatively rare cause of fatal coronary artery occlusion after paradoxical embolism. PMID- 29488058 TI - Fatal intoxication with antidepressants: a case with many culprits. AB - Serotonin-specific reuptake inhibitors (SSRIs) are generally considered safe drugs but fatal adverse effects do sometimes occur, often as a consequence of interactions with other serotonin active drugs. Polypharmacy is usually a problem that the elderly encounter, but it can also have dire consequences for young people, especially when an underlying heart condition is present. Thus, failure to diagnose heart disease and the use of contraindicated medications can be a lethal combination, irrespective of age. Here we present a case of a young adult suffering from bipolar disorder who used a combination of two SSRIs (citalopram and fluoxetine) and a monoamine oxidase inhibitor (MAO; moclobemide) with tragic consequences. The deceased also suffered from undiagnosed hypertrophic cardiomyopathy and was carrier of a genotype that may have predisposed him to increased sensitivity to SSRIs. The apparent difficulty in establishing the manner of death in this case is also discussed. PMID- 29488059 TI - Age modifies the risk factor profiles for acute kidney injury among recently diagnosed type 2 diabetic patients: a population-based study. AB - The incidence of acute kidney injury (AKI) rises with age and is associated with multiple risk factors. Here, we compared the risk factors for AKI between younger and older incident diabetic patients to examine the trends in risk alteration for individual factors across different age groups. Between 2007 and 2013, we selected all incident type 2 diabetic adults from the Taiwan National Health Insurance registry, stratified based on age: young (< 65 years), old (>= 65 but < 75 years), and older-old (>= 75 years). All factors with potential renal influence (e.g., comorbidities, medications, and diagnostics/procedures) were recorded during the study period, with a nested case-controlled approach utilized to identify independent risk factors for AKI in each age group. Totally, 930,709 type 2 diabetic patients were categorized as young (68.7%), old (17.7%), or older old (13.6%). Older-old patients showed a significantly higher incidence of AKI than the old and the young groups. Cardiovascular morbidities (hypertension, atrial fibrillation, acute coronary syndrome, and cerebrovascular disease) were shown to increase the risk of AKI, although the risk declined with increasing age. Chronic obstructive pulmonary disease and receiving cardiac catheterization elevated the risk of AKI preferentially in the older-old/old and older-old group, respectively, while the administration of angiotensin-converting enzyme/alpha blocker and angiotensin receptor blocker/calcium channel blocker reduced the risk of AKI preferentially in the older-old and older-old/old group, respectively. In conclusion, our findings highlight the importance of devising age-specific risk factor panels for AKI in patients with recently diagnosed type 2 diabetes. PMID- 29488060 TI - Recruitment of African American Churches to Participate in Cancer Early Detection Interventions: A Community Perspective. AB - This article describes the process used to engage and recruit African American churches to serve as participants in two multi-year behavioural cancer research interventions from a community perspective. Community-based organizations used purposive sampling in engaging and recruiting advisory panel members and churches to participate in these interventions. Trust, respect, open dialogue with participants, and commitment to address community health needs contributed to successful engagement and recruitment of African American churches to serve as participants in these cancer research projects. Our results may help others engage and recruit African American churches to participate in future interventions. PMID- 29488061 TI - Using Drones to Study Human Beings: Ethical and Regulatory Issues. AB - Researchers have used drones to track wildlife populations, monitor forest fires, map glaciers, and measure air pollution but have only begun to consider how to use these unmanned aerial vehicles to study human beings. The potential use of drones to study public gatherings or other human activities raises novel issues of privacy, confidentiality, and consent, which this article explores in depth. It argues that drone research could fall into several different categories: non human subjects research (HSR), exempt HSR, or non-exempt HSR. In the case of non exempt HSR, it will be difficult for institutional review boards to approve studies unless they are designed so that informed consent can be waived. Whether drone research is non-HSR, exempt HSR, or non-exempt HSR, it is important for investigators to consult communities which could be affected by the research. PMID- 29488063 TI - Deficit of IgG2 in HIV-positive pregnant women is responsible of inadequate IgG2 levels in their HIV-uninfected children in Malawi. AB - BACKGROUND: Transplacental passage of IgGs is impaired in HIV + pregnant women, possibly determining an inadequate immunological protection in their children. We aimed to determine the impact of maternal immunological IgG profile and immunoactivation status on the efficiency of transplacental passage of IgG subclasses in HIV + mothers. METHODS: 16 mother/infants pairs were studied in Malawi. Mothers received antiretroviral therapy (ART) from the third trimester of pregnancy. Determinations of pre-ART levels of maternal sCD14, of IgG subclasses in mothers at delivery and in their 1-month-old infants, were performed using commercial ELISA kits. RESULTS: At delivery, after a median of 10 weeks of ART, 12/16 mothers were hypergammaglobulinemic, with IgG levels (20.5 mg/ml, 95% CI:18.8-26.8) directly correlated to the plasmatic levels of sCD14 (r = 0.640, p = 0.014). IgG1 levels (17.9 mg/ml) accounted for 82% of IgG, IgG3 and IgG4 levels were in the normal range. A profound deficit of IgG2 was observed both in mothers (0.60 mg/ml) and in infants (0.14 mg/ml). Placental transfer ratio (range 0.16 0.42) did not show a selective impairment between the different IgG subclasses. The transplacental passage of all IgG subclasses was decreased in the presence of maternal IgG over 16 mg/ml (significantly for IgG1, p = 0.031) and of high levels of sCD14 (p = 0.063). CONCLUSIONS: Transplacental passage was reduced for all IgG subclasses and inversely correlated to high levels of maternal IgGs and to the degree of immunoactivation. The profound depression of IgG2 in mothers suggests that IgG2 neonatal levels mostly reflect the maternal deficit rather than a selective impairment of IgG2 transfer. PMID- 29488062 TI - Progress of Regenerative Therapy in Orthopedics. AB - PURPOSE OF REVIEW: To conduct a thorough appraisal of recent and inventive advances in the field of bone tissue engineering using biomaterials, cell-based research, along with the incorporation of biomimetic properties using surface modification of scaffolds. RECENT FINDINGS: This paper will provide an overview on different biomaterials and emerging techniques involved in the fabrication of scaffolds, brief description of signaling pathways involved in osteogenesis, and the effect of surface modification on the fate of progenitor cells. The current strategies used for regenerative medicine like cell therapy, gene transfer, and tissue engineering have opened numerous therapeutic avenues for the treatment of various disabling orthopedic disorders. Precise strategy utilized for the reconstruction, restoration, or repair of the bone-related tissues exploits cells, biomaterials, morphogenetic signals, and appropriate mechanical environment to provide the basic constituents required for creating new tissue. Combining all the above strategies in clinical trials would pave the way for successful "bench to bedside" transformation in bone healing. PMID- 29488064 TI - Percutaneous Laser Ablation of Unifocal Papillary Thyroid Microcarcinoma: Utility of Conventional Ultrasound and Contrast-Enhanced Ultrasound in Assessing Local Therapeutic Response. AB - PURPOSE: To investigate the use of conventional ultrasound and contrast-enhanced ultrasound (CEUS) in assessing local therapeutic response of percutaneous laser ablation (PLA) for papillary thyroid microcarcinoma (PTMC). METHODS: Sixty-four patients with 64 PTMCs who were referred to our hospital from November 2013 to July 2016 were treated with PLA. The extent of ablation was assessed by CEUS at 10-20 min and 7 days after PLA. The size and volume of the ablation zone were evaluated on conventional ultrasound at 1 h, 1, 3, 6 and 12 months, and every half-year thereafter, and recurrences were also recorded. Ultrasound-guided fine needle aspiration biopsy (FNAB) of the ablated area was performed at 1, 6 and 12 months after PLA. RESULTS: Two incomplete ablations were detected by CEUS, and a second ablation was performed. The mean largest diameter and volume of the ablated area on CEUS at 10-20 min and 7 days after PLA were significantly larger than those of pre-treatment on conventional ultrasound (p < 0.05, for both). At the last follow-up, the mean largest diameter was reduced from 4.6 +/- 1.5 to 0.6 +/- 1.3 mm (p < 0.0.5), and the average volume was 41.0 +/- 40.4 mm3, which decreased to 1.8 +/- 6.7 mm3 (p < 0.0.5). A cervical metastatic lymph node was detected on ultrasound and confirmed by ultrasound-guided FNAB at 30 months after PLA. CONCLUSIONS: CEUS could play a crucial role in assessing the completeness of PLA for treating PTMC, and conventional ultrasound can not only guide the FNAB process but also is important in the follow-up of PTMC after PLA. PMID- 29488065 TI - Neoadjuvant Chemoradiotherapy for Patients with cT3/Nearly T4 Esophageal Cancer: Is Sarcopenia Correlated with Postoperative Complications and Prognosis? AB - BACKGROUND: Since the clinical impact of sarcopenia on multimodal therapy for patients with esophageal cancer is not well understood, this study was conducted to determine the influence of sarcopenia on the efficacy of neoadjuvant chemoradiotherapy (NACRT) for locally advanced esophageal cancer. METHODS: The skeletal muscle index was quantified at the level of the third lumbar vertebra on computed tomography images, and sarcopenia was defined as a skeletal muscle index that was less than the average for each gender. We compared treatment outcomes in patients with cT3 and nearly T4 thoracic esophageal squamous cell carcinoma between the sarcopenia group (n = 85) and the non-sarcopenia group (n = 72). RESULTS: The 5-year survival rates were 33.4% in the non-sarcopenia group and 31.5% in the sarcopenia group; these differences were not significant. The prognosis of the patients with sarcopenia was worse than that of the patients without sarcopenia in the surgery-alone group, but there was no difference between patients with and without sarcopenia in the NACRT group. CONCLUSIONS: NACRT could be a useful option for patients with locally advanced esophageal squamous cell carcinoma, even for those with sarcopenia, without increasing the incidence of morbidity and mortality. PMID- 29488067 TI - Blunt Cerebrovascular Artery Injury and Stroke in Severely Injured Patients: An International Multicenter Analysis: Reply. PMID- 29488066 TI - Prophylactic Central Neck Dissection for Papillary Thyroid Carcinoma with Clinically Uninvolved Central Neck Lymph Nodes: A Systematic Review and Meta analysis. AB - BACKGROUND: Central neck dissection and total thyroidectomy are standard treatments for patients with papillary thyroid carcinoma (PTC) with clinically involved central nodes. However, prophylactic central neck dissection (pCND) in patients with clinically uninvolved cN0 has been beneficial in some studies but ineffective in others. We conducted a meta-analysis to evaluate the efficacy and safety of pCND in patients with central neck lymph nodes cN0 PTC. METHODS: The PubMed, EMBASE, Cochrane Library, and Scopus databases and the ClinicalTrials.gov registry were electronically searched for studies published until September 2017. The meta-analysis was conducted to calculate the pooled effect size by using random-effects model. Treatment efficacies were measured by determining locoregional recurrence (LRR). Secondary outcomes included transient recurrent laryngeal nerve (RLN) injury, permanent RLN injury, transient hypocalcemia, and permanent hypocalcemia. RESULTS: Twenty-three retrospective and prospective cohort studies involving 18,376 patients were reviewed. Patients who underwent pCND had significantly lower LRR (odds ratio [OR] 0.65; 95% confidence interval [CI] 0.48-0.88) but significantly higher incidence rates of transient RLN injury (OR 2.03; 95% CI 1.32-3.13), transient hypocalcemia (OR 2.23; 95% CI 1.84-2.70), and permanent hypocalcemia (OR 2.22; 95% CI 1.58-3.13) than that of no pCND group. CONCLUSION: Compared with no pCND, pCND significantly reduces LRR but is accompanied by numerous adverse effects. The clinical decision should be made after the shared decision-making process of clinicians and patients. PMID- 29488068 TI - Heavy Metal Components in Blood and Urinary Stones of Urolithiasis Patients. AB - Lifestyle, food intake, and exposure to chemicals are potential risk factors for the development of calcium urolithiasis. Pb, Cd, and Hg have been proved to cause renal illness, and urinary tract stones might be caused by exposure to metals. Therefore, this study aimed to measure the concentration of metals in urinary tract stones and blood simultaneously in urolithiasis patients. Moreover, we intended to determine whether urinary tract stones can be regarded as a biomarker of exposure or an effect marker in a population with environmental exposure to metals. Thirty-five urolithiasis patients (case) and 34 healthy inhabitants (control) were recruited in this study. The contents of Pb, Cd, Cr, Cu, Ni, As, Zn, and Hg were determined in urinary stones and blood in the case and control groups. The most abundant metals were Zn and Cu in blood and Zn and Ni in urinary stones. Significantly higher levels of Zn, Ni, and As were found in calcium phosphate stones than in calcium oxalate or uric acid stones. The majority of metals were not present at consistent levels in both blood and urinary stones, except for Zn. Urinary stones might be explained as providing another metabolic pathway for metal contamination. Moreover, as the metals with the highest content in urinary stones were Ni and Zn, and Ni content was very much higher than in other countries, contamination by Ni should be further taken into consideration if there is any serious contamination in Taiwan. PMID- 29488069 TI - Decoding Auditory Saliency from Brain Activity Patterns during Free Listening to Naturalistic Audio Excerpts. AB - In recent years, natural stimuli such as audio excerpts or video streams have received increasing attention in neuroimaging studies. Compared with conventional simple, idealized and repeated artificial stimuli, natural stimuli contain more unrepeated, dynamic and complex information that are more close to real-life. However, there is no direct correspondence between the stimuli and any sensory or cognitive functions of the brain, which makes it difficult to apply traditional hypothesis-driven analysis methods (e.g., the general linear model (GLM)). Moreover, traditional data-driven methods (e.g., independent component analysis (ICA)) lack quantitative modeling of stimuli, which may limit the power of analysis models. In this paper, we propose a sparse representation based decoding framework to explore the neural correlates between the computational audio features and functional brain activities under free listening conditions. First, we adopt a biologically-plausible auditory saliency feature to quantitatively model the audio excerpts and meanwhile develop sparse representation/dictionary learning method to learn an over-complete dictionary basis of brain activity patterns. Then, we reconstruct the auditory saliency features from the learned fMRI-derived dictionaries. After that, a group-wise analysis procedure is conducted to identify the associated brain regions and networks. Experiments showed that the auditory saliency feature can be well decoded from brain activity patterns by our methods, and the identified brain regions and networks are consistent and meaningful. At last, our method is evaluated and compared with ICA method and experimental results demonstrated the superiority of our methods. PMID- 29488070 TI - Cost Effectiveness of Alectinib vs. Crizotinib in First-Line Anaplastic Lymphoma Kinase-Positive Advanced Non-Small-Cell Lung Cancer. AB - BACKGROUND: The recently completed ALEX trial demonstrated that alectinib improved progression-free survival, and delayed time to central nervous system progression compared with crizotinib in patients with anaplastic lymphoma kinase positive non-small-cell lung cancer. However, the long-term clinical and economic impact of using alectinib vs. crizotinib has not been evaluated. The objective of this study was to determine the potential cost utility of alectinib vs. crizotinib from a US payer perspective. METHODS: A cost-utility model was developed using partition survival methods and three health states: progression free, post-progression, and death. ALEX trial data informed the progression-free and overall survival estimates. Costs included drug treatments and supportive care (central nervous system and non-central nervous system). Utility values were obtained from trial data and literature. Sensitivity analyses included one-way and probabilistic sensitivity analyses. RESULTS: Treatment with alectinib vs. crizotinib resulted in a gain of 0.91 life-years, 0.87 quality-adjusted life years, and incremental costs of US$34,151, resulting in an incremental cost effectiveness ratio of US$39,312/quality-adjusted life-year. Drug costs and utilities in the progression-free health state were the main drivers of the model in the one-way sensitivity analysis. From the probabilistic sensitivity analysis, alectinib had a 64% probability of being cost effective at a willingness-to-pay threshold of US$100,000/quality adjusted life-year. CONCLUSIONS: Alectinib increased time in the progression-free state and quality-adjusted life-years vs. crizotinib. The marginal cost increase was reflective of longer treatment durations in the progression-free state. Central nervous system-related costs were considerably lower with alectinib. Our results suggest that compared with crizotinib, alectinib may be a cost-effective therapy for treatment-naive patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer. PMID- 29488072 TI - Evaluation of surface dose and image quality using the half-scan mode in chest computed tomography-guided interventional radiology: a phantom study. AB - The authors aimed to evaluate the effects of the half-scan mode on image quality and physician exposure to radiation in computed tomography (CT)-guided interventional radiology (IVR) to the right lung using an intermittent CT fluoroscopy technique for measuring phantom surface dose distribution and image noise. For the half-scan mode, settings at 0 degrees , 90 degrees , 180 degrees , and 270 degrees were used as the central axis of the X-ray exposure range on the chest phantom. With the center of the ventral side in the chest phantom defined as 0 degrees , optically stimulated luminescent dosimeters were attached at five positions at 30 degrees intervals on the right side of the phantom surface. Securing a space for device operation during the procedure is necessary. The couch was shifted downward by 50 mm to reproduce the conditions used for measurement in clinical settings. Image noise and contrast-to-noise ratio were measured to assess image quality; subjective evaluation was performed using simulated lung nodules placed in the phantom. The phantom surface dose distribution in the measured half-scan mode depended on the angle setting. Additionally, the phantom surface dose in the half-scan mode at the 90 degrees setting was reduced by approximately 50%; however, image quality was clearly decreased. In CT-guided IVR to the right lung, using a lead drape and half-scan mode according to the procedural situation is important. PMID- 29488073 TI - Arterial supply to the rabbit adrenal gland. AB - The adrenal gland regulates stress responses by releasing steroid hormones, whose synthesis and secretion are influenced by adrenal blood flow. Adrenalectomy is commonly performed in rabbits to study the function of the adrenal gland. Although knowledge of the arterial supply to the adrenal gland forms the anatomical basis of the surgery, its description in prior studies is incomplete for the rabbit. Therefore, we observed the adrenal arteries in 27 male and 11 female New Zealand White rabbits using the colored latex injection method. The branching pattern of the adrenal arteries was divided into three major types based on the number of parent arteries that gave rise to the adrenal arteries. Thirty-four percent of right halves exhibited one parent artery and were categorized as type 1. Fifty-five percent of right halves and 76% of left halves had two parent arteries and were categorized as type 2. Eleven percent of right halves and 24% of left halves had three parent arteries and were categorized as type 3. The number of adrenal arteries varied from 3 to 16 on the right, 3 to 18 on the left, and 9 to 30 in total in each individual. These findings demonstrate the remarkable individual variation in arterial supply to the rabbit adrenal gland, suggesting that such variations should always be considered during experimental treatments in the rabbit. PMID- 29488074 TI - Removal of an endometrioid stromal sarcoma from the inferior vena cava and right atrium. AB - Entometrioid stromal sarcomas are seen in extra-uterine as well as extra-gonadal sites and have a strong association with endometriosis. Although having better prognosis than other sarcomas, yet these tumors may relapse (whether local or distant) in up to 56% of cases, even as late as 20 years after surgery. We report a case of a 30-year-old female patient with a mass in the inferior vena cava and right atrium which was surgically removed using cardiopulmonary bypass and deep hypothermic circulatory arrest and turned to be an entometrioid stromal sarcoma. The patient gave a history of endometriosis followed by the appearance of a low grade ovarian endometrioid stromal sarcoma 4 years before the development of the mass in the IVC and right atrium. PMID- 29488071 TI - BRAF and MEK Inhibitors: Use and Resistance in BRAF-Mutated Cancers. AB - The mitogen activated protein kinase/extracellular signal-related kinase (MAPK/ERK) signaling pathway serves an integral role in growth, proliferation, differentiation, migration, and survival of all mammalian cells. Aberrant signaling of this pathway is often observed in several types of hematologic and solid malignancies. The most frequent insult to this signaling cascade, leading to its constitutive activation, is to the serine/threonine kinase rapidly accelerating fibrosarcoma (RAF). Considering this, the development and approval of various small-molecule inhibitors targeting the MAPK/ERK pathway has become a mainstay of treatment as either mono- or combination therapy in these cancers. Although effective initially, a major clinical barrier with these inhibitors is the relapse of patients due to drug resistance. Knowledge of the mechanisms of resistance to these drugs is still premature, highlighting the need for a more in depth understanding of how patients become insensitive to these pharmacologic interventions. Herein, we will succinctly summarize the milestones in the approval of select MAPK/ERK pathway inhibitors, their use in patients, and major modes of resistance. PMID- 29488075 TI - Surgical management of colloid cysts in children: experience at a tertiary care center. AB - INTRODUCTION: Colloid cysts are uncommon lesions in the pediatric age group, which most commonly occur in the fourth through fifth decades. The authors hereby report a series of 36 patients with colloid cysts in the pediatric age group. MATERIAL AND METHOD: A retrospective chart review was conducted on all patients with colloid cyst who underwent surgery in our institute between November 2003 and December 2016 (13 years). Patients above the age of 18 were excluded from the study. They were analyzed based on clinical presentation, radiological findings, surgical approaches, and outcome. RESULTS: There were 36 pediatric patients selected for the study. Age ranged from 8 to 18 years. The male-to-female ratio was 3.5:1. Headache and vomiting were the most common symptoms, and papilledema is the most common clinical sign. The mean duration of symptoms was 9 months (range 1 day to 5 years), but 27 (75%) of the children had precipitous symptoms just before presentation. Preoperative CT showed a hyperdense non-enhancing lesion in the majority of cases. Endoscopic excision was done in 13; 5 patients underwent transcortical transventricular excision, while transcallosal approach was opted for in 17 patients. In one patient, the colloid cyst could not be removed endoscopically and had to be converted to transcortical transventricular approach. Postoperatively, five patients developed CSF leak. They were successfully managed conservatively. One patient had operative site extra dural hematoma and underwent re-exploration, and two patients had transient hemiparesis which improved spontaneously. The median follow-up period was 9 months in the 30 available patients. Though no formal neuropsychological testing was done at follow-up, all children appeared to be doing well without memory disturbances. CONCLUSION: Pediatric colloid cysts are less common and may show rapid deterioration. Timely surgery results in a permanent cure with minimum morbidity. The results of either micro neurosurgical or endoscopic operative excision of colloid cysts in children are excellent. All children who are symptomatic with raised intracranial pressure due to a third ventricular colloid cyst should undergo definitive surgery. There were no major permanent deficits in memory or disconnection syndromes observed with the limited anterior colostomy. PMID- 29488076 TI - Does a systematic algorithm matter for the management of ventriculoperitoneal shunt perforations of the gastrointestinal tract? PMID- 29488077 TI - Shunt surgery for early-onset severe hydrocephalus in methylmalonic acidemia: report on two cases and review of the literature. AB - OBJECT: Methylmalonic acidemia (MMA) with early-onset severe hydrocephalus is rare. In this paper, we described two cases of MMA with hydrocephalus and review the literature to elucidate the clinical features of the disease, treatment options, and follow-up results. METHODS: The PubMed and Embase databases were searched for clinical reports on MMA with severe hydrocephalus, and two unreported cases were presented to illustrate the clinical spectrum. RESULTS: Six cases of MMA with severe hydrocephalus were observed in the previous literature. Our two patients with severe hydrocephalus but not bulging fontanelle received a ventriculo-peritoneal shunt, and intracranial hypertension was confirmed in both cases during the operation. These patients' clinical symptoms significantly improved after the operation. CONCLUSIONS: Intracranial hypertension can exist in early-onset severe hydrocephalus in MMA, even if the bulging anterior fontanelle is not apparent. These patients could benefit from a ventriculo-peritoneal shunt. PMID- 29488078 TI - Cerebellar atrophy with T2/FLAIR hyperintense cerebellar cortex: a new imaging phenotype of combined complex II/III deficiency. PMID- 29488079 TI - Characterization of Aroma-Active Components and Antioxidant Activity Analysis of E-jiao (Colla Corii Asini) from Different Geographical Origins. AB - E-jiao (Colla Corii Asini, CCA) has been widely used as a healthy food and Chinese medicine. Although authentic CCA is characterized by its typical sweet and neutral fragrance, its aroma components have been rarely investigated. This work investigated the aroma-active components and antioxidant activity of 19 CCAs from different geographical origins. CCA extracts obtained by simultaneous distillation and extraction were analyzed by gas chromatography-mass spectrometry (GC-MS), gas chromatography-olfactometry (GC-O) and sensory analysis. The antioxidant activity of CCAs was determined by ABTS and DPPH assays. A total of 65 volatile compounds were identified and quantified by GC-MS and 23 aroma-active compounds were identified by GC-O and aroma extract dilution analysis. The most powerful aroma-active compounds were identified based on the flavor dilution factor and their contents were compared among the 19 CCAs. Principal component analysis of the 23 aroma-active components showed 3 significant clusters. Canonical correlation analysis between antioxidant assays and the 23 aroma-active compounds indicates strong correlation (r = 0.9776, p = 0.0281). Analysis of aroma-active components shows potential for quality evaluation and discrimination of CCAs from different geographical origins. PMID- 29488080 TI - Hyperkalemia in patients treated with endoradiotherapy combined with amino acid infusion is associated with severe metabolic acidosis. AB - BACKGROUND: Amino acid co-infusion for renal protection in endoradiotherapy (ERT) applied as prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) or peptide receptor radionuclide therapy (PRRT) has been shown to cause severe hyperkalemia. The pathophysiology behind the rapid development of hyperkalemia is not well understood. We hypothesized that the hyperkalemia should be associated with metabolic acidosis. RESULTS: Twenty-two patients underwent ERT. Prior to the first cycle, excretory kidney function was assessed by mercapto acetyltriglycine (MAG-3) renal scintigraphy, serum biochemistry, and calculated glomerular filtration rate (eGFR). All patients received co-infusion of the cationic amino acids L-arginine and L-lysine for nephroprotection. Clinical symptoms, electrolytes, and acid-base status were evaluated at baseline and after 4 h. No patient developed any clinically relevant side effects. At baseline, acid base status and electrolytes were normal in all patients. Excretory kidney function was normal or only mildly impaired in all except two patients with stage 3 renal insufficiency. All patients developed hyperkalemia. Base excess and HCO3- were significantly lower after 4 h. In parallel, mean pH dropped from 7.36 to 7.29. There was a weak association between calculated (r = - 0.21) as well as MAG 3-derived GFR (r = - 0.32) and the rise in potassium after 4 h. CONCLUSION: Amino acid co-infusion during ERT leads to severe metabolic acidosis which induces hyperkalemia by potassium hydrogen exchange. This novel finding implies that commercially available bicarbonate solutions might be an easy therapeutic option to correct metabolic acidosis rapidly. PMID- 29488081 TI - A review of publication bias in the gastroenterology literature. AB - In systematic reviews and meta-analyses, publication bias is particularly problematic, given that combining only statistically significant outcomes is likely to overestimate the true effect of an intervention since non-significant findings have been omitted. We examined practices for evaluating publication bias from gastroenterology literature. We performed a PubMed search to identify systematic reviews published in American Journal of Gastroenterology, Gut, and Gastroenterology from 2005 to 2015. Of the 304 found, 215 studies were eligible for inclusion based on relevant study characteristics. There were 190 systematic reviews which used at least one method to evaluate publication bias and/or included ten or more primary studies. There were 115/190 (60.53%) systematic reviews which used at least one method to evaluate publication bias. Most (105/115, 91.27%) qualified reviews used at least one method to evaluate publication bias and 78/115 (67.83%) used a combination of methods. The most common methods were funnel plot (100/115, 86.96%), Egger's regression (67/115, 58.26%), and Begg's (28/115, 24.35%). Of the 115 reviews that performed evaluations, 26 (22.61%) conducted these analyses with fewer than ten primary studies, and a minority (24/115, 20.87%) reached the conclusion that publication bias was present in their work. While methods to assess publication bias were frequently noted among qualified systematic reviews, these methods are limited in value and could be improved by incorporating approaches that assess the degree of publication bias severity. PMID- 29488082 TI - Prognostic Role of Liver Stiffness Measurements Using Magnetic Resonance Elastography in Patients with Compensated Chronic Liver Disease. AB - PURPOSE: To retrospectively evaluate the prognostic role of liver stiffness (LS) measurement using magnetic resonance elastography (MRE) in patients with compensated chronic liver disease (cCLD). METHODS: We enrolled 217 patients with cCLD who underwent MRE. After mean follow-up of 45.0 +/- 17.6 months, cumulative incidence (CI) of hepatocellular carcinoma (HCC) occurrence, development of decompensation and overall survival (OS) were estimated using the Kaplan-Meier method. Prognostic factors were evaluated using the Cox proportional hazard regression model. RESULTS: During the follow-up period, HCC occurred in 33 patients, and 1-, 3- and 5-year CIs of HCC occurrence were 3.8%, 14.8% and 18.9%, respectively. The LS value was a significant predictive factor for HCC occurrence [p < 0.001, hazard ratio (HR) = 1.59 per unit (1.25-2.03)]. Eighteen patients experienced hepatic decompensation, and 1-, 3- and 5-year CIs of decompensation were 2.8%, 7.3% and 11.3%, respectively. The LS value was also significantly associated with decompensation development [p < 0.001, HR = 2.02 per unit (1.37 2.98)]. Fourteen patients died, and 1-, 3- and 5-year OSs were 99.1%, 98.0% and 89.8%, respectively. The LS value was demonstrated to be a significant affecting factor for OS [p = 0.008, HR = 1.39 per unit (1.10-1.78)]. CONCLUSIONS: LS obtained from MRE was a significant predictive factor for the development of decompensation, HCC occurrence and OS in cCLD patients. KEY POINTS: * Liver stiffness (LS) values obtained from MRE can provide prognostic information. * The LS value was a significant predictive factor for occurrence of hepatocellular carcinoma. * The LS value was significantly associated with development of hepatic decompensation. * Survival of compensated chronic liver disease patients was affected by the LS value. PMID- 29488083 TI - Contrast media injection protocol optimization for dual-energy coronary CT angiography: results from a circulation phantom. AB - OBJECTIVES: To investigate the minimum iodine delivery rate (IDR) required to achieve diagnostic coronary attenuation (300 HU) with dual-energy coronary CTA. METHODS: Acquisitions were performed on a circulation phantom with a third- generation dual-source CT scanner. Contrast media was injected for a fixed time whilst IDRs varied from 1.0 to 0.3 gI/s in 0.1-gI/s intervals. Noise-optimized virtual monoenergetic imaging (VMI+) reconstructions from 40 to 90 keV in 5 keV increments were generated. Contrast-to-noise ratio (CNR) and coronary HU were measured for each injection. RESULTS: VMI+ from 40-70 keV reached diagnostic attenuation with at least one IDR. The minimum IDR achieving a diagnostic attenuation ranged from 0.4 gI/s at 40 keV (312.8 HU) to 1.0 gI/s at 70 keV (334.1 HU). Attenuation values reached with IDR of 1.0 gI/s were significantly higher at each keV level (p<0.001). CNR showed a near perfect correlation with the IDR (rho>=0.962; p<0.001), the IDR of 1.0 gI/s provided the highest CNR at each keV level, achieving the highest overall value at 40 keV (54.0+/-3.1). CONCLUSIONS: IDRs from 0.4-1.0 gI/s associated with VMI+ from 40-70 keV provide diagnostic coronary attenuation with dual-energy coronary CTA. KEY POINTS: * Iodine delivery rate (IDR) is a major determinant of contrast enhancement. * Low keV noise-optimized monoenergetic images (VMI+) maximize iodine attenuation. * Low-keV VMI+ allows for lower IDRs while maintaining adequate coronary attenuation. * Lowest IDR to reach 300 HU was 0.4 gI/s, 40 keV VMI+. PMID- 29488084 TI - Pulmonary arterial stiffening in COPD and its implications for right ventricular remodelling. AB - BACKGROUND: Pulmonary pulse wave velocity (PWV) allows the non-invasive measurement of pulmonary arterial stiffening, but has not previously been assessed in COPD. The aim of the current study was to assess PWV in COPD and its association with right ventricular (RV) remodelling. METHODS: Fifty-eight participants with COPD underwent pulmonary function tests, 6-min walk test and cardiac MRI, while 21 healthy controls (HCs) underwent cardiac MRI. Thirty-two COPD patients underwent a follow-up MRI to assess for longitudinal changes in RV metrics. Cardiac MRI was used to quantify RV mass, volumes and PWV. Differences in continuous variables between the COPD and HC groups was tested using an independent t-test, and associations between PWV and right ventricular parameters was examined using Pearson's correlation coefficient. RESULTS: Those with COPD had reduced pulsatility (COPD (mean+/-SD):24.88+/-8.84% vs. HC:30.55+/-11.28%, p=0.021), pulmonary acceleration time (COPD:104.0+/-22.9ms vs. HC: 128.1+/ 32.2ms, p<0.001), higher PWV (COPD:2.62+/-1.29ms-1 vs. HC:1.78+/-0.72ms-1, p=0.001), lower RV end diastolic volume (COPD:53.6+/-11.1ml vs. HC:59.9+/-13.0ml, p=0.037) and RV stroke volume (COPD:31.9+/-6.9ml/m2 vs. HC:37.1+/-6.2ml/m2, p=0.003) with no difference in mass (p=0.53). PWV was not associated with right ventricular parameters. CONCLUSIONS: While pulmonary vascular remodelling is present in COPD, cardiac remodelling favours reduced filling rather than increased afterload. Treatment of obstructive lung disease may have greater effect on cardiac function than treatment of pulmonary vascular disease in most COPD patients KEY POINTS: * Pulmonary pulse wave velocity (PWV) is elevated in COPD. * Pulmonary PWV is not associated with right ventricular remodelling. * Right ventricular remodelling is more in keeping with that of reduced filling. PMID- 29488085 TI - The changing face of cancer diagnosis: From computational image analysis to systems biology. AB - ?: KEY POINTS: * Radiomics and radiogenomics will merge radiology, nuclear medicine, pathology and laboratory medicine. * Automation of image data analysis will change the daily routine work. * Image-guided therapy and handling complex radiogenomic data will play a major role. PMID- 29488086 TI - Amide proton transfer imaging seems to provide higher diagnostic performance in post-treatment high-grade gliomas than methionine positron emission tomography. AB - OBJECTIVES: To compare the diagnostic performance of amide proton transfer (APT) imaging and 11-C methionine positron emission tomography (MET-PET) for in vivo molecular imaging of protein metabolism in post-treatment gliomas. MATERIALS AND METHODS: This study included 43 patients (12 low and 31 high grade) with post treatment gliomas who underwent both APT and MET-PET imaging within 3 weeks. APT weighted voxel values and semi-quantitative tumour-to-normal ratios (TNR) were obtained from tumour portions. The voxel-wise relationships between TNR and APT were assessed. The diagnostic performance for recurrence of high-grade gliomas was calculated, using the area under the receiver operating characteristic curve (AUC) with maximum (TNRmax and APTmax) and 90% histogram values (TNR90 and APT90). RESULTS: A moderate positive correlation between TNR and APT was found in low-grade recurrences (r = 0.47, p < 0.001), but not in high-grade ones (r = 0.24, p < 0.001). For distinguishing recurrence in post-treatment high-grade gliomas, APTmax (AUC, 0.88) and APT90 (AUC, 0.78-0.83) had a similar to better diagnostic performance than TNRmax (AUC, 0.71, p = 0.08) or TNR90 (AUC, 0.53 0.59, p = 0.01-0.05). CONCLUSIONS: In post-treatment high-grade gliomas, APT provides different regional information to MET-PET and provides higher diagnostic performance. This difference needs to be considered when using APT or MET-PET as a surrogate marker for tumour protein metabolism. KEY POINTS: * APT and TNR values in low-grade recurrence showed a moderate voxel-wise correlation. * APT and TNR demonstrated regional differences in post-treatment high-grade gliomas. * APT90 showed better diagnostic performance than TNR90 in high-grade recurrence. PMID- 29488087 TI - Bacterial culture and antibiotic susceptibility in patients with acute appendicitis. AB - PURPOSE: Essential treatment of acute appendicitis is surgical resection with the use of appropriate antibiotics. In order to effectively treat acute appendicitis, it is important to identify the microorganism of acute appendicitis and evaluate the effective antibiotics. METHODS: A total of 694 patients who underwent appendectomy for acute appendicitis and had positive microbial result between 2006 and 2015 were recruited. For microbial assessment, luminal contents of the appendix were swabbed after appendectomy. In patients with periappendiceal abscess, the specimens were obtained from abscess fluid. The patient characteristics, operative data, use of antibiotics, the results of microbiology, and postoperative morbidities including surgical site infection (SSI) were retrospectively reviewed. RESULTS: The mean age was 38.2 (+/- 19.8) years, and 422 patients (60.8%) were male. Most of the operations were performed by conventional laparoscopy (83.1%), followed by single-port laparoscopy (11.8%). The most common microorganism was Escherichia coli (64.6%), which was susceptible to amoxicillin/clavulanate, ciprofloxacin, most cephalosporins, piperacillin/tazobactam, and imipenem. The second most common microorganism was Pseudomonas aeruginosa (16.4%), which was resistant to amoxicillin/clavulanate and cefotaxime. The rate of postoperative morbidity was 8.6%, and the most common type was superficial SSI (6.2%), followed by ileus (1.2%), gastroenteritis (0.7%), and organ/space SSI (0.3%). P. aeruginosa (odds ratio = 2.128, 95% confidence interval 1.077-4.206, P = 0.030) was the only significant microorganism associated with SSI according to multivariate analysis adjusting for other clinical factors. CONCLUSIONS: In perforated appendicitis, the use of empirical antibiotics seems to be safe. In some cases of Pseudomonas infection, adequate antibiotics should be considered. PMID- 29488088 TI - The presence of occipital hair in the pilonidal sinus cavity-a triple approach to proof. AB - PURPOSE: Hair in the pilonidal sinus is not growing within the sinus cavity, as hair follicles are not present there. Not few pilonidal patients do not have intergluteal hair, which is said to be the causative agent of folliculitis and pilonidal genesis. So, what is the real source of the hair forming the typical pilonidal hair nest? METHODS: A trifold approach was used: First, axial hair strength testing of pilonidal hair and body hair harvested from head, lower back (glabella sacralis), and cranial third of intergluteal fold. Hair strength match was compared clinically. Second, comparative morphological examination by expert forensic biologist of hair from sinus and dorsal body hair. Third, statistical Bayesian classification of every single sinus hair based on its strength was done to determine the most probable region of origin. RESULTS: Using clinical hair strength comparison, in 13/20 patients, head hair is the stiffest hair, followed by intergluteal hair. Only in 6/20 patients, this is the case with hair from the glabella sacralis. According to comparative morphological comparison, a minimum of 5 of 13 hair nests with possible hair allocation examined contain hair from the occiput. In 5/18 nests, hair could not be determined to a specific location though. Statistical classification with correction for multiple testing shows that 2 nests have hair samples that are at least 100 times more probable to originate from head or lower back than from intergluteal fold. CONCLUSION: We saw our null hypothesis that "hair in the sinus cavity is from the intergluteal region" rejected by each of three different approaches. There is strong evidence that occipital hair is present regularly in pilonidal sinus nests. We should start thinking of occipital hair as an important hair source for the development of the pilonidal hair nest. PMID- 29488089 TI - Pheochromocytoma diagnosed during pregnancy: lessons learned from a series of ten patients. AB - BACKGROUND: Pheochromocytoma (PHEO) in pregnancy is a life-threatening condition. Its management is challenging with regards to the timing and type of surgery. METHODS: A retrospective review of the management of ten patients diagnosed with pheochromocytoma during pregnancy was performed. Data were collected on the initial diagnostic workup, symptoms, treatment, and follow-up. RESULTS: PHEO was diagnosed in ten patients who were between the 10th and the 29th weeks of pregnancy. Six patients had none to mild symptoms, while four had complications of paroxysmal hypertension. Imaging investigations consisted of MRI, CT scan and ultrasounds. All had urinary metanephrines, measured as part of their workup. Three patients had MEN 2A, one VHL syndrome, one suspected SDH mutation. All patients were treated either with alpha/beta blockers or calcium channel blockers to stabilize their clinical conditions. Seven patients underwent a laparoscopic adrenalectomy before delivery. Three out of these seven patients had a bilateral PHEO and underwent a unilateral adrenalectomy of the larger tumor during pregnancy, followed by a planned cesarean section and a subsequent contralateral adrenalectomy within a few months after delivery. Three patients had emergency surgery for maternal or fetal complications, with C-section followed by concomitant or delayed adrenalectomy. All newborns from the group of planned surgery were healthy, while two out three newborns within the emergency surgery group died shortly after delivery secondary to cardiac and pulmonary complications. CONCLUSIONS: PHEO in pregnancy is a rare condition. Maternal and fetal prognosis improved over the last decades, but still lethal consequences may be present if misdiagnosed or mistreated. A thorough multidisciplinary team approach should be tailored on an individual basis to better manage the pathology. Unilateral adrenalectomy in a pregnant patient with bilateral PHEO may be an option to avoid the risk of adrenal insufficiency after bilateral adrenalectomy. PMID- 29488090 TI - Oncological and surgical result of hepatoma after robot surgery. AB - BACKGROUND: Most liver resections are currently performed using an open approach. Robotic hepatectomy has been suggested as a safe and effective approach for hepatocellular carcinoma; however, studies regarding oncological and surgical outcomes are still limited. Accordingly, we performed this study to compare the surgical and oncological outcomes between robotic and open approaches. METHODS: Between June, 2013 and July, 2016, a total of 63 HCC patients undergoing robotic hepatectomy, and 177 patients undergoing open hepatectomy were included in this study to assess the surgical and oncological outcomes after hepatectomy. The data of demographic, clinical features, hepatitis profile, tumor characters, TNM stage, surgical type, pathological outcomes, and postoperative results were collected prospectively and analyzed retrospectively. RESULTS: The demographic and clinical features of patients with HCC in both groups were statistically comparable. The robotic group had longer operative times (296 +/- 84 vs. 182 +/- 51 min, p = 0.032). The postoperative complications rate was slightly lower in the robotic group (11.1 vs. 15.3%, p = 0.418). The rate of Ro resection was similar in both groups (93.7 vs. 96%, p = 0.56). The length of hospital stay was significantly shorter in the robotic group (6.21 +/- 2.06 vs. 8.18 +/- 6.99 days, p = 0.001). The overall recurrence rate of HCC was lower in the robotic group (27 vs. 37.3%, p = 0.140). The 1, 2, 3 year disease-free survival rates were 72.5, 64.3, and 61.6%, respectively, for the open group, while they were 77.8, 71.9, and 71.9%, respectively, for the robotic group, (p = 0.325). The 1, 2, 3 year overall survival rates were 95.4, 92.3, and 92.3%, respectively, for the open group, while they were 100, 97.7, and 97.7%, respectively, for the robotic group (p = 0.137). CONCLUSION: Robotic surgery is a safe and feasible procedure for liver resection in selected patients. The oncological and surgical outcomes of robotic hepatectomy were comparable to open surgery. The robotic hepatectomy carried significantly shorter length of hospital stay. PMID- 29488091 TI - Laparoendoscopic rendezvous in the treatment of cholecysto-choledocholitiasis: a single series of 200 patients. AB - BACKGROUND AND AIM: Although the ideal management of cholecysto choledocholitiasis is controversial, the two-stage approach, namely the common bile duct (CBD) clearance through endoscopic retrograde cholangiopancreatography (ERCP) followed by laparoscopic cholecystectomy, remains the standard way of management. However, whenever feasible, the one-stage approach, using the so called "laparoendoscopic rendezvous" (LERV) technique, offers some advantages, mainly reducing the hospital stay and the risk of post-ERCP pancreatitis. The aim of this study was to evaluate the safety and the efficacy of the one-stage approach, and to compare our results with data from available large studies. MATERIALS AND METHODS: We reviewed our series of consecutive patients with cholecysto-choledocholitiasis treated by LERV from January 2003, to October 2016. Both elective and emergency cases were included. The primary end-point was the efficacy to obtain the CBD stones clearance. Secondary end-points were morbidity and mortality, operative time, conversion rate, and in-hospital stay. RESULTS: A total of 200 patients underwent a LERV procedure for the intra-operative diagnosis by intra-operative cholangiogram of cholecysto-choledocholitiasis. In 187 patients (93.5%), it was possible to cannulate the cystic duct with the jag wire. Success rate was 95%. Conversion rate was 3%. The mean operative time was 135 min and the mean in-hospital stay was 4 days. 29 (14.5%) were the early complications, six mild pancreatitis. Four patients required re-operation during the hospital stay. 11 patients (5.5%) developed late complications during a median follow-up of 57.7 months. CONCLUSIONS: Our results confirm that LERV technique is a safe procedure with high success rates for the treatment of cholecysto-choledocholitiasis. The major advantages include the single-stage treatment, the shorter hospital stay, and the lower incidence of post-ERCP pancreatitis. PMID- 29488092 TI - Characteristics of the parathyroid gland in endoscopic thyroidectomy with the application of an image enhancement system. AB - BACKGROUND: To assist surgeons in identifying and preserving the parathyroid gland (PTG) in endoscopic thyroidectomy (ET), we have summarized the characteristics of the PTG and the surrounding tissues in ET by applying the Storz Professional Image Enhancement System (SPIES). METHODS: From November 2014 to May 2016, 182 patients with 613 suspected PTGs were included in our study. The shape, color, area, and density of surface blood vessels (SBVs); whether they were encapsulated with adipose tissue; and whether congestion was present during the operation were summarized. The kappa coefficient of interobserver agreement in assessing the area and the density of SBVs of suspected PTGs with and without Spectra A (SA) and Spectra B (SB) modalities were calculated. Multiple binary logistic regression analyses were performed to determine the predictive value of different characteristics for detecting the PTG in ET with the application of SPIES. RESULTS: With visual identification and histopathological results as reference standards, 291 targeted tissues were identified as PTGs, 256 as adipose tissue, 43 as lymph nodes, and 23 as thyroid tissue. The kappa coefficients of interobserver agreement in assessing SBV density with or without the SA and SB modalities were 0.944 +/- 0.013 and 0.859 +/- 0.021, respectively, and those in assessing SBV area were 0.937 +/- 0.014 and 0.841 +/- 0.022, respectively. In the comparison between PTGs and other tissues, multiple binary logistic regression analysis revealed that shape, color, SBV density, congestion, and whether tissue was encapsulated with adipose tissue were independent predictive factors of PTGs. CONCLUSION: With the application of SPIES, the shape, color, density of SBVs, adipose tissue encapsulation, and congestion were independent factors that predicted PTGs in ET. The SA and SB modalities of SPIES could improve the reliability of SBV density and area classifications in targeted tissues. PMID- 29488094 TI - Comparison of fosfomycin against fluoroquinolones for transrectal prostate biopsy prophylaxis. PMID- 29488093 TI - A blunt dissection technique using the LigaSure vessel-sealing device improves perioperative outcomes and postoperative splenic-vessel patency after laparoscopic spleen- and splenic-vessel-preserving distal pancreatectomy. AB - BACKGROUND: We have recently performed a blunt dissection technique using LigaSure technology for laparoscopic spleen- and splenic-vessel-preserving distal pancreatectomy to reduce the risk of bleeding during the dissection of the splenic vessels. The aim of this study was to compare the utility of the blunt dissection technique and a conventional dissection technique during laparoscopic spleen- and splenic-vessel-preserving distal pancreatectomy. METHODS: Fifty-five patients who underwent laparoscopic spleen- and splenic-vessel-preserving distal pancreatectomy performed by a single surgeon between March 2003 and December 2015 were enrolled in this retrospective single-center study. The patients were divided into the LigaSure group (n = 23) and non-LigaSure group (n = 26). Perioperative clinical outcomes and the postoperative patency of the preserved splenic vessels in the two groups were compared. RESULTS: The patient and tumor characteristics did not differ significantly between the two groups. The incidence of postoperative complications was similar in the two groups. However, the mean operative time (145 vs. 231.1 min, P = 0.001), intraoperative blood loss (95.6 vs. 360 ml, P = 0.001), and postoperative hospital stay (6.4 vs. 9.8 days, P = 0.001) were significantly lower in the LigaSure group than in the non LigaSure group, respectively. The splenic artery patency rate was similar in both groups, but the splenic vein patency was significantly better in the LigaSure group than in the non-LigaSure group (total occlusion rate: 4.5 vs. 30.8%, respectively, P = 0.017). CONCLUSION: The results of this study suggest that the blunt dissection technique using a LigaSure reduces the operating time and intraoperative blood loss during laparoscopic spleen- and splenic-vessel preserving distal pancreatectomy and increases the patency of the preserved splenic vessels. PMID- 29488095 TI - The impact of time to metastasis on overall survival in patients with prostate cancer. AB - PURPOSE: Time to metastasis is often used as a surrogate parameter of treatment success in clinical trials for prostate cancer. However, it has not been shown that there is a clear correlation between time to metastasis and overall survival. Our objective was to evaluate the impact of time to metastasis on OS in patients with prostate cancer. METHODS: Between 2008 and 2015, 269 patients with mPCa were included in this retrospective study with a median follow-up of 7.1 years. Patients were divided into three groups: (1) Presentation with metastasis within three months of initial diagnosis (de-novo-M); (2) patients free of metastasis initially but developed metastasis more than 6 months prior to castration resistance (CSPC-M); (3) patients who developed metastasis within 6 months of becoming castration resistant or after (CRPC-M). RESULTS: There was a significant decrease in OS when metastases were present at diagnosis (median 6.39 years) compared to CRPC-M (19.07) and CSPC-M (18.19 years). De-novo-M and CSPC-M showed a longer OS from occurrence of metastasis to death when compared to CRPC M, although reaching CRPC earlier. There was no difference in OS between the groups once castration resistance was reached. Time from initial diagnosis to metastasis and to CRPC was correlated with OS and remained important prognosticators in multivariate Cox-regression (p < 0.01 for both). CONCLUSIONS: Time from diagnosis to CRPC (all patients) and time to metastasis (for CRPC-M and CSPC-M patients) are significant prognosticators of overall survival and are therefore valid surrogates in a study setting. Therefore, time to CRPC should be prolonged as long as possible. PMID- 29488096 TI - Oncologic outcomes of patients with positive surgical margin after partial nephrectomy: a 25-year single institution experience. AB - PURPOSE: To evaluate oncologic outcomes and management of patients with microscopic positive surgical margin (PSM) after partial nephrectomy (PN) for renal cell carcinoma (RCC). METHODS: We reviewed our database to identify patients who underwent PN between 1990 and 2015 for RCC and had PSM on final pathology. A 1:3 matching was performed to a negative surgical margin (NSM) cohort. Kaplan-Meier method and log-rank test were used to estimate survival and differences in outcomes, respectively. Cox proportional hazards models were conducted to estimate the Hazards ratio. RESULTS: A total of 2297 patients underwent PN at our institution, of which 1863 (81%) had RCC. Microscopic PSM was found in 34 (1.8%) RCC patients who were matched to 100 patients with NSM. Of these 34 patients, local recurrence (n = 4), distant kidney recurrences (n = 4), and metastases (n = 5) developed during a median follow-up of 62 months. Bilateral tumors/tumors in a solitary kidney (n = 12/13, 92%), and multifocal tumors (n = 7/13, 54%) were found in patients who developed recurrence/metastasis. PSM patients were at a higher risk of shorter overall survival (p = 0.001), local recurrence-free survival (p = 0.003), distant recurrence-free survival (p = 0.032) and metastasis-free survival (p = 0.018). There was statistically significant association between PSM and bilateral tumors, prior treated RCC at presentation and higher nephrometry score in multivariable model. CONCLUSIONS: There was a low rate of microscopic PSM in our large cohort of patients undergoing PN despite tumor complexity. Higher nephrometry score, bilateral tumors, and prior treated RCC independently predicted PSM which showed worse survival, recurrence and metastasis compared to patients with NSM. PMID- 29488097 TI - The Massive Online Needs Assessment (MONA) to inform the development of an emergency haematology educational blog series. AB - BACKGROUND: Online educational resources are criticized as being teacher-centred, failing to address learner's needs. Needs assessments are an important precursor to inform curriculum development, but these are often overlooked or skipped by developers of online educational resources due to cumbersome measurement tools. Novel methods are required to identify perceived and unperceived learning needs to allow targeted development of learner-centred curricula. OBJECTIVES: To evaluate the feasibility of performing a novel technique dubbed the Massive Online Needs Assessment (MONA) for the purpose of emergency haematology online educational curricular planning, within an online learning community (affiliated with the Free Open Access Medical education movement). METHODS: An online survey was launched on CanadiEM.org using an embedded Google Forms survey. Participants were recruited using the study website and a social media campaign (utilizing Twitter, Facebook, Blogs, and a poster) targeting a specific online community. Web analytics were used to monitor participation rates in addition to survey responses. RESULTS: The survey was open from 20 September to 10 December 2016 and received 198 complete responses representing 6 medical specialties from 21 countries. Most survey respondents identified themselves as staff physicians (n = 109) and medical trainees (n = 75). We identified 17 high-priority perceived needs, 17 prompted needs, and 10 topics with unperceived needs through our MONA process. CONCLUSIONS: A MONA is a feasible, novel method for collecting data on perceived, prompted, and unperceived learning needs to inform an online emergency haematology educational blog. This methodology could be useful to the developers of other online education resources. PMID- 29488098 TI - i-Assess: Evaluating the impact of electronic data capture for OSCE. AB - INTRODUCTION: Tablet-based assessments offer benefits over scannable-paper assessments; however, there is little known about the impact to the variability of assessment scores. METHODS: Two studies were conducted to evaluate changes in rating technology. Rating modality (paper vs tablets) was manipulated between candidates (Study 1) and within candidates (Study 2). Average scores were analyzed using repeated measures ANOVA, Cronbach's alpha and generalizability theory. Post-hoc analyses included a Rasch analysis and McDonald's omega. RESULTS: Study 1 revealed a main effect of modality (F (1,152) = 25.06, p < 0.01). Average tablet-based scores were higher, (3.39/5, 95% CI = 3.28 to 3.51), compared with average scan-sheet scores (3.00/5, 95% CI = 2.90 to 3.11). Study 2 also revealed a main effect of modality (F (1, 88) = 15.64, p < 0.01), however, the difference was reduced to 2% with higher scan-sheet scores (3.36, 95% CI = 3.30 to 3.42) compared with tablet scores (3.27, 95% CI = 3.21 to 3.33). Internal consistency (alpha and omega) remained high (>0.8) and inter-station reliability remained constant (0.3). Rasch analyses showed no relationship between station difficulty and rating modality. DISCUSSION: Analyses of average scores may be misleading without an understanding of internal consistency and overall reliability of scores. Although updating to tablet-based forms did not result in systematic variations in scores, routine analyses ensured accurate interpretation of the variability of assessment scores. CONCLUSION: This study demonstrates the importance of ongoing program evaluation and data analysis. PMID- 29488099 TI - Expression of the ADHD candidate gene Diras2 in the brain. AB - The distinct subgroup of the Ras family member 2 (DIRAS2) gene has been found to be associated with attention-deficit/hyperactivity disorder (ADHD) in one of our previous studies. This gene is coding for a small Ras GTPase with unknown function. DIRAS2 is highly expressed in the brain. However, the exact neural expression pattern of this gene was unknown so far. Therefore, we investigated the expressional profile of DIRAS2 in the human and murine brain. In the present study, qPCR analyses in the human and in the developing mouse brain, immunocytological double staining on murine hippocampal primary cells and RNA in situ hybridization (ISH) on brain sections of C57BL/6J wild-type mice, have been used to reveal the expression pattern of DIRAS2 in the brain. We could show that DIRAS2 expression in the human brain is the highest in the hippocampus and the cerebral cortex, which is in line with the ISH results in the mouse brain. During mouse brain development, Diras2 levels strongly increase from prenatal to late postnatal stages. Co-expression studies indicate Diras2 expression in glutamatergic and catecholaminergic neurons. Our findings support the idea of DIRAS2 as a candidate gene for ADHD as the timeline of its expression as well as the brain regions and cell types that show Diras2 expression correspond to those assumed to underlie the pathomechanisms of the disease. PMID- 29488100 TI - Effect of long-term treatment with classical neuroleptics on NPQ/spexin, kisspeptin and POMC mRNA expression in the male rat amygdala. AB - Neuroleptics modulate the expression level of some regulatory neuropeptides in the brain. However, if these therapeutics influence the peptidergic circuits in the amygdala remains unclear. This study specifies the impact profile of the classical antipsychotic drugs on mRNA expression of the spexin/NPQ, kisspeptin-1 and POMC in the rat amygdala. Animals were treated with haloperidol and chlorpromazine for 28 days prior to transcript quantification via qPCR. Haloperidol and chlorpromazine induced a change in the expression of all neuropeptides analyzed. Both drugs led to the decrease of Kiss-1 expression, whereas in POMC and spexin/NPQ their up-regulation in the amygdala was detected. These modulating effects on may represent alternative, so far unknown mechanisms, of classical antipsychotic drugs triggering pharmacological responses. PMID- 29488101 TI - A simplified ultrasonography-guided approach for neurotoxin injection into the obliquus capitis inferior muscle in spasmodic torticollis. AB - The obliquus capitis inferior (OCI) muscle may be crucially involved in generating the tremulous component of spasmodic torticollis. This study was undertaken to evaluate the efficacy of a simplified ultrasonography-guided approach of botulinum neurotoxin injection into the OCI in the management of spasmodic torticollis. Here, a novel off-plane technique of ultrasonography guided botulinum neurotoxin injection into the OCI is demonstrated on video. We investigated its effect in five patients with tremulous torticollis with only partial response to conventional injection technique not injecting OCI. On ultrasonography the OCI and its neighboring structures (greater occipital nerve, vertebrae C1 and C2) were clearly displayed. Unlike the previously proposed approach with axial OCI imaging and in-plane medio-lateral needle insertion, we applied here an off-plane needle insertion technique. With this, the ultrasonography guidance of needle insertion was easier using the sagittal imaging plane rather than the axial plane. Compared to botulinum neurotoxin injection into more superficial neck muscles only, additional ultrasonography guided botulinum neurotoxin injection into the OCI led to a higher benefit (self rated improvement of cervical dystonia, p = 0.026, Mann-Whitney test), especially of the tremulous component (p = 0.007), even though the total botulinum neurotoxin dose was not changed. We conclude that selected patients with tremulous torticollis may benefit from botulinum neurotoxin injection into the OCI. PMID- 29488102 TI - Therapeutics for Adult Nail Psoriasis and Nail Lichen Planus: A Guide for Clinicians. AB - Nail psoriasis (NP) and nail lichen planus (NLP) can be limiting, stigmatizing and difficult to treat. Dermatologists commonly treat psoriasis and lichen planus but when associated onychodystrophy is present or is an isolated finding, some develop apprehension. The goal of this review is to develop therapeutic ladders to be used as a guide for the management of NP and NLP in everyday clinical practice. Evidence-based therapies for NP are robust and range from topical treatments to conventional systemic therapies (i.e., methotrexate, cyclosporine), new oral agents (i.e., apremilast and tofacitinib), and biologics. The literature for treatment of NLP is severely limited, with therapy mainly consisting of topical, intralesional, or systemic corticosteroids or methotrexate. PMID- 29488103 TI - Multi-centre phase IV trial to investigate the immunogenicity of a new liquid formulation of recombinant human growth hormone in adults with growth hormone deficiency. AB - PURPOSE: To investigate whether a new liquid formulation of recombinant human growth hormone (r-hGH) induces the production of binding antibodies (BAbs) in adults with congenital or adult-onset growth hormone deficiency (GHD). METHODS: Men or women aged 19-65 years with adult growth hormone deficiency who were r-hGH naive or had stopped treatment >= 1 month before screening were treated with between 0.15 and 0.30 mg/day r-hGH liquid formulation for 39 weeks. The primary endpoint was the proportion of patients who developed BAbs at any time. Secondary endpoints were the proportion of patients with BAbs who became positive for neutralising antibodies, the effects on biomarkers of r-hGH exposure, safety, and adherence to treatment downloaded from the easypodTM connect software. RESULTS: Seventy-eight patients (61.5% men) with mean age 44.5 years (range 21-65) started and 68 (87.2%) completed the 39-week treatment period. 82.1% were treatment naive; all were negative for BAbs to r-hGH at baseline. The median (interquartile range) duration of treatment [273 (267.0-277.0) days] was consistent with patients receiving the required doses, and mean treatment adherence measured using easypodTM connect was 89.3%. The proportion of patients who developed BAbs was 0% (95% confidence interval 0-4.68%) and biomarker profiles were consistent with exposure to r-hGH. 92.3% of patients reported >= 1 adverse event during treatment. Most events were mild or moderate and no new safety concerns were detected. CONCLUSIONS: The low immunogenicity profile of the liquid formulation was consistent with that for the freeze-dried formulation, and no new safety concerns were reported. PMID- 29488104 TI - Identification of ortho-Substituted Benzoic Acid/Ester Derivatives via the Gas Phase Neighboring Group Participation Effect in (+)-ESI High Resolution Mass Spectrometry. AB - Benzoic acid/ester/amide derivatives are common moieties in pharmaceutical compounds and present a challenge in positional isomer identification by traditional tandem mass spectrometric analysis. A method is presented for exploiting the gas-phase neighboring group participation (NGP) effect to differentiate ortho-substituted benzoic acid/ester derivatives with high resolution mass spectrometry (HRMS1). Significant water/alcohol loss (>30% abundance in MS1 spectra) was observed for ortho-substituted nucleophilic groups; these fragment peaks are not observable for the corresponding para and meta substituted analogs. Experiments were also extended to the analysis of two intermediates in the synthesis of suvorexant (Belsomra) with additional analysis conducted with nuclear magnetic resonance (NMR), density functional theory (DFT), and ion mobility spectrometry-mass spectrometry (IMS-MS) studies. Significant water/alcohol loss was also observed for 1-substituted 1, 2, 3-triazoles but not for the isomeric 2-substituted 1, 2, 3-triazole analogs. IMS-MS, NMR, and DFT studies were conducted to show that the preferred orientation of the 2 substituted triazole rotamer was away from the electrophilic center of the reaction, whereas the 1-subtituted triazole was oriented in close proximity to the center. Abundance of NGP product was determined to be a product of three factors: (1) proton affinity of the nucleophilic group; (2) steric impact of the nucleophile; and (3) proximity of the nucleophile to carboxylic acid/ester functional groups. Graphical Abstract ?. PMID- 29488105 TI - Combining Bootstrap Aggregation with Support Vector Regression for Small Blood Pressure Measurement. AB - Blood pressure measurement based on oscillometry is one of the most popular techniques to check a health condition of individual subjects. This paper proposes a support vector using fusion estimator with a bootstrap technique for oscillometric blood pressure (BP) estimation. However, some inherent problems exist with this approach. First, it is not simple to identify the best support vector regression (SVR) estimator, and worthy information might be omitted when selecting one SVR estimator and discarding others. Additionally, our input feature data, acquired from only five BP measurements per subject, represent a very small sample size. This constitutes a critical limitation when utilizing the SVR technique and can cause overfitting or underfitting, depending on the structure of the algorithm. To overcome these challenges, a fusion with an asymptotic approach (based on combining the bootstrap with the SVR technique) is utilized to generate the pseudo features needed to predict the BP values. This ensemble estimator using the SVR technique can learn to effectively mimic the non linear relations between the input data acquired from the oscillometry and the nurse's BPs. PMID- 29488106 TI - Bachmann bundle pacing reduces atrial electromechanical delay in type 1 myotonic dystrophy patients. AB - BACKGROUND: Atrial electromechanical delay (AEMD) is an echocardiographic parameter correlated with the onset of supraventricular arrhythmias in several clinical conditions. Inter-atrial septal pacing in the region of Bachmann's bundle (BB) has been shown to be safe and feasible in myotonic dystrophy type 1 (DM1) patients, with a low rate of sensing and pacing defects. The aim of this study was to assess the impact of temporary BB pacing compared with right atrial appendage (RAA) pacing on AEMD in DM1 patients undergoing pacemaker (PM) implantation for cardiac rhythm abnormalities. METHODS: The study enrolled 70 consecutive DM1 patients undergoing PM implantation for cardiac rhythm abnormalities in accordance with the current guidelines. Seventy age- and sex matched non-DM1 patients undergoing dual-chamber PM implantation for cardiac rhythm abnormalities were used as controls. The atrial pacing lead was temporarily positioned in the RAA and on the right side of the inter-atrial septum in the region of Bachmann's bundle. For each site (BB and RAA), temporary atrial pacing in the AAI mode was established at 10 beats per minute above the sinus rate and a detailed trans-thoracic echocardiogram with tissue Doppler (TDI) analysis was recorded after at least 10 min of atrial pacing to evaluate AEMD. RESULTS: Temporary RAA pacing did not show statistically significant differences in inter-AEMD (48.2 +/- 17.8 vs 50.5 +/- 16.5 ms; P = 0.8), intra-left AEMD (43.3 +/- 15.5 vs 44.6 +/- 15.8 ms; P = 0.1), or intra-right-AEMD (14.1 +/- 4.2 vs 15.4 +/- 5.8 ms; P = 0.9), in comparison with sinus rhythm. Temporary BB pacing determined a significantly lower inter-AEMD (36.1 +/- 17.1 vs 50.5 +/- 16.5 ms; P = 0.001) and intra-left AEMD (32.5 +/- 15.2 vs 44.6 +/- 15.8 ms; P = 0.001) values in comparison with temporary RAA pacing. No statistically significant difference was found in intra-right AEMD (12.2 +/- 4.6 vs 15.4 +/- 5.8 ms; P = 0.2). In the control group, neither temporary RAA pacing nor temporary BB pacing showed statistically significant differences in inter-AEMD, intra-left AEMD, or intra-right AEMD values in comparison with sinus rhythm. CONCLUSIONS: In DM1 patients undergoing dual-chamber PM implantation, atrial pacing in the Bachmann bundle region is associated with significantly lower echocardiographic indices of atrial electromechanical delay (inter-AEMD and intra-left AEMD) in comparison with RAA pacing. PMID- 29488107 TI - Mapping the Growth of Heterogeneous Forms of Externalizing Problem Behavior Between Early Childhood and Adolescence:A Comparison of Parent and Teacher Ratings. AB - We compared long-term growth patterns in teachers' and mothers' ratings of Overt Aggression, Covert Aggression, Oppositional Defiance, Impulsivity/inattention, and Emotion Dysregulation across developmental periods spanning kindergarten through grade 8 (ages 5 to 13 years). We also determined whether salient background characteristics and measures of child temperament and parenting risk differentially predicted growth in discrete categories of child externalizing symptoms across development. Participants were 549 kindergarten-age children (51% male; 83% European American; 17% African American) whose problem behaviors were rated by teachers and parents each successive year of development through 8th grade. Latent growth curve analyses were performed for each component scale, contrasting with an overall index of externalizing, in a piecewise fashion encompassing two periods of development: K-1and grades 1-8. Our findings showed that there were meaningful differences and similarities between informants in their levels of concern about specific forms of externalizing problems, patterns of change in problem behavior reports across development, and in the extent to which their ratings of specific problems were associated with distal and proximal covariates. Thus, these data provided novel information about issues that have received scant empirical attention and have important implications for understanding the development and prevention of children's long-term externalizing problems. PMID- 29488108 TI - Personality Correlates of Self-Injury in Adolescent Girls: Disentangling the Effects of Lifetime Psychopathology. AB - Adolescent non-suicidal self-injury (aNSSI) is associated with abnormal scores on personality traits, such as high neuroticism. However, no studies to date have examined personality facets of self-injury in a cohort younger than college-age. Plus, adolescent psychopathologies, especially Depressive Disorders, are associated with a similar personality profile and are highly comorbid with aNSSI. Consequently, it remains unclear whether personality provides insights about aNSSI in youth beyond that due to underlying psychopathology. 550 community dwelling 13- to 15-year-old never-depressed adolescent girls were interviewed for lifetime aNSSI and lifetime psychopathology. Personality traits, broad domains and specific facets, were assessed by self-report. Never-depressed adolescent girls who endorse aNSSI often met lifetime criteria for psychiatric disorders (NSSI: 20/43; 46.5% vs. non-aNSSI: 131/507; 26.1%). aNSSI and lifetime psychopathology were each independently associated with several traits (e.g., high neuroticism and conscientiousness), whereas some traits only discriminated aNSSI (e.g., high melancholia, a facet of neuroticism related to sadness and negative self-evaluation) or lifetime psychopathology independent of each other (e.g., low positive emotionality; low agreeableness). Furthermore, a multivariate model identified high melancholia, high openness to experience, and low conscientiousness as incrementally independent correlates of lifetime aNSSI over and above psychiatric illness. Proneness to melancholia, interest in new things, and poor self-control incrementally track aNSSI in never-depressed adolescent girls. Importantly, this emerges early in course (13-15 years of age) and is independent of lifetime psychiatric diagnosis. Implications for updating etiological models and clinical utility of personality assessment are discussed. PMID- 29488109 TI - Computational investigation of the molecular conformation-dependent binding mode of (E)-beta-farnesene analogs with a heterocycle to aphid odorant-binding proteins. AB - Odorant-binding proteins (OBPs) play an important role as ligand-transfer filters in olfactory recognition in insects. (E)-beta-farnesene (EBF) is the main component of the aphid alarm pheromone and could keep aphids away from crops to prevent damage. Computational insight into the molecular binding mode of EBF analogs containing a heterocycle based on the structure of Megoura viciae OBP 3 (MvicOBP3) was obtained by molecular docking and molecular dynamics simulations. The results showed that high affinity EBF analogs substituted with an aromatic ring present a unique binding conformation in the surface cavity of MvicOBP3. A long EBF chain was located inside the cavity and was surrounded by many hydrophobic residues, while the substituted aromatic ring was exposed to the outside due to limitations from the formation of multiple hydrogen bonds. However, the low activity EBF analogs displayed an exactly inverted binding pose, with EBF loaded on the external side of the protein cavity. The affinity of the recently synthesized EBF analogs containing a triazine ring was evaluated in silico based on the binding modes described above and in vitro through fluorescence competitive binding assay reported later. Compound N1 not only showed a similar binding conformation to that of the high affinity analogs but was also found to have a much higher docking score and binding affinity than the other analogs. In addition, the docking score results correlated well with the predicted logP values for these EBF analogs, suggesting highly hydrophobic interactions between the protein and ligand. These studies provide an in silico screening model for the binding affinity of EBF analogs in order to guide their rational design based on aphid OBPs. PMID- 29488111 TI - Social enrichment improves social recognition memory in male rats. AB - The social environment is thought to have a strong impact on cognitive functions. In the present study, we investigated whether social enrichment could affect rats' memory ability using the "Different Objects Task (DOT)," in which the levels of memory load could be modulated by changing the number of objects to be remembered. In addition, we applied the DOT to a social discrimination task using unfamiliar conspecific juveniles instead of objects. Animals were housed in one of the three different housing conditions after weaning [postnatal day (PND) 21]: social-separated (1 per cage), standard (3 per cage), or social-enriched (10 per cage) conditions. The object and social recognition tasks were conducted on PND 60. In the sample phase, the rats were allowed to explore a field in which 3, 4, or 5 different, unfamiliar stimuli (conspecific juveniles through a mesh or objects) were presented. In the test phase conducted after a 5-min delay, social separated rats were able to discriminate the novel conspecific from the familiar ones only under the condition in which three different conspecifics were presented; social-enriched rats managed to recognize the novel conspecific even under the condition of five different conspecifics. On the other hand, in the object recognition task, both social-separated and social-enriched rats were able to discriminate the novel object from the familiar ones under the condition of five different objects. These results suggest that social enrichment can enhance social, but not object, memory span. PMID- 29488110 TI - Individual identity and affective valence in marmoset calls: in vivo brain imaging with vocal sound playback. AB - As with humans, vocal communication is an important social tool for nonhuman primates. Common marmosets (Callithrix jacchus) often produce whistle-like 'phee' calls when they are visually separated from conspecifics. The neural processes specific to phee call perception, however, are largely unknown, despite the possibility that these processes involve social information. Here, we examined behavioral and whole-brain mapping evidence regarding the detection of individual conspecific phee calls using an audio playback procedure. Phee calls evoked sound exploratory responses when the caller changed, indicating that marmosets can discriminate between caller identities. Positron emission tomography with [18F] fluorodeoxyglucose revealed that perception of phee calls from a single subject was associated with activity in the dorsolateral prefrontal, medial prefrontal, orbitofrontal cortices, and the amygdala. These findings suggest that these regions are implicated in cognitive and affective processing of salient social information. However, phee calls from multiple subjects induced brain activation in only some of these regions, such as the dorsolateral prefrontal cortex. We also found distinctive brain deactivation and functional connectivity associated with phee call perception depending on the caller change. According to changes in pupillary size, phee calls from a single subject induced a higher arousal level compared with those from multiple subjects. These results suggest that marmoset phee calls convey information about individual identity and affective valence depending on the consistency or variability of the caller. Based on the flexible perception of the call based on individual recognition, humans and marmosets may share some neural mechanisms underlying conspecific vocal perception. PMID- 29488112 TI - Spatial perseveration error by alpacas (Vicugna pacos) in an A-not-B detour task. AB - Spatial perseveration has been documented for domestic animals such as mules, donkeys, horses and dogs. However, evidence for this spatial cognition behavior among other domestic species is scarce. Alpacas have been domesticated for at least 7000 years yet their cognitive ability has not been officially reported. The present article used an A-not-B detour task to study the spatial problem solving abilities of alpacas (Vicugna pacos) and to identify the perseveration errors, which refers to a tendency to maintain a learned route, despite having another available path. The study tested 51 alpacas, which had to pass through a gap at one end of a barrier in order to reach a reward. After one, two, three or four repeats (A trials), the gap was moved to the opposite end of the barrier (B trials). In contrast to what has been found in other domestic animals tested with the same task, the present study did not find clear evidence of spatial perseveration. Individuals' performance in the subsequent B trials, following the change of gap location, suggests no error persistence in alpacas. Results suggest that alpacas are more flexible than other domestic animals tested with this same task, which has important implications in planning proper training for experimental designs or productive purposes. These results could contribute toward enhancing alpacas' welfare and our understanding of their cognitive abilities. PMID- 29488113 TI - The Sulfolobus solfataricus RecQ-like DNA helicase Hel112 inhibits the NurA/HerA complex exonuclease activity. AB - ATPase/Helicases and nucleases play important roles in DNA end-resection, a critical step during homologous recombination repair in all organisms. In hyperthermophilic archaea the exo-endonuclease NurA and the ATPase HerA cooperate with the highly conserved Mre11-Rad50 complex in 3' single-stranded DNA (ssDNA) end processing to coordinate repair of double-stranded DNA breaks. Little is known, however, about the assembly mechanism and activation of the HerA-NurA complex. In this study we demonstrate that the NurA exonuclease activity is inhibited by the Sulfolobus solfataricus RecQ-like Hel112 helicase. Inhibition occurs both in the presence and in the absence of HerA, but is much stronger when NurA is in complex with HerA. In contrast, the endonuclease activity of NurA is not affected by the presence of Hel112. Taken together these results suggest that the functional interaction between NurA/HerA and Hel112 is important for DNA end resection in archaeal homologous recombination. PMID- 29488114 TI - A Smart Paclitaxel-Disulfiram Nanococrystals for Efficient MDR Reversal and Enhanced Apoptosis. AB - PURPOSE: A multidrug resistance (MDR) modulator, disulfiram (DSF), was incorporated into pure paclitaxel (PTX) nanoparticles to construct a smart paclitaxel-disulfiram nanococrystals (PTX-DSF Ns) stabilized by beta lactoglobulin (beta-LG), with the aim to reverse MDR and therefore enhnce cytotoxicity towards Taxol-resistant A549 cells (A549/TAX). METHOD: PTX-DSF Ns was prepared by antisolvent precipitation method. Flow cytometry was used to determine the cell uptake, drug efflux inhibition, cell cycle phase arrest and apoptosis. MDR-1 gene expression level was detected by real time quantitative PCR and gel electrophoresis. RESULTS: PTX-DSF Ns prepared from the optimized formulation had an optimum diameter of 160 nm, was stable and had a high drug loading capacity. Importantly, the uptake of PTX-DSF Ns in A549/TAX cells was 14 fold greater than the uptake of PTX Ns. Furthermore, PTX-DSF Ns promoted 5-folds increase in apoptosis, enabled 7-folds reduction in the IC50, and rendered 8.9 fold decrease in the dose compared with free PTX. CONCLUSION: PTX-DSF Ns with a precise mass ratio offer efficient cytotoxicity against Taxol-resistant cells and a novel approach for codelivery and sensitizing MDR cancer to chemotherapy. In addition, the use of nanosuspensions as a combined treatment provides a new research avenue for nanosuspensions. PMID- 29488115 TI - Human Respiratory Syncytial Virus and Streptococcus pneumoniae Infection in Wild Bonobos. AB - Despite being important conservation tools, tourism and research may cause transmission of pathogens to wild great apes. Investigating respiratory disease outbreaks in wild bonobos, we identified human respiratory syncytial virus and Streptococcus pneumoniae as causative agents. A One Health approach to disease control should become part of great ape programs. PMID- 29488117 TI - The Effect of the Post 2001 Reforms on FMD Risks of the International Live Animal Trade. AB - The 2001 UK foot and mouth disease (FMD) epidemic marked a change in global FMD management, focusing less on trade isolation than on biosecurity within countries where FMD is endemic. Post 2001 policy calls for the isolation of disease-free zones in FMD-endemic countries, while increasing the opportunities for trade. The impact of the change on disease risk has yet to be tested. In this paper, we estimate an empirical model of disease risk that tests for the impact of trade volumes before and after 2001, controlling for biosecurity measures. In the pre 2001 regime, we find that poor biosecurity was associated with the probability of reporting an outbreak. In the post 2001 regime, the risks changed, with trade being a much greater source of risk. We discuss the trade-off between trade restrictions and biosecurity measures in the management of FMD disease risks. PMID- 29488118 TI - Involvement of CD8+ T cells in the development of renal hemorrhage in a mouse model of hemorrhagic fever with renal syndrome. AB - Hemorrhagic fever with renal syndrome (HFRS) is caused by hantavirus infection. Although host immunity is thought to be involved in the pathogenesis of HFRS, the mechanism remains to be elucidated. A mouse model of HFRS, which showed renal hemorrhage similar to that seen in patients, has been developed previously. In this study, we aimed to clarify whether CD4+ and CD8+ T cells are involved in the development of renal hemorrhage in the mouse model. At 2 days before virus inoculation, CD4+ or CD8+ T cells in 6-week-old BALB/c mice were depleted by administration of antibodies. The CD4+ T cell-depleted mice developed signs of disease such as transient weight loss, ruffled fur and renal hemorrhage as in non depleted mice. In contrast, the CD8+ T cell-depleted mice showed no signs of disease. After determination of CTL epitopes on the viral glycoprotein in BALB/c mice, the quantity of virus-specific CTLs was analyzed using an MHC tetramer. The quantity of virus-specific CTLs markedly increased in spleens and kidneys of virus-infected mice. However, the quantity in high-pathogenic clone-infected mice was comparable to that in low-pathogenic clone-infected mice. We previously reported that the high-pathogenic clone propagated more efficiently than the low pathogenic clone in kidneys of mice during the course of infection. Therefore, there is a possibility that the balance between quantities of the target and effector is important for disease outcome. In conclusion, this study showed that CD8+ T cells are involved in the development of renal hemorrhage in a mouse model of HFRS. PMID- 29488119 TI - Characterization of an Australian isolate of taro bacilliform virus and development of an infectious clone. AB - The badnavirus taro bacilliform virus (TaBV) has been reported to infect taro (Colocasia esculenta L.) and other edible aroids in several South Pacific island countries, but there are no published reports from Australia. Using PCR and RCA, we identified and characterized an Australian TaBV isolate. A terminally redundant cloned copy of the TaBV genome was generated and shown to be infectious in taro following agro-inoculation. This is the first report of TaBV from Australia and also the first report of an infectious clone for this virus. PMID- 29488120 TI - Are animals a source of Stenotrophomonas maltophilia in human infections? Contributions of a nationwide molecular study. AB - Stenotrophomonas maltophilia (Sm) is an archetypal environmental opportunistic bacterium responsible for health care-associated infections. The role of animals in human Sm infections is unknown. This study aims to reveal the genetic and phylogenetic relationships between pathogenic strains of Sm, both animal and human, and identify a putative role for animals as a reservoir in human infection. We phenotypically and genotypically characterized 61 Sm strains responsible for animal infections (mainly respiratory tract infections in horses) from a French nationwide veterinary laboratory network. We tested antimicrobial susceptibility and performed MLST and genogrouping using the concatenation of the seven housekeeping genes from the original MLST scheme. Excluding the eight untypeable strains owing to the lack of gene amplification, only 10 out of the 53 strains yielded a known ST (ST5, ST39, ST162, ST8, ST27, ST126, ST131). The genogroup distribution highlighted not only genogroups (genogroups 5 and 9) comprised exclusively of animal strains but also genogroups shared by human and animal strains. Interestingly, these shared genogroups were primarily groups 2 and 6, which have previously been identified as the two most frequent genogroups among human-pathogenic Sm strains, especially among respiratory pathogens. The antimicrobial susceptibility testing underlined the presence of acquired resistance: 18.8 and 7.5% of the tested isolates were resistant to the sulfonamide-trimethoprim combination and ciprofloxacin, respectively. Animal strains of Sm shared phylogenetic traits with some of the most successful human strains. The exact relationships between the human and animal strains, and the genetic support of these common traits, need to be determined. PMID- 29488121 TI - A multicenter, randomized trial comparing efficacy and safety of paclitaxel/capecitabine and cisplatin/capecitabine in advanced gastric cancer. AB - BACKGROUND: We compared efficacy and safety of paclitaxel/capecitabine therapy followed by capecitabine for maintenance (PACX) versus cisplatin/capecitabine therapy (XP) in advanced gastric cancer. METHODS: Multicenter, randomized, phase III trial was conducted in China (December 2009-February 2014). Adults (n = 320) with histologically confirmed, untreated metastatic/unresectable gastric or gastroesophageal junction adenocarcinoma; with >= 1 measureable lesions according to Response Evaluation Criteria in Solid Tumors 1.0 criteria; Karnofsky performance score >= 70 and life expectancy >= 3 months were randomized (1:1) to PACX or XP. PACX group received paclitaxel 80 mg/m2 intravenous on days 1 and 8; capecitabine 1000 mg/m2 orally BD on days 1-14, followed by a 7-day rest interval for 4 cycles, followed by maintenance capecitabine at same dosage/schedule until disease progression, unendurable adverse events or death. XP group received cisplatin intravenous 80 mg/m2 on day 1 and capecitabine at same dosage/schedule as PACX group per cycle for 6 cycles. RESULTS: Median progression-free survival (5.0 versus 5.3 months; hazard ratio [95% CI]: 0.906; 0.706-1.164; p = 0.44) and overall survival (12.5 versus 11.8 months; hazard ratio: 0.878 [0.685-1.125]; p = 0.30) were not significantly different between PACX and XP groups. Objective response rate was significantly higher (43.1 versus 28.8%; p = 0.012) and disease control rate was similar (77.5 versus 72.5%; p = 0.75) in PACX versus XP, respectively. Quality of life was significantly improved in PACX versus XP after three treatment cycles. Many treatment-related adverse events were significantly lesser in PACX than XP. CONCLUSIONS: First-line chemotherapy with PACX is effective with milder toxicities in advanced gastric cancer, but could not replace XP. PMID- 29488122 TI - A phase II trial of capecitabine plus cisplatin (XP) for patients with advanced gastric cancer with early relapse after S-1 adjuvant therapy: XParTS-I trial. AB - BACKGROUNDS: In Japan, standard regimens for advanced gastric cancer (AGC) include S-1 chemotherapy. The standard treatment for early relapse after adjuvant chemotherapy with fluoropyrimidine alone is platinum-based chemotherapy, while the standard treatment for early relapse after adjuvant chemotherapy with fluoropyrimidine plus platinum is second-line chemotherapy. To evaluate the efficacy and safety of capecitabine plus cisplatin (XP) treatment for AGC patients who relapse within 6 months after S-1-based therapy, we conducted a multicenter phase II trial (NCT01412294). METHODS: HER2-negative gastric cancer patients treated with adjuvant chemotherapy including S-1 for more than 12 weeks and relapsed within 6 months were treated with capecitabine 1000 mg/m2 bid for 14 days plus cisplatin 80 mg/m2 on day 1 of a 3-week cycle. The primary endpoint was PFS; secondary endpoints were OS, time to treatment failure, overall response rate (ORR) and safety. RESULTS: Forty patients (median age 64) were enrolled; of those, 37 (92.5%) received adjuvant S-1 monotherapy. Median PFS was 4.4 months (95% CI 3.6-5.1), which was longer than the 2-month protocol-specified threshold (p < 0.001). Median OS was 13.7 months (95% CI 9.0-17.7) and ORR was 8/30 (26.7%) (95% CI 14.2-44.4). Most common grade >= 3 adverse events were neutropenia (23%), anemia (18%), elevated serum creatinine (18%), fatigue (13%), diarrhea (7.5%), and anorexia (7.5%). CONCLUSIONS: XP was safe and effective in patients with early relapse after S-1 adjuvant chemotherapy for curatively resected gastric cancers. XP may be a good option for the treatment of patients after early failure after adjuvant S-1. TRIAL REGISTRATION: NCT01412294. PMID- 29488123 TI - Surgical Management of Giant Hepatic Hemangioma: Single Center's Experience with 144 Patients. AB - BACKGROUND: Hepatic hemangioma (HH) is the most common benign solid tumor of the liver. The aim of this study is to review our experiences of surgical treatment for giant HH and to show the impact of HH size and type of surgical resection on surgical outcomes. PATIENTS AND METHODS: This is a retrospective study of the cases who underwent surgery for giant HH during the period from January 2000 to April 2017. RESULTS: Elective surgery was performed for 144 patients who had giant HH. The median diameter of resected HH was 10 cm (5-31 cm). Enucleation was performed for 92 (63.9%) patients and anatomical resection was required in 52 (36.1%) patients. No statistical difference between enucleation and resection as regards intraoperative and postoperative findings. The amount of intraoperative blood loss is significantly more in HH > 10 cm (300 vs. 575 ml, P = 0.007), the need of blood transfusion was significantly more in HH > 10 cm (P = 0.000), and the operation time was significantly longer in HH > 10 cm (120 vs. 180 min, P = 0.000). The size of HH had no significant effect as regards the development of postoperative complications. CONCLUSION: Giant hemangioma can be treated surgically with low incidence of morbidity and mortality. No statistical difference between enucleation and resection as regards surgical outcomes. In left lobe HH, HH located deeper in posterior hepatic segments and in multiple HH, hepatic resection is preferred. The size of the HH had significant impact intraoperative blood loss and operative time. PMID- 29488124 TI - Meta-Analysis of Enhanced Recovery Protocols in Bariatric Surgery. AB - BACKGROUND: Enhanced recovery after surgery (ERAS) guidelines, fast-track protocols, and alternative clinical pathways have been widely promoted in a variety of disciplines leading to improved outcomes in post-operative morbidity and length of stay (LOS). This meta-analysis assesses the implications of standardized management protocols in bariatric surgery. METHODS: The PRISMA guidelines were adhered to. Databases were searched with the application of pre defined inclusion and exclusion criteria. Results were reported as mean differences or pooled odds ratios (OR) with 95% confidence intervals (95% CI). Individual protocols and surgical approaches were assessed through subgroup analysis, and sensitivity analysis of methodological quality was performed. RESULTS: A total of 1536 studies were screened; 13 studies were eventually included for meta-analysis involving a total of 6172 patients. Standardized perioperative techniques were associated with a savings of 19.5 min in operative time (p < 0.01), as well as a LOS which was shortened by 1.5 days (p < 0.01). Pooled post-operative morbidity rates also favored enhanced recovery care protocols (OR 0.7%, 95% CI 0.6-0.9%, p < 0.01). CONCLUSION: Bariatric surgery involves a complex cohort of patients who require high-quality evidence-based care to improve outcomes. Consensus guidelines on the feasibility of ERAS and alternative clinical pathways are required in the setting of bariatric surgery. PMID- 29488125 TI - Surgical Strategy Based on Indocyanine Green Test for Chemotherapy-Associated Liver Injury and Long-Term Outcome in Colorectal Liver Metastases. AB - BACKGROUND: It remains unclear whether the presence of chemotherapy-induced liver injury (CALI) or impaired liver functional reserve affects the long-term outcome. This study assessed the applicability and long-term effects of using criteria based on the indocyanine green (ICG) test results in selecting the operative procedure among patients with colorectal liver metastases (CRLM) who had a risk of CALI. STUDY DESIGN: CRLM patients who received preoperative chemotherapy including oxaliplatin and/or irinotecan prior to a curative hepatectomy between 2007 and 2017 were included. For each case, the minimum required future remnant liver volume and operative procedure were decided based on the ICG retention rate at 15 min (ICG R15). Patients with an ICG R15 > 10% and who had undergone a major hepatectomy were categorized in a marginal liver functional reserve (MHML) group. RESULTS: Overall, 161 patients were included; 77 of them had an ICG R15 > 10%, and 57 had pathological liver injury (PLI). After the median follow-up time of 30.9 months, the 5-year overall survival rate was 36.1%. The presence of an impaired ICG test result or CALI did not negatively impact the overall and recurrence-free survival outcomes. A multivariate analysis revealed that the presence of four or more nodules of liver metastases was the only independent predictor of a poor overall survival. A significantly larger proportion of patients in the MHML group (n = 37) had a 25% or larger increase in splenic volume (30 vs. 13%; P = 0.024). CONCLUSION: The presence of an impaired ICG test result or PLI did not affect the long-term outcome after individually selected operative procedure. However, patients undergoing MHML had a higher possibility of developing a > 25% splenic volume increase after hepatectomy. PMID- 29488126 TI - Long-term risk of second malignancies in women after breast conservation therapy for ductal carcinoma in situ or early-stage breast cancer. AB - PURPOSE: Women with ductal carcinoma in situ (DCIS) or early-stage breast cancer have an excellent prognosis, but their risk of developing second malignant neoplasms (SMNs) is not well established. We analyzed SMNs in a large cohort with long follow-up after breast conservation therapy. METHODS: The study population comprised 755 women with DCIS (n = 135) or stage I-II breast carcinoma (n = 620). Subjects were aged 25-89 (median 55) years when they underwent breast-conserving surgery followed by radiotherapy to the entire breast (60-68Gray) between 1992 and 2001. Additional treatment included hormonal therapy and/or chemotherapy based on clinical characteristics. SMNs were grouped by site. The rate of SMNs over time was determined using the Kaplan-Meier method. To compare the probability of developing SMNs overall and for specific organs or sites, probability estimates were obtained for a 55-year-old female from the Surveillance, Epidemiology, and End Results Program (SEER). RESULTS: Median follow-up from radiotherapy was 13.8 years. The 15-year age-adjusted probability of developing any SMN was 12.0%, close to the SEER rate of 12.1% for a non-breast malignancy. Systemic therapy and higher-dose radiotherapy (> 63 Gray) were not associated with significantly increased risks of SMNs. Compared to SEER, significantly increased risk was noted for gynecologic cancers and melanoma. CONCLUSIONS: Most SMNs were unrelated to treatment, and the 15-year incidence was similar to that of cancer in the SEER control group-findings that should be reassuring to patients. Further risk reduction is expected from prophylactic gynecologic surgery. Continued investigations into genetic links with melanoma are warranted. PMID- 29488127 TI - Combined Strategies to Improve the Expression of Recombinant Sterol C24 Methyltransferase from Leishmania braziliensis in E. coli. AB - Among the neglected tropical diseases, leishmaniasis stands out for its worldwide distribution and diversity of symptoms. Cutaneous leishmaniasis (CL), for instance, is endemic in 18 countries, but the available drugs to fight it have high toxicity and low patient adherence. In order to overcome this, dilemma drugs that target enzymes which are absent in the human host, such as Leishmania braziliensis sterol C24-methyltransferase (SMT-C24, EC 2.1.1.41), are needed. However, medicinal chemistry efforts toward this goal have been hampered by the low yield of soluble recombinant SMT-C24 afforded by currently available expression systems. Herein, we show that a combination of molecular biology and chromatographic strategies may increase the yield of LbSMT-C24 in up to fivefold. These results lay the ground for future investigation of this enzyme as a drug target. PMID- 29488128 TI - The Role of Calcium in Differentiation of Human Adipose-Derived Stem Cells to Adipocytes. AB - Differentiation process of mesenchymal stem cells (MSCs) into adipocyte is involved in obesity. Multiple factors such as Ca2+ play important roles in different stages of this process. Because of the complicated roles of Ca2+ in adipogenesis, the aim of present investigation was to study the influx and efflux of Ca2+ into and out of the cells during adipogenesis. Adipose-derived MSCs were used to differentiate into adipocytes. MSCs were exposed to 2.5 mM Ca2+ or 1.8 mM Ca2+ plus calcium ionophore, A23187, for 3 days. Lipid staining, triglycerides (TG) content, and glyceraldehyde phosphate dehydrogenase (GAPDH) activity were evaluated to confirm the efficiency of the differentiation. Gene expression of GLUT4, PPARgamma2, RAR-alpha, and calreticulin, as well as the protein levels of GLUT4 and PPARgamma2 were determined. Ca2+ and in particular Ca2+ plus A23187 significantly lowered the efficiency of differentiation accompanied by decrease in intracellular TG deposits, GAPDH activity and alleviation of gene, and protein levels of GLUT4 and PPARgamma2. While calreticulin and RAR-alpha were remarkably upregulated in A23187 group. This study showed the inhibitory effects of calcium in adipogenesis. Additionally, it indicated the greater inhibitory effect of calreticulin and RAR-alpha in controlling adipogenesis by higher levels of calcium. PMID- 29488129 TI - Paradigm shift regarding the transversalis fascia, preperitoneal space, and Retzius' space. AB - BACKGROUND: There has been confusion in the anatomical recognition when performing inguinal hernia operations in Japan. From now on, a paradigm shift from the concept of two-dimensional layer structure to the three-dimensional space recognition is necessary to promote an understanding of anatomy. ANATOMY AND EMBRYOLOGY: Along with the formation of the abdominal wall, the extraperitoneal space is formed by the transversalis fascia and preperitoneal space. The transversalis fascia is a somatic vascular fascia originating from an arteriovenous fascia. It is a dense areolar tissue layer at the outermost of the extraperitoneal space that runs under the diaphragm and widely lines the body wall muscle. The umbilical funiculus is taken into the abdominal wall and transformed into the preperitoneal space that is a local three-dimensional cavity enveloping preperitoneal fasciae composed of the renal fascia, vesicohypogastric fascia, and testiculoeferential fascia. The Retzius' space is an artificial cavity formed at the boundary between the transversalis fascia and preperitoneal space. In the underlay mesh repair, the mesh expands in the range spanning across the Retzius' space and preperitoneal space. PMID- 29488130 TI - Mitochondria, its DNA and telomeres in ageing and human population. AB - In the last decades, studies about ageing have become more essential as our population grows older. The incidence of age-related diseases increases, which pose challenges both for societies and individuals in terms of life quality and economic impact. Understanding ageing and ageing-related processes will help us to slow down or even prevent these diseases and provide opportunities for healthy ageing; additionally, we all want to live longer. Ageing is a consequence of the interaction between processes that occur over time and genetics interacting with various disease states and an individual's lifestyle. There are several hallmarks of ageing that are generally accepted, but neither of the theories appears to be fully satisfactory. The focus of this article is on two theories of ageing: telomere shortening and mitochondrial DNA (mtDNA) alterations and dysfunction. We discuss characteristic molecular features such as mitochondrial haplogroups, telomere length, mtDNA copy number and heteroplasmy, and how all these traits come together in the ageing population. The recent evidence shows the existence of a strong linkage between these two theories suggesting common molecular mechanisms and a complicated telomere-mitochondria interplay during the humans' ageing. However, this relationship is still not completely understood, which is why it needs more attention. PMID- 29488132 TI - Spirituality for Mental Health and Well-Being of Adult Refugees in Europe. AB - This article reports on a pre- and post-test experimental study with 4504 refugees in 38 camps across nine destination countries. The aim was to examine the role of spirituality and a specially designed spiritual education programme in promoting mental health of refugees. A pre- and post-test experimental design has been used with three scales to examine the outcome measures: (1) the trauma screening questionnaire (2) life orientation test-revised and (3) mental health inventory-38. Results showed that compared with pre-test scores, the average post test scores of the refugees on the trauma questionnaire were lower, and higher on optimism measure, and mental health inventory. Voluntary participation, full attendance and self-practice willingness were favourable predictors of refugee mental health. Hierarchical regression model showed that self-practice willingness was the most important predictor of positive mental health of refugees. Findings make a case for interventions for refugees grounded in cultural competency and spirituality. PMID- 29488131 TI - Mechanisms of Oral Tolerance. AB - Oral tolerance is a state of systemic unresponsiveness that is the default response to food antigens in the gastrointestinal tract, although immune tolerance can also be induced by other routes, such as the skin or inhalation. Antigen can be acquired directly by intestinal phagocytes, or pass through enterocytes or goblet cell-associated passages prior to capture by dendritic cells (DCs) in the lamina propria. Mucin from goblet cells acts on DCs to render them more tolerogenic. A subset of regulatory DCs expressing CD103 is responsible for delivery of antigen to the draining lymph node and induction of Tregs. These DCs also imprint gastrointestinal homing capacity, allowing the recently primed Tregs to home back to the lamina propria where they interact with macrophages that produce IL-10 and expand. Tregs induced by dietary antigen include Foxp3+ Tregs and Foxp3- Tregs. In addition to Tregs, T cell anergy can also contribute to oral tolerance. The microbiota plays a key role in the development of oral tolerance, through regulation of macrophages and innate lymphoid cells that contribute to the regulatory phenotype of gastrointestinal dendritic cells. Absence of microbiota is associated with a susceptibility to food allergy, while presence of Clostridia strains can suppress development of food allergy through enhancement of Tregs and intestinal barrier function. It is not clear if feeding of antigens can also induce true immune tolerance after a memory immune response has been generated, but mechanistic studies of oral immunotherapy trials demonstrate shared pathways in oral tolerance and oral immunotherapy, with a role for Tregs and anergy. An important role for IgA and IgG antibodies in development of immune tolerance is also supported by studies of oral tolerance in humans. The elucidation of key pathways in oral tolerance could identify new strategies to increase efficacy of immunotherapy treatments for food allergy. PMID- 29488133 TI - Examining Difference in Immigration Stress, Acculturation Stress and Mental Health Outcomes in Six Hispanic/Latino Nativity and Regional Groups. AB - Little is known about the specific behavioral health impact of acculturation stressors that affect Hispanic/Latino immigrant sub-groups. These immigration related stressors and traumatic events may have differential impact on depression depending on country/region of origin. Using a measure of immigration and acculturation stress, the current study sought to determine differences in the impact of stress on six sub-groups of Hispanic immigrants. Data on stress and depression were examined using a large, representative adult immigrant sample (N = 641). Controlling for age, gender and years in the US, factorial analysis of covariance revealed significant differences on total Hispanic Stress Inventory 2 (HSI2) stress appraisal scores based on country/region of origin. Pair wise comparisons between country/region of origin groups revealed that Mexicans had higher levels of stress compared to Cuban or Dominican immigrants. Several patterns of differential stress were also found within sub-domains of the HSI2. Using regression models, HSI2 stress appraisals and their interaction with country of origin proved to not be significant predictors of depression (PHQ9), while gender and age were significant. Differences in HSI2 stress that are based on nativity may be moderated by cultural resilience that ultimately serves a protective role to prevent the onset of depression. PMID- 29488134 TI - Visualization of Altered Hippocampal Connectivity in an Animal Model of Alzheimer's Disease. AB - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and neurodegeneration in the hippocampus. Despite the pathological importance of the hippocampal degeneration in AD, little topographical evidence exists of impaired hippocampal connectivity in patients with AD. To investigate the anatomical connections of the hippocampus, we injected the neurotracer 1,1'-dioctadecyl-3,3,3'3,3'-tetramethyl-indocarbocyanine perchlorate (DiI) into the hippocampi of 5XFAD mice, which were used as an animal model of AD. In wild-type controls, DiI-containing cells were found in the entorhinal cortex, medial septum, locus coeruleus, dorsal raphe, substantia nigra pars compacta, and olfactory bulb. Hippocampal inputs were decreased in multiple brain regions in the 5XFAD mice compared to wild-type littermate mice. These results are the first to reveal alterations at the cellular level in hippocampal connectivity in the brains of 5XFAD mice. These results suggest that anatomical mapping of hippocampal connectivity will elucidate new pathogenic mechanisms and therapeutic targets for AD treatment. PMID- 29488136 TI - Ambra1 Shapes Hippocampal Inhibition/Excitation Balance: Role in Neurodevelopmental Disorders. AB - Imbalances between excitatory and inhibitory synaptic transmission cause brain network dysfunction and are central to the pathogenesis of neurodevelopmental disorders. Parvalbumin interneurons are highly implicated in this imbalance. Here, we probed the social behavior and hippocampal function of mice carrying a haploinsufficiency for Ambra1, a pro-autophagic gene crucial for brain development. We show that heterozygous Ambra1 mice (Ambra+/-) are characterized by loss of hippocampal parvalbumin interneurons, decreases in the inhibition/excitation ratio, and altered social behaviors that are solely restricted to the female gender. Loss of parvalbumin interneurons in Ambra1+/- females is further linked to reductions of the inhibitory drive onto principal neurons and alterations in network oscillatory activity, CA1 synaptic plasticity, and pyramidal neuron spine density. Parvalbumin interneuron loss is underlined by increased apoptosis during the embryonic development of progenitor neurons in the medial ganglionic eminence. Together, these findings identify an Ambra1-dependent mechanism that drives inhibition/excitation imbalance in the hippocampus, contributing to abnormal brain activity reminiscent of neurodevelopmental disorders. PMID- 29488137 TI - Alterations in System xc- Expression in the Retina of Type 1 Diabetic Rats and the Role of Nrf2. AB - Nrf2 (nuclear factor erythroid 2-related factor 2), a transcription factor that controls expression of several proteins that are related to cellular antioxidant capacity, such as the subunit xCT of the system xc-, is dysregulated in diabetes. Recently, it was described that system xc- is decreased in the retina after 3 weeks of diabetes. So, in the present work, the temporal relationship between xCT and Nrf2 in the retina of diabetic animals was investigated. Diabetes was induced in male Wistar rats (200 g) by a single injection of streptozotocin, and retinas were collected after 1, 2, and 6 months of diabetes induction. Expression of xCT, Nrf2 activity, and binding to antioxidant-responsive element (ARE) sequence were evaluated. Glutathione and reactive oxygen species (ROS) levels were also assessed. After 1 month of diabetes, Nrf2 activity, xCT expression, and glutathione levels were reduced whereas ROS were increased. Although glutathione and ROS levels remain unchanged until later stages, Nrf2 activity and xCT expression returned to normal levels after 2 months. However, they were decreased again at 6 months of diabetes. Accordingly, Nrf2 binding to xCT ARE sequence followed the same pattern of Nrf2 activity and xCT expression. These data showed that retinal xCT expression is regulated by Nrf2 in diabetic condition. The results also demonstrated a temporal relationship between Nrf2 and system xc- which could be implicated in the initiation of oxidative stress in retina in diabetes. PMID- 29488135 TI - Thioredoxin-Interacting Protein (TXNIP) in Cerebrovascular and Neurodegenerative Diseases: Regulation and Implication. AB - Neurological diseases, including acute attacks (e.g., ischemic stroke) and chronic neurodegenerative diseases (e.g., Alzheimer's disease), have always been one of the leading cause of morbidity and mortality worldwide. These debilitating diseases represent an enormous disease burden, not only in terms of health suffering but also in economic costs. Although the clinical presentations differ for these diseases, a growing body of evidence suggests that oxidative stress and inflammatory responses in brain tissue significantly contribute to their pathology. However, therapies attempting to prevent oxidative damage or inhibiting inflammation have shown little success. Identification and targeting endogenous "upstream" mediators that normalize such processes will lead to improve therapeutic strategy of these diseases. Thioredoxin-interacting protein (TXNIP) is an endogenous inhibitor of the thioredoxin (TRX) system, a major cellular thiol-reducing and antioxidant system. TXNIP regulating redox/glucose induced stress and inflammation, now is known to get upregulated in stroke and other brain diseases, and represents a promising therapeutic target. In particular, there is growing evidence that glucose strongly induces TXNIP in multiple cell types, suggesting possible physiological roles of TXNIP in glucose metabolism. Recently, a significant body of literature has supported an essential role of TXNIP in the activation of the NOD-like receptor protein (NLRP3) inflammasome, a well-established multi-molecular protein complex and a pivotal mediator of sterile inflammation. Accordingly, TXNIP has been postulated to reside centrally in detecting cellular damage and mediating inflammatory responses to tissue injury. The majority of recent studies have shown that pharmacological inhibition or genetic deletion of TXNIP is neuroprotective and able to reduce detrimental aspects of pathology following cerebrovascular and neurodegenerative diseases. Conspicuously, the mainstream of the emerging evidences is highlighting TXNIP link to damaging signals in endothelial cells. Thereby, here, we keep the trend to present the accumulative data on CNS diseases dealing with vascular integrity. This review aims to summarize evidence supporting the significant contribution of regulatory mechanisms of TXNIP with the development of brain diseases, explore pharmacological strategies of targeting TXNIP, and outline obstacles to be considered for efficient clinical translation. PMID- 29488139 TI - A Novel Plasma-Based Fluid for Particle Image Velocimetry (PIV): In-Vitro Feasibility Study of Flow Diverter Effects in Aneurysm Model. AB - Particle image velocimetry (PIV) is a commonly used method for in vitro investigation of fluid dynamics in biomedical devices, such as flow diverters for intracranial aneurysm treatment. Since it is limited to transparent blood substituting fluids like water-glycerol mixture, the influence of coagulation and platelet aggregation is neglected. We aimed at the development and the application of a modified platelet rich plasma as a new PIV fluid with blood-like rheological and coagulation properties. In standardized intracranial aneurysm silicone models, the effect of this new PIV plasma on the fluid dynamics before and after flow diverter implantation was evaluated and compared with water glycerol measurements. The flow diverting effect was strongly dependent on the used fluid, with considerably lower velocities achieved using PIV plasma, despite the same starting viscosity of both fluids. Moreover, triggering coagulation of PIV plasma allowed for intra-aneurysmal clot formation. We presented the first in vitro PIV investigation using a non-Newtonian, clottable PIV plasma, demonstrating a mismatch to a standard PIV fluid and allowing for thrombus formation. PMID- 29488141 TI - Stroke and the Remembered Body: You See Me Directed by Linda S. Brown, 2015. PMID- 29488138 TI - Intranasal Cotinine Plus Krill Oil Facilitates Fear Extinction, Decreases Depressive-Like Behavior, and Increases Hippocampal Calcineurin A Levels in Mice. AB - Failure in fear extinction is one of the more troublesome characteristics of posttraumatic stress disorder (PTSD). Cotinine facilitates fear memory extinction and reduces depressive-like behavior when administered 24 h after fear conditioning in mice. In this study, it was investigated the behavioral and molecular effects of cotinine, and other antidepressant preparations infused intranasally. Intranasal (IN) cotinine, IN krill oil, IN cotinine plus krill oil, and oral sertraline were evaluated on depressive-like behavior and fear retention and extinction after fear conditioning in C57BL/6 mice. Since calcineurin A has been involved in facilitating fear extinction in rodents, we also investigated changes of calcineurin in the hippocampus, a region key on contextual fear extinction. Short-term treatment with cotinine formulations was superior to krill oil and oral sertraline in reducing depressive-like behavior and fear consolidation and enhancing contextual fear memory extinction in mice. IN krill oil slowed the extinction of fear. IN cotinine preparations increased the levels of calcineurin A in the hippocampus of conditioned mice. In the light of the results, the future investigation of the use of IN cotinine preparations for the extinction of contextual fear memory and treatment of treatment-resistant depression (TRD) in PTSD is discussed. PMID- 29488140 TI - Health-promoting behaviors benefit the mental health of cirrhotic outpatients. AB - PURPOSE: The objectives of this study were to survey the frequency of engaging in a health-promoting lifestyle in patients with liver cirrhosis, and examine the mediating effects of a health-promoting lifestyle on relationships of symptoms and psychological distress with the quality of life (QOL). METHODS: A cross sectional study was conducted to recruit 148 cirrhotic outpatients from the gastroenterology outpatient department of one medical university hospital. All study participants completed self-administered questionnaires comprising a multidimensional symptoms scale, Hospital Anxiety and Depression Scale, short form Chinese health-promoting lifestyle profile, and the Taiwanese version of the Short-Form 36. Hierarchical linear regression and mediation models were used to evaluate the effect of a health-promoting lifestyle on the QOL. RESULTS: Results showed these cirrhotic outpatients reported low frequencies of health-promoting behaviors in their daily activities and had poor mental health but superior physical health. The hierarchical linear regression model found that depression, anxiety, and a health-promoting lifestyle were significant determinants of mental health. The mediation analysis further identified that a health-promoting lifestyle acted as a significant mediator which ameliorated the effects of depression and anxiety on the mental health aspect of the QOL. CONCLUSIONS: A health-promoting lifestyle can improve the mental health of the QOL. Healthcare professionals can develop effective health-promoting interventions to manage and improve the mental health of cirrhotic patients. PMID- 29488143 TI - Targeted 5-HT1F Therapies for Migraine. AB - Migraine is a common neurological disease characterised by the presence of attacks of unilateral, severe head pain accompanied by other symptoms. Although it has been classified as the sixth most disabling disorder, the available therapeutic options to treat this condition have not progressed accordingly. The advance in the development of 5-HT1 receptor agonists for migraine, including 5 HT1B/D and 5-HT1F receptor agonists, has meant a major step forward towards the progression of a better treatment for migraine. Triptans have a limited efficacy, and their effect on vasoconstriction makes them unsafe for patients with cardiovascular and/or cerebrovascular diseases. Therefore, novel effective antimigraine treatments without cardiovascular effects are required, such as selective 5-HT1F receptor agonists (ditans). Lasmiditan has much higher affinity for the 5-HT1F receptor than for the vasoconstrictor 5-HT1B receptor. This has been confirmed in preclinical studies performed to date, where lasmiditan showed no effect on vasoconstriction, and in clinical trials, where healthy individuals and patients did not report cardiac events due to treatment with lasmiditan, although it should be confirmed in larger cohorts. Lasmiditan crosses the blood brain barrier and may act both centrally and peripherally on 5-HT1F receptors expressed on trigeminal neurons. It is a well-tolerated compound that does not induce major adverse events. Although ongoing phase III clinical trials are needed to confirm its efficacy and safety, lasmiditan might offer an alternative to treat acute migraine with no associated cardiovascular risk. This review will focus on the characterisation of 5-HT1 receptor agonists and their effects as migraine therapies. PMID- 29488142 TI - Safety and Incidence of Cardiovascular Events in Chinese Patients with Acute Coronary Syndrome Treated with Ticagrelor: the 12-Month, Phase IV, Multicenter, Single-Arm DAYU Study. AB - PURPOSE: Ticagrelor is an orally administered, reversibly binding, direct-acting P2Y12 receptor antagonist previously evaluated in several phase III trials. This phase IV, multicenter, single-arm trial assessed the safety and incidence of cardiovascular (CV) events with ticagrelor in Chinese patients experiencing an acute coronary syndrome (ACS). METHODS: Patients hospitalized with an ACS received ticagrelor (180 mg loading dose, 90 mg twice daily thereafter) plus low dose aspirin (75-100 mg/day) for up to 12 months. Safety was evaluated via PLATO defined bleeding events, adverse events (AEs), serious AEs, and laboratory measurements. The incidence of major CV events was also evaluated. RESULTS: The safety population included 2001 patients. During ticagrelor treatment, 426 (21.3%) patients had at least one PLATO-defined bleeding AE, mainly minimal bleedings (n = 333). Major bleeding events occurred in 27 (1.3%) patients, including fatal/life-threatening bleeding in 17 (0.8%) patients and other major bleeding in 11 (0.5%) patients, with a Kaplan-Meier estimate of patients with the event (95% CI) of 1.6% (1.1-2.3%). In total, 784 (39.2%) patients had at least one non-bleeding AE, the majority of which were mild in severity. The composite endpoint of CV death, myocardial infarction, and stroke occurred in 83 (4.1%) patients. CONCLUSIONS: Ticagrelor plus low-dose aspirin for up to 1 year was associated with a low rate of major bleeding events and a low incidence of major CV events (CV death, myocardial infarction, stroke) in Chinese patients with ACS. The overall safety profile of ticagrelor in this population was in line with current prescribing information. PMID- 29488144 TI - Anti-herpetic Medications and Reduced Risk of Dementia in Patients with Herpes Simplex Virus Infections-a Nationwide, Population-Based Cohort Study in Taiwan. AB - This retrospective cohort study is to investigate the association between herpes simplex virus (HSV) infections and dementia, and the effects of anti-herpetic medications on the risk involved, using Taiwan's National Health Insurance Research Database (NHIRD). We enrolled a total of 33,448 subjects, and identified 8362 with newly diagnosed HSV infections and 25,086 randomly selected sex- and age-matched controls without HSV infections in a ratio of 1:3, selected from January 1, to December 31, 2000. A multivariable Cox proportional hazards regression model was used to evaluate the risk of developing dementia in the HSV cohort. This analysis revealed an adjusted hazard ratio of 2.564 (95% CI: 2.351 2.795, P < 0.001) for the development of dementia in the HSV-infected cohort relative to the non-HSV cohort. Thus, patients with HSV infections may have a 2.56-fold increased risk of developing dementia. A risk reduction of dementia development in patients affected by HSV infections was found upon treatment with anti-herpetic medications (adjusted HR = 0.092 [95% CI 0.079-0.108], P < 0.001). The usage of anti-herpetic medications in the treatment of HSV infections was associated with a decreased risk of dementia. These findings could be a signal to clinicians caring for patients with HSV infections. Further research is, therefore, necessary to explore the underlying mechanism(s) of these associations. PMID- 29488145 TI - The prognostic significance of surgical treatment for excessive elderly patients with soft tissue sarcoma. AB - BACKGROUND: Soft tissue sarcoma (STS) mainly occurs in middle-aged and senior citizens. Although a poorer prognosis has been reported for older patients, few studies have examined advanced elderly excessive older patients. We evaluated the clinical features of advanced elderly patients with STS. METHODS: One hundred and forty-four patients were included in this retrospective study, and we divided them into two groups based on a cut-off age of 85 (older and younger groups). The patients' information, including age, tumor type, location, size, presence of metastasis, AJCC stage, FNCLCC classification, treatment-related factors, local and distant relapse, and outcome, was collected. We compared the clinical courses between the 2 groups. RESULTS: In all patients, the frequency of chemotherapy in the older group was significantly lower than in the younger group (P < 0.01), and the follow-up period in the older group was significantly shorter than in the younger group (P < 0.01). Surgical treatment was refused more frequently in the older group (P = 0.01). The older group showed a significantly poorer prognosis (P < 0.05). However, in patients with localized disease at presentation treated with surgery, there was no significant difference in prognosis between the 2 groups. Only surgical treatment affected the prognosis in older patients (P < 0.01). CONCLUSION: Although the prognosis of advanced elderly STS patients is generally poor, that of STS patients with surgical treatment is not poor. Only surgical treatment intervention strongly influences the prognosis, and so the prognosis may be improved with aggressive surgical treatment. PMID- 29488146 TI - Phrase-Final Words in Greek Storytelling Speech: A Study on the Effect of a Culturally-Specific Prosodic Feature on Short-Term Memory. AB - Prosodic patterns of speech appear to make a critical contribution to memory related processing. We considered the case of a previously unexplored prosodic feature of Greek storytelling and its effect on free recall in thirty typically developing children between the ages of 10 and 12 years, using short ecologically valid auditory stimuli. The combination of a falling pitch contour and, more notably, extensive final-syllable vowel lengthening, which gives rise to the prosodic feature in question, led to statistically significantly higher performance in comparison to neutral phrase-final prosody. Number of syllables in target words did not reveal substantial difference in performance. The current study presents a previously undocumented culturally-specific prosodic pattern and its effect on short-term memory. PMID- 29488147 TI - Precisely positioning the tip of an instrument inserted through an orifice with a free wrist robot: application to prostate biopsies. AB - PURPOSE: Robots with a spherical unactuated wrist can be used for minimally invasive surgery. With such a robot, positioning the wrist center controls the instrument tip position when assuming that the insertion site behaves like a lever with a fixed and known fulcrum. In practice, this assumption is not always respected. In this paper we first study the practical consequences of this problem in terms of tip precision positioning. We then propose a robotic control scheme that improves the precision compared to the fixed point assumption approach. METHODS: In the first part of the paper, data recorded during robot assisted transrectal needle positioning for prostate biopsies (nine patients) are exploited to quantify the positioning error induced by the use of a fixed point hypothesis in the positioning process. In the second part of the paper advanced control techniques allow for the online identification of a locally linear system that describes a model characterized by anisotropy and center displacement. A laboratory apparatus is used to demonstrate the resulting improvement on tip positioning precision. RESULTS: Errors obtained by processing the clinical data reach 7.5 mm at the tip in average. Errors obtained with the laboratory apparatus drop from 2.4 mm in average to 0.8 mm when using real-time model update. PMID- 29488148 TI - Unidimensional factor models imply weaker partial correlations than zero-order correlations. AB - In this paper we present a new implication of the unidimensional factor model. We prove that the partial correlation between two observed variables that load on one factor given any subset of other observed variables that load on this factor lies between zero and the zero-order correlation between these two observed variables. We implement this result in an empirical bootstrap test that rejects the unidimensional factor model when partial correlations are identified that are either stronger than the zero-order correlation or have a different sign than the zero-order correlation. We demonstrate the use of the test in an empirical data example with data consisting of fourteen items that measure extraversion. PMID- 29488149 TI - Abnormal functional connectivity density in sleep-deprived subjects. AB - Sleep deprivation (SD) can alter the intrinsic brain functional organization. However, its effects on intrinsic low-frequency connectivity in the whole brain have not been well characterized. In this study, we used voxel-based functional connectivity density (FCD) analysis to investigate the effects of SD on the spontaneous functional organization of the brain. Thirty-seven healthy participants underwent this within-subject crossover functional magnetic resonance imaging (fMRI) study during rested wakefulness (RW) and after 36 h of total sleep deprivation (TSD). Decreased long-/short-range FCDs were observed in the posterior cingulate cortex, precuneus, inferior parietal lobule, dorsolateral prefrontal cortex, dorsomedial prefrontal cortex, and ventromedial prefrontal cortex. Increased long-/short-range FCDs were found in the sensory integration and arousal regulating areas, including the postcentral gyrus, thalamus, superior temporal gyrus, and occipital-temporal cortex. Moreover, a significant negative correlation was found between the short-range FCD of the PCC and the reaction time of Psychomotor Vigilance Task. In the present study, spontaneous functional organization with significant group-wise differences between RW and TSD sessions was identified. Our findings extend our understanding of the neural mechanism of how brain activity is altered in sleep-deprived individuals. PMID- 29488150 TI - Stroke Prevention with Oral Anticoagulants: Summary of the Evidence and Efficacy Measures as an Aid to Treatment Choices. AB - Atrial fibrillation (AF) is an established risk factor for a first or recurrent stroke. Despite proven efficacy in preventing stroke in patients with AF, warfarin is underused, partly due to safety concerns. Recent randomized trials have shown that non-vitamin K antagonist oral anticoagulants (NOACs) such as dabigatran (a direct thrombin inhibitor) and apixaban, edoxaban, and rivaroxaban (factor Xa inhibitors) are not only non-inferior or superior to warfarin but also demonstrate a decreased risk of cerebrovascular bleeding among patients with AF and moderate to high risk of stroke. Additionally, NOACs have an advantage of requiring no monitoring of the international normalized ratio compared with warfarin. This review summarizes the published literature on NOACs for the primary and secondary prevention of ischemic strokes, with an emphasis on the expected absolute benefits from the introduction of such agents. As compared with warfarin, NOACs significantly reduce the risk of hemorrhagic stroke, and only dabigatran (150 mg twice daily) was found to significantly reduce the risk of ischemic stroke. However, measures of relative benefits from medical interventions do not immediately provide the estimated benefit to be derived from an individual patient, something best done by considering the expected absolute benefit. The number needed to treat (NNT) is presented for various outcomes in the phase 3 trials of NOACs. Despite the important progress achieved with the introduction of NOACs, the availability of at least four agents with different efficacy and safety performances in comparison with warfarin prompts the question of whether any of these agents is preferable to another. It is hoped that future studies on the efficacy, safety, and economic performance of NOACs will further allow for rational choices within this important therapeutic class. Meanwhile, the NNT may be a valid metric to be considered by clinicians faced with the need to make such choices. PMID- 29488151 TI - A Review of the Role of the Pharmacist in Heart Failure Transition of Care. AB - : This article reviews current literature on the role of pharmacists in the transition of care (TOC) for patients with heart failure (HF) and the impact of their contributions on therapeutic and economic outcomes. Optimizing the TOC for patients with HF from the hospital to the community/home is crucial for improving outcomes and decreasing high rates of hospital readmissions, which are associated with increased morbidity, mortality, and costs. A multidisciplinary team approach to the management of patients with HF facilitates the transition from the hospital to the ambulatory care setting, allowing for the consideration of medical, pharmacological, and lifestyle variables that impact the care of individual patients. Pharmacist participation on both inpatient and outpatient teams can provide a variety of services that have been shown to reduce hospital readmission rates and benefit patient management and treatment. These include medication reconciliation, patient education, medication dosage titration and adjustment, patient monitoring, development of disease management pathways, promotion of medication adherence, and postdischarge follow-up. In addition, as new pharmacologic treatments for HF become available, pharmacists can raise awareness of optimal drug use by maximizing education related to efficacy (e.g., adherence) and safety (e.g., potential side effects and drug interactions). Improving understanding of HF and its treatment will enable increased pharmacist involvement in the TOC that should lead to improved outcomes and reduced healthcare costs. FUNDING: Novartis. PMID- 29488152 TI - Efficacy and Safety of GPR119 Agonist DS-8500a in Japanese Patients with Type 2 Diabetes: a Randomized, Double-Blind, Placebo-Controlled, 12-Week Study. AB - INTRODUCTION: G protein-coupled receptor 119 (GPR119) is a promising target for the treatment of type 2 diabetes mellitus (T2DM), as both insulin and glucagon like peptide-1 secretion can be promoted with a single drug. We compared the efficacy and safety of the GPR119 agonist DS-8500a with placebo and sitagliptin 50 mg in Japanese patients with T2DM. METHODS: This randomized, double-blind, parallel-group comparison study was conducted in Japan (trial registration NCT02628392, JapicCTI-153068). Eligible patients aged >= 20 years with T2DM and hemoglobin A1c (HbA1c) >= 7.0% and < 10.0% were randomized to receive placebo, DS 8500a (25, 50, or 75 mg), or sitagliptin 50 mg once daily for 12 weeks. The primary efficacy endpoint was change in HbA1c from baseline to week 12. Secondary endpoints included change in fasting plasma glucose (FPG), glucose AUC0-3h during a meal tolerance test, 2-hour postprandial glucose (2hr-PPG), and changes in lipid parameters (total, low-density lipoprotein (LDL-) and high-density lipoprotein (HDL-) cholesterol, and triglycerides) at week 12. Safety endpoints included adverse events, hypoglycemia, and clinical/laboratory variables. RESULTS: DS-8500a demonstrated dose-dependent HbA1c lowering compared with placebo at week 12: change from baseline - 0.23% (p = 0.0173), - 0.37% (p = 0.0001), and - 0.44% (p < 0.0001) in the 25-mg, 50-mg, and 75-mg groups, respectively. At 50- and 75-mg doses, DS-8500a significantly lowered FPG, glucose AUC0-3h, and 2hr-PPG compared with placebo. The glucose-lowering effect was maintained up to 12 weeks. DS-8500a did not lower any of the above parameters to a greater extent than sitagliptin. Compared with placebo and sitagliptin, DS 8500a 50 and 75 mg significantly reduced total cholesterol, LDL-cholesterol, and triglycerides, and significantly increased HDL-cholesterol. All DS-8500a doses were well tolerated. Two cases of clinically relevant drug-related hypoglycemia occurred in the DS-8500a 50-mg group. CONCLUSION: DS-8500a was well tolerated and demonstrated significant glucose-lowering effects and favorable changes in lipid profiles up to 12 weeks in Japanese patients with T2DM. FUNDING: Daiichi Sankyo Co. Ltd. PMID- 29488153 TI - Personality as a Social Process: where Peter Giordano Meets Boris Parygin. AB - In this paper I comment on the "Individual personality is best understood as process, not structure: A Confucian-inspired perspective" article by Peter Giordano (Culture & Psychology, 23(4), 502-518 (2017)), which addresses the question of how to comprehend a personality which is continuously changing and varying with changes in social contexts and situations. The issue which Giordano turns up I believe to be of great importance and topicality in the quickly changing globalizing contemporary world. Giordano's paper highlights an important problem in the development of contemporary personality psychology, but much remains to be clarified concerning his process-centric model. I introduce the theory of Boris Parygin, which can make a contribution to the discussion of personality as a process. Parygin's theory addresses the same issues that Giordano focuses on: human personality exists and develops in the context of social situation. Parygin's theoretical model of personality involves two personality schemas: a "static" one and a "dynamic" one. The "structure" and the "process" -centered approaches are joint here to complement each other. Personality life-span development, formation of personality structures, is considered as a process of interaction and dialectical confrontation with the social environment, in the course of which the personality, originally engendered by social factors, builds up its autonomy and realizes its unique individual spiritual potential. PMID- 29488154 TI - Evaluation of the Pharmacokinetics and Safety of a Single Oral Dose of Fasiglifam in Subjects with Mild or Moderate Hepatic Impairment. AB - BACKGROUND AND AIMS: Fasiglifam, a potent, selective novel agonist of G protein coupled receptor 40, stimulates insulin secretion at elevated blood glucose levels in a glucose-dependent manner. This study evaluated the potential effect of hepatic impairment on the pharmacokinetics and safety of a single dose of fasiglifam and its metabolite M-I. Fasiglifam's clinical development was halted due to liver safety concerns. METHODS: In this phase I, open-label study, subjects with mild or moderate hepatic impairment, along with matched controls (gender, weight, age, and smoking status), received a single, 25-mg oral dose of fasiglifam. Blood samples were collected through 336 h post-dose for pharmacokinetic evaluation. RESULTS: Overall, 73% of subjects were male with a mean age of 54 years. Compared with normal hepatic function subjects (n = 14), mean systemic fasiglifam exposure (Cmax and AUCinfinity) was reduced in mild (n = 8) and moderate (n = 8) hepatic impairment subjects by approximately 20-40%. However, the observed percent unbound drug plasma concentration appeared comparable across all groups. Mean oral clearance was higher and terminal half life lower in subjects with mild or moderate hepatic impairment compared with normal hepatic function subjects. Fasiglifam M-I systemic exposure increased by approximately twofold in subjects with mild or moderate hepatic impairment compared with those with normal hepatic function. Fasiglifam was well tolerated, and there were no reports of hypoglycemia. CONCLUSION: Hepatic status did not significantly impact systemic exposure of fasiglifam in this study, in fact, a decrease was observed, suggesting no dose reduction would be required for patients with hepatic impairment. PMID- 29488155 TI - Community Empowerment Partners (CEPs): A Breast Health Education Program for African-American Women. AB - Peer educators have been shown to provide effective interventions in breast cancer screening. Few studies have compared the effects of peer education on breast cancer knowledge among peer educators and the community members who are subsequently reached through the peer education. Further, little is known as to whether those who received the education then go on to educate others in the community. The purpose of this study is to address those gaps. Using a pre- and post-test study design, we trained peer educators, provided the educators with resources to train community members, and assessed changes in knowledge. We sought to train ten educators and recommended each train ten community members in breast cancer knowledge and screening strategies. A total of 14 peer educators were trained, who subsequently trained a total of 121 community members, of whom 94 were African American women. Peer educators and community members, showed comparable increases in knowledge. Community members who were educated also increased intention to discuss breast cancer and breast cancer screening with their family, friends, and acquaintances. Our study suggests that it is feasible to train peer educators to increase knowledge among community members to the same level that they themselves experience when trained. Further, community members are interested in sharing information learned related to how much they learn from peer educators. PMID- 29488157 TI - Implementing evidence-based interventions to prevent readmissions in the real world. PMID- 29488156 TI - A bibenzyl from Dendrobium ellipsophyllum induces apoptosis in human lung cancer cells. AB - Failure of current chemotherapeutic drugs leads to the recurrence of tumor pathology and mortality in lung cancer patients. This study aimed to evaluate the anticancer activity and related mechanisms of 4,5,4'-trihydroxy-3,3' dimethoxybibenzyl (TDB), a bibenzyl extracted from Dendrobium ellipsophyllum Tang and Wang, in human lung cancer cells. Cytotoxicity of TDB (0-300 uM) in different types of human lung cancer cells (H460, H292 and H23) and human dermal papilla cells (DPCs) was evaluated via MTT viability assay. Selective anticancer activity of TDB against human lung cancer cells was demonstrated with a high IC50 (approximately > 300 uM) in DPCs, while IC50 in human lung cancer H460, H292 and H23 cells was approximately 100 +/- 5.18, 100 +/- 8.73 and 188.89 +/- 8.30 uM, respectively. After treatment with 50 uM of TDB for 24 h, flow cytometry analysis revealed the significant increase of early and late apoptosis with absence of necrosis cell death in human lung cancer cells. The up-regulation of p53, a tumor suppressor protein, was elucidated in human lung cancer cells treated with 10-50 uM of TDB. Alteration to down-stream signaling of p53 including activation of pro apoptosis protein (Bcl-2-associated X protein; Bax), reduction of anti-apoptosis (B cell lymphoma 2; Bcl-2 and myeloid cell leukemia 1; Mcl-1) and suppression on protein kinase B (Akt) survival pathway were notified in TDB-treated lung cancer cells. The information obtained from this study strengthens the potential development of TDB as an anticancer compound with a favorable human safety profile and high efficacy. PMID- 29488158 TI - From the Editors' Desk: Equal Rights for General Internists? PMID- 29488159 TI - Capsule Commentary on Zebrowski et al., So Tired: Predictive Utility of Baseline Sleep Screening in a Longitudinal Observational Survey Cohort of First-Year Residents. PMID- 29488160 TI - Capsule Commentary on Turner et al., Randomized Trial of Chronic Pain Self management Program in Community or Clinic for Low-Income Primary Care Patients. PMID- 29488161 TI - Role of PET/MRI in oral cavity and oropharyngeal cancers based on the 8th edition of the AJCC cancer staging system: a pictorial essay. AB - The American Joint Committee on Cancer (AJCC) released the 8th edition of the AJCC cancer staging manual in 2017 that includes significant modifications from the 7th edition in the sections on oral cavity cancer (OCC) and oropharyngeal cancer (OPC). These highlights comprise the incorporation of the depth of invasion and exclusion of extrinsic tongue muscle involvement in the T staging of OCC, the separation of OPC staging based on the high-risk human papilloma virus status, and the inclusion of extranodal extension in N staging. The recent introduction of integrated positron emission tomography and magnetic resonance imaging (PET/MRI) with 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG) has demonstrated the advantages of simultaneous PET and MR imaging with higher soft tissue contrast, multiplanar image acquisition, and functional imaging capability. This pictorial essay discusses the role of 18F-FDG PET/MRI in the diagnosis of OCC and OPC based on the new cancer staging system. PMID- 29488162 TI - Vincenzo Malacarne (1744-1816) and the First Description of the Human Cerebellum. AB - Vincenzo Malacarne, professor of medicine, surgery, and obstetrics in Turin, Pavia, and Padua, Italy, represented a perfect example of an eighteenth century "letterato", combining interests in humanities, sciences, and politics, embodying the ideal of an encyclopedic and universal culture. He made important contributions in anatomy and surgery, teratology, obstetrics, neurology, and history of medicine, adopting a interdisciplinary approach based on the correlation between anatomy, surgery, and clinics. He deserves a special place in the history of neurology because of the first complete description of the human cerebellum. He quantified the units of the cerebellar internal structures, the lamellae being numbered for a systematic description of the human cerebellum. He thought the mental faculties depended on their number, considering a relation between the number of cerebellar lamellae and the expression of intellectual faculties. In this way, he made first statistics on human faculties. He advanced the concept that the number of cerebellar folia was influenced by the environment, thus providing the first nature-nurture hypothesis made on the basis of observations, and the concept of neuroplasticity in the scientific literature. Finally, he also contributed to the emergence of a new science, namely electrophysiology, because he laid down experimental foundations of a project on the recording of brain electricity, comparing the structure of the human brain with Volta's galvanic pillar. PMID- 29488163 TI - Goodness of fit tests for estimating equations based on pseudo-observations. AB - We study regression models for mean value parameters in survival analysis based on pseudo-observations. Such parameters include the survival probability and the cumulative incidence in a single point as well as the restricted mean life time and the cause-specific number of years lost. Goodness of fit techniques for such models based on cumulative sums of pseudo-residuals are derived including asymptotic results and Monte Carlo simulations. Practical examples from liver cirrhosis and bone marrow transplantation are also provided. PMID- 29488164 TI - Empagliflozin Induces Transient Diuresis Without Changing Long-Term Overall Fluid Balance in Japanese Patients With Type 2 Diabetes. AB - INTRODUCTION: Empagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, ameliorates hyperglycemia in patients with type 2 diabetes (T2D) by inducing sustained glucosuria. Empagliflozin treatment was previously associated with a transient increase in 24-h urine volume in Caucasian patients with T2D, however comparable evidence in Japanese T2D individuals is scarce. We therefore assessed acute and chronic changes in 24-h urine volume and fluid intake with empagliflozin in Japanese patients with T2D. METHODS: In this randomized, double blind, placebo-controlled, parallel-group, multiple-dose, 4-week trial, 100 Japanese patients with T2D were randomized to receive either 1, 5, 10, or 25 mg empagliflozin or placebo once-daily. Changes from baseline in 24-h urine volume and fluid intake were assessed at days 1, 27, and 28 after the initiation of empagliflozin. RESULTS: The 24-h urine volume and fluid intake were comparable across all treatment groups at baseline. Patients treated with either 10 or 25 mg empagliflozin (i.e., the licensed doses in Japan) showed a significant increase in 24-h urine volume compared to placebo at day 1 (mean change from baseline: + 0.83, + 1.08, and + 0.29 L/day in the empagliflozin 10 and 25 mg groups and the placebo group, respectively; both p < 0.001 vs. placebo). However, 24-h urine volume levels in the empagliflozin groups were comparable to placebo at day 27 and 28 (differences vs placebo < 0.1 L/day; p > 0.05). The 24-h fluid intake was comparable across all study groups throughout the entire study period. No events consistent with dehydration were reported during empagliflozin treatment. CONCLUSION: Treatment initiation with empagliflozin in Japanese patients with T2D was associated with transient diuresis; however, overall urine volume returned towards baseline levels within 4 weeks of treatment. These findings are consistent with a physiological, adaptive mechanism of the kidney to maintain overall body fluid balance in response to treatment initiation with a SGLT2 inhibitor. TRIAL REGISTRATION NUMBER: NCT00885118. FUNDING: Nippon Boehringer Ingelheim Co., Ltd. PMID- 29488165 TI - Quantifying the Value of Multidimensional Assessment Models for Acute Concussion: An Analysis of Data from the NCAA-DoD Care Consortium. AB - BACKGROUND: Many concussion assessment methods exist, but few studies quantify the performance of these methods to determine which can best assess acute concussion alone or in combination. OBJECTIVES: The objectives of this study were to evaluate: (1) selected concussion assessments for acute concussion assessment; (2) the utility of change scores for acute concussion assessment; and (3) concussion assessment capabilities when constrained to limited clinical data or objective clinical measures. METHODS: The 'acute concussion' group contained assessments from < 6 h post-injury (n = 560) and 24-48 h post-injury (n = 733). The 'normal performance' group contained assessments from baseline testing (n = 842) and unrestricted return to play (n = 707) timepoints. Univariate and multivariate logistic regression models were created separately for < 6- and 24- to 48-h timepoints. Models were evaluated on sensitivity, specificity, and area under the receiver operating characteristic curve. RESULTS: Within the univariate analysis, Sport Concussion Assessment Tool symptom assessments had the highest combination of sensitivity, specificity, and area under the receiver operating characteristic curve, with values up to 0.93, 0.97, and 0.98, respectively. Full models had a sensitivity, specificity, and area under the receiver operating characteristic curve up to 0.94, 0.97, and 0.99, respectively, and outperformed all univariate models, raw score models, and objective models. Objective models were outperformed by all multivariate models and the univariate models containing only Sport Concussion Assessment Tool symptom assessments. CONCLUSION: Results support the use of multidimensional assessment batteries over single instruments and suggest the importance of self-reported symptoms in acute concussion assessment. Balance assessments, however, may not provide additional benefit when symptom and neurocognitive assessments are available. Additionally, change scores provide some clinical utility over raw scores, but the difference may not be clinically meaningful. PMID- 29488166 TI - Analysis of Lower Extremity Proprioception for Anterior Cruciate Ligament Injury Prevention: Current Opinion. AB - Lower extremity musculoskeletal injuries-such as ACL injury-are common, and the majority of those injuries occur without external player contact. In order to prevent non-contact musculoskeletal injuries, athletes must rely on accurate sensory information (such as visual, vestibular, and somatosensory) and stabilize joints during athletic tasks. Previously, proprioception tests (the senses of joint position, movement, tension or force) have been examined using static tests. Due to the role of proprioception in achievement of joint stability, it is essential to explore the development of dynamic proprioception tests. In this current opinion, the basic background on proprioception is covered, and the research gaps and future directions are discussed. PMID- 29488167 TI - Thrombohemorrhagic events, disease progression, and survival in polycythemia vera and essential thrombocythemia: a retrospective survey in Miyazaki prefecture, Japan. AB - Polycythemia vera (PV) and essential thrombocythemia (ET) are associated with life-threatening thrombohemorrhagic events, and disease progression and development of non-hematological malignancies also reduce long-term survival. We retrospectively surveyed thrombohemorrhagic events and overall survival (OS) in 62 PV and 117 ET patients. The cumulative incidences of thrombohemorrhagic events in PV and ET patients were 11.3 and 10.3%, and the incidence rates were 2.42 and 1.85 per 100 person-years. The combined incidence rates of disease progression and development of non-hematological malignancies in PV and ET patients were 1.73 and 1.69 per 100 person-years. The incidence rates of thrombohemorrhagic events in our Japanese PV/ET patients were lower than those reported by most Western studies, but were comparable to those in the largest prospective observational study in ET patients. The combined incidence rates of disease progression and development of non-hematological malignancies were similar between Japanese and Western PV/ET patients. In ET patients, the conventional risk stratification model based on the presence of advanced age or history of thrombosis was useful to predict thrombosis risk, and both the conventional model and the International Prognostic Score of thrombosis in ET based on the above 2 risk factors plus increased leukocyte count could predict poor survival. PMID- 29488169 TI - What topics caught your attention in 2017? PMID- 29488168 TI - miR-150 regulates B lymphocyte in autoimmune hemolytic anemia/Evans syndrome by c Myb. AB - The objective of the study was to study the regulation of B lymphocytes in patients with autoimmune hemolytic anemia (AIHA)/Evans syndrome. From October 2015 to May 2016, 35 patients with AIHA/Evans in the Department of Hematology, Tianjin Medical University General Hospital were enrolled into this study. c-Myb mRNA and miR-150 expression in B lymphocytes were measured using real-time PCR (RT-PCR). Correlation between c-Myb and miR-150 and clinical parameters in patients with AIHA/Evans were analyzed. c-Myb mRNA expression in hemolysis patients was significantly higher than in remission patients and CLL patients, negatively correlated with hemoglobin (Hb) level and complement 3(C3) levels, and positively correlated with total bilirubin (TBIL) concentration and indirect bilirubin (IBIL) concentration. miR-150 expression in hemolysis patients was significantly lower than in patients in remission and CLL patients. miR-150 was negatively correlated with TBIL and IBIL, and positively correlated with Hb, C3. c-Myb mRNA expression levels in hemolytic episode patients were negatively correlated with the expression levels of miR-150. The expression of c-Myb, a regulatory factor of B lymphocytes, is increased in B lymphocytes of AIHA/Evans patients, while miR-150 expression is decreased. c-Myb was negatively correlated with miR-150. PMID- 29488170 TI - Hyaluronic acid-modified betamethasone encapsulated polymeric nanoparticles: fabrication, characterisation, in vitro release kinetics, and dermal targeting. AB - Atopic dermatitis (AD) is a chronically relapsing eczematous skin disease characterised by frequent episodes of rashes, severe flares, and inflammation. Till date, there is no absolute therapy for the treatment of AD; however, topical corticosteroids (TCs) are the majorly prescribed class of drugs for the management of AD in both adults and children. Though, topical route is most preferable; however, limited penetration of therapeutics across the startum cornum (SC) is one of the major challenges for scientists. Therefore, the present study was attempted to fabricate a moderate-potency TC, betamethasone valerate (BMV), in the form of chitosan nanoparticles (CS-NPs) for optimum dermal targeting and improved penetration across the SC. To further improve the targeting efficiency of BMV and to potentiate its therapeutic efficacy, the fabricated BMV-CS-NPs were coated with hyaluronic acid (HA). The prepared NPs were characterised for particle size, zeta potential, polydispersity index (PDI), entrapment efficiency, loading capacity, crystallinity, thermal behaviour, morphology, in vitro release kinetics, drug permeation across the SC, and percentage of drug retained into various skin layers. Results showed that optimised HA-BMV-CS-NPs exhibited optimum physicochemical characteristics including finest particle size (< 300 +/- 28 nm), higher zeta potential (+ 58 +/- 8 mV), and high entrapment efficiency (86 +/- 5.6%) and loading capacity (34 +/- 7.2%). The in vitro release study revealed that HA-BMV-CS-NPs displayed Fickian diffusion-type mechanism of release in simulated skin surface (pH 5.5). Drug permeation efficiency of BMV was comparatively higher in case of BMV-CS-NPs; however, the amount of drug retained into the epidermis and the dermis was comparatively higher in case of HA-BMV-CS-NPs, compared to BMV-CS-NPs. Conclusively, we anticipate that HA-BMV-CS-NPs could be a promising nanodelivery system for efficient dermal targeting of BMV and improved anti-AD efficacy. PMID- 29488171 TI - Evaluation and optimization of pH-responsive niosomes as a carrier for efficient treatment of breast cancer. AB - Tamoxifen citrate (TXC) is commonly indicated to prevent cell multiplication and development of breast cancer. However, it is usually associated with limited activity and development of toxicity and resistance. This study aimed to describe an in situ pH-responsive niosomes as a carrier for localized and sustained delivery of TXC. The thin film hydration method was utilized to produce TXC niosomes using sorbitan monostearate and cholesterol of 1:1 Molar ratio. The produced formula displayed nano-spherical shape with entrapment efficiency (EE) of 88.90 +/- 0.72% and drug release of 49.2 +/- 1.51% within 8 h. This formula was incorporated into chitosan/glyceryl monooleate (CH/GMO) as a localized in situ pH-responsive hydrogel delivery system. Different formulae were produced by Design-Expert software based on user-defined response surface design utilizing different chitosan concentration (A) and GMO concentration (B) characterized for mean viscosity (R2) and in vitro release studies (R1). The results displayed that R1 was significantly antagonistic with both of A and B while R2 was significantly synergistic with both of them. The optimum formula was selected and capped with gold as an ideal candidate for computed tomography (CT) to evaluate the efficacy and tissue distribution of TXC utilizing Ehrlich carcinoma mice model. The optimum formula showed localized TXC in a tumour and consequently a significant anti-tumour efficacy compared with free TXC. Based on these outcomes, the novel in situ pH-responsive TXC-loaded noisome could be a promising formula for the efficient treatment of breast cancer. PMID- 29488172 TI - Pharmacology of Pimasertib, A Selective MEK1/2 Inhibitor. AB - Pimasertib belongs to the growing family of mitogen activated protein kinase (MEK1/2) inhibitors undergoing clinical development for various cancer indications. Since the MEK inhibition in several cell signalling transduction cascades within tumours was considered therapeutically beneficial, number of clinical investigations of pimasertib have been reported. Despite being orally bioavailable in cancer patients, pimasertib undergoes faster clearance with a short elimination half-life. In addition, due to occurrence of toxicity, the development of pimasertib appears to be stalled. Case studies are provided on the possible utilization of pimasertib in combination therapies with other approved drugs. Based on the review, it appeared that there was the need to identify the optimal dose and the dosing regimen of pimasertib to provide a balance between safety and efficacy when combined with approved therapies. PMID- 29488173 TI - A Unified Model of Behavioral Health Integration in Primary Care. PMID- 29488174 TI - Conspiracy Beliefs Are Not Necessarily a Barrier to Engagement in HIV Care Among Urban, Low-Income People of Color Living with HIV. AB - BACKGROUND: HIV-related "conspiracy beliefs" include ideas about the genocidal origin of HIV to target minority people, and the notion that a cure for HIV is being deliberately withheld. Previous literature suggests that these beliefs may negatively affect engagement in HIV care and ART adherence, but little is known about how people who are disengaged from care may think about these ideas. METHODS: Twenty-seven semi-structured interviews were conducted with low-income Black and Latinx people living with HIV in NYC who were currently disengaged from, or recently re-engaged in, HIV care. FINDINGS: The data suggest that HIV related "conspiracy beliefs" are not necessarily a barrier to care. Regardless of whether or not people endorsed these ideas, participants were largely dismissive, and prioritized focusing on managing their HIV and overall health and life challenges. RECOMMENDATIONS: Interventions aiming to improve ART adherence and retention in HIV care should focus on building trust between clinicians and populations that have experienced historical, as well as ongoing, marginalization. HIV care providers should ask patients open-ended questions specifically about their beliefs about HIV and ART in order to address potential suspicion. Moving away from the phrase "conspiracy beliefs" in favor of more neutral language, such as "HIV-related beliefs," can enable us to better understand these ideas in the context of people's daily lives. CONCLUSIONS: Further research is needed to better understand how structural inequality may shape how people experience mistrust, and how mistrust may factor into the constellation of barriers to consistent engagement in HIV care. PMID- 29488176 TI - Arterialized blood from a central venous catheter after cardiac surgery: a puzzle for the intensivist. PMID- 29488175 TI - Endoglin haploinsufficiency is associated with differential regulation of extracellular matrix production during skin fibrosis and cartilage repair in mice. AB - Transforming growth factor (TGF)-beta is a multifunctional growth factor with potent pro-fibrotic effects. Endoglin is a TGF-beta co-receptor that strongly regulates TGF-beta signaling in a variety of cell types. Although aberrant regulation of TGF-beta signaling is known to play a key role in fibrotic diseases such as scleroderma and impaired cartilage repair, the significance of endoglin function in regulating these processes is poorly understood. Here we examined whether endoglin haploinsufficiency regulates extracellular (ECM) protein expression and fibrotic responses during bleomycin induced skin fibrosis and surgically induced osteoarthritis, using endoglin-heterozygous (Eng+/-) mice and wild-type (Eng+/+) littermates. Skin fibrosis was induced by injecting mice intradermally with bleomycin or vehicle. Osteoarthritis was induced surgically by destabilization of medial meniscus. Dermal thickness, cartilage integrity and ECM protein expression were then determined. Eng+/- mice subjected to bleomycin challenge show a marked decrease in dermal thickness (P < 0.005) and reduced collagen content and decreased collagen I, fibronectin, alpha-smooth muscle actin levels as compared to Eng+/+ mice, both under basal and bleomycin treated conditions. Eng+/- mice undergoing surgically induced osteoarthritis show no differences in the degree of cartilage degradation, as compared to Eng+/+ mice, although chondrocytes isolated from Eng+/- display markedly enhanced collagen II levels. Our findings suggest that endoglin haploinsufficiency in mice ameliorates bleomycin-induced skin fibrosis suggesting that endoglin represents a pro fibrotic factor in the mouse skin. However, endoglin haploinsufficiency does not protect these mice from surgically indiced cartilage degradation, demonstrating differential regulation of endoglin action during skin and cartilage repair. PMID- 29488177 TI - Temperature-related tachycardia during rewarming from hypothermic cardiopulmonary bypass in a patient with a leadless cardiac pacemaker. PMID- 29488178 TI - Long-term continuous erector spinae plane block for palliative pain control in a patient with pleural mesothelioma. PMID- 29488179 TI - An Efficient Implementation of Deep Convolutional Neural Networks for MRI Segmentation. AB - Image segmentation is one of the most common steps in digital image processing, classifying a digital image into different segments. The main goal of this paper is to segment brain tumors in magnetic resonance images (MRI) using deep learning. Tumors having different shapes, sizes, brightness and textures can appear anywhere in the brain. These complexities are the reasons to choose a high capacity Deep Convolutional Neural Network (DCNN) containing more than one layer. The proposed DCNN contains two parts: architecture and learning algorithms. The architecture and the learning algorithms are used to design a network model and to optimize parameters for the network training phase, respectively. The architecture contains five convolutional layers, all using 3 * 3 kernels, and one fully connected layer. Due to the advantage of using small kernels with fold, it allows making the effect of larger kernels with smaller number of parameters and fewer computations. Using the Dice Similarity Coefficient metric, we report accuracy results on the BRATS 2016, brain tumor segmentation challenge dataset, for the complete, core, and enhancing regions as 0.90, 0.85, and 0.84 respectively. The learning algorithm includes the task-level parallelism. All the pixels of an MR image are classified using a patch-based approach for segmentation. We attain a good performance and the experimental results show that the proposed DCNN increases the segmentation accuracy compared to previous techniques. PMID- 29488180 TI - First report of Candida bracarensis in Mexico: hydrolytic enzymes and antifungal susceptibility pattern. AB - Candida bracarensis is an emerging cryptic species within the Candida glabrata clade. To date, little is known about its epidemiology, virulence, and antifungal susceptibility. This study documents the occurrence of C. bracarensis for the first time in Mexico and focuses on its in vitro production of hydrolytic enzymes, as well as antifungal susceptibility to echinocandins. This strain was isolated from a vaginal swab of a female with vulvovaginal candidosis; exhibited a very strong activity of aspartyl proteinase, phospholipase, and hemolysin; and was susceptible to caspofungin, anidulafungin, and micafungin (MIC = 0.031 MUg/mL). Data obtained could contribute to the knowledge of the epidemiology and virulence attributes of this yeast as a fungal opportunistic human pathogen. PMID- 29488181 TI - Testing culture purity in prokaryotes: criteria and challenges. AB - Reliance on pure cultures was introduced at the beginning of microbiology as a discipline and has remained significant although their adaptive properties are essentially dissimilar from those of mixed cultures and environmental populations. They are needed for (i) taxonomic identification; (ii) diagnostics of pathogens; (iii) virulence and pathogenicity studies; (iv) elucidation of metabolic properties; (v) testing sensitivity to antibiotics; (vi) full-length genome assembly; (vii) strain deposition in microbial collections; and (viii) description of new species with name validation. Depending on the specific task there are alternative claims for culture purity, i.e., when conventional criteria are satisfied or when looking deeper is necessary. Conventional proof (microscopic and plating controls) has a low resolution and depends on the observer's personal judgement. Phenotypic criteria alone cannot prove culture purity and should be complemented with genomic criteria. We consider the possible use of DNA high-throughput culture sequencing data to define criteria for only one genospecies, axenic state detection panel and only one genome. The second and third of these are preferable, although their resolving capacity (depth) is limited. Because minor contaminants may go undetected, even with deep sequencing, the reliably pure culture would be a clonal culture launched from a single cell or trichome (multicellular bacterium). Although this type of culture is associated with technical difficulties and cannot be employed on a large scale (the corresponding inoculums may have low chances of growth when transferred to solid media), it is hoped that the high-throughput culturing methods introduced by 'culturomics' will overcome this obstacle. PMID- 29488182 TI - Interaction of Saccharomyces cerevisiae-Lactobacillus fermentum-Dekkera bruxellensis and feedstock on fuel ethanol fermentation. AB - The alcoholic fermentation for fuel ethanol production in Brazil occurs in the presence of several microorganisms present with the starter strain of Saccharomyces cerevisiae in sugarcane musts. It is expected that a multitude of microbial interactions may exist and impact on the fermentation yield. The yeast Dekkera bruxellensis and the bacterium Lactobacillus fermentum are important and frequent contaminants of industrial processes, although reports on the effects of both microorganisms simultaneously in ethanolic fermentation are scarce. The aim of this work was to determine the effects and interactions of both contaminants on the ethanolic fermentation carried out by the industrial yeast S. cerevisiae PE-2 in two different feedstocks (sugarcane juice and molasses) by running multiple batch fermentations with the starter yeast in pure or co-cultures with D. bruxellensis and/or L. fermentum. The fermentations contaminated with D. bruxellensis or L. fermentum or both together resulted in a lower average yield of ethanol, but it was higher in molasses than that of sugarcane juice. The decrease in the CFU number of S. cerevisiae was verified only in co-cultures with both D. bruxellensis and L. fermentum concomitant with higher residual sucrose concentration, lower glycerol and organic acid production in spite of a high reduction in the medium pH in both feedstocks. The growth of D. bruxellensis was stimulated in the presence of L. fermentum resulting in a more pronounced effect on the fermentation parameters than the effects of contamination by each microorganism individually. PMID- 29488183 TI - Variations on a theme: evolution of the phage-shock-protein system in Actinobacteria. AB - The phage shock protein (Psp) stress-response system protects bacteria from envelope stress through a cascade of interactions with other proteins and membrane lipids to stabilize the cell membrane. A key component of this multi gene system is PspA, an effector protein that is found in diverse bacterial phyla, archaea, cyanobacteria, and chloroplasts. Other members of the Psp system include the cognate partners of PspA that are part of known operons: pspF||pspABC in Proteobacteria, liaIHGFSR in Firmicutes, and clgRpspAMN in Actinobacteria. Despite the functional significance of the Psp system, the conservation of PspA and other Psp functions, as well as the various genomic contexts of PspA, remain poorly characterized in Actinobacteria. Here we utilize a computational evolutionary approach to systematically identify the variations of the Psp system in ~450 completed actinobacterial genomes. We first determined the homologs of PspA and its cognate partners (as reported in Escherichia coli, Bacillus subtilis, and Mycobacterium tuberculosis) across Actinobacteria. This survey revealed that PspA and most of its functional partners are prevalent in Actinobacteria. We then found that PspA occurs in four predominant genomic contexts within Actinobacteria, the primary context being the clgRpspAM system previously identified in Mycobacteria. We also constructed a phylogenetic tree of PspA homologs (including paralogs) to trace the conservation and evolution of PspA across Actinobacteria. The genomic context revealed that PspA shows changes in its gene-neighborhood. The presence of multiple PspA contexts or of other known Psp members in genomic neighborhoods that do not carry pspA suggests yet undiscovered functional implications in envelope stress response mechanisms. PMID- 29488184 TI - Hormone receptors status: a strong determinant of the kinetics of brain metastases occurrence compared with HER2 status in breast cancer. AB - Breast cancer (BC) metastatic behavior varies according to the hormone receptors (HR) and HER2 statuses. Indeed, patients with triple-negative (TN) and HER2+ tumors are at higher risk of brain metastases (BM). The objective of this multinational cohort was to evaluate BM kinetics depending on the BC subtype. We retrospectively analyzed a series of BC patients with BM diagnosed in four European institutions (1996-2016). The delay between BC and BM diagnoses (BM-free survival) according to tumor biology was estimated with the Kaplan-Meier method. A multivariate analysis was performed using the Cox proportional hazards regression model. 649 women were included: 32.0% HER2-/HR+, 24.8% TN, 22.2% HER2+/HR- and 21.0% HER2+/HR+ tumors. Median age at BM diagnosis was 56 (25-85). In univariate analysis, BM-free survival differed depending on tumor biology: HER2-/HR+ 5.3 years (95% CI 4.6-5.9), HER2+/HR+ 4.4 years (95% CI 3.4-5.2), HER2+/HR- 2.6 years (95% CI 2.2-3.1) and TN 2.2 years (95% CI 1.9-2.7) (p < 0.001). It was significantly different between HR+ and HR- tumors (5.0 vs. 2.5 years, p < 0.001), and between HER2+ and HER2- tumors (3.2 vs. 3.8 years, p = 0.039). In multivariate analysis, estrogen-receptors (ER) and progesterone receptors (PR) negativity, but not HER2 status, were independently associated with BM-free survival (hazard ratio = 1.36 for ER, p = 0.013, 1.31 for PR, p = 0.021, and 1.01 for HER2+ vs. HER2- tumors, p = 0.880). HR- and HER2+ tumors are overrepresented in BC patients with BM, supporting a higher risk of BM in these biological subtypes. HR status, but not HER2 status, impacts the kinetics of BM occurrence. PMID- 29488185 TI - The combination of vitamin D deficiency and overweight affects muscle mass and function in older post-menopausal women. AB - BACKGROUND: It has been suggested that overweight and obese individuals have an increased risk to develop vitamin D deficiency, commonly associated with poor muscle performance. The relationship among fat mass, vitamin D status, and skeletal muscle is still debated. AIMS: To evaluate the effects of the combination of hypovitaminosis D and overweight on muscle mass and strength, and physical performance in post-menopausal women. METHODS: In this cross-sectional study, we recruited post-menopausal women referring to a physiatric outpatient service for the management of osteoporosis over a 36-month period. We compared four groups: (1) normal weight with hypovitaminosis D; (2) overweight with normal serum 25(OH)D3; (3) overweight with hypovitaminosis D; and (4) normal weight with normal serum 25(OH)D3 (control group). Outcome measures were: appendicular lean mass-to-BMI ratio; hand grip strength; and short physical performance battery. RESULTS: We analysed 368 women (mean aged 67.2 +/- 7.8 years): 95 normal weight with hypovitaminosis D, 90 overweight with normal levels of 25(OH)D3, 96 overweight with hypovitaminosis D, and 87 normal weight with normal levels of 25(OH)D3. Overweight women with hypovitaminosis D had a significant risk of reduced muscle mass (OR 5.70; p < 0.001), strength (OR 12.05; p < 0.001), and performance (OR 5.84; p < 0.001) compared to controls. Normal weight women with hypovitaminosis D had only a greater risk of an impairment of muscle strength (OR 7.30; p < 0.001) and performance (OR 3.16; p < 0.001). DISCUSSION: According to our findings, both hypovitaminosis D and overweight should be investigated in post-menopausal women because of their negative effects on skeletal muscle mass and function. CONCLUSIONS: This study demonstrated that hypovitaminosis D is associated to impaired muscle function and its combination with overweight might lead also to muscle wasting in a cohort of post-menopausal women. PMID- 29488186 TI - Managing Extremity Soft Tissue Sarcoma Patients: Surgery Alone or in Combination with Radiotherapy? An Editorial on the Paper by Fiore et al. PMID- 29488187 TI - Adjuvant Therapy Is Associated With Improved Survival in Resected Perihilar Cholangiocarcinoma: A Propensity Matched Study. AB - BACKGROUND: There are limited well-controlled studies that conclusively demonstrate a benefit of adjuvant therapy in resected perihilar cholangiocarcinoma. Most studies include all biliary tract tumors as one entity despite the heterogeneity of these diseases. METHODS: We identified patients with resected perihilar cholangiocarcinoma from the National Cancer Database between 2006 and 2013. Patients who received adjuvant therapy (AT) were compared to an observation (OB) cohort by propensity score matching. RESULTS: We identified 1846 patients: 1053 patients (57%) in the OB group, and 793 (43%) in the AT group. Patients who received adjuvant therapy were more likely to be younger, have a higher rate of private insurance, have higher T and N stage tumors, and were more likely to have positive resection margins. After 1:1 propensity score matching, 577 OB group patients were compared with 577 AT group patients. The AT cohort was associated with better overall survival compared with the OB cohort (hazard ratio [HR] 0.73; 95% confidence interval [CI] 0.64-0.83). The median survival was 29.5 and 23.3 months for the AT and OB groups, respectively (P < 0.01). Subgroup analysis demonstrated a survival advantage for adjuvant therapy in disease with positive resection margins (HR 0.53; 95% CI 0.42-0.67). CONCLUSIONS: Adjuvant therapy is associated with improved survival in resected perihilar cholangiocarcinoma, especially in disease with positive resection margins. This study supports the use of adjuvant therapy in high-risk patients. PMID- 29488188 TI - Progression of Colorectal Liver Metastases from the End of Chemotherapy to Resection: A New Contraindication to Surgery? AB - BACKGROUND: Not all patients with resectable colorectal liver metastases (CLM) benefit from liver resection (LR); only patients with disease progression during chemotherapy are excluded from surgery. OBJECTIVE: This study was performed to determine whether tumor behavior (stable disease/progression) from the end of chemotherapy to LR impacts prognosis. METHODS: Patients undergoing LR after tumor response or stabilization during chemotherapy were considered. Overall, 128 patients who underwent examination by two imaging modalities (computed tomography/magnetic resonance imaging) after chemotherapy with a > 3-week interval between the two imaging modalities were analyzed. Any variation in CLM size was registered. Tumor progression was defined according to the response evaluation criteria in solid tumors (RECIST) criteria. RESULTS: Among 128 patients with stable disease or partial response to preoperative chemotherapy, 32 (25%) developed disease progression in the chemotherapy to LR interval, with a disease progression rate of 17% when this interval was < 8 weeks. Survival was lower among patients with progression than those with stable disease [3-year overall survival (OS) 23.0 vs. 52.4%, and recurrence-free survival (RFS) 6.3% vs. 21.6%; p < 0.001]. Survival was extremely poor in patients with early progression (< 8 weeks) (0.0% 2-year OS, 12.5% 6-month RFS). Disease progression in the chemotherapy to LR interval was an independent negative prognostic factor for OS and RFS [hazard ratio 3.144 and 2.350, respectively; p < 0.001]. CONCLUSIONS: Early disease progression in the chemotherapy to LR interval occurred in approximately 15% of patients and was associated with extremely poor survival. Even if these data require validation, the risk for early disease progression after chemotherapy should be considered, and, if progression is evident, the indication for surgery should be cautiously evaluated. PMID- 29488189 TI - Concomitant Mediastinoscopy Increases the Risk of Postoperative Pneumonia After Pulmonary Lobectomy. AB - BACKGROUND: Mediastinoscopy is considered the gold standard for preresectional staging of lung cancer. We sought to examine the effect of concomitant mediastinoscopy on postoperative pneumonia (POP) in patients undergoing lobectomy. METHODS: All patients in our institutional database (2008-2015) undergoing lobectomy who did not receive neoadjuvant therapy were included in our study. The relationship between mediastinoscopy and POP was examined using univariate (Chi square) and multivariate analyses (binary logistic regression). In order to validate our institutional findings, lobectomy data in the National Surgical Quality Improvement Program (NSQIP) from 2005 to 2014 were analyzed for these associations. RESULTS: Of 810 patients who underwent a lobectomy at our institution, 741 (91.5%) surgeries were performed by video-assisted thoracic surgery (VATS) and 487 (60.1%) patients underwent concomitant mediastinoscopy. Univariate analysis demonstrated an association between mediastinoscopy and POP in patients undergoing VATS [odds ratio (OR) 1.80; p = 0.003], but not open lobectomy. Multivariate analysis retained mediastinoscopy as a variable, although the relationship showed only a trend (OR 1.64; p = 0.1). In the NSQIP cohort (N = 12,562), concomitant mediastinoscopy was performed in 9.0% of patients, with 44.5% of all the lobectomies performed by VATS. Mediastinoscopy was associated with POP in patients having both open (OR1.69; p < 0.001) and VATS lobectomy (OR 1.72; p = 0.002). This effect remained in multivariate analysis in both the open and VATS lobectomy groups (OR 1.46, p = 0.003; and 1.53, p = 0.02, respectively). CONCLUSIONS: Mediastinoscopy may be associated with an increased risk of POP after pulmonary lobectomy. This observation should be examined in other datasets as it potentially impacts preresectional staging algorithms for patients with lung cancer. PMID- 29488190 TI - Barriers to the Interpretation of Body Composition in Colorectal Cancer: A Review of the Methodological Inconsistency and Complexity of the CT-Defined Body Habitus. AB - BACKGROUND: Measurement of body composition by computed tomography (CT) is an advancing field. Sarcopenia, myosteatosis, and visceral obesity (VO) have been identified as predictive of survival in colorectal cancer (CRC). We performed a systematic review of contemporary studies to characterize this association and highlight methodological inconsistencies. METHODS: MEDLINE and PubMed were queried for articles published from January 2000 on, with populations of resectable CRC and with CT-measured body composition and survival data. The study quality was assessed by two independent reviewers using the Newcastle-Ottawa Scale. RESULTS: Twenty studies met inclusion criteria, with a total of 8895 patients. Only two of the studies scored as high quality and nine as moderate quality. The remaining nine studies scored as low quality. Ten studies considered sarcopenia and 12 considered visceral obesity (VO). Cutoff points to define sarcopenia, myosteatosis, and VO were identified by optimal stratification, quartiles, or median values. The prevalence of sarcopenia varied from 15 to 60%, which based on study population and cutoff value used. Sarcopenia was associated with worse overall and disease-free survival in eight of the included studies. Myosteatosis was considered in three studies with a prevalence of 19-78%. It was significantly predictive of worse overall and disease-free survival in all three studies. VO had a prevalence of 14-70% and was inconsistently predictive of survival outcomes. CONCLUSIONS: There is a lack of methodological consistency within the currently published literature. Despite this, sarcopenia and myosteatosis, but not VO, are consistently associated with worse survival outcomes, when population and cancer-specific cutoffs are utilized. PMID- 29488191 TI - Image-Based 2D Re-Projection for Attenuation Substitution in PET Neuroimaging. AB - PURPOSE: In dual modality positron emission tomography (PET)/magnetic resonance imaging (MRI), attenuation correction (AC) methods are continually improving. Although a new AC can sometimes be generated from existing MR data, its application requires a new reconstruction. We evaluate an approximate 2D projection method that allows offline image-based reprocessing. PROCEDURE: 2 Deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) brain scans were acquired (Siemens HR+) for six subjects. Attenuation data were obtained using the scanner's transmission source (SAC). Additional scanning was performed on a Siemens mMR including production of a Dixon-based MR AC (MRAC). The MRAC was imported to the HR+ and the PET data were reconstructed twice: once using native SAC (ground truth); once using the imported MRAC (imperfect AC). The re-projection method was implemented as follows. The MRAC PET was forward projected to approximately reproduce attenuation-corrected sinograms. The SAC and MRAC images were forward projected and converted to attenuation-correction factors (ACFs). The MRAC ACFs were removed from the MRAC PET sinograms by division; the SAC ACFs were applied by multiplication. The regenerated sinograms were reconstructed by filtered back projection to produce images (SUBAC PET) in which SAC has been substituted for MRAC. Ideally SUBAC PET should match SAC PET. Via coregistered T1 images, FreeSurfer (FS; MGH, Boston) was used to define a set of cortical gray matter regions of interest. Regional activity concentrations were extracted for SAC PET, MRAC PET, and SUBAC PET. RESULTS: SUBAC PET showed substantially smaller root mean square error than MRAC PET with averaged values of 1.5 % versus 8.1 %. CONCLUSIONS: Re-projection is a viable image-based method for the application of an alternate attenuation correction in neuroimaging. PMID- 29488192 TI - [Apathy, depression and cognitive functioning in patients with MCI and dementia]. AB - BACKGROUND: In dementia, apathy and depression are often seen as one disorder because of the many overlapping symptoms. However, for therapy a correct differentiation is essential. Moreover, apathy and depression are likely both associated with different cognitive deficits and progression of the disease. In this research we give an overview of cognitive domains associated with apathy and depression in MCI patients and report how often both disorders occur in a population sample. METHOD: We administered the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to 117 cognitively healthy controls (GC), 97 patients with mild cognitive impairment (MCI) and 50 patients with dementia (DEM). In addition, the Apathy Evaluation Scale clinical version (AES-C) and the Geriatric Depression Scale (GDS) were administered. RESULTS: The number of patients with apathy increased with cognitive decline with respectively 3.4%, 10.4% and 41.5% of patients in the GC, MCI and DEM group. The prevalence of isolated depression was highest in the MCI group (18.8%). Correlation analyses in the MCI group showed that apathy and not depression was associated with a deficit in encoding, attention and global cognitive functioning. CONCLUSION: The prevalence of apathy and depressive symptoms is different in patients with MCI, DEM and GC, and within the MCI group apathy and depression are associated with different cognitive domains. PMID- 29488193 TI - Influence of Formulation Factors on the Aerosol Performance and Stability of Lysozyme Powders: a Systematic Approach. AB - With the growing interest in developing biologics for pulmonary delivery, systematic fast screening methods are needed for rapid development of formulations. Due to the labile nature of macromolecules, the development of stable, biologically active formulations with desired aerosol performance imposes several challenges both from a formulation and processing perspective. In this study, spray-freeze-drying was used to develop respirable protein powders. In order to systematically map the selected design space, lysozyme aqueous pre formulations were prepared based on a constrained mixture design of experiment. The physicochemical properties of the resulting powders were characterized and the effects of formulation factors on aerosol performance and protein stability were systematically screened using a logic flow chart. Our results elucidated several relevant formulation attributes (density, total solid content, protein:sugars ratio) required to achieve a stable lysozyme powder with desirable characteristics for pulmonary delivery. A similar logical fast screening strategy could be used to delineate the appropriate design space for different types of proteins and guide the development of powders with pre-determined aerodynamic properties. PMID- 29488194 TI - Contact Angle Measurements: an Alternative Approach Towards Understanding the Mechanism of Increased Drug Dissolution from Ethylcellulose Tablets Containing Surfactant and Exploring the Relationship Between Their Contact Angles and Dissolution Behaviors. AB - The addition of surfactant in tablet was a well-defined approach to improve drug dissolution rate. While the selected surfactant played a vital role in improving the wettability of tablet by medium, it was equally important to improve the dissolution rate by permeation effect due to production of pores or the reduced inter-particle adhesion. Furthermore, understanding the mechanism of dissolution rate increased was significant. In this work, contact angle measurement was taken up as an alternative approach for understanding the dissolution rate enhancement for tablet containing surfactant. Ethylcellulose, as a substrate, was used to prepare tablet. Four surfactants, sodium dodecyl sulfate (SDS), sodium dodecylbenzenesulfonate (SDBS), dodecyltrimethylammonium bromide (DTAB), and sodium lauryl sulfonate (SLS), were used. Berberine hydrochloride, metformin hydrochloride, and rutin were selected as model drugs. The contact angle of tablet in the absence and presence of surfactant was measured to explore the mechanism. The dissolution test was investigated to verify the mechanism and to establish a correlation with the contact angle. The result showed that the mechanism was the penetration effect rather than the wetting effect. The dissolution increased with a reduction in the contact angle. DTAB was found to obtain the highest level of dissolution enhancement and the lowest contact angle, while SDS, SDBS, and SLS were found to be the less effective in both dissolution enhancement and contact angle decrease. Therefore, contact angle was a good indicator for dissolution behavior besides exploring the mechanism of increased dissolution, which shows great potential in formula screening. PMID- 29488195 TI - Encapsulation in Polymeric Microparticles Improves Daptomycin Activity Against Mature Staphylococci Biofilms-a Thermal and Imaging Study. AB - Eradication of Gram-positive biofilms is a critical aspect in implant-associated infection treatment. Although antibiotic-containing particulate carriers may be a promising strategy for overcoming biofilm tolerance, the assessment of their interaction with biofilms has not been fully explored. In the present work, the antibiofilm activity of daptomycin- and vancomycin-loaded poly(methyl methacrylate) (PMMA) and PMMA-Eudragit RL 100 (EUD) microparticles against methicillin-resistant Staphylococcus aureus (MRSA) and polysaccharide intercellular adhesin-positive S. epidermidis biofilms was investigated using isothermal microcalorimetry (IMC) and fluorescence in situ hybridization (FISH). The minimal biofilm inhibitory concentrations (MBIC) of MRSA biofilms, as determined by IMC, were 5 and 20 mg/mL for daptomycin- and vancomycin-loaded PMMA microparticles, respectively. S. epidermidis biofilms were less susceptible, with a MBIC of 20 mg/mL for daptomycin-loaded PMMA microparticles. Vancomycin-loaded microparticles were ineffective. Adding EUD to the formulation caused a 4- and 16 fold reduction of the MBIC values of daptomycin-loaded microparticles for S. aureus and S. epidermidis, respectively. FISH corroborated the IMC results and provided additional insights on the antibiofilm effect of these particles. According to microscopic analysis, only daptomycin-loaded PMMA-EUD microparticles were causing a pronounced reduction in biofilm mass for both strains. Taken together, although IMC indicated that a biofilm inhibition was achieved, microscopy showed that the biofilm was not eradicated and still contained FISH positive, presumably viable bacteria, thus indicating that combining the two techniques is essential to fully assess the effect of microparticles on staphylococcal biofilms. PMID- 29488196 TI - A Mechanistic Study to Determine the Structural Similarities Between Artificial Membrane Strat-MTM and Biological Membranes and Its Application to Carry Out Skin Permeation Study of Amphotericin B Nanoformulations. AB - Type of biological membrane used in skin permeation experiment significantly affects skin permeation and deposition potential of tested formulations. In this study, a comparative study has been carried out to evaluate the potential of a synthetic membrane (Strat-MTM) with rat, human, and porcine ear skin to carry out skin permeation study of nanoformulations of a high molecular weight drug, amphotericin B. Results demonstrated that the permeation of this high molecular weight drug through Strat-MTM showed close similitude to human skin. Value of correlation coefficient (R2) of log diffusion between Strat-MTM and human skin was found to be 0.99 which demonstrated the similarities of Strat-MTM membrane to the human skin. In similarity factor analysis, the value of f2 was also found to be 85, which further demonstrated the similarities of Strat-MTM membrane to human skin. Moreover, scanning electron microscopy (SEM), transmission electron microscopy (TEM), and Brunauer-Emmett-Teller (BET) analysis of synthetic and biological membranes depicted almost similar morphological features (thickness, pore size, surface morphology, and diameter) of synthetic membrane with human skin. The results of the study demonstrated Strat-MTM as a better alternative to carry out skin permeation experiment due to the consistent results, reproducibility, easy availability, and minimum variability with human skin. PMID- 29488197 TI - Development and Performance of a Highly Sensitive Model Formulation Based on Torasemide to Enhance Hot-Melt Extrusion Process Understanding and Process Development. AB - The aim of this work was to investigate the use of torasemide as a highly sensitive indicator substance and to develop a formulation thereof for establishing quantitative relationships between hot-melt extrusion process conditions and critical quality attributes (CQAs). Using solid-state characterization techniques and a 10 mm lab-scale co-rotating twin-screw extruder, we studied torasemide in a Soluplus(r) (SOL)-polyethylene glycol 1500 (PEG 1500) matrix, and developed and characterized a formulation which was used as a process indicator to study thermal- and hydrolysis-induced degradation, as well as residual crystallinity. We found that torasemide first dissolved into the matrix and then degraded. Based on this mechanism, extrudates with measurable levels of degradation and residual crystallinity were produced, depending strongly on the main barrel and die temperature and residence time applied. In addition, we found that 10% w/w PEG 1500 as plasticizer resulted in the widest operating space with the widest range of measurable residual crystallinity and degradant levels. Torasemide as an indicator substance behaves like a challenging to-process API, only with higher sensitivity and more pronounced effects, e.g., degradation and residual crystallinity. Application of a model formulation containing torasemide will enhance the understanding of the dynamic environment inside an extruder and elucidate the cumulative thermal and hydrolysis effects of the extrusion process. The use of such a formulation will also facilitate rational process development and scaling by establishing clear links between process conditions and CQAs. PMID- 29488198 TI - Correction to: Behaviour and risk assessment of fluopyram and its metabolite in cucumber (Cucumis sativus) fruit and in soil. AB - Unfortunately, the original publication of this paper contains a mistake. The correct name of the 3rd Author is Sunny H. Patel. The original article has been corrected. PMID- 29488199 TI - The influencing factors of CO2 emission intensity of Chinese agriculture from 1997 to 2014. AB - In China, agriculture produces the greatest chemical oxygen demand (COD) emissions in wastewater and the most methane (CH4) emissions. It is imperative that agricultural pollution in China be reduced. This study investigated the influencing factors of the CO2 emission intensity of Chinese agriculture from 1997 to 2014. We analyzed the influencing factors of the CO2 emission intensity through the first-stage least-square regression. We also analyzed determinants of innovation through the second-stage least-square regression. We found that innovation negatively affected the CO2 emission intensity in the model of the nation. FDI positively affected innovation in China. It is important to enhance indigenous innovation for green agriculture through labor training and collaboration between agriculture and academia. PMID- 29488200 TI - Evaluation of nanoparticle emissions from a laser printer in an experimental chamber and estimation of the human particle dose. AB - The aim of this study was to evaluate the nanoparticle emissions from a laser printer in a chamber in conjunction with emissions from printers in a print room (PR) and to characterize the processes that lead to increased nanoparticle concentrations, as well as to estimate the human particle dose of the printers' users. Measurements were conducted in a small stainless steel environmental chamber under controlled conditions, where the evolution of particle size distributions (PSDs) with time and printed pages was studied in detail. Printer was generating nanoparticles (vast majority ? 50 nm with mode on ~ 15 nm) primarily during cold startup. Previously, 1-week sampling was also done in a PR at the Technical University of Crete, where the tested laser printer is installed along with three other printers. Similarly, as it was observed in the chamber study, printers' startup on any given day was characterized by a sharp increase in particle number (PN) concentrations. Average measured PN concentrations during printing hours in PR (5.4 * 103 #/cm3) is similar to the one observed in chamber measurements (6.7 * 103 #/cm3). The ExDoM2 dosimetry model was further applied to calculate the deposition of particles in the human respiratory tract. More precisely, the increase in particle dose for an adult Caucasian male was 14.6- and 24.1-fold at printers' startup, and 1.2- and 5.2-fold during printing in the PR and experimental chamber, respectively, compared to the exposure dose at background concentrations (BCs). PMID- 29488201 TI - Depth treatment of coal-chemical engineering wastewater by a cost-effective sequential heterogeneous Fenton and biodegradation process. AB - In this study, a sequential Fe0/H2O2 reaction and biological process was employed as a low-cost depth treatment method to remove recalcitrant compounds from coal chemical engineering wastewater after regular biological treatment. First of all, a chemical oxygen demand (COD) and color removal efficiency of 66 and 63% was achieved at initial pH of 6.8, 25 mmol L-1 of H2O2, and 2 g L-1 of Fe0 in the Fe0/H2O2 reaction. According to the gas chromatography-mass spectrometer (GC-MS) and gas chromatography-flame ionization detector (GC-FID) analysis, the recalcitrant compounds were effectively decomposed into short-chain organic acids such as acetic, propionic, and butyric acids. Although these acids were resistant to the Fe0/H2O2 reaction, they were effectively eliminated in the sequential air lift reactor (ALR) at a hydraulic retention time (HRT) of 2 h, resulting in a further decrease of COD and color from 120 to 51 mg L-1 and from 70 to 38 times, respectively. A low operational cost of 0.35 $ m-3 was achieved because pH adjustment and iron-containing sludge disposal could be avoided since a total COD and color removal efficiency of 85 and 79% could be achieved at an original pH of 6.8 by the above sequential process with a ferric ion concentration below 0.8 mg L-1 after the Fe0/H2O2 reaction. It indicated that the above sequential process is a promising and cost-effective method for the depth treatment of coal-chemical engineering wastewaters to satisfy discharge requirements. PMID- 29488202 TI - UV-irradiated 2-methyl-4'-(methylthio)-2-morpholinopropiophenone-containing injection solution produced frameshift mutations in the Ames mutagenicity assay. AB - In previous studies, we detected the photoinitiators 1-hydroxycyclohexyl phenyl ketone (1-HCHPK), methyl 2-benzoylbenzoate (MBB), and 2-methyl-4'-(methylthio)-2 morpholinopropiophenone (MTMP) in intravenous injection solutions. In addition, we reported that 1-HCHPK, MBB, and MTMP exhibited cytotoxicity towards normal human peripheral blood mononuclear cells. A previous in vitro study reported that a free-radical photoinitiator introduced covalently bound purine residues into DNA. However, little is known about the in vitro mutagenicity of 1-HCHPK, MBB, and MTMP. In the present in vitro study, we evaluated the mutagenicity of 1 HCHPK, MBB, and MTMP using the Ames test. We found that untreated 1-HCHPK, MBB, and MTMP were not mutagenic in S. typhimurium strain TA97, TA98, TA100, TA102, or TA1535, regardless of the presence/absence of S9 activation. However, ultraviolet (UV) light-irradiated MTMP exhibited mutagenicity in S. typhimurium strain TA97 in the absence of S9 activation. In conclusion, we suggest that exposure to UV irradiated MTMP, including in intravenous injection solutions, can result in frameshift mutations. PMID- 29488203 TI - Combined toxicities of copper nanoparticles with carbon nanotubes on marine microalgae Skeletonema costatum. AB - To investigate the combined toxicities of copper nanoparticles (nano-Cu) with carbon nanotubes (CNTs) on marine microalgae Skeletonema costatum, algal growth inhibition tests were carried out. Toxicities of nano-Cu with CNTs and without CNTs on microalgae were determined, respectively. Chlorophyll content and photosynthetic efficiency (PhiPSII) were determined to compare negative effects of nano-Cu with CNTs and without CNTs on photosynthesis. The concentration of Cu2+ released by nano-Cu into the medium was determined, and interactions between nano-Cu and CNTs were analyzed to study toxic mechanisms of combined toxicities of nano-Cu with CNTs. It was found that both nano-Cu and CNTs could inhibit the growth of the microalgae; however, the toxicity of CNTs on the microalgae was far lower than that of nano-Cu. The maximum growth inhibition ratio (IR) of nano-Cu on the microalgae was 86% appearing at 96 h under 1.0 mg/L nano-Cu treatment, while the maximum IR of CNTs on the microalgae was 58% at 96 h under 200 mg/L CNT treatment. CNTs could reduce the toxicity of nano-Cu on the microalgae in processes of growth and photosynthesis. Adsorption of Cu2+ on CNTs and aggregate between Cu and CNTs in the medium were main reasons for attenuation of toxicity of nano-Cu with adding CNTs. PMID- 29488205 TI - COPD Course and Comorbidities: Are There Gender Differences? AB - The prevalence of chronic obstructive pulmonary disease (COPD) has increased more rapidly in women than in men during the past two decades. Clinical presentation, comorbidities and prognosis may differ between genders and may influence management decisions. The influence of gender on COPD expression has not been clearly explained to date. Thus, the aim of this study was to evaluate significant differences between women and men suffering from COPD, regarding clinical presentation, pulmonary function test results, comorbidities, and prognosis. We prospectively recruited 470 patients with stable COPD with a history of smoking (152 women, 318 men, mean age 65.5 +/- 8.8 vs. 66.6 +/- 9.4 years, respectively). Comorbidities and exacerbations were recorded. Spirometry, body plethysmography, carbon monoxide diffusing capacity and 6-min walk tests were performed. The BODE prognostic score was also calculated. We found that women smoked less in comparison to men (30.4 vs. 41.9 pack-years, p < 0.05), showed more exacerbations (2.5 vs. 1.7, p = 0.01), higher forced expiratory volume in 1 s (FEV1%predicted), and increased residual volume/total lung capacity (RV/%TLC), but they had the same intensity of dyspnea. Women showed fewer comorbidities, on average, per patient (5.4 vs. 6.4, p = 0.002), but had a higher prevalence of at least seven comorbidities per patient (48.7% of women vs. 33.0% of men, p < 0.05). Women also had a significantly worse prognosis (4.6 vs. 3.1 BODE score, p < 0.05) that correlated with the number of comorbidities (r = 0.33, p < 0.01). In conclusion, this study strongly supports the existence of different gender phenotypes in COPD, especially regarding exacerbations, comorbidities, and prognosis. The gender difference may indicate a need for a targeted assessment and management of COPD in women and men. PMID- 29488204 TI - Mechanisms of copper stress alleviation in Citrus trees after metal uptake by leaves or roots. AB - Nutritional disorders caused by copper (Cu) have affected citrus orchards. Since Cu is foliar sprayed as a pesticide to control citrus diseases, this metal accumulates in the soil. Thereby, we evaluated the effects of Cu leaf absorption after spray of different metal sources, as well as roots absorption on growth, nutritional status, and oxidative stress of young sweet orange trees. Two experiments were carried out under greenhouse conditions. The first experiment was set up with varying Cu levels to the soil (nil Cu, 0.5, 2.0, 4.0 and 8.0 g of Cu per plant as CuSO4.5H2O), whereas the second experiment with Cu application via foliar sprays (0.5 and 2.0 g of Cu per plant) and comparing two metal sources (CuSO4.5H2O or Cu(OH)2). Copper was mainly accumulated in roots with soil supply, but an increase of oxidative stress levels was observed in leaves. On the other hand, Cu concentrations were higher in leaves that received foliar sprays, mainly as Cu(OH)2. However, when sulfate was foliar sprayed, plants exhibited more symptoms of injuries in the canopy with decreased chlorophyll contents and increased hydrogen peroxide and lipid peroxidation levels. Copper toxicity was characterized by sap leakage from the trunk and twigs, which is the first report of this specific Cu excess symptom in woody trees. Despite plants with 8.0 g of Cu soil-applied exhibiting the sap leakage, growth of new plant parts was more vigorous with lower oxidative stress levels and injuries compared to those with 4.0 g of Cu soil-applied (without sap leakage). With the highest level of Cu applied via foliar as sulfate, Cu was eliminated by plant roots, increasing the rhizospheric soil metal levels. Despite citrus likely exhibiting different mechanisms to reduce the damages caused by metal toxicity, such as responsive enzymatic antioxidant system, metal accumulation in the roots, and metal exclusion by roots, excess Cu resulted in damages on plant growth and metabolism when the metal was taken up either by roots or leaves. PMID- 29488206 TI - Rehabilitation of Neuromotor Disabilities in Aquatic Microgravity Environment. AB - The aquatic environment has a high potential in rehabilitation treatment of acute lesions and in chronic diseases. The Safe Bearing Back method is proposed to stimulate the reorganization of deteriorated sensory neuromotor skills. The aim of the present study was to verify the effectiveness and the long-term maintenance of the benefits of a specific thermal rehabilitation training in neuromotor and neurological disabilities. Seventy four patients were evaluated using the Functional Independence Measure (FIM), Tinetti Gait-Balance Scale (TIN), and Visual Analog Scale (VAS) for pain. In addition, a general health index was developed, conceived as a linear combination, with unit weights, of the normalized FIM, TIN, and VAS indicators. Measurements were made at T1 (baseline before treatment), T2 (after a five-month treatment, which was the end of treatment), and T3 (6 months after the end of treatment). Self-sufficiency, walking ability, and subjective pain perception were improved after the treatment. The improvement tapered off during the six-month-long follow-up, but the patients' condition remained well compared with the baseline level before the implementation of the treatment program. We conclude that hydrokinesitherapy with the Safe Bearing Back method demonstrates is clearly effective in the immediate and medium-term rehabilitation of neuromotor diseases. PMID- 29488207 TI - The Role of Health Locus of Control in Pain Intensity Outcome of Conservatively and Operatively Treated Hand Surgery Patients. AB - PURPOSE: Psychological factors have shown to be associated with treatment outcomes in hand injury patients. This study aimed to investigate the role of health locus of control (HLOC) and its dimensions internal, social-external, and fatalistic-external HLOC in treatment outcomes of hand injury patients. METHOD: One hundred thirty-two consecutive patients of a tertiary center for hand surgery undergoing treatment for acute hand injury or degenerative hand problems were included in this study. Pretreatment levels of depression, anxiety, HLOC, and pain intensity were measured, along with pain intensity levels at 4-month follow up. Hierarchical regression analyses were calculated to test for moderation effects of the HLOC dimensions on the relationship between pretreatment and follow-up pain intensity. RESULTS: Controlling for age, gender, treatment modality, source of hand pain, and depressive symptoms, a moderation effect emerged (beta = - 0.16, p < 0.05), such that among patients higher in initial pain intensity, those lower in social-external HLOC experienced higher pain intensity at follow-up compared to those with high social-external HLOC. Internal HLOC and fatalistic-external HLOC did not moderate the effect of initial pain intensity on pain intensity at follow-up. CONCLUSION: Hand injury patients suffering greater initial pain intensity who also had lower versus higher social external HLOC experienced less favorable treatment outcome. This finding suggests that if patients with high initial pain succeed in transferring perceived health control to professionals and to gain confidence in treatment and clinicians, treatment outcome could be improved in hand surgery. PMID- 29488208 TI - Time-dependent changes in bone healing capacity of scaphoid fractures and non unions. AB - The scaphoid is the most frequently fractured carpal bone and prone to non-union due to mechanical and biological factors. Whereas the importance of stability is well documented, the evaluation of biological activity is mostly limited to the assessment of vascularity. The purpose of this study was to select histological and immunocytochemical parameters that could be used to assess healing potential after scaphoid fractures and to correlate these findings with time intervals after fracture for the three parts of the scaphoid (distal, gap and proximal). Samples were taken during operative intervention in 33 patients with delayed or non-union of the scaphoid. Haematoxylin and Eosin (HE), Azan, Toluidine, von Kossa and Tartrate-resistant acid phosphatase (TRAP) staining were used to characterise the samples histologically. We determined distribution of collagen 1 and 2 by immunocytochemistry, and scanning electron microscopy (SEM) was used to investigate the ultrastructure. To analyse the samples, parameters for biological healing status were defined and grouped according to healing capacity in parameters with high, partial and little biological activity. These findings allowed scoring of biological healing capacity, and the ensuing results were correlated with different time intervals after fracture. The results showed reduced healing capacity over time, but not all parts of the scaphoid were affected in the same way. For the distal fragment, regression analysis showed a statistically significant correlation between summarised healing activity scores and time from initial fracture (r = -0.427, P = 0.026) and decreasing healing activity for the gap region (r = -0.339, P = 0.090). In contrast, the analyses of the proximal parts for all patients did not show a correlation (r = 0.008, P = 0.969) or a decrease in healing capacity, with reduced healing capacity already at early stages. The histological and immunocytochemical characterisation of scaphoid non-unions (SNUs) and the scoring of healing parameters make it possible to analyse the healing capacity of SNUs at certain time points. This information is important as it can assist the surgeon in the selection of the most appropriate SNU treatment. PMID- 29488209 TI - Decorin-mediated oncosuppression - a potential future adjuvant therapy for human epithelial cancers. AB - Currently, the multifaceted role of the extracellular matrix (ECM) in tumourigenesis has been realized. One ECM macromolecule exhibiting potent oncosuppressive actions in tumourigenesis is decorin, the prototype of the small leucine-rich proteoglycan gene family. The actions of decorin include its ability to function as an endogenous pan-receptor tyrosine kinase inhibitor, a regulator of both autophagy and mitophagy, as well as a modulator of the immune system. In this review, we will discuss these topics in more detail. We also provide a summary of preclinical studies exploring the value of decorin-mediated oncosuppression, as a potential future adjuvant therapy for epithelial cancers. LINKED ARTICLES: This article is part of a themed section on Translating the Matrix. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.1/issuetoc. PMID- 29488210 TI - Metabolic obesity phenotypes and risk of colorectal cancer in postmenopausal women. AB - Obesity has been postulated to increase the risk of colorectal cancer by mechanisms involving insulin resistance and the metabolic syndrome. We examined the associations of body mass index (BMI), waist circumference, the metabolic syndrome, metabolic obesity phenotypes and homeostasis model-insulin resistance (HOMA-IR-a marker of insulin resistance) with risk of colorectal cancer in over 21,000 women in the Women's Health Initiative CVD Biomarkers subcohort. Women were cross-classified by BMI (18.5-<25.0, 25.0-<30.0 and >=30.0 kg/m2 ) and presence of the metabolic syndrome into 6 phenotypes: metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy overweight (MHOW), metabolically unhealthy overweight (MUOW), metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO). Neither BMI nor presence of the metabolic syndrome was associated with risk of colorectal cancer, whereas waist circumference showed a robust positive association. Relative to the MHNW phenotype, the MUNW phenotype was associated with increased risk, whereas no other phenotype showed an association. Furthermore, HOMA-IR was not associated with increased risk. Overall, our results do not support a direct role of metabolic dysregulation in the development of colorectal cancer; however, they do suggest that higher waist circumference is a risk factor, possibly reflecting the effects of increased levels of cytokines and hormones in visceral abdominal fat on colorectal carcinogenesis. PMID- 29488211 TI - Monoclonal antibodies against metzincin targets. AB - The metzincin clan of metalloproteinases includes the MMP, disintegrin and metalloproteinase (ADAM) and ADAM with thrombospondin motifs families, which cleave extracellular targets in a wide range of (patho)physiological processes. Antibodies constitute a powerful tool to modulate the activity of these enzymes for both therapeutic and research purposes. In this review, we give an overview of monoclonal antibodies (mAbs) that have been tested in preclinical disease models, human trials and important studies of metzincin structure and function. Initial attempts to develop therapeutic small molecule inhibitors against MMPs were hampered by structural similarities between metzincin active sites and, consequently, off-target effects. Therefore, more recently, mAbs have been developed that do not bind to the active site but bind to surface-exposed loops that are poorly conserved in closely related family members. Inhibition of protease activity by these mAbs occurs through a variety of mechanisms, including (i) barring access to the active site, (ii) disruption of exosite binding, and (iii) prevention of protease activation. These different modes of inhibition are discussed in the context of the antibodies' potency, selectivity and, importantly, the effects in models of disease and clinical trials. In addition, various innovative strategies that were used to generate anti-metzincin mAbs are discussed. LINKED ARTICLES: This article is part of a themed section on Translating the Matrix. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.1/issuetoc. PMID- 29488213 TI - Evolution of the vertebrate heart. PMID- 29488215 TI - Abstracts for the Australasian Academy of Cerebral Palsy and Developmental Medicine, Auckland, New Zealand, 21-24 March 2018. PMID- 29488212 TI - Associations of metabolic syndrome and C-reactive protein with mortality from total cancer, obesity-linked cancers and breast cancer among women in NHANES III. AB - Although metabolic syndrome (MetS) is a prognostic factor for cancer occurrence, the association of MetS and cancer mortality remains unclear. The purpose of this study was to evaluate whether MetS, components of MetS and C-reactive protein (CRP) are associated with cancer mortality in women. A total of 400 cancer deaths, with 140 deaths from obesity-linked-cancers (OLCas), [breast (BCa), colorectal, pancreatic and endometrial], linked through the National Death Index, were identified from 10,104 eligible subjects aged >=18 years. Cox proportional hazards regression was used to estimate multivariable-adjusted hazard ratios (HR) for cancer mortality. MetS was associated with increased deaths for total cancer [HR = 1.33, 95% confidence interval (CI) 1.04-1.70] and BCa [HR = 2.1, 95% CI, 1.09-4.11]. The risk of total cancer [HR = 1.7, 95% CI, 1.12-2.68], OLCas [HR = 2.1, 95% CI, 1.00-4.37] and BCa [HR = 3.8, 95% CI, 1.34-10.91] mortality was highest for women with all MetS components abnormal, compared to those without MetS. Linear associations of blood-pressure [HR = 2.5, 1.02-6.12, Quartile (Q) 4 vs Q1, p trend = 0.004] and blood-glucose [HR = 2.2, 1.04-4.60, Q4 vs. Q1, p trend = 0.04] with total-OLCas mortality were observed. A threefold increased risk of BCa mortality was observed for women with enlarged waist circumference, >=100.9 cm, [HR = 3.5, 1.14-10.51, p trend = 0.008] and in those with increased blood glucose, >=101 mg/dL, [HR = 3.2, 1.11-9.20, p trend = 0.03] compared to those in Q1. None of the components of MetS were associated with total-cancer mortality. CRP was not associated with cancer mortality. In conclusion, MetS is associated with total-cancer and breast-cancer mortality, with waist circumference, blood pressure and blood glucose as independent predictors of OLCas and BCa mortality. PMID- 29488214 TI - Pharmacological inhibition of the Notch pathway enhances the efficacy of androgen deprivation therapy for prostate cancer. AB - Although androgen deprivation therapy (ADT) is a standard treatment for metastatic prostate cancer, this disease inevitably recurs and progresses to ADT resistant stage after this therapy. Accordingly, understanding the mechanism of resistance to ADT and finding new approach to enhance the efficacy of ADT may provide a major benefit to PCa patients. In our study, we found upregulated expression of Notch receptors is positive associated with ADT-resistance progression. Using fluorescent Notch signaling reporter system, we observed that endogenous Notch signaling could be activated after treatment of androgen deprivation in LNCaP cells via activation of Notch3. In addition, exogenous activation of the Notch signaling though Dox-induced overexpression of any Notch intracellular domains (NICD1-4) could enhance the resistance of PCa cells to ADT under ex vivo 3D culture conditions and upregulate expression of ADT resistance associated phospho-p38 and Bcl-2 in LNCaP cells. As a result, pharmacological inhibition of the Notch pathway using gamma-secretase inhibitor (GSI), DAPT, downregulated both phospho-p38 and Bcl-2 expression and significantly enhanced the efficacy of ADT in androgen sensitive PCa cells with impaired proliferation and 3D colony formation, increased apoptosis and remarkable inhibition of tumor growth in murine subcutaneous xenograft model. These results indicate that activated Notch signaling contributes to ADT resistance, and suggest that inhibition of the Notch pathway may be a promising adjuvant therapy of ADT for PCa. PMID- 29488217 TI - A global database and "state of the field" review of research into ecosystem engineering by land animals. AB - Ecosystem engineers have been widely studied for terrestrial systems, but global trends in research encompassing the range of taxa and functions have not previously been synthesised. We reviewed contemporary understanding of engineer fauna in terrestrial habitats and assessed the methods used to document patterns and processes, asking: (a) which species act as ecosystem engineers and with whom do they interact? (b) What are the impacts of ecosystem engineers in terrestrial habitats and how are they distributed? (c) What are the primary methods used to examine engineer effects and how have these developed over time? We considered the strengths, weaknesses and gaps in knowledge related to each of these questions and suggested a conceptual framework to delineate "significant impacts" of engineering interactions for all terrestrial animals. We collected peer reviewed publications examining ecosystem engineer impacts and created a database of engineer species to assess experimental approaches and any additional covariates that influenced the magnitude of engineer impacts. One hundred and twenty-two species from 28 orders were identified as ecosystem engineers, performing five ecological functions. Burrowing mammals were the most researched group (27%). Half of all studies occurred in dry/arid habitats. Mensurative studies comparing sites with and without engineers (80%) were more common than manipulative studies (20%). These provided a broad framework for predicting engineer impacts upon abundance and species diversity. However, the roles of confounding factors, processes driving these patterns and the consequences of experimentally adjusting variables, such as engineer density, have been neglected. True spatial and temporal replication has also been limited, particularly for emerging studies of engineer reintroductions. Climate change and habitat modification will challenge the roles that engineers play in regulating ecosystems, and these will become important avenues for future research. We recommend future studies include simulation of engineer effects and experimental manipulation of engineer densities to determine the potential for ecological cascades through trophic and engineering pathways due to functional decline. We also recommend improving knowledge of long-term engineering effects and replication of engineer reintroductions across landscapes to better understand how large-scale ecological gradients alter the magnitude of engineering impacts. PMID- 29488219 TI - Diffusion tensor imaging correlates of early markers of depression in youth at high-familial risk for bipolar disorder. AB - BACKGROUND: Mood disorders are familial psychiatric diseases, in which patients show reduced white matter (WM) integrity. We sought to determine whether WM integrity was affected in young offspring at high-familial risk of mood disorder before they go on to develop major depressive disorder (MDD). METHODS: The Bipolar Family study is a prospective longitudinal study examining young individuals (age 16-25 years) at familial risk of mood disorder on three occasions 2 years apart. This study used baseline imaging data, categorizing groups according to clinical outcome at follow-up. Diffusion tensor MRI data were acquired for 61 controls and 106 high-risk individuals, the latter divided into 78 high-risk subjects who remained well throughout the study ('high-risk well') and 28 individuals who subsequently developed MDD ('high-risk MDD'). Voxel-wise between-group comparison of fractional anisotropy (FA) based on diagnostic status was performed using tract-based spatial statistics (TBSS). RESULTS: Compared to controls, both high-risk groups showed widespread decreases in FA (pcorr < .05) at baseline. Although FA in the high-risk MDD group negatively correlated with subthreshold depressive symptoms at the time of scanning (pcorr < .05), there were no statistically significant differences at p-corrected levels between the two high-risk groups. CONCLUSIONS: These results suggest that decreased FA is related to the presence of familial risk for mood disorder along with subdiagnostic symptoms at the time of scanning rather than predictive of subsequent diagnosis. Due to the difficulties performing such longitudinal prospective studies, we note, however, that this latter analysis may be underpowered due to sample size within the high-risk MDD group. Further clinical follow-up may clarify these findings. PMID- 29488218 TI - Ebselen has lithium-like effects on central 5-HT2A receptor function. AB - BACKGROUND AND PURPOSE: Lithium's antidepressant action may be mediated by inhibition of inositol monophosphatase (IMPase), a key enzyme in Gq -protein coupled receptor signalling. Recently, the antioxidant agent ebselen was identified as an IMPase inhibitor. Here, we investigated both ebselen and lithium in models of the 5-HT2A receptor, a Gq -protein coupled receptor involved in lithium's actions. EXPERIMENTAL APPROACH: 5-HT2A receptor function was assessed in mice by measuring the behavioural (head-twitches, ear scratches) and molecular (cortical immediate early gene [IEG] mRNA; Arc, c-fos, Egr2) responses to 5-HT2A receptor agonists. Ebselen and lithium were administered either acutely or repeatedly prior to assessment of 5-HT2A receptor function. Because lithium and 5 HT2A receptor antagonists augment the action of selective serotonin reuptake inhibitors (SSRIs), ebselen was tested for this activity by co-administration with the SSRI citalopram in microdialysis (extracellular 5-HT) experiments. KEY RESULTS: Acute and repeated administration of ebselen inhibited behavioural and IEG responses to the 5-HT2A receptor agonist DOI. Repeated lithium also inhibited DOI-evoked behavioural and IEG responses. In comparison, a selective IMPase inhibitor (L-690330) attenuated the behavioural response to DOI whereas glycogen synthase kinase inhibitor (AR-A014418) did not. Finally, ebselen enhanced the increase in extracellular 5-HT induced by citalopram, and also increased regional brain 5-HT synthesis. CONCLUSIONS AND IMPLICATIONS: Our data demonstrated lithium mimetic effects of ebselen in different experimental models of 5-HT2A receptor function, probably mediated by IMPase inhibition. This evidence of lithium-like neuropharmacological effects of ebselen adds further support for the clinical testing of ebselen in mood disorders, including as an antidepressant augmenting agent. PMID- 29488220 TI - Rebuttal letter in response to Professor R.H. Anderson's letter 'Evolution of the vertebrate heart'. PMID- 29488222 TI - To the Editor. PMID- 29488221 TI - The Genetic Structure of Human Populations Studied Through Short Insertion Deletion Polymorphisms. AB - In a landmark study Rosenberg et al. (2002) analyzed human genome diversity with 377 microsatellites in the HGDP-CEPH Genome Diversity Panel and reported that the populations were structured into five geographical regions: America, Sub-Saharan Africa, East Asia, Oceania and a cluster composed of Europe, the Middle East and Central Asia. They also observed that the within-population component accounted for 93-95%, and that the among-regions portion was only 3.6%, of the total genetic variance. We have also studied the HGDP-CEPH Diversity Panel (1064 individuals from 52 populations) with a set of 40 biallelic slow-evolving short insertion-deletion polymorphisms (indels). We confirmed the partition of worldwide diversity into five genetic clusters that correspond to major geographic regions. Using the indels we have also disclosed an among-regions component of genetic variance considerably larger (12.1%) than had been estimated using microsatellites. Our study demonstrates that a set of 40 well-chosen biallelic markers is sufficient for the characterization of human population structure at the global level. PMID- 29488223 TI - To the Editor. PMID- 29488224 TI - Lack of Association Between Genetic Variation in 9 Innate Immunity Genes and Baseline CRP Levels. AB - It is well-known that baseline levels of C-reactive protein (CRP) are an independent cardiovascular risk factor. We hypothesized that genetic variation with significant influence on CRP levels might be found in genes of the innate immunity system. We performed a candidate gene association study examining common single nucleotide polymorphisms in 9 innate immunity genes (CARD15, IRAK1, IRAK4, LBP, LY86, MEFV, TLR2, TLR4 and NFKB1) in relation to CRP levels. Seven hundred and seventeen subjects from the Women's Health Study population were studied: 359 and 358 samples with extremely low (<0.2 mg/liter) and high (>5 mg/liter) CRP levels, respectively. SNPs were identified from publicly available resequencing data, using a minor allele frequency threshold of >5% and a linkage disequilibrium (LD)-based strategy (r2 > 0.8) to select 63 LD-independent markers. One non-synonymous SNP in TLR4 and two non-synonymous SNPs in CARD15, previously associated with atherosclerosis and Crohn's disease, respectively, were also studied. Univariate, haplotype and gene-gene interaction analyses all indicated no significant association with CRP levels. Although this work excludes a significant association of common SNPs in these nine genes with CRP levels, it is possible that rarer alleles in these genes, or variation in other innate immunity genes, could be associated with variation in CRP. PMID- 29488226 TI - Impact of previous biologic use on the efficacy and safety of brodalumab and ustekinumab in patients with moderate-to-severe plaque psoriasis: integrated analysis of the randomized controlled trials AMAGINE-2 and AMAGINE-3. AB - BACKGROUND: Biologics are being used increasingly to treat moderate-to-severe psoriasis. Efficacy may differ in patients with previous exposure to biologics. OBJECTIVES: To investigate the impact of previous biologic exposure on the efficacy and safety of brodalumab and ustekinumab in patients with moderate-to severe plaque psoriasis. METHODS: Two placebo- and ustekinumab-controlled phase III clinical trials. There was an initial 12-week induction phase where patients were treated with brodalumab [210 mg or 140 mg every 2 weeks (Q2W)], ustekinumab or placebo. Efficacy end points included >= 75% improvement in Psoriasis Area and Severity Index (PASI 75) and static Physician's Global Assessment (score of 0 or 1) vs. placebo, PASI 100 vs. ustekinumab, Dermatology Life Quality Index and Psoriasis Symptom Inventory. Adverse events were monitored throughout. RESULTS: In total, 493 patients [334 (27%) brodalumab 210 mg Q2W and 159 (26%) ustekinumab] had received prior biologics; 150 (12%) and 62 (10%), respectively, reported previously failed treatment with a biologic. Brodalumab efficacy in patients with or without previous exposure to biologics was statistically equivalent: 40.9% and 39.5% of biologic-naive and -experienced patients achieved PASI 100 at week 12, compared with 21.1% and 17.0% with ustekinumab (both P < 0.001). In patients where prior biologics had been successful or failed, 41.7% and 32.0% achieved PASI 100, compared with 21.1% and 11.3% with ustekinumab. Tolerability was similar, and did not appear to be influenced by previous treatment with biologics. CONCLUSIONS: The efficacy of brodalumab 210 mg Q2W was similar regardless of prior biological therapy (P = 0.31, 0.32 and 0.64 for PASI 75, 90 and 100, respectively). Almost twice as many patients achieved PASI 100 or complete clearance with brodalumab at week 12 compared with ustekinumab; the differences were most noticeable where previous biologics had failed. Both treatments were well tolerated. PMID- 29488225 TI - Low concentrations of glyphosate-based herbicide cause complete loss of sperm motility of yellowtail tetra fish Astyanax lacustris. AB - Environmental relevant concentrations of glyphosate-based herbicide as 50 ug l-1 , 300 ug l-1 and 1800 ug l-1 can affect sperm quality of yellowtail tetra fish Astyanax lacustris. Viability of sperm cells was impaired at 300 ug l-1 , a concentration that is within legal limits in U.S.A. waterbodies, while motility was impaired at 50 ug l-1 , which is the more stringent limit set in Brazilian law. Therefore, environment protection agencies must review regulations of glyphosate-based herbicides on water bodies. PMID- 29488227 TI - HBV pre-core mutant in genotype-D infected children is selected during HBeAg/anti HBe seroconversion and leads to HBeAg negative chronic hepatitis B in adulthood. AB - Selection of HBeAg defective HBV mutants (mt) during childhood might influence infection outcome in adults. Aim of this study was to correlate the dynamics of pre-core HBV mutant (pre-C mt) selection with virological/clinical outcomes in children followed-up until adulthood. Eighty subjects (50-M/30-F), 70 HBeAg positive (87.5%), and 10 (12.5%) HBeAg-negative/anti-HBe-positive at the admission, mostly genotype D infected (91.2%), with median age of 6.5 (range: 0.2 17) years, were followed-up for 14.3 years (range: 1.1-24.5); 46 (57.5%) received IFN treatment. HBV-DNA and q-HBsAg were tested by commercial assays, Pre-Core 1896 mt by direct-sequence, oligo-hybridization-assay, and allele-specific-PCR (sensitivity: 30%, 10%, and 0.1% of total viremia). HBeAg/anti-HBe seroconversion (SC) occurred in 55/70 (78.6%) children. After SC, 8 (14.6%) developed HBeAg negative chronic hepatitis (CHB), 41 (74.5%) remain with HBeAg-negative chronic infection, and 6 (10.9%) lost HBsAg. Baseline HBV-DNA and HBsAg were lower in SC than in no-SC children (median: 7.35 vs 8.95 Log IU/mL, P = 0.005, and 4.72 vs 5.04 Log IU/mL, P = 0.015). The prevalence of pre-C mt increased rapidly (10-40%) around SC. Eventually, pre-C mt was detected in 100% of CHB, in 33% of chronic infections without disease, and in 16% of subjects who cleared HBsAg (P < 0.001). HBV-DNA levels remained slightly higher in carriers of HBeAg negative infection with dominant/mixed pre-C mt populations, than in those with dominant pre-C wt (mean Log IU/mL: 3.83 and 3.42 vs 2.67, P = 0.007). In conclusion, pre-C-mt is selected during HBeAg/anti-HBe SC in children with poor control of HBV replication, leading to HBeAg-negative chronic-active-hepatitis during adulthood. PMID- 29488228 TI - Cytochrome P450 2C9-natural antiarthritic interactions: Evaluation of inhibition magnitude and prediction from in vitro data. AB - Many dietary supplements are promoted to patients with osteoarthritis (OA) including the three naturally derived compounds, glucosamine, chondroitin and diacerein. Despite their wide spread use, research on interaction of these antiarthritic compounds with human hepatic cytochrome P450 (CYP) enzymes is limited. This study aimed to examine the modulatory effects of these compounds on CYP2C9, a major CYP isoform, using in vitro biochemical assay and in silico models. Utilizing valsartan hydroxylase assay as probe, all forms of glucosamine and chondroitin exhibited IC50 values beyond 1000 MUM, indicating very weak potential in inhibiting CYP2C9. In silico docking postulated no interaction with CYP2C9 for chondroitin and weak bonding for glucosamine. On the other hand, diacerein exhibited mixed-type inhibition with IC50 value of 32.23 MUM and Ki value of 30.80 MUM, indicating moderately weak inhibition. Diacerein's main metabolite, rhein, demonstrated the same mode of inhibition as diacerein but stronger potency, with IC50 of 6.08 MUM and Ki of 1.16 MUM. The docking of both compounds acquired lower CDOCKER interaction energy values, with interactions dominated by hydrogen and hydrophobic bondings. The ranking with respect to inhibition potency for the investigated compounds was generally the same in both in vitro enzyme assay and in silico modeling with order of potency being diacerein/rhein > various glucosamine/chondroitin forms. In vitro-in vivo extrapolation of inhibition kinetics (using 1 + [I]/Ki ratio) demonstrated negligible potential of diacerein to cause interaction in vivo, whereas rhein was predicted to cause in vivo interaction, suggesting potential interaction risk with the CYP2C9 drug substrates. PMID- 29488229 TI - Nation-wide surveillance of human acute respiratory virus infections between 2013 and 2015 in Korea. AB - The prevalence of eight respiratory viruses detected in patients with acute respiratory infections (ARIs) in Korea was investigated through analysis of data recorded by the Korea Influenza and Respiratory Viruses Surveillance System (KINRESS) from 2013 to 2015. Nasal aspirate and throat swabs specimens were collected from 36 915 patients with ARIs, and viral nucleic acids were detected by real-time (reverse-transcription) polymerase chain reaction for eight respiratory viruses, including human respiratory syncytial viruses (HRSVs), influenza viruses (IFVs), human parainfluenza viruses (HPIVs), human coronaviruses (HCoVs), human rhinovirus (HRV), human adenovirus (HAdV), human bocavirus (HBoV), and human metapneumovirus (HMPV). The overall positive rate of patient specimens was 49.4% (18 236/36 915), 5% of which carried two or more viruses simultaneously. HRV (15.6%) was the most predominantly detected virus, followed by IFVs (14.6%), HAdV (7.5%), HPIVs (5.8%), HCoVs (4.2%), HRSVs (3.6%), HBoV (1.9%), and HMPV (1.6%). Most of the ARIs were significantly correlated with clinical symptoms of fever, cough, and runny nose. Although HRV and HAdV were frequently detected throughout the year in patients, other respiratory viruses showed apparent seasonality. HRSVs and IFVs were the major causative agents of acute respiratory diseases in infants and young children. Overall, this study demonstrates a meaningful relationship between viral infection and typical manifestations of known clinical features as well as seasonality, age distribution, and co-infection among respiratory viruses. Therefore, these data could provide useful information for public health management and to enhance patient care for primary clinicians. PMID- 29488230 TI - Molecular epidemiology of rotavirus gastroenteritis in Japan during 2014-2015: Characterization of re-emerging G2P[4] after rotavirus vaccine introduction. AB - Rotavirus vaccines have been available in Japan since 2011. This study conducted to monitor the trend of group A rotavirus (RVA) genotypes 3 years after vaccine introduction. A total of, 539 fecal samples were collected from children with acute gastroenteritis in six regions during July 2014-June 2015. Among them, 178 samples (33.0%) were positive for RVA. The most predominant genotype was G1P[8] (35.9%) followed by G2P[4] (26.4%), G9P[8] (21.3%), G3P[8] (4.5%), and G3P[9] (4.5%). The detection rate of G2P[4] was increased soon after vaccine introduction. Sequence analyses of VP7 and VP4 genes of the representative G2P[4] strains were found to be clustered in sub-lineage IVa of lineage IV. It is noteworthy that one amino acid substitution in the antigenic epitope (Q114P) of VP4 gene was found in representative G2P[4] strains of the current study. However, it is unclear whether the change in antigenic epitope is due to the effect of vaccination or due to natural variation, warranting further continuous monitoring of rotavirus evolution after vaccine introduction. PMID- 29488232 TI - Quantification of the duodenal eosinophil content in adults: a necessary step for an evidence-based diagnosis of duodenal eosinophilia. AB - BACKGROUND: The normal content of eosinophils in the adult duodenum remains undefined. Therefore, there is no foundation for evidence-based criteria to diagnose eosinophilic duodenitis. AIM: This study aimed at: (1) establishing the range of the eosinophil density in the mucosa of the duodenum of normal adults, and (2) determining the biopsy-based prevalence of isolated eosinophilic duodenitis in a large population of adults. METHODS: We counted intact eosinophils in three separate high-power fields (hpf area = 0.237 mm2 each) with the highest densities of eosinophils from the duodenal biopsy specimens of 370 consecutive adults (60% women) with no history of small intestinal disease and a normal duodenal histology. From a large database we also extracted patients with a diagnosis of elevated duodenal eosinophilia and reviewed their biopsies and clinical history. RESULTS: The mean eosinophil count for the 370 patients was 8.2 eos/hpf with a standard deviation of +/- 6.3. Twenty-seven of the 370 had eosinophil counts outside the 95% range, which was calculated as: mean + 1.96 * SD = 20.4 eos/hpf. In a database of 458 668 adult subjects, 31 patients (6.8/100 000) had elevated duodenal eosinophilia; 21 of these had other gastrointestinal organs involved by eosinophilia, suggesting eosinophilic gastroenteritis. No significant association between duodenal eosinophilia and any specific symptom was observed. CONCLUSIONS: This study suggests that in this diverse US population, a cut-off count of 20 eos/hpf would be useful to separate patients with normal from those with elevated duodenal eosinophilic infiltrations. The clinical implications of duodenal eosinophilia, particularly when it is not an expression of eosinophilic gastroenteritis, remain to be established. PMID- 29488231 TI - The measurement of cognitive reactivity to sad mood in patients remitted from major depressive disorder. AB - OBJECTIVES: Cognitive reactivity (CR) to sad mood is a risk factor for major depressive disorder (MDD). CR is usually measured by assessing change on the Dysfunctional Attitudes Scale (DAS-change) after sad mood-induction. It has, however, been suggested that the versions of the DAS (A/B) are not interchangeable, impacting the reliability and validity of the change score. The Leiden Index of Depression Sensitivity-Revised (LEIDS-R) is an alternative self report measure of CR. Studies examining the relationship between LEIDS-R and DAS change have shown mixed results. We examined whether scores of these CR measures differed between remitted MDD and controls, the relationship between these CR measures, and the effect of order of DAS administration on DAS-change. DESIGN: Cross-sectional design with two groups (remitted MDD and controls). METHODS: Sixty-eight MDD patients remitted from >=2 previous episodes, not taking antidepressants, and 43 never-depressed controls participated in a mood-induction and filled in the DAS-A/B in randomized order before and after mood-induction, and LEIDS-R separately. RESULTS: LEIDS-R scores and pre-mood-induction DAS scores were significantly higher in remitted MDD than controls (p < .001, Cohen's d = 1.48; p = .001, Cohen's d = 0.66, respectively). DAS-change did not differ between these groups (p = .67, Cohen's d = 0.08). LEIDS-R correlated with DAS change (r = .30, p = .042), but only in the group that filled in DAS-B before DAS A. In remitted MDD, DAS-change was dependent on the order of DAS versions before and after mood-induction (10.6 +/- 19.0 vs. -1.2 +/- 10.5, for order B-A and A-B, respectively), with a significant group * order interaction (p = .012). CONCLUSIONS: Existing DAS versions are not interchangeable, which compromises the usefulness of mood-inductions in clinical practice. The LEIDS-R seems a valid measure of cognitive vulnerability to depression. PRACTITIONER POINTS: Clinical implications: Cognitive reactivity (CR) is a risk factor of depressive recurrence. The current measurement of CR, by assessing change on the Dysfunctional Attitudes Scale (DAS) after mood-induction, is not reliable. The Leiden Index Depression Sensitivity-Revised (LEIDS-R) is an alternative CR measure. In contrast to mood-induction, it reliably assesses depression vulnerability. The use of mood-inductions for clinical/research purposes is unnecessary. LIMITATIONS OF THE STUDY: We were not able to examine the effect of previous treatment, which could have affected results as psychological treatments probably have differential effects on CR. Examining un-medicated patients may have led to selection of a sample not completely representative for the general MDD population. We did not administer both parallel versions of the DAS (A/B) before and after mood-induction. This might have provided better understanding of their differential sensitivity to change. PMID- 29488233 TI - Clinician-rated and self-reported psychotic-like experiences in individuals accessing a specialist Youth Mental Health Service. AB - AIM: The prevalence of psychotic-like experiences (PLEs) was explored in a sample of 14- to 25-year-olds with non-psychotic mental health difficulties. Associations between PLEs, psychopathology, functioning, trauma history, and pathways to care were examined. METHODS: Data were collected for 202 young people. Clinicians rated PLEs using the Primary Care Checklist (PCC) and functioning using Global Assessment Scales. Eighty-three young people completed self-report assessments of PLEs using the Prodromal Questionnaire (PQ-16) and measures of social anxiety, depression, trauma history, and pathways to care. RESULTS: There was a high prevalence of PLEs in the sample. The prevalence of PLEs was higher when young people self-rated their experiences. Endorsement frequencies for PLEs ranged from 3.5 to 24% on the PCC and 22 to 70% on the PQ 16. Higher scores on the PQ-16 were associated with more pathways into care and greater exposure to traumatic life events. CONCLUSIONS: PLEs are common in young people with non-psychotic mental health difficulties and may reflect increased severity and complexity of mental health difficulties. Routine screening and further assessment of PLEs are important in understanding and responding to such experiences. Screening should include self-rating of PLEs as well as clinician rated scales. PRACTITIONER POINTS: Clinical Implications Psychotic-like experiences are common in young people with severe non-psychotic mental health problems and should be routinely screened in mental health services. Psychotic like experiences were found to be more prevalent when using a self-report screening tool compared to a clinician-rated measure. The presence of psychotic like experiences may reflect more severe and complex mental health problems and may also cause delays in young people accessing the right kind of support. ;Limitations This study only assessed the presence or absence of psychotic-like experiences. Further studies should use more detailed assessments to understand more about the nature of such experiences and how they are appraised and responded to. This study is cross-sectional, and therefore, the direction of the relationships between psychotic-like experiences and depression, anxiety, functioning, and trauma cannot be specified. Longitudinal studies are needed to examine the impact of psychotic-like experiences on long-term outcomes. PMID- 29488234 TI - Framing a 'social problem': Emotion in anti-abortion activists' depiction of the abortion debate. AB - Social psychological research on activism typically focuses on individuals' social identifications. We complement such research through exploring how activists frame an issue as a social problem. Specifically, we explore anti abortion activists' representation of abortion and the abortion debate's protagonists so as to recruit support for the anti-abortion cause. Using interview data obtained with UK-based anti-abortion activists (N = 15), we consider how activists characterized women having abortions, pro-abortion campaigners, and anti-abortion campaigners. In particular, we consider the varied ways in which emotion featured in the representation of these social actors. Emotion featured in different ways. Sometimes, it was depicted as constituting embodied testament to the nature of reality. Sometimes, it was depicted as blocking the rational appraisal of reality. Our analysis considers how such varied meanings of emotion shaped the characterization of abortion and the abortion debate's protagonists such that anti-abortion activists were construed as speaking for women and their interests. We discuss how our analysis of the framing of issues as social problems complements and extends social psychological analyses of activism. PMID- 29488235 TI - Characterization of imatinib mesylate formulations distributed in South American countries: Determination of genotoxic impurities by UHPLC-MS/MS and dissolution profile. AB - Imatinib mesylate (IM) is an anti-neoplasic drug used for the treatment of cancer. Recent new guidelines specify daily doses and concentration limits for genotoxic impurities (GTIs) in pharmaceutical final products. Therefore, in this work an analytical method using UHPLC-MS/MS was developed, validated and applied to characterize IM tablets for two GTIs: N-(2-methyl-5-aminophenyl)-4-(3-pyridyl) 2-pyrimidine amine (Imp. 1), and N-[4-methyl-3-(4-methyl-3-yl-pyrimidin-2 ylamino)-phenyl]-4- chloromethyl benzamide (Imp. 2), simultaneously. Additionally, dissolution data of IM tablets were compared using a methodology recommended by the US Food and Drug Administration. The UHPLC method utilized an Acquity BEH C18 (150 * 2.1 mm, 1.7 MUm) maintained at 40 degrees C. The mobile phase consisted of ammonium formate 0.063% (phase A) and acetonitrile plus 0.05% formic acid (phase B) in gradient elution. A sensitive method for determination of previously mentioned GTIs in IM tablets was successfully developed and applied. Overall, the formulations analyzed in this work showed low levels of Imp. 1 and Imp. 2. However, the sample named D1 showed very high levels of Imp. 1 and failed to meet the requirements established by the US Food and Drug Administration for dissolution data. Periodic verification of GTIs in pharmaceutical formulations is important to minimize safety risks, so analytical methods to determine it need be available and implemented in routine analysis. PMID- 29488236 TI - Distorted weight perception correlates with disordered eating attitudes in Kuwaiti college women. AB - OBJECTIVE: We investigated the presence of disordered eating attitudes and weight perception among young women at body mass index (BMI) values that correspond to underweight, normal weight, overweight, and obese weight status. METHOD: Data were collected from 1,147 female undergraduate students (89% Kuwaiti nationals) recruited from Kuwait University through employment of the eating attitude test (EAT-26) together with an anonymous, self-administered questionnaire to determine the prevalence of symptomatology indicative of anorexia nervosa and bulimia nervosa. RESULTS: The mean EAT-26 scores differed significantly between the weight categories. More students with overweight and obesity scored above the established EAT-26 cut off value indicating at risk of disordered eating compared to students who were at a normal weight or underweight (52.1% vs. 38.8%, respectively, X2 (1) =16.1, p < .001). Logistic regression analyses showed significantly higher odds ratios (ORs) for the groups with overweight and obesity for dieting and bulimic behaviors, while women at normal and underweight had higher ORs for restrictive oral control behaviors associated with anorexia nervosa. Distorted weight perception was found in all weight categories. DISCUSSION: The high proportion of disordered eating attitudes among Kuwaiti college women could not be attributed to obesity alone as the type of disordered eating behavior varied more by weight perception than by weight status. The high levels of eating disorder related symptoms could be due to a combination of the social influences, diet, and lifestyle of college students. Such factors need to be considered by healthcare professionals as early as possible with more focused programs towards promotion of healthy weight for college students. PMID- 29488237 TI - The use of cytapheresis in the treatment of infectious diseases. AB - Cytapheresis (removal of cellular blood components) has been employed for treatment of infectious diseases since the 1960s. Techniques have included thrombocytapheresis (buffy coat apheresis) for loiasis, erythrocytapheresis for malaria and babesiosis, and leukocytapheresis for pertussis-associated lymphocytosis. Published data on these applications is largely limited to case level data and small observational studies; as such, recommendations for or against the use of cytapheresis in the treatment of infections have been extrapolated from these limited (and at times flawed) data sets. Consequently, utilization of cytapheresis in many instances is not uniform between institutions, and typically occurs at the discretion of treating medical teams. This review revisits the existing literature on the use of cytapheresis in the treatment of four infections (loasis, malaria, babesiosis, and pertussis) and examines the rationale underlying current treatment recommendations concerning its use. PMID- 29488238 TI - Potencies of vitamin D analogs, 1alpha-hydroxyvitamin D3 , 1alpha-hydroxyvitamin D2 and 25-hydroxyvitamin D3 , in lowering cholesterol in hypercholesterolemic mice in vivo. AB - Vitamin D3 and the synthetic vitamin D analogs, 1alpha-hydroxyvitamin D3 [1alpha(OH)D3 ], 1alpha-hydroxyvitamin D2 [1alpha(OH)D2 ] and 25-hydroxyvitamin D3 [25(OH)D3 ] were appraised for their vitamin D receptor (VDR) associated potencies as cholesterol lowering agents in mice in vivo. These precursors are activated in vivo: 1alpha(OH)D3 and 1alpha(OH)D2 are transformed by liver CYP2R1 and CYP27A1 to active VDR ligands, 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2 D3 ] and 1alpha,25-dihydroxyvitamin D2 [1,25(OH)2 D2 ], respectively. 1alpha(OH)D2 may also be activated by CYP24A1 to 1alpha,24-dihydroxyvitamin D2 [1,24(OH)2 D2 ], another active VDR ligand. 25(OH)D3 , the metabolite formed via CYP2R1 and or CYP27A1 in liver from vitamin D3 , is activated by CYP27B1 in the kidney to 1,25(OH)2 D3 . In C57BL/6 mice fed the high fat/high cholesterol Western diet for 3 weeks, vitamin D analogs were administered every other day intraperitoneally during the last week of the diet. The rank order for cholesterol lowering, achieved via mouse liver small heterodimer partner (Shp) inhibition and increased cholesterol 7alpha-hydroxylase (Cyp7a1) expression, was: 1.75 nmol/kg 1alpha(OH)D3 > 1248 nmol/kg 25(OH)D3 (dose ratio of 0.0014) > > 1625 nmol/kg vitamin D3 . Except for 1.21 nmol/kg 1alpha(OH)D2 that failed to lower liver and plasma cholesterol contents, a significant negative correlation was observed between the liver concentration of 1,25(OH)2 D3 formed from the precursors and liver cholesterol levels. The composite results show that vitamin D analogs 1alpha(OH)D3 and 25(OH)D3 exhibit cholesterol lowering properties upon activation to 1,25(OH)2 D3 : 1alpha(OH)D3 is rapidly activated by liver enzymes and 25(OH)D3 is slowly activated by renal Cyp27b1 in mouse. PMID- 29488239 TI - Risk of intraocular and other extracutaneous involvement in patients with cutaneous juvenile xanthogranuloma. AB - BACKGROUND/OBJECTIVES: Cutaneous juvenile xanthogranuloma is an uncommon, usually benign disease affecting infants and young children. Ocular and other systemic involvement have been reported, but their incidence is unclear, and the utility of routine screening is not well established. Our aim was to characterize the risk of ocular and systemic complications in children with cutaneous juvenile xanthogranuloma. METHODS: In this retrospective study, we reviewed the medical charts of children with cutaneous juvenile xanthogranuloma seen at Ann and Robert H. Lurie Children's Hospital, Chicago, Illinois, between January 2000 and December 2015. A comprehensive literature review was also performed. RESULTS: Of 338 children with cutaneous juvenile xanthogranuloma, 76 (median age 6 months, 51% female) met inclusion criteria. The most frequently involved site was the head and neck region (40%). In 39 patients (51%), there was a single lesion. Multiple lesions (>5) were evident in 20 patients (26%). Most cutaneous juvenile xanthogranulomas were micronodular (77%). None of the patients had ocular involvement. One patient had multiple asymptomatic hepatic nodules on imaging that regressed spontaneously within several months. Literature review of pediatric cutaneous juvenile xanthogranuloma series, including our cohort, revealed that the incidence of ocular manifestations is 0.24% (7/2949) and of systemic manifestations is 0.75% (22/2949). CONCLUSION: Cutaneous juvenile xanthogranulomas are generally limited to the skin. Because eye involvement is rare, a routine eye examination is of low yield and probably not warranted in children with no ocular or visual symptoms. New recommendations for systemic screening could not be drawn from this study. PMID- 29488240 TI - Optical and pharmacological strategies of myopia control. AB - Recent increases in global myopia prevalence rates have raised significant concerns as myopia increases the lifelong risk of various sight-threatening ocular conditions. This growing public health burden has generated significant research interests into understanding both its aetiology and developing effective methods to slow down or stop its development, methods collectively termed 'myopia control'. The growing body of research has demonstrated benefits of various optical and pharmacological treatments resulting in myopia control management increasingly becoming a part of main stream clinical practice. This review will discuss the peer-reviewed literature on the efficacy of various myopia control interventions including multifocal spectacles and contact lenses, orthokeratology and pharmaceutical eye drops, as well as potential future research directions. PMID- 29488241 TI - Acquired perforating collagenosis in a non-diabetic patient with advanced prostate carcinoma: A review of perforating dermatosis associated with malignancy. PMID- 29488242 TI - Familial papular epidermal nevus with "skyline" basal cell layer and multiple pilomatricomas: A new association? AB - Papular epidermal nevus with "skyline" basal cell layer is a newly described keratinocytic nevus. Recently, papular epidermal nevus with "skyline" basal cell layer has been reported in association with extracutaneous involvement, and the term papular epidermal nevus with "skyline" basal cell layer syndrome is used to indicate a neurocutaneous syndrome characterized by the presence of papular epidermal nevus with "skyline" basal cell layer and different neurologic symptoms that seem to improve during infancy and adolescence. Multiple pilomatricomas have been reported in association with various syndromes. We report herein papular epidermal nevus with "skyline" basal cell layer associated with multiple pilomatricomas in two members of a family with the aim of drawing attention to this peculiar epidermal nevus to improve our knowledge of the syndrome. PMID- 29488243 TI - HLA-DRB1*04:05 in two cases of Vogt-Koyanagi-Harada disease-like uveitis developing from an advanced melanoma patient treated by sequential administration of nivolumab and dabrafenib/trametinib therapy. AB - Although uveitis is reported as a rare adverse event (AE) associated with dabrafenib/trametinib therapy or nivolumab, the occurrence of severe uveitis is extremely rare. We describe two cases of Vogt-Koyanagi-Harada (VKH)-like uveitis developing after the sequential administration of nivolumab and dabrafenib/trametinib therapy. Interestingly, both cases had HLA-DRB1*04:05, which is strongly associated with VKH disease, and achieved biologically complete remission after the treatment for uveitis. Our cases suggest a possible correlation between VKH-like uveitis as an AE and the clinical outcomes of sequential administration of nivolumab and dabrafenib/trametinib therapy for the treatment of advanced melanoma. PMID- 29488245 TI - In-vivo patellar tracking in individuals with patellofemoral pain and healthy individuals. AB - Understanding of the exact cause of patellofemoral pain has been limited by methodological challenges to evaluate in-vivo joint motion. This study compared six degree-of-freedom patellar motion during a dynamic lunge task between individuals with patellofemoral pain and healthy individuals. Knee joints of eight females with patellofemoral pain and ten healthy females were imaged using a CT scanner in supine lying position, then by a dual-orthogonal fluoroscope while they performed a lunge. To quantify patellar motion, the three-dimensional models of the knee bones, reconstructed from CT scans, were registered on the fluoroscopy images using the Fluomotion registration software. At full knee extension, the patella was in a significantly laterally tilted (PFP: 11.77 degrees +/- 7.58 degrees vs. healthy: 0.86 degrees +/- 4.90 degrees ; p = 0.002) and superiorly shifted (PFP: 17.49 +/- 8.44 mm vs. healthy: 9.47 +/- 6.16 mm, p = 0. 033) position in the patellofemoral pain group compared with the healthy group. There were also significant differences between the groups for patellar tilt at 45 degrees , 60 degrees , and 75 degrees of knee flexion, and for superior-inferior shift of the patella at 30 degrees flexion (p <= 0.031). In the non-weight-bearing knee extended position, the patella was in a significantly laterally tilted position in the patellofemoral pain group (7.44 degrees +/- 6.53 degrees ) compared with the healthy group (0.71 degrees +/- 4.99 degrees ). These findings suggest the critical role of passive and active patellar stabilizers as potential causative factors for patellar malalignment/maltracking. Future studies should investigate the associations between patellar kinematics with joint morphology, muscle activity, and tendon function in a same sample for a thorough understanding of the causes of patellofemoral pain. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res. PMID- 29488244 TI - In vivo hyperpolarization transfer in a clinical MRI scanner. AB - PURPOSE: The purpose of this study was to investigate the feasibility of in vivo 13 C->1 H hyperpolarization transfer, which has significant potential advantages for detecting the distribution and metabolism of hyperpolarized 13 C probes in a clinical MRI scanner. METHODS: A standalone pulsed 13 C RF transmit channel was developed for operation in conjunction with the standard 1 H channel of a clinical 3T MRI scanner. Pulse sequences for 13 C power calibration and polarization transfer were programmed on the external hardware and integrated with a customized water-suppressed 1 H MRS acquisition running in parallel on the scanner. The newly developed RF system was tested in both phantom and in vivo polarization transfer experiments in 1 JCH -coupled systems: phantom experiments in thermally polarized and hyperpolarized [2-13 C]glycerol, and 1 H detection of [2-13 C]lactate generated from hyperpolarized [2-13 C]pyruvate in rat liver in vivo. RESULTS: Operation of the custom pulsed 13 C RF channel resulted in effective 13 C->1 H hyperpolarization transfer, as confirmed by the characteristic antiphase appearance of 1 H-detected, 1 JCH -coupled doublets. In conjunction with a pulse sequence providing 190-fold water suppression in vivo, 1 H detection of hyperpolarized [2-13 C]lactate generated in vivo was achieved in a rat liver slice. CONCLUSION: The results show clear feasibility for effective 13 C->1 H hyperpolarization transfer in a clinical MRI scanner with customized heteronuclear RF system. PMID- 29488246 TI - Unusual association between digital mucous cyst and acquired ungual fibrokeratoma: A case report. PMID- 29488247 TI - Selective measurement of 1 H-1 H scalar couplings from crowded chemical shift regions: Combined pure shift and spin-echo modulation approach. AB - JHH scalar couplings carry rich structural information and their measurements are fundamental in the 1 H NMR based elucidation of small and medium molecules, which, however, are hampered in the presence of large J-coupling network. Further, enhanced spectral resolution is often essential for precise determination of a specific set of 1 H-1 H J-couplings among the complex J multiplets. In the light of the recent advancements in homodecoupling pure shift strategies, here, we report absorption mode, band-selective refocused pure shift spin-echo method, which helps in determining 1 H-1 H J-couplings from crowded spectral regions. The importance of the present band-selective refocused pure shift spin-echo experiment is exemplified for 2 steroid molecules, estradiol and testosterone. PMID- 29488248 TI - Case of pyoderma gangrenosum-like sporotrichosis caused by Sporothrix globosa in a patient with ulcerative colitis. PMID- 29488249 TI - Hypothesis tests for stratified mark-specific proportional hazards models with missing covariates, with application to HIV vaccine efficacy trials. AB - This article develops hypothesis testing procedures for the stratified mark specific proportional hazards model with missing covariates where the baseline functions may vary with strata. The mark-specific proportional hazards model has been studied to evaluate mark-specific relative risks where the mark is the genetic distance of an infecting HIV sequence to an HIV sequence represented inside the vaccine. This research is motivated by analyzing the RV144 phase 3 HIV vaccine efficacy trial, to understand associations of immune response biomarkers on the mark-specific hazard of HIV infection, where the biomarkers are sampled via a two-phase sampling nested case-control design. We test whether the mark specific relative risks are unity and how they change with the mark. The developed procedures enable assessment of whether risk of HIV infection with HIV variants close or far from the vaccine sequence are modified by immune responses induced by the HIV vaccine; this question is interesting because vaccine protection occurs through immune responses directed at specific HIV sequences. The test statistics are constructed based on augmented inverse probability weighted complete-case estimators. The asymptotic properties and finite-sample performances of the testing procedures are investigated, demonstrating double robustness and effectiveness of the predictive auxiliaries to recover efficiency. The finite-sample performance of the proposed tests are examined through a comprehensive simulation study. The methods are applied to the RV144 trial. PMID- 29488250 TI - The M2 triangle: gp130 binding cytokines drive macrophages to promote tumor growth. PMID- 29488251 TI - Time-resolved contrast-enhanced MR angiography with single-echo Dixon fat suppression. AB - PURPOSE: Dixon-based fat suppression has recently gained interest for dynamic contrast-enhanced MRI, but multi-echo techniques require longer scan times and reduce temporal resolution compared to single-echo alternatives without fat suppression. The purpose of this work is to demonstrate accelerated single-echo Dixon imaging with high spatial and temporal resolution. THEORY AND METHODS: Real valued water and fat images can be obtained from a single measurement if the shared initial phase and that due to DeltaB0 are assumed known a priori. An expression for simultaneous sensitivity encoding (SENSE) unfolding and fat-water separation is derived for the general undersampling case, and simplified under the special case of uniform Cartesian undersampling. In vivo experiments were performed in extremities and brain with SENSE acceleration factors of up to R = 8. RESULTS: Single-echo Dixon reconstruction of highly undersampled data was successfully demonstrated. Dynamic contrast-enhanced water and fat images provided high spatial and temporal resolution dynamic images with image update times shorter than previous single-echo Dixon work. CONCLUSION: Time-resolved contrast-enhanced MRI with single-echo Dixon fat suppression shows high image quality, improved vessel delineation, and reduced sensitivity to motion when compared to time-subtraction methods. PMID- 29488253 TI - Visual problems associated with traumatic brain injury. AB - Traumatic brain injury (TBI) and its associated concussion are major causes of disability and death. All ages can be affected but children, young adults and the elderly are particularly susceptible. A decline in mortality has resulted in many more individuals living with a disability caused by TBI including those affecting vision. This review describes: (1) the major clinical and pathological features of TBI; (2) the visual signs and symptoms associated with the disorder; and (3) discusses the assessment of quality of life and visual rehabilitation of the patient. Defects in primary vision such as visual acuity and visual fields, eye movement including vergence, saccadic and smooth pursuit movements, and in more complex aspects of vision involving visual perception, motion vision ('akinopsia'), and visuo-spatial function have all been reported in TBI. Eye movement dysfunction may be an early sign of TBI. Hence, TBI can result in a variety of visual problems, many patients exhibiting multiple visual defects in combination with a decline in overall health. Patients with chronic dysfunction following TBI may require occupational, vestibular, cognitive and other forms of physical therapy. Such patients may also benefit from visual rehabilitation, including reading-related oculomotor training and the prescribing of spectacles with a variety of tints and prism combinations. PMID- 29488252 TI - Benzodiazepine and Z-drug prescribing in Ireland: analysis of national prescribing trends from 2005 to 2015. AB - AIMS: The aim of this study was to examine prescribing trends for benzodiazepines and Z-drugs to General Medical Services (GMS) patients in Ireland. METHODS: A repeated cross-sectional analysis of the national pharmacy claims database was conducted for GMS patients aged >=16 years from 2005 to 2015. Prescribing rates per 1000 eligible GMS population were calculated with 95% confidence intervals (CIs). Negative binomial regression was used to determine longitudinal trends and compare prescribing rates across years, gender and age groups. Duration of supply and rates of concomitant benzodiazepine and Z-drug prescribing were determined. Age (16-44, 45-64, >=65 years) and gender trends were investigated. RESULTS: Benzodiazepine prescribing rates decreased significantly from 225.92/1000 population (95% CI 224.94-226.89) in 2005 to 166.07/1000 population (95% CI 165.38-166.75) in 2015 (P < 0.0001). Z-drug prescribing rates increased significantly from 95.36/1000 population (95% CI 94.73-96.00) in 2005 to 109.11/1000 population (95% CI 108.56-109.67) in 2015 (P = 0.048). Approximately one-third of individuals dispensed either benzodiazepines or Z-drugs were receiving long-term prescriptions (>90 days). The proportion of those receiving >1 benzodiazepine and/or Z-drug concomitantly increased from 11.9% in 2005 to 15.3% in 2015. Benzodiazepine and Z-drug prescribing rates were highest for older women (>=65 years) throughout the study period. CONCLUSIONS: Benzodiazepine prescribing to the GMS population in Ireland decreased significantly from 2005 to 2015, and was coupled with significant increases in Z-drug prescribing. The study shows that benzodiazepine and Z-drug prescribing is common in this population, with high proportions of individuals receiving long-term prescriptions. Targeted interventions are needed to reduce potentially inappropriate long-term prescribing and use of these medications in Ireland. PMID- 29488254 TI - Quantitative evaluation of early retinal changes in children with type 1 diabetes mellitus without retinopathy. AB - BACKGROUND: To investigate whether abnormal glucose metabolism and duration of diabetes mellitus (DM) caused the thinning in retinal layers in children with type 1 DM without retinopathy by using spectral domain optical coherence tomography (SD-OCT) and to compare the results obtained with those in healthy children. METHODS: This cross-sectional prospective study included 73 patients with type 1 DM (DM group) and 62 age-matched control subjects (control group). The duration of DM and the glycosylated haemoglobin (HbA1c) levels of the diabetic children were recorded. Macular and peripapillary retinal nerve fibre layer (RNFL) thickness measurements obtained by SD-OCT were compared. RESULTS: There were significant differences in the mean values of the temporal inner, temporal outer and inferior outer macular thickness measurements between the groups (p = 0.031, p = 0.028 and p = 0.039, respectively). Moreover, the children with type 1 DM showed significantly thinner global, temporal superior and nasal inferior RNFL thickness measurements compared to the controls (p = 0.035, p = 0.022 and p = 0.034, respectively). Additionally, both the mean duration of DM and the mean HbA1c values were inversely and statistically significantly correlated with the mean temporal outer macular thickness and global RNFL thickness measurements in the DM group. CONCLUSIONS: Retinal neural changes, which can be shown by SD-OCT, may be present in diabetic eyes even before clinically detectable retinal vasculopathy. Macular and RNFL thickness measurements might be useful indicators for early detection of diabetic retinopathy in the future. PMID- 29488255 TI - Multicolor Upconversion Nanoprobes Based on a Dual Luminescence Resonance Energy Transfer Assay for Simultaneous Detection and Bioimaging of [Ca2+ ]i and pHi in Living Cells. AB - Intracellular [Ca2+ ]i and pHi have a close relationship, and their abnormal levels can result in cell dysfunction and accompanying diseases. Thus, simultaneous determination of [Ca2+ ]i and pHi can more accurately investigate complex biological processes in an integrated platform. Herein, multicolor upconversion nanoparticles (UCNPs) were prepared with the advantages of no spectral overlapping, single NIR excitation wavelengths, and greater tissue penetration depth. The upconversion nanoprobes were easily prepared by the attachment of two fluorescent dyes, Fluo-4 and SNARF-4F. Based on the dual luminescence resonance energy transfer (LRET) process, the blue and green fluorescence of the UCNPs were specially quenched and selectively recovered after the detachment and/or absorbance change of the attached fluorescent dyes, enabling dual detection. Importantly, the developed nanoprobe could successfully be applied for the detection of [Ca2+ ]i and pHi change in adenosine triphosphate (ATP) and ethylene glycol tetraacetic acid (EGTA) stimulation in living cells. PMID- 29488256 TI - Effects of acidification on the isotopic ratios of Neotropical otter tooth dentin. AB - RATIONALE: Stable carbon and nitrogen isotope ratios are widely used in ecological studies providing important information on the trophic ecology and habitat use of consumers. However, some factors may lead to isotopic variability, which makes difficult the interpretation of data, such as the presence of inorganic carbon in mineralized tissues. In order to remove the inorganic carbon, acidification is a commonly used treatment. METHODS: The effects of two methods of acidification were tested: (i) dentin acidification with 10% HCl using the 'drop-by-drop' technique, and (ii) dentin acidification in an 'HCl atmosphere', by exposing the dentin to vaporous 30% hydrochloric acid. Results were compared with untreated subsamples. The stable carbon and nitrogen ratios of untreated and acidified subsamples were measured using an elemental analyzer coupled to an isotope ratio mass spectrometer. RESULTS: The nitrogen isotopic ratios were statistically different between the two acidification treatments, but no significant changes in carbon isotopic ratios were found in acidified and untreated samples. CONCLUSIONS: The results indicated that acidification had no effect on carbon isotopic ratios of Neotropical otter tooth dentin, while introducing a source of error in nitrogen isotopic ratios. Therefore, we conclude that acidification is an unnecessary step for C and N stable isotope analysis. PMID- 29488257 TI - Animal models of l-dopa-induced dyskinesia in Parkinson's disease. AB - Understanding the biological mechanisms of l-dopa-induced motor complications is dependent on our ability to investigate these phenomena in animal models of Parkinson's disease. The most common motor complications consist in wearing-off fluctuations and abnormal involuntary movements appearing when plasma levels of l dopa are high, commonly referred to as peak-dose l-dopa-induced dyskinesia. Parkinsonian models exhibiting these features have been well-characterized in both rodent and nonhuman primate species. The first animal models of peak-dose l dopa-induced dyskinesia were produced in monkeys lesioned with N-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) and treated chronically with l-dopa to elicit choreic movements and dystonic postures. Seminal studies were performed in these models using both metabolic mapping and electrophysiological techniques, providing fundamental pathophysiological insights that have stood the test of time. A decade later, it was shown possible to reproduce peak-dose l-dopa-induced dyskinesia in rats and mice rendered parkinsonian with nigrostriatal 6 hydroxydopamine lesions. When treated with l-dopa, these animals exhibit abnormal involuntary movements having both hyperkinetic and dystonic components. These models have enabled molecular- and cellular-level investigations into the mechanisms of l-dopa-induced dyskinesia. A flourishing literature using genetically engineered mice is now unraveling the role of specific genes and neural circuits in the development of l-dopa-induced motor complications. Both non-human primate and rodent models of peak-dose l-dopa-induced dyskinesia have excellent construct validity and provide valuable tools for discovering therapeutic targets and evaluating potential treatments. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29488258 TI - An Expeditious Route to trans-Configured Tetrahydrothiophenes Enabled by Fe(OTf)3 -Catalyzed [3+2] Cycloaddition of Donor-Acceptor Cyclopropanes with Thionoesters. AB - A synthetic route to trans-configured tetrahydrothiophenes (THTs) through Fe(OTf)3 -promoted [3+2] cycloaddition of donor-acceptor cyclopropanes with thionoesters was developed. The cycloaddition proceeded in high yield with high diastereoselectivity, affording transient alpha-alkoxy THTs. Not only aromatic and aliphatic thionoesters, but also thionolactone were applicable to the present iron catalysis. Further transformation of the S,O-ketal functionality of the product was achieved in a highly trans diastereoselective manner. Moreover, the utility of our methodology was clearly demonstrated by the synthesis of enantioenriched trans-configured THTs. PMID- 29488259 TI - The role of socioeconomic status in the relationship between detention and self rated health among prison detainees in Belgium. AB - Prisoners are known to report worse health than the general population. Research has also shown that the prison population counts disproportionally more people with a lower socioeconomic status (SES), making it difficult to determine whether the worse self-reported health of prisoners is an effect of their detention or of their lower SES. This study assesses the influence of being in prison on self rated health and if (and how) this relationship is mediated by SES. Data from detainees were collected in 12 Flemish prisons. To compare with the general population, data from the Belgian national health survey 2013 were used. To estimate the direct and indirect effect of being in prison on self-reported health, mediation analysis was carried out by means of natural effect models using nested counterfactuals. Following previous literature we find that prisoners report worse health than the general population and that SES has a significant influence on subjective health. Our results showed that the direct effect (exp(B) = 3.43; [95% CI: 2.924-4.024]) of being in prison on self-reported health is larger than the indirect effect (through SES) (exp(B) = 1,236; [95% CI: 1.195-1.278]), thus contradicting the hypotheses in previous literature that the SES is the main explanation for variation in self-reported health among prisoners. Lastly, the effect of SES on health is more important for the general population compared to detainees, suggesting that for prisoners the effect of being in prison seems to surpass the effect of SES on health. PMID- 29488260 TI - Climate change, disease range shifts, and the future of the Africa lion. PMID- 29488261 TI - Usefulness of ascites cytology for the evaluation of chemotherapy response in ovarian carcinosarcoma. PMID- 29488262 TI - Communicating laboratory results through a Web site: Patients' priorities and viewpoints. AB - BACKGROUND: Patients can access laboratory results using various technologies. The aim of this study was to integrate the laboratory results into the hospital Web site based on patients' viewpoints and priorities and to measure patients' satisfaction. METHODS: This descriptive-analytical study was conducted in 2015. First, a questionnaire was distributed among 200 patients to assess patients' priorities to receive laboratory results through the Web site. Second, those who agreed (n = 95) to receive their laboratory results through the Web site were identified. Then, the required changes were made to the hospital Web site based on patients' viewpoints and priorities. Third, patients were divided into two groups. The first group received their laboratory results through the Web site on the date had been announced during their visit to the laboratory. The second group was informed by SMS once their results were shown on the Web site. After receiving laboratory results, patients' satisfaction was evaluated. RESULTS: More than half of the participants (n = 53, 55.8%) were highly satisfied with receiving the results electronically. The higher number of people in SMS group (n = 9, 20.9%) reported that they were satisfied with time-saving compared to other group (n = 2, 3.8%) (P = .04). Participants after receiving the results through the Web site considered the functionalities of reprinting (P < .0001) and timeliness (P = .017) more important. CONCLUSION: Integrating laboratory results into the hospital Web site based on the patients' viewpoints and priorities can improve patient satisfaction and lower the patients' concern regarding confidentiality of their results. PMID- 29488263 TI - High-Density Stretchable Electrode Grids for Chronic Neural Recording. AB - Electrical interfacing with neural tissue is key to advancing diagnosis and therapies for neurological disorders, as well as providing detailed information about neural signals. A challenge for creating long-term stable interfaces between electronics and neural tissue is the huge mechanical mismatch between the systems. So far, materials and fabrication processes have restricted the development of soft electrode grids able to combine high performance, long-term stability, and high electrode density, aspects all essential for neural interfacing. Here, this challenge is addressed by developing a soft, high density, stretchable electrode grid based on an inert, high-performance composite material comprising gold-coated titanium dioxide nanowires embedded in a silicone matrix. The developed grid can resolve high spatiotemporal neural signals from the surface of the cortex in freely moving rats with stable neural recording quality and preserved electrode signal coherence during 3 months of implantation. Due to its flexible and stretchable nature, it is possible to minimize the size of the craniotomy required for placement, further reducing the level of invasiveness. The material and device technology presented herein have potential for a wide range of emerging biomedical applications. PMID- 29488264 TI - Silylative Reductive Amination of alpha,beta-Unsaturated Aldehydes: A Convenient Synthetic Route to beta-Silylated Secondary Amines. AB - Described here is a reductive amination/hydrosilylation cascade of alpha,beta unsaturated aldehydes mediated by a Lewis acidic borane catalyst. The present reaction system provides an one-pot synthetic route towards beta-silylated secondary amines that have not been accessible by other previous catalysis. Comparative 1 H NMR studies on the silylative reduction of enimines revealed that steric bulkiness of primary amine reactants strongly affects both catalytic efficiency and regioselectivity. This strategy was applicable to a broad range of substrates and amenable to one-pot gram-scale synthesis. Moreover, a diastereoselective introduction of the beta-silyl group was also found to be feasible (d.r. up to 71:29). PMID- 29488265 TI - Beta-propeller-associated neurodegeneration can present with dominant or isolated parkinsonism. PMID- 29488266 TI - A survey of tobacco dependence treatment guidelines content in 61 countries. AB - AIMS: To assess tobacco dependence treatment guidelines content in accordance with Article 14 of the World Health Organization (WHO) Framework Convention on Tobacco Control (FCTC) and its guidelines, and association between content and country income level. DESIGN: Cross-sectional study. SETTING: On-line survey from March to July 2016. PARTICIPANTS: Contacts in 77 countries, including 68 FCTC Parties, six Signatories and three non-Parties which had indicated having guidelines in previous surveys, or had not been surveyed before. MEASUREMENTS: A nine-item questionnaire on guidelines content, key recommendations, writing and dissemination. FINDINGS: We received responses from contacts in 63 countries (82%); 61 had guidelines. The majority are for doctors (93%), primary care (92%) and nurses (75%). All recommend brief advice, 82% recording tobacco use in medical notes, 98% nicotine replacement therapy (NRT), 61% quitlines, 31% text messaging and 87% intensive specialist support, and 54% stress the importance of health-care workers not using tobacco. Only 57% have a dissemination strategy, and 62% have not been updated for 5 or more years. Compared with high-income countries, quitlines are less likely to be recommended in upper middle-income countries guidelines [odds ratio (OR) = 0.15, 95% confidence interval (CI) = 0.04 0.61] and intensive specialist support in lower middle-income countries guidelines (OR = 0.01, 95% CI = 0.00-0.20). Guidelines updating is associated positively with country income level (P = 0.027). CONCLUSIONS: Although most tobacco dependence treatment guidelines in the 61 countries assessed in 2016 follow the World Health Organization's Framework Convention on Tobacco Control Article 14 recommendations and do not differ significantly by income level, improvements are needed in keeping guidelines up-to-date, applying good writing practices and developing a dissemination strategy. PMID- 29488267 TI - A Fast, Reversible, and Robust Gradient Nanocomposite Hydrogel Actuator with Water-Promoted Thermal Response. AB - Poly(N-isopropylacrylamide)/Laponite (PNIPAM/Laponite) gradient nanocomposite hydrogel actuators are developed as temperature-controlled actuators with excellent performance using a facile electrophoresis method. The actuators exhibit a rapid (20 s response time) and reversible response, as well as large deformation (bending angle of 231 degrees ), which is due to the graded forces generated by the thermo-induced anisotropic shrinkage and extension of the gradient hydrogels. A good linear relationship is observed between the maximum bending angles and the corresponding temperatures for the actuators with fixed sizes. Moreover, the gradient hydrogel with high water content achieved larger actuation angles and shorter response time than the one with low water content, showing an interesting water-promoted effect. Meanwhile, different types of actuators are designed to suit for more specific scenarios, and may be used for various applications, such as biosensing, artificial organization, and transportation of targeted objects. PMID- 29488268 TI - Trends in the use of illicit substances in Thailand: Results from national household surveys. AB - INTRODUCTION AND AIMS: Thailand borders some of the world's largest methamphetamine and opioid producing countries and trafficking routes. Thailand's 'War on Drugs' campaign was launched in 2003. This study reports trends in illicit substance use in Thailand over the period 2001-2011. DESIGN AND METHODS: National Household surveys on illicit drug use were conducted in 2001, 2003, 2007, 2008 and 2011. A stratified multi-stage cluster random sampling technique was implemented for each survey. Provinces in four regions were systematically selected using a probability proportionate to the size of the targeted population. Participants were interviewed using structured questionnaires on their history of substance use. RESULTS: The prevalence of illicit drug use within the past drastically decreased from 4.5% in 2001 to 1.0% in 2003 (P < 0.05). Since 2003, the prevalence of illicit use within the past year varied between 1.0% and 1.3%. By 2011, it was estimated that 0.84% have used kratom (a substance derived from Mitragyna speciosa) within the past year. Around 0.20% and 0.19% reported using cannibis and yaba (metamphetamine tablet) within a year of the 2011 survey. Other types of illicit drugs were less commonly used in Thailand. DISCUSSION AND CONCLUSIONS: There was a decrease in prevalence of illicit drug use within the past year between 2001 and 2003 in Thailand. Since 2003, the past year prelavence of illicit drug use has remained relatively stable. From 2001 to 2011, cannabis, kratom and yaba have remained the three most commonly reported types of illicit drugs used in Thailand. PMID- 29488269 TI - Characteristic findings of cervical Papanicolaou tests from transgender patients on androgen therapy: Challenges in detecting dysplasia. AB - INTRODUCTION: The characteristic features of Papanicolaou (Pap) tests collected from female-to-male (FTM) transgender patients on androgen therapy have not been well defined in the literature. FTM transgender patients require cervical cancer screening with the same recommended frequency as cis-gender females. Dysplasia remains challenging to differentiate from atrophy. Without pertinent history, the atrophic findings in younger transgender patients can be misinterpreted as high grade dysplasia. METHODS: A review of all cervical Pap tests of transgender patients receiving androgen therapy (2010-2017) was performed. Bethesda diagnosis, cytomorphological features, HPV testing and cervical biopsy results were reviewed. RESULTS: Eleven transgender patients receiving androgen therapy were identified with 23 cervical Pap tests, 11 HPV tests and five cervical biopsies performed. A review of the Pap tests demonstrated: 57% negative for intraepithelial lesion; 13% unsatisfactory; 13% atypical squamous cells of undetermined significance; 13% atypical squamous cells - cannot exclude high grade squamous intraepithelial lesion; and 4% high-grade squamous intraepithelial lesion. The rates of abnormal tests were higher than our age-matched cis-gender atrophic cohort rates of unsatisfactory (0.5%), atypical squamous cells of undetermined significance (7%), atypical squamous cells-cannot exclude high-grade squamous intraepithelial lesion (0%) and high-grade squamous intraepithelial lesion (0.5%). The cytological findings from liquid-based preparations included dispersed and clustered parabasal-type cells, scattered degenerated cells, smooth evenly dispersed chromatin, and occasional mild nuclear enlargement and irregularity. Dysplastic cells had larger nuclei, hyperchromatic clumped chromatin, and more irregular nuclear contours. CONCLUSIONS: The evaluation of dysplasia can be challenging on Pap tests from transgender patients on androgen therapy. The cohort evaluated had higher rates of unsatisfactory and abnormal Pap tests. Pathologists should be familiar with the distinctive cytomorphological changes in the Pap tests from patients on androgen therapy to evaluate them appropriately. PMID- 29488270 TI - Evolution of diagnostic criteria and assessments for Parkinson's disease mild cognitive impairment. AB - Mild cognitive impairment has gained recognition as a construct and a potential prodromal stage to dementia in both Alzheimer's disease and Parkinson's disease (PD). Although mild cognitive impairment has been recognized in the Alzheimer's disease field, it is a relatively more recent topic of interest in PD. Recent advances include the development of diagnostic criteria for PD mild cognitive impairment to provide more uniform definitions for clinical and research use. Studies reveal that mild cognitive impairment in PD is frequent, but also heterogeneous, with variable clinical presentations, differences in its progression to dementia, and likely differences in underlying pathophysiology. Application of the International Parkinson and Movement Disorder Society PD Mild Cognitive Impairment Task Force diagnostic criteria has provided insights regarding cognitive measures, functional assessments, and other key topics that may require additional refinement. Furthermore, it is important to consider definitions of PD mild cognitive impairment in the landscape of other related Lewy body disorders, such as dementia with Lewy bodies, and in the context of prodromal and early-stage PD. This article examines the evolution of mild cognitive impairment in concept and definition, particularly in PD, but also in related disorders such as Alzheimer's disease and dementia with Lewy bodies; the development and application of International Parkinson and Movement Disorder Society PD Mild Cognitive Impairment diagnostic criteria; and insights and future directions for the field of PD mild cognitive impairment. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29488271 TI - Black/White disparities in pregnant women in the United States: An examination of risk factors associated with Black/White racial identity. AB - This paper explores racial disparities and risk factors of adverse pregnancy outcomes in Black and White pregnant women in the US. The study uses a cross sectional approach to explore Black and White disparities using data from the 2012 National Survey on Drug Use and Health (NSDUH), which collects interview data from approximately 70,000 randomly selected participants. We included several self-reported conditions that we categorised as individual and social stressors (e.g. measures of institutionalised racism, individual health behaviours, access to quality care and social context factors). We used descriptive statistics, univariate and multivariate analyses in risk factors of adverse pregnancy outcomes between Black and White women. Black women who were pregnant had a lower socioeconomic status and experienced more measures of institutionalised racism compared to White women who were pregnant. More white women who were pregnant were married, had higher levels of educational attainment, higher income levels, and greater employment opportunities. White pregnant women also had higher levels of private health insurance and less dependency on government programmes for access to healthcare. Results from the regressions indicated that Black pregnant women were less likely to be married (OR = 0.01), less likely to have higher income levels (OR = 0.31) and less likely to be employed (OR = 0.52). However, Black pregnant women were more likely to be younger (OR = 1.82). For the health-eroding behaviours, Black pregnant women were less likely to smoke (OR = 0.53) and use alcohol (0.52). After assessing the SES Household-level stressors (access to healthcare), Black pregnant women were more likely to have Medicaid/CHIP (OR = 3.21) and health coverage through government assistant programmes (OR = 3.80); however, less likely to have private health insurance (OR = 0.38). There are differences in risk factors of adverse pregnancy outcomes between White and Black pregnant women based on measures of individual level/social stressors, institutionalised racism, health behaviours and access to care. PMID- 29488272 TI - The Vicarious Trauma Scale: Confirmatory factor analysis and psychometric properties with a sample of victim advocates. AB - Vicarious trauma is referred to as the detrimental change in the manner that professionals understand and interpret material, as a result of exposure to second-hand traumatic material (McCann & Pearlman [1990] Journal of Traumatic Stress, 3:131). According to Aparicio et al. (Health & Social Work, 2013, 38:199), vicarious trauma comprises both affective and cognitive components and, while it is distinct from posttraumatic stress disorder (PTSD), it is associated with similar symptoms, including re-experiencing and avoiding traumatic material and experiencing depressed mood. The purpose of this study was to analyse the psychometric properties of the Victim Trauma Scale (VTS) and provide additional support, supplementing the findings of Aparicio et al. (2013), but instead using victim advocates as participants (n = 142). The survey was open between February 2016 and February 2017. More than 96% of participants were in paid employment positions, as more than 80% reporting working 40 or more hours a week. Aparicio et al. (2013) found that the VTS was two-dimensional (affective and cognitive); however, after examining the goodness of fit of the two-factor model using a confirmatory factor analysis (CFA) approach, this study concluded that the two dimensional model was not a good fit. Due to the poor goodness of fit of the two factor model and the post hoc EFA resulting in a one-factor model, our data do not support the findings of Aparicio et al. (2013). Further, the findings suggest the VTS is an acceptable measure of vicarious trauma, as demonstrated by the high internal consistency and the single-factor loading. PMID- 29488273 TI - Homeless people's experiences of medical respite care following acute hospitalisation in Denmark. AB - The aim of this study was to explore homeless people's health perspectives and experiences of a 2-week medical respite care programme following acute hospitalisation. There is a high level of health inequality when comparing the health status of homeless people to the general population, including increased mortality and morbidity. Homelessness predisposes an increased risk of infectious disease, cancer and chronic illness, such as diabetes and cardiovascular disease. Moreover, homeless people have a higher frequency of acute hospitalisation than general population estimates. In order to facilitate the transition from hospitalisation back to life on the streets, homeless people who were acutely hospitalised in the Capital Region of Denmark were offered 2 weeks of medical respite care from the day of discharge by a non-governmental organisation. This is a qualitative study with a phenomenological hermeneutical approach based on narrative interviews of 12 homeless people who received medical respite care from 1 March 2016 to 30 September 2016. Data were collected through individual semi structured interviews and analysed according to Lindseth and Norberg's presentation of Paul Ricoeur's theory of interpretation. The analysis identified four themes: (i) basic needs are of highest priority; (ii) a safe environment provides security and comfort; (ii) social support is just as important as healthcare; and (iv) restitution facilitates reflection. The findings indicated that the medical respite care centre provided a place of rest and restitution following hospitalisation, which made room for self-reflection among the homeless people regarding their past and present life, and also their wishes for a better future. This study also indicates that a medical respite care stay can contribute to the creation of a temporary condition in which the basic needs of the homeless people are met, enabling them to be more hopeful and to think more positively about the future. PMID- 29488274 TI - Electroacupuncture for patients with refractory functional dyspepsia: A randomized controlled trial. AB - BACKGROUND: To test the efficacy of electroacupuncture for patients with refractory functional dyspepsia (FD). METHODS: A 24-week, 2-arm, single-blind, randomized controlled trial was conducted at three hospitals in China. Patients with refractory FD were randomly assigned to receive 20 sessions of authentic or sham electroacupuncture in a treatment duration of 4 weeks. The primary outcome was complete absence of dyspeptic symptoms at 16 weeks after initiation of acupuncture (week 16). The secondary outcomes included adequate relief of dyspeptic symptoms, Leeds Dyspepsia Questionnaire (LDQ), Nepean Dyspepsia Index (NDI), and adverse events. Intention-to-treat analysis was performed. KEY RESULTS: Two hundred patients were included, of which 196 (98%) completed follow up data at week 24. At week 16, 17 (17%) patients in the authentic electroacupuncture group vs 6 (6%) patients in the sham group achieved the primary outcome (P = .014). Sixty-two (62%) patients had adequate relief in the authentic electroacupuncture group, as compared to 22 (22%) in the sham group (P = .001). The scores of LDQ and NDI were significantly improved in both groups at week 16, and patients in the authentic electroacupuncture group have more improvements (LDQ, mean difference, -2.2, 95% confidence interval, -2.3 to -2.1, P < .001; NDI, -7.3, -10.5 to -4.2, P < .001). Results were similar for all the outcomes assessed at week 24. No serious adverse events were reported in both groups. CONCLUSION: Acupuncture efficaciously improves dyspeptic symptoms in patients with refractory FD. PMID- 29488275 TI - Evaluation of salivary heme oxygenase-1 as a potential biomarker of early Parkinson's disease. AB - BACKGROUND AND HYPOTHESIS: To date, there are no chemical analytes, including biochemical indices of oxidative stress, metabolites of alpha-synuclein protein, and differential protein expression patterns on proteomic profiling, for use in clinics as a diagnostic biomarker of idiopathic PD. OBJECTIVES: Heme oxygenase-1 has been implicated in the pathogenesis of PD. The objective of this study is to ascertain whether salivary heme oxygenase-1 may serve as a biomarker for early idiopathic PD. METHODS: Fifty-eight PD patients and 59 non-neurological disease controls were recruited. Levels of heme oxygenase-1 expression were assayed using enzyme-linked immunosorbent assay and western blot analysis of whole, unstimulated saliva. Analyses were adjusted by sex, l-dopa exposure, and relevant comorbidities. RESULTS: We documented: (1) the presence of 32-kDa heme oxygenase 1 protein in human saliva; (2) significantly higher mean heme oxygenase-1 protein concentrations in saliva of PD patients relative to control values; (3) no variability in salivary heme oxygenase-1 levels with sex, age, l-dopa equivalence, or comorbidities; and (4) significantly higher mean salivary heme oxygenase-1 concentrations in patients with H & Y stage 1 PD (early) than control subjects and stage 2 and stage 3 PD patients. The area under the receiver operating characteristic curve that separated controls from PD H & Y stage 1 was 76% (95% confidence interval: 63-90). CONCLUSIONS: Salivary heme oxygenase-1 concentrations may provide a useful, noninvasive, and relatively inexpensive biomarker of early idiopathic PD. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29488276 TI - Allelic variant in the glucagon-like peptide 1 receptor gene associated with greater effect of liraglutide and exenatide on gastric emptying: A pilot pharmacogenetics study. AB - BACKGROUND: Weight loss in response to the long-acting GLP-1 receptor (GLP1R) analog, liraglutide, is correlated with delay in gastric-emptying (GE). The aim of this pilot study was to assess whether specific genetic variants in GLP1R or TCF7L2 are associated with delayed GE and weight loss in obese patients treated with liraglutide or the short-acting GLP-1 agonist, exenatide. METHODS: We evaluated in obese individuals the associations of genetic variations of GLP1R (rs6923761) and TCF7L2 (rs7903146) on GE T1/2 and weight from two trials that evaluated separately exenatide, 5 MUg BID for 30 days, or liraglutide, 3 mg daily for 5 weeks. Data were analyzed using the dominant genetic model and intention-to treat analysis. KEY RESULTS: There was a significant correlation between changes in weight and GE T1/2 (rs = -.382, P = .004). GLP1R rs6923761 minor allele A (AA_AG) carriers who received either exenatide or liraglutide had greater delay in GE T1/2 relative to baseline (117.9 +/- 27.5 [SEM] minutes and 128.9 +/- 38.32 minutes) compared to GG genotype (95.8 +/- 30.4 minutes and 61.4 +/- 21.4 minutes, respectively; P = .11). There was a non-significant difference in weight loss based on GLP1R rs6923761 genotype after 5 weeks of treatment. There were no significant correlations with TCF7L2 (rs7903146) genotype. CONCLUSIONS & INFERENCES: The minor A allele of GLP1R (rs6923761) is associated with greater delay in GE T1/2 in response to liraglutide and exenatide. These studies provide data to plan pharmacogenetics testing of the hypothesis that GLP1R (rs6923761) influences weight loss in response to GLP1R agonists. PMID- 29488277 TI - The increase in medial prefrontal glutamate/glutamine concentration during memory encoding is associated with better memory performance and stronger functional connectivity in the human medial prefrontal-thalamus-hippocampus network. AB - The classical model of the declarative memory system describes the hippocampus and its interactions with representational brain areas in posterior neocortex as being essential for the formation of long-term episodic memories. However, new evidence suggests an extension of this classical model by assigning the medial prefrontal cortex (mPFC) a specific, yet not fully defined role in episodic memory. In this study, we utilized 1H magnetic resonance spectroscopy (MRS) and psychophysiological interaction (PPI) analysis to lend further support for the idea of a mnemonic role of the mPFC in humans. By using MRS, we measured mPFC gamma-aminobutyric acid (GABA) and glutamate/glutamine (GLx) concentrations before and after volunteers memorized face-name association. We demonstrate that mPFC GLx but not GABA levels increased during the memory task, which appeared to be related to memory performance. Regarding functional connectivity, we used the subsequent memory paradigm and found that the GLx increase was associated with stronger mPFC connectivity to thalamus and hippocampus for associations subsequently recognized with high confidence as opposed to subsequently recognized with low confidence/forgotten. Taken together, we provide new evidence for an mPFC involvement in episodic memory by showing a memory-related increase in mPFC excitatory neurotransmitter levels that was associated with better memory and stronger memory-related functional connectivity in a medial prefrontal thalamus-hippocampus network. PMID- 29488278 TI - An augmented aging process in brain white matter in HIV. AB - OBJECTIVE: HIV infection and aging are both associated with neurodegeneration. However, whether the aging process alone or other factors associated with advanced age account for the progression of neurodegeneration in the aging HIV positive (HIV+) population remains unclear. METHODS: HIV+ (n = 70) and HIV negative (HIV-, n = 34) participants underwent diffusion tensor imaging (DTI) and metrics of microstructural properties were extracted from regions of interest (ROIs). A support vector regression model was trained on two independent datasets of healthy adults across the adult life-span (n = 765, Cam-CAN = 588; UiO = 177) to predict participant age from DTI metrics, and applied to the HIV dataset. Predicted brain age gap (BAG) was computed as the difference between predicted age and chronological age, and statistically compared between HIV groups. Regressions assessed the relationship between BAG and HIV severity/medical comorbidities. Finally, correlation analyses tested for associations between BAG and cognitive performance. RESULTS: BAG was significantly higher in the HIV+ group than the HIV- group F (1, 103) = 12.408, p = .001). HIV RNA viral load was significantly associated with BAG, particularly in older HIV+ individuals (R2 = 0.29, F(7, 70) = 2.66, p = .021). Further, BAG was negatively correlated with domain-level cognitive function (learning: r = -0.26, p = .008; memory: r = 0.21, p = .034). CONCLUSIONS: HIV infection is associated with augmented white matter aging, and greater brain aging is associated with worse cognitive performance in multiple domains. PMID- 29488281 TI - Disarming the Red Queen: plant invasions, novel weapons, species coexistence, and microevolution. PMID- 29488279 TI - Origin-Specific Adhesive Interactions of Mesenchymal Stem Cells with Platelets Influence Their Behavior After Infusion. AB - We investigated the adhesive behavior of mesenchymal stem cells (MSC) in blood, which might influence their fate when infused as therapy. Isolated human bone marrow MSC (BMMSC) or umbilical cord MSC (UCMSC) adhered efficiently from flow to the matrix proteins, collagen, or fibronectin, but did not adhere to endothelial selectins. However, when suspended in blood, BMMSC no longer adhered to collagen, while UCMSC adhered along with many aggregated platelets. Neither MSC adhered to fibronectin from flowing blood, although the fibronectin surface did become coated with a platelet monolayer. UCMSC induced platelet aggregation in platelet rich plasma, and caused a marked drop in platelet count when mixed with whole human or mouse blood in vitro, or when infused into mice. In contrast, BMMSC did not activate platelets or induce changes in platelet count. Interestingly, isolated UCMSC and BMMSC both adhered to predeposited platelets. The differences in behavior in blood were attributable to expression of podoplanin (an activating ligand for the platelet receptor CLEC-2), which was detected on UCMSC, but not BMMSC. Thus, platelets were activated when bound to UCMSC, but not BMMSC. Platelet aggregation by UCMSC was inhibited by recombinant soluble CLEC-2, and UCMSC did not cause a reduction in platelet count when mixed with blood from mice deficient in CLEC-2. We predict that both MSC would carry platelets in the blood, but their interaction with vascular endothelium would depend on podoplanin induced activation of the bound platelets. Such interactions with platelets might target MSC to damaged tissue, but could also be thrombotic. Stem Cells 2018;36:1062-1074. PMID- 29488282 TI - Bringing down the wall one brick at a time. PMID- 29488280 TI - Research frontiers for improving our understanding of drought-induced tree and forest mortality. AB - Accumulating evidence highlights increased mortality risks for trees during severe drought, particularly under warmer temperatures and increasing vapour pressure deficit (VPD). Resulting forest die-off events have severe consequences for ecosystem services, biophysical and biogeochemical land-atmosphere processes. Despite advances in monitoring, modelling and experimental studies of the causes and consequences of tree death from individual tree to ecosystem and global scale, a general mechanistic understanding and realistic predictions of drought mortality under future climate conditions are still lacking. We update a global tree mortality map and present a roadmap to a more holistic understanding of forest mortality across scales. We highlight priority research frontiers that promote: (1) new avenues for research on key tree ecophysiological responses to drought; (2) scaling from the tree/plot level to the ecosystem and region; (3) improvements of mortality risk predictions based on both empirical and mechanistic insights; and (4) a global monitoring network of forest mortality. In light of recent and anticipated large forest die-off events such a research agenda is timely and needed to achieve scientific understanding for realistic predictions of drought-induced tree mortality. The implementation of a sustainable network will require support by stakeholders and political authorities at the international level. PMID- 29488283 TI - A scalable multi-process model of root nitrogen uptake. PMID- 29488284 TI - Haemoglobin Titusville: A case study and review of the literature. PMID- 29488285 TI - Assessing the reliability of the NIST library during routine GC-MS analyses: Structure and spectral data corroboration for 5,5-diphenyl-1,3-dioxolan-4-one during a recent OPCW proficiency test. PMID- 29488287 TI - Electro-acupuncture at ST37 and ST25 induce different effects on colonic motility via the enteric nervous system by affecting excitatory and inhibitory neurons. AB - BACKGROUND: On the basis of the importance of the enteric nervous system (ENS) in gastrointestinal motility, we hypothesized that the ENS may mediate the therapeutic efficacy of electro-acupuncture (EA) in constipation by regulating the mechanisms underlying the effects of EA on gastrointestinal function. METHODS: Model mice with constipation were generated by gastric instillation of 0 4 degrees C normal saline. Defecation time and stool (form and wet and dry weight) were assessed. The effect of EA at ST37 or ST25 on colorectal motility and proximal colonic motility was assessed using a water-filled balloon. The expression of protein gene product 9.5 (PGP9.5), the cholinergic neuron marker acetyltransferase (ChAT) and the anticholinergic neuron marker nitric oxide synthase (nNOS) was detected by immunohistochemistry, real-time quantitative polymerase chain reaction (qPCR) and western blot analysis. KEY RESULTS: ST37 and ST25 improved colorectal pressure; however, ST37 but not ST25 improved proximal colonic pressure. In the proximal colon, the expression of PGP9.5 returned to normal after EA at ST 37, while EA at ST25 did not have this effect. In addition, qPCR and western blot analysis showed that ST37 could downregulate the expression of nNOS and upregulate the expression of ChAT to normal levels, while ST25 could only downregulate the expression of nNOS to normal levels. CONCLUSIONS AND INFERENCES: Electro-acupuncture at specific acupoints can improve intestinal motility in constipation by altering the ENS and differentially affecting excitatory and inhibitory neurons, restoring the coordination between contraction and relaxation muscles, and working in concert with the central nervous system and peripheral neural pathways. PMID- 29488286 TI - Interactions among plants, bacteria, and fungi reduce extracellular enzyme activities under long-term N fertilization. AB - Atmospheric nitrogen (N) deposition has enhanced soil carbon (C) stocks in temperate forests. Most research has posited that these soil C gains are driven primarily by shifts in fungal community composition with elevated N leading to declines in lignin degrading Basidiomycetes. Recent research, however, suggests that plants and soil microbes are dynamically intertwined, whereby plants send C subsidies to rhizosphere microbes to enhance enzyme production and the mobilization of N. Thus, under elevated N, trees may reduce belowground C allocation leading to cascading impacts on the ability of microbes to degrade soil organic matter through a shift in microbial species and/or a change in plant microbe interactions. The objective of this study was to determine the extent to which couplings among plant, fungal, and bacterial responses to N fertilization alter the activity of enzymes that are the primary agents of soil decomposition. We measured fungal and bacterial community composition, root-microbial interactions, and extracellular enzyme activity in the rhizosphere, bulk, and organic horizon of soils sampled from a long-term (>25 years), whole-watershed, N fertilization experiment at the Fernow Experimental Forest in West Virginia, USA. We observed significant declines in plant C investment to fine root biomass (24.7%), root morphology, and arbuscular mycorrhizal (AM) colonization (55.9%). Moreover, we found that declines in extracellular enzyme activity were significantly correlated with a shift in bacterial community composition, but not fungal community composition. This bacterial community shift was also correlated with reduced AM fungal colonization indicating that declines in plant investment belowground drive the response of bacterial community structure and function to N fertilization. Collectively, we find that enzyme activity responses to N fertilization are not solely driven by fungi, but instead reflect a whole ecosystem response, whereby declines in the strength of belowground C investment to gain N cascade through the soil environment. PMID- 29488288 TI - Changes in consumption of opioid analgesics in Israel 2009 to 2016: An update focusing on oxycodone and fentanyl formulations. AB - PURPOSE: The purpose of the study is to assess opioid (morphine, methadone, oxycodone, pethidine, and fentanyl) consumption in Israel during 2009 to 2016 and identify recent trends. METHODS: Data for all treatment settings, private and public, for the years 2009 to 2016, were extracted from the Israel Ministry of Health's Pharmaceutical Administration database. The data were used to calculate defined daily doses (DDD) per 1000 inhabitants per day, of the various drugs. RESULTS: Consumption of the 5 opioids increased by 68%, from 3.40 DDD/1000 inhabitants/day in 2009 to 5.72 DDD/1000 inhabitants/day in 2016. This trend resulted mostly from increases in oxycodone consumption from 0.50 DDD/1000 inhabitants/day to 2.03 DDD/1000 inhabitants/day (namely, 4-fold) and in fentanyl consumption, from 1.09 DDD/1000 inhabitants/day to 2.33 DDD/1000 inhabitants/day (about 2-fold). The use of the 3 remaining opioids decreased substantially as follows: pethidine from 0.03 DDD/1000/day in 2009 to 0.007 DDD/1000 inhabitants/day in 2016 (-67%), methadone from 1.61 DDD/1000 inhabitants/day to 1.20 DDD/1000 inhabitants/day (-25%), and morphine from 0.17 DDD/1000 inhabitants/day to 0.15 DDD/1000 inhabitants/day (-12%). An increasing trend was also observed in the use of oxycodone/naloxone (Targin) and oxycodone/acetaminophen (Percocet) combinations, while a decrease was observed in the use of pure oxycodone formulations. CONCLUSIONS: The increase in opioid consumption persisted throughout the years 2009 to 2016. This has been associated with substantial changes in the patterns of prescribing opioids, characterized by increases in oxycodone and fentanyl prescriptions and decreases in morphine, methadone, and pethidine prescriptions. A national program aiming to ensure safe use of opioids in the treatment of chronic pain is warranted. PMID- 29488290 TI - Inhibition of ZERO-BK by PKC is involved in carbachol-induced enhancement of rat colon smooth muscle motility. AB - BACKGROUND: Muscarinic acetylcholine receptor (mAChR) activation is an important factor to enhance the motility of gastrointestinal (GI) smooth muscle. Large conductance Ca2+ -activated potassium (BK) channels are widely expressed in GI smooth muscle. Roles of BK in carbachol (a mAChR agonist) induced enhancement of GI motility and the molecular mechanisms remains unknown and were investigated in this study. METHODS: Colonic smooth muscle (CSM) strip was perfused to record motility in vitro. The patch-clamp technique was used to record BK currents. RT PCR was used to detect the expression of BK channels in rat CSM tissues. Two different types BK channels were constructed in HEK293 cells to investigate the regulation mechanism. Paired t tests were set with a P < .05 regarded as significant. KEY RESULTS: Carbachol enhanced CSM contraction through M3 receptor (M3 R) were attenuated by IbTX, an inhibitor of BK. Carbachol inhibited BK currents in CSM cells and Go6983, an inhibitor of protein kinase C (PKC), reversed the effect. PKC activator, phorbol 12-myristate 13-acetate (PMA), inhibited BK currents. Two types of BK channels (ZERO-BK and STREX-BK) were detected in CSM. ZERO- but not STREX-BK channels expressed in HEK293 cells were inhibited by PMA. CONCLUSION: Our results provide strong evidence that inhibition of ZERO-BK but not STREX-BK channels via PKC pathway is involved in the enhancement of CSM motility by mAChR activation. Besides the activation of BK by an increase in intracellular calcium, inhibition of BK played an important role in GI motility regulation during mAChR activation. PMID- 29488289 TI - Intraoperative blood transfusion in pediatric patients undergoing renal transplant-Effect of renal graft size. AB - In pediatric RT, donor allograft size often exceeds the expected recipient norms, especially in younger recipients. An "oversize" graft might not only present a technical- and space-related challenge, but may possibly lead to increased demands in perioperative volume requirements due to the disparity between donor and recipient in renal blood flow. We evaluated transfusion practices at a single tertiary institution with special consideration of kidney graft size, hypothesizing that oversize graft kidneys might lead to a quantifiable increased need of blood transfusion in smaller recipients. Retrospective analysis of all patients who underwent pediatric RT from January 2004 to June 2014 at a tertiary pediatric centre was performed. Variables analyzed included patient age, weight, pre- and postoperative Hb concentration, graft size, EBL, amount of intraoperative blood transfusion, and preoperative use of erythropoietin. Based on graft size in relation to patient's age, a SMR and an OvR were identified. A subcohort of age-matched pairs was used to allow for comparison between groups. We calculated the expected procedure- and transfusion-induced changes in Hb and compared these changes to the observed difference in pre- vs postoperative Hb to assess the influence of graft size on transfusion requirements. RT was performed in 188 pediatric recipients during the study period. In the matched cohort, percentage of transfused patients during transplantation in the OvR group was more than double compared with SMR (89% vs 39%, P < .001); similarly, the median number of transfused PRBC units in OvR was 1, while the median of SMR did not receive transfusion (P < .001). The difference between expected (calculated) and observed change in Hb was significantly higher in OvR with a median of 1.9 g/dL compared with SMR with a median of 1.0 g/dL (P = .026). Correspondingly, the calculated median volume taken up by a regular size kidney was significantly higher with 213 mL compared with 313 mL (P = .031) taken up by an oversize graft kidney. Median estimated intraoperative blood loss was significantly higher in OvR than in SMR (6.9 mL/kg, vs 5.3 mL/kg, respectively; P = .04). Median postoperative Hb was similar among groups (10.4 g/dL vs 10.6 g/dL for SMR vs OvR, respectively). Transplantation of an oversized kidney in pediatric RT recipients is associated with a quantifiable higher need for blood transfusion. This may be caused by a higher intraoperative EBL and/or greater blood volume sequestered by the larger renal allograft and requires further evaluation. PMID- 29488291 TI - Clinicians' views of the training, use and maintenance of phonetic transcription in speech and language therapy. AB - BACKGROUND: The critical role of phonetic transcription in the assessment, diagnosis and management of speech disorders is well established and thus pre registration degrees dedicate numerous hours to phonetic training. However, this training is not always fully used in clinical work and clinicians may find it difficult to maintain their skills, suggesting a 'theory/practice gap'. AIMS: This paper surveys speech and language therapists' (SLTs) views of their training, practice and maintenance of transcription in order to investigate the posited theory/practice gap and to explore how education in phonetics is translated into practice. METHODS & PROCEDURES: A total of 759 SLTs from the UK were surveyed via an online questionnaire. Multiple-choice questions were analysed using descriptive statistics, and free-text comments were analysed thematically. OUTCOMES & RESULTS: Thirty-five per cent of SLTs found learning phonetics quite easy, and 30% quite difficult. Respondents suggested that more time was needed to practise transcription in and out of the classroom; nevertheless, the majority felt at least equipped to undertake transcription after their training. A total of 75% of SLTs require transcription for their role, with 61% using it often or all the time. Some 45% use a mix of broad and narrow transcription, with 41% using only broad transcription. Those not using narrow transcription attributed this to lack of confidence. A total of 57% of SLTs did not feel supported to maintain transcription skills in the workplace, and 80% had never attended a refresher course in transcription, with 75% wishing to do so. CONCLUSIONS & IMPLICATIONS: As many clinicians found it difficult to learn transcription, there is an opportunity to provide more transcription practice both in and beyond the classroom. Despite most clinicians feeling equipped to undertake transcription upon completion of their training, and a large majority requiring transcription for their role, a theory/practice gap is apparent in the relatively small number of clinicians using narrow transcription exclusively, and those not using it expressing lack of confidence in their skills. Additionally, as many clinicians have never attended refresher training in transcription, and rely on their course notes to maintain their skills, more provision of opportunities for revision should be made available. With clinicians remembering a need for more practice during their training, and expressing a desire for more training opportunities in practice, there is an opportunity for clinicians, educators and regulatory bodies to work together to provide packages of transcription training material that can be used by students and practitioners to maintain and extend their skills. PMID- 29488292 TI - Patterns of prednisone use during pregnancy in women with rheumatoid arthritis: Daily and cumulative dose. AB - PURPOSE: To characterize prednisone use in pregnant women with rheumatoid arthritis using individual-level heat-maps and clustering individual trajectories of prednisone dose, and to evaluate the association between prednisone dose trajectory groups and gestational length. METHODS: This study included pregnant women with rheumatoid arthritis who enrolled in the MotherToBaby Autoimmune Diseases in Pregnancy Study (2003-2014) before gestational week 20 and reported prednisone use without another oral glucocorticoid during pregnancy (n = 254). Information on medication use and pregnancy outcomes was collected by telephone interview plus by medical record review. Prednisone daily dose and cumulative dose were plotted by gestational day using a heat map for each individual. K means clustering was used to cluster individual trajectories of prednisone dose into groups. The associations between trajectory group and demographics, disease severity measured by the Health Assessment Questionnaire at enrollment, and gestational length were evaluated. RESULTS: Women used prednisone 3 to 292 days during pregnancy, with daily doses ranging from <1 to 60 mg. Total cumulative dose ranged from 8 to 6225 mg. Disease severity, non-biologic disease modifying anti-rheumatic drug use, and gestational length varied significantly by trajectory group. After adjusting for disease severity, non-biologic disease modifying anti-rheumatic drug use, and other covariates, the highest vs lowest daily dose trajectory group was associated with reduced gestational age at delivery (beta: -2.3 weeks (95%: -3.4, -1.3)), as was the highest vs lowest cumulative dose trajectory group (beta: -2.6 weeks (95%: -3.6, -1.5)). CONCLUSIONS: In pregnant women with rheumatoid arthritis, patterns of higher prednisone dose were associated with shorter gestational length compared with lower dose. PMID- 29488293 TI - Forest resilience to drought varies across biomes. AB - Forecasted increase drought frequency and severity may drive worldwide declines in forest productivity. Species-level responses to a drier world are likely to be influenced by their functional traits. Here, we analyse forest resilience to drought using an extensive network of tree-ring width data and satellite imagery. We compiled proxies of forest growth and productivity (TRWi, absolutely dated ring-width indices; NDVI, Normalized Difference Vegetation Index) for 11 tree species and 502 forests in Spain corresponding to Mediterranean, temperate, and continental biomes. Four different components of forest resilience to drought were calculated based on TRWi and NDVI data before, during, and after four major droughts (1986, 1994-1995, 1999, and 2005), and pointed out that TRWi data were more sensitive metrics of forest resilience to drought than NDVI data. Resilience was related to both drought severity and forest composition. Evergreen gymnosperms dominating semi-arid Mediterranean forests showed the lowest resistance to drought, but higher recovery than deciduous angiosperms dominating humid temperate forests. Moreover, semi-arid gymnosperm forests presented a negative temporal trend in the resistance to drought, but this pattern was absent in continental and temperate forests. Although gymnosperms in dry Mediterranean forests showed a faster recovery after drought, their recovery potential could be constrained if droughts become more frequent. Conversely, angiosperms and gymnosperms inhabiting temperate and continental sites might have problems to recover after more intense droughts since they resist drought but are less able to recover afterwards. PMID- 29488294 TI - Agreement between paternal self-reported medication use and records from a national prescription database. AB - PURPOSE: Father's medication use is of interest in fertility studies and as negative control exposures in pregnancy medication safety studies. We sought to compare self-report to prescription records to understand how reliably each of these sources of information may be used. METHODS: We compared self-reported medication use in the 6 months prior to pregnancy from fathers participating in the Norwegian Mother and Child Cohort Study to records of dispensed prescriptions from the Norwegian Prescription Database that overlapped in time. Medications from 3 main categories were assessed: prescription medications used chronically, prescription medications used episodically, and over-the-counter/prescription medications (predominantly obtained without prescription). We calculated agreement between self-report and dispensing records using Cohen's kappa statistic. RESULTS: We included 42 848 pregnancies with the father's prescription data available for the 9 months before pregnancy. Prescription medications used chronically including antiepileptics, antipsychotics, and antidepressants showed substantial agreement between self-report and prescription records: kappa statistics 0.87, 0.63, and 0.74, respectively. Prescription medications used episodically like anti-infectives, opioids, anxiolytics, and hypnotics and sedatives showed worse agreement: kappa 0.19, 0.32, 0.40, 0.32. Over-the counter/prescription medications like paracetamol and nonsteroidal anti inflammatory drugs had slight agreement: kappa 0.02 and 0.20. CONCLUSIONS: There is good agreement between paternal self-report and prescription data for prescribed medications used chronically and substantially less for medications used episodically. Suboptimal agreement for episodic medications suggests poor recall (for questionnaires) or false positives due to noncompliance (prescription data). Not surprisingly, use of medications available both with and without a prescription is not well captured using prescription databases alone. PMID- 29488295 TI - Association of health literacy with health information-seeking preference in older people: A correlational, descriptive study. AB - Low health literacy has been recognized as a potential barrier to obtaining knowledge and maintaining self-care in older people. However, little is known about information-seeking preference in relation to health literacy among older people. The aim of the present study was to understand the influence of health literacy on the information-seeking preference of older people. A total of 129 community-residing Korean older people completed a survey in 2016. The findings revealed that health literacy was a significant predictor of information-seeking preference in older people after controlling for demographic and illness variables. Our study highlights the important need to incorporate strategies to increase the desire for information seeking in older people, in addition to adopting communication strategies that address low health literacy. PMID- 29488296 TI - Intramolecular Aza-Diels-Alder Reactions of ortho-Quinone Methide Imines: Rapid, Catalytic, and Enantioselective Assembly of Benzannulated Quinolizidines. AB - Aza-Diels-Alder reactions (ADARs) are powerful processes that furnish N heterocycles in a straightforward fashion. Intramolecular variants offer the additional possibility of generating bi- and polycyclic systems with high stereoselectivity. We report herein a novel Bronsted acid catalyzed process in which ortho-quinone methide imines tethered to the dienophile via the N substituent react in an intramolecular ADAR to form complex quinolizidines and oxazinoquinolines in a one-step process. The reactions proceed under very mild conditions, with very good yields and good to very good diastereo- and enantioselectivities. Furthermore, the process was extended to a domino reaction that efficiently combines substrate synthesis, ortho-quinone methide imine formation, and ADAR. PMID- 29488297 TI - Photomodulating Gene Expression by Using Caged siRNAs with Single-Aptamer Modification. AB - Caged siRNAs incorporating terminal modification were rationally designed for photochemical regulation of gene silencing induced by RNA interference (RNAi). Through the conjugation of a single oligonucleotide aptamer at the 5' terminus of the antisense RNA strand, enhancement of the blocking effect for RNA-induced silencing complex (RISC) formation/processing was expected, due both/either to the aptamers themselves and/or to their interaction with large binding proteins. Two oligonucleotide aptamers (AS1411 and MUC-1) were chosen for aptamer-siRNA conjugation through a photolabile linker. This caging strategy was successfully used to photoregulate gene expression both of firefly luciferase and of green fluorescent protein (GFP) in cells. Further patterning experiments revealed that spatial regulation of GFP expression was successfully achieved by using the aptamer-modified caged siRNA and light activation. We expect that further optimized caged siRNAs featuring aptamer conjugation will be promising for practical applications to spatiotemporal photoregulation of gene expression in the future. PMID- 29488298 TI - On PAR: A feasibility study of the Promoting Adult Resilience programme with mental health nurses. AB - Mental health settings are recognized as complex, unpredictable environments, and challenging interpersonal situations are common for nurses in acute adult mental health services. Occupational stressors include verbal aggression and physical assault and are correlated with poor physical and mental health outcomes for nurses. There is a clear need for proactive approaches that address the negative impacts of stressors on the mental health nursing workforce. Resilience interventions are a preventive approach to strengthening skills for addressing workplace stress, improving health and well-being, and preventing adverse outcomes associated with occupational stressors. The aim of this study was to evaluate the feasibility of a workplace resilience education programme for nurses in high-acuity adult mental health settings. The outcomes were measured using a single-group pretest post-test design with follow-up at 3 months postintervention. The feasibility and acceptability of the programme were identified with descriptors of mental health, well-being, resilience, facilitator fidelity checklists, and participant satisfaction questionnaires. The programme was found to be feasible for nurses working in high-acuity inpatient settings. There were significant changes to mental health, well-being, and workplace resilience. The programme was delivered with fidelity by facilitators and accepted with high levels of satisfaction by participants. The study findings indicated that nurses can benefit from resilience education that equips them with cognitive, emotion regulation, and relational skills, in conjunction with available external supports and resources, to address workplace challenges. There is a need for comprehensive organizational approaches that include individual, work unit, and organizational-level strategies to support staff well-being. PMID- 29488299 TI - Essential Professional Nursing Practices in mental health: A cross-sectional study of hospital inpatient care. AB - Quality organizational structures and nursing practices are key to positive patient outcomes. Whereas structures have been largely studied over the past few decades, less is known of the nursing practices that account for patient outcomes, such as patient satisfaction. This is especially true in psychiatric, mental health care settings. The aim of the present study is to determine the relative importance of eight Essential Professional Nursing Practices (EPNPs) on the satisfaction of hospitalized patients on mental health care units. A cross sectional design was selected; 226 point-of-care mental health nurses completed the online EPNP questionnaire in Spring 2015. Statistical analyses included MANOVAs and a 2-step linear regression. A significant relationship was found between university preparation and scores on two EPNP subscales: autonomous decision-making and practicing with competent nurses. Scores on patient advocacy and control over practice subscales were significantly related to nurse-rated patient satisfaction. The findings reinforce the positive link between university education and the work of nurses and highlight the power dynamics that are salient in mental health care. The pertinence of EPNPs in psychiatric settings is brought to the fore, with practices of patient advocacy and nurse control over care examined in relation to empowerment. Implications for clinical and administrative leaders are addressed, with a focus on strategies for empowering patients and nurses. PMID- 29488300 TI - A Porous Network of Bismuth Used as the Anode Material for High-Energy-Density Potassium-Ion Batteries. AB - Potassium-ion batteries (KIBs) are plagued by a lack of materials for reversible accommodation of the large-sized K+ ion. Herein we present, the Bi anode in combination with the dimethoxyethane-(DME) based electrolyte to deliver a remarkable capacity of ca. 400 mAh g-1 and long cycle stability with three distinct two-phase reactions of Bi<-> KBi2 <->K3 Bi2 <->K3 Bi. These are ascribed to the gradually developed three-dimensional (3D) porous networks of Bi, which realizes fast kinetics and tolerance of its volume change during potassiation and depotassiation. The porosity is linked to the unprecedented movement of the surface Bi atoms interacting with DME molecules, as suggested by DFT calculations. A full KIB of Bi//DME-based electrolyte//Prussian blue of K0.72 Fe[Fe(CN)6 ] is demonstrated to present large energy density of 108.1 Wh kg-1 with average discharge voltage of 2.8 V and capacity retention of 86.5 % after 350 cycles. PMID- 29488301 TI - Soft Phonon Modes Leading to Ultralow Thermal Conductivity and High Thermoelectric Performance in AgCuTe. AB - Crystalline solids with intrinsically low lattice thermal conductivity (kappaL ) are crucial to realizing high-performance thermoelectric (TE) materials. Herein, we show an ultralow kappaL of 0.35 Wm-1 K-1 in AgCuTe, which has a remarkable TE figure-of-merit, zT of 1.6 at 670 K when alloyed with 10 mol % Se. First principles DFT calculation reveals several soft phonon modes in its room temperature hexagonal phase, which are also evident from low-temperature heat capacity measurement. These phonon modes, dominated by Ag vibrations, soften further with temperature giving a dynamic cation disorder and driving the superionic transition. Intrinsic factors cause an ultralow kappaL in the room temperature hexagonal phase, while the dynamic disorder of Ag/Cu cations leads to reduced phonon frequencies and mean free paths in the high-temperature rocksalt phase. Despite the cation disorder at elevated temperatures, the crystalline conduits of the rigid anion sublattice give a high power factor. PMID- 29488302 TI - First reported case in Australia: a rare case of lymphangioma of the gallbladder. PMID- 29488303 TI - Evaluation of the effect of rifampin on the pharmacokinetics of the Smoothened inhibitor glasdegib in healthy volunteers. AB - AIMS: This study aimed to evaluate the effect of a strong CYP3A inducer, rifampin, on glasdegib pharmacokinetics in healthy volunteers. METHODS: In an open-label, fixed-sequence, two-period Phase 1 study, subjects received a single 100-mg oral dose of glasdegib alone or following once-daily pre-treatment with 600 mg rifampin. Glasdegib pharmacokinetics were calculated using a noncompartmental analysis. RESULTS: Twelve healthy male volunteers (3 whites, 5 blacks and 4 others) were enrolled in the study. Mean age, weight, height and body mass index was 37.8 years, 83.0 kg, 177.3 cm and 26.5 kg (m2 ) -1 , respectively. When dosed alone, glasdegib geometric mean (% coefficient of variation) area under the plasma concentration-time curve from time zero to infinity (AUCinf ) was 8145 ng * h ml-1 (23%) and maximum observed concentration (Cmax ) was 703.2 ng ml-1 (19%). With rifampin, glasdegib AUCinf and Cmax decreased, with an adjusted geometric mean ratio (90% confidence interval) 29.66% (26.17-33.62) for AUCinf and 64.71% (57.21-73.19) for Cmax . Mean terminal half life decreased from 13.39 to 5.11 hours, geometric mean apparent oral clearance increased from 12.27 to 41.38 l h-1 , whereas median time to Cmax remained similar (1.50 vs. 1.25 hours) in the presence of rifampin. All adverse events (n = 29) were mild in severity and resolved by the end of the study. CONCLUSIONS: Co administration of rifampin expectedly decreased glasdegib AUCinf and Cmax by ~70% and ~35%, respectively. These results will help to formulate recommendations for dosing strategies in combination with CYP3A inducers in situations where co administration may be necessary. (clinicaltrials.gov identifier: NCT02430545). PMID- 29488304 TI - Objectively measured physical activity and cognitive function in urban-dwelling older adults. AB - AIM: Physical activity (PA) and cognition have reportedly been associated with each other. However, it remains to be elucidated what intensities of PA are most strongly associated with cognition. In the current study, we aimed to determine the association between the intensities of objectively measured PA and cognitive function. METHODS: The present study was a cross-sectional analysis of the data obtained at registration in a randomized control trial in Toyota, Japan. Participants were community-dwelling older adults who had cognitive complaints. A battery of neuropsychological and physical assessments was carried out. Daily PA data were collected with the activity monitor. PA was categorized into one of three activity levels defined as light (<3.0 metabolic equivalents; LPA), moderate and vigorous (3.0 metabolic equivalents) activity. Partial correlation analysis was used to investigate the correlation between PA and cognition, with adjustments for age, sex and school years. We then carried out a multiple regression analysis to investigate the association of cognitive performance with PA, adjusting for insulin resistance or depressive mood. RESULTS: Partial correlation adjusted for age, sex and schooling years showed that LPA was significantly correlated with the Digit Symbol Substitution test, Trail Making Test (TMT) part A and TMT-B, whereas moderate and vigorous activity showed no correlations. Multiple regression analysis with several models with different adjustments showed that LPA was associated with the Digit Symbol Substitution test, TMT-A and TMT-B independently from insulin resistance or depressive mood. CONCLUSIONS: In the current study, we found that LPA was significantly associated with the performance of executive functional assessments. Geriatr Gerontol Int 2018; 18: 922-928. PMID- 29488305 TI - Tumor-Targeting Anti-MicroRNA-155 Delivery Based on Biodegradable Poly(ester amine) and Hyaluronic Acid Shielding for Lung Cancer Therapy. AB - Anti-microRNA-155 (anti-miR-155), an oligonucleotide with a complimentary sequence to microRNA-155, holds great promise for lung cancer therapy, and thus some cationic materials have been used to deliver anti-miR-155 into lung tumors. Although the gene delivery capacity in vitro was favorable, the application in vivo was limited by rapid removal and significant cytotoxicity, which were mainly caused by the positive charge of the gene complexes. Therefore, it was necessary to develop a novel carrier to decrease the positive charge and increase the gene delivery capacity into the tumor site. In this paper, biodegradable poly(ester amine) (PEA) was used to condense anti-miR-155 into PEA/anti-miR-155 complexes, and natural anionic polysaccharide hyaluronic acid (HA) was modified with a lung tumor cell targeting peptide and then coated on the surface of gene complexes. The formed hyaluronic acid shielding, PEA/anti-miR-155/HA-peptide complexes were monodispersed, and the particle size and zeta potential were 362.7 nm and -10.17 mV, respectively. In addition, the PEA/anti-miR-155/HA-peptide complexes had good biocompatibility and stability in vitro, and the lung tumor growth inhibitions of PEA/anti-miR-155/HA-peptide in vitro and in vivo were also excellent. The PEA/anti-miR-155/HA-peptide complexes play an active role in tumor growth inhibition and could be useful for lung cancer therapy. PMID- 29488306 TI - 2-Tridecanone impacts surface-associated bacterial behaviours and hinders plant bacteria interactions. AB - Surface motility and biofilm formation are behaviours which enable bacteria to infect their hosts and are controlled by different chemical signals. In the plant symbiotic alpha-proteobacterium Sinorhizobium meliloti, the lack of long-chain fatty acyl-coenzyme A synthetase activity (FadD) leads to increased surface motility, defects in biofilm development and impaired root colonization. In this study, analyses of lipid extracts and volatiles revealed that a fadD mutant accumulates 2-tridecanone (2-TDC), a methylketone (MK) known as a natural insecticide. Application of pure 2-TDC to the wild-type strain phenocopies the free-living and symbiotic behaviours of the fadD mutant. Structural features of the MK determine its ability to promote S. meliloti surface translocation, which is mainly mediated by a flagella-independent motility. Transcriptomic analyses showed that 2-TDC induces differential expression of iron uptake, redox and stress-related genes. Interestingly, this MK also influences surface motility and impairs biofilm formation in plant and animal pathogenic bacteria. Moreover, 2 TDC not only hampers alfalfa nodulation but also the development of tomato bacterial speck disease. This work assigns a new role to 2-TDC as an infochemical that affects important bacterial traits and hampers plant-bacteria interactions by interfering with microbial colonization of plant tissues. PMID- 29488307 TI - The pre-rRNA processing factor Nop53 regulates fungal development and pathogenesis via mediating production of reactive oxygen species. AB - Botrytis cinerea is a necrotrophic plant fungal pathogen that annually causes enormous economic losses worldwide. The ribosome is an organelle for cellular protein biosynthesis. However, little is known about how the ribosome operates as a machine to mediate microbial pathogenesis. Here, we demonstrate that Nop53, a late-acting factor for 60S ribosomal subunit maturation, is crucial for the pathogen's development and virulence. BcNop53 is functionally equivalent to yeast nop53p. Complementation of BcNOP53 completely restored the growth defect of the yeast Deltanop53 mutant. BcNop53 is located in nuclei and disruption of BcNOP53 also dramatically impaired pathogen growth. Deletion of BcNOP53 blocked infection structure formation and abolished virulence of the pathogen, possibly due to reduced production of reactive oxygen species. Moreover, loss of BcNOP53 impaired pathogen conidiation and stress adaptation, altered conidial and sclerotial morphology, retarded conidium and sclerotium germination as well as reduced the activities of cell-wall degradation-associated enzymes. Sclerotium production was, however, increased. Complementation with the wild-type BcNOP53 allele rescued defects found in the DeltaBcnop53 mutant. Our work establishes a systematic elucidation of Nop53 in regulating microbial development and pathogenesis, provides novel insights into ribosomal processes that regulate fungal pathogenesis, and may open up new targets for addressing fungal diseases. PMID- 29488308 TI - Scrutinizing Defects and Defect Density of Selenium-Doped Graphene for High Efficiency Triiodide Reduction in Dye-Sensitized Solar Cells. AB - Understanding the impact of the defects/defect density of electrocatalysts on the activity in the triiodide (I3- ) reduction reaction of dye-sensitized solar cells (DSSCs) is indispensable for the design and construction of high-efficiency counter electrodes (CEs). Active-site-enriched selenium-doped graphene (SeG) was crafted by ball-milling followed by high-temperature annealing to yield abundant edge sites and fully activated basal planes. The density of defects within SeG can be tuned by adjusting the annealing temperature. The sample synthesized at an annealing temperature of 900 degrees C exhibited a superior response to the I3- reduction with a high conversion efficiency of 8.42 %, outperforming the Pt reference (7.88 %). Improved stability is also observed. DFT calculations showed the high catalytic activity of SeG over pure graphene is a result of the reduced ionization energy owing to incorporation of Se species, facilitating electron transfer at the electrode-electrolyte interface. PMID- 29488309 TI - A novel T4SS-mediated DNA transfer used by pXO16, a conjugative plasmid from Bacillus thuringiensis serovar israelensis. AB - The entomopathogenic Bacillus thuringiensis serovar israelensis displays peculiar conjugative transfer capabilities, accounted for by the large conjugative plasmid pXO16 (350 kb). The efficient and fast conjugative transfers are accompanied by a macroscopic aggregation of bacterial partners. Moreover, pXO16 has proven capable of effective mobilization and the retro-transfer of both mobilizable and 'non mobilizable' plasmids. In this work, the aggregation phenomenon is shown to promote pXO16 transfer while not being mandatory for transfer. Transfer of pXO16 to B. thuringiensis recipient strains that do not display aggregation is observed as well, hence enlarging the previously defined host range. The use of variant calling analysis of transconjugants allowed for observation of up to 791 kb chromosomal regions mobilization. Previous analysis of pXO16 did not reveal any Type IV Secretion System (T4SS) homologs, which suggested the presence of an unusual conjugative system. A FtsK/SpOIIIE ATPase gene proved here to be necessary for conjugative transfer. Additionally, the analysis of natural restriction-modification systems in both conjugative partners gave credit to a ssDNA transfer mechanism. A 'transfer israelensis plasmid' (tip) region containing this ATPase gene was shown to code for other potential T4SS proteins, illustrating a conjugative system distantly related to the other known Gram positive T4SSs. PMID- 29488310 TI - Fluoroethylene Carbonate Enabling a Robust LiF-rich Solid Electrolyte Interphase to Enhance the Stability of the MoS2 Anode for Lithium-Ion Storage. AB - As a high-capacity anode for lithium-ion batteries (LIBs), MoS2 suffers from short lifespan that is due in part to its unstable solid electrolyte interphase (SEI). The cycle life of MoS2 can be greatly extended by manipulating the SEI with a fluoroethylene carbonate (FEC) additive. The capacity of MoS2 in the electrolyte with 10 wt % FEC stabilizes at about 770 mAh g-1 for 200 cycles at 1 A g-1 , which far surpasses the FEC-free counterpart (ca. 40 mAh g-1 after 150 cycles). The presence of FEC enables a robust LiF-rich SEI that can effectively inhibit the continual electrolyte decomposition. A full cell with a LiNi0.5 Co0.3 Mn0.2 O2 cathode also gains improved performance in the FEC-containing electrolyte. These findings reveal the importance of controlling SEI formation on MoS2 toward promoted lithium storage, opening a new avenue for developing metal sulfides as high-capacity electrodes for LIBs. PMID- 29488311 TI - Why prescribe exercise as therapy in type 2 diabetes? We have a pill for that! AB - The majority of T2D cases are preventable through a healthy lifestyle, leaving little room for questions that lifestyle should be the first line of defence in the fight against the development of T2D. However, when it comes to the clinical care of T2D, the potential efficacy of lifestyle is much less clear-cut, both in terms of impacting the pathological metabolic biomarkers of the disease, and long term complications. A healthy diet, high leisure-time physical activity, and exercise are considered to be cornerstones albeit adjunct to drug therapy in the management of T2D. The prescription and effective implementation of structured exercise and other lifestyle interventions in the treatment of T2D have not been routinely used. In this article, we critically appraise and debate our reflections as to why exercise and physical activity may not have reached the status of a viable and effective treatment in the clinical care of T2D to the same extent as pharmaceutical drugs. We argue that the reason why exercise therapy is not utilized to a satisfactory degree is multifaceted and primarily relates to a "vicious cycle" with lack of proven efficacy on T2D complications and a lack of proven effectiveness on risk factors in the primary care of T2D. Furthermore, there is a lack of experimental research establishing the optimal dose of exercise. This precludes widespread and sustained implementation of physical activity and exercise in the clinical treatment of T2D will not succeed. PMID- 29488312 TI - Simultaneous Fenton-like Ion Delivery and Glutathione Depletion by MnO2 -Based Nanoagent to Enhance Chemodynamic Therapy. AB - Chemodynamic therapy (CDT) utilizes iron-initiated Fenton chemistry to destroy tumor cells by converting endogenous H2 O2 into the highly toxic hydroxyl radical (. OH). There is a paucity of Fenton-like metal-based CDT agents. Intracellular glutathione (GSH) with . OH scavenging ability greatly reduces CDT efficacy. A self-reinforcing CDT nanoagent based on MnO2 is reported that has both Fenton like Mn2+ delivery and GSH depletion properties. In the presence of HCO3- , which is abundant in the physiological medium, Mn2+ exerts Fenton-like activity to generate . OH from H2 O2 . Upon uptake of MnO2 -coated mesoporous silica nanoparticles (MS@MnO2 NPs) by cancer cells, the MnO2 shell undergoes a redox reaction with GSH to form glutathione disulfide and Mn2+ , resulting in GSH depletion-enhanced CDT. This, together with the GSH-activated MRI contrast effect and dissociation of MnO2 , allows MS@MnO2 NPs to achieve MRI-monitored chemo chemodynamic combination therapy. PMID- 29488313 TI - Dental hygiene education exceeds the degrees granted: A pilot study. AB - OBJECTIVE: Despite expansion of the scope of practice and clinical responsibilities of dental hygienists since 1945, the degrees granted for dental hygiene remain the same. The majority of dental hygienists complete 4 or even 5 years of college to receive an associate's degree while a few earn a baccalaureate degree. The aim of this study was to determine whether an associate's degree appropriately matches the current level of dental hygiene education. METHODOLOGY: This retrospective, analytical pilot study compared contact hours required for dental hygiene programmes in 1945 and three community college dental hygiene programmes and one university programme in Arizona currently. Comparisons were made to determine the relationship between contact hours and credits granted today and how these credit levels relate to the degrees conferred. RESULTS: Today, an associate's degree requires 60 credits. Descriptive statistics revealed that 2-year dental hygienists in 1945 completed the equivalent of 112 contact hours compared to 157 contact hours for associate degree dental hygienists today, a difference of 45 contact hours. Bachelor degree dental hygienists complete 170 contact hours, a difference of 13 contact hours more than associate degree dental hygienists today. This pilot study is limited by the small sample size of dental hygiene programmes included. Further studies are needed that include a broad diversity of dental hygiene programmes. CONCLUSION: Dental hygiene education has grown and expanded significantly since 1945, surpassing the requirements for a 2-year associate's degree. PMID- 29488315 TI - The stepwise development of the lamprey visual system and its evolutionary implications. AB - Lampreys, which represent the oldest group of living vertebrates (cyclostomes), show unique eye development. The lamprey larva has only eyespot-like immature eyes beneath a non-transparent skin, whereas after metamorphosis, the adult has well-developed image-forming camera eyes. To establish a functional visual system, well-organised visual centres as well as motor components (e.g. trunk muscles for locomotion) and interactions between them are needed. Here we review the available knowledge concerning the structure, function and development of the different parts of the lamprey visual system. The lamprey exhibits stepwise development of the visual system during its life cycle. In prolarvae and early larvae, the 'primary' retina does not have horizontal and amacrine cells, but does have photoreceptors, bipolar cells and ganglion cells. At this stage, the optic nerve projects mostly to the pretectum, where the dendrites of neurons in the nucleus of the medial longitudinal fasciculus (nMLF) appear to receive direct visual information and send motor outputs to the neck and trunk muscles. This simple neural circuit may generate negative phototaxis. Through the larval period, the lateral region of the retina grows again to form the 'secondary' retina and the topographic retinotectal projection of the optic nerve is formed, and at the same time, the extra-ocular muscles progressively develop. During metamorphosis, horizontal and amacrine cells differentiate for the first time, and the optic tectum expands and becomes laminated. The adult lamprey then has a sophisticated visual system for image-forming and visual decision-making. In the adult lamprey, the thalamic pathway (retina-thalamus-cortex/pallium) also transmits visual stimuli. Because the primary, simple light-detecting circuit in larval lamprey shares functional and developmental similarities with that of protochordates (amphioxus and tunicates), the visual development of the lamprey provides information regarding the evolutionary transition of the vertebrate visual system from the protochordate-type to the vertebrate-type. PMID- 29488314 TI - Local delivery of tetramethylpyrazine eliminates the senescent phenotype of bone marrow mesenchymal stromal cells and creates an anti-inflammatory and angiogenic environment in aging mice. AB - Aging drives the accumulation of senescent cells (SnCs) including stem/progenitor cells in bone marrow, which contributes to aging-related bone degenerative pathologies. Local elimination of SnCs has been shown as potential treatment for degenerative diseases. As LepR+ mesenchymal stem/progenitor cells (MSPCs) in bone marrow are the major population for forming bone/cartilage and maintaining HSCs niche, whether local elimination of senescent LepR+ MSPCs delays aging-related pathologies and improves local microenvironment need to be well defined. In this study, we performed local delivery of tetramethylpyrazine (TMP) in bone marrow of aging mice, which previously showed to be used for the prevention and treatment of glucocorticoid-induced osteoporosis (GIOP). We found the increased accumulation of senescent LepR+ MSPCs in bone marrow of aging mice, and TMP significantly inhibited the cell senescent phenotype via modulating Ezh2 H3k27me3. Most importantly, local delivery of TMP improved bone marrow microenvironment and maintained bone homeostasis in aging mice by increasing metabolic and anti-inflammatory responses, inducing H-type vessel formation, and maintaining HSCs niche. These findings provide evidence on the mechanisms, characteristics and functions of local elimination of SnCs in bone marrow, as well as the use of TMP as a potential treatment to ameliorate human age-related skeletal diseases and to promote healthy lifespan. PMID- 29488317 TI - Novel 2D Layered Molybdenum Ditelluride Encapsulated in Few-Layer Graphene as High-Performance Anode for Lithium-Ion Batteries. AB - Molybdenum ditelluride nanosheets encapsulated in few-layer graphene (MoTe2 /FLG) are synthesized by a simple heating method using Te and Mo powder and subsequent ball milling with graphite. The as-prepared MoTe2 /FLG nanocomposites as anode materials for lithium-ion batteries exhibit excellent electrochemical performance with a highly reversible capacity of 596.5 mAh g-1 at 100 mA g-1 , a high rate capability (334.5 mAh g-1 at 2 A g-1 ), and superior cycling stability (capacity retention of 99.5% over 400 cycles at 0.5 A g-1 ). Ex situ X-ray diffraction and transmission electron microscopy are used to explore the lithium storage mechanism of MoTe2 . Moreover, the electrochemical performance of a MoTe2 /FLG//0.35Li2 MnO3 .0.65LiMn0.5 Ni0.5 O2 full cell is investigated, which displays a reversible capacity of 499 mAh g-1 (based on the MoTe2 /FLG mass) at 100 mA g-1 and a capacity retention of 78% over 50 cycles, suggesting the promising application of MoTe2 /FLG for lithium-ion storage. First-principles calculations exhibit that the lowest diffusion barrier (0.18 eV) for lithium ions along pathway III in the MoTe2 layered structure is beneficial for improving the Li intercalation/deintercalation property. PMID- 29488316 TI - Receptor-ligand and parasite protein-protein interactions in Plasmodium vivax: Analysing rhoptry neck proteins 2 and 4. AB - Elucidating receptor-ligand and protein-protein interactions represents an attractive alternative for designing effective Plasmodium vivax control methods. This article describes the ability of P. vivax rhoptry neck proteins 2 and 4 (RON2 and RON4) to bind to human reticulocytes. Biochemical and cellular studies have shown that two PvRON2- and PvRON4-derived conserved regions specifically interact with protein receptors on reticulocytes marked by the CD71 surface transferrin receptor. Mapping each protein fragment's binding region led to defining the specific participation of two 20 amino acid-long regions selectively competing for PvRON2 and PvRON4 binding to reticulocytes. Binary interactions between PvRON2 (ligand) and other parasite proteins, such as PvRON4, PvRON5, and apical membrane antigen 1 (AMA1), were evaluated and characterised by surface plasmon resonance. The results revealed that both PvRON2 cysteine-rich regions strongly interact with PvAMA1 Domains II and III (equilibrium constants in the nanomolar range) and at a lower extent with the complete PvAMA1 ectodomain and Domains I and II. These results strongly support that these proteins participate in P. vivax's complex invasion process, thus providing new pertinent targets for blocking P. vivax merozoites' specific entry to their target cells. PMID- 29488318 TI - Are the MDS-UPDRS-Based Composite Scores Clinically Applicable? AB - BACKGROUND: The International Parkinson and Movement Disorder Society-sponsored UPDRS (MDS-UPDRS) is a powerful clinical outcome measure. OBJECTIVES: To evaluate the feasibility of various MDS-UPDRS-based composite scores and determine their minimal clinically important difference threshold values. METHODS: Overall, 1,113 paired investigations of 452 patients were reviewed implementing three different techniques simultaneously. RESULTS: Based on the ordinal regression modeling, the MDS-UPDRS II+III, MDS-UPDRS I+II+III, and the total score of MDS-UPDRS are clinically applicable outcome measures. Any improvement greater than 4.9 points or any worsening more than 4.2 points on MDS-UPDRS II+III represent a minimal, yet clinically meaningful, change. In reference to MDS-UPDRS I+II+III, the smallest changes considered clinically relevant were 6.7 and 5.2 points for improvement and deterioration, respectively. The thresholds for the total score of MDS-UPDRS were 7.1 points for improvement and 6.3 points for worsening. CONCLUSIONS: Our findings support the application of various MDS-UPDRS-based composite scores. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29488319 TI - Identification of transcripts potentially involved in neural tube closure using RNA sequencing. AB - Anencephaly is a fatal human neural tube defect (NTD) in which the anterior neural tube remains open. Zebrafish embryos with reduced Nodal signaling display an open anterior neural tube phenotype that is analogous to anencephaly. Previous work from our laboratory suggests that Nodal signaling acts through induction of the head mesendoderm and mesoderm. Head mesendoderm/mesoderm then, through an unknown mechanism, promotes formation of the polarized neuroepithelium that is capable of undergoing the movements required for closure. We compared the transcriptome of embryos treated with a Nodal signaling inhibitor at sphere stage, which causes NTDs, to embryos treated at 30% epiboly, which does not cause NTDs. This screen identified over 3,000 transcripts with potential roles in anterior neurulation. Expression of several genes encoding components of tight and adherens junctions was significantly reduced, supporting the model that Nodal signaling regulates formation of the neuroepithelium. mRNAs involved in Wnt, FGF, and BMP signaling were also differentially expressed, suggesting these pathways might regulate anterior neurulation. In support of this, we found that pharmacological inhibition of FGF-receptor function causes an open anterior NTD as well as loss of mesodermal derivatives. This suggests that Nodal and FGF signaling both promote anterior neurulation through induction of head mesoderm. PMID- 29488320 TI - Simple and rapid system for two-dimensional gel electrophoresis technique: A laboratory exercise for high school students. AB - Polyacrylamide gel electrophoresis (PAGE) is the most classical technique favored worldwide for resolution of macromolecules in many biochemistry laboratories due to its incessant advanced developments and wide modifications. These ever-growing advancements in the basic laboratory equipments lead to emergence of many expensive, complex, and tricky laboratory equipments. Practical courses of biochemistry at high school or undergraduate levels are often affected by these complications. Two dimensional gel electrophoresis technique (2D-PAGE) used for resolving thousands of proteins in a gel is a combination of isoelectric focusing (first dimension gel electrophoresis technique) and sodium-dodecylsulphate PAGE (second dimension gel electrophoresis technique or SDS-PAGE). Two different laboratory equipments are needed to carry out effective 2D-PAGE technique, which also invites extra burden to the school laboratory. Here, we describe a low cost, time saving and simple gel cassette for protein 2D-PAGE technique that uses easily fabricated components and routine off-the-shelf materials. The performance of the apparatus was verified in a practical exercise by a group of high school students with positive outcomes. (c) 2018 by The International Union of Biochemistry and Molecular Biology, 46(3):237-244, 2018. PMID- 29488321 TI - Polyplex Particles Based on Comb-Like Polyethylenimine/Poly(2-ethyl-2-oxazoline) Copolymers: Relating Biological Performance with Morphology and Structure. AB - The present contribution is focused on feasibility of using comb-like copolymers of polyethylenimine with poly(2-ethyl-2-oxazoline) (LPEI-comb-PEtOx) with varying grafting densities and degrees of polymerization of PEI and PEtOx to deliver DNA molecules into cells. The copolymers form small and well-defined particles at elevated temperatures, which are used as platforms for binding and condensing DNA. The electrostatic interactions between particles and DNA result in formation of sub-100 nm polyplex particles of narrow size distribution and different morphology and structure. The investigated gene delivery systems exhibit transfection efficiency dependent on the copolymer chain topology, shape of the polyplex particles, and internalization pathway. Flow cytometry shows enhanced transfection efficiency of the polyplexes with elongated and ellipsoidal morphology. The preliminary biocompatibility study on a panel of human cell lines shows that pure copolymers and polyplexes thereof are practically devoid of cytotoxicity. PMID- 29488322 TI - Heterojunction Hybrid Solar Cells by Formation of Conformal Contacts between PEDOT:PSS and Periodic Silicon Nanopyramid Arrays. AB - Surface nanotexturing with excellent light-trapping property is expected to significantly increase the conversion efficiency of solar cells. However, limited by the serious surface recombination arising from the greatly enlarged surface area, the silicon (Si) nanotexturing-based solar cells cannot yet achieve satisfactory high efficiency, which is more prominent in organic/Si hybrid solar cells (HSCs) where a uniform polymer layer can rarely be conformably coated on nanotextured substrate. Here, the HSCs featuring advanced surface texture of periodic upright nanopyramid (UNP) arrays and hole-conductive conjugated polymers, poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS), are investigated. The tetramethylammonium hydroxide etching is used to smooth the surface morphologies of the Si-UNPs, leading to reduced surface defect states. The uniform Si-UNPs together with silane chemical-incorporated PEDOT:PSS solution enable the simultaneous realization of excellent broadband light absorption as well as enhanced electrical contact between the textured Si and the conducting polymer. The resulting PEDOT:PSS/Si HSCs textured with UNP arrays show a promising power conversion efficiency of 13.8%, significantly higher than 12.1% of the cells based on the-state-of-the-art surface texture with random pyramids. These results provide a viable route toward shape-controlled nanotexturing-based high-performance organic/Si HSCs. PMID- 29488323 TI - Augmented reality experimentation on oxygen gas generation from hydrogen peroxide and bleach reaction. AB - The appreciation and understanding of gas generation through processes is vital in biochemical education. In this work, an augmented reality tool is reported to depict the redox reaction between hydrogen peroxide and sodium hypochlorite solutions, two ubiquitous oxidizing agents, to create oxygen, a combustible gas. As it operates out of smartphones or tablets, students are able to conduct the exercise collaboratively, respond in a manner similar to an actual physical experiment, and able to depict the oxygen volume changes in relation to the volume of hydrogen peroxide of different concentrations used. The tool offers to help students acquire bench skills by limiting handing risks and to mitigate possible student anxiety on handling chemical materials and implements in the laboratory. The feedback received from Year 11 and 12 high school student participants in an outreach exercise indicate the overall effectiveness of this tool. (c) 2018 by The International Union of Biochemistry and Molecular Biology, 46(3):245-252, 2018. PMID- 29488324 TI - Community-based education: Experiences of undergraduate dental therapy students at the University of KwaZulu-Natal, South Africa. AB - BACKGROUND: Community-based education (CBE) is a learning strategy that provides meaningful opportunities for students to apply theory learnt in a larger social and cultural context in various community settings. Although the benefits of CBE to health professional students are well documented, to date, there is little evidence describing dental therapy students' experiences. OBJECTIVES: To describe the experience of CBE by undergraduate dental therapy students in the School of Health Sciences at the University of KwaZulu-Natal. METHODS: This descriptive study, conducted in 2016, gives insight into the experiences of community-based education among dental therapy students using a self-administered questionnaire eliciting qualitative data. Ethical clearance was obtained from the institution. RESULTS: Students reported perceived benefits of improved professional and personal growth, and a deeper understanding of cultural, social and economic influences on oral health care. Some of the perceived challenges included language barrier, limited resources and adapting to new environments. CONCLUSION: The reported experiences of undergraduate dental therapy students involved in community-based clinical training suggest that students gained awareness of the context-specific challenges facing communities and health professionals in different oral health settings. PMID- 29488326 TI - Abstracts of the Caribbean Urological Association 19th Annual Conference San Fernando, Trinidad and Tobago, West Indies, 03rd-05th November, 2017. PMID- 29488325 TI - Resilience to aging in the regeneration-capable flatworm Macrostomum lignano. AB - Animals show a large variability of lifespan, ranging from short-lived as Caenorhabditis elegans to immortal as Hydra. A fascinating case is flatworms, in which reversal of aging by regeneration is proposed, yet conclusive evidence for this rejuvenation-by-regeneration hypothesis is lacking. We tested this hypothesis by inducing regeneration in the sexual free-living flatworm Macrostomum lignano. We studied survival, fertility, morphology, and gene expression as a function of age. Here, we report that after regeneration, genes expressed in the germline are upregulated at all ages, but no signs of rejuvenation are observed. Instead, the animal appears to be substantially longer lived than previously appreciated, and genes expressed in stem cells are upregulated with age, while germline genes are downregulated. Remarkably, several genes with known beneficial effects on lifespan when overexpressed in mice and C. elegans are naturally upregulated with age in M. lignano, suggesting that molecular mechanism for offsetting negative consequences of aging has evolved in this animal. We therefore propose that M. lignano represents a novel powerful model for molecular studies of aging attenuation, and the identified aging gene expression patterns provide a valuable resource for further exploration of anti aging strategies. PMID- 29488328 TI - Phosphodiesterase (PDE5) inhibition assay for rapid detection of erectile dysfunction drugs and analogs in sexual enhancement products. AB - Products marketed as dietary supplements for sexual enhancement are frequently adulterated with phosphodiesterase-5 (PDE5) inhibitors, which are erectile dysfunction drugs or their analogs that can cause adverse health effects. Due to widespread adulteration, a rapid screening assay was developed to detect PDE5 inhibitors in adulterated products. The assay employs fluorescence detection and is based on measuring inhibition of PDE5 activity, the pharmacological mechanism shared among the adulterants. Initially, the assay reaction scheme was established and characterized, followed by analysis of 9 representative PDE5 inhibitors (IC50 , 0.4-4.0 ng mL-1 ), demonstrating sensitive detection in matrix free solutions. Next, dietary supplements serving as matrix blanks (n = 25) were analyzed to determine matrix interference and establish a threshold value; there were no false positives. Finally, matrix blanks were spiked with 9 individual PDE5 inhibitors, along with several mixtures. All 9 adulterants were successfully detected (<= 5 % false negative rate; n = 20) at a concentration of 1.00 mg g-1 , which is over 5 times lower than concentrations commonly encountered in adulterated products. A major distinction of the PDE5 inhibition assay is the ability to detect adulterants without prior knowledge of their chemical structures, demonstrating a broad-based detection capability that can address a continuously evolving threat of new adulterants. The PDE5 inhibition assay can analyze over 40 samples simultaneously within 15 minutes and involves a single incubation step and simple data analysis, all of which are advantageous for combating the widespread adulteration of sex-enhancement products. PMID- 29488327 TI - Antimicrobial photodynamic inactivation is potentiated by the addition of selenocyanate: Possible involvement of selenocyanogen? AB - We previously showed that antimicrobial photodynamic inactivation (aPDI) of Gram positive and Gram-negative bacteria mediated by the phenothiazinium dye, methylene blue (MB), was potentiated by the addition of potassium thiocyanate (10 mM). The mechanism was suggested to involve a singlet oxygen-mediated reaction with SCN to form sulfite and cyanide and then to produce sulfur trioxide radical anion. We now report that potassium selenocyanate (concentrations up to 100 mM) can also potentiate (up to 6 logs of killing) aPDI mediated by a number of different photosensitizers (PS): MB, rose bengal and 5,10,15,20-tetrakis(4 sulfonatophenyl)porphyrin dihydrochloride (as low as 200 nM). When a mixture of selenocyanate with these PS in solution was illuminated and then bacteria were added after the light, there was up to 6 logs of killing (Gram-negative > Gram positive) but the antibacterial species decayed rapidly (by 20 minutes). Our hypothesis to explain this antibacterial activity is the formation of selenocyanogen (SeCN)2 by reaction with singlet oxygen (1 O2 ) as shown by quenching of 1 O2 by SeCN and increased photoconsumption of oxygen. The fact that lead tetraacetate reacted with SeCN (literature preparation of (SeCN)2 ) also produced a short-lived antibacterial species supports this hypothesis. PMID- 29488329 TI - Method comparison of two non-invasive dual-wavelength spectrophotometric retinal oximeters in healthy young subjects during normoxia. AB - PURPOSE: Spectrophotometric retinal oximetry is a non-invasive technology for measuring oxygen saturation in arterioles and venules (SaO2 , SvO2 ). We compared two commercially available systems: the Oxymap T1 (Oxymap ehf., Reykjavik, Iceland) and the Dynamic Vessel Analyzer (DVA, Imedos, Jena, Germany). METHODS: Twenty healthy adults were included after giving informed consent. Two measurement cycles 30 min apart, including Oxymap T1, DVA, arterialized capillary blood draw of the earlobe (ScO2 ) and peripheral oxygen saturation using finger pulse oximetry (SpO2 ) were scheduled. RESULTS: SaO2 (p > 0.0004) but not SvO2 (p < 0.05) was statistically significantly different between the retinal oximeters used. Agreement between devices using repeated SO2 measurements resulted in a standard deviation (SD) of differences of 3.5% in retinal arterioles and 4.8% in venules. Bland-Altman plot using the mean of a participant's two measurements from each device showed an average mean difference of 4.4% (95% confidence limits of agreement: -8.6 to 17.4) and -3.3% (95% confidence limits of agreement: -28.8 to 22.2) for SaO2 and SvO2 , respectively. Comparison of mean SaO2 and SvO2 with mean ScO2 and SpO2 indicated that SO2 measurements were generally higher in ScO2 and SpO2 . CONCLUSION: This study shows very good repeatability for both devices, which is consistent with the literature. However, it does not show sufficient concordance between SaO2 measurements from both devices, indicating that patients should be followed by one device only. Differences in absorbance wavelengths used and image post-processing may explain the differences. PMID- 29488331 TI - Inhibition of Lats1/p-YAP1 pathway mitigates neuronal apoptosis and neurological deficits in a rat model of traumatic brain injury. AB - AIMS: To investigate the roles of Lats1/p-YAP1 pathway in TBI-induced neuronal apoptosis and neurological deficits in rats. RESULTS: We found that Lats1 and YAP1 were expressed in cerebral cortex neurons of Sprague-Dawley rats, and the phosphorylation levels of Lats1 and YAP1 in injured regions were significantly increased after TBI. Furthermore, inhibition of Lats1 not only decreased the level of p-YAP1, but also attenuated neuronal apoptosis and neurological impairment. CONCLUSIONS: Our work demonstrates that inhibition of Lats1/p-YAP1 pathway mitigates neuronal apoptosis and neurological deficits in a rat model of TBI. PMID- 29488330 TI - ALK-rearrangement in non-small-cell lung cancer (NSCLC). AB - The ALK gene encodes a transmembrane tyrosine kinase receptor. ALK is physiologically expressed in the nervous system during embryogenesis, but its expression decreases postnatally. ALK first emerged in the field of oncology in 1994 when it was identified to fuse to NPM1 in anaplastic large-cell lymphoma. Since then, ALK has been associated with other types of cancers, including non small-cell lung cancer (NSCLC). More than 19 different ALK fusion partners have been discovered in NSCLC, including EML4, KIF5B, KLC1, and TPR. Most of these ALK fusions in NSCLC patients respond well to the ALK inhibitor, crizotinib. In this paper, we reviewed fusion partner genes with ALK, detection methods for ALK rearrangement (ALK-R), and the ALK-tyrosine kinase inhibitor, crizotinib, used in NSCLC patients. PMID- 29488333 TI - Are you interested in joining the BACCN national board? PMID- 29488332 TI - Critical care research and the wisdom of hindsight. PMID- 29488335 TI - Professional Advisors News. PMID- 29488334 TI - What's in this Issue. PMID- 29488336 TI - *CALLING ALL MANAGERS* - Critical Care Unit Membership. PMID- 29488338 TI - Research in Critical Care - Conference opportunity for BACCN members. PMID- 29488339 TI - Future Events - Bookings Open. PMID- 29488340 TI - BACCN Dragon's Den 2018 - Apply now! PMID- 29488341 TI - 33rd Annual BACCN Conference 2018, Bournemouth: Sustainability in Excellence - The Future of Critical Care. PMID- 29488342 TI - PGE2-EP3 signaling exacerbates hippocampus-dependent cognitive impairment after laparotomy by reducing expression levels of hippocampal synaptic plasticity related proteins in aged mice. AB - AIM: Multifactors contribute to the development of postoperative cognitive dysfunction (POCD), of which the most important mechanism is neuroinflammation. Prostaglandin E2 (PGE2) is a key neuroinflammatory molecule and could modulate hippocampal synaptic transmission and plasticity. This study was designed to investigate whether PGE2 and its receptors signaling pathway were involved in the pathophysiology of POCD. METHODS: Sixteen-month old male C57BL/6J mice were exposed to laparotomy. Cognitive function was evaluated by fear conditioning test. The levels of PGE2 and its 4 distinct receptors (EP1-4) were assessed by biochemical analysis. Pharmacological or genetic methods were further applied to investigate the role of the specific PGE2 receptors. RESULTS: Here, we found that the transcription and translation level of the EP3 receptor in hippocampus increased remarkably, but not EP1, EP2, or EP4. Immunofluorescence results showed EP3 positive cells in the hippocampal CA1 region were mainly neurons. Furthermore, pharmacological blocking or genetic suppression of EP3 could alleviate surgery-induced hippocampus-dependent memory deficits and rescued the expression of plasticity-related proteins, including cAMP response element binding protein (CREB), activity-regulated cytoskeletal-associated protein (Arc), and brain-derived neurotrophic factor (BDNF) in hippocampus. CONCLUSION: This study showed that PGE2-EP3 signaling pathway was involved in the progression of POCD and identified EP3 receptor as a promising treatment target. PMID- 29488343 TI - Management of distal radius fractures in the emergency department: A long-term functional outcome measure study with the Disabilities of Arm, Shoulder and Hand (DASH) scores. AB - OBJECTIVE: Distal radius fracture (DRF) is a common presentation to the ED. However, little is known about the long-term functional outcome of these patients following their initial management in the ED. METHODS: In order to evaluate the long-term functional outcome of DRF, we collected the Disabilities of Arm, Shoulder and Hand (DASH) scores from the patients who attended our ED with DRF between January 2014 and June 2015. We divided the patients into two groups based on their overall management: (i) conservative group who did not have any surgical interventions; and (ii) open reduction internal fixation (ORIF) group who needed surgical interventions in the theatre. Multiple linear regression models were used to identify the statistically significant predictor variables. RESULTS: Out of the 229 patients whom we contacted, 128 patients responded. The response rate was 56%. The majority of the patients belonged to the conservative group (n = 87, 75%), while one-quarter of the patients were in the ORIF group (n = 29, 25%). DASH score was higher in the ORIF group (median = 12.1, 95% confidence interval 5.6-25) than the conservative group (median = 6, 95% confidence interval 1.7 16.4). This difference between the groups was statistically significant (unadjusted P = 0.017, Wilcoxon test). Multiple linear regression models revealed that the management group and age of the patients were significant predictors for DASH score. CONCLUSION: Conservative management had lower DASH scores signifying better functional outcomes. Further prospective multicentre studies may be suggested to assess the generalisability of the study. PMID- 29488344 TI - High contrast imaging and flexible photomanipulation for quantitative in vivo multiphoton imaging with polygon scanning microscope. AB - In this study, we introduce two key improvements that overcome limitations of existing polygon scanning microscopes while maintaining high spatial and temporal imaging resolution over large field of view (FOV). First, we proposed a simple and straightforward means to control the scanning angle of the polygon mirror to carry out photomanipulation without resorting to high speed optical modulators. Second, we devised a flexible data sampling method directly leading to higher image contrast by over 2-fold and digital images with 100 megapixels (10 240 * 10 240) per frame at 0.25 Hz. This generates sub-diffraction limited pixels (60 nm per pixels over the FOV of 512 MUm) which increases the degrees of freedom to extract signals computationally. The unique combined optical and digital control recorded fine fluorescence recovery after localized photobleaching (r ~10 MUm) within fluorescent giant unilamellar vesicles and micro-vascular dynamics after laser-induced injury during thrombus formation in vivo. These new improvements expand the quantitative biological-imaging capacity of any polygon scanning microscope system. PMID- 29488345 TI - Chronic use of teething gel causing salicylate toxicity. PMID- 29488346 TI - Reduction of intraocular pressure after bariatric surgery. AB - PURPOSE: To investigate the effects of bariatric surgery on intraocular pressure (IOP). METHODS: We prospectively enroled consecutive obese patients who underwent a laparoscopic sleeve gastrectomy procedure. We measured IOP prior to and 3-6 months following surgery and recorded medical and demographical parameters. RESULTS: Thirty-two patients completed all evaluations. Mean age was 40.5 +/- 12 and 24 (75%) were men. Following surgery, mean body-mass index (BMI) decreased from 42 +/- 6 to 31 +/- 8 (p < 0.001). The mean IOP decreased from 16.9 +/- 4 mmHg to 14.1 +/- 3 mmHg (p < 0.001). The extent of IOP reduction was correlated with the baseline IOP (Pearson r = 0.737, p < 0.001) and central corneal thickness (Pearson r = 0.453, p = 0.010). CONCLUSION: In a cohort of obese individuals undergoing sleeve gastrectomy, there was a significant decrease in IOP measured 3-6 months after the procedure. Our results suggest that significant weight loss could have beneficial effects on IOP in obese individuals with ocular hypertension which might enable avoidance of antiglaucoma medications. The high likelihood of a reduction in IOP should be taken into account when considering bariatric surgery in such patients. PMID- 29488347 TI - Random peptide mixtures as new crop protection agents. AB - Many types of crops are severely affected by at least one important bacterial disease. Chemical control of bacterial plant diseases in the field vastly relies on copper-based bactericides, yet with limited efficacy. In this study, we explored the potential of two random peptide mixture (RPM) models as novel crop protection agents. These unique peptide mixtures consist of random combination of l-phenylalanine and l- or d-lysine (FK-20 and FdK-20, respectively) along the 20 mer chain length of the peptides. Both RPMs displayed powerful bacteriostatic and bactericidal activities towards strains belonging to several plant pathogenic bacterial genera, for example, Xanthomonas, Clavibacter and Pseudomonas. In planta studies in the glasshouse revealed that RPMs significantly reduced disease severity of tomato and kohlrabi plants infected with Xanthomonas perforans and Xanthomonas campestris pv. campestris respectively. Moreover, RPM effects on reduction in disease severity were similar to those exerted by the commercial copper-based bactericide Kocide 2000 that was applied at a 12-fold higher concentration of the active compound relative to the RPM treatments. Importantly, the two tested RPM compounds had no toxic effect on survival of bees and Caco-2 mammalian cells. This study demonstrates the potential of these innovative RPMs to serve as crop protection agents against crop diseases caused by phytopathogenic bacteria. PMID- 29488348 TI - Buffering roles of (pro)renin receptor in starvation-induced autophagy of skeletal muscles. AB - Autophagy is an intracellular catabolic process contributing to the regulation of nutrient homeostasis and cellular remodeling. Studies revealed that the nuclear translocation of transcription factor EB (TFEB) plays a key role in lysosomal biogenesis and autophagic pathways. The (pro)renin receptor [(P)RR] is a multifunctional protein playing a pivotal role in regulation of the tissue renin angiotensin system and is known as an essential constituent of vacuolar H+ ATPase, considered to be necessary for the autophagy-lysosome pathway. On the basis of these findings, we postulated that (P)RR may also contribute to the regulation of starvation-induced autophagy. In this study, starvation increased the expression of (P)RR and autophagy-related genes, especially, in the skeletal muscles of mice. In C2C12 mouse myoblast cells, starvation increased (P)RR expression and TFEB translocation, leading to the expression of autophagy-related genes. Knockdown of (P)RR enhanced both the TFEB translocation to the nucleus and the expression of autophagy-related genes during starvation. These results suggest that (P)RR plays a buffering role in starvation-induced autophagy by affecting the nuclear translocation of TFEB. Thus, (P)RR, which increases during starvation, is one of the important factors that control autophagy in the skeletal muscles. (P)RR may act as a buffer to reduce excessive TFEB-dependent autophagy flux. PMID- 29488349 TI - Insights into microbial involvement in desert varnish formation retrieved from metagenomic analysis. AB - Desert varnishes are dark rock coatings observed in arid environments and might resemble Mn-rich coatings found on Martian rocks. Their formation mechanism is not fully understood and the possible microbial involvement is under debate. In this study, we applied DNA metagenomic Shotgun sequencing of varnish and surrounding soil to evaluate the composition of the microbial community and its potential metabolic function. We found that the alpha diversity was lower in varnish compared to soil samples (p value < 0.05), suggesting distinct populations with significantly higher abundance of Actinobacteria, Proteobacteria and Cyanobacteria within the varnish. Additionally, we observed increased levels of transition metal metabolic processes in varnish compared to soil samples. Nevertheless, potentially relevant enzymes for varnish formation were detected at low to insignificant levels in both niches, indicating no current direct microbial involvement in Mn oxidation. This finding is supported by quantitative genomic analysis, elemental analysis, fluorescence imaging and scanning transmission X-ray microscopy. We thus conclude that the distinct microbial communities detected in desert varnish originate from settled Aeolian microbes, which colonized this nutrient-enriched niche, and discuss possible indirect contributions of microorganisms to the formation of desert varnish. PMID- 29488350 TI - Transglycosylation: A Key Reaction to Access Alkylpolyglycosides from Lignocellulosic Biomass. AB - An overview is provided on the recent advances in transglycosylation of cellulose and hemicellulose with either short-chain or long-chain alkyl alcohols. Catalytic processes are compared in terms of yield, selectivity and space-time yield, with a view to identifying the most promising pathways for future developments. In this context, the synthesis of alkylpolyglycosides directly from lignocellulosic biomass is discussed while keeping in mind the impact of the botanical origin on the transglycosylation reaction and the product distribution. A section dedicated to the physicochemical properties and ecological footprint of alkylpolyglycosides is also included. PMID- 29488351 TI - Risk for Complicated Immigration Transition: New Diagnosis for NANDA International. AB - OBJECTIVE: The objective of this article is to describe the developmental processes for the creation of the new diagnosis risk for complicated immigration transition for the NANDA-I. METHODS: The study followed the recommended steps of developmental processes for NANDA-I. The identification of risk factors,which cause those who have migrated to feel vulnerable, is the result of two different research studies aimed at identifying nursing diagnosis related to the immigration process. RESULTS: A proposal of label, definition and risk factors of risk for complicated immigration transition. CONCLUSIONS: This new nursing diagnosis will reinforce the strategies for nursing interventions directed to empower immigrant people to acquire and/or develop the resources needed to cope with the immigration process. PMID- 29488352 TI - Microbial community networks associated with variations in community respiration rates during upwelling in nearshore Monterey Bay, California. AB - Respiration of organic material is a central process in the global carbon (C) cycle catalysed by diverse microbial communities. In the coastal ocean, upwelling can drive variation in both community respiration (CR) and the microbial community, but linkages between the two are not well-understood. We measured CR rates and analysed microbial dynamics via 16S rRNA gene sequencing, to assess whether CR correlated with upwelling irrespective of changes in the microbial community, or if the particular microbial community present was a factor in explaining variations in CR. CR varied significantly over time as a function of temperature, dissolved oxygen (DO) and chlorophyll-all of which are altered by upwelling-but also varied with a 'subnetwork' (i.e., a group of microbial taxa that covaried with one another) of the whole community. One subnetwork was associated with higher CR and warmer temperatures, while another was associated with lower CR and DO. Our results suggest that CR in the coastal ocean varies with both environmental variables, and a portion of the microbial community that is not directly correlated with upwelling intensity. PMID- 29488353 TI - Effects of microRNA-133b on retinal vascular endothelial cell proliferation and apoptosis through angiotensinogen-mediated angiotensin II- extracellular signal regulated kinase 1/2 signalling pathway in rats with diabetic retinopathy. AB - PURPOSE: This study aimed to explore the effects of microRNA-133b (miR-133b) on diabetic retinopathy (DR) by targeting angiotensinogen (AGT) through the angiotensin-II (AngII) extracellular signal-regulated kinase 1/2 (ERK1/2) signalling pathway in rats. METHODS: The DR rat model was established using retinal tissues of DR rats and normal rats. Immunohistochemistry was performed to detect the protein expressions of AGT and CD34 in retinal tissues. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were applied to detect miR-133b expression, AGT, AngII, ERK1/2 mRNA, and protein expressions in tissues and cells after transfection. Retinal vascular endothelial cells were cultured and divided into normal, blank, miR-133b mimics, miR-133b mimics negative control (NC), miR-133b inhibitors, miR-133b inhibitors NC, siRNA NC, siRNA-AGT, and miR-133b inhibitors + siRNA-AGT groups. 3-(4,5-dimethyl-2 thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay was performed to detect cell proliferation. Cell cycle and apoptosis were evaluated using flow cytometry. RESULTS: Compared with normal rats, AGT and CD34 were expressed more frequently in DR rats. MicroRNA (miR)-133b expression was downregulated but AGT, AngII, ERK1 and ERK2 mRNA expressions were upregulated in retinal tissues of DR rats. When compared to the normal group, all other groups displayed decreased cell proliferation, increased cell number in G0/G1, decreased cell number in S stage, increased cell apoptosis rate and declined miR-133b expression. As well, significant increased expressions of AGT and the AngII-ERK1/2 pathway-related proteins were observed in retinal vascular endothelial cells in all groups except the normal group. The miR-133b mimics and siRNA-AGT groups had increased cell proliferation, decreased cell number in the G0/G1 phase, increased cell number in S stage, decreased cell apoptosis rate and decreased expressions of AGT and AngII ERK1/2 pathway-related proteins than the miR-133b inhibitors + siRNA-AGT group. The miR-133b inhibitors group exhibited opposite trends compared with the miR 133b mimics and siRNA-AGT groups. CONCLUSION: The study provides data to suggest that miR-133b induces proliferation and inhibits apoptosis of retinal vascular endothelial cells by targeting AGT through the AngII-ERK1/2 signalling pathway in DR rats. PMID- 29488354 TI - Xanthomonas citri T6SS mediates resistance to Dictyostelium predation and is regulated by an ECF sigma factor and cognate Ser/Thr kinase. AB - Plant-associated bacteria of the genus Xanthomonas cause disease in a wide range of economically important crops. However, their ability to persist in the environment is still poorly understood. Predation by amoebas represents a major selective pressure to bacterial populations in the environment. In this study, we show that the X. citri type 6 secretion system (T6SS) promotes resistance to predation by the soil amoeba Dictyostelium discoideum. We found that an extracytoplasmic function (ECF) sigma factor (EcfK) is required for induction of T6SS genes during interaction with Dictyostelium. EcfK homologues are found in several environmental bacteria in association with a gene encoding a eukaryotic like Ser/Thr kinase (pknS). Deletion of pknS causes sensitivity to amoeba predation and abolishes induction of T6SS genes. Phosphomimetic mutagenesis of EcfK identified a threonine residue (T51) that renders EcfK constitutively active in standard culture conditions. Moreover, susceptibility of DeltapknS to Dictyostelium predation can be overcome by expression of the constitutively active version EcfKT51E from a multicopy plasmid. Together, these results describe a new regulatory cascade in which PknS functions through activation of EcfK to promote T6SS expression. Our work reveals an important aspect of Xanthomonas physiology that affects its ability to persist in the environment. PMID- 29488355 TI - Individualized treatment strategies for hyperuricemia informed by a semi mechanistic exposure-response model of uric acid dynamics. AB - To provide insight into pharmacological treatment of hyperuricemia we developed a semi-mechanistic, dynamical model of uric acid (UA) disposition in human. Our model represents the hyperuricemic state in terms of production of UA (rate, PUA), its renal filtration (glomerular filtration rate, GFR) and proximal tubular reabsorption (fractional excretion coefficient, FE). Model parameters were estimated using data from 9 Phase I studies of xanthine oxidase inhibitors (XOI) allopurinol and febuxostat and a novel uricosuric, the selective UA reabsorption inhibitor lesinurad, approved for use in combination with a XOI. The model was qualified for prediction of the effect of patients' GFR and FE on concentration of UA in serum (sUA) and UA excretion in urine and their response to drug treatment, using data from 2 Phase I and 4 Phase III studies of lesinurad. Percent reduction in sUA from baseline by a XOI is predicted to be independent of GFR, FE or PUA. Uricosurics are more effective in underexcreters of UA or patients with normal GFR. Co-administration of a XOI and an uricosuric agent should be considered for patients with high sUA first in the treatment algorithm of gout before uptitration of XOI. The XOI dose in combination with a uricosuric can be reduced compared to XOI alone for the same target sUA to the degree dependent on patient's GFR and FE. This exposure-response model of UA can be used to rationally select the best drug treatment option to lower elevated sUA in gout patients under differing pathophysiological situations. PMID- 29488356 TI - P2X7 receptor antagonism ameliorates renal dysfunction in a rat model of sepsis. AB - Sepsis is a major clinical problem associated with significant organ dysfunction and high mortality. The ATP-sensitive P2X7 receptor activates the NLRP3 inflammasome and is a key component of the innate immune system. We used a fluid resuscitated rat model of fecal peritonitis and acute kidney injury (AKI) to investigate the contribution of this purinergic receptor to renal dysfunction in sepsis. Six and 24 h time-points were chosen to represent early and established sepsis, respectively. A selective P2X7 receptor antagonist (A-438079) dissolved in dimethyl sulfoxide (DMSO) was infused 2 h following induction of sepsis. Compared with sham-operated animals, septic animals had significant increases in heart rate (-1(-4 to 8)% vs. 21(12-26)%; P = 0.003), fever (37.4(37.2-37.6) degrees C vs. 38.6(38.2-39.0) degrees C; P = 0.0009), and falls in serum albumin (29(27-30)g/L vs. 26(24-28); P = 0.0242). Serum IL-1beta (0(0-10)(pg/mL) vs. 1671(1445-33778)(pg/mL); P < 0.001) and renal IL-1beta (86(50-102)pg/mg protein vs. 200 (147-248)pg/mg protein; P = 0.0031) were significantly elevated in septic compared with sham-operated animals at 6 h. Serum creatinine was elevated in septic animals compared with sham-operated animals at 24 h (23(22-25) MUmol/L vs. 28 (25-30)MUmol/L; P = 0.0321). Renal IL-1beta levels were significantly lower in A-438079-treated animals compared with untreated animals at 6 h (70(55-128)pg/mg protein vs. 200(147-248)pg/mg protein; P = 0.021). At 24 h, compared with untreated animals, A-438079-treated animals had more rapid resolution of tachycardia (22(13-36)% vs. -1(-6 to 7)%; P = 0.019) and fever (39.0(38.6-39.1) degrees C vs. 38.2(37.6-38.7) degrees C; P < 0.024), higher serum albumin (23(21 25)g/L vs. (27(25-28)g/L); P = 0.006), lower arterial lactate (3.2(2.5-4.3)mmol/L vs. 1.4(0.9-1.8)mmol/L; P = 0.037), and lower serum creatinine concentrations (28(25-30)MUmol/L vs. 22(17-27)MUmol/L; P = 0.019). P2X7 A treatment ameliorates the systemic inflammatory response and renal dysfunction in this clinically relevant model of sepsis-related AKI. PMID- 29488357 TI - In Focus: Innovative crop protection for 21st century food security. PMID- 29488358 TI - Effect of KCNQ1 G229D mutation on cardiac pumping efficacy and reentrant dynamics in ventricles: Computational study. AB - There is growing interest in genetic arrhythmia since mutations in gene which encodes the ion channel underlie numerous arrhythmias. Hasegawa et al reported that G229D mutation in KCNQ1 underlies atrial fibrillation due to significant shortening of action potential duration (APD) in atrial cells. Here, we predicted whether KCNQ1 G229D mutation affects ventricular fibrillation generation, although it shortens APD slightly compared with the atrial cell. We analyzed the effects of G229D mutation on electrical and mechanical ventricle behaviors (not considered in previous studies). We compared action potential shapes under wild type and mutant conditions. Electrical wave propagations through ventricles were analyzed during sinus rhythm and reentrant conditions. IKs enhancement due to G229D mutation shortened the APD in the ventricular cells (6%, 0.3%, and 8% for endo, M, and epi-cells, respectively). The shortened APD contributed to 7% shortening of QT intervals, 29% shortening of wavelengths, 20% decrease in intraventricular pressure, and increase in end-systolic volume 17%, end-diastolic volume 7%, and end-diastolic pressure 11%, which further resulted in reduction in stroke volume as well as cardiac output (28%), ejection fraction 33% stroke work 44%, and ATP consumption 28%. In short, using computational model of the ventricle, we predicted that G229D mutation decreased cardiac pumping efficacy and increased the vulnerability of ventricular fibrillation. PMID- 29488359 TI - Secretome profiling of Propionibacterium freudenreichii reveals highly variable responses even among the closely related strains. AB - This study compared the secretomes (proteins exported out of the cell) of Propionibacterium freudenreichii of different origin to identify plausible adaptation factors. Phylosecretomics indicated strain-specific variation in secretion of adhesins/invasins (SlpA, InlA), cell-wall hydrolysing (NlpC60 peptidase, transglycosylase), protective (RpfB) and moonlighting (DnaK, GroEL, GaPDH, IDH, ENO, ClpB) enzymes and/or proteins. Detailed secretome comparison suggested that one of the cereal strains (JS14) released a tip fimbrillin (FimB) in to the extracellular milieu, which was in line with the electron microscopy and genomic analyses, indicating the lack of surface-associated fimbrial-like structures, predicting a mutated type-2 fimbrial gene cluster (fimB-fimA-srtC2) and production of anchorless FimB. Instead, the cereal strain produced high amounts of SlpB that tentatively mediated adherent growth on hydrophilic surface and adherence to hydrophobic material. One of the dairy strains (JS22), producing non-covalently bound surface-proteins (LspA, ClpB, AraI) and releasing SlpA and InlA into the culture medium, was found to form clumps under physiological conditions. The JS22 strain lacked SlpB and displayed a non-clumping and biofilm forming phenotype only under conditions of increased ionic strength (300 mM NaCl). However, this strain cultured under the same conditions was not adherent to hydrophobic support, which supports the contributory role of SlpB in mediating hydrophobic interactions. Thus, this study reports significant secretome variation in P. freudenreichii and suggests that strain-specific differences in protein export, modification and protein-protein interactions have been the driving forces behind the adaptation of this bacterial species. PMID- 29488361 TI - Theoretical characterization of annular array as a volumetric optoacoustic ultrasound handheld probe. AB - Optoacoustic ultrasound (OPUS) is a promising hybridized technique for simultaneous acquisition of functional and morphological data. The optical specificity of optoacoustic leverages the diagnostic aptitude of ultrasonography beyond anatomy. However, this integration has been rarely practiced for volumetric imaging. The challenge lies in the effective imaging probes that preserve the functionality of both modalities. The potentials of a sparse annular array for volumetric OPUS imaging are theoretically investigated. In order to evaluate and optimize the performance characteristics of the probe, series of analysis in the framework of system model matrix was carried out. The two criteria of voxel crosstalk and eigenanalysis have been employed to unveil information about the spatial sensitivity, aliasing, and number of definable spatial frequency components. Based on these benchmarks, the optimal parameters for volumetric handheld probe are determined. In particular, the number, size, and the arrangement of the elements and overall aperture dimension were investigated. The result of the numerical simulation suggests that the segmented annular array of 128 negatively focused elements with 1lambda * 20lambda size, operating at 5-MHz central frequency showcases a good agreement with the physical requirement of both imaging systems. We hypothesize that these features enable a high-throughput volumetric passive/active ultrasonic imaging system with great potential for clinical applications. PMID- 29488360 TI - The effects of exercise and passive heating on the sweat glands ion reabsorption rates. AB - The sweat glands maximum ion reabsorption rates were investigated (n = 12, 21.7 +/- 3.0 years, 59.4 +/- 9.8 kg, 166.9 +/- 10.4 cm and 47.1 +/- 7.5 mL/kg/min) during two separate endogenous protocols; cycling at 30% (LEX) and 60% VO2max (MEX) and one exogenous trial; passive heating (PH) (43 degrees C water lower leg immersion) in 27 degrees C, 50%RH. Oesophageal temperature (Tes ), skin temperature (Tsk ), and forearm, chest and lower back sweat rate (SR) and galvanic skin conductance (GSC) were measured. Salivary aldosterone was measured pre-and postheating (n = 3). Using the ?SR threshold for an increasing ?GSC to identify maximum sweat ion reabsorption rate revealed higher reabsorption rates during MEX compared to PH (mean of all regions: 0.63 +/- 0.28 vs. 0.44 +/- 0.3 mg/cm2 /min, P < 0.05). It was not possible to identify the ion reabsorption rate during LEX for some participants. Tes and mean Tsk were different between conditions but mean body temperature (Tb ) and local Tsk (forearm, chest and back) were similar (P > 0.05). Aldosterone increased more during MEX (72.8 +/- 36.6 pg/mL) compared to PH (39.2 +/- 17.5 pg/mL) and LEX (1.8 +/- 9.7 pg/mL). The back had a higher threshold than the forearm (P < 0.05) but it was similar to the chest (P > 0.05) (mean of all conditions; 0.64 +/- 0.33, 0.42 +/- 0.25, 0.54 +/- 0.3 mg/cm2 /min, respectively). Although the differences between conditions may be influenced by thermal or nonthermal mechanism, our results indicate a possibility that the sweat glands maximum ion reabsorption rates may be different between exercise and passive heating without mediating skin regional differences. PMID- 29488362 TI - Factors affecting measurement of optic parameters by time-resolved near-infrared spectroscopy in breast cancer. AB - The purpose of this study was to evaluate the effects of the thickness and depth of tumors on hemoglobin measurements in breast cancer by optical spectroscopy and to demonstrate tissue oxygen saturation (SO2) and reduced scattering coefficient (MUs') in breast tissue and breast cancer in relation to the skin-to-chest wall distance. We examined 53 tumors from 44 patients. Total hemoglobin concentration (tHb), SO2, and MUs' were measured by time-resolved spectroscopy (TRS). The skin to-chest wall distance and the size and depth of tumors were measured by ultrasonography. There was a positive correlation between tHb and tumor thickness, and a negative correlation between tHb and tumor depth. SO2 in breast tissue decreased when the skin-to-chest wall distance decreased, and SO2 in tumors tended to be lower than in breast tissue. In breast tissue, there was a negative correlation between MUs' and the skin-to-chest wall distance, and MUs' in tumors was higher than in breast tissue. Measurement of tHb in breast cancer by TRS was influenced by tumor thickness and depth. Although SO2 seemed lower and MUs' was higher in breast cancer than in breast tissue, the skin-to-chest wall distance may have affected the measurements. PMID- 29488364 TI - Wide-field absolute transverse blood flow velocity mapping in vessel centerline. AB - We propose a wide-field absolute transverse blood flow velocity measurement method in vessel centerline based on absorption intensity fluctuation modulation effect. The difference between the light absorption capacities of red blood cells and background tissue under low-coherence illumination is utilized to realize the instantaneous and average wide-field optical angiography images. The absolute fuzzy connection algorithm is used for vessel centerline extraction from the average wide-field optical angiography. The absolute transverse velocity in the vessel centerline is then measured by a cross-correlation analysis according to instantaneous modulation depth signal. The proposed method promises to contribute to the treatment of diseases, such as those related to anemia or thrombosis. PMID- 29488363 TI - Processing methods for photoacoustic Doppler flowmetry with a clinical ultrasound scanner. AB - Photoacoustic flowmetry (PAF) based on time-domain cross correlation of photoacoustic signals is a promising technique for deep tissue measurement of blood flow velocity. Signal processing has previously been developed for single element transducers. Here, the processing methods for acoustic resolution PAF using a clinical ultrasound transducer array are developed and validated using a 64-element transducer array with a -6 dB detection band of 11 to 17 MHz. Measurements were performed on a flow phantom consisting of a tube (580 MUm inner diameter) perfused with human blood flowing at physiological speeds ranging from 3 to 25 mm / s. The processing pipeline comprised: image reconstruction, filtering, displacement detection, and masking. High-pass filtering and background subtraction were found to be key preprocessing steps to enable accurate flow velocity estimates, which were calculated using a cross-correlation based method. In addition, the regions of interest in the calculated velocity maps were defined using a masking approach based on the amplitude of the cross correlation functions. These developments enabled blood flow measurements using a transducer array, bringing PAF one step closer to clinical applicability. PMID- 29488365 TI - Variable aperture-based ptychographical iterative engine method. AB - A variable aperture-based ptychographical iterative engine (vaPIE) is demonstrated both numerically and experimentally to reconstruct the sample phase and amplitude rapidly. By adjusting the size of a tiny aperture under the illumination of a parallel light beam to change the illumination on the sample step by step and recording the corresponding diffraction patterns sequentially, both the sample phase and amplitude can be faithfully reconstructed with a modified ptychographical iterative engine (PIE) algorithm. Since many fewer diffraction patterns are required than in common PIE and the shape, the size, and the position of the aperture need not to be known exactly, this proposed vaPIE method remarkably reduces the data acquisition time and makes PIE less dependent on the mechanical accuracy of the translation stage; therefore, the proposed technique can be potentially applied for various scientific researches. PMID- 29488366 TI - Topography and refractometry of sperm cells using spatial light interference microscopy. AB - Characterization of spermatozoon viability is a common test in treating infertility. Recently, it has been shown that label-free, phase-sensitive imaging can provide a valuable alternative for this type of assay. We employ spatial light interference microscopy (SLIM) to perform high-accuracy single-cell phase imaging and decouple the average thickness and refractive index information for the population. This procedure was enabled by quantitative-phase imaging cells on media of two different refractive indices and using a numerical tool to remove the curvature from the cell tails. This way, we achieved ensemble averaging of topography and refractometry of 100 cells in each of the two groups. The results show that the thickness profile of the cell tail goes down to 150 nm and the refractive index can reach values of 1.6 close to the head. PMID- 29488367 TI - Oral dydrogesterone vs. vaginal progesterone capsules for luteal-phase support in women undergoing embryo transfer: a systematic review and meta-analysis. AB - OBJECTIVE: To identify, appraise, and summarize the evidence from randomized controlled trials (RCTs) comparing oral dydrogesterone to vaginal progesterone capsules for luteal-phase support (LPS) in women offered fresh or frozen embryo transfers following in vitro fertilization. METHODS: Two independent authors screened the literature for papers based on titles and abstracts, then selected the studies, extracted data, and assessed the risk of bias. Dydrogesterone and progesterone were compared based on risk ratios (RR) and the precision of the estimates was assessed through the 95% confidence interval (CI). RESULTS: An electronic search performed on June 7, 2017 retrieved 376 records, nine of which were papers deemed eligible and included in this systematic review and quantitative analysis. Good quality evidence indicates that oral dydrogesterone provided at least similar results than vaginal progesterone capsules on live birth/ongoing pregnancy (RR=1.08, 95%CI=0.92-1.26, I2=29%, 8 RCTs, 3,386 women) and clinical pregnancy rates (RR 1.10, 95% CI 0.95 to 1.27; I2=43%; 9 RCTs; 4,061 women). Additionally, moderate quality evidence suggests there is no relevant difference on miscarriage rates (RR=0.92, 95%CI=0.68-1.26, I2=6%, 8 RCTs, 988 clinical pregnancies; the quality of the evidence was downgraded because of imprecision). CONCLUSIONS: Good quality evidence from RCTs suggest that oral dydrogesterone provides at least similar reproductive outcomes than vaginal progesterone capsules when used for LPS in women undergoing embryo transfers. Dydrogesterone is a reasonable option and the choice of either of the medications should be based on cost and side effects. PMID- 29488368 TI - Janus Membranes with Charged Carbon Nanotube Coatings for Deemulsification and Separation of Oil-in-Water Emulsions. AB - Oil/water separation, especially for those surfactant-stabilized oil-in-water (O/W) emulsions, is required to protect our ecological environment from destruction. Janus membranes with a function of deemulsification appear as a kind of efficient materials for the separation of O/W emulsions because of a precise adjustment of the surface nature for the hydrophilic and hydrophobic layers. However, existing strategies of membrane preparation suffer from complicated multisteps, leading to uncontrolled thickness of the hydrophilic deemulsification layer. Herein, we present a facile and tunable method to prepare a series of Janus membranes consisting of negatively or positively charged carbon nanotubes (CNTs) and hydrophobic microfiltration membranes by vacuum filtration. The thickness of the hydrophilic CNT coating is thus well-controlled by engineering the amount of CNTs deposited on the substrate membrane. The prepared Janus membranes are effective for the separation of both heavy oil and light oil from O/W emulsions through deemulsification owing to the charge-screening effect. It is very interesting that those membranes displaying a combination of water contact angle and underwater oil contact angle both above 90 degrees have a unique oil delivery behavior and thus high separation performance of oil from O/W emulsions. Such Janus membranes can retrieve 89% of oil in 40 min from the 1,2 dichloroethane/water emulsions with the droplet size of 19 MUm. This easy-to prepare and easy-to-tune strategy provides feasibilities for practical applications of Janus membranes to the deemulsification and separation of O/W emulsions. PMID- 29488369 TI - Facile Tuning the Detection Spectrum of Organic Thin Film Photodiode via Selective Exciton Activation. AB - Here, we introduce a method of tuning the high-detectivity spectra of the organic photodiode (OPD) to fabricate a thin-film filter-less full-color image sensor. The strategically introduced PIN junction enables a selective activation of excitons generated from the photons with low extinction coefficient in the active layer such that the separated holes/electrons can contribute to the external current. In addition, we show that a well-defined PIN junction blocks the injection of nonallowed charge carriers, leading to very low dark current and near-ideal diode characteristics. Consequently, the high specific detectivity over 1.0 * 1012 Jones are observed from R/G/B-selective thin-film OPDs. PMID- 29488370 TI - Super Nonlinear Electrodeposition-Diffusion-Controlled Thin-Film Selector. AB - Selector elements with high nonlinearity are an indispensable part in constructing high density, large-scale, 3D stackable emerging nonvolatile memory and neuromorphic network. Although significant efforts have been devoted to developing novel thin-film selectors, it remains a great challenge in achieving good switching performance in the selectors to satisfy the stringent electrical criteria of diverse memory elements. In this work, we utilized high-defect density chalcogenide glass (Ge2Sb2Te5) in conjunction with high mobility Ag element (Ag-GST) to achieve a super nonlinear selective switching. A novel electrodeposition-diffusion dynamic selector based on Ag-GST exhibits superior selecting performance including excellent nonlinearity (<5 mV/dev), ultra-low leakage (<10 fA), and bidirectional operation. With the solid microstructure evidence and dynamic analyses, we attributed the selective switching to the competition between the electrodeposition and diffusion of Ag atoms in the glassy GST matrix under electric field. A switching model is proposed, and the in-depth understanding of the selective switching mechanism offers an insight of switching dynamics for the electrodeposition-diffusion-controlled thin-film selector. This work opens a new direction of selector designs by combining high mobility elements and high-defect-density chalcogenide glasses, which can be extended to other materials with similar properties. PMID- 29488371 TI - Ni2P Entwined by Graphite Layers as a Low-Pt Electrocatalyst in Acidic Media for Oxygen Reduction. AB - A simple and feasible strategy was reported to construct Ni2P nanostructures entwined by graphite layers (Ni2P/GC). In this process, a commercial amino phosphonic acid chelating resin was adopted as both the phosphorus and carbon resources. Then, Ni2+ was introduced into the resin framework via ionic exchange and chelation to form a resin-Ni2+ precursor. After carbonization, the highly dispersed Ni2P particles, coupled with thin graphite layers, were simultaneously synthesized in situ. A ternary 7.5% Pt-Ni2P/GC catalyst was further obtained by loading 7.5 wt % Pt on Ni2P/GC. For the oxygen reduction reaction in acidic media, the 7.5% Pt-Ni2P/GC catalyst exhibited even more positive onset (1.03 V) and half-wave (0.93 V) potentials, as well as a rather higher mass activity of 565.3 mA mgPt-1 and a better long-term stability than those of the commercial 20% Pt/C (JM) electrocatalyst. The improved reaction kinetics is mainly attributed to the synergistic effect between Pt and Ni2P/GC. This work not only provides a method for the synthesis of phosphides but also gives insight into the synergy between Pt and Ni2P, which is helpful for the development of more low-Pt catalysts in acidic media. PMID- 29488372 TI - Tailoring Structure and Field-Effect Characteristics of Ultrathin Conjugated Polymer Films via Phase Separation. AB - A phase-separation method has been developed to control the semiconductor thickness and molecular arrangement via the semiconducting/insulating polymer blend system. The thickness of the poly(3-hexylthiophene) film has been regulated from 10.5 +/- 1.4 nm down to 1.9 +/- 0.8 nm with a favorable self-assembly degree and the mobility ranging from 0.21 to 0.03 cm2 V-1 s-1. The ultrathin films show high bias stability and weak decay after 24 days with a bottom-gate configuration. Benefited from a good molecular order, the films have low activation energy and a 2D charge transport profile in semiconductor layers. Moreover, this blending process can be used as a general strategy of thickness control in flexible low-voltage devices and donor-acceptor-conjugated polymers. PMID- 29488373 TI - Direct Observation of Simultaneous Immobilization of Cadmium and Arsenate at the Brushite-Fluid Interface. AB - Cadmium (Cd2+) and Arsenate (As5+) are the main toxic elements in soil environments and are easily taken up by plants. Unraveling the kinetics of the adsorption and subsequent precipitation/immobilization on mineral surfaces is of considerable importance for predicting the fate of these dissolved species in soils. Here we used in situ atomic force microscopy (AFM) to image the dissolution on the (010) face of brushite (dicalcium phosphate dihydrate, CaHPO4.2H2O) in CdCl2- or Na2HAsO4-bearing solutions over a broad pH and concentration range. During the initial dissolution processes, we observed that Cd or As adsorbed on step edges to modify the morphology of etch pits from the normal triangular shape to a four-sided trapezium. Following extended reaction times, the respective precipitates were formed on brushite through a coupled dissolution-precipitation mechanism. In the presence of both CdCl2 and Na2HAsO4 in reaction solutions at pH 8.0, high-resolution transmission electron microscopy (HRTEM) showed a coexistence of both amorphous and crystalline phases, i.e., a mixed precipitate of amorphous and crystalline Cd(5- x)Ca x(AsO4)(3- y)(PO4) yOH phases was detected. These direct dynamic observations of the transformation of adsorbed species to surface precipitates may improve the mechanistic understanding of the calcium phosphate mineral interface-induced simultaneous immobilization of both Cd and As and subsequent sequestration in diverse soils. PMID- 29488374 TI - Vertically Aligned and Interconnected SiC Nanowire Networks Leading to Significantly Enhanced Thermal Conductivity of Polymer Composites. AB - Efficient heat removal via thermal management materials has become one of the most critical challenges in the development of modern microelectronic devices. However, previously reported polymer composites exhibit limited enhancement of thermal conductivity, even when highly loaded with thermally conductive fillers, because of the lack of efficient heat transfer pathways. Herein, we report vertically aligned and interconnected SiC nanowire (SiCNW) networks as efficient fillers for polymer composites, achieving significantly enhanced thermal conductivity. The SiCNW networks are produced by freeze-casting nanowire aqueous suspensions followed by thermal sintering to consolidate the nanowire junctions, exhibiting a hierarchical architecture in which honeycomb-like SiCNW layers are aligned. The composite obtained by infiltrating SiCNW networks with epoxy resin, at a relatively low SiCNW loading of 2.17 vol %, represents a high through-plane thermal conductivity (1.67 W m-1 K-1) compared to the pure matrix, which is equivalent to a significant enhancement of 406.6% per 1 vol % loading. The orderly SiCNW network which can act as a macroscopic expressway for phonon transport is believed to be the main contributor for the excellent thermal performance. This strategy provides insights for the design of high-performance composites with potential to be used in advanced thermal management materials. PMID- 29488375 TI - Eriochrome Black T-Eu3+ Complex as a Ratiometric Colorimetric and Fluorescent Probe for the Detection of Dipicolinic Acid, a Biomarker of Bacterial Spores. AB - A novel ratiometric colorimetric and fluorescent dual probe based on Eriochrome Black T (EBT)-Eu3+ complex was designed to detect dipicolinic acid (DPA), a major constituent of bacterial spores, with high sensitivity and selectivity. UV-vis titration experiments demonstrated that EBT and Eu3+ ions formed a 1:1 coordination pair in water. In the presence of Eu3+ ions, the blue solution of EBT changed to magenta, however, upon the addition of DPA, the magenta color changed to blue immediately and characteristic fluorescence emission from DPA Eu3+ complex was observed. In addition, the sensitivity of the system was further evaluated on Geobacillus stearothermophilus spores and as low as 2.5 * 105 spores were detected. PMID- 29488376 TI - Influence of Environmentally Affected Hole-Transport Layers on Spatial Homogeneity and Charge-Transport Dynamics of Organic Solar Cells. AB - After organic photovoltaic (OPV) cells achieved efficiency of more than 10%, the control of stability and degradation mechanisms of solar cells became a prominent task. The increase of device efficiency due to incorporation of a hole-transport layer (HTL) in bulk-heterojunction solar cells has been extensively reported. However, the most widely used HTL material, poly(3,4 ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS), is frequently suspected to be the dominating source for device instability under environmental conditions. Thereby, effects like photooxidation and electrode corrosion are often reported to shorten device lifetime. However, often in environmental device studies, the source of degradation, whether being from the HTL, the active layer, or the metal cathode is rather difficult to distinguish because the external diffusion of oxygen and water affects all components. In this study, different HTLs, namely, those prepared from traditional PEDOT:PSS and also two types of molybdenum trioxide (MoO3) are exposed to different environments, such as oxygen, light, or humidity, prior to device finalization under inert conditions. This allows investigating any effects within the HTL and from reactions at its interface to the indium tin oxide electrode or the active layer. The surface and bulk chemistry of the exposed HTL has been monitored and discussed in context to the observed device physics, dynamic charge transport, and spatial performance homogeneity of the corresponding OPV device. The results show that merely humidity exposure of the HTL leads to decreased device performance for PEDOT:PSS, but also for one type of the tested MoO3. The losses are related to the amount of absorbed water in the HTL, inducing loss of active area in terms of interfacial contact. The device with PEDOT:PSS HTL after humid air exposure showed seriously decreased photocurrent by microdelamination of swelling/shrinkage of the hygroscopic layer. The colloidal MoO3 with water-based precursor solution presents slight decay of solar cell performance, also here caused by swelling/shrinking reaction, but by a combination of in-plane particle contact and resistance scaling with particle expansion. However, the device with quasi continuous and alcohol-based MoO3 showed unharmed stable electrical performance. PMID- 29488377 TI - Plasmonic Sensor Could Enable Label-Free DNA Sequencing. AB - We demonstrated a proof-of-principle concept of a label-free platform that enables nucleic acid sequencing by binding methodology. The system utilizes gold surfaces having high fidelity plasmonic nanohole arrays which are very sensitive to minute changes of local refractive indices. Our novel surface chemistry approach ensures accurate identification of correct bases at individual positions along a targeted DNA sequence on the gold surface. Binding of the correct base on the gold sensing surface triggers strong spectral variations within the nanohole optical response, which provides a high signal-to-noise ratio and accurate sequence data. Integrating our label-free sequencing platform with a lens-free imaging-based device, we reliably determined targeted DNA sequences by monitoring the changes within the plasmonic diffraction images. Consequently, this new label free surface chemistry technique, integrated with plasmonic lens-free imaging platform, will enable monitoring multiple biomolecular binding events, which could initiate new avenues for high-throughput nucleic acid sequencing. PMID- 29488378 TI - Solvent-Assisted Thermal-Pressure Strategy for Constructing High-Quality CH3NH3PbI3- xCl x Films as High-Performance Perovskite Photodetectors. AB - High-quality CH3NH3PbI3-xCl x films have attracted research interests in photoelectric devices because of their improved carrier diffusion length and charge mobility. Herein, a solvent-assisted thermal-pressure strategy is developed to promote the secondary growth of perovskite grains in the films. Highly oriented perovskite films are then obtained with large-sized grains (5-10 MUm). As a consequence, the photodetectors based on the high-quality CH3NH3PbI3- xCl x films exhibit enhanced ophtoelectrical performance, including high on/off ratio (>2.1 * 104), fast response time (54/63 MUs), and high detectivity (~1.3 * 1012). This work suggests an effective approach for high-quality perovskite films, which will be promising candidates for other high-efficiency photoelectric devices. PMID- 29488379 TI - Mechanistic Analysis of Oxygen Vacancy-Driven Conductive Filament Formation in Resistive Random Access Memory Metal/NiO/Metal Structures. AB - Electrically switchable resistive random access memories have drawn much interest as nonvolatile memory device candidates based on metal-insulator-metal (MIM) structure concepts. However, atomic level mechanisms that lead to conductive filament (CF) formation in MIM structures are often lacking, such as for the system with NiO as the oxide layer, which was found promising for resistive random access memory (RRAM) device applications. In this work, using density functional theory with a Hubbard-type on-site Coulomb correction, which we carefully benchmarked, we analyzed the intrinsic propensity toward CF formation in NiO upon introduction of oxygen vacancies, including interfacial effects of Ag or Pt electrodes. First, for stoichiometric MIM structural models, contributions from metal-induced gap states to the electronic density of states (DOS) were identified, accommodating oxygen vacancy states and showing that the interface region is reduced more easily than the bulklike region, for example, for the Ag/NiO/Ag structure. Moreover, a tendency toward oxygen vacancy clustering was demonstrated, important for CF formation. Indeed, by introducing ordered oxygen vacancies into the oxide layer for both MIM models, several extended defect states within the forbidden gap have resulted, which lead to defect-assisted transport. These were shown to be influenced by the spatial distribution and number of oxygen vacancies in the filament, where the degree of reduction of Ni atoms changes based on the immediate surroundings. Projected electronic DOS for individual Ni atoms in regions near and away from oxygen vacancies indicated that those Ni close to oxygen vacancies contribute most to the conductivity. Interestingly, based on charge analyses, these atoms are revealed to undergo significant reduction, generating a locally conductive region in the oxide layer that consists of metallic/near-metallic Ni (Ni0), formed through local reduction. PMID- 29488380 TI - Morphology Determines Conductivity and Seebeck Coefficient in Conjugated Polymer Blends. AB - The impact of nanoscale morphology on conductivity and Seebeck coefficient in p type doped all-polymer blend systems is investigated. For a strongly phase separated system (P3HT:PTB7), we achieve a Seebeck coefficient that peaks at S ~ 1100 MUV/K with conductivity sigma ~ 3 * 10-3 S/cm for 90% PTB7. In marked contrast, for well-mixed systems (P3HT:PTB7 with 5% diiodooctane (DIO), P3HT:PCPDTBT), we find an almost constant S ~ 140 MUV/K and sigma ~ 1 S/cm despite the energy levels being (virtually) identical in both cases. The results are interpreted in terms of a variable range hopping (VRH) model where a peak in S and a minimum in sigma arise when the percolation pathway contains both host and guest sites, in which the latter acts as energetic trap. For well-mixed blends of the investigated compositions, VRH enables percolation pathways that only involve isolated guest sites, whereas the large distance between guest clusters in phase-separated blends enforces (energetically unfavorable) hops via the host. The experimentally observed trends are in good agreement with the results of atomistic kinetic Monte Carlo simulations accounting for the differences in nanoscale morphology. PMID- 29488381 TI - Operation of Kelvin Effect in the Activities of an Antifreeze Protein: A Molecular Dynamics Simulation Study. AB - Ice growth and melting inhibition activities of antifreeze proteins (AFPs) are better explained by the adsorption-inhibition mechanism. Inhibition occurs as a result of the Kelvin effect induced by adsorbed protein molecules onto the surface of seed ice crystal. However, the Kelvin effect has not been explored by the state-of-the-art experimental techniques. In this work, atomistic molecular dynamics simulations have been carried out with Tenebrio molitor antifreeze protein ( TmAFP) placed at ice-water interface to probe the Kelvin effect in the mechanism of AFPs. Simulations show that, below equilibrium melting temperature, ice growth is inhibited through the convex ice-water interface formation toward the water phase and, above equilibrium melting temperature, ice melting is inhibited through the concave ice-water interface formation inward to ice phase. Simulations further reveal that the radius of curvature of the interface formed to stop the ice growth increases with decrease in the degree of supercooling. Our results are in qualitative agreement with the theoretical prediction of the Kelvin effect and thus reveal its operation in the activities of AFPs. PMID- 29488383 TI - Polydopamine Nanosphere/Gold Nanocluster (Au NC)-Based Nanoplatform for Dual Color Simultaneous Detection of Multiple Tumor-Related MicroRNAs with DNase-I Assisted Target Recycling Amplification. AB - A novel fluorescence resonance energy transfer (FRET)-based platform using polydopamine nanospheres (PDANSs) as energy acceptors and dual colored Au NCs as energy donors for simultaneous detection of multiple tumor-related microRNAs with DNase-I-assisted target recycling amplification was developed for the first time. On the basis of monitoring the change of the recovered fluorescence intensity at 445 and 575 nm upon the addition of targets miRNA-21 and let-7a, these two microRNAs (miRNAs) can be simultaneously quantitatively detected, with detection limits of 4.2 and 3.6 pM (3sigma) for miRNA-21 and let-7a, which was almost 20 times lower than that without DNase I. Additionally, semiquantitative determination of miRNA-21 and let-7a can also be realized through photovisualization. Most importantly, serums from normal and breast cancer patients can be visually and directly discriminated without any sample pretreatment by confocal microscope experiments, demonstrating promising potential for auxiliary clinical diagnosis. PMID- 29488382 TI - Advancing the Use of Passive Sampling in Risk Assessment and Management of Sediments Contaminated with Hydrophobic Organic Chemicals: Results of an International Ex Situ Passive Sampling Interlaboratory Comparison. AB - This work presents the results of an international interlaboratory comparison on ex situ passive sampling in sediments. The main objectives were to map the state of the science in passively sampling sediments, identify sources of variability, provide recommendations and practical guidance for standardized passive sampling, and advance the use of passive sampling in regulatory decision making by increasing confidence in the use of the technique. The study was performed by a consortium of 11 laboratories and included experiments with 14 passive sampling formats on 3 sediments for 25 target chemicals (PAHs and PCBs). The resulting overall interlaboratory variability was large (a factor of ~10), but standardization of methods halved this variability. The remaining variability was primarily due to factors not related to passive sampling itself, i.e., sediment heterogeneity and analytical chemistry. Excluding the latter source of variability, by performing all analyses in one laboratory, showed that passive sampling results can have a high precision and a very low intermethod variability (=3 fundus photographs between baseline (1986-1988) and time of cognitive assessment (2010-2015: N = 119; 52% male; mean age and type 1 diabetes duration 43 and 34 years, respectively). Central retinal arteriolar equivalent and central retinal venular equivalent were estimated via computer-based methods; overall magnitude and speed of narrowing were quantified as cumulative average and slope, respectively. Median regression models estimated associations of central retinal arteriolar equivalent and central retinal venular equivalent measures with cognitive impairment status, adjusted for type 1 diabetes duration. Interactions with HbA1c, proliferative retinopathy and white matter hyperintensities were assessed. RESULTS: Compared with participants without cognitive impairment, those with clinically relevant cognitive impairment experienced 1.8% greater and 31.1% faster central retinal arteriolar equivalent narrowing during prior years (t = 2.93, p = 0.004 and t = -3.97, p < 0.0001, respectively). Interactions with HbA1c, proliferative retinopathy and white matter hyperintensities were not significant. No associations were found between central retinal arteriolar equivalent at baseline, at time of cognitive testing, or any central retinal venular equivalent measures, and cognitive impairment. CONCLUSION: Long-term arterial retinal changes could indicate type 1 diabetes-related cognitive impairment. Studies examining longitudinal central retinal arteriolar equivalent changes as early biomarkers of cognitive impairment risk are warranted. PMID- 29488398 TI - Cervical spine immobilisation in the elderly: a literature review. AB - Developed populations are ageing rapidly and by 2040, approximately 1 in 4 adults will be over 65 years of age. This is resulting in higher incidence of traumatic injury in older patients. Cognitive and physical comorbidities in this group can pose significant challenges. Due to mechanisms of injury and pre-existing degenerative spinal disease, cervical spine fractures are particularly prevalent in elderly patients. These are associated with significant morbidity and mortality. In this literature review we examine current evidence surrounding the use of cervical spine immobilisation in elderly patients in the pre-hospital and emergency department setting and also as a treatment option for cervical spine fractures. We explore evidence surrounding the complications that can arise from cervical spine immobilisation, including the development of pressure sores, raised intracranial pressure, dysphagia, breathing difficulties, delirium, compliance issues, mobility and functional outcome. PMID- 29488399 TI - Laboratory and Benchtop Performance of a Mealtime Insulin-Delivery System. AB - BACKGROUND: A basal bolus insulin regimen requires multiple daily insulin injections, which might discourage patient adherence. As a potential solution, a mealtime insulin-delivery system-a 3-day wearable bolus-only patch-was designed to manually administer mealtime insulin discreetly by actuating buttons through clothing, without the need for multiple needle sticks. METHOD: Extensive functional testing of the patch included dose accuracy (from initial fill of the device to empty), pressure-vacuum leak testing, last-dose lockout and occlusion detection (safety alert features that lock the dosing buttons when no insulin is delivered), assessments of insulin drug stability, toxicological risk (including chemical testing), and system biocompatibility. RESULTS: Dosing accuracy was 2 units +/-10% (with U-100 insulin) over a range of environmental conditions, with >=95% reliability and confidence. The fluid seal performance and the safety alert features performed with >=95% reliability and >=95% confidence. The system met acceptable standards for insulin (U-100 lispro and aspart) stability for its intended 3-day use, in addition to the operational requirements. The toxicological risk assessment and demonstrated biocompatibility suggested that the patch is safe for human use. CONCLUSIONS: Benchtop performance showed that the bolus-only patch is a safe, accurate, and reliable device for mealtime insulin delivery. PMID- 29488400 TI - Corrigendum: Foot-and-mouth disease virus infection stimulates innate immune signaling in the mouse macrophage RAW 264.7 cells. PMID- 29488401 TI - New pharmacological insights of Galactia glaucescens. AB - Galactia glaucescens leaves are popularly used against snakebites in Brazil. The hydroethanolic extract from aerial parts of G. glaucescens (HEGg) was assayed against the neurotoxicity and myotoxicity induced by Bothrops jararacussu venom. A traditional myographic technique was applied for neurotoxicity and the resulting muscles were treated routinely by light microscopy analysis for myotoxicity. Additionally, the antimicrobial potential of HEGg was evaluated against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa strains, as well as Rutin was isolated for the first time in this specie using chromatographic and spectroscopic methods and its antiophidian property was assessed. HEGg totally prevents the neurotoxicity and myotoxicity effects caused by B. jararacussu, but did not show any antimicrobial effect. Concluding, HEGg and Rutin were able to counteract the toxic effects of the venom and confirmed the antiophidian potential, but not antimicrobial, of G. glaucescens as an alternative for neutralization of B. jararacussu venom. PMID- 29488402 TI - The association between circulating endostatin and a disturbed circadian blood pressure pattern in patients with type 2 diabetes. AB - BACKGROUND: Endostatin, cleaved from collagen XVIII in the extracellular matrix, is a promising circulating biomarker for cardiovascular damage. It possesses anti angiogenic and anti-fibrotic functions and has even been suggested to be involved in blood pressure regulation. Less is known if endostatin levels relate to circadian blood pressure patterns. In the present paper we studied the association between circulating levels of endostatin and nocturnal dipping in blood pressure. METHODS: We used the CARDIPP-study, a cohort of middle aged, type 2 diabetics (n = 593, 32% women), with data on both 24-hour and office blood pressure, serum-endostatin, cardiovascular risk factors, and incident major cardiovascular events. Nocturnal dipping was defined as a >10% difference between day- and night-time blood pressures. RESULTS: Two-hundred four participants (34%) were classified as non-dippers. The mean endostatin levels were significantly higher in non-dippers compared to dippers (mean +/- standard deviation: 62.6 +/- 1.8 ug/l vs. 58.7 +/- 1.6 ug/l, respectively, p = .007). Higher serum levels of endostatin were associated with a diminished decline in nocturnal blood pressure adjusted for age, sex, HbA1c, mean systolic day blood pressure, hypertension treatment, glomerular filtration rate, and prevalent cardiovascular disease (regression coefficient per SD increase of endostatin -0.01, 95% CI, -0.02-( 0.001), p = .03). Structural equation modelling analyses suggest that endostatin mediates 7% of the association between non-dipping and major cardiovascular events. CONCLUSION: We found an independent association between higher circulating levels of endostatin and a reduced difference between day- and night time systolic blood pressure in patients with type 2 diabetes. Yet endostatin mediated only a small portion of the association between non-dipping and cardiovascular events arguing against a clinical utility of our findings. PMID- 29488403 TI - More action needed: Psychotropic prescribing in Australian residential aged care. AB - OBJECTIVE: For at least two decades, concerns have been raised about inappropriate psychotropic prescribing in Australian residential aged care facilities, due to their modest therapeutic benefit and increased risk of falls and mortality. To date, the majority of prevalence data has been collected in Sydney exclusively and it is not known if recent initiatives to promote appropriate psychotropic prescribing have impacted utilisation. Thus, we aimed to comprehensively analyse psychotropic use in a large national sample of residential aged care facility residents. METHOD: A cross-sectional, retrospective cohort study of residents from 150 residential aged care facilities distributed nationally during April 2014-October 2015. Antipsychotic, anxiolytic/hypnotic and antidepressant utilisation was assessed, along with anticonvulsant and anti-dementia drug use. Negative binomial regression analysis was used to examine variation in psychotropic use. RESULTS: Full psychotropic prescribing data was available from 11,368 residents. Nearly two-thirds (61%) were taking psychotropic agents regularly, with over 41% prescribed antidepressants, 22% antipsychotics and 22% of residents taking benzodiazepines. Over 30% and 11% were charted for 'prn' (as required) benzodiazepines and antipsychotics, respectively. More than 16% of the residents were taking sedating antidepressants, predominantly mirtazapine. South Australian residents were more likely to be taking benzodiazepines ( p < 0.05) and residents from New South Wales/Australian Capital Territory less likely to be taking them ( p < 0.01), after adjustment for rurality and size of residential aged care facility. Residents located in New South Wales/Australian Capital Territory were also significantly less likely to take antidepressants ( p < 0.01), as were residents from outer regional residential aged care facilities ( p < 0.01). Antipsychotic use was not associated with State, rurality or residential aged care facility size. CONCLUSION: Regular antipsychotic use appears to have decreased in residential aged care facilities but benzodiazepine prevalence is higher, particularly in South Australian residential aged care facilities. Sedating antidepressant and 'prn' psychotropic prescribing is widespread. Effective interventions to reduce the continued reliance on psychotropic management, in conjunction with active promotion of non-pharmacological strategies, are urgently required. PMID- 29488404 TI - NADH-methemoglobin reductase activity: adult versus child. PMID- 29488405 TI - Has flibanserin revolutionized the treatment of hypoactive sexual desire disorder or is there still room for more effective therapeutics? PMID- 29488406 TI - Intraperitoneal chemotherapy for ovarian cancer using sustained-release implantable devices. AB - INTRODUCTION: Epithelial ovarian cancer (EOC) remains to be the most lethal of all gynecological malignancies mainly due to its asymptomatic nature. The late stages are manifested with predominant metastases confined to the peritoneal cavity. Although there has been a substantial progress in the treatment avenue with different therapeutic interventions, the overall survival rate of patients remain poor due to relapse and drug resistance. Areas covered: The pharmacokinetic advantages offered by intraperitoneal (IP) chemotherapy due to peritoneal-plasma barrier can be potentially exploited for EOC relapse treatment. The ability to retain high concentrations of chemo-drugs with high AUC peritoneum/plasma for prolonged durations in the peritoneal cavity can be utilized effectively through the clinical adoption of drug delivery systems (DDSs) which obviates the need for indwelling catheters. The metronomic dosing strategy could enhance anti-tumor efficacy with a continuous, low dose of chemo drugs providing minimal systemic toxicity. Expert opinion: The development of a feasible, non-catheter based, IP DDS, retaining the peritoneal-drug levels, with less systemic levels could offer significant survival advantages as a patient compliant therapeutic strategy. Suturable-implantable devices based on metronomic dosing, eluting drug in a sustained manner at low doses, could be implanted surgically post-debulking for treatment of refractory EOC patients. PMID- 29488407 TI - Predicting fitness-to-drive following stroke using the Occupational Therapy - Driver Off Road Assessment Battery. AB - INTRODUCTION: It is difficult to determine if, or when, individuals with stroke are ready to undergo on-road fitness-to-drive assessment. The Occupational Therapy - Driver Off Road Assessment Battery was developed to determine client suitability to resume driving. The predictive validity of the Battery needs to be verified for people with stroke. AIM: Examine the predictive validity of the Occupational Therapy - Driver Off Road Assessment Battery for on-road performance among people with stroke. METHOD: Off-road data were collected from 148 people post stroke on the Battery and the outcome of their on-road assessment was recorded as: fit-to-drive or not fit-to-drive. RESULTS: The majority of participants (76%) were able to resume driving. A classification and regression tree (CART) analysis using four subtests (three cognitive and one physical) from the Battery demonstrated an area under the curve (AUC) of 0.8311. Using a threshold of 0.5, the model correctly predicted 98/112 fit-to-drive (87.5%) and 26/36 people not fit-to-drive (72.2%). CONCLUSION: The three cognitive subtests from the Occupational Therapy - Driver Off Road Assessment Battery and potentially one of the physical tests have good predictive validity for client fitness-to-drive. These tests can be used to screen client suitability for proceeding to an on-road test following stroke. Implications for Rehabilitation: Following stroke, drivers should be counseled (including consideration of local legislation) concerning return to driving. The Occupational Therapy - Driver Off Road Assessment Battery can be used in the clinic to screen people for suitability to undertake on road assessment. Scores on four of the Occupational Therapy - Driver Off Road Assessment Battery subtests are predictive of resumption of driving following stroke. PMID- 29488408 TI - Patient and family engagement in Alberta Health Services: Improving care delivery and research outcomes. AB - Engaging patients and families in research and the design of quality improvement is an essential component of Patient and Family Centred Care (PFCC). Alberta Health Services (AHS) has been engaging patients and families to promote a cultural shift towards PFCC. The AHS trains patient and family advisors to share their experiences and encourages staff to work with advisors to co-design improvements in care. This article briefly describes the role and growth of patient and family advisors, advisory groups, and the participation of advisors in research initiatives through AHS' Strategic Clinical NetworksTM. It also describes recent efforts to build AHS' patient and family engagement capacity by introducing standard patient engagement training, supporting the creation of the innovative Patient and Community Engagement Research internship program, and by developing tools to measure the impact of patient and advisors on AHS. And finally, this article provides key learnings for health leaders. PMID- 29488409 TI - Editor's presentation. PMID- 29488410 TI - Obituary: Romualdo Belardinelli. PMID- 29488411 TI - Bifidobacterial strains shared by mother and child as source of probiotics. AB - Importance of bifidobacteria as part of the infant intestinal microbiota has been highlighted. Their acquisition is influenced by the mode of birth and the feed regime afterwards, with a special role of the maternal microbiota. The presence of the same shared bifidobacterial strains between breast milk and infant faeces in 14 mother-infant pairs was assessed by means of pulsed-field gel electrophoresis (PFGE) genotyping. Four shared strains of Bifidobacterium breve (2), Bifidobacterium longum subsp. infantis and B. longum subsp. longum were found in breast milk-infant faeces pairs. Two years later, a second survey yielded four shared strains of the species Bifidobacterium adolescentis, Bifidobacterium bifidum, B. longum subsp. longum and Bifidobacterium pseudocatenulatum. Moreover, a B. bifidum strain was found to be shared by the infant faeces of the first study and the mother faeces tested two years later, pointing out a long term persistence. Some of the selected bifidobacterial strains showed probiotic potential due to their survival to gastrointestinal conditions and their ability to form biofilms. PMID- 29488412 TI - New probiotic strains for inflammatory bowel disease management identified by combining in vitro and in vivo approaches. AB - Alterations in the gut microbiota composition play a key role in the development of chronic diseases such as inflammatory bowel disease (IBD). The potential use of probiotics therefore gained attention, although outcomes were sometimes conflicting and results largely strain-dependent. The present study aimed to identify new probiotic strains that have a high potential for the management of this type of pathologies. Strains were selected from a large collection by combining different in vitro and in vivo approaches, addressing both anti inflammatory potential and ability to improve the gut barrier function. We identified six strains with an interesting anti-inflammatory profile on peripheral blood mononuclear cells and with the ability to restore the gut barrier using a gut permeability model based on Caco-2 cells sensitized with hydrogen peroxide. The in vivo evaluation in two 2,4,6-trinitrobenzene sulfonic acid-induced murine models of colitis highlighted that some of the strains exhibited beneficial activities against acute colitis while others improved chronic colitis. Bifidobacterium bifidum PI22, the strain that exhibited the most protective capacities against acute colitis was only slightly efficacious against chronic colitis, while Bifidobacterium lactis LA804 which was less efficacious in the acute model was the most protective against chronic colitis. Lactobacillus helveticus PI5 was not anti-inflammatory in vitro but the best in strengthening the epithelial barrier and as such able to significantly dampen murine acute colitis. Interestingly, Lactobacillus salivarius LA307 protected mice significantly against both types of colitis. This work provides crucial clues for selecting the best strains for more efficacious therapeutic approaches in the management of chronic inflammatory diseases. The strategy employed allowed us to identify four strains with different characteristics and a high potential for the management of inflammatory diseases, such as IBD. PMID- 29488414 TI - Factors affecting local control of pulmonary oligometastases treated with stereotactic body radiotherapy. AB - BACKGROUND: Oligometastases refers to a state of limited metastatic disease. The use of local ablative therapies to patients with oligometastases can result in durable state of remission or long-term cure. Stereotactic body radiotherapy (SBRT) is a highly conformal radiation technique that delivers ablative doses to the target. The study aimed to evaluate local control (LC) and identify factors associated with poor LC in patients with pulmonary oligometastases treated with SBRT. Primary endpoint of the study was to assess LC; secondary endpoint was to determine factors associated with LC. MATERIAL AND METHODS: Criteria used for selection of patients with oligometastases included: metastatic disease limited to a maximum of two organs and no more than five metastatic lesions at time of treatment. Peripheral tumors were treated with 51-60 Gy in three fractions or a single fraction of 30 Gy. Central tumors received a dose of 45-60 Gy in 5-8 fractions. RESULTS: In 206 patients, 327 pulmonary oligometastases were treated with SBRT. Median follow-up was 22 months (range 2-100). LC at 2 and 3 years was 85% and 83%, respectively. On univariate analysis, biological equivalent dose assuming an alpha/beta ratio of 10 (BED10) < 100 Gy (HR 3.09), single-fraction SBRT (HR 2.83), synchronous metastasis (HR 1.99), and pre-SBRT chemotherapy (HR 2.79) were significantly associated with inferior LC. In the multivariable analysis BED10 <100 Gy (HR 3.59), pre-SBRT chemotherapy (HR 2.61) and presence of synchronous metastasis (HR 2.21) remained independently associated with poor LC. CONCLUSIONS: SBRT achieved an excellent LC of 85% at 2 years. Although retrospective in nature, our study identified three factors associated with inferior LC. These factors may help to refine SBRT practice for pulmonary oligometastases in the future. PMID- 29488415 TI - Health, Social, and Functional Characteristics of Older Adults With Continuing Care Needs: Implications for Integrated Care. AB - OBJECTIVE: To identify older adults who could benefit from integrated care, we examined (a) health, social, and functional characteristics of older, hospitalized adults who required continuing care on discharge and (b) associations between these characteristics and potentially unnecessary health care use. METHOD: Personal characteristics were extracted from patient charts ( N = 214) and examined in relation to three outcomes: discharge to institutional care, unnecessary hospital stay (alternative level of care), and long hospital stay. RESULTS: Twenty-nine percent of the sample was discharged to an institution, 32.7% was coded as alternate level of care, and 27.6% had a long length of stay. Independent predictors of potentially avoidable health care use were mental and behavioral issues, living alone, functional status, and preadmission concerns about the patient managing in the community. DISCUSSION: High users of health care services were identifiable prior to hospital admission, supporting the use of community-based integrated care approaches. PMID- 29488416 TI - Neurodevelopmental disorders: prevalence and comorbidity in children referred to mental health services. AB - BACKGROUND: Accurate prevalence rates of the neurodevelopmental disorders (ND) and comorbid conditions in child and adolescent mental health services (CAMHS) are essential for treatment planning and organization of health care. However, valid and reliable prevalence estimates from Nordic CAMHS populations are scarce, and the published findings vary. AIMS: To report prevalence rates of ND (attention-deficit hyperactivity disorder: ADHD, tic disorder: TD or autism spectrum disorder: ASD) and comorbid disorders by a validated diagnostic instrument in children referred to CAMHS outpatient clinics. METHODS: Parents of 407 consecutively referred children aged 7-13 years were interviewed with the semistructured interview schedule for affective disorders and schizophrenia, present and lifetime version (Kiddie-SADS-PL) at time of admittance. RESULTS: One or more ND was diagnosed in 226 children (55.5%; 69.9% boys): ADHD (44.5%; 68.5% boys); TD (17.7%; 77.8% boys) and ASD (6.1%; 76% boys). Among children with ND 70 (31.0%) had only one ND with no comorbid disorder, 49 (21.7%) had more than one ND (homotypic comorbidity) and 131 (58%) had a non-ND psychiatric disorder (heterotypic comorbidity). Anxiety disorders were the most frequently occurring heterotypic comorbidity in all three ND. Comorbid depressive disorder was associated with older age, and comorbid anxiety disorder with female gender. CONCLUSION: In children referred to CAMHS, ND constitute the most frequently occurring group of disorders, with high rates of both homotypic and heterotypic comorbidity. This needs to be taken into consideration in health service planning and treatment delivery. PMID- 29488417 TI - Pitfalls of Frozen Section in Gynecological Pathology: A Case of Endometrial Tumor With Sex Cord-Like Elements. AB - Endometrial stromal tumor with sex cord-like elements (ESTSCLE) is a rare entity that shares similar histological features with uterine tumors resembling ovarian sex cord tumors (UTROSCT). Differentiating the 2 entities involves ample sampling of the tissue to distinguish the percentage of sex cord components within the tissue, genetic studies, and immunohistochemical staining. Frozen section provides limited information for exclusion of either tumor; and the tumor is rare enough that the diagnosis may not be considered with the limited sampling; therefore, deferral of diagnosis to permanent sections may be appropriate. PMID- 29488418 TI - Isolated large vessel pulmonary vasculitis leading to pulmonary artery aneurysm formation: a case report and literature review. AB - Pulmonary artery (PA) vasculitis occurs in association with primary vasculitides in particular, giant cell arteritis, Takayasu's arteritis, or Behcet's disease-or secondary vasculitis as a result of infections or malignancy. However, PA vasculitis in isolation and with concomitant aneurysmal dilation is an unusual finding. We present a rare case of PA aneurysm secondary to isolated PA vasculitis in an asymptomatic patient with no features of systemic vasculitis. This case highlights one of the first cases of PA vasculitis managed with surgical resection alone. PMID- 29488419 TI - The potential of gut microbiota and fecal volatile organic compounds analysis as early diagnostic biomarker for necrotizing enterocolitis and sepsis in preterm infants. AB - INTRODUCTION: Although the exact pathophysiological mechanisms of both necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) in preterm infants are yet to be elucidated, evidence is emerging that the gut microbiota plays a key role in their pathophysiology. Areas covered: In this review, initial microbial colonization and factors influencing microbiota composition are discussed. For both NEC and LOS, an overview of studies investigating preclinical alterations in gut microbiota composition and fecal volatile organic compounds (VOCs) is provided. Fecal VOCs are considered to reflect not only gut microbiota composition, but also their metabolic activity and concurrent interaction with the host. Expert review: Heterogeneity in study protocols and applied analytical techniques hampers reliable comparison between outcomes of different microbiota studies, limiting the ability to draw firm conclusions. This dilemma is illustrated by the finding that study results often cannot be reproduced, or even contradict each other. A NEC- and sepsis specific microbial or metabolic signature has not yet been discovered. Identification of 'disease-specific' VOCs and microbiota composition may increase understanding on pathophysiological mechanisms and may allow for development of an accurate screening tool, opening avenues towards timely identification and initiation of targeted treatment for preterm infants at increased risk for NEC and sepsis. PMID- 29488420 TI - Sense of clubhouse community belonging and empowerment. AB - BACKGROUND: While the neighborhood community literature well documents a link between participation in supportive and effective community groups or activities and empowerment, there is as yet little empirical evidence of this relationship in the context of community mental health programs. AIM: The primary purpose of the study was to examine the relationship between sense of community belonging and empowerment among members of mental health clubhouses. METHODS: A secondary analysis using a hierarchical regression model was conducted on cross-sectional structured interview data collected through a self-report questionnaire from 102 clubhouse members from six clubhouses in the United States and Finland. RESULTS: The results indicated that members' sense of clubhouse community belonging positively contributes to their empowerment. CONCLUSION: Fostering sense of community belonging appears to be a valid approach to catalyze empowerment. Study limitations and future research agendas were discussed. PMID- 29488421 TI - Detailed deposition analysis of inertial and diffusive particles in a rat nasal passage. AB - Rats have been widely used as surrogates for evaluating the health effects of inhaled airborne particulate matter. To provide a thorough understanding of particle transport and deposition mechanisms in the rat nasal airway, this article presents a computational fluid dynamics (CFD) study of particle exposure in a realistic rat nasal passage under a resting flow condition. Particles covering a diameter range from 1 nm to 4 um were passively released in front of the rat's breathing zone, and the Lagrangian particle tracking approach was used to calculate individual particle trajectories. Detailed particle deposition analysis shows the deposition of inertial particles >2 um is high in the rat nasal vestibule and more than 70% of all inhaled inertial particles were trapped in this region. While for diffusive nanoparticles, the vestibule filtration effect is reduced, only less than 60% of inhaled nanoparticles were blocked by the anterior nasal structures. The particle exposure in the olfactory region only shows notable deposition for diffusive nanoparticles, which peaks at 9.4% for 5 nm particles. Despite the olfactory deposition remains at a low level, the ratio between the olfactory and the main passage is kept around 30-40% for 10-800 nm particles, which indicates a particle-size-independent distribution pattern in the main nasal passage and olfactory. This study provides a deep understanding of particles deposition features in a rat nasal passage, and the research findings can aid toxicologist in inter-species exposure-response extrapolation study. PMID- 29488422 TI - Species composition of the genus Scombrops (Teleostei, Scombropidae) in the waters around the Japanese Archipelago: detection of a cryptic species. AB - Current literature states that family Scombropidae consists of a single genus Scombrops comprising three species worldwide, with two of them, Scombrops boops and Scombrops gilberti, distributed in the waters around the Japanese Archipelago. Although these two scombropids are commercially important species, little is known about the ecology of these fishes. It is difficult to discriminate between these two species based on external characteristics because of their morphological similarity. Here, we report two different morphotypes characterized by the relative growth between the otolith size and the standard length (SL) of the scombropid specimens caught in southern waters off Kyushu Island, Japan, and show the genetic relationship between the morphotypes by means of phylogenetic analyses using complete DNA sequences of the cytochrome b gene. The relationship between otolith weight and SL was significantly different between specimens < 505 mm SL and those > 550 mm SL. Phylogenetic analysis demonstrated that the sequences from these scombropid specimens formed three clades: two corresponded to S. boops and S. gilberti, while the third did not correspond to any sequence recorded in databases, suggesting that these specimens are undescribed scombropid species. Almost all the specimens with SL < 505 mm (n = 76) were identified as S. boops, and only nine as S. gilberti. On the other hand, almost all the specimens with SL > 550 mm (n = 41) fell in the unidentified group except for four specimens, whose sequences were identical to that of S. boops. PMID- 29488423 TI - Ferucarbotran-loaded red blood cells as long circulating MRI contrast agents: first in vivo results in mice. AB - AIM: The encapsulation of superparamagnetic iron oxide contrast agents in red blood cells (RBCs) could overcome their rapid removal by reticulo-endothelial system improving their stability in blood circulation. MATERIALS & METHODS: Murine ferucarbotran-loaded RBCs were tested in vivo as new contrasting agents in MRI application. RESULTS: A superior visualization of organs and cerebral vessels was evidenced in ferucarbotran-loaded RBCs-treated mice compared with the controls. The signal enhancement lasted for days, while the contrast from bulk ferucarbotran disappeared after few minutes. CONCLUSION: Ferucarbotran-loaded RBCs showed to improve diagnostic imaging and their use may extend the time frame for MRI and magnetic resonance angiography since to date the time frame for data acquisition has been limited to the first pass. PMID- 29488424 TI - Time- and dose-related effects of amyloid beta1-40 on retina and optic nerve morphology in rats. AB - PURPOSE: Amyloid beta (Abeta) is known to contribute to the pathophysiology of retinal neurodegenerative diseases such as glaucoma. Effects of intravitreal Abeta(1-42) on retinal and optic nerve morphology in animal models have widely been studied but not those of Abeta(1-40). Hence, we evaluated the time- and dose related effects of intravitreal Abeta(1-40) on retinal and optic nerve morphology. Since oxidative stress and brain derived neurotrophic factor (BDNF) are associated with Abeta-induced neuronal damage, we also studied dose and time related effects of Abeta(1-40) on retinal oxidative stress and BDNF levels. MATERIALS AND METHODS: Five groups of rats were intravitreally administered with vehicle or Abeta(1-40) in doses of 1.0, 2.5, 5 and 10 nmol. Animals were sacrificed and eyes were enucleated at weeks 1, 2 and 4 post-injection. The retinae were subjected to morphometric analysis and TUNEL staining. Optic nerve sections were stained with toluidine blue and were graded for neurodegenerative effects. The estimation of BDNF and markers of oxidative stress in retina were done using ELISA technique. RESULTS AND CONCLUSIONS: It was observed that intravitreal Abeta(1-40) causes significant retinal and optic nerve damage up to day 14 post-injection and there was increasing damage with increase in dose. However, on day 30 post-injection both the retinal and optic nerve morphology showed a trend towards normalization. The observations made for retinal cell apoptosis, retinal glutathione, superoxide dismutase activity and BDNF were in accordance with those of morphological changes with deterioration till day 14 and recovery by day 30 post-injection. The findings of this study may provide a guide for selection of appropriate experimental conditions for future studies. PMID- 29488425 TI - Amikacin-containing self-emulsifying delivery systems via pulmonary administration for treatment of bacterial infections of cystic fibrosis patients. AB - AIM: The aim of the study was to develop self-emulsifying delivery systems (SEDDS) exhibiting improved permeation rate for pulmonary delivery of amikacin for treatment of cystic fibrosis (CF) patients. MATERIALS & METHODS: Solubility of amikacin in lipids was improved by hydrophobic ion pairing with sodium myristyl sulfate. The complex was loaded into SEDDS. Drug-release studies were performed and the permeation properties of SEDDS through human CF mucus were examined. RESULTS: A total of 10% complex could be loaded into SEDDS. SEDDS exhibited sustained release. Up to twofold more amounts of amikacin permeated through the CF mucus compared with reference. CONCLUSION: The developed SEDDS with amikacin may be a promising tool for the treatment of certain bacterial infections of CF patients. PMID- 29488426 TI - MRI-only based radiation therapy of prostate cancer: workflow and early clinical experience. AB - BACKGROUND: Magnetic resonance imaging (MRI) is the most comprehensive imaging modality for radiation therapy (RT) target delineation of most soft tissue tumors including prostate cancer. We have earlier presented step by step the MRI-only based workflow for RT planning and image guidance for localized prostate cancer. In this study we present early clinical experiences of MRI-only based planning. MATERIAL AND METHODS: We have analyzed the technical planning workflow of the first 200 patients having received MRI-only planned radiation therapy for localized prostate cancer in Helsinki University Hospital Cancer center. Early prostate specific antigen (PSA) results were analyzed from n = 125 MRI-only patients (n = 25 RT only, n = 100 hormone treatment + RT) and were compared with the corresponding computed tomography (CT) planned patient group. RESULTS: Technically the MRI-only planning procedure was suitable for 92% of the patients, only 8% of the patients required supplemental CT imaging. Early PSA response in the MRI-only planned group showed similar treatment results compared with the CT planned group and with an equal toxicity level. CONCLUSION: Based on this retrospective study, MRI-only planning procedure is an effective and safe way to perform RT for localized prostate cancer. It is suitable for the majority of the patients. PMID- 29488427 TI - Amelioration of right ventricular systolic function and stiffness in a patient with idiopathic pulmonary arterial hypertension treated with oral triple combination therapy. AB - Right ventricular (RV) function is an important determinant of the prognosis in patients with pulmonary arterial hypertension (PAH). In the context of recent therapeutic progress, there is an increasing need for better monitoring of RV function for management of PAH. We present the case of a 42-year-old woman with idiopathic PAH who was treated with three oral pulmonary vasodilators, i.e. tadalafil, ambrisentan, and beraprost. At the baseline assessment, the mean pulmonary arterial pressure (mPAP) was 45 mmHg, cardiac index (CI) was 1.36 L/min/m2, and pulmonary vascular resistance (PVR) was elevated to 21.3 Wood units (WU). However, three months after the start of combination treatment, mPAP and PVR decreased to 42 mmHg and 7.5 WU, respectively, and conventional indices of RV function, such as CI, right atrial area, and right atrial pressure also improved. Beyond three months, however, there were no further improvements in mPAP, PVR, or indices of RV function. In addition, we calculated three recently introduced indices of intrinsic RV function: end-systolic elastance (Ees; an index of RV contractility), Ees/arterial elastance ratio (Ees/Ea; an index of RV/pulmonary arterial coupling), and beta (an index of RV stiffness) using cardiac magnetic resonance imaging and Swan-Ganz catheterization measurements. Notably, in contrast to conventional parameters, Ees, Ees/Ea, and beta showed persistent improvement during the entire two-year follow-up. The application of Ees, Ees/Ea, and beta may play an additional role in a comprehensive assessment of RV function in PAH. PMID- 29488428 TI - Tar level of cigarettes smoked and risk of smoking-related diseases. AB - BACKGROUND: Opinions differ on the relationship between tar level and risk of smoking-related disease. However, except for lung cancer, few reviews have evaluated the epidemiological evidence. Here the relationship of tar level to risk of the four main smoking-related diseases is considered. METHODS: Papers comparing risk of lung cancer, COPD, heart disease or stroke in smokers of lower and higher tar yield cigarettes were identified from reviews and searches, relative risk estimates being extracted comparing the lowest and highest tar groups. Meta-analyses investigated heterogeneity by various study characteristics. RESULTS: Twenty-six studies were identified, nine of prospective design and 17 case-control. Two studies grouped cigarettes by nicotine rather than tar. Seventeen studies gave results for lung cancer, 16 for heart disease, five for stroke and four for COPD. Preferring relative risks adjusted for daily amount smoked, where adjusted and unadjusted estimates were available, combined estimates for lowest versus highest tar (or nicotine) groups were 0.78 (95% confidence interval 0.70-0.88) for lung cancer, 0.86 (0.81-0.91) for heart disease, 0.77 (0.62-0.95) for stroke and 0.81 (0.65-1.02) for COPD. Lower risks were generally evident in subgroups by publication period, gender, study design, location and extent of confounder adjustment. Estimates were similar preferring data unadjusted for amount smoked or excluding nicotine-based estimates. CONCLUSIONS: Despite evidence that smokers substantially compensate for reduced cigarette yields, the results clearly show lower risks in lower tar smokers. Limitations of the evidence are discussed, but seem unlikely to affect this conclusion. PMID- 29488429 TI - Corrigendum. AB - Gottlieb, L. N. & Gottlieb, B. (2017). Strengths-Based Nursing: A Process for Implementing a Philosophy Into Practice. Journal of Family Nursing, 23, 319-340. Doi: 10.1177/1074840717717731 The authors have identified changes to certain sentences, which they believe are important for their article. These edits are outlined below. Page 328, 8th line from bottom Incorrect sentence: To illustrate, a point-of-care nurse, Jenette Schoon, who works in a long-term children's rehabilitation hospital had been unhappy with the way family discharge planning meetings has been conducted. Correct sentence: To illustrate, a point-of-care nurse, Jenette Schoon, who works in a long-term children's rehabilitation hospital wanted to improve how family team goal planning meetings were conducted. Page 330, 12th line from bottom Incorrect sentence: We chose Hospital for Sick Kids (HSK), a quaternary care hospital, and Holland Bloorview Children's Rehabilitation Hospital (HB), Toronto, Canada, because they were early adopters of SBN and their institutional values aligned with SBN. Correct sentence: SickKids, a quaternary care hospital, and Holland Bloorview Kid's Rehabilitation Hospital (HB), Toronto, Canada, because they were early adopters of SBN and their institutional values aligned with SBN. Page 330, 4th line from bottom Incorrect sentence: In addition, a survey of clinical leaders from HSK and HB was undertaken to assess their learning needs and interest in understanding SBN, as well as the management/leadership concepts and skills that could be offered in a formal SBN management and leadership training program. Correct sentence: In addition, a survey of clinical leaders from SickKids and HB was undertaken to assess their learning needs and interest in understanding SBN, as well as the management/leadership concepts and skills that could be offered in a formal SBN management and leadership training program. Page 334, 15th line from bottom Incorrect sentence: For example, at HB Nursing Department adopted SBN as their nursing philosophy. Correct sentence: For example, at HB Nursing Profession adopted SBN as their nursing philosophy. Page 334, 12th line from bottom Incorrect sentence: Dr. Marilyn Ballantyne, HB's Chief Nursing Executive/Clinical Investigator finds that Strengths-Based Care can help her nursing department achieve the hospital's vision Correct sentence: HB's Chief Nursing Executive/Clinician Investigator finds that Strengths-Based Care can help her achieve the hospital vision. PMID- 29488433 TI - Correction to: Mousavi et al., Comparison between maternal and neonatal outcome of PPROM in the cases of amniotic fluid index (AFI) of more and less than 5 cm. PMID- 29488430 TI - Endoscopic management of refractory gastroesophageal reflux disease. AB - OBJECTIVE: Despite the therapeutic and surgical interventions for the management of gastroesophageal reflux disease (GERD), yet the high cost and the post operative complications had led to a significant socioeconomic burden. The aim was to evaluate the safety and efficacy of endoscopic band ligation (EBL) in the management of refractory GERD. METHODS: A total of 150 patients with refractory GERD were assigned to an EBL group (banding was done at four quadrants just at the gastroesophageal junction (GEJ) (n = 75) or to a control group (optimized dose of PPI, n = 75). Follow-up for both groups by upper GI endoscopy to evaluate the site of the Z line from the incisors, the width of the GEJ and the coaptation of GEJ around the endoscope on retroflection. PH monitoring was performed every 3 months with GERD- QoL assessment monthly for 1 year. RESULTS: In EBL group; 58 patients (77.3%) needed 1 session, 17 patients (22.7%) needed 2 sessions. 4 rubber bands were utilized in 44 patients (58.7%), 3 rubber bands in 31 patients (41.3%). Follow-up for 1 year revealed a highly significant improvement of the GERD- QoL score, the site of Z line with significant reduction of reflux episodes and symptom index when compared to the medical treatment group. In EBL group; there were no major adverse events including bleeding, post band ulcers, stenosis at one year follow up. CONCLUSION: The current study provides a novel endoscopic intervention to treat refractory GERD, which is safe, cost-effective, with no major adverse effects at one year follow up. PMID- 29488434 TI - Phylogeographic pattern of Liza affinis populations in Chinese coastal waters: estimation of larval dispersal potential. AB - To examine phylogeographic pattern of Liza affinis populations in Chinese coastal waters, eight geographic populations were collected and analyzed using sequence analysis based on the first hypervariable region of mitochondrial control region. A total of 117 haplotypes from eight populations were obtained from 223 individuals and 22 of them were shared among different populations. High values of haplotype diversity and nucleotide diversity were observed for eight populations. The topology of the NJ tree was shallow, and there were no significant genealogical branches or clusters corresponding to sampling localities. The values of pairwise Fst ranged from -0.009 to 0.171 and most of them were not statistically significant after sequential Bonferroni correction. The results of LAMARC also indicated no significant population genetic structure in L. affinis along the Chinese coast. The demographic history of Liza affinis examined by neutrality tests and mismatch distribution analysis suggested a population expansion event dating back to late Pleistocene. The potential larval dispersal ability coupled with the present ocean currents and the late Pleistocene environment should be responsible for the present phylogeographic pattern of Liza affinis. PMID- 29488435 TI - Methotrexate treatment of generalized granuloma annulare: a retrospective case series. AB - BACKGROUND: Management of generalized granuloma annulare (GGA) poses challenges for both patients and dermatologists. Currently, there are no established first line therapies for GGA and the available therapeutic modalities are based on individual case reports and a few small case series. Further, there are limited publications assessing the efficacy of methotrexate in treating GGA. OBJECTIVE: To evaluate the efficacy and adverse effects associated with methotrexate treatment of GGA. METHODS: Descriptive retrospective case series of 11 patients with GGA receiving methotrexate. RESULTS: Sixty four percent of patients receiving methotrexate noted improvement of their skin disease, of which 43% achieved complete clearance and 57% partial clearance. Initial dose of methotrexate ranged from 12.5 to 15 mg weekly, administered either orally or subcutaneously. The majority of patients tolerated the treatment well. However, 18% of patients experienced the adverse effects of either GI upset or hair loss. LIMITATIONS: This case series lacks a control group and therefore has low internal validity. The lack of a disease severity and therapy responsiveness measurement tool made quantifying disease improvement inexact. CONCLUSIONS: Methotrexate can be a successful and well-tolerated treatment option for patients with generalized GA. PMID- 29488437 TI - Investigating the relationship between plasma neuropeptide-S levels and clinical depression. AB - PURPOSE: Neuropeptide-S (NPS) is a novel 20-amino acid peptide, mainly expressed in the central nervous system and endocrine tissues. NPS has been linked to anxiety and fear-related behaviors. The association of NPS with depression in a human population has not been previously examined. The aim of the current study was to explore the potential association of NPS with clinical depression and comorbid anxiety. MATERIALS AND METHODS: Seventy-nine patients diagnosed with major depressive disorder and seventy-eight controls were included in the study. The Hamilton Depression Scale (HAM-D) and Hamilton Anxiety Scale (HAM-A) were used to measure depression and anxiety levels, respectively. Venous blood samples were obtained to measure plasma NPS levels. RESULTS: There were no statistically significant differences between the patients and controls in terms of sex, marital status, and smoking status. Plasma NPS levels were also not significantly different between the patients and controls. In patients with major depressive disorder, HAM-A and HAM-D scores were significantly higher than those of controls. No correlation was found between plasma NPS levels and age, body mass index (BMI), median HAM-A scores, and median HAM-D scores. CONCLUSIONS: Despite a significantly high level of comorbid anxiety among the patient group, we found no relationship between plasma NPS levels and depressive symptomatology. PMID- 29488438 TI - Direct acting antivirals for the treatment of hepatitis C in ethnic minority populations. AB - INTRODUCTION: Direct acting antivirals (DAA's) have revolutionized the treatment of hepatitis C (HCV). However, questions persist concerning their efficacy in minority populations. Areas covered: In this review, the authors review outcomes for treatment of HCV by race and ethnicity among the clinical trials that have led to the current recommended treatments for HCV. The authors highlight the efficacy and safety differences by race and ethnicity. They also highlight deficiencies within the literature including small populations of racial/ethnic minorities within HCV clinical trials. DAA's can achieve cure rates for HCV over 95% with the use of once daily medications that have minimal side effects and few significant drug-drug interactions. Regimens with high pan-genotypic efficacy have further simplified treatment paradigms. The purpose of this review is to describe the data on DAA's in treating HCV in racial/ethnic populations. Expert opinion: While the overall data in racial/ethnic minority populations is sparse, DAA's appear to have high efficacy in curing HCV in diverse racial/ethnic populations. Although achieving high sustained virologic response (SVR) rates, there are also data that suggests that some disparities in SVR persist, especially when considering shorter regimens for HCV treatment in racial/ethnic populations. PMID- 29488436 TI - Neuroimaging of the Injured Pediatric Brain: Methods and New Lessons. AB - Traumatic brain injury (TBI) is a significant public health problem in the United States, especially for children and adolescents. Current epidemiological data estimate over 600,000 patients younger than 20 years are treated for TBI in emergency rooms annually. While many patients experience a full recovery, for others there can be long-lasting cognitive, neurological, psychological, and behavioral disruptions. TBI in youth can disrupt ongoing brain development and create added family stress during a formative period. The neuroimaging methods used to assess brain injury improve each year, providing researchers a more detailed characterization of the injury and recovery process. In this review, we cover current imaging methods used to quantify brain disruption post-injury, including structural magnetic resonance imaging (MRI), diffusion MRI, functional MRI, resting state fMRI, and magnetic resonance spectroscopy (MRS), with brief coverage of other methods, including electroencephalography (EEG), single-photon emission computed tomography (SPECT), and positron emission tomography (PET). We include studies focusing on pediatric moderate-severe TBI from 2 months post injury and beyond. While the morbidity of pediatric TBI is considerable, continuing advances in imaging methods have the potential to identify new treatment targets that can lead to significant improvements in outcome. PMID- 29488439 TI - Useful life lessons for health and well-being: adults' reflections of childhood experiences illuminate the phenomenon of the inner child. AB - PURPOSE: The aim of this study was to describe and gain more knowledge about the phenomenon of the inner child in relation to health and well-being reflected in events during childhood experienced by adults. METHOD: In this hermeneutical phenomenological study, 20 adults, 10 men and 10 women aged 22-68, were interviewed. RESULTS: The analysis of the data illuminated the phenomenon of the inner child in one theme: Gaining useful life lessons through childhood experiences, made up by four sub-themes: Sharing relationships, playing to heal, being strong or frail and supporting the next generation. CONCLUSION: The participants' experiences of events during childhood were illuminating the phenomenon of the inner child as promoting or hindering health and well-being and impact human adaptation throughout life. Our findings indicate that the participants learned useful life lessons suggesting that experiences during childhood can help us to adapt across the life span and over generations, and this is the essence of the inner child. Our findings also contribute to the health literacy discussion and detail how knowledge and action competency is developed in mental, social and existential dimensions of health and well-being. PMID- 29488440 TI - Microvascular endothelial function and cognitive performance: The ELSA-Brasil cohort study. AB - Impaired microvascular endothelial function may be implicated in the etiology of cognitive decline. Yet, current data on this association are inconsistent. Our objective is to investigate the relation of microvascular endothelial function to cognitive performance in the ELSA-Brasil cohort study. A total of 1521 participants from ELSA-Brasil free of dementia underwent peripheral arterial tonometry (PAT) to quantify microvascular endothelial function (PAT-ratio and mean baseline pulse amplitude (BPA)) and cognitive tests that covered the domains of memory, verbal fluency, and executive function at baseline. Cognitive tests in participants aged 55 years old and above were repeated during the second examination (mean follow-up: 3.5 (0.3) years). Linear regression and generalized linear models were used to evaluate the association between endothelial function, global cognitive performance, and performance on specific cognitive domains. In unadjusted cross-sectional analyses, we found that BPA and PAT-ratio were associated with worse global cognitive performance (mean difference for BPA: 0.07, 95% CI: -0.11; -0.03, p<0.01; mean difference for PAT-ratio: 0.11, 95% CI: 0.01; 0.20, p=0.02), worse performance on learning, recall, and word recognition tests (BPA: -0.87, 95% CI: -1.21; -0.52, p<0.01; PAT-ratio: 1.58, 95% CI: 0.80; 2.36, p<0.01), and only BPA was associated with worse performance in verbal fluency tests (-0.70, 95% CI: -1.19; -0.21, p<0.01). Adjustments for age, sex, and level of education rendered the associations statistically non-significant. Longitudinally, there was no association between microvascular endothelial and cognitive functions. The associations between microvascular endothelial function and cognition are explained by age, sex, and educational level. Measures of microvascular endothelial function may be of limited value with regard to preclinical cognitive deficits. PMID- 29488441 TI - Rare congenital cardiac anomalies in an asymptomatic athlete. PMID- 29488442 TI - Factors Associated With Timely Blood Glucose Testing and Insulin Administration in Patients Receiving Mealtime Insulin Coverage in Medical Surgical Units. AB - Purpose The purpose of the study was to identify the rate and factors associated with timely mealtime capillary blood glucose (CBG) testing and insulin coverage in hospitalized patients with diabetes. Methods A descriptive-correlational design was used with a random sample of patients (n = 77) and nurses (n = 36) on a medicine and a neuroscience unit of a large Magnet hospital. After written consent was obtained, post-meal patient and nurse interviews were conducted to collect information about patient, nurse, and situational factors known to influence timely mealtime diabetes care. Results Timely CBG testing occurred on 85.7% of the patient participants, and 71.4% received timely insulin coverage. Timely CBG testing was associated (unadjusted) with telling the patient care associate to obtain a finger stick (FS) prior to meals and patient off the unit during mealtime. The odds of having insulin administered on time was significantly and independently associated with the nurse caring for fewer patients, patients waiting for insulin prior to eating, and patients knowing pre meal FS was high. Conclusions One situational factor and 2 patient factors were independently associated with timely insulin coverage prior to meals. Interventions aimed at raising staff awareness of these factors and providing tailored education to patients may improve the odds of having insulin administered on time. PMID- 29488443 TI - "What an eye-opener" - a qualitative study of vulnerable citizens participating in a municipality-based intervention. AB - PURPOSE: To explore how psychologically vulnerable citizens experienced performing their everyday-life activities, identify activities experienced as particularly challenging and evaluate the significance of the Acceptance and Commitment Theory-based (ACT)-based program, Well-being in Daily Life, had on the participants everyday-life activities. METHODS: Semi-structured interviews were conducted with eight participants from the Well-being in Daily Life program. Data were analysed using Systematic Text Condensation. RESULTS AND CONCLUSION: The participants experienced anxiety, fatigue, lack of structure, and chaos when performing their everyday-life activities; in addition to being uncertain about the limitations of their own resources. Furthermore, balancing between demands and resources was challenging, also leading to uncertainty and identity conflicts that contributed to the participants' concerns about re-entering the workforce. The program enabled the participants to develop social skills and trust which contributed to providing the participants with confidence, individually-tailored possibilities for developing new competencies and courage; thus, facilitating their recovery process. PMID- 29488444 TI - Rapid Recovery of Liver Transplantation Recipients by Implementation of Fast Track Care Steps: What Is Holding Us Back? AB - A body of scientific studies has shown that early extubation is safe and cost effective in a large number of liver transplant (LT) recipients including pediatric patients. However, fast-track practices are not universally accepted, and debate still lingers about whether these interventions are safe and serve the patients' best interest. In this article, we focus on reasons why physicians still have a persistent, although diminishing, reluctance to adopt fast-track protocols. We stress the importance of collection/analysis of perioperative data, adoption of a consensus-based standardized protocol for perioperative care, and formation of LT anesthesia focused teams and leadership. We conclude that the practice of early extubation and fast-tracking after LT surgery could help improve anesthesia performance, safety, and cost-effectiveness. PMID- 29488445 TI - Critical Importance of Low-Dose Tissue Plasminogen Activator Policy for Treating Intraoperative Pulmonary Thromboembolism During Liver Transplantation. AB - Tissue plasminogen activator (tPA) has been reported to treat intraoperative pulmonary thromboembolism (PTE) during liver transplantation (LT). However, tPA administration is often delayed due to fear of uncontrolled bleeding and storage in a refrigerator outside of operating rooms. Various dosages of tPA were used. We hypothesize that a policy of tPA storage and low dosage use improves patient outcomes. At a transplantation center, a multidisciplinary committee has implemented a tPA policy since April 2014, which includes the following: (1) timely administering of low-dose tPA (0.5-4 mg) for intraoperative PTE; (2) keeping 2 vials of tPA (2 mg/vial) in the operating room at room temperature; and (3) transferring unused tPA vials to the cardiology catheterization laboratory for next-day use. A prospective observational study was conducted to record the incidence and outcome of PTE during LTs. Over the next 19 months, 99 adult deceased donor LTs were performed with 1 (1.0%) intraoperative PTE. A 45-year-old woman with hepatitis C developed PTE within 5 minutes after graft reperfusion. A 2-mg tPA was immediately administered via a central venous line with hemodynamic improvement and clot lysis. Thromboelastography was normalized in 90 minutes. Five LT cases developing intraoperative PTE have been reported to receive "standard" dosages of tPA (20-110 mg) or urokinase (4400 IU/kg), which were administered more than 20 minutes after the diagnosis of PTE. One intraoperative death and one later mortality were noted with intracranial hemorrhages/infarction of 3 cases. The multidisciplinary low-dose tPA policy for PTE was suggested to be effective. PMID- 29488446 TI - Using empirical Bayes predictors from generalized linear mixed models to test and visualize associations among longitudinal outcomes. AB - Medical research is often designed to investigate changes in a collection of response variables that are measured repeatedly on the same subjects. The multivariate generalized linear mixed model (MGLMM) can be used to evaluate random coefficient associations (e.g. simple correlations, partial regression coefficients) among outcomes that may be non-normal and differently distributed by specifying a multivariate normal distribution for their random effects and then evaluating the latent relationship between them. Empirical Bayes predictors are readily available for each subject from any mixed model and are observable and hence, plotable. Here, we evaluate whether second-stage association analyses of empirical Bayes predictors from a MGLMM, provide a good approximation and visual representation of these latent association analyses using medical examples and simulations. Additionally, we compare these results with association analyses of empirical Bayes predictors generated from separate mixed models for each outcome, a procedure that could circumvent computational problems that arise when the dimension of the joint covariance matrix of random effects is large and prohibits estimation of latent associations. As has been shown in other analytic contexts, the p-values for all second-stage coefficients that were determined by naively assuming normality of empirical Bayes predictors provide a good approximation to p-values determined via permutation analysis. Analyzing outcomes that are interrelated with separate models in the first stage and then associating the resulting empirical Bayes predictors in a second stage results in different mean and covariance parameter estimates from the maximum likelihood estimates generated by a MGLMM. The potential for erroneous inference from using results from these separate models increases as the magnitude of the association among the outcomes increases. Thus if computable, scatterplots of the conditionally independent empirical Bayes predictors from a MGLMM are always preferable to scatterplots of empirical Bayes predictors generated by separate models, unless the true association between outcomes is zero. PMID- 29488447 TI - Sample size determination for semiparametric analysis of current status data. AB - Semiparametric transformation models, which include the Cox proportional hazards and proportional odds models as special cases, are popular in current practice of survival analysis owing to that, in contrast to parametric models, no assumption on the baseline distribution is required. Although sample size calculations for semiparametric survival analysis with right-censored data are available, no such calculation exits in literature for semiparametric analysis with current status data, where only an examination time and whether the event occurs prior to the examination are observable. We develop sample size calculation for semiparametric two-group comparison or regression analysis with current status data. The proposed formula can be readily implemented with given effect size, power level, covariate group proportions, covariate-specific examination (censoring) time distributions, and proportions of events observed in the control group at a few knot points in the study period. Simulation results show that the proposed sample size calculation is adequate in the sense that it leads to studies with empirical power very close to the planned power level. We illustrate practical applications of the proposal through examples from an animal tumorigenicity study and a cross sectional survey on osteoporosis status in the elderly. PMID- 29488448 TI - MethodCompare: An R package to assess bias and precision in method comparison studies. AB - Bland and Altman's limits of agreement have been used in many clinical research settings to assess agreement between two methods of measuring a quantitative trait. However, when the variances of the measurement errors of the two methods are different, limits of agreement can be misleading. MethodCompare is an R package that implements a new statistical methodology, developed by Taffe in 2016. MethodCompare produces three new plots, the "bias plot", the "precision plot", and the "comparison plot" to visually evaluate the performance of the new measurement method against the reference method. The method is illustrated on three simulated examples. Note that the Taffe method assumes that there are several measurements from reference standard and possibly as few as one measurement from the new method for each individual. PMID- 29488450 TI - Midwest Nursing Research Society News. PMID- 29488451 TI - Theaflavin-3-gallate specifically interacts with phosphatidylcholine, forming a precipitate resistant against the detergent action of bile salt. AB - Black tea is a highly popular beverage, and its pigments, polymerized catechins such as theaflavins (TFs), are attracting attention due to their beneficial health effects. In this study, to test the inhibitory activities of TFs on the intestinal absorption of cholesterol, we investigated their effects on phosphatidylcholine (PC) vesicles in the absence or presence of a bile salt. (-) Epicatechin gallate, (-)-epigallocatechin gallate, and TFs formed insoluble complexes with PC vesicles. Galloylated TFs such as TF2A, TF2B, and TF3 precipitated far more than other polyphenols. The subsequent addition of taurocholate redispersed the polyphenol-PC complexes, except that a large amount of TF2A remained insoluble. After incubation with taurocholate-PC micelles, TF2A elevated the turbidity of the micelle solution, providing red sediments. The TF2A specific effect was dependent on the PC concentration. These results suggest that TF2A interacts with PC and aggregates in a specific manner different from catechins and other TFs. PMID- 29488452 TI - Isovaleronitrile co-induced with its precursor, l-leucine, by herbivory in the common evening primrose stimulates foraging behavior of the predatory blue shield bug. AB - Herbivore-induced plant volatiles play important roles in plant-insect and plant plant interactions. The common evening primrose, Oenothera biennis, is often infested by the flea beetle, Altica oleracea, on which the predatory blue shield bug, Zicrona caerulea, is usually found. This observation suggests that the predatory bug can discriminate infested plants from intact ones to locate its prey. In this study, l-leucine-derived nitrogen-containing compounds [isovaleronitrile (3-methylbutanenitrile), (E/Z)-isovaleraldoxime and 3-methyl-1 nitrobutane] and some terpenes were identified as a characteristic volatile blend from herbivore-infested O. biennis leaves by gas chromatography/mass spectrometry, chemical synthesis, and incorporation assays using deuterium labeled l-leucine. Volatile emission was also elicited by exogenous methyl jasmonate (MeJA), but not by mechanical damage. l-Leucine accumulated temporarily in O. biennis leaves after MeJA treatment prior to isovaleronitrile emission. Behavioral assays revealed that Z. caerulea showed a strong preference for herbivore-infested leaves, their volatiles, and isovaleronitrile in laboratory conditions. PMID- 29488453 TI - Structural analysis and taste evaluation of gamma-glutamyl peptides comprising sulfur-containing amino acids. AB - The structures, flavor-modifying effects, and CaSR activities of gamma-glutamyl peptides comprising sulfur-containing amino acids were investigated. The chemical structures, including the linkage mode of the N-terminal glutamic acid, of gamma L-glutamyl-S-(2-propenyl)-L-cysteine (gamma-L-glutamyl-S-allyl-L-cysteine) and its sulfoxide isolated from garlic were established by comparing their NMR spectra with those of authentic peptides prepared using chemical methods. Mass spectrometric analysis also enabled determination of the linkage modes in the glutamyl dipeptides by their characteristic fragmentation. In sensory evaluation, these peptides exhibited flavor-modifying effects (continuity) in umami solutions less pronounced but similar to that of glutathione. Furthermore, the peptides exhibited intrinsic flavor due to the sulfur-containing structure, which may be partially responsible for their flavor-modifying effects. In CaSR assays, gamma-L glutamyl-S-methyl-L-cysteinylglycine was most active, which indicates that the presence of a medium-sized aliphatic substituent at the second amino acid residue in gamma-glutamyl peptides enhances CaSR activity. PMID- 29488454 TI - Response to Alert on Possible Infections with Mycobacterium chimaera From Contaminated Heater-Cooler Devices in Hospitals Participating in the Canadian Nosocomial Infection Surveillance Program (CNISP). AB - Canadian hospitals were made aware of the risk of Mycobacterium chimaera infection associated with heater-cooler units (HCUs) through alerts issued by the US food and Drug Administration (FDA) and the US Centers for Disease Control and Prevention (CDC). In response, most hospitals conducted retrospective reviews for infections, informed exposed patients, and initiated a requirement for informed consent with HCU use. Infect Control Hosp Epidemiol 2018;39:482-484. PMID- 29488455 TI - Sensitivity, Specificity, and Public-Health Utility of Clinical Case Definitions Based on the Signs and Symptoms of Cholera in Africa. AB - During 2014, Africa reported more than half of the global suspected cholera cases. Based on the data collected from seven countries in the African Cholera Surveillance Network (Africhol), we assessed the sensitivity, specificity, and positive and negative predictive values of clinical cholera case definitions, including that recommended by the World Health Organization (WHO) using culture confirmation as the gold standard. The study was designed to assess results in real-world field situations in settings with recent cholera outbreaks or endemicity. From June 2011 to July 2015, a total of 5,084 persons with suspected cholera were tested for Vibrio cholerae in seven different countries of which 35.7% had culture confirmation. For all countries combined, the WHO case definition had a sensitivity = 92.7%, specificity = 8.1%, positive predictive value = 36.1%, and negative predictive value = 66.6%. Adding dehydration, vomiting, or rice water stools to the case definition could increase the specificity without a substantial decrease in sensitivity. Future studies could further refine our findings primarily by using more sensitive methods for cholera confirmation. PMID- 29488456 TI - Nasopharyngeal Carriage of Streptococcus pneumoniae in Children in Coastal Kenya. AB - Streptococcus pneumoniae (SP) is a leading cause of child mortality globally, killing around half a million children aged 5 years and less per year. Nasopharyngeal carriage of SP is a prerequisite to disease, and the prevalence of colonization reaches 100% within the first few years of life. Serotype prevalence varies geographically, impacting the serotype coverage of pneumococcal vaccines, and serotype prevalence data are limited from large regions of the world, including sub-Saharan Africa. We enrolled 323 unvaccinated children, aged 4-7 years from coastal Kenya and obtained nasopharyngeal swab samples before and after vaccination with the 10-valent pneumococcal vaccine. Vaccination did not reduce the overall prevalence of pneumococcal carriage in our cohort, with 65 (20%) children colonized before vaccination and 63 (19.4%) colonized postvaccination. However, the prevalence of vaccine-included serotypes (vaccine strains) declined from 43% to 19% of positive swabs, whereas non-vaccine serotypes increased from 46% to 73%. This study contributes to the few data available regarding pneumococcal carriage and serotype prevalence in Kenya and is in concordance with reports of dynamic serotype replacement, driven by vaccine pressure. PMID- 29488457 TI - Defining Diarrhea: A Population-Based Validation Study of Caregiver-Reported Stool Consistency in the Amhara Region of Ethiopia. AB - Diarrhea is a leading cause of death among children aged less than five years globally. Most studies of pediatric diarrhea rely on caregiver-reported stool consistency and frequency to define the disease. Research on the validity of caregiver-reported diarrhea is sparse. We collected stool samples from 2,398 children participating in two clinical trials in the Amhara region of Ethiopia. The consistency of each stool sample was graded by the child's caregiver and two trained laboratory technicians according to an illustrated stool consistency scale. We assessed the reliability of graded stool consistency among the technicians, and then compared the caregiver's grade with the technician's grade. We also tested if the illustrated stool consistency scale could improve the validity of caregiver's report. The weighted kappa measuring the agreement between the two laboratory technicians reached 0.90 after 500 stool samples were graded. The sensitivity of caregiver-reported loose or watery stool was 15.5% (95% confidence interval [CI]: 9.7, 24.2) and the specificity was 98.4% (95% CI 97.1, 99.1). With the illustrated scale, the sensitivity was 68.5% (95% CI: 58.5, 77.1) and the specificity was 86.1% (95% CI: 79.3, 90.9). The results indicate that caregiver-reported stool consistency using the terms "loose or watery" does not accurately describe stool consistency as graded by trained laboratory technicians. Given the predominance of using caregiver-reported stool consistency to define diarrheal disease, the low sensitivity identified in this study suggests that the burden of diarrheal disease may be underestimated and intervention effects could be biased. The illustrated scale is a potential low lost tool to improve the validity of caregiver-reported stool consistency. PMID- 29488458 TI - Experimental Infection of White-Tailed Deer (Odocoileus virginanus) with Heartland Virus. AB - Heartland virus (HRTV) is a phlebovirus suspected to be transmitted by Amblyomma americanum, commonly known as the lone star tick, and reported to cause illness in humans, which is characterized by thrombocytopenia and leukopenia. Heartland virus-reactive antibodies have been detected in a variety of wildlife species including white-tailed deer (WTD). To better understand the potential role of deer in the epidemiology of HRTV, we experimentally inoculated five WTD fawns with HRTV and monitored for clinical disease, viremia, virus shedding, and seroconversion. None of the animals showed signs of clinical disease, and there was no detectable viremia or virus shedding postinoculation. Two wild-caught fawns entered the study with preexisting antibody titers against HRTV. All animals showed minimal immune responses against HRTV after needle inoculation. In conclusion, this study does not indicate that WTD are a likely reservoir for HRTV in natural settings. PMID- 29488459 TI - Case Report: Delayed or Recurrent Plasmodium falciparum Malaria in Migrants: A Report of Three Cases with a Literature Review. AB - Emerging evidence indicates that migrants from Plasmodium falciparum endemic regions are at risk of delayed presentation of P. falciparum malaria. We report three cases of P. falciparum malaria occurring years after arrival in Europe. All patients were originally from Sub-Saharan Africa. Two subjects had controlled human immunodeficiency virus infection and one was a pregnant woman. We performed a literature review of all published cases of delayed presentation of P. falciparum in migrants and identified 32 additional cases. All cases but one originate from sub-Saharan Africa. There was a median time of 36 months between the last visit to a malaria-endemic country and clinical malaria (range: 3 months to 10 years). Pregnancy was the most frequently reported risk factor (11/35 or 31.4%). Parasitemia was <= 0.1% in 38% of cases (11/29 reported), and no death was reported. The underlying possible mechanisms for this delayed presentation in migrants from an endemic area probably include the persistence of submicroscopic parasitemia combined with decaying P. falciparum-specific immunity. Suspicion of P. falciparum delayed malaria should remain high in migrants, mainly from sub Saharan Africa, even without a recent travel history, especially in those presenting risk factors for impaired parasite clearance or distinct immune responses such as pregnancy and HIV infection. In these patients, new prevention and screening strategies should be studied and blood safety policies adapted. PMID- 29488460 TI - A Prospective Hospital Study to Evaluate the Diagnostic Accuracy of Rapid Diagnostic Tests for the Early Detection of Leptospirosis in Laos. AB - Leptospirosis is a globally important cause of acute febrile illness, and a common cause of non-malarial fever in Asia, Africa, and Latin America. Simple rapid diagnostic tests (RDTs) are needed to enable health-care workers, particularly in low resource settings, to diagnose leptospirosis early and give timely targeted treatment. This study compared four commercially available RDTs to detect human IgM against Leptospira spp. in a head-to-head prospective evaluation in Mahosot Hospital, Lao PDR. Patients with an acute febrile illness consistent with leptospirosis (N = 695) were included in the study during the 2014 rainy season. Samples were tested with four RDTs: ("Test-it" [Life Assay, Cape Town, South Africa; N = 418]; "Leptorapide" [Linnodee, Ballyclare, Northern Ireland; N = 492]; "Dual Path Platform" [DPP] [Chembio, Medford, NY; N = 530]; and "SD-IgM" [Standard Diagnostics, Yongin, South Korea; N = 481]). Diagnostic performance characteristics were calculated and compared with a composite reference standard combining polymerase chain reaction (PCR) (rrs), microscopic agglutination tests (MATs), and culture. Of all patients investigated, 39/695 (5.6%) were positive by culture, PCR, or MAT. The sensitivity and specificity of the RDTs ranged greatly from 17.9% to 63.6% and 62.1% to 96.8%, respectively. None of the investigated RDTs reached a sensitivity or specificity of > 90% for detecting Leptospira infections on admission. In conclusion, our investigation highlights the challenges associated with Leptospira diagnostics, particularly in populations with multiple exposures. These findings emphasize the need for extensive prospective evaluations in multiple endemic settings to establish the value of rapid tools for diagnosing fevers to allow targeting of antibiotics. PMID- 29488461 TI - Effectiveness of a Household Water, Sanitation and Hygiene Package on an Outpatient Program for Severe Acute Malnutrition: A Pragmatic Cluster-Randomized Controlled Trial in Chad. AB - Water, sanitation and hygiene (WASH) interventions have a small but measurable benefit on stunting, but not on wasting. Our objective was to assess the effectiveness of a household WASH package on the performance of an Outpatient Therapeutic feeding Program (OTP) for severe acute malnutrition (SAM). We conducted a cluster-randomized controlled trial embedded in a routine OTP. The study population included 20 health centers (clusters) from Mao and Mondo districts in Chad. Both arms received the OTP. The intervention arm received an additional household WASH package (chlorine, soap, water storage container, and promotion on its use). The primary objective measures were the relapse rates to SAM at 2 and 6 months post-recovery. The secondary objectives included the recovery rate from SAM, the time-to-recovery, the weight gain, and the diarrhea longitudinal prevalence in OTP. The study lasted from April 2015 to May 2016. Among the 1,603 recruited children, 845 were in the intervention arm and 758 in the control arm. No differences in the relapse rates were noticed at 2 (-0.4%; P = 0.911) and 6 (-1.0%; P = 0.532) months. The intervention decreased the time-to recovery (-4.4 days; P = 0.038), improved the recovery rate (10.5%; P = 0.034), and the absolute weight gain (3.0 g/d; P = 0.014). No statistical differences were noticed for the diarrhea longitudinal prevalence (-1.7%; P = 0.223) and the weight gain velocity (0.4 g/kg/d; P = 0.086). Our results showed that adding a household WASH package did not decrease post-recovery relapse rates but increased the recovery rate among children admitted in OTP. We recommend further robust trials in other settings to confirm our results. PMID- 29488462 TI - "Kala-Azar is a Dishonest Disease": Community Perspectives on Access Barriers to Visceral Leishmaniasis (Kala-Azar) Diagnosis and Care in Southern Gadarif, Sudan. AB - Early diagnosis and treatment is the principal strategy to control visceral leishmaniasis (VL), or kala-azar in East Africa. As VL strikes remote rural, sparsely populated areas, kala-azar care might not be accessed optimally or timely. We conducted a qualitative study to explore access barriers in a longstanding kala-azar endemic area in southern Gadarif, Sudan. Former kala-azar patients or caretakers, community leaders, and health-care providers were purposively sampled and thematic data analysis was used. Our study participants revealed the multitude of difficulties faced when seeking care. The disease is well known in the area, yet misconceptions about causes and transmission persist. The care-seeking itineraries were not always straightforward: "shopping around" for treatments are common, partly linked to difficulties in diagnosing kala-azar. Kala-azar is perceived to be "hiding," requiring multiple tests and other diseases must be treated first. Negative perceptions on quality of care in the public hospitals prevail, with the unavailability of drugs or staff as the main concern. Delay to seek care remains predominantly linked to economic constraint: albeit treatment is for free, patients have to pay out of pocket for everything else, pushing families further into poverty. Despite increased efforts to tackle the disease over the years, access to quality kala-azar care in this rural Sudanese context remains problematic. The barriers explored in this study are a compelling reminder of the need to boost efforts to address these barriers. PMID- 29488464 TI - Modeling-based determination of physiological parameters of systemic VOCs by breath gas analysis, part 2. AB - In a recent paper (Unterkofler et al 2015 J. Breath Res. 9 036002) we presented a simple two compartment model which describes the influence of inhaled concentrations on exhaled breath concentrations for volatile organic compounds (VOCs) with small Henry constants. In this paper we extend this investigation concerning the influence of inhaled concentrations on exhaled breath concentrations for VOCs with higher Henry constants. To this end we extend our model with an additional compartment which takes into account the influence of the upper airways on exhaled breath VOC concentrations. PMID- 29488463 TI - Malaria in Southeastern China from 2012 to 2016: Analysis of Imported Cases. AB - To study the epidemiological distribution and the incident trends of imported malaria from 2012 to 2016 in Zhejiang Province, southeastern China, we collected data on malaria from the Information System for Parasitic Disease Control and Prevention. A total of 1,003 malaria cases were reported during 2012-2016, and all of these cases were imported. Plasmodium falciparum was the predominant species (76.3%) in Zhejiang Province. The percentage of Plasmodium vivax decreased from 33.6% to 8.1%, whereas the percentage of Plasmodium ovale and Plasmodium malariae increased. Most cases were male (89.8%), mostly in the age group of 21-50 years (82.6%). Businessmen (33.0%), workers (21.0%), farmers (18.8%), and overseas laborers (11.7%) were at high risk. The origin of the largest number of imported cases was Africa (89.5%), followed by Asia (10.0%) and Oceania (0.5%). The time interval from illness onset to confirmation was found to be significantly associated with the complications of patients. Out of 3,461 febrile individuals tested during reactive case detection, 10 malaria-positive individuals were identified. Effective surveillance and response system should be strengthened to prevent the reintroduction of malaria. PMID- 29488465 TI - Depth dependant element analysis of PbMg1/3Nb2/3O3 using muonic x-rays. AB - The relaxor PbMg1/3Nb2/3O3 (PMN) has received attention due to its potential applications as a piezoelectric when doped with PbTiO3 (PT). Previous results have found that there are two phases existing in the system, one linked to the near-surface regions of the sample, the other in the bulk. However, the exact origin of these two phases is unclear. In this paper, depth dependant analysis results from negative muon implantation experiments are presented. It is shown that the Pb content is constant throughout all depths probed in the sample, but the Mg and Nb content changes in the near-surface region below 100 MUm. At an implantation depth of 60 MUm, it is found that there is a 25% increase in Mg content, with a simultaneous 5% decrease in Nb content in order to maintain charge neutrality. These results show that the previously observed skin effects in PMN are due to a change in concentration and unit cell. PMID- 29488467 TI - Validating Fricke dosimetry for the measurement of absorbed dose to water for HDR 192Ir brachytherapy: a comparison between primary standards of the LCR, Brazil, and the NRC, Canada. AB - Two Fricke-based absorbed dose to water standards for HDR Ir-192 dosimetry, developed independently by the LCR in Brazil and the NRC in Canada have been compared. The agreement in the determination of the dose rate from a HDR Ir-192 source at 1 cm in a water phantom was found to be within the k = 1 combined measurement uncertainties of the two standards: D NRC/D LCR = 1.011, standard uncertainty = 2.2%. The dose-based standards also agreed within the uncertainties with the manufacturer's stated dose rate value, which is traceable to a national standard of air kerma. A number of possible influence quantities were investigated, including the specific method for producing the ferrous sulphate Fricke solution, the geometry of the holder, and the Monte Carlo code used to determine correction factors. The comparison highlighted the lack of data on the determination of G(Fe3+) in this energy range and the possibilities for further development of the holders used to contain the Fricke solution. The comparison also confirmed the suitability of Fricke dosimetry for Ir-192 primary standard dose rate determinations at therapy dose levels. PMID- 29488466 TI - Density functional theory computational study of ferroelectricity and piezoelectricity in BaTiO3/PbTiO3 (0 1 1) superlattices. AB - The structure, ferroelectricity (FE), and piezoelectricity of epitaxial BaTiO3/PbTiO3 (BTO/PTO) (0 1 1) superlattices are studied using density functional theory calculations. Our results show that compressive strain arising from the SrTiO3 (0 1 1) substrate stabilizes the (BTO) m /(PTO) n (0 1 1) superlattices in orthorhombic phase with the FE polarization along [0 1 1] direction. Tuning the BTO contents significantly changes the structural, ferroelectric and piezoelectric properties. The FE polarization of superlattices significantly drops with increasing BTO contents, which can be attributed to depolarization of the PTO layers. The averaged c/a ratio of the whole superlattices exhibits anomalous non-monotonic relation with respect to BTO contents. Interestingly, our results predict the (0 1 1) superlattices can enhance the piezoelectric coefficient e 33 with a maximum value at ~67% BTO concentration. This result suggests a potential avenue to design high performance piezoelectric materials with less Pb contents. In-depth analysis reveals the B site Ti cation as the origin for the enhanced e 33 value, which implies the potential of B-site cation engineering in perovskite heterostructure designs. PMID- 29488468 TI - Microwave hydrothermal synthesis and upconversion properties of Yb3+/Er3+ doped YVO4 nanoparticles. AB - Yb3+ and Er3+ doped YVO4 (Yb3+/Er3+:YVO4) nanoparticles with highly efficient near-infrared to visible upconversion properties have been synthesized by microwave hydrothermal process. Uniform-sized Yb3+/Er3+:YVO4 nanoparticles were synthesized within 1 h at 140 degrees C which is relatively faster than the conventional hydrothermal process. Under 980 nm laser excitation, strong green and less strong red emissions are observed which are attributed to 2H11/2, 4S3/2 to 4I15/2 and 4F9/2 to 4I15/2 transitions of Er3+ respectively. The emission intensity is found to depend strongly on the concentration of Yb3+. The quadratic dependence of upconversion intensity on the excitation power indicates that the upconversion process is governed by two-photon absorption process. PMID- 29488469 TI - Entanglement entropy and entanglement spectrum of Bi1-x Sb x (1 1 1) bilayers. AB - We study topological properties of Bi1-x Sb x bilayers in the (1 1 1) plane using entanglement measures. Electronic structures are investigated within multi orbital tight-binding model and structural stability is confirmed through first principles calculations. The topologically non-trivial nature of the bismuth bilayer is proved by the presence of spectral flow in the entanglement spectrum. We consider topological phase transitions driven by a composition change x, an applied external electric field in Bi bilayers and strain in Sb bilayers. Composition- and strain-induced phase transitions reveal a finite discontinuity in the entanglement entropy. This quantity remains a continuous function of the electric field strength, but shows a finite discontinuity in the first derivative. We relate the difference in behavior of the entanglement entropy to the breaking of inversion symmetry in the last case. PMID- 29488470 TI - Mapping nanoscale effects of localized noise-source activities on photoconductive charge transports in polymer-blend films. AB - We develolped a method to directly image the nanoscale effects of localized noise source activities on photoconducting charge transports in domain structures of phase-separated polymer-blend films of Poly(9,9-di-n-octylfluorenyl-2,7-diyl) and Poly(9,9-di-n-octylfluorene-alt-benzothiadiazole). For the imaging, current and noise maps of the polymer-blend were recorded using a conducting nanoprobe in contact with the surface, enabling the conductivity (sigma) and noise-source density (N T) mappings under an external stimulus. The blend-films exhibited the phase-separation between the constituent polymers at domains level. Within a domain, high sigma (low N T) and low sigma (high N T) regions were observed, which could be associated with the ordered and disordered regions of a domain. In the N T maps, we observed that noise-sources strongly affected the conduction mechanism, resulting in a scaling behavior of sigma ? [Formula: see text] in both ordered and disordered regions. When a blend film was under an influence of an external stimulus such as a high bias or an illumination, an increase in the sigma was observed, but that also resulted in increases in the N T as a trade off. Interestingly, the Deltasigma versus DeltaN T plot exhibited an unusual scaling behavior of Deltasigma ? [Formula: see text] which is attributed to the de-trapping of carriers from deep traps by the external stimuli. In addition, we found that an external stimulus increased the conductivity at the interfaces without significantly increasing their N T, which can be the origin of the superior performances of polymer-blend based devices. These results provide valuable insight about the effects of noise-sources on nanoscale optoelectronic properties in polymer-blend films, which can be an important guideline for improving devices based on polymer-blend. PMID- 29488471 TI - Exploring the formation and electronic structure properties of the g-C3N4 nanoribbon with density functional theory. AB - The optical properties and condensation degree (structure) of polymeric g-C3N4 depend strongly on the process temperature. For polymeric g-C3N4, its structure and condensation degree depend on the structure of molecular strand(s). Here, the formation and electronic structure properties of the g-C3N4 nanoribbon are investigated by studying the polymerization and crystallinity of molecular strand(s) employing first-principle density functional theory. The calculations show that the width of the molecular strand has a significant effect on the electronic structure of polymerized and crystallized g-C3N4 nanoribbons, a conclusion which would be indirect evidence that the electronic structure depends on the structure of g-C3N4. The edge shape also has a distinct effect on the electronic structure of the crystallized g-C3N4 nanoribbon. Furthermore, the conductive band minimum and valence band maximum of the polymeric g-C3N4 nanoribbon show a strong localization, which is in good agreement with the quasi monomer characters. In addition, molecular strands prefer to grow along the planar direction on graphene. These results provide new insight on the properties of the g-C3N4 nanoribbon and the relationship between the structure and properties of g-C3N4. PMID- 29488472 TI - Phase transition studies of Na3Bi system under uniaxial strain. AB - We investigated the electronic properties and phase transitions of Na3Bi in four structural phases (space groups P63/mmc, P [Formula: see text] c1, Fm [Formula: see text] m and Cmcm) under constant-volume uniaxial strain using the first principles method. For P63/mmc and P [Formula: see text] c1-Na3Bi, an important phase transition from a topological Dirac semimetal (TDS) to a topological insulator appears under compression strain around 4.5%. The insulating gap increases with the increasing compressive strain and up to around 0.1 eV at a strain of 10%. However, both P63/mmc and P [Formula: see text] c1-Na3Bi still keep the properties of a TDS within a tensile strain of 0-10%, although the Dirac points move away from the Gamma point along Gamma-A in reciprocal space as the tensile strain increases. The Na3Bi with space group Fm [Formula: see text] m is identified as a topological semimetal with the inverted bands between Na-3s and Bi-6p and a parabolic dispersion in the vicinity of Gamma point. Interestingly, for Fm [Formula: see text] m-Na3Bi, both compression and tensile strain lead to a TDS which is identified by calculating surface Fermi arcs and topological invariants at time-reversal planes (k z = 0 and k z = pi/c) in reciprocal space. Additionally, we confirmed the high pressure phase Cmcm-Na3Bi is an ordinary insulator with a gap of about 0.62 eV. It is noteworthy that its gap almost keeps constant around 0.60 eV within a compression strain of 0-10%. In contrast, a remarkable phase transition from an insulator to a metal phase appears under tensile strain. Moreover, this phase transition is highly sensitive to tensile strain and takes place only at a strain 1.0%. These strain-induced electronic structures and phase transitions of the Na3Bi system in various phases are important due to their possible applications under high pressure in future electronic devices. PMID- 29488474 TI - [Short bowel syndrome]. AB - The paper gives information on the classification, pathogenesis, and clinical manifestations of short bowel syndrome following after intestinal resection. It discusses the treatment and rehabilitation of patients with this condition. PMID- 29488473 TI - Tetramethylpyrazine Showed Therapeutic Effects on Sepsis-Induced Acute Lung Injury in Rats by Inhibiting Endoplasmic Reticulum Stress Protein Kinase RNA-Like Endoplasmic Reticulum Kinase (PERK) Signaling-Induced Apoptosis of Pulmonary Microvascular Endothelial Cells. AB - BACKGROUND Acute lung injury (ALI) is a life-threatening complication of sepsis. Tetramethylpyrazine (TMP) has been used in the clinical treatment of vascular diseases. The aim of this study was to investigate the therapeutic effects and possible involved mechanisms on ALI. MATERIAL AND METHODS Cecal ligation and puncture (CLP) was used to establish a sepsis model in rats. TMP at various dosages were administrated to rats using a intragastric method. Animal survival rate was calculated. The lung functions were evaluated by lung weight/dry weight ratio (W/D), PaO2, dynamic compliance (DC), and airway resistance index (ARI). Pulmonary microvascular endothelial cells (PMVECs) were isolated from lungs harvested from rats with sepsis. TUNEL assay was used to detect apoptosis. Protein expression and phosphorylation levels were assessed by western blotting. RESULTS TMP administration increased the survival rate of septic rats. TMP also decreased W/D and DC, but increased PaO2 and ARI in septic rats. Moreover, PMVECs apoptosis was inhibited in septic rats that received TMP treatment. The expression levels of GRP78, ATF4, caspase-12, active caspase-3, as well as the phosphorylation levels of PERK and eIF2alpha were suppressed in PMVECs isolated from TMP-treated septic rats. CONCLUSIONS TMP alleviated sepsis-induced ALI by suppressing PMVECs apoptosis via PERK/eIF2alpha/ATF4/CHOP apoptotic signaling in endoplasmic reticulum stress. PMID- 29488475 TI - [Anxiety-related blood pressure variability in patients with atrial fibrillation after cardioembolic stroke]. AB - AIM: To investigate whether of anxiety-related blood pressure (BP) variability can be corrected in patients with atrial fibrillation (AF) who have experienced cardioembolic stroke (CES). SUBJECTS AND METHODS: The investigation enrolled 125 patients (mean age, 68.5+/-5.7 years) with AF, who had experienced CES. The patients were randomized into 2 groups by the envelope technique: 1) 63 patients received antihypertensive drugs and an anxiolytic (adaptol) (a study group); 2) 62 patients had antihypertensive drugs only (a comparison group). Effectiveness was evaluated 2 and 6 weeks later from the time course of changes in BP readings obtained by 24-hour Holter monitoring in relation to reactive anxiety (RA) and personal anxiety (PA) scores. The latter were determined using the Spielberger Hanin Anxiety Self-Esteem scale. RESULTS: The patients with AF who had experienced CES were noted to have high BP variability associated with increased RA and PA scores. Group 1 showed statistically significant improvements in RA and PA 2 and 6 weeks after the start of treatment. The efficiency of anti-anxiety therapy (adaptol at a dose of 500 to 1500 mg/day) in combination with antihypertensive drugs is confirmed by the normalized circadian BP profile. CONCLUSION: The incorporation of an anxiolytic into pharmacotherapy regimens could improve BP, namely, to reduce and stabilize its circadian profile. PMID- 29488476 TI - [Treatment for ventricular arrhythmias in the absence of structural heart disease: from guidelines to clinical practice]. AB - AIM: To determine criteria for choosing management tactics in patients with ventricular arrhythmias (VA) in the absence of structural heart disease from the point of view of physicians and patients in clinical practice and to compare the immediate results of antiarrhythmic drug therapy (ADT) and radiofrequency ablation (RFA) with the trends in arrhythmic syndrome in the non-treatment group. SUBJECTS AND METHODS: Examinations were made in 90 patients (23 men and 67 women) (mean age, 44 (31; 57) years) with VA in the absence of structural heart disease. Preference was given to RFA (n = 32 (36%)), ADT (n = 37 (41%)), and follow-up tactics (n = 21 (23%)). At baseline and 1 month, Holter ECG monitoring was done; quality of life (QOL) was assessed; and anxiety and depression levels were detected using the SF-36 and HADS questionnaires. In addition, 71 physicians were surveyed about their preferences to the treatment of VA in individuals without structural heart disease. RESULTS: In the total group of patients, VA was unambiguously accompanied by the symptoms only in 47%. The signs of anxiety and depression were identified in 41 and 14% of cases, respectively. The efficiency of RFA was comparable to that of ADT (p > 0.1): a positive antiarrhythmic effect was observed in 71.9% of the patients in the RFA group and in 67.6% in the ADT group. During one month, 38.1% of the patients in the follow-up group showed a spontaneous substantial reduction in the number of ventricular premature beats (VPBs) or disappearance of unstable ventricular tachycardia (UVT), which met the criteria for a positive effect. At baseline, the QOL indicators on a social functioning scale in the RFA group were worse than those in the ADT group. At the same time, most QOL indicators in the patients who have chosen a wait-and-see tactic were significantly higher than those in the RFA and ADT subgroups. The patients treated with ethacyzin in the ADT group more frequently achieved a positive effect. In the interviewed physicians' opinion, the choice of a tactic depended on the impact of arrhythmia on health status (68%), the number of VPBs per day (61%), and the presence of UVT (56%). RFA or ADT was most often recommended when there were 10,000-15,000 or more VPBs per day ((49 and 35% of the respondents, respectively). 46.5% of the respondents stated that beta blockers were the drug of choice for idiopathic frequent VPBs. Only 30% of the respondents considered it appropriate to restrict to a follow-up in the presence of asymptomatic VPBs. CONCLUSION: Patient management in clinical practice generally complies with the current guidelines; however, much importance is attached to the severity of arrhythmia (the number of VPBs per day, the presence of UVT) in addition to the presence of symptoms. In the opinion of most physicians, the initiation of treatment is justified when there are 10,000-15,000 and more per day. QOL assessment may be promising in choosing the optimal management tactics for these patients. Treatment should not be initiated immediately in patients with a high level of QOL, especially in those with arrhythmia lasting less than 12 months, by taking into account that there can be a spontaneous improvement in 38% of cases within the next month. The immediate results of ADT and RFA are comparable in patients with VA in the absence of structural heart disease. The Class IC antiarrhythmic drug ethacyzin is the most effective agent that ensures positive changes in arrhythmic syndrome in 66.7% of cases with the rate of side effects being in 17.8%. PMID- 29488477 TI - [Analysis of the effectiveness and long-term results of formation of adaptive immunity in the use of various medications and vaccination schemes against pneumococcal infection in patients with chronic obstructive pulmonary disease]. AB - AIM: To assess the long-term clinical results of vaccination with pneumococcal polysaccharide and conjugated polysaccharide vaccines in the separate and sequential use, by determining the optimal vaccination schedule in adult patients with chronic obstructive pulmonary disease (COPD) and to investigate adaptive immunity levels. SUBJECTS AND METHODS: The clinical effects of vaccination were evaluated in patients with COPD within 1 and 4 years after immunization against pneumococcal infection using various schemes, as well as the time course of changes in adaptive immunity indicators was examined. RESULTS: Four years after vaccination, the 13-valent pneumococcal conjugate vaccine (PCV13)/23-valent pneumococcal polysaccharide vaccine (PPV23) group showed a decline in the number of patients with COPD exacerbations by 50% (p<0.001) and reductions in the number of antimicrobial chemotherapy cycles by 47.8% (p<0.001) and in that of hospitalizations by 87.5% (p<0.001). At 1 year after vaccination versus at baseline, the COPD patients vaccinated against pneumococcal disease, regardless of the drug and schedule of vaccination, displayed elevated levels of IgG antibodies to the mixture of capsular polysaccharides included in PPV23 and PCV13. CONCLUSION: It has been indicated that a complex of basic therapy for patients with COPD should include initial vaccination with PCV13, followed by administration of a booster dose of PPV23. PMID- 29488478 TI - [Therapy for acute/subacute musculoskeletal pain: results of the ATUSA (Analgesic Treatment Using a Systemic Algorithm) observational study]. AB - AIM: To evaluate the efficiency of therapy for acute/subacute musculoskeletal pain (MSP) by applying an individualized pathogenetic approach (an algorithm) elaborated on the basis of Russian experts' recommendations. SUBJECTS AND METHODS: A total of 262 physicians treating patients with rheumatic diseases participated in the ATUSA (Analgesic Treatment Using a Systemic Algorithm) program. The study enrolled 3,304 patients (54.3% women, 45.7% men; mean age, 48.6+/-14.3 years) with osteoarthritis, nonspecific back pain (NBP), and rheumatic diseases of periarticular soft tissues, who had experienced MSP. Treatment was performed in accordance with the following algorithm: the first prescribed medication was nonsteroidal anti-inflammatory drugs (NSAIDs) (aceclofenac): paracetamol and/or tramadol and a topical NSAID in case of contraindications and muscle relaxants in case of indications. The results of treatment were assessed after 7, 14, and 28 days. The treatment was corrected during each visit; the NSAID was, if necessary, changed; corticosteroids were locally injected; antidepressants or anticonvulsant drugs were used. The investigators assessed dynamic changes in pain using a 0-10 paint intensity numeric rating scale (NRS), the number of patients, in whom MSP was completely relieved, and satisfaction with treatment. RESULTS: The first prescribed medication was oral NSAIDs in 97.5% of the patients and those in combination with a muscle relaxant in 67.6%. By visit 4, MSP decreased from 6.9+/-1.5 to 2.2+/-1.3 NRS scores. After 28 days, only 16.2% of patients continued to need analgesics. 88.4% of the patients rated treatment results as good or excellent. NSAID switching was required in 8.1% of cases; local glucocorticosteroid injections were needed in 1.9%; there was a need for the use of an antidepressant or anticonvulsant in 1.5% and for hospitalization in 0.25%. Adverse events were observed in 2.2% of patients. The efficiency of treatment (complete pain relief after 28 days) was influenced by the following factors: NRS diagnosis (OR, 2.24; 95% CI, 1.67 to 3.11), age >=65 years (OR, 0.72; 95% CI, 0.52 to 0.98), moderate pain (NRS scores of <=7) at the beginning of the study (OR, 2.63; 95% CI, 1.99 to 3.48), mild/moderate pain (NRS scores of <4) after 7 days of therapy (OR, 2.5; 95% CI, 1.89 to 3.33), and the use of muscle relaxants (OR, 1.77; 95% CI, 1.23 to 2.96) (p<0.05 for all comparisons). CONCLUSION: The comprehensive pathogenetic approach used in analgesic therapy provides an effective and relatively safe relief of MSP in most patients with NBP and osteoarthritis. PMID- 29488479 TI - [Biomarkers of bone remodeling in ankylosing spondylitis patients using nonsteroidal anti-inflammatory drugs: results of an ETHICS research program]. AB - AIM: To evaluate changes in the concentration of biomarkers for osteoproliferation and bone resorption in ankylosing spondylitis (AS) patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs) in different regimens. SUBJECTS AND METHODS: Forty patients with AS (according to the modified New York criteria), who had BASDAI >= 4.0 at baseline and at 52 weeks of on-demand NSAID treatment were examined and randomized into 2 groups: 1) 30 patients who used continuously oral tenoxicam 20 mg daily (a study group); 2) 10 patients who continued previous therapy (a comparison group). BASDAI and ASDAS were calculated; the serum levels of C-reactive protein, C-terminal type I procollagen propeptide (PICP), and C-terminal telopeptide of type I collagen (CTX-I) were measured at baseline and at 52 and 56 weeks of treatment. A control group consisted of 19 healthy volunteers. RESULTS: The continuous use of NSAIDs (tenoxicam) decreased higher baseline BASDAI and ASDAS scores. There were no changes in the indicators of AS activity in the patients who took on-demand NSAIDs. Baseline CTX-I levels did not differ between the patients with AS and the healthy individuals; those declined during continuous intake of tenoxicam and remained unchanged during on-demand administration. In the patients with AS, baseline PICP levels exceeded those in the healthy individuals. In the tenoxicam treated patients, the concentrations of PICP at baseline and at 52 and 56 weeks were 17.1+/-9.0, 16.8+/-9.9, and 13.29+/-6.7 ng/ml, respectively (p=0.0001 for differences between the baseline and week 56 levels); in the comparison group, PICP levels did not change statistically significantly (p>=0.05 for all intergroup comparisons). CONCLUSION: Changing the inefficient long-term on-demand use of NSAIDs to their continuous intake is associated with a rapid decrease in clinical AS activity (within 4 weeks) with a reduction in the higher baseline concentration of the marker for osteoproliferation and in the normal level of the marker for bone resorption. PMID- 29488480 TI - [Experience in using Prolia in patients with postmenopausal osteoporosis in clinical practice]. AB - AIM: To evaluate the efficiency and safety of long-term Prolia therapy in patients with postmenopausal osteoporosis (OP). SUBJECTS AND METHODS: The open prospective study enrolled 98 women (mean age, 68+/-9 years; mean menopause duration, 17+/-4 years) with postmenopausal OP, who were followed up in an outpatient setting at the National Medical Research Center for Preventive Medicine and who had been treated with denosumab 60 mg subcutaneously every 6 months for 12 months or more. The maximum follow-up period was 4 years: 48, 29, 11, and 10 patients were treated for 12, 24, 36, and 48 months, respectively. The patients were allocated into 2 groups: those who received and those who had not previously received antiosteoporotic therapy. Bone mineral density (BMD) was measured using dual-energy X-ray densitometry of the lumbar spine (LI-LIV) and proximal femur (PF). The ten-year probability of major osteoporotic fractures was estimated once in 72 patients not previously receiving antiosteoporotic therapy before the prescription of denosumab. RESULTS: In the patients not previously receiving therapy, the median 10-year probability of major fractures using the FRAX algorithm was 14.9%; that of femoral neck (FN) fractures was 3.7%. During denosumab treatment, the BMD increase in the lumbar spine was 4.2% at 12 months, 7.5% at 24 months, was 8.8% at 36 months; that in FN was 3.1, 3.9, and 5.3%, that in PF was 2.8, 4.1, and 5%; and that in the 1/3 forearm was 0.9, 1.4, and 2.6%, respectively (p < 0.001). In the persons receiving and not previously receiving the therapy, the BMD increase was similar, i.e. there was an additional positive effect when switching to denosumab. The decrease in the serum concentration of C terminal telopeptide of type I collagen (CTX-I) was 54% at 6 months after initiation of denosumab therapy (p < 0.001) and 72% at 12 months (p<0.001); and the achieved marker level remained unchanged at 48 months. Transition from the OP zone to osteopenia one was noted in 23 patients with low BMD (T-score -2.5 SD) in LI-LII and in 12 patients with that in FN at 12 months of denosumab therapy and this was in 25 patients at 24 months. Nine-eight patients receiving the first Prolia injection refused to continue treatment on their own; adverse events were not the reason for drug discontinuation. CONCLUSION: Therapy with denosumab was effective in increasing BMD in routine outpatient practice and in allowing 25% of patients to achieve target values of this indicator. The marked decrease in the level of the bone resorption marker STX suggested that the drug had antiresorptive potency. The frequency of adverse reactions was low, confirming the good tolerability and safety profile of the drug. The convenience of the scheme and route of drug administration contributed to strict compliance with the doctor's recommendations. Denosumab was effective in increasing BMD not only in untreated patients, but also in those who had previously received antiosteoporotic therapy. The pharmacokinetic characteristics of denosumab, which contribute to its uniform distribution in trabecular and cortical bone tissue, regardless of active bone remodeling, and the fact that the clearance of the drug is independent of kidney function offer an advantage of administering the drug to patients with significant loss of FN and radius BMD and of reducing kidney function. PMID- 29488481 TI - [Predictors of the efficiency of short-term interferon-containing therapy using direct-acting antiviral drugs in patients with chronic hepatitis C virus genotype 1]. AB - AIM: To identify predictors for the high efficiency of short-term interferon containing antiviral therapy (AVT) using direct-acting antivirals (DAAs) in patients with chronic hepatitis C (CHC) virus (HCV) type 1 (CHC-1). MATERIAL AND METHODS: A total of 2,798 case histories of patients aged 18 to 60 years who received AVT using peginterferon, ribavirin in combination with DAAs for CHC-1, which was stopped at 10 to 14 weeks, were selected from the archives of the healthcare facilities of the Moscow Region. The inclusion criteria were aviremia achieved when AVT was discontinued; therapy using the dose recommended in compliance with the international standards; and adherence during treatment. RESULTS: The analysis included 179 case histories, including 158 cases of discontinuation of triple AVT using a protease inhibitor (telaprevir) and 22 cases of that of quadruple treatment (QT) with asunaprevir and daclatasvir. There were two main factors predicting a high probability of achieving a sustained virological response (SVR) in patients with HCV-1 during short-term triple AVT: viremia at 28 days of AVT, which was registered by a highly sensitive polymerase chain reaction (PCR) assay (its analytical sensitivity was 12 IU/ml), and the genotype CC of interleukin-28B (IL-28B) rs12979860. With a combination of these two factors, recovery was observed in 100% of cases. SVR was observed in all cases of QT discontinuation, regardless of the stage of fibrosis and the subtype of CHC genotype. However, the resulting sample was unrepresentative. CONCLUSION: Triple AVT using a protease inhibitor may be reduced in patients with CHC-1 and the CC allelic variant in IL-28B if viremia is achieved at 28 days of AVT, as evidenced by highly sensitive PCR assay. Short-term QT needs further investigation. PMID- 29488482 TI - [Optimization of therapy for hepatobiliary disorders in psoriatic patients]. AB - AIM: To optimize management tactics in patients with diseases of the liver and gallbladder in the presence of progressive psoriasis. SUBJECTS AND METHODS: The investigation enrolled 78 patients with nonalcoholic fatty liver disease (NAFLD) and different forms of gallbladder abnormality in the presence of progressive moderate and severe psoriasis. The patients were randomly divided into 2 groups: 1) phosphogliv; 2) ursosan with the main active ingredient ursodeoxycholic acid (UDCA). A prospective follow-up study accompanied by dynamic clinical, laboratory, and instrumental monitoring was carried out for 24 weeks. Clinical, biochemical, and ultrasound studies, including liver elastography, were applied. RESULTS: The use of UDCA (Ursosan 15 mg/kg for 24 weeks) to treat NAFLD and gallbladder abnormality in methotrexate-treated patients with progressive moderate and severe psoriasis contributed to the normalization of hepatic steatosis index, lipid composition, and lithogenic index, to the reduction of biliary sludge, and to the stabilization of liver fibrosis. Improvement in the functional status of the liver and gallbladder has contributed to the achievement of a more complete remission of dermatosis. CONCLUSION: The effects of UDCA in the therapy of NAFLD and gallbladder abnormality in patients with progressive psoriasis were greater than those of phosphogliv. PMID- 29488483 TI - [Common variable immune deficiency in adults: focus on pulmonary complications]. AB - Common variable immune deficiency is the most common form of a group of primary immunodeficiencies in adult patients. Pulmonary complications occupy leading positions. It is the development of recurrent bronchopulmonary inflammatory diseases that is considered to be one of the main causes of death and disability in patients with this disease. By presenting two clinical cases with long diagnostic delays, the authors try to attract the attention of specialists of related professions, which will minimize the development of irreversible complications in the patients. PMID- 29488484 TI - [Malnutrition: from pathogenesis to current methods for diagnosis and treatment]. AB - Progressive weight loss is a frequent companion to somatic pathology. The risk of death is known to increase dramatically among those with a body mass index of less than 19 kg/m2. Even mild weight loss in the presence of severe diseases can have a substantial impact on the course of the disease. The paper presents current views on malnutrition, its prevalence in the presence of various somatic diseases, and clinical significance. It describes the basic pathogenetic components of weight loss and the possible ways of correcting nutritional status. Particular emphasis is placed on the methods of nutritional support that is currently regarded as one of the most important components of a comprehensive approach to treating patients with chronic diseases. The authors give recommendations for the assessment of the nutritional status of patients in clinical practice and algorithms for their malnutrition management. PMID- 29488485 TI - [Nonalcoholic fatty liver disease without obesity: the problem to be solved]. AB - It is generally agreed that nonalcoholic fatty liver disease (NAFLD) is a component of metabolic syndrome and is frequently associated with obesity, type 2 diabetes mellitus, atherogenic dyslipidemia, and other components of the syndrome. However, there is no doubt that not all overweight people develop NAFLD and, conversely, the latter may be present in normal weight individuals. The prevalence of NAFLD without obesity in different countries is very variable from 3 to 30%. Its risk factors are considered to be both exogenous (for example, excess intakes of cholesterol and rapidly assimilable fructose) and genetically determined (allelic variants of the genes encoding adiponutrin, the cholesteryl ester transport protein, sterol-regulatory element-binding protein 2). The methods for the diagnosis of NAFLD without obesity do not differ in essence from those for classic NAFLD. Analysis of the conducted investigations gives grounds to claim that lifestyle modification as exercises and dietary restrictions improves biochemical parameters and histological pattern. The efficiency of drug treatments needs further investigation. PMID- 29488486 TI - [A rationally grounded approach to treating gout with regard to its onset and course and the presence of comorbidity according to the European League against Rheumatism (EULAR 2016) recommendations]. AB - The review analyzes in detail the management of gout, which takes into account its onset and course and the presence of comorbidity. Emphasis is placed on drug and non-drug treatments and urate-lowering therapy in patients with kidney dysfunction. Along with allopurinol, the urate-lowering drug febuxostat is first recommended in Russia. The purpose of this review is to notify physicians of the possibility of achieving the target uric acid levels when treating gout with hyperuricemia. PMID- 29488487 TI - [A paradigm of early gonarthrosis: a review of the current diagnostic and treatment options (Part 1)]. AB - The prevalence of chronic joint diseases, among which osteoarthritis (OA) prevails, continues to grow worldwide. So far, many OA patients starting to get any kind of treatment only at the stage of organ failure, when the progression of the pathological process cannot be considerably delayed. The long-felt need for a change in thinking how to effectively diagnose and treat OA patients at early stage induced to prepare this review. Its first part is devoted to discussion of the limitations of traditional approaches and to analysis of the current diagnostic capabilities, particularly the clinical features of early OA, its morphological characteristics based on the magnetic resonance imaging and arthroscopic criteria, as well as the perspectives of biochemical and genetic markers implementation. PMID- 29488488 TI - [Department of Otorhinolaryngology of the Faculty of General Medicine, Ministry of Health of the Russian Federation: from the beginning to the present time]. AB - This article is devoted to the history of academic, research, and clinical activities of the Department of Otorhinolaryngology of the Faculty of General Medicine, N.I. Pirogov Russian National Research Medical University. PMID- 29488489 TI - [The history of organization of the research laboratories based at the Department of Otorhinolaryngology of the Faculty of General Medicine]. AB - This article was designed to describe the history of the establishment and development of the research divisions based at the Department of Otorhinolaryngology of the Faculty of General Medicine, N.I. Pirogov Russian National Research Medical University, including laser, vestibulogical, and audiological laboratories. The authors present an overview of the main research activities and achievements of the Department with special reference to the management of Meniere's disease, cochlear-vestibular disorders associated with sensorineural hearing loss, injuries to the organs of hearing, and diseases of the central nervous system. Also discussed are the peculiarities of the laser assisted medical care and the possibilities for the application of therapeutic and surgical lasers for the purposes of the practical otorhinolaryngological work. PMID- 29488490 TI - [The pedagogical activities at the Department of Otorhinolaryngology of the Faculty of General Medicine]. AB - This article was designed to substantiate the main principles of the academic process as practiced at the Department of Otorhinolaryngology of the N.I. Pirogov Russian National Research Medical University under the current conditions of the ongoing modernization of the system of higher medical education. The authors emphasize the necessity of the combination of theoretical and practical training with special reference to the specific features of the curricular and extracurricular activities. The importance of the formation of the properly functioning teaching staff is underscored. To enhance the efficiency of the educational process, the wide application of the computer-assisted technologies is recommended that can be simultaneously used to improve the methods for diagnostics and treatment of various pathological conditions. The activities based at the specialized students' scientific circle may prove very helpful to facilitate the acquisition of the necessary theoretical knowledge and practical skills by the medical students and thereby to promote the formation of professional otorhinolaryngologists. PMID- 29488491 TI - [The peculiar features of vestibular function disorders associated with Meniere's disease]. AB - AIM: The objective of the present study was to reveal the special aspects of vestibular dysfunction in the patients presenting with unilateral Meniere's disease (MD) during the attack-free intervals. METHODS: The study included 23 patients suffering from unilateral MD; all of them were examined with the use of tonal threshold audiometry, videonystagmography, the caloric test and video head impulse test (vHIT). RESULTS: The study has demonstrated that the patients with MD are characterized, during the attack-free intervals, by the absence of latent spontaneous nystagmus in conjunction with the positive results of the head shaking test. Moreover, asymmetry of the results of the caloric test together with the normal results of the video head-impulse test is shown to be the characteristic feature of the patients with unilateral MD. The analysis of the degree of sensorineural hearing loss, the caloric test data, and coefficient of labyrinth asymmetry (CLAS) gave evidence of the tendency toward the elevation of the hearing threshold with increasing CLAS. PMID- 29488492 TI - [The compensation of the vestibulo-ocular reflex during rehabilitation of the patients presenting with vestibular neuritis]. AB - AIM: The objective of the present study was to elucidate the mechanisms behind the compensation of the vestibular ocular reflex and evaluate the effectiveness of vestibular rehabilitation in the patients presenting with vestibular neuritis (VN) with the application of the video head-impulse test (vHIT) and the dynamic visual acuity test (DVAT). METHODS: The study included 26 patients with vestibular neuritis whose condition was assessed by scoring based on the dizziness handicap inventory, the dynamic visual acuity test, and the video head impulse test with the evaluation of saccades and the degree of eye-head movement coordination (gain) before and after the course of vestibular rehabilitation. RESULTS: The study has demonstrated that the course of vestibular rehabilitation of the patients presenting with vestibular neuritis resulted in a significant decrease in the scores of dizziness estimated based on the dizziness handicap inventory and an improvement of dynamic visual acuity in the case of the complete gain recovery as well as in the case of persisting impairment of the gain and the development of sufficient 'covert' saccade. Vestibular rehabilitation was unsuccessful in the patients with persistereduced gain and simultaneous development of 'covert' and 'overt' saccades. PMID- 29488493 TI - [The peculiar features of the clinical course of Meniere's disease associated with benign paroxysmal positional vertigo]. AB - AIM: The objective of the present study was to evaluate the frequency of occurrence and clinical features of vertigo spells in the patients presenting with Meniere's disease (MD) associated with benign paroxysmal positional vertigo (BPPV). METHODS: A total of 104 patients with MD were available for the observation. All of them underwent the comprehensive examination that included the audiological study and vestibular tests, such as the Dix-Hallpike test and the roll-test for BPPV diagnostics. A structured questionnaire was used to calculate the average number of vertigo spells per month during the period of 6 months and the mean duration of the vertigo spells; the presence or the absence of changes in hearing ability during the spells as well as the severity of vertigo were determined with the use of the 10-point visual analogue scale. RESULTS: The patients suffering from BPPV associated with Meniere's disease presented with the following clinical features which distinguished them from the patients with idiopathic BPPV (p<0.05): (1) a higher percentage of female patients; (2) a longer duration of clinical symptoms; (3) the frequent involvement of the horizontal semicircular canal; (4) a greater incidence of canal paresis; (5) more therapeutic sessions needed for the recovery in conjunction with a higher rate of recurrence. CONCLUSION: The frequency of association of MD and BPPV was estimated at 14.4%. Such association of MD was more frequently observed in the elderly patients (older than 60 years) (p<0.05). The clinical manifestations of the vertigo spells in the patients having MD associated with BPPV occurred with an enhanced frequency; their mean duration was relatively short due to the presence of both long and short positional vertigo attacks characterized by the absence of hearing changes during the spells and the equal severity of vertigo (p < 0,05). PMID- 29488494 TI - [The specific microbiological and clinical features of acute otitis media]. AB - The objective of the present study was to elucidate the specific features of the clinical course of acute otitis media as well as the peculiarities of the vestibular function and the microbial paysage associated with this pathological condition under the present-day conditions. The study included 135 patients presenting with acute otitis media (AOM) at different stages of the disease. The discharge obtained from the tympanic cavity of all the patients was examined with the use of polymerase chain reaction in real time, audiological and vestibulogical methods. The distinctive features of acute otitis medium associated with Streptococcus pneumoniae infection were found to be the intense pain syndrome with the symptoms of intoxication, well apparent inflammatory changes in the tympanic membrane as revealed by otoscopy, the increased frequency of sensorineural impairment of hearing, and the characteristic type B tympanometric curve. Typical of AOM associated with Haemophilus influenza infection are the mild pain syndrome, weak changes in the tympanic membrane as revealed by otoscopy, conductive hearing loss, and the type C tympanometric curve. PMID- 29488495 TI - [The characteristics of broad-band tympanometry in the volunteers with the unaffected hearing]. AB - AIM: The objective of the present work was to elucidate the characteristics of broad-band tympanometry in the healthy subjects with the unaffected hearing ability. The study involved 54 volunteers (27 men and 27 women) at the age from 21 to 55 years exhibiting no pathologic changes in the ear system as confirmed by the tone threshold audiometry, otoacoustic emission, tympaometry at a frequency of 226 Hz, and reflexometry. All the participants of the study underwent absorbance measurements by broad-band tympanometry within the frequency range from 226 to 8,000 Hz at an ambient pressure. Five parameters have been detected which reflected the major characteristics of the absorbance curve, such as the maximum sound power absorbance ratio; the frequency at which the ear structures absorbed the maximum sound power; the frequency at which the absorbance ratio bounces off the plateau; the frequency at which the absorbance ratio plummets to plateau; and the frequency range within which the absorbance ratio underwent the most pronounced changes. The results obtained in the present study give evidence of response stability and the absence of the statistically significant differences in the absorbance parameters between the men and women obtained by their analysis for the ipsilateral and contralateral ears. PMID- 29488496 TI - [The application of contrast-enhanced X-ray salpingography for the evaluation of the effectiveness of catheterization of the acoustic tube with the use of the Eustachian catheters]. AB - The objective of the present study was to evaluate the effectiveness of the administration of a medication into the middle ear structures during catheterization of the acoustic tube (AT) in the course of the contrast-enhanced X-ray salpingographic investigation. The study included 18 patients (18 ears) presenting with chronic otitis media and the perforated tympanic membrane without the disturbances of the ventilation function of the auditory tube. All the patients were allocated to two groups depending on the type of the Eustachian catheters being used. Group 1 was comprised of 9 patients treated with the use of traditional Giyot's catheter, group 2 was composed of another nine patients who were treated with the use of the Eustachian catheters having an original shape with a specific configuration of its distal part. The X-ray studies were carried out before and after catheterization of the acoustic tube with the administration of 1 ml of the hypaque contrast medium. The study has demonstrated that the X-ray contrast agent did not penetrate into the inner structures of the middle ear of the patients comprising group 1 whereas in the patients of the second group the contrast medium reached as far as the bony portion of the acoustic tube. PMID- 29488497 TI - [Otomycosis: the modern view of etiology and management]. AB - This article deals with the modern approaches to the diagnostics and treatment of fungal ear infection depending on the localization of the inflammatory process and the species of the causative fungal agent with special reference to the factors underlying the development of otomycosis under the present-day conditions based on the results of the analysis of the studies carried out during the period from 2010 to 2014. The materials of the examination of 2152 patients who applied for the medical care to various clinical departments of the Institute and were found to present with chronic inflammatory ear pathology were available for the analysis. Fungal lesions were diagnosed in 495 (23%) patients with this condition. Fungal lesions of the external ear were the predominant form of pathology; they were documented in 331 (67%) patients. Fungal otitis media was diagnosed in 85 (17%) patients and fungal lesions of the postoperative cavity in 79 (16%) patients suffering from otomycosis. 65% of the patients presenting with external fungal otitis, 20% of those with fungal otitis media, and 95% of the patients with inflammation of the postoperative cavity were infected with mold fungi dominated by the genus Aspergillus spp. 79 (16%) patients suffering from otomycosis. In 35% of the patients presenting with fungal external otitis, 80% of those with fungal otitis media, and 5% of the patients with inflammation of the postoperative cavity of the middle ear, the causative agents of the disease were the fungi Candida spp. The authors describe the modern schemes for the treatment of otomycosis elaborated at the L.I. Sverzhevskiy Research Institute of Clinical Otorhinolaryngology. PMID- 29488498 TI - [The modern approach to the treatment of subglottic laryngeal stenosis]. AB - : The objective of the present study was to optimize the treatment of patients with subglottic laryngeal stenosis. MATERIAL AND METHODS: We have examined a total of 14 patients presenting with subglottic laryngeal stenosis. The etiological factors and underlying conditions of laryngeal stenosis were the prolonged intubation in 4 patients, Wegener granulomatosis in 6 patients, and idiopathic stenosis of the larynx in 4 patients. All the patients underwent balloon dilatation with the application of the video endoscopic technique. RESULTS: The surgical treatment of all the patients made it possible to achieve the persistent expansion of the lumen of the subglottic part of the larynx, to shorten the periods of the in-patient treatment and rehabilitation of the patients. Restenosis of laryngeal lining stenting was observed in one patient presenting with Wegener's granulomatosis which was associated with the relapse of the underlying disease. PMID- 29488499 TI - [The clinical and functional condition of the larynx in the patients of the elder age group presenting with chronic oedematous polypoidal laryngitis]. AB - This article was designed to report the results of the evaluation of the clinical and functional condition of the larynx in the patients of the elder age group presenting with chronic oedematous polypoidal laryngitis before and after their surgical treatment. A total of 60 patients at the age from 60 to 72 years were available for the examination; all of them had a concomitant somatic or ENT pathology. The clinical and functional conditions of the larynx in the patients of the elder age group were studied, with special reference to those suffering from chronic oedematous polypoidal laryngitis before the surgical intervention, that determined the overall clinical picture of the disease characterized in the first place by the predominance of the severe polypoid process with the combination of the organic and functional laryngeal pathology. The specific clinical and functional features of the larynx were identified after the surgical treatment that exerted the appreciable influence on the postoperative course of the disease and the duration of dysphonia. The peculiarities of postoperative laryngitis are described. Its catarrhal form was diagnosed in 42% of the patients. The strong inflammatory reaction with exudation and formation of fibrin films was documented in 58% of the patients while 83% of them exhibited formation of the functional component of dysphonia that required the application of the additional therapeutic measures for the complete restoration of the vocal function taking into consideration the age-related alteration of the larynx together with the long-term postoperative observation of the patients. PMID- 29488500 TI - [The peculiar features of the microbial paysage and the problems of antibacterial therapy of the inflammatory ENT diseases in the patients presenting with diabetes mellitus]. AB - This article is focused on the peculiar features of the ENT microbial paysage in the patients presenting with diabetes mellitus. We have examined a total of 310 patients including 145 suffering from the pyoinflammatory ENT diseases and concomitant diabetes mellitus. The study has demonstrated that the microbial biocenoses of the ENT organs in the diabetic patients are dominated by the potentially pathogenic and transitory microflora whereas the saccharolytic microflora and the non-fermentative bacteria (pseudomonades) concentrate in the foci of ENT inflammation. The spectrum of microorganism that occur in the areas of inflammation are shown to depend on the quality of compensation of diabetes mellitus. PMID- 29488501 TI - [Antimicrobial anti-inflammatory photodynamic and light-emitting-diode phototherapy of the consequences of the gunshot and mine-blast injury to the face, head, and neck including damage to the ENT organs]. AB - The objective of the present study was the enhancement of the effectiveness of the treatment of the consequences of the gunshot wounds and mine-blast injuries inflicted to the face, head, and neck encountered in the otolaryngological practice as well as the prevention of the formation of the large demarcation areas in the injured tissues and the preparation of these tissues for the further restorative treatment. Anti-microbial and anti-inflammatory photodynamic therapy (PDT) as well as light-emitting-diode (LED) phototherapy were carried out in 20 patients who suffered gunshot wounds and mine-blast injuries to the face, head, and neck. The photodynamic therapy was performed with the use of an aqueous solution of methylene blue at a concentration of 0.1%, the 'Alod-1' infrared laser ('Granat' modification, Russia), and the 'AFS-Solaris' light-emitting diode based phototherapeutic apparatus (Russia). The analysis of the results of the study has demonstrated the high efficiency of the proposed approach that made it possible to prevent the development of severe septic complications, reduce the amount of drug therapy, significantly shorten duration of the treatment, and create the conditions for the earlier rehabilitation and further plastic and cosmetic restoration of the tissue structures. PMID- 29488502 TI - [The species composition and sensitivity of pathogenic microflora responsible for the development of otitis externa diffusa to the components of Polidexa]. AB - The objective of the present work was to study microflora of the external auditory meatus in the patients presenting with bacterial otitis externa diffusa. The authors have analyzed the results of microbiological investigations involving 102 patients with this condition undergoing the treatment with 'Polidexa'. The characteristic of species composition of microflora associated with otitis externa diffusa is presented. The sensitivity of the most common pathogens responsible for the development of this pathology towards antibiotics contained in ear drops has been analysed. The advantages of the use Polidexa for the treatment of this acute ear disease are described. PMID- 29488503 TI - [Observation of the intra-adenoid cysts in the nasopharynx]. AB - The objective of the present study was to demonstrate the clinical significance and possibilities of diagnostics and treatment of the intra-adenoid cysts in the nasopharynx as exemplified by an original observation of an individual case. The cystic structures in the nasopharynx rarely manifest themselves clinically and are known to produce the non-specific symptoms. The patients admitted to the L.I. Sverzhevskiy Research Institute of Clinical Otorhinolaryngology for the surgical treatment of nasopharyngeal cysts account for 0.05% of the total number of the hospitalized subjects. This article reports a case of two large intra-adenoid cysts in the nasopharynx of one patient complicated by bilateral exudative otitis media. The successful outcome of the surgical treatment of this condition was achieved by means of endonasal marsupilization of the cysts under the laser assisted endoscopic control with simultaneous bilateral shunting of the tympanic cavity. PMID- 29488504 TI - [Pseudohypoacusis associated with Munchausen's syndrome]. AB - The authors describe a rare clinical case of psychogenic hearing loss in a female patient presenting Munchausen's syndrome with special reference to the objective and subjective methods designed to evaluate the hearing ability and used for diagnostics of this condition. PMID- 29488505 TI - [The modern approaches to the evaluation of the importance of chronic inflammation in the mucous membrane of the middle ear]. AB - Despite the ever growing progress in antibiotic therapy and the advent of the new methods for this purpose, the number of patients suffering from chronic focal infection of the ENT organs has not decreased during the last decades which turns the problem of chronization of inflammation into a serious challenge for the physicians as exemplified by chronic inflammation in the mucous membrane of the middle ear. Pathological changes in the middle ear make up a large fraction of ENT diseases of importance not only for otorhinolaryngologists but also for the specialists in the related medical disciplines. The present article is an overview of etiological, pathogenetic, and pathomorphological aspects of chronization of the inflammation process that are known to occur in the mucous membrane of the middle ear. In the overwhelming majority of the cases, the main cause of the conversion of acute inflammation in the middle ear into the chronic condition is the inadequate (incorrect), inopportune or incomplete treatment of the acute inflammatory process in the middle ear. PMID- 29488506 TI - [The peculiarities of the clinical picture and treatment of inflammatory ENT diseases in the frequently ill children]. AB - The objective of the present study was the analysis of the current state of the problem of the frequently ill children. The authors present the classification of the frequently ill children together with information concerning the influence of various factors on the incidence of pediatric pathologies with special reference to the major pathogenic agents responsible for the formation of the areas of chronic inflammation in the ENT organs of the children. The approaches to the treatment and rehabilitation of the patients belonging to this age group requiring the follow-up monitoring are considered. It is concluded that the comprehensive strategy is needed for providing the adequate care to such children including specific preventive vaccination, well-timed adequate treatment of acute respiratory conditions, rehabilitative therapy with the use of the adaptogenic substances, the development of resistance to the cold and other unfavourable factors, implementation of the relevant socio-medical programs. PMID- 29488507 TI - Corrigendum: Unifying Speed-Accuracy Trade-Off and Cost-Benefit Trade-Off in Human Reaching Movements. AB - [This corrects the article on p. 615 in vol. 11, PMID: 29379424.]. PMID- 29488508 TI - Corrigendum: Thymoquinone Inhibits Virulence Related Traits of Cronobacter sakazakii ATCC 29544 and Has Anti-biofilm Formation Potential. AB - [This corrects the article on p. 2220 in vol. 8, PMID: 29234307.]. PMID- 29488509 TI - Erratum: Increased cathepsin K levels in human atherosclerotic plaques are associated with plaque instability. AB - [This corrects the article DOI: 10.3892/etm.2017.4935.]. PMID- 29488510 TI - Corrigendum: Corrections to the funding. Quantification of the tug-back by measuring the pulling force and micro computed tomographic evaluation. AB - [This corrects the article on p. 273 in vol. 42, PMID: 29142875.]. PMID- 29488511 TI - Correction: Hoops et al., Dopamine Development in the Mouse Orbital Prefrontal Cortex is Protracted and Sensitive to Amphetamine in Adolescence (eNeuro January/February 2018, 5(1) e0372-17.2017 1-9 https://doi.org/10.1523/ENEURO.0372 17.2017. AB - [This corrects the article DOI: 10.1523/ENEURO.0372-17.2017.][This corrects the article DOI: 10.1523/ENEURO.0372-17.2017.]. PMID- 29488512 TI - Response: Commentary: Parent-Reported Behavioral and Psychiatric Problems Mediate the Relationship between Sleep Disordered Breathing and Cognitive Deficits in School-Aged Children. PMID- 29488513 TI - Two distinct penicillin binding proteins promote cell division in different Salmonella lifestyles. AB - The bacterial cell wall preserves cell integrity in response to external insults and the internal turgor pressure. The major component of the cell wall is the peptidoglycan (PG); a giant macromolecule formed by glycan chains cross-linked by short peptides. The PG is synthesized by a stepwise process that includes cytosolic and periplasmic reactions. The building subunits -muropeptides- are incorporated into the growing macromolecule by transglycolyslation (TG) and transpeptidation (TP) reactions, which constitute the last biosynthetic steps. TP reactions, involving cleavage of the terminal D Ala-D-Ala bond in the stem peptide, are carried out by enzymes known generically as penicillin-binding proteins (PBPs) due to their capacity to bind beta lactam antibiotics, which are D Ala-D-Ala structural analogues. On an average, bacterial genomes harbour a minimum of 10 PBP-encoding genes, most of them non-essential. This dispensability has led to the widely accepted concept of functional redundancy for many PBPs. An exemption is the PBP dedicated to build the septal PG required to separate daughter cells during cell division. To date, this division specific PBP was reported as unique in all known bacteria and, as a consequence, "essential". Our recent results obtained in the intracellular bacterial pathogen Salmonella enterica serovar Typhimurium challenges this view since this bacterium has two PBPs that can independently build the division septum. One of these two division PG enzymes is orthologue of the division-specific PBP3 of Escherichia coli. The second enzyme, named PBP3SAL, is absent in non-pathogenic bacteria and, at least in S. Typhimurium, displays PG biosynthetic activity restricted to acidic conditions. Our work also revealed that it is possible to generate a S. Typhimurium mutant defective in PBP3, which cannot divide at neutral pH. PMID- 29488514 TI - Reproducibility of single protein explosions induced by X-ray lasers. AB - Single particle imaging (SPI) using X-ray pulses has become increasingly attainable with the advent of high-intensity free electron lasers. Eliminating the need for crystallized samples enables structural studies of molecules previously inaccessible by conventional crystallography. While this emerging technique already demonstrates substantial promise, some obstacles need to be overcome before SPI can reach its full potential. One such problem is determining the spatial orientation of the sample at the time of X-ray interaction. Existing solutions rely on diffraction data and are computationally demanding and sensitive to noise. In this in silico study, we explore the possibility of aiding these methods by mapping the ion distribution as the sample undergoes a Coulomb explosion following the intense ionization. By detecting the ions ejected from the fragmented sample, the orientation of the original sample should be possible to determine. Knowledge of the orientation has been shown earlier to be of substantial advantage in the reconstruction of the original structure. 150 explosions of each of twelve separate systems - four polypeptides with different amounts of surface bound water - were simulated with molecular dynamics (MD) and the average angular distribution of carbon and sulfur ions was investigated independently. The results show that the explosion maps are reproducible in both cases, supporting the idea that orientation information is preserved. Additional water seems to restrict the carbon ion trajectories further through a shielding mechanism, making the maps more distinct. For sulfurs, water has no significant impact on the trajectories, likely due to their higher mass and greater ionization cross section, indicating that they could be of particular interest. Based on these findings, we conclude that explosion data can aid spatial orientation in SPI experiments and could substantially improve the capabilities of the novel technique. PMID- 29488515 TI - Color selective manipulation in Li2ZnGe3O8:Mn2+ by multiple-cation substitution on different crystal-sites. AB - Controlling the occupation sites of Mn2+ emitters by multiple-cation substitution, the Li2ZnGe3O8:Mn2+ phosphor could be optionally tuned in the green to NIR region. For the Mn2+ single doped Li2ZnGe3O8 phosphor, the tetrahedral coordinated Mn2+ (ZnO4 site) affords a green emission, and the octahedrally coordinated Mn2+ (ZnO6 site) shows an NIR (832 nm) emission. Interestingly, the Li2ZnGe3O8 host has three cation crystallographic sites, in which the octahedrally coordinated Mn2+ could exhibit a red emission by occupying GeO6 sites. The different luminescence centers for Mn2+ have been demonstrated using time-resolved emission spectra (TRES), excitation spectra and the decay curves. However, how to selectively regulate these fluorescence emissions corresponding to the different occupation sites is critical. In this paper, a common effect between the group's transition and energy transfer makes it possible to enhance the green emission (ZnO4 site) continuously and to restrain the NIR emission (ZnO6 site) through increasing the Zn/Li ratio in the Li2ZnGe3O8:Mn2+ phosphor. When Zn2+ is substituted by bigger ions from Ca to Sr and Ba, the local environments of Mn2+ around ZnO6 are influenced which leads to part of the Mn2+ emitters occupying the Ge4+ site, and it has the most enhanced effect on the Mn red-emission (GeO6 site). In general, we show that the spectral property of Mn2+ in different occupation sites could be efficiently regulated within the Li2ZnGe3O8 host, and provide a method for photoluminescence tuning. PMID- 29488516 TI - Compromise in uncertainty estimation by modelling and validation approaches for an HPLC-UV method for measurement of biochemical indicators of vitamins A and E. AB - It is common practice nowadays to associate the measurement uncertainty to the measurand, in order to judge the quality of a result related to the measurement process. However, the improvement of this parameter as well as the adaptation of its estimation modes always remain an analytical challenge, especially in chemical testing. In this paper, we outline a measurement uncertainty estimation mode based on the one-point linear calibration equation to fully establish a "bottom-up" approach for estimating the measurement uncertainty of a multi-point calibration-based HPLC-UV quantitative method. To demonstrate this estimation mode, we have followed as an example of interest the influences resulting from the simultaneous determination of two biochemical indicators, namely the human plasma vitamers retinol and alpha-tocopherol. Results from this estimation showed consistency when compared to those obtained from the validation-based alternative method, where the relative expanded uncertainties were found, at a 95% confidence level, to be less than 15% for the low concentration ranges of the two molecules. However, the modelling approach shows all the benefits of its use to identify and quantify all the uncertainty contributions arising from the different steps of the analytical process and seems to be quite achievable for comparative HPLC methods. PMID- 29488517 TI - Single gold nanoparticle plasmonic spectroscopy for study of chemical-dependent efflux function of single ABC transporters of single live Bacillus subtilis cells. AB - ATP-binding cassette (ABC) membrane transporters serve as self-defense transport apparatus in many living organisms and they can selectively extrude a wide variety of substrates, leading to multidrug resistance (MDR). The detailed molecular mechanisms remain elusive. Single nanoparticle plasmonic spectroscopy highly depends upon their sizes, shapes, chemical and surface properties. In our previous studies, we have used the size-dependent plasmonic spectra of single silver nanoparticles (Ag NPs) to study the real-time efflux kinetics of the ABC (BmrA) transporter and MexAB-OprM transporter in single live cells (Gram-positive and Gram-negative bacterium), respectively. In this study, we prepared and used purified, biocompatible and stable (non-aggregated) gold nanoparticles (Au NPs) (12.4 +/- 0.9 nm) to study the efflux kinetics of single BmrA membrane transporters of single live Bacillus subtillis cells, aiming to probe chemical dependent efflux functions of BmrA transporters and their potential chemical sensing capability. Similar to those observed using Ag NPs, accumulation of the intracellular Au NPs in single live cells (WT and DeltaBmrA) highly depends upon the cellular expression of BmrA and the NP concentration (0.7 and 1.4 nM). The lower accumulation of intracellular Au NPs in WT (normal expression of BmrA) than DeltaBmrA (deletion of bmrA) indicates that BmrA extrudes the Au NPs out of the WT cells. The accumulation of Au NPs in the cells increases with NP concentration, suggesting that the Au NPs most likely passively diffuse into the cells, similar to antibiotics. The result demonstrates that such small Au NPs can serve as imaging probes to study the efflux function of the BmrA membrane transporter in single live cells. Furthermore, the dependence of the accumulation rate of intracellular Au NPs in single live cells upon the expression of BmrA and the concentration of the NPs is about twice higher than that of the same sized Ag NPs. This interesting finding suggests the chemical-dependent efflux kinetics of BmrA and that BmrA could distinguish nearly identical sized Au NPs from Ag NPs and might possess chemical sensing machinery. PMID- 29488518 TI - A natural food ingredient based on ergosterol: optimization of the extraction from Agaricus blazei, evaluation of bioactive properties and incorporation in yogurts. AB - In recent years, mycosterols have emerged as potential functional ingredients for the development of sterol-enriched food products and dietary supplements. Agaricus blazei is a mushroom rich in bioactive compounds. For commercial purposes, their fruiting bodies must obey rigid morphological criteria. Those not conforming to these criteria are usually discarded, although this does not mean impairment of their content in bioactives. The aim of the present work was to propose the use of commercially discarded A. blazei fruiting bodies for obtaining an extract rich in ergosterol as a fortifier ingredient for yogurts. For extraction, the Soxhlet technology was used and the highest ergosterol yield (around 12%) was achieved in the 5th cycle, yielding 58.53 +/- 1.72 ug of ergosterol per 100 g of mushroom (dry weight). The ergosterol rich extract presented notable antioxidant and antimicrobial properties, besides showing no hepatotoxicity. When added to the yogurts it significantly enhanced their antioxidant properties. Furthermore, it did not significantly alter the nutritional or the individual fatty acid profiles of the final dairy products. Thus, A. blazei fruiting bodies that do not conform to the commercial requirements of the market and are normally discarded could be exploited for obtaining a natural high added-value food additive, following the circular bioeconomy concept. PMID- 29488519 TI - Facile one-pot green synthesis of Au-Ag alloy nanoparticles using sucrose and their composition-dependent photocatalytic activity for the reduction of 4 nitrophenol. AB - Au-Ag alloy nanoparticles (NPs) less than 10 nm in size were synthesized using sucrose as a reductant and surfactant. Au-Ag alloy NPs with a homogeneous composition were continuously obtained by changing the synthesis time from 2 to 40 min in one pot. Based on the UV-Vis, ICP, TEM, HR-TEM, EDX and SAED analyses, the synthesis mechanism of Au-Ag alloy NPs was deduced. Under hydrolysis conditions, sucrose showed a stronger reducibility compared with glucose, fructose and their mixture. And the as-prepared Au-Ag alloy NPs exhibited a superior photocatalytic activity and stability for the reduction of 4-nitrophenol due to the abundant hydroxyl groups of sucrose and the synergistic effect between Au and Ag elements. The rate constant of 4-nitrophenol reduction could be linearly controlled by the composition of Au-Ag alloy NPs or their synthesis time. It was indicated that the photocatalytic activity of Au-Ag alloy NPs could be predetermined as early as their synthesis process. The above methods of controlling the rate constant provide promising routes for other photocatalytic reactions using bimetallic NPs as photocatalysts. PMID- 29488520 TI - A computational study of supported Cu-based bimetallic nanoclusters for CO oxidation. AB - In this study, we used DFT calculations to investigate the bi-functional nature of Cu-based alloy nanoclusters (NCs) supported on CeO2(111) for CO oxidation. More specifically, we studied the reaction pathways on Cu3Pt7 and Cu3Rh7via the O2 associative (OCOO) and dissociative mechanisms. We find that CO oxidation on Cu3Pt7 proceeds via the O2 dissociation pathway, while Cu3Rh7 prefers the OCOO mechanism. Combined with our previous results on Cu3Au7, we find that bi functional CO oxidation on Cu-based alloys follows a Bronsted-Evans-Polanyi relationship, which provides a useful metric for the design of bi-functional alloyed catalysts. PMID- 29488521 TI - Nickel(ii) complexes of a 3N ligand as a model for diketone cleaving unusual nickel(ii)-dioxygenase enzymes. AB - Diketone substrate bound nickel(ii) complexes of 2,6-bis(1 methylbenzimidazolyl)pyridine have been synthesized and characterized as relevant active site models for unusual diketone cleaving Ni(ii)-dependent enzymes Ni-ARD and DKDO. The average Ni-Npy/benzim bond distances (2.050-2.107 A) of model complexes are almost identical to the Ni-NHis bond distances of NiII-ARD (2.02 2.19 A). The reaction of these adducts with dioxygen exhibited C-C cleavage with the rate of kO2, 5.24-73.71 * 10-3 M-1 s-1. The phenyl substituted adduct regioselectively elicits 52% of benzoic acid as the major product. PMID- 29488522 TI - Insights into the effect of donor ability on photophysical properties of dihydroindeno[2,1-c]fluorene-based imide derivatives. AB - The photophysical properties of dihydroindeno[2,1-c]fluorene-based imide (DHIFI) derivatives were investigated by steady-state and time-resolved spectroscopy as well as quantum chemical calculations. The hybridized local excited and charge transfer state (HLCT) was introduced to interpret the intercrossing of localized excited (LE) and charge transfer (CT) states. The large extent of CT in the HLCT state of a molecule with a strong electron donor (dimethylaniline) at the terminal site results in strong interaction between the dipole moments of the excited state and polar solvents. Time-resolved spectroscopy results show the formation of a stabilized ICT state in several picoseconds, which results in fluorescence quenching and less possibility of intersystem crossing to the triplet state. In contrast, a molecule with a weak electron donor (benzene) displays less fluorescence quenching. The slowing down of geometry relaxation in the weak-electron-donor molecule increases the possibility of ISC to the triplet state from the unrelaxed HLCT state. PMID- 29488523 TI - Production of monoclonal antibodies in microfluidic devices. AB - Herein, a microfluidic device with cistern design for cultivation of adherent eukaryotic cells for the production of recombinant proteins is presented. The geometric configuration of the microchannels in the device provided laminar flow with reduced velocity profiles in the cisterns, resulting in an adequate microenvironment for long-term adherent cell growth with passive pumping flow cycles of 24 hours. CHO-ahIFNalpha2b and HEK-ahIFNalpha2b adherent cell lines expressing a novel anti-hIFN-alpha2b recombinant monoclonal antibody (MAb) for the treatment of systemic lupus erythematosus were cultured on the surface of PDMS/glass microchannels coated with poly-d-lysine. A 24 day culture of CHO ahIFNalpha2b cells resulted in MAb concentrations up to 166.4 MUg mL-1 per day. The productivity of CHO-ahIFNalpha2b and HEK-ahIFNalpha2b cell lines was higher in the microdevice compared to that obtained using the adherent cell culture method (T-flask), with a 5.89- and 7.31-fold increase, respectively. Moreover, biological analysis of the MAbs produced in the microdevice showed no significant differences in the neutralizing antiproliferative activity of the hIFN-alpha2b or the cytokine cell signaling compared to the MAbs produced with cell adherent methods. These results suggest that this microfluidic device is suitable for long term culture of mammalian cells and can improve the productivity of cells expressing recombinant MAbs with potential for therapeutic use without affecting the quality attributes of the product. PMID- 29488524 TI - Nanoarchitectures in dye-sensitized solar cells: metal oxides, oxide perovskites and carbon-based materials. AB - Dye-sensitized solar cells (DSSCs) have aroused great interest and been regarded as a potential renewable energy resource among the third-generation solar cell technologies to fulfill the 21st century global energy demand. DSSCs have notable advantages such as low cost, easy fabrication process and being eco-friendly in nature. The progress of DSSCs over the last 20 years has been nearly constant due to some limitations, like poor long-term stability, narrow absorption spectrum, charge carrier transportation and collection losses and poor charge transfer mechanism for regeneration of dye molecules. The main challenge for the scientific community is to improve the performance of DSSCs by using different approaches, like finding new electrode materials with suitable nanoarchitectures, dyes in composition with promising semiconductors and metal quantum dot fluorescent dyes, and cost-effective hole transporting materials (HTMs). This review focuses on DSSC photo-physics, which includes charge separation, effective transportation, collection and recombination processes. Different nanostructured materials, including metal oxides, oxide perovskites and carbon-based composites, have been studied for photoanodes, and counter electrodes, which are crucial to achieve DSSC devices with higher efficiency and better stability. PMID- 29488525 TI - Dynamic monitoring of transmembrane potential changes: a study of ion channels using an electrical double layer-gated FET biosensor. AB - In this research, we have designed, fabricated and characterized an electrical double layer (EDL)-gated AlGaN/GaN high electron mobility transistor (HEMT) biosensor array to study the transmembrane potential changes of cells. The sensor array platform is designed to detect and count circulating tumor cells (CTCs) of colorectal cancer (CRC) and investigate cellular bioelectric signals. Using the EDL FET biosensor platform, cellular responses can be studied in physiological salt concentrations, thereby eliminating complex automation. Upon investigation, we discovered that our sensor response follows the transmembrane potential changes of captured cells. Our whole cell sensor platform can be used to monitor the dynamic changes in the membrane potential of cells. The effects of continuously changing electrolyte ion concentrations and ion channel blocking using cadmium are investigated. This methodology has the potential to be used as an electrophysiological probe for studying ion channel gating and the interaction of biomolecules in cells. The sensor can also be a point-of-care diagnostic tool for rapid screening of diseases. PMID- 29488526 TI - Reassignment of 'magic numbers' for Au clusters of decahedral and FCC structural motifs. AB - Calculations of low free energy structures of gold clusters with a few hundred to a few thousand atoms have been performed. For the study to be computationally feasible, a systematic scheme for generating low energy atomic structures with a given structural motif and a chosen size is used. Comparison of the relative stability of clusters with the decahedral and FCC motifs reveals periodic windows of stability for asymmetric, open-shell FCC clusters while the stability of the decahedral structural motif shows a smoother variation in stability with cluster size. As a result, the FCC structural motif is most stable for clusters with around 440, 610, 800, 1050... atoms, while the decahedral motif is more stable for atomic numbers of around 525, 705, 925, 1175... These new 'magic numbers' represent regions around which a number of asymmetric, open shell clusters of a given motif are most stable, in contrast to the discrete set of highly symmetric magic size structures that are commonly cited. As temperature is raised, the decahedral motif gains stability over the FCC motif. These results help explain reported experimental observations and can guide future laboratory preparations of shape selected clusters. PMID- 29488527 TI - Black phosphorus nanosheets for rapid microRNA detection. AB - Herein, for the first time, a sensitive sensing platform for rapid detection of microRNA was developed by employing black phosphorus nanosheets as the fluorescence quenching material. The biosensor displayed a good linear response to microRNA ranging from 10 nM to 1000 nM. Moreover, the biosensor could distinguish triple nucleotide polymorphism. PMID- 29488528 TI - Primary aminomethyl derivatives of kaempferol: hydrogen bond-assisted synthesis, anticancer activity and spectral properties. AB - A series of primary aminomethyl derivatives of kaempferol were synthesized by a combination strategy involving two steps of the Mannich reaction and SN2 nucleophilic substitution. The structures of the products show that the preferential aminomethylations are in the position C-6 or C-8 of the A-ring of kaempferol, especially the latter. Interestingly, the experimental data indicate that the intermolecular hydrogen bonding plays a key role in the formation of primary aminomethyl products of kaempferol. The formation of appropriate hydrogen bonds between strong nucleophilic amino acids and phenol is essential for the smooth reaction of the SN2 nucleophilic substitution. The SN2 mechanism hypothesis involving a hydrogen bond-assisted process was also supported by the density functional theory (DFT) analysis. An antiproliferative test of synthetic compounds shows the moderate to potent cytotoxic activity against three human cancer cell lines (HeLa, HCC1954, and SK-OV-3) by the CCK-8 assay. Compound 4e shows selective antiproliferative activity against HeLa cells with a low IC50 value (4.27 MUm) and is worthy of further development. Another interesting result is that the maximum emission bands for most metal complexes are located at about 480 nm, but the ones for Tm and Yb complexes appear at about 533 nm. PMID- 29488529 TI - Catalyst-free synthesis of thiazolidines via sequential hydrolysis/rearrangement reactions of 5-arylidenethiazolidin-4-ones at room temperature. AB - A catalyst-free sequential reaction involving hydrolysis and intramolecular aza Michael addition was developed for synthesizing functionalized thiazolidines from 5-arylidenethiazolidin-4-ones at room temperature. A series of thiazolidine-5 carboxylic acids were prepared in good to excellent yields (up to 97% yield) and excellent diastereoselectivities (up to >20 : 1 dr). This methodology was applicable to the construction of derivatives of thiacloprid and flutianil with good yields. PMID- 29488530 TI - Expanding the roles for 2-oxoglutarate-dependent oxygenases in plant metabolism. AB - Covering: up to 2018 2-Oxoglutarate-dependent oxygenases (2ODOs) comprise a large enzyme superfamily in plant genomes, second in size only to the cytochromes P450 monooxygenase (CYP) superfamily. 2ODOs participate in both primary and specialized plant pathways, and their occurrence across all life kingdoms points to an ancient origin. Phylogenetic evidence supports substantial expansion and diversification of 2ODOs following the split from the common ancestor of land plants. More conserved roles for these enzymes include oxidation within hormone metabolism, such as the recently described capacity of Dioxygenase for Auxin Oxidation (DAO) for governing auxin homeostasis. Conserved structural features among 2ODOs has provided a basis for continued investigation into their mechanisms, and recent structural work is expected to illuminate intriguing reactions such as that of 1-aminocyclopropane-1-carboxylic acid oxidase (ACCO). Phylogenetic radiation among this superfamily combined with neo- and subfunctionalization has enabled recruitment to highly specialized pathways, including those yielding medicines, flavours, dyes, poisons, and compounds important for plant-environment interactions. Catalytic versatility of 2ODOs in plants and across broader taxa continues to inspire biochemists tasked with the discovery of new enzymes. This highlight article summarizes recent reports up to 2018 of 2ODOs within plant metabolism. Furthermore, the respective contributions of 2ODOs and other oxidases to natural product biosynthesis are discussed as a framework for continued discovery. PMID- 29488531 TI - Concerted motions and large-scale structural fluctuations of Trichoderma reesei Cel7A cellobiohydrolase. AB - Cellobiohydrolases (CBHs) are key enzymes for the saccharification of cellulose and play major roles in industrial settings for biofuel production. The catalytic core domain of these enzymes exhibits a long and narrow binding tunnel capable of binding glucan chains from crystalline cellulose and processively hydrolyze them. The binding cleft is topped by a set of loops, which are believed to play key roles in substrate binding and cleavage processivity. Here, we present an analysis of the loop motions of the Trichoderma reesei Cel7A catalytic core domain (TrCel7A) using conventional and accelerated molecular dynamics simulations. We observe that the loops exhibit highly coupled fluctuations and cannot move independently of each other. In the absence of a substrate, the characteristic large amplitude dynamics of TrCel7A consists of breathing motions, where the loops undergo open-and-close fluctuations. Upon substrate binding, the open-close fluctuations of the loops are quenched and one of the loops moves parallel to the binding site, possibly to allow processive motion along the glucan chain. Using microsecond accelerated molecular dynamics, we observe large scale fluctuations of the loops (up to 37 A) and the entire exposure of the TrCel7A binding site in the absence of the substrate, resembling an endoglucanase. These results suggest that the initial CBH-substrate contact and substrate recognition by the enzyme are similar to that of endoglucanases and, once bound to the substrate, the loops remain closed for proper enzymatic activity. PMID- 29488532 TI - Hydrogen-motivated electrolysis of sodium carbonate with extremely low cell voltage. AB - Hydrogen-motivated electrolysis of Na2CO3 for energy-saving production of NaOH and CO2/NaHCO3 is realized by the hydrogen oxidation reaction to insert proton into anolyte and the hydrogen evolution reaction to extract proton out of catholyte. Electrolytic voltage at 100 mA cm-2 is as low as 0.88 V; this voltage is only 35% of the voltage used in the traditional electrolysis. PMID- 29488533 TI - Flow dynamics control endothelial permeability in a microfluidic vessel bifurcation model. AB - Endothelial barrier function is known to be regulated by a number of molecular mechanisms; however, the role of biomechanical signals associated with blood flow is comparatively less explored. Biomimetic microfluidic models comprised of vessel analogues that are lined with endothelial cells (ECs) have been developed to help answer several fundamental questions in endothelial mechanobiology. However, previously described microfluidic models have been primarily restricted to single straight or two parallel vessel analogues, which do not model the bifurcating vessel networks typically present in physiology. Therefore, the effects of hemodynamic stresses that arise due to bifurcating vessel geometries on ECs are not well understood. Here, we introduce and characterize a microfluidic model that mimics both the flow conditions and the endothelial/extracellular matrix (ECM) architecture of bifurcating blood vessels to systematically monitor changes in endothelial permeability mediated by the local flow dynamics at specific locations along the bifurcating vessel structure. We show that bifurcated fluid flow (BFF) that arises only at the base of a vessel bifurcation and is characterized by stagnation pressure of ~38 dyn cm-2 and approximately zero shear stress induces significant decrease in EC permeability compared to the static control condition in a nitric oxide (NO)-dependent manner. Similarly, intravascular laminar shear stress (LSS) (3 dyn cm-2) oriented tangential to ECs located downstream of the vessel bifurcation also causes a significant decrease in permeability compared to the static control condition via the NO pathway. In contrast, co-application of transvascular flow (TVF) (~1 MUm s 1) with BFF and LSS rescues vessel permeability to the level of the static control condition, which suggests that TVF has a competing role against the stabilization effects of BFF and LSS. These findings introduce BFF at the base of vessel bifurcations as an important regulator of vessel permeability and suggest a mechanism by which local flow dynamics control vascular function in vivo. PMID- 29488534 TI - Clean chlorination of silica surfaces by a single-site substitution approach. AB - A chlorination method for the selective substitution of well-defined isolated silanol groups of the silica surface has been developed using the catalytic Appel reaction. Spectroscopic analysis, complemented by elemental microanalysis studies, reveals that a quantitative chlorination could be achieved with highly dehydroxylated silica materials that exclusively possess non-hydrogen bonded silanol groups. The employed method did not leave any carbon or phosphorus residue on the silica surface and can be regarded as a promising tool for the future functionalization of metal oxide surfaces. PMID- 29488536 TI - Cationic two-dimensional inorganic networks of antimony oxide hydroxide for Lewis acid catalysis. AB - We have successfully synthesized a rare example of inorganic layered materials possessing a positive charge, which is well outside the isostructural set of layered double hydroxides. This layered architecture consists of two-dimensional corrugated [Sb2O2(OH)]+ layers with linear alpha,omega-alkanedisulfonate anions residing in the interlamellar space. This cationic material displays a chemical robustness under highly acidic aqueous conditions (pH = 1). Combining the robust nature and the high density of SbIII sites on the exposed crystal facets, our cationic layered material is an efficient, recyclable catalyst for cyanosilylation of benzaldehyde derivatives with trimethylsilyl cyanide. In addition, the Lewis acidity of the SbIII sites also catalyzes the ketalization of carbonyl groups under "green" solvent-free conditions. PMID- 29488537 TI - Metal complexes of a novel heterocyclic benzimidazole ligand formed by rearrangement-cyclization of the corresponding Schiff base. Electrosynthesis, structural characterization and antimicrobial activity. AB - The electrochemical oxidation of anodic metals (M = cobalt, nickel, copper, zinc and cadmium) in a solution of the ligand 1H-anthra[1,2-d]imidazol-6,11-dione-2-[2 hydroxyphenyl] [H2L] afforded homoleptic [ML] compounds. The addition to the electrochemical cell of coligands (L') such as 2,2'-bipyridine (bpy) or 1,10 phenanthroline (phen) allowed the synthesis, in one step, of heteroleptic [MLL'] compounds. The crystal structures of H2L (1), [CoL(MeOH)]2 (2), [CoL(phen)]2 (3), [NiL(bpy)]2 (4), [CuL(bpy)] (5), [CuL(phen)] (6) and [CdL(bpy)]2 (7) have been determined by X-ray diffraction techniques. The crystal structures of 2, 3, 4 and 7 consist of dimeric species in which both metallic atoms are connected through two phenolate bridges in a penta-coordinated (2) or hexa-coordinated (3, 4 and 7) environment. Copper compounds 5 and 6 are monomeric species with the metal in a pentacoordinated [N4O] environment. In all the compounds, the main interactions responsible for the crystal packing are classic (N-HO, O-HN and O-HO) and non classic (C-HO and C-HN) hydrogen bond interactions, and pi interactions (pi-pi stacking and C-Hpi). All compounds were also characterized by microanalysis, IR spectroscopy, FAB mass spectrometry and 1H NMR spectroscopy. Magnetic susceptibility data were measured for 2-4 over the temperature range 2-300 K, and their analysis has revealed the occurrence of intramolecular antiferromagnetic coupling for 2 (J = -2 cm-1) and ferromagnetic coupling for 3 (J = 7.8 cm-1) and 4 (J = 2.8 cm-1) [J being the isotropic magnetic coupling parameter]. The nature of the magnetic coupling in 2-4 is correlated with the magnitude of the M Ophenolate-M angle between the phenolate bridge and the metallic centers [M(ii) = Co, Ni]. The in vitro antimicrobial properties of the novel ligand and its metal complexes were detected against Gram positive and Gram negative bacteria and fungi. [NiL(bpy)]2 and all tested Cd(ii) complexes were the most active compounds, showing the highest inhibitory effect against bacilli (MIC 1.5-3 MUg mL-1) and Sarcina, Streptococci and Haemophilus influenzae bacterial strains (MIC 12-50 MUg mL-1), while almost no antifungal properties were observed. PMID- 29488541 TI - In situ photo-patterning of pressure-resistant hydrogel membranes with controlled permeabilities in PEGDA microfluidic channels. AB - We report the fabrication of highly permeable membranes in poly(ethylene glycol) diacrylate (PEGDA) channels, for investigating ultra- or micro-filtration, at the microfluidic scale. More precisely, we used a maskless UV projection setup to photo-pattern PEG-based hydrogel membranes on a large scale (mm-cm), and with a spatial resolution of a few microns. We show that these membranes can withstand trans-membrane pressure drops of up to 7 bar without any leakage, thanks to the strong anchoring of the hydrogel to the channel walls. We also report in situ measurements of the Darcy permeability of these membranes, as a function of the deposited energy during photo-polymerization, and their formulation composition. We show that the use of PEG chains as porogens, as proposed in [Lee et al., Biomacromolecules, 2010, 11, 3316], significantly increases the porosity of the hydrogels, up to Darcy permeabilities of about 1.5 * 10-16 m2, while maintaining the strong mechanical stability of the membranes. We finally illustrate the opportunities offered by this technique, by investigating frontal filtration of colloidal dispersions in a straight microfluidic channel. PMID- 29488542 TI - Water molecule induced reversible single-crystal-to-single-crystal transformation between two trinuclear Fe(ii) complexes with different spin crossover behaviour. AB - A 4-amino-1,2,4-triazole (NH2-trz) based linear trinuclear Fe(ii) complex of [Fe3(NH2-trz)6(SCN)4(H2O)2](SCN)2.H2O (1) has been hydrothermally synthesized by the reaction of a NH2-trz ligand with FeSO4. A single crystal of complex 1 is able to extrude one lattice water and one coordinated water, leading to another single crystal of complex 1a with a formula [Fe3(NH2-trz)6(SCN)5(H2O)](SCN) by heating. Complex 1a can be reversed to 1 upon the reabsorption of water. Single crystal X-ray diffraction analysis reveals that these two complexes consist of a linear trinuclear core where a central Fe1 ion is coordinated to six nitrogen atoms from six bridged NH2-trz ligands and one of the terminal Fe2 ions is coordinated to five nitrogen atoms and one oxygen atom. The terminal Fe3 ion in 1 coordinates to five nitrogen atoms and one oxygen atom; however, the terminal Fe3 ion in 1a coordinates to six nitrogen atoms. Magnetic susceptibility measurements demonstrate that they exhibited gradual spin crossover (SCO) for the central Fe(ii) ion; however, different spin transition temperatures were displayed for complexes 1 and 1a (T1/2 = 202 K for 1 and 160 K for 1a). These different spin transition temperatures arise from the different intermolecular hydrogen bonding interactions in the two complexes. PMID- 29488543 TI - Association of traditional cardiovascular risk factors with carotid atherosclerosis among adults at a teaching hospital in south-western Nigeria. AB - BACKGROUND: Traditional cardiovascular risk factors (CVRFs), which include age, gender, hypertension, diabetes mellitus, dyslipidaemia, smoking, alcohol consumption, chronic kidney disease and obesity, have been shown to be associated with atherosclerosis. We aimed to evaluate the impact of traditional CVRFs on carotid atherosclerosis (CA) in a sample of Nigerian adults. METHODS: We examined 162 subjects with traditional CVRFs in a cross-sectional study. Demographic and clinical data, including history of hypertension, diabetes mellitus, smoking, alcohol intake and chronic kidney disease, as well as systolic and diastolic blood pressure, weight and height were collected. Serum creatinine, fasting blood glucose and lipid profiles were also determined. Carotid intima-media thickness (CIMT) and presence of carotid plaque (CP) were evaluated by high-frequency B mode ultrasound. Chi-squared and regression analyses were carried out to determine associations between variables of CIMT and CVRF. RESULTS: Increased CIMT was associated with all CVRFs (p < 0.05) except gender (p > 0.05), while CP was associated with older age, obesity, hypertension and dyslipidaemia (p < 0.05). We found prevalence of increased CIMT was 53.7%, while that of CP was 16.1%. The prevalence of CA (increased CIMT and CP) also increased with increasing number of CVRFs in the subjects. Age >= 50 years, hypertension, dyslipidaemia, obesity and alcohol intake explained 78.7% of variance in CIMT, while age >= 50 years and hypertension explained 38.0% of variance in CP. CONCLUSIONS: CA was associated with presence and increasing number of traditional CVRFs. A significant percentage of variance in CA was, however, unexplained by traditional CVRFs. PMID- 29488544 TI - ? PMID- 29488545 TI - [Bloodstream infection in patients receiving hematopoietic stem cell transplant. Seven years of experience with adults and children]. AB - BACKGROUND: Bloodstream infection is a common complication, which can be life threatening for hematopoietic stem cells transplant recipients. OBJECTIVE: To analyze the characteristics of bloodstream infections in hematopoietic stem cell transplant recipients. MATERIALS AND METHODS: Observational, retrospective study. We reviewed the records of 451 patients (autologous and allogeneic transplants) from January 2009 to October 2015. RESULTS: 99 positive blood cultures in 73 patients with bloodstream infection (16%) were found. Mortality attributable to infectious causes was 17%. From the 99 bloodstream infection, 63% were caused by gram-negative bacilli (Escherichia coli 45%, Klebsiella spp 23%, Pseudomonas spp 11% Acinetobacter spp % and other bacilli 15%), 33% by gram-positive cocci, 3% by fungi and 1% by gram-positive bacilli. The gram-negative bacilli were ciprofloxacin resistant (81%), piperacillin/tazobactam resistant (48%), extended spectrum beta-lactamase (ESBL) producing Enterobacteriaceae (40%), cefepime resistant (39%) and there was no resistance noted to amikacin. DISCUSSION: There is a higher frequency of gram-negative bacilli infection, with a high percentage of multiresistant microorganisms and high resistance to empirical antibiotic treatment. PMID- 29488546 TI - [Prevalence of Bartonella henselae in blood donors and risk of blood transmission in Chile]. AB - BACKGROUND: Bartonella henselae is the causal agent of cat scratch disease in immunocompetent persons and bacterial angiomatosis in immunocompromised patients. In Chile, the prevalence of antibodies against B. henselae in healthy children and adolescents is 13.3%, in persons with occupational risk 60.5%, and in cats 85.6%. There are no published data regarding the seroprevalence in blood donors in our country, so determining if B. henselae is present in the blood of donors at the time of donation is very important, since this microorganism can survive up to 35 days in the red blood cells stored in a blood bank at 4 degrees C. OBJECTIVE: To determine the prevalence of B. henselae in blood donors. METHODOLOGY: 140 donor blood samples were analyzed to detect the presence of B. henselae, using the polymerase chain reaction technique. RESULTS: 13.6% of the blood donors with positive polymerase chain reaction for B. henselae were obtained. The sequence of the amplified fragments showed an identity of over 98% with respect to B. henselae reference sequences. CONCLUSION: The risk of blood transmission is due to a country with high B. henselae infection. PMID- 29488547 TI - [Evaluation of antimicrobial consumption in a Neonatology Unit: a team work to promote the rational use of antibiotics]. AB - BACKGROUND: Antibiotics (ATB) are drugs widely used in hospitalized newborns. The indiscriminate use of ATBs promote the rise of resistant bacteria to the most commonly indicated antimicrobials. In addition, ATB prescription presents associations to morbidity, such as bronchopulmonary dysplasia, necrotizing enterocolitis, late sepsis and even death. All of the above leads to an increase in health care costs. AIM: To record and to evaluate trends of antibiotic use over time in hospitalized NB in the Neonatology Unit at Dr. Sotero del Rio Hospital, in order to objectify the changes in the usual practice of the ATM indication. A secondary objective was to assess its impact on antimicrobial resistance. METHODS: Cohort, observational, prospective unicenter study which included all hospitalized patients between January 2011 and December 2014. Birth weight, hospitalization days, ATB indication and days of ATB use were recorded for each patient. The use of ATB was quantified by means of different rates; days of indication of one or more ATBs for global consumption (RUA), total sum of days of use (TSUA) and for the most frequently used ATBs. Each calculated rate for 100 days hospitalized. In addition, the antimicrobial susceptibility of the most frequently isolated bacteria in our service: coagulase-negative Staphylococcus (SCN) and Gram-negative bacilli (BGN) were recorded continuously. RESULTS: The 34.7% of the hospitalized patients received some type of antimicrobial agent. ATBs were 32.3% of medicines used. The most widely used was ampicillin (with 20.2% of the total) and cefadroxyl (with 11.6%). The RUA did not change during the study time, but STUA decreased by 10.7% between 2011 and 2014 with p < 0.05. When subgroup analyzes were divided by weight ranges, in the < 750 g group, the use of vancomycin decreased in use by 9.9% and an increase of 18.8% for metronidazole was observed. On the other hand, there was an increase in the use of the piperacillin-tazobactam regimen in the range > 1,500 g. When evaluating antimicrobial susceptibility, there was a decrease in susceptibility for oxacillin in SCN between 2011 and 2014 from 27% to 10.3% respectively. In addition, for Gram negative there was a decrease from 76.9% to 40.5% in susceptibility to third generation cephalosporins, mainly due to Klebsiella pneumoniae, which became the predominantly isolated BGN with an increase of 6.7% to 50% between 2011 and 2014, respectively. For K. pneumoniae the loss of susceptibility to third generation cephalosporins decreased from 77% to 22%. Finally, amikacin showed an activity over 85% in all BGNs between 2011 and 2014. CONCLUSIONS: It is advisable to plan and to maintain a continuous record of ATB consumption, as well as therapy and prophylaxis, being categorized by ATB type and range of newborn weight. It is of considerable importance to analyze and to evaluate the susceptibility of microorganisms. It is essential that an interdisciplinary team prepare this recording, and to continuously provide feedback to professionals who maintain the functioning of neonatal care units. PMID- 29488548 TI - [Zika: Probability of establishment of its vector, Aedes aegypti, in Chile]. AB - The Zika virus has raised world alarm in recent years, representing a major public health problem. In this study we evaluated the potential risk of exposure to Zika virus in Chile, associated with the probability of establishment of the vector Aedes aegypti in the country. Niche modelling techniques were used to project the bioclimatic requirements of the vector (global niches), identifying zones of high suitability for the species within the country. Then, the potential distribution of the vector in Chile was overlapped with the human population density, estimating the risk associated to the potential co-occurrence of both in a spatially explicit manner. We identified bioclimatic suitability for A. aegypti in continental Chile, from the northern tropical area to temperate regions, mainly in coastal zones. The exposed population could reach 1.8 million people, with 1.3 million in a medium level of potential risk and 21,000 in a high level. These results support that there is a significant probability of success for the Zika virus main vector to colonize continental Chile in case of an introduction. Therefore, prevention, monitoring, and control play an important role in avoiding the arrival of this vector to our country. PMID- 29488549 TI - [Epidemiology of oral HPV infection in young healthy individuals]. AB - BACKGROUND: HPV infection is the most common sexually transmitted viral infection, and is associated with several neoplasms. AIM: To describe the epidemiology, natural history and risk factors associated with oral HPV infection in asymptomatic young adults. METHODS: A prospective and longitudinal study was conducted, including subjects without oral pathology, who were sampled from the oral mucosa. All subjects with positive results were re-sampled 6 months later. The presence of HPV was identified by PCR. Demographic and sexual behavior data were obtained with a survey that was responded without the intervention of the researcher. RESULTS: 102 samples were collected from subject of 18-26 years old, 60 (58.8%) were male. The prevalence of the virus was 6.9%; all positive subjects had active sexual life. Same-gender relationships were the only variable associated with the presence of the virus (p < 0.05). At six months all subjects had eliminated the virus. CONCLUSION: Oral HPV infection is transient and is associated to same-gender relationships, mainly women who have sex with women. PMID- 29488550 TI - [Enterobacteriaceae susceptibility to piperacillin/tazobactam in a Chilean pediatric hospital]. AB - INTRODUCTION: Enterobacteriaceae are a group of gram-negative rods that can cause serious infections in humans. A susceptibility in Klebsiella pneumoniae of 79.4% to piperacillin/tazobactam (PIP/TAZO) is reported in pediatric hospitals in Chile. There is no published data published to date regarding PIP/TAZO susceptibility to other Enterobacteriaceae species in this population. AIM: To measure the in vitro PIP/TAZO susceptibility in Enterobacteriaceae isolates from patients in a pediatric hospital in Chile. METHODS: Descriptive and prospective study of Enterobacteriaceae positive cultures from patients assisting to the "Hospital de ninos Roberto del Rio" (HRRIO) between January 2013 and August 2014. PIP/TAZO susceptibility was established by gradient diffusion method (E-test(r)) according to the 2014 CLSI standards. RESULTS: 163 cases were included. The average age was 4 years and 15 days. 70.6% were female. 79.7% of samples were urine cultures. PIP/TAZO susceptibility in Enterobacteriaceae was 95.1% (n = 155). The intermediate susceptibility was 1.8% (n = 3). DISCUSSION: The isolates studied present high susceptibility to PIP/TAZO. This finding could be explained by the fact that this population has not been exposed to this antimicrobial therapy and also the low rates for ESBL in pediatric infections. PMID- 29488551 TI - [Incidence of multi-resistant bacteria in Intensive Care Units of Chilean hospitals]. AB - INTRODUCTION: Incidence of multi-resistant bacteria is an indicator that permits better estimation of the magnitude of bacterial resistance in hospitals. AIM: To evaluate the incidence of relevant multi-drug resistant bacteria in intensive care units (ICUs) of Chile. METHODS: Participating hospitals submitted information about the number of isolates from infected or colonized patients with 7 epidemiologically relevant multi-resistant bacteria in adult and pediatric ICUs between January 1, 2014 and October 31, 2015 and the number of bed days occupied in these units in the same period was requested. With these data incidence was calculated per 1,000 patient days for each unit. RESULTS: Information from 20 adults and 9 pediatric ICUs was reviewed. In adult ICUs the bacteria with the highest incidence were K. pneumoniae ESBL [4.72 * 1,000 patient day (1.21-13.89)] and oxacillin -resistant S. aureus [3.85 (0.71-12.66)]. In the pediatric units the incidence was lower, highlighting K. pneumoniae ESBL [2.71 (0-7.11)] and carbapenem -resistant P. aeruginosa [1.61 (0.31-9.25)]. CONCLUSION: Important differences between hospitals in the incidence of these bacteria were observed. Incidence of multi-resistant bacteria in adult ICU was significantly higher than in pediatric ICU for most of the studied bacterias. PMID- 29488552 TI - [Safety of fluoroquinolones: risks usually forgotten for the clinician]. AB - Quinolones are a group of widely used antimicrobials. Although they are considered safe for patients, knowledge of the safety profile is necessary so that professionals become aware of what is necessary to monitor. At the musculoskeletal level, quinolones have the potential to damage cartilage, causing even tendon rupture in infrequent cases. Hypoglycemia / hyperglycemia has been observed at the endocrine level, thus, careful monitoring of glycemia in patients with quinolone is recommended in diabetic patients. At the cardiovascular level, arrhythmias induced by these antimicrobials are rare but severe. At the level of the nervous system, the appearance of alterations of the central nervous system and the peripheral neuropathy are emphasized. When assessing the safety of quinolones, it is important to consider potential interactions with other substances (medical products). In children it is preferred not to use fluoroquinolones because of the potential risk of cartilage damage and growth, effects that do not seem to be so dramatic in the face of new evidence. Despite optimism, the safety of the treatment of these antimicrobials should be evaluated in every pediatric patient. PMID- 29488553 TI - [Statement from the Immunization Committee of the Chilean Infectious Diseases Society in reference to vaccine refusal and mandatory policy on vaccination]. AB - Although vaccines have had a tremendous impact in public health they are questioned by certain groups that consider them unnecessary or unsafe and argue in favor of the right to decide to be vaccinated or not. However vaccines must have special considerations because unlike other medical decisions, not vaccinating has consequences not only for the individual but also for other members of the community. Immunizing a high proportion of the population limits the circulation of an infectious agent attaining what is called herd immunity that protects the susceptible members of the group. For this reason many countries consider vaccination mandatory as a responsibility of every citizen. This committee agrees with this view but thinks other strategies should be implemented as well, such as special educational efforts for the public and parents addressing benefits and real risks of vaccinating. Also health care professionals should be trained in vaccines. The notification system for adverse events currently available should be improved and be more accessible. Persons truly affected by adverse events due to vaccination should receive on time responses and be offered psychological and financial support. Finally all stakeholders should make coordinated efforts to work together to deliver messages that answer concerns on vaccines and bring confidence back to the public. PMID- 29488554 TI - ? PMID- 29488555 TI - [From scrophula to mycobacterial lymphadenitis]. AB - In the 19th century it was widely believed that both tuberculosis and cervical lymph node swelling, known as scrophula, affected individuals predisposed to an inherited "diathetic constitution". In 1882 Robert Koch proved that human tuberculosis and scrophulous lesions were caused by the bacillus Mycobacterium tuberculosis. In the early twentieth century it was stated that Mycobacterium bovis, the bacillus of cattle tuberculosis, could also cause cervical lymphoadenitis in humans, especially in children, by the intake of milk from sick cows. The incidence of this condition decreased after the infection was controlled in cattle and pasteurization of the milk was introduced. A type of granulomatous necrotizing and suppurative cervico-facial lymphadenitis associated to non-tuberculous mycobacteria was described in 1956. It mainly affects children younger than 5 years old, particularly those born in countries with non-endemic tuberculosis. Tuberculous cervical lymphadenitis is prevalent in young adults from tuberculosis-endemic countries and in HIV-infected subjects. Infectious etiology displaced the importance of a personal disposition in the development of scrophula. Nevertheless, mutations that confer susceptibility to mycobacterial infection are currently investigated. PMID- 29488556 TI - [Disseminated actinomycosis with central nervous system involvement]. AB - Actinomycosis is very rare, as well as the central nervous system (CNS) condition associated with it, presenting a mortality up to 28%. Its manifestations could be similar to infectious conditions from other etiologies, thus, having a better understanding of the entity increases clinical suspicion and also it can provide a timely treatment. The clinical case of an adult with edema in an upper extremity is presented as a manifestation of thrombophlebitis and an abscessed axillary lesion, in which actinomycetes infection was confirmed. He presented a haematogenous spread with CNS involvement, with fatal ending. PMID- 29488557 TI - [Erythrodermic psoriasis in young man: suspect HIV infection]. AB - HIV infection can be manifested with different skin symptoms, which are sometimes considered infection markers. Erythrodermic psoriasis is a possible manifestation, which is a widespread form of psoriasis. We report a clinical case of a young man suspected of HIV infection due to a psoriatic erythroderma confirmed by biopsies, associated with Kaposi sarcoma. Afterwards, HIV infection was confirmed by serological tests. Antiretroviral therapy was started, with positive response at one month of treatment. Erythrodermic psoriasis can be considered a skin marker of HIV infection when occurs in previously healthy patients or in recalcitrant psoriasis. PMID- 29488558 TI - [Orf virus in human, confirmation in case report from Chile]. AB - Infection with the orf virus, also known as contagious ecthyma, is recognized as an occupational zoonosis worldwide. It is diagnosed by cutaneous lesions that progress rapidly from macules to papules, vesicles and pustules. The clinical case of a student of veterinary medicine who had had contact with goats, clinically healthy and without apparent lesions, which occured 19 days ago, is reported. She presented two vesicular lesions that coalesced to form a larger lesion surrounded by an erythematous halo. The lesions were compatible with the classical presentation of those produced by the orf virus in humans. The presence of the orf virus was confirmed by a nested PCR from biopsy tissue. It is one of the first cases confirmed by molecular techniques in humans in Chile. PMID- 29488559 TI - [Cervical lymphadenitis caused by no typhoid Salmonella in a diabetic patient]. AB - No Typhoid Salmonella infection is one of the most common and widely spread foodborne diseases worldwide. Although most cases are limited to the gastrointestinal tract, extraintestinal involvement is not uncommon. However, adenitis as an isolated manifestation, is an unusual form of the disease. We report a case of Salmonella no Typhoid cervical lymphadenitis in a 67-year-old female with a recent diagnosis of diabetes mellitus, who was treated with surgery and ciprofloxacin. PMID- 29488560 TI - [Skin lesions of a disseminated histoplasmosis in Peru]. AB - The dermatological manifestations of disseminated histoplasmosis present in about 17% of the cases, is a challenge for its diagnosis. We report the case of a patient from the northern coast of Peru, who presented diffuse dermal lesions, erythema-violaceous nodules, and ulcers histopathologically compatible with the infection of the genus Histoplasma var. capsulatum. PMID- 29488561 TI - [Implementation in the midst of complexity: using ethnography to study health care-associated infection prevention and control Am J Infect Control 2017; 45: 1058-63. Knobloch M J, Thomas K V, Patterson E, Zimbric M L, Musuuza J, Safdar N]. PMID- 29488562 TI - [Chilean and Peruvian epidemiology of HIV infection]. PMID- 29488563 TI - [Direct antivirals for the treatment of chronic hepatitis C virus infection. Experience in 106 patients]. PMID- 29488564 TI - [Effectiveness and safety of oral anticoagulation treatment with acenocoumarol in non-valvular atrial fibrillation]. PMID- 29488565 TI - [Electrophysiological severity of carpal tunnel syndrome according to age in adult patients]. PMID- 29488566 TI - [Correlates of physical inactivity: Findings from the Chilean National Health Survey 2009-2010]. PMID- 29488567 TI - [Tako-tsubo syndrome. Analysis of 37 cases]. PMID- 29488568 TI - [Impact of different overhead cost allocation methods of public hospitals on the cost-effectiveness ranking of 47 health programs]. PMID- 29488569 TI - [Interdisciplinary experience for the design of health care products]. PMID- 29488570 TI - [Psychosocial risks and professional integration of foreign physicians: a study on conflict management in Chile]. PMID- 29488571 TI - [Out of hospital cardiac arrest events at an urban Hospital in Chile]. PMID- 29488572 TI - [Decision making and consents given by demented patients. Are they valid?] AB - In Chile, more than 180 thousand people (1% of the population) have some form of dementia. The figure should increase to approximately 600,000 (3% of Chileans) by 2050. This disease poses major challenges to the society. One of them is the effective recognition of the autonomy and responsibility of the person living with this condition. This article aims to review the clinical assessment of competence, its agreement with the Chilean legal system and the challenges that the assessment of competence poses in clinical decision-making and the capacity of an individual make decisions, according to the new international obligations subscribed by Chile. It is concluded that inclusion is a pending challenge, reflected among other things, by the non-compliance with binding rules such as Article 12 of the Convention on the Rights of Persons with Disabilities, which affirms that persons with disabilities have the right to be recognized as a person everywhere, before the law. PMID- 29488573 TI - [Prognostic factors of ulcerative colitis at the moment of diagnosis]. AB - The clinical presentation of ulcerative colitis at the moment of diagnosis is variable, and its clinical course is difficult to predict. It can range from a quiescent to a refractory chronic course that may require hospitalization and surgical procedures. It can also have complications such as colorectal cancer. In this review we discuss the role of demographic, clinical, endoscopic, histological and associated factors, which can help to predict the clinical course of the disease at the moment of diagnosis, and to individualize therapy according to this clinical risk. Accurate identification of patients with a newly diagnosed ulcerative colitis who are at high risk of an unfavorable outcome is still a challenge. However, an effective evaluation allows an early diagnosis, a timely and effective treatment. PMID- 29488574 TI - [Concern for residents' wellbeing, an issue discussed at the latin american conference on resident education (LACRE) 2017]. AB - At the end of May 2017, the third version of the Latin American Conference on Resident Education, LACRE, was held in Chile; it convened 433 people from 14 regional countries. Chronic stress and emotional exhaustion of residents was one of the topics discussed. Reports from different countries documented that about half of residents suffer from burnout. This is, they are emotionally drained, indifferent towards their patients and with a sense of low personal fulfillment at work. This article describes the contributions presented in LACRE about interventions or institutional programs designed to reduce burnout and promote self-care of residents. The relevance of these initiatives is discussed in the current global context, considering the available evidence on the effectiveness of interventions to promote well-being among residents. International experts are making renewed and eloquent calls to medical educators and organizations to get involved in the solution of the erosion of resident wellbeing during the residence. PMID- 29488575 TI - [Fundal variceal bleeding treated with balloon occluded endoscopic inyection sclerotherapy. Report of two cases]. AB - Management of gastrointestinal bleeding caused by fundal varices is particularly difficult to manage. The options are: transjugular intrahepatic portosystemic shunt (TIPS), endoscopic injection of cyanoacrylate or balloon-occluded retrograde transvenous obliteration (BRTO). We report a 63 year-old male with a cirrhosis caused by hepatitis C and a 66 year-old female with a cirrhosis caused by a non-alcoholic steatohepatitis. Both patients had a gastrointestinal bleeding caused by fundal varices and were treated with sclerotherapy with cyanoacrylate assisted with BRTO. Flow was interrupted in the gastro-renal shunt by a femoral access in both patients. The male patient had a new bleeding two months later and died. In the female patient an endosonography performed nine months after the procedure showed absence of remaining varices. PMID- 29488576 TI - [Rectal diffuse large B cell lymphoma appearing after immunosuppression for ulcerative colitis. Report of one case]. AB - Primary colorectal lymphoma is a rare form of presentation of gastrointestinal tract lymphomas. Inflammatory bowel disease and its treatment are risk factors for its development. We report a 47-year-old male patient with Ulcerative Colitis of two years of evolution, treated initially with azathioprine and later on with infliximab. Due to a relapse in symptoms after the second dose of infliximab, a new coloncoscopy was performed showing a rectal ulcerative lesion, corresponding to a large cell Non-Hodgkin's Lymphoma. The patient was successfully treated with RCHOP chemotherapy (Rituximab cyclophosphamide doxorubicin vincristine prednisone). He is currently in disease remission. PMID- 29488577 TI - [Lupus enteritis as initial manifestation of systemic lupus erythematosus. Report of one case]. AB - Although gastrointestinal symptoms are not rare in Systemic lupus erythematosus, enteritis is an atypical manifestation of the disease. We report a 54 year-old woman who presented acute symptoms of diarrhea, fever and abdominal pain, receiving empiric antibiotic therapy for bacterial enteritis with no response. Computed tomography showed diffuse small intestine inflammation and serositis. Antinuclear antibodies, anti-Ro and anti-La were positive on blood tests. A lupic enteropathy was diagnosed and steroid treatment was initiated, with subsequent clinical improvement. PMID- 29488578 TI - [Non-bacterial thrombotic endocarditis. Report of one case]. AB - Marantic or nonbacterial thrombotic endocarditis is characterized for the presence of vegetations formed by a meshwork of fibrin and other cellular material similar a blood clot, without the presence of microorganisms. It is often related with tumors and chronic inflammatory states. We report a 49 years old female with a history of weight loss and asthenia, presenting with multiple cerebrovascular attacks and fever. Blood cultures were negative and the fever did not subside with antibiotic treatment. Trans esophageal echocardiogram showed a mitral valve vegetation and thickening of the free edge of both leaflets. In search of the etiology of such a case, a primary pancreatic cancer with distant metastases was found. We cannot rule out the differential diagnosis with bacterial endocarditis with negative blood cultures, although the clinical context supports a non-infectious etiology. PMID- 29488579 TI - [Review of the internal structure of a satisfaction survey]. PMID- 29488580 TI - [Work-life balance: A new indicator of the wellbeing of healthcare professionals]. PMID- 29488581 TI - [Increase in body mass index during the last four decades in Chile: from undernutrition to obesity]. PMID- 29488582 TI - [CORRECTION]. PMID- 29488583 TI - [Brief history of Candida, white but not so much]. PMID- 29488584 TI - [Epidemiology, species, antifungal resistance and outcome of candidemia in a university hospital in Buenos Aires, Argentina for 16 years]. AB - BACKGROUND: The epidemiology of candidemia vary by region. AIM: To determine the epidemiology of candidemia in a hospital for 16 years. MATERIAL AND METHODS: Episodes of candidemia occurred in the Hospital de Clinicas of Buenos Aires were reviewed, from 01/01/98 to 31/12/13. RESULTS: 374 episodes of candidemia were identified. The incidence was 2.21/1,000 discharges and increased from 1.96 (1998 2005) to 2.25 (2006-2013) (p = 0.023). Candidemia was diagnosed: 5.4% in neonates, 1.7% in infants, 6.5% in children, 31.8% in adults and 52.7% in elderly adults over 64 years old. The episodes were caused by C. albicans (40.9%), C. parapsilosis (21.7%), C. tropicalis (15.5%), C. glabrata (13.9%), other species of Candida (5.1%) and more than one species of Candida (2.9%). The 5.3% of the isolates were resistant to fluconazole. 74% of patients were treated. Initial treatments were with fluconazole (70.3%), amphotericin B deoxycholate (25%), echinocandins or lipidic amphotericin (4,7%). The 81% of central venous catheters were taken off. Mortality rate was of 47.9%, but in the elderly adults was of 60.8%. CONCLUSION: The incidence of candidemia showed an increase over the years. It was higher in the elderly adults, being the group with worse outcomes. PMID- 29488585 TI - [Epidemiology and antifungal susceptibility of species producing candidemia in Valdivia, Chile]. AB - BACKGROUND: Candidemia disease in Chile is not very known, despite being a very common and serious disease. AIM: To analyze incidence and susceptibility profile of species from the genus Candida in Hospital Base Valdivia. MATERIAL AND METHODS: All candidemia cases presented between March 2009 and August 2011 in our institution were identified. Species distribution and susceptibility were studied through the disk diffusion method. RESULTS: Twenty-seven candidemia episodes were studied. Incidence varied from 0.3 to 0.7 by a thousand discharges (according to clinical service). Risk factors were hospitalization, preliminary use of antibiotics, aged people and underlying disease (renal failure, heart and lung disease). The most frequent species was C. albicans, followed by C. tropicalis, C. glabrata and C. krusei. Voriconazole was the antifungal showing the best in vitro performance. Amphotericin B, fluconazole and itraconazole presented variable results. DISCUSSION: Incidence found was superior to that described in developed countries. Candida albicans constitute the most frequent species, with high sensitivity levels to fluconazole; Candida no albicans species must be monitored. Developing new research on the topic appears as fundamental to detect potential epidemiological variations. PMID- 29488586 TI - [Cost evaluation of ventilator-associated pneumonia in adult patients in a general hospital in Chile]. AB - BACKGROUND: Ventilator-associated pneumonia (VAP) is an adverse event that increases morbidity, mortality and costs due to a prolonged stay and requirement of microbiological studies and antimicrobial therapy. There is not recent data of VAP costs in Chile. AIM: To evaluate additional costs in adult patients with VAP compared to controls in a general hospital in the Metropolitan Area. PATIENTS AND METHODS: Use of the PAHO paired casecontrol protocol for cost evaluation associated to nosocomial infections and estimation of cost in excess per VAP event. Length of stay (LOS) in excess, antimicrobial consumption in daily-defined doses (DDD), and number of microbiological studies were compared between both groups. RESULTS: From 2012 to 2015, 18 patients with VAP events were identified with their respective controls. LOS exceeded 6.1 days on average among patients with VAP respect to controls (p < 0.05). DDD was higher among patients with VAP (difference 11.7 DDD) as well as number of cultures (3.2 higher on average, p < 0.05). Cost in excess per VAP event reached 4,475 USD. CONCLUSIONS: In our Centre, VAP events are associated to a higher LOS, antimicrobial consumption and microbiological studies. PMID- 29488587 TI - [Prevalence of HIV, hepatitis B virus and Treponema pallidum in inmates in the Preventive Detention Center of Arica, Chile]. AB - BACKGROUND: The risk groups for sexual transmitted diseases (STDs) are sex workers, drug addicts, young people in early sexual initiation, and population in prison. AIM: To determine the prevalence of HIV, Treponema pallidum and hepatitis B Virus (HBV) in male inmates at the Preventive Detention Center (CDP) of Arica. METHODS: The study was conducted in 140 inmates, with informed consent. Epidemiological survey and blood sampling was conducted. The positive tests were sent to the Hospital Regional of Arica for confirmation and the National Reference Laboratory for confirmation. RESULTS: STD prevalence was 13.6%. The most prevalent was VDRL positive (7.1%) followed by HIV infection (5.7%) and HBV (2.9%). The highest rate (57.9%) occurred in individuals under 31 years old. 63.2% were in an overcrowded situation, 42.1% of cases corresponded to those whose age of sexual activity onset of was before age 15 and 94.7% used drugs. CONCLUSIONS: The study reasserts the predisposing factors for the transmission of STDs as age, early sexual debut, drug abuse and overcrowding, noting that prisons are highly vulnerable environments where overcrowding, sexual condition, early sexual initiation, high drug abuse and the lacking spouses visits provide an epidemiological context favorable for increased STD. PMID- 29488588 TI - [Frequency, antimicrobial susceptibility and adherence patterns of Salmonella enterica isolated from chicken meat, beef and pork from Mexico City]. AB - BACKGROUND: Food of animal origin is often involved in salmonellosis outbreaks. AIM: To evaluate the frequency of Salmonella enterica in chicken, beef and pork ground meat (a total of 2,592 samples) obtained from travelling markets and supermarkets at the Iztapalapa area of Mexico City, in order to determine the antimicrobial susceptibility and adherence capacity of isolated strains. METHODS: Isolation of S. enterica was carried out according to the BAM-FDA, the microbial susceptibility according with CLSI and adherence assay on HEp-2 cell line according with Baffone et al., 2001. RESULTS: S. enterica was isolated from 511 of all the analyzed samples (19.7%), from which 244 (47.7%), 152 (29.7%) and 115 (22.5%) corresponded to chicken, beef and pork ground meat, respectively. The highest frequency of resistance of S. enterica to antimicrobials was to ampicillin and chloramphenicol in chicken, perfloxacin and ampicillin in beef and carbenicillin, ampicillin, chloramphenicol, cefotaxime and perfloxacin in pork. Ninety percent of the strains showed an aggregative adherence pattern on HEp-2 cells. CONCLUSION: The frequency of S. enterica on meat products is high, which is the reason why a proper cooking of these ground meats is important in order to reduce the risk of acquiring salmonellosis. PMID- 29488589 TI - [Polyomavirus in immunocompromised patients: the South America's situation]. AB - Forty-six years after the identification of the first polyomaviruses in humans (PyV) still there are strong concerns to find new types related to pathologies of different organs in immunocompromised patients. At the time of this review, 15 PyV have been described, many of them without being clearly associated with diseases. In our country, as in much of South America, the knowledge and research of these infectious agents are insufficient, so we systematized what is known about these viruses and their relationship with different human systems with emphasis on immunocompromised and we pointed out data published in our continent. Thus, we hope to encourage the study of these infections. PMID- 29488590 TI - [KPC: Klebsiella pneumoniae carbapenemase, main carbapenemase in Enterobacteriaceae]. AB - The dissemination of carbapenemase-producing Enterobacteriaceae is currently considered a serious clinical problem due to the failure in the treatment of infections produced by them. Among the carbapenemases, the enzyme KPC has spread worldwide and has been identified in the main enterobacterial species related with healthcareassociated infections, although Klebsiella pneumoniae is the predominant specie. The blaKPC gene is transported, mainly by the transposon Tn4401, detected in various enterobacterial species of different sequence types (ST) and geographical origin. In addition, new genetic platforms that are distinguished, from Tn4401 because of insertions or deletions of other genes have been described. Plasmids containing the blaKPC gene can be conjugative and mobilizable non-conjugative plasmids, and can carry other genetic determinants of resistance. The KPC-producing strains may have different levels of resistance to carbapenems, due to the involvement of additional mechanisms such as different expression levels of porins and efflux pumps associated with the production of extended spectrum beta-lactamases and/or AmpC. However, the carbapenemases, with KPC as the most common enzyme, provide higher levels of resistance. PMID- 29488591 TI - ? PMID- 29488592 TI - [Clinical and microbiological characteristics of skin and soft tissue infections caused by Staphylococcus aureus in children in a hospital in Medellin from 2013 to 2015]. AB - BACKGROUND: Skin and soft tissue infections (SSTI) are very common in children and Staphylococcus aureus is the main agent, with an increase of methicillin resistant strains (MRSA) in recent years. AIM: To identify the frequency of MRSA in skin and soft tissue infections (SSTI) in children from a high complex hospital in Medellin, Colombia. METHODS: This is a descriptive, retrospective study, information was obtained from medical records. We included patients younger than 18 years with SSTI due to S. aureus who did not meet criteria for invasive disease. RESULTS: The prevalence of MRSA in this population was 31%. The main diagnosis was cutaneous abscess (68%), followed by surgical site infection (15%) and non-purulent cellulitis (6%). Eighty five percent of the patients had at least 1 comorbidity. All isolates were sensitive to rifampicin and cotrimoxazole and 8% of the isolates were resistant to clindamycin. There was a higher prevalence of MRSA in patients under 2 years compared to older (60 vs 23%, p = 0,0109). CONCLUSION: In view of the high prevalence of MRSA in SSTI, empirical treatment with adequate coverage for MRSA is recommended, especially for patients under 2 years of age. PMID- 29488593 TI - [Some information regarding the historical development of typhoid fever in Chile]. AB - During the historical development of typhoid fever in Chile, its confusion with other infectious diseases is particularly noteworthy, especially with murine typhus, a problem that was mainly resolved during the 1918 epidemic. The importance of chloramphenicol treatment is also highlighted, which meant an enormous improvement in typhoid/paratyphoid fevers, in combination with public health and health education actions that allowed to almost eliminate these infectious diseases in our country. PMID- 29488594 TI - [Dengue in a newborn]. AB - Dengue is the disease transmitted by arthropods of major importance in public health; however its presence in the neonatal stage is poorly studied, with few cases described worldwide. We present the case report of a neonate who started illness at 12 days of age, characterized by fever and irritability. He was hospitalized for suspicion of neonatal sepsis; later he presented thrombocytopenia and due the antecedent of his mother with diagnosis of dengue after childbirth, dengue tests were obtained in the neonate, resulting positive, then support treatment and fluid treatment is performed, with subsequent recovery. Dengue in the neonatal stage should always be suspected in areas where the disease is endemic and management guides should be proposed. PMID- 29488596 TI - [Focal brain lesion due to cerebral aspergillosis in a patient with AIDS. Case report and literature review]. AB - Cerebral aspergillosis is a rare disease with high mortality rates in AIDS patients. It is important to take this into account in the differential diagnosis of a brain expansive lesion. A high level of suspicion is required to make an early diagnosis. We present a case of an HIV-infected patient with progresive neurological disease caused by Aspergillus flavi. We review 40 previously published cases of central nervous system aspergillosis in patients with AIDS. PMID- 29488595 TI - [Chronic and severe anemia caused by Ancylostoma duodenale in Ecuador. Diagnosis by duodenoscopy]. AB - For 11 years, a 38-year-old male residing in a subtropical region of Ecuador, was repeatedly diagnosed with chronic anemia, and treated with blood transfusions in a hospital of province of Cotopaxi, Ecuador. He was transferred to Quito for severe anemia, having hemoglobin of 4 g/dL. Duodenoscopy was performed and adult nematodes, identified later as Ancylostoma duodenale, were observed. The patient was successfully treated with albendazole for five consecutive days and given blood transfusions. In the control visit at eight months, without anemia and no hookworm ova in the stool examined were found. PMID- 29488597 TI - [Burkitt's lymphoma in a school boy with slow progression perinatally acquired HIV]. AB - Children with perinatal human immunodeficiency virus (HIV) infection can present early or late clinical disease. HIV-associated lymphoma is a later manifestation that is associated with advanced immunosuppression (acquired immunodeficiency syndrome -AIDS). This is a case of a 9-year-old boy with recent diagnosis of HIV with Burkitt's lymphoma as first clinical manifestation. In children, the frequency of this association is very low and there are few cases reported. PMID- 29488598 TI - [Monoarticular tuberculosis of the wrist: a case report]. AB - Monoarticular tuberculosis of the wrist is a rare presentation of primary tuberculosis, being more common skeletal forms involving the spine. Extraspinal tuberculous osteomyelitis is rare and comprises only 2 to 3% of all cases of osteoarticular Mycobacterium tuberculosis infections. We present a case of a 49 years old female patient, who worked as an hospital cleaning employed without other comorbidity. After a low energy injury of the wrist she suffered pain syndrome diagnosticated as a flexor tendinopathy, managed with nonsteroidal antiinflammatory drugs and physical therapy. Eight months later patient evolves with chronic pain in range of motion of right wrist joint, leading to a complete radiological, surgical biopsy and cultures. Histology, and molecular biology confirmed the wrist joint tuberculosis diagnosis. Pharmacological treatment and physical therapy were initiated with appropriated response. PMID- 29488599 TI - [Pneumocystis jiroveci pneumonia following infliximab therapy in patient with Crohn's disease]. AB - There are no evidence-based guidelines about prophylaxis against Pneumocystis jiroveci pneumonia in inflammatory bowel disease. We report a case of P. jiroveci pneumonia in patient with Crohn's disease receiving infliximab and methotrexate. This case emphasizes the importance of considering the possibility of this infection in inflammatory bowel disease patients treated on biological therapy. PMID- 29488600 TI - [Reflections about the importance and impact of the development of vaccines against arbovirosis]. PMID- 29488601 TI - [Procalcitonin-guided decision making for duration of antibiotic therapy in neonates with suspected early-onset sepsis]. PMID- 29488602 TI - ? PMID- 29488603 TI - MicroRNA-124 suppresses growth and aggressiveness of osteosarcoma and inhibits TGF-beta-mediated AKT/GSK-3beta/SNAIL-1 signaling. AB - Osteosarcoma is one of the most common malignant tumors in adolescent populations and the prognosis remains incompletely understand. Previous reports have demonstrated that microRNA-124 (miR-124) has inhibitory effects on various human malignancies and is associated with tumor progression. However, the clinical significance and potential mechanisms of miR-124 in the progression of osteosarcoma is not clearly understood. In this study, the potential molecular mechanism of miR-124 in osteosarcoma tumorigenesis, growth and aggressiveness was investigated. The growth, proliferation, apoptosis, migration and invasion of osteosarcoma cells were investigated following miR-124 transfection were determined by colony formation assay, western blotting, immunofluorescence, migration/invasion assays and reverse transcription-quantitative polymerase chain reaction. In vivo anti-cancer effects of miR-124 were analyzed by a tumor growth assay, immunohistochemistry and survival rate observations. The results demonstrated that miR-124 transfection significantly decreased integrin expression in osteosarcoma cells, and further inhibited growth, proliferation, migration and invasion of osteosarcoma cells. Flow cytometry assays indicated that miR-124 transfection attenuated apoptosis resistance of osteosarcoma to tunicamycin, potentially via the downregulation of P53 and Bcl-2 apoptosis regulator expression. Mechanistic assays demonstrated that miR-124 transfection suppressed TGF-beta expression in osteosarcoma. An animal study revealed that tumor growth was reduced in tumor cells transfected with miR-124 compared with control cells, and the survival rate was prolonged in mice with miR-124 transfected xenografts compared with control tumors. In conclusion, these results indicate that miR-124 transection inhibits the growth and aggressive of osteosarcoma, potentially via suppression of TGF-beta-mediated AKT/GSK 3beta/snail family transcriptional repressor 1 (SNAIL-1) signaling, suggesting miR-124 may be a potential anti-cancer agent/target for osteosarcoma therapy. PMID- 29488604 TI - Effect of tumor necrosis factor-alpha-induced protein 8 on the immune response of CD4+ T lymphocytes in mice following acute insult. AB - Tumor necrosis factor-alpha-induced protein 8 (TNFAIP8), which was the first identified member of the TNFAIP8 family, shares considerable sequence homology with other members of the TNFAIP8 family. It is expressed in various normal human tissues, with relatively higher levels detected in lymphoid tissues and the placenta. The present study aimed to examine the effect of TNFAIP8 on cell mediated immunity of cluster of differentiation (CD)4+ T lymphocytes in a cecal ligation and puncture (CLP) murine model. A total of 100 male mice were randomly divided into four groups as follows: The sham injury group (n=30), the CLP group (n=30), the CLP with lentivirus-RNA-TNFAIP8 group (n=20) and the CLP with negative control group (n=20), and they were sacrificed 24 h following CLP. Splenic CD4+ T cells were isolated using MACS microbeads. T cell proliferation was analyzed using the MTT assay, and cytokine levels were determined with ELISA kits. Upregulation of TNFAIP8 by lentivirus-RNA-TNFAIP8 infection was demonstrated to promote CD4+ T lymphocyte proliferative activity following CLP, and the increase in TNFAIP8 expression in vivo affected splenic CD4+ T lymphocyte polarization following CLP-induced sepsis. In conclusion, TNFAIP8 expression following CLP may be associated with the pathogenesis of immune dysfunction in splenic T lymphocytes in mice. PMID- 29488605 TI - Grim-19 expressed by recombinant adenovirus for esophageal neoplasm target therapy. AB - Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EA) are the two most common types of esophageal cancer, which is the sixth highest cause of cancer-associated mortality and the eighth most common cancer worldwide. Gene associated with retinoid-interferon (IFN)-induced mortality-19 (Grim-19) is reported to be a cell death activator that may be used to define mechanisms involved in IFN-beta- and retinoic acid-induced cell death and apoptosis in a number of tumor cell lines. The present study constructed a recombinant adenovirus expressing Grim-19 (rAd-Grim-19) and investigated its therapeutic outcomes in ESCC cells and tumor-bearing mice. Grim-19 expression was detected in EC-109 (ESCC) cells by reverse transcription-quantitative polymerase chain reaction and western blot analysis. Tumor cell death and apoptosis induced by rAd Grim-19 in EC-109 cells were analyzed by flow cytometry. The inhibitory effects of rAd-Grim-19 on EC-109 growth were determined by MTT assays. Furthermore, the therapeutic effects of rAd-Grim-19 were investigated in EC-109-bearing mice. The results demonstrated that Grim-19 mRNA and protein expression was downregulated in EC-109 esophageal carcinoma cells compared with Het-1A normal esophageal epithelial cells. In addition, EC-109 cells exhibited a significant reduction in tumor cell growth in the rAd-Grim-19 group compared with the control groups. Furthermore, rAd-Grim-19 increased EC-109 cell apoptosis compared with the control group. These results indicated that rAd-Grim-19 may regulate tumor cell growth and apoptosis. Additionally, the results demonstrated that rAd-Grim-19 led to beneficial outcomes and prolonged the survival of esophageal tumor-bearing mice. In conclusion, the present study demonstrated that rAd-Grim-19 may have potential as an antitumor agent for esophageal neoplasms and may therefore be beneficial for patients with esophageal neoplasms. PMID- 29488606 TI - Isoflurane reduces pain and inhibits apoptosis of myocardial cells through the phosphoinositide 3-kinase/protein kinase B signaling pathway in mice during cardiac surgery. AB - Heart bypass surgery is the most common treatment for myocardial ischemia. Clinical investigations have revealed that isoflurane anesthesia is efficient to alleviate pain during cardiac surgery, including heart bypass surgery. Previous studies have revealed the protective effects of isoflurane on myocardial cells of patients with myocardial ischemia during the perioperative period. The present study aimed to investigate the mechanism underlying the protective effects of isoflurane on myocardial cells in mice with myocardial ischemia. ELISA, flow cytometry, immunofluorescence and western blotting were used to analyze the effects of isoflurane anesthesia on myocardial cells. Briefly, myocardial cell apoptosis and viability, pain, phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway expression and the pharmacodynamics of isoflurane were studied in mice treated with isoflurane for heart bypass surgery. The results demonstrated that isoflurane anesthesia efficiently attenuated pain in mice during surgery. Viability and apoptosis of myocardial cells was also improved by isoflurane in vitro and in vivo. The PI3K/AKT pathway was upregulated in myocardial cells on day 3 post-operation. Mechanistically, isoflurane promoted PI3K/AKT activation, upregulated B-cell lymphoma 2 (Bcl-2)-associated X protein and Bcl-2 expression levels, and reduced the expression levels of caspase-3 and caspase-8 in myocardial cells. In conclusion, the findings indicated that isoflurane is beneficial for pain attenuation and inhibits apoptosis of myocardial cells via the PI3K/AKT signaling pathway in mice during cardiac surgery. PMID- 29488607 TI - The expression of microRNA-23a regulates acute myocardial infarction in patients and in vitro through targeting PTEN. AB - Cardiovascular disease is responsible for one of the highest rates of fatality worldwide. The present study investigated the presence and influence of microRNA (miRNA)-23a in the regulation of acute myocardial infarction (AMI). A total of 6 patients with AMI and 6 normal volunteers without myocardial disease were included, and blood samples were taken to analyze the expression of miRNA-23a by reverse transcription-quantitative polymerase chain reaction. miRNA-23a expression in patients with AMI was downregulated compared with the normal group. In H9C2 cells treated with H2O2, upregulation of miRNA-23a expression increased the superoxide dismutase, glutathione and catalase activity levels, and suppressed the malonaldehyde activity level, as determined by ELISA. Western blot analysis and a caspase-3 substrate assay demonstrated that upregulation of miRNA 23a expression suppressed the Bcl-2-associated X (Bax)/Bcl-2 protein expression ratio, caspase-3 activity level and tumor suppressor p53 (p53) protein expression in H2O2-induced H9C2 cells. Furthermore, downregulation of phosphatase and tensin homolog (PTEN), by the PTEN inhibitor bpV(HOpic), increased miRNA-23a expression and suppressed the Bax/Bcl-2 protein expression ratio, caspase-3 activity level and p53 protein expression in H2O2-induced H9C2 cells. Therefore, the results of the present study indicate that the expression of miRNA-23a may regulate AMI through targeting PTEN in patients and in vitro, and PTEN/miRNA-23a may therefore be potential targets for the clinical treatment of AMI. PMID- 29488608 TI - Kupffer cell depletion by gadolinium chloride aggravates liver injury after brain death in rats. AB - Brain death (BD) impairs liver function in potential donors, and is associated with hormonal and metabolic changes or molecular effects with pro-inflammatory activation. Resident macrophages in the liver named Kupffer cells (KCs) undergo pro- or anti-inflammatory pathway activation, which affects liver function. However, the role of the KCs in liver dysfunction following BD has not been fully elucidated. The aim of the present study was to investigate the role of KCs in liver dysfunction in the context of BD and the effects of their inhibition by gadolinium chloride (GdCl3). Rats were randomly divided into the following groups: Control, BD with GdCl3 pretreatment and BD with normal saline pretreatment. Liver function, hepatic pathological histology and cytokine levels in the liver were assessed. Apoptosis and apoptosis-related proteins [cleaved caspase-3, caspase-3 and apoptosis regulator Bcl-2 (Bcl-2)] were evaluated. GdCl3 significantly aggravated liver injury by elevating alanine aminotransferase and aspartate aminotransferase levels (P<0.05) by inhibiting KCs. Interleukin (IL) 1beta and tumor necrosis factor alpha levels in the GdCl3 group were significantly increased compared with those in the control and saline groups (P<0.01). However, IL-10 levels in the GdCl3 group were significantly reduced compared with those in the saline group (P<0.05). Caspase-3 and cleaved caspase-3 activation, and apoptosis induction in the context of BD were also significantly aggravated by the depletion of KCs, whereas Bcl-2 was significantly suppressed by the administration of GdCl3. The present study indicated that GdCl3 efficiently inhibits the activity of KCs, and is involved in the onset of liver injury through its effects on pro-inflammatory and anti-inflammatory activation. KCs are protective in the liver in the context of BD. This protection appears to be due to KCs secretion of the potent anti-inflammatory cytokine IL-10, suggesting that KCs are an attractive target for the prevention and treatment of liver injury in the context of BD in rats. PMID- 29488609 TI - Ebselen suppresses inflammation induced by Helicobacter pylori lipopolysaccharide via the p38 mitogen-activated protein kinase signaling pathway. AB - Ebselen is a seleno-organic compound that has been demonstrated to have antioxidant and anti-inflammatory properties. A previous study determined that ebselen inhibits airway inflammation induced by inhalational lipopolysaccharide (LPS), however, the underlying molecular mechanism remains to be elucidated. The present study investigated the effect of ebselen on the glutathione peroxidase (GPX)-reactive oxygen species (ROS) pathway and interleukin-8 (IL-8) expression induced by Helicobacter pylori LPS in gastric cancer (GC) cells. Cells were treated with 200 ng/ml H. pylori-LPS in the presence or absence of ebselen for various durations and concentrations (umol/l). The expression of toll-like receptor 4 (TLR4), GPX2, GPX4, p38 mitogen-activated protein kinase (p38 MAPK), phosphorylated-p38 MAPK, ROS production and IL-8 expression were detected with western blotting or ELISA. The present study revealed that TLR4 expression was upregulated; however, GPX2 and GPX4 expression was reduced following treatment with H. pylori LPS, which led to increased ROS production, subsequently altering the IL-8 expression level in GC cells. Additionally, it was determined that ebselen prevented the reduction in GPX2/4 levels induced by H. pylori LPS, however, TLR4 expression was not affected. Ebselen may also block the expression of IL-8 by inhibiting phosphorylation of p38 MAPK. These data suggest ebselen may inhibit ROS production triggered by H. pylori LPS treatment via GPX2/4 instead of TLR4 signaling and reduce phosphorylation of p38 MAPK, resulting in altered production of IL-8. Ebselen may, therefore, be a potential therapeutic agent to mediate H. pylori LPS-induced cell damage. PMID- 29488610 TI - Local intra-articular injection of vascular endothelial growth factor accelerates articular cartilage degeneration in rat osteoarthritis model. AB - In the pathophysiology of osteoarthritis (OA), articular cartilage degeneration exhibits a significant role. Vascular endothelial growth factor (VEGF) is considered to be an effective angiogenic factor and a crucial regulator of articular cartilage degeneration in the development of OA. Therefore, the present study aimed to investigate the underlying influences of exogenous VEGF on articular cartilage degeneration in OA model rat. A total of 24 male Sprague Dawley rats were randomly allocated into 3 groups. In the normal saline (NS) and VEGF groups, animals received bilateral anterior cruciate ligament (ACL) transection to establish the OA model; at 4 weeks post-surgery, the rats received local intra-articular injections of 100 ul NS or VEGF solution, respectively, every week for 4 weeks. The Control group received neither surgery nor injections. All animals were sacrificed at 12 weeks following surgery. Prominent cartilage degeneration was observed in rats in the NS- and VEGF-injected groups. The extent and the grade of cartilage damage in the VEGF-injected group were notably more severe compared with those in the NS-treated group. Western blotting results demonstrated that the expression levels of aggrecan and type II collagen were significantly reduced in OA model rats that were treated with VEGF. In addition, the expression levels of matrix metalloproteinase (MMP)-3, MMP-9, MMP 13, a disintegrin and metalloproteinase with thrombospondin motifs (a disintegrin and metalloproteinase; ADAMTS)-4, -5 and -12, type III collagen and transforming growth factor-beta1 were significantly increased following VEGF administration. Results from the present study indicated that VEGF may exhibit a promoting role in the development of OA by destroying articular cartilage matrix. PMID- 29488611 TI - miR-205-5p/PTK7 axis is involved in the proliferation, migration and invasion of colorectal cancer cells. AB - MicroRNAs (miRNAs) are small non-coding RNAs, which are critical in a diverse range of biological processes, including development, differentiation, homeostasis, and in the formation of diseases by accelerating and/or inhibiting the translation of mRNAs. The present study aimed to examine the potential role of miRNA (miR)-205-5p in the developmental process of colorectal cancer (CRC) through protein-tyrosine kinase 7 (PTK7). Initially, TargetScan was used to predict the miRNA target sites in the sequence of the PTK7 3'-untranslated region. It was then found that the mRNA expression level of miR-205-5p was lower in CRC cells, determined using reverse transcription-quantitative polymerase chain reaction analysis, and there was a negative correlation between miR-205-5p and PTK7 in CRC tissues. It was also found that miR-205-5p regulated the gene transcription of PTK7, determined using a luciferase reporter assay. The results of RT-qPCR and western blot analyses in human colorectal cancer revealed that miR 205-5p suppressed the expression of PTK7. Finally, it was revealed that miR-205 5p restricted the proliferation ability of CRC cells through inhibiting PTK7, which was determined using colony forming and 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assays. miR-205-5p accelerated cell apoptosis through inhibiting PTK7, demonstrated using Annexin V-FITC/propidium iodide staining. The results of a Transwell assay indicated that miR-205-5p inhibited the migration and invasion abilities of CRC cells through inhibiting PTK7. Therefore, miR-205 5p is involved in the proliferation, migration and invasion of CRC through inhibiting PTK7. PMID- 29488613 TI - Association of the PPARgamma/PI3K/Akt pathway with the cardioprotective effects of tacrolimus in myocardial ischemic/reperfusion injury. AB - Myocardial ischemia/reperfusion injury (MIRI) induces severe arrhythmias and has a high risk of mortality. The aim of the present study was to investigate the effect of tacrolimus on arrhythmias, cardiac function, oxidative stress and myocardium apoptosis induced by MIRI, and to elucidate the underlying mechanism. The effects of MIRI and tacrolimus on arrhythmias, cardiac function parameters, myocardial oxidative stress and apoptosis were investigated in a rat model of MIRI. The phosphorylation of peroxisome proliferator-activated receptor gamma (PPARgamma) and protein kinase B (Akt) was investigated via western blotting. After rats were treated with inhibitors of PPARgamma/phosphoinositide 3-kinase (PI3K)/Akt, cardiac function parameters were measured. The results demonstrated that the MIRI procedure induced arrhythmias and significant impairment of cardiac function, oxidative stress and apoptosis in cardiomyocytes (P<0.05). Tacrolimus significantly alleviated the arrhythmias and impairment of cardiac function and inhibited the oxidative stress and apoptosis in cardiomyocytes (P<0.05). The phosphorylation of PPARgamma and Akt was significantly activated by tacrolimus, whereas inhibitors of PPARgamma/PI3K/Akt significantly abolished the effects of tacrolimus (P<0.05). Together, these results suggest that tacrolimus may protect rats from MIRI through activation of the PPARgamma/PI3K/Akt pathway. PMID- 29488612 TI - Piperine depresses the migration progression via downregulating the Akt/mTOR/MMP 9 signaling pathway in DU145 cells. AB - Piperine, an alkaloid derived from natural products, has been demonstrated to exert antitumor activities in vivo and in vitro. However, its anti-tumor effect has not yet been illustrated in the prostate cancer (PCa) metastatic process. Thus, the present study explored the influence of piperine on PCa and the underlying molecular mechanism. Cell migration was detected via the Transwell chamber model. Total protein was identified by western blot analysis. The data revealed that piperine markedly repressed cell proliferation and migration, and induced apoptosis in PCa DU145. In addition, LY294002, an protein kinase B (Akt) inhibitor, greatly suppressed the expression level of phospho (p)-Akt, matrix metalloproteinase (MMP)-9 and p-mammalian target of rapamycin (mTOR), suggesting that the activation of the Akt/mTOR/MMP-9 signaling pathway may participate in regulating cell migration in PCa. Furthermore, piperine reduced the expression of p-Akt, MMP-9 and p-mTOR. Together, these data indicated that piperine may serve as a promising novel therapeutic agent to better overcome PCa metastasis. PMID- 29488614 TI - Penehyclidine hydrochloride inhibits TLR4 signaling and inflammation, and attenuates blunt chest trauma and hemorrhagic shock-induced acute lung injury in rats. AB - Blunt chest trauma with hemorrhagic shock (THS) frequently induces pulmonary inflammation that leads to acute lung injury (ALI). Penehyclidine hydrochloride (PHC) possesses anti-inflammatory properties that may attenuate the systemic inflammatory response. The present study aimed to evaluate the molecular mechanism of PHC in modifying THS-induced ALI in rats. Rats underwent either THS or a sham procedure. At 6 h subsequent to blunt chest trauma, arterial blood was drawn for blood gas and pro-inflammatory factors analyses, and lung tissue samples were collected to examine pulmonary histopathological alterations, the wet/dry weight ratio, myeloperoxidase activity, and the protein expression levels of Toll-like receptor 4 (TLR4), phosphorylated (p-)p38 mitogen-activated protein kinase (MAPK), nuclear factor (NF)-kappaB and activator protein-1 (AP-1). THS caused significant reductions in heart rate and mean arterial blood pressure, and was associated with significant increases in tumor necrosis factor-alpha, interleukin (IL)-6, IL-1beta, p-p38MAPK, NF-kappaB and AP-1 activation, in addition to TLR4 expression, in the lung. PHC effectively attenuated THS-induced ALI, and inhibited TLR4 expression, reduced the activation of p-p38MAPK, NF kappaB and AP-1, and downregulated the expression of pro-inflammatory mediators. In conclusion, the results of the present study demonstrated that PHC may exert an anti-inflammatory effect and attenuate THS-induced ALI by inhibiting the TLR4 signaling pathway. These preclinical findings may offer a novel therapeutic strategy to restrict TLR4 overactivation in ALI. PMID- 29488615 TI - High sucrose/fat diet and isosorbide mononitrate increase insulin resistance, nitric oxide production and myocardial apoptosis in a hypertensive rat model. AB - The present study aimed to investigate the association between insulin resistance (IR), nitric oxide (NO) production and myocardial apoptosis in a background of coexisting hypertension in a rodent animal model. A hypertensive rat model was established by feeding Wistar and spontaneously hypertensive rats (SHR) with a high sucrose/fat (HSF) diet for 12 weeks, in conjunction with isosorbide mononitrate (ISMN). Increased IR, NO content, apoptotic gene and protein expression, and morphological alterations within rat myocardium were evaluated. Following a total of 12 weeks of feeding with HSF and ISMN resulted in increased IR and NO content within the myocardial tissue of Wistar and SHR rats. HSF and ISMN activated myocardial apoptosis by downregulating the gene transcription and protein expression levels of the anti-apoptotic B-cell lymphoma 2 (Bcl-2), and increasing the pro-apoptotic Bcl-2 associated X protein. Apoptosis was demonstrated by DNA fragmentation in terminal deoxynucleotidyl-transferase mediated dUTP nick end labelling assay. In all experiments, the combination of HSF and ISMN was associated with more pronounced effects, indicating the possible synergistic effects. In addition, the correlation analysis in the Wistar rats fed with HSF only, revealed a positive association between NO production and IR. The results of the present study indicated that HSF and ISMN simultaneously increased IR, NO production and myocardial apoptosis in the hypertensive rat model, and may therefore contribute to investigations into the long-term clinical use of ISMN in hypertensive patients. PMID- 29488616 TI - MicroRNA-378 enhances migration and invasion in cervical cancer by directly targeting autophagy-related protein 12. AB - Cervical cancer is the second most common type of cancer among women worldwide and a leading cause of mortality in women. Metastases reduce the overall survival rate in patients with cervical cancer. Thus, it is clinically urgent to investigate the molecular mechanism of cervical cancer metastasis. The aim of the present study was to investigate the mechanism of microRNA (miR)-378 in the metastasis of cervical cancer. In the present study, miR-378 expression levels were significantly upregulated in cervical cancer tissues and cervical intraepithelial neoplasia III tissues when compared with normal cervix tissues. Re-expression of miR-378 significantly promoted tumor migration and invasion in vitro, and metastasis in vivo, while downregulation of miR-378 suppressed the effect in vitro. Luciferase reporter assay revealed that autophagy-related protein 12 (ATG12) was a direct target of miR-378 and its expression was downregulated by miR-378. In cervical cancer tissues with lymph node metastasis, miR-378 was upregulated while ATG12 was downregulated when compared with lymph node negative cases. To the best of our knowledge, the present study is the first to provide evidence that miR-378 may be associated with ATG12. Collectively, the data of the present study suggested that miR-378 may function as an oncogene by promoting metastasis in cervical cancer. The finding that miR-378 targets ATG12 indicated that miR-378 may have a potential role in autophagy. These findings may provide novel insights into the mechanism of metastasis in cervical cancer and a novel therapeutic target for the treatment of cervical cancer. PMID- 29488617 TI - Expression of Toll-like receptor 4 on mast cells in gingival tissues of human chronic periodontitis. AB - The purpose of the present study was to examine the expression of Toll-like receptor 4 (TLR4) on mast cells in gingival tissues of human chronic periodontitis. A total of 68 donors, including 23 with mild chronic periodontitis, 25 with advanced chronic periodontitis and 20 healthy controls, were included in the present study. Gingival specimens from the donors were fixed in 4% neutral formalin, stained with hematoxylin and eosin for histologic observation, stained for immunohistochemical identification of TLR4 in gingival tissues, and stained with double immunofluorescence for the identification of TLR4 on mast cells in gingival tissues. The results revealed that the expression of TLR4 in the gingival tissues and on mast cells in the gingival tissues of patients with chronic periodontitis were significantly higher, compared with those of the normal control group (P<0.05). The expression levels of TLR4 in the gingival tissues and on mast cells in patients with advanced chronic periodontitis were significantly higher, compared with those in patients with mild chronic periodontitis (P<0.05). In conclusion, the expression of TLR4 in gingival tissues and on mast cells increased with the severity of chronic periodontitis, suggesting that TLR4, particularly mast cell TLR4, may be important in the disease process of human chronic periodontitis. PMID- 29488618 TI - Metabolomics analysis reveals an effect of homocysteine on arachidonic acid and linoleic acid metabolism pathway. AB - An increase in serum homocysteine level has been associated with an increased risk of vascular disease; however, the biochemical mechanisms that underlie these effects remain largely unknown. The present study aimed to use high-performance liquid chromatography-mass spectrometry (HPLC-MS) to demonstrate the effects of serum homocysteine on human blood metabolites. A total of 75 fasting serum samples were investigated in the present study. Using a threshold of 15 umol/l serum homocysteine level, samples were divided into high- and low-homocysteine groups, and the serum extracts were analyzed with an HPLC-MS-based method. A total of 269 features exhibited significant differences and correlation with serum homocysteine levels in the electrospray ionization-positive [ESI(+)] mode, and 69 features were identified in the ESI(-) mode between the two groups. The principal component analysis plot revealed a separation between the high- and the low-homocysteine groups. Metabolite set enrichment analysis identified arachidonic acid metabolism and linoleic acid metabolism as the two pathways with significantly enriched differences. These results revealed that arachidonic acid and linoleic acid metabolism may be associated with serum homocysteine levels and may be involved in homocysteine-induced vascular disease. PMID- 29488619 TI - ATRA improves endothelial dysfunction in atherosclerotic rabbits by decreasing CAV-1 expression and enhancing eNOS activity. AB - The aim of the present study was to explore the protective effects and possible mechanisms of all-trans-retinoic acid (ATRA) against atherosclerosis (AS). Rabbits were randomly allocated for standard or high-fat diet with or without ATRA. After 12 weeks, the aortic rings of the rabbits were removed. Endothelium dependent relaxation (EDR) induced by acetylcholine and non-endothelium-dependent relaxation induced by sodium nitroprusside in the thoracic aorta were evaluated. NO level and eNOS activity were measured according to the protocol of NO and eNOS ELISA kits. The permeability and morphology of the arterial walls were identified by immunofluorescence and H&E staining respectively. The expression of caveolin-1 (CAV-1) and occludin was analyzed using western blotting and immunohistochemistry. The EDR function was significantly reduced in the AS rabbits compared with the normal group, however it was elevated following treatment with ATRA. The eNOS activity and NO level were reduced in the AS group, however were notably increased following oral administration of ATRA. There was an enhancement of endothelial permeability in the AS group compared with the normal group, which decreased following ATRA treatment. Western blot analysis and immunohistochemical analysis identified an increase in occludin expression after treatment with ATRA, in contrast to CAV-1 expression under the same conditions. ATRA is able to ameliorate high-fat-induced AS in rabbits, which is mediated through the activation of eNOS and downregulating CAV-1 expression. PMID- 29488620 TI - Mirror Induced Headaches: A New Self Image Trigger for Migraine Attacks? PMID- 29488621 TI - Impact of In-Hospital Death on Spending for Bereaved Spouses. AB - OBJECTIVE: To examine how patients' location of death relates to health care utilization and spending for surviving spouses. DATA SOURCES/STUDY SETTING: Health and Retirement Study (HRS) 2000-2012 linked to the Dartmouth Atlas and Medicare claims data. STUDY DESIGN: This was an observational study. We matched bereaved spouses whose spouses died in a hospital to those whose spouses died outside the hospital using propensity scores based on decedent and spouse demographic and clinical characteristics, care preferences, and regional practice patterns. DATA COLLECTION/EXTRACTION METHODS: We identified 1,348 HRS decedents with surviving spouses. We linked HRS data from each dyad with Medicare claims and regional characteristics. PRINCIPAL FINDINGS: In multivariable models, bereaved spouses of decedents who died in the hospital had $3,106 higher Medicare spending 12 months postdeath (p = .04) compared to those whose spouses died outside a hospital. Those surviving spouses were also significantly more likely to have an ED visit (OR = 1.5; p < .01) and hospital admission (OR = 1.4; p = .02) in the year after their spouse's in-hospital death. Increased Medicare spending for surviving spouses persisted through the 24-month period postdeath ($5,310; p = .02). CONCLUSIONS: Bereaved spouses of decedents who died in the hospital had significantly greater Medicare spending and health care utilization themselves after their spouses' death. PMID- 29488622 TI - Predictive validity of developmental screening in young children with sickle cell disease: a longitudinal follow-up study. AB - AIM: To assess the predictive validity of developmental screenings in children with sickle cell disease (SCD) for academic outcomes and stroke risk. METHOD: Parent questionnaires and medical record data were collected for a cohort receiving developmental screenings between September 2004 and May 2008 as toddlers or early school age. Screening outcomes were dichotomized (positive, negative) by a priori criteria. Questionnaires assessed school and social functioning, services received, and quality of life. Medical record data assessed general SCD morbidity and stroke risk. RESULTS: Forty-one toddlers (mean age 2y 5mo; 25 males, 16 females) and 49 early school-age children (mean age 6y 5mo; 26 males, 23 females) completed follow-up. The mean follow-up period was 8 years 6 months (range 6.1-10.8y). For toddlers, positive screenings for language delays predicted lower academic performance (p=0.023). For older children, positive screenings for cognitive delays predicted more frequent academic/attentional problems at school (p<0.001), grade retention (p=0.007), and lower academic performance (p=0.001). Positive screenings were associated with an earlier onset of school problems and lower quality of life. Positive screenings for language/cognitive delays predicted increased stroke risk (both p<0.05). INTERPRETATION: Screening for language or cognitive development in young children with SCD predicts academic outcomes and stroke risk. WHAT THIS PAPER ADDS: Developmental screening predicts academic outcomes in sickle cell disease. Children with concerning language/cognitive screenings have early-onset school difficulties. Developmental screenings may help predict cerebrovascular complications. PMID- 29488623 TI - 2p24.2 (rs7552) is a susceptibility locus for nonsyndromic cleft lip with or without cleft palate in the Brazilian population. AB - The population of Brazil is highly admixed, with each individual showing variable levels of Amerindian, European and African ancestry, which may interfere in the genetic susceptibility of known risk loci to nonsyndromic cleft lip with or without cleft palate (NSCL+/-P). Here, we investigated 5 reported genome-wide loci for NSCL+/-P in an ancestry-structured case-control study containing 1697 Brazilian participants (831 NSCL+/-P and 866 healthy controls). SNPs rs7552 in 2q24.2, rs8049367 in 16p13.3, rs1880646, rs7406226, rs9891446 in 17p13, rs1588366 in 17q23.2 and rs73039426 in 19q13.11 were genotyped using TaqMan allelic discrimination assays and genomic ancestry was estimated using a panel of 40 biallelic short insertion/deletion polymorphic markers informative of the Brazilian population. Logistic regression analysis of the single-markers revealed rs7552 in 2p24.2 as a susceptibility risk marker for NSCL+/-P, yielding an odds ratio (OR) of 1.71 (95% confidence interval (CI): 1.31-2.24, P = 9 * 10-6 ) in the homozygous state. Several SNP-SNP interactions containing rs7552 reached significance after adjustment for multiple tests (both Bonferroni assumption and 1000 permutation test), with the most significant interaction involving the 3 loci among rs7552, rs9891446 and rs73039426 (P = 6.1 * 10-9 and p1000 permutation = 0.001). Our study is the first to support the association of rs7552 in 2p24.2 with NSCL+/-P in the highly admixed Brazilian population. PMID- 29488624 TI - Regulatory network analysis of LINC00472, a long noncoding RNA downregulated by DNA hypermethylation in colorectal cancer. AB - Colorectal cancer (CRC), one of the common malignant cancers in the world, is caused by accumulated alterations of genetic and epigenetic factors over a long period of time. Along with that protein-coding genes being identified as oncogenes or tumor suppressors in CRC, a number of lncRNAs have also been found to be associated with CRC. Considering the important regulatory role of lncRNAs, the first goal of this study was to identify CRC-associated lncRNAs from a public database. One such lncRNA, LINC00472, was verified to be downregulated in CRC cell lines and cancer tissues compared with adjacent tissues. In addition, the down-regulation of LINC00472 seemed to be caused by DNA hypermethylation at its promoter region. Furthermore, the expression of LINC00472 and DNA methylation of promoter were significantly correlated with clinicopathological features. And DNA hypermethylation of LINC00472 may serve as a better diagnostic biomarker than its expression for CRC. Finally, we predicted the functions of LINC00472 and constructed a regulatory network and found LINC00472 may be involved in cell cycle and cell proliferation processes. Our results may provide a clue to further research into the function and regulatory mechanism of LINC00472 in CRC. PMID- 29488626 TI - The effect of positive and negative memory bias on anxiety and depression symptoms among adolescents. AB - OBJECTIVE: To examine the interaction effect of anxiety and depression on the intentional forgetting of positive and negative valence words. METHODS: One hundred fifty-five grade 7 to grade 10 students participated in the study. The item-method directed forgetting paradigm was used to examine the intentional forgetting of positive-valence, negative-valence, and neutral-valence words. RESULTS: Negative-valence words were recognized better than either positive valence or neutral-valence words. The results revealed an anxiety main effect (p = .01, LLCI = -.09, and ULCI = -.01) and a depression main effect (p = .04, LLCI = .00, and ULCI = .24). The anxiety score was negative, whereas the depression score was positively related to the directed forgetting of negative-valence words. Regression-based moderation analysis revealed a significant anxiety * depression interaction effect on the directed forgetting of positive-valence words (p = .02, LLCI = .00, and ULCI = .01). Greater anxiety was associated with more directed forgetting of positive-valance words only among participants with high depression scores. With negative-valence words, the anxiety * depression interaction effect was not significant (p = .15, LLCI = - .00, and ULCI = .01). CONCLUSION: Therapeutic strategies to increase positive memory bias may reduce anxiety symptoms only among those with high depression scores. Interventions to reduce negative memory bias may reduce anxiety symptoms irrespective of levels of depression. PMID- 29488625 TI - Arginase-1 is neither constitutively expressed in nor required for myeloid derived suppressor cell-mediated inhibition of T-cell proliferation. AB - Although previous reports suggest that tumor-induced myeloid-derived suppressor cells (MDSC) inhibit T cells by L-arginine depletion through arginase-1 activity, we herein show that arginase-1 is neither inherently expressed in MDSC nor required for MDSC-mediated inhibition. Employing Percoll density gradients, large expansions of MDSC in the bone marrow of tumor-bearing mice were isolated and demonstrated potent inhibition in T-cell proliferation activated by TCR-ligation, Concanavalin A, PMA plus ionomycin, or IL-2. Despite demonstrating characteristic immunosuppressive capacity, these MDSC exhibit no arginase-1 expression and/or exert their inhibitory effects independent of arginase-1 activity. However, arginase-1 expression in MDSC can be induced by exposure to TCR-activated T cells or their culture medium, but not T cells activated by other means or growing tumor cells. Further investigation reveals multiple cytokines secreted by TCR activated T cells as orchestrating two signaling-relay axes, IL-6-to-IL-4 and GM CSF/IL-4-to-IL-10, leading to arginase-1 expression in MDSC. Specifically, IL-6 signaling increases IL-4R, enabling IL-4 to induce arginase-1 expression; similarly, GM-CSF in concert with IL-4 induces IL-10R, allowing IL-10-mediated induction. Surprisingly, our study indicates that induction of arginase-1 expression is not conducive to the critical MDSC-mediated inhibition toward T cells, which is rather dependent on direct cell contacts undiminished by PD-L1 blockade or SIRPalpha deficiency. PMID- 29488627 TI - Pyrosequencing method for sensitive detection of HBV drug resistance mutations. AB - Hepatitis B (HBV) drug resistance assay is important for guiding therapy after the development of virologic breakthrough for patients receiving nucleoside/-tide analog therapy. However, the existing genotyping tools are either costly or lack sensitivity to detect mixed genotypes, and an improved method of resistant mutation detection is needed. An assay protocol for clinical application using pyrosequencing method was developed, capable of detecting all known validated HBV polymerase gene mutations that impart resistance to lamivudine, adefovir, tenofovir, and entecavir. Sixty-eight serum samples with known HBV resistance genotypes, previously tested with either Sanger sequencing assay or commercial line probe assay, were used for validation. Where there were discrepancies between the two methods, clonal sequencing by Sanger's method was used for confirmation. The modified pyrosequencing method accurately identified all the cloned polymerase genotypes and was able to distinguish as little as 5% of the mutant populations. This assay can be performed on serum sample with HBV DNA as low as 13.5 IU/mL. The cost per test was less than existing commercial assay. HBV drug resistance pyrosequencing assay was accurate, more sensitive and cheaper compared with the existing methods. It can detect minor populations of drug resistant clones earlier, before the drug resistant clones become dominant, allowing the opportunity for an earlier change of therapy. PMID- 29488628 TI - Effect of prenatal mindfulness training on depressive symptom severity through 18 months postpartum: A latent profile analysis. AB - OBJECTIVE: We examined whether prenatal mindfulness training was associated with lower depressive symptoms through 18-months postpartum compared to treatment as usual (TAU). METHOD: A controlled, quasi-experimental trial compared prenatal mindfulness training (MMT) to TAU. We collected depressive symptom data at post intervention, 6-, and 18-months postpartum. Latent profile analysis identified depressive symptom profiles, and multinomial logistic regression examined whether treatment condition predicted profile. RESULTS: Three depressive symptom severity profiles emerged: none/minimal, mild, and moderate. Adjusting for relevant covariates, MMT participants were less likely than TAU participants to be in the moderate profile than the none/minimal profile (OR = 0.13, 95% CI = 0.03-0.54, p = .005). CONCLUSIONS: Prenatal mindfulness training may have benefits for depressive symptoms during the transition to parenthood. PMID- 29488629 TI - The influence of mindfulness, self-compassion, psychological flexibility, and posttraumatic stress disorder on disability and quality of life over time in war veterans. AB - OBJECTIVES: Posttraumatic stress disorder (PTSD) strongly predicts greater disability and lower quality of life (QOL). Mindfulness-based and other third wave behavior therapy interventions improve well-being by enhancing mindfulness, self-compassion, and psychological flexibility. We hypothesized that these mechanisms of therapeutic change would comprise a single latent factor that would predict disability and QOL after accounting for PTSD symptom severity. METHOD: Iraq and Afghanistan war veterans (N = 117) completed a study of predictors of successful reintegration. Principal axis factor analysis tested whether mindfulness, self-compassion, and psychological flexibility comprised a single latent factor. Hierarchical regression tested whether this factor predicted disability and QOL 1 year later. RESULTS: Mindfulness, self-compassion, and psychological flexibility comprised a single factor that predicted disability and QOL after accounting for PTSD symptom severity. PTSD symptoms remained a significant predictor of disability but not QOL. CONCLUSIONS: Targeting these mechanisms may help veterans achieve functional recovery, even in the presence of PTSD symptoms. PMID- 29488630 TI - Detection of live Salmonella enterica in fresh-cut vegetables by a TaqMan-based one-step reverse transcription real-time PCR. AB - : Fresh-cut produce is at greater risk of Salmonella contamination. Detection and early warning systems play an important role in reducing the dissemination of contaminated products. One-step Reverse Transcription Polymerase Chain Reaction (RT-qPCR) targeting Salmonella tmRNA with or without a 6-h enrichment was evaluated for the detection of Salmonella in fresh-cut vegetables after 6-h storage. LOD of one-step RT-qPCR was 1.0 CFU per ml (about 100 copies tmRNA per ml) by assessed 10-fold serially diluted RNA from 106 CFU per ml bacteria culture. Then, one-step RT-qPCR assay was applied to detect viable Salmonella cells in 14 fresh-cut vegetables after 6-h storage. Without enrichment, this assay could detect 10 CFU per g for fresh-cut lettuce, cilantro, spinach, cabbage, Chinese cabbage and bell pepper, and 102 CFU per g for other vegetables. With a 6-h enrichment, this assay could detect 10 CFU per g for all fresh-cut vegetables used in this study. Moreover, this assay was able to discriminate viable cells from dead cells. This rapid detection assay may provide potential processing control and early warning method in fresh-cut vegetable processing to strengthen food safety assurance. SIGNIFICANCE AND IMPACT OF THE STUDY: Significance and Impact of the Study: Fresh-cut produce is at greater risk of Salmonella contamination. Rapid detection methods play an important role in reducing the dissemination of contaminated products. One-step RT-qPCR assay used in this study could detect 10 CFU per g Salmonella for 14 fresh-cut vegetables with a 6-h short enrichment. Moreover, this assay was able to discriminate viable cells from dead cells. This rapid detection assay may provide potential processing control and early warning method in fresh-cut vegetable processing to strengthen food safety assurance. PMID- 29488631 TI - Aerated Steam Sanitization of Whole Fresh Cantaloupes Reduces and Controls Rind Associated Listeria but Enhances Fruit Susceptibility to Secondary Colonization. AB - : Recent bacterial illnesses and outbreaks associated with the consumption of fresh and fresh-cut fruit and vegetables emphasize the need to supply produce that is microbiologically safe while retaining its quality and nutrient value. We assessed the capacity of aerated steam to reduce initial levels and control the posttreatment proliferation of a 4-strain mixture of Listeria innocua, a surrogate for L. monocytogenes, and microflora native to the rind of whole cantaloupes. Studies were conducted at the pilot-scale level by passing deliberately contaminated melons through a prototype stainless-steel, continuous feed heating device. Exposure for 240 s to aerated steam heated to 85 degrees C achieved a mean reduction in surface-inoculated L. innocua of 3.9 +/- 0.6 log10 CFU/cm2 (n = 3) and decreased background microorganisms (yeast, moulds, and coliforms) to undetectable levels. No significant outgrowth of surviving L. innocua or yeast and moulds was observed on heat-treated melons during their storage at 4, 7, and 10 degrees C for 14 days. Treated fruit continued to respire. Although rind quality was altered, edible fleshy portions remained largely unaffected. Cantaloupe inoculated with L. innocua subsequent to its exposure to aerated steam provided a suitable environment for surrogate growth (mean 3.3 log10 increase in rind density over 10 days at 7 degrees C), whereas its proliferation was restricted on nonheated cantaloupe (mean 0.7 log10 increase). Steam sanitization provides an effective means for the control of pathogen and spoilage organisms, but the proliferation of surrogate organisms on heated cantaloupes raises concern regarding the impact of postprocessing contamination on consumer health risk. PRACTICAL APPLICATION: Water vapor (steam) at a high temperature can be used to sanitize the surface of fresh, whole cantaloupe melons in a continuous-feed manner. Both Listeria bacteria and spoilage organisms are markedly reduced from initial levels and survivor outgrowth severely restricted during subsequent refrigerated storage. This approach to microorganism control is likely most applicable in situations where rinds and flesh are to be separated immediately via further processing. PMID- 29488633 TI - Group III/IV muscle afferents play an independent role in arterial baroreflex resetting during exercise in humans: is it the end of the road? PMID- 29488632 TI - Inactivation of Escherichia Coli O157:H7 and Listeria Innocua by Benzoic Acid, Ethylenediaminetetraacetic Acid and Their Combination in Model Wash Water and Simulated Spinach Washing. AB - : An antimicrobial effect of benzoic acid (BA) and ethylenediaminetetraacetic acid (EDTA) was evaluated as a potential antimicrobial treatment against Escherichia coli O157:H7 and Listeria innocua. A 30 min exposure to the combination of 15 mM BA and 1 mM EDTA at 22 degrees C resulted in approximately 3 logarithmic reductions in stationary phase E. coli O157:H7. Logarithmic phase E. coli O157:H7 was more sensitive (P < 0.05) to the treatment and 1 mM EDTA alone caused more than 5 logarithmic reductions. L. innocua was also sensitive to a treatment with 15 mM BA alone, which induced 5 logarithmic reductions. By increasing the temperature of the solution containing 15 mM BA and 1 mM EDTA to 40 degrees C, more than 5 logarithmic reductions in stationary phase E. coli O157:H7 was observed after 5 min of treatment. However, the antimicrobial effect was attenuated (reaching less than 1 logarithmic reductions) at 4 degrees C. In addition, the combined BA and EDTA treatment retained its antimicrobial effect against E. coli O157:H7 for at least 6 cycles of treatment over 6 days at room temperature (22 degrees C). In a simulated spinach washing study, 15 mM BA and 1 mM EDTA together were able to prevent cross-contamination of E. coli O157:H7. The results highlight the potential use of combination of BA (15 mM) and EDTA (1 mM) to address microbial risk from E. coli O157:H7 and L. innocua in fresh produce industry. PRACTICAL APPLICATION: This study demonstrates the effectiveness of benzoic acid (BA) and EDTA mixture in inactivating bacteria in the water used for produce washing and reducing the incidence of cross-contamination during washing of fresh produce. Use of BA + EDTA mixture has significant benefits such as: (a) ability to be reused, (b) effectiveness in the presence of organic matter, and (c) reduced need of monitoring wash water conditions such as pH, concentration and organic matter. PMID- 29488634 TI - Analysis of growth and lipid production characteristics of Chlorella vulgaris in artificially constructed consortia with symbiotic bacteria. AB - The aim was to study the effect of artificially constructed consortia of microalgae-bacterial symbionts on growth and lipid production by Chlorella vulgaris (C. vulgaris), as well as the inter-relationship between microalgae and bacterial in a photoautotrophic system. The results showed that compared to an axenic culture of C. vulgaris, H1 co-culture system (axenic C. vulgaris Stenotrophomona smaltophilia) had the strongest effect on the C. vulgaris growth. The biomass, specific growth rate and maximum productivity of C. vulgaris were increased by 21.9, 20.4, and 18%, respectively. The bacteria in co-culture system had a significant effect on the accumulation of lipid and fatty acid components of C. vulgaris: the content of lipid was increased by 8.2-33.83%, and the components of the saturated fatty acids and oleic acids also had an obvious improvement. The results indicate that the microalgae-bacterial co-culture system can improve microalgal biomass and the quality of biodiesel. PMID- 29488636 TI - Adapted MS/MSALL Shotgun Lipidomics Approach for Analysis of Cardiolipin Molecular Species. AB - Cardiolipin (Ptd2 Gro) is a complex, doubly charged phospholipid located in the inner mitochondrial membrane where it plays an essential role in regulating bioenergetics. Abnormalities in Ptd2 Gro content or composition have been associated with mitochondrial dysfunction in a variety of disease states. Here, we report the development of an adapted high-resolution data-independent acquisition (DIA) MS/MSALL shotgun lipidomic method to enhance the accuracy and reproducibility of Ptd2 Gro molecular species quantitation from biological samples. Utilizing the doubly charged molecular ions and the isotopic pattern with negative mode electrospray ionization mass spectrometry (ESI-MS) using an adapted MS/MSALL approach, we profiled more than 150 individual Ptd2 Gro species, including monolysocardiolipin (MLPtd2 Gro). The method described in this study demonstrated high reproducibility, sensitivity, and throughput with a wide dynamic range. This high-resolution MS/MSALL shotgun lipidomics approach could be extended to screening aberrations of Ptd2 Gro metabolism involved in mitochondrial dysfunction in various pathological conditions and diseases. PMID- 29488635 TI - Stretch-induced Ca2+ independent ATP release in hippocampal astrocytes. AB - KEY POINTS: Similar to neurons, astrocytes actively participate in synaptic transmission via releasing gliotransmitters. The Ca2+ -dependent release of gliotransmitters includes glutamate and ATP. Following an 'on-cell-like' mechanical stimulus to a single astrocyte, Ca2+ independent single, large, non quantal, ATP release occurs. Astrocytic ATP release is inhibited by either selective antagonist treatment or genetic knockdown of P2X7 receptor channels. Our work suggests that ATP can be released from astrocytes via two independent pathways in hippocampal astrocytes; in addition to the known Ca2+ -dependent vesicular release, larger non-quantal ATP release depends on P2X7 channels following mechanical stretch. ABSTRACT: Astrocytic ATP release is essential for brain functions such as synaptic long-term potentiation for learning and memory. However, whether and how ATP is released via exocytosis remains hotly debated. All previous studies of non-vesicular ATP release have used indirect assays. By contrast, two recent studies report vesicular ATP release using more direct assays. In the present study, using patch clamped 'ATP-sniffer cells', we re investigated astrocytic ATP release at single-vesicle resolution in hippocampal astrocytes. Following an 'on-cell-like' mechanical stimulus of a single astrocyte, a Ca2+ independent single large non-quantal ATP release occurred, in contrast to the Ca2+ -dependent multiple small quantal ATP release in a chromaffin cell. The mechanical stimulation-induced ATP release from an astrocyte was inhibited by either exposure to a selective antagonist or genetic knockdown of P2X7 receptor channels. Functional P2X7 channels were expressed in astrocytes in hippocampal brain slices. Thus, in addition to small quantal ATP release, larger non-quantal ATP release depends on P2X7 channels in astrocytes. PMID- 29488637 TI - Human Liver Fatty Acid Binding Protein-1 T94A Variant, Nonalcohol Fatty Liver Disease, and Hepatic Endocannabinoid System. AB - Hepatic endocannabinoids (EC) and their major binding/"chaperone" protein (i.e., liver fatty acid binding protein-1 [FABP1]) are associated with development of nonalcoholic fatty liver (NAFLD) in animal models and humans. Since expression of the highly prevalent human FABP1 T94A variant induces serum lipid accumulation, it is important to determine its impact on hepatic lipid accumulation and the EC system. This issue was addressed in livers from human subjects expressing only wild-type (WT) FABP1 T94T (TT genotype) or T94A variant (TC or CC genotype). WT FABP1 males had lower total lipids (both neutral cholesteryl esters, triacylglycerols) and phospholipids than females. WT FABP1 males' lower lipids correlated with lower levels of the N-acylethanolamide DHEA and 2 monoacylglycerols (2-MAG) (2-OG, 2-PG). T94A expression in males increased the hepatic total lipids (triacylglycerol, cholesteryl ester), which is consistent with their higher level of CB1-potentiating 2-OG and lower antagonistic EPEA. In contrast, in females, T94A expression did not alter the total lipids, neutral lipids, or phospholipids, which is attributable to the higher cannabinoid receptor-1 (CB1) agonist arachidonoylethanolamide (AEA) and its CB1-potentiator OEA being largely offset by reduced potentiating 2-OG and increased antagonistic EPEA. Taken together, these findings indicate that T94A-induced alterations in the hepatic EC system contribute at least in part to the hepatic accumulation of lipids associated with NAFLD, especially in males. PMID- 29488639 TI - A New Year and a New Publishing Partnership With Wiley. PMID- 29488638 TI - New Insights into the Anti-Inflammatory and Antioxidant Properties of Nitrated Phospholipids. AB - Nitro-fatty acids (NO2 -FA) have been widely studied with regard to their identification, structural characterization, and biological actions. NO2 -FA could also be present endogenously esterified to phospholipids (PL), and NO2 -PL were already detected in cardiac mitochondria from diabetic rats and cardiomyoblasts subjected to starvation. However, the biological actions of NO2 PL have been overlooked. In this study, we evaluate the antioxidant and anti inflammatory potential of the nitrated 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphocholine (POPC) formed in vitro by incubation with NO2 BF4 , in a well recognized mimetic model of nitroxidative stress. Nitrated POPC showed anti radical ability to reduce both 2,2-diphenyl-1-picrylhydrazyl radical (DPPH* ) (IC20 = 225 +/- 4 MUg/mL; Trolox equivalent (TE) = 86 +/- 6 MUmol Trolox/g lipid) and 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid radical cation (ABTS*+ ) (IC50 = 124 +/- 2 MUg/mL; TE = 152 +/- 9 MUmol Trolox/g lipid). Also, higher lag times were achieved in oxygen radical absorbance capacity (ORAC) assay for nitrated POPC, indicating a faster reaction with oxygen-derived radicals (TE = 1.03 +/- 0.22 and TE = 1.30 +/- 0.16 mmol Trolox/g lipid for nonmodified and nitrated POPC, respectively). Nitrated POPC showed the ability to inhibit lipid oxidation induced by the hydroxyl radical generated under Fenton reaction conditions, monitored by electrospray ionization (ESI) mass spectrometry (MS) using phosphatidylcholine (PtdCho) liposomes as a model of cell membrane. Nitrated POPC showed anti-inflammatory potential, as assessed by the inhibition of inducible nitric oxide synthase (iNOS) expression in RAW 264.7 macrophages activated by the Toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS) in a well-described in vitro model of inflammation. Altogether, this study provides new clues regarding the antioxidant and anti-inflammatory potential of nitrated POPC, which should be explored in depth. PMID- 29488640 TI - Curcumin Attenuates Lipopolysaccharide-Induced Hepatic Lipid Metabolism Disorder by Modification of m6 A RNA Methylation in Piglets. AB - N6 -methyladenosine (m6 A) regulates gene expression and affects cellular metabolism. In this study, we checked whether the regulation of lipid metabolism by curcumin is associated with m6 A RNA methylation. We investigated the effects of dietary curcumin supplementation on lipopolysaccharide (LPS)-induced liver injury and lipid metabolism disorder, and on m6 A RNA methylation in weaned piglets. A total of 24 Duroc * Large White * Landrace piglets were randomly assigned to control, LPS, and CurL (LPS challenge and 200 mg/kg dietary curcumin) groups (n = 8/group). The results showed that curcumin reduced the increase in relative liver weight as well as the concentrations of aspartate aminotransferase and lactate dehydrogenase induced by LPS injection in the plasma and liver of weaning piglets (p < 0.05). The amounts of total cholesterol and triacylglycerols were decreased by curcumin compared to that by the LPS injection (p < 0.05). Additionally, curcumin reduced the expression of Bcl-2 and Bax mRNA, whereas it increased the p53 mRNA level in the liver (p < 0.05). Curcumin inhibited the enhancement of SREBP-1c and SCD-1 mRNA levels induced by LPS in the liver. Notably, dietary curcumin affected the expression of METTL3, METTL14, ALKBH5, FTO, and YTHDF2 mRNA, and increased the abundance of m6 A in the liver of piglets. In conclusion, the protective effect of curcumin in LPS-induced liver injury and hepatic lipid metabolism disruption might be due to the increase in m6 A RNA methylation. Our study provides mechanistic insights into the effect of curcumin in protecting against hepatic injury during inflammation and metabolic diseases. PMID- 29488641 TI - Short-Chain Fatty Acids Enhance the Lipid Accumulation of 3T3-L1 Cells by Modulating the Expression of Enzymes of Fatty Acid Metabolism. AB - Short-chain fatty acids (SCFA) such as acetic acid, propionic acid, and butyric acid are produced by fermentation by gut microbiota. In this paper, we investigate the effects of SCFA on 3T3-L1 cells and the underlying molecular mechanisms. The cells were treated with acetic acid, propionic acid, or butyric acid when cells were induced to differentiate into adipocytes. MTT assay was employed to detect the viability of 3T3-L1 cells. Oil Red O staining was used to visualize the lipid content in 3T3-L1 cells. A triglyceride assay kit was used to detect the triacylglycerol content in 3T3-L1 cells. qRT-PCR and Western blot were used to evaluate the expression of metabolic enzymes. MTT results showed that safe concentrations of acetic acid, propionic acid, and butyric acid were less than 6.4, 3.2, and 0.8 mM, respectively. Oil Red O staining and triacylglycerols detection results showed that treatment with acetic acid, propionic acid, and butyric acid accelerated the 3T3-L1 adipocyte differentiation. qRT-PCR and Western blot results showed that the expressions of lipoprotein lipase (LPL), adipocyte fatty acid binding protein 4 (FABP4), fatty acid transporter protein 4 (FATP4), and fatty acid synthase (FAS) were significantly increased by acetic acid, propionic acid, and butyric acid treatment during adipose differentiation (p < 0.05). In conclusion, SCFA promoted lipid accumulation by modulating the expression of enzymes of fatty acid metabolism. PMID- 29488642 TI - Small but wise: Common marmosets (Callithrix jacchus) use acoustic signals as cues to avoid interactions with blonde capuchin monkeys (Sapajus flavius). AB - Vocalizations are often used by animals to communicate and mediate social interactions. Animals may benefit from eavesdropping on calls from other species to avoid predation and thus increase their chances of survival. Here we use both observational and experimental evidence to investigate eavesdropping and how acoustic signals may mediate interactions between two sympatric and endemic primate species (common marmosets and blonde capuchin monkeys) in a fragment of Atlantic Rainforest in Northeastern Brazil. We observed 22 natural vocal encounters between the study species, but no evident visual or physical contact over the study period. These two species seem to use the same area throughout the day, but at different times. We broadcasted alarm and long distance calls to and from both species as well as two control stimuli (i.e., forest background noise and a loud call from an Amazonian primate) in our playback experiments. Common marmosets showed anti-predator behavior (i.e., vigilance and flight) when exposed to blonde capuchin calls both naturally and experimentally. However, blonde capuchin monkeys showed no anti-predator behavior in response to common marmoset calls. Blonde capuchins uttered long distance calls and looked in the direction of the speaker following exposure to their own long distance call, whereas they fled when exposed to their own alarm calls. Both blonde capuchin monkeys and common marmosets showed fear behaviors in response to the loud call from a primate species unknown to them, and showed no apparent response to the forest background noise. Common marmoset responses to blonde capuchin calls suggests that the latter is a potential predator. Furthermore, common marmosets appear to be eavesdropping on calls from blonde capuchin monkeys to avoid potentially costly encounters with them. PMID- 29488643 TI - Like an ace up the sleeve: an interview study of nurses' experiences of the contact with relatives in a somatic emergency ward. AB - Research indicates that active involvement of patients' relatives generally has a positive impact on patients' hospitalisation, including patient safety. Campaigns urge relatives to ask questions in relation to nursing care and treatment to enhance patient safety and to increase involvement of both patient and relatives. The question is how nurses experience relatives who ask questions. The aim of this study was to explore how nurses experienced contact with patients' relatives during admissions to a somatic emergency ward including nurses' experience of relatives asking questions related to nursing care and treatment. Six nurses were interviewed. The participants gave written consent to participate after receiving both oral and written information about the study. Data were analysed using combined theory and data-driven qualitative content analysis. The findings formed three main themes: (i) relatives' involvement as a means to efficiency during hospitalisation, (ii) relatives welcomed on the terms of the system and (iii) tension between high ideals and frustrating realities. The six interviews answered the research questions. However, more interviews could have broadened the study and contributed with further details. The nurses experienced relatives as an important resource - 'an ace up the sleeve', while reality seemed to challenge the relationship between nurses and relatives. The study contributes to discussions before development and implementation of specific initiatives aiming at increasing involvement of relatives of patients in a somatic emergency ward. PMID- 29488644 TI - Case series of aortic arch disease treated with branched stent-grafts. AB - BACKGROUND: Surgical repair of aortic arch pathology is complex and associated with significant morbidity and mortality. Alternative approaches have been developed to reduce these risks, including the use of thoracic stent-grafts with fenestrations or in combination with bypass procedures to maintain supra-aortic trunk blood flow. Branched stent-grafts are a novel approach to treat aortic arch pathology. METHODS: Consecutive patients with aortic arch disease presenting to a single university hospital vascular centre were considered for branched stent graft repair (October 2010 to January 2017). Patients were assessed in a multidisciplinary setting including a cardiologist, cardiac surgeon and vascular surgeon. All patients were considered prohibitively high risk for standard open surgical repair. The study used reporting standards for endovascular aortic repair and PROCESS (Preferred Reporting of Case Series in Surgery) guidelines. RESULTS: Some 30 patients (25 men) underwent attempted branch stent-graft repair. Mean age was 68 (range 37-84) years. Eighteen patients had chronic aortic dissection, 11 patients had an aneurysm and one had a penetrating ulcer. Fourteen patients had disease in aortic arch zone 0, six in zone 1 and ten in zone 2. Twenty-five patients had undergone previous aortic surgery and 24 required surgical revascularization of the left subclavian artery. Technical success was achieved in 27 of 30 patients. Four patients had an endoleak (type Ia, 1; type II, 3). The in-hospital mortality rate was three of 30. Mean length of follow-up was 12.0 (range 1.0-67.8) months, during which time 12 patients required an aortic-related reintervention. CONCLUSION: Repair of aortic arch pathology using branched stent-grafting appears feasible. Before widespread adoption of this technology, further studies are required to standardize the technique and identify which patients are most likely to benefit. PMID- 29488646 TI - Risk of malignancy in resected pancreatic mucinous cystic neoplasms. AB - BACKGROUND: Pancreatic mucinous cystic neoplasms (MCNs) are rare mucin-producing cystic tumours defined by the presence of ovarian-type stroma. MCNs have a malignant potential and thus surgery is frequently performed. The aim of this cohort study was to define better the criteria for surgical resection in patients with MCN. METHODS: This multicentre retrospective study included all resected MCNs between 2003 and 2015 in participating centres. Lesions without ovarian-type stroma were excluded. Patient characteristics, preoperative findings, histopathology findings and follow-up data were recorded. RESULTS: The study included 211 patients; their median age was 53 (range 18-82) years, and 202 (95.7 per cent) were women. Median preoperative tumour size was 55 (range 12-230) mm. Thirty-four of the 211 (16.1 per cent) were malignant, and high-grade dysplasia (HGD) was found in a further 13 (6.2 per cent). One-third of MCNs in men were associated with invasive cancer, compared with 15.3 per cent in women. Five cases of malignant transformation occurred in MCNs smaller than 4 cm. All cases of malignancy or HGD were associated with symptoms or features of concern on preoperative cross-sectional imaging. In multivariable analysis, raised carbohydrate antigen 19-9 (odds ratio (OR) 10.54, 95 per cent c.i. 2.85 to 218.23; P < 0.001), tumour size (OR 4.23, 3.02 to 11.03; P = 0.001), mural nodules (OR 3.55, 1.31 to 20.55; P = 0.002) and weight loss (OR 3.40, 2.34 to 12.34; P = 0.034) were independent factors predictive of malignant transformation. CONCLUSIONS: Small indeterminate MCNs with no symptoms or features of concern may safely be observed as they have a low risk of malignant transformation. PMID- 29488647 TI - Cellular and molecular imaging of the arteries in the age of precision medicine. PMID- 29488648 TI - Hybrid and total endovascular repair of the aortic arch. AB - BACKGROUND: Recent advances in endovascular technology have enabled minimally invasive repair of the aortic arch, with specifically designed stent-grafts. This article reviews hybrid and total endovascular repair in the management of aortic arch pathology. METHODS: Studies relating to aortic arch management were identified using MEDLINE and Embase, focusing on endovascular repair. RESULTS: Hybrid arch repair is associated with an early mortality rate of some 12 per cent, and carries significant risk of stroke (up to 15 per cent), paraplegia (up to 6 per cent), retrograde dissection (up to 6.5 per cent) and proximal endoleak (6 per cent). Despite patients being of overall higher perioperative risk, hybrid repair has morbidity and early mortality rates comparable to those of open arch replacement. However, rates of freedom from aortic rupture or reintervention are significantly lower in the longer term, owing to the incidence of endoleak. Total endovascular arch repair may be achieved by the use of parallel stents or in situ fenestration in the emergency setting, or use of custom-made devices (scalloped, fenestrated or branched stent-grafts) in the elective setting. Reports of these relatively novel technologies suggest acceptable short-term outcomes, but long term data are still awaited. CONCLUSION: Repair of aortic arch pathology presents a formidable challenge for endovascular technology. Open aortic arch repair remains the standard in younger, fitter patients, but endovascular technology and experience continue to evolve with encouraging early outcomes and expanding indications. PMID- 29488649 TI - Optimized wound closure using a biomechanical abdominal model. AB - BACKGROUND: Suturing techniques for midline abdominal wall incisions vary between surgeons. This study uses a biomechanical abdominal model to assess tissue stretch using different suturing techniques for midline laparotomy closure. METHODS: Deformation tests were performed on the linea alba of 48 porcine abdominal walls. Each pattern was tested three times at pressures ranging from 0 to 20 kPa using different continuous suturing techniques and a control. RESULTS: There was a sevenfold improvement when the best performing bite separation and bite width ([5, 16] mm) was compared with the most poorly performing combination ([15, 4] mm). The traditional bite and width separation ([10, 10] mm) and the recently proposed combination ([5, 5] mm) may not be optimal, and substantial improvements in surgical outcome may be achieved by changing to a [5,16]-mm combination. CONCLUSION: These findings suggest using a small bite separation (5 mm) and large bite width (16 mm) during abdominal wound closure may be optimal. Surgical relevance Suturing techniques for midline abdominal wall incisions vary between surgeons. This experimental study suggests substantial potential for improved tissue apposition by changing the suturing approach from the traditional clinical recommendation of 10 mm for both bite separation and bite width to a bite separation of 5 mm and a bite width of 16 mm. These findings support recent European Hernia Society guidelines and the recent randomized STITCH (Suture Techniques to Reduce the Incidence of The inCisional Hernia) trial, which found that small separations are more effective than large separations, but suggest that they should be combined with large bite depths. PMID- 29488651 TI - Adverse outcome pathway networks I: Development and applications. AB - Based on the results of a Horizon Scanning exercise sponsored by the Society of Environmental Toxicology and Chemistry that focused on advancing the adverse outcome pathway (AOP) framework, the development of guidance related to AOP network development was identified as a critical need. This not only included questions focusing directly on AOP networks, but also on related topics such as mixture toxicity assessment and the implementation of feedback loops within the AOP framework. A set of two articles has been developed to begin exploring these concepts. In the present article (part I), we consider the derivation of AOP networks in the context of how it differs from the development of individual AOPs. We then propose the use of filters and layers to tailor AOP networks to suit the needs of a given research question or application. We briefly introduce a number of analytical approaches that may be used to characterize the structure of AOP networks. These analytical concepts are further described in a dedicated, complementary article (part II). Finally, we present a number of case studies that illustrate concepts underlying the development, analysis, and application of AOP networks. The concepts described in the present article and in its companion article (which focuses on AOP network analytics) are intended to serve as a starting point for further development of the AOP network concept, and also to catalyze AOP network development and application by the different stakeholder communities. Environ Toxicol Chem 2018;37:1723-1733. (c) 2018 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC. PMID- 29488652 TI - Quantum Crystallography: Current Developments and Future Perspectives. AB - Crystallography and quantum mechanics have always been tightly connected because reliable quantum mechanical models are needed to determine crystal structures. Due to this natural synergy, nowadays accurate distributions of electrons in space can be obtained from diffraction and scattering experiments. In the original definition of quantum crystallography (QCr) given by Massa, Karle and Huang, direct extraction of wavefunctions or density matrices from measured intensities of reflections or, conversely, ad hoc quantum mechanical calculations to enhance the accuracy of the crystallographic refinement are implicated. Nevertheless, many other active and emerging research areas involving quantum mechanics and scattering experiments are not covered by the original definition although they enable to observe and explain quantum phenomena as accurately and successfully as the original strategies. Therefore, we give an overview over current research that is related to a broader notion of QCr, and discuss options how QCr can evolve to become a complete and independent domain of natural sciences. The goal of this paper is to initiate discussions around QCr, but not to find a final definition of the field. PMID- 29488653 TI - Boosting Luminescence of Planar-Fluorophore-Tagged Metal-Organic Cages Via Weak Supramolecular Interactions. AB - A variety of planar organic fluorophores (R=phenyl, naphthalenyl, pyrenyl) and luminescence promotors (X=Cl, Br, I) were equipped, respectively, on the alternatively arranged vertices of cubic ZnII -imidazolate cages through orthogonal subcomponent self-assembly. It was found that supramolecular interactions, especially weak C-H???X interactions, play a key role in activating an efficient radiative pathway, coupled with reduced nonradiative decay rate through metal coordination, therefore significantly boosting the emission quantum yields of the system. This finding provides a strategy that utilizes molecular geometry and supramolecular interactions to modulate the emission efficiency of luminescent cage-based materials. PMID- 29488654 TI - Analysis of cost of component replacement versus entire device replacement during artificial urinary sphincter revision surgery. AB - AIM: To identify the costs of replacing an entire malfunctioning AUS device versus an individual component at the time of device malfunction. METHODS: Decision analysis was performed by analyzing the costs associated with revising a malfunctioning artificial urinary sphincter using one of two techniques: either individual or entire device replacement. Costs were determined by including actual institutional costs. Model assumptions were based on a summary of published literature and were created based on a time horizon of 0-5 years since the original, primary AUS was placed, and models were created for malfunction of each individual component. Sensitivity analysis was done adjusting for costs of the device and failure rates. RESULTS: Total costs to replace an individual component were $8330 for the pump, $7611 for the cuff, and $5599 for the balloon, while entire device replacement cost $15 069. Over a 5-year time horizon the cost per patient for replacement of a balloon, pump, or cuff were $14 407, $17 491, and $15 212, respectively, versus $18 001 if the entire device was replaced. To be less costly to replace the entire device, balloon, pump, and cuff failure rates would need to be >55%, >25%, or >37.5% during the first 2 years after placement. CONCLUSION: In the event of failure of the artificial urinary sphincter, cost analysis demonstrates that removal and replacement of the entire device is more expensive than replacement of a malfunctioning component at any point up to 5 years after initial AUS placement. PMID- 29488655 TI - Clinical outcomes of non-surgical management of detrusor leak point pressures above 40 cm water in adults with congenital neurogenic bladder. AB - AIMS: Neurogenic bladders (NGB) with detrusor leak point pressures >40 cm H2 O (dLPP > 40) have been associated with deterioration of renal function in children with myelomeningocele. For these children, careful pressure management preserves renal function. However, similar evidence is lacking in adult congenital urology (ACU) patients with NGB. We describe renal functional outcomes of non-surgical management of adults with dLPP > 40 or premicturition detrusor pressure (PMDP) >40 cm H2 O, consisting of close follow-up with urodynamic studies (UDS) and renal ultrasound (RUS), paired with adjustments to clean intermittent catheterization (CIC) frequency, anticholinergics, and addition of onabotulinumtoxinA toxin (BTX) injection. METHODS: We retrospectively reviewed the UDS of all patients at an ACU clinic from 2011 to 2016. Patients with dLPP/PMDP > 40 cm who elected for non-surgical management were included. We describe their management and renal functional outcomes. RESULTS: A total of 33/42 patients with dLPP/PMDP > 40 elected for non-surgical management. 28/33 (85%) were successfully managed without bladder augmentation or urinary diversion at follow-up of nearly 3 years. The median index dLPP/PMDP was 49 cm H2 O (IQR 44, 63) and final dLPP/PMDP was 28 (IQR 18, 43). There was a significant decrease in dLPP/PMDP and increase in bladder compliance between index and final UDS (P < 0.001). No patients advanced their CKD stage and 6/10 with baseline hydronephrosis had improvement or resolution of hydronephrosis with non-surgical management. CONCLUSIONS: A non-surgical protocol for ACU patients with NGB and dLPP/PMDP > 40, utilizing CIC, anticholinergics, and BTX is safe and effective when coupled with coordinated care and close follow-up. PMID- 29488656 TI - Tuning Mg(II) Selectivity: Comparative Analysis of the Photophysical Properties of Four Fluorescent Probes with an Alkynyl-Naphthalene Fluorophore. AB - Four alkynyl-1-naphthyl fluorophores have been synthesised with tri- or pentadentate ligating groups suited to the binding of magnesium. Their photophysical and binding properties for magnesium, calcium and zinc ions have been assessed using absorption, emission and excitation spectroscopy. Each compound has a pKa value between 6.2 and 5.1 and exhibits no significant pH response around pH 7.2. Enhanced selectivity for Mg2+ over Ca2+ was observed with a pentadentate phosphinate substituted system, compared to its carboxylate analogue, due to a 10-fold lowering of affinity for the Ca2+ ion. In each case, the overall dissociation constants for Mg2+ fall in the low mm range. PMID- 29488657 TI - Roux-en-Y gastric bypass is an effective bridge to kidney transplantation: Results from a single center. AB - Body mass index (BMI) > 35-40 kg/m2 is often a contraindication, while Roux-en-Y gastric bypass (RYGB) is performed to enable kidney transplantation. This single center retrospective study evaluated pre- and post-transplant outcomes of 31 morbidly obese patients with end-stage renal disease having RYGB before kidney transplantation between July 2009 and June 2014. Fourteen RYGB patients were subsequently transplanted. Nineteen recipients not having GB with a BMI >= 36 kg/m2 at transplantation were used as historical controls. Mean BMI (+/-SE) before RYGB was 43.5 +/- 0.7 kg/m2 (range: 35.4-50.5 kg/m2 ); 87.1% (27/31) achieved a BMI < 35 kg/m2 . The percentage having improved diabetes/hypertension control was 29.0% (9/31); 25.8% (8/31) had complications (mostly minor) after RYGB. Among transplanted patients, blacks/Hispanics comprised 78.6% (11/14) and 84.2% (16/19) of RYGB and controls; 57.1% (8/14) and 63.2% (12/19) had a (mostly long-standing) pretransplant history of diabetes. While biopsy-proven acute rejection (BPAR) occurred significantly higher among RYGB vs control patients (6/14 vs 3/19, P = .03), patients developing T-cell BPAR were also significantly more likely to have a tacrolimus (TAC) trough level < 4.0 ng/mL within 3 weeks of T-cell BPAR (P = .0007). In Cox's model, the impact of having a TAC level < 4.0 ng/mg remained significant (P = .007) while the effect of RYGB was no longer significant (P = .13). Infections, graft, and patient survival were not significantly different. Despite obvious effectiveness in achieving weight loss, RYGB will need more careful post-transplant monitoring given the observed higher BPAR rate. PMID- 29488658 TI - Protective action of bone marrow mesenchymal stem cells in immune tolerance of allogeneic heart transplantation by regulating CD45RB+ dendritic cells. AB - BACKGROUND: Bone marrow-derived mesenchymal stem cells (BMSCs) could exert a potent immunosuppressive effect and therefore may have a therapeutic potential in T-cell-dependent pathologies. We aimed to examine the effects of BMSCs on immune tolerance of allogeneic heart transplantation and the involvement of CD45RB+ dendritic cells (DCs). METHODS: Bone marrow-derived DCs and BMSCs were co cultured, with CD45RB expression on the surface of DCs measured by flow cytometry. qRT-PCR and Western blotting were used to detect mRNA and protein levels. Cytometric bead array was performed to determine the serum level of IL 10. Survival time of transplanted heart and expression of CD4+ , CD8+ , IL-2, IL 4, IL-10, IFN-gamma were determined. Immunofluorescence assay was employed to determine intensity of C3d and C4d. RESULTS: DCs co-cultured with BMSCs showed increased CD45RB and Foxp3 levels. CD45RB+ DCs co-cultured with T-cells CD4+ displayed increased T-cell CD4+ Foxp3 ratio and IL-10 than DCs. Both of them extended survival time of transplanted heart, decreased histopathological classification and score, intensity of C3d, C4d, proportion of CD4+ , expression levels of IL-2 and IFN-gamma, and increased the CD4+ Foxp3 ratio and levels of IL 4 and IL-10. CD45RB+ DCs achieved better protective effects than DCs. CONCLUSION: BMSCs increased the expression of CD45RB in the bone marrow-derived DCs, thereby strengthening immunosuppression capacity of T cells and immune tolerance of allogeneic heart transplantation. PMID- 29488659 TI - Electron- and Hydride-Reservoir Organometallics as Precursors of Catalytically Efficient Transition Metal Nanoparticles in Water. AB - Nanoparticles (NPs) are actively investigated for their efficient use in catalysis, but their means of synthesis is a key factor influencing their catalytic properties owing to surface coverage with byproducts. Here, neutral electron- and hydride-rich late transition metal organometallics are compared for the synthesis of late transition metal NPs in the presence of poly(vinylpirolidone) (PVP). In particular, the effect of electron-reservoir donors, hydride-reservoir donors, and electron-rich dimers yielding NPs electrostatically stabilized by cationic organometallics are compared in terms of NP size and catalytic efficiency. The catalytic reactions scrutinized with excellent results include 4-nitrophenol reduction to 4-aminophenol by NaBH4 for the AuNPs and PdNPs, and Suzuki-Miyaura reactions for the PdNPs. The nature of the reductant has more influence on the NP size in the case of AuNPs than PdNPs, and the best NP catalysts are obtained with hydride-reservoir complexes as reductants. The less bulky hydride donors are superior, with the complex [CoCp(n4 -C5 H6 )] (Cp=n5 -C5 H5 ) giving the NPs with the best catalyst efficiencies for both reactions. Protection of the NP cores by the organometallic sandwich salt is found to be the key to catalytic efficiency. PMID- 29488660 TI - Carbon Nanotubes Encapsulated in Coiled-Coil Peptide Barrels. AB - Specific functionalization of 1D nanomaterials such as near infrared (nIR) fluorescent single-walled carbon nanotubes (SWCNTs) is essential for colloidal stability and tailoring of their interactions with the environment. Here, we show that de novo designed alpha-helical coiled-coil peptide barrels (alphaHBs) with appropriate pores encapsulate and solubilize SWCNTs. In contrast, barrels without or with narrow pores showed a much smaller efficiency. Absorption/fluorescence spectroscopy and atomic force microscopy indicate that the SWCNTs are incorporated into the alphaHB's pore. The resulting hybrid SWCNT@alphaHBs display periodic surface coverage with a 40 nm pitch and remain fluorescent in the nIR. This approach presents a novel concept to encapsulate, discriminate and functionalize SWCNTs non-covalently with peptides and holds great promise for future applications in bioimaging or drug delivery. PMID- 29488661 TI - The pregnancy hormone human chorionic gonadotropin differentially regulates plasmacytoid and myeloid blood dendritic cell subsets. AB - PROBLEM: Dendritic cells (DCs) are critically involved in fetal fate due to their capability to promote either immunity or tolerance to foreign fetal antigens. Our study aimed to investigate whether the hormone human chorionic gonadotropin (hCG) affects different peripheral blood DC (PBDCs) subsets. METHOD OF STUDY: PBDCs were isolated from non-pregnant women, stimulated and co-cultured with hCG producing JEG-3 or non hCG-producing SWAN-71 trophoblasts as well as with two different hCG preparations. The total and mature number of each PBDC subset were assessed. Additionally, the secretion of cytokines was determined in the presence or absence of hCG. RESULTS: We found no significant effects; neither from trophoblasts nor from the hCG preparations on PBDC cellularity. JEG-3 cells and both hCG preparations significantly hampered the maturation of MDC1, while SWAN 71 cells did not provoke any changes on this regard. We observed an altered ability of PBDCs to secrete cytokines in the presence of both trophoblasts and both hCG preparations. CONCLUSION: Our data propose that hCG is not a key regulator of cellular alterations within PBDCs. However, under inflammatory conditions, hCG seems to keep the delicate balance between PDC and MDC and retains a tolerogenic MDC1 profile and this may contribute to tolerance maintenance. PMID- 29488664 TI - Accurate pH Sensing using Hyperpolarized 129 Xe NMR Spectroscopy. AB - In the search for powerful non-invasive methods for pH measurement, NMR usually suffers from biases, especially for heterogeneous samples or tissues. In this Communication, using the signals of hyperpolarized 129 Xe encapsulated in a pair of water-soluble cryptophanes, we show that a differential pH measurement can be achieved, free from most of these biases, by monitoring the difference between their chemical shifts. PMID- 29488662 TI - Mycobacteriophage Fruitloop gp52 inactivates Wag31 (DivIVA) to prevent heterotypic superinfection. AB - Bacteriophages engage in complex dynamic interactions with their bacterial hosts and with each other. Bacteria have numerous mechanisms to resist phage infection, and phages must co-evolve by overcoming bacterial resistance or by choosing an alternative host. Phages also compete with each other, both during lysogeny by prophage-mediated defense against viral attack and by superinfection exclusion during lytic replication. Phages are enormously diverse genetically and are replete with small genes of unknown function, many of which are not required for lytic growth, but which may modulate these bacteria-phage and phage-phage dynamics. Using cellular toxicity of phage gene overexpression as an assay, we identified the 93-residue protein gp52 encoded by Cluster F mycobacteriophage Fruitloop. The toxicity of Fruitloop gp52 overexpression results from interaction with and inactivation of Wag31 (DivIVA), an essential Mycobacterium smegmatis protein organizing cell wall biosynthesis at the growing cellular poles. Fruitloop gene 52 is expressed early in lytic growth and is not required for normal Fruitloop lytic replication but interferes with Subcluster B2 phages such as Hedgerow and Rosebush. We conclude that Hedgerow and Rosebush are Wag31 dependent phages and that Fruitloop gp52 confers heterotypic superinfection exclusion by inactivating Wag31. PMID- 29488663 TI - Impact of Florida's prescription drug monitoring program and pill mill law on high-risk patients: A comparative interrupted time series analysis. AB - PURPOSE: We quantified the effects of Florida's prescription drug monitoring program and pill mill law on high-risk patients. METHODS: We used QuintilesIMS LRx Lifelink data to identify patients receiving prescription opioids in Florida (intervention state, N: 1.13 million) and Georgia (control state, N: 0.54 million). The preintervention, intervention, and postintervention periods were July 2010 to June 2011, July 2011 to September 2011, and October 2011 to September 2012. We identified 3 types of high-risk patients: (1) concomitant users: patients with concomitant use of benzodiazepines and opioids; (2) chronic users: long-term, high-dose, opioid users; and (3) opioid shoppers: patients receiving opioids from multiple sources. We compared changes in opioid prescriptions between Florida and Georgia before and after policy implementation among high-risk/low-risk patients. Our monthly measures included (1) average morphine milligram equivalent per transaction, (2) total opioid volume across all prescriptions, (3) average days supplied per transaction, and (4) total number of opioid prescriptions dispensed. RESULTS: Among opioid-receiving individuals in Florida, 6.62% were concomitant users, 1.96% were chronic users, and 0.46% were opioid shoppers. Following policy implementation, Florida's high-risk patients experienced relative reductions in morphine milligram equivalent (opioid shoppers: -1.08 mg/month, 95% confidence interval [CI] -1.62 to -0.54), total opioid volume (chronic users: -4.58 kg/month, CI -5.41 to -3.76), and number of dispensed opioid prescriptions (concomitant users: -640 prescriptions/month, CI 950 to -340). Low-risk patients generally did not experience statistically significantly relative reductions. CONCLUSIONS: Compared with Georgia, Florida's prescription drug monitoring program and pill mill law were associated with large relative reductions in prescription opioid utilization among high-risk patients. PMID- 29488665 TI - Activation of Acetonitrile with (C2 F5 )3 PF2 and Amines. AB - Acetonitrile is deprotonated by a combination of the strong Lewis acid (C2 F5 )3 PF2 and triethylamine. The resulting cyanomethyl function is bound to the phosphorus moiety, affording the highly stable salt [HNEt3 ][P(C2 F5 )3 F2 (CH2 CN)]. Salt metathesis reactions furnished the corresponding [Cu(MeCN)2 ]+ and [Ag(MeCN)]+ derivatives in which the CH2 CN substituent of the anion [P(C2 F5 )3 F2 (CH2 CN)]- coordinates to the metal. An investigation of the gas separation capability of the silver salt [Ag(MeCN)][P(C2 F5 )3 F2 (CH2 CN)] shows an uptake of 1.7 equivalents of isobutene from a propane/isobutene mixture. The reaction of (C2 F5 )3 PF2 with acetonitrile and diethylamine furnishes [P(C2 F5 )3 F2 {NHC(CH3 )NEt2 }]-a phosphate featuring an amidine ligand which formally results from hydroamination of acetonitrile by HNEt2 . Exchange of HNEt2 with the primary amines H2 NPh and H2 NBu leads to comparable amidine salts that exhibit a solvent dependent conformational isomerism. PMID- 29488666 TI - Seasonal, interannual and decadal drivers of tree and grass productivity in an Australian tropical savanna. AB - Tree-grass savannas are a widespread biome and are highly valued for their ecosystem services. There is a need to understand the long-term dynamics and meteorological drivers of both tree and grass productivity separately in order to successfully manage savannas in the future. This study investigated the interannual variability (IAV) of tree and grass gross primary productivity (GPP) by combining a long-term (15 year) eddy covariance flux record and model estimates of tree and grass GPP inferred from satellite remote sensing. On a seasonal basis, the primary drivers of tree and grass GPP were solar radiation in the wet season and soil moisture in the dry season. On an interannual basis, soil water availability had a positive effect on tree GPP and a negative effect on grass GPP. No linear trend in the tree-grass GPP ratio was observed over the 15 year study period. However, the tree-grass GPP ratio was correlated with the modes of climate variability, namely the Southern Oscillation Index. This study has provided insight into the long-term contributions of trees and grasses to savanna productivity, along with their respective meteorological determinants of IAV. PMID- 29488667 TI - A revised model for the control of fatty acid synthesis by master regulator Spo0A in Bacillus subtilis. AB - In starving Bacillus subtilis cells, the accDA operon encoding two subunits of the essential acetyl-CoA carboxylase (ACC) has been proposed to be tightly regulated by direct binding of the master regulator Spo0A to a cis element (0A box) in the promoter region. When the 0A box is mutated, biofilm formation and sporulation have been reported to be impaired. Here, we present evidence that two 0A boxes, one previously known (0A-1) and another newly discovered (0A-2) in the accDA promoter region are positively and negatively regulated by Spo0A~P respectively. Cells with mutated 0A boxes experience slight delays in sporulation, but eventually sporulate with high efficiency. In contrast, cells harboring a single mutated 0A-2 box are deficient for biofilm formation, while cells harboring either a mutated 0A-1 box or both mutated 0A boxes form biofilms. We further show that the essential ACC enzyme localizes on or near the cell membrane by directly observing a functional GFP fusion to one of the enzyme's subunits. Collectively, we propose a revised model in which accDA is primarily transcribed by a major sigmaA -RNA polymerase, while Spo0A~P plays an additional role in the fine-tuning of accDA expression upon starvation to support proper biofilm formation and sporulation. PMID- 29488668 TI - Evaluation of chromogenic factor IX assays by automated protocols. AB - INTRODUCTION: Chromogenic substrate assays (CSA) to measure Factor IX (FIX) have recently become commercially available. However, information on their performance characteristics and use in diagnostic haemostasis laboratories remains limited. AIM: To evaluate the Hyphen Biomed (Hyphen) and Rossix FIX CSAs on fully automated coagulation analysers and compare them to the FIX one-stage assay (OSA). This study was conducted in a tertiary referral haemostasis laboratory associated with a haemophilia treatment centre. METHODS: Automated CSA protocols were adapted to the Sysmex CS2500 (CS2500) and Diagnostica Stago STA-R (STA-R) analysers. Samples assayed were from healthy volunteers, haemophilia B patients and FIX deficient plasma spiked with either plasma derived, recombinant or extended half-life FIX products. RESULTS: Reference intervals for Hyphen and Rossix assays were 73 IU/dL to 164 IU/dL and 73 IU/dL to 168 IU/dL, respectively, on the CS2500 analyser; and 84 IU/dL to 165 IU/dL for the Rossix assay on the STA R. Repeatability across all method/analyser combinations resulted in CVs ranging from 0.8% to 5.4%. Between run reproducibility gave CVs <6.7% for all method/analyser combinations. In spiked samples, FIX recoveries were mostly within an acceptable limit of 100 +/- 25% for BeneFIX(r) , Rixubis(r) and Alprolix(r) with some differences between CSAs. CONCLUSION: Both commercial factor FIX CSA kits can be adapted for Stago and Sysmex automated coagulation analysers. Reagent cost and workflow practices will need to be considered. These assays are potentially more consistent than OSA in measurement of replacement FIX products in haemophilia B patients. PMID- 29488669 TI - Prospects for research in haemophilia with real-world data-An analysis of German registry and secondary data. AB - INTRODUCTION AND AIM: Open questions in haemophilia, such as effectiveness of innovative therapies, clinical and patient-reported outcomes (PROs), epidemiology and cost, await answers. The aim was to identify data attributes required and investigate the availability, appropriateness and accessibility of real-world data (RWD) from German registries and secondary databases to answer the aforementioned questions. METHODS: Systematic searches were conducted in BIOSIS, EMBASE and MEDLINE to identify non-commercial secondary healthcare databases and registries of patients with haemophilia (PWH). Inclusion of German patients, type of patients, data elements-stratified by use in epidemiology, safety, outcomes and health economics research-and accessibility were investigated by desk research. RESULTS: Screening of 676 hits, identification of four registries [national PWH (DHR), national/international paediatric (GEPARD, PEDNET), international safety monitoring (EUHASS)] and seven national secondary databases. Access was limited to participants in three registries and to employees in one secondary database. One registry asks for PROs. Limitations of secondary databases originate from the ICD-coding system (missing: severity of haemophilia, presence of inhibitory antibodies), data protection laws and need to monitor reliability. CONCLUSION: Rigorous observational analysis of German haemophilia RWD shows that there is potential to supplement current knowledge and begin to address selected policy goals. To improve the value of existing RWD, the following efforts are proposed: ethical, legal and methodological discussions on data linkage across different sources, formulation of transparent governance rules for data access, redefinition of the ICD-coding, standardized collection of outcome data and implementation of incentives for treatment centres to improve data collection. PMID- 29488670 TI - A rare case of late development of inhibitor in haemophilia B with a complex course, and review of the literature. PMID- 29488671 TI - Age-related changes in the social behavior of tufted capuchin monkeys. AB - The effects of aging on the social behavior of nonhuman primates is little understood, especially in New World monkeys. We studied the members of a colony of tufted capuchin monkeys (Sapajus sp.) in order to evaluate age related changes in their social behavior. We conducted observations on 25 subjects aged 4-36 years, living in captive social groups. We found that affiliative interactions (grooming and proximity) decreased with age, and that grooming was increasingly directed to a single preferred partner. Manipulation of objects in the environment also decreased with age, while locomotion and aggression showed no change. Overall, these results concur with previous findings on both human and nonhuman primates, and cast doubts on interpretations of age associated changes in human social behavior that rely of uniquely human advanced cognitive capacities. PMID- 29488672 TI - Iron-Catalyzed Chemoselective Reduction of alpha,beta-Unsaturated Ketones. AB - An iron-catalyzed chemo- and diastereoselective reduction of alpha,beta unsaturated ketones into the corresponding saturated ketones in mild reaction conditions is reported herein. DFT calculations and experimental work underline that transfer hydride reduction is a more facile process than hydrogenation, unveiling the fundamental role of the base. PMID- 29488673 TI - Mechanism-Based Condition Screening for Sustainable Catalysis in Single-Electron Steps by Cyclic Voltammetry. AB - A cyclic-voltammetry-based screening method for Cp2 TiX-catalyzed reactions is introduced. Our mechanism-based approach enables the study of the influence of various additives on the electrochemically generated active catalyst Cp2 TiX, which is in equilibrium with catalytically inactive [Cp2 TiX2 ]- . Thioureas and ureas are most efficient in the generation of Cp2 TiX in THF. Knowing the precise position of the equilibrium between Cp2 TiX and [Cp2 TiX2 ]- allowed us to identify reaction conditions for the bulk electrolysis of Cp2 TiX2 complexes and for Cp2 TiX-catayzed radical arylations without having to carry out the reactions. Our time- and resource-efficient approach is of general interest for the design of catalytic reactions that proceed in single-electron steps. PMID- 29488674 TI - Relationship of nurses' intrapersonal characteristics with work performance and caring behaviors: A cross-sectional study. AB - This study aimed to describe intrapersonal characteristics (professional values, personality, empathy, and job involvement), work performance as perceived by nurses, and caring behaviors as perceived by patients, and to examine the relationships among these variables. A cross-sectional design was employed. A sample was recruited of 218 nurses and 116 patients in four private hospitals and four public hospitals. Data were collected using self-report measures. Data analysis included descriptive statistics, exploratory and confirmatory factor analyses, hierarchical linear modelling, correlations, and structural equation modeling. Nurses perceived their work performance to be of high quality. Among the intrapersonal characteristics, nurses had high scores for professional values, and moderately high scores for personality, empathy and job involvement. Patients perceived nurses' caring behaviors as moderately high. Professional values of nurses were the only selected intrapersonal characteristic with a statistically significant positive relationship, of practical importance, with work performance as perceived by nurses and with caring behaviors as perceived by patients at ward level. Managers can enhance nurses' work performance and caring behaviors through provision of in-service training that focuses on development of professional values. PMID- 29488675 TI - Analyte-Triggered DNA-Probe Release from a Triplex Molecular Beacon for Nanopore Sensing. AB - A new nanopore sensing strategy based on triplex molecular beacon was developed for the detection of specific DNA or multivalent proteins. The sensor is composed of a triplex-forming molecular beacon and a stem-forming DNA component that is modified with a host-guest complex. Upon target DNA hybridizing with the molecular beacon loop or multivalent proteins binding to the recognition elements on the stem, the DNA probe is released and produces highly characteristic current signals when translocated through alpha-hemolysin. The frequency of current signatures can be used to quantify the concentrations of the target molecules. This sensing approach provides a simple, quick, and modular tool for the detection of specific macromolecules with high sensitivity and excellent selectivity. It may find useful applications in point-of-care diagnostics with a portable nanopore kit in the future. PMID- 29488676 TI - Treatment with insulin is associated with worse outcome in patients with chronic heart failure and diabetes. AB - AIMS: Up to one-third of patients with diabetes mellitus and heart failure (HF) are treated with insulin. As insulin causes sodium retention and hypoglycaemia, its use might be associated with worse outcomes. METHODS AND RESULTS: We examined two datasets: 24 012 patients with HF from four large randomized trials and an administrative database of 4 million individuals, 103 857 of whom with HF. In the former, survival was examined using Cox proportional hazards models adjusted for baseline variables and separately for propensity scores. Fine-Gray competing risk regression models were used to assess the risk of hospitalization for HF. For the latter, a case-control nested within a population-based cohort study was conducted with propensity score. Prevalence of diabetes mellitus at study entry ranged from 25.5% to 29.5% across trials. Insulin alone or in combination with oral hypoglycaemic drugs was prescribed at randomization to 24.4% to 34.5% of the patients with diabetes. The rates of death from any cause and hospitalization for HF were higher in patients with vs. without diabetes, and highest of all in patients prescribed insulin [propensity score pooled hazard ratio for all-cause mortality 1.27 (1.16-1.38), for HF hospitalization 1.23 (1.13-1.33)]. In the administrative registry, insulin prescription was associated with a higher risk of all-cause death [odds ratio (OR) 2.02, 95% confidence interval (CI) 1.87-2.19] and rehospitalization for HF (OR 1.42, 95% CI 1.32-1.53). CONCLUSIONS: Whether insulin use is associated with poor outcomes in HF should be investigated further with controlled trials, as should the possibility that there may be safer alternative glucose-lowering treatments for patients with HF and type 2 diabetes mellitus. PMID- 29488677 TI - Pyrrolidines and Piperidines by Ligand-Enabled Aza-Heck Cyclizations and Cascades of N-(Pentafluorobenzoyloxy)carbamates. AB - Ligand-enabled aza-Heck cyclizations and cascades of N (pentafluorobenzoyloxy)carbamates are described. These studies encompass the first examples of efficient non-biased 6-exo aza-Heck cyclizations. The methodology provides direct and flexible access to carbamate protected pyrrolidines and piperidines. PMID- 29488678 TI - Monotherapy with a novel intervenolin derivative, AS-1934, is an effective treatment for Helicobacter pylori infection. AB - BACKGROUND: Helicobacter pylori (H. pylori) infection causes various gastrointestinal diseases including gastric cancer. Hence, eradication of this infection could prevent these diseases. The most popular first-line treatment protocol to eradicate H. pylori is termed "triple therapy" and consists of a proton pump inhibitor (PPI), clarithromycin, and amoxicillin or metronidazole. However, the antibiotics used to treat H. pylori infection are hindered by the antibiotics-resistant bacteria and by their antimicrobial activity against intestinal bacteria, leading to side effects. Therefore, an alternative treatment with fewer adverse side effects is urgently required to improve the overall eradication rate of H. pylori. OBJECTIVE: The aim of this study was to assess the effectiveness and mechanism of action of an antitumor agent, intervenolin, and its derivatives as an agent for the treatment of H. pylori infection. RESULTS: We demonstrate that intervenolin, and its derivatives showed selective anti-H. pylori activity, including antibiotic-resistant strains, without any effect on intestinal bacteria. We showed that dihydroorotate dehydrogenase, a key enzyme for de novo pyrimidine biosynthesis, is a target and treatment with intervenolin or its derivatives decreased the protein and mRNA levels of H. pylori urease, which protects H. pylori against acidic conditions in the stomach. Using a mouse model of H. pylori infection, oral monotherapy with the intervenolin derivative AS-1934 had a stronger anti-H. pylori effect than the triple therapy commonly used worldwide to eradicate H. pylori. CONCLUSION: AS-1934 has potential advantages over current treatment options for H. pylori infection. PMID- 29488679 TI - A case of cytokeratin-negative sarcomatoid malignant pleural mesothelioma. PMID- 29488680 TI - Bizarre and scary ECG in yew leaves poisoning: Report of successful treatment. AB - Yew leaves poisoning is a rare life-threatening intoxication, whose diagnosis can be difficult. Initial symptoms are nausea, vomiting, abdominal pain, dizziness, tachycardia, muscle weakness, confusion, beginning within 1 hr from ingestion and followed by bradycardia, ventricular arrhythmias, ventricular fibrillation, severe hypotension, and death. Taxine-derived alkaloids are responsible for the toxicity of the yew leaves, blocking sodium and calcium channels, and causing conduction abnormalities. Because of lack of a specific antidote and limited efficacy of common antiarrhythmic drugs, prompt diagnosis, detoxification measures, and immediate hemodynamic support (also with transvenous cardiac stimulation) are essential. PMID- 29488681 TI - Functional characterization of recombinant snake venom rhodocytin: rhodocytin mutant blocks CLEC-2/podoplanin-dependent platelet aggregation and lung metastasis. AB - : Essentials We generated recombinant rhodocytin that could aggregate platelets via CLEC-2. Recombinant wild-type rhodocytin formed heterooctamer with four alpha and beta-subunits. Asp 4 in alpha-subunit of rhodocytin was required for binding to CLEC-2. Inhibitory mutant of rhodocytin blocked podoplanin-dependent hematogenous metastasis. SUMMARY: Background Rhodocytin, a disulfide-linked heterodimeric C-type lectin from Calloselasma rhodostoma consisting of alpha subunits and beta-subunits, induces platelet aggregation through C-type lectin like receptor 2 (CLEC-2). CLEC-2 is a physiological binding partner of podoplanin (PDPN), which is expressed on some tumor cell types, and is involved in tumor cell-induced platelet aggregation and tumor metastasis. Thus, modified rhodocytin may be a possible source of anti-CLEC-2 drugs for both antiplatelet and antimetastasis therapy. However, its molecular function has not been well characterized, because of the lack of recombinant rhodocytin that induces platelet aggregation. Objective To produce recombinant rhodocytin, in order to verify its function with mutagenesis, and to develop an anti-CLEC-2 drug based on the findings. Methods We used Chinese hamster ovary cells to express recombinant rhodocytin (wild-type [WT] and mutant), which was analyzed for induction/inhibition of platelet aggregation with light transmission aggregometry, the formation of multimers with blue native PAGE, and binding to CLEC-2 with flow cytometry. Finally, we investigated whether mutant rhodocytin could suppress PDPN-induced metastasis in an experimental lung metastasis mouse model. Results Functional WT] rhodocytin (alphaWTbetaWT) was obtained by coexpression of both subunits. Asp4 in alpha-subunits of rhodocytin was required for CLEC-2 binding. alphaWTbetaWT formed a heterooctamer similarly to native rhodocytin. Moreover, an inhibitory mutant of rhodocytin (alphaWTbetaK53A/R56A), forming a heterotetramer, bound to CLEC-2 without inducing platelet aggregation, and blocked CLEC-2-PDPN interaction-dependent platelet aggregation and experimental lung metastasis. Conclusion These findings provide molecular characterization information on rhodocytin, and suggest that mutant rhodocytin could be used as a therapeutic agent to target CLEC-2. PMID- 29488682 TI - Platelet packing density is an independent regulator of the hemostatic response to injury. AB - : Essentials Platelet packing density in a hemostatic plug limits molecular movement to diffusion. A diffusion-dependent steep thrombin gradient forms radiating outwards from the injury site. Clot retraction affects the steepness of the gradient by increasing platelet packing density. Together, these effects promote hemostatic plug core formation and inhibit unnecessary growth. SUMMARY: Background Hemostasis studies performed in vivo have shown that hemostatic plugs formed after penetrating injuries are characterized by a core of highly activated, densely packed platelets near the injury site, covered by a shell of less activated and loosely packed platelets. Thrombin production occurs near the injury site, further activating platelets and starting the process of platelet mass retraction. Tightening of interplatelet gaps may then prevent the escape and exchange of solutes. Objectives To reconstruct the hemostatic plug macro- and micro-architecture and examine how platelet mass contraction regulates solute transport and solute concentration in the gaps between platelets. Methods Our approach consisted of three parts. First, platelet aggregates formed in vitro under flow were analyzed using scanning electron microscopy to extract data on porosity and gap size distribution. Second, a three-dimensional (3-D) model was constructed with features matching the platelet aggregates formed in vitro. Finally, the 3-D model was integrated with volume and morphology measurements of hemostatic plugs formed in vivo to determine how solutes move within the platelet plug microenvironment. Results The results show that the hemostatic mass is characterized by extremely narrow gaps, porosity values even smaller than previously estimated and stagnant plasma velocity. Importantly, the concentration of a chemical species released within the platelet mass increases as the gaps between platelets shrink. Conclusions Platelet mass retraction provides a physical mechanism to establish steep chemical concentration gradients that determine the extent of platelet activation and account for the core-and-shell architecture observed in vivo. PMID- 29488683 TI - Sensitive and selective detection of Cu(II) ion: A new effective 1,8 naphthalimide-based fluorescence 'turn off' sensor. AB - The present study reports the development of a new 1,8-naphthalimide-based fluorescent sensor V for monitoring Cu(II) ions. The sensor exhibited pH independence over a wide pH range 2.52-9.58, and indicated its possible use for monitoring Cu(II) ions in a competitive pH medium. The sensor also showed high selectivity and sensitivity towards the Cu(II) ions over other competitive metal ions in DMSO-HEPES buffer (v/v, 1:1; pH 7.4) with a fluorescence 'turn off' mode of 79.79% observed. A Job plot indicated the formation of a 1:1 binding mode of the sensor with Cu(II) ions. The association constant and detection limit were 1.14 * 106 M-1 and 4.67 * 10-8 M, respectively. The fluorescence spectrum of the sensor was quenched due to the powerful paramagnetic nature of the Cu(II) ions. Potential application of this sensor was also demonstrated when determining Cu(II) ion levels in two different water samples. PMID- 29488684 TI - Re: Cassava flour slurry as a low-cost alternative to commercially available gel for obstetrical ultrasound: a blinded non-inferiority trial comparison of image quality. PMID- 29488685 TI - Modified Synthesis Strategies for the Stabilization of low n Tin O2n-1 Magneli Phases. AB - Titanium reduced oxides TiO2-x occupy, since long time, a prominent place on the landscape of binary metal oxides because of their intriguing ability to form extended defects that affect both the formation of new superlattices and different electronic behaviours. Related to these features, a wide range of practical applications has been achieved. Moved by the conviction of the great potential of understanding the influence of the reactivity, compositional variations and size effects on their functional properties, the aim of this personal account is the optimization of a recently developed strategy for the stabilization of low n Tin O2n-1 terms. In particular, we will focus on the Ti4 O7 composition as well as the incorporation of transition metals, like Mn, in order to deal with new reduced Magneli phases. PMID- 29488686 TI - Molecular identification of four novel cytochrome P450 genes related to the development of resistance of Spodoptera exigua (Lepidoptera: Noctuidae) to chlorantraniliprole. AB - BACKGROUND: The beet armyworm, Spodoptera exigua, is an omnivorous insect that damages a variety of crops worldwide. Chlorantraniliprole is a new diamide insecticide that acts on the ryanodine receptors in insects. The aim of this study was to explore key genes related to the development of chlorantraniliprole resistance in S. exigua. RESULTS: Transcriptomes were compared between beet armyworms from a susceptible laboratory strain (Sus-Lab) and Sus-Lab screened with LC25 sublethal doses of chlorantraniliprole for six generations (SE-Sel). Ten of 11 cytochrome P450 genes with upregulated expression verified by quantitative reverse transcription polymerase chain reaction (qRT-PCR) in SE-Sel strains were detected in SE-PZ16 and SE-ZY16, two extremely resistant field populations. In addition, expression of four new cytochrome P450 genes, CYP9A21v1, CYP9A21v2, CYP9A21v3 and CYP9A21v4, was shown in the two field populations and was significantly higher in the SE-Sel strain than in the Sus-Lab strain (P < 0.05). Their full-length and protein tertiary structures were also cloned and predicted. The function of CYP9A21v3 was analysed by RNA interference, and the relative expression of CYP9A21v3 in the SE-ZY16 population after feeding on dsRNA was lower than in the control group. Moreover, mortality rates in insects treated at the LC50 of chlorantraniliprole after dsRNA feeding were significantly higher than in the control group 24 h after treatment (P < 0.05). CONCLUSION: Overexpression of CYP9A21v3 may be a primary factor in the development of chlorantraniliprole resistance in beet armyworms. (c) 2018 Society of Chemical Industry. PMID- 29488687 TI - Re: Clinical practice patterns on the use of magnesium sulphate for treatment of pre-eclampsia and eclampsia: a multi-country survey: Magnesium sulphate regimens for eclampsia: should we adopt same 'gold standard' for all women? PMID- 29488688 TI - Does mating disruption of Planococcus ficus and Lobesia botrana affect the diversity, abundance and composition of natural enemies in Israeli vineyards? AB - BACKGROUND: Mating disruption (MD) employs high doses of a pest's synthetic sex pheromone in agricultural plots, to interfere with its reproduction. MD is assumed to have few behavioral effects on non-target arthropods, because sex pheromones are highly species-specific and non-toxic. Nevertheless, some natural enemies use their host's sex pheromones as foraging cues, and thus may be attracted to MD plots. To investigate this hypothesis, we compared parasitoid and spider assemblages in paired plots in five Israeli vineyards during 2015. One plot was MD-treated against two key pests, Lobesia botrana (Denis & Schiffermuller) and Planococcus ficus (Signoret). Both plots were insecticide treated as needed. Natural enemies were suction-sampled and collected from pheromone-baited monitoring traps. RESULTS: The total abundance, species diversity and species composition of most natural enemies were unaffected by MD. An important exception involved P. ficus' main parasitoid, Anagyrus sp. nr. pseudococci (Girault). Anagyrus sp. nr. pseudococci females were mainly captured in control plots, while male captures were low and not influenced by MD. Parasitized P. ficus occurred only in MD plots. CONCLUSION: Non-target effects of MD involved mostly A. sp. nr. pseudococci females and hardly affected other natural enemies. These findings support the use of MD as an environmentally friendly pest management strategy. (c) 2018 Society of Chemical Industry. PMID- 29488689 TI - Morphological changes in hair melanosomes by aging. AB - Various changes appear in hair by aging, and graying is the most remarkable one. Changes in melanocytes have been well studied as the cause; however, little is known about the change in melanosomes which have a role of carrying melanin pigments into hair shafts. Using pigmented hairs of Japanese females from their age of 4-75, I isolated melanosomes and observed them. As a result, I found a significant change in the morphology of hair melanosomes with age. They were ellipsoidal on the whole and there was no age dependence in the major axis, while the minor axis significantly increased and its frequency distribution broadened with age. The anticipated volume of the melanosome of the oldest person hairs was about twice larger than that of child hairs. This enlargement of melanosome seems to be a cause of the age-related color change in pigmented hairs from brown to black. PMID- 29488690 TI - Directed C-H Bond Oxidation of Bridged Cycloalkanes Catalyzed by Palladium(II) Acetate. AB - We have developed a synthesis of 1,2-substituted adamantane carboxylic acids and further bridged cycloalkanes (cage compounds) by palladium acetate-catalyzed C-H bond oxidation. Acetoxylation of cycloalkane framework was performed using picolylamide as a directing group. Modification of the substrate, ligand design and variation of reaction conditions enabled us to study the mechanism of acetoxylation of aliphatic compounds. Post-functionalization reactions and cleavage of the directing group were developed. For the first time the synthesis and characterization of a beta-C3 -tri-substituted adamantane derivatives was achieved. PMID- 29488691 TI - Sensitivity of ivacaftor to drug-drug interactions with rifampin, a cytochrome P450 3A4 inducer. AB - The CFTR potentiator ivacaftor is responsible for significant clinical improvements among a subset of patients with cystic fibrosis. Because it is a substrate of the cytochrome P450 system, specifically CYP3A4/5, ivacaftor is subject to significant drug-drug interactions, including due to commonly used antimicrobials such as rifampin. While the interaction of rifampin and ivacaftor has been examined in vitro, severe adverse events resulting from this interaction have not been reported in the literature. In this report, we describe the termination of steady, long-term improvement in a patient taking ivacaftor, resulting from the use of rifampin and precipitating a significant pulmonary exacerbation. PMID- 29488692 TI - One-pot Annulation for Biaryl-fused Monocarba-closo-dodecaborate through Aromatic B-H Bond Disconnection. AB - We have developed a one-pot annulation reaction of monocarba-closo-dodecaborate with cyclic diaryliodonium salts to afford biaryl-fused derivatives. Aryl functionalities are introduced at both the 1-carbon and unreactive ortho-boron vertices of the "sigma-aromatic" carborane cage without the need for pre functionalization. DFT calculations revealed that the palladium-catalyzed C-B bond-formation step in this process proceeds through a concerted metalation deprotonation (CMD)-type pathway for the B-H bond disconnection on the aromatic cage, though such bonds are generally regarded as hydridic. PMID- 29488693 TI - Spherical and Worm-Like Micelles from Fructose-Functionalized Polyether Block Copolymers. AB - This paper presents the synthesis and characterization of d-fructose modified poly(ethylene glycol) (Fru-PEG) and fructose modified poly(ethylene glycol)-block poly(ethyl hexyl glycidyl ether) (Fru-PEG-b-PEHG) that are both prepared by initiation with isopropyliden protected fructose, followed by deprotection of the sugar. The block copolymers are self-assembled into micelles, and are subsequently characterized by cryo-TEM and dynamic light scattering. The fluorescent dye Nile red is encapsulated as a model hydrophobic compound and fluorescent marker to perform initial uptake tests with breast cancer cells. The uptake of sugar and nonsugar decorated micelles is compared. PMID- 29488694 TI - The conformation of bovine serum albumin adsorbed to the surface of single all dielectric nanoparticles following light-induced heating. AB - Interaction between nanoparticles and biomolecules leads to the formation of biocompatible or bioadverse complexes. Despite the rapid development of nanotechnologies for biology and medicine, relatively little is known about the structure of such complexes. Here, we report on the changes in conformation of a blood protein (bovine serum albumin) adsorbed on the surface of single all dielectric nanoparticles (silicon and germanium) following light-induced heating to 640 K. This protein is considerably more resistant to heat when adsorbed on the nanoparticle than when in solution or in the solid state. Intriguingly, with germanium nanoparticles this heat resistance is more pronounced than with silicon. These observations will facilitate biocompatible usage of all-dielectric nanoparticles. PMID- 29488695 TI - When parasitoids deal with the spatial distribution of their hosts: consequences for both partners. AB - Insect parasitoids developing inside hosts face a true challenge: hosts are scattered in the field and their localization and selection require the use of complex and sometime confusing information. It was assumed for a long time that small-brained organisms like parasitoids have evolved simple and efficient behavioral mechanisms, leading them to be adapted to a given ecological situation, for example, the spatial distribution of hosts in the habitat. However, hosts are not static and their distribution may also vary through generations and within the life of parasitoid individuals. We investigated if and how parasitoids deal with such a spatial complexity in a mesocosm experiment. We used the Aphidius rhopalosiphi/Sitobion avenae parasitoid/host system to investigate if parasitoid females experiencing different host aggregation levels exhibit different foraging behaviors independently of the number of hosts in the environment. We showed that A. rhopalosiphi females exploited hosts more intensively both within and among patches at higher host aggregation levels. We discussed the adaptiveness of such behaviors in the light of evolution and biological control. PMID- 29488696 TI - HIV/HCV/HBV testing in the emergency department: a feasibility and seroprevalence study. AB - OBJECTIVES: The aims of this study were to to assess the feasibility of simultaneous testing for the blood-borne viruses (BBV), HIV, hepatitis C (HCV) and hepatitis B (HBV), in the Emergency Department (ED) and ascertain the seroprevalence for these three viruses in this setting. METHODS: A pilot BBV testing program was undertaken as part of routine clinical care in the ED. All ED attendees aged between 16 and 65 years old who were able to consent were tested over a 55 week period on an opt out basis. Patients with positive test results were linked to clinical services. Interventions aimed at improving testing rates were implemented and evaluated by quality improvement (QI) methodology. RESULTS: Of 25,520 age-eligible ED attendees, 6108 (24%) underwent BBV testing; an additional 1160 (4.5%) underwent a standalone HIV test (total of 7268 (28%) individuals).There were 83/7268 (1.1%) non-negative (ie reactive or equivocal) results for HIV and 103/6108 (1.7%) and 32/6108 (0.52%) for anti-HCV IgG and HBsAg, respectively. Of these, 12 (0.17%), 16 (0.26%) and 8 (0.13%) were new reactive tests for HIV, HCV and HBV, respectively, which were able to be confirmed on a second test. Specific QI interventions led to temporary increases in testing rates. CONCLUSIONS: An opt out BBV testing program in the ED is feasible and effective at finding new cases. However, the testing rate was low at 24%. Although QI interventions led to some improvement in testing rates, further studies are required to identify ways to achieve sustained increases in testing in this setting. PMID- 29488697 TI - Monitoring anonymous HIV testing in Estonia from 2005 to 2015. AB - OBJECTIVES: In Estonia, a network of anonymous and free of charge HIV testing sites has been operating since 1988. Services are provided by health care organizations and financed by the National Institute for Health Development from the state budget. The objective of this analysis was to assess anonymous HIV testing in Estonia from 2005 to 2015. METHODS: We used data collected from the National Institute for Health Development's annual reports, Health Board and Estonian Health Insurance Fund. RESULTS: In Estonia, more than 200 000 HIV-tests are performed annually, and of these approximately 5-6% are within anonymous HIV testing sites. The percentage tested with rapid tests in anonymous testing sites has increased from 15% in 2010 to 53% in 2015. Furthermore, up to 65% of all newly diagnosed HIV-cases have been detected in these sites. The proportion of HIV-positive tests has decreased from 3.8% to 0.5% in anonymous testing sites and from 0.3% to 0.1% in general health care. Simultaneously, the cost of detecting one new HIV case has increased almost six times. CONCLUSIONS: This analysis reveals that anonymous HIV testing services are well accepted by the general population as well as vulnerable populations. The positivity rate among those tested in anonymous testing sites remains higher than among all people tested, showing that the sites reach more of those who are at higher risk of HIV. In the light of decreasing positivity rate, more attention should be paid to people with higher HIV risk and increasing access to testing in community based settings. PMID- 29488698 TI - HIV testing for key populations in Europe: A decade of technological innovation and patient empowerment complement the role of health care professionals. AB - OBJECTIVES: With persisting high numbers of new HIV diagnoses in Europe, HIV testing remains an important aspect of HIV prevention. The traditional centralized and medicalized HIV testing approach has been complemented with newly developed and evaluated non-traditional approaches. Two important factors guided this process: technological innovation and empowerment of the patient. METHODS: We present a matrix to develop an HIV testing approach, and elaborate on three commonly used ones: community based testing, self-testing, and self-sampling. Despite non-traditional HIV testing approaches, barriers for testing remain. A potential disadvantage for users is the risk for false-reactive test results. As users receive an orientation test result, a reactive result should be confirmed. Another issue is the window phase, which is longer for some orientation tests compared to a traditional, laboratory-based test. RESULTS: Future implementation of non-traditional HIV testing approaches will depend on legal frameworks throughout Europe. Community testing centers may additionally improve empowerment of key populations by expanding their portfolio to testing and treatment for sexually transmitted infections. Community engagement and ownership may imply a shrinking role for health care providers, but they remain crucial actors for personalized information, counselling and referral to specialized HIV-care for many people. CONCLUSIONS: A highly effective HIV testing strategy to reduce undiagnosed people living with HIV in Europe is needed. Any approach, chosen according to the principles outlined in this paper, should reach the right people, diagnose them in the most accurate way, and optimize linkage to care. PMID- 29488699 TI - Knowledge, actual and potential use of HIV self-sampling testing kits among MSM recruited in eight European countries. AB - AIM: To describe the knowledge as well as current and potential use of self sampling kits among men who have sex with men (MSM) and to analyse their preferred biological sample and result communication method. METHODS: We analyse data of MSM of HIV negative or unknown serostatus from an online survey conducted in eight countries (Belgium, Denmark, Germany, Greece, Portugal, Romania, Slovenia and Spain) between April and December 2016. It was advertised mainly in gay dating websites. We conduct a descriptive analysis of the main characteristics of the participants, and present data on indicators of knowledge, use and potential use of HIV self-sampling as well as their preferences regarding blood or saliva sample and face or non-face-to-face result communication by country of residence. RESULTS: A total of 8.226 participants of HIV negative or unknown serostatus were included in the analysis. Overall, 25.5% of participants knew about self-sampling (range: 18.8-47.2%) and 1.1% had used it in the past (range: 0.3-8.9%). Potential use was high, with 66.6% of all participants reporting that they would have already used it if available in the past (range: 62.1-82.1%). Most (78.6%) reported that they would prefer using a blood-based kit, and receiving the result of the test through a non-face-to-face-method (70.8%), even in the case of receiving a reactive result. CONCLUSION: The high potential use reported by MSM recruited in eight different European countries suggests that self-sampling kits are a highly acceptable testing methodology that could contribute to the promotion of HIV testing in this population. PMID- 29488700 TI - Monitoring HIV-indicator condition guided HIV testing in Estonia. AB - OBJECTIVES: The aim of the study was to assess indicator condition (IC) guided HIV testing in Estonia from 2012-2015. METHODS: We used Estonian Health Insurance Fund (EHIF) data. EHIF is the core purchaser of health care services in Estonia, covering health care costs for insured people (94% of the total population). After health care services' provision, the provider sends an invoice to EHIF, which includes patient information (e.g. age, gender, diagnoses based on ICD-10) and services provided (e.g. what tests were performed). RESULTS: Among the ICs analysed, the highest proportion of patients tested was among those presenting with infectious mononucleosis-like illness (27-33% of patients) and viral hepatitis (28-32%), the lowest proportion of patients tested was among those presenting with herpes zoster (4-5%) and pneumonia (4-8%). Women were tested somewhat less than men, especially in cases of sexually transmitted infections (9 13% and 18-21%, respectively). CONCLUSIONS: Our data shows that IC-guided HIV testing rates are low in Estonia. Therefore, it is critical to follow Estonian HIV testing guidelines, which recommend IC-guided testing. In general, health insurance data can be used to monitor IC-guided HIV testing. PMID- 29488701 TI - The COBATEST network: monitoring and evaluation of HIV community-based practices in Europe, 2014-2016. AB - OBJECTIVE: The objective of this paper is to describe the data collected by the CBVCT services from the Community-based testing (COBATEST) network, from 2014 to 2016, in order to provide an insight into community-based voluntary counselling and testing (CBVCT) services' testing activity in Europe. METHODS: A descriptive analysis of HIV testing activity in CBVCT services that are using the COBATEST tools was performed for the period 2014-2016. RESULTS: During the study period, a total of 30 329 HIV tests were performed on 27 934 individuals, of which 1.8% were reactive. Of these reactive tests, 75.8% had a confirmatory test, 92.2% of those were confirmed as positive, and 90.38% of the confirmed positives were linked to care. The total number of tests performed over the study period increased 19.31%. The proportion of confirmatory tests increased from 63.0% to 90.0% and proportion linked to care increased from 84.1% to 93.8%. Most of the tested individuals were men (70.6%), aged between 21 and 35 years (58.5%) and non foreign born (68.1%). A high proportion of individuals tested were men who have sex with men (MSM; 42.2%). The percentage of reactive screening tests was particularly high among transgender people (8.37%) and among male sex workers (6.38%). Repeat testers had a higher percentage of reactive tests (2.02%) than those tested for first time (1.1%). CONCLUSIONS: These results prove the feasibility of collecting standardized data from CBVCT services in different countries across Europe and demonstrate the usefulness of such data. PMID- 29488702 TI - Factors associated with delayed linkage to care following HIV diagnosis in the WHO European Region. AB - OBJECTIVES: To describe linkage to HIV care following diagnosis in Europe and to identify factors associated with delayed linkage. METHODS: We analysed data of adults (aged >= 15 years) diagnosed with HIV from 2010 to 2014 in 31 European countries. Linkage to care was calculated using the time between HIV diagnosis and first CD4 count. Linkage was considered delayed if the CD4 count was taken more than 3 months after diagnosis. Logistic regression was used to determine factors for delayed linkage. RESULTS: Of the 120 129 adults diagnosed from 2010 to 2014, 4560 were previously diagnosed elsewhere, 808 died within 3 months of diagnosis and 54 731 people were missing CD4 count and/or date information. Among the 60 030 people included, linkage to care within 3 months was 96%. A lower bound (LB) for this was 55%, when those missing CD4 data were assumed not to be linked. Prompt linkage varied significantly by region [Western: 97% (LB: 65%); Central: 90% (LB: 65%); Eastern: 91% (LB: 11%)] and risk group. In multivariable analysis, delayed linkage to care was associated with: acquiring HIV through injecting drug use/heterosexual contact, being diagnosed in Central/Eastern Europe and having a first CD4 count > 200 cells/MUL. People of older age at diagnosis and those diagnosed after 2011 were more likely to be linked promptly. Associations differed by region. CONCLUSIONS: Among those with CD4 data available, linkage to care is prompt. However, HIV surveillance must be strengthened and data quality improved, particularly in Eastern Europe. Our findings highlight disparities in care access and significant differences between regions. PMID- 29488703 TI - Role of pretest counseling sessions on increasing subjective knowledge about HIV and hepatitis transmission among the beneficiaries of a free of charge, voluntary counseling and testing program in Constanta, Romania. AB - OBJECTIVES: To describe the characteristics of clients who enrolled into of an opt-in, HIV, HBV & HCV Voluntary Counseling and Testing Program in Dobrogea Region, Romania (VCT) and to identify the utility of the pre-test counseling sessions in increasing subjective perception regarding transmission knowledge for the clients attending the VCT program. METHODS: Cross sectional data collection, between August 2015 and September 2016. Sociodemographic and behavioral information were collected for the clients who enrolled at two Baylor centers. Counselors were trained regarding the delivery of standardized information during the session, to reduce variation. After the pre-test session clients evaluated the subjective level of knowledge (SK) increase regarding viral transmission. RESULTS: 3065 clients were screened at the two centers and completed the SK increase assessment after the pre-test session. About 9% of all persons tested had reactive results to any of the infections in the context of high exposure risks for 62% and low hepatitis B vaccination rates (8%). 78% of attendees perceived that their knowledge regarding HIV and viral hepatitis transmission increasing with more than 60% as the result of the pretest counselling; more information was gained about hepatitis transmission compared with HIV. CONCLUSION: Cumulative prevalence in Dobrogea community is high. The NGO-run VCT program is helping the healthcare system to efficiently screen for undiagnosed HIV and hepatitis cases. Pre-test counselling is directly contributing to increasing SK among attendees. Routine HIV and hepatitis integrated pre-test counseling should be considered as a good-practice even in settings where it is not compulsory by law. PMID- 29488704 TI - Factors associated with HCV test uptake in heroin users entering substitution treatment in Greece. AB - OBJECTIVES: People who inject drugs (PWID) represent the main risk group for hepatitis C virus (HCV) infection in most middle and high-income countries. Testing PWID is considered as an important prevention measure. Identification of PWID characteristics associated with HCV testing may contribute to strategies targeting the containment of the HCV and HIV epidemics in Greece. METHODS: Anonymous behavioural data from 2747 heroin users were collected upon entry in 38 opioid substitution treatment (OST) clinics in Greece during the period 2013 2015. HCV test uptake was the dependent variable while covariates included sociodemographic and addiction-related variables, mostly derived from the EMCDDA treatment demand indicator protocol. RESULTS: Among 2299 cases with complete data on HCV testing, 83.5% reported any HCV testing uptake, with 61.2% reporting a recent test (< 12 months). In the multivariate analyses, any previous HCV testing uptake was associated with age >= 25 years, past drug treatment attempt, injecting or sniffing the primary substance, injection history >= 5 years, and syringe sharing earlier than the past 12 months. Past HCV test uptake was higher among those reporting full-time employment and 2-4 years injecting histories, and lower among residents of Athens. Recent testing was positively associated with female gender and polysubstance use. CONCLUSION: Any previous HCV testing uptake is high among PWID entering OST in Greece and is associated with older age, longer injecting histories and past drug-related treatment attempts. Efforts to prevent and mitigate the ongoing HCV test epidemic among PWID in Greece should combine treatment with scaling up of screening, targeting especially those younger than 25 years and at the beginning of their hazardous use. PMID- 29488705 TI - Key findings on legal and regulatory barriers to HIV testing and access to care across Europe. AB - OBJECTIVE: The aim of this work within OptTEST by HiE has been to demonstrate the role of legal and regulatory barriers in hindering access to HIV testing, treatment and care across Europe and to produce tools to help dismantle them. METHODS: An online survey to assess country-specific data on legal and regulatory barriers distributed widely across the WHO Europe region. Literature reviews conducted in January-October 2015 in English, in November 2015 in Russian, and updated in April 2017. Semi-structured interviews were conducted with 25 key actors within the HIV field to feed into case studies and tip sheets on how to dismantle legal and regulatory barriers. RESULTS: More than 160 individuals and organisations from 49 countries across the WHO European region provided responses which were analysed and cross checked with other data sources and a searchable database produced (legalbarriers.peoplewithhiveurope.org). The conducted literature reviews yielded 88 papers and reports which identify legal and regulatory barriers to key populations' access to HV testing and care. Based on the interviews with key actors, ranging from PLHIV activists to government officials, on lessons-learned, a series of tip sheets and ten case studies were written-up intended to inform and inspire the HIV community to address and overcome existing barriers (opttest.eu/Tools). CONCLUSION: While some of the barriers identified may require major changes to wider health systems, or long term legal reform, many are open to a simple change in regulations or custom and practice. We have the tools. Why can't we finish the job? PMID- 29488706 TI - BCN Checkpoint: same-day confirmation of reactive HIV rapid test with Point Of Care HIV-RNA accelerates linkage to care and reduces anxiety. AB - BACKGROUND: The introduction in 2006 of the rapid HIV test by BCN Checkpoint in a non-clinical setting has been a successful step forwards in the uptake of testing. Nevertheless, HIV serostatus should be reported as HIV positive only when a reactive result has been tested again using a different assay (WHO guidelines 2015). The standard confirmation test has been the Western Blot (WB) test. However confirmation results take around 7 days to come back. AIMS: This study explores the possibility of Point of Care PCR testing for a same-day confirmation. MATERIALS AND METHODS: Between March 2015 and September 2016 a POC PCR test (Xpert(r) HIV-1 Qual) was performed in parallel to the Western Blot test after a reactive HIV rapid test (Alere DetermineTM HIV-1/2 Ag/Ab Combo and AlereTM HIV Combo). HIV confirmed positive cases received emotional support by peers, were informed and prepared for treatment initiation and rapidly linked to HIV clinic. RESULTS: During the study period 11 455 tests were performed to 7163 clients. A total of 249 reactive rapid HIV tests were found. For analysis a total of 33 cases were excluded due to the lack of PCR and/or WB test. Results of comparison of the 216 cases showed 194 concordant positive confirmations and 14 concordant negative results. In three cases PCR was positive and WB negative. In five cases PCR was negative and WB positive. CONCLUSION: The POC PCR assay is easy to use and feasible in a community-based center. Reducing time for confirmation to 90 min has been possible in 91.2% (197/216) of cases with positive PCR result. In cases of a negative PCR result an additional test (WB, Elisa or PCR quantitative) was needed to distinguish false positive results (6.5%) from viral load results below level of detection (2.3%). Clients expressed satisfaction with same-day confirmation and less anxiety. PMID- 29488708 TI - Monitoring response to hepatitis B and C in EU/EEA: testing policies, availability of data on care cascade and chronic viral hepatitis-related mortality - results from two surveys (2016). AB - OBJECTIVES: The World Health Organization (WHO) developed a European Regional Action Plan (EAP) to fast-track action towards the goal of eliminating viral hepatitis. Robust monitoring is essential to assess national programme performance. The purpose of this study was to assess the availability of selected monitoring data sources in European Union/European Economic Area (EU/EEA) Member States (MS). METHODS: Availability of data sources at EU/EEA level was assessed using two surveys distributed to 31 EU/EEA MS in 2016. The two surveys covered (A) availability of policy documents on testing; testing practices and monitoring; monitoring of diagnosis and treatment initiation, and; (B) availability of data on mortality attributable to chronic viral hepatitis. RESULTS: Just over two-thirds of EU/EEA MS responded to the surveys. 86% (18/21) reported national testing guidance covering HBV, and 81% (17/21) covering HCV; while 33% (7/21) and 38% (8/21) of countries, respectively, monitored the number of tests performed. 71% (15/21) of countries monitored the number of chronic HBV cases diagnosed and 33% (7/21) the number of people treated. Corresponding figures for HCV were 48% (10/21) and 57% (12/21). 27% (6/22) of countries reported availability of data on mortality attributable to chronic viral hepatitis. CONCLUSIONS: The results of this study suggest that sources of information in EU/EEA Member States to monitor the progress towards the EAP milestones and targets related to viral hepatitis diagnosis, cascade of care and attributable mortality are limited. Our analysis should raise awareness among EU/EEA policy makers and stimulate higher prioritisation of efforts to improve the monitoring of national viral hepatitis programmes. PMID- 29488709 TI - [Medical imaging in tumor precision medicine: opportunities and challenges]. AB - Tumor precision medicine is an emerging approach for tumor diagnosis, treatment and prevention, which takes account of individual variability of environment, lifestyle and genetic information. Tumor precision medicine is built up on the medical imaging innovations developed during the past decades, including the new hardware, new imaging agents, standardized protocols, image analysis and multimodal imaging fusion technology. Also the development of automated and reproducible analysis algorithm has extracted large amount of information from image-based features. With the continuous development and mining of tumor clinical and imaging databases, the radiogenomics, radiomics and artificial intelligence have been flourishing. Therefore, these new technological advances bring new opportunities and challenges to the application of imaging in tumor precision medicine. PMID- 29488707 TI - The HepHIV 2017 Conference in Malta: joining forces for the earlier diagnosis of HIV and viral hepatitis. AB - OBJECTIVES: The objective of the article is to provide an overview of the results of the HepHIV 2017 Conference organized by the HIV in Europe initiative under the Maltese EU Presidency in January 2017. METHODS: A thourough review of all conference presentations (oral and poster presentations) was performed to retrieve the key outcomes of the conference. RESULTS: The key result from the conference was a call to action summarising key priorities in HIV and viral hepatitis testing and linkage to care. This included improving monitoring of viral hepatitis and HIV, mixing testing strategies and ensuring policy support. The important contribution and outcomes of EU funded projects OptTEST and EuroHIVEdat was highlighted. CONCLUSION: An integrated approach to earlier testing and linkage to care across diseases is needed in Europe and the HepHIV conferences create an important forum to reach this aim. PMID- 29488710 TI - [Accurate imaging diagnosis and evaluation of pancreatic cancer]. AB - Pancreatic cancer is a highly malignant tumor and surgical resection is the only curative treatment option. In order to improve the prognosis of patients with pancreatic cancer, it is very important to diagnose and evaluate pancreatic cancer accurately and early. Imaging examinations play an important role in tumor detection, staging and surgical resectability evaluation, which can provide reliable evidences for diagnosis and treatment of pancreatic cancer. At present, the imaging techniques commonly used for diagnosis of pancreatic cancer include conventional ultrasound, endoscopic ultrasonography, PET-CT, multi-detector row CT (MDCT), magnetic resonance imaging (MRI), in which MDCT and MRI are the most widely used. In this article, the application and research progress of imaging in accurate diagnosis and evaluation of pancreatic cancer are reviewed. PMID- 29488711 TI - [Research progress of CT/MRI parametric response map in precision evaluation of therapeutic response of cancer patients]. AB - Intratumor spatial heterogeneity has been ignored in evaluating tumor therapeutic effect with conventional imaging methods. The voxel-based parametric response map (PRM) derived from CT or MRI may accurately, objectively and timely evaluate the tumor response to therapy, by comparing changes of the functional parameters before and after treatment. This approach may improve the imaging monitoring and the sensitivity of spatial resolution related to tumor changes after treatment. Thus, PRM may help to improve the treatment plan and prognosis evaluation for patients. This article reviews progress on CT/MRI PRM in precision evaluation of therapeutic response of cancer patients. PMID- 29488712 TI - [Advances on correlation of PET-CT findings with breast cancer molecular subtypes, treatment response and prognosis]. AB - In recent years, PET-CT has an increasing importance in the diagnosis and treatment of breast cancer. PET-CT scan can be used as a noninvasive method for molecular subtyping of breast cancer, and prediction of therapeutic effect and prognosis of patients. Studies have revealed that luminal A subtype has a significantly lower maximum standard intake value (SUVmax) than the other subtypes; triple-negative and human epidermal growth factor receptor 2 (HER2) positive tumors have relatively high SUVmax than luminal B subtype, but the specificity and sensitivity of SUVmax in diagnosis of molecular subtypes are very low, so its clinical application is limited. In predicting the effectiveness of the treatment and the prognosis of the patients, the decreased uptake of fluorodeoxyglucose (FDG) is correlated with better therapeutic effect. In addition, patients with high FDG uptake have worse survival outcomes. New tracers, such as 18F-fluoroestradiol (18F-FES) and[89Zr]trastuzumab play an important role in molecular subtyping of breast cancer. 18F-FES PET-CT can effectively evaluate the estrogen receptor (ER) status of breast cancer and the response to endocrine therapy.[89Zr]trastuzumab PET-CT can evaluate the expression of HER2 and localization of HER2-overexpressing tumors, but their specificities and sensitivities are also low. In this article, we review the recent advances on the correlation of PET-CT findings with molecular subtypes, treatment response and prognosis of breast cancer. PMID- 29488713 TI - [Rat endothelial progenitor cells labeled with Molday IONTM EverGreen and in vitro MRI study]. AB - OBJECTIVE: To investigate the feasibility of labeling endothelial progenitor cells (EPCs) with a novel dual modal contrast agent Molday IONTM EverGreen(MIEG) and its performance in vitro MRI. METHODS: EPCs were isolated from rat bone marrow and labeled with 10, 20, 50 MUg/mL MIEG, respectively. The labeling rates were identified by Prussian blue staining and fluorescence microscopy. The vitality of EPCs labeled with 20 MUg/mL MIEG was detected by trypan blue exclusion test at 1 d, 1 w, 2 w, and 6 w after labeling. EPCs labeled with different concentrations of MIEG were scanned by 3.0T MRI with T1 weighted and T2 weighted imaging. RESULTS: The labeling rates for EPCs labeled with different concentrations of MIEG were greater than 98%,and the cytoplasm of labeled EPCs was present with Prussian blue staining. Although the green lighting level went down, the labeling rate at 6 w after labeling was greater than 90%. Trypan blue exclusion test showed that there was no significant difference in the vitality between EPCs labeled with MIEG at 1 d, 1 w, 2 w and 6 w after labeling and EPCs without labeling (all P>0.05). There was no difference in signal intensity on T1 weighted image among EPCs labeled with different concentrations of MIEG. However, the signal intensity on T2 weighted image was reduced in all labeled groups, and the signal reduction became more apparent with increased concentration of MIEG. CONCLUSIONS: EPCs can be effectively labeled by MIEG without interference on the cell viability at the labeled concentration of 20 MUg/mL. The signal intensity change of labeled cells can be detected sensitively by T2 weighted imaging at 3.0T MRI. PMID- 29488714 TI - [Correlation between high signal intensity in cerebrum nucleus on unenhanced T1 weighted MR images and number of previous gadolinium-based contrast agent administration]. AB - OBJECTIVE: To explore the correlation between the number of previous gadolinium based contrast agent administrations and high signal intensity (SI) in the cerebrum nucleus on unenhanced T1-weighted magnetic resonance images. METHODS: Thirty-nine patients who previously underwent at least three contrast-enhanced brain MRI examinations were enrolled in the study. The right globus pallidus, right thalamus, right dentate nucleus, pons and white matter of right frontal lobe were selected as region of interests (ROI). The mean SIs of the ROI were measured on unenhanced T1-weighted images. The SI ratios of globus pallidus, right thalamus, right dentate nucleus and pons to white matter were calculated, respectively. The correlation of SI ratio variation with the number of previous contrast agent administration and clinical features was analyzed with Spearman analysis. RESULTS: The dentate nucleus-to-white matter SI ratios of the last and first MRI scan were 1.113+/-0.136 and 1.014+/-0.096(P<0.01), respectively; while the SI ratio differences between the last and first MRI scan of globus pallidus to-white matter, the thalamus-to-white matter and the pons-to-white matter were not significant (all P>0.05). The dentate nucleus-to-white matter SI ratio was correlated with the number of previous gadolinium-based contrast agent administrations (r=0.329, P<0.05), but not with age, sex, underlying disease, treatment and history of diabetes (all P>0.05). CONCLUSIONS: High SI in the dentate nucleus on unenhanced T1-weighted images may be a consequence of the number of previous gadolinium-based contrast agent administrations. PMID- 29488715 TI - [Quantitative analysis of enhanced MRI features for predicting epidermal growth factor receptor gene amplification in glioblastoma multiforme with radiomic method]. AB - OBJECTIVE: To assess the value of contrast enhanced MRI features for predicting epidermal growth factor receptor (EGFR) gene amplification in glioblastoma multiforme (GBM) with radiomic method. METHODS: Eighty patients with EGFR status examined GBM were retrospectively reviewed. The data were randomly divided into a training dataset (60%) and test dataset (40%). Texture features of each case were extracted from the enhanced region and the edema region in contrast enhanced MR images. Principal component analysis was used for dimension reduction. Random forest model, support vector machine model and neural network model were built. Area under the curve (AUC) of the receiver operating characteristics curve was used to assess the performance of models with test dataset. RESULTS: A total of 542 features were extracted from the enhanced region and the edema region. Forty eight principal components were obtained, which accounted for 100% accumulation contribution rate, and the first 31 principal components were selected for models building, which accounted for 98.5% accumulation contribution rate. The values of AUCs were 0.74, 0.69 and 0.63 for random forest model, support vector machine model and neural network model in the test dataset, respectively. CONCLUSIONS: Radiomic method with proper model may have a potential role in predicting the EGFR gene status with enhanced MRI features derived from the enhanced region and the edema region in patients with glioblastoma multiforme. PMID- 29488716 TI - [Application of dynamic-contrast enhanced magnetic resonance pharmacokinetic models in differential diagnosis of cellular uterine leiomyoma]. AB - OBJECTIVE: To assess the application of the dynamic-contrast enhanced magnetic resonance imaging(DCE-MRI)pharmacokinetics models in differential diagnosis of cellular uterine leiomyoma. METHODS: Sixty four patients with uterine leiomyoma confirmed by surgery and pathology were enrolled in the study between September 2015 and September 2016, including 30 cases of classical leiomyoma, 13 cases of cellular leiomyoma and 21 cases of degenerative leiomyoma. All patients underwent DCE-MRI before surgery. Reference region (RR) model, extended tofts (ET) model and exchange (EC) model were used to quantitatively analyze DCE-MRI data, and their differences among different pathological types of uterine leiomyoma were observed. Receiver operating characteristic (ROC) curve was used to evaluate the efficiency of the quantitative perfusion parameters in differential diagnosis of cellular uterine leiomyoma. RESULTS: The values of Ktrans(transfer constant), Kep(efflux rate constant) in RR model, Ktrans, Kep, Vp (blood plasma volume ratio) in ET model and Ve(plasma volume ratio), Fp(plasma flow)in EC model of cellular uterine leiomyoma were higher than those of classical type(P<0.05 or P<0.01). The values of Ktrans, Kep in RR model,Ktrans,Kep, Ve,Vp in ET model and Ve,Vp,Fp in EC model of cellular uterine leiomyoma were higher than those of degenerative uterine leiomyoma(P<0.05 or P<0.01). There were no significant differences in other quantitative perfusion parameters among three types of uterine leiomyoma (all P>0.05). ROC curves revealed that the Ktrans of the ET model was more effective in diagnosing cellular uterine leiomyoma, the area under the curve (AUC) was 0.929, and the sensitivity and specificity were 92.3% and 83.7%, respectively; meanwhile, the AUCs of Fp of the EC model, Ktrans of the RR model and Kep of the ET model in diagnosis of cellular uterine leiomyoma were 0.867, 0.849 and 0.837, the sensitivities were 91.7%, 84.6% and 92.3%, and the specificities were 78.0%, 76.0% and 73.5%, respectively. CONCLUSIONS: Three pharmacokinetics models can be used in the differentiation of cellular uterine leiomyoma from other types of uterine leiomyoma. Ktrans of the ET model has higher sensitivity and specificity in differential diagnosis of cellular uterine leiomyoma. PMID- 29488718 TI - [Diagnostic value of dual energy CT for lymph node metastasis in patients with non-small cell lung cancer]. AB - OBJECTIVE: To assess the diagnostic value of dual energy CT for lymph node metastasis in patients with non-small cell lung cancer (NSCLC). METHODS: Forty NSCLC patients, including 15 cases of squamous cell carcinoma and 25 cases of adenocarcinoma, underwent dual energy CT examination in pre-contrast and venous phase contrast scans, then the CT attenuation value of the lung cancer lesions and 85 mediastinal enlarged lymph nodes (the short diameter >= 5 mm, 53 metastatic and 32 non-metastatic) were measured at different energy levels (40 190 keV, spacing 10 keV) in venous phase contrast. CT spectral curves of the lung cancer lesions, hilus pulmonis and mediastinal enlarged lymph nodes were produced automatically, through comparing their CT spectral curves slope to judge whether or not the lymph nodes were metastatic. Receiver operating characteristic (ROC) curve was used to evaluate the efficiency of CT spectral curve in diagnosis of lymph node metastasis. RESULTS: The CT spectral curves slopes of the lung cancer, metastatic lymph nodes and non-metastatic lymph nodes were 1.10+/-0.11, 1.08+/ 0.07 and 1.54+/-0.17, respectively. There was no significant difference in curve slope between metastatic lymph nodes and lung cancer (t=-1.32,P>0.05); while there was significant difference between non-metastatic lymph nodes and lung cancer (t=-2.58,P<0.05). The CT spectral curve slope ratios of metastatic and non metastatic lymph nodes to lung cancer were 0.98+/-0.05 and 1.40+/-0.12, respectively (t=-2.86,P<0.05). ROC curve showed that taking CT spectral curve slope ratio of 1.15 as cut-off value for the diagnosis of metastatic lymph nodes, the sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 81.1%, 87.5%, 91.5%, 73.7% and 83.5%, respectively. CONCLUSIONS: Dual energy CT is of value in improving the diagnostic accuracy of lymph node metastasis in NSCLC patients before treatment. PMID- 29488717 TI - [Association of parameters in dynamic contrast-enhanced MRI using reference region model with prognostic factors and molecular subtypes of breast cancer]. AB - OBJECTIVE: To investigate the association of parameters in dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) using reference region model with prognostic factors and molecular subtypes of breast cancer. METHODS: MRI and pathological data of 50 patients with pathologically confirmed invasive ductal carcinoma of the breast were retrospectively analyzed. Reference region model was applied to analyze pharmacokinetic quantitative parameters including volume transfer constant (RR Ktrans), rate constant (Kep) and the ratio of Ktrans to extracellular space volume (Ktrans/Ve). The associations of the above parameters with prognostic factors and molecular subtypes of breast cancer were analyzed. RESULTS: RR Ktrans and Kep were significantly higher in patients of histological grade 3 compared with those of histological grade 1 & 2 (all P<0.05); and the patients with estrogen receptor (ER)-negative and/or progesterone receptor (PR) negative also had higher RR Ktrans and Kep than those with ER-positive or PR positive (all P<0.05). For immunohistochemistry, RR Ktrans and Kep were significantly higher in triple negative breast cancer compared with luminal type breast cancer (all P<0.05). CONCLUSIONS: High RR Ktrans and Kep are associated with poor prognosis of breast cancer, and which can also be used to distinguish molecular subtypes of breast cancer. PMID- 29488719 TI - [Value of 18F-FDG PET-CT in detection of primary lesion and pelvic lymph node metastasis in FIGO stages IA2-IIA cervical cancer]. AB - OBJECTIVE: To assess the value of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-CT (PET-CT) in detection of primary tumor and pelvic lymph node metastasis in International Federation of Gynecology and Obstetrics (FIGO) stages IA2-IIA cervical cancer. METHODS: The clinical data of 91 patients with FIGO stagesIA2-IIA cervical cancer were retrospectively analyzed. The sensitivity of 18F-FDG PET-CT in detection of cervical cancer was calculated. The long diameter, short diameter and SUVmax were compared between metastatic lymph nodes (MLN) and non-metastatic lymph nodes (NMLN). The optimal cut-off values of different indexes were determined by receiver operating characteristic (ROC) curve and area under curve (AUC), and the sensitivity, specificity and accuracy were calculated. RESULTS: 18F-FDG PET-CT examinations were positive in 89 patients (89/91, 96.7%). The short diameters of NMLN and MLN were (6.50+/-2.31)mm and (4.21+/-1.49)mm(t=4.855, P<0.05); the SUVmax of NMLN and MLN were 4.56+/-3.34 and 1.92+/-1.41(t=31.685, P<0.05). ROC AUCs of the short diameter and SUVmax in diagnosis of metastatic lymph nodes were 0.802 and 0.861. Taken short diameter >= 5.05 mm and SUVmax >= 2.05 as cut-off values, the corresponding sensitivity, specificity and accuracy in diagnosis of metastatic lymph nodes were 85.0%, 93.0% and 86.8%, respectively. CONCLUSIONS: 18F-FDG PET-CT is sensitive to detect primary lesion and pelvic lymph node metastases in FIGO stages IA2-II A cervical cancer, and the highest diagnostic accuracy may be obtained by taking short diameter >= 5.05 mm and SUVmax >= 2.05 as the standard. PMID- 29488720 TI - [Expression and prognostic value of memory T lymphocyte in patients with non small cell lung cancer following radiotherapy]. AB - OBJECTIVE: To investigate the expression and prognostic value of memory T lymphocyte in patients with non-small cell lung cancer(NSCLC) following radiotherapy. METHODS: Forty-six patients with NSCLC receiving radiotherapy in Ningbo Medical Center Lihuili Hospital from February 2010 to May 2012 were enrolled in the study and 50 healthy subjects served as the control group. The central memory T cell (TCM) and effector memory T cell (TEM) in peripheral blood CD4+, CD8+ cells were detected by flow cytometry. Survival of patients was analyzed by Kaplan-Meier curve, and the relationship between clinical features, memory T lymphocyte changes and overall survival was analyzed by multivariate Cox regression model. RESULTS: CD4+TCM, CD4+TEM, CD8+TCM levels and CD4+/CD8+ TEM of NSCLC patients were significantly lower than those of the control group, while CD4+/CD8+ TCM was significantly higher than that of the control group(all P<0.05). In NSCLC patients, CD4+TCM, CD4+TEM and CD8+TCM were decreased and CD8+TEM levels were increased 4 weeks after radiotherapy(all P<0.05); CD4+TCM, CD4+TEM and CD8+TCM at 12-week after radiotherapy were increased significantly compared with those at 4-week after radiotherapy(all P<0.05). Multivariate Cox regression analysis showed that the change of CD4+TCM after radiotherapy was correlated with the overall survival (95% CI:1.135-2.994, P<0.01). The survival rate and overall survival time for patients with decreasing CD4+ TCM were 23.1% and 10.7 months (95% CI:0.29-12.41), while those of patients with stable CD4+ TCM were 52.7% and 27.4 months (95% CI:0.00-31.26), and those of patients with increasing CD4+ TCM were 66.4% and 37.4 months (95% CI:0.33-29.21), respectively. CONCLUSIONS: NSCLC patients show a significant immunosuppression at the initial stage after radiotherapy, and then a gradual improvement. Change of memory T lymphocyte after radiotherapy can be used to help predicting the prognosis of the patients. PMID- 29488721 TI - [Gestational trophoblastic diseases in cesarean scar: an analysis of 20 cases]. AB - OBJECTIVE: To analyze the clinical features, diagnosis and treatment of gestational trophoblastic diseases in cesarean scar. METHODS: Clinical data of three cases of gestational trophoblastic diseases in cesarean scar diagnosed in Women's Hospital, Zhejiang University School of Medicine during December 2011 and December 2016 were collected. And literature search was performed in Wanfang data, VIP, CNKI, PubMed, ISI Web of Knowledge and EMbase database. RESULTS: A total of 20 cases of gestational trophoblastic diseases were included in the analysis. Clinical features were mainly abnormal vaginal bleeding after menopause, artificial abortion or medical abortion, which might be accompanied by abdominal pain. Serum beta-human chorionic gonadotropin (beta-hCG) levels were increased in 19 patients. The sonographic features were increase of uterine volume, honeycomb-like abnormal intrauterine echo (or described as multiple cystic dark area, multiple anechoic area and multiple liquid dark area) or heterogeneity echo conglomeration, and no clear bound with muscular layer in some cases. There were abundant blood flow signals inside or around the lesions. The ultrasonography indicated that the lesions were located in the anterior side of the uterine isthmus with the involvement of cesarean section scar. In 12 cases with lesions in cesarean scar shown by preliminary diagnosis, 9 underwent uterine artery embolization (UAE) for pretreatment; the blood loss greater than 1500 mL was observed in only one case without UAE; no patient received hysterectomy. In 8 patients whose lesions were not shown in cesarean scar, only one case received UAE pretreatment, and hysterectomy was performed in 3 cases due to blood loss greater than 1500 mL. Two cases were lost in follow-up and no death was reported in remaining 18 cases. The serum beta-hCG levels returned to normal or satisfactory level during the follow-up in 17 cases with increased beta-hCG levels before treatment and no recurrence was observed. CONCLUSIONS: The misdiagnosis rate and missed diagnosis rate of gestational trophoblastic diseases in cesarean section scar are high. The identification of cesarean section scar involvement and UAE may reduce the bleeding and avoid hysterectomy. PMID- 29488722 TI - [Geographic spatial pattern of digestive system cancers in Yiwu city]. AB - OBJECTIVE: To analyze the geographic spatial patterns and risk areas of main digestive system cancers in Yiwu city. METHODS: Newly diagnosed cases of esophageal, gastric and colorectal cancer during 2010-2014 were obtained from Yiwu Center for Disease Control and Prevention (CDC). The household registration population data in 2013 were obtained from public security bureau. Hierarchy clustering and partitioning regionalization method was used to generate geographic units. Global Moran's I was used to evaluate whether cancer incidence was significantly clustered in space, Anselin Local Moran's I was used to identify statistically significant hot spots, cold spots, and spatial outliers, and Spatial Scan Statistics was implemented to analyze the relative risk of cancers in different areas. RESULTS: The 5-year average incidence of esophageal, gastric and colorectal cancers were 9.99/100 000, 34.01/100 000 and 31.46/100 000, respectively. Males showed significantly higher incidence than females. The incidence was heterogeneous throughout the study area. Spatial Scan analysis revealed that southern Yiwu presented a significantly higher male esophageal cancer (RR=1.78) and gastric cancer (RR=1.87) risk. The central area of Yiwu showed a significantly lower female esophageal cancer risk (RR=0.00) and male stomach cancer risk (RR=0.63) and the northern Yiwu exhibited a significantly lower female colorectal cancer risk (RR=0.48). CONCLUSIONS: The incidence of main digestive tract cancers shows a heterogeneous distribution in Yiwu city. PMID- 29488723 TI - [Application of CT scan in diagnosis of pathological type and origin of metastatic ovarian tumors]. AB - OBJECTIVE: To evaluate the application of CT scan in diagnosis of pathological types and origins of metastatic ovarian tumors. METHODS: Clinical data, histopathological results and CT images of 43 patients with pathologically-proved metastatic ovarian tumor were retrospectively analyzed. Diagnostic values of CT imaging for pathological type and origin of metastatic ovarian tumors were evaluated. RESULTS: The pathological types of metastatic ovarian tumor were related to the size of the lesion (P<0.01), while not related to the sites of lesion (unilateral or bilateral), the cystic-solid and mixed lesions with or without separation (all P>0.05). Metastatic ovarian tumors of colorectal origin were usually unilateral lesions, and showed cystic or cystic-solid masses, while those of gastric origin were usually bilateral lesions, and showed solid or solid based masses. CONCLUSIONS: CT imaging may be of value in diagnosis of pathological types and origin of metastatic ovarian tumor. PMID- 29488724 TI - [Value of ultrasonography in diagnosis of xanthogranulomatous cholecystitis]. AB - OBJECTIVE: To assess the value of ultrasonography in differential diagnosis of xanthogranulomatous cholecystitis (XGC) and wall-thickening type of gallbladder cancer (GBC). METHODS: The clinical features and sonographic finding of 31 patients with XGC and 36 patients with wall-thickening type of GBC were retrospectively reviewed. The diagnosis of all cases was confirmed by pathological examination, and the ultrasonographic manifestations of the thickening of the gallbladder wall, intramural hypoechoic nodules, gallbladder mucosa line, gallbladder stones, biliary dilatation and gallbladder-liver boundary were compared between two groups. RESULTS: There were significant differences in the intramural hypoechoic nodules, the continuous gallbladder wall mucosal line and dilatation of bile duct between XGC and GBC groups (all P<0.05), while no statistically significant differences in the other sonographic features(all P>0.05). In the six positive sonographic features of the XGC patients, the intramural hypoechoic nodules and the continuous mucosa line of the gallbladder wall had highest accuracy in the diagnosis of XGC(64.2% and 65.7%). CONCLUSIONS: Intramural hypoechoic nodule and the continuous mucosal line are characteristic sonographic features of XGC, which can be used for the diagnosis of XGC. PMID- 29488725 TI - [Comparison of double-balloon endoscopy and multi-detector row computed tomography in diagnosis of small intestinal tumors]. AB - OBJECTIVE: To compare the diagnostic value of double-balloon endoscopy (DBE) and multi-detector row computed tomography (MDCT) for small intestinal tumors. METHODS: The clinical data of 88 patients with small intestinal tumor who underwent DBE and MDCT examinations during January 2010 and December 2016 was retrospectively analyzed. The diagnostic value of DBE and MDCT for small intestinal tumor was compared. RESULTS: The positive rate of small intestinal tumors by DBE (92.0%, 81/88) was significantly higher than that of MDCT (75.0%, 66/88, P<0.01). The positive rates for malignant small intestinal tumors by DBE and MDCT were the same (91.1%), but the rate of histological qualitation was higher in DBE than that in MDCT (94.1% vs 76.5%, chi2=6.331, P<0.05); the positive rates for benign tumors or the tumors <3 cm in diameter by DBE were significantly higher than those by MDCT (96.8% vs 48.4%, 88.2% vs 47.1%, respectively, chi2=18.235 and 13.170, both P<0.01); also DBE had a higher positive rate for small intestinal tumor presenting gastrointestinal bleeding (97.2% vs 77.8%, chi2=6.222, P<0.05). CONCLUSIONS: The diagnostic value of small intestinal tumor by DBE is significantly higher than that of MDCT. The combination of two methods may improve the diagnostic accuracy for small intestinal tumor. PMID- 29488726 TI - [Research progress on genes mutations related to sulfa drug resistance in Pneumocystis jirovecii]. AB - Pneumocystis jirovecii pneumonia is an opportunistic infection among immunocompromised people. Studies have found that the increased resistance to sulfa drugs of Pneumocystis jirovecii may be associated with the mutation of dihydropteroate synthase (DHPS) gene and dihydrofolate reductase (DHFR) genes, but the mechanism is still unclear. The mutation of DHPS and DHFR genes may be the result of sulfa drugs selection or spontaneous genetic polymorphism, and it can be acquired from person-to-person transmission. This article reviews the cause, molecular epidemiology of DHPS and DHFR gene mutation, and the relationship between DHPS and DHFR gene mutation and clinical outcomes. PMID- 29488727 TI - Antibiotics for acute bronchitis. AB - The mission of the Cochrane Nursing Care Field (CNCF) is to improve health outcomes through increasing the use of the Cochrane Library and supporting Cochrane's role by providing an evidence base for nurses and healthcare professionals who deliver, lead or research nursing care. The CNCF produces Cochrane Corner columns, summaries of recent nursing-care-relevant Cochrane Reviews that are regularly published in collaborating nursing-related journals. Information on the processes CNCF has developed can be accessed at: cncf.cochrane.org/evidence-transfer-program-review-summaries. This is a Cochrane review summary of: Smith SM, Fahey T, Smucny J et al (2017) Antibiotics for acute bronchitis. Cochrane Database of Systematic Reviews. Issue 6. CD000245. doi: 10.1002/14651858.CD000245.pub4. PMID- 29488728 TI - Using a systematic approach to assess an acutely unwell patient with catatonia: a case study. AB - Patients in acute settings may present with a variety of signs and symptoms; however, the principles of assessment are applicable to all acutely unwell patients. This article details a case study of a patient who presented to the author's medical ward in a catatonic state, and was assessed using the ABCDE (airway, breathing, circulation, disability, exposure) approach. Catatonia is a disturbed mental state in which a patient exhibits abnormal behaviour, such as the inability to speak and non-responsiveness to stimuli, alongside immobility. Although catatonia is a rare condition, it is important that nurses can identify its signs and symptoms, because it can be fatal if not treated appropriately and rapidly. Thus, it is crucial for nurses to be able to systematically assess acutely unwell patients, including those with catatonia, using the ABCDE approach. PMID- 29488729 TI - Nursing management of people experiencing homelessness at the end of life. AB - Homelessness is a complex and multidimensional issue often involving a combination of personal vulnerability, the limitations of social housing, and inadequacies in welfare support. Providing palliative and end-of-life care to people experiencing homelessness is challenging, both to individuals receiving care and nurses aiming to meet their complex needs. This article discusses what is understood by the concept of 'homelessness' and examines the barriers to accessing effective healthcare for people who are homeless and have life-limiting conditions. The authors review the research into end of life care for people experiencing homelessness and identify areas for further investigation, notably the lack of evidence regarding the end of life care priorities of these individuals. There is a focus on the availability of healthcare services for people who are homeless at the end of life, as well as the factors that should be considered if evidence-based healthcare services for this group of people are to be improved in the future. PMID- 29488730 TI - Hospitals prepare for possible increase in Zika cases. PMID- 29488732 TI - New proton therapy center provides advanced care. PMID- 29488731 TI - Safety program cuts slips, falls and legal fees at hospital campus. PMID- 29488733 TI - OHA earns award for gains in hand-hygiene compliance. PMID- 29488734 TI - A hospital perspective on sustainable operations. PMID- 29488735 TI - Power monitoring generates efficiency. PMID- 29488736 TI - Security plans stress prevention. Facilities see more patients with behavioral and opioid issues. PMID- 29488737 TI - Architecture for population health. How facility designs can help to build healthy communities. PMID- 29488739 TI - Functional foundations. Flooring that helps to improve health care facilities operations. PMID- 29488738 TI - BIM facilities applications. Three areas that can benefit from building information modeling. PMID- 29488740 TI - Becoming an essential member of your organization. PMID- 29488741 TI - Medical gas system regulations. Implications of the move to the 2012 edition of NFPA 99. PMID- 29488742 TI - Putting emphasis on customer service. How front-line staff can help to improve patient satisfaction. PMID- 29488743 TI - Corrigendum PMID- 29488744 TI - Magnetic Oleosome as a Functional Lipophilic Drug Carrier for Cancer Therapy. AB - In the present study, we fabricated magnetic oleosomes functionalized with recombinant proteins as a new carrier for oil-based lipophilic drugs for cancer treatment. The bioengineered oleosome is composed of neutral lipids surrounded by a phospholipid monolayer with embedded oleosin fusion proteins. The oleosin was genetically fused to a nanobody of a green fluorescent protein (GFP). A recombinant protein consisting of immunoglobulin-binding protein LG fused to GFP was used to couple the oleosome to an antibody for targeted delivery to breast cancer cells. The lipid core of the oleosome was loaded with magnetic nanoparticles and carmustine as the lipophilic drug. The magnetic oleosome was characterized using transmission electron microscopy and dynamic light scattering. Moreover, the specific delivery of oleosome into the target cancer cell was investigated via confocal microscopy. To examine the cell viability of the delivered oleosome, a conventional 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay was carried out. Furthermore, an animal study was conducted to confirm the effect resulting from the delivery of the anticancer drug-loaded oleosomes. Taken together, the fabricated lipophilic drug-loaded magnetic oleosome can be a powerful tool for oil-based drug delivery agent for cancer therapy. PMID- 29488745 TI - Enhanced Interfacial Adhesion by Reactive Carbon Nanotubes: New Route to High Performance Immiscible Polymer Blend Nanocomposites with Simultaneously Enhanced Toughness, Tensile Strength, and Electrical Conductivity. AB - Physically anchoring carbon nanotubes (CNTs) onto the interface of immiscible polymer blends has been extensively reported; however, enhancement of physical properties of the blends has seldom been achieved. Herein, we used CNTs with reactive epoxide groups and long poly(methyl methacrylate) (PMMA) tails as a thermodynamic compatibilizer for immiscible poly vinylidene fluoride/poly l lactide (PVDF/PLLA) blends. The CNTs acted as an efficient compatibilizer and bridged the two phases through physical entanglement and chemical reaction. The sea-island structure of the blend transformed into a bicontinuous structure for CNT contents greater than 3 wt %. The mechanical properties, including ductility and tensile strength, thermal properties, and electrical conductivities were all enhanced by the CNTs compatibilizer. This strategy thermodynamically compatibilized by reactive nanofillers paves the way for advanced blend nanocomposites. PMID- 29488746 TI - Ion Distribution Profiling in an Ion Mobility Spectrometer by Laser-Induced Fluorescence. AB - Measuring the ion distribution pattern in a drift tube under atmospheric pressure is very useful for studies of ion motion and design of ion mobility spectrometers (IMS); however, no mature method is available for conducting such measurements at present. We propose a simple and low-cost technique for profiling the two dimensional ion distribution in any cross section of a drift tube. Similar to particle-image velocimetry, we first send sample ions with fluorescence properties into the drift tube and use a receiving plate to collect and accumulate them. Then, the receiving plate is illuminated by exciting light, and the ion distribution appears as a fluorescence image. In this study, Rhodamine 6G was selected as a typical fluorescence-tracer particle. Electrospray ionization (ESI) was chosen as an ionization source to keep the fluorophore undamaged. A plasma-cleaned coverslip was placed at the detection position as a receiving plate. When a layer of ions was collected, the slide was placed under the exciting light with a wavelength of 473 nm. A camera with a 490 nm high-pass light filter was used to capture the fluorescence image representing the ion distribution. The measured-ion detection efficiency of the method was 156 ion/dN, which is equivalent to the level of IonCCD. In addition, we studied the ion passing characteristics of a Bradbury-Nielsen (BN) ion shutter and the ion focusing effect in the drift tube using this method. The two-dimensional ion distribution images behind the ion shutter and the images of the focused ion spot were first observed experimentally. Further theoretical analysis yielded the same conclusions as the experimental results, proving the feasibility of this method and producing a deeper understanding of ion motion in the IMS. This method has promising prospective application to the design, debugging, and optimization of IMS instruments and hyphenated systems. PMID- 29488747 TI - A Time-of-Flight Secondary Ion Mass Spectrometry/Multivariate Analysis (ToF SIMS/MVA) Approach To Identify Phase Segregation in Blends of Incompatible but Extremely Similar Resins. AB - This work presents a data analysis extension to a well-established methodology for the assessment of organic coatings using imaging time-of-flight secondary ion mass spectrometry (ToF-SIMS). Such an approach produced results that can be analyzed using a multivariate analysis (MVA) procedure that performs the simultaneous processing of spatially and chemically related datasets. The coatings consist of two commercial resins that yield extremely similar spectra, and there are no peaks of sufficient intensity that are uniquely diagnostic of either material to provide an unambiguous identification of each. In order to resolve the problem, in addition to microtome-based sample preparation steps of tapers for the analysis through sample thickness, standard samples in cured and uncured conditions are introduced and measured in the same fashion as the specimens under investigation. The resulting ToF-SIMS imaging datasets have been processed using non-negative matrix factorization (NMF), which enabled identification of phase separation in the cured coatings. PMID- 29488748 TI - NOTA Complexes with Copper(II) and Divalent Metal Ions: Kinetic and Thermodynamic Studies. AB - H3nota derivatives are among the most studied macrocyclic ligands and are widely used for metal ion binding in biology and medicine. Despite more than 40 years of chemical research on H3nota, the comprehensive study of its solution chemistry has been overlooked. Thus, the coordination behavior of H3nota with several divalent metal ions was studied in detail with respect to its application as a chelator for copper radioisotopes in medical imaging and therapy. In the solid state structure of the free ligand in zwitterionic form, one proton is bound in the macrocyclic cavity through a strong intramolecular hydrogen-bond system supporting the high basicity of the ring amine groups (log Ka = 13.17). The high stability of the [Cu(nota)]- complex (log KML = 23.33) results in quantitative complex formation, even at pH <1.5. The ligand is moderately selective for Cu(II) over other metal ions (e.g., log KML(Zn) = 22.32 and log KML(Ni) = 19.24). This ligand forms a more stable complex with Mg(II) than with Ca(II) and forms surprisingly stable complexes with alkali-metal ions (stability order Li(I) > Na(I) > K(I)). Thus, H3nota shows high selectivity for small metal ions. The [Cu(nota)]- complex is hexacoordinated at neutral pH, and the equatorial N2O2 interaction is strengthened by complex protonation. Detailed kinetic studies showed that the Cu(II) complex is formed quickly (millisecond time scale at cCu ~ 0.1 mM) through an out-of-cage intermediate. Conversely, conductivity measurements revealed that the Zn(II) complex is formed much more slowly than the Cu(II) complex. The Cu(II) complex has medium kinetic inertness (tau1/2 46 s; pH 0, 25 degrees C) and is less resistant to acid-assisted decomplexation than Cu(II) complexes with H4dota and H4teta. Surprisingly, [Cu(nota)]- decomplexation is decelerated in the presence of Zn(II) ions due to the formation of a stable dinuclear complex. In conclusion, H3nota is a good carrier of copper radionuclides because the [Cu(nota)]- complex is predominantly formed over complexes with common impurities in radiochemical formulations, Zn(II) and Ni(II), for thermodynamic and, primarily, for kinetic reasons. Furthermore, the in vivo stability of the [Cu(nota)]- complex may be increased due to the formation of dinuclear complexes when it interacts with biometals. PMID- 29488749 TI - Contemporary Mobilization of Legacy Pb Stores by DOM in a Boreal Peatland. AB - We examined how different landscape areas in a catchment containing a northern ombrotrophic peatland and upland mineral soils responded to dramatic decreases in atmospheric deposition of lead (Pb). Pb concentrations in the outflow stream from the peatland measured from 2009-2015 indicated continued mobilization and export of Pb derived from historic inputs to the bog. In contrast, Pb concentrations in surface peat and runoff from upland mineral soils have declined in response to reductions in atmospheric deposition. Relative to the early 1980s, Pb concentrations in the streamflow decreased only ~50%, while Pb in surface peat and upland subsurface runoff decreased by more than 90%. Water level fluctuations in the slow-accumulating peat have allowed dissolved organic matter (DOM) to continue mobilizing Pb deposited in the peatland decades earlier. Strong correlations between dissolved organic carbon (DOC) and Pb concentrations in outflow from the peatland and in bog porewaters demonstrate Pb mobility related to DOM production. Peat stores of Pb in 2016 were less than or equal to those reported in the early 1980s despite the dry mass inventory increasing by 60-80%. Much of the loss in Pb stored in peat can be accounted for by stream runoff from the peatland. PMID- 29488751 TI - Human Apolipoprotein A1 at Solid/Liquid and Liquid/Gas Interfaces. AB - An X-ray reflectivity study on the adsorption behavior of human apolipoprotein A1 (apoA1) at hydrophilic and hydrophobic interfaces is presented. It is shown that the protein interacts via electrostatic and hydrophobic interactions with the interfaces, resulting in the absorption of the protein. pH dependent measurements at the solid/liquid interface between silicon dioxide and aqueous protein solution show that in a small pH range between pH 4 and 6, adsorption is increased due to electrostatic attraction. Here, the native shape of the protein seems to be conserved. In contrast, the adsorption at the liquid/gas interface is mainly driven by hydrophobic effects, presumably by extending the hydrophobic regions of the amphipathic helices, and results in a conformational change of the protein during adsorption. However, the addition of differently charged membrane forming lipids at the liquid/gas interface illustrates the ability of apoA1 to include lipids, resulting in a depletion of the lipids from the interface. PMID- 29488752 TI - Controlling Ligand Exchange through Macrocyclization. AB - Ligand exchange at a sterically hindered palladium center was investigated for six different ligands. The palladium atom was coordinated to a tridentate, NNN pincer bis(amido)pyridine macrocycle to produce a square-planar complex, in which an acetonitrile molecule occupies one of the coordination sites. Kinetic studies showed that ligand exchange at the palladium center proceeds through an associative mechanism and, as a consequence, is impeded by the small size of the metallomacrocycle cavity. The ligand-exchange rate on the palladium center between acetonitrile and six different ligands has been investigated and compared to the exchange rate on the corresponding open form. Our results demonstrate that macrocyclization of ligands is a way to modify the rate of guest exchange in a square-planar metal complex. PMID- 29488750 TI - High-Frequency/High-Field Electron Paramagnetic Resonance and Theoretical Studies of Tryptophan-Based Radicals. AB - Tryptophan-based free radicals have been implicated in a myriad of catalytic and electron transfer reactions in biology. However, very few of them have been trapped so that biophysical characterizations can be performed in a high precision context. In this work, tryptophan derivative-based radicals were studied by high-frequency/high-field electron paramagnetic resonance (HFEPR) and quantum chemical calculations. Radicals were generated at liquid nitrogen temperature with a photocatalyst, sacrificial oxidant, and violet laser. The precise g-anisotropies of l- and d-tryptophan, 5-hydroxytryptophan, 5 methoxytryptophan, 5-fluorotryptophan, and 7-hydroxytryptophan were measured directly by HFEPR. Quantum chemical calculations were conducted to predict both neutral and cationic radical spectra for comparison with the experimental data. The results indicate that under the experimental conditions, all radicals formed were cationic. Spin densities of the radicals were also calculated. The various line patterns and g-anisotropies observed by HFEPR can be understood in terms of spin-density populations and the positioning of oxygen atom substitution on the tryptophan ring. The results are considered in the light of the tryptophan and 7 hydroxytryptophan diradical found in the biosynthesis of the tryptophan tryptophylquinone cofactor of methylamine dehydrogenase. PMID- 29488753 TI - Allenylic Carbonates in Enantioselective Iridium-Catalyzed Alkylations. AB - An enantioconvergent C(sp3)-C(sp3) coupling between racemic allenylic electrophiles and alkylzinc reagents has been developed. An Ir/(phosphoramidite,olefin) catalyst provides access to highly enantioenriched allenylic substitution products (93-99% ee) with complete regiocontrol (>50:1 rr in all cases) over the corresponding 1,3-diene isomers which are obtained predominantly when other metal catalysts are emplyed. The synthetic utility of the products obtained was highlighted in a variety of stereoselective transition metal-catalyzed difunctionalization reactions. Furthermore, a combination of experimental and theoretical studies provide support for a putative reaction mechanism wherein enantiodetermining C-C coupling occurs via nucleophilic attack on a highly planarized aryl butadienylium pi-system that is coordinated to the Ir center in an eta2-fashion. PMID- 29488754 TI - One-Pot Synthetic Approach toward Porphyrinatozinc and Heavy-Atom Involved Zr NMOF and Its Application in Photodynamic Therapy. AB - Herein, we report an iodine-attached Zn(II)-porphyrinic dicarboxylic building block (ZnDTPP-I2-2H, 1) that can be introduced into UiO-66 NMOF via one-pot synthetic approach to generate a new ZnDTPP-I2 doped UiO-66 type nano metal organic framework (NMOF) of ZnDTPP-I2?UiO-66 (2). Compared to its homologous iodine-free NMOF of ZnDTPP?UiO-66 (4), ZnDTPP-I2?UiO-66 (2) with heavy iodine atoms is a more effective nanosized photosensitizer for singlet oxygen generation under physiological conditions. As expected, 2 displayed a high photodynamic therapy efficacy for treatment of liver cancer cells in vitro. PMID- 29488755 TI - Identification of 21,22-Dehydroazaspiracids in Mussels ( Mytilus edulis) and in Vitro Toxicity of Azaspiracid-26. AB - Azaspiracids (AZAs) are marine biotoxins produced by the genera Azadinium and Amphidoma, pelagic marine dinoflagellates that may accumulate in shellfish resulting in human illness following consumption. The complexity of these toxins has been well documented, with more than 40 structural variants reported that are produced by dinoflagellates, result from metabolism in shellfish, or are extraction artifacts. Approximately 34 MUg of a new AZA with MW 823 Da (AZA26 (3)) was isolated from blue mussels ( Mytilus edulis), and its structure determined by MS and NMR spectroscopy. AZA26, possibly a bioconversion product of AZA5, lacked the C-20-C-21 diol present in all AZAs reported thus far and had a 21,22-olefin and a keto group at C-23. Toxicological assessment of 3 using an in vitro model system based on Jurkat T lymphocyte cells showed the potency to be ~30-fold lower than that of AZA1. The corresponding 21,22-dehydro-23-oxo-analogue of AZA10 (AZA28) and 21,22-dehydro analogues of AZA3, -4, -5, -6, -9, and -10 (AZA25, -48 (4), -60, -27, -49, and -61, respectively) were also identified by HRMS/MS, periodate cleavage reactivity, conversion from known analogues, and NMR (for 4 that was present in a partially purified sample of AZA7). PMID- 29488757 TI - Lewis-Bronsted Acid Pairs in Ga/H-ZSM-5 To Catalyze Dehydrogenation of Light Alkanes. AB - The active sites for propane dehydrogenation in Ga/H-ZSM-5 with moderate concentrations of tetrahedral aluminum in the lattice were identified to be Lewis Bronsted acid pairs. With increasing availability, Ga+ and Bronsted acid site concentrations changed inversely, as protons of Bronsted acid sites were exchanged with Ga+. At a Ga/Al ratio of 1/2, the rate of propane dehydrogenation was 2 orders of magnitude higher than with the parent H-ZSM-5, highlighting the extraordinary activity of the Lewis-Bronsted acid pairs. Density functional theory calculations relate the high activity to a bifunctional mechanism that proceeds via heterolytic activation of the propane C-H bond followed by a monomolecular elimination of H2 and desorption of propene. PMID- 29488758 TI - Ab Initio Study of Decay Dynamics of 1-Nitronaphthalene Initiated from the S2(pipi* + nNOpi*) State. AB - Irradiation of nitro-PAHs in solution at ambient conditions leads to formation of its lowest excited triplet, dissociation intermediates nitrogen oxide (NO*) and aryloxy radical (Ar-O*). Experimental and theoretical studies demonstrated that Franck-Condon excited singlet state SFC(pipi*) to a receiver, higher-energy triplet state Tn(npi*) controlled the ultrafast population of the triplet state and, hence, the slight fluorescence yield of nitronaphthalenes. However, the detailed information about the curve-crossings of potential energy surfaces and the major channels for forming T1 species and Ar-O* radical were unclear. Here, by using the CASSCF//CASPT2 method, an efficient decay channel is revealed: S2-FC 1NN -> S2-MIN-1NN or S2T3-MIN-1NN -> T3-MIN-1NN or T3T2-MIN-1NN-> T2-MIN-1NN or T2T1-MIN-1NN -> T1-MIN-1NN. This explains the high yield of T1-1NN species and minor yield of Ar-O* and NO* radicals. The calculation results suggest the bifurcation processes take place predominantly after the internal conversion to the T1-1NN state via T2T1-MIN-1NN, one leads to T1-MIN-1NN, while the other to T1 MIN-ISO to produce Ar-O* and NO* radicals. PMID- 29488759 TI - Synthesis, Characterization, and Thermal Properties of N-alkyl beta-Diketiminate Manganese Complexes. AB - A series of N, N'-dialkyl-beta-diketiminato manganese(II) complexes was synthesized and characterized by single crystal X-ray diffraction, UV-vis and FTIR spectroscopy, and then assayed for volatility, thermal stability, and surface reactivity relevant to vapor-phase film growth processes. Bis( N, N' dimethyl-4-amino-3-penten-2-imine) manganese(II), 1, and bis( N- N'-diisopropyl-4 amino-3-penten-2-imine) manganese(II), 2, specifically, emerge as the most promising candidates, balancing volatility (sublimation temperatures < 100 degrees C at 100 mTorr) with coordinative unsaturation and reactivity, as revealed by rapid release of ligand in the presence of a silica surface. Good correlation is observed between buried volume calculations and relative surface reactivity data, indicating that metal availability resulting from sterically open ligand alkyl substituents increases surface reactivity. The thermal stability, volatility, and reactivity exhibited by these compounds render them promising precursors for the growth of manganese oxide films via vapor-phase growth processes. PMID- 29488760 TI - Catalytic Azoarene Synthesis from Aryl Azides Enabled by a Dinuclear Ni Complex. AB - Azoarenes are valuable chromophores that have been extensively incorporated as photoswitchable elements in molecular machines and biologically active compounds. Here, we report a catalytic nitrene dimerization reaction that provides access to structurally and electronically diverse azoarenes. The reaction utilizes aryl azides as nitrene precursors and generates only gaseous N2 as a byproduct. By circumventing the use of a stoichiometric redox reagent, a broad range of organic functional groups are tolerated, and common byproducts of current methods are avoided. A catalyst featuring a Ni-Ni bond is found to be uniquely effective relative to those containing only a single Ni center. The mechanistic origins of this nuclearity effect are described. PMID- 29488761 TI - Impact of Crop Husbandry Practices and Environmental Conditions on Wheat Composition and Quality: A Review. AB - The increasing interest in the production of bread wheat ( Triticum aestivum L.) with specific quality traits requires a shift from the current breeding goal, being yield, to improved compositional and, consequently, functional traits. Since wheat is a key food crop, this must be attained while maintaining or even further increasing yield. Furthermore, as compositional requirements for specific applications are not well-defined, both protein and gluten content as well as the enzymatic activity remain most important. Given that these traits are majorly impacted by both genotype and environment, it is very complex to predict and ultimately control them. Different strategies, such as applying optimized agronomic practices, can temper these uncontrollable determinants which are equally important to steer wheat quality. As current research on their contribution to specific traits is highly fragmented, this report provides a comprehensive review of the influence of crop husbandry and environmental conditions on wheat yield and composition. PMID- 29488762 TI - Ethanol Controls the Self-Assembly and Mesoscopic Properties of Human Insulin Amyloid Spherulites. AB - Protein self-assembly into amyloid fibrils or highly hierarchical superstructures is closely linked to neurodegenerative pathologies as Alzheimer's and Parkinson's diseases. Moreover, protein assemblies also emerged as building blocks for bioinspired nanostructured materials. In both the above mentioned fields, the main challenge is to control the growth and properties of the final protein structure. This relies on a more fundamental understanding of how interactions between proteins can determine structures and functions of biomolecular aggregates. Here, we identify a striking effect of the hydration of the single human insulin molecule and solvent properties in controlling hydrophobicity/hydrophilicity, structures, and morphologies of a superstructure named spherulite, observed in connection to Alzheimer's disease. Depending on the presence of ethanol, such structures can incorporate fluorescent molecules with different physicochemical features and span a range of mechanical properties and morphologies. A theoretical model providing a thorough comprehension of the experimental data is developed, highlighting a direct connection between the intimate physical protein-protein interactions, the growth, and the properties of the self-assembled superstructures. Our findings indicate structural variability as a general property for amyloid-like aggregates and not limited to fibrils. This knowledge is pivotal not only for developing effective strategies against pathological amyloids but also for providing a platform to design highly tunable biomaterials, alternative to elongated protein fibrils. PMID- 29488763 TI - Identification of Key Intermediates during the NO and H2S Crosstalk Signaling Pathways. AB - The stable isomers and electronic states of [S,S,N,O]- species are investigated with a special focus on the most relevant isomers that could be involved in the NO/H2S cross-talk pathways in biological media. This work identifies eight stable anions, among which are the already known cis-SSNO- and trans-SSNO- molecules and a new NO3--like anionic species, NS2O-. Our computations show that the previously determined structure in lab experiment is trans-SSNO-, which is not relevant for biological activity in vivo. Instead, NS2O- is proposed as the most likely key intermediate in vivo during important biological processes. This result alleviates the corresponding controversy in the literature. PMID- 29488764 TI - Optical Properties of Single- and Double-Functionalized Small Diamondoids. AB - The rational control of the electronic and optical properties of small functionalized diamond-like molecules, the diamondoids, is the focus of this work. Specifically, we investigate the single- and double- functionalization of the lower diamondoids, adamantane, diamantane, and triamantane with -NH2 and -SH groups and extend the study to N-heterocyclic carbene (NHC) functionalization. On the basis of electronic structure calculations, we predict a significant change in the optical properties of these functionalized diamondoids. Our computations reveal that -NH2 functionalized diamondoids show UV photoluminescence similar to ideal diamondoids while -SH substituted diamondoids hinder the UV photoluminescence due to the labile nature of the S-H bond in the first excited state. This study also unveils that the UV photoluminescence nature of -NH2 diamondoids is quenched upon additional functionalization with the -SH group. The double-functionalized derivative can, thus, serve as a sensitive probe for biomolecule binding and sensing environmental changes. The preserved intrinsic properties of the NHC and the ideal diamondoid in NHC-functionalized-diamondoids suggests its utilization in diamondoid-based self-assembled monolayers (SAM), whose UV-photoluminescent signal would be determined entirely by the functionalized diamondoids. Our study aims to pave the path for tuning the properties of diamondoids through a selective choice of the type and number of functional groups. This will aid the realization of optoelectronic devices involving, for example, large-area SAM layers or diamondoid-functionalized electrodes. PMID- 29488765 TI - Halides Held by Bifurcated Chalcogen-Hydrogen Bonds. Effect of MU(S,N-H)Cl Contacts on Dimerization of Cl(carbene)PdII Species. AB - The reaction of cis-[PdCl2(CNCy)2] (1) with thiazol-2-amines (2-10) leads to the C,N-chelated diaminocarbene-like complexes [PdCl{ C(N(H)4,5-R2-thiazol-2 yl)NHCy}(CNCy)] (11-14; 82-91%) in the case of 4,5-R2-thiazol-2-amines (R, R = H, H (2), Me, Me (3), -(CH2)4- (4)) and benzothiazol-2-amine (5) or gives the diaminocarbene species cis-[PdCl2{C(N(H)Cy)N(H)4-R-thiazol-2-yl}(CNCy)] (15-19; 73-93%) for the reaction with 4-aryl-substituted thiazol-2-amines (R = Ph (6), 4 MeC6H4 (7), 4-FC6H4 (8), 4-ClC6H4 (9), 3,4-F2C6H3 (10)). Inspection of the single crystal X-ray diffraction data for 15-17 and 19 suggests that the structures of all these species exhibit previously unrecognized bifurcated chalcogen-hydrogen bonding MU(S,N-H)Cl and also PdII...PdII metallophilic interactions. These noncovalent interactions collectively connect two symmetrically located molecules of 15-17 and 19, resulting in their solid-state dimerization. The existence of the MU(S,N-H)Cl system and its strength (6-9 kcal/mol) were additionally verified/estimated by a Hirshfeld surface analysis and DFT calculations combined with a topological analysis of the electron density distribution within the formalism of Bader's theory (AIM method) and NBO analysis. The observed noncovalent interactions are jointly responsible for the dimerization of 15-19 not only in the solid phase but also in CHCl3 solutions, as predicted theoretically by DFT calculations and confirmed experimentally by FTIR, HRESI-MS, 1H NMR, and diffusion coefficient NMR measurements. Available CCDC data were processed under the new moiety angle, and the observed MU(S,E-H)Cl systems were classified accordingly to E (E = N, O, C) type atoms. PMID- 29488766 TI - Cyclopiamines C and D: Epoxide Spiroindolinone Alkaloids from Penicillium sp. CML 3020. AB - Cyclopiamines C (1) and D (2) were isolated from the extract of Penicillium sp. CML 3020, a fungus sourced from an Atlantic Forest soil sample. Their structures and relative configuration were determined by 1D and 2D NMR, HRMS, and UV/vis data analysis. Cyclopiamines C and D belong to a small subset of rare spiroindolinone compounds containing an alkyl nitro group and a 4,5-dihydro-1 H pyrrolo[3,2,1- ij]quinoline-2,6-dione ring system. NMR and MS/HRMS data confirmed the presence of an epoxide unit (C-17-O-C-18) and a hydroxy group at C-5, not observed for their known congeners. Cytotoxic and antimicrobial activities were evaluated. PMID- 29488767 TI - Intramolecular Hydrogen Bonding Appetency for Conformational Penchants in Oxalohydrazide Fluoro Derivatives: NMR, MD, QTAIM, and NCI Studies. AB - The conformational stability of synthesized diphenyloxalohydrazide and dibenzoyloxalohydrazide fluoro derivatives has been investigated by extensive NMR studies that are ascertained by various levels of theoretical calculations. Two dimensional 1H-19F HOESY NMR experiments revealed the close spatial proximity between two NMR-active nuclei, confirming the hydrogen bond (HB)-mediated interaction between them, further aiding in establishing the probable stable conformations of these molecules. The relaxed potential energy scan disclosed the energy-minimized most stable structure among the several possible multiple conformations, which is in concurrence with NMR interpretations. Atomistic molecular dynamics simulations have been employed to unequivocally establish the conformational stability and the nature of HB formation at varied temperatures. With the possibility of occurrence of a number of probable conformations, the percentage of occurrences of different types of HBs in them was determined by MD simulations. Their population analysis was carried out using a Boltzmann distribution, in addition to deriving their Gibbs free energies. The molecular interactions governing the stable conformations have not only been ascertained by experimental NMR interpretations but also corroborated by other theoretical computations, viz., quantum theory of atoms in molecules (QTAIM) and noncovalent interaction (NCI). PMID- 29488768 TI - Separating T Cell Targeting Components onto Magnetically Clustered Nanoparticles Boosts Activation. AB - T cell activation requires the coordination of a variety of signaling molecules including T cell receptor-specific signals and costimulatory signals. Altering the composition and distribution of costimulatory molecules during stimulation greatly affects T cell functionality for applications such as adoptive cell therapy (ACT), but the large diversity in these molecules complicates these studies. Here, we develop and validate a reductionist T cell activation platform that enables streamlined customization of stimulatory conditions. This platform is useful for the optimization of ACT protocols as well as the more general study of immune T cell activation. Rather than decorating particles with both signal 1 antigen and signal 2 costimulus, we use distinct, monospecific, paramagnetic nanoparticles, which are then clustered on the cell surface by a magnetic field. This allows for rapid synthesis and characterization of a small number of single signal nanoparticles which can be systematically combined to explore and optimize T cell activation. By increasing cognate T cell enrichment and incorporating additional costimulatory molecules using this platform, we find significantly higher frequencies and numbers of cognate T cells stimulated from an endogenous population. The magnetic field-induced association of separate particles thus provides a tool for optimizing T cell activation for adoptive immunotherapy and other immunological studies. PMID- 29488756 TI - Perturbations of Native Membrane Protein Structure in Alkyl Phosphocholine Detergents: A Critical Assessment of NMR and Biophysical Studies. AB - Membrane proteins perform a host of vital cellular functions. Deciphering the molecular mechanisms whereby they fulfill these functions requires detailed biophysical and structural investigations. Detergents have proven pivotal to extract the protein from its native surroundings. Yet, they provide a milieu that departs significantly from that of the biological membrane, to the extent that the structure, the dynamics, and the interactions of membrane proteins in detergents may considerably vary, as compared to the native environment. Understanding the impact of detergents on membrane proteins is, therefore, crucial to assess the biological relevance of results obtained in detergents. Here, we review the strengths and weaknesses of alkyl phosphocholines (or foscholines), the most widely used detergent in solution-NMR studies of membrane proteins. While this class of detergents is often successful for membrane protein solubilization, a growing list of examples points to destabilizing and denaturing properties, in particular for alpha-helical membrane proteins. Our comprehensive analysis stresses the importance of stringent controls when working with this class of detergents and when analyzing the structure and dynamics of membrane proteins in alkyl phosphocholine detergents. PMID- 29488769 TI - Long-range Anisotropic Structural Films and Fibers Formed from Lyotropic Liquid Crystal Gels Containing Hetero-double-helices with C16 Terminal Groups. AB - Long-range anisotropic structural materials exhibit notable optical and mechanical properties, and described here is an efficient method of synthesizing such materials involving self-assembly of well-defined monodispersed organic molecules. Hetero-double-helices are formed in toluene using a pseudoenantiomeric mixture of an ethynylhelicene (M)-tetramer with C16 terminal groups and a (P) pentamer. When the concentration of the mixture was increased, the hetero-double helices self-assembled to form lyotropic liquid crystal gels. On evaporating the solvent by drop-casting, a long-range ani-sotropic structural film with a single domain and a size of up to centimeter order was spontaneously formed. Kinetics analysis of the film formation indicated the generation of perpendicularly aligned liquid crystal domains at the interface of the liquid and solid phases. When the lyotropic liquid crystal gel was extruded into methanol, a long-range anisotropic structural fiber with a single domain was formed. Different shapes of long-range anisotropic structural mate-rials were obtained by different mechanical treatments of lyotropic liquid crystal gels. PMID- 29488770 TI - Reductive Denitration of Nitroarenes. AB - The Pd-catalyzed reductive denitration of nitroarenes has been achieved via a direct cleavage of the C-NO2 bonds. The catalytic conditions reported exhibit a broad substrate scope and good functional-group compatibility. Notably, the use of inexpensive propan-2-ol as a mild reductant suppresses the competitive formation of anilines, which are normally formed by other conventional reductions. Mechanistic studies have revealed that alcohols serve as efficient hydride donors in this reaction, possibly through beta-hydride elimination from palladium alkoxides. PMID- 29488771 TI - Specific Substates of Ras To Interact with GAPs and Effectors: Revealed by Theoretical Simulations and FTIR Experiments. AB - The oncogenic Ras protein adopts various specific conformational states to execute its function in signal transduction. The large number of Ras structures obtained from X-ray and NMR experiments illustrates the diverse conformations that Ras adopts. It is difficult, however, to connect specific structural features with Ras functions. We report the free-energy landscape of Ras.GTP based on extensive explicit solvent simulations. The free-energy map clearly shows that the functional state 2 of Ras.GTP in fact has two distinct substates, denoted here as "Tyr32in" and "Tyr32out". Unbiased MD simulations show that the two substrates interconvert on the submicrosecond scale in solution, pointing to a novel mechanism for Ras.GTP to selectively interact with GAPs and effectors. This proposal is further supported by time-resolved FTIR experiments, which demonstrate that Tyr32 destabilizes the Ras.GAP complex and facilitates an efficient termination of Ras signaling. PMID- 29488772 TI - [AR-V7 Androgen Receptor Variant as a Predictor of Response to Androgen-receptor Targeting Agents Used to Treat Castration-refractory Metastatic Prostate Cancer]. AB - BACKGROUND: Several systemic treatment options are currently available for patients with metastatic castration-refractory prostate cancer (mCRPC), including the androgen-receptor targeting agents (ARTA) enzalutamide and abiraterone, the taxanes docetaxel and cabazitaxel, and the radioisotope drug 223-radium dichloride. In some patients with mCRCP, alternative splicing of androgen receptor (AR) mRNA occurs, resulting in the formation of a truncated AR lacking the androgen-binding domain. These receptors activate downstream signalling pathways even without the ligand. Recent studies show that the presence of the AR V7 (ARV - AR variants) splicing variant is associated with resistance to ARTA. Bec>ause the presence of AR-V7 does not affect the efficacy of other systemic therapies used in mCRCPs, particularly taxanes, AR-V7 is a candidate predictive biomarker for the individualisation of mCRCP treatment. Two types of assays based on mRNA or abnormal protein detection are used to detect AR-V7 in circulating tumour cells. AIM: To describe the current status of AR-V7 testing in mCRPC and possible applications of this method for predicting outcomes of ARTA therapy. CONCLUSION: The percentage of CTC AR-V7+ in ARTA-naive men is relatively low at baseline, but in patients pretreated with ARTA, the prevalence of AR-V7 increases to 19-34%. Given the relatively high expected prevalence, AR-V7 testing may be economically feasible in this population. The proportion of AR-V7+ patients responding to ARTA retreatment appears to be very low, at only 4.8%. AR-V7 testing could thus be useful if an ARTA switch is considered in a patient progressing onto an ARTA drug. Both protein-based tests and mRNA-based tests are currently undergoing clinical validation in prospective studies, with results expected within a year.Key words: prostate cancer - abiraterone - enzalutamide - alternative splicing - drug resistanceSubmitted: 30. 8. 2017Accepted: 5. 11. 2017 doc. MUDr. Tomas Buchler, Ph.D. received honorary lectures and publications from Astellas and Janssen and a travel grant from Janssen. Supported by Ministry of Health, Czech Republic - conceptual development of research organization Thomayer Hospital - TN 0064190. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. PMID- 29488773 TI - [Curcumine (Turmeric - Curcuma longa) as a Supportive Phytotherapeutic Treatment in Oncology]. AB - BACKGROUND: Turmeric (Curcuma longa) is mainly known as a constituent of curry spice. The main active ingredient, responsible for most of its biological effects, is the polyphenol curcumin. AIM: This review aims to provide a comprehensive overview of studies evaluating the benefits of therapeutic curcumin use in oncology. Preclinical studies provide information on the mechanism of action and potential toxicity of curcumin. Clinical studies have so far focused mainly on safety, pharmacokinetics, and determination of the optimal dose of curcumin. However, there are a growing number of trials evaluating the anti-tumor and oncopreventive effects of curcumin and its effect in alleviating the adverse effects of chemotherapeutics and radiotherapy. So far, the results have been optimistic and should encourage further research. The main problem associated with curcumin treatment is its low oral bioavailability, which means it must administrated at high doses to be effective. Therefore, curcumin is more appropriate as a local treatment for areas such as the intestine, mucous membrane, or the skin, where there is no need for a strong systemic effect. Curcumin has a good safety profile when used up to several grams. Curcumin can also be used as a food supplement for people at increased risk of oncological disease, such as heavy smokers or those with pre-cancerous lesions. Due to its good safety profile, curcumin can be recommended to oncological patients who request a natural treatment.Key words: phytotherapy - drug-herb interactions - cancer - adverse effects - curcumine - turmeric - Curcuma longaSubmitted: 20. 7. 2017Accepted: 25. 9. 2017 This publication was written at Masaryk University as part of the project "Behavioural psychopharmacology and pharmacokinetics in preclinical drug research", number MUNI/A/1132/2017 with the support of the Specific University Research Grant, as provided by the Ministry of Education, Youth and Sports of the Czech Republic in the year 2018. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. PMID- 29488774 TI - [Controversy over the Use of Proton Therapy for the Treatment of Tumors of Central Nervous System]. AB - BACKGROUND: Proton beam therapy (PBT) is one of the most discussed topics in contemporary oncology. PBT is characterized by certain physical properties that make it theoretically better as a treatment than standard photon therapy. On the other hand, there are some uncertainties regarding the localization of the dose peak (Bragg peak) in real clinical situations and the value of radiobiological effectiveness at the end of proton beam. Unfortunately, the high expectations of PBT have not been fulfilled in published clinical studies. AIM: In the present article, the results of PBT are compared with those of standard photon therapy for the treatment of low-and high-grade gliomas, pituitary adenomas, vestibular schwannomas, chordomas and chondrosarcomas, and pediatric central nervous system tumors. PBT was not better in tumor control or in reducing toxicity than photon therapy. The higher risk of post-radiation brain tissue necrosis after PBT is alarming. PBT is mostly considered for pediatric tumors, because the radiobiological models predict lower damage to neurocognitive functions and a reduction in secondary malignancies. However, this hypothesis has its opponents and sufficient clinical data to justify the models are still lacking. The cost of PBT is several times higher than that of photon therapy. RESULTS: PBT is a revolutionary technology in modern radiotherapy, but so far, clinical data have not proved it to be superior to that of standard photon therapy. PBT should be considered on an individual basis in cases where modern photon therapy cannot meet the dose limits of healthy tissues.Key words: proton therapy - neoplasms - central nervous systemSubmitted: 24. 10. 2017Accepted: 23. 11. 2017 The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. PMID- 29488775 TI - [Cancer Treatment-induced Changes in Renal Function in Patients with Tumors - Update on Current Knowledge]. AB - BACKGROUND: Renal abnormalities associated with malignancy are common with renal impairment occurring in about 60% of patients with tumors. Kidney disease may occur as a result of direct or indirect effects of tumors on kidneys and the urinary tract. Systematic oncology treatment can affect renal function in two ways, via direct toxic effects on kidney structure and indirectly via dehydration or tumor lysis syndrome. Since 2004, the Food and Drug Administration has approved a number of potentially nephrotoxic chemotherapeutics, targeted drugs, and immunotherapeutics for the treatment of solid tumors. AIM: This article provides an overview of the latest information on the nephrotoxicity associated with the use of new drugs. CONCLUSION: Despite the development of new drug treatments, including targeted therapy and immunotherapy, the risk of kidney involvement persists. The mechanisms of action of these new drugs are different from those of classical chemotherapy, and their use is usually associated with only mild to moderate side effects. In clinical trials, patients with pre existing renal insufficiency are not present in most cases. Deterioration of renal function may significantly affect the treatment strategy and therefore careful renal function monitoring should be an integral part of each clinical trial.Key words: renal failure - toxicity - immunotherapy - chemotherapySubmitted: 7. 7. 2017Accepted: 7. 9. 2017 The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. PMID- 29488776 TI - [Current Status of Checkpoint Inhibitors in the Treatment of Esophageal and Gastric Tumors - Overview of Studies]. AB - BACKGROUND: Despite recent advances in oncological treatment, gastric and esophageal cancer remain neoplastic diseases with poor prognoses. The only potential curative treatment is surgical resection with adjuvant or neoadjuvant chemotherapy/chemoradiotherapy. Targeted therapy of metastatic disease unfortunately does not provide better outcomes than for other tumor types, with the exception of trastuzumab and ramucirumab, which have relatively limited efficacy. Immunotherapy is a rapidly evolving treatment that has influenced the treatment guidelines for many tumors. In the present review, we summarize clinical trials of checkpoint inhibitors for the treatment of gastric and esophageal cancer, including published results and the perspectives of ongoing trials. RESULTS AND DISCUSSION: Gastric and esophageal cancer are tumors with high mutation loads that have attracted considerable attention since the beginning of interest in immunotherapy. Phase I clinical trials (Keynote 012, Javelin, KEYNOTE 028) have demonstrated efficacy and acceptable toxicity. These studies were followed by phase II clinical trials (KEYNOTE 059, CheckMate 032, JapicCTI-No.142422), which showed about a 10-30% overall tumor response rate and confirmed the predictive role of PD-L1 expression. Ongoing phase III clinical trials (CheckMate 648, KEYNOTE 181, KEYNOTE 590, CheckMate 577) should finally confirm whether checkpoint inhibitors have a role to play in a palliative and adjuvant setting. CONCLUSION: Checkpoint inhibitors are perspective treatment modalities for gastric and esophageal tumors.Key words: stomach neoplasms - esophageal neoplasms - immunotherapySubmitted: 19. 9. 2017Accepted: 22. 10. 2017 The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. PMID- 29488777 TI - Non-melanoma Skin Cancer - a Clinicopathological Study of Patients with Basal Cell Carcinoma and Squamous Cell Carcinoma. AB - BACKGROUND: Non-melanoma skin cancer (NMSC) is the most common malignancy in Caucasians. It mainly includes two major keratinocyte tumors - basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). The objective of the study was to analyze and compare the clinicopathological differences between patients with BCC and SCC of the skin. MATERIAL AND METHODS: A cohort of 541 patients with a total of 719 BCCs, and 126 patients with a total of 162 SCCs were retrospectively analyzed. RESULTS: While there was virtually the same proportion of men (49.91%) and women (50.09%) in BCC patients, SCCs occurred more frequently in men (68.2%) than in women (31.8%). The mean age of the individuals with BCC and SCC was 70.8 and 78.2 years, resp. The number of BCCs rises from 50 years of age and this increase showed a linear trend up to 80 years, subsequently followed by decline. SCC lesions occur more rapidly from 70 years of age followed by a sharp increase that exhibited an exponential relationship. BCCs and SCCs occurred predominantly on the head and neck region, comprising a total of 69.8% and 81.4% of the cases, resp. However, BCC lesions were seen more often on the face and SCC lesions were diagnosed more frequently on the extra-facial parts of the head. Further, BCCs occurred more frequently on the trunk, and particularly on the back, compared to SCCs. CONCLUSION: Although BCC and SCC are covered under common term NMSC, they manifest several clinicopathological differences. Despite sharing common etiologic determinants, at least from the onco-epidemiologic perspective, they should be considered separately.Key words: non-melanoma skin cancer - basal cell carcinoma - squamous cell carcinoma. PMID- 29488778 TI - Surgical Treatment of Ampullary Adenocarcinoma - Single Center Experience and a Review of Literature. AB - BACKGROUND: Adenocarcinomas of ampulla of the Vater are relatively uncommon tumors of the gastrointestinal tract. In premalignant lesions endoscopic treatment predominate. According to some authors even early adenocarcinomas (limited to mucosa) can be solved endoscopically. In malignant lesions affecting deeper layers (including submucosa) surgical therapy is the most important. The article summarises the current view for a surgical treatment of ampullary adenocarcinomas and presents results concerning our group of patients. MATERIALS AND METHODS: In 2012-2016 a total number of 17 patients underwent resection for a tumor of ampulla of the Vater. Patients underwent standard staging, were presented before a multidisciplinary committee and referred to a surgical treatment. The main measured parameters were the type of surgical procedure, 30 day morbidity and mortality, histopathologic result and subsequent oncologic treatment. The Leeds Pathology Protocol was used to evaluate the specimens after pancreaticoduodenectomy (PD). RESULTS: PD (n = 9) was a more often performed procedure than the transduodenal surgical ampullectomy (TSA) (n = 8). TSA predominated in polymorbid patients. Histological results (n = 17) established adenoma with high-grade dysplasia in 4 patients, the diagnosis of adenocarcinoma was set in 13 patients. Eight patients underwent adjuvant oncologic therapy (2 had adjuvant chemotherapy, 6 had combination of chemoradiotherapy). CONCLUSION: Premalignant neoplasias of ampulla of the Vater can be mostly solved by endoscopy. If endoscopic resection is not possible surgical therapy is indicated. PD is preferred procedure in the diagnosis of adenocarcinoma. In high-risk and polymorbid patients, with no suspicion for a metastatic lymph nodes, TSA can be considered. Endoscopic ultrasonography is the imaging modality of choice for local staging of ampulla of the Vater and has important role in deciding between endoscopic, local surgical excision (TSA) or radical resection (PD). Our results confirmed rightfulness to perform TSA especially in elderly or polymorbid patients, where in histopathologic specimens evaluation in TSA procedures early T stage and more favorable grading predominated.Key words: adenocarcinoma of the ampulla of Vater - duodenum - endoscopic resection - ampullectomy - pancreaticoduodenectomy - surgery. PMID- 29488779 TI - [Patient with Three EGFR Mutations - Gradual Development of Resistance to Previous Targeted Treatment]. AB - BACKGROUND: Patients with sensitive EGFR mutations are already being treated with first and second generation tyrosine kinase inhibitors (TKIs). However, resistance to these drugs occurs over time, and over half of all cases is caused by a mutation (T790M) in the EGFR kinase domain. Osimertinib offers a new treatment option that overcomes this problem. Unfortunately, resistance to this drug also develops after several months of treatment and is caused by another mutation (C797S) in EGFR. CASE REPORT: Our case report provides evidence for the progressive development of EGFR-TKI resistance in a patient with a deletion of exon 19 in the EGFR gene. First, based on a mutation (T790M) identified after afatinib treatment and a subsequent mutation (C797S) mutation identified after osimertinib treatment. We mention overcoming this resistance (C797S) mutation by using 4th generation EGFR-TKI and other alternative procedures (chemotherapy, immunotherapy, and combinations of older EGFR-TKI generations). We also mention a rare case of peritoneal metastasis that occurred after previous treatment with osimertinib that we attempted to ameliorate by using erlotinib because the impaired condition of the patient did not allow treatment by chemotherapy. There are documented cases in which erlotinib has been successfully given to patients with peritoneal metastases and patients with the EGFR mutation C797S following progression to afatinib. This was not the case in our patient, probably because of the remaining EGFR mutation T790M. CONCLUSION: In our case report, erlotinib did not show efficacy after progression to osimetinib. Nowadays, chemotherapy is the only possible treatment in patients with good a performance status. The next generation of TKIs are undergoing promising developments.Key words: EGFR - deletion on exon 19 - mutation T790M - mutation C797S - afatinib - osimertinibSubmitted: 12. 9. 2017Accepted: 12. 10. 2017 This project was supported by grant AZV 17-30 748A. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. PMID- 29488780 TI - [Pedicled Flaps for Reconstruction of Head and Neck Region]. AB - BACKGROUND: There has been a consistent increase in the number of publications on pedicled flaps for the reconstruction of post ablation defects in the oropharyngeal area. In principle, tissue is lifted from a donor site and moved to a recipient site without disruption of blood supply. The donor site is an exact anatomically defined region of tissue that is capable of sustaining its own blood supply. The benefits of pedicled flaps include lower technical demands that obviate the need for microsurgical anastomosis and shorter operating times. For this reason, they are mostly indicated in elderly and at risk patients. The aim of this paper is to describe our experience with the regional (pedicled) (submental, supraclavicular) flaps with a focus on reliability, function, cosmesis, donor site morbidity, and oncological safety. MATERIAL AND METHODS: Reconstructive techniques using distal flaps are described in 12 patients. A submental flap for reconstruction was used in 7 patients. In 5 patients, we used the supraclavicular flap. A total of 9 patients were treated primarily for squamous cell carcinoma of the orofacial region, and 3 for low-grade adenocarcinoma of the small salivary gland. RESULTS: In 5 patients, there was successful engraftment of the submental flap. Ischemia and necrosis of the edges of the flap occurred in 1 case. In one patient, the 3rd day after surgery, the flap was almost totally necrotised. The supraclavicular flap in 4 patiets healed completely, 1 time during the postoperative period it was infected with partial loss of the outer part of the flap from the pre auricular region. In one case there was necrosis of the terminal part of the flap in the reconstructed part of the tongue, the defect was healed by granulation tissue. In all patients, after reconstruction using supraclavicular and submental flaps, the donor site closed primarily with minimal morbidity. CONCLUSION: Regional (pedicled) flaps are thin, and pliable with good cosmetic and functional results. Reconstruction using these flaps can be accomplished in one-stage with minimum morbidity of the donor site.Key words: pedicled flap - surgical flap - head and neck cancersSubmitted: 11. 5. 2017Accepted: 5. 11. 2017 The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. PMID- 29488784 TI - Emotional and behavioural symptoms, risk behaviours and academic success in Chilean Mapuche and non-Mapuche adolescents. AB - INTRODUCTION: There is controversy over the real existence of differences in mental health and academic performance between the Mapuche ethnic minority male adolescents and the male adolescents not belonging to this ethnicity in Chile. OBJECTIVE: In consequence, the aim of this study was to investigate the differences in emotional and behavioural symptoms, risky behaviours and academic success on the Chilean Mapuche and non-Mapuche adolescents. DESIGN: The sample consisted of 233 adolescents of which 119 were Mapuche adolescents and 114 were non-Mapuche adolescents. RESULTS: The results showed that the Mapuche adolescents do not have more anxiety problems and depression than the non-Mapuche adolescents. Furthermore, the Mapuche adolescents present less drug consumption and behavioural problems. Moreover, there were no differences in academic performance. CONCLUSIONS: This study provides social interest data of the adolescents' mental health, which can be useful for the country's socio-sanitary and political decisions. Future studies should investigate these and other variables related to the mental health of minorities in greater depth. PMID- 29488785 TI - Highs and lows of hyperoxia: physiological, performance, and clinical aspects. AB - Molecular oxygen (O2) is a vital element in human survival and plays a major role in a diverse range of biological and physiological processes. Although normobaric hyperoxia can increase arterial oxygen content ([Formula: see text]), it also causes vasoconstriction and hence reduces O2 delivery in various vascular beds, including the heart, skeletal muscle, and brain. Thus, a seemingly paradoxical situation exists in which the administration of oxygen may place tissues at increased risk of hypoxic stress. Nevertheless, with various degrees of effectiveness, and not without consequences, supplemental oxygen is used clinically in an attempt to correct tissue hypoxia (e.g., brain ischemia, traumatic brain injury, carbon monoxide poisoning, etc.) and chronic hypoxemia (e.g., severe COPD, etc.) and to help with wound healing, necrosis, or reperfusion injuries (e.g., compromised grafts). Hyperoxia has also been used liberally by athletes in a belief that it offers performance-enhancing benefits; such benefits also extend to hypoxemic patients both at rest and during rehabilitation. This review aims to provide a comprehensive overview of the effects of hyperoxia in humans from the "bench to bedside." The first section will focus on the basic physiological principles of partial pressure of arterial O2, [Formula: see text], and barometric pressure and how these changes lead to variation in regional O2 delivery. This review provides an overview of the evidence for and against the use of hyperoxia as an aid to enhance physical performance. The final section addresses pathophysiological concepts, clinical studies, and implications for therapy. The potential of O2 toxicity and future research directions are also considered. PMID- 29488798 TI - Short- and long-term effectiveness of a smartphone application for improving measures of adiposity: A randomised clinical trial - EVIDENT II study. AB - BACKGROUND: Evidence on the efficacy of smartphone applications (apps) for reducing body weight and other measurements of adiposity sustainably is not conclusive. OBJECTIVE: To evaluate the effect of adding an app for 3 months to traditional counselling on physical activity (PA) and a heart-healthy diet for the modification of measurements of adiposity at 3 and 12 months after intervention. METHODS: This randomised clinical trial included 833 subjects. The counselling and app group (IG) had 415 subjects, while 418 were included in the counselling only group (CG). The primary outcome was adiposity measurements at 3 and 12 months after intervention. The secondary outcome was the effect of the intervention by sex. INTERVENTION: Counselling on a heart-healthy diet and PA was given to both groups. The IG also received training in the use of a smartphone app designed to promote a heart-healthy diet and PA, and this group was given access to this application for 3 months. Outcome measurements included waist circumference (WC), body mass index (BMI) and Clinica Universidad de Navarra - body adiposity estimator (CUN-BAE). RESULTS: In the IG at 12 months, the following decreased: WC -0.72 cm (95% confidence interval [CI]: -2.35 to -0.02) and CUN-BAE -0.35 (95% CI: -0.63 to -0.06). These decreases were only observed in women. After baseline adjustment, the beneficial effect was maintained in the IG compared to the CG at 12 months in terms of WC (-0.67; 95% CI: -0.29 to -0.02) and CUN-BAE (-0.57; 95% CI: -1.10 to -0.04), but only in women. CONCLUSIONS: An intervention of nutritional counselling and PA plus the smartphone app with personalised recommendations compared to CG showed beneficial results in terms of reduction of abdominal obesity and the percentage of body fat in women, but not in men. PMID- 29488799 TI - Secondary prevention care and effect: Total and low-density lipoprotein cholesterol levels and lipid-lowering drug use in women and men after incident myocardial infarction - The Tromso Study 1994-2016. AB - BACKGROUND: Secondary prevention guidelines after myocardial infarction (MI) are gender neutral, but underutilisation of treatment in women has been reported. DESIGN: We investigated the change in total and low-density lipoprotein (LDL) cholesterol levels and lipid-lowering drug (LLD) use after first-ever MI in a population-based study. METHODS: We followed 10,005 participants (54% women) attending the Tromso Study 1994-1995 and 8483 participants (55% women) attending the Tromso Study 2007-2008 for first-ever MI up to their participation in 2007 2008 and 2015-2016, respectively. We used linear and logistic regression models to investigate sex differences in change in lipid levels. RESULTS: A total of 395 (MI cohort I) and 132 participants (MI cohort II) had a first-ever MI during 1994 2008 and 2007-2013, respectively. Mean change in total cholesterol was -2.34 mmol/L (SD 1.15) in MI cohort I, and in LDL cholesterol was -1.63 mmol/L (SD 1.12) in MI cohort II. Men had a larger decrease in lipid levels compared to women: the linear regression coefficient for change was -0.33 (95% confidence interval [CI] -0.51 to -0.14) for total cholesterol and -0.21 (95% CI -0.37 to 0.04) for LDL cholesterol, adjusted for baseline lipid value, age and cohort. Men had 73% higher odds (95% CI 1.15-2.61) of treatment target achievement compared to women, adjusted for baseline lipid value, age and cohort. LLD use was reported in 85% of women and 92% of men in MI cohort I, and 80% in women and 89% in men in MI cohort II. CONCLUSIONS: Compared to men, women had significantly less decrease in lipid levels after MI, and a smaller proportion of women achieved the treatment target. PMID- 29488808 TI - Comparison of treatment with an Alexandrite picosecond laser and Nd:YAG nanosecond laser for removing blue-black Chinese eyeliner tattoos. AB - OBJECTIVE: To retrospectively evaluate the efficacy of an Alexandrite picosecond laser versus Nd:YAG nanosecond laser for removing blue-black eyeliner tattoos which have existed more than 10 years. METHODS: A total of 40 patients were treated with an Alexandrite picosecond laser in our department from August 2015 to July 2017, with a fluence of 1.96-6.37J/cm2, spot size of 2.0-3.6 mm, and pulse width of 750 ps. Another 32 patients were treated with an Nd:YAG nanosecond laser, with a fluence of 2.80-7.00 J/cm2, spot size of 3 mm, and pulse width of 5 20 ns. All analysed patients completed at least one treatment and follow-up. RESULTS: The median number of treatment for all the patients was 1 (range, 1-4). After a single session, no difference was found between the two lasers for the eyeliner removal (p > 0.05). For the people who achieved an excellent response of tattoo clearance, there was still no difference between the two groups (p > 0.05). Transient side effects were observed in two groups, but neither group had significant adverse reactions. CONCLUSIONS: To treat blue-black Chinese eyeliner tattoos over 10 years, Alexandrite picosecond laser does not provide better clearance than the Nd:YAG nanosecond laser. PMID- 29488809 TI - Acute stress disorder and C-reactive protein in patients with acute myocardial infarction. PMID- 29488810 TI - Relative peak exercise oxygen pulse is related to sudden cardiac death, cardiovascular and all-cause mortality in middle-aged men. AB - Background Preliminary evidence suggests that peak exercise oxygen pulse - peak oxygen uptake/heart rate-, a variable obtained during maximal cardiopulmonary exercise testing and a surrogate of stroke volume, is a predictor of mortality. We aimed to assess the associations of peak exercise oxygen pulse with sudden cardiac death, fatal coronary heart disease and cardiovascular disease and all cause mortality. Design A prospective study. Methods Peak exercise oxygen pulse was assessed in a maximal cycling test at baseline in 2227 middle-aged men of the Kuopio Ischaemic Heart Disease cohort study using expired gas variables and electrocardiograms. Relative peak exercise oxygen pulse was obtained by dividing the absolute value by body weight. Results During a median follow-up of 26.1 years 1097 subjects died; there were 220 sudden cardiac deaths, 336 fatal coronary heart diseases and 505 fatal cardiovascular diseases. Relative peak exercise oxygen pulse (mean 19.5 (4.1) mL per beat/kg/102) was approximately linearly associated with each outcome. Comparing extreme quartiles of relative peak exercise oxygen pulse, hazard ratios (95% confidence intervals) for sudden cardiac death, fatal coronary heart disease and cardiovascular disease, and all cause mortality on adjustment for cardiovascular risk factors were 0.55 (0.36 0.83), 0.58 (0.42-0.81), 0.60 (0.46-0.79) and 0.59 (0.49-0.70), respectively ( P < 0.001 for all). The hazard ratios were unchanged on further adjustment for C reactive protein and the use of beta-blockers. The addition of relative peak exercise oxygen pulse to a cardiovascular disease mortality risk prediction model significantly improved risk discrimination (C-index change 0.0112; P = 0.030). Conclusion Relative peak exercise oxygen pulse measured during maximal exercise was linearly and inversely associated with fatal cardiovascular and all-cause mortality events in middle-aged men. In addition, relative peak exercise oxygen pulse provided significant improvement in cardiovascular disease mortality risk assessment beyond conventional risk factors. PMID- 29488811 TI - Is exercise becoming a danger for our health? The complex relationship between exercise and atrial fibrillation. PMID- 29488812 TI - Poor oral health and coronary artery disease: Association or causality? PMID- 29488814 TI - Erratum. PMID- 29488813 TI - Investigation of ERG Gene Expression in Iranian Patients with Multiple Sclerosis. AB - INTRODUCTION: Multiple sclerosis (MS) is a common neuro-inflammatory disease arising from interplay of multiple genetic and nongenetic factors. The complex etiology of MS highlights the importance of investigation in various populations exposed to different genetic and environmental risk factors and combination of the results of these studies for elucidation of the MS underlying mechanisms and management of this disease. The role of ETS-related gene (ERG) in inflammation and immune response has been suggested by different investigations. However, a very limited number of studies have been performed about the contribution of this gene in pathogenesis and risk of MS. METHODS: The present study investigated the association of ERG mRNA expression with MS by reverse transcription quantitative PCR (RT-qPCR) for the first time in peripheral blood samples of 50 Iranian MS patients and 50 controls. RESULTS: There was no statistically significant difference in the expression of the ERG between patients and controls. Also, no correlation was detected between the expression of this gene and age of onset, disease duration and Expanded Disability Status Scale. CONCLUSION: The findings of the current study revealed no association between ERG expression and MS, at least in the Iranian patients studied. However, more in-depth and comprehensive investigations should be included to evaluate the exact relevance of this gene to the development of autoimmune diseases such as MS. PMID- 29488815 TI - Random Changes of Accommodation Stimuli: An Automated Extension of the Flippers Accommodative Facility Test. AB - PURPOSE: To study the accommodative dynamics for predictable and unpredictable stimuli using manual and automated accommodative facility tests Materials and Methods: Seventeen young healthy subjects were tested monocularly in two consecutive sessions, using five different conditions. Two conditions replicated the conventional monocular accommodative facility tests for far and near distances, performed with manually held flippers. The other three conditions were automated and conducted using an electro-optical system and open-field autorefractor. Two of the three automated conditions replicated the predictable manual accommodative facility tests. The last automated condition was a hybrid approach using a novel method whereby far and near-accommodative-facility tests were randomly integrated into a single test of four unpredictable accommodative demands. RESULTS: The within-subject standard deviations for far- and near distance-accommodative reversals were (+/-1,+/-1) cycles per minute (cpm) for the manual flipper accommodative facility conditions and (+/-3, +/-4) cpm for the automated conditions. The 95% limits of agreement between the manual and the automated conditions for far and near distances were poor: (-18, 12) and (-15, 3). During the hybrid unpredictable condition, the response time and accommodative response parameters were significantly (p < 0.05) larger for accommodation than disaccommodation responses for high accommodative demands only. The response times during the transitions 0.17/2.17 D and 0.50/4.50 D appeared to be indistinguishable between the hybrid unpredictable and the conventional predictable automated tests. CONCLUSIONS: The automated accommodative facility test does not agree with the manual flipper test results. Operator delays in flipping the lens may account for these differences. This novel test, using unpredictable stimuli, provides a more comprehensive examination of accommodative dynamics than conventional manual accommodative facility tests. Unexpectedly, the unpredictability of the stimulus did not to affect accommodation dynamics. Further studies are needed to evaluate the sensitivity of this novel hybrid technique on individuals with accommodative anomalies. PMID- 29488816 TI - A 2017 update: Challenging the cosmetic procedural delay following oral isotretinoin therapy. AB - For decades it has been widely accepted that elective procedures should be delayed for at least 6-months following completion of isotretinoin therapy. However, numerous 2017 publications demonstrate the need for change in best practice. The evidence has yet to be succinctly summarized in a single article or in a stand-alone quick reference algorithm for physicians. This article's review of all 2017 publications confirms that the 6-month delay is not necessary for all procedures and provides a simple algorithmic approach to summarize the updated recommendations for procedural delay of cosmetic procedures following systemic isotretinoin therapy. This is a useful tool for clinicians and allows patients to receive the most appropriate and timely cosmetic therapy to minimize the psychosocial impact of the skin condition. PMID- 29488817 TI - Innovative approaches to cervical cancer screening in low- and middle-income countries. AB - The estimated cervical cancer burden is over ten-fold greater in low- and middle income countries (LMICs) than in high-income countries. This health gap is thought to be primarily due to limited access to effective screening and treatment programs for cervical pre-cancer and cancer in such settings. The World Health Organization advocates a policy of 'screen and treat' approach to cervical screening in LMICs and subsequently visual inspection of the cervix with acetic acid (VIA) or Lugo's iodine (VILI), followed by ablative cervical cryotherapy if indicated, and this policy has been implemented in many high-burden settings. The performance of VIA/VILI as a primary screening tool for the detection of cervical pre-cancer and cancer has, however, been inconsistent. Recently, many high-income countries have integrated HPV-DNA testing into their cervical cancer screening programs. The comparatively high cost and resource requirements of HPV-based screening have to date prevented many LMICs from doing the same. A significant development has been the entrance of innovative, easy-to-use and highly accurate HPV tests that can be provided at point of care; these could enable LMICs to implement 'test and treat' approaches for cervical cancer screening. PMID- 29488818 TI - Effects of oral contraceptives on ovulation induction in in vitro fertilization patients with premature ovarian insufficiency. AB - OBJECTIVE: To report a case series of in vitro fertilization patients with premature ovarian insufficiency, who were treated with oral contraceptives to reduce follicle stimulating hormone levels. METHOD: This was a consecutive case series in a tertiary teaching hospital in China. Twenty-two women with refractory and idiopathic premature ovarian insufficiency were administered a drospirenone/ethinylestradiol oral contraceptive orally. The main outcome measures were the number of oocytes retrieved and the number of embryos frozen. RESULTS: There were total 106 oral contraceptive treatment cycles and 53 oocyte retrieval cycles in 20 patients (91%, 20/22; 2.4 cycles per woman, 53/22). The total number of oocytes retrieved was 48 in 17 patients (77%, 17/22; 2.2 oocytes per woman, 48/22), and the total number of embryos frozen was 33 in 16 patients (73%, 16/22; 1.5 embryos per woman, 33/22). CONCLUSION: Oral contraception may be an effective method to induce ovulation for some patients with premature ovarian insufficiency. PMID- 29488819 TI - Social Media in Sport Science and Medicine: With Great Power Comes Great Responsibility. PMID- 29488820 TI - Safety and feasibility of transcranial direct current stimulation in amyotrophic lateral sclerosis - a pilot study with a single subject experimental design. AB - INTRODUCTION: Transcranial direct current stimulation (tDCS) has been explored as a neuromodulatory tool to prime motor function in several neurological disorders. Studies using tDCS in amyotrophic lateral sclerosis (ALS) are limited. We investigated the safety, feasibility and effects of long-term tDCS in an individual with ALS. METHODS: A 36-year-old male diagnosed with clinically definite ALS received 12 sessions each of anodal, sham, and cathodal tDCS. Outcome measures included disease progression (revised ALS functional rating scale (ALSFRS-R)), clinical measures of endurance and mobility, and corticomotor excitability. RESULTS: No adverse events or change in disease progression were noticed during the study. Small improvement in gait speed (15% increase) was noticed with anodal tDCS only. CONCLUSIONS: This case study demonstrates the safety and feasibility of long-term facilitatory and inhibitory tDCS on a single participant with ALS. This study serves as a guideline for implementing tDCS in future ALS trials. PMID- 29488823 TI - Drivers of multidimensional eco-innovation: empirical evidence from the Brazilian industry. AB - The study analyses the relationships between the main drivers of eco-innovation introduced by innovative industries, focused on cooperation strategy. Eco innovation is analysed by means of a multidimensional identification strategy, showing the relationships between the independent variables and the variable of interest. The literature discussing environmental innovation is different from the one discussing other types of innovation inasmuch as it seeks to grasp its determinants and to mostly highlight the relevance of environmental regulation. The key feature of this paper is that it ascribes special relevance to cooperation strategy with external partners and to the propensity of innovative industry introducing eco-innovation. A sample of 35,060 Brazilian industries were analysed, between 2003 and 2011, by means of Binomial, Multinomial and Ordinal logistic regressions with microdata collected with the research and innovation department (PINTEC) from the Brazilian Institute of Geography and Statistics (Instituto Brasileiro de Geografia e Estatistica). The econometric results estimated by the Logit Multinomial method suggest that the cooperation with external partners practiced by innovative industries facilitates the adoption of eco-innovation in dimension 01 with probability of 64.59%, 57.63% in dimension 02 and 81.02% in dimension 03. The data reveal that the higher the degree of eco innovation complexity, the harder industries seek to obtain cooperation with external partners. When calculating with the Logit Ordinal and Binomial models, cooperation increases the probability that the industry is eco-innovative in 65.09% and 89.34%, respectively. Environmental regulation and innovation in product and information management were also positively correlated as drivers of eco-innovation. PMID- 29488824 TI - Reading and Writing Skills in Children With Specific Learning Disabilities With and Without Developmental Coordination Disorder. AB - This pilot study is to investigate the influence of a developmental coordination disorder (DCD) comorbidity in a group of children with learning disability (LD). Reading and writing were assessed to investigate if the coexistence of a motor impairment can worsen writing quality, speed, and reading accuracy. A sample of 33 LD children (aged 7-11 years) was divided in two subgroups, on the base of their scores on the Movement Assessment Battery for Children: LD-only (n = 14) and LD with a comorbidity for DCD (LD-DCD, n = 19). No differences were found in handwriting speed, but significant differences were found in handwriting quality: LD-DCD children showed a worst performance. Reading words and nonwords accuracy was more impaired in LD-only children than in LD-DCD children. Group differences suggest a poorer phonological decoding of the LD-only sample, whereas worst cursive handwriting legibility scores are typical of the motor-impaired subgroup. PMID- 29488826 TI - Impact of activated sludge ozonation on filamentous bacteria viability and possible added benefits. AB - Ozone was applied to return activated sludge in full-scale to study how ozone impacts filamentous bacteria viability (Live/Dead(r)). Additionally, the ozonated sludges were subjected to anaerobic digestion trials and analysis of micropollutants (MPs). Ozone treatment (3-4.8 g O3/kg total suspended solids) improved the settling properties of the sludge by lowering the diluted sludge volume with 7-35%. Ozone inactivated filamentous bacteria outside the floc structures and the fraction of inactivated filaments increased with an increasing ozone dose. It was observed that ozone treatment may act selectively towards different types of filaments. With respect to the two dominating morphotypes present, Type 0041 filamentous bacteria were found to be more resistant to ozone attack than Microthrix parvicella. Thus, higher ozone doses may be required to mitigate sludge bulking caused by Type 0041 filaments. No effects could be discerned by ozone addition on neither the methane production of the sludge nor on the concentrations of MPs analysed for this study. The lack of effect on both methane production and micropollutant removal was deemed to be caused by insufficient ozone doses. PMID- 29488825 TI - Language processing and executive functions in early treated adults with phenylketonuria (PKU). AB - We provide an in-depth analysis of language functions in early-treated adults with phenylketonuria (AwPKUs, N = 15-33), as compared to age- and education matched controls (N = 24-32; N varying across tasks), through: a. narrative production (the Cinderella story), b. language pragmatics comprehension (humour, metaphors, inferred meaning), c. prosody discrimination d. lexical inhibitory control and planning (Blocked Cyclic Naming; Hayling Sentence Completion Test, Burgess & Shallice, 1997). AwPKUs exhibited intact basic language processing (lexical retrieval, phonology/articulation, sentence construction). Instead, deficits emerged in planning and reasoning abilities. Compared to controls, AwPKUs were: less informative in narrative production (lower rate of Correct Information Units); slower in metaphorical understanding and inferred meaning; less accurate in focused lexical-search (Hayling test). These results suggest that i) executive deficits in PKU cannot be explained by an accumulation of lower order deficits and/or general speed impairments, ii) executive functions engage dedicated neurophysiological resources, rather than simply being an emergent property of lower-level systems. PMID- 29488827 TI - The Digest. PMID- 29488828 TI - Effect of Different Shooting Techniques in Floorball on Accuracy and Velocity in Experienced Male Floorball Players. AB - The aims of this study were to investigate the effect of four different shooting techniques (slap, sweeper, drag, and wrist shots) in floorball on velocity and accuracy in experienced floorball players, and to investigate whether target height has an influence on these shooting performances. Ten experienced male floorball players (age, 21 +/- 4 years; body mass, 81.5 +/- 10 kg; body height, 1.85 +/- 0.07 m; and years of experience, 6.9 +/- 3.1 years) shot as hard as possible and tried to hit the upper and lower targets with four different shooting techniques from a 4-m distance. The main findings were that shooting techniques and target height could influence ball velocity in the expected way from slap to sweeper shots and drag to wrist shots, whereas accuracy did not change, and thereby, did not follow any velocity-accuracy trade-off like Fitts' law. PMID- 29488821 TI - Bacterial-Host Interactions: Physiology and Pathophysiology of Respiratory Infection. AB - It has long been thought that respiratory infections are the direct result of acquisition of pathogenic viruses or bacteria, followed by their overgrowth, dissemination, and in some instances tissue invasion. In the last decades, it has become apparent that in contrast to this classical view, the majority of microorganisms associated with respiratory infections and inflammation are actually common members of the respiratory ecosystem and only in rare circumstances do they cause disease. This suggests that a complex interplay between host, environment, and properties of colonizing microorganisms together determines disease development and its severity. To understand the pathophysiological processes that underlie respiratory infectious diseases, it is therefore necessary to understand the host-bacterial interactions occurring at mucosal surfaces, along with the microbes inhabiting them, during symbiosis. Current knowledge regarding host-bacterial interactions during asymptomatic colonization will be discussed, including a plausible role for the human microbiome in maintaining a healthy state. With this as a starting point, we will discuss possible disruptive factors contributing to dysbiosis, which is likely to be a key trigger for pathobionts in the development and pathophysiology of respiratory diseases. Finally, from this renewed perspective, we will reflect on current and potential new approaches for treatment in the future. PMID- 29488829 TI - Is Tourism Marriage of Young Girls in Egypt a Form of Child Sexual Abuse? A Family Exploitation Perspective. AB - Tourism marriage in Egypt is considered a part of the child marriage phenomenon, as parents following false interpretations of Islamic teachings offer up their daughters for short-term sexual relationships in return for money from tourists. This exploratory study used qualitative methods to interview 42 parents who reside in the city of Darasa, Giza, Egypt, whose daughters were persuaded to engage in tourism marriage. Eight social work students utilized an interview guide that contained 10 questions exploring how parents strike deals with tourists and avoid all legal and traditional procedures of marriage in Egypt. The findings of this study were summarized in six distinct themes, which show evidence of family exploitation of young women. This experience likely increases the child's vulnerability to psychological, social, and physical consequences. PMID- 29488830 TI - Translating Evidence-Based Practice for Managing Comorbid Substance Use and Mental Illness Using a Multimodal Training Package. AB - OBJECTIVE: Comorbid mental health and substance use problems are highly prevalent in substance use treatment settings and generally lead to poorer treatment outcomes. Pathways to Comorbidity Care (PCC) is a multimodal training program developed to encourage an integrated service approach to improve clinicians capacity to identify and manage comorbid substance use and mental health outcomes within public drug and alcohol treatment settings. METHODS: In this paper we describe the concepts underlying the PCC package and the use of implementation science to assess and overcome potential barriers, including clinicians preferences, knowledge about best practice, and professional culture. RESULTS: The training components include didactic seminars, group workshops run by a local clinical champion on relevant subjects such as motivational interviewing and cognitive behavioral therapy, individual clinical consultation, and feedback with a senior clinical psychologist. The PCC also includes an online portal containing comorbidity resources including manuals, guidelines, and booster webinars. Finally, we describe the evaluation of PCC implementation. CONCLUSIONS: Drug and alcohol services need to be equipped to treat the majority of comorbid mental health conditions in their clients. We anticipate that this multimodal training package, which applies the principles of implementation science, will facilitate effective and integrated care for these vulnerable clients. PMID- 29488831 TI - Enlisting friends to reduce sexual victimization risk: There's an app for that... but nobody uses it. AB - OBJECTIVE: The Circle of Six (Co6) phone application (app), winner of the White House's Apps Against Abuse Challenge, seeks to incorporate friends into sexual victimization (SV) risk reduction. Despite its growing presence on college campuses, the feasibility/acceptability of the app to college women is unknown. This mixed methods study sought to fill this gap. PARTICIPANTS: College women (N = 44) participated in summer/fall 2015. METHODS: Participants completed questionnaires, used the Co6 app for two months, and returned to report their experiences. RESULTS: Consistent with the app's aim, women reported greater intentions to help friends versus strangers in sexually aggressive situations. However, app use was low over follow-up. Reasons women gave for not using the app included redundancy with existing smart phone features and discomfort with group messaging. Some saw the app as an emergency only resource. CONCLUSIONS: The Co6 app may not meet the real world needs of college women. PMID- 29488832 TI - "What Will My Friends Think?" Social Consequences for Danish Victims of Sexual Assaults in Peer Groups. AB - Being exposed to sexual assaults has numerous psychological and social consequences, which may interfere with the adolescent's still-ongoing development. This article focuses on social consequences for adolescents exposed to sexual assault by someone from their peer group. Participants were 148 in number and 15-18 year olds (M = 16.34 years, 90.5% female) from Centre for Victims of Sexual Assault's "Youth Programme." A mixed methods design combined extensive survey data collected from the 148 adolescents and five case stories. Almost half of the assaults (47.4%) were committed by someone from the victim's social circle who was not a family member. Only 30.5% of these victims reported the assault to the police. Fear of social consequences was the main reason for not reporting. The majority of the participants described failure to thrive in school in the aftermath of the assault, for example, because the assailant attended the same school. Result furthermore showed how social relations can be complicated due to an assault and subsequent reactions, which can result in isolation for the victim and exclusion from their peer group. Sexual assaults in peer groups have great impact on the victim's well-being. Understanding and support from peers is of the utmost importance. Implications for practice are discussed. PMID- 29488833 TI - Prevention of Child Sexual Abuse within the Family System: Guidelines for an Educational Social Group Work Program. AB - Children have the right to be brought up in safe environments. However, this right is often infringed by people who are supposed to provide love, care, and protection to children. These people can include biological fathers, step fathers, brothers, cousins, aunts, mothers, and uncles. Violation of children takes place in a variety of ways, however, for the purpose of this paper, the focus is on child sexual abuse within the family system. A literature review is adopted as the methodology for the discussions in this paper. The purpose of this paper is firstly to demonstrate that child sexual abuse happens within the family system in South Africa, and secondly, to argue that the prevention of child sexual abuse should start within the family system and this can be achieved by conducting educational social group work sessions on child sexual abuse with the family members. PMID- 29488834 TI - Associations among trauma, depression, and alcohol use profiles and treatment motivation and engagement in college students. AB - OBJECTIVE: This study examined how profiles of alcohol use and symptoms of common mental health disorders (depression and posttraumatic stress disorder [PTSD]) influenced the perceived need for and actual seeking of different types of treatment (for alcohol versus psychological distress) in college student drinkers. PARTICIPANTS: Undergraduate students (n = 164) were assessed between September 2009 and August 2015. METHODS: We classified students into different symptom profiles using model-based clustering and compared these profiles on a variety of variables. RESULTS: The cluster model yielded three profiles: Low Risk (n = 66), Concomitant (n = 35), and Heavy Drinking (n = 63). Students in these profiles significantly differed in alcohol consumption, alcohol-related cognitions and problems, and perceptions of need and prior engagement in treatment. CONCLUSION: A variety of strategies can be used to engage students experiencing heavy drinking and/or mental health problems into treatment on campus. PMID- 29488835 TI - Determining the Appropriateness of the "What If" Situations Test (WIST) with Turkish Pre-Schoolers. AB - Measurement instruments are needed to assess the child's sexual abuse prevention program. The purpose of the study was to determine the reliability and validity of the WIST (What If Situations Test) for Turkish culture. Participants were children of the 3-6 age group attending pre-school education institutions and the sample size was identified by means of a power analysis. Seventy children were identified as the sample with 0.85 power and 0.05 type I error according to the power analysis. Language validity, content validity, internal validity coefficient (Cronbach alpha coefficient), and test-retest analyses were conducted in terms of validity and reliability in the scope of efforts for adaptation to Turkish culture. Firstly, Kendall W = 0.83 was the score for the expert opinions concerning the content validity of the language validity scale. It was found that the Cronbach alpha coefficients were between 0.68 and 0.90 for the scale sub dimensions of appropriate and inappropriate recognition, saying, doing, telling, and reporting. The test-retest reliability of the scale was found to be r = 0.89 and the test-retest reliabilities for the sub-dimensions (appropriate recognition, inappropriate recognition, say skills, do skills, tell skills, and reporting skills) were between r = 0.48 and r = 0.92. The test-retest reliability for the Personal Safety Questionnaire (PSQ), as having complimentary items to the WIST, was found to be r = 0.82. The reliability and validity analysis of the 'What If' Situations Test (WIST), used to evaluate pre-schoolers' skills regarding self-protection against sexual abuse, showed that the Test's adaptation to Turkish culture was reliable and valid. PMID- 29488836 TI - Predicting intention to use nicotine replacement therapy in people attending residential treatment for substance dependency. AB - INTRODUCTION: Nicotine Replacement Therapy (NRT) is recommended as a frontline smoking cessation tool for people attending mental health and substance dependence treatment services. Previous research suggests that NRT is underutilized in these settings. To improve the use of NRT amongst people attending residential treatment for substance use disorders (SUDs) it is important that the factors influencing smokers' decisions to use NRT are understood. The study aimed to examine: (1) smoking cessation strategies used by participants in previous quit attempts, (2) participants' attitudes towards NRT (i.e. safety concerns and perceived efficacy), and (3) the predictors of participants' intention to use NRT to support future quit attempts. METHODS: Participants completed a cross-sectional survey that examined their smoking behaviours, previous experiences using smoking cessation strategies, attitudes and beliefs regarding NRT, and intention to use NRT as part of future quit attempts (N = 218). All participants were attending residential treatment for substance use disorders provided by We Help Ourselves (WHOS), a large provider of specialist alcohol and other drug treatment in Australia. RESULTS: The majority of respondents (98%) reported that they had smoked regularly in their lifetime, and 89% were current smokers. Forty-five percent of the current smokers reported that they had previously used NRT to support a quit attempt, with 54% reporting that they intended to use NRT to support a future quit attempt. Intentions to use NRT were not related to the participants' mental health status or the participants' perceptions regarding the safety or potential drawbacks associated with using NRT. However, participants were more likely to report that they would use NRT to support future quit attempts if they were female, had previously used NRT and perceived NRT to be effective. CONCLUSIONS: Improving the use of evidence based smoking cessation strategies within substance use treatment continues to be a priority. To enhance the use of NRT among consumers attending mental health and addiction treatment services, NRT should be universally offered. Future research should consider strategies that help to improve participants' positive perceptions regarding the efficacy of NRT. PMID- 29488837 TI - Computer-aided neurophysiology and imaging with open-source PhysImage. AB - Improved integration between imaging and electrophysiological data has become increasingly critical for rapid interpretation and intervention as approaches have advanced in recent years. Here, we present PhysImage, a fork of the popular public-domain ImageJ that provides a platform for working with these disparate sources of data, and we illustrate its utility using in vitro preparations from murine embryonic and neonatal tissue. PhysImage expands ImageJ's core features beyond an imaging program by facilitating integration, analyses, and display of 2D waveform data, among other new features. Together, with the Micro-Manager plugin for image acquisition, PhysImage substantially improves on closed-source or blended approaches to analyses and interpretation, and it furthermore aids post hoc automated analysis of physiological data when needed as we demonstrate here. Developing a high-throughput approach to neurophysiological analyses has been a major challenge for neurophysiology as a whole despite data analytics methods advancing rapidly in other areas of neuroscience, biology, and especially genomics. NEW & NOTEWORTHY High-throughput analyses of both concurrent electrophysiological and imaging recordings has been a major challenge in neurophysiology. We submit an open-source solution that may be able to alleviate, or at least reduce, many of these concerns by providing an institutionally proven mechanism (i.e., ImageJ) with the added benefits of open-source Python scripting of PhysImage data that eases the workmanship of 2D trace data, which includes electrophysiological data. Together, with the ability to autogenerate prototypical figures shows this technology is a noteworthy advance. PMID- 29488838 TI - Spatiotemporal evolution of focal epileptiform activity from surface and laminar field recordings in cat neocortex. AB - New devices that use targeted electrical stimulation to treat refractory localization-related epilepsy have shown great promise, although it is not well known which targets most effectively prevent the initiation and spread of seizures. To better understand how the brain transitions from healthy to seizing on a local scale, we induced focal epileptiform activity in the visual cortex of five anesthetized cats with local application of the GABAA blocker picrotoxin while simultaneously recording local field potentials on a high-resolution electrocorticography array and laminar depth probes. Epileptiform activity appeared in the form of isolated events, revealing a consistent temporal pattern of ictogenesis across animals with interictal events consistently preceding the appearance of seizures. Based on the number of spikes per event, there was a natural separation between seizures and shorter interictal events. Two distinct spatial regions were seen: an epileptic focus that grew in size as activity progressed, and an inhibitory surround that exhibited a distinct relationship with the focus both on the surface and in the depth of the cortex. Epileptiform activity in the cortical laminae was seen concomitant with activity on the surface. Focus spikes appeared earlier on electrodes deeper in the cortex, suggesting that deep cortical layers may be integral to recruiting healthy tissue into the epileptic network and could be a promising target for interventional devices. Our study may inform more effective therapies to prevent seizure generation and spread in localization-related epilepsies. NEW & NOTEWORTHY We induced local epileptiform activity and recorded continuous, high-resolution local field potentials from the surface and depth of the visual cortex in anesthetized cats. Our results reveal a consistent pattern of ictogenesis, characterize the spatial spread of the epileptic focus and its relationship with the inhibitory surround, and show that focus activity within events appears earliest in deeper cortical layers. These findings have potential implications for the monitoring and treatment of refractory epilepsy. PMID- 29488839 TI - Pharmacological assessment of the contribution of the arterial baroreflex to sympathetic discharge patterns in healthy humans. AB - To study how changes in baroreceptor afferent activity affect patterns of sympathetic neural activation, we manipulated arterial blood pressure with intravenous nitroprusside (NTP) and phenylephrine (PE) and measured action potential (AP) patterns with wavelet-based methodology. We hypothesized that 1) baroreflex unloading (NTP) would increase firing of low-threshold axons and recruitment of latent axons and 2) baroreflex loading (PE) would decrease firing of low-threshold axons. Heart rate (HR, ECG), arterial blood pressure (BP, brachial catheter), and muscle sympathetic nerve activity (MSNA, microneurography of peroneal nerve) were measured at baseline and during steady-state systemic, intravenous NTP (0.5-1.2 ug.kg-1.min-1, n = 13) or PE (0.2-1.0 ug.kg-1.min-1, n = 9) infusion. BP decreased and HR and integrated MSNA increased with NTP ( P < 0.01). AP incidence (326 +/- 66 to 579 +/- 129 APs/100 heartbeats) and AP content per integrated burst (8 +/- 1 to 11 +/- 2 APs/burst) increased with NTP ( P < 0.05). The firing probability of low-threshold axons increased with NTP, and recruitment of high-threshold axons was observed (22 +/- 3 to 24 +/- 3 max cluster number, 9 +/- 1 to 11 +/- 1 clusters/burst; P < 0.05). BP increased and HR and integrated MSNA decreased with PE ( P < 0.05). PE decreased AP incidence (406 +/- 128 to 166 +/- 42 APs/100 heartbeats) and resulted in fewer unique clusters (15 +/- 2 to 9 +/- 1 max cluster number, P < 0.05); components of an integrated burst (APs or clusters per burst) were not altered ( P > 0.05). These data support a hierarchical pattern of sympathetic neural activation during manipulation of baroreceptor afferent activity, with rate coding of active neurons playing the predominant role and recruitment/derecruitment of higher threshold units occurring with steady-state hypotensive stress. NEW & NOTEWORTHY To study how changes in baroreceptor afferent activity affect patterns of sympathetic neural activation, we manipulated arterial blood pressure with intravenous nitroprusside and phenylephrine and measured sympathetic outflow with wavelet-based methodology. Baroreflex unloading increased sympathetic activity by increasing firing probability of low-threshold axons (rate coding) and recruiting new populations of high-threshold axons. Baroreflex loading decreased sympathetic activity by decreasing the firing probability of larger axons (derecruitment); however, the components of an integrated burst were unaffected. PMID- 29488822 TI - Neuronal Cell Death. AB - Neuronal cell death occurs extensively during development and pathology, where it is especially important because of the limited capacity of adult neurons to proliferate or be replaced. The concept of cell death used to be simple as there were just two or three types, so we just had to work out which type was involved in our particular pathology and then block it. However, we now know that there are at least a dozen ways for neurons to die, that blocking a particular mechanism of cell death may not prevent the cell from dying, and that non neuronal cells also contribute to neuronal death. We review here the mechanisms of neuronal death by intrinsic and extrinsic apoptosis, oncosis, necroptosis, parthanatos, ferroptosis, sarmoptosis, autophagic cell death, autosis, autolysis, paraptosis, pyroptosis, phagoptosis, and mitochondrial permeability transition. We next explore the mechanisms of neuronal death during development, and those induced by axotomy, aberrant cell-cycle reentry, glutamate (excitoxicity and oxytosis), loss of connected neurons, aggregated proteins and the unfolded protein response, oxidants, inflammation, and microglia. We then reassess which forms of cell death occur in stroke and Alzheimer's disease, two of the most important pathologies involving neuronal cell death. We also discuss why it has been so difficult to pinpoint the type of neuronal death involved, if and why the mechanism of neuronal death matters, the molecular overlap and interplay between death subroutines, and the therapeutic implications of these multiple overlapping forms of neuronal death. PMID- 29488840 TI - Sensorimotor control of the trunk in sitting sway referencing. AB - We developed a sway-referenced system for sitting to highlight the role of vestibular and visual contributions to trunk control. Motor control was investigated by measuring trunk kinematics in the frontal plane while manipulating visual availability and introducing a concurrent cognitive task. We examined motor learning on three timescales (within the same trial, minutes), within the same test session (1 h), and between sessions (1 wk). Posture sway was analyzed through time-based measures [root mean square (RMS) sway and RMS velocity], frequency-based measures (amplitude spectra), and parameterized feedback modeling. We found that posture differed in both magnitude and frequency distribution during sway referencing compared with quiet sitting. Modeling indicated that sway referencing caused greater uncertainty/noise in sensory feedback and motor outputs. Sway referencing was also associated with lower active stiffness and damping model parameters. The influence of vision and a cognitive task was more apparent during sway referencing compared with quiet sitting. Short-term learning was reflected by reduced RMS velocity in quiet sitting immediately following sway referencing. Longer term learning was evident from one week to the next, with a 23% decrease in RMS sway and 9% decrease in RMS velocity. These changes occurred predominantly during cognitive tests at lower frequencies and were associated with lower sensory noise and higher stiffness and integral gains in the model. With the findings taken together, the sitting sway referenced test elicited neural changes consistent with optimal integration and sensory reweighting, similar to standing, and should be a valuable tool to closely examine sensorimotor control of the trunk. NEW & NOTEWORTHY We developed the first sway-referenced system for sitting to highlight the role of vestibular and visual contributions to trunk control. A parametric feedback model explained sensorimotor control and motor learning in the task with and between two test sessions. The sitting sway-referenced test elicited neural changes consistent with optimal integration and sensory reweighting, similar to standing, and should be a valuable tool to closely examine sensorimotor control of the trunk. PMID- 29488841 TI - Dissociable signatures of visual salience and behavioral relevance across attentional priority maps in human cortex. AB - Computational models posit that visual attention is guided by activity within spatial maps that index the image-computable salience and the behavioral relevance of objects in the scene. These spatial maps are theorized to be instantiated as activation patterns across a series of retinotopic visual regions in occipital, parietal, and frontal cortex. Whereas previous research has identified sensitivity to either the behavioral relevance or the image-computable salience of different scene elements, the simultaneous influence of these factors on neural "attentional priority maps" in human cortex is not well understood. We tested the hypothesis that visual salience and behavioral relevance independently impact the activation profile across retinotopically organized cortical regions by quantifying attentional priority maps measured in human brains using functional MRI while participants attended one of two differentially salient stimuli. We found that the topography of activation in priority maps, as reflected in the modulation of region-level patterns of population activity, independently indexed the physical salience and behavioral relevance of each scene element. Moreover, salience strongly impacted activation patterns in early visual areas, whereas later visual areas were dominated by relevance. This suggests that prioritizing spatial locations relies on distributed neural codes containing graded representations of salience and relevance across the visual hierarchy. NEW & NOTEWORTHY We tested a theory which supposes that neural systems represent scene elements according to both their salience and their relevance in a series of "priority maps" by measuring functional MRI activation patterns across human brains and reconstructing spatial maps of the visual scene. We found that different regions indexed either the salience or the relevance of scene items, but not their interaction, suggesting an evolving representation of salience and relevance across different visual areas. PMID- 29488843 TI - Change of cortical foot activation following 70 days of head-down bed rest. AB - Head-down tilt bed rest (HDBR) has been used as a spaceflight analog to study some of the effects of microgravity on human physiology, cognition, and sensorimotor functions. Previous studies have reported declines in balance control and functional mobility after spaceflight and HDBR. In this study we investigated how the brain activation for foot movement changed with HDBR. Eighteen healthy men participated in the current HDBR study. They were in a 6 degrees head-down tilt position continuously for 70 days. Functional MRI scans were acquired to estimate brain activation for foot movement before, during, and after HDBR. Another 11 healthy men who did not undergo HDBR participated as control subjects and were scanned at four time points. In the HDBR subjects, the cerebellum, fusiform gyrus, hippocampus, and middle occipital gyrus exhibited HDBR-related increases in activation for foot tapping, whereas no HDBR-associated activation decreases were found. For the control subjects, activation for foot tapping decreased across sessions in a couple of cerebellar regions, whereas no activation increase with session was found. Furthermore, we observed that less HDBR-related decline in functional mobility and balance control was associated with greater pre-to-post HDBR increases in brain activation for foot movement in several cerebral and cerebellar regions. Our results suggest that more neural control is needed for foot movement as a result of HDBR. NEW & NOTEWORTHY Long duration head-down bed rest serves as a spaceflight analog research environment. We show that brain activity in the cerebellum and visual areas during foot movement increases from pre- to post-bed rest and then shows subsequent recovery. Greater increases were seen for individuals who exhibited less decline in functional mobility and balance control, suggestive of adaptive changes in neural control with long-duration bed rest. PMID- 29488844 TI - Children's Disclosure of Sexual Abuse: A Systematic Review of Qualitative Research Exploring Barriers and Facilitators. AB - This study evaluates and synthesizes qualitative evidence addressing factors affecting a child's decision to disclose an experience of sexual abuse. Childhood sexual abuse is a devastating crime, with long-term negative impacts. Understanding the factors that affect a child's decision to disclose is vital. Disclosure enables access to support and protection, both therapeutically and legally. A systematic review was conducted focusing on factors affecting a child's decision to disclose an experience of sexual abuse. Seven studies were identified, quality appraisal undertaken, and meta-ethnography used to synthesize the studies. Six new super-ordinate themes were developed: Fear of what will happen; Others' reactions: fear of disbelief; Emotions and impact of the abuse; An opportunity to tell; Concern for self and others; and Feelings toward the abuser. Themes indicated the importance of support, structure, and opportunity to facilitate disclosure and should be utilized by agencies to develop practices that facilitate disclosures. PMID- 29488842 TI - Selective modulation of visual sensitivity during fixation. AB - During periods of steady fixation, we make small-amplitude ocular movements, termed microsaccades, at a rate of 1-2 every second. Early studies provided evidence that visual sensitivity is reduced during microsaccades-akin to the well established suppression associated with larger saccades. However, the results of more recent work suggest that microsaccades may alter retinal input in a manner that enhances visual sensitivity to some stimuli. Here we parametrically varied the spatial frequency of a stimulus during a detection task and tracked contrast sensitivity as a function of time relative to microsaccades. Our data reveal two distinct modulations of sensitivity: suppression during the eye movement itself and facilitation after the eye has stopped moving. The magnitude of suppression and facilitation of visual sensitivity is related to the spatial content of the stimulus: suppression is greatest for low spatial frequencies, while sensitivity is enhanced most for stimuli of 1-2 cycles/ degrees , spatial frequencies at which we are already most sensitive in the absence of eye movements. We present a model in which the tuning of suppression and facilitation is explained by delayed lateral inhibition between spatial frequency channels. Our data show that eye movements actively modulate visual sensitivity even during fixation: the detectability of images at different spatial scales can be increased or decreased depending on when the image occurs relative to a microsaccade. NEW & NOTEWORTHY Given the frequency with which we make microsaccades during periods of fixation, it is vital that we understand how they affect visual processing. We demonstrate two selective modulations of contrast sensitivity that are time-locked to the occurrence of a microsaccade: suppression of low spatial frequencies during each eye movement and enhancement of higher spatial frequencies after the eye has stopped moving. These complementary changes may arise naturally because of sluggish gain control between spatial channels. PMID- 29488845 TI - Pupillary Correlates of Fluctuations in Sustained Attention. AB - The current study examined pupillary correlates of fluctuations and lapses of sustained attention. Participants performed a sustained attention task with either a varied ISI or a fixed ISI (fixed at 2 or 8 sec) while pupil responses were continuously recorded. The results indicated that performance was worse when the ISI was varied or fixed at 8 sec compared with when the ISI was fixed at 2 sec, suggesting that varied or long ISI conditions require greater intrinsic alertness compared with constant short ISIs. In terms of pupillary responses, the results demonstrated that slow responses (indicative of lapses) were associated with greater variability in tonic pupil diameter, smaller dilation responses during the ISI, and subsequently smaller dilation responses to stimulus onset. These results suggest that lapses of attention are associated with lower intrinsic alertness, resulting in a lowered intensity of attention to task relevant stimuli. Following a lapse of attention, performance, tonic pupil diameter, and phasic pupillary responses, all increased, suggesting that attention was reoriented to the task. These results are consistent with the notion that pupillary responses track fluctuations in sustained attention. PMID- 29488846 TI - Deep Brain Stimulation of the Subthalamic Nucleus Does Not Affect the Decrease of Decision Threshold during the Choice Process When There Is No Conflict, Time Pressure, or Reward. AB - During a decision process, the evidence supporting alternative options is integrated over time, and the choice is made when the accumulated evidence for one of the options reaches a decision threshold. Humans and animals have an ability to control the decision threshold, that is, the amount of evidence that needs to be gathered to commit to a choice, and it has been proposed that the subthalamic nucleus (STN) is important for this control. Recent behavioral and neurophysiological data suggest that, in some circumstances, the decision threshold decreases with time during choice trials, allowing overcoming of indecision during difficult choices. Here we asked whether this within-trial decrease of the decision threshold is mediated by the STN and if it is affected by disrupting information processing in the STN through deep brain stimulation (DBS). We assessed 13 patients with Parkinson disease receiving bilateral STN DBS six or more months after the surgery, 11 age-matched controls, and 12 young healthy controls. All participants completed a series of decision trials, in which the evidence was presented in discrete time points, which allowed more direct estimation of the decision threshold. The participants differed widely in the slope of their decision threshold, ranging from constant threshold within a trial to steeply decreasing. However, the slope of the decision threshold did not depend on whether STN DBS was switched on or off and did not differ between the patients and controls. Furthermore, there was no difference in accuracy and RT between the patients in the on and off stimulation conditions and healthy controls. Previous studies that have reported modulation of the decision threshold by STN DBS or unilateral subthalamotomy in Parkinson disease have involved either fast decision-making under conflict or time pressure or in anticipation of high reward. Our findings suggest that, in the absence of reward, decision conflict, or time pressure for decision-making, the STN does not play a critical role in modulating the within-trial decrease of decision thresholds during the choice process. PMID- 29488847 TI - Modulating Episodic Memory Alters Risk Preference during Decision-making. AB - When choosing between options that vary in risk, we often rely on our experience with options-our episodic memories-to make that choice. Although episodic memory has been demonstrated to be critically involved in value-based decision-making, it is not clear how these memory processes contribute to decision-making that involves risk. To investigate this issue, we tested a group of participants on a repeated-choice risky decision-making task. Before completing this task, half of the participants were given a well-validated episodic induction task-a brief training procedure in recollecting the details of a past experience-known to engage episodic memory processes, and the other half were given a general impressions induction task. Our main finding was that risk-taking following the general impressions induction task was significantly lower than following the episodic induction task. In a follow-up experiment, we tested risk-taking in another group of participants without any prior induction task and found that risk-taking from this no-induction (baseline) group was more similar to the episodic induction than to the general impression group. Overall, these findings suggest engaging episodic memory processes when learning about decision outcomes can alter apparent risk-taking behavior in decision-making from experience. PMID- 29488848 TI - Transient Alpha and Beta Synchrony Underlies Preparatory Recruitment of Directional Motor Networks. AB - Modulations in motor cortical beta and alpha activity have been implicated in the preparation, execution, and termination of voluntary movements. The functional role of motor cortex beta activity is yet to be defined, though two opposing theories prevail. The idling cortex theory suggests that large-scale motor networks, in the absence of input, revert to an intrinsic oscillatory state. The alternative theory proposes that beta activity promotes postural tone at the expense of voluntary movement. These theories are primarily based on observations of event-related desynchronization associated with movement onset. Here, we explore the changes in alpha and beta oscillatory activity associated with the specific behavioral patterns during an established directional uncertainty paradigm. We demonstrate that, consistent with current proposals, alpha and beta desynchronization reflects a process of disengagement from existing networks to enable the creation of functional assemblies. We demonstrate that, following desynchronization, a novel signature of transient alpha synchrony underlies the recruitment of functional assemblies required for directional control. Although alpha and beta desynchronization are dependent upon the number of cues presented, they are not predictive of movement preparation. However, the transient alpha synchrony occurs only when participants have sufficient information to prepare for movement and shows a direct relationship with behavioral performance measures. PMID- 29488849 TI - Dopamine Receptors Influence Internally Generated Oscillations during Rule Processing in Primate Prefrontal Cortex. AB - Neural oscillations in distinct frequency bands in the prefrontal cortex (pFC) are associated with specialized roles during cognitive control. How dopamine modulates oscillations to structure pFC functions remains unknown. We trained macaques to switch between two numerical rules and recorded local field potentials from pFC while applying dopamine receptor targeting drugs using microiontophoresis. We show that the D1 and D2 family receptors (D1Rs and D2Rs, respectively) specifically altered internally generated prefrontal oscillations, whereas sensory-evoked potentials remained unchanged. Blocking D1Rs or stimulating D2Rs increased low-frequency theta and alpha oscillations known to be involved in learning and memory. In contrast, only D1R inhibition enhanced high frequency beta oscillations, whereas only D2R stimulation increased gamma oscillations linked to top-down and bottom-up attentional processing. These findings suggest that dopamine alters neural oscillations relevant for executive functioning through dissociable actions at the receptor level. PMID- 29488851 TI - Auditory Attention Causes Gain Enhancement and Frequency Sharpening at Successive Stages of Cortical Processing-Evidence from Human Electroencephalography. AB - Previous findings have suggested that auditory attention causes not only enhancement in neural processing gain, but also sharpening in neural frequency tuning in human auditory cortex. The current study was aimed to reexamine these findings. Specifically, we aimed to investigate whether attentional gain enhancement and frequency sharpening emerge at the same or different processing levels and whether they represent independent or cooperative effects. For that, we examined the pattern of attentional modulation effects on early, sensory driven cortical auditory-evoked potentials occurring at different latencies. Attention was manipulated using a dichotic listening task and was thus not selectively directed to specific frequency values. Possible attention-related changes in frequency tuning selectivity were measured with an adaptation paradigm. Our results show marked disparities in attention effects between the earlier N1 deflection and the subsequent P2 deflection, with the N1 showing a strong gain enhancement effect, but no sharpening, and the P2 showing clear evidence of sharpening, but no independent gain effect. They suggest that gain enhancement and frequency sharpening represent successive stages of a cooperative attentional modulation mechanism that increases the representational bandwidth of attended versus unattended sounds. PMID- 29488852 TI - Contributions of Intraindividual and Interindividual Differences to Multisensory Processes. AB - Most evidence on the neural and perceptual correlates of sensory processing derives from studies that have focused on only a single sensory modality and averaged the data from groups of participants. Although valuable, such studies ignore the substantial interindividual and intraindividual differences that are undoubtedly at play. Such variability plays an integral role in both the behavioral/perceptual realms and in the neural correlates of these processes, but substantially less is known when compared with group-averaged data. Recently, it has been shown that the presentation of stimuli from two or more sensory modalities (i.e., multisensory stimulation) not only results in the well established performance gains but also gives rise to reductions in behavioral and neural response variability. To better understand the relationship between neural and behavioral response variability under multisensory conditions, this study investigated both behavior and brain activity in a task requiring participants to discriminate moving versus static stimuli presented in either a unisensory or multisensory context. EEG data were analyzed with respect to intraindividual and interindividual differences in RTs. The results showed that trial-by-trial variability of RTs was significantly reduced under audiovisual presentation conditions as compared with visual-only presentations across all participants. Intraindividual variability of RTs was linked to changes in correlated activity between clusters within an occipital to frontal network. In addition, interindividual variability of RTs was linked to differential recruitment of medial frontal cortices. The present findings highlight differences in the brain networks that support behavioral benefits during unisensory versus multisensory motion detection and provide an important view into the functional dynamics within neuronal networks underpinning intraindividual performance differences. PMID- 29488850 TI - Age-related Differences in Prestimulus Subsequent Memory Effects Assessed with Event-related Potentials. AB - Prestimulus subsequent memory effects (preSMEs)-differences in neural activity elicited by a task cue at encoding that are predictive of later memory performance-are thought to reflect differential engagement of preparatory processes that benefit episodic memory encoding. We investigated age differences in preSMEs indexed by differences in ERP amplitude just before the onset of a study item. Young and older adults incidentally encoded words for a subsequent memory test. Each study word was preceded by a task cue that signaled a judgment to perform on the word. Words were presented for either a short (300 msec) or long (1000 msec) duration with the aim of placing differential benefits on engaging preparatory processes initiated by the task cue. ERPs associated with subsequent successful and unsuccessful recollection, operationalized here by source memory accuracy, were estimated time-locked to the onset of the task cue. In a late time window (1000-2000 msec after onset of the cue), young adults demonstrated frontally distributed preSMEs for both the short and long study durations, albeit with opposite polarities in the two conditions. This finding suggests that preSMEs in young adults are sensitive to perceived task demands. Although older adults showed no evidence of preSMEs in the same late time window, significant preSMEs were observed in an earlier time window (500-1000 msec) that was invariant with study duration. These results are broadly consistent with the proposal that older adults differ from their younger counterparts in how they engage preparatory processes during memory encoding. PMID- 29488853 TI - Probing Electrophysiological Indices of Perceptual Awareness across Unisensory and Multisensory Modalities. AB - The neural underpinnings of perceptual awareness have been extensively studied using unisensory (e.g., visual alone) stimuli. However, perception is generally multisensory, and it is unclear whether the neural architecture uncovered in these studies directly translates to the multisensory domain. Here, we use EEG to examine brain responses associated with the processing of visual, auditory, and audiovisual stimuli presented near threshold levels of detectability, with the aim of deciphering similarities and differences in the neural signals indexing the transition into perceptual awareness across vision, audition, and combined visual-auditory (multisensory) processing. More specifically, we examine (1) the presence of late evoked potentials (~>300 msec), (2) the across-trial reproducibility, and (3) the evoked complexity associated with perceived versus nonperceived stimuli. Results reveal that, although perceived stimuli are associated with the presence of late evoked potentials across each of the examined sensory modalities, between-trial variability and EEG complexity differed for unisensory versus multisensory conditions. Whereas across-trial variability and complexity differed for perceived versus nonperceived stimuli in the visual and auditory conditions, this was not the case for the multisensory condition. Taken together, these results suggest that there are fundamental differences in the neural correlates of perceptual awareness for unisensory versus multisensory stimuli. Specifically, the work argues that the presence of late evoked potentials, as opposed to neural reproducibility or complexity, most closely tracks perceptual awareness regardless of the nature of the sensory stimulus. In addition, the current findings suggest a greater similarity between the neural correlates of perceptual awareness of unisensory (visual and auditory) stimuli when compared with multisensory stimuli. PMID- 29488854 TI - Implementing and sustaining evidence-based practice in health care: The Bridge Model experience. AB - This qualitative study analyzed the experience of community-based organizations (CBOs) implementing and sustaining the Bridge Model of Transitional Care, a social work-based health service intervention for reducing hospital readmissions. We conducted semi-structured interviews with clinical supervisors from 13 CBOs that received Bridge Model training between 2012 and 2015. CBOs faced significant challenges implementing and sustaining transitional care programs, particularly related to building effective and sustainable partnerships with hospitals. Additional barriers to program implementation and sustainability included financial barriers and staff turnover. Facilitators to implementation and sustainability included organizational champions, organizational culture, and value of evidence. Recommendations for CBOs to implement health service interventions include gaining early buy-in from hospital partners, creating a contractual arrangement with the hospital partner, understanding changes in health-care payment models, diversifying funding sources, developing an evaluation plan, and nurturing organizational champions. PMID- 29488855 TI - Critique of the Vatican's Role in Recent Child Protection Practice: A Brief Report. AB - The current report aims to clarify the practices and implicit intentions of the Holy See in addressing child sexual abuse (CSA) by clerics in the twenty-first century. Church investigation reports, United Nations reports, press coverage, and academic literature were explored to understand the relationship between Church intention and practice. Various types of literature highlight the Roman Catholic Church (RCC) as an organization that is self-referential and self defensive, with the implicit aim of protecting the reputation of RCC at the expense of children. Organizational responses are seen as promoting the protection of perpetrating clerics, resulting in the spread of CSA by clergy nationally and globally. Recommendations are made for the introduction of modern day management practices in RCC, filtered through a faithful understanding of gospel principles. The authors suggest that the United Nations may be an important vehicle for fostering leverage for change in RCC child protection practice. PMID- 29488857 TI - Racial/ethnic differences in body weight perception among U.S. college students. AB - OBJECTIVE: To examine racial/ethnic differences in weight perception by sex among U.S. college students. PARTICIPANTS: a national sample (N = 70,267) of college students selected from 2- and 4-year postsecondary institutions (N = 62) during the Fall semester from 2011 to 2014. METHODS: This is a secondary data analysis using 4 years of American College Health Association-National College Health Assessment IIb data. Sex-stratified multinomial logistic regression was performed to investigate racial/ethnic differences in body weight perception. RESULTS: Compared with non-Hispanic whites, non-Hispanic black men and women were more likely to underestimate their body weight (p < .01). Asian men and women were more likely to overestimate their body weight than non-Hispanic whites (p < .001). CONCLUSIONS: Weight-related interventions should take into account racial/ethnic differences in body weight perception. PMID- 29488856 TI - Reflective Debriefing: A Social Work Intervention Addressing Moral Distress among ICU Nurses. AB - Health-care workers may experience moral distress when they are unable to act as they believe is ethically appropriate in their clinical work. A social worker facilitated protocol called Reflective Debriefing was developed and tested for alleviating moral distress through regular debriefings with nursing staff on an intensive care unit (ICU). Forty-two ICU nurses completed a Moral Distress Scale Revised (MDS-R) at the beginning and end of a 6-month period, during which time regular debriefings were offered. The overall level of moral distress on the ICU surveyed was found to be low to moderate. The top three most frequent situations causing moral distress reported by most nurses in this study were related to the provision of nonbeneficial care in the ICU. Participants reported gaining the most benefit from feeling empowered to constructively confront other staff members about truth-telling in giving a prognosis. Nurses' overall response to the intervention was positive, with 100% of participants requesting to continue the Reflective Debriefing sessions either on a monthly or on an as-needed basis. The response to the intervention emphasized the importance of interprofessional collaboration to successfully combat moral distress among health-care workers and may protect them from burnout, detachment, and even quitting their profession. PMID- 29488859 TI - Corrigendum to parental age and the occurrence of sporadic brain arteriovenous malformations. PMID- 29488858 TI - Social Workers' Perceptions of Job Satisfaction, Interdisciplinary Collaboration, and Organizational Leadership. AB - To address job satisfaction, and therefore employment retention, of hospice social workers, this study examined how relationships with other members of the interdisciplinary hospice team and perceptions of hospice leadership may be associated with job satisfaction of hospice social workers. The sample of 203 hospice social workers was recruited by e-mailing invitations to hospice social workers identified by hospice directors in three states, use of online social media sites accessed by hospice social workers, and snowball sampling. Study measures included professional experience, hospice characteristics, interdisciplinary collaboration, perception of servant leadership, and intrinsic and extrinsic job satisfaction. Variables significant in the model for intrinsic satisfaction were perception of servant leadership, interdisciplinary collaboration, and feeling valued by the hospice physician. Variables significant in the model for extrinsic satisfaction were perception of servant leadership, interdisciplinary collaboration, feeling valued by the hospice physician, and number of social workers at the hospice. Interdisciplinary collaboration was more important for intrinsic job satisfaction and leadership style was more important for extrinsic job satisfaction. Profit status of the hospice, experience of the social worker, caseload size, and other variables were not significant in either model. These results support previous findings that leadership style of the hospice director and relationships with hospice colleagues are important for hospice social workers' job satisfaction. Such low-cost modifications to the hospice work environment, albeit not simple, may improve job satisfaction of hospice social workers. PMID- 29488861 TI - Trans-sacral epiduroscopic laser decompression versus the microscopic open interlaminar approach for L5-S1 disc herniation. AB - CONTEXT/OBJECTIVE: Trans-sacral epiduroscopic laser decompression (SELD) is an alternative to microscopic open lumbar discectomy (OLD). SELD and OLD for L5-S1 lumbar disc herniation (LDH) have not been compared. We compared clinical results, including pain control, between SELD and OLD. DESIGN: Retrospective analysis. SETTING: Korean hospital. PARTICIPANTS: Eighty patients treated with SELD (n = 40) or microscopic OLD (n = 40) for L5-S1 LDH. INTERVENTIONS: N/A. OUTCOME MEASURES: Clinical data were compared over 6 months. Functional status was evaluated using Oswestry Disability Index (ODI, 0-100%) and time to return to work. Preoperative and postoperative pain was measured using a visual analog scale (VAS, 0-10). Radiological assessment was performed preoperatively and postoperatively. RESULTS: The ODI and VAS scores for leg and back pain significantly improved in both groups. At 6-months after the procedure, the average ODI decreased to 13.2 +/- 11.2 from 54.5 +/- 14.5 for SELD and 9.5 +/- 10.4 from 57.5 +/- 16.0 for OLD. The average leg VAS decreased to 1.9 +/- 1.2 from 6.0 +/- 1.4 for SELD and 2.3 +/- 1.3 from 6.7 +/- 1.6 for OLD. Back VAS reduced to 2.6 +/- 1.3 from 7.2 +/- 1.5 for OLD. Time to return to work was 1.1 +/- 1.1 weeks for SELD and 5.4 +/- 2.1 weeks for OLD. Clinical outcomes of SELD were non-inferior to those of OLD in terms of pain control. CONCLUSION: A scar free procedure and early return to normal life are advantages of SELD. PMID- 29488860 TI - Training in Evidence-Based Practices Increases Likelihood to Integrate Different HIV Prevention Services with Substance-Using Clients. AB - : Providers of social and public health services ("providers") often use HIV prevention strategies with substance-using clients to decrease HIV transmission and infection. This article examines factors that facilitate providers' use of select HIV-prevention strategies. Sample comprises 379 providers from 36 agencies in New York City. OUTCOMES: sexual risk assessments; risk reduction counseling; condom demonstration; and referrals to HIV testing. PREDICTORS: training; job satisfaction; staff collaboration. The authors used multilevel logistic regression and linear multilevel models. HIV prevention training was associated with increased performance of each outcome. The odds of conducting several outcomes were higher for providers trained in evidence-based interventions. Staff collaboration and job satisfaction were associated with provision of multiple outcomes. This study shows training and collaboration/satisfaction as significantly influencing providers to use prevention strategies. Providers ought to be trained in multiple modalities, and agencies ought to prioritize collaborative environments that promote job satisfaction. PMID- 29488862 TI - Reclassification of Mameliella phaeodactyli, Mameliella atlantica, Ponticoccus lacteus and Alkalimicrobium pacificum as later heterotypic synonyms of Mameliella alba and an emended description of Mameliella alba. AB - The aim of the study was to reclarify the taxonomic status of four species, Mameliella phaeodactyli, Mameliella atlantica, Ponticoccus lacteus and Alkalimicrobium pacificum, by using a polyphasic taxonomic approach. A combination of physiological properties of the four type strains, KD53T, L6M1-5T, JL351T and F15T, was consistent with those of the closest type strain JLT354-WT of Mameliella alba. The 16S rRNA gene sequences of the five type strains shared 100 % identity. The close relationship between the five strains was underpinned by the results of chemotaxonomic characteristics, including the fatty acids, quinone and polar lipids. The pairwise digital DNA-DNA hybridization values among the five strains were well above 70 %, considered the threshold value for species definition. In this case a further statement of Rule 24a applies, in which priority of names is determined by the date of the original publication. Hence, we propose that that Mameliella phaeodactyli, Mameliella atlantica, Ponticoccus lacteus and Alkalimicrobium pacificum should be regarded as later heterotypic synonyms of Mameliella alba. PMID- 29488863 TI - Porphyromonas gingivalis hydrogen sulfide enhances methyl mercaptan-induced pathogenicity in mouse abscess formation. AB - Porphyromonas gingivalis produces hydrogen sulfide (H2S) from l-cysteine. However, the role of H2S produced by P. gingivalis in periodontal inflammation is unclear. In this study, we identified the enzyme that catalyses H2S production from l-cysteine and analysed the role of H2S using a mouse abscess model. The enzyme identified was identical to methionine gamma-lyase (PG0343), which produces methyl mercaptan (CH3SH) from l-methionine. Therefore, we analysed H2S and CH3SH production by P. gingivalis W83 and a PG0343-deletion mutant (DeltaPG0343) with/without l-cysteine and/or l-methionine. The results indicated that CH3SH is produced constitutively irrespective of the presence of l methionine, while H2S was greatly increased by both P. gingivalis W83 and DeltaPG0343 in the presence of l-cysteine. In contrast, CH3SH production by DeltaPG0343 was absent irrespective of the presence of l-methionine, and H2S production was eliminated in the absence of l-cysteine. Thus, CH3SH and H2S production involves different substrates, l-methionine or l-cysteine, respectively. Based on these characteristics, we analysed the roles of CH3SH and H2S in abscess formation in mice by P. gingivalis W83 and DeltaPG0343. Abscess formation by P. gingivalis W83, but not DeltaPG0343, differed significantly in the presence and absence of l-cysteine. In addition, the presence of l-methionine did not affect the size of abscesses generated by P. gingivalis W83 and DeltaPG0343. Therefore, we conclude that H2S produced by P. gingivalis does not induce inflammation; however, H2S enhances inflammation caused by CH3SH. Thus, these results suggest the H2S produced by P. gingivalis plays a supportive role in inflammation caused by methionine gamma-lyase. PMID- 29488864 TI - Identification of interactions among host and bacterial proteins and evaluation of their role early during Shigella flexneri infection. AB - Shigella species cause diarrhoea by invading and spreading through the epithelial layer of the human colon. The infection triggers innate immune responses in the host that the bacterium combats by translocating into the host cell cytosol via a type 3 secretion system bacterial effector proteins that interfere with host processes. We previously demonstrated that interaction of the Shigella type 3 secreted effector protein IcsB with the host protein Toca-1 inhibits the innate immune response microtubule-associated protein light-chain 3 (LC3)-associated phagocytosis, and that IcsB interaction with Toca-1 is required for inhibition of this host response. Here, we show that Toca-1 in vitro precipitated not only IcsB, but also the type 3 secreted proteins OspC3, IpgD and IpaB. OspC3 and IpgD precipitation with Toca-1 was dependent on IcsB. Early during infection, most of these proteins localized near intracellular Shigella. We examined whether interactions among these proteins restrict innate host cell responses other than LC3-associated phagocytosis. In infected cells, OspC3 blocks production and secretion of the mature pro-inflammatory cytokine IL-18; however, we found that interaction of OspC3 with IcsB, either directly or indirectly via Toca-1, was not required for OspC3-mediated restriction of IL-18 production. These results indicate that interactions of the host protein Toca-1 with a subset of type 3 effector proteins contribute to the established function of some, but not all involved, effector proteins. PMID- 29488865 TI - Farm-to-fork investigation of an outbreak of Shiga toxin-producing Escherichia coli O157. AB - Fifteen cases of Shiga toxin-producing Escherichia coli (STEC) O157 infection were associated with the consumption of contaminated food from two related butchers' premises in the north-east of England. Ten cases were admitted to hospital and seven cases developed haemolytic uraemic syndrome. A case control study found a statistically significant association with the purchase of raw and/or ready-to-eat (RTE) food supplied by the implicated butchers' shops. Isolates of STEC O157 were detected in two raw lamb burgers taken from one of the butchers' premises. Subsequent environmental sampling identified STEC O157 in bovine faecal samples on the farm supplying cattle to the implicated butchers for slaughter. Whole genome sequencing (WGS) was performed on the Illumina HiSeq 2500 platform on all cultures isolated from humans, food and cattle during the investigation. Quality trimmed Illumina reads were mapped to the STEC O157 reference genome Sakai using bwa-mem, and single nucleotide polymorphisms (SNPs) were identified using gatk2. Analysis of the core genome SNP positions (>90 % consensus, minimum depth 10*, mapping quality (MQ)>=30) revealed that all isolates from humans, food and cattle differed by two SNPs. WGS analysis provided forensic-level microbiological evidence to support the epidemiological links between the farm, the butchers' premises and the clinical cases. Cross contamination from raw meat to RTE foods at the butchers' premises was the most plausible transmission route. The evidence presented here highlights the importance of taking measures to mitigate the risks of cross-contamination in this setting. PMID- 29488866 TI - Thalassotalea insulae sp. nov., isolated from tidal flat sediment. AB - A Gram-stain-negative, aerobic, motile and rod-shaped or ovoid bacterial strain, designated JDTF-40T, was isolated from a tidal flat in Jindo, an island of the Republic of South Korea. Strain JDTF-40T grew optimally at pH 7.0-8.0, at 30 degrees C and in the presence of 2 % (w/v) NaCl. The neighbour-joining phylogenetic tree based on 16S rRNA gene sequences showed that strain JDTF-40T fell within the cluster comprising the type strains of Thalassotalea species. Strain JDTF-40T exhibited 16S rRNA gene sequence similarity values of 93.8-95.7 % to the type strains of Thalassotalea species. Strain JDTF-40T contained Q-8 as the predominant ubiquinone and summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) and C16 : 0 as the major fatty acids. The major polar lipids of strain JDTF-40T were phosphatidylglycerol, phosphatidylethanolamine, one unidentified aminolipid, one unidentified glycolipid and three unidentified lipids. The DNA G+C content of strain JDTF-40T was 41.3 mol%. Differential phenotypic properties, together with the phylogenetic distinctiveness, demonstrated that strain JDTF-40T is distinct from recognized species of the genus Thalassotalea. On the basis of the data presented here, strain JDTF-40T is considered to represent a novel species of the genus Thalassotalea, for which the name Thalassotalea insulae sp. nov. is proposed. The type strain is JDTF-40T (=KACC 19433T=KCTC 62186T=NBRC 113040T). PMID- 29488867 TI - Gene drive inhibition by the anti-CRISPR proteins AcrIIA2 and AcrIIA4 in Saccharomyces cerevisiae. AB - Given the widespread use and application of the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas gene editing system across many fields, a major focus has been the development, engineering and discovery of molecular means to precisely control and regulate the enzymatic function of the Cas9 nuclease. To date, a variety of Cas9 variants and fusion assemblies have been proposed to provide temporally inducible and spatially controlled editing functions. The discovery of a new class of 'anti-CRISPR' proteins, evolved from bacteriophage in response to the prokaryotic nuclease-based immune system, provides a new platform for control over genomic editing. One Cas9-based application of interest to the field of population control is that of the 'gene drive'. Here, we demonstrate use of the AcrIIA2 and AcrIIA4 proteins to inhibit active gene drive systems in budding yeast. Furthermore, an unbiased mutational scan reveals that titration of Cas9 inhibition may be possible by modification of the anti-CRISPR primary sequence. PMID- 29488869 TI - Tinnitus and Self-Harm Revisited. PMID- 29488868 TI - Arcobacter canalis sp. nov., isolated from a water canal contaminated with urban sewage. AB - Four bacterial strains recovered from shellfish (n=3) and from the water (n=1) of a canal contaminated with urban sewage were recognized as belonging to a novel species of the genus Arcobacter (represented by strain F138-33T) by using a polyphasic characterization. All the new isolates required 2 % NaCl to grow. Phylogenetic analyses based on 16S rRNA gene sequences indicated that all strains clustered together, with the most closely related species being Arcobacter marinus and Arcobactermolluscorum. However, phylogenetic analyses using the concatenated sequences of housekeeping genes (atpA, gyrB, hsp60, gyrA and rpoB) showed that all the novel strains formed a distinct lineage within the genus Arcobacter. Results of in silico DNA-DNA hybridization and the average nucleotide identity between the genome of strain F138-33T and those of the closely related species A. marinus and other relatively closely related species such as A. molluscorum and Arcobacterhalophilus were all below 70 and 96 %, respectively. All the above results, together with the 15 physiological and biochemical tests that could distinguish the newly isolated strains from the closely related species, confirmed that these strains represent a novel species for which the name Arcobacter canalis sp. nov. is proposed, with the type strain F138-33T (=CECT 8984T=LMG 29148T). PMID- 29488870 TI - Speech Understanding and Sound Source Localization by Cochlear Implant Listeners Using a Pinna-Effect Imitating Microphone and an Adaptive Beamformer. AB - BACKGROUND: Sentence understanding scores for patients with cochlear implants (CIs) when tested in quiet are relatively high. However, sentence understanding scores for patients with CIs plummet with the addition of noise. PURPOSE: To assess, for patients with CIs (MED-EL), (1) the value to speech understanding of two new, noise-reducing microphone settings and (2) the effect of the microphone settings on sound source localization. RESEARCH DESIGN: Single-subject, repeated measures design. For tests of speech understanding, repeated measures on (1) number of CIs (one, two), (2) microphone type (omni, natural, adaptive beamformer), and (3) type of noise (restaurant, cocktail party). For sound source localization, repeated measures on type of signal (low-pass [LP], high-pass [HP], broadband noise). STUDY SAMPLE: Ten listeners, ranging in age from 48 to 83 yr (mean = 57 yr), participated in this prospective study. INTERVENTION: Speech understanding was assessed in two noise environments using monaural and bilateral CIs fit with three microphone types. Sound source localization was assessed using three microphone types. DATA COLLECTION AND ANALYSIS: In Experiment 1, sentence understanding scores (in terms of percent words correct) were obtained in quiet and in noise. For each patient, noise was first added to the signal to drive performance off of the ceiling in the bilateral CI-omni microphone condition. The other conditions were then administered at that signal-to-noise ratio in quasi random order. In Experiment 2, sound source localization accuracy was assessed for three signal types using a 13-loudspeaker array over a 180 degrees arc. The dependent measure was root-mean-score error. RESULTS: Both the natural and adaptive microphone settings significantly improved speech understanding in the two noise environments. The magnitude of the improvement varied between 16 and 19 percentage points for tests conducted in the restaurant environment and between 19 and 36 percentage points for tests conducted in the cocktail party environment. In the restaurant and cocktail party environments, both the natural and adaptive settings, when implemented on a single CI, allowed scores that were as good as, or better, than scores in the bilateral omni test condition. Sound source localization accuracy was unaltered by either the natural or adaptive settings for LP, HP, or wideband noise stimuli. CONCLUSION: The data support the use of the natural microphone setting as a default setting. The natural setting (1) provides better speech understanding in noise than the omni setting, (2) does not impair sound source localization, and (3) retains low-frequency sensitivity to signals from the rear. Moreover, bilateral CIs equipped with adaptive beamforming technology can engender speech understanding scores in noise that fall only a little short of scores for a single CI in quiet. PMID- 29488871 TI - An Argument for Self-Report as a Reference Standard in Audiology. AB - BACKGROUND: The primary components of a diagnostic accuracy study are an index test, the target condition (or disorder), and a reference standard. According to the Standards for Reporting Diagnostic Accuracy statement, the reference standard should be the best method available to independently determine if the results of an index test are correct. Pure-tone thresholds have been used as the "gold standard" for the validation of some tests used in audiology. Many studies, however, have shown a lack of agreement between the audiogram and the patient's perception of hearing ability. For example, patients with normal audiograms may report difficulty understanding speech in the presence of background noise. PURPOSE: The primary purpose of this article is to present an argument for the use of self-report as a reference standard for diagnostic studies in the field of audiology. This will be in the form of a literature review on pure-tone threshold measures and self-report as reference standards. The secondary purpose is to determine the diagnostic accuracy of pure-tone threshold and Hearing-in-Noise Test (HINT) measures for the detection of a speech-recognition-in-noise disorder. RESEARCH DESIGN: Two groups of participants with normal pure-tone thresholds were evaluated. The King-Kopetzky syndrome (KKS) group was made up of participants with the self-report of speech-recognition-in-noise difficulties. The control group was made up of participants with no reports of speech-recognition-in-noise problems. The reference standard was self-report. Diagnostic accuracy of HINT and pure-tone threshold measures was determined by measuring group differences, sensitivity and specificity, and the area under the curve (AUC) for receiver operating characteristic (ROC) curves. STUDY SAMPLE: Forty-seven participants were tested. All participants were native speakers of American English. Twenty two participants were in the control group and 25 in the KKS group. The groups were matched for age. DATA COLLECTION AND ANALYSIS: Pure-tone threshold data were collected using the Hughson-Westlake procedure. Speech-recognition-in-noise data was collected using a software system and the standard HINT protocol. Statistical analyses were conducted using descriptive, correlational, two-sample t tests, and logistic regression. RESULTS: The literature review revealed that self-report has been used as a reference standard in investigations of patients with normal audiograms and the perception of difficulty understanding speech in the presence of background noise. Self-report may be a better indicator of hearing ability than pure-tone thresholds in some situations. The diagnostic accuracy investigation revealed statistically significant differences between control and KKS groups for HINT performance (p < 0.01), but not for pure-tone threshold measures. Better sensitivity was found for the HINT Composite score (88%) than pure-tone average (PTA; 28%). The specificities for the HINT Composite score and PTA were 77% and 95%, respectively. ROC curves revealed a greater AUC for the HINT Composite score (AUC = 0.87) than for PTA (AUC = 0.51). CONCLUSION: Self report is a reasonable reference standard for studies on the diagnostic accuracy of speech-recognition-in-noise tests. For individuals with normal pure-tone thresholds, the HINT demonstrated a higher degree of diagnostic accuracy than pure-tone thresholds for the detection of speech-recognition-in-noise disorder. PMID- 29488872 TI - Test-Retest Reliability and Minimal Detectable Change of Randomized Dichotic Digits in Learning-Disabled Children: Implications for Dichotic Listening Training. AB - BACKGROUND: Evaluation of dichotic listening to digits is a common part of many studies for diagnosis and managing auditory processing disorders in children. Previous researchers have verified test-retest relative reliability of dichotic digits results in normal children and adults. However, detecting intervention related changes in the ear scores after dichotic listening training requires information regarding trial-to-trial typical variation of individual ear scores that is estimated using indices of absolute reliability. Previous studies have not addressed absolute reliability of dichotic listening results. PURPOSE: To compare the results of the Persian randomized dichotic digits test (PRDDT) and its relative and absolute indices of reliability between typical achieving (TA) and learning-disabled (LD) children. RESEARCH DESIGN: A repeated measures observational study. STUDY SAMPLE: Fifteen LD children were recruited from a previously performed study with age range of 7-12 yr. The control group consisted of 15 TA schoolchildren with age range of 8-11 yr. DATA COLLECTION AND ANALYSIS: The Persian randomized dichotic digits test was administered on the children under free recall condition in two test sessions 7-12 days apart. We compared the average of the ear scores and ear advantage between TA and LD children. Relative indices of reliability included Pearson's correlation and intraclass correlation (ICC2,1) coefficients and absolute reliability was evaluated by calculation of standard error of measurement (SEM) and minimal detectable change (MDC) using the raw ear scores. RESULTS: The Pearson correlation coefficient indicated that in both groups of children the ear scores of test and retest sessions were strongly and positively (greater than +0.8) correlated. The ear scores showed excellent ICC coefficient of consistency (0.78-0.82) and fair to excellent ICC coefficient of absolute agreement (0.62-0.74) in TA children and excellent ICC coefficients of consistency and absolute agreement in LD children (0.76-0.87). SEM and SEM% of the ear scores in TA children were 1.46 and 1.44% for the right ear and 4.68 and 5.47% for the left ear. SEM and SEM% of the ear scores in LD children were 4.55 and 5.88% for the right ear to 7.56 and 12.81% for the left ear. MDC and MDC% of the ear scores in TA children varied from 4.03 and 3.99% for the right ear to 12.93 and 15.13% for the left ear. MDC and MDC% of the ear scores in LD children varied from 12.57 and 16.25% for the right ear to 20.89 and 35.39% for the left ear. CONCLUSIONS: The LD children indicated test-retest relative reliability as high as TA children in the ear scores measured by PRDDT. However, within-subject variations of the ear scores calculated by indices of absolute reliability were considerably higher in LD children versus TA children. The results of the current study could have implications for detecting real training-related changes in the ear scores. PMID- 29488873 TI - Description, Normative Data, and Utility of the Hearing Aid Skills and Knowledge Test. AB - BACKGROUND: The ability to manage hearing aids is crucial for successful outcomes and for maintaining hearing aid use. It is therefore important to have a tool that can effectively identify which hearing aid management skills are lacking so that the audiologist can provide additional education and training on that skill. Such a tool can also provide useful quantitative data for researchers. PURPOSE: To collect normative data (Experiment 1) and assess inter- and intrarater reliability (Experiment 2) for a hearing aid management assessment tool known as the Hearing Aid Skills and Knowledge (HASK) test. STUDY SAMPLE: Two hundred thirty-six new hearing aid users recruited from the VA Portland Health Care System and 126 experienced hearing aid users recruited from the local Portland community participated in Experiment 1. The veteran participants were taking part in a larger hearing aid study, and the community participants were recruited at community events that took place around Portland, OR. Three clinical audiologists and two AuD students completing their fourth year externship participated in Experiment 2. DATA COLLECTION AND ANALYSIS: In Experiment 1, HASK data were collected from the new hearing aid users at 4-8 wk and 6-8 mo after the fitting of their first pair of hearing aids, and from experienced users on a single occasion. In addition, self-reported hearing aid use, benefit, and satisfaction were assessed for all participants. The audiologists/students in Experiment 2 watched and independently scored videos of six individuals completing the HASK. Intraclass correlation coefficients (ICCs) across audiologists were computed for HASK scores. Three audiologists/students rated at least one video on two occasions to provide interrater reliability data. RESULTS: Mean performance on the HASK was about 70% for knowledge and 80% for skills for both the new and experienced hearing aid users. Performance did not change among the new users between the 4-8 wk and 6-8 mo administration. The specific skills lacking were associated with advanced management abilities (cleaning and troubleshooting). Experiment 2 revealed ICCs for inter- and intrarater reliability for HASK to range from 0.76 to 0.94, showing acceptable to excellent reliability. CONCLUSIONS: The HASK is a quick and easy test with good-to-excellent inter- and intrarater reliability. It can effectively identify which hearing aid management skills are lacking so that the audiologist can provide additional education and training on those skills. Data show performance is ~70% for knowledge and 80% for skills and this does not change with hearing aid experience. The significant positive correlations between HASK scores and hearing aid use and satisfaction highlight the notion that ability to manage hearing aids successfully is integral to good hearing aid outcome. PMID- 29488874 TI - Investigation of Extended Bandwidth Hearing Aid Amplification on Speech Intelligibility and Sound Quality in Adults with Mild-to-Moderate Hearing Loss. AB - BACKGROUND: Advances in digital signal processing have made it possible to provide a wide-band frequency response with smooth, precise spectral shaping. Several manufacturers have introduced hearing aids that are claimed to provide gain for frequencies up to 10-12 kHz. However, there is currently limited evidence and very few independent studies evaluating the performance of the extended bandwidth hearing aids that have recently become available. PURPOSE: This study investigated an extended bandwidth hearing aid using measures of speech intelligibility and sound quality to find out whether there was a significant benefit of extended bandwidth amplification over standard amplification. RESEARCH DESIGN: Repeated measures study designed to examine the efficacy of extended bandwidth amplification compared to standard bandwidth amplification. STUDY SAMPLE: Sixteen adult participants with mild-to-moderate sensorineural hearing loss. INTERVENTION: Participants were bilaterally fit with a pair of Widex Mind 440 behind-the-ear hearing aids programmed with a standard bandwidth fitting and an extended bandwidth fitting; the latter provided gain up to 10 kHz. DATA COLLECTION AND ANALYSIS: For each fitting, and an unaided condition, participants completed two speech measures of aided benefit, the Quick Speech-in-Noise test (QuickSINTM) and the Phonak Phoneme Perception Test (PPT; high-frequency perception in quiet), and a measure of sound quality rating. RESULTS: There were no significant differences found between unaided and aided conditions for QuickSINTM scores. For the PPT, there were statistically significantly lower (improved) detection thresholds at high frequencies (6 and 9 kHz) with the extended bandwidth fitting. Although not statistically significant, participants were able to distinguish between 6 and 9 kHz 50% better with extended bandwidth. No significant difference was found in ability to recognize phonemes in quiet between the unaided and aided conditions when phonemes only contained frequency content <6 kHz. However significant benefit was found with the extended bandwidth fitting for recognition of 9-kHz phonemes. No significant difference in sound quality preference was found between the standard bandwidth and extended bandwidth fittings. CONCLUSIONS: This study demonstrated that a pair of currently available extended bandwidth hearing aids was technically capable of delivering high-frequency amplification that was both audible and useable to listeners with mild-to-moderate hearing loss. This amplification was of acceptable sound quality. Further research, particularly field trials, is required to ascertain the real-world benefit of high-frequency amplification. PMID- 29488875 TI - Thoughts about Suicide and Self-Harm in Patients with Tinnitus and Hyperacusis. AB - BACKGROUND: There are conflicting reports with regard to the relationship between suicidal ideations and tinnitus and hyperacusis. Audiology departments play a major role in offering therapy and support for patients experiencing tinnitus and hyperacusis. If suicidal and self-harm ideations among patients seen in audiology clinics are high, then it would be important to screen for them to make onward referrals to mental health services. PURPOSE: The aim of this study was to assess the prevalence of and factors related to suicidal and self-harm ideations in patients with tinnitus and hyperacusis seen at an audiology outpatient service. RESEARCH DESIGN: This study was a part of a service evaluation survey using a correlational design. STUDY SAMPLE: All patients who sought help concerning their tinnitus or hyperacusis from an audiology clinic of the National Health Service in the United Kingdom in a 1-yr period were asked to complete the survey questionnaires (n = 402). DATA COLLECTION AND ANALYSIS: The focus of this article is on analysis of the patients' responses about suicidal and self-harm ideations as measured via the Patient Health Questionnaire, item 9, and their associated factors. RESULTS: A total of 150/402 of patients answered the question about suicidal and self-harm ideations. Of these, 13% indicated that they had suicidal or self-harm ideations in the past 2 weeks. Suicidal and self-harm ideations were moderately correlated with scores on the anxiety and depression subscales of the hospital anxiety and depression scale. Suicidal and self-harm ideations decreased with increasing age. There were small statistically significant correlations between suicidal and self-harm ideations and tinnitus handicap, hyperacusis handicap, insomnia, and scores on the visual analog scale (VAS) of effect of tinnitus on life. The correlations between suicidal and self-harm ideations and gender, pure-tone average of the worse and better ears, uncomfortable loudness levels of the worse ears, and VAS of tinnitus loudness and annoyance were not statistically significant. A regression model showed that abnormal depression scores increased the chance of suicidal and self-harm ideations by a factor of 6.2 (95% confidence interval = 1.13-34.1, p = 0.036). CONCLUSIONS: Audiologists offering tinnitus and hyperacusis rehabilitation should screen for suicidal and self-harm ideations among patients, especially for those with comorbid depression, and make onward referral to appropriate services when needed. PMID- 29488876 TI - Response to Drs. Iliadou and Eleftheriadis Regarding "Auditory Processing Disorder (APD) as the Sole Manifestation of a Cerebellopontine and Internal Auditory Canal Lesion". PMID- 29488877 TI - Response to the Letter from Dr. Vermiglio Regarding Iliadou and Eleftheriadis (2017): CAPD is Classified in ICD-10 as H93.25. PMID- 29488879 TI - The transcription factors Runx3 and ThPOK cross-regulate acquisition of cytotoxic function by human Th1 lymphocytes. AB - Cytotoxic CD4 (CD4CTX) T cells are emerging as an important component of antiviral and antitumor immunity, but the molecular basis of their development remains poorly understood. In the context of human cytomegalovirus infection, a significant proportion of CD4 T cells displays cytotoxic functions. We observed that the transcriptional program of these cells was enriched in CD8 T cell lineage genes despite the absence of ThPOK downregulation. We further show that establishment of CD4CTX-specific transcriptional and epigenetic programs occurred in a stepwise fashion along the Th1-differentiation pathway. In vitro, prolonged activation of naive CD4 T cells in presence of Th1 polarizing cytokines led to the acquisition of perforin-dependent cytotoxic activity. This process was dependent on the Th1 transcription factor Runx3 and was limited by the sustained expression of ThPOK. This work elucidates the molecular program of human CD4CTX T cells and identifies potential targets for immunotherapy against viral infections and cancer. PMID- 29488880 TI - Shorter cortical adaptation in dyslexia is broadly distributed in the superior temporal lobe and includes the primary auditory cortex. AB - Studies of the performance of individuals with dyslexia in perceptual tasks suggest that their implicit inference of sound statistics is impaired. Previously, using two-tone frequency discrimination, we found that the effect of previous trials' frequencies on the judgments of individuals with dyslexia decays faster than the effect on controls' judgments, and that the adaptation (decrease of neural response to repeated stimuli) of their ERP responses to tones is shorter (Jaffe-Dax et al., 2017). Here, we show the cortical distribution of these abnormal dynamics of adaptation using fast-acquisition fMRI. We find that faster decay of adaptation in dyslexia is widespread, although the most significant effects are found in the left superior temporal lobe, including the auditory cortex. This broad distribution suggests that the faster decay of implicit memory of individuals with dyslexia is a general characteristic of their cortical dynamics, which also affects sensory cortices. PMID- 29488883 TI - Less invasive fractional flow reserve measurement from 3-dimensional quantitative coronary angiography and classic fluid dynamic equations. AB - AIMS: The aim of this study was to develop a simplified model of FFR calculation (FFRsim) derived from three-dimensional (3D) coronary angiographic data and classic fluid dynamic equations without using finite element analysis. METHODS AND RESULTS: Intracoronary pressure measurements were performed by pressure wire sensors. The lumens of the interrogated vessel segments were reconstructed in 3D. The coronary artery volumetric flow was calculated based on the velocity of the contrast material. Pressure gradients were computed by classic fluid dynamic equations. The diagnostic power of the simplified computation of the FFR (FFRsim) was assessed by comparing the results with standard invasive FFR measurements (FFRmeas) in 68 vessels with a single stenosis. We found a strong correlation between the FFRsim and the FFRmeas (r=0.86, p<0.0001). The sensitivity and specificity for predicting the abnormal FFR of <=0.80 (indicating haemodynamically significant stenosis) were 90% and 100%, respectively. The area under the curve (AUC) was 0.96. To achieve 100% negative and positive predictive values we defined the FFRsim >0.88 and the FFRsim <=0.8 ranges. In our patient population, these ranges were found in 69% of the cases. CONCLUSIONS: According to our simplified model, the invasive FFR measurement can be omitted without misclassification in pre-specified ranges of the calculated FFRsim. PMID- 29488881 TI - Explosive mutation accumulation triggered by heterozygous human Pol epsilon proofreading-deficiency is driven by suppression of mismatch repair. AB - Tumors defective for DNA polymerase (Pol) epsilon proofreading have the highest tumor mutation burden identified. A major unanswered question is whether loss of Pol epsilon proofreading by itself is sufficient to drive this mutagenesis, or whether additional factors are necessary. To address this, we used a combination of next generation sequencing and in vitro biochemistry on human cell lines engineered to have defects in Pol epsilon proofreading and mismatch repair. Absent mismatch repair, monoallelic Pol epsilon proofreading deficiency caused a rapid increase in a unique mutation signature, similar to that observed in tumors from patients with biallelic mismatch repair deficiency and heterozygous Pol epsilon mutations. Restoring mismatch repair was sufficient to suppress the explosive mutation accumulation. These results strongly suggest that concomitant suppression of mismatch repair, a hallmark of colorectal and other aggressive cancers, is a critical force for driving the explosive mutagenesis seen in tumors expressing exonuclease-deficient Pol epsilon. PMID- 29488882 TI - Maternal Plasma per- and Polyfluoroalkyl Substance Concentrations in Early Pregnancy and Maternal and Neonatal Thyroid Function in a Prospective Birth Cohort: Project Viva (USA). AB - BACKGROUND: Prenatal exposure to some per- and polyfluoroalkyl substances (PFASs) may disrupt maternal and neonatal thyroid function, which is critical for normal growth and neurodevelopment. OBJECTIVES: We examined associations of PFAS exposure during early pregnancy with maternal and neonatal thyroid hormone levels. METHODS: We studied 732 mothers and 480 neonates in Project Viva, a longitudinal prebirth cohort in Boston, Massachusetts. We quantified six PFASs, including perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), and maternal thyroid hormones [thyroxine (T4), Free T4 Index (FT4I), thyroid stimulating hormone (TSH)] in plasma samples collected at a median 9.6 wk gestation and neonatal T4 levels from postpartum heel sticks. We estimated associations of PFAS concentrations with thyroid hormone levels using covariate adjusted linear regression models and explored effect measure modification by maternal thyroid peroxidase antibody (TPOAb) status and infant sex. RESULTS: PFAS concentrations were not associated with maternal T4, but PFOA, perfluorohexane sulfonate (PFHxS), and 2-(N-methyl-perfluorooctane sulfonamido) acetate (MeFOSAA) were inversely associated with maternal FT4I [e.g., -1.87% (95% confidence interval (CI): -3.40, -0.31) per interquartile (IQR) increase in PFOA]. PFAS concentrations [PFOA, PFOS, and perfluorononanoate (PFNA)] were inversely associated with TSH levels in TPOAb-positive women only. Prenatal PFOS, PFOA, and PFHxS concentrations were inversely associated with T4 levels in male [e.g., PFHxS, quartile 4 vs.1: -2.51MUg/dL (95% CI: -3.99, -1.04 )], but not female neonates [0.40MUg/dL (95% CI: -0.98, 1.79)]. CONCLUSIONS: In this study, prenatal exposure to some PFASs during early pregnancy was inversely associated with maternal FT4I and neonatal T4 in male infants. These results support the hypothesis that prenatal exposure to PFASs influences thyroid function in both mothers and infants. https://doi.org/10.1289/EHP2534. PMID- 29488884 TI - High-pressure post-dilation following transcatheter valve-in-valve implantation in small surgical valves. AB - AIMS: Residual gradients >20 mmHg after transcatheter valve-in-valve (ViV) implantation are associated with worse survival. This study aimed to evaluate the feasibility of high-pressure post-dilation with a non-compliant balloon after transcatheter ViV implantation in small surgical valves to optimise haemodynamics. METHODS AND RESULTS: Thirty patients underwent ViV implantation in surgical valves with internal dimension <=19 mm. High-pressure post-dilation to 16-20 atmospheres with a non-compliant balloon was performed in 12 patients and 18 patients underwent ViV without post-dilation. SAPIEN 3 and Evolut valves were used in 10 and two patients, respectively. The mean aortic valve (AV) gradient decreased by 11.3 mmHg following high-pressure post-dilation (18.7+/-7.9 mmHg immediately post ViV to 7.5+/-2.6 mmHg following high-pressure post-dilation, p<0.01). There were no cases of aortic root rupture. High-pressure post-dilation, compared to no post-dilation, was associated with lower invasive AV mean gradients at the end of the ViV procedure (8.2+/-3.5 mmHg vs. 17.3+/-7.9 mmHg, p=0.001) as well as lower day 1 (18.0+/-4.5 mmHg vs. 25.0+/-8.1 mmHg, p=0.016) and 30-day gradients (19.8+/-2.5 vs. 26.5+/-11.0, p=0.038) on transthoracic echocardiography. CONCLUSIONS: High-pressure post-dilation of small surgical valves following transcatheter ViV implantation results in a significant improvement in post-procedure haemodynamics. PMID- 29488885 TI - Successful transcatheter aortic valve replacement using a self-expanding bioprosthesis in a patient with a unicuspid aortic valve associated with severe regurgitation and cardiogenic shock. PMID- 29488886 TI - Quality difference of neointima following the implantation of everolimus-eluting bioresorbable scaffolds and metallic stents in patients with ST-elevation myocardial infarction: quantitative assessments by light intensity, light attenuation, and backscatter on optical coherence tomography in the TROFI II trial. AB - AIMS: We aimed to assess possible differences in neointimal quality after everolimus-eluting bioresorbable scaffold (BVS) implantation in comparison with cobalt-chromium everolimus-eluting scaffold (CoCr-EES) implantation by optical frequency domain imaging (OFDI). METHODS AND RESULTS: This study is a post hoc analysis of the TROFI II trial assessing neointimal quality six months after the implantation of BVS (N=82) and CoCr-EES (N=87) in STEMI patients. Neointimal light property analysis by OFDI fully automatically computed light attenuation, backscatter and light intensity for superficial and deep neointima. High light attenuation/backscatter and high light intensity are reportedly associated with lipidic change and tissue maturation, respectively. Superficial and deep neointima in BVS presented lower light attenuation than CoCr-EES (superficial: 0.77+/-0.15 vs. 1.27+/-0.55 mm-1, p<0.001; deep: 0.88+/-0.20 vs. 1.17+/-0.27 mm 1, p<0.001). Superficial neointima in BVS showed comparable backscatter to that of CoCr-EES (4.81+/-0.52 vs. 4.94+/-0.61, p=0.141), while deep neointima in BVS showed lower backscatter than that of CoCr-EES (4.60+/-0.62 vs. 4.97+/-0.62, p<0.001). Light intensity of superficial neointima was comparable between both arms (139+/-13 vs. 144+/-30, p=0.236), whereas light intensity of deep neointima in BVS was lower than CoCr-EES (129+/-14 vs. 138+/-21, p<0.001). CONCLUSIONS: The present OFDI comparison suggested that tissue maturation was comparable but lipidic change of neointima was less prominent after BVS than after CoCr-EES implantation. PMID- 29488887 TI - Novel predictors of mild paravalvular aortic regurgitation in SAPIEN 3 transcatheter aortic valve implantation. AB - AIMS: Paravalvular leak (PVL) remains an important issue in TAVI. The Edwards SAPIEN 3 (S3) valve has reduced PVL but in up to one third of patients mild leak remains. Our study aimed to identify predictors of mild PVL after TAVI with the S3 valve. METHODS AND RESULTS: From October 2015 to May 2017, 122 consecutive patients underwent S3 TAVI for symptomatic severe aortic stenosis. Thirty-three patients with mild PVL on transthoracic echocardiography at 30-day follow-up were compared to 89 with none/trace PVL. Thirty-day mortality was 2.5% (n=3), with zero stroke and major vascular complications. There were no differences between the two groups in patient characteristics, annular and left ventricular outflow tract (LVOT) sizing, distribution and severity of annular calcification, valve implantation technique, post-dilatation and implant depth. Mild PVL was associated with higher annular eccentricity (p=0.04) and moderate-severe LVOT calcification (p=0.03). Independent predictors of mild PVL were LVOT eccentricity (OR 1.05 per % ellipticity, 95% CI: 1.02-1.09, p=0.005), discordant sizing (OR 3.08, 95% CI: 1.20-7.90, p=0.02) and three-leaflet calcification (OR 13.3, 95% CI: 2.66-66.7, p=0.002). CONCLUSIONS: LVOT eccentricity and discordant sizing predict PVL after S3 TAVI. Further studies are needed to understand their mechanism and significance. PMID- 29488888 TI - In-hospital outcomes after transcatheter or surgical aortic valve replacement in younger patients less than 75 years old: a propensity-matched comparison. AB - AIMS: Randomised trials comparing transcatheter aortic valve replacement (TAVR) with surgical aortic valve replacement (SAVR) have included mainly elderly patients >80 years. The authors investigated comparative in-hospital outcomes of younger patients <75 years undergoing transfemoral (TF) TAVR or isolated SAVR. METHODS AND RESULTS: A total of 6,972 patients aged 65-74 years undergoing TF TAVR or SAVR between 2013 and 2014 were identified from the observational German Quality Assurance Registry on Aortic Valve Replacement (AQUA), which comprises all TAVR and SAVR procedures performed in Germany. Analyses were performed for the overall unmatched cohort as well as for 1,388 propensity-matched patients. Overall, 82.4% of patients <75 years needing treatment for aortic valve stenosis received SAVR. Patients undergoing TF-TAVR were older and had more comorbidities with higher predicted risk of death. After propensity-matching, in-hospital mortality (1.3% vs. 1.9%, p=0.39), neurologic complications (1.0% vs. 2.1%, p=0.09), and myocardial infarctions (0 vs. 0.3%, p=0.16) were not different after TF-TAVR or SAVR. Postoperative delirium was more frequent after SAVR (8.9% vs. 2.4%, p<0.001), whereas the need for new pacemaker was 4 times higher after TF TAVR (13.3% vs. 3.5%, p<0.001). CONCLUSIONS: Younger patients <75 years undergoing TF-TAVR or SAVR had similar outcomes with the exception of more frequent need for new pacemaker implantation and less frequent incidence of post operative dialysis and delirium in TF-TAVR patients. Whether these similar in hospital outcomes are replicable in the longer-term events in TF-TAVR and SAVR remains to be proven in future studies. PMID- 29488889 TI - [Perceptions regarding pharmacotherapy and effective treatment disease in people diagnosed with bipolar disorder]. AB - Bipolar disorder (BD) encompasses neuro-cognitive disturbances leading to psychological and social consequences affecting the quality of life of those suffering from it. However, the number of studies on the lived experience of people with BD about the treatment provided is relatively scant. The aim of this study is to investigate the lived experience of people with BD, focused on their perceptions and meanings about the treatment provided for their disorder. A qualitative, phenomenological design was applied. Following informed consent, thirteen people agreed to participate in the study, according to purposeful sampling and thematic saturation. Data collection was achieved through individual, semistructural interviews with open-ended questions, of a 30 minutes to an hour. The rigor of the analysis was validated according to Munhall's and van Manen's criteria. With regard to the main themes emerged, those revolved mainly around the social stigmatization following psychotropic medication. Further, the participants described anguish, fear and insecurity about the winding road nature of the disease, a condition that seemed to be worsened mainly due to discontinuation of medication, or alterations of the therapeutic schema. Interestingly, some of the participants described medication as a nutrient ingredient that kept them alive, thus revealing the importance they attached to psychotropic medication. Participants highlighted the importance of psychotropic medication, along with psychotherapy and personal effort, as well as education on topics related to psychopathology and treatment interventions for BD. Control over the clinical outcome of the disorder and self-management of the symptoms seem to be the ultimate need of people suffering from BD, with a core association to the effective medication and psycho-education. Based on that, interventions aiming to patients' education in self-management skills are suggested. Furthermore, interventions towards the sensitization of the community on the biological aspects of mental disorders are proposed, tackling issues as stigma and medication concerns. PMID- 29488890 TI - [Clinical guidelines for the management of schizophrenia:Aims and limitations (Iota)]. AB - The initiative for the development of national treatment guidelines, dates back to the '90s. In Greece, however, National Clinical Guidelines for the management of schizophrenia were first formulated in 2014 when a Working Group was set up for this purpose by the Greek Ministry of Health. The objective of this Working Group was to provide evidence-based recommendations covering the pharmacological and psychosocial treatment of schizophrenia as well as the development of appropriate treatment services. The Working Group utilized the NICE Guideline (National Institute of Clinical Excellence, 2010, 2014) for the management of Psychosis & Schizophrenia as the main guide to develop the Greek National Guidelines , and in addition the American Psychiatric Association (APA) Practice Guideline for the Treatment of Patients with Schizophrenia (APA 2004), the Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the treatment of schizophrenia and related disorders (Royal Australian and New Zealand College of Psychiatrists 2005) , as well as other relevant sources. The Working Group also took into consideration the available Greek bibliography as well as the external evaluations of the Greek psychiatric reform programs. A special effort was made to adapt the international experience to the current Greek landscape with the constraints resulting from the uneven dispersion of mental health services, the lack of coordination between services, the incomplete sectorization of mental health services provided as part of the National Health System, the still underdeveloped Primary Care Health Service, and last but not least the difficult economic situation in Greece. After the preparation of the draft guidelines, a thorough consultation followed with the relevant stakeholders, including mental health professionals, user associations and representatives of the Greek Ombudsman. Additionally, the Hellenic Psychiatric Association established an Expert Committee in Spring 2016, that contributed with its observations to the final exercise. This article will be followed by two further publications (incorporating the Hellenic Psychiatric Association comments) which include: (1) the summary recommendations regarding the pharmacological, psychological and psychosocial interventions in the treatment of schizophrenia, and (2) the summary recommendations regarding: (a) the role of primary health care service and the role of the family physician in the treatment of schizophrenia (b) the summary recommendations regarding continuity of care and c) the summary recommendations regarding community interventions with documented effectiveness in the treatment of schizophrenia. PMID- 29488891 TI - [Restraints in Greek mental health services: Ethics, practice and costs]. AB - The use of physical and mechanical restraints in mental health services in Greece arise many ethical and practical issues. The justification of the use of such procedures is rather controversial and subjective to scientific debate. The practice of restraint puts both patients and staff at risk for injury and death. Moreover, restraints can be traumatic even when they do not result in any physical injury to the patient. The types of the physical adverse events include dehydration, suffocation, circulation disturbances, skin problems, loss of strength and mobility, incontinence, etc. Research studies regarding the use of restraints are limited, although individual, professional, and social impact is extensive. Worldwide many associations involving patients, care givers and patient rights authorities have disapproved such techniques as inhumane and against recent scientific evidence. Nevertheless, the methods are being used for highly agitated and violent patients in mental health hospitals in order to protect the patients and others towards physical harms. Verbal de-escalation strategies should be attempted prior to the use of any form of restraint. Although there are no strict guidelines in Greece for the use of the least restrictive and effective treatment for an agitated and/or violent patient there are certain occasions that restraints cannot be avoided. Physical, chemical and mechanical restraints should never be used for the sake of convenience or punishment. The healthcare professionals understand and follow proper procedures when restraining a patient to ensure safety and dignity of the person. Failure to follow guidelines is subjective to legal actions by the patient, the family and the independent mental health authorities. Restraining comes in many forms, like chemical, physical and mechanical. Clinical judgment must be applied to determine the necessity of any restrictive decision. Consultant psychiatrists, mental health nurses and ward staff are involved to the initial assessment, the level of restriction, the procedure of restraints, the follow-up and the reassessment of the level of safety, due to the guidelines and the wide range of complication concerns. Further to the clear public, medical and operational concerns for the restraints, these procedures are expensive for the mental health services. In our study we estimated the costs of the procedures per patient, excluding the medication costs. According to our data each mechanical restraint costs at least ? 57.28 and each seclusion ? 47.16 respectively for up to 2 hours of duration and increase according to the prolongation of the restraint procedures. PMID- 29488892 TI - [The concept of the "limit": Alpha metapsychological approach of the Freudian theory]. AB - This article is referring to the study of the "limit" according to a metapsychological point of view. The main definition of this concept concerns its double possibility to relate and to separate the internal from the external reality. It is about a review of the post-freudian work: the theoretical contribution of the authors P. Federn, D. Anzieu and D.W. Winnicott is viewed through the conceptualisation of the "limit". Also, the study of A. Green, who is the author who proposed not only the concept of the "limit" but also the concept of the "double limit". P. Federn distinguished the Ego in its mental and its physical dimension, in his work which is concentrated on the study of the Ego. According to him, these two dimensions are at the same time related one to the other and seen separately in a healthy functioning psychism. The function of the limit as it is expressed in his theoretical background is absent in the field of psychosis, so according to P. Federn, psychosis is an "illness of the Ego". D. Anzieu expressed the notion of the "Ego-skin" in order to put into theoretical terms its protecting factor considering it also as an analogue with the function of the Ego, regarding the exchanges between the external and the psychic reality. Emphasis is given to the creation of the "Ego-skin" during the first period of life in the relationship between the mother and the infant. Based on the study of the primary period of life, the contribution of D. W. Winnicott concerning the wording of the function of the limit is decisive, as he introduced the theory of the transitionnality, seen as the third reality which is located between the internal and the external reality. A. Green, finally, is the main author who introduced this term as throughout his theoretical work the term got its shape, as he referred to its metapsychological dimension, because the function of the limit is the one which has to be seen as the central dimension of the healthy psychic functioning. Based on this theoretical approach, the psychopathological expression of the concept is studied as well. As a conclusion of this review it is shown that S. Freud was the first who has studied, at least indirectly, the concept of the "limit" by introducing the theory of instincts and throughout his later works. PMID- 29488893 TI - [Women's sexual function through sexual response models: From DSM-IV to DSM-5]. AB - Until recently, DSM classifications regarding women's sexual dysfunctions were based on definitions that mainly derived from experts opinions, rather than clinical or epidemiological studies. Additionally, this classification was the same for men and women, taking for granted the existence of a single sexual response model for men and women. More specifically, the main models that were described and prevailed were the linear models of Master's & Johnson and Kaplan, as well as the circular model of Rosemary Basson that followed. The differences between linear and circular models have to do mainly with the fact that stages of sexual response overlap with each other in the circular model, while the initiation of sexual activity may not need the presence of spontaneous sexual desire. In linear models, the stages of sexual desire, arousal, orgasm and resolution follow each other in a stable manner, in contrary to circular models where sexual desire may not be neither the first stage nor the main reason for sexual activity. In this case, reasons for sexual activity may vary, focusing also on other aspects of human sexuality and personality and not only on innate sexual desire. DSM-5 based the classification of sexual dysfunctions on the circular model, although there is still not enough evidence to prove that all men and women can be represented by the same sexual response model throughout the lifespan. Apart from the aforementioned sexual response models, also other models have been described by several investigators, making an important effort to give a more accurate and complete description of human sexual function, as well as its disorders. The present article makes an attempt to review the sexual response models that have been described by the literature up to date, as well as to relate them to the DSM-IV and DSM-5 classifications. PMID- 29488894 TI - [Poor insight and psychosis]. AB - A variety of phenomena might be considered as reflecting impaired insight in psychosis, like failure to recognize signs, symptoms or disease, failure to derive appropriate cognitive representations, despite recognition of the disease, and misattribution of the source or cause of the disease. The unawareness of tardive dyskinesia symptoms in schizophrenic patients points that self-awareness deficits in schizophrenia may be domain specific. Poor insight is an independent phenomenological and a prevalent feature in psychotic disorders in general, and in schizophrenia in particular, but we don't know yet if delusions in schizophrenia are the result of an entirely normal attempt to account for abnormal perceptual experiences or a product of abnormal experience but of normal reasoning. The theoretical approaches regarding impaired insight include the disturbed perceptual input, the impaired linkage between thought and emotion and the breakdown of the process of self-monitoring and error checking. The inability to distinguish between internally and externally generated mental events has been described by the metarepresentation theory. This theory includes the awareness of ones' goals, which leads to disorders of willed action, the awareness of intention, which leads to movement disorders, and the awareness of intentions of others, which leads to paranoid delusions. The theory of metarepresentation implies mainly output mechanisms, like the frontal cortex, while the input mechanism implies posterior brain systems, including the parietal lobe. There are many similarities between the disturbances of awareness seen in schizophrenia and those seen as a result of known neurological impairment. Neuropsychological models of impaired insight typically attribute the disturbance to any of a variety of core deficits in the processing of information. In this respect, lack of insight is on conceptual par with alogia, apraxia or aphasia in reflecting disturbed cognitive processing. In this direction, research have implicated the role of self-monitoring in disorders of awareness and many of the core symptoms of schizophrenia, and has been suggested that these symptoms are the result of a disturbance of a medial frontal system involving anterior hippocampus, cingulated gyrus, supplementary motor area, and dorsolateral prefrontal cortex. Poor insight seems to be something more than a symptom or an epi-phenomenon and its mechanism may constitute a core factor into the psychosis process. Also, poor insight would be involves a common mechanism for many other mental disorders or even it would be an independent and trans-diagnostic factor into the human personality, probably like the dimension of psychotism. PMID- 29488895 TI - [The concept of urban resilience and its relation to resilience in mental health: Prospects for research in schizophrenia]. AB - The relationship between schizophrenia and the city is well known and widely documented in the literature, albeit with many questions still unanswered. While it is clear that there is a higher incidence of schizophrenia in cities, there is little known on causality - or its direction - in that relationship. Also, despite the fact that several clinical and epidemiological parameters play a role in the relationship between schizophrenia and the city, this relationship has not been investigated or interpreted holistically. In particular, biological, psychological and social parameters have been extensively explored, usually in isolation, but not as a part of the wider urban environment. A concept that could potentially offer such integration between the urban environment and the biopsycho- social approach may be the concept of psychological resilience. Psychological resilience is a central notion of Preventive Psychiatry, both in theory and in practice. It refers to a person's ability to cope with adversity and to recover. It describes, in holistic terms, the psychological potential that each person has, taking together all positive psychological factors but also their functioning and reactions in their own environment. It is intriguing that the same concept, (even by the same name - urban resilience), exists in relation to urban planning and architecture, referring to a city's ability to help its inhabitants and systems to withstand and recover from adversity. As with people, the factors that make a city resilient are many and complex. Surprisingly, however, the factors that define psychological and urban resilience are conceptually related, as ultimately both serve the person/citizen. Thus, the factors that make up urban resilience may be complementary to the factors that make up mental resilience and vice versa. Consequently, not only is the conceptual affinity of urban resilience and psychological resilience logical, but also the individual factors that define the two are also related. It would be interesting to study these factors and to examine the role of resilience (or lack thereof) in the occurrence of mental illness - in particular schizophrenia - in cities. In this paper we present the concepts of psychological and urban resilience, we identify the factors that characterize urban resilience, and define its practical relationship with psychological resilience in the case of schizophrenia. Finally, we explore the potential and prospects of this novel multidisciplinary approach for tackling schizophrenia, for use in public health, and for further research. PMID- 29488896 TI - [The relationship between forgivingness, mental health and psychotherapy]. AB - Forgivingness occupies a prominent place in religions as well as in various philosophical systems of ethics and can be defined as the free, personal distancing from feelings of rage and resentment toward a person or persons having committed an injustice. The main psychological function of forgiveness consists in allowing for the replacement of negative emotions by positive ones, such as generosity, goodness, compassion, empathy, or even love toward the offender. It must be emphasized that forgiveness is independent from reconciliation, and it is not simply a form of tolerance, justification, oblivion, underestimation, denial or amnesty. Intrapsychic processes are sufficient and necessary for the genesis of forgiveness, although it is likely that these are also influenced by complex interpersonal events. Current research identifies various dimensions of forgiveness, which must be distinguished from each other, as they differ both on the level of causes, as well as on that of effects. The observation that forgiveness has a positive effect on mental health is not new, it is, however, only recently that comprehensive theories have been constructed and scientific research has been developed regarding the relationship between forgiveness and psychopathology. Over the recent years, there has been an increasing number of studies affirming the beneficial effects of forgiveness on a broad spectrum of aspects of mental health and well-being, despite the lack of complete clarification of underlying mechanisms. The positive connection between forgiveness and mental health could be mediated through direct or indirect mechanisms interacting not only on a biological level, but also in the psychological and social realm of human existence. One direct way could be the avoidance of ruminative thoughts reinforcing and maintaining negative emotions such as resentment, hatred, anger, anxiety and fear. Moreover, forgiveness cultivates empathy and promotes altruistic forms of behavior, facilitating the preservation of relationships and protecting from prolonged distress. An indirect mechanism could involve various forms of health behavior, interpersonal functionality and social supportive networks, factors universally accepted as contributing to mental health. Owing to the positive influence of forgiveness on health issues, various modes of intervention have been proposed and implemented using forgiveness either independently or from within the conceptual framework of specific psychotherapeutic methods. The aim of these interventions is to express negative emotions, to liberate the subject from the vicious circle of rumination, and to overcome resentment in a positive way. Thus, there is an obvious need to further promote forgivingness as a subject of psychological and psychiatric research, and to foreground findings and possible clinical psychotherapeutic applications. PMID- 29488897 TI - [Surrealism and madness]. AB - This article attempts an approach of madness by surrealism, as reflected in the pathway of the surrealist movement. In the light of enlargement of the concept of mental illness and the experience of madness, an approach is being attempted regarding the early surrealist views as they precursory appear e.g. from the case of Hieronymus Bosch to the meeting of the dominant psychiatry and the surrealist movement in the 19th and 20th century. Then, the paper attempts to present the main positions of representatives of the movement, such as Breton, Dali and Kalas. These three surrealists were chosen among others, for this brief report, as the representatives of three remarkable moments in the surrealistic route. Breton introduces the element of fiction and hyper-reality while he questions the distinction between normal and abnormal element. Dali with his paranoid critical method reconciles actual representations with mythical and symbolic elements, breaking through the limits between objectivity and subjectivity. Kalas puts forward the social origin of insanity along with the fundamental surrealist notions of individual freedom and will. For a more complete understanding of this attempt, it was considered useful to include elements of the main views on madness from the standpoint of a critical approach in psychiatry and psychology. The surrealistic view seems to be close to this critical approach which is likely to have been affected by it on the level in which the movements and scientific fields meet and interact. The relationship between surrealism, the notion and expression of madness and the absurd seems to be inherent to the very development of the movement through its core and individual pursuits. In conclusion, the relationship between surrealism and the notion and expression of the madness and the absurd seems to be inherent to the very birth of the movement through its main positions and pursuits. The question of so-called reality, its overshoot and the vision of a hyperreality that will incorporates the challenges and contradictions of this reality, are points loudly expressed through artistic activities and scientific researches and practices. A common ground to all these aspects is the liberation of desire, the questioning of rationality, the integration and acceptance of the absurd, as well as, the dispute of it as such, and finally the social change-driven by the individual psychological development. PMID- 29488898 TI - Magnetic field induced mixing of light hole excitonic states in (Cd, Mn)Te/(Cd, Mg)Te core/shell nanowires. AB - A detailed magneto-photoluminescence study of individual (Cd, Mn)Te/(Cd, Mg)Te core/shell nanowires grown by molecular beam epitaxy is performed. First of all, an enhancement of the Zeeman splitting due to sp-d exchange interaction between band carriers and Mn-spins is evidenced in these nanostructures. Then, it is found that the value of this splitting depends strongly on the magnetic field direction with respect to the nanowire axis. The largest splitting is observed when the magnetic field is applied perpendicular and the smallest when it is applied parallel to the nanowire axis. This effect is explained in terms of magnetic field induced valence band mixing and evidences the light hole character of the excitonic emission. The values of the light and heavy hole splitting are determined for several individual nanowires based on the comparison of experimental results to theoretical calculations. PMID- 29488899 TI - GaAs droplet quantum dots with nanometer-thin capping layer for plasmonic applications. AB - We report on the growth and optical characterization of droplet GaAs quantum dots (QDs) with extremely-thin (11 nm) capping layers. To achieve such result, an internal thermal heating step is introduced during the growth and its role in the morphological properties of the QDs obtained is investigated via scanning electron and atomic force microscopy. Photoluminescence measurements at cryogenic temperatures show optically stable, sharp and bright emission from single QDs, at visible wavelengths. Given the quality of their optical properties and the proximity to the surface, such emitters are good candidates for the investigation of near field effects, like the coupling to plasmonic modes, in order to strongly control the directionality of the emission and/or the spontaneous emission rate, crucial parameters for quantum photonic applications. PMID- 29488900 TI - Effect of organic and inorganic nitrates on cerebrovascular pulsatile power transmission in patients with heart failure and preserved ejection fraction. AB - OBJECTIVE: Increased penetration of pulsatile power to the brain has been implicated in the pathogenesis of age-related cognitive dysfunction and dementia, a common comorbidity in patients with heart failure and preserved ejection fraction (HFpEF). However, there is a lack of knowledge on the effects of organic and inorganic nitrates administration in this population on the power carried by pressure and flow waves traveling through the proximal aorta and penetrating the carotid artery into the brain microvasculature. APPROACH: We assessed aortic and carotid hemodynamics non-invasively in two sub-studies: (1) at baseline and after administration of 0.4 mg of sublingual nitroglycerine (an organic nitrate; n = 26); and (2) in a randomized controlled trial of placebo (PB) versus inorganic nitrate administration (beetroot-juice (BR), 12.9 mmol NO3; n = 16). MAIN RESULTS: Wave and hydraulic power analysis demonstrated that NTG increased total hydraulic power (from 5.68% at baseline to 8.62%, P = 0.001) and energy penetration (from 8.69% to 11.63%; P = 0.01) from the aorta to the carotid, while inorganic nitrate administration did not induce significant changes in aortic and carotid wave power (power: 5.49%PB versus 6.25%BR, P = 0.49; energy: 8.89%PB versus 10.65%BR, P = 0.27). SIGNIFICANCE: Organic nitrates, but not inorganic nitrates, increase the amount of hydraulic energy transmitted into the carotid artery in subjects with HFpEF. These findings may have implications for the adverse effect profiles of these agents (such as the differential incidence of headaches) and for the pulsatile hemodynamic stress of the brain microvasculature in this patient population. PMID- 29488901 TI - Graphene nanoribbon as an elastic damper. AB - Heterostructures composed of dissimilar two-dimensional nanomaterials can have nontrivial physical and mechanical properties which are potentially useful in many applications. Interestingly, in some cases, it is possible to create heterostructures composed of weakly and strongly stretched domains with the same chemical composition, as has been demonstrated for some polymer chains, DNA, and intermetallic nanowires supporting this effect of two-phase stretching. These materials, at relatively strong tension forces, split into domains with smaller and larger tensile strains. Within this region, average strain increases at constant tensile force due to the growth of the domain with the larger strain, at the expense of the domain with smaller strain. Here, the two-phase stretching phenomenon is described for graphene nanoribbons with the help of molecular dynamics simulations. This unprecedented feature of graphene that is revealed in our study is related to the peculiarities of nucleation and the motion of the domain walls separating the domains of different elastic strain. It turns out that the loading-unloading curves exhibit a hysteresis-like behavior due to the energy dissipation during the domain wall nucleation and motion. Here, we put forward the idea of implementing graphene nanoribbons as elastic dampers, efficiently converting mechanical strain energy into heat during cyclic loading unloading through elastic extension where domains with larger and smaller strains coexist. Furthermore, in the regime of two-phase stretching, graphene nanoribbon is a heterostructure for which the fraction of domains with larger and smaller strain, and consequently its physical and mechanical properties, can be tuned in a controllable manner by applying elastic strain and/or heat. PMID- 29488902 TI - A review of classification algorithms for EEG-based brain-computer interfaces: a 10 year update. AB - OBJECTIVE: Most current electroencephalography (EEG)-based brain-computer interfaces (BCIs) are based on machine learning algorithms. There is a large diversity of classifier types that are used in this field, as described in our 2007 review paper. Now, approximately ten years after this review publication, many new algorithms have been developed and tested to classify EEG signals in BCIs. The time is therefore ripe for an updated review of EEG classification algorithms for BCIs. APPROACH: We surveyed the BCI and machine learning literature from 2007 to 2017 to identify the new classification approaches that have been investigated to design BCIs. We synthesize these studies in order to present such algorithms, to report how they were used for BCIs, what were the outcomes, and to identify their pros and cons. MAIN RESULTS: We found that the recently designed classification algorithms for EEG-based BCIs can be divided into four main categories: adaptive classifiers, matrix and tensor classifiers, transfer learning and deep learning, plus a few other miscellaneous classifiers. Among these, adaptive classifiers were demonstrated to be generally superior to static ones, even with unsupervised adaptation. Transfer learning can also prove useful although the benefits of transfer learning remain unpredictable. Riemannian geometry-based methods have reached state-of-the-art performances on multiple BCI problems and deserve to be explored more thoroughly, along with tensor-based methods. Shrinkage linear discriminant analysis and random forests also appear particularly useful for small training samples settings. On the other hand, deep learning methods have not yet shown convincing improvement over state of-the-art BCI methods. SIGNIFICANCE: This paper provides a comprehensive overview of the modern classification algorithms used in EEG-based BCIs, presents the principles of these methods and guidelines on when and how to use them. It also identifies a number of challenges to further advance EEG classification in BCI. PMID- 29488903 TI - Assessment of ankle muscle activation by muscle synergies in healthy and post stroke gait. AB - OBJECTIVE: Impaired ankle dorsal and plantar flexor function is a frequent sequela of stroke. A better assessment of ankle muscle activation would be highly significant for stroke rehabilitation. The challenge in implementing current electromyography (EMG)-based assessments is due to problems with the variability and individuality of ankle muscle EMG profiles during walking. We have been studying a new technique using the muscle synergy method to quantify the characteristics that underlie ankle muscle activation to address this issue. APPROACH: We processed surface EMG signals from ankle muscles and gait parameters collected from 20 healthy and 22 post-stroke subjects during walking. A non negative matrix factorization algorithm was used to extract muscle synergies. MAIN RESULTS: Our results suggest a featured muscle synergy structure (R = 0.84, 95% CI: 0.83-0.85) underlying ankle muscle activation in both healthy and post-stroke subjects. The structure of the featured muscle synergy was robust in the same subjects across different conditions in the healthy group (R = 0.97, 95% CI: 0.96-0.98) and the post-stroke group (R = 0.95, 95% CI: 0.88-0.97). Compared to the stroke group, the synergy patterns of healthy subjects showed better regularity and higher inter-subject similarity (P = 0.001). In addition, the results of muscle synergies were indicative of locomotor performance. SIGNIFICANCE: The innovative quantitative results of this study can help us to better understand ankle muscle activation and will be a reference for clinical assessments and intervention studies. PMID- 29488904 TI - A novel near-infrared nanomaterial with high quantum efficiency and its applications in real time in vivo imaging. AB - Fluorescence imaging signal is severely limited by the quantum efficiency and emission wavelength. To overcome these challenges, novel NIR-emitting K5NdLi2F10 nanoparticles under NIR excitation was introduced as fluorescence imaging probe for the first time. The photostability of K5NdLi2F10 nanoparticles in the water, phosphate buffer saline, fetal bovine serum and living mice was investigated. The fluorescence signal was detected with depths of 3.5 and 2.0 cm in phantom and pork tissue, respectively. Fluorescence spectrum with a significant signal-to background ratio of 10:1 was captured in living mice. Moreover, clear NIR images were virtualized for the living mice after intravenous injection. The imaging ability of nanoparticles in tumor-beard mice were evaluated, the enrichment of K5NdLi2F10 nanoparticles in tumor site due to the enhanced permeability and retention effect was confirmed. The systematic studies of toxicity, bio distribution and in-vivo dynamic imaging suggest that these materials give high biocompatibility and low toxicity. These NIR-emitting nanoparticles with high quantum efficiency, high penetration and low toxicity might facilitate tumor identification in deep tissues more sensitively. PMID- 29488905 TI - Track, calculate and optimise eye lens doses of interventional cardiologists using mEyeDose and mEyeDose_X. AB - The European epidemiological study EURALOC aimed to establish a dose response relationship for low dose radiation induced eye lens opacities using interventional cardiologists as the study group. Within the EURALOC project, two dosimetry methodologies were developed serving as the basis for cumulative eye lens dose assessment. Besides being the cornerstone of the epidemiological part of the project, these dosimetry methodologies were also used to develop two calculation tools, 'mEyeDose' and 'mEyeDose_X' which enable to track, calculate, optimise and analyse eye lens doses in interventional cardiology. mEyeDose was developed as a Mobile Web App and serves as a readily accessible, highly didactic educational tool for interventional cardiologists whereas the user-friendly desktop application mEyeDose_X is designed for radiation protection professionals. Both tools are freely available and can be used for a wide range of purposes such as optimisation of working practices, calculation of cumulative eye lens doses or risk assessment prior to routine eye lens dose monitoring. PMID- 29488906 TI - Hiromichi Kamitsubo (1933-2017). PMID- 29488907 TI - Anisotropy enhanced X-ray scattering from solvated transition metal complexes. AB - Time-resolved X-ray scattering patterns from photoexcited molecules in solution are in many cases anisotropic at the ultrafast time scales accessible at X-ray free-electron lasers (XFELs). This anisotropy arises from the interaction of a linearly polarized UV-Vis pump laser pulse with the sample, which induces anisotropic structural changes that can be captured by femtosecond X-ray pulses. In this work, a method for quantitative analysis of the anisotropic scattering signal arising from an ensemble of molecules is described, and it is demonstrated how its use can enhance the structural sensitivity of the time-resolved X-ray scattering experiment. This method is applied on time-resolved X-ray scattering patterns measured upon photoexcitation of a solvated di-platinum complex at an XFEL, and the key parameters involved are explored. It is shown that a combined analysis of the anisotropic and isotropic difference scattering signals in this experiment allows a more precise determination of the main photoinduced structural change in the solute, i.e. the change in Pt-Pt bond length, and yields more information on the excitation channels than the analysis of the isotropic scattering only. Finally, it is discussed how the anisotropic transient response of the solvent can enable the determination of key experimental parameters such as the instrument response function. PMID- 29488908 TI - Quantum regime of a plasma-wave-pumped free-electron laser in the presence of an axial magnetic field. AB - The quantum regime of a plasma-whistler-wave-pumped free-electron laser (FEL) in the presence of an axial-guide magnetic field is presented. By quantizing both the plasma whistler field and axial magnetic field, an N-particle three dimensional Hamiltonian of quantum-FEL (QFEL) has been derived. Employing Heisenberg evolution equations and introducing a new collective operator which controls the vertical motion of electrons, a quantum dispersion relation of the plasma whistler wiggler has been obtained analytically. Numerical results indicate that, by increasing the intrinsic quantum momentum spread and/or increasing the axial magnetic field strength, the bunching and the radiation fields grow exponentially. In addition, a spiking behavior of the spectrum was observed with increasing cyclotron frequency which provides an enormous improvement in the coherence of QFEL radiation even in a limit close-to-classical regime, where an overlapping of these spikes is observed. Also, an upper limit of the intrinsic quantum momentum spread which depends on the value of the cyclotron frequency was found. PMID- 29488909 TI - Multifarious injection chamber for molecular structure study (MICOSS) system: development and application for serial femtosecond crystallography at Pohang Accelerator Laboratory X-ray Free-Electron Laser. AB - The multifarious injection chamber for molecular structure study (MICOSS) experimental system has been developed at the Pohang Accelerator Laboratory X-ray Free-Electron Laser for conducting serial femtosecond crystallography. This system comprises several instruments such as a dedicated sample chamber, sample injectors, sample environment diagnostic system and detector stage for convenient distance manipulation. Serial femtosecond crystallography experiments of lysozyme crystals have been conducted successfully. The diffraction peaks have reached to ~1.8 A resolution at the photon energy of 9.785 keV. PMID- 29488910 TI - Compact coherence enhancement by subharmonic self-seeding in X-ray free-electron laser facilities. AB - X-ray free-electron lasers (FELs) are cutting-edge scientific tools able to generate transversely coherent radiation with very high power and ultra-short pulse durations. The self-seeding mechanism has been proven to increase the longitudinal coherence of the FEL radiation but its efficiency could be significantly improved, especially for soft X-rays. This paper proposes the enhancement of the performance of self-seeding by combining it with the harmonic generation mechanism. In particular, by starting the process with a subharmonic of the wavelength of interest, the coherence of the produced radiation is improved, the undulator beamline becomes more compact, and the monochromator realization is simplified. Numerical simulations for SwissFEL are presented showing that the method can be employed, within a given space, to increase the spectral brightness by one order of magnitude or more with respect to standard self-seeding. This coherence enhancement will be fundamental for many photon science applications and techniques such as resonant inelastic X-ray scattering. PMID- 29488911 TI - Time-resolved ion imaging at free-electron lasers using TimepixCam. AB - The application of a novel fast optical-imaging camera, TimepixCam, to molecular photoionization experiments using the velocity-map imaging technique at a free electron laser is described. TimepixCam is a 256 * 256 pixel CMOS camera that is able to detect and time-stamp ion hits with 20 ns timing resolution, thus making it possible to record ion momentum images for all fragment ions simultaneously and avoiding the need to gate the detector on a single fragment. This allows the recording of significantly more data within a given amount of beam time and is particularly useful for pump-probe experiments, where drifts, for example, in the timing and pulse energy of the free-electron laser, severely limit the comparability of pump-probe scans for different fragments taken consecutively. In principle, this also allows ion-ion covariance or coincidence techniques to be applied to determine angular correlations between fragments. PMID- 29488912 TI - An X-ray harmonic separator for next-generation synchrotron X-ray sources and X ray free-electron lasers. AB - An X-ray prism for the extraction of a specific harmonic of undulator radiation is proposed. By using the prism in a grazing incidence geometry, the beam axes of fundamental and harmonics of undulator radiation are separated with large angles over 10 urad, which enables the selection of a specific harmonic with the help of apertures, while keeping a high photon flux. The concept of the harmonic separation was experimentally confirmed using X-ray beams from the X-ray free electron laser SACLA. PMID- 29488913 TI - Efficiency and coherence preservation studies of Be refractive lenses for XFELO application. AB - Performance tests of parabolic beryllium refractive lenses, considered as X-ray focusing elements in the future X-ray free-electron laser oscillator (XFELO), are reported. Single and double refractive lenses were subject to X-ray tests, which included: surface profile, transmissivity measurements, imaging capabilities and wavefront distortion with grating interferometry. Optical metrology revealed that surface profiles were close to the design specification in terms of the figure and roughness. The transmissivity of the lenses is >94% at 8 keV and >98% at 14.4 and 18 keV. These values are close to the theoretical values of ideal lenses. Images of the bending-magnet source obtained with the lenses were close to the expected ones and did not show any significant distortion. Grating interferometry revealed that the possible wavefront distortions produced by surface and bulk lens imperfections were on the level of ~lambda/60 for 8 keV photons. Thus the Be lenses can be succesfully used as focusing and beam collimating elements in the XFELO. PMID- 29488914 TI - Multi-channel in situ dynamic light scattering instrumentation enhancing biological small-angle X-ray scattering experiments at the PETRA III beamline P12. AB - Small-angle X-ray scattering (SAXS) analysis of biomolecules is increasingly common with a constantly high demand for comprehensive and efficient sample quality control prior to SAXS experiments. As monodisperse sample suspensions are desirable for SAXS experiments, latest dynamic light scattering (DLS) techniques are most suited to obtain non-invasive and rapid information about the particle size distribution of molecules in solution. A multi-receiver four-channel DLS system was designed and adapted at the BioSAXS endstation of the EMBL beamline P12 at PETRA III (DESY, Hamburg, Germany). The system allows the collection of DLS data within round-shaped sample capillaries used at beamline P12. Data obtained provide information about the hydrodynamic radius of biological particles in solution and dispersity of the solution. DLS data can be collected directly prior to and during an X-ray exposure. To match the short X-ray exposure times of around 1 s for 20 exposures at P12, the DLS data collection periods that have been used up to now of 20 s or commonly more were substantially reduced, using a novel multi-channel approach collecting DLS data sets in the SAXS sample capillary at four different neighbouring sample volume positions in parallel. The setup allows online scoring of sample solutions applied for SAXS experiments, supports SAXS data evaluation and for example indicates local inhomogeneities in a sample solution in a time-efficient manner. Biological macromolecules with different molecular weights were applied to test the system and obtain information about the performance. All measured hydrodynamic radii are in good agreement with DLS results obtained by employing a standard cuvette instrument. Moreover, applying the new multi-channel DLS setup, a reliable radius determination of sample solutions in flow, at flow rates normally used for size exclusion chromatography-SAXS experiments, and at higher flow rates, was verified as well. This study also shows and confirms that the newly designed sample compartment with attached DLS instrumentation does not disturb SAXS measurements. PMID- 29488915 TI - High-energy-resolution diced spherical quartz analyzers for resonant inelastic X ray scattering. AB - A novel diced spherical quartz analyzer for use in resonant inelastic X-ray scattering (RIXS) is introduced, achieving an unprecedented energy resolution of 10.53 meV at the Ir L3 absorption edge (11.215 keV). In this work the fabrication process and the characterization of the analyzer are presented, and an example of a RIXS spectrum of magnetic excitations in a Sr3Ir2O7 sample is shown. PMID- 29488916 TI - Quantitative investigation of linear arbitrary polarization in an APPLE-II undulator. AB - Insertion devices are utilized at synchrotron radiation facilities around the world for their capability to provide a high-brilliance X-ray beam. APPLE-II type undulators are especially important for their capacity to switch between a variety of photon beam polarization states. A high-precision soft X-ray polarimeter has been used to investigate the polarization calibration of an APPLE II undulator (period length lambdau = 64 mm) installed on beamline I06 at Diamond Light Source. Systematic measurement of the beam polarization state at a range of linear arbitrary angles has been compared with the expected result for a given set of undulator gap and row phase parameters calculated from theory. Determination of the corresponding Stokes-Poincare parameters from the measured data reveals a discrepancy between the two. The limited number of energy/polarization combinations included in the undulator calibration tables necessitates the use of interpolated values for the missing points which is expected to contribute to the discrepancy. However, by modifying the orbit of the electron beam through the undulator by at least 160 um it has been found that for certain linear polarizations the discrepancies can be corrected. Overall, it is suggested that complete correction of the Stokes-Poincare parameters for all linear angles would require alteration of both these aspects. PMID- 29488918 TI - X-ray position-sensitive duo-lateral diamond detectors at SOLEIL. AB - The performance of a diamond X-ray beam position monitor is reported. This detector consists of an ionization solid-state chamber based on a thin single crystal chemical-vapour-deposition diamond with position-sensitive resistive electrodes in a duo-lateral configuration. The detector's linearity, homogeneity and responsivity were studied on beamlines at Synchrotron SOLEIL with various beam sizes, intensities and energies. These measurements demonstrate the large and homogeneous (absorption variation of less than 0.7% over 500 um * 500 um) active area of the detector, with linear responses independent of the X-ray beam spatial distribution. Due to the excellent charge collection efficiency (approaching 100%) and intensity sensitivity (0.05%), the detector allows monitoring of the incident beam flux precisely. In addition, the in-beam position resolution was compared with a theoretical analysis providing an estimation of the detector's beam position resolution capability depending on the experimental conditions (X-ray flux, energy and readout acquisition time). PMID- 29488919 TI - Characterization of a quadrant diamond transmission X-ray detector including a precise determination of the mean electron-hole pair creation energy. AB - Precise monitoring of the incoming photon flux is crucial for many experiments using synchrotron radiation. For photon energies above a few keV, thin semiconductor photodiodes can be operated in transmission for this purpose. Diamond is a particularly attractive material as a result of its low absorption. The responsivity of a state-of-the art diamond quadrant transmission detector has been determined, with relative uncertainties below 1% by direct calibration against an electrical substitution radiometer. From these data and the measured transmittance, the thickness of the involved layers as well as the mean electron hole pair creation energy were determined, the latter with an unprecedented relative uncertainty of 1%. The linearity and X-ray scattering properties of the device are also described. PMID- 29488917 TI - Commissioning of a multi-beamline femtoslicing facility at SOLEIL. AB - The investigation of ultrafast dynamics, taking place on the few to sub picosecond time scale, is today a very active research area pursued in a variety of scientific domains. With the recent advent of X-ray free-electron lasers (XFELs), providing very intense X-ray pulses of duration as short as a few femtoseconds, this research field has gained further momentum. As a consequence, the demand for access strongly exceeds the capacity of the very few XFEL facilities existing worldwide. This situation motivates the development of alternative sub-picosecond pulsed X-ray sources among which femtoslicing facilities at synchrotron radiation storage rings are standing out due to their tunability over an extended photon energy range and their high stability. Following the success of the femtoslicing installations at ALS, BESSY-II, SLS and UVSOR, SOLEIL decided to implement a femtoslicing facility. Several challenges were faced, including operation at the highest electron beam energy ever, and achievement of slice separation exclusively with the natural dispersion function of the storage ring. SOLEIL's setup also enables, for the first time, delivering sub-picosecond pulses simultaneously to several beamlines. This last feature enlarges the experimental capabilities of the facility, which covers the soft and hard X-ray photon energy range. In this paper, the commissioning of this original femtoslicing facility is reported. Furthermore, it is shown that the slicing induced THz signal can be used to derive a quantitative estimate for the degree of energy exchange between the femtosecond infrared laser pulse and the circulating electron bunch. PMID- 29488920 TI - Evaluation of the UFXC32k photon-counting detector for pump-probe experiments using synchrotron radiation. AB - This paper presents the performance of a single-photon-counting hybrid pixel X ray detector with synchrotron radiation. The camera was evaluated with respect to time-resolved experiments, namely pump-probe-probe experiments held at SOLEIL. The UFXC camera shows very good energy resolution of around 1.5 keV and allows the minimum threshold setting to be as low as 3 keV keeping the high-count-rate capabilities. Measurements of a synchrotron characteristic filling mode prove the proper separation of an isolated bunch of photons and the usability of the detector in time-resolved experiments. PMID- 29488921 TI - Polarization-independent absorption enhancement in a graphene square array with a cascaded grating structure. AB - The polarization-independent enhanced absorption effect of graphene in the near infrared range is investigated. This is achieved by placing a graphene square array on top of a dielectric square array backed by a two-dimensional multilayer grating. Total optical absorption in graphene can be attributed to critical coupling, which is achieved through the combined effect of guided-mode resonance with the dielectric square array and the photonic band gap with the two dimensional multilayer grating. To reveal the physical origin of such a phenomenon, the electromagnetic field distributions for both polarizations are illustrated. The designed graphene absorber exhibits near-unity polarization independent absorption at resonance with an ultra-narrow spectrum. Moreover, the polarization-independent absorption can be tuned simply by changing the geometric parameters. The results may have promising potential for the design of graphene based optoelectronic devices. PMID- 29488922 TI - Transmission of an X-ray beam through a two-dimensional photonic crystal and the Talbot effect. AB - Results of computer simulations of the transmission of an X-ray beam through a two-dimensional photonic crystal as well as the propagation of an X-ray beam in free space behind the photonic crystal are reported. The photonic crystal consists of a square lattice of silicon cylinders of diameter 0.5 um. The amount of matter in the path of the X-ray beam rapidly decreases at the sides of the cylinder projections. Therefore the transmission is localized near the boundaries, and appears like a channeling effect. The iterative method of computer simulations is applied. This method is similar to the multi-slice method that is widely used in electron microscopy. It allows a solution to be obtained with acceptable accuracy. A peculiarity in the intensity distribution inside the Talbot period zT in free space was found when the intensity is approximately equal to the initial value at a distance 0.46zT, and it is shifted by half a period at distance 0.5zT. The reason for this effect is the existence of a periodic phase of the wavefunction of radiation inside the intensity peaks. Simulations with zero phase do not show this effect. Symmetry rules for the Talbot effect are discussed. PMID- 29488923 TI - X-ray reflectivity from curved liquid interfaces. AB - X-ray reflectivity studies of the structure of liquid-vapour and liquid-liquid interfaces at modern sources, such as free-electron lasers, are currently impeded by the lack of dedicated liquid surface diffractometers. It is shown that this obstacle can be overcome by an alternative experimental approach that uses the natural curvature of a liquid drop for variation of the angle of incidence. Two modes of operation are shown: (i) sequential reflectivity measurements by a nanometre beam and (ii) parallel acquisition of large ranges of a reflectivity curve by micrometre beams. The feasibility of the two methods is demonstrated by studies of the Hg/vapour, H2O/vapour and Hg/0.1 M NaF interface. The obtained reflectivity curves match the data obtained by conventional techniques up to 5alphac in micro-beam mode and up to 35alphac in nano-beam mode, allowing observation of the Hg layering peak. PMID- 29488924 TI - Automatic Debye-Scherrer elliptical ring extraction via a computer vision approach. AB - The accurate calibration of powder diffraction data acquired from area detectors using calibration standards is a crucial step in the data reduction process to attain high-quality one-dimensional patterns. A novel algorithm has been developed for extracting Debye-Scherrer rings automatically using an approach based on computer vision and pattern recognition techniques. The presented technique requires no human intervention and, unlike previous approaches, makes no restrictive assumptions on the diffraction setup and/or rings. It can detect complete rings as well as portions of them, and works on several types of diffraction images with various degrees of ring graininess, textured diffraction patterns and detector tilt with respect to the incoming beam. PMID- 29488926 TI - An electrochemical cell with sapphire windows for operando synchrotron X-ray powder diffraction and spectroscopy studies of high-power and high-voltage electrodes for metal-ion batteries. AB - A new multi-purpose operando electrochemical cell was designed, constructed and tested on the Swiss-Norwegian Beamlines BM01 and BM31 at the European Synchrotron Radiation Facility. Single-crystal sapphire X-ray windows provide a good signal to-noise ratio, excellent electrochemical contact because of the constant pressure between the electrodes, and perfect electrochemical stability at high potentials due to the inert and non-conductive nature of sapphire. Examination of the phase transformations in the Li1-xFe0.5Mn0.5PO4 positive electrode (cathode) material at C/2 and 10C charge and discharge rates, and a study of the valence state of the Ni cations in the Li1-xNi0.5Mn1.5O4 cathode material for Li-ion batteries, revealed the applicability of this novel cell design to diffraction and spectroscopic investigations of high-power/high-voltage electrodes for metal ion batteries. PMID- 29488925 TI - Real-space analysis of radiation-induced specific changes with independent component analysis. AB - A method of analysis is presented that allows for the separation of specific radiation-induced changes into distinct components in real space. The method relies on independent component analysis (ICA) and can be effectively applied to electron density maps and other types of maps, provided that they can be represented as sets of numbers on a grid. Here, for glucose isomerase crystals, ICA was used in a proof-of-concept analysis to separate temperature-dependent and temperature-independent components of specific radiation-induced changes for data sets acquired from multiple crystals across multiple temperatures. ICA identified two components, with the temperature-independent component being responsible for the majority of specific radiation-induced changes at temperatures below 130 K. The patterns of specific temperature-independent radiation-induced changes suggest a contribution from the tunnelling of electron holes as a possible explanation. In the second case, where a group of 22 data sets was collected on a single thaumatin crystal, ICA was used in another type of analysis to separate specific radiation-induced effects happening on different exposure-level scales. Here, ICA identified two components of specific radiation-induced changes that likely result from radiation-induced chemical reactions progressing with different rates at different locations in the structure. In addition, ICA unexpectedly identified the radiation-damage state corresponding to reduced disulfide bridges rather than the zero-dose extrapolated state as the highest contrast structure. The application of ICA to the analysis of specific radiation induced changes in real space and the data pre-processing for ICA that relies on singular value decomposition, which was used previously in data space to validate a two-component physical model of X-ray radiation-induced changes, are discussed in detail. This work lays a foundation for a better understanding of protein specific radiation chemistries and provides a framework for analysing effects of specific radiation damage in crystallographic and cryo-EM experiments. PMID- 29488927 TI - Nuclear resonance reflectivity from a [57Fe/Cr]30 multilayer with the Synchrotron Mossbauer Source. AB - Mossbauer reflectivity spectra and nuclear resonance reflectivity (NRR) curves have been measured using the Synchrotron Mossbauer Source (SMS) for a [57Fe/Cr]30 periodic multilayer, characterized by the antiferromagnetic interlayer coupling between adjacent 57Fe layers. Specific features of the Mossbauer reflectivity spectra measured with pi-polarized radiation of the SMS near the critical angle and at the 'magnetic' maximum on the NRR curve are analyzed. The variation of the ratio of lines in the Mossbauer reflectivity spectra and the change of the intensity of the 'magnetic' maximum under an applied external field has been used to reveal the transformation of the magnetic alignment in the investigated multilayer. PMID- 29488928 TI - Energy-dependent dead-time correction in digital pulse processors applied to silicon drift detector's X-ray spectra. AB - Dead-time effects in X-ray spectra taken with a digital pulse processor and a silicon drift detector were investigated when the number of events at the low energy end of the spectrum was more than half of the total, at counting rates up to 56 kHz. It was found that dead-time losses in the spectra are energy dependent and an analytical correction for this effect, which takes into account pulse pile up, is proposed. This and the usual models have been applied to experimental measurements, evaluating the dead-time fraction either from the calculations or using the value given by the detector acquisition system. The energy-dependent dead-time model proposed fits accurately the experimental energy spectra in the range of counting rates explored in this work. A selection chart of the simplest mathematical model able to correct the pulse-height distribution according to counting rate and energy spectrum characteristics is included. PMID- 29488929 TI - Small-angle scattering of polychromatic X-rays: effects of bandwidth, spectral shape and high harmonics. AB - Polychromatic X-ray sources can be useful for photon-starved small-angle X-ray scattering given their high spectral fluxes. Their bandwidths, however, are 10 100 times larger than those using monochromators. To explore the feasibility, ideal scattering curves of homogeneous spherical particles for polychromatic X rays are calculated and analyzed using the Guinier approach, maximum entropy and regularization methods. Monodisperse and polydisperse systems are explored. The influence of bandwidth and asymmetric spectra shape are explored via Gaussian and half-Gaussian spectra. Synchrotron undulator spectra represented by two undulator sources of the Advanced Photon Source are examined as an example, as regards the influence of asymmetric harmonic shape, fundamental harmonic bandwidth and high harmonics. The effects of bandwidth, spectral shape and high harmonics on particle size determination are evaluated quantitatively. PMID- 29488930 TI - Counting-loss correction for X-ray spectroscopy using unit impulse pulse shaping. AB - High-precision measurement of X-ray spectra is affected by the statistical fluctuation of the X-ray beam under low-counting-rate conditions. It is also limited by counting loss resulting from the dead-time of the system and pile-up pulse effects, especially in a high-counting-rate environment. In this paper a detection system based on a FAST-SDD detector and a new kind of unit impulse pulse-shaping method is presented, for counting-loss correction in X-ray spectroscopy. The unit impulse pulse-shaping method is evolved by inverse deviation of the pulse from a reset-type preamplifier and a C-R shaper. It is applied to obtain the true incoming rate of the system based on a general fast slow channel processing model. The pulses in the fast channel are shaped to unit impulse pulse shape which possesses small width and no undershoot. The counting rate in the fast channel is corrected by evaluating the dead-time of the fast channel before it is used to correct the counting loss in the slow channel. PMID- 29488932 TI - Finite lifetime broadening of calculated X-ray absorption spectra: possible artefacts close to the edge. AB - X-ray absorption spectra calculated within an effective one-electron approach have to be broadened to account for the finite lifetime of the core hole. For methods based on Green's function this can be achieved either by adding a small imaginary part to the energy or by convoluting the spectra on the real axis with a Lorentzian. By analyzing the Fe K- and L2,3-edge spectra it is demonstrated that these procedures lead to identical results only for energies higher than a few core-level widths above the absorption edge. For energies close to the edge, spurious spectral features may appear if too much weight is put on broadening via the imaginary energy component. Special care should be taken for dichroic spectra at edges which comprise several exchange-split core levels, such as the L3-edge of 3d transition metals. PMID- 29488931 TI - Tris-amidoximate uranyl complexes via eta2 binding mode coordinated in aqueous solution shown by X-ray absorption spectroscopy and density functional theory methods. AB - The present study sheds some light on the long-standing debate concerning the coordination properties between uranyl ions and the amidoxime ligand, which is a key ingredient for achieving efficient extraction of uranium. Using X-ray absorption fine structure combined with theoretical simulation methods, the binding mode and bonding nature of a uranyl-amidoxime complex in aqueous solution were determined for the first time. The results show that in a highly concentrated amidoxime solution the preferred binding mode between UO22+ and the amidoxime ligand is eta2 coordination with tris-amidoximate species. In such a uranyl-amidoximate complex with eta2 binding motif, strong covalent interaction and orbital hybridization between U 5f/6d and (N, O) 2p should be responsible for the excellent binding ability of the amidoximate ligand to uranyl. The study was performed directly in aqueous solution to avoid the possible binding mode differences caused by crystallization of a single-crystal sample. This work also is an example of the simultaneous study of local structure and electronic structure in solution systems using combined diagnostic tools. PMID- 29488933 TI - Solid energy calibration standards for P K-edge XANES: electronic structure analysis of PPh4Br. AB - P K-edge X-ray absorption near-edge structure (XANES) spectroscopy is a powerful method for analyzing the electronic structure of organic and inorganic phosphorus compounds. Like all XANES experiments, P K-edge XANES requires well defined and readily accessible calibration standards for energy referencing so that spectra collected at different beamlines or under different conditions can be compared. This is especially true for ligand K-edge X-ray absorption spectroscopy, which has well established energy calibration standards for Cl (Cs2CuCl4) and S (Na2S2O3.5H2O), but not neighboring P. This paper presents a review of common P K edge XANES energy calibration standards and analysis of PPh4Br as a potential alternative. The P K-edge XANES region of commercially available PPh4Br revealed a single, highly resolved pre-edge feature with a maximum at 2146.96 eV. PPh4Br also showed no evidence of photodecomposition when repeatedly scanned over the course of several days. In contrast, we found that PPh3 rapidly decomposes under identical conditions. Density functional theory calculations performed on PPh3 and PPh4+ revealed large differences in the molecular orbital energies that were ascribed to differences in the phosphorus oxidation state (III versus V) and molecular charge (neutral versus +1). Time-dependent density functional theory calculations corroborated the experimental data and allowed the spectral features to be assigned. The first pre-edge feature in the P K-edge XANES spectrum of PPh4Br was assigned to P 1s -> P-C pi* transitions, whereas those at higher energy were P 1s -> P-C sigma*. Overall, the analysis suggests that PPh4Br is an excellent alternative to other solid energy calibration standards commonly used in P K-edge XANES experiments. PMID- 29488935 TI - A Li K-edge XANES study of salts and minerals. AB - The first comprehensive Li K-edge XANES study of a varied suite of Li-bearing minerals is presented. Drastic changes in the bonding environment for lithium are demonstrated and this can be monitored using the position and intensity of the main Li K-absorption edge. The complex silicates confirm the assignment of the absorption edge to be a convolution of triply degenerate p-like states as previously proposed for simple lithium compounds. The Li K-edge position depends on the electronegativity of the element to which it is bound. The intensity of the first peak varies depending on the existence of a 2p electron and can be used to evaluate the degree of ionicity of the bond. The presence of a 2p electron results in a weak first-peak intensity. The maximum intensity of the absorption edge shifts to lower energy with increasing SiO2 content for the lithium aluminosilicate minerals. The bond length distortion of the lithium aluminosilicates decreases with increasing SiO2 content, thus increased distortion leads to an increase in edge energy which measures lithium's electron affinity. PMID- 29488934 TI - X-ray Raman spectroscopy of lithium-ion battery electrolyte solutions in a flow cell. AB - The effects of varying LiPF6 salt concentration and the presence of lithium bis(oxalate)borate additive on the electronic structure of commonly used lithium ion battery electrolyte solvents (ethylene carbonate-dimethyl carbonate and propylene carbonate) have been investigated. X-ray Raman scattering spectroscopy (a non-resonant inelastic X-ray scattering method) was utilized together with a closed-circle flow cell. Carbon and oxygen K-edges provide characteristic information on the electronic structure of the electrolyte solutions, which are sensitive to local chemistry. Higher Li+ ion concentration in the solvent manifests itself as a blue-shift of both the pi* feature in the carbon edge and the carbonyl pi* feature in the oxygen edge. While these oxygen K-edge results agree with previous soft X-ray absorption studies on LiBF4 salt concentration in propylene carbonate, carbon K-edge spectra reveal a shift in energy, which can be explained with differing ionic conductivities of the electrolyte solutions. PMID- 29488936 TI - Enhancement of measurement accuracy of X-ray PIV in comparison with the micro-PIV technique. AB - The X-ray PIV (particle image velocimetry) technique has been used as a non invasive measurement modality to investigate the haemodynamic features of blood flow. However, the extraction of two-dimensional velocity field data from the three-dimensional volumetric information contained in X-ray images is technically unclear. In this study, a new two-dimensional velocity field extraction technique is proposed to overcome technological limitations. To resolve the problem of finding a correction coefficient, the velocity field information obtained by X ray PIV and micro-PIV techniques for disturbed flow in a concentric stenosis with 50% severity was quantitatively compared. Micro-PIV experiments were conducted for single-plane and summation images, which provide similar positional information of particles as X-ray images. The correction coefficient was obtained by establishing the relationship between velocity data obtained from summation images (VS) and centre-plane images (VC). The velocity differences between VS and VC along the vertical and horizontal directions were quantitatively analysed as a function of the geometric angle of the test model for applying the present two dimensional velocity field extraction technique to a conduit of arbitrary geometry. Finally, the two-dimensional velocity field information at arbitrary positions could be successfully extracted from X-ray images by using the correction coefficient and several velocity parameters derived from VS. PMID- 29488937 TI - Microbubbles containing gadolinium as contrast agents for both phase contrast and magnetic resonance imaging. AB - Portal vein imaging is an important method for investigating portal venous disorders. However, the diagnostic requirements are not usually satisfied when using single imaging techniques. Diagnostic accuracy can be improved by combining different imaging techniques. Contrast agents that can be used for combined imaging modalities are needed. In this study, the feasibility of using microbubbles containing gadolinium (MCG) as contrast agents for both phase contrast imaging (PCI) and magnetic resonance imaging (MRI) are investigated. MCG were made by encapsulating sulfur hexafluoride (SF6) gas with gadolinium and lyophilized powder. Absorption contrast imaging (ACI) and PCI of MCG were performed and compared in vitro. MCG were injected into the main portal trunk of living rats. PCI and MRI were performed at 2 min and 10 min after MCG injection, respectively. PCI exploited the differences in the refractive index and visibly showed the MCG, which were not detectable by ACI. PCI could facilitate clear revelation of the MCG-infused portal veins. The diameter of the portal veins could be determined by the largest MCG in the same portal vein. The minimum diameter of clearly detected portal veins was about 300 um by MRI. These results indicate that MCG could enhance both PCI and MRI for imaging portal veins. The detection sensitivity of PCI and MRI could compensate for each other when using MCG contrast agents for animals. PMID- 29488938 TI - MONCH detector enables fast and low-dose free-propagation phase-contrast computed tomography of in situ mouse lungs. AB - Due to the complexity of the underlying pathomechanism, in vivo mouse lung disease models continue to be of great importance in preclinical respiratory research. Longitudinal studies following the cause of a disease or evaluating treatment efficacy are of particular interest but challenging due to the small size of the mouse lung and the fast breathing rate. Synchrotron-based in-line phase-contrast computed tomography imaging has been successfully applied in lung research in various applications, but mostly at dose levels that forbid longitudinal in vivo studies. Here, the novel charge-integrating hybrid detector MONCH is presented, which enables imaging of mouse lungs at a pixel size of 25 um, in less than 10 s and with an entrance dose of about 70 mGy, which therefore will allow longitudinal lung disease studies to be performed in mouse models. PMID- 29488940 TI - A high-energy-resolution resonant inelastic X-ray scattering spectrometer at ID20 of the European Synchrotron Radiation Facility. AB - An end-station for resonant inelastic X-ray scattering and (resonant) X-ray emission spectroscopy at beamline ID20 of ESRF - The European Synchrotron is presented. The spectrometer hosts five crystal analysers in Rowland geometry for large solid angle collection and is mounted on a rotatable arm for scattering in both the horizontal and vertical planes. The spectrometer is optimized for high energy-resolution applications, including partial fluorescence yield or high energy-resolution fluorescence detected X-ray absorption spectroscopy and the study of elementary electronic excitations in solids. In addition, it can be used for non-resonant inelastic X-ray scattering measurements of valence electron excitations. PMID- 29488939 TI - FemtoMAX - an X-ray beamline for structural dynamics at the short-pulse facility of MAX IV. AB - The FemtoMAX beamline facilitates studies of the structural dynamics of materials. Such studies are of fundamental importance for key scientific problems related to programming materials using light, enabling new storage media and new manufacturing techniques, obtaining sustainable energy by mimicking photosynthesis, and gleaning insights into chemical and biological functional dynamics. The FemtoMAX beamline utilizes the MAX IV linear accelerator as an electron source. The photon bursts have a pulse length of 100 fs, which is on the timescale of molecular vibrations, and have wavelengths matching interatomic distances (A). The uniqueness of the beamline has called for special beamline components. This paper presents the beamline design including ultrasensitive X ray beam-position monitors based on thin Ce:YAG screens, efficient harmonic separators and novel timing tools. PMID- 29488941 TI - Software for the data analysis of the arrival-timing monitor at SACLA. AB - X-ray free-electron laser (XFEL) pulses from SPring-8 Angstrom Compact free electron LAser (SACLA) with a temporal duration of <10 fs have provided a variety of benefits in scientific research. In a previous study, an arrival-timing monitor was developed to improve the temporal resolution in pump-probe experiments at beamline 3 by rearranging data in the order of the arrival-timing jitter between the XFEL and the synchronized optical laser pulses. This paper presents Timing Monitor Analyzer (TMA), a software package by which users can conveniently obtain arrival-timing data in the analysis environment at SACLA. The package is composed of offline tools that pull stored data from cache storage, and online tools that pull data from a data-handling server in semi-real time during beam time. Users can select the most suitable tool for their purpose, and share the results through a network connection between the offline and online analysis environments. PMID- 29488942 TI - GAPD: a GPU-accelerated atom-based polychromatic diffraction simulation code. AB - GAPD, a graphics-processing-unit (GPU)-accelerated atom-based polychromatic diffraction simulation code for direct, kinematics-based, simulations of X ray/electron diffraction of large-scale atomic systems with mono-/polychromatic beams and arbitrary plane detector geometries, is presented. This code implements GPU parallel computation via both real- and reciprocal-space decompositions. With GAPD, direct simulations are performed of the reciprocal lattice node of ultralarge systems (~5 billion atoms) and diffraction patterns of single-crystal and polycrystalline configurations with mono- and polychromatic X-ray beams (including synchrotron undulator sources), and validation, benchmark and application cases are presented. PMID- 29488943 TI - Real-time diffraction computed tomography data reduction. AB - Diffraction imaging is an X-ray imaging method which uses the crystallinity information (cell parameter, orientation) as a signal to create an image pixel by pixel: a pencil beam is raster-scanned onto a sample and the (powder) diffraction signal is recorded by a large area detector. With the flux provided by third generation synchrotrons and the speed of hybrid pixel detectors, the acquisition speed of these experiments is now limited by the transfer rate to the local storage as the data reduction can hardly be performed in real time. This contribution presents the benchmarking of a typical data analysis pipeline for a diffraction imaging experiment like the ones performed at ESRF ID15a and proposes some disruptive techniques to decode CIF binary format images using the computational power of graphics cards to be able to perform data reduction in real time. PMID- 29488944 TI - miXAFS: a program for X-ray absorption fine-structure data analysis. AB - A new program called miXAFS for the analysis of X-ray absorption fine-structure (XAFS) data is presented. miXAFS can analyze the XAFS functions simultaneously for all measured X-ray absorption edges of the constituent elements in a sample under the constraints for the structural parameters over the edges. The program provides a surface plot of the R-factor as a function of two structural parameters, which is useful to validate the optimized structural parameters. The structural parameters can be obtained from the XAFS data in a few steps using the setting file and batch process. The program, which is coded in MATLAB and freely available, runs on Macintosh and Windows operating systems. It has a graphical user interface and loads experimental data and XAFS functions in a variety of ASCII data formats. PMID- 29488946 TI - Absorbed dose calculations for macromolecular crystals: improvements to RADDOSE. Erratum. AB - Corrections to an equation and a figure in the paper by Paithankar et al. (2009). [J. Synchrotron Rad. 16, 152-162] are made. PMID- 29488947 TI - Innovative sanitation approaches could address multiple development challenges. AB - Globally, more than 60% of the human population live without safely managed sanitation services or even lack access to basic sanitation facilities. In addition, most of the wastewater produced in the world is discharged without proper treatment. Integrated approaches are needed to address these issues and curb the resulting adverse impacts on public health and the environment, and associated societal economic losses. The United Nations 2030 Agenda for Sustainable Development provides an important framework towards more sustainable sanitation development, in terms of both safe sanitation access and wastewater management. Innovative solutions that treat and enable productive safe use of water, and facilitate recovery of nutrients and organic matter from waste resources are booming. Some examples of trends are decentralized solutions, separation of waste flows, low-or no-flushing toilets, and converting faecal sludge to energy. These alternative technologies show huge potential to address many development challenges, contributing to multiple sustainable development goals but achieving upscaling has proved to be a major challenge. A paradigm shift to 'treatment for reuse' instead of 'treatment for disposal' is already taking place in the wastewater sector. Nevertheless, a better understanding of driving forces and enabling environments, new organizational models based on more service-oriented sanitation provision, and highlighting potential multiple societal benefits to attract investments from new sectors are identified areas that need further attention. PMID- 29488948 TI - Treatment wetlands in decentralised approaches for linking sanitation to energy and food security. AB - Treatment wetlands (TWs) are engineered systems that mimic the processes in natural wetlands with the purpose of treating contaminated water. Being a simple and robust technology, TWs are applied worldwide to treat various types of water. Besides treated water for reuse, TWs can be used in resources-oriented sanitation systems for recovering nutrients and carbon, as well as for growing biomass for energy production. Additionally, TWs provide a large number of ecosystem services. Integrating green infrastructure into urban developments can thus facilitate circular economy approaches and has positive impacts on environment, economy and health. PMID- 29488949 TI - Changes in the two-dimensional and perimeter-based fractal dimensions of kaolinite flocs during flocculation: a simple experimental study. AB - In this study, Couette flow experiments were performed to estimate the temporal evolution of the 2D and perimeter-based fractal dimension values of kaolinite flocs during flocculation. The fractal dimensions were calculated based on the projected surface area, perimeter length and length of the longest axis of the flocs as determined by sampling observation and an image-processing system. The 2D fractal dimension, which relates the longest axis length and projected surface area of flocs, was found to decrease with the flocculation time, corresponding to the production of some porous flocs from the flow shear. This fractal dimension finally reached a steady state, which resulted from a dynamic equilibrium among the floc growth, floc breakage and floc restructuring. The perimeter-based fractal dimension, which characterizes the relationship between the projected surface area and the perimeter of flocs, increases with flocculation time because the flow shear increases the collisions among the primary particles, and some irregular flocs are formed. The perimeter-based fractal dimension reaches a steady level because of the balance among floc aggregation, breakage and restructuring. In addition, a stronger turbulent flow shear makes the steady state of fractal dimensions occur early during flocculation. PMID- 29488950 TI - Separate As(V) from solution by mesoporous Y-Al binary oxide: batch experiments. AB - Contaminant arsenic(V) has been regarded as one of the top-priority pollutants to remove from water. In this contribution, different mesoporous Y-Al binary oxides were prepared by the wet impregnation method via varying the molar ratio of Y/Al in the range of 0.029 to 0.116. The manufactured materials were employed as adsorbent to separate arsenic(V) from water. The adsorbent was characterized by N2 adsorption-desorption isotherm, point of zero charge (PZC) and Fourier transform infrared (FT-IR). Furthermore, the effect of experimental parameters on adsorption performance was evaluated by batch experiments, including the molar ratio of Y/Al, adsorbent dosages and contact time, initial concentration, initial pH and temperature. The results indicated that the adsorbent presented an optimal adsorption performance for As(V) uptake when the molar ratio of Y/Al was 0.058. The obtained experimental data were best fitted by Langmuir isotherm and the maximum adsorption capacity was 60.93 mg/g at pH 6.6 +/- 0.1. Additionally, according to the results of adsorption kinetics, it was pronounced that adsorption process was complied with pseudo-second-order model. The adsorption thermodynamic suggested that the adsorption of As(V) is endothermic and spontaneous natural. Moreover, based on the results of FT-IR, PZC and initial pH, it is demonstrated that ion-exchange and electrostatic interaction were the dominating adsorption mechanism. PMID- 29488951 TI - Multi-point monitoring of nitrous oxide emissions in three full-scale conventional activated sludge tanks in Europe. AB - The large global warming potential of nitrous oxide (N2O) is currently of general concern for the water industry, especially in view of a new regulatory framework concerning the carbon footprint of water resource recovery facilities (WRRFs). N2O can be generated through different biological pathways and from different treatment steps of a WRRF. The use of generic emission factors (EF) for quantifying the emissions of WRRFs is discouraged. This is due to the number of different factors that can affect how much, when and where N2O is emitted from WRRFs. The spatial and temporal variability of three WRRFs in Europe using comparable technologies is presented. An economically feasible and user-friendly method for accounting for the contribution of anoxic zones via direct gas emission measurements was proven. The investigation provided new insights into the contribution from the anoxic zones versus the aerobic zones of biological WRRF tanks and proved the unsuitability of the use of a single EF for the three WRRFs. Dedicated campaigns for N2O emissions assessment are to be advised. However, similarities in the EF magnitude can be found considering treatment strategy and influent water composition. PMID- 29488952 TI - Process auditing and performance improvement in a mixed wastewater-aqueous waste treatment plant. AB - The wastewater treatment process is based on complex chemical, physical and biological mechanisms that are closely interconnected. The efficiency of the system (which depends on compliance with national regulations on wastewater quality) can be achieved through the use of tools such as monitoring, that is the detection of parameters that allow the continuous interpretation of the current situation, and experimental tests, which allow the measurement of real performance (of a sector, a single treatment or equipment) and comparison with the following ones. Experimental tests have a particular relevance in the case of municipal wastewater treatment plants fed with a strong industrial component and especially in the case of plants authorized to treat aqueous waste. In this paper a case study is presented where the application of management tools such as careful monitoring and experimental tests led to the technical and economic optimization of the plant: the main results obtained were the reduction of sludge production (from 4,000 t/year w.w. (wet weight) to about 2,200 t/year w.w.) and operating costs (e.g. from 600,000 ?/year down to about 350,000 ?/year for reagents), the increase of resource recovery and the improvement of the overall process performance. PMID- 29488953 TI - Efflux pumps genes of clinical origin are related to those from fluconazole resistant Candida albicans isolates from environmental water. AB - Efflux pumps coded for by CDR1, CDR2, FLU1 and MDR1 genes could be responsible for the observed resistant phenotypes in azole-resistant Candida albicans from environmental water. This was demonstrated for clinical isolates. The aim of this study was to determine the presence and genetic similarity between efflux pump genes from clinical and environmental C. albicans isolates. Yeasts were isolated and identified using 26S rRNA gene sequencing. Disk diffusion tests were conducted. PCR was used to detect the presence of efflux genes. The fragments were sequenced and subjected to BLAST and subsequent phylogenetic analysis. Thirty seven C. albicans were identified from five selected rivers; Mooi River (19 isolates), Harts River (9 isolates), Marico River (5 isolates), Crocodile River (3 isolates) and Schoonspruit River (1 isolate). All the isolates were completely resistant to azoles. Efflux pump genes were detected in most (>=60%) of the isolates. Phylogenetic analysis showed high sequence similarity between sequences from environmental isolates and clinical isolates. Resistance to the azoles and the detection of efflux pump genes renders these antifungal agents ineffective. This is a major problem, particularly for the immune-compromised sector of the community of the North West Province and warrants further investigation. PMID- 29488954 TI - Combined treatment of organic material in oilfield fracturing wastewater by coagulation and UV/H2O2/ferrioxalate complexes process. AB - Organic material is considered to be a main component of oilfield fracturing wastewater (OFW). This work is intended to optimize the experimental conditions for the maximum oxidative degradation of organic material by coagulation and the UV/H2O2/ferrioxalate complexes process. Optimal reaction conditions are proposed based on the chemical oxygen demand (COD) removal efficiency. The overall removal efficiency of COD reached 83.8% when the dilution ratio of raw wastewater was 1:2, the pH was 4 and the FeCl3 loading was 1,000 mg/L in the coagulation process; the dosage of H2O2 (30%,v/v) was 0.6% (v/v) and added in three steps, the n(H2O2)/n(Fe2+) was 2:1, n(Fe2+)/n(C2O42-) was 3:1 and the pH was 4 in the UV/H2O2/ferrioxalate complexes process; the pH was adjusted to 8.5-9 with NaOH and then 2 mg/L of cationic polyacrylamide (CPAM) was added in the neutralization and flocculation process. The decrease in COD during the coagulation process reduced the required H2O2 dosage and improve efficiency in the subsequent UV/H2O2/ferrioxalate complexes process. Furthermore, there was a significant increase of 13.4% in the COD removal efficiency with the introduction of oxalate compared with UV/Fenton. Experimental results show that the coagulation and UV/H2O2/ferrioxalate complexes process could efficiently remove the organic material dissolved in OFW. An optimal combination of these parameters produced treated wastewater that met the GB8978-1996' Integrated Wastewater Discharge Standard' level III emission standard. PMID- 29488955 TI - Adsorption and desorption of uranium(VI) onto humic acids derived from uranium enriched lignites. AB - Humic acids (HAs) were extracted and characterized from three kinds of uranium enriched lignites from Yunnan province, China. Batch experiments were used to study the adsorption and desorption behavior of uranium (VI) onto these HAs and a commercial HA. The results showed that the optimum pH level at which all the HAs adsorbed uranium(VI) ranged from 5 to 8. The high uranium content of the HAs was released into the solution at the pH values between 1 and 3; when the HA dosage was 2.5 g L-1, the maximum concentration of uranium was 44.14 MUg L-1. This shows that HAs derived from uranium-enriched lignites may present a potential environmental risk when used in acidic conditions. The experimental data were found to comply with the pseudo-second-order kinetic model, and the adsorption isotherms fit the Langmuir and Freundlich models well. The desorption experiments revealed that the sorption mechanism was controlled by the complex interactions between the organic ligands of the HAs and uranium(VI). The uranium present in the HAs may not affect the adsorption capacity of the uranium(VI), but the carboxylic and phenolic hydroxyl groups in the HAs play a significant role in controlling the adsorption capacity. PMID- 29488956 TI - Investigation of surface and filtration properties of TiO2 coated ultrafiltration polyacrylonitrile membranes. AB - In the present work, the surface and filtration properties of TiO2 coated polyacrylonitrile ultrafiltration membranes were investigated. The membranes were coated using the physical deposition method. The appropriate TiO2 coverage proved to be 0.3 mg/cm2, which formed a hydrophilic cake layer on the membrane surface. The cleanability without chemicals and the retention of the coated membranes was compared to the neat membrane after model oily wastewater filtration. The cleaning sustained of rinsing with distilled water and ultraviolet (UV) irradiation of the fouled membranes. The coated membranes have better antifouling properties; higher flux values during oily water filtration and by the mentioned cleaning process a significantly better flux recovery can be achieved. The amount of the catalyst and the irradiation time are limiting factors to the effectiveness of the cleaning process. The UV irradiation increases the wettability of the fouled membrane surface by degrading the oil layer. The coating, the continuous use, and the cleaning process do not significantly affect the membrane retention expressed in chemical oxygen demand. PMID- 29488957 TI - Adsorption and catalytic oxidation of organic pollutants using Fe-zeolite. AB - In this work, a natural zeolite, modified and loaded with iron (NZ-A-Fe) as a heterogeneous catalyst, was characterized for its suitability as a permeable reactive barrier (PRB) material for treatment of aromatic hydrocarbons in groundwater. Adsorption and oxidation processes were analyzed. Batch adsorption tests for benzene, toluene and xylene (BTX) aqueous concentrated solutions were performed at neutral pH. Kinetic adsorption was described with the pseudo-second order model. Experiments were performed using a stirred batch reactor with near 11 mM initial BTX concentration applying NZ-A-Fe as solid catalyst and H2O2 as an oxidant. BTX removal reached 80% in 600 min in these experimental conditions. Catalytic oxidation was described with a pseudo-first-order kinetic model. No significant iron leaching was detected during all the experiences. These investigations show that coupling adsorption with catalytic oxidation with this novel system is a promising procedure to simultaneously remove BTX from moderately concentrated aqueous solution at neutral pH in groundwater. PMID- 29488958 TI - Evaluation of alkalinity spatial distribution in an up-flow fixed bed anaerobic digester. AB - In this paper, an experimental study upon alkalinity and hydrodynamic behavior in an anaerobic up-flow fixed bed reactor for the treatment of tequila vinasses is presented. Measurements of volatile fatty acids, pH, alkalinity and bicarbonate were obtained at three sampling points in the reactor in the axial axis. Then, the spatial distribution of alkalinity is studied and discussed. Moreover, for further control process purposes, a hydrodynamic model based on the use of two interconnected two-steps reduced AM2 type models is proposed and its parameters are identified using experimental data. PMID- 29488959 TI - Utilization of lime-dried sludge for eco-cement clinker production: effects of different feeding points. AB - Co-processing lime-dried sludge (LDS) in cement kilns is an appropriate technique to solve the problem of LDS disposal and promote the sustainable development for cement industry. However, there were limited studies that investigated the effects of feeding points on product quality and cement kiln emissions. In this study, simulated experiments were conducted by dividing the feeding points into high-temperature zones (HTZs) and raw mill (RM). Cement quality and major cement kiln emission characteristics were comprehensively investigated. The results showed that in terms of burnability, compressive strength and microstructure, the optimum co-processing amount of LDS were 9 wt% when feeding at RM, while 6% when feeding at HTZs. Meanwhile, the organic emissions of RM samples were mainly low environmental risk compounds of amides and nitrogenous heterocyclic compounds. Inorganic gaseous pollutions of NOX and SO2, respectively, were 8.11 mg/g DS and 12.89 mg/g DS, compared with 7.61 mg/g DS and 4.44 mg/g DS for HTZs. However, all the cement kiln emissions concentration were still much lower than standard requirements. Overall, RM had a bigger LDS co-processing capacity and higher, but acceptable, cement kiln emissions. Feeding LDS via RM could dispose larger amounts of sludge and provide more alternative materials for cement manufacturing. PMID- 29488960 TI - Evaluation of a novel anti-biofouling microorganism (Bacillus sp. T5) for control of membrane biofouling and its effect on bacterial community structure in membrane bioreactors. AB - The effects of a newly isolated quorum quenching (QQ) bacteria (Bacillus sp. T5) on the microbial community has been evaluated via the Illumina sequencing method. Membrane bioreactors (MBRs) operated with this novel QQ bacterium to evaluate the improvement in the performance of MBR. Anti-biofouling effect of T5 was enhanced as 71% compared to the control reactor. Also, QQ bacteria did not have any negative effect on the removal of organics during the process. Gram-negative bacteria were found to be dominant over Gram-positive bacteria. Proteobacteria, Actinobacteria, Bacteroidetes, Acidobacteria, Firmicutes, and Chloroflexi were dominant phyla in the control and QQ reactors. The proportion of Alphaproteobacteria was most significant among Proteobacteria. The relative abundances of Actinobacteria, Acidobacteria, and Firmicutes were significantly affected by Quorum quenching mechanism. On the other hand, QQ activity of Bacillus sp. T5 significantly influenced the relative abundance of Proteobacteria, Bacteroidetes, and Chloroflexi. The QQ process appeared to generate variations in the structure of the microbial community. According to the results of the molecular analyses, the syntrophic interaction of Bacillus sp. T5 and indigenous Gram-negative and Gram-positive bacterial community is critical to the performance of MBRs. PMID- 29488961 TI - Biodegradation and toxicity of melamine at high activated sludge concentrations in a membrane bioreactor. AB - Melamine is recalcitrant and toxic to bacteria in conventional activated sludge systems. In this study, we investigated the degradation and toxicity of melamine in a membrane bioreactor (MBR) system operated at high activated sludge concentrations (~8.5 g TSS/L). Melamine was dosed at 3 mg/L for about 100 days. The average melamine removal efficiency in the MBR system was 20 +/- 11%. Meanwhile, batch studies showed the acclimated sludge from the MBR had higher removal efficiencies after the depletion of readily biodegradable substrate (acetate) while non-acclimated sludge did not remove any melamine. As acclimated sludge had removal efficiencies ranging from 33 +/- 6% (by 1.7 g TSS/L biomass) to 41 +/- 10% (by 8.5 g TSS/L biomass), microbial specialists with unique hydrolytic enzymes in the acclimated sludge were likely responsible for melamine degradation. Since bacteria prefer to use readily biodegradable substrates for growth in the MBR, the population of microbial specialists capable of degrading melamine or the capability of cometabolism appeared not to increase with an increase in biomass concentration. Nevertheless, because of high sludge concentrations and thus low mass ratio of toxic melamine to biomass in the MBR, the long-term melamine exposure did not affect MBR activated sludge performance. PMID- 29488962 TI - Post-treatment of tannery wastewater using pilot scale horizontal subsurface flow constructed wetlands (polishing). AB - In the present study, a pilot scale horizontal subsurface flow constructed wetland (CW) system planted with Phragmites karka; longitudinal profile was studied. The wetland was fed with tannery wastewater, pretreated in a two-stage anaerobic digester followed by a sequence batch reactor. Samples from each CW were taken and analyzed using standard methods. The removal efficiency of the CW system in terms of biological oxygen demand (BOD), chemical oxygen demand (COD), Cr and total coliforms were 91.3%, 90%, 97.3% and 99%, respectively. The removal efficiency for TN, NO3- and NH4+-N were 77.7%, 66.3% and 67.7%, respectively. Similarly, the removal efficiency of SO42-, S2- and total suspended solids (TSS) were 71.8%, 88.7% and 81.2%, respectively. The concentration of COD, BOD, TN, NO3 N, NH4+-N, SO42 and S2- in the final treated effluent were 113.2 +/- 52, 56 +/- 18, 49.3 +/- 13, 22.75 +/- 20, 17.1 +/- 6.75, 88 +/- 120 and 0.4 +/- 0.44 mg/L, respectively. Pollutants removal was decreased in the first 12 m and increased along the CW cells. P. karka development in the first cell of CW was poor, small in size and experiencing chlorosis, but clogging was higher in this area due to high organic matter settling, causing a partial surface flow. The performance of the pilot CW as a tertiary treatment showed that the effluent meets the permissible discharge standards. PMID- 29488963 TI - Evaluating the suitability of tungsten, titanium and stainless steel wires as current collectors in microbial fuel cells. AB - An appropriate current collector (CC) is crucial for harvesting substantial power in a microbial fuel cell (MFC). In the present study, stainless steel (SS) and titanium wires were used as the CCs for both the anode and cathode of MFC-1 and MFC-2, respectively. Tungsten wire (TW) was used as the anode CC in MFC-3, with SS wire as the cathode CC. In MFC-4, TW was used as the cathode CC with SS wire as the anode CC, and in MFC-5 both electrode CCs were TW. The power density, current density, oxidation current and bio-capacitance were compared to select the best and most cost effective CC material to enhance the power output of MFCs. Maximum power densities (mW/m2) of 32.28, 93.10, 225.38, 210.74, and 234.88 were obtained in MFC-1, MFC-2, MFC-3, MFC-4, and MFC-5, respectively. The highest current density (639.86 mA/m2) and coulombic efficiency (23.12 +/- 1.5%) achieved in MFC-5 showed TW to be the best CC for both electrodes. The maximum oxidation current of 7.4 mA and 7 mA and bio-capacitance of 10.3 mF/cm2 and 9.7 mF/cm2 were achieved in MFC-3 and MFC-5, respectively, suggesting TW is the best as the anode CC and SS wire as the cathode CC to reduce MFC fabrication costs. PMID- 29488964 TI - Nutrient leaching from extensive green roofs with different substrate compositions: a laboratory study. AB - To investigate nutrient leaching from extensive green roofs, green roof platforms were established to investigate the effluent quantity and quality during artificial rainfall. When the influent volume reached three times the empty bed volume, for which the cumulative rainfall was around 300 mm, the effluent TP and COD concentrations of green roof platforms filled with peat soil did not tend to stabilize. For a long-term operation, the substrate depths had little significant influence on TN, TP and COD concentrations of the green roof effluents. A normalized cumulative emission process method was proposed to discuss the difference in various pollutant leaching processes. Obvious differences in the leaching process of different contaminants for green roof platforms filled with various substrates were observed. For the green roof filled with modified substrates, the nitrogen and phosphorus pollutant leaching rates were relatively high in the initial stage of green roof operation and the phosphorus leaching rate was higher than that of nitrogen. The green roof is a sink for TN, but not for TP and COD in this study. The outcomes are critical for the selection of green roof substrates and also contribute to green roof maintenance. PMID- 29488965 TI - The model binary/ternary mixtures for actual EPS solution extracted from the activated sludge in MBR using dead-end membrane filtration cell. AB - In order to find a model solution to simulate actual extracellular polymeric substances (EPS) solution in terms of filterability behavior, a series of experiments were conducted in a dead-end unstirred cell with 0.1 MUm polyvinylidene fluoride membranes using binary/ternary mixtures consisting of sodium alginate (SA), bovine serum albumin (BSA) and humic acid (HA). Three target parameters (cumulative filtrate volume (CFV), specific cake resistance (alphac) and rejection (R)) were compared and the roles of mixture components were investigated. The order of degree of influence on CFV, alphac and R in ternary mixture was SA (94.5%, 85.6% and 88.2%, respectively) > BSA (5.2%, 10.3% and 8.0%) > HA (0.3%, 4.1% and 3.8%). Meanwhile, when the composition of ternary mixture was SA/BSA/HA = 285.1/150.1/10.2 mg.L-1, the deviation for CFV, alphac and R was 7.65%, 19.6% and 7.27%, respectively, while the corresponding values for the most suitable binary solution (SA/BSA = 140.4/50.35 mg.L-1) were -12%, 1% and 164% respectively. This indicated that the ternary solution demonstrated a more accurate estimation than the binary solution for imitating the filterability of actual EPS solution. Therefore, the ternary mixture could be employed efficiently to replace the actual EPS solution in terms of three target parameters in practice applications. PMID- 29488966 TI - Application of a moving-bed biofilm reactor for sulfur-oxidizing autotrophic denitrification. AB - Sulfur-oxidizing autotrophic denitrification (SO-AD) was investigated in a laboratory-scale moving-bed biofilm reactor (MBBR) at a sewage temperature of 22 degrees C. A synthetic wastewater with nitrate, sulfide and thiosulfate was fed into the MBBR. After 20 days' acclimation, the reduced sulfur compounds were completely oxidized and nitrogen removal efficiency achieved up to 82%. The operation proceeded to examine the denitrification by decreasing hydraulic retention time (HRT) from 12 to 4 h in stages. At steady state, this laboratory scale SO-AD MBBR achieved the nitrogen removal efficiency of 94% at the volumetric loading rate of 0.18 kg N.(mreactor3.d)-1. The biofilm formation was examined periodically: the attached volatile solids (AVS) gradually increased corresponding to the decrease of HRT and stabilized at about 1,300 mg AVS.Lreactor-1 at steady state. This study demonstrated that without adding external organic carbon, SO-AD can be successfully applied in moving-bed carriers. The application of SO-AD MBBR has shown the potential for sulfur containing industrial wastewater treatment, brackish wastewater treatment and the upgrading of the activated sludge system. Moreover, the study provides direct design information for the full-scale MBBR application of the sulfur-cycle based SANI process. PMID- 29488967 TI - Seasonal movement of trace-element discharge in a typical south-Indian suburban community. AB - Four conventional activated sludge sewage treatment plants (STPs) in Southern India were chosen to investigate the occurrence of major ions and trace metals in dissolved fraction of the wastewater. Samples were collected from inlet and outlet of STPs during the pre-monsoon and monsoon seasons. Except for a few elements (Mn, Mo and Ni), the concentrations of the rest increased at the outlet of STPs, suggesting that there is an addition of these elements during the treatment process. The increase in concentrations at the STP outlet ranged from 1.25 times for Mn to 3,254 times for Ag during the pre-monsoon. In the monsoon, the increase ranged from 1.75 (Fe) to 1,510 (Ag). This suggests that there is a substantial anthropogenic input of these elements as they pass through the treatment process. Removal rates of elements in STPs also varied. 59% of Mn was removed during the treatment process during pre-monsoon as compared to 67% removal during monsoon. PMID- 29488968 TI - Infectious helminth ova in wastewater and sludge: A review on public health issues and current quantification practices. AB - Raw and partially treated wastewater has been widely used to maintain the global water demand. Presence of viable helminth ova and larvae in the wastewater raised significant public health concern especially when used for agriculture and aquaculture. Depending on the prevalence of helminth infections in communities, up to 1.0 * 103 ova/larvae can be presented per litre of wastewater and 4 gm (dry weight) of sludge. Multi-barrier approaches including pathogen reduction, risk assessment, and exposure reduction have been suggested by health regulators to minimise the potential health risk. However, with a lack of a sensitive and specific method for the quantitative detection of viable helminth ova from wastewater, an accurate health risk assessment is difficult to achieve. As a result, helminth infections are difficult to control from the communities despite two decades of global effort (mass drug administration). Molecular methods can be more sensitive and specific than currently adapted culture-based and vital stain methods. The molecular methods, however, required more and thorough investigation for its ability with accurate quantification of viable helminth ova/larvae from wastewater and sludge samples. Understanding different cell stages and corresponding gene copy numbers is pivotal for accurate quantification of helminth ova/larvae in wastewater samples. Identifying specific genetic markers including protein, lipid, and metabolites using multiomics approach could be utilized for cheap, rapid, sensitive, specific and point of care detection tools for helminth ova and larva in the wastewater. PMID- 29488969 TI - Combined yeast and microalgal cultivation in a pilot-scale raceway pond for urban wastewater treatment and potential biodiesel production. AB - A mixed culture of oleaginous yeast Lipomyces starkeyi and wastewater native microalgae (mostly Scenedesmus sp. and Chlorella sp.) was performed to enhance lipid and biomass production from urban wastewaters. A 400 L raceway pond, operating outdoors, was designed and used for biomass cultivation. Microalgae and yeast were inoculated into the cultivation pond with a 2:1 inoculum ratio. Their concentrations were monitored for 14 continuous days of batch cultivation. Microalgal growth presented a 3-day initial lag-phase, while yeast growth occurred in the first few days. Yeast activity during the microalgal lag-phase enhanced microalgal biomass productivity, corresponding to 31.4 mgTSS m-2 d-1. Yeast growth was limited by low concentrations in wastewater of easily assimilated organic substrates. Organic carbon was absorbed in the first 3 days with a 3.7 mgC L-1 d-1 removal rate. Complete nutrient removal occurred during microalgal linear growth with 2.9 mgN L-1 d-1 and 0.96 mgP L-1 d-1 removal rates. Microalgal photosynthetic activity induced high pH and dissolved oxygen values resulted in natural bactericidal and antifungal activity. A 15% lipid/dry weight was measured at the end of the cultivation time. Fatty acid methyl ester (FAME) analysis indicated that the lipids were mainly composed of arachidic acid. PMID- 29488970 TI - Plant growth and nutrient uptake in treatment wetlands for water with low pollutant concentration. AB - The objective of this study was to determine how macrophytes commonly used in treatment wetlands (TWs) respond to water with low pollutant concentration. We measured pollutant removal efficiency and compared growth and nutrient uptake of five macrophytes in demonstration scale units (volume >40 m3) irrigated by water with pollutant concentrations representative of average urban stormwater quality. All species showed a strong productivity gradient along the beds, starting with high biomass - high density near the inlet, then decreasing progressively with distance. Cyperus was by far the most productive species. Phragmites and Thalia had higher biomass in the first few metres of the beds than Typha and Arundo. In terms of pollutant removal, decreasing plant growth may be interpreted as indicative of high efficiency when caused by nutrient depletion. Differences in aboveground biomass between species did not translate into measurable differences in removal efficiency at the outlet. Although Phragmites australis is the species most commonly used in TWs, under the low nutrient load, Cyperus had twice its biomass, and higher N and P uptake. These results highlight the importance of considering wastewater characteristics when selecting macrophyte species for TWs. PMID- 29488971 TI - Effects of phenol on sulfate reduction by mixed microbial culture: kinetics and bio-kinetics analysis. AB - Mixed microbial culture collected from the wastewater treatment plant of Indian Institute of Technology Guwahati (IITG) was further grown in anaerobic condition in presence of sulfate where lactate was added as a carbon source. Sulfate addition was increased stepwise up to 1,000 mg l-1 before phenol was added at increasing concentrations from 10 mg l-1 to 300 mg l-1. Kinetics of sulfate, phenol and chemical oxygen demand reduction were studied and experimental findings were analyzed using various bio-models to estimate the bio-kinetic coefficients. This is the first detailed report on kinetics and bio-kinetic studies of sulfate reduction in presence of phenol. Experimental results showed that there was no inhibition of sulfate reduction and microbial growth up to 100 mg l-1 phenol addition. However, inhibition to different degrees was observed at higher phenol addition. The experimental data of microbial growth and substrate consumption in presence of phenol fitted well to the Edward model (R2 = 0.85, root mean square error = 0.001011) with maximum specific growth rate = 0.052 h-1, substrate inhibition constant = 88.05 mg l-1 and half saturation constant = 58.22 mg l-1. The characteristics of the cultured microbes were determined through a series of analysis and microbial tests. PMID- 29488972 TI - Microbial characteristics of landfill leachate disposed by aerobic moving bed biofilm reactor. AB - An aerobic moving bed biofilm reactor (MBBR) was applied to treat landfill leachate generated from a domestic waste incineration plant. Pollutant removal efficiency of this reactor under stable operating condition was studied. The biomass, bacteria species, and microbial metabolism in this reactor were investigated. These results showed that the average removal efficiency of chemical oxygen demand (COD) and ammonia nitrogen in the aerobic MBBR achieved 64% and 97% in the optimum conditions, respectively. The three-dimensional fluorescence spectrum revealed that the content of soluble microbial byproducts from extracellular polymeric substances extraction in suspended sludge was much higher than that on biofilm, and the types of pollutants were various in different regions of the reactor. It also indicated that the MBBR system had a stable, rich and regular microorganism community, including large amounts of nitrifying bacteria and denitrifying bacteria. Scanning electron microscopy suggested that biofilm attached to the packing provided a good anoxic-aerobic micro environment system to achieve a high metabolic activity, which favored COD and ammonia removal. PMID- 29488973 TI - Influence of heavy metal ions on the spectra and charge characteristics of DOM of municipal sewage secondary effluent. AB - The spectral and charged characteristics of dissolved organic matter (DOM) in municipal sewage secondary effluent influenced by heavy metal ions were studied by three-dimensional fluorescence spectroscopy, ultraviolet spectrometry, etc. As the Cu(II) concentration increased, the fluorescence intensity of the DOM's fluorescence peak reduced. When the Cu(II) concentration was 100 MUmol/L, the fluorescence intensity of the humic-like acid in the DOM reduced by 19.5%-27.6%. However, there was no obvious change in the fluorescence intensity when Cd(II) was added. According to the modified Stern-Volmer equation, the conditional stability constant lgK and the proportion of the fluorescent functional groups of the DOM binding with Cu(II) were 2.19-2.69 and 16%-48%, respectively. The UV253/UV203 value changed little with the additional dosage of metal ions below 10 MUmol/L, which increased as the concentration of Cu(II) or Pb(II) increased from 10-100 MUmol/L. As the metal concentrations increase, the absolute values of the Zeta potential and the particle sizes of the DOM basically increased. The results showed that Cu(II) had the strongest binding ability to the groups that emitted fluorescence in the secondary effluent DOM compared to Pb(II) and Cd(II). PMID- 29488974 TI - Ecology and performance of aerobic granular sludge treating high-saline municipal wastewater. AB - The successful development of aerobic granular sludge (AGS) for secondary wastewater treatment has been linked to a dedicated anaerobic feeding phase, which enables key microbes such as poly-phosphate-accumulating organisms (PAOs) and glycogen-accumulating organisms to gain a competitive advantage over floc forming organisms. The application of AGS to treat high-saline sewage and its subsequent impacts on microbial ecology, however, are less well understood. In this study, the impacts of high-saline sewage on AGS development, performance and ecology were investigated using molecular microbiology methods. Two feeding strategies were compared at pilot scale: a full (100%) anaerobic feed; and a partial (33%) anaerobic feed. The results were compared to a neighbouring full scale conventional activated sludge (CAS) system (100% aerobic). We observed that AGS developed under decreased anaerobic contact showed a comparable formation, stability and nitrogen removal performance to the 100% anaerobically fed system. Analysis of the microbial ecology showed that the altered anaerobic contact had minimal effect on the abundances of the functional nitrifying and denitrifying bacteria and Archaea; however, there were notable ecological differences when comparing different sized granules. In contrast to previous work, a large enrichment in PAOs in AGS was not observed in high-saline wastewater, which coincided with poor observed phosphate removal performance. Instead, AGS exhibited a substantial enrichment in sulfide-oxidising bacteria, which was complemented by elemental analysis that identified the presence of elemental sulfur precipitation. The potential role for these organisms in AGS treating high saline wastewater is discussed. PMID- 29488975 TI - Removal of antibiotic resistant E. coli in two Norwegian wastewater treatment plants and by nano- and ultra-filtration processes. AB - The effectivity of different treatment stages at two large wastewater treatment plants (WWTPs) located in Oslo, Norway, to remove antibiotic resistant Escherichia coli from municipal wastewater was investigated. The WWTPs were effective in reducing the total cultivable E. coli. The E. coli in WWTP samples were mainly resistant to ampicillin (6-27%) and trimethoprim-sulfamethoxazole (5 24%), and, to a lesser extent, tetracycline (3-14%) and ciprofloxacin (0-7%). In the first WWTP, a clear decrease in the percentage of E. coli resistant to these antibiotics was found, with the main removal occurring during physical/chemical treatment. In the second WWTP, the percentage of cultivable resistant E. coli did not display a considerable change. During laboratory-scale membrane filtration of WWTP effluents using ultrafiltration (UF) and nanofiltration (NF) membranes, all E. coli, including those resistant to antibiotics, were removed completely. The results imply that UF and NF processes are potent measures to remove antibiotic resistant bacteria (ARB) during post-treatment of WWTP effluents, thus reducing the potential spread of antibiotic resistance in the receiving aquatic environment. PMID- 29488976 TI - Enhanced adsorption of ciprofloxacin by KOH modified biochar derived from potato stems and leaves. AB - Potato stems and leaves biochar (PB) was prepared by pyrolysis at a temperature of 500 degrees C under anoxic conditions. In order to strengthen the adsorption capacity, biochar was modified with alkaline solution (alkali modified biochar, APB). Two kinds of biochars were adopted as adsorbents to remove ciprofloxacin (CIP) from aqueous solution. The adsorption behavior of CIP onto biochar before and after alkali modified including adsorption kinetics and isotherms were investigated. The effects of different factors (equilibrium time, pH, temperature and initial concentration) during the adsorption process were also investigated. Biochar samples were characterized by Fourier transform infrared (FTIR), scanning electron microscopy (SEM), and nitrogen adsorption-desorption isotherm. The results showed that the alkali treated biochar possessed more mesopores than raw biochar, and accordingly exhibited a more excellent adsorption performance (23.36 mg.g-1) than raw biochar. Hydrophobic interaction, hydrogen-bonding interaction, electrostatic interaction, and pi - pi interaction were the adsorption mechanisms for CIP uptake onto the two adsorbents. PMID- 29488978 TI - Predicting Pain After Tooth Extraction: Pain Prediction Index. AB - AIMS: To identify relevant variables that may predict pain after routine extraction of erupted teeth, to construct a Pain Prediction Index (PPI) based on these variables, and to verify how these variables are related by using valid structural equation modeling (ie, path analysis). METHODS: This study was designed as an observational prospective study for postoperative memory of pain after dental extraction of erupted teeth. Data from a total of 781 surgical procedures related to dental extractions were included. Pain was self-reported by the patients and was evaluated by a verbal category scale (VCS) on the seventh postoperative day. The database was searched for predictive variables that were significantly (P < .05) associated with postoperative pain. RESULTS: Pain was scored by patients as none in 65.4% of cases (511); light in 22.9% (179); moderate in 11% (86); and severe in 0.6% (5). Seven predictive variables were strongly related to postoperative pain: gender (female); age (younger than 33); number of extracted teeth (three); surgical technique (surgical flap, ostectomy, or teeth sectioning); number of local anesthetic cartridges (more than three); time in surgery (greater than 25 minutes); and any surgical complications. These variables were used to compose the PPI. The retained PPI classified 66.3% of the patients correctly for both pain and no pain; however, when more than three points were scored on the PPI, it correctly predicted pain in 55.6% of cases. CONCLUSION: The present study identified seven predictive variables that were strongly related to postextraction pain and documented that the PPI could correctly predict pain in the majority of patients. PMID- 29488977 TI - Micropollutant removal from black water and grey water sludge in a UASB-GAC reactor. AB - The effect of granular activated carbon (GAC) addition on the removal of diclofenac, ibuprofen, metoprolol, galaxolide and triclosan in a up-flow anaerobic sludge blanket (UASB) reactor was studied. Prior to the reactor studies, batch experiments indicated that addition of activated carbon to UASB sludge can decrease micropollutant concentrations in both liquid phase and sludge. In continuous experiments, two UASB reactors were operated for 260 days at an HRT of 20 days, using a mixture of source separated black water and sludge from aerobic grey water treatment as influent. GAC (5.7 g per liter of reactor volume) was added to one of the reactors on day 138. No significant difference in COD removal and biogas production between reactors with and without GAC addition was observed. In the presence of GAC, fewer micropollutants were washed out with the effluent and a lower accumulation of micropollutants in sludge and particulate organic matter occurred, which is an advantage in micropollutant emission reduction from wastewater. However, the removal of micropollutants by adding GAC to a UASB reactor would require more activated carbon compared to effluent post-treatment. Additional research is needed to estimate the effect of bioregeneration on the lifetime of activated carbon in a UASB-GAC reactor. PMID- 29488979 TI - Modulation of Jaw Muscle Motor Response and Wake-Time Parafunctional Tooth Clenching With Music. AB - AIMS: To evaluate the effects of Guided Music Listening (GML) on masticatory muscles and on the amplitude of wake-time tooth clenching in individuals with higher vs lower frequency of clenching episodes. METHODS: The electromyographic (EMG) activity of the right masseter was recorded during three 20-minute music (relaxing, stress/tension, and favorite) tasks and a control no-music task in 10 (mean age +/- standard deviation [SD] = 21.4 +/- 3.0 years) and 11 (22.6 +/- 2.9 years) healthy volunteers with higher (HP) vs lower (LP) frequency of tooth clenching episodes, respectively. EMG episodes greater than 10% of the maximum voluntary contraction (EMG activity of the masseter during tooth clenching) and below 10% (EMG activity during rest) were analyzed. Nonparametric tests were used to assess between-group and within-group (between-task) differences in primary outcome measures. RESULTS: In both groups, EMG activity during rest was the greatest during the stress/tension task, and it was the lowest during the favorite task in the LP group and the relaxing task in the HP group (all P < .001). In the HP group, the amplitude of clenching episodes was significantly lower during the favorite and stress/tension tasks than during the relaxing task (all P < .05), while in the LP group, it was significantly lower during the stress/tension task than during the control task (P = .001). The experiment did not affect the frequency or duration of clenching episodes. CONCLUSION: GML modulates masticatory muscle activity. The response to GML depends on the frequency of clenching and the type of music. PMID- 29488984 TI - Porous organic cage stabilised palladium nanoparticles: efficient heterogeneous catalysts for carbonylation reaction of aryl halides. AB - Porous organic cage stabilised palladium nanoparticles were successfully prepared using methanol as a mild reductant. The as-prepared porous composite materials show high catalytic activity for the carbonylation reaction of aryl halides under mild conditions. PMID- 29488985 TI - Energy vs. density on paths toward more exact density functionals. AB - Recently, the progression toward more exact density functional theory has been questioned, implying a need for more formal ways to systematically measure progress, i.e. a "path". Here I use the Hohenberg-Kohn theorems and the definition of normality by Burke et al. to define a path toward exactness and "straying" from the "path" by separating errors in rho and E[rho]. A consistent path toward exactness involves minimizing both errors. Second, a suitably diverse test set of trial densities rho' can be used to estimate the significance of errors in rho without knowing the exact densities which are often inaccessible. To illustrate this, the systems previously studied by Medvedev et al., the first ionization energies of atoms with Z = 1 to 10, the ionization energy of water, and the bond dissociation energies of five diatomic molecules were investigated using CCSD(T)/aug-cc-pV5Z as benchmark at chemical accuracy. Four functionals of distinct designs was used: B3LYP, PBE, M06, and S-VWN. For atomic cations regardless of charge and compactness up to Z = 10, the energy effects of the different rho are <4 kJ mol-1 (chemical accuracy) defined here as "normal", even though these four functionals ranked very differently in the previous test. Thus, the "off-path" behavior for such cations is energy-wise insignificant. An interesting oscillating behavior in the density sensitivity is observed vs. Z, explained by orbital occupation effects. Finally, it is shown that even large "normal" problems such as the Co-C bond energy of cobalamins can use simpler (e.g. PBE) trial densities to drastically speed up computation by loss of a few kJ mol-1 in accuracy. The proposed method of using a test set of trial densities to estimate the sensitivity and significance of density errors of functionals may be useful for testing and designing new balanced functionals with more systematic improvement of densities and energies. PMID- 29488986 TI - Improved NOE fitting for flexible molecules based on molecular mechanics data - a case study with S-adenosylmethionine. AB - The use of molecular dynamics (MD) calculations to derive relative populations of conformers is highly sensitive to both timescale and parameterisation of the MD. Where these calculations are coupled with NOE data to determine the dynamics of a molecular system, this can present issues if these populations are thus relied upon. We present an approach that refines the highly accurate PANIC NMR methodology combined with clustering approaches to generate conformers, but without restraining the simulations or considering the relative population distributions generated by MD. Combining this structural sampling with NOE fitting, we demonstrate, for S-adenosylmethionine (aqueous solution at pH 7.0), significant improvements are made to the fit of populations to the experimental data, revealing a strong overall preference for the syn conformation of the adenosyl group relative to the ribose ring, but with less discrimination for the conformation of the ribose ring itself. PMID- 29488987 TI - Controlled synthesis of organic single-crystalline nanowires via the synergy approach of the bottom-up/top-down processes. AB - The controlled fabrication of organic single-crystalline nanowires (OSCNWs) with a uniform diameter in the nanoscale via the bottom-up approach, which is just based on weak intermolecular interaction, is a great challenge. Herein, we utilize the synergy approach of the bottom-up and the top-down processes to fabricate OSCNWs with diameters of 120 +/- 10 nm through stepwise evolution processes. Specifically, the evolution processes vary from the self-assembled organic micro-rods with a quadrangular pyramid-like end-structure bounded with {111}s and {11-1}s crystal planes to the "top-down" synthesized organic micro rods with the flat cross-sectional {002}s plane, to the organic micro-tubes with a wall thickness of ~115 nm, and finally to the organic nanowires. Notably, the anisotropic etching process caused by the protic solvent molecules (such as ethanol) is crucial for the evolution of the morphology throughout the whole top down process. Therefore, our demonstration opens a new avenue for the controlled fabrication of organic nanowires, and also contributes to the development of nanowire-based organic optoelectronics such as organic nanowire lasers. PMID- 29488988 TI - Oxocarbon-functionalized graphene as a lithium-ion battery cathode: a first principles investigation. AB - In recent years, organic-based, especially carbonyl-based, Li-ion battery electrode materials have attracted great attention due to their low-cost, environmentally friendly nature and strong Li-ion bonding abilities. However, new research is required to further increase the electron mobility and cycling performance of organic materials. The performance of a high-carbonyl C6O6 molecule-functionalized graphene electrode for Li-ion batteries is investigated using the density functional theory. The binding energy calculations indicate that the C6O6 molecule is adsorbed on graphene via physisorption. C6O6@graphene maintains excellent electronic conductivity with 1 to 6 Li ions. By our statistical method, the reduced voltage of the C6O6@graphene cathode displays a voltage between 2.6 V and 1.5 V with 2 phases from 1 to 6 Li ions with energy density of approximately 155 mA h g-1. The results obtained reveal that C6O6@graphene is a promising electrode material for renewable Li-ion batteries. PMID- 29488989 TI - Re-examining ammonia addition to the Criegee intermediate: converging to chemical accuracy. AB - Stabilized Criegee intermediates (SCI) are formed during the ozonolysis of unsaturated hydrocarbons and have been implicated in the formation of hydroxyl radicals and aerosols. Previous theoretical research [S. Jorgenson and A. Gross, J. Phys. Chem. A, 2009, 113, 10284-10290] computed the rate constants for addition of ammonia to simple SCIs, but reported a wide distribution of quantum chemical energies, depending on the basis set used. We report optimized geometries for these reactions at the CCSD(T)/ANO2 and CCSD(T)/ANO1 levels, and CCSD(T)/CBS energies with perturbative quadruples corrections. We find the inclusion of perturbative quadruples corrections elevates the energy of the transition state by 0.76-0.88 kcal mol-1 relative to the reactants, which qualitatively changes the reaction surface. We calculate rate constants and find that Jorgenson and Gross previously overestimated the rate constants for ammonia addition to SCIs, but were within an order of magnitude. This supports the previous conclusion of Vereecken et al. [L. Vereecken, H. Harder and A. Novelli, Phys. Chem. Chem. Phys., 2012, 14, 14682-14695] that ammonia addition to SCIs is a negligible sink of Criegee intermediates. PMID- 29488991 TI - Wetting, meniscus structure, and capillary interactions of microspheres bound to a cylindrical liquid interface. AB - Wetting, meniscus structure, and capillary interactions for polystyrene microspheres deposited on constant curvature cylindrical liquid interfaces, constructed from nonvolatile ionic or oligomeric liquids, were studied by optical interferometry and optical microscopy. The liquid interface curvature resulted from the preferential wetting of finite width lines patterned onto planar silicon substrates. Key variables included sphere diameter, nominal (or average) contact angle, and deviatoric interfacial curvature. Menisci adopted the quadrupolar symmetry anticipated by theory, with interfacial deformation closely following predicted dependences on sphere diameter and nominal contact angle. Unexpectedly, the contact angle was not constant locally around the contact line, the nominal contact angle varied among seemingly identical spheres, and the maximum interface deviation did not follow the predicted dependence on deviatoric interfacial curvature. Instead, this deviation was up to an order-of-magnitude larger than predicted. Trajectories of neighboring microspheres visually manifested quadrupole-quadrupole interactions, eventually producing square sphere packings that foreshadow interfacial assembly as a potential route to hierarchical 2D particle structures. PMID- 29488992 TI - Revisiting the colloidal fundamentals of water-dispersible polyesters: interactions and self-assembly of polymer nanoaggregates in water. AB - Water-dispersible sulfopolyesters are a major class of film-forming and solution modifying polymers, which are routinely used in applications such as inks, adhesives, coatings, and personal care products. Since these polyesters are designed to be used as waterborne dispersions, understanding their colloidal interactions in dispersions is critical for their application. By using a range of commercially available water-dispersible sulfopolyesters as a model system, we investigated the relationship between their molecular composition, colloidal interactions, and phase equilibria. We established how these polyesters undergo different molecular configurations and nanoaggregated states, depending on the nature of the liquid medium. For example, the polyesters are in a solvated molecular form in certain organic solvents, whereas they self-assemble into compact nanoaggregates in water. We found that the interactions of these nanoaggregates follow the classical DLVO theory of critical colloidal coagulation where the stability of these nanoparticles is extremely sensitive to multivalent electrolytes (i.e., Ccrit ? z-6). By using static, dynamic, and electrophoretic light scattering, we correlate their nanoscale intermolecular and interparticle interactions with corresponding macroscale phase behavior in both organic medium and water, based on the theoretical framework of second virial coefficients. We present a model for nanoaggregate formation in water based on the critical surface charge density of these nanoparticles. Such fundamental understanding of colloidal interactions could be used to efficiently control and improve the colloidal stability and film-formation ability of these polyesters and may enable the design of novel high-performance surfactant-free waterborne dispersion systems. PMID- 29488990 TI - Tracking fast cellular membrane dynamics with sub-nm accuracy in the normal direction. AB - Cellular membranes are important biomaterials with highly dynamic structures. Membrane dynamics plays an important role in numerous cellular processes, but precise tracking it is challenging due to the lack of tools with a highly sensitive and fast detection capability. Here we demonstrate a broad bandwidth optical imaging technique to measure cellular membrane displacements in the normal direction at sub-nm level detection limits and 20 MUs temporal resolution (1 Hz-50 kHz). This capability allows us to study the intrinsic cellular membrane dynamics over a broad temporal and spatial spectrum. We measured the nanometer scale stochastic fluctuations of the plasma membrane of HEK-293 cells, and found them to be highly dependent on the cytoskeletal structure of the cells. By analyzing the fluctuations, we further determine the mechanical properties of the cellular membranes. We anticipate that the method will contribute to the understanding of the basic cellular processes, and applications, such as mechanical phenotyping of cells at the single-cell level. PMID- 29488994 TI - Enantioselective synthesis of chiral oxazolines from unactivated ketones and isocyanoacetate esters by synergistic silver/organocatalysis. AB - A multicatalytic approach that combines a bifunctional Bronsted base-squaramide organocatalyst and Ag+ as Lewis acid has been applied in the reaction of unactivated ketones with tert-butyl isocyanoacetate to give chiral oxazolines bearing a quaternary stereocenter. The formal [3+2] cycloaddition provided high yields of the corresponding cis-oxazolines with good diastereoselectivity and excellent enantioselectivity, being applied to aryl-alkyl and alkyl-alkyl ketones. PMID- 29488993 TI - Rapid and simple purification of elastin-like polypeptides directly from whole cells and cell lysates by organic solvent extraction. AB - Elastin-like polypeptides (ELP) are a well-known class of proteins that are being increasingly utilized in a variety of biomedical applications, due to their beneficial physicochemical properties. A unifying feature of ELP is their demonstration of a sequence tunable inverse transition temperature (Tt) that enables purification using a simple, straightforward process called inverse transition cycling (ITC). Despite the utility of ITC, the process is inherently limited to ELP with an experimentally accessible Tt. Since the underlying basis for the ELP Tt is related to its high overall hydrophobicity, we anticipated that ELP would be excellent candidates for purification by organic extraction. We report the first method for rapidly purifying ELP directly from whole E. coli cells or clarified lysates using pure organic solvents and solvent mixtures, followed by aqueous back extraction. Our results show that small ELP and a large ELP-fusion protein can be isolated in high yield from whole cells or cell lysates with greater than 95% purity in less than 30 min and with very low levels of LPS and DNA contamination. PMID- 29488995 TI - Complex crystalline structures in a two-dimensional core-softened system. AB - A transition from a square to a hexagonal lattice is studied in a 2D system of particles interacting via a core-softened potential. Due to the presence of two length scales of repulsion, different local configurations with four, five, and six neighbors are possible, leading to the formation of complex crystals. The previously proposed interpolation method is generalized to calculate pair correlations in crystals whose unit cell consists of more than one particle. The high efficiency of the method is illustrated using a snub square lattice as a representative example. Molecular dynamics simulations show that the snub square lattice is broken upon heating, generating a high-density quasicrystalline phase with 12-fold symmetry (HD12 phase). A simple theoretical model is proposed to explain the physical mechanism responsible for this phenomenon: with an increase in the density (from square to hexagonal phases), the concentrations of different local configurations randomly realized through a plane tiling change, which minimizes the energy of the system. The calculated phase diagram in the intermediate density range justifies the existence of the HD12 phase and demonstrates a cascade of first-order transitions "square - HD12 - hexagonal" solid phases with increasing density. The results allow us to better understand the physical mechanisms responsible for the formation of quasicrystals, and, therefore, should be of interest for broad community in materials science and soft matter. PMID- 29488996 TI - Tailoring the mechanical properties of gelatin methacryloyl hydrogels through manipulation of the photocrosslinking conditions. AB - Photo-crosslinkable hydrogels, in particular gelatin methacryloyl (GelMa), are gaining increasing importance in biofabrication and tissue engineering. While GelMa is often described as mechanically 'tunable', clear relationships linking the photocrosslinking conditions to reaction rates, and the resulting mechanical properties, have not been described. Meanwhile the conditions employed in the literature are disparate, and difficult to compare. In this work, in situ rheological measurements were used to quantify the relative rate of reaction of GelMa hydrogels with respect to light intensity, exposure time and photo initiator concentration. In addition the UV degradation of the photo-initiator Irgacure 2959 was measured by UV-vis spectroscopy, and used to estimate the rate of free radical production as a function of light exposure. Using these data an expression was derived which predicts the mechanical properties of GelMa hydrogels produced across a wide range of crosslinking conditions. The model was validated through fabrication of a GelMa gradient which matched predicted properties. Human mesenchymal stem cells encapsulated in crosslinked GelMa exhibited high (>90%) viability post encapsulation, however metabolic activity over one week was influenced by the intensity of light used during crosslinking. The expressions described may be used to aid rational choices of GelMa photocrosslinking conditions, especially in cell encapsulation experiments where minimising the cytotoxic elements in the reaction is a priority. PMID- 29488997 TI - Through-conjugation of two phosphaalkyne ('C[triple bond, length as m-dash]P') moieties mediated by a bimetallic scaffold. AB - Through-conjugation of two phosphaalkyne moieties within an isolable molecule is demonstrated for the first time with the synthesis of [{Ru(dppe)2}2{MU-(C[triple bond, length as m-dash]C)2C6H4-p}(C[triple bond, length as m-dash]P)2], via base induced desilylation of [{Ru(dppe)2}2{MU-(C[triple bond, length as m-dash]C)2C6H4 p}(eta1-P[triple bond, length as m-dash]CSiMe3)2]2+. The nature of the cyaphide ligands and their influence upon the bimetallic core are studied electrochemically. PMID- 29488998 TI - Fluorescent and charge transport properties of columnar phases made of mono and bi-phenazine derivatives. AB - Mesogenic dibenzophenazine derivatives have been synthesized and their liquid crystalline, fluorescent and electrochemical properties have been studied. All compounds form the Colhd phase, one of them (4-hydroxyphenyl 2,3,6,7 tetrakisoctyloxy-dibenzo[a,c]phenazine-11-carboxylate, 4) additionally shows an unusual columnar structure with p2mg symmetry, which is a partially lamellarized columnar phase. The emission spectra exhibit a huge Stokes shift that is due to the different molecular conformation in ground and excited states. The non dispersive hole transport current under UV laser illumination was observed and the charge mobility in the range 10-4-10-3 cm2 V-1 s-1 was determined with the time of flight (ToF) method. The measurements have been interpreted according to the Gaussian disorder model, providing material parameters that reflect the energetic distribution of localized states (diagonal disorder, sigma) and distribution of coupling parameters between transport sites (off-diagonal disorder, Sigma). PMID- 29488999 TI - XUV photodesorption of carbon cluster ions and ionic photofragments from a mixed methane-water ice. AB - The photochemical processing of a CH4 : D2O 1 : 3.3 ice mixture adsorbed on an HOPG surface in the XUV regime was investigated using pulses obtained from the Free-electron LASer in Hamburg (FLASH) facility. Ice films were exposed to femtosecond pulses with a photon energy of hnu = 40.8 eV, consistent with the HeII resonance line. Cationic species desorbing directly from the ice films were detected using time-of-flight (ToF) mass spectrometry. Simple ions formed through the fragmentation of the parent molecules and subsequent recombination reactions were detected and are consistent with efficient D+ and H+ ejection from the parent species, similar to the case for low energy electron irradiation. The FEL fluence dependencies of these ions are linear or exhibit a non-linear order of up to 3. In addition, a series of Cn+ cluster ions (with n up to 12) were also identified. These ions display a highly non-linear desorption yield with respect to the FEL fluence, having an order of 6-10, suggesting a complex multi-step process involving the primary products of CH4 fragmentation. Two-pulse correlation measurements were performed to gain further insight into the underlying reaction dynamics of the photo-chemical reactions. The yield of the D2O derived products displayed a different temporal behaviour with respect to the Cn+ ions, indicating the presence of very different reaction pathways to the two families of ionic products. PMID- 29489000 TI - Tuning the electronic and magnetic properties of InSe nanosheets by transition metal doping. AB - Magnetic two-dimensional materials have attracted considerable attention for their significant potential application in spintronics. Here, we systematically study the electronic structures and magnetic properties of a 3d transition metal doped InSe monolayer based on density functional theory (DFT). Our results show that InSe monolayer can be turned into a half-metal when the Ti, Cr, or Ni atom is doped. Further calculations indicate that the Cr-InSe monolayer possesses a robust ferromagnetic ground state due to the effective p-d exchange. The predicted Curie temperature of Cr-InSe is above the room temperature, showing a powerful potential in spintronics. Application in the spin valve is also explored using quantum transport simulations. Our results indicate that the magnetoresistance of a Cr-InSe spin valve attains 100% due to the half-metallic characteristics. These findings may pave the way for designing 2D nano-devices for future spin transport applications. PMID- 29489001 TI - Susceptibility of sodA- and sodB-deficient Escherichia coli mutant towards antimicrobial photodynamic inactivation via the type I-mechanism of action. AB - Photodynamic antimicrobial chemotherapy (PACT) is a multi-target method to inactivate pathogenic microorganisms by exciting a photosensitizer (PS) with visible light of appropriate wavelength in the presence of molecular oxygen (3O2). There are two major pathways by which reactive oxygen species (ROS) are produced. In type I (TI)-reactions, radicals such as superoxide (O2-) and hydroxyl radicals (OH) are generated by electron transfer. In type II (TII) reactions, highly reactive singlet oxygen (1O2) is produced by direct energy transfer. This study investigated the efficiency of PACT in Gram-negative Escherichia coli wild type (EC WT) and the mutant Escherichia coli PN134 (EC PN134) which is not able to produce SOD A and SOD B, by means of two different photosensitizers (PS) from different chemical classes with different 1O2 quantum yields: methylene blue (MB) and 5,10,15,20-tetrakis(1-methyl-4 pyridinio)porphyrin tetra(p-toluenesulfonate) (TMPyP). Mutants, which lack antioxidant enzymes, were particularly susceptible towards TI-PACT. In the case of PACT with MB, quenching agents such as superoxide dismutase (SOD) and catalase (CAT) were sufficient for protecting both the wild type and the mutant, whereas they were not in PACT with TMPyP. The genetic levels of sodA and sodB were examined after photodynamic treatment regarding their potential resistance. This study showed that - under the photodynamic conditions presented in this study - expression of sodA and sodB was not directly influenced by PACT-generated oxidative stress, although SOD enzymes are part of the major defense machinery against oxidative stress and were thus expected to be upregulated. Overall the susceptibility of EC PN134 and EC WT differed towards photodynamic inactivation via TI-mechanism of action. Thus, already existing defense mechanisms against ROS in bacteria might influence the susceptibility against TI-PACT, while this was not the case using TII-photosensitizers. PMID- 29489006 TI - Stereoselective synthesis of alpha-methyl and alpha-alkyl ketones from esters and alkenes via cyclopropanol intermediates. AB - Alkenes bearing a stereocenter in the allylic position were found to undergo Kulinkovich hydroxycyclopropanation with good diastereoselectivity. For the isomerization of the resulting cyclopropanols to diastereomerically enriched alpha-methyl ketones, a new mild regioselective method has been developed. A sequence of stereoselective cyclopropanation and cyclopropanol ring opening was successfully employed for the construction of the C20 stereocenter in steroids. PMID- 29489007 TI - UV and pH-responsive supra-amphiphiles driven by combined interactions for controlled self-assembly behaviors. AB - In order to fabricate a novel supra-amphiphile with multiple stimulus properties, we developed the strategy of introducing a bi-functional linker to bridge the hydrophilic and hydrophobic building blocks together, by utilizing more than one kind of interaction. We characterized the assembled structure and morphology of the supra-amphiphile using transmission electron microscopy (TEM), dynamic light scattering (DLS) and X-ray diffraction (XRD). 1H NMR and UV-vis spectroscopy studies revealed that the amphiphile was constructed by the effect of host-guest recognition and a dynamic covalent bond, which could be switched ''on'' and ''off'' via UV irradiation and pH variation stimuli, respectively. This responsiveness realized finely controllable self-assembly behaviors of the supra amphiphile, which was thus able to encapsulate and release the drug model rhodamine B. PMID- 29489008 TI - A bead-spring chain as a one-dimensional polyelectrolyte gel. AB - The physical principles underlying expansion of a single-chain polyelectrolyte coil caused by Coulomb repulsions among its ionized groups, and the expansion of a cross-linked polyelectrolyte gel, are probably the same. In this paper, we analyze a "one-dimensional" version of a gel, namely, a linear chain of charged beads connected by Hooke's law springs. In the Debye-Huckel range of relatively weak Coulomb strength, where counterion condensation does not occur, the springs are realistically stretched on a nanolength scale by the repulsive interactions among the beads, if we use a spring constant normalized by the inverse square of the solvent Bjerrum length. The persistence length and radius of gyration counter intuitively decrease when Coulomb strength is increased, if analyzed in the framework of an OSF-type theory; however, a buckling theory generates the increase that is consistent with bead-spring simulations. PMID- 29489010 TI - Centre for Genomic Regulation - a hub for Integrative Biology in Barcelona. PMID- 29489009 TI - Differential cellular localization of CELSR2 and ING4 and correlations with hormone receptor status in breast cancer. AB - CELSR2 is postulated to be a receptor involved in contact-mediated communication; however, its expression and function in cancer remain unknown. ING4 is a tumor suppresor encoded by the ING4 gene which inhibits cell growth. The expression of CELSR2 and ING4 in breast tumors and in benign epithelial cells have been analyzed and correlated with HER2, ER, and PR status. Immunohistochemistry was used to analyze the expression of CELSR2 and ING4 protein in breast tumors and benign epithelial cells. The differential cellular localization of both markers was analyzed and results were also correlated with HER2, ER, and PR status. CELSR2 and ING4 cytoplasmic expression was significantly stronger in tumors than in benign epithelial cells, while the nuclear expression of both markers was significantly stronger in benign epithelial cells than in tumors. When comparing the two markers in the same type of tissues, the nuclear expression of CELSR2 was significantly stronger than cytoplasmic in benign epithelial cells, while there was no significant difference in the cellular localization of CELSR2 in tumors. For ING4, the cytoplasmic expression was significantly stronger than nuclear expression in tumors, while in benign epithelial cells, ING4 was expressed at similar levels in both compartments. There was no correlation between CELSR2 expression and HER2, ER, and PR status in tumors. However, the cytoplasmic expression of ING4 was associated with HER2 positivity in tumors. Both CELSR2 and ING4 display increased cytoplasmic staining in breast cancer cells compared to benign epithelium, suggesting a possible role of both genes in the pathogenesis of human mammary neoplasia. PMID- 29489011 TI - Live training versus e-learning to teach implementation of listener response programs. AB - Discrete-trial teaching is an effective teaching procedure that must be implemented with high integrity to produce optimal learning. Behavioral Skills Training (BST) has proven effective for staff training; however, BST is time and labor intensive. Computer-based instruction (CBI) programs may provide a more efficient and cost-effective alternative to live training if the CBI program is as effective as BST in producing accurate implementation. The current study compared CBI to BST to train novice undergraduate students to conduct discrete trial teaching. Participants were randomly assigned to one of the two conditions and assessed prior to and after the completion of training. Results indicated that although both BST and CBI were effective at training participants to implement discrete-trial teaching, BST was slightly but significantly more effective whereas CBI quickly created a return on the investment of product development. PMID- 29489012 TI - Displaced children with cancer in Lebanon: A sustained response to an unprecedented crisis. AB - BACKGROUND: The unrest in Syria has resulted in an escalating refugee crisis. The postwar lack of health care infrastructure in Iraq has also resulted in Iraqis seeking health care in neighboring countries. Pediatric cancer is largely curable, although its treatment is expensive and complex. Strategies to implement pediatric cancer care with curative intent in these vulnerable populations are lacking. METHODS: To assess the feasibility of a collaborative approach for the provision of care to displaced children with cancer, this study reviewed the experience of the authors over the past 6 years in Lebanon, the country with the highest number of refugees per capita in the world. RESULTS: The American University of Beirut Medical Center and the Children's Cancer Center of Lebanon Foundation, in partnership with St. Jude Children's Research Hospital and the American Lebanese Syrian Associated Charities, established 3 successive funding programs to treat displaced children with cancer along with a continuous assessment of resource utilization. Between 2011 and 2017, 575 non-Lebanese children suspected to have cancer were evaluated. Of those, 311 received direct medical support, with 107 receiving full-treatment coverage and 204 receiving limited-workup/specialty services; the remaining 264 patients received medical consultations. CONCLUSIONS: In addition to providing lifesaving humanitarian support, the coordination of care delivery, including the establishment of guidelines for prioritization, can help direct future efforts. Many patients continue to be in dire need of support, and this should be addressed via collaboration among governmental, nongovernmental, and health care organizations. Cancer 2018;124:1464-72. (c) 2018 American Cancer Society. PMID- 29489013 TI - Ion-modified nanoparticles induce different apatite formation in cervical dentine. AB - AIM: To investigate if crystallinity and ultrastructure are modified when cervical dentine is treated with four different nanogels-based solutions for remineralizing purposes. METHODOLOGY: Experimental nanogels based on polymeric nanoparticles (NPs) and zinc, calcium or doxycycline-loaded NPs were applied to citric acid etched dentine to facilitate the occlusion of tubules and the mineralization of the dentine surface. Dentine surfaces were studied by X-ray diffraction and transmission electron microscopy through selected area diffraction and bright-field imaging. RESULTS: Crystals at the dentine surface were identified as hydroxyapatite with the highest crystallographic maturity and crystallite size in dentine treated with Zn-NPs-based gel. Texture increased in all samples from 24 h to 7 days, except in dentine surfaces treated with Zn-NPs gel. Polyhedral, plate-like and drop-like shaped apatite crystals constituted the bulk of minerals in dentine treated with Zn-NPs gel, after 7 days. Polymorphic, cubic and needle-like shaped crystals distinguished minerals, with more amorphous characteristics in dentine treated with Ca-NPs gel after 7 days than that found when Zn-NPs were applied. Doxycycline-NPs produced the smallest crystallites with poor crystallinity, maturity and chemical stability. CONCLUSIONS: Crystalline and amorphous phases of newly formed hydroxyapatite were described in both types of dentine treated with Zn-NPs as well as Ca-NPs gels with multiple shapes of crystallites. Crystal shapes ranged from rounded/drop-like or plate-like crystals to needle-like or polyhedral and cubic apatite appearance. PMID- 29489014 TI - Health equity for displaced children with cancer in the Middle East. PMID- 29489015 TI - Predictors and Outcomes of Revisits in Older Adults Discharged from the Emergency Department. AB - OBJECTIVES: To study predictors of emergency department (ED) revisits and the association between ED revisits and 90-day functional decline or mortality. DESIGN: Multicenter cohort study. SETTING: One academic and two regional Dutch hospitals. PARTICIPANTS: Older adults discharged from the ED (N=1,093). MEASUREMENTS: At baseline, data on demographic characteristics, illness severity, and geriatric parameters (cognition, functional capacity) were collected. All participants were prospectively followed for an unplanned revisit within 30 days and for functional decline and mortality 90 days after the initial visit. RESULTS: The median age was 79 (interquartile range 74-84), and 114 participants (10.4%) had an ED revisit within 30 days of discharge. Age (hazard ratio (HR)=0.96, 95% confidence interval (CI)=0.92-0.99), male sex (HR=1.61, 95% CI=1.05-2.45), polypharmacy (HR=2.06, 95% CI=1.34-3.16), and cognitive impairment (HR=1.71, 95% CI=1.02-2.88) were independent predictors of a 30-day ED revisit. The area under the receiver operating characteristic curve to predict an ED revisit was 0.65 (95% CI=0.60-0.70). In a propensity score-matched analysis, individuals with an ED revisit were at higher risk (odds ratio=1.99 95% CI=1.06 3.71) of functional decline or mortality. CONCLUSION: Age, male sex, polypharmacy, and cognitive impairment were independent predictors of a 30-day ED revisit, but no useful clinical prediction model could be developed. However, an early ED revisit is a strong new predictor of adverse outcomes in older adults. PMID- 29489016 TI - Multistep Unified Models Using Prior Knowledge for the Prediction of Drug Clearance in Neonates and Infants. AB - Allometric approaches are widely used for interspecies scaling for the prediction of pharmacokinetic (PK) parameters during drug development. The concept of allometry can also be extended to predict PK parameters from adults to children. Three methods for extrapolating pediatric clearance were developed and evaluated using the clearance values of 4 drugs. The first method was established using a simple allometric (SA) model with estimated coefficient and exponent based on data ranging from children older than 2 years to adult. Then we developed a unified multistep single-exponent (MSE) and multistep body-weight-dependent exponent (MBDE) models. The major steps in these 2 new methods include generating pseudopredicted clearance for unobserved new populations such as preterm neonates, term neonates, and infants. Subsequent steps involve incorporating the pseudopredicted clearance with the actual PK data from older children and adults. All 3 models were then used to predict drug clearance in children <=2 years old (N = 278). Drug clearance was predicted with mean absolute error of 29.6, 14.2, and 12.9 using SA, MSE, MBDE, respectively. The root mean square error was 65.9, 29.8, 24.7 for SA, MSE, MBDE, respectively. Approximately 41%, 72%, and 74% of the children's clearance data were within 0.5 to 1.5-fold of the observed values when drug clearance was extrapolated using SA, MSE, and MBDE models, respectively. The present multistep unified extrapolation approaches improved the prediction of clearance from preterm neonates to 2 years of age and may have practical use for first-in-pediatric dose selection. PMID- 29489017 TI - Economic Evaluation of a Catheter-Associated Urinary Tract Infection Prevention Program in Nursing Homes. AB - OBJECTIVE: To assess the economic effect and cost effectiveness of a targeted catheter-associated urinary tract infection (CAUTI) prevention intervention in the nursing home (NH) setting. DESIGN: Randomized clinical trial. SETTING: Community-based NHs (N=12). PARTICIPANTS: NH residents with indwelling urinary catheters (N=418). INTERVENTION: Standard care versus infection prevention program involving barrier precautions, active surveillance, and NH staff education. MEASUREMENTS: Costs of the intervention, costs of disease, and health outcomes were used to calculate an incremental cost-effectiveness ratio for the intervention. Data came from intervention results and the literature and outcomes were analyzed over one year. RESULTS: A 120-bed NH would have program costs of $20,279/year. The cost of disease treatment would be reduced by $54,316 per year, resulting in a $34,037 net cost savings. Most of this savings would come from fewer CAUTI hospitalizations ($39,180), with $15,136 in savings from CAUTI care within the NH. The intervention also yielded a gain of 0.197 quality-adjusted life-years (QALYs). Taking into account uncertainty in all parameters suggests there is an 85% chance that the intervention is cost-saving. CONCLUSIONS: The CAUTI prevention program is expected to benefit payers by reducing costs and improving health outcomes. Because the savings accrue to payers and not to NHs, payers such as Medicare and private insurers may want to provide incentives for NHs to implement such programs. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01062841. PMID- 29489018 TI - Use of the CRISPR/Cas9-based epigenetic gene activation system In Vivo: A new potential therapeutic modality. PMID- 29489019 TI - Alcohol Use Disorder and Posttraumatic Stress Disorder: An Introduction. PMID- 29489020 TI - ATTACHMENT IN INFANTS WITH CLEFT LIP AND/OR PALATE: MARGINAL SECURITY AND ITS CHANGES OVER TIME. AB - This study examines the attachment quality and how this changed over time among infants who had cleft lip and palate (CLP), by conducting a prospective longitudinal study addressing the effects of this type of perinatal event on the parent-infant relationship and the emotional development of the infants. At 12 months of age, the Strange Situation Paradigm (SSP; M. Ainsworth, M.C. Blehar, E. Waters, & T. Wall, 1978) was administered to a sample of 38 CLP infants (born between 2003 and 2010) and 17 healthy controls. At 4 years of age, the Attachment Story Completion Task (ASCT; I. Bretherton, D. Ridgeway, & J. Cassidy, 1990) was administered to 32 individuals from the CLP sample and 14 from the control group. As reported in the literature, CLP infants display secure attachment behaviors as frequently as do control infants (55%). However, a more detailed analysis of the attachment scales revealed that CLP infants show more avoidance and less proximity seeking. In addition, a closer examination of the subcategories of attachment styles revealed that most CLP infants (71%) displayed distal attachment strategies such as the B1/B2 or A1/A2 subcategories. At 4 years old, CLP infants clearly displayed more deactivation and less security than did the control sample. Moreover, when detailing the evolution of attachment individually, almost 60% of the CLP children showing distal strategies at 12 months became deactivated or disorganized when they reached 4 years. Indeed, subtle differences in attachment behaviors at 12 months old-which can be considered marginally secure at that age-may reveal attachment vulnerabilities, which seem to be more apparent over the course of development. PMID- 29489021 TI - Valsartan Effective for Malignant Hypertension after Aortic Dissection with Renal Artery Involvement. AB - When aortic dissections extend to the renal arteries, reductions in renal blood flow can cause marked increases in renin production. The resultant rise in angiotensin II can lead to difficult-to-control blood pressure, despite normal postdissection antihypertensive agents. We highlight a case of a postdissection patient with malignant hypertension refractory to eight different enteral antihypertensives. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers had been held due to postoperative acute kidney injury. A single dose of valsartan, administered on day 12, produced a marked drop in blood pressure, alleviation of encephalopathy, and allowed for cancellation of a planned tracheostomy. A serum renin level was found to be 50 times the normal upper limit. In patients with aortic dissection and renal artery involvement, angiotensin-modifying agents may warrant earlier administration to combat this unique cause of hypertension. PMID- 29489022 TI - IGNORING CHILDREN'S BEDTIME CRYING: THE POWER OF WESTERN-ORIENTED BELIEFS. AB - Ignoring children's bedtime crying (ICBC) is an issue that polarizes parents as well as pediatricians. While most studies have focused on the effectiveness of sleep interventions, no study has yet questioned which parents use ICBC. Parents often find children's sleep difficulties to be very challenging, but factors such as the influence of Western approaches to infant care, stress, and sensitivity have not been analyzed in terms of ICBC. A sample of 586 parents completed a questionnaire to investigate the relationships between parental factors and the method of ICBC. Data were analyzed using structural equation modeling. Latent variables were used to measure parental stress (Parental Stress Scale; J.O. Berry & W.H. Jones, 1995), sensitivity (Situation-Reaction-Questionnaire; Y. Hanggi, K. Schweinberger, N. Gugger, & M. Perrez, 2010), Western-oriented parental beliefs (Rigidity), and children's temperament (Parenting Stress Index; H. Troster & R.R. Abidin). ICBC was used by 32.6% (n = 191) of parents in this study. Parents' Western-oriented beliefs predicted ICBC. Attitudes such as feeding a child on a time schedule and not carrying it out to prevent dependence were associated with letting the child cry to fall asleep. Low-sensitivity parents as well as parents of children with a difficult temperament used ICBC more frequently. Path analysis shows that parental stress did not predict ICBC. The results suggest that ICBC has become part of Western childrearing tradition. PMID- 29489023 TI - KRAS mutation is predictive of outcome in patients with pulmonary sarcomatoid carcinoma. AB - AIMS: Pulmonary sarcomatoid carcinoma (PSC) is a poorly differentiated non-small cell lung carcinoma (NSCLC) with aggressive behaviour. This study aimed to evaluate the prognostic clinicopathological and genetic characteristics of PSCs. METHODS AND RESULTS: Fifty-three cases of surgically treated PSCs were selected, 23 of which were subjected to mutation and copy number variation analysis using the 50-gene Ion AmpliSeq Cancer Panel. The majority of the patients were male (32 of 53, 60.3%) and smokers (51 of 53, 96.2%). Overall, 25 (47.1%) patients died within 2-105 months (mean = 22.7 months, median = 15 months) after diagnosis, and 28 were alive 3-141 months (mean = 38.7 months, median = 21.5 months) after diagnosis. Five-year overall survival was 12.5%. KRAS codon 12/13 mutation in adenocarcinomas (P = 0.01), age more than 70 years (P = 0.008) and tumour size >=4.0 cm (P = 0.02) were associated strongly with worse outcome. TP53 (17 of 23, 74.0%) and KRAS codon 12 of 13 mutations (10 of 23, 43.4%) were the most common genetic alterations. Potentially actionable variants were identified including ATM (four of 23, 17.3%), MET, FBXW7 and EGFR (two of 23, 8.7%), AKT1, KIT, PDGFRA, HRAS, JAK3 and SMAD4 (one of 23, 4.3%). MET exon 14 skipping and missense mutations were identified in two (11.1%) cases with adenocarcinoma histology. Copy number analysis showed loss of RB1 (three of 23, 13%) and ATM (two of 23, 8.7%). Copy number gains were seen in EGFR (two of 23, 13.0%) and in one (4.3%) of each PIK3CA, KRAS, MET and STK11. CONCLUSIONS: Potentially targetable mutations can be identified in a subset of PSC, although most tumours harbour currently untargetable prognostically adverse TP53 and KRAS mutations. PMID- 29489024 TI - Participatory action as a research method with public health nurses. AB - AIM: This article explores and describes participatory action research (PAR) as a preferred method in addressing nursing practice issues. This is the first study that used PAR with public health nurses (PHNs) in Canada to develop a professional practice model. BACKGROUND: Participatory action research is a sub category of action research that incorporates feminist and critical theory with foundations in the field of social psychology. For nurses, critical analysis of long-established beliefs and practices through PAR contributes to emancipatory knowledge regarding the impact of traditional hierarchies on their practice. DESIGN: This study used participatory action, a non-traditional but systematic research method, which assisted participants to develop a solution to a long standing organizational issue. METHOD: The stages of generating concerns, participatory action, acting on concerns, reflection and evaluation were implemented from 2012 - 2013 in an urban Canadian city, to develop a professional practice model for PHNs. FINDINGS: Four sub-themes specific to PAR are discussed. These are "participatory action research engaged PHNs in development of a professional practice model;" "the participatory action research cycles of "Look, Think, Act" expanded participants' views;" "participatory action research increased awareness of organizational barriers;" and "participatory action research promoted individual empowerment and system transformation." CONCLUSIONS: This study resulted in individual and system change that may not have been possible without the use of PAR. The focus was engagement of participants and recognition of their lived experience, which facilitated PHNs' empowerment, leadership and consciousness-raising. PMID- 29489025 TI - Expression of PD-L1, indoleamine 2,3-dioxygenase and the immune microenvironment in gastric adenocarcinoma. AB - AIMS: The tumour microenvironment is increasingly important in several tumours. We studied the relationship of key players of immune microenvironment with clinicopathological parameters in gastric adenocarcinomas. METHODS AND RESULTS: Tissue microarrays were constructed from gastrectomy specimens, 2004-13. Immunohistochemistry was performed for programmed cell death ligand 1 (PD-L1), indoleamine 2,3-dioxygenase (IDO), tryptophanyl-tRNA synthetase (WARS), guanylate binding protein 5 (GBP5), tumour-infiltrating lymphocytes (TIL) expressing CD3/CD8/FoxP3/PD1 and mismatch repair proteins (MMRs) MLH1, PMS2, MSH2 and MSH6. Clinicopathological parameters and clinical follow-up were recorded. The study included 86 patients; median follow-up was 34 months (0-148). Tumour types were 45% tubular, 38% diffuse, 17% mixed. PD-L1 was positive in 70%, epithelial IDO in 58%, stromal IDO in 91%, epithelial WARS in 67%, stromal WARS in 100%, epithelial GBP5 in 53% and stromal GBP5 in 71%. MMR-deficiency was found in 22%. There was no difference in biomarker expression by histological subtype, with the exception of fewer diffuse-type being MMR-deficient. Low stromal IDO was associated with decreased progression-free, overall and disease-specific survival. PD-L1-positive tumours were larger with MMR-deficiency and with increasing TILs, and had significantly higher FoxP3TILs. CONCLUSIONS: PD-L1 is expressed in a large proportion of gastric carcinomas, suggesting that therapy targeting this pathway could be relevant to many patients. PD-L1 expression and MMR-deficiency are associated with increased TILs and larger tumour size, emphasising their role in tumour biology. Higher stromal IDO expression is associated with better prognosis. Finally, we observed that immune modulators WARS and GBP5 are expressed highly in gastric adenocarcinomas, suggesting an important role in tumour pathobiology. PMID- 29489026 TI - Application of seminal plasma to female genital tract prior to embryo transfer in assisted reproductive technology cycles (IVF, ICSI and frozen embryo transfer). AB - BACKGROUND: The female genital tract is not exposed to seminal plasma during standard assisted reproductive technology (ART) cycles. However, it is thought that the inflammatory reaction triggered by seminal plasma may be beneficial by inducing maternal tolerance to paternal antigens expressed by the products of conception, and may increase the chance of successful implantation and live birth. OBJECTIVES: To assess the effectiveness and safety of application of seminal plasma to the female genital tract prior to embryo transfer in ART cycles. SEARCH METHODS: We searched the following databases from inception to October 2017: Cochrane Gynaecology and Fertility Group Specialised Register of Controlled Trials, Cochrane Central Register of Studies Online (CRSO), MEDLINE, Embase, CINAHL and PsycINFO. We also searched trial registers for ongoing trials, including International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. Other sources searched were; Web of Knowledge, OpenGrey, LILACS, PubMed, Google Scholar and the reference lists of relevant articles. SELECTION CRITERIA: We included randomised controlled trials (RCTs) conducted among women undergoing ART, comparing any procedure that would expose the female genital tract to seminal plasma during the period starting five days before embryo transfer and ending two days after it versus no seminal plasma application. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed risk of bias, and extracted data. We pooled data to calculate relative risks (RRs) and 95% confidence intervals (CIs). We assessed statistical heterogeneity using the I2 statistic. We assessed the overall quality of the evidence for the main outcomes using GRADE methods. Our primary outcomes were live birth rate and miscarriage rate. Secondary outcomes were live birth/ongoing pregnancy rate, clinical pregnancy rate, multiple pregnancy rate, ectopic pregnancy rate and the incidence of other adverse events. MAIN RESULTS: We included 11 RCTs (3215 women). The quality of the evidence ranged from very low to low. The main limitations were risk of bias (associated with poor reporting of allocation concealment and other methods) and imprecision for the primary outcome of live birth rate.Live birth rates: There was insufficient evidence to determine whether there was a difference between the groups with respect to live birth rates (RR 1.10, 95% CI 0.86 to 1.43; participants = 948; studies = 3; I2 = 0%). Low quality evidence suggests that if the live birth rate following standard ART is 19% it will be between 16% and 27% with seminal plasma application.Miscarriage rate: There was insufficient evidence to determine whether there was a difference between the groups (RR 1.01, 95% CI 0.57 to 1.79; participants = 1209; studies = 4; I2 = 0%). Low quality evidence suggests that if the miscarriage rate following standard ART is 3.7%, the miscarriage rate following seminal plasma application will be between 2.1% and 6.6%.Live birth or ongoing pregnancy rates: Seminal plasma application makes little or no difference in live birth or ongoing pregnancy rates (RR 1.19, 95% CI 0.95 to 1.49; participants = 1178; studies = 4; I2 = 4%, low quality evidence). The evidence suggests that if the live birth or ongoing pregnancy rate following standard ART is 19.5% it will be between 18.5% and 29% with seminal plasma application.Clinical pregnancy rates: Seminal plasma application may increase clinical pregnancy rates (RR 1.15, 95% CI 1.01 to 1.31; participants = 2768; studies = 10; I2 = 0%). Very low quality evidence suggests that if the clinical pregnancy rate following standard ART is 22.0% it will be between 22.2% and 28.8% with seminal plasma application. This finding should be regarded with caution, as a post-hoc sensitivity analysis restricted to studies at overall low risk of bias did not find a significant difference between the groups (RR 1.06, 95% CI 0.81 to 1.39; participants = 547; studies = 3; I2 = 0%).Multiple pregnancy rate: Seminal plasma application may make little or no difference to multiple pregnancy rates (RR 1.11, 95% CI 0.76 to 1.64; participants = 1642; studies = 5; I2 = 9%). Low quality evidence suggests that if the multiple pregnancy rate following standard ART is 7%, the multiple pregnancy rate following seminal plasma application will be between 5% and 11.4%.Ectopic pregnancy: There was insufficient evidence to determine whether seminal plasma application influences the risk of ectopic pregnancy (RR 1.59, 95% CI 0.20 to 12.78, participants =1521; studies = 5; I2 = 0%) .Infectious complications or other adverse events: No data were available on these outcomes AUTHORS' CONCLUSIONS: In women undergoing ART, there was insufficient evidence to determine whether there was a difference between the seminal plasma and the standard ART group in rates of live birth (low-quality evidence) or miscarriage (low quality evidence). There was low quality evidence suggesting little or no difference between the groups in rates of live birth or ongoing pregnancy (composite outcome). We found low quality evidence that seminal plasma application may be associated with more clinical pregnancies than standard ART. There was low quality evidence suggesting little or no difference between the groups in rates of multiple pregnancy. There was insufficient evidence to reach any conclusions about the risk of ectopic pregnancy, and no data were available on infectious complications or other adverse events.We conclude that seminal plasma application is worth further investigation, focusing on live birth and miscarriage rates. PMID- 29489027 TI - Extraskeletal osteosarcoma: MDM2 and H3K27me3 analysis of 19 cases suggest disease heterogeneity. AB - AIMS: Extraskeletal osteosarcoma (ESOS) is a sarcoma in the non-skeletal tissue that directly produces neoplastic osteoid or bone. De-differentiated liposarcoma (DDLPS) and malignant peripheral nerve sheath tumour (MPNST) are the two most common types of sarcoma that can harbour heterologous osteosarcomatous differentiation. We aimed to determine the potential relationship of ESOS to DDLPS and MPNST. METHODS AND RESULTS: We investigated MDM2 and H3K27me3 status in 19 cases of ESOS, two of which contained a low-grade component. The ESOS affected deep soft tissues (n = 10), superficial soft tissues (n = 3) and organs (n = 6). Among 10 deep soft-tissue ESOS, six showed MDM2 amplification, four of which also harboured CDK4 co-amplification. Both ESOS with a low-grade component showed co amplification for MDM2 and CDK4. Among the six organ-based ESOS three giant cell rich ESOS showed an H3K27me3 deficiency (one in primary and two in metastatic sites). Using targeted next generation sequencing, an H3K27me3-deficient ESOS showed EED homozygous deletion, while none of the three showed alterations in NF1, CDKN2A or SUZ12 genes. During median follow-up of 20 months, all six patients with MDM2-amplified ESOS lived for 3-103 months, while two of the three patients with H3K27me3-deficient ESOS died from this disease in 4 and 20 months, respectively. CONCLUSION: We demonstrate that ESOS may include at least two small subsets: an MDM2-amplified deep soft-tissue ESOS (which may be related to DDLPS) and an H3K27me3-deficient organ-based ESOS (which is probably unrelated to MPNST). Larger studies are required to validate the present observations and investigate the clinical implications of such subcategorisation. PMID- 29489028 TI - Surviving ICU: Stories of recovery. AB - AIM: The aim of this study was to investigate stories of recovery through the lens of intensive care unit (ICU) survivors. BACKGROUND: Survival from ICUs is increasing, as are associated physical and psychological complications. Despite the significant impact on survivors, there is inadequate support provision in Australia and world-wide for this population. DESIGN: An interpretive biographical approach of intensive care survivors' experiences of recovery. METHODS: Data were collected during 2014-2015 from diaries, face to face interviews, memos and field notes. Six participants diarized for 3 months commencing 2 months after hospital discharge. At 5 months, participants were interviewed about the content of their diaries and symbols and signifiers in them to create a shared meaning. Analysis of diaries and interviews were undertaken using two frameworks to identify themes throughout participants' stories and provides a unique portrait of recovery through their individual lens. FINDINGS: Participants considered their lives had irreparably changed and yet felt unsupported by a healthcare system that had "saved" them. This view through their lens identified turmoil, which existed between their surface and inner worlds as they struggled to conform to what recovery "should be". CONCLUSION: The novel biographical methods provided a safe and creative way to reveal survivors' inner thoughts and feelings. Participants' considered creating their stories supported their recovery process and in particular enabled them to reflect on their progress. Findings from this study may lead to increased awareness among health care providers about problems survivors face and improved support services more broadly, based on frameworks appropriate for this population. PMID- 29489030 TI - From equity to power: Critical Success Factors for Twinning between midwives, a Delphi study. AB - AIMS: To gain consensus for Critical Success Factors associated with Twinning in Midwifery. BACKGROUND: International publications identify midwifery as important for improving maternity care worldwide. Midwifery is a team effort where midwives play a key role. Yet their power to take on this role is often lacking. Twinning has garnered potential to develop power in professionals, however, its success varies because implementation is not always optimal. Critical Success Factors have demonstrated positive results in the managerial context and can be helpful to build effective Twinning relationships. DESIGN: We approached 56 midwife Twinning experts from 19 countries to participate in three Delphi rounds between 2016 - 2017. METHODS: In round 1, experts gave input through an open ended questionnaire and this was analysed to formulate Critical Success Factors statements that were scored on a 1-7 Likert scale aiming to gain consensus in rounds 2 and 3. These statements were operationalized for practical use such as a check list in planning, monitoring and evaluation in the field. FINDINGS: Thirty three experts from 14 countries took part in all three Delphi rounds, producing 58 initial statements. This resulted in 25 Critical Success Factors covering issues of management, communication, commitment and values, most focus on equity. CONCLUSION: The Critical Success Factors formulated represent the necessary ingredients for successful Twinning by providing a practical implementation framework and promote further research into the effect of Twinning. Findings show that making equity explicit in Twinning may contribute towards the power of midwives to take on their identified key role. PMID- 29489031 TI - Blood tolerogenic monocytes and low proportions of dendritic cell subpopulations are hallmarks of human tuberculosis. AB - BACKGROUND: The immune mechanisms underlying the pathogenesis of tuberculosis (TB) need better understanding to improve TB management, as the disease still causes more than 1.5 million deaths annually. This study tested the hypothesis that a modulation of the proportions or activation status of APC during Mycobacterium tuberculosis infection may impact on the course of the disease. PROCEDURE: Proportions of circulating APC subsets and the expression of stimulatory (CD86), inhibitory (ILT-3, ILT-4, ILT-7), or apoptosis-inducing (PDL 1, PDL-2) molecules were analyzed in 2 independent cohorts, on blood monocytes and dendritic cell (DC) subsets from patients with active or latent TB infection (aTB /LTBI) and from uninfected subjects. RESULTS: Higher proportions of classical CD14+ CD16- and intermediate CD14+ CD16+ monocytes, and lower proportions of plasmacytoid DC (pDC) and type 2 myeloid DC were observed in the blood from untreated patients with aTB compared with those with LTBI and with healthy subjects, with an early normalization of the proportions of pDC during treatment. In addition, monocytes from M. tuberculosis-infected subjects expressed higher levels of ILT-3, ILT-4, and PDL-1 compared with healthy controls, these differences being more important for patients with aTB than for those with LTBI. CONCLUSIONS: These results confirm the hypothesis of a modulation of the proportions and activation status of APC during M. tuberculosis infection and suggest that these cells could play a role in driving the course of M. tuberculosis infection. PMID- 29489029 TI - Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia. AB - BACKGROUND: Fibromyalgia is a clinically defined chronic condition of unknown etiology characterized by chronic widespread pain that often co-exists with sleep disturbances, cognitive dysfunction and fatigue. People with fibromyalgia often report high disability levels and poor quality of life. Drug therapy, for example, with serotonin and noradrenaline reuptake inhibitors (SNRIs), focuses on reducing key symptoms and improving quality of life. This review updates and extends the 2013 version of this systematic review. OBJECTIVES: To assess the efficacy, tolerability and safety of serotonin and noradrenaline reuptake inhibitors (SNRIs) compared with placebo or other active drug(s) in the treatment of fibromyalgia in adults. SEARCH METHODS: For this update we searched CENTRAL, MEDLINE, Embase, the US National Institutes of Health and the World Health Organization (WHO) International Clinical Trials Registry Platform for published and ongoing trials and examined the reference lists of reviewed articles, to 8 August 2017. SELECTION CRITERIA: We selected randomized, controlled trials of any formulation of SNRIs against placebo or any other active treatment of fibromyalgia in adults. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data, examined study quality, and assessed risk of bias. For efficacy, we calculated the number needed to treat for an additional beneficial outcome (NNTB) for pain relief of 50% or greater and of 30% or greater, patient's global impression to be much or very much improved, dropout rates due to lack of efficacy, and the standardized mean differences (SMD) for fatigue, sleep problems, health-related quality of life, mean pain intensity, depression, anxiety, disability, sexual function, cognitive disturbances and tenderness. For tolerability we calculated number needed to treat for an additional harmful outcome (NNTH) for withdrawals due to adverse events and for nausea, insomnia and somnolence as specific adverse events. For safety we calculated NNTH for serious adverse events. We undertook meta-analysis using a random-effects model. We assessed the evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS: We added eight new studies with 1979 participants for a total of 18 included studies with 7903 participants. Seven studies investigated duloxetine and nine studies investigated milnacipran against placebo. One study compared desvenlafaxine with placebo and pregabalin. One study compared duloxetine with L-carnitine. The majority of studies were at unclear or high risk of bias in three to five domains.The quality of evidence of all comparisons of desvenlafaxine, duloxetine and milnacipran versus placebo in studies with a parallel design was low due to concerns about publication bias and indirectness, and very low for serious adverse events due to concerns about publication bias, imprecision and indirectness. The quality of evidence of all comparisons of duloxetine and desvenlafaxine with other active drugs was very low due to concerns about publication bias, imprecision and indirectness.Duloxetine and milnacipran had no clinically relevant benefit over placebo for pain relief of 50% or greater: 1274 of 4104 (31%) on duloxetine and milnacipran reported pain relief of 50% or greater compared to 591 of 2814 (21%) participants on placebo (risk difference (RD) 0.09, 95% confidence interval (CI) 0.07 to 0.11; NNTB 11, 95% CI 9 to 14). Duloxetine and milnacipran had a clinically relevant benefit over placebo in patient's global impression to be much or very much improved: 888 of 1710 (52%) on duloxetine and milnacipran (RD 0.19, 95% CI 0.12 to 0.26; NNTB 5, 95% CI 4 to 8) reported to be much or very much improved compared to 354 of 1208 (29%) of participants on placebo. Duloxetine and milnacipran had a clinically relevant benefit compared to placebo for pain relief of 30% or greater. RD was 0.10; 95% CI 0.08 to 0.12; NNTB 10, 95% CI 8 to 12. Duloxetine and milnacipran had no clinically relevant benefit for fatigue (SMD -0.13, 95% CI -0.18 to -0.08; NNTB 18, 95% CI 12 to 29), compared to placebo. There were no differences between either duloxetine or milnacipran and placebo in reducing sleep problems (SMD -0.07; 95 % CI -0.15 to 0.01). Duloxetine and milnacipran had no clinically relevant benefit compared to placebo in improving health-related quality of life (SMD -0.20, 95% CI -0.25 to -0.15; NNTB 11, 95% CI 8 to 14).There were 794 of 4166 (19%) participants on SNRIs who dropped out due to adverse events compared to 292 of 2863 (10%) of participants on placebo (RD 0.07, 95% CI 0.04 to 0.10; NNTH 14, 95% CI 10 to 25). There was no difference in serious adverse events between either duloxetine, milnacipran or desvenlafaxine and placebo (RD -0.00, 95% CI -0.01 to 0.00).There was no difference between desvenlafaxine and placebo in efficacy, tolerability and safety in one small trial.There was no difference between duloxetine and desvenlafaxine in efficacy, tolerability and safety in two trials with active comparators (L-carnitine, pregabalin). AUTHORS' CONCLUSIONS: The update did not change the major findings of the previous review. Based on low- to very low-quality evidence, the SNRIs duloxetine and milnacipran provided no clinically relevant benefit over placebo in the frequency of pain relief of 50% or greater, but for patient's global impression to be much or very much improved and in the frequency of pain relief of 30% or greater there was a clinically relevant benefit. The SNRIs duloxetine and milnacipran provided no clinically relevant benefit over placebo in improving health-related quality of life and in reducing fatigue. Duloxetine and milnacipran did not significantly differ from placebo in reducing sleep problems. The dropout rates due to adverse events were higher for duloxetine and milnacipran than for placebo. On average, the potential benefits of duloxetine and milnacipran in fibromyalgia were outweighed by their potential harms. However, a minority of people with fibromyalgia might experience substantial symptom relief without clinically relevant adverse events with duloxetine or milnacipran.We did not find placebo-controlled studies with other SNRIs than desvenlafaxine, duloxetine and milnacipran. PMID- 29489032 TI - Ghrelin for the management of cachexia associated with cancer. AB - BACKGROUND: Cancer sufferers are amongst the most malnourished of all the patient groups. Studies have shown that ghrelin, a gut hormone can be a potential therapeutic agent for cachexia (wasting syndrome) associated with cancer. A variety of mechanisms of action of ghrelin in people with cancer cachexia have been proposed. However, safety and efficacy of ghrelin for cancer-associated cachexia have not been systematically reviewed. The aim of this review was to assess whether ghrelin is associated with better food intake, body composition and survival than other options for adults with cancer cachexia. OBJECTIVES: To assess the efficacy and safety of ghrelin in improving food intake, body composition and survival in people with cachexia associated with cancer. SEARCH METHODS: We searched CENTRAL, MEDLINE and Embase without language restrictions up to July 2017. We also searched for ongoing studies in trials registers, performed handsearching, checked bibliographic references of relevant articles and contacted authors and experts in the field to seek potentially relevant research. We applied no restrictions on language, date, or publication status. SELECTION CRITERIA: We included randomised controlled (parallel-group or cross-over) trials comparing ghrelin (any formulation or route of administration) with placebo or an active comparator in adults (aged 18 years and over) who met any of the international criteria for cancer cachexia. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility. Two review authors then extracted data and assessed the risk of bias for individual studies using standard Cochrane methodology. For dichotomous variables, we planned to calculate risk ratio with 95% confidence intervals (CI) and for continuous data, we planned to calculate mean differences (MD) with 95% CI. We assessed the evidence using GRADE and created 'Summary of findings' tables. MAIN RESULTS: We screened 926 individual references and identified three studies that satisfied the inclusion criteria. Fifty-nine participants (37 men and 22 women) aged between 54 and 78 years were randomised initially, 47 participants completed the treatment. One study had a parallel design and two had a cross-over design. The studies included people with a variety of cancers and also differed in the dosage, route of administration, frequency and duration of treatment.One trial, which compared ghrelin with placebo, found that ghrelin improved food intake (very low-quality evidence) and had no adverse events (very low-quality evidence). Due to unavailability of data we were unable to report on comparisons for ghrelin versus no treatment or alternative experimental treatment modalities, or ghrelin in combination with other treatments or ghrelin analogues/ghrelin mimetics/ghrelin potentiators. Two studies compared a higher dose of ghrelin with a lower dose of ghrelin, however due to differences in study designs and great diversity in the treatment provided we did not pool the results. In both trials, food intake did not differ between participants on higher-dose and lower-dose ghrelin. None of the included studies assessed data on body weight. One study reported higher adverse events with a higher dose as compared to a lower dose of ghrelin.All studies were at high risk of attrition bias and bias for size of the study. Risk of bias in other domains was unclear or low.We rated the overall quality of the evidence for primary outcomes (food intake, body weight, adverse events) as very low. We downgraded the quality of the evidence due to lack of data, high or unclear risk of bias of the studies and small study size. AUTHORS' CONCLUSIONS: There is insufficient evidence to be able to support or refute the use of ghrelin in people with cancer cachexia. Adequately powered randomised controlled trials focusing on evaluation of safety and efficacy of ghrelin in people with cancer cachexia is warranted. PMID- 29489033 TI - Cortical Matrix Mineral Density Measured Noninvasively in Pre- and Postmenopausal Women and a Woman With Vitamin D-Dependent Rickets. AB - Reduced bone mineral density (BMD) may be due to reduced mineralized bone matrix volume, incomplete secondary mineralization, or reduced primary mineralization. Because bone biopsy is invasive, we hypothesized that noninvasive image acquisition at high resolution can accurately quantify matrix mineral density (MMD). Quantification of MMD was confined to voxels attenuation photons above 80% of that produced by fully mineralized bone matrix because attenuation at this level is due to variation in mineralization, not porosity. To assess accuracy, 9 cadaveric distal radii were imaged at a voxel size of 82 microns using high resolution peripheral quantitative computed tomography (HR-pQCT; XtremeCT, Scanco Medical AG, Bruttisellen, Switzerland) and compared with VivaCT 40 (uCT) at 19 micron voxel size. Associations between MMD and porosity were studied in 94 healthy vitamin D-replete premenopausal women, 77 postmenopausal women, and in a 27-year-old woman with vitamin D-dependent rickets (VDDR). Microstructure and MMD were quantified using StrAx (StraxCorp, Melbourne, Australia). MMD measured by HR pQCT and uCT correlated (R = 0.87; p < 0.0001). The precision error for MMD was 2.43%. Cortical porosity and MMD were associated with age (r2 = 0.5 and -0.4, respectively) and correlated inversely in pre- and postmenopausal women (both r2 = 0.9, all p < 0.001). Porosity was higher, and MMD was lower, in post- than in premenopausal women (porosity 40.3% +/- 7.0 versus 34.7% +/- 3.5, respectively; MMD 65.4% +/- 1.8 versus 66.6% +/- 1.4, respectively, both p < 0.001). In the woman with VDDR, MMD was 5.6 SD lower and porosity was 5.6 SD higher than the respective trait means in premenopausal women. BMD was reduced (Z-scores femoral neck -4.3 SD, lumbar spine -3.8 SD). Low-radiation HR-pQCT may facilitate noninvasive quantification of bone's MMD and microstructure in health, disease, and during treatment. (c) 2018 American Society for Bone and Mineral Research. PMID- 29489034 TI - Uric acid as an independent predictor of coronary artery disease in essential hypertension: Data from an 8-year-follow-up study. AB - The role of serum uric acid (SUA) in cardiovascular risk prediction remains to be further determined. We assessed the predictive value of SUA for the incidence of coronary artery disease (CAD) in 2287 essential hypertensive patients who were followed up for a mean period of 8 years. The distribution of SUA levels at baseline was split by the median (5.2 mg/dL) and subjects were classified into those with high and low values. Hypertensives who developed CAD (n = 57) compared to those without CAD at follow-up (n = 2230) had at baseline higher SUA. In multivariate Cox regression model, among established confounders, high SUA (hazard ratio = 1.216, P = .016) turned out to be independent predictor of CAD. In essential hypertensive patients SUA independently predicts CAD. PMID- 29489035 TI - Pesticides as risk factors for head and neck cancer: A review. AB - Humans may be exposed to pesticides such as fungicides, herbicides, and insecticides, during occupational and non-occupational activities. Pesticides could be related to cancer development mainly because of their effects on the endocrine and immune systems and their cumulative effect. The present review evaluated in current literature evidence of an association between exposure to pesticides and the occurrence of head and neck cancer (HNC). A literature search for cohort studies was conducted in the PubMed, Web of science, and Cochrane databases. Methodological quality of each study was rated with the Scottish Intercollegiate Guidelines Network (SIGN) checklist. One thousand one hundred and thirty-two studies were identified. Thirty-two were included. Most of the studies found addressed occupational exposure to pesticides and were conducted in Europe and North America. Eleven high-quality studies were found. Most of them found no association between exposure to pesticides and increased risk of HNC. Two studies found some evidence of a positive association between pesticide (malathion and atrazine) exposure and thyroid cancer. The literature review does not support a clear evidence for association between pesticides exposure and HNC. Only limited evidence points to a positive association between exposure to some pesticides and thyroid cancer. Further standardized studies based on appropriate designs are required to clarify the effect of pesticides on the genesis of HNC, considering dose, length of exposure, and type of pesticide. PMID- 29489036 TI - Hereditary palmoplantar keratodermas. Part I. Non-syndromic palmoplantar keratodermas: classification, clinical and genetic features. AB - The term palmoplantar keratoderma (PPK) indicates any form of persistent thickening of the epidermis of palms and soles and includes genetic as well as acquired conditions. We review the nosology of hereditary PPKs that comprise an increasing number of entities with different prognoses, and a multitude of associated cutaneous and extracutaneous features. On the basis of the phenotypic consequences of the underlying genetic defect, hereditary PPKs may be divided into the following: (i) non-syndromic, isolated PPKs, which are characterized by a unique or predominant palmoplantar involvement; (ii) non-syndromic PPKs with additional distinctive cutaneous and adnexal manifestations, here named complex PPKs; (iii) syndromic PPKs, in which PPK is associated with specific extracutaneous manifestations. To date, the diagnosis of the different hereditary PPKs is based mainly on clinical history and features combined with histopathological findings. In recent years, the exponentially increasing use of next-generation sequencing technologies has led to the identification of several novel disease genes, and thus substantially contributed to elucidate the molecular basis of such a heterogeneous group of disorders. Here, we focus on hereditary non-syndromic isolated and complex PPKs. Syndromic PPKs are reviewed in the second part of this 2-part article, where other well-defined genetic diseases, which may present PPK among their phenotypic manifestations, are also listed and diagnostic and therapeutic approaches for PPKs are summarized. PMID- 29489037 TI - In rape trauma PTSD, patient characteristics indicate which trauma-focused treatment they are most likely to complete. AB - BACKGROUND: Dropout rates for effective therapies for posttraumatic stress disorder (PTSD) can be high, especially in practice settings. Although clinicians have intuitions regarding what treatment patients may complete, there are few systematic data to drive those judgments. METHODS: A multivariable model of dropout risk was constructed with randomized clinical trial data (n = 160) comparing prolonged exposure (PE) and cognitive processing therapy (CPT) for rape induced PTSD. A two-step bootstrapped variable selection algorithm was applied to identify moderators of dropout as a function of treatment condition. Employing identified moderators in a model, fivefold cross-validation yielded estimates of dropout probability for each patient in each condition. Dropout rates between patients who did and did not receive their model-indicated treatment were compared. RESULTS: Despite equivalent dropout rates across treatments, patients assigned to their model-indicated treatment were significantly less likely to drop out relative to patients who did not (relative risk = 0.49 [95% CI: 0.29 0.82]). Moderators included in the model were: childhood physical abuse, current relationship conflict, anger, and being a racial minority, all of which were associated with higher likelihood of dropout in PE than CPT. CONCLUSIONS: Individual differences among patients affect the likelihood they will complete a particular treatment, and clinicians can consider these moderators in treatment planning. In the future, treatment selection models could be used to increase the percentage of patients who will receive a full course of treatment, but replication and extension of such models, and consideration of how best to integrate them into routine practice, are needed. PMID- 29489038 TI - Impact and change of attitudes toward Internet interventions within a randomized controlled trial on individuals with depression symptoms. AB - BACKGROUND: Most individuals with depression do not receive adequate treatment. Internet interventions may help to bridge this gap. Research on attitudes toward Internet interventions might facilitate the dissemination of such interventions by identifying factors that help or hinder uptake and implementation, and by clarifying who is likely to benefit. This study examined whether attitudes toward Internet interventions moderate the effects of a depression-focused Internet intervention, and how attitudes change over the course of treatment among those who do or do not benefit. METHODS: We recruited 1,004 adults with mild-to moderate depression symptoms and investigated how attitudes toward Internet interventions are associated with the efficacy of the program deprexis, and how attitudes in the intervention group change from pre to post over a 3 months intervention period, compared to a control group (care as usual). This study consists of a subgroup analysis of the randomized controlled EVIDENT trial. RESULTS: Positive initial attitudes toward Internet interventions were associated with greater efficacy (eta2p = .014) independent of usage time, whereas a negative attitude (perceived lack of personal contact) was associated with reduced efficacy (eta2p = .012). Users' attitudes changed during the trial, and both the magnitude and direction of attitude change were associated with the efficacy of the program over time (eta2p = .030). CONCLUSIONS: Internet interventions may be the most beneficial for individuals with positive attitudes toward them. Informing potential users about evidence-based Internet interventions might instill positive attitudes and thereby optimize the benefits such interventions can provide. Assessing attitudes prior to treatment might help identify suitable users. PMID- 29489039 TI - Exploring the in situ expression of vascular endothelial growth factor and endoglin in pemphigus foliaceus variants and pemphigus vulgaris. AB - BACKGROUND: Erythroderma is a severe manifestation of pemphigus foliaceus (PF), a blistering disease mediated by IgG autoantibodies against desmoglein 1. Increasing evidence supports the contribution of angiogenic mediators in the pathogenesis of erythroderma. OBJECTIVE: To evaluate the in situ expression of vascular endothelial growth factor (VEGF) and endoglin in patients with PF with erythroderma. METHODS: Formalin-fixed paraffin-embedded skin samples obtained from patients with erythrodermic PF (n = 19; 12 patients with endemic PF), non erythrodermic PF (n = 17), pemphigus vulgaris (PV; n = 10), psoriasis (n = 10) and healthy individuals (HI; n = 10) were processed in an automated immunohistochemistry platform utilizing anti-VEGF and anti-endoglin as primary antibodies. Reactivity was evaluated both manually (0 = negative; 1+ = mild; 2+ = intense) and through an automated microvessel analysis algorithm. RESULTS: Vascular endothelial growth factor expression in erythrodermic PF was higher than in non-erythrodermic PF (P = 0.034) and in HI (P = 0.004), and similar to psoriasis (P = 0.667) and PV (P = 0.667). In non-erythrodermic PF, VEGF positivity was similar to HI (P = 0.247), and lower than psoriasis (P = 0.049) and PV (P = 0.049). Both erythrodermic and non-erythrodermic PF presented similar endoglin expression (P = 0.700). In addition, endoglin positivity during erythrodermic PF was similar to psoriasis (P = 0.133) and lower than PV (P = 0.0009). Increased expression of in situVEGF suggests that healing processes are triggered in response to tissue damage led by autoantibodies in PF, especially during erythroderma. Reduced endoglin positivity suggests that an unbalanced angiogenesis may occur during erythrodermic PF. Further studies may help to confirm if the regulation of VEGF and endoglin expression in patients with PF can contribute to control the healing process and enable disease remission. CONCLUSION: Overexpression of VEGF in erythrodermic PF as well as in PV and psoriasis points out a dysregulated repair process in severe forms of these diseases and suggests VEGF and endoglin could act as prognostic markers and future therapeutic targets to enable proper healing in PF. PMID- 29489040 TI - Minimum effective betamethasone dosage on the neurological phenotype in patients with ataxia-telangiectasia: a multicenter observer-blind study. AB - BACKGROUND AND PURPOSE: Ataxia-telangiectasia (A-T) is a rare neurodegenerative disease, due to A-T mutated (ATM) gene mutations, which typically presents with signs of progressive neurological dysfunction, cerebellar ataxia and uncoordinated movements. A-T severely affects patients' quality of life. Successful treatment options are still not available. The aim of this multicenter study, performed with a blind evaluation procedure, was to define the minimal effective dosage of oral betamethasone, thus preventing the occurrence of side effects. METHODS: Nine A-T patients were enrolled to receive betamethasone at increasing dosages of 0.001, 0.005 and 0.01 mg/kg/day. Neurological assessment and the evaluation of quality of life were performed through the Scale for the Assessment and Rating of Ataxia and the Italian version of the Childhood Health Assessment Questionnaire (CHAQ) at each time-point. The drug safety profile was evaluated. Patients were categorized as responders, partial responders and non responders. RESULTS: Four of nine patients had a benefit at a dose of 0.005 mg/kg/day of oral betamethasone. Using the higher dosage, only one additional patient had a positive response. Conversely, a daily dose of 0.001 mg/kg was ineffective. A correlation between the serum adrenocorticotropic hormone levels and the clinical response was observed. Five of 30 CHAQ items improved in four patients. CONCLUSIONS: These data suggest that a short-term betamethasone oral treatment, at a daily dosage of 0.005 mg/kg, is effective in some patients. Pre existing risk factors for side effects should be taken into account before therapy. PMID- 29489041 TI - Obsessive-compulsive disorder and the risk of subsequent mental disorders: A community study of adolescents and young adults. AB - BACKGROUND: Comorbidity of obsessive-compulsive disorder (OCD) with other mental disorders has been demonstrated repeatedly. Few longitudinal studies, however, have evaluated the temporal association of prior OCD and subsequent mental disorders across the age period of highest risk for first onset of mental disorders. We examined associations between prior OCD and a broad range of subsequent mental disorders and simulated proportions of new onsets of mental disorders that could potentially be attributed to prior OCD, assuming a causal relationship. METHODS: Data from 3,021 14- to 24-year-old community subjects were prospectively collected for up to 10 years. DSM-IV OCD and other DSM-IV mental disorders were assessed with the Munich-Composite International Diagnostic Interview. We used adjusted time-dependent proportional hazard models to estimate the temporal associations of prior OCD with subsequent mental disorders. RESULTS: Prior OCD was associated with an increased risk of bipolar disorders (BIP; [hazard ratio, HR = 6.9, 95% confidence interval, CI, (2.8,17.3)], bulimia nervosa [HR = 6.8 (1.3,36.6)], dysthymia [HR = 4.4 (2.1,9.0)], generalized anxiety disorder (GAD; [HR = 3.4 (1.1,10.9)], and social phobia [HR = 2.9 (1.1,7.7)]). Of these outcome disorders, between 65 and 85% could be attributed to OCD in the exposed group, whereas between 1.5 and 7.7% could be attributed to OCD in the total sample. CONCLUSIONS: This study provides strong evidence that prior OCD is associated with an increased risk of subsequent onset of BIP, bulimia nervosa, dysthymia, GAD, and social phobia among adolescents and young adults. Future studies should evaluate if early treatment of OCD can prevent the onset of these subsequent mental disorders. PMID- 29489043 TI - Issue Information - ToC. PMID- 29489044 TI - Issue Information - Editorial Board. PMID- 29489042 TI - Ecological momentary assessment of smoking behaviors in native and converted intermittent smokers. AB - BACKGROUND AND OBJECTIVES: About 22% of adult smokers in the U.S. are intermittent cigarette smokers (ITS). ITS can be further classified as native ITS who never smoked daily and converted ITS who formerly smoked daily but reduced to intermittent smoking. Ecological momentary assessment (EMA) was conducted to determine the behaviors and experiences that are associated with the decision to smoke. METHODS: The study included 24 native ITS and 36 converted ITS (N = 60) from the Pennsylvania Adult Smoking Study. A baseline questionnaire, daily log, and an EMA smoking log that assessed emotions, activities, and smoking urges was filled out with each cigarette for 1 week to capture 574 smoking sessions. RESULTS: Both groups had very low levels of cigarette dependence. Both groups were more tempted to smoke in positive or negative situations than situations associated with habituation. EMA showed that the most common emotional state during smoking sessions was positive (47%), followed by negative (32%), neutral (16%), and mixed (5%) emotions. Smokers were more likely to smoke during activities of leisure (48%) than during performative duties (29%), social (16%) or interactive occasions (7%). Converted ITS were more likely to smoke alone compared to native ITS (p < .001). DISCUSSION AND CONCLUSIONS: ITS report minimal levels of dependence when captured on traditional scales of nicotine dependence, yet experience loss of autonomy and difficulty quitting. The majority of the ITS reported positive emotions and leisure activities while smoking, and smoked during the evening. SCIENTIFIC SIGNIFICANCE: The current paper identifies environmental and behavioral factors that are associated with smoking among ITS in real time. (Am J Addict 2018;27:131-138). PMID- 29489045 TI - Identifying women veterans with unhealthy alcohol use using gender-tailored screening. AB - BACKGROUND AND OBJECTIVES: To assess the impact of gender-tailored alcohol screening criteria. METHODS: Among N = 1,349 women, we calculated the proportion screening positive for unhealthy alcohol use with non-tailored versus gender tailored criteria (a gender-tailored binge-drinking item, lower screen-positive threshold, or both). RESULTS: Three percent more women screened positive with a modified binge-drinking question, most reporting risky drinking. Fifteen percent more women screened positive with a lower threshold; most did not report risky drinking. DISCUSSION AND CONCLUSIONS: Gender-tailored binge-drinking questions may improve detection of women's unhealthy alcohol use. SCIENTIFIC SIGNIFICANCE: These results can inform future efforts to improve alcohol screening for women. (Am J Addict 2018;27:97-100). PMID- 29489046 TI - Suicidal ideation in military veterans with alcohol dependence and PTSD: The role of hostility. AB - BACKGROUND AND OBJECTIVES: Suicide is a significant public health problem among US military Veterans with rates exceeding civilian samples. Alcohol dependence (AD) and posttraumatic stress disorder (PTSD) are both associated with increases in suicidality. Given that risk of suicide is higher among those with both disorders, the study of relevant risk factors among those in this group is important. The current investigation focused on one such factor, hostility, and examined both overt hostility (ie, hostility that is more behavioral in nature and directed outwardly) and covert hostility (ie, hostility that is cognitive in nature and introspective) and their relationships to suicidal ideation. METHODS: Ninety-three Veterans participating in a randomized, double-blind, placebo controlled treatment study evaluating the efficacy of the alpha-adrenergic agonist prazosin completed measures assessing overt hostility, covert hostility, and suicidal ideation at baseline. Depression symptoms and PTSD symptom severity also were assessed. RESULTS: Of the total sample, 60 participants (63.8%) indicated that they experienced suicidal ideation at some point in their lives. Covert hostility, in addition to PTSD symptom severity were found to be associated with the presence of lifetime suicidal ideation. Furthermore, depression symptoms were found to be associated with greater intensity of that ideation. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: Findings highlight the importance of covert hostility as it relates to suicidal ideation among those with comorbid PTSD and AD and provides information which may help inform treatment approaches for high-risk military Veterans. (Am J Addict 2018;27:124 130). PMID- 29489047 TI - Investigating the mechanism underlying urinary continence recovery after radical prostatectomy: effectiveness of a longer urethral stump to prevent urinary incontinence. AB - OBJECTIVE: To assess the chronological changes in urinary incontinence and urethral function before and after radical prostatectomy (RP), and to compare the findings of pelvic magnetic resonance imaging (MRI) before and after RP to evaluate the anatomical changes. PATIENTS AND METHODS: In total, 185 patients were evaluated with regard to the position of the distal end of the membranous urethra (DMU) on a mid-sagittal MRI slice and urethral sphincter function using the urethral pressure profilometry. The patients also underwent an abdominal leak point pressure test before RP and at 10 days and 12 months after RP. The results were then compared with the chronological changes in urinary incontinence. RESULTS: The MRI results showed that the DMU shifted proximally to an average distance of 4 mm at 10 days after RP and returned to the preoperative position at 12 months after RP. Urethral sphincter function also worsened 10 days after RP, with recovery after 12 months. The residual length of the urethral stump and urinary incontinence were significantly associated with the migration length of the DMU at 10 days after RP. The residual length of the urethral stump was a significant predictor of urinary incontinence after RP. CONCLUSION: This is the first study to elucidate that the slight vertical repositioning of the membranous urethra after RP causes chronological changes in urinary incontinence. A long urethral residual stump reduces urinary incontinence after RP. PMID- 29489048 TI - Narrow-Bandgap Chalcogenoviologens for Electrochromism and Visible-Light-Driven Hydrogen Evolution. AB - A series of electron-accepting chalcogen-bridged viologens with narrow HOMO-LUMO bandgaps and low LUMO levels is reported. The optoelectronic properties of chalcogenoviologens can be readily tuned through heavy atom substitution (S, Se and Te). Herein, in situ electrochemical spectroscopy was performed on the proof of-concept electrochromic devices (ECD). E-BnV2+ (E=Se, Te; BnV2+ =benzyl viologen) was used for the visible-light-driven hydrogen evolution due to the strong visible-light absorption. Remarkably, E-BnV2+ was not only used as a photosensitizer, but also as an electron mediator, providing a new strategy to explore photocatalysts. The higher apparent quantum yield of Se-BnV2+ could be interpreted in terms of different energy levels, faster electron-transfer rates and faster formation of radical species. PMID- 29489049 TI - Reply to Happle R. et al. Koebner's sheep in Wolf's clothing: does the isotopic response exists as a distinct phenomenon? PMID- 29489051 TI - The depth of follicular extension in actinic keratosis correlates with the depth of invasion in squamous cell carcinoma: implication for clinical treatment. AB - BACKGROUND: Actinic keratosis (AK) may show extension down follicles, not only in cases with full-thickness epidermal atypia ('bowenoid' AK), but also in cases with atypia limited to the epidermal basalis. Previous studies have demonstrated that, in bowenoid AK, follicular extension is usually superficial, being limited to the upper follicular segment. Little is known about the depth of follicular involvement in cases of invasive squamous cell carcinoma of the skin (iSCC) arising from AK and the role of the follicle in iSCC pathogenesis. OBJECTIVE: This study investigated the relationship between follicular extension of atypical keratinocytes in an AK and the development of iSCC from the follicular wall. The depth of follicular extension was correlated with the depth invasion of iSCC. Differences between the differentiated and classical pathways of iSCC were also examined. METHODS: We performed a retrospective histologic review of 193 biopsy specimens of iSCC with an associated AK. We assessed the presence and depth of follicular extension of atypical keratinocytes in the AK, using tumour (Breslow) thickness and the follicular unit level (infundibular, isthmic and subisthmic), as well as iSCC being present directly adjacent to the follicular basalis. RESULTS: Follicular extension was present in 25.9% of the cases (50 cases), usually extending into the lower follicular segment. The iSCC was present directly adjacent to the follicular basalis in 58% of the cases (29 cases), correlating highly with the depth of follicular extension (infundibular: 3/12; isthmic: 21/33; subisthmic 5/5). CONCLUSION: The depth of follicular extension of atypical keratinocytes in an AK correlates with the development of depth of invasion of an associated iSCC, irrespective of the pathway of origin. It is therefore important to note the presence and the depth of follicular extension when diagnosing an AK, as follicular extension likely accounts for a significant proportion of recurrent AK and the development of iSCC following superficial treatment modalities. PMID- 29489050 TI - Urinary, bowel and sexual health in older men from Northern Ireland. AB - OBJECTIVES: To provide data on the prevalence of urinary, bowel and sexual dysfunction in Northern Ireland (NI), to act as a baseline for studies of prostate cancer outcomes and to aid service provision within the general population. SUBJECTS AND METHODS: A cross-sectional postal survey of 10 000 men aged >=40 years in NI was conducted and age-matched to the distribution of men living with prostate cancer. The EuroQoL five Dimensions five Levels (EQ-5D-5L) and 26-item Expanded Prostate Cancer Composite (EPIC-26) instruments were used to enable comparisons with prostate cancer outcome studies. Whilst representative of the prostate cancer survivor population, the age-distribution of the sample differs from the general population, thus data were generalised to the NI population by excluding those aged 40-59 years and applying survey weights. Results are presented as proportions reporting problems along with mean composite scores, with differences by respondent characteristics assessed using chi-squared tests, analysis of variance, and multivariable log-linear regression. RESULTS: Amongst men aged >=60 years, 32.8% reported sexual dysfunction, 9.3% urinary dysfunction, and 6.5% bowel dysfunction. In all, 38.1% reported at least one problem and 2.1% all three. Worse outcome was associated with increasing number of long-term conditions, low physical activity, and higher body mass index (BMI). Urinary incontinence, urinary irritation/obstruction, and sexual dysfunction increased with age; whilst urinary incontinence, bowel, and sexual dysfunction were more common among the unemployed. CONCLUSION: These data provide an insight into sensitive issues seldom reported by elderly men, which result in poor general health, but could be addressed given adequate service provision. The relationship between these problems, raised BMI and low physical activity offers the prospect of additional health gain by addressing public health issues such as obesity. The results provide essential contemporary population data against which outcomes for those living with prostate cancer can be compared. They will facilitate greater understanding of the true impact of specific treatments such as surgical interventions, pelvic radiation or androgen-deprivation therapy. PMID- 29489052 TI - Desmopressin for treating nocturia in men. AB - OBJECTIVES: To assess the effects of desmopressin as compared to other interventions in the treatment of nocturia in men. MATERIALS AND METHODS: We performed a comprehensive search using multiple databases and abstract proceedings with no restrictions on the language of publication or publication status, up until August 2017. We included randomised or quasi-randomised trials. Inclusion criteria were men with nocturia defined as one or more voids per night. Two review authors independently examined full-text reports, identified relevant studies, assessed the eligibility of studies for inclusion, extracted data, and assessed risk of bias. We performed statistical analyses using a random-effects model and assessed the quality of the evidence (QoE) according to Grades of Recommendation, Assessment, Development and Evaluation (GRADE). RESULTS: We included 14 studies with 2 966 randomised men across five comparisons (we did not include one comparison [desmopressin vs behaviour modification] in the abstract due to a lack of data with regard to primary outcomes). Desmopressin vs placebo: based on short-term follow-up (<=3 months), desmopressin may have a similar effect on the number of nocturnal voids (mean difference [MD] -0.46, 95% confidence interval [CI] -0.94 to 0.01; low QoE). We are uncertain about the effect of desmopressin on major adverse events (risk ratio [RR] 0.97, 95% CI: 0.10-9.03; very low QoE). For intermediate-term follow-up (3-12 months), desmopressin may reduce the number of nocturnal voids in an appreciable number of men (MD -0.85, 95% CI: -1.17 to -0.53; low QoE). Desmopressin may result in little or no difference in major adverse events (RR 3.05, 95% CI: 0.13-73.39; low QoE). We found no evidence on quality of life. Desmopressin vs alpha-blocker (AB): based on short-term follow-up, desmopressin likely has a similar effect on the number of nocturnal voids (MD 0.30, 95% CI: -0.20 to 0.80; moderate QoE) and quality of life (MD 0.00, 95% CI: -0.35 to 0.35; moderate QoE). There were no major adverse events in either study group. Desmopressin plus AB vs AB alone: based on short-term follow-up, combined therapy likely results in a small, unimportant reduction in the number of nocturnal voids (MD -0.47, 95% CI: -0.73 to -0.21; moderate QoE) and quality of life (MD -0.29, 95% CI: -0.51 to -0.07; moderate QoE). The risk of major adverse events may be similar (RR 0.30, 95% CI: 0.01-7.32; low QoE). Desmopressin plus AB vs AB plus an anticholinergic: based on short-term follow-up, combined therapy likely results in little or no difference in the number of nocturnal voids (MD -0.43, 95% CI: -0.97 to 0.11; moderate QoE). We found no evidence on quality of life. There were no major adverse events in either study group. CONCLUSIONS: Desmopressin may reduce the number of nocturnal voids compared to placebo up to 12 months of follow-up without increase in major adverse events. The effect on the number of nocturnal voids is likely similar to that of ABs with very infrequent major adverse events. There appears to be no added benefit in the combined use of an AB or an anticholinergic with desmopressin. PMID- 29489053 TI - Answer to Tatu AL, Nwabudike LC: Koebner's sheep in Wolf's clothing - does the isotopic response exist as a distinct phenomenon? PMID- 29489054 TI - Retrospective evaluation of plasma cholesterol concentration in septic dogs and its association with morbidity and mortality: 51 cases (2005-2015). AB - OBJECTIVE: To determine whether plasma cholesterol concentrations in dogs with sepsis is associated with morbidity or in-hospital mortality. DESIGN: Retrospective cohort study from 2005-2015. SETTING: Two private referral centers. ANIMALS: Fifty-one dogs diagnosed with sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Dogs were classified as septic if they displayed >=2 criteria of the systemic inflammatory response syndrome in conjunction with a documented underlying infectious cause. Dogs were excluded if they had been diagnosed previously with any concurrent illness reported to alter plasma cholesterol concentrations. Plasma cholesterol concentrations at the time of sepsis diagnosis were statistically analyzed for association with morbidity, as measured by the presence of organ dysfunction, the number of dysfunctional organs, duration of hospitalization, cost of hospitalization, and in-hospital mortality. Twenty-eight (55%) dogs survived to discharge, 15 (29%) were euthanized during hospitalization, and 8 (16%) died despite treatment. While median cholesterol concentrations were significantly different when comparing survivors to discharge versus nonsurvivors who died naturally despite treatment (P = 0.0245), they were not significantly different when comparing survivors to all nonsurvivors (P = 0.1821). Receiver operating characteristic curve analysis showed a cholesterol cutoff of 4.5 mmol/L (174 mg/dL) with a sensitivity of 75% and a specificity of 50% for predicting in-hospital mortality. For surviving dogs, plasma cholesterol concentrations were not associated with increased length of hospital stay. Number of dysfunctional organs and plasma cholesterol concentration were the 2 most significant individual predictors for survival, and when incorporated into a multivariate logistic regression model used for prediction, the model yielded a sensitivity of 94% and specificity of 63%. CONCLUSION: Plasma cholesterol concentration can provide prognostic information in dogs with sepsis. Further prospective studies investigating the role of cholesterol in sepsis are needed. PMID- 29489055 TI - Think global, act local: Responsibility for the liver transplant candidate. PMID- 29489056 TI - Biomimetic scaffolds and dynamic compression enhance the properties of chondrocyte- and MSC-based tissue-engineered cartilage. AB - Adult chondrocytes are surrounded by a protein- and glycosaminoglycan-rich extracellular matrix and are subjected to dynamic mechanical compression during daily activities. The extracellular matrix and mechanical stimuli play an important role in chondrocyte biosynthesis and homeostasis. In this study, we aimed to develop scaffold and compressive loading conditions that mimic the native cartilage micro-environment and enable enhanced chondrogenesis for tissue engineering applications. Towards this aim, we fabricated porous scaffolds based on silk fibroin (SF) and SF with gelatin/chondroitin sulfate/hyaluronate (SF GCH), seeded the scaffolds with either human bone marrow mesenchymal stromal cells (BM-MSCs) or chondrocytes, and evaluated their performance with and without dynamic compression. Human chondrocytes derived from osteoarthritic joints and BM MSCs were seeded in scaffolds, precultured for 1 week, and subjected to compression with 10% dynamic strain at 1 Hz, 1 hr/day for 2 weeks. When dynamic compression was applied, chondrocytes significantly increased expression of aggrecan (ACAN) and collagen X (COL10A1) up to fivefold higher than free-swelling controls. In addition, dynamic compression dramatically improved the chondrogenesis and chondrocyte biosynthesis cultured in both SF and SF-GCH scaffolds evidenced by glycosaminoglycan (GAG) content, GAG/DNA ratio, and immunostaining of collagen type II and aggrecan. However, both chondrocytes and BM-MSCs cultured in SF-GCH scaffolds under dynamic compression showed higher GAG content and compressive modulus than those in SF scaffolds. In conclusion, the micro-environment provided by SF-GCH scaffolds and dynamic compression enhances chondrocyte biosynthesis and matrix accumulation, indicating their potential for cartilage tissue engineering applications. PMID- 29489057 TI - Assessing glucose and oxygen diffusion in hydrogels for the rational design of 3D stem cell scaffolds in regenerative medicine. AB - Hydrogels are attractive biomaterials for replicating cellular microenvironments, but attention needs to be given to hydrogels diffusion properties. A large body of literature shows the promise of hydrogels as 3D culture models, cell expansion systems, cell delivery vehicles, and tissue constructs. Surprisingly, literature seems to have overlooked the important effects of nutrient diffusion on the viability of hydrogel-encapsulated cells. In this paper, we present the methods and results of an investigation into glucose and oxygen diffusion into a silated hydroxypropylmethylcellulose (Si-HPMC) hydrogel. Using both an implantable glucose sensor and implantable oxygen sensor, we continuously monitored core glucose concentration and oxygen concentration at the centre of hydrogels. We demonstrated that we could tune molecular transport in Si-HPMC hydrogel by changing the polymer concentration. Specifically, the oxygen diffusion coefficient was found to significantly decrease from 3.4 * 10-10 to 2.4 * 10-10 m2 s-1 as the polymer concentration increased from 1% to 4% (w/v). Moreover, it was revealed during in vitro culture of cellularized hydrogels that oxygen depletion occurred before glucose depletion, suggesting oxygen diffusion is the major limiting factor for cell survival. Insight was also gained into the mechanism of action by which oxygen and glucose diffuse. Indeed, a direct correlation was found between the average polymer crosslinking node size and glucose parameters, and this correlation was not observed for oxygen. Overall, these experiments provide useful insights for the analysis of nutrient transport and gas exchange in hydrogels and for the development of future cellular microenvironments based on Si-HPMC or similar polysaccharide hydrogels. PMID- 29489058 TI - Novel injectable gellan gum hydrogel composites incorporating Zn- and Sr-enriched bioactive glass microparticles: High-resolution X-ray microcomputed tomography, antibacterial and in vitro testing. AB - Mineralization of hydrogel biomaterials is desirable to improve their suitability as materials for bone regeneration. In this study, gellan gum (GG) hydrogels were formed by simple mixing of GG solution with bioactive glass microparticles of 45S5 composition, leading to hydrogel formation by ion release from the amorphous bioactive glass microparticles. This resulted in novel injectable, self-gelling composites of GG hydrogels containing 20% bioactive glass. Gelation occurred within 20 min. Composites containing the standard 45S5 bioactive glass preparation were markedly less stiff. X-ray microcomputed tomography proved to be a highly sensitive technique capable of detecting microparticles of diameter approximately 8 MUm, that is, individual microparticles, and accurately visualizing the size distribution of bioactive glass microparticles and their aggregates, and their distribution in GG hydrogels. The widely used melt-derived 45S5 preparation served as a standard and was compared with a calcium-rich, sol gel derived preparation (A2), as well as A2 enriched with zinc (A2Zn5) and strontium (A2Sr5). A2, A2Zn, and A2Sr bioactive glass particles were more homogeneously dispersed in GG hydrogels than 45S5. Composites containing all four bioactive glass preparations exhibited antibacterial activity against methicillin resistant Staphylococcus aureus. Composites containing A2Zn5 and A2Sr5 bioactive glasses supported the adhesion and growth of osteoblast-like cells and were considerably more cytocompatible than 45S5. All composites underwent mineralization with calcium-deficient hydroxyapatite upon incubation in simulated body fluid. The extent of mineralization appeared to be greatest for composites containing A2Zn5 and 45S5. The results underline the importance of the choice of bioactive glass when preparing injectable, self-gelling composites. PMID- 29489059 TI - Identification and validation of a multi-assay algorithm for cross-sectional HIV incidence estimation in populations with subtype C infection. AB - INTRODUCTION: Cross-sectional methods can be used to estimate HIV incidence for surveillance and prevention studies. We evaluated assays and multi-assay algorithms (MAAs) for incidence estimation in subtype C settings. METHODS: We analysed samples from individuals with subtype C infection with known duration of infection (2442 samples from 278 adults; 0.1 to 9.9 years after seroconversion). MAAs included 1-4 of the following assays: Limiting Antigen Avidity assay (LAg Avidity), BioRad-Avidity assay, CD4 cell count and viral load (VL). We evaluated 23,400 MAAs with different assays and assay cutoffs. We identified the MAA with the largest mean window period, where the upper 95% confidence interval (CI) of the shadow was <1 year. This MAA was compared to the LAg-Avidity and BioRad Avidity assays alone, a widely used LAg algorithm (LAg-Avidity <1.5 OD-n + VL >1000 copies/mL), and two MAAs previously optimized for subtype B settings. We compared these cross-sectional incidence estimates to observed incidence in an independent longitudinal cohort. RESULTS: The optimal MAA was LAg-Avidity <2.8 OD n + BioRad-Avidity <95% + VL >400 copies/mL. This MAA had a mean window period of 248 days (95% CI: 218, 284), a shadow of 306 days (95% CI: 255, 359), and provided the most accurate and precise incidence estimate for the independent cohort. The widely used LAg algorithm had a shorter mean window period (142 days, 95% CI: 118, 167), a longer shadow (410 days, 95% CI; 318, 491), and a less accurate and precise incidence estimate for the independent cohort. CONCLUSIONS: An optimal MAA was identified for cross-sectional HIV incidence in subtype C settings. The performance of this MAA is superior to a testing algorithm currently used for global HIV surveillance. PMID- 29489061 TI - Obituary. PMID- 29489060 TI - Molecular genetic characteristics of influenza A virus clinically isolated during 2011-2016 influenza seasons in Korea. AB - BACKGROUND: The influenza virus is reportedly associated with 3-5 million cases of severe illness and 250 000-500 000 deaths annually worldwide. OBJECTIVES: We investigated the variation of influenza A virus in Korea and examined the association with death. METHODS: A total of 13 620 cases were enrolled in the Hospital-based Influenza Morbidity & Mortality surveillance system in Korea during 2011-2016. Among these cases, a total of 4725 were diagnosed with influenza using RT-PCR (influenza A; n = 3696, influenza B; n = 928, co infection; n = 101). We used 254 viral sequences from the 3696 influenza A cases for phylogenetic analysis using the BioEdit and MEGA 6.06 programs. RESULTS: We found that the sequences of A/H3N2 in the 2011-2012 season belong to subgroup 3C.1, whereas the sequences in the 2012-2013 season pertain to subgroup 3C.2. The sequences in the 2013-2014 and 2014-2015 seasons involve subgroups 3C.3a and 3C.2a. The A/H1N1pdm09 subtype belongs to subgroup 6 and contains two clusters. In addition, sequence analysis confirmed the several substitutions of internal genes and gene substitutions associated with drug resistance (I222V in NA and S31N in M2) in the fatal cases. While statistical analysis found no significant associations between genetic differences in the viruses and mortality, mortality was associated with certain host factors, such as chronic lung disease. CONCLUSIONS: In conclusion, influenza A virus clade changes occurred in Korea during the 2011-2016 seasons. These data, along with antigenic analysis, can aid in selecting effective vaccine strains. We confirmed that fatality in influenza A cases was related to underlying patient diseases, such as chronic lung disease, and further studies are needed to confirm associations between mortality and viral genetic substitutions. PMID- 29489062 TI - Embryonic Stem Cell-Derived Mesenchymal Stem Cells (MSCs) Have a Superior Neuroprotective Capacity Over Fetal MSCs in the Hypoxic-Ischemic Mouse Brain. AB - Human mesenchymal stem cells (MSCs) have huge potential for regenerative medicine. In particular, the use of pluripotent stem cell-derived mesenchymal stem cells (PSC-MSCs) overcomes the hurdle of replicative senescence associated with the in vitro expansion of primary cells and has increased therapeutic benefits in comparison to the use of various adult sources of MSCs in a wide range of animal disease models. On the other hand, fetal MSCs exhibit faster growth kinetics and possess longer telomeres and a wider differentiation potential than adult MSCs. Here, for the first time, we compare the therapeutic potential of PSC-MSCs (ES-MSCs from embryonic stem cells) to fetal MSCs (AF-MSCs from the amniotic fluid), demonstrating that ES-MSCs have a superior neuroprotective potential over AF-MSCs in the mouse brain following hypoxia ischemia. Further, we demonstrate that nuclear factor (NF)-kappaB-stimulated interleukin (IL)-13 production contributes to an increased in vitro anti inflammatory potential of ES-MSC-conditioned medium (CM) over AF-MSC-CM, thus suggesting a potential mechanism for this observation. Moreover, we show that induced pluripotent stem cell-derived MSCs (iMSCs) exhibit many similarities to ES-MSCs, including enhanced NF-kappaB signaling and IL-13 production in comparison to AF-MSCs. Future studies should assess whether iMSCs also exhibit similar neuroprotective potential to ES-MSCs, thus presenting a potential strategy to overcome the ethical issues associated with the use of embryonic stem cells and providing a potential source of cells for autologous use against neonatal hypoxic-ischemic encephalopathy in humans. Stem Cells Translational Medicine 2018;7:439-449. PMID- 29489063 TI - Plasma kallikrein activates the epithelial sodium channel in vitro but is not essential for volume retention in nephrotic mice. AB - AIM: Recent work has demonstrated that activation of the epithelial sodium channel (ENaC) by aberrantly filtered serine proteases causes sodium retention in nephrotic syndrome. The aim of this study was to elucidate a potential role of plasma kallikrein (PKLK) as a candidate serine protease in this context. METHODS: We analysed PKLK in the urine of patients with chronic kidney disease (CKD, n = 171) and investigated its ability to activate human ENaC expressed in Xenopus laevis oocytes. Moreover, we studied sodium retention in PKLK-deficient mice (klkb1-/- ) with experimental nephrotic syndrome induced by doxorubicin injection. RESULTS: In patients with CKD, we found that PKLK is excreted in the urine up to a concentration of 2 MUg mL-1 which was correlated with albuminuria (r = .71) and overhydration as assessed by bioimpedance spectroscopy (r = .44). PKLK increased ENaC-mediated whole-cell currents, which was associated with the appearance of a 67 kDa gamma-ENaC cleavage product at the cell surface consistent with proteolytic activation. Mutating a putative prostasin cleavage site in gamma ENaC prevented channel stimulation by PKLK. In a mouse model for nephrotic syndrome, active PKLK was present in nephrotic urine of klkb1+/+ but not of klkb1 /- mice. However, klkb1-/- mice were not protected from ENaC activation and sodium retention compared to nephrotic klkb1+/+ mice. CONCLUSION: Plasma kallikrein is detected in the urine of proteinuric patients and mice and activates ENaC in vitro involving the putative prostasin cleavage site. However, PKLK is not essential for volume retention in nephrotic mice. PMID- 29489064 TI - Long non-coding RNA CASC15 regulates gastric cancer cell proliferation, migration and epithelial mesenchymal transition by targeting CDKN1A and ZEB1. AB - Long non-coding RNA (lncRNA) is responsible for a diverse range of cellular functions, such as transcriptional and translational regulation and variance in gene expression. The lncRNA CASC15 (cancer susceptibility candidate 15) is a long intergenic non-coding RNA (lincRNA) locus in chromosome 6p22.3. Previous research shows that lncRNA CASC15 is implicated in the biological behaviors of several cancers such as neuroblastoma and melanoma. Here, we aimed to explore in detail how CASC15 contributes to the growth of gastric cancer (GC). As predicted, the expression of CASC15 was enriched in GC tissues and cell lines as compared with healthy tissues and cells using qRT-PCR. The Kaplan-Meier method was used to demonstrate that high expression of CASC15 is linked to a poor prognosis for patients suffering from GC. Additionally, functional experiments proved that the down- or up-regulation of CASC15 inhibited or facilitated cell proliferation via the induction of cell cycle arrest and apoptosis, and also suppressed or accelerated cell migration and invasion by affecting the progression of the epithelial-to-mesenchymal transition (EMT). In vivo experiments showed that the knockdown of CASC15 lessened the tumor volume and weight and influenced the EMT process. This was confirmed by western blot assays and immunohistochemistry, indicating impaired metastatic ability in nude mice. CASC15 involvement in the tumorigenesis of GC occurs when CASC15 interacts with EZH2 and WDR5 to modulate CDKN1A in nucleus. Additionally, the knockdown of CASC15 triggered the silencing of ZEB1 in cytoplasm, which was shown to be associated with the competitive binding of CASC15 to miR-33a-5p. PMID- 29489065 TI - Clinical Indicators for Evaluation of Outcomes of Impaired Tissue Integrity in Orthopedic Patients: Consensus Study. AB - PURPOSE: To select outcomes from the Nursing Outcomes Classification (NOC) to evaluate impaired tissue integrity in patients undergoing orthopedic surgeries, and develop conceptual and operational definitions for their indicators. METHODS: A consensus study involving 10 nurses from clinical practice. A 100% consensus was established in the outcomes selection. FINDINGS: Wound Healing: Primary intention (1102) with two indicators: (110214) Scar formation, and (110201) Skin approximation were selected. Four indicators were grouped to evaluate inflammatory signs together with foul wound odor and six for drainage. CONCLUSIONS: These indicators direct the outcomes evaluation for wound healing. IMPLICATIONS FOR NURSING PRACTICE: Support to the definition the priority interventions in nursing process documentation. PMID- 29489066 TI - Confirmation of the Cardiac Safety of PGF2alpha Receptor Antagonist OBE022 in a First-in-Human Study in Healthy Subjects, Using Intensive ECG Assessments. AB - OBE022, a new orally active prostaglandin F2alpha receptor antagonist (OBE022) with myometrial selectivity is being developed to reduce uterine contractions during preterm labor. This first-in-human study evaluated the effect of OBE022 following multiple doses on the QT interval in 23 healthy postmenopausal women, using the effect of a meal on QTc to demonstrate assay sensitivity. We report the cardiac safety outcome performed during the multiple ascending part of this trial. OBE022 was administered after a standardized breakfast on day 1 and in the fasted state from day 3 to day 9 wth a standardized lunch 4 hours after administration. Concentration-effect modeling was used to assess the effect of prodrug OBE022 and parent OBE002 on QTc after a single dose (days 1 and 3) and multiple doses (day 9). The concentration-response analysis showed the absence of QTc prolongation at all doses tested. Two-sided 90% confidence intervals of the geometric mean Cmax for estimated QTc effects of OBE022 and OBE002 of all dose groups were consistently below the threshold of regulatory concern. The sensitivity of this study to detect small changes in the QTc was confirmed by a significant shortening of the QTc on days 1, 3, and 9 after standardized meals. This study establishes that neither prodrug OBE022 nor parent OBE002 prolong the QTc interval. The observed food effect on the QT interval validated the assay on all assessment days. Both the change from predose, premeal and the change from premeal, postdose demonstrated the specificity of the method. PMID- 29489067 TI - Sex differences in insulin and glucagon responses for glucose homeostasis in young healthy Japanese adults. AB - It has been reported that glucose responses during the oral glucose tolerance test differ between healthy women and men. However, it remains unknown what factors contribute to these differences between the sexes. The present study analyzed the insulin and glucagon responses during the oral glucose tolerance test in 25 female and 38 male healthy young adults aged 22-30 years. The plasma glucose levels at 120 min were significantly higher in women than men. Insulin secretion was significantly greater at 30, 90 and 120 min from baseline in women than men. Glucagon suppression was greater at 30 and 120 min from baseline in men than women when determined by a sandwich enzyme-linked immunosorbent assay glucagon kit. These results suggest that the differences in glucose responses during the oral glucose tolerance test are mediated by the difference between the sexes in bi-hormonal responses in healthy individuals. PMID- 29489068 TI - Children with ADHD draw-and-tell about what makes their life really good. AB - PURPOSE: The purpose of this study was to engage children with attention deficit hyperactivity disorder (ADHD) in a developmentally sensitive way to explore the children's subjective well-being. Explicitly, their life satisfaction, or what makes their life "really good." To date, little is known about the subjective life experience of children with ADHD or how incorporating children's views separate from the purview of adults and pathology might enhance our understanding or change our approach to evaluation and/or intervention. DESIGN AND METHODS: A parallel convergent mixed-methods design was used to collect data from a convenience sample of children with ADHD (N = 20) ages 7 to 11 years old. This article focuses solely on the qualitative data obtained through semi-structured interviews using the art-based approach draw-and-tell conversation (DTC). The DTC data were analyzed using qualitative content analysis. In addition, each parent (N = 20) independently completed demographic and health-related forms to provide descriptive and contextual variables. RESULTS: Three themes were discerned in the DTC analysis-activity, nature, and connections. Most children (90%) described engaging in some form of activity, often outdoors, and with others; though the focus of activity was varied. Nature was evidenced directly and indirectly in many of the children's (85%) stories. Over half (65%) of the children described some variation in relational connection across a continuum that contributed to, or detracted from, their sense of well-being/life satisfaction. PRACTICE IMPLICATIONS: Children shared that doing things, outdoors, with others, [emphasis added] made their life "really good". Children's stories yielded insightful and actionable information that is relevant to each individual child/family, and to nursing assessment, intervention, and advocacy. These child-granted insights also extend our attention beyond pharmacological and behavioral focused interventions, to include the children's own innate health promoting interests that help to make their life really good. PMID- 29489069 TI - Clinical significance of serum interleukin-8 and soluble tumor necrosis factor like weak inducer of apoptosis levels in patients with diabetic nephropathy. AB - AIMS/INTRODUCTION: Recent studies suggest that chronic inflammatory responses are important in the development of diabetic nephropathy (DN). Various inflammatory and angiogenesis molecules affect the pathogenesis and progression of DN. Inflammation damages the microcirculation and causes kidney damage. In the present study, we studied changes in interleukin-8 (IL-8) and soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) levels in patients with DN, and investigated the clinical significance of these two inflammatory factors. MATERIALS AND METHODS: Participants were categorized into healthy controls (n = 30) and patients with type 2 diabetes mellitus (n = 124). The type 2 diabetes mellitus group was further subdivided into the normoalbuminuria (n = 34), microalbuminuria (MAU; n = 46,) and proteinuria (MaAU; n = 44,) groups. Patients with DN were included in the MAU and MaAU groups. Total cholesterol, triglyceride, low-density lipoprotein cholesterol, glycosylated hemoglobin, fasting blood glucose, 2-h postprandial blood glucose, blood urea nitrogen, serum creatinine, 24-h urine microalbumin, IL-8 and sTWEAK levels were measured. Logistic regression was used to analyze the factors associated with proteinuria. RESULTS: In the healthy controls, normoalbuminuria, MAU and MaAU groups, we found that IL-8 levels increased, whereas sTWEAK levels decreased (P < 0.05). IL-8 might be an independent risk factor and serum sTWEAK a protective factor for MAU and MaAU. Serum levels of sTWEAK, IL-8 and microalbumin were significantly correlated in the MAU and MaAU groups. CONCLUSIONS: Serum IL-8 and sTWEAK levels might be markers that can be used for an early diagnosis of DN. PMID- 29489070 TI - The Efficacy of Metacognitive Training for Delusions in Patients With Schizophrenia: A Meta-Analysis of Randomized Controlled Trials Informs Evidence Based Practice. AB - BACKGROUND: Metacognitive training (MCT) was developed in 2007 and widely used to modify the delusions for patient with schizophrenia. However, its effectiveness remains unclear. AIMS: To investigate the overall effectiveness of MCT for delusion in schizophrenia patients from 2007 to 2016, and to investigate the variables (intervention approach, intervention dose, and participant factors) of an MCT study that could influence the effect size. METHODS: Parallel-arm design of MCT for delusions published from 2007 to 2016 were collected and then cross referenced using these keywords: delusion (psychosis or psychotic or schizophrenia) and metacognitive (training or therapy or intervention). The quality of the studies was evaluated and the effect size and the moderating variables of MCT on delusion were determined. RESULTS: A total of 11 studies on the effect of MCT for delusion were investigated. The MCT had a moderate immediate postintervention effect (g = -0.38) and a lasting effect after 6 months (g = -0.35). In terms of immediate effect, moderating variables with significant differences between them were (a) individual approach versus group-based approach and mixed approach, and (b) eastern country versus western country. LINKING EVIDENCE TO ACTION: MCT could be used as a valuable nonpharmacologic intervention to reduce delusions in clinical settings. The individual modularized MCT approach had a beneficial effect and is recommended to healthcare professionals as an application for patients with schizophrenia or delusional disorder. PMID- 29489071 TI - Pure Laparoscopic Living Donor Left Lateral Sectionectomy in Pediatric Transplantation: A Propensity Score Analysis on 220 Consecutive Patients. AB - Left lateral sectionectomy for donor hepatectomy is a well-established alternative to deceased donor pediatric liver transplantation. However, very little is available on the laparoscopic approach (laparoscopic left lateral sectionectomy [L-LLS]). With the aim to assess safety, reproducibility under proctorship, and outcomes following living donor liver transplantation in children, a comparative single-center series using propensity score matching (PSM) to evaluate open left lateral sectionectomy (O-LLS) versus L-LLS was carried out in a relatively short time period in a high-volume pediatric transplant center. A retrospective, observational, single-center, PSM study was conducted on 220 consecutive living donor hepatectomies from January 2011 to April 2017. The variables considered for PSM were as follows: year of operation, recipient age, indication for transplant, recipient weight, donor sex, donor age, and donor body mass index. After matching, 72 O-LLSs were fit to be compared with 72 L-LLSs. Operative time and warm ischemia time were significantly longer in L LLSs, whereas blood loss and overall donor complication rates were significantly lower. Postoperative day 1 and 4 pain scores were significantly less in the L-LLS group (P = 0.015 and 0.003, respectively). The length of hospital stay was significantly shorter in L-LLS (4.6 versus 4.1 days; P = 0.014). Overall donor biliary complications were 9 (12.5%) and 1 (1.4%) for O-LLS and L-LLS (P = 0.022), respectively. Vascular complications occurred in 3 (4.2%) children without graft loss in the laparoscopic group. The 1-, 3-, and 5-year overall patient survival rates were 98.5%, 90.9%, and 90.9% in the O-LLS group and in the L-LLS group 94.3%, 92.7%, and 86.8% (P = 0.28). In conclusion, L-LLS for donor hepatectomy is a safe and reproducible technique yielding better donor perioperative outcomes with respect to the conventional approach with similar recipient outcomes. PMID- 29489072 TI - Eponymous Psychiatric Syndromes Revisited. AB - This report provides an anthology of psychiatric eponyms. Clinically, many of these described syndromes represent valid diagnostic constructs and may accommodate the atypical cases that defy the official diagnostic designation in the current classificatory systems in psychiatry. PMID- 29489073 TI - Cannabis Withdrawal in Adults With Attention-Deficit/Hyperactivity Disorder. AB - Objective: Cannabis withdrawal has not been studied in adults with attention deficit/hyperactivity disorder (ADHD) who have high rates of cannabis use. We aimed to describe cannabis withdrawal, motivations to quit, and strategies to quit cannabis use in cannabis-dependent adults with ADHD. Methods: Twenty-three adults with ADHD enrolled in a controlled clinical trial of pharmacotherapy (atomoxetine) for cannabis dependence (DSM-IV criteria) completed the Marijuana Quit Questionnaire (MJQQ) to provide information on their "most serious" quit attempt made without formal treatment. The study was conducted between November 2005 and June 2008. Results: Participants were predominantly male (82.6%, n = 19), with a mean (SD) age of 27.4 (8.5) years (range, 18-53) at the start of their index quit attempt. The most common motive for quitting cannabis was "to save money" (87%, n = 20); the most common strategy to maintain abstinence was "stopped associating with people who smoke marijuana" (43%, n = 10). Almost all (96%, n = 22) subjects reported >= 1 cannabis withdrawal symptom; 7 (30%) met DSM 5 diagnostic criteria for cannabis withdrawal syndrome. Conclusions: Participants with comorbid ADHD and cannabis dependence reported withdrawal symptoms similar to other samples of non-treatment-seeking cannabis-dependent adults with no psychiatric comorbidity. These findings suggest that ADHD does not influence cannabis withdrawal in the way that it does tobacco (nicotine) withdrawal. Trial Registration: Data used in this secondary analysis came from ClinicalTrials.gov identifier: NCT00360269. PMID- 29489074 TI - Delirious Mania in a Geriatric Patient. PMID- 29489075 TI - Psychological Aspects of Factitious Disorder. AB - Factitious disorder can present in multiple health care settings, with patients intentionally producing symptoms to assume the sick role. This assumption of the sick role can result in multiple hospitalizations with unnecessary diagnostic workup, as well as invasive diagnostic procedures that can lead to worrisome side effects. Differential diagnoses that should be ruled out include malingering, somatic symptom disorder, and anxiety disorders. For many providers, patients with factitious disorder can be a challenge to treat because the etiology of the disorder remains unclear. There are multiple psychological theories that attempt to explain the motivation and thought process behind the voluntary production of symptoms. Some of these theories have addressed disruptive attachments during childhood, possible intergenerational transfer of the disorder, personal identity conflicts, somatic illness as a form of masochistic activity toward oneself, and intrapsychic conflicts. Confrontation and psychotherapy with a multidisciplinary team has been proposed as a form of treatment. An understanding of the psychological factors associated with factitious disorder can help providers understand the rationale behind the patient's presentation and aid in the formulation of a treatment plan. PMID- 29489078 TI - Sluggish Cognitive Tempo as a Possible Predictor of Methylphenidate Response in Children With ADHD: A Randomized Controlled Trial. AB - OBJECTIVE: To examine whether sluggish cognitive tempo (SCT) symptomatology moderates dose response to methylphenidate and whether the impact of SCT on medication response is distinct from attention-deficit/hyperactivity disorder (ADHD) subtype effects. METHODS: Stimulant-naive children with ADHD predominantly inattentive type (ADHD-I; n = 126) or ADHD combined type (ADHD-C; n = 45) aged 7 11 years were recruited from the community from September 2006 to June 2013 to participate in a prospective, randomized, double-blind, 4-week crossover trial of long-acting methylphenidate. ADHD diagnosis and subtype were established according to DSM-IV criteria using a structured interview and teacher ADHD symptom ratings. SCT symptoms were assessed using a teacher-rated scale with 2 factors (Sluggish/Sleepy and Daydreamy). Primary outcomes included (1) categorization of children as methylphenidate responders, methylphenidate nonresponders, or placebo responders by 2 blinded physicians and (2) parent and teacher ratings of child behavior on the Vanderbilt ADHD Diagnostic Rating Scales while subjects were on treatment with placebo or 1 of 3 methylphenidate dosages (low, medium, high). RESULTS: Increased SCT Sluggish/Sleepy factor scores were associated with being a methylphenidate nonresponder or placebo responder rather than a methylphenidate responder (P = .04). Sluggish/Sleepy factor scores were also linked to diminished methylphenidate dose response for parent- and teacher rated inattention symptoms (Sluggish/Sleepy factor * dose P = .004). SCT Daydreamy symptoms and ADHD subtype (ADHD-I vs ADHD-C) were not associated with methylphenidate responder status and did not moderate methylphenidate dose response for inattention symptoms. CONCLUSIONS: SCT Sluggish/Sleepy symptoms, but not SCT Daydreamy symptoms or ADHD subtype, predicted methylphenidate nonresponse. This novel finding, if replicated, may have important implications for assessing SCT as part of ADHD care. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01727414. PMID- 29489076 TI - Pathways to Late-Life Suicidal Behavior: Cluster Analysis and Predictive Validation of Suicidal Behavior in a Sample of Older Adults With Major Depression. AB - OBJECTIVE: Clinical heterogeneity is a key challenge to understanding suicidal risk, as different pathways to suicidal behavior are likely to exist. We aimed to identify such pathways by uncovering latent classes of late-life depression cases and relating them to prior and future suicidal behavior. METHODS: Data were collected from June 2010 to September 2015. In this longitudinal study we examined distinct associations of clinical and cognitive/decision-making factors with suicidal behavior in 194 older (50+ years) nondemented, depressed patients; 57 nonpsychiatric healthy controls provided benchmark data. The DSM-IV was used to establish diagnostic criteria. We identified multivariate patterns of risk factors, defining clusters based on personality traits, perceived social support, cognitive performance, and decision-making in an analysis blinded to participants' history of suicidal behavior. We validated these clusters using past and prospective suicidal ideation and behavior. RESULTS: Of 5 clusters identified, 3 were associated with high risk for suicidal behavior: (1) cognitive deficits, dysfunctional personality, low social support, high willingness to delay future rewards, and overrepresentation of high-lethality attempters; (2) high-personality pathology (ie, low self-esteem), minimal or no cognitive deficits, and overrepresentation of low-lethality attempters and ideators; (3) cognitive deficits, inability to delay future rewards, and similar distribution of high- and low-lethality attempters. There were significant between-cluster differences in number (P < .001) and lethality (P = .002) of past suicide attempts and in the likelihood of future suicide attempts (P = .010, 30 attempts by 22 patients, 2 fatal) and emergency psychiatric hospitalizations to prevent suicide (P = .005, 31 participants). CONCLUSIONS: Three pathways to suicidal behavior in older patients were found, marked by (1) very high levels of cognitive and dispositional risk factors suggesting a dementia prodrome, (2) dysfunctional personality traits, and (3) impulsive decision-making and cognitive deficits. PMID- 29489077 TI - Inflammation and Improvement of Depression Following Electroconvulsive Therapy in Treatment-Resistant Depression. AB - OBJECTIVE: Electroconvulsive therapy (ECT) is the most robust acute treatment for severe major depressive disorder, yet clinical response is variable. Inflammation is associated with depression, especially in women, and levels of C-reactive protein (CRP) and interleukin (IL)-6 predict response to antidepressant medications. This study evaluated whether markers of inflammation predicted response to electroconvulsive therapy (ECT) in patients with treatment-resistant depression and to what extent this association differed between men and women. METHODS: In patients (N = 29) who had a current major depressive episode diagnosed using DSM-IV-TR criteria and were scheduled to undergo ECT at an academic referral center, levels of CRP, IL-6, IL-8, and tumor necrosis factor alpha and severity of depressive symptoms (Montgomery-Asberg Depression Rating Scale [MADRS]) were prospectively evaluated before ECT treatment, after the second ECT session, and again at the completion of the index treatment series. Data were collected between December 2011 and December 2014. The primary outcome was end-of-treatment MADRS score. RESULTS: In multivariate analyses, higher levels of IL-6 at baseline, but not other inflammatory markers or clinical variables, were associated with lower end-of-treatment MADRS score (P = .01). When stratified by sex, IL-6 remained a significant predictor of end-of-treatment MADRS for women (P = .02) but not men (P = .1), and CRP emerged as a significant predictor for women (P = .04) but not men (P = .66). CRP and IL-6 increased from baseline to the second ECT session (P values < .01) and returned to baseline levels at end of treatment; these changes did not relate to MADRS score over the course of ECT. CONCLUSIONS: Levels of IL-6 prior to ECT treatment may be useful in identifying those depressed patients most likely to benefit from ECT treatment. In contrast, acute changes in IL-6 and CRP may reflect spikes in inflammatory response related to the initiation of seizure therapy, but not mood. Assessment of pretreatment inflammatory biomarkers, especially in women, might be useful in guiding treatment decision-making in treatment-resistant depression. PMID- 29489079 TI - [Formulation of new generation drug delivery system for dry powder inhalation.] AB - Based on the formulation method the dry powder inhalers (DPIs) can be divided in too types: carrier-based and carrier-free drug delivery systems. The newest researches report about several high potency carrier-free formulations, where the active ingredient and the excipients are together formulated to the DPI form. However, in Hungary the commercially available DPIs are carrier-based (e.g. lactose), which means that only the mic-onized active ingredient reaches the deeper lungs, the big carrier deposits in the upper airways. The present work is about formulating a high efficacy mannitol-based Pulmonary Drug Delivery System (PDDS), which is able to delivery different types of active ingredients to the deeper lungs with higher deposition rate. The present study involves the physico chemical and aerodynamical characterisation of mannitol-based PDDS. The results demonstrated the use of the appropriate excipients (leucine, poly-vinyl-alcohol, cyclodextrine) and solvent combination (ethanol-water) during the co-spray drying, increases the inhalation properties of the mannitol. Such carrier systems with optimized properties can increase the aerolization efficacy of the active ingredient. PMID- 29489080 TI - [The pharmaceutical chemistry of azole antifungals.] AB - Azole antifungals are a group of compounds that play essential rule in the treatment of surface and deep mycoses. They can be used externally to treat fungal infections of skin, mucous membranes and external genitalia but they are also suitable for oral treatment of systemic mycoses. Structurally they are classified into two groups: imidazoles and triazoles. Triazole antimycotics have wider spectrum of activity, favorable pharmacokinetics, they are of milder side effects and sofar less developed anti-fungal resistance. This paper provides an overview on the history, synthe- sis, physico-chemical properties, structure activity relationships of azole antifungals but it also deals with their pharmacological properties and mechanism of action. PMID- 29489081 TI - [Formulation and special investigations of innovative intraoral solid dosage forms.] AB - During our work, we summarized the types of solid dosage forms which were in the focus of attention in the last years because of their innovative pharmaceutical technology solution and simple use. The biopharmaceutics of solid dosage forms for intraoral use and the advantages of the use of these dosages forms were presented in general. However, these dosage forms cannot always be prepared with conventional pharmaceutical processes, therefore the special pharmaceutical solutions which can be applied for their preparation were presented. In addition to testing the European Pharmacopoeia dosage forms, the special tests which can be applied for the characterization of innovative solid dosage forms were highlighted. PMID- 29489082 TI - [Pharmaceutical counseling of non-conventional dosage forms concerning the health literacy and the patient adherence in public medication dispensing -Questionnaire surveys in Hungarian community pharmacies.] AB - Although the non-conventional dosage forms (e.g. modified release per oral systems or transdermal patches) have more significant advantages than other conventional dosage forms, the pa- tients have to apply them correctly in their home medicine using to reach the effective and safe therapy. A guideline of relevant application instructions contribute to development of an effective pharmaceutical counseling in community pharmacies. The counseling and advices can improve the patients' knowledge concerning application rules of different new dosage forms (health- literacy) with patient adherence. Finally it will result more effective and safer therapies. The aim of our Hungarian questionnaire surveys was to explore the patients' drug application habits or application errors and improve special verbal counseling of mentioned non-conventional dosage forms in community pharmacies. Understandable patient information leaflets were developed about application rules and besides the levels of patients' reading comprehension was evaluated in case of the leaflet of medicinal patches. The results show that a properly developed text is useful for the majority of patients but they need the verbal explanation as well, moreover there is a demand for the verbal counseling in community pharmacies. The most common application errors were explored and the most effective instructions or application rules were collected for the pharmacists and patients concerning the modified release tablets or capsules and transdermal patches. PMID- 29489083 TI - [Jan Evangelista Purkyne and his instruments for microscopic research.] AB - The results obtained during the studies of the microscopic structure of animal and human tissues by the famous 19th century Czech scientist Jan Evangelista Purkyne are already sufficiently described in a variety of older and newer publications. The contents of the present paper are an overview of the microscopes and other tools and instruments that Purkyne and his assistants and pupils used for research of tissue histology and during teaching, and in whose development there were directly involved. A brief overview of the development of the cutting engines suggests that the first microtome, from which all modern sliding microtomes are derived, originated under the supervision of Purkyne at the Institute of Physiology in Wroclaw. Purkyne and his assistants thus not only obtained priority results in the field of the structure of animal and human tissues, but also substantially contributed to the development of instruments and equipment for their study, which is often forgotten today. PMID- 29489084 TI - [Chronic fatifue syndrome.] AB - Chronic fatigue syndrome - CFS is a disease that lasts about 6 months in adults and in children three months. Other names are myalgia encephalomyelitis, postviral immune syndrome, chronic fatigue immune dysfunction syndrome. The reasons are biological, genetical, infectious or psychological. The paper discusses the history of chronic fatigue syndrome, epidemiology and its prevalence, clinical course, pathophysiology, diagnosis, therapy and prognosis, and also economics. PMID- 29489085 TI - [Diabetic cardiomyopathy: pathophysiological mechanisms of structural and functional changes.] AB - Diabetes mellitus is a powerful risk factor for cardiovascular disease associated with high morbidity and mortality rates. Diabetic patients also have an increased incidence of heart failure which has been traditionally attributed to the presence of ischemic or hypertensive heart disease. However, the diabetic milieu is itself noxious to the heart, and cardiomyopathy can develop independent of elevated blood pressure, coronary artery disease or other risk factors with the potential to lead to a progressive development of heart failure. Diabetic car- diomyopathy is characterized by significant changes in function and structure of the heart. They have been studied in numerous diabetic experimental models in animals, mostly rodents. Revealing of potential underlying mechanisms of these pathophysiological alterations holds the promise to design new pharmacological strategies for diabetic patients. Our current review provides an update on functional and structural alterations in the diabetic heart and pathophysiological mechanisms of their development and progression. PMID- 29489086 TI - [The influence of physical load on the propriate immune and physiological parameters.] AB - Chronic fatigue syndrome is a disease detected in recent 15 or 20 years. Overtrained athletes, people living in stress, the ones with disturbed immunity or people suffering from some of the infectious diseases are the most threatened ones. During ultra-long-distance run, human immune, physiological a biochemical parameters drift of their physiological ranges. The values could increase or decrease. The samples of serum of ultramarathon runners, who took part in the National Ultramarathon Mastership, were collected and measured before and after the race. The parameters include IgA, IgM, IgG and C3 part of complement. Statistically important increases in IgA and IgG concentrations after the race were observed. The changes of concentrations of IgM and C3 part of complement was not statistically important. IgG is responsible for the activation of complement, secondary immune reactions and the neutralization of bacterial toxins. IgA in the role of muckal imunoglobulin helps immune cells to swallow heterogenous particles, germs and toxins. Our immune syst6m is more threatened by heterogenous infectious diseases and even the chronic fatigue syndrome. PMID- 29489087 TI - MutL protein homologue 1(MLH1) in colon adenocarcinomas of the dog: minireview. AB - The mismatch repair gene MLH1 is a gene encoding the mismatch repair protein MutL homolog 1 (MLH1), important for repairing mutations generated during DNA replication. MLH1 absence has been observed in human gastrointestinal tumours as well as tumours of the female reproductive tract. We describe the functions of MLH 1 in cell cycle regulation and DNA mismatch repair. In this sense we discuss foriegn knowledges, in which the canine colon adencarcinoma is less frequently diagnosed in Czech and Slovak regions. We briefly described a molecular mechanism of evolution of MSI+ and MSI- colorectal carcinomas in human, and this was confronted with the current opinion of canine colon adenocarcinomas. We suppose that canine colon adenocarcinomas may occur in higher frequency, but they are underdiagnosed in the clinical veterinary practice. At the end, we describe two cases of dogs diagnosed with colorectal adenocarcinoma. The authors propose the centralized collection of colon adenocarcinoma samples from dogs, in one reference veterinary histopathological laboratory, which would analyse mismatch repair proteins. PMID- 29489088 TI - Vincenc Alexandr Bohdalek (1801-1883) and his contributions in the field of neuroscience. AB - Vincenc Alexandr Bohdalek (Vincenz Alexander Bochdalek) is known primarily as an anatomist and pathologist and entered into the history of anatomy by describing a number of anatomical structures. Unfortunately his findings in the field of neuroscience are, with few exceptions, almost unknown. Current reviewtherefore partially fills a gap in the evaluation of the contributions of Bohdalek and based on available archival sources provides an overview of his results in the field of the nervous system research, which accounts for almost half of his works. He studied in detailpredominantly the innervation of eye, upper jaw, hard palate,auditory system and meninges, and surprisingly also dealt with the tissue regeneration. Bohdalek's works also show that he tried to find a physiological explanation to the observed anatomical and pathological findings, therefore he could be considered as a pioneer of the field, which is now called as func- tional anatomy. Present overview of his neuroscience works, including his complete bibliography,partially fills a huge debt to Bohdalek. Key words: nerves, brain, Bohdalek, 19th century. PMID- 29489089 TI - Stem cell conditioned medium for cell-free therapies. AB - Stem cells become an effective tool for treatment of a variety of defects and diseases. Recently, it appears that the therapeutic effect of stem cells lies not only in their integration and differentiation into cells of the tissue, but especially in their paracrine activity, i.e. the ability to secrete trophic and growth factors, cytokines and chemokines that have regenerative and anti inflammatory effects. Conditioned medium (CM) containing secretory products of stem cells can thus be used in cell-free therapy which represents an alternative to the cell-based therapy, with advantage of lower risks, the possibility of allogenic administration and mass production. Preclinical studies confirm that the therapeutic effect of CM is comparable to the effect of the application of stem cells. The aim of this paper is to summarize the results of studies using CM from different types of stem cells in regenerative medicine and simultaneously develop an overview of the factors that can modify cellular secretion and the composition of CM. PMID- 29489090 TI - Drug sensitization induced by prenatal methamphetamine exposure. AB - Women, who abuse drugs during pregnancy, expose not just themselves but also their developing fetus to impairing effects, which can have potentially harmful and even long-term effects on the exposed children. For some years, methamphetamine (MA) has dominated the illicit drug market in the Czech Republic and Slovakia; additionally this drug is on the rise worldwide. It is one of the most accessible drugs, and in many cases the first choice drug for many drug addicted pregnant women; in part due to its anorectic and stimulant effects. These women are rarely aware of the consequences of their behavior and their pregnancy is hardly ever a good enough reason for giving up drug use. These findings are supported by many experimental studies that show the damaging effects of maternal MA exposure on their offspring. There is growing evidence that exposure to MA in utero not only causes birth defects and delays in infant development, but also impairs the brain reward neural pathways of a developing offspring in such a way, that it could increase the predisposition for drug addiction later in life. Previously published animal studies have shown that offspring of mothers exposed to MA during pregnancy are more sensitive to MA when they encounter this drug later in adulthood. With respect to increased sensitivity, the term of sensitization has been introduced. It is defined as augmented psychomotor activity, which can be observed after drug re administration following discontinuation of repeated drug exposure, and has been demonstrated to develop not only after repeated drug administration in adulthood, but also after chronic prenatal exposure. Results from our studies have shown that prenatal MA exposure can influence the sensitivity to the effects of some drugs, given as a challenge, in adulthood, specifically to those with a similar action mechanism. Our findings indicate that cross-sensitization between prenatal MA exposure and adult drug treatment cannot be simply termed as a general drug addiction, since it seems that the mechanism by which a drug impairs specific neurotransmitter systems plays an important role. The study findings show that although the offspring of MA-addicted mothers have altered sensitivity to certain drugs in adulthood, they do not display increased active drug-seeking behavior. Therefore, if we extrapolate the results to humans, it appears that there is a relatively little risk that a person, whose mother abused MA during pregnancy, will actively seek out drugs. PMID- 29489091 TI - Metabolically healthy obese individuals -- mechanisms and clinical relevance. AB - Obesity is associated with an increased risk of premature death and represents a fast growing worldwide health problem. Although it has been long recognized that obesity is associated with an impaired insulin sensitivity, significantly increases the risk of developing type 2 diabetes, dyslipidemia, fatty liver disease, hypertension, cardiovascular disease and certain types of cancers, a subgroup of obese individuals called metabolic healthy obese seems to be protected from metabolic and cardiovascular obesity comorbidities. This article focuses on potential mechanisms underlying the healthy obese phenotype (protection against development of hepatic steatosis, inflammation of visceral adipose tissue, ectopic fat deposition and adipose tissue dysfunction) and on clinical relevance of this interesting subgroup of obese individuals. Additionally, definition, epidemiology and stability of healthy obese phenotype are discussed. PMID- 29489092 TI - In vitro skin models in the optimization of skin formulations. AB - BACKGROUND: Transdermal drug delivery is assumed to have a growing importance in drug development recently, thus it is crucial to optimize the penetration properties of drug into through the skin. Most of the current developments rely on the use of appropriate ex vivo animal or artificial models. However, the limited availability of human skin and the increasing restrictions in connection with animal testing encouraged the searchfor suitable artificial skin models. METHOD: For the review, we have searched the databases of scientific and medical research to collect the available publications about the in vitro skin models. Furthermore, we overviewed the methods of the DataBase service on ALternative Methods to animal experimentation (DB-ALM) database and the guidelines of Organisation for Economic Co-operation and Development (OECD). RESULTS: In vitro skin models have advantages like reproducibility, relatively low cost, easy storage, uncomplicated handling, and they offer a possibility for rapid screening and faster optimization of skin formulations. Furthermore, their composition can be easily modified which allows studying the relationship between certain pathological conditions and barrier function. However, the limitations of these models are needed to be taken into account. CONCLUSION: This review attempts to provide an overview of the most frequently used models, focusing on their limitations and advantages. Accessibility, easiness of the application, cost and the respective limitations have to be considered in order to choose the most appropriate in vitro model for the particular objective. PMID- 29489093 TI - [Measuring anxiety with behavior analysis software and comparing human observations with EthoVision XT in the elevated plus maze paradigm.] AB - INTRODUCTION: The reproduction of anxiety in laboratory animals is a renewing problem whenever a new drug is to be tested for its anxiolytic effect. Some gold standard tests, such as the elevated plus maze test, are always considered to be used as reference. However, many controversial results for different anxiolytics were reported in elevated plus maze test. The analysis methods used by different labs could be the source of variability of the results. Human observations were the most commonly used since the 90's, when behavior analysis software appeared. In each lab, specific procedures for reducing bias in ethopharmacological experiments were implemented, but the performance of human observers was rarely compared to software assisted analysis. METHODS: Four analysts and 24 trials were involved, each analyst having to do all the analyses during which they had to register eight parameters. All trials were also analyzed with the EthoVision XT (Noldus IT, Netherlands). RESULTS: Several crucial parameters of the elevated plus maze test were significantly different between the analysts (p<0.05). The results registered by human observers were summarized and compared to the results of automatic analysis, which showed significant difference in the case of closed arm entry and total distance (p<0.001). CONCLUSIONS: In this study, it was shown that despite all precautionary measures taken to reduce the variability and bias among observers the results were clearly different from those registered by behavior analysis software. As a conclusion, it can be stated that the behavior analysis methods need some kind of standardization in order to be comparable between labs, preferably the use of the same software and/or settings. PMID- 29489094 TI - [Polyphenolic compounds analysis and antioxidant activity in fruits of Prunus spinosa L.] AB - INTRODUCTION: Prunus spinosa L. (blackthorn, sloe) is a com- mon species in the wild flora of Europe. Marmalade, syrup, and alcoholic beverages have been prepared from fruits. In folk medicine they'are used due to the astringent effect. However there are few studies on these indigenous fruits. According to the literature they contain tannins, anthocyanins, sugars, vitamin C etc. METHODS: Our objective is to determine the antioxidant activity as related to their phenolic composition. For this purpose we prepared extracts using methanol, methanol-water (1: 1) and water. The antioxidant activity was determined by DPPH method and by photochemiluminescens (PCL) method. The total polyphenols, total anthocyanins and flavonoids were determined by colorimetric methods. Individual polyphenols were identified by a RP-HPLC-UVIVIS method. RESULTS: The antioxidant activity decreased in the extracts as follows: methanol > methanol-water > water (IC50= 1.33 mg/ml for DPPH; 11.94 MUmol AAEIml for PCL > IC50 = 1.87 mg/ml for DPPH; 10.35 MUmol AAElml for PCL > IC50 = 15.29 mg/ml for DPPH, 1.89 MUmol AAElml for PCL) which is cor- related with the total polyphenol content (369 mg/100g > 244 mg1100g > 101 mg1100g) and total anthocyanin content (37.11 mg/100 g > 16.33 mg/100g > 7.76 mg/100g). The fla- vonoid content is similar in the three extracts (between 35.82 - 37.32 mg1100 g). The HPLC analysis shows high chloro- genic and neochlorogenic acid levels, followed by glycosides of quercetin. CONCLUSIONS: Our results demonstrated that blackthorn fruits are a rich source of phenolic compounds, with anti- oxidant activity, which are best extracted with methanol or methanol-water. PMID- 29489095 TI - [Formulation possibilities of self-emulsifying drug deliv- ery systems, microemulsions and nanoemulsions.] AB - Objective The aim of this review is to introduce the self-emulsifying drug delivery systems which can be used to improved the bioavailability of poorly water soluble drug substances. Methods The review summarizes the most prominent results of the lipid based medicinal preparations, such as microemulsions and nanoemulsions developed in the last two decades. Results The analysis of the references details the lipid based formulation classification systems, the most common excipients, the quality attributes depending on the ingredients, as well as the differences in the characteristics of micro- and nanoemulsions. Conclusions The summary demonstrates the formulation possibilities of self emulsifying drug delivery systems, which may increase the applicability and are promising to improve the therapeutic effectiveness. PMID- 29489096 TI - [CLINICAL ASPECTS OF THE BLOOD LACTATE DYNAMICS DURING OPERATIONS ON THE HEART AND THE AORTA IN CONDITIONS OF CARDIOPULMONARY BYPASS.] AB - BACKGROUND: The frequency and the causes for the development of hyperlactatemia during operations on the heart and aorta in conditions of cardiopulmonary bypass (CB) is not adequately described in the literature. THE AIM: To study the clinical significance of the lactate dynamics in arterial blood depending on the source ofpathology, stages of operation, basic parameters of cardiopulmonary bypass, the characteristics of the post-perfusion period, and to identify ways to prevent the development of intraoperative hyperlactatemia in surgical interventions on the heart and aorta. MATERIALS AND METHODS: 420 adult cardiac surgery patients operated on the heart and ascending aorta were examined. All patients were operated on under balanced General anesthesia, CB in hypothermic or normothermic mode. Lactate level in arterial blood and the frequency of hyperlactatemia were analyzed at the following stages of operation: after induction of anesthesia, prebypass period, during CB, in the postbypass period and at the time of admission of the patient in the ICU. During CB we analyzed the duration of the CB, the degree of hemodilution, calculated value of oxygen delivery. Oxygen consumption was recorded in the current mode, the monitor CDI 500. Hyperlactatemia was considered the concentration of lactate above 3 mmol/L. RESULTS: Preperfusion period in all groups of cardiac surgery patients was characterized by a normal level of blood lactate in the absolute majority ofpatients, the frequency of hyperlactatemia did not exceed 1%. Hemodynamic stability was achieved without the use of catecholamines by optimizing volemia and heart rate. While CB showed a trend of increasing lactate on average in comparison with the previous period in patients operated on the heart. Duration CB less than 3 hours was not a factor in the development of hyperlactatemia, provided that oxygen delivery in all patients during perfusion exceeded 300 ml/min/m2, hematocrit ofperfusate at the end of CB was at 25-27% in most patients. To maintain it at a large hemodilution the ultrafiltration hemoconcentration was used. The frequency of hyperlactatemia was 3%. A significant increase in lactate concentration at the end of the CB to 3.39k1,3 mmol/l (range of 2.1-7.2 mmol/l) on the background of metabolic acidosis found only in patients with circulatory arrest due to receipt of blood products of anaerobic glycolysis after the resumption of the CB. They have frequency of hyperlactatemia risen to 29%. The lac- tate average value at admission ofpatients in the ICU with application of 50-60% ofpatients in dopamine/dobutrex at a dose of 5 mcg/kg/min and reaching the targets of transfusion therapy was slightly higher in the baseline period and corresponded to the upper level of normal values. Only during operations on the aortic arch under conditions of circulatory arrest, the concentration of lactate at the end of the operation was 3,4+1,1 mmol/l with a tendency to decrease in comparison with the period of the CB. From 88 to 93% patients during operations on the heart and ascending aorta without circulatory arrest and 64% ofpatients after operations on the aortic arch with circulatory arrest were admitted to the ICU with a normal lactate level in arterial blood Conclusion. The duration ofperfusion less than 3 hours in the conditions of these indicators preservation is not a risk factor for the development of hyperlactatemia. In postbypass period during operations on the heart and aorta without circulatory arrest about 90% ofpatients transferred to the intensive care unit (ICU) with normal values of lactate. During operations on the aortic arch with circulatory arrest about 60% ofpatients have normal levels of lactate at admission from the operating room to the ICU. PMID- 29489097 TI - [CONTINUOUS HEMOGLOBIN MONITORING USING PULSE CO-OXIMETRY IN CARDIAC SURGERY.] AB - THE AIM: To assess the accuracy ofcontinuous hemoglobin monitoring using pulse co oximetry and revealfactors affecting the results of the measurements during early postoperative period in cardiac surgery. MATERIALS AND METHODS: 27 patients undergoing off-pump CABG and 16patients after elective complex (repair or replacement of two or more valves) or combined (valve and coronary artery) cardiac surgery requiring CPB were enrolled into a prospective observational study. Both groups received continuous hemoglobin monitoring using pulse co oximetry (SpHb). During early postoperative period SpHb was compared with hemoglobin concentration in the arterial blood (Hbart). RESULTS: Wefoundpositive correlation between SpHb and Hb in both groups (rho =0,29, p < 0,05 u rho=0,34; p<0.005 respectively). The Bland-Altman analysis showed a bias ? limits of agreement (?I.96 SD) between the continuously measured hemoglobin and reference arterial blood hemoglobin concentration of -6,0 ? 41,0 g/l in the off-pump group and 7,7 k 31,0 g/l in the CPB group. CONCLUSIONS: Hemoglobin measurement using pulse co-oximetry does not provide acceptable accuracy during early postoperative period in cardiac surgery. Applicability of this technology is influenced by vascular tone, systemic and regional tissue hypoperfusion. PMID- 29489098 TI - [A COMPARISON OF TWO APPROACHES FOR INTRAOPERATIVE LEVOSIMENDAN ADMINISTRATION IN CARDIAC SURGICAL PATIENTS WITH SEVERE LEFT VENTRICLE DYSFUNCTION.] AB - BACKGROUND: It is proved that levosimendan administration improves overall outcome and reduces mortality in high risk cardiac patients. However up to now there is no optimal scheme of its use in intraoperative settings. THE AIM: To compare two approaches of levosimendan administration in patients with left ventricle ejectionfraction less than 35% who underwent cardiac surgery. MATERIALS AND METHODS: After approval by the local ethics Committee, 40 patients older than 18 years with severe preoperative left ventricular dysfunction (left ventricle ejection fraction less than 35%), who were planned for cardiac surgery operation with cardiopulmonary bypass and cardioplegia were randomly assigned to two groups of 20 patients each. In group I (n=20) infusion of levosimendan started intraoperatively after induction of anesthesia, a loading dose of 6 mg/kg with subsequent injection of a dose of 0.1 MUg/kg/minfor 24 hours. In group 2 (n=20) bolus of levosimendan 24 MUg/kg was injected 15 min before aortic clamping. Anesthesia and methods of cardiopulmonary bypass in the groups did not differ Results. We got thefavorable clinical results in a group of 'full" levosimendan dose (12.5 mg as a daily infusion with an, initial bolus of 6 mg/kg just after the induction of anesthesia) in terms ofreduction of the total dose ofsympathomimetics andpostoperative troponin T level in comparison with the group where levosimendan was administered as a single bolus. (24 mg/kg) 15 minutes prior to aortic clamping. CONCLUSION: Based on these data it can be assumed that the use of prolonged infusion of levosimendan in a dosage of 12.5 mg is preferable to a single bolus 24 MUg/kg. PMID- 29489099 TI - [CLINICAL SIGNIFICANCE OF CARDIAC BIOMARKERS INCREASING AND THEIR INTERRELATIONS IN SURGERY WITH CARDIO-PULMONARY BYPASS.] AB - BACKGROUND: Levelfor cardiac troponin I (TrI) and MB-fraction of creatine kinase (CKMB) increases in cardiomyocyte necrosis, and B-type natriuretic peptide (of BNP) increasing reflects ventricular overload. THE AIM: to study the dynamics of BNP, TRI and CKMV in myocardial revascularisation with cardio-pulmonary bypass and to evaluate the clinical significance of these biomarkers elevated levels and establishing the relationship between BNP and markers of myocardial damage in the perioperative period Materials and methods. The study included 52 patients aged 62.5 (54.75; 70) years. Biomarkers concentrations was determined by immunofluorescence. RESULTS: The initial value of BNP were 57.9 (38.675;88.5) pg/ml, and then increased (p<0,01): at the end of the operation up to 91.75 (59.6;132.75) pg/ml, at 1st day following surgery - up to 260 (157;407) pg/ml, and at 2nd day - up to 184 (115.25;274.5) pg/ml. TrI and CKMV increased (p<0,01) up to 0.95 (0.4175;1.4525) ng/ml and up to 13.1 (5.575;15.525) U/L at the end of surgery, and up to 1,355 (0.76;3.8) ng/ml and 10.5 (5;18.325) U/L at thr Istpostoperative day. Preoperative BNP level and TrI level at the end of surgery were the predictors (p 0.05). CONCLUSIONS: Combined spinal-paravertebral block for total hip arthroplasty is an effective and safe method of pain relief. PMID- 29489104 TI - [POSTRESUSCITATION CICATRICIAL TRACHEAL STENOSIS. CURRENT STATE OF THE PROBLEM - THE SUCCESSES, THE HOPES AND DISAPPOINTMENTS.] AB - BACKGROUND: Currently, the trend continues to increase the number ofpatients with cicatricial tracheal stenosis (CTS). Therefore, prevention and treatment ofthis disease remains topical. The main cause ofcicatricial tracheal stenosis is damaging the trachea during mechanical ventilation. The scheme ofprevention of this disease in Russia hasn't brought the desired results. THE AIM: to clarify the modern etiology of cicatricial tracheal stenosis, to identify the trend in incidence rates, to determine whether there is an optimal safe alternative to tracheostomy including the use of minimally invasive techniques, to improve diagnostic and therapeutic algorithm at various stages of assistance, and also to study the results of innovative operations and new ways of maintaining gas exchange. MATERIALS AND METHODS: 1128 patients with cicatricial tracheal stenosis was treated from 1963 to 2015 in Petrovsky National Research Centre of Surgery and IMSechenov First Moscow State Medical University. Over time methods of di- agnosis, methods of anesthesia and operations have been varied. In this regard all patients were divided into two groups depending on the period of time from 1963 to 2000 (297 patients) andfrom 2001 to 2015 (831 patients). In recent decades there is a steady increase in the number of treated patients. So, if in the first group during the year operational treatment about the CTS 8,0 patients were underwent, in the second - to 55.4. Cicatricial tracheal stenosis appeared after lung mechanical ventilation at 1025 (for 90.9%) patients. They have undergone both radical one-stage treatment and multi-stage and sequential intraluminal procedures. In general there is a clear trend towards more aggressive surgical tactics. So, if in thefirst group, the tracheal resection with anastomosis was performedin 59 patients only, the second-330. Thefrequency ofpostoperative complications and mortality in the second group ofpatients was 12.9 and 0.7 %, respectively. RESULTS: Only a reasonable combination of all treatment methods, the principle of "every patient his own version of operation" allows to minimize the risk oftreatment and to get a good lasting result. Proof of such provision may be the fact that the frequency of complications and postoperative mortality at our patients have had a tendency to decrease and currently stands at 12.9 and 0.7 %, respectively for many years. It is 2.3 and 9.6 times less, respectively, than in the periodfrom 1963 to 2000. It appears that further reduction of these indicators will be at a slower pace, afurther solution of the CTS problem will be based on the prevention of disease. CONCLUSION: Prevention of cicatricial tracheal stenosis in the departments of reanimation and intensive care is currently inadequate. It requires fundamentally new approaches, but reform still has not brought the desired results. Diagnosis of the CTS at an early stage allows early treatment and to avoid complex and risky operations. Increasingly important, apart tracheoscopy for diagnosis of tracheomalacia purchase dynamic computed tomography and magnetic resonance - tomography. Treatment ofpatients with CTS requires a multidisciplinary approach, individual selection operations for a particular patient. The general trend of the further development of tracheal surgery is associated with an increase in the number of simultaneous resections, including at the long, two-level stenosis, as well as at relapse. The patients who had refused treatment or have elected him palliative options made possible surgery. The frequency of postoperative comnlications and mortality decreased significantiv, including after extensive and traumatic operations on the trachea. PMID- 29489105 TI - [INDICATIONS FOR RESPIRATORY SUPPORT AT PATIENTS WITH STROKE AND NOSOCOMIAL PNEUMONIA.] AB - 80 patients with cerebral stroke and nosocomial pneumonia ofwhich formed 2 groups of 40 patients each were included in the study. The groups were matched for severity at the beginning of the study. All patients received comprehensive treatment in the conditions of the neurological intensive care unit in 2011-2015 in the O.M Filatov clinical city hospital N2 15, Moscow. Patients from both groups were transferred on mechanical lung ventilation: group I - in the presence of severe clinical picture of respiratory distress and/or depression of consciousness, and group 2 -with deviations from the norm of acid-base status of blood parameters. The results of the study shows the first clinical and laboratory criteria for the transfer patients on mechanical lung ventilation, which are the changes of indicators in blood acid-base status (pH, lactate, glucose, pCO2, po2) and the degree of neurological deficit, not the clinical picture in the form of severe respiratory failure in patients with cerebral stroke. PMID- 29489106 TI - [USING A VISUAL ANALOGUE SCALE FOR ASSESSING THE SEVERITY OF PAIN SYNDROME AFTER CESAREAN SECTION, DEPENDING ON THE METHOD OF ANESTHESIA.] AB - THE AIM: To compare efficiency of various techniques of anesthesia after Cesarean section on degree ofpain expression in randomized clinical trial. MATERIALS AND METHODS: 120 puerperas aged from 21 till 33 years who were undergone to Caesarean section were studied. Patients were divided into four equal groups by number of observations. In groups 1st and 2nd patients were performed local anesthesia with continuous and bolus anesthetic. In group 3rd were performed bilateral blockade of the cross-space belly. In the 4th groups was used multimodal analgesia system. Each patient during the postoperative period was estimated the severity ofpain on a visual analog scale at rest and movement at 3, 6, 12, 24 and 48 hours. RESULTS: Intensity ofpain after surgery in patients of all groups decreased and reached lows of 48 hours after a Cesarean section. At the same time the 2nd group ofpatients (6,1 ? 1,4) had pain significantly less than that ofpuerperas from the 3rd and the 4th groups (13,2 J 2,4 and 18,0 ? 2,7). Meanwhile, indices offemale patients pain severity from the 1st and 2nd groups of the study were not statistically different. When studying distribution ofpatients on degree ofpostoperative pain it is established that atpuerperas of the 1st and 2nd group pains prevailed weak (47% and 67%) and moderately expressed (50% and 33%). In the 3rd group expression of a pain syndrome in all cases was moderate. In the fourth group the pain syndrome was considerably more expressed (the moderated - 53%; the strong - 4 7%). CONCLUSION: Pain syndrome after Cesarean section using the localanalgesia with continuous or bolus is reduced by 28-35%, which was significantly more than the blockade of the cross-space stomach and systemic analgesia. PMID- 29489107 TI - [PRACTICE OF CLINICAL NUTRITION IN PEDIATRIC INTENSIVE CARE UNITS: RESULTS OF THE "NUTRIPED-2015" RESEARCH.] AB - The secondstudy of nutritional support in the pediatric intensive care unit in critical conditions in Russia "NutriPed-2015" were presented. The authors noted that modern clinical nutrition technologies were widely used among 167 critical patients aged 0 to 18 years in 31 PICU in Russia. The number ofpatients receiving all components of the preparations for parenteral nutrition has increased significantly in comparison with the study NutriPed-2013. There were the wider use of last generation lipids for parenteral nutrition, multi-chamber containers in children older than 2 years were used in 2 times more often, the vast number ofpatients was carried out calculation of energy needs in the present time. The main problems for solve are the individual methods ofcalculating energy andprotein needs, resolution dysfunction ofthe gastrointestinal tract, the active introduction of assessing the effectiveness of nutritional support in the PICU. PMID- 29489108 TI - [SUPPORT LUNG VENTILATION IN COMPLEX OF ANESTETIC MANAGEMENT DURING HIGH TRAUMATIC OPERATIONS IN VASCULAR SURGERY.] AB - BACKGROUND: Rejection from prolonged mechanical ventilation with conversion to support ventilation modes during the surgery and subsequent immediate extubation at the end of the surgery could be the method ofprophylaxis ofpostoperative respiratory complications. THE AIM: To improve the results of surgical treatment of patients with infrarenal aorta injury due to the development and implementation to the anesthetic management complex the modes of support ventilation. MATERIALS AND METHODS: 2-staged clinical trial on patients undergoing surgery on infrarenal aorta was conducted. At the 1st stage patients were assessed for opportunity of immediate or early extubation and support ventilation initiation. At the 2nd stage support modes during the intraoperative ventilation were introducted into clinical praxis. RESULTS: Based on received data we concluded that not everyone patient needed intra- and postoperative mechanical ventilation in spite ofprolonged duration of the surgery and large surgical trauma. Inclusion in the protocol of anesthesia support ventilation strategy decreases requirement ofparalytic agents and their side effects. CONCLUSION: Applying the support ventilation modes during the anesthesia gives a chance of immediate and early extubation after the surgery and decreases the number of critical events and respiratory complications. PMID- 29489109 TI - [MODERN ASPECTS OF THE SAFE USE OF EXTENSION QT INTERVAL MEDICINES.] AB - Prolongation of QTinterval is apredictor offatal cardiac arrhythmias and sudden death. In clinical practice, medicines with possible and conditional risk of QTprolongation are combine. The danger of such interactions could be enhanced if medi- cines interact themselves at metabolic rate. The interaction of drugs with possible and conditional risk of QTprolongation and interaction of these drugs with drugs that can influence the metabolic activity of cytochrome P450 isoenzymes require specific attention from physicians. Predictability of QTprolongation by drug-drug interactions at metabolic rate in drug administration will increase the safety of pharmacotherapy of drugs with possible and conditional risk of QTprolongation. PMID- 29489110 TI - [REVIEW OF THE CURRENT METHODS OF RESPIRATORY SUPPORT FOR TRACHEAL SURGERY.] AB - Currently, surgery on the trachea underwent significant progress including in the latest methods of complex resections and reconstructions of the respiratory tract. In this regard, anesthesiologist needs the knowledge and skills of using various special respiratory techniques. Modern respiratory methods in tracheal surgery are "shunt-breath", high frequency jet ventilation, methods of extracorporeal oxygenation and respiratory relatively new technology - apneic oxygenation. This review deals with the pathophysiologicalfeatures of each of these techniques. Searching for information was made on the database: Scientific electronic library, Central Scientific Medical Library, PubMed, Scopus and Web of Science. PMID- 29489111 TI - [THE ROLE PLEIOTROPIC EFFECTS OF CALCIUM CHANNEL BLOCKER LERCANIDIPINE IN PERIOPERATIVE THERAPY OF ARTERIAL HYPERTENSION.] AB - This review presents the data of assessing antihypertensive efficacy and tolerability vasoselective high-lipophilic the 3d generations calcium channel blocker lercanidpine. The inhibition of the calcium ions flow through the membranes of smooth muscle cells of blood vessels causes peripheral, cerebral, renal and coronary vasodilation decreasing total peripheral vascular resistance and, consequently, blood pressure (BP) lowering and improve regional circulation. During reception of lercanidipine the level of norepinephrine remains the same even when using high doses of the drug. Negative inotropic effect does not occur therefore, lercanidipine can be used in the treatment of myocardial ischemia. Renal protection properties slow down the development and progression ofchronic renalfailure (CRF). The drug can be successfully used in patients with arterial hypertension, chronic renalfailure, diabetic and non-diabetic nephropathy. Lercanidpine also may be effectively used in the treatment of hypertension with associated clinical conditions: bronchial asthma, chronic obstructive pulmonary disease, bradiarrythmias, atrioventricular blockade 2-3 degree, sinus node dysfunction, peripheral arteries deseases with symptoms of the extremities ischemia, sleep disturbance, depression, dystonia, asthenic and cephalgic syndme in the frame of the cerebrovascular insufficiency manifestations. Therapy with lercanidpine, in addition to lowering blood pressure, can help to nephroprotection, neuroprotection, antianginal effect, the regression of left ventricular hypertrophy, improvement of lipid metabolism and glucose tolerance. With over 30 years experience in the application and modification of the molecular structure, slow the onset of action and superior long-lasting effect reception of letranidipine well-tolerated and provides a high adherence ofpatients to the treatment of hypertension. PMID- 29489112 TI - [In process.] PMID- 29489113 TI - [In process.] AB - Internationally, Helmut RENNERT (1920-1994) was one of the most renowned representatives of psychiatry in the GDR. From 1958 until 1984 he was the chair of the department of psychiatry and neurology at the Martin Luther University in Halle-Wittenberg. He was also the chairman of the Association for Neurology and Psychiatry of the GDR for many years. The textbook on neurology and psychiatry which he prepared together with Rudolf LEMKE (1906-1957) turned into the standard textbook for training and education in the GDR. RENNERT became well known primarily with his model of the universal genesis of endogenous psychoses in which he propagated the idea of unitary psychosis. In 1965 he became a member of the German National Academy of Sciences Leopoldina and as vice- president he represented the medical section. RENNERT belonged to the so-called second generation of professors which established itself at the end of the 1950s at university clinics in the GDR. As the leading experts and academic lecturers they influenced the field with respect to education and research for the entire time the GDR existed. This generation of professors maintained a strong bond with their academic teachers and continued their tradition in the sense of a "school" for the most part independent of political circumstances and restrictions. PMID- 29489114 TI - [In process.] AB - Whoever turns to the history of photosynthesis research in the twentieth century is soon confronted with the fact that one of its most exciting periods, the years from 1938 to 1955 (and even beyond), was in large part overshadowed by a bitter controversy in which many of the leading scientists in the field were involved: the dispute on the minimal quantum requirement - or, its inverse: the maximum quantum yield - of photosynthesis. On the one side was Otto H. WARBURG (1883 1970), who, in 1923, had found that 4-5 light quanta were required for one molecule of oxygen; and who would never accept any other value. On the other side were a number of highly renowned American photosynthesis researchers, among others Robert EMERSON (1903-1959), James FRANCK (1882-1964) and Hans GAFFRON (1902-1979), who contested this value and argued, instead, that 8-12 light quanta were required for one molecule oxygen. This value is still accepted today. In this paper, the course of the controversy is reconstructed on the basis of numerous documents and correspondences that so far have not received much attention. The historically contingent factors will be analyzed that made this controversy so atrocious; however, I will argue that the dispute was not primarily about reputation and glory but in large parts driven by the keen interest of the scientific community to solve a difficult research question - notwiith standing the fact that WARBURG failed to comply with scientific conventions of methodical transparency and mutual. PMID- 29489115 TI - [In process.] AB - The story, which unfolds here, is a cultural history of science, one that closely analyzes the content of science. My story deals with an object, a gene. I use the CCR5 gene as a heuristic tool in order to probe the boundaries between science and society. Three important themes are discussed in this essay: genes as commodities (intellectual property and gene patents); alleles, natural selection, and the resistance to disease; and race and genomics. This is in part a story about neoliberalism, laissez-faire goverenments, free and open markets, the increase of privatization, and biotechnology. Many claim that the United States Patent and Trademake Office's (henceforth, USPTO) leniency in granting gene patenting led to the growth of biotechnology. I maintain the opposite: the growth of biotechnology led to decision to patent genes. My story is one of the present, a genealogy to borrow FOUCAULT'S and NIETZsCHE's terminology. How has it come about that genes are patentable entities, and that human classificatory schemes are usually based on race, although there are an infinite number of possibilities to characterize human variation? There are always alternatives, and historians are obliged to present those alternatives and explain why they were never chosen. I also use the concept of genealogy in the classical biological sense, i.e. to trace the passing of alleles from one generation to another. While this essay is similar to earlier studies dealing with the biography of objects, particularly scientific objects, the history told here is not a biography of the CCR5 gene, as that story is still ongoing. Rather, this essay concentrates upon a twenty-year period of the gene's life from the mid-1990s to the present. I am interested in understanding how it is we have reached the point we have today with respect to the relationship between science and society, and I use the CCR5 gene as a vehicle for that analysis. PMID- 29489116 TI - [In process.] AB - The programme of the Academia Naturae Curiosorum (today the German Academy of the Sciences Leopoldina) was considerably revised less than twenty years after its creation, in 1652. At the heart of this reform lay the Miscellanea curiosa, the journal that ,,the Curiosi" now started publishing. The ,,epistemic genre" (Gianna PoMATA) they chose for the articles in the Miscellanea curiosa was the observatio. Writing an observatio implied singling out a nugget of experience and documenting it in writing. In the first half-century of its existence, rare things of nature figured prominently in the Miscellanea curiosa. Physicians from all over Europe sent in a seemingly endless stream of reports on monsters. This was increasingly considered as problematic by leading members and functionaries of the academy. Their reluctance to accept ever more observationes on monsters for publication in the Miscellanea curiosa can in part be accounted for by reference to the rarity paradox: preternatural phenomena, by definition rare, seemed to be almost ubiquitous in the naturalist discourse of the period. Furthermore, many of the manuscripts on monsters sent in for publication did not live up to expectations. Even more worrisome, the Curiosi could not but note that monsters were still often interpreted as prodigies bearing divine messages. They had the potential to cause unrest and disorder among the populace and therefore had to be handled with particular care. PMID- 29489117 TI - Facial Transplants: What are Authentic Faces? AB - Do our faces reflect who we are? Or do they display the person we would like to be? Or even the person our society would like us to be? What is the difference between "enhancement" and "reconstruction", between "improving" facial features and restoring them? To what extent is the definition of these terms determined by cultural assumptions, particularly when it comes to what makes our appearance "authentic"? This article critically investigates the frequently circulating opinion that face transplants serve to reconstruct, while cosmetic surgery "improves" our appearance according to our wishes. The historical case study presented here begins with the history of nose operations in Berlin in the 19" century and ends with the practice of face transplants in the 21st century. PMID- 29489118 TI - [In process.] AB - Missionary pharmacy developed as a special type of the European pharmacy from the 16th to the 18th centuries in the overseas missions in the context of the proclamation of the Christian faith, the European expansion and the beginning globalization. As this type of pharmacy was determined by the specific circumstances of the medical-pharmaceutical situation in the mission countries as well as by the knowledge of the missionaries themselves, it can be defined as missionary pharmacy. It followed principally the model of the medieval monastery pharmacy and paved the way for the Medical Mission at the beginning of the 19th century. Different lines of development on various levels of exchange, forming, documenting and transmission of knowledge shaped the concept of the missionary pharmacy. The activities in the context of the missionary pharmacy initiated a global transfer of drugs and the referring pharmaceutical knowledge, which was institutionalized by the pharmacies of the Jesuits and essentially influenced the development of the Materiae medicae and the development of modern pharmacy all around the globe. The trading routes of typical drugs like the Fever bark and compositions can reconstruct this international transfer of knowledge. Still nowadays, knowledge of the missionary pharmacy, especially about genuine plants of the non-European countries, can be interesting for the development of new phytotherapeutics and possibly active substances. PMID- 29489119 TI - [In process.] AB - The essay presents a critical analysis of KUHN's theory of the historical development of the sciences and of scientific revolutions from the perspective of the historiography of science. It focusses on KUHNS'S concept of structure, his intemalistic model of scientific change in history as well as his assumptions about the duration of scientific revolutions and the relation between continuity and discontinuity. PMID- 29489120 TI - [In process.] AB - The "Akademie der Naturforscher" (Academy of Natural Scientists) was founded in 1652; in 1687 Emperor LEOPOLD 1. raised it in the rank of an imperial academy (Sacri Romani Imperii Academia Caesareo-Leopoldina Naturae Curiosorum). The president and the editor of the academic periodical (Director Ephemeridum) got the same privileges as imperial physicians. Based on this the duties of the physicians and their status within the court hierarchy are explained. During the reign of LEOPOLD I there were 61 persons who worked as physicians at court. The prosopographical analysis shows their distribution to the households of the members of the imperial family. Other aspects are their origin, their education and their relationship to the University of Vienna. Finally we learn about the imperial physicians as members of the Academy and as mediators between the Academy and the court. PMID- 29489121 TI - [In process.] AB - Two of the most important life scientists in the GDR were the botanist, plant biochemist and pharmacist Kurt MOTHES (1900-1983) and the geneticist and plant breeder Hans STUBBE (1902-1989). Both started their successful careers during the period of NS dictatorship. MOTHES was a full professor of botany at the University of K6nigsberg from 1935 to 1945. After working at the Kaiser Wilhelm Institute for Plant Breeding Research in Mincheberg and at the Kaiser Wilhelm Institute for Biology in Berlin-Dahlem, STUBBE oversaw the establishment of a Kaiser Wilhelm Institute for Crop Plant Research near Vienna in 1943, which was moved to Stecklenberg in the Harz Mountains in 1945 and later to Gatersleben. While MOTHEs was being held as a Soviet prisoner of war from 1945 to 1949, STUBBE was able to set up his institute in Gatersleben in the eastern part of Germany and held influential positions at Martin Luther University in Halle (Saale) as a professor for genetics and as the founding dean of the Faculty of Agriculture. After his release from war captivity, MOTHES, with STUBBE'S support, was able to continue his research at STUBBE'S institute in Gatersleben as the head of the Department for Chemical Physiology. There MOTHES was offered espe- cially favourable conditions by East German standards which led him to turn down other job offers, like the position of professor of botany at the University of Leipzig which was vacant at the time. In addition, MOTHES was also of- fered teaching opportunities in the Faculty of Natural Sciences at the University of Halle, again thanks to STUBBE'S support. In 1951 STUBBE became a founding member and president of the German Academy of Agricultural Sciences at Berlin, and in 1954 MOTHEs became president of the German Academy of Sciences Leopoldina. Both were also influential members of the German Academy of Sciences at Berlin (later the GDR's Academy of Sciences). This article investigates how their collaboration developed into an ever-increasing competitiveness which came to a head as an embroiled dispute resulting from differences in scientific and scientific policy views. In the process a battle was fought over research resources so that, what was at first an apparently personal quarrel, affected the course of research promotion at an institutional level in the area of life sciences in the GDR. Despite several attempts at mediation, old age finally forced the adversaries to put aside their differences. PMID- 29489122 TI - [In process.] AB - The children from families of officers of the "Soviet forces temporarily stationed in the territory of the GDR" were treated on an in- and out-patient basis in East German paediatric clinics from 1945 to 1994. Since paediatric wards were not a regular component of military hospitals, newborns, infants and toddlers who became ill were sent to regional paediatric clinics for "special treatment" or in cases of emergency. This exception, regulated by law between the USSR and the GDR, required the approval of the garrison commander or the military doctor, though, in practice, this was circumvented. Linguistic problems could be resolved and no special rate of morbidity was observed in Russian children. Financing was arranged through contracts that had to be intricately negotiated when the Soviet troops were withdrawn after the German Reunification. Despite the heavily charged relationship historically between the inhabitants of East Germany and the occupying power imposed upon them, Russian children received good treatment and were tenderly cared for in the hospitals. Russian mothers impressively placed their unwavering trust in the nurses and physicians. PMID- 29489123 TI - [Not Available.] AB - In the center stage of this third and last part of the author's treatise about the life and the oeuvre of the German humanist, biochemist, and Nobel Prize Winner Otto MEYERHOF (1884-1951) is the first half of his life. As a young man, in the age of 16 and after a severe renal disease, Otto MEYERHOF spent 1900/1901 five months in Egypt, where he, led by his cousin Max MEYERHOF, Egyptologist and Ophthalmologist, studied the country and its people as well as its architecture and history. During his medical courses he became acquainted with the philosopher Leonard NELSON, who stimulated him to study the Kantian-Friesian philosophy, about which he published several papers. Simultaneously MEYERHOF became seriously interested in GOETHE'S method of natural investigation. About this topic he gave two famous lectures, 1909 in Berlin and 1949 in his American exile in New York. From 1903 MEYERHOF attended medical courses and conducted advanced training courses for workers at the University of Berlin. 1907 in the Heidelberg philosophical circle MEYERHOF became acquainted with Otto WARBURG. 1909 MEYERHOF earned a doctorate in medicine with the thesis "Contributions to a psychological theory of mental disorders". In the years 1911/12 a deep change occurred in MEYERHOF'S scientific career, in the course of which he turned to active experimental research in natural science. However, MEYERHOF remained true to philosophy and his friendship to Leonard NELSON. When Otto MEYERHOF in 1911 obtained a Badian scholarship for experimental research work in the Zoological Station in Naples, a tight collaboration with Otto WARBURG in sea urchin egg biology began. In 1912 MEYERHOF published a famous paper on "The energetics of cellular processes", which became the guideline for his prospective scientific work. In the same year he habilitated at the Medical School of the Kiel University with an enzymological study, and he joined the Physiological Institute of Kiel as unpaid private lecturer. Because of a severe chronic renal disease, which burdened himself from childhood, he became exempted from military service. In the years after 1917 he published several papers on fermentation, glycolysis, and respiration of animal cells and yeast and started after 1918 an extensive experimental project on "Muscle Metabolism and Mechanical Work". In this study he brought together different aspects of muscle metabolism and muscle activity: aerobiosis and anaerobiosis, muscular work, muscular exhaustion, and muscular recovery with glycogen degradation, glycogen synthesis as well as lactic acid formation and lactic acid utilization with muscular oxygen uptake. With this comprehensive experimental approach MEYERHOF in only few years built up a grandiose work about the correlations between muscle metabolism and muscular work. For this brilliant research Otto MEYERHOF and his British colleague Sir Archibald Vivian HILL received the Nobel Prize 1922 for Physiology or Medicine. The two investigators received the honor for their discoveries in the coordination of muscular performance with chemical, physical and thermodynamic processes, MEYERHOF "for his discovery of the fixed relationship between oxygen consumption and lactic acid metabolism in muscle" and HILL "for his research into the quantitative relations between heat production and muscular work". As explicated in the two preceding papers of the author Otto MEYERHOF and his first and longest collaborator Karl LOHMANN from 1925 till 1938 clarified chemically most of the intermediates and enzymatic reactions of the glycolytic pathway, also named Embden-Meyerhof-Pamas-pathway. Because of the antijewish pogrome in Germany MEYERHOF escaped 1938 from Heidelberg and accepted a French offer to continue his research in Paris. But after the German troops occupied France MEYERHOF again had to flee. He, his wife and their youngest son Walter breached through France, Spain to Portugal. From Lisbon he arrived by ship USA. PMID- 29489124 TI - ? PMID- 29489125 TI - [2018 new recommendations for dyslipidemia : a critical review of evidence]. AB - Dyslipidemia is an important cardiovascular risk factor. Its management should be individualized according to cardiovascular risk, which can be estimated using PROCAM score, taking into account patients' comorbidities. Cardiovascular risk is classified as low, moderated or high. The Swiss Atherosclerosis Association (AGLA) recently published new recommendations that we are describing taking into account evidence of recent studies, in order to avoid overmedicalisation. Lifestyle interventions should always be implemented and are the main therapy for most patients in primary prevention. A secondary etiology should be excluded, as its treatment can often normalize the lipid disturbance. Familial dyslipidemia should be looked for, as it is associated with a particularly high cardiovascular risk, and because of its specific management. PMID- 29489126 TI - [Statin-associated muscle symptoms : Current management in 2018]. AB - Statins are the first line treatment in hyperlipidemia, either in primary or secondary prevention of cardiovascular diseases. One of the most prescribed drug class worldwide, this drug class is often the focus of highly publicized drug controversies. Various adverse effects have been attributed to statins, in particular statin-associated muscle symptoms (SAMS). This condition varies in severity (from frequent isolated myalgia to rare severe myositis, even rhabdomyolysis) and often leads to treatment termination. Because SAMS are a daily challenge in clinical practice, we review here the recent medical literature on this topic and suggest a management strategy to be shared with the patient as an active partner. PMID- 29489128 TI - [Screening for atherosclerosis to prevent cardiovascular risk : a pro-contra debate]. AB - Detecting atherosclerosis using imaging techniques is the subject of intense debate in the scientific community. Among the arguments in favor of screening, a better identification or better stratification of cardiovascular risk is mentioned, compared to cardiovascular risk scores based solely on traditional risk factors, such as blood pressure or cholesterol levels. Imaging techniques are also used to monitor the progression of atherosclerosis among patients using lipid-lowering or antihypertensive drugs in primary prevention. However, several experts in recent years have challenged the clinical utility of these imaging techniques in asymptomatic adults. This article proposes a debate " for or against " to describe the main arguments for or against the use of imaging for screening for atherosclerosis. PMID- 29489127 TI - [Subclinical hypothyroidism : should we still treat elderly patients? Clinical implications of a new trial in primary care]. AB - Subclinical hypothyroidism, defined as an elevated level of thyrotropin hormone (TSH) and normal thyroxin, is more frequent in women and above 65 years old. This condition is associated with an increased cardiovascular risk, in particular with TSH > 10,0 mIU/L. Although overt hypothyroidism is rare (prevalence of 0,3 %), levothyroxine has become the most prescribed medication in the US, while its indications are still debated. The European-funded TRUST trial showed no improvement in Hypothyroid Symptoms and Tiredness scores among patients >= 65 years with subclinical hypothyroidism treated with levothyroxine, and no improvement in blood pressure, weight, muscle strength and cognition. The results of this study call for a revision of the current international recommendations on the treatment of subclinical hypothyroidism. PMID- 29489129 TI - [Current update on PCKS9 inhibitors]. AB - PCSK9 (proprotein convertase subtilisin kexin 9) monoclonal antibodies (mAb) are new therapeutic agents to lower efficiently LDL-cholesterol levels. New data from large clinical trials suggest that the addition of PCSK9 mAb to statins can reduce the incidence of major adverse cardiovascular events in very high risk patients. Alirocumab and evolocumab are two agents available in Switzerland with specific limitations for reimbursement. PCSK9 mAb should be considered in patients with clinical atherosclerotic cardiovascular disease (ASCVD), as well as in patients with familial hypercholesterolemia without ASCVD who have substantially high LDL-cholesterol levels despite the use of statin at maximally tolerated dose with or without ezetimibe, or intolerance to appropriate doses of several statins. PMID- 29489131 TI - ? PMID- 29489130 TI - [Strategies for cardiovascular disease prevention]. AB - Atherosclerosis is a disease which develops very gradually over decades. Under the influence of modifiable cardiovascular risk factors, such as blood pressure, LDL-cholesterol level, smoking or lifestyle, clinical symptoms of atherosclerosis manifest more or less early in life. When cardiovascular risk factors accumulate, the risk of having a cardiovascular event increases and the benefits of prevention measures are greater. This article summarizes existing strategies for controlling modifiable cardiovascular risk factors in primary prevention. The physician can rely on an interprofessional network of cardiovascular prevention. Managing risk factors while respecting the autonomy and priorities of the patient will bring the greatest benefit. PMID- 29489132 TI - ? PMID- 29489133 TI - ? PMID- 29489134 TI - ? PMID- 29489136 TI - ? PMID- 29489135 TI - ? PMID- 29489137 TI - Health care systems find that smaller hospitals meet the mission. PMID- 29489138 TI - Energy-efficiency success measured in millions saved. PMID- 29489139 TI - ES award winner says work, attitude come from the heart. PMID- 29489140 TI - Children's hospital builds bonds with student training. PMID- 29489217 TI - Establishing a hospital security plan that works. PMID- 29489300 TI - Backup power system serves up solution. PMID- 29489301 TI - Comfort Zones. Palliative and hospice care designs create calming environments that put patients and families first. PMID- 29489302 TI - Case 31-2017: A 19-Month-Old Girl with Failure to Thrive. PMID- 29489303 TI - Case 31-2017: A 19-Month-Old Girl with Failure to Thrive. PMID- 29489304 TI - Making the CASE. Modular furnishings provide long-term savings by adjusting to changes and growth. PMID- 29489305 TI - WALL SYSTEMS BUILT TO MOVE. Prefabricated solutions help to improve flexibility, infection prevention and patient privacy. PMID- 29489306 TI - Emergency department management of smoke inhalation injury in adults. AB - Smoke inhalation injury portends increased morbidity and mortality in fire exposed patients. Upper airway thermal burns, inflammation from lower airway irritants, and systemic effects of carbon monoxide and cyanide can contribute to injury. A standardized diagnostic protocol for inhalation injury is lacking, and management remains mostly supportive. Clinicians should maintain a high index of suspicion for concomitant traumatic injuries. Diagnosis is mostly clinical, aided by bronchoscopy and other supplementary tests. Treatment includes airway and respiratory support, lung protective ventilation, 100% oxygen or hyperbaric oxygen therapy for carbon monoxide poisoning, and hydroxocobalamin for cyanide toxicity. Due to its progressive nature, many patients with smoke inhalation injury warrant close monitoring for development of airway compromise. PMID- 29489307 TI - Emergency department management of smoke inhalation injury in adults [digest]. AB - Smoke inhalation injury portends increased morbidity and mortality in fire exposed patients. Upper airway thermal burns, inflammation from lower airway irritants, and systemic effects of carbon monoxide and cyanide can contribute to injury. A standardized diagnostic protocol for inhalation injury is lacking, and management remains mostly supportive. Clinicians should maintain a high index of suspicion for concomitant traumatic injuries. Diagnosis is mostly clinical, aided by bronchoscopy and other supplementary tests. Treatment includes airway and respiratory support, lung protective ventilation, 100% oxygen or hyperbaric oxygen therapy for carbon monoxide poisoning, and hydroxocobalamin for cyanide toxicity. Due to its progressive nature, many patients with smoke inhalation injury warrant close monitoring for development of airway compromise. [Points & Pearls is a digest of Emergency Medicine Practice.]. PMID- 29489308 TI - Calculated decisions: Abbreviated Injury Score (AIS) for inhalation injury PMID- 29489309 TI - Calculated decisions: RADS (Radiologist's Score) for smoke inhalation injury PMID- 29489321 TI - Electrostatic Functionalization and Passivation of Water-Exfoliated Few-Layer Black Phosphorus by Poly Dimethyldiallyl Ammonium Chloride and Its Ultrafast Laser Application. AB - Few-layer black phosphorus (BP) which exhibits excellent optical and electronic properties, has great potential applications in nanodevices. However, BP inevitably suffers from the rapid degradation in ambient air because of the high reactivity of P atoms with oxygen and water, which greatly hinders its wide applications. Herein, we demonstrate the electrostatic functionalization as an effective way to simultaneously enhance the stability and dispersity of aqueous phase exfoliated few-layer BP. The poly dimethyldiallyl ammonium chloride (PDDA) is selected to spontaneously and uniformly adsorb on the surface of few-layer BP via electrostatic interaction. The positive charge-center of the N atom of PDDA, which passivates the lone-pair electrons of P, plays a critical role in stabilizing the BP. Meanwhile, the PDDA could serve as hydrophilic ligands to improve the dispersity of exfoliated BP in water. The thinner PDDA-BP nanosheets can stabilize in both air and water even after 15 days of exposure. Finally, the uniform PDDA-BP-polymer film was used as a saturable absorber to realize passive mode-locking operations in a fiber laser, delivering a train of ultrafast pulses with the duration of 1.2 ps at 1557.8 nm. This work provides a new way to obtain highly stable few-layer BP, which shows great promise in ultrafast optics application. PMID- 29489322 TI - Medium-Bandgap Small-Molecule Donors Compatible with Both Fullerene and Nonfullerene Acceptors. AB - Much effort has been devoted to the development of new donor materials for small molecule organic solar cells due to their inherent advantages of well-defined molecular weight, easy purification, and good reproducibility in photovoltaic performance. Herein, we report two small-molecule donors that are compatible with both fullerene and nonfullerene acceptors. Both molecules consist of an (E)-1,2 di(thiophen-2-yl)ethane-substituted (TVT-substituted) benzo[1,2-b:4,5 b']dithiophene (BDT) as the central unit, and two rhodanine units as the terminal electron-withdrawing groups. The central units are modified with either alkyl side chains (DRBDT-TVT) or alkylthio side chains (DRBDT-STVT). Both molecules exhibit a medium bandgap with complementary absorption and proper energy level offset with typical acceptors like PC71BM and IDIC. The optimized devices show a decent power conversion efficiency (PCE) of 6.87% for small-molecule organic solar cells and 6.63% for nonfullerene all small-molecule organic solar cells. Our results reveal that rationally designed medium-bandgap small-molecule donors can be applied in high-performance small-molecule organic solar cells with different types of acceptors. PMID- 29489323 TI - Enzyme Mimicry for Combating Bacteria and Biofilms. AB - Bacterial infection continues to be a growing global health problem with the most widely accepted treatment paradigms restricted to antibiotics. However, antibiotics overuse and misuse have triggered increased multidrug resistance, frustrating the therapeutic outcomes and leading to higher mortalities. Even worse, the tendency of bacteria to form biofilms on living and nonliving surfaces further increases the difficulty in confronting bacteria because the extracellular matrix can act as a robust barrier to prevent the penetration of antibiotics and resist environmental stress. As a result, the inability to completely eliminate bacteria and biofilms often leads to persistent infection, implant failure, and device damage. Therefore, it is of paramount importance to develop alternative antimicrobial agents while avoiding the generation of bacterial resistance. Taking lessons from natural enzymes for destroying cellular structural integrity or interfering with metabolisms such as proliferation, quorum sensing, and programmed death, the construction of artificial enzymes to mimic the enzyme functions will provide unprecedented opportunities for combating bacteria. Moreover, compared to natural enzymes, artificial enzymes possess much higher stability against stringent conditions, easier tunable catalytic activity, and large-scale production for practical use. In this Account, we will focus on our recent progress in the design and synthesis of artificial enzymes as a new generation of "antibiotics", which have been demonstrated as promising applications in planktonic bacteria inactivation, wound/lung disinfection, as well as biofilm inhibition and dispersion. First, we will introduce direct utilization of the intrinsic catalytic activities of artificial enzymes without dangerous chemical auxiliaries for killing bacteria under mild conditions. Second, to avoid the toxicity caused by overdose of H2O2 in conventional disinfections, we leveraged artificial enzymes with peroxidase-mimic activities to catalyze the generation of hydroxyl radicals at low H2O2 levels while achieving efficient antibacterial outcomes. Importantly, the feasibility of these artificial enzymes was further demonstrated in vivo by mitigating mice wound and lung disinfection. Third, by combining artificial enzymes with stimuli-responsive materials, smart on-demand therapeutic modalities were constructed for thwarting bacteria in a controllable manner. For instance, a photoswitchable "Band-Aid" like hydrogel doped with artificial enzymes was developed for efficiently killing bacteria without compromising mammal cell proliferation, which was promising for accelerating wound healing. Lastly, regarding the key roles that extracellular DNAs (eDNAs) play in maintaining biofilm integrity, we further designed a multinuclear metal complex-based DNase-mimetic artificial enzyme toward cleaving the eDNA for inhibiting biofilm formation and dispersing the established biofilms. We expect that our rational designs would boost the development of artificial enzymes with different formulations as novel antibacterial agents for clinical and industrial applications. PMID- 29489324 TI - Tuning and Switching a Plasmonic Quantum Dot "Sandwich" in a Nematic Line Defect. AB - We study the quantum-mechanical effects arising in a single semiconductor core/shell quantum dot (QD) controllably sandwiched between two plasmonic nanorods. Control over the position and the "sandwich" confinement structure is achieved by the use of a linear-trap liquid crystal (LC) line defect and laser tweezers that "push" the sandwich together. This arrangement allows for the study of exciton-plasmon interactions in a single structure, unaltered by ensemble effects or the complexity of dielectric interfaces. We demonstrate the effect of plasmonic confinement on the photon antibunching behavior of the QD and its luminescence lifetime. The QD behaves as a single emitter when nanorods are far away from the QD but shows possible multiexciton emission and a significantly decreased lifetime when tightly confined in a plasmonic "sandwich". These findings demonstrate that LC defects, combined with laser tweezers, enable a versatile platform to study plasmonic coupling phenomena in a nanoscale laboratory, where all elements can be arranged almost at will. PMID- 29489325 TI - Understanding the Effects of Nanocapsular Mechanical Property on Passive and Active Tumor Targeting. AB - The physicochemical properties of nanoparticles (size, charge, and surface chemistry, etc.) influence their biological functions often in complex and poorly understood ways. This complexity is compounded when the nanostructures involved have variable mechanical properties. Here, we report the synthesis of liquid filled silica nanocapsules (SNCs, ~ 150 nm) having a wide range of stiffness (with Young's moduli ranging from 704 kPa to 9.7 GPa). We demonstrate a complex trade-off between nanoparticle stiffness and the efficiencies of both immune evasion and passive/active tumor targeting. Soft SNCs showed 3 times less uptake by macrophages than stiff SNCs, while the uptake of PEGylated SNCs by cancer cells was independent of stiffness. In addition, the functionalization of stiff SNCs with folic acid significantly enhanced their receptor-mediated cellular uptake, whereas little improvement for the soft SNCs was conferred. Further in vivo experiments confirmed these findings and demonstrated the critical role of nanoparticle mechanical properties in regulating their interactions with biological systems. PMID- 29489326 TI - Composition-Dependent Functionality of Copper Vanadate Photoanodes. AB - To understand functional roles of constituent elements in ternary metal oxide photoanodes, essential photoelectrochemical (PEC) properties are systematically analyzed on a series of copper vanadate compounds with different Cu:V elemental ratios. Homogeneous and highly continuous thin films of beta-Cu2V2O7, gamma Cu3V2O8, Cu11V6O26, and Cu5V2O10 are grown via reactive co-sputtering and their performance characteristics for the light-driven oxygen evolution reaction are evaluated. All four compounds have similar bandgaps in the range of 1.83-2.03 eV, though Cu-rich phases exhibit stronger optical absorption and higher charge separation efficiencies. Transient photocurrent analysis reveals a reduction of surface catalytic activity with increasing Cu:V elemental ratio due to competitive charge recombination at Cu-related surface states. This comprehensive analysis of PEC functionalities-including photon absorption, carrier separation, and heterogeneous charge transfer-informs strategies for improving PEC activity in the copper vanadate materials system and provides insights that may aid discovery, design, and engineering of new photoelectrode materials. PMID- 29489327 TI - Near Infrared Light Sensitive Ultraviolet-Blue Nanophotoswitch for Imaging-Guided "Off-On" Therapy. AB - Photoswitchable materials are important in broad applications. Recently appeared inorganic photoswitchable upconversion nanoparticles (PUCNPs) become a competitive candidate to surmount the widespread issue of the organic counterparts -photobleaching. However, current PUCNPs follow solely Yb3+/Nd3+ cosensitizing mode, which results in complex multilayer doping patterns and imperfectness of switching in UV-blue region. In this work, we have adopted a new strategy to construct Nd3+ free PUCNPs-NaErF4@NaYF4@NaYbF4:0.5%Tm@NaYF4. These PUCNPs demonstrate the superior property of photoswitching. A prominent UV-blue emission from Tm3+ is turned on upon 980 nm excitation, which can be completely turned off by 800 nm light. The quasi-monochromatic red upconversion emission upon 800 nm excitation-a distinct feature of undoping NaErF4 upconversion system endows the PUCNPs with promising image-guided photoinduced "off-on" therapy in biomedicine. As a proof-of-concept we have demonstrated the imaging-guided photodynamic therapy (PDT) of cancer, where 800 nm excitation turns off the UV blue emission and leaves the emission at 660 nm for imaging. Once the tumor site is targeted, excitation switching to 980 nm results in UV-blue emission and the red emission. The former is used to induce PDT, whereas the latter is to monitor the therapeutic process. Our study implies that this upconversion photoswitching material is suitable for real-time imaging and image-guided therapy under temporal and spatial control. PMID- 29489328 TI - Supercompressible Coaxial Carbon Nanotube@Graphene Arrays with Invariant Viscoelasticity over -100 to 500 degrees C in Ambient Air. AB - Vertically aligned carbon nanotube (CNT) arrays have been recognized as promising cushion materials because of their superior thermal stability, remarkable compressibility, and viscoelastic characteristics. However, most of the previously reported CNT arrays still suffer from permanent shape deformation at only moderate compressive strains, which considerably restricts their practical applications. Here, we demonstrate a facile strategy of fabricating supercompressible coaxial CNT@graphene (CNT@Gr) arrays by using a two-step route involving encapsulating polymer layers onto plastic CNT arrays and subsequent annealing processes. Notably, the resulting CNT@Gr arrays are able to almost completely recover from compression at a strain of up to 80% and retain ~80% recovery even after 1000 compression cycles at a 60% strain, demonstrating their excellent compressibility. Furthermore, they possess outstanding strain- and frequency-dependent viscoelastic responses, with storage modulus and damping ratio of up to ~6.5 MPa and ~0.19, respectively, which are nearly constant over an exceptionally broad temperature range of -100 to 500 degrees C in ambient air. These supercompressibility and temperature-invariant viscoelasticity together with facile fabrication process of the CNT@Gr arrays enable their promising multifunctional applications such as energy absorbers, mechanical sensors, and heat exchangers, even in extreme environments. PMID- 29489329 TI - Gelation, Phase Separation, and Fibril Formation in Aqueous Hydroxypropylmethylcellulose Solutions. AB - The thermoresponsive behavior of a hydroxypropylmethylcellulose (HPMC) sample in aqueous solutions has been studied by a powerful combination of characterization tools, including rheology, turbidimetry, cryogenic transmission electron microscopy (cryoTEM), light scattering, small-angle neutron scattering (SANS), and small-angle X-ray scattering (SAXS). Consistent with prior literature, solutions with concentrations ranging from 0.3 to 3 wt % exhibit a sharp drop in the dynamic viscoelastic moduli G' and G" upon heating near 57 degrees C. The drop in moduli is accompanied by an abrupt increase in turbidity. All the evidence is consistent with this corresponding to liquid-liquid phase separation, leading to polymer-rich droplets in a polymer-depleted matrix. Upon further heating, the moduli increase, and G' exceeds G", corresponding to gelation. CryoTEM in dilute solutions reveals that HPMC forms fibrils at the same temperature range where the moduli increase. SANS and SAXS confirm the appearance of fibrils over a range of concentration, and that their average diameter is ca. 18 nm; thus gelation is attributable to formation of a sample-spanning network of fibrils. These results are compared in detail with the closely related and well studied methylcellulose (MC). The HPMC fibrils are generally shorter, more flexible, and contain more water than with MC, and the resulting gel at high temperatures has a much lower modulus. In addition to the differences in fibril structure, the key distinction between HPMC and MC is that the former undergoes liquid-liquid phase separation prior to forming fibrils and associated gelation, whereas the latter forms fibrils first. These results and their interpretation are compared with the prior literature, in light of the relatively recent discovery of the propensity of MC and HPMC to self-assemble into fibrils on heating. PMID- 29489330 TI - Control of Oxidation and Spin State in a Single-Molecule Junction. AB - The oxidation and spin state of a metal-organic molecule determine its chemical reactivity and magnetic properties. Here, we demonstrate the reversible control of the oxidation and spin state in a single Fe porphyrin molecule in the force field of the tip of a scanning tunneling microscope. Within the regimes of half integer and integer spin state, we can further track the evolution of the magnetocrystalline anisotropy. Our experimental results are corroborated by density functional theory and wave function theory. This combined analysis allows us to draw a complete picture of the molecular states over a large range of intramolecular deformations. PMID- 29489332 TI - Electrochemical Biosensor Using DNA Embedded Phosphorothioate Modified RNA for Mercury Ion Determination. AB - Mercury (Hg) and its compounds, originating from a variety of natural and anthropogenic sources, are ubiquitous in the natural environment, and cause severe environmental contamination and pose irreversible harm to human health. A fast and accurate sensing approach is of significant importance for mercury detection. Here, a label-free biosensor using Hg(II)-induced cleavage of phosphorothioate (PS) modified RNA was exploited. We designed a specific single stranded DNA embedded with four PS-modified RNA (Hg-DPR) to improve the cleavage reaction yield, and then Hg-DPR was covalently linked with single-walled carbon nanotube field effect transistor (SWNTs/FET) via a peptide bond. The Hg-DPR can be efficiently cleaved after exposure to Hg(II), which further causes the conductivity of the SWNTs to change. Using the relative resistance change, the Hg DPR/SWNTs/FET successfully detected Hg(II) levels as low as 10 pM, and the calibration curves were linear in the range of 50 pM to 100 nM and 100 nM to 10 MUM. Additionally, Hg-DPR/SWNTs/FET exhibited excellent sensitivity, portability, and low-cost for Hg(II) detection. PMID- 29489331 TI - Enhanced High-Temperature Cyclic Stability of Al-Doped Manganese Dioxide and Morphology Evolution Study Through in situ NMR under High Magnetic Field. AB - In this work, Al-doped MnO2 (Al-MO) nanoparticles have been synthesized by a simple chemical method with the aim to enhance cycling stability. At room temperature and 50 degrees C, the specific capacitances of Al-MO are well maintained after 10 000 cycles. Compared with pure MnO2 nanospheres (180.6 F g-1 at 1 A g-1), Al-MO also delivers an enhanced specific capacitance of 264.6 F g-1 at 1 A g-1. During the cycling test, Al-MO exhibited relatively stable structure initially and transformed to needlelike structures finally both at room temperature and high temperature. In order to reveal the morphology evolution process, in situ NMR under high magnetic field has been carried out to probe the dynamics of structural properties. The 23Na spectra and the SEM observation suggest that the morphology evolution may follow pulverization/reassembling process. The Na+ intercalation/deintercalation induced pulverization, leading to the formation of tiny MnO2 nanoparticles. After that, the pulverized tiny nanoparticles reassembled into new structures. In Al-MO electrodes, doping of Al3+ could slow down this structure evolution process, resulting in a better electrochemical stability. This work deepens the understanding on the structural changes in faradic reaction of pseudocapacitive materials. It is also important for the practical applications of MnO2-based supercapacitors. PMID- 29489333 TI - Plasmon-Resonance-Energy-Transfer-Based Spectroscopy on Single Nanoparticles: Biomolecular Recognition and Enzyme Kinetics. AB - The small absorption cross sections of most molecules led to the low sensitivity of traditional optical absorption spectroscopy. This obstacle might be overcome by applying the near-field plasmon resonance energy transfer (PRET) between plasmonic nanoparticle and surrounding molecules. In this work, we utilized PRET based spectroscopy on single gold nanostars to study the specific biomolecule recognition and enzyme kinetics choosing biotin-SA pair and DNase I as models. By analyzing the changes of absorption spectra for black hole quencher 3 (BHQ3), derived from spectra difference, we explored the kinetics of specific biomolecule recognition and enzyme digestion in different physiological environment, and we found that the viscosities of media and the sizes of molecules play vital role in biomolecular recognition and enzyme digestion. Compared with the traditional optical absorption spectroscopy techniques, PRET-based spectroscopy offers a nanoscopic resolution owing to the small size of the probe, is more sensitive and achieves detection on the order of hundreds or even dozens of molecules, and can achieve high selectivity due to the specific biomolecular recognition. This method might be used in the fields of molecular diagnostics, drug discovery, cell systems, and clinical diagnostics. PMID- 29489334 TI - Crown Ether Effects on the Location of Charge Carriers in Electrospray Droplets: Implications for the Mechanism of Protein Charging and Supercharging. AB - "Native" electrospray ionization (ESI) mass spectrometry (MS) aims to transfer proteins from solution into the gas phase while maintaining solution-like structures and interactions. The ability to control the charge states of protein ions produced in these experiments is of considerable importance. Supercharging agents (SCAs) such as sulfolane greatly elevate charge states without significantly affecting the protein structure in bulk aqueous solution. The origin of native ESI supercharging remains contentious. According to one model, SCAs trigger unfolding within ESI droplets. In contrast, the "charge trapping model" envisions that SCAs impede the ejection of charge carriers (e.g., NH4+ or Na+) from the droplet. We addressed this controversy experimentally and computationally by employing 18C6 crown ether as a mechanistic probe in native ESI-MS experiments on holo-myoglobin. Remarkably, 18C6 suppressed the supercharging capability of sulfolane. Molecular dynamics (MD) simulations reproduced the experimental charge states. The MD data revealed that 18C6 altered the location of charge carriers in the ESI droplets. Without 18C6, sulfolane covered the droplets in an ionophobic layer that impeded charge carrier access to the surface. In contrast, 18C6 complexation caused charge carrier enrichment in this surface layer, thereby promoting charge ejection. For late droplets, all the water had left and the protein was encapsulated in sulfolane; charge ejection at this stage continued only in the presence of 18C6. As a result, evaporation to dryness of charge-depleted water/sulfolane/18C6 droplets produced low protein charge states, whereas charge-abundant water/sulfolane droplets generated high charge states. Our data support the view that native ESI supercharging is caused by charge trapping. Unfolding within the droplet may play an ancillary role under some conditions, but for the cases examined here, protein structural changes are not a causative factor for supercharging. Our conclusions are bolstered by dendrimer supercharging experiments. PMID- 29489335 TI - Radiolabeling Silica-Based Nanoparticles via Coordination Chemistry: Basic Principles, Strategies, and Applications. AB - As one of the most biocompatible and well-tolerated inorganic nanomaterials, silica-based nanoparticles (SiNPs) have received extensive attention over the last several decades. Recently, positron emission tomography (PET) imaging of radiolabeled SiNPs has provided a highly sensitive, noninvasive, and quantitative readout of the organ/tissue distribution, pharmacokinetics, and tumor targeting efficiency in vivo, which can greatly expedite the clinical translation of these promising NPs. Encouraged by the successful PET imaging of patients with metastatic melanoma using 124I-labeled ultrasmall SiNPs (known as Cornell dots or C dots) and their approval as an Investigational New Drug (IND) by the United States Food and Drug Administration, different radioisotopes (64Cu, 89Zr, 18F, 68Ga, 124I, etc.) have been reported to radiolabel a wide variety of SiNPs-based nanostructures, including dense silica (dSiO2), mesoporous silica (MSN), biodegradable mesoporous silica (bMSN), and hollow mesoporous silica nanoparticles (HMSN). With in-depth knowledge of coordination chemistry, abundant silanol groups (-Si-O-) on the silica surface or inside mesoporous channels not only can be directly used for chelator-free radiolabeling but also can be readily modified with the right chelators for chelator-based labeling. However, integrating these labeling strategies for constructing stably radiolabeled SiNPs with high efficiency has proven difficult because of the complexity of the involved key parameters, such as the choice of radioisotopes and chelators, nanostructures, and radiolabeling strategy. In this Account, we present an overview of recent progress in the development of radiolabeled SiNPs for cancer theranostics in the hope of speeding up their biomedical applications and potential translation into the clinic. We first introduce the basic principles and mechanisms for radiolabeling SiNPs via coordination chemistry, including general rules of selecting proper radioisotopes, engineering silica nanoplatforms (e.g., dSiO2, MSN, HMSN) accordingly, and chelation strategies for enhanced labeling efficiency and stability, on which our group has focused over the past decade. Generally, the medical applications guide the choice of specific SiNPs for radiolabeling by considering the inherent functionality of SiNPs. The radioisotopes can then be determined according to the amenability of the particular SiNPs for chelator-based or chelator-free radiolabeling to obtain high labeling stability in vivo, which is a prerequisite for PET to truly reflect the behavior of SiNPs since PET imaging detects the isotopes rather than nanoparticles. Next, we highlight several recent representative biomedical applications of radiolabeled SiNPs including molecular imaging to detect specific lesions, PET-guided drug delivery, SiNP-based theranostic cancer agents, and clinical studies. Finally, the challenges and prospects of radiolabeled SiNPs are briefly discussed toward clinical cancer research. We hope that this Account will clarify the recent progress on the radiolabeling of SiNPs for specific medical applications and generate broad interest in integrating nanotechnology and PET imaging. With several ongoing clinical trials, radiolabeled SiNPs offer great potential for future patient stratification and cancer management in clinical settings. PMID- 29489336 TI - Rewiring Calcium Signaling for Precise Transcriptional Reprogramming. AB - Tools capable of modulating gene expression in living organisms are very useful for interrogating the gene regulatory network and controlling biological processes. The catalytically inactive CRISPR/Cas9 (dCas9), when fused with repressive or activating effectors, functions as a versatile platform to reprogram gene transcription at targeted genomic loci. However, without temporal control, the application of these reprogramming tools will likely cause off target effects and lack strict reversibility. To overcome this limitation, we report herein the development of a chemical or light-inducible transcriptional reprogramming device that combines photoswitchable genetically encoded calcium actuators with dCas9 to control gene expression. By fusing an engineered Ca2+ responsive NFAT fragment with dCas9 and transcriptional coactivators, we harness the power of light to achieve photoinducible transcriptional reprogramming in mammalian cells. This synthetic system (designated CaRROT) can also be used to document calcium-dependent activity in mammals after exposure to ligands or chemicals that would elicit calcium response inside cells. PMID- 29489337 TI - Lactate Racemase Nickel-Pincer Cofactor Operates by a Proton-Coupled Hydride Transfer Mechanism. AB - Lactate racemase (LarA) of Lactobacillus plantarum contains a novel organometallic cofactor with nickel coordinated to a covalently tethered pincer ligand, pyridinium-3-thioamide-5-thiocarboxylic acid mononucleotide, but its function in the enzyme mechanism has not been elucidated. This study presents direct evidence that the nickel-pincer cofactor facilitates a proton-coupled hydride transfer (PCHT) mechanism during LarA-catalyzed lactate racemization. No signal was detected by electron paramagnetic resonance spectroscopy for LarA in the absence or presence of substrate, consistent with a +2 metal oxidation state and inconsistent with a previously proposed proton-coupled electron transfer mechanism. Pyruvate, the predicted intermediate for a PCHT mechanism, was observed in quenched solutions of LarA. A normal substrate kinetic isotope effect ( kH/ kD of 3.11 +/- 0.17) was established using 2-alpha-2H-lactate, further supporting a PCHT mechanism. UV-visible spectroscopy revealed a lactate-induced perturbation of the cofactor spectrum, notably increasing the absorbance at 340 nm, and demonstrated an interaction of the cofactor with the inhibitor sulfite. A crystal structure of LarA provided greater resolution (2.4 A) than previously reported and revealed sulfite binding to the pyridinium C4 atom of the reduced pincer cofactor, mimicking hydride reduction during a PCHT catalytic cycle. Finally, computational modeling supports hydride transfer to the cofactor at the C4 position or to the nickel atom, but with formation of a nickel-hydride species requiring dissociation of the His200 metal ligand. In aggregate, these studies provide compelling evidence that the nickel-pincer cofactor acts by a PCHT mechanism. PMID- 29489338 TI - Potential and Limitations of Nanocelluloses as Components in Biocomposite Inks for Three-Dimensional Bioprinting and for Biomedical Devices. AB - Three-dimensional (3D) printing has rapidly emerged as a new technology with a wide range of applications that includes biomedicine. Some common 3D printing methods are based on the suitability of biopolymers to be extruded through a nozzle to construct a 3D structure layer by layer. Nanocelluloses with specific rheological characteristics are suitable components to form inks for 3D printing. This review considers various nanocelluloses that have been proposed for 3D printing with a focus on the potential advantages, limitations, and requirements when used for biomedical devices and when used in contact with the human body. PMID- 29489339 TI - New Blood Test SEEKs To Detect and Localize Cancer before It's Too Late. PMID- 29489340 TI - A Facile Approach for Synthesis and Intracellular Delivery of Size Tunable Cationic Peptide Functionalized Gold Nanohybrids in Cancer Cells. AB - Peptide-based drug delivery systems have become a mainstay in the contemporary medicinal field, resulting in the design and development of better pharmaceutical formulations. However, most of the available reports employ tedious multiple reaction steps for the conjugation of bioactive cationic peptides with drug delivery vehicles. To overcome these limitations, the present work describes a one-step approach for facile and time efficient synthesis of highly cationic cell penetrating peptide functionalized gold nanoparticles and their intracellular delivery. The nanoconstruct was synthesized by the reduction of gold metal ions utilizing cell penetrating peptide (CPP), which facilitated the simultaneous synthesis of metal nanoparticles and the capping of the peptide over the nanoparticle surface. The developed nanoconstruct was thoroughly characterized and tested for intracellular delivery into HeLa cells. Intriguingly, a high payload of cationic peptide over gold particles was achieved, in comparison to conventional conjugation methods. Moreover, this method also provides the ability to control the size and peptide payload of nanoparticles. The nanoconstructs produced showed enhanced cancer cell penetration (MUM) and significant cytotoxic effect compared to unlabeled gold nanoparticles. Therefore, this novel approach may also have significant future potential to kill intracellular hidden dreaded pathogens like the human immunodeficiency virus, Mycobacterium tuberculosis, and so forth. PMID- 29489341 TI - The Chemistry of Inorganic Precursors during the Chemical Deposition of Films on Solid Surfaces. AB - The deposition of thin solid films is central to many industrial applications, and chemical vapor deposition (CVD) methods are particularly useful for this task. For one, the isotropic nature of the adsorption of chemical species affords even coverages on surfaces with rough topographies, an increasingly common requirement in microelectronics. Furthermore, by splitting the overall film depositing reactions into two or more complementary and self-limiting steps, as it is done in atomic layer depositions (ALD), film thicknesses can be controlled down to the sub-monolayer level. Thanks to the availability of a vast array of inorganic and metalorganic precursors, CVD and ALD are quite versatile and can be engineered to deposit virtually any type of solid material. On the negative side, the surface chemistry that takes place in these processes is often complex, and can include undesirable side reactions leading to the incorporation of impurities in the growing films. Appropriate precursors and deposition conditions need to be chosen to minimize these problems, and that requires a proper understanding of the underlying surface chemistry. The precursors for CVD and ALD are often designed and chosen based on their known thermal chemistry from inorganic chemistry studies, taking advantage of the vast knowledge developed in that field over the years. Although a good first approximation, however, this approach can lead to wrong choices, because the reactions of these precursors at gas-solid interfaces can be quite different from what is seen in solution. For one, solvents often aid in the displacement of ligands in metalorganic compounds, providing the right dielectric environment, temporarily coordinating to the metal, or facilitating multiple ligand-complex interactions to increase reaction probabilities; these options are not available in the gas-solid reactions associated with CVD and ALD. Moreover, solid surfaces act as unique "ligands", if these reactions are to be viewed from the point of view of the metalorganic complexes used as precursors: they are bulky and rigid, can provide multiple binding sites for a single reaction, and can promote unique bonding modes, especially on metals, which have delocalized electronic structures. The differences between the molecular and surface chemistry of CVD and ALD precursors can result in significant variations in their reactivity, ultimately leading to unpredictable properties in the newly grown films. In this Account, we discuss some of the main similarities and differences in chemistry that CVD/ALD precursors follow on surfaces when contrasted against their known behavior in solution, with emphasis on our own work but also referencing other key contributions. Our approach is unique in that it combines expertise from the inorganic, surface science, and quantum-mechanics fields to better understand the mechanistic details of the chemistry of CVD and ALD processes and to identify new criteria to consider when designing CVD/ALD precursors. PMID- 29489342 TI - Sensitivity-Enhanced Four-Dimensional Amide-Amide Correlation NMR Experiments for Sequential Assignment of Proline-Rich Disordered Proteins. AB - Proline is prevalent in intrinsically disordered proteins (IDPs). NMR assignment of proline-rich IDPs is a challenge due to low dispersion of chemical shifts. We propose here new sensitivity-enhanced 4D NMR experiments that correlate two pairs of amide resonances that are either consecutive (NH i-1, NH i) or flanking a proline at position i-1 (NH i-2, NH i). The maximum 2-fold enhancement of sensitivity is achieved by employing two coherence order-selective (COS) transfers incorporated unconventionally into the pulse sequence. Each COS transfer confers an enhancement over amplitude-modulated transfer by a factor of ?2 specifically when transverse relaxation is slow. The experiments connect amide resonances over a long fragment of sequence interspersed with proline. When this method was applied to the proline-rich region of B cell adaptor protein SLP-65 (pH 6.0) and alpha-synuclein (pH 7.4), which contain a total of 52 and 5 prolines, respectively, 99% and 92% of their nonprolyl amide resonances have been successfully assigned, demonstrating its robustness to address the assignment problem in large proline-rich IDPs. PMID- 29489343 TI - Impact of Bioinspired Nanotopography on the Antibacterial and Antibiofilm Efficacy of Chitosan. AB - Chitosan derived from chitin is one of the most abundant naturally occurring biocompatible polymers obtained from fungi and arthropods. In this work, we report the enhancement in the bactericidal efficacy of CHI in the presence of a sharp nanotopography. High-aspect ratio nanostructured surface (NSS) was fabricated using a single-step deep reactive ion etching technique (DRIE). Post fabrication, CHI coating was carried out using a layer-by-layer (LBL) dip coating process on the flat and nanostructured surfaces. Antibacterial efficacy of the flat silicon surface coated with CHI (Si_CHI) and NSS coated with CHI (NSS_CHI) was tested against both Gram-negative (G-ve) bacteria E. coli and Gram-positive (G+ve) bacteria S. aureus. NSS_CHI exhibited superior antibacterial property against G-ve and G+ve microbes as compared with Si_CHI and NSS substrates. Scanning electron microscopy (SEM) and fluorescence microscopy were used to study the morphology and viability of the bacteria on all the surfaces. Also, biofilm quantification was carried out on all the engineered surfaces for both E. coli and S. aureus using crystal violet (CV) staining. NSS_CHI was found to have the minimum biofilm formation on its surface exhibiting its superior antibacterial property. This study shows that the antibacterial and antibiofilm efficiency of CHI can be augmented by combining it with a sharp nanotopography. PMID- 29489345 TI - Changes in Cuticular Wax Composition of Two Blueberry Cultivars during Fruit Ripening and Postharvest Cold Storage. AB - Cuticular wax plays an important role for the quality of blueberry fruits. In this study, the cuticular wax composition of two blueberry cultivars, 'Legacy' ( Vaccinium corymbosum) and 'Brightwell' ( Vaccinium ashei), was examined during fruit ripening and postharvest cold storage. The results showed that wax was gradually deposited on the epidermis of blueberry fruits and the content of major wax compounds, except that for diketones, increased significantly during fruit ripening. The total wax content was 2-fold greater in 'Brightwell' blueberries than that in 'Legacy' blueberries during fruit ripening. The total wax content of both cultivars decreased during 30 days of storage at 4 degrees C, and the variation of cuticular wax composition was cultivar-dependent. The content of diketones decreased significantly in 'Legacy' blueberries, while the content of triterpenoids and aliphatic compounds showed different fold changes in 'Brightwell' blueberries after 30 days of storage at 4 degrees C. Overall, our study provided a quantitative and qualitative overview of cuticular wax compounds of blueberry fruits during ripening and postharvest cold storage. PMID- 29489344 TI - d-Fagomine Attenuates High Glucose-Induced Endothelial Cell Oxidative Damage by Upregulating the Expression of PGC-1alpha. AB - d-Fagomine, an analogue of 1-deoxynojirimycin (DNJ), has been shown to have hypoglycemic activity. This study is aimed at investigating if d-fagomine could attenuate high glucose-induced oxidative stress in human umbilical vein endothelial cells (HUVECs) and elucidate the underlying mechanism. Our results showed that d-fagomine reduced intracellular reactive oxygen species (ROS) production and malondialdehyde (MDA) levels. It also reversed the decrease of superoxide dismutases (SOD) and glutathione reductase (GR) activity, suggesting an inhibitory effect of d-fagomine on oxidative damage in HUVECs. d-Fagomine restored the loss of mitochondrial membrane potential, implying its protective role on mitochondrial function. In addition, d-fagomine activated the AMPK signaling pathway through LKB1, increased the expression of SIRT1 and PGC-1alpha, and attenuated the inhibitory effect on SIRT1 and PGC-1alpha activity caused by AMPK and SIRT1 inhibitor. d-Fagomine attenuated high glucose-induced oxidative stress in HUVECs through the AMPK/SIRT1/PGC-1alpha pathway. PMID- 29489346 TI - Gold Nanorods as Surface-Enhanced Raman Spectroscopy Substrates for Rapid and Sensitive Analysis of Allura Red and Sunset Yellow in Beverages. AB - Synthetic colorants in food can be a potential threat to human health. In this study, surface-enhanced Raman spectroscopy (SERS) coupled with gold nanorods as substrates is proposed to analyze allura red and sunset yellow in beverages. The gold nanorods with different aspect ratios were synthesized, and their long-term stability, SERS activity, and the effect of the different salts on the SERS signal were investigated. The results demonstrate that gold nanorods have a satisfactory stability (stored up to 28 days). SERS coupled with gold nanorods exhibit stronger sensitivity. MgSO4 was chosen to improve the SERS signal of sunset yellow, and no salts could enhance the SERS signal of allura red. The lowest concentration was 0.10 mg/L for both colorant standard solutions. The successful prediction results using SERS were much closer to those obtained by high-performance liquid chromatography for the sample in beverages. SERS combined with gold nanorods shows potential for analyzing food colorants and other food additives as a rapid, convenient, and sensitive method. PMID- 29489348 TI - A Novel Multi-Charged Draw Solute That Removes Organic Arsenicals from Water in a Hybrid Membrane Process. AB - The potential of forward osmosis for water treatment can only be maximized with suitable draw solutes. Here a three-dimensional, multicharge draw solute of decasodium phytate (Na10-phytate) is designed and synthesized for removing organic arsenicals from water using a hybrid forward osmosis (FO) - membrane distillation (MD) process. Efficient water recovery is achieved using Na10 phytate as a draw solute with a water flux of 20.0 LMH and negligible reverse solute diffusion when 1000 ppm organic arsenicals as the feed and operated under ambient conditions with FO mode. At 50 degrees C, the novel draw solute increases water flux by more than 30% with water fluxes higher than 26.0 LMH on the FO side, drastically enhancing water recovery efficiency. By combining the FO and MD processes into a single hybrid process, a 100% recovery of Na10-phytate draw solute was achieved. Crucially, organic arsenicals or Na10-phytate draw solutes are both rejected 100% and not detected in the permeate of the hybrid process. The complete rejection of both organic arsenicals and draw solutes using hybrid membrane processes is unprecedented; creating a new application for membrane separations. PMID- 29489347 TI - Precise Antibody-Independent m6A Identification via 4SedTTP-Involved and FTO Assisted Strategy at Single-Nucleotide Resolution. AB - Innovative detection techniques to achieve precise m6A distribution within mammalian transcriptome can advance our understanding of its biological functions. We specifically introduced the atom-specific replacement of oxygen with progressively larger atoms (sulfur and selenium) at 4-position of deoxythymidine triphosphate to weaken its ability to base pair with m6A, while maintaining A-T* base pair virtually the same as the natural one. 4SedTTP turned out to be an outstanding candidate that endowed m6A with a specific signature of RT truncation, thereby making this "RT-silent" modification detectable with the assistance of m6A demethylase FTO through next-generation sequencing. This antibody-independent, 4SedTTP-involved and FTO-assisted strategy is applicable in m6A identification, even for two closely gathered m6A sites, within an unknown region at single-nucleotide resolution. PMID- 29489349 TI - Replica Exchange Gaussian Accelerated Molecular Dynamics: Improved Enhanced Sampling and Free Energy Calculation. AB - Through adding a harmonic boost potential to smooth the system potential energy surface, Gaussian accelerated molecular dynamics (GaMD) provides enhanced sampling and free energy calculation of biomolecules without the need of predefined reaction coordinates. This work continues to improve the acceleration power and energy reweighting of the GaMD by combining the GaMD with replica exchange algorithms. Two versions of replica exchange GaMD (rex-GaMD) are presented: force constant rex-GaMD and threshold energy rex-GaMD. During simulations of force constant rex-GaMD, the boost potential can be exchanged between replicas of different harmonic force constants with fixed threshold energy. However, the algorithm of threshold energy rex-GaMD tends to switch the threshold energy between lower and upper bounds for generating different levels of boost potential. Testing simulations on three model systems, including the alanine dipeptide, chignolin, and HIV protease, demonstrate that through continuous exchanges of the boost potential, the rex-GaMD simulations not only enhance the conformational transitions of the systems but also narrow down the distribution width of the applied boost potential for accurate energetic reweighting to recover biomolecular free energy profiles. PMID- 29489350 TI - Microporenic Acids A-G, Biofilm Inhibitors, and Antimicrobial Agents from the Basidiomycete Microporus Species. AB - The need for effective compounds to combat antimicrobial resistance and biofilms which play important roles in human infections continues to pose a major health challenge. Seven previously undescribed acyclic diterpenes linked to isocitric acid by an ether linkage, microporenic acids A-G (1-7), were isolated from the cultures of a hitherto undescribed species of the genus Microporus (Polyporales, Basidiomycota) originating from Kenya's Kakamega forest. Microporenic acids D and E (4 and 5) showed antimicrobial activity against a panel of Gram positive bacteria and a yeast, Candida tenuis. Moreover, microporenic acids A and B (1 and 2) demonstrated dose-dependent inhibition of biofilm formation by Staphylococcus aureus. Compound 1 further showed significant activity against Candida albicans and Staphylococcus aureus preformed biofilms. PMID- 29489351 TI - Development of a Reverse Phase HPLC Retention Index Model for Nontargeted Metabolomics Using Synthetic Compounds. AB - The MolFind application has been developed as a nontargeted metabolomics chemometric tool to facilitate structure identification when HPLC biofluids analysis reveals a feature of interest. Here synthetic compounds are selected and measured to form the basis of a new, more accurate, HPLC retention index model for use with MolFind. We show that relatively inexpensive synthetic screening compounds with simple structures can be used to develop an artificial neural network model that is successful in making quality predictions for human metabolites. A total of 1955 compounds were obtained and measured for the model. A separate set of 202 human metabolites was used for independent validation. The new ANN model showed improved accuracy over previous models. The model, based on relatively simple compounds, was able to make quality predictions for complex compounds not similar to training data. Independent validation metabolites with feature combinations found in three or more training compounds were predicted with 97% sensitivity while metabolites with feature combinations found in less than three training compounds were predicted with >90% sensitivity. The study describes the method used to select synthetic compounds and new descriptors developed to encode the relationship between lipophilic molecular subgraphs and HPLC retention. Finally, we introduce the QRI (qualitative range of interest) modification of neural network backpropagation learning to generate models simultaneously based on quantitative and qualitative data. PMID- 29489352 TI - Shedding Light on Important Waters for Drug Design: Simulations versus Grid-Based Methods. AB - Water molecules play an important role in the association of drugs with their pharmaceutical targets. For this reason, calculating the energetic contribution of water is essential to make accurate predictions of compounds' affinity and selectivity. Water molecules can also modify the binding mode of compounds by forming water bridges, or clusters, that stabilize a particular orientation of the ligand. Several computational methods have been developed for solvent mapping, but few studies have attempted to compare them in a drug design context. In this paper, four commercially available solvent mapping tools (SZMAP, WaterFLAP, 3D-RISM, and WaterMap) are evaluated on three different protein targets. The methods were compared by looking at their ability to predict the structure-activity relations of lead compounds. All methods were found to be useful to some degree and to improve the predictions from docking alone. However, the only simulation-based approach tested, WaterMap, was found in some cases to be more accurate than grid-based methods. PMID- 29489353 TI - Historical Review on the Identification of Mesifurane, 2,5-Dimethyl-4-methoxy-3(2 H)-furanone, and Its Occurrence in Berries and Fruits. AB - Mesifurane, 2,5-dimethyl-4-methoxy-3(2 H)-furanone, is a natural compound used a worldwide as a flavoring for foods, beverages, and cosmetics. Global sales of mesifurane are around $100 million. Its significance as a flavor-impact compound in some Nordic berries was discovered in the early 1970s in Finland. Synthesized mesifurane was used as a key compound in aroma mixes exploited in a Finnish patent. Mesifurane is a significant flavorant in arctic brambles, mangoes, strawberries, and many other fruits and berries and is an enzymatic methylation product of 2,5-dimethyl-4-hydroxy-3(2 H)-furanone. Because of the obscurity of the information on the history of the commonly used trivial name, mesifurane, it is time to lift the veil and reveal the background of the present situation. The key player was a northern berry, arctic bramble ( Rubus arcticus), the Finnish name of which is mesimarja. Forty years ago, aroma research was limited by technical factors, but nowadays there is a surplus of information. PMID- 29489354 TI - Formation and Occurrence of Iodinated Tyrosyl Dipeptides in Disinfected Drinking Water. AB - Iodinated disinfection byproducts (I-DBPs) are highly toxic, but few precursors of I-DBPs have been investigated. Tyrosine-containing biomolecules are ubiquitous in surface water. Here we investigated the formation of I-DBPs from the chloramination of seven tyrosyl dipeptides (tyrosylglycine, tyrosylalanine, tyrosylvaline, tyrosylhistidine, tyrosylglutamine, tyrosylglutamic acid, and tyrosylphenylalanine) in the presence of potassium iodide. High resolution mass spectrometry and tandem mass spectrometry (MS/MS) analyses of the benchtop reaction solutions found that all seven precursors formed both I- and Cl substituted tyrosyl dipeptide products. Iodine substitutions occurred on the 3- and 3,5-positions of the tyrosyl-phenol ring while chlorine substituted on the free amino group. To reach the needed sensitivity to detect iodinated tyrosyl dipeptides in authentic waters, we developed a high performance liquid chromatography (HPLC)-MS/MS method with multiple reaction monitoring mode and solid phase extraction. HPLC-MS/MS analysis of tap and corresponding raw water samples, collected from three cities, identified four iodinated peptides, 3-I /3,5-di-I-Tyr-Ala and 3-I-/3,5-di-I-Tyr-Gly, in the tap waters but not in the raw waters. The corresponding precursors, Tyr-Ala and Tyr-Gly, were also detected in the same tap and raw water samples. This study demonstrates that iodinated dipeptides exist as DBPs in drinking water. PMID- 29489355 TI - N-Methylation of isoDGR Peptides: Discovery of a Selective alpha5beta1-Integrin Ligand as a Potent Tumor Imaging Agent. AB - Specific targeting of the integrin subtype alpha5beta1 possesses high potential in cancer diagnosis and therapy. Through sequential N-methylation, we successfully converted the biselective alpha5beta1/alphavbeta6 peptide c(phg- isoDGR-k) into a potent peptidic RGD binding alpha5beta1 subtype selective ligand c(phg- isoDGR-( NMe)k). Nuclear magnetic resonance spectroscopy and molecular modeling clarified the molecular basis of its improved selectivity profile. To demonstrate its potential in vivo, c(phg- isoDGR-( NMe)k) was trimerized with the chelator TRAP and used as a positron-emission tomography tracer for monitoring alpha5beta1 integrin expression in a M21 mouse xenograft. PMID- 29489356 TI - Accurate Evaluation of Real-Time Density Functional Theory Providing Access to Challenging Electron Dynamics. AB - We demonstrate that electronic excitations and their transition densities can be obtained from real-time density functional theory calculations with great accuracy by relating the data from numerical propagation to the analytical form of the electronic response after a boost excitation. The latter is derived in this article. This approach facilitates quantitatively obtaining oscillator strengths, identifying excitations that carry very small oscillator strengths, and assessing electronic couplings from transition densities based on comparatively short propagation times. These features are of interest in particular for studying light-harvesting systems. For demonstration purposes, we study the Q band excitations of bacteriochlorophyll a (BChl a) and calculate coupling strengths between two BChl a's to check the validity of the dipole dipole and pure Coulomb coupling mechanisms. For further illustration, we investigate the paradigm test system Na4 and the coupling between two Na2 dimers. PMID- 29489357 TI - Lathyroxins A and B, Phytotoxic Monosubstituted Phenols Isolated from Ascochyta lentis var. lathyri, a Fungal Pathogen of Grass Pea ( Lathyrus sativus). AB - Ascochyta lentis var. lathyri has recently been reported to be the causal agent of Ascochyta blight of grass pea ( Lathyrus sativus), a disease characterized by the appearance of necrotic lesions of leaves and stems. Considering the novelty of the pathogen and the possible involvement of secondary metabolites in symptom appearance, a study was carried out to ascertain the capability of this fungus to produce bioactive metabolites. Some phytotoxic phenols were isolated from the culture filtrates of the fungus. In particular, two new phytotoxic metabolites, named lathyroxins A and B, were characterized by spectroscopic methods as 4-(2 hydroxy-3,3-dimethoxypropyl)phenol and 3-(4-hydroxyphenyl)propane-1,2-diol, respectively, and the R absolute configuration of C-2 of their 2-dimethoxy- and 2,3-diol-propyl side chain was assigned. Moreover, other well-known fungal metabolites, namely, p-hydroxybenzaldehyde, p-methoxyphenol, and tyrosol, were also identified. Lathyroxins A and B showed interesting phytotoxic properties, being able to cause necrosis on leaves and to inhibit seed germination and rootlet elongation. Moreover, both of the new metabolites had no effect against bacteria, arthropods, and nematodes. PMID- 29489358 TI - Convergent Strategy to Dizocilpine MK-801 and Derivatives. AB - A convergent total synthesis of MK-801 has been achieved. Key synthetic transformations include a multicomponent Barbier-type reaction to construct the alpha-branched amine, a selective Heck alpha-coupling tactic to generate the exocyclic alkene skeleton, and a late-stage intramolecular hydroamination reaction between the exocyclic alkene and the secondary protected amine. The efficacy of this method was demonstrated by the synthesis of two news analogues substituted on the aromatic rings. PMID- 29489359 TI - Quasi-Diabatic Representation for Nonadiabatic Dynamics Propagation. AB - We develop a nonadiabatic dynamics propagation scheme that allows interfacing diabatic quantum dynamics methods with commonly used adiabatic electronic structure calculations. This scheme uses adiabatic states as the quasi-diabatic (QD) states during a short-time quantum dynamics propagation. At every dynamical propagation step, these QD states are updated based on a new set of adiabatic basis. Using the partial linearized density matrix (PLDM) path-integral method as one specific example for diabatic dynamics approaches, we demonstrate the accuracy of the QD scheme with a wide range of model nonadiabatic systems as well as the on-the-fly propagations with density functional tight-binding (DFTB) calculations. This study opens the possibility to combine accurate diabatic quantum dynamics methods with adiabatic electronic structure calculations for nonadiabatic dynamics propagations. PMID- 29489360 TI - Complex Coacervation of Milk Proteins with Sodium Alginate. AB - Beta-lactoglobulin (BLG) and bovine serum albumin (BSA) coacervate formation with sodium alginate (ALG) was investigated by turbidimetric analysis, zeta potential, particle size, viscosity, transmission electron microscopy (TEM) and isothermal titration calorimetric (ITC) measurements as a function of pH (1.0-7.0) and protein/alginate mixing ratio (1:1, 1.5:1, 2:1, 1:0, and 0:1 wt.). Critical pH values of phase transitions for BSA-ALG complexes (pHC, pHphi1, and pHphiphi2) representing the formation of soluble and insoluble complexes of a protein-ALG mixture (2:1) at pH 4.8, 4.2, and 1.8, respectively. In the case of BLG-ALG, critical pH values (pHC, pHphi1, and pHphi2) were found to be 4.8, 4.2, and 1.6, respectively. The pHopt values, expressed by the highest optical density, were pH 2.8 for BSA-ALG and 2.4 for BLG-ALG. TEM and zeta-potential results showed that maximum coacervate formation occurred at pH 4.2 for both protein-polysaccharide solutions. The interaction between BLG-ALG and BSA-ALG was spontaneously exothermic at pH 4.2 according to ITC measurements. The findings of this study provide insights to a thorough understanding about the nature of interactions between milk proteins and ALG and formulate new applications for food, pharmaceutical, nutraceutical, and cosmetics applications. PMID- 29489361 TI - Penicilindoles A-C, Cytotoxic Indole Diterpenes from the Mangrove-Derived Fungus Eupenicillium sp. HJ002. AB - Three new indole diterpenes, penicilindoles A-C (1-3), were isolated from the mangrove-derived fungus Eupenicillium sp. HJ002. Their planar structures and absolute configurations were determined by interpretation of NMR spectroscopic data, HR-ESIMS, and X-ray diffraction analysis using Cu Kalpha radiation. The cytotoxic and antibacterial activities were evaluated in vitro; penicilindole A (1) showed cytotoxic activity against human A549 and HepG2 cell lines with IC50 values of 5.5 and 1.5 MUM, respectively. PMID- 29489362 TI - Primary Transfer Step in the Light-Driven Ion Pump Bacteriorhodopsin: An Irreversible U-Turn Revealed by Dynamic Nuclear Polarization-Enhanced Magic Angle Spinning NMR. AB - Despite much attention, the path of the highly consequential primary proton transfer in the light-driven ion pump bacteriorhodopsin (bR) remains mysterious. Here we use DNP-enhanced magic angle spinning (MAS) NMR to study critical elements of the active site just before the Schiff base (SB) deprotonates (in the L intermediate), immediately after the SB has deprotonated and Asp85 has become protonated (in the Mo intermediate), and just after the SB has reprotonated and Asp96 has deprotonated (in the N intermediate). An essential feature that made these experiments possible is the 75-fold signal enhancement through DNP. 15N(SB) 1H correlations reveal that the newly deprotonated SB is accepting a hydrogen bond from an alcohol and 13C-13C correlations show that Asp85 draws close to Thr89 before the primary proton transfer. Concurrently, 15N-13C correlations between the SB and Asp85 show that helices C and G draw closer together just prior to the proton transfer and relax thereafter. Together, these results indicate that Thr89 serves to relay the SB proton to Asp85 and that creating this pathway involves rapprochement between the C and G helices as well as chromophore torsion. PMID- 29489363 TI - Fluorescence of Hydroxyphenyl-Substituted "Click" Triazoles. AB - The structural and optical properties of hydroxyphenyl-substituted-1,2,3-triazole molecules ("click" triazoles) are described. "Click" triazoles are prepared from the copper(I)-catalyzed azide-alkyne cycloaddition reactions. The alkyne-derived C4 substituent of a "click" triazole engages in electronic conjugation more effectively with the triazolyl core than the azide-derived N1 substituent. Furthermore, triazolyl group exerts a stronger electron-withdrawing effect on the N1 than the C4 substituent. Therefore, the placement of an electron-donating group at either C4 or N1 position and the presence or the absence of an intramolecular hydrogen bond (HB) have profound influences on the optical properties of these compounds. The reported "click" triazoles have fluorescence quantum yields in the range of 0.1-0.3 and large apparent Stokes shifts (8000-13 000 cm-1) in all tested solvents. Deprotonation of "click" triazoles with a C4 hydroxyphenyl group increases their Stokes shifts; while the opposite (or quenching) occurs to the triazoles with an N1 hydroxyphenyl substituent. For the triazoles that contain intramolecular HBs, neither experimental nor computational results support a model of excited state intramolecular proton transfer (ESIPT). Rather, the excited state internal (or intramolecular) charge transfer (ICT) mechanism is more suitable to explain the fluorescence properties of the hydroxyphenyl-substituted "click" triazoles; specifically, the large Stokes shifts of these compounds. PMID- 29489364 TI - Confinement of Aggregation-Induced Emission Molecular Rotors in Ultrathin Two Dimensional Porous Organic Nanosheets for Enhanced Molecular Recognition. AB - Despite the rapid development of molecular rotors over the past decade, it still remains a huge challenge to understand their confined behavior in ultrathin two dimensional (2D) nanomaterials for molecular recognition. Here, we report an all carbon, 2D pi-conjugated aromatic polymer, named NUS-25, containing flexible tetraphenylethylene (TPE) units as aggregation-induced emission (AIE) molecular rotors. NUS-25 bulk powder can be easily exfoliated into micrometer-sized lamellar freestanding nanosheets with a thickness of 2-5 nm. The dynamic behavior of the TPE rotors is partially restricted through noncovalent interactions in the ultrathin 2D nanosheets, which is proved by comparative experimental studies including AIE characteristics, size-selective molecular recognition, and theoretical calculations of rotary energy barrier. Because of the partially restricted TPE rotors, NUS-25 nanosheets are highly fluorescent. This property allows NUS-25 nanosheets to be used as a chemical sensor for the specific detection of acenaphthylene among a series of polycyclic aromatic hydrocarbons (PAHs) via fluorescent quenching mechanism. Further investigations show that NUS 25 nanosheets have much higher sensitivity and selectivity than their stacked bulk powder and other similar polymers containing dynamic TPE rotors. The highly efficient molecular recognition can be attributed to the photoinduced electron transfer (PET) from NUS-25 nanosheets to acenaphthylene, which is investigated by time-resolved photoluminescence measurements (TRPL), excitation and emission spectra, and density functional theory (DFT) calculations. Our findings demonstrate that confinement of AIE molecular rotors in 2D nanomaterials can enhance the molecular recognition. We anticipate that the material design strategy demonstrated in this study will inspire the development of other ultrathin 2D nanomaterials equipped with smart molecular machines for various applications. PMID- 29489365 TI - Quasi-Classical Trajectory Dynamics Study of the Cl(2P) + C2H6 -> HCl(v,j) + C2H5 Reaction. Comparison with Experiment. AB - To understand and simulate the dynamics behavior of the title reaction, QCT calculations were performed on a recently developed global analytical potential energy surface, PES-2017. These calculations combine the classical description of the dynamics with pseudoquantization in the reactants and products to perform a theoretical/experimental comparison on the same footing. Thus, in the products a series of constraints are included to analyze the HCl(v = 0,j) product, which is experimentally detected. At collision energies of 5.5 and 6.7 kcal mol-1 the largest fraction of available energy is deposited as translation, 67%, while the ethyl radical shows significant internal energy, 27%, and so it does not act as a spectator of the reaction, thus reproducing recent experimental evidence. The HCl(v=0, j) rotational distribution is cold, peaking at j = 2, only one unit hotter than experiment, which represents an error of 0.12 kcal mol-1. At a collision energy of 5.5 kcal mol-1 product translational distribution is slightly hotter than experiment, but at 6.7 kcal mol-1 agreement with recent experiments is practically quantitative, suggesting that the first experiments should be revised. In addition, we observe that the HCl(v=0, j) scattering distribution shifts from isotropic at low values of j to backward at high values of j, which is in agreement with experimental data. Finally, no evidence was found for the "chattering" mechanism suggested to explain the low translational energy of the HCl product in the backward scattering region. In sum, agreement with experiments of a series of sensible dynamic properties permits us to be optimistic on the quality and accuracy of the theoretical tools used in the present work, QCT and PES-2017. PMID- 29489366 TI - NMR, Raman, and DFT Study of Lyotropic Chromonic Liquid Crystals of Biomedical Interest: Tautomeric Equilibrium and Slow Self-Assembling in Sunset Yellow Aqueous Solutions. AB - Temperature and composition effects in Sunset Yellow FCF (SSY) aqueous solutions were studied by the 1H, 15N NMR as well as Raman spectroscopy passing through all phase transitions between isotropic phase (I) and chromonic phases-nematic (N) and columnar (M). It was shown that the tautomeric equilibrium in SSY is strongly shifted toward the hydrazone form. The corresponding equilibrium constant p KT = 2.5 was deduced using the density functional theory solvent model density model. The dominance of the hydrazone form was confirmed experimentally using the long range 1H-15N correlation, widely known as heteronuclear multiple bond correlation. The peak found in the 1H NMR spectra at ca. 14.5 ppm can be attributed to the proton in the intramolecular N-H...O bond. The existence of this signal shows that (i) the growth of the SSY aggregates is accompanied by the segregation of water in the intercolumnar areas with no access for exchange with the N-H protons in the internal layers of the columnar stacks and that (ii) the lifetime of those aggregates is >=10-8 s or even longer. The temperature dependences of H2O chemical shift and Raman O-H stretching band shape show that water confined in the intercolumnar areas behaves as in the neat substance. When the sample is heated and the transition from M phase to N phase occurs, the molecular motion of water is seen to change in a manner similar to that when water is melting. The equilibration time for N + M-> M is very long because of slow supramolecular restructuring, i.e., the growing of columnar stacks and building of hexagonal arrays. If the sample is cooled down to the temperature below N -> M transition relatively fast, the structural changes are behind, and the system falls into supercooled state. In this case, the system evolves via long-lasting self-assembling from the supercooled state to the equilibrium. This process affects the shape of the 1H NMR signal and is easy to monitor. PMID- 29489367 TI - Three-Dimensional Non-Close-Packed Structures of Oppositely Charged Colloids Driven by pH Oscillation. AB - The implementation of non-close-packed structures in colloids is challenging. Using Brownian dynamics simulations, we study the nonequilibrium self-assembly in suspensions of oppositely charged particles, whose charge magnitude is responsive to the pH of the solution. Under the fast pH-oscillating condition, various non close-packed (e.g., graphitelike and diamondlike) structures are obtained. Here, changing the amplitude of the pH oscillation is an effective way to fabricate colloidal dynamic structures. To clarify the underlying mechanism of the dynamic self-assembly, the analysis of effective potential is adopted. A dimensionless parameter, the ratio of effective repulsion and attraction, is introduced to reflect the subtle interactions in the system. We find that the imbalance between repulsion and attraction is the cause of structural diversity. Madelung energy is used to study the stability of these structures. Our results provide a new way to fabricate non-close-packed structures in colloids, which has potential applications in the synthesis of photonic crystals. PMID- 29489368 TI - Theoretical Study on the Aza-Diels-Alder Reaction Catalyzed by PHCl2 Lewis Acid via Pnicogen Bonding. AB - The reaction mechanism of the Aza-Diels-Alder (A-D-A) cycloaddition reaction between X2C?NNH2, where X = H, F, Cl, Br, and 1,3-butadiene catalyzed by a PHCl2 Lewis acid was characterized using density functional theory calculations. The influences of various substituents of X on the studied reaction were analyzed using the activation strain model (ASM), which is also termed as the distortion interaction model. Calculations showed that the smallest and largest values of the activation energies belong to the substituents of F and Br, respectively. The activation energy of the studied reactions was decreased within 8.6 kcal.mol-1 in the presence of PHCl2 catalyst. Investigations showed that the pnicogen bonding is adequately capable of activating the A-D-A reaction. The quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analysis were implemented to understand the nature of C4,Cbut...CXIm and C1,Cbut...NXIm bonds at the TS structures. Additionally, the energy decomposition analysis (EDA) based on the ETS-NOCV scheme was used to characterize the nature of C4,Cbut...CXIm and C1,Cbut...NXIm bond. The results of the study mirror the fact that the PHCl2 Lewis acid may be suggested as a simple suitable catalyst for experimental studies on the A-D-A reactions. PMID- 29489369 TI - How Methylation Modifies the Photophysics of the Native All- trans-Retinal Protonated Schiff Base: A CASPT2/MD Study in Gas Phase and in Methanol. AB - A comparison between the free-energy surfaces of the all- trans-retinal protonated Schiff base (RPSB) and its 10-methylated derivative in gas phase and methanol solution is performed at CASSCF//CASSCF and CASPT2//CASSCF levels. Solvent effects were included using the average solvent electrostatic potential from molecular dynamics method. This is a QM/MM (quantum mechanics/molecular mechanics) method that makes use of the mean field approximation. It is found that the methyl group bonded to C10 produces noticeable changes in the solution free-energy profile of the S1 excited state, mainly in the relative stability of the minimum energy conical intersections (MECIs) with respect to the Franck Condon (FC) point. The conical intersections yielding the 9- cis and 11- cis isomers are stabilized while that yielding the 13- cis isomer is destabilized; in fact, it becomes inaccessible by excitation to S1. Furthermore, the planar S1 minimum is not present in the methylated compound. The solvent notably stabilizes the S2 excited state at the FC geometry. Therefore, if the S2 state has an effect on the photoisomerization dynamics, it must be because it permits the RPSB population to branch around the FC point. All these changes combine to speed up the photoisomerization in the 10-methylated compound with respect to the native compound. PMID- 29489370 TI - Crossover of the Power-Law Exponent for Carbon Nanotube Conductivity as a Function of Salinity. AB - On the basis of the Poisson-Boltzmann equation in cylindrical coordinates, we calculate the conductivity of a single charged nanotube filled with electrolyte. The conductivity as a function of the salt concentration follows a power-law, the exponent of which has been controversially discussed in the literature. We use the co-ion-exclusion approximation and obtain the crossover between different asymptotic power-law behaviors analytically. Numerically solving the full Poisson Boltzmann equation, we also calculate the complete diagram of exponents as a function of the salt concentration and the pH for tubes with different radii and p Ka values. We apply our theory to recent experimental results on carbon nanotubes using the p Ka as a fit parameter. In good agreement with the experimental data, the theory shows power-law behavior with the exponents 1/3 at high pH and 1/2 at low pH, with a crossover depending on salt concentration, tube radius and p Ka. PMID- 29489372 TI - Excited-State Proton Transfer in Thiazolo-[4, 5-d]thiazo Heterocyclic Systems and the Geometry Alterations' Effect on Photophysical Characters: A Theoretical Study. AB - Thiazolo-[4,5- d]-thiazo-frame (tztz) compounds are important heteroaromatic organic systems, which recently became a subject of several studies in the field of organic electronics and organic photovoltaics. The most important physical nature of these systems is reported to be an equilibrium between enol and keto forms following excited-state proton transfer. This process originates from a flat trend of the S1 PE (potential energy) profile along the proton transfer coordinate. In the present work, we determined and interpreted the excited-state proton transfer and photophysical nature of these systems extensively by means of the MP2/CC2 and CASSCF theoretical approaches. Also, the effects of amine (-NH2) and cyano (-CN) substitutions were taken into account comprehensively by considering the transition energies and proton transfer pathways of the resulting tztz derivatives. It has been predicted that the physical nature of the excited state intramolecular proton transfer, as the main character of these systems, is being affected significantly by substitutions. For all of the considered tztz derivatives, a conical intersection (CI) between ground and the S1 excited state was predicted. This CI makes the considered species capable to be responsible for photochromism and photoswitching as well. PMID- 29489371 TI - Hybrid Biomimetic Interfaces Integrating Supported Lipid Bilayers with Decellularized Extracellular Matrix Components. AB - This paper describes the functionalization of solid supported phospholipid bilayer with decellularized extracellular matrix (dECM) components, toward the development of biomimetic platforms that more closely mimic the cell surface environment. The dECM was obtained through a combination of chemical and enzymatic treatments of mouse adipose tissue that contains collagen, fibronectin, and glycosaminoglycans (GAGs). Using amine coupling chemistry, the dECM components were attached covalently to the surface of a supported lipid bilayer containing phospholipids with reactive carboxylic acid headgroups. The bilayer formation and the kinetics of subsequent dECM conjugation were monitored by quartz crystal microbalance with dissipation (QCM-D). Fluorescence recovery after photobleaching (FRAP) confirmed the fluidity of the membrane after functionalization with dECM. The resulting hybrid biomimetic interface supports the attachment and survival of the human hepatocyte Huh 7.5 and maintains the representative hepatocellular function. Importantly, the platform is suitable for monitoring the lateral organization and clustering of cell-binding ligands and growth factor receptors in the presence of the rich biochemical profile of tissue derived ECM components. PMID- 29489373 TI - Effect of Ligand Modification on the Mechanism of Electrocatalytic Hydrogen Production by Ni(pyridinethiolate)3- Derivatives. AB - The effects of ligand modification on the catalytic mechanism of hydrogen production by Ni(PyS)3- derivatives, made with electron-withdrawing and -donating substitutions to the pyridinethiolate (PyS)- ligands, are studied experimentally and computationally using density functional theory. Thermodynamic data, spin density maps, and frontier molecular orbital diagrams were generated for reaction intermediates. Comparison of computed values for E0 and p Ka with experimental values supports the proposed mechanisms. The rate of electrochemical hydrogen production is correlated with the effect of ligand modification. Notably, the presence of an electron-donating substituent favors an alternative mechanism for hydrogen production. Computationally it was determined that the electron-donating substituent causes deviation from the original chemical-electrochemical-chemical electrochemical (CECE) mechanism of Ni(PyS)3- to a CCEE mechanism, while the CECE mechanism is maintained for all catalysts substituted with electron-withdrawing groups. PMID- 29489374 TI - Identifying Strong Covalent Interactions with Pauli Energy. AB - As one of the most widely used chemical concepts whose origin can be traced back to Lewis theory of bonding a century ago, a covalent bond involves sharing one or more pairs of electrons between atoms. A strong covalent interaction (SCI) is such a covalent bond that two or more electron pairs are shared, yielding a double, triple, quadruple, or even higher bond order. Despite its ubiquity and usefulness, a robust and generally applicable approach to accurately identify strong covalent interactions and determine their bond orders is still lacking. In this work, an SCI index is proposed from density functional theory using the Pauli energy, which is the contribution of the Pauli exclusion principle to the kinetic energy. Illustrative examples from organic, inorganic, and organometallic systems were provided. Its close relationship with the electron localization function (ELF) was elucidated. Both ELF and SCI generate similar results. Two complexes with a quintuple metal-metal bond have been confirmed. A stronger than quintuple bond has been showcased. This work should provide a robust approach to determine bond orders for strong covalent interactions in complex systems, pinpoint the physiochemical origin of strong covalent interactions, and rationalize the usefulness of both SCI and ELF. These tools should be able to be applied to other systems in different fields to effectively appreciate strong covalent interactions. PMID- 29489375 TI - Hydrophobic Attraction Measured between Asymmetric Hydrophobic Surfaces. AB - The interaction forces between silica surfaces modified to different degrees of hydrophobicity were measured using colloidal probe atomic force microscopy (AFM). A highly hydrophobic silica particle was prepared with octadecyltrichlorosilane (OTS), and the interaction forces were measured against silica substrates modified to produce surfaces of varying hydrophobicity. The interaction forces between the highly hydrophobic particle and a completely hydrophilic silicon wafer surface fitted well to the DLVO theory, indicating that no additional (non DLVO) forces act between the surfaces. When the silicon wafer surface was treated to produce a contact angle of water on surface of 40 degrees , an additional attractive force that is longer ranged than the van der Waals force was observed between the surfaces. The range and magnitude of the attractive force increase with the contact angle of water on the substrate. Beyond the effect on the contact angle, the hydrocarbon chain length and the terminal groups of hydrophobic layer on the substrate only have a minor effect on the magnitude of the force, even when the substrate is terminated with polar carboxyl groups, provided the hydrophobicity of the other surface is high. PMID- 29489376 TI - Liquid-Like, Self-Healing Aluminum Oxide during Deformation at Room Temperature. AB - Effective protection from environmental degradation relies on the integrity of oxide as diffusion barriers. Ideally, the passivation layer can repair its own breaches quickly under deformation. While studies suggest that the native aluminum oxide may manifest such properties, it has yet to be experimentally proven because direct observations of the air-environmental deformation of aluminum oxide and its initial formation at room temperature are challenging. Here, we report in situ experiments to stretch pure aluminum nanotips under O2 gas environments in a transmission electron microscope (TEM). We discovered that aluminum oxide indeed deforms like liquid and can match the deformation of Al without any cracks/spallation at moderate strain rate. At higher strain rate, we exposed fresh metal surface, and visualized the self-healing process of aluminum oxide at atomic resolution. Unlike traditional thin-film growth or nanoglass consolidation processes, we observe seamless coalescence of new oxide islands without forming any glass-glass interface or surface grooves, indicating greatly accelerated glass kinetics at the surface compared to the bulk. PMID- 29489377 TI - Fabrication of Hexagonal-Prismatic Granular Hydrogel Sheets. AB - Natural soft materials are often composed of proteins that self-assemble into well-defined structures and display mechanical properties that cannot be matched by manmade materials. These materials are frequently mimicked with hydrogels whose mechanical properties depend on their composition and the type and density of cross-links. Protocols to tune these parameters are well established and routinely used. The mechanical properties of hydrogels also depend on their structure; this parameter is more difficult to control. In this paper, we present a method to produce hexagonal-prismatic granular hydrogel sheets with well defined structures and heterogeneous cross-link densities. The hydrogel sheets are made of self-assembled covalently cross-linked 40-120 MUm diameter hexagonal prismatic hydrogel particles that display a narrow size distribution. The structure and microscale surface roughness of the hydrogels sheets can be tuned with the polymerization conditions, their chemical composition with that of the individual hydrogel particles, and their mechanical properties with the cross link density. Remarkably, the hydrogels composed of hexagonal-prismatic microparticles are significantly stiffer than unstructured counterparts. These results demonstrate that the stiffness of hydrogels can be tuned by controlling their micrometer-scale structure without altering their composition. Thereby, they open up new possibilities to design soft materials whose performance more closely resembles that of natural ones. PMID- 29489378 TI - Quantitative in Situ SEM High Cycle Fatigue: The Critical Role of Oxygen on Nanoscale-Void-Controlled Nucleation and Propagation of Small Cracks in Ni Microbeams. AB - This Letter presents a quantitative in situ scanning electron microscope (SEM) nanoscale high and very high cycle fatigue (HCF/VHCF) investigation of Ni microbeams under bending, using a MEMS microresonator as an integrated testing machine. The novel technique highlights ultraslow fatigue crack growth (average values down to ~10-14 m/cycle) that has heretofore not been reported and that indicates a discontinuous process; it also reveals strong environmental effects on fatigue lives that are 3 orders of magnitude longer in a vacuum than in air. This ultraslow fatigue regime does not follow the well documented fatigue mechanisms that rely on the common crack tip stress intensification, mediated by dislocation emission and associated with much larger crack growth rates. Instead, our study reveals fatigue nucleation and propagation mechanisms that mainly result from room temperature void formation based on vacancy condensation processes that are strongly affected by oxygen. This study therefore shows significant size effects governing the bending high/very high cycle fatigue behavior of metals at the micro- and nanoscales, whereby the stress concentration effect at the tip of a growing small fatigue crack is assumed to be greatly reduced by the effect of the bending-induced extreme stress gradients, which prevents any significant cyclic crack tip opening displacement. In this scenario, ultraslow processes relying on vacancy formation at the subsurface or in the vicinity of a crack tip and subsequent condensation into voids become the dominant fatigue mechanisms. PMID- 29489379 TI - Synthesis of 2-(Trifluoromethyl)indoles via Domino Trifluoromethylation/Cyclization of 2-Alkynylanilines. AB - A new method for the synthesis of 2-(trifluoromethyl)indoles using easily accessible 2-alkynylanilines and a well-established fluoroform-derived CuCF3 reagent is described. This method utilizes a domino trifluoromethylation/cyclization strategy to construct the indole cores with no ambiguity of the CF3 position. The intriguing 3-formyl-2-(trifluoromethyl)indoles can also be synthesized by this protocol, which are useful intermediates for the preparation of trifluoromethylated drug analogues. The ultimate CF3 source is the inexpensive industrial byproduct fluoroform. PMID- 29489380 TI - Surface Functionalization of Ti6Al4V via Self-assembled Monolayers for Improved Protein Adsorption and Fibroblast Adhesion. AB - Although metallic biomaterials find numerous biomedical applications, their inherent low bioactivity and poor osteointegration had been a great challenge for decades. Surface modification via silanization can serve as an attractive method for improving the aforementioned properties of such substrates. However, its effect on protein adsorption/conformation and subsequent cell adhesion and spreading has rarely been investigated. This work reports the in-depth study of the effect of Ti6Al4V surface functionalization on protein adsorption and cell behavior. We prepared self-assembled monolayers (SAMs) of five different surfaces (amine, octyl, mixed [1:1 ratio of amine:octyl], hybrid, and COOH). Synthesized surfaces were characterized by Fourier transform infrared-attenuated total reflection (FTIR-ATR) spectroscopy, contact angle goniometry, profilometry, and field emission scanning electron microscopy (FESEM). Quantification of adsorbed mass of bovine serum albumin (BSA) and fibronectin (FN) was determined on different surfaces along with secondary structure analysis. The adsorbed amount of BSA was found to increase with an increase in surface hydrophobicity with the maximum adsorption on the octyl surface while the reverse trend was detected for FN adsorption, having the maximum adsorbed mass on the COOH surface. The alpha helix content of adsorbed BSA increased on amine and COOH surfaces while it decreased for other surfaces. Whereas increasing beta-turn content of the adsorbed FN with the increase in the surface hydrophobicity was observed. In FN, RGD loops are located in the beta-turn and consequently the increase in Delta adhered cells (%) was predominantly increased with the increasing Delta beta-turn content (%). We found hybrid surfaces to be the most promising surface modifier due to maximum cell adhesion (%) and proliferation, larger nuclei area, and the least cell circularity. Bacterial density increased with the increasing hydrophobicity and was found maximum for the amine surface (theta = 63 +/- 1 degrees ) which further decreased with the increasing hydrophobicity. Overall, modified surfaces (in particular hybrid surface) showed better protein adsorption and cell adhesion properties as compared to unmodified Ti6Al4V and can be potentially used for tissue engineering applications. PMID- 29489382 TI - Adsorption and Fibrillization of Islet Amyloid Polypeptide at Self-Assembled Monolayers Studied by QCM-D, AFM, and PM-IRRAS. AB - Aggregation and fibrillization of human islet amyloid polypeptide (hIAPP) plays an important role in the development of type 2 diabetes mellitus. Understanding the interaction of hIAPP with interfaces such as cell membranes at a molecular level therefore represents an important step toward new therapies. Here, we investigate the fibrillization of hIAPP at different self-assembled alkanethiol monolayers (SAMs) by quartz crystal microbalance with dissipation monitoring (QCM D), atomic force microscopy (AFM), and polarization-modulated infrared reflection absorption spectroscopy (PM-IRRAS). We find that hydrophobic interactions with the CH3-terminated SAM tend to retard hIAPP fibrillization compared to the carboxylic acid-terminated SAM where attractive electrostatic interactions lead to the formation of a three-dimensional network of interwoven fibrils. At the hydroxyl- and amino-terminated SAMs, fibrillization appears to be governed by hydrogen bonding between the peptide and the terminating groups which may even overcome electrostatic repulsion. These results thus provide fundamental insights into the molecular mechanisms governing amyloid assembly at interfaces. PMID- 29489383 TI - Adsorption Mechanism of 4-Amino-5-mercapto-1,2,4-triazole as Flotation Reagent on Chalcopyrite. AB - A novel compound 4-amino-5-mercapto-1,2,4-triazole was first synthesized, and its selective adsorption mechanism on the surface of chalcopyrite was comprehensively investigated using UV-vis spectra, zeta-potential, Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy measurements (XPS), time-of flight secondary ion mass spectrometry (ToF-SIMS), and first principles calculations. The experimental and computational results consistently demonstrated that AMT would chemisorb onto the chalcopyrite surface by the formation of a five-membered chelate ring. The first principles periodic calculations further indicated that AMT would prefer to adsorb onto Cu rather than Fe due to the more negative adsorption energy of AMT on Cu in the chalcopyrite (001) surface, which was further confirmed by the coordination reaction energies of AMT-Cu and AMT-Fe based on the simplified cluster models at a higher accuracy level (UB3LYP/Def2-TZVP). The bench-scale results indicated that the selective index improved significantly when using AMT as a chalcopyrite depressant in Cu-Mo flotation separation. PMID- 29489381 TI - A Direct Comparison of in Vitro and in Vivo Nucleic Acid Delivery Mediated by Hundreds of Nanoparticles Reveals a Weak Correlation. AB - Endothelial cells and macrophages play active roles in disease and as a result are important targets for nucleic acid therapies. While thousands of chemically distinct lipid nanoparticles (LNPs) can be synthesized to deliver nucleic acids, studying more than a few LNPs in vivo is challenging. As a result, it is difficult to understand how nanoparticles target these cells in vivo. Using high throughput LNP barcoding, we quantified how well LNPs delivered DNA barcodes to endothelial cells and macrophages in vitro, as well as endothelial cells and macrophages isolated from the lung, heart, and bone marrow in vivo. We focused on two fundamental questions in drug delivery. First, does in vitro LNP delivery predict in vivo LNP delivery? By comparing how 281 LNPs delivered barcodes to endothelial cells and macrophages in vitro and in vivo, we found in vitro delivery did not predict in vivo delivery. Second, does LNP delivery change within the microenvironment of a tissue? We quantified how 85 LNPs delivered barcodes to eight splenic cell populations, and found that cell types derived from myeloid progenitors tended to be targeted by similar LNPs, relative to cell types derived from lymphoid progenitors. These data demonstrate that barcoded LNPs can elucidate fundamental questions about in vivo nanoparticle delivery. PMID- 29489384 TI - Mitochondrial inner membrane protein (mitofilin) knockdown induces cell death by apoptosis via an AIF-PARP-dependent mechanism and cell cycle arrest. AB - Mitofilin is an inner membrane protein that has been defined as a mitochondria shaping protein in controlling and maintaining mitochondrial cristae structure and remodeling. We determined the role of mitofilin in cell survival by investigating the mechanism underlying mitofilin knockdown-induced cell death by apoptosis. Cultured H9c2 myoblasts and HEK 293 cells were treated with mitofilin siRNA or scrambled siRNA for 24 h. Cell death (apoptosis), caspase 3 activity and cell cycle phases were assessed by flow cytometry, while cytochrome c release and intracellular ATP production were measured by ELISA. Mitofilin, apoptosis inducing factor (AIF) and poly(ADP-ribose) polymerase (PARP) expression were measured by Western blot analysis and calpain activity was assessed using a calpain activity kit. Mitochondrial images were taken using electron microscopy. We found that mitofilin knockdown increases apoptosis mainly via activation of the AIF-PARP pathway leading to nuclear fragmentation that is correlated with S phase arrest of the cell cycle. Knockdown of mitofilin also led to mitochondrial swelling and damage of cristae that is associated with the increase in reactive oxygen species production and mitochondrial calpain activity, as well as a marked decrease in intracellular ATP production and mitochondrial membrane potential. Together, these results indicate that mitofilin knockdown by siRNA increases calpain activity that presumably leads to mitochondrial structural degradation resulting in a critical reduction of mitochondrial function that is responsible for the increase in cell death by apoptosis via an AIF-PARP mechanism and associated with nuclear fragmentation, and S phase arrest of the cell cycle. PMID- 29489387 TI - Hydrolysis of Phosphate Esters Catalyzed by Inorganic Iron Oxide Nanoparticles Acting as Biocatalysts. AB - Phosphorus ester hydrolysis is one of the key chemical processes in biological systems, including signaling, free-energy transaction, protein synthesis, and maintaining the integrity of genetic material. Hydrolysis of this otherwise kinetically stable phosphoester and/or phosphoanhydride bond is induced by enzymes such as purple acid phosphatase. Here, I report that, as in previously reported aged inorganic iron ion solutions, the iron oxide nanoparticles in the solution, which are trapped in a dialysis membrane tube filled with the various iron oxides, significantly promote the hydrolysis of the various phosphate esters, including the inorganic polyphosphates, with enzyme-like kinetics. This observation, along with those of recent studies of iron oxide, vanadium pentoxide, and molybdenum trioxide nanoparticles that behave as mimics of peroxidase, bromoperoxidase, and sulfite oxidase, respectively, indicates that the oxo-metal bond in the oxide nanoparticles is critical for the function of these corresponding natural metalloproteins. These inorganic biocatalysts challenge the traditional concept of replicator-first scenarios and support the metabolism-first hypothesis. As biocatalysts, these inorganic nanoparticles with enzyme-like activity may work in natural terrestrial environments and likely were at work in early Earth environments as well. They may have played an important role in the C, H, O, S, and P metabolic pathway with regard to the emergence and early evolution of life. Key Words: Enzyme-Hydrolysis-Iron oxide-Nanoparticles Origin of life-Phosphate ester. Astrobiology 18, 294-310. PMID- 29489388 TI - Achieving Breastfeeding Equity: A Study of a National Breastfeeding Initiative. AB - BACKGROUND: Equity in breastfeeding could reduce excess morbidity and mortality among children and mothers of color. Few programs that support breastfeeding have been evaluated for their capacity to create equity. The aim of this study was to assess the extent to which a diverse set of national breastfeeding programs actively promoted equity. SUBJECTS AND METHODS: Qualitative data collection was conducted between December 2012 and July 2013 by visits to 29 of 58 breastfeeding programs selected by the funder. Programs underwent a site visit with open-ended interviews of staff. Investigators used Atlas.ti software to code data and content analysis of qualitative evaluation data. Key categories and themes were identified to answer the questions: how do the programs conceptualize equity? and how do the organizations operationalize an approach to equity? RESULTS: Programs had widely divergent and often limited conceptualizations of equity. Nine categories describe the equity approaches' programs used. The social, political, and environmental contexts in which programs operated varied in the degree of challenge they pose for implementing equity-focused breastfeeding methods. We found only a few programs that matched the social, cultural, and economic realities and context of women of color. CONCLUSIONS: Breastfeeding equity programs need to explicitly define and envision outcomes, and need to identify equity inhibiting policies and practices. Equity attainment is more likely to emerge from institutional transformational processes that collaborate with the populations at risk. These findings have implications for other programs addressing equity in health. PMID- 29489386 TI - A Hydrothermal-Sedimentary Context for the Origin of Life. AB - Critical to the origin of life are the ingredients of life, of course, but also the physical and chemical conditions in which prebiotic chemical reactions can take place. These factors place constraints on the types of Hadean environment in which life could have emerged. Many locations, ranging from hydrothermal vents and pumice rafts, through volcanic-hosted splash pools to continental springs and rivers, have been proposed for the emergence of life on Earth, each with respective advantages and certain disadvantages. However, there is another, hitherto unrecognized environment that, on the Hadean Earth (4.5-4.0 Ga), would have been more important than any other in terms of spatial and temporal scale: the sedimentary layer between oceanic crust and seawater. Using as an example sediments from the 3.5-3.33 Ga Barberton Greenstone Belt, South Africa, analogous at least on a local scale to those of the Hadean eon, we document constant permeation of the porous, carbonaceous, and reactive sedimentary layer by hydrothermal fluids emanating from the crust. This partially UV-protected, subaqueous sedimentary environment, characterized by physical and chemical gradients, represented a widespread system of miniature chemical reactors in which the production and complexification of prebiotic molecules could have led to the origin of life. Key Words: Origin of life-Hadean environment-Mineral surface reactions-Hydrothermal fluids-Archean volcanic sediments. Astrobiology 18, 259-293. PMID- 29489389 TI - Mothers' Concerns for Personal Safety and Privacy While Breastfeeding: An Unexplored Phenomenon. AB - BACKGROUND: Preliminary qualitative research in upstate NY shows new mothers are worried about safety while breastfeeding. Little is known regarding prevalence of these concerns and their effect on breastfeeding outcomes. OBJECTIVES: (1) Determine frequency of breastfeeding safety and privacy concerns; (2) Explore their association with breastfeeding outcomes. METHODS: Mothers were surveyed immediately and 1-month postpartum about breastfeeding goals; both surveys addressed privacy and safety concerns at home, work, and in public. Outcome data included breastfeeding intent, exclusivity, and duration. Breastfeeding/non breastfeeding mothers were compared using Chi-square and multivariate analyses. RESULTS: A total of 279 women enrolled. Of these 82.8% initiated breastfeeding; at 1-month 72% provided any breast milk, and 44% were exclusively breastfeeding. About 99% felt safe breastfeeding at home; 25% reported privacy concerns; and 5% felt "vulnerable or unsafe" while breastfeeding. At 1-month, 49% agreed there was a safe place to breastfeed/express milk at work (20% unsure). Non-breastfeeding mothers expressed more safety concerns outside home/at work: 18% breastfeeding versus 28% non-breastfeeding outside home; 27% breastfeeding versus 40% non breastfeeding at work. Nearly 54% who reported feeling vulnerable/unsafe with breastfeeding initiated breastfeeding, compared with 86% not reporting this concern (p = 0.008). Fewer women initiating breastfeeding reported vulnerability/safety (3% breastfeeding versus 14% non-breastfeeding, p = 0.008) or privacy (22% breastfeeding versus 40% non-breastfeeding, p = 0.19) concerns. Associations held after controlling for age, race, parity, insurance, geography, and marital-status. Significant associations between initiation, privacy, and safety concerns did not extend to duration or exclusivity. CONCLUSION: Many breastfeeding women reported safety and privacy concerns, especially outside the home and at work, which may influence breastfeeding initiation. Further study may identify methods to address these issues, potentially increasing breastfeeding rates. PMID- 29489390 TI - Baby-Friendly Practices Minimize Newborn Infants Weight Loss. AB - INTRODUCTION: It is accepted that newborns lose weight in the first few days of life. Baby-Friendly practices that support breastfeeding may affect newborn weight loss. The objective of this study were: 1) To determine whether Baby Friendly practices are associated with term newborn weight loss day 0-2 in three feeding categories (exclusively breastfed, mixed formula fed and breastfed, and formula fed). 2) To determine whether Baby-Friendly practices increase exclusive breast feeding rates in different ethnic populations. MATERIALS AND METHODS: This was a retrospective case-control study. Term newborn birth weight, neonatal weights days 0-2, feeding type, type of birth, and demographic information were collected for 1,000 births for the year before Baby-Friendly designation (2010) and 1,000 in 2013 (after designation). Ultimately 683 in the first group and 518 in the second met the inclusion criteria. RESULTS: Mean weight loss decreased day 0-2 for infants in all feeding types after the initiation of Baby-Friendly practices. There was a statistically significant effect of Baby-Friendly designation on weight loss for day 0-2 in exclusively breastfed infants (p < 0.01) after controlling for birth weight. Exclusive breast feeding increased in all ethnic groups after Baby-Friendly practices were put in place. CONCLUSION: There was a decrease in mean weight loss day 0-2 regardless of feeding type after Baby-Friendly designation. Exclusive breast feeding increased in the presence of Baby-Friendly practices. PMID- 29489391 TI - Kinesins and Myosins: Molecular Motors that Coordinate Cellular Functions in Plants. AB - Kinesins and myosins are motor proteins that can move actively along microtubules and actin filaments, respectively. Plants have evolved a unique set of motors that function as regulators and organizers of the cytoskeleton and as drivers of long-distance transport of various cellular components. Recent progress has established the full complement of motors encoded in plant genomes and has revealed valuable insights into the cellular functions of many kinesin and myosin isoforms. Interestingly, several of the motors were found to functionally connect the two cytoskeletal systems and thereby to coordinate their activities. In this review, we discuss the available genetic, cell biological, and biochemical data for each of the plant kinesin and myosin families from the context of their subcellular mechanism of action as well as their physiological function in the whole plant. We particularly emphasize work that illustrates mechanisms by which kinesins and myosins coordinate the activities of the cytoskeletal system. PMID- 29489392 TI - Meiotic Recombination: Mixing It Up in Plants. AB - Meiosis halves diploid chromosome numbers to haploid levels that are essential for sexual reproduction in most eukaryotes. Meiotic recombination ensures the formation of bivalents between homologous chromosomes (homologs) and their subsequent proper segregation. It also results in genetic diversity among progeny that influences evolutionary responses to selection. Moreover, crop breeding depends upon the action of meiotic recombination to rearrange elite traits between parental chromosomes. An understanding of the molecular mechanisms that drive meiotic recombination is important for both fundamental research and practical applications. This review emphasizes advances made during the past 5 years, primarily in Arabidopsis and rice, by summarizing newly characterized genes and proteins and examining the regulatory mechanisms that modulate their action. PMID- 29489393 TI - Exploring the Spatiotemporal Organization of Membrane Proteins in Living Plant Cells. AB - Plasma membrane proteins have important roles in transport and signal transduction. Deciphering the spatiotemporal organization of these proteins provides crucial information for elucidating the links between the behaviors of different molecules. However, monitoring membrane proteins without disrupting their membrane environment remains difficult. Over the past decade, many studies have developed single-molecule techniques, opening avenues for probing the stoichiometry and interactions of membrane proteins in their native environment by providing nanometer-scale spatial information and nanosecond-scale temporal information. In this review, we assess recent progress in the development of labeling and imaging technology for membrane protein analysis. We focus in particular on several single-molecule techniques for quantifying the dynamics and assembly of membrane proteins. Finally, we provide examples of how these new techniques are advancing our understanding of the complex biological functions of membrane proteins. PMID- 29489394 TI - Reactive Oxygen Species in Plant Signaling. AB - As fixed organisms, plants are especially affected by changes in their environment and have consequently evolved extensive mechanisms for acclimation and adaptation. Initially considered by-products from aerobic metabolism, reactive oxygen species (ROS) have emerged as major regulatory molecules in plants and their roles in early signaling events initiated by cellular metabolic perturbation and environmental stimuli are now established. Here, we review recent advances in ROS signaling. Compartment-specific and cross-compartmental signaling pathways initiated by the presence of ROS are discussed. Special attention is dedicated to established and hypothetical ROS-sensing events. The roles of ROS in long-distance signaling, immune responses, and plant development are evaluated. Finally, we outline the most challenging contemporary questions in the field of plant ROS biology and the need to further elucidate mechanisms allowing sensing, signaling specificity, and coordination of multiple signals. PMID- 29489395 TI - Trends in Global Agricultural Land Use: Implications for Environmental Health and Food Security. AB - The eighteenth-century Malthusian prediction of population growth outstripping food production has not yet come to bear. Unprecedented agricultural land expansions since 1700, and technological innovations that began in the 1930s, have enabled more calorie production per capita than was ever available before in history. This remarkable success, however, has come at a great cost. Agriculture is a major cause of global environmental degradation. Malnutrition persists among large sections of the population, and a new epidemic of obesity is on the rise. We review both the successes and failures of the global food system, addressing ongoing debates on pathways to environmental health and food security. To deal with these challenges, a new coordinated research program blending modern breeding with agro-ecological methods is needed. We call on plant biologists to lead this effort and help steer humanity toward a safe operating space for agriculture. PMID- 29489396 TI - Genomics-Informed Insights into Endosymbiotic Organelle Evolution in Photosynthetic Eukaryotes. AB - The conversion of free-living cyanobacteria to photosynthetic organelles of eukaryotic cells through endosymbiosis transformed the biosphere and eventually provided the basis for life on land. Despite the presumable advantage conferred by the acquisition of photoautotrophy through endosymbiosis, only two independent cases of primary endosymbiosis have been documented: one that gave rise to the Archaeplastida, and the other to photosynthetic species of the thecate, filose amoeba Paulinella. Here, we review recent genomics-informed insights into the primary endosymbiotic origins of cyanobacteria-derived organelles. Furthermore, we discuss the preconditions for the evolution of nitrogen-fixing organelles. Recent genomic data on previously undersampled cyanobacterial and protist taxa provide new clues to the origins of the host cell and endosymbiont, and proteomic approaches allow insights into the rearrangement of the endosymbiont proteome during organellogenesis. We conclude that in addition to endosymbiotic gene transfers, horizontal gene acquisitions from a broad variety of prokaryotic taxa were crucial to organelle evolution. PMID- 29489397 TI - Essential Roles of Local Auxin Biosynthesis in Plant Development and in Adaptation to Environmental Changes. AB - It has been a dominant dogma in plant biology that the self-organizing polar auxin transport system is necessary and sufficient to generate auxin maxima and minima that are essential for almost all aspects of plant growth and development. However, in the past few years, it has become clear that local auxin biosynthesis is required for a suite of developmental processes, including embryogenesis, endosperm development, root development, and floral initiation and patterning. Moreover, it was discovered that local auxin biosynthesis maintains optimal plant growth in response to environmental signals, including light, temperature, pathogens, and toxic metals. In this article, I discuss the recent progress in auxin biosynthesis research and the paradigm shift in recognizing the important roles of local auxin biosynthesis in plant biology. PMID- 29489398 TI - Cell and Developmental Biology of Plant Mitogen-Activated Protein Kinases. AB - Plant mitogen-activated protein kinases (MAPKs) constitute a network of signaling cascades responsible for transducing extracellular stimuli and decoding them to dedicated cellular and developmental responses that shape the plant body. Over the last decade, we have accumulated information about how MAPK modules control the development of reproductive tissues and gametes and the embryogenic and postembryonic development of vegetative organs such as roots, root nodules, shoots, and leaves. Of key importance to understanding how MAPKs participate in developmental and environmental signaling is the characterization of their subcellular localization, their interactions with upstream signal perception mechanisms, and the means by which they target their substrates. In this review, we summarize the roles of MAPK signaling in the regulation of key plant developmental processes, and we survey what is known about the mechanisms guiding the subcellular compartmentalization of MAPK modules. PMID- 29489399 TI - Macroevolutionary Patterns of Flowering Plant Speciation and Extinction. AB - Species diversity is remarkably unevenly distributed among flowering plant lineages. Despite a growing toolbox of research methods, the reasons underlying this patchy pattern have continued to perplex plant biologists for the past two decades. In this review, we examine the present understanding of transitions in flowering plant evolution that have been proposed to influence speciation and extinction. In particular, ploidy changes, transitions between tropical and nontropical biomes, and shifts in floral form have received attention and have offered some surprises in terms of which factors influence speciation and extinction rates. Mating systems and dispersal characteristics once predominated as determining factors, yet recent evidence suggests that these changes are not as influential as previously thought or are important only when paired with range shifts. Although range extent is an important correlate of speciation, it also influences extinction and brings an applied focus to diversification research. Recent studies that find that past diversification can predict present-day extinction risk open an exciting avenue for future research to help guide conservation prioritization. PMID- 29489400 TI - Preadaptation and Naturalization of Nonnative Species: Darwin's Two Fundamental Insights into Species Invasion. AB - Predicting which nonnative species become invasive is critical for their successful management, and Charles Darwin provided predictions based on species' relatedness. However, Darwin provided two opposing predictions about the relatedness of introduced nonnatives to indigenous species. First, environmental fit is the dominant factor determining invader success; thus, we should expect that invasive species are closely related to local native residents. Alternatively, if competition is important, we should expect successful invaders are distantly related to the native residents. These opposing expectations are referred to as Darwin's naturalization conundrum. The results of studies that examine nonnative species relatedness to natives are largely inconsistent. This inconsistency arises from the fact that studies occur at different spatial and temporal scales, and at different stages of invasion, and so implicitly examine different mechanisms. Further, while species have evolved ecological differences, the mode and tempo of evolution can affect species' differences, complicating the predictions from simple hypotheses. We outline unanswered questions and provide guidelines for collecting the data required to test competing hypotheses. PMID- 29489401 TI - Cervical Spine Injury From Unrecognized Craniocervical Instability in Severe Pierre Robin Sequence Associated With Skeletal Dysplasia. AB - Pierre Robin Sequence (PRS) can be associated with skeletal dysplasias, presenting with craniocervical instability and devastating spinal injury if unrecognized. The authors present the case of an infant with PRS and a type II collagenopathy who underwent multiple airway-securing procedures requiring spinal manipulation before craniocervical instability was identified. This resulted in severe cervical cord compression due to odontoid fracture and occipitoatlantoaxial instability. This case highlights the importance of early cervical spine imaging and cautious manipulation in infants with PRS and suspected skeletal dysplasia. PMID- 29489402 TI - Abnormalities Associated With the Cavum Septi Pellucidi on Fetal MRI: What Radiologists Need to Know. AB - OBJECTIVE: Screening the cavum septi pellucidi (CSP), more commonly referred to as the "cavum septum pellucidum," is a required component of the fetal anatomic survey during second-trimester ultrasound (US). The inability to identify the normal appearance of this structure warrants further evaluation because septal insufficiency is associated with multiple brain malformations. In this article, we discuss embryology, normal anatomy, and prenatal evaluation of the CSP as well as the differential diagnosis of associated abnormalities. CONCLUSION: The CSP is an essential part of the CNS evaluation on second-trimester US; if its normal appearance cannot be confirmed by 20 weeks' gestational age, further evaluation is warranted. Fetal MRI, in either the second or third trimester, has become an important tool in further characterization of the associated abnormalities. However, when fetal MRI is not possible, postnatal MRI can also be used and will help to differentiate primary from secondary absence and will aid in providing prognostic information and therapeutic options for patients. PMID- 29489403 TI - Section Editor's Notebook: New Beginning and Voices From Around the World-Annual Focus on Pediatric Imaging Issue. PMID- 29489404 TI - Sonographic-MRI Correlation After Percutaneous Sampling of Targeted Breast Ultrasound Lesions: Initial Experiences With Limited-Sequence Unenhanced MRI for Postprocedural Clip Localization. AB - OBJECTIVE: The purpose of this study is to determine the frequency of correlation of sonographic and MRI findings after percutaneous sampling of presumed ultrasound correlates to suspicious lesions detected on breast MRI and to describe our initial experiences with limited-sequence MRI for postprocedural clip verification. MATERIALS AND METHODS: Between January 1, 2014, and March 31, 2016, a total of 1947 contrast-enhanced breast MRI examinations were performed, and 245 targeted ultrasound examinations were conducted to identify correlates to suspicious MRI findings. We retrospectively identified all lesions that underwent ultrasound-guided sampling of a presumed sonographic correlate and for which a subsequent postprocedural limited-sequence unenhanced MR image for clip localization was available. This consisted of a T1-weighted non-fat-saturated and a T2-weighted fat-saturated sequence. Frequencies of sonographic-MRI correlation were quantified. RESULTS: The study cohort consisted of 35 patients with 38 presumed correlates that underwent ultrasound-guided sampling with postprocedural MRI for clip verification. The mean time from percutaneous sampling to postprocedural MRI examination was 1 day. Ten presumed sonographic correlates (26%) were found to localize to a site distinct from the lesion originally identified on MRI. One of these discordant cases revealed malignancy on subsequent MRI-guided biopsy, whereas the presumed sonographic correlate was found to be benign. No patient or lesion characteristics were associated with significantly different frequencies of correlation. CONCLUSION: In our initial experiences with MRI performed for postprocedural clip verification, 26% of presumed correlates to suspicious lesions detected on MRI were not the actual correlate, and 10% of these discordant cases ultimately revealed malignancy. Radiologists should take caution presuming that lesions identified on ultrasound actually represent the suspicious lesions detected on MRI. MRI for clip verification may be useful if ultrasound-guided sampling is pursued. PMID- 29489405 TI - Imaging Patterns of Injuries After the 2015 Amtrak Philadelphia Train Derailment. AB - OBJECTIVE: The purpose of this article is to describe the injury patterns observed in the 2015 Philadelphia Amtrak train derailment. CONCLUSION: Fractures accounted for most observed injuries, but uncommon and potentially serious injuries included posterior sternoclavicular dislocation and mesenteric contusion. Imaging plays a critical role in the triage of patients during mass casualty events, and familiarity with the injury patterns associated with high velocity unrestrained blunt force trauma will aid diagnosis in any future similar occurrence. PMID- 29489406 TI - Utility of Pelvic CT for Surveillance of T2-T4 Renal Cell Carcinoma After Nephrectomy With Curative Intent. AB - OBJECTIVE: The purpose of this study was to determine whether routine pelvic imaging is necessary during postoperative surveillance of pathologic T2-T4 renal cell carcinoma after nephrectomy for curative intent. MATERIALS AND METHODS: A retrospective single-institution cohort study with 603 subjects undergoing partial or radical nephrectomy of T2-T4 renal cell carcinoma with curative intent was conducted from January 1, 2000, through December 31, 2015. Clinical and imaging (CT or MRI) follow-up findings were evaluated in a prospectively maintained registry to determine the timing and location of recurrent and metastatic disease. The primary outcome was the proportion of subjects with positive or equivocal findings in the pelvis and negative findings in the chest and abdomen. Binomial CIs were calculated and compared with a prespecified minimum detection threshold of 5%. RESULTS: The T category distribution was as follows: T2 (28.9% [174/603]), T3 (70.3% [424/603]), and T4 (0.8% [5/603]). Most (81.8% [493/603]) of the patients underwent radical nephrectomy, and 27.0% (163/603) had recurrence or metastasis (mean time to first recurrence, 600 +/- 695 days). Pelvic imaging findings were negative in 97.0% (585/603) of cases. Four subjects (0.7% [95% CI, 0.2-1.7%]) had isolated positive findings in the pelvis (p < 0.0001 vs the 5% threshold). Two (0.3% overall [95% CI, 0.04-1.1%]) of these positive findings were in subjects who did not have symptoms. CONCLUSION: Routine pelvic imaging of patients undergoing surveillance for asymptomatic T2-T4 renal cell carcinoma after nephrectomy performed with curative intent has minimal value and probably should not be performed. PMID- 29489407 TI - CT Features of Ovarian Tumors: Defining Key Differences Between Serous Borderline Tumors and Low-Grade Serous Carcinomas. AB - OBJECTIVE: The objective of our study was to investigate whether the CT features of serous borderline tumors (SBTs) differ from those of low-grade serous carcinomas (LGSCs) and to evaluate if mutation status is associated with distinct CT phenotypes. MATERIALS AND METHODS: This retrospective study included 59 women, 37 with SBT and 22 with LGSC, who underwent CT before primary surgical resection. Thirty of 59 patients were genetically profiled. Two radiologists (readers 1 and 2) independently and retrospectively reviewed CT examinations for qualitative features and quantified total tumor volumes (TTVs), solid tumor volumes (STVs), and solid proportion of ovarian masses. Univariate and multivariate associations of the CT features with histopathologic diagnoses and mutations were evaluated, and interreader agreement was determined. RESULTS: At multivariate analysis, the presence of bilateral ovarian masses (p = 0.03), the presence of peritoneal disease (PD) (p = 0.002), and higher STV of ovarian masses (p = 0.002) were associated with LGSC. The presence of nodular PD pattern (p < 0.001 each reader) and the presence of PD calcifications (reader 1, p = 0.02; reader 2, p = 0.003) were associated with invasive peritoneal lesions (i.e., LGSC). The presence of bilateral ovarian masses (p = 0.04 each reader), PD (reader 1, p = 0.01; reader 2, p = 0.004), and higher STV (p = 0.03 for each reader) were associated with the absence of BRAF mutation (i.e., wild type [wt]-BRAF). CONCLUSION: The CT features of LGSCs were distinct from those of SBTs. The CT manifestations of LGSC and the wt-BRAF phenotype were similar. PMID- 29489408 TI - Preoperative MDCT Assessment of Resectability in Borderline Resectable Pancreatic Cancer: Effect of Neoadjuvant Chemoradiation Therapy. AB - OBJECTIVE: The purpose of this study is to evaluate the diagnostic performance of MDCT in assessing tumor resectability in patients with borderline resectable pancreatic cancers after receiving neoadjuvant chemoradiation therapy (CRT) in comparison with those undergoing upfront surgery. SUBJECTS AND METHODS: Thirty seven patients with borderline resectable pancreatic cancers were randomly allocated to the neoadjuvant CRT group (arm 1; n = 18) or up-front surgery group (arm 2; n = 19). Three radiologists rated the likelihood of local resectability on a 5-point scale at preoperative MDCT in two separate sessions (session 1: post CRT of arm 1, baseline of arm 2; session 2: using new imaging criteria reflecting the changes during CRT of arm 1). The AUC of each reviewer, as well as sensitivity, specificity, and accuracy based on consensus interpretation, were compared between arms and sessions. RESULTS: For local resectability (n = 30), AUC values at session 1 were 0.664, 0.669, and 0.588 for reviewers 1, 2, and 3, respectively, and were not significantly different between arms 1 (n = 15; 0.759, 0.713, and 0.593) and 2 (n = 15; 0.852, 0.685, and 0.722) (p > 0.05). In arm 1, MDCT sensitivity, specificity, accuracy were 22%, 100%, and 53%, respectively, at session 1 versus 78%, 67%, and 73%, respectively, at session 2 (p > 0.05). CONCLUSION: In patients with borderline resectable pancreatic cancers, neoadjuvant CRT did not significantly decrease the performance of MDCT for the prediction of local resectability. However, by considering post-CRT changes, such as nonprogression in tumor-vascular contact, MDCT may provide better sensitivity for locally resectable disease. PMID- 29489409 TI - MRI-Ultrasound Fusion Targeted Biopsy of Prostate Imaging Reporting and Data System Version 2 Category 5 Lesions Found False-Positive at Multiparametric Prostate MRI. AB - OBJECTIVE: The purpose of this study was to determine imaging and clinical features associated with Prostate Imaging Reporting and Data System (PI-RADS) category 5 lesions identified prospectively at multiparametric MRI (mpMRI) that were found benign at MRI-ultrasound fusion targeted biopsy. MATERIALS AND METHODS: Between January 2015 and July 2016, 325 men underwent prostate mpMRI followed by MRI-ultrasound fusion targeted biopsy of 420 lesions prospectively identified and assessed with PI-RADS version 2. The frequency of clinically significant prostate cancer (defined as Gleason score >= 7) among PI-RADS 5 lesions was determined. Lesions with benign pathologic results were retrospectively reassessed by three abdominal radiologists and categorized as concordant or discordant between mpMRI and biopsy results. Multivariate logistic regression was used to identify factors associated with benign disease. Bonferroni correction was used. RESULTS: Of the 98 PI-RADS 5 lesions identified in 89 patients, 18% (18/98) were benign, 10% (10/98) were Gleason 6 disease, and 71% (70/98) were clinically significant prostate cancer. Factors associated with benign disease at multivariate analysis were lower prostate-specific antigen density (odds ratio [OR], 0.88; p < 0.001) and apex (OR, 3.54; p = 0.001) or base (OR, 7.11; p = 0.012) location. On secondary review of the 18 lesions with benign pathologic results, 39% (7/18) were scored as benign prostatic hyperplasia nodules, 28% (5/18) as inflammatory changes, 5% (1/18) as normal anatomic structures, and 28% (5/18) as discordant with imaging findings. CONCLUSION: PI RADS 5 lesions identified during routine clinical interpretation are associated with a high risk of clinically significant prostate cancer. A benign pathologic result was significantly correlated with lower prostate-specific antigen density and apex or base location and most commonly attributed to a benign prostatic hyperplasia nodule. Integration of these clinical features may improve the interpretation of high-risk lesions identified with mpMRI. PMID- 29489410 TI - Diagnostic Utility of a Likert Scale Versus Qualitative Descriptors and Length of Capsular Contact for Determining Extraprostatic Tumor Extension at Multiparametric Prostate MRI. AB - OBJECTIVE: The purpose of this study is to determine the reproducibility and diagnostic performance of a Likert scale in comparison with the European Society of Urogenital Radiology (ESUR) criteria and tumor-pseudocapsule contact length (TCL) for the detection of extraprostatic extension (EPE) at multiparametric MRI. MATERIALS AND METHODS: This was a retrospective review of all men who underwent multiparametric MRI followed by prostatectomy between November 2015 and July 2016. Multiparametric 3-T MRI studies with an endorectal coil were independently reviewed by five readers who assigned the likelihood of EPE using a 1-5 Likert score, ESUR criteria, and TCL (> 10 mm). EPE outcome (absent or present) for the index lesion at whole-mount histopathologic analysis was the standard of reference. Odds ratios (ORs) and areas under the ROC curve (Az) were used for diagnostic accuracy. The interreader agreement was determined using a weighted kappa coefficient. A p < 0.05 was considered significant. RESULTS: Eighty men met the eligibility criteria. At univariate analysis, the Likert score showed the strongest association (OR, 1.8) with EPE, followed by prostate-specific antigen level (OR, 1.7), ESUR score (OR, 1.6), and index lesion size (OR, 1.2). At multivariable analysis, higher Likert score (OR, 1.8) and prostate-specific antigen level (OR, 1.6-1.7) were independent predictors of EPE. The Az value for Likert scores was statistically significantly higher (0.79) than that for TCL (0.74; p < 0.01), but not statistically significantly higher than the value for ESUR scores (0.77; p = 0.17). Interreader agreement with Likert (kappa = 0.52) and ESUR scores (kappa = 0.55) was moderate and slightly superior to that for TCL (kappa = 0.43). Except for TCL among inexperienced readers (kappa = 0.34), reader experience did not affect interreader agreement. CONCLUSION: A Likert score conveying the degree of suspicion at multiparametric MRI is a stronger predictor of EPE than is either ESUR score or TCL and may facilitate informed decision making, patient counseling, and treatment planning. PMID- 29489411 TI - Who Refers Musculoskeletal Extremity Imaging Examinations to Radiologists? AB - OBJECTIVE: The purpose of this study is to identify the specialty characteristics of providers referring musculoskeletal (MSK) extremity imaging examinations to radiologists, so as to better understand the drivers of MSK imaging utilization and potentially improve the appropriateness of such imaging examinations. MATERIALS AND METHODS: Data on provider referral for MSK extremity imaging services were extracted from the 2014 Medicare Referring Provider Utilization for Procedures public use file, which aggregates data on diagnostic procedures according to referring provider identities and service codes. MSK extremity imaging services were identified using Neiman Institute Types of Service codes. The referring provider specialty was identified from cross-linked Medicare provider characteristics files. RESULTS: For 4,275,647 MSK extremity imaging examinations ordered, the most common specialties of the referring providers were orthopedic surgery (37.6% of ordered examinations), internal medicine (20.2%), family practice (14.8%), emergency medicine (7.9%), and rheumatology (5.7%). Orthopedic surgery was the referring specialty that most commonly ordered MSK extremity CT (33,465 ordered examinations; for all other specialties, < 2000 examinations), MRI (325,485 examinations; for all other specialities, < 20,000 examinations), and radiography (1,249,748 examinations; for all other specialities, < 850,000 examinations), whereas internal medicine was the referring specialty that most commonly ordered MSK extremity ultrasound examinations (8052 ordered examinations; for all other specialties, < 6000 examinations). Among the select specialties most relevant to MSK imaging, the most frequent referrers after orthopedic surgeons were rheumatologists, for radiography (236,057 ordered examinations) and ultrasound (2034 examinations), and podiatrists, for CT (1201 examinations) and MRI (19,159 examinations). The most commonly ordered individual MSK extremity imaging services were knee radiography, with 190,354 examinations ordered by orthopedic surgeons; hand radiography, with 66,167 examinations ordered by rheumatologists; foot radiography, with 137,042 examinations ordered by podiatrists; shoulder radiography, with 11,299 examinations ordered by sports medicine specialists; and hip radiography, with 9838 examinations ordered by physiatrists. CONCLUSION: Referral patterns for MSK imaging vary considerably by provider specialty. Referral pattern insights may guide targeted efforts by radiologists to ensure the appropriateness of such examinations. PMID- 29489412 TI - Neonatal Lung Disorders: Pattern Recognition Approach to Diagnosis. AB - OBJECTIVE: Lung disease is a common indication for neonates to require medical attention, and neonatal chest radiographs are among the most common studies interpreted by pediatric radiologists. Radiographic features of many neonatal lung disorders overlap, and it may be difficult to differentiate among conditions. CONCLUSION: This review presents an up-to-date practical approach to the radiologic diagnosis of neonatal lung disorders, with a focus on pattern recognition and consideration of clinical history, patient age, and symptoms. PMID- 29489413 TI - Anomalous Extratemporal Facial Nerve in Oculoauriculovertebral Spectrum. AB - Facial nerve dysfunction is common in oculoauriculovertebral spectrum (OAVS). However, the course of the nerve has rarely been described. A 23-year-old woman with OAVS underwent excision of microtic ear remnants in preparation for an osseointegrated prosthesis and suffered iatrogenic transection of the facial nerve-the pes anserinus was within the subcutaneous tissue 15 mm posterior and 15 mm cephalad to the external acoustic meatus. The patient underwent primary nerve repair and regained nearly complete preoperative function. When considering reconstruction for OAVS patients, clinicians should have a high index of suspicion for anomalous facial nerve anatomy. PMID- 29489414 TI - Morphologic Evaluation for Safe Le Fort I Osteotomy in Cleft Lip and Palate. AB - OBJECTIVE: The present study aimed to determine the structure and morphology of the maxilla in patients with cleft lip and palate to ensure safe Le Fort I osteotomy. PATIENTS: A total of 34 sides of 17 patients with unilateral cleft lip and palate (nonsyndromic cases) were included in this study. The control group included 10 sides of 5 patients who exhibited skeletal mandibular protrusion without malformation. METHODS: Finite element analysis was performed to examine the distribution of occlusal force over the maxilla, and continuous 3-dimensional measurement was performed at the sites of stress concentration. RESULTS: In patients with cleft lip and palate, bones at the lateral border of the piriform aperture and the anterior wall of the maxillary sinus were significantly thicker than those in controls ( P < .05). Furthermore, the attachment of the pterygomaxillary junction was wider and thicker ( P < .05), and the anterior distance to the descending palatine artery was shorter ( P < .01) in patients with cleft lip and palate than in controls. Our results further indicated that alveolar bone grafting may significantly influence bone thickness and the attachment state of the pterygomaxillary junction. CONCLUSIONS: Our results suggest that the complications of LFI can be reduced in patients with cleft lip and palate by ensuring proper understanding of each patient's maxillary anatomy and bone thickness, as well as the location of the descending palatine artery and the attachment state of the pterygomaxillary junction. PMID- 29489416 TI - Common Variants in ALPL Gene Contribute to the Risk of Kidney Stones in the Han Chinese Population. AB - OBJECTIVE: Kidney stone formation is a complex disorder that likely results from both dietary and genetic factors. A recent study identified an association between the risk of kidney stones and polymorphisms in the ALPL gene, but the study needs replication. To confirm whether the ALPL gene is universally associated with kidney stones, the present study further investigated polymorphisms of the ALPL gene in a Han Chinese population. METHODS: A total of 331 kidney stone patients and 553 unrelated healthy controls were included in the present case-control study. We conducted genetic analyses to detect the association of 19 tagging single nucleotide polymorphisms (SNPs) with kidney stones. In addition, we examined the relations between targeted SNP(s) and several clinical characteristics of kidney stones in the patients. RESULTS: Genetic association analyses using logistic regression models identified one ALPL SNP, rs1256328, which was significantly associated with the kidney stone disease status (OR = 1.52, p = 0.0009). No significant results were obtained through association tests between genotypes of this SNP and the various clinical characteristics of kidney stone patients. CONCLUSION: The ALPL SNP, rs1256328, was identified as being significantly associated with kidney stone disease status in a large Chinese Han cohort. Our study replicated a previous genome-wide association study that was conducted in an Icelandic population. PMID- 29489415 TI - Novel GREM1 Variations in Sub-Saharan African Patients With Cleft Lip and/or Cleft Palate. AB - OBJECTIVE: Cleft lip and/or cleft palate (CL/P) are congenital anomalies of the face and have multifactorial etiology, with both environmental and genetic risk factors playing crucial roles. Though at least 40 loci have attained genomewide significant association with nonsyndromic CL/P, these loci largely reside in noncoding regions of the human genome, and subsequent resequencing studies of neighboring candidate genes have revealed only a limited number of etiologic coding variants. The present study was conducted to identify etiologic coding variants in GREM1, a locus that has been shown to be largely associated with cleft of both lip and soft palate. PATIENTS AND METHOD: We resequenced DNA from 397 sub-Saharan Africans with CL/P and 192 controls using Sanger sequencing. Following analyses of the sequence data, we observed 2 novel coding variants in GREM1. These variants were not found in the 192 African controls and have never been previously reported in any public genetic variant database that includes more than 5000 combined African and African American controls or from the CL/P literature. RESULTS: The novel variants include p.Pro164Ser in an individual with soft palate cleft only and p.Gly61Asp in an individual with bilateral cleft lip and palate. The proband with the p.Gly61Asp GREM1 variant is a van der Woude (VWS) case who also has an etiologic variant in IRF6 gene. CONCLUSION: Our study demonstrated that there is low number of etiologic coding variants in GREM1, confirming earlier suggestions that variants in regulatory elements may largely account for the association between this locus and CL/P. PMID- 29489417 TI - Compensations in Bone Morphology and the Dentition in Patients With Untreated Unilateral Cleft Lip and Palate: A Cone-Beam Computed Tomographic Analysis. AB - OBJECTIVE: The purpose of this study was to quantitatively assess dentoalveolar and skeletal compensations in patients with untreated unilateral cleft lip and palate (UCLP). We hypothesized that there are significant skeletal and dental adaptations in UCLP cases compared to a comparison maxillary crossbite group. DESIGN: A convenience retrospective sample of 30 patients with UCLP and a comparison group of 30 patients with unilateral posterior crossbite without CLP. Cone-beam computed tomography scans (CBCTs) were used to evaluate dental and skeletal compensations. In addition, alveolar bone thickness was measured at 2-mm increments in mesiodistal and faciolingual cross-sectional views along the long axis of the central incisors. Alveolar bone height was measured, and the percentage of root length supported by bone was calculated. RESULTS: Compensations for unilateral cleft lip and palate were restricted to the cleft site and adjacent structures. Dental compensations include alteration in the position of cleft-adjacent maxillary incisors and maxillary canines. No gross skeletal compensations were found. Alveolar support of cleft adjacent incisors was similar to controls except for measurements in the most coronal and apical regions. The cleft group contralateral incisors exhibited buttressing effects and had significantly higher alveolar thickness in the coronal half of the tooth. There was less (5%) alveolar coverage of the cleft-facing aspect of the central incisor root than all other incisors. CONCLUSION: The bone adaptation to the presence of a cleft was localized in the vicinity of the cleft, and adaptations in the mandible were not apparent. PMID- 29489418 TI - Otologic Outcomes With Two Different Surgical Protocols in Patients With a Cleft Palate: A Retrospective Study. AB - OBJECTIVE: To compare otologic outcomes in patients with cleft palate who underwent 2 different surgical protocols. DESIGN: Monocentric retrospective analysis of medical reports. PATIENTS, PARTICIPANTS: All consecutively treated patients affected by a cleft palate, born between January 1998 and December 2002 (group 1) and between January 2007 and December 2010 (group 2). INTERVENTIONS: Patients in group 1 underwent Veau-Wardill-Kilner palatoplasty at 10 months and had ventilation tubes inserted in case of otitis media with effusion (OME) during surgery. Patients in group 2 underwent Sommerlad intravelar veloplasty at 5 months. Ventilation tubes were inserted only in case of persistent OME. MAIN OUTCOME MEASURE(S): The need for a second set of ventilation tubes to be inserted in case of persistent OME, the presence of OME at the age of 2 years, and tympanic abnormalities at the age of 5 years were analyzed. RESULTS: There was no statistically significant difference either for the presence of OME at the age of 2 years (27 [45%] vs 32 [57.14%], respectively, in groups 1 and 2; P = .191) or for tympanic abnormalities at the age of 5 years (20 [33.33%] vs 15 [26.79%]; P = .433). Statistically significant difference was found for the need to insert a second set of ventilation tubes in case of persistent OME (29 [48.33%] vs 12 [21.42%], respectively; P = .02). CONCLUSION: Early Sommerlad intravelar veloplasty may reduce persistent OME and consequently the need for ventilation tubes insertion, compared to later Veau-Wardill-Kilner palatoplasty. PMID- 29489420 TI - Syphilis incidence in men who have sex with men with human immunodeficiency virus comorbidity and the importance of integrating sexually transmitted infection prevention into HIV care. AB - INTRODUCTION: Syphilis continues to be a growing epidemic among men who have sex with men (MSM), particularly for those living with the human immunodeficiency virus (HIV). In 2016, MSM accounted for 80% of primary and secondary syphilis diagnoses in men in the United States; almost half of who were also HIV-infected. The synergistic relationship between HIV and syphilis has significant implications not only for HIV patient management, but also for sexually transmitted infection (STI) control among MSM. Areas covered: We review the literature on STI screening and treatment barriers at the patient-, provider-, and health system-levels, and present strategies to incorporate STI prevention into HIV care settings. Expert commentary: Integration of STI prevention into HIV care is paramount to stop the epidemic of not only syphilis, but also other curable STIs like gonorrhea and chlamydia. Although guidelines have been established for STI testing in HIV-infected MSM, screening rates continue to be lower than desired. Gonorrhea and chlamydia screening is below 50% in HIV infected MSM; interventions that improve testing of those two infections must be implemented. For syphilis control, other additional strategies such as chemoprophylaxis should be considered given syphilis screening is above 50% in HIV-infected MSM. PMID- 29489419 TI - A Novel Cx50 Insert Mutation from a Chinese Congenital Cataract Family Impairs Its Cellular Membrane Localization and Function. AB - Mutations in GJA8 are associated with hereditary autosomal dominant and recessive cataract formation. In this study, a novel insert mutation in GJA8 was identified in a Chinese congenital cataract family and cosegregated with the disease in this pedigree. This insert mutation introduces five additional amino acid residues YAVHY after histidine at the 95 site (p.H95_A96insYAVHY) within the second transmembrane (TM2) domain of Cx50 protein (Cx50-insert). Ectopic expression of Cx50-insert protein impairs the hemichannel functions and gap junction activity compared to wild-type Cx50 protein in human lens epithelial cells. Cx50-insert proteins were mislocated from cytoplasmic membrane to endoplasmic reticulum and lysosome. In mouse lens tissue, our results showed that Cx50 predominant expresses in epithelial cells and fiber cells at the transition zone of lens hinting its roles in lens differentiation. Taken together, these data suggest that the novel insert mutation in the TM2 domain of Cx50 protein, which impairs its trafficking to the cell membrane and gap-junction function, is associated with the cataract formation in this Chinese pedigree. PMID- 29489421 TI - Voluntary- and Involuntary-Distraction Engagement: An Exploratory Study of Individual Differences. AB - Objective The aim of this study was to explore individual differences in voluntary and involuntary driver-distraction engagement. Background Distractions may stem from intentional engagement in secondary tasks (voluntary) or failing to suppress non-driving-related stimuli or information (involuntary). A wealth of literature has examined voluntary distraction; involuntary distraction is not particularly well understood. Individual factors, such as age, are known to play a role in how drivers engage in distractions. However, it is unclear which individual factors are associated with voluntary- versus involuntary-distraction engagement and whether there is a relation between how drivers engage in these two distraction types. Method Thirty-six participants, ages 25 to 39, drove in a simulator under three conditions: voluntary distraction with a self-paced visual manual task on a secondary display, involuntary distraction with abrupt onset of irrelevant visual-audio stimuli on the secondary display, and no distraction. Results The number of glances toward the secondary display under voluntary distraction was not correlated to that under involuntary distraction. The former was associated with gender, age, annual mileage, and self-reported distraction engagement; such associations were not observed for the latter. Accelerator release time in response to lead-vehicle braking was delayed similarly under both conditions. Conclusion Propensity to engage in voluntary distractions appears to be not related to the inability of suppressing involuntary distractions. Further, voluntary and involuntary distraction both affect braking response. These findings have implications for design of in-vehicle technologies, which may be sources of both distraction types. PMID- 29489422 TI - The conflicted practice: Municipal occupational therapists' experiences with assessment of clients with cognitive impairments. AB - BACKGROUND: The practice of Norwegian occupational therapists (OTs) in municipal practice is a little explored area and with the Coordination Reform Act from 2012, Norwegian OTs in municipal practice have received responsibilities concerning clients with cognitive impairments. The aim of this study was to explore municipal OTs experiences with assessment of clients with cognitive impairments. METHOD: Fourteen individual interviews with OTs who worked with clients with cognitive impairments, were conducted. An inductive thematic analysis, using text condensation and coding, was performed. RESULTS: The results revealed three themes; power of occupation, advantages and disadvantages of assessments used and the need for competencies within municipal services. The participants emphasized using observation in the assessment process and reflected on pros and cons of the standardized assessment tools they used. They expressed a need for competence development, although it was difficult to prioritize to do so. CONCLUSION: This study illustrated a conflicted practice related to choices OTs make in their practices. They valued the importance of working occupation based, however, they chose to use impairment based standardized assessments. They expressed a need to engage in professional development, but due to heavy workloads, the limited power they experienced and lack of knowledge, this was difficult. PMID- 29489423 TI - Tumor Immunology and Immunotherapy for Head and Neck Squamous Cell Carcinoma. AB - The immune system plays an important role in the evolution of malignancy and has become an important target for novel antineoplastic agents. This review article focuses on key features of tumor immunology, including the role of immunotherapy in general and as it pertains to head and neck squamous cell carcinoma. Side effects, resistance mechanisms, and therapeutic monitoring strategies pertaining to immunotherapy are discussed. PMID- 29489424 TI - Altered Immune-Related Gene Expressions Indicate Oral Cancer Nodal Disease. AB - Lymph nodal disease (LN+) is the most significant prognostic factor of oral squamous cell carcinoma (OSCC). Current risk indicator(s) for guiding elective neck dissection (END) is insufficient for clinically node-negative (cN0) patients, resulting in under- or overtreatment. While the role of immunological events in tumorigenesis and metastasis is evident, the prognostic implication in OSCC remains unclear. The study objective was to investigate large-scale immune related gene expression and determine its prognostic value on node-free survival (NFS). We analyzed patients who received intent-to-cure surgery with at least 3 y of follow-up and known outcome of LN through a pan-Canadian surgical trial. Total RNA was extracted from surgical tissues with >70% tumor content and analyzed on a 730-gene panel (NanoString nCounter(r) PanCancer Immune Panel). We first profiled gene expression in a fresh-frozen (FF) discovery set to identify differentially expressed (DE) genes, which were then used in unsupervised clustering analysis to identify patient subgroups. The prognostic value of the identified DE genes was then validated on formalin-fixed, paraffin-embedded (FFPE) samples. A total of 177 RNA samples were derived from 89 FF and 88 FFPE surgical tissues, of which 45 (51%) and 40 (45%), respectively, were from patients who developed LN+. We identified 6 DE genes overexpressed in LN+ tumors (false discovery rate <0.001; log2 fold change >1). Clustering analysis separated the patients into 2 subgroups (CM1, CM2), with CM2 exhibiting significantly increased expression and worse 5-y NFS rate (28%; P < 0.001). The prognostic value of these 6 candidate genes was validated on FFPE samples, which were also separated into 2 distinct prognostic groups, confirming the association between increased gene expression and poor 5-y NFS (CM1, 70.3%; CM2, 43.3%; P = 0.01). This is the first study identifying a panel of immune-related genes associated with NFS that can potentially be used clinically stratifying the risk of LN+ at the time of OSCC diagnosis. PMID- 29489425 TI - Bone Morphogenetic Protein 2 Coordinates Early Tooth Mineralization. AB - Formation of highly organized dental hard tissues is a complex process involving sequential and ordered deposition of an extracellular scaffold, followed by its mineralization. Odontoblast and ameloblast differentiation involves reciprocal and sequential epithelial-mesenchymal interactions. Similar to early tooth development, various Bmps are expressed during this process, although their functions have not been explored in detail. Here, we investigated the role of odontoblast-derived Bmp2 for tooth mineralization using Bmp2 conditional knockout mice. In developing molars, Bmp2LacZ reporter mice revealed restricted expression of Bmp2 in early polarized and functional odontoblasts while it was not expressed in mature odontoblasts. Loss of Bmp2 in neural crest cells, which includes all dental mesenchyme, caused a delay in dentin and enamel deposition. Immunohistochemistry for nestin and dentin sialoprotein (Dsp) revealed polarization defects in odontoblasts, indicative of a role for Bmp2 in odontoblast organization. Surprisingly, pSmad1/5/8, an indicator of Bmp signaling, was predominantly reduced in ameloblasts, with reduced expression of amelogenin ( Amlx), ameloblastin ( Ambn), and matrix metalloproteinase ( Mmp20). Quantitative real-time polymerase chain reaction (RT-qPCR) analysis and immunohistochemistry showed that loss of Bmp2 resulted in increased expression of the Wnt antagonists dickkopf 1 ( Dkk1) in the epithelium and sclerostin ( Sost) in mesenchyme and epithelium. Odontoblasts showed reduced Wnt signaling, which is important for odontoblast differentiation, and a strong reduction in dentin sialophosphoprotein ( Dspp) but not collagen 1 a1 ( Col1a1) expression. Mature Bmp2-deficient teeth, which were obtained by transplanting tooth germs from Bmp2 deficient embryos under a kidney capsule, showed a dentinogenesis imperfecta type II-like appearance. Micro-computed tomography and scanning electron microscopy revealed reduced dentin and enamel thickness, indistinguishable primary and secondary dentin, and deposition of ectopic osteodentin. This establishes that Bmp2 provides an early temporal, nonredundant signal for directed and organized tooth mineralization. PMID- 29489426 TI - An Explanation for How FGFs Predict Species-Specific Tooth Cusp Patterns. AB - Species-specific cusp patterns result from the iterative formation of enamel knots, the epithelial signaling centers, at the future cusp positions. The expressions of fibroblast growth factors (FGFs), especially Fgf4, in the secondary enamel knots in the areas of the future cusp tips are generally used to manifest the appearance of species-specific tooth shapes. However, the mechanism underlying the predictive role of FGFs in species-specific cusp patterns remains obscure. Here, we demonstrated that gerbils, which have a lophodont pattern, exhibit a striped expression pattern of Fgf4, whereas mice, which have a bunodont pattern, have a spotted expression pattern, and these observations verify the predictive role of Fgf4 in species-specific cusp patterns. By manipulating FGFs' signaling in the inner dental epithelium of gerbils, we provide evidence for the intracellular participation of FGF signaling, specifically FGF4 and FGF20, in Rac1- and RhoA-regulated cellular geometry remolding during the determination of different cusp patterns. Our study presents a novel explanation of how different FGF expression patterns produce different cusp patterns and implies that a conserved intracellular FGF-GTPase signaling module might represent an underlying developmental basis for evolutionary changes in cusp patterns. PMID- 29489427 TI - Alterations in DNA Damage Response and Repair Genes as Potential Marker of Clinical Benefit From PD-1/PD-L1 Blockade in Advanced Urothelial Cancers. AB - Purpose Alterations in DNA damage response and repair (DDR) genes are associated with increased mutation load and improved clinical outcomes in platinum-treated metastatic urothelial carcinoma. We examined the relationship between DDR alterations and response to PD-1/PD-L1 blockade. Methods Detailed demographic, treatment response, and long-term outcome data were collected on patients with metastatic urothelial carcinoma treated with atezolizumab or nivolumab who had targeted exon sequencing performed on pre-immunotherapy tumor specimens. Presence of DDR alterations was correlated with best objective response per Response Evaluation Criteria in Solid Tumors (RECIST) and progression-free and overall survival. Results Sixty patients with urothelial cancer enrolled in prospective trials of anti-PD-1/PD-L1 antibodies met inclusion criteria. Any DDR and known or likely deleterious DDR mutations were identified in 28 (47%) and 15 (25%) patients, respectively. The presence of any DDR alteration was associated with a higher response rate (67.9% v 18.8%; P < .001). A higher response rate was observed in patients whose tumors harbored known or likely deleterious DDR alterations (80%) compared with DDR alterations of unknown significance (54%) and in those whose tumors were wild-type for DDR genes (19%; P < .001). The correlation remained significant in multivariable analysis that included presence of visceral metastases. DDR alterations also were associated with longer progression-free and overall survival. Conclusion DDR alterations are independently associated with response to PD-1/PD-L1 blockade in patients with metastatic urothelial carcinoma. These observations warrant additional study, including prospective validation and exploration of the interaction between tumor DDR alteration and other tumor/host biomarkers of immunotherapy response. PMID- 29489428 TI - Breast Cancer Diagnosis and Treatment After High-Deductible Insurance Enrollment. AB - Purpose High-deductible health plans (HDHPs) require substantial out-of-pocket spending and might delay crucial health services. Breast cancer treatment delays of as little as 2 months are associated with adverse outcomes. Methods We used a controlled prepost design with survival analysis to assess timing of breast cancer care events among 273,499 women age 25 to 64 years without evidence of breast cancer before inclusion. Women were included if continuously enrolled for 1 year in a low-deductible ($0 to $500) plan followed by up to 4 years in a HDHP (at least $1,000 deductible) after an employer-mandated switch. Study inclusion was on a rolling basis, and members were followed between 2003 and 2012. The comparison group comprised 2.4 million contemporaneously matched women whose employers offered only low-deductible plans. Measures were times to first diagnostic breast imaging (diagnostic mammogram, breast ultrasound, or breast magnetic resonance imaging), breast biopsy, incident early-stage breast cancer diagnosis, and breast cancer chemotherapy. Outcomes were analyzed by using Cox models and adjusted for age-group, morbidity score, poverty level, US region, index date, and employer size. Results After the index date, HDHP members experienced delays in receipt of diagnostic imaging (adjusted hazard ratio [aHR], 0.95; 95% CI, 0.94 to 0.96), biopsy (aHR, 0.92; 95% CI, 0.89 to 0.95), early stage breast cancer diagnosis (aHR, 0.83; 0.78 to 0.90), and chemotherapy initiation (aHR, 0.79; 95% CI, 0.72 to 0.86) compared with the control group. Conclusion Women switched to HDHPs experienced delays in diagnostic breast imaging, breast biopsy, early-stage breast cancer diagnosis, and chemotherapy initiation. Additional research should determine whether such delays cause adverse health outcomes, and policymakers should consider selectively reducing out-of-pocket costs for key breast cancer services. PMID- 29489430 TI - Reply to L. Fornaro et al. PMID- 29489431 TI - CALGB 80101 and the Final Call for Preoperative Chemotherapy in Gastric Cancer. PMID- 29489432 TI - Challenges of Interpreting Registry Data in Prostate Cancer: Interpreting Retrospective Results Along With or in Absence of Clinical Trial Data. PMID- 29489429 TI - Nut Consumption and Survival in Patients With Stage III Colon Cancer: Results From CALGB 89803 (Alliance). AB - Purpose Observational studies have reported increased colon cancer recurrence and mortality in patients with states of hyperinsulinemia, including type 2 diabetes, obesity, sedentary lifestyle, and high glycemic load diet. Nut intake has been associated with a lower risk of type 2 diabetes, metabolic syndrome, and insulin resistance. However, the effect of nut intake on colon cancer recurrence and survival is not known. Patients and Methods We conducted a prospective, observational study of 826 eligible patients with stage III colon cancer who reported dietary intake on food frequency questionnaires while enrolled onto a randomized adjuvant chemotherapy trial. Using Cox proportional hazards regression, we assessed associations of nut intake with cancer recurrence and mortality. Results After a median follow-up of 6.5 years, compared with patients who abstained from nuts, individuals who consumed two or more servings of nuts per week experienced an adjusted hazard ratio (HR) for disease-free survival of 0.58 (95% CI, 0.37 to 0.92; Ptrend = .03) and an HR for overall survival of 0.43 (95% CI, 0.25 to 0.74; Ptrend = .01). In subgroup analysis, the apparent benefit was confined to tree nut intake (HR for disease-free survival, 0.54; 95% CI, 0.34 to 0.85; Ptrend = .04; and HR for overall survival, 0.47; 95% CI, 0.27 to 0.82; Ptrend = .04). The association of total nut intake with improved outcomes was maintained across other known or suspected risk factors for cancer recurrence and mortality. Conclusion Diets with a higher consumption of nuts may be associated with a significantly reduced incidence of cancer recurrence and death in patients with stage III colon cancer. PMID- 29489433 TI - Brachytherapy-Based Radiotherapy and Radical Prostatectomy Are Associated With Similar Survival in High-Risk Localized Prostate Cancer. AB - Purpose There are no randomized trials to guide treatment decisions between radiotherapeutic and surgical options for patients with high-risk localized prostate cancer. Comparative studies have been limited by their ability to match patients on the basis of pretreatment prognostic variables and to adjust for the cancer-related, medical, and socioeconomic differences between patients who choose radiotherapeutic or surgical approaches. Methods We analyzed the outcome of all patients in the National Cancer Database with high-risk, clinically localized prostate cancer with complete prognostic data who were treated with either radical prostatectomy (RP), external beam radiotherapy (EBRT) combined with androgen deprivation (AD), or EBRT plus brachytherapy with or without AD. Inverse probability of treatment weighting was used to adjust for covariable imbalance among treatment groups. The weighted time-dependent Cox proportional hazards model was then used to estimate the effects of treatment groups on survival, accounting for differential treatment initiation times. A predictive model of pathologic nodal (pLN) status was built using prostate-specific antigen level, Gleason score, and clinical T stage; predicted pLN status was used to repeat the inverse probability of treatment weighting and time-dependent Cox proportional hazards model. Results A total of 42,765 patients were analyzed. There was no statistically significant difference in survival between RP and EBRT plus brachytherapy with or without AD (hazard ratio [HR], 1.17; 95% CI, 0.88 to 1.55). However, EBRT plus AD was associated with higher mortality than RP (HR, 1.53; 95% CI, 1.22 to 1.92). Adjustment for predicted pLN status did not yield statistically different results. A sensitivity analysis showed that EBRT plus AD >= 7920 cGy narrowed the difference, but a significantly higher mortality remained (HR, 1.33; 95% CI, 1.05 to 1.68). Conclusion After comprehensively adjusting for imbalances in prostate cancer prognostic factors, other medical conditions, and socioeconomic factors, this analysis showed no statistical difference in survival between patients treated with RP versus EBRT plus brachytherapy with or without AD. EBRT plus AD was associated with lower survival. PMID- 29489435 TI - The clinical significance of concomitant bacteriuria in patients with Staphylococcus aureus bacteremia. A review and meta-analysis. AB - BACKGROUND: Staphylococcus aureus bacteriuria (SABU) concomitant to S. aureus bacteremia (SAB) has been associated with deep-seated infections and worse prognosis. However, the relevant studies were small and inconsistent. Here, we aim to provide a review of the relevant literature, and a meta-analysis of these studies. METHODS: We searched PubMed and Scopus for studies comparing patients with SAB and concomitant SABU to patients with SAB without SABU. RESULTS: Nine relevant studies were identified, involving 1429 patients with SAB, of whom 18.5% (n = 265) had concomitant SABU. Pooling the results of those studies, SABU was significantly associated with endocarditis, bone/joint infection and septic embolism. SABU was also associated with persistent SAB, and higher mortality. CONCLUSIONS: Although SABU may be a useful marker of complicated SAB, the current literature has several limitations. Larger prospective studies are required to clarify the value of SABU in clinical decision making. PMID- 29489434 TI - Targeting the DNA Damage Response in OSCC with TP53 Mutations. AB - Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer worldwide and in the United States. OSCC remains a major cause of morbidity and mortality in patients with head and neck cancers. Tobacco and alcohol consumption alone or with chewing betel nut are potential risk factors contributing to the high prevalence of OSCC. Multimodality therapies, including surgery, chemotherapy, biologic therapy, and radiotherapy, particularly intensity modulated radiotherapy (IMRT), are the current treatments for OSCC patients. Despite recent advances in these treatment modalities, the overall survival remains poor over the past years. Recent data from whole-exome sequencing reveal that TP53 is commonly mutated in human papillomavirus-negative OSCC patients. Furthermore, these data stressed the importance of the TP53 gene in suppressing the development and progression of OSCC. Clinically, TP53 mutations are largely associated with poor survival and tumor resistance to radiotherapy and chemotherapy in OSCC patients, which makes the TP53 mutation status a potentially useful molecular marker prognostic and predictive of clinical response in these patients. Several forms of DNA damage have been shown to activate p53, including those generated by ionizing radiation and chemotherapy. The DNA damage stabilizes p53 in part via the DNA damage signaling pathway that involves sensor kinases, including ATM and ATR and effector kinases, such as Chk1/2 and Wee1, which leads to posttranscriptional regulation of a variety of genes involved in DNA repair, cell cycle control, apoptosis, and senescence. Here, we discuss the link of TP53 mutations with treatment outcome and survival in OSCC patients. We also provide evidence that small-molecule inhibitors of critical proteins that regulate DNA damage repair and replication stress during the cell cycle progression, as well as other molecules that restore wild-type p53 activity to mutant p53, can be exploited as novel therapeutic approaches for the treatment of OSCC patients bearing p53 mutant tumors. PMID- 29489436 TI - Patient radiation dose and fluoroscopy time during ERCP: a single-center, retrospective study of influencing factors. AB - OBJECTIVES: Recently, both the number and the complexity with associated increased technical difficulty of therapeutic ERCP procedures have significantly increased resulting in longer procedural and fluoroscopy times. During ERCP, the patient is exposed to ionizing radiation and the consequent radiation dose depends on multiple factors. The aim of this study was to identify factors affecting fluoroscopy time and radiation dose in patients undergoing ERCP. MATERIALS AND METHODS: Data related to patient demographics, procedural characteristics and radiation exposure in ERCP procedures (n = 638) performed between August 2013 and August 2015 was retrospectively reviewed and analyzed. Statistically significant factors identified by univariate analyses were included in multivariate analysis with fluoroscopy time (FT) and dose area product (DAP) as dependent variables. Effective dose (ED) was estimated from DAP measurements using conversion coefficient. RESULTS: The factors independently associated with increased DAP during ERCP were age, gender, radiographer, complexity level of ERCP, cannulation difficulty grade, bile duct injury and biliary stent placement. In multivariate analysis the endoscopist, the complexity level of ERCP, cannulation difficulty grade, pancreatic duct leakage, bile duct dilatation and brushing were identified as predictors for a longer FT. The mean DAP, FT, number of acquired images and ED for all ERCP procedures were 2.33 Gy.cm2, 1.84 min, 3 and 0.61 mSv, respectively. CONCLUSIONS: Multiple factors had an effect on DAP and FT in ERCP. The awareness of these factors may help to predict possible prolonged procedures causing a higher radiation dose to the patient and thus facilitate the use of appropriate precautions. PMID- 29489437 TI - Antibody Responses to a Quadrivalent Hepatitis C Viral-Like Particle Vaccine Adjuvanted with Toll-Like Receptor 2 Agonists. AB - The development of an effective preventative hepatitis C virus (HCV) vaccine will reside, in part, in its ability to elicit neutralizing antibodies (NAbs). We previously reported a genotype 1a HCV virus like particle (VLP) vaccine that produced HCV specific NAb and T cell responses that were substantially enhanced by Toll-like receptor 2 (TLR2) agonists. We have now produced a quadrivalent genotype 1a/1b/2a/3a HCV VLP vaccine and tested the ability of two TLR2 agonists, R4Pam2Cys and E8Pam2Cys, to stimulate the production of NAb. We now show that our vaccine with R4Pam2Cys or E8Pam2Cys produces strong antibody and NAb responses in vaccinated mice after just two doses. Total antibody titers were higher in mice inoculated with vaccine plus E8Pam2Cys compared to HCV VLPs alone. However, the TLR2 agonists did not result in stronger NAb responses compared to vaccine without adjuvant. Such a vaccine could provide a substantial addition to the overall goal to eliminate HCV. PMID- 29489438 TI - Isolation of Peripheral Blood CD8 T Cells Specific to Porcine Reproductive and Respiratory Syndrome Virus Utilizing Porcine CD137 Activation Marker. AB - CD137 is a costimulatory molecule transiently expressed on activated T cells after mitogen or antigen stimulation that can be exploited for isolating antigen specific T cells as reported in mouse models. By utilizing an antiporcine CD137 monoclonal antibody (mAb, clone 3B9) developed in our laboratory, we isolated virus-specific CD8beta T cells from peripheral blood of pigs experimentally infected with different porcine reproductive and respiratory syndrome virus (PRRSV) strains. Similar to mouse, porcine CD8beta T cells also express CD137 transiently upon Concavalin A stimulation while the unstimulated cells did not. Most frequently, virus-specific CD8beta T cells were isolated at low levels from peripheral blood of pigs experimentally infected with PRRSV strains VR2385, NADC20, and MN184B at 49 and 63 days postinfection. The results suggest that porcine CD137-specific mAb is a useful tool for isolating virus-specific CD8 T cells from peripheral blood and tissues of pigs after in vitro stimulation with viral antigen. PMID- 29489440 TI - TRPM7 Mediates Mechanosensitivity in Adult Rat Odontoblasts. AB - Odontoblasts, with their strategic arrangement along the outermost compartment of the dentin-pulp complex, have been suggested to have sensory function. In addition to their primary role in dentin formation, growing evidence shows that odontoblasts are capable of sensing mechanical stimulation. Previously, we found that most odontoblasts express TRPM7, the nonselective mechanosensitive ion channel reported to be critical in Mg2+ homeostasis and dentin mineralization. In line with this finding, we sought to elucidate the functional expression of TRPM7 in odontoblasts by pharmacological approaches and mechanical stimulation. Naltriben, a TRPM7-specific agonist, induced calcium transient in the majority of odontoblasts, which was blocked by TRPM7 blockers such as extracellular Mg2+ and FTY720 in a dose-dependent manner. Mechanical stretch of the odontoblastic membrane with hypotonic solution also induced calcium transient, which was blocked by Gd3+, a nonselective mechanosensitive channel blocker. Calcium transient induced by hypotonic solution was also blocked by high extracellular Mg2+ or FTY720. When TRPM7-mediated calcium transients in odontoblasts were analyzed on the subcellular level, remarkably larger transients were detected in the distal odontoblastic process compared with the soma, which was further verified with comparable immunocytochemical analysis. Our results demonstrate that TRPM7 in odontoblasts can serve as a mechanical sensor, with its distribution to facilitate intracellular Ca2+ signaling in the odontoblastic process. These findings suggest TRPM7 as a mechanical transducer in odontoblasts to mediate intracellular calcium dynamics under diverse pathophysiological conditions of the dentin. PMID- 29489439 TI - The NOTCH Pathway in Head and Neck Squamous Cell Carcinoma. AB - Comprehensive genomic analyses have been performed for head and neck squamous cell carcinoma (HNSCC), revealing a significant rate of NOTCH1 mutations and identifying NOTCH1 as the second most frequently mutated gene after TP53. Most NOTCH1 mutations are considered inactivating, indicating that NOTCH1 is a tumor suppressor gene. On the other hand, cohorts from Asian populations with HNSCC have shown activating NOTCH1 mutations. HNSCC with NOTCH1 mutations have a worse prognosis than the NOTCH1 wild-type tumors. Additional data on other NOTCH family members have shown that NOTCH promotes HNSCC progression. NOTCH family members, including NOTCH pathway genes, are upregulated in HNSCC compared with normal tissues, and inhibition of the NOTCH pathway decreases cell proliferation and invasion. NOTCH activity in HNSCC is therefore contextual, and NOTCH in HNSCC is considered to have a bimodal role as a tumor suppressor and an oncogene. In this review, recent understandings of NOTCH pathway genes, including NOTCH genes, in HNSCC are described. In addition, the implications of NOTCH pathway alteration for HNSCC-specific NOTCH-targeted cancer therapy are explored. PMID- 29489441 TI - Targeted Applications of Unmanned Aerial Vehicles (Drones) in Telemedicine. AB - INTRODUCTION: Advances in technology have revolutionized the medical field and changed the way healthcare is delivered. Unmanned aerial vehicles (UAVs) are the next wave of technological advancements that have the potential to make a huge splash in clinical medicine. UAVs, originally developed for military use, are making their way into the public and private sector. Because they can be flown autonomously and can reach almost any geographical location, the significance of UAVs are becoming increasingly apparent in the medical field. MATERIALS AND METHODS: We conducted a comprehensive review of the English language literature via the PubMed and Google Scholar databases using search terms "unmanned aerial vehicles," "UAVs," and "drone." Preference was given to clinical trials and review articles that addressed the keywords and clinical medicine. RESULTS: Potential applications of UAVs in medicine are broad. Based on articles identified, we grouped UAV application in medicine into three categories: (1) Prehospital Emergency Care; (2) Expediting Laboratory Diagnostic Testing; and (3) Surveillance. Currently, UAVs have been shown to deliver vaccines, automated external defibrillators, and hematological products. In addition, they are also being studied in the identification of mosquito habitats as well as drowning victims at beaches as a public health surveillance modality. CONCLUSIONS: These preliminary studies shine light on the possibility that UAVs may help to increase access to healthcare for patients who may be otherwise restricted from proper care due to cost, distance, or infrastructure. As with any emerging technology and due to the highly regulated healthcare environment, the safety and effectiveness of this technology need to be thoroughly discussed. Despite the many questions that need to be answered, the application of drones in medicine appears to be promising and can both increase the quality and accessibility of healthcare. PMID- 29489442 TI - The Long Shadow of Rivalry: Rivalry Motivates Performance Today and Tomorrow. AB - Research has established that competing head to head against a rival boosts motivation and performance. The present research investigated whether rivalry can affect performance over time and in contests without rivals. We examined the long term effects of rivalry through archival analyses of postseason performance in multiple high-stakes sports contexts: National Collegiate Athletic Association (NCAA) Division I Men's Basketball and the major U.S. professional sports leagues: National Basketball Association (NBA), National Football League (NFL), Major League Baseball (MLB), and National Hockey League (NHL). Econometric analyses revealed that postseason performance of a focal team's rival in year N predicted that focal team's postseason performance in year N + 1. Follow-up analyses suggested that the performance boost was especially pronounced when one's rival won the previous tournament. These results establish that rivalry has a long shadow: A rival team's success exerts such a powerful motivational force that it drives performance outside of direct competition with one's rival and even after a significant delay. PMID- 29489443 TI - Will MACRA Improve Physician Reimbursement? PMID- 29489445 TI - Whole-Genome Analysis of an Extensively Drug-Resistant Acinetobacter baumannii Strain XDR-BJ83: Insights into the Mechanisms of Resistance of an ST368 Strain from a Tertiary Care Hospital in China. AB - Acinetobacter baumannii is an important pathogen of nosocomial infections. Nosocomial outbreaks caused by antibiotic-resistant A. baumannii remain a significant challenge. Understanding the antibiotic resistance mechanism of A. baumannii is critical for clinical treatment. The purpose of this study was to determine the whole-genome sequence (WGS) of an extensively drug-resistant (XDR) A. baumannii strain, XDR-BJ83, which was associated with a nosocomial outbreak in a tertiary care hospital of China, and to investigate the antibiotic resistance mechanism of this strain. The WGS of XDR-BJ83 was performed using single-molecule real-time sequencing. The complete genome of XDR-BJ83 consisted of a 4,011,552-bp chromosome and a 69,069-bp plasmid. The sequence type of XDR-BJ83 was ST368, which belongs to clonal complex 92 (CC92). The chromosome of XDR-BJ83 carried multiple antibiotic resistance genes, antibiotic efflux pump genes, and mobile genetic elements, including insertion sequences, transposons, integrons, and resistance islands. The plasmid of XDR-BJ83 (pBJ83) was a conjugative plasmid carrying type IV secretion system. These results indicate that the presence of multiple antibiotic resistance genes, efflux pumps, and mobile genetic elements is likely associated with resistance to various antibiotics in XDR-BJ83. PMID- 29489444 TI - Opposite Effect of Opuntia ficus-indica L. Juice Depending on Fruit Maturity Stage on Gastrointestinal Physiological Parameters in Rat. AB - The phytochemical composition and the effect of the green and ripe Opuntia ficus indica juice on some gastrointestinal (GI) physiological parameters such as stomach emptying and small-intestinal motility and permeability were determined in rats administered multiple concentrations of the prickly pear juice (5, 10, and 20 mL kg-1, b.w., p.o.). Other separate groups of rats were received, respectively; sodium chloride (0.9%, b.w., p.o.), clonidine (alpha-2-adrenergic agonist, 1 mg kg-1, b.w., i.p.), yohimbine (alpha-2-adrenergic antagonist, 2 mg kg-1, b.w., i.p.), and loperamide (5 mg kg-1, b.w., p.o.). In vivo reverse effect of juice on GI physiological parameters was investigated using a charcoal meal test, phenol-red colorimetric method, loperamide-induced acute constipation, and castor oil-caused small-bowel hypersecretion. However, the opposite in vitro influence of juice on intestinal permeability homeostasis was assessed by the Ussing chamber system. Mature prickly pear juice administration stimulated significantly and dose dependently the GI transit (GIT; 8-26%) and gastric emptying (0.9-11%) in a rat model. Conversely, the immature prickly pear juice reduced gastric emptying (7-23%), GIT (10-28%), and diarrhea (59-88%). Moreover, the standard drugs have produced their antagonistic effects on GI physiological functions. The permeability of the isolated perfused rat small-intestine has a paradoxical response flowing prickly pear juices administration at diverse doses and maturity grade. Most importantly, the quantitative phytochemical analyses of both juices showed a different composition depending on the degree of maturity. In conclusion, the prickly pear juice at two distinct phases of maturity has different phytochemical characteristics and opposite effects on GI physiological actions in rat. PMID- 29489446 TI - Prenatal Selective Serotonin Reuptake Inhibitor Use and Associated Risk for Gestational Hypertension and Preeclampsia: A Meta-Analysis of Cohort Studies. AB - BACKGROUND: To analyze existing cohort studies and provide evidence for the use of prenatal selective serotonin reuptake inhibitor (SSRI) monotherapy and the associated risk of gestational hypertension and preeclampsia. METHODS: A comprehensive search of English language articles published before 30th April 2017 was conducted on PubMed, EMBASE, and the Web of Science databases. Using data acquired, we summarized the relative risks (RRs) and 95% confidence intervals (CIs) of gestational hypertension and preeclampsia using the random effects model. Heterogeneity between studies was also assessed with the I2 statistic. RESULTS: Seven cohort studies with 1,108,261 individuals were included for analysis. Compared with nonusers, those undertaking prenatal SSRI monotherapy were more likely to develop gestational hypertension or preeclampsia (summarized RR = 1.21, 95% CI: 1.05-1.40, I2 = 71.3%), gestational hypertension (summarized RR = 1.14, 95% CI: 1.00-1.30, I2 = 5.7%), and preeclampsia (summarized RR = 1.32, 95% CI: 0.99-1.78, I2 = 83.3%). In addition, although subgroup analyses, which were stratified by study design, number of cases, geographic location, duration of SSRI monotherapy, registry databases, and adjustment for potential confounders and risk factors, were consistent with the main findings, not all of these showed statistical significance. No evidence of publication bias was detected. CONCLUSIONS: Women who receive SSRI monotherapy during pregnancy are at increased risk of gestational hypertension and preeclampsia. PMID- 29489447 TI - Is There an Association Between Use of Amoxicillin-Clavulanate and Resistance to Third-Generation Cephalosporins in Klebsiella pneumoniae and Escherichia coli at the Hospital Level? AB - AIMS: Amoxicillin-clavulanate is extensively used in European hospitals. Whether the hospital use of amoxicillin-clavulanate is associated with nonsusceptibility to third-generation cephalosporins (3GC) in Klebsiella pneumoniae is unknown. Our aim was to assess the relationship between the hospital use of amoxicillin clavulanate and 3GC nonsusceptibility in K. pneumoniae and Escherichia coli. METHODS: Yearly data of antibiotic use and 3GC nonsusceptibility in K. pneumoniae and E. coli were obtained from 33 French hospitals between 2011 and 2016. Decreased susceptibility to 3GC and Extended-Spectrum Beta-Lactamase (ESBL) production were modelled from antibiotic use with linear mixed models on years 2011 to 2015, and validated on year 2016. RESULTS: Nonsusceptibility to 3GC increased in K. pneumoniae and E. coli. In a multivariable model that included year and use of 3GC and fluoroquinolones as explanatory variables, amoxicillin clavulanate use was protective against 3GC nonsusceptibility in K. pneumoniae (incidence rate ratio [IRR], 0.992 [0.988-0.997]), and with ESBL production in K. pneumoniae (IRR, 0.989 [0.985-0.992]). The correlation coefficient between observed and predicted numbers of 3GC-nonsusceptible K. pneumoniae in 2016 was 0.95 (95% confidence interval, 0.89-0.98). There was no significant association between amoxicillin-clavulanate use and 3GC nonsusceptibility in E. coli. CONCLUSION: Amoxicillin-clavulanate hospital use was protective against nonsusceptibility to 3GC in K. pneumoniae. Conversely, it was not associated with susceptibility to 3GC in E. coli. To decrease the hospital use of 3GC and fluoroquinolones, and 3GC nonsusceptibility in K. pneumoniae, it may be acceptable to increase the hospital use of amoxicillin-clavulanate. Interventional studies are necessary to confirm this hypothesis. PMID- 29489448 TI - First Description in Greece of mphC-Positive Staphylococci Causing Subclinical Mastitis in Ewes. AB - The aim of the present study was to describe the first mphC-positive staphylococci, including two Staphylococcus lentus (Sle-087lar and Sle-091lar) and one Staphylococcus xylosus (Sxy-228lar), isolated from samples of animal origin, in Greece. Isolates Sle-087lar and Sxy-228lar were resistant to erythromycin, whereas Sle-091lar was resistant to erythromycin and lincomycin. All three isolates were susceptible to the remaining antibiotics. PCR screening showed that isolate Sle-091lar carried also ermB. For Sxy-228lar, whole-genome sequencing (WGS) and de novo assembly obtained an mphC-positive contig of 57.3-kb exhibiting high similarity with the genome of mphC-negative S. xylosus S170. However, mphC of Sxy-228lar was 91% similar to that found in plasmid pJW2311 from S. xylosus JW2311. Additionally, WGS data showed that Sle-087lar and Sle-091lar harbored mphC-carrying sequences being highly similar to the recently announced genome of the mphC-carrying S. lentus isolate 050AP from Tanzania. However, differences were observed in the mphC environment, suggesting the independent acquisition of the gene by each isolate. Sle-091lar also harbored transposon Tn917, which carries ermB resistance gene, integrated into S. lentus chromosome. These findings indicated that acquisition of resistance genes can lead to the emergence of multiresistant staphylococci, causing animal infections with economic burden. PMID- 29489449 TI - Hepatoprotective Effect of Essential Oils from Hyptis crenata in Sepsis-Induced Liver Dysfunction. AB - No specific therapeutics are available for the treatment of sepsis-induced liver dysfunction, a clinical complication strongly associated with the high mortality rate of septic patients. This study investigated the effect of the essential oil of Hyptis crenata (EOHc), a lamiaceae plant used to treat liver disturbances in Brazilian folk medicine, on liver function during early sepsis. Sepsis was induced by the cecal ligation and puncture (CLP) model. Rats were divided into four groups: Sham, Sham+EOHc, CLP, and CLP+EOHc. EOHc (300 mg/kg) was orally administered 12 and 24 h after surgery. The animals were sacrificed for blood collection and liver tissue samples 48 h after surgery. Hepatic function was evaluated by measuring serum bilirubin, alkaline phosphatase (ALP), aspartate aminotransferase, and alanine aminotransferase (ALT) levels. The levels of malondialdehyde and the activity of superoxide dismutase, catalase, and GSH peroxidase (GSH-Px) were measured for assessment of oxidative stress. Liver morphology was analyzed by hematoxylin and eosin staining. EOHc normalized serum ALP, ALT, and bilirubin levels and inhibited morphological changes. In addition, we observed that EOHc inhibited elevation in hepatic lipid peroxidation and reduction of the glutathione peroxidase activity induced by sepsis. Our data show that EOHc plays a protective effect against liver injury induced by sepsis. PMID- 29489450 TI - Therapeutic Procedures for Malignant Ascites in a Palliative Care Outpatient Clinic. AB - BACKGROUND: The optimal treatment of malignant ascites (MA) and feasibility of the management with free drainage remain unclear. OBJECTIVE: To study the success of drainage, complications, and survival after paracentesis or insertion of an indwelling tunneled catheter (TC) for the MA performed on a day-case basis. DESIGN AND SETTING: We evaluated 118 paracenteses and 48 insertions of TCs performed in 104 patients with MA at the Palliative Care Outpatient Unit of Tampere University Hospital. RESULTS: Drainage of ascites fluid (median 3700 mL; range 300-13,200 mL) was successful in all cases. The complication rates were 7% and 25% for paracenteses and TCs, respectively. Most of the complications were minor. Repeated procedures were needed in 64% and 10% of the paracenteses and insertions of TCs, respectively, (p < 0.001). Median survival after the first procedure was 40 days (interquartile range, IQR: 17-115). Patients with pancreatic cancer had shorter median survival (19 days; IQR: 9-35) compared with other patients (47 days; IQR: 23-143) (age-adjusted HR 2.73; 95% CI: 1.65-4.52), whereas patients receiving chemotherapy had longer median survival (112 days; IQR: 43-205) compared with patients without chemotherapy (25 days; IQR: 14-52) (age-adjusted HR 2.48; 95% CI: 1.58-3.89). The volume of removed ascites fluid was not associated with survival. CONCLUSIONS: Free drainage of MA seems feasible in an outpatient clinic. Early insertion of TC should be considered to avoid repeated paracenteses. However, in patients with pancreatic cancer, paracentesis might be an accepted alternative due to their short life expectancy. PMID- 29489451 TI - Erratum. PMID- 29489454 TI - Optical molecular imaging of corpora amylacea in human brain tissue. AB - Label-free multiphoton imaging constitutes a promising technique for clinical diagnosis and therapeutic monitoring. Corpora amylacea (CoA) are starch-like structures often found in the diseased brain, whose origin and role in nervous pathologies are still a matter of debate. Recently, CoA in the diseased human hippocampus were found to be second harmonic generation (SHG) active. Here, we show that CoA formed in other parts of the diseased brain and in brain neoplasms display a similar SHG activity. The SHG pattern of CoA depended on laser polarization, indicating that a radial structure is responsible for their nonlinear activity. Vibrational spectroscopy was used to study the biochemistry underlying the SHG activity. Infrared (IR) and Raman spectroscopy showed that CoA contain polyglucosans that are biochemically similar to glycogen, but with an unusual structure that is similar to amylopectin, which justifies the nonlinear activity of CoA. Our findings explain the SHG activity of CoA and demonstrate that CoA in the pathological brain are amenable to label-free multiphoton imaging. Further research will clarify whether intraoperative assessment of CoA can be diagnostically exploited. PMID- 29489452 TI - The small molecule ISRIB rescues the stability and activity of Vanishing White Matter Disease eIF2B mutant complexes. AB - eIF2B is a dedicated guanine nucleotide exchange factor for eIF2, the GTPase that is essential to initiate mRNA translation. The integrated stress response (ISR) signaling pathway inhibits eIF2B activity, attenuates global protein synthesis and upregulates a set of stress-response proteins. Partial loss-of-function mutations in eIF2B cause a neurodegenerative disorder called Vanishing White Matter Disease (VWMD). Previously, we showed that the small molecule ISRIB is a specific activator of eIF2B (Sidrauski et al., 2015). Here, we report that various VWMD mutations destabilize the decameric eIF2B holoenzyme and impair its enzymatic activity. ISRIB stabilizes VWMD mutant eIF2B in the decameric form and restores the residual catalytic activity to wild-type levels. Moreover, ISRIB blocks activation of the ISR in cells carrying these mutations. As such, ISRIB promises to be an invaluable tool in proof-of-concept studies aiming to ameliorate defects resulting from inappropriate or pathological activation of the ISR. PMID- 29489455 TI - Aromatase in normal and diseased liver. AB - Background A potential correlation between sex hormones, such as androgens and estrogens, and the development and progression of hepatocellular carcinoma (HCC) has been proposed. However, its details, in particular, aromatase status in diseased human liver has remained largely unknown. Materials and methods We immunolocalized aromatase, 17beta-hydroxysteroid dehydrogenase (17beta-HSD) type 1 and 17beta-HSD type 2 in a total of 155 cases, consisting of normal liver (n = 10), nonalcoholic steatohepatitis (NASH) (n = 18), primary sclerosing cholangitis (PSC) (n = 6), primary biliary cholangitis (PBC) (n = 13), biliary atresia (n = 18), alcoholic hepatitis (n = 11), hepatitis C virus (HCV) (n = 31), HCV sustained virologic response (HCV-SVR) (n = 10), hepatitis B virus (HBV) (n = 20), HBV sustained virologic response (HBV-SVR) (n = 8) and infants (n = 10). Results Immunoreactivity scores of aromatase in HBV (59.5 +/- 30.9), HBV-SVR (68.1 +/- 33.5) and infants (100.5 +/- 36.6) were significantly higher than those in normal liver (26.0 +/- 17.1). Scores of 17beta-HSD type 1 in any etiology other than HBV (116.3 +/- 23.7) and infants (120.0 +/- 28.5) were significantly lower than those in normal liver (122.5 +/- 8.6). Scores of 17beta-HSD type 2 in NASH (74.4 +/- 36.6) were significantly lower than those in normal liver (128.0 +/- 29.7). Conclusion High immunoreactivity scores of aromatase and 17beta-HSD type 1 in the patients with HBV suggest a correlation between HBV infection and in situ estrogen synthesis in hepatocytes. PMID- 29489453 TI - Opposite regulation of inhibition by adult-born granule cells during implicit versus explicit olfactory learning. AB - Both passive exposure and active learning through reinforcement enhance fine sensory discrimination abilities. In the olfactory system, this enhancement is thought to occur partially through the integration of adult-born inhibitory interneurons resulting in a refinement of the representation of overlapping odorants. Here, we identify in mice a novel and unexpected dissociation between passive and active learning at the level of adult-born granule cells. Specifically, while both passive and active learning processes augment neurogenesis, adult-born cells differ in their morphology, functional coupling and thus their impact on olfactory bulb output. Morphological analysis, optogenetic stimulation of adult-born neurons and mitral cell recordings revealed that passive learning induces increased inhibitory action by adult-born neurons, probably resulting in more sparse and thus less overlapping odor representations. Conversely, after active learning inhibitory action is found to be diminished due to reduced connectivity. In this case, strengthened odor response might underlie enhanced discriminability. PMID- 29489456 TI - Phytochemical profile, antimicrobial, antioxidant and antiobesity activities of Scolymus angiospermus Gaertn. Four fractions from Jericho/Palestine. PMID- 29489457 TI - Is fish oil supplementation effective on maternal serum FBS, oral glucose tolerance test, hemoglobin and hematocrit in low risk pregnant women? A triple blind randomized controlled trial. PMID- 29489458 TI - Template mediated protein self-assembly as a valuable tool in regenerative therapy. AB - The assembly of natural proteinaceous biopolymers into macro-scale architectures is of great importance in synthetic biology, soft-material science and regenerative therapy. The self-assembly of protein tends to be limited due to anisotropic interactions among protein molecules, poor solubility and stability. Here, we introduce a unique platform to self-immobilize diverse proteins (fibrous and globular, positively and negatively charged, low and high molecular weight) using silicon surfaces with pendant -NH2 groups via a facile one step diffusion limited aggregation (DLA) method. All the experimental proteins (type I collagen, bovine serum albumin and cytochrome C) self-assemble into seaweed-like branched dendritic architectures via classical DLA in the absence of any electrolytes. The notable differences in branching architectures are due to dissimilarities in protein colloidal sub-units, which is typical for each protein type, along with the heterogeneous distribution of surface -NH2 groups. Fractal analysis of assembled structures is used to explain the underlying route of fractal deposition; which concludes how proteins with different functionality can yield similar assembly. Further, the nano-micro-structured surfaces can be used to provide functional topographical cues to study cellular responses, as demonstrated using rat bone marrow stem cells. The results indicate that the immobilization of proteins via DLA does not affect functionality, instead serving as topographical cues to guide cell morphology. This indicates a promising design strategy at the tissue-material interface and is anticipated to guide future surface modifications. A cost-effective standard templating strategy is therefore proposed for fundamental and applied particle aggregation studies, which can be used at multiple length scales for biomaterial design and surface reformation. PMID- 29489459 TI - Presepsin and Inflammatory Markers Correlate With Occurrence and Severity of Nonocclusive Mesenteric Ischemia After Cardiovascular Surgery. AB - OBJECTIVES: To prospectively evaluate the relationship of established inflammatory markers and presepsin on nonocclusive mesenteric ischemia and to correlate presepsin levels to the occurrence and severity of nonocclusive mesenteric ischemia. DESIGN: Patients were prospectively enrolled and blood samples taken, followed by a retrospective evaluation of laboratory values and angiographic findings. The study was ethics committee approved. SETTINGS: Patients with clinical suspicion of nonocclusive mesenteric ischemia underwent catheter angiography of the superior mesenteric artery. Images were assessed by two experienced radiologists on consensus basis using a previously published standardized reporting system (Homburg-Nonocclusive Mesenteric Ischemia-Score). Two groups were formed according to the severity of nonocclusive mesenteric ischemia, mild and severe, patients without clinical signs of nonocclusive mesenteric ischemia formed the reference group. These data were correlated to inflammatory blood markers assessed pre- and postoperatively: C-reactive protein, leucocytes, procalcitonin, and presepsin as well as outcome data. PATIENTS: Between January 2010 and March 2011, a total of 839 patients undergoing cardiovascular surgery participated in this study. MEASUREMENTS AND MAIN RESULTS: Mild nonocclusive mesenteric ischemia was diagnosed in 4.5%, and severe nonocclusive mesenteric ischemia in 3.2%. Median postoperative presepsin concentrations were significantly greater in mild and severe nonocclusive mesenteric ischemia than in non-nonocclusive mesenteric ischemia. Statistics showed that postoperative presepsin better discriminated mild and severe nonocclusive mesenteric ischemia than any other tested biomarker. CONCLUSIONS: Elevated postoperative plasma presepsin concentrations are an independent predictor of mild and severe nonocclusive mesenteric ischemia. The established inflammatory blood markers significantly correlate with the development and severity of nonocclusive mesenteric ischemia. PMID- 29489460 TI - The Period 2 Enhancer Nobiletin as Novel Therapy in Murine Models of Circadian Disruption Resembling Delirium. AB - OBJECTIVES: Delirium occurs in approximately 30% of critically ill patients, and the risk of dying during admission doubles in those patients. Molecular mechanisms causing delirium are largely unknown. However, critical illness and the ICU environment consistently disrupt circadian rhythms, and circadian disruptions are strongly associated with delirium. Exposure to benzodiazepines and constant light are suspected risk factors for the development of delirium. Thus, we tested the functional role of the circadian rhythm protein Period 2 (PER2) in different mouse models resembling delirium. DESIGN: Animal study. SETTING: University experimental laboratory. SUBJECTS: Wildtype, Per2 mice. INTERVENTIONS: Midazolam, lipopolysaccharide (lipopolysaccharide), constant light, nobiletin, or sham-treated animals. MEASUREMENTS AND MAIN RESULTS: Midazolam significantly reduced the expression of PER2 in the suprachiasmatic nucleus and the hippocampus of wild-type mice. Behavioral tests following midazolam exposure revealed a robust phenotype including executive dysfunction and memory impairment suggestive of delirium. These findings indicated a critical role of hippocampal expressed PER2. Similar results were obtained in mice exposed to lipopolysaccharide or constant light. Subsequent studies in Per2 mice confirmed a functional role of PER2 in a midazolam-induced delirium-like phenotype. Using the small molecule nobiletin to enhance PER2 function, the cognitive deficits induced by midazolam or constant light were attenuated in wild type mice. CONCLUSIONS: These experiments identify a novel role for PER2 during a midazolam- or constant light-induced delirium-like state, highlight the importance of hippocampal PER2 expression for cognitive function, and suggest the PER2 enhancer nobiletin as potential therapy in delirium-like conditions associated with circadian disruption. PMID- 29489461 TI - Simultaneous Venoarterial Extracorporeal Membrane Oxygenation and Percutaneous Left Ventricular Decompression Therapy with Impella Is Associated with Improved Outcomes in Refractory Cardiogenic Shock. AB - Venoarterial extracorporeal membrane oxygenation (VA-ECMO) has been used for refractory cardiogenic shock; however, it is associated with increased left ventricular afterload. Outcomes associated with the combination of a percutaneous left ventricular assist device (Impella) and VA-ECMO remains largely unknown. We retrospectively reviewed patients treated for refractory cardiogenic shock with VA-ECMO (2014-2016). The primary outcome was all-cause mortality within 30 days of VA-ECMO implantation. Secondary outcomes included duration of support, stroke, major bleeding, hemolysis, inotropic score, and cardiac recovery. Outcomes were compared between the VA-ECMO cohort and VA-ECMO + Impella (ECPELLA cohort). Sixty six patients were identified: 30 ECPELLA and 36 VA-ECMO. Fifty-eight percentage of VA-ECMO patients (n = 21) had surgical venting, as compared with 100% of the ECPELLA cohort (n = 30) which had Impella (+/-surgical vent). Both cohorts demonstrated relatively similar baseline characteristics except for higher incidence of ST-elevation myocardial infarction (STEMI) and percutaneous coronary intervention (PCI) in the ECPELLA cohort. Thirty-day all-cause mortality was significantly lower in the ECPELLA cohort (57% vs. 78%; hazard ratio [HR] 0.51 [0.28-0.94], log rank p = 0.02), and this difference remained intact after correcting for STEMI and PCI. No difference between secondary outcomes was observed, except for the inotrope score which was greater in VA-ECMO group by day 2 (11 vs. 0; p = 0.001). In the largest US-based retrospective study, the addition of Impella to VA-ECMO for patients with refractory cardiogenic shock was associated with lower all-cause 30 day mortality, lower inotrope use, and comparable safety profiles as compared with VA-ECMO alone. PMID- 29489462 TI - Monitoring of Antiplatelet Therapy in Children on Ventricular Assist Device Support: Comparison of Multiplate and Thromboelastography Platelet Mapping. AB - The optimal method for monitoring antiplatelet therapy in children supported with ventricular assist devices (VADs) is unknown. We conducted a retrospective study to compare Thromboelastography Platelet Mapping (TEG/PM) with multiple electrode platelet aggregometry (MEA) on a Multiplate analyzer (Roche Diagnostics, Mannheim, Germany). We analyzed data from 66 paired blood samples from 9 patients <16 years of age on VAD where platelet function was simultaneously measured with TEG/PM and MEA. Antiplatelet dose-response relationships and intraindividual variability during steady state therapy were determined. Agreement in determination of therapeutic antiplatelet therapy was poor (arachidonic acid, kappa 0.23; adenosine diphosphate [ADP], kappa 0.13). Rate of aspirin and clopidogrel resistance was much higher when determined using TEG/PM than MEA. In patients receiving >=5 mg/kg/day aspirin, 72% of TEG/PM measurements showed subtherapeutic response compared with 11% of MEA measurements. There was evidence of a dose-response relationship with clopidogrel and MEA ADP-induced aggregation (R = 0.56; p < 0.0001); however, there was no association between dose and TEG/PM% ADP inhibition (p = 0.15). Intraindividual variability in platelet reactivity was far greater when measured by TEG/PM during steady state therapy. Multiple electrode platelet aggregometry appears to be more reliable than TEG/PM for monitoring antiplatelet therapy in children supported with VAD. PMID- 29489463 TI - Association of Pulsatility with Gastrointestinal Bleeding in a Cohort of HeartMate II Recipients. AB - Gastrointestinal bleeding (GIB) is common in patients with continuous-flow left ventricular assist devices (CF-LVADs) possibly because of changes in blood flow. We aimed to test the hypothesis that a low pulsatility index (PI) is associated with an increased hazard of overt GIB in patients with CF-LVADs. We conducted a retrospective cohort study of patients who had a HeartMate II (HMII) CF-LVAD implanted at our center. The study end-point was the first overt GIB causing or occurring during a hospitalization between 6 days and 6 months after HMII implantation. HMII PI was recorded at 48 hours and at 1, 3, and 6 month intervals after implantation. We analyzed the associations of PI and clinical variables with the hazard of overt GIB. Ninety-five patients met eligibility criteria. PI ranged from 2.5 to 5.9 (low PI < 4.15 and high PI >= 4.15 on the basis of receiver operating characteristic curve analysis). Seventeen (18%) patients experienced overt GIB. In a multivariable model, only lower baseline hemoglobin was a significant predictor of an increased hazard of overt GIB. After adjusting for the baseline hemoglobin, low PI was independently associated with an increased hazard of overt GIB in our cohort of HMII recipients. PMID- 29489464 TI - Estimated Cost Savings: Everyone With Diabetes Counts (EDC) Program. AB - Everyone with Diabetes Counts (EDC) is a national disparities reduction program funded by the Centers for Medicare & Medicaid Services to improve outcomes in the underserved minority, diverse, and rural populations. This analysis evaluates West Virginia's pilot program of diabetes self-management education (DSME), one component of EDC. We frequency-matched 422 DSME completers to 1688 others by demographics and enrollment from Medicare fee-for service claims. We estimated savings associated with reduced hospitalizations in multivariable negative binomial models. DSME completers had 29% fewer hospitalizations (adjusted P < .0069). We estimated savings of $35 900 per 100 DSME completers in West Virginia. PMID- 29489465 TI - Renin-angiotensin system blockade reduces cardiovascular events in nonheart failure, stable patients with prior coronary intervention. AB - BACKGROUND: The effects of renin-angiotensin system (RAS) blockade on the clinical outcome in patients with stable coronary artery disease (SCAD) are conflicting. We evaluated the long-term effects of RAS blockers (angiotensin converting enzyme inhibitor or angiotensin receptor blocker) on the clinical outcomes in patients with SCAD without heart failure (HF) who underwent percutaneous coronary intervention (PCI) with drug-eluting stent using a large scale, multicenter, prospective cohort registry. METHODS: A total of 5722 patients with SCAD were enrolled and divided into two groups according to the use of RAS blockers after PCI: RAS blocker group included 4070 patients and no RAS blocker group included 1652 patients. Exclusion criteria were left ventricular ejection fraction less than 50% and the history of HF or myocardial infarction. A major adverse cardiovascular event (MACE) was defined as a composite of cardiovascular death, nonfatal myocardial infarction, and stroke. RESULTS: During a median follow-up of 29.7 months, RAS blockers were associated with a significant reduction in the risk of MACE [adjusted hazard ratio (HR): 0.781; 95% confidence interval (CI): 0.626-0.975; P=0.015] and all-cause death (adjusted HR: 0.788; 95% CI: 0.627-0.990; P=0.041) but did not affect the risk of coronary revascularization. In the propensity score matched cohort, overall findings were consistent (MACE: adjusted HR: 0.679; 95% CI: 0.514-0.897; P=0.006; all-cause death: adjusted HR: 0.723; 95% CI: 0.548-0.954; P=0.022), and the benefit of RAS blockade was maintained in all predefined subgroups. CONCLUSION: This study demonstrated that RAS blockers were effective preventive therapies for reducing long-term cardiovascular events in patients with SCAD without HF who underwent PCI. PMID- 29489466 TI - Silent Witnesses: Faculty Reluctance to Report Medical Students' Professionalism Lapses. AB - PURPOSE: Assessing students' professionalism is a critical component of medical education. Nonetheless, faculty reluctance to report professionalism lapses remains a significant barrier to the effective identification, management, and remediation of such lapses. The authors gathered information from faculty who supervise medical students to better understand their perceived barriers to reporting. METHOD: In 2015-2016, data were collected using a group concept mapping methodology, which is an innovative, asynchronous, structured mixed methods approach using qualitative and quantitative measures to identify themes characterizing faculty reluctance to report professionalism lapses. Participants from four U.S. and Canadian medical schools brainstormed, sorted, and rated statements about perceived barriers to reporting. Multidimensional scaling and hierarchical cluster analyses were used to analyze these data. RESULTS: Of 431 physicians invited, 184 con-tributed to the brainstorming task (42.7%), 48 completed the sorting task (11.1%), and 83 completed the rating task (19.3%). Participants identified six barriers or themes to reporting lapses. The themes "uncertainty about the process," "ambiguity about the 'facts,'" "effects on the learner," and "time constraints" were rated highest as perceived barriers. Demographic subgroup analysis by gender, years of experience supervising medical students, years since graduation, and practice discipline revealed no significant differences (P > .05). CONCLUSIONS: The decision to report medical students' professionalism lapses is more complex and nuanced than a binary choice to report or not. Faculty face challenges at the systems level and individual level. The themes identified in this study can be used for faculty development and to improve processes for reporting students' professionalism lapses. PMID- 29489467 TI - Advancing Health Professions Education Research by Creating a Network of Networks. AB - Producing the best evidence to show educational outcomes, such as competency achievement and credentialing effectiveness, across the health professions education continuum will require large multisite research projects and longitudinal studies. Current limitations that must be overcome to reach this goal include the prevalence of single-institution study designs, assessments of a single curricular component, and cross-sectional study designs that provide only a snapshot in time of a program or initiative rather than a longitudinal perspective.One solution to overcoming these limitations is to develop a network of networks that collaborates, using longitudinal approaches, across health professions and regions of the United States. Currently, individual networks are advancing educational innovation toward understanding the effectiveness of educational and credentialing programs. Examples of such networks include (1) the American Medical Association's Accelerating Change in Medical Education initiative, (2) the National Center for Interprofessional Practice and Education, and (3) the Accreditation Council for Graduate Medical Education's Accreditation System. In this Invited Commentary, the authors briefly profile these existing networks, identify their progress and the challenges they have encountered, and propose a vigorous way forward toward creating a national network of networks designed to determine the effectiveness of health professions education and credentialing. PMID- 29489469 TI - Animal Companionship and Risk of Suicide. PMID- 29489468 TI - The Influence of Hearing Aid Gain on Gap-Detection Thresholds for Children and Adults With Hearing Loss. AB - OBJECTIVES: The objective of this experiment was to examine the contributions of audibility to the ability to perceive a gap in noise for children and adults. Sensorineural hearing loss (SNHL) in adulthood is associated with a deficit in gap detection. It is well known that reduced audibility in adult listeners with SNHL contributes to this deficit; however, it is unclear the extent to which hearing aid amplification can restore gap-detection thresholds, and the effect of childhood SNHL on gap-detection thresholds have not been described. For adults, it was hypothesized that restoring the dynamic range of hearing for listeners with SNHL would lead to approximately normal gap-detection thresholds. Children with normal hearing (NH) exhibit poorer gap-detection thresholds than adults. Because of their hearing loss, children with SNHL have less auditory experience than their peers with NH. Yet, it is unknown the extent to which auditory experience impacts their ability to perceive gaps in noise. Even with the provision of amplification, it was hypothesized that children with SNHL would show a deficit in gap detection, relative to their peers with normal hearing, because of reduced auditory experience. DESIGN: The ability to detect a silent interval in noise was tested by adapting the stimulus level required for detection of gap durations between 3 and 20 ms for adults and children with and without SNHL. Stimulus-level thresholds were measured for participants with SNHL without amplification and with two prescriptive procedures-the adult and child versions of the desired sensation level i/o program-using a hearing aid simulator. The child version better restored the normal dynamic range than the adult version. Adults and children with NH were tested without amplification. RESULTS: When fitted using the procedure that best restored the dynamic range, adults with SNHL had stimulus-level thresholds similar to those of adults with normal hearing. Compared to the children with NH, the children with SNHL required a higher stimulus level to detect a 5-ms gap, despite having used the procedure that better restored the normal dynamic range of hearing. Otherwise, the two groups of children had similar stimulus-level thresholds. CONCLUSION: These findings suggest that apparent deficits in temporal resolution, as measured using stimulus-level thresholds for the detection of gaps, are dependent on age and audibility. These novel results indicate that childhood SNHL may impair temporal resolution as measured by stimulus-level thresholds for the detection of a gap in noise. This work has implications for understanding the effects of amplification on the ability to perceive temporal cues in speech. PMID- 29489470 TI - Biologic Impact of Mechanical Power at High and Low Tidal Volumes in Experimental Mild Acute Respiratory Distress Syndrome. AB - BACKGROUND: The authors hypothesized that low tidal volume (VT) would minimize ventilator-induced lung injury regardless of the degree of mechanical power. The authors investigated the impact of power, obtained by different combinations of VT and respiratory rate (RR), on ventilator-induced lung injury in experimental mild acute respiratory distress syndrome (ARDS). METHODS: Forty Wistar rats received Escherichia coli lipopolysaccharide intratracheally. After 24 h, 32 rats were randomly assigned to be mechanically ventilated (2 h) with a combination of different VT (6 ml/kg and 11 ml/kg) and RR that resulted in low and high power. Power was calculated as energy (DeltaP,L/E,L) * RR (DeltaP,L = transpulmonary driving pressure; E,L = lung elastance), and was threefold higher in high than in low power groups. Eight rats were not mechanically ventilated and used for molecular biology analysis. RESULTS: Diffuse alveolar damage score, which represents the severity of edema, atelectasis, and overdistension, was increased in high VT compared to low VT, in both low (low VT: 11 [9 to 14], high VT: 18 [15 to 20]) and high (low VT: 19 [16 to 25], high VT: 29 [27 to 30]) power groups. At high VT, interleukin-6 and amphiregulin expressions were higher in high-power than in low-power groups. At high power, amphiregulin and club cell protein 16 expressions were higher in high VT than in low VT. Mechanical energy and power correlated well with diffuse alveolar damage score and interleukin-6, amphiregulin, and club cell protein 16 expression. CONCLUSIONS: In experimental mild ARDS, even at low VT, high mechanical power promoted ventilator-induced lung injury. To minimize ventilator-induced lung injury, low VT should be combined with low power. PMID- 29489471 TI - Do Patients Live Longer After THA and Is the Relative Survival Diagnosis specific? AB - BACKGROUND: Hip replacements are successful in restoring mobility, reducing pain, and improving quality of life. However, the association between THA and the potential for increased life expectancy (as expressed by mortality rate) is less clear, and any such association could well be influenced by diagnosis and patient related, socioeconomic, and surgical factors, which have not been well studied. QUESTIONS/PURPOSES: (1) After controlling for birth year and sex, are Swedish patients who underwent THA likely to survive longer than individuals in the general population? (2) After controlling for relevant patient-related, socioeconomic/demographic factors and surgical factors, does relative survival differ across the various diagnoses for which THAs were performed in Sweden? METHODS: Data from the Swedish Hip Arthroplasty Register, linked to administrative health databases, were used for this study. We identified 131,808 patients who underwent THA between January 1, 1999, and December 31, 2012. Of these, 21,755 had died by the end of followup. Patient- and surgery-specific data in combination with socioeconomic data were available for analysis. We compared patient survival (relative survival) with age- and sex-matched survival data in the entire Swedish population according to Statistics Sweden. We used multivariable modeling proceeded with a Cox proportional hazards model in transformed time. RESULTS: Patients undergoing elective THA had a slightly improved survival rate compared with the general population for approximately 10 years after surgery. At 1 year after surgery, the survival in patients undergoing THA was 1% better than the expected survival (r = 1.01; 95% confidence interval [CI], 1.01-1.02; p < 0.001); at 5 years, this increased to 3% (r = 1.03; 95% CI, 1.03-1.03; p < 0.001); at 10 years, the difference was 2% (r = 1.02; 95% CI, 1.02 1.03; p < 0.001); and by 12 years, there was no difference between patients undergoing THA and the general population (r = 1.01; 95% CI, 0.99-1.02; p = 0.13). Using the diagnosis of primary osteoarthritis as a reference, hip arthroplasties performed for sequelae of childhood hip diseases had a similar survival rate (hazard ratio [HR], 1.02; 95% CI, 0.88-1.18; p = 0.77). Patients undergoing surgery for osteonecrosis of the femoral head (HR, 1.69; 95% CI, 1.60 1.79; p < 0.001), inflammatory arthritis (HR, 1.49; 95% CI, 1.38-1.61; p < 0.001), and secondary osteoarthritis (HR, 2.46; 95% CI, 2.03-2.99; p < 0.001) all had poorer relative survival. Comorbidities and the Elixhauser comorbidity index had a negative association with relative survival. Level of achieved education (middle level of education: HR, 0.90, 95% CI, 0.87-0.93, p < 0.001; high level: 0.76, 95% CI, 0.73-0.80, p < 0.001) and marital status (single status: HR, 1.33; 95% CI, 1.28-1.38; p < 0.001) were also negatively associated with survival. CONCLUSIONS: Whereas it has been known that in most patients, THA improves quality of life, this study demonstrates that it also is associated with a slightly increased life expectancy that lasts for approximately 10 years after surgery, especially among patients whose diagnosis was primary osteoarthritis. This adds further proof of a health-economic value for this surgical intervention. The reasons for the increase in relative survival are unknown but are probably multifactorial. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29489472 TI - Development and validation of a scoring index to predict the presence of lesions in capsule endoscopy in patients with suspected Crohn's disease of the small bowel: a Spanish multicenter study. AB - BACKGROUND: Capsule endoscopy (CE) is the first-line investigation in cases of suspected Crohn's disease (CD) of the small bowel, but the factors associated with a higher diagnostic yield remain unclear. OBJECTIVE: Our aim is to develop and validate a scoring index to assess the risk of the patients in this setting on the basis of biomarkers. PATIENTS AND METHODS: Data on fecal calprotectin, C reactive protein, and other biomarkers from a population of 124 patients with suspected CD of the small bowel studied by CE and included in a PhD study were used to build a scoring index. This was first used on this population (internal validation process) and after that on a different set of patients from a multicenter study (external validation process). RESULTS: An index was designed in which every biomarker is assigned a score. Three risk groups have been established (low, intermediate, and high). In the internal validation analysis (124 individuals), patients had a 10, 46.5, and 81% probability of showing inflammatory lesions in CE in the low-risk, intermediate-risk, and high-risk groups, respectively. In the external validation analysis, including 410 patients from 12 Spanish hospitals, this probability was 15.8, 49.7, and 80.6% for the low risk, intermediate-risk, and high-risk groups, respectively. CONCLUSION: Results from the internal validation process show that the scoring index is coherent, and results from the external validation process confirm its reliability. This index can be a useful tool for selecting patients before CE studies in cases of suspected CD of the small bowel. PMID- 29489473 TI - Worldwide incidence of hepatocellular carcinoma cases attributable to major risk factors. AB - To facilitate regionally specific liver cancer prevention and control, this study estimates the fraction of hepatocellular carcinoma (HCC) cases attributable to five major liver cancer risk factors by geographic region. Prevalence estimates of major HCC risk factors, including chronic infection with hepatitis B and hepatitis C, alcohol drinking, tobacco smoking, obesity, and diabetes, were extracted for each country from the literature, along with recent incidence and risk estimate data, to calculate regionally specific population attributable fractions. Overall, 44% of HCC cases worldwide were attributable to chronic hepatitis B infection, with the majority of cases occurring in Asia. Hepatitis C was responsible for 21% of cases. Lifestyle risk factors such as alcohol drinking and obesity were responsible for a larger percentage of cases in North America and Western, Central, and Eastern Europe. In addition, strong sex disparities were observed when looking at lifestyle risk factors, particularly tobacco smoking, in Asia and Africa. Prominent risk factors for HCC vary depending on the region. Our findings provide useful data for developing regionally specific guidelines for liver cancer prevention and control worldwide. PMID- 29489474 TI - High Expression of Ubiquitin C-terminal Hydrolase L1 Is Associated With Poor Prognosis in Endometrial Cancer Patients. AB - OBJECTIVE: The ubiquitin C-terminal hydrolase L1 (UCHL1) plays a key role in tumor invasion and metastasis. Ubiquitin C-terminal hydrolase L1 is overexpressed in various cancers and reported to be correlated with a poor prognosis. The objective of this study was to determine the prognostic significance of UCHL1 in endometrial cancer. METHODS: The expression of UCHL1 in endometrial cancer was assessed using quantitative reverse transcription polymerase chain reaction and immunohistochemistry in 56 and 215 resected tumor specimens, respectively. RESULTS: The 4-year survival rates of the high UCHL1 messenger RNA expression group and high UCHL1 protein expression group were 78% and 71%, respectively, compared with 96% and 95% for the low UCHL1 messenger RNA expression group and low UCHL1 protein expression group, respectively. Kaplan-Meier and log-rank tests indicated a significant correlation between expression of UCHL1 and disease-free survival and overall survival. Moreover, multivariate stepwise Cox proportional hazard regression model analysis showed that UCHL1 was a significant independent marker for predicting a poor disease-free survival and overall survival. In 43 patients with metastatic lesions, immunohistochemical analysis of metastatic lesions revealed that the recurrence rate and mortality rate were 62% and 41%, respectively, in 29 UCHL1-positive patients and 36% and 29%, respectively, in 14 UCHL1-negative patients. CONCLUSIONS: The results of this study suggest that high UCHL1 expression is a strong marker of poor prognosis of endometrial cancer. Furthermore, we suggest that UCHL1 may be involved in the development of distant metastasis in endometrial cancer. PMID- 29489475 TI - Tumor Size, an Additional Risk Factor of Local Recurrence in Low-Risk Endometrial Cancer: A Large Multicentric Retrospective Study. AB - OBJECTIVE: The identification of patients with endometrial cancer (EC) at higher risk for relapse is critical to individualize and better tailor postoperative treatment. No evidence is available regarding the possible association between tumor size (TS) and the risk of local recurrence. The purpose of this study was to analyze the correlation between TS and risk/type of recurrence in EC patients, stratified according to the new European Society of Medical Oncology-European Society of Gynecological Oncology-European Society for Radiotherapy and Oncology classification. METHODS: Data of patients with histologically proven EC who received primary surgical treatment between November 1999 and June 2015 were retrospectively retrieved from 5 institutions. Optimal TS cutoff was calculated using a receiver operating characteristic curve. Site of recurrence as a function of TS and groups of risk were analyzed. Local recurrence-free survival, recurrence-free survival, and overall survival were calculated using the Kaplan Meier method. RESULTS: Data of 1166 patients were analyzed. Among them, 514 (44.1%) had low-risk EC, 174 (14.9%) had intermediate risk EC, 173 (14.8%) had high-intermediate risk EC, and 305 (26.2%) had high-risk EC. A total of 134 (11.5%) women had recurrence: 47 (4%) of them had local relapse, 30 (2.6%) had locoregional relapse, and 57 (4.9%) had distant relapse. Tumor size 25 mm or greater emerged as the threshold for the prediction of a higher rate of local recurrence (P < 0.0001, hazard ratio = 18.2, P = 0.005) and a lower local recurrence-free survival and recurrence-free survival (P < 0.0001) only in patients with low-risk EC. There was no statistically significant correlation between TS and recurrence in the other risk groups. CONCLUSIONS: In this very large series, tumor size emerges as an independent prognostic factor of local recurrence in women with low-risk EC and could be a valuable additional criterion to personalize the treatment approach to these patients. PMID- 29489476 TI - Mothering With Advanced Ovarian Cancer: "You've Got to Find That Little Thing That's Going to Make You Strong". AB - BACKGROUND: Mothers with ovarian cancer are at risk of experiencing additional demands given their substantial symptom burden and accelerated disease progression. OBJECTIVE: This study describes the experience of mothers with ovarian cancer, elucidating the interaction between their roles as mothers and patients with cancer. METHODS: We conducted a secondary analysis of focus groups with women with advanced ovarian cancer. Using descriptive coding, we developed a coding framework based on emerging findings and group consensus. We then identified higher-order themes capturing the breadth of experiences described by mothers with ovarian cancer. RESULTS: Eight of the 13 participants discussed motherhood. The mean age of participants was 48.38 (SD, 7.17) years. All women were white (9/9), most had some college education (6/9), and the majority were married (5/9). Mean time since diagnosis was 7.43 (SD, 4.69) months; more than half of women (5/9) were currently receiving treatment. Themes and exemplar quotes reflected participants' evolving self-identities from healthy mother to cancer patient to woman mothering with cancer. Subthemes related to how motherhood was impacted by symptoms, demands of treatment, and the need to gain acceptance of living with cancer. CONCLUSIONS: The experience of motherhood impacts how women experience cancer and how they evolve as survivors. Similarly, cancer influences mothering. IMPLICATIONS FOR PRACTICE: Healthcare providers should understand and address the needs of mothers with ovarian cancer. This study adds to the limited literature in this area and offers insight into the unique needs faced by women mothering while facing advanced cancer. PMID- 29489477 TI - Uncertainty and Quality of Life in Women With Breast Cancer: Moderating Role of Coping Styles. AB - BACKGROUND: The negative relationship between uncertainty and quality of life is well reported in the literature. Also, there is abundant research linking coping strategies to cancer patients' quality of life. However, there exists a paucity of information on the moderating effect of coping styles on the relationship between uncertainty and quality of life in cancer patients. OBJECTIVE: The aim of this study was to examine whether uncertainty in illness is negatively correlated with quality of life and whether this relationship is moderated by coping strategies, namely, problem-focused, avoidant, and active emotional coping. METHODS: A convenience sample of 135 Malaysian women with breast cancer participated in the study. Participants completed measures of uncertainty in illness, quality of life, and coping styles. RESULTS: Uncertainty in breast cancer was negatively related to quality of life (beta = -0.379, P < .001), and active emotional coping was found to moderate this negative relationship (beta = 0.155, P < .05). The model explained 22.20% of the variance of quality of life. CONCLUSION: Lack of information about breast cancer, treatment, hospitalization, and disease recurrence is related to poorer quality of life. However, this negative relationship becomes weaker when active emotional coping strategies are used. IMPLICATIONS FOR PRACTICE: Nurses and health providers should help patients reduce their uncertainty in illness by providing them information on breast cancer or referring them to relevant sources. Moreover, they could reduce the deleterious effect of uncertainty on quality of life by encouraging patients to use more active emotional coping strategies. PMID- 29489478 TI - Understanding Functional Communication in Head and Neck Cancer Survivors Using a Mixed Methods Design. AB - BACKGROUND: Functional communication, defined as everyday communication with family and friends, at work, and in the community, is an important but understudied concept in the head and neck cancer (HNC) survivor population. OBJECTIVE: The aim of this study was to better understand functional communication by using a mixed methods approach. METHODS: Head and neck cancer survivors participated in semistructured interviews and completed self-report questionnaires assessing multiple aspects of well-being and health-related quality of life (HRQOL). These qualitative and quantitative data were collected concurrently, analyzed separately, and then integrated. RESULTS: Survivors' perceptions of functional communication ranged from "Communication is good" to "Communication has changed" to "Communication is difficult." Using these qualitative results, survivors were categorized into 3 mutually exclusive groups. Clinically meaningful cut points were exceeded on measures of depressive symptoms (18%), state (40%) and trait (54%) anxiety, and pain (18%). Health-related quality of life scores were moderate to high for the sample as a whole. Statistically significant group differences were found only on the HNC-specific measure of HRQOL. A surprising finding was that the lowest mean score on social function was in the "Communication has changed" group. This group perceived changes in speech and voice that bothered them when communicating in social situations, although their speech was clear to a listener. CONCLUSION: An underrecognized subpopulation of HNC survivors may exist, whose day-to-day functional communication has changed in ways that impact their relationships and sense of self. IMPLICATIONS FOR PRACTICE: Clinical identification of this subpopulation and provision of appropriate interventions are essential to facilitate optimal HRQOL after HNC treatment. PMID- 29489479 TI - Changes in Siblings Over Time After the Death of a Brother or Sister From Cancer. AB - BACKGROUND: Limited research has examined the impact of a child's death from cancer on siblings. Even less is known about how these siblings change over time. OBJECTIVE: This study compared changes in siblings 1 (T1) and 2 (T2) years after the death of a brother or sister from cancer based on bereaved parent and sibling interviews. METHODS: Participants across 3 institutions represented 27 families and included bereaved mothers (n = 21), fathers (n = 15), and siblings (n = 26) ranging from 8 to 17 years old. Participants completed semistructured interviews. Content analysis identified emerging themes and included frequency counts of participant responses. McNemar tests examined differences in the frequency of responses between T1 and T2 data. RESULTS: Participants reported similar types of changes in bereaved siblings at both time points, including changes in sibling relationships, life perspectives, their personal lives, and school performance. A new theme of "openness" emerged at T2. Frequencies of responses differed according to mother, father, or sibling informant. Overall, participants less frequently reported changes at T2 versus T1. Compared with findings in the first year, participants reported greater sibling maturity at follow-up. CONCLUSION: Overall changes in bereaved siblings continued over 2 years with less frequency over time, with the exception of increases in maturity and openness. IMPLICATIONS FOR PRACTICE: Providers can educate parents regarding the impact of death of a brother or sister over time. Nurses can foster open communication in surviving grieving siblings and parents as potential protective factors in families going through their grief. PMID- 29489480 TI - The Brief Perceived Cognitive Impairment Scale-Korean: A Validation Study. AB - BACKGROUND: Practical brief measures are needed for clinicians and researchers to identify and effectively manage cognitive impairment in cancer patients. OBJECTIVE: This study evaluated the reliability (ie, internal consistency reliability) and validity (ie, construct, convergent, concurrent, and known-group validity) of the Brief Perceived Cognitive Impairment Scale-Korean (BPCIS-K). METHODS: From a university hospital, 249 cancer patients participated. The BPCIS K was constructed with 6 items evaluating key aspects of cognitive impairment in cancer patients. For internal consistency reliability, Cronbach's alpha and item total correlations were evaluated. For construct validity, confirmatory factor analysis was performed. For convergent validity, Pearson correlations were tested with the Functional Assessment of Cancer Therapy-Cognitive Function. For concurrent validity, Pearson correlations were tested with the Functional Assessment of Chronic Illness Therapy-Fatigue. For known-group validity, t tests were performed. RESULTS: The BPCIS-K showed high internal consistency reliability (Cronbach's alpha = .92; item-total correlations ranged from 0.76 to 0.81). Factor analysis confirmed the scale is unidimensional. It is highly associated with another validated cognitive impairment measure (r = -0.91, P < .001) and moderately correlated with a fatigue measure (r = -0.52, P < .001). In known group validity, female and patients undergoing treatment experienced more severe impairment than did male patients and patient awaiting treatment (P = .05, P = .08, respectively). CONCLUSION: The BPCIS-K is valid and reliable for assessing cancer patients' perceived cognitive impairment, particularly in concentration, memory, and executive functions. IMPLICATION FOR PRACTICE: This study introduces a practical brief measure to clinicians and researchers. PMID- 29489481 TI - The Mediating Role of Exercise on Relationships Between Fatigue, Sleep Quality, and Quality of Life for Adolescents With Cancer. AB - BACKGROUND: Fatigue and poor sleep are two of the most common and most distressing symptoms for adolescents with cancer. These 2 symptoms concurrently heighten distress, further decreasing quality of life (QoL). OBJECTIVES: The aims of this study were to describe the degree of exercise involvement, fatigue, sleep quality, and QoL among adolescents with cancer and to determine whether exercise mediates the relationships between (a) fatigue and QoL and (b) sleep quality and QoL. METHODS: A cross-sectional study of 100 participants was conducted. Multiple regression was performed to examine the mediation relationship. RESULTS: Participants in the off-treatment group had a significantly higher degree of exercise involvement, as well as less fatigue, greater sleep quality, and less QoL distress. Exercise partially mediated the adverse effect of fatigue on QoL for adolescents undergoing cancer treatment, accounting for 49.80% of the total variation; exercise partially mediated the adverse effect of poor sleep on QoL for adolescents both in treatment and in survivorship, accounting for 42.06% and 28.71% of the total variations, respectively. CONCLUSION: Exercise partially mediated the relationship between fatigue and QoL for adolescents in cancer treatment and partially mediated the relationship between sleep quality and QoL both for those in cancer treatment and for those in survivorship. IMPLICATIONS FOR PRACTICE: Developing tailored exercise programs based on both treatment status and the degree of fatigue and sleep quality is important. In-service education that enhances nurses' awareness of the importance of exercise in improving adolescents' QoL is recommended. PMID- 29489482 TI - Hospital Variations in Clinical Complications and Patient-reported Outcomes at 2 Years After Immediate Breast Reconstruction. AB - OBJECTIVE: Our objectives were to investigate case-mix adjusted hospital variations in 2-year clinical and patient-reported outcomes following immediate breast reconstruction. BACKGROUND: Over the past few decades, variations in medical practice have been viewed as opportunities to promote best practices and high-value care. METHODS: The Mastectomy Reconstruction Outcomes Consortium Study is an National Cancer Institute-funded longitudinal, prospective cohort study assessing clinical and patient-reported outcomes of immediate breast reconstruction after mastectomy at 11 leading medical centers. Case-mix adjusted comparisons were performed using generalized linear mixed-effects models to assess variation across the centers in any complication, major complications, satisfaction with outcome, and satisfaction with breast. RESULTS: Among 2252 women in the analytic cohort, 1605 (71.3%) underwent implant-based and 647 (28.7%) underwent autologous breast reconstruction. There were significant differences in the sociodemographic and clinical characteristics, and distribution of procedure types at the different Mastectomy Reconstruction Outcomes Consortium Study centers. After case-mix adjustments, hospital variations in the rates of any and major postoperative complications were observed. Medical center odds ratios for major complication ranged from 0.58 to 2.13, compared with the average major complication rate across centers. There were also meaningful differences in satisfaction with outcome (from the lowest to highest of -2.79-2.62) and in satisfaction with breast (-2.82-2.07) compared with the average values. CONCLUSIONS: Two-year postoperative complications varied widely between hospitals following post-mastectomy breast reconstruction. These variations represent an important opportunity to improve care through dissemination of best practices and highlight the limitations of extrapolating single-institution level data and the ongoing challenges of studying hospital based outcomes for this patient population. PMID- 29489483 TI - The Beneficial Effects of Minimizing Blood Loss in Pancreatoduodenectomy. AB - OBJECTIVE: The aim of this study was to elucidate the impact of intraoperative blood loss on outcomes following pancreatoduodenectomy (PD). BACKGROUND: The negative impact of intraoperative blood loss on outcomes in PD has long been suspected but not well characterized, particularly those factors that may be within surgeons' control. METHODS: From 2001 to 2015, 5323 PDs were performed by 62 surgeons from 17 institutions. Estimated blood loss (EBL) was discretized (0 to 300, 301 to 750, 751 to 1300, and >1300 mL) using optimal scaling methodology. Multivariable regression, adjusted for patient, surgeon, and institutional variables, was used to identify associations between EBL and perioperative outcomes. Factors associated with both increased and decreased EBL were elucidated. The relative impact of surgeon-modifiable contributors was estimated through beta coefficient standardization. RESULTS: The median EBL of the series was 400 mL [interquartile range (IQR) 250 to 600]. Intra-, post-, and perioperative transfusion rates were 15.8%, 24.8%, and 37.2%, respectively. Progressive EBL zones correlated with intra- but not postoperative transfusion in a dose-dependent fashion (P < 0.001), with a key threshold of 750 mL EBL (8.14% vs 40.9%; P < 0.001). Increasing blood loss significantly correlated with poor perioperative outcomes. Factors associated with increased EBL were trans anastomotic stent placement, neoadjuvant chemotherapy, pancreaticogastrostomy reconstruction, multiorgan or vascular resection, and elevated operative time, of which 38.7% of the relative impact was "potentially modifiable" by the surgeon. Conversely, female sex, small duct, soft gland, minimally invasive approach, pylorus-preservation, biological sealant use, and institutional volume (>=67/year) were associated with decreased EBL, of which 13.6% was potentially under the surgeon's influence. CONCLUSION: Minimizing blood loss contributes to fewer intraoperative transfusions and better perioperative outcomes for PD. Improvements might be achieved by targeting modifiable factors that influence EBL. PMID- 29489484 TI - Short-term Preoperative Diet Decreases Bleeding After Partial Hepatectomy: Results From a Multi-institutional Randomized Controlled Trial. AB - BACKGROUND: Our previous case series suggested that a 1-week, low-calorie and low fat diet was associated with decreased intraoperative blood loss in patients undergoing liver surgery. OBJECTIVE: The current study evaluates the effect of this diet in a randomized controlled trial. METHODS: We randomly assigned 60 patients with a body mass index >=25 kg/m to no special diet or an 800-kcal, 20 g fat, and 70 g protein diet for 1 week before liver resection. Surgeons were blinded to diet assignment. Hepatic glycogen stores were evaluated using periodic acid Schiff (PAS) stains. RESULTS: Ninety four percent of the patients complied with the diet. The diet group consumed fewer daily total calories (807 vs 1968 kcal, P < 0.001) and fat (21 vs 86 g, P < 0.001) than the no diet group. Intraoperative blood loss was less in the diet group: mean blood loss 452 vs 863 mL (P = 0.021). There was a trend towards decreased transfusion in the diet group (138 vs 322 mL, P = 0.06). The surgeon judged the liver to be easier to manipulate in the diet group: 1.86 versus 2.90, P = 0.004. Complication rate (20% vs 17%), length of stay (median 5 vs 4 days) and mortality did not differ between groups. There was no difference in hepatic steatosis between groups. There was less glycogen in hepatocytes in the diet group (PAS stain score 1.61 vs 2.46, P < 0.0001). CONCLUSIONS: A short-course, low-fat, and low-calorie diet significantly decreases bleeding and makes the liver easier to manipulate in hepatic surgery. PMID- 29489485 TI - Increased Rate of Long-term Mortality Among Burn Survivors: A Population-based Matched Cohort Study. AB - OBJECTIVE: To estimate long-term mortality following major burn injury compared with matched controls. SUMMARY BACKGROUND DATA: The effect of sustaining a major burn injury on long-term life expectancy is poorly understood. METHODS: Using health administrative data, all adults who survived to discharge after major burn injury between 2003 and 2013 were matched to between 1 and 5 uninjured controls on age, sex, and the extent of both physical and psychological comorbidity. To account for socioeconomic factors such as residential instability and material deprivation, we also matched on marginalization index. The primary outcome was 5 year all-cause mortality, and all patients were followed until death or March 31, 2014. Cumulative mortality estimates were estimated using the Kaplan-Meier method. Cox proportional hazards modeling was used to estimate the association of burn injury with mortality. RESULTS: In total, 1965 burn survivors of mean age 44 (standard deviation 17) years with median total body surface area burn of 15% [interquartile range (IQR) 5-15] were matched to 8671 controls and followed for a median 5 (IQR 2.5-8) years. Five-year mortality was significantly greater among burn survivors (11 vs 4%, P < 0.001). The hazard ratio was greatest during the first year (4.15, 95% CI 3.17-5.42), and declined each year thereafter, reaching 1.65 (95% CI 1.02-2.67) in the fifth year after discharge. Burn survivors had increased mortality related to trauma (mortality rate ratio, MRR 9.8, 95% CI 5 19) and mental illness (MRR 9.1, 95% CI 4-23). CONCLUSIONS: Burn survivors have a significantly higher rate of long-term mortality than matched controls, particularly related to trauma and mental illness. Burn follow-up should be focused on injury prevention, mental healthcare, and detection and treatment of new disease. PMID- 29489486 TI - Achievements and Challenges in Facial Transplantation. AB - : The first facial transplantation in 2005 ushered in a new era in reconstructive surgery, offering new possibilities for the repair of severe disfigurements previously limited by conventional techniques. Advances in allograft design, computerized preoperative planning, surgical technique, and postoperative revisions have helped push the boundaries in this new frontier of vascularized composite allotransplantation. Over the past 12 years, 40 of these procedures have been performed across the world, offering the field the opportunity to reflect on current outcomes. Successes achieved in the brief history of facial transplantation have resulted in a new set of obstacles the field must now overcome. In this review, we aim to highlight the achievements, major challenges, and future directions of this rapidly evolving field. PMID- 29489487 TI - Portal Inflow Modulation by Somatostatin During Major Liver Resection With a High Risk of Postoperative Liver Failure. PMID- 29489488 TI - Bile Duct Injury and Minimal Invasive Surgery Repair (Laparoscopic and Robotic). PMID- 29489490 TI - The Whiteboard Technique: Personalized Communication to Improve Operating Room Teamwork. PMID- 29489493 TI - Effects on the diagnosis change and on the disability level for individuals with disorder of consciousness: which predictors? AB - Prediction of the functional recovery in patients with disorders of consciousness (DOC) is still complex because of the different numbers of variables that influence the possibility of observing changes in clinical outcome. The aim of the present study is to identify the best set of predictors of the change in DOC diagnosis among different pharmacotherapy and nonpharmacotherapy indicators. This study analyzed data collected in a longitudinal, two-evaluation, multicenter project conducted in 90 centers. We analyzed the predictor effects of physical and cognitive treatments, duration of disease, etiology, age, and sex (nonpharmacological treatments) as well as the use of antiparkinson, psycholeptic, psychoanaleptic, and muscle-relaxant drugs (pharmacological variables). Ordered logistic models, linear regression models with bootstrap estimation, and model averaging procedures were used. The results showed that physical and cognitive treatments [best predictor: odds ratio (OR)=413.3, P<0.001], age (OR=0.964, P<0.001), and use of psycholeptic drugs (negative effect: OR=0.373, P=0.039) were the variables that contributed in general toward a change in diagnosis. Notably, the use of psycholeptic drugs seemed to impede the functional recovery in patients with DOC, so serious reflections on its use will be made. PMID- 29489489 TI - MySurgeryRisk: Development and Validation of a Machine-learning Risk Algorithm for Major Complications and Death After Surgery. AB - : MINI: In a single-center cohort of 51,457 adult surgical patients, we have developed and validated an automated machine-learning algorithm that uses existing clinical data in electronic health records to forecast the risk for major complications and death after any type of surgery with high sensitivity and high specificity. OBJECTIVE: To accurately calculate the risk for postoperative complications and death after surgery in the preoperative period using machine learning modeling of clinical data. BACKGROUND: Postoperative complications cause a 2-fold increase in the 30-day mortality and cost, and are associated with long term consequences. The ability to precisely forecast the risk for major complications before surgery is limited. METHODS: In a single-center cohort of 51,457 surgical patients undergoing major inpatient surgery, we have developed and validated an automated analytics framework for a preoperative risk algorithm (MySurgeryRisk) that uses existing clinical data in electronic health records to forecast patient-level probabilistic risk scores for 8 major postoperative complications (acute kidney injury, sepsis, venous thromboembolism, intensive care unit admission >48 hours, mechanical ventilation >48 hours, wound, neurologic, and cardiovascular complications) and death up to 24 months after surgery. We used the area under the receiver characteristic curve (AUC) and predictiveness curves to evaluate model performance. RESULTS: MySurgeryRisk calculates probabilistic risk scores for 8 postoperative complications with AUC values ranging between 0.82 and 0.94 [99% confidence intervals (CIs) 0.81-0.94]. The model predicts the risk for death at 1, 3, 6, 12, and 24 months with AUC values ranging between 0.77 and 0.83 (99% CI 0.76-0.85). CONCLUSIONS: We constructed an automated predictive analytics framework for machine-learning algorithm with high discriminatory ability for assessing the risk of surgical complications and death using readily available preoperative electronic health records data. The feasibility of this novel algorithm implemented in real time clinical workflow requires further testing. PMID- 29489494 TI - Mineralocorticoid receptor-related markers and outcome of major depression: focus on blood pressure and electrolytes. AB - A close association between vegetative regulation and affect is common knowledge. Recently, the role of aldosterone and the activity of its receptor [mineralocorticoid receptor (MR)] in the clinical outcome for treatment with standard antidepressants has been shown including low systolic blood pressure and a low concentration of plasma sodium (Na), both of which appear to be related to therapy resistance to standard antidepressants. We carried out a retrospective analysis of a double-blind placebo-controlled trial of St John's wort extract LI160 in 247 outpatients with major depression. The study did not show a difference between the treatment groups; therefore, a pooled dataset of the 6 week completer population of the trial was analyzed. The focus was on the moderating effect of blood pressure and electrolytes on clinical outcome (relative change in Montgomery-Asberg Depression Rating Scale). Low Na/K ratio and high K at screening predicted worse outcome after 6 weeks as measures with the Montgomery-Asberg Depression Rating Scale (P<0.01). Systolic blood pressure at the same time point did not influence the treatment outcome. In conclusion, signs of reduced peripheral MR sensitivity, as reflected by a lower plasma Na/K ratio and/or higher K concentration, predict worse outcome. This is in line with our recent data as well as neuroendocrine findings. The data indicate that widely collected biomarkers, which are related to MR activity, may be useful to identify patients, who are at risk of nonresponse to antidepressant treatment. PMID- 29489495 TI - Health service utilization and medical costs among patients with schizophrenia receiving long-acting injectable risperidone versus oral risperidone: a nationwide retrospective matched cohort study in Taiwan. AB - The aim of the nationwide retrospective matched cohort study was to evaluate health service utilization and medical costs between patients with schizophrenia who received long-acting injectable (LAI) risperidone and those who took risperidone orally. Data were sourced from the 2008 to 2013 Psychiatric Inpatient Medical Claim Dataset in Taiwan. The sample selection process was performed by propensity score matching. Finally, there were 691 patients in the exposed cohort and 1382 patients in the unexposed cohort. Each patient was individually followed for a 1-year period. Two-part models and generalized estimating equations were used to evaluate health service utilization and direct medical costs of patients. Analytical results showed that patients receiving LAI risperidone had used outpatient services significantly more, had greater hospital admissions, and had shorter lengths of stay than those who took risperidone orally. Furthermore, compared with their counterparts in the unexposed group, patients in the exposed group had incurred higher medical costs because of costs incurred from increased utilization of outpatient service and hospital admissions, under the special context of the healthcare system in Taiwan, a single-payer universal health coverage system with low copayment rates. In summary, this study suggested that patients with schizophrenia treated with LAI risperidone had shorter lengths of stay, higher medical costs largely because of increased utilization of outpatient service and hospital admissions, compared with those who took risperidone orally. PMID- 29489496 TI - In Vivo Confocal Microscopic Study of Hard Contact Lens-Induced Lipid Keratopathy Secondary to Corneal Neovascularization in a Rabbit Hypercholesterolemic Model. AB - OBJECTIVES: In vivo confocal microscopy was used to observe the morphological presentations and anatomical correlations between corneal neovascularization (NV) and intracorneal lipid deposition in a rabbit model of contact lens (CL)-induced lipid keratopathy secondary to corneal NV. METHODS: Rabbits were divided into 3 groups: (1) 8-week normal diet, (2) 8-week high-cholesterol diet, and (3) 4-week normal diet followed by 4-week high-cholesterol diet. Corneal NV was induced by closed-eye CL. The formation and maturation of corneal NV were shown by immunohistochemical staining against CD31 and high-molecular-weight melanoma associated antigen. In vivo confocal microscopy identified corneal NV and lipid deposition. Acquired images for each eye were arranged and mapped into subconfluent montages. RESULTS: In group 1, corneal NV sprouting formed from the peripheral to the central cornea by the end of week 4. Pericytes around vessels were shown after 2 weeks of CL wear. In group 2, lipid deposition started from the peripheral cornea and progressively covered the whole cornea. In group 3, lipid deposition was found first in the central cornea after 2 weeks of high cholesterol diet and progressed to cover the peripheral cornea. In vivo confocal microscopy demonstrated four different patterns of intracorneal lipid deposition: spindle shapes arranged randomly or in parallel, amorphous shapes, multiangular shapes, and mixed types. Intracorneal lipid deposition was distributed from basal corneal epithelium to deep stroma. CONCLUSIONS: Intracorneal lipids tend to accumulate around newly formed corneal NV but can extend to the area covered with mature NV. In vivo confocal microscopy can demonstrate various shapes and depths of intracorneal lipid deposition. PMID- 29489497 TI - Association of Axial Length Growth and Topographic Change in Orthokeratology. AB - OBJECTIVES: To investigate the topographic factors related to axial length (AL) growth rate in orthokeratology. METHODS: Clinical data of myopic children with orthokeratology lenses from 2010 to 2016 were investigated. Corneal topography (Orbscan II) and IOLMaster-measured AL at baseline and every posttreatment visit were analyzed. Optical map topographies from baseline- and posttreatment stabilized corneas were analyzed to calculate the refractive power difference between the apex and the periphery (apex-periphery refractive power difference [ARPD]), which estimates the change of peripheral refraction. A generalized estimating equation (GEE) was used to assess the associations between AL growth and topographic changes in both eyes. RESULTS: The mean baseline spherical equivalent (SE) was -2.40+/-1.12 diopters (D) and the mean AL was 24.38+/-0.77 mm. Over a mean follow-up period of 41.9 months, the mean AL growth rate was 0.22+/-0.15 mm/year. In a univariable GEE analysis, age at initial lens wear, baseline AL, baseline SE, central corneal thickness (CCT), baseline apex power, and posttreatment ARPD on optical topography maps were all significantly correlated with AL growth rate (P<0.001, 0.009, 0.024, 0.011, 0.010, and 0.006, respectively). In a multivariable GEE, CCT and posttreatment ARPD were identified as significant factors (P=0.014 and 0.016, respectively). CONCLUSIONS: The AL growth rate was significantly associated with CCT and posttreatment relative peripheral refractive power, in addition to age at initial lens wear. These associations might possibly demonstrate an effect of treatment-induced peripheral refraction changes on retardation of myopic progression, whereas younger age might significantly influence both AL growth rate and corneal deformation. PMID- 29489498 TI - Analysis of Two Orthokeratology Lens Designs and Comparison of Their Optical Effects on the Cornea. AB - PURPOSE: This study aims to analyze two commercial orthokeratology lens designs and compare their optical effects at the corneal level. METHODS: This is a retrospective study on subjects seeking an orthokeratology fitting for myopia management at the Universite de Montreal clinic between January 2013 and August 2015. Group A included the first 64 subjects fitted with a 4-curve lens design (Paragon CRT; Paragon) who met the inclusion criteria, whereas group B included the same number of subjects fitted with a 5-curve lens design (Dreamlens; Polymer Technology, Rochester, NY). Topographic tangential maps were collected at baseline and 3 months after fitting. The differential map was generated for each patient and analyzed, which involved determining the radius of the central distance zone (CDZ) and the power and width of the high convex zone (HCZ). Results were compared between the two groups, taking baseline refraction into account. Finally, a correlation was estimated between topographic data and corneal parameters (flat and steep K, the corneal eccentricity of each principal meridian). RESULTS: The CDZ for group A is significantly larger than the one generated for group B both horizontally (t(126)=12.12, P<0.01) and vertically (t(126)=15.690, P<0.01). However, there was no significant difference regarding the HCZ power generated. The only correlations found were a strong positive association between CDZ radius and HCZ power generated by lens A nasally (r=0.450; P=0.000) and temporally (r=0.558; P=0.000), and a weaker association between the baseline refractive error, along with the nasal (r=0.237; P=0.033) and temporal (r=0.288; P=0.028) HCZ power for lens B. CONCLUSION: The four- and five-curve orthokeratology lens designs generate significantly different optical modifications on the cornea. This can affect reports on orthokeratology efficacy for myopia management as well as the lens selection when used for myopia correction. PMID- 29489500 TI - Prenatal diagnosis. PMID- 29489501 TI - Prenatal transplantation of human amniotic fluid stem cells for spinal muscular atrophy. AB - PURPOSE OF REVIEW: To review the current medical and stem-cell therapy for spinal muscular atrophy (SMA) and prenatal transplantation of amniotic fluid stem cells in the future. RECENT FINDINGS: SMA is an autosomal recessive inheritance of neurodegenerative disease, which is caused of the mutation in survival motor neuron. The severe-type SMA patients usually die from the respiratory failure within 2 years after birth. Recently, researchers had found that 3-methyladenine could inhibit the autophagy and had the capacity to reduce death of the neurons. The first food and drug administration-approved drug to treat SMA, Nusinersen, is a modified antisense oligonucleotide to target intronic splicing silencer N1 just recently launched. Not only medical therapy, but also stem cells including neural stem cells, embryonic stem cells, mesenchymal stem cells, and induced pluripotent stem cells could show the potential to repair the injured tissue and differentiate into neuron cells to rescue the SMA animal models. Human amniotic fluid stem cells (HAFSCs) share the potential of mesenchymal stem cells and could differentiate into tri-lineage-relative cells, which are also having the ability to restore the injured neuro-muscular function. In this review, we further demonstrate the therapeutic effect of using HAFSCs to treat type III SMA prenatally. HAFSCs, similar to other stem cells, could also help the improvement of SMA with even longer survival. SUMMARY: The concept of prenatal stem-cell therapy preserves the time window to treat disease in utero with much less cell number. Stem cell alone might not be enough to correct or cure the SMA but could be applied as the additional therapy combined with antisense oligonucleotide in the future. PMID- 29489502 TI - Updates in fetal spina bifida repair. AB - PURPOSE OF REVIEW: To examine updates in fetal spina bifida surgical repair, as well as promising results emerging from translational medicine. RECENT FINDINGS: Although the Management of Myelomeningocele Study sponsored by the National Institutes of Health helped establish the neonatal benefits of prenatal spina bifida repair via uterine hysterotomy, also known as 'open' fetal surgery, fetoscopic approaches may yield better maternal and obstetric outcomes. SUMMARY: Spina bifida is a severe congenital malformation associated with significant neonatal and childhood morbidity and mortality. Although 'open' fetal spina bifida repair has become the standard prenatal surgical approach due to proven neonatal benefit, this approach is associated with significant maternal and obstetric risks. Recent developments from multidisciplinary clinical and translational research have highlighted the potential for novel fetoscopic surgical approaches to decrease maternal morbidity and reduce obstetric risks. Moreover, novel stem cell therapies coupled with in-utero medical approaches targeting the pathophysiological pathways associated with spina bifida are likely to make additional significant impact. PMID- 29489503 TI - Evaluation of stillbirth. AB - PURPOSE OF REVIEW: To review current evidence regarding the most useful tests for evaluation of potential causes of stillbirth. RECENT FINDINGS: Stillbirth remains one of the most devastating obstetric complications. Recent advances include work investigating the highest yield diagnostic tests for determining a cause of death in stillbirths. Placental pathology and fetal autopsy improve the diagnostic yield when combined with maternal clinical history. Additional tools include genetic evaluation, and testing for antiphospholipid antibodies and fetal maternal hemorrhage based on the clinical scenario. However, routine testing for heritable thrombophilias or infection has not proven to be useful. In cases in which fetal autopsy is not acceptable to patients or possible for logistical reasons, alternative forms of fetal evaluation should be considered. SUMMARY: A systematic approach to stillbirth evaluation is useful in identifying a potential cause of death. This should incorporate clinical information as well as placental pathology and fetal autopsy. Based on clinical characteristics further testing may be indicated. PMID- 29489504 TI - Apoptosis as a Prognostic Factor in Colorectal Carcinoma: Comparison of TUNEL Method and Immunohistochemical Expression of Caspase-3. AB - The development of colorectal cancer is known to be characterized by a sequence of events during which normal colonic epithelium gradually transforms to carcinoma, the adenoma-carcinoma sequence. Apoptosis plays an important role in the development and maintenance of tissue homeostasis. Currently, there is no agreement in the literature about the prognosis of apoptosis in colorectal cancer. The number of studies examining the expression of caspases in colorectal cancer is very limited, and they have not examined any correlation between expression and patient survival. This study included histologic samples from 179 patients diagnosed with colon cancer. We used the TdT-mediated X-dUTP nick end labeling method and caspase-3 labeling to identify the degree of apoptosis. Our results show that lower apoptotic index measured by TdT-mediated X-dUTP nick end labeling method and lower immnuhistochemical expression of caspase-3 is associated with shorter disease-free survival and overall survival. However, only apoptotic index is proven to be an independent survival indicator. The results of our study are consistent with the proposed models of carcinogenesis of colorectal cancer that emphasize resistance to apoptosis as a decisive factor in the progression of the disease and resistance to treatment. PMID- 29489506 TI - Expression of H3.3 G34W Distinguishes Giant Cell Tumor of Bone From Its Major Giant Cell-containing Bone and Soft Tissue Mimics, in Particular Aneurysmal Bone Cyst and Giant Cell Tumor of Soft Tissue. PMID- 29489505 TI - Is Sclerosing Angiomatoid Nodular Transformation an IgG4-associated Sclerosing Disease? PMID- 29489507 TI - SOFAT as a Putative Marker of Osteoclasts in Bone Lesions. AB - Secreted osteoclastogenic factor of activated T cells (SOFAT) is a novel activated human T-cell-secreted cytokine that induce osteoclastogenesis in a RANKL-independent manner. The aim of this study was to evaluate the immunohistochemical expression of SOFAT in intraosseous and extraosseous lesions. Thirty-two oral biopsies were divided into 2 groups: (1) intraosseous lesions-4 cases of cherubism, 5 central giant cell lesions, 3 osteoblastomas, 3 cementoblastomas, 2 periapical lesions and (2) extraosseous lesions-5 peripheral giant cell lesions, 5 cases of oral paracoccidioidomycosis, and 5 foreign body reactions. Immunohistochemistry was performed for SOFAT and tartrate-resistant acid phosphatase. Image analysis consisted of a descriptive evaluation of the immunohistochemical staining pattern observed. Tartrate-resistant acid phosphatase-positive lesions included those containing multinucleated giant cells (MGC) from both groups. SOFAT was positive in MGC of the intraosseous lesions group, except in periapical foreign body reactions as well as extraosseous lesions. SOFAT was shown to be a putative marker of osteoclasts, which proved useful to differentiate them from multinucleated macrophages. Osteoclast induction may be both dependent and independent from the RANK/RANKL/OPG pathway and independent from the bone microenvironment. PMID- 29489508 TI - EZH2 Expression in Intestinal Neuroendocrine Tumors. AB - Neuroendocrine tumors (NETs) arise from the cells present throughout the diffuse endocrine system. These neoplasms were previously regarded as rare, but in fact are increasing in incidence (3.65/100 000 individuals/y). Enhancer of zeste homolog 2 (EZH2) plays a crucial role in cell cycle regulation, and it was reported to be overexpressed in several tumors. The aim of the study was to investigate EZH2 expression, also related with proliferation rate, and p53 expression in NETs of the intestine encompassing a group of tumors primary to the stomach, appendix, small intestine, and colon. The specimens from 33 patients with neuroendrocrine tumors were investigated by immunohistochemistry for EZH2, p53, and Ki-67. Only 10 of 33 (30.3%) cases showed high EZH2 expression. High EZH2 levels significantly associated with elevated proliferation rates (P=0.0012) and with elevated percentage of positive cells for p53 (P=0.011). Our results suggest an association between p53 and the EZH2 pathway in NETs. EZH2 could represent a potential target antigen in cancer immunotherapy. PMID- 29489509 TI - The Amount of Melanin Influences p16 Loss in Spitzoid Melanocytic Lesions: Correlation With CDKN2A Status by FISH and MLPA. AB - AIMS: The risk assessment of spitzoid lesions is one of the most difficult challenges in dermatopathology practice. In this regard, the loss of p16 expression and the homozygous deletion of CDKN2A, have been pointed in the literature as reliable indicators of high risk. However, these findings are poorly reproducible, and the molecular bases underlying the loss of p16 expression remain unclear. We aimed to identify the underlying events causing loss of CDKN2A/p16 in spitzoid tumors. MATERIALS AND METHODS: We evaluated the immunohistochemical expression of p16, and the presence of CDKN2A genetic alterations detected through fluorescence in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA), in a series of 130 Spitz nevi, 20 atypical spitzoid tumors, and 11 spitzoid melanoma. RESULTS: We found a significant loss of p16 expression in cases with high amount of melanin content in the 3 groups (P<0.000001) and a similar proportion of p16-negative cases in the group of Spitz nevi and atypical spitzoid tumors. MLPA allowed the recognition of CDKN2A microdeletions, which correlated with p16 loss (P=0.01). MLPA and FISH were more accurate than immunohistochemistry to detect CDKN2A alterations; although contrary to MLPA, FISH fails to recognize CDKN2A microdeletions. CONCLUSIONS: According to our results, p16 expression may be useful in the study of cases with atypical features and low melanin content, but it has no value in highly pigmented spitzoid lesions. PMID- 29489510 TI - Clinicopathologic Significance of Intestinal-type Molecules' Expression and Different EGFR Gene Status in Pulmonary Adenocarcinoma. AB - Variant pulmonary adenocarcinoma with intestinal-type molecules shares similar molecular expression with colorectal carcinoma. However, expression of such molecules and their association with survival time with clinicopathologic parameters, such as epidermal growth factor receptor (EGFR) gene status in other types of pulmonary adenocarcinoma, has been rarely demonstrated. Sixty patients with resected pulmonary adenocarcinoma were divided into the enteric differentiation group (I group, n=30) and the usual group (U group, n=30). Immunohistochemical staining was used to assess the expression of carcinoembryonic antigen (CEA), Villin, CK20, and caudal-related homeobox 2 (CDX2). EGFR gene status was examined by Fluorescence Quantitative polymerase chain reaction. Kaplan-Meier survival curve was drawn by GraphPad Prism 5.0 software. The results showed that there was a significant difference between the 2 groups (P<0.05) in the expression of Villin, CK20, and CDX2, whereas the expression of CEA showed no significant difference (P>0.05). Compared with the U group, patients in the I group were mainly female individuals and in clinical stages III to IV, prone to lymph node metastasis (P<0.05). The patients in the I group with CDX2CK20 phenotype (tumor size>5 cm) had a shorter survival time (P<0.05), and EGFR gene status was not associated with median survival time and the expression of CEA, Villin, CK20, and CDX2 (P>0.05). Thus, our research indicates that patients with enteric differentiation have unique clinical characteristics and different prognosis, which may play important roles in diagnosis and choosing therapeutic strategies for pulmonary adenocarcinoma patients in clinical practice. PMID- 29489511 TI - Loss of pRB in Conjunctival Squamous Cell Carcinoma: A Predictor of Poor Prognosis. AB - Conjunctival squamous cell carcinoma (SCC) is the most common tumor of conjunctival epithelium. It is associated with risk of permanent visual impairment and has the capability to recur, metastasize, and cause death. Deregulation of cell cycle control has been reported in a number of malignancies. The aim of the present study was to assess expression of G1/S cell cycle regulatory proteins [retinoblastoma protein (pRb)/P16/cyclin D1] in conjunctival SCC. Forty-four prospective cases of conjunctival SCC from a tertiary eye care referral center in northern India were included in this study. American Joint Committee on Cancer (AJCC) staging was performed and patients were followed up for 46+/-3.2 months. pRb loss was seen in 87% and overexpression of p16 and cyclin D1 in 36% and 66%, respectively. Kaplan-Meier analysis revealed reduced disease-free survival in patients with pRb loss (P=0.006). On univariate analysis, pRb loss (P=0.02), orbital invasion (P=0.03), and AJCC stage >=T3 (P=0.03) emerged as significant high-risk features. On multivariate analysis pRb loss emerged as the most significant poor prognostic indicator in conjunctival SCC cases. Our findings suggest pRb loss to be a useful indicator of aggressive behavior and is recommended for identifying high-risk conjunctival SCC patients. PMID- 29489512 TI - Androgen Receptors in Resected Ductal Carcinoma In Situ of Breast: Novel Insights With Possible Implications for Testing and Targeted Endocrine Chemoprevention Trials. AB - Mammary ductal carcinoma in situ (DCIS) is classically treated by combinations of excision, radiation, and endocrine therapy, based upon the specific needs of individual patients. Estrogen receptor (ER) status is generally assessed by immunohistochemistry (IHC) in newly diagnosed cases of DCIS, and endocrine therapy in this setting is thought to be chemopreventive. The potential impact of androgens on mammary carcinogenesis has been studied in recent years, and several authors have proposed androgen receptor (AR) IHC testing and targeted antiandrogenic therapy in patients with locally advanced or metastatic triple negative invasive breast cancer (ie, negative for ER and progesterone receptor and HER-2). Very little has been published on AR in DCIS. We report results of AR IHC on archival tissue blocks from 221 adult female patients, each of whom underwent definitive breast resection of DCIS. Of the 221 cases, 72 (33%) were shown to express AR in their DCIS at or above the 10% threshold often used for invasive carcinoma. AR expression was seen in all grades of DCIS. Of the 72 positive AR cases, 21 (29%) were ER negative, corresponding to 10% (21/221) of all patients. The majority of the AR-positive cases were high grade, and the most common histologic subtype in this subset was a solid growth pattern with apocrine features. Early data from clinical trials evaluating AR antagonists in invasive/metastatic triple-negative breast cancer suggest that some patients may benefit from androgen blockade. IHC testing and potential clinical trials of AR antagonists for chemoprevention in patients with AR-positive and ER-negative DCIS could be considered. PMID- 29489514 TI - Terrien Marginal Degeneration Complicated by a Corneoscleral Cyst. AB - PURPOSE: To describe a case of inflammatory Terrien's marginal degeneration (TMD) in a young Chinese girl complicated by a corneoscleral cyst who ultimately underwent surgical treatment with cyst excision, corneal patch graft and amniotic membrane graft. METHODS: Case report. RESULTS: A 12-year-old Chinese female presented initially with redness and discharge from her right eye with bilateral superior corneal thinning. The patient was diagnosed with TMD. She subsequently developed a corneoscleral cyst 2 years later which doubled in size within 1 year. The patient underwent a cyst excision with lamellar corneal patch graft and amniotic membrane grafting. Histopathological examination of the cyst wall showed a lining of squamous epithelium, consistent with a corneoscleral cyst. CONCLUSIONS: This is an interesting case highlighting the rare complication of corneoscleral cyst in a young patient with inflammatory TMD. Excision of the cyst with a corneal patch graft and amniotic membrane grafting without any chemical cautery is effective in preventing recurrence. PMID- 29489515 TI - Clinically Significant Enhancement of Voriconazole Efficacy by Moxifloxacin and Gentamicin in Fungal Keratitis. AB - PURPOSE: To report the effect of topical antibiotics moxifloxacin 0.3% and gentamicin 0.3% on the clinical efficacy of topical antifungal agent voriconazole 1% in cases of culture- or biopsy-proven fungal keratitis. METHODS: Two cases of fungal keratitis in which the addition of topical moxifloxacin or moxifloxacin and gentamicin led to an improved clinical response to topical voriconazole were reviewed retrospectively. RESULTS: One patient with clinical resistance of his fungal keratitis to both topical voriconazole and natamycin had resolution of his keratitis with the addition of topical moxifloxacin and gentamicin to voriconazole. One patient who had a poor response to topical voriconazole had a dramatic response to the increase of the voriconazole regimen and addition of moxifloxacin. CONCLUSIONS: In a subset of patients with fungal keratitis, the addition of topical moxifloxacin 0.3% or moxifloxacin 0.3% and gentamicin 0.3% may enhance the therapeutic effect of topical voriconazole 1%. PMID- 29489516 TI - Five Keratoplasties From One Donor Cornea. AB - PURPOSE: To describe the feasibility of same-day, consecutive use of a single donor cornea in 5 patients with corneal pathology, who required anterior lamellar and endothelial keratoplasties. METHODS: Descemet membrane (DM) with endothelium was completely stripped from a single corneoscleral button and punched out from the endothelial side with a circular, standard punch. Using a custom-made punch for linear cutting of DM, we obtained 4 quarter-grafts (Q-graft). The denuded and punched-out corneal stroma was transplanted in 1 patient with keratoconus, using the big-bubble deep anterior lamellar keratoplasty (DALK) technique. The 4 DM Q grafts were consecutively transplanted to 4 patients with Fuchs dystrophy using the quarter Descemet membrane endothelial keratoplasty (Q-DMEK or 1/4 DMEK) technique. RESULTS: All surgical procedures were performed successfully during 1 surgical session. No intraoperative or postoperative complications requiring intervention were observed. Six months after surgery, the decimal best-corrected visual acuity achieved was 0.66 after DALK and 0.95 +/- 0.1 (range, 0.8-1.0) in the 4 Q-DMEK cases; the endothelial cell density was 1680 +/- 254 cells/mm (range, 1492-2039 cells/mm). Six months postoperatively, all corneas were clear. CONCLUSIONS: In this limited series, we demonstrate that 1 donor cornea can be successfully used for 5 recipients. Although performing DALK and Q-DMEK on a single day is technically challenging, it is feasible and can dramatically reduce the shortage and the cost of corneal tissue. Strict case selection is necessary. Further study on this approach is required. PMID- 29489517 TI - Topical Interferon Alpha-2b Induced Reactive Lymphoid Hyperplasia Masquerading as Orbital Extension of Ocular Surface Squamous Neoplasia. AB - PURPOSE: The use of topical interferon alpha-2b is a well-established treatment for ocular surface squamous neoplasia. There have been numerous reports on its efficacy and high safety profile. Benign reactive lymphoid hyperplasia in ocular tissues has not been previously documented by histopathology after interferon treatment. METHODS: This case report describes a 55-year-old man who had successful resolution of his ocular surface squamous neoplasia after topical treatment, but developed forniceal tissue deposits. RESULTS: The appearance of the lesions was unexpected and alerted the clinician to the possibility of further neoplastic extension. CONCLUSIONS: Excisional biopsy of the lesions confirmed benign reactive lymphoid hyperplasia and resolved with no recurrence. PMID- 29489518 TI - "Off-the-Shelf" K2-EDTA for Calcific Band Keratopathy. AB - PURPOSE: To explore the effectiveness of "off-the-shelf" dipotassium ethylenediaminetetraacetic acid (K2-EDTA) as an alternative to sodium EDTA as chelation therapy in removal of calcific band keratopathy (CBK). METHODS: This study was a retrospective case series involving 4 patients with CBK who underwent superficial keratectomy and subsequent chelation therapy with K2-EDTA in a single center (Coastal Eye Clinic) by the same surgeon. Visual acuity and symptomatic relief were the main outcomes measured in our study. RESULTS: All 4 participants in this study were female with an average age of 80.3 years. Three of the patients with reasonable baseline visual acuity experienced improved visual acuity at 1 month. The other patient with multiple ocular comorbidities and severely reduced visual potential reported symptomatic pain relief at 1-month follow-up after the intervention. CONCLUSIONS: K2-EDTA seems to be an effective alternative to disodium EDTA in its ability to clear calcific plaques and restore visual function. Because of the logistical difficulties associated with acquiring disodium EDTA, and the relative abundance of K2-EDTA in health-care facilities, we believe that our findings warrant further investigation into its use as a more accessible and cost-effective chelating agent in CBK. PMID- 29489519 TI - Standardizing the Descemet Membrane Endothelial Keratoplasty Graft Preparation Method in the Eye Bank-Experience of 527 Descemet Membrane Endothelial Keratoplasty Tissues: A Proposed Modification. PMID- 29489520 TI - Reply. PMID- 29489521 TI - Unusual Complications Related to Spinal Implants. PMID- 29489522 TI - Development of Bilateral Facet Cysts Causing Recurrent Symptoms After Decompression and the Placement of an Intralaminar Implant: A Case Report. AB - CASE: We report the development of bilateral symptomatic facet joint cysts in a 78-year-old man who had been treated with decompression and placement of a coflex device (Paradigm Spine) at L3-L4 and L4-L5. Preoperative imaging clearly demonstrated fluid in the facet joints without cysts. He underwent standard surgical treatment, but developed symptomatic facet joint cysts at 4 months postoperatively. The patient was treated with a revision decompression and replacement of the devices; there were no issues at the 32-month follow-up. CONCLUSION: While the coflex device has possible long-term biomechanical advantages, vigilance with adherence to appropriate decompression surgical technique is necessary. PMID- 29489523 TI - Reconstruction of the Shoulder Joint with a Custom-Made Ceramic Implant After a Total Scapulectomy: A Case Report. AB - CASE: We describe a 22-year-old woman who underwent total scapulectomy and shoulder joint reconstruction with use of a custom-made ceramic implant composed of hydroxyapatite and beta-tricalcium phosphate (beta-TCP) for a recurrent atypical perineurioma that had arisen from the scapula. CONCLUSION: To our knowledge, there have been no previous reports of shoulder joint reconstruction with use of a custom-made ceramic implant after a total scapulectomy. The patient showed excellent function of the new shoulder joint and good range of motion without pain or dislocation at 18 months postsurgery. This new method of reconstructing the shoulder joint after a total scapulectomy appears useful and promising. PMID- 29489524 TI - Unilateral Snapping Biceps Femoris Tendon with an Anomalous Insertion Treated with Anatomic Repositioning and Lengthening with a Single Suture Anchor: A Report of Two Cases. AB - CASE: A snapping biceps femoris tendon, a rare etiology for symptomatic pain in the lateral aspect of the knee, has been reported infrequently. We report 2 cases of an acutely symptomatic unilateral snapping biceps femoris tendon with an intraoperatively intact anomalous insertion onto the tibia, which were treated with anatomic repositioning and "pie-crust" lengthening via a single suture anchor. CONCLUSION: Anatomic repositioning and lengthening is a novel technique that successfully resolved the painful snapping and allowed full return to competitive sports by 6 months postoperatively, with maintenance of improvement at >=14 months postoperatively. PMID- 29489526 TI - Bronchiectasis update. AB - PURPOSE OF REVIEW: Bronchiectasis, once thought to be an orphan disease, is being diagnosed with increased frequency in the United States and around the world. The present review aims to provide an update on recent publications on the diagnosis and management of bronchiectasis. RECENT FINDINGS: Two large bronchiectasis patient registries have published initial reports regarding demographics and other patient data in 2017. Updates on the microbiology, microbiome, and inflammation in patients with bronchiectasis are clarifying the complexities of airway infection in this disease. A consensus definition of 'exacerbation' in bronchiectasis has been agreed upon this year. Reports on novel treatments, including the repurposing of older therapies, have also been published in 2016 2017. A new European guideline for the management of adult bronchiectasis is also now available. SUMMARY: Bronchiectasis, a resurgent disease, is now being better defined with a rapidly expanding portfolio of demographic, clinical, and therapeutic research and publications. PMID- 29489527 TI - Implementation of an Oxytocin Checklist to Improve Clinical Outcomes. AB - BACKGROUND: Oxytocin is one of the most common drugs administered in obstetrics. Since its designation as a high-alert medication by the Institute for Safe Medication Practices in 2007, there has been much attention to oxytocin administration during labor. Oxytocin is generally safe when administered correctly, but adverse perinatal outcomes can occur during uterine tachysystole. PURPOSE: The purpose of this project was to evaluate and compare results of maternal and fetal outcomes of induction of labor for women at term prior to and after implementation of a newly developed oxytocin checklist. PROJECT DESIGN AND METHODS: To evaluate the practice change associated with the implementation of the new oxytocin checklist, 200 cases based on retrospective medical record reviews were compared with 200 cases after implementation. RESULTS: Use of the checklist was associated with several significant clinical outcomes, including decreases in tachysystole, decreases in cesarean births for concern about fetal status based on electronic fetal monitoring data, decreases in length of first stage labor, and decreases in maximum dose of oxytocin. CLINICAL IMPLICATIONS: Results are similar to previous research. Early physician buy-in, clinical team education, and ongoing evaluation enhanced facilitation of the oxytocin checklist. Clinical outcomes were favorable. PMID- 29489528 TI - Perceptions of Adult Women on Losing Their Mothers at an Early Age: Implications for Nursing Care During Childbirth. AB - PURPOSE: To explore the lived experience of women over the age of 21 who lost their mothers before the age of 18. METHODS: Using qualitative methodology, motherless child-adult women were gathered through emails, word of mouth, and snowballing techniques. Interviews were conducted at the convenience of the women. The women coparticipated with identification of emerging themes using thematic analysis. RESULTS: Eight women who lost their mothers before the age of 18 participated. Eight themes emerged: (1) Understanding: For wounded hearts only; (2) Coming apart: Finding my mother's daughter and self-worth; (3) Unconditional love: Grieving for and identifying with my champion; (4) Finding help: Filling the empty place with God; (5) Pitying the motherless child: Making it worse; (6) Filling in: Others as mother; (7) The ebb and flow: Grieving; and (8) Becoming mother: Taking on the Role. CLINICAL IMPLICATIONS: The nurse has the opportunity to improve care for women who lost their mothers before the age of 18 years. During pregnancy, childbirth, and childrearing, the woman may feel sad and anxious without the guidance of her mother. Special ways of caring may be instituted to provide her comfort such as allowing and encouraging her to bring a special item of her mother's to procedures and events so that she may feel connected with her, allowing someone to stand in for her mother, perhaps assisting in finding of another motherless child adult to be with her as needed, and the voicing of understanding of her loss while remaining nonjudgmental about her emotions during these times. PMID- 29489529 TI - Finding the Fertile Phase: Low-Cost Luteinizing Hormone Sticks Versus Electronic Fertility Monitor. AB - PURPOSE: To investigate if generic Wondfo ovulation sticks (WLH) are sufficiently sensitive to the luteinizing hormone (LH) surge in urine when used with the Marquette Fertility Algorithm. The electronic hormonal fertility monitor (EHFM) is highly accurate in detecting the LH surge but cost of the monitor and the accompanying test sticks has increased over the last several years. The EHFM is sensitive to detect the LH surge at 20 milli-international units per milliliter (mIU/mL); the WLH sticks are slightly less sensitive at 25 mIU/mL. STUDY DESIGN AND METHODS: A convenience sample of women using the Marquette Method of Natural Family Planning with the EHFM to avoid pregnancy were recruited (N = 54). Each participant used the EHFM every morning after cycle day 6 and tested morning and evening urine with the WLH stick until the day following detection of the LH surge on the EHFM. RESULTS: Forty-two women provided 219 cycles. Frequency of LH surge detection was 182/219 (83.1%) for EHFM and 203/219 (92.7%) for WLH sticks. Agreement between the EHFM and the WLH on the day of the LH surge was 97.7%. High fertility readings providing a warning of peak fertility at least 5 days before peak was 67% for the WLH; the EHFM was 47.7%. Paired sample correlations for high fertility was .174 (p = .014) and paired sample differences t was -4.729 (p = .000). CLINICAL IMPLICATIONS: The WLH stick is sufficiently sensitive to use in place of the EFHM for determining peak fertility and with the Marquette Fertility algorithm. Even with minimal use, WLH sticks cost about half the price of the monitor strips and provide more flexibility of use. Cost differences increase with the number of sticks used per cycle. Further research with a larger sample is needed to verify results. PMID- 29489530 TI - Use of FLIR ONE Smartphone Thermography in Burn Wound Assessment. AB - OBJECTIVE: Forward-looking infrared (FLIR) thermography technology uses a handheld camera that measures skin infrared emissivity, captures photographs, and can be analyzed through specialized software. Forward-looking infrared images can be used to analyze and correlate burn wound temperature with burn depth, burn progression, and the number of days needed for healing. FLIR ONE is a miniature, smartphone-compatible thermal imaging camera that has been used to assess inflammation in diabetic foot ulcers, as well as locating perforators in flap surgery. However, FLIR ONE's reliability in burn wound assessment has not been evaluated. This case series investigates the accuracy of FLIR ONE in comparison with the widely used indocyanine green (ICG) angiography in assessing burn wounds. METHODS: Five acute third-degree burn wounds were assessed using ICG angiography and FLIR ONE imaging (infrared thermography) to determine burn extent before surgical intervention. Patients were taken to the operating room within 48 hours of presentation; FLIR ONE images were captured approximately 35 to 45 cm above the wound surface. Margins of unsalvageable tissue as determined by ICG and FLIR ONE were marked and compared. RESULTS: The area of unsalvageable tissue as determined by FLIR ONE closely corresponded to the area determined by ICG. FLIR ONE overestimated unsalvageable tissue margins by approximately 1 to 2 cm. The area estimated by ICG consistently overlapped with more than 90% of the area estimated by FLIR ONE. CONCLUSIONS: There is a strong correlation between FLIR ONE and ICG when assessing salvageable tissue in third-degree burn wounds. FLIR ONE maximizes the convenience and cost-effectiveness of infrared thermography technology but may overestimate unsalvageable tissue area. FLIR ONE is promising as an adjunct to current imaging modalities such as ICG but requires further study for comparison. PMID- 29489531 TI - Opinions on Authorship: A Survey of Plastic Surgery Residents and Fellows. AB - BACKGROUND: Scientific publications are the cornerstone of scholarly activities. The importance of appropriately assigned authorship cannot be overstated. Hence, we felt it prudent to examine the perception of plastic surgery trainees regarding authorship. We hypothesized that plastic surgery trainees would not be in compliance with International Committee of Medical Journal Editors guidelines when determining what constitutes an authorship justifying contribution. METHODS: An online survey describing 4 distinct scenarios was distributed to plastic surgery trainees at 2 academic institutions using the Qualtrics research software (Provo, UT). Additional parameters queried included level of training and number of publications. Linear regression models were used to test correlation between responses and level of training and number of publications. RESULTS: Thirty-three of 48 trainees responded (response rate, 68.8%). All respondents had previously authored publications, with the majority (54.5%) having at least 10 publications. Although none of the scenarios presented justified authorship based on international guidelines, 33.3% of respondents believed that authorship was warranted in at least 3 of the 4 presented scenarios. Linear regression comparing for demographic variables to number of perceived authorship scenarios found a mild-moderate positive correlation with level of training (R = 0.34, P = 0.05) and number of publications (R = 0.32, P = 0.07). CONCLUSIONS: Plastic surgery trainees do not seem to be familiar with guidelines regarding authorship justifying contributions. It is important to raise awareness regarding criteria that warrant authorship and to educate our residents and fellows in matters of appropriate scholarly conduct because nothing short of the credibility of our scientific endeavors is otherwise in question. PMID- 29489532 TI - Course Review: Birmingham and Coventry Hand and Forearm Cadaveric Dissection Course. AB - Hand surgery constitutes an important part of plastic surgery and orthopedic training curricula. Although the value of simulation-based training is being increasingly recognized, attendance at such courses may be limited owing to cost, availability, and non-learner-centered schedules.The Birmingham and Coventry hand and forearm cadaveric dissection course is a 1-day course with a loose agenda that offers an inexpensive and learner-centered approach toward surgical access, dissection, and soft tissue coverage in the upper limb. This course is held in Coventry, United Kingdom, at a cost of L165 ($220 US dollars). In this review, we provide an evaluation of the course. PMID- 29489533 TI - Complications and Patient-Reported Outcomes in Male-to-Female Vaginoplasty-Where We Are Today: A Systematic Review and Meta-Analysis. AB - INTRODUCTION: There is an increased need for evidence-based practices in male-to female (MtF) transgender vaginoplasty. Although there are a multitude of surgical techniques, there is a paucity of data comparing these procedures. A systematic review of retrospective studies on the outcomes of MtF vaginoplasty was conducted to minimize surgical complications and improve patient outcomes for transgender patients. METHODS: Applying the Preferred Reporting Items for Systematic Review and Meta-Analysis, a comprehensive search of several databases from 1985 to November 7, 2017, was conducted. The databases included PubMed, Ovid MEDLINE Epub Ahead of Print, Ovid Medline In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, and Web of Science. The resulting publications were screened, and those that met our specified inclusion/exclusion criteria were analyzed. The DerSimonian and Laird random-effects model was used to pool complications and patient-reported outcomes. RESULTS: A total of 471 articles were initially identified, of which 46 met our eligibility criteria. A total of 3716 cases were analyzed. Overall incidence of complications included the following: 2% (1%-6%) fistula, 14% (10% 18%) stenosis and strictures, and 1% (0%-6%) tissue necrosis, and 4% (2%-10%) prolapse (upper and lower limits of the 95% confidence interval). Patient reported outcomes included a satisfaction rate of 93% (79%-100%) with overall results, 87% (75%-96%) with functional outcomes, and 90% (79%-98%) with esthetic outcomes. Ability to have orgasm was reported in 70% (54%-84%) of patients. The regret rate was 1% (0%-3%). The length of the vaginal cavity was 12.5 cm (6.3-4.4 cm). CONCLUSIONS: Multiple surgical techniques have demonstrated safe and reliable means of MtF vaginoplasty with low overall complication rates and with a significant improvement in the patient's quality of life. Studies using different techniques in a similar population and standardized patient-reported outcomes are required to further analyze outcomes among the different procedures and to establish best-practice guidelines. PMID- 29489534 TI - Utilization of Microdissected Thin Perforator Flap Technique in the Treatment of Bulky and Deformed Skin Flaps. AB - BACKGROUND: This study investigates the feasibility and clinical impact of the microdissected thin perforator skin flap strategy on bulky and deformed skin flaps during second-stage revision surgery. METHODS: Seventeen patients were selected and underwent the microdissected thin perforator skin flap technique to treat bulky and deformed skin flaps after free flap reconstruction between October 2013 and October 2015. Perforator vessels were isolated and protected under a microscope. Subdermal fat with a thickness of 4 mm to 7 mm was preserved, and excess adipose tissue was resected. RESULTS: No skin flap necrosis was observed after the operation in all 17 patients, and all wounds healed without complications. Patients were followed up for 3 to 24 months, with an average follow-up time of 10 months. The skin flaps maintain normal color and texture. Both appearance and function of the recipient sites were improved significantly. CONCLUSIONS: The utilization of microdissected thin perforator flap technique to further thin bulky skin flaps at the second stage can be effective in a single operation. The blood supply of all free flaps was preserved, with no evidence of necrosis or healing complications. This technique offers an effective approach for secondary thinning of bulky free flaps. PMID- 29489535 TI - Process of Care in Breast Reconstruction and the Impact of a Dual-Trained Surgeon. AB - BACKGROUND: For postmastectomy reconstruction, the most common model in the United States is a two-team approach, consisting of breast and plastic surgeon. In other countries, a single-surgeon approach trained in both plastic and oncologic surgery is well described. We hypothesized that a dual-trained breast and plastic surgeon would decrease the postoperative care burden for the patient without compromising outcomes and serve as a model for team-centered breast reconstruction care. METHODS: A retrospective review was performed of patients undergoing mastectomy with immediate expander reconstruction from January 2013 to October 2014. Patient data up to 1 year postoperatively was recorded. Patients were stratified by treatment to "single-surgeon" or "two-surgeon" team. Demographic and operative data were recorded. Google Maps was used to calculate travel distance. A standard of mean cost of travel per mile and mean hourly wage for San Diego County was used. The primary outcome was the total number of postoperative clinic visits. In addition, factors predictive of postoperative clinic visits were evaluated. RESULTS: During the study period, 147 patients were included in analysis (69, single-surgeon; 78, two-surgeon). The mean cost of travel per mile was US $59.2 cents and mean hourly wage for San Diego County was US $25.49. For the 1-year follow-up period, patients with the single surgeon had a mean (SD) of 9.3 (3.72) postoperative visits compared with 15.6 (3.96) for patients in the two-surgeon team (P < 0.0001).There were no statistical differences between groups in the rate of complications. In the final model, treatment team, bilateral mastectomies, and complications (operative and nonoperative) were significant predictors of the total number of postoperative visits. Patients in the two-surgeon team spent an additional 11.13 hours and 216 miles commuting and in clinic. In total, the additional 6.3 clinic visits for patients in the two-surgeon team resulted in an average of US $695.33 additional dollars spent on travel and lost wages. CONCLUSIONS: Single-surgeon patients required fewer postoperative visits. Fewer postoperative clinic visits may have significant socioeconomic and psychological benefits to patients. Given these results, we believe that streamlining care into an integrated multidisciplinary model would be beneficial. PMID- 29489536 TI - The Quality of Systematic Reviews in Head and Neck Microsurgery: A Perspective from Plastic Surgery and Otolaryngology. AB - INTRODUCTION: In recent years, there has been a push to publish higher level of evidence studies in medicine, particularly in plastic surgery. Well-conducted systematic reviews are considered the strongest level of evidence in medicine, recently becoming the key process indicators for quality delivery. A varying quality of systematic reviews, however, has led to concerns of their validity in clinical decision-making. We perform a quality analysis of systematic reviews published in head and neck microsurgery by the surgical specialties of plastic surgery and otolaryngology. MATERIALS AND METHODS: An evaluation of systematic reviews published on microsurgery in 13 high-impact surgical journals was conducted by searching PubMed and Scopus. Two authors independently performed searches, screened for eligibility, and extracted data from included articles. Discrepancies were resolved by discussion and consensus. Assessment of Multiple Systematic Reviews (AMSTAR) criteria were used to assess methodological quality. RESULTS: The initial database search retrieved 166 articles. After removing duplicates, screening titles and abstracts, 26 articles remained for full text review. Seven did not focus on head and neck microsurgery and were further excluded, leaving 19 systematic reviews for final analysis. Of those, 10 systematic reviews were published by otolaryngology, and 9 were published by plastic surgery. Median AMSTAR score was 8 for otolaryngology, 7 for plastic surgery, and 8 overall, reflecting "fair to good" quality. The number of systematic reviews on head and neck microsurgery markedly increased over time. Of note, both the AMSTAR score and the number of systematic reviews published by plastic surgery have steadily increased from 2014 to 2016, whereas those published by otolaryngology have remained relatively stable since 2010. CONCLUSIONS: Our review shows a trend toward publishing more systematic reviews. The increasing quantity and quality of systematic reviews published by plastic surgeons indicates recognition in the need for higher levels of evidence in plastic surgery, as well as growing interest and advances in microsurgery. Given these trends, familiarity with quality assessment guidelines, such as AMSTAR, will remain important in providing a basis for building relevant value-based quality measures. PMID- 29489537 TI - Functional and Aesthetic Outcomes in Free Flap Reconstruction of Intraoral Defects With Lip-Split Versus Non-Lip-Split Incisions. AB - BACKGROUND: Traditional free flap reconstruction of complex intraoral defects often uses large lip-splitting incisions. To reduce morbidity and preserve aesthetics, we have adopted a more technically demanding visor technique obviating an incision through the lower lip through which the resection and reconstruction are performed. METHODS: A retrospective review was performed of patients who underwent free flap reconstruction of intraoral defects over 7 years by a single plastic surgeon (C.H.R.) at a single institution. Patients were included if they underwent a resection from the mandible, tongue, or floor of mouth followed by free tissue transfer as a reconstructive approach. Patients were excluded if they underwent reconstruction of an area that does not traditionally require a lip incision, such as a maxillectomy or laryngeal defect. An ablative approach was taken via a lip-split technique or visor technique. Wound complications, margins of resection, and functional outcomes were assessed. Two standardized questionnaires (Derriford Appearance Scale Short Form and Quality of Life Questionnaire for Head and Neck Cancer) were used to assess psychological distress and dysfunction from disfigurement, speech quality, and oral function. Preoperative and postoperative patient photos were evaluated. RESULTS: Of 27 patients (mean +/- SD age, 58.33 +/- 13.02 years), 52% (14) had visor reconstructions whereas 48% (13) had lip-splitting reconstructions. About 78.6% of visor patients had widely-free margins compared with 46.2% of the lip split patients. No differences in surgical-site complications between the lip split and visor group (38.5% vs 28.6%) or in operative times were observed. Ninety-three percent of visor patients versus 54% of lip-split patients tolerated oral feeds at 1 year. Lip-split patients rated their quality of eating and speech worse than the visor patients (Quality of Life Questionnaire for Head and Neck Cancer mean score, 2.2 vs 1.56). Patients and clinical staff deemed visor reconstructions resulted in less visible sequelae. CONCLUSIONS: A visor technique with no lip-split incision for intraoral free flap reconstruction is an oncologically safe technique to consider that may improve cosmetic and functional outcomes for head and neck reconstruction patients. PMID- 29489538 TI - Predictors of Postoperative Complications of Craniosynostosis Repair in the National Inpatient Sample. AB - INTRODUCTION: Timing of intervention and complication profiles in surgical repair of craniosynostosis have been widely debated. Early intervention is frequently promoted as a means of decreasing morbidity while maintaining favorable outcomes via minimally invasive techniques such as endoscopic strip craniectomy. Immediate postoperative morbidity due to complications of early vs late intervention remains a key element in comparing timing and technique for craniosynostosis repair. In addition, concurrent fronto-orbital advancement with open cranial vault remodeling may increase the risk of postoperative complications. We present an evaluation of surgical timing and the presence of fronto-orbital advancement as independent predictors of in-hospital complications after craniosynostosis repair. METHODS: Retrospective analysis was performed in the National Inpatient Sample database from 1998 to 2009. Patients younger than 3 years having undergone elective surgical repair for craniosynostosis were identified. Comorbidities, demographics, transfusion status, and syndromic diagnosis were included as covariates. A multivariate regression model was used to characterize the association between age at the time of surgery and in-hospital complications. A subgroup analysis using the variable of concurrent fronto-orbital advancement was restricted to patients 8 to 24 months of age to exclude endoscopic craniosynostosis repair, which is traditionally repaired less than 6 months of age. Multivariate logistic regression was used to assess the impact of concurrent fronto-orbital advancement on postoperative complications. RESULTS: A total of 6010 craniosynostosis surgery cases (42.9%, age 0-7 months; 29.5%, age 8-12 months; and 27.6%, age 13-36 months) were included. Patients in the 7-to 12-month age group were more likely to experience complications when compared with the 0- to 6-month age group (odds ratio [OR],1.32; P < 0.05) and 13-to 36-month age group (OR, 1.32; P = 0.056). Syndromic patients (OR, 1.92; P < 0.001) and patients receiving an intraoperative blood transfusion (OR, 1.60; P < 0.05) demonstrated an increased risk for complications. In the subanalysis of 2936 patients aged 8 to 24 months, 15.1% of patients received frontoorbital advancement, which was associated with a significantly increased risk of complications (OR, 1.43; P < 0.05). CONCLUSIONS: Intermediate age (7-12 months) and concurrent fronto-orbital repair were independent risk factors for immediate postoperative complications. These findings may better inform the decision-making process for craniosynostosis repair in terms of timing and need for concurrent fronto-orbital reconstruction. PMID- 29489539 TI - The P1 Method: Prepectoral Breast Reconstruction to Minimize the Palpable Implant Edge and Upper Pole Rippling. AB - BACKGROUND: Prepectoral prosthetic-based breast reconstruction has become increasingly popular as an alternative to the partial or total submuscular approach. Potential issues with the prepectoral approach include a noticeable superior implant edge and implant rippling. These concerns are particularly apparent in thin patients. We introduce a novel muscle-sparing technique in which a partial-thickness slip of pectoralis muscle is created in an otherwise prepectoral plane to mask these upper pole defects, mask superior implant rippling, and provide greater implant support (The P1 Method). METHODS: A retrospective review of all patients undergoing modified prepectoral (P1) breast reconstruction at a single institution over 2 years was undertaken. Data pertaining to patient demographics, mastectomy type/weight, reconstruction type, and esthetic and surgical outcomes were collected. Outcomes were analyzed using Fisher exact and Student t tests. RESULTS: Fifty patients (93 breasts) were identified during the study period. Mean final follow-up was 63 weeks (range, 53 85 weeks). Patients undergoing P1 reconstructions achieved improved esthetic results with less implant rippling and complete elimination of animation deformity seen on postoperative clinical images or at final follow-up. CONCLUSIONS: As prepectoral prosthetic-based breast reconstruction becomes more popular, architectural adaptations will be made to improve surgical and patient centered outcomes. The P1 Method is effective in improving the superomedial contour in thin patients, minimizes upper pole rippling, and provides greater overall implant support. PMID- 29489540 TI - Isolated Compression of the Ulnar Nerve Motor Branch: A Case Series With 3 Unique Etiologies. AB - BACKGROUND: Although ulnar neuropathies are commonly encountered, isolated involvement of the motor branch is exceedingly rare. Previous reports of this entity describe compression as the deep motor branch passes through the piso hamate hiatus and the adductor pollicis hiatus. This case series described 3 cases of motor branch compression due to unique etiologies which resolved after surgery. METHODS: A retrospective chart review identified patients with compression of the ulnar nerve motor branch. From these patients, 3 were selected with a unique etiology for compression. Patient demographics, objective and subjective findings, and pathology identified during surgery were recorded and analyzed. RESULTS: Eight patients had compression of the ulnar nerve motor branch and 3 unique etiologies were selected; an intraneural ganglion, a constricting leash of vessels, and a series of compressing fibrous bands. All required surgery, and each patient had full resolution of symptoms by 1 year postoperatively. DISCUSSION: Patients presenting with complaints of weakness with a positive Froment and Egawa signs but a negative Wartenberg sign and no sensory complaints can be a diagnostic dilemma. Compression of the ulnar nerve motor branch must be considered, and here we present 3 unique cases. Activity modification in those presenting early may be curative, although many ultimately require surgery. In the cases presented here, all patients experienced full resolution of their symptoms by 1 year after surgery. PMID- 29489541 TI - Evaluation of the Effectiveness of an Alar Transfixion Suture for the Correction of a Vestibular Web and Alar-Facial Groove: A Photogrammetric Analysis. AB - BACKGROUND: Alar transfixion sutures are commonly used for vestibular web correction. The purpose of this study was to evaluate the long-term results of the use of alar transfixion sutures in patients with a unilateral cleft lip nasal deformity using photogrammetric analysis. METHODS: The study included 42 patients who were divided into child and adult groups. A total of 4 measurement items were evaluated from a basal view by photogrammetry using standardized clinical photographic techniques preoperatively, immediately postoperatively, 3 months postoperatively, and 6 months postoperatively. RESULTS: When the preoperative and last postoperative values were compared, no significant changes in any measurement items were noted in the adult group. In the child group, the proportional index (the ratio of the cleft side to the noncleft side) of the alar slope line inclination was significantly increased, but other measurement items showed no significant change. When the measurement items were compared between time points, no significant changes in any measurement items were noted in the adult group. In the child group, the proportional indexes of the alar length, the width between the subnasale and the alare, and the webbing degree were significantly decreased immediately postoperatively compared with the preoperative values. However, these significant changes were diminished at 3 months postoperatively. The proportional index of the alar slope line inclination was significantly increased at 3 months postoperatively compared with the preoperative value, but the significant change was diminished at 6 months postoperatively. CONCLUSIONS: The alar transfixion suture procedure is not effective for correcting a vestibular web and alar-facial groove. PMID- 29489542 TI - Long-Segment Tracheal Reconstruction With Free Radial Forearm Flap Reinforced by Rib Cartilage. AB - Long-segment tracheal reconstruction remains a challenge. The ideal tracheal substitute should be an epithelialized tube to prevent stenosis and sufficiently rigid to maintain airflow patency. An autologous technique using a radial forearm free flap reinforced by rib cartilage has been recently described for tracheal reconstruction. We report here two cases of complex tracheal reconstruction with a modification of this technique, which consists of the creation of two independent skin paddles to allow the reconstruction of the trachea and a second adjacent defect (eg, cervical skin, esophagus). Airway patency was achieved with no stenosis, prolonged stenting, fistula, or necrosis after 26 and 44 months, respectively. We suggest that the satisfactory outcome obtained with this modified technique is a valuable option for tracheal and adjacent defect reconstruction without the need for a second flap. PMID- 29489543 TI - Complex Intraoral Reconstruction Using a Single Free Anterolateral Thigh Flap and Supermicrosurgery After Corrosive Ingestion in a 14-Month-Old Child. AB - Oral chemical burn injuries induce more damage to the underlying tissues with extensive scarring. It is very well known that alkali causes severe liquefaction necrosis and injury to the deeper tissues. Pediatric facial burns must be managed thoroughly and always require complex reconstruction, which is a challenging process. So, any reconstructive surgeon must be aware of all the deformities that may have significant functional and aesthetic impact on the burn survivors especially children. Few medical studies addressed pediatric microsurgical reconstruction for oral burn injuries induced by chemical materials. Anterolateral thigh (ALT) free flap is a common flap with a multitude of indications. The purpose of this article is to present the youngest case in the medical literature of caustic intraoral scarring managed with a very thin free anterolateral thigh flap in a 14-month-old child who underwent reconstruction of his inner cheek, the angle of the mouth and tongue using supermicrosurgery techniques. Further development of the surgical techniques is required to establish early and safe intraoral pediatric microsurgery with a long-term follow up. PMID- 29489544 TI - Pressure Sores and Systemic Inflammatory Response Syndrome: UC Davis Quality Improvement Initiative. AB - BACKGROUND: The National Pressure Ulcer Advisory Panel estimates pressure sore care to approach $11 billion annually. It is not uncommon for these patients to present to the emergency department (ED) with a chief concern of a pressure sore, while concurrently carrying an undiagnosed infectious process that is the culprit for the acute presentation, rather than the chronic pressure injury. We aim to identify patients who met systemic inflammatory response syndrome (SIRS) criteria at ED presentation who were referred to plastic and reconstructive surgery for pressure sore debridement prior to a complete medical workup. We hypothesize that a restructuring of the ED triaging system would help conserve hospital resources, reduce costs of pressure sore management, and improve patient care and outcomes by first treating primary, underlying pathologies. METHODS: This is a retrospective chart review of 36 patients who presented to the University of California, Davis Medical Center Emergency Department with a pressure sore and met SIRS criteria, but obtained a plastic surgery consult prior to a full medical workup. We defined SIRS based on standardized criteria: temperature greater than 100.4 degrees F or less than 96.8 degrees F, pulse rate greater than 90 beats/min, respiratory rate greater than 20 breaths/min or PaCO2 less than 32 mm Hg, white blood cell count greater than 12,000, less than 4000, or greater than 10% bands. RESULTS: Fifty percent of patients (18/36) met SIRS criteria at ED presentation for their pressure sores. Of these SIRS patients, 9 (50%) had a diagnosis of urinary tract infection or urosepsis, 6 (33.3%) had sepsis of undefined origin, and 3 (16.7%) had other diagnoses such as osteomyelitis or acute respiratory distress syndrome. CONCLUSIONS: Half of patients consulted while in the University of California, Davis Medical Center Emergency Department with pressure sores met SIRS criteria and received a plastic and reconstructive surgery consult prior to a full medical workup. We propose a new algorithm for triaging pressure sore patients be established in our institution that emphasizes a medical and surgical collaborative approach in order to reduce cost, conserve resources, and improve patient care. PMID- 29489545 TI - A Novel Method for Quantifying Intracranial Volume Change by Distraction Osteogenesis for Craniosynostosis. AB - INTRODUCTION: Methods of reporting quantitative results for distraction osteogenesis (DO) of craniosynostosis have been inconsistent. Therefore, the efficacy of differing techniques and timing in regard to volume change is not well established, with no uniform metric for comparisons. Given that cranial vault remodeling with DO may be completed with different approaches, analysis was made to determine (1) the relative efficiency of different approaches in expanding intracranial volume (ICV) and (2) the impact of adjusting for ICV growth on measured DO efficiency. METHODS: Patients with craniosynostosis were treated with open cranial vault reconstruction combined with internal distraction. Preoperative and postoperative computed tomography scans were used to quantify ICV change. The metric was determined by dividing percent ICV change by total distraction length. The metric was used as a proxy for efficiency to compare posterior and anterior distraction between groups using the Mann-Whitney U test and within a subgroup of patients who underwent 2-stage distraction using the Wilcoxon matched-pairs signed rank test. RESULTS: Twenty patients underwent cranial vault remodeling with DO: 14 unicoronal, 3 bicoronal, 2 multisutural, and 1 lambdoid. Results are reported in medians. Distraction efficiency was 0.99%/mm for primary anterior, unilateral distraction for unicoronal patients (n = 13, aged 9.1 months) and 4.28%/mm for posterior distraction using multiple distractors (n = 4, aged 6.3 months). In terms of the metric, primary posterior distraction was significantly more efficient than primary anterior distraction (P = 0.007). Three patients who had undergone primary posterior distraction later underwent secondary anterior distraction. Again, posterior distraction was shown to be significantly more efficient (5.16 vs 0.62, P = 0.050). For the unicoronal patients who received anterior unilateral distraction, an adjusted metric was calculated to account for normal intracranial growth. This was found to be 0.39%/mm, which was significantly different from the unadjusted metric (P = 0.0001). CONCLUSIONS: Posterior distraction is more efficient for ICV expansion than anterior distraction, which may have implications for the choice of approach for craniosynostosis repair. In addition, this is the first report of a novel standardized metric for analyzing ICV change achieved by DO. This tool allows for adjusting the efficiency metric for expected ICV growth, which significantly impacts its value. PMID- 29489546 TI - Mastectomy Skin Necrosis After Breast Reconstruction: A Comparative Analysis Between Autologous Reconstruction and Implant-Based Reconstruction. AB - BACKGROUND: Mastectomy skin necrosis is a significant problem after breast reconstruction. We sought to perform a comparative analysis on this complication between patients undergoing autologous breast reconstruction and patients undergoing 2-stage expander implant breast reconstruction. METHODS: A retrospective review was performed on consecutive patients undergoing autologous breast reconstruction or 2-stage expander implant breast reconstruction by the senior author from 2006 through 2015. Patient demographic factors including age, body mass index, history of diabetes, history of smoking, and history of radiation to the breast were collected. Our primary outcome measure was mastectomy skin necrosis. Fisher exact test was used for statistical analysis between the 2 patient cohorts. The treatment patterns of mastectomy skin necrosis were then analyzed. RESULTS: We identified 204 patients who underwent autologous breast reconstruction and 293 patients who underwent 2-stage expander implant breast reconstruction. Patients undergoing autologous breast reconstruction were older, heavier, more likely to have diabetes, and more likely to have had prior radiation to the breast compared with patients undergoing implant-based reconstruction. The incidence of mastectomy skin necrosis was 30.4% of patients in the autologous group compared with only 10.6% of patients in the tissue expander group (P < 0.001). The treatment of this complication differed between these 2 patient groups. In general, those with autologous reconstructions were treated with more conservative means. Although 37.1% of patients were treated successfully with local wound care in the autologous group, only 3.2% were treated with local wound care in the tissue expander group (P < 0.001). Less than half (29.0%) of patients in the autologous group were treated with an operative intervention for this complication compared with 41.9% in the implant-based group (P = 0.25). CONCLUSIONS: Mastectomy skin necrosis is significantly more likely to occur after autologous breast reconstruction compared with 2-stage expander implant-based breast reconstruction. Patients with autologous reconstructions are more readily treated with local wound care compared with patients with tissue expanders, who tended to require operative treatment of this complication. Patients considering breast reconstruction should be counseled appropriately regarding the differences in incidence and management of mastectomy skin necrosis between the reconstructive options. PMID- 29489547 TI - Complications After Two-Stage Expander Implant Breast Reconstruction Requiring Reoperation: A Critical Analysis of Outcomes. AB - BACKGROUND: Two-stage expander implant breast reconstruction is commonly performed after mastectomy. Salvage and long-term outcomes after development of complications have not been well described. We examined a single surgeon's experience to study the rate of reoperation secondary to complications after first-stage expander placement and to evaluate their outcomes. Better understanding of salvage techniques may help guide future management. METHODS: We performed a retrospective analysis of consecutive patients who underwent placement of a tissue expander (TE) for breast reconstruction between December 2006 and August 2015 with the senior author. Patient demographics including age, body mass index, medical comorbidities, history of smoking, and history of radiation to the breast were collected. Surgical factors including timing of reconstruction (immediate vs delayed) and location of TE (total submuscular vs with acellular dermal matrix) were recorded. Complications were analyzed, as were patients who underwent reoperation in the setting of developing a complication. RESULTS: We analyzed 282 patients who underwent 453 implant-based breast reconstructions. Of these, 39 patients and 45 breasts required a reoperation after development of a postoperative complication. Return to the operating room was associated with higher body mass index (29 vs 24, P < 0.001), higher TE initial fill volume (299 mL vs 169 mL, P < 0.001), and preoperative radiation (31% vs 13%, P = 0.001). Complications resulting in reoperation included infection (60%), mastectomy skin necrosis (27%), and TE extrusion through thin mastectomy skin (11%). The affected TE was removed and exchanged in 17 patients (38%), autologous flap reconstruction occurred in 16 patients (36%), and TE was explanted without replacement in 12 patients (27%). CONCLUSIONS: Infectious complications including cellulitis and abscess formation accounted for most cases requiring reoperation after TE placement for breast reconstruction. More than a quarter of patients who underwent a reoperation ultimately lost their implants. Patients undergoing two-stage expander implant breast reconstruction should be appropriately counseled regarding the possibility of requiring a reoperation in the setting of developing a complication. PMID- 29489548 TI - Mechanical Complications Related to the Retention Screws of Prefabricated Metal Abutments With Different Angulations: A Retrospective Study With 916 Implants. AB - OBJECTIVES: The present retrospective study assessed the clinical performance of abutment screws from prefabricated metal abutments and compared technical complication rates between straight and angled abutments. MATERIALS AND METHODS: Dental charts were selected for patients with dental implant rehabilitations delivered between 1998 and 2012. Abutment angulation, prosthetic screw type, and presence of complications that occurred during the selected time period were collected. Technical complications registered included abutment screw loosening and/or fractures detected during clinical and radiographic examinations. The chi square test was used for statistical analysis. RESULTS: Abutment angulations were divided into 2 groups: G1) prefabricated straight abutments and G2) prefabricated angled conical mini UCLA-type abutments. A total of 916 implants (799 straight and 117 angled conical mini UCLA-type abutments) were evaluated. G1 showed 91.1% had absence of failures, which were clinically defined as any screw loosening or fracture; and 8.9% reported some type of technical complication. G2 showed 92.3% and 7.7%, with and without technical complications, respectively. CONCLUSIONS: No significant differences were observed between abutment angulation and technical complications. PMID- 29489549 TI - Effect of Various Laser Wavelengths on Temperature Changes During Periimplantitis Treatment: An in vitro Study. AB - PURPOSE: This study aimed to investigate and compare temperature change during implant decontamination with different laser types (carbon dioxide [Co2]/diode/neodymium-doped yttrium aluminum garnet [Nd:YAG]/erbium-doped yttrium aluminum garnet [Er:YAG]/antimicrobial photodynamic therapy [aPDT]). MATERIAL AND METHODS: Sixty implants were inserted into a bone block cut from a sheep's mandible. A 3 * 8 mm vertical lesion was made at the buccal of each implant. The bone block was placed into a 37 degrees C water bath to simulate the in vivo oral condition. A K-type thermocouple was placed in contact with the implant to register temperature changes at 3 points (apical/middle/coronal). RESULTS: In the entire laser irradiations, the mean of temperature changes remains below 10 degrees C. The apical temperature rise was higher than the coronal and middle regions (P < 0.05), and the apical temperature took longer time to reach the initial temperature (37 degrees C) (P < 0.001). Temperature changes over 10 degrees C occurred at the apical point of the implants with the Co2, Nd:YAG, and diode laser irradiations; however, only the Co2 laser reached the statistical significance in this regard (P < 0.05). CONCLUSION: Our findings indicate the promising results of Er:YAG laser and aPDT in implant decontamination. Precaution should be taken in the application of Nd:YAG, diode, and especially Co2 lasers. PMID- 29489551 TI - Next-generation sequencing in neuromuscular diseases: Erratum. PMID- 29489552 TI - Nephrogenic Adenoma in the Setting of Refractory Labial Agglutination in an Elderly Woman. AB - BACKGROUND: Severe labial agglutination can be refractory to outpatient management and can lead to voiding dysfunction in postmenopausal women. Labial agglutination is often a sequela of long-standing inflammatory processes, which include untreated lichen planus, lichen sclerosus, and atrophic vaginitis. CASE: An 82-year-old parous woman presented with severe labial agglutination and complete obstruction of her vaginal introitus, causing obstructive voiding symptoms. She underwent a surgical procedure to release the fused labia. Pathologic evaluation of a vulvar biopsy revealed nephrogenic adenoma, which is an uncommon benign lesion usually presenting in the urinary tract. CONCLUSIONS: Refractory, severe labial agglutination in postmenopausal women can lead to significant voiding dysfunction, and the underlying chronic inflammation may result in pathologic changes such as nephrogenic adenoma. Pathologic tissue diagnosis is important to plan appropriate surveillance for patients with this chronic condition. PMID- 29489553 TI - Is There an Association Between Bothersome Urinary Symptoms and Postpartum Depression? AB - OBJECTIVE: Bothersome urinary symptoms are often present postpartum. The objective of this study was to examine the association between bothersome urinary symptoms and screening positive for postpartum depression. METHODS: Women presenting at the routine 6-week postpartum visit were screened for risk of depression with the Edinburgh Postnatal Depression Scale. A questionnaire comprising delivery characteristics and demographics, 20-item Postpartum Symptom Inventory (PSI), Urinary Distress Inventory (UDI) short form, Incontinence Impact Questionnaire (IIQ) short form, and history of depression and antidepressant use was completed. Scores were then compared. RESULTS: Data from 104 women were analyzed, with 89% reporting excellent or good health; 73% delivered vaginally; 22% reported a history of depression, and 7% were taking an antidepressant. Twelve percent were classified as at risk of depression. Median UDI score was 5.6 (range, 0-44.4). Median IIQ score was 0 (range, 0-85.7). There was no statistically significant association between bothersome urinary symptoms and the odds of screening positive for depression using either the UDI (adjusted odds ratio [OR], 2.9; 95% confidence interval [CI], 0.7-12.5) or the IIQ (adjusted OR, 0.5; 95% CI, 0.1-2.9). The UDI score was associated with elevated PSI scores as PSI scores increased by 5.4 points if a woman had a UDI score that was greater than zero versus a UDI score of zero, controlling for education level, age, and whether the patient had a cesarean delivery (95% CI, 2.2-8.6; P = 0.001). The UDI score was not associated with antidepressant use (OR, 2.4; 95% CI, 0.5-13.2). The IIQ score had no associations with PSI score (adjusted difference in means, 2.9; 95% CI, -0.9 to 6.8; P = 0.13) or antidepressant use (OR, 1.9; 95% CI, 0.4-9.3). CONCLUSIONS: No statistically significant association between bothersome urinary symptoms and the odds of screening positive for increased risk of postpartum depression was found. Future work in this area is needed. PMID- 29489554 TI - Evaluation of Smartphone Pelvic Floor Exercise Applications Using Standardized Scoring System. AB - OBJECTIVE: The aim of this study was to identify smartphone Kegel and pelvic floor exercise applications (apps) and identify those with superior functionality, features, and accuracy. METHODS: We identified a complete list of Kegel and pelvic floor exercise applications by searching iTunes and Google Play stores for "pelvic floor," "pelvic floor exercises," "Kegel," and "Kegel exercises." We used a modified APPLICATIONS scoring system to evaluate all identified apps. RESULTS: We identified 120 apps related to Kegel exercises. Apps unrelated to the pelvic floor, unavailable in English, or duplicated on a separate platform were excluded from the analysis, leaving 90 unique apps. After a preliminary review, we excluded an additional 58 apps that were nonfunctional, required a biofeedback device, or intended for pregnant women. The final 32 apps included 15 paid and 17 free apps. Paid apps had higher rates of privacy features than free apps (80% vs 53%), used more images and figures (53% vs 41%), and were more likely to cite primary literature in their descriptions (33% vs 29%). Paid apps were also more likely to have tech support available (73% vs 53%). Overall score, however, was almost identical between the groups, with paid apps averaging 9.93 and free apps 9.41. The highest rated free and paid app both received a score of 12, consisting of Kegel Trainer and Kegel Trainer Pro, respectively. CONCLUSION: The quality of the apps is markedly variable in both the paid and unpaid applications. Using the APPLICATIONS scoring system, the apps were very similar in overall quality and value. PMID- 29489555 TI - Predictors of Opioid Administration in the Acute Postoperative Period. AB - OBJECTIVES: Our primary objective was to evaluate age as a predictor of postanesthesia care unit (PACU) opioid administration in women undergoing reconstructive pelvic surgery. Our secondary objective was to identify additional predictors of PACU opioid administration. METHODS: We conducted a retrospective cohort study of women undergoing outpatient urogynecologic surgery for pelvic organ prolapse and/or stress urinary incontinence between September 2015 to October 2016 at 1 academic medical center. We compared 2 cohorts (1) women older than 65 years and (2) women older than 65 years. Our primary outcome was any opioid medication administered during the PACU admission. RESULTS: A total of 183 women were included in the study; 124 (68%) were younger than 65 years, and 59 (32%) were 65 years or older. For our primary outcome, women younger than 65 years were more likely to be given any opioids in PACU than women 65 years (70% vs 54%, P = 0.04, respectively). Women younger than 65 years were also given higher total amounts of opioid narcotics postoperatively (9.0 +/- 8.3 vs 5.1 +/- 6.0 mg, P < 0.05). For our secondary outcome, we found that PACU opioid administration was associated with midurethral sling (MUS) surgery (70% MUS vs 30% no MUS, P = 0.04) and high maximum PACU pain score (97% high vs 3% low, P < 0.01). CONCLUSIONS: In women undergoing urogynecologic surgery, age younger than 65 years is a predictor of high PACU pain score and resultant PACU opioid dispensation. This population should be targeted in future studies addressing the use of nonopioid multimodal therapies in the treatment of postoperative pain. PMID- 29489556 TI - Same-Day Discharge After Robotic-Assisted Sacrocolpopexy. AB - OBJECTIVE: The aim of the study was to compare unplanned postoperative encounters in women discharged same day versus later after robotic-assisted sacrocolpopexy (RA-SCP). METHODS: This is a retrospective cohort study of women who underwent RA SCP at a tertiary care center January 2013 to September 2015. Women were divided into 2 cohorts based on their day of discharge: (1) same day or (2) postoperative day 1 (POD >= 1) or later. Our primary outcome was unplanned provider visits (clinic, urgent care, emergency department, or hospital readmission) during the 6 weeks after surgery. Secondary outcomes included unplanned postdischarge nurse or physician phone calls. Logistic regression models were created to control for potential confounders. RESULTS: Two hundred seventy-two women were included; 80 underwent same-day discharge versus 192 discharged POD 1 or later (187 on POD 1, 5 on POD 2). Women discharged same day were older (61.3 vs 58.5 years, P < 0.05), more likely to have a start time before noon (85% vs 67.6%, P < 0.01), received less intraoperative intravenous fluids (1153 mL vs 1536 mL, P < 0.01), had shorter procedures (237 vs 256 minutes, P < 0.01), and spent more time in the postanesthesia care unit (213 vs 158 minutes, P < 0.01). There were no differences in unplanned provider visits between women discharged same day versus later (18.8% vs 27.6%, P = 0.12). No differences were observed in unplanned clinic visits, emergency department visits, or readmissions. In logistic regression models, unplanned provider visits (odds ratio = 0.35, 95% confidence interval = 0.30-1.54) and phone calls (odds ratio = 0.69, 95% confidence interval = 0.54-2.58) were not significantly different between groups. CONCLUSIONS: Same day discharge after RA-SCP is safe and does not result in increased health care utilization (provider visits or postoperative phone calls). PMID- 29489557 TI - Impact of Trainee Involvement on Complication Rates Following Pelvic Reconstructive Surgery. AB - OBJECTIVE: Trainee involvement in surgical procedures has been associated with longer surgical times and increased rates of certain complications. There has been limited study of the impact trainee involvement has on outcomes in urogynecologic surgery. We sought to determine the impact of resident and fellow involvement in pelvic reconstructive surgeries on 30-day complication rates. METHODS: Using the American College of Surgeons National Surgical Quality Improvement Program database, patients who underwent pelvic floor surgery were identified between 2010 and 2015. Patients were stratified into 3 groups: no trainee, resident, or fellow involvement. The primary outcome was the composite complication rate. Three-group comparison was performed using Kruskal-Wallis analysis. If statistically significant, then pairwise analysis was performed between the reference group (attending alone) and experimental groups (resident or fellow). Additional pairwise analysis was performed between the fellow and resident groups. Logistic regression was used to identify factors associated with an increased risk of complications. RESULTS: Seven thousand seven hundred fifty two surgical cases met all criteria for inclusion; 2440 (31.4%) included residents, and 646 (8.3%) included fellows. The median operating times were significantly higher in the resident and fellow groups compared with the attending-alone group (109 minutes [interquartile range, 55-164 minutes) compared with 110 minutes [interquartile range, 61-174 minutes] compared with 72 minutes [interquartile range, 38-113 minutes], P < 0.001). After multivariable logistic regression, trainee participation did not result in an increase in complication rate. Preoperative transfusion (adjusted odds ratio [aOR], 7.82; 95% confidence interval [CI], 2.03-30.09), coagulopathy (aOR, 3.18; 95% CI, 1.74-5.82), nonwhite race (aOR, 1.57; 95% CI, 1.31-1.89), insulin-dependent diabetes (aOR, 1.68; 95% CI, 1.03-2.72), American Society of Anesthesiologists class greater than 2 (aOR, 1.46; 95% CI, 1.21-1.77), length of stay (aOR, 1.04, 95%CI:1.02-1.06), operating time (aOR, 1.01; 95% CI, 1.00-1.03), and undergoing a sling procedure (aOR, 1.18; 95% CI, 1.01-1.41) were associated with higher complication rates. CONCLUSIONS: Resident and fellow involvement during pelvic reconstructive surgery is associated with longer operating times but does not increase the risk of complications within 30 days of the procedure. PMID- 29489558 TI - In Reply: Precision of Optic Nerve Head and Retinal Nerve Fiber Layer Parameter Measurements by Spectral-domain Optical Coherence Tomography, Methodological Issues on Reproducibility. PMID- 29489559 TI - IDEAL IMPLANT Structured Breast Implants: Core Study Results at 6 Years. AB - BACKGROUND: The structured breast implant uses different technology than saline or silicone gel implants, making it a third type of implant. The U.S. Food and Drug Administration and Health Canada granted approval in November of 2014. This implant is filled with saline but has an internal structure consisting of a series of nested shells that support the upper pole when upright and control fluid movement. It combines certain key features and benefits of saline and silicone gel implants. As with saline, the filler is only saline, which women like for peace of mind in case of rupture/deflation. As with silicone gel, it has a natural feel, but without the risk of silent rupture and U.S. Food and Drug Administration-recommended magnetic resonance imaging scans-women can simply look in the mirror and know their implants are intact. METHODS: This U.S. trial enrolled 502 women: 399 primary augmentations and 103 replacements of existing augmentation implants. Investigators were 45 American Board of Plastic Surgery certified plastic surgeons at 35 sites. Of the 502 women enrolled, 438 (87.3 percent) completed 6-year follow-up visits, a higher percentage than other Core breast implant trials. RESULTS: At 6 years, patient satisfaction was 89.7 percent for primary and 91.6 percent for replacement augmentations; surgeon satisfaction was 92.6 percent for primary and 94.0 percent for replacement augmentation. Kaplan-Meier adverse event rates were as follows: Baker grade III and IV capsular contracture, 5.7 percent for primary and 11.5 percent for replacement augmentation; and rupture/deflation, 1.8 percent for primary and 4.7 percent for replacement augmentation. CONCLUSION: Six-year results from 438 women show that the structured breast implant has high patient and surgeon satisfaction, a low rate of capsular contracture, and a low rate of rupture/deflation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 29489560 TI - Dual-Energy Computed Tomography-Based Display of Bone Marrow Edema in Incidental Vertebral Compression Fractures: Diagnostic Accuracy and Characterization in Oncological Patients Undergoing Routine Staging Computed Tomography. AB - PURPOSE: The aim of this study was to evaluate the diagnostic performance of virtual noncalcium (VNCa) dual-energy computed tomography (DECT) reconstructions enabling visualization of bone marrow edema for characterization of incidental thoracolumbar compression fractures in routine thoracoabdominal staging computed tomography (CT). MATERIALS AND METHODS: We retrospectively analyzed 51 oncological patients without suspected fracture or indicative complaints presenting at least 1 thoracolumbar compression fracture on routine thoracoabdominal staging DECT who had been examined between October 2015 and June 2017 using third-generation dual-source CT, had a previous CT within 3 months before, and also had undergone additional magnetic resonance imaging within 14 days, which served as the standard of reference. Three independent and blinded radiologists initially evaluated all vertebrae on conventional grayscale DECT series; after at least 8 weeks, observers reevaluated all cases using grayscale and color-coded VNCa DECT images. The age of each fracture was determined as either acute, chronic, or inconclusive. Specificity, sensitivity, and intraobserver and interobserver agreements were calculated taking into account clustering. RESULTS: A total of 98 vertebral compression fractures were detected in 51 patients (20 women, 31 men; median of 1 fracture per patient). The reference standard defined 45 as acute and 53 as chronic. For identification of only acute fractures (cutoff 1), the combination of grayscale and VNCa image series showed a higher sensitivity (91% vs 47%; P < 0.001) but equal specificity (both 100%) compared with analysis of grayscale images alone. When defining a positive finding as a fracture considered either acute or inconclusive (cutoff 2), combined analysis of grayscale and VNCa images showed similar sensitivity (96% vs 93%; P = 0.28) but significantly higher specificity (96% vs 75%; P < 0.001) compared with evaluation of grayscale images alone. Area under the curve analysis for detection of vertebral compression fractures showed superior results for reading of grayscale and VNCa image series (0.98) compared with analysis of grayscale images alone (0.89; P < 0.001). CONCLUSION: Dual-energy CT-derived color-coded VNCa reconstructions substantially improve the characterization of incidental thoracolumbar compression fractures seen on routine thoracoabdominal staging DECT by allowing for visualization of bone marrow edema. PMID- 29489561 TI - Pulse Width in Electroconvulsive Therapy: How Brief Is Brief? PMID- 29489562 TI - BILATERAL ENTEROCOCCUS FAECALIS ENDOPHTHALMITIS WITH MULTIPLE RECURRENCES. AB - PURPOSE: To describe the first case report of a bilateral recurrent Enterococcus faecalis endophthalmitis postcataract surgery. METHODS: Case report with a description of the timeline, diagnosis, and management of a patient with bilateral recurrent E. faecalis endophthalmitis. RESULTS: An 89-year-old man presented 6 weeks' postcataract surgery with pain, tearing, and blurred vision in the left eye. B-scan ultrasonography revealed vitritis and cultures postvitrectomy grew E. faecalis. There was gradual improvement in vision postintravitreal vancomycin administration. Four years later, the patient experienced another episode of E. faecalis endophthalmitis in the right eye postcataract extraction, followed by several additional episodes in both eyes posttreatment. CONCLUSION: Enterococcus faecalis is a rare but highly virulent cause of endophthalmitis that may remain sequestered in the capsular bag, despite aggressive treatment. Even after recurrent episodes, early vitrectomy and aggressive antibiotic therapy may prove to be effective in preventing vision loss. PMID- 29489564 TI - Diagnostic and Therapeutic Challenges. PMID- 29489563 TI - SILDENAFIL CITRATE INDUCED RETINAL TOXICITY-ELECTRORETINOGRAM, OPTICAL COHERENCE TOMOGRAPHY, AND ADAPTIVE OPTICS FINDINGS. AB - BACKGROUND/PURPOSE: To report a case of persistent retinal toxicity associated with a high dose of sildenafil citrate intake. METHODS: Single retrospective case report. RESULTS: A 31-year-old white man with no medical history presented with complaints of bilateral multicolored photopsias and erythropsia (red-tinted vision), shortly after taking sildenafil citrate-purchased through the internet. Patient was found to have cone photoreceptor damage, demonstrated using electroretinogram, optical coherence tomography, and adaptive optics imaging. The patient's symptoms and the photoreceptor structural changes persisted for several months. CONCLUSION: Sildenafil citrate is a widely used erectile dysfunction medication that is typically associated with transient visual symptoms in normal dosage. At high dosage, sildenafil citrate can lead to persistent retinal toxicity in certain individuals. PMID- 29489565 TI - EFFECT OF OPTIC DISK-FOVEA DISTANCE ON MEASUREMENTS OF INDIVIDUAL MACULAR INTRARETINAL LAYERS IN NORMAL SUBJECTS. AB - PURPOSE: To investigate the effect of optic disk-fovea distance (DFD) on measurements of macular intraretinal layers using spectral domain optical coherence tomography in normal subjects. METHODS: One hundred and eighty-two eyes from 182 normal subjects were imaged using spectral domain optical coherence tomography. The average thicknesses of eight macular intraretinal layers were measured using an automatic segmentation algorithm. Partial correlation test and multiple regression analysis were used to determine the effect of DFD on thicknesses of intraretinal layers. RESULTS: Disk-fovea distance correlated negatively with the overall average thickness in all the intraretinal layers (r <= -0.17, all P <= 0.025) except the ganglion cell layer and photoreceptor. In multiple regression analysis, greater DFD was associated with thinner nerve fiber layer (6.78 MUm decrease per each millimeter increase in DFD, P < 0.001), thinner ganglion cell-inner plexiform layer (2.16 MUm decrease per each millimeter increase in DFD, P = 0.039), thinner ganglion cell complex (8.94 MUm decrease per each millimeter increase in DFD, P < 0.001), thinner central macular thickness (18.16 MUm decrease per each millimeter increase in DFD, P < 0.001), and thinner total macular thickness (15.94 MUm decrease per each millimeter increase in DFD, P < 0.001). CONCLUSION: Thinner measurements of macular intraretinal layers were significantly associated with greater DFD. A clinical assessment of macular intraretinal layers in the evaluation of various macular diseases should always be interpreted in the context of DFD. PMID- 29489566 TI - Internal Limiting Membrane Peeling-Repositioning Technique for Macular Hole After Macular Hemorrhage Associated With Rupture of Retinal Arterial Macroaneurysm. PMID- 29489567 TI - A Comprehensive Review of Low-Speed Rear Impact Volunteer Studies and a Comparison to Real-World Outcomes. AB - STUDY DESIGN: This study combined all prior research involving human volunteers in low-speed rear-end impacts and performed a comparative analysis of real-world crashes using the National Automotive Sampling System - Crashworthiness Data System. OBJECTIVE: The aim of this study was to assess the rates of neck pain between volunteer and real-world collisions as well as the likelihood of an injury beyond symptoms as a function of impact severity and occupant characteristics in real-world collisions. SUMMARY OF BACKGROUND DATA: A total of 51 human volunteer studies were identified that produced a dataset of 1984 volunteer impacts along with a separate dataset of 515,601 weighted occupants in real-world rear impacts. METHODS: Operating-characteristic curves were created to assess the utility of the volunteer dataset in making predictions regarding the overall population. Change in speed or delta-V was used to model the likelihood of reporting symptoms in both real-world and volunteer exposures and more severe injuries using real-world data. Logistic regression models were created for the volunteer data and survey techniques were used to analyze the weighted sampling scheme with the National Automotive Sampling System database. RESULTS: Symptom reporting rates were not different between males and females and were nearly identical between laboratory and real-world exposures. The minimal risk of injury predicted by real-world exposure is consistent with the statistical power of the large number of volunteer studies without any injury beyond the reporting of neck pain. CONCLUSION: This study shows that volunteer studies do not under-report symptoms and are sufficient in number to conclude that the risk of injury beyond neck strain under similar conditions is essentially zero. The real-world injury analyses demonstrate that rear impacts do not produce meaningful risks of cervical injury at impacts of similar and greater severity to those of the volunteer research. Future work concerning the mechanism of whiplash-related trauma should focus on impacts of severity greater than those in the current literature. LEVEL OF EVIDENCE: 3. PMID- 29489568 TI - Effectiveness and Downstream Healthcare Utilization for Patients That Received Early Physical Therapy Versus Usual Care for Low Back Pain: A Randomized Clinical Trial. AB - STUDY DESIGN: Randomized controlled trial. OBJECTIVE: The aim of this study was to compare early physical therapy versus usual care in patients with low back pain. SUMMARY OF BACKGROUND DATA: Early physical therapy (PT) has been associated with reduced downstream healthcare utilization in retrospective studies, but not investigated prospectively in the military health system. METHODS: Military service members seeking care from a general practitioner were recruited. Patients attended a 20-minute self-management class with focus on psychosocial resilience and then randomized to usual care only (UC) versus immediately starting a 3-week physical therapy program (PT). Primary outcome was the Oswestry Disability Index at 1 year. Secondary outcomes included Oswestry scores at 4- and 12-week follow up, numeric pain rating scale, global rating of change, and healthcare utilization at 1 year. Analysis of covariance was used to compare differences between groups, significance set at 0.05. TRIAL REGISTRATION: clinicaltrials.gov: NCT01556581 RESULTS.: A total of 119 patients (mean age 27.2 years; mean BMI 27.8 kg/m; 15.1% female) enrolled (61 randomized to UC; 58 to PT). No between-group differences found on the Oswestry after 1 year. A between-group difference in Oswestry was present at 4 weeks (mean difference = 4.4; 95% CI: 0.41-10.1; P = 0.042) favoring PT. Total 1-year mean healthcare costs did not differ significantly between groups (UC $5037; 95 CI $4171-$6082 and PT $5299; 95 CI $4367-$6431). The portion of total mean healthcare costs related to low back pain was lower for UC ($1096; 95% CI $855-$1405) compared to PT ($2016, 95% CI $1570 $2590). CONCLUSION: There was no difference between usual care and early PT after 1 year. PT provided greater improvement in disability after 4 weeks. As both groups improved, the impact of the education may have been underestimated. Patients in the PT group utilized greater back-pain-related healthcare resources, but overall healthcare costs did not differ compared to UC. LEVEL OF EVIDENCE: 2. PMID- 29489569 TI - Demystifying the "Triple Point: " Technical Nuances of the Fronto-Orbital Advancement. AB - Removal of the fronto-orbital bandeau is one of the most critical components for procedures designed to correct anomalies of the craniofacial skeleton and remodel the anterior calvarial vault. It is also used to improve exposure of the anterior cranial fossa. It is arguably one of the more difficult portions of some craniofacial procedures. While the technique for fronto-orbito-sphenoid osteotomy has been frequently described, it has only been minimally detailed. Separation of bone in this region remains challenging due to the bone thickness, adjacent vital structures, and limited direct visibility. The present paper describes the anatomy of this particular region, which the authors have termed the "triple point", to facilitate successful osteotomy and avoid potential injury. PMID- 29489570 TI - Adult Cranioplasty Reconstruction With Customized Cranial Implants: Preferred Technique, Timing, and Biomaterials. AB - INTRODUCTION: Complex cranial defects requiring delayed reconstruction present numerous challenges. Delayed cranioplasties accompany frequent complications approaching an incidence of 35 to 40%. Therefore, the authors sought to collate their experience in hopes of sharing their perspective on several topics including technique, timing, and preferred biomaterials. METHODS: The authors' 5 year consecutive experience over 430 customized cranial implants is described herein. Since its inception in 2012, the authors' team has employed the pericranial-onlay cranioplasty technique instead of the standard epidural approach. Optimal timing for cranioplasty is determined using objective criteria such as scalp healing and parenchymal edema, close collaboration with neuroplastic surgery, conversion from autologous bone to sterile implant in instances of questionable viability/storage, and the first-line use of solid poly(methylmethacrylate) implants for uncomplicated, delayed cases, first-line porous polyethylene (MEDPOR) implants for single-stage cranioplasty, and first line polyether-ether-ketone implants for cases with short notice. Furthermore, the use of the pterional design algorithm with temporal bulking for all customized implants has helped to correct and/or prevent temporal hollowing deformities. RESULTS: The authors' team has observed a three-fold reduction in reported complications as compared with the existing literature, with a major complication rate of 11%. The multidisciplinary center has provided an optimal stage for synergy and improved outcomes versus standard cranioplasty techniques. CONCLUSION: Secondary cranial reconstruction, or cranioplasty, can be challenging due to numerous reasons. These best practices, developed in collaboration with neuroplastic surgery and neurosurgery, appear to encompass the largest published experience to date. The authors find this approach to be both safe and reliable. PMID- 29489571 TI - Pain Management for Nonsyndromic Craniosynostosis: Adequate Analgesia in a Pediatric Cohort? AB - BACKGROUND: Postoperative pain following open craniosynostosis repair has not been studied extensively and is sometimes thought to be inconsequential. The purpose of this study was to assess postoperative pain in this pediatric population. METHODS: We performed a retrospective chart review of patients (n = 54) undergoing primary open craniosynostosis repair from 2010 to 2016. Demographics, length of stay (LOS), pain scores, emesis events, and perioperative analgesics were reviewed. Multivariable regression models were designed to assess for independent predictors of LOS and emesis. RESULTS: A high proportion had moderate to severe pain on postoperative day 0 (56.5%) and day 1 (60.9%). Opioid administered in postoperative period was 1.40 mg/kg/d in morphine milligram equivalent (MME) (+/-1.07 mg/kg/d MME). Majority of patients transitioned to enteral opioids on postoperative day 1 (24.5%) or day 2 (49.1%). Ketorolac was administered to 11.1% (n = 6). Emesis was documented in 50% of patients. LOS revealed a positive association with age (P = 0.006), weight (P = 0.009), and day of transition to enteral opioids (P < 0.001); association with emesis was trending toward significance (P = 0.054). There was no association between overall LOS and amount of opioids administered postoperatively (P = 0.68). Postoperative emesis did not have any significant association with age, sex, weight, total amount of postoperative opioid administered, use of ketorolac, or intraoperative steroid use. CONCLUSION: Open craniosynostosis repair is associated with high levels of pain and low utilization of nonopioid analgesics. Strategies to improve pain, decrease emesis and LOS include implementation of multimodal analgesia period and avoidance of enteral medications in the first 24 hours after surgery. PMID- 29489572 TI - Maxillary Hypoplasia With Congenital Oligodontia Treated by Maxillary Distraction Osteogenesis. AB - It is known that congenitally missing teeth can often cause differences in craniofacial morphology; however, there are few reported cases of orthognathic surgical treatment for these patients. Herein, the authors report a rare case of maxillary hypoplasia with congenital oligodontia treated by maxillary distraction osteogenesis with internal device. A 17-year-old male presenting with multiple tooth agenesis and maxillary recession was referred to our hospital for orthognathic surgical treatment. Preoperative simulation surgery was performed using Full-Color 3-dimensional salt model. After surgery, improvement in maxillary recession and occlusal stability was observed. This report demonstrates the advantages of the method used herein, which includes reduction in operating time with increase in the safety of the procedure. PMID- 29489573 TI - Simple Technique for Reducing the Buccal Fat Pad During Mandibular Orthognathic Surgery. AB - Sagittal split ramus osteotomy and intraoral vertical ramus osteotomy are commonly performed for the correction of jaw deformities. However, during mandibular orthognathic surgeries such as sagittal split ramus osteotomy and intraoral vertical ramus osteotomy , the authors sometimes encounter exposure of the buccal fat pad (BFP), which decreases the surgical field. The exposed BFP makes it difficult to perform these operations, may result in unexpected complications, and may increase the operation time. Therefore, the authors herein describe a simple, safe, and convenient technique for reducing the volume of the exposed BFP during mandibular orthognathic surgery using an electric knife in the coagulation mode. PMID- 29489574 TI - Evaluation of the Olfactory Function With the "Sniffin' Sticks" Test After Endoscopic Transsphenoidal Pituitary Surgery. AB - The aim of this study was to evaluate the olfactory function of patients who had undergone endoscopic transsphenoidal pituitary surgery. In this prospective study, the "Sniffin' Sticks" test was performed between June 2016 and April 2017 at Izmir Katip Celebi University Ataturk Training and Research Hospital. Thirty patients who were scheduled to undergo endoscopic transsphenoidal pituitary surgery were evaluated preoperatively and 8 weeks postoperatively using the Sniffin' Sticks test battery for olfactory function, odor threshold, smell discrimination, and odor identification. The patients were evaluated preoperatively by an otolaryngologist. The patients' demographic data and olfactory functions were analyzed with a t test and Wilcoxon-labeled sequential test. The study group comprised 14 women (46.7%) and 16 men (53.3%) patients. The mean age of the patients was 37.50 +/- 9.43 years (range: 16-53 years). We found a significant difference in the preoperative and postoperative values of the odor recognition test (P = 0.017); however, there was no significant difference between the preoperative and postoperative odor threshold values (P = 0.172) and odor discrimination values (P = 0.624). The threshold discrimination identification test scores were not significant (P = 0.110). The olfactory function of patients who were normosmic preoperatively was not affected postoperatively. This study shows that the endoscopic transsphenoidal technique for pituitary surgery without nasal flap has no negative effect on the olfactory function. PMID- 29489575 TI - Frontal Mucocele Extended Orbita and Endoscopic Marsupialization Technique. AB - Mucocele is benign, slow-growing, mucous-filled cystic lesions that arise in the paranasal sinuses. It causes progressive distension of the bony walls and induces compressive symptoms. Surgical treatment of paranasal sinus mucoceles includes endoscopic approach or external approach. The authors report a patient of frontal mucocele who presented with a history of progressive unilateral protrusion. Computed tomography scan revealed a large mucocele of the frontal sinus with orbital extension on the same side. He was successfully treated with endoscopic marsupialization without any serious complications. PMID- 29489576 TI - A Reduction Technique for Depressed Medial Maxillary Fractures. AB - The authors developed a technique for reducing the fractured segment by introducing an elevator through the accessory maxillary ostium (AMO).Through an upper gingivolabial vestibular incision, the fractured segments were exposed. In cases where no cleft was available for inserting the elevator, the blunt end of a Cottle elevator was inserted into the AMO via a nasal approach. The curved blunt end of a Cottle elevator was inserted into the middle meatus and the AMO was felt at the medial wall of the maxillary sinus. With gentle pressure, the tip was pushed into the maxillary sinus, and then pushed forward about 2 cm. An upward force was applied until the depressed segment was reduced to its original position. Through a gingivolabial vestibular incision, alignment of the reduced segments could be seen. Miniplate fixation can be applied. If the reduced segments are stable or too many segments are present, the fracture can be stabilized using tissue glue.The authors propose that in medial maxillary fractures where no cleft for the elevator is available, the fractured segment can be mobilized by introducing an elevator through the AMO. PMID- 29489577 TI - Unilateral Orticochea Pharyngoplasty for Unilateral Velopharyngeal Dysfunction: Long-Term Outcomes Data. AB - A unilateral deficit in velopharyngeal closure during speech production is an unusual presentation of velopharyngeal dysfunction (VPD) and few solutions have been described for this problem. This report details the long-term outcomes using this technique. We performed a retrospective chart review of all the patients who underwent a unilateral Orticochea pharyngoplasty for VPD. The authors identified 10 patients treated with 11 unilateral pharyngoplasty at a single tertiary care institutional setting. The mean age at repair was 8.6 years. The mean length of follow-up was 7.6 years. All the patients demonstrated improvement in velopharyngeal closure and speech resonance with 4 showing complete resolution of VPD. There were no revisions required or complications. One patient, after 10.7 years, required a unilateral procedure on the contralateral side which resulted in complete resolution of VPD postoperatively. PMID- 29489578 TI - Ablation of Buccal Cancer and Functionality Buccal Reconstruction Using an Individuation Anterolateral Thigh Flap. AB - The complex area for reconstruction of the head and the neck is the buccal because of difficult anatomy of this region. This article aimed to describe our individualized design for the reconstruction of the buccal using an different categories anterolateral thigh (ALT) flap. Ninety-four patients were involved in this study. Among 94cases, the number of using the musculocutaneous ALT flap was 57, using the fasciocutaneous ALT flap was 25, and using the thin ALT flap was 12. Postoperative vessel thrombosis occurred in 8 flaps, and required operative exploration in the perioperative period, 6 flaps were complete survival after the salvages, 2 flap was failure. The ALT flap represents a very good choice for the reconstruction of the complex defects at the cheek level. The flap can replace large volumes of tissues and the skin island is large and can be used both for the tegument reconstruction and for the oral mucosa reconstruction. PMID- 29489579 TI - A Rare Cause of Recurrent Cerebral Ischemia and Syncope: Eagle Syndrome. AB - Eagle syndrome is defined as symptomatic elongation of the styloid process or calcification of the stylohyoid and stilomandibular ligament. The syndrome was described by WW Eagle in 1937. The styloid process is located between the internal and external carotid arteries and laterally in the tonsillar fossa. Patients with cerebrovascular ischemia causing syncope or hemiparesia due to Eagle syndrome are rarely published in the literature. The authors presented a patient with recurrent cerebrovascular attacks due to long styloid process. PMID- 29489580 TI - Nasolabial Morphology Following Nasoalveolar Molding in Infants With Unilateral Cleft Lip and Palate. AB - AIM: The aim of the present study is to evaluate the effects of nasoalveolar molding (NAM) therapy on nasolabial morphology three dimensionally, and compare the nasolabial linear and surface distance measurements in infants with unilateral cleft lip and palate. METHODS: Facial plaster casts of 42 infants with unilateral cleft lip and palate taken at the onset (pre-NAM) and finishing stage (post-NAM) of NAM were scanned with 3dMDface stereophotogrammetry system (3dMD, Atlanta, GA). Nineteen nasolabial linear and surface distance measurements were performed on three-dimensional images. In addition to standard descriptive statistical calculations (means and SDs), pre- and post-NAM measurements were evaluated by paired t test. RESULTS: All measurements except lip gap, nostril floor width, and nostril diameter increased between pre-NAM and post-NAM. Nostril and lip height increased significantly on the cleft side (P < 0.05). No differences were present between linear and surface distance measurements except for nasal width measurement. CONCLUSIONS: Nasal and lip symmetry improved with NAM. The use of surface distance measurements may be advised particularly for continuous and curved anatomic structures in which circumference differences are expected. PMID- 29489581 TI - Postextraction Dental Implant in the Aesthetic Zone, Socket Shield Technique Versus Conventional Protocol. AB - The aim of this randomized controlled trial was to evaluate the survival rate, the marginal bone level, and the aesthetic outcome; at 3 years' follow-up, of dental implants placed into a high-esthetic aesthetic zone by comparing 2 techniques of postextraction implant with immediate loading: the socket shied technique and the conventional insertion technique.Several clinical studies suggested that the avulsion of a dental element causes dimensional alterations of both soft and hard tissues at the postextractive site. To increase the aesthetic outcomes, the "socket-shield technique" has been proposed. This method involves maintaining the vestibular root portion and immediate insertion of the dental implant in close proximity to the root.Patients enrolled in this study were randomized to receive a postextraction implant in the aesthetic zone, either with the socket shied technique or with the conventional insertion technique. Implant survival, marginal bone level, and the pink aesthetic score were the outcomes evaluated.Implant survival rate was 100% in both the groups at 3 years. Implants inserted with the socket shield technique showed better values of both marginal bone level and pink aesthetic score (P < 0.05).Although such preliminary results need to be further confirmed, the socket shield technique seems to be a safe surgical technique that allows an implant rehabilitation characterized by better aesthetic outcomes. PMID- 29489583 TI - Imaging in Congenital and Hereditary Abnormalities of the Interventricular Septum: Clinical Anatomy and Diagnostic Clues. AB - Early identification of congenital heart diseases, specifically those affecting the structural integrity and function of the interventricular septum, in childhood is important toward decreasing the morbidity and mortality of those affected. We review the pertinent clinical and imaging manifestations for those with ventricular septal defects, ventricular septal aneurysms, tetralogy of Fallot, and hypertrophic (obstructive) cardiomyopathy, in addition to discussing first-line imaging studies, including echocardiography, and indications for advanced imaging. PMID- 29489584 TI - Cardiac Positron Emission Tomography-Magnetic Resonance Imaging: Current Status and Future Directions. AB - Simultaneous acquisition positron emission tomography-magnetic resonance imaging (PET-MRI) has the ability to combine anatomic information derived from cardiac MRI with quantitative capabilities of cardiac PET and MRI and the promise of molecular imaging by specific PET tracers. This combination of cardiac PET and MRI delivers a robust and comprehensive clinical examination. It has the potential to assess various cardiovascular conditions, including assessment of myocardial ischemia, infarction, and function, as well as specific characterization of inflammatory and infiltrative heart diseases such as cardiac sarcoid and amyloid. It also offers fascinating possibilities in imaging other cardiovascular-related disease states, such as tumor imaging and vascular imaging. In this review, we begin with a general overview of the potentials of PET-MRI in cardiovascular imaging, followed by a discussion of the technical challenges unique to cardiovascular PET-MRI. We then discuss PET-MRI in various cardiovascular disease imaging applications. Potential limitations of PET-MRI and future directions are also considered. PMID- 29489585 TI - Perceptual expertise impacts preattentive processing of visual simple feature: a visual mismatch negativity study. AB - Perceptual expertise can be defined as enhanced abilities of discriminating, learning, and recognizing object of special categories. It is unclear whether the perceptual expertise effects occur at the preattentive stage. In the present study, visual mismatch negativity (vMMN) elicited by deviant orientation (90 degrees /270 degrees vs. 0 degrees ) for faces, houses, and arrows, respectively, was investigated. Compared with standard stimuli (0 degrees orientation), the orientation changes elicited posterior vMMNs for all deviant stimuli. vMMN amplitudes were similar between houses and arrows, except the significant delayed peak latency for houses. Importantly, compared with houses and arrows, vMMN elicited by the orientation change of faces was significantly decreased and delayed. These data indicated that the perceptual expertise for faces relevant to high-level configural processing impaired the change detection of low-level visual features at the preattentive stage of information processing. PMID- 29489586 TI - Attenuation of deep semantic processing during mind wandering: an event-related potential study. AB - Although much research shows that early sensory and attentional processing is affected by mind wandering, the effect of mind wandering on deep (i.e. semantic) processing is relatively unexplored. To investigate this relation, we recorded event-related potentials as participants studied English-Spanish word pairs, one at a time, while being intermittently probed for whether they were 'on task' or 'mind wandering'. Both perceptual processing, indexed by the P2 component, and deep processing, indexed by a late, sustained slow wave maximal at parietal electrodes, was attenuated during periods preceding participants' mind wandering reports. The pattern when participants were on task, rather than mind wandering, is similar to the subsequent memory or difference in memory effect. These results support previous findings of sensory attenuation during mind wandering, and extend them to a long-duration slow wave by suggesting that the deeper and more sustained levels of processing are also disrupted. PMID- 29489587 TI - Cortical auditory evoked responses in cochlear implant users with early-onset single-sided deafness: indicators of the development of bilateral auditory pathways. AB - Cochlear implantation (CI) for early-onset single-sided deafness (SSD) provides a unique insight into the development and cortical reorganization of binaural pathways. This case series aimed to investigate the impact of duration of deafness on CI outcomes as measured by cortical evoked auditory potentials (CAEPs). Four adults with early-onset SSD were studied after CI. The adults had a duration of deafness of 22, 24, 42, and 38 years before implantation. CAEPs and speech perception in noise were used to investigate binaural cortical pathways and function. Our four patients lost their hearing at the ages of 3, 6, 5, and 6 (S1, S2, S3, and S4, respectively). CAEPs were present bilaterally in S2, S3, and S4. S1's, who had the least experience with a CI, cortical responses at 1 month after CI activation showed cortical responses from the CI ipsilateral pathway, but no responses from the CI contralateral pathway. At 3 and 6 months, S1 showed significant cortical responses from the CI contralateral pathway for two speech tokens. An improvement in speech perception in noise testing was observed in all four participants. This case series indicates that long duration of deafness for early-onset SSD is not a contraindication for CI and may not impact the long-term outcomes in this population. The electrical stimulation from the CI integrates with the normal-hearing ear to produce bilateral cortical projections and functional improvement in speech perception in noise. These early data provide surprisingly positive results and call for larger scale research to be carried out. PMID- 29489588 TI - Disruption of the GluA2/GAPDH complex using TAT-GluA2NT1-3-2 peptide protects against AMPAR-mediated excitotoxicity after epilepsy. AB - Excitotoxicity and neuronal death following epilepsy involve alpha-amino-3 hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). It forms a protein complex with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and co-internalizes upon activation of AMPA receptors after epilepsy. Disruption of the GluA2/GAPDH complex with an interfering peptide, TAT-GluA2NT1-3-2, protects cells against AMPAR-mediated excitotoxicity, which have been identified in in-vitro and in-vivo models of brain ischemia. We postulated that disruption of the GluA2/GAPDH interaction with the TAT-GluA2NT1-3-2 peptide would also protect against AMPAR induced neuronal injury in an in-vivo model of status epilepticus (SE). In the present study, we divided pilocarpine-induced SE Wistar rats into three main groups: the TAT-GluA2NT1-3-2 peptide group, the TAT-GluA2NT-scram peptide group, and the normal saline group, and injected different doses of peptides stereotaxically into the hippocampus of SE rats to investigate whether the GluA2/GAPDH interaction could be disrupted by our TAT-GluA2NT1-3-2 peptide and determine its most appropriate dose. Then, the dose was administered stereotaxically at different time points after SE to determine the best administration time of neuronal protection. We found that the TAT-GluA2NT1-3-2 peptide can disrupt the GluA2/GAPDH interaction and protects against epilepsy induced neuronal damage. The GluA2/GAPDH interaction may be a novel therapeutic target for epilepsy. PMID- 29489589 TI - Quantification of Iodine Concentration Using Single-Source Dual-Energy Computed Tomography in a Calf Liver. AB - OBJECTIVE: To evaluate the accuracy of single-source dual-energy computed tomography (ssDECT) in iodine quantification using various segmentation methods in an ex vivo model. METHODS: Ten sausages, injected with variable quantities of iodinated contrast, were inserted into 2 livers and scanned with ssDECT. Material density iodine images were reconstructed. Three radiologists segmented each sausage. Iodine concentration, volume, and absolute quantity were measured. Agreement between the measured and injected iodine was assessed with the concordance correlation coefficient (CCC). Intrareader agreement was assessed using the intraclass correlation coefficient (ICC). RESULTS: Air bubbles were observed in sausage (IX). Sausage (X) was within the same view as hyper attenuating markers used for localization. With IX and X excluded, CCC and ICC were greater than 0.98 and greater than 0.88. When included, CCC and ICC were greater than 0.94 and greater than 0.79. CONCLUSIONS: Iodine quantification was reproducible and precise. However, accuracy reduced in sausages consisting of air filled cavities and within the same view as hyperattenuating markers. PMID- 29489590 TI - Procedure-Oriented Torsional Anatomy of the Carpal Tunnel. PMID- 29489591 TI - Multidetector Computed Tomography Imaging: Effect of Sparse Sampling and Iterative Reconstruction on Trabecular Bone Microstructure. AB - Multidetector computed tomography-based trabecular bone microstructure analysis ensures promising results in fracture risk prediction caused by osteoporosis. Because multidetector computed tomography is associated with high radiation exposure, its clinical routine use is limited. Hence, in this study, we investigated in 11 thoracic midvertebral specimens whether trabecular texture parameters are comparable derived from (1) images reconstructed using statistical iterative reconstruction (SIR) and filtered back projection as criterion standard at different exposures (80, 150, 220, and 500 mAs) and (2) from SIR-based sparse sampling projections (12.5%, 25%, 50%, and 100%) and equivalent exposures as criterion standard. Twenty-four texture features were computed, and those that showed similar values between (1) filtered back projection and SIR at the different exposure levels and (2) sparse sampling and equivalent exposures and reconstructed with SIR were identified. These parameters can be of equal value in determining trabecular bone microstructure with lower radiation exposure using sparse sampling and SIR. PMID- 29489592 TI - Significance and Prevalence of Haziness Surrounding the Hepatic Artery and Celiac Axis on Computed Tomographic Imaging After Pancreaticoduodenectomy. AB - PURPOSE: This study was conducted to assess the prevalence and significance of "haziness" around the hepatic artery and celiac axis in patients after pancreaticoduodenectomy. METHODS: This retrospective study was conducted on 116 patients who underwent pancreaticoduodenectomy or a similar procedure and had no clinical evidence of tumor recurrence or malignancy within 2 years from the date of surgery. RESULTS: Most images exhibited at least mild to moderate haziness around the hepatic artery and celiac axis. Patients with benign vs malignant results on formal pathology had no significant difference in severity of findings. Haziness remained in the mild to moderate range 2 years after surgery. CONCLUSIONS: Mild to moderate soft tissue stranding with increased attenuation around the hepatic artery and celiac axis is a common finding after pancreaticoduodenectomy that may persist for years after surgery. Such haziness alone has low specificity for tumor recurrence and should not be regarded as an indicator of malignancy. PMID- 29489593 TI - Orbital Interstitial Fluid: Evidence of a Potential Pathway for Extracranial Cerebrospinal Fluid Absorption. AB - BACKGROUND AND PURPOSE: The aim of the study was to describe the prevalence and characteristics of orbital interstitial fluid seen on magnetic resonance (MR) images of infants and young children. MATERIALS AND METHODS: Fat-suppressed axial T2-weighted MR images of 100 consecutive infants and young children (<6 years) without orbital pathology were retrospectively reviewed by 2 neuroradiologists. The presence, location, and extent of high-signal orbital interstitial fluid were characterized and tabulated as a function of age. RESULTS: Orbital interstitial fluid was detected in 90 (90%) of the 100 subjects overall, present in 100% (75/75) of infants and children younger than 3 years, 75% (12/16) of those aged 3 to 5 years, and 33% (3/9) of those aged 5 to 6 years. The fluid was bilateral and symmetric in all cases. Two morphologic patterns were distinguished, which often co-existed: (1) a focal discrete curvilinear band of fluid in the posterior lateral orbit, more common in younger patients, and (2) an ill-defined, lace-like pattern primarily in the superior orbit seen in subjects of all ages. CONCLUSIONS: Orbital interstitial fluid as detected by fat-suppressed T2-weighted MR imaging is a nearly universal finding in infants and young children and should not be considered pathologic. It may have either a focal or lace-like pattern or both. Orbital interstitial fluid decreases in size and prevalence as a function of age but is still present in nearly half of children aged 4 to 6 years. Possible explanations concerning the nature and origin of this fluid are presented, including the fascinating possibility that the fluid represents an extracranial pathway for outflow of cerebrospinal fluid. PMID- 29489594 TI - Comparison Between Isotropic 3-Dimensional Fat-Suppressed T2-Weighted Fast Spin Echo (FSE) and Conventional 2-Dimensional Fat-Suppressed Proton-Weighted FSE Shoulder Magnetic Resonance Imaging at 3-T in Patients With Shoulder Pain. AB - OBJECTIVE: The aims of this study were to compare isotropic 3-dimensional fat suppressed T2-weighted fast spin echo (FSE) imaging (T2FS) with 2-dimensional fat suppressed proton-density-weighted FSE imaging (2D-PDFS) and evaluate feasibility of isotropic 3-dimensional FSE shoulder imaging at 3-T magnetic resonance imaging (MRI). METHODS: Seventy-eight patients who underwent shoulder MRI were evaluated. Three-dimensional T2FS and 2D-PDFS were qualitatively graded for delineation of anatomic structures. In quantitative analysis, mean relative signal intensity and relative signal contrast between each structure of the shoulder were compared. RESULTS: Three-dimensional T2FS showed significantly higher scores for rotator cuff (P = 0.020), lower scores for bone (P < 0.001), and higher relative contrast of rotator cuff to fluid (P < 0.001) and labrum to fluid (P < 0.001) in comparison with 2D-PDFS. No significant difference in relative signal intensity of the rotator cuff, labrum, joint fluid, cartilage, and bone marrow was demonstrated. CONCLUSIONS: Isotropic 3-dimensional FSE MRI has similar image quality and diagnostic performance to conventional 2-dimensional sequence in evaluation of the rotator cuff. PMID- 29489595 TI - The Ability of Dual-Energy Computed Tomography to Distinguish Normal Bone Marrow From Metastases Using Bone Marrow Color Maps. AB - OBJECTIVE: The objective of this study was to determine if dual-energy computed tomography bone marrow color maps can improve sensitivity, specificity, accuracy, and confidence of detection of bone metastases. METHODS: Institutional review board approved this retrospective review of a consecutive series of cancer patients. Two radiologists first evaluated the fused 120 kV computed tomography images and recorded a number of suspicious lesions, confidence level, and Hounsfield units for each lesion. After a time gap, the studies were randomized for a second review with dual-energy computed-tomography bone marrow color maps. RESULTS: Eighteen patients and 1105 bones were reviewed. A total of 227 true metastatic lesions were present. With bone marrow color map review, sensitivity increased from 76.2% to 86.8%, for reader 1, and from 80.2% to 92.8%, for reader 2. Specificity and accuracy also increased. Confidence level increased for 12 lesions. CONCLUSIONS: Dual-energy computed-tomography bone marrow color map analysis of patients with metastatic cancers can improve the sensitivity, specificity, accuracy, and confidence level for the detection of bone metastases. PMID- 29489596 TI - Effect of Leptin on Marrow Adiposity in Ovariectomized Rabbits Assessed by Proton Magnetic Resonance Spectroscopy. AB - OBJECTIVE: Leptin acts to influence bone metabolism through indirect hypothalamic relay and direct peripheral pathways. Leptin enhances the differentiation of mesenchymal stem cells to the osteoblast rather than the adipocyte lineage, but the in vivo impacts of leptin on ovariectomy (OVX)-induced marrow adiposity are poorly understood. In this work, we aimed to address this question. METHODS: Forty-five female New Zealand rabbits were divided into sham + vehicle, OVX + vehicle, and OVX + leptin for 5 months. Magnetic resonance spectroscopy and dual energy x-ray absorptiometry were performed to longitudinally evaluate marrow fat fraction and bone density at 0, 2.5, and 5 months, respectively. At the end of experiment, quantitative parameters of marrow adipocytes were assessed by histopathology. RESULTS: Estrogen-deficient rabbits markedly exhibited expansion of marrow fat in a time-dependent manner, with a variation of marrow fat fraction (+19.7%) at 2.5 months relative to baseline conditions, and it was maintained until 5 months (+49.2%; all P < 0.001), which was accompanied by diminished bone density. Adipocyte diameter, density, and adipocytes area percentage in the OVX controls was increased by 50.7%, 76.3%, and 135.5%, respectively, relative to the sham controls (all P < 0.001). These OVX-induced marrow adiposity and bone loss were partly restored by leptin treatment. Treatment with leptin prevented OVX induced increases in bone turnover in rabbits. CONCLUSIONS: Early leptin administration inhibits the adipogenic effect of estrogen deficiency in terms of reverting marrow fat expansion seen in OVX rabbits. Magnetic resonance spectroscopy may be a useful tool for longitudinal and interventional assessments in osteoporosis. PMID- 29489597 TI - Intra-Aortic Balloon Pump Simulating Thoracic Aortic Dissection. AB - We present a 70-year-old woman who had an intra-aortic balloon pump (IABP) in its deflated state in the aorta during a computed tomography angiogram scan. The scan was performed to assess for aortic dissection. The deflated IABP created a curvilinear filling defect in the aortic lumen that suggested an intimal flap. Herein, we described the finding and suggest key features that can help distinguish between this intra-aortic device and a true dissection. This distinction between the device and aortic dissection is not only important because of the potential pitfall of a false positive diagnosis but also because an IABP itself can lead to an aortic dissection and therefore its computed tomography features should be recognized in both its inflated and deflated state. PMID- 29489598 TI - Targeting Osteogenesis-Angiogenesis Coupling for Bone Repair. PMID- 29489599 TI - Youth Victims of Violence Report Worse Quality of Life Than Youth With Chronic Diseases. AB - OBJECTIVES: Measuring health-related quality of life (HRQOL) provides the patient's perspective of his/her well-being and offers a unique outcome measure to demonstrate the impact of violence on the victim. To date, no study has described HRQOL in youth victims of violence in the United States. The purpose of this study was to describe HRQOL in youth victims of violence as compared with healthy youth and youth with chronic disease. METHODS: We conducted an exploratory cross-sectional study of the HRQOL of victims of violence aged 8 to 18 years. Descriptive statistics were reported for participant and injury demographics. One sample t tests were used to compare the sample population's HRQOL to known HRQOL of healthy populations and specific disease populations. RESULTS: Fifty-eight victims of violence participated in the study. Youth victims of violence had significantly worse mean HRQOL scores (mean, 71.4) compared with healthy youth in overall functioning (mean, 83.9), P < 0.001. Youth victims of violence reported worse psychosocial (mean, 67.6), emotional (mean, 62.9), and school (mean, 63.8) functioning than youth with obesity (mean, 72.1, 68.6, 75.0, respectively) and cancer (mean, 72.1, 72.2, 68.3, respectively). Mean Patient Reported Outcomes Measurement Information System T scores for youth victims of violence were significantly worse in anxiety (T = 51.9) and depression (T = 52.4) compared with youth with obesity (T = 48.3, 49.2), cancer (T = 47.7, 47.6), and sickle cell disease (T = 43, 44). CONCLUSIONS: Youth victims of violence suffer significant impairment in HRQOL compared with healthy populations and youth with specific disease burdens. Future studies into violence prevention effectiveness should use HRQOL as a comparative outcome measure to better tailor post injury management and interventions. PMID- 29489600 TI - Use of Complementary Health Approaches for Acute Complaints Presenting to the Emergency Department. AB - OBJECTIVE: This study aimed to determine the prevalence of complementary health approaches (CHAs) specifically for acute complaints in patients assessed in a pediatric emergency department (ED) and factors associated with use. METHODS: A cross-sectional survey was offered to patients between the age of 28 days and 18 years assessed at a tertiary pediatric ED between December 2014 and July 2015. Univariate and multivariate logistic regressions were used to identify variables associated with CHA use. RESULTS: Of 475 potential participants, 412 (86.7%) participated, of which 369 (89.5%) completed the survey. Overall, 28.7% (95% confidence interval [CI], 24.3-33.5) reported using any CHA for their child to treat the presenting complaint in the prior 72 hours to the ED visit. Gastrointestinal complaints had the highest use of CHA (46.3% of presentations endorsed use). The most common complementary health products used were vitamins and minerals (40.9%; 95% CI, 31.2-51.4); the most common complementary health practice used was massage (37.2%; 95% CI, 24.4-52.1). Multivariate analysis showed lower odds of using CHA for rash/skin complaint (odds ratio, 0.23; 95% CI, 0.09-0.59; P < 0.01) or musculoskeletal/extremity complaints (odds ratio, 0.23; 95% CI, 0.07-0.75; P = 0.01) compared with use for fever. No statistically significant association was found between CHAs use and child's sex, child's age, private insurance, or caregiver education. CONCLUSIONS: Caregivers commonly use CHA for acute pediatric complaints requiring an ED visit, with greatest use for gastrointestinal complaints. Clinicians should consider the use and safety of CHA when evaluating children presenting to the ED with acute conditions. PMID- 29489601 TI - The Not-So-Soft Spot: Pathophysiology of the Bulging Fontanelle in Association With Roseola. AB - Roseola infantum is a clinical syndrome characterized by high fever followed by the emergence of a rash. Case reports have documented an association between bulging fontanelles and roseola. We propose a novel mechanism for the development of intracranial hypertension caused by human herpesvirus 6-induced cytokine elevation leading to increased cerebrospinal fluid production. PMID- 29489602 TI - Stiff Neck and Drooling in a Young Girl. AB - A 3-year-old girl was brought to the emergency department 4 days after she was playing with a button battery and subsequently had a choking episode. The patient was seen immediately at a different emergency department and was discharged home after a normal chest x-ray finding and able to tolerate an oral challenge with liquids. She was later evaluated by her primary care physician and started on amoxicillin for possible pharyngitis. On examination in our emergency department, the patient had pooling of secretions and was unwilling to range her neck due to pain. Soft tissue neck x-ray confirmed a 20-mm button battery in the esophagus with air lucencies in the prevertebral soft tissues. PMID- 29489604 TI - Out-of-Hospital Cardiac Arrest Due to Ventricular Fibrillation in a 5-Year-Old Pediatric Patient. AB - Out-of-hospital cardiac arrest in pediatric population is rare and predominantly has respiratory aetiology. Authors present the relatively unique case of out-of hospital cardiac arrest in 5-years old pediatric patient due to ventricular fibrillation (VF) as the initial rhythm during the advanced life support. The patient was resuscitated by his parents and the initial rhythm was VF. After defibrillation the patient was admitted to the pediatric intensive care were another two episodes of VF was detected and treated. After standard postresuscitation care, patient was weaned from sedation and extubated with good neurologic outcome. Genetic screening of the 7 genes associated with cardiac channelopathies (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, RYR2, CASQ2) found mutation in gene KCHN2 and gene SCN5A, that were according to actual data considered benign. This case highlights the need for automated external defibrillator implementation in basic life support also in pediatric population and possible role of genetic predisposition in emergence of fibrillation. PMID- 29489603 TI - Emergency Information Forms for Children With Medical Complexity: A Qualitative Study. AB - OBJECTIVES: Children with medical complexity (CMC) are at risk for poor outcomes during medical emergencies. Emergency information forms (EIFs) provide essential medical information for CMC during emergencies; however, they are not widely used. We sought to identify factors related to optimal care for CMC to inform development of EIFs for CMC. METHODS: We interviewed 26 stakeholders, including parents of CMC, healthcare providers, health information technology, and privacy compliance experts. We inquired about barriers and facilitators to emergency care of CMC, as well as the desired content, structure, ownership, and maintenance of an EIF. Audio recordings were transcribed and analyzed inductively for common themes using thematic analysis techniques. RESULTS: Providers identified problems with documentation and poor caregiver understanding as major barriers to care. Parents reported poor provider understanding of their child's condition as a barrier. All groups reported that summary documents facilitate quality care. Recommended content included demographic/contact information, medical history, medications, allergies, advance directives, information about the patient's disease, and an action plan for anticipated emergencies. Twenty-three participants indicated a preference for electronic EIFs; 19 preferred a Web-based EIF that syncs with the medical record, with paper or portable electronic copies. Although 13 participants thought that EIFs should be patient owned to ensure availability during emergencies, 19 expected medical providers to create and update EIFs. CONCLUSIONS: Stakeholders interviewed reported a preference for Web based, sync-capable EIFs with portable copies. Emergency information forms could be maintained by providers but owned by patients to optimize emergency care and align with the concept of the medical home. PMID- 29489605 TI - Spontaneous Spinal Epidural Hematoma in an Infant. AB - A spontaneous spinal epidural hematoma is a collection of blood in the spinal epidural space that occurs in the absence of trauma. They most commonly present in the fourth to fifth decade in life with acute onset neck or back pain with delayed neurologic deficit. However, this presentation is often complicated in children because of the limitations in the pediatric neurologic exam. Magnetic resonance imaging is the imaging modality of choice for diagnosis. Here is a rare case of an infant spontaneous spinal epidural hematoma whose diagnosis was delayed because of a recent history of fever and viral pharyngitis before his development of neurologic deficits. Spontaneous spinal epidural hematomas are a rare phenomenon, which often present with nonspecific symptoms in the pediatric population. This diagnosis should be considered to initiate treatment in a timely manner. The treatment typically is emergent surgical decompression to minimize the risk of permanent neurologic deficit. PMID- 29489606 TI - Child Car Safety: A Parental Survey at a Tertiary Care Emergency Treatment Center in Greece. AB - OBJECTIVES: This study aimed to assess parental behavior in terms of child restraint systems (CRS) use under emergency conditions while driving to the hospital's outpatient settings as well as their routine child car safety (CCS) practices. METHODS: A cross-sectional survey of parents/caregivers transporting children 13 years or younger was conducted at the Emergency Treatment Center of a pediatric tertiary care center in Athens, Greece. Participants completed a questionnaire inquiring about the possession of CRS, and type and use of appropriate CRS while driving to the Emergency Treatment Center and under routine conditions. In addition, presence and type of parental education with regard to CCS and the use of seat belts among drivers were assessed. RESULTS: Of 444 participants, 51.4% children were carried restrained, although 48.6% were fastened in an improper seat for their age, in contrast with 23.7% who travel unrestrained on a daily basis. Forward-facing restraint seats were most popular, with 53.9% total use even in children younger than 2 years or older than 4 years, whereas booster seats (9.4%) and rear-facing restraint seats (18.2%) were inappropriately disfavored. Children younger than 4 years, male drivers, and drivers who had received information on CCS had higher odds of using CRS. The proportion of those had never been provided any CCS education was 38.5%. CONCLUSIONS: Child restraint systems use was inappropriately low under routine conditions and declined even further under emergency circumstances. Most children younger than 2 years and older than 4 years traveled inappropriately restrained in a forward-facing restraint seat. Parents should be more intensively educated on child car safety seat and the proper CRS use. PMID- 29489607 TI - Nephrogenic Diabetes Insipidus in Childhood: Assessment of Volume Status and Appropriate Fluid Replenishment. AB - Patients affected by nephrogenic diabetes insipidus (NDI) can present with hypernatremic dehydration, and first-line rehydration schemes are completely different from those largely applied in usual conditions determining a mild to severe hypovolemic dehydration/shock. In reporting the case of a patient affected by NDI and presenting with severe dehydration triggered by acute pharyngotonsillitis and vomiting, we want to underline the difficulties in managing this condition. Restoring the free-water plasma amount in patients affected by NDI may not be easy, but some key points can help in the first line management of these patients: (1) hypernatremic dehydration should always be suspected; (2) even in presence of severe dehydration, skin turgor may be normal and therefore the skinfold recoll should not be considered in the dehydration assessment; (3) decreased thirst is an important red flag for dehydration; (4) if an incontinent patient with NDI appears to be dehydrated, it is important to place the urethral catheter to accurately measure urine output and to be guided in parenteral fluid administration; (5) if the intravenous route is necessary, the more appropriate fluid replenishment is 5% dextrose in water with an infusion rate that should slightly exceed the urine output; (6) the 0.9% NaCl solution (10 mL/kg) should only be used to restore the volemia in a shocked NDI patient; and (7) it could be useful to stop indomethacin administration until complete restoration of hydration status to avoid a possible worsening of a potential prerenal acute renal failure. PMID- 29489608 TI - The Impact of a Displayed Checklist on Simulated Pediatric Trauma Resuscitations. AB - BACKGROUND: Advanced Trauma Life Support resuscitation follows a strict protocolized approach to the initial trauma evaluation. Despite this structure, elements of the primary and secondary assessments can still be omitted. The aim of this study is to determine if a cognitive aid checklist reduces omissions and speeds the time to assessment completion. We additionally investigated if a displayed checklist improved performance further. METHODS: A series of 131 simulated trauma resuscitations were performed. Teams were randomized to 1 of 3 arms (no checklist, handheld checklist, or displayed). The scenarios were recorded and analyzed to determine time to completion and absolute completion of tasks of the primary and secondary survey. The workload of individual team members was assessed via NASA-TLX. RESULTS: There was no difference in time to completion of surveys among the 3 arms. In the primary survey, there was a nonsignificant increase in the number of completed tasks with the use of the displayed checklist. In the secondary survey, there was a significant improvement in task completion with the displayed checklists with improved evaluation of the pelvis (P = 0.011), lower extremities (P = 0.048), and covering the patient (P = 0.046). There was a significant improvement in performance in those reported among nurse documenters with use of the displayed checklist. CONCLUSIONS: Despite a structured approach to trauma resuscitations, omissions still occur. The use of a displayed checklist improves performance and reduces omissions without delaying assessment. Better compliance with Advanced Trauma Life Support protocols may improve patient outcomes. PMID- 29489609 TI - Sudden Onset of Severe Cervical Pain in an Adolescent Girl: Case Report and Review of Literature. AB - A previously healthy 13-year-old girl presented with a 9-day history of acute onset severe neck pain associated with limited range of movement. Medical evaluation at day 2 was suggestive of muscle contracture, and she was discharged home with diazepam, antiinflammatory agents, and rest; however, she returned because of progressive clinical worsening with left arm distal paresthesia and paralysis since day 3. There was no history of trauma or other systemic complaints, and her familial medical history was unremarkable.Physical examination revealed left cervical and paravertebral tenderness on palpation with severe limitation of cervical and trunk movements; neurologic examination revealed left forearm and hand weakness and paralysis (grade II/V) with thenarhypothenar atrophy. Laboratory studies including coagulation profile were normal. Magnetic resonance imaging revealed an epidural hematoma from C4-T1 without underlying cause apparent on magnetic resonance angiography. On day 12, she underwent C3-7 laminotomy with laminoplasty and complete drainage of the hematoma. After 5 months of follow-up, she displays no neurological deficits. The spontaneous spinal epidural hematoma is a rare neurosurgical emergency in children. It usually presents acutely with neurologic deficits, but the initial presentation may be atypical or insidious, delaying diagnosis and intervention. Definitive diagnosis is made by magnetic resonance imaging and implies a high index of suspicion. Surgical drainage of the hematoma is the mainstay of treatment with favorable prognosis even in cases with a delayed diagnosis. PMID- 29489610 TI - Intravenous Paracetamol Overdose: A Pediatric Case Report. AB - Paracetamol is a common antipyretic often used to treat children with fever and pain. With the increasing administration of intravenous (IV) paracetamol, there will be the associated risk of medication dosing errors. We report a case of IV paracetamol overdose in a child with fever during hospital admission. A IV paracetamol dosing error occurred, with delayed recognition resulting in transient hepatotoxicity, with a peak alanine transaminase of 1946 IU/L and aspartate transaminase of 1633 IU/L. PMID- 29489611 TI - Oculocardiac Reflex in a Pediatric Trauma Patient. AB - We describe the case of a 6-year-old boy who presented to a tertiary care emergency department after a motor vehicle accident with facial trauma and bradycardia. The patient was found to have an orbital floor fracture and inferior rectus muscle entrapment with resulting bradycardia secondary to the oculocardiac reflex. The oculocardiac reflex is an uncommon cause of bradycardia in the setting of trauma but should be considered because it can necessitate surgical intervention. PMID- 29489612 TI - High sodium intake and arterial stiffness. PMID- 29489613 TI - Cardio-ankle vascular index and carotid-femoral pulse wave velocity: limits and strengths. PMID- 29489614 TI - Light and shade of the pulse waveform analysis. PMID- 29489615 TI - Sex differences in hypertension and other cardiovascular diseases. PMID- 29489616 TI - Who might benefit from Systolic Blood Pressure Intervention Trial's lower blood pressure targets? LIFE in the fast lane. PMID- 29489617 TI - Hypertensive disorders of pregnancy. PMID- 29489618 TI - Reply. PMID- 29489619 TI - Medical science is based on evidence (answer to Spronck et al.'s refutation: physics cannot be disputed). PMID- 29489620 TI - Reply: Medical science is based on facts and evidence. PMID- 29489621 TI - Facebook advertising for disseminating hypertension knowledge to older Chinese adults. PMID- 29489622 TI - Application of the wave-reservoir approach to different aortic sites: overstretching the concept. PMID- 29489623 TI - Reply - Aortic Reservoir Pressure - not overstretching but testing. PMID- 29489624 TI - Estimates of Prevalence of Cognitive Impairment From Research Studies Can Be Affected by Selection Bias. PMID- 29489625 TI - Theory Use and Usefulness in Scientific Advancement. PMID- 29489626 TI - Nursing's Boundary Work: Theory Development and the Making of Nursing Science, ca. 1950-1980. AB - BACKGROUND: Beginning in the late 1950s and intensifying through the 1960s and 1970s, nurse educators, researchers, and scholars worked to establish nursing as an academic discipline. These nursing leaders argued that the development of nursing theory was not only critical to nursing's academic project but also to improving nursing practice and patient care. OBJECTIVES: The purpose of the article is to examine the context for the development of nursing theory and the characteristics of early theory development from the 1950s through the early 1980s. METHODS: The methods used were historical research and analysis of the social, cultural, and political context of nursing theory development from the 1950s through the early 1980s. How this context influenced the work of nurse theorists and researchers in these decades was addressed. RESULTS: The development of nursing theory was influenced by a context that included the increasing complexity of patient care, the relocation of nursing education from hospital-based diploma schools to colleges and universities, and the ongoing efforts of nurses to secure more professional autonomy and authority in the decades after World War II. In particular, from the 1960s through the early 1980s, nurse theorists, researchers, and educators viewed the establishment of nursing science, underpinned by nursing theory, as critical to establishing nursing as an academic discipline. To define nursing science, nurse theorists and researchers engaged in critical boundary work in order to draw epistemic boundaries between nursing science and the existing biomedical and behavioral sciences. DISCUSSION: By the early 1980s, the boundary work of nurse theorists and researchers was incomplete. Their efforts to define nursing science and establish nursing as an academic discipline were constrained by generational and intraprofessional politics, limited resources, the gendered and hierarchical politics, and the complexity of drawing disciplinary boundaries for a discipline that is inherently interdisciplinary. PMID- 29489627 TI - Erratum: In the article, Health Care Provider Views on Transitioning from Task Shifting to Advanced Practice Nursing in Tanzania, that published in the January/February issue of Nursing Research, there was an error. PMID- 29489628 TI - The Impact of the Photocopier on Peer Review and Nursing Theory. AB - OVERVIEW: Two influential publications in nursing, Nursing Research and Perspectives on Nursing Theory, are used to illustrate how a specific technology change-the invention and marketing of the photocopier-influenced knowledge dissemination and information utilization in nursing, perhaps in ways not immediately apparent. METHODS: Content analysis and historical comparison, using editorials from Nursing Research, historical reports on technology development, and personal reflections on the genesis of Perspectives on Nursing Theory are used to create an argument for the role of technology in peer review, information utilization, and knowledge development in nursing. CONCLUSION: Multiple forces influence nursing science. Scholars should be alert to data inputs from many sources and respond accordingly. PMID- 29489629 TI - Key Issues in Nursing Theory: Developments, Challenges, and Future Directions. AB - BACKGROUND: Today, we face a situation some call the "profession at the crossroads." The problem is the development of the profession being threatened by an imbalance among philosophical, conceptual/theoretical, and empirical inquiry. OBJECTIVES: The aims of this project are to (a) examine the development and contributions of theory, (b) outline the challenges we face in knowledge development, and (c) provide a structure for disciplinary knowledge that provides a unifying focus and renovates theories' place in nursing science that can direct the future of developing knowledge for practice. METHODS: A personal narrative along with literature reviews. Narrative strategies included my own publications on theory, some relevant unpublished speeches, memories of meetings checked with concurrent attendees, and similar or dissimilar points of view in nursing theory textbooks. RESULTS: Contributions of theoretical work in the 20th century included maturing of the discipline, clarifying the theoretical focus of nursing as holistic persons with processes and patterns for environmental integration to attain health, a plurality of grand theories for articulating and testing of theories in practice and research, identification of the mutual impact of theory and education and major conferences, and contributions globally. Twenty-first century developments used all levels of theories particularly for research. Questions are raised about the evaluation of theory. Detours and dead ends for theory development involved metatheory debates and specific events. Challenges identified relate to rapid changes in society, healthcare, and science. A pathway for the future is presented in a figure with its description of the structure of nursing knowledge. DISCUSSION: The potential of this structure for developing future theory-based nursing knowledge for practice is envisioned, and strategies for creating this future are suggested. PMID- 29489630 TI - A Philosophical Model of the Nature of Nursing. AB - BACKGROUND: Today, when nurses are expected to manage large stores of data while providing precision care to individuals or groups of patients, it seems more important than ever that we understand the nature of nursing. Recently, there has been a renewed interest in examining what nursing is and how a clear understanding would impact nursing practice. OBJECTIVE: The goal of this article is to review an ontological account of nursing that seeks to understand the nature of nursing by showing the relation between the goal and structure of nursing care in association with the persons who are its recipients and practitioners. DISCUSSION: Nursing is directed to the care and well-being of persons, prevention of illness, restoration of health, and alleviation of suffering. Following the lead of many prior nurse theorists, I argue that nursing is a coherent unity of practice. Its various activities often occur in a clinically intimate interaction and are colored and shaped by the existential concern of the persons involved. Nursing care is directed to all the numerous aspects of the human person, is governed by a broadly ethical mandate and unified by its caring goal. Furthermore, these interactions in their reality, intimacy, and complexity allow for a kind of knowledge that is important for and unique to nursing. PMID- 29489631 TI - The Fundamentals of Care Framework as a Point-of-Care Nursing Theory. AB - BACKGROUND: Nursing theories have attempted to shape the everyday practice of clinical nurses and patient care. However, many theories-because of their level of abstraction and distance from everyday caring activity-have failed to help nurses undertake the routine practical aspects of nursing care in a theoretically informed way. OBJECTIVE: The purpose of the paper is to present a point-of-care theoretical framework, called the fundamentals of care (FOC) framework, which explains, guides, and potentially predicts the quality of care nurses provide to patients, their carers, and family members. DISCUSSION: The theoretical framework is presented: person-centered fundamental care (PCFC)-the outcome for the patient and the nurse and the goal of the FOC framework are achieved through the active management of the practice process, which involves the nurse and the patient working together to integrate three core dimensions: establishing the nurse patient relationship, integrating the FOC into the patient's care plan, and ensuring that the setting or context where care is transacted and coordinated is conducive to achieving PCFC outcomes. Each dimension has multiple elements and subelements, which require unique assessment for each nurse-patient encounter. IMPLICATIONS: The FOC framework is presented along with two scenarios to demonstrate its usefulness. The dimensions, elements, and subelements are described, and next steps in the development are articulated. PMID- 29489632 TI - Temporal Immediacy: A Two-System Theory of Mind for Understanding and Changing Health Behaviors. AB - BACKGROUND: Health promotion and chronic disease management both require behavior change, but people find it hard to change behavior despite having good intentions. The problem arises because patients' narratives about experiences and intentions are filtered through memory and language. These narratives inaccurately reflect intuitive decision-making or actual behaviors. OBJECTIVES: We propose a principle-temporal immediacy-as a moderator variable that explains which of two mental systems (narrative or intuitive) will be activated in any given situation. We reviewed multiple scientific areas to test temporal immediacy as an explanation for findings. METHODS: In an iterative process, we used evidence from philosophy, cognitive neuroscience, behavioral economics, symptom science, and ecological momentary assessment to develop our theoretical perspective. These perspectives each suggest two cognitive systems that differ in their level of temporal immediacy: an intuitive system that produces behavior in response to everyday states and a narrative system that interprets and explains these experiences after the fact. FINDINGS: Writers from Plato onward describe two competing influences on behavior-often with moral overtones. People tend to identify with the language-based narrative system and blame unhelpful results on the less accessible intuitive system, but neither is completely rational, and the intuitive system has strengths based on speed and serial processing. The systems differ based on temporal immediacy-the description of an experience as either "now" or "usually"-with the intuitive system generating behaviors automatically in real time and the narrative system producing beliefs about the past or future. DISCUSSION: The principle of temporal immediacy is a tool to integrate nursing science with other disciplinary traditions and to improve research and practice. Interventions should build on each system's strengths, rather than treating the intuitive system as a barrier for the narrative system to overcome. Nursing researchers need to study the roles and effects of both systems. PMID- 29489633 TI - Nursing Theory, Terminology, and Big Data: Data-Driven Discovery of Novel Patterns in Archival Randomized Clinical Trial Data. AB - BACKGROUND: The growth and diversification of nursing theory, nursing terminology, and nursing data enable a convergence of theory- and data-driven discovery in the era of big data research. Existing datasets can be viewed through theoretical and terminology perspectives using visualization techniques in order to reveal new patterns and generate hypotheses. The Omaha System is a standardized terminology and metamodel that makes explicit the theoretical perspective of the nursing discipline and enables terminology-theory testing research. OBJECTIVE: The purpose of this paper is to illustrate the approach by exploring a large research dataset consisting of 95 variables (demographics, temperature measures, anthropometrics, and standardized instruments measuring quality of life and self-efficacy) from a theory-based perspective using the Omaha System. Aims were to (a) examine the Omaha System dataset to understand the sample at baseline relative to Omaha System problem terms and outcome measures, (b) examine relationships within the normalized Omaha System dataset at baseline in predicting adherence, and (c) examine relationships within the normalized Omaha System dataset at baseline in predicting incident venous ulcer. METHODS: Variables from a randomized clinical trial of a cryotherapy intervention for the prevention of venous ulcers were mapped onto Omaha System terms and measures to derive a theoretical framework for the terminology-theory testing study. The original dataset was recoded using the mapping to create an Omaha System dataset, which was then examined using visualization to generate hypotheses. The hypotheses were tested using standard inferential statistics. Logistic regression was used to predict adherence and incident venous ulcer. RESULTS: Findings revealed novel patterns in the psychosocial characteristics of the sample that were discovered to be drivers of both adherence (Mental health Behavior: OR = 1.28, 95% CI [1.02, 1.60]; AUC = .56) and incident venous ulcer (Mental health Behavior: OR = 0.65, 95% CI [0.45, 0.93]; Neuro-musculo-skeletal function Status: OR = 0.69, 95% CI [0.47, 1.00]; male: OR = 3.08, 95% CI [1.15, 8.24]; not married: OR = 2.70, 95% CI [1.00, 7.26]; AUC = .76). DISCUSSION: The Omaha System was employed as ontology, nursing theory, and terminology to bridge data and theory and may be considered a data-driven theorizing methodology. Novel findings suggest a relationship between psychosocial factors and incident venous ulcer outcomes. There is potential to employ this method in further research, which is needed to generate and test hypotheses from other datasets to extend scientific investigations from existing data. PMID- 29489635 TI - Culture Shifts: From Cultural to Structural Theorizing in Nursing. AB - BACKGROUND: As a discipline, nursing emphasizes the importance of culture to care. Cultural competence is seen in nursing practice, education, and research as essential for addressing health disparities-particularly racial and ethnic disparities. There now is broad consensus that the causes for health disparities lie beyond the individual and are found in the structures of society. Current cultural competency theories and conceptual models, however, focus on the individual and do little to address the social/structural determinants of health. APPROACH: Reviewing the literature on cultural competency, current theorizing on culture and healthcare in nursing, and critiques of this theorizing is summarized. Emerging models that highlight the structural features of society influencing health are described. KEY POINTS: Cultural competency theorizing has been embraced in nursing, but its effectiveness in reducing health disparities has yet to be demonstrated. A shift in how the discipline addresses health disparities is needed. New theoretical approaches, such as fundamental causes theory, the health impact pyramid, ecological models, and structural competency, emphasize larger social determinants of health and should be more fully utilized in nursing. IMPLICATIONS: Nurse theorists need to clarify the usefulness of the emerging theories to the discipline, nurse educators should incorporate structural theories and concepts into curricula, practicing nurses will want to include structural screening assessment tools in their provision of care, and nurse researchers will need to develop skills in conducting and measuring the impacts of structural interventions. PMID- 29489634 TI - Expanding Regulation Theory With Oxytocin: A Psychoneurobiological Model for Infant Development. AB - BACKGROUND: Oxytocin (OT), an affiliation hormone released during supportive social interactions, provides an exemplar of how social environments are reflected in our neurobiology from the beginning of life. A growing body of OT research has uncovered previously unknown functions of OT, including modulation of parenting behaviors, neuroprotection, affiliation, and bonding. Regulation theory provides a strong framework for describing how the maternal care environment affects infant neurodevelopment through a symphony of molecules that form the neurobiological milieu of the developing infant brain. OBJECTIVES: The purpose of this article was to expand on regulation theory by discussing how OT based processes contribute to infant neurobiology and by proposing a new model for maternal-infant nursing practice and research. APPROACH: We structure our discussion of the socially based, neurobiological processes of OT through its effects in the nested hierarchies of genetic, epigenetic, molecular, cellular, neural circuit, multiorgan, and behavioral levels. Our discussion is also presented chronologically, as OT works through a positive feedback loop during infant neurodevelopment, beginning prenatally and continuing after birth. IMPLICATIONS: Nurses are in a unique position to use innovative discoveries made by the biologic sciences to generate new nursing theories that inform clinical practice and inspire the development of innovative interventions that maximize the infant's exposure to supportive maternal care. PMID- 29489636 TI - Defining and Theorizing About Culture: The Evolution of the Cultural Determinants of Help-Seeking, Revised. AB - BACKGROUND: The recent interest in defining and theorizing about social determinants of health has illuminated the importance of culture as a central phenomenon of interest. However, cultural processes appear in multiple places in social determinants of health models, and their specifics are not delineated or operationalized. OBJECTIVES: This theory development article describes the complexity of defining cultural variables and uses medical anthropology to show how cultural domains, constructs, and variables can be defined. METHODS: Using cultural anthropology theory, empirical work, and a literature synthesis as a starting point, the evolution of the cultural determinants of help-seeking theory is explored and the revision of the theory is highlighted. RESULTS: The expanded theory include structural concepts as control variables, reframes illness as "suffering," and adds concepts of course, cure, manageability, meaning in life, functioning, social negativity, and perceived need. DISCUSSION: Strategies for and benefits of isolating and operationalizing cultural variables for middle range theory development and testing are discussed. PMID- 29489637 TI - The Preconscious Awareness to Action Framework: An Application to Promote Testicular Awareness. AB - BACKGROUND: Health outcomes among men are markedly poorer than women. Testicular disorders can be life-threatening if left untreated. Few studies promoting awareness of testicular disorders have been underpinned by theory. Theory-based interventions are more likely to achieve positive health outcomes than interventions that lack a theoretical foundation. OBJECTIVES: The purpose of the study is to present a theory-focused analysis of the preconscious awareness to action framework (PAAF), developed to enhance testicular awareness and help seeking intentions and behaviors among men. METHODS: The following approach was used to develop the PAAF: The empirical literature on men's awareness of testicular disorders was reviewed. A qualitative study was conducted to explore men's awareness of testicular disorders, help-seeking intentions for testicular symptoms, and preferred learning strategies in relation to testicular disorders and symptoms. An iterative narrative review process of the theoretical literature on health promotion and symptom appraisal was undertaken. RESULTS: The PAAF comprises seven steps: preconscious awareness, unconscious awareness, conscious awareness, unconscious appraisal, conscious appraisal, intention, and behavior. The concept of testicular awareness was developed to familiarize men with their own testes and promote timely help-seeking. DISCUSSION: Researchers are encouraged to use the PAAF to design health-promoting interventions aimed at enhancing testicular awareness, symptom appraisal, and help-seeking. PMID- 29489638 TI - Theory and Theorizing in Nursing Science: Commentary from the Nursing Research Special Issue Editorial Team. AB - BACKGROUND: Articles from three landmark symposia on theory for nursing-published in Nursing Research in 1968-1969-served as a key underpinning for the development of nursing as an academic discipline. The current special issue on Theory and Theorizing in Nursing Science celebrates the 50th anniversary of publication of these seminal works in nursing theory. OBJECTIVE: The purpose of this commentary is to consider the future of nursing theory development in light of articles published in the anniversary issue. APPROACH: The Editorial Team for the special issue identified core questions about continued nursing theory development, as related to the nursing metaparadigm, practice theory, big data, and doctoral education. Using a dialogue format, the editors discussed these core questions. DISCUSSION: The classic nursing metaparadigm (health, person, environment, nursing) was viewed as a continuing unifying element for the discipline but is in need of revision in today's scientific and practice climates. Practice theory and precision healthcare jointly arise from an emphasis on individualization. Big data and the methods of e-science are challenging the assumptions on which nursing theory development was originally based. Doctoral education for nursing scholarship requires changes to ensure that tomorrow's scholars are prepared to steward the discipline by advancing (not reifying) past approaches to nursing theory. CONCLUSION: Ongoing reexamination of theory is needed to clarify the domain of nursing, guide nursing science and practice, and direct and communicate the unique and essential contributions of nursing science to the broader health research effort and of nursing to healthcare. PMID- 29489639 TI - Eastern Nursing Research Society: 30th Annual Scientific Sessions Abstracts. PMID- 29489640 TI - A rare case report of a saddle pulmonary embolism presenting with high grade fevers, responsive to anticoagulation. AB - RATIONALE: Pulmonary embolism can manifest by a myriad of clinical symptoms. High grade fever is a rare presentation of thromboembolic phenomenon. PATIENT CONCERNS: A middle aged woman presented with high grade fevers. DIAGNOSES: Patient remained febrile despite broad spectrum antibiotics. All cultures were negative. CT angiogram of the chest was done, eliciting a large saddle embolus. INTERVENTIONS: Intravenous tissue plasminogen activator (t-PA) was administered and subsequently started on anticoagulation. Patient became afebrile 3 days after initiation of anticoagulation and all antibiotics were discontinued. OUTCOMES: We demonstrate a case of a saddle pulmonary embolism presenting with high grade fevers that responded to anticoagulation. LESSONS: It is imperative to include pulmonary embolism in the differential diagnosis, when presented with high-grade fever in patients with unclear diagnosis. PMID- 29489641 TI - Radiofrequency ablation for treatment of locally recurrent thyroid cancer presenting as a metastatic lymph node with dense macrocalcification: A case report and literature review. AB - RATIONALE: Long-term recurrence rate of differentiated thyroid carcinoma has been reported to be as high as 30%. Repeat surgery may be challenging due to normal tissue plane distortion secondary to postoperative fibrosis, especially for small sized recurrences. Recently, radiofrequency ablation (RFA) has been suggested to be a safe and effective alternative for high-risk patients or those who refuse surgery. Nonetheless, the efficacy of RFA remains questionable for densely calcified lymph nodes, which would have an increased likelihood of leaving residues after RFA. PATIENT CONCERNS: We present a case of a successful combined treatment of a metastatic lymph node with dense macrocalcification with the use of a single RFA session and radioactive iodine (RAI) ablation in a patient with a previous history of total thyroidectomy and neck node dissection for papillary thyroid carcinoma. DIAGNOSES: A 71-year-old man with papillary thyroid carcinoma underwent total thyroidectomy and neck node dissection followed by RAI ablation. The stimulated serum thyroglobulin level was 4.74 ng/mL at the time of RAI ablation, and the follow-up ultrasonography 3 months later revealed a 15-mm lymph node with dense macrocalcification at the right cervical level III. INTERVENTIONS: After confirming metastasis on cytology, the lesion was treated with ultrasound-guided RFA. OUTCOMES: The single RFA session combined with RAI ablation led to biochemical remission at 5 months after RFA, and complete resolution of structural recurrence including macrocalcification was observed 7 months after the second RAI (1 year after RFA). The patient remained free of recurrence at the 5-year follow-up. LESSONS: RFA may offer a safe and effective alternative to 'berry picking' surgery in cases of surgical ineligibility or patient refusal of surgery even when the target lesions contain dense macrocalcification. PMID- 29489642 TI - Impact of heavy smoking on the benefits from first-line EGFR-TKI therapy in patients with advanced lung adenocarcinoma. AB - Smoking is a risk factor for nonsmall cell lung carcinoma (NSCLC) and is associated with a lower response to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI). The purpose of this study is to examine the impact of the smoking status on the benefits from first-line EGFR-TKI in NSCLC patients with EGFR mutation.This was a retrospective study of 159 patients with advanced NSCLC treated at the Beijing Hospital between January 2011 and December 2016. The follow-up was censored on December 2017. EGFR mutation status, smoking (nonsmoker vs <30 packs/year (light smoker) vs >=30 packs/year (heavy smoker)), treatment, treatment response, and progression-free survival (PFS) were collected from the charts.Median follow-up was 10.0 (1.0-36.6) months. Response rate was lower in heavy smokers compared with nonheavy smokers (19.0% vs 71.7%, P < .001). There was no difference in PFS between nonsmokers (median, 10.5 months) and light smoker (median, 11.0 months), and these 2 groups were pooled together. PFS was longer in nonheavy smokers compared with heavy-smokers (median, 10.7 vs 6.0 months, P < .001). Smoking >= 30 packs/year (HR = 2.48, 95% CI: 1.55-3.98, P < .001) was associated with PFS.In patients with advanced NSCLC, the benefits and PFS of EGFR-TKI were better for nonheavy smokers than for heavy smokers. PMID- 29489643 TI - Wet beriberi with multiple organ failure remarkably reversed by thiamine administration: A case report and literature review. AB - RATIONALE: Circulatory failure, especially with low systemic vascular resistance (SVR), as observed in septic shock, thyrotoxicosis, and anemia, is a particular pattern that should suggest thiamine (vitamin B1) deficiency. The clinical picture of wet beriberi secondary to thiamine deficiency only demonstrates non specific clinical manifestations. For a diagnosis of wet beriberi, medical history is very important. Interestingly, imprisonment was also found to be related to thiamine deficiency. This article presents a rare case of wet beriberi associated with multiple organ failure (MOF) in a prison patient with years of heavy alcohol consumption. PATIENT CONCERNS: The patient reported repetitive symptoms of nausea, vomiting, respiratory distress, and palpitations for a period of 1 month; dyspnea and edema for 5 days; and decreased blood pressure and urine volume for 2 days. DIAGNOSES: The heart failure patient had a history of dietary deficiency. Right heart catheterization showed high cardiac output (CO) and low SVR. Measurement of serum thiamine concentration was low. The most important factor was that the hemodynamic indices were remarkably reversed by thiamine administration. INTERVENTIONS: The patient started treatment with thiamine (100 mg) by intramuscular injection, together with basic supportive care. OUTCOMES: The hemodynamic indices improved within 12 hours after thiamine administration. Echocardiographic examinations revealed right ventricular function improvement within a few days, which were normal within a month. LESSONS: A diagnosis of wet beriberi should be considered for a prison patient who has unexplained heart failure, lactic acidosis, and/or MOF. Moreover, the patient should be empirically given thiamine administration without delay. PMID- 29489644 TI - A case report of limbic encephalitis in a metastatic colon cancer patient during first-line bevacizumab-combined chemotherapy. AB - RATIONALE: Paraneoplastic limbic encephalitis (PLE) is one of the most common causes of neurologic paraneoplastic syndromes, with unclear pathogenesis. While several reports published in the last decades showed the occurrence of PLE in a variety of cancers, only a few cases have been associated with colon cancer. PATIENT CONCERNS: In February 2017, a 54-year-old man with clinical history of radically resected colon cancer started first line chemotherapy with FOLFOXIRI plus bevacizumab, after radiological diagnosis of multiple liver and bone metastases. During the third cycle of treatment, the patient developed psychomotor agitation and hallucinations followed by severe consciousness level reduction and cognitive impairment. DIAGNOSES: Magnetic resonance imaging showed hyperintense signals in both hippocampal areas, insula and right cingulate gyrus on fluid attenuated inversion recovery, diffusion weighted imaging, and T2 weighted images, highly suggestive of limbic encephalitis. Other causes (brain metastases, toxicity of chemotherapeutic agents, and infections) were excluded. INTERVENTIONS: Empirical immunosuppressive treatment (high-dose immunoglobulins and corticosteroids) was administered and chemotherapy was resumed. OUTCOMES: A slowly progressive improvement in neurological condition has been observed, even though radiological signs of limbic encephalitis are still evident. LESSONS: The present case highlights the complex diagnostic process of PLE, and the lack of a standard treatment. Moreover, the absence of correlation between PLE and tumor progression or tumor burden, and the opportunity of treating underlying neoplasm is discussed. PMID- 29489645 TI - Electroacupuncture for postoperative pain management after total knee arthroplasty: Protocol for a systematic review and meta-analysis. AB - BACKGROUND: Total knee arthroplasty (TKA) is one of the most common joint replacement surgeries in the United States. Postoperative pain is still a major complication after TKA. Electroacupuncture (EA) has been commonly used in clinical practice for pain after TKA, but its effects and safety remain uncertain. This protocol is described for a systematic review to investigate the beneficial effects and safety of EA for postoperative pain after TKA. METHODS: Randomized controlled trials (RCTs) related to EA treatment of pain after TKA will be collected from 3 databases of English literature, namely PubMed, Embase, and Cochrane Library, and 4 databases of Chinese literatures, namely CBM, CNKI, VIP and Wanfang database. The retrieved trials will be those published from the time when the respective databases were built to January 2018. The therapeutic effects according to the change from baseline in the amount of pain measured by the visual analogue scale (VAS) or numerical rating scale, will be accepted as the primary outcomes. We will use RevMan V.5.3 software as well to compute the data synthesis carefully when a meta-analysis is allowed. RESULTS: This systematic review and meta-analysis will provide a high-quality synthesis of current evidence of EA for pain after TKA. CONCLUSION: The conclusion of our systematic review will provide evidence to judge whether EA is an effective intervention for patient with postoperative pain after TKA. PROSPERO REGISTRATION NUMBER: PROSPERO CRD 42018082407. PMID- 29489646 TI - The significance of microsatellite instability in colorectal cancer after controlling for clinicopathological factors. AB - The colorectal cancer (CRC) patients with microsatellite instability (MSI) have distinct clinicopathological characteristics consisting of factors predicting positive and negative outcomes, such as a high lymph node harvest and poor differentiation. In this study, we measured the value of MSI as a prognostic factor after controlling for these discrepant factors. A total of 603 patients who underwent curative surgery for stages I to III colorectal cancer were enrolled. The patients were divided into microsatellite instability high (MSI-H) and microsatellite stable/microsatellite instability low (MSS/MSI-L) groups. Propensity score matching was used to match clinicopathological factors between the 2 groups. MSI-H patients had a high lymph node harvest (median: 31.0 vs 23.0, P < .001), earlier-stage tumors (P < .001), advanced T stage (89.3% vs 74.0%, P = .018), and poor differentiation (19.6% vs 2.0%, P < .001). Survival analysis showed better survival in the MSI-H group, but the difference was not statistically significant (P = .126). Propensity score matching was performed for significant prognostic factors identified by Cox hazard regression. After the matching, the survival difference by MSI status was estimated to be larger than before, and reached statistical significance (P = .045). In conclusion, after controlling for pathological characteristics, MSI-H could be a potent prognostic factor regarding patient survival. PMID- 29489647 TI - Risk factors and community intervention for nonalcoholic fatty liver disease in community residents of Urumqi, China. AB - This study is to investigate the prevalence and risk factors of nonalcoholic fatty liver disease (NAFLD) and to analyze the effect of comprehensive community intervention on NAFLD in community residents in Urumqi, China.Cluster sampling method with street community as a unit was adopted in this study. Questionnaire survey, body measurement, blood biochemistry (including liver function, fasting blood glucose [FPG], and uric acid [UA]) examination as well as liver B ultrasound were performed. Then, comprehensive intervention was conducted in NAFLD patients.A total of 1000 people were enrolled, including 344 men and 656 women, with an average age of 51.79 +/- 4.28 years. Of them, 660 were Han Chinese, 327 were Uygur, and 13 were Hui. The overall prevalence rate of NAFLD was 54.3%. The prevalence rate of NAFLD is higher in middle-aged population and is higher in ethnic minority than that in Han. NAFLD was associated with the past medical history of metabolic diseases. The factors of body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), waist circumference, hip circumference, neck circumference, subcutaneous fat thickness, FPG, alanine aminotransferase, and aspartate aminotransferase were identified as risk factors for NFALD. Neck circumference predicts the occurrence of NAFLD in female better, whereas subcutaneous fat predicts the occurrence of NAFLD in male better. After 8 months of community intervention in NAFLD patients, the changes of BMI, SBP, DBP, waist circumference, neck circumference, subcutaneous fat thickness, and UA were statistically significant (P < .05).The prevalence rate of NAFLD is high in Urumqi, China. Community intervention is effective in reducing the degree of NAFLD and promoting the overall health of NAFLD patients. PMID- 29489648 TI - Correlation analysis between work-related musculoskeletal disorders and the nursing practice environment, quality of life, and social support in the nursing professionals. AB - We aim to analyze the correlated influential factors between work-related musculoskeletal disorders (WMSDs) and nursing practice environment and quality of life and social support.From January 2015 to October 2015, cluster sampling was performed on the nurses from 12 hospitals in the 6 areas in Xinjiang. The questionnaires including the modified Nordic Musculoskeletal Questionnaire, Practice Environment Scale (PES), the Mos 36-item Short Form Health Survey, and Social Support Rating Scale were used to investigate. Multivariate logistic regression analysis was used to explore the influential factors of WMSDs.The total prevalence of WMSDs was 79.52% in the nurses ever since the working occupation, which was mainly involved waist (64.83%), neck (61.83%), and shoulder (52.36%). Multivariate logistic regression analysis indicated age (>=26 years), working in the Department of Surgery, Department of Critical Care, Outpatient Department, and Department of Anesthesia, working duration of >40 hours per week were the risk factors of WMSDs in the nurses. The physiological function (PF), body pain, total healthy condition, adequate working force and financial support, and social support were the protective factors of WMSDs.The prevalence of WMSDs in the nurses in Xinjiang Autonomous Region was high. PF, bodily pain, total healthy condition, having adequate staff and support resources to provide quality patient care, and social support were the protective factors of WMSDs in the nurses. PMID- 29489649 TI - Fingernail selenium levels in relation to the risk of obesity in Chinese children: A cross-sectional study. AB - Selenium (Se) has been suggested to be beneficial to obesity development. However, limited studies have evaluated the association between Se and childhood obesity and the findings are inconsistent.The aim of this study was to examine the association of Se levels with obesity in children in a cross-sectional study.A total of 62 obese (21 girls) and 65 normal-weight children (27 girls) aged 7 to 13 years were recruited in Shanghai, China. Obesity was defined as body mass index (BMI) >= its 95th age- and sex-specific percentile for children. Participant demographic data and parental information were obtained through a self-administered questionnaire. Se concentration in fingernail clippings was quantified using flame atomic absorption spectrophotometry.The average age was 10.9 years (standard deviation = 1.0) and the mean BMI was 21.2 kg/m (standard deviation = 5.0). Fingernail Se levels were relatively higher among normal-weight children as compared with obese participants, though the difference was not statistically significant (P = .79). Se levels were inversely associated with the risk of childhood obesity after adjustment for potential confounders. The multivariable-adjusted odds ratio (95% confidence interval) was 0.24 (0.07-0.84) comparing participants in the highest with those who in the lowest tertile of Se levels (Plinear-trend = .03).Our study supported an inverse association between fingernail Se levels and the risk of obesity in Chinese children. Data generated from the present study are useful for designing future prospective cohort studies and/or randomized clinical trials. PMID- 29489650 TI - Diagnosis and treatment of chronic lateral ankle instability with ligamentum bifurcatum injury: An observational study. AB - This study aimed to report our institution's experience in the diagnosis and treatment of chronic lateral ankle instability (CLAI) with ligamentum bifurcatum (LB) injury.This retrospective study included 218 consecutive patients with CLAI who underwent surgery from January 2012 to December 2015. The 218 patients received tendon allograft reconstruction of the lateral ligament. CLAI was combined with LB injury in 51.4% (112/218) of patients. The 112 patients with concurrent LB injury had this treated simultaneously; 36 patients underwent excision of the anterior process of the calcaneus, 68 underwent LB repair, and 8 underwent LB reconstruction. Patients returned for a clinical and radiologic follow-up evaluation at an average of 31 (range, 24-35) months postoperatively. Outcomes were assessed by comparison of pre- and postoperative American Orthopaedic Foot and Ankle Society (AOFAS) scores, visual analog scale pain scores, Karlsson scores, and radiographic assessment.Of the patients with concurrent LB injury, 82.1% (92/112) returned for final evaluation. Postoperatively, most patients recovered very well. However, the outcome was not ideal in those who underwent excision of the anterior process of the calcaneus; there were significant postoperative decreases in talar tilt (P < .05) and anterior drawer (P < .05), but there was no significant postoperative improvement in visual analog scale pain score and AOFAS score. Patients who underwent LB repair or reconstruction had an excellent or good outcome regarding patient subjective self-assessment, pain scores, Karlsson scores, and AOFAS scores at final follow-up.Patients with CLAI often have concurrent LB injury. The diagnosis of LB injury can be missed or delayed. Clinicians should closely examine the LB in cases of CLAI, and should surgically repair or reconstruct the LB when necessary. PMID- 29489651 TI - Hyperbaric oxygen treatment for Parkinson's disease with severe depression and anxiety: A case report. AB - RATIONALE: Patients with Parkinson's disease (PD) frequently suffer from psychiatric disorders, and treating these symptom whereas managing the motor symptoms associated with PD can be a therapeutic challenge. PATIENT CONCERNS: We report a case of PD patient with severe depression and anxiety that refused to be treated with dopaminagonists or SSRIs, the most common treatments for PD patients suffering from psychiatric symptoms. DIAGNOSES: Parkinson's disease with severe depression and anxiety. INTERVENTIONS: This man was treated with hyperbaric oxygen treatment for 30 days. OUTCOMES: Clinical assessment scores for depression and anxiety, including Unified Parkinson's Disease Rating ScaleI (UPDRS I), UPDRS II, Hanmilton Depression Rating Scale, and Hamiliton Anxiety Rating Scale, were improved following the hyperbaric oxygen treatment. LESSONS: Hyperbaric oxygen treatment may be a potential therapeutic method for PD patient suffering from depression and anxiety. Further research is needed to validate this finding and explore a potential mechanism. PMID- 29489652 TI - Physical and nutrition statuses of geriatric patients after trauma-related hospitalization: Data from the Korean National Health and Nutrition Examination Survey 2013-2015. AB - Population aging is associated with increasing numbers of geriatric trauma patients, and various studies have evaluated their short-term outcomes, assessment, and treatment. However, there is insufficient information regarding their long-term outcomes. This study evaluated the physical and nutritional statuses of geriatric patients after trauma-related hospitalization.Data regarding physical and nutritional status were obtained from the Korean National Health and Nutrition Examination Survey VI (2013-2015).A total of 21,069 individuals participated in the survey, including 5650 geriatric individuals. After excluding individuals with missing data, 3731 cases were included in the analyses. The average age was 68 years, and most individuals were women (n = 2055, 55.08%). There were 94 patients had been hospitalized because of trauma. Trauma-related hospitalization among geriatric patients was significantly associated with reduced strength exercise (23.56% vs 12.99%, P = .043), activity limitations caused by joint pain (0.65% vs 3.31%, P = .028), self-care problems (8.00% vs 16.77%, P = .008), pain or discomfort (29.48% vs 40.51%, P = .024), hypercholesterolemia (27.37% vs 39.36%, P = .037), and mastication discomfort (39.98% vs 57.85% P = .005). The adjusted analyses revealed that trauma-related hospitalization was independently associated with activity limitations caused by joint pain (odds ratio [OR]: 5.04, 95% confidence interval [CI]: 1.29-19.67, P = .020), self-care problems (OR: 2.24, 95% CI: 1.11-4.53, P = .025), pain or discomfort (OR: 1.77, 95% CI: 1.08-2.89, P = .023), and mastication discomfort (OR: 2.06, 95% CI: 1.22-3.46, P = .007).Medical staff should be aware that geriatric patients have relatively poor physical and nutritional statuses after trauma-related hospitalization, and manage these patients accordingly. PMID- 29489653 TI - Effect of hypoglycemic agents on survival outcomes of lung cancer patients with diabetes mellitus: A meta-analysis. AB - BACKGROUND: To assess the association between hypoglycemic agents and prognosis of lung cancer patients with diabetes. METHODS: A comprehensive literature search was performed in PubMed, Web of Science, Embase, and Cochrane Library until May 2017. The search yielded 2593 unique citations, of which 18 articles met inclusion criteria. The hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated by a fixed-effects or random-effects model. RESULTS: The pooled HRs favoring metformin users were 0.77 for overall survival (OS) (n = 15, 95% CI: 0.68-0.86) and 0.50 for disease-free survival (n = 5, 95% CI: 0.39-0.64). One study assessed the relationship between metformin and cancer-specific survival (CSS), reporting no significant results. No significant association between insulin and OS (n = 2, HR: 0.95, 95% CI: 0.79-1.13) or CSS (n = 2, HR: 1.03, 95% CI: 0.76-1.41) was noted. One study evaluated association of sulfonylureas with lung cancer survival and reported no clinical benefit (HR: 1.10, 95% CI: 0.87-1.40). One study reported no association of thiazolidinediones with lung cancer survival (HR: 1.04, 95% CI: 0.65-1.66). CONCLUSIONS: This meta analysis demonstrated that metformin exposure might improve survival outcomes in lung cancer patients with diabetes. PMID- 29489654 TI - Vulvar cancer in Ethiopia: A cohort study on the characteristics and survival of 86 patients. AB - Vulvar cancer (VC) is strongly associated with human papilloma virus (HPV) infections and immunosuppression (e.g., HIV). However, there is limited information on VC patient characteristics and survival in parts of sub-Saharan Africa, including Ethiopia, where chronic HPV and HIV infections are prevalent. The aim of this study is to provide a first view on VC patient characteristics in a sub-Saharan African setting.We present a retrospective analysis of records of 86 VC patients diagnosed between January 2010 and October 2015 at Addis Ababa University Hospital and other major health facilities in Ethiopia. Follow-up for vital status was obtained by telephone contact with patients or relatives. The primary endpoint was all-cause mortality.The median age of the patients was 39 (range: 20-85) years, 83% with known HIV status were positive and 81% presented with FIGO stages 2 or 3. The median follow-up time for surviving patients was 17 months (range: 0.1-65.0 months). The 1- and 2-year survival rates were 80% and 51%, respectively. Approximately 37% of patients received surgery, 38% received radiotherapy, and 33% received chemotherapy. Patients who received therapy had better survival than those who did not [adjusted hazard ratios: surgery, 0.44 (95% CI, 0.19-1.03); radiotherapy, 0.36 (95% CI, 0.14-0.90); chemotherapy, 0.42 (95% CI, 0.15-1.12)].A substantial proportion of VC patients in Ethiopia present at a late stage and receive suboptimal treatment. HIV infections appear to be a common comorbid condition. These conditions result in poor outcomes. PMID- 29489657 TI - Agenesis of the dorsal pancreas: a rare cause of insulin-dependent diabetes without abdominal pain: Case report. AB - RATIONALE: Agenesis of the dorsal pancreas is a very rare condition with an unknown pathology and etiology, although it may be associated with autosomal dominant or X-linked dominant inheritance or retinoic acid and hedgehog signaling pathway alterations. This condition usually manifests with abdominal pain or pancreatitis, although some cases are asymptomatic. Approximately 50% of affected patients with this disorder present with hyperglycemia or various other anomalies. PATIENT CONCERNS: We report the case of a 23-year-old Chinese woman who visited the Department of Endocrinology and Metabolism with insulin-dependent diabetes but no specific symptoms, signs, or other deformities. Severe diabetic retinopathy indicated a long period of hyperglycemia. DIAGNOSIS: Agenesis of the dorsal pancreas was observed incidentally during the common diagnosis of diabetes, and the diagnosis was established using magnetic resonance imaging, diffusion-weighted imaging, and magnetic resonance cholangiopancreatography. INTERVENTIONS: Following the diagnosis of diabetes, insulin replacement therapy was initiated at a dosage of up to 45 U per day. The patient's blood glucose level was monitored, and the insulin dosage was adjusted accordingly. OUTCOMES: The patient's blood glucose levels gradually normalized after insulin treatment and were subsequently maintained with intensive insulin therapy. Treatment for diabetic retinopathy was provided by the Ophthalmology Department. LESSONS: Agenesis of the dorsal pancreas should be considered in a young patient diagnosed with diabetes who presents with obvious diabetes-related complications (e.g., renal, retinal, or neurological) inconsistent with the course of the disease or a history of other congenital anomalies. We recommend the routine use of computed tomography or magnetic resonance imaging when examining young patients with diabetes. PMID- 29489655 TI - Genome-wide association study of maternal genetic effects and parent-of-origin effects on food allergy. AB - Previous genetic studies of food allergy (FA) have mainly focused on inherited genotypic effects. The role of parental genotypic effects remains largely unexplored. Leveraging existing genome-wide association study (GWAS) data generated from the Chicago Food Allergy Study, we examined maternal genotypic and parent-of-origin (PO) effects using multinomial likelihood ratio tests in 588 complete and incomplete Caucasian FA trios. We identified 1 single nucleotide polymorphism with significant (P < 5*10) maternal effect on any FA (rs4235235), which is located in a noncoding RNA (LOC101927947) with unknown function. We also identified 3 suggestive (P < 5*10) loci with maternal genetic effects: 1 for any FA (rs976078, in a gene desert region on 13q31.1) and 2 for egg allergy (rs1343795 and rs4572450, in the ZNF652 gene, where genetic variants have been associated with atopic dermatitis). Three suggestive loci with PO effect were observed: 1 for peanut allergy (rs4896888 in the ADGB gene) and 2 for any FA in boys only (rs1036504 and rs2917750 in the IQCE gene). Findings from this family based GWAS of FA provided some preliminary evidence on maternal genotypic or PO effects on FA. Additional family-based studies are needed to confirm our findings and gain new insight into maternal and paternal genetic contribution to FA. PMID- 29489656 TI - The impact of early enteral nutrition on pediatric patients undergoing gastrointestinal anastomosis a propensity score matching analysis. AB - This study was conducted to assess the clinical advantages of early enteral nutrition (EEN) in pediatric patients who underwent surgery with gastrointestinal (GI) anastomosis.EEN has been associated with clinical benefits in various aspect of surgical intervention, including GI function recovery and postoperative complications reduction. Evaluable data documenting clinical advantages with EEN for pediatric patients after surgery with GI anastomosis are limited.We retrospectively reviewed the medical records of 575 pediatric patients undergoing surgical intervention with GI anastomosis. Among them, 278 cases were managed with EEN and the remaining cases were set as late enteral nutrition (LEN) group. Propensity score (PS) matching was conducted to adjust biases in patient selection. Enteral feeding related complications were evaluated with symptoms, including serum electrolyte abnormalities, abdominal distention, abdominal cramps, and diarrhea. Clinical outcomes, including GI function recovery, postoperative complications, length of hospital stay, and postoperative follow up, were assessed according to EEN or LEN.Following PS matching, the baseline variables of the 2 groups were more comparable. There were no differences in the incidence of enteral feeding-related complications. EEN was associated with postoperative GI function recovery, including time to first defecation (3.1 +/- 1.4 days for EEN vs 3.8 +/- 1.0 days for LEN, risk ratio [RR], 0.62; 95% confidence interval [CI] 0.43-1.08, P = .042). A lower total episodes of complication, including infectious complications and major complications were noted in patients with EEN than in patients with LEN (117 [45.9%] vs 137 [53.7%]; OR, 0.73, 95% CI 0.52-1.03, P = .046). Mean postoperative length of stay in the EEN group was 7.4 +/- 1.8 days versus 9.2 +/- 1.4 days in the LEN group (P = .007). Furthermore, the incidence of adhesive small bowel obstruction was lower for patients with laxative administration compared with control, but no significant difference was attained (P = .092)EEN was safe and associated with clinical benefits, including shorten hospital stay, and reduced overall postoperative complications on pediatric patients undergoing GI anastomosis. PMID- 29489658 TI - Positron emission tomography/computed tomography scan of Vogt-Koyanagi-Harada syndrome with associated autoimmune thyroid disease: A case report and literature review. AB - RATIONALE: Vogt-Koyanagi-Harada (VKH) syndrome is a rare disease and could be associated with autoimmune thyroid disease (AITD). This report was aimed to investigate the utility of F-fludeoxyglucose positron emission tomography/computed tomography (F-FDG PET/CT) for the diagnosis of VKH syndrome with AITD and to perform a literature review on the association between the 2 diseases. PATIENT CONCERNS: A 55-year-old woman without the history of ocular trauma suffered from chronic headache. She was presented with painful blurred vision of both eyes with headache for 2 weeks. Ophthalmic evaluations revealed panuveitis, exudative retinal detachment, and papilloedema in both eyes. The clinical symptoms and presentations are compatible with the diagnosis of VKH syndrome. Other examinations for intraocular infection, malignancy, and lupus choroidopathy were of negative results. The result of contrast-enhanced computed tomography (CT) of the brain was normal. Due to the history of cancer in the patient's families, a F-FDG PET/CT whole-body scan was performed. The result indicated a focal of 2-fluoro-2-deoxy-D-glucose (FDG) uptake at the right upper lobe of the thyroid. Therefore, the patient's thyroid function was examined and the result indicated euthyroidism with detectable thyroid peroxidase/thyroglobulin antibodies. DIAGNOSES: VKH syndrome with associated AITD. INTERVENTIONS: Treatment with intravenous pulse systemic methylprednisolone (1000 mg daily) was prescribed for 3 days and then shifted gradually to tapered oral steroid medication. OUTCOMES: Symptoms of papillitis and serous retinal detachment of VKH syndrome was relieved after steroid treatment LESSONS:: F fludeoxyglucose positron emission tomography/computed tomography (F-FDG PET/CT) can be used for the effective diagnosis of VKH syndrome with AITD. PMID- 29489659 TI - An innovative method for placing a double-lumen irrigation-suction tube in the management of abdominal infection: A case report. AB - RATIONALE: Currently, the use of double-lumen irrigation-suction tube for drainage has become increasingly more common. However, the insertion process is complex, and the position of the double cannula placed in this manner is not accurate. We developed a method for placing the drainage tube and use it in the treatment of an abdominal infection. PATIENT CONCERNS: A 51-year-old man with an abdominal infection due to colonic anastomotic fistula was admitted. Routine laboratory tests revealed an elevated white blood cell count (17 * 10/L) and C reactive protein level (78 mg/L). Computed tomography (CT) revealed that the peritoneal cavity was filled with fluid. DIAGNOSES: The patient was diagnosed with colonic anastomosis fistula by gastrointestinal radiography. Abdominal infection was diagnosed based on CT scan, inflammatory markers, and patient signs and symptoms. INTERVENTIONS: Two punctures were performed. After skin expansion, the source of infection was drained with a suction catheter (diameter = 1.0 cm) under continuous negative pressure of 150 to 200 millibars, along with continuous saline irrigation at 300 mL/h. OUTCOMES: Pus in the abdomen drained completely. The abdominal infection was controlled. There were no adverse events. LESSONS: Abdominal infection in fistulas is a fatal disease. The main therapeutic target is full drainage at an early stage. Precise positioning of the tube, continuous negative pressure irrigation and drainage are key points in the treatment. PMID- 29489660 TI - Primary pulmonary myoepithelial carcinoma in a young woman: A case report and review of literature. AB - RATIONALE: Myoepithelial carcinoma mainly occurs in the salivary glands, but myoepithelial carcinoma of the lung is extremely rare neoplasm whose biological behavior and clinical course still remain to be fully elucidated. Although considered as low-grade carcinoma, these tumors have a high rate of recurrence or distant metastasis. PATIENT CONCERNS: To date there are only 11 cases of pulmonary myoepithelial carcinoma reported in the English literature. We report a case of a 24-year-old woman diagnosed with primary pulmonary myoepithelial carcinoma. Informed consent was obtained from the patient. DIAGNOSES: The tumor derived from superior lobe of left lung and exhibited only myoepithelial differentiation without any ductal formation by histopathological and immunohistochemical analysis. INTERVENTIONS: The patient underwent the left superior lobe resection. In addition, we first introduce second-generation sequencing technology as a novel strategy for primary pulmonary myoepithelial carcinoma, and these tumors should be included in the differential diagnosis of thoracic neoplasms. OUTCOMES: The patient was alive with no evidence of disease for up to 12 months. LESSONS: Individualized treatment is the promising clinical strategy for thoracic neoplasms, and the underlying molecular events should be investigated to find the potential therapeutic targets. PMID- 29489661 TI - Complete fracture-dislocation of the thoracolumbar spine without neurological deficit: A case report and review of the literature. AB - RATIONALE: Traumatic fracture of the thoracolumbar junction (T10-L2) is the most common fracture of the spinal column. Due to the disruption of the entire vertebrae column, the fracture-dislocation of the thoracolumbar spine is almost invariably associated with neurological injury. A complete fracture-dislocation of the thoracolumbar spine without neurological deficit is a rare entity. PATIENT CONCERNS: A 38-year-old man presented with severe low back pain after an accident when he was building a house. Comprehensive neurological examinations revealed intact neurological function. DIAGNOSES: The plain X-ray and computed tomography revealed a complete facture-dislocation of the L1 to L2 vertebrae. INTERVENTIONS: The patient underwent posterior reduction and internal fixation with screws and rods. OUTCOMES: The neurological function was preserved postoperatively. The patient returned to work after 6 months. LESSONS: Early diagnosis is important before performing any dangerous maneuvers. Given the results of this case and the relevant literature, the prognosis of these patients is promising following surgical intervention. PMID- 29489662 TI - Motor development delay in offspring is associated with prenatal telbivudine exposure. AB - Telbivudine is an orally nucleoside analog with potent and specific antihepatitis B virus (HBV) activity, and it has been reported to block mother-to-infant transmission. However, few studies have focused on the safety of prenatal exposure for offspring development.This is a prospective noninterventional study. Participants were enrolled during delivery through the Women's Hospital of Zhejiang University School of Medicine between January 2012 and September 2013. Neonate's umbilical cord arterial blood (UCAB) was collected after delivery. Hepatitis B virus DNA copy, HBV serology, alanine aminotransferase (ALT), creatine kinase (CK), creatinine (CRE), and blood urea nitrogen (BUN) were measured. The development of the offspring was evaluated by the Chinese Revision of Bayley Scales of Child Development (BSCD-CR) at 12 to 24 months old.Around 30 and 31 chronic hepatitis B mothers were recruited in untreated group (non-LdT group) and telbivudine-treatment group (LdT group), respectively, and 2 children (one in non-LdT group and 1 in LdT group) were lost in follow-up. Sixty-one normal women and their children were recruited as a normal control (control group). Compared with non-LdT group, telbivudine treatment effectively blocks HBV transmission from mother to infant. However, CK in UCAB was significantly increased in the LdT group. Moreover, children with prenatal telbivudine exposure showed lower level of serum creatinine than non-LdT group, reduction of psychomotor developmental index and increased risk of motor development delay.Prenatal telbivudine exposure is correlated with motor development delay in offspring. PMID- 29489663 TI - MRI and CT contrast media extravasation: A systematic review. AB - BACKGROUND: This systematic review combines data from multiple papers on contrast media extravasation to identify factors contributing to increased extravasation risk. METHODS: Data were extracted from 17 papers reporting 2191 extravasations in 1,104,872 patients (0.2%) undergoing computed tomography (CT) or magnetic resonance imaging (MRI). RESULTS: Extravasation rates were 0.045% for gadolinium based contrast agents (GBCA) and nearly 6-fold higher, 0.26% for iodinated contrast agents. Factors associated with increased contrast media extravasations included: older age, female gender, using an existing intravenous (IV) instead of placing a new IV in radiology, in-patient status, use of automated power injection, high injection rates, catheter location, and failing to warm up the more viscous contrast media to body temperature. CONCLUSION: Contrast media extravasation is infrequent but nearly 6 times less frequent with GBCA for MRI compared with iodinated contrast used in CT. PMID- 29489664 TI - Risk factors for severe bronchiolitis caused by respiratory virus infections among Mexican children in an emergency department. AB - Severe bronchiolitis is the most common reason for hospitalization among children younger than 2 years. This study analyzed the prevalence of community-acquired respiratory virus infection and the risk factors for hospitalization of Mexican children with severe bronchiolitis treated in an Emergency department.This retrospective study included 134 children 2 years or younger with severe viral bronchiolitis, and 134 healthy age-matched controls. The study period was September 2012 to January 2015. We determined the viral etiology and coinfections with multiple viruses and compared the risk factors detected in children with severe viral bronchiolitis with those in the control group.A total of 153 respiratory viruses in these 134 patients, single or mixed infections, were identified: respiratory syncytial virus (RSV) type A or B was the most frequently detected (23.6% and 17.6%, respectively), followed by rhinovirus (RV; 16.3%) and parainfluenza virus (PIV) type 3 (12.4%). Coinfections of 2 respiratory viruses were found in 14.2% of cases; all cases had either RSV type A or B with another virus, the most common being parainfluenza virus or rhinovirus. Exposure to cigarette smoking was independently associated with hospitalization for severe bronchiolitis (OR, 3.5; 95% CI, 1.99-6.18; P = .0001), and having completed the vaccination schedule for their age was a protective factor against adverse outcome (OR, 0.55; 95% CI, 0.35-0.87; P = .010).RSV is a common infection among young children with severe bronchiolitis; thus, developing a vaccine against RSV is essential. Campaigns to reinforce the importance of avoiding childhood exposure to cigarette smoke are also needed. PMID- 29489665 TI - Real-time PCR assays for diagnosing brucellar spondylitis using formalin-fixed paraffin-embedded tissues. AB - It is difficult to diagnose brucellar spondylitis because of its nonspecific clinical, radiological, and histological characteristics. This study aimed to determine whether real-time polymerase chain reaction (PCR) using formalin-fixed paraffin-embedded (FFPE) tissues was superior to conventional serum-based methods for diagnosing brucellar spondylitis.This retrospective study included 31 patients with brucellosis and a control group of 20 people with no history of brucellosis or exposure to Brucella spp. Samples from all patients with brucellar spondylitis were evaluated using Giemsa staining, the standard tube agglutination (STA) test, blood culture, and real-time PCR.The brucellar spondylitis was acute in 7 patients (22.6%), subacute in 15 patients (48.4%), and chronic in 9 patients (29%). Serological assays provided positive results for 25 patients (80.1%), real time PCR provided positive results for 29 patients (93.5%), and blood cultures provided positive results for 11 patients (35.5%). The real-time PCR provided sensitivity of 93.5%, specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 100%. The corresponding values for the STA test were 80.1%, 100%, 100%, and 76.9%, respectively. Real-time PCR provided better sensitivity than Giemsa staining, the STA test, and blood culture, although the difference between PCR and STA was not statistically significant (P = .22). B melitensis was the only pathogen that was detected in patient with brucellar spondylitis using real-time PCR.These results suggest that real-time PCR provides a high sensitivity for diagnosing brucellar spondylitis. Furthermore, the real-time PCR results indicate that B melitensis was the causative pathogen in these cases. PMID- 29489666 TI - Comparison of the short-term outcomes between delta-shaped anastomosis and conventional Billroth I anastomosis after laparoscopic distal gastrectomy: A meta analysis. AB - BACKGROUND: The conventional Billroth I anastomosis (cBIA) after laparoscopic distal gastrectomy (LDG) is performed through circular staple extracorporeally. Now, delta-shaped anastomosis (DA), which is performed using a linear stapler intracorporeally, becomes popular. We conducted a meta-analysis to compare the effectiveness and safety between the 2 techniques. METHODS: A systematic literature search was performed using PubMed, Ovid, and the Cochrane Library Central. Participants of any age and sex, who underwent DA, or cBIA after LDG, were considered following inclusion criteria. RESULTS: A total of 11 articles, published between 2010 and 2017, fulfilled the selection criteria. The total sample size of these studies was 2729 cases, including DA group 1008 cases and cBIA group 1721 cases. Compared to cBIA group, patients in DA group had less blood loss (mean deviation [MD] = -0.68, 95% confidence interval [CI] = -0.15 to 0.31, P < .001), fewer administration of analgesics (MD = -0.82, 95% CI = -1.58 to -0.05, P = .04), lower NRS score on POD 1 (MD = -0.84, 95% CI = -1.34 to 0.33, P = .001), lower NRS score on POD 3 (MD = -0.38, 95% CI = -0.50 to -0.26, P < .001). Furthermore, compared to cBIA group, obese patients in DA group had fewer total number of complications (MD = 0.46, 95% CI = 0.22 to 0.95, P = .04), shorter postoperative hospital stays (MD = -0.73, 95% CI = -1.18 to -0.28, P = .001), earlier first flatus (MD = -0.30, 95% CI = -0.50 to -0.10, P = .004), fewer administration of analgesics (MD = -1.08, 95% CI = -1.61 to -0.55, P < .001), lower NRS score on POD 1 (MD = -0.68, 95% CI = -0.99 to -0.37, P < .001) and lower NRS score on POD 3 (MD = -0.63, 95% CI = -0.86 to -0.40, P < .001). CONCLUSIONS: Compared with cBIA, DA is a safe and feasible procedure, with similar surgical outcomes and postoperative complications. In terms of postoperative recovery, DA is less invasive with quicker resume than cBIA, especially for the obese patients. PMID- 29489667 TI - Predictors of mortality in ST-elevation MI patients: A prospective study. AB - We aimed to define factors predicting mortality in patients having ST elevation myocardial infarction (STEMI) who had Primary Percutaneous Coronary Intervention (PCI) in our setting.This is a prospective study on patients presenting to the emergency department with STEMI who underwent PCI during a 12-month period. Physiological parameters were calculated using the vital signs and age of patients. Time-based factors in the institutional protocol were collected. Univariate analysis was performed to define significant factors that affected mortality. Significant factors were then entered into a logistic regression model. Factors significantly affecting mortality were defined. Receiving operating characteristic curve was applied to define the best predictors of mortality.A total of 167 consecutive patients were studied; 128 (76.6%) were males. The mean (SD) age of the patients was 61.9 (12.8) years. The logistic regression model showed that significant factors were age (P = .002), Modified Shock Index, MSI (P = .028), systolic blood pressure (P = .028), and time between consultation and activation of catheter laboratory (P = .047). The cut-off points with best prediction of mortality were age of 71.5 years, systolic blood pressure of less than 95 mmHg, MSI of 0.85, and a time more than 3.5 minutes between consultation and activation of catheter laboratory.Our study shows that significant predictors of 30-days mortality of STEMI were age, systolic blood pressure on presentation, MSI, and the time between consultation and catheter laboratory activation. Improving prehospital resuscitation and activation of the catheter laboratory by emergency physicians may reduce mortality in our setting. PMID- 29489668 TI - Extracranial vertebral artery dissection: Findings and advantages of ultrasonography. AB - Vertebral artery dissection (VAD) is not uncommon in the young adult population. Owing to the various clinical manifestations; the diagnosis of VAD mainly depends on imaging examinations. Ultrasound has found an increasingly wide utilization in the diagnosis of VAD because of the continuous improvement in the resolution of ultrasonic instruments and accessibility.We retrospectively collected the data of patients with a US-proven extracranial vertebral artery dissection. In accordance with the sonographic findings, all patients were classified as having intramural hematoma, double-lumen dissection, and occlusion dissection. The patients' age, sex, risk factors for cerebrovascular diseases, and sonographic characteristics were analyzed.A total of 37 cases of US-proven extracranial vertebral artery dissections were included in this study. Thirty patients presented with intramural hematoma dissection, 1 had double-lumen dissection and 6 had occlusion dissection. No dissecting aneurysm was found in any of the patients. Concerning a subsequent angiographic examination, 13 patients failed to undergo the examination for various reasons. The remaining 24 patients underwent digital subtraction angiography (DSA), magnetic resonance angiography (MRA), and computerized tomographic angiography (CTA), among whom 1 patient with intramural hematoma was underdiagnosed because the DSA result was interpreted as normal. One patient who underwent CTA had a contrast allergy. In the remaining patients, the results of other imaging examinations were consistent with the US results.Intramural hematoma dissection is the most common type of extracranial vertebral artery dissection. Over other angiographic examinations US has a big diagnostic advantage for its direct view, accuracy, and low cost. PMID- 29489669 TI - Effects of problem-based learning in Chinese radiology education: A systematic review and meta-analysis. AB - BACKGROUND: In recent years, the problem-based learning (PBL) teaching method has been extensively applied as an experimental educational method in Chinese radiology education. However, the results of individual studies were inconsistent and inconclusive. A meta-analysis was performed to evaluate the effects of PBL on radiology education in China. METHODS: Databases of Chinese and English languages were searched from inception up to November 2017. The standard mean difference (SMD) with its 95% confidence interval (95% CI) was used to determine the over effects of PBL compared with the traditional teaching method. RESULTS: Seventeen studies involving 1487 participants were included in this meta-analysis. Of them, 16 studies provided sufficient data for the pooled analysis and showed that PBL teaching method had a positive effect on achieving higher theoretical scores compared with the traditional teaching method (SMD = 1.20, 95% CI [0.68, 1.71]). Thirteen studies provided sufficient data on skill scores, and a significant difference in favor of PBL was also observed (SMD = 2.10, 95% CI [1.38, 2.83]). Questionnaire surveys were applied in most of the included studies and indicated positive effects of PBL on students' learning interest, scope of knowledge, team spirit, and oral expression. CONCLUSION: The result shows that PBL appears to be more effective on radiology education than traditional teaching method in China. However, the heterogeneity of the included studies cannot be neglected. Further well-designed studies about this topic are needed to confirm the above findings. PMID- 29489671 TI - Assessment of liver fibrosis in Egyptian chronic hepatitis B patients: A comparative study including 5 noninvasive indexes: Erratum. PMID- 29489670 TI - Body mass index and the risk of low femoral artery puncture in coronary angiography under fluoroscopy guidance. AB - The inferior border of the femoral head (IBFH) is widely used as a landmark in femoral artery puncture during invasive coronary angiography (ICA). However, application of this technique can be challenging especially in obese patients. This study was performed to investigate the association between body mass index (BMI) and the risk of low puncture in femoral artery puncture.A total of 464 patients (64.8 +/- 11.1 years, 55.8% male) who underwent ICA via trans-femoral access were retrospectively reviewed. IBFH was used as a landmark for a skin nick and the femoral artery cannulation site was confirmed by femoral angiography. Cannulation at the bifurcation of the common femoral artery (CFA) or below were considered low puncture.Twenty-nine patients (5.8%) were identified as having an angiographically high CFA bifurcation and low femoral artery puncture occurred in 27 (93.1%) patients of them. Among patients with normal bifurcation (n = 464), low puncture occurred in 74 (15.9%) patients. Underweight (BMI < 18.5 kg/m) or obese (BMI >= 30 kg/m) patients were more common in the low puncture group than in the proper puncture group (36.5% vs. 5.9%, P < .001). Multivariable analysis showed underweight or obesity (odd ratio, 9.10; 95% confidential interval, 4.77 17.35; P < .001) was an independent risk factor of low puncture even after controlling for clinical covariates. The average distance from IBFH to the CFA puncture site was shorter in patients with underweight (1.74 +/- 0.71 cm) or obesity (1.75 +/- 0.60 cm) than in those with normal BMI or overweight (2.07 +/- 0.83 cm) (P = .030). Trigonometric calculation showed that the average distance from IBFH to the CFA puncture site was 0.5 to 2.59 cm (mean = 1.32 cm) shorter in underweight patients compared with those of normal weight or overweight patients.In patients with normal CFA bifurcation, underweight or obesity were associated with increased risk of low puncture. The puncture site should be chosen about 1 finger width more proximal to IBFH for ICA in such patients. PMID- 29489672 TI - The clinical and laboratory features of neurosyphilis in HIV-infected patients: A retrospective study in 92 patients. AB - Neurosyphilis (NS) is an important component of central nervous system diseases among HIV-infected patients. However, its characteristics are not very clear. A retrospective analysis of clinical and laboratory findings was performed in 92 NS patients with HIV infection from a tertiary hospital in Shanghai, China. The patients had a median age of 38 years and a median CD4 count of 198 cells/MUL. In all, 44.6% (41/92) were diagnosed as asymptomatic NS (ANS), 23.9% (22/92) as syphilitic meningitis, 17.4% (16/92) as cerebrovascular NS, and 14.1% (13/92) as parenchymal syphilis. A quarter of patients (23/92) complicated with ocular syphilis (OS), 60.9% (14/23) of which were ANS. The serum tolulized red unheated serum test (TRUST) titers were <=1:8 in 15 patients (16.3%), 1:16-1:128 in 51 patients (55.4%), and >=1:256 in 26 patients (28.3%). Sixty-nine patients (75.0%) had both cerebrospinal fluid (CSF) TRUST and Treponema pallidum particle assay reactive. CSF pleocytosis and protein elevation were found in 58.7% and 53.3% of patients, respectively. Syphilitic meningitis was more likely to present with CSF pleocytosis than ANS (P = .001), cerebrovascular NS (P < .001), and parenchymal NS (P < .001). The proportion of patients with CSF elevated protein was lower in ANS group than that in syphilitic meningitis (P = .003), cerebrovascular NS (P = .001), and parenchymal NS groups (P = .025), and was higher in sero-TRUST titers <=1:8 group than that in 1:16-1:128 (P = .01) and 1:256-1:1024 groups (P = .005).This study revealed that ANS was the most common clinical type of NS in HIV infected patients, which should be considered in HIV and syphilis co-infection patients without neurologic symptoms, especially in those with OS. Different patterns of NS might have different CSF features which may also vary with sero TRUST titers. PMID- 29489673 TI - Ultrasonographic features and clinicopathologic characteristics of macrofollicular variant papillary thyroid carcinoma. AB - Macrofollicular variant papillary thyroid carcinoma (MFV-PTC) is defined as papillary thyroid carcinoma with macrofollicles of >200 MUm in more than 50% of the cross-sectional area of the specimen. The aim of this study was to evaluate the clinicopathologic characteristics of the MFV-PTC treated in the Yonsei University College of Medicine.Between September 2007 and July 2012, 18,697 patients with PTC were treated in our institution. Of these, 10 patients (0.05%) were diagnosed as the MFV-PTC in final pathologic report.Mean age of 10 patients were 42.5 years old, ranging from 26 to 69 years. Twelve lesions were found in 10 patients. On preoperative ultrasonographic examination, most of tumors looked like benign nodules. The tumor nodules varied in size from 0.3 to 3.5 cm in greatest dimension. Microscopically, the macrofollicles were surrounded by cuboidal cells with hyperchromatic nuclei and occupied entire nodule.MFV-PTC showed the benign appearance in ultrasonography. To avoid misdiagnosis of MFV PTC, clinicians should be aware of the characteristics of MFV-PTC and perform ultrasonography with fine needle aspiration biopsy appropriately. PMID- 29489674 TI - A case report: the use of ultrasound guided peripheral nerve block during above knee amputation in a severely cardiovascular compromised patient who required continuous anticoagulation. AB - RATIONALE: Although lower-extremity surgeries are mainly performed under general or central neuraxial anesthesia, ultrasound-guided peripheral nerve block (PNB) can be a good alternative, especially for patients who require continuous anticoagulation treatment and present with poor cardiovascular conditions. PATIENTS CONCERNS: The patient required continuous anticoagulation treatment due to the high risk of thromboembolism and poor cardiovascular conditions. DIAGNOSES: The patient required lower-extremity amputation due to atherosclerotic and thromboembolic obstruction. INTERVENTIONS: We decided to progress the operation under peripheral nerve block. The sciatic, femoral, lateral femoral cutaneous nerve and anterior branch of the obturator nerve were blocked under ultrasound guidance. Sixty ml of a local anesthetic (equal mix of 1% lidocaine and 0.375% ropivacaine) was administered for the block. OUTCOMES: Sufficient sensory block at the area of amputation was obtained, and the patient's vital signs were stable throughout surgery. LESSONS: Ultrasound-guided peripheral nerve block can be an excellent anesthetic technique for patients receiving radical surgery at the proximal lower extremities, especially patients who are critically ill and considered high risk. PMID- 29489675 TI - Diagnostic value of chest CT combined with x-ray for premature infants with bronchopulmonary dysplasia. AB - Bronchopulmonary dysplasia (BPD) is a common chronic lung disease in the newborns. Staging of BPD severity does not have a high predictive value for the outcomes. This study was aimed to assess the diagnostic value of chest computed tomography (CT) combined with x-ray for premature infants with BPD.Twenty-five premature infants with mild BPD and 20 premature infants with moderate to severe BPD treated at our hospital from January 2015 to December 2015 were randomly selected. The imaging features were compared between premature infants with different severity of BPD.In mild BPD group, the incidence of increased lung opacity (at 3-10 and 29 days) were significantly higher than those in infants with moderate to severe BPD (P = .034, P = .003, respectively). However, the incidences of stage III BPD (3-10 days) and stage IV BPD (11-27 days) were significantly lower in infants with mild BPD than those in infants with moderate to severe BPD (P = .013, P = .033, respectively). The chest x-ray score in the mild BPD group was significantly lower than that in moderate to severe BPD group [3.0 (1.0) vs 5.0 (1.0), P < .001]. Spearman rank correlation analysis indicated that chest x-ray score had significant correlation (r = 0.787, P < .001) with the clinical severity. In the mild BPD group, the chest CT scan score was 11.52 +/- 3.49, which was considerably lower than that in the moderate to severe BPD group (24.70 +/- 4.32) (P < .001). Moreover, the severity of BPD in the premature infants was significantly correlated to the chest CT scan score (r = 0.855, P < .001).Chest CT combined with x-ray is an effective method for predicting the severity of BPD in premature infants. PMID- 29489676 TI - Epidemiology of abdominal aortic aneurysms in a Chinese population during introduction of endovascular repair, 1994 to 2013: A retrospective observational study. AB - The aim of this study was to examine changes in abdominal aortic aneurysm repair and mortality during a period when endovascular aneurysm repair (EVAR) was introduced.Open repair surgery was the mainstay of treatment for abdominal aortic aneurysm (AAA), but EVAR is increasingly utilized. Studies in the Western population have reported improved short-term or postoperative mortality and shorter length of hospital stay with EVAR. However, scant data are available in the Chinese population.We conducted a retrospective observational study using the database of the Hospital Authority, which provides public health care to most of the Hong Kong population. AAA patients admitted to public hospitals for intact repair or rupture from 1994 to 2013 were included in this study. We calculated the incidence of ruptured AAA, annual repair rates according to type of AAA and surgery, as well as death rates (operative and overall short-term). We calculated whether there were significant changes over time and compared short-term mortality between open surgery and EVAR.One thousand eight hundred eighty-five patients were admitted for intact repair and 1306 patients were admitted for AAA rupture, of whom 795 underwent rupture repair. Intact repair rates significantly increased in all age groups (7.3-37.8%, P < .001) over the study period.The incidence of ruptured AAA increased, in all age groups, except in < 64 years old. By 2013, 85% of intact repairs and 55.4% of rupture repair were done by EVAR. Over time, there was a significant decrease in operative mortality for intact repair (16.5 in 1994 to 7.1 in 2013, P = .01) and rupture repair (59.7 in 1994 to 30.8 in 2013, P = .003). Over the same time period, short-term AAA-related deaths decreased by more than half (73% in 1994 to 24% in 2013, P < .001), with a significant decline in all age groups, except < 64 years old. Short-term mortality was significantly lower for EVAR than for open repair (17.2% vs 40.3%, P < .01).Short-term AAA-related deaths have declined likely due to decreased operative mortality and rupture deaths during the period of EVAR introduction and expansion. PMID- 29489677 TI - Clinical and imaging features of granular cell tumor of the neurohypophysis: A retrospective analysis. AB - The aim of this study was to explore x-ray computed tomography (CT) and magnetic resonance imaging (MRI) characteristics specific to granular cell tumors (GCTs) of the neurohypophysis.The clinical and imaging data of 6 patients with operation proven GCTs of the neurohypophysis were analyzed retrospectively.There were 6 patients with GCTs of the neurohypophysis confirmed pathologically. Five of the tumors were purely suprasellar lesions distinct from the intrasellar pituitary gland. One tumor was both intra- and suprasellar. Solid tumors were hyperattenuated and enhanced homogeneously on CT, while showing isointensity on T1WI and heterogeneous hypointensity on T2WI, with homogeneous (4/5) or inhomogeneous (1/5) enhancement. The cystic tumor showed hypointensity on T1WI and hyperintensity on T2WI, with ring enhancement. "Star-like crack sign" was seen in 2 larger solid cases. Calcification was absent in all cases.Well circumscribed intra and/or suprasellar masses, hyperattenuated and homogeneously enhancing on CT, hypointensity on T2WI, rarely seen calcification, should arouse suspicion of GCTs of the neurohypophysis. PMID- 29489678 TI - The accuracy of magnifying narrow band imaging (ME-NBI) in distinguishing between cancerous and noncancerous gastric lesions: A meta-analysis. AB - BACKGROUND: Previous clinical trials have demonstrated the diagnostic accuracy of magnifying narrow-band (ME-NBI) for gastric cancerous lesions, but the results are inconsistent. The purpose of this meta-analysis is to investigate the accuracy of ME-NBI in distinguishing between cancerous and noncancerous gastric lesions. METHODS: Systematic literature searches were conducted until October 2016 in PubMed, Embase by 2 independent reviewers. Meta-analysis was performed to calculate the pooled sensitivity, specificity. Two authors independently evaluated studies for inclusion, rated methodological quality, and abstracted relevant data. Meta-analytic method was used to construct summary receiver operating characteristic curves, and pooled sensitivity, specificity were calculated. RESULTS: Nine studies enrolling 5398 lesions were included. The pooled sensitivity, specificity were 88% (95% confidence interval [CI]: 78-93%), 96% (95% CI: 91-98%), respectively. The area under the curve (AUC) was 0.97. There was a large heterogeneity between the included studies. Studies with lesions <= 10 mm still had a high pooled sensitivity of 81% (95% CI: 73-90%) and specificity of 97% (95% CI: 95-100%). Studies which analyzed resected specimens had a sensitivity of 91% (95 CI: 82-99%) and specificity of 88% (95% CI: 83-94%), and studies which analyzed biopsied specimens had a sensitivity of 85% (95 CI: 74 96%) and specificity of 99% (95% CI: 98-99%). CONCLUSIONS: ME-NBI is highly accurate and consistent to distinguish between gastric cancerous and noncancerous lesions. PMID- 29489679 TI - Publication trend, resource utilization, and impact of the US National Cancer Database: A systematic review. AB - BACKGROUND: The utilization and impact of the studies published using the National Cancer Database (NCDB) is currently unclear. In this study, we aim to characterize the published studies, and identify relatively unexplored areas for future investigations. METHODS: A literature search was performed using PubMed in January 2017 to identify all papers published using NCDB data. Characteristics of the publications were extracted. Citation frequencies were obtained through the Web of Science. RESULTS: Three hundred 2 articles written by 230 first authors met the inclusion criteria. The number of publications grew exponentially since 2013, with 108 articles published in 2016. Articles were published in 86 journals. The majority of the published papers focused on digestive system cancer, while bone and joints, eye and orbit, myeloma, mesothelioma, and Kaposi Sarcoma were never studied. Thirteen institutions in the United States were associated with more than 5 publications. The papers have been cited for a total of 9858 times since the publication of the first paper in 1992. Frequently appearing keywords congregated into 3 clusters: "demographics," "treatments and survival," and "statistical analysis method." Even though the main focuses of the articles captured a extremely wide range, they can be classified into 2 main categories: survival analysis and characterization. Other focuses include database(s) analysis and/or comparison, and hospital reporting. CONCLUSION: The surging interest in the use of NCDB is accompanied by unequal utilization of resources by individuals and institutions. Certain areas were relatively understudied and should be further explored. PMID- 29489680 TI - Miller-Fisher syndrome complicated by Bickerstaff brainstem encephalitis: A case report. AB - RATIONALE: Bickerstaff brainstem encephalitis (BBE) and Miller-Fisher syndrome (MFS) might be a pedigree disease. Herein, we report a rare case that fits the diagnoses of both MFS and BBE. PATIENT CONCERNS: A 48-year-old woman was hospitalized due to blurred vision and unsteady gait lasting for 9 days, and numbness of the limbs lasting for 6 days. Physical examination showed restricted eye movement without nystagmus, bilateral flattening of forehead and nasolabial folds, and positive eyelash sign. Her tongue deviated to the left when protruded. She had negative tendon reflex, bilateral Babinski signs, hypalgesia, and numbness in all limbs. She had positive Romberg sign and failed the right heel knee-tibia tests. Her brain diffusion-weighted magnetic resonance imaging (DWI) showed an abnormally high circular signal in the brainstem surrounding the fourth ventricle. She also had cerebral spinal fluid (CSF) albuminocytological dissociation and GQ1b-IgG antibodies in both CSF and serum. DIAGNOSES: The case fits the diagnoses of both MFS and BBE. INTERVENTIONS: The patient was treated with dexamethasone. OUTCOMES: The condition of the patient significantly improved after the administration of dexamethasone. Her symptoms had continued to improve by the 6-week and 2-month follow-ups. LESSONS: These results suggest that BBE and MFS might be a pedigree disease and timely hormone therapy is expected to improve patients'outcomes. PMID- 29489681 TI - A comparison of the pharmacokinetic and pharmacodynamic properties of nitroglycerin according to the composition of the administration set: A preliminary study. AB - BACKGROUND: There is a risk of drug sorption into an intravenous administration set composed of polyvinyl chloride (PVC), polyurethane (PU), or polyolefin (PO). This has implications on the dose of the active ingredient the patient receives, and thus therapeutic success. This study aimed to determine the plasma concentration of nitroglycerin and the effect of nitroglycerin on patients based on the composition of the administration set. METHODS: Using a randomized, open labeled, 3 * 3 crossover method, 9 volunteers were assigned to 3 groups. In period I, nitroglycerin (100 MUg/mL) was infused via a PVC- (group A), PU- (group B), or PO-based (group C) administration set. In period II, PU- (group A), PO- (group B), and PVC-based (group C) administration sets were used, and in period III, PO- (group A), PVC- (group B), and PU-based (group C) administration sets were used. The rate of drug administration in all periods was 12 mL/hour for 30 minutes using an infusion pump. Blood samples were collected, and the plasma concentrations of nitroglycerin were analyzed using validated high-performance liquid chromatography coupled with tandem mass spectrometry. Blood pressure was determined using a sphygmomanometer applied to the other upper arm at an interval of 5 minutes. RESULTS: We observed that the mean plasma concentration of nitroglycerin over time when administered using a PO-based tube was higher than that when using a PU- or PVC-based tube. When the percent change of the mean arterial pressure from baseline at each time point was compared among groups, there were statistically significant differences between PU and PO or PVC at most points during nitroglycerin infusion. CONCLUSION: Our results showed higher nitroglycerin plasma concentration and lower arterial pressure when a PO-based administration set was used than when a PVC- or PU-based administration set was used. PO-based administration sets may be more appropriate for nitroglycerin administration compared to those composed of PVC or PU. PMID- 29489682 TI - The clinical characteristics and the features of immunophenotype of peripheral lymphocytes of adult onset chronic active Epstein-Barr virus disease at a Tertiary Care Hospital in Beijing. AB - Chronic active Epstein-Barr virus (CAEBV) infection is a rare disease with high mortality. Most of CAEBV patients have been reported from Japan and are pediatric cases.The goal was to describe the clinical characteristics and the immunophenotypic features of peripheral lymphocytes in adult onset CAEBV patients.We retrospectively reviewed and analyzed all adult onset CAEBV cases admitted to Peking Union Medical College Hospital (PUMCH) between 2012 and 2016. Demographic, clinical, laboratory data, and the immunophentyping data of peripheral lymphocytes were collected.There were 28 adult onset CAEBV patients. The median age was 45 (range, 20-81). Most of the patients presented with fever; splenomegaly; lymphadenopathy and hepatitis. Unlike pediatric cases reported, the manifestations of cardiovascular diseases in our patients were pulmonary arterial hypertension, decreased cardiac function and aorta vasculitis. Prevalence of interstitial pneumonitis in our patients were comparatively higher and prevalence of hypersensitivity to mosquito bites were comparatively lower than that reported by Japan. In this study, CAEBV patients had decreased B cell, NK cell, CD4 cell and CD8 cell counts. The prevalence of low level of B cells, NK cells, CD4 cells was relatively higher than reported ever.Chinese adult onset CAEBV patients have different clinical characteristics and are featured by an immunosuppression status as demonstrated by decreased B cell, NK cell, CD4 cell and CD8 cell. PMID- 29489683 TI - Assessment of visual evoked potentials in patients eligible for penetrating keratoplasty. AB - Corneal opacities can obstruct ophthalmology examination in patients before penetrating keratoplasty (PK).To assess the usefulness of visual evoked potentials (VEPs) in estimating postoperative visual acuity (VA) in patients eligible for (PK) with opaque cornea in 1 eye and good VA in the fellow eye.In this observational study, the mean age of 52 males and 48 females was 57.17 +/- 15.99 (21-87 years old). A total of 100 patients eligible for PK underwent an ophthalmological examination including VA and a VEP examination. The P2/P2 ratio was calculated. The correlation coefficient of the VA and the P2/P2 ratio was evaluated 1, 6, and 12 months after PK.A positive correlation of the P2/P2 ratio and VA 1, 6, and 12 months after PK were observed.VEPs including the P2/P2 ratio can be useful in estimating postoperative VA in patients eligible for PK. PMID- 29489685 TI - Small intestinal diverticulum with bleeding: Case report and literature review. AB - RATIONALE: Small intestinal diverticulum with bleeding is an important reason for obscure gastrointestinal bleeding (OGB) , in addition to tumor and vascular diseases. Small intestinal diverticulum with bleeding is difficult to detect by barium meal and angiographic methods and has been regarded as an important cause of obscure gastrointestinal tract bleeding in adolescents. Because of its complicated etiology and non-specific clinical manifestations, it is relatively difficult to detect small intestinal diverticulum with bleeding, especially in patients with a large amount of bleeding and hemodynamic instability. PATIENT CONCERNS: This retrospective study collects clinical statistics of 19 patients admitted to our hospital from January 2010 to December 2016. Patients who had small intestinal diverticulum patients with bleeding were included in this study. Patients who were taking anticoagulants were excluded DIAGNOSES:: Small intestinal diverticulum patients with bleeding. INTERVENTIONS: This retrospective study describes the clinical features of patients with small intestinal diverticulum whose main symptom was gastrointestinal bleeding and analyze the literature on this topic, with particular reference to the clinical characteristics, pathological features, and choice of examination methods. LESSONS: Small intestinal diverticulum with bleeding is a common cause of obscure gastrointestinal bleeding, but it is difficult to detect using normal examination methods. For patients with repeated gastrointestinal bleeding and no positive results found on gastroscopy and colonoscopy, endoscopy of the small intestine and CTE with contrast can be considered as a diagnostic modality. PMID- 29489684 TI - Predictive factors for clinically significant pharmacist interventions at hospital admission. AB - Pharmaceutical care activities at hospital admission have a significant impact on patient safety. The objective of this study was to identify predictive factors for clinically significant pharmacist interventions (PIs) performed during medication reconciliation and medication review at patient hospital admission.A 4 week prospective study was conducted in 4 medicine wards. At hospital admission, medication reconciliation and medication review were conducted and PIs were performed by the pharmaceutical team. The clinical impact of PIs was determined using the clinical economic and organizational (CLEO) tool. Clinical characteristics, laboratory results, and medication data for each patient were collected and analyzed as potential predictive factors of clinically significant PIs. Univariate and multivariate binary logistic regression were subsequently used to identify independent predictive factors for clinically relevant PIs.Among 265 patients admitted, 150 patients were included. Among 170 PIs performed at hospital admission, 71 were related to unintentional discrepancies (41.8%) during medication reconciliation, and 99 were related to drug-related problems (DRPs) (58.8%) during medication review. Overall, 115 PIs (67.7%) were considered to have a clinical impact. By multivariate analysis, number of medications >=5 (P = .01) based on the best possible medication history, and Charlson comorbidity index score >=2 (P < .01) were found to be independent predictive factors of clinically significant PIs at hospital admission.Identifying predictive factors of clinically significant PIs is valuable to optimize clinical pharmacist practices at hospital admission during both medication reconciliation and medication review. These 2 steps of the pharmaceutical care process improve medication safety at hospital admission. PMID- 29489687 TI - Misdiagnosis of idiopathic hypoparathyroidism: A case report and literature review. AB - RATIONALE: Idiopathic hypoparathyroidism (IHP) is a rare endocrine condition, which is frequently represented by neuropsychiatric disorders. Hence, the misdiagnosis rate of the disease is rather high, especially for neurologists. PATIENT CONCERNS: We reported a case of misdiagnosed, atypical IHP. In addition, the literature on IHP and the misdiagnosis published in China in the past 2 decades has been reviewed and summarized. DIAGNOSES: Blood testing confirmed that parathyroid hormone (PTH) = 0 pg/mL and the final diagnosis was IHP. INTERVENTIONS AND OUTCOMES: With calcium and vitamin D supplementation, the patient's myasthenia improved significantly, and muscle enzymes returned to normal gradually. One-year follow-up demonstrated that the patient's myasthenia disappeared, and the blood calcium and PTH levels were normal. In addition, the literature on IHP and the misdiagnosis published in China in the past 2 decades has been reviewed and summarized. LESSONS: The misdiagnosis rate of IHP in China was high in the past 2 decades, which might be attributed to the misdiagnosis as epilepsy or mental diseases. A clinician should be able to understand the disease and emphasize the screening of high-risk population, especially for those patients with hypocalcemia, hyperphosphatemia, and increased blood creatine kinase with unknown causes or nontypical clinical symptoms. PMID- 29489686 TI - A gastrointestinal stromal tumor with acute bleeding: Management and nursing. AB - RATIONALE: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors involving the gastrointestinal tract. A small percentage of GISTs may cause acute gastrointestinal bleeding, which requires urgent surgical intervention. PATIENT CONCERNS: In this case report, we present a 62-year-old male patient with who was hospitalized due to acute bleeding. DIAGNOSES: The patient was diagnosed as GIST with low risk. INTERVENTIONS: The patient was treated endoscopically with polidocanol sclerotherapy. OUTCOMES: The mass was removed completely, and the patient was discharged at day 9 after operation. LESSONS: This case indicates that GIST can present as massive upper gastrointestinal bleeding and urgent endoscopic sclerotherapy can be life-saving. The endoscopical intervention may be a good alternative for emergency. PMID- 29489688 TI - A trial case of medical treatment for primary headache using telemedicine. AB - RATIONALE: Video-based treatment in telemedicine is a potential alternative to face-to-face treatment. We describe our trial use of telemedicine to treat a patient with primary headache. PATIENT CONCERNS: A 25-year-old woman visited our branch hospital with a chief complaint of recurrent headache. Our branch hospital had no headache specialist, so a headache specialist at our main hospital provided treatment remotely. DIAGNOSES: She was diagnosed with migraine without aura by the headache specialist using telemedicine. INTERVENTIONS: The branch hospital physician and the headache specialist used video conferencing to interview and examine the patient and share cranial magnetic resonance imaging (MRI). Audio and camera angle/zoom could be adjusted during interviews, and high quality video was continuously displayed at both hospitals simultaneously without lag between audio and video. Temporal/spatial resolution was sufficient for proper neurological evaluation. MRI had sufficient image quality and resolution for detailed interpretation. A prescription for medication was issued by the branch hospital physician and confirmed by the headache specialist. OUTCOMES: Zolmitriptan was effective in treating her migraine. LESSONS: Telemedicine was useful for treating this primary headache patient and can contribute to regional health care. Future challenges in telemedicine include expanding its use to other areas within the purview of general physicians and headache specialists, covering implementation and maintenance costs, providing adequate explanations to patients and family members, ensuring security of video transmissions, maintaining patient medical records, and supervising treatment. PMID- 29489689 TI - Case report of refractory pericardial effusion associated with lymphatic fistula due to surgical injury during sternotomy. AB - RATIONALE: A 35-year old Chinese female was admitted to hospital with refractory pericardial effusions 10 days post mitral valve replacement via median sternotomy. We performed an exploratory resternotomy and found lymphatic leakage on the surface of the diaphragm which was continuously emitting a light yellow fluid. PATIENT CONCERNS: The patient complained of no obvious discomfort except for the concern of massive pericardial effusion drainage. DIAGNOSES: Exploratory resternotomy and biochemical testing lead to a supradiaphragmatic lymphatic fistula being diagnosed as the cause of the refractory pericardial effusion. INTERVENTIONS: The fistula was closed with a continuous suture and no other fistulas were found after a thorough exploration. OUTCOMES: The patient was discharged home on postoperative day 5 and recovery was uneventful. LESSONS: In this case a timely exploratory resternotomy proved effective in seeking the cause of and treating pericardial effusion following cardiac surgery. PMID- 29489690 TI - A case report of Brugada-like ST-segment elevation probably due to coronary vasospasm. AB - RATIONALE: Vasospastic angina is caused by sudden occlusive vasoconstriction of a segment of an epicardial artery, with transient ST-segment elevation on electrocardiography. Brugada Syndrome is an inherited arrhythmogenic cardiac disorder with a diagnostic electrocardiography characterized by coved-type ST segment elevation in right precordial leads (V1-V3). Those two diseases usually have no correlation. In this report, we discuss an interesting case of a patient who was diagnosed as vasospastic angina according to his coronary angiography, but his electrocardiography showed a Brugada-like ST-segment elevation. PATIENT CONCERNS: Our patient had a 9-month history of temporary but progressive substernal burning sensation with acid bilges of shoulders and arms, as well as profuse sweating at night. DIAGNOSES: Although he had no abnormal laboratory test result, no dysfunctional recorded echocardiogram or documented arrhythmia after being admitted to the hospital, his electrocardiography showed a Brugada-like ST segment elevation. The coronary angiography result confirmed a diagnosis of vasospastic angina. INTERVENTIONS: The patient was prescribed diltiazem, aspirin, isosorbide mononitrate and rosuvastatin and was strongly advised to quit cigarettes and alcohol. OUTCOMES: Follow-up at half a year turned out well. LESSONS: This case links Brugada syndrome to coronary vasospasm. They may share similar mechanisms. Provocation test and gene test needs to be ran to distinguish both. Long-term follow-up is essential for it may bring a warning sign for life threatening ventricular arrhythmias. PMID- 29489691 TI - Preliminary study of time maximum intensity projection computed tomography imaging for the detection of early ischemic change in patient with acute ischemic stroke. AB - Noncontrast computed tomography (NCCT) has been used for the detection of early ischemic change (EIC); however, correct interpretation of NCCT findings requires much clinical experience. This study aimed to assess the accuracy of time maximum intensity projection computed tomography technique (tMIP), which reflects the maximum value for the time phase direction from the dynamic volume data for each projected plane, for detection of EIC, against that of NCCT.Retrospective review of NCCT, cerebral blood volume in CT perfusion (CTP-CBV), and tMIP of 186 lesions from 280 regions evaluated by Alberta Stroke Program Early CT Score (ASPECTS) in 14 patients with acute middle cerebral artery stroke who had undergone whole brain CTP using 320-row area detector CT was performed. Four radiologists reviewed EIC on NCCT, CTP-CBV, and tMIP in each ASPECTS region at onset using the continuous certainty factor method. Receiver operating characteristic analysis was performed to compare the relative performance for detection of EIC. The correlations were evaluated.tMIP-color showed the best discriminative value for detection of EIC. There were significant differences in the area under the curve for NCCT and tMIP-color, CTP-CBV (P < .05). Scatter plots of ASPECTS showed a positive significant correlation between NCCT, tMIP-gray, tMIP-color, and the follow-up study (NCCT, r = 0.32, P = .0166; tMIP-gray, r = 0.44, P = .0007; tMIP color, r = 0.34, P = .0104).Because tMIP provides a high contrast parenchymal image with anatomical and vascular information in 1 sequential scan, it showed greater accuracy for detection of EIC and predicted the final infarct extent more accurately than NCCT based on ASPECTS. PMID- 29489692 TI - Therapeutic time window for the effects of erythropoietin on astrogliosis and neurite outgrowth in an in vitro model of spinal cord injury. AB - BACKGROUND: The objective of this study was to investigate the underlying molecular mechanisms and the therapeutic time window for preventing astrogliosis with erythropoietin (EPO) treatment after in vitro modeled spinal cord injury (SCI). METHODS: Cultured rat spinal cord astrocytes were treated with kainate and scratching to generate an in vitro model of SCI. EPO (100U/mL or 300U/mL) was added immediately or 2, 4, or 8 hours after injury. Some cultures were also treated with AG490, an inhibitor of the EPO-EPO receptor (EpoR) pathway mediator Janus kinase 2 (JAK2). To evaluate neurite extension, rat embryonic spinal cord neurons were seeded onto astrocyte cultures and treated with EPO immediately after injury in the presence or absence of anti-EpoR antibody. RESULTS: EPO treatment at up to 8 hours after injury reduced the expression of axonal growth inhibiting molecules (glial fibrillary acidic protein, vimentin, and chondroitin sulfate proteoglycan), cytoskeletal regulatory proteins (Rho-associated protein kinase and ephephrin A4), and proinflammatory cytokines (tumor necrosis factor alpha, transforming growth factor-beta, and phosphorylated-Smad3) in a dosedependent manner (P < .001). Most effects peaked with EPO treatment 2-4hours after injury. Additionally, EPO treatment up to 4 hours after injury promoted expression of the EpoR (>2-fold) and JAK2 (>3-fold) in a dose-dependent manner (P < .001), whereas co-treatment with AG490 precluded these effects (P < .001). EPO treatment up to 4hours after injury also enhanced axonal b-III tubulin immunoreactivity (>12-fold), and this effect was precluded by co-treatment with an anti-EpoR antibody (P < .001). CONCLUSIONS: EPO treatment within 8 hours after injury reduced astrogliosis, and EPO treatment within 4 hours promoted neurite outgrowth. EPO therapy immediately after spinal cord injury may regulate glia to generate an environment permissive of axonal regeneration. PMID- 29489693 TI - Reliability and validity of the Chinese CECA10 questionnaire for Chinese patients with condyloma acuminata. AB - Condyloma acuminata (CA) is a sexually transmitted disease that affects quality of life (QOL). CECA10 is an English-language questionnaire for assessing QOL in patients with CA, but there is no equivalent in China. This study aimed to develop a validated and reliable Chinese version of CECA10.The Chinese CECA10 was developed from the English version by forward translation, back translation, comparison with the original, cultural adjustments, and a pre-test (5 patients). The Chinese CECA10 and EuroQol Five Dimensions Three Level Questionnaire (EQ-5D 3L) was administered to patients with CA. Content validity (item/scale content validity indexes, I-CVI/S-CVI), test-retest reliability (intraclass coefficient, ICC), internal consistency (Cronbach alpha), criterion validity (comparison with the Dermatology Life Quality Index, DLQL, using Spearman correlation analysis), construct validity (exploratory factor analysis), and discriminant validity (between subgroups based on number of warts, number of recurrences, or number of sites involved) were assessed.The Chinese CECA10 had good test-retest reliability (ICC = 0.98, P < .001), internal consistency (Cronbach alpha values of 0.88, 0.84, and 0.83 for the total questionnaire, psychological dimension, and sexual dimension, respectively), content validity (I-CVI = 1 for all items), and criterion validity (r = -0.50, P < .001). Exploratory factor analysis extracted 2 factors with a cumulative contribution of 61.75%; the factor loading with each item was >0.4. Discriminant validity was not high. The mean CECA10 and EQ-VAS scores of 211 patients with CA (28.19 +/- 7.16 years; 139 males) were 34.56 +/- 19.01 and 64.64 +/- 19.28, respectively.The Chinese CECA10 has good reliability and validity for evaluating the QOL of Chinese patients with CA. PMID- 29489694 TI - Zolpidem-induced sneezing: A case report of positive rechallenge. AB - INTRODUCTION: Zolpidem, as an imidazopyridine, is a widely prescribed drug in clinical practice for short-term treatment of insomnia. Nevertheless, there have been a number of cases associated with the adverse effects of the stated drug recently. Further to the existing reports of adverse reactions to zolpidem, the current script is going to report a case in which zolpidem has induced acute repetitive sneezes. CONCLUSIONS: A high dose of zolpidem may contribute to interruption to the neurons function involved in the sneezing pathway. PMID- 29489695 TI - A case report of POEMS syndrome with renal involvement as immunotactoid glomerulopathy. AB - RATIONALE: POEMS syndrome is a rare multi-system disorder, which sometimes involves the kidney. Immunotactoid glomerulopathy (ITG) is an uncommon glomerular disease resulted from deposits of immunoglobulins and its derivatives. ITG caused by POEMS syndrome is rarely reported. PATIENT CONCERNS: A 63-year-old man was presented with acute kidney injury. In addition, it's found that he had abnormal serum free kappa /lambda ratio, polyneuropathy, Castleman's disease, organomegaly, endocrinopathy and skin changes. DIAGNOSES: POEMS syndrome was diagnosed, Renal biopsy revealed an ITG. INTERVENTIONS: Dexamethasone and thalidomide were given, as well as hemodialysis and other supportive treatments. OUTCOMES: The patient's extrarenal manifestations improved gradually and his renal function also showed slight improvement. LESSONS: ITG caused by POEMS syndrome is rare, however, it makes sense that the monoclonal proteins produced by the plasma cells could cause ITG. Chemotherapy similar to that employed in multiple myeloma may be beneficial for these patients. PMID- 29489696 TI - Duplicated middle cerebral artery origin with an aneurysm. AB - RATIONALE: Middle cerebral artery (MCA) anomalies are relatively rare and often related to aneurysms. Familiarity with these anomalies is important in resolving problems that arise in the complex angioarchitecture. Reports often describe that aneurysms that are related to accessory or duplicated MCA are often located at its origin. PATIENT CONCERNS: A 59-year-old man presented with a headache for 10 days, without nausea and vomiting. The physical examination was negative. DIAGNOSIS: A computed tomography (CT) scan revealed an intracerebral hematoma in the deep right frontal lobe, near the caudate nucleus. Digital subtraction angiography (DSA) revealed an anomalous duplicated origin of the right MCA, with occlusion of the main MCA trunk as well as twisting and dilation of the accessory MCA trunk. A wide-necked aneurysm was located at a sharp curve of the tortuous accessory MCA trunk. A ruptured aneurysm related to a duplicated MCA origin was diagnosed. INTERVENTIONS: Open surgery was rejected by the patient; hence, palliative endovascular coil embolization of the larger daughter sac was performed. OUTCOMES: The postoperative course was uneventful. There was no rebleeding at 8-months follow-up. LESSONS: MCA anomalies are relatively rare and often related to aneurysms. It is important to be familiar with these anomalies as related lesions often manifest within a complex angioarchitecture. Aneurysms at the trunk of an anomalous MCA are a rare entity and open surgery may be recommended. PMID- 29489697 TI - Delayed hepatic rupture post ultrasound-guided percutaneous liver biopsy: A case report. AB - RATIONALE: Hemorrhage, one of complications after liver biopsy, is often identified immediately after the procedure while delayed liver rupture is relatively rare. PATIENT CONCERNS: A 45-year-old woman was diagnosed with undetermined liver cirrhosis and abnormal liver function. To determine the etiology and severity of liver cirrhosis, ultrasound-guided liver biopsy was arranged. The patients did not complain any pain during the procedure. Ultrasound examination on postoperative day1 (POD 1) and MRI on POD 3 showed no evidence of hematoma and ascites. On POD 7, however, the patient was taken to the hospital with a sudden onset of pain in the right upper quadrant of the abdomen. DIAGNOSES: Contrast-enhanced computed tomography revealed liver rupture of right inferior segment of the liver with subcapsular hematoma. INTERVENTIONS: Patient was treated with infusion of 2-unit red blood cell suspension, fluid and hemostatics. OUTCOMES: The vital signs of the patient were stabilized after the therapy. The follow-up ultrasound 1 month later showed a shrunken subcapsular hematoma measuring 4.2 * 2.1 cm at the right lobe. LESSONS: Whenever a liver biopsy procedure is performed, the care should be taken to avoid puncturing those areas that may have liver incisure. Moreover, the patient need to rest for several days and to avoid heavy activities, which is one of the major risk factors for post-procedure bleeding. PMID- 29489698 TI - Never too old to fight breast cancer: A case report. AB - RATIONALE: Breast cancer is the most common cancer affecting females worldwide and its lifetime risk increases with age. Human epidermal growth factor receptor gene-2 (HER-2) positive breast cancer represents about 20% of all breast cancers, 1 out of 10 is diagnosed in women over 70 years of age. It tends to be more aggressive and to spread more quickly than other subtypes, but the introduction in clinical practice of new anti-HER-2 agents combined with chemotherapy has significantly improved progression free and overall survival. Elderly patients are frequently undertreated because of concerns about their age, performance status, and comorbidities. Here, we report a case of an octogenarian patient treated with T-DM1 with brilliant results. PATIENT CONCERNS: An 87 years old woman affected with HER-2 positive breast cancer presented progression of disease with lymph node and skin metastases after 3 lines of chemoimmunotherapy. DIAGNOSES: Breast cancer in elderly patient, lymph node, and skin metastases. INTERVENTIONS: Chemoimmunotherapy (trastuzumab emtansine). OUTCOME: Objective response of the disease and significant clinical benefit. LESSONS: This case clearly suggests that age and comorbidities do not always represent an absolute contraindication to combined treatments. PMID- 29489699 TI - Prostatic cyst in general practice: A case report and literature review. AB - RATIONALE: Prostatic cyst is a rare disease of the prostate especially in general practice. As it is often asymptomatic, how to manage it is still unfamiliar with, general practitioners (GPs). PATIENT CONCERNS: The 24-year-old man presented with left back discomfort for 1 week without severe pain, dysuria, or fever. DIAGNOSES: Ultrasonography revealed the presence of a 14*14 mm cystic lesion. INTERVENTIONS: The patient was given the medicine and regular follow-up. OUTCOMES: Several days later, he recovered without lower back discomfort. LESSONS: Patients with prostatic cyst of small size and no symptom should be follow-up regularly. Although prostatic cyst of progressive symptoms, large size (2.5 cm or larger), or high serum prostate-specific antigen (PSA) should be timely referred to urological specialists. PMID- 29489700 TI - A new surgical treatment for abdominal wall defects: A vascularized ribs-pleural transfer technique that can be used with or without a thoracic umbilical flap a case report. AB - RATIONALE: Abdominal wall defects are common after tumor resection. PATIENT CONCERNS: We report an 83-year-old male patient with recurrent tumors in his abdomen, and who had an incision wound that could not be directly closed. Mesh was not suitable because the wound was infected. DIAGNOSES: Abdominal wall defect result from the resection of recurrent tumor. INTERVENTIONS: We carried out a vascularized ribs-pleural transfer operation. OUTCOMES: After the surgery, the patient gained a functional recovery. No evidence of recurrence was noted 1 year after operation, and the patient showed no symptoms of abdominal compression syndrome. LESSONS: We discuss the clinical diagnosis, treatment, and follow up and argue that the vascularized ribs-pleural transfer technique is a good method to deal with abdominal wall defects. PMID- 29489702 TI - Be Exceptional. Be a CRNI(r). PMID- 29489701 TI - Macrophage inhibitory cytokine-1 versus carbohydrate antigen 19-9 as a biomarker for diagnosis of pancreatic cancer: A PRISMA-compliant meta-analysis of diagnostic accuracy studies. AB - BACKGROUND: Because of the high malignant degree of pancreatic cancer (PC), the early diagnosis of PC is of great concern. Macrophage inhibitory cytokine-1 (MIC 1) was reported to be a potential diagnostic biomarker, but its diagnostic value is indeterminate. Therefore, we performed this meta-analysis to compare it to carbohydrate antigen 19-9 (CA19-9), the most frequently used serum biomarker in PC. MATERIAL AND METHODS: After a systematic review of the relevant studies, the pooled diagnostic indices, including sensitivity, specificity, positive/negative likelihood ratio (PLR/NLR), diagnostic odds ratio (DOR), summary receiver operating characteristic curve (sROC), and area under the SROC curve (AUC) were used to evaluate the diagnostic value of MIC-1 and CA19-9 for PC. These indices were pooled with random-effects models. We explored the heterogeneity by meta regression. RESULTS: Fourteen studies comprising a total of 2826 subjects were included in our meta-analysis. The summary estimates for MIC-1 and CA19-9 are listed as follows: sensitivity, 80% [95% confidence interval (CI) 78-82] versus 71% (95% CI 68-73); specificity, 85% (95% CI 83-87) versus 88% (95% CI 86-90); DOR, 24.57 (95% CI 14.00-43.10) versus 17.65 (95% CI 11.65-26.76); area under sROC (AUC), 0.8945 versus 0.8322; PLR, 5.18 (95% CI 3.24-8.26) versus 5.34 (95% CI 3.78-7.54); and NLR, 0.23 (95% CI 0.19-0.29) versus 0.32 (95% CI 0.28-0.37). CONCLUSION: These data demonstrate that serum MIC-1 has a comparable diagnostic accuracy to CA19-9 for PC. PMID- 29489703 TI - Antibody Formation in Transfusion Therapy. AB - The production of antibodies following blood transfusions is a complex process that involves many recipient and donor factors. Inflammation in the recipient is one important factor. As knowledge of the immune system, of oxygen, carbon dioxide, and nitric oxide pathways, and of hemostasis grows, more specific therapies will allow precise manipulation of the immune system and safer transfusions. Communication of patients' transfusion and immunotherapy histories with the laboratory, attention to detail in labeling pretransfusion specimens, checking patient and blood product identification before administration, and closely monitoring patients during transfusions remain critical to minimizing risks during transfusion therapy. PMID- 29489704 TI - Factors Contributing to Phlebitis Among Adult Patients Admitted in the Medical Surgical Units of a Central Hospital in Harare, Zimbabwe. AB - This descriptive survey identified factors contributing to phlebitis among 46 adult inpatients using a systematic random sample. The visual infusion phlebitis score was used for assessment. All participants had phlebitis, with stage 4 being most frequent. Factors identified were gender (males-91.7%); immunosuppression (human immunodeficiency virus-63.0%; diabetes-100%; immunosuppressive drugs-100%; absolute leucocyte count <1000 MUL-100%); number of catheters inserted (>1 90.9%); site of catheterization (dorsum of wrist-100%); catheter dwell time (2-4 days-100%); catheter gauge (18-gauge-75%); catheter securement (unsecured/contaminated dressing-90%); regularity of catheter flushing (catheter never flushed-72.7%); and continuous infusion (94.2%). PMID- 29489706 TI - Optimizing Drug Delivery of Small-Volume Infusions. AB - When administering intermittent secondary intravenous infusions, commonly referred to as intravenous piggyback (IVPB) infusions, residual medication remains in the administration set and bag. No previous studies exist examining the optimal technique to infuse the residual medication. The aims of this study were to identify various IVPB ancillary techniques used to administer medication residing in the secondary administration set and bag following an infusion, evaluate the potential drug loss associated with each technique, and recommend a standard ancillary technique for administration of select small-volume IVPB infusions. Qualitative and quantitative tests were performed, leading to a recommendation for a standard ancillary technique for select small-volume IVPB infusions. PMID- 29489705 TI - Antimicrobial Efficacy of a New Chlorhexidine-based Device Against Staphylococcus aureus Colonization of Venous Catheters. AB - Vascular catheters are a major cause of nosocomial bloodstream infections. ChloraLock (ATTWILL Medical Solutions, Inc, West Jordan, UT, and ICU Medical, Inc, San Clemente, CA) is a novel antimicrobial device containing chlorhexidine digluconate (CHG) that is fitted onto a syringe and infuses CHG into the catheter lumen during locking. The objective of this study was to evaluate the antimicrobial efficacy of ChloraLock with in vitro tests and its ability to reduce Staphylococcus aureus contamination of catheters in the external jugular veins of Yorkshire swine. ChloraLock significantly reduced the bacterial load in the in vitro tests by up to 6 log10 colony-forming units (CFU) and by 3 to 4 log10 CFU/lumen in vivo in a swine model with 0.9% NaCl catheter locks. PMID- 29489707 TI - Selection of Single- Versus Double-Lumen Peripherally Inserted Central Catheters and the Influence on Alteplase Use. AB - The purpose of this article is to share the efforts of one institution in reducing risk of central line-associated bloodstream infections (CLABSIs). The aim is to review alteplase use as a marker for peripherally inserted central catheter (PICC) occlusions, which may increase risk of CLABSIs. The discovery that alteplase use increased with the number of PICC lumens allowed for exploration of ordering and placement practices. Following education, placement of double-lumen PICCs decreased. PMID- 29489708 TI - Does a Dedicated Lumen for Parenteral Nutrition Administration Reduce the Risk of Catheter-Related Bloodstream Infections? A Systematic Literature Review. AB - Guidelines recommend using single-lumen central vascular access devices (CVADs) for the administration of parenteral nutrition (PN) or lipid-based solutions, or a dedicated lumen on a multilumen CVAD. Publications reviewed by the authors reported comparative rates of catheter-related bloodstream infection (CR-BSI) in patients with CVADs who received PN through a dedicated lumen compared with those who had PN administered through multilumen CVADs. Two studies included 650 patients with 1349 CVADs. CR-BSIs were equally distributed between the 2 groups. Both studies were poorly reported and had significant risk of bias. These results should be interpreted with caution. PMID- 29489709 TI - A Randomized Controlled Study to Evaluate the Effectiveness of 2 Treatment Methods in Reducing Incidence of Short Peripheral Catheter-Related Phlebitis. AB - Short peripheral catheter (SPC)-related phlebitis can lead to bloodstream infections and affect patients' quality of life. A randomized trial was carried out to evaluate the effectiveness of 2 treatment methods in reducing the incidence of SPC-related phlebitis. The 2 treatment methods differed in terms of the cleansing solution used before insertion and dressing material used after removal. The results demonstrated that the type of cleansing solution and postremoval dressing material did not make a difference in the incidence of phlebitis. Strict adherence to aseptic techniques and prompt removal of the SPC remained the cornerstone in the prevention of phlebitis. PMID- 29489710 TI - The Match Heart Rate and Running Profile of Elite Under-21 Hurlers During Competitive Match-Play. AB - Young, D, Mourot, L, Beato, M, and Coratella, G. The match heart rate and running profile of elite under-21 hurlers during competitive match-play. J Strength Cond Res 32(10): 2925-2933, 2018-The aims of the current study were to examine the physical and physiological demands of elite under-21 male hurling match-play across halves of play and between positions. Global positioning systems (10 Hz) and heart rate (HR) monitors were used to collect data from 95 players during 10 games. Total distance (TD), relative speed, high-speed running (HSR), sprint distance, total sprints, and mean length of sprint was 6,688 +/- 942 m, 112 +/- 16 m.min, 661 +/- 203 m, 274 +/- 111 m, 18 +/- 8 m, and 16 +/- 5 m, respectively. Players' mean HR (HRmean) and peak HR (HRpeak) was 165 +/- 9 b.min and 190 +/- 7 b.min, respectively. Decrements in TD (p < 0.05, effect size [ES] = 0.81), HSR (p < 0.05, ES = 0.69), and HRmean (p < 0.05, ES = 0.80) were found between halves. Full backs covered significantly less TD than half backs (p < 0.05, ES = -1.24), midfielders (p < 0.05, ES = -1.39), and half forwards (p < 0.05, ES = -1.85). Half forwards covered a greater TD than full forwards (p < 0.05, ES = 0.94), greater HSR than full backs (p < 0.05, ES = 1.13), and greater sprint distance than half backs (p < 0.05, ES = 1.41). Between-half decreases were evident in TD, HSR, and HRmean, with no significant positional differences observed in TD, HSR, number of sprints, length of sprint, HRpeak, and HRmean between half backs, midfielders, and half forwards. The current findings provide data that coaches should consider to customize training program design for under-21 hurlers. PMID- 29489711 TI - Frequency Speed of Kick Test Performance Comparison Between Female Taekwondo Athletes of Different Competitive Levels. AB - Santos, JFS and Franchini, E. Frequency speed of kick test performance comparison between female taekwondo athletes of different competitive levels. J Strength Cond Res 32(10): 2934-2938, 2018-Construct validity is a desirable characteristic in any performance test to differentiate athletes. However, no taekwondo-specific test was investigated with this purpose. The purpose of this study was to compare female taekwondo athletes grouped in different competitive levels. Forty-two female taekwondo athletes divided into International/National (median [interquartile range]; n = 21, age: 20 [18-25] years; body mass: 60 [53-72] kg; height: 164 [161-170] cm; and practice time: 8 [5-13] years) and State/Regional group (median [interquartile range]; n = 21; age: 18 [17-25] years; body mass: 57 [52-63] kg; height: 165 [160-172] cm; and practice time: 5 [2-8] years) volunteered to participate in this study. The female taekwondo athletes performed frequency speed of kick test (FSKT) with 10 seconds (FSKT10s) and intermittent 90 seconds (FSKTmult) during the competitive period. Differences between international/national and state/regional group were observed, with superiority to international/national group, for FSKT10s (U = 114.5, p = 0.007, ESr (effect size) = -0.42 [small]), FSKT1 (U = 127.0, p = 0.016, ESr = -0.37 [small]), FSKT2 (U = 108.5, p = 0.004, ESr = -0.45 [small]), FSKT3 (U = 127.0, p = 0.015, ESr = 0.37 [small]), and FSKTtotal (U = 124.0, p = 0.015, ESr = -0.38 [small]). Based on the results of this study, the FSKT seems to be a good tool to discriminate performance of female taekwondo athletes and could be used by coaches and athletes in their evaluation routines. PMID- 29489712 TI - Using Load-Velocity Relationships to Predict 1rm in Free-Weight Exercise: A Comparison of the Different Methods. AB - The purpose of this study was to investigate the reliability and validity of predicting 1-repetition maximum (1RM) in trained individuals using a load velocity relationship. Twenty strength-trained men (age: 24.3+/-2.9 years, height: 180.1+/-5.9 cm, body mass: 84.2+/-10.5 kg) were recruited and visited the laboratory on three occasions. The load-velocity relationship was developed using the mean concentric velocity of repetitions performed at loads between 20% and 90% 1RM. Predicted 1RM was calculated using 3 different methods discussed in existing research; minimal velocity threshold 1RM (1RMMVT), load at zero velocity 1RM (1RMLD0) and force-velocity 1RM methods (1RMFV). The reliability of 1RM predictions was examined using intraclass correlation coefficient (ICC) and coefficient of variation (CV). 1RMMVT demonstrated the highest reliability (ICC=0.92-0.96, CV=3.6-5.0%), followed by 1RMLD0 (ICC=0.78-0.82, CV=8.2-8.6%) and 1RMFV (ICC=-0.28-0.00, CV= N/A). Both 1RMMVT and 1RMLD0 were very strongly correlated with measured 1RM (r=0.91-0.95). The only method which was not significantly different to measured 1RM was the 1RMLD0 method. However, when analyzed on an individual basis (using Bland-Altman plots), all methods exhibited a high degree of variability. Overall, the results suggest that the 1RMMVT and 1RMLD0 predicted 1RM values could be used to monitor strength progress in trained individuals without the need for maximal testing. However, given the significant differences between 1RMMVT and measured 1RM, and the high variability associated with individual predictions performed using each method, they cannot be used interchangeably; therefore, it is recommended that predicted 1RM is not used to prescribe training loads as has been previously suggested. PMID- 29489713 TI - Contributions of Lower Body Strength Parameters to Critical Power and Anaerobic Work Capacity. AB - This study examined the contribution of lower body strength and isokinetic peak torque measures to the prediction of critical power (CP) and anaerobic work capacity (AWC). Fourteen recreationally trained males (mean +/- SD age: 22.4 +/- 2.5 yrs; height: 177.9 +/- 7.7 cm; body mass: 84.2 +/- 12.4 kg) with anaerobic training experience completed this study. The lower body strength measures included one repetition max (1RM) bilateral back squat [BSq], isokinetic peak torque at 30 degrees .sec [PT30] and isokinetic peak torque at 240 degrees .sec [PT240]) of the dominant leg. The CP and AWC were determined from the 3-min all out CP cycle ergometer test (CP3MT), with the resistance set at 4.5% of the total body mass. The CP was defined as the mean power output over the final 30s of the test and the AWC was calculated using the equation, AWC = 150s (P150 - CP), where P150 equals the mean power output for the first 150s. Stepwise regression analyses indicated that only BSq contributed significantly to the prediction of AWC (AWC = 0.0527[BSq] + 8.094 [SEE = 2.151 kJ; p = 0.012]), with a correlation of r = 0.423. None of the strength parameters significantly predicted CP. These findings indicated that BSq strength accounted for 42% of the variance in AWC, but lower body strength was not related to CP. The current results indirectly supports the unique metabolic characteristics of both CP and AWC in providing separate measures of an individual's aerobic and anaerobic capabilities, respectively. PMID- 29489714 TI - Effects of combined balance and plyometric training on athletic performance in female basketball players. AB - The purpose of this study was to examine the effect of 8 weeks combined balance and plyometric training on the physical fitness of female adolescent basketball players. Twenty six healthy regional-level players were randomly assigned to either an experimental group (E; n = 16, age = 16.4 +/- 0.5) or a control group (C; n = 10, age = 16.5 +/- 0.5). C maintained their normal basketball training schedule, whereas for 8 weeks E replaced a part of their standard regimen by biweekly combined training sessions. Testing before and after training included the Squat Jump (SJ), Countermovement Jump (CMJ), Drop Jump (DJ), 5, 10 and 20-m sprints, Stork Balance Test (SBT), Y-Balance Test (YBT) and Modified Illinois Change of Direction Test (MICODT). Results indicated no significant inter-group differences in SJ and CMJ height; however, E increased their DJ height (p<0.05, Cohens'd = 0.11). No significant inter-group differences were found for sprint performance or SBT, but dynamic YBT tended to a significant group interaction (p = 0.087, d = 0.006). Post hoc analysis also showed a significant increase of MICODT for E (Delta 6.68%, p = 0.041, d = 0.084). In summary, the addition of 8 weeks of balance and plyometric training to regular in-season basketball training proved a safe and feasible intervention that enhanced DJ height, balance, and agility for female adolescent basketball players relative to the standard basketball training regimen. PMID- 29489715 TI - Force-Velocity Relationship in three Different Variations of Prone Row Exercises. AB - This study examined the force-velocity relationship and tested the possibility of determining the relative loading intensity (% 1RM) in three different variations of prone row exercises. Thirty male top-level athletes from two different sports (National Team rugby union players and professional mixed martial arts fighters) were submitted to maximum dynamic strength assessments in the free prone bench pull, bent over barbell row, and bent over Smith-machine row, following standard procedures encompassing lifts performed from 40 to 100% of 1RM. The mean velocity, mean propulsive velocity, and peak velocity were measured in all attempts. Linear regression analyses were performed to establish the relationships between the different measures of bar-velocities and %1RM. The actual (obtained during the assessments) and predicted 1RM values (based on the predictive equations) for each exercise were compared using a paired t-test. In all exercises, the predicted 1RM scores - based on all velocity variables- were not different from their respective actual values. The close linear relationships between bar-velocities and distinct %1RM (coefficient of determination >= 80%, in all experimental conditions) allow precise determination of relative load and maximum dynamic strength, and enable coaches and sports scientists to use the different velocity outputs to rapidly and accurately monitor their athletes on a daily basis. PMID- 29489716 TI - The effect of barbell load on vertical jump landing force-time characteristics. AB - The aim of this study was to quantify the effect that barbell load has on the jump height and force-time characteristics of the countermovement jump (CMJ). Fifteen strengthtrained men (mean +/- SD: age 23 +/- 2 years, mass 84.9 +/- 8.1 kg, height 1.80 +/- 0.05 m) performed three CMJ with no additional load, and with barbell loads of 25%, 50%, 75%, and 100% of body mass on two force plates recording at 1000 Hz. Propulsion and landing force-time characteristics were obtained from force-time data and compared using analysis of variance and effect sizes. Jump height decreased significantly as load increased (26 to 71%, d = 1.80 to 6.87). During propulsion, impulse increased with load up to 75% of body mass (6 to 9%, d = 0.71 to 1.08), mean net force decreased (10 to 43%, d = 0.50 to 2.45) and time increased (13 to 50%, d = 0.70 to 2.57). During landing, impulse increased as load increased up to 75% of body mass (5 to 12%, d = 0.54 to 1.01), mean net force decreased (13 to 38%, d = 0.41 to 1.24), and time increased (20 to 47%, d = 0.65 to 1.47). Adding barbell load to CMJ significantly decreases CMJ height. Furthermore, CMJ with additional barbell load increases landing phase impulse. However, while mean net force decreases as barbell load increases, landing time increases so that jumpers are exposed to mechanical load for longer. Practitioners should exercise caution when implementing loaded CMJ to assess their athletes. PMID- 29489717 TI - The Effectiveness of A Functional Movement Assessment and 4-Week Exercise Training Program for Female High School Athletes. AB - The extent to which young females participate in school-sponsored athletics has grown significantly over the past two decades. The number of females in high school sports increased for the 25th consecutive year in 2012-2013, reaching an all-time record. Unfortunately, sports-related injury rates for female athletes have also continued to rise. A body of research exists to suggest that dysfunctional movement may be linked to increased risk of injury, and training programs designed to improve movement patterns are effective to both enhance performance and reduce the risk of injury. Effective training programs incorporate corrective exercises to retrain dysfunctional movement patterns. The Functional Movement ScreenTM (FMSTM) is a tool developed to assess 7 fundamental movement patterns. The FMSTM has been used extensively with a wide range of athletes at various levels of performance. The aim of this study was to investigate the effectiveness of a movement-training program with female high school athletes using the FMSTM. The overall purpose was to assess the effectiveness of a 4-week corrective exercise-training program at improving FMSTM scores. Data analysis using Wilcoxon Signed Rank Test revealed a statistically significant change in total group FMSTM scores (Z=-2.214, p=0.027) following the corrective exercise-training program. Mean total group FMSTM scores increased from 14.43 +/- 1.90 (pre-test) to 17.29 +/- 1.38. to 18.0 (post-test). Findings suggest that positive outcomes to a corrective exercise-training program, which targets specific movement impairments, can be achieved in a relatively short period of time. PMID- 29489718 TI - Sex Differences in Y-Balance Performance in Elite Figure Skaters. AB - Asymmetrical dynamic balance compared to normative populations have been associated with increased risk of injury in athletes, however it is unclear if the current data are similar to balance performance in figure skaters. Therefore, the purpose of this study was to compare performance on the y-balance test between sexes and disciplines in elite figure skaters. Thirty-two senior level figure skaters from 3 different disciplines (singles, dance, pair) completed the y-balance test on the take-off and landing leg. Absolute differences between limbs (cm), normalized differences between limbs (% leg length), and composite scores (% leg length) were calculated for all skaters. A multivariate analysis of variance was used to identify differences in performance based on discipline and sex. Females had a greater absolute difference between limbs (Mean Difference = 3.62cm) and a greater normalized difference between limbs on the posterolateral reach compared to males (Mean Difference = -4.26% leg length). Ice dancers had larger composite scores on the take-off leg compared to pair skaters (Mean Difference = 6.42%). These results suggest that male and female figure skaters demonstrate differences in dynamic balance in the posterolateral direction, with female skaters exhibiting decreased reach on the landing leg, which may suggest asymmetrical hip strength in female figure skaters and increase risk of lower extremity injury in the landing leg. Sport performance professionals should consider these sex differences when designing strength programs for elite figure skaters. PMID- 29489719 TI - Vertical and Horizontal Asymmetries are Related to Slower Sprinting and Jump Performance in Elite Youth Female Soccer Players. AB - Inter-limb asymmetries have been shown to be greater during vertical jumping compared to horizontal jumping. Notable inter-limb differences have also been established at an early age in male youth soccer players. Furthermore, given the multi-planar nature of soccer, establishing between-limb differences from multiple jump tests is warranted. At present, a paucity of data exists regarding asymmetries in youth female soccer players and their effects on physical performance. The aims of this study were to quantify inter-limb asymmetries from unilateral jump tests and examine their effects on speed and jump performance. Nineteen elite youth female soccer players performed a single leg countermovement jump (SLCMJ), single, triple, and crossover hops for distance and a 20 m sprint test. Test reliability was good to excellent (ICC = 0.81-0.99) and variability acceptable (CV = 1.74-5.42%). A one-way ANOVA highlighted larger asymmetries from the SLCMJ compared to all other jump tests (p < 0.05). Pearson's correlations portrayed significant relationships between vertical asymmetries from the SLCMJ and slower sprint times (r = 0.49-0.59). Significant negative relationships were also found between horizontal asymmetries during the triple hop test and horizontal jump performance (r = -0.47 to -0.58) and vertical asymmetries during the SLCMJ and vertical jump performance (r = -0.47 to -0.53). The results from this study highlight that the SLCMJ appears to be the most appropriate jump test for identifying between-limb differences with values ~12% showing negative associations with sprint times. Furthermore, larger asymmetries are associated with reduced jump performance and would appear to be direction-specific. Practitioners can use this information as normative data to be mindful of when quantifying inter-limb asymmetries and assessing their potential impact on physical performance in youth female soccer players. PMID- 29489720 TI - Differences in physical performance according to the competitive level in amateur handball players. AB - The aim of this study was to compare physical performance in amateur handball players of two different competitive levels. Thirty-four senior handball players were divided into two groups according to their competitive level (regional category: REG or national category: NAC). Although no significant differences were found between groups in any of the horizontal (HJ) or vertical jump (VJ) variables (p>0.05), NAC players obtained a better performance in the repeated sprint ability (RSA) test (RSABest [the best attempt] and RSATT [the total time in the total of sprints] in 15 m and 30 m), in change of direction ability (CODA) and in the Yo-Yo Intermittent Recovery test Level 1 (YYIR1) test (p<0.01, ES= 1.32-1.75, large). A significant association was observed between the body mass index (BMI) and the HJ or VJ capacity (r= -0.35 to -0.55, p<0.01), the RSA15mBest and RSA30mBest (r= 0.41 to 0.59, p<0.01) and YYIR1 distance (r= -0.54, p<0.05), and a also between the performance in the HJ or the VJ and the RSA15mBest and RSA30mBest, the CODA and the YYIR1 and between the RSA30mBest and the YYIR1 (r= 0.54, p<0.05). Specific strength and conditioning programs should aim toward improving RSA, CODA and YYIR1, as these abilities may be needed at higher levels of competition. The programs also should aim toward improved HJ and VJ abilities, given their association with RSA, CODA and YYIR1 performance. Moreover, maintaining an adequate BMI may aid players to sustain greater physical performance levels. PMID- 29489721 TI - Post-Exercise Ingestion of Low or High Molecular Weight Glucose Polymer Solution Does Not Improve Cycle Performance in Female Athletes. AB - The current study sought to evaluate the effects of post-exercise ingestion of a high molecular weight glucose polymer solution (HMW) compared to an isocaloric low molecular weight solution (LMW) or placebo (PLA) on subsequent cycling performance in female athletes. In a randomized, double-blind, placebo controlled, cross-over design, 10 competitive female cyclists (Mean +/- SD; Age = 25.7 +/- 5.0 yrs; VO2peak = 49.7 +/- 4.3 ml[BULLET OPERATOR]kg[BULLET OPERATOR]min) completed three testing sessions separated by 7-10 days. Visits consisted of a ride-to-exhaustion (RTE) at 75% VO2peak, followed by immediate consumption of 700 mL containing either: 1.2 g[BULLET OPERATOR]kg LMW (maltodextrin/dextrose/fructose); 1.2 g[BULLET OPERATOR]kg HMW (Vitargo(r)); or 0.066 g[BULLET OPERATOR]kg PLA (noncaloric flavoring). After 2 hours rest, participants performed a 15-minute time-trial (TT). Respiratory exchange ratio (RER) was assessed via indirect calorimetry during exercise. Total body water (TBW) was measured using bioelectrical impedance to assess fluid balance. When covaried for estrogen, there was no treatment effect on distance (km; p=0.632) or power output (watts; p=0.974) during the 15-minute TT. RER was not significantly different during the LMW and HWM TTs (p>0.999), but both were significantly higher than PLA (p=0.039, p=0.001, respectively). Changes in TBW pre- to post exercise were not significantly different between trials (p=0.777). Despite benefits of HMW on cycling performance previously reported in males, current results demonstrate no ergogenic effect of HMW or LMW in females. Sex differences in substrate utilization may account for the discrepancy, and further research involving performance nutrition for female athletes is merited. PMID- 29489722 TI - Biomechanical, anthropometric, and psychological determinants of barbell back squat strength. AB - Previous investigations of strength have only focused on biomechanical or psychological determinants, while ignoring the potential interplay and relative contributions of these variables. The purpose of this study was to investigate the relative contributions of biomechanical, anthropometric, and psychological variables to the prediction of maximum parallel barbell back squat strength. Twenty-one college-aged participants (male = 14; female = 7; age = 23 +/- 3 years) reported to the laboratory for two visits. The first visit consisted of anthropometric, psychometric, and parallel barbell back squat one-repetition maximum (1RM) testing. On the second visit, participants performed isometric dynamometry testing for the knee, hip, and spinal extensors in a sticking point position-specific manner. Multiple linear regression and correlations were used to investigate the combined and individual relationships between biomechanical, anthropometric, and psychological variables and squat 1RM. Multiple regression revealed only one statistically predictive determinant: fat free mass normalized to height (standardized estimate +/- SE = 0.6 +/- 0.3; t(16) = 2.28; p = 0.037). Correlation coefficients for individual variables and squat 1RM ranged from r = 0.79-0.83, with biomechanical, anthropometric, experiential, and sex predictors showing the strongest relationships, and psychological variables displaying the weakest relationships. These data suggest that back squat strength in a heterogeneous population is multifactorial and more related to physical rather than psychological variables. PMID- 29489723 TI - Upper respiratory tract infection and mucosal immunity in young ice hockey players during the pre-tournament training period. AB - The aim of this study was to determine the effects of 17 days of training during preparation for the Ice Hockey Under 18 World Championship of the Polish ice hockey national team on the mucosal immune function and monitor upper respiratory tract infection (URTI) incidence before, during and after the competition. Twelve male ice hockey players (age 17.7+/-0.5 years) were recruited for this study. The first saliva/blood collection took place at the beginning of the training camp (without training at the training camp), the second one was conducted on the 9th day of the training camp immediately after the intensification of training, and the third collection was carried out on the 13th day of training (4 days before leaving for the World Championship) in the tapering phase. To assess the mucosal immune function, concentrations of secretory immunoglobulin A (sIgA), sIgA1, and sIgA2 were analyzed in saliva. Cortisol concentration and creatine kinase activity were determined in blood, as indicators of stress and muscle damage, respectively. The Wisconsin Upper Respiratory Symptom Survey-21 questionnaire was used to assess URTI symptoms. A significant increase in the sIgA1 and sIgA2 concentrations was observed in the third collection compared with the second time point (114.45+/-33.00 vs 77.49+/-27.29 and 88.97+/-25.33 vs 71.65+/-32.44 U, respectively). There were no statistically significant correlations between the URTI incidence and saliva variables. In conclusion, the tapering period positively affects the mucosal immune function, especially sIgA1 and sIgA2 concentrations, with no significant change in frequency of URTI in young ice hockey players. PMID- 29489724 TI - Examination of coach and player perceptions of recovery and exertion. AB - : Monitoring training and recovery are essential for exercise programming. Athletes can validly assess training load (TL) via the session rating of perceived exertion (SRPE) technique. However, it is unclear if coaches can successfully use this model. PURPOSE: This study compared coach and athlete perceptions of effort and recovery and evaluated the efficacy of perceptually based TL monitoring. METHODS: Participants included 56 athletes (Women's volleyball, soccer, and basketball and Men's basketball) and their coaches (n = 4). Perceived recovery was estimated via the Perceived Recovery Status scale. TL scores were calculated using the Edward's HR method and by multiplying SRPE by duration. Coaches provided an intended SRPE (SRPE-CI) before practice. SRPE was independently estimated by coaches (SRPE-CO) and athletes (SRPE-A) ~15-20 minutes post-practice. Paired t-tests and Pearson correlations were applied to make comparisons (alpha <= 0.05). RESULTS: SRPE-CI, SRPE-CO, SRPE-A TLs were strongly correlated with Edwards' HR-based TLs (R = 0.74, 0.73, and 0.76, respectively). SRPE-CI (5.5 +/- 1.9) and SRPE-CO (5.0 +/- 1.9) was higher than SRPE-A (4.5 +/- 1.9). Coaches estimated recovery (RPR-C) higher than athletes (RPR-A) (7.1 +/- 1.3 vs 5.8 +/- 1.6). CONCLUSIONS: TL estimates were strongly correlated with Edwards' TL regardless of information source (coach or athlete) or time point (SRPE-CI TL or SRPE-CO TL). Results suggest coaches' perceptions validly indicated TL. Coaches' perceptions provide parallel information (correlated strongly with Edwards TL), but not identical information (demonstrated by differences in SRPE) as athlete perceptions. Differences in perceived recovery indicate coaches overestimate recovery when compared to athletes' perceptions. PMID- 29489725 TI - Improved Performance in Master Runners Competing in the European Championships between 1978 and 2014. AB - The performance trends in elite runners have been well investigated, but we have no knowledge about performance trends and the difference between the sexes in elderly runners competing at a high level in varying distances. The purpose of this study was to investigate the performance of these age groups. Data from seventeen European Championships held between 1978 and 2014 were analyzed for various race distances (i.e. 100 m, 200 m, 400 m, 800 m, 1500 m, 5000 m, 10,000 m and marathon). Running speed for the top 8 female and male finalists for each age group (35-99 years, split into 5 year gaps) and each race distance were included. A two-way analysis of variance compared the effects of sex, race distance, age group and calendar year on speed. Subsequent comparisons between race distances, age groups or calendar years were carried out using a post-hoc Bonferroni test. Our analysis shows that men were faster than women in all distances and the difference between the sexes was greater in the shorter distances. Speed was higher for shorter distances than for longer distances. Younger participants were faster than older ones, and the effect of age group was the largest for the 200 m. There was a minor effect of calendar year on speed in the 100 m, 200 m, 1500 m, 10,000 m and marathon, and a minor calendar year*sex interaction on running speed was shown for the 200 m. For athletes and coaches, the current study demonstrates that both male and female athletes improved their running performance over time and that the sex gap may have reached its limit. PMID- 29489726 TI - The single-leg Roman chair hold is more effective than the Nordic hamstring curl in improving hamstring strength-endurance in Gaelic footballers with previous hamstring injury. AB - Poor hamstring strength-endurance is a risk factor for hamstring injuries. This study investigated the effectiveness of the single-leg Roman hold and Nordic hamstring curl in improving hamstring strength-endurance. Twelve Gaelic footballers (mean +/- standard deviation age, height and mass were 25.17 +/- 3.46 years, 179.25 +/- 5.88 cm, 85.75 +/- 4.75 kilo) with a history of hamstring injury were randomized into 2 groups that performed 6 weeks of either Nordic hamstring curl, or single-leg Roman chair hold training. The single-leg hamstring bridge (SLHB) was measured pre- and post- intervention. The Roman chair group showed a very likely moderate magnitude improvement on SLHB performance for both legs (23.7% for the previously injured leg [90% confidence interval 9.6% to 39.6%] and 16.9% for the non-injured leg [6.2% to 28.8%]). The Nordic curl group showed a likely trivial change in SLHB performance for the non-injured leg (-2.1% [-6.7% to 2.6%]) and an unclear, but possibly trivial change for the previously injured leg (0.3% [-5.6% to 6.6%]). The Roman chair group improved very likely more with a moderate magnitude in both the non-injured (19.5% [8.0% to 32.2%]) and the previously injured leg (23.3% [8.5% to 40.0%]) compared to the Nordic curl group. This study demonstrated that 6-weeks single-leg Roman chair training substantially improved SLHB performance, suggesting that it may be an efficacious strategy to mitigate hamstring (re-) injury risk. Conversely, 6-weeks Nordic curl training did not substantially improve SLHB performance, suggesting this may not be the intervention of choice for modifying this risk factor. PMID- 29489727 TI - High-frequency resistance training is not more effective than low-frequency resistance training in increasing muscle mass and strength in well-trained men. AB - We studied the effects of two different weekly frequency resistance training (RT) protocols over eight weeks on muscle strength and muscle hypertrophy in well trained men. Twenty-three subjects (age: 26.2+/-4.2 years; RT experience: 6.9+/ 3.1 years) were randomly allocated into the two groups: low frequency (LFRT, n = 12) or high frequency (HFRT, n = 11). The LFRT performed a split-body routine, training each specific muscle group once a week. The HFRT performed a total-body routine, training all muscle groups every session. Both groups performed the same number of sets (10-15 sets) and exercises (1-2 exercise) per week, 8-12 repetitions maximum (70-80% of 1RM), five times per week. Muscle strength (bench press and squat 1RM) and lean tissue mass (dual-energy x-ray absorptiometry) were assessed prior to and at the end of the study. Results showed that both groups improved (p<0.001) muscle strength [LFRT and HFRT: bench press = 5.6 kg (95% Confidence Interval (CI): 1.9 - 9.4) and 9.7 kg (95%CI: 4.6 - 14.9) and squat = 8.0 kg (95%CI: 2.7 - 13.2) and 12.0 kg (95%CI: 5.1 - 18.1), respectively] and lean tissue mass (p = 0.007) [LFRT and HFRT: total body lean mass = 0.5 kg (95%CI: 0.0 - 1.1) and 0.8 kg (95%CI: 0.0 - 1.6), respectively] with no difference between groups (bench press, p = 0.168; squat, p = 0.312 and total body lean mass, p = 0.619). Thus, HFRT and LFRT are similar overload strategies for promoting muscular adaptation in well-trained subjects when the sets and intensity are equated per week. PMID- 29489728 TI - Normative reference values for high school-aged American football players. AB - The purpose of the present report was to provide test- and position-specific normative reference values for combine test results based on a large, nationally representative sample of high school-aged American football players in their freshman, sophomore, and junior classes. Cross-sectional anthropometric and performance data were obtained from 12 different high school American football recruiting combines between March 7, 2015 and January 9, 2016 across the United States. Subjects included a sample (n=7,478) of high school-aged American football athletes in their junior (n=3,779), sophomore (n=2,514), and freshman (n=1,185) classes. The database included combine date, school state, position, class, height, weight, 40-yard dash (40YD), pro-agility (PA), 3-cone (3C), vertical jump (VJ), broad jump (BJ), and power push-up (PPU). Each player self classified their American football positions as defensive back (DB), defensive end (DE), defensive linemen (DL), linebacker (LB), offensive linemen (OL), quarterback (QB), running back (RB), tight end (TE), or wide receiver (WR). Test- and position- specific normative values were generated by aggregating data from freshmen, sophomore, and junior classes. Mean differences were found among classes for all positions and all measurements (p<=0.05), except for TE weight (p>0.05). Greater difference for all variables were observed from freshmen to sophomore classes than from sophomore to junior classes. These normative reference values may provide realistic comparisons and evaluations in performance for young American football players, parents, and coaches with collegiate football aspirations. High school strength and conditioning professionals should use these norms to set attainable goals and reward accomplishments for young football players. PMID- 29489729 TI - Evaluating Physical Workload by Position During Match in Elite Bandy. AB - Blomqvist, S, Ervasti, PE, and Elcadi, GH. Evaluating physical workload by position during match in elite bandy. J Strength Cond Res 32(9): 2616-2622, 2018 To improve current understandings of physical workload (WL) in elite bandy, 10 bandy players were monitored for heart rate (HR) during 13 matches over 1 championship season. Participants were divided into 5 subgroups according to playing position-libero, defender, halves, midfielder, and forward. Heart rate measurements were analyzed with 2 different methods to compute physical WL-(a) percentage of total time spent in different HR zones (HRres) and (b) WL based on the Edwards method. Also determined was the time spent at HR levels above the lactate threshold (LT). A one-way analysis of variance was used for analysis. For WL, according to the Edwards method, significant differences (p = 0.05) were shown between the groups with defenders presenting the highest scores, and forwards and liberos the lowest. A significant difference (p = 0.05) was found between liberos and halves and the other positions as to how much time they spent in zone 70-80% of HRres. In 91-100% of HRres, there was a distinct difference between defenders and the other positions and also forwards differed significantly from liberos, defenders, and halves (p = 0.05). The libero spent only 1% of the time over the LT, whereas the midfielder spent approximately 27% of the time over the LT. Overall, defenders showed the greatest WL during a match and liberos the lowest. The practical implications of these findings can help coaches and trainers design training methods specific to each position and individualized training sessions for each player in elite bandy. PMID- 29489730 TI - A Biomechanical Analysis of the Effects of Bouncing the Barbell in the Conventional Deadlift. AB - The purpose of this study is to analyze biomechanical differences between the bounce and pause styles of deadlifting. Twenty physically active males performed deadlifts at their 75% one repetition maximum testing utilizing both pause and bounce techniques in a within-subjects randomized study design. The average peak height the barbell attained from the three bounce style repetitions was used to compute a compatible phase for analysis of the pause style repetitions. Net joint moment impulse (NJMI), work, average vertical ground reaction force (vGRF), vGRF impulse and phase time were computed for two phases, lift off to peak barbell height and the entire ascent. Additionally, the ankle, knee, hip, and trunk angles at the location of peak barbell height. During the lift off to peak barbell height phase, although each of the joints demonstrated significantly less NJMI and work during the bounce style, the hip joint was impacted the most. The average vGRF was greater for the bounce however the vGRF impulse was greater for the pause. The NJMI results for the ascent phase were similar to the lift off to peak barbell height phase, while work was significantly less for the bounce condition compared to the pause condition across all three joints. Strength and conditioning specialists utilizing the deadlift should be aware that the bounce technique does not allow the athlete to develop maximal force production in the early portion of the lift. Further analyses should focus on joint angles and potential vulnerability to injury when the barbell momentum generated from the bounce is lost. PMID- 29489731 TI - Performance in 100-km ultra-marathoners - At which age it reaches its peak? AB - The number of those participating in 100-km ultra-marathon has increased over the last years; however, we have limited knowledge about performance trends in this sport, and particularly the effect of age. The aim of the present study was to analyze the age when women and men runners achieve their peak performance considering 1- and 5-year age group intervals, and examining all or the fastest (i.e. top ten) participants in each age group. We analyzed 370,051 athletes (i.e. 44,601 women and 325,450 men) who finished a 100-km ultra-marathon between 1959 and 2016, and studied the age of peak performance using a second-order non-linear regression analysis. The age of peak performance was 40-44 years in women and 45 49 years in men when all finishers were analysed, whereas it was 30-34 years in women and 35-39 years in men when the top ten finishers were considered in 5-year age groups. When we analyzed finishers in 1-year age groups, we found the age of peak performance at 41 years in women and 45 years in men considering all finishers, and at 39 years in women and 41 years in men considering the top ten finishers. In conclusion, the age of peak performance was younger in women than in men, which might reflect the overall younger age of women participants than men. Compared to previous studies, we observed the peak performance at an age older by ~10 years, which could be attributed to an increase of finishers' age across calendar years. Since the knowledge of the age of peak performance is unique for each sport, coaches and fitness trainers might benefit from the findings of the present study in the long-term training of their athletes. PMID- 29489732 TI - Associatons Between Self-Reported Well-being and Neuromuscular Performance During a Professional Rugby Union Season. AB - Hills, SP, Rogerson, DJ. Associatons between self-reported well-being and neuromuscular performance during a professional rugby union season. J Strength Cond Res 32(9): 2498-2509, 2018-Self-reported wellness is often used to monitor fatigue responses to training and competition. Constraints within team sports mean short-form wellness questionnaires are typically preferred to literature validated documents. This research aimed to assess the relationship between self reported wellness and neuromuscular (NM) performance during a professional rugby union season, and to identify changes in these parameters over a 12-week period. On the first training day each week, before activity, 37 players rated 5 wellness subscales ("fatigue/vigor," "upper-body soreness," "lower-body soreness," "mood," and "sleep quality/duration") on a 1-5 Likert scale (1 representing the lowest wellness), and 5-repetition countermovement jumps (CMJs) were completed after a warm-up. Each week, total wellness, wellness subscales, and 4 CMJ measures for each participant were calculated as change from baseline. Within-participant correlations were determined between changes in wellness and CMJ measures, whereas week-to week differences and differences from baseline were assessed using Wilcoxon signed-rank tests. Within-participant correlations were compared for players grouped by age and position. Wellness and CMJ scores fluctuated according to physical stress, persisted beneath baseline throughout, and showed declining trends over 12 weeks. Very large (r = 0.7-0.89)/large (r = 0.5-0.69) correlations were identified between wellness and CMJ variables (positive: velocity, dip, time; negative: duration), and each wellness subscale displayed large/very large positive correlations with CMJ velocity. This was true for all subgroups, although subtle differences existed between ages and positions. It was concluded that players' subjective wellness is a useful tool, ideally used within a broader monitoring scheme, for monitoring ongoing NM fatigue, which increased from week to week. PMID- 29489733 TI - Reliability and Sensitivity of Neuromuscular and Perceptual Fatigue Measures in Collegiate Men's Basketball. AB - The purpose of this study was to establish the reliability and sensitivity of a countermovement jump (CMJ) and perceptual wellness questionnaire in NCAA Division I men's basketball players. Twelve male collegiate basketball athletes completed 3 maximal CMJ's on a portable force plate and a customized perceptual wellness questionnaire prior to training on non-consecutive days. CMJ variables were derived from computer software and used in analysis. All CMJ variables expressed acceptable trial-to-trial reliability (CV < 8%) except eccentric duration (CV = 8.3%). Peak absolute and relative power, and absolute mean power and force were capable of detecting small performance changes with CV% < SWC%. Similar trends were observed for interday reliability with the exception of flight time to contraction time (FT:CT) (CV = 10.9%), jump height (CV =12.1%), concentric duration (CV = 9.1%) and total duration (CV = 13.6%). Perceptual wellness showed acceptable interday reliability (CV = 6.9%), however was unable to detect the SWC. When assessing the CMJ, selected variables can be used to monitor acute and chronic changes in performance. CMJ variables relating to the eccentric phase may respond differently to typical CMJ variables and may provide insight into the loading mechanisms of response. Perceptual wellness questionnaires also prove to be a reliable subjective fatigue monitoring tool. PMID- 29489734 TI - Transcranial Direct Current Stimulation of the Temporal Lobe Does Not Affect High Intensity Work Capacity. AB - Stimulation of the left insular cortex may affect heart rate variability (HRV) and exercise effort perception. These studies investigated the effects transcranial direct current stimulation (tDCS) and electrode orientation on HRV and repeated maximal knee extensions. In study 1, following sham stimulation, anodal left temporal lobe stimulation, or anodal right temporal lobe stimulation, 10 male and 10 female subjects (age=21.0+/-1.5 yr) completed 50 maximum isokinetic extensions at 180 degrees s. There was a significant effect of stimulation condition on HRV for only one (SD2; p=.037; eta=.159) of five HRV metrics. There was no significant effect on isokinetic fatigue percent, or isokinetic work (all p>=.278; all eta<=.065). It has been proposed that placing the cathode electrode on the shoulder, may differentially affect tDCS. Therefore, in study 2, the effects of electrode orientation on tDCS-induced changes in HRV was assessed in ten healthy females and eight healthy males (21.6+/-2.5 yr) who completed cephalic, extracephalic, and sham trials. In the cephalic montage, the anode was placed over the left temporal lobe and the cathode was placed over right prefrontal cortex. In the extracephalic montage, the cathode was placed on the shoulder on the same side of the body as the anode. Neither cephalic nor extracephalic montages affected HRV (all p>=.152; all eta<=.105). These data suggest that anodal tDCS of the insular cortex has little effect on HRV, and does not improve high-intensity exercise performance in the current population. Therefore, anodal tDCS applied over the left temporal lobe is not recommended for high intensity performance enhancement. PMID- 29489735 TI - Cancer Management in Kabuki Syndrome: The First Case of Wilms Tumor and a Literature Review. AB - A 3-year-old Japanese girl treated for hypoplastic left heart syndrome and Dandy Walker syndrome was diagnosed with Kabuki syndrome (KS) with a mutation of KMT2D; c.13285C>T:p.Q4429*. Concurrently, macrohematuria portended the diagnosis of Wilms tumor. Postoperative chemotherapy has achieved complete remission despite a prolonged and reduced regimen due to liver dysfunction and convulsions. Cancer predisposition has been suggested for KS due to oncogenic mutations in KMT2D or KDM6A. The first case of nephroblastoma exemplified the treatability of malignancies in KS patients, as shown in the 9 cases reviewed. Active screening and intervention are recommended for the cure of malignancy in KS children. PMID- 29489736 TI - Current State of the Opioid Epidemic as it Pertains to Pediatric Orthopaedics From the Advocacy Committee of the Pediatric Orthopaedic Society of North America. AB - INTRODUCTION: The opioid epidemic in the United States has reached crisis proportions. Urgent response is needed. Hydrocodone in combination with acetaminophen is the most prescribed drug in the United States. The most common source of opioids available for misuse is the unused portions of postoperative prescriptions. Among high school seniors, 80% of those who reported nonmedical use of prescription opioids previously had legitimate prescriptions but recreationally used leftover doses. Roughly one-quarter of patients do not take any of their postoperatively prescribed opioids and the remainder take one-third to two-thirds of the prescribed doses. METHODS: A summary of the literature is presented beginning from historical perspective to current status and pertinent strategies in dealing with this complicated problem. This review includes data from an electronic survey of the members of the Pediatric Orthopaedic Society of North America (POSNA) with regard to the prescriptions they would provide for 7 treatment scenarios. RESULTS: Strategies for the preoperative, intraoperative, and postoperative phases of management of pain as well as strategies for education, research, and advocacy are presented. The Pediatric Orthopaedic Society of North America survey yielded 264 respondents. The 3 most commonly used opioid medications were hydrocodone, oxycodone, and acetaminophen with codeine, in that order, for most of the scenarios. The time period covered by postoperative prescriptions varied considerably. CONCLUSIONS: The magnitude of this problem is overwhelming. Education of care providers, patients and families, standardization of narcotic prescribing practices which incorporate patient characteristics, and appropriate plans for disposal of unused narcotics are immediate concepts to consider in correcting this problem. Long-term issues to tackle will be changing patient a family expectations, legislation, and obtaining additional resources directed towards this issue. PMID- 29489737 TI - Effects of Clonidine on the Cardiovascular, Renal and Inflammatory Responses to Experimental Bacteremia. AB - INTRODUCTION: Supra-clinical doses of clonidine appear beneficial in experimental sepsis, but there is limited understanding of the effects of clonidine at clinically relevant doses. METHODS: In conscious sheep, with implanted renal and pulmonary artery flow probes, sepsis was induced by infusion of live Escherichia coli. At 24 hours, a high clinical dose of clonidine (HCDC) [1.0 MUg/kg/h], a low clinical dose of clonidine (LCDC) [0.25 MUg/kg/h] or vehicle, was infused for 8 hours. RESULTS: Animals developed hyperdynamic, hypotensive sepsis with acute kidney injury. The HCDC decreased heart rate (153 +/- 6 to 119 +/- 7 bpm) and cardiac output (5.6 +/- 0.4 to 5.0 +/- 0.4 L/min), with no reduction in mean arterial pressure (MAP). In contrast, LCDC increased cardiac output with peripheral vasodilatation. Both doses induced a large transient increase in urine output, an increase in plasma osmolality and, with the high dose, an increase in plasma arginine vasopressin. Sepsis increased plasma interleukin-6 (IL-6) and IL 10 and clonidine further increased IL-10 (1.6 +/- 0.1 to 3.3 +/- 0.7 ng/mL), but not IL-6. Clonidine reduced rectal temperature. During recovery from sepsis, MAP returned to baseline values more rapidly in the HCDC group (p < 0.001). CONCLUSIONS: In hyperdynamic, hypotensive sepsis, the effects of clonidine at clinically relevant doses are complex and dose dependent. HCDC attenuated sepsis related increases in heart rate and cardiac output, with little effect on arterial pressure. It also induced a water diuresis, increased AVP, reduced body temperature and had an anti-inflammatory action. Low-dose clonidine had similar but less pronounced effects, except that it induced moderate vasodilatation and increased cardiac output. PMID- 29489738 TI - Hemorrhagic Shock/Resuscitation Reduces the M2 Phenotype of Alveolar Macrophages: A Potential Mechanism Contributing to Increased LPS-Induced Lung Injury. AB - Major hemorrhage is a significant contributor to the morbidity and mortality resulting from traumatic injury. In addition to its role in in early mortality, hemorrhagic shock followed by resuscitation (HS/R) is known to initiate immunological events which contribute to the development of organ dysfunction. The pathogenesis of acute lung injury following HS/R involves macrophage activation. Recent studies have shown that macrophage function may in part be regulated by polarization towards classical M1 pro-inflammatory cells or alternatively activated anti-inflammatory M2 cells. We hypothesized that alteration in the M1/M2 phenotypic balance of alveolar macrophages in the lung may contribute to a pro-inflammatory state following HS/R. Using a murine model, we show that HS/R causes a rapid reduction in surface CD206 and CD36, markers of M2 cells, as well as in CD206 mRNA. M1 markers including surface CD80 and TNFalpha and iNOS mRNA were increased, albeit in a somewhat delayed time course. The prostaglandin 5-deoxyDelta12,14 prostaglandin J2 (15d-PGJ2), known to polarize cells towards M2, restored levels of M2 macrophages towards control and prevented lung injury, as assessed by bronchoalveolar protein content. Adoptive cell transfer of in vitro M2 polarized macrophages also reduced lung inflammation/injury following hemorrhagic shock. Together, these studies demonstrate that HS/R increases M1/M2 ratio, predominantly by lowering M2 cells, and thus enhances the proinflammatory state. Various strategies aimed at promoting M2 polarization may lessen the magnitude of inflammation and injury. This represents a novel approach to the prevention/treatment of lung injury in critically ill trauma patients. PMID- 29489739 TI - From cell to heart: the impact of the cell organelles dysfunction on heart disease. AB - : Cellular morphology reflects biologic behavior and activity of the tissue and of the organ also reflects the genetic and molecular biology of the cells themselves. This intermediary position places examination of the cell in a key role to our understanding of the innumerable processes that affect this closely knit chain, from molecules to host. A large volume of the cell is occupied by organelles that come in a variety of shapes and sizes. Organelles are dynamic to maintain homeostasis and adjust to the various functions of the cell. The cardiovascular system is metabolically very active and is therefore particularly vulnerable to defects of the cellular substructures, such as the mitochondrial respiratory chain. Given the functional complexity of the cardiovascular system, it is not surprising that defects in cell organelles produce diverse clinical manifestations. Organelle dysfunction is being recognized as the basis of a wide variety of heart diseases. In this review, the authors discuss the relationship between organelle structure and function in myocardial cells and how these organelles have been linked to the cardiovascular diseases. PMID- 29489740 TI - Coffee in hypertensive women with asymptomatic peripheral arterial disease: a potential nutraceutical effect. PMID- 29489741 TI - Clinical recommendations of cardiac magnetic resonance, Part II: inflammatory and congenital heart disease, cardiomyopathies and cardiac tumors: a position paper of the working group 'Applicazioni della Risonanza Magnetica' of the Italian Society of Cardiology: Erratum. PMID- 29489743 TI - Putting microfluidics in other people's hands. PMID- 29489742 TI - Elevated Levels of Serum beta2-Glycoprotein I/Oxidized Low-Density Lipoprotein Complexes Are Associated with Cerebral Infarction in Patients with Type 2 Diabetes Mellitus. AB - BACKGROUND To determine whether the levels of b2-glycoprotein I (b2-GPI)/oxidized low-density lipoprotein (oxLDL) complexes are correlated with cerebral infarction in patients with type 2 diabetes mellitus (T2DM). MATERIAL AND METHODS The levels of beta2-GPI/oxLDL complexes, oxLDL, routine lipid/lipoprotein parameters, oxidative stress molecules, and inflammatory factors were measured in 78 healthy controls, 82 diabetics without cerebral infarction, and 79 diabetics with cerebral infarction. Correlation, multiple linear regression, and logistic regression analyses were performed. RESULTS Serum beta2-GPI/oxLDL complexes and oxLDL levels were significantly elevated in cerebral infarction in patients with T2DM (beta2-GPI/oxLDL: 1.09+/-0.16 U/mL; oxLDL: 47.83+/-8.17 mmol/L) compared with T2DM without cerebral infarction (b2-GPI/oxLDL: 0.95+/-0.13 U/mL; oxLDL: 41.24+/-7.12 mmol/L) and healthy controls (beta2-GPI/oxLDL: 0.81+/-0.12 U/mL; oxLDL: 27.97+/-4.57 mmol/L). The levels of beta2-GPI/oxLDL complex in lacunar infarction (1.16+/-0.15 U/ml) were significantly higher than atherothrombotic infarction (1.07+/-0.19 U/ml) and cardioembolic infarction (1.00+/-0.23 U/ml). In all patients with T2DM, the beta2-GPI/oxLDL levels were positively correlated with total cholesterol (r=0.474, p=0.001) and triglycerides (r=0.431, p=0.003). oxLDL levels were positively correlated with total cholesterol (r=0.445, p=0.002). The logistic regression analysis indicated that elevated b2-GPI/oxLDL and oxLDL levels were independently associated with diabetic cerebral infarction. CONCLUSIONS Elevated levels of serum b2-GPI/oxLDL complexes are associated with cerebral infarction in patients with T2DM, especially in those with lacunar infarction. PMID- 29489744 TI - Picky: a simple online PRM and SRM method designer for targeted proteomics. PMID- 29489745 TI - RNA dynamics revealed by metabolic RNA labeling and biochemical nucleoside conversions. PMID- 29489746 TI - hichipper: a preprocessing pipeline for calling DNA loops from HiChIP data. PMID- 29489747 TI - Hierarchical neural architecture underlying thirst regulation. AB - Neural circuits for appetites are regulated by both homeostatic perturbations and ingestive behaviour. However, the circuit organization that integrates these internal and external stimuli is unclear. Here we show in mice that excitatory neural populations in the lamina terminalis form a hierarchical circuit architecture to regulate thirst. Among them, nitric oxide synthase-expressing neurons in the median preoptic nucleus (MnPO) are essential for the integration of signals from the thirst-driving neurons of the subfornical organ (SFO). Conversely, a distinct inhibitory circuit, involving MnPO GABAergic neurons that express glucagon-like peptide 1 receptor (GLP1R), is activated immediately upon drinking and monosynaptically inhibits SFO thirst neurons. These responses are induced by the ingestion of fluids but not solids, and are time-locked to the onset and offset of drinking. Furthermore, loss-of-function manipulations of GLP1R-expressing MnPO neurons lead to a polydipsic, overdrinking phenotype. These neurons therefore facilitate rapid satiety of thirst by monitoring real-time fluid ingestion. Our study reveals dynamic thirst circuits that integrate the homeostatic-instinctive requirement for fluids and the consequent drinking behaviour to maintain internal water balance. PMID- 29489748 TI - Hierarchical roles of mitochondrial Papi and Zucchini in Bombyx germline piRNA biogenesis. AB - PIWI-interacting RNAs (piRNAs) are small regulatory RNAs that bind to PIWI proteins to control transposons and maintain genome integrity in animal germ lines. piRNA 3' end formation in the silkworm Bombyx mori has been shown to be mediated by the 3'-to-5' exonuclease Trimmer (Trim; known as PNLDC1 in mammals), and piRNA intermediates are bound with PIWI anchored onto mitochondrial Tudor domain protein Papi. However, it remains unclear whether the Zucchini (Zuc) endonuclease and Nibbler (Nbr) 3'-to-5' exonuclease, both of which have pivotal roles in piRNA biogenesis in Drosophila, are required for piRNA processing in other species. Here we show that the loss of Zuc in Bombyx had no effect on the levels of Trim and Nbr, but resulted in the aberrant accumulation of piRNA intermediates within the Papi complex, and that these were processed to form mature piRNAs by recombinant Zuc. Papi exerted its RNA-binding activity only when bound with PIWI and phosphorylated, suggesting that complex assembly involves a hierarchical process. Both the 5' and 3' ends of piRNA intermediates within the Papi complex showed hallmarks of PIWI 'slicer' activity, yet no phasing pattern was observed in mature piRNAs. The loss of Zuc did not affect the 5'- and 3'-end formation of the intermediates, strongly supporting the idea that the 5' end of Bombyx piRNA is formed by PIWI slicer activity, but independently of Zuc, whereas the 3' end is formed by the Zuc endonuclease. The Bombyx piRNA biogenesis machinery is simpler than that of Drosophila, because Bombyx has no transcriptional silencing machinery that relies on phased piRNAs. PMID- 29489749 TI - The mechanism of eukaryotic CMG helicase activation. AB - The initiation of eukaryotic DNA replication occurs in two discrete stages: first, the minichromosome maintenance (MCM) complex assembles as a head-to-head double hexamer that encircles duplex replication origin DNA during G1 phase; then, 'firing factors' convert each double hexamer into two active Cdc45-MCM-GINS helicases (CMG) during S phase. This second stage requires separation of the two origin DNA strands and remodelling of the double hexamer so that each MCM hexamer encircles a single DNA strand. Here we show that the MCM complex, which hydrolyses ATP during double-hexamer formation, remains stably bound to ADP in the double hexamer. Firing factors trigger ADP release, and subsequent ATP binding promotes stable CMG assembly. CMG assembly is accompanied by initial DNA untwisting and separation of the double hexamer into two discrete but inactive CMG helicases. Mcm10, together with ATP hydrolysis, then triggers further DNA untwisting and helicase activation. After activation, the two CMG helicases translocate in an 'N terminus-first' direction, and in doing so pass each other within the origin; this requires that each helicase is bound entirely to single stranded DNA. Our experiments elucidate the mechanism of eukaryotic replicative helicase activation, which we propose provides a fail-safe mechanism for bidirectional replisome establishment. PMID- 29489751 TI - Recognition of DHN-melanin by a C-type lectin receptor is required for immunity to Aspergillus. AB - Resistance to infection is critically dependent on the ability of pattern recognition receptors to recognize microbial invasion and induce protective immune responses. One such family of receptors are the C-type lectins, which are central to antifungal immunity. These receptors activate key effector mechanisms upon recognition of conserved fungal cell-wall carbohydrates. However, several other immunologically active fungal ligands have been described; these include melanin, for which the mechanism of recognition is hitherto undefined. Here we identify a C-type lectin receptor, melanin-sensing C-type lectin receptor (MelLec), that has an essential role in antifungal immunity through recognition of the naphthalene-diol unit of 1,8-dihydroxynaphthalene (DHN)-melanin. MelLec recognizes melanin in conidial spores of Aspergillus fumigatus as well as in other DHN-melanized fungi. MelLec is ubiquitously expressed by CD31+ endothelial cells in mice, and is also expressed by a sub-population of these cells that co express epithelial cell adhesion molecule and are detected only in the lung and the liver. In mouse models, MelLec was required for protection against disseminated infection with A. fumigatus. In humans, MelLec is also expressed by myeloid cells, and we identified a single nucleotide polymorphism of this receptor that negatively affected myeloid inflammatory responses and significantly increased the susceptibility of stem-cell transplant recipients to disseminated Aspergillus infections. MelLec therefore recognizes an immunologically active component commonly found on fungi and has an essential role in protective antifungal immunity in both mice and humans. PMID- 29489750 TI - The SMAD2/3 interactome reveals that TGFbeta controls m6A mRNA methylation in pluripotency. AB - The TGFbeta pathway has essential roles in embryonic development, organ homeostasis, tissue repair and disease. These diverse effects are mediated through the intracellular effectors SMAD2 and SMAD3 (hereafter SMAD2/3), whose canonical function is to control the activity of target genes by interacting with transcriptional regulators. Therefore, a complete description of the factors that interact with SMAD2/3 in a given cell type would have broad implications for many areas of cell biology. Here we describe the interactome of SMAD2/3 in human pluripotent stem cells. This analysis reveals that SMAD2/3 is involved in multiple molecular processes in addition to its role in transcription. In particular, we identify a functional interaction with the METTL3-METTL14-WTAP complex, which mediates the conversion of adenosine to N6-methyladenosine (m6A) on RNA. We show that SMAD2/3 promotes binding of the m6A methyltransferase complex to a subset of transcripts involved in early cell fate decisions. This mechanism destabilizes specific SMAD2/3 transcriptional targets, including the pluripotency factor gene NANOG, priming them for rapid downregulation upon differentiation to enable timely exit from pluripotency. Collectively, these findings reveal the mechanism by which extracellular signalling can induce rapid cellular responses through regulation of the epitranscriptome. These aspects of TGFbeta signalling could have far-reaching implications in many other cell types and in diseases such as cancer. PMID- 29489752 TI - Regeneration of the lung alveolus by an evolutionarily conserved epithelial progenitor. AB - Functional tissue regeneration is required for the restoration of normal organ homeostasis after severe injury. Some organs, such as the intestine, harbour active stem cells throughout homeostasis and regeneration; more quiescent organs, such as the lung, often contain facultative progenitor cells that are recruited after injury to participate in regeneration. Here we show that a Wnt-responsive alveolar epithelial progenitor (AEP) lineage within the alveolar type 2 cell population acts as a major facultative progenitor cell in the distal lung. AEPs are a stable lineage during alveolar homeostasis but expand rapidly to regenerate a large proportion of the alveolar epithelium after acute lung injury. AEPs exhibit a distinct transcriptome, epigenome and functional phenotype and respond specifically to Wnt and Fgf signalling. In contrast to other proposed lung progenitor cells, human AEPs can be directly isolated by expression of the conserved cell surface marker TM4SF1, and act as functional human alveolar epithelial progenitor cells in 3D organoids. Our results identify the AEP lineage as an evolutionarily conserved alveolar progenitor that represents a new target for human lung regeneration strategies. PMID- 29489753 TI - Environment dominates over host genetics in shaping human gut microbiota. AB - Human gut microbiome composition is shaped by multiple factors but the relative contribution of host genetics remains elusive. Here we examine genotype and microbiome data from 1,046 healthy individuals with several distinct ancestral origins who share a relatively common environment, and demonstrate that the gut microbiome is not significantly associated with genetic ancestry, and that host genetics have a minor role in determining microbiome composition. We show that, by contrast, there are significant similarities in the compositions of the microbiomes of genetically unrelated individuals who share a household, and that over 20% of the inter-person microbiome variability is associated with factors related to diet, drugs and anthropometric measurements. We further demonstrate that microbiome data significantly improve the prediction accuracy for many human traits, such as glucose and obesity measures, compared to models that use only host genetic and environmental data. These results suggest that microbiome alterations aimed at improving clinical outcomes may be carried out across diverse genetic backgrounds. PMID- 29489756 TI - Electric-current-induced unidirectional propagation of surface plasmon polaritons. AB - Nonreciprocity and one-way propagation of optical signals are crucial for modern nanophotonic technology, and typically achieved using magneto-optical effects requiring large magnetic biases. Here we suggest a fundamentally novel approach to achieve unidirectional propagation of surface plasmon-polaritons (SPPs) at metal-dielectric interfaces. We employ a direct electric current in metals, which produces a Doppler frequency shift of SPPs due to the uniform drift of electrons. This tilts the SPP dispersion, enabling one-way propagation, as well as zero and negative group velocities. The results are demonstrated for planar interfaces and cylindrical nanowire waveguides. PMID- 29489757 TI - Fourier transform spectroscopy by repetition rate sweeping of a single electro optic frequency comb. AB - We demonstrate the operation of a Fourier transform spectrometer that operates by sweeping the pulse repetition frequency of an electro-optic frequency comb. Incorporating a length-imbalanced interferometer, this single-comb system is analogous to a conventional dual-comb system, but with a greatly simplified design. The functionality of the spectrometer is demonstrated via the high resolution spectrum measurement of an H13C14N reference gas cell. PMID- 29489758 TI - Dysprosium-doped ZBLAN fiber laser tunable from 2.8 MUm to 3.4 MUm, pumped at 1.7 MUm. AB - We demonstrate a mid-infrared dysprosium-doped fluoride fiber laser with a continuously tunable output range of 573 nm, pumped by a 1.7 MUm Raman fiber laser. To the best of our knowledge, this represents the largest tuning range achieved to date from any rare-earth-doped fiber laser and, critically, spans the 2.8-3.4 MUm spectral region, which contains absorption resonances of many important functional groups and is uncovered by other rare-earth ions. Output powers up to 170 mW are achieved, with 21% slope efficiency. We also discuss the relative merits of the 1.7 MUm pump scheme, including possible pump excited-state absorption. PMID- 29489755 TI - Pan-cancer genome and transcriptome analyses of 1,699 paediatric leukaemias and solid tumours. AB - Analysis of molecular aberrations across multiple cancer types, known as pan cancer analysis, identifies commonalities and differences in key biological processes that are dysregulated in cancer cells from diverse lineages. Pan-cancer analyses have been performed for adult but not paediatric cancers, which commonly occur in developing mesodermic rather than adult epithelial tissues. Here we present a pan-cancer study of somatic alterations, including single nucleotide variants, small insertions or deletions, structural variations, copy number alterations, gene fusions and internal tandem duplications in 1,699 paediatric leukaemias and solid tumours across six histotypes, with whole-genome, whole exome and transcriptome sequencing data processed under a uniform analytical framework. We report 142 driver genes in paediatric cancers, of which only 45% match those found in adult pan-cancer studies; copy number alterations and structural variants constituted the majority (62%) of events. Eleven genome-wide mutational signatures were identified, including one attributed to ultraviolet light exposure in eight aneuploid leukaemias. Transcription of the mutant allele was detectable for 34% of protein-coding mutations, and 20% exhibited allele specific expression. These data provide a comprehensive genomic architecture for paediatric cancers and emphasize the need for paediatric cancer-specific development of precision therapies. PMID- 29489759 TI - Nodal-line dynamics via exact polynomial solutions for coherent waves traversing aberrated imaging systems. AB - We obtain exact polynomial solutions for two-dimensional coherent complex scalar fields propagating through arbitrary aberrated shift-invariant linear imaging systems. These solutions are used to model nodal-line dynamics of coherent fields output by such systems. PMID- 29489760 TI - Cavity solitons in a microring dimer with gain and loss. AB - We address a pair of vertically coupled microring resonators with gain and loss pumped by a single-frequency field. Coupling between microrings results in a twofold splitting of the single microring resonance that increases when gain and losses decrease, giving rise to two cavity soliton (CS) families. We show that the existence regions of CSs are tunable and that both CS families can be stable in the presence of an imbalance between gain and losses in the two microrings. These findings enable experimental realization of frequency combs in configurations with active microrings and contribute toward the realization of compact multisoliton comb sources. PMID- 29489761 TI - Silicon microdisk-based full adders for optical computing. AB - Due to the projected saturation of Moore's law, as well as the drastically increasing trend of bandwidth with lower power consumption, silicon photonics has emerged as one of the most promising alternatives that has attracted a lasting interest due to the accessibility and maturity of ultra-compact passive and active integrated photonic components. In this Letter, we demonstrate a ripple carry electro-optic 2-bit full adder using microdisks, which replaces the core part of an electrical full adder by optical counterparts and uses light to carry signals from one bit to the next with high bandwidth and low power consumption per bit. All control signals of the operands are applied simultaneously within each clock cycle. Thus, the severe latency issue that accumulates as the size of the full adder increases can be circumvented, allowing for an improvement in computing speed and a reduction in power consumption. This approach paves the way for future high-speed optical computing systems in the post-Moore's law era. PMID- 29489762 TI - AlN based piezoelectric micromirror. AB - Aiming to pursue a micromirror possessing many desired characteristics, such as linear control, low power consumption, fast response, and easy fabrication, a new piezoelectric actuation strategy is presented. Different from conventional piezoelectric actuation cases, we first propose using AlN film as the active layer for actuating the micromirror. Owing to its good CMOS compatible deposition and patterning techniques, the AlN based piezoelectric micromirror has been successfully fabricated with a modified silicon-on-insulator-based microelectromechanical system (MEMS) process. At the same time, various mirror movement modes operating at high frequencies and excellent linear relationship between the movement and the control signal both have been experimentally demonstrated. PMID- 29489763 TI - Simultaneous imaging of flow and sound using high-speed parallel phase-shifting interferometry. AB - In this Letter, simultaneous imaging of flow and sound by using parallel phase shifting interferometry and a high-speed polarization camera is proposed. The proposed method enables the visualization of flow and sound simultaneously by using the following two factors: (i) injection of the gas, whose density is different from the surrounding air, makes the flow visible to interferometry, and (ii) time-directional processing is applied for extracting the small-amplitude sound wave from the high-speed flow video. An experiment with a frame rate of 42,000 frames per second for visualizing the flow and sound emitted from a whistle was conducted. By applying time-directional processing to the obtained video, both flow emitted from the slit of the whistle and a spherical sound wave of 8.7 kHz were successively captured. PMID- 29489764 TI - Continuous-wave modulation of a femtosecond oscillator using coherent molecules. AB - We describe a new method to broaden the frequency spectrum of a femtosecond oscillator in the continuous-wave (CW) domain. The method relies on modulating the femtosecond laser using four-wave mixing inside a Raman-based optical modulator. We prepare the modulator by placing deuterium molecules inside a high finesse cavity and driving their fundamental vibrational transition using intense pump and Stokes lasers that are locked to the cavity modes. With the molecules prepared, any laser within the optical region of the spectrum can pass through the system and be modulated in a single pass. This constitutes a CW optical modulator at a frequency of 90 THz with a steady-state single-pass efficiency of ~10-6 and transient (10 MUs-time-scale) single-pass efficiency of ~10-4. Using our modulator, we broaden the initial Ti:sapphire spectrum centered at 800 nm and produce upshifted and downshifted sidebands centered at wavelengths of 650 nm and 1.04 MUm, respectively. PMID- 29489754 TI - The landscape of genomic alterations across childhood cancers. AB - Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7 8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials. PMID- 29489766 TI - Performance comparisons between semiconductor and fiber amplifier gain assistance in a recirculating frequency shifter. AB - Recirculating frequency shifter (RFS) loops can be used for electronically programmable, variable-spacing multiline spectrum generation, which can benefit the development of fully flexible optical communications and other frequency comb applications. Here, we report on and explain the observation of significant performance variations between chip-based gain in semiconductor optical amplifiers (SOA) and fiber-based gain in erbium-doped fiber amplifiers (EDFA) when used as the gain element in the RFS. Previously, SOAs and EDFAs have been demonstrated in different RFS experiments and studied separately from each other; thus, discussion mainly focused on the noise from amplified spontaneous emission. We show that SOA effects, including four wave mixing, can be measured, which impose limits to the wavelength spacing of the combs, and that this effect is mitigated by increasing the RF drive frequency of the RFS and operating SOA in deeper saturation. PMID- 29489765 TI - Hilbert-Huang single-shot spatially multiplexed interferometric microscopy. AB - Hilbert-Huang single-shot spatially multiplexed interferometric microscopy (H2S2MIM) is presented as the implementation of a robust, fast, and accurate single-shot phase estimation algorithm with an extremely simple, low-cost, and highly stable way to convert a bright field microscope into a holographic one using partially coherent illumination. Altogether, H2S2MIM adds high-speed (video frame rate) quantitative phase imaging capability to a commercially available nonholographic microscope with improved phase reconstruction (coherence noise reduction). The technique has been validated using a 20*/0.46 NA objective in a regular Olympus BX-60 upright microscope for static, as well as dynamic, samples showing perfect agreement with the results retrieved from a temporal phase shifting algorithm. PMID- 29489767 TI - Effect of flip-chip height on the optical performance of conformal white-light emitting diodes. AB - To improve the optical performance of the conformal white light-emitting diodes (LEDs), previous studies mainly focus on the phosphor structures design by simulations and experiments methods. However, one of the most critical parameters, i.e., the height of chips, is barely studied. In this study, we have experimentally investigated the effect of the flip-chip height on the optical performance of conformal white LEDs. The results show that larger chip height can cause lower radiant power and luminous flux, while wider viewing angles can be achieved. By selecting a suitable chip height of 200 MUm, superior color uniformity for white LEDs can be obtained with only 168 K correlated color temperature (DeltaCCT). This study can provide a new perspective to improve the color uniformity without changing the phosphor structures or using special scattering elements; moreover, it can facilitate the selection of a proper chip height, considering different illumination requirements. Further investigations on the chip height considering packaging structures are still necessary to improve the luminous flux and the color uniformity simultaneously. PMID- 29489768 TI - High-power visible-enhanced all-fiber supercontinuum generation in a seven-core photonic crystal fiber pumped at 1016 nm. AB - An 80 W 350-2400 nm monolithic supercontinuum (SC) source is reported. The high power SC is generated in a uniform multi-core photonic crystal fiber (PCF) pumped by a 1016 nm pulsed fiber laser. The specially designed PCF has seven 4.5 MUm diameter cores, a 0.85 air-filling fraction, and a zero dispersion wavelength (ZDW) of 991 nm. The 1016 nm pulsed laser delivers up to 114 W average power, which is believed to be the highest currently reported for picosecond fiber lasers working below 1020 nm. In order to ensure a robust and compact all-fiber structure, the pump laser is fusion spliced to the PCF using a selective air-hole collapse technique, achieving an ultra-low splicing loss of 0.2 dB despite the severe mode field mismatch. The proximity of the pump wavelength to the ZDW of PCF leads to enhanced visible generation. The output SC has a high spectral density of up to 108 mW/nm (at 580 nm) and over 50 mW/nm across the entire visible waveband. The achieved short-wavelength edge and high-spectral-power density in the visible region, to the best of our knowledge, are the best results reported for high-power visible SC sources. PMID- 29489769 TI - Fiber taper diameter characterization using forward Brillouin scattering. AB - We propose a fast and non-destructive method to characterize the absolute diameter and uniformity of micrometer-scale fiber tapers using a pump and probe forward Brillouin scattering setup. The fundamental torsional-radial acoustic mode supported by the wire is excited using a pulsed pump laser and oscillates at a frequency that is inversely proportional to the taper waist diameter. This standing time-varying torsional-radial wave induces polarization modulation on a probe signal, whose spectrum structure reveals the sample diameter and its non uniformity. By comparing our results with measurements using scanning-electron microscopy, a relative deviation of 1% or less was demonstrated, and diameter non uniformity of less than 0.5% could be detected. PMID- 29489770 TI - Mid-infrared multispectral tissue imaging using a chalcogenide fiber supercontinuum source. AB - We present, to the best of our knowledge, the first demonstration of mid-infrared supercontinuum (SC) tissue imaging at wavelengths beyond 5 MUm using a fiber coupled SC source spanning 2-7.5 MUm. The SC was generated in a tapered large mode-area chalcogenide photonic crystal fiber in order to obtain broad bandwidth, high average power, and single-mode output for diffraction-limited imaging performance. Tissue imaging was demonstrated in transmission at selected wavelengths between 5.7 (1754 cm-1) and 7.3 MUm (1370 cm-1) by point scanning over a sub-millimeter region of colon tissue, and the results were compared to images obtained from a commercial instrument. PMID- 29489771 TI - Photonics-based coherent wideband linear frequency modulation pulsed signal generation. AB - A photonics-based scheme is proposed to generate wideband linear frequency modulation pulses with broadly tunable carrier frequencies for coherent radars. The approach integrates the concept of the microwave-photonic multiplication and coherent beating to enable reconfiguration of the bandwidth and carrier frequency of the generated pulses. The phase fluctuation between two beating arms is suppressed by a stabilization technique based on an optical phase-locked loop to maintain the pulse-to-pulse phase coherence. Further, we also demonstrate a coherent radar system, including the generation, wireless transmission and detection of the radar echo signal in the Ka-band. The coherent integration of several echo signals is achieved. About 8 dB of signal-to-noise ratio improvement is obtained with every ten-fold of integration times. The range resolution of the radar system is ~3.75 cm, which is close to the theoretical prediction. PMID- 29489772 TI - Highly efficient all-fiber continuous-wave Raman graded-index fiber laser pumped by a fiber laser. AB - We report for the first time, to the best of our knowledge, an all-fiber Raman graded-index (GRIN) fiber laser pumped by a fiber laser. This configuration points to potential future power and brightness increases. Continuous-wave power of 135 W with an M2 value of 2.5 was obtained at a wavelength of 1081 nm with an optical-to-optical efficiency of 68%. A commercial GRIN core fiber acts as the Raman fiber in a power oscillator configuration that includes fiber Bragg gratings (FBGs) written onto the GRIN fiber. The efficiency and brightness demonstrated here are, to the best of our knowledge, the highest reported in any Raman GRIN fiber laser. A brightness enhancement of the pump beam by a factor of 5.6 is attained due to the transverse profiles of Raman gain and FBG reflection in the GRIN fiber. PMID- 29489773 TI - Multichannel photonic Hilbert transformers based on complex modulated integrated Bragg gratings. AB - Multichannel photonic Hilbert transformers (MPHTs) are reported. The devices are based on single compact spiral integrated Bragg gratings on silicon with coupling coefficients precisely modulated by the phase of each grating period. MPHTs with up to nine wavelength channels and a single-channel bandwidth of up to ~625 GHz are achieved. The potential of the devices for multichannel single-sideband signal generation is suggested. The work offers a new possibility of utilizing wavelength as an extra degree of freedom in designing radio-frequency photonic signal processors. Such multichannel processors are expected to possess improved capacities and a potential to greatly benefit current widespread wavelength division multiplexed systems. PMID- 29489774 TI - 24-26 GHz radio-over-fiber and free-space optics for fifth-generation systems. AB - This Letter outlines radio-over-fiber combined with radio-over-free-space optics (RoFSO) and radio frequency free-space transmission, which is of particular relevance for fifth-generation networks. Here, the frequency band of 24-26 GHz is adopted to demonstrate a low-cost, compact, and high-energy-efficient solution based on the direct intensity modulation and direct detection scheme. For our proof-of-concept demonstration, we use 64 quadrature amplitude modulation with a 100 MHz bandwidth. We assess the link performance by exposing the RoFSO section to atmospheric turbulence conditions. Further, we show that the measured minimum error vector magnitude (EVM) is 4.7% and also verify that the proposed system with the free-space-optics link span of 100 m under strong turbulence can deliver an acceptable EVM of <9% with signal-to-noise ratio levels of 22 dB and 10 dB with and without turbulence, respectively. PMID- 29489775 TI - Passive-demodulation pulse interferometry for ultrasound detection with a high dynamic range. AB - In the optical detection of ultrasound, resonators with high Q-factors are often used to maximize sensitivity. However, increasing the Q-factor of a resonator may reduce the linear range of the interrogation scheme, making it more susceptible to strong external perturbations and incapable of measuring strong acoustic signals. In this Letter, a passive-demodulation scheme for pulse interferometry was developed for high dynamic-range measurements. The passive scheme was based on an unbalanced Mach-Zehnder interferometer and a 90 degrees optical hybrid, which was implemented in a dual-polarization all-fiber setup. We demonstrated the passive scheme for detecting ultrasound bursts with pressure levels for which the response of conventional, active interferometric techniques became nonlinear. PMID- 29489776 TI - Extending the field of view by a scattering window in an I-COACH system. AB - Interferenceless coded aperture correlation holography (I-COACH) is an incoherent digital holography technique developed to record and reconstruct 3D images of objects without two-wave interference. Herein, we introduce a novel technique to extend the field of view (FOV) of I-COACH beyond the limit imposed by the ratio between the finite area of the image sensor and the magnification of the optical system. Light diffracted from a point object located on the optical axis is modulated by a pseudorandom coded phase mask, and the central part of the point spread hologram (PSH) on the image sensor is recorded. The point object is shifted laterally to predetermined lateral locations in order to collect the exterior parts of the PSH. The recorded PSHs are stitched together to produce a synthetic PSH (SPSH) with an area nine times that of any individual PSH recorded by the image sensor. An object with a lateral extent beyond the FOV limit of the image sensor is placed at the same axial location as the point object, and the object hologram is recorded. The object is reconstructed by a cross-correlation between the zero-padded object hologram and the SPSH. Hence, the object parts beyond the FOV limit of the image sensor are recovered. An SPSH library is created for different axial planes, and the corresponding axial planes of the object are reconstructed. PMID- 29489777 TI - Quantitative evaluation of light-matter interaction parameters in organic single crystal microcavities. AB - Investigation of physics on light-matter interaction and strong coupling formation in organic microcavities is important to characterize the device structure enabling efficient room-temperature polariton condensation. In this study, we evaluate quantitatively the light-matter interaction parameters for three types of organic single-crystal microcavities and discuss the effects of microcavity structures on the strong coupling formation. We found that improvement in cavity quality factor causes a reduction in the photon damping constant, which results in an increase in the Rabi splitting energy. Moreover, when we used a metal thin film as the cavity mirror, it was revealed that the exciton damping became 30 times stronger than that in a dielectric mirror cavity. These experimental findings are very intriguing to achieve low-threshold or electrically pumped organic polariton devices. PMID- 29489778 TI - Absolute sensitivity of phase measurement in an SU(1,1) type interferometer. AB - Absolute sensitivity is measured for the phase measurement in an SU(1,1) type interferometer, and the results are compared to that of a Mach-Zehnder interferometer operated under the condition of the same intra-interferometer intensity. The interferometer is phase locked to a point with the largest quantum noise cancellation, and a simulated phase modulation is added in one arm of the SU(1,1) interferometer. Both the signal and noise level are estimated at the same frequency range, and we obtained 3 dB improvement in sensitivity for the SU(1,1) interferometer over the Mach-Zehnder interferometer. Our results demonstrate a direct phase estimation and may pave the way for practical applications of a nonlinear interferometer. PMID- 29489779 TI - Standoff analysis of laser-produced plasmas using laser-induced fluorescence. AB - We report the use of laser-induced fluorescence (LIF) of laser ablation (LA) plumes for standoff applications. The standoff analysis of Al, as major and minor species in samples, is performed in a nanosecond laser-produced plasma created at a distance of ~10 m. The LIF of LA plumes is carried out by resonantly exciting an Al transition at 394.4 nm (S1/22-P1/22) using a continuous wave (cw) tunable laser and by collecting the direct-line fluorescence signal at 396.15 nm. The spectral resolution of LIF is obtained by scanning the cw tunable LIF laser across the selected Al transition. Our results highlight that LIF provides enhanced signal intensity, emission persistence, and spectral resolution when compared to thermally excited emission. PMID- 29489780 TI - Coherent frequency division with a degenerate synchronously pumped optical parametric oscillator. AB - Synchronously pumped optical parametric oscillators (OPOs) are important tools for frequency comb (FC) generation in the mid-IR spectral range, where few suitable laser gain materials exist. For degenerate OPOs, self-phase-locking to the pump FC has been demonstrated. Here, we present a phase noise study of the carrier envelope offset frequency, revealing a -6 dB reduction compared to the pump FC over a wide Fourier frequency range. These results demonstrate that a degenerate OPO can be an ideal coherent frequency divider without any excess noise. PMID- 29489781 TI - Ring-Airy beams at the wavelength limit. AB - We demonstrate that paraxial ring-Airy beams can approach the wavelength limit, while observing a counterintuitive, strong enhancement of their focal peak intensity. Using numerical simulations, we show that this behavior is a result of the coherent constructive action of paraxial and nonparaxial energy flow. A simple theoretical model enables us to predict the parameter range over which this is possible. PMID- 29489782 TI - Optically powered radio-over-fiber system based on center- and offset-launching techniques using a conventional multimode fiber. AB - We demonstrate radio-over-fiber (RoF) transmission with a 10-W feed power-over fiber (PWoF) using a conventional multimode fiber (MMF). In this scheme, the modal dispersion and feed light crosstalk in the MMF are effectively mitigated by the combination of center-launching (CL) and offset-launching (OL) techniques. The CL is used for propagating the feed light into lower-order modes in the MMF, while the OL is used not only for propagating the optical data signals into higher-order modes in the MMF, but also for mitigating the modal dispersion. We successfully achieved significant improvement in the RoF transmission performance with the 10-W feed PWoF and extended the link length up to 4 km, owing to the two techniques. PMID- 29489783 TI - Compact CWDM interleaver based on an interfering loop containing a one dimensional Fabry-Perot cavity. AB - We propose and experimentally demonstrate a compact silicon photonic interleaver based on an interfering loop containing a 1D Fabry-Perot (FP) cavity for coarse wavelength division multiplexing (CWDM) applications. The interleaver consists of a directional coupler and a FP cavity designed to minimize the channel crosstalk. Instead of using an off-chip optical circulator, the reflection light of the interleaver can be separated from the input by placing two identical interleavers in a Mach-Zehnder interferometer (MZI) structure for practical applications. We also study the impacts of fabrication errors of the MZI structure. The fabricated device has a footprint of 64 MUm*70 MUm and a channel spacing of ~19 nm. The maximum crosstalk is -16 dB in a wavelength range from 1508 nm to 1590 nm. PMID- 29489784 TI - Radical passive bleaching of Tm-doped silica fiber with deuterium. AB - We demonstrate the almost complete 2 um laser power recovery of the gamma-ray irradiated thulium (Tm)-doped silica fiber under deuterium loading. The optical optical slope efficiency and the cladding absorption spectra of the Tm-doped fiber with gamma-ray irradiation and deuterium treatment have been measured for comparison. It was found that the slope efficiency of the irradiated Tm-doped fiber could be recovered to 96.1% of the pristine after deuterium bleaching, which significantly degraded from 60.7% to 25.3% after irradiation. Meanwhile, the additional absorption attenuation of the irradiated Tm-doped with D2 treatment completely vanished. Based on the comprehensive comparison of cladding absorption spectra, the probable mechanism of the deuterium bleaching effect on irradiated Tm-doped fiber has also been discussed. PMID- 29489785 TI - Improved atmospheric effect elimination method for the roughness estimation of painted surfaces. AB - We propose a method for eliminating the atmospheric effect in polarimetric imaging remote sensing by using polarimetric imagers to simultaneously detect ground targets and skylight, which does not need calibrated targets. In addition, calculation efficiencies are improved by the skylight division method without losing estimation accuracy. Outdoor experiments are performed to obtain the polarimetric bidirectional reflectance distribution functions of painted surfaces and skylight under different weather conditions. Finally, the roughness of the painted surfaces is estimated. We find that the estimation accuracy with the proposed method is 6% on cloudy weather, while it is 30.72% without atmospheric effect elimination. PMID- 29489786 TI - Thermal stability of volume Bragg gratings in chloride photo-thermo-refractive glass after femtosecond laser bleaching. AB - We demonstrate that the Joule heating of the volume Bragg grating recorded in chloride photo-thermo-refractive glass can be suppressed by bleaching the silver nanoparticles with intense ultrashort laser pulses. Measurement of the bleached grating angular selectivity showed that, at the signal wavelength at 972 nm, the spectral drift is 0.5 nm at the CW laser diode beam intensity as high as 145 W/cm2. Thus, the bleaching of silver nanoparticles results in the improved thermal stability of transmission gratings, allowing one to employ them to control the powerful CW laser radiation. PMID- 29489787 TI - Acousto-optic tunable spectral filtration of stereoscopic images. AB - We propose a new technique for three-dimensional (3-D) imaging in arbitrary spectral intervals. It is based on a simultaneous diffraction of two divergent stereoscopic light beams on a single acoustic wave propagating in a uniaxial birefringent crystal. We discuss in detail this configuration of acousto-optic (AO) interaction, derive basic relations, and experimentally demonstrate the applicability of the proposed approach to 3-D spectral imaging. A stereo-imager of this type may be produced as an ultra-compact embeddable optical element, which is promising for many imaging applications. PMID- 29489788 TI - Surface mode with large field enhancement in dielectric-dimer-on-mirror structures. AB - Plasmonic nanostructures with accessible and strongly enhanced fields are useful for a variety of applications related to surface-enhanced light-matter interaction. We describe a method to migrate localized fields from a metal to dielectric surface. By arranging low-index contrast dielectric dimers on an optically thick metal film, a narrow-linewidth resonant mode is formed through diffraction coupling, with accessible enhancement away from a metal surface. The enhancement in the electric field intensity is over 2000 by dielectric dimers with a 100 nm gap and 720 nm period, and the resonant linewidth is about 0.35 nm around the wavelength of 725 nm. The dispersion of this periodic structure allows resonant enhancement of not only emission but also excitation. The design principle provides a means to tune the narrow-linewidth resonance over a wide wavelength range from ultraviolet to near-infrared. PMID- 29489789 TI - Compact and efficient mid-IR OPO source pumped by a passively Q-switched Tm:YAP laser. AB - We describe a compact and efficient mid-infrared (mid-IR) source based on zinc germanium phosphide (ZGP) and cadmium silicon phosphide (CSP) optical parametric oscillators (OPOs), operating in near degenerate condition, directly pumped by a 1.94 MUm thulium (Tm)-doped yttrium-aluminum-perovskite (YAP) laser. The Tm:YAP laser is passively Q-switched by a chromium-doped zinc sulfide saturable absorber, and is operated to 4 W average power with a peak power of 29 kW. The laser emission was used to pump CSP and ZGP doubly resonant linear OPO cavities, generating a maximum 3.5-4.2 MUm mid-IR emission of 2.5 W for CSP and 2.3 W for ZGP, with maximum optical conversion efficiencies of 65% and 58%, respectively, achieved for the two OPO crystals. PMID- 29489790 TI - Effect of soot self-absorption on color-ratio pyrometry in laminar coflow diffusion flames. AB - This Letter reports on the effect of self-absorption on measured temperature for color-ratio soot pyrometry with a color camera. A series of increasingly nitrogen diluted atmospheric pressure ethylene/air laminar coflow diffusion flames are studied, providing flames with different optical path lengths, soot loading, and soot optical properties. Numerical calculations are used to simulate the change in collected flame emission signal with and without light attenuation using experimentally measured maps of the soot absorption coefficient. This parameter implicitly contains information about soot volume fraction and soot optical properties. The ratio of these calculations is used to correct the raw color channel signals, resulting in temperature maps with improved accuracy. The change in calculated temperature varies spatially within each flame, with the maximum correction quantified to be 22 K for a flame with a maximum optical depth of 0.31. This correction is as much as 42 and 75 K for simulated flames with the same optical properties, structure, and a factor of two and five increase in soot volume fraction, respectively. PMID- 29489791 TI - Toward real-time volumetric tomography for combustion diagnostics via dimension reduction. AB - Volumetric tomography for combustion diagnostics is experiencing significant progress during the past few years due to its capability of imaging evolving turbulent flows. Such capability facilitates the understanding of the mechanisms behind complicated combustion phenomena such as lean blowout, acoustic oscillations, and formation of soot particles. However, these techniques are not flawless and suffer from high computational cost which prevents them from applications where real-time reconstructions and online monitoring are necessary. In this Letter, we propose a new reconstruction method that can effectively reduce the dimension of the inversion problem, which can then be solved with a minimum computational effort. This method and a classical iterative method were tested against each other using a proof-of-concept experiment in which endoscopic computed tomography of chemiluminescence (CTC) was implemented. The results show that the proposed method can dramatically reduce the computational time and, at the same time, maintain similar reconstruction accuracy, as opposed to the classical approach. Although this Letter was discussed under the context of CTC, it can be applied universally to other modalities of volumetric tomography such as volumetric laser-induced fluorescence. PMID- 29489792 TI - Tailorable chiral optical response through coupling among plasmonic meta-atoms with distinct shapes. AB - Chiral plasmonic nanostructures with giant and tunable chiral optical responses hold great potential in chiral sensing applications for chemistry, biology, and pharmacy, etc. For the origin of the chiral optical response of artificial plasmonic chiral assemblies, resonant and off-resonant coupling mechanisms have been figured out. However, most existing chiral plasmonic assemblies are based on only one mechanism, where strong optical chirality always compromises with spectral tunability. To release the trade-off between the strength and spectral tunability, we employ a combination of resonant and off-resonant coupling mechanisms and demonstrate a pronounced and tailorable chiral optical response based on plasmonic meta-atoms with distinct shapes. We anticipate that our strategy provides more flexibility in designing chiral plamsonic nanostructures and promotes the field further towards customized chiral plasmonic platforms. PMID- 29489793 TI - Miniature probe for in vivo optical- and acoustic-resolution photoacoustic microscopy. AB - We present a miniature probe capable of both optical-resolution (OR) and acoustic resolution (AR) photoacoustic microscopy. A gradient-index-lens fiber and a multimode fiber are used to deliver light for OR and AR illumination, respectively. The probe achieves lateral resolution of 3.1 MUm for OR mode and 46 249 MUm (at depth of 1.2-4.3 mm) for AR mode, respectively. The size of the probe attains 3.7 mm in diameter, which can be used for endoscopic applications. In vivo imaging of several different parts of a mouse demonstrates the excellent imaging ability of the probe. PMID- 29489794 TI - Power-flow-based design strategy for Bloch surface wave biosensors. AB - We propose a novel semi-analytic design strategy for dielectric one-dimensional multilayer biosensors that is based on a relation between the angular sensitivity and the optical power flow of the Bloch surface wave guided by the multilayer. We show that our strategy can be used to optimize both the sensor's sensitivity and figure-of-merit without the need for extensive numerical parameter sweeps. PMID- 29489795 TI - Experimental characterization of nonlinear interference noise as a process of intersymbol interference. AB - We demonstrate a method for experimentally characterizing the second order statistics of nonlinear interference noise (NLIN) as an intersymbol interference (ISI) process. The method enables measurement of the properties of high-order ISI coefficients, which have been largely overlooked in the past. The ability of measuring these statistics is imperative for designing effective NLIN mitigation schemes. The variance, temporal correlation times, and cross correlations of the various ISI coefficients are evaluated in several system implementations. PMID- 29489796 TI - NALM-based bismuth-doped fiber laser at 1.7 MUm. AB - We demonstrate, to the best of our knowledge, the first bismuth-doped fiber laser operating at 1.7 MUm mode-locked by means of Kerr nonlinearity. The laser setup has a figure-of-eight all-fiber design with a nonlinear amplifying loop mirror (NALM) and yields 17 ps pulses with a 3.57 MHz repetition rate and the energy 84 pJ. Using the master oscillator power amplifier scheme with a bismuth fiber amplifier, the output pulse energy of 5.7 nJ was achieved. Further pulse compression in the fiber compressor shortened pulses to 630 fs. The operation of the master oscillator was modeled using the nonlinear Schrodinger equation. Calculated data are in good agreement with experimental results. PMID- 29489797 TI - Laser wakefield acceleration with mid-IR laser pulses. AB - We report on, to the best of our knowledge, the first results of laser plasma wakefield acceleration driven by ultrashort mid-infrared (IR) laser pulses (lambda=3.9 MUm, 100 fs, 0.25 TW), which enable near- and above-critical density interactions with moderate-density gas jets. Relativistic electron acceleration up to ~12 MeV occurs when the jet width exceeds the threshold scale length for relativistic self-focusing. We present scaling trends in the accelerated beam profiles, charge, and spectra, which are supported by particle-in-cell simulations and time-resolved images of the interaction. For similarly scaled conditions, we observe significant increases in the accelerated charge, compared to previous experiments with near-infrared (lambda=800 nm) pulses. PMID- 29489798 TI - Silicon arrayed waveguide gratings at 2.0-MUm wavelength characterized with an on chip resonator. AB - Low-loss arrayed waveguide gratings (AWGs) are demonstrated at a 2.0-MUm wavelength. These devices promote rapidly developing photonic applications, supported by the recent development of mid-infrared lasers integrated on silicon (Si). Multi-spectral photonic integrated circuits at 2.0-MUm are envisioned since the AWGs are fabricated with the 500-nm-thick Si-on-insulator platform compatible with recently demonstrated lasers and semiconductor optical amplifiers on Si. Characterization with the AWG-ring method improves the on-chip transmission uncertainty to ~6% compared to the conventional method with an uncertainty of ~53%. Channel losses of ~2.4 dB are found, with -31 dB crosstalk per channel. Fully integrated multi-spectral sources at 2.0 MUm with pump lasers, low-loss multiplexers, and an output amplifier are now feasible. PMID- 29489799 TI - Femtosecond laser direct writing of ion exchangeable multifunctional microstructures. AB - We report on the fabrication of ion exchangeable microstructures by femtosecond laser direct writing of an ion exchange photopolymer, poly(2-acrylamido-2-methyl 1-propanesulfonic acid) (PAMPS). The resultant microstructures are negatively charged in aqueous solution, and can adsorb positively charged species, such as metal ions, nanoparticles, and proteins by electrostatic interaction, forming functional components for chip functionalization. In addition, it is possible to modify the microstructures with positively charged species that make the microstructures sensitive to negatively charged species. As a typical example, a crossed 3D microvessel functionalized with antibodies was fabricated, which reveals great potential for organ-on-a-chip systems. The fabrication of ion exchangeable microstructures holds great promise for flexible chip functionalization. PMID- 29489800 TI - Coded aperture structured illumination digital holographic microscopy for superresolution imaging. AB - This paper proposes a coded aperture structured illumination (CASI) technique in digital holographic microscopy (DHM). A CASI wave is generated using two binary phase codes (0 degrees and 120 degrees ) for spatial phase shifting. The generated CASI wave then interferes with a reference wave to form a coded Fresnel hologram at a single exposure with compressive sensing (CS) to avoid the temporal phase-shifting process of the structured illumination (SI). The CS algorithm is applied to retrieve the missing data of decoded phase-shifted SI-modulated waves, which are used to separate overlapped spatial frequencies for obtaining a larger spatial frequency coverage to provide superresolution imaging. Two phase-only spatial light modulators are applied to generate a directional SI pattern for obtaining a coded aperture with a suitable size to perform one-shot acquisition in the DHM system. PMID- 29489801 TI - Spatially resolved control of fictitious magnetic fields in a cold atomic ensemble. AB - Effective and unrestricted engineering of atom-photon interactions requires precise spatially resolved control of light beams. The significant potential of such manipulations lies in a set of disciplines ranging from solid-state to atomic physics. Here we use a Zeeman-like ac-Stark shift caused by a shaped laser beam to perform rotations of spins with spatial resolution in a large ensemble of cold rubidium atoms. We show that inhomogeneities of light intensity are the main source of dephasing and, thus, decoherence; yet, with proper beam shaping, this deleterious effect is strongly mitigated allowing rotations of 15 rad within one spin-precession lifetime. Finally, as a particular example of a complex manipulation enabled by our scheme, we demonstrate a range of collapse-and revival behaviors of a free-induction decay signal by imprinting comb-like patterns on the atomic ensemble. PMID- 29489802 TI - Generation of colorful Airy beams and Airy imaging of letters via two-photon processed cubic phase plates. AB - In this Letter, we demonstrate the observation of colorful Airy beams and Airy imaging of letters, which we called Airy letters here, generated through the continuous cubic phase microplate (CCPP) elaborately fabricated by femtosecond laser two-photon processing. The fabricated CCPP with both micro size (60 MUm*60 MUm*1.1 MUm) and continuous variation of phase shows a good agreement with the designed CCPP. Chromatic Airy beams and Airy letters "USTC" are experimentally generated via the CCPP illuminated by white light. In addition, superior properties of Airy letters are explored, demonstrating that the Airy letters inherit the nondiffraction, self-healing, and transverse acceleration characteristics of Airy beams. Our work paves the way toward integrated optics, light separation, optical imaging, and defective information recovery. PMID- 29489803 TI - Direct transfer of pump amplitude to parametric down-converted photons. AB - In general, the spatial distribution of individual photons (signal or idler) generated by spontaneous parametric down-conversion (SPDC) does not evidently show any particular spatial mode structure because of their randomness in generation and the incoherent nature. Here, we numerically showed that all individual photons generated by the SPDC process carry the transverse amplitude as that of the pump and then confirmed it experimentally. The pump amplitude is revealed in SPDC when individual photons are spatially filtered from the total SPDC distribution. This is observed simply by imaging the photons that are filtered using a minimum-sized aperture. The phase measurements showed that the observed mode distribution does not possess the transverse phase distribution as that of the pump. PMID- 29489804 TI - Anomalous resonant reflection in a Fabry-Perot cavity filled with weakly scattering medium. AB - In this work, we fabricated a metallic Fabry-Perot cavity, filled with a weakly scattering medium of unsintered solgel silica, on a glass substrate. We found anomalous asymmetric resonance reflection spectra of this structure, besides the effects of scattering loss in cavity. The asymmetric reflection is shown to be dependent on the media on both sides of the cavity. It is thought that, as the weakly scattering medium locates between highly reflecting boundaries and the cavity length is far less than the mean free path of light in the medium, light scattering in the medium is enhanced at the resonance conditions and the scattering centers act as elementary sources emitting the scattered incoherent light to the outside of the cavity from both its ends. The asymmetric reflection then results from lossy total internal reflection of the scattered light at one of the boundaries, eventually leaking to the outside of the cavity with the higher index and contributing to the measured backside reflectance. PMID- 29489805 TI - Single phonon source based on a giant polariton nonlinear effect. AB - We propose a single phonon source based on nitrogen-vacancy (NV) centers, which are located in a diamond phononic crystal resonator. The strain in the lattice would induce the coupling between the NV centers and the phonon mode. The strong coupling between the excited state of the NV centers and the phonon is realized by adding an optical laser driving. This four-level NV center system exhibits coherent population trapping and yields giant resonantly enhanced acoustic nonlinearities, with zero linear susceptibility. Based on this nonlinearity, the single phonon source can be realized. We numerically calculate g(2)(0) of the single phonon source. We discuss the effects of the thermal noise and the external driving strength. PMID- 29489806 TI - Generation of multifocal irradiance patterns by using complex Fresnel holograms. AB - We experimentally demonstrate Fresnel holograms able to produce multifocal irradiance patterns with micrometric spatial resolution. These holograms are assessed from the coherent sum of multiple Fresnel lenses. The utilized encoded technique guarantees full control over the reconstructed irradiance patterns due to an optimal codification of the amplitude and phase information of the resulting complex field. From a practical point of view, a phase-only spatial light modulator is used in a couple of experiments addressed to obtain two- and three-dimensional distributions of focal points to excite both linear and non linear optical phenomena. PMID- 29489807 TI - 20 kHz CH2O and OH PLIF with stereo PIV. AB - Planar laser-induced fluorescence (PLIF) of hydroxyl (OH) and formaldehyde (CH2O) radicals was performed alongside stereo particle image velocimetry (PIV) at a 20 kHz repetition rate in a highly turbulent Bunsen flame. A dual-pulse burst-mode laser generated envelopes of 532 nm pulse pairs for PIV as well as a pair of 355 nm pulses, the first of which was used for CH2O PLIF. A diode-pumped solid-state Nd:YAG/dye laser system produced the excitation beam for the OH PLIF. The combined diagnostics produced simultaneous, temporally resolved two-dimensional fields of OH and CH2O and two-dimensional, three-component velocity fields, facilitating the observation of the interaction of fluid dynamics with flame fronts and preheat layers. The high-fidelity data acquired surpass the previous state of the art and demonstrate dual-pulse burst-mode laser technology with the ability to provide pulse pairs at both 532 and 355 nm with sufficient energy for scattering and fluorescence measurement at 20 kHz. PMID- 29489808 TI - Nonlinear characterization of a silicon integrated Bragg waveguide filter. AB - Bragg waveguides are promising optical filters for pump suppression in spontaneous four-wave mixing (FWM) photon sources. In this work, we investigate the generation of unwanted photon pairs in the filter itself. We do this by taking advantage of the relation between spontaneous and classical FWM, which allows for the precise characterization of the nonlinear response of the device. The pair generation rate estimated from the classical measurement is compared with the theoretical value calculated by means of a full quantum model of the filter, which also allows investigation of the spectral properties of the generated pairs. We find a good agreement between theory and experiment, confirming that stimulated FWM is a valuable approach to characterize the nonlinear response of an integrated filter, and that the pairs generated in a Bragg waveguide are not a serious issue for the operation of a fully integrated nonclassical source. PMID- 29489809 TI - Development of molecular-selective differential interference contrast microscopy utilizing stimulated Raman scattering. AB - Development of a differential interference contrast (DIC) stimulated Raman scattering (SRS) microscope is presented. In the apparatus, a coherent SRS signal generated from the sample is overlapped with a reference beam that is also focused on the same sample. The signal intensity correlates with the height difference between the point generating the SRS signal and the focal point of the reference beam. We applied the developed apparatus for imaging of Si surfaces with structures with heights of 50-350 nm. We also obtained the DIC-SRS image of the Si surface buried by liquid crystal. The structures of the interface between Si and liquid crystal were well observed when both the SRS signals due to Si and liquid crystal were utilized. It was also revealed that DIC-SRS microscopy is an effective tool to obtain molecular-selective images of structured interfaces with a height of less than several tens of nanometers buried by optically transparent media. PMID- 29489810 TI - Passively Q-switched mid-infrared laser pulse generation with gold nanospheres as a saturable absorber. AB - High-quality gold (Au) nanospheres (Au-NPs) with a diameter of 52 nm were prepared by the seeded growth method. The mid-infrared (MIR) nonlinear saturable absorption properties were measured by a balanced twin-detector measurement technique. With the as-prepared Au-NPs saturable absorber (SA), an efficient passively Q-switched laser was realized at 2.95 MUm for the first time, to the best of our knowledge. Under an absorbed pump power of 4.0 W, a maximum output power of 268 mW was obtained with the shortest pulse width of 734 ns and repetition rate of 91 kHz, corresponding to the pulse energy up to 2.95 MUJ. The results indicate that Au-NPs are promising candidates as SAs for MIR laser pulse generation. PMID- 29489811 TI - Femtosecond two-photon-excited backward lasing of atomic hydrogen in a flame. AB - We report on an observation of bi-directional 656 nm lasing action of atomic hydrogen in a premixed CH4/air flame induced by resonant femtosecond 205 nm two photon excitation. In particular, the backward-propagating lasing pulse is characterized in the spatial and temporal domains for the sake of a single-ended diagnostic. Its picosecond-scale duration and smooth temporal profile enable spatially resolved detection of hydrogen atoms in the millimeter range, which is successfully demonstrated using two narrow welding flames. PMID- 29489812 TI - Terahertz radiation in graphene hyperbolic medium excited by an electric dipole. AB - In this Letter, the enhanced and directional radiation in a wide terahertz (THz) frequency range in a graphene hyperbolic medium excited by an electric dipole is presented. The numerical simulations and theoretical analyses indicate that the enhanced radiation comes from the strong surface plasmon couplings in the graphene hyperbolic medium, consisting of alternative graphene and dielectric substrate layers. The simulation results also show that the peak power flow of the enhanced THz radiation in the graphene hyperbolic medium is dramatically enhanced by more than 1 order of magnitude over that in a general medium within a certain distance from the dipole, and the electromagnetic fields are strongly concentrated in a narrow angle. Also, the radiation fields can be manipulated, and the fields' angular distributions can be tuned by adjusting the dielectric permittivity and thickness of the substrates, and the chemical potential of graphene. Accordingly, it provides a good opportunity for developing miniature, integratable, high-power-density, and tunable radiation sources in the THz band at room temperature. PMID- 29489813 TI - Generation of high-energy, kilohertz-rate narrowband tunable ultraviolet pulses using a burst-mode dye laser system. AB - Typical commercial pulsed dye laser systems used in the generation of narrowband, tunable ultraviolet radiation for planar laser-induced fluorescence (PLIF) imaging are optimized for either high (~5-10 kHz) repetition rates at comparatively low ultraviolet pulse energies (hundreds of microjoules) or high output pulse energies (>10 mJ) at comparatively low repetition rates (~10 Hz). In this work we use a frequency-doubled Nd:YAG burst-mode laser to pump a custom dye laser system for high pulse energies and repetition rates of 7.5, 10, and 20 kHz at 566 nm. The frequency-doubled output of over 2.2 mJ/pulse at 283 nm, which can be used for PLIF imaging of combustion radicals, is an order of magnitude higher per pulse energy as compared with continuously pulsed dye laser systems and is ~3* higher in overall efficiency than a burst-mode optical parametric oscillator at similar wavelengths. The influence of repetition rate, pump energy, and dye concentration on the output conversion efficiency and pulse-to-pulse stability of the current system is discussed. PMID- 29489814 TI - Reversals and limitations on high-intensity, life-sustaining treatments. AB - IMPORTANCE: Critically ill patients often receive high-intensity life sustaining treatments (LST) in the intensive care unit (ICU), although they can be ineffective and eventually undesired. Determining the risk factors associated with reversals in LST goals can improve patient and provider appreciation for the natural history and epidemiology of critical care and inform decision making around the (continued) use of LSTs. METHODS: This is a single institution retrospective cohort study of patients receiving life sustaining treatment in an academic tertiary hospital from 2009 to 2013. Deidentified patient electronic medical record data was collected via the clinical data warehouse to study the outcomes of treatment limiting Comfort Care and do-not-resuscitate (DNR) orders. Extended multivariable Cox regression models were used to estimate the association of patient and clinical factors with subsequent treatment limiting orders. RESULTS: 10,157 patients received life-sustaining treatment while initially Full Code (allowing all resuscitative measures). Of these, 770 (8.0%) transitioned to Comfort Care (with discontinuation of any life-sustaining treatments) while 1,669 (16%) patients received new DNR orders that reflect preferences to limit further life-sustaining treatment options. Patients who were older (Hazard Ratio(HR) 1.37 [95% CI 1.28-1.47] per decade), with cerebrovascular disease (HR 2.18 [95% CI 1.69-2.81]), treated by the Medical ICU (HR 1.92 [95% CI 1.49-2.49]) and Hematology-Oncology (HR 1.87 [95% CI 1.27-2.74]) services, receiving vasoactive infusions (HR 1.76 [95% CI 1.28, 2.43]) or continuous renal replacement (HR 1.83 [95% CI 1.34, 2.48]) were more likely to transition to Comfort Care. Any new DNR orders were more likely for patients who were older (HR 1.43 [95% CI 1.38-1.48] per decade), female (HR 1.30 [95% CI 1.17-1.44]), with cerebrovascular disease (HR 1.45 [95% CI 1.25-1.67]) or metastatic solid cancers (HR 1.92 [95% CI 1.48-2.49]), or treated by Medical ICU (HR 1.63 [95% CI 1.42 1.86]), Hematology-Oncology (HR 1.63 [95% CI 1.33-1.98]) and Cardiac Care Unit Heart Failure (HR 1.41 [95% CI 1.15-1.72]). CONCLUSION: Decisions to reverse or limit treatment goals occurs after more than 1 in 13 trials of LST, and is associated with older female patients, receiving non-ventilator forms of LST, cerebrovascular disease, and treatment by certain medical specialty services. PMID- 29489816 TI - Formal comment on: Myhrvold (2016) Dinosaur metabolism and the allometry of maximum growth rate. PLoS ONE; 11(11): e0163205. AB - In his 2016 paper, Myhrvold criticized ours from 2014 on maximum growth rates (Gmax, maximum gain in body mass observed within a time unit throughout an individual's ontogeny) and thermoregulation strategies (ectothermy, endothermy) of 17 dinosaurs. In our paper, we showed that Gmax values of similar-sized extant ectothermic and endothermic vertebrates overlap. This strongly questions a correct assignment of a thermoregulation strategy to a dinosaur only based on its Gmax and (adult) body mass (M). Contrary, Gmax separated similar-sized extant reptiles and birds (Sauropsida) and Gmax values of our studied dinosaurs were similar to those seen in extant similar-sized (if necessary scaled-up) fast growing ectothermic reptiles. Myhrvold examined two hypotheses (H1 and H2) regarding our study. However, we did neither infer dinosaurian thermoregulation strategies from group-wide averages (H1) nor were our results based on that Gmax and metabolic rate (MR) are related (H2). In order to assess whether single dinosaurian Gmax values fit to those of extant endotherms (birds) or of ectotherms (reptiles), we already used a method suggested by Myhrvold to avoid H1, and we only discussed pros and cons of a relation between Gmax and MR and did not apply it (H2). We appreciate Myhrvold's efforts in eliminating the correlation between Gmax and M in order to statistically improve vertebrate scaling regressions on maximum gain in body mass. However, we show here that his mass-specific maximum growth rate (kC) replacing Gmax (= MkC) does not model the expected higher mass gain in larger than in smaller species for any set of species. We also comment on, why we considered extant reptiles and birds as reference models for extinct dinosaurs and why we used phylogenetically-informed regression analysis throughout our study. Finally, we question several arguments given in Myhrvold in order to support his results. PMID- 29489815 TI - Prolonging herd immunity to cholera via vaccination: Accounting for human mobility and waning vaccine effects. AB - BACKGROUND: Oral cholera vaccination is an approach to preventing outbreaks in at risk settings and controlling cholera in endemic settings. However, vaccine derived herd immunity may be short-lived due to interactions between human mobility and imperfect or waning vaccine efficacy. As the supply and utilization of oral cholera vaccines grows, critical questions related to herd immunity are emerging, including: who should be targeted; when should revaccination be performed; and why have cholera outbreaks occurred in recently vaccinated populations? METHODS AND FINDINGS: We use mathematical models to simulate routine and mass oral cholera vaccination in populations with varying degrees of migration, transmission intensity, and vaccine coverage. We show that migration and waning vaccine efficacy strongly influence the duration of herd immunity while birth and death rates have relatively minimal impacts. As compared to either periodic mass vaccination or routine vaccination alone, a community could be protected longer by a blended "Mass and Maintain" strategy. We show that vaccination may be best targeted at populations with intermediate degrees of mobility as compared to communities with very high or very low population turnover. Using a case study of an internally displaced person camp in South Sudan which underwent high-coverage mass vaccination in 2014 and 2015, we show that waning vaccine direct effects and high population turnover rendered the camp over 80% susceptible at the time of the cholera outbreak beginning in October 2016. CONCLUSIONS: Oral cholera vaccines can be powerful tools for quickly protecting a population for a period of time that depends critically on vaccine coverage, vaccine efficacy over time, and the rate of population turnover through human mobility. Due to waning herd immunity, epidemics in vaccinated communities are possible but become less likely through complementary interventions or data driven revaccination strategies. PMID- 29489817 TI - Climate change adaptation benefits of potential conservation partnerships. AB - We evaluate the world terrestrial network of protected areas (PAs) for its partnership potential in responding to climate change. That is, if a PA engaged in collaborative, trans-boundary management of species, by investing in conservation partnerships with neighboring areas, what climate change adaptation benefits might accrue? We consider core tenets of conservation biology related to protecting large areas with high environmental heterogeneity and low climate change velocity and ask how a series of biodiversity adaptation indicators change across spatial scales encompassing potential PA and non-PA partners. Less than 1% of current world terrestrial PAs equal or exceed the size of established and successful conservation partnerships. Partnering at this scale would increase the biodiversity adaptation indicators by factors up to two orders of magnitude, compared to a null model in which each PA is isolated. Most partnership area surrounding PAs is comprised of non-PAs (70%), indicating the importance of looking beyond the current network of PAs when promoting climate change adaptation. Given monumental challenges with PA-based species conservation in the face of climate change, partnerships provide a logical and achievable strategy for helping areas adapt. Our findings identify where strategic partnering efforts in highly vulnerable areas of the world may prove critical in safeguarding biodiversity. PMID- 29489818 TI - Regional cerebral effects of ketone body infusion with 3-hydroxybutyrate in humans: Reduced glucose uptake, unchanged oxygen consumption and increased blood flow by positron emission tomography. A randomized, controlled trial. AB - Ketone bodies are neuroprotective in neurological disorders such as epilepsy. We randomly studied nine healthy human subjects twice-with and without continuous infusion of 3-hydroxybutyrate-to define potential underlying mechanisms, assessed regionally (parietal, occipital, temporal, cortical grey, and frontal) by PET scan. During 3-hydroxybutyrate infusions concentrations increased to 5.5+/-0.4 mmol/l and cerebral glucose utilisation decreased 14%, oxygen consumption remained unchanged, and cerebral blood flow increased 30%. We conclude that acute 3-hydroxybutyrate infusion reduces cerebral glucose uptake and increases cerebral blood flow in all measured brain regions, without detectable effects on cerebral oxygen uptake though oxygen extraction decreased. Increased oxygen supply concomitant with unchanged oxygen utilisation may contribute to the neuroprotective effects of ketone bodies. PMID- 29489819 TI - Combinations of plant water-stress and neonicotinoids can lead to secondary outbreaks of Banks grass mite (Oligonychus pratensis Banks). AB - Spider mites, a cosmopolitan pest of agricultural and landscape plants, thrive under hot and dry conditions, which could become more frequent and extreme due to climate change. Recent work has shown that neonicotinoids, a widely used class of systemic insecticides that have come under scrutiny for non-target effects, can elevate spider mite populations. Both water-stress and neonicotinoids independently alter plant resistance against herbivores. Yet, the interaction between these two factors on spider mites is unclear, particularly for Banks grass mite (Oligonychus pratensis; BGM). We conducted a field study to examine the effects of water-stress (optimal irrigation = 100% estimated evapotranspiration (ET) replacement, water stress = 25% of the water provided to optimally irrigated plants) and neonicotinoid seed treatments (control, clothianidin, thiamethoxam) on resident mite populations in corn (Zea mays, hybrid KSC7112). Our field study was followed by a manipulative field cage study and a parallel greenhouse study, where we tested the effects of water-stress and neonicotinoids on BGM and plant responses. We found that water-stress and clothianidin consistently increased BGM densities, while thiamethoxam-treated plants only had this effect when plants were mature. Water-stress and BGM herbivory had a greater effect on plant defenses than neonicotinoids alone, and the combination of BGM herbivory with the two abiotic factors increased the concentration of total soluble proteins. These results suggest that spider mite outbreaks by combinations of changes in plant defenses and protein concentration are triggered by water-stress and neonicotinoids, but the severity of the infestations varies depending on the insecticide active ingredient. PMID- 29489820 TI - An economic evaluation of an integrated care pathway in geriatric rehabilitation for older patients with complex health problems. AB - BACKGROUND: Integrated care pathways which cover multiple care settings are increasingly used as a tool to structure care, enhance coordination and improve transitions between care settings. However, little is known about their economic impact. The objective of this study is to determine the cost-effectiveness and cost-utility of an integrated care pathway designed for patients with complex health problems transferring from the hospital, a geriatric rehabilitation facility and primary care. METHODS: This economic evaluation was performed from a societal perspective alongside a prospective cohort study with two cohorts of patients. The care as usual cohort was included before implementation of the pathway and the care pathway cohort after implementation of the pathway. Both cohorts were measured over nine months, during which intervention costs, healthcare costs, patient and family costs were identified. The outcome measures were dependence in activities of daily living (measured with the KATZ-15) and quality adjusted life years (EQ-5D-3L). Costs and effects were bootstrapped and various sensitivity analyses were performed to assess robustness of the results. RESULTS: After nine months, the average societal costs were significantly lower for patients in the care pathway cohort (?50,791) versus patients in the care as usual cohort (?62,170; CI = -22,090, -988). Patients in the care pathway cohort had better scores on the KATZ-15 (1.04), indicating cost-effectiveness. No significant differences were found between the two groups on QALY scores (0.01). CONCLUSIONS: The results of this study indicate that the integrated care pathway is a cost-effective intervention. Therefore, dissemination of the integrated care pathway on a wider scale could be considered. This would provide us the opportunity to confirm the findings of our study in larger economic evaluations. When looking at QALYs, no effects were found. Therefore, it is also recommended to explore if therapy in geriatric rehabilitation could also pay attention to other quality of life-related domains, such as mood and social participation. PMID- 29489821 TI - Design, monitoring and evaluation of a direct payments approach for an ecotourism strategy to reduce illegal hunting and trade of wildlife in Lao PDR. AB - Ecotourism as a strategy for achieving biodiversity conservation often results in limited conservation impact relative to its investment and revenue return. In cases where an ecotourism strategy has been used, projects are frequently criticized for not providing sufficient evidence on how the strategy has reduced threats or improved the status of the biodiversity it purports to protect. In Lao PDR, revenue from ecotourism has not been directly linked to or dependent on improvements in biodiversity and there is no evidence that ecotourism enterprises have contributed to conservation. In other developing countries, direct payments through explicit contracts in return for ecosystem services have been proposed as a more cost-effective means for achieving conservation, although further research is needed to evaluate the impact of this approach. To address this need, a new model was tested in the Nam Et-Phou Louey National Protected Area (NPA) in Lao PDR using a direct payments approach to create ecotourism incentives for villagers to increase wildlife populations. Over a four-year period, we monitored along a theory of change to evaluate assumptions about the linkages between intermediate results and biological outcomes. Preliminary results show a negative correlation between ecotourism benefits and hunting infractions in target villages; no increase in hunting sign in the ecotourism sector of the NPA relative to a three-fold increase in hunting sign across the NPA's non-tourism sectors; and an overall increase in wildlife sightings. This case provides key lessons on the design of a direct payments approach for an ecotourism strategy, including how to combine threat monitoring and data on wildlife sightings to evaluate strategy effectiveness, on setting rates for wildlife sightings and village fees, and the utility of the approach for protecting very rare species. PMID- 29489822 TI - Ligand-induced perturbation of the HIF-2alpha:ARNT dimer dynamics. AB - Hypoxia inducible factors (HIFs) are transcription factors belonging to the basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) protein family with a role in sensing oxygen levels in the cell. Under hypoxia, the HIF-alpha degradation pathway is blocked and dimerization with the aryl hydrocarbon receptor nuclear translocator (ARNT) makes HIF-alpha transcriptionally active. Due to the common hypoxic environment of tumors, inhibition of this mechanism by destabilization of HIF alpha:ARNT dimerization has been proposed as a promising therapeutic strategy. Following the discovery of a druggable cavity within the PAS-B domain of HIF 2alpha, research efforts have been directed to identify artificial ligands that can impair heterodimerization. Although the crystallographic structures of the HIF-2alpha:ARNT complex have elucidated the dimer architecture and the 0X3 inhibitor placement within the HIF-2alpha PAS-B, unveiling the inhibition mechanism requires investigation of how ligand-induced perturbations could dynamically propagate through the structure and affect dimerization. To this end, we compared evolutionary features, intrinsic dynamics and energetic properties of the dimerization interfaces of HIF-2alpha:ARNT in both the apo and holo forms. Residue conservation analysis highlighted inter-domain connecting elements that have a role in dimerization. Analysis of domain contributions to the dimerization energy demonstrated the importance of bHLH and PAS-A of both partners and of HIF 2alpha PAS-B domain in dimer stabilization. Among quaternary structure oscillations revealed by Molecular Dynamics simulations, the hinge-bending motion of the ARNT PAS-B domain around the flexible PAS-A/PAS-B linker supports a general model for ARNT dimerization in different heterodimers. Comparison of the HIF-2alpha:ARNT dynamics in the apo and 0X3-bound forms indicated a model of inhibition where the HIF-2alpha-PAS-B interfaces are destabilised as a result of water-bridged ligand-protein interactions and these local effects allosterically propagate to perturb the correlated motions of the domains and inter-domain communication. These findings will guide the design of improved inhibitors to contrast cell survival in tumor masses. PMID- 29489823 TI - Diet during pregnancy and infancy and risk of allergic or autoimmune disease: A systematic review and meta-analysis. AB - BACKGROUND: There is uncertainty about the influence of diet during pregnancy and infancy on a child's immune development. We assessed whether variations in maternal or infant diet can influence risk of allergic or autoimmune disease. METHODS AND FINDINGS: Two authors selected studies, extracted data, and assessed risk of bias. Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to assess certainty of findings. We searched Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica dataBASE (EMBASE), Web of Science, Central Register of Controlled Trials (CENTRAL), and Literatura Latino Americana em Ciencias da Saude (LILACS) between January 1946 and July 2013 for observational studies and until December 2017 for intervention studies that evaluated the relationship between diet during pregnancy, lactation, or the first year of life and future risk of allergic or autoimmune disease. We identified 260 original studies (964,143 participants) of milk feeding, including 1 intervention trial of breastfeeding promotion, and 173 original studies (542,672 participants) of other maternal or infant dietary exposures, including 80 trials of maternal (n = 26), infant (n = 32), or combined (n = 22) interventions. Risk of bias was high in 125 (48%) milk feeding studies and 44 (25%) studies of other dietary exposures. Evidence from 19 intervention trials suggests that oral supplementation with nonpathogenic micro-organisms (probiotics) during late pregnancy and lactation may reduce risk of eczema (Risk Ratio [RR] 0.78; 95% CI 0.68-0.90; I2 = 61%; Absolute Risk Reduction 44 cases per 1,000; 95% CI 20-64), and 6 trials suggest that fish oil supplementation during pregnancy and lactation may reduce risk of allergic sensitisation to egg (RR 0.69, 95% CI 0.53-0.90; I2 = 15%; Absolute Risk Reduction 31 cases per 1,000; 95% CI 10-47). GRADE certainty of these findings was moderate. We found weaker support for the hypotheses that breastfeeding promotion reduces risk of eczema during infancy (1 intervention trial), that longer exclusive breastfeeding is associated with reduced type 1 diabetes mellitus (28 observational studies), and that probiotics reduce risk of allergic sensitisation to cow's milk (9 intervention trials), where GRADE certainty of findings was low. We did not find that other dietary exposures-including prebiotic supplements, maternal allergenic food avoidance, and vitamin, mineral, fruit, and vegetable intake-influence risk of allergic or autoimmune disease. For many dietary exposures, data were inconclusive or inconsistent, such that we were unable to exclude the possibility of important beneficial or harmful effects. In this comprehensive systematic review, we were not able to include more recent observational studies or verify data via direct contact with authors, and we did not evaluate measures of food diversity during infancy. CONCLUSIONS: Our findings support a relationship between maternal diet and risk of immune-mediated diseases in the child. Maternal probiotic and fish oil supplementation may reduce risk of eczema and allergic sensitisation to food, respectively. PMID- 29489824 TI - Why snakebite patients in Myanmar seek traditional healers despite availability of biomedical care at hospitals? Community perspectives on reasons. AB - BACKGROUND: Snakebite is a major public health problem in many developing countries. Farmers are particularly exposed to snakes, and due to their rural location often experience delays in accessing formal healthcare. The reasons to use traditional healers may include difficulties in accessing formal healthcare, certain beliefs about snakes and snake venom, tradition, and trust in the capacity of traditional healers. Traditional healing, however, may have serious consequences in terms of delays or added complications. There is little in-depth current information about the reasons for its continued use for snakebite. As part of a health services development project to improve health outcomes for snakebite patients, community attitudes to the use of traditional healers were explored in the Mandalay region of Myanmar. METHODOLOGY & FINDINGS: With the objective of learning from local communities, information was generated in three communities using participatory appraisal methods with the communities, and focus group discussions with the local healthcare staff. Many snakebite victims in these communities use traditional healing. Reasons include transport difficulties, low cost for traditional healing, inadequacy of anti-snake venom in the formal healthcare sector, and traditional beliefs, as traditional healing practices are rooted in many cultural and traditional factors. The communities reported that even if access to medical care were improved, traditional healing would continue to be used. CONCLUSION: These findings point to the need for working with traditional healers for prevention, appropriate first aid and timely access to effective treatment for snakebite. PMID- 29489825 TI - AMModels: An R package for storing models, data, and metadata to facilitate adaptive management. AB - Agencies are increasingly called upon to implement their natural resource management programs within an adaptive management (AM) framework. This article provides the background and motivation for the R package, AMModels. AMModels was developed under R version 3.2.2. The overall goal of AMModels is simple: To codify knowledge in the form of models and to store it, along with models generated from numerous analyses and datasets that may come our way, so that it can be used or recalled in the future. AMModels facilitates this process by storing all models and datasets in a single object that can be saved to an .RData file and routinely augmented to track changes in knowledge through time. Through this process, AMModels allows the capture, development, sharing, and use of knowledge that may help organizations achieve their mission. While AMModels was designed to facilitate adaptive management, its utility is far more general. Many R packages exist for creating and summarizing models, but to our knowledge, AMModels is the only package dedicated not to the mechanics of analysis but to organizing analysis inputs, analysis outputs, and preserving descriptive metadata. We anticipate that this package will assist users hoping to preserve the key elements of an analysis so they may be more confidently revisited at a later date. PMID- 29489826 TI - Depression and its correlations with health-risk behaviors and social capital among female migrants working in entertainment venues in China. AB - OBJECTIVES: Among the dramatic increased internal migration in China in past three decades, a considerable proportion of young females migrated to urban areas and found employment in "entertainment venues", who may be vulnerable to psychological distress. This study examines the prevalence of depression and explores its associations with health-risk behaviors and social capital among this subgroup. METHODS: 358 female migrants were recruited from entertainment venues in a rapidly growing urban city in China. A survey which included measures of depressive symptoms, health-risk behaviors, social capital, and socio demographic characteristics was administered. Multivariable logistic regression was conducted to identify the independent correlates of depression. RESULTS: Of participants, 31.0% had clinically significant depressive symptoms (CES-D score >= 16). In multivariable models, greater likelihood of depressive symptoms was associated with working in massage centers/hotels (OR = 3.20, 95% CI: 1.80-5.70), having probable alcohol dependence (OR = 2.25, 95% CI: 1.22-4.16), self-reported lifetime use of illicit drugs (OR = 2.98, 95% CI: 1.26-7.06), growing up in a non nuclear family (OR = 2.46, 95% CI: 1.18-5.16), and poor social capital (OR = 6.01, 95% CI = 2.02-17.87). CONCLUSION: Intervention strategies to address the high prevalence of depression among female migrants are needed, and should also aim to reduce problematic alcohol and drug use, improve social capital, and target women working in massage centers or hotels. PMID- 29489827 TI - Middle and Later Stone Age chronology of Kisese II rockshelter (UNESCO World Heritage Kondoa Rock-Art Sites), Tanzania. AB - The archaeology of East Africa during the last ~65,000 years plays a central role in debates about the origins and dispersal of modern humans, Homo sapiens. Despite the historical importance of the region to these discussions, reliable chronologies for the nature, tempo, and timing of human behavioral changes seen among Middle Stone Age (MSA) and Later Stone Age (LSA) archaeological assemblages are sparse. The Kisese II rockshelter in the Kondoa region of Tanzania, originally excavated in 1956, preserves a >= 6-m-thick archaeological succession that spans the MSA/LSA transition, with lithic artifacts such as Levallois and bladelet cores and backed microliths, the recurrent use of red ochre, and >5,000 ostrich eggshell beads and bead fragments. Twenty-nine radiocarbon dates on ostrich eggshell carbonate make Kisese II one of the most robust chronological sequences for understanding archaeological change over the last ~47,000 years in East Africa. In particular, ostrich eggshell beads and backed microliths appear by 46-42 ka cal BP and occur throughout overlying Late Pleistocene and Holocene strata. Changes in lithic technology suggest an MSA/LSA transition that began 39 34.3 ka, with typical LSA technologies in place by the Last Glacial Maximum. The timing of these changes demonstrates the time-transgressive nature of behavioral innovations often linked to the origins of modern humans, even within a single region of Africa. PMID- 29489828 TI - Evaluation of the novel avocado/soybean unsaponifiable Arthrocen to alter joint pain and inflammation in a rat model of osteoarthritis. AB - BACKGROUND: Avocado/soybean unsaponifiables such as Arthrocen have been reported to reduce cartilage catabolism and chondrocytic synthesis of inflammatory mediators associated with osteoarthritis (OA). While there is some clinical evidence that avocado/soybean unsaponifiables can reduce OA pain, no preclinical studies have corroborated this observation. The present study determined whether addition of an avocado/soybean unsaponifiable (Arthrocen) to the drinking water of OA rats reduced direct and referred joint pain. METHODS: OA was induced in male Wistar rats by intra-articular injection of sodium monoiodoacetate (MIA: 0.3mg) and animals were allowed to recover for 14 days. Arthrocen was added to the drinking water which was available to animals ad libitum. On day 30, joint pain was assessed by dynamic incapacitance while referred pain was determined by von Frey hair algesiometry. RESULTS: The joint damage induced by MIA injection was severe and was consistent with end-stage OA. Arthrocen consumption (approximately 35 mg/day) attenuated the joint oedema associated with MIA injection. Hindlimb weight bearing also significantly improved in Arthrocen treated rats (P<0.05); however, von Frey hair mechanosensitivity was unaffected by this treatment. CONCLUSIONS: These data indicate that Arthrocen has the potential to reduce joint inflammation and pain associated with end-stage OA. PMID- 29489830 TI - Assessing national nutrition security: The UK reliance on imports to meet population energy and nutrient recommendations. AB - Nutrition security describes the adequacy of the food supply to meet not only energy but also macronutrient and micronutrient requirements for the population. The aim of this study was to develop a method to assess trends in national nutrition security and the contribution of imports to nutrition security, using the UK as a case study. Food supply data from FAO food balance sheets and national food composition tables were used to estimate the nutrient content of domestically produced food, imported food and exported food. Nutrition security was defined as the total nutrient supply (domestic production, minus exports, plus imports) to meet population-level nutrient requirements. The results showed that the UK was nutrition secure over the period 1961-2011 for energy, macronutrients and key micronutrients, with the exception of total carbohydrates and fibre, which may be due to the loss of fibre incurred by processing cereals into refined products. The supply of protein exceeded population requirements and could be met with domestic production alone. Even excluding all meat there was sufficient protein for population requirements. The supply of total fat, saturated fat and sugar considerably exceeded the current dietary recommendation. As regards nutrition security in 2010, the UK was reliant on imported foods to meet energy, fibre, total carbohydrate, iron, zinc and vitamin A requirements. This analysis demonstrates the importance of including nutrients other than energy to determine the adequacy of the food supply. The methodology also provides an alternative perspective on food security and self-sufficiency by assessing the dependency on imports to meet population level nutritional requirements. PMID- 29489829 TI - Trophic effects of adipose-tissue-derived and bone-marrow-derived mesenchymal stem cells enhance cartilage generation by chondrocytes in co-culture. AB - AIMS: Combining mesenchymal stem cells (MSCs) and chondrocytes has great potential for cell-based cartilage repair. However, there is much debate regarding the mechanisms behind this concept. We aimed to clarify the mechanisms that lead to chondrogenesis (chondrocyte driven MSC-differentiation versus MSC driven chondroinduction) and whether their effect was dependent on MSC-origin. Therefore, chondrogenesis of human adipose-tissue-derived MSCs (hAMSCs) and bone marrow-derived MSCs (hBMSCs) combined with bovine articular chondrocytes (bACs) was compared. METHODS: hAMSCs or hBMSCs were combined with bACs in alginate and cultured in vitro or implanted subcutaneously in mice. Cartilage formation was evaluated with biochemical, histological and biomechanical analyses. To further investigate the interactions between bACs and hMSCs, (1) co-culture, (2) pellet, (3) Transwell(r) and (4) conditioned media studies were conducted. RESULTS: The presence of hMSCs-either hAMSCs or hBMSCs-increased chondrogenesis in culture; deposition of GAG was most evidently enhanced in hBMSC/bACs. This effect was similar when hMSCs and bAC were combined in pellet culture, in alginate culture or when conditioned media of hMSCs were used on bAC. Species-specific gene expression analyses demonstrated that aggrecan was expressed by bACs only, indicating a predominantly trophic role for hMSCs. Collagen-10-gene expression of bACs was not affected by hBMSCs, but slightly enhanced by hAMSCs. After in-vivo implantation, hAMSC/bACs and hBMSC/bACs had similar cartilage matrix production, both appeared stable and did not calcify. CONCLUSIONS: This study demonstrates that replacing 80% of bACs by either hAMSCs or hBMSCs does not influence cartilage matrix production or stability. The remaining chondrocytes produce more matrix due to trophic factors produced by hMSCs. PMID- 29489831 TI - Simple analytical model reveals the functional role of embodied sensorimotor interaction in hexapod gaits. AB - Insects have various gaits with specific characteristics and can change their gaits smoothly in accordance with their speed. These gaits emerge from the embodied sensorimotor interactions that occur between the insect's neural control and body dynamic systems through sensory feedback. Sensory feedback plays a critical role in coordinated movements such as locomotion, particularly in stick insects. While many previously developed insect models can generate different insect gaits, the functional role of embodied sensorimotor interactions in the interlimb coordination of insects remains unclear because of their complexity. In this study, we propose a simple physical model that is amenable to mathematical analysis to explain the functional role of these interactions clearly. We focus on a foot contact sensory feedback called phase resetting, which regulates leg retraction timing based on touchdown information. First, we used a hexapod robot to determine whether the distributed decoupled oscillators used for legs with the sensory feedback generate insect-like gaits through embodied sensorimotor interactions. The robot generated two different gaits and one had similar characteristics to insect gaits. Next, we proposed the simple model as a minimal model that allowed us to analyze and explain the gait mechanism through the embodied sensorimotor interactions. The simple model consists of a rigid body with massless springs acting as legs, where the legs are controlled using oscillator phases with phase resetting, and the governed equations are reduced such that they can be explained using only the oscillator phases with some approximations. This simplicity leads to analytical solutions for the hexapod gaits via perturbation analysis, despite the complexity of the embodied sensorimotor interactions. This is the first study to provide an analytical model for insect gaits under these interaction conditions. Our results clarified how this specific foot contact sensory feedback contributes to generation of insect like ipsilateral interlimb coordination during hexapod locomotion. PMID- 29489832 TI - Do singles or couples live healthier lifestyles? Trends in Queensland between 2005-2014. AB - OBJECTIVES: To compare the frequency of and trends in healthy lifestyle factors between singles and couples. METHODS: Cross-sectional data from annual surveys conducted from 2005-2014 were used. The pooled sample included 15,001 Australian adults (mean age: 52.9 years, 50% male, 74% couples) who participated in the annual Queensland Social Survey via computer-assisted telephone interviews. Relationship status was dichotomised into single and couple. Binary logistic regression was used to assess associations between relationship status, and the frequency of and trends in healthy lifestyle factors. RESULTS: Compared to singles, couples were significantly more likely to be a non-smoker (OR = 1.82), and meet recommendations for limited fast food (OR = 1.12), alcohol consumption (OR = 1.27) and fruit and vegetable intake (OR = 1.24). Fruit and vegetable intake was not significantly associated with relationship status after adjusting for the other healthy lifestyle factors. Conversely, couples were significantly less likely to be within a normal weight range (OR = 0.81). In both singles and couples, the trend data revealed significant declines in the rates of normal weight (singles: OR = 0.97, couples: OR = 0.97) and viewing TV for less than 14 hours per week (singles: OR = 0.85, couples: OR = 0.84), whilst non-smoking rates significantly increased (singles: OR = 1.12, couples: OR = 1.03). The BMI trend was no longer significant when adjusting for health behaviours. Further, in couples, rates of meeting recommendations for physical activity and fruit/vegetable consumption significantly decreased (OR = 0.97 and OR = 0.95, respectively), as did rates of eating no fast food (OR = 0.96). These trends were not significant when adjusting for the other healthy lifestyle factors. In singles, rates of meeting alcohol recommendations significantly increased (OR = 1.08). CONCLUSIONS: Health behaviour interventions are needed in both singles and couples, but relationship status needs to be considered in interventions targeting alcohol, fast food, smoking and BMI. Further research is needed to understand why health behaviours differ by relationship status in order to further improve interventions. PMID- 29489833 TI - Immune checkpoint inhibitor PD-1 pathway is down-regulated in synovium at various stages of rheumatoid arthritis disease progression. AB - Immune checkpoint blockade with therapeutic anti-cytotoxic T lymphocyte associated antigen (CTLA)-4 (Ipilimumab) and anti-programmed death (PD)-1 (Nivolumab and Pembrolizumab) antibodies alone or in combination has shown remarkable efficacy in multiple cancer types, concomitant with immune-related adverse events, including arthralgia and inflammatory arthritis (IA) in some patients. Herein, using Nivolumab (anti-PD-1 antagonist)-responsive genes along with transcriptomics of synovial tissue from multiple stages of rheumatoid arthritis (RA) disease progression, we have interrogated the activity status of PD-1 pathway during RA development. We demonstrate that the expression of PD-1 was increased in early and established RA synovial tissue compared to normal and OA synovium, whereas that of its ligands, programmed death ligand-1 (PD-L1) and PD-L2, was increased at all the stages of RA disease progression, namely arthralgia, IA/undifferentiated arthritis, early RA and established RA. Further, we show that RA patients expressed PD-1 on a majority of synovial tissue infiltrating CD4+ and CD8+ T cells. Moreover, enrichment of Nivolumab gene signature was observed in IA and RA, indicating that the PD-1 pathway was downregulated during RA disease progression. Furthermore, serum soluble (s) PD-1 levels were increased in autoantibody positive early RA patients. Interestingly, most of the early RA synovium tissue sections showed negative PD-L1 staining by immunohistochemistry. Therefore, downregulation in PD-1 inhibitory signaling in RA could be attributed to increased serum sPD-1 and decreased synovial tissue PD L1 levels. Taken together, these data suggest that agonistic PD1 antibody-based therapeutics may show efficacy in RA treatment and interception. PMID- 29489834 TI - The switch between cataract surgical settings: Evidence from a time series analysis across 20 EU countries. AB - OBJECTIVES: To analyze trajectories of cataract surgery rates and to confirm the switch between inpatient cases and day surgery or outpatient cases. DESIGN: Pooled, cross-sectional, time series analysis. METHODS: Data on 20 European countries from 2004 to 2014 retrieved from the OECD. RESULTS: The number of cataract surgery cases per 100,000 population has increased since 2004 (b = 31.1, p < 0.001, 95% CI = 26.7, 35.6). A reversal of the inpatient cases and same-day cases was found: the first ones decreased (b = -14.7, p < 0.001, 95% CI = -17.7, 11.8) while day surgery and outpatient cases increased (b = 37.5, p < 0.001, 95% CI = 31.6, 43.4, and b = 8.3, p = 0.001, 95% CI = 3.6, 13.1, respectively). Since 2004, the ratio of day surgery and outpatient cases to inpatient cases has grown significantly (b = 3.3, p < 0.001, 95% CI = 2.5, 4.0), reaching a share of 31.7 in 2014. However, this slope of 3.3 was not constant and slowed over the years: from 4.5 per year during the first five years to 1.9 in the second five. No association was found between cataract surgery rate and two regressors: elderly people, and health care expenditure per capita. CONCLUSION: EU countries have preserved cataract surgery, and this preservation is probably affected by the switch from inpatient to same-day surgery, thanks to the decrease in the cost and equivalent clinical outcomes. However, the slope of the switch slowed over time. Consequently, health care systems must support this process of change especially through reforms in financial and organizational fields. PMID- 29489835 TI - An integrative description of Macrobiotus shonaicus sp. nov. (Tardigrada: Macrobiotidae) from Japan with notes on its phylogenetic position within the hufelandi group. AB - Tardigrade research in Japan dates back over 100 years, and to date, 167 species of this ecdysozoan phylum have been reported from the country. Of these species, the Macrobiotus hufelandi complex has been represented only by the nominal taxon of this group, Macrobiotus hufelandi. In this article, a new species of the hufelandi group from Japan, Macrobiotus shonaicus sp. nov., is described using integrative taxonomy. In addition to the detailed morphological and morphometric data, obtained using phase contrast light microscopy (PCM) and scanning electron microscopy (SEM), we provide DNA sequences of four molecular markers (both nuclear and mitochondrial). The new species belongs to the persimilis subgroup and is most similar to M. anemone from USA, M. naskreckii from Mozambique, and M. patagonicus from Argentina, but it can be easily distinguished from these species by the presence of thin flexible filaments on terminal discs of the egg process. By the latter character, the new species is most similar to M. paulinae and M. polypiformis, but it can be easily distinguished from them by having a solid egg surface between egg processes (i.e., without pores or reticulum). A phylogenetic analysis of available DNA sequences of the COI marker for the hufelandi group revealed that the new species clusters with the two other species that exhibit filaments on egg process discs (M. paulinae and M. polypiformis) and with two species that have entire egg processes modified into filaments (M. kristenseni and M. scoticus). All five species form a clade distinct from all other sequenced species of the hufelandi group with typical mushroom- or inverted goblet-shaped egg processes, which may suggest that the ancestor of the five species with atypical egg processes had a mutation allowing derivations from the mushroom or inverted chalice-like shape of egg processes. PMID- 29489837 TI - How does language change as a lexical network? An investigation based on written Chinese word co-occurrence networks. AB - Language is a complex adaptive system, but how does it change? For investigating this process, four diachronic Chinese word co-occurrence networks have been built based on texts that were written during the last 2,000 years. By comparing the network indicators that are associated with the hierarchical features in language networks, we learn that the hierarchy of Chinese lexical networks has indeed evolved over time at three different levels. The connections of words at the micro level are continually weakening; the number of words in the meso-level communities has increased significantly; and the network is expanding at the macro level. This means that more and more words tend to be connected to medium central words and form different communities. Meanwhile, fewer high-central words link these communities into a highly efficient small-world network. Understanding this process may be crucial for understanding the increasing structural complexity of the language system. PMID- 29489836 TI - The Ebola-effect in Guinea 2014-15: Tangled trends of malaria care in children under-five. AB - INTRODUCTION: The 2014-15 Ebola outbreak in West Africa was disruptive for the general health services in the affected countries. This study assessed the impact of the outbreak on the reported number and management of malaria in children under-five in rural Guinea. MATERIALS AND METHODS: A retrospective cross sectional study was conducted in nineteen health centres in two rural, malaria endemic health districts, one at the epicentre of the outbreak (Gueckedou) and one (Koubia) spared by Ebola. Routine surveillance data at health facility level were compared over similar periods of high malaria transmission in both districts before, during and after the outbreak. RESULTS: There were significant declines in the number of visits during the Ebola outbreak (3,700) in Gueckedou compared to before (4,616) and after it (4,195), while this trend remained more stable within the three periods for Koubia. Differences were nonetheless significant in both districts (p<0.001). In 2014, during the peak of the outbreak, the overall number of malaria cases treated exceeded the number of confirmed malaria cases in Gueckedou. There were decreases in antimalarial treatment provision in August and November 2014. In contrast, during 2015 and 2016, the proportion of malaria positive cases and those treated were closely aligned. During the peak of the Ebola outbreak, there was a significant decrease in oral antimalarial drug administration, which corresponded to an increase in injectable antimalarial treatments. Stock-outs in rapid diagnostic tests were evident and prolonged in Gueckedou during the outbreak, while more limited in Koubia. CONCLUSION: The Ebola outbreak of 2014-15 in Guinea had a significant impact on the admission and management of malaria in children under-five. This study identifies potential challenges in the delivery of care for those at highest risk for malaria mortality during an Ebola outbreak and the need to improve preparedness strategies pre-Ebola and health systems recovery post-Ebola. PMID- 29489838 TI - Susceptibility and tolerance of rice crop to salt threat: Physiological and metabolic inspections. AB - Salinity threat is estimated to reduce global rice production by 50%. Comprehensive analysis of the physiological and metabolite changes in rice plants from salinity stress (i.e. tolerant versus susceptible plants) is important to combat higher salinity conditions. In this study, we screened a total of 92 genotypes and selected the most salinity tolerant line (SS1-14) and most susceptible line (SS2-18) to conduct comparative physiological and metabolome inspections. We demonstrated that the tolerant line managed to maintain their water and chlorophyll content with lower incidence of sodium ion accumulation. We also examined the antioxidant activities of these lines: production of ascorbate peroxidase (APX) and catalase (CAT) were significantly higher in the sensitive line while superoxide dismutase (SOD) was higher in the tolerant line. Partial least squares discriminant analysis (PLS-DA) score plots show significantly different response for both lines after the exposure to salinity stress. In the tolerant line, there was an upregulation of non-polar metabolites and production of sucrose, GABA and acetic acid, suggesting an important role in salinity adaptation. In contrast, glutamine and putrescine were noticeably high in the susceptible rice. Coordination of different strategies in tolerant and susceptible lines show that they responded differently after exposure to salt stress. These findings can assist crop development in terms of developing tolerance mechanisms for rice crops. PMID- 29489839 TI - Global migration of clinical research during the era of trial registration. AB - BACKGROUND: Since the site of human subjects research has public health, regulatory, ethical, economic, and social implications, we sought to determine the global distribution and migration of clinical research using an open-access trial registry. METHODS: We obtained individual clinical trial data including location of trial sites, dates of operation, funding source (United States government, pharmaceutical industry, or organization), and clinical study phase (1, 1/2, 2, 2/3, or 3) from ClinicalTrials.gov. We used the World Bank's classification of each country's economic development status ["High Income and a Member of the Organization for Economic Co-operation and Development (OECD)", "High Income and Non-Member of the OECD", "Upper-Middle Income", "Lower-Middle Income", or "Low Income"] and United Nations Populations Division data for country-specific population estimates. We analyzed data from calendar year 2006 through 2012 by number of clinical trial sites, cumulative trial site-years, trial density (trial site-years/106 population), and annual growth rate (%) for each country, and by development category, funding source, and clinical study phase. RESULTS: Over a 7-year period, 89,647 clinical trials operated 784,585 trial sites in 175 countries, contributing 2,443,850 trial site-years. Among those, 652,200 trial sites (83%) were in 25 high-income OECD countries, while 37,195 sites (5%) were in 91 lower-middle or low-income countries. Trial density (trial site-years/106 population) was 540 in the United States, 202 among other high-income OECD countries (excluding the United States), 81 among high-income non-OECD countries, 41 among upper-middle income countries, 5 among lower-middle income countries, and 2 among low-income countries. Annual compound growth rate was positive (ranging from 0.8% among low-income countries to 14.7% among lower middle income countries) among all economic groups, except the United States ( 0.5%). Overall, 29,191 trials (33%) were funded by industry, 4,059 (5%) were funded by the United States government, and 56,397 (63%) were funded by organizations. Countries with emerging economies (low- and middle-income) operated 19% of phase 3 trial sites, as compared to only 6% of phase 1 trial sites. CONCLUSION: Human clinical research remains concentrated in high-income countries, but operational clinical trial sites, particularly for phase 3 trials, may be migrating to low- and middle-income countries with emerging economies. PMID- 29489841 TI - Australian general practitioners' knowledge, attitudes and practices towards breastfeeding. AB - The aim of this study was to explore the knowledge, attitudes and practices of established general practitioners (GPs) in relation to breastfeeding. 10 GPs in the Australian Nepean Blue Mountains Health District were interviewed and the interviews transcribed and analyzed thematically. Emergent themes from each interview were identified and then compared between and across the 10 interviews. Five themes emerged following the analysis: breastfeeding knowledge and training; attitudes towards breastfeeding; GPs' role in relation to breast feeding; GPs' practices; influence of male gender. All the GPs interviewed had positive attitudes towards breastfeeding, however they were often lacking in knowledge and conviction to be able to provide strong support to women during their breastfeeding journey. Some reported ambivalence in their encouragement of breastfeeding due to their desire to maintain a good relationship with women who chose not to feed this way. Nine of the GPs had little or no formal breastfeeding training and relied mainly on personal experience. Their clinics did not provide formal breastfeeding support including a written breastfeeding friendly policy and most GPs were not proactive in creating such an environment. We hope that the results from this study will assist in developing breastfeeding policies and professional education to support GPs in this role. PMID- 29489840 TI - Low free 25-hydroxyvitamin D and high vitamin D binding protein and parathyroid hormone in obese Caucasians. A complex association with bone? AB - BACKGROUND: Studies have shown altered vitamin D metabolism in obesity. We assessed differences between obese and normal-weight subjects in total, free, and bioavailable 25-hydroxyvitamin D (25(OH)D, 25(OH)DFree, and 25(OH)DBio, respectively), vitamin D binding protein (DBP), parathyroid hormone (PTH) and bone traits. METHODS: 595 37-47-year-old healthy Finnish men and women stratified by BMI were examined in this cross-sectional study. Background characteristic and intakes of vitamin D and calcium were collected. The concentrations of 25(OH)D, PTH, DBP, albumin and bone turnover markers were determined from blood. 25(OH)DFree and 25(OH)DBio were calculated. pQCT was performed at radius and tibia. RESULTS: Mean+/-SE (ANCOVA) 25(OH)DFree (10.8+/-0.6 vs 12.9+/-0.4 nmol/L; P = 0.008) and 25(OH)DBio (4.1+/-0.3 vs 5.1+/-0.1 nmol/L; P = 0.003) were lower in obese than in normal-weight women. In men, 25(OH)D (48.0+/-2.4 vs 56.4+/-2.0 nmol/L, P = 0.003), 25(OH)DFree (10.3+/-0.7 vs 12.5+/-0.6 pmol/L; P = 0.044) and 25(OH)DBio (4.2+/-0.3 vs 5.1+/-0.2 nmol/L; P = 0.032) were lower in obese. Similarly in all subjects, 25(OH)D, 25(OH)DFree and 25(OH)DBio were lower in obese (P<0.001). DBP (399+/-12 vs 356+/-7mg/L, P = 0.008) and PTH (62.2+/-3.0 vs 53.3+/-1.9 ng/L; P = 0.045) were higher in obese than in normal-weight women. In all subjects, PTH and DBP were higher in obese (P = 0.047and P = 0.004, respectively). In obese women, 25(OH)D was negatively associated with distal radius trabecular density (R2 = 0.089, P = 0.009) and tibial shaft cortical strength index (CSI) (R2 = 0.146, P = 0.004). 25(OH)DFree was negatively associated with distal radius CSI (R2 = 0.070, P = 0.049), radial shaft cortical density (CorD) (R2 = 0.050, P = 0.045), and tibial shaft CSI (R2 = 0.113, P = 0.012). 25(OH)DBio was negatively associated with distal radius CSI (R2 = 0.072, P = 0.045), radial shaft CorD (R2 = 0.059, P = 0.032), and tibial shaft CSI (R2 = 0.093, P = 0.024). CONCLUSIONS: The associations between BMI and 25(OH)D, 25(OH)DFree, and 25(OH)DBio, DBP, and PTH suggest that obese subjects may differ from normal-weight subjects in vitamin D metabolism. BMI associated positively with trabecular bone traits and CSI in our study, and slightly negatively with cortical bone traits. Surprisingly, there was a negative association of free and bioavailable 25(OH)D and some of the bone traits in obese women. PMID- 29489842 TI - A formative evaluation of the implementation of a medication safety data collection tool in English healthcare settings: A qualitative interview study using normalisation process theory. AB - BACKGROUND: Reducing medication-related harm is a global priority; however, impetus for improvement is impeded as routine medication safety data are seldom available. Therefore, the Medication Safety Thermometer was developed within England's National Health Service. This study aimed to explore the implementation of the tool into routine practice from users' perspectives. METHOD: Fifteen semi structured interviews were conducted with purposely sampled National Health Service staff from primary and secondary care settings. Interview data were analysed using an initial thematic analysis, and subsequent analysis using Normalisation Process Theory. RESULTS: Secondary care staff understood that the Medication Safety Thermometer's purpose was to measure medication safety and improvement. However, other uses were reported, such as pinpointing poor practice. Confusion about its purpose existed in primary care, despite further training, suggesting unsuitability of the tool. Decreased engagement was displayed by staff less involved with medication use, who displayed less ownership. Nonetheless, these advocates often lacked support from management and frontline levels, leading to an overall lack of engagement. Many participants reported efforts to drive scale-up of the use of the tool, for example, by securing funding, despite uncertainty around how to use data. Successful improvement was often at ward-level and went unrecognised within the wider organisation. There was mixed feedback regarding the value of the tool, often due to a perceived lack of "capacity". However, participants demonstrated interest in learning how to use their data and unexpected applications of data were reported. CONCLUSION: Routine medication safety data collection is complex, but achievable and facilitates improvements. However, collected data must be analysed, understood and used for further work to achieve improvement, which often does not happen. The national roll-out of the tool has accelerated shared learning; however, a number of difficulties still exist, particularly in primary care settings, where a different approach is likely to be required. PMID- 29489843 TI - DJ-1 based peptide, ND-13, promote functional recovery in mouse model of focal ischemic injury. AB - Stroke is a leading cause of death worldwide and inflicts serious long-term damage and disability. The vasoconstrictor Endothelin-1, presenting long-term neurological deficits associated with excitotoxicity and oxidative stress is being increasingly used to induce focal ischemic injury as a model of stroke. A DJ-1 based peptide named ND-13 was shown to protect against glutamate toxicity, neurotoxic insults and oxidative stress in various animal models. Here we focus on the benefits of treatment with ND-13 on the functional outcome of focal ischemic injury. Wild type C57BL/6 mice treated with ND-13, after ischemic induction in this model, showed significant improvement in motor function, including improved body balance and motor coordination, and decreased motor asymmetry. We found that DJ-1 knockout mice are more sensitive to Endothelin-1 ischemic insult than wild type mice, contributing thereby additional evidence to the widely reported relevance of DJ-1 in neuroprotection. Furthermore, treatment of DJ-1 knockout mice with ND-13, following Endothelin-1 induced ischemia, resulted in significant improvement in motor functions, suggesting that ND-13 provides compensation for DJ-1 deficits. These preliminary results demonstrate a possible basis for clinical application of the ND-13 peptide to enhance neuroprotection in stroke patients. PMID- 29489845 TI - High spatial variation in population size and symbiotic performance of Rhizobium leguminosarum bv. trifolii with white clover in New Zealand pasture soils. AB - Biological nitrogen fixation through the legume-rhizobia symbiosis is important for sustainable pastoral production. In New Zealand, the most widespread and valuable symbiosis occurs between white clover (Trifolium repens L.) and Rhizobium leguminosarum bv. trifolii (Rlt). As variation in the population size (determined by most probable number assays; MPN) and effectiveness of N-fixation (symbiotic potential; SP) of Rlt in soils may affect white clover performance, the extent in variation in these properties was examined at three different spatial scales: (1) From 26 sites across New Zealand, (2) at farm-wide scale, and (3) within single fields. Overall, Rlt populations ranged from 95 to >1 x 108 per g soil, with variation similar at the three spatial scales assessed. For almost all samples, there was no relationship between rhizobia population size and ability of the population to fix N during legume symbiosis (SP). When compared with the commercial inoculant strain, the SP of soils ranged between 14 to 143% efficacy. The N-fixing ability of rhizobia populations varied more between samples collected from within a single hill country field (0.8 ha) than between 26 samples collected from diverse locations across New Zealand. Correlations between SP and calcium and aluminium content were found in all sites, except within a dairy farm field. Given the general lack of association between SP and MPN, and high spatial variability of SP at single field scale, provision of advice for treating legume seed with rhizobia based on field-average MPN counts needs to be carefully considered. PMID- 29489844 TI - Phalangeal joints kinematics in ostrich (Struthio camelus) locomotion on sand. AB - In ostriches, the toes are the only body parts that contact loose sand surfaces. Thus, toe interphalangeal joint motions may play vital biomechanical roles. However, there is little research on ostrich phalangeal joint movements while walking or running on sand. The results from the three-dimensional motion track analysis system Simi Motion show that gait pattern has no significant effect on the key indicators (angles at touch-down, mid-stance, lift-off and range of motion) of the toe joint angles. The motion of the toe phalanges when walking and running on sand is basically the same. The ground medium is the key factor that changes the toe postures adopted by ostriches during the stance phase in slow to fast locomotion. The 3rd toe and the 4th toe are connected by the interphalangeal ligament, and the motions of the MTP3 and MTP4 joints are highly synchronized on a loose sand substrate. The 3rd toe and 4th toe are coupled to maintain static balance in slow locomotion and dynamic balance in fast locomotion. In addition, the gait pattern has a marked effect on the range of forward displacement of the toenail (YTN). The ostrich toenail plays an important role in preventing slip and provides traction at push-off in a sandy environment. The metatarsophalangeal joint plays an important role in energy saving during fast locomotion on loose sand substrates. Simulation reveals that the particle velocity field, particle force field and sand particle disturbance in the running gait are denser than those in the walking gait. PMID- 29489846 TI - Habitat selection and seasonal movements of young bearded seals (Erignathus barbatus) in the Bering Sea. AB - The first year of life is typically the most critical to a pinniped's survival, especially for Arctic phocids which are weaned at only a few weeks of age and left to locate and capture prey on their own. Their seasonal movements and habitat selection are therefore important factors in their survival. During a cooperative effort between scientists and subsistence hunters in October 2004, 2005, and 2006, 13 female and 13 male young (i.e., age <2) bearded seals (Erignathus barbatus) were tagged with satellite-linked dive recorders (SDRs) in Kotzebue Sound, Alaska. Shortly after being released, most seals moved south with the advancing sea-ice through the Bering Strait and into the Bering Sea where they spent the winter and early spring. The SDRs of 17 (8 female and 9 male) seals provided frequent high-quality positions in the Bering Sea; their data were used in our analysis. To investigate habitat selection, we simulated 20 tracks per seal by randomly selecting from the pooled distributions of the absolute bearings and swim speeds of the tagged seals. For each point in the observed and simulated tracks, we obtained the depth, sea-ice concentration, and the distances to sea-ice, open water, the shelf break and coastline. Using logistic regression with a stepwise model selection procedure, we compared the simulated tracks to those of the tagged seals and obtained a model for describing habitat selection. The regression coefficients indicated that the bearded seals in our study selected locations near the ice edge. In contrast, aerial surveys of the bearded seal population, predominantly composed of adults, indicated higher abundances in areas farther north and in heavier pack ice. We hypothesize that this discrepancy is the result of behavioral differences related to age. Ice concentration was also shown to be a statistically significant variable in our model. All else being equal, areas of higher ice concentration are selected for up to about 80%. The effects of sex and bathymetry were not statistically significant. The close association of young bearded seals to the ice edge in the Bering Sea is important given the likely effects of climate warming on the extent of sea-ice and subsequent changes in ice edge habitat. PMID- 29489847 TI - Reproductive period, endogenous estrogen exposure and dementia incidence among women in Latin America and China; A 10/66 population-based cohort study. AB - BACKGROUND: Exposure to endogenous estrogen may protect against dementia, but evidence remains equivocal. Such effects may be assessed more precisely in settings where exogenous estrogen administration is rare. We aimed to determine whether reproductive period (menarche to menopause), and other indicators of endogenous estrogen exposure are inversely associated with dementia incidence. METHODS: Population-based cohort studies of women aged 65 years and over in urban sites in Cuba, Dominican Republic, Puerto Rico and Venezuela, and rural and urban sites in Peru, Mexico and China. Sociodemographic and risk factor questionnaires were administered to all participants, including ages at menarche, birth of first child, and menopause, and parity, with ascertainment of incident 10/66 dementia, and mortality, three to five years later. RESULTS: 9,428 women participated at baseline, with 72-98% responding by site. The 'at risk' cohort comprised 8,466 dementia-free women. Mean age varied from 72.0 to 75.4 years, lower in rural than urban sites and in China than in Latin America. Mean parity was 4.1 (2.4-7.2 by site), generally higher in rural than urban sites. 6,854 women with baseline reproductive period data were followed up for 26,463 person years. There were 692 cases of incident dementia, and 895 dementia free deaths. Pooled meta-analysed fixed effects, per year, for reproductive period (Adjusted Sub-Hazard Ratio [ASHR] 1.001, 95% CI 0.988-1.015) did not support any association with dementia incidence, with no evidence for effect modification by APOE genotype. No association was observed between incident dementia and; ages at menarche, birth of first child, and menopause: nulliparity; or index of cumulative endogenous estrogen exposure. Greater parity was positively associated with incident dementia (ASHR 1.030, 95% CI 1.002-1.059, I2 = 0.0%). CONCLUSIONS: We found no evidence to support the theory that natural variation in cumulative exposure to endogenous oestrogens across the reproductive period influences dementia incidence in late life. PMID- 29489848 TI - Food claims and nutrition facts of commercial infant foods. AB - Composition claim, nutrition claim and health claim are often found on the commercial complementary food packaging. The introduction of complementary foods (CFs) to infants is a turning point in the development of their eating behavior, and their commercial use for Taiwanese infants is growing. In Taiwan, lots of the advertisements for CFs employed health or nutrition claims to promote the products, but the actual nutritional content of these CFs is not clear. The aim of this study was to compare the food claims of commercial complementary food products with their actual nutrition facts. A sample of 363 commercial CFs was collected from websites, local supermarkets, and other food stores, and their nutrition-related claims were classified into composition, nutrition, and health categories. Although the World Health Organization recommends that infants should be exclusively breastfed for the first 6 months, 48.2% of the commercial CFs were targeted at infants younger than 6 months. Therefore, marketing regulations should be implemented to curb early weaning as a result of products targeted at infants younger than 6 months. More than 50% of Taiwanese commercial CFs have high sugar content and more than 20% were high in sodium. Products with health claims, such as "provides good nutrition to children" or "improves appetite," have higher sodium or sugar content than do those without such claims. Moreover, products with calcium or iron content claims did not contain more calcium or iron than products without such claims. Additionally, a significantly greater proportion of the products with "no added sugar" claims were classified as having high sugar content as compared to those without such claims. Parents cannot choose the healthiest food products for their children by simply focusing on food claims. Government should regulate the labeling of nutrition facts and food claims for foods targeted at infants younger than 12 months. PMID- 29489849 TI - Monitoring blood-flow in the mouse cochlea using an endoscopic laser speckle contrast imaging system. AB - Laser speckle contrast imaging (LSCI) enables continuous high-resolution assessment of microcirculation in real-time. We applied an endoscope to LSCI to measure cochlear blood-flow in an ischemia-reperfusion mouse model. We also explored whether using xenon light in combination with LSCI facilitates visualization of anatomical position. Based on a previous preliminary study, the appropriate wavelength for penetrating the thin bony cochlea was 830 nm. A 2.7-mm diameter endoscope was used, as appropriate for the size of the mouse cochlea. Our endoscopic LSCI system was used to illuminate the right cochlea after dissection of the mouse. We observed changes in the speckle signals when we applied the endoscopic LSCI system to the ischemia-reperfusion mouse model. The anatomical structure of the mouse cochlea and surrounding structures were clearly visible using the xenon light. The speckle signal of the cochlea was scattered, with an intensity that varied between that of the stapes (with the lowest signal), the negative control, and the stapedial artery (with the highest signal), the positive control. In the cochlear ischemia-reperfusion mouse model, the speckle signal of the cochlea decreased during the ischemic phase, and increased during the reperfusion phase, clearly reflecting cochlear blood-flow. The endoscopic LSCI system generates high-resolution images in real-time, allowing visualization of blood-flow and its changes in the mouse cochlea. Anatomical structures were clearly matched using LSCI along with visible light. PMID- 29489850 TI - Assessment of the Fitbit Charge 2 for monitoring heart rate. AB - Fitness trackers are devices or applications for monitoring and tracking fitness related metrics such as distance walked or run, calorie consumption, quality of sleep and heart rate. Since accurate heart rate monitoring is essential in fitness training, the objective of this study was to assess the accuracy and precision of the Fitbit Charge 2 for measuring heart rate with respect to a gold standard electrocardiograph. Fifteen healthy participants were asked to ride a stationary bike for 10 minutes and their heart rate was simultaneously recorded from each device. Results showed that the Fitbit Charge 2 underestimates the heart rate. Although the mean bias in measuring heart rate was a modest -5.9 bpm (95% CI: -6.1 to -5.6 bpm), the limits of agreement, which indicate the precision of individual measurements, between the Fitbit Charge 2 and criterion measure were wide (+16.8 to -28.5 bpm) indicating that an individual heart rate measure could plausibly be underestimated by almost 30 bpm. PMID- 29489851 TI - Compact or spread? A quantitative spatial model of urban areas in Europe since 1990. AB - Changes in urban residential density represent an important issue in terms of land consumption, the conservation of ecosystems, air quality and related human health problems, as well as the consequential challenges for urban and regional planning. It is the decline of residential densities, in particular, that has often been used as the very definition of sprawl, describing a phenomenon that has been extensively studied in the United States and in Western Europe. Whilst these studies provide valuable insights into urbanization processes, only a handful of them have reflected the uneven dynamics of simultaneous urban growth and shrinkage, using residential density changes as a key indicator to uncover the underlying dynamics. This paper introduces a contrasting analysis of recent developments in both de- and re-concentration, defined as decreasing or increasing residential densities, respectively. Using a large sample of European cities, it detects differences in density changes between successional population growth/decline. The paper shows that dedensification, found in some large cities globally, is not a universal phenomenon in growing urban areas; neither the increasing disproportion between a declining demand for and an increasing supply of residential areas nor actual concentration processes in cities were found. Thus, the paper provides a new, very detailed perspective on (de)densification in both shrinking and growing cities and how they specifically contribute to current land take in Europe. PMID- 29489852 TI - Modeling and analysis of biomagnetic blood Carreau fluid flow through a stenosis artery with magnetic heat transfer: A transient study. AB - We present a numerical investigation of tapered arteries that addresses the transient simulation of non-Newtonian bio-magnetic fluid dynamics (BFD) of blood through a stenosis artery in the presence of a transverse magnetic field. The current model is consistent with ferro-hydrodynamic (FHD) and magneto hydrodynamic (MHD) principles. In the present work, blood in small arteries is analyzed using the Carreau-Yasuda model. The arterial wall is assumed to be fixed with cosine geometry for the stenosis. A parametric study was conducted to reveal the effects of the stenosis intensity and the Hartman number on a wide range of flow parameters, such as the flow velocity, temperature, and wall shear stress. Current findings are in a good agreement with recent findings in previous research studies. The results show that wall temperature control can keep the blood in its ideal blood temperature range (below 40 degrees C) and that a severe pressure drop occurs for blockages of more than 60 percent. Additionally, with an increase in the Ha number, a velocity drop in the blood vessel is experienced. PMID- 29489853 TI - Modeling intrinsic potential for beaver (Castor canadensis) habitat to inform restoration and climate change adaptation. AB - Through their dam-building activities and subsequent water storage, beaver have the potential to restore riparian ecosystems and offset some of the predicted effects of climate change by modulating streamflow. Thus, it is not surprising that reintroducing beaver to watersheds from which they have been extirpated is an often-used restoration and climate-adaptation strategy. Identifying sites for reintroduction, however, requires detailed information about habitat factors information that is not often available at broad spatial scales. Here we explore the potential for beaver relocation throughout the Snohomish River Basin in Washington, USA with a model that identifies some of the basic building blocks of beaver habitat suitability and does so by relying solely on remotely sensed data. More specifically, we developed a generalized intrinsic potential model that draws on remotely sensed measures of stream gradient, stream width, and valley width to identify where beaver could become established if suitable vegetation were to be present. Thus, the model serves as a preliminary screening tool that can be applied over relatively large extents. We applied the model to 5,019 stream km and assessed the ability of the model to correctly predict beaver habitat by surveying for beavers in 352 stream reaches. To further assess the potential for relocation, we assessed land ownership, use, and land cover in the landscape surrounding stream reaches with varying levels of intrinsic potential. Model results showed that 33% of streams had moderate or high intrinsic potential for beaver habitat. We found that no site that was classified as having low intrinsic potential had any sign of beavers and that beaver were absent from nearly three quarters of potentially suitable sites, indicating that there are factors preventing the local population from occupying these areas. Of the riparian areas around streams with high intrinsic potential for beaver, 38% are on public lands and 17% are on large tracts of privately-owned timber land. Thus, although there are a large number of areas that could be suitable for relocation and restoration using beavers, current land use patterns may substantially limit feasibility in these areas. PMID- 29489854 TI - Multistate matrix population model to assess the contributions and impacts on population abundance of domestic cats in urban areas including owned cats, unowned cats, and cats in shelters. AB - Concerns over cat homelessness, over-taxed animal shelters, public health risks, and environmental impacts has raised attention on urban-cat populations. To truly understand cat population dynamics, the collective population of owned cats, unowned cats, and cats in the shelter system must be considered simultaneously because each subpopulation contributes differently to the overall population of cats in a community (e.g., differences in neuter rates, differences in impacts on wildlife) and cats move among categories through human interventions (e.g., adoption, abandonment). To assess this complex socio-ecological system, we developed a multistate matrix model of cats in urban areas that include owned cats, unowned cats (free-roaming and feral), and cats that move through the shelter system. Our model requires three inputs-location, number of human dwellings, and urban area-to provide testable predictions of cat abundance for any city in North America. Model-predicted population size of unowned cats in seven Canadian cities were not significantly different than published estimates (p = 0.23). Model-predicted proportions of sterile feral cats did not match observed sterile cat proportions for six USA cities (p = 0.001). Using a case study from Guelph, Ontario, Canada, we compared model-predicted to empirical estimates of cat abundance in each subpopulation and used perturbation analysis to calculate relative sensitivity of vital rates to cat abundance to demonstrate how management or mismanagement in one portion of the population could have repercussions across all portions of the network. Our study provides a general framework to consider cat population abundance in urban areas and, with refinement that includes city-specific parameter estimates and modeling, could provide a better understanding of population dynamics of cats in our communities. PMID- 29489855 TI - Mammalian carnivore occupancy is inversely related to presence of domestic dogs in the high Andes of Ecuador. AB - Although the Andes have long been occupied by people, habitat loss, fragmentation through deforestation, and other human activities such as introduction of invasive species have increased drastically during the past century. The Ecuadorian Andes are considered a biodiversity hotspot. However, the fauna and threats to the region are poorly studied, and understanding of factors that shape the distribution of species in habitats disturbed by human activities is needed to identify and mitigate region-wide threats to wildlife. We evaluated factors associated with patterns of occurrence of Andean carnivores in landscapes of the northern Ecuadorian Andes, particularly habitat loss, fragmentation, and occupancy of domestic dogs, and determined whether thresholds occurred for these factors beyond which carnivore occurrence declined markedly. Five study areas (each 20 x 20 km) were surveyed with a total effort of 2,800 camera trap nights. Occupancies of four of the eight carnivores known from the region were best predicted by occupancy of domestic dogs rather than measures of habitat loss and fragmentation [Andean fox (Pseudalopex culpaeus), puma (Puma concolor), striped hog-nosed skunk (Conepatus semistriatus), and Andean bear (Tremarctos ornatus)]. The two largest carnivores, puma and Andean bear, demonstrated significant threshold responses to the presence of domestic dogs at two sites. Four smaller carnivores were recorded too infrequently to model occupancy, and at least two of these species appear to be in decline. The magnitude of domestic dog impacts on native species in tropical areas like the Ecuadorian Andes currently are not recognized. Results of our study indicate that small and large carnivores are in urgent need of conservation and clearly point to dogs as a significant threat to a broad range of native species. PMID- 29489856 TI - Implicit emotion regulation in adolescent girls: An exploratory investigation of Hidden Markov Modeling and its neural correlates. AB - Numerous data demonstrate that distracting emotional stimuli cause behavioral slowing (i.e. emotional conflict) and that behavior dynamically adapts to such distractors. However, the cognitive and neural mechanisms that mediate these behavioral findings are poorly understood. Several theoretical models have been developed that attempt to explain these phenomena, but these models have not been directly tested on human behavior nor compared. A potential tool to overcome this limitation is Hidden Markov Modeling (HMM), which is a computational approach to modeling indirectly observed systems. Here, we administered an emotional Stroop task to a sample of healthy adolescent girls (N = 24) during fMRI and used HMM to implement theoretical behavioral models. We then compared the model fits and tested for neural representations of the hidden states of the most supported model. We found that a modified variant of the model posited by Mathews et al. (1998) was most concordant with observed behavior and that brain activity was related to the model-based hidden states. Particularly, while the valences of the stimuli themselves were encoded primarily in the ventral visual cortex, the model based detection of threatening targets was associated with increased activity in the bilateral anterior insula, while task effort (i.e. adaptation) was associated with reduction in the activity of these areas. These findings suggest that emotional target detection and adaptation are accomplished partly through increases and decreases, respectively, in the perceived immediate relevance of threatening cues and also demonstrate the efficacy of using HMM to apply theoretical models to human behavior. PMID- 29489857 TI - The Rosacea-specific Quality-of-Life instrument (RosQol): Revision and validation among Chinese patients. AB - Rosacea is a common chronic facial disorder that affects patients' health-related quality of life; the only questionnaire designed specifically for rosacea is the Rosacea-specific Quality-of-Life instrument (RosQol). However, the questionnaire has not been validated among Chinese patients. This study aimed to validate the Chinese version of the RosQol. First, we translated the questionnaire into Chinese. Then, rosacea patients completed the RosQol and Dermatology Life Quality Index, indicating the disease's impact on their lives. We also collected patients' demographic and clinical data, including symptom self-evaluation scores and rosacea severity scores. Internal consistency was determined by using Cronbach's alpha, test-retest reliability, and Spearman's correlation. Criterion related validity and internal construct validity were also determined. Most RosQol items showed good internal consistency. However, items 13 and 19 were not sufficiently sensitive for use in the Chinese population; we deleted them and constructed the adjusted Chinese-version RosQol, which had good reliability and validity. When patients' clinical symptoms changed, the scores on the relevant dimensions of the adjusted RosQol also changed. Some RosQol items were not suitable for use in the Chinese sample. The adjusted Chinese-version RosQol was easy to complete, well received by patients, and demonstrated acceptable validity and reliability. PMID- 29489858 TI - Tricks of the trade: Mechanism of brood theft in an ant. AB - Thievery is ubiquitous in the animal kingdom, social insects not being an exception. Brood is invaluable for the survival of social insect colonies and brood theft is well documented in ants. In many species the stolen brood act as slaves in the thief colony as they take up tasks related to foraging, defence and colony maintenance. Slave-making (dulotic) ants are at an advantage as they gain workforce without investing in rearing immature young, and several slave-making species have been recorded in temperate regions. In the current study we investigate brood theft in a primitively eusocial ponerine ant Diacamma indicum that inhabits the tropics. In the context of colony relocation we asked how thieves steal brood and what victim colonies do to prevent theft. While exposed nests increased colonies' vulnerability, the relocation process itself did not enhance the chances of theft. Various aggressive interactions, in particular immobilization of intruders helped in preventing theft. Thieves that acted quickly, stayed furtive and stole unguarded brood were found to be successful. This comprehensive study of behavioural mechanism of theft reveals that these are the 'tricks' adopted by thieves. PMID- 29489859 TI - Emollient use alters skin barrier and microbes in infants at risk for developing atopic dermatitis. AB - BACKGROUND: Emollients are a mainstay of treatment in atopic dermatitis (AD), a disease distinguished by skin bacterial dysbiosis. However, changes in skin microbiota when emollients are used as a potential AD preventative measure in infants remain incompletely characterized. RESULTS: We compared skin barrier parameters, AD development, and bacterial 16S ribosomal RNA gene sequences of cheek, dorsal and volar forearm samples from 6-month-old infants with a family history of atopy randomized to receive emollients (n = 11) or no emollients (controls, n = 12). The emollient group had a lower skin pH than the control group. The number of bacterial taxa in the emollient group was higher than in the control group at all sites. The Streptococcus salivarius proportion was higher in the emollient versus control groups at all sites. S. salivarius proportion appeared higher in infants without AD compared to infants with AD. A decrease in S. salivarius abundance was further identified in a separate larger population of older children demonstrating an inverse correlation between AD severity at sampling sites and S. salivarius proportions. CONCLUSIONS: The decreased skin pH and the increased proportion of S. salivarius after long-term emollient use in infants at risk for developing AD may contribute to the preventative effects of emollients in high-risk infants. PMID- 29489860 TI - Phylodynamics and evolutionary epidemiology of African swine fever p72-CVR genes in Eurasia and Africa. AB - African swine fever (ASF) is a complex infectious disease of swine that constitutes devastating impacts on animal health and the world economy. Here, we investigated the evolutionary epidemiology of ASF virus (ASFV) in Eurasia and Africa using the concatenated gene sequences of the viral protein 72 and the central variable region of isolates collected between 1960 and 2015. We used Bayesian phylodynamic models to reconstruct the evolutionary history of the virus, to identify virus population demographics and to quantify dispersal patterns between host species. Results suggest that ASFV exhibited a significantly high evolutionary rate and population growth through time since its divergence in the 18th century from East Africa, with no signs of decline till recent years. This increase corresponds to the growing pig trade activities between continents during the 19th century, and may be attributed to an evolutionary drift that resulted from either continuous circulation or maintenance of the virus within Africa and Eurasia. Furthermore, results implicate wild suids as the ancestral host species (root state posterior probability = 0.87) for ASFV in the early 1700s in Africa. Moreover, results indicate the transmission cycle between wild suids and pigs is an important cycle for ASFV spread and maintenance in pig populations, while ticks are an important natural reservoir that can facilitate ASFV spread and maintenance in wild swine populations. We illustrated the prospects of phylodynamic methods in improving risk-based surveillance, support of effective animal health policies, and epidemic preparedness in countries at high risk of ASFV incursion. PMID- 29489861 TI - The Dox-pDC - A murine conditionally immortalized plasmacytoid dendritic cell line with native immune profile. AB - Plasmacytoid dendritic cells (pDC) constitute a very rare blood cell population and play a significant role in immune response and immune-mediated disorders. Investigations on primary pDCs are hindered not only due to their rarity but also because they represent a heterogeneous cell population which is difficult to culture ex vivo. We generated a conditionally immortalized pDC line (Dox-pDC) from mice with Doxycycline-inducible SV40 Large T Antigen with a comparable immune profile to primary pDCs. The Dox-pDC secrete pro- and anti-inflammatory cytokines upon Toll-like receptor 9 stimulation and upregulate their MHCI, MHCII and costimulatory molecules. Further, the Dox-pDC activate and polarize naive T cells in vivo and in vitro in response to the model antigen Ovalbumin. Due to their long-term culture stability and their robust proliferation Dox-pDC represent a reliable alternative to primary mouse pDC. PMID- 29489862 TI - Time course of blast-induced injury in the rat auditory cortex. AB - Blast exposure is an increasingly significant health hazard and can have a range of debilitating effects, including auditory dysfunction and traumatic brain injury. To assist in the development of effective treatments, a greater understanding of the mechanisms of blast-induced auditory damage and dysfunction, especially in the central nervous system, is critical. To elucidate this area, we subjected rats to a unilateral blast exposure at 22 psi, measured their auditory brainstem responses (ABRs), and histologically processed their brains at 1 day, 1 month, and 3-month survival time points. The left and right auditory cortices was assessed for astrocytic reactivity and axonal degenerative changes using glial fibrillary acidic protein immunoreactivity and a silver impregnation technique, respectively. Although only unilateral hearing loss was induced, astrocytosis was bilaterally elevated at 1 month post-blast exposure compared to shams, and showed a positive trend of elevation at 3 months post-blast. Axonal degeneration, on the other hand, appeared to be more robust at 1 day and 3 months post-blast. Interestingly, while ABR threshold shifts recovered by the 1 and 3-month time points, a positive correlation was observed between rats' astrocyte counts at 1 month post-blast and their threshold shifts at 1 day post-blast. Taken together, our findings suggest that central auditory damage may have occurred due to biomechanical forces from the blast shockwave, and that different indicators/types of damage may manifest over different timelines. PMID- 29489863 TI - In vivo screening platform for shiga toxin-producing Escherichia coli (STEC) using Caenorhabditis elegans as a model. AB - Shiga toxin-producing Escherichia coli (STEC) strains are the main cause of bacillary dysentery, although STEC strains generally induce milder disease symptoms compared to Shigella species. This study aimed to determine the virulence of STEC using the nematode Caenorhabditis elegans as a model host. Worm killing, fertility and bacterial colonisation assays were performed to examine the potential difference in the virulence of STEC strains compared to that of the control E. coli OP50 strains on which worms were fed. A statistically significant difference in the survival rates of C. elegans was observed in that the STEC strains caused death in 8-10 days and the E. coli OP50 strains caused death in 15 days. STEC strains severely reduced the fertility of the worms. The intestinal load of bacteria in the adult stage nematodes harbouring the E. coli OP50 strains was found to be 3.5 log CFU mL-1. In contrast, the STEC strains E15, E18 and E22 harboured 4.1, 4.2 and 4.7 log CFU ml-1 per nematode, respectively. The heat killed STEC strains significantly increased the longevity of the worms compared to the non-heated STEC strains. In addition, PCR-based genomic profiling of shiga toxin genes, viz., stx1 and stx2, identified in selected STEC strains revealed that these toxins may be associated with the virulence of the STEC strains. This study demonstrated that C. elegans is an effective model to examine and compare the pathogenicity and virulence variation of STEC strains to that of E. coli OP50 strains. PMID- 29489864 TI - Cholesterol esterification inhibition and gemcitabine synergistically suppress pancreatic ductal adenocarcinoma proliferation. AB - Recent advances have recognized metabolic reprogramming as an underlying mechanism for cancer drug resistance. However, the role of cholesterol metabolism in drug resistance remain elusive. Herein, we report an increased accumulation of cholesteryl ester in gemcitabine-resistant pancreatic ductal adenocarcinoma (PDAC) cells. A potent inhibitor of acyl-CoA cholesterol acyltransferase-1 (ACAT 1), avasimibe, effectively suppressed proliferation of gemcitabine-resistant PDAC cells. Combination of avasimibe and gemcitabine showed strong synergistic effect in suppressing PDAC cell viability in vitro and tumor growth in vivo. Immunoblotting analysis suggests downregulation of Akt by avasimibe is likely to contribute to the synergism. Collectively, our study demonstrates a new combinational therapeutic strategy to overcome gemcitabine resistance for PDAC treatment. PMID- 29489865 TI - Evaluation of the INTERGROWTH-21st Neurodevelopment Assessment (INTER-NDA) in 2 year-old children. AB - BACKGROUND: The INTER-NDA is a novel assessment of early child development measuring cognition, language, motor skills, behaviour, attention, and socio emotional reactivity in 2 year olds in 15 minutes. Here, we present the results of an evaluation of the INTER-NDA against the Bayley Scales of Infant Development III edition (BSID-III), its sensitivity and specificity and its psychometric properties. METHODS: Eighty-one infants from Oxford, UK, aged 23.1-28.3 months, were evaluated using the INTER-NDA and the BSID-III. The agreement between the INTER-NDA and the BSID-III was assessed using interclass correlations (for absolute agreement), Bland-Altman analyses (for bias and limits of agreement), and sensitivity and specificity analyses (for accuracy). The internal consistency of the INTER-NDA and uni-dimensionality of its subscales were also determined. RESULTS: The interclass correlation coefficients between the BSID-III and the INTER-NDA cognitive, motor and behaviour scores ranged between 0.745 and 0.883 (p<0.001). The Bland-Altman analysis showed little to no bias in the aforementioned subscales. The sensitivity and specificity of INTER-NDA cognitive scores <=1 SD below the mean are 66.7% and 98.6% respectively, with moderate agreement between INTER-NDA and BSID-III classifications (kappa = 0.72, p<0.001). The sensitivity and specificity of INTER-NDA scores <2 SD below the mean, in predicting low BSID-III scores (<70), are 100% each for cognition, and 25% and 100% respectively for language. More than 97% of children who scored in the normal range of the INTER-NDA (<1SD below mean) also scored in the normal range in the BSID-III (>=85). The INTER-NDA demonstrates satisfactory internal consistency and its subscales demonstrate good unidimensionality. CONCLUSION: The INTER-NDA shows good agreement with the BSID-III, and demonstrates satisfactory psychometric properties, for the assessment of ECD at 22-28 months. PMID- 29489866 TI - Identification and characterization of microRNAs in the intestinal tissues of sheep (Ovis aries). AB - Sheep are small ruminants, and their long intestines exhibit high digestive and absorptive capacity in many different rearing conditions; however, the genetic bases of this characteristic remains unclear. MicroRNAs (miRNAs) play a major role in maintaining both intestinal morphological structure as well as in regulating the physiological functions of this organ. However, no study has reported on the miRNA expression profile in the intestinal tissues of sheep. Here, we analyzed and identified the miRNA expression profile of three different intestinal tissues (i.e., duodenum, cecum, and colon) of sheep (Ovis aries) using high-throughput sequencing and bioinformatic methods. In total, 106 known miRNAs were identified, 458 conserved miRNAs were detected, 192 unannotated novel miRNAs were predicted, and 195 differentially expressed miRNAs were found between the different tissues. Additionally, 3,437 candidate target genes were predicted, and 17 non-redundant significantly enriched GO terms were identified using enrichment analysis. A total of 99 candidate target genes were found to significantly enriched in 4 KEGG biological pathways. A combined regulatory network was constructed based on 92 metabolism-related candidate target genes and 65 differentially expressed miRNAs, among which 7 miRNAs were identified as hub miRNAs. Via these mechanisms, miRNAs may play a role in maintaining intestinal homeostasis and metabolism. This study helps to further explain the mechanisms that underlie differences in tissue morphology and function in three intestinal segments of sheep. PMID- 29489867 TI - Dynamics of male canine germ cell development. AB - Primordial germ cells (PGCs) are precursors of gametes that can generate new individuals throughout life in both males and females. Additionally, PGCs have been shown to differentiate into embryonic germ cells (EGCs) after in vitro culture. Most studies investigating germinative cells have been performed in rodents and humans but not dogs (Canis lupus familiaris). Here, we elucidated the dynamics of the expression of pluripotent (POU5F1 and NANOG), germline (DDX4, DAZL and DPPA3), and epigenetic (5mC, 5hmC, H3K27me3 and H3K9me2) markers that are important for the development of male canine germ cells during the early (22 30 days post-fertilization (dpf)), middle (35-40 dpf) and late (45-50 dpf) gestational periods. We performed sex genotype characterization, immunofluorescence, immunohistochemistry, and quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) analyses. Furthermore, in a preliminary study, we evaluated the capacity of canine embryo PGCs (30 dpf) to differentiate into EGCs. To confirm the canine EGCs phenotype, we performed alkaline phosphatase detection, immunohistochemistry, electron and transmission scanning microscopy and RT-qPCR analyses. The PGCs were positive for POU5F1 and H3K27me3 during all assessed developmental periods, including all periods between the gonadal tissue stage and foetal testes development. The number of NANOG, DDX4, DAZL, DPPA3 and 5mC-positive cells increased along with the developing cords from 35-50 dpf. Moreover, our results demonstrate the feasibility of inducing canine PGCs into putative EGCs that present pluripotent markers, such as POU5F1 and the NANOG gene, and exhibit reduced expression of germinative genes and increased expression of H3K27me3. This study provides new insight into male germ cell development mechanisms in dogs. PMID- 29489868 TI - Quantification of abdominal aortic calcification: Inherent measurement errors in current computed tomography imaging. AB - OBJECTIVE: Quantification software for coronary calcification is often used to measure abdominal aortic calcification on computed tomography (CT) images. However, there is no evidence substantiating the reliability and accuracy of these tools in this setting. Differences in coronary and abdominal CT acquisition and presence of intravascular contrast may affect the results of these tools. Therefore, this study investigates the effects of CT acquisition parameters and iodine contrast on automated quantification of aortic calcium on CT. METHODS: Calcium scores, provided in volume and mass, were assessed by automated calcium quantification software on CT scans. First, differences in calcium scores between the abdominal and coronary CT scanning protocols were assessed by imaging a thorax phantom containing calcifications of 9 metrical variations. Second, aortic calcification was quantified in 50 unenhanced and contrast-enhanced clinical abdominal CT scans at a calcification threshold of 299 Hounsfield Units (HU). Also, the lowest possible HU threshold for calcifications was calculated per individual patient and compared to a 130 HU threshold between contrast-enhanced and unenhanced CT images, respectively. RESULTS: No significant differences in volume and mass scores between the abdominal and the coronary CT protocol were found. However, volume and mass of all calcifications were overestimated compared to the physical volume and mass (volume range: 0-649%; mass range: 0-2619%). In comparing unenhanced versus contrast-enhanced CT images showed significant volume differences for both thresholds, as well as for mass differences for the 130 vs patient-specific threshold (230 +/- 22.6 HU). CONCLUSION: Calcification scoring on CT angiography tends to grossly overestimate volume and mass suggesting a low accuracy and reliability. These are reduced further by interference of intravascular contrast. Future studies applying calcium quantification tools on CT angiography imaging should acknowledge these issues and apply corrective measures to ensure the validity of their outcomes. PMID- 29489869 TI - Do people with multiple sclerosis want to know their prognosis? A UK nationwide study. AB - BACKGROUND: Multiple sclerosis (MS) has a varied and uncertain trajectory. The recent development of analytical processing tools that draw on large longitudinal patient databases facilitates personalised long-term prognosis estimates. This has the potential to improve both shared treatment decision-making and psychological adjustment. However, there is limited research on how people with MS feel about prognosis communication and forecasting. This study investigated the prognosis communication experiences and preferences of people with MS and explored whether clinical, demographic and psychological factors are associated with prognosis information preferences. METHODS: 3175 UK MS Register members (59% of those with active accounts) completed an online survey containing 17 questions about prognosis communication experiences, attitudes and preferences. Participants also completed validated questionnaires measuring coping strategies, tendencies to seek out ('monitor') or avoid ('blunt') information in threatening situations, and MS risk perceptions and reported their clinical and sociodemographic characteristics. Data already held on the MS Register about participants' quality of life, anxiety and depression symptoms and MS impact were obtained and linked to the survey data. RESULTS: 53.1% of participants had never discussed long-term prognosis with healthcare professionals. 54.2% lacked clarity about their long-term prognosis. 76% had strong preferences for receiving long term prognosis information. 92.8% were interested in using tools that generate personalised predictions. Most participants considered prognostication useful for decision-making. Participants were more receptive to receiving prognosis information at later time-points, versus at diagnosis. A comprehensive set of sociodemographic, clinical and psychological variables predicted only 7.9% variance in prognosis information preferences. CONCLUSIONS: People with MS have an appetite for individualised long-term prognosis forecasting and their need for information is frequently unmet. Clinical studies deploying and evaluating interventions to support prognostication in MS are now needed. This study indicates suitable contexts and patient preferences for initial trials of long term prognosis tools in clinical settings. PMID- 29489870 TI - Conceptualizing 20 years of engaged scholarship: A scoping review. AB - Engaged scholarship, a movement that has been growing steadily since 1995, offers a new way of bridging gaps between the university and civil society. Numerous papers and reports have been published since Boyer's foundational discourse in 1996. Yet, beyond a growing interest in orienting universities' missions, we observed a lack a formal definition and conceptualization of this movement. Based on a scoping review of the literature over the past 20 years, the objective of this article is to propose a conceptualization of engaged scholarship. More specifically, we define its values, principles, and processes. We conclude with a discussion of the implications of this new posture for faculty and students, as well as for the university as an institution. PMID- 29489871 TI - Current opinions and recommendations of paediatric healthcare professionals - The importance of tablets: Emerging orally disintegrating versus traditional tablets. AB - The appropriate prescribing of paediatric dosage forms is paramount in providing the desired therapeutic effect alongside successful medication adherence with the paediatric population. Often it is the opinion of the healthcare practitioner that dictates which type of dosage form would be most appropriate for the paediatric patient, with liquids being both the most commonly available and most commonly used. Orally disintegrating tablets (ODTs) are an emerging dosage form which provide many benefits over traditional dosage forms for paediatric patients, such as rapid disintegration within the oral cavity, and the reduction in the risk of choking. However the opinion and professional use of healthcare practitioners regarding ODT's is not known. This study was designed to assess the opinions of several types of healthcare professionals (n = 41) regarding ODTs, using a survey across two hospital sites. Results reaffirmed the popularity of liquids for prescribing in paediatrics, with 58.0% of participants preferring this dosage form. ODTs emerged as the second most popular dosage form (30.0%), with healthcare practitioners indicating an increasing popularity amongst patients in the hospital setting, belief with 63.0% of practitioners agreeing that many liquid formulations could be substituted with a suitable ODT. The desired properties of an ideal ODT were also identified by healthcare practitioners preferring a small, fast disintegrating tablet (90.2% and 95.1% respectively), with the taste, disintegration time and flavour being the three most important attributes identified (29.5%, 28.7% and 21.7% respectively). This study provided a pragmatic approach in assessing healthcare professional's opinions on ODTs, highlighting the ideas and thoughts of practitioners who are on the frontline of paediatric prescribing and treatment and gave an indication to their preference for ODT properties. PMID- 29489872 TI - Novel paddle stroke analysis for elite slalom kayakers: Relationship with force parameters. AB - This study was divided into two complementary parts. In Part 1, we proposed a novel paddle strokes analysis based on the force signal from a 30-s all-out tethered test; and compared these results with video recordings. In Part 2, we investigated the relationship between force data from the same test with paddle stroke results from both methods. Eleven male elite slalom kayakers (Brazilian national team) were evaluated. The tethered test was conducted for force parameters analysis (peak-force, mean-force, impulse). Video recording analysis was conducted, and the performed strokes (V.NumberPaddle) was counted and frequency (V.FrequencyPaddle) calculated by the V.NumberPaddle divided by 30 (i.e. total time of test). The new method consisted of performed strokes and frequency achievement from a load cell force signal analysis (S.NumberPaddle and S.FrequencyPaddle, respectively). Paired test-t did not show difference between methods results, but significant correlations were only obtained for the number of paddle strokes. Force parameters were only correlated with S.NumberPaddle and S.FrequencyPaddle. Overall, considering the theoretical and practical application, we propose that the new method should be used as an alternative to the video recording. PMID- 29489873 TI - An informational view of accession rarity and allele specificity in germplasm banks for management and conservation. AB - Germplasm banks are growing in their importance, number of accessions and amount of characterization data, with a large emphasis on molecular genetic markers. In this work, we offer an integrated view of accessions and marker data in an information theory framework. The basis of this development is the mutual information between accessions and allele frequencies for molecular marker loci, which can be decomposed in allele specificities, as well as in rarity and divergence of accessions. In this way, formulas are provided to calculate the specificity of the different marker alleles with reference to their distribution across accessions, accession rarity, defined as the weighted average of the specificity of its alleles, and divergence, defined by the Kullback-Leibler formula. Albeit being different measures, it is demonstrated that average rarity and divergence are equal for any collection. These parameters can contribute to the knowledge of the structure of a germplasm collection and to make decisions about the preservation of rare variants. The concepts herein developed served as the basis for a strategy for core subset selection called HCore, implemented in a publicly available R script. As a proof of concept, the mathematical view and tools developed in this research were applied to a large collection of Mexican wheat accessions, widely characterized by SNP markers. The most specific alleles were found to be private of a single accession, and the distribution of this parameter had its highest frequencies at low levels of specificity. Accession rarity and divergence had largely symmetrical distributions, and had a positive, albeit non-strictly linear relationship. Comparison of the HCore approach for core subset selection, with three state-of-the-art methods, showed it to be superior for average divergence and rarity, mean genetic distance and diversity. The proposed approach can be used for knowledge extraction and decision making in germplasm collections of diploid, inbred or outbred species. PMID- 29489874 TI - Does the rising placebo response impact antihypertensive clinical trial outcomes? An analysis of data from the Food and Drug Administration 1990-2016. AB - BACKGROUND: Recent studies show that placebo response has grown significantly over time in clinical trials for antidepressants, ADHD medications, antiepileptics, and antidiabetics. Contrary to expectations, trial outcome measures and success rates have not been impacted. This study aimed to see if this trend of increasing placebo response and stable efficacy outcome measures is unique to the conditions previously studied or if it occurs in trials for conditions with physiologically-measured symptoms, such as hypertension. METHOD: For this reason, we evaluated the efficacy data reported in the US Food and Drug Administration Medical and Statistical reviews for 23 antihypertensive programs (32,022 patients, 63 trials, 142 treatment arms). Placebo and medication response, effect sizes, and drug-placebo differences were calculated for each treatment arm and examined over time using meta-regression. We also explored the relationship of sample size, trial duration, baseline blood pressure, and number of treatment arms to placebo/drug response and efficacy outcome measures. RESULTS: Like trials of other conditions, placebo response has risen significantly over time (R2 = 0.093, p = 0.018) and effect size (R2 = 0.013, p = 0.187) drug-placebo difference (R2 = 0.013, p = 0.182) and success rate (134/142, 94.4%) have remained unaffected, likely due to a significant compensatory increase in antihypertensive response (R2 = 0.086, p<0.001). Treatment arms are likely overpowered with sample sizes increasing over time (R2 = 0.387, p<0.0001) and stable, large effect sizes (0.78 +/-0.37). The exploratory analysis of sample size, trial duration, baseline blood pressure, and number of treatment arms yielded mixed results unlikely to explain the pattern of placebo response and efficacy outcomes over time. The magnitude of placebo response had no relationship to effect size (p = 0.877), antihypertensive-placebo differences (p = 0.752), or p-values (p = 0.963) but was correlated with antihypertensive response (R2 = 0.347, p<0.0001). CONCLUSIONS: As hypothesized, this study shows that placebo response is increasing in clinical trials for hypertension without any evidence of this increase impacting trial outcomes. Attempting to control placebo response in clinical trials for hypertension may not be necessary for successful efficacy outcomes. In exploratory analysis, we noted that despite finding significant relationships, none of the trial or patient characteristics we examined offered a clear explanation of the rise in placebo and stability in outcome measures over time. Collectively, these data suggest that the phenomenon of increasing placebo response and stable efficacy outcomes may be a general trend, occurring across trials for various psychiatric and medical conditions with physiological and non-physiological endpoints. PMID- 29489875 TI - The ProQOL-21: A revised version of the Professional Quality of Life (ProQOL) scale based on Rasch analysis. AB - The Professional Quality of Life scale is a measure intended to provide practitioners and researchers with an indication of a caring professional's compassion satisfaction, burnout, and secondary traumatic stress. While this measure has been used extensively in nursing research, owing to the relevancy of patient-care associated satisfaction and fatigue within this profession, information regarding the construct validity of this measure is less well represented in the literature. We examined the construct validity of the Professional Quality of Life scale using a Rasch analysis procedure on each of its three scales, as a means of substantiating their measurement adequacy. Responses on the Professional Quality of Life scale from 1615 registered nurses (age x = 46.48 years, SD = 11.78) were analysed. While support for the measurement adequacy (invariance, person/item fit, and unidimensionality) of the compassion satisfaction scale was found, the burnout and secondary traumatic stress scales did not demonstrate adequate measurement properties. We instead present an alternative measurement model of these subscales, involving items from each, to form a robust measure of compassion fatigue, and provide recoding, scoring, and normed scores for both measures. Our findings indicate that use of the Professional Quality of Life scale's burnout and secondary traumatic stress scales may require caution, while our revised compassion satisfaction and fatigue scales provide robust measurement options for practitioners and researchers. PMID- 29489876 TI - Modulation of the peripheral blood transcriptome by the ingestion of probiotic yoghurt and acidified milk in healthy, young men. AB - The metabolic health benefits of fermented milks have already been investigated using clinical biomarkers but the development of transcriptomic analytics in blood offers an alternative approach that may help to sensitively characterise such effects. We aimed to assess the effects of probiotic yoghurt intake, compared to non-fermented, acidified milk intake, on clinical biomarkers and gene expression in peripheral blood. To this end, a randomised, crossover study was conducted in fourteen healthy, young men to test the two dairy products. For a subset of seven subjects, RNA sequencing was used to measure gene expression in blood collected during postprandial tests and after two weeks daily intake. We found that the postprandial response in insulin was different for probiotic yoghurt as compared to that of acidified milk. Moreover changes in several clinical biomarkers were associated with changes in the expression of genes representing six metabolic genesets. Assessment of the postprandial effects of each dairy product on gene expression by geneset enrichment analysis revealed significant, similar modulation of inflammatory and glycolytic genes after both probiotic yoghurt and acidified milk intake, although distinct kinetic characteristics of the modulation differentiated the dairy products. The aryl hydrocarbon receptor was a major contributor to the down-regulation of the inflammatory genesets and was also positively associated with changes in circulating insulin at 2h after yoghurt intake (p = 0.05). Daily intake of the dairy products showed little effect on the fasting blood transcriptome. Probiotic yoghurt and acidified milk appear to affect similar gene pathways during the postprandial phase but differences in the timing and the extent of this modulation may lead to different physiological consequences. The functional relevance of these differences in gene expression is supported by their associations with circulating biomarkers. PMID- 29489877 TI - Effect of a first responder on survival outcomes after out-of-hospital cardiac arrest occurs during a period of exercise in a public place. AB - INTRODUCTION: The deployment of first responders in a public place is one of the interventions that is used for increasing bystander cardiopulmonary resuscitation (CPR) of out-of-hospital cardiac arrests (OHCA). We studied the association between the presence of a first responder and the survival of OHCA that occurred during a period of exercise in a public place. METHODS: All of the adult OHCAs of a presumed cardiac etiology that occurred during a period of exercise in a public place and that were witnessed by a bystander between 2013 and 2015 were analyzed. The main exposure of interest was the characteristics of the bystander (first responder vs. layperson). The endpoints were the provision of bystander CPR and good neurological recovery. Multivariable logistic regression analysis, adjusting for patient-environment and prehospital factors, was performed. RESULTS: A total of 870 patients had a cardiac arrest during a period of exercise in a public place, and 58 (6.7%) patients were witnessed by the first responder. The OHCAs witnessed by first responders were more likely to result in bystander CPR than those witnessed by laypersons (89.7% vs. 75.4%, p = 0.01, adjusted OR (95% CI): 3.51 (1.44-8.55)). In terms of good neurological recovery, the OHCAs witnessed by first responders had a higher likelihood than the patients witnessed by laypersons (37.9% vs, 24.0%, p = 0.02, adjusted OR (95% CI): 2.92 (1.33-6.40)). CONCLUSION: The OHCAs occurred during a period of exercise in a public place and whom first responders witnessed were more likely to receive bystander CPR and to have a neurologically intact survival. PMID- 29489878 TI - Subclinical recurrent neck pain and its treatment impacts motor training-induced plasticity of the cerebellum and motor cortex. AB - The cerebellum processes pain inputs and is important for motor learning. Yet, how the cerebellum interacts with the motor cortex in individuals with recurrent pain is not clear. Functional connectivity between the cerebellum and motor cortex can be measured by a twin coil transcranial magnetic stimulation technique in which stimulation is applied to the cerebellum prior to stimulation over the motor cortex, which inhibits motor evoked potentials (MEPs) produced by motor cortex stimulation alone, called cerebellar inhibition (CBI). Healthy individuals without pain have been shown to demonstrate reduced CBI following motor acquisition. We hypothesized that CBI would not reduce to the same extent in those with mild-recurrent neck pain following the same motor acquisition task. We further hypothesized that a common treatment for neck pain (spinal manipulation) would restore reduced CBI following motor acquisition. Motor acquisition involved typing an eight-letter sequence of the letters Z,P,D,F with the right index finger. Twenty-seven neck pain participants received spinal manipulation (14 participants, 18-27 years) or sham control (13 participants, 19-24 years). Twelve healthy controls (20-27 years) also participated. Participants had CBI measured; they completed manipulation or sham control followed by motor acquisition; and then had CBI re-measured. Following motor acquisition, neck pain sham controls remained inhibited (58 +/- 33% of test MEP) vs. healthy controls who disinhibited (98 +/- 49% of test MEP, P<0.001), while the spinal manipulation group facilitated (146 +/- 95% of test MEP, P<0.001). Greater inhibition in neck pain sham vs. healthy control groups suggests that neck pain may change cerebellar motor cortex interaction. The change to facilitation suggests that spinal manipulation may reverse inhibitory effects of neck pain. PMID- 29489879 TI - CD4+ CD25+ FOXP3+ T cell frequency in the peripheral blood is a biomarker that distinguishes intestinal tuberculosis from Crohn's disease. AB - BACKGROUND: Distinguishing between Crohn's Disease (CD) and Intestinal Tuberculosis (ITB) has been a challenging task for clinicians due to their similar presentation. CD4+FOXP3+ T regulatory cells (Tregs) have been reported to be increased in patients with pulmonary tuberculosis. However, there is no such data available in ITB. The aim of this study was to investigate the differential expression of FOXP3+ T cells in patients with ITB and CD and its utility as a biomarker. METHODS: The study prospectively recruited 124 patients with CD, ITB and controls: ulcerative colitis (UC) and patients with only haemorrhoidal bleed. Frequency of CD4+CD25+FOXP3+ Tregs in peripheral blood (flow cytometry), FOXP3 mRNA expression in blood and colonic mucosa (qPCR) and FOXP3+ T cells in colonic mucosa (immunohistochemistry) were compared between controls, CD and ITB patients. RESULTS: Frequency of CD4+CD25+FOXP3+ Treg cells in peripheral blood was significantly increased in ITB as compared to CD. Similarly, significant increase in FOXP3+ T cells and FOXP3 mRNA expression was observed in colonic mucosa of ITB as compared to CD. ROC curve showed that a value of >32.5% for FOXP3+ cells in peripheral blood could differentiate between CD and ITB with a sensitivity of 75% and a specificity of 90.6%. CONCLUSION: Phenotypic enumeration of peripheral CD4+CD25+FOXP3+ Treg cells can be used as a non-invasive biomarker in clinics with a high diagnostic accuracy to differentiate between ITB and CD in regions where TB is endemic. PMID- 29489880 TI - Response to formal comment on Myhrvold (2016) submitted by Griebeler and Werner (2017). AB - Griebeler and Werner offer a formal comment on Myhrvold, 2016 defending the conclusions of Werner and Griebeler, 2014. Although the comment criticizes several aspects of methodology in Myhrvold, 2016, all three papers concur on a key conclusion: the metabolism of extant endotherms and ectotherms cannot be reliably classified using growth-rate allometry, because the growth rates of extant endotherms and ectotherms overlap. A key point of disagreement is that the 2014 paper concluded that despite this general case, one can nevertheless classify dinosaurs as ectotherms from their growth rate allometry. The 2014 conclusion is based on two factors: the assertion (made without any supporting arguments) that the comparison with dinosaurs must be restricted only to extant sauropsids, ignoring other vertebrate groups, and that extant sauropsid endotherm and ectotherm growth rates in a data set studied in the 2014 work do not overlap. The Griebeler and Werner formal comment presents their first arguments in support of the restriction proposition. In this response I show that this restriction is unsupported by established principles of phylogenetic comparison. In addition, I show that the data set studied in their 2014 work does show overlap, and that this is visible in one of its figures. I explain how either point effectively invalidates the conclusion of their 2014 paper. I also address the other methodological criticisms of Myhrvold 2016, and find them unsupported. PMID- 29489881 TI - Impairment of vascular strain in patients with obstructive sleep apnea. AB - BACKGROUND: Obstructive sleep apnea (OSA) is an independent risk factor for the development of cardiovascular diseases. Aim of this present study was to evaluate and extend recent research on the influence of obstructive sleep apnea on vascular strain. METHODS: A total number of 98 patients were integrated in the study. Patients were grouped according to the Apnea-Hypopnea-Index (AHI) in patients with mild-to-moderate OSA (5/h <= AHI < 30/h), severe OSA (AHI >= 30/h) and controls (AHI < 5/h). Groups were matched in age, body-mass-index and cardiovascular risks. Vascular strain of common carotid arteries was assessed by ultrasound speckle-tracking. A minor group of 30 patients and controls further underwent assessment of vascular strain of brachial and femoral arteries. Additionally, all patients underwent blood testing to reveal potential influences of inflammatory markers on arterial stiffness. In additional analysis we examined the effect of statin therapy on vascular strain. RESULTS: Patients with OSA showed significantly reduced values of vascular strain of common carotid arteries. Radial and circumferential strains were significantly lower in both patients with mild-to-moderate (p = .05) and patients with severe OSA (p = .001) compared to control. Vascular strain parameters of brachial and femoral arteries showed no consistent results. There were no significant correlations of inflammatory markers with vascular strain parameters. No significant differences in vascular strain were detected between statin and non-statin groups. CONCLUSION: Patients with OSA show significantly reduced vascular strain assessed by ultrasound-based speckle-tracking. Vascular stiffness increases with the severity of the disease. Target vessels to assess vascular strain in patients with OSA are common carotid arteries, whereas other sites of the arterial tree are not reliable. No significant impact of current statin therapy on vascular strain was found. Further studies are needed to evaluate potential benefit of statins in secondary prevention of atherosclerosis in OSA. PMID- 29489882 TI - Validation of the C.A.R.E. stimulus set of 640 animal pictures: Name agreement and quality ratings. AB - Stimulus sets are valuable tools that can facilitate the work of researchers designing experiments. Images of faces, and line drawings of objects have been developed and validated, however, pictures of animals, that do not contain backgrounds, have not been made available. Here we present image agreement and quality ratings for a set of 640 color images of animals on a transparent background, across 60 different basic categories (e.g. cat, dog, frog, bird), some with few, and others with many exemplars. These images were normed on 302 participants. Image agreement was measured both with respect to the proportion of participants that provided the same name as well as the H-statistic for each image. Image quality was measured both overall, and with respect to the accuracy of participants' naming of the basic category. Word frequency of each basic and superordinate category based on the English Lexicon Project (Balota, et al., 2007) and the HAL database (Kucera & Francis, 1976) are provided as are Age of Acquisition (Kuperman, Stadthagen-Gonzalez, & Brysbaert, 2012) data. PMID- 29489883 TI - Mechanical properties of provisional dental materials: A systematic review and meta-analysis. AB - Provisional restorations represent an important phase during the rehabilitation process, knowledge of the mechanical properties of the available materials allows us to predict their clinical performance. At present, there is no systematic review, which supports the clinicians' criteria, in the selection of a specific material over another for a particular clinical situation. The purpose of this systematic review and meta-analysis was to assess and compare the mechanical properties of dimethacrylates and monomethacrylates used in fabricating direct provisional restorations, in terms of flexural strength, fracture toughness and hardness. This review followed the PRISMA guidelines. The searches were conducted in PubMed, Embase, Web of Science, Scopus, the New York Academy of Medicine Grey Literature Report and were complemented by hand-searching, with no limitation of time or language up to January 10, 2017. Studies that assess and compare the mechanical properties of dimethacrylate- and monomethacrylate-based provisional restoration materials were selected. A quality assessment of full-text articles were performed according to modified ARRIVE and CONSORT criteria and modified Cochrane Collaboration's tool for in vitro studies. Initially, 256 articles were identified. After removing the duplicates and applying the selection criteria, 24 articles were included in the qualitative synthesis and 7 were included in the quantitative synthesis (meta-analysis). It may be concluded that dimethacrylate based provisional restorations presented better mechanical behavior than monomethacrylate-based ones in terms of flexural strength and hardness. Fracture toughness showed no significant differences. Within the monomethacrylate group, polymethylmethacrylate showed greater flexural strength than polyethylmethacrylate. PMID- 29489884 TI - Design, innovation, and rural creative places: Are the arts the cherry on top, or the secret sauce? AB - OBJECTIVE: Creative class theory explains the positive relationship between the arts and commercial innovation as the mutual attraction of artists and other creative workers by an unobserved creative milieu. This study explores alternative theories for rural settings, by analyzing establishment-level survey data combined with data on the local arts scene. The study identifies the local contextual factors associated with a strong design orientation, and estimates the impact that a strong design orientation has on the local economy. METHOD: Data on innovation and design come from a nationally representative sample of establishments in tradable industries. Latent class analysis allows identifying unobserved subpopulations comprised of establishments with different design and innovation orientations. Logistic regression allows estimating the association between an establishment's design orientation and local contextual factors. A quantile instrumental variable regression allows assessing the robustness of the logistic regression results with respect to endogeneity. An estimate of design orientation at the local level derived from the survey is used to examine variation in economic performance during the period of recovery from the Great Recession (2010-2014). RESULTS: Three distinct innovation (substantive, nominal, and non-innovators) and design orientations (design-integrated, "design last finish," and no systematic approach to design) are identified. Innovation- and design-intensive establishments were identified in both rural and urban areas. Rural design-integrated establishments tended to locate in counties with more highly educated workforces and containing at least one performing arts organization. A quantile instrumental variable regression confirmed that the logistic regression result is robust to endogeneity concerns. Finally, rural areas characterized by design-integrated establishments experienced faster growth in wages relative to rural areas characterized by establishments using no systematic approach to design. PMID- 29489885 TI - Infection prevention and control training and capacity building during the Ebola epidemic in Guinea. AB - BACKGROUND: During the 2014-2016 Ebola epidemic in West Africa, a key epidemiological feature was disease transmission within healthcare facilities, indicating a need for infection prevention and control (IPC) training and support. METHODS: IPC training was provided to frontline healthcare workers (HCW) in healthcare facilities that were not Ebola treatment units, as well as to IPC trainers and IPC supervisors placed in healthcare facilities. Trainings included both didactic and hands-on components, and were assessed using pre-tests, post tests and practical evaluations. We calculated median percent increase in knowledge. RESULTS: From October-December 2014, 20 IPC courses trained 1,625 Guineans: 1,521 HCW, 55 IPC trainers, and 49 IPC supervisors. Median test scores increased 40% (interquartile range [IQR]: 19-86%) among HCW, 15% (IQR: 8-33%) among IPC trainers, and 21% (IQR: 15-30%) among IPC supervisors (all P<0.0001) to post-test scores of 83%, 93%, and 93%, respectively. CONCLUSIONS: IPC training resulted in clear improvements in knowledge and was feasible in a public health emergency setting. This method of IPC training addressed a high demand among HCW. Valuable lessons were learned to facilitate expansion of IPC training to other prefectures; this model may be considered when responding to other large outbreaks. PMID- 29489886 TI - Identification of relevant drugable targets in diffuse large B-cell lymphoma using a genome-wide unbiased CD20 guilt-by association approach. AB - Forty percent of patients with diffuse large B-cell lymphoma (DLBCL) show resistant disease to standard chemotherapy (CHOP) in combination with the anti CD20 monoclonal antibody rituximab (R). Although many new anti-cancer drugs were developed in the last years, it is unclear which of these drugs can be safely combined to improve standard therapy without antagonizing anti-CD20 efficacy. In this study, we aimed to identify rituximab compatible drug-target combinations for DLBCL. For this, we collected gene expression profiles of 1,804 DLBCL patient samples. Subsequently, we performed a guilt-by-association analysis with MS4A1 (CD20) and prioritized the 500 top-ranked CD20-associated gene probes for drug target interactions. This analysis showed the well-known genes involved in DLBCL pathobiology, but also revealed several genes that are relatively unknown in DLBCL, such as WEE1 and PARP1. To demonstrate potential clinical relevance of these targets, we confirmed high protein expression of WEE1 and PARP1 in patient samples. Using clinically approved WEE1 and PARP1 inhibiting drugs in combination with rituximab, we demonstrated significantly improved DLBCL cell killing, also in rituximab-insensitive cell lines. In conclusion, as exemplified by WEE1 and PARP1, our CD20-based genome-wide analysis can be used as an approach to identify biological relevant drug-targets that are rituximab compatible and may be implemented in phase 1/2 clinical trials to improve DLBCL treatment. PMID- 29489888 TI - Measuring and modelling the quality of 40 post-disaster mental health and psychosocial support programmes. AB - Disasters can have an enormous impact on the health and well-being of those affected. Internationally, governments and service providers are often challenged to address complex psychosocial problems. Ideally, the potentially broad range of support activities include a coherent, high-quality mental health and psychosocial support (MHPSS) programme. We present a theory-driven quantitative analysis of the quality of 40 MHPSS programmes, mostly implemented in European disaster settings. The objective is to measure quality domains recognized as relevant in the literature and to empirically test associations. During the EU project "Operationalizing Psychosocial Support in Crisis" (OPSIC) an evaluation survey was designed and developed for this purpose and completed by 40 MHPSS programme coordinators involved in different mass emergencies and disasters. We analysed the survey data in two steps. Firstly, we used the data to operationalize quality domains of a MHPSS programme, tested constructs and assessed their internal consistency reliability. A total of 26 out of 44 survey items clustered into three of the four domains identified within the theoretical framework: "planning and delivery system" (Cronbach's alpha 0.82); "general evaluation criteria" (Cronbach's alpha 0.82); and "essential psychosocial principles" (Cronbach's alpha 0.75). "Measures and interventions applied", theoretically a potential fourth domain, could not be confirmed to empirically cluster together. Secondly, several models with associations between domains and measures and interventions were tested and compared. The model with the best fit suggests that in MHPSS programmes with a higher planning and delivery systems score, a larger number of measures and interventions from evidence-informed guidelines are applied. In such programmes, coordinators are more positive about general evaluation criteria and the realization of essential psychosocial principles. Moreover, the analyses showed that some measures and interventions are more likely to be applied in programmes with more evolved planning and delivery systems, yet for most measures and interventions the likelihood of being applied is not linked to planning and delivery system status, nor to coordinator perceptions concerning psychosocial principles and evaluation criteria. Further research is necessary to validate and expand the findings and to learn more about success factors and obstacles for MHPSS programme implementation. PMID- 29489887 TI - Accelerating access to quality TB care for pediatric TB cases through better diagnostic strategy in four major cities of India. AB - BACKGROUND: Diagnosis of TB in children is challenging, and is largely based on positive history of contact with a TB case, clinical and radiological findings, often without microbiological confirmation. Diagnostic efforts are also undermined by challenges in specimen collection and the limited availability of high sensitivity, rapid diagnostic tests that can be applied with a quick turnaround time. The current project was undertaken in four major cities of India to address TB diagnostic challenges in pediatric population, by offering free of cost Xpert testing to pediatric presumptive TB cases, thereby paving the way for better TB care. METHODS: A high throughput lab was established in each of the four project cities, and linked to various health care providers across the city through rapid specimen transportation and electronic reporting linkages. Free Xpert testing was offered to all pediatric (0-14 years) presumptive TB cases (both pulmonary and extra-pulmonary) seeking care at public and private health facilities. RESULTS: The current project enrolled 42,238 pediatric presumptive TB cases from April, 2014 to June, 2016. A total of 3,340 (7.91%, CI 7.65-8.17) bacteriologically confirmed TB cases were detected, of which 295 (8.83%, CI 7.9 9.86) were rifampicin-resistant. The level of rifampicin resistance in the project cohort was high. Overall Xpert yielded a high proportion of valid results and TB detection rates were more than three-fold higher than smear microscopy. The project provided same-day testing and early availability of results led to rapid treatment initiation and success rates and very low rates of treatment failure and loss to follow-up. CONCLUSION: The current project demonstrated the feasibility of rolling out rapid and upfront Xpert testing for pediatric presumptive TB cases through a single Xpert lab per city in an efficient manner. Rapid turnaround testing time facilitated prompt and appropriate treatment initiation. These results suggest that the upfront Xpert assay is a promising solution to address TB diagnosis in children. The high levels of rifampicin resistance detected in presumptive pediatric TB patients tested under the project are a major cause of concern from a public health perspective which underscores the need to further prioritize upfront Xpert access to this vulnerable population. PMID- 29489889 TI - Being aware of the painful body: Validation of the German Body Awareness Questionnaire and Body Responsiveness Questionnaire in patients with chronic pain. AB - Body awareness is an attentional focus on and awareness of internal body sensations. This study aimed to validate German versions of the Body Awareness Questionnaire (BAQ) and the Body Responsiveness Questionnaire (BRQ) in chronic pain patients and to assess their associations with pain-related variables and to assess their responsiveness to intervention. The instruments were translated to German and administered to 512 chronic pain patients (50.3+/-11.4 years, 91.6% female) to assess their factor structure and reliability. Cronbach's alpha for the BAQ total score was 0.86. Factor analysis of the BRQ revealed the two factors Importance of Interoceptive Awareness (Cronbach's alpha = 0.75) and Perceived Connection (Cronbach's alpha = 0.75) and the single-item Suppression of Bodily Sensations. The BAQ was independently associated with lower mindfulness, self esteem, stress, and depression; Importance of Interoceptive Awareness with mindfulness, self-acceptance, self-esteem, and physical contact; Perceived Connection with self-acceptance, vitality, and lower sensory pain; Suppression of Bodily Sensations with lower self-esteem, physical contact, and higher depressive symptoms. After a 10-week multimodal mind-body program (n = 202), the BAQ and Importance of Interoceptive Awareness increased and pain intensity and Suppression of Bodily Sensation decreased. In conclusion, body awareness and body responsiveness are associated with pain-related variables in patients with chronic pain. Mind-body interventions may positively influence both pain and body awareness, hinting at a potential mechanism of action of these interventions to be tested in further research. PMID- 29489890 TI - Prosecution of non-disclosure of HIV status: Potential impact on HIV testing and transmission among HIV-negative men who have sex with men. AB - BACKGROUND: Non-disclosure criminal prosecutions among gay, bisexual and other men who have sex with men (MSM) are increasing, even though transmission risk is low when effective antiretroviral treatment (ART) is used. Reduced HIV testing may reduce the impact of HIV "test and treat" strategies. We aimed to quantify the potential impact of non-disclosure prosecutions on HIV testing and transmission among MSM. METHODS: MSM attending an HIV and primary care clinic in Toronto completed an audio computer-assisted self-interview questionnaire. HIV negative participants were asked concern over non-disclosure prosecution altered their likelihood of HIV testing. Responses were characterized using cross tabulations and bivariate logistic regressions. Flow charts modelled how changes in HIV testing behaviour impacted HIV transmission rates controlling for ART use, condom use and HIV status disclosure. RESULTS: 150 HIV-negative MSM were recruited September 2010 to June 2012. 7% (9/124) were less or much less likely to be tested for HIV due to concern over future prosecution. Bivariate regression showed no obvious socio/sexual demographic characteristics associated with decreased willingness of HIV testing to due concern about prosecution. Subsequent models estimated that this 7% reduction in testing could cause an 18.5% increase in community HIV transmission, 73% of which was driven by the failure of HIV positive but undiagnosed MSM to access care and reduce HIV transmission risk by using ART. CONCLUSIONS: Fear of prosecution over HIV non-disclosure was reported to reduce HIV testing willingness by a minority of HIV-negative MSM in Toronto; however, this reduction has the potential to significantly increase HIV transmission at the community level which has important public health implications. PMID- 29489891 TI - Subcellular distribution of ERK phosphorylation in tyrosine and threonine depends on redox status in murine lung cells. AB - Activation of ERK1/2 implies the phosphorylation of tyrosine (pTyr) and threonine (pThr) by MEK1/2; both reactions were thought to be cytoplasmic, promoting ERK to reach the nucleus where it activates several transcription factors. In addition, H2O2 concentrations are known to modulate ERK intracellular translocation, which impacts on cellular proliferation. In this context, the objective of this work was to study the sequence of ERK phosphorylation under two redox conditions and to analyze a putative mitochondrial contribution to this process, in LP07 murine lung cells. A time-course of H2O2 administration was used and ERK phosphorylation was analyzed in cytosol, mitochondria and nuclei. At 1MUM H2O2, a proliferative redox stimulus, immunoblot revealed a fast and transient increase in cytosol pTyr and a sustained increase in mitochondrial pTyr content. The detection for pThr/pTyrERK (2pERK) showed in cytosol a marked increase at 5 minutes with a fast dephosphorylation after that time, for both H2O2 concentrations. However, at 50 MUM H2O2, an anti-proliferative condition, 2pERK was gradually retained in mitochondria. Interestingly, these results were confirmed by in vivo experiments using mice treated with a highly oxidizing agent [H2O2]. By the use of two ERK2 mutant constructions, where Tyr and Thr were replaced by alanine, we confirmed that 2pERK relied almost completely on pThr183. Confocal microscopy confirmed ERK subcellular distribution dependence on the incidence of cytosolic pTyr and mitochondrial pThr at 1MUM H2O2. This work shows for the first time, both in vitro and in vivo, an ERK cycle involving a cross-talk between cytosol and mitochondria phosphorylation events, which may play a significant role in cell cycle progression, proliferation or differentiation under two different redox conditions. PMID- 29489892 TI - Inhibition of proanthocyanidin A2 on porcine reproductive and respiratory syndrome virus replication in vitro. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is a widely prevalent and endemic swine pathogen that causes significant economic losses for the global pig industry annually. Currently, the most prevalent strategy for PRRSV control remains the prevention of virus transmission, with highly effective therapeutic agents and vaccines still lacking. Proanthocyanidin A2 (PA2) belongs to the family of tea polyphenols, which have been reported to exhibit a range of biological activities including anti-oxidative, cardio-protective, anti-tumoural, anti-bacterial, anti-viral, and anti-inflammatory effects in vitro as well as in vivo. Here, we demonstrate that PA2 exhibits potent anti-viral activity against PRRSV infection in Marc-145 cells. Similar inhibitory effects were also found in porcine alveolar macrophages, the primary target cell type of PRRSV infection in pigs in vivo. For traditional type II PRRSV CH-1a strain and high pathogenic GD XH strain and GD-HD strain, PA2 exhibited broad-spectrum and comparable inhibitory activities in vitro with EC50 ranging from 2.2 to 3.2 MUg/ml. Treatment of PRRSV-infected Marc-145 cells with PA2 significantly inhibited viral RNA synthesis, viral protein expression and progeny virus production in a dose dependent manner. In addition, PA2 treatment reduced gene expressions of cytokines (TNF-alpha, IFN-alpha, IL-1beta and IL-6) induced by PRRSV infection in PAMs. Mechanistically, PA2 inhibited PRRSV replication by targeting multiple pathways including blockade of viral entry and progeny virus release. Altogether, our findings suggest that PA2 has the potential to serve as a novel prophylactic and therapeutic strategies against PRRSV infection. PMID- 29489894 TI - Correction: Role of computed tomography angiography on the management of overt obscure gastrointestinal bleeding. AB - [This corrects the article DOI: 10.1371/journal.pone.0172754.]. PMID- 29489893 TI - RSV hijacks cellular protein phosphatase 1 to regulate M2-1 phosphorylation and viral transcription. AB - Respiratory syncytial virus (RSV) RNA synthesis occurs in cytoplasmic inclusion bodies (IBs) in which all the components of the viral RNA polymerase are concentrated. In this work, we show that RSV P protein recruits the essential RSV transcription factor M2-1 to IBs independently of the phosphorylation state of M2 1. We also show that M2-1 dephosphorylation is achieved by a complex formed between P and the cellular phosphatase PP1. We identified the PP1 binding site of P, which is an RVxF-like motif located nearby and upstream of the M2-1 binding region. NMR confirmed both P-M2-1 and P-PP1 interaction regions in P. When the P PP1 interaction was disrupted, M2-1 remained phosphorylated and viral transcription was impaired, showing that M2-1 dephosphorylation is required, in a cyclic manner, for efficient viral transcription. IBs contain substructures called inclusion bodies associated granules (IBAGs), where M2-1 and neo synthesized viral mRNAs concentrate. Disruption of the P-PP1 interaction was correlated with M2-1 exclusion from IBAGs, indicating that only dephosphorylated M2-1 is competent for viral mRNA binding and hence for a previously proposed post transcriptional function. PMID- 29489895 TI - Gamma-band auditory steady-state response after frontal tDCS: A double-blind, randomized, crossover study. AB - The effects of transcranial direct current stimulation (tDCS) likely depend on cortical N-methyl-D-aspartic acid (NMDA) neurotransmission; however, no previous studies have reported tDCS-mediated modulation of cortical NMDA neurotransmission in humans. The gamma-band auditory steady-state response (ASSR) to a 40 Hz stimulation likely reflects the integrity of cortical NMDA neurotransmission. The present study tested whether the effect of tDCS is reflected in gamma-band ASSRs during a 40 Hz stimulation. Using a double-blind, randomized, crossover study, we performed magnetoencephalography (MEG) and measured the ASSR in 24 healthy participants during 40 Hz of auditory stimulation after prefrontal tDCS (2 mA) or sham (i.e., placebo) treatment. Our results failed to reveal significant differences in any brain between the two conditions after the application of a frequency of approximately 40 Hz. Based on these results, the ASSR is an insufficient method to detect the effect of tDCS on cortical NMDA neurotransmission. Unexpectedly, the results revealed an enhanced beta-band event related spectral perturbation (ERSP) in the left motor cortex after tDCS compared with that observed after the sham stimuli. Given that beta-band oscillations reflect many functions in motor cortices, the tDCS for the frontal areas had some effect on the left motor cortex while the participants were focusing on not pressing the button with their right index finger. An additional study with an adequate psychological task is necessary to draw a conclusion regarding this unexpected result. PMID- 29489897 TI - Experimental study on electromagnetic-assisted ZnO nanofluid flooding for enhanced oil recovery (EOR). AB - Recently, nano-EOR has emerged as a new frontier for improved and enhanced oil recovery (IOR & EOR). Despite their benefits, the nanoparticles tend to agglomerate at reservoir conditions which cause their detachment from the oil/water interface, and are consequently retained rather than transported through a porous medium. Dielectric nanoparticles including ZnO have been proposed to be a good replacement for EOR due to their high melting point and thermal properties. But more importantly, these particles can be polarized under electromagnetic (EM) irradiation, which provides an innovative smart Nano-EOR process denoted as EM-Assisted Nano-EOR. In this study, parameters involved in the oil recovery mechanism under EM waves, such as reducing mobility ratio, lowering interfacial tensions (IFT) and altering wettability were investigated. Two-phase displacement experiments were performed in sandpacks under the water wet condition at 95 degrees C, with permeability in the range of 265-300 mD. A crude oil from Tapis oil field was employed; while ZnO nanofluids of two different particle sizes (55.7 and 117.1 nm) were prepared using 0.1 wt. % nanoparticles that dispersed into brine (3 wt. % NaCl) along with SDBS as a dispersant. In each flooding scheme, three injection sequential scenarios have been conducted: (i) brine flooding as a secondary process, (ii) surfactant/nano/EM-assisted nano flooding, and (iii) second brine flooding to flush nanoparticles. Compare with surfactant flooding (2% original oil in place/OOIP) as tertiary recovery, nano flooding almost reaches 8.5-10.2% of OOIP. On the other hand, EM-assisted nano flooding provides an incremental oil recovery of approximately 9-10.4% of OOIP. By evaluating the contact angle and interfacial tension, it was established that the degree of IFT reduction plays a governing role in the oil displacement mechanism via nano-EOR, compare to mobility ratio. These results reveal a promising way to employ water-based ZnO nanofluid for enhanced oil recovery purposes at a relatively high reservoir temperature. PMID- 29489896 TI - PGRP-LD mediates A. stephensi vector competency by regulating homeostasis of microbiota-induced peritrophic matrix synthesis. AB - Peptidoglycan recognition proteins (PGRPs) and commensal microbes mediate pathogen infection outcomes in insect disease vectors. Although PGRP-LD is retained in multiple vectors, its role in host defense remains elusive. Here we report that Anopheles stephensi PGRP-LD protects the vector from malaria parasite infection by regulating gut homeostasis. Specifically, knock down of PGRP-LD (dsLD) increased susceptibility to Plasmodium berghei infection, decreased the abundance of gut microbiota and changed their spatial distribution. This outcome resulted from a change in the structural integrity of the peritrophic matrix (PM), which is a chitinous and proteinaceous barrier that lines the midgut lumen. Reduction of microbiota in dsLD mosquitoes due to the upregulation of immune effectors led to dysregulation of PM genes and PM fragmentation. Elimination of gut microbiota in antibiotic treated mosquitoes (Abx) led to PM loss and increased vectorial competence. Recolonization of Abx mosquitoes with indigenous Enterobacter sp. restored PM integrity and decreased mosquito vectorial capacity. Silencing PGRP-LD in mosquitoes without PM didn't influence their vector competence. Our results indicate that PGPR-LD protects the gut microbiota by preventing hyper-immunity, which in turn promotes PM structurally integrity. The intact PM plays a key role in limiting P. berghei infection. PMID- 29489899 TI - A multiscale approach to mapping seabed sediments. AB - Benthic habitat maps, including maps of seabed sediments, have become critical spatial-decision support tools for marine ecological management and conservation. Despite the increasing recognition that environmental variables should be considered at multiple spatial scales, variables used in habitat mapping are often implemented at a single scale. The objective of this study was to evaluate the potential for using environmental variables at multiple scales for modelling and mapping seabed sediments. Sixteen environmental variables were derived from multibeam echosounder data collected near Qikiqtarjuaq, Nunavut, Canada at eight spatial scales ranging from 5 to 275 m, and were tested as predictor variables for modelling seabed sediment distributions. Using grain size data obtained from grab samples, we tested which scales of each predictor variable contributed most to sediment models. Results showed that the default scale was often not the best. Out of 129 potential scale-dependent variables, 11 were selected to model the additive log-ratio of mud and sand at five different scales, and 15 were selected to model the additive log-ratio of gravel and sand, also at five different scales. Boosted Regression Tree models that explained between 46.4 and 56.3% of statistical deviance produced multiscale predictions of mud, sand, and gravel that were correlated with cross-validated test data (Spearman's rhomud = 0.77, rhosand = 0.71, rhogravel = 0.58). Predictions of individual size fractions were classified to produce a map of seabed sediments that is useful for marine spatial planning. Based on the scale-dependence of variables in this study, we concluded that spatial scale consideration is at least as important as variable selection in seabed mapping. PMID- 29489898 TI - Effects of clinical pathway implementation on antibiotic prescriptions for pediatric community-acquired pneumonia. AB - BACKGROUND: Italian pediatric antimicrobial prescription rates are among the highest in Europe. As a first step in an Antimicrobial Stewardship Program, we implemented a Clinical Pathway (CP) for Community Acquired Pneumonia with the aim of decreasing overall prescription of antibiotics, especially broad-spectrum. MATERIALS AND METHODS: The CP was implemented on 10/01/2015. We collected antibiotic prescribing and outcomes data from children aged 3 months-15 years diagnosed with CAP from 10/15/2014 to 04/15/2015 (pre-intervention period) and from 10/15/2015 to 04/15/2016 (post-intervention period). We assessed antibiotic prescription differences pre- and post-CP, including rates, breadth of spectrum, and duration of therapy. We also compared length of hospital stay for inpatients and treatment failure for inpatients and outpatients. Chi-square and Fisher's exact test were used to compare categorical variables and Wilcoxon rank sum test was used to compare quantitative outcomes. RESULTS: 120 pre- and 86 post intervention clinic visits were identified with a diagnosis of CAP. In outpatients, we observed a decrease in broad-spectrum regimens (50% pre-CP vs. 26.8% post-CP, p = 0.02), in particular macrolides, and an increase in narrow spectrum (amoxicillin) post-CP. Post-CP children received fewer antibiotic courses (median DOT from 10 pre-CP to 8 post-CP, p<0.0001) for fewer days (median LOT from 10 pre-CP to 8 post-CP, p<0.0001) than their pre-CP counterparts. Physicians prescribed narrow-spectrum monotherapy more frequently than broad spectrum combination therapy (DOT/LOT ratio 1.157 pre-CP vs. 1.065 post-CP). No difference in treatment failure was reported before and after implementation (2.3% pre-CP vs. 11.8% post-CP, p = 0.29). Among inpatients we also noted a decrease in broad-spectrum regimens (100% pre-CP vs. 66.7% post-CP, p = 0.02) and the introduction of narrow-spectrum regimens (0% pre-CP vs. 33.3% post-CP, p = 0.02) post-CP. Hospitalized patients received fewer antibiotic courses post-CP (median DOT from 18.5 pre-CP to 10 post-CP, p = 0.004), while there was no statistical difference in length of therapy (median LOT from 11 pre-CP to 10 post CP, p = 0.06). Days of broad spectrum therapy were notably lower post-CP (median bsDOT from 17 pre-CP to 4.5 post-CP, p <0.0001). No difference in treatment failure was reported before and after CP implementation (16.7% pre-CP vs. 15.4% post-CP, p = 1). CONCLUSIONS: Introduction of a CP for CAP in a Pediatric Emergency Department led to reduction of broad-spectrum antibiotic prescriptions, of combination therapy and of duration of treatment both for outpatients and inpatients. PMID- 29489900 TI - Characterization and clinical enrichment of HLA-C*07:02-restricted Cytomegalovirus-specific CD8+ T cells. AB - Human Cytomegalovirus (CMV) reactivation remains a major source of morbidity in patients after solid organ and hematopoietic stem cell transplantation (HSCT). Adoptive T cell therapy (ACT) with CMV-specific T cells is a promising therapeutic approach for HSCT recipients, but might be counteracted by CMV's immune evasion strategies. HLA-C*07:02 is less susceptible to viral immune evasion suggesting HLA-C*07:02-restricted viral epitopes as promising targets for ACT. For a better understanding of HLA-C*07:02-restricted CMV-specific T cells we used recently generated reversible HLA-C*07:02/IE-1 multimers (Streptamers) recognizing a CMV-derived Immediate-Early-1 (IE-1) epitope and analyzed phenotypic and functional T cell characteristics. Initially, we detected very high frequencies of HLA-C*07:02/IE-1 multimer+ T cells (median = 11.35%), as well as robust functional responses after stimulation with IE-1 peptide (IFNgamma+; median = 5.02%) in healthy individuals. However, MHC-multimer+ and IFNgamma secreting T cell frequencies showed a relatively weak correlation (r2 = 0.77), which could be attributed to an unexpected contribution of CMV-epitope independent KIR2DL2/3-binding of HLA-C*07:02/IE-1 multimers. Therefore, we developed a MHC-multimer double-staining approach against a cancer epitope specific HLA-C*07:02 multimer to identify truly HLA-C*07:02/IE-1 epitope-specific T cells. The frequencies of these truly HLA-C*07:02/IE-1 multimer+ T cells were still high (median = 6.86%) and correlated now strongly (r2 = 0.96) with IFNgamma secretion. Interestingly, HLA-C*07:02/IE-1-restricted T cells contain substantial numbers with a central memory T cell phenotype, indicating high expansion potential e.g. for ACT. In line with that, we developed a clinical enrichment protocol avoiding epitope-independent KIR-binding to make HLA-C*07:02/IE-1 restricted T cells available for ACT. Initial depletion of KIR-expressing CD8+ T cells followed by HLA-C*07:02/IE-1 Streptamer positive selection using paramagnetic labeling techniques allowed to enrich successfully HLA-C*07:02/IE-1 restricted T cells. Such specifically enriched populations of functional HLA C*07:02/IE-1-restricted T cells with significant central memory T cell content could become a potent source for ACT. PMID- 29489902 TI - Effects of human interleukins in the transgenic gene reporter cell lines IZ-VDRE and IZ-CYP24 designed to assess the transcriptional activity of vitamin D receptor. AB - The role of vitamin D receptor (VDR) in immune responses has been broadly studied and it has been shown that activated VDR alters the levels of some interleukins (ILs). In this study, we studied the opposite, i.e. whether 13 selected pro inflammatory and anti-inflammatory ILs influence the transcriptional activity of human VDR. The experimental models of choice were two human stably transfected gene reporter cell lines IZ-VDRE and IZ-CYP24, which were designed to evaluate the transcriptional activity of VDR. The gene reporter assays revealed inhibition of calcitriol-induced luciferase activity by IL-4 and IL-13, when 1 ng/mL of these two compounds decreased the effect of calcitriol down to 60% of the control value. Consistently, calcitriol-induced expression of CYP24A1 mRNA was also significantly decreased by IL-4 and IL-13. The expression of VDR and CYP27B1 mRNAs was not influenced by any of the 13 tested ILs. These data suggest possible cross-talk between the VDR signalling pathway and IL-4- and IL-13-mediated cell signalling. PMID- 29489901 TI - Impact of 9p deletion and p16, Cyclin D1, and Myc hyperexpression on the outcome of anaplastic oligodendrogliomas. AB - OBJECTIVE: To study the presence of 9p deletion and p16, cyclin D1 and Myc expression and their respective diagnostic and prognostic interest in oligodendrogliomas. METHODS: We analyzed a retrospective series of 40 consecutive anaplastic oligodendrogliomas (OIII) from a single institution and compared them to a control series of 10 low grade oligodendrogliomas (OII). Automated FISH analysis of chromosome 9p status and immunohistochemistry for p16, cyclin D1 and Myc was performed for all cases and correlated with clinical and histological data, event free survival (EFS) and overall survival (OS). RESULTS: Chromosome 9p deletion was observed in 55% of OIII (22/40) but not in OII. Deletion was highly correlated to EFS (median = 29 versus 53 months, p<0.0001) and OS (median = 48 versus 83 months, p<0.0001) in both the total cohort and the OIII population. In 9p non-deleted oligodendrogliomas, p16 hyperexpression correlated with a shorter OS (p = 0.02 in OII and p = 0.0001 in OIII) whereas lack of p16 expression was correlated to a shorter EFS and OS in 9p deleted OIII (p = 0.001 and p = 0.0002 respectively). Expression of Cyclin D1 was significantly higher in OIII (median expression 45% versus 14% for OII, p = 0.0006) and was correlated with MIB-1 expression (p<0.0001), vascular proliferation (p = 0.002), tumor necrosis (p = 0.04) and a shorter EFS in the total cohort (p = 0.05). Hyperexpression of Myc was correlated to grade (median expression 27% in OII versus 35% in OIII, p = 0.03), and to a shorter EFS in 9p non-deleted OIII (p = 0.01). CONCLUSION: Chromosome 9p deletion identifies a subset of OIII with significantly worse prognosis. The combination of 9p status and p16 expression level identifies two distinct OIII populations with divergent prognosis. Hyperexpression of Bcl1 and Myc appears highly linked to anaplasia but the prognostic value is unclear and should be investigated further. PMID- 29489903 TI - Design and synthesis of constrained bicyclic molecules as candidate inhibitors of influenza A neuraminidase. AB - The rise of drug-resistant influenza A virus strains motivates the development of new antiviral drugs, with different structural motifs and substitution. Recently, we explored the use of a bicyclic (bicyclo[3.1.0]hexane) analogue of sialic acid that was designed to mimic the conformation adopted during enzymatic cleavage within the neuraminidase (NA; sialidase) active site. Given that our first series of compounds were at least four orders of magnitude less active than available drugs, we hypothesized that the new carbon skeleton did not elicit the same interactions as the cyclohexene frameworks used previously. Herein, we tried to address this critical point with the aid of molecular modeling and we proposed new structures with different functionalization, such as the introduction of free ammonium and guanidinium groups and ether side chains other than the 3-pentyl side chain, the characteristic side chain in Oseltamivir. A highly simplified synthetic route was developed, starting from the cyclopropanation of cyclopentenone and followed by an aziridination and further functionalization of the five-member ring. This allowed the efficient preparation of a small library of new bicyclic ligands that were characterized by enzyme inhibition assays against influenza A neuraminidases N1, its H274Y mutant, and N2. The results show that none of the new structural variants synthesized, including those containing guanidinium groups rather than free ammonium ions, displayed activity against influenza A neuraminidases at concentrations less than 2 mM. We conclude that the choice and positioning of functional groups on the bicyclo[3.1.0]hexyl system still need to be properly tuned for producing complementary interactions within the catalytic site. PMID- 29489904 TI - The variations on the aerodynamics of a world-ranked wheelchair sprinter in the key-moments of the stroke cycle: A numerical simulation analysis. AB - Biomechanics plays an important role helping Paralympic sprinters to excel, having the aerodynamic drag a significant impact on the athlete's performance. The aim of this study was to assess the aerodynamics in different key-moments of the stroke cycle by Computational Fluid Dynamics. A world-ranked wheelchair sprinter was scanned on the racing wheelchair wearing his competition gear and helmet. The sprinter was scanned in three different positions: (i) catch (hands in the 12h position on the hand-rim); (ii) the release (hands in the 18h position on the hand-rim) and; (iii) recovery phase (hands do not touch the hand-rim and are hyperextended backwards). The simulations were performed at 2.0, 3.5, 5.0 and 6.5 m/s. The mean viscous and pressure drag components, total drag force and effective area were retrieved after running the numerical simulations. The viscous drag ranged from 3.35 N to 2.94 N, pressure drag from 0.38 N to 5.51 N, total drag force from 0.72 N to 8.45 N and effective area from 0.24 to 0.41 m2. The results pointed out that the sprinter was submitted to less drag in the recovery phase, and higher drag in the catch. These findings suggest the importance of keeping an adequate body alignment to avoid an increase in the drag force. PMID- 29489905 TI - Arithmetic learning in advanced age. AB - Acquisition of numerical knowledge and understanding of numerical information are crucial for coping with the changing demands of our digital society. In this study, we assessed arithmetic learning in older and younger individuals in a training experiment including brain imaging. In particular, we assessed age related effects of training intensity, prior arithmetic competence, and neuropsychological variables on the acquisition of new arithmetic knowledge and on the transfer to new, unknown problems. Effects were assessed immediately after training and after 3 months. Behavioural results showed higher training effects for younger individuals than for older individuals and significantly better performance after 90 problem repetitions than after 30 repetitions in both age groups. A correlation analysis indicated that older adults with lower memory and executive functions at baseline could profit more from intensive training. Similarly, training effects in the younger group were higher for those individuals who had lower arithmetic competence and executive functions prior to intervention. In younger adults, successful transfer was associated with higher executive functions. Memory and set-shifting emerged as significant predictors of training effects in the older group. For the younger group, prior arithmetic competence was a significant predictor of training effects, while cognitive flexibility was a predictor of transfer effects. After training, a subgroup of participants underwent an MRI assessment. A voxel-based morphometry analysis showed a significant interaction between training effects and grey matter volume of the right middle temporal gyrus extending to the angular gyrus for the younger group relative to the older group. The reverse contrast (older group vs. younger group) did not yield any significant results. These results suggest that improvements in arithmetic competence are supported by temporo-parietal areas in the right hemisphere in younger participants, while learning in older people might be more widespread. Overall, our study indicates that arithmetic learning depends on the training intensity as well as on person-related factors including individual age, arithmetic competence before training, memory, and executive functions. In conclusion, we suggest that major progress can be also achieved by older participants, but that interventions have to take into account individual variables in order to provide maximal benefit. PMID- 29489906 TI - Medication changes after switching from CONCERTA(r) brand methylphenidate HCl to a generic long-acting formulation: A retrospective database study. AB - BACKGROUND: Observational studies of switching from branded to generic formulations of the same drug substance often lack appropriate comparators for the subjects who switched. Three generic formulations were deemed equivalent to Concerta: an authorized generic (AG) identical except for external packaging, and two other generics (EG). OBJECTIVE: Compare the incidence of a combined endpoint (switching back to Concerta, changing the use of immediate release methylphenidate (MPH), stopping all long-acting methylphenidate, or starting a new medication) among people switched from Concerta to the AG versus the EG. METHODS: Cohort study from the Truven CCAE database of people aged 6 to 65 diagnosed with ADHD, treated with Concerta, and switched to the EG or to the AG formulation. RESULTS: In the EG arm 24.6% and in the AG arm 19.7% of subjects switched back to Concerta. The proportion of subjects meeting the combined endpoint was 39.5% in the EG arm, 32.9% in the AG arm, a crude risk ratio of 1.20 (95% CI 0.94, 1.54). After adjustment by propensity score stratification, the adjusted odds ratio (OR) was 1.23 (95% CI 0.90, 1.70). In an unplanned analysis using a different method of adjustment, the adjusted OR was 1.00 (95% CI 0.69, 1.44). DISCUSSION: This study did not detect a difference between the proportion of people who met the study endpoint in the two study arms, i.e. between those who switched to a generic formulation that was identical to Concerta except for external packaging and those who switched to the comparison generics. The high incidence of the combined endpoint in the AG arm demonstrates the need for an appropriate comparator in studies of this type. TRIAL REGISTRATION: ClinicalTrials.gov NCT02730572. PMID- 29489907 TI - Effects of new beta-type Ti-40Nb implant materials, brain-derived neurotrophic factor, acetylcholine and nicotine on human mesenchymal stem cells of osteoporotic and non osteoporotic donors. AB - INTRODUCTION: Treatment of osteoporotic fractures is still challenging and an urgent need exists for new materials, better adapted to osteoporotic bone by adjusted Young's modulus, appropriate surface modification and pharmaceuticals. MATERIALS AND METHODS: Titanium-40-niobium alloys, mechanically ground or additionally etched and titanium-6-aluminium-4-vanadium were analyzed in combination with brain-derived neurotrophic factor, acetylcholine and nicotine to determine their effects on human mesenchymal stem cells in vitro over 21 days using lactate dehydrogenase and alkaline phosphatase assays, live cell imaging and immunofluorescence microscopy. RESULTS: Cell number of human mesenchymal stem cells of osteoporotic donors was increased after 14 d in presence of ground titanium-40-niobium or titanium-6-aluminium-4-vanadium, together with brain derived neurotrophic factor. Cell number of human mesenchymal stem cells of non osteoporotic donors increased after 21 d in presence of titanium-6-aluminium-4 vanadium without pharmaceuticals. No significant increase was measured for ground or etched titanium-40-niobium after 21 d. Osteoblast differentiation of osteoporotic donors was significantly higher than in non osteoporotic donors after 21 d in presence of etched, ground titanium-40-niobium or titanium-6 aluminium-4-vanadium accompanied by all pharmaceuticals tested. In presence of all alloys tested brain-derived neurotrophic factor, acetylcholine and nicotine increased differentiation of cells of osteoporotic donors and accelerated it in non osteoporotic donors. CONCLUSION: We conclude that ground titanium-40-niobium and brain-derived neurotrophic factor might be most suitable for subsequent in vivo testing. PMID- 29489908 TI - Not "just" an intravenous line: Consumer perspectives on peripheral intravenous cannulation (PIVC). An international cross-sectional survey of 25 countries. AB - Peripheral intravascular cannula/catheter (PIVC) insertion is a common invasive procedure, but PIVC failure before the end of therapy is unacceptably high. As PIVC failure disrupts treatment and reinsertion can be distressing for the patient, prevention of PIVC failure is an important patient outcome. Consumer participation in PIVC care to prevent failure is an untapped resource. This study aimed to understand consumers' PIVC experience; establish aspects of PIVC insertion and care relevant to them; and to compare experiences of adult consumers to adult carers of a child. An international, web-based, cross sectional survey was distributed via social media inviting adult consumers and adult carers of a child under 18 years who had experienced having a PIVC in the last five years (one survey each for adults and adult carers) to complete a 10 item survey. As such, sampling bias is a limitation and results should be carefully considered in light of this. There were 712 respondents from 25 countries, mainly female (87.1%) and adults (80%). A little over 50% of adults described insertion as moderately painful or worse, with level of insertion difficulty (0-10 scale) identified as moderate (median 4, IQR 1, 7). Adult carers reported significantly more pain during insertion and insertion difficulty (both p < 0.001). Rates of first insertion attempt failure were higher in children compared with adults (89/139 [64%] vs 221/554 [40%]; p < 0.001), and 23% of children required >= 4 attempts, compared with 9% of adults (p < 0.0001). Three themes from open-ended question emerged: Significance of safe and consistent PIVC care; Importance of staff training and competence; and Value of communication. The PIVC experience can be painful, stressful and frustrating for consumers. Priorities for clinicians and policy makers should include use of pain relief as standard practice to reduce the pain associated with PIVC insertion and developing strategies to increase first PIVC insertion attempt success particularly for children and older consumers. PMID- 29489910 TI - Systematic review of palm oil consumption and the risk of cardiovascular disease. AB - BACKGROUND: The high amount of saturated fatty acids (SFA) coupled with the rising availability and consumption of palm oil have lead to the assumption that palm oil contributes to the increased prevalence of cardiovascular diseases worldwide. We aimed at systematically synthesising the association of palm oil consumption with cardiovascular disease risk and cardiovascular disease-specific mortality. METHODS: We systematically searched Central, Medline and Embase databases up to June 2017 without restriction on setting or language. We performed separate searches based on the outcomes: coronary heart disease and stroke, using keywords related to these outcomes and palm oil. We searched for published interventional and observational studies in adults (Age: >18 years old). Two investigators extracted data and a consensus was reached with involvement of a third. Only narrative synthesis was performed for all of the studies, as the data could not be pooled. RESULTS: Our search retrieved 2,738 citations for stroke with one included study and 1,777 citations for coronary heart disease (CHD) with four included studies. Palmitic acid was reported to be associated with risk of myocardial infarction (MI) (OR 2.76; 95%CI = 1.39-5.47). Total SFA intake was reported to be not significant for risk of MI. Varying intake of fried foods, highest contributor to total SFA with 36% of households using palm oil for frying, showed no significant associations to risk of MI. Odds of developing first non-fatal acute MI was higher in palm oil compared to soybean oil with 5% trans-fat (OR = 1.33; 95%CI = 1.09-1.62) than palm oil compared to soybean oil with 22% trans-fat (OR = 1.16; 95%CI = 0.86-1.56). Nevertheless, these risk estimates were non-significant and imprecise. The trend amongst those taking staple pattern diet (characterised by higher palm oil, red meat and added sugar consumption) was inconsistent across the factor score quintiles. During the years of 1980 and 1997, for every additional kilogram of palm oil consumed per capita annually, CHD mortality risk was 68 deaths per 100,000 (95% CI = 21-115) in developing countries and 17 deaths per 100,000 (95%CI = 5.3-29) in high-income countries, whereas stroke was associated with 19 deaths per 100,000 (95%CI = -12 49) and 5.1 deaths per 100,000 (95% CI: -1.2-11) respectively. The evidence for the outcomes of this review were all graded as very low. The findings of this review should be interpreted with some caution, owing to the lack of a pooled effect estimate of the association, significant bias in selection criteria and confounding factors, inclusion of other food items together with palm oil, and the possible out-dated trend in the ecological study. CONCLUSION: In view of the abundance of palm oil in the market, quantifying its true association with CVD outcomes is challenging. The present review could not establish strong evidence for or against palm oil consumption relating to cardiovascular disease risk and cardiovascular disease-specific mortality. Further studies are needed to establish the association of palm oil with CVD. A healthy overall diet should still be prioritised for good cardiometabolic health. PMID- 29489909 TI - Long non-coding RNA SPRY4-IT1 promotes cell proliferation and invasion by regulation of Cdc20 in pancreatic cancer cells. AB - Accumulating evidence has demonstrated that long non-coding RNAs (lncRNAs) play a critical role in the development of human cancers including pancreatic cancer. Long non-coding RNA SPRY4-IT1 (sprouty4-intron transcript 1) has been reported to play an oncogenic role in various types of human carcinomas. However, the role of SPRY4-IT1 in pancreatic cancer is unclear. The objective of this study was to determine the function of SPRY4-IT1 on proliferation and invasion in pancreatic cancer. In the current study, we dissected the function and mechanism of SPRY4 IT1 by multiple approaches including Real-time RT-PCR, Western blotting analysis, MTT assay, Wound healing assay, Transwell assay, and transfection. We found that down-regulation of SPRY4-IT1 inhibited cell growth and induced cell apoptosis in pancreatic cancer cells. Moreover, SPRY4-IT1 knockdown induced cell cycle arrest at G0/G1 phase. Furthermore, inhibition of SPRY4-IT1 retarded cell migration and invasion in pancreatic cancer cells. Overexpression of SPRY4-IT1 enhanced cell growth and invasion, and inhibited cell apoptosis in pancreatic cancer cells. Mechanistically, suppression of SPRY4-IT1 inhibited the expression of Cdc20 in pancreatic cancer cells. Our findings demonstrated that inhibition of SPRY4-IT1 could be a potential therapeutic approach for the treatment of pancreatic cancer. PMID- 29489911 TI - Partial versus radical nephrectomy for T1b-2N0M0 renal tumors: A propensity score matching study based on the SEER database. AB - PURPOSE: Controversy continues on the tailored therapy for patients with larger renal cell carcinoma (RCC). We investigated whether partial nephrectomy (PN) can improve patient prognosis compared to radical nephrectomy (RN) and the indications for each approach in patients with T1b-2N0M0 RCC. MATERIALS AND METHODS: A total of 9907 patients were identified from the Surveillance, Epidemiology, and End Results database from 2004 to 2012. Propensity scores were used to balance the selection bias of undergoing PN. Overall (OS) and cancer specific survival (CSS) of patients undergoing PN and RN were compared. Cases were subdivided to investigate the advantages of each procedure. RESULTS: Overall, 1418 (14.3%) patients underwent PN. Before matching, PN led to better OS and CSS than RN in both Kaplan-Meier analysis and Cox regression (each p<0.01). For 1412 matched cohorts, PN was no longer associated with significantly better OS (HR: 1.19, 95% CI: 0.98-1.44), but still with a better CSS (HR: 1.66, 95% CI: 1.18-2.27) compared with RN. Further subgroup analysis indicated that patients, who were male, single living, old than 65 years, with T1b stage or clear-cell histologic type, may obtained more oncologic benefit from PN compared to RN. CONCLUSIONS: When tumor localization and technical feasibility have been taken into account, similar long-term survival was achieved in overall among two nephrectomy modalities, but patients, who were male, old than 65 years, with T1b stage or clear-cell histologic type, got a better survival after receiving PN compared to RN. PMID- 29489912 TI - Use of the ureteral access sheath during ureteroscopy: A systematic review and meta-analysis. AB - The debate still rages on for the usefulness of ureteral access sheath (UAS). Therefore, a meta-analysis to discuss the effects of applying UAS during ureteroscopy was performed. The protocol for the review is available on PROSPERO (CRD42017052327). A literature search was conducted up to November, 2017 using the Web of science, PUBMED, EMBASE and Cochrane Library. The quality of articles was assessed by the Jadad scale and Newcastle Ottawa Scale (NOS). Egger's test and the trim-and-fill method were used to evaluate publication bias. Effect sizes were calculated by pooled odds ratio (ORs) and mean differences (MDs). Sensitivity analyses and subgroup analyses were performed to explore the origin of heterogeneity. Eight trials with a total of 3099 patients and 3127 procedures were identified. Results showed no significant difference in stone-free rate (SFR) (OR = 0.83, 95% CI 0.52-1.33, P = 0.45), intraoperative complications (OR = 1.16, 95% CI 0.81-7.69, P = 0.88), operative time (MD = 4.09, 95% CI -15.08 23.26, P = 0.68) and hospitalization duration (MD = -0.13, 95% CI -0.32-0.06, P = 0.18). However, the incidence of postoperative complications was higher in UAS group (OR = 1.46, 95% CI 1.06-2.00, P = 0.02). Evidence from meta-analysis indicated that the use of UAS during ureteroscopy did not manifest advantages. However, given the intrinsic restrictions of the quality of selected articles, more randomized controlled trials (RCTs) are warranted to update the findings of this analysis. PMID- 29489913 TI - Prevalence, sleep characteristics, and comorbidities in a population at high risk for obstructive sleep apnea: A nationwide questionnaire study in South Korea. AB - OBJECTIVE: To determine the prevalence, sleep characteristics, and comorbidities associated with a high risk for obstructive sleep apnea (OSA) in the Korean adult population. METHODS: We analyzed data from 2,740 subjects who responded to a nationwide questionnaire survey of sleep characteristics. Those who qualified under two or more symptom categories of the Berlin questionnaire were defined as "at high risk for OSA". We investigated their socio-demographic information, sleep habits, and medical and psychiatric comorbidities. Logistic regression analyses were performed to identify factors and consequences significantly associated with a high risk for OSA. RESULTS: The prevalence of a high risk for OSA was 15.8% (95% confidence interval [CI] 14.5-17.2%). Multiple logistic regression analysis showed that old age (>= 70 years, odds ratio [OR] 2.68) and body mass index >= 25 kg/m2 (OR 10.75) were significantly related with a high risk for OSA, whereas regular physical activity (OR 0.70) had a protective effect. Subjective sleep characteristics associated with a high risk for OSA were perceived insufficient sleep (OR 1.49), excessive daytime sleepiness (OR 1.88), and insomnia (OR 3.70). In addition, hypertension (OR 5.83), diabetes mellitus (OR 2.54), hyperlipidemia (OR 2.85), and anxiety (OR 1.63) were comorbid conditions independently associated with a high risk for OSA. CONCLUSIONS: This is the first study to demonstrate the prevalence of a high risk for OSA in a nationwide representative sample of the Korean adult population. These findings elucidate the epidemiology and clinical characteristics of those at high risk for OSA. PMID- 29489914 TI - Auxin Response Factors (ARFs) are potential mediators of auxin action in tomato response to biotic and abiotic stress (Solanum lycopersicum). AB - Survival biomass production and crop yield are heavily constrained by a wide range of environmental stresses. Several phytohormones among which abscisic acid (ABA), ethylene and salicylic acid (SA) are known to mediate plant responses to these stresses. By contrast, the role of the plant hormone auxin in stress responses remains so far poorly studied. Auxin controls many aspects of plant growth and development, and Auxin Response Factors play a key role in the transcriptional activation or repression of auxin-responsive genes through direct binding to their promoters. As a mean to gain more insight on auxin involvement in a set of biotic and abiotic stress responses in tomato, the present study uncovers the expression pattern of SlARF genes in tomato plants subjected to biotic and abiotic stresses. In silico mining of the RNAseq data available through the public TomExpress web platform, identified several SlARFs as responsive to various pathogen infections induced by bacteria and viruses. Accordingly, sequence analysis revealed that 5' regulatory regions of these SlARFs are enriched in biotic and abiotic stress-responsive cis-elements. Moreover, quantitative qPCR expression analysis revealed that many SlARFs were differentially expressed in tomato leaves and roots under salt, drought and flooding stress conditions. Further pointing to the putative role of SlARFs in stress responses, quantitative qPCR expression studies identified some miRNA precursors as potentially involved in the regulation of their SlARF target genes in roots exposed to salt and drought stresses. These data suggest an active regulation of SlARFs at the post-transcriptional level under stress conditions. Based on the substantial change in the transcript accumulation of several SlARF genes, the data presented in this work strongly support the involvement of auxin in stress responses thus enabling to identify a set of candidate SlARFs as potential mediators of biotic and abiotic stress responses. PMID- 29489915 TI - Detection of human bocavirus in Saudi healthy blood donors. AB - Human bocavirus is associated with respiratory disease worldwide, mainly in children. There are conflicting results, however, regarding the existence of the HBoV in blood donors. Three hundred whole blood samples from non-immunodeficient healthy blood donors were screened for the presence of HBoV by polymerase chain reaction. The HBoV genotype of positive samples was determined using direct gene sequencing. Twenty-one out of the three hundred blood samples were found to be positive for HBoV. Sequence analysis of the positive samples revealed that all the strains were related to the HBoV-1 type with a low rate of variation among the detected sequences. It was concluded that there is a considerable risk of contracting HBoV from a blood transfusion from normal healthy individuals. PMID- 29489916 TI - Protective effects of tiotropium alone or combined with budesonide against cadmium inhalation induced acute neutrophilic pulmonary inflammation in rats. AB - As a potent bronchodilator, the anti-inflammatory effects of tiotropium and its interaction with budesonide against cadmium-induced acute pulmonary inflammation were investigated. Compared to values obtained in rats exposed to cadmium, cytological analysis indicated a significant decrease of total cell and neutrophil counts and protein concentration in bronchoalveolar lavage fluid (BALF) in rats pretreated with tiotropium (70MUg/15ml or 350MUg/15ml). Zymographic tests showed a decrease of MMP-2 activity in BALF in rats pretreated only with high concentration of tiotropium. Histological examination revealed a significant decrease of the severity and extent of inflammatory lung injuries in rats pretreated with both tested concentrations of tiotropium. Though tiotropium (70MUg/15ml) or budesonide (250MUg/15ml) could not reduce cadmium-induced bronchial hyper-responsiveness, their combination significantly decreased bronchial contractile response to methacholine. These two drugs separately decreased the neutrophil number and protein concentration in BALF but no significant interaction was observed when both drugs were combined. Although no inhibitory effects on MMP-2 and MMP-9 was observed in rats pretreated with budesonide alone, the combination with the ineffective dose of tiotropium induced a significant reduction on these parameters. The inhibitory effect of tiotropium on lung injuries was not influenced by budesonide which alone induced a limited action on the severity and extent of inflammatory sites. Our findings show that tiotropium exerts anti-inflammatory effects on cadmium-induced acute neutrophilic pulmonary inflammation. The combination of tiotropium with budesonide inhibits cadmium-induced inflammatory injuries with a synergistic interaction on MMP-2 and MMP-9 activity and airway hyper-responsiveness. PMID- 29489918 TI - Regional inequalities in premature mortality in Great Britain. AB - Premature mortality exhibits strong spatial patterns in Great Britain. Local authorities that are located further North and West, that are more distant from its political centre London and that are more urban tend to have a higher premature mortality rate. Premature mortality also tends to cluster among geographically contiguous and proximate local authorities. We develop a novel analytical research design that relies on spatial pattern recognition to demonstrate that an empirical model that contains only socio-economic variables can eliminate these spatial patterns almost entirely. We demonstrate that socioeconomic factors across local authority districts explain 81 percent of variation in female and 86 percent of variation in male premature mortality in 2012-14. As our findings suggest, policy-makers cannot hope that health policies alone suffice to significantly reduce inequalities in health. Rather, it requires strong efforts to reduce the inequalities in socio-economic factors, or living conditions for short, in order to overcome the spatial disparities in health, of which premature mortality is a clear indication. PMID- 29489917 TI - In silico prediction of neuropeptides in Hymenoptera parasitoid wasps. AB - Parasitoid wasps of the order Hymenoptera, the most diverse groups of animals, are important natural enemies of arthropod hosts in natural ecosystems and can be used in biological control. To date, only one neuropeptidome of a parasitoid wasp, Nasonia vitripennis, has been identified. This study aimed to identify more neuropeptides of parasitoid wasps, by using a well-established workflow that was previously adopted for predicting insect neuropeptide sequences. Based on publicly accessible databases, totally 517 neuropeptide precursors from 24 parasitoid wasp species were identified; these included five neuropeptides (CNMamide, FMRFamide-like, ITG-like, ion transport peptide-like and orcokinin B) that were identified for the first time in parasitoid wasps, to our knowledge. Next, these neuropeptides from parasitoid wasps were compared with those from other insect species. Phylogenetic analysis suggested the divergence of AST-CCC within Hymenoptera. Further, the encoding patterns of CAPA/PK family genes were found to be different between Hymenoptera species and other insect species. Some neuropeptides that were not found in some parasitoid superfamilies (e.g., sulfakinin), or considerably divergent between different parasitoid superfamilies (e.g., sNPF) might be related to distinct physiological processes in the parasitoid life. Information of neuropeptide sequences in parasitoid wasps can be useful for better understanding the phylogenetic relationships of Hymenoptera and further elucidating the physiological functions of neuropeptide signaling systems in parasitoid wasps. PMID- 29489920 TI - Obesity and chronic kidney disease: A population-based study among South Koreans. AB - Obesity and chronic kidney disease (CKD) are major global health problems. There are very little data concerning the prevalence and its associated factors of obesity in non-dialyzed patients who have different stages of CKD. Therefore, in this study, we examined the prevalence of obesity and its associated factors according to the stages of CKD. We used nationwide representative data from the Korean National Health and Nutrition Examination Survey, which was conducted over a 7-year period from 2008 to 2014 by the Korea Centers for Disease Control and Prevention. The results indicated that: (1) general obesity and abdominal obesity were more prevalent in patients with CKD compared to those without CKD; (2) the prevalence of general obesity and abdominal obesity was highest in stage 2 CKD; (3) stages 3a and 3b were the factors associated with general obesity, and stage 3a was significantly associated with abdominal obesity; (4) the association between general obesity/abdominal obesity and CKD disappeared in people with advanced stage 4/5 CKD; and (5) the presence of comorbidities contributed to the development of both general obesity and abdominal obesity. The findings of this study might support the idea that weight loss is a good potential intervention for the prevention of disease progression in moderate CKD (stage 3), but not severe CKD (stage 4/5). PMID- 29489919 TI - An evaluation of longitudinal changes in serum uric acid levels and associated risk of cardio-metabolic events and renal function decline in gout. AB - OBJECTIVE: Gout patients have a high burden of co-morbid conditions including diabetes mellitus (DM), chronic kidney disease (CKD), and cardiovascular disease (CVD). We sought to evaluate the association between changes in serum uric acid (SUA) levels over time and the risk of incident DM, CVD, and renal function decline in gout patients. METHODS: An observational cohort study was conducted among enrollees of private health insurance programs in the US between 2004 and 2015. Gout patients were included on the index date of a SUA measurement >=6.8 mg/dl. The exposure of interest was cumulative change in SUA levels from baseline. Hazard ratios (HR) and 95% confidence intervals (CI) for incident DM, incident CVD, and renal function decline (>=30% reduction in glomerular filtration rate) were derived using marginal structural models with stabilized inverse probability weights accounting for baseline confounders (age, gender, co morbidities, co-medications) and time-varying confounders (serum creatinine, blood urea nitrogen, glycated hemoglobin). RESULTS: Among 26,341 patients with gout, the average age was 62, 75% were men, and the median baseline SUA was 8.6 mg/dl (interquartile range 7.7 to 9.5). The incidence rates/100 person-years (95% CI) were 1.63 (1.51-1.75) for DM, 0.77 (0.70-0.84) for CVD, and 4.32 (4.14-4.49) for renal function decline. The adjusted HR (95% CI) per 3 mg/dl reduction in SUA, corresponding on average to achieving the target level of <6 mg/dl in this population, was 1.04 (0.92-1.17) for DM, 1.07 (0.89-1.29) for CVD, and 0.85 (0.78 0.92) for renal function decline. CONCLUSIONS: Reduction in SUA in patients with gout may be associated with a reduced risk of renal function decline, but not with DM or CVD. PMID- 29489921 TI - Safety Huddle Intervention for Reducing Physiologic Monitor Alarms: A Hybrid Effectiveness-Implementation Cluster Randomized Trial. AB - BACKGROUND: Monitor alarms occur frequently but rarely warrant intervention. OBJECTIVE: This study aimed to determine if a safety huddle-based intervention reduces unit-level alarm rates or alarm rates of individual patients whose alarms are discussed, as well as evaluate implementation outcomes. DESIGN: Unit-level, cluster randomized, hybrid effectiveness-implementation trial with a secondary patient-level analysis. SETTING: Children's hospital. PATIENTS: Unit-level: all patients hospitalized on 4 control (n = 4177) and 4 intervention (n = 7131) units between June 15, 2015 and May 8, 2016. Patient-level: 425 patients on randomly selected dates postimplementation. INTERVENTION: Structured safety huddle review of alarm data from the patients on each unit with the most alarms, with a discussion of ways to reduce alarms. MEASUREMENTS: Unit-level: change in unit level alarm rates between baseline and postimplementation periods in intervention versus control units. Patient-level: change in individual patients' alarm rates between the 24 hours leading up to huddles and the 24 hours after huddles in patients who were discussed versus not discussed in huddles. RESULTS: Alarm data informed 580 huddle discussions. In unit-level analysis, intervention units had 2 fewer alarms/patient-day (95% CI: 7 fewer to 6 more, P = .50) compared with control units. In patient-level analysis, patients discussed in huddles had 97 fewer alarms/patientday (95% CI: 52-138 fewer, P < .001) in the posthuddle period compared with patients not discussed in huddles. Implementation outcome analysis revealed a low intervention dose of 0.85 patients/unit/day. CONCLUSIONS: Safety huddle-based alarm discussions did not influence unit-level alarm rates due to low intervention dose but were effective in reducing alarms for individual children. PMID- 29489922 TI - Update in Hospital Medicine: Practical Lessons from the Literature. AB - BACKGROUND: Hospital Medicine has a widening scope of practice. This article provides a summary of recent highimpact publications for busy clinicians who provide care to hospitalized adults. METHODS: The authors reviewed articles published between March 2016 and March 2017 for the Update in Hospital Medicine presentations at the 2017 Society of Hospital Medicine and Society of General Internal Medicine annual meetings. Nine of the 20 articles presented were selected for this review based on the article quality and potential to influence practice. RESULTS: The key insights gained include: pulmonary embolism may be a more common cause of syncope and acute exacerbation of COPD than previously recognized; nonthoracic low-tesla MRI is safe following a specific protocol for patients with cardiac devices implanted after 2001; routine inpatient blood cultures for fever are of a low yield with a false positive rate similar to the true positive rate; chronic opioid use after surgery occurs more frequently than in the general population; high-sensitivity troponin and a negative ECG performed 3 hours after an episode of chest pain can rule out acute myocardial infarction; sitting at patients' bedsides enhances patients' perception of provider communication; 5 days of antibiotics for community-acquired pneumonia is equivalent to longer courses; oral proton pump inhibitors (PPI) are as effective as IV PPIs after an esophagogastroduodenoscopy (EGD) for the treatment of bleeding peptic ulcers. CONCLUSIONS: Recent research provides insight into how we approach common medical problems in the care of hospitalized adults. These articles have the potential to change or confirm current practices. PMID- 29489923 TI - When are Oral Antibiotics a Safe and Effective Choice for Bacterial Bloodstream Infections? An Evidence-Based Narrative Review. AB - Bacterial bloodstream infections (BSIs) are a major cause of morbidity and mortality in the United States. Traditionally, BSIs have been managed with intravenous antimicrobials. However, whether intravenous antimicrobials are necessary for the entirety of the treatment course in BSIs, especially for uncomplicated episodes, is a more controversial matter. Patients that are clinically stable, without signs of shock, or have been stabilized after an initial septic presentation, may be appropriate candidates for treatment of BSIs with oral antimicrobials. There are risks and costs associated with extended courses of intravenous agents, such as the necessity for long-term intravenous catheters, which entail risks for procedural complications, secondary infections, and thrombosis. Oral antimicrobial therapy for bacterial BSIs offers several potential benefits. When selected appropriately, oral antibiotics offer lower cost, fewer side effects, promote antimicrobial stewardship, and are easier for patients. The decision to use oral versus intravenous antibiotics must consider the characteristics of the pathogen, the patient, and the drug. In this narrative review, the authors highlight areas where oral therapy is a safe and effective choice to treat bloodstream infection, and offer guidance and cautions to clinicians managing patients experiencing BSI. PMID- 29489924 TI - The Design and Evaluation of the Comprehensive Hospitalist Assessment and Mentorship with Portfolios (CHAMP) Ultrasound Program. AB - BACKGROUND: Literature supports the use of point-ofcare ultrasound performed by the treating hospitalist in the diagnosis of common diseases. There is no consensus on the training paradigm or the evaluation of skill retention for hospitalists. OBJECTIVE: To evaluate the effectiveness of a comprehensive bedside ultrasound training program with postcourse competency assessments for hospitalists. DESIGN: A retrospective report of a training program with 53 hospitalists. The program consisted of online modules, a 3-day in-person course, portfolios, 1-day refresher training, monthly scanning, and assessments. Hospitalists were rated by using similar pre- and postcourse competency assessments and self-rating parameters during the 3-day and refresher courses. SETTING: A large tertiary-care center. RESULTS: Skills increased after the 3-day course from a median preassessment score of 15% correct (interquartile range [IQR] 10%-25%) to a median postassessment score of 90% (IQR 80%-95%; P < .0001). At the time of the refresher course, the median precourse skills score had decreased to 65% correct (IQR 35%-90%), which improved to 100% postcourse (IQR 85%-100%; P < .0001). Skills scores decreased significantly less between the post 3-day course assessment and pre 1-day refresher course for hospitalists who completed portfolios (mean decrease 13.6% correct; P < .0001) and/or monthly scanning sessions (mean decrease 7.3% correct; P < .0001) compared with hospitalists who did not complete these items. CONCLUSIONS: A comprehensive longitudinal ultrasound training program including competency assessments improved ultrasound acquisition skills with hospitalists. Skill retention remained high in those who completed portfolios and/or monthly scanning sessions along with a 1-day in-person refresher course. PMID- 29489925 TI - The Harm We Do: The Environmental Impact of Medicine. AB - While often unseen and infrequently discussed, the environmental impact of hospital systems and healthcare providers is substantial. However, some US hospitals and healthcare systems have developed innovative approaches to reduce their environmental impact while reducing costs. In this perspective, we discuss how hospitalists may support ongoing environmental efforts through education and awareness, measurement and amelioration, public reporting, and individual actions. Given the extent of healthcare's impact on the environment, the benefits of interventions, and the link between hospitalists and hospitals, We must minimize the harm we do. PMID- 29489926 TI - Interventions to Improve Follow-Up of Laboratory Test Results Pending at Discharge: A Systematic Review. AB - Failure to follow up test results pending at discharge (TPAD) from hospitals or emergency departments is a major patient safety concern. The purpose of this review is to systematically evaluate the effectiveness of interventions to improve follow-up of laboratory TPAD. We conducted literature searches in PubMed, CINAHL, Cochrane, and EMBASE using search terms for relevant health care settings, transition of patient care, laboratory tests, communication, and pending or missed tests. We solicited unpublished studies from the clinical laboratory community and excluded articles that did not address transitions between settings, did not include an intervention, or were not related to laboratory TPAD. We also excluded letters, editorials, commentaries, abstracts, case reports, and case series. Of the 9,592 abstracts retrieved, 8 met the inclusion criteria and reported the successful communication of TPAD. A team member abstracted predetermined data elements from each study, and a senior scientist reviewed the abstraction. Two experienced reviewers independently appraised the quality of each study using published LMBPTM A-6 scoring criteria. We assessed the body of evidence using the A-6 methodology, and the evidence suggested that electronic tools or one-on-one education increased documentation of pending tests in discharge summaries. We also found that automated notifications improved awareness of TPAD. The interventions were supported by suggestive evidence; this type of evidence is below the level of evidence required for LMBPTM recommendations. We encourage additional research into the impact of these interventions on key processes and health outcomes. PMID- 29489927 TI - ? PMID- 29489928 TI - Activity pattern of medium and large sized mammals and density estimates of Cuniculus paca (Rodentia: Cuniculidae) in the Brazilian Pampa. AB - Between July 2014 and April 2015, we conducted weekly inventories of the circadian activity patterns of mammals in Passo Novo locality, municipality of Alegrete, southern Brazil. The vegetation is comprised by a grassy-woody steppe (grassland). We used two camera traps alternately located on one of four 1 km transects, each separated by 1 km. We classified the activity pattern of species by the percentage of photographic records taken in each daily period. We identify Cuniculus paca individuals by differences in the patterns of flank spots. We then estimate the density 1) considering the area of riparian forest present in the sampling area, and 2) through capture/recapture analysis. Cuniculus paca, Conepatus chinga and Hydrochoerus hydrochaeris were nocturnal, Cerdocyon thous had a crepuscular/nocturnal pattern, while Mazama gouazoubira was cathemeral. The patterns of circadian activity observed for medium and large mammals in this Pampa region (southern grasslands) may reflect not only evolutionary, biological and ecological affects, but also human impacts not assessed in this study. We identified ten individuals of C. paca through skin spot patterns during the study period, which were recorded in different transects and months. The minimum population density of C. paca was 3.5 individuals per km2 (resident animals only) and the total density estimates varied from 7.1 to 11.8 individuals per km2, when considering all individuals recorded or the result of the capture/recapture analysis, respectively. PMID- 29489929 TI - New records of Helminths in Reptiles from five states of Brazil. AB - Forty five specimens representing nine species of reptile (Salvator merianae, Enyalius bilineatus, Amphisbaena alba, Xenopholis undulatus, Chironius fuscus, Helicops angulatus, Chironius flavolineatus, Erythrolamprus viridis and Crotalus durissus) collected in five Brazilian states were examined for helminths. Twelve helminth species were found as follow: nine Nematoda (Physaloptera tupinambae, Strongyluris oscari, Paracapillaria sp., Dracunculus brasiliensis, Physaloptera liophis, Serpentirhabias sp. 1, Serpentirhabias sp. 2, Serpentirhabias sp. 3 and Aplectana sp.), one Cestoda (Semenoviella amphisbaenia), one Trematoda (Paracotyletrema sp.), and one Acantocephala (Centrorhynchus sp.). Ten new host records and seven new locality records were reported. PMID- 29489930 TI - ELECTROLYTE AND MINERAL COMPOSITION OF TERM DONOR HUMAN MILK BEFORE AND AFTER PASTEURIZATION AND OF RAW MILK OF PRETERM MOTHERS. AB - OBJECTIVE: To determine and compare the concentrations of electrolytes and minerals in three different types of maternal milk samples: term donor milk before pasteurization, term donor milk after pasteurization and raw milk of mothers of preterm newborns at bedside. METHODS: Descriptive cross-sectional study. Concentrations of calcium (Ca), phosphorous (P), magnesium (Mg), sodium (Na) and potassium (K) were measured in random samples of three human breast milk groups. Samples were analyzed using acid mineralization assisted by microwave radiation and further analysis by inductively coupled plasma optical emission spectrometry. Concentrations were expressed in mg/L, described as mean and standard deviation. The one-way ANOVA and Tukey's post-test were applied to determine the variability between the means of each group. Significance level was set at 5%. RESULTS: There was a significant reduction in the content of Ca (259.4+/-96.8 vs. 217.0+/-54.9; p=0.003), P (139.1+/-51.7 vs. 116.8+/-33.3; p=0.004) and K (580.8+/-177.1 vs. 470.9+/-109.4; p<0.0001) in donor maternal milk before and after pasteurization. Samples of raw milk presented higher contents of Na than the donated milk (twice). The elements P and Ca would only reach the daily intake levels recommended by the European Society of Pediatric Gastroenterology, Hepatology and Nutrition if at least 60 mL of milk could be offered every 3 hours. Mg levels were not different between the three groups. CONCLUSIONS: There was a significant reduction in Ca, P and K levels in samples after pasteurization. The Na value in raw milk, collected at bedside, was higher than in the samples of donor's milk before pasteurization. PMID- 29489931 TI - [Medicine and social discipline in 19th-century Brazil]. PMID- 29489933 TI - Analysis of the antimicrobial and anti-caries effects of TiF4 varnish under microcosm biofilm formed on enamel. AB - : Titanium tetrafluoride (TiF4) is known for interacting with enamel reducing demineralization. However, no information is available about its potential antimicrobial effect. OBJECTIVES: This study evaluated the antimicrobial and anti caries potential of TiF4 varnish compared to NaF varnish, chlorhexidine gel (positive control), placebo varnish and untreated (negative controls) using a dental microcosm biofilm model. MATERIAL AND METHODS: A microcosm biofilm was produced on bovine enamel previously treated with the varnishes, using inoculum from human saliva mixed with McBain saliva, under 0.2% sucrose exposure, for 14 days. All experiments were performed in biological triplicate (n=4/group in each experiment). Factors evaluated were: bacterial viability (% dead and live bacteria); CFU counting (log10 CFU/mL); and enamel demineralization (transverse microradiography - TMR). Data were analysed using ANOVA/Tukey's test or Kruskal Wallis/Dunn's test (p<0.05). RESULTS: Only chlorhexidine significantly increased the number of dead bacteria (68.8+/-13.1% dead bacteria) compared to untreated control (48.9+/-16.1% dead bacteria). No treatment reduced the CFU counting (total microorganism and total streptococci) compared to the negative controls. Only TiF4 was able to reduce enamel demineralization (DeltaZ 1110.7+/-803.2 vol% MUm) compared to both negative controls (untreated: DeltaZ 4455.3+/-1176.4 vol% MUm). CONCLUSIONS: TiF4 varnish has no relevant antimicrobial effect. Nevertheless, TiF4 varnish was effective in reducing enamel demineralization under this model. PMID- 29489934 TI - Effect of gamma-lactones and gamma-lactams compounds on Streptococcus mutans biofilms. AB - : Considering oral diseases, antibiofilm compounds can decrease the accumulation of pathogenic species such as Streptococcus mutans at micro-areas of teeth, dental restorations or implant-supported prostheses. OBJECTIVE: To assess the effect of thirteen different novel lactam-based compounds on the inhibition of S. mutans biofilm formation. MATERIAL AND METHODS: We synthesized compounds based on gamma-lactones analogues from rubrolides by a mucochloric acid process and converted them into their corresponding gamma-hydroxy-gamma-lactams by a reaction with isobutylamine and propylamine. Compounds concentrations ranging from 0.17 up to 87.5 MUg mL-1 were tested against S. mutans. We diluted the exponential cultures in TSB and incubated them (37 degrees C) in the presence of different gamma-lactones or gamma-lactams dilutions. Afterwards, we measured the planktonic growth by optical density at 630 nm and therefore assessed the biofilm density by the crystal violet staining method. RESULTS: Twelve compounds were active against biofilm formation, showing no effect on bacterial viability. Only one compound was inactive against both planktonic and biofilm growth. The highest biofilm inhibition (inhibition rate above 60%) was obtained for two compounds while three other compounds revealed an inhibition rate above 40%. CONCLUSIONS: Twelve of the thirteen compounds revealed effective inhibition of S. mutans biofilm formation, with eight of them showing a specific antibiofilm effect. PMID- 29489935 TI - Influence of Helicobacter pylori culture supernatant on the ecological balance of a dual-species oral biofilm. AB - : Dental caries is a chronic progressive disease occurring in the tooth hard tissue due to multiple factors, in which bacteria are the initial cause. Both Streptococcus mutans and Streptococcus sanguinis are main members of oral biofilm. Helicobacter pylori may also be detected in dental plaque, playing an important role in the development of dental caries. OBJECTIVE: The aim of this study was to investigate the effect of H. pylori culture supernatant on S. mutans and S. sanguinis dual-species biofilm and to evaluate its potential ability on affecting dental health. MATERIAL AND METHODS: The effect of H. pylori supernatant on single-species and dual-species biofilm was measured by colony forming units counting and fluorescence in situ hybridization (FISH) assay, respectively. The effect of H. pylori supernatant on S. mutans and S. sanguinis extracellular polysaccharides (EPS) production was measured by both confocal laser scanning microscopy observation and anthrone-sulfuric acid method. The effect of H. pylori supernatant on S. mutans gene expression was measured by quantitative real-time PCR (qRT-PCR) assays. RESULTS: H. pylori supernatant could inhibit both S. mutans and S. sanguinis biofilm formation and EPS production. S. sanguinis inhibition rate was significantly higher than that of S. mutans. Finally, S. mutans bacteriocin and acidogenicity related genes expression were affected by H. pylori culture supernatant. CONCLUSION: Our results showed that H. pylori could destroy the balance between S. mutans and S. sanguinis in oral biofilm, creating an advantageous environment for S. mutans, which became the dominant bacteria, promoting the formation and development of dental caries. PMID- 29489936 TI - Comparison of primary human gingival fibroblasts from an older and a young donor on the evaluation of cytotoxicity of denture adhesives. AB - : Denture adhesives (DA) improve the retention and stability of ill-fitting dentures, especially for older adults. These materials should be biocompatible, i.e., they cannot cause undesired biological responses and be non-cytotoxic to oral tissues. However, in vitro testing of DA biocompatibility employing primary cell culture may possibly be affected by other factors, such as the donor age. OBJECTIVE: To compare the cytotoxicity of three different denture adhesives when assessed in primary gingival fibroblasts from a young donor or from an older donor, as well as the release of the basic fibroblast growth factor (bFGF), and the inflammatory response marker interleukin-6 (IL-6). MATERIAL AND METHODS: Gingival fibroblasts isolated from a 30- and a 62-year-old donor were assayed for proliferation (1-7 days) and sensitivity to latex (positive control). Fibroblasts were indirectly exposed to Corega Ultra (cream), Corega powder and Fixodent Original for a 24 h period and assayed by XTT and Crystal Violet tests. The release of IL-6 and bFGF by exposed cells was determined by ELISA. RESULTS: While cells from the young donor presented higher cell growth after 7 days, the sensitivity to increasing concentrations of latex extracts was very similar between young and older cells. Both XTT and CVDE detected no difference between the DA and the control group. All materials induced higher levels of IL-6 and bFGF compared to control. Cells from the older donor exposed to Corega Ultra released lower levels of cytokine and growth factor. CONCLUSIONS: All materials were considered non-cytotoxic, but affected cytokine and growth factor release. The biological differences found between fibroblasts from both donors could be due to individual or age-related factors. The authors suggest the use of cells from older donors on studies of dental products aimed at older patients, to better simulate their physiological response. PMID- 29489937 TI - The value of fine needle aspiration cytology in the clinical management of rare salivary gland tumors. AB - : Salivary gland tumors are relatively rare neoplasms, mostly located in the parotid gland, and few are malignant. Preoperative evaluation of salivary gland tumors includes fine needle aspiration cytology (FNAC). OBJECTIVE: The purpose of this study was to determine the importance of FNAC in the evaluation of rare salivary gland neoplasms. MATERIAL AND METHODS: Four cases of rare salivary gland tumors were included, which were preoperatively assessed by clinical investigation, computed tomography, and FNAC. RESULTS: The presented cases include myoepithelial carcinoma, oncocytic carcinoma, undifferentiated lymphoepithelial carcinoma, and marginal zone lymphoma. CONCLUSION: FNAC is a reliable diagnostic tool for common salivary gland neoplasms; however, rare tumors often represent diagnostic challenges. Clinical relevance In such rare tumors, the role of aspiration cytology may be limited to establishing the dignity of the lesion (benign/malignant). This knowledge enables the surgeon to choose the most appropriate therapeutic procedure. A definitive diagnosis of rare tumors (either epithelial or nonepithelial) is obtained by histological examination; cytology is limited in this regard due to overlapping features. PMID- 29489938 TI - The effects of IL-10 gene polymorphism on serum, and gingival crevicular fluid levels of IL-6 and IL-10 in chronic periodontitis. AB - OBJECTIVE: Anti-inflammatory cytokines play a crucial role in periodontitis by inhibiting synthesis of pro-inflammatory cytokines. The purpose of this study was to evaluate the effect of interleukin-10 (-597) gene polymorphism and genotype distributions on chronic periodontitis (CP) development and IL-6 and IL-10 levels in gingival crevicular fluid (GCF) and serum before and after non-surgical periodontal treatment. MATERIAL AND METHODS: The study population consisted of 55 severe generalized CP patients as CP group and 50 healthy individuals as control group. Plaque index, gingival index, probing depth and clinical attachment level were recorded and GCF and blood samples were taken at both the baseline and the sixth week after non-surgical periodontal treatment. PCR-RFLP procedure was used for gene analyses and cytokine levels were measured via ELISA. RESULTS: IL-10 genotype distribution was significantly different between CP and control groups (p=0.000, OR:7, 95%CI, 2.83-60.25). Clinical measurements significantly improved in the CP group after periodontal treatment (p<0.05). Periodontal treatment significantly decreased GCF IL-6 and IL-10 levels. No significant difference was found in clinical parameters between IL-10 AA and AC+CC genotypes at both the baseline and the sixth week (p>0.05). Sixth week GCF IL-10 levels were significantly lower in patients carrying IL-10 AC+CC genotype compared to the patients carrying IL-10 AA genotype (p<0.05). Serum IL-6 and IL-10 levels were lower in patients carrying the IL-10 AA genotype compared to patients with IL-10 AC+CC genotype, but the difference was not significant (p>0.05). CONCLUSION: IL 10 AA genotype carriers had lower IL-6 and IL-6/10 levels in serum; however, GCF IL-6/10 levels were similar in both genotypes. Within the limitations of our study, a possible association between IL-10(-597) gene polymorphism and CP might be considered. PMID- 29489939 TI - [A health survey in riverine communities in Amazonas State, Brazil]. AB - Population-based health surveys are important tools for identifying disease determinants, especially in regions with widely dispersed populations and low health system coverage. The aim of this study was to describe the principal methodological aspects and to describe the socioeconomic, demographic, and health characteristics of the riverine populations of Coari, Amazonas State, Brazil. This was a population-based cross-sectional study in river-dwelling communities in the rural area of Coari, from April to July 2015. The probabilistic cluster sample consisted of 492 individuals. The results showed that the majority of the river-dwellers were females (53%), had up to 9 years of schooling (68.5%), and earned a monthly family income equivalent to one-third the minimum wage. The health problems reported in the previous 30 days featured conditions involving pain (45.2%). The main healthcare resources were allopathic medicines (70.3%), exceeding herbal remedies (44.3%). The river-dwellers travel an average of 60.4km and take some 4.2 hours to reach the urban area of Coari. The riverine population generally presents low economic status and limited access to the urban area. Health problems are mostly solved with allopathic medicines. Geographic characteristics, as barriers to access to health services and to improvements in living conditions for the riverine population, can limit the collection of epidemiological data on these populations. PMID- 29489940 TI - [History of Brazil's tobacco control policy from 1986 to 2016]. AB - This study analyzes Brazil's tobacco control policy from 1986 to 2016, seeking to describe the policy's history and discuss its achievements, limits, and challenges. The study adopted a political economics approach and contributions from public policy analysis. Data were based on a search of the literature, documents, and secondary sources and semi-structured interviews with stakeholders involved in the policy. Factors related to the domestic and international contexts, the political process, and the policy's content influenced the institutional characteristics of tobacco control in the country. The study emphasizes the consolidation of Brazil's social rejection of smoking, government structuring of the policy, action by civil society, and Brazil's prestige in the international scenario. Inter-sector tobacco control measures like price and tax increases on cigarettes, the promotion of smoke-free environments, and the enforcement of health warnings contributed to the important reduction in prevalence of smoking. Implementation of the World Health Organization Framework Convention on Tobacco Control in Brazil, beginning in 2006, contributed to the expansion and consolidation of the national policy. However, tobacco-related economic interests limited the implementation of some strategic measures. The challenges feature the medium- and long-term sustainability of tobacco control and the solution to barriers involving crop diversification on current tobacco growing areas, the fight against the illegal cigarette trade, and interference in the policy by the tobacco industry. PMID- 29489941 TI - Collective Health on the move: the 12th Brazilian Congress of Collective Health (Abrascao 2018). PMID- 29489942 TI - Young women's contraceptive practices: a household survey in the city of Sao Paulo, Brazil. AB - The last decade has witnessed initiatives to expand access to contraceptives in Brazil. However, the last population-based study on contraception was undertaken in 2006. A household survey in 2015 investigated contraceptive practices in women 15 to 44 years of age living in the city of Sao Paulo. The current study selected data on young women 15 to 19 years of age. The objectives were to identify the prevalence of contraception, the contraceptives used, sources, and differences in contraceptive practices. The young women are part of a probabilistic study sample. Differences in contraception use were compared by multiple logistic regression analysis. A total of 633 young women were interviewed, of whom 310 (48.5%) were sexually initiated. Of these, 60% reported emergency contraception use at least once in their lives. Emergency contraception use was directly proportional to age and lifetime number of partners. Prevalence of contraception was 81%. The odds of current contraception use were higher among young women residing in the health district of the city with the better social conditions, Catholics, those who reported sexual relations in the previous 30 days, and those with history of an obstetrics and gynaecology visit in the previous year, and inversely proportional to the lifetime number of sex partners. Male condoms and the pill were the most common methods (28.2% and 23%). Most of the women purchased their contraceptives in retail pharmacies (75.2%), and the Brazilian Unified National Health System (SUS) was only a significant source for injectable hormonal contraceptives. Government support for women's sexual and reproductive rights is still insufficient. PMID- 29489943 TI - [Assessment of the incompleteness of the maternal schooling variable in Live Birth Certificate databases in Brazilian state capitals, 1996-2013]. AB - The article assessed the quality of completion of the maternal school variable in Brazilian state capitals and its regional distribution, based on the Brazilian Information System on Live Births (SINASC) with processed data from live birth certificates. A descriptive study was conducted in the time series from 1996 to 2013, with a total de 12,062,064 births, of which 11,442,494 (94.86%) had valid information on the maternal schooling variable. The results were calculated as the number of incomplete results in the variable per 1,000 live births, and the trend was assessed with the Joinpoint software, version 4.3.1. According to regional analysis, the South of Brazil showed a downward trend in incompleteness of maternal schooling throughout the study in all the state capitals of that region. Most of the country's other state capitals also showed improvement in the variable's completeness. However, there were different trends in some state capitals, even with greater incompleteness at the end of the period when compared to the beginning. SINASC proved to be a valuable source of data on mothers and their newborns, besides information on conditions in labor, delivery, and birth in the country. Maternal schooling, considered an important factor for obstetric and neonatal outcomes, is particularly useful for elaborating and evaluating policies and measures in maternal and child health. Thus, to achieve maximum completeness in data on this variable requires joint effort by health professionals and administrators, thereby guaranteeing the data's trustworthiness. PMID- 29489944 TI - Evaluation of outpatient services in the Brazilian Unified National Health System for persons living with HIV: a comparison of 2007 and 2010. AB - Health services play a crucial role in reaching the 90-90-90 target of controlling the HIV epidemic. This study evaluates the organization of Brazilian health services in improving, monitoring, and retention in HIV care and adherence support. Percentage variation (PV) was used to compare the responses by services to an evaluation questionnaire on organizational quality (Qualiaids) in 2007 and 2010. The study analyzed the 419 services that completed the questionnaire in 2007 (83.1% of respondents) and 2010 (63.6%). Management actions of retention and support although increased in the period, but remained at low rates, for example: systematic meetings for case discussion (32.7% in 2010; PV = 19.8%) and recording of missed medical appointments (35.3%; PV = 36.8%). Patient care actions related to adherence to ART remained largely exclusive to the attending physician. The supply of funds and resources from the Federal Government (medicines and specific HIV tests) remained high for the vast majority of the services (~90%). It will not be possible to achieve a significant decrease in HIV transmission as long as retention in treatment is not a priority in all the health services. PMID- 29489945 TI - User satisfaction with public and private dental services for different age groups in Brazil. AB - This article aimed to describe the levels of user satisfaction in different age groups and to study the association between user satisfaction and different types of dental services in a representative sample of Brazilians. This study is based on the Brazilian Oral Health Survey, which evaluated the dental health of adolescents, adults and older adults in 177 Brazilian cities. The outcome variable was user satisfaction, related to the last dental visit, evaluated in a five-level Likert-type scale. The main exposure variable was the type of dental service (public service, private service, health plan or insurance). The independent variables were DMFT (decay, missing and filled teeth); pain intensity in the past six months; reason for the last dental visit; perceived need for treatment; frequency of use of dental services; sex; equivalent income; and educational level. An ordered logistic regression analysis was performed separately for each age group. Few participants evaluated the services as bad or very bad (4.3% of adolescents, 6.1% of adults and 4.1% of older adults). In the crude model, the use of public services was associated with lower satisfaction than the use of private services and health plans between all groups. However, after adjusting by covariates, this association remained only in adolescents, who showed lower satisfaction with the public service compared to the private service and health plans. In general, Brazilians are satisfied with dental services, but, among adolescents, the use of public services was associated with lower satisfaction. Public services may be focused on issues related to children, adults and older adults, and not to the adolescent audience, which has specific demands. PMID- 29489946 TI - [Prevalence of Chagas disease among blood donors in Piaui State, Brazil, from 2004 to 2013]. AB - Despite the decline in prevalence of Chagas disease in Brazil, the Northeast region of the country has favorable conditions for its resurgence. The study aimed to analyze positive Chagas disease serology rates among blood donors in Piaui State from 2004 to 2013. Prevalence of positive Chagas disease serology in blood donor screening was 1%, ranging from 0.4% in the Urucui Regional Health District to 2.4% in the Sao Raimundo Nonato Regional Health District. Of the state's 220 municipalities, 58.6% reported cases. Only 34.5% of the positive samples in screening were referred for complementary tests, and 84.4% of these showed negative results. Our findings suggest the possibility of persistent vector-borne transmission in areas of Piaui State and the need for measures to improve complementary testing in positive cases detected by screening. PMID- 29489947 TI - Anomalies and contradictions in an airport construction project: a historical analysis based on Cultural-Historical Activity Theory. AB - Large construction projects involve the functioning of a complex activity system (AS) in network format. Anomalies such as accidents, delays, reworks, etc., can be explained by contradictions that emerge historically in the system. The aim of this study was to analyze the history of an airport construction project to understand the current contradictions and anomalies in the AS and how they emerged. A case study was conducted for this purpose, combining Collective Work Analysis, interviews, observations, and analysis of documents that provided the basis for sessions in the Change Laboratory, where a participant timeline was elaborated with the principal events during the construction project. Based on the timeline, a historical analysis of the airport's AS revealed critical historical events and contradictions that explained the anomalies that occurred during the project. The analysis showed that the airport had been planned for construction with politically determined deadlines that were insufficient and inconsistent with the project's complexity. The choice of the contract modality, which assigned responsibility to a joint venture for all of the project's phases, was another critical historical event, because it allowed launching the construction before a definitive executive project had been drafted. There were also different cultures in companies working together for the first time in the context of a project with time pressures and outsourcing of activities without the necessary coordination. Identifying these contradictions and their historical origins proved essential for understanding the current situation and efforts to prevent similar situations in the future. PMID- 29489948 TI - [Effect of the Family Health Strategy on hospitalizations for primary care sensitive conditions in infants in Bahia State, Brazil]. AB - This study aimed to assess the effect of the expansion of the Family Health Strategy (FHS) on hospitalizations for primary care sensitive conditions (PCSCs) in children under one year of age. This was a longitudinal ecological study with the use of panel data, for which the analytical units were the 417 municipalities (counties) in Bahia State, Brazil, from 2000 to 2012. Data were obtained from the official health information systems. The hospitalization rate for PCSCs was the outcome and FHS coverage was the principal exposure. The co-variables referred to demographic and socioeconomic characteristics and the local availability of pediatric beds. Bivariate and multivariate panel data analyses were performed, with negative binomial response and fixed effects models, using crude and adjusted relative risk (RR) as the measure of association, with the respective confidence intervals. To control for trend effect, the models were adjusted for time. From 2000 to 2012, 248,944 hospitalizations for PCSCs were recorded in children under one year, and the median municipal rate of hospitalizations for PCSCs decreased by 52.5% during the period, ranging from 96.9 to 46.0 avoidable hospitalizations per 1,000 live births. After adjusting the model, the reduction in avoidable hospitalizations was maintained at the different FHS coverage levels. This study demonstrated the effects of the consolidation of the FHS on hospitalizations for PCSCs in infants, which indicates the importance of strengthening primary care measures in order to offer case-resolving care during the first contact with the health system and avoid unnecessary hospitalizations. PMID- 29489950 TI - [The inadequacy of official classification of work accidents in Brazil]. AB - Traditionally, work accidents in Brazil have been categorized in government documents and legal and academic texts as typical work accidents and commuting accidents. Given the increase in urban violence and the increasingly precarious work conditions in recent decades, this article addresses the conceptual inadequacy of this classification and its implications for the underestimation of work accidents in the country. An alternative classification is presented as an example and a contribution to the discussion on the improvement of statistics on work-related injuries in Brazil. PMID- 29489949 TI - [American tegumentary leishmaniasis: a multivariate analysis of the spatial circuits for production of cases in Minas Gerais State, Brazil, 2007 to 2011]. AB - The aim of this study was to explain the association between social-environmental factors and major land uses and the occurrence of cases of American tegumentary leishmaniasis (ATL) in the spatial circuits of production in Minas Gerais State, Brazil. This was an analytical-type ecological study based on secondary data on ATL divided by three-year period from 2007 to 2011, in which the analytical units were municipalities belonging to the spatial circuits. Two distinct stages were performed. The first was the elaboration of thematic maps with identification of the circuits. In the second, a new indicator, ATL cases by population density, was associated with social-environmental indicators and major land uses, submitted to multivariate principal components analysis (PCA). During the periods studied, three circuits were identified, distributed in the major regions of Northern Minas Gerais, Rio Doce Valley, and Greater Metropolitan Belo Horizonte. There was a strong association between ATL by population density and temporary crops, natural pasture, natural forest, unusable lands, and rural population, and a weak association with planted pasture. The association of cases with the major land uses variable in different agricultural profiles shows the occupational nature of ATL, associated mainly with rural workers. The association of the disease with environmental variables and deficient basic sanitation also proved relevant in the transmission profile in spatial circuits of production in Minas Gerais. PMID- 29489951 TI - Young men in juvenile detention centers in Rio de Janeiro, Brazil: gender, sexuality, masculinity and health implications. AB - This article presents results for young men's health based on an intervention study on gender, sexuality, and health of adolescents and young men in conflict with the law, deprived of their freedom, and subject to socio-educational confinement in Rio de Janeiro, Brazil. The themes addressed included questions on overall health, mental health, and sexual and reproductive health, analyzed from a relational gender perspective and social construction of masculinities. The majority of these young men are black, from low-income communities, with low schooling levels, and ranging in age from 14 to 21 years of age; some of them are fathers. The study showed that these young men have been exposed to police and social violence from a very early age and have been deprived of their freedom due to involvement with the drug traffic, homicides, or episodes of sexual violence. The male and female health professionals that work with them report that the most common health problems are skin conditions, mental disorders, and sexually transmissible infections. Male chauvinism and rigid notions of gender and sexuality are important factors in the views of these young men on health (especially sexual and reproductive). Their discourse takes violence and paternity for granted as important signs in the public demonstration of masculinity. There is an urgent need to include discussions on gender and sexuality in health professionals' training and activities with these young men. It is also necessary to call attention to the strong influence of gender concepts, social group, and sexual orientation in practices, interpersonal relations, and health promotion. PMID- 29489952 TI - [Integration of primary care in the healthcare network: analysis of the components in the external evaluation of the PMAQ-AB]. AB - This cross-sectional study examined the integration of primary care in the healthcare network of the Brazilian Unified National Health System (SUS), using the Gradual Response Model of Item Response Theory. Based on data from 17,202 teams that participated in the National Program for Access and Quality Improvement in Primary Care (PMAQ-AB, 2012), we measured gradients of integration to identify the teams' profile by level of integration. The results show that the items pertaining to matrix support measures (medical consultations, case discussions, shared clinical action, joint elaboration of therapeutic projects, permanent educational activities, work process discussions, interventions in the territory, and visits with primary care professionals) improved the performance of primary care teams. Communications devices between teams reinforced this understanding. Still, the approximately 50% of answers associated with the worst scenario for some study items evidenced the need to upgrade the integration between primary care activities and specialized care for the consolidation of comprehensive primary healthcare. PMID- 29489953 TI - Introduction of inappropriate complementary feeding in the first year of life and associated factors in children with low socioeconomic status. AB - The study aimed to identify factors associated with the introduction of inappropriate complementary feeding in the first year of life in children living in municipalities (counties) with low socioeconomic statusl. This was a cross sectional multicenter study in 1,567 children 12 to 59 months of age in 48 municipalities participating in the Brazil Without Poverty plan in the South of Brazil. A structured questionnaire was applied to the children's parents to obtain socio-demographic information and the age at which inappropriate complementary foods were introduced for the first time in complementary feeding. Prevalence of introduction of sugar before four months of age was 35.5% (n = 497; 95%CI: 33.1-38.0). The prevalence rates for the introduction of cookies/crackers, creamy yogurt, and jelly before six months of age were 20.4% (n = 287; 95%CI: 18.3-22.3), 24.8% (n = 349; 95%CI: 22.4-27.1), and 13.8% (n = 192; 95%CI: 12.0 15.7), respectively. Associations were identified between low maternal schooling (PR = 1.25; 95%CI: 1.03-1.51) and low monthly family income (PR = 1.22; CI95%: 1.01-1.48) and the introduction of inappropriate complementary feeding. The study identified the introduction of inappropriate complementary feeding in the first year of life among children in municipalities with high socioeconomic vulnerability in the South of Brazil, associated with low maternal schooling and low monthly family income. PMID- 29489954 TI - Advanced maternal age and its association with placenta praevia and placental abruption: a meta-analysis. AB - This study aimed to investigate the existence and magnitude of the association between advanced maternal age (AMA) and occurrence of placenta praevia (PP) and placental abruption (PA) among nulliparous and multiparous women, by a systematic review and meta-analysis. We searched articles published between January 1, 2005 and December 31, 2015, in any language, in the following databases: PubMed, Scopus, Web of Science, and LILACS. Women were grouped into two age categories: up to 34 years old and 35 years or older. The Newcastle-Ottawa Scale was used to evaluate the methodological quality of the studies. A meta-analysis was conducted for the PP and PA outcomes, using a meta-regression model to find possible covariates associated with heterogeneity among the studies and Egger's test to assess publication bias. The protocol of this systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) system (CRD42016045594). Twenty-three studies met the criteria and were included in the meta-analysis. For both outcomes, an increase in age increased the magnitude of association strength, and PP (OR = 3.16, 95%CI: 2.79-3.57) was more strongly associated with AMA than PA (OR = 1.44, 95%CI: 1.35-1.54). For parity, there was no difference between nulliparous and multiparous women considered older for the PP and PA outcomes. Our review provided very low-quality evidence for both outcomes, since it encompasses observational studies with high statistical heterogeneity, diversity of populations, no control of confounding factors in several cases, and publication bias. However, the confidence intervals were small and there is a dose-response gradient, as well as a large magnitude of effect for PP. PMID- 29489956 TI - Erratum. AB - [This corrects the article doi: 10.1590/0004-282x20170125]. PMID- 29489955 TI - Characterization of aphasia in aneurysmal subarachnoid hemorrhage. AB - PURPOSE: Characterize the profile of aphasic syndromes determined by aneurysmal subarachnoid hemorrhage (aSAH) of the left middle cerebral artery (LMCA). METHODS: An analytical, retrospective, cross-sectional study was conducted using a database of cognitive assessments of 193 patients with aSAH admitted to Hospital da Restauracao between March 2007 and November 2009. Of these, a total of 26 patients with aSAH in the LMCA territory confirmed by digital angiography were selected. Aphasia was assessed through the Montreal-Toulouse Language Assessment Alpha Version Protocol (Alpha Version) and the CERAD Neuropsychological Test Battery (Verbal fluency). RESULTS: Language and verbal fluency impairments were identified in patients with aSAH in the LMCA territory when compared with the control population (50 individuals). Of the 26 patients with aSAH, 11 presented aphasic characteristics preoperatively. CONCLUSION: The results of this research corroborate the literature, showing that the aSAH frame causes cognitive impairments even in the preoperative phase for aneurysm occlusion. Considering the observed aspects, the predominant aphasic syndromes characterize comprehension aphasia due to sequels in the posterior cerebral artery territory. PMID- 29489957 TI - Too good to be true. PMID- 29489958 TI - Does Parkinson's disease start in the gut? AB - Current understanding of the pathophysiology of Parkinson's disease suggests a key role of the accumulation of alpha-synuclein in the pathogenesis. This critical review highlights major landmarks, hypotheses and controversies about the origin and progression of synucleinopathy in Parkinson's disease, leading to an updated review of evidence suggesting the enteric nervous system might be the starting point for the whole process. Although accumulating and compelling evidence favors this theory, the remaining knowledge gaps are important points for future studies. PMID- 29489960 TI - Effect of virtual reality in Parkinson's disease: a prospective observational study. AB - OBJECTIVE: To assess the effectiveness of balance exercises by means of virtual reality games in Parkinson's disease. METHODS: Sixteen patients were submitted to anamnesis, otorhinolaryngological and vestibular examinations, as well as the Dizziness Handicap Inventory, Berg Balance Scale, SF-36 questionnaire, and the SRT, applied before and after rehabilitation with virtual reality games. RESULTS: Final scoring for the Dizziness Handicap Inventory and Berg Balance Scale was better after rehabilitation. The SRT showed a significant result after rehabilitation. The SF-36 showed a significant change in the functional capacity for the Tightrope Walk and Ski Slalom virtual reality games (p < 0.05), as well as in the mental health aspect of the Ski Slalom game (p < 0.05). The Dizziness Handicap Inventory and Berg Balance Scale showed significant changes in the Ski Slalom game (p < 0.05). There was evidence of clinical improvement in patients in the final assessment after virtual rehabilitation. CONCLUSION: The Tightrope Walk and Ski Slalom virtual games were shown to be the most effective for this population. PMID- 29489959 TI - Chronic treatment with carvacrol improves passive avoidance memory in a rat model of Parkinson's disease. AB - The present study investigated the effects of carvacrol on motor and memory deficits as well as hyperalgesia in the 6-OHDA-lesioned rat model of Parkinson's disease. The animals were subjected to unilateral microinjection of 6-OHDA into the medial forebrain bundle and treated with carvacrol (25, 50 and 100 mg/kg, ip) for six weeks after surgery. The 6-OHDA-lesioned rats showed contralateral rotations towards the lesion side, which was accompanied by learning and memory deficits in a passive avoidance test and a decrease in tail withdrawal latency in a tail flick test at the end of week 6. The results also showed that treatment with carvacrol at a dose of 25 mg/kg ameliorated memory deficits, with no effect on rotations and hyperalgesia in lesioned rats. In conclusion, carvacrol improves memory impairments in rats with Parkinson's disease; therefore, it may serve as an adjunct therapy for the alleviation of memory deficits in Parkinson's disease patients. PMID- 29489961 TI - Driving and visual deficits in stroke patients. AB - OBJECTIVE: The aim of the present study was to conduct an exploratory assessment of visual impairment following stroke, and to discuss the possibilities of reintroducing patients to the activity of driving. METHODS: The Useful Field of View test was used to assess visual processing and visual attention. RESULTS: A total of 18 patients were included in the study, and were assigned to either the drive group (n = 9) or the intention group (n = 9). In the drive group, one patient was categorized as moderate-to-high risk; whereas, in the intention group, one patient was categorized as low-to-moderate risk. Additionally, two patients in the intention group were categorized as high risk. The patients did not perceive their visual deficits as a limitation. CONCLUSION: Visual attention is an interference factor in terms of the safe performance of driving after a stroke. All patients showed a high level of interest for the independence provided through being able to drive. PMID- 29489962 TI - Relationship between visuospatial episodic memory, processing speed and executive function: are they stable over a lifespan? AB - The present study evaluated the association between episodic memory, executive function and processing speed in a sample with different age ranges. We tested the hypothesis that processing speed, executive function and memory are more strongly associated during childhood and old age. We evaluated 571 participants, aged six to 92 years, divided into four age groups: children/adolescents, young adults, middle-aged adults and older adults. Correlation analyses suggested that the shared variance between the processing speed and memory is strong in childhood but weak across other age ranges. Executive function, however, had a stronger association both in childhood and in old age, when compared with the intermediate stages. We conclude that the effects of processing speed and executive function on memory are not stable across human development. These functions may be compensatory mechanisms for memory functioning in childhood and old age. PMID- 29489963 TI - Naming and verbal learning in adults with Alzheimer's disease, mild cognitive impairment and in healthy aging, with low educational levels. AB - Language assessment seems to be an effective tool to differentiate healthy and cognitively impaired aging groups. This article discusses the impact of educational level on a naming task, on a verbal learning with semantic cues task and on the MMSE in healthy aging adults at three educational levels (very low, low and high) as well as comparing two clinical groups of very low (0-3 years) and low education (4-7 years) patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) with healthy controls. The participants comprised 101 healthy controls, 17 patients with MCI and 19 with AD. Comparisons between the healthy groups showed an education effect on the MMSE, but not on naming and verbal learning. However, the clinical groups were differentiated in both the naming and verbal learning assessment. The results support the assumption that the verbal learning with semantic cues task is a valid tool to diagnose MCI and AD patients, with no influence from education. PMID- 29489964 TI - Traumatic brain injury pharmacological treatment: recommendations. AB - This article presents the recommendations on the pharmacological treatment employed in traumatic brain injury (TBI) at the outpatient clinic of the Cognitive Rehabilitation after TBI Service of the Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, Brazil. A systematic assessment of the consensus reached in other countries, and of articles on TBI available in the PUBMED and LILACS medical databases, was carried out. We offer recommendations of pharmacological treatments in patients after TBI with different symptoms. PMID- 29489965 TI - A new motor screening assessment for children at risk for motor disorders: construct validity. AB - OBJECTIVE: To develop a motor screening assessment and provide preliminary evidence of its psychometric properties. METHODS: A sample of 365 elementary school students was assessed, with structural equation modeling applied to obtain evidence of the adequacy of the factor structure of the motor screening assessment. As well, differential item functioning was used to evaluate whether various identifiable subgroups of children (i.e., sex and grade) perform particular tasks differently. RESULTS: Overall, girls obtained higher scores than boys while, for both sexes, the assessment scores increased with age. Furthermore, differential item function analysis revealed that the precision of the test was highest for those with moderate to low motor performance, suggesting that this tool would be appropriate for identifying individuals with movement difficulties. CONCLUSION: Although further tests of its psychometric properties are required, the motor screening assessment appears to be a reliable, valid, and quickly-administered tool for screening children's movements. PMID- 29489966 TI - Guillain, Barraquer and I. AB - The year 2016 was the centennial anniversary of the recognition of the Guillain Barre syndrome, which was first described by George Guillain, Jean-Alexandre Barre and Andre Strohl. In celebration of the centennial, this historical review describes aspects of the contributions of Guillain and the Spanish neurologist, Barraquer-Bordas and a brief account of the Fourth International Neurological Congress, which brought together Guillain and Barraquer-Bordas. There were many outstanding Brazilian physicians at that meeting. Finally, the author describes his interaction with Barraquer-Bordas and provides an account of his influence in shaping a generation of Brazilian neurologists, including himself. PMID- 29489967 TI - Augusta Marie Dejerine-Klumpke: much more than just Dejerine's wife. AB - Augusta Marie Dejerine-Klumpke (1859-1927) was a formidable neurologist, neuroanatomist and researcher in France. One of the first women to be accepted for medical internship, externship and research in Paris, Augusta made her name studying and teaching anatomy, histology and dissection, attending clinical activities in neurology, obstetrics, pediatrics and neurologic trauma, performing necropsies, and writing scientific papers and book chapters. Her main research in neurology awarded her an eponym for the avulsion of the lowest root of the brachial plexus (Klumpke's palsy). Married to her professor, the remarkable Dr. Joseph Jules Dejerine, Augusta continued her career and became the first female president of the French Society of Neurology. PMID- 29489968 TI - Stendhal syndrome: a clinical and historical overview. AB - It could be argued that one of the few unifying qualities all human beings share is the ability to appreciate beauty. While the object of beauty may change from one person to another, the awe and the thrill experienced by an enthralled beholder remains the same. Sometimes, this experience can be so overwhelming it can bring someone to the edge of existence. A very rare condition, known as aesthetic syndrome and, more commonly, Stendhal syndrome, entails a clinical phenomenon in which the presence of a beautiful piece of work or architecture causes dysautonomic symptoms such as tachycardia, diaphoresis, chest pains and loss of consciousness. We present an historical and clinical review of this condition. PMID- 29489969 TI - Lambert-Eaton myasthenic syndrome: the 60th anniversary of Eaton and Lambert's pioneering article. AB - This historical review describes the contribution of Drs. Lee M. Eaton and Edward H. Lambert to the diagnosis of myasthenic syndrome on the 60th anniversary of their pioneering article (JAMA 1957) on the disease. There are important landmarks in their article on a disorder of the neuromuscular junction associated with thoracic neoplasm and the electrophysiological criteria for Lambert-Eaton myasthenic syndrome (LEMS). After 60 years, the main electrophysiological criteria described in Eaton and Lambert's pioneering article are still currently useful in the diagnosis of LEMS. PMID- 29489970 TI - Globus pallidus restricted diffusion associated with vigabatrin therapy. PMID- 29489971 TI - Elevated neutrophil-to-lymphocyte ratio in the diagnosis of Hashimoto's thyroiditis. AB - OBJECTIVE: Hashimoto's thyroiditis (HT) is an autoimmune inflammatory disorder. The purpose of this study was to determine the neutrophil-to-lymphocyte ratio (NLR), a novel marker of inflammation, in patients with HT and to compare these values with those from healthy subjects. METHOD: A total of 154 participants were included in the study, 90 HT patients and 64 healthy volunteers. Retrospectively, demographic and laboratory data of the subjects were obtained from our institution's database. Patients with active infection, diabetes mellitus, malignancy, other chronic inflammatory diseases, hematologic disorders and patients on aspirin or steroid treatment were excluded from the study. Values for complete blood count (CBC) and serum laboratory parameters of HT patients were the baseline values obtained at the time of HT diagnosis. Control subjects consisted of healthy volunteers who visited our institution for a routine check up. RESULTS: Age, gender and CBC parameters were not different between the HT group and the control group; however, the NLR of HT group (2.1 [1.3-5.8]) was significantly higher than the control group (1.9 [0.6-3.3]), p=0.04. CONCLUSION: Increased NLR may be useful as an indicator of the presence of HT, especially in complicated cases. NLR is inexpensive and easy to determine. Larger, prospective studies are required to determine its usefulness in assessing diagnostic potential and treatment outcomes in HT patients. PMID- 29489972 TI - Concomitant testicular infection by Zika virus and Schistosoma mansoni. PMID- 29489973 TI - The impact of HSF on endometrium. AB - OBJECTIVE: We conducted the research in order to explore the impact of hydrosalpinx fluid (HSF) on endometrium. METHOD: HSF group: 261 patients with HSF scheduled to undergo laparoscopic surgery 3 to 7 days after menstruation in our center. Hysteroscopy would also be performed in order to observe the endometrial morphology during the surgery. Sixty (60) patients would be randomly selected for endometrial biopsy in order to detect the inflammatory cytokines TNF-a and IL-2 mRNA. Non-HSF group: 210 patients with no evidence of HSF due to chronic salpingitis or pelvic adhesion. IVF-ET treatment was performed after eliminating the factor of male infertility and hysteroscopy was conducted before the treatment. Fifty (50) patients underwent endometrial biopsy in order to detect TNF-a and IL-2 mRNA. RESULTS: Hysteroscopy was performed in 261 patients with HSF and 210 patients without HSF. The incidence rate of endometritis manifestation among these two groups of patients was 37.2% (97/261) and 20.5% (43/210), respectively. The incidence rate of endometritis in the patients with HSF is significantly higher than in the patients without HSF (p<0.05). Sixty (60) patients from the HSF group and 50 patients from the non-HSF group were regrouped according to inflammatory and normal manifestation after the endometrial biopsy. There were 49 patients in the inflammatory manifestation group and 61 patients in the normal manifestation group. RT-PCR technology was adopted to detect the expression of inflammatory cytokines TNF-a and IL-2 mRNA in endometrial tissue. The level of TNF-a mRNA expression in endometrial tissues with inflammatory manifestation was higher than in normal endometrium (76.75+/-11.95 vs. 23.45+/ 9.75, p<0.01). There are significant differences between them. The level of IL-2 mRNA expression in endometrial tissues with inflammatory manifestation was higher than that found in normal endometrium (80.56+/-13.35 vs. 35.12+/-8.35, p<0.01). There are significant differences between them. CONCLUSION: Chronic endometritis is related to HSF and may therefore affect endometrial receptivity. PMID- 29489974 TI - Prostate cancer - Therapy with radium-223. PMID- 29489975 TI - Oncological results of surgical treatment versus organ-function preservation in larynx and hypopharynx cancer. AB - INTRODUCTION: Since the beginning of the 1990s, non-surgical radiochemotherapy treatment has become popular with the prospect of maintaining oncological results and preserving the organ in patients with advanced squamous cell carcinoma of the larynx and hypopharynx. However, subsequent studies demonstrated increased recurrence and mortality after the non-surgical treatment became popular. OBJECTIVE: To compare the oncological results of surgical and non-surgical treatments of patients with larynx and hypopharynx cancer and to evaluate the variables associated with disease recurrence. METHOD: This is a retrospective cohort study of 134 patients undergoing surgical (total or partial laryngectomy) or non-surgical (isolated radiotherapy, chemotherapy or induction chemotherapy followed by radiotherapy and chemotherapy) treatment, with 62 patients in the surgical group and 72 in the non-surgical group. RESULTS: Disease-free survival rates were higher in the surgical group (81.7% vs. 62.2%; p=0.028), especially in III/IV stages (p=0.018), locally advanced tumors T3 and T4a (p=0.021) and N0/N1 cases (p=0.005). The presence of cervical lymph nodes, especially N2/N3, was considered a risk factor for disease recurrence in both groups (HR=11.82; 95CI 3.42-40.88; p<0.0001). Patients not undergoing surgical treatment were 3.8 times more likely to develop recurrence (HR=3.76; 95CI 1.27-11.14; p=0.039). CONCLUSION: Patients with larynx or hypopharynx cancer non-surgically treated had a poorer disease-free survival, especially in cases with locally advanced tumors (T3 and T4a) and in which the neck was only slightly affected (N0/N1). PMID- 29489976 TI - Sickle cell retinopathy: A literature review. AB - Hemoglobinopathies are a group of hereditary diseases that cause quantitative or qualitative changes in the shape, function or synthesis of hemoglobin. One of the most common is sickle cell anemia, which, due to sickling of erythrocytes, causes vaso-occlusive phenomena. Among the possible ocular manifestations, the most representative is retinopathy, which can lead to blindness if left untreated. Therefore, periodic ophthalmologic monitoring of these patients is important for early diagnosis and adequate therapeutic management, which can be done localy by treating the lesions in the eyes, or systemically. PMID- 29489978 TI - ERRATUM. AB - [This corrects the article doi: 10.1590/1806-9282.63.09.771]. PMID- 29489977 TI - The safety and clinical efficacy of recombinant human granulocyte colony stimulating factor injection for colon cancer patients undergoing chemotherapy. AB - OBJECTIVE: The present study was designed to evaluate safety and efficacy of recombinant human granulocyte colony stimulating factor (G-CSF) injection and whether this regimen could reduce the incidence of adverse events caused by chemotherapy. METHOD: A total of 100 patients with colon cancer who were treated with chemotherapy in our hospital from January 2011 to December 2014 were randomly divided into two groups, with 50 patients in each group. The patients in the treatment group received G-CSF 24 hours after chemotherapy for consecutive three days; the patients in the control group received the same dose of normal saline. Routine blood tests were performed 7 days and 14 days after chemotherapy. RESULTS: Compared with the control group, the incidences of febrile neutropenia and leukocytopenia in the treatment group were significantly lower (p<0.05). In addition, the incidence of liver dysfunction in the treatment group was lower than that of the control group, without statistical significance. The incidence of myalgia in the treatment was higher than that of the control group without statistical significance. CONCLUSION: The present study indicated that G-CSF injection after chemotherapy is safe and effective for preventing adverse events in colon cancer patients with chemotherapy. PMID- 29489979 TI - Gaucher's disease in a patient presenting with hip and abdominal pain. AB - Gaucher's disease is characterized by glucocerebroside accumulation in the cells of the reticuloendothelial system. There are three subtypes. The most common is type 1, known as the non-neuropathic form. Pancytopenia, hepatosplenomegaly and bone lesions occur as a result of glucocerebroside accumulation in the liver, lung, spleen and bone marrow in these patients. Findings associated with liver, spleen or bone involvement may be seen at radiological analysis. Improvement in extraskeletal system findings is seen with enzyme replacement therapy. Support therapy is added in patients developing infection, anemia or pain. We describe a case of hepatosplenomegaly, splenic infarction, splenic nodules and femur fracture determined at radiological imaging in a patient under monitoring due to Gaucher's disease. PMID- 29489980 TI - Correlation between GDF-15 gene polymorphism and the formation of collateral circulation in acute ST-elevation myocardial infarction. AB - OBJECTIVE: To explore the correlation between growth differentiation factor 15 (GDF-15) -3148C/G polymorphism and the formation of collateral circulation in acute ST-elevation myocardial infarction (STEMI) in Han population of Taiyuan area. METHOD: The present study included 92 STEMI patients and 56 normal controls based on coronary angiography; STEMI group was divided into collateral group and non-collateral group according to Rentrop's grading method. Polymerase chain reaction (PCR) and DNA sequencing methods were used to detect and analyze the GDF 15 -3148C/G polymorphism in all participants. RESULTS: There was significant difference in GDF-15 -3148C/G CC and GC distribution between STEMI group and control group (p=0.009); the allele frequencies between these two groups were also significant different (p=0.016); and the risk genotype for STEMI was CC with increased OR=2.660. For STEMI group, GDF-15 -3148C/G CC and GC distribution was also significantly different between patients with and without collateral (p=0.048), and CC genotype significantly promote the formation of collateral circulation. However, there were no significant differences in allele frequencies between these two subgroups of STEMI. CONCLUSION: There was correlation between GDF-15-3148C/G polymorphism and the formation of collateral circulation in patients with acute STEMI. PMID- 29489981 TI - Undergraduate research in medical education. PMID- 29489982 TI - Implementation of a standardized out-of-hospital management method for Parkinson dysphagia. AB - OBJECTIVE: Our objective is to explore the effectiveness and feasibility of establishing a swallowing management clinic to implement out-of-hospital management for Parkinson disease (PD) patients with dysphagia. METHOD: Two hundred seventeen (217) voluntary PD patients with dysphagia in a PD outpatient clinic were divided into a control group with 100 people, and an experimental group with 117 people. The control group was given dysphagia rehabilitation guidance. The experimental group was presented with the standardized out-of hospital management method as overall management and information and education materials. Rehabilitation efficiency and incidence rate of dysphagia, as well as relevant complications of both groups were compared after a 6-month intervention. RESULTS: Rehabilitation efficiency and the incidence rate of dysphagia including relevant complications of patients treated with the standardized out-of-hospital management were compared with those seen in the control group. The differences have distinct statistics meaning (p<0.01). CONCLUSION: Establishing a swallowing management protocol for outpatient setting can effectively help the recovery of the function of swallowing, reduce the incidence rate of dysphagia complications and improve the quality of life in patients with PD. PMID- 29489983 TI - Pelvic floor muscle training for overactive bladder symptoms - A prospective study. AB - INTRODUCTION: Pelvic floor muscle training (PFMT) involves the contraction of the puborectal, anal sphincter and external urethral muscles, inhibiting the detrusor contraction, what justify its use in the treatment of overactive bladder (OAB) symptoms. OBJECTIVE: To verify the effects of isolated PFMT on the symptoms of OAB. METHOD: Prospective clinical trial with 27 women with mixed urinary incontinence (MUI), with predominance of OAB symptoms and loss >= 2 g in the pad test. It was evaluated: pelvic floor muscles (PFMs) function (digital palpation and manometry); urinary symptoms (nocturia, frequency and urinary loss); degree of discomfort of OAB symptoms; and quality of life (Incontinence Quality-of-Life Questionnaire [I-QoL]). The PFMT program consisted of 24 outpatient sessions (2x/week + home PFMT). The Mann-Whitney and Wilcoxon tests (with a significance level of 5%) were used to analyse the data. RESULTS: There was a significant improvement of the urinary symptoms to the pad test (5.8+/-9.7, p<0.001), urinary loss (0.7+/-1.1, p=0.005) and nocturia (0.8+/-0.9, p=0.011). Reduction in the degree of discomfort of urinary symptoms was observed according to OAB-V8 questionnaire (10.0+/-7.7, p=0.001). There were also significant results in PFMs function: Oxford (3.6+/-0.9, p=0.001), endurance (5.2+/-1.8, p<0.001), fast (8.9+/-1.5, p<0.001) and manometry (26.6+/-15.8, p=0.003). In addition, quality of life had a significant improvement in the three domains evaluated by I-QoL. CONCLUSION: The PFMT without any additional guidelines improves the symptomatology, the function of PFMs and the quality of life of women with OAB symptoms. PMID- 29489984 TI - Cogan's syndrome - A rare aortitis, difficult to diagnose but with therapeutic potential. AB - The inflammation of aortic wall, named aortitis, is a rare condition that can be caused by a number of pathologies, mainly inflammatory or infectious in nature. In this context, the occurrence of combined audiovestibular and/or ocular manifestations eventually led to the diagnosis of Cogan's syndrome, making it the rare case, but susceptible to adequate immunosuppressive treatment and satisfactory disease control. PMID- 29489985 TI - Obstructive sleep apnea syndrome and sleep quality in hypertensive patients. AB - INTRODUCTION: Obstructive sleep apnea and hypopnea syndrome (OSAHS) is one of the developmental factors of high blood pressure (HBP), a relevant global public health problem. OSAHS is characterized by the reduction or complete cessation of respiratory airflow due to intermittent airway collapse. Additionally, significant changes in sleep rhythm and pattern are observed in these patients. OBJECTIVE: To evaluate the association between OSAHS and sleep quality in essential and resistant hypertensives. METHOD: A cross-sectional, observational study evaluated 43 hypertensive patients treated at the outpatient clinics of the Faculdade de Medicina do ABC (FMABC) who were medicated with two or more antihypertensive drugs and divided into nonresistant or resistant to treatment. RESULTS: Group I (using up to two antihypertensive agents - 60.47% of the sample) presented mean systolic blood pressure (SBP) of 127.5+/-6.4 mmHg, mean diastolic blood pressure (DBP) of 79.6+/-5.2 mmHg, mean body mass index (BMI) of 27.2+/-5.3 kg/m2 and mean age of 51.2+/-15.1 years. Group II (using more than two antihypertensive drugs - 37.2% of the sample) presented mean SBP of 132.1+/-9.3 mmHg, mean DBP of 84.5+/-5.8 mmHg, mean BMI of 27.2+/-7.2 kg/m2 and mean age of 55.5+/-13.4 years. The patients presented low quality of sleep/sleep disorder evaluated by the Pittsburgh Sleep Quality Index (PSQI), which represents a preponderant factor for OSAHS. CONCLUSION: Patients at high risk for OSAHS had poor sleep quality and high levels of DBP, suggesting a causal relation between these parameters. However, they did not present a higher prevalence of resistant high blood pressure (RHBP). PMID- 29489986 TI - The role of regulatory T cells, interleukin-10 and in vivo scintigraphy in autoimmune and idiopathic diseases - Therapeutic perspectives and prognosis. AB - Previous studies have demonstrated the expression of the CD25 marker on the surface of naturally occurring T cells (Tregs) of mice, which have a self reactive cellular profile. Recently, expression of other markers that aid in the identification of these cells has been detected in lymphocyte subtypes of individuals suffering of autoimmune and idiopathic diseases, including: CD25, CTLA-4 (cytotoxic T-lymphocyte antigen 4), HLA-DR (human leukocyte antigen) and Interleukin 10 (IL-10), opening new perspectives for a better understanding of an association between such receptors present on the cell surface and the prognosis of autoimmune diseases. The role of these molecules has already been described in the literature for the modulation of the inflammatory response in infectious and parasitic diseases. Thus, the function, phenotype and frequency of expression of the a-chain receptor of IL-2 (CD25) and IL-10 in lymphocyte subtypes were investigated. Murine models have been used to demonstrate a possible correlation between the expression of the CD25 marker (on the surface of CD4 lymphocytes) and the control of self-tolerance mechanisms. These studies provided support for the presentation of a review of the role of cells expressing IL-2, IL-10, HLA-DR and CTLA-4 receptors in the monitoring of immunosuppression in diseases classified as autoimmune, providing perspectives for understanding peripheral regulation mechanisms and the pathophysiology of these diseases in humans. In addition, a therapeutic approach based on the manipulation of the phenotype of these cells and ways of scintigraphically monitoring the manifestations of these diseases by labeling their receptors is discussed as a perspective. In this paper, we have included the description of experiments in ex vivo regulation of IL-10 and synthesis of thio-sugars and poly-sugars to produce radiopharmaceuticals for monitoring inflammation. These experiments may yield benefits for the treatment and prognosis of autoimmune diseases. PMID- 29489987 TI - Practices and obstetric interventions in women from a state in the Northeast of Brazil. AB - OBJECTIVE: To describe practices and interventions used during labor and childbirth and factors associated with such practices in puerperae in the state of Sergipe. METHOD: A cross-sectional study with 768 postpartum women from 11 maternity hospitals interviewed 6 hours after delivery, and hospital records review. The associations between best practices and interventions used during labor and delivery with exposure variables were described using simple frequencies, percentages, crude and adjusted odds ratio (ORa) with the confidence interval. RESULTS: Of the women in the study, 10.6% received food and 27.8% moved during labor; non-pharmacological methods for pain relief were performed in 26.1%; a partogram was filled in 39.4% of the charts; and an accompanying person was present in 40.6% of deliveries. Oxytocin, amniotomy and labor analgesia were used in 59.1%, 49.3% and 4.2% of women, respectively. Lithotomy position during childbirth was used in 95.2% of the cases, episiotomy in 43.9% and Kristeller maneuver in 31.7%. The variables most associated with cesarean section were private financing (ORa=4.27, 95CI 2.44-7.47), higher levels of education (ORa=4.54, 95CI 2.56-8.3) and high obstetric risk (ORa=1.9, 95CI 1.31-2.74). Women whose delivery was funded privately were more likely to have an accompanying person present (ORa=2.12, 95CI 1.18-3.79) and to undergo labor analgesia (ORa=4.96, 95CI 1.7-14.5). CONCLUSION: Best practices are poorly performed and unnecessary interventions are frequent. The factors most associated with c-section were private funding, greater length of education and high obstetric risk. PMID- 29489988 TI - Association between excess weight and beverage portion size consumed in Brazil. AB - OBJECTIVE To describe the beverage portion size consumed and to evaluate their association with excess weight in Brazil. METHODS We used data from the National Dietary Survey, which included individuals with two days of food record aged over 20 years (n = 24,527 individuals). The beverages were categorized into six groups: soft drink, 100% fruit juice, fruit drink, alcoholic beverage, milk, and coffee or tea. We estimated the average portion consumed for each group and we evaluated, using linear regression, the association between portion size per group and the variables of age, sex, income, and nutritional status. We tested the association between portion size and excess weight using Poisson regression, adjusted for age, sex, income, and total energy intake. RESULTS The most frequently consumed beverages in Brazil were coffee and tea, followed by 100% fruit juices, soft drinks, and milk. Alcoholic beverages presented the highest average in the portion size consumed, followed by soft drinks, 100% fruit juice, fruit drink, and milk. Portion size showed positive association with excess weight only in the soft drink (PR = 1.19, 95%CI 1.10-1.27) and alcoholic beverage groups (PR = 1.20, 95%CI, 1.11-1.29), regardless of age, sex, income, and total energy intake. CONCLUSIONS Alcoholic beverages and soft drinks presented the highest averages in portion size and positive association with excess weight. Public health interventions should address the issue of portion sizes offered to consumers by discouraging the consumption of large portions, especially sweetened and low nutritional beverages. PMID- 29489989 TI - Analysis of the national school feeding program in the municipality of Vicosa, state of Minas Gerais. AB - OBJECTIVE To analyze the implementation of the Brazilian National School Feeding Program as a food and nutritional security policy in public schools. METHODS This a cross-sectional study, with a quantitative and qualitative approach, carried out with 268 schoolchildren aged eight to nine years from the public school system of Vicosa, state of Minas Gerais, Brazil, in 2015. Interviews were carried out using semi-structured questionnaires with the children, parents, cooks, nutritionists, trainer of the Technical Assistance and Rural Extension Company, and president of the School Feeding Council. In order to analyze the implementation of the National School Feeding Program in Vicosa, we evaluated the direct weighing of the food served in the schools using mechanical balances with a capacity of up to 10 kg and the perception of the social players involved in the implementation of the National School Feeding Program. The children were questioned about the acceptance of and adherence to the food offered, in addition to the habit of bringing food from home. Parents reported knowledge about the School Feeding Program and Council. The qualitative analysis consisted of content analysis and quantitative analysis using the chi-square test, Fisher's exact test, and Mann-Whitney test. We adopted the statistical significance of 5% for quantitative analysis. RESULTS Children reported low adherence to the school feeding program and most of them used to bring food from home. Irregularities were identified in the implementation of the National School Feeding Program, such as: inadequate number of nutritionists, suspension of Council meetings, inadequate infrastructure in the areas of preparation and distribution of meals, lack of training of cooks, lack of nutritional adequacy of the food offered, and lack of actions on food and nutritional education. The Program complied with the recommendations for purchasing food from family farms. CONCLUSIONS The National School Feeding Program presented many irregularities in Vicosa. It is important to monitor the problems identified for better reformulation and planning of the Program, in order to guarantee the food and nutritional security of the children served. PMID- 29489990 TI - Leprosy and gender in Brazil: trends in an endemic area of the Northeast region, 2001-2014. AB - OBJECTIVE To analyze, stratifield by gender, trends of the new case leprosy detection rates in the general population and in children; of grade 2 disability, and of proportion of multibacillary cases, in the state of Bahia, Brazil from 2001 to 2014. METHODS A time series study based on leprosy data from the National Information System for Notifiable Diseases. The time trend analysis included Poisson regression models by infection points (Joinpoint) stratified by gender. RESULTS There was a total of 40,054 new leprosy cases with a downward trend of the overall detection rate (Average Annual Percent Change [AAPC = -0.4, 95%CI 2.8-1.9] and a non-significant increase in children under 15 years (AAPC = 0.2, 95%CI -3.9-4.5). The proportion of grade 2 disability among new cases increased significantly (AAPC = 4.0, 95%CI 1.3-6.8), as well as the proportion of multibacillary cases (AAPC = 2.2, 95%CI 0.1-4.3). Stratification by gender showed a downward trend of detection rates in females and no significant change in males; in females, there was a more pronounced upward trend of the proportion of multibacillary and grade 2 disability cases. CONCLUSIONS Leprosy is still highly endemic in the state of Bahia, with active transmission, late diagnosis, and a probable hidden endemic. There are different gender patterns, indicating the importance of early diagnosis and prompt treatment, specifically in males without neglecting the situation among females. PMID- 29489991 TI - Socioeconomic status in childhood and obesity in adults: a population-based study. AB - OBJECTIVE To test whether there is an association between socioeconomic status in childhood and measures of body mass index, waist circumference and the presence of overall and abdominal obesity in adult life. METHODS A cross-sectional analysis of a population-based cohort study, including a sample of adults (22-63 years old) living in Florianopolis, Southern Brazil. The socioeconomic status in childhood was analyzed through the education level of the participant's parents. Height, weight and waist circumference were measured by previously trained interviewers. Linear and logistic regressions with adjustment for confounding factors and stratification of data according to gender were used. RESULTS Of the 1,222 adults evaluated, 20.4% (95%CI 18.1-22.8) presented overall obesity and 24.8% (95%CI 22.4-27.4), abdominal obesity. The body mass index and waist circumference averages among women were, respectively, 1.2 kg/m2 (95%CI -2.3- 0.04) and 2.8 cm (95%CI -5.3- -0.2) lower among those with higher socioeconomic status in childhood. Among men, waist circumference was 3.9 cm (95%CI 1.0-6.8) higher in individuals with higher socioeconomic status in childhood. Regarding obesity, women of higher socioeconomic status in childhood had lower odds of abdominal obesity (OR = 0.56, 95%CI 0.34-0.90), and no such association was observed among men. CONCLUSIONS The socioeconomic status in childhood influences body mass index, waist circumference and obesity in adults, with a difference in the direction of association according to gender. The higher socioeconomic status among men and the lower socioeconomic status among women were associated with higher adiposity indicators. PMID- 29489992 TI - Mental health in primary care: an evaluation using the Item Response Theory. AB - OBJECTIVE To determine the items of the Brazilian National Program for Improving Access and Quality of Primary Care that better evaluate the capacity to provide mental health care. METHODS This is a cross-sectional study carried out using the Graded Response Model of the Item Response Theory using secondary data from the second cycle of the National Program for Improving Access and Quality of Primary Care, which evaluates 30,523 primary care teams in the period from 2013 to 2014 in Brazil. The internal consistency, correlation between items, and correlation between items and the total score were tested using the Cronbach's alpha, Spearman's correlation, and point biserial coefficients, respectively. The assumptions of unidimensionality and local independence of the items were tested. Word clouds were used as one way to present the results. RESULTS The items with the greatest ability to discriminate were scheduling of the agenda according to risk stratification, keeping of records of the most serious cases of users in psychological distress, and provision of group care. The items that required a higher level of mental health care in the parameter of location were the provision of any type of group care and the provision of educational and mental health promotion activities. Total Cronbach's alpha coefficient was 0.87. The items that obtained the highest correlation with total score were the recording of the most serious cases of users in psychological distress and scheduling of the agenda according to risk stratification. The final scores obtained oscillated between -2.07 (minimum) and 1.95 (maximum). CONCLUSIONS There are important aspects in the discrimination of the capacity to provide mental health care by primary health care teams: risk stratification for care management, follow-up of the most serious cases, group care, and preventive and health promotion actions. PMID- 29489993 TI - Challenges on the epidemiological and economic burden of diabetes and hypertension in Mexico. AB - OBJECTIVE To analyze the epidemiological and economic burden of the health services demand due to diabetes and hypertension in Mexico. METHODS Evaluation study based on a time series study that had as a universe of study the assured and uninsured population that demands health services from the three main institutions of the Health System in Mexico: The Health Department, the Mexican Institute of Social Security, and Institute of Services and Social Security for State Workers. The financing method was based on instrumentation and consensus techniques for medium case management. In order to estimate the epidemiological changes and financial requirements, a time series of observed cases for diabetes and hypertension 1994-2013 was integrated. Probabilistic models were developed based on the Box-Jenkins technique for the period of 2013-2018 with 95% confidence intervals and p < 0.05. RESULTS Comparing results from 2013 versus 2018, in the five regions, different incremental trends of 14%-17% in epidemiological changes and 58%-66% in the economic burden for both diseases were observed. CONCLUSIONS If the risk factors and the different models of care remained as they currently are in the three institutions analyzed, the financial consequences would be of greater impact for the Mexican Institute of Social Security, following in order of importance the Institute of Services and Social Security for State Workers and lastly the Health Department. The financial needs for both diseases will represent approximately 13%-15% of the total budget allocated to the uninsured population and 15%-17% for the population insured depending on the region. PMID- 29489994 TI - Dengue in Araraquara, state of Sao Paulo: epidemiology, climate and Aedes aegypti infestation. AB - OBJECTIVE To describe the epidemiology of dengue in a medium-sized city in the state of Sao Paulo. METHODS Data, such as circulating serotypes, severe cases and deaths, age group, sex, among others, were obtained on reported and confirmed dengue cases in Araraquara, state of Sao Paulo, between 1991 and 2015. Climatic and infestation data were also analyzed. These variables were evaluated descriptively, using statistical measures such as frequencies, averages, minimum and maximum. Dengue incidence rates were calculated according to month, year, age and sex, and time series of dengue cases, infestation, and climatic variables. RESULTS Approximately 16,500 cases of dengue fever were reported between 1991 and 2015. The highest number of reports was recorded in 2015 (7,811 cases). In general, the age group with the highest number of reports is between 20 and 59 years old. The highest incidences, generally between March and May, occurred after the increase in rainfall and infestation in January. CONCLUSIONS Increased levels of infestation due to rainfall are reflected in incidence rates of the disease. It is fundamental to know the epidemiology of dengue in medium-sized cities. Such information can be extended to diseases such as Zika and Chikungunya, which are transmitted by the same vector and were reported in the city. The intensification of surveillance efforts in periods before epidemics could be a strategy to be considered to control the viral spread. PMID- 29489995 TI - Private dental insurance expenditure in Brazil. AB - OBJECTIVE To quantify the household expenditure per capita and to estimate the percentage of Brazilian households that have spent with dental insurance. METHODS We analyzed data from 55,970 households that participated in the research Pesquisa de Orcamentos Familiares in 2008-2009. We have analyzed the annual household expenditure per capita with dental insurance (business and private) according to the Brazilian states and the socioeconomic and demographic characteristics of the households (sex, age, race, and educational level of the head of the household, family income, and presence of an older adult in the household). RESULTS Only 2.5% of Brazilian households have reported spending on dental insurance. The amount spent per capita amounted to R$5.10 on average, most of which consisted of private dental insurance (R$4.70). Among the characteristics of the household, higher educational level and income were associated with higher spending. Sao Paulo was the state with the highest household expenditure per capita (R$10.90) and with the highest prevalence of households with expenditures (4.6%), while Amazonas and Tocantins had the lowest values, in which both spent less than R$1.00 and had a prevalence of less than 0.1% of households, respectively. CONCLUSIONS Only a small portion of the Brazilian households has dental insurance expenditure. The market for supplementary dentistry in oral health care covers a restricted portion of the Brazilian population. PMID- 29489996 TI - Evidence of validity of the Stress-Producing Life Events (SPLE) instrument. AB - OBJECTIVE Evaluate the construct validity of a list of eight Stressful Life Events in pregnant women. METHODS A cross-sectional study was conducted with 1,446 pregnant women in Sao Luis, MA, and 1,364 pregnant women in Ribeirao Preto, SP (BRISA cohort), from February 2010 to June 2011. In the exploratory factorial analysis, the promax oblique rotation was used and for the calculation of the internal consistency, we used the compound reliability. The construct validity was determined by means of the confirmatory factorial analysis with the method of estimation of weighted least squares adjusted by the mean and variance. RESULTS The model with the best fit in the exploratory analysis was the one that retained three factors with a cumulative variance of 61.1%. The one-factor model did not obtain a good fit in both samples in the confirmatory analysis. The three-factor model called Stress-Producing Life Events presented a good fit (RMSEA < 0.05; CFI/TLI > 0.90) for both samples. CONCLUSIONS The Stress-Producing Life Events constitute a second order construct with three dimensions related to health, personal and financial aspects and violence. This study found evidence that confirms the construct validity of a list of stressor events, entitled Stress Producing Life Events Inventory. PMID- 29489997 TI - Work of community health agents in the Family Health Strategy: meta-synthesis. AB - OBJECTIVE To systematize and analyze the evidence from qualitative studies that address the perception of Brazilian Community Health Agents about their work. METHODS This is a systematic review of the meta-synthesis type on the work of community health agents, carried out from the Virtual Health Library using the descriptors "Agente Comunitario de Saude" and "Trabalho", in Portuguese. The strategy was constructed by crossing descriptors, using the Boolean operator "AND", and filtering Brazilian articles, published from 2004 to 2014, which resulted in 129 identified articles. We removed quantitative or quanti qualitative research articles, essays, debates, literature reviews, reports of experiences, and research that did not include Brazilian Community Health Agents as subjects. Using these criteria, we selected and analyzed 33 studies that allowed us to identify common subjects and differences between them, to group the main conclusions, to classify subjects, and to interpret the content. RESULTS The analysis resulted in three thematic units: characteristics of the work of community health agents, problems related to the work of community health agents, and positive aspects of the work of community health agents. On the characteristics, we could see that the work of the community health agents is permeated by the political and social dimensions of the health work with predominant use of light technologies. The main input is the knowledge that this professional obtains with the contact with families, which is developed with home visits. On the problems in the work of community health agents, we could identify the lack of limits in their attributions, poor conditions, obstacles in the relationship with the community and teams, weak professional training, and bureaucracy. The positive aspects we identified were the recognition of the work by families, resolution, bonding, work with peers, and work close to home. CONCLUSIONS This review provided an overview of the difficulties and positive aspects that are present in the daily work of community health agents. Given this, we have raised two challenges. The first one refers to how public policy makers need to appropriation the research results and the second one refers to the need to invest in studies that are designed to generate solutions for the difficulties faced by community health agents in their work. PMID- 29489998 TI - Falls among older adults in the South of Brazil: prevalence and determinants. AB - OBJECTIVE Evaluate the prevalence and the factors associated with the occurrence of falls among older adults. METHODS A cross-sectional study with a representative sample of 1,451 elderly residents in the urban area of Pelotas, RS, in 2014. A descriptive analysis of the data was performed and the prevalence of falls in the last year was presented. The analysis of demographic, socioeconomic, behavioral and health factors associated with the outcome was performed using Poisson regression with adjustment for robust variance according to the hierarchical model. The variables were adjusted to each other within each level and for the higher level. Those with p <= 0.20 were maintained in the model for confounding control and those with p < 0.05 were considered to be associated with the outcome. RESULTS The prevalence of falls among older adults in the last year was 28.1% (95%CI 25.9-30.5), and most occurred in the person's own residence. Among the older adults who fell, 51.5% (95%CI 46.6-56.4) had a single fall and 12.1% (95%CI 8.9-15.3) had a fracture as a consequence, usually in the lower limbs. The prevalence of falls was higher in women, adults of advanced age, with lower income and schooling level, with functional incapacity for instrumental activities, and patients with diseases such as diabetes, heart disease, and arthritis. CONCLUSIONS The occurrence of falls reached almost a third of the older adults, and the prevalence was higher in specific segments of the population in question. About 12% of the older adults who fell fractured some bone. The factors associated with the occurrence of falls identified in this study may guide measures aimed at prevention in the older adult population. PMID- 29489999 TI - Elementary screening of lymph node metastatic-related genes in gastric cancer based on the co-expression network of messenger RNA, microRNA and long non-coding RNA. AB - Gastric cancer (GC) is the fifth most common cancer and the third leading cause of cancer-related deaths worldwide. The high mortality might be attributed to delay in detection and is closely related to lymph node metastasis. Therefore, it is of great importance to explore the mechanism of lymph node metastasis and find strategies to block GC metastasis. Messenger RNA (mRNA), microRNA (miRNA) and long non-coding RNA (lncRNA) expression data and clinical data were downloaded from The Cancer Genome Atlas (TCGA) database. A total of 908 differentially expressed factors with variance >0.5 including 542 genes, 42 miRNA, and 324 lncRNA were screened using significant analysis microarray algorithm, and interaction networks were constructed using these differentially expressed factors. Furthermore, we conducted functional modules analysis in the network, and found that yellow and turquoise modules could separate samples efficiently. The groups classified in the yellow and turquoise modules had a significant difference in survival time, which was verified in another independent GC mRNA dataset (GSE62254). The results suggested that differentially expressed factors in the yellow and turquoise modules may participate in lymph node metastasis of GC and could be applied as potential biomarkers or therapeutic targets for GC. PMID- 29490000 TI - Propofol inhibits proliferation, migration, and invasion but promotes apoptosis by regulation of Sox4 in endometrial cancer cells. AB - Propofol is an intravenous sedative hypnotic agent of which the growth-inhibitory effect has been reported on various cancers. However, the roles of propofol in endometrial cancer (EC) remain unclear. This study aimed to explore the effects of propofol on EC in vitro and in vivo. Different concentrations of propofol were used to treat Ishikawa cells. Colony number, cell viability, cell cycle, apoptosis, migration, and invasion were analyzed by colony formation, MTT, flow cytometry, and Transwell assays. In addition, the pcDNA3.1-Sox4 and Sox4 siRNA plasmids were transfected into Ishikawa cells to explore the relationship between propofol and Sox4 in EC cell proliferation. Tumor weight in vivo was measured by xenograft tumor model assay. Protein levels of cell cycle-related factors, apoptosis-related factors, matrix metalloproteinases 9 (MMP9), matrix metalloproteinases 2 (MMP2) and Wnt/beta-catenin pathway were examined by western blot. Results showed that propofol significantly decreased colony numbers, inhibited cell viability, migration, and invasion but promoted apoptosis in a dose-dependent manner in Ishikawa cells. Moreover, propofol reduced the expression of Sox4 in a dose-dependent manner. Additionally, propofol significantly suppressed the proportions of Ki67+ cells, but Sox4 overexpression reversed the results. Furthermore, in vivo assay results showed that propofol inhibited tumor growth; however, the inhibitory effect was abolished by Sox4 overexpression. Moreover, propofol inhibited Sox4 expression via inactivation of Wnt/beta-catenin signal pathway. Our study demonstrated that propofol inhibited cell proliferation, migration, and invasion but promoted apoptosis by regulation of Sox4 in EC cells. These findings might indicate a novel treatment strategy for EC. PMID- 29490001 TI - Nitrogen single-breath washout test for evaluating exercise tolerance and quality of life in patients with chronic obstructive pulmonary disease. AB - Pulmonary function tests (PFTs) traditionally used in clinical practice do not accurately predict exercise intolerance in patients with chronic obstructive pulmonary disease (COPD). The aim of this study was to assess whether the nitrogen single-breath washout (N2SBW) test explains exercise intolerance and poor quality of life in stable COPD patients. This cross-sectional study included 31 patients with COPD subjected to PFTs (including the N2SBW test) and a cardiopulmonary exercise test (CPET). Patients were also evaluated using the following questionnaires: the COPD assessment test (CAT), the 36-Item Short Form Health Survey (SF36) and St. George's Respiratory Questionnaire (SGRQ). Peak oxygen uptake (peak VO2) was negatively correlated with the phase III slope of the N2SBW (SIIIN2) (r=-0.681, P<0.0001) and positively correlated with forced expiratory volume in one second (FEV1; r=0.441, P=0.013). Breathing reserve was negatively correlated with SIIIN2, closing volume/vital capacity, and residual volume (RV) (r=-0.799, P<0.0001; r=-0.471, P=0.007; r=-0.401, P=0.025, respectively) and positively correlated with FEV1, forced vital capacity (FVC) and FEV1/FVC (r=0.721; P<0.0001; r=0.592, P=0.0004; r=0.670, P<0.0001, respectively). SIIIN2 and CAT were independently predictive of VO2 and breathing reserve at peak exercise. RV, FVC, and FEV1 were independently predictive of the SF36-physical component summary, SF36-mental component summary, and breathing reserve, respectively. The SGRQ did not present any independent variables that could explain the model. In stable COPD patients, inhomogeneity of ventilation explains a large degree of exercise intolerance assessed by CPETs and, to a lesser extent, poor quality of life. PMID- 29490002 TI - Correlation between serum 25-hydroxyvitamin D levels and carotid intima-media thickness in a Brazilian population descended from African slaves. AB - Hypovitaminosis D has been identified as a possible new cardiovascular risk factor. However, the results of studies correlating serum vitamin D levels with markers of subclinical atherosclerosis have been conflicting. The aim of this study was to correlate serum levels of 25-hydroxyvitamin D [25(OH)D] with carotid intima-media thickness (C-IMT) and conventional cardiovascular risk factors in Afro-descendants. A cross-sectional analysis was performed on a sample of 382 individuals from a cohort of descendants of African slaves, inhabitants of "Quilombola" communities, with a mean age of 57.79 +/-15.3 years, 54.5% of whom were women. Socio-demographic and clinical data were collected and biochemical tests were performed, including serum levels of 25(OH)D by electrochemiluminescence and urinary albumin excretion, evaluated by the albumin/creatinine ratio (ACR) in a spot urine sample. All participants underwent high-resolution ultrasonography for C-IMT measurement. Hypovitaminosis D was defined as serum 25(OH)D levels <30 ng/mL. The mean serum 25(OH)D levels were 50.4+/-13.5 ng/mL, with a low prevalence of hypovitaminosis D (4.86%). By simple linear correlation, a significant inverse association between 25(OH)D levels and C-IMT (r=-0.174, P=0.001) was observed. However, after multiple linear regression analysis, the significance of the association between serum levels of 25(OH)D and C-IMT measurement was lost (beta=-0.039, P=0.318) and only male gender, age, smoking, systolic blood pressure, glucose and low density lipoprotein (LDL) cholesterol remained significantly associated with C-IMT. Levels of 25(OH)D were independently and positively associated with HDL-cholesterol and inversely associated with age and ACR. In conclusion, no independent association between 25(OH)D levels and C-IMT was observed in this population. On the other hand, there was an inverse association with albuminuria, a marker of endothelial lesion. PMID- 29490003 TI - Clinical and radiographic outcomes of upper thoracic versus lower thoracic upper instrumented vertebrae for adult scoliosis: a meta-analysis. AB - The aim of this study was to evaluate the clinical and radiographic outcomes of upper thoracic (UT) versus lower thoracic (LT) upper instrumented vertebrae (UIV) for adult scoliosis by meta-analysis. We conducted a literature search in three databases to retrieve related studies up to March 15, 2017. The preliminary screened studies were assessed by two reviewers according to the selection criteria. All analyses were carried out using the statistical software package R version 2.31. Odds ratios (OR) with 95% confidence intervals (CI) were used to describe the results. The I2 statistic and Q statistic test were used for heterogeneity assessment. Egger's test was performed to detect publication bias. To assess the effect of each study on the overall pooled OR or standardized mean difference (SMD), sensitive analysis was conducted. Ten trials published between 2007 and 2015 were eligible and included in our study. Meta-analysis revealed that the UT group was associated with more blood loss (SMD=0.4779, 95%CI=0.3349 0.6209, Z=6.55, P<0.0001) and longer operating time (SMD=0.5780, 95%CI=0.1971 0.958, Z=2.97, P=0.0029) than the LT group. However, there was no significant difference in Oswestry Disability Index, Scoliosis Research Society (SRS) function subscores, radiographic outcomes including sagittal vertical axis, lumbar lordosis, and thoracic kyphosis, length of hospital stay, and revision rates between the two groups. No evidence of publication bias was found between the two groups. Fusion from the lower thoracic spine (below T10) has as advantages a shorter operation time and less blood loss than upper thoracic spine (above T10) in posterior long-segment fixation for degenerative lumbar scoliosis. PMID- 29490005 TI - Diversity of Cortico-descending Projections: Histological and Diffusion MRI Characterization in the Monkey. AB - The axonal composition of cortical projections originating in premotor, supplementary motor (SMA), primary motor (a4), somatosensory and parietal areas and descending towards the brain stem and spinal cord was characterized in the monkey with histological tract tracing, electron microscopy (EM) and diffusion MRI (dMRI). These 3 approaches provided complementary information. Histology provided accurate assessment of axonal diameters and size of synaptic boutons. dMRI revealed the topography of the projections (tractography), notably in the internal capsule. From measurements of axon diameters axonal conduction velocities were computed. Each area communicates with different diameter axons and this generates a hierarchy of conduction delays in this order: a4 (the shortest), SMA, premotor (F7), parietal, somatosensory, premotor F4 (the longest). We provide new interpretations for i) the well-known different anatomical and electrophysiological estimates of conduction velocity; ii) why conduction delays are probably an essential component of the cortical motor command; and iii) how histological and dMRI tractography can be integrated. PMID- 29490006 TI - Prominent Ear Correction: A Comprehensive Review of Fascial Flaps in Otoplasty. AB - Over the last 100 years, more than 200 different methods have been described to correct prominent ear deformity. These techniques revolved around various combinations of postauricular incision, cartilage scoring, and strategic suture placement to reapproximate the antihelical fold and correct angular deformity. In the last two decades, fascial flap techniques have become prominent in otoplasty. This article gives a comprehensive review of the different surgical techniques employed to construct fascial flaps and their contributions to otoplasty. PMID- 29490004 TI - Repeatability of the "flash-replenishment" method in contrast-enhanced ultrasound for the quantitative assessment of hepatic microvascular perfusion. AB - This study aimed to evaluate the feasibility and repeatability of the flash replenishment method in contrast-enhanced ultrasound (CEUS) perfusion imaging and assess quantitatively microvascular perfusion in the liver. Twenty healthy New Zealand rabbits were submitted to CEUS perfusion imaging with continuous intravenous infusion. Using flash-replenishment kinetics, the dynamic process of depletion and refilling of microbubble contrast agent was recorded. The hepatic microvascular perfusion parameters were calculated, including region of interest, peak intensity (PI), area under the curve (AUC), and hepatic artery to vein transit time (HA-HVTT). A consistency test was performed for multiple measurements by the same operator and blind measurements by two different operators. The hepatic perfusion imaging of 3*108 bubbles/min had minimal error and the best imaging effect and repeatability. The variability of the perfusion parameter measured at 3 cm depth under the liver capsule was at a minimum with coefficient of variation of 3.9%. The interclass correlation coefficient (ICC) of measurements taken by the same operator was 0.985, (95% confidence interval, CI=0.927-0.998). Measurements taken by two operators had good consistency and reliability, with the ICC of 0.948 (95%CI=0.853-0.982). The PI and AUC of liver parenchyma after reperfusion were lower than before blocking; and HA-HVTT was significantly longer than before blocking (P<0.05). The flash-replenishment method in CEUS perfusion imaging showed good stability and repeatability, which provide a valuable experimental basis for the quantitative assessment of hepatic microvascular perfusion in clinical practice. PMID- 29490007 TI - Associations between human fungiform papillae and responsiveness to oral stimuli: effects of individual variability, population characteristics, and methods for papillae quantification. AB - Fungiform papillae (FP) on human tongue are the proxy structures designated to oral stimuli detection and transduction. However, the role of their density (fungiform papillae/cm2) in explaining oral sensitivity is still controversial. While early studies generally found that the responsiveness to oral stimuli increased as the number of papillae increased, recent large-scale studies failed to confirm this finding. The present paper reviews relevant studies dealing with the relationship between FP density and responsiveness to oral sensations including: fundamental tastes, 6-n-propyl-2-thiouracil (PROP), and sensations from trigeminal stimulation. Manual methods and automated methods for papillae detection and quantification are reviewed and their advantages and limitations highlighted. The main factors affecting FP density and functionality (age, gender, pathologic impairments) are also considered. Possible bias related to methodological issues in counting technique (equipment used, area and location of the tongue to count, procedures to validate the count), population sample (demographics), and sensory response collection (threshold or supra-threshold stimuli, intensity scaling) are illustrated. The lack of information related to the variability in taste pores density and the possible impairments due to nerve damages, may obscure the relationship between FPD and oral responsiveness. PMID- 29490008 TI - A global network of biomedical relationships derived from text. AB - Motivation: The biomedical community's collective understanding of how chemicals, genes and phenotypes interact is distributed across the text of over 24 million research articles. These interactions offer insights into the mechanisms behind higher order biochemical phenomena, such as drug-drug interactions and variations in drug response across individuals. To assist their curation at scale, we must understand what relationship types are possible and map unstructured natural language descriptions onto these structured classes. We used NCBI's PubTator annotations to identify instances of chemical, gene and disease names in Medline abstracts and applied the Stanford dependency parser to find connecting dependency paths between pairs of entities in single sentences. We combined a published ensemble biclustering algorithm (EBC) with hierarchical clustering to group the dependency paths into semantically-related categories, which we annotated with labels, or 'themes' ('inhibition' and 'activation', for example). We evaluated our theme assignments against six human-curated databases: DrugBank, Reactome, SIDER, the Therapeutic Target Database, OMIM and PharmGKB. Results: Clustering revealed 10 broad themes for chemical-gene relationships, 7 for chemical-disease, 10 for gene-disease and 9 for gene-gene. In most cases, enriched themes corresponded directly to known database relationships. Our final dataset, represented as a network, contained 37 491 thematically-labeled chemical gene edges, 2 021 192 chemical-disease edges, 136 206 gene-disease edges and 41 418 gene-gene edges, each representing a single-sentence description of an interaction from somewhere in the literature. Availability and implementation: The complete network is available on Zenodo (https://zenodo.org/record/1035500). We have also provided the full set of dependency paths connecting biomedical entities in Medline abstracts, with associated sentences, for future use by the biomedical research community. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29490010 TI - SECLAF: a webserver and deep neural network design tool for hierarchical biological sequence classification. AB - Summary: Artificial intelligence tools are gaining more and more ground each year in bioinformatics. Learning algorithms can be taught for specific tasks by using the existing enormous biological databases, and the resulting models can be used for the high-quality classification of novel, un-categorized data in numerous areas, including biological sequence analysis. Here, we introduce SECLAF, a webserver that uses deep neural networks for hierarchical biological sequence classification. By applying SECLAF for residue-sequences, we have reported [Methods (2018), https://doi.org/10.1016/j.ymeth.2017.06.034] the most accurate multi-label protein classifier to date (UniProt-into 698 classes-AUC 99.99%; Gene Ontology-into 983 classes-AUC 99.45%). Our framework SECLAF can be applied for other sequence classification tasks, as we describe in the present contribution. Availability and implementation: The program SECLAF is implemented in Python, and is available for download, with example datasets at the website https://pitgroup.org/seclaf/. For Gene Ontology and UniProt based classifications a webserver is also available at the address above. PMID- 29490011 TI - Awake Surgery for a Violin Player: Monitoring Motor and Music Performance, A Case Report. AB - Objective: We report the case of a professional violin player who underwent an awake craniotomy to resect a tumor in the left supplementary motor area, an area involved in motor planning. Method: A careful pre- and intraoperative monitoring plan for music performance and complex motor function was established that could be used in combination with cortical stimulation. Results: The patient suffered an epileptic seizure during cortical stimulation. The monitoring of complex motor and musical functions was implemented with the patient playing the violin while the resection was performed. Almost complete resection was achieved with no notable postoperative deficits contributing to functional impairment. Conclusions: The multidisciplinary approach, involving neurosurgery, neuropsychology, anesthesiology, and clinical neurophysiology, allowed us to successfully cope with the theoretical and practical challenges associated with tailored care for a professional musician. The music and motor monitoring plan is reported in detail to enable other sites to reproduce and adapt it accordingly. PMID- 29490009 TI - Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1-TGF-beta OTX2-SNAIL via PTEN inhibition. AB - Genetic modifications during development of paediatric groups 3 and 4 medulloblastoma are responsible for their highly metastatic properties and poor patient survival rates. PRUNE1 is highly expressed in metastatic medulloblastoma group 3, which is characterized by TGF-beta signalling activation, c-MYC amplification, and OTX2 expression. We describe the process of activation of the PRUNE1 signalling pathway that includes its binding to NME1, TGF-beta activation, OTX2 upregulation, SNAIL (SNAI1) upregulation, and PTEN inhibition. The newly identified small molecule pyrimido-pyrimidine derivative AA7.1 enhances PRUNE1 degradation, inhibits this activation network, and augments PTEN expression. Both AA7.1 and a competitive permeable peptide that impairs PRUNE1/NME1 complex formation, impair tumour growth and metastatic dissemination in orthotopic xenograft models with a metastatic medulloblastoma group 3 cell line (D425-Med cells). Using whole exome sequencing technology in metastatic medulloblastoma primary tumour cells, we also define 23 common 'non-synonymous homozygous' deleterious gene variants as part of the protein molecular network of relevance for metastatic processes. This PRUNE1/TGF-beta/OTX2/PTEN axis, together with the medulloblastoma-driver mutations, is of relevance for future rational and targeted therapies for metastatic medulloblastoma group 3.10.1093/brain/awy039_video1awy039media15742053534001. PMID- 29490012 TI - Maintenance of Physical Function 1 Year After Exercise Intervention in At-Risk Older Adults: Follow-up From the LIFE Study. AB - Background: Structured physical activity interventions delay the onset of disability for at-risk older adults. However, it is not known if at-risk older adults continue to participate in physical activity or maintain mobility benefits after cessation of structured intervention. Methods: One thousand six hundred and thirty-five sedentary men and women aged 70-89 years with Short Physical Performance Battery (SPPB) scores of 9 or less and able to walk 400 m were randomized to a structured, moderate-intensity physical activity (PA) program consisting of center-based (twice/week) and home-based (three to four times per week) aerobic, resistance, and flexibility training or a health education (HE) program combined with upper extremity stretching. Results: Most of the participants (88% of HE and 87% of PA) returned for a follow-up visit (POST) 1 year after cessation of formal intervention. The HE group reported about 1-hour less activity per week than the PA group at end of intervention (LAST TRIAL; 68.9; 95% confidence interval [CI] = -86.5 to -51.3) but similar weekly activity at POST (-13.5; 95% CI = -29.5 to 2.47). SPPB did not differ between the two groups at LAST TRIAL (-0.06; 95% CI = -0.31 to 0.19) nor POST (-0.18; 95% CI = 0.45 to 0.088). Conclusions: Although sedentary at-risk older adults increased their physical activity during a structured physical activity intervention, they did not continue at this level following the cessation of intervention. Future exercise interventions need to include novel methods to support older adults in continued physical activity following structured interventions. PMID- 29490013 TI - The Temporal Dynamics of Brain Plasticity in Aging. AB - Cognitive training has been suggested as a possible remediation of decline in brain structure with older age. However, it is unknown whether training effects are transient or enduring, as no studies have examined training-induced plasticity relative to decline in older adults across extended periods with multiple intervention phases. We investigated the temporal dynamics of brain plasticity across periods on and off memory training, hypothesizing that (1) a decline in white matter (WM) microstructure would be observed across the duration of the study and (2) that periods of memory training would moderate the WM microstructural decline. In total, 107 older adults followed a 40-week program, including 2 training periods separated by periods with no intervention. The general decline in WM microstructure observed across the duration of the study was moderated following the training periods, demonstrating that cognitive training may mitigate age-related brain deterioration. The training-related improvements were estimated to subside over time, indicating that continuous training may be a premise for the enduring attenuation of neural decline. Memory improvements were largely maintained after the initial training period, and may thus not rely on continuous training to the same degree as WM microstructure. PMID- 29490014 TI - The Circadian Clock in White and Brown Adipose Tissue: Mechanistic, Endocrine, and Clinical Aspects. AB - Obesity is a major risk factor for the development of illnesses, such as insulin resistance and hypertension, and has become a serious public health problem. Mammals have developed a circadian clock located in the hypothalamic suprachiasmatic nuclei (SCN) that responds to the environmental light-dark cycle. Clocks similar to the one located in the SCN are found in peripheral tissues, such as the kidney, liver, and adipose tissue. The circadian clock regulates metabolism and energy homeostasis in peripheral tissues by mediating activity and/or expression of key metabolic enzymes and transport systems. Knockouts or mutations in clock genes that lead to disruption of cellular rhythmicity have provided evidence to the tight link between the circadian clock and metabolism. In addition, key proteins play a dual role in regulating the core clock mechanism, as well as adipose tissue metabolism, and link circadian rhythms with lipogenesis and lipolysis. Adipose tissues are distinguished as white, brown, and beige (or brite), each with unique metabolic characteristics. Recently, the role of the circadian clock in regulating the differentiation into the different adipose tissues has been investigated. In this review, the role of clock proteins and the downstream signaling pathways in white, brown, and brite adipose tissue function and differentiation will be reviewed. In addition, chronodisruption and metabolic disorders and clinical aspects of circadian adiposity will be addressed. PMID- 29490016 TI - Gap Junctions Interconnect Different Subtypes of Parvalbumin-Positive Interneurons in Barrels and Septa with Connectivity Unique to Each Subtype. AB - Parvalbumin (PV)-positive interneurons form dendritic gap junctions with one another, but the connectivity among gap junction-coupled dendrites remains uninvestigated in most neocortical areas. We visualized gap junctions in layer 4 of the mouse barrel cortex and examined their structural details. PV neurons were divided into 4 types based on the location of soma and dendrites within or outside barrels. Type 1 neurons that had soma and all dendrites inside a barrel, considered most specific to single vibrissa-derived signals, unexpectedly formed gap junctions only with other types but never with each other. Type 2 neurons inside a barrel elongated dendrites outward, forming gap junctions within a column that contained the home barrel. Type 3 neurons located outside barrels established connections with all types including Type 4 neurons that were confined inside the inter-barrel septa. The majority (33/38, 86.8%) of dendritic gap junctions were within 75 MUm from at least 1 of 2 paired somata. All types received vesicular glutamate transporter 2-positive axon terminals preferentially on somata and proximal dendrites, indicating the involvement of all types in thalamocortical feedforward regulation in which proximal gap junctions may also participate. These structural organizations provide a new morphological basis for regulatory mechanisms in barrel cortex. PMID- 29490015 TI - Isoform-level gene expression patterns in single-cell RNA-sequencing data. AB - Motivation: RNA sequencing of single cells enables characterization of transcriptional heterogeneity in seemingly homogeneous cell populations. Single cell sequencing has been applied in a wide range of researches fields. However, few studies have focus on characterization of isoform-level expression patterns at the single-cell level. In this study, we propose and apply a novel method, ISOform-Patterns (ISOP), based on mixture modeling, to characterize the expression patterns of isoform pairs from the same gene in single-cell isoform level expression data. Results: We define six principal patterns of isoform expression relationships and describe a method for differential-pattern analysis. We demonstrate ISOP through analysis of single-cell RNA-sequencing data from a breast cancer cell line, with replication in three independent datasets. We assigned the pattern types to each of 16 562 isoform-pairs from 4929 genes. Among those, 26% of the discovered patterns were significant (P<0.05), while remaining patterns are possibly effects of transcriptional bursting, drop-out and stochastic biological heterogeneity. Furthermore, 32% of genes discovered through differential-pattern analysis were not detected by differential-expression analysis. Finally, the effects of drop-out events and expression levels of isoforms on ISOP's performances were investigated through simulated datasets. To conclude, ISOP provides a novel approach for characterization of isoform-level preference, commitment and heterogeneity in single-cell RNA-sequencing data. Availability and implementation: The ISOP method has been implemented as a R package and is available at https://github.com/nghiavtr/ISOP under a GPL-3 license. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29490017 TI - Enhancing fatty acid utilization ameliorates mitochondrial fragmentation and cardiac dysfunction via rebalancing optic atrophy 1 processing in the failing heart. AB - Aims: Heart failure (HF) is characterized by reduced fatty acid (FA) utilization associated with mitochondrial dysfunction. Recent evidence has shown that enhancing FA utilization may provide cardioprotection against HF. Our aim was to investigate the effects and the underlying mechanisms of cardiac FA utilization on cardiac function in response to pressure overload. Methods and results: Transverse aortic constriction (TAC) was used in C57 mice to establish pressure overload-induced HF. TAC mice fed on a high fat diet (HFD) exhibited increased cardiac FA utilization and improved cardiac function and survival compared with those on control diet. Such cardioprotection could also be provided by cardiac specific overexpression of CD36. Notably, both HFD and CD36 overexpression attenuated mitochondrial fragmentation and improved mitochondrial function in the failing heart. Pressure overload decreased ATP-dependent metalloprotease (YME1L) expression and induced the proteolytic cleavage of the dynamin-like guanosine triphosphatase OPA1 as a result of suppressed FA utilization. Enhancing FA utilization upregulated YME1L expression and subsequently rebalanced OPA1 processing, resulting in restoration of mitochondrial morphology in the failing heart. In addition, cardiac-specific overexpression of YME1L exerted similar cardioprotective effects against HF to those provided by HFD or CD36 overexpression. Conclusions: These findings demonstrate that enhancing FA utilization ameliorates mitochondrial fragmentation and cardiac dysfunction via rebalancing OPA1 processing in pressure overload-induced HF, suggesting a unique metabolic intervention approach to improving cardiac functions in HF. PMID- 29490018 TI - Prediction of potential disease-associated microRNAs using structural perturbation method. AB - Motivation: The identification of disease-related microRNAs (miRNAs) is an essential but challenging task in bioinformatics research. Similarity-based link prediction methods are often used to predict potential associations between miRNAs and diseases. In these methods, all unobserved associations are ranked by their similarity scores. Higher score indicates higher probability of existence. However, most previous studies mainly focus on designing advanced methods to improve the prediction accuracy while neglect to investigate the link predictability of the networks that present the miRNAs and diseases associations. In this work, we construct a bilayer network by integrating the miRNA-disease network, the miRNA similarity network and the disease similarity network. We use structural consistency as an indicator to estimate the link predictability of the related networks. On the basis of the indicator, a derivative algorithm, called structural perturbation method (SPM), is applied to predict potential associations between miRNAs and diseases. Results: The link predictability of bilayer network is higher than that of miRNA-disease network, indicating that the prediction of potential miRNAs-diseases associations on bilayer network can achieve higher accuracy than based merely on the miRNA-disease network. A comparison between the SPM and other algorithms reveals the reliable performance of SPM which performed well in a 5-fold cross-validation. We test fifteen networks. The AUC values of SPM are higher than some well-known methods, indicating that SPM could serve as a useful computational method for improving the identification accuracy of miRNA-disease associations. Moreover, in a case study on breast neoplasm, 80% of the top-20 predicted miRNAs have been manually confirmed by previous experimental studies. Availability and implementation: https://github.com/lecea/SPM-code.git. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29490019 TI - It is time to apply biclustering: a comprehensive review of biclustering applications in biological and biomedical data. AB - Biclustering is a powerful data mining technique that allows clustering of rows and columns, simultaneously, in a matrix-format data set. It was first applied to gene expression data in 2000, aiming to identify co-expressed genes under a subset of all the conditions/samples. During the past 17 years, tens of biclustering algorithms and tools have been developed to enhance the ability to make sense out of large data sets generated in the wake of high-throughput omics technologies. These algorithms and tools have been applied to a wide variety of data types, including but not limited to, genomes, transcriptomes, exomes, epigenomes, phenomes and pharmacogenomes. However, there is still a considerable gap between biclustering methodology development and comprehensive data interpretation, mainly because of the lack of knowledge for the selection of appropriate biclustering tools and further supporting computational techniques in specific studies. Here, we first deliver a brief introduction to the existing biclustering algorithms and tools in public domain, and then systematically summarize the basic applications of biclustering for biological data and more advanced applications of biclustering for biomedical data. This review will assist researchers to effectively analyze their big data and generate valuable biological knowledge and novel insights with higher efficiency. PMID- 29490020 TI - Erratum to: Perioperative Corticosteroids Reduce Short-Term Edema and Ecchymosis in Rhinoplasty: A Meta-Analysis. PMID- 29490021 TI - ShinyKGode: an interactive application for ODE parameter inference using gradient matching. AB - Motivation: Mathematical modelling based on ordinary differential equations (ODEs) is widely used to describe the dynamics of biological systems, particularly in systems and pathway biology. Often the kinetic parameters of these ODE systems are unknown and have to be inferred from the data. Approximate parameter inference methods based on gradient matching (which do not require performing computationally expensive numerical integration of the ODEs) have been getting popular in recent years, but many implementations are difficult to run without expert knowledge. Here, we introduce ShinyKGode, an interactive web application to perform fast parameter inference on ODEs using gradient matching. Results: ShinyKGode can be used to infer ODE parameters on simulated and observed data using gradient matching. Users can easily load their own models in Systems Biology Markup Language format, and a set of pre-defined ODE benchmark models are provided in the application. Inferred parameters are visualized alongside diagnostic plots to assess convergence. Availability and implementation: The R package for ShinyKGode can be installed through the Comprehensive R Archive Network (CRAN). Installation instructions, as well as tutorial videos and source code are available at https://joewandy.github.io/shinyKGode. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29490022 TI - Optimal Schedule for Assessing Home BP Variability: The Finn-Home Study. AB - BACKGROUND: Current guidelines make no recommendations on the optimal timing or number of measurements for assessing home blood pressure variability (HBPV). Our aim was to elucidate the optimal schedule for measuring HBPV in relation to cardiovascular risk. METHODS: In total, 1,706 Finnish adults (56.5 +/- 8.5 years; 54% women) self-measured their home blood pressure (HBP) twice in the morning and evening during 7 consecutive days. The participants were followed up for cardiovascular events. We examined the association between HBPV (coefficient of variation based on 2 through 7 measurement days) and cardiovascular events using Cox regression models adjusted for HBP and other cardiovascular risk factors. RESULTS: During a follow-up of 11.8 +/- 3.1 years, 216 cardiovascular events occurred. Systolic morning HBPV based on three (hazard ratio [HR], 1.039; 95% confidence interval, 1.006-1.074, model c statistic 0.737) through seven (HR, 1.057; 95% confidence interval, 1.012-1.104, model c statistic 0.737) measurement days was significantly associated with cardiovascular events. Agreement in classification to normal vs. increased morning day-to-day HBPV between consecutive measurement days became substantial (kappa = 0.69 for systolic and kappa = 0.68 for diastolic) after the fourth measurement day. The associations of diastolic HBPV, evening HBPV, all-day HBPV, and variability based on first measurements of each measurement occasion, with cardiovascular outcomes were nonsignificant or remained significant only after the sixth measurement day. CONCLUSIONS: Our results suggest systolic HBP should be measured twice in the morning for at least 3 days when assessing HBPV. Increasing the number of measurement days from 3 to 7 results in marginal improvement in prognostic accuracy. PMID- 29490023 TI - Functional mitral stenosis after mitral valve repair for Type II dysfunction: determinants and impacts on long-term outcome. AB - OBJECTIVES: This study was performed to analyse the impacts of functional mitral stenosis (MS) following mitral valve (MV) repair on late cardiac function and new onset of atrial fibrillation or survival. METHODS: We retrospectively reviewed 602 patients with mitral regurgitation who underwent MV repair for Type II dysfunction from 2001. Functional MS was diagnosed when the mean transmitral pressure gradient (MTPG) was >=5 mmHg on postoperative echocardiography. We analysed preoperative and surgical risk factors for functional MS (MS group). We then compared long-term outcomes and late cardiac function over time between patients in the MS and no-MS groups using a mixed-effects model with repeated measures. RESULTS: On postoperative echocardiography, 51 patients had an MTPG of >=5 mmHg (MS group) and 551 had an MTPG of <5 mmHg (no-MS group). Only the ring size was an independent predictor of MS (28.8 +/- 2.1 mm in the no-MS group vs 28.0 +/- 1.9 mm in the MS group, P = 0.004). During follow-up, increases in the tricuspid regurgitation (TR) pressure gradient (PRV-RA) and TR severity over time were significantly greater in the MS group than in the no-MS group (PRV-RA: 0.72 +/- 0.16 vs 0.35 +/- 0.17 mmHg per year, respectively, P = 0.03; TR severity: 0.072 +/- 0.014 vs 0.034 +/- 0.015 per year, respectively, P = 0.0113). Moreover, the 10-year rate of new onset of atrial fibrillation was significantly lower in the MS group than in the no-MS group (37.5% vs 16.9%, respectively; log-rank P = 0.003). CONCLUSIONS: Annuloplasty using a small-sized ring in MV repair caused a postoperative high MTPG, which induced an elevation in the pulmonary artery pressure and residual TR grade and causing new onset of atrial fibrillation despite a competent MV. PMID- 29490025 TI - Distribution of Methadone and Metabolites in Skeletal Tissue. AB - In forensic toxicology, when extended time has elapsed before discovery of the body, the most commonly analyzed specimens are often degraded or not available at all due to decomposition. In this case, skeletal tissue may be the only specimen left. Nevertheless, very limited research is found on the drug disposition in bone, making toxicological interpretation very difficult. Since methadone is linked to almost 50% of drug abuse fatalities in Belgium, an easy extraction and quantification method was developed and validated to investigate the distribution pattern of methadone and its metabolites in skeletal tissue after chronic dosing. In this study, Wistar rats were administered a subcutaneous daily methadone dose of 3 mg/kg for 139 days. After dissection, single whole bones or bone parts underwent a methanolic extraction. The final extract was analyzed using LC-ESI(+) MS-MS for methadone, EDDP and EMDP. Methadone and its metabolites were proven to be detectable and quantifiable in skeletal tissue of chronically dosed rats using a fast and easy methanol extraction. Within bone, comparison showed that bone marrow yields the highest concentration. Trabecular bone also showed to be the best type of bone tissue for sampling. Between bone comparison, proved the humerus to be the best bone type for sampling. The concentrations found in tibiae and humeri appeared to be dose dependent for methadone with a variance of <9%. However, for other bones the variance in methadone concentration ranged from 24 to 32%. A possible explanation is seen in the lower vascularization of these bones. For the metabolites, no correlation was seen. This could be explained by the highly inter-individual metabolism of methadone. However, skeletal tissue concentration showed no correlation to blood for methadone nor its metabolites. Using the developed method, quantitative information about methadone after chronic administration was only found in the humeri and tibiae. PMID- 29490026 TI - Significant Patient Impact Observed Upon Implementation of Point-of-Care Early Infant Diagnosis Technologies in an Observational Study in Malawi. AB - Background: In Malawi in 2014, <20% of human immunodeficiency virus (HIV)-exposed infants received an early infant diagnosis (EID) test in the first 2 months of life and only 30% of HIV-infected children were on antiretroviral therapy (ART). We sought to understand the potential patient impact of improving timely infant diagnosis and treatment initiation through implementation of point-of-care (POC) EID technologies in Malawi. Methods: In this observational study, POC EID technologies were introduced into routine services at 7 health facilities across Malawi in September 2015. The primary outcome was the proportion of HIV-infected infants initiating ART within 60 days of sample collection in the POC arm compared to the baseline arm with conventional laboratory-based EID testing. Results: The time from sample collection to result received by the patient decreased significantly from 56 days (interquartile range [IQR], 30-81 days) in the baseline arm to <1 day in the POC arm (P < .001). Of the HIV-infected infants, the time between sample collection and ART initiation was reduced from 38 days (IQR, 30-54 days) in the baseline arm to <1 day (IQR, 0-1 day) in the POC arm (P = .019). Furthermore, the proportion of HIV-infected infants initiated on ART within 60 days of sample collection increased significantly from 41.9% to 91.1% after the introduction of POC (adjusted risk ratio, 2.28; P < .001). Conclusions: ART initiation rates were significantly improved with the implementation of same-day POC EID testing compared with referred, longer turnaround laboratory-based testing. PMID- 29490024 TI - Addition of Granulocyte/Monocyte Apheresis to Oral Prednisone for Steroid dependent Ulcerative Colitis: A Randomized Multicentre Clinical Trial. AB - Background and Aims: Steroid-dependency occurs in up to 30% of patients with ulcerative colitis [UC]. In this setting, few drugs have demonstrated efficacy in inducing steroid-free remission. The aim of this study was to evaluate the efficacy and safety of adding granulocyte/monocyte apheresis [GMA] to oral prednisone in patients with steroid-dependent UC. Methods: This was a randomized, multicentre, open trial comparing 7 weekly sessions of GMA plus oral prednisone [40 mg/day and tapering] with prednisone alone, in patients with active, steroid dependent UC [Mayo score 4-10 and inability to withdraw corticosteroids in 3 months or relapse within the first 3 months after discontinuation]. Patients were stratified by concomitant use of thiopurines at inclusion. A 9-week tapering schedule of prednisone was pre-established in both study groups. The primary endpoint was steroid-free remission [defined as a total Mayo score <=2, with no subscore >1] at Week 24, with no re-introduction of corticosteroids. Results: In all 123 patients were included [63 GMA group, 62 prednisone alone]. In the intention-to-treat analysis, steroid-free remission at Week 24 was achieved in 13% (95% confidence interval [CI] 6-24) in the GMA group and 7% [95% CI 2-16] in the control group [p = 0.11]. In the GMA group, time to relapse was significantly longer (hazard ratio [HR] 1.7 [1.16-2.48], P = 0.005) and steroid-related adverse events were significantly lower [6% vs 20%, P < 0.05]. Conclusions: In a randomized trial, the addition of 7 weekly sessions of GMA to a conventional course of oral prednisone did not increase the proportion of steroid-free remissions in patients with active steroid-dependent UC, though it delayed clinical relapse. PMID- 29490027 TI - Corrigendum to 'Sutureless prosthesis for failed small Mitroflow valves: the Perceval-after-Mitroflow procedure' [Interact CardioVasc Thorac Surg 2018; doi:10.1093/icvts/ivx434]. PMID- 29490028 TI - Chilocorus cacti (Coleoptera: Coccinellidae) as a Biological Control Agent of the Wild Cochineal (Hemiptera: Dactylopiidae) of Prickly Pear Cactus. AB - The wild cochineal (Dactylopius opuntiae Cockerell) (Hemiptera: Dactylopiidae) is considered to be the most important pest in cactus pear plantations. In Mexico, there are seven natural enemies that provide natural biological control of D. opuntiae. However, their role and impact have not been evaluated. In this article, we report on aspects of the population biology of Chilocorus cacti L. (Coleoptera: Coccinellidae), which is considered one of the main natural enemies of D. opuntiae. We also conducted experiments to evaluate the consumption of C. cacti by this predator when fed nymphs and adult females of D. opuntiae. Changes in the survival function of D. opuntiae in the presence or absence C. cacti were also identified. Both larvae and adults of C. cacti prefer to consume D. opuntiae nymphs because the wax produced by adult females presents a significant obstacle. The survival analysis showed that the presence of C. cacti had significant negative effects on D. opuntiae survival. C. cacti significantly increased its abundance while reducing the density of adult female D. opuntiae, but this impact occurred only after they had consumed the more preferred nymphs. For this reason, natural enemies other than C. cacti may be required to achieve adequate levels of biological control. PMID- 29490029 TI - "Tough Times Have Become Good Times": Resilience in Older Adults With a Low Socioeconomic Position. AB - Background and Objectives: This qualitative study applied a resilience perspective to socioeconomic inequalities in the functioning of older adults. We aimed to gain insight into how some older adults managed to age successfully despite having a low socioeconomic position (SEP) throughout their lives. Research Design and Methods: Semistructured interviews were conducted with 11 resilient adults over the age of 79 years participating in the Longitudinal Aging Study Amsterdam, the Netherlands. Participants were defined as resilient on the basis of having a low lifetime SEP and favorable trajectories of physical, mental, and social functioning. Grounded Theory coding techniques were applied to identify themes reflecting distinct ways in which participants dealt with what they indicated were the most significant adversities in their lives. The analysis focused on experiences linked to socioeconomic conditions. Results: Six themes reflecting psychological, behavioral, and social factors were derived from the data: drawing support from social contacts; investing in younger generations; taking actions to manage or improve socioeconomic conditions; putting the impact of a low SEP into perspective; persevering; and resigning oneself to adversity. Discussion and Implications: Findings suggest that successful aging despite a low SEP throughout one's lifetime requires considerable psychological and social resources. In addition, resignation and specific manifestations of generativity are identified as new elements of resilience. These findings may help to reduce the stereotyping of older adults with a low SEP, and nuance the heroic image of resilience as something that is primarily attributable to extraordinary individual abilities or efforts. PMID- 29490030 TI - Cytomegalovirus Shedding in Seropositive Pregnant Women From a High Seroprevalence Population: The Brazilian Cytomegalovirus Hearing and Maternal Secondary Infection Study. AB - Background: Most congenital cytomegalovirus (CMV) infections in highly seropositive populations occur in infants born to women with preexisting CMV seroimmunity. Although essential for developing prevention strategies, CMV shedding patterns in pregnant women with nonprimary infections have not been characterized. We investigated correlates of CMV shedding in a cohort of seropositive pregnant women. Methods: In a prospective study, saliva, urine, vaginal swabs, and blood were collected from 120 CMV-seropositive women in the first, second, and third trimesters and 1 month postpartum. Specimens were tested for CMV DNA by polymerase chain reaction. We analyzed the contribution of the specific maternal characteristics to viral shedding. Results: CMV shedding was detected at least once in 42 (35%) women. Mothers living with or providing daily care to young children (3-6 years) were twice as likely to shed CMV at least once compared to women with less exposure to young children (58% vs 26%; adjusted relative risk [aRR], 2.21; 95% confidence interval [CI], 1.37-3.56). Living in crowded households (>=2 people per room) was associated with viral shedding (64% vs 31%; aRR, 1.99; 95% CI, 1.26-3.13). Sexual activity as indicated by the number of sexual partners per year or condom use was not found to be a correlate of viral shedding. Conclusions: CMV shedding is relatively frequent in seropositive pregnant women. The association between virus shedding and caring for young children as well as crowded living conditions may provide opportunities for increased exposures that could lead to CMV reinfections in seropositive women. PMID- 29490032 TI - Heart Rate, Beta Blocker Use, and Outcomes of Heart Failure with Reduced Ejection Fraction. AB - Background: High resting heart rate (HR; >=70 beats/minute) is associated with worse clinical outcomes in heart failure with reduced ejection fraction (HFrEF). Aims: HR, guideline-directed medical therapy (GDMT) with BB, and cardiovascular (CV) outcomes were evaluated in a large integrated health network. Methods: Using electronic health records we examined patients with chronic HFrEF (EF <= 35%) in sinus rhythm with at least 1 year of follow-up and available serial HR and medication data between January 1, 2000 and December 31, 2014. Results: Among 6,071 patients followed for median of 1,330 days across 73,586 total visits, median HR remained stable over time with 61.2% of the follow up period with HR >= 70 beats/minute. At baseline, 27.9% of patients were on >= 50% GDMT target BB dose; 16.2% subjects at baseline and 19.4% at the end of follow up had HR >= 70 beats/minute despite receiving >=50% of target BB dose. In adjusted analyses, baseline HR was associated with all-cause mortality/HF hospitalization (hazard ratio 1.28 per 15 beats/minute HR increase; p < 0.001). In comparison, hazard ratio for BB dose was 0.97 (per 77.2 mg increase; p = 0.36). When evaluating patients based on HR and BB dose there was a significant difference in the cumulative hazard for all-cause mortality or HF hospitalization (p < 0.001). For HF hospitalization, hazard appeared to be more closely associated with HR rather than BB dose (p = 0.01). Conclusion: In a real-world analysis, high resting HR was common in HFrEF patients and associated with adverse outcomes. Opportunities exist to improve GDMT and achieve HR control. PMID- 29490031 TI - Metformin Use in PCOS Pregnancies Increases the Risk of Offspring Overweight at 4 Years of Age: Follow-Up of Two RCTs. AB - Context: Metformin is used in pregnancy in women with gestational diabetes mellitus, polycystic ovary syndrome (PCOS), and obesity. Metformin passes the placenta. Objective: To explore the effects of metformin use in PCOS pregnancies on offspring growth to 4 years of age. Design: Follow-up study of two randomized, double-blind, placebo-controlled trials. Setting: Secondary care centers. Eleven public hospitals in Norway. Participants: One hundred eighty-two children of mothers with PCOS who participated in two randomized controlled trials. Intervention: Metformin 1700 or 2000 mg/d or placebo from first trimester to delivery in the original studies. No intervention in the current study. Main Outcome Measures: Height, weight, body mass index (BMI), and overweight/obesity at 4 years of age and head circumference at 1 year of age, converted to z scores. Results: The difference in height z score means between the groups at 4 years of age was nonsignificant (0.07 [95% confidence interval (CI): -0.22 to 0.36]; P = 0.651). At 4 years of age, the metformin group had higher weight z score than the placebo group [difference in means: 0.38 (0.07 to 0.69); P = 0.017] and higher BMI z score [difference in means: 0.45 (0.11 to 0.78); P = 0.010]. There were more overweight/obese children in the metformin group [26 (32%)] than in the placebo group [14 (18%)] at 4 years of age [odds ratio: 2.17 (1.04 to 4.61); P = 0.038]. The difference in mean head circumference z score at 1 year of age was 0.27 (-0.04 to 0.58; P = 0.093). Conclusion: Metformin-exposed children had higher BMI and increased prevalence of overweight/obesity at 4 years of age. PMID- 29490033 TI - Natural History and Ecology of Soldier Beetles (Coleoptera: Cantharidae) in the Mexican Tropical Dry Forests. AB - Until today, most information about the natural history and ecology of soldier beetles came from temperate zones, mainly from Holarctic areas, while tropical regions have been poorly studied. The aim of this contribution is to compile and synthesize information concerning the natural history and ecology of Cantharidae (Coleoptera) from the Mexican tropical dry forest (TDF), to serve as a starting point for more in-depth study of the group in one of the Mexico's most endangered ecosystems. All compiled data on the family have been organized into the following topics: distributional patterns and habitat preferences, feeding behavior and host plants, and daily and seasonal activity cycles. For the first time, it was provided a list of host plants for TDF Cantharidae genera and species, and it was also observed a high ecological diversity in the phenology and behavior of TDF Cantharidae assemblages. Further research concerning cantharids and other TDF insects needs to have a more comprehensive and integrated approach toward understanding the patterns of distribution and diversity, and elucidating the role that cantharids play in ecosystems, especially in TDF, which is one of the most endangered ecosystem in the world. PMID- 29490035 TI - Samurai cannulation (direct true-lumen cannulation) for acute Stanford Type A aortic dissection. AB - OBJECTIVES: In this study, we investigated early outcomes of patients who underwent surgical aortic repair for acute Stanford Type A aortic dissection at the Kitasato University Hospital and compared the results of Samurai cannulation (direct true-lumen cannulation) with other cannulation options. METHODS: Inpatient and outpatient records were retrospectively reviewed. RESULTS: Among the 100 patients who were operated on for acute Type A aortic dissection between April 2011 and April 2017, sole Samurai cannulation was used in 61 patients (Group S) and other cannulation options were used in the remaining 39 patients (Group O). No significant difference was observed in preoperative demographics between the groups. True-lumen cannulation was successful in all Group S patients, whereas 3 cannulation-related complications were observed in Group O patients. In Group S, the 30-day and in-hospital mortality occurred in 3 (5%) and 4 (7%) patients, respectively, and in Group O, these occurred in 3 (8%), and 6 (15%) patients, respectively. Four patients in each group (7% and 10%) experienced disabling or fatal strokes. Early mortality or stroke rate between the groups were not significantly different. During follow-up, there was no statistically significant difference between the groups in terms of survival, freedom from aorta-related death or freedom from aortic events. CONCLUSIONS: Early outcomes of the initial series of surgery for Stanford Type A aortic dissection with Samurai cannulation was favourable with acceptable mortality and stroke rates without cannulation-related complications. Samurai cannulation represents an easy, safe and reasonable option for cardiopulmonary bypass in surgery for acute Stanford Type A aortic dissection. PMID- 29490036 TI - Cloning and characterization of the novel d-aspartyl endopeptidase, paenidase, from Paenibacillus sp. B38. AB - Paenidase is the first micro-organism-derived d-aspartyl endopeptidase that specifically recognizes an internal d-Asp residue to cleave [d-Asp]-X peptide bonds. Using peptide sequences obtained from the protein, we performed PCR with degenerate primers to amplify the paenidase I-encoding gene. Nucleotide sequencing revealed that mature paenidase I consist of 322 amino acid residues and that the protein is encoded as a pro-protein with a 197-amino-acid N-terminal extension compared to the mature protein. Paenidase I exhibits amino acid sequence similarity to several penicillin-binding proteins. In addition, paenidase I was classified into peptidase family S12 based on a MEROPS database search. Family S12 contains serine-type d-Ala-d-Ala carboxypeptidases that have three active site residues (Ser, Lys and Tyr) in the conserved motifs Ser-Xaa-Thr Lys and Tyr-Xaa-Asn. These motifs were conserved in the primary structure of paenidase I, and the role of these residues was confirmed by site-directed mutagenesis. PMID- 29490037 TI - Rainfall and Coconut Accession Explain the Composition and Abundance of the Community of Potential Auchenorrhyncha Phytoplasma Vectors in Brazil. AB - Coconut plantations are attacked by the lethal yellowing (LY), which is spreading rapidly with extremely destructive effects in several countries. The disease is caused by phytoplasmas that occur in the plant phloem and are transmitted by Haplaxius crudus (Van Duzee) (Auchenorrhyncha: Cixiidae). Owing to their phloem sap feeding habit, other planthopper species possibly act as vectors. Here, we aimed at assessing the seasonal variation in the Auchenorrhyncha community in six dwarf coconut accessions. Also, we assessed the relative contribution of biotic (coconut accession) and abiotic (rainfall, temperature) in explaining Auchenorrhyncha composition and abundance. The Auchenorrhyncha community was monthly evaluated for 1 yr using yellow sticky traps. Among the most abundant species, Oecleus sp., Balclutha sp., Deltocephalinae sp.2, Deltocephalinae sp.3, Cenchreini sp., Omolicna nigripennis Caldwell (Derbidae), and Cedusa sp. are potential phytoplasma vectors. The composition of the Auchenorrhyncha community differed between dwarf coconut accessions and periods, namely, in March and April (transition from dry to rainy season) and August (transition from rainy to dry season). In these months, Oecleus sp. was predominantly found in the accessions Cameroon Red Dwarf, Malayan Red Dwarf, and Brazilian Red Dwarf Gramame, while Cenchreini sp. and Bolbonota sp. were dominant in the accessions Brazilian Yellow Dwarf Gramame, Malayan Yellow Dwarf, and Brazilian Green Dwarf Jequi. We conclude that dwarf coconut host several Auchenorrhyncha species potential phytoplasma vectors. Furthermore, coconut accessions could be exploited in breeding programs aiming at prevention of LY. However, rainfall followed by accessions mostly explained the composition and abundance of the Auchenorrhyncha community. PMID- 29490034 TI - Cohort Profile: The Colon Cancer Family Registry Cohort (CCFRC). PMID- 29490038 TI - Genetic Pedigree Analysis of the Pilot Breeding Program for the Rediscovered Galapagos Giant Tortoise from Floreana Island. AB - An aim of many captive breeding programs is to increase population sizes for reintroduction and establishment of self-sustaining wild populations. Genetic analyses play a critical role in these programs: monitoring genetic variation, identifying the origin of individuals, and assigning parentage to track family sizes. Here, we use genetic pedigree analyses to examine 3 seasons of a pilot breeding program for the Floreana island Galapagos giant tortoise, C. niger, that had been declared extinct for ~150 years until individuals with mixed ancestry were recently discovered. We determined that 8 of 9 founding individuals were assigned parentage to at least 1 of 130 offspring produced, though there was considerable reproductive skew. In addition, we observed that genetic diversity of the progeny was lower than that of the founders. Despite the observed reproductive skew, we did not see evidence for assortative mating based on relatedness, but there was a trend toward reduced fitness when more related individuals bred. Finally, we found that the majority of progeny had ancestry assigned to the Floreana species (mean +/- SE = 0.51 +/- 0.02), though individual estimates varied. The success of these pilot seasons bodes well for a larger breeding program to help restore the previously extinct tortoise from Floreana island. Future efforts should continue to monitor for reproductive skew and assortative mating to maintain allelic diversity. We would also recommend forming smaller breeding groups and rotating individuals among them to prevent long-term reproductive skew among pairs. PMID- 29490040 TI - Reducing inappropriate prescribing of antibiotics in English primary care: evidence and outlook. AB - Antibiotics are indispensable for treating bacterial infections, but their effectiveness is threatened by the emergence and spread of antibacterial resistance. Antibiotics are unique among drugs since the more they are used, the less effective they become because bacterial resistance is likely to develop. In response to this threat, the UK government aims to reduce inappropriate antibiotic prescribing in humans by 50% by 2020. A team at Public Health England has found that at least 20% of antibiotic prescriptions in primary care in England were inappropriate, which, if correct, implies that antibiotic prescribing nationally needs to be reduced by 10% by 2020. These data are published in five articles in a Supplement to JAC entitled Appropriateness of antibiotic prescribing in English primary care. Inappropriate prescribing was found in every general practice included in the analyses so each one should attempt to reduce unnecessary prescriptions, not just high-prescribing practices. An ambition of 10% reduction in antibiotic prescriptions seems attainable when compared with the reduction targets of other European countries. The need for substantial improvements in data quality that are necessary to further safeguard this precious resource is also highlighted by the authors in this Supplement. PMID- 29490039 TI - Association of leisure-time physical activity with total and cause-specific mortality: a pooled analysis of nearly a half million adults in the Asia Cohort Consortium. AB - Background: Most previous studies evaluating the association between leisure-time physical activity (LTPA) and risk of death were conducted among generally healthy individuals of European ancestry. We investigated the association of LTPA with all-cause and cause-specific mortality among East Asian populations, including healthy individuals and those with existing chronic diseases, which has been less well characterized. Methods: We performed pooled analyses among 467 729 East Asian individuals recruited in nine prospective cohorts included in the Asia Cohort Consortium. Cox proportional hazards regressions were used to derive hazard ratios (HRs) and 95% confidence intervals (CIs) associated with LTPA after adjusting for age, sex, education and marital and smoking status. Results: During a mean follow-up period of 13.6 years, 65 858 deaths were identified. Compared with those who reported no or less than 1 h of LTPA per week, an inverse association was observed between the amount of LTPA and all-cause and cause specific mortality (P for trend < 0.001). The strength of the inverse association was stronger for death due to cardiovascular diseases and causes other than cancer deaths. An inverse association of LTPA with total mortality was observed among individuals with a severe and often life-threatening disease: cancer, stroke or coronary heart disease [hazard ratio (HR) = 0.81, 95% CI = 0.73-0.89 for high vs low LTPA) and those with other chronic diseases such as diabetes or hypertension (HR = 0.86, 95% CI = 0.80-0.93 for high vs low LTPA). No clear modifying effects by sex, body mass index or smoking status were identified. Conclusions: Regular participation in LTPA is associated with reduced mortality in middle-aged and elder Asians regardless pre-existing health conditions. PMID- 29490041 TI - Solution-Focused Wellness: A Randomized Controlled Trial of College Students. AB - Heightened stress levels and compromised well-being are common among college students. Current trends on college campuses include an increase in the number of students experiencing mental health issues and an increase in students seeking help, illustrating a need for evidence-based brief interventions that improve student wellness. This research study used a randomized controlled study design to examine the effects of a short-term (seven-week), solution-focused wellness intervention on perceived stress and wellness of college students. Repeated measures analysis of variance results demonstrated that the effect of group membership across time was significant for both perceived wellness and stress (p < .01). Effect sizes using partial eta2 statistics were large for both outcome variables. Findings indicate that a brief solution-focused wellness intervention can significantly improve perceptions of wellness and reduce stress among college students and is more effective than treatment as usual. Intervention replicability allows for dissemination across varied academic groups and locations, and potential generalization across populations. PMID- 29490042 TI - The Emerging Role of Social Work in Primary Health Care: A Survey of Social Workers in Ontario Family Health Teams. AB - Primary health care systems are increasingly integrating interprofessional team based approaches to care delivery. As members of these interprofessional primary health care teams, it is important for social workers to explore our experiences of integration into these newly emerging teams to help strengthen patient care. Despite the expansion of social work within primary health care settings, few studies have examined the integration of social work's role into this expanding area of the health care system. A survey was conducted with Canadian social work practitioners who were employed within Family Health Teams (FHTs), an interprofessional model of primary health care in Ontario emerging from a period of health care reform. One hundred and twenty-eight (N = 128) respondents completed the online survey. Key barriers to social work integration in FHTs included difficulties associated with a medical model environment, confusion about social work role, and organizational barriers. Facilitators for integration of social work in FHTs included adequate education and competencies, collaborative engagement, and organizational structures. PMID- 29490043 TI - Physical Activity and Inflammatory Bowel Disease. PMID- 29490044 TI - Apical-to-basolateral transepithelial transport of cow's milk caseins by intestinal Caco-2 cell monolayers: MS-based quantitation of cellularly degraded alpha- and beta-casein fragments. AB - Casein (CN) is the major milk protein to nourish infants but, in certain population, it causes cow's milk allergy, indicating the uptake of antigenic CN and their peptides through the intestinal epithelium. Using human intestinal Caco 2 cell monolayers, the apical-to-basal transepithelial transport of CN was investigated. Confocal microscopy using component-specific antibodies showed that alphas1-CN antigens became detectable as punctate signals at the apical-side cytoplasm and reached to the cytoplasm at a tight-junction level within a few hours. Such intracellular CN signals were more remarkable than those of the other antigens, beta-lactoglobulin and ovalbumin, colocalized in part with an early endosome marker protein (EEA1) and decreased in the presence of cytochalasin D or sodium azide and also at lowered temperature at 4 degrees C. Liquid chromatography coupled with mass spectroscopy analysis of the protein fraction in the basal-side medium identified the alphas1-CB fragment including the N-terminal region and the alphas2-CN fragment containing the central part of polypeptide at 100-1,000 fmol per well levels. Moreover, beta-CN C-terminal overlapping peptides were identified in the peptide fraction below 10 kDa of the basal medium. These results suggest that CNs are partially degraded by cellular proteases and/or peptidases and immunologically active CN fragments are transported to basal side of the cell monolayers. PMID- 29490045 TI - Biomarkers of preconception stress and the incidence of pregnancy loss. AB - STUDY QUESTION: Are biomarkers of preconception stress associated with pregnancy loss? SUMMARY ANSWER: Preconception stress, as measured by basal salivary cortisol and alpha-amylase concentrations, is not associated with pregnancy loss. WHAT IS KNOWN ALREADY: Many studies, most of which have been retrospective, have identified an association between stressful life events and perceived stress and miscarriage. STUDY DESIGN, SIZE, DURATION: A prospective pregnancy study with preconception enrollment was conducted between 2005 and 2009. Among the 344 women who became pregnant during the Longitudinal Investigation of Fertility and the Environment (LIFE) study, 337 (98%) had salivary biomarker data for analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Couples planning pregnancy were followed for up to 12 months as they tried to become pregnant and through pregnancy if it occurred. Participating women collected a basal saliva sample on the morning following enrollment and a second on the morning following their next menses to measure cortisol and alpha-amylase, biomarkers of stress. Women used home pregnancy tests on the day of expected menses. A pregnancy loss was defined as a negative pregnancy test following a positive pregnancy test, the onset of menses, or for pregnancies that survived to clinical recognition, recognition of the loss by a healthcare provider. MAIN RESULTS AND THE ROLE OF CHANCE: Among the 337 couples, the median age of female and male partners was 29 and 31 years, respectively. Most of the women were non-Hispanic white (83%) and highly educated. There were 97 pregnancy losses reported among the 337 pregnancies. The median gestational age at loss was 6 weeks 5 days with only two losses occurring in the second trimester. Using Cox proportional hazards models, we found no clear pattern of association between two preconceptional biomarkers of stress (salivary cortisol and alpha-amylase concentrations) modeled both continuously or in tertiles and incident pregnancy loss after adjustment for confounders. LIMITATIONS REASONS FOR CAUTION: Our prior work suggests that women enrolled in the LIFE Study had lower stress levels than women in the general population. Owing to concerns regarding participant burden, we were unable to collect serial saliva measurements, which would have allowed us to examine the association between stress in early pregnancy and pregnancy loss. Further, with regard to the measurement of perceived stress, the Cohen's Perceived Stress Scale was only administered at baseline. While every attempt was made to ensure diversity in the cohort, non-Hispanic white women were over-represented, therefore it is possible that the results might not be generalizable to all women. WIDER IMPLICATIONS OF THE FINDINGS: In one of the largest studies in the USA to prospectively capture data on the incidence of early pregnancy loss, we found no clear association between two biomarkers of preconception stress (measured in saliva) and pregnancy loss. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts #N01-HD-3-3355, N01-HD-3-3356, N01 HD-3358). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 29490047 TI - Reoperation 7 years after sternal reconstruction with a porcine acellular dermal matrix. AB - The number of chest wall reconstructions with a biologic mesh is increasing, but its long-term durability is unproven. A 73-year-old man underwent a complex sternal reconstruction 7 years ago with porcine acellular dermal matrix after postoperative repair of his ruptured right ventricle after coronary artery bypass grafting. He recently presented with unstable angina. Cardiac catheterization showed occluded saphenous vein grafts, and the patient required repeat coronary artery bypass grafting. Upon re-entry into the chest, the mesh was completely incorporated into the surrounding tissues and maintained long-term durability. PMID- 29490048 TI - Alfalfa and Pastures: Sources of Pests or Generalist Natural Enemies? AB - Pierce's disease of grapevine and almond leaf scorch disease are both caused by the bacterial pathogen Xylella fastidiosa Wells et al. In the Central Valley of California, Draeculacephala minerva Ball (Hemiptera: Cicadellidae) is the most common vector of X. fastidiosa. As alfalfa fields and pastures are considered source habitats for D. minerva, it is recommended that almond orchards and vineyards should be distanced from alfalfa and pastures. Here, risk of alfalfa and pastures serving as sources of D. minerva was compared to the potential benefit of alfalfa and pastures serving as sources of generalist natural enemies belonging to the families Chrysopidae and Coccinellidae. Populations of D. minerva were greatest in pastures, whereas chrysopids were least abundant in pastures, and coccinellids were only moderately more abundant in pastures than in vineyards or almond orchards. Accordingly, risk of pastures serving as a source of D. minerva was not offset by any potential benefit of pastures serving as a source of chrysopids or coccinellids. Abundance of D. minerva in alfalfa was low, whereas abundance of chrysopids and coccinellids in alfalfa was high. Thus, well maintained alfalfa fields were a minor source of D. minerva that may contribute chrysopids and coccinellids to surrounding habitats. Spissistilus festinus (Say) (Hemiptera: Membracidae), a recently identified vector of grapevine red blotch virus, was abundant in alfalfa fields and was observed in vineyards. Thus, a full evaluation of the risk of planting vineyards near alfalfa may require considering risk associated with movement of S. festinus. PMID- 29490046 TI - High admission prevalence of fluoroquinolone resistance in third-generation cephalosporin-resistant Enterobacteriaceae in German university hospitals. AB - Objectives: Fluoroquinolone resistance (FQR) in third-generation cephalosporin resistant Enterobacteriaceae (3GCRE) presents serious limitations to antibiotic therapy. The aim of this study was to investigate whether the FQR proportion among 3GCRE differs between community-acquired (CA) and hospital-acquired (HA) isolates. Methods: In a prospective observational study covering 2014 and 2015, we monitored the occurrence of 3GCRE in adult hospitalized patients in six German university hospitals. 3GCRE clinical isolates were subdivided into CA and HA. Multivariable analysis identified factors associated with in vitro non susceptibility to ciprofloxacin. Results: The dataset included 5721 3GCRE isolates of which 52.9% were HA and 52.7% exhibited FQR. Interestingly, the FQR proportion was higher in CA 3GCRE than in HA 3GCRE (overall, 60.1% versus 46.2%, respectively, P < 0.001). Multivariable analysis adjusting for age confirmed community acquisition as a risk factor for FQR [adjusted rate ratio (aRR) 1.33, 95% CI 1.17-1.53]. Escherichia coli and Klebsiella spp. were associated with a much higher FQR proportion than other Enterobacteriaceae species (aRR 8.14, 95% CI 6.86-9.65 and aRR 7.62 with 95% CI 6.74-8.61, respectively). Conclusions: The high FQR proportion observed among CA 3GCRE, particularly in E. coli and Klebsiella spp., indicates that selection pressure in the outpatient setting needs to be addressed with antibiotic stewardship and other interventions in order to limit further spread of MDR. PMID- 29490049 TI - Prognostic factors for post-recurrence survival in patients with completely resected Stage III (N2) non-small-cell lung cancer. AB - OBJECTIVES: The aim of this study was to investigate the prognostic factors for post-recurrence survival (PRS) in patients with completely resected Stage III (N2) non-small-cell lung cancer. METHODS: A number of clinicopathological factors were evaluated to identify the prognostic factors for recurrence-free survival using Cox proportional hazards models in 245 patients who underwent complete resection of pathological Stage III (N2) non-small-cell lung cancer. Additional post-recurrence data were evaluated, including the presence of symptoms of recurrence, the recurrence pattern, the treatment modality and the recurrence free interval (RFI). The prognostic effects of clinicopathological factors before recurrence and the additional post-recurrence data on PRS were analysed. RESULTS: A total of 124 patients experienced recurrence during a median follow-up period of 39.8 months. Twenty-one patients were symptomatic at the time of initial recurrence, and the mean RFI was 14.0 months. Loco-regional recurrence was observed in 38 (31%) patients, distant metastasis in 33 (27%) patients and both in 53 (42%) patients. The initial treatment modality was surgery in 17 (14%) patients, chemotherapy in 66 (53%) patients, radiotherapy in 17 (14%) patients and chemoradiotherapy in 18 (15%) patients. The median duration of PRS was 30.5 months (range 1-109 months), and the 1-, 3- and 5-year PRS rates were 72%, 43% and 23%, respectively. A shorter RFI and radiotherapy for the treatment of recurrence were found to be independent prognostic factors for PRS in the multivariable analysis. CONCLUSIONS: The prognostic factors for recurrence-free survival were not associated with PRS, and a shorter RFI and radiotherapy for the treatment of recurrence were found to be negative prognostic factors for PRS. PMID- 29490050 TI - Psychometric Evaluation of the PROMIS(r) Pediatric Psychological and Physical Stress Experiences Measures. AB - Objective: To provide psychometric evaluation of the PROMIS(r) Pediatric Psychological and Physical Stress Experiences measures. Methods: Across two studies, Psychological and Physical Stress Experiences items were administered to 2,875 children aged 8-17 years and 2,212 parents of children aged 5-17 years. Analyses included descriptive statistics, reliability, factor analysis, differential item functioning (DIF), and assessment of construct validity. Items were calibrated using item response theory to estimate item parameters representative of the United States. Recommended eight- and four-item short forms were constructed for child- and parent-report versions of the Psychological and Physical Stress Experiences item banks. Results: Final item banks were unidimensional and items were locally independent and free from impactful DIF. Psychological Stress banks include 19 child-report and 12 parent-proxy items. Physical Stress banks include 26 child-report and 26 parent-proxy items. All instruments have strong internal consistency and retest-reliability, and provide precise estimates of varying stress levels. The instruments' construct validity was evidenced by known-group comparisons and convergence with legacy measures. Conclusions: The Patient Reported Outcome Measurement Information System (PROMIS) Pediatric Psychological and Physical Stress item banks and short forms provide efficient, precise, and valid assessments of children's stress experiences. PMID- 29490051 TI - Contralateral Supracerebellar-Infratentorial Approach for Resection of Thalamic Cavernous Malformations. AB - BACKGROUND: Surgical resection of cavernous malformations (CM) in the posterior thalamus, pineal region, and midbrain tectum is technically challenging owing to the presence of adjacent eloquent cortex and critical neurovascular structures. Various supracerebellar infratentorial (SCIT) approaches have been used in the surgical armamentarium targeting lesions in this region, including the median, paramedian, and extreme lateral variants. Surgical view of a posterior thalamic CM from the traditional ipsilateral vantage point may be obscured by occipital lobe and tentorium. OBJECTIVE: To describe a novel surgical approach via a contralateral SCIT (cSCIT) trajectory for resecting posterior thalamic CMs. METHODS: From 1997 to 2017, 75 patients underwent the SCIT approach for cerebrovascular/oncologic pathology by the senior author. Of these, 30 patients underwent the SCIT approach for CM resection, and 3 patients underwent the cSCIT approach. Historical patient data, radiographic features, surgical technique, and postoperative neurological outcomes were evaluated in each patient. RESULTS: All 3 patients presented with symptomatic CMs within the right posterior thalamus with radiographic evidence of hemorrhage. All surgeries were performed in the sitting position. There were no intraoperative complications. Neuroimaging demonstrated complete CM resection in all cases. There were no new or worsening neurological deficits or evidence of rebleeding/recurrence noted postoperatively. CONCLUSION: This study establishes the surgical feasibility of a contralateral SCIT approach in resection of symptomatic thalamic CMs It demonstrates the application for this procedure in extending the surgical trajectory superiorly and laterally and maximizing safe resectability of these deep CMs with gravity assisted brain retraction. PMID- 29490052 TI - Transcatheter aortic valve implantation and off-pump coronary artery bypass surgery: an effective hybrid procedure in selected patients. AB - OBJECTIVES: Simultaneous surgical off-pump coronary revascularization and transcatheter aortic valve implantation (TAVI) as a hybrid procedure may be a therapeutic option for patients with a TAVI indication who are not suitable for percutaneous coronary intervention and for patients who have an indication for combined surgical aortic valve implantation and coronary artery bypass grafting but present with a porcelain aorta. Early outcomes of these patients are analysed in this study. METHODS: From February 2011 to April 2017, hybrid TAVI/off-pump coronary artery bypass (OPCAB) was performed in 12 (60%) patients, hybrid TAVI/minimally invasive direct coronary artery bypass in 6 (30%) patients and staged TAVI/OPCAB in 2 (10%) patients. Endpoints of this study were 30-day mortality, device success and postoperative adverse events as defined by the updated Valve Academic Research Consortium (VARC-2). RESULTS: The median age at the time of surgery was 77 years [interquartile range (IQR), 70-81] with a median logistic EuroSCORE and Society of Thoracic Surgeons' Predicted Risk score of 16.1% (IQR, 9.3-28.1) and 3.9% (IQR, 2.2-5.6), respectively. The median Synergy between PCI with Taxus and Cardiac Surgery score was 16.5 (IQR, 9.8-22.8). TAVI implantation routes were transaortic in 9 (45%) patients, transapical and transfemoral in 5 (25%) patients each and trans-subclavian in 1 (5%) patient. Complete myocardial revascularization was achieved in 75% of patients. Device success rate was 100%. Paravalvular aortic regurgitation did not exceed mild in any patient. Stroke/transient ischaemic attack, vascular complications and myocardial infarction were not observed. Re-exploration for bleeding was required in 1 (5%) patient. Thirty-day mortality was 0%. CONCLUSIONS: Hybrid OPCAB/MIDCAB and TAVI prove to be a safe and effective alternative treatment option in selected higher risk patients. PMID- 29490053 TI - Learning Influences Host Versus Nonhost Discrimination and Postalighting Searching Behavior in the Tephritid Fruit Fly Parasitoid Diachasmimorpha kraussii (Hymenoptera: Braconidae). AB - Compared with the extensive body of research on the olfactory behavior of parasitoids of leaf-feeding insects, less is known about the fine-tuning of olfactory behavior in parasitoids that use fruit-feeding insects as hosts. We investigated whether a tephritid fruit fly parasitoid, Diachasmimorpha kraussii (Fullaway) (Hymenoptera: Braconidae), could discriminate between odors of fruits infested by larvae of a host species, Bactrocera tryoni (Froggatt) (Diptera: Tephritidae), compared to fruits infested by non-host larvae, Drosophila melanogaster (Diptera: Drosophilidae). Female wasps showed a significant preference for nectarines infested with B. tryoni, over uninfested fruits or fruits infested with D. melanogaster. When wasps were given prior experience of host or nonhost infested fruit, females demonstrated an increased ability to discriminate between host and nonhost related odors, but only when they were conditioned on host-infested (as opposed to nonhost infested) fruit. Insects provided with both host and nonhost stimuli showed no greater discriminatory learning compared to those provided with the rewarding stimuli alone. Previous experience also influenced postalighting behavior. Naive females, and females with experience ovipositing at the top of fruit, oriented preferentially to the top of fruits upon alighting, while those with experience ovipositing at the base of fruits showed a significant difference in orientation, with 70% of wasps orientating preferentially toward the base. Similar learning-related changes were seen in search time and probing behavior. We discuss how pre- and post-alighting learning fine-tunes the behavioral responses of foraging wasps to their local environment. PMID- 29490054 TI - Acaricide-Mediated Competition Between the Sibling Species Tetranychus cinnabarinus and Tetranychus urticae. AB - The carmine spider mite (Tetranychus cinnabarinus [Acarifonnes: Tetranychidae]) and the two-spotted spider mite (Tetranychus urticae [Acarifonnes: Tetranychidae]) are two notorious pests of agricultural crops. Control of these pests has been dependent upon using different kinds of acaricides. The purpose of this study was to determine the differential responses of these two pest species collected from crops in the same field to acaricide treatments. Field trials have shown that without spraying acaricides, T. cinnabarinus will displace T. urticae. However, the application of abamectin has the potential to change the composition of spider mite complexes and facilitate the interspecific competition of T. urticae against T. cinnabarinus when both are fed on cowpeas and eggplants. Moreover, T. urticae is more prone to develop resistance than T. cinnabarinus when selected in the laboratory using cyflumetofen or fenpropathrin. After 20 generations of acaricide selection, the activities of detoxifying enzymes were considerably higher in T. urticae with more detoxifying enzymes upregulated after selection in this species. The results of this study demonstrate that differential responses to acaricide treatments have made it possible for T. urticae to overcome the competitive advantage present in T. cinnabarinus during the absence of acaricide application. PMID- 29490056 TI - Age-Stage, Two-Sex Life Tables of the Lady Beetle (Coleoptera: Coccinellidae) Feeding on Different Aphid Species. AB - Life table and predation data were collected for Coccinella septempunctata (Linnaeus) (Coleoptera: Coccinellidae) feeding on three different host aphid species, Aphis craccivora (Koch) (Hemiptera: Aphididae), Lipaphis erysimi (Kaltenbach) (Hemiptera: Aphididae), and Myzus persicae (Sulzer) (Hemiptera: Aphididae), under laboratory conditions, using age-stage, two-sex life table. The preadult developmental period of C. septempunctata was the shortest on M. persicae (21.12 d) and the longest on A. craccivora (28.81 d). Net reproductive rate (R0) ranged from 77.31 offspring per individual on A. craccivora to 165.97 offspring per individual on M. persicae. Mean generation time (T) ranged from 39.10 d on M. persicae to 51.96 d on L. erysimi. Values of the intrinsic rate of increase (r) decreased in the order M. persicae, A. craccivora, and L. erysimi (0.1302, 0.0864 and 0.0848 d-1, respectively). The highest finite rate of increase (lambda) was observed on M. persicae (1.1391 d-1) and the lowest was observed on A. craccivora and L. erysimi (1.0903 and 1.0885 d-1, respectively). This information will be useful in relation to the mass rearing of C. septempunctata in biological control systems. PMID- 29490055 TI - ATF7 mediates TNF-alpha-induced telomere shortening. AB - Telomeres maintain the integrity of chromosome ends and telomere length is an important marker of aging. The epidemiological studies suggested that many types of stress including psychosocial stress decrease telomere length. However, it remains unknown how various stresses induce telomere shortening. Here, we report that the stress-responsive transcription factor ATF7 mediates TNF-alpha-induced telomere shortening. ATF7 and telomerase, an enzyme that elongates telomeres, are localized on telomeres via interactions with the Ku complex. In response to TNF alpha, which is induced by various stresses including psychological stress, ATF7 was phosphorylated by p38, leading to the release of ATF7 and telomerase from telomeres. Thus, a decrease of ATF7 and telomerase on telomeres in response to stress causes telomere shortening, as observed in ATF7-deficient mice. These findings give credence to the idea that various types of stress might shorten telomere. PMID- 29490057 TI - Breast Cancer Risk Model Requirements for Counseling, Prevention, and Screening. AB - Background: Incorporation of polygenic risk scores and mammographic density into models to predict breast cancer incidence can increase discriminatory accuracy (area under the receiver operating characteristic curve [AUC]) from 0.6 for models based only on epidemiologic factors to 0.7. It is timely to assess what impact these improvements will have on individual counseling and on public health prevention and screening strategies, and to determine what further improvements are needed. Methods: We studied various clinical and public health applications using a log-normal distribution of risk. Results: Provided they are well calibrated, even risk models with AUCs of 0.6 to 0.7 provide useful perspective for individual counseling and for weighing the harms and benefits of preventive interventions in the clinic. At the population level, they are helpful for designing preventive intervention trials, for assessing reductions in absolute risk from reducing exposure to modifiable risk factors, and for resource allocation (although a higher AUC would be desirable for risk-based allocation). Other public health applications require higher AUCs that can only be achieved with risk predictors 1.6 to 8.8 times as strong as all those yet discovered combined. Such applications are preventing an appreciable proportion of population disease when employing a high-risk prevention strategy and deciding who should be screened for subclinical disease. Conclusions: Current and foreseeable risk models are useful for counseling and some prevention activities, but given the daunting challenge of achieving, for example, an AUC of 0.8, considerable effort should be put into finding effective preventive interventions and screening strategies with fewer adverse effects. PMID- 29490058 TI - Potential for reducing inappropriate antibiotic prescribing in English primary care. AB - Objectives: To identify and quantify inappropriate systemic antibiotic prescribing in primary care in England, and ultimately to determine the potential for reduction in prescribing of antibiotics. Methods: Primary care data from 2013 15 recorded in The Health Improvement Network (THIN) database were used. Potentially inappropriate prescribing events in the database were identified by: (i) comparing prescribing events against treatment guidelines; (ii) comparing actual proportions of consultations resulting in prescription for a set of conditions with the ideal proportions derived from expert opinion; and (iii) identifying high prescribers and their number of prescriptions above an age- and body-system-specific benchmark. Results: Applying the most conservative assumptions, 8.8% of all systemic antibiotic prescriptions in English primary care were identified as inappropriate, and in the least conservative scenario 23.1% of prescriptions were inappropriate. All practices had non-zero reduction potentials, ranging from 6.4% to 43.5% in the middle scenario. The four conditions that contributed most to inappropriate prescribing were sore throat (23.0% of identified inappropriate prescriptions), cough (22.2%), sinusitis (7.6%) and acute otitis media (5.7%). One-third of all antibiotic prescriptions lacked an informative diagnostic code. Conclusions: This work demonstrates (i) the existence of substantial inappropriate antibiotic prescribing and (ii) poor diagnostic coding in English primary care. All practices (not just the high prescribers) should engage in efforts to improve antimicrobial stewardship. Better diagnostic coding, more precise prescribing guidelines and a deeper understanding of appropriate long-term uses of antibiotics would allow identification of further potential for reductions. PMID- 29490059 TI - Explaining variation in antibiotic prescribing between general practices in the UK. AB - Objectives: Primary care practices in England differ in antibiotic prescribing rates, and, anecdotally, prescribers justify high prescribing rates based on their individual case mix. The aim of this paper was to explore to what extent factors such as patient comorbidities explain this variation in antibiotic prescribing. Methods: Primary care consultation and prescribing data recorded in The Health Improvement Network (THIN) database in 2013 were used. Boosted regression trees (BRTs) and negative binomial regression (NBR) models were used to evaluate associations between predictors and antibiotic prescribing rates. The following variables were considered as potential predictors: various infection related consultation rates, proportions of patients with comorbidities, proportion of patients with inhaled/systemic corticosteroids or immunosuppressive drugs, and demographic traits. Results: The median antibiotic prescribing rate was 65.6 (IQR 57.4-74.0) per 100 registered patients among 348 English practices. In the BRT model, consultation rates had the largest total relative influence on antibiotic prescribing rate (53.5%), followed by steroid and immunosuppressive drugs (31.6%) and comorbidities (12.2%). Only 21% of the deviance could be explained by an NBR model considering only comorbidities and age and gender, whereas 57% of the deviance could be explained by the model considering all variables. Conclusions: The majority of practice-level variation in antibiotic prescribing cannot be explained by variation in prevalence of comorbidities. Factors such as high consultation rates for respiratory tract infections and high prescribing rates for corticosteroids could explain much of the variation, and as such may be considered in determining a practice's potential to reduce prescribing. PMID- 29490060 TI - Actual versus 'ideal' antibiotic prescribing for common conditions in English primary care. AB - Objectives: Previous work based on guidelines and expert opinion identified 'ideal' prescribing proportions-the overall proportion of consultations that should result in an antibiotic prescription-for common infectious conditions. Here, actual condition-specific prescribing proportions in primary care in England were compared with ideal prescribing proportions identified by experts. Methods: All recorded consultations for common infectious conditions (cough, bronchitis, exacerbations of asthma or chronic obstructive pulmonary disease, sore throat, rhinosinusitis, otitis media, lower respiratory tract infection, upper respiratory tract infection, influenza-like illness, urinary tract infection, impetigo, acne, gastroenteritis) for 2013-15 were extracted from The Health Improvement Network (THIN) database. The proportions of consultations resulting in an antibiotic prescription were established, concentrating on acute presentations in patients without relevant comorbidities. These actual prescribing proportions were then compared with previously established 'ideal' proportions by condition. Results: For most conditions, substantially higher proportions of consultations resulted in an antibiotic prescription than was deemed appropriate according to expert opinion. An antibiotic was prescribed in 41% of all acute cough consultations when experts advocated 10%. For other conditions the proportions were: bronchitis (actual 82% versus ideal 13%); sore throat (actual 59% versus ideal 13%); rhinosinusitis (actual 88% versus ideal 11%); and acute otitis media in 2- to 18-year-olds (actual 92% versus ideal 17%). Substantial variation between practices was found. Conclusions: This work has identified substantial overprescribing of antibiotics in English primary care, and highlights conditions where this is most pronounced, particularly in respiratory tract conditions. PMID- 29490062 TI - Antibiotics in primary care in England: which antibiotics are prescribed and for which conditions? AB - Objectives: To analyse antibiotic prescribing behaviour in English primary care with particular regard to which antibiotics are prescribed and for which conditions. Methods: Primary care data from 2013-15 recorded in The Health Improvement Network (THIN) database were analysed. Records with a prescription for systemic antibiotics were extracted and linked to co-occurring diagnostic codes, which were used to attribute prescriptions to clinical conditions. We further assessed which antibiotic classes were prescribed and which conditions resulted in the greatest share of prescribing. Results: The prescribing rate varied considerably among participating practices, with a median of 626 prescriptions/1000 patients (IQR 543-699). In total, 69% of antibiotic prescriptions (n = 3 156 507) could be linked to a body system and/or clinical condition. Of these prescriptions, 46% were linked to conditions of the respiratory tract, including ear, nose and throat (RT/ENT); leading conditions within this group were cough symptoms (22.7%), lower respiratory tract infection (RTI) (17.9%), sore throat (16.7%) and upper RTI (14.5%). After RT/ENT infections, infections of the urogenital tract (22.7% of prescriptions linked to a condition) and skin/wounds (16.4%) accounted for the greatest share of prescribing. Penicillins accounted for 50% of all prescriptions, followed by macrolides (13%), tetracyclines (12%) and trimethoprim (11%). Conclusions: The majority of antibiotic prescriptions in English primary care were for infections of the respiratory and urinary tracts. However, in almost one-third of all prescriptions no clinical justification was documented. Antibiotic prescribing rates varied substantially between practices, suggesting that there is potential to reduce prescribing in at least some practices. PMID- 29490061 TI - Defining the appropriateness and inappropriateness of antibiotic prescribing in primary care. AB - Objectives: To assess the appropriateness of prescribing systemic antibiotics for different clinical conditions in primary care, and to quantify 'ideal' antibiotic prescribing proportions in conditions for which antibiotic treatment is sometimes but not always indicated. Methods: Prescribing guidelines were consulted to define the appropriateness of antibiotic therapy for the conditions that resulted in antibiotic prescriptions between 2013 and 2015 in The Health Improvement Network (THIN) primary care database. The opinions of subject experts were then formally elicited to quantify ideal antibiotic prescribing proportions for 10 common conditions. Results: Of the antibiotic prescriptions in THIN, 52.5% were for conditions that could be assessed using prescribing guidelines. Among these, the vast majority of prescriptions (91.4%) were for conditions where antibiotic appropriateness is conditional on patient-specific indicators. Experts estimated low ideal prescribing proportions in acute, non-comorbid presentations of many of these conditions, such as cough (10% of patients), rhinosinusitis (11%), bronchitis (13%) and sore throat (13%). Conversely, antibiotics were believed to be appropriate in 75% of non-pregnant women with non-recurrent urinary tract infection. In impetigo and acute exacerbation of chronic obstructive pulmonary disease, experts clustered into distinct groups that believed in either high or low prescribing. Conclusions: In English primary care, most antibiotics are prescribed for conditions that only sometimes require antibiotic treatment, depending on patient-specific indicators. Experts estimated low ideal prescribing proportions in many of these conditions. Incomplete prescribing guidelines and disagreement about prescribing in some conditions highlight further research needs. PMID- 29490063 TI - Mimicking physiological O2 tension in the female reproductive tract improves assisted reproduction outcomes in pig. AB - STUDY QUESTION: Is O2 tension in the pig oviduct and uterus affected by the estrous cycle stage and the animal's age, and can the outcome of in vitro embryo development be improved by mimicking these physiological values? SUMMARY ANSWER: O2 tension within the pig reproductive organs is affected by the animal's age, and values close to those measured in vivo have a positive impact on embryo development and quality when used during IVF and embryo culture (EC). WHAT IS KNOWN ALREADY: To obtain a healthy embryo in vitro, it is necessary to adopt a culture microenvironment that approximates physiological conditions. Despite advances in surgical procedures and sensitive probes that allow accurate assessment of in vivo O2 tension, few such studies have been conducted recently in mammals. In addition, no reference values of physiological O2 tension in the reproductive tract exist for large animal models such as pig, and the effect of O2 tension on ART outcomes is unknown. STUDY DESIGN, SIZE, DURATION: This study was conducted in pigs. We measured oviductal and uterine O2 tension (n = 29 and 13, respectively) and then examined how the use of the physiological values in pig IVF and EC affected pig ART output (n = 1447 oocytes). PARTICIPANTS/MATERIALS, SETTING, METHODS: The oviductal and uterine O2 tension at the different stages of the estrous cycle was monitored using a laparo-endoscopic single-site surgery (LESS) assisted approach along with a flexible and thin miniaturized luminescent probe. Two groups of pigs, Large-white * Landrace breed, were used: for the first group, 16 pre-pubertal gilts (5 months old and 95 kg) were induced to ovulate with equine chorionic gonadotropin (eCG) and human chorionic gonadotropin (hCG); in the second group 13 mature sows (24-48 months and 185 kg) were used. IVF and EC were performed at two different O2 tensions: Atmospheric O2 (20%) and the mean in vivo value measured (7%). At 18-20 h post insemination (hpi), a small sample of presumptive zygotes were fixed, stained and examined under epifluorescence microscopy to assess the fertilization rates. At 48 hpi, cleavage was evaluated under the stereomicroscope. Finally, at 180 hpi, development to the blastocyst stage was quantified, blastocyst morphology was assessed, and embryos were fixed and stained to count the mean cell number per blastocyst. MAIN RESULTS AND THE ROLE OF CHANCE: The mean O2 content within the pig oviduct and uterus was always lower than in ambient air. The average O2 percentage was higher in gilts (10.0%) than in sows (7.6%) (P < 0.0001). The cleavage rate of porcine in vitro fertilized embryos maintained under 7% O2 during IVF and EC was significantly higher (60.0 +/- 2.3) compared with those cultured under 20% O2 (32.0 +/- 2.2) (P < 0.05). An increase in the number of cells in embryos cultured under the low O2 concentration (88.9 +/- 5.9) was observed compared to those cultured under 20% O2 (59.0 +/- 5.0) (P < 0.05). LARGE SCALE DATA: None. LIMITATIONS, REASONS FOR CAUTION: Although minimally invasive surgery was used the effect of anesthesia and manipulations on O2 tension within the organs are unknown. WIDER IMPLICATIONS OF THE FINDINGS: Using physiological oxygen concentrations in IVF/EC could improve ART outcomes. STUDY FUNDING AND COMPETING INTEREST(S): This study was funded by Spanish Ministry of Economy and Competitiveness (MINECO) and European Regional Development Fund (FEDER). Grants AGL2012-40180-C03-01 and AGL2015-66341-R. The authors declare no conflict of interest. PMID- 29490064 TI - Roles of AGCVIII Kinases in the Hypocotyl Phototropism of Arabidopsis Seedlings. AB - Regulation of protein function by phosphorylation and dephosphorylation is an important mechanism in many cellular events. The phototropin blue-light photoreceptors, plant-specific AGCVIII kinases, are essential for phototropic responses. Members of the D6 PROTEIN KINASE (D6PK) family, representing a subfamily of the AGCVIII kinases, also contribute to phototropic responses, suggesting that possibly further AGCVIII kinases may potentially control phototropism. The present study investigates the functional roles of Arabidopsis (Arabidopsis thaliana) AGCVIII kinases in hypocotyl phototropism. We demonstrate that D6PK family kinases are not only required for the second but also for the first positive phototropism. In addition, we find that a previously uncharacterized AGCVIII protein, AGC1-12, is involved in the first positive phototropism and gravitropism. AGC1-12 phosphorylates serine residues in the cytoplasmic loop of PIN-FORMED 1 (PIN1) and shares phosphosite preferences with D6PK. Our work strongly suggests that the D6PK family and AGC1-12 are critical components for both hypocotyl phototropism and gravitropism, and that these kinases control tropic responses mainly through regulation of PIN-mediated auxin transport by protein phosphorylation. PMID- 29490065 TI - INSM1 Expression Is Frequent in Primary Central Nervous System Neoplasms but Not in the Adult Brain Parenchyma. AB - Tumors with a neuronal component comprise a small percentage of central nervous system (CNS) neoplasms overall, but the presence of neuronal differentiation has important diagnostic, prognostic, and therapeutic implications. Insulinoma associated protein 1 (INSM1) is a transcription factor with strong nuclear immunostaining in neuroendocrine cells and neoplasms of neuroendocrine origin; however, its expression in the CNS in normal brain and in neoplastic cells has not been fully explored. Here, we present immunostaining results from a large number of archival CNS tissue specimens, including 416 tumors. Nuclear immunostaining for INSM1 was frequently seen in medulloblastomas (87%, n = 94). Diffuse nuclear INSM1 immunostaining was detected in all central neurocytomas and pituitary adenomas. Patchy to rare staining with INSM1 was also seen in other high-grade embryonal tumors and high-grade gliomas. In normal brain tissue, specific nuclear INSM1 immunohistochemical staining was only seen in early neuronal development. Notably, nuclear INSM1 staining was not seen in adult normal brain, including areas of gliosis. These findings indicate that nuclear INSM1 immunostaining may serve as a strong nuclear marker in the brain for neoplasms of neuroendocrine or immature neuronal differentiation, when used in concert with other immunostains. PMID- 29490066 TI - Dual Antiplatelet Therapy Combining Aspirin and Ticagrelor for Intracranial Stenting Procedures: A Retrospective Single Center Study of 154 Consecutive Patients With Unruptured Aneurysms. AB - BACKGROUND: Dual antiplatelet therapy (DAPT) associating aspirin + clopidogrel is commonly utilized in neurovascular interventions despite unpredictable clopidogrel efficacy with 4% to 50% of patients considered nonresponders. Ticagrelor is an antiplatelet agent with low resistance rates but unknown efficacy and safety in neurovascular patients. OBJECTIVE: To evaluate frequency of ischemic and hemorrhagic events in patients treated with aspirin and ticagrelor when associated with perioperative heparin bolus for unruptured aneurysms treated with intracranial stents. METHODS: One hundred fifty-four consecutive patients with unruptured intracranial aneurysms treated by stent procedures (113 = flow diverter stent [FDS], 41 = stent-assisted coiling) were retrospectively analyzed. All patients received aspirin and ticagrelor without platelet function testing. Patients were separated in 2 groups following perioperative heparin dose: group I = 70 U/kg; group II = 50 U/kg. FDS versus stent-assisted coiling procedures were also separately analyzed. RESULTS: Nine patients (5.8%) presented symptomatic neurological complications poststenting (3 ischemic, 6 hemorrhagic): 8 patients received 70 U/kg of heparin (11.1%) and 1 patient received 50 U/kg (1.2%; P < .009). Four patients died (2.6%) during the 3 mo follow-up period-all deaths were correlated to intracranial hemorrhage: 3 at group I and 1 at group II (P < .251). No difference in complications or death was observed considering separately FDS and stent-assisted coiling procedures. CONCLUSION: This study did not find more neurological complications than in previous neurointerventional reports using DAPT with aspirin + ticagrelor or aspirin + clopidogrel. Overall number of neurological complications was lower when a lower dose of heparin was administered. Neurovascular studies comparing clopidogrel to ticagrelor and different doses of heparin are necessary to demonstrate which association is more efficient with lower complication rates. PMID- 29490067 TI - Degree Day Requirements for Kudzu Bug (Hemiptera: Plataspidae), a Pest of Soybeans. AB - Understanding the phenology of a new potential pest is fundamental for the development of a management program. Megacopta cribraria Fabricius (Hemiptera: Plataspidae), kudzu bug, is a pest of soybeans first detected in the United States in 2009 and in Maryland in 2013. We observed the phenology of kudzu bug life stages in Maryland, created a Celsius degree-day (CDD) model for development, and characterized the difference between microhabitat and ambient temperatures of both kudzu, Pueraria montana (Lour.) Merr. (Fabales: Fabaceae) and soybeans, Glycine max (L.) Merrill (Fabales: Fabaceae). In 2014, low population numbers yielded limited resolution from field phenology observations. We observed kudzu bug populations persisting within Maryland; but between 2013 and 2016, populations were low compared to populations in the southeastern United States. Based on the degree-day model, kudzu bug eggs require 80 CDD at a minimum temperature of 14 degrees C to hatch. Nymphs require 545 CDD with a minimum temperature of 16 degrees C for development. The CDD model matches field observations when factoring a biofix date of April 1 and a minimum preoviposition period of 17 d. The model suggests two full generations per year in Maryland. Standard air temperature monitors do not affect model predictions for pest management, as microhabitat temperature differences did not show a clear trend between kudzu and soybeans. Ultimately, producers can predict the timing of kudzu bug life stages with the CDD model for the use of timing management plans in soybean fields. PMID- 29490068 TI - Gradual External Ventricular Drainage Weaning Reduces The Risk of Shunt Dependency After Aneurysmal Subarachnoid Hemorrhage: A Pooled Analysis. AB - BACKGROUND: Chronic posthemorrhagic hydrocephalus necessitating shunt placement is a common complication of subarachnoid hemorrhage (SAH). OBJECTIVE: To evaluate the role of external ventricular drainage (EVD) weaning on risk of shunt dependency after SAH. METHODS: Two German university hospitals with different EVD management regimes (rapid weaning [RW] vs gradual weaning [GW]) pooled the data of their observational cohorts containing altogether 1171 consecutive SAH patients treated between January 2005 and December 2012. Development and timing of shunt dependency in SAH survivals were the endpoints of the study. RESULTS: The final cohort consisted of 455 and 510 SAH survivors treated in the centers with RW and GW, respectively. Mortality rates, as well as baseline demographic, clinical, and radiographic parameters, showed no differences between the centers. Patients with GW were less likely to develop shunt dependency (27.5% vs 34.7%, P = .018), Multivariate analysis confirmed independent association between RW regime and shunt dependency (P = .026). Shunt-dependent SAH patients undergoing GW required significantly longer time until shunting (mean 29.8 vs 21.7 d, P < .001) and hospital stay (mean 39 vs 34.4 d, P = .03). In addition, patients with GW were at higher risk for secondary shunt placement after successful initial weaning (P = .001). The risk of cerebrospinal fluid infection was not associated with the weaning regime (15.3% vs 12.9%, P = .307). CONCLUSION: At the expense of longer treatment, GW may decrease the risk of shunt dependency after SAH without an additional risk for infections. Due to the risk of secondary shunt dependency, SAH patients with GW require proper posthospital neurological care. PMID- 29490069 TI - Morphometric Analysis of Adult Dermacentor parumapertus Neumann (Acari: Ixodidae) From Various Locations Within its Geographical Range. AB - Dermacentor parumapertus Neumann (Acari: Ixodidae), a tick primarily associated with rabbits which occurs over much of the western United States, has a fairly large north-to-south distribution, being found from central Idaho southward into northern Mexico. This mostly obscure tick species has recently been the focus of attention due to the discovery of a unique strain of Rickettsia parkeri associated with it which appears closely related to a Rickettsia sp. found in the Atlantic rainforest of Brazil. Historically, a morphological variety of this species was reported in the literature based on significant variation in ornamentation of the tick throughout its range. This study examines several key morphological characters to determine if there are indeed more than one distinct population of this species throughout its range. PMID- 29490070 TI - Temporal Delays Along the Neurosurgical Care Continuum for Traumatic Brain Injury Patients at a Tertiary Care Hospital in Kampala, Uganda. AB - BACKGROUND: Significant care continuum delays between acute traumatic brain injury (TBI) and definitive surgery are associated with poor outcomes. Use of the "3 delays" model to evaluate TBI outcomes in low- and middle-income countries has not been performed. OBJECTIVE: To describe the care continuum, using the 3 delays framework, and its association with TBI patient outcomes in Kampala, Uganda. METHODS: Prospective data were collected for 563 TBI patients presenting to a tertiary hospital in Kampala from 1 June to 30 November 2016. Four time intervals were constructed along 5 time points: injury, hospital arrival, neurosurgical evaluation, computed tomography (CT) results, and definitive surgery. Time interval differences among mild, moderate, and severe TBI and their association with mortality were analyzed. RESULTS: Significant care continuum differences were observed for interval 3 (neurosurgical evaluation to CT result) and 4 (CT result to surgery) between severe TBI patients (7 h for interval 3 and 24 h for interval 4) and mild TBI patients (19 h for interval 3 and 96 h for interval 4). These postarrival delays were associated with mortality for mild (P = .05) and moderate TBI (P = .03) patients. Significant hospital arrival delays for moderate TBI patients were associated with mortality (P = .04). CONCLUSION: Delays for mild and moderate TBI patients were associated with mortality, suggesting that quality improvement interventions could target current triage practices. Future research should aim to understand the contributors to delays along the care continuum, opportunities for more effective resource allocation, and the need to improve prehospital logistical referral systems. PMID- 29490072 TI - Potential of Human Nucleus Pulposus-Like Cells Derived From Umbilical Cord to Treat Degenerative Disc Disease. AB - BACKGROUND: Degenerative disc disease (DDD) is a common spinal disorder that manifests with neck and lower back pain caused by the degeneration of intervertebral discs (IVDs). Currently, there is no treatment to cure this debilitating ailment. OBJECTIVE: To investigate the potential of nucleus pulposus (NP)-like cells (NPCs) derived from human umbilical cord mesenchymal stem cells (MSCs) to restore degenerated IVDs using a rabbit DDD model. METHODS: NPCs differentiated from MSCs were characterized using quantitative real-time reverse transcription polymerase chain reaction and immunocytochemical analysis. MSCs and NPCs were labeled with fluorescent dye, PKH26, and transplanted into degenerated IVDs of a rabbit model of DDD (n = 9 each). Magnetic resonance imaging of the IVDs was performed before and after IVD degeneration, and following cell transplantation. IVDs were extracted 8 wk post-transplantation and analyzed by various biochemical, immunohistological, and molecular techniques. RESULTS: NPC derivatives of MSCs expressed known NP-specific genes, SOX9, ACAN, COL2, FOXF1, and KRT19. Transplanted cells survived, dispersed, and integrated into the degenerated IVDs. IVDs augmented with NPCs showed significant improvement in the histology, cellularity, sulfated glycosaminoglycan and water contents of the NP. In addition, expression of human genes, SOX9, ACAN, COL2, FOXF1, KRT19, PAX6, CA12, and COMP, as well as proteins, SOX9, ACAN, COL2, and FOXF1, suggest NP biosynthesis due to transplantation of NPCs. Based on these results, a molecular mechanism for NP regeneration was proposed. CONCLUSION: The findings of this study demonstrating feasibility and efficacy of NPCs to regenerate NP should spur interest for clinical studies to treat DDD using cell therapy. PMID- 29490071 TI - Randomized Noninferiority Trial of Telephone vs In-Person Disclosure of Germline Cancer Genetic Test Results. AB - Background: Germline genetic testing is standard practice in oncology. Outcomes of telephone disclosure of a wide range of cancer genetic test results, including multigene panel testing (MGPT) are unknown. Methods: Patients undergoing cancer genetic testing were recruited to a multicenter, randomized, noninferiority trial (NCT01736345) comparing telephone disclosure (TD) of genetic test results with usual care, in-person disclosure (IPD) after tiered-binned in-person pretest counseling. Primary noninferiority outcomes included change in knowledge, state anxiety, and general anxiety. Secondary outcomes included cancer-specific distress, depression, uncertainty, satisfaction, and screening and risk-reducing surgery intentions. To declare noninferiority, we calculated the 98.3% one-sided confidence interval of the standardized effect; t tests were used for secondary subgroup analyses. Only noninferiority tests were one-sided, others were two sided. Results: A total of 1178 patients enrolled in the study. Two hundred eight (17.7%) participants declined random assignment due to a preference for in-person disclosure; 473 participants were randomly assigned to TD and 497 to IPD; 291 (30.0%) had MGPT. TD was noninferior to IPD for general and state anxiety and all secondary outcomes immediately postdisclosure. TD did not meet the noninferiority threshold for knowledge in the primary analysis, but it did meet the threshold in the multiple imputation analysis. In secondary analyses, there were no statistically significant differences between arms in screening and risk-reducing surgery intentions, and no statistically significant differences in outcomes by arm among those who had MGPT. In subgroup analyses, patients with a positive result had statistically significantly greater decreases in general anxiety with telephone disclosure (TD -0.37 vs IPD +0.87, P = .02). Conclusions: Even in the era of multigene panel testing, these data suggest that telephone disclosure of cancer genetic test results is as an alternative to in-person disclosure for interested patients after in-person pretest counseling with a genetic counselor. PMID- 29490073 TI - HpoR, a novel c-di-GMP effective transcription factor, links the second messenger's regulatory function to the mycobacterial antioxidant defense. AB - Cyclic di-GMP (c-di-GMP) is a global signaling molecule that widely modulates diverse cellular processes. However, whether or not the c-di-GMP signal participates in regulation of bacterial antioxidant defense is unclear, and the involved regulators remain to be explored. In this study, we characterized HpoR as a novel c-di-GMP effective transcription factor and found a link between the c di-GMP signal and the antioxidant regulation in Mycobacterium smegmatis. H2O2 stress induces c-di-GMP accumulation in M. smegmatis. High level of c-di-GMP triggers expression of a redox gene cluster, designated as hpoR operon, which is required for the mycobacterial H2O2 resistance. HpoR acts as an inhibitor of the hpoR operon and recognizes a 12-bp motif sequence within the upstream regulatory region of the operon. c-di-GMP specifically binds with HpoR at a ratio of 1:1. Low concentrations of c-di-GMP stimulate the DNA-binding activity of HpoR, whereas high concentrations of the signal molecule inhibit the activity. Strikingly, high level of c-di-GMP de-represses the intracellular association of HpoR with the regulatory region of the hpoR operon in M. smegmatis and enhances the mycobacterial H2O2 resistance. Therefore, we report a novel c-di-GMP effective regulator in mycobacteria, which extends the second messenger's function to bacterial antioxidant defense. PMID- 29490074 TI - Expanding RNA binding specificity and affinity of engineered PUF domains. AB - Specific manipulation of RNA is necessary for the research in biotechnology and medicine. The RNA-binding domains of Pumilio/fem-3 mRNA binding factors (PUF domains) are programmable RNA binding scaffolds used to engineer artificial proteins that specifically modulate RNAs. However, the native PUF domains generally recognize 8-nt RNAs, limiting their applications. Here, we modify the PUF domain of human Pumilio1 to engineer PUFs that recognize RNA targets of different length. The engineered PUFs bind to their RNA targets specifically and PUFs with more repeats have higher binding affinity than the canonical eight repeat domains; however, the binding affinity reaches the peak at those with 9 and 10 repeats. Structural analysis on PUF with nine repeats reveals a higher degree of curvature, and the RNA binding unexpectedly and dramatically opens the curved structure. Investigation of the residues positioned in between two RNA bases demonstrates that tyrosine and arginine have favored stacking interactions. Further tests on the availability of the engineered PUFs in vitro and in splicing function assays indicate that our engineered PUFs bind RNA targets with high affinity in a programmable way. PMID- 29490075 TI - Demography and Mass-Rearing Harmonia dimidiata (Coleoptera: Coccinellidae) Using Aphis gossypii (Hemiptera: Aphididae) and Eggs of Bactrocera dorsalis (Diptera: Tephritidae). AB - We compared rearing Harmonia dimidiata (F.) (Coleoptera: Coccinellidae) on four combinations of Aphis gossypii Glover (Hemiptera: Aphididae), and eggs of Bactrocera dorsalis Hendel (Diptera: Tephritidae), using the age-stage, two-sex life table. The four combinations were: both larvae and adults were reared on aphids; larvae were reared on aphids and adults were reared on fresh fruit fly eggs; larvae were reared on lyophilized fruit fly eggs and adults were reared on aphids; and larvae were reared on lyophilized eggs and adults were reared on fresh eggs. The highest intrinsic rate of increase (r = 0.1125 d-1) and net reproductive rate (R0 = 260.7 offspring) were observed when both larval and adult stages of H. dimidiata were reared on A. gossypii. When B. dorsalis eggs were used as rearing media for larvae, adults, or both, the values of r and R0 were significantly decreased. The lowest values (r = 0.0615 d-1 and R0 = 38.6 offspring) were observed when both larvae and adults were reared entirely on B. dorsalis eggs. Despite the lower r and R0 values, our results showed that B. dorsalis eggs could be considered as an adequate, less expensive alternative diet for rearing H. dimidiata because of the time and labor savings resulting from the ease of preparation and the ability to store the eggs for timely usage. The mass rearing analysis showed that the most economical rearing system was to rear larvae on A. gossypii and adults on B. dorsalis eggs. PMID- 29490076 TI - Advancing Simulation-Based Education in Pain Medicine. AB - Background: The Accreditation Council for Graduate Medical Education (ACGME) has recently implemented milestones and competencies as a framework for training fellows in Pain Medicine, but individual programs are left to create educational platforms and assessment tools that meet ACGME standards. Objectives: In this article, we discuss the concept of milestone-based competencies and the inherent challenges for implementation in pain medicine. We consider simulation-based education (SBE) as a potential tool for the field to meet ACGME goals through advancing novel learning opportunities, engaging in clinically relevant scenarios, and mastering technical and nontechnical skills. Results: The sparse literature on SBE in pain medicine is highlighted, and we describe our pilot experience, which exemplifies a nascent effort that encountered early difficulties in implementing and refining an SBE program. Conclusions: The many complexities in offering a sophisticated simulated pain curriculum that is valid, reliable, feasible, and acceptable to learners and teachers may only be overcome with coordinated and collaborative efforts among pain medicine training programs and governing institutions. PMID- 29490077 TI - Stabilization of the methyl-CpG binding protein ZBTB38 by the deubiquitinase USP9X limits the occurrence and toxicity of oxidative stress in human cells. AB - Reactive oxygen species (ROS) are a byproduct of cell metabolism, and can also arise from environmental sources, such as toxins or radiation. Depending on dose and context, ROS have both beneficial and deleterious roles in mammalian development and disease, therefore it is crucial to understand how these molecules are generated, sensed, and detoxified. The question of how oxidative stress connects to the epigenome, in particular, is important yet incompletely understood. Here we show that an epigenetic regulator, the methyl-CpG-binding protein ZBTB38, limits the basal cellular production of ROS, is induced by ROS, and is required to mount a proper response to oxidative stress. Molecularly, these functions depend on a deubiquitinase, USP9X, which interacts with ZBTB38, deubiquitinates it, and stabilizes it. We find that USP9X is itself stabilized by oxidative stress, and is required together with ZBTB38 to limit the basal generation of ROS, as well as the toxicity of an acute oxidative stress. Our data uncover a new nuclear target of USP9X, show that the USP9X/ZBTB38 axis limits, senses and detoxifies ROS, and provide a molecular link between oxidative stress and the epigenome. PMID- 29490078 TI - Evaluating State-Level Differences in E-cigarette and Cigarette Use Among Adults in the United States Between 2012 and 2014: Findings From the National Adult Tobacco Survey. AB - Objective: To examine the association between state-level tobacco control measures and current use estimates of both e-cigarettes and cigarettes, while accounting for socio-demographic correlates. Methods: Using the 2012-2013 and 2013-2014 National Adult Tobacco Survey (NATS), we assessed prevalence estimates of US adults' e-cigarette and cigarette current use. Four state groups were created based on the combined state-specific prevalence of both products: low cigarette/e-cigarette (n = 15), high cigarette/e-cigarette (n = 16), high cigarette/low e-cigarette (n = 11), and low cigarette/high e-cigarette) (n = 9). To evaluate the implementation of state-level tobacco control measures, Tobacco Control Index (TCI) was calculated using the State of Tobacco Control annual reports for 2012 and 2013. Multinomial logistic regression models were used to examine differences among the four groups on socio-demographic factors and TCI. Low cigarette/e-cigarette group was used as the referent group. Results: Current use estimates of each product varied substantially by state; current e-cigarette use was highest in Oklahoma (10.3%) and lowest in Delaware (2.7%), and current cigarette use was highest in West Virginia (26.1%), and lowest in Vermont (12.6%). Compared to low cigarette/e-cigarette, all other US-state categories had significantly lower TCI scores (high cigarette/e-cigarette: adjusted Relative Risk Ratio [aRRR] = 0.61; 95% confidence interval [CI]: 0.60-0.61, high cigarette/low e-cigarette: aRRR = 0.74; 95% CI: 0.73-0.74, and low cigarette/high e-cigarette: aRRR = 0.72; 95% CI: 0.71-073). Conclusions: Enforcing existing tobacco control measures likely interacts with e-cigarette use despite being cigarette-focused. Continuing to monitor e-cigarette use is critical to establish baseline use and evaluate future e-cigarette specific federal and state-level tobacco regulatory actions while accounting for the existing tobacco control environment. Implications: This study investigates state-level current use estimates of e-cigarettes and cigarettes among US adults; and their association with four existing tobacco control measures. The overall score of these measures was negatively associated with state-level current use estimates such that states with low current e-cigarette and cigarette use had the highest mean overall score. This study assesses the potential relationship between existing state level tobacco control measures and e-cigarette use and calls for improving the enforcement of the known-to-work tobacco control measures across all US states, while developing evidence-based regulations and interventions specific to e cigarettes within the existing US tobacco use environment. PMID- 29490079 TI - A Blood RNA Signature Detecting Severe Disease in Young Dengue Patients at Hospital Arrival. AB - Background: Early detection of severe dengue can improve patient care and survival. To date, no reliable single-gene biomarker exists. We hypothesized that robust multigene signatures exist. Methods: We performed a prospective study on Cambodian dengue patients aged 4 to 22 years. Peripheral blood mononuclear cells (PBMCs) were obtained at hospital admission. We analyzed 42 transcriptomic profiles of patients with secondary dengue infected with dengue serotype 1. Our novel signature discovery approach controls the number of included genes and captures nonlinear relationships between transcript concentrations and severity. We evaluated the signature on secondary cases infected with different serotypes using 2 datasets: 22 PBMC samples from additional patients in our cohort and 32 whole blood samples from an independent cohort. Results: We identified an 18-gene signature for detecting severe dengue in patients with secondary infection upon hospital admission with a sensitivity of 0.93 (95% confidence interval [CI], .82 .98), specificity of 0.67 (95% CI, .53-.80), and area under the receiver operating characteristic curve (AUC) of 0.86 (95% CI, .75-.97). At validation, the signature had empirical AUCs of 0.85 (95% CI, .69-1.00) and 0.83 (95% CI, .68 .98) for the PBMCs and whole blood datasets, respectively. Conclusions: The signature could detect severe dengue in secondary-infected patients upon hospital admission. Its genes offer new insights into the pathogenesis of severe dengue. PMID- 29490080 TI - Thrips advisor: exploiting thrips-induced defences to combat pests on crops. AB - Plants have developed diverse defence mechanisms to ward off herbivorous pests. However, agriculture still faces estimated crop yield losses ranging from 25% to 40% annually. These losses arise not only because of direct feeding damage, but also because many pests serve as vectors of plant viruses. Herbivorous thrips (Thysanoptera) are important pests of vegetable and ornamental crops worldwide, and encompass virtually all general problems of pests: they are highly polyphagous, hard to control because of their complex lifestyle, and they are vectors of destructive viruses. Currently, control management of thrips mainly relies on the use of chemical pesticides. However, thrips rapidly develop resistance to these pesticides. With the rising demand for more sustainable, safer, and healthier food production systems, we urgently need to pinpoint the gaps in knowledge of plant defences against thrips to enable the future development of novel control methods. In this review, we summarize the current, rather scarce, knowledge of thrips-induced plant responses and the role of phytohormonal signalling and chemical defences in these responses. We describe concrete opportunities for breeding resistance against pests such as thrips as a prototype approach for next-generation resistance breeding. PMID- 29490082 TI - The impact of the interventionist-participant relationship on treatment adherence and weight loss. AB - Little is known about the impact of the relationship built between interventionists and their participants on weight loss. Our objective is to determine whether stronger early (i.e., 4 weeks) participant-interventionist bond is associated with significantly greater weight loss success and treatment adherence. Three hundred and ninety-eight participants received an online group behavioral weight control program over 18 months. Weight was measured objectively at baseline and at 6 and 18 months. At 4 weeks, participants completed the Working Alliance Inventory (WAI) bonding subscale, which measures the collaborative bond with the interventionist. Adherence (i.e., session attendance and online self-monitoring diary completion) was recorded by the interventionists. Participant-interventionist bond at 4 weeks was significantly associated with weight loss at 6 months (t(322) = -2.14, p = .03) but not at 18 months (t(290) = 0.53, p = .60). The model indicated that participant interventionist bond at 4 weeks was a significant predictor of adherence at 6 months (b = .063, standard error [SE] = .30, p = .04), and 6 month adherence was a significant predictor of weight loss at 6 months (b = -.594, SE = .049, p < .0001). The indirect effect of the WAI-Bond subscale was significant (b = -.037, p = .03, 95% confidence interval: -.074, -.002) and accounted for 54% of the total effect of participant-interventionist bond on weight loss. However, the total weight loss explained by WAI-Bond subscale was small (0.04 kg). Participant interventionist bond between participant and interventionist is an early predictor of treatment adherence and weight loss success at 6 months; however, the degree of weight loss explained by participant-interventionist bond is small and was not maintained at 18 months. PMID- 29490081 TI - Noncanonical substrate preference of lambda exonuclease for 5'-nonphosphate-ended dsDNA and a mismatch-induced acceleration effect on the enzymatic reaction. AB - Lambda exonuclease (lambda exo) plays an important role in the resection of DNA ends for DNA repair. Currently, it is also a widely used enzymatic tool in genetic engineering, DNA-binding protein mapping, nanopore sequencing and biosensing. Herein, we disclose two noncanonical properties of this enzyme and suggest a previously undescribed hydrophobic interaction model between lambda exo and DNA substrates. We demonstrate that the length of the free portion of the substrate strand in the dsDNA plays an essential role in the initiation of digestion reactions by lambda exo. A dsDNA with a 5' non-phosphorylated, two nucleotide-protruding end can be digested by lambda exo with very high efficiency. Moreover, we show that when a conjugated structure is covalently attached to an internal base of the dsDNA, the presence of a single mismatched base pair at the 5' side of the modified base may significantly accelerate the process of digestion by lambda exo. A detailed comparison study revealed additional pi-pi stacking interactions between the attached label and the amino acid residues of the enzyme. These new findings not only broaden our knowledge of the enzyme but will also be very useful for research on DNA repair and in vitro processing of nucleic acids. PMID- 29490083 TI - beta-Cyanoalanine Synthase Action in Root Hair Elongation is Exerted at Early Steps of the Root Hair Elongation Pathway and is Independent of Direct Cyanide Inactivation of NADPH Oxidase. AB - In Arabidopsis thaliana, cyanide is produced concomitantly with ethylene biosynthesis and is mainly detoxified by the beta-cyanoalanine synthase CAS-C1. In roots, CAS-C1 activity is essential to maintain a low level of cyanide for proper root hair development. Root hair elongation relies on polarized cell expansion at the growing tip, and we have observed that CAS-C1 locates in mitochondria and accumulates in root hair tips during root hair elongation, as shown by observing the fluorescence in plants transformed with the translational construct ProC1:CASC1-GFP, containing the complete CAS-C1 gene fused to green fluorescent protein (GFP). Mutants in the SUPERCENTIPEDE (SCN1) gene, that regulate the NADPH oxidase gene ROOT HAIR DEFECTIVE 2 (RHD2)/AtrbohC, are affected at the very early steps of the development of root hair that do not elongate and do not show a preferential localization of the GFP accumulation in the tips of the root hair primordia. Root hairs of mutants in CAS-C1 or RHD2/AtrbohC, whose protein product catalyzes the generation of ROS and the Ca2+ gradient, start to grow out correctly, but they do not elongate. Genetic crosses between the cas-c1 mutant and scn1 or rhd2 mutants were performed, and the detailed phenotypic and molecular characterization of the double mutants demonstrates that scn1 mutation is epistatic to cas-c1 and cas-c1 is epistatic to rhd2 mutation, indicating that CAS-C1 acts in early steps of the root hair development process. Moreover, our results show that the role of CAS-C1 in root hair elongation is independent of H2O2 production and of a direct NADPH oxidase inhibition by cyanide. PMID- 29490084 TI - Polyamine- and Amino Acid-Related Metabolism: The Roles of Arginine and Ornithine are Associated with the Embryogenic Potential. AB - The mechanisms that control polyamine (PA) metabolism in plant cell lines with different embryogenic potential are not well understood. This study involved the use of two Araucaria angustifolia cell lines, one of which was defined as being blocked, in that the cells were incapable of developing somatic embryos, and the other as being responsive, as the cells could generate somatic embryos. Cellular PA metabolism was modulated by using 5 mM arginine (Arg) or ornithine (Orn) at two time points during cell growth. Two days after subculturing with Arg, an increase in citrulline (Cit) content was observed, followed by a higher expression of genes related to PA catabolism in the responsive cell line; whereas, in the blocked cell line, we only observed an accumulation of PAs. After 14 d, metabolism was directed towards putrescine accumulation in both cell lines. Exogenous Arg and Orn not only caused a change in cellular contents of PAs, but also altered the abundance of a broader spectrum of amino acids. Specifically, Cit was the predominant amino acid. We also noted changes in the expression of genes related to PA biosynthesis and catabolism. These results indicate that Arg and Orn act as regulators of both biosynthetic and catabolic PA metabolites; however, we suggest that they have distinct roles associated with embryogenic potential of the cells. PMID- 29490085 TI - Vitamin D supplementation for improvement of chronic low-grade inflammation in patients with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. AB - Background: Vitamin D has been proposed to have anti-inflammatory properties; however, the effect of vitamin D supplementation on inflammation in type 2 diabetes has not been established. Objective: The aim of this systematic review and meta-analysis was to examine the effect of vitamin D supplementation on inflammatory markers in patients with type 2 diabetes and to identify relevant gaps in knowledge. Data sources: MEDLINE, CINAHL, Embase, and EBM Reviews were searched systematically from inception to January 25, 2017. Study selection: Randomized controlled trials (RCTs) investigating the effects of vitamin D supplementation (any form, route, and duration, and with any cosupplementation) compared with placebo or usual care on inflammatory markers in patients with type 2 diabetes were selected. Data extraction: Study and sample characteristics and aggregate outcome data were extracted, risk of bias was determined, and quality of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. Results: Twenty-eight RCTs were included, 20 of which had data available for pooling. In meta-analyses of 20 RCTs (n = 1270 participants), vitamin D-supplemented groups had lower levels of C reactive protein (standardized mean difference [SMD] -0.23; 95%CI, -0.37 to 0.09; P = 0.002) and tumor necrosis factor alpha (SMD -0.49; 95%CI, -0.84 to 0.15; P = 0.005), a lower erythrocyte sedimentation rate (SMD -0.47; 95%CI, -0.89 to -0.05; P = 0.03), and higher levels of leptin (SMD 0.42; 95%CI, 0.04-0.81; P = 0.03) compared with control groups. No differences were observed for adiponectin, interleukin 6, or E-selectin (all P > 0.05). In meta-regression and subgroup analyses, age, sex, body mass index, duration of diabetes, baseline vitamin D status, and dose and duration of supplementation did not alter the results. Conclusions: This meta-analysis provides level 1 evidence that vitamin D supplementation may reduce chronic low-grade inflammation in patients with type 2 diabetes. Systematic Review Registration: PROSPERO CRD42016047755. Available at: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=47755 (9/15/2016). PMID- 29490086 TI - The Association Between the Use of the Education Benefits from the G.I. Bill and Veterans' Health. AB - Background: There is limited knowledge on the impact of education on veterans' health in the United States. This study specifically examines the relationship between the education benefits from the G.I. Bill and veterans' health. Methods: This study used data from the 2010 National Survey of Veterans. The subjects for this study were 5,052 veterans who were eligible to receive G.I. Bill benefits, representing a total of about 12.7 million non-institutionalized veterans in the United States in 2010. The dependent variables included self-reported health status and smoking behavior. The key independent variable was whether veterans used the education benefits from the G.I. Bill compared with those who were eligible but did not use them. Findings: Results from multivariate regression analyses showed that those who used the education benefits from the G.I. Bill were 4% less likely to report fair/poor health (p < 0.01) and 3% less likely to report any smoking (p < 0.05) compared with those who did not use the education benefits. Additional analyses showed that using the education benefits to attend college decreased the probability of being in fair/poor health by 4% (p < 0.10) and being a smoker by 4% (p < 0.05) compared with those who did not attend college but used their benefits for non-college attainment such as business, technical, or vocational schools. More importantly, a larger association was found between the use of the education benefits from the G.I. Bill to obtain a college degree and fair/poor health (7%, p < 0.05) and smoking behavior (9%, p < 0.01) compared with those who attended college but did not obtain a college degree. Discussion: This study shows that providing opportunities for service members to complete their education also has important health benefits. PMID- 29490087 TI - ECG Changes of Severe Hypokalemia. PMID- 29490088 TI - When compliments don't hit but critiques do: an fMRI study into self-esteem and self-knowledge in processing social feedback. AB - Introduction: The way we view ourselves may play an important role in our responses to interpersonal interactions. In this study, we investigate how feedback valence, consistency of feedback with self-knowledge and global self esteem influence affective and neural responses to social feedback. Methods: Participants (N = 46) with a high range of self-esteem levels performed the social feedback task in an MRI scanner. Negative, intermediate and positive feedback was provided, supposedly by another person based on a personal interview. Participants rated their mood and applicability of feedback to the self. Analyses on trial basis on neural and affective responses are used to incorporate applicability of individual feedback words. Results: Lower self esteem related to low mood especially after receiving non-applicable negative feedback. Higher self-esteem related to increased PCC and precuneus activation (i.e., self-referential processing) for applicable negative feedback. Lower self esteem related to decreased mPFC, insula, ACC and PCC activation (i.e, self referential processing) during positive feedback and decreased TPJ activation (i.e., other referential processing) for applicable positive feedback. Discussion: Self-esteem and consistency of feedback with self-knowledge appear to guide our affective and neural responses to social feedback. This may be highly relevant for the interpersonal problems that individuals face with low self esteem and negative self-views. PMID- 29490089 TI - Use of Mathematical Optimization Models to Derive Healthy and Safe Fish Intake. AB - Background: Recommended fish intake differs substantially from observed fish intake. In Denmark, ~15% of the population consumes the state-recommended fish intake. How much fish individuals eat varies greatly, and this variation cannot be captured by considering the fish intake of the average population. Objective: We developed a method intended to provide realistic and achievable personalized dietary recommendations based on an individual's body weight and current fish intake. The objective of the study was to propose specific fish intake levels for individuals that meet the recommendations for eicosapentaenoic acid, docosahexaenoic acid, and vitamin D without violating the permitted intake recommendations for methyl mercury, dioxins, and polychlorinated biphenyls. Methods: Two mathematical optimization models were developed that apply quadratic programming to model personalized recommended fish intake, fulfilling criteria on nutrients and contaminants, while simultaneously deviating as little as possible from observed individual intake. A recommended intake for 8 fish species was generated for each individual in a group of 3016 Danes (1552 women and 1464 men, aged 18-75 y), whose fish intakes and body weights were known from a national dietary survey. Results: Individual, personal dietary recommendations were successfully modeled. Modeled fish intake levels were compared to observed fish intakes. For women, the average proposed increase in fish intake was 14 g/wk for lean fish and 63 g/wk for fatty fish; and for men these numbers were 12 and 55 g/wk, respectively. Conclusions: Using fish intake as an example, we show how quadratic programming models may be used to advise individual consumers how to optimize their diet, taking both benefits and risks into account. This approach has the potential to increase compliance with dietary guidelines by targeting the individual consumers and minimizing the need for large and ultimately unrealistic behavior changes. PMID- 29490090 TI - Additional Common Bean in the Diet of Malawian Children Does Not Affect Linear Growth, but Reduces Intestinal Permeability. AB - Background: Chronic malnutrition, as manifested by linear growth faltering, is pervasive among rural African children. Improvements in complementary feeding may decrease the burden of environmental enteric dysfunction (EED) and thus improve growth in children during the critical first 1000 d of development. Objective: We tested the hypothesis that systematically including common bean or cowpea into complementary feeding would reduce EED and growth faltering among children in rural Malawi. Methods: This was a double-blind clinical trial in which children 12-23 mo of age were randomly assigned to receive complementary feeding with 1 of 3 foods: roasted cowpea or common bean flour, or an isoenergetic amount of corn soy blend as a control food for 48 wk. Children aged 12-23 mo received 155 kcal/d and thereafter until 35 mo received 200 kcal/d. The primary outcomes were change in length-for-age z score (LAZ) and improvements in a biomarker of EED, the percentage of lactulose (%L) excreted as part of the lactulose:mannitol dual sugar absorption test. Anthropometric measurements and urinary %L excretion were compared between the 2 intervention groups and the control group separately with the use of linear mixed model analyses for repeated measures. Results: A total of 331 children completed the clinical trial. Compliance with the study interventions was excellent, with >90% of the intervention flour consumed as intended. No significant effects on LAZ, change in LAZ, or weight-for-length z score were observed due to either intervention legume, compared to the control. %L was reduced with common bean consumption (effect estimate was -0.07 percentage points of lactulose, P = 0.0007). The lactulose:mannitol test was not affected by the legume intervention. Conclusion: The addition of common bean to complementary feeding of rural Malawian children during the second year of life led to an improvement in a biomarker of gut health, although this did not directly translate into improved linear growth. This trial was registered at clinicaltrials.gov as NCT02472301. PMID- 29490091 TI - Kenneth John Carpenter, Ph.D. (1923-2016). PMID- 29490093 TI - Arginine Metabolism Is Altered in Adults with A-beta + Ketosis-Prone Diabetes. AB - Background: A-beta + ketosis-prone diabetes (KPD) is a subset of type 2 diabetes in which patients have severe but reversible beta cell dysfunction of unknown etiology. Plasma metabolomic analysis indicates that abnormal arginine metabolism may be involved. Objective: The objective of this study was to determine the relation between gut microbiome and arginine metabolism and the relation between arginine availability and beta cell function in KPD patients compared with control participants. Methods: Kinetics of arginine and related metabolites were measured with stable isotope tracers, and insulin secretory responses to arginine and glucose were determined under euglycemic and hyperglycemic conditions in 6 KPD patients and 6 age-, gender-, and body mass index-matched control participants. Glucose potentiation of arginine-induced insulin secretion was performed in a different set of 6 KPD and 3 control participants. Results: Arginine availability was higher in KPD patients during euglycemia [53.5 +/- 4.3 (mean +/- SEM) compared with 40.3 +/- 2.4 MUmol . kg lean body mass (LBM)-1 . h 1, P = 0.03] but declined more in response to hyperglycemia (Delta 10.15 +/- 2.6 compared with Delta 3.20 +/- 1.3 MUmol . kg LBM-1 . h-1, P = 0.041). During hyperglycemia, ornithine flux was not different between groups but after an arginine bolus, plasma ornithine AUC trended higher in KPD patients (3360 +/- 294 compared with 2584 +/- 259 min . MUmol . L-1, P = 0.08). In both euglycemia and hyperglycemia, the first-phase insulin responses to glucose stimulation were lower in KPD patients (euglycemic insulin AUC 282 +/- 108 compared with 926 +/- 257 min . MUU . mL-1, P = 0.02; hyperglycemic insulin AUC 358 +/- 79 compared with 866 +/- 292 min . MUU . mL-1, P = 0.05), but exogenous arginine restored first-phase insulin secretion in KPD patients to the level of control participants. Conclusion: Compared with control participants, KPD patients have increased arginine availability in the euglycemic state, indicating a higher requirement. This is compromised during hyperglycemia, with an inadequate supply of arginine to sustain metabolic functions such as insulin secretion. Exogenous arginine administration restores a normal insulin secretory response. PMID- 29490092 TI - Blueberry Supplementation Influences the Gut Microbiota, Inflammation, and Insulin Resistance in High-Fat-Diet-Fed Rats. AB - Background: Gut microbiota dysbiosis has been linked to obesity-associated chronic inflammation. Microbiota manipulation may therefore affect obesity related comorbidities. Blueberries are rich in anthocyanins, which have anti inflammatory properties and may alter the gut microbiota. Objective: We hypothesized that blueberry supplementation would alter the gut microbiota, reduce systemic inflammation, and improve insulin resistance in high-fat (HF) diet-fed rats. Methods: Twenty-four male Wistar rats (260-270 g; n = 8/group) were fed low-fat (LF; 10% fat), HF (45% fat), or HF with 10% by weight blueberry powder (HF_BB) diets for 8 wk. LF rats were fed ad libitum, whereas HF and HF_BB rats were pair-fed with diets matched for fiber and sugar contents. Glucose tolerance, microbiota composition (16S ribosomal RNA sequencing), intestinal integrity [villus height, gene expression of mucin 2 (Muc2) and beta-defensin 2 (Defb2)], and inflammation (gene expression of proinflammatory cytokines) were assessed. Results: Blueberry altered microbiota composition with an increase in Gammaproteobacteria abundance (P < 0.001) compared with LF and HF rats. HF feeding led to an ~15% decrease in ileal villus height compared with LF rats (P < 0.05), which was restored by blueberry supplementation. Ileal gene expression of Muc2 was ~150% higher in HF_BB rats compared with HF rats (P < 0.05), with expression in the LF group not being different from that in either the HF or HF_BB groups. Tumor necrosis factor alpha (Tnfa) and interleukin 1beta (Il1b) gene expression in visceral fat was increased by HF feeding when compared with the LF group (by 300% and 500%, respectively; P < 0.05) and normalized by blueberry supplementation. Finally, blueberry improved markers of insulin sensitivity. Hepatic insulin receptor substrate 1 (IRS1) phosphorylation at serine 307:IRS1 ratio was ~35% higher in HF rats compared with LF rats (P < 0.05) and HF_BB rats. Conclusion: In HF-diet-fed male rats, blueberry supplementation led to compositional changes in the gut microbiota associated with improvements in systemic inflammation and insulin signaling. PMID- 29490095 TI - Development of an In Vivo and In Vitro Ileal Fermentation Method in a Growing Pig Model. AB - Background: Substantial microbial fermentation may occur mainly in the lower small intestine (SI) of human adults, but there is no established methodology to determine this. Objective: The study aimed to develop a combined in vivo and in vitro methodology for ileal fermentation based on the pig as an animal model for digestion in human adults. Methods: Several aspects of a combined in vivo/in vitro ileal fermentation assay were evaluated. Male 9-wk-old pigs (n = 30; mean +/- SD body weight: 23 +/- 1.6 kg) were fed a human-type diet (143, 508, 45, 49, and 116 g/kg dry matter diet of crude protein, starch, total lipid, ash, and total dietary fiber) for 15 d. On day 15, pigs were killed, and the last third of the SI was collected to prepare an ileal digesta-based inoculum. Terminal jejunal digesta (last 50 cm of the second third of the SI) were collected as substrate for the assay to test the form of substrate (fresh or freeze-dried), origin (location in jejunum or SI) of the substrate, storage of the inoculum, incubation time (1.2-6.8 h), pH of the medium, and inoculum concentration (6-26 mg inoculum/100 mg substrate). Results: The group of donor pigs used to prepare the inoculum, form of the substrate, origin of the substrate, origin of the inoculum (location in the SI), storage of the inoculum, incubation time, and inoculum concentration did not influence the in vitro ileal organic matter (OM) fermentability (P > 0.05). The in vitro ileal OM fermentability decreased when the pH of the medium increased from 5.5 to 7.5 (31% to 28%; P <= 0.05). Predicted (in vivo/in vitro) apparent ileal OM digestibility was similar to the value measured in vivo. Conclusions: Thirty-percent of the terminal jejunal digesta OM was fermented in the ileum. Fiber fermentation in the ileum can be studied using the optimized in vivo/in vitro ileal fermentation method. PMID- 29490094 TI - Joint Data Analysis in Nutritional Epidemiology: Identification of Observational Studies and Minimal Requirements. AB - Background: Joint data analysis from multiple nutrition studies may improve the ability to answer complex questions regarding the role of nutritional status and diet in health and disease. Objective: The objective was to identify nutritional observational studies from partners participating in the European Nutritional Phenotype Assessment and Data Sharing Initiative (ENPADASI) Consortium, as well as minimal requirements for joint data analysis. Methods: A predefined template containing information on study design, exposure measurements (dietary intake, alcohol and tobacco consumption, physical activity, sedentary behavior, anthropometric measures, and sociodemographic and health status), main health related outcomes, and laboratory measurements (traditional and omics biomarkers) was developed and circulated to those European research groups participating in the ENPADASI under the strategic research area of "diet-related chronic diseases." Information about raw data disposition and metadata sharing was requested. A set of minimal requirements was abstracted from the gathered information. Results: Studies (12 cohort, 12 cross-sectional, and 2 case-control) were identified. Two studies recruited children only and the rest recruited adults. All studies included dietary intake data. Twenty studies collected blood samples. Data on traditional biomarkers were available for 20 studies, of which 17 measured lipoproteins, glucose, and insulin and 13 measured inflammatory biomarkers. Metabolomics, proteomics, and genomics or transcriptomics data were available in 5, 3, and 12 studies, respectively. Although the study authors were willing to share metadata, most refused, were hesitant, or had legal or ethical issues related to sharing raw data. Forty-one descriptors of minimal requirements for the study data were identified to facilitate data integration. Conclusions: Combining study data sets will enable sufficiently powered, refined investigations to increase the knowledge and understanding of the relation between food, nutrition, and human health. Furthermore, the minimal requirements for study data may encourage more efficient secondary usage of existing data and provide sufficient information for researchers to draft future multicenter research proposals in nutrition. PMID- 29490096 TI - Metabolomic Markers of Essential Fatty Acids, Carnitine, and Cholesterol Metabolism in Adults and Adolescents with Phenylketonuria. AB - Background: Individuals with phenylketonuria (PKU) have a risk of cognitive impairment and inflammation. Many follow a low-phenylalanine (low-Phe) diet devoid of animal protein in combination with medical foods (MFs). Objective: To assess lipid metabolism in participants with PKU consuming amino acid MFs (AA MFs) or glycomacropeptide MFs (GMP-MFs), we conducted fatty acid and metabolomics analyses. Methods: We used subsets of fasting plasma and urine samples from our randomized crossover trial in which participants with early-treated classical and variant (milder) PKU consumed a low-Phe diet combined with AA-MFs or GMP-MFs for 3 wk each. Fatty acid profiles of red blood cell (RBC) membranes were determined for 25 adults (aged 18-49 y) with PKU and 143 control participants. Metabolomics analyses of plasma and urine samples were conducted by Metabolon for 9-10 adolescent and adult participants with PKU and for 15 control participants. Results: RBC fatty acid profiles were not significantly different with AA-MFs or GMP-MFs. PKU participants showed higher total n-6:n-3 (omega-6:omega-3) fatty acids (mean +/- SD percentages of total fatty acids: AA-MF = 5.45% +/- 1.07%; controls = 4.33%; P < 0.001) and lower docosahexaenoic acid (DHA; AA-MF = 3.21% +/- 0.98%; controls = 3.70% +/- 1.01%; P = 0.02) and eicosapentaenoic acid (AA-MF = 0.33% +/- 0.12%; controls = 0.60% +/- 0.43%; P < 0.001) in RBCs than did control participants. Despite higher carnitine intake from AA-MFs than GMP-MFs (mean +/- SE intake: AA-MFs = 58.6 +/- 5.3 mg/d; GMP-MFs = 0.3 +/- 0.01 mg/d; P < 0.001), plasma concentrations of carnitine were similar and not different from those in the control group (AA-MF compared with GMP-MF, P = 0.73). AA-MFs resulted in higher urinary excretion of trimethylamine N-oxide (TMAO), which is synthesized by bacteria from carnitine, compared with GMP-MFs (mean +/- SE scaled intensity-TMAO: AA-MFs = 1.2 +/- 0.1, GMP-MFs = 0.9 +/- 0.1; P = 0.005). Plasma deoxycarnitine was lower in PKU participants than in control participants, suggesting reduced carnitine biosynthesis in PKU (AA-MF = 0.9 +/- 0.1; GMP-MF = 1.0 +/- 0.1; controls = 1.3 +/- 0.1; AA-MF compared with controls, P = 0.01; GMP MF compared with controls, P = 0.04). Conclusions: Supplementation with DHA is needed in PKU. Carnitine supplementation of AA-MFs shows reduced bioavailability due, in part, to bacterial degradation to TMAO, whereas the bioavailability of carnitine is greater with prebiotic GMP-MFs. This trial was registered at www.clinicaltrials.gov as NCT01428258. PMID- 29490097 TI - A High-Fat Compared with a High-Carbohydrate Breakfast Enhances 24-Hour Fat Oxidation in Older Adults. AB - Background: The ability to oxidize fat is associated with a lower risk of chronic metabolic disease. Preclinical data in mice showed that a high-fat "breakfast" increased 24-h fat oxidation relative to a high-carbohydrate breakfast. Objectives: The objectives of this study were to determine whether the timing of macronutrient intake in humans affects daily fuel utilization and to examine associations between fuel utilization and metabolic indexes. Methods: Participants were 29 healthy sedentary men and women (aged 55-75 y) with a body mass index (kg/m2) between 25 and 35. Participants were randomly assigned to receive either a high-fat breakfast (FB; 35% carbohydrate, 20% protein, 45% fat; n = 13) or a high-carbohydrate breakfast (CB; 60% carbohydrate, 20% protein, 20% fat; n = 16) for 4 wk while consuming a "neutral" lunch and dinner. Twenty-four hour and postprandial respiratory quotients (RQs) were measured by whole-room indirect calorimetry. Insulin and glucose measures including insulin sensitivity were determined by an oral-glucose-tolerance test. Measures were taken at baseline and after the 4-wk intervention. Group-by-time interactions were determined by 2-factor repeated-measures mixed-model ANOVA. Pearson's correlation analyses were used to determine associations of 24-h RQs with metabolic measures after the intervention. Results: There was a significant group-by-time interaction for change in the 24-h RQ [FB (mean +/- SD): 0.88 +/- 0.02 to 0.86 +/ 0.02; CB: 0.88 +/- 0.02 for both; P < 0.05], breakfast RQ (FB: 0.88 +/- 0.03 to 0.86 +/- 0.03; CB: 0.89 +/- 0.02 to 0.90 +/- 0.02; P < 0.01), and lunch RQ (FB: 0.089 +/- 0.03 to 0.85 +/- 0.03; CB: 0.89 +/- 0.03 for both; P < 0.01). In the CB group at follow-up, 24-h RQ was positively associated with fasting glucose (r = 0.66, P < 0.05), glucose area under the curve (AUC) (r = 0.51, P < 0.05), and insulin AUC (r = 0.52, P < 0.05) and inversely associated with insulin sensitivity (r = -0.51, P < 0.05). Conclusions: The macronutrient composition of breakfast affects substrate utilization throughout the day in older adults. The consumption of a high-fat, lower-carbohydrate breakfast may reduce the risk of metabolic disease. This trial was registered at www.clinicaltrials.gov as NCT03164200. PMID- 29490099 TI - Higher Mediterranean Diet Quality Scores and Lower Body Mass Index Are Associated with a Less-Oxidized Plasma Glutathione and Cysteine Redox Status in Adults. AB - Background: Both systemic redox status and diet quality are associated with risk outcomes in chronic disease. It is not known, however, the extent to which diet quality influences plasma thiol/disulfide redox status. Objective: The purpose of this study was to investigate the influence of diet, as measured by diet quality scores and other dietary factors, on systemic thiol/disulfide redox status. Methods: We performed a cross-sectional study of 685 working men and women (ages >=18 y) in Atlanta, GA. Diet was assessed by 3 diet quality scores: the Alternative Healthy Eating Index (AHEI), Dietary Approaches to Stop Hypertension (DASH), and the Mediterranean Diet Score (MDS). We measured concentrations of plasma glutathione (GSH), cysteine, their associated oxidized forms [glutathione disulfide (GSSG) and cystine (CySS), respectively], and their redox potentials (EhGSSG and EhCySS) to determine thiol/disulfide redox status. Linear regression modeling was performed to assess relations between diet and plasma redox after adjustment for age, body mass index (BMI), sex, race, and history of chronic disease. Results: MDS was positively associated with plasma GSH (beta = 0.02; 95% CI: 0.003, 0.03) and total GSH (GSH + GSSG) (beta = 0.02; 95% CI: 0.003, 0.03), and inversely associated with the CySS:GSH ratio (beta = -0.02; 95% CI: -0.04, 0.004). There were significant independent associations between individual MDS components (dairy, vegetables, fish, and monounsaturated fat intake) and varying plasma redox indexes (P < 0.05). AHEI and DASH diet quality indexes and other diet factors of interest were not significantly correlated with plasma thiol and disulfide redox measures. Conclusion: Adherence to the Mediterranean diet was significantly associated with a favorable plasma thiol/disulfide redox profile, independent of BMI, in a generally healthy working adult population. Although longitudinal studies are warranted, these findings contribute to the feasibility of targeting a Mediterranean diet to improve plasma redox status. PMID- 29490098 TI - The Multiple Faces of the Metal Transporter ZIP14 (SLC39A14). AB - The SLC39A family of metal transporters was identified through homologies with the Zrt- and Irt-like (ZIP) proteins from yeast and plants. Of all the ZIP transporters, ZIP14 is arguably the most robustly characterized in terms of function at the integrative level. Mice with a global knockout of Zip14 are viable, thus providing the opportunity to conduct physiologic experiments. In mice, Zip14 expression is highly tissue specific, with the greatest abundance in the jejunum > liver > heart > kidney > white adipose tissue > skeletal muscle > spleen > pancreas. A unique feature of Zip14 is its upregulation by proinflammatory conditions, particularly increased interleukin 6 (IL-6) and nitric oxide. The transcription factors AP-1, ATF4, and ATF6alpha are involved in Zip14 regulation. ZIP14 does not appear to be zinc-regulated. The Zip14 knockout phenotype shows multiple sites of ZIP14 function, including the liver, adipose tissue, brain, pancreas, and bone. A prominent feature of the Zip14 ablation is a reduction in intestinal barrier function and onset of metabolic endotoxemia. Many aspects of the phenotype are accentuated with age and accompany increased circulating IL-6. Studies with 65Zn, 59Fe [nontransferrin-bound iron (NTBI)] and 54Mn show that ZIP14 transports these metals. At a steady state, the plasma concentrations of zinc, NTBI, and manganese are such that zinc ions are the major substrate available for ZIP14 at the cell surface. Upregulation of ZIP14 accounts for the hypozincemia and hepatic zinc accumulation associated with acute inflammation and sepsis and is required for liver regeneration and resistance to endoplasmic reticulum (ER) stress. Zip14 ablation in mice produces a defect in manganese excretion that leads to excess manganese accumulation in the brain that produces characteristics of Parkinsonism. PMID- 29490100 TI - A High-Fat Breakfast Enhances 24-Hour Fat Oxidation in Older Adults. PMID- 29490102 TI - The Pathways from a Behavior Change Communication Intervention to Infant and Young Child Feeding in Bangladesh Are Mediated and Potentiated by Maternal Self Efficacy. AB - Background: Although self-efficacy is a potential determinant of feeding and care behaviors, there is limited empirical analysis of the role of maternal self efficacy in low- and middle-income countries. In the context of behavior change interventions (BCIs) addressing complementary feeding (CF), it is possible that maternal self-efficacy can mediate or enhance intervention impacts. Objective: In the context of a BCI in Bangladesh, we studied the role of maternal self-efficacy for CF (MSE-CF) for 2 CF behaviors with the use of a theoretically grounded empirical model of determinants to illustrate the potential roles of MSE-CF. Methods: We developed and tested a locally relevant scale for MSE-CF and included it in a survey (n = 457 mothers of children aged 6-24 mo) conducted as part of a cluster-randomized evaluation. Qualitative research was used to inform the selection of 2 intervention-targeted behaviors: feeding green leafy vegetables in the last 24 h (GLV) and on-time introduction of egg (EGG) between 6 and 8 mo of age. We then examined direct, mediated, and potentiated paths of MSE-CF in relation to the impacts of the BCI on these behaviors with the use of regression and structural equation modeling. Results: GLV and EGG were higher in the intensive group than in the nonintensive control group (16.0 percentage points for GLV; P < 0.001; 11.2 percentage points for EGG; P = 0.037). For GLV, MSE-CF mediated (beta = 0.345, P = 0.010) and potentiated (beta = 0.390, P = 0.038) the effect of the intensive group. In contrast, MSE-CF did not mediate or potentiate the effect of the intervention on EGG. Conclusions: MSE-CF was a significant mediator and potentiator for GLV but not for EGG. The divergent findings highlight the complex determinants of individual specific infant and young child feeding behaviors. The study shows the value of measuring behavioral determinants, such as MSE-CF, that affect a caregiver's capability to adopt intervention-targeted behaviors. PMID- 29490101 TI - omega-3 and omega-6 Fatty Acid Supplementation May Reduce Autism Symptoms Based on Parent Report in Preterm Toddlers. AB - Background: Children born preterm are at increased risk of autism spectrum disorder (ASD). n-3 (omega-3) Combined with n-6 (omega-6) fatty acids including gamma-linolenic acid (GLA) may benefit children born preterm showing early signs of ASD. Previous trials have reported that docosahexaenoic acid (DHA) promotes cognitive development in preterm neonates and n-3 fatty acids combined with GLA improve attention-deficit-hyperactivity disorder. Objectives: The objectives of the pilot Preemie Tots Trial were 1) to confirm the feasibility of a full-scale trial in toddlers born very preterm and exhibiting ASD symptoms and 2) to explore the effects of supplementation on parent-reported ASD symptoms and related behaviors. Methods: This was a 90-d randomized, fully blinded, placebo-controlled trial in 31 children 18-38 mo of age who were born at <=29 wk of gestation. One group was assigned to daily Omega-3-6-9 Junior (Nordic Naturals, Inc.) treatment (including 338 mg eicosapentaenoic acid, 225 mg DHA, and 83 mg GLA), and the other group received canola oil (124 mg palmitic acid, 39 mg stearic acid, 513 mg linoleic acid, 225 mg alpha-linolenic acid, and 1346 mg oleic acid). Mixed effects regression analyses followed intent-to-treat analysis and explored effects on parent-reported ASD symptoms and related behaviors. Results: Of 31 children randomly assigned, 28 had complete outcome data. After accounting for baseline scores, those assigned to treatment exhibited a greater reduction in ASD symptoms per the Brief Infant Toddler Social Emotional Assessment ASD scale than did those assigned to placebo (difference in change = - 2.1 points; 95% CI: - 4.1, - 0.2 points; standardized effect size = - 0.71). No other outcome measure reflected a similar magnitude or a significant effect. Conclusions: This pilot trial confirmed adequate numbers of children enrolled and participated fully in the trial. No safety concerns were noted. It also found clinically-significant improvements in ASD symptoms for children randomly assigned to receive Omega-3-6 9 Junior, but effects were confined to one subscale. A future full-scale trial is warranted given the lack of effective treatments for this population. This trial was registered at www.clinicaltrials.gov as NCT01683565. PMID- 29490103 TI - Postprandial Gastrointestinal Function Differs after Acute Administration of Sourdough Compared with Brewer's Yeast Bakery Products in Healthy Adults. AB - Background: Europeans consume large quantities of bakery products, although these are known as one of the food categories that potentially leads to postprandial symptoms (such as fullness and bloating). Objective: The aim of this study was to evaluate the effects of sourdough baked goods on gastric emptying and gastrointestinal fermentation and symptoms in healthy people. Methods: In a double-blind, randomized crossover study, 2 sourdough croissants (SCs) or 2 brewer's yeast croissants (BCs) were served as single meals to 17 healthy adults [9 women; age range: 18-40 y; body mass index range (in kg/m2): 18-24]. Gastric volume (GV) was evaluated by magnetic resonance to calculate gastric-emptying rate in the 3-h interval after croissant ingestion. A hydrogen breath test was performed to measure hydrogen production after SC and BC ingestion. Palatability and postprandial gastrointestinal symptoms (discomfort, nausea, fullness, and bloating) over a 4-h period after the meal were evaluated. The area under the curve (AUC) was used to evaluate the overall effects on all variables tested. Results: The total GV AUC was reduced by 11% during the 3 h after the consumption of SCs compared with BCs (P = 0.02). Hydrogen production during the 4-h interval after ingestion of SCs was 30% lower than after BCs (P = 0.03). SCs were rated as being >2 times as palatable as BCs (P < 0.001). The overall severity of postprandial symptoms was 36% lower during the 4 h after intake of SCs compared with BCs (P = 0.05). Conclusion: Sourdough bakery products could promote better postprandial gastrointestinal function in healthy adults and be more acceptable than those prepared with brewer's yeast. This trial was registered at www.clinicaltrials.gov as NCT03207516. PMID- 29490104 TI - Socioeconomic Inequalities Persist Despite Declining Stunting Prevalence in Low- and Middle-Income Countries. AB - Background: Global stunting prevalence has been nearly halved between 1990 and 2016, but it remains unclear whether this decline has benefited poor and rural populations within low- and middle-income countries (LMICs). Objective: We assessed time trends in stunting among children <5 y of age (under-5) according to household wealth and place of residence in 67 LMICs. Methods: Stunting prevalence was analyzed in 217 nationally representative Demographic and Health Surveys and Multiple Indicator Cluster Surveys from 67 countries with >=2 surveys between 1993 and 2014. National estimates were stratified by wealth and area of residence, comparing the poorest 40% with the wealthiest 60%, and those residing in urban and rural areas. Time trends were calculated for LMICs by using multilevel regression models weighted by under-5 population, with stratification by wealth and by residence. Trends in absolute (slope index of inequality; SII) and relative (concentration index; CIX) inequalities were calculated. Results: Mean prevalences in 1993 were 53.7% in low-income and 48.2% in middle-income countries, with annual average linear declines of 0.76 and 0.72 percentage points (pp), respectively. Although similar slopes of declines were observed for the poorest 40% and wealthiest 60% groups in all countries (0.78 and 0.74 pp, respectively), absolute and relative inequalities increased over time in low income countries (SII increased from -19.3% in 1993 to -23.7% in 2014 and CIX increased from -6.2% to -10.8% in the same period). In middle-income countries, socioeconomic inequalities remained stable. Overall, stunting prevalence decreased more rapidly among rural than for urban children (0.78 and 0.55 pp, respectively). Conclusions: The prevalence of stunting is decreasing. Poor-rich gaps are stable in middle-income countries and slightly increasing in low-income countries. Rural-urban inequalities are decreasing over time. PMID- 29490105 TI - Physical Activity Duration but Not Energy Expenditure Differs between Daily and Intermittent Breakfast Consumption in Adolescent Girls: A Randomized Crossover Trial. AB - Background: It is not known whether breakfast frequency affects physical activity (PA) in children or adolescents. Objective: This study examined the effect of daily compared with intermittent breakfast consumption on estimated PA energy expenditure (PAEE) in adolescent girls. Methods: Under a randomized crossover design, 27 girls [mean +/- SD age: 12.4 +/- 0.5 y, body mass index (in kg/m2): 19.3 +/- 3.0] completed two 7-d conditions. A standardized breakfast (~1674 kJ) was consumed every day before 0900 in the daily breakfast consumption (DBC) condition. The standardized breakfast was consumed on only 3 d before 0900 in the intermittent breakfast consumption (IBC) condition, alternating with breakfast omission on the remaining 4 d (i.e., only water consumed before 1030). Combined heart rate accelerometry was used to estimate PAEE throughout each condition. Statistical analyses were completed by using condition * time of day repeated measures ANOVA. The primary outcome was PAEE and the secondary outcome was time spent in PA. Results: Daily estimated PAEE from sedentary or light-, moderate-, or vigorous-intensity PA and total PAEE were not significantly different between the conditions. The condition * time of day interaction for sedentary time (P = 0.05) indicated that the girls spent an additional 11.5 min/d being sedentary in the IBC condition compared with the DBC condition from 1530 to bedtime (P = 0.04). Light PA was 19.8 min/d longer in the DBC condition than in the IBC condition (P = 0.05), which was accumulated from waking to 1030 (P = 0.04) and from 1530 to bedtime (P = 0.03). There were no significant differences in time spent in moderate PA or vigorous PA between the conditions. Conclusions: Adolescent girls spent more time in light PA before 1030 and after school and spent less time sedentary after school when a standardized breakfast was consumed daily than when consumed intermittently across 7 d. However, breakfast manipulation did not affect estimated daily PAEE. This trial was registered at www.isrctn.com as ISRCTN74579070. PMID- 29490106 TI - Arginine Metabolism and A-beta + Ketosis-Prone Diabetes. PMID- 29490107 TI - Invasive predator tips the balance of symmetrical competition between native coral-reef fishes. AB - The importance of competition and predation in structuring ecological communities is typically examined separately such that interactions between these processes are seldom understood. By causing large reductions in native prey, invasive predators may modify native species interactions. I conducted a manipulative field experiment in The Bahamas to investigate the possibility that the invasive Pacific red lionfish (Pterois volitans) alters competition between planktivorous fairy and blackcap basslets (Gramma loreto and Gramma melacara, respectively). Competition between these coral-reef fishes is known to have symmetrical effects on the juveniles of both species, whereby the feeding positions under reef ledges and growth rates of these individuals are hindered. Following baseline censuses of local populations of competing basslets, I simultaneously manipulated the abundance of lionfish on entire reefs, and the abundance of basslets in local populations under isolated ledges within each reef, resulting in three treatments: unmanipulated control populations of both basslets, reduced abundance of fairy basslet, and reduced abundance of blackcap basslet. For eight weeks, I measured the change in biomass and feeding position of 2-5 cm size classes of each basslet species and calculated the growth rates of ~2 cm individuals using a standard mark-and-recapture method. Experimental populations were filmed at dusk using automated video cameras to quantify the behavior of lionfish overlapping with basslets. Video playback revealed lionfish hunted across all ledge positions, regardless of which basslet species were present, yet lionfish differentially reduced the biomass of only juvenile (2 cm) fairy basslet. Predation reduced the effects of interspecific competition on juvenile blackcap basslet as evidenced by corresponding shifts in feeding position toward coveted front edges of ledges and increases in growth rates that were comparable to the response of these fish in populations where competition was experimentally reduced. Thus, an invasive marine predator altered the outcome of interspecific competition via differential predation, which tipped the balance of competition between native prey species from symmetrical to asymmetrical effects on juveniles. This study reveals a newly demonstrated context in which predation can indirectly facilitate prey, further broadening our understanding of the interactive effects of predation and competition in the context of invasive species. PMID- 29490109 TI - Mid-esophageal bicaval versus short-axis view of interatrial septum in two dimensional transesophageal echocardiography for diagnosis and measurement of atrial septal pouches. AB - BACKGROUND: Recent studies suggest that the left-sided septal pouch (SP) may increase the risk of cryptogenic stroke and act as an arrhythmogenic substrate. The aim of this study was to compare two transesophageal echocardiography (TEE) projections of the interventricular septum: mid-esophageal bicaval and short-axis views toward evaluating their ability to detect SPs. MATERIALS AND METHODS: A total of 146 patients with both bicaval and short-axis TEE views were included in this study. The presence of SPs was determined, and they were evaluated for morphology. RESULTS: Irrespective of TEE projection view, the left SP was detected in 74 cases (50.7%), right SP in 16 cases (11.0%), and double in one case (0.7%). Agreement between both projections occurred in 119 cases (81.5%) with a weighted kappa coefficient of 0.68 (good agreement). We detected more left SPs from the bicaval view compared to the short-axis view; however, the observed difference was statistically insignificant (72 vs 59, P = .13). The detection of right SPs was higher in the short-axis view, but also statistically insignificant (9 vs 13, P = .38). Bland-Altman analysis revealed a significant difference in the left SP depth with higher values in the bicaval than short-axis view (systematic difference = 1.17 mm, LoA: -4.88-7.22 mm, P = .02, ICC = 0.58). CONCLUSIONS: The mid-esophageal bicaval view should be preferable over mid esophageal short-axis view of interatrial septum for the diagnosis and measurement of the left SP. PMID- 29490110 TI - A Chromium Hydroxide/MIL-101(Cr) MOF Composite Catalyst and Its Use for the Selective Isomerization of Glucose to Fructose. AB - A metal-organic framework (MOF)-based catalyst, chromium hydroxide/MIL-101(Cr), was prepared by a one-pot synthesis method. The combination of chromium hydroxide particles on and within Lewis acidic MIL-101 accomplishes highly selective conversion of glucose to fructose in the presence of ethanol, matching the performance of optimized Sn-containing Lewis acidic zeolites. Differently from zeolites, NMR spectroscopy studies with isotopically labeled molecules demonstrate that isomerization of glucose to fructose on this catalyst, proceeds predominantly via a proton transfer mechanism. PMID- 29490108 TI - The stable oxygen isotope ratio of resin extractable phosphate derived from fresh cattle faeces. AB - RATIONALE: Phosphorus losses from agriculture pose an environmental threat to watercourses. A new approach using the stable oxygen isotope ratio of oxygen in phosphate (delta18 OPO4 value) may help elucidate some phosphorus sources and cycling. Accurately determined and isotopically distinct source values are essential for this process. The delta18 OPO4 values of animal wastes have, up to now, received little attention. METHODS: Phosphate (PO4 ) was extracted from cattle faeces using anion resins and the contribution of microbial PO4 was assessed. The delta18 OPO4 value of the extracted PO4 was measured by precipitating silver phosphate and subsequent analysis on a thermal conversion elemental analyser at 1400 degrees C, with the resultant carbon monoxide being mixed with a helium carrier gas passed through a gas chromatography (GC) column into a mass spectrometer. Faecal water oxygen isotope ratios (delta18 OH2O values) were determined on a dual-inlet mass spectrometer through a process of headspace carbon dioxide equilibration with water samples. RESULTS: Microbiological results indicated that much of the extracted PO4 was not derived directly from the gut fauna lysed during the extraction of PO4 from the faeces. Assuming that the faecal delta18 OH2O values represented cattle body water, the predicted pyrophosphatase equilibrium delta18 OPO4 (Edelta18 OPO4 ) values ranged between +17.9 and +19.90/00, while using groundwater delta18 OH2O values gave a range of +13.1 to +14.00/00. The faecal delta18 OPO4 values ranged between +13.2 and +15.30/00. CONCLUSIONS: The fresh faecal delta18 OPO4 values were equivalent to those reported elsewhere for agricultural animal slurry. However, they were different from the Edelta18 OPO4 value calculated from the faecal delta18 OH2O value. Our results indicate that slurry PO4 is, in the main, derived from animal faeces although an explanation for the observed value range could not be determined. PMID- 29490111 TI - Transition-Metal-Catalyzed Regioselective Asymmetric Mono-Hydrogenation of Dienes and Polyenes. AB - Organic compounds containing multiple C=C bonds are attractive substrates for catalytic asymmetric hydrogenation. The full saturation of prochiral double bonds, controlling the creation of two or more stereocenters in one step, is obviously a remarkable goal. However, another fascinating and useful option is to selectively introduce a new defined stereogenic center while leaving other double bonds untouched. Thus, the retained functionalities can be further exploited in synthesis. Examples of regio- and enantioselective mono-hydrogenations of polyolefins are highlighted in this Concept article, and are divided according to the nature of the reduced double bond and the transition-metal catalyst used. Alkenes bearing coordinating functional groups are often preferentially hydrogenated by Rh- and Ru-complexes, while the more recently developed Ir-based catalysts promote the selective saturation on alkyl-substituted olefins. Relevant applications of this effective methodology in the synthesis of natural products are included to demonstrate its value in organic synthesis. PMID- 29490112 TI - Selective Hydrogen Atom Abstraction through Induced Bond Polarization: Direct alpha-Arylation of Alcohols through Photoredox, HAT, and Nickel Catalysis. AB - The combination of nickel metallaphotoredox catalysis, hydrogen atom transfer catalysis, and a Lewis acid activation mode, has led to the development of an arylation method for the selective functionalization of alcohol alpha-hydroxy C-H bonds. This approach employs zinc-mediated alcohol deprotonation to activate alpha-hydroxy C-H bonds while simultaneously suppressing C-O bond formation by inhibiting the formation of nickel alkoxide species. The use of Zn-based Lewis acids also deactivates other hydridic bonds such as alpha-amino and alpha-oxy C-H bonds. This approach facilitates rapid access to benzylic alcohols, an important motif in drug discovery. A 3-step synthesis of the drug Prozac exemplifies the utility of this new method. PMID- 29490113 TI - Global longitudinal strain and long-term outcomes in asymptomatic extracardiac sarcoid patients with no apparent cardiovascular disease. AB - PURPOSE: Global longitudinal strain (GLS) is increasingly accepted as a predictor of mortality in various clinical settings. This study tested the hypothesis that GLS is associated with increased event rate in patients with extracardiac sarcoidosis, who have no overt symptoms of cardiovascular disease and preserved ejection fraction (EF). METHODS: We retrospectively studied 117 patients with extracardiac sarcoidosis and 45 age- and sex-matched controls, who underwent comprehensive echocardiographic study, while GLS was measured by an offline speckle tracking algorithm. Patients who had signs and symptoms of cardiovascular disease at the time of the examination were excluded from the study. Patients were followed for an average of 57.1 months. Primary endpoint was defined as a composite endpoint of heart failure-related hospitalizations, need for device therapy, arrhythmias, and all-cause mortality. RESULTS: The age of patients was 42 +/- 6 years old (43 men). Events were recorded in 10 patients (8.5%). Tissue Doppler revealed E/Em 7.9 +/- 3.5, while EF was 54.2 +/- 3.5%. Global longitudinal strain was 14.4 +/- 3%, and a cutoff value <=-13.6% for GLS was considered more associated with adverse outcomes (AUC 0.84). After adjustment for multiple potential confounders (age, gender, hypertension, diabetes, E/Em, and EF), GLS remained strongly associated with adverse outcomes (HR 0.8, 0.63 to 0.98 95% C.I, P = .04). CONCLUSIONS: In conclusion, among patients with extracardiac sarcoidosis and no symptoms of cardiovascular disease, even when EF is preserved, GLS seems to be strongly associated with adverse future events. PMID- 29490114 TI - Jimmie Holland and the development of psycho-oncology in Africa. PMID- 29490115 TI - Transition Metal Ions Promote the Bioavailability of Hydrophobic Therapeutics: Cu and Zn Interactions with RNA Polymerase I Inhibitor CX5461. AB - Low aqueous solubility is a major barrier to the clinical application of otherwise promising drug candidates. We demonstrate that this issue can be resolved in medicinal molecules containing potential ligating groups, through the addition of labile transition-metal ions. Incubation of the chemotherapeutic CX5461 with Cu2+ or Zn2+ enables solubilization at neutral pH but does not affect intrinsic cytotoxicity. Spectroscopic and computational studies demonstrate that this arises from coordination to the pyrazine functionality of CX5461 and may involve bidentate coordination at physiological pH. PMID- 29490116 TI - Supplementation of specific carbohydrates results in enhanced deposition of chondrogenic-specific matrix during mesenchymal stem cell differentiation. AB - Repair or regeneration of hyaline cartilage in knees, shoulders, intervertebral discs, and other assorted joints is a major therapeutic target. To date, therapeutic strategies utilizing chondrocytes or mesenchymal stem cells are limited by expandability or the generation of mechanically inferior cartilage. Our objective is to generate robust cartilage-specific matrix from human mesenchymal stem cells suitable for further therapeutic development. Human mesenchymal stem cells, in an alginate 3D format, were supplied with individual sugars and chains which comprise the glycan component of proteoglycans in articular cartilage (galactose, hyaluronic acid, glucuronic acid, and xylose) during chondrogenesis. After an initial evaluation for proteoglycan deposition utilizing Alcian blue, the tissue was further evaluated for viability, structural elements, and hypertrophic status. With the further addition of serum, a substantial increase was observed in viability, the amount of proteoglycan deposition, glycosaminoglycan production, and an enhancement of Hyaluronic Acid, Collagen II and Aggrecan deposition. Suppression of hypertrophic markers (COL1A1, COL10A1, MMP13, and RUNX2) was also observed. When mesenchymal stem cells were supplied with the raw building materials of proteoglycans and a limited amount of serum during chondrogenesis, it resulted in the generation of viable hyaline-like cartilage with deposition of structural components which exceeded previously reported in vitro-based cartilage. PMID- 29490117 TI - Taking Advantage of Hydrophobic Fluorine Interactions for Self-Assembled Quantum Dots as a Delivery Platform for Enzymes. AB - Self-assembly of nanoparticles provides unique opportunities as nanoplatforms for controlled delivery. By exploiting the important role of noncovalent hydrophobic interactions in the engineering of stable assemblies, nanoassemblies were formed by the self-assembly of fluorinated quantum dots in aqueous medium through fluorine-fluorine interactions. These nanoassemblies encapsulated different enzymes (laccase and alpha-galactosidase) with encapsulation efficiencies of >=74 %. Importantly, the encapsulated enzymes maintained their catalytic activity, following Michaelis-Menten kinetics. Under an acidic environment the nanoassemblies were slowly disassembled, thus allowing the release of encapsulated enzymes. The effective release of the assayed enzymes demonstrated the feasibility of this nanoplatform to be used in pH-mediated enzyme delivery. In addition, the as-synthesized nanoassemblies, having a diameter of about 50 nm, presented high colloidal stability and fluorescence emission, which make them a promising multifunctional nanoplatform. PMID- 29490118 TI - Assessment of the wish to hasten death in patients with advanced cancer: A comparison of 2 different approaches. AB - INTRODUCTION: The Desire for Death Rating Scale (DDRS) and the short form of the Schedule of Attitudes toward Hastened Death (SAHD-5) are different approaches to assessing the wish to hasten death (WTHD). Both have clinical threshold scores for identifying individuals with a meaningfully elevated WTHD. However, the agreement between the 2 measures and patient opinions about assessment of the WTHD are unknown. OBJECTIVES: To compare the DDRS and SAHD-5 and to analyze patient opinions about assessment of the WTHD. METHODS: The WTHD was assessed in 107 patients with advanced cancer using both the DDRS and SAHD-5. Patients were subsequently asked their opinion about this assessment. RESULTS: Correlation between scores on the SAHD-5 and the DDRS was moderate, Spearman rho = 0.67 (P < .01). The SAHD-5 identified 13 patients (12.1%) at risk of the WTHD, and the DDRS identified 6 patients (5.6%) with a moderate-high WTHD (P > .05). Concordance between the DDRS and SAHD-5 in identifying individuals with an elevated WTHD was poor when using recommended cut-off scores, kappa = 0.37 (P < 0.01) but could be improved by using different thresholds. Only 4 patients (3.8%) regarded the assessment questions as bothersome, and 90.6% considered it important that health care professionals inquire about the WTHD. CONCLUSIONS: The SAHD-5 and DDRS appear to be appropriate methods for assessing the WTHD and could provide complementary information in clinical practice: the SAHD-5 to screen for risk of the WTHD and the DDRS as a clinical interview to explore it in greater detail. Assessment of the WTHD is well accepted by palliative care cancer patients. PMID- 29490119 TI - Social network, autonomy, and adherence correlates of future time perspective in patients with head and neck cancer. AB - OBJECTIVE: Socioemotional selectivity theory proposes that, with more limited future time perspective (FTP), the meaning of individual life goals shifts from instrumental and long-term goals, such as autonomy, to emotionally meaningful and short-term life goals, especially concerning meaningful social relationships. Adverse side effects of cancer therapy may conflict with the realization of emotionally meaningful goals leading to nonadherence. In line with the theoretical assumptions, this study aimed to investigate (a) associations among disease symptoms, physical and cognitive limitations, and FTP and (b) among FTP, family network size, striving for autonomy, and treatment adherence. METHOD: One hundred fifty-seven patients (43-90 years; 75% male) with head and/or neck cancer of a German University Medical Centre completed a questionnaire measuring FTP, age, disease symptoms, physical and cognitive functioning, family network size, and treatment adherence. Autonomy was assessed with a card sort task. RESULTS: A structural equation model yielded an acceptable fit chi2 (28) = 44.41, P = .025, chi2 /df = 1.59, root mean square error of approximation = 0.06 (90% CI = 0.02, 0.09), Tucker-Lewis Index = 0.92, and Comparative Fit Index = 0.96. An increased level of disease symptoms and physical and cognitive limitations was related to a shorter subjective FTP. Furthermore, individuals with a limited FTP reported a smaller family network, a lowered quest for autonomy, and lower treatment adherence. CONCLUSIONS: Hypotheses derived from socioemotional selectivity theory were supported by the data. Longitudinal investigations should follow to corroborate findings and to focus on underlying mechanisms as improving patients FTP may play a crucial role in future disease management programs. PMID- 29490120 TI - Cancer survivors' understanding of the cause and cure of their illness: Religious and secular appraisals. AB - OBJECTIVE: Little is known about survivors' understanding of the cause of their cancer and of their recovery, nor how these ways of understanding relate to their well-being. No study has examined both secular and religious appraisals of the same event. The current study aimed to examine both religious (God) and secular (self) appraisals of both the cause (attributions) and course/cure of cancer in relation to multiple aspects of adjustment. METHODS: Data were obtained from a sample of cancer survivors at Time 1 (n = 250) and 1 year later (Time 2, n = 167). RESULTS: Cancer survivors endorsed higher appraisals relating to course/cure of their cancer than those relating to cause, and they endorsed both secular and religious appraisals. Appraisals of the cause and course/cure of cancer were differentially related to adjustment, such that self-attributions of cause and God-attributions of cause were related to negative aspects of adjustment (eg, negative affect and pessimism), while appraisals of self and God's control over the course/cure were related to positive aspects of adjustment (eg, perceived positive life and health changes since cancer). Religiosity did not moderate most of relationships between religious appraisals and adjustment outcomes. CONCLUSIONS: Secular and religious appraisals of cancer are not mutually exclusive, and religious appraisals are associated with adjustment regardless of survivors' religiosity. Appraisals relating to cause and course/cure have differential relationships with well-being. Addressing cancer survivors' appraisals-religious or nonreligious-in a therapeutic setting may be beneficial regardless of their reported religiosity. PMID- 29490121 TI - Effects of the source gap on transmission efficiency of a quadrupole mass spectrometer. AB - RATIONALE: Recent trends towards miniature and portable quadrupole mass spectrometry (QMS) entail challenges in instrumental sensitivity, which is influenced by 3D fringe field effects on ion transmission in the Quadrupole Mass Filter (QMF). The relationship of these effects with the gap from the ion source to the QMF entrance (source gap) is significant and little explored. We examine transmission characteristics experimentally and use the results to test the predictive accuracy of a recently developed 3D QMF simulation model. The model is then applied to directly investigate optimal transmission m/z ranges across multiple source gaps. METHODS: A portable single filter quadrupole mass spectrometer is used to analyse transmission characteristics across a range of common gases. We use an experimental approach originally proposed by Ehlert, enhanced with a novel method for absolute calibration of the transmission curve. Custom QMF simulation software employs the boundary element method (BEM) to compute accurate 3D electric fields. This is used to study the effects of the source gap on transmission efficiency. RESULTS: Experimental findings confirm a centrally peaked transmission curve; simulations correctly predict the optimal transmission location (in m/z) and percentage, and extend the experimental trend. We compare several methods for determining fringe field length, demonstrating how the size of the physical source gap influences both the length and the intensity of the fringe field at the QMF entrance. A complex relationship with ion transmission is revealed in which different source gaps promote optimal transmission at differing m/z ranges. CONCLUSIONS: The presented results map the relationship between the source gap and transmission efficiency for the given instrument, using a simulation method transferrable to other setups. This is of importance to miniature and portable quadrupole mass spectrometers design for specific applications, for the first time enabling the source gap to be tailored for optimal transmission in the desired mass range. PMID- 29490122 TI - Using ideal distributions of the time since habitat was disturbed to build metrics for evaluating landscape condition. AB - Developing a standardized approach to measuring the state of biodiversity in landscapes undergoing disturbance is crucial for evaluating and comparing change across different systems, assessing ecosystem vulnerability and the impacts of destructive activities, and helping direct species recovery actions. Existing ecosystem metrics of condition fail to acknowledge that a particular community could be in multiple states, and the distribution of states could worsen or improve when impacted by a disturbance process, depending on how far the current landscape distribution of states diverges from pre-anthropogenic impact baseline conditions. We propose a way of rapidly assessing regional-scale condition in ecosystems where the distribution of age classes representing increasing time since last disturbance is suspected to have diverged from an ideal benchmark reference distribution. We develop two metrics that (1) compare the observed mean time since last disturbance with an expected mean and (2) quantify the summed shortfall of vegetation age-class frequencies relative to a reference age-class distribution of time since last disturbance. We demonstrate the condition metrics using two case studies: (1) fire in threatened southwestern Australian proteaceaous mallee-heath and (2) impacts of disturbance (fire and logging) in the critically endangered southeastern Australian mountain ash Eucalyptus regnans forest on the yellow-bellied glider Petaurus australis. We explore the effects of uncertainty in benchmark time since last disturbance, and evaluate metric sensitivity using simulated age-class distributions representing alternative ecosystems. By accounting for and penalizing too-frequent and too-rare disturbances, the summed shortfall metric is more sensitive to change than mean time since last disturbance. We find that mountain ash forest is in much poorer condition (summed shortfall 38.5 out of 100 for a 120-yr benchmark disturbance interval) than indicated merely by loss of extent (84% of vegetation remaining). Proteaceaous mallee-heath is in worse condition than indicated by loss of extent for an upper benchmark interval of 80 yr, but condition almost doubles for the minimum tolerable time since last disturbance interval of 20 yr. To fully describe ecosystem degradation, we recommend that our summed shortfall metric, focused on habitat quality and informed by biologically meaningful baselines, be added to existing condition measures focused on vegetation extent. This will improve evaluation of change in ecosystem states and enhance management of ecosystems in poor condition. PMID- 29490124 TI - Psychogenic Polydipsia in a Woman With Anorexia Nervosa: Case Report and Recommendations. PMID- 29490123 TI - Synthesis, Structure, and Magnetism of Tris(amide) [Ln{N(SiMe3 )2 }3 ]1- Complexes of the Non-traditional +2 Lanthanide Ions. AB - A new series of Ln2+ complexes has been synthesized that overturns two previous generalizations in rare-earth metal reduction chemistry: that amide ligands do not form isolable complexes of the highly reducing non-traditional Ln2+ ions, and that yttrium is a good model for the late lanthanides in these reductive reactions. Reduction of Ln(NR2 )3 (R=SiMe3 ) complexes in THF under Ar with M=K or Rb in the presence of 2.2.2-cryptand (crypt) forms crystallographically characterizable [M(crypt)][Ln(NR2 )3 ] complexes not only for the traditional Tm2+ ion and the configurational crossover ions, Nd2+ and Dy2+ , but also for the non-traditional Gd2+ , Tb2+ , Ho2+ , and Er2+ ions. Crystallographic data as well as UV/Vis, magnetic susceptibility, and density functional theory studies are consistent with the accessibility of 4fn 5d1 configurations for Ln2+ ions in this tris(silylamide) ligand environment. The Dy2+ complex, [K(crypt)][Dy(NR2 )3 ], has a higher magnetic moment than previously observed for any monometallic complex: 11.67 MUB . PMID- 29490125 TI - Corticosteroid use in management of pediatric emergency conditions [digest]. AB - Corticosteroids have been used for over half a century to treat various inflammatory disorders; however, their use in many pediatric conditions remains controversial. This issue reviews evidence on corticosteroid treatment in acute asthma exacerbations, croup, acute pharyngitis, anaphylaxis, acute spinal injury, and bacterial meningitis. While corticosteroids are clearly indicated for management of asthma exacerbations and croup, they are not universally recommended for potential spinal cord injury. Due to insufficient data or conflicting data, corticosteroids may be considered in children with acute pharyngitis, anaphylaxis, and bacterial meningitis. [Points & Pearls is a digest of Pediatric Emergency Medicine Practice]. PMID- 29490126 TI - Corticosteroid use in management of pediatric emergency conditions. AB - Corticosteroids have been used for over half a century to treat various inflammatory disorders; however, their use in many pediatric conditions remains controversial. This issue reviews evidence on corticosteroid treatment in acute asthma exacerbations, croup, acute pharyngitis, anaphylaxis, acute spinal injury, and bacterial meningitis. While corticosteroids are clearly indicated for management of asthma exacerbations and croup, they are not universally recommended for potential spinal cord injury. Due to insufficient data or conflicting data, corticosteroids may be considered in children with acute pharyngitis, anaphylaxis, and bacterial meningitis. PMID- 29490127 TI - Building automation moves to next level. Experts predict BAS to provide automated data and automated actions. PMID- 29490128 TI - Handling hazardous drugs in health care. USP 800 brings new guidelines to hospital pharmacies. PMID- 29490129 TI - A data-driven approach to ES work. Key indicators to achieve environmental services excellence. PMID- 29490130 TI - Baldrige Award process drives new patient tower planning. Memorial Hermann Sugar Land uses quality techniques in expansion. PMID- 29490131 TI - Medical center generates ongoing energy-saving gains. PMID- 29490132 TI - Nanopore Analysis of the 5-Guanidinohydantoin to Iminoallantoin Isomerization in Duplex DNA. AB - In DNA, guanine oxidation yields diastereomers of 5-guanidinohydantoin (Gh) as one of the major products. In nucleosides and single-stranded DNA, Gh is in a pH dependent equilibrium with its constitutional isomer iminoallantoin (Ia). Herein, the isomerization reaction between Gh and Ia was monitored in duplex DNA using a protein nanopore by measuring the ionic current when duplex DNA interacts with the pore under an electrophoretic force. Monitoring current levels in this single molecule method proved to be superior for analysis of population distributions in an equilibrating mixture of four isomers in duplex DNA as a function of pH. The results identified Gh as a major isomer observed when base paired with A, C, or G at pH 6.4-8.4, and Ia was a minor isomer of the reaction mixture that was only observed when the pH was >7.4 in the duplex DNA context. The present results suggest that Gh will be the dominant isomer in duplex DNA under physiological conditions regardless of the base-pairing partner in the duplex. PMID- 29490133 TI - Multi-State VALBOND for Atomistic Simulations of Hypervalent Molecules, Metal Complexes, and Reactions. AB - The implementation, validation, and application of the multi-state VALBOND method for transition-metal-containing and hypervalent molecules are presented. This approach is particularly suited for molecules with unusual shapes and systems that need to be described by a superposition of resonance structures, each of which satisfies the octet rule. The implementation is based on the original VALBOND force field and allows us to smoothly switch between resonance structures, each of which can be characterized by its own force field, including varying charge distributions and coupling terms between the states. The implementation conserves total energy for simulations in the gas phase and in solution and is applied to a number of topical systems. For the small hypervalent molecule ClF3, the barrier for pseudorotation is found to be 4.3 kcal/mol, which compares favorably with the experimentally measured value of 4.8 kcal/mol. A transition-metal-containing complex, cisplatin, is characterized by six resonance states, for which the vibrational spectrum is found to be in good agreement with experiment. Finally, umbrella sampling simulations of the SN2 reaction BrMe + Cl- -> Br- + MeCl in solution yield a barrier height of 24.6 kcal/mol, in good agreement with experiment (24.7 kcal/mol). PMID- 29490134 TI - Photodissociation of Free Metalloporphyrin Dimer Multianions. AB - We have used action photofragmentation spectroscopy in the visible spectral range (410 to 650 nm) to investigate the optical properties of different monomeric and dimeric M(II)-meso-tetra-(4-sulfonatophenyl)-porphyrin (with M = Pd(II), Cu(II), Zn(II)) multianions isolated in the gas phase without solvent. In particular, we report the position of the Q-bands (S0 -> S1 transitions) as a function of charge state, counterions, oligomerization, and dimer structure type. The results for the monomers (charge states = 4- and 3-, sodiated and protonated) are in good agreement with TDDFT calculations and condensed-phase spectra. For both homo and heterometallic dimers, photofragmentation spectra were recorded for two charge states, 5- and 3-, corresponding to coplanar and cofacial structure types, respectively. The fragmentation patterns observed for the dimers depend significantly on charge state, with fragmentation into monomers being dominant for the 5- species, while the 3- charge state predominantly fragments by SO2 loss. The monomer -> dimer Q-band spectral shifts observed in the gas phase were compared with the optical properties of porphyrin aggregates in solution. PMID- 29490136 TI - Molecular Mechanism of Alternative P450-Catalyzed Metabolism of Environmental Phenolic Endocrine-Disrupting Chemicals. AB - Understanding the bioactivation mechanisms to predict toxic metabolites is critical for risk assessment of phenolic endocrine-disrupting chemicals (EDCs). One mechanism involves ipso-substitution, which may contribute to the total turnover of phenolic EDCs, yet the detailed mechanism and its relationship with other mechanisms are unknown. We used density functional theory to investigate the P450-catalyzed ipso-substitution mechanism of the prominent xenoestrogen bisphenol A. The ipso-substitution proceeds via H-abstraction from bisphenol A by Compound I, followed by essentially barrierless OH-rebound onto the ipso-position forming a quinol, which can spontaneously decompose into the carbocation and hydroquinone. This carbocation can further evolve into the highly estrogenic hydroxylated and dimer-type metabolites. The H-abstraction/OH-rebound reaction mechanism has been verified as a general reaction mode for many other phenolic EDCs, such as bisphenol analogues, alkylphenols and chlorophenols. The identified mechanism enables us to effectively distinguish between type I (eliminating substituent as anion) and type II (eliminating-substituent as cation) ipso substitution in various phenolic EDCs. We envision that the identified pathways will be applicable for prediction of metabolites from phenolic EDCs whose fate are affected by this alternative type of P450 reactivity, and accordingly enable the screening of these metabolites for endocrine-disrupting activity. PMID- 29490135 TI - Superconducting-Magnet-Based Faraday Rotation Spectrometer for Real Time in Situ Measurement of OH Radicals at 106 Molecule/cm3 Level in an Atmospheric Simulation Chamber. AB - Atmospheric simulation chambers play vital roles in the validation of chemical mechanisms and act as a bridge between field measurements and modeling. Chambers operating at atmospheric levels of OH radicals (106-107 molecule/cm3) can significantly enhance the possibility for investigating the discrepancies between the observation and model predications. However, few chambers can directly detect chamber OH radicals at ambient levels. In this paper, we report on the first combination of a superconducting magnet with midinfrared Faraday rotation spectroscopy (FRS) for real time in situ measurement of the OH concentration in an atmospheric simulation chamber. With the use of a multipass enhanced FRS, a detection limit of 3.2 * 106 OH/cm3 (2sigma, 4 s) was achieved with an absorption path length of 108 m. The developed FRS system provided a unique, self-calibrated analytical instrument for in situ direct measurement of chamber OH concentration. PMID- 29490137 TI - Real-Time Evaluation of Bacterial Viability Using Gold Nanoparticles. AB - Real-time evaluation of bacterial viability is important for various purposes such as hygiene management, development of antibacterial agents, and effective utilization of bacterial resources. Here, we demonstrate a simple procedure for evaluating bacterial viability using gold nanoparticles (Au NPs). The color of bacterial suspensions containing Au NPs strongly depended on the bacterial viability. We found that the dispersion state of Au NPs affected the color of the suspension, based on the interaction of Au NPs with substances secreted by the bacteria. This color change was easily recognized with the naked eye, and viability was accurately determined by measuring the absorbance at a specific wavelength. This method was applicable to various bacterial species, regardless of whether they were Gram-positive or Gram-negative. PMID- 29490139 TI - Spray-Drying-Assisted Layer-by-Layer Assembly of Alginate, 3 Aminopropyltriethoxysilane, and Magnesium Hydroxide Flame Retardant and Its Catalytic Graphitization in Ethylene-Vinyl Acetate Resin. AB - Alginates (nickel alginate, NiA; copper alginate, CuA; zinc alginate, ZnA) and 3 aminopropyltriethoxysilane (APTES) were alternately deposited on a magnesium hydroxide (MH) surface by the spray-drying-assisted layer-by-layer assembly technique, fabricating some efficient and environmentally benign flame retardants (M-FR, including Ni-FR, Cu-FR, and Zn-FR). The morphology, chemical compositions, and structures of M-FR were investigated. With 50 wt % loading, compared with EVA28+MH, the peak heat release rate, smoke production rate, and CO production rate of EVA28+Ni-FR decreased by 50.78%, 61.76%, and 66.67%, respectively. The metals or metal oxide nanoparticles arising from alginates could catalyze the pyrolysis intermediates of EVA into graphene and amorphous carbon, which could bind the inorganic compounds (the decomposition products of MH and APTES) together and form some more protective barriers. For each M-FR, the flame retardant and smoke suppression efficiency were different, which were caused by the diverse carbonization and graphitization behaviors of three alginates. ZnA generated some ZnO aggregations and could not catalyze the graphitization of intermediates. For CuA, the catalytic graphitization was limited by the tightly binding graphene layer. As for NiA, the configuration of the Ni atom could not provide strong binding of Ni substrate and carbon. The liquid-like Ni nanoparticles could restructure and get out from firm graphene shells, so the catalytic graphitization of NiA was efficient and sustainable. This work displayed the catalytic graphitization mechanism of alginates while exploring a simple and novel strategy for fabricating efficient green flame retardants. PMID- 29490138 TI - Structure from Dynamics: Vibrational Dynamics of Interfacial Water as a Probe of Aqueous Heterogeneity. AB - The structural heterogeneity of water at various interfaces can be revealed by time-resolved sum-frequency generation spectroscopy. The vibrational dynamics of the O-H stretch vibration of interfacial water can reflect structural variations. Specifically, the vibrational lifetime is typically found to increase with increasing frequency of the O-H stretch vibration, which can report on the hydrogen-bonding heterogeneity of water. We compare and contrast vibrational dynamics of water in contact with various surfaces, including vapor, biomolecules, and solid interfaces. The results reveal that variations in the vibrational lifetime with vibrational frequency are very typical, and can frequently be accounted for by the bulk-like heterogeneous response of interfacial water. Specific interfaces exist, however, for which the behavior is less straightforward. These insights into the heterogeneity of interfacial water thus obtained contribute to a better understanding of complex phenomena taking place at aqueous interfaces, such as photocatalytic reactions and protein folding. PMID- 29490140 TI - Elucidating an Amorphous Form Stabilization Mechanism for Tenapanor Hydrochloride: Crystal Structure Analysis Using X-ray Diffraction, NMR Crystallography, and Molecular Modeling. AB - By the combined use of powder and single-crystal X-ray diffraction, solid-state NMR, and molecular modeling, the crystal structures of two systems containing the unusually large tenapanor drug molecule have been determined: the free form, ANHY, and a dihydrochloride salt form, 2HCl. Dynamic nuclear polarization (DNP) assisted solid-state NMR (SSNMR) crystallography investigations were found essential for the final assignment and were used to validate the crystal structure of ANHY. From a structural informatics analysis of ANHY and 2HCl, conformational ring differences in one part of the molecule were observed which influence the relative orientation of a methyl group on a ring nitrogen and thereby impact the crystallizability of the dihydrochloride salt. From quantum chemistry calculations, the dynamics between different ring conformations in tenapanor is predicted to be fast. Addition of HCl to tenapanor results in general in a mixture of protonated ring conformers and hence a statistical mix of diastereoisomers which builds up the amorphous form, a-2HCl. This was qualitatively verified by 13C CP/MAS NMR investigations of the amorphous form. Thus, to form any significant amount of the crystalline material 2HCl, which originates from the minor (i.e., energetically less stable) ring conformations, one needs to involve nitrogen deprotonation to allow exchange between the minor and major conformations of ANHY in solution. Thus, by controlling the solution pH value to well below the p Ka of ANHY, the equilibrium between ANHY and 2HCl can be controlled and by this mechanism the crystallization of 2HCl can be avoided and the amorphous form of the dichloride salt can therefore be stabilized. PMID- 29490141 TI - Porous PVdF/GO Nanofibrous Membranes for Selective Separation and Recycling of Charged Organic Dyes from Water. AB - Graphene oxide (GO) membranes are robust and continue to attract great attention due to their fascinating properties, despite their potential issues regarding stability and selectivity in aqueous-phase processing. That being said, however, the functional moieties of GO could be used for membrane surface modification, while ensuring simultaneous removal and recycling of industrial organic dyes. Herein, we present a versatile porous structured polyvinylidene fluoride-graphene oxide (PVdF-GO) nanofibrous membranes (NFMs), prepared by using simple and straightforward electrospinning approach for selective separation and filtration. The GO nanosheets were distributed homogeneously throughout the PVdF nanofiber, regulating the surface morphology and performance of PVdF-GO NFM. The PVdF-GO NFMs possesses high mechanical strength and surface free energy (SFE), consequently resulting high permeation and filtration efficiency as compared to PVdF NFM. The selectivity (99%) toward positively charged dyes based on electrostatic attraction, while maintaining rejection (100%) for negatively charged dye from mixed solutions highlight the role of GO in PVdF-GO NFM, owing to uniform pores and negatively charged surface. In addition, the actual efficiency of NFMs could be recovered easily up to three consecutive filtration cycles by regeneration, thereby assuring high stability. The high permeation, purification and filtration efficiency, good stability and recycling of PVdF-GO NFMs are promising for use in practical water purification and applications, particularly for selective filtration and recycling of dyes. PMID- 29490142 TI - Azomethine Ylide Cycloaddition Approach toward Dendrobine: Synthesis of 5 Deoxymubironine C. AB - A concise route to the azatricyclo[6.2.1.04,11]undecane core of (-)-dendrobine and (-)-mubironine C is described wherein an unstabilized azomethine ylide cycloaddition provides the complete carbon framework of the natural products. The cyclization precursor is made in short order from ( R)-carvone through an unconventional high-pressure Ireland-Claisen reaction. Attempts to install a final hydroxyl group through an intramolecular lactonization strategy and the observation of an unexpected and highly complex enal-ene product are also reported. PMID- 29490143 TI - Organocatalytic Approach for Short Asymmetric Synthesis of ( R)-Paraconyl Alcohol: Application to the Total Syntheses of IM-2, SCB2, and A-Factor gamma Butyrolactone Autoregulators. AB - ( R)-Paraconyl alcohol is found to be a key intermediate for the syntheses of many gamma-butyrolactone autoregulators. The chiral auxiliary approach and enzymatic resolution are the two common strategies employed so far in the literature for the asymmetric synthesis of ( R)-paraconyl alcohol. Herein, we report the first organocatalytic approach for the short asymmetric synthesis of ( R)-paraconyl alcohol in four steps and by a single column purification. Asymmetric syntheses of IM-2, SCB2, and A-factor gamma-butyrolactone autoregulators were achieved from ( R)-paraconyl alcohol in three steps. PMID- 29490145 TI - Cause or Effect? The Elusive Role of Regulatory T Cells in Tuberculosis. PMID- 29490144 TI - Characterizing the Surface Roughness Length Scales of Lactose Carrier Particles in Dry Powder Inhalers. AB - Surface roughness is well recognized as a critical physical property of particulate systems, particularly in relation to adhesion, friction, and flow. An example is the surface property of carrier particles in carrier-based dry powder inhaler (DPI) formulations. The numerical characterization of roughness remains rather unsatisfactory due to the lack of spatial (or length scale) information about surface features when a common amplitude parameter such as average roughness ( Ra) is used. An analysis of the roughness of lactose carrier particles at three different length scales, designed for specificity to the study of interactive mixtures in DPI, was explored in this study. Three Ra parameters were used to represent the microscale, intermediate scale, and macroscale roughness of six types of surface-modified carriers. Coating of micronized lactose fines on coarse carrier particles increased their microroughness from 389 to 639 nm while the macroroughness was not affected. Roller compaction at higher roll forces led to very effective surface roughening, particularly at longer length scales. Changes in Ra parameters corroborated the visual observations of particles under the scanning electron microscope. Roughness at the intermediate scale showed the best correlation with the fine particle fraction (FPF) of DPI formulations. From the range of 250 to 650 nm, every 100 nm increase in the intermediate roughness led to ~8% increase in the FPF. However, the effect of surface roughness was greatly diminished when fine lactose (median size, 9 MUm) of comparable amounts to the micronized drug were added to the formulation. The combination of roughness parameters at various length scales provided much discriminatory surface information, which then revealed the "quality" of roughness necessary for improving DPI performance. PMID- 29490147 TI - Underreporting of Interstitial Lung Abnormalities on Lung Cancer Screening Computed Tomography. PMID- 29490146 TI - MiR-378 promotes the cell proliferation of osteosarcoma through down-regulating the expression of Kruppel-like factor 9. AB - MicroRNAs (miRNAs) are small non-coding RNAs that play important roles in a variety of biological processes. Dysregulation of miRNAs is tightly associated with the malignancy of cancers. Aberrant expression of miR-378 has been observed in human cancers; however, the function of miR-378 in osteosarcoma (OS) remains largely unknown. Here, we showed that miR-378 was highly expressed in human OS tissues and cell lines. Overexpression of miR-378 significantly promoted the cell proliferation of OS cells. Molecular studies identified Kruppel-like factor-9 (KLF9) as a functional downstream target of miR-378. MiR-378 directly bound to the mRNA 3'-UTR region of KLF9 and suppressed the expression of KLF9. Highly expressed KLF9 reversed the promoting effect of miR-378 on the proliferation of OS cells. The expression level of miR-378 was negatively correlated with that of KLF9 in OS tissues. Collectively, our results demonstrated the molecular interaction between miR-378 and KLF9, indicating the therapeutic potential of miR 378 for OS. PMID- 29490148 TI - Double-Opposing Z-Plasty for Secondary Surgical Management of Velopharyngeal Insufficiency Following Primary Furlow Palatoplasty. AB - OBJECTIVE: The present study investigates the efficacy of performing a "palate rerepair" utilizing a double-opposing z-palatoplasty (DOZ) following primary Furlow palatoplasty. DESIGN: Retrospective study. SETTING: Tertiary referral academic center for craniofacial surgery. PATIENTS: 15 consecutive patients who presented with velopharyngeal insufficiency (VPI) after primary Furlow palatoplasty. MAIN OUTCOME MEASURES: All subjects were evaluated using the perceptual speech assessment (PSA) scale. Criteria for inclusion in the study were (1) velopharyngeal gap size on phonation of 7 mm or less and (2) lateral wall motion at least 40% normal. RESULTS: Mean PSA score was 7.13 + 3.31 (range 3 13) preoperatively, and decreased to 1.80 + 2.83 (range 0-11; P < .001 vs baseline) 3 months or more after surgery. A sphincter pharyngoplasty was performed as a tertiary procedure in 2 patients due to persistent nasal air emission. There was no symptomatic airway compromise following secondary or tertiary management in all patients. Presence of a cleft lip, lateral wall motion, and velopharyngeal gap size did not impact outcomes. CONCLUSIONS: We have demonstrated that a DOZ performed secondarily is anatomically possible following Furlow palatoplasty and can restore function of the levator muscle despite significant scarring following primary repair. This approach respects anatomic principles of palatoplasty without eliminating the possibility for extrapalatal procedures should velopharyngeal competence not be achieved. PMID- 29490149 TI - Endotracheal and Endobronchial Metastases of Small Cell Lung Cancer. PMID- 29490150 TI - Tuberculosis Mortality in the United States: Epidemiology and Prevention Opportunities. AB - RATIONALE: More information on risk factors for death from tuberculosis in the United States could help reduce the tuberculosis mortality rate, which has remained steady for over a decade. Objective(s) To identify risk factors for tuberculosis-related death in adults. METHODS: We performed a retrospective study of 1,304 adults with tuberculosis who died before treatment completion and 1,039 frequency-matched controls who completed tuberculosis treatment in 2005-2006 in thirteen states reporting 65% of U.S. tuberculosis cases. We used in-depth record abstractions and a standard algorithm to classify deaths in persons with tuberculosis as tuberculosis-related or not. We then compared these classifications to causes of death as coded in death certificates. We used multivariable logistic regression to calculate adjusted odds ratios (aOR) for predictors of tuberculosis-related death among adults compared with those who completed tuberculosis treatment. RESULTS: Of 1,304 adult deaths, 942 (72%) were tuberculosis-related, 272 (21%) were not, and 90 (7%) couldn't be classified. Of 847 tuberculosis-related deaths with death certificates available, 378 (45%) did not list tuberculosis as a cause of death. Adjusting for known risks, we identified new risks for tuberculosis-related death during treatment: absence of pyrazinamide in the initial regimen (aOR=3.4, 95% CI=1.9-6.0); immunosuppressive medications (aOR=2.5, 95% CI=1.1-5.6); incomplete TB diagnostic evaluation (aOR=2.2, 95% CI=1.5-3.3), and an alternative non-TB diagnosis prior to TB diagnosis (aOR=1.6, 95% CI=1.2-2.2). Conclusions Most persons who died with tuberculosis had a tuberculosis-related death. Intensive record review revealed tuberculosis as a cause of death more often than did death certificate diagnoses. New tools, such as a TB mortality risk score based on our study findings, may identify TB patients for in-hospital interventions to prevent death. PMID- 29490151 TI - On beyond Zebra (and the Apnea-Hypopnea Index) in Obstructive Sleep Apnea. PMID- 29490152 TI - The impact of private online video consulting in primary care. PMID- 29490153 TI - Thoracolithiasis: A Rare Cause of Multiple Nodules. PMID- 29490154 TI - A Full-Length Pulmonary Artery Dissection. PMID- 29490155 TI - The Cancer Mortality Risk Project - Cancer Mortality Risks by Anatomic Site: Part 1 - Introductory Overview; Part II - Carcinoma of the Colon: 20-Year Mortality Follow-up Derived from 1973-2013 (NCI) SEER*Stat Survival Database. AB - This introductory overview describes the recommencement of the Cancer Mortality Risks project, a systematic medical-actuarial comparative analysis of selected cancer mortality risks originally initiated by the authors in the year 2002 utilizing the National Cancer Institute (NCI) SEER*Stat 4.2.3 (Surveillance, Epidemiology, and End Results) database between 1973 and 2002 and released April 3, 2002. This study is based on approximately 40 major invasive cancer anatomic sites used in previous conversions of the National Cancer Institute SEER survival data to comparative mortality in the Medical Risks monographs published in 19761 and 1990.2 Anatomic site-specific cancer mortality abstracts of SEER survival data containing 20-year comparative mortality follow-up by cohort entry-period, histologic type, age, sex, race, stage, grade and other variables was proposed for publication as a monograph, compendium or a series of concise but detailed mortality articles. PMID- 29490156 TI - A Notch Hiding in the R Wave. AB - A benign appearing ECG is found to contain subtle clues suggestive of underlying structural heart disease. PMID- 29490157 TI - Relapse and Mortality Risk of Stage I Testicular Cancer. AB - OBJECTIVES: - To assess the medical insurance risk for patients with stage I testicular cancer (TC), by calculating the overall mortality risk with and without relapse, and compare it to men from the Danish population. BACKGROUND: - Testicular cancer is the most common malignancy in young males. Outcomes of a Danish cohort of 3366 patients with stage I TC (1366 non-seminomas (NSTC) and 2000 Seminomas (STC)), were analyzed. METHOD: - The data were analyzed by the "illness-death" model. For the analysis of the transitions between diagnosis, relapse and death we adopted a parametric approach, where the relationship between the intensities and the effect of covariates were specified by Poisson regression models for NSTC and STC individually. RESULTS: - In the NSTC group, 422 patients relapsed. Six relapses (1.4%) occurred after 5 years of follow-up. In the STC group, 389 relapsed. The relapse rate after 5 years was 4.1%. The overall mortality analyses showed that the standardized mortality ratio (SMR) for men with NSTC without relapse, was slightly lower than in the matched general population of Danish men (SMR = 0.9). In STC patients without relapse, SMR was 0.80. Relapse raised the overall mortality by a factor 2.0 for NSTC and 1.5 for STC. CONCLUSIONS: - The fact that few relapses occur 5 years after diagnosis is an important finding for risk assessment in life insurance. It makes it possible to insure men diagnosed with stage I TC, who have not experienced relapse 5 years after diagnosis, on normal terms. PMID- 29490158 TI - Mesenteric Panniculitis. AB - Mesenteric panniculitis is a rare, benign, and chronic fibrosing inflammatory disease that affects the adipose tissue of the small intestine and colon. PMID- 29490160 TI - JIM Reading List. PMID- 29490159 TI - All-Cause Mortality for Life Insurance Applicants with a History of Prostate Cancer. AB - OBJECTIVE: - To determine the all-cause mortality of life insurance applicants diagnosed with prostate cancer currently or at some time in the past. BACKGROUND: - Prostate cancer is common and a frequent cause of cancer death. Both the frequency of prostate cancer in men and its propensity for causing premature mortality require insurance company medical directors and underwriters to have a good understanding of prostate cancer-related mortality trends, patterns, and outcomes in the insured population. METHODOLOGY: - Life insurance applicants with reported prostate cancer were extracted from data covering United States residents between November 2007 and November 2014. Information about these applicants was matched to the Social Security Death Master (SSDMF) file for deaths occurring from 2007 to 2011 and to another commercially available death source file (Other Death Source, ODS) for deaths occurring from 2007 to 2014 to determine vital status. Actual to Expected (A/E) mortality ratios were calculated using the Society of Actuaries 2015 Valuation Basic Table (2015VBT), select and ultimate table (age last birthday) and the 2013 US population as expected mortality ratios. All expected bases were not smoker distinct. RESULTS: - The study covered applicants between the ages of 45 and 75 and had approximately 405,000 person-years of exposure. Older aged applicants had a lower mortality ratio than those who were younger. Applicants 45 to 54 had the highest mortality ratios in the first year after diagnosis which steadily decreased in years 6 to 10 with an increase in the mortality ratio for those over 10 years from diagnosis. Relative mortality rate was close to unity for those with localized cancer across all age groups. The mortality ratio was 2 to 4 times greater for those with cancer in 1 positive node, and much greater with 3 positive nodes. For each time-from-diagnosis category, the relative mortality ratios compared to age were highest in the 45-54 age group. The A/E mortality ratios based on the 2015VBT were consistently 3 to 4 times that of the mortality ratios based on the 2013 US population. CONCLUSION: - The mortality patterns of insurance applicants with prostate cancer were similar to that observed in individuals with prostate cancer in the general population. Applicant age, time to diagnosis and cancer severity were the most significant variables to predict mortality. PMID- 29490161 TI - NT-proBNP Predicts All-Cause Mortality in a Population of Insurance Applicants, Follow-up Analysis and Further Observations. AB - OBJECTIVE: - Further refine the independent value of NT-proBNP, accounting for the impact of other test results, in predicting all-cause mortality for individual life insurance applicants with and without heart disease. METHOD: - Using the Social Security Death Master File and multivariate analysis, relative mortality was determined for 245,322 life insurance applicants ages 50 to 89 tested for NT-proBNP (almost all based on age and policy amount) along with other laboratory tests and measurement of blood pressure and BMI. RESULTS: - NT-proBNP values <=75 pg/mL included the majority of applicants denying heart disease and had the lowest risk, while values >500 pg/mL for females and >300 pg/mL for males had very high relative risk. Those admitting to heart disease had a higher mortality risk for each band of NT-proBNP relative to those denying heart disease but had a similar and equally predictive risk curve. CONCLUSION: - NT-proBNP is a strong independent predictor of all-cause mortality in the absence or presence of known heart disease but the range of values associated with increased risk varies by sex. PMID- 29490162 TI - Rebooting Human Immunology. AB - Recent progress in both conceptual and technological approaches to human immunology have rejuvenated a field that has long been in the shadow of the inbred mouse model. This is a healthy development both for the clinical relevance of immunology and for the fact that it is a way to gain access to the wealth of phenomenology in the many human diseases that involve the immune system. This is where we are likely to discover new immunological mechanisms and principals, especially those involving genetic heterogeneity or environmental influences that are difficult to model effectively in inbred mice. We also suggest that there are likely to be novel immunological mechanisms in long-lived, less fecund mammals such as human beings since they must remain healthy far longer than short-lived rodents in order for the species to survive. PMID- 29490163 TI - Exploiting Nanobodies' Singular Traits. AB - The unique class of heavy chain-only antibodies, present in Camelidae, can be shrunk to just the variable region of the heavy chain to yield VHHs, also called nanobodies. About one-tenth the size of their full-size counterparts, nanobodies can serve in applications similar to those for conventional antibodies, but they come with a number of signature advantages that find increasing application in biology. They not only function as crystallization chaperones but also can be expressed inside cells as such, or fused to other proteins to perturb the function of their targets, for example, by enforcing their localization or degradation. Their small size also affords advantages when applied in vivo, for example, in imaging applications. Here we review such applications, with particular emphasis on those areas where conventional antibodies would face a more challenging environment. PMID- 29490164 TI - Regulation of the Cell Biology of Antigen Cross-Presentation. AB - Antigen cross-presentation is an adaptation of the cellular process of loading MHC-I molecules with endogenous peptides during their biosynthesis within the endoplasmic reticulum. Cross-presented peptides derive from internalized proteins, microbial pathogens, and transformed or dying cells. The physical separation of internalized cargo from the endoplasmic reticulum, where the machinery for assembling peptide-MHC-I complexes resides, poses a challenge. To solve this problem, deliberate rewiring of organelle communication within cells is necessary to prepare for cross-presentation, and different endocytic receptors and vesicular traffic patterns customize the emergent cross-presentation compartment to the nature of the peptide source. Three distinct pathways of vesicular traffic converge to form the ideal cross-presentation compartment, each regulated differently to supply a unique component that enables cross presentation of a diverse repertoire of peptides. Delivery of centerpiece MHC-I molecules is the critical step regulated by microbe-sensitive Toll-like receptors. Defining the subcellular sources of MHC-I and identifying sites of peptide loading during cross-presentation remain key challenges. PMID- 29490165 TI - The Immune Response to Mycobacterium tuberculosis in HIV-1-Coinfected Persons. AB - Globally, about 36.7 million people were living with HIV infection at the end of 2015. The most frequent infection co-occurring with HIV-1 is Mycobacterium tuberculosis-374,000 deaths per annum are attributable to HIV-tuberculosis, 75% of those occurring in Africa. HIV-1 infection increases the risk of tuberculosis by a factor of up to 26 and alters its clinical presentation, complicates diagnosis and treatment, and worsens outcome. Although HIV-1-induced depletion of CD4+ T cells underlies all these effects, more widespread immune deficits also contribute to susceptibility and pathogenesis. These defects present a challenge to understand and ameliorate, but also an opportunity to learn and optimize mechanisms that normally protect people against tuberculosis. The most effective means to prevent and ameliorate tuberculosis in HIV-1-infected people is antiretroviral therapy, but this may be complicated by pathological immune deterioration that in turn requires more effective host-directed anti inflammatory therapies to be derived. PMID- 29490166 TI - Inhibition of Vascular Adhesion Protein-1 for Treatment of Graft-Versus-Host Disease in Mice. AB - Graft-versus-host disease (GVHD) is a potentially lethal complication of hematopoietic stem cell transplantation (HSCT). GVHD comprises acute and chronic forms. To date, several approaches to treat acute GVHD or chronic GVHD have been reported. However, there is no literature precedent regarding all-in-one methods to address the 2 GVHD types. Severe inflammation in organs affected by GVHD is highly problematic, and vascular adhesion protein-1 (VAP-1) is known to be detrimentally involved in various inflammatory diseases. Based on the previous reports, we envisaged that there would be a link between GVHD and VAP-1, and we strived to create effective therapies for the 2 types of GVHD using a mouse model of GVHD. Our investigation indicated that expression of VAP-1 was elevated in organs disordered by GVHD. Hence, we subsequently attempted to block VAP-1 by using a novel inhibitor. Our results indicate that systemic injection of the inhibitor prevented aberrant influx of inflammatory cells into tissues and thereby mitigate GVHD-elicited inflammation and fibrosis. Collectively, our study suggests that the increased expression of VAP-1 is detrimentally associated with the development of GVHD and that the blockade of VAP-1 could be a promising medical modality to combat the acute and chronic variants.-Mukai, S., Ogawa, Y., Kawakami, Y., Mashima, Y., Tsubota, K. Inhibition of vascular adhesion protein-1 for treatment of graft-versus-host disease in mice. PMID- 29490167 TI - New maresin conjugates in tissue regeneration pathway counters leukotriene D4 stimulated vascular responses. AB - Resolution of acute inflammation is governed, in part, by lipid mediator class switching from proinflammatory eicosanoids to specialized proresolving mediators, including a recently identified new pathway of mediators, termed maresin conjugates in tissue regeneration (MCTR), which includes MCTR1, MCTR2, and MCTR3. Here, we addressed whether each MCTR can impact the known vascular actions of cysteinyl leukotrienes. Leukotriene D4 (LTD4; 1.5 nmol/mouse) initiated vascular leakage in mouse cremaster vessels, which was reduced (>75%) by MCTR1 and MCTR2 (0.15 nmol each). With isolated Ciona intestinalis (sea squirt) primordial hearts, LTD4 (1-100 nM) induced negative inotropic action and lowered heartbeats 20-30%. Each MCTR (1-100 nM) prevented LTD4-reduced heart rates. With human cysteinyl leukotriene receptor-1 (CysLT1) expressed in CHO cells, each MCTR (10 100 nM) significantly reduced LTD4-initiated signaling. To assess the contribution of CysLT1 in the proresolving actions of MCTR, we carried out human macrophage (MPhi) phagocytosis. Each MCTR (0.1-10 nM) stimulated human MPhi phagocytosis of live Escherichia coli, whereas LTD4 did not stimulate phagocytosis. MCTR-activated phagocytosis was significantly blocked by a pharmacologic receptor antagonist (MK571). With both CHO-CysLT1 and human MPhis, each MCTR competed for specific [3H]-LTD4 binding with apparent lower affinity than LTD4. Thus, each MCTR functionally interacts with human CysLT1 to pharmacologically counter-regulate vascular responses and stimulate physiologic phagocytosis with MPhis.-Chiang, N., Riley, I. R., Dalli, J., Rodriguez, A. R., Spur, B. W., Serhan, C. N. New maresin conjugates in tissue regeneration pathway counters leukotriene D4-stimulated vascular responses. PMID- 29490169 TI - Uropathogenic Escherichia coli virulence factor hemolysin A causes programmed cell necrosis by altering mitochondrial dynamics. AB - Uropathogenic Escherichia coli (UPEC) is the most common cause of urinary tract infections. In this study, UPEC strains harboring hemolysin A (HlyA) did not induce programmed cell death pathways by the activation of caspases. Instead, the UPEC pore-forming toxin HlyA triggered an increase in mitochondrial Ca2+ levels and manipulated mitochondrial dynamics by causing fragmentation of the mitochondrial network. Alterations in mitochondrial dynamics resulted in severe impairment of mitochondrial functions by loss of membrane potential, increase in reactive oxygen species production, and ATP depletion. Moreover, HlyA caused disruption of plasma membrane integrity that was accompanied by extracellular release of the danger-associated molecules high-mobility group box 1 (HMGB1) and histone 3 (H3). Our results indicate that UPEC induced programmed cell necrosis by irreversibly impairing mitochondrial function. This finding suggests a strategy devised by UPEC at the onset of infection to escape early innate immune response and silently propagate inside host cells.-Lu, Y., Rafiq, A., Zhang, Z., Aslani, F., Fijak, M., Lei, T., Wang, M., Kumar, S., Klug, J., Bergmann, M., Chakraborty, T., Meinhardt, A., Bhushan, S. Uropathogenic Escherichia coli virulence factor hemolysin A causes programmed cell necrosis by altering mitochondrial dynamics. PMID- 29490170 TI - Durvalumab in Stage III Non-Small-Cell Lung Cancer. PMID- 29490171 TI - Correcting the Record on a Fracture Risk Assessment Tool. PMID- 29490168 TI - Antioxidant defense and protection against cardiac arrhythmias: lessons from a mammalian hibernator (the woodchuck). AB - Hibernating animals show resistance to hypothermia-induced cardiac arrhythmias. However, it is not clear whether and how mammalian hibernators are resistant to ischemia-induced arrhythmias. The goal of this investigation was to determine the susceptibility of woodchucks ( Marmota monax) to arrhythmias and their mechanisms after coronary artery occlusion at the same room temperature in both winter, the time for hibernation, and summer, when they do not hibernate. By monitoring telemetric electrocardiograms, we found significantly higher arrhythmia scores, calculated as the severity of arrhythmias, with incidence of ventricular tachycardia, ventricular fibrillation, and thus sudden cardiac death (SCD) in woodchucks in summer than they had in winter. The level of catalase expression in woodchuck hearts was significantly higher, whereas the level of oxidized Ca2+/calmodulin-dependent protein kinase II (CaMKII) was lower in winter than it was in summer. Ventricular myocytes isolated from woodchucks in winter were more resistant to H2O2-induced early afterdepolarizations (EADs) compared with myocytes isolated from woodchucks in summer. The EADs were eliminated by inhibiting CaMKII (with KN-93), l-type Ca current (with nifedipine), or late Na+ current (with ranolazine). In woodchucks, in the summer, the arrhythmia score was significantly reduced by overexpression of catalase ( via adenoviral vectors) or the inhibition of CaMKII (with KN-93) in the heart. This study suggests that the heart of the mammalian hibernator is more resistant to ischemia-induced arrhythmias and SCD in winter. Increased antioxidative capacity and reduced CaMKII activity may confer resistance in woodchuck hearts against EADs and arrhythmias during winter. The profound protection conferred by catalase overexpression or CaMKII inhibition in this novel natural animal model may provide insights into clinical directions for therapy of arrhythmias.-Zhao, Z., Kudej, R. K., Wen, H., Fefelova, N., Yan, L., Vatner, D. E., Vatner, S. F., Xie, L.-H. Antioxidant defense and protection against cardiac arrhythmias: lessons from a mammalian hibernator (the woodchuck). PMID- 29490172 TI - Rhinofacial Entomophthoromycosis. PMID- 29490173 TI - Reduction in Firearm Injuries during NRA Annual Conventions. PMID- 29490175 TI - Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin's Lymphoma. PMID- 29490174 TI - An Unexpected Expectoration. PMID- 29490176 TI - Swell Findings in Hydrogels. PMID- 29490177 TI - Treating Onchocerciasis in Regions in Which Loa loa Is Endemic. PMID- 29490178 TI - Out of the Straitjacket. PMID- 29490179 TI - Case 37-2017: A Man with Unintentional Opioid Overdose. PMID- 29490180 TI - Breast-Cancer Recurrence after Stopping Endocrine Therapy. PMID- 29490181 TI - Antibody-Mediated Encephalitis. PMID- 29490182 TI - Friction in the Path to Use of Biosimilar Drugs. PMID- 29490183 TI - A Role for Hydrocortisone Therapy in Septic Shock? PMID- 29490184 TI - More on an Unconscious Patient with a DNR Tattoo. PMID- 29490186 TI - HIV Drug Resistance. PMID- 29490187 TI - Interstitial Keratitis in Cogan's Syndrome. PMID- 29490188 TI - DNA Nanotechnology-Enabled Interfacial Engineering for Biosensor Development. AB - Biosensors represent biomimetic analytical tools for addressing increasing needs in medical diagnosis, environmental monitoring, security, and biodefense. Nevertheless, widespread real-world applications of biosensors remain challenging due to limitations of performance, including sensitivity, specificity, speed, and reproducibility. In this review, we present a DNA nanotechnology-enabled interfacial engineering approach for improving the performance of biosensors. We first introduce the main challenges of the biosensing interfaces, especially under the context of controlling the DNA interfacial assembly. We then summarize recent progress in DNA nanotechnology and efforts to harness DNA nanostructures to engineer various biological interfaces, with a particular focus on the use of framework nucleic acids. We also discuss the implementation of biosensors to detect physiologically relevant nucleic acids, proteins, small molecules, ions, and other biomarkers. This review highlights promising applications of DNA nanotechnology in interfacial engineering for biosensors and related areas. PMID- 29490189 TI - Nano-Enabled Approaches to Chemical Imaging in Biosystems. AB - Understanding and predicting how biosystems function require knowledge about the dynamic physicochemical environments with which they interact and alter by their presence. Yet, identifying specific components, tracking the dynamics of the system, and monitoring local environmental conditions without disrupting biosystem function present significant challenges for analytical measurements. Nanomaterials, by their very size and nature, can act as probes and interfaces to biosystems and offer solutions to some of these challenges. At the nanoscale, material properties emerge that can be exploited for localizing biomolecules and making chemical measurements at cellular and subcellular scales. Here, we review advances in chemical imaging enabled by nanoscale structures, in the use of nanoparticles as chemical and environmental probes, and in the development of micro- and nanoscale fluidic devices to define and manipulate local environments and facilitate chemical measurements of complex biosystems. Integration of these nano-enabled methods will lead to an unprecedented understanding of biosystem function. PMID- 29490190 TI - Wearable and Implantable Sensors for Biomedical Applications. AB - Mobile health technologies offer great promise for reducing healthcare costs and improving patient care. Wearable and implantable technologies are contributing to a transformation in the mobile health era in terms of improving healthcare and health outcomes and providing real-time guidance on improved health management and tracking. In this article, we review the biomedical applications of wearable and implantable medical devices and sensors, ranging from monitoring to prevention of diseases, as well as the materials used in the fabrication of these devices and the standards for wireless medical devices and mobile applications. We conclude by discussing some of the technical challenges in wearable and implantable technology and possible solutions for overcoming these difficulties. PMID- 29490191 TI - Gas Cluster Ion Beams for Secondary Ion Mass Spectrometry. AB - Gas cluster ion beams (GCIBs) provide new opportunities for bioimaging and molecular depth profiling with secondary ion mass spectrometry (SIMS). These beams, consisting of clusters containing thousands of particles, initiate desorption of target molecules with high yield and minimal fragmentation. This review emphasizes the unique opportunities for implementing these sources, especially for bioimaging applications. Theoretical aspects of the cluster ion/solid interaction are developed to maximize conditions for successful mass spectrometry. In addition, the history of how GCIBs have become practical laboratory tools is reviewed. Special emphasis is placed on the versatility of these sources, as size, kinetic energy, and chemical composition can be varied easily to maximize lateral resolution, hopefully to less than 1 micron, and to maximize ionization efficiency. Recent examples of bioimaging applications are also presented. PMID- 29490192 TI - Electrochemical Probes of Microbial Community Behavior. AB - Advances in next-generation sequencing technology along with decreasing costs now allow the microbial population, or microbiome, of a location to be determined relatively quickly. This research reveals that microbial communities are more diverse and complex than ever imagined. New and specialized instrumentation is required to investigate, with high spatial and temporal resolution, the dynamic biochemical environment that is created by microbes, which allows them to exist in every corner of the Earth. This review describes how electrochemical probes and techniques are being used and optimized to learn about microbial communities. Described approaches include voltammetry, electrochemical impedance spectroscopy, scanning electrochemical microscopy, separation techniques coupled with electrochemical detection, and arrays of complementary metal-oxide-semiconductor circuits. Microbial communities also interact with and influence their surroundings; therefore, the review also includes a discussion of how electrochemical probes optimized for microbial analysis are utilized in healthcare diagnostics and environmental monitoring applications. PMID- 29490193 TI - (Multi)functional Atomic Force Microscopy Imaging. AB - Incorporating functionality to atomic force microscopy (AFM) to obtain physical and chemical information has always been a strong focus in AFM research. Modifying AFM probes with specific molecules permits accessibility of chemical information via specific reactions and interactions. Fundamental understanding of molecular processes at the solid/liquid interface with high spatial resolution is essential to many emerging research areas. Nanoscale electrochemical imaging has emerged as a complementary technique to advanced AFM techniques, providing information on electrochemical interfacial processes. While this review presents a brief introduction to advanced AFM imaging modes, such as multiparametric AFM and topography recognition imaging, the main focus herein is on electrochemical imaging via hybrid AFM-scanning electrochemical microscopy. Recent applications and the challenges associated with such nanoelectrochemical imaging strategies are presented. PMID- 29490185 TI - Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. AB - BACKGROUND: Septic shock is characterized by dysregulation of the host response to infection, with circulatory, cellular, and metabolic abnormalities. We hypothesized that therapy with hydrocortisone plus fludrocortisone or with drotrecogin alfa (activated), which can modulate the host response, would improve the clinical outcomes of patients with septic shock. METHODS: In this multicenter, double-blind, randomized trial with a 2-by-2 factorial design, we evaluated the effect of hydrocortisone-plus-fludrocortisone therapy, drotrecogin alfa (activated), the combination of the three drugs, or their respective placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included mortality at intensive care unit (ICU) discharge and hospital discharge and at day 28 and day 180 and the number of days alive and free of vasopressors, mechanical ventilation, or organ failure. After drotrecogin alfa (activated) was withdrawn from the market, the trial continued with a two-group parallel design. The analysis compared patients who received hydrocortisone plus fludrocortisone with those who did not (placebo group). RESULTS: Among the 1241 patients included in the trial, the 90-day mortality was 43.0% (264 of 614 patients) in the hydrocortisone-plus-fludrocortisone group and 49.1% (308 of 627 patients) in the placebo group (P=0.03). The relative risk of death in the hydrocortisone-plus fludrocortisone group was 0.88 (95% confidence interval, 0.78 to 0.99). Mortality was significantly lower in the hydrocortisone-plus-fludrocortisone group than in the placebo group at ICU discharge (35.4% vs. 41.0%, P=0.04), hospital discharge (39.0% vs. 45.3%, P=0.02), and day 180 (46.6% vs. 52.5%, P=0.04) but not at day 28 (33.7% and 38.9%, respectively; P=0.06). The number of vasopressor-free days to day 28 was significantly higher in the hydrocortisone-plus-fludrocortisone group than in the placebo group (17 vs. 15 days, P<0.001), as was the number of organ-failure-free days (14 vs. 12 days, P=0.003). The number of ventilator-free days was similar in the two groups (11 days in the hydrocortisone-plus fludrocortisone group and 10 in the placebo group, P=0.07). The rate of serious adverse events did not differ significantly between the two groups, but hyperglycemia was more common in hydrocortisone-plus-fludrocortisone group. CONCLUSIONS: In this trial involving patients with septic shock, 90-day all-cause mortality was lower among those who received hydrocortisone plus fludrocortisone than among those who received placebo. (Funded by Programme Hospitalier de Recherche Clinique 2007 of the French Ministry of Social Affairs and Health; APROCCHSS ClinicalTrials.gov number, NCT00625209 .). PMID- 29490194 TI - Abnormal mTOR Activation in Autism. AB - The mechanistic target of rapamycin (mTOR) is an important signaling hub that integrates environmental information regarding energy availability and stimulates anabolic molecular processes and cell growth. Abnormalities in this pathway have been identified in several syndromes in which autism spectrum disorder (ASD) is highly prevalent. Several studies have investigated mTOR signaling in developmental and neuronal processes that, when dysregulated, could contribute to the development of ASD. Although many potential mechanisms still remain to be fully understood, these associations are of great interest because of the clinical availability of mTOR inhibitors. Clinical trials evaluating the efficacy of mTOR inhibitors to improve neurodevelopmental outcomes have been initiated. PMID- 29490195 TI - Biological and Genetic Characterization of New and Known Necroviruses Causing an Emerging Systemic Necrosis Disease of Corn Salad (Valerianella locusta) in France. AB - An emerging systemic necrosis disease of corn salad was first observed in the Nantes region of France in the late 2000s. Classical virology and high-throughput sequencing approaches demonstrated that the disease is associated with four different necroviruses: tobacco necrosis virus A (TNVA), tobacco necrosis virus D (TNVD), olive mild mosaic virus (OMMV), and a novel recombinant Alphanecrovirus for which the name corn salad necrosis virus (CSNV) is proposed. Satellite tobacco necrosis virus was also frequently observed. Koch's postulates were completed for all four agents, each one alone being able to cause systemic necrosis of varying severity in corn salad. OMMV was the most frequently observed virus and causes the most severe symptoms. TNVA was the second, both in terms of prevalence and symptom severity while TNVD and CSNV were only rarely observed and caused the less severe symptoms. The emergence of this systemic disease may have been favored by the short and repeated cropping cycles used for corn salad, possibly allowing the selection of necrovirus isolates with an improved ability to systemically invade this specialty crop. PMID- 29490196 TI - Structural Plasticity in Adulthood with Motor Learning and Stroke Rehabilitation. AB - The development of advanced noninvasive techniques to image the human brain has enabled the demonstration of structural plasticity during adulthood in response to motor learning. Understanding the basic mechanisms of structural plasticity in the context of motor learning is essential to improve motor rehabilitation in stroke patients. Here, we review and discuss the emerging evidence for motor learning-related structural plasticity and the implications for stroke rehabilitation. In the clinical context, a few studies have started to assess the effects of rehabilitation on structural measures to understand recovery poststroke and additionally to predict intervention outcomes. Structural imaging will likely have a role in the future in providing measures that inform patient stratification for optimal outcomes. PMID- 29490197 TI - Basic and Translational Neuroscience of Childhood-Onset Dystonia: A Control Theory Perspective. AB - Dystonia is a collection of symptoms with involuntary muscle activation causing hypertonia, hyperkinetic movements, and overflow. In children, dystonia can have numerous etiologies with varying neuroanatomic distribution. The semiology of dystonia can be explained by gain-of-function failure of a feedback controller that is responsible for stabilizing posture and movement. Because postural control is maintained by a widely distributed network, many different anatomic regions may be responsible for symptoms of dystonia, although all features of dystonia can be explained by uncontrolled activation or hypersensitivity of motor cortical regions that can cause increased reflex gain, inserted postures, or sensitivity to irrelevant sensory variables. Effective treatment of dystonia in children requires an understanding of the relationship between etiology, anatomy, and the specific mechanism of failure of postural stabilization. PMID- 29490199 TI - Dynamics at Conical Intersections. AB - The nonadiabatic coupling of electronic and vibrational degrees of freedom is the defining feature of electronically excited states of polyatomic molecules. Once considered a theoretical curiosity, conical intersections (CIs) are now generally accepted as being the dominant source of coupled charge and vibrational energy flow in molecular excited states. Passage through CIs leads to the conversion of electronic to vibrational energy, which drives the ensuing photochemistry, isomerization being a canonical example. It has often been remarked that the CI may be thought of as a transition state in the excited state. As such, we expect that both the direction and the velocity of approach to the CI will matter. We explore this suggestion by looking for dynamical aspects of passage through CIs and for analogies with well-known concepts from ground-state reaction dynamics. Great progress has been made in the development of both experimental techniques and ab initio dynamics simulations, to a degree that direct comparisons may now be made. Here we compare time-resolved photoelectron spectroscopy results with on the-fly ab initio multiple spawning calculations of the experimental observables, thereby validating each. We adopt a phenomenological approach and specifically concentrate on the excited-state dynamics of the C=C bond in unsaturated hydrocarbons. In particular, we make use of selective chemical substitution (such as replacing an H atom by a methyl group) so as to alter the inertia of certain vibrations relative to others, thus systematically varying (mass-weighted) directions and velocities of approach to a CI. Chemical substituents, however, may affect both the nuclear and electronic components of the total wave function. The former, which we call an inertial effect, influences the direction and velocity of approach. The latter, which we call a potential effect, modifies the electronic structure and therefore the energetic location and topography of the potential energy surfaces involved. Using a series of examples, we discuss both types of effects. We argue that there is a need for dynamical pictures and simple models of nonadiabatic dynamics at CIs and hope that the phenomenology presented here will help inspire such developments. PMID- 29490198 TI - Who cares for the carers at hospital discharge at the end of life? A qualitative study of current practice in discharge planning and the potential value of using The Carer Support Needs Assessment Tool (CSNAT) Approach. AB - BACKGROUND: Carer factors prevent patients achieving timely and appropriate hospital discharge. There is a lack of research into interventions to support carers at hospital discharge. AIM: To explore whether and how family carers are currently supported during patient discharge at end of life; to assess perceived benefits, acceptability and feasibility of using The Carer Support Needs Assessment Tool (CSNAT) Approach in the hospital setting to support carers. DESIGN: Qualitative. SETTING/PARTICIPANTS: Three National Health Service Trusts in England: focus groups with 40 hospital and community-based practitioners and 22 carer interviews about experiences of carer support during hospital discharge and views of The CSNAT Approach. Two workshops brought together 14 practitioners and five carers to discuss implementation issues. Framework analysis was conducted. RESULTS: Current barriers to supporting carers at hospital discharge were an organisational focus on patients' needs, what practitioners perceived as carers' often 'unrealistic expectations' of end-of-life caregiving at home and lack of awareness of patients' end-of-life situation. The CSNAT Approach was viewed as enabling carer support and addressing difficulties of discussing the realities of supporting someone at home towards end of life. Implementation in hospital required organisational considerations of practitioner workload and training. To enhance carer support, a two-stage process of assessment and support (hospital with community follow-up) was suggested using the CSNAT as a carer-held record to manage the transition. CONCLUSION: This study identifies a novel intervention, which expands the focus of discharge planning to include assessment of carers' support needs at transition, potentially preventing breakdown of care at home and patient readmissions to hospital. PMID- 29490200 TI - Chemical Kinetics for Bridging Molecular Mechanisms and Macroscopic Measurements of Amyloid Fibril Formation. AB - Understanding how normally soluble peptides and proteins aggregate to form amyloid fibrils is central to many areas of modern biomolecular science, ranging from the development of functional biomaterials to the design of rational therapeutic strategies against increasingly prevalent medical conditions such as Alzheimer's and Parkinson's diseases. As such, there is a great need to develop models to mechanistically describe how amyloid fibrils are formed from precursor peptides and proteins. Here we review and discuss how ideas and concepts from chemical reaction kinetics can help to achieve this objective. In particular, we show how a combination of theory, experiments, and computer simulations, based on chemical kinetics, provides a general formalism for uncovering, at the molecular level, the mechanistic steps that underlie the phenomenon of amyloid fibril formation. PMID- 29490201 TI - Computational Photophysics in the Presence of an Environment. AB - Most processes triggered by ultraviolet (UV) or visible (vis) light in nature take place in complex biological environments. The first step in these photophysical events is the excitation of the absorbing system or chromophore to an electronically excited state. Such an excitation can be monitored by the UV vis absorption spectrum. A precise calculation of the UV-vis spectrum of a chromophore embedded in an environment is a challenging task that requires the consideration of several ingredients, besides an accurate electronic-structure method for the excited states. Two of the most important are an appropriate description of the interactions between the chromophore and the environment and accounting for the vibrational motion of the whole system. In this contribution, we review the most common theoretical methodologies to describe the environment (including quantum mechanics/continuum and quantum mechanics/molecular mechanics models) and to account for vibrational sampling (including Wigner sampling and molecular dynamics). Further, we illustrate in a series of examples how the lack of these ingredients can lead to a wrong interpretation of the electronic features behind the UV-vis absorption spectrum. PMID- 29490202 TI - Connections Between Theory and Experiment for Gold and Silver Nanoclusters. AB - Ligand-stabilized gold and silver nanoparticles are of tremendous current interest in sensing, catalysis, and energy applications. Experimental and theoretical studies have closely interacted to elucidate properties such as the geometric and electronic structures of these fascinating systems. In this review, the interplay between theory and experiment is described; areas such as optical absorption and doping, where the theory-experiment connections are well established, are discussed in detail; and the current status of these connections in newer fields of study, such as luminescence, transient absorption, and the effects of solvent and the surrounding environment, are highlighted. Close communication between theory and experiment has been extremely valuable for developing an understanding of these nanocluster systems in the past decade and will undoubtedly continue to play a major role in future years. PMID- 29490203 TI - Membrane-Mediated Cooperativity of Proteins. AB - Besides direct protein-protein interactions, indirect interactions mediated by membranes play an important role for the assembly and cooperative function of proteins in membrane shaping and adhesion. The intricate shapes of biological membranes are generated by proteins that locally induce membrane curvature. Indirect curvature-mediated interactions between these proteins arise because the proteins jointly affect the bending energy of the membranes. These curvature mediated interactions are attractive for crescent-shaped proteins and are a driving force in the assembly of the proteins during membrane tubulation. Membrane adhesion results from the binding of receptor and ligand proteins that are anchored in the apposing membranes. The binding of these proteins strongly depends on nanoscale shape fluctuations of the membranes, leading to a fluctuation-mediated binding cooperativity. A length mismatch between receptor ligand complexes in membrane adhesion zones causes repulsive curvature-mediated interactions that are a driving force for the length-based segregation of proteins during membrane adhesion. PMID- 29490204 TI - Computational Design of Clusters for Catalysis. AB - When small clusters are studied in chemical physics or physical chemistry, one perhaps thinks of the fundamental aspects of cluster electronic structure, or precision spectroscopy in ultracold molecular beams. However, small clusters are also of interest in catalysis, where the cold ground state or an isolated cluster may not even be the right starting point. Instead, the big question is: What happens to cluster-based catalysts under real conditions of catalysis, such as high temperature and coverage with reagents? Myriads of metastable cluster states become accessible, the entire system is dynamic, and catalysis may be driven by rare sites present only under those conditions. Activity, selectivity, and stability are highly dependent on size, composition, shape, support, and environment. To probe and master cluster catalysis, sophisticated tools are being developed for precision synthesis, operando measurements, and multiscale modeling. This review intends to tell the messy story of clusters in catalysis. PMID- 29490205 TI - Enhancing Analytical Separations Using Super-Resolution Microscopy. AB - Super-resolution microscopy is becoming an invaluable tool to investigate structure and dynamics driving protein interactions at interfaces. In this review, we highlight the applications of super-resolution microscopy for quantifying the physics and chemistry that occur between target proteins and stationary-phase supports during chromatographic separations. Our discussion concentrates on the newfound ability of super-resolved single-protein spectroscopy to inform theoretical parameters via quantification of adsorption desorption dynamics, protein unfolding, and nanoconfined transport. PMID- 29490206 TI - Sensing Chirality with Rotational Spectroscopy. AB - Chiroptical spectroscopy techniques for the differentiation of enantiomers in the condensed phase are based on an established paradigm that relies on symmetry breaking using circularly polarized light. We review a novel approach for the study of chiral molecules in the gas phase using broadband rotational spectroscopy, namely microwave three-wave mixing, which is a coherent, nonlinear, and resonant process. This technique can be used to generate a coherent molecular rotational signal that can be detected in a manner similar to that in conventional Fourier transform microwave spectroscopy. The structure (and thermal distribution of conformations), handedness, and enantiomeric excess of gas-phase samples can be determined unambiguously by employing tailored microwave fields. We discuss the theoretical and experimental aspects of the method, the significance of the first demonstrations of the technique for enantiomer differentiation, and the method's rapid advance into a robust choice to study molecular chirality in the gas phase. Very recently, the microwave three-wave mixing approach was extended to enantiomer-selective population transfer, an important step toward spatial enantiomer separation on the fly. PMID- 29490207 TI - Addressing the Challenge of Molecular Change: An Interim Report. AB - Invited by the editorial committee of the Annual Review of Physical Chemistry to "contribute my autobiography," I present it here, as I understand the term. It is about my parents, my mentors, my coworkers, and my friends in learning and the scientific problems that we tried to address. Courtesy of the editorial assistance of Annual Reviews, some of the science is in the figure captions and sidebars. I am by no means done: I am currently trying to fuse the quantitative rigor of physical chemistry with systems biology while also dealing with a post Born-Oppenheimer regime in electronic dynamics and am attempting to instruct molecules to perform advanced logic. PMID- 29490208 TI - Characterization of Intermediate Oxidation States in CO2 Activation. AB - Redox chemistry during the activation of carbon dioxide involves changing the charge state in a CO2 molecular unit. However, such changes are usually not well described by integer formal charges, and one can think of COO functional units as being in intermediate oxidation states. In this article, we discuss the properties of CO2 and CO2-based functional units in various charge states. Besides covering isolated CO2 and its ions, we describe the CO2-based ionic species formate, oxalate, and carbonate. Finally, we provide an overview of CO2 based functional groups and ligands in clusters and metal-organic complexes. PMID- 29490209 TI - Elementary Chemical Reactions in Surface Photocatalysis. AB - Photocatalytic hydrogen evolution and organic degradation on oxide materials have been extensively investigated in the last two decades. Great efforts have been dedicated to the study of photocatalytic reaction mechanisms of a variety of molecules on TiO2 surfaces by using surface science methods under ultra-high vacuum (UHV) conditions, providing fundamental understanding of surface chemical reactions in photocatalysis. In this review, we summarize the recent progress in the study of photocatalysis of several important species (water, methanol, and aldehydes) on different TiO2 surfaces. The results of these studies have provided us deep insights into the elementary processes of surface photocatalysis and stimulated a new frontier of research in this area. Based on the results of these studies, a new dynamics-based photocatalysis model is also discussed. PMID- 29490210 TI - Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders: major depression summary. AB - INTRODUCTION: In December 2015, the Royal Australian and New Zealand College of Psychiatrists published a comprehensive set of mood disorder clinical practice guidelines for psychiatrists, psychologists and mental health professionals. This guideline summary, directed broadly at primary care physicians, is an abridged version that focuses on major depression. It emphasises the importance of shared decision making, tailoring personalised care to the individual, and delivering care in the context of a therapeutic relationship. In practice, the management of depression is determined by a multitude of factors, including illness severity and putative aetiology, with the principal objectives of regaining premorbid functioning and improving resilience against recurrence of future episodes. Main recommendations: The guidelines emphasise a biopsychosocial lifestyle approach and provide the following specific clinical recommendations: Alongside or before prescribing any form of treatment, consideration should be given to the implementation of strategies to manage stress, ensure appropriate sleep hygiene and enable uptake of healthy lifestyle changes. For mild to moderate depression, psychological management alone is an appropriate first line treatment, especially early in the course of illness. For moderate to severe depression, pharmacological management is usually necessary and is recommended first line, ideally in conjunction with psychosocial interventions. Changes in management as a result of the guidelines: The management of depression is anchored within a therapeutic relationship that attends to biopsychosocial lifestyle aspects and psychiatric diagnosis. The guidelines promote a broader approach to the formulation and management of depression, with treatments tailored to depressive subtypes and administered with clear steps in mind. Lifestyle and psychological therapies are favoured for less severe presentations, and concurrent antidepressant prescription is reserved for more severe and otherwise treatment refractory cases. PMID- 29490211 TI - Don't lose sight: last drinks laws reduce violent assaults. PMID- 29490212 TI - Fewer orbital fractures treated at St Vincent's Hospital after lockout laws introduced in Sydney. PMID- 29490214 TI - Potential solutions to improve the governance of multicentre health services research. PMID- 29490215 TI - Oral disease contributes to illness burden and disparities. PMID- 29490216 TI - Insulinoma: important in the differential diagnosis of persistent hypoglycaemia unrelated to diabetes. PMID- 29490217 TI - Sudden onset dyspnoea and recurrent stridor. PMID- 29490218 TI - Educational research: current trends, evidence base and unanswered questions. PMID- 29490219 TI - Guided by the research design: choosing the right statistical test. PMID- 29490220 TI - The many costs of homelessness. PMID- 29490221 TI - Characteristics of people attending psychiatric clinics in inner Sydney homeless hostels. AB - OBJECTIVE: To describe the characteristics of people attending mental health clinics at shelters for the homeless in inner city Sydney. DESIGN: Retrospective review of medical records of homeless hostel clinic attenders. SETTING: Mental health clinics located in three inner city homeless hostels. PARTICIPANTS: Consecutive series of clinic attenders, 21 July 2008 - 31 December 2016. MAIN OUTCOME MEASURES: Demographic characteristics; social, medical and mental health histories of homeless people. RESULTS: 2388 individual patients were seen at the clinics during the 8.5-year study period. Their mean age was 42 years (standard deviation, 13 years), 93% were men, and 56% were receiving disability support pensions. 59% of attenders had been homeless for more than a year, and 34% of all attenders reported sleeping in the open. The most common diagnoses were substance use disorder (66%), psychotic illness (51%), acquired brain injury (14%), and intellectual disability (5%). Most patients had more than one diagnosis. Early life and recent trauma was reported by 42% of patients. Pathways to homelessness included release from prison (28% of the homeless), discharge from a psychiatric hospital (21%), loss of public housing tenancy (21%), and inability to pay rent because of problem gambling. CONCLUSIONS: The high rates of substance use and mental disorder among homeless people in inner Sydney confirms the need for increased access to treatment for these conditions in this setting. Homelessness among those with mental illness might be reduced by developing alternative housing models, and supporting people with multiple problems to retain tenancy. PMID- 29490223 TI - Why medically unexplained symptoms and health anxiety don't need to make your heart sink. PMID- 29490222 TI - Predictors of respiratory failure in patients with Guillain-Barre syndrome: a systematic review and meta-analysis. AB - OBJECTIVE: To systematically review the literature regarding the ability of clinical features to predict respiratory failure in patients with Guillain-Barre syndrome (GBS). DATA SOURCES: We searched the PubMed and Ovid MEDLINE databases with the search terms "guillain barre syndrome" OR "acute inflammatory demyelinating polyneuropathy" OR "acute motor axonal neuropathy" OR "acute motor sensory axonal neuropathy" AND "respiratory failure" OR "mechanical ventilation". We excluded articles that did not report the results of original research (eg, review articles, letters), were case reports or series (ten or fewer patients), were not available in English, reported research in paediatric populations (16 years of age or younger), or were interventional studies. Article quality was assessed with the Newcastle-Ottawa quality assessment scale. DATA SYNTHESIS: Thirty-four relevant studies were identified. Short time from symptom onset to hospital admission (less than 7 days), bulbar (odds ratio [OR], 9.0; 95% CI, 3.94 20.6; P < 0.001) or neck weakness (OR, 6.36; 95% CI, 2.32-17.5; P < 0.001), and severe muscle weakness at hospital admission were associated with increased risk of intubation. Facial weakness (OR, 3.74; 95% CI, 2.05-6.81; P < 0.001) and autonomic instability (OR, 6.40; 95% CI, 2.83-14.5; P < 0.001) were significantly more frequent in patients requiring intubation in our meta-analyses; however, the differences were not statistically significant in individual multivariable analysis studies. Four predictive models have been developed to assess the risk of respiratory failure for patients with GBS, each with good to excellent discriminative power (area under the receiver operating characteristic curve, 0.79-0.96). CONCLUSIONS AND RELEVANCE: Early identification of GBS patients at risk of respiratory failure could reduce the rates of adverse outcomes associated with delayed intubation. Algorithms that predict a patient's risk of subsequent respiratory failure at hospital admission appear more reliable than individual clinical variables. PMID- 29490224 TI - Acupuncture for analgesia in the emergency department: a multicentre, randomised, equivalence and non-inferiority trial. PMID- 29490225 TI - Acupuncture for analgesia in the emergency department: a multicentre, randomised, equivalence and non-inferiority trial. PMID- 29490226 TI - A review of student contribution to the Medical Journal of Australia between 2001 and 2014. PMID- 29490228 TI - Finding the fun. PMID- 29490227 TI - Hepatitis C in Australia - a role for general practitioners? PMID- 29490230 TI - Pinprick hypo- and hyperalgesia in diabetic rats: Can diet content affect experimental outcome? AB - Existing literature concerning the effect of experimentally-induced diabetes on pain thresholds in rodent models remains controversial. In this work, we describe a phenotypical switch from streptozotocin-induced pinprick hypoalgesia to hyperalgesia observed in the same laboratory, in the same strain of rats, obtained from the same vendor, and measured by the same technique carried out by the investigators. This switch was observed around January 2015, at the time when there was a change in the diet of rats at the Radley North Carolina Charles River facility. These data support the contention that diet may significantly modify disease progression, including progression of signs of diabetic neuropathy. PMID- 29490231 TI - In situ evidence of cellular senescence in Thymic Epithelial Cells (TECs) during human thymic involution. AB - Cellular senescence, an age-related process in response to damage and stress, also occurs during normal development and adult life. The thymus is a central lymphoepithelial organ of the immune system that exhibits age-related changes termed thymic involution. Since the mechanisms regulating thymic involution are still not well elucidated, we questioned whether cellular senescence is implicated in this process. We demonstrate, for the first time in situ, that cellular senescence occurs during human thymic involution using SenTraGorTM, a novel chemical compound that is applicable in archival tissue material, providing thus further insights in thymus histophysiology. PMID- 29490232 TI - SUMOylation, aging and autophagy in neurodegeneration. AB - Protein homeostasis is essential for the wellbeing of several cellular systems. Post-translational modifications (PTM) coordinate various pathways in response to abnormal aggregation of proteins in neurodegenerative disease states. In the presence of accumulating misfolded proteins and toxic aggregates, the small ubiquitin-like modifier (SUMO) is associated with various substrates, including chaperones and other recruited factors, for refolding and for clearance via proteolytic systems, such as the ubiquitin-proteasome pathway (UPS), chaperone mediated autophagy (CMA) and macroautophagy. However, these pathological aggregates are also known to inhibit both the UPS and CMA, further creating a toxic burden on cells. This review suggests that re-routing cytotoxic aggregates towards selective macroautophagy by modulating the SUMO pathway could provide new mechanisms towards neuroprotection. PMID- 29490233 TI - Influence of the test method on in vitro drug release from intravitreal model implants containing dexamethasone or fluorescein sodium in poly (d,l-lactide-co glycolide) or polycaprolactone. AB - Sustained intravitreal dexamethasone (DX) administration with the FDA and EMA approved Ozurdex(r) implant is indicated for the treatment of macular edema and non-infectious uveitis. Since drug release after intravitreal application cannot be determined in vivo in human eyes, the characterization of drug release in vitro in addition to animal models is of great importance. The aim of this study was to provide information about the influence of the test method on the in vitro drug release from intravitreal model implants. The following test methods were used: a shaking incubator experiment in reagent tubes, the small volume USP apparatus 7, the Vitreous Model (VM) and a system simulating the impact of movement on the VM (Eye Movement System, EyeMoS). Cylindrical model implants composed of DX and PLGA (poly (d,l-lactide-co-glycolide)) and additional polycaprolactone (PCL) implants containing fluorescein sodium (FS) as a model substance were produced by hot melt extrusion and were cut to a length of approximately 6 mm. Drug release was studied in ringer buffer pH 7.4 and in a modified polyacrylamide gel (PAAG) as vitreous substitute. In combination with the VM, the shape, the gel structure and a partial liquefaction (50%) were simulated in vitro. Swelling, disintegration, fragmentation, surface enlargement and changes in shape of the PLGA model implants were observed during the drug release study. We experienced that not each of the test methods and media were suitable for drug release studies of the PLGA implants. Marked differences in the release profiles were observed depending on the employed test method. These results emphasize the necessity to understand the underlying in vivo processes and to transfer the knowledge about the release determining factors into reliable in vitro test systems. PMID- 29490234 TI - How attention modulates encoding of dynamic stimuli in older adults. AB - Aging is marked by memory decline that is exacerbated with attentional loading. Portraying older adults' neural functions when encoding information in conditions of high and low attentional load is a necessary step toward understanding this phenomenon. Furthermore, the information gained may be used to devise strategies aimed to prevent age-related decline in memory. To address this issue, a group of older adults underwent fMRI scanning while encoding short movies under two levels of attentional loading. High attentional load was associated with increased inter subject correlation (inter-SC) in only a subset of prefrontal regions that were previously identified in younger adults. It was also associated with lower inter SC in task-relevant visual regions, suggesting that as load increased, visual processing became less synchronized across participants. Critically, while we have shown that inter-SC in the dorsal posterior cingulate cortex (dPCC) was increased for younger adults at high load, older adults did not generally show this effect. However, those older adults who did display this pattern also displayed a 'younger-like' memory profile. These results point to a pivotal role of the dPCC in the interplay between attention and memory across the lifespan. PMID- 29490235 TI - Premature hippocampus-dependent memory decline in middle-aged females of a genetic rat model of depression. AB - Aging and major depressive disorder are risk factors for dementia, including Alzheimer's Disease (AD), but the mechanism(s) linking depression and dementia are not known. Both AD and depression show greater prevalence in women. We began to investigate this connection using females of the genetic model of depression, the inbred Wistar Kyoto More Immobile (WMI) rat. These rats consistently display depression-like behavior compared to the genetically close control, the Wistar Kyoto Less Immobile (WLI) strain. Hippocampus-dependent contextual fear memory did not differ between young WLI and WMI females, but, by middle-age, female WMIs showed memory deficits compared to same age WLIs. This deficit, measured as duration of freezing in the fear provoking-context was not related to activity differences between the strains prior to fear conditioning. Hippocampal expression of AD-related genes, such as amyloid precursor protein, amyloid beta 42, beta secretase, synucleins, total and dephosphorylated tau, and synaptophysin, did not differ between WLIs and WMIs in either age group. However, hippocampal transcript levels of catalase (Cat) and hippocampal and frontal cortex expression of insulin-like growth factor 2 (Igf2) and Igf2 receptor (Igf2r) paralleled fear memory differences between middle-aged WLIs and WMIs. This data suggests that chronic depression-like behavior that is present in this genetic model is a risk factor for early spatial memory decline in females. The molecular mechanisms of this early memory decline likely involve the interaction of aging processes with the genetic components responsible for the depression like behavior in this model. PMID- 29490236 TI - Snakebites as cause of deaths in the Western Brazilian Amazon: Why and who dies? Deaths from snakebites in the Amazon. AB - Snake envenoming represents a major burden for public health worldwide. In the Amazon, the official number of cases and deaths detected is probably underestimated because of the difficulty riverine and indigenous populations have reaching health centers in order to receive medical assistance. Thus, integrated analysis of health information systems must be used in order to improve adequate health policies. The aim of this work is to describe a series of deaths and identify risk factors for lethality from snakebites in the state of Amazonas, Brazil. All deaths from snakebites reported to the Brazilian Notifiable Diseases Surveillance System (SINAN) and to the Mortality Information System (SIM; ICD10 10th revision, X.29), from 2007 to 2015, were included. Variables were assessed by blocks with distal (ecological variables), intermediate (demographics) and proximal (clinical variables) components to identify predictors of case fatality. A total of 127 deaths from snakebites were recorded, with 58 pairs found through linkage of the SINAN and SIM databases (45.7%), 37 (29.1%) deaths found only in SINAN and 32 (25.2%) found only in the SIM. Deaths occurred mostly in males (95 cases; 74.8%) living in rural areas (78.6%). The most affected age group was the >=61 years old (36 cases; 28.4%). Snakebites were presumably due to Bothrops snakes in 68.5% of the cases and Lachesis in 29.5% based on clinico epidemiological diagnosis. A proportion of 26.2% of the cases received treatment over 24 h after the bite ocurred. On admission, cases were mostly classified as severe (65.6%). Overall, 28 patients (22.0%). Deceased without any medical assistance Antivenom was given to 53.5%. In the multivariate analysis, a distance from Manaus >300 km [OR = 3.40 (95%CI = 1.99-5.79); (p < 0.001)]; age >=61 years [OR = 4.31 (95%CI = 1.22-15.21); (p = 0.023)] and Indigenous status [OR = 5.47 (95%CI = 2.37-12.66); (p < 0.001)] were independently associated with case fatality from snakebites. Severe snakebites [OR = 16.24 (95%CI = 4.37-60.39); (p < 0.001)] and a lack of antivenom administration [OR = 4.21 (95%CI = 1.30-13.19); (p = 0.014)] were also independently associated with case fatality. Respiratory failure/dyspnea, systemic bleeding, sepsis and shock were recorded only among fatal cases. In conclusion, i) death from snakebites was underreported in the mortality surveillance system; ii) older age groups living in remote municipalities and indigenous peoples were the population groups most prone to death; iii) lack or underdosage of antivenom resulted in higher case fatality and iv) systemic bleeding, circulatory shock, sepsis and acute respiratory failure were strongly associated to fatal outcome. PMID- 29490237 TI - Evaluation of monoclonal antibody-based direct, rapid immunohistochemical test for rabies diagnosis. AB - Rabies is a major public health problem in developing countries in Asia and Africa. Although a number of laboratory diagnoses can be used for rabies control, the WHO and OIE recommended gold standard for rabies diagnosis is the direct fluorescent antibody test (FAT). However, FAT is not widely used in developing countries because of deficient financial sources to procure fluorescent microscope. Recently the direct rapid immunohistochemical test (dRIT) has been developed and has a worldwide promising application, particularly in developing countries, since its result can be read by inexpensive light microscopy, in addition to be consistent with that of FAT. However, no commercial conjugated antibody is available to meet the laboratory demand. We describe here the production of a monoclonal antibody (MAb) against rabies virus (RABV) N protein and its use as a biotinylated conjugate in a dRIT. Tested against a batch of 107 brain specimens representing a wide phylogenetic diversity of RABV collected from different animal species with multiple geographical origins in China, results showed that the dRIT had 100% specificity (95% CI 0.93-1.00) and 96.49% sensitivity (95% CI 0.88-1.00) as compared with the gold standard FAT. It therefore provides a simple, economical alternative to FAT, particularly for use in rabies diagnosis in developing countries. PMID- 29490238 TI - Chasing a Protein's Tail: Detection of Polypeptide Translocation through Nanopores. PMID- 29490239 TI - Time to Stop Telling Biophysics Students that Light Is Primarily a Wave. AB - Standard pedagogy introduces optics as though it were a consequence of Maxwell's equations and only grudgingly admits, usually in a rushed aside, that light has a particulate character that can somehow be reconciled with the wave picture. Recent revolutionary advances in optical imaging, however, make this approach more and more unhelpful: How are we to describe two-photon imaging, FRET, localization microscopy, and a host of related techniques to students who think of light primarily as a wave? I was surprised to find that everything I wanted my biophysics students to know about light, including image formation, x-ray diffraction, and even Bessel beams, could be expressed as well (or better) from the quantum viewpoint pioneered by Richard Feynman. Even my undergraduate students grasp this viewpoint as well as (or better than) the traditional one, and by mid-semester they are already well positioned to integrate the latest advances into their understanding. Moreover, I have found that this approach clarifies my own understanding of new techniques. PMID- 29490240 TI - Tropomyosins Regulate the Severing Activity of Gelsolin in Isoform-Dependent and Independent Manners. AB - The actin cytoskeleton fulfills numerous key cellular functions, which are tightly regulated in activity, localization, and temporal patterning by actin binding proteins. Tropomyosins and gelsolin are two such filament-regulating proteins. Here, we investigate how the effects of tropomyosins are coupled to the binding and activity of gelsolin. We show that the three investigated tropomyosin isoforms (Tpm1.1, Tpm1.12, and Tpm3.1) bind to gelsolin with micromolar or submicromolar affinities. Tropomyosin binding enhances the activity of gelsolin in actin polymerization and depolymerization assays. However, the effects of the three tropomyosin isoforms varied. The tropomyosin isoforms studied also differed in their ability to protect pre-existing actin filaments from severing by gelsolin. Based on the observed specificity of the interactions between tropomyosins, actin filaments, and gelsolin, we propose that tropomyosin isoforms specify which populations of actin filaments should be targeted by, or protected from, gelsolin-mediated depolymerization in living cells. PMID- 29490241 TI - Intrinsically Disordered Protein Ntr2 Modulates the Spliceosomal RNA Helicase Brr2. AB - Precursor messenger RNA splicing is mediated by the spliceosome, a large and dynamic molecular machine composed of five small nuclear RNAs and numerous proteins. Many spliceosomal proteins are predicted to be intrinsically disordered or contain large disordered regions, but experimental validation of these predictions is scarce, and the precise functions of these proteins are often unclear. Here, we show via circular dichroism spectroscopy, dynamic light scattering, and NMR spectroscopy that the yeast spliceosomal disassembly factor Ntr2 is largely intrinsically disordered. Peptide SPOT analyses, analytical size exclusion chromatography, and surface plasmon resonance measurements revealed that Ntr2 uses an N-terminal region to bind the C-terminal helicase unit of the Brr2 RNA helicase, an enzyme involved in spliceosome activation and implicated in splicing catalysis and spliceosome disassembly. NMR analyses suggested that Ntr2 does not adopt a tertiary structure and likely remains disordered upon complex formation. RNA binding and unwinding studies showed that Ntr2 downregulates Brr2 helicase activity in vitro by modulating the fraction of helicase molecules productively bound to the RNA substrate. Our data clarify the nature of a physical link between Brr2 and Ntr2, and point to the possibility of a functional Ntr2-Brr2 interplay during splicing. PMID- 29490243 TI - Rare Dissipative Transitions Punctuate the Initiation of Chemical Denaturation in Proteins. AB - Protein unfolding dynamics are bound by their degree of entropy production, a quantity that relates the amount of heat dissipated by a nonequilibrium process to a system's forward and time-reversed trajectories. We here explore the statistics of heat dissipation that emerge in protein molecules subjected to a chemical denaturant. Coupling large molecular dynamics datasets and Markov state models with the theory of entropy production, we demonstrate that dissipative processes can be rigorously characterized over the course of the urea-induced unfolding of the protein chymotrypsin inhibitor 2. By enumerating full entropy production probability distributions as a function of time, we first illustrate that distinct passive and dissipative regimes are present in the denaturation dynamics. Within the dissipative dynamical region, we next find that chymotrypsin inhibitor 2 is strongly driven into unfolded states in which the protein's hydrophobic core has been penetrated by urea molecules and disintegrated. Detailed analyses reveal that urea's interruption of key hydrophobic contacts between core residues causes many of the protein's native structural features to dissolve. PMID- 29490242 TI - Quantitative Characterization of Metastability and Heterogeneity of Amyloid Aggregates. AB - Amyloids are heterogeneous assemblies of extremely stable fibrillar aggregates of proteins. Although biological activities of the amyloids are dependent on its conformation, quantitative evaluation of heterogeneity of amyloids has been difficult. Here we use disaggregation of the amyloids of tetramethylrhodamine labeled Abeta (TMR-Abeta) to characterize its stability and heterogeneity. Disaggregation of TMR-Abeta amyloids, monitored by fluorescence recovery of TMR, was negligible in native buffer even at low nanomolar concentrations but the kinetics increased exponentially with addition of denaturants such as urea or GdnCl. However, dissolution of TMR-Abeta amyloids is different from what is expected in the case of thermodynamic solubility. For example, the fraction of soluble amyloids is found to be independent of total concentration of the peptide at all concentrations of the denaturants. Additionally, soluble fraction is dependent on growth conditions such as temperature, pH, and aging of the amyloids. Furthermore, amyloids undissolved in a certain concentration of the denaturant do not show any further dissolution after dilution in the same solvent; instead, these require higher concentrations of the denaturant. Taken together, our results indicate that amyloids are a heterogeneous ensemble of metastable states. Furthermore, dissolution of each structurally homogeneous member requires a unique threshold concentration of denaturant. Fraction of soluble amyloids as a function of concentration of denaturants is found to be sigmoidal. The sigmoidal curve becomes progressively steeper with progressive seeding of the amyloids, although the midpoint remains unchanged. Therefore, heterogeneity of the amyloids is a major determinant of the steepness of the sigmoidal curve. The sigmoidal curve can be fit assuming a normal distribution for the population of the amyloids of various kinetic stabilities. We propose that the mean and the standard deviation of the normal distribution provide quantitative estimates of mean kinetic stability and heterogeneity, respectively, of the amyloids in a certain preparation. PMID- 29490244 TI - Unraveling the Motions behind Enterovirus 71 Uncoating. AB - Enterovirus 71 can be a severe pathogen in small children and immunocompromised adults. Virus uncoating is a critical step in the infection of the host cell; however, the mechanisms that control this process remain poorly understood. We applied normal mode analysis and perturbation response scanning to several complexes of the virus capsid and present a coarse-graining approach to analyze the full capsid. We show that our method offers an alternative to expressing the system as a set of rigid blocks and accounts for the interconnection between nodes within each subunit and protein interfaces across the capsid. In our coarse grained approach, the modes associated with capsid expansion are captured in the first three nondegenerate modes and correspond to the changes observed in structural studies of the virus. We show that the resolution of the analysis may be modified without losing information on the global motions leading to uncoating. Perturbation response scanning revealed that a protomer cannot serve as a functional unit to explain deformations of the capsid. Instead, we define a pentamer as the minimum functional unit to investigate changes within the capsid. From the modal analysis and perturbation response scanning, we locate a hotspot region surrounding the fivefold axis. The range of the effect of these single, hotspot residues extend to 140 A. The perturbation of internal capsid residues in this region displayed greatest propensity to capsid expansion, thus indicating the significant role that the RNA genome may play in triggering uncoating. PMID- 29490245 TI - Integrating NMR, SAXS, and Atomistic Simulations: Structure and Dynamics of a Two Domain Protein. AB - Multidomain proteins with two or more independently folded functional domains are prevalent in nature. Whereas most multidomain proteins are linked linearly in sequence, roughly one-tenth possess domain insertions where a guest domain is implanted into a loop of a host domain, such that the two domains are connected by a pair of interdomain linkers. Here, we characterized the influence of the interdomain linkers on the structure and dynamics of a domain-insertion protein in which the guest LysM domain is inserted into a central loop of the host CVNH domain. Expanding upon our previous crystallographic and NMR studies, we applied SAXS in combination with NMR paramagnetic relaxation enhancement to construct a structural model of the overall two-domain system. Although the two domains have no fixed relative orientation, certain orientations were found to be preferred over others. We also assessed the accuracies of molecular mechanics force fields in modeling the structure and dynamics of tethered multidomain proteins by integrating our experimental results with microsecond-scale atomistic molecular dynamics simulations. In particular, our evaluation of two different combinations of the latest force fields and water models revealed that both combinations accurately reproduce certain structural and dynamical properties, but are inaccurate for others. Overall, our study illustrates the value of integrating experimental NMR and SAXS studies with long timescale atomistic simulations for characterizing structural ensembles of flexibly linked multidomain systems. PMID- 29490246 TI - HullRad: Fast Calculations of Folded and Disordered Protein and Nucleic Acid Hydrodynamic Properties. AB - Hydrodynamic properties are useful parameters for estimating the size and shape of proteins and nucleic acids in solution. The calculation of such properties from structural models informs on the solution properties of these molecules and complements corresponding structural studies. Here we report, to our knowledge, a new method to accurately predict the hydrodynamic properties of molecular structures. This method uses a convex hull model to estimate the hydrodynamic volume of the molecule and is orders of magnitude faster than common methods. It works well for both folded proteins and ensembles of conformationally heterogeneous proteins and for nucleic acids. Because of its simplicity and speed, the method should be useful for the modification of computer-generated, intrinsically disordered protein ensembles and ensembles of flexible, but folded, molecules in which rapid calculation of experimental parameters is needed. The convex hull method is implemented in a Python script called HullRad. The use of the method is facilitated by a web server and the code is freely available for batch applications. PMID- 29490247 TI - Highly Disordered Amyloid-beta Monomer Probed by Single-Molecule FRET and MD Simulation. AB - Monomers of amyloid-beta (Abeta) protein are known to be disordered, but there is considerable controversy over the existence of residual or transient conformations that can potentially promote oligomerization and fibril formation. We employed single-molecule Forster resonance energy transfer (FRET) spectroscopy with site-specific dye labeling using an unnatural amino acid and molecular dynamics simulations to investigate conformations and dynamics of Abeta isoforms with 40 (Abeta40) and 42 residues (Abeta42). The FRET efficiency distributions of both proteins measured in phosphate-buffered saline at room temperature show a single peak with very similar FRET efficiencies, indicating there is apparently only one state. 2D FRET efficiency-donor lifetime analysis reveals, however, that there is a broad distribution of rapidly interconverting conformations. Using nanosecond fluorescence correlation spectroscopy, we measured the timescale of the fluctuations between these conformations to be ~35 ns, similar to that of disordered proteins. These results suggest that both Abeta40 and Abeta42 populate an ensemble of rapidly reconfiguring unfolded states, with no long-lived conformational state distinguishable from that of the disordered ensemble. To gain molecular-level insights into these observations, we performed molecular dynamics simulations with a force field optimized to describe disordered proteins. We find, as in experiments, that both peptides populate configurations consistent with random polymer chains, with the vast majority of conformations lacking significant secondary structure, giving rise to very similar ensemble averaged FRET efficiencies. PMID- 29490248 TI - Role of the Disulfide Bond in Prion Protein Amyloid Formation: A Thermodynamic and Kinetic Analysis. AB - Prion diseases are associated with the structural conversion of prion protein (PrP) to a beta-sheet-rich aggregate, PrPSc. Previous studies have indicated that a reduction of the disulfide bond linking C179 and C214 of PrP yields an amyloidlike beta-rich aggregate in vitro. To gain mechanistic insights into the reduction-induced aggregation, here I characterized how disulfide bond reduction modulates the protein folding/misfolding landscape of PrP, by examining 1) the equilibrium stabilities of the native (N) and aggregated states relative to the unfolded (U) state, 2) the transition barrier separating the U and aggregated states, and 3) the final structure of amyloidlike misfolded aggregates. Kinetic and thermodynamic experiments revealed that disulfide bond reduction decreases the equilibrium stabilities of both the N and aggregated states by ~3 kcal/mol, without changing either the amyloidlike aggregate structure, at least at the secondary structural level, or the transition barrier of aggregation. Therefore, disulfide bond reduction modulates the protein folding/misfolding landscape by entropically stabilizing disordered states, including the U and transition state of aggregation. This also indicates that the equilibrium stability of the N state, but not the transition barrier of aggregation, is the dominant factor determining the reduction-induced aggregation of PrP. PMID- 29490249 TI - Lipid-Protein Interplay in Dimerization of Juxtamembrane Domains of Epidermal Growth Factor Receptor. AB - Transmembrane (TM) helix and juxtamembrane (JM) domains (TM-JM) bridge the extracellular and intracellular domains of single-pass membrane proteins, including epidermal growth factor receptor (EGFR). TM-JM dimerization plays a crucial role in regulation of EGFR kinase activity at the cytoplasmic side. Although the interaction of JM with membrane lipids is thought to be important to turn on EGF signaling, and phosphorylation of Thr654 on JM leads to desensitization, the underlying kinetic mechanisms remain unclear. In particular, how Thr654 phosphorylation regulates EGFR activity is largely unknown. Here, combining single-pair FRET imaging and nanodisc techniques, we showed that phosphatidylinositol 4,5-bis phosphate (PIP2) facilitated JM dimerization effectively. We also found that Thr654 phosphorylation dissociated JM dimers in the membranes containing acidic lipids, suggesting that Thr654 phosphorylation electrostatically prevented the interaction with basic residues in JM and acidic lipids. Based on the single-molecule experiment, we clarified the kinetic pathways of the monomer (inactive state)-to-dimer (active state) transition of JM domains and alteration in the pathways depending on the membrane lipid species and Thr654 phosphorylation. PMID- 29490250 TI - The Chemical Potential of Plasma Membrane Cholesterol: Implications for Cell Biology. AB - Cholesterol is abundant in plasma membranes and exhibits a variety of interactions throughout the membrane. Chemical potential accounts for thermodynamic consequences of molecular interactions, and quantifies the effective concentration (i.e., activity) of any substance participating in a process. We have developed, to our knowledge, the first method to measure cholesterol chemical potential in plasma membranes. This was accomplished by complexing methyl-beta-cyclodextrin with cholesterol in an aqueous solution and equilibrating it with an organic solvent containing dissolved cholesterol. The chemical potential of cholesterol was thereby equalized in the two phases. Because cholesterol is dilute in the organic phase, here activity and concentration were equivalent. This equivalence allowed the amount of cholesterol bound to methyl-beta-cyclodextrin to be converted to cholesterol chemical potential. Our method was used to determine the chemical potential of cholesterol in erythrocytes and in plasma membranes of nucleated cells in culture. For erythrocytes, the chemical potential did not vary when the concentration was below a critical value. Above this value, the chemical potential progressively increased with concentration. We used standard cancer lines to characterize cholesterol chemical potential in plasma membranes of nucleated cells. This chemical potential was significantly greater for highly metastatic breast cancer cells than for nonmetastatic breast cancer cells. Chemical potential depended on density of the cancer cells. A method to alter and fix the cholesterol chemical potential to any value (i.e., a cholesterol chemical potential clamp) was also developed. Cholesterol content did not change when cells were clamped for 24-48 h. It was found that the level of activation of the transcription factor STAT3 increased with increasing cholesterol chemical potential. The cholesterol chemical potential may regulate signaling pathways. PMID- 29490251 TI - Selective Interaction of Colistin with Lipid Model Membranes. AB - Although colistin's clinical use is limited due to its nephrotoxicity, colistin is considered to be an antibiotic of last resort because it is used to treat patients infected with multidrug-resistant bacteria. In an effort to provide molecular details about colistin's ability to kill Gram-negative (G(-)) but not Gram-positive (G(+)) bacteria, we investigated the biophysics of the interaction between colistin and lipid mixtures mimicking the cytoplasmic membrane of G(+), G(-) bacteria as well as eukaryotic cells. Two different models of the G(-) outer membrane (OM) were assayed: lipid A with two deoxy-manno-octulosonyl sugar residues, and Escherichia coli lipopolysaccharide mixed with dilaurylphosphatidylglycerol. We used circular dichroism and x-ray diffuse scattering at low and wide angle in stacked multilayered samples, and neutron reflectivity of single, tethered bilayers mixed with colistin. We found no differences in secondary structure when colistin was bound to G(-) versus G(+) membrane mimics, ruling out a protein conformational change as the cause of this difference. However, bending modulus KC perturbation was quite irregular for the G(-) inner membrane, where colistin produced a softening of the membranes at an intermediate lipid/peptide molar ratio but stiffening at lower and higher peptide concentrations, whereas in G(+) and eukaryotic mimics there was only a slight softening. Acyl chain order in G(-) was perturbed similarly to KC. In G(+), there was only a slight softening and disordering effect, whereas in OM mimics, there was a slight stiffening and ordering of both membranes with increasing colistin. X-ray and neutron reflectivity structural results reveal colistin partitions deepest to reach the hydrocarbon interior in G(-) membranes, but remains in the headgroup region in G(+), OM, and eukaryotic mimics. It is possible that domain formation is responsible for the erratic response of G(-) inner membranes to colistin and for its deeper penetration, which could increase membrane permeability. PMID- 29490253 TI - Spatial Fluctuations at Vertices of Epithelial Layers: Quantification of Regulation by Rho Pathway. AB - In living matter, shape fluctuations induced by acto-myosin are usually studied in vitro via reconstituted gels, whose properties are controlled by changing the concentrations of actin, myosin, and cross-linkers. Such an approach deliberately avoids consideration of the complexity of biochemical signaling inherent to living systems. Acto-myosin activity inside living cells is mainly regulated by the Rho signaling pathway, which is composed of multiple layers of coupled activators and inhibitors. Here, we investigate how such a pathway controls the dynamics of confluent epithelial tissues by tracking the displacements of the junction points between cells. Using a phenomenological model to analyze the vertex fluctuations, we rationalize the effects of different Rho signaling targets on the emergent tissue activity by quantifying the effective diffusion coefficient, and the persistence time and length of the fluctuations. Our results reveal an unanticipated correlation between layers of activation/inhibition and spatial fluctuations within tissues. Overall, this work connects regulation via biochemical signaling with mesoscopic spatial fluctuations, with potential application to the study of structural rearrangements in epithelial tissues. PMID- 29490252 TI - Hypotonic Challenge of Endothelial Cells Increases Membrane Stiffness with No Effect on Tether Force. AB - Regulation of cell volume is a fundamental property of all mammalian cells. Multiple signaling pathways are known to be activated by cell swelling and to contribute to cell volume homeostasis. Although cell mechanics and membrane tension have been proposed to couple cell swelling to signaling pathways, the impact of swelling on cellular biomechanics and membrane tension have yet to be fully elucidated. In this study, we use atomic force microscopy under isotonic and hypotonic conditions to measure mechanical properties of endothelial membranes including membrane stiffness, which reflects the stiffness of the submembrane cytoskeleton complex, and the force required for membrane tether formation, reflecting membrane tension and membrane-cytoskeleton attachment. We find that hypotonic swelling results in significant stiffening of the endothelial membrane without a change in membrane tension/membrane-cytoskeleton attachment. Furthermore, depolymerization of F-actin, which, as expected, results in a dramatic decrease in the cellular elastic modulus of both the membrane and the deeper cytoskeleton, indicating a collapse of the cytoskeleton scaffold, does not abrogate swelling-induced stiffening of the membrane. Instead, this swelling induced stiffening of the membrane is enhanced. We propose that the membrane stiffening should be attributed to an increase in hydrostatic pressure that results from an influx of solutes and water into the cells. Most importantly, our results suggest that increased hydrostatic pressure, rather than changes in membrane tension, could be responsible for activating volume-sensitive mechanisms in hypotonically swollen cells. PMID- 29490254 TI - Stochastic Model of Maturation and Vesicular Exchange in Cellular Organelles. AB - The dynamical organization of membrane-bound organelles along intracellular transport pathways relies on vesicular exchange between organelles and on the maturation of the organelle's composition by enzymatic reactions or exchange with the cytoplasm. The relative importance of each mechanism in controlling organelle dynamics remains controversial, in particular for transport through the Golgi apparatus. Using a stochastic model, we identify two classes of dynamical behavior that can lead to full maturation of membrane-bound compartments. In the first class, maturation corresponds to the stochastic escape from a steady state in which export is dominated by vesicular exchange, and is very unlikely for large compartments. In the second class, it occurs in a quasi-deterministic fashion and is almost size independent. Whether a system belongs to the first or second class is largely controlled by homotypic fusion. PMID- 29490255 TI - Simulation of Cell Patterning Triggered by Cell Death and Differential Adhesion in Drosophila Wing. AB - The Drosophila wing exhibits a well-ordered cell pattern, especially along the posterior margin, where hair cells are arranged in a zigzag pattern in the lateral view. Based on an experimental result observed during metamorphosis of Drosophila, we considered that a pattern of initial cells autonomously develops to the zigzag pattern through cell differentiation, intercellular communication, and cell death (apoptosis) and performed computer simulations of a cell-based model of vertex dynamics for tissues. The model describes the epithelial tissue as a monolayer cell sheet of polyhedral cells. Their vertices move according to equations of motion, minimizing the sum total of the interfacial and elastic energies of cells. The interfacial energy densities between cells are introduced consistently with an ideal zigzag cell pattern, extracted from the experimental result. The apoptosis of cells is modeled by gradually reducing their equilibrium volume to zero and by assuming that the hair cells prohibit neighboring cells from undergoing apoptosis. Based on experimental observations, we also assumed wing elongation along the proximal-distal axis. Starting with an initial cell pattern similar to the micrograph experimentally obtained just before apoptosis, we carried out the simulations according to the model mentioned above and successfully reproduced the ideal zigzag cell pattern. This elucidates a physical mechanism of patterning triggered by cell apoptosis theoretically and exemplifies, to our knowledge, a new framework to study apoptosis-induced patterning. We conclude that the zigzag cell pattern is formed by an autonomous communicative process among the participant cells. PMID- 29490256 TI - Theory of Epithelial Cell Shape Transitions Induced by Mechanoactive Chemical Gradients. AB - Cell shape is determined by a balance of intrinsic properties of the cell as well as its mechanochemical environment. Inhomogeneous shape changes underlie many morphogenetic events and involve spatial gradients in active cellular forces induced by complex chemical signaling. Here, we introduce a mechanochemical model based on the notion that cell shape changes may be induced by external diffusible biomolecules that influence cellular contractility (or equivalently, adhesions) in a concentration-dependent manner-and whose spatial profile in turn is affected by cell shape. We map out theoretically the possible interplay between chemical concentration and cellular structure. Besides providing a direct route to spatial gradients in cell shape profiles in tissues, we show that the dependence on cell shape helps create robust mechanochemical gradients. PMID- 29490258 TI - Deciphering the Dynamical Origin of Mixed Population during Neural Stem Cell Development. AB - Neural stem cells (NSCs) often give rise to a mixed population of cells during differentiation. However, the dynamical origin of these mixed states is poorly understood. In this article, our mathematical modeling study demonstrates that the bone morphogenetic protein 2 (BMP2) mediated disparate differentiation dynamics of NSCs in central and peripheral nervous systems essentially function through two distinct bistable switches that are mutually interconnected via a mushroom-like bifurcation. Stochastic simulations of the model reveal that the mixed population originates due to the existence of these bistable switching regulations and that the maintenance of such mixed states depends on the level of stochastic fluctuations of the system. It further demonstrates that due to extrinsic variability, cells in an NSC population can dynamically transit from mushroom to a unique isola kind of bifurcation state, which essentially extends the range of the BMP2-driven mixed population state during differentiation. Importantly, the model predicts that by individually altering the expression level of key regulatory proteins, the NSCs can be converted entirely to a preferred phenotype for BMP2 doses that previously resulted in a mixed population. Our findings show that efficient neuronal regeneration can be achieved by systematically maneuvering the differentiation dynamics. PMID- 29490257 TI - Impact of Tissue Factor Localization on Blood Clot Structure and Resistance under Venous Shear. AB - The structure and growth of a blood clot depend on the localization of tissue factor (TF), which can trigger clotting during the hemostatic process or promote thrombosis when exposed to blood under pathological conditions. We sought to understand how the growth, structure, and mechanical properties of clots under flow are shaped by the simultaneously varying TF surface density and its exposure area. We used an eight-channel microfluidic device equipped with a 20- or 100-MUm long collagen surface patterned with lipidated TF of surface densities ~0.1 and ~2 molecules/MUm2. Human whole blood was perfused at venous shear, and clot growth was continually measured. Using our recently developed computational model of clot formation, we performed simulations to gain insights into the clot's structure and its resistance to blood flow. An increase in TF exposure area resulted not only in accelerated bulk platelet, thrombin, and fibrin accumulation, but also in increased height of the platelet mass and increased clot resistance to flow. Moreover, increasing the TF surface density or exposure area enhanced platelet deposition by approximately twofold, and thrombin and fibrin generation by greater than threefold, thereby increasing both clot size and its viscous resistance. Finally, TF effects on blood flow occlusion were more pronounced for the longer thrombogenic surface than for the shorter one. Our results suggest that TF surface density and its exposure area can independently enhance both the clot's occlusivity and its resistance to blood flow. These findings provide, to our knowledge, new insights into how TF affects thrombus growth in time and space under flow. PMID- 29490259 TI - Neutrophil-lymphocyte ratio is increased in elderly patients with first episode depression, but not in recurrent depression. AB - Association between inflammation and depression, especially in elderly patients, leads to conclusions about their shared influence on risk of cardiovascular disease and death. It might be found useful to predict those issues by monitoring inflammatory parameters, such as neutrophil/lymphocyte ratio (NLR). The aim of this study was to determine the NLR in elderly patients with unipolar depression compared with non-depressed elderly patients. NLR was measured in 684 Caucasian subjects (depressed: n = 465, non-depressed: n = 219), aged >= 60 (depressed: mean age 74.8 +/- 7.8 years, non-depressed: mean age: 71.1 +/- 5.7 years). There were two subgroups within depressed patients: first episode depression (n = 138, 29.6%) and recurrent depression (n = 328, 70.3%). NLR was calculated as ratio between absolute neutrophil count to absolute lymphocyte count. NLR was significantly higher in unmedicated patients with depression compared with healthy control (2.10 +/- 2.13 vs. 2.01 +/- 0.75, p = 0.004). It was higher in first episode depression compared with recurrent depression (2.11 +/- 1.76 vs 1.64 +/- 1.04, p < 0.05). There was a positive correlation with severity of symptoms. We found non-specific effect of treatment with antidepressants or antipsychotics on lower NLR. Increased NLR in patients with first episode of depression compared to recurrent depression and healthy control may have important clinical consequences. Severity of symptoms are positively correlated with NLR, which may indicate that with increasing severity of depression, the risk of cardiovascular events is also rising, which leads to higher mortality. In elderly patients with depression even a small reduction of such risk may translate into better prognosis and improve quality of live. The difference between first episode and recurrent depression in terms of inflammatory biomarkers requires further studies. PMID- 29490260 TI - A TRACER 3D Co-Culture tumour model for head and neck cancer. AB - Cancer-associated fibroblasts (CAFs) are a key component of the tumour microenvironment and have been shown to play an important role in the progression of cancer. To probe these tumour-stroma interactions, we incorporated CAFs derived from head and neck cancer patients and squamous carcinoma cells of the hypopharynx (FaDu) into the Tissue Roll for the Analysis of Cellular Environment and Response (TRACER) platform to establish a co-culture platform that simulates the CAF-tumour microenvironmental interactions in head and neck tumours. TRACER culture involves infiltrating cells into a thin fibrous scaffold and then rolling the resulting biocomposite around a mandrel to generate a 3D and layered structure. Patterning the fibrous scaffold biocomposite during fabrication enables control over the specific location of different cell populations in the rolled configuration. Here, we optimized the seeding densities and configurations of the CAF and FaDu cell tissue sections to enable a robust 3D co-culture system under normoxic conditions. Co-culture of CAFs with FaDu cells produced negligible effects on radiation resistance, but did produce increases in proliferation rate and invasive cell migration at 24 and 48 h of culture. Our study provides the basis for use of our in vitro co-culture TRACER model to investigate the tumour stroma interactions, and to bridge the translational gap between preclinical and clinical studies. PMID- 29490261 TI - Heat stress-induced nuclear transport mediated by Hikeshi confers nuclear function of Hsp70s. AB - The prime feature of eukaryotic cells is the separation of the intracellular space into two compartments, the nucleus and the cytoplasm. Active nuclear transport is crucial for the maintenance of this separation. In this report, we focus on a nuclear transport receptor named Hikeshi, which mediates the heat stress-induced nuclear import of 70-kDa heat shock proteins (Hsp70s), and discuss how the same protein can function differently depending on the cellular compartment in which it is localized. Hsp70 is a molecular chaperone that is predominantly localized in the cytoplasm under normal conditions but is known to accumulate in the nucleus under conditions of heat stress. Although the reported function of Hsp70 is mostly attributed to its molecular function in the cytoplasm, the functions of Hsp70 may extend beyond molecular chaperone activity in the nucleus. PMID- 29490262 TI - A Single Administration of CRISPR/Cas9 Lipid Nanoparticles Achieves Robust and Persistent In Vivo Genome Editing. AB - The development of clinically viable delivery methods presents one of the greatest challenges in the therapeutic application of CRISPR/Cas9 mediated genome editing. Here, we report the development of a lipid nanoparticle (LNP)-mediated delivery system that, with a single administration, enabled significant editing of the mouse transthyretin (Ttr) gene in the liver, with a >97% reduction in serum protein levels that persisted for at least 12 months. These results were achieved with an LNP delivery system that was biodegradable and well tolerated. The LNP delivery system was combined with a sgRNA having a chemical modification pattern that was important for high levels of in vivo activity. The formulation was similarly effective in a rat model. Our work demonstrates that this LNP system can deliver CRISPR/Cas9 components to achieve clinically relevant levels of in vivo genome editing with a concomitant reduction of TTR serum protein, highlighting the potential of this system as an effective genome editing platform. PMID- 29490263 TI - Resistance to BET Inhibitor Leads to Alternative Therapeutic Vulnerabilities in Castration-Resistant Prostate Cancer. AB - BRD4 plays a major role in the transcription networks orchestrated by androgen receptor (AR) in castration-resistant prostate cancer (CRPC). Several BET inhibitors (BETi) that displace BRD4 from chromatin are being evaluated in clinical trials for CRPC. Here, we describe mechanisms of acquired resistance to BETi that are amenable to targeted therapies in CRPC. BETi-resistant CRPC cells displayed cross-resistance to a variety of BETi in the absence of gatekeeper mutations, exhibited reduced chromatin-bound BRD4, and were less sensitive to BRD4 degraders/knockdown, suggesting a BRD4-independent transcription program. Transcriptomic analysis revealed reactivation of AR signaling due to CDK9 mediated phosphorylation of AR, resulting in sensitivity to CDK9 inhibitors and enzalutamide. Additionally, increased DNA damage associated with PRC2-mediated transcriptional silencing of DDR genes was observed, leading to PARP inhibitor sensitivity. Collectively, our results identify the therapeutic limitation of BETi as a monotherapy; however, our BETi resistance data suggest unique opportunities for combination therapies in treating CRPC. PMID- 29490266 TI - Nap1l1 Controls Embryonic Neural Progenitor Cell Proliferation and Differentiation in the Developing Brain. AB - The precise function and role of nucleosome assembly protein 1-like 1 (Nap1l1) in brain development are unclear. Here, we find that Nap1l1 knockdown decreases neural progenitor cell (NPC) proliferation and induces premature neuronal differentiation during cortical development. A similar deficiency in embryonic neurogenesis was observed in Nap1l1 knockout (KO) mice, which were generated using the CRISPR-Cas9 system. RNA sequencing (RNA-seq) analysis indicates that Ras-associated domain family member 10 (RassF10) may be the downstream target of Nap1l1. Furthermore, we found that Nap1l1 regulates RassF10 expression by promoting SETD1A-mediated H3K4 trimethylation at the RassF10 promoter. Nap1l1 KO defects may be rescued by RassF10 overexpression, suggesting that Nap1l1 controls NPC differentiation through RassF10. Our findings reveal an essential role for the Nap1l1 histone chaperone in cortical neurogenesis during early embryonic brain development. PMID- 29490264 TI - SynDIG4/Prrt1 Is Required for Excitatory Synapse Development and Plasticity Underlying Cognitive Function. AB - Altering AMPA receptor (AMPAR) content at synapses is a key mechanism underlying the regulation of synaptic strength during learning and memory. Previous work demonstrated that SynDIG1 (synapse differentiation-induced gene 1) encodes a transmembrane AMPAR-associated protein that regulates excitatory synapse strength and number. Here we show that the related protein SynDIG4 (also known as Prrt1) modifies AMPAR gating properties in a subunit-dependent manner. Young SynDIG4 knockout (KO) mice have weaker excitatory synapses, as evaluated by immunocytochemistry and electrophysiology. Adult SynDIG4 KO mice show complete loss of tetanus-induced long-term potentiation (LTP), while mEPSC amplitude is reduced by only 25%. Furthermore, SynDIG4 KO mice exhibit deficits in two independent cognitive assays. Given that SynDIG4 colocalizes with the AMPAR subunit GluA1 at non-synaptic sites, we propose that SynDIG4 maintains a pool of extrasynaptic AMPARs necessary for synapse development and function underlying higher-order cognitive plasticity. PMID- 29490265 TI - A NuRD Complex from Xenopus laevis Eggs Is Essential for DNA Replication during Early Embryogenesis. AB - DNA replication in the embryo of Xenopus laevis changes dramatically at the mid blastula transition (MBT), with Y RNA-independent random initiation switching to Y RNA-dependent initiation at specific origins. Here, we identify xNuRD, an MTA2 containing assemblage of the nucleosome remodeling and histone deacetylation complex NuRD, as an essential factor in pre-MBT Xenopus embryos that overcomes a functional requirement for Y RNAs during DNA replication. Human NuRD complexes have a different subunit composition than xNuRD and do not support Y RNA independent initiation of DNA replication. Blocking or immunodepletion of xNuRD inhibits DNA replication initiation in isolated nuclei in vitro and causes inhibition of DNA synthesis, developmental delay, and embryonic lethality in early embryos. xNuRD activity declines after the MBT, coinciding with dissociation of the complex and emergence of Y RNA-dependent initiation. Our data thus reveal an essential role for a NuRD complex as a DNA replication factor during early Xenopus development. PMID- 29490267 TI - Ubiquitination of MBNL1 Is Required for Its Cytoplasmic Localization and Function in Promoting Neurite Outgrowth. AB - The Muscleblind-like protein family (MBNL) plays an important role in regulating the transition between differentiation and pluripotency and in the pathogenesis of myotonic dystrophy type 1 (DM1), a CTG expansion disorder. How different MBNL isoforms contribute to the differentiation and are affected in DM1 has not been investigated. Here, we show that the MBNL1 cytoplasmic, but not nuclear, isoform promotes neurite morphogenesis and reverses the morphological defects caused by expanded CUG RNA. Cytoplasmic MBNL1 is polyubiquitinated by lysine 63 (K63). Reduced cytoplasmic MBNL1 in the DM1 mouse brain is consistent with the reduced extent of K63 ubiquitination. Expanded CUG RNA induced the deubiqutination of cytoplasmic MBNL1, which resulted in nuclear translocation and morphological impairment that could be ameliorated by inhibiting K63-linked polyubiquitin chain degradation. Our results suggest that K63-linked ubiquitination of MBNL1 is required for its cytoplasmic localization and that deubiquitination of cytoplasmic MBNL1 is pathogenic in the DM1 brain. PMID- 29490268 TI - The alpha2delta-1-NMDA Receptor Complex Is Critically Involved in Neuropathic Pain Development and Gabapentin Therapeutic Actions. AB - alpha2delta-1, commonly known as a voltage-activated Ca2+ channel subunit, is a binding site of gabapentinoids used to treat neuropathic pain and epilepsy. However, it is unclear how alpha2delta-1 contributes to neuropathic pain and gabapentinoid actions. Here, we show that Cacna2d1 overexpression potentiates presynaptic and postsynaptic NMDAR activity of spinal dorsal horn neurons to cause pain hypersensitivity. Conversely, Cacna2d1 knockdown or ablation normalizes synaptic NMDAR activity increased by nerve injury. alpha2delta-1 forms a heteromeric complex with NMDARs in rodent and human spinal cords. The alpha2delta-1-NMDAR interaction predominantly occurs through the C terminus of alpha2delta-1 and promotes surface trafficking and synaptic targeting of NMDARs. Gabapentin or an alpha2delta-1 C terminus-interfering peptide normalizes NMDAR synaptic targeting and activity increased by nerve injury. Thus, alpha2delta-1 is an NMDAR-interacting protein that increases NMDAR synaptic delivery in neuropathic pain. Gabapentinoids reduce neuropathic pain by inhibiting forward trafficking of alpha2delta-1-NMDAR complexes. PMID- 29490269 TI - Precision of Discrete and Rhythmic Forelimb Movements Requires a Distinct Neuronal Subpopulation in the Interposed Anterior Nucleus. AB - The deep cerebellar nuclei (DCN) represent output channels of the cerebellum, and they transmit integrated sensorimotor signals to modulate limb movements. But the functional relevance of identifiable neuronal subpopulations within the DCN remains unclear. Here, we examine a genetically tractable population of neurons in the mouse interposed anterior nucleus (IntA). We show that these neurons represent a subset of glutamatergic neurons in the IntA and constitute a specific element of an internal feedback circuit within the cerebellar cortex and cerebello-thalamo-cortical pathway associated with limb control. Ablation and optogenetic stimulation of these neurons disrupt efficacy of skilled reach and locomotor movement and reveal that they control positioning and timing of the forelimb and hindlimb. Together, our findings uncover the function of a distinct neuronal subpopulation in the deep cerebellum and delineate the anatomical substrates and kinematic parameters through which it modulates precision of discrete and rhythmic limb movements. PMID- 29490270 TI - Spontaneous Vesicle Fusion Is Differentially Regulated at Cholinergic and GABAergic Synapses. AB - The locomotion of C. elegans is balanced by excitatory and inhibitory neurotransmitter release at neuromuscular junctions. However, the molecular mechanisms that maintain the balance of synaptic transmission remain enigmatic. Here, we investigated the function of voltage-gated Ca2+ channels in triggering spontaneous release at cholinergic and GABAergic synapses. Recordings of the miniature excitatory/inhibitory postsynaptic currents (mEPSCs and mIPSCs, respectively) showed that UNC-2/CaV2 and EGL-19/CaV1 channels are the two major triggers for spontaneous release. Notably, however, Ca2+-independent spontaneous release was observed at GABAergic but not cholinergic synapses. Functional screening led to the identification of hypomorphic unc-64/Syntaxin-1A and snb 1/VAMP2 mutants in which mEPSCs are severely impaired, whereas mIPSCs remain unaltered, indicating differential regulation of these currents at cholinergic and GABAergic synapses. Moreover, Ca2+-independent spontaneous GABA release was nearly abolished in the hypomorphic unc-64 and snb-1 mutants, suggesting distinct mechanisms for Ca2+-dependent and Ca2+-independent spontaneous release. PMID- 29490271 TI - Two Parallel Pathways Assign Opposing Odor Valences during Drosophila Memory Formation. AB - During olfactory associative learning in Drosophila, odors activate specific subsets of intrinsic mushroom body (MB) neurons. Coincident exposure to either rewards or punishments is thought to activate extrinsic dopaminergic neurons, which modulate synaptic connections between odor-encoding MB neurons and MB output neurons to alter behaviors. However, here we identify two classes of intrinsic MB gamma neurons based on cAMP response element (CRE)-dependent expression, gammaCRE-p and gammaCRE-n, which encode aversive and appetitive valences. gammaCRE-p and gammaCRE-n neurons act antagonistically to maintain neutral valences for neutral odors. Activation or inhibition of either cell type upsets this balance, toggling odor preferences to either positive or negative values. The mushroom body output neurons, MBON-gamma5beta'2a/beta'2mp and MBON gamma2alpha'1, mediate the actions of gammaCRE-p and gammaCRE-n neurons. Our data indicate that MB neurons encode valence information, as well as odor information, and this information is integrated through a process involving MBONs to regulate learning and memory. PMID- 29490273 TI - Action Selection and Flexible Switching Controlled by the Intralaminar Thalamic Neurons. AB - Learning processes contributing to appropriate selection and flexible switching of behaviors are mediated through the dorsal striatum, a key structure of the basal ganglia circuit. The major inputs to striatal subdivisions are provided from the intralaminar thalamic nuclei, including the central lateral nucleus (CL) and parafascicular nucleus (PF). Thalamostriatal neurons in the PF modulate the acquisition and performance of stimulus-response learning. Here, we address the roles of the CL thalamostriatal neurons in learning processes by using a selective neural pathway targeting technique. We show that the CL neurons are essential for the performance of stimulus-response learning and for behavioral flexibility, including reversal and attentional set-shifting of learned responses. In addition, chemogenetic suppression of neural activity supports the requirements of these neurons for behavioral flexibility. Our results suggest that the main contribution of the CL thalamostriatal neurons is functional control of the basal ganglia circuit linked to the prefrontal cortex. PMID- 29490274 TI - Oligodendrocytes in the Mouse Corpus Callosum Maintain Axonal Function by Delivery of Glucose. AB - In the optic nerve, oligodendrocytes maintain axonal function by supplying lactate as an energy substrate. Here, we report that, in acute brain slices of the mouse corpus callosum, exogenous glucose deprivation (EGD) abolished compound action potentials (CAPs), which neither lactate nor pyruvate could prevent. Loading an oligodendrocyte with 20 mM glucose using a patch pipette prevented EGD mediated CAP reduction in about 70% of experiments. Loading oligodendrocytes with lactate rescued CAPs less efficiently than glucose. In mice lacking connexin 47, oligodendrocyte filling with glucose did not prevent CAP loss, emphasizing the importance of glial networks for axonal energy supply. Compared with the optic nerve, the astrocyte network in the corpus callosum was less dense, and loading astrocytes with glucose did not prevent CAP loss during EGD. We suggest that callosal oligodendrocyte networks provide energy to sustain axonal function predominantly by glucose delivery, and mechanisms of metabolic support vary across different white matter regions. PMID- 29490272 TI - A Drosophila Model of Intellectual Disability Caused by Mutations in the Histone Demethylase KDM5. AB - Mutations in KDM5 family histone demethylases cause intellectual disability in humans. However, the molecular mechanisms linking KDM5-regulated transcription and cognition remain unknown. Here, we establish Drosophila as a model to understand this connection by generating a fly strain harboring an allele analogous to a disease-causing missense mutation in human KDM5C (kdm5A512P). Transcriptome analysis of kdm5A512P flies revealed a striking downregulation of genes required for ribosomal assembly and function and a concomitant reduction in translation. kdm5A512P flies also showed impaired learning and/or memory. Significantly, the behavioral and transcriptional changes in kdm5A512P flies were similar to those specifically lacking demethylase activity. These data suggest that the primary defect of the KDM5A512P mutation is a loss of histone demethylase activity and reveal an unexpected role for this enzymatic function in gene activation. Because translation is critical for neuronal function, we propose that this defect contributes to the cognitive defects of kdm5A512P flies. PMID- 29490277 TI - Quantitative Operating Principles of Yeast Metabolism during Adaptation to Heat Stress. AB - Microorganisms evolved adaptive responses to survive stressful challenges in ever changing environments. Understanding the relationships between the physiological/metabolic adjustments allowing cellular stress adaptation and gene expression changes being used by organisms to achieve such adjustments may significantly impact our ability to understand and/or guide evolution. Here, we studied those relationships during adaptation to various stress challenges in Saccharomyces cerevisiae, focusing on heat stress responses. We combined dozens of independent experiments measuring whole-genome gene expression changes during stress responses with a simplified kinetic model of central metabolism. We identified alternative quantitative ranges for a set of physiological variables in the model (production of ATP, trehalose, NADH, etc.) that are specific for adaptation to either heat stress or desiccation/rehydration. Our approach is scalable to other adaptive responses and could assist in developing biotechnological applications to manipulate cells for medical, biotechnological, or synthetic biology purposes. PMID- 29490275 TI - Aspirin Recapitulates Features of Caloric Restriction. AB - The age-associated deterioration in cellular and organismal functions associates with dysregulation of nutrient-sensing pathways and disabled autophagy. The reactivation of autophagic flux may prevent or ameliorate age-related metabolic dysfunctions. Non-toxic compounds endowed with the capacity to reduce the overall levels of protein acetylation and to induce autophagy have been categorized as caloric restriction mimetics (CRMs). Here, we show that aspirin or its active metabolite salicylate induce autophagy by virtue of their capacity to inhibit the acetyltransferase activity of EP300. While salicylate readily stimulates autophagic flux in control cells, it fails to further increase autophagy levels in EP300-deficient cells, as well as in cells in which endogenous EP300 has been replaced by salicylate-resistant EP300 mutants. Accordingly, the pro-autophagic activity of aspirin and salicylate on the nematode Caenorhabditis elegans is lost when the expression of the EP300 ortholog cpb-1 is reduced. Altogether, these findings identify aspirin as an evolutionary conserved CRM. PMID- 29490276 TI - P2RY1/ALK3-Expressing Cells within the Adult Human Exocrine Pancreas Are BMP-7 Expandable and Exhibit Progenitor-like Characteristics. AB - Treatment of human pancreatic non-endocrine tissue with Bone Morphogenetic Protein 7 (BMP-7) leads to the formation of glucose-responsive beta-like cells. Here, we show that BMP-7 acts on extrainsular cells expressing PDX1 and the BMP receptor activin-like kinase 3 (ALK3/BMPR1A). In vitro lineage tracing indicates that ALK3+ cell populations are multipotent. PDX1+/ALK3+ cells are absent from islets but prominently represented in the major pancreatic ducts and pancreatic duct glands. We identified the purinergic receptor P2Y1 (P2RY1) as a surrogate surface marker for PDX1. Sorted P2RY1+/ALK3bright+ cells form BMP-7-expandable colonies characterized by NKX6.1 and PDX1 expression. Unlike the negative fraction controls, these colonies can be differentiated into multiple pancreatic lineages upon BMP-7 withdrawal. RNA-seq further corroborates the progenitor-like nature of P2RY1+/ALK3bright+ cells and their multilineage differentiation potential. Our studies confirm the existence of progenitor cells in the adult human pancreas and suggest a specific anatomical location within the ductal and glandular networks. PMID- 29490278 TI - S. aureus Evades Macrophage Killing through NLRP3-Dependent Effects on Mitochondrial Trafficking. AB - Clinical severity of Staphylococcus aureus respiratory infection correlates with alpha toxin (AT) expression. AT activates the NLRP3 inflammasome; deletion of Nlrp3, or AT neutralization, protects mice from lethal S. aureus pneumonia. We tested the hypothesis that this protection is not due to a reduction in inflammasome-dependent cytokines (IL-1beta/IL-18) but increased bactericidal function of macrophages. In vivo, neutralization of AT or NLRP3 improved bacterial clearance and survival, while blocking IL-1beta/IL-18 did not. Primary human monocytes were used in vitro to determine the mechanism through which NLRP3 alters bacterial killing. In cells treated with small interfering RNA (siRNA) targeting NLRP3 or infected with AT-null S. aureus, mitochondria co-localize with bacterial-containing phagosomes. Mitochondrial engagement activates caspase-1, a process dependent on complex II of the electron transport chain, near the phagosome, promoting its acidification. These data demonstrate a mechanism utilized by S. aureus to sequester itself from antimicrobial processes within the cell. PMID- 29490279 TI - USP2a Supports Metastasis by Tuning TGF-beta Signaling. AB - TGF-beta has been demonstrated to promote tumor metastasis, and the regulatory mechanisms are poorly understood. Here, we report the role of USP2a in promoting metastasis by facilitating TGF-beta-triggered signaling. USP2a interacts with TGFBR1 and TGFBR2 upon TGF-beta stimulation and removes K33-linked polyubiquitin chains from Lys502 of TGFBR1, promoting the recruitment of SMAD2/3. Simultaneously, TGFBR2 phosphorylates Ser207/Ser225 of USP2a, leading to the disassociation of SMAD2/3 from TGFBR1. The phosphorylation of USP2a and SMAD2 is positively correlated in human tumor biopsies, and USP2a is hyper-phosphorylated in lung adenocarcinomas with lymph node invasion. Depletion or pharmacologic inhibition of USP2a dampens TGF-beta-triggered signaling and metastasis. Our findings have characterized an essential role of USP2a as a potential target for treatment of metastatic cancers. PMID- 29490280 TI - GNA11 Q209L Mouse Model Reveals RasGRP3 as an Essential Signaling Node in Uveal Melanoma. AB - Uveal melanoma (UM) is characterized by mutually exclusive activating mutations in GNAQ, GNA11, CYSLTR2, and PLCB4, four genes in a linear pathway to activation of PLCbeta in almost all tumors and loss of BAP1 in the aggressive subset. We generated mice with melanocyte-specific expression of GNA11Q209L with and without homozygous Bap1 loss. The GNA11Q209L mice recapitulated human Gq-associated melanomas, and they developed pigmented neoplastic lesions from melanocytes of the skin and non-cutaneous organs, including the eye and leptomeninges, as well as at atypical sites, including the lymph nodes and lungs. The addition of Bap1 loss increased tumor proliferation and cutaneous melanoma size. Integrative transcriptome analysis of human and murine melanomas identified RasGRP3 to be specifically expressed in GNAQ/GNA11-driven melanomas. In human UM cell lines and murine models, RasGRP3 is specifically required for GNAQ/GNA11-driven Ras activation and tumorigenesis. This implicates RasGRP3 as a critical node and a potential target in UM. PMID- 29490282 TI - Spatial Representation of Feeding and Oviposition Odors in the Brain of a Hawkmoth. AB - Female hawkmoths, Manduca sexta, use olfactory cues to locate nectar sources and oviposition sites. We investigated if the behavioral significance of odorants is represented already in the antennal lobe, the first olfactory neuropil of the insect's brain. Using in vivo calcium imaging, we first established a functional map of the dorsal surface of the antennal lobe by stimulating the moths with 80 ecologically relevant and chemically diverse monomolecular odorants. We were able to address 23 olfactory glomeruli, functional subunits of the antennal lobe, in each individual female. Next, we studied the relevance of the same odorants with two-choice experiments (odorant versus solvent) in a wind tunnel. Depending on odorant identity, naive moths made attempts to feed or to oviposit at the scented targets. A correlation of wind tunnel results with glomerular activation patterns revealed that feeding and oviposition behaviors are encoded in the moth's antennal lobe by the activation of distinct groups of glomeruli. PMID- 29490281 TI - PHLDA1 Mediates Drug Resistance in Receptor Tyrosine Kinase-Driven Cancer. AB - Development of resistance causes failure of drugs targeting receptor tyrosine kinase (RTK) networks and represents a critical challenge for precision medicine. Here, we show that PHLDA1 downregulation is critical to acquisition and maintenance of drug resistance in RTK-driven cancer. Using fibroblast growth factor receptor (FGFR) inhibition in endometrial cancer cells, we identify an Akt driven compensatory mechanism underpinned by downregulation of PHLDA1. We demonstrate broad clinical relevance of our findings, showing that PHLDA1 downregulation also occurs in response to RTK-targeted therapy in breast and renal cancer patients, as well as following trastuzumab treatment in HER2+ breast cancer cells. Crucially, knockdown of PHLDA1 alone was sufficient to confer de novo resistance to RTK inhibitors and induction of PHLDA1 expression re sensitized drug-resistant cancer cells to targeted therapies, identifying PHLDA1 as a biomarker for drug response and highlighting the potential of PHLDA1 reactivation as a means of circumventing drug resistance. PMID- 29490284 TI - Potency Analysis of Mesenchymal Stromal Cells Using a Combinatorial Assay Matrix Approach. AB - Assays that can characterize MSC immune potency need to be identified for use in advanced clinical trials. MSCs possess a number of putative regenerative and immunomodulatory properties, and an assay matrix approach may best capture involved effector pathways. We have tested two assay systems to measure the potency of MSCs derived from human subjects: MSC secretome analysis and a quantitative RNA-based array for genes specific to immunomodulatory and homing properties of MSCs. Secretome analysis identified a unique cytokine signature that is upregulated by MSCs or downregulated in responder PBMCs and correlated with T cell suppression. Use of interferon-gamma as a surrogate for the action of activated PBMCs on MSCs served as an alternative for the use of human PBMCs as responder cells in a potency assay. Our approach and results define and simplify the multifunctional or matrix responses of MSCs and may serve as a platform for robust potency analysis. PMID- 29490283 TI - Large-Scale Arrayed Analysis of Protein Degradation Reveals Cellular Targets for HIV-1 Vpu. AB - Accessory proteins of lentiviruses, such as HIV-1, target cellular restriction factors to enhance viral replication. Systematic analyses of proteins that are targeted for degradation by HIV-1 accessory proteins may provide a better understanding of viral immune evasion strategies. Here, we describe a high throughput platform developed to study cellular protein stability in a highly parallelized matrix format. We used this approach to identify cellular targets of the HIV-1 accessory protein Vpu through arrayed coexpression with 433 interferon stimulated genes, followed by differential fluorescent labeling and automated image analysis. Among the previously unreported Vpu targets identified by this approach, we find that the E2 ligase mediating ISG15 conjugation, UBE2L6, and the transmembrane protein PLP2 are targeted by Vpu during HIV-1 infection to facilitate late-stage replication. This study provides a framework for the systematic and high-throughput evaluation of protein stability and establishes a more comprehensive portrait of cellular Vpu targets. PMID- 29490285 TI - Lanostane triterpenes from the mushroom Ganoderma resinaceum and their inhibitory activities against alpha-glucosidase. AB - Eighteen previously undescribed lanostane triterpenes and thirty known analogues were obtained from the fruiting bodies of Ganoderma resinaceum. Resinacein C was isolated from a natural source for the first time. The structures of all the above compounds were elucidated by extensive spectroscopic analysis and comparisons of their spectroscopic data with those reported in the literature. Furthermore, in an in vitro assay, Resinacein C, ganoderic acid Y, lucialdehyde C, 7-oxo-ganoderic acid Z3, 7-oxo-ganoderic acid Z, and lucidadiol showed strong inhibitory effects against alpha-glucosidase compared with the positive control drug acarbose. The structure-activity relationships of ganoderma triterpenes on alpha-glucosidase inhibition showed that the C-24/C-25 double bond is necessary for alpha-glucosidase inhibitory activity. Moreover, the carboxylic acid group at C-26 and the hydroxy group at C-15 play important roles in enhancing inhibitory effects of these triterpenes. PMID- 29490286 TI - Half-lives of 101Rhg and 108Agm. AB - Using long-term gamma-ray spectroscopy with high resolution germanium detectors and a ratio method, the half-lives of 101Rhg and 108Agm have been determined to be 4.07 +/- 0.05 years and 448 +/- 27 years, respectively. These results are compared with previously reported values. PMID- 29490287 TI - Use of Copper Intrauterine Device in Transgender Male Adolescents. AB - Transgender men need contraception if engaging in intercourse with a cis-gender male partner. The copper IUD is an effective, non-hormonal contraceptive well suited for trans-males even while utilizing gender affirming hormone therapy. A gender-neutral medical facility with well-trained and sensitive staff is the ideal setting to provide such contraceptive care. PMID- 29490288 TI - Use of medications to decrease bleeding during surgical abortion: a survey of abortion providers' practices in the United States. AB - OBJECTIVE: Our objective was to document current practices of abortion providers on the use of medications to decrease bleeding during surgical abortion. STUDY DESIGN: We emailed surveys to 336 abortion providers through a professional listserv to elicit information on their use of medications to prevent and treat bleeding during first- and second-trimester surgical abortion. RESULTS: One hundred sixty-eight (50%) providers responded to our survey. The majority were obstetrician-gynecologists (83%) working in an academic practice (66%). Most completed a fellowship in family planning (87%) and currently perform abortions up to 22 or 24weeks of gestation (63%). Seventy-two percent routinely used prophylactic medications for bleeding. Providers who routinely used medications to prevent bleeding most commonly chose vasopressin (83%). Providers preferred methylergonovine as a treatment for excessive bleeding in the second trimester, followed by misoprostol. CONCLUSION: We found that most providers routinely use medications to prevent bleeding and use several different regimens to treat bleeding during abortion. IMPLICATIONS: We found that surgical abortion providers use a range of medications to prevent and treat hemorrhage at the time of surgical abortion. Scant evidence is available to guide abortion providers on the use of medications to decrease hemorrhage during surgical abortion. To provide evidence-based recommendations for the prevention and treatment of clinically significant bleeding, researchers should target the most commonly used interventions. PMID- 29490289 TI - Maintaining physiologic testosterone levels during combined oral contraceptives by adding dehydroepiandrosterone: II. Effects on sexual function. A phase II randomized, double-blind, placebo-controlled study. AB - OBJECTIVE: The objective was to evaluate the effect of combined oral contraceptives (OCs) on sexual function, either alone or together with dehydroepiandrosterone (DHEA). STUDY DESIGN: An exploratory randomized, double blind, placebo-controlled, comparative, crossover study was conducted in 81 OC users. Subjects discontinued their OC for one cycle before being randomized for 10cycles to a 30-mcg ethinyl estradiol (EE)/levonorgestrel (LNG) OC or a 30-mcg EE/drospirenone (DRSP) OC, along with daily use of 50mg dehydroepiandrosterone (DHEA) or placebo during five OC cycles before crossing over from DHEA to placebo or the reverse for another fivecycles. First, the effect on sexual function of five OC cycles + placebo was compared to baseline. Then, the effect of five OC cycles + DHEA was compared to the OC+placebo. Results regarding endocrine changes have been published separately. Primary efficacy outcomes of the current study were genital response (measured by vaginal pulse amplitude [VPA]) and sexual feelings (measured by the subjective self-assessment questionnaire [SSAQ]) to self-induced erotic fantasy and visual sexual stimuli in a laboratory setting and measures of desire and arousability using a sexual function diary (SFD). Secondary efficacy outcomes were the Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale Revised. RESULTS: Eighty-one women were enrolled, and 74 women completed the study. Five cycles of OC+placebo resulted in a significant decline compared to baseline of four out of six SFD self-ratings of sexual desire and arousability with both OCs. The LNG OC also resulted in significant declines in the FSFI scores (baseline vs. LNG OC+placebo: total score, 28.7+/-3.7 vs. 25.6+/-7.4; arousal, 5.0+/-0.7 vs. 4.5+/-1.4; lubrication, 5.2+/-0.9 vs. 4.6+/-1.7; pain, 4.9+/-0.9 vs. 4.5+/-1.4), but no changes were observed using the DRSP OC. In the laboratory setting, five cycles of OC+DHEA showed no significant differences with placebo except for a significant increase in genital sensations (SSAQ) during erotic fantasy (OC+placebo vs. OC+DHEA: 3.3+/ 1.4 vs. 3.6+/-1.5; p<.05). No significant changes were observed for genital response (VPA) and the other two variables of the SSAQ assessed after visual erotic stimulus exposure. Using the SFD, 5 out of 10 variables showed a significant improvement with DHEA. Partner's initiative was rejected less often with OC+DHEA compared to placebo (OC+placebo vs. OC+DHEA: 1.1+/-1.5 vs. 0.8+/ 1.0; p<.05). Women with free testosterone levels in the upper quartile during DHEA co-administration showed significantly better effects on sexual arousal and desire compared to the three lower quartiles (lower vs. upper quartiles: sexual arousability: 25.0+/-19.8 vs. 41.2+/-29.0; sexual desire: 5.6+/-3.7 vs. 9.6+/ 8.0; desire for sex with partner: 4.9+/-3.1 vs. 8.6+/-7.4; number of sex fantasies: 3.0+/-3.2 vs. 5.5+/-4.4; all p<.05). CONCLUSIONS: In this exploratory study, OC use was associated with decreases in some measures of sexual functioning, whereas others remained unchanged. Maintaining or restoring physiological testosterone concentrations by the co-administration of DHEA to the OC may prevent these effects on sexuality, particularly in women with relatively high but physiologic levels of free testosterone during DHEA co-administration. IMPLICATIONS: The results of this exploratory study warrant further testing of the hypothesis that restoration and/or preservation of physiologic testosterone levels during OC use by co-administration of DHEA has favorable effects on those aspects of sexual function compromised by OCs. PMID- 29490290 TI - Medicaid and fulfillment of desired postpartum sterilization. AB - OBJECTIVE: We sought to assess fulfillment of sterilization requests while accounting for the complex interplay between insurance, clinical and social factors in a contemporary context that included both inpatient and outpatient postpartum sterilization procedures. STUDY DESIGN: This is a retrospective single center cohort chart review study of 1331 women with a documented contraceptive plan at time of postpartum discharge of sterilization. We compared sterilization fulfillment within 90days of delivery, time to sterilization and rate of subsequent pregnancy after nonfulfillment between women with Medicaid and women with private insurance. RESULTS: A total of 475 of 1030 Medicaid-insured and 100 of 154 privately insured women received postpartum sterilization (46.1% vs. 64.9%, p<.001). Women with Medicaid had a longer time from delivery to completion of the sterilization request (p<.001). After adjusting for age, parity, gestational age, mode of delivery, adequacy of prenatal care, race/ethnicity, marital status and education level, private insurance status was not associated with either sterilization fulfillment [odds ratio 0.94, 95% confidence interval (CI) 0.54-1.64] or time to sterilization (hazard ratio 1.03, 95% C.I. 0.73-1.34). Of the 555 Medicaid-insured women who did not receive a postpartum sterilization, 267 (48.1%) had valid Title XIX sterilization consent forms at time of delivery. Of women who did not receive sterilization, 132 of 555 Medicaid patients and 5 of 54 privately insured patients became pregnant within 1 year (23.8% vs. 9.3%, p=.023). CONCLUSION: Differences in fulfillment rates of postpartum sterilization and time to sterilization between women with Medicaid versus private insurance are similar after adjusting for relevant clinical and demographic factors. Women with Medicaid are more likely than women with private insurance to have a short interval repeat pregnancy after an unfulfilled sterilization request. IMPLICATIONS: Efforts are needed to ensure that Medicaid recipients who desire sterilization receive timely services. PMID- 29490291 TI - Prognostic Role of Pretreatment Plasma D-Dimer in Patients with Solid Tumors: a Systematic Review and Meta-Analysis. AB - BACKGROUND/AIMS: Elevated pretreatment plasma D-dimer level has been reported as an unfavorable prognostic indicator in several malignancies. The aim of this meta analysis was to evaluate the prognostic value of elevated D-dimer level in solid tumors. METHODS: A comprehensive search of electronic databases up to June 10, 2017 was carried out by two independent reviewers. We included studies exploring the association between pretreatment plasma D-dimer level and patients' survival outcomes in solid tumors. Overall survival (OS) was regarded as primary outcome and progression-free survival (PFS), disease-free survival (DFS) as well as cancer-specific survival (CSS) were chosen as secondary outcomes. Hazard ratio and 95% confidence interval (CI) were extracted directly or indirectly from included studies. RESULTS: 49 studies with 13001 patients were included in our meta-analysis. Elevated D-dimer was markedly associated with poor OS (pooled HR = 1.90, 95% CI = 1.63 - 2.20, P < 0.001). The effect was observed in all different tumor sites, disease stages, cut-off values and ethnicities. Meanwhile, patients with a high plasma D-dimer had a shorter PFS (HR = 1.46, 95% CI = 1.22-1.76; P < 0.001), DFS (HR = 2.02, 95% CI = 1.56-2.62) and CSS (HR = 2.04, 95% CI= 1.58 - 2.64). CONCLUSIONS: Analysis of the pretreatment plasma D-dimer might provide useful information to predict prognosis in patients with solid tumors. PMID- 29490292 TI - TOP3B: A Novel Candidate Gene in Juvenile Myoclonic Epilepsy? AB - Juvenile myoclonic epilepsy (JME) is characterized by seizures, severe cognitive abnormalities, and behavior impairments. These features could evolve over time and get worse, especially when the encephalopathy is pharmacoresistant. Thus, genetic studies should provide a better understanding of infantile epilepsy syndromes. Herein, we investigate the genetics of JME in a consanguineous family analyzing the copy number variations detected using over 700 K SNP arrays. We identified a 254-kb deletion in the 22q11.2 region, including only the TOP3B gene, detected in the patient and her father. TOP3B encodes a topoisomerase DNA (III) beta protein and has been implicated in several neurological diseases such as schizophrenia and autism. In this study, we discuss the implication of the 22q11.2 region in neurodevelopmental disorders and the association of TOP3B with epilepsy. PMID- 29490293 TI - TGF-beta1 Promotes Hepatocellular Carcinoma Invasion and Metastasis via ERK Pathway-Mediated FGFR4 Expression. AB - BACKGROUND/AIMS: TGF-beta1 is beneficial during early liver disease but is tumor progressive during late stages especially for hepatocellular carcinoma (HCC). Thus, exploring the underlying mechanisms may provide information about a potentially therapeutic role of TGF-beta1 in HCC. METHODS: Western blot and real time quantitative PCR were used to quantify FGFR4 expression in HCC cell lines and a normal liver cell line. After constructing the best silencing FGFR4 expression vector, migration and invasiveness of TGF-beta1 in HCC was studied in vitro and in vivo. Western blot was used to study the mechanism of TGF-beta1 induction on FGFR4 expression with various inhibitors. RESULTS: HepG2 cell lines had the most FGFR4 expression, and data show that silencing FGFR4 suppressed cell proliferation, invasion and migration in HCC induced by TGF-beta1 in vitro and in vivo. Moreover, TGF-beta1 induced FGFR4 expression through the ERK pathway. CONCLUSION: Promoting FGFR4 expression via the ERK pathway, TGF-beta1 contributes to HCC invasion and metastasis. PMID- 29490294 TI - Massive Proteinuria-Induced Injury of Tubular Epithelial Cells in Nephrotic Syndrome is Not Exacerbated by Furosemide. AB - BACKGROUND/AIMS: Massive proteinuria, a significant sign of nephrotic syndrome (NS), has the potential to injure tubular epithelial cells (TECs). Furosemide is widely used for the treatment of edema, a common manifestation of NS. However, whether furosemide treatment affects massive proteinuria-induced TEC injury in patients with NS is unknown. METHODS: The effect of furosemide on TEC damage was investigated in vitro. In addition, a clinical study was conducted to study whether the short-term treatment of nephrotic edema with furosemide could exacerbate TEC injury. RESULTS: The proliferation of in vitro human kidney-2 (HK 2) cells exposed to massive urinary protein (8 mg/mL) significantly decreased (P<0.05), while the levels of kidney injury molecule-1 (Kim-1) and neutrophil gelatinase associated lipocalin (NGAL) in the supernatants significantly increased (P<0.05). Importantly, furosemide treatment did not further increase the expression of Kim-1 and NGAL in HK-2 cells upregulated by massive proteinuria. For the clinical study, 26 patients with NS, all prescribed the recommended dosage of prednisone (1 mg/kg/day), were randomly assigned to two groups. One group (n=13) received furosemide (60-120 mg/day, intravenously) for 1 week; the remaining participants (control group) did not receive furosemide or any other diuretics. The results showed that the 24-h urine volume in the furosemide-treated group was slightly, but not significantly, higher than that in the control group (P>0.05). In addition, serum levels of BUN, Scr, Cys C, and urinary Kim-1 and NGAL were not significantly different between the two groups (all P>0.05). Twenty-three patients underwent a renal biopsy. Of these, 22 patients exhibited vacuolar degeneration of the TECs; 8 patients showed brush border membrane shedding of the TECs; and 12 patients showed protein casts. However, there were no significant differences between the two groups (all P>0.05). CONCLUSION: In summary, massive proteinuria induced the injury of TECs in patients with NS, and furosemide treatment did not aggravate this injury. PMID- 29490295 TI - Inhibition of Collagen Related Peptide Induced Platelet Activation and Apoptosis by Ceritinib. AB - BACKGROUND/AIMS: The anaplastic lymphoma (tyrosine) kinase (ALK) inhibitor ceritinib triggers apoptosis of tumor cells and eryptosis of erythrocytes. Blood platelets may similarly enter a state resembling apoptosis, which could be triggered by activation with collagen related peptide (CRP). CRP-induced platelet apoptosis is characterized by cell membrane scrambling with phosphatidylserine exposure to the platelet surface and cell shrinkage, preceded by externalization of Ca2+ channel Orai1, increase of cytosolic Ca2+-activity ([Ca2+]i), formation of reactive oxygen species (ROS), and caspase activation. The present study explored whether ceritinib triggers platelet apoptosis and/or modifies the CRP induced apoptosis. METHODS: Platelets isolated from wild-type mice were exposed for 30 minutes to ceritinib (1.5 ug/ml) without or with 2.5 - 15 min pretreatment with CRP (2 ug/ml or 5 ug/ml). Flow cytometry was employed to estimate cytosolic Ca2+-activity ([Ca2+]i) from Fluo-3 fluorescence, ROS abundance from 2',7' dichlorodihydrofluorescein diacetate fluorescence, platelet degranulation from P selectin abundance, integrin activation from alphaIIbbeta3 integrin abundance, caspase activity utilizing an Active Caspase-3 Staining kit, phosphatidylserine abundance from annexin-V-binding, platelet volume from forward scatter and aggregation utilizing staining with CD9-APC and CD9-PE. RESULTS: In the absence of CRP, ceritinib slightly, but significantly decreased [Ca2+]i without significantly modifying the other measured parameters. CRP significantly increased [Ca2+]i, ROS abundance, P-selectin abundance, activated alphaIIbbeta3 integrin, annexin-V-binding, caspase activity as well as aggregation and decreased cell volume, all effects significantly blunted in the presence of ceritinib. CONCLUSIONS: The present observations uncover a novel, unexpected effect of ceritinib, i.e. inhibition of CRP-induced platelet activation and apoptosis. PMID- 29490296 TI - Resveratrol Alleviates Inflammatory Responses and Oxidative Stress in Rat Kidney Ischemia-Reperfusion Injury and H2O2-Induced NRK-52E Cells via the Nrf2/TLR4/NF kappaB Pathway. AB - BACKGROUND: Ischemia-reperfusion injury (IRI) is one of the major causes of postoperative renal allograft dysfunction, which is mainly the result of proinflammatory reactions including inflammatory responses, oxidative stress, and metabolic disorders. Resveratrol (RSV) plays an important role in protecting various organs in IRI because it reduces oxidative stress, lessens the inflammatory response, and exerts anti-apoptotic effects. The aim of this study was to demonstrate the renoprotective effect of RSV in inhibiting inflammatory responses, reducing oxidative stress, and decreasing cell apoptosis in vivo and in vitro. METHODS: RSV was administered before renal ischemia and H2O2 induction. Serum and kidneys were harvested 24 h after reperfusion and NRK-52E cells were collected 4 h after H2O2 stimulation. Serum creatinine and blood urea nitrogen were used to assess renal function. Hematoxylin and eosin staining was performed to assess histological injury. Quantitative real-time PCR and enzyme-linked immunosorbent assay were used to assess proinflammatory cytokine expression. Oxidative stress-related proteins, such as Nrf2 and TLR4, were evaluated by western blot. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay was used to detect apoptotic cells in tissues, and western blot was used to evaluate the expression of caspase-3, -8, and -9 in this study. RESULTS: RSV inhibited inflammatory responses and improved renal function after renal IRI. Additionally, RSV decreased oxidative stress and reduced cell apoptosis by upregulating Nrf2 expression, downregulating the TLR4/NF-kappaB signaling pathway, and by decreasing caspase-3 activity and caspase cascades. CONCLUSION: Our study demonstrated the mechanisms underlying RSV renoprotection. We found that RSV exerts its greatest effects by blocking inflammatory responses, lowering oxidative stress, and reducing apoptosis via the Nrf2/TLR4/NF-kappaB pathway. PMID- 29490298 TI - Mortality in Elderly Waiting-List Patients Versus Age-Matched Kidney Transplant Recipients: Where is the Risk? AB - The number of elderly patients on the waiting list (WL) for kidney transplantation (KT) has risen significantly in recent years. Because KT offers a better survival than dialysis therapy, even in the elderly, candidates for KT should be selected carefully, particularly in older waitlisted patients. Identification of risk factors for death in WL patients and prediction of both perioperative risk and long-term post-transplant mortality are crucial for the proper allocation of organs and the clinical management of these patients in order to decrease mortality, both while on the WL and after KT. In this review, we examine the clinical results in studies concerning: a) risk factors for mortality in WL patients and KT recipients; 2) the benefits and risks of performing KT in the elderly, comparing survival between patients on the WL and KT recipients; and 3) clinical tools that should be used to assess the perioperative risk of mortality and predict long-term post-transplant survival. The acknowledgment of these concerns could contribute to better management of high-risk patients and prophylactic interventions to prolong survival in this particular population, provided a higher mortality is assumed. PMID- 29490297 TI - Hypouricemic and Nephroprotective Effects of an Active Fraction from Polyrhachis Vicina Roger On Potassium Oxonate-Induced Hyperuricemia in Rats. AB - BACKGROUND/AIMS: The objective of this study is to evaluate the hypouricemic and nephroprotective effects of an active fraction from Polyrhachis vicina Roger (AFPR) in potassium oxonate-induced hyperuricemic rats. METHODS: Hyperuricemia was induced by potassium oxonate in male rats. AFPR was orally administered to hyperuricemic rats for 12 consecutive weeks. Serum, liver and kidney samples were collected for effects and mechanism analysis. The levels of serum uric acid (SUA) were measured by the phosphotungstic acid method, xanthine oxidase (XOD) activity in the hepatic and serum samples were measured by ultraviolet spectrophotometry, serum levels of interleukin-1 (IL-1beta), interleukin-1 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were measured by ELISA, the levels of serum creatinine (SCr), blood urea nitrogen (BUN), super oxide dismutase (SOD) and malondialdehyde (MDA) in serum were determined by colorimetric method. Protein expression of renal URAT1, GLUT9, and OAT1 were analyzed by Western blot. RESULTS: AFPR significantly decreased the levels of SUA, serum and hepatic XOD, SCr, BUN, and MDA as well as increased SOD. In addition, AFPR treatment significantly reduced the levels of proinflammatory cytokines in serum, including IL-1beta, IL-6 and TNF-alpha. Moreover, we found the significant decrease in protein expression of URAT1 and GLUT9, and the significant increase in protein expression of OAT1 in the kidney in AFPR treated groups compared to the model groups of hyperuricemia. CONCLUSION: These findings suggest that AFPR has anti-hyperuricemic activity attributed to the inhibition of uric acid generation in the liver and probably to the enhancement of urate excretion in the kidney, and possess nephroprotective effect in hyperuricemic rats due to its anti-inflammatory and antioxidant activities. PMID- 29490299 TI - Inhibition of Autophagy Attenuated Ethylene Glycol Induced Crystals Deposition and Renal Injury in a Rat Model of Nephrolithiasis. AB - BACKGROUND/AIMS: Nephrolithiasis is a common and frequently occurring disease, its exact pathogenesis is remains unclear. Emerging data suggest that autophagy plays a vital role in the pathophysiological processes of kidney diseases. Therefore, this study was designed to investigate the potential role of autophagy in the formation of calcium oxalate (CaOx) kidney stones in rat model. METHODS: Thirty-two rats were randomly divided into four groups (eight rats/group): untreated control group, stone model group, rapamycin-treated group, chloroquine treated group. Rat models of CaOx nephrolithiasis was administration of 0.75% ethylene glycol (EG) in their drinking water for 4 weeks. Western blot and transmission electron microscope (TEM) were used to detect the expression of autophagy related protein LC3-II, BECN1 and p62 and autophagic vacuoles respectively. Renal function was evaluated by measuring the levels of serum CRE and BUN. Renal tubular injury markers NGAL and Kim-1 was determined by ELISA kits. Von Kossa staining was used to assess crystal deposits and histological tissue injury. TUNEL staining was employed to assess apoptosis of the renal tubular cell. RESULTS: Compare with the controls, the expression of autophagy related protein LC3-II, BECN1 and number of autophagic vacuoles were increased significantly, whereas the p62 protein level was decreased in the stone model group. The levels of apoptosis, serum CRE and BUN, NGAL and Kim-1 in the stone model group were increased compared with the control group and crystals deposition and renal injury were increased significantly. However, the levels of autophagy, kidney injury and crystal deposition were decreased by chloroquine but increased by rapamycin. CONCLUSION: These findings suggested that rats were administration of ethylene glycol could lead to the formation of CaOx nephrolithiasis and autophagy activation. Inhibiting autophagy could be an effective therapeutic approach for decreasing the formation of nephrolithiasis. PMID- 29490300 TI - Palmitic Acid-Induced Podocyte Apoptosis via the Reactive Oxygen Species Dependent Mitochondrial Pathway. AB - BACKGROUND/AIMS: Chronic kidney disease (CKD) is often accompanied by hyperlipidemia, which accelerates progression of the disease. Podocyte injury can lead to dysfunction of the glomerular filtration barrier, which is associated with proteinuria, a risk marker for the progression of CKD. Our previous studies demonstrated that palmitic acid (PA) can induce podocyte apoptosis; however, the underlying mechanisms are unclear. In the present study, we investigated the specific molecular mechanisms of PA-induced apoptosis in cultured podocytes. METHODS: We cultured mouse podocytes and treated them with PA. Then, cell viability was measured using the Cell Counting Kit-8 colorimetric assay, lipid uptake was assessed by Oil Red O staining and boron-dipyrromethene staining, apoptosis was measured by flow cytometry, mitochondrial injury was assessed by JC 1 staining and transmission electron microscopy, and mitochondrial production of reactive oxygen species (ROS) was evaluated by fluorescence microscopy using the MitoSOX Red reagent. The effects of PA on the mitochondria-mediated caspase activation pathway were investigated by examining the expression of caspase-8, cleaved caspase-9, cleaved caspase-3, cleaved poly (ADP-ribose) polymerase (PARP), B-cell lymphoma 2 (Bcl-2), Bax, Bid, cytochrome c, and Fas-associated protein with death domain (FADD) using western blotting. The translocation of Bax and cytochrome c were detected by immunofluorescence. RESULTS: PA treatment significantly increased lipid accumulation and induced podocyte apoptosis. We investigated whether the two primary apoptosis signaling pathways (death receptor mediated pathway and mitochondria-mediated pathway) were involved in the execution of PA-induced podocyte apoptosis, and found that the levels of FADD, caspase-8, and Bid did not significantly change during this process. Meanwhile, PA treatment induced an increase in Bax protein expression and a decrease in Bcl 2 protein expression, with Bax translocation to the mitochondria. Furthermore, PA treatment induced mitochondrial impairment, and triggered the release of cytochrome c from the mitochondria to cytosol, with a concomitant dose-dependent increase in the levels of cleaved caspase-9, cleaved caspase-3, and PARP. Meanwhile, PA treatment increased mitochondrial production of ROS, and the mitochondria-targeted antioxidant mitoTEMPO significantly ameliorated PA-induced podocyte apoptosis. CONCLUSION: Our findings indicated that PA induced caspase dependent podocyte apoptosis through the mitochondrial pathway, and mitochondrial ROS production participated in this process, thus potentially contributing to podocyte injury. PMID- 29490301 TI - Mdia1 is Crucial for Advanced Glycation End Product-Induced Endothelial Hyperpermeability. AB - BACKGROUND/AIMS: Disruption of endothelial barrier integrity in response to advanced glycation end products (AEGs) stimulation contributes to vasculopathy associated with diabetes mellitus. Mammalian diaphanous-related formin (mDia1) has been reported to bind to the cytoplasmic domain of the receptor for advanced glycation end products (RAGE), which induces a series of cellular processes. This study directly evaluated the participation of mDia1 in AGE-induced hyperpermeability and revealed the precise intracellular signal transductions of this pathological process. METHODS: Human umbilical vein endothelial cells (HUVECs) were used in the in vitro studies. Trans-endothelial electric resistance and permeability coefficient for dextran (Pd) were measured to analyze cell permeability. Western blotting, immunofluorescence staining and flow cytometry assay were performed to investigate the underlying mechanism. Dextran flux across the mesentery in mice was monitored to investigate in vivo microvascular permeability. RESULTS: we found that AGEs evoked Nox4 membrane translocation, reactive oxygen species production, phosphorylation of Src and VE-cadherin, dissociation of adherens junctions and eventual endothelial hyperpermeability through RAGE-mDia1 binding. Cells overexpressing mDia1 by recombinant adenovirus infection showed stronger cellular responses induced by AGEs. Down-regulation of mDia1 by infection with an adenovirus encoding siRNA or blockade of RAGE-mDia1 binding by transfection with RAGE mutant plasmids into HUVECs abolished these AGE induced effects. Furthermore, knockdown of mDia1 using an adenovirus or genetical knockout of RAGE in C57 mice rescued AGE-evoked microvascular hyperpermeability. CONCLUSION: Our study revealed that mDia1 plays a critical role in AGE-induced microvascular hyperpermeability through binding to RAGE. PMID- 29490302 TI - Endocrine Treatment with 2 Years of Tamoxifen versus 2 Years of Exemestane in Postmenopausal Patients with High-Risk Early Breast Cancer and Persisting Circulating Tumor Cells - First Results of the SUCCESS C Endocrine Treatment Sub Study. AB - BACKGROUND: Optimal choice and sequence of endocrine treatment following adjuvant chemotherapy in postmenopausal early breast cancer patients are still under discussion and treatment stratification factors are missing. PATIENTS AND METHODS: Postmenopausal women with HER2-negative, hormone receptor-positive tumors and persisting circulating tumor cells (CTCs; assessed using the FDA approved CellSearch(r) System, Janssen Diagnostics, LLC) after chemotherapy were randomized to 2 years of tamoxifen followed by 3 years of exemestane (tamoxifen exemestane group, n = 54) or 5 years of exemestane (exemestane-only group, n = 54). CTCs were again assessed after the first 2 years of endocrine treatment. In addition, safety data were compared between the 2 groups. RESULTS: The 2 groups were well-balanced with regard to baseline characteristics. The CTC clearance rate after 2 years was 89% in the exemestane-only group and 97% in the tamoxifen exemestane group (exact Fisher test, p = 0.36). The safety profile showed good tolerability with few grade 3 or 4 adverse events in both groups. CONCLUSION: The similar CTC clearance rate after 2 years of endocrine therapy with exemestane or tamoxifen, and the safety profiles obtained may indicate comparable efficacy and tolerability of both endocrine treatment regimens. However, these results have to be confirmed by final survival and safety analysis. PMID- 29490303 TI - Brain Beta-Catenin Signalling During Stress and Depression. AB - Beta-catenin is a protein with dual functions in the cell, playing a role in both adhesion between cells as well as gene transcription via the canonical Wnt signalling pathway. In the canonical Wnt signalling pathway, beta-catenin again plays multiple roles. In the embryonic stage, the regulation of beta-catenin levels activates genes that govern cell proliferation and differentiation. In an adult organism, beta-catenin continues to regulate the cell cycle - as a result over-expression of beta-catenin may lead to cancer. In the brain, dysfunctions in Wnt signalling related to beta-catenin levels may also cause various pathological conditions like Alzheimer's disease, Parkinson's disease, and depression. Beta catenin can be influenced by stressful conditions and increases in glucocorticoid levels. In addition, beta-catenin can be regulated by neurotransmitters such as serotonin and dopamine. Fluctuations in beta-catenin in brain regions under duress have been associated with depressive-like behaviours. It is theorized that the change in behaviour can be attributed to the regulation of Dicer by beta catenin. Dicer, a protein that produces micro-RNAs in the cell, is a target gene for beta-catenin. Amongst the micro-RNA that it produces are those involved in stress resilience. In this way, beta-catenin has taken its place in the well studied biochemistry of stress and depression, and future research into this interesting protein may yet yield fruitful results in that field. PMID- 29490305 TI - Erratum. PMID- 29490304 TI - Association between Rheumatoid Arthritis and Pulmonary Hypertension: Data from the French Pulmonary Hypertension Registry. AB - BACKGROUND: Precapillary pulmonary hypertension (PH), and particularly pulmonary arterial hypertension (PAH), is a life-threatening complication of connective tissue diseases (systemic sclerosis, systemic lupus erythematosus, and mixed connective tissue disease). The relationship between PH and rheumatoid arthritis (RA) has not been clearly established. OBJECTIVES: The aim of the study was to evaluate the relationship between precapillary PH and RA. METHODS: We identified patients with PH and suspected RA included in the French PH Registry between 1 May 2004 and 31 December 2012 and evaluated the prevalence of confirmed RA in this population. RA phenotypes, clinical, functional, and hemodynamic data, and patient outcomes were recorded. RESULTS: RA was confirmed in 20 patients (70% female; mean age 52 years) with precapillary PH, including 10 patients with PAH, 6 with severe PH due to lung disease, and 4 with chronic thromboembolic PH. The prevalence of RA was 0.35% (95% CI: 0.23-0.54) in the French PH Registry and 0.58% (95% CI: 0.30-1.11) in idiopathic PAH, comparable to that in the general population. The RA phenotype was characterized by the presence of specific RA autoantibodies and joint erosions in 75% of the patients. The outcomes of PH in the RA patients were unremarkable compared to those in other patients from the registry, and RA therapies had no major impact on the cardiopulmonary parameters. CONCLUSION: When precapillary PH occurs in RA patients, all PH subsets may be identified. The RA prevalence in the French PH Registry is similar to that in the general population, which does not support a specific association or an indication for PH screening in RA patients. PMID- 29490306 TI - Role of Calcium Sensing Receptor in Streptozotocin-Induced Diabetic Rats Exposed to Renal Ischemia Reperfusion Injury. AB - BACKGROUND/AIMS: Renal ischemia/reperfusion (I/R) injury (RI/RI) is a common complication of diabetes, and it may be involved in altering intracellular calcium concentrations at its onset, which can result in inflammation, abnormal lipid metabolism, the production of reactive oxygen species (ROS), and nitroso redox imbalance. The calcium-sensing receptor (CaSR) is a G-protein coupled receptor, however, the functional involvement of CaSR in diabetic RI/ RI remains unclear. The present study was intended to investigate the role of CaSR on RI/RI in diabetes mellitus (DM). METHODS: The bilateral renal arteries and veins of streptozotocin (STZ)-induced diabetic rats were subjected to 45-min ischemia followed by 2-h reperfusion with or without R-568 (agonist of CaSR) and NPS-2143 (antagonist of CaSR) at the beginning of I/R procedure. DM without renal I/R rats served as control group. The expressions of CaSR, calmodulin (CaM), and p47phox in the renal tissue were analyzed by qRT-PCR and Western blot. The renal pathomorphology, renal function, oxidative stress, inflammatory response, and calcium disorder were evaluated by detection of a series of indices by hematoxylin-eosin (HE) staining, transmission electron microscope (TEM), commercial kits, enzyme-linked immunosorbent assay (ELISA), and spectrophotofluorometry, respectively. RESULTS: Results showed that the expressions of CaSR, CaM, and p47phox in I/R group were significantly up regulated as compared with those in DM group, which were accompanied by renal tissue injury, increased calcium, oxidative stress, inflammation, and nitroso redox imbalance. CONCLUSION: These results suggest that activation of CaSR is involved in the induction of damage of renal tubular epithelial cell during diabetic RI/RI, resulting in lipid peroxidation, inflammatory response, nitroso redox imbalance, and apoptosis. PMID- 29490308 TI - Lower Serum Irisin Levels Are Associated with Increased Vascular Calcification in Hemodialysis Patients. AB - BACKGROUND/AIMS: Vascular calcification, which involves an active cellular transformation of vascular smooth muscle cells into bone forming cells, is prevalent and predicts mortality in dialysis patients. Its mechanisms are complex and unclear. We presume that irisin, a newly identified myokine also may play roles in vascular calcification in hemodialysis patients. This study aims to evaluate serum irisin levels and establish their relation to vascular calcification and other parameters in hemodialysis patients. METHODS: A total of 150 patients on maintenance hemodialysis treatment and 38 age- and sex-matched healthy controls were enrolled in this cross-sectional study. Serum irisin concentrations were measured by ELISA. Vascular calcification was evaluated by abdominal aortic calcification scores. RESULTS: Serum irisin concentrations were significantly lower in hemodialysis patients than in controls [52.8 (22.0, 100.0) vs. 460.8 (434.8, 483.4) ng/ml, P<0.01]. In addition, irisin was negatively correlated with the parathyroid hormone level (P=0.01). The HD patients with vascular calcification showed significantly lower serum irisin concentrations [39.0 (21.7, 86.2) vs.79.0 (39.5, 130.2) ng/mL, P<0.01]. Compared with the group without vascular calcification multivariate logistic regression analyses revealed that serum irisin, HD vintage and age were significant independent determinant factors for vascular calcification in HD patients. CONCLUSION: Our results are the first to provide a clinical evidence of the association between serum irisin and vascular calcification in HD patients. Lower irisin levels, long-term hemodialysis and old ages are independent risk factors in HD patients. PMID- 29490307 TI - Real-World Experience with Nintedanib in Patients with Idiopathic Pulmonary Fibrosis. AB - BACKGROUND: Nintedanib, an oral tyrosine kinase inhibitor, has been shown to slow down the progression of idiopathic pulmonary fibrosis (IPF) in two randomised placebo-controlled trials by reducing the annual decline in forced vital capacity (FVC). However, real-world experience is limited. OBJECTIVE: To assess the efficacy and safety of nintedanib in a large cohort of patients treated at a tertiary referral site for interstitial lung diseases. METHODS: The records of patients with a confirmed diagnosis of IPF were reviewed. Full medical history, pulmonary function, and adverse events (AEs) were recorded from each clinic visit. Disease progression was defined as a reduction in FVC >=5% and/or in diffusing capacity of the lung for carbon monoxide >=15% according to recent publications. Only patients with a treatment duration >=3 months were included in the efficacy evaluation. RESULTS: A total of 64 patients were treated. Mean +/- standard deviation (SD) FVC was 71 +/- 21% predicted, and the mean time from diagnosis to initiation of nintedanib treatment was 23.8 months. Nearly half of patients (n = 30, 47%) had received prior pirfenidone treatment. The mean duration of follow-up was 11 months. At 6 months following initiation of nintedanib, 67% of the patients were stable. The mean +/- SD change in percent predicted FVC from baseline was 0.2 +/- 7.8% at 3 months, -1.3 +/- 7.9% at 6 months, and -2.1 +/- 9% at 9 months. Diarrhoea was the most common AE experienced by 33% of patients and was generally manageable. CONCLUSION: The results from this real-world clinical setting support findings from previously conducted clinical trials and show that nintedanib is effective for the management of IPF and is associated with disease stabilisation. Nintedanib is generally well tolerated. PMID- 29490311 TI - Good Morning Future: Complementary Medicine's Next 25 Years. PMID- 29490314 TI - Expert opinions. PMID- 29490310 TI - Clinical and Radiographic Peri-Implant Parameters and Whole Salivary Interleukin 1beta and Interleukin-6 Levels among Type-2 Diabetic and Nondiabetic Patients with and without Peri-Implantitis. AB - OBJECTIVE: The aim was to assess the peri-implant clinical and radiographic parameters and whole salivary levels of interleukin (IL)-1beta and IL-6 among type 2 diabetic and nondiabetic patients with and without peri-implantitis. MATERIAL AND METHODS: Ninety-one implants were placed in patients without type 2 diabetes mellitus (39 patients with and 52 patients without peri-implantitis; group 1). Eighty implants were placed in patients with diabetes (35 patients with and 45 patients without peri-implantitis; group 2). Peri-implant plaque index, bleeding on probing, probing depth, and marginal bone loss were measured. Unstimulated whole saliva samples were collected and IL-1beta and IL-6 levels were measured using standard techniques. p < 0.05 was considered statistically significant. RESULTS: In group 1, plaque index (p < 0.001), bleeding on probing (p < 0.001), probing depth (p < 0.001), and whole salivary IL-1beta (p < 0.001) and IL-6 (p < 0.001) levels were significantly higher in patients with peri implantitis than in those without peri-implantitis. Plaque index, bleeding on probing, probing depth, and marginal bone loss were comparable among all of the patients in group 2. Among patients with peri-implantitis, plaque index (p < 0.001), bleeding on probing (p < 0.001), probing depth (p < 0.001), marginal bone loss (p < 0.001), and whole salivary IL-1beta (p < 0.001) and IL-6 (p < 0.001) levels were significantly higher in those with diabetes than in those without diabetes. CONCLUSION: Among individuals without diabetes, peri-implant plaque index, bleeding on probing, probing depth, marginal bone loss, and whole salivary IL-1 beta and IL-6 levels were higher among patients with peri-implantitis compared to patients without peri-implantitis. Among patients with diabetes, the severity of the measured parameters appears to be influenced by the glycemic status rather than by peri-implantitis. PMID- 29490312 TI - Case Reports of Acne and Homeopathy. AB - BACKGROUND: Acne vulgaris is a self-limiting disorder of the pilosebaceous unit. The aesthetic aspect of the disorder may provoke depression and diminish the quality of life. A number of agents are used for acne treatment, e.g., retinoids, antibiotics, benzoic acid, azelaic acid, and hormones. These agents have side effects, sometimes severe ones. CASE REPORTS: Presented are 2 cases of severe acne treated with individualized homeopathic medicines. Both patients were treated using the classical method of homeopathy, i.e., a single medicine based on the patient's individual characteristics was prescribed. The cases were documented photographically at onset and during the course of treatment. Both patients went into remission following treatment, and long-term follow-up suggested that the therapy remained efficacious long after cessation of treatment. No significant side effects were noted. CONCLUSIONS: Homeopathic medicines may be useful as stand-alone treatment of patients with severe acne vulgaris. A case series suggested a remission rate of more than 80% using individualized homeopathic treatment. The treatment remained efficacious long after cessation and is not accompanied by significant side-effects. It is to be hoped that this presentation will stimulate research interest into homeopathic medicines as stand-alone or adjunct treatments of acne. PMID- 29490315 TI - Coronary Stent Placement in Patients with Stable Angina - an Ongoing Debate. PMID- 29490316 TI - Clinical Challenges in the Growing Medical Marijuana Field. AB - Unique clinical challenges arise with the growing number of patients who possess medical marijuana cards. Medical marijuana patients with mental disorders can have worsening symptoms with marijuana use. Often there is sparse continuity of care between the patient and the medical marijuana practitioner. Lack of communication between the patient's treating practitioners and the practitioner who has authorized the medical marijuana can be problematic. This article is a discussion of the new clinical challenges practitioners are likely to encounter with the growing number of medical marijuana patients. PMID- 29490317 TI - Child sexual exploitation: cautionary lessons from England. PMID- 29490318 TI - The elephant - or donkey - in the exam room. PMID- 29490319 TI - Daily Safety Briefs (DSB) focus on improving safety at Hasbro Children's Hospital. PMID- 29490320 TI - Neurotherapeutics: Recent Developments. PMID- 29490321 TI - Moving Towards a Cure for MS: Increased Immunosuppression and Striving for No Evidence of Disease Activity (NEDA). AB - Multiple sclerosis (MS) is a chronic central nervous system demyelinating disease. The cause is unknown, but likely results from a combination of genetic predisposition and environmental exposures leading to autoimmune destruction of the brain and spinal cord. The most common phenotype of MS is relapsing-remitting (RRMS), characterized by episodes of neurological symptoms, typically lasting days to weeks, followed by symptom remission. After years of disease, the majority of RRMS cases transform into secondary progressive MS (SPMS), characterized by slowly worsening symptoms and progressive neurological disability, which may or may not be also accompanied by superimposed relapses. A third distinct phenotype, primary progressive MS (PPMS) is characterized by slowly worsening neurological symptoms and disability from disease onset, without clinical relapses.1 The first disease-modifying agent was approved by the FDA in 1993. There are now 14 FDA-approved disease-modifying therapies (DMTs) with almost all agents indicated for relapsing forms of MS. The medical management of multiple sclerosis has changed dramatically over the past decade as the number of available DMTs has increased (See Table 1). Most of the newer agents have been shown to decrease clinical relapse rates to a greater degree than the older agents. These DMTs frequently also decrease the rate of disability progression in MS. With the increased immunosuppression of the newer therapies comes the potential for more serious side effects. Balancing efficacy with potential adverse events is a primary consideration of patients and clinicians treating MS today. The potential for near complete control of the disease is becoming a reality in select cases, and a new goal of "no evidence of disease activity" (NEDA) may be supplanting the previous aim of relapse rate reduction. PMID- 29490322 TI - Updates in Stroke Treatment. AB - In this article, we discuss major advances in the treatment and prevention of ischemic stroke that have taken placed in the past 3 years. The most important advance in acute stroke treatment is the validation and widespread adoption of intra-arterial therapies for the treatment of acute ischemic stroke. Five clinical trials spanning multiple continents were published in early 2015 that proved that intra-arterial treatment - both with and without tPA - is beneficial in improving functional recovery after stroke. Emerging literature (including the DAWN trial) also suggests that patients can be treated up to 24 hours after the onset of symptoms based on the size of the infarct core obtained using MRI Perfusion or CT Perfusion imaging. With respect to stroke secondary prevention, widespread adoption of long-term cardiac monitoring has increased the detection rate of atrial fibrillation (as demonstrated in the EMBRACE and CRYSTAL-AF trials). Pioglitazone (an oral hypoglycemic agent of the thiazolidinedione drug class) was shown in the IRIS trial to reduce the risk of recurrent stroke in patients with impaired glucose tolerance who had not developed type 2 diabetes mellitus. PMID- 29490323 TI - Parkinson's disease: A Quick Update. AB - Parkinson's disease is a neurodegenerative disorder characterized by motor and non-motor symptoms. Although the diagnosis still relies on the presence of motor signs, new diagnostic criteria have been proposed to incorporate recent observations in order to improve accuracy. The cornerstone of therapy remains dopamine replacement with L-Dopa. However, new therapies, with different modes of action, or administration have become available to improve management. PMID- 29490324 TI - Fighting Fire with Fire: Surgical Options for Patients with Drug-Resistant Epilepsy. AB - While antiepileptic drugs (AEDs) provide adequate seizure control for most patients with epilepsy, ~30% continue to have seizures despite treatment with two or more AEDs.1 In addition to direct harm from seizures, poor epilepsy control correlates with higher mortality, morbidity, 2, 3 and cost to the healthcare system.4 In the subset of patients with persistent seizures despite medical management, surgical intervention and neuromodulation may be more effective. Primary care physicians and general neurologists should be aware of non-AED treatment options that are standard of care for drug- resistant epilepsy (DRE). PMID- 29490325 TI - Suboptimal Opioid Prescribing: A Practice Change Project. AB - In the U.S. in 2015, the proportion of people dependent on opioids approached one percent, and opioid overdose rivaled auto accidents as the leading cause of accidental death. The literature suggests a credible link between increased opioid prescribing and increased opioid addiction. Accordingly, some have suggested that limiting the number of opioid prescriptions (and the number of doses per prescription) might be effective in reducing the number of opioid related deaths. Toward this end, we designed and piloted an evidence-based quality-improvement project in four urgent care clinics. Results of the intervention were monitored with data from a state-sponsored prescription drug monitoring program (PDMP) by comparing opioid prescribing before and after adoption of the guideline, and in this manner, a statistically significant (P < 0.05) decline in the rate of opioid prescribing was revealed. On average, 2.43 fewer opioid prescriptions were written, per provider, per week, in weeks five through eight after promulgation (5.21, SD =4.37) than in the eight weeks before promulgation (7.64, SD =7.73). Our results suggest that implementing a simple opioid-prescribing guideline, with monitoring, can reduce sub-optimal opioid prescribing, and therefore the volume of opioids available in the community for diversion, abuse, and addiction. PMID- 29490326 TI - A 57-year-old man with a spontaneous carotid artery dissection. PMID- 29490327 TI - Human Papillomavirus (HPV) Vaccination Coverage among Rhode Island Adolescents, 2008-2016. PMID- 29490332 TI - Reducing Racial/Ethnic Disparities in Cardiovascular Genetic Testing. PMID- 29490333 TI - Association of Body Mass Index With Lifetime Risk of Cardiovascular Disease and Compression of Morbidity. AB - Importance: Prior studies have demonstrated lower all-cause mortality in individuals who are overweight compared with those with normal body mass index (BMI), but whether this may come at the cost of greater burden of cardiovascular disease (CVD) is unknown. Objective: To calculate lifetime risk estimates of incident CVD and subtypes of CVD and to estimate years lived with and without CVD by weight status. Design, Setting, and Participants: In this population-based study, we used pooled individual-level data from adults (baseline age, 20-39, 40 59, and 60-79 years) across 10 large US prospective cohorts, with 3.2 million person-years of follow-up from 1964 to 2015. All participants were free of clinical CVD at baseline with available BMI index and CVD outcomes data. Data were analyzed from October 2016 to July 2017. Exposures: World Health Organization-standardized BMI categories. Main Outcomes and Measures: Total CVD and CVD subtype, including fatal and nonfatal coronary heart disease, stroke, congestive heart failure, and other CVD deaths. Heights and weights were measured directly by investigators in each study, and BMI was calculated as weight in kilograms divided by height in meters squared. We performed (1) modified Kaplan Meier analysis to estimate lifetime risks, (2) adjusted competing Cox models to estimate joint cumulative risks for CVD or noncardiovascular death, and (3) the Irwin restricted mean to estimate years lived free of and with CVD. Results: Of the 190 672 in-person examinations included in this study, the mean (SD) age was 46.0 (15.0) years for men and 58.7 (12.9) years for women, and 140 835 patients (73.9%) were female. Compared with individuals with a normal BMI (defined as a BMI of 18.5 to 24.9), lifetime risks for incident CVD were higher in middle-aged adults in the overweight and obese groups. Compared with normal weight, among middle-aged men and women, competing hazard ratios for incident CVD were 1.21 (95% CI, 1.14-1.28) and 1.32 (95% CI, 1.24-1.40), respectively, for overweight (BMI, 25.0-29.9), 1.67 (95% CI, 1.55-1.79) and 1.85 (95% CI, 1.72-1.99) for obesity (BMI, 30.0-39.9), and 3.14 (95% CI, 2.48-3.97) and 2.53 (95% CI, 2.20 2.91) for morbid obesity (BMI, >=40.0). Higher BMI had the strongest association with incident heart failure among CVD subtypes. Average years lived with CVD were longer for middle-aged adults in the overweight and obese groups compared with adults in the normal BMI group. Similar patterns were observed in younger and older adults. Conclusions and Relevance: In this study, obesity was associated with shorter longevity and significantly increased risk of cardiovascular morbidity and mortality compared with normal BMI. Despite similar longevity compared with normal BMI, overweight was associated with significantly increased risk of developing CVD at an earlier age, resulting in a greater proportion of life lived with CVD morbidity. PMID- 29490334 TI - Association of Racial/Ethnic Categories With the Ability of Genetic Tests to Detect a Cause of Cardiomyopathy. AB - Importance: Individuals of all races/ethnicities have a fundamental right to access health care and benefit from advances in science and medicine, including genetic testing. Objective: To determine whether detection rates for cardiomyopathy genetic testing differed between white people, Asian people, and underrepresented minorities (individuals of black, Hispanic, Native American, Alaskan Native, or Pacific Islander descent). Design, Setting, and Participants: We conducted a cross-sectional analysis of the genetic panel test results of 5729 probands who had a suspected diagnosis or family history of cardiomyopathy and who had been referred for testing between October 2003 and December 2017. Testing was performed at the Laboratory for Molecular Medicine at Partners Personalized Medicine in Cambridge, Massachusetts. Results were stratified into 3 categories of self-reported race/ethnicity: white, Asian, and underrepresented minorities. Main Outcomes and Measures: The primary outcome was whether a pathogenic or likely pathogenic variant was identified that explained the features or family history of cardiomyopathy. A secondary outcome was the number of test results that were inconclusive because of the presence of 1 or more variants of uncertain significance in the absence of an explanation for cardiomyopathy features or family history. Results: A total of 5729 probands were studied (of whom 3523 [61.5%] were male). Of these, 4539 (79.2%) were white, 348 (6.1%) were Asian individuals, and 842 (14.7%) were underrepresented minorities. Positive detection occurred in 1314 white individuals (29.0%) compared with 155 underrepresented minorities (18.4%; chi21 = 39.8; P < .001) and 87 Asian individuals (25.0%; chi21 = 2.5; P = .12). Inconclusive results were found in 1115 white individuals (24.6%) compared with 335 underrepresented minorities (39.8%; chi21 = 83.6; P < .001) and 136 Asian individuals (39.2%; chi21 = 35.8; P < .001). Conclusions and Relevance: These results show a significantly higher positive detection rate and a significantly lower rate of inconclusive results in white individuals in comparison with underrepresented minorities. This suggests greater clinical usefulness of genetic testing for cardiomyopathy in white persons in comparison with people of other racial/ethnic groups. This clear disparity warrants further study to understand the gaps in usefulness, which may derive from a lack of clinical testing and research in underrepresented minority populations, in the hopes of improving genetic testing outcomes for cardiomyopathy in nonwhite groups. PMID- 29490335 TI - Time to Add a Fifth Pillar to Bedside Physical Examination: Inspection, Palpation, Percussion, Auscultation, and Insonation. AB - Inspection, palpation, percussion, and auscultation have been the 4 pillars of clinical bedside medicine. Although these basic methods of physical examination have served us well, traditional bedside examination, for a number of reasons including diminishing interest and expertise, performs well less than what is required of a modern diagnostic strategy. Improving the performance of physical examination is vital given that it is crucial to guide diagnostic possibilities and further testing. Current efforts at improving physical examination skills during medical training have not been very successful, and incorporating appropriate technology at the bedside might improve its performance. Selective use of bedside ultrasound (or insonation) can be one such strategy that could be incorporated as the fifth component of the physical examination. Seeing pathology through imaging might improve interest in physical examination among trainees, and permit appropriate downstream testing and possibly superior decision making. Current ultrasound technology makes this feasible, and further miniaturization of ultrasound devices and reduced cost will allow for routine use at the bedside. It is time to have a wider debate and a possible consensus about updates required to enhance current paradigms of physical examination. PMID- 29490336 TI - Genetic Testing for Inherited Cardiac Diseases in Underserved Populations of Non European Ancestry: Double Disparity. PMID- 29490337 TI - Price and the Evolution of the Physical Examination. PMID- 29490338 TI - Development of Velopharyngeal Closure for Vocalization During the First 2 Years of Life. AB - Purpose: The vocalizations of young infants often sound nasalized, suggesting that the velopharynx is open during the 1st few months of life. Whereas acoustic and perceptual studies seemed to support the idea that the velopharynx closes for vocalization by about 4 months of age, an aeromechanical study contradicted this (Thom, Hoit, Hixon, & Smith, 2006). Thus, the current large-scale investigation was undertaken to determine when the velopharynx closes for speech production by following infants during their first 2 years of life. Method: This longitudinal study used nasal ram pressure to determine the status of the velopharynx (open or closed) during spontaneous speech production in 92 participants (46 male, 46 female) studied monthly from age 4 to 24 months. Results: The velopharynx was closed during at least 90% of the utterances by 19 months, though there was substantial variability across participants. When considered by sound category, the velopharynx was closed from most to least often during production of oral obstruents, approximants, vowels (only), and glottal obstruents. No sex effects were observed. Conclusion: Velopharyngeal closure for spontaneous speech production can be considered complete by 19 months, but closure occurs earlier for speech sounds with higher oral pressure demands. PMID- 29490340 TI - Retinal and Choroidal Microvasculature in Nonarteritic Anterior Ischemic Optic Neuropathy: An Optical Coherence Tomography Angiography Study. AB - Purpose: To analyze retinal and choroidal microvasculature in patients with nonarteritic anterior ischemic optic neuropathy (NAION) by using optical coherence tomography angiography (OCT-A). Methods: In this case-control retrospective observational study, patients with atrophic NAION (at least 3 months after onset of symptoms) and normal subjects underwent a complete ophthalmic examination including spectral-domain OCT, visual field (VF), and OCT A. Whole en face image vessel density (wiVD) was used to assess retinal blood flow of the radial peripapillary capillaries (RPCs), circumpapillary RPC vessel density (cpVD), superficial capillary plexus (SCP), deep capillary plexus (DCP), and choriocapillaris (CC). Statistical correlations between wiVD measurements and visual acuity, VF parameters, retinal nerve fiber layer (RNFL), and combined thickness of retinal ganglion cell and inner plexiform layers were analyzed. Results: Twenty-four patients (26 eyes) with NAION and 24 age-matched normal controls (NCs) (24 eyes) were included. OCT-A showed significant reduction of the RPC wiVD (P < 0.0001) and the cpVD (P < 0.0001) in NAION eyes compared with NC and correlated with RNFL thickness (P = 0.002, P = 0.004), visual acuity (P = 0.042), and mean deviation of the VF (P = 0.001). Macular OCT angiograms showed capillary rarefaction in the SCP (P < 0.0001) and DCP (P < 0.0001) in the NAION group, both correlated with visual acuity (P = 0.02, P = 0.024). However, wiVD of the CC was not significantly different between the two groups in the peripapillary (P = 0.218) and macular (P = 0.786) areas. Conclusions: OCT-A provided detailed visualization of the peripapillary and macular retinal capillary rarefaction, correlated with VF and visual acuity loss. OCT-A could be a useful tool for quantifying and monitoring ischemia in NAION. PMID- 29490339 TI - Enteral Arg-Gln Dipeptide Administration Increases Retinal Docosahexaenoic Acid and Neuroprotectin D1 in a Murine Model of Retinopathy of Prematurity. AB - Purpose: Low levels of the long chain polyunsaturated fatty acid (LCPUFA) docosahexaenoic acid (DHA) have been implicated in retinopathy of prematurity (ROP). However, oral DHA suffers from poor palatability and is associated with increased bleeding in premature infants. We asked whether oral administration of the neutraceutical arginine-glutamine (Arg-Glu) could increase retinal DHA and improve outcomes in a mouse model of oxygen-induced retinopathy (OIR). Methods: Postnatal day 7 (P7) pups were maintained at 75% oxygen for 5 days and then returned to room air on P12. Pups were gavaged twice daily with Arg-Gln or vehicle from P12 to P17 and eyes were harvested for analysis on P17. Vaso obliteration and vascular density were assessed on retinal flat mounts and preretinal neovascularization was assessed on retinal cross sections. Retinas were used for measurement of DHA and 10,17S-docosatriene (neuroprotectin D1, NPD1), a key DHA-derived lipid, and for analysis by reverse-phase protein array (RPPA). Results: With Arg-Gln treatment, retinal DHA and NPD1 levels were increased in OIR pups. Arg-Gln reduced preretinal neovascularization by 39 +/- 6% (P < 0.05) relative to vehicle control. This was accompanied by a restoration of vascular density of the retina in the pups treated with Arg-Gln (73.0 +/- 3.0%) compared to vehicle (53.1 +/- 3.4%; P < 0.05). Arg-Gln dipeptide restored OIR induced signaling changes toward normoxia and was associated with normalization of insulin-like growth factor receptor 1 signaling and reduction of apoptosis and an increase in anti-apoptosis proteins. Conclusions: Arg-Gln may serve as a safer and easily tolerated nutraceutical agent for prevention or treatment of ROP. PMID- 29490342 TI - An Investigation of the Effects of Riboflavin Concentration on the Efficacy of Corneal Cross-Linking Using an Enzymatic Resistance Model in Porcine Corneas. AB - Purpose: To investigate riboflavin concentration on enzymatic resistance following corneal cross-linking (CXL). Methods: Ninety-six porcine eyes were divided into five groups in two treatment runs. Group 1 remained untreated. Group 2 received riboflavin 0.05%, group 3 riboflavin 0.1%, group 4 riboflavin 0.2%, and group 5 riboflavin 0.3%. Treated eyes underwent CXL with ultraviolet A at 9 mW/cm2 for 10 minutes. Eight-millimeter discs from each cornea were submerged in pepsin digest solution. In the first run, disc diameters were measured daily. After 10 days, dry weights were recorded from five samples in each group. In the second run, dry weights were recorded in five samples in each group at 10 and 20 days. Results: CXL-treated corneas took longer to digest than untreated (P < 0.001). Although eyes treated with higher riboflavin concentrations generally took longer to digest, there were no significant differences between groups (P = 0.3). Dry weights at 10 days demonstrated, with each increase in concentration, an increase in weight of residual undigested tissue (P < 0.001). In the second run, with each increase in riboflavin concentration there was an increase in weight of residual tissue (P < 0.001) at 10 days. At 20 days, the dry weight was lower with 0.05% riboflavin compared to 0.3% (P < 0.001) and 0.2% and 0.1% solutions (P < 0.05), with no other difference between groups. Conclusions: There is a consistent dose-response curve with higher concentrations of riboflavin achieving greater CXL efficacy, suggesting that manipulation of riboflavin dosage as well as the UVA protocol can be used to optimize CXL. PMID- 29490341 TI - Novel Combination BMP7 and HGF Gene Therapy Instigates Selective Myofibroblast Apoptosis and Reduces Corneal Haze In Vivo. AB - Purpose: We tested the potential of bone morphogenic protein 7 (BMP7) and hepatocyte growth factor (HGF) combination gene therapy to treat preformed corneal fibrosis using established rabbit in vivo and human in vitro models. Methods: Eighteen New Zealand White rabbits were used. Corneal fibrosis was produced by alkali injury. Twenty-four hours after scar formation, cornea received topically either balanced salt solution (BSS; n = 6), polyethylenimine conjugated gold nanoparticle (PEI2-GNP)-naked plasmid (n = 6) or PEI2-GNP plasmids expressing BMP7 and HGF genes (n = 6). Donor human corneas were used to obtain primary human corneal fibroblasts and myofibroblasts for mechanistic studies. Gene therapy effects on corneal fibrosis and ocular safety were evaluated by slit-lamp microscope, stereo microscopes, quantitative real-time PCR, immunofluorescence, TUNEL, modified MacDonald-Shadduck scoring system, and Draize tests. Results: PEI2-GNP-mediated BMP7+HGF gene therapy significantly decreased corneal fibrosis in live rabbits in vivo (Fantes scale was 0.6 in BMP7+HGF-treated eyes compared to 3.3 in -therapy group; P < 0.001). Corneas that received BMP7+HGF demonstrated significantly reduced mRNA levels of profibrotic genes: alpha-SMA (3.2-fold; P < 0.01), fibronectin (2.3-fold, P < 0.01), collagen I (2.1-fold, P < 0.01), collagen III (1.6-fold, P < 0.01), and collagen IV (1.9 fold, P < 0.01) compared to the -therapy corneas. Furthermore, BMP7+HGF-treated corneas showed significantly fewer myofibroblasts compared to the -therapy controls (83%; P < 0.001). The PEI2-GNP introduced >104 gene copies per microgram DNA of BMP7 and HGF genes. The recombinant HGF rendered apoptosis in corneal myofibroblasts but not in fibroblasts. Localized topical BMP7+HGF therapy showed no ocular toxicity. Conclusions: Localized topical BMP7+HGF gene therapy treats corneal fibrosis and restores transparency in vivo mitigating excessive healing and rendering selective apoptosis in myofibroblasts. PMID- 29490343 TI - Sampling the Visual Field Based on Individual Retinal Nerve Fiber Layer Thickness Profile. AB - Purpose: Current perimeters use fixed grid patterns. We test whether a grid based on an individual's retinal nerve fiber layer (RNFL) thickness profile would find more visual field (VF) defects. Methods: We describe the defect-based method for choosing test locations. First, the 26 VF locations with the highest positive predictive value to detect glaucoma from the 24-2 pattern are chosen. An additional 26 locations are chosen from a 2 * 2 degree grid based on RNFL thickness. An individualized map was used to relate VF locations to peripapillary RNFL thickness. To test whether the 52 locations chosen by the defect-based method find more defects than other test grids, we collected a 386-location (2 * 2 degree grid) VF measurement on 23 glaucoma participants and classed each location in the dataset as either abnormal or normal using a suprathreshold test. Using this data, defect-based sampling was compared to: a method that sampled VF locations uniformly around the optic nerve head (ONH); the 24-2 pattern; a polar pattern; and a reduced polar pattern. The outcome measure was the number of abnormal points that were selected as test locations. Results: For 8 eyes, no method found more abnormal points than would be expected by chance (hypergeometric distribution, P < 0.05). Of the remaining 15 eyes, the defect based method identified more abnormal locations on nine eyes, which was significantly better than the other three sampling schemes (24-2: 2 eyes, P < 0.001; polar: 2 eyes, P < 0.001; reduced polar: 2 eyes, P < 0.004; and uniform: 1 eye, P < 0.001). Conclusions: Using structural information to choose locations to test in a VF for individual patients identifies more abnormal locations than using existing grid patterns and uniform sampling based on structure. PMID- 29490344 TI - Type VII Collagen in the Human Accommodation System: Expression in Ciliary Body, Zonules, and Lens Capsule. AB - Purpose: To investigate intraocular expression of COL7A1 and its protein product type VII collagen, particularly at the accommodation system. Methods: Eyes from 26 human adult donors were used. COL7A1 expression was analyzed in ex vivo ciliary epithelium by microarray. Type VII collagen distribution was examined by Western blot analysis, immunohistochemistry. and immuno-electron microscopy. Results: COL7A1 is expressed by pigmented and nonpigmented ciliary epithelia. Type VII collagen is distributed particularly at the strained parts of the accommodation system. Type VII collagen was associated with various basement membranes and with ciliary zonules. Anchoring fibrils were not visualized. Conclusions: Type VII collagen distribution at strained areas suggests a supporting role in tissue integrity. PMID- 29490345 TI - Light-Dependent OCT Structure Changes in Photoreceptor Degenerative rd 10 Mouse Retina. AB - Purpose: Using optical coherence tomography (OCT) to analyze the effects of light/dark adaptation in a mouse model of inherited photoreceptor degeneration (rd10), and to study dynamics of subretinal fluid during the progress of retinal degeneration. Methods: rd10 and wild-type (WT) C57BL/6J mice were reared in cyclic light or darkness and imaged with Bioptigen UHR-OCT or Spectralis HRA+OCT after adaptation to either light or darkness. Results: OCT images from rd10 mice were analyzed at three progressive stages of degeneration. After light adaptation, stage I (postnatal age [P]26-29) eyes demonstrated no apparent subretinal fluid. At stage II (P32-38), subretinal fluid was present and restricted to parapapillary area, while at stage III (P44-45) extensive subretinal fluid was present across many retinal areas. Following overnight dark adaptation, WT eyes showed a large reduction in outer retinal thickness (4.6 +/- 1.4 MUm, n = 16), whereas this change was significantly smaller in stage I rd10 eyes (1.5 +/- 0.5 MUm, n = 14). In stage II rd10 eyes, dark-adaptation significantly reduced the extent of subretinal fluid, with the amount of reduction correlating with the amount of fluid pre-existing in the light-adapted state. However, dark-adaptation did not significantly alter the amount of subretinal fluid observed in stage III rd10 mice. In addition, dark-rearing of rd10 mice from P6 to P30 slowed retinal degeneration. Conclusions: Visual experience in the form of light/dark adaptation exerts a significant effect on outer retinal structure in the context of photoreceptor degeneration. This effect may arise from light-dependent alterations in fluid transport across the RPE monolayer, and promote photoreceptor survival as induced by dark-rearing. PMID- 29490346 TI - The Genetics of Usher Syndrome in the Israeli and Palestinian Populations. AB - Purpose: Usher syndrome (USH) is the most common cause for deaf-blindness. It is genetically and clinically heterogeneous and prevalent in populations with high consanguinity rate. We aim to characterize the set of genes and mutations that cause USH in the Israeli and Palestinian populations. Methods: Seventy-four families with USH were recruited (23 with USH type 1 [USH1], 33 with USH2, seven with USH3, four with atypical USH, and seven families with an undetermined USH type). All affected subjects underwent a full ocular evaluation. A comprehensive genetic analysis, including Sanger sequencing for the detection of founder mutations, homozygosity mapping, and whole exome sequencing in large families was performed. Results: In 79% of the families (59 out of 74), an autosomal recessive inheritance pattern could be determined. Mutation detection analysis led to the identification of biallelic causative mutations in 51 (69%) of the families, including 21 families with mutations in USH2A, 17 in MYO7A, and seven in CLRN1. Our analysis revealed 28 mutations, 11 of which are novel (including c.802G>A, c.8558+1G>T, c.10211del, and c.14023A>T in USH2A; c.285+2T>G, c.2187+1G>T, c.3892G>A, c.5069_5070insC, c.5101C>T, and c.6196C>T in MYO7A; and c.15494del in GPR98). Conclusions: We report here novel homozygous mutations in various genes causing USH, extending the spectrum of causative mutations. We also prove combined sequencing techniques as useful tools to identify novel disease-causing mutations. To the best of our knowledge, this is the largest report of a genetic analysis of Israeli and Palestinian families (n = 74) with different USH subtypes. PMID- 29490347 TI - Beneficial Effects of Spatial Remapping for Reading With Simulated Central Field Loss. AB - Purpose: People with central field loss (CFL) lose information in the scotomatous region. Remapping is a method to modify images to present the missing information outside the scotoma. This study tested the hypothesis that remapping improves reading performance for subjects with simulated CFL. Methods: Circular central scotomas, with diameters ranging from 4 degrees to 16 degrees , were simulated in normally sighted subjects using an eye tracker on either a head-mounted display (HMD) (experiments 1, 2) or a traditional monitor (experiment 3). In the three experiments, reading speed was measured for groups of 7, 11, and 13 subjects with and without remapping of text. Results: Remapping increased reading speed in all three experiments. On the traditional monitor, it increased reading speed by 34% (8 degrees ), 38% (12 degrees ), and 35% (16 degrees ). In the two HMD experiments, remapping increased reading speed only for the largest scotoma size, possibly due to latency of updating of the simulated scotoma. Conclusions: Remapping significantly increased reading speed in simulated CFL subjects. Additional testing should examine the efficacy of remapping for reading and other visual tasks for patients with advanced CFL. PMID- 29490349 TI - Changes in Choroidal Thickness After Intravitreal Injection of Anti-Vascular Endothelial Growth Factor in Pachychoroid Neovasculopathy. AB - Purpose: We evaluate changes in choroidal thickness after intravitreal injection (IVI) therapy for pachychoroid neovasculopathy (PNV). Methods: An observational, retrospective, consecutive case series was studied of 18 patients (18 eyes) who underwent anti-vascular endothelial growth factor (VEGF) therapy for PNV. The 18 fellow eyes in these patients were used as controls. All eyes were evaluated with swept-source optical coherence tomography (SS-OCT) and optical coherence tomography angiography (OCTA). Results: Mean patient age was 68.3 +/- 7.0 years. Mean follow-up was 16.4 +/- 2.0 months. No differences in the best-corrected visual acuity (BCVA) of the affected eyes were observed between baseline and 12 month follow-up (median Early Treatment of Diabetic Retinopathy Study [ETDRS] score, 77.5 vs. 76 letters, P = 0.074; median logMAR, 0.22 vs. 0.22, P = 0.453). However, subfoveal choroidal thickness (SFCT) decreased significantly from a mean of 317.7 +/- 39.9 MUm at baseline to 266.9 +/- 56.3 MUm at 12 months (P <= 0.001). Median change in SFCT at 12 months was 44.0 MUm (range, 17-133 MUm). SFCT decreased by 16% from baseline to month 12. The change in SFCT at 12 months was highly correlated with the number of IVI (rs = 0.762, P <= 0.001). No significant changes in SFCT were observed in the fellow eyes over the 12-month study period (median, 267.5 vs. 267.0 MUm; P = 0.930). Conclusions: Choroidal thickness decreased significantly from baseline to month 12 in eyes with PNV treated with anti-VEGF injections. This reduction might be attributable to a reduction in choroidal vascular permeability and, thus, with a decrease in PNV activity. Prospective studies are needed to confirm these findings. PMID- 29490348 TI - Corneal Nerve Fractal Dimension: A Novel Corneal Nerve Metric for the Diagnosis of Diabetic Sensorimotor Polyneuropathy. AB - Objective: Corneal confocal microscopy (CCM), an in vivo ophthalmic imaging modality, is a noninvasive and objective imaging biomarker for identifying small nerve fiber damage. We have evaluated the diagnostic performance of previously established CCM parameters to a novel automated measure of corneal nerve complexity called the corneal nerve fiber fractal dimension (ACNFrD). Methods: A total of 176 subjects (84 controls and 92 patients with type 1 diabetes) with and without diabetic sensorimotor polyneuropathy (DSPN) underwent CCM. Fractal dimension analysis was performed on CCM images using purpose-built corneal nerve analysis software, and compared with previously established manual and automated corneal nerve fiber measurements. Results: Manual and automated subbasal corneal nerve fiber density (CNFD) (P < 0.0001), length (CNFL) (P < 0.0001), branch density (CNBD) (P < 0.05), and ACNFrD (P < 0.0001) were significantly reduced in patients with DSPN compared to patients without DSPN. The areas under the receiver operating characteristic curves for identifying DSPN were comparable: 0.77 for automated CNFD, 0.74 for automated CNFL, 0.69 for automated CNBD, and 0.74 for automated ACNFrD. Conclusions: ACNFrD shows comparable diagnostic efficiency to identify diabetic patients with and without DSPN. PMID- 29490351 TI - Relations Among Foveal Blood Flow, Retinal-Choroidal Structure, and Visual Function in Retinitis Pigmentosa. AB - Purpose: To investigate the relationships between foveal blood flow as measured by laser speckle flowgraphy (LSFG), the retinal-choroidal structure in enhanced depth imaging-optical coherence tomography (EDI-OCT), and central visual function in patients with retinitis pigmentosa (RP). Methods: We studied 52 consecutive typical RP patients <=50 years old and 21 age- and sex-matched controls. The mean blur rate (MBR), which represents the blood flow volume, was calculated in a 2.4 mm2 area centered on the fovea by LSFG. Subfoveal horizontal EDI-OCT images were recorded, and the choroidal area, choroidal hyporeflective area, and choroidal hyperreflective area were analyzed in the central 2.4-mm-wide region. The central foveal thickness (CFT), subfoveal choroidal thickness (SCT), and ellipsoid zone (EZ) width were also measured. Visual acuity (VA) and retinal sensitivity (Humphrey 10-2 program) were measured in the RP patients. Results: The MBR, choroidal area, hyporeflective area, hyperreflective area, and SCT were significantly decreased in the RP patients (all P < 0.001, versus controls). Spearman's rank testing demonstrated no significant correlation between the MBR and the choroidal structural parameters in the RP patients. Decreased MBR was significantly associated with reductions in VA, retinal sensitivity, CFT, and EZ width (all P < 0.05). The choroidal structural parameters did not correlate with central visual function, and the choroidal area, hyperreflective area, and SCT were inversely associated with CFT (all P < 0.05). Conclusions: These results demonstrated the divergence between the choroidal structure and blood function, and suggest that decreased choroidal flow, rather than the structural alteration, is closely associated with foveal degeneration in RP. PMID- 29490350 TI - Intravitreal Stanniocalcin-1 Enhances New Blood Vessel Growth in a Rat Model of Laser-Induced Choroidal Neovascularization. AB - Purpose: The purpose of this study was to investigate the impact of stanniocalcin 1 (STC-1), a photoreceptor-protective glycoprotein, on the development of choroidal neovascularization (CNV) in relation to VEGF and its main receptor (VEGFR2) expression after laser injury. Methods: In rats, CNV was induced by laser photocoagulation in both eyes, followed by intravitreal injection of STC-1 in the right eye and vehicle or denatured STC-1 injection in the left eye as control. Two weeks after laser injury, fundus autofluorescence (FAF) imaging and fundus fluorescein angiography (FFA) were performed. Fluorescein leakage from CNV was graded using a defined scale system. The size of CNV was quantified with spectral domain optical coherence tomography (SD-OCT), fluorescein-labeled choroid-sclera flat mounts, and hematoxylin-eosin staining. Protein expressions were evaluated by Western blot. Results: Photocoagulation produced a well circumscribed area of CNV. With STC-1 treatment, CNV lesions assessed by FAF were increased by 50% in both intensity and area. The CNV lesions were also increased with SD-OCT, flat-mount, and histologic analyses. FFA disclosed enhanced fluorescein leakage in CNV lesions in STC-1 treated eyes. The STC-1 protein was detected in the choroidal tissue and its level was increased with CNV lesions in correlation with VEGF and VEGFR2 expressions. Intravitreal administration of STC 1 significantly increased choroidal expression of both VEGF and VEGFR2 proteins. Conclusions: Chorodial tissue expresses STC-1, which seemingly acts as a stress response protein by enhancing pathological new blood vessel growth in laser induced CNV. It is likely that STC-1 promotes CNV development via VEGF signaling. PMID- 29490352 TI - Rapid Objective Assessment of Contrast Sensitivity and Visual Acuity With Sweep Visual Evoked Potentials and an Extended Electrode Array. AB - Purpose: Sweep visual evoked potentials (sVEPs) provide an implicit, objective, and sensitive evaluation of low-level visual functions such as visual acuity and contrast sensitivity. For practical and traditional reasons, sVEPs in ophthalmologic examinations have usually been recorded over a single or a limited number of electrodes over the medial occipital region. Here we examined whether a higher density of recording electrodes improves the estimation of individual low level visual thresholds with sVEPS, and to which extent such testing could be streamlined for clinical application. Methods: To this end, we tested contrast sensitivity and visual acuity in 26 healthy adult volunteers with a 68-electrode electroencephalogram (EEG) system. Results: While the most sensitive electrophysiologic response was found at the traditional medial occipital electrode Oz in a small majority of individuals, it was found at neighboring electrodes for the remaining participants. At the group level, lower spatial frequencies were also associated with right lateralized responses. More generally, visual function was evaluated more sensitively based on EEG recorded at the most sensitive electrode defined individually for each participant. Our data suggest that recording over seven posterior electrodes while limiting the testing session to less than 15 minutes ensures a sensitive and consistent estimation of acuity and contrast sensitivity threshold estimates in every individual. Conclusions: The present study shows that sampling from a larger number of posterior scalp electrodes is relevant to optimize visual function assessment and could be achieved efficiently in the time-constrained clinical setting. PMID- 29490353 TI - Association of Long Noncoding RNAs Polymorphisms With Ankylosing Spondylitis, Vogt-Koyanagi-Harada Disease, and Behcet's Disease. AB - Purpose: Long noncoding RNAs (lncRNAs) are emerging as important regulators of inflammatory immune responses, whereby genetic variants may affect this biologic function. This study aimed to investigate the association of 110 single nucleotide polymorphisms (SNPs) of lncRNAs, known to be associated with autoimmune disease, in patients with ocular Vogt-Koyanagi-Harada (VKH) disease, Behcet's disease (BD), and acute anterior uveitis (AAU) with or without ankylosing spondylitis (AS). Methods: A two-stage case-control study was performed on 1626 VKH patients, 384 BD patients, 624 AAU with AS, 751 AAU without AS, 720 AS without AAU, and 3305 healthy subjects. lncRNAs 110 SNPs were genotyped using MassARRAY System or TaqMan SNP assays. The gene expression and cytokine production were measured using real-time PCR or ELISA. Results: The frequency of the C allele of rs4937362 in RP11-264E20.1 was markedly decreased in the AS without AAU group compared with controls (Combined P = 9.37 * 10-7, odds ratio [OR] = 0.73). An increased frequency of the A allele of rs6871626 between UBLCP1, IL12B, and LOC285627 was found in VKH patients compared with controls (Combined P = 1.88 * 10-4, OR = 1.19). UBLCP1, IL12B, and LOC285627 were expressed in human uveal tissues. Functional studies showed a decreased LOC285627 mRNA expression in peripheral blood mononuclear cells (PBMCs) and an increased IL 10 production in PBMCs following LPS stimulation in rs6871626 CC genotype carriers. Conclusions: Our study is the first to show that rs4937362/RP11 264E20.1 is associated with AS and that rs6871626 is associated with VKH disease in Chinese Han. The protective rs6871626 genotype was shown to regulate the expression of LOC285627 and to increase the production of the anti-inflammatory cytokine IL-10. PMID- 29490354 TI - How Should Surgeons Interpret Operating Room Costs?: Valuing Our Time. PMID- 29490355 TI - Trends of Gender-Affirming Surgery Among Transgender Patients in the United States. PMID- 29490356 TI - A Reassessment of Blaming Mass Shootings on Mental Illness. PMID- 29490357 TI - A Day in the Life: Planned Parenthood Physician Provides Reproductive Health Care to the Underserved. PMID- 29490358 TI - The Role of the Physician in Patient Perceptions of Barriers to Primary Adherence With Acne Medications. AB - Importance: Primary nonadherence with acne medications is high but commonly underreported to prescribing physicians. Objectives: To describe patient experiences with primary nonadherence to medications for acne and to identify physician-level factors that may improve adherence in this population. Design, Setting, and Participants: A qualitative analysis was conducted from structured interviews with patients reporting nonadherence with acne medications at a large academic health system in the Philadelphia, Pennsylvania, area. Three hundred eighty-five patients from 4 dermatology practices in the Philadelphia area were screened for primary nonadherence with a newly prescribed acne medication. Twenty six patients participated in structured interviews conducted between November 30, 2016, and January 31, 2017. Main Outcomes and Measures: Thematic analysis of the transcripts was performed to detect recurrent themes and divergent ideas with a focus on modifiable physician-level factors that might improve primary adherence to medications for acne. Results: Participants (19 [73%] women, 6 [23%] aged <26 years, 15 [58%] aged 26-40 years, and 5 [19%] aged >40 years) reported cost as the major barrier to initiating therapy. Despite anticipating this barrier, they rarely brought up costs with physicians during the initial visit and generally did not expect their physician to be knowledgeable in this area. Although patients experienced inconvenience and frustration when unable to fill their prescriptions, this experience did not appear to negatively affect their satisfaction with the prescribing physician. Nevertheless, warning patients that the preferred medication may be expensive, having a plan of action if patients were unable to fill the prescription, and securing the patient's commitment to the plan were described as actions that the physicians could take to improve primary adherence. Conclusions and Relevance: Physician-level interventions to improve primary adherence to medications for acne may have an impact on nonadherence with costly medications, although they may not affect patient satisfaction with the prescribing physician. PMID- 29490360 TI - Transoral Endoscopic Thyroidectomy-An Emerging Remote Access Technique for Thyroid Excision. PMID- 29490359 TI - Real-world Effectiveness of Pharmacologic Treatments for the Prevention of Rehospitalization in a Finnish Nationwide Cohort of Patients With Bipolar Disorder. AB - Importance: Mood stabilizers and antipsychotics are the main maintenance treatments for bipolar disorder. Lithium is considered to be the most effective mood stabilizer, but very little is known about overall health outcomes associated with specific treatments and the comparative long-term effectiveness of specific psychotropics or routes of administration in the prevention of rehospitalizations. Objective: To study the comparative effectiveness of pharmacologic treatments in the prevention of rehospitalization in a nationwide cohort of patients with bipolar disorder. Design, Setting, and Participants: This cohort study examined the risk of psychiatric, cardiovascular, and all-cause hospitalization from January 1, 1987, to December 31, 2012, among all patients in Finland who had been hospitalized for bipolar disorder (N = 18 018; mean follow up time, 7.2 years) using prospectively gathered nationwide databases for hospitalization and dispensed medications. The primary analysis was within individual analysis, in which each individual was used as his or her own control to eliminate selection bias. The study adjusted for the effect of concomitant psychotropic medications, duration of illness, and the temporal orders of exposure and nonexposure periods. Statistical analysis was conducted from January 1, 1996, to December 31, 2012. Main Outcomes and Measures: Adjusted hazard ratios (HRs) for rehospitalization were calculated. Results: Among the cohort (9558 women and 8460 men; mean [SD] age, 46.6 [17.0] years), 9721 patients (54.0%) had at least 1 psychiatric rehospitalization. In comparison between use and no use among specific agents reaching nominal statistical significance, risperidone long acting injection (HR, 0.58 [95% CI, 0.34-1.00]), gabapentin (HR, 0.58 [95% CI, 0.44-0.77]), perphenazine long-acting injection (HR, 0.60 [95% CI, 0.41-0.88]), and lithium carbonate (HR, 0.67 [95% CI, 0.60-0.73]) were associated with the lowest risk of psychiatric rehospitalization. Concerning all-cause hospitalization, lithium (HR, 0.71 [95% CI, 0.66-0.76]) was associated with the lowest risk. The most frequently used antipsychotic treatment, quetiapine fumarate, showed only modest effectiveness (risk of psychiatric rehospitalization: HR, 0.92 [95% CI, 0.85-0.98]; risk of all-cause hospitalization: HR, 0.93 [95% CI, 0.88-0.98]). Long-acting injections were associated with substantially better outcomes compared with identical oral antipsychotics (risk of psychiatric rehospitalization: HR, 0.70 [95% CI, 0.55 0.90]; risk of all-cause hospitalization: HR, 0.70 [95% CI, 0.57-0.86]). Results from sensitivity analyses showed consistent beneficial effects only for lithium and for long-acting injections compared with their oral counterparts. Conclusions and Relevance: Lithium was the most effective mood stabilizer, and long-acting injections the most effective antipsychotics, in preventing hospitalization due to mental or physical illness. PMID- 29490362 TI - Surgeon Practice Patterns of Arthroscopic Partial Meniscectomy for Degenerative Disease in the United States: A Measure of Low-Value Care. PMID- 29490361 TI - A Pilot Study to Investigate the Relationship Between Interaural Differences in Temporal Bone Anatomy and Normal Variations in Caloric Asymmetry. AB - Purpose: This study assesses interaural differences in temporal bone anatomy in subjects with normal caloric findings. Method: Eligible patients included those referred to the Duke University Medical Center otology clinic complaining of dizziness, with a head computed tomography scan and caloric stimulation results within normal ranges (inter-ear difference <= 10% or < 25% unilateral weakness). Three-dimensional reconstructions of computed tomography scans in 11 patients were used to calculate the surface area and volume of lateral semicircular canals (LSCCs), mastoid airspaces, mastoid bones, and internal auditory canal diameter and circumference. Percent differences in interaural temporal bone anatomy (i.e., left-to-right asymmetry) were analyzed and correlated with warm caloric inter-ear difference (WCD) and clinically indicated caloric predictor asymmetry. Results: A multivariate model predicting WCD from 9 interaural anatomic variables demonstrated a Pearson's coefficient of 0.999. A similarly constructed model of the clinically indicated caloric predictor demonstrated a Pearson's coefficient of 0.999. The univariate correlation was strongest for WCD versus Proctor internal auditory canal diameter (r = 0.476; p = .139) and WCD versus lateral semicircular canal surface-area-to-volume ratio (r = -0.474; p = .141). Conclusions: This pilot study provides multivariate models that predict caloric asymmetry in subjects without vestibular pathologic findings per caloric testing, based on interaural differences across variables of the temporal bone anatomy. Supplemental Material: https://doi.org/10.23641/asha.5895988. PMID- 29490363 TI - Weighing the Risks and Benefits of Hormonal Contraception. PMID- 29490364 TI - A Cross-Sectional Study on the Hearing Threshold Levels Among People in Qinling, Qinghai, and Nanjing, China. AB - Purpose: This study aimed to investigate the hearing threshold among different age groups, genders, and geographic areas in China to provide some insight into the appropriate clinical interventions for hearing loss. Method: Using a systematic random sampling technique, 562 participants from Qinling, Qinghai, and Nanjing were included. Participants in the same area were divided into 3 groups according to their age. Pure-tone audiometric thresholds were measured at octave and interoctave frequencies of 0.125-16 kHz for each subject. Results: There were significant differences in auditory thresholds at nearly all frequencies among young, middle-aged, and elderly people, and hearing thresholds increased with increasing age. People generally had the best hearing ability in Nanjing, better hearing ability in Qinghai, and the worst hearing ability in Qinling. Significant differences in hearing thresholds were found between males and females at several frequencies in Qinling. Conclusion: People living in the rural area of Qinling in China had higher hearing threshold levels, particularly males, and hearing thresholds increased with age. PMID- 29490366 TI - Understanding Costs of Care in the Operating Room. AB - Importance: Increasing value requires improving quality or decreasing costs. In surgery, estimates for the cost of 1 minute of operating room (OR) time vary widely. No benchmark exists for the cost of OR time, nor has there been a comprehensive assessment of what contributes to OR cost. Objectives: To calculate the cost of 1 minute of OR time, assess cost by setting and facility characteristics, and ascertain the proportion of costs that are direct and indirect. Design, Setting, and Participants: This cross-sectional and longitudinal analysis examined annual financial disclosure documents from all comparable short-term general and specialty care hospitals in California from fiscal year (FY) 2005 to FY2014 (N = 3044; FY2014, n = 302). The analysis focused on 2 revenue centers: (1) surgery and recovery and (2) ambulatory surgery. Main Outcomes and Measures: Mean cost of 1 minute of OR time, stratified by setting (inpatient vs ambulatory), teaching status, and hospital ownership. The proportion of cost attributable to indirect and direct expenses was identified; direct expenses were further divided into salary, benefits, supplies, and other direct expenses. Results: In FY2014, a total of 175 of 302 facilities (57.9%) were not for profit, 78 (25.8%) were for profit, and 49 (16.2%) were government owned. Thirty facilities (9.9%) were teaching hospitals. The mean (SD) cost for 1 minute of OR time across California hospitals was $37.45 ($16.04) in the inpatient setting and $36.14 ($19.53) in the ambulatory setting (P = .65). There were no differences in mean expenditures when stratifying by ownership or teaching status except that teaching hospitals had lower mean (SD) expenditures than nonteaching hospitals in the inpatient setting ($29.88 [$9.06] vs $38.29 [$16.43]; P = .006). Direct expenses accounted for 54.6% of total expenses ($20.40 of $37.37) in the inpatient setting and 59.1% of total expenses ($20.90 of $35.39) in the ambulatory setting. Wages and benefits accounted for approximately two-thirds of direct expenses (inpatient, $14.00 of $20.40; ambulatory, $14.35 of $20.90), with nonbillable supplies accounting for less than 10% of total expenses (inpatient, $2.55 of $37.37; ambulatory, $3.33 of $35.39). From FY2005 to FY2014, expenses in the OR have increased faster than the consumer price index and medical consumer price index. Teaching hospitals had slower growth in costs than nonteaching hospitals. Over time, the proportion of expenses dedicated to indirect costs has increased, while the proportion attributable to salary and supplies has decreased. Conclusions and Relevance: The mean cost of OR time is $36 to $37 per minute, using financial data from California's short-term general and specialty hospitals in FY2014. These statewide data provide a generalizable benchmark for the value of OR time. Furthermore, understanding the composition of costs will allow those interested in value improvement to identify high-yield targets. PMID- 29490367 TI - Indoor Tanning, Sunless Tanning, and Sun-Protection Behaviors Among Sexual Minority Men. PMID- 29490365 TI - Temporal Trends in Gender-Affirming Surgery Among Transgender Patients in the United States. AB - Importance: Little is known about the incidence of gender-affirming surgical procedures for transgender patients in the United States. Objectives: To investigate the incidence and trends over time of gender-affirming surgical procedures and to analyze characteristics and payer status of transgender patients seeking these operations. Design, Setting, and Participants: In this descriptive observational study from 2000 to 2014, data were analyzed from the National Inpatient Sample, a representative pool of inpatient visits across the United States. The initial analyses were done from June to August 2015. Patients of interest were identified by International Classification of Diseases, Ninth Revision, diagnosis codes for transsexualism or gender identity disorder. Subanalysis focused on patients with procedure codes for surgery related to gender affirmation. Main Outcomes and Measures: Demographics, health insurance plan, and type of surgery for patients who sought gender-affirming surgery were compared between 2000-2005 and 2006-2011, as well as annually from 2012 to 2014. Results: This study included 37 827 encounters (median [interquartile range] patient age, 38 [26-49] years) identified by a diagnosis code of transsexualism or gender identity disorder. Of all encounters, 4118 (10.9%) involved gender affirming surgery. The incidence of genital surgery increased over time: in 2000 2005, 72.0% of patients who underwent gender-affirming procedures had genital surgery; in 2006-2011, 83.9% of patients who underwent gender-affirming procedures had genital surgery. Most patients (2319 of 4118 [56.3%]) undergoing these procedures were not covered by any health insurance plan. The number of patients seeking these procedures who were covered by Medicare or Medicaid increased by 3-fold in 2014 (to 70) compared with 2012-2013 (from 25). No patients who underwent inpatient gender-affirming surgery died in the hospital. Conclusions and Relevance: Most transgender patients in this national sample undergoing inpatient gender-affirming surgery were classified as self-pay; however, an increasing number of transgender patients are being covered by private insurance, Medicare, or Medicaid. As coverage for these procedures increases, likely so will demand for qualified surgeons to perform them. PMID- 29490368 TI - Enthusiasm and Skepticism About Using National Registers to Analyze Psychotropic Drug Outcomes. PMID- 29490369 TI - Methotrexate-Associated B-Cell Lymphoproliferative Disease in a Patient With Cutaneous T-Cell Lymphoma. PMID- 29490370 TI - Supported Employment for Persons With Posttraumatic Stress Disorder. PMID- 29490372 TI - Pustular Eruption (Iododerma?) in a Patient With Cancer Treated With Complementary and Alternative Medicine. PMID- 29490371 TI - Effect of Evidence-Based Supported Employment vs Transitional Work on Achieving Steady Work Among Veterans With Posttraumatic Stress Disorder: A Randomized Clinical Trial. AB - Importance: Posttraumatic stress disorder (PTSD) often interferes with a person's ability to obtain or sustain employment, which leads to premature exit from the labor force and reduced income. Objective: To determine whether individual placement and support (IPS)-supported employment is more effective than stepwise vocational rehabilitation involving transitional work assignments at helping veterans with PTSD attain steady, competitive employment. Design, Setting, and Participants: The Veterans Individual Placement and Support Toward Advancing Recovery (VIP-STAR) study was a prospective, multisite, randomized clinical trial that included 541 unemployed veterans with PTSD at 12 Veterans Affairs medical centers. Data were collected from December 23, 2013, to May 3, 2017. Intent-to treat analysis was performed. Interventions: Individual placement and support is a supported employment intervention that rapidly engages people with disabilities in community job development to obtain work based on their individual job preferences. Transitional work is a stepwise vocational rehabilitation intervention that assigns people temporarily to noncompetitive jobs as preparation for competitive employment in the community. Main Outcomes and Measures: A priori hypotheses were that, compared with those in transitional work, more participants in the IPS group would become steady workers (primary) and earn more income from competitive jobs (secondary) over 18 months. Steady worker was defined as holding a competitive job for at least 50% of the 18-month follow-up period. Results: A total of 541 participants (n = 271 IPS; n = 270 transitional work) were randomized. Mean (SD) age was 42.2 (11) years; 99 (18.3%) were women, 274 (50.6%) were white, 225 (41.6%) were African American, and 90 (16.6%) were of Hispanic, Spanish, or Latino ethnicity. More participants in the IPS group achieved steady employment than in the transitional work group (105 [38.7%] vs 63 [23.3%]; odds ratio, 2.14; 95% CI, 1.46-3.14). A higher proportion of IPS participants attained any competitive job (186 [68.6%] vs 154 [57.0%]; P = .005) and had higher cumulative earnings from competitive jobs (median [interquartile range] $7290 [$23 174] in IPS vs $1886 [$17 167] in transitional work; P = .004). Conclusions and Relevance: This multisite trial demonstrated significantly greater effectiveness of IPS-supported employment over stepwise transitional work vocational rehabilitation for veterans living with chronic PTSD. The results provide supporting evidence for increasing access to IPS for veterans living with PTSD. Trial Registration: clinicaltrials.gov Identifier: NCT01817712. PMID- 29490373 TI - Patient Preferences for Follow-up After Recent Excision of a Localized Melanoma. AB - Importance: The standard model of follow-up posttreatment of localized melanoma relies on clinician detection of recurrent or new melanoma, through routinely scheduled clinics (clinician-led surveillance). An alternative model is to increase reliance on patient detection of melanoma, with fewer scheduled visits and increased support for patients' skin self-examination (SSE) (eg, using smartphone apps to instruct, prompt and record SSE, and facilitate teledermatology; patient-led surveillance). Objective: To determine the proportion of adults treated for localized melanoma who prefer the standard scheduled visit frequency (as per Australian guideline recommendations) or fewer scheduled visits (adapted from the Melanoma Follow-up [MELFO] study of reduced follow-up). Design, Setting, and Participants: This survey study used a telephone interview for surveillance following excision of localized melanoma at an Australian specialist center. We invited a random sample of 400 patients who had completed treatment for localized melanoma in 2014 to participate. They were asked about their preferences for scheduled follow-up, and experience of follow up in the past 12 months. Those with a recurrent or new primary melanoma diagnosed by the time of interview (0.8-1.7 years since first diagnosis) were asked about how it was first detected and treated. SSE practices were also assessed. Main Outcomes and Measures: Proportion preferring standard vs fewer scheduled clinic visits, median delay between detection and treatment of recurrent or new primary melanoma, and SSE practices. Results: Of the 262 people who agreed to be interviewed, the mean (SD) age was 64.3 (14.3) years, and 93 (36%) were women. Among the 230 people who did not have a recurrent or new primary melanoma, 149 vs 81 preferred the standard vs fewer scheduled clinic visits option (70% vs 30% after adjusting for sampling frame). Factors independently associated with preferring fewer visits were a higher disease stage, melanoma on a limb, living with others, not having private health insurance, and seeing a specialist for another chronic condition. The median delay between first detection and treatment of recurrent or new primary melanoma was 7 and 3 weeks, respectively. Only 8% missed a scheduled visit, while 40% did not perform SSE or did so at greater than 3-month intervals. Conclusions and Relevance: Some patients with melanoma may prefer fewer scheduled visits, if they are supported to do SSE and there is rapid clinical review of anything causing concern (patient-led surveillance). PMID- 29490374 TI - Immunophenotypic CD56 Variation Within a Single Patient With Blastic Plasmacytoid Dendritic Cell Neoplasm. PMID- 29490375 TI - Pustular Eruption (Iododerma?) in a Patient With Cancer Treated With Complementary and Alternative Medicine-Reply. PMID- 29490376 TI - Targeting Complex Sentences in Older School Children With Specific Language Impairment: Results From an Early-Phase Treatment Study. AB - Purpose: This study investigated the effects of a complex sentence treatment at 2 dosage levels on language performance of 30 school-age children ages 10-14 years with specific language impairment. Method: Three types of complex sentences (adverbial, object complement, relative) were taught in sequence in once or twice weekly dosage conditions. Outcome measures included sentence probes administered at baseline, treatment, and posttreatment phases and comparisons of pre-post performance on oral and written language tests and tasks. Relationships between pretest variables and treatment outcomes were also explored. Results: Treatment was effective at improving performance on the sentence probes for the majority of participants; however, results differed by sentence type, with the largest effect sizes for adverbial and relative clauses. Significant and clinically meaningful pre-post treatment gains were found on a comprehensive oral language test, but not on reading and writing measures. There was no treatment advantage for the higher dosage group. Several significant correlations indicated a relationship between lower pretest scores and higher outcome measures. Conclusions: Results suggest that a focused intervention can produce improvements in complex sentence productions of older school children with language impairment. Future research should explore ways to maximize gains and extend impact to natural language contexts. Supplemental Material: https://doi.org/10.23641/asha.5923318. PMID- 29490377 TI - Lithium Treatment in Children and Adolescents. AB - INTRODUCTION: There is a resurgence of interest in lithium treatment of bipolar disorders in part related to its unique anti-suicidal and neuroprotective effects. METHODS: This is a narrative review of key studies pertaining to the effectiveness and tolerability of lithium treatment in pediatric populations. RESULTS: Evidence supports that lithium is an effective and generally well tolerated acute treatment for pediatric mania compared to placebo. Lithium may be less effective than risperidone for treating chronic mixed/manic symptoms in young children but comparable to anticonvulsants. However, in comparison, risperidone was associated with higher weight gain and prolactin levels. There is a lack of evidence inform maintenance treatment in children who benefit from lithium. Other indications that require further study include treatment of refractory or recurrent major depression in children at confirmed familial risk of bipolar disorder, as well as the treatment of acute suicidal ideation/behavior and refractory aggression. DISCUSSION: There is inadequate data about the full variety of benefit and tolerability of lithium treatment in pediatric patients. However, given the potential for protection against suicide and neurotoxic effects of illness, further studies should be a priority. PMID- 29490378 TI - Role of Routine Dilatations after Anorectal Reconstruction-Comparison of Two Tertiary Centers. AB - AIM: Regular anal dilatations are commonly recommended in the postoperative management following posterior sagittal anorectoplasty (PSARP) in anorectal malformations (ARM). We hypothesized that routine postoperative dilatations may not affect surgical outcomes following PSARP. We compare surgical outcomes of routine postoperative dilatations versus no routine postoperative dilatations from two United Kingdom tertiary pediatric surgical centers. METHODS: This is retrospective records review of patients undergoing definitive surgery for ARM in two tertiary surgical centers in the UK over 5 years. Center A used a protocol of routine postoperative dilatations, and center B used a protocol, which used dilatations only for clinical indications of stricture. Data collected included ARM type, operative procedures, and postoperative interventions. All post operative interventions under general anesthesia (GA) were compared between groups. RESULTS: From 2011 to 2015, 49 procedures (46 PSARPs) were performed in center A and 54 (52 PSARPs) in center B. Median follow up period was 31 months (interquartile range [IQR] 18-48). The first postoperative anal calibration under GA was documented for 43 (86%) patients in center A and for 42 (78%) patients in center B. Following this, center A followed routine postoperative dilatation (RPD) at home, and center B reserved further dilatations for specific indications. RPD was performed for 100% of patients in center A versus 8% in center B. Further anal dilatations under GA were performed in 19 (38%) children in center A and in 17 (34%) children in center B (p = 0.68). In center A, 10 patients (22%) needed further surgery versus 14 (28%) in center B (p = 0.48). CONCLUSION: The use of routine postoperative dilatations does not significantly improve surgical outcomes following PSARP in ARM. PMID- 29490379 TI - Treatment of Unstable Pediatric Tibia Shaft Fractures in Finland. AB - BACKGROUND: Surgical treatment of pediatric tibia shaft fractures has gained popularity despite closed reduction and cast-immobilization providing good long term results. There is no consensus about optimal methods and satisfactory quality of treatment. MATERIALS AND METHODS: During 2010 to 2014, 226 pediatric patients were treated under anesthesia for tibia shaft fractures in Finland's five university hospitals. A total of 164 (73%) patients had closed fractures of the tibia or both tibia and fibula without other injuries (62 tibia only and 102 both tibia and fibula). Forty-one (18%) had open tibia fractures, 16 had additional fractures, and 5 (2%) had sustained a polytrauma (Injury Severity Score [ISS] > 15). Treatment methods, follow-up protocols, complications, and the outcome were analyzed. RESULTS: A total of 143 (63%) of the tibia fractures were treated surgically: 87 (53%) closed fractures, 36 (88%) open fractures, 15 (94%) with additional fractures, and 5 (2%) polytrauma patients. The rate of surgical treatment of closed tibia fractures was significantly higher in patients older than 10 and in patients with a concomitant fibula fracture. Fasciotomy was done in 33 (15%) patients. Reoperations were performed in 13 (6%) patients because of unsatisfactory treatment (inappropriate primary reduction 6, malunion 6, and non union 1). There were no differences between the five university hospitals in treatment or follow-up protocols. CONCLUSION: Internal fixation is used for the majority of tibia shaft fractures treated under anesthesia in university hospitals in Finland. Serious fracture or treatment related complications are very rare, but the percentage (6%) of re-operations because of unsatisfactory standard of treatment should be lower and could probably be improved by concentrating internal fixation to fewer hands. A prospective randomized controlled trial comparing non-operative treatment to intramedullary nailing in pediatric tibia fractures should be performed. PMID- 29490380 TI - [Attention-deficit/hyperactivity disorder (ADHD) in adult psychiatry: Data on 12 month prevalence, risk factors and comorbidity]. AB - AIMS AND METHODS: To examine the 12-month prevalence, risk factors, and comorbidity of ADHD in a collective of adult psychiatric patients admitted to an open general ward in a psychiatric hospital in Schleswig-Holstein (Germany) over a period of one year (n = 166). RESULTS: The 12 months prevalence of ADHD was 59.0 % (severe symptomatology: 33.1 %), high rates of comorbid disorders (92.9 % depression, 5.1 % bipolar disorder, 28.6 % anxiety disorder, 30.6 % emotional unstable (Borderline) personality disorder, 31.6 % avoidant personality disorder, 18.4 % dependent personality disorder, 25.5 % combined personality disorder, 10.2 % obsessive-compulsive personality disorder, 26.5 % PTSD, 25.5 % restless legs syndrome, 24.5 % adiposity, 11.2 % eating disorder, 45.9 % learning difficulty, 51.0 % nicotine dependency, 4.1 % alcohol dependency, 7.1 % illegal substance dependency), risk factors for ADHD, a high genetic risk (72.4 %) and problems in psychosocial functioning. CONCLUSIONS: Because of the high prevalence of ADHD in hospitalized psychiatric patients, it is mandatory to examine these for the presence of ADHD using questionnaires and identify comorbid diseases. PMID- 29490381 TI - [Hypertensive crisis and posterior reversible encephalopathy syndrome (PRES)]. AB - The urgency and intensity of therapeutic response to a hypertensive crisis are governed by the presence or absence of acute end-organ damage, which define hypertensive emergency and hypertensive urgency, respectively. In case of hypertensive urgency a slow and moderate lowering of blood pressure by oral antihypertensive agents seems adequate, while the approach to hypertensive emergency has to be tailored to the specific type of organ failure. Optimal blood pressure management in the context of neurovascular emergencies is made difficult by contradictory data from observational and interventional studies. It might prove advantageous to individualize treatment according to characteristics such as the location of persistent vessel occlusion or the presence of collaterals. Reversible posterior encephalopathy may present with atypical features that might make diagnosis difficult. Clevidipine might be a welcome supplement to current intravenous antihypertensive agents in neurological disease. PMID- 29490382 TI - [Major depression and liver disease: the role of microbiome and inflammation]. AB - Depression and liver disease are closely associated. Every third patient with liver cirrhosis or hepatitis shows depressive symptoms. On the other hand, every third patient with depressive disorder develops an alcohol disorder at some point during his / her life. A crucial link between depression and hepatic disease seems to be inflammatory processes in which the microbiome and increased intestinal permeability of the intestine play a pivotal role. Depression as well as liver disease, alcohol consumption, stress, and aging processes disturb the delicate balance of intestinal microbiota resulting in increased intestinal permeability. Therefore, bacteria or their metabolites such as the endotoxine lipopolysaccharide are able to reach the blood circulation resulting in inflammation in the liver as well as in the brain via a cytokine cascade, which in turn can lead to liver changes, depression, obesity, and metabolic syndrome. Therefore, liver values, blood glucose levels, and metabolic parameters should be closely monitored in patients with depressive disorders, and in the case of patients with hepatic diseases, increased attention should be given to depressive symptoms, diabetes and obesity. PMID- 29490383 TI - Comprehensive HPTLC Fingerprinting for Quality Control of an Herbal Drug - The Case of Angelica gigas Root. AB - The quality of herbal drugs is usually controlled using several tests recommended in a monograph. HPTLC is the method of choice for identification in many pharmacopoeias. If combined with a suitable reference material for comparison, HPTLC can provide information beyond identification and thus may simplify quality control. This paper describes, as a proof of concept, how HPTLC can be applied to define specifications for an herbal reference material and to control the quality of an herbal drug according to these specifications. Based on multiple batches of cultivated Angelica gigas root, a specific HPTLC method for identification was optimized. This method can distinguish 27 related species. It also can detect the presence of mixtures of A. gigas with two other Angelica species traded as "Dang gui" and is suitable as well for quantitative assessment of samples in a test for minimum content of the sum of decursin and decursinol angelate. The new concept of "comprehensive HPTLC fingerprinting" is proposed: HPTLC fingerprints (images), which are used for identification, are converted into peak profiles and the intensities of selected zones are quantitatively compared to those of the corresponding zones of the reference material. Following a collaborative trial involving three laboratories in three countries, the method was applied to check the quality of further candidates for establishing an appropriate reference material. In conclusion, this case demonstrates that a single HPTLC analysis can provide information about identity, purity, and minimum content of markers of an herbal drug. PMID- 29490384 TI - A Monoclonal Antibody-Based Enzyme-Linked Immunosorbent Assay for Determination of Homoharringtonine. AB - Homoharringtonine (HHT), also known as omacetaxine, is a natural compound found in the genus Cephalotaxus and is a promising pharmaceutical drug used for the treatment of chronic or accelerated phase chronic myeloid leukemia. As a tool for the quantitative determination of HHT, a specific monoclonal antibody against HHT (MAb 6A1) was generated by conjugates prepared via sodium periodate-mediated oxidation. The developed indirect competitive enzyme-linked immunosorbent assay (icELISA) using MAb 6A1 was found to be highly specific and sensitive with a limit of detection for HHT of 48.8 ng/mL. Validation assays to evaluate precision and accuracy of the method were conducted by the use of intra- and inter-assay analysis, recovery test, and comparison analysis between the amounts of HHT determined by ELISA and high-performance liquid chromatography. These results revealed that the established icELISA using MAb 6A1 is specific, sensitive, and reliable enough to be applied to the qualitative analysis for HHT. Furthermore, the results of this study support the usefulness of sodium periodate as a reagent for the conjugation between Cephalotaxus alkaloids and proteins for producing specific antibodies. PMID- 29490385 TI - Potential Therapeutic Benefits of Green and Fermented Rooibos (Aspalathus linearis) in Dermal Wound Healing. AB - The process of wound healing constitutes an ordered sequence of events that provides numerous opportunities for therapeutic intervention to improve wound repair. Rooibos, Aspalathus linearis, is a popular ingredient in skin care products, however, little scientific data exists exploring its therapeutic potential. In the present study, we evaluated the effects of fermented and aspalathin-enriched green rooibos in various in vitro models representative of dermal wound healing. Treatment of RAW 264.7 macrophages with fermented rooibos resulted in increased nitric oxide production as well as increased levels of cellular inducible nitric oxide synthase and cyclooxygenase-2, which are typical markers for classically activated macrophages. In contrast, the green extract was devoid of such activity. Using glycated gelatin as a model to mimic diabetic wounds, only the green extract showed potential to reduce cyclooxygenase-2 levels. Considering the role of reactive oxygen species in wound healing, the effects of rooibos on oxidative stress and cell death in human dermal fibroblasts was evaluated. Both fermented and green rooibos decreased cellular reactive oxygen species and attenuated apoptotic/necrotic cell death. Our findings highlight several properties that support the therapeutic potential of rooibos, and demonstrate that green and fermented rooibos present distinctly different properties with regards to their application in wound healing. The proinflammatory nature of fermented rooibos may have therapeutic value for wounds characterised with a delayed initial inflammatory phase, such as early diabetic wounds. The green extract is more suited to wounds burdened with excessive inflammation as it attenuated cyclooxygenase-2 levels and effectively protected fibroblasts against oxidative stress. PMID- 29490386 TI - Antiangiogenic Activity and Cytotoxicity of Triterpenoids and Homoisoflavonoids from Massonia pustulata and Massonia bifolia. AB - The Hyacinthaceae family (sensu APGII), with approximately 900 species in around 70 genera, plays a significant role in traditional medicine in Africa as well as across Europe and the Middle and Far East. The dichloromethane extract of the bulbs of Massonia pustulata (Hyacinthaceae sensu APGII) yielded two known homoisoflavonoids, (R)-5-hydroxy-3-(4-hydroxybenzyl)-7-methoxy-4-chromanone 1: and 5-hydroxy-3-(4-hydroxybenzyl)-7-methoxy-4-chromone 2: and four spirocyclic nortriterpenoids, eucosterol 3: , 28-hydroxyeucosterol 4: and two previously unreported triterpenoid derivatives, (17S,23S)-17alpha,23-epoxy-3beta,22beta,29 trihydroxylanost-8-en-27,23-olide 5: , and (17S, 23S)-17alpha,23-epoxy-28,29 dihydroxylanost-8-en-3-on-27,23-olide 6: . Compounds 1, 2, 3: , and 5: were assessed for cytotoxicity against CaCo-2 cells using a neutral red uptake assay. Compounds 1, 2: , and 5: reduced cell viability by 70% at concentrations of 30, 100, and 100 uM, respectively. Massonia bifolia yielded three known homoisoflavonoids, (R)-(4'-hydroxy)-5-hydroxy-7-methoxy-4-chromanone 1: , (R)-(4' hydroxy)-5,7-dihydroxy-4-chromanone 7: and (R)-(3'-hydroxy-4'-methoxy)-5,7 dihydroxy-4-chromanone 9: , two previously unreported homoisoflavonoids, (E)-3 benzylidene-(3',4'-dihydroxy)-5-hydroxy-7-methoxy-4-chromanone 8: and (R)-(3',4' dihydroxy)-5-hydroxy-7-methoxy-4-chromanone 10,: and a spirocyclic nortriterpenoid, 15-deoxoeucosterol 11: . Compounds 1, 1AC, 7, 8, 9,: and 10: were screened for antiangiogenic activity against human retinal microvascular endothelial cells. Some compounds showed dose-dependent antiproliferative activity and blocked endothelial tube formation, suggestive of antiangiogenic activity. PMID- 29490387 TI - "Vascular Outlining": Augmented Imaging for Transfemoral Access-A Preclinical Investigation. AB - BACKGROUND: Advanced visualization software tools have been used in clinics to improve the safety and accuracy of transcatheter procedure. Imaging techniques have greatly evolved during the era of transcatheter aortic valve implantation (TAVI). In a retrospective analysis, we investigated the feasibility of augmented fluoroscopy for iliofemoral access using a novel "Vascular Outlining" roadmapping technology. METHODS: The Vascular Outlining prototype device (Philips Healthcare) application was used with iliofemoral angiography of 10 patients undergoing transfemoral TAVI. The software processes any conventional angiographic sequences, extracting the static outline of vessels and projecting the two-dimensional vessel margins as a roadmap on live fluoroscopy. Post processed results were clinically assessed to determine whether the technical performance of the tool is sufficient. RESULTS: Augmented imaging was possible in all investigated angiography sequences. The analysis of software-generated images showed accurate projection of the two-dimensional outline of the iliofemoral vessels as an overlay on the live fluoroscopy image in most cases. Overlay inaccuracy was only observed in cases with low contrast or patient movement. CONCLUSION: In static and contrasted angiography sequences, "Vascular Outlining" showed accurate image overlay. We identified that the quality of the vascular outline is dependent on the opacification of the contrast injection and the stability of the patient on the table. With further development. this application might increase the accuracy of femoral puncture and reduce the incidence of vascular complications. Clinical trials are needed to confirm these hypotheses. PMID- 29490389 TI - Minimally Invasive versus Conventional LVAD-Implantation-An Analysis of the Literature. AB - This review aims to provide an overview on recent data to evaluate minimally invasive (MVAD) and conventional (CVAD) left ventricular assist device (LVAD) implantation. A comprehensive literature search of PubMed, Cochrane Library, and ClinicalTrials.gov was conducted up to April 2017. A total of 183 studies were identified; 13 studies met inclusion criteria. The review revealed a trend toward a lower rate of transfusion, and shorter time for cardiopulmonary bypass, as well as a lower 30-day mortality rate for MVAD. This review indicates that there are possible benefits of minimally invasive LVAD implantation, even though the state of literature is poor. PMID- 29490388 TI - Minimally Invasive Mitral Valve Surgery in Re-Do Cases-The New Standard Procedure? AB - BACKGROUND: Minimally invasive mitral valve surgery (MIMVS) is superior to "classical" mitral valve surgery via a sternotomy regarding wound healing and postoperative pain. It is however a more challenging procedure. Patients' preference is leading clearly toward minimally invasive approaches, and surgeons are driven by upcoming new technologies in interventional procedures such as the MitraClip. Especially in re-do cases, the access via right mini-thoracotomy, as previously non-operated situs, is a possible advantage over a re-sternotomy. We therefore retrospectively analyzed our result regarding MIMVS in re-do cases at our institute. METHODS: From January 2011 and June 2016, 33 operations were MIMVS re-do procedures. Mean age was 60 years (+/-16 years), and 51% were male. RESULTS: Sixty-one percent were elective cases, 29% were urgent cases, and 9% were emergency operations. Operation times, cardiopulmonary bypass (CPB) times, and clamp times were 235 minutes (+/-51 min), 149 minutes (+/-42 min), and 62 minutes (+/-45min), respectively. Mitral valve repair and replacement was performed in 24% (n = 8) and 76% (n = 25), respectively. Overall in-hospital mortality, apoplexy, and re-operation rates (all for bleeding) were 0% (n = 0), 3% (n = 1), and 9% (n = 3). New onset of dialysis was required in two (6%) patients. Two (6%) patients developed superficial wound infection. Overall intensive care unit (ICU) and hospital stay was 3 days (+/-4 days) and 15 days (+/-7 days), respectively. CONCLUSION: MIMVS for re-do cases can be performed with minimal mortality and morbidity and therefore represents a safe alternative to conventional mitral valve surgery in cardiac re-do operations. However, postoperative morbidity is highly dependent on preoperative patient status. PMID- 29490390 TI - [Hereditary Optic Neuropathies]. AB - Hereditary optic nerve disorders are rare. For ophthalmologists, Leber's hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA) are of particular relevance. LHON and ADOA are diseases of the retinal ganglion cells and are caused by mitchochondrial dysfunction. LHON is based on mutations of the mitochondrial, ADOA of the nuclear DNA. LHON is a disease that usually leads to severe visual impairment (visual acuity < 0.1). Since there is an approved therapy for LHON (Idebenone [Raxone]), the diagnosis has to be confirmed immediately by means of molecular genetic diagnostics. ADOA usually shows less severe visual impairment, begins in childhood, and progresses gradually, often for a long time without any noticeable worsening. Family history (dominant heredity) and blue colour vision disorder are the leading indicators for the diagnosis of ADOA, which should be confirmed by molecular genetic testing. Optic nerve diseases can also occur in the context of hereditary, syndromic disorders. Ophthalmologically relevant are Wolfram syndrome, Friedreich's ataxia and Charcot Marie-Tooth disease. In all hereditary optic nerve disorders, foods containing cyanide and smoking should be avoided. Excessive alcohol consumption is considered to be a trigger of LHON and possibly harmful in other hereditary optic neuropathies. In the management of patients with hereditary optic nerve disorders, aspects of rehabilitation as well as social and psychological care should be considered. PMID- 29490391 TI - [Microbial keratitis: Understand, recognize, and treat - part 1: General aspects and characteristics of bacterial keratitis]. AB - Infectious inflammation of the cornea (microbial keratitis) represents a potentially vision threatening disease. Depending on the infectious agent and the course of the disease it can result in a complete loss of the involved eye. Early diagnosis and accurate treatment are mandatory to maintain a sufficient visual acuity. The purpose of this review is to highlight and discuss characteristic clinical features, diagnostic procedures, and therapeutic aspects of three major forms of microbial keratitis (bacteria, fungi, and acanthamoeba; the latter two in the 2nd part of this article). PMID- 29490392 TI - [Microbial keratitis - part 2: Specific aspects of mycotic and acanthamoeba keratitis]. PMID- 29490393 TI - [Non-organic Visual Loss]. AB - Non-organic visual loss is a frequent challenge in ophthalmic practice. In children most patients are prepubertal females. The most frequent manifestation in this age-group is a bilateral unexplained decrease of visual acuity. In adulthood patients often indicate a degree of visual loss after an accident or a disease - that could not be explained by the eye condition alone. Non-organic visual loss may be frustrating for both, patients and physicians. The aim of the present article is to sensitize ophthalmologists to this condition and to provide a diagnostic frame and strategy how to manage patients with such a diagnosis. PMID- 29490394 TI - Central Scotoma after Removal of Silicone Oil in Retinal Detachment: A Multimodal Imaging Case Report. PMID- 29490395 TI - [Correlation of Quantitative Metamorphopsia Measurement and Central Retinal Thickness in Diabetic Macular Edema and Age-Related Exsudative Macular Degeneration]. AB - BACKGROUND: Amsler Test is the standard used to detect metamorphopsia. To develop a tool to quantitatively measure and monitor metamorphopsia, the computer-based test "AMD - A Metamorphopsia Detector(r)" was developed. This study was performed to examine the correlation of metamorphopsia index (MI) and central retinal thickness (CRT) in exsudative age-related macular degeneration (AMD) and diabetic macular edema (DME). MATERIAL AND METHODS: Sixty-six eyes of 66 patients, DME: 19 (11 males, 8 females; age 42 - 76); AMD: 47 (13 male, 34 female; age 56 - 93) were included in this convenient sample study and classified as having or not having macular edema (central 500 um, Cirrus HD-OCT). Best corrected monocular distance visual acuity (BCVA), Amsler Test, Metamorphopsia Index of AMD - A Metamorphopsia Detector, binocular ophthalmoscopy, central retinal thickness (SD OCT) and fluorescein angiography, if necessary, were performed. Correlation of central retinal thickness and metamorphopsia index was evaluated by Spearman correlation. RESULTS: Mean BCVA (logMAR) was 0.27 (SD 0.3) in DME and 0.29 (SD 0.2) in AMD. Spearman's rho as a measure for correlation between CRT and MI was 0.88 (p < 0.001) in DME and 0.56 (p < 0.001) in AMD. CONCLUSIONS: Correlation of CRT und MI was high in DME and moderate in AMD. Future studies will examine if metamorphopsia measurement is a feasible tool for detection of conversion into neovascular AMD and for (self-)monitoring. PMID- 29490396 TI - Long-term Follow-up of Canaliculotomies after Canaliculitis. AB - BACKGROUND: Canaliculitis is often misdiagnosed. There are several conservative and surgical treatment options. PATIENTS AND METHODS: Retrospective analysis of 14 canaliculotomies in 10 patients with canaliculitis. The overall length of the surgically induced opening was measured and compared to the corresponding untreated lacrimal punctae. Lacrimal duct concrements were liberated and sent for microbiological and histological analysis. Patient satisfaction and relief of symptoms were documented as well as clinical findings. RESULTS: Mean age was 59 +/- 10 years (36 - 73 years) with balanced gender distribution. Mean follow-up time was 13 +/- 8 months (4 - 27 months). Canaliculotomy was performed on 12 out of 14 inflamed canaliculi; in 2 cases, 3-snip punctoplasty was sufficient. The surgically induced length of the cuts was 1.7 +/- 0.9 mm (0.4 - 3.7 mm). In 13 out of 14 cases, macroscopic concrements were found intraoperatively and actinomyces was verified histologically. Nine patients were free of symptoms postoperatively, and one patient manifested markedly less epiphora. CONCLUSIONS: The canaliculi remained open within the long-term follow-up period without any drawbacks to the lacrimal outflow. No recurrent infections were seen. PMID- 29490397 TI - The Association between Cervical Exam after Ripening with Foley Balloon Catheter and Outcomes of Nulliparous Labor Induction. AB - OBJECTIVE: Evaluate the association between cervical examination after ripening with Foley catheter and labor induction outcomes. MATERIALS AND METHODS: In this retrospective cohort, nulliparous women with singleton, viable gestation undergoing cervical ripening with Foley catheter were compared based on cervical status after catheter removal or expulsion: favorable (modified Bishop score >= 5) or unfavorable (score < 5). Bivariable and multivariable analyses were performed to determine whether cervical examination postripening was associated with time to delivery and chance of vaginal delivery. RESULTS: A total of 774 women were eligible. Women with favorable examination postripening had lower body mass index (BMI) and more favorable admission cervical examination. The frequency of vaginal delivery was higher in women with favorable cervical examination postripening (57.9% versus 46.8%, p < 0.01). Median durations from Foley removal or expulsion to complete dilation (8.6 h versus 11.5 h) and vaginal delivery (10.4 h versus 13.2 h) were shorter for women with favorable cervical examination postripening (p < 0.001). In multivariable analysis, favorable examination postripening remained associated with vaginal delivery (adjusted odds ratio 1.39, 95% confidence interval 1.04-1.87), and time to vaginal delivery (adjusted hazard ratio 1.39, 95% confidence interval 1.13-1.70). CONCLUSION: A favorable modified Bishop score after cervical ripening with Foley balloon catheter is associated with higher chance of vaginal delivery and shorter labor duration. PMID- 29490398 TI - Embryonic Stem Cells and Infertility. AB - Embryonic stem cells (ESCs) have the ability to differentiate into several cell lineages and self-renew. Through a spontaneous process, ESCs can differentiate into germ cells of various stages, partly due to their self-renewal ability and their microenvironment culture. Human and mouse ESC differentiation into putative primordial germ cells (PGCs) has been demonstrated by several studies; in fact, derivation of functional mouse male gametes has also been reported. However, the exact underlying mechanisms are yet to be understood properly, and as such clinical applications of ESC-derived PGC remains controversial. Nonetheless, this technique can still serve as a potential treatment option for infertility. This review centers on the available reports on the possible application of ESC for infertility treatment. PMID- 29490399 TI - Hyperglycosylated hCG and Placenta Accreta Spectrum. AB - OBJECTIVE: We aimed to evaluate the relationship between hyperglycosylated human chorionic gonadotropin (hCG-H) and placenta accreta spectrum (PAS) in the second and third trimesters of pregnancy. STUDY DESIGN: This was a case-control study of PAS and controls. hCG-H was measured in the second and third trimesters of pregnancy in women with pathologically confirmed cases of PAS and in gestational age-matched controls without PAS. We compared serum hCG-H levels in cases and controls, calculated summary statistics for diagnostic accuracy, and used receiver operating characteristic (ROC) curves to define an optimal cut-point for diagnosis of PAS using hCG-H. RESULTS: Thirty case samples and 30 control samples were evaluated for hCG-H. Mean hCG-H was lower in the case compared with control group (7.8 +/- 5.9 MUg/L vs. 11.8 +/- 8.8 MUg/L, p = 0.03). At an optimal cut-point for hCG-H of <=7.6 MUg/L, the sensitivity, specificity, positive likelihood ratios, negative likelihood ratios, and area under the ROC curve were 66.7%, 69.7%, 2.20%, 0.48%, and 0.68%, respectively. CONCLUSION: Hyperglycosylated hCG levels in the second and third trimesters of pregnancy were lower in patients with PAS than in controls, but hCG-H showed only modest capability as a diagnostic test for PAS. PMID- 29490400 TI - Trends in Knee Articular Cartilage Treatments: An American Board of Orthopaedic Surgery Database Study. AB - This study aims to evaluate the trends in treatment of knee articular cartilage lesions over the past decade using data obtained from the American Board of Orthopaedic Surgery (ABOS) Part II database. The ABOS Part II database was queried from 2004 to 2013 for chondroplasty, microfracture, and osteochondral grafting procedures. All cases were analyzed for patient age and operating surgeon's fellowship training status. Univariate analysis including chi-square test for categorical variables and Student's t-test for continuous variables was performed to determine if any significant changes in practice patterns were present. Linear regression analyses were utilized to examine temporal trends in procedures performed and fellowship training status. From 2004 to 2013, 25,938 procedures addressing articular cartilage lesions from 3,586 surgeons were identified in the ABOS database. 46.8% of these orthopaedic surgeons had completed a 1-year sports medicine fellowship. Sixty-six percent of cartilage surgeries were performed by sports medicine-trained surgeons. The articular cartilage surgical volume decreased from 3,126 cases in 2004 to 1,690 cases in 2013. The most common procedure coded overall was chondroplasty (80.23%) followed by microfracture (21.37%) and osteochondral grafting (2.1%). The mean age of patients undergoing chondroplasty was 46.9 years; this was significantly higher than microfracture (mean age 40.5 years) or osteochondral grafting procedures (mean age 31.6 years), p < 0.0005. The age of all patients undergoing cartilage surgery significantly decreased between 2004 and 2013, p < 0.001. A dramatic decrease in reported chondroplasty volume was observed between 2011 and 2012. Concurrent osteotomies were used in <1% of procedures addressing cartilage injuries, while 65% of patients underwent concurrent meniscectomy. These described trends are most pronounced in surgeons with sports medicine fellowship training. In conclusion, knee articular cartilage surgical volume and patient age have both sharply declined since 2011, a trend driven by sports medicine-trained Part II examinees. This trend correlates with changes in billing and coding practices, as well as improved education from high-level studies. PMID- 29490401 TI - More Severe Preoperative Kellgren-Lawrence Grades of Knee Osteoarthritis were Partially Associated with Better Postoperative Patient-Reported Outcomes in TKA Patients. AB - Total knee arthroplasty (TKA) is a successful procedure, although up to 20% of patients remain dissatisfied. Preoperative identification of appropriate TKA candidates is essential for improving satisfaction. This study investigated if preoperative radiographic severity was associated with postoperative pain, function, and quality of life after TKA. We performed a cross-sectional cohort study including 327 TKA patients. Radiographic severity was determined by two independent radiologists using the Kellgren and Lawrence (KL) score. The Knee Injury and Osteoarthritis Outcome Score (KOOS), the New Knee Society Score (New KSS), and Anterior Knee Pain Score (AKPS) were collected. We evaluated the association between KL grade and patient-reported outcome measures (PROMs) with the use of regression analysis techniques. Out of 228 responders, 195 patients completed the questionnaire sufficiently. Forty-seven patients were classified as KL grades 1 to 2, and 144 patients were classified as KL grades 3 to 4. The inter observer reliability between both radiologists was substantial (kappa = 0.67). After adjusting for age, sex, and body mass index (BMI), the New KSS subscales symptoms and expectations, and the KOOS subscale quality of life were significantly higher in the KL grades 3 to 4 group. However, neither the remaining KOOS subscales and AKPS nor KOOS change scores differed between both groups. Thus, more severe osteoarthritis (OA) resulted in better outcomes after TKA, although this association was not observed for all PROMs. The use of new PROMs, such as the New KSS, could be more reliable because of lower ceiling effects than the KOOS. Investigating the value of additional methods to assess radiographic severity (such as semi-flexed knee radiographs and MRI) is imperative to reliably identify knee OA. PMID- 29490402 TI - Return to Sports after Unicompartmental Knee Arthroplasty: Reality or Utopia? A 48-Month Follow-Up Prospective Study. AB - : Unicompartmental knee arthroplasty (UKA) has increased in popularity in the last years, also in younger and more active patients with great expectancies. The purpose of our study was to investigate the change in sports activities before and after medial UKA. We surveyed 53 athletic patients; all underwent cemented medial UKA, to determine not only their subjective and objective evaluation of clinical status with Hospital for Special Surgery (HSS) and visual analog score (VAS) score, but also their sporting and recreational activities at a mean follow up of 48 +/- 6 months (range, 18-56 months). At the last follow-up, 48 of 53 patients were engaged in sports and recreational disciplines, resulting in a return to activity rate of 90%. No early failure and no cases of revision were reported. The frequency of activities (sessions per week) and the time session remained constant at the time of survey. The most common activities after surgery were hiking, cycling, and swimming. Several high-impact activities, as well as skiing and football, had a significant decrease in participating patients. There were no gender-, age- and body mass index (BMI)-related differences. UKA can be considered a viable alternative in relatively young patients with high functional requirements and the correct indications, however, warning the patients about the risks of polyethylene wear and early loosening of the prosthetic components as a result of the resumption of sporting activities in high impact. LEVEL OF EVIDENCE: Prospective case series, level 4. PMID- 29490403 TI - Femoral Component Sizing in Oxford Unicompartmental Knee Replacement: Existing Guidelines Do Not Work for Indian Patients. AB - Oxford unicompartmental knee replacement (OUKR) has shown excellent long-term clinical outcomes as well as implant survival when used for correct indications with optimal surgical technique. Anteromedial osteoarthritis is highly prevalent in Indian patients, and OUKR is the ideal treatment option in such cases. Uncertainty prevails about the best method to determine femoral component size in OUKR. Preoperative templating has been shown to be inaccurate, while height- and gender-based guidelines based on European population might not apply to the Indian patients. Microplasty instrumentation introduced in 2012 introduced the sizing spoon, which has the dual function of femoral component sizing and determining the level of tibia cut. We aimed to check the accuracy of sizing spoon and also to determine whether the present guidelines are appropriate for use in the Indian patients. A total of 130 consecutive Oxford mobile bearing medial cemented UKR performed using the Microplasty instrumentation were included. The ideal femoral component size for each knee was recorded by looking for overhang and underhang in post-operative lateral knee radiograph. The accuracy of previous guidelines was determined by applying them to our study population. Previously published guidelines (which were based on Western population) proved to be accurate in only 37% of cases. Hence, based on the demographics of our study population, we formulated modified height- and gender based guidelines, which would better suit the Indian population. Accuracy of modified guidelines was estimated to be 74%. The overall accuracy of sizing spoon (75%), when used as an intraoperative guide, was similar to that of modified guidelines. Existing guidelines for femoral component sizing do not work in Indian patients. Modified guidelines and use of intraoperative spoon should be used to choose the optimal implant size while performing OUKR in Indian patients. PMID- 29490404 TI - A Modern Approach to Preventing Prosthetic Joint Infections. AB - Total knee arthroplasty (TKA) is recognized as one of the most successful surgical procedures performed today. One of the most common and dreaded complications of TKA is postoperative infection. To prevent infections, it is critical to identify patients at high risk through analyzing their risk factors, and help in addressing them prior to surgery. The effort to prevent infection must be carried through every step of the surgical process, from preoperative counseling to intraoperative measures and postoperative protocols. Hair removal, the application of antiseptics, the utilization of antibiotics, barbed sutures, smart dressings, and antibacterial washes are some of the avenues surgeons may explore to help prevent infection. PMID- 29490405 TI - Anterior Knee Pain in Children and Adolescents: Overview and Management. AB - Anterior knee pain (AKP) is a common presenting complaint for pediatricians and orthopaedic surgeons and is often seen in young athletes. AKP is multifactorial and has a broad differential diagnosis. The growth changes, biomechanics, and anatomy around the knee add to the complexity of diagnosis and treatment of AKP. Common causes of AKP include Osgood-Schlatter's disease, patellar tendinitis, and patellofemoral instability. In the diagnosis of AKP, it is important to rule out serious and morbid causes of pain, including infection and tumor. It is crucial to complete a detailed history and physical examination and obtain appropriate imaging studies. In general, the majority of patients will respond to nonoperative measures targeted to correct neuromuscular control and kinetic chain dysfunction. PMID- 29490406 TI - Distal Femoral Physeal Fractures. AB - Physeal fractures of the distal femoral are rare injuries accounting for less than 2% of all physeal injuries, and tend to have a worse prognosis than similar injuries in other locations. This article reviews the evaluation (including imaging), classification, and treatment of these injuries, and discusses their most important complications and their management, including vascular injury and growth arrest. PMID- 29490407 TI - Best Practices for Health Informatician Involvement in Interprofessional Health Care Teams. PMID- 29490408 TI - Nonmodal Clinical Decision Support and Antimicrobial Restriction Effects on Rates of Fluoroquinolone Use in Uncomplicated Infections. AB - BACKGROUND: Medication alert overrides remain persistently high over the past decade, influenced by factors such as "alert fatigue" and lack of provider acceptance. OBJECTIVE: We compared the aggregate rate of fluoroquinolone (FQ) prescribing for the treatment of acute sinusitis, acute bronchitis, and uncomplicated urinary tract infections (UTIs) in adult inpatients prior to (historical control group) and after (prospective intervention group) implementation of a program requiring indication when ordering FQ antibiotics in combination with a nonmodal best-practice alert regarding the latest U.S. Food and Drug Administration (FDA) recommendations. We then compared rates of prescribing among provider type, severity of infection, and patient age. METHODS: Qualified orders were defined as new FQ orders for acute sinusitis, acute bronchitis, and uncomplicated UTI for adult inpatients between July 2016 through September 2016 (control) or November 2016 through January 2017 (intervention). The primary endpoint was a provider-initiated FQ order for a target indication. Secondary endpoints included FQ orders by provider type and patient age. Rates of FQ use among the target indications were compared between groups by chi-square test of independence with Yates' correction in the analysis of the primary endpoint and Fisher's exact test for secondary endpoints. RESULTS: FQ prescribing for acute bronchitis, and uncomplicated UTI occurred at a rate of 86/350 (24.6%) and 62/394 (15.7%) in the control and experimental groups, respectively (p = 0.0035). No patients receiving FQ qualified for a diagnosis of acute sinusitis. CONCLUSION: A program combining FQ restriction in combination with nonmodal messaging may have decreased the rate of prescribing for acute bronchitis and uncomplicated UTI, although the contributions of each individual element could not be rigorously assessed. PMID- 29490409 TI - Effects of Low- and High-Dose Chemotherapy Agents on Thrombogenic Properties of Extracellular Vesicles Derived from Breast Cancer Cell Lines. AB - BACKGROUND: The involvement of extracellular vesicles (EVs) in cancer-associated thrombosis (CT) is unclear. This study aimed to explore the properties of EVs derived from breast cancer (BC) cells following exposure to high- or low-dose chemotherapeutic agents and evaluate thrombogenic effects of these EVs on endothelial cells (ECs). METHODS: EVs were isolated from BC cell lines (non metastatic MCF7, high-metastatic MDA-MB-231), pre-exposed to serum-free medium (control), with or without increasing doses of doxorubicin or paclitaxel. EV structure and size were studied using electron microscopy and Nano-sight. Antigen levels were measured by fluorescence-activated cell sorting (FACS). EV effects on EC thrombogenicity were assessed using FACS, factor Xa chromogenic assay and RT PCR. RESULTS: Serum-free medium BC cell resulted in EV shedding that additionally increased when MDA-MB-231 cells were exposed to high doses of both agents. Tissue factor (TF) levels were similarly low (9-13%) in all EVs compared with the high expression on their parental MDA-MB-231 cells (76-83%). EVs derived from MDA-MB-231 cells stimulated with high-dose doxorubicin demonstrated significantly (fivefold; p < 0.001) elevated levels of negatively charged phospholipids, a 97% decrease in TF pathway inhibitor (TFPI) levels and a sixfold increase (p < 0.001) in procoagulant activity. These EVs also enhanced EC thrombogenicity. Effects of EVs originating from MCF7 cells were less pronounced. CONCLUSION: These findings suggest that thrombogenic properties of BC-derived EVs may depend on the type and dose of the applied chemotherapy agent and may also be affected by the cell metastatic nature. PMID- 29490410 TI - Effect of Additional Treatments Combined with Conventional Therapies in Pregnant Patients with High-Risk Antiphospholipid Syndrome: A Multicentre Study. AB - The effect of additional treatments combined with conventional therapy on pregnancy outcomes was examined in high-risk primary antiphospholipid syndrome (PAPS) patients to identify the most effective treatment strategy. The study's inclusion criteria were (1) positivity to lupus anticoagulant alone or associated with anticardiolipin and/or anti-beta2 glycoprotein I antibodies; (2) a history of severe maternal-foetal complications (Group I) or a history of one or more pregnancies refractory to conventional therapy leading to unexplained foetal deaths not associated with severe maternal-foetal complications (Group II). Two different additional treatments were considered: oral-low-dose steroids (10-20 mg prednisone daily) and/or 200 to 400 mg daily doses of hydroxychloroquine and parenteral-intravenous immunoglobulins at 2 g/kg per month and/or plasma exchange. The study's primary outcomes were live birth rates and pregnancy complications. A total of 194 pregnant PAPS patients attending 20 tertiary centres were retrospectively enrolled. Hydroxychloroquine was found to be linked to a significantly higher live birth rate with respect to the other oral treatments in the Group II patients. The high (400 mg) versus low (200 mg) doses of hydroxychloroquine (p = 0.036) and its administration before versus during pregnancy (p = 0.021) were associated with a significantly higher live birth rate. Hydroxychloroquine therapy appeared particularly efficacious in the PAPS patients without previous thrombosis. Parenteral treatments were associated with a significantly higher live birth rate with respect to the oral ones (p = 0.037), particularly in the Group I patients. In conclusion, some additional treatments were found to be safe and efficacious in high-risk PAPS pregnant women. PMID- 29490411 TI - Hormonal Contraceptives and Risk of Breast Cancer: How to Explain it without Controversy. PMID- 29490412 TI - Influence of Sexual Function on the Social Relations and Quality of Life of Women with Premature Ovarian Insufficiency. AB - OBJECTIVE: To evaluate the impact of sexual function (SF) in the quality of life (QoL) of women with premature ovarian insufficiency (POI). METHODS: Case-control study in which 80 women with POI were evaluated using estrogen plus progestogen therapy, compared with 80 women matched by age (+/-2 years) and presenting preserved gonadal function. Sexual function was evaluated using the Female Sexual Function Index (FSFI), and the QoL was evaluated using the World Health Organization's (WHO) QoL assessment instrument (WHOQoL-BREF). RESULTS: The mean age of the women with POI and of the control group was 38.4 +/- 7.3 years and 38.1 +/- 7.3 years respectively. The QoL, was worse among the POI group, and there were significant differences in the physical (63.4 +/- 17.4 and 72.7 +/- 15.2 respectively, p = 0.0004) and psychological (63.2 +/- 14.6 and 69.3 +/- 13.9 respectively, p = 0.0075) domains among this group when compared with the control group. Women with POI presented significantly lower arousal, lubrication, orgasm and satisfaction, more dyspareunia and a worse FSFI scores when compared with the control group. All aspects of SF correlate directly with the worsening of the QoL regarding social relationships. CONCLUSION: Women with POI showed worse QoL and SF than the control group. The psychological aspects (desire, excitement, orgasm and sexual satisfaction) of SF had greater influence on the parameters of the QoL, while the physical aspects (pain and lubrication) had a low impact on the QoL. The poor SF in women with POI is directly correlated with a worsening across multiple domains of the QoL; however, the negative impact is particularly important in the social domain. These results suggest that the improvement in sexuality can improve the social interactions of women with POI. PMID- 29490413 TI - Modified Pereira Suture as an Effective Option to Treat Postpartum Hemorrhage due to Uterine Atony. AB - Nowadays, postpartum hemorrhage is the major cause of maternal mortality and morbidity worldwide. Uterine atony is its main cause; thus, prophylactic measures, as well as medical and surgical fast approaches, have been developed to manage it. The uterine compression sutures are a possible treatment that preserves the uterus and, consequently, the fertility potential. Bearing that in mind, we report two cases of postpartum hemorrhage after caesarean section, successfully treated with a new modification of Pereira suture - longitudinal and transverse uterine sutures were applied after no response was registered to the first-line therapies. Both women recovered, and the postpartum evaluation revealed a normal uterus with an adequate blood supply, suggesting potential fertility, as described in the literature regarding this kind of therapeutic approach. PMID- 29490414 TI - Lung cancer screening: national consensus is an important step toward implementation. AB - none. PMID- 29490415 TI - Concentration of 8-isoprostanes in the exhaled breath condensate as a marker of oxidative stress in patients with type 1 diabetes. AB - INTRODUCTION: Type 1 diabetes is an insulin deficiency-based chronic disease. It leads to the development of hyperglycaemia, which plays a key role in the initiation and progression of tissue damage in patients with diabetes. This mostly results from oxidative stress, whose increased severity is observed in this group of patients. Increased levels of 8-isoprostanes are seen in many inflammatory diseases, including asthma, COPD and cystic fibrosis. These diseases demonstrated the usefulness of the exhaled breath condensate (EBC) for extracting material for markers of oxidative stress, including 8-isoprostanes. The purpose of this study was to assess the severity of oxidative stress measured with 8 isoprostane concentrations in the exhaled breath condensate in healthy subjects and in patients with type 1 diabetes with and without vascular complications. MATERIAL AND METHODS: 33 patients assigned to the control group, type 1 diabetes without complications group and type 1 diabetes group with advanced complications were included in the study. Retinopathy, nephropathy or neuropathy have been reported as a criterion distinguishing between complicated and uncomplicated diabetes. EBC was obtained for each subject. 8-isoprostane concentrations were determined in serum and EBC by ELISA. RESULTS AND CONCLUSIONS: Mean (+/- SD) blood levels of 8-isoprostane in patients with type 1 diabetes mellitus without complications and those with type 1 diabetes with advanced complications were significantly higher compared to the control group (178.17 [135.73] vs. 183.34 [200.41] vs. 47.13 [25.20] pg/ml; p < 0.05). The mean (+/- SD) concentration of 8 isoprostane in EBC was lower in diabetic patients with type 1 diabetes with advanced complications than in patients with type 1 diabetes without advanced complications and in the control group (8.32 [4.60] vs. 19.13 [22.35] vs. 28.17 [35.11] pg/ml; p < 0.05). Measurement of 8-isoprostanes in the EBC in patients with type 1 diabetes does not appear to be a good diagnostic tool for monitoring the activity of oxidative stress in these patients. PMID- 29490416 TI - An eleven-year retrospective cross-sectional study on pulmonary alveolar proteinosis. AB - INTRODUCTION: Pulmonary alveolar proteinosis (PAP) is a rare disease in the field of pulmonary medicine. The efficacy of whole-lung lavage (WLL) as the treatment of PAP had never been evaluated in the Iranian population. Therefore, there is a real need to investigate the characteristics of PAP and also to evaluate the efficacy of WLL in this rare disease. The study aimed to investigate demographic features, clinical presentation and treatment outcomes of the disease in Iranian PAP patients. MATERIAL AND METHODS: Data of 45 patients with definite diagnosis of PAP, who had regular follow-ups from March 2004 to March 2015 at an Iranian referral respiratory hospital, were collected. Whole-lung lavages (WLL) efficacy was assessed by comparing spirometric, arterial blood gas parameters and six minute walk test (6MWT) results before and after all lavages. RESULTS: Mean age at diagnosis of disease was 30.33 +/- 14.56 years. Four patients (8.8%) reported non-massive hemoptysis and three subjects (6.6%) had concomitant pulmonary tuberculosis. In 71.1% of cases, transbronchial lung biopsy and bronchoalveolar lavage were sufficient for diagnosis. Spirometric results and arterial blood gas parameters and 6MWD improved significantly after all the lavages. Four patients (8.8%) died because of respiratory failure. The only variable capable of predicting treatment failure was the history of hemoptysis. CONCLUSION: The study revealed sufficiency of WLL as the PAP patients' treatment. Also hemoptysis was found to be the independent factor that can predict treatment failure. PMID- 29490417 TI - Is bronchoscopy always justified in diagnosis of haemoptysis? AB - INTRODUCTION: Fiber-optic bronchoscopy (FOB) is commonly performed in the first line in diagnostic process of haemoptysis. However, lots of evidences suggest that in haemoptysis FOB do not always provide additional, useful information to radiological diagnostics. Therefore, this study aimed to evaluate the validity of performing FOB as a method of choice in first line diagnostics of haemoptysis. MATERIAL AND METHODS: Data comprised consecutively collected results from patients referred for FOB assessment for clinical purposes were retrospectively analysed. We included all examinations, which were performed due to haemoptysis as the only indication, excluding any other lung-related conditions. RESULTS: 114 patients were finally included to the study. The median age was 59 (IQR: 46 64.75). Active bleeding was visualized during examination of 13 (11.4%) patients. Patients with active bleeding did not differ significantly according to age: 59 (54-69) vs 59 (45-64) years; W = 532.5, p-value = 0.27, and gender: c2 = 1.68, p value = 0.2. On the other hand, in 29 (25.44%) patients, FOB revealed no visible abnormalities. This subgroup of patients was significantly younger - 46 (34-62) years vs 60 (53-67) years; W = 782, p-value = 0.003. CONCLUSION: Low number of visualized active bleeding sites suggest overuse of bronchoscopy in diagnosis of haemoptysis. Indications for this examination should be reconsidered especially in young patients with non-massive haemoptysis. PMID- 29490418 TI - Nontuberculous mycobacterial lung disease in a patient with COPD and bronchiectasis, with radiological signs of lung tumor. AB - Mycobacterial lung disease is caused by nontuberculous mycobacteria (NTM), also known as atypical mycobacteria. NTM are widely distributed in the environment, particularly in soil and water; they may colonize the airways, gastrointestinal tract and genitourinary system, without the apparent signs of disease. Nevertheless, in some risk groups such as patients with chronic lung diseases or with immunodeficiency, mycobacterial lung disease is identified. Recently, increased recognition of mycobacterial lung disease in chronic obstructive pulmonary disease (COPD) patients has been observed, especially in those treated with high doses of inhaled corticosteroids. In the present paper, we describe the patient treated for many years due to COPD and bronchiectasis, with clinical and radiological picture suggestive of lung tumor, in whom final diagnosis of mycobacterial lung disease caused by Mycobacterium avium was made. PMID- 29490420 TI - The role of surgical resection in Unicentric Castleman's disease: a systematic review. AB - INTRODUCTION: Castleman's disease is a rare benign lymphoproliferative disorder of unknown etiology. The disease occurs in two clinical forms with different prognoses, treatments and symptoms: a unicentric form (UCD), which is solitary, localized, and a multicentric form characterized by generalized lymphadenopathy and systemic symptoms. This article aims to review the current literature to consolidate the evidence surrounding the curative potential of surgical treatment to the unicentric type. MATERIAL AND METHODS: A systematic review of English language literature was performed and databases (Medline, Pubmed, the Cochrane Database and grey literature) were searched to identify articles pertaining to the treatment of unicentric form of Castleman's disease. Each article was critiqued by two authors using a structured appraisal tool, and stratified according to the level of evidence. RESULTS: After application of inclusion criteria, 14 studies were included. There were no prospective randomized control studies identified. One meta-analysis including 278 patients with UCD reported that resective surgery is safe and should be considered the gold standard for treatment. Seven retrospective studies enhance this standpoint. Radiotherapy (RT) has been used in six studies with controversial results. CONCLUSIONS: We conclude that surgical resection appears to be the most effective treatment for Unicentric Castleman's Disease of the thoracic cavity. Radiotherapy can also achieve clinical response and cure in selected patients. PMID- 29490419 TI - Inflammatory myofibroblastic tumor of the lung. AB - Inflammatory myofibroblastic tumors (IMT) of the lung, first reported in 1939, are considered a subset of inflammatory pseudo -tumors. They are a distinctive lesions composed of myofibroblastic spindle cells accompanied by an inflammatory infiltrate of plasma cells, lymphocytes, and eosinophils. IMTs may be benign, invade surrounding structures, undergo malignant transformation, recur or may even metastasize. They can occur due to a genetic mutation or can occur secondary to infectious or autoimmune diseases. Patients may be asymptomatic, or present with cough, hemoptysis, dyspnea, pleuritic pain, constitutional symptoms or pneumonia. In this article we review the pathophysiology, genetics, clinical presentation, imaging findings of IMT of the lung. We also discuss the various surgical and non-surgical treatment options and the prognosis associated with this disease. PMID- 29490421 TI - Dry powder inhalers - between the doctor and the patient. AB - The article briefly presents currently accessible dry powder inhalers (DPI). Basing on the data from the literature, we discussed the most common mistakes related to the utilisation of DPI as well as their clinical and economic consequences. We also extensively analysed all factors that may influence the efficacy and safety of inhaler therapy of asthma and COPD, mostly with the use of DPI. In addition, we indicated the potential to improve the efficacy of inhaler therapy from the doctor and COPD or asthma patient perspective. We also presented a DPI choice algorithm including the patient's preferences and competences. PMID- 29490422 TI - Consensus statement on a screening programme for the detection of early lung cancer in Poland. AB - INTRODUCTION: Lung cancer is the most common cancer in Poland and worldwide, and the leading cause of cancer-related deaths. Compared to the present day, the annual number of new cases of lung cancer will have increased by approximately 50%, by 2030. The overall ratio of mortality to incidence totals 0.87 and is among the highest. The five-year survival rate in Poland has recently achieved 13.4%. In 2015, lung cancer screening using low-dose computed tomography (LDCT) was introduced to routine clinical practice in the United States following the publication of the largest randomised study, The National Lung Screening Trial. The implementation of screening programmes in Poland and the rest of Europe also seems unavoidable. Due to the differences, both in the socioeconomic considerations and healthcare funding, compared to that in the United States, the current approach comes down to the awaited results of the European randomised study, NELSON. MATERIAL AND METHODS: During the meeting of an expert panel at the "Torakoneptunalia 2016" conference in Jastarnia, Poland, a decision was made to summarise and publish the current data on LDCT lung cancer screening in the form of recommendations, or a position statement. The document was prepared by a team composed of a radiologist, thoracic surgeons, pulmonologists, clinical oncologists, epidemiologists, internists, health prevention specialists and pathologists. It reflects the current body of knowledge about lung cancer, its diagnosis and treatment, and provides recommendations on early detection of lung cancer using LDCT. The recommendations address the screening procedure, the requirements for the teams conducting the screening, and the requirements for radiologists, pathologists and surgeons involved in the diagnosis and treatment of patients. RESULTS: While awaiting the results of the NELSON study and the European position statement on lung cancer screening methodology, the multidisciplinary group of experts presents their position, laying grounds for the development of an action plan for early detection of lung cancer in the upcoming future in Poland. CONCLUSIONS: Primary and secondary prophylaxis are the principal ways to reduce lung cancer mortality. While smoking cessation is a task of utmost importance, it must be accompanied by an effective screening programme if the outcome of the disease is to be improved. PMID- 29490423 TI - Crystal structure of B-cell co-receptor CD19 in complex with antibody B43 reveals an unexpected fold. AB - CD19 is a transmembrane protein expressed on malignant B cells, but not in other lineages or other tissues, which makes it an attractive target for monoclonal antibody-mediated immunotherapy. Anti-CD19 antibody B43 was utilized in a bispecific T-cell engager (BiTE) blinatumomab that demonstrated potency for the treatment of relapsed acute lymphoblastic leukemia. To gain insight into the mechanism of action of the antibody, the crystal structure of B43 Fab was determined in complex with CD19 and in the unbound form. The structure revealed the binding epitope, explained the lack of cross-reactivity toward non-human species, and suggested the key-and-lock mechanism of antigen recognition. Most unexpectedly, the structure revealed a unique molecular topology of CD19. Rather than a tandem of c-type immunoglobulin folds predicted from the amino acid sequence, the extracellular domain of CD19 exhibits an elongated beta-sandwich formed by two immunoglobulin folds by swapping their C-terminal halves. This is the first structure of CD19, which has no sequence homologs. PMID- 29490424 TI - Giant coronary artery aneurysm with a coronary artery fistula to the pulmonary artery. PMID- 29490425 TI - Aspidosperma pyrifolium Mart: neuroprotective, antioxidant and anti-inflammatory effects in a Parkinson's disease model in rats. AB - OBJECTIVES: Aspidosperma species are used for several diseases, especially for malaria in Brazil. Although the genus is object of pharmacological studies, almost none are found on Aspidosperma pyrifolium. We investigate neuroprotective, antioxidant and anti-inflammatory properties of the APSE-Aq fraction (benzoic acid glycosylated derivative) on Parkinson's disease model. METHODS: Male Wistar rats were subjected to a 6-hydroxydopamine injection into the right striatum and treated or not with APSE-Aq (100 or 200 mg/kg, p.o.). The sham-operated group was injected with saline. Two weeks later, animals were subjected to behavioural, neurochemical and immunohistochemical evaluation. The data were analysed by ANOVA and Tukey test. KEY FINDINGS: The APSE-Aq-treated group shows a partial recovery of behavioural changes as compared with the untreated-6-hydroxydopamine group. A partial recovery was also observed in nitrite contents and lipid peroxidation. APSE-Aq treatments significantly reversed decreases in striatal dopamine and metabolites in the untreated 6-hydroxydopamine group. Immunostainings for markers as tyrosine hydroxylase and dopamine transporter decreased in the untreated 6 hydroxydopamine group and values recovered after APSE-Aq treatments. Similar data were seen for TNF-alpha. CONCLUSION: APSE-Aq presents neuroprotective, antioxidant and anti-inflammatory activities. Considering that APSE-Aq is chemically related to salicylic acid, it may act on similar targets. PMID- 29490427 TI - Icodextrin reduces the risk of congestive heart failure in peritoneal dialysis patients. AB - PURPOSE: Icodextrin can enhance ultrafiltration and consequently improve fluid balance and can control blood pressure and reduce left ventricular mass for peritoneal dialysis (PD) patients. This study investigated whether icodextrin use could reduce the risk of congestive heart failure (CHF) for PD patients. METHODS: From the Taiwan National Health Insurance database, we identified 5462 newly diagnosed end-stage renal disease patients undergoing PD from 2005 to 2010. Incidence rates and hazard ratio of CHF were estimated for patients with and without icodextrin treatment by the end of 2011. RESULTS: Among PD patients, icodextrin users had an overall 26% lower incidence of CHF than non-users (13.7 vs 18.6 per 1000 person-years). Relatively, the adjusted hazard ratio was 0.67 (95% CI = 0.52-0.87) for users compared with non-users. Among PD patients with diabetes, the incident CHF in icodextrin users was 37.5% lower than that in non users (17.8 vs 28.5 per 1000 person-years). Among PD patients without diabetes, the incident CHF in icodextrin users was 30.4% lower than that in non-users (11.0 vs 15.8 per 1000 person-years). CONCLUSIONS: Icodextrin solution could reduce the risk of new-onset CHF, particularly effective when diabetic PD patients use it. PMID- 29490426 TI - Demonstration of a novel Xp22.2 microdeletion as the cause of familial extreme skewing of X-inactivation utilizing case-parent trio SNP microarray analysis. AB - BACKGROUND: We report a kindred referred for molecular investigation of severe hemophilia A in a young female in which extremely skewed X-inactivation was observed in both the proband and her clinically normal mother. METHODS: Bidirectional Sanger sequencing of all F8 gene coding regions and exon/intron boundaries was undertaken. Methylation-sensitive restriction enzymes were utilized to investigate skewed X-inactivation using both a classical human androgen receptor (HUMARA) assay, and a novel method targeting differential methylation patterns in multiple informative X-chromosome SNPs. Illumina Whole Genome Infinium microarray analysis was performed in the case-parent trio (proband and both parents), and the proband's maternal grandmother. RESULTS: The proband was a cytogenetically normal female with severe hemophilia A resulting from a heterozygous F8 pathogenic variant inherited from her similarly affected father. No F8 mutation was identified in the proband's mother, however, both the proband and her mother both demonstrated completely skewed X-chromosome inactivation (100%) in association with a previously unreported 2.3 Mb deletion at Xp22.2. At least three disease-associated genes (FANCB, AP1S2, and PIGA) were contained within the deleted region. CONCLUSIONS: We hypothesize that true "extreme" skewing of X-inactivation (>=95%) is a rare occurrence, but when defined correctly there is a high probability of finding an X-chromosome disease causing variant or larger deletion resulting in X-inactivation through a survival disadvantage or cell lethal mechanism. We postulate that the 2.3 Mb Xp22.2 deletion identified in our kindred arose de novo in the proband's mother (on the grandfather's homolog), and produced extreme skewing of X-inactivation via a "cell lethal" mechanism. We introduce a novel multitarget approach for X inactivation analysis using multiple informative differentially methylated SNPs, as an alternative to the classical single locus (HUMARA) method. We propose that for females with unexplained severe phenotypic expression of an X-linked recessive disorder trio-SNP microarray should be undertaken in combination with X inactivation analysis. PMID- 29490429 TI - Phylogenetic spread of sequence data affects fitness of SOD1 consensus enzymes: Insights from sequence statistics and structural analyses. AB - Non-natural protein sequences with native-like structures and functions can be constructed successfully using consensus design. This design strategy is relatively well understood in repeat proteins with simple binding function, however detailed studies are lacking in globular enzymes. The SOD1 family is a good model for such studies due to the availability of large amount of sequence and structure data motivated by involvement of human SOD1 in the fatal motor neuron disease amyotrophic lateral sclerosis (ALS). We constructed two consensus SOD1 enzymes from multiple sequence alignments from all organisms and eukaryotic organisms. A significant difference in their catalytic activities shows that the phylogenetic spread of the sequences used affects the fitness of the construct obtained. A mutation in an electrostatic loop and overall design incompatibilities between bacterial and eukaryotic sequences were implicated in this disparity. Based on this analysis, a bioinformatics approach was used to classify mutations thought to cause familial ALS providing a unique high level view of the physical basis of disease-causing aggregation of human SOD1. PMID- 29490428 TI - DNA methylation of imprinted gene control regions in the regression of low-grade cervical lesions. AB - The role of host epigenetic mechanisms in the natural history of low-grade cervical intraepithelial neoplasia (CIN1) is not well characterized. We explored differential methylation of imprinted gene regulatory regions as predictors of the risk of CIN1 regression. A total of 164 patients with CIN1 were recruited from 10 Duke University clinics for the CIN Cohort Study. Participants had colposcopies at enrollment and up to five follow-up visits over 3 years. DNA was extracted from exfoliated cervical cells for methylation quantitation at CpG (cytosine-phosphate-guanine) sites and human papillomavirus (HPV) genotyping. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression to quantify the effect of methylation on CIN1 regression over two consecutive visits, compared to non-regression (persistent CIN1; progression to CIN2+; or CIN1 regression at a single time-point), adjusting for age, race, high risk HPV (hrHPV), parity, oral contraceptive and smoking status. Median participant age was 26.6 years (range: 21.0-64.4 years), 39% were African American, and 11% were current smokers. Most participants were hrHPV-positive at enrollment (80.5%). Over one-third of cases regressed (n = 53, 35.1%). Median time-to-regression was 12.6 months (range: 4.5-24.0 months). Probability of CIN1 regression was negatively correlated with methylation at IGF2AS CpG 5 (HR = 0.41; 95% CI = 0.23-0.77) and PEG10 DMR (HR = 0.80; 95% CI = 0.65-0.98). Altered methylation of imprinted IGF2AS and PEG10 DMRs may play a role in the natural history of CIN1. If confirmed in larger studies, further research on imprinted gene DMR methylation is warranted to determine its efficacy as a biomarker for cervical cancer screening. PMID- 29490430 TI - Valve-in-valve transcatheter aortic valve implantation with CoreValve/Evolut R(c) for degenerated small versus bigger bioprostheses. AB - OBJECTIVES: We present our single center experience with Medtronic CoreValve and Evolut R regarding procedural outcome and 3 years follow-up in patients with degenerated bioprostheses. METHODS: From 1645 patients who underwent transfemoral TAVI at our institution between February 2009 and December 2016, 37 patients with degenerated bioprosthesis were treated with Medtronic CoreValve/Evolut R. All data concerning baseline characteristic, procedural outcomes and follow-up were entered into a dedicated database. RESULTS: Mean age was 83.9 +/- 4.4 years and patients showed an average logistic EuroSCORE of 33.2 +/- 16.7%. Successful ViV deployment was achieved in all cases, a permanent pacemaker was implanted in 16.2%, no periinterventional stroke and no coronary obstruction occurred. Mortality at 30 days was 2.7%, at 1-year follow-up 5.7% and at three years 13.5%. Depending on bioprosthesis size <23 mm versus >=23 mm echocardiographic mean gradients post implantation were significantly higher in the smaller bioprostheses, 22.8 mmHg +/- 9.4 mmHg versus 15.1 +/- 7.1, P = 0.013. CONCLUSION: ViV-TAVI with CoreValve/R is demonstrated to be safe and effective in terms of no coronary obstruction and very low mortality up to 3 years despite slightly higher mean transprosthetic gradients especially in very small bioprostheses. PMID- 29490432 TI - Immigration is the most likely reason for the generational change in melanoma incidence in Queensland, Australia. PMID- 29490431 TI - Sex-based differences in bleeding and long-term adverse events after percutaneous coronary intervention in older patients with coronary artery disease. AB - OBJECTIVES: Differences in outcomes for women and men after percutaneous coronary intervention (PCI) in older patients remain controversial. Herein, we compared 2 year outcomes by sex in Chinese older patients undergoing PCI. METHODS: A total of 4926 consecutive patients (33.6% women, age >=60 years, mean age 67.4 +/- 5.7 years) who underwent PCI at a single center in China from January 2013 to December 2013 were included in this study. The primary endpoint was 2-year risk of bleeding according to the Bleeding Academic Research Consortium definitions. The secondary endpoints included 2-year risk of major adverse cardiovascular and cerebrovascular events (MACCE). Hazard ratios were generated using multivariable Cox regression. RESULTS: Compared with men, women had significantly higher rates of in-hospital all-cause mortality (0.8% vs 0.2%, P = 0.001), cardiac death (0.5% vs 0.1%, P = 0.006), MACCE (2.4% vs 1.5%, P = 0.017), and bleeding (0.4% vs 0.1%, P = 0.015). At 2-year follow up, there were no differences between men and women for all-cause mortality (1.9% vs 1.8%, P = 0.839) and 2-year MACCE (13.1% vs 11.8%, P = 0.216). However, women had a higher risk of 2-year bleeding (9.2% vs 6.2%, P < 0.001), which persisted after adjusting for baseline differences and treatment characteristics (hazard ratio 1.35, 95% confidence interval 1.06-1.71; P = 0.014). CONCLUSION: We found that older women undergoing PCI were at increased risk of 2-year bleeding compared with men. Further dedicated studies are needed to confirm these findings. PMID- 29490433 TI - In response to: Immigration is the most likely reason for the generational change in melanoma incidence in Queensland, Australia. PMID- 29490434 TI - Endothelial progenitor cells contribute to neovascularization of non-small cell lung cancer via histone deacetylase 7-mediated cytoskeleton regulation and angiogenic genes transcription. AB - To supply tumor tissues with nutrients and oxygen, endothelial progenitor cells (EPCs) home to tumor sites and contribute to neovascularization. Although the precise mechanism of EPCs-induced neovascularization remains poorly understood in non-small cell lung cancer (NSCLC), histone deacetylase 7 (HDAC7) is considered as a critical regulator. To explore the function of HDAC7 in neovascularization induced by EPCs, tube formation assay, immunofluorescence, microarray, Western blot analysis and animal models were performed. In vitro, HDAC7 abrogation led to the activation of Rho-associated coiled-coil containing protein kinase/myosin light chain 2 pathway concomitant with ERK dephosphorylation, causing the instability of cytoskeleton and collapse of tube formation. In vivo, absence of HDAC7 impaired the vascular lumen integrity and decreased the functional blood perfusion, inhibiting the growth of tumor. At the level of transcription, HDAC7 silencing upregulated antiangiogenic genes and suppressed proangiogenic genes collectively, turning off the angiogenic switch during vessel formation. Taken together, HDAC7 plays a dual role in maintaining the structural and nonstructural functions of EPCs. Our work demonstrates the molecular mechanism by which HDAC7 contributes to the angiogenic property of EPCs and provides a rational basis for specific targeting of antiangiogenic strategies in lung cancer. PMID- 29490435 TI - Active-shooter incident ends safely at VA building. PMID- 29490436 TI - AHE certification program takes infection prevention to higher level. PMID- 29490437 TI - ASHE's director stresses key strategic imperatives. PMID- 29490438 TI - 2017 Hospital Construction Survey. PMID- 29490439 TI - Designing for dignity. Strategies to improve child and adolescent behavioral health environments. PMID- 29490440 TI - PRESSURE POINTS. Planning and maintaining air isolation rooms. PMID- 29490441 TI - 'Edutainment' systems focus on patient needs. Mobility and customization aid patient education and engagement. PMID- 29490442 TI - ACHA certification stands test of time. Organization grows in tandem with health care design profession. PMID- 29490444 TI - Researchers explore ways to improve patient room cleaning. PMID- 29490443 TI - ES programs for ambulatory facilities. Six ways to ensure effective cleaning in the outpatient environment. PMID- 29490446 TI - Health system cuts energy use with help from ASHE program. PMID- 29490445 TI - Decentralized nursing units may come with unintended consequences. PMID- 29490447 TI - Medical center offers GPS app to navigate campus. PMID- 29490449 TI - Temperature monitoring keeps meds safe. PMID- 29490450 TI - 2017 VISTA AWARDS. ASHE honorees leverage cutting-edge project-delivery models and technology while putting patients first. PMID- 29490448 TI - Applying 'design thinking' to health care organizations. PMID- 29490451 TI - Designs to remember. Facility plans focus on facilitating high-quality, person centered care for a growing population with dementia. PMID- 29490452 TI - Wireless plans. Increasing dependence on technology drives health care organizations to assess current and future needs. PMID- 29490453 TI - Efficient materials management. Design and operations advice for productive supply activity. PMID- 29490454 TI - Hospital plumbing system advances. Manufactures design smart products to meet sanitary and sustainability needs. PMID- 29490455 TI - Eight workforce planning steps. Devising an effective and verifiable ES budget. PMID- 29490456 TI - Proteome-Level Analysis of Metabolism- and Stress-Related Proteins during Seed Dormancy and Germination in Gnetum parvifolium. AB - Gnetum parvifolium is a rich source of materials for traditional medicines, food, and oil, but little is known about the mechanism underlying its seed dormancy and germination. In this study, we analyzed the proteome-level changes in its seeds during germination using isobaric tags for relative and absolute quantitation. In total, 1,040 differentially expressed proteins were identified, and cluster analysis revealed the distinct time points during which signal transduction and oxidation-reduction activity changed. Gene Ontology analysis showed that "carbohydrate metabolic process" and "response to oxidative stress" were the main enriched terms. Proteins associated with starch degradation and antioxidant enzymes were important for dormancy-release, while proteins associated with energy metabolism and protein synthesis were up-regulated during germination. Moreover, protein-interaction networks were mainly associated with heat-shock proteins. Furthermore, in accord with changes in the energy metabolism- and antioxidant-related proteins, indole-3-acetic acid, Peroxidase, and soluble sugar content increased, and the starch content decreased in almost all six stages of dormancy and germination analyzed (S1-S6). The activity of superoxide dismutase, abscisic acid, and malondialdehyde content increased in the dormancy stages (S1 S3) and then decreased in the germination stages (S4-S6). Our results provide new insights into G. parvifolium seed dormancy and germination at the proteome and physiological levels, with implications for improving seed propagation. PMID- 29490457 TI - In Depth Analysis of Chiroptical Properties of Enones Derived from Abietic Acid. AB - With the use of inexpensive commercially available abietic acid, a whole series of abietane enones were prepared in high yields. The structures of all the products obtained were determined by comprehensive spectroscopic analysis with particular emphasis on the use of advanced NMR techniques, comparison with previously reported data and, where possible, by single crystal X-ray diffraction. However, in cases where X-ray crystallography was not applicable or compounds tested were unstable, a final stereochemical assignment could be inferred only by electronic circular dichroism (ECD) supported by vibrational circular dichroism to increase credibility. To reveal the relationship between structure and chiroptical properties, we used combined experimental and theoretical analysis of geometries, structural parameters, and chiroptical properties of all enones synthesized. A thorough analysis of their conformational flexibility by examining the effect of solvent and temperature on the ECD spectra was also used to achieve desired objectives. As a result, the impact of substituents adjacent to the enone chromophore on the conformation was determined by demonstrating that even slight changes in the position of hydroxyl and isopropyl groups attached to carbon C13 may substantially affect ECD curves' pattern, leading in some cases to Cotton effects sign reversal. PMID- 29490458 TI - Developing Microfluidic Sensing Devices Using 3D Printing. AB - This short perspective assesses the present landscape for desktop 3D printing to design and fabricate sensors, in particular, those associated with microfluidics and multiplexing. Lots of advanced devices have already been reported, and this article briefly surveys interesting achievements. Microfluidics can be designed and optimized faster and more easily on low cost desktop 3D printers that with competing methods. Rapid prototyping leads directly to a final (marketable) product fabricated on the same 3D printer. While resolution is not as good as lithographic approaches, very often channel and feature resolution on the order of 100 MUm obtainable with SLA 3D printers is perfectly suitable for the desired sensing device. Two examples from our team's research are used to illustrate how using a 3D printer along with simple automation can reduce a complex microfluidic sensing procedure to a much simpler automated one. Future possibilities for sensor technology are discussed. PMID- 29490459 TI - Insights into the Structure of Liquid Water from Nuclear Quantum Effects on the Density and Compressibility of Ice Polymorphs. AB - Nuclear quantum effects lead to an anomalous shift of the volume of hexagonal ice; heavy ice has a larger volume than light ice. Furthermore, this anomaly in ice increases with temperature and persists in liquid water up to the boiling point. To gain more insight, we study nuclear quantum effects on the density and compressibility of several ice-like structures and crystalline ice phases. By calculating the anisotropic contributions to the stain tensor, we analyze how the compressibility changes along different directions in hexagonal ice, and find that hexagonal ice is softer along the x- y plane than the z-direction. Furthermore, by performing ab initio density functional theory calculations with a van der Waals functional and with the quasiharmonic approximation, we find an anomalous isotope effect in the bulk modulus of hexagonal ice: heavy ice has a smaller bulk modulus than light ice. In agreement with the experiments, we also obtain an anomalous isotope effect for clathrate hydrate structure I. For the rest of the ice polymorphs, the isotope effect is (i) anomalous for ice IX, Ih, Ic, clathrate, and low density liquid-like (LDL-like) amorphous ice; (ii) normal at T = 0 K and becomes anomalous with increasing temperature for ice IX, II, high density liquid-like (HDL-like) amorphous ices, and ice XV; and (iii) normal for ice VIII up to the melting point. There is a transition from an anomalous isotope effect to a normal isotope effect for both the volume and bulk modulus, as the density (compressibility) of the structures increases (decreases). This result can explain the anomalous isotope effect in liquid water: as the compressibility decreases from the melting point to the compressibility minimum temperature, the difference between the volumes of the heavy and light water rapidly decreases, but the effect stays anomalous up to the boiling temperature as the hydrogen bond network is never completely broken by fully filling all of the interstitial sites. PMID- 29490460 TI - Lab-on-a-Valve Mesofluidic Platform for On-Chip Handling of Carbon-Coated Titanium Dioxide Nanotubes in a Disposable Microsolid Phase-Extraction Mode. AB - Mesofluidic lab-on-a-valve (LOV) platforms have been proven suitable to accommodate automatic micro-solid-phase extraction (MUSPE) approaches with on chip handling of micrometer-bead materials in a fully disposable mode to prevent sample cross-contamination and pressure-drop effects. The efficiency of the extraction process notably depends upon the sorptive capacity of the material because the sorbent mass is usually down to 10 mg in LOV devices. Nanomaterials, capitalizing upon their enhanced surface-to-volume ratio and diversity of potential chemical moieties, are appealing alternatives to microbead sorbents. However, the handling and confinement of nanomaterials in fluidic chip structures have been challenging to date. This is most likely a consequence of the aggregation tendency of a number of nanomaterials, including carbon-based sorbents, that leads to excessive back-pressure in flowing systems along with irreproducible bead loading. This paper addresses these challenges by ad hoc synthesis of hybrid nanomaterials, such as porous carbon-coated titanium dioxide nanotubes (TiO2-NT@pC). Tailoring of the surface polarity of the carbon coating is proven to foster the dispersion of TiO2-NT@pC in LOV settings while affording superior extraction capability of moderately nonpolar species from aqueous matrices. The determination of trace-level concentrations of butylparaben (BPB) and triclosan (TCS) in seawater samples is herein selected as a proof-of-concept of the exploitation of disposable nanomaterials in LOV. The mesofluidic platform accommodating MUSPE features online hyphenation to liquid chromatography/tandem mass spectrometry (LC/MS/MS) for reliable determination of the target analytes with excellent limits of detection (0.5 and 0.6 ng/L for BPB and TCS, respectively) and intermediate precision (relative standard deviation <5.8%). For 5.0 mL of sample and 200 MUL of eluent, enrichment factors of 23 and 14 with absolute extraction efficiencies of 90% +/- 14% and 58 +/- 8% for BPB and TCS, respectively, were obtained. The relative recovery values of 107% (BPB) and 97% (TCS) in seawater demonstrate the applicability of online LOV-LC/MS/MS using TiO2 NT@pC for handling troublesome environmental samples. PMID- 29490462 TI - Virtual Issue Highlighting Articles That Describe New Methodologies Soon To Be Considered for Publication in JPC. PMID- 29490461 TI - Borylene Insertion into Cage B-H Bond: A Route to Electron-Precise B-B Single Bond. AB - A new strategy to construct electron-precise B-B single bond via direct borylene insertion into B-H bond is described. Reduction of bromoborylene stabilized by carborane-fused silylenes with 2 equiv of sodium gives a new compound with a B-B single bond. Both experimental and density functional theory results suggest that such an electron-precise B-B single bond is formed via in situ generated borylene insertion into B-H bond. PMID- 29490463 TI - Spotlights: Volume 9, Issue 5. PMID- 29490464 TI - High resolution imaging and 3D analysis of Ag nanoparticles in cells with ToF SIMS and delayed extraction. AB - Within this study, the authors use human mesenchymal stem cells incubated with silver nanoparticles (AgNPs) as a model system to systematically investigate the advantages and drawbacks of the fast imaging delayed extraction mode for two dimensional and three-dimensional (3D) analyses at the cellular level. The authors compare the delayed extraction mode with commonly employed measurement modes in terms of mass and lateral resolution, intensity, and dose density. Using the delayed extraction mode for single cell analysis, a high mass resolution up to 4000 at m/z = 184.08 combined with a lateral resolution up to 360 nm is achieved. Furthermore, the authors perform 3D analyses with Ar-clusters (10 keV) and O2+ (500 eV) as sputter species, combined with Bi3+ and delayed extraction for analysis. Cell compartments like the nucleus are visualized in 3D, whereas no realistic 3D reconstruction of intracellular AgNP is possible due to the different sputter rates of inorganic and organic cell materials. Furthermore, the authors show that the sputter yield of Ag increases with the decreasing Ar cluster size, which might be an approach to converge the different sputter rates. PMID- 29490465 TI - Radiation exposure during TACE procedures using additional cone-beam CT (CBCT) for guidance: safety and precautions. AB - Background During transarterial chemoembolization (TACE), cone-beam computed tomography (CBCT) can be used for tumor and feeding vessel detection as well as postembolization CT imaging. However, there will be additional radiation exposure from CBCT. Purpose To evaluate the additional dose raised through CBCT-assisted guidance in comparison to TACE procedures guided with pulsed digital subtraction angiography (DSA) alone. Material and Methods In 70 of 140 consecutive patients undergoing TACE for liver cancer, CBCT was used to facilitate the TACE. Cumulative dose area product (DAP), cumulative kerma(air), DAP values of DSA, total and cine specific fluoroscopy times (FT) of 1375 DSA runs, and DAP of 91 CBCTs were recorded and analyzed using Spearman's correlation, Mann-Whitney U test, and Kruskal-Wallis test. P values < 0.05 were considered significant. Results Additional CBCT increased DAP by 2% ( P = 0.737), kerma(air) by 24.6% ( P = 0.206), and FT by 0.02% ( P = 0.453). Subgroup analysis revealed that postembolization CBCT for detection of ethiodized oil deposits added more DAP to the procedure. Performing CBCT-assisted TACE, DSA until first CBCT contributed about 38% to the total DAP. Guidance CBCT acquisitions conduced to 6% of the procedure's DAP. Additional DSA for guidance after CBCT acquisition required approximately 46% of the mean DAP. The last DSA run for documentation purposes contributed about 10% of the DAP. Conclusion CBCT adds radiation exposure in TACE. However, the capability of CBCT to detect vessels and overlay in real-time during fluoroscopy facilitates TACE with resultant reduction of DAPs up to 46%. PMID- 29490466 TI - Differences Between Moderate to Severely Cognitively Impaired Fallers Versus Nonfallers in Nursing Homes. AB - INTRODUCTION: The purpose of this study was to test differences in psychotropic medication, function, physical activity, agitation, resistiveness to care, comorbidities, and depression among moderate to severely cognitively impaired nursing home residents who were fallers versus nonfallers. METHODS: This was a secondary data analysis using baseline data from a randomized controlled trial testing the Function and Behavior Focused Care intervention across 12 nursing homes. The sample included 336 older adults, the majority of whom were female and white. RESULTS: There was a significant difference in the total number of comorbidities, agitation, the total number of psychotropic medications, depressive symptoms, and physical activity between those who fell and those who did not fall (Pillai-Bartlett trace = 4.91; P < .001). DISCUSSION: Findings support prior work except with regard to medication use, cognition, and function. Due to inconsistent findings, additional research is recommended particularly with regard to the use of specific drug groups and medications. PMID- 29490468 TI - Pathways to Retention in HIV Care Among U.S. Veterans. AB - Retaining HIV patients in clinical care is a critical component of the HIV care continuum, impacting not only patients' virologic suppression, but their overall health and wellbeing. Understanding reasons for patient drop-out is therefore important to improve HIV outcomes and reduce transmission. This study used qualitative in-depth interviews with patients who dropped out of HIV care (n = 16) from the Atlanta Veterans Affairs Medical Center, to explore their reasons for drop-out and how they negotiate barriers to return to care. Results show three interlinked "pathways" leading to patient drop-out -wellness, illness, and medication pathways. These pathways encompass both barriers to retention and triggers to resume clinic visits, with patients following different pathways at different times in their lives. Perhaps the strongest deterrent to continuing clinic visits was participants' self-perception of wellness, which often outweighed clinical indicators of wellness. These pathways suggest that multiple approaches are needed to improve treatment retention, including reducing clinic based barriers, addressing basic needs that are barriers to clinic visits, and empowering patients to view clinic visits as a facilitator to maintaining their overall health rather than only a reaction to illness. PMID- 29490467 TI - The association between discrimination and PTSD in African Americans: exploring the role of gender. AB - BACKGROUND: Research has demonstrated the adverse impact that discrimination has on physical and mental health. However, few studies have examined the association between discrimination and symptoms of posttraumatic stress disorder (PTSD). There is evidence that African Americans experience higher rates of PTSD and are more likely to develop PTSD following trauma exposure than Whites, and discrimination may be one reason for this disparity. PURPOSE: To examine the association between discrimination and PTSD among a cross-sectional sample largely comprising African American women, controlling for other psychosocial stressors (psychological distress, neighborhood safety, crime). METHODS: A sample of 806 participants was recruited from two low-income predominantly African American neighborhoods. Participants completed self-report measures of PTSD symptoms, perceived discrimination, perceived safety, and psychological distress. Information on neighborhood crime was obtained through data requested from the city. Multivariate linear regression models were estimated to assess adjusted relationships between PTSD symptoms and discrimination. RESULTS: Discrimination was significantly associated with PTSD symptoms with a small effect size, controlling for relevant sociodemographic variables. This association remained consistent after controlling for psychological distress, perceived safety, and total neighborhood crime. There was no evidence of a gender by discrimination interaction. Participants who experienced any discrimination were significantly more likely to screen positive for PTSD. CONCLUSIONS: Discrimination may contribute to the disparate rates of PTSD experienced by African Americans. PTSD is associated with a range of negative consequences, including poorer physical health, mental health, and quality of life. These results suggest the importance of finding ways to promote resilience in this at-risk population. PMID- 29490470 TI - Who Are the Turkers? A Characterization of MTurk Workers Using the Personality Assessment Inventory. AB - As online data collection services such as Amazon's Mechanical Turk (MTurk) gain popularity, the quality and representativeness of such data sources have gained research attention. To date, the majority of existing studies have compared MTurk workers with undergraduate samples, localized community samples, or other Internet-based samples, and thus, there remains little known about the personality and mental health constructs of MTurk workers relative to a national representative sample. The present study addresses these limitations and broadens the scope of existing research through the use of the Personality Assessment Inventory, a multiscale, self-report questionnaire which provides information regarding data validity and personality and psychopathology features standardized against a national U.S. census-matched normative sample. Results indicate that MTurk workers generally provide high-quality data and are reasonably representative of the general population across most psychological dimensions assessed. However, several distinguishing features of MTurk workers emerged that were consistent with prior findings of such individuals, primarily involving somewhat higher negative affect and lower social engagement. PMID- 29490469 TI - Vitamin D3 supplementation in adults with bronchiectasis: A pilot study. AB - Vitamin D supplementation prevents acute respiratory infections and, through modulating innate and adaptive immunity, could have a potential role in bronchiectasis management. The primary aims of this pilot study were to assess serum 25-hydroxyvitamin D (25(OH)D) levels in New Zealand adults with bronchiectasis, and their 25(OH)D levels after vitamin D3 supplementation. Adults with bronchiectasis received an initial 2.5 mg vitamin D3 oral loading dose and 0.625 mg vitamin D3 weekly for 24 weeks. The primary outcome was serum 25(OH)D levels before and after vitamin D3 supplementation. Secondary outcomes (time to first infective exacerbation, exacerbation frequency, spirometry, health-related quality of life measures, sputum bacteriology and cell counts and chronic rhinosinusitis) were also assessed. This study is registered with the Australian New Zealand Clinical Trials Registry (ACTRN 12612001222831). The initial, average 25(OH)D level was 71 nmol/L (95% confidence interval (CI): [58, 84]), rising to 218 nmol/L (95% CI: [199, 237]) at 12 weeks and 205 nmol/L (95% CI: [186, 224]) at 24 weeks. The initial serum cathelicidin level was 25 nmol/L (95% CI: [17, 33]), rising to 102 nmol/L (95% CI: [48, 156]) at 12 weeks and 151 nmol/L (95% CI: [97, 205]) at 24 weeks. Over the 24-week study period, we observed statistically significant changes of 1.11 (95% CI: [0.08, 2.14]) in the Leicester Cough Questionnaire and -1.97 (95% CI: [-3.71, -0.23]) in the Dartmouth COOP charts score. No significant adverse effects were recorded. Many New Zealand adults with bronchiectasis have adequate 25(OH)D levels. Weekly vitamin D3 supplementation significantly improved 25(OH)D levels. PMID- 29490471 TI - A Systematic Review of Placental Biomarkers Predicting Small-for-Gestational-Age Neonates. AB - BACKGROUND: Neonates born small for gestational age (SGA) face increased risk of neonatal mortality, childhood developmental problems, and adult disease. The placenta is a key factor in SGA development because of its multiple biological processes that underlie fetal growth. However, valid and reliable placental biomarkers of SGA have not been determined. OBJECTIVES: The objective of this article was to systematically identify and review studies examining associations between placental biomarkers and SGA and assess those biomarkers' predictive value. METHODS: Use of the matrix method and the PRISMA guidelines ensured systematic identification of relevant articles based on selection criteria. PubMed, CINAHL, and EMBASE were searched for English articles published in 2005 2016 that addressed relationships between placental biomarkers and SGA. RESULTS: The search captured 466 articles; 13 met selection criteria. The review identified 14 potential placental biomarkers for SGA, with placental growth factor and soluble fms-like tyrosine kinase 1 being the most commonly studied. However, findings for these and other biomarkers have often been contradictory. Thus, no placental biomarkers have been confirmed as reliable for predicting SGA. CONCLUSION: The inconsistent findings suggest low placental biomarker reliability, perhaps due to the multifactorial nature of SGA. This review is novel in its focus on identifying potential placental biomarkers for SGA, producing a better understanding of how placental function underlies fetal growth. Nevertheless, use of placental biomarkers alone may not be adequate for predicting SGA. Therefore, combinations of biomarkers and other predictive tests should be evaluated for their ability to predict risk of SGA. PMID- 29490472 TI - Comparison of Hair Cortisol Levels and Perceived Stress in Mothers Who Deliver at Preterm and Term. AB - OBJECTIVE: To evaluate relationships between hair cortisol levels and perceived stress in mothers who deliver preterm and term. We hypothesized that the rate of change in cortisol levels would be greater in the preterm delivery group. METHODS: This preliminary study compared hair cortisol levels and Perceived Stress Scale (PSS) scores in predominately Caucasian mothers who delivered preterm ( n = 22) and term ( n = 30). We collected PSS and hair samples of >=10 cm in length from mothers after delivery. Hair was segmented into three sections, and cortisol was measured using enzyme-linked immunosorbent assay. RESULTS: The mean gestational age was 31.45 ( SD = 4.2) weeks for preterm deliveries and 39.45 ( SD = 1.1) for term. Cortisol differed significantly in the third trimester between mothers delivering term and preterm ( t = 2.16, df = 48, p = .04) and trended toward significance in the second trimester ( t = 1.88, df = 48, p = .06). PSS differed significantly between the two groups ( t = -2.96, df = 50, p = .05). Our data did not provide support for our hypothesis. CONCLUSION: There appeared to be a blunted, flattened pattern of change in cortisol levels across gestation in the women who delivered preterm, suggesting diminished hypothalamic pituitary-adrenal axis responsiveness in mechanisms that promote preterm labor. Future studies are needed to further evaluate best strategies for measuring the mechanisms of allostatic load during pregnancy along with the psychoneuroendocrine and immune triggers and placental responses that lead to premature birth. PMID- 29490473 TI - Mental Disorder, Psychological Distress, and Functional Status in Canadian Military Personnel. AB - OBJECTIVE: We examined the overlap between mood and anxiety disorders and psychological distress and their associations with functional status in Canadian Armed Forces (CAF) personnel. METHOD: Data on Regular Forces personnel ( N = 6700) were derived from the 2013 Canadian Forces Mental Health Survey, a nationally representative survey of the CAF personnel. Current psychological distress was assessed using the Kessler K10 scale. Past-month mood and anxiety disorders were assessed using the World Health Organization World Mental Health Composite Diagnostic Interview. RESULTS: The prevalence of psychological distress was the same as that of any past-month mood or anxiety disorder (7.1% for each). A total of 3.8% had both distress and past-month mood or anxiety disorder, 3.3% had past-month disorder without psychological distress, while another 3.3% had psychological distress in the absence of a past-month mood or anxiety disorder. After adjusting for age, sex, marital, education, income, language, element, rank, and alcohol use disorder, individuals with both psychological distress and past-month mood and anxiety disorders exhibited the highest levels of disability, days out of role, and work absenteeism relative to those with neither mental disorders nor psychological distress. Relative to individuals with both disorder and distress, those who endured distress in the absence of mental disorder exhibited lower, but meaningful, levels of disability compared with those with neither disorder nor distress. CONCLUSIONS: Disability is most severe among CAF personnel with both distress and past-month mood and anxiety disorders. Nevertheless, distress in the absence of disorder is prevalent and is associated with meaningful levels of disability. PMID- 29490474 TI - Mental Health Screening and Differences in Access to Care among Prisoners. AB - OBJECTIVE: Disparities in mental health care exist between regional and demographic groups. While screening is recommended as part of a correctional mental health strategy, little work has been done to explore whether it can narrow regional and demographic disparities in access to care. We compared treatment access rates by sex, race, age, and region in relation to screening results. METHODS: We conducted a retrospective cohort study using administrative data. All 7965 admissions to the prison system were followed for a median of 14 months. RESULTS: Males and non-Indigenous minority racial groups had lower rates of treatment regardless of screening results; they were less likely both to self report needs and to receive treatment if these needs were reported. Regional differences revealed higher treatment rates in Atlantic Canada and Ontario, as well as higher rates of inmates self-reporting needs on screening who did not receive treatment in the Atlantic, Quebec, and Pacific regions. There were minimal differences between inmates of different age groups. CONCLUSIONS: Findings suggest potential resource gaps and/or differences in the performance of screening to detect mental health needs across demographic and regional groups. Screening did not narrow, and may have widened, differences between groups. PMID- 29490476 TI - Psychosocial predictors in the transition from acute to chronic pain: a systematic review. AB - Chronic non-cancer pain (CNCP) is a major health problem which psychosocial factors have significant implications in. There is a gap in regards to evidence for the prevention of chronicity specifically addressing psychological and social domains. Four databases were searched with terms related to "psychosocial", "acute pain", and "chronic pain". A total of 1,389 studies were identified in which titles, abstracts, and full texts were assessed for inclusion criteria. A data template was used to capture pertinent details, and overall themes and patterns were organized according to type of pain examined and psychosocial variables measured. Of the 18 articles that met inclusion criteria, fifteen (83%) of the articles reported an association between psychosocial factors and chronicity. A total of 5 of the studies (29%) demonstrated that depression was a possible predictor and 6 (35%) of the studies found fear-avoidance to be associated with chronicity. This review provides evidence that psychosocial factors are associated with chronicity within CNCP. These results suggest a need for targeting psychosocial predictors in prevention and early intervention through clinical guidelines and a national strategy to support a cultural change in pain care. PMID- 29490477 TI - Hypertrophic Cardiomyopathy: A Vicious Cycle Triggered by Sarcomere Mutations and Secondary Disease Hits. AB - SIGNIFICANCE: Hypertrophic cardiomyopathy (HCM) is a cardiac genetic disease characterized by left ventricular hypertrophy, diastolic dysfunction, and myocardial disarray. Disease onset occurs between 20 and 50 years of age, thus affecting patients in the prime of their life. HCM is caused by mutations in sarcomere proteins, the contractile building blocks of the heart. Despite increased knowledge of causal mutations, the exact path from genetic defect leading to cardiomyopathy is complex and involves additional disease hits. Recent Advances: Laboratory-based studies indicate that HCM development not only depends on the primary sarcomere impairment caused by the mutation but also on secondary disease-related alterations in the heart. Here we propose a vicious mutation induced disease cycle, in which a mutation-induced energy depletion alters cellular metabolism with increased mitochondrial work, which triggers secondary disease modifiers that will worsen disease and ultimately lead to end-stage HCM. CRITICAL ISSUES: Evidence shows excessive cellular reactive oxygen species (ROS) in HCM patients and HCM animal models. Oxidative stress markers are increased in the heart (oxidized proteins, DNA, and lipids) and serum of HCM patients. In addition, increased mitochondrial ROS production and changes in endogenous antioxidants are reported in HCM. Mutant sarcomeric protein may drive excessive levels of cardiac ROS via changes in cardiac efficiency and metabolism, mitochondrial activation and/or dysfunction, impaired protein quality control, and microvascular dysfunction. FUTURE DIRECTIONS: Interventions restoring metabolism, mitochondrial function, and improved ROS balance may be promising therapeutic approaches. We discuss the effects of current HCM pharmacological therapies and potential future therapies to prevent and reverse HCM. Antioxid. Redox Signal. 00, 000-000. PMID- 29490478 TI - Validation of the Acoustic Voice Quality Index Version 03.01 and the Acoustic Breathiness Index in the Spanish language. AB - OBJECTIVE: The aim of this study was to validate the Acoustic Voice Quality Index 03.01 (AVQIv3) and the Acoustic Breathiness Index (ABI) in the Spanish language. METHOD: Concatenated voice samples of continuous speech (cs) and sustained vowel (sv) from 136 subjects with dysphonia and 47 vocally healthy subjects were perceptually judged for overall voice quality and breathiness severity. First, to reach a higher level of ecological validity, the proportions of cs and sv were equalized regarding the time length of 3 seconds sv part and voiced cs part, respectively. Second, concurrent validity and diagnostic accuracy were verified. RESULTS: A moderate reliability of overall voice quality and breathiness severity from 5 experts was used. It was found that 33 syllables as standardization of the cs part, which represents 3 seconds of voiced cs, allows the equalization of both speech tasks. A strong correlation was revealed between AVQIv3 and overall voice quality and ABI and perceived breathiness severity. Additionally, the best diagnostic outcome was identified at a threshold of 2.28 and 3.40 for AVQIv3 and ABI, respectively. CONCLUSIONS: The AVQIv3 and ABI showed in the Spanish language valid and robust results to quantify abnormal voice qualities regarding overall voice quality and breathiness severity. PMID- 29490479 TI - The contribution of internet use in personal networks of support for long-term condition self-management. AB - Objectives To describe the individual and network characteristics of the personal communities of people using the internet and the role of offline support, network resources and community participation in using the internet for condition management. Methods Secondary analysis of survey data using logistic regression analysis to determine the factors associated with differential internet use for condition management. This study involved 300 participants from 19 primary care providers in Manchester in 2010 and 2011. Results Using the internet is associated with age, deprivation, education and having access to a personal network member who understands how to fix computer problems. Those using the internet for condition management received more offline emotional work. No associations were found between using the internet for health and other types of offline support. Those using the internet for support reported lower levels of happiness. Conclusion Network processes and engagement shape online contact and use of resources for condition management. Those with access to personal networks who provide emotional work are likely to make use of online resources during non crisis situations, suggesting that these resources act as an extension of offline network support. Those with greater levels of unhappiness may more frequently look to the internet for support. PMID- 29490481 TI - Drawing the answers: Sketching to support free and probed recall by child witnesses and victims with autism spectrum disorder. AB - The success of witness interviews in the criminal justice system depends on the accuracy of information obtained, which is a function of both amount and quality of information. Attempts to enhance witness retrieval such as mental reinstatement of context have been designed with typically developed adults in mind. In this article, the relative benefits of mental and sketch reinstatement mnemonics are explored with both typically developing children and children with autism. Children watched a crime event video, and their retrieval of event information was examined in free and probed recall phases of a cognitive interview. As expected, typically developing children recalled more correct information of all types than children with autism during free and probed recall phases. Sketching during free recall was more beneficial for both groups in both phases in reducing the amount of incorrect items, but the relative effect of sketching on enhancing retrieval accuracy was greater for children with autism. The results indicate the benefits of choosing retrieval mnemonics that are sensitive to the specific impairments of autistic individuals and suggest that retrieval accuracy during interviews can be enhanced, in some cases to the same level as that of typically developing individuals. PMID- 29490480 TI - What about the men? Gender parity in occupational therapy: Qu'en est-il des hommes? La parite hommes-femmes en ergotherapie. AB - BACKGROUND: Gender parity is frequently raised as an equity issue in occupational therapy, with strategies proposed to recruit more men. PURPOSE: This article explores whether this is a legitimate equity concern. KEY ISSUES: Most employment is gender segregated; when gender balances change, the field either re-genders feminine or creates gender-segregated internal divisions. Men avoid feminized jobs because they pay less and hold less social status. They are a "step down" for men. In such jobs, men are disproportionately pushed into management positions, with better pay, more prestige, and less hands-on care. Equity issues concern structural barriers to success in particular employment fields. Though they may feel discomfort in a feminized field, men do not face structural barriers in occupational therapy. IMPLICATIONS: Broader challenges to traditional gender norms are needed, but there is no evidence that gender parity is an equity concern or that recruitment targeting masculinity would make a difference. PMID- 29490482 TI - Drawing links between the autism cognitive profile and imagination: Executive function and processing bias in imaginative drawings by children with and without autism. AB - Little is known about the relation between cognitive processes and imagination and whether this relation differs between neurotypically developing children and children with autism. To address this issue, we administered a cognitive task battery and Karmiloff-Smith's drawing task, which requires children to draw imaginative people and houses. For children with autism, executive function significantly predicted imaginative drawing. In neurotypically developing controls, executive function and cognitive-perceptual processing style predicted imaginative drawing, but these associations were moderated by mental age. In younger (neurotypically developing) children, better executive function and a local processing bias were associated with imagination; in older children, only a global bias was associated with imagination. These findings suggest that (a) with development there are changes in the type of cognitive processes involved in imagination and (b) children with autism employ a unique cognitive strategy in imaginative drawing. PMID- 29490483 TI - Meta-analysis of parent-mediated interventions for young children with autism spectrum disorder. AB - A number of studies of parent-mediated interventions in autism spectrum disorder have been published in the last 15 years. We reviewed 19 randomized clinical trials of parent-mediated interventions for children with autism spectrum disorder between the ages of 1 and 6 years and conducted a meta-analysis on their efficacy. Meta-analysis outcomes were autism spectrum disorder symptom severity, socialization, communication-language, and cognition. Quality of evidence was rated as moderate for autism spectrum disorder symptom severity, communication language, and cognition, and very low for socialization. Weighted Hedges' g varied from 0.18 (communication-language) to 0.27 (socialization) and averaged 0.23 across domains. We also examined the relationship between outcome and dose of parent training, type of control group, and type of informant (parent and clinician). Outcomes were not significantly different based on dose of treatment. Comparing parent training to treatment-as-usual did not result in significantly different treatment effects than when parent training was compared to an active comparison group. Based on parent report only, treatment effects were significant for communication-language and non-significant for socialization, yet the opposite was found based on clinician-rated tools. This meta-analysis suggests that while most outcome domains of parent-delivered intervention are associated with small effects, the quality of research is improving. PMID- 29490484 TI - Different aberrant mentalizing networks in males and females with autism spectrum disorders: Evidence from resting-state functional magnetic resonance imaging. AB - Previous studies have found that individuals with autism spectrum disorders show impairments in mentalizing processes and aberrant brain activity compared with typically developing participants. However, the findings are mainly from male participants and the aberrant effects in autism spectrum disorder females and sex differences are still unclear. To address these issues, this study analyzed intrinsic functional connectivity of mentalizing regions using resting-state functional magnetic resonance imaging data of 48 autism spectrum disorder males and females and 48 typically developing participants in autism brain imaging data exchange. Whole-brain analyses showed that autism spectrum disorder males had hyperconnectivity in functional connectivity of the bilateral temporal-parietal junction, whereas autism spectrum disorder females showed hypoconnectivity in functional connectivity of the medial prefrontal cortex, precuneus, and right temporal-parietal junction. Interaction between sex and autism was found in both short- and long-distance functional connectivity effects, confirming that autism spectrum disorder males showed overconnectivity, while autism spectrum disorder females showed underconnectivity. Furthermore, a regression analysis revealed that in autism spectrum disorder, males and females demonstrated different relations between the functional connectivity effects of the mentalizing regions and the core autism spectrum disorder deficits. These results suggest sex differences in the mentalizing network in autism spectrum disorder individuals. Future work is needed to examine how sex interacts with other factors such as age and the sex differences during mentalizing task performance. PMID- 29490485 TI - Saccadic eye movements in adults with high-functioning autism spectrum disorder. AB - In this study, we examined the accuracy and dynamics of visually guided saccades in 20 adults with autism spectrum disorder, as compared to 20 typically developed adults using the Step/Overlap/Gap paradigms. Performances in participants with autistic spectrum disorder were characterized by preserved Gap/Overlap effect, but reduced gain and peak velocity, as well as a greater trial-to-trial variability in task performance, as compared to the control group. While visual orienting and attentional engagement were relatively preserved in individuals with autistic spectrum disorder, overall these findings provide evidence that abnormal oculomotor behavior in autistic spectrum disorder reflects an altered sensorimotor control due to cerebellar abnormalities, rather than a deficit in the volitional control of eye movements. This study contributes to a growing body of evidence implicating this structure in the physiopathology of autism. PMID- 29490486 TI - Eye-tracking study on facial emotion recognition tasks in individuals with high functioning autism spectrum disorders. AB - The eye-tracking experiment was carried out to assess fixation duration and scan paths that individuals with and without high-functioning autism spectrum disorders employed when identifying simple and complex emotions. Participants viewed human photos of facial expressions and decided on the identification of emotion, the negative-positive emotion orientation, and the degree of emotion intensity. Results showed that there was an atypical emotional processing in the high-functioning autism spectrum disorder group to identify facial emotions when eye-tracking data were compared between groups. We suggest that the high functioning autism spectrum disorder group prefers to use a rule-bound categorical approach as well as featured processing strategy in the facial emotion recognition tasks. Therefore, the high-functioning autism spectrum disorder group more readily distinguishes overt emotions such as happiness and sadness. However, they perform more inconsistently in covert emotions such as disgust and angry, which demand more cognitive strategy employment during emotional perception. Their fixation time in eye-tracking data demonstrated a significant difference from that of their controls when judging complex emotions, showing reduced "in" gazes and increased "out" gazes. The data were in compliance with the findings in their emotion intensity ratings which showed individuals with autism spectrum disorder misjudge the intensity of complex emotions especially the emotion of fear. PMID- 29490487 TI - Relationship between the broad autism phenotype, social relationships and mental health for mothers of children with autism spectrum disorder. AB - This study aimed to examine the mechanisms responsible for the association between the broad autism phenotype and depressive symptoms in mothers of a child with autism spectrum disorder. A total of 98 mothers who had a child with autism spectrum disorder between the ages of 2 and 16 years completed assessments of maternal broad autism phenotype, child behavior problems, romantic relationship satisfaction, friend support, family support, and maternal depressive symptoms. Results indicated that only romantic relationship satisfaction was a significant mediator of the relationship between maternal broad autism phenotype social abnormalities and maternal depressive symptoms, where greater broad autism phenotype social abnormalities were associated with lower relationship satisfaction, which in turn was associated with increased depressive symptoms. Child behavior problems were directly related to increased depressive symptoms. Implications regarding maternal mental health outcomes within this population as well as intervention implications are discussed. PMID- 29490488 TI - HeartBeat. PMID- 29490489 TI - Cannabidiol, an Adjunct Player in the Antipsychosis Arsenal. PMID- 29490490 TI - Suicide Rates, Psychiatric Hospital Bed Numbers, and Unemployment Rates From 1999 to 2015: A Population-Based Study in Hong Kong. PMID- 29490492 TI - Understanding Pregnancy's Protective Effect on Drug Use Within a Developmental Framework. PMID- 29490494 TI - A Geriatrics Perspective on Dementia Prevention and Treatment. PMID- 29490495 TI - Internet-Based Psychotherapy: How Far Can We Go? PMID- 29490496 TI - Corticotropin-Releasing Hormone Binding Protein: Stress, Psychopathology, and Antidepressant Treatment Response. PMID- 29490498 TI - Medical Marijuana and the Opioid Epidemic: Response to Theriault and Schlesinger. PMID- 29490499 TI - Potential Impact of Medical Marijuana on Nonmedical Opioid Use. PMID- 29490500 TI - The Mental Health Mission Aboard the USNS Comfort During Humanitarian Operations in Puerto Rico. PMID- 29490501 TI - Therapeutic Potential of Physical Exercise in Early Psychosis. PMID- 29490502 TI - Augmentation of therapeutic potential of curcumin using nanotechnology: current perspectives. AB - Curcumin, an active principle of Curcuma longa, is extracted from the rhizome. Its therapeutic efficiency has been proved using various in vitro and in vivo models. Inflammatory, neoplastic and preneoplastic diseases are the major targets using curcumin as therapeutic agent. Feasible clinical formulations could not be obtained because of its lack of solubility, stability and higher degradation rate. Recently, many techniques have been evolved to improve the physicochemical properties of pharmacological compounds, thereby increasing their biological activity. Curcumin has been developed using various techniques, particularly micro and nanotechnology to improve its stability and bioavailability. This review focuses on the studies pertaining to the delivery of curcumin in the form of micro and nanosize formulations for the treatment of a variety of diseases. PMID- 29490503 TI - Characterization of the c9orf72 GC-rich low complexity sequence in two cohorts of Italian and Turkish ALS cases. AB - Large expansions of a noncoding GGGGCC repeat in the C9orf72 gene are the main cause of amyotrophic lateral sclerosis (ALS). The GGGGCC repeat is contiguous with another GC-rich region. Recent studies reported a significantly higher frequency of insertions/deletions within the GC-rich region in patients carrying the GGGGCC expansion. A GTGGT motif comprised within the GC-rich region, which joins two 100% GC sequences, was frequently deleted, supporting the hypothesis that these deletions could make the region more prone to slippage and pathological expansion. To confirm this hypothesis, we sequenced the GC-rich region adjacent the GGGGCC repeat in ALS patients, 116 C9orf72 expansion carriers, 219 non-carriers, and 223 healthy controls, from Italian and Turkish cohorts. Deletions were significantly more frequent in C9orf72 expansion carriers (6%) compared to non-carrier ALS patients (0.46%, OR =14.00, 95% CI =1.71-306.59, p = 0.003), to controls (0%, OR =16.29, 95% CI =2.12-725.99, p = 4.86 * 10-4) and to the whole cohort of non-carriers (0.2%, OR =28.51, 95% CI =3.47-618.91, p = 9.58 * 10-5). Among expansion carriers, deletions with or without the GTGGT motif were equally distributed (4 vs. 3). The frequency of insertions was not statistically different between C9orf72 expansion carriers and any other group including the whole cohort of non-carriers (p = 0.439, Fisher's exact test). Our data confirmed the association between deletions within GC-rich region and the GGGGCC expansion in Italian and Turkish cases, although we did not confirm a role of the GTGGT element deletion. Further studies will be therefore necessary to assess the causal relationships between contiguous deletions of the GC-rich region and the GGGGCC expansion. PMID- 29490504 TI - The role of transvaginal ultrasound in screening for ovarian cancer. AB - Ovarian cancer is a low-prevalence postmenopausal cancer with a high mortality rate and is the fifth most lethal cancer in women. The most common serous subtype with TP53 mutations spreads rapidly throughout the peritoneal cavity (stage III/IV) when 5-year survival is 10%. If diagnosed while confined to the ovary (stage I), the survival rate exceeds 90%. This is the rationale for screening. Annual transvaginal ultrasound (TVU) scans used as a primary screening modality or as a second-line test following primary screening with serum CA125 (multimodal) have been investigated in several trials. Only two large randomized controlled trials have provided mortality data. The US Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial studied over 78 000 women (randomized to screening with either TVU or CA125, or control) over 6 years with 14 years follow up and found no mortality benefit from screening and increased morbidity in the screened arm. The UK Collaborative Trial of Ovarian Cancer Screening studied over 202 000 women randomized to TVU, multimodal or control in a 1 : 1 : 2 ratio over 7-11 years with 11 years follow-up. CA125 was interpreted by the Risk of Ovarian Cancer algorithm which identifies a rise in the level rather than a fixed cut off. There was a late reduction in mortality after 7 years in the screened arm (23% in the multimodal arm and 21% in the TVU arm), but the overall reduction was not significant. Further follow-up may reveal whether TVU has a primary or secondary role in ovarian cancer screening. PMID- 29490505 TI - Abiraterone acetate/androgen deprivation therapy combination versus docetaxel/androgen deprivation therapy combination in advanced hormone-sensitive prostate cancer: a network meta-analysis on safety and efficacy. AB - BACKGROUND: A major, yet precisely studied, shift has occurred in the treatment of advanced hormone-sensitive prostate cancer (HSPC) by the addition of docetaxel to androgen deprivation therapy (ADT) in the first line. Recently, two landmark trials showed that abiraterone acetate (AA) can be an effective alternative along with ADT in the same setting. We implemented a network meta-analysis to compare the safety and efficacy of the two combinations. METHODS: PubMed database, ASCO and ESMO meeting library databases of all results published until June 2017 were searched using the keywords: "prostate cancer" AND "docetaxel" OR "abiraterone acetate". Efficacy endpoints including progression-free survival (PFS) and overall survival (OS), and safety endpoints (including treatment related deaths and selected adverse events) were assessed. RESULTS: Twenty relevant studies were retrieved and assessed for eligibility. Of those trials, eight were found potentially eligible. Inconsistent reporting of efficacy outcomes limited our analysis to M1 HSPC. The pooled hazard ratios (HRs) of OS and PFS of the direct comparison of abiraterone acetate plus ADT versus ADT were 0.63 (95% CI: 0.545 0.717) and 0.38 (95% CI: 0.34-0.43), respectively. Meanwhile, in the trials of docetaxel plus ADT the pooled HRs of OS and PFS were 0.75 (95% CI: 0.65-0.86) and 0.634 (95% CI: 0.57-0.70), respectively. The indirect comparison showed that the HRs of OS and PFS in DOC + ADT in comparison to AA + ADT were 1.2 (95% CI: 0.98 1.46) and 1.65 (1.40-1.94), respectively. The pooled RR of treatment-related mortality in docetaxel + ADT versus AA + ADT was 1.438 (95% CI: 0.508-4.075). CONCLUSION: Patients with metastatic HSPC (mHSPC) who received abiraterone acetate with ADT had better PFS and less toxicity compared to those receiving docetaxel with ADT. A trend towards superior OS and fewer treatment-related deaths was also observed, but was statistically non-significant. In view of lacking clear OS advantage, the choice between docetaxel and AA should include a discussion with the patient about the potential toxicities and impact on quality of life of each regimen. PMID- 29490506 TI - Safety and effectiveness of physostigmine: seeing the trees for the forest plot. PMID- 29490507 TI - Hikers poisoned: Veratrum steroidal alkaloid toxicity following ingestion of foraged Veratrum parviflorum. AB - INTRODUCTION: Steroidal alkaloids are found in plants of the genus Veratrum. Their toxicity manifests as gastrointestinal symptoms followed by a Bezold Jarisch reflex: hypopnea, hypotension, and bradycardia. Some Veratrum steroidal alkaloids are also teratogens interfering with the hedgehog-2 signaling pathway, which causes cyclopsia and holoprosencephaly. We present a case of accidental poisoning from Veratrum parviflorum mistaken for the edible Allium tricoccum (ramps, wild leek). CASE HISTORY: A 27-year-old man and his 25-year-old wife presented to the emergency department with nausea, vomiting, hypotension, and bradycardia after foraging and ingesting plants that they believed to be a local native species of wild leek. METHODS: We collected and analyzed the implicated fresh plant material and both patients' serum/plasma. We used liquid chromatography-mass spectroscopy and high-resolution electrospray ionization time of flight tandem mass spectrometry to extract and characterize steroidal alkaloids from the foraged plant and patients' serum. RESULTS: Our V. parviflorum samples contained verazine, veratramine, veratridine, and cyclopamine. DISCUSSION: Steroidal alkaloids have been previously isolated from Veratrum viride and Veratrum album and toxicity has been reported mainly from V. album species. CONCLUSION: V. parviflorum toxicity manifests with gastrointestinal and cardiac symptoms. Treatment is symptomatic and supportive as with previous case reports of toxicity with other Veratrum species. PMID- 29490508 TI - A backward glance. AB - Medical illustrators have sought statutory regulation and a protected title to demonstrate credibility and status within the field of healthcare and to enhance practitioner's reputation. This has proved to be a challenging journey that has been intensely political. This paper summarises that journey to date. PMID- 29490509 TI - Efficacy and safety of tamsulosin 0.4 mg single pills for treatment of Asian patients with symptomatic benign prostatic hyperplasia with lower urinary tract symptoms: a randomized, double-blind, phase 3 trial. AB - OBJECTIVE: To verify the efficacy and safety of tamsulosin 0.4 mg and tamsulosin 0.2 mg compared with those of placebo in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). METHODS: A total of 494 patients from multiple centers participated in this double-blind, randomized, phase 3 trial. Eligible patients were randomly assigned to the tamsulosin 0.4 mg group, tamsulosin 0.2 mg group or placebo group. The International Prostate Symptom Score (IPSS), maximum flow rate (Qmax), post-void residual (PVR) urine volume, blood pressure, heart rate and adverse events were compared among the three groups at 4, 8 and 12 weeks. RESULTS: A total of 494 BPH patients were analyzed. There were no differences in the baseline characteristics among the three groups. After 12 weeks of treatment, total IPSS was improved in the 0.2 mg and 0.4 mg tamsulosin groups; however, the extent of improvement was greater in the 0.4 mg group than in the 0.2 mg group (0.4 mg: -9.59 vs. 0.2 mg: 5.61; least-squares mean difference [95% confidence interval]: -3.95 [-5.01, 2.89], p < .0001). In addition, in the patients with severe symptoms (IPSS >=20), total IPSS was improved the most in the 0.4 mg group (-11.27 +/- 5.00, p < .0001). Qmax and PVR were improved in the 0.4 mg and 0.2 mg groups; however, the differences were not statistically significant between treatment groups. No patients experienced any serious adverse effects in any of the three groups. CONCLUSIONS: Tamsulosin 0.4 mg and 0.2 mg appear to be superior to placebo treatment, and tamsulosin 0.4 mg is more effective than 0.2 mg in terms of total IPSS improvement. Tamsulosin 0.4 mg has favorable efficacy and tolerability in Asian men with symptomatic BPH. ClinicalTrials.gov Identifier: NCT02390882. PMID- 29490510 TI - High thoracic ossification of ligamentum flavum causing partial Horner syndrome. AB - We report a case of high thoracic ossification of the ligamentum flavum (OLF) causing a partial Horner's syndrome. A 57-year-old man developed a walking disorder, as well as right-sided miosis and anhidrosis. Magnetic resonance imaging demonstrated a spinal cord compressing T2-T3 OLF. The patient improved after surgery. PMID- 29490511 TI - Patterns of pain medication use in older individuals with cardiovascular disease. AB - BACKGROUND: Pain is common in older adults and clinicians are often faced by many challenges when selecting appropriate treatment due to age-related changes in pharmacokinetics, pharmacodynamics, increased comorbidities, and polypharmacy. METHODS: This study assessed the patterns of pain medications used at home among older adults admitted to the cardiology service in a tertiary care teaching center in the US from March to May 2016. A retrospective chart review was conducted where adults, 65 years of age or older, with cardiovascular diseases admitted to the cardiology service and taking at least one pain medication at home were studied. RESULTS: Out of 404 patients who were admitted to the cardiology service, 228 (56.4%) were on at least one pain medication. Among the admitted patients, 64.2% of the females received at least one pain medication, as compared to 49% of the males (p = 0.002). Participants had a mean age of 76.34 +/ 7.43 years, and received a mean of 1.81 +/- 0.83 pain medications. Neuropathic pain was the most common indication (33.4%), followed by arthritis (17.5%), and cancer (15.8%). The most commonly used pain medications were gabapentin/pregabalin 79 (34.6%), acetaminophen plus an opiate 78 (34.2%), opiates 56 (24.6%), tramadol 36 (15.8%), followed by non-selective NSAIDs 21 (9.2%). Twelve (5.3%) patients received duplication of pain medications, while 14 (5.7%) received an inappropriate combination of pain medications. Twenty-three patients (10.1%) received muscle relaxants in conjunction with pain medications, 20 of which are considered poorly tolerated by older adults. CONCLUSION: This stufy described the patterns of use of pain medications among older adults with cardiovascular disease. Careful selection of appropriate pain medications based on different clinical parameters is very essential to avoid prescribing inappropriate therapy that can lead to patient harm. PMID- 29490512 TI - A retrospective study to assess resource utilization and costs in patients with post-stroke spasticity in the United Kingdom. AB - OBJECTIVE: Post-stroke spasticity (PSS) is a common complication following stroke. This study describes the differences in healthcare resource utilization between patients who do and do not develop PSS in the UK. METHODS: Adults registered in The Health Improvement Network database with a recorded stroke between 2007 and 2011 were included. PSS was identified through Read codes; machine learning was used to retrospectively identify unrecorded PSS events. Patients with diagnosed or predicted PSS in the 12 months after stroke were matched to those with no PSS on age, sex, number of strokes, socioeconomic status, and comorbidities using the nearest neighbor algorithm. Utilization and costs associated with general practitioner visits, nurse visits, hospitalizations, referrals to specialists, laboratory tests, and medications in the 12 months after stroke were compared. RESULTS: Overall, 2,951 PSS cases were matched to 37,753 controls. During the first year, more PSS cases visited a physiotherapist (19% vs 7%) and occupational therapist (12% vs 5%) compared to controls. A greater proportion of cases were also referred to specialists (76% vs 64%) and hospitalized (33% vs 9%) compared to controls. Medication for spasticity was, on average, 14.68 prescriptions for cases and 5.64 for controls. Total mean costs per patient were L1,270 (standard deviation [SD] = 772) and L635 (SD = 273) for cases and controls, respectively. CONCLUSION: Costs after stroke for patients developing PSS are twice as high compared to patients who do not develop it, with the major driver being the number of hospital admissions. This highlights the need for better recording and closer management of PSS. PMID- 29490513 TI - Comparison between single- and dual-porosity models for fluid transport in predicting lesion volume following saline-infused radiofrequency ablation. AB - A recent study by Ooi and Ooi (EH Ooi, ET Ooi, Mass transport in biological tissues: Comparisons between single- and dual-porosity models in the context of saline-infused radiofrequency ablation, Applied Mathematical Modelling, 2017, 41, 271-284) has shown that single-porosity (SP) models for describing fluid transport in biological tissues significantly underestimate the fluid penetration depth when compared to dual-porosity (DP) models. This has raised some concerns on whether the SP model, when coupled with models of radiofrequency ablation (RFA) to simulate saline-infused RFA, could lead to an underestimation of the coagulation size. This paper compares the coagulation volumes obtained following saline-infused RFA predicted based on the SP and DP models for fluid transport. Results showed that the SP model predicted coagulation zones that are consistently 0.5 to 0.9 times smaller than that of DP model. This may be explained by the low permeability value of the tissue interstitial space, which causes the majority of the saline to flow through the vasculature. The absence of fluid flow tracking in the vasculature in the SP model meant that any flow of saline into the vasculature is treated as losses and do not contribute to the saline penetration depth of the tissue. Comparisons with experimental results from the literature revealed that the DP models predicted coagulation zone sizes that are closer to the experimental values than the SP models. This supports the hypothesis that the SP model is a poor choice for simulating the outcome of saline-infused RFA. PMID- 29490514 TI - miR-192 suppresses T follicular helper cell differentiation by targeting CXCR5 in childhood asthma. AB - The aim of this study was to investigate the role of miR-192 in differentiation of T follicular helper cells in childhood asthma. Blood samples were taken from eighteen children with acute asthma attacks and fifteen healthy children (HC). Quantitative real-time PCR and Western blotting were used to detect the expression levels of miR-192, C-X-C chemokine receptor type 5 (CXCR5), B-cell lymphoma 6 (BCL-6) and inducible T-cell costimulator (ICOS). The flow cytometry was performed to detect the proportion of CD4 + CXCR5+ Tfh cells on CD4 + T lymphocytes. The enzyme-linked immunosorbent assay (ELISA) was carried out to determine the plasma concentrations of total IgE and IL-21. The effect of miR-192 on the T follicular helper cells differentiation by targeting CXCR5 was determined by dual-luciferase reporter assay. Children with asthma had lower levels of miR-192 than HC. The proportion of CD4 + CXCR + Tfh cells was significantly higher in the acute asthma group than HC. Similarly, the plasma concentration of total IgE and IL-21 in the acute group markedly increased compared with the HC, and IgE concentration was positively correlated with the proportion of CD4 + CXCR5 + Tfh cells. Furthermore, the expression levels of CXCR5, Bcl-6 and ICOS were significantly higher in the acute group than in the HC. While the proportion of CD4 + CXCR5 + Tfh cells, IL-21, CXCR5, Bcl-6 and ICOS were obviously lower in the CD4 + T cells transfected with miR-192 plasmid than that in miR-192 + CXCR5 group and control group. In conclusion, miR-192 blocks the activation pathway of Tfh cells by targeting CXCR5, which is a reasonable cellular target for therapeutic intervention. PMID- 29490515 TI - Interpreting the Tinnitus Questionnaire (German version): what individual differences are clinically important? AB - OBJECTIVE: Reporting of clinical significance is recommended because findings can be statistically significant without being relevant to patients. For aiding clinical interpretation of the Tinnitus Questionnaire (TQ), many investigators use a 5-point change cut-off as a minimal clinically important difference (MCID). But there are shortcomings in how this value was originally determined. DESIGN: The MCID was evaluated by analysing retrospective clinical data on the TQ (German version). Following recommended standards, multiple estimates were computed using anchor- and distribution-based statistical methods. These took into account not only patients' experience of clinical improvement, but also measurement reliability. STUDY SAMPLE: Pre- and post-intervention scores were assessed for 202 patients. RESULTS: Our six estimates ranged from 5 to 21 points in TQ change score from pre- to post- intervention. The 5-point TQ change score was obtained using a method that considered change between groups, and did not account for measurement error or bias. The size of the measurement error was considerable, and this comprises interpretation of individual patient change scores. CONCLUSIONS: To enhance confidence that a TQ change over time in individual patients is clinically meaningful, we advise at least the median MCID of 12 points. PMID- 29490517 TI - Effectiveness of earmuffs in protecting hearing during shooting practice: a case study. AB - OBJECTIVE: This investigation was designed to determine the effectiveness of earmuffs worn by a single individual during shooting practice. DESIGN: Single subject experimental design. STUDY SAMPLE: A 21-year old female recreational shooter, who practiced shooting on a regular basis while using earmuffs participated in the study. She reported occasional noise exposures of other types including car races and demolition derbies but no hearing difficulties or symptoms such as tinnitus. Her auditory sensitivity was within normal limits. On each test-day, distortion product otoacoustic emissions (DPOAEs) were recorded in a sound-attenuated booth before and after a shooting practice session conducted while using earmuffs. Data were collected across six different days, across six weeks, to allow recovery from each of the six shooting practice sessions. The participant was requested to refrain from other noisy activities in between sessions. RESULTS: Significant changes in DPOAE signal-to-noise ratios (SNRs) were apparent following the shooting sessions, at 1184 and 4761 Hz in the left ear suggesting that the hearing protection worn by the individual was insufficient to completely protect her hearing. CONCLUSIONS: It is possible to assess the effectiveness of hearing protection worn by individual shooters using repeated measurements of DPOAEs embedded in a single case-research design. PMID- 29490516 TI - Association between Toxoplasma gondii infection and history of blood transfusion: a case-control seroprevalence study. AB - Objectives This study was performed to determine the association between seropositivity to Toxoplasma gondii and a history of blood transfusion. Methods Patients who had undergone blood transfusion (n = 410) and age- and sex-matched controls who had not undergone blood transfusion (n = 1230) were examined for anti- T. gondii IgG and IgM antibodies using enzyme-linked immunoassays. Results Anti- T. gondii IgG antibodies were detected in 57 (13.9%) patients and in 129 (10.5%) controls with a borderline difference [odds ratio (OR) = 1.37, 95% confidence interval (CI) = 0.98-1.92]. High anti- T. gondii IgG antibody levels (>150 IU/mL) were found in 27 (47.4%) of the 57 anti- T. gondii IgG-positive patients and in 37 (28.7%) of the 129 anti- T. gondii IgG positive controls with a significant difference (OR = 2.23, 95% CI = 1.17-4.26). Anti- T. gondii IgM antibodies were found in 13 (22.8%) of the 57 seropositive patients and in 37 (28.7%) of the 129 seropositive controls, but the difference was not significant (OR = 0.73, 95% CI = 0.35-1.52). Seroprevalence was significantly higher in patients aged >50 years than in controls of the same age and in female patients than in female controls. Conclusions These findings indicate that a history of blood transfusion is a risk factor for T. gondii infection. PMID- 29490519 TI - Cost and outcome of a community-based paediatric hearing screening programme in rural India with application of tele-audiology for follow-up diagnostic hearing assessment. AB - OBJECTIVE: This study evaluated the cost and outcome of a community-based hearing screening programme in which village health workers (VHWs) screened children in their homes using a two-step DPOAE screening protocol. Children referred in a second screening underwent tele diagnostic ABR testing in a mobile tele-van using satellite connectivity or at local centre using broadband internet at the rural location. DESIGN: Economic analysis was carried out to estimate cost incurred and outcome achieved for hearing screening, follow-up diagnostic assessment and identification of hearing loss. Two-way sensitivity analysis determined the most beneficial cost-outcome. STUDY SAMPLE: 1335 children under 5 years of age underwent screening by VHWs. RESULTS: Nineteen of the 22 children referred completed the tele diagnostic evaluation. Five children were identified with hearing loss. The cost-outcomes were better when using broadband internet for tele-diagnostics. The use of least expensive human resources and equipment yielded the lowest cost per child screened (Rs.1526; $23; ?21). When follow-up expenses were thus maximised, the cost per child was reduced considerably for diagnostic hearing assessment (Rs.102,065; $1532; ?1368) and for the cost per child identified (Rs.388,237; $5826; ?5204). CONCLUSION: Settings with constrained resources can benefit from a community-based programme integrated with tele diagnostics. PMID- 29490518 TI - European 17 countries consensus endorses more approaches to APD than reported in Wilson 2018. PMID- 29490520 TI - Survival and functional and oncological outcomes following intersphincteric resection for low rectal cancer: short-term results. AB - Objective This study was performed to evaluate the 1-year survival rate and functional outcomes of 20 patients who underwent intersphincteric resection (ISR) for low rectal cancer. Methods Twenty patients who underwent ISR for low rectal cancer were followed up for 1 year. Complications, functional outcomes objectified by the Wexner score, and oncological outcomes were assessed. Results The short-term survival rate was 100%. The median Wexner score was <=10 in all patients at 12 months after surgery. Signs of local recurrence were absent, and antigen levels remained within the reference ranges 1 year postoperatively. Conclusions ISR is a feasible alternative in highly selected patients who primarily refuse a colostomy bag and present with type II or III tumors. In the present study, patient-reported continence was satisfactory, and the absence of a colostomy bag increased patients' quality of life. The oncological outcomes were satisfactory at 1 year postoperatively. PMID- 29490522 TI - Interventional therapies for relief of obstruction in hypertrophic cardiomyopathy: discussion and proposed clinical algorithm. AB - Hypertrophic cardiomyopathy (HCM), a disease formerly thought rare in clinical practice, is now believed to affect as many as 1 in 300 individuals, regardless of race or gender. Rising awareness, coupled with advanced imaging and the development of dedicated HCM centers of excellence, has led to more patients coming to clinical presentation. While some are diagnosed at a young age, others are diagnosed in middle age or well into advanced age. Unfortunately, many such patients have progressed clinically to overt heart failure, or have some combination of advanced symptoms including dyspnea, angina, pre-syncope or syncope, palpitations, and edema. Anatomic subsets, including those with mid ventricular obstruction or apical disease, with or without apical aneurysm, have also been seen in increasing frequency. Fortunately, both percutaneous and surgical invasive options are available across the spectrum of disease severity and anatomy, with outcomes continuing to improve as the techniques and experience evolve. Advances in both approaches allow targeted and individualized treatment of the majority of these patients. This review will focus on interventional approaches to relief of obstruction, and will provide a current clinical algorithm from our center for determining when an interventional approach may be recommended or optimal over a surgical approach, and vice versa. PMID- 29490523 TI - The Empathy Tank as a revised model for fostering empathy in medical education. AB - Empathy has been difficult to sustain and foster in medical training. Based on empirical evidence and intuitive human experience, this paper proposes that empathy can be re-conceptualized as a dynamic reservoir, referred to as an "empathy tank." Physicians and learners who have personally experienced or received much empathy will naturally have a stronger tendency and greater capacity for empathy than others who have experienced little. These instances of empathy that fill the "empathy tank" can take the form of personal experiences, re-experiencing memories, and vicarious experiences. As this reservoir is filled, the empathy therein can more readily be poured out to others. Thus, all trainees should be educated to recognize first and foremost their personal need for empathy that they share with patients and subsequently seek encounters that highlight these empathic experiences. Three practical implications for educational interventions are discussed: (1) Learners and preceptors should recognize instances in training of perceived inadequacy as opportunities to provide empathy, (2) Interventions should target foundational rather than secondary issues in empathy, and (3) Interventions should enable empathy in learners to be self-sustaining. PMID- 29490521 TI - Toll-like receptor 4 regulates insulin signal transduction in retinal Muller cells. AB - Dysfunctional insulin signalling is a causative factor in type-2 diabetes. While insulin signal transduction has been well investigated in many tissues, less is known in retinal tissues. We have previously reported that toll-like receptor 4 (TLR4) is involved in retinal damage in diabetes. We used TLR4 retinal Muller cell-specific knockout mice and Muller cells in culture to investigate the effects of loss of TLR4 on Muller cell insulin signal transduction. Loss of TLR4 in the mouse retinal Muller cells led to increased insulin receptor and Akt phosphorylation, with reduced insulin receptor substrate 1 (IRS-1) phosphorylation on serine 307, which was associated with reduced cleavage of caspase 3. In retinal Muller cells grown in high glucose, insulin signal transduction was impaired, but these responses were reduced with cells were transfected with TLR4 siRNA. Taken together, the data suggest that TLR4 regulates insulin signal transduction in retinal Muller cells. PMID- 29490524 TI - High power microwave ablation of normal swine lung: impact of duration of energy delivery on adverse event and heat sink effects. AB - PURPOSE: The purpose of this study is to assess the impact of duration of energy delivery on adverse events (AEs) and heat sink effects during high power microwave ablation (MWA) of normal swine lung. MATERIALS AND METHODS: High power (100 W) MWA was performed with short (2 min, 18 ablations) or long (10 min, nine ablations) duration of energy delivery in unilateral lung of swine (n = 10). CT imaging was done prior to sacrifice at 2 or 28 d post-treatment, with additional imaging at 7 and 14 d for the latter cohort. Ablation zones were assessed with CT imaging and histopathology analysis. Differences in AEs and ablation characteristics between groups were compared with Fisher's exact test and Student's t-test, respectively. RESULTS: There were no significant differences in formation of air-filled needle tract, cavitation, and pneumonia (p > 0.5) between the treatment groups. Intra-procedural pneumothorax requiring chest tube placement occurred in three animals. Substantial (>20%, p = 0.01) intra procedural ablation zone distortion was observed in both groups. The presence of large airways or blood vessels did not result in heat sink effect within the ablation zones and was not indicative of reduced ablation size. Increased energy delivery yielded larger (8.9 +/- 3.1 cm3 vs. 3.4 +/- 1.7 cm3, p < 0.001) spherical ablations (sphericity: 0.70 +/- 0.10 vs. 0.56 +/- 0.13, p = 0.01). CONCLUSIONS: High power MWA of normal lung with longer duration of energy delivery can create larger spherical ablations, without significant differences in post-procedure AEs when compared with shorter energy delivery time. PMID- 29490525 TI - The alignment imperative in curriculum renewal. AB - RATIONALE: There are perennial calls for MD curricula to reform in order to meet the changing needs of students, patients, and society. And yet, efforts at renewal have also been suggested to have minimal impact on the pedagogy and outcomes of medical education. One reason may be misalignment between the components of the curriculum during design and implementation. The University of Toronto MD program recently renewed its undergraduate preclinical Foundations curriculum. Mindful of the pitfalls of misalignment, the renewal process focused deliberately on alignment between the various components of the curriculum: instructional methods, student assessment, faculty development, and the larger purpose of serving students and society. INNOVATION: Educational evidence was used to drive the alignment process which resulted in three major changes. First, we created a spiral curriculum centered on 72 virtual patient cases designed to integrate content and prepare students for clinical learning. Second, we introduced a novel medical psychiatry component to address a core societal need in mental health. This exposed students early to experiences of complexity, ambiguity, and integrated patient care. Lastly, a shift to assessment for learning and programmatic assessment was designed and implemented concurrently to reinforce the pedagogy of the curriculum. Synchronous faculty development was developed for the new roles required of faculty. CONCLUSIONS: Early program evaluation shows alignment of these curricular components requires ongoing attention and resources in order to be successful. The potential benefits of this alignment are well prepared students who can meet the needs of their patients and society in an increasingly complex health system. PMID- 29490526 TI - Public awareness of the need to call emergency medical services following the onset of acute myocardial infarction and associated factors in Japan. AB - Objectives Early recognition of acute myocardial infarction (AMI) and early activation of emergency medical services (EMS) are essential to reduce delays in patient care. We investigated public awareness of the need to call EMS at onset of AMI and evaluated associated factors. Methods In January 2008, a nationwide population-based survey using quota sampling was conducted in Japan. The primary outcome measure was responsiveness to promptly calling EMS at AMI onset, subdivided by on-time (daytime) and off-time (nights and holidays) hours. Results In total, 1200 participants were surveyed. Their mean age was 46.3 years (standard deviation, 17.4), and 50.3% (n=604) were women. A total of 11.6% (n=139) answered that they would call EMS during on-time hours, and 27.5% (n=330) stated that they would call during off-time hours. Multivariable analysis showed that the participants' age, female sex, education level, and self-confidence regarding their understanding of AMI were significant associated factors. The associated factors were almost identical during the off-time hours; only sex was no longer significant. Conclusions Public awareness of the need to call EMS at AMI onset in Japan was low. Previous intervention studies that were not effective may not have targeted groups with significant risk factors. PMID- 29490527 TI - STEPS in the basic clinical skills curriculum. AB - PURPOSE: Historically medical curricula evolved through significant developmental milestones in teaching methodologies. This paper follows the growth chart of the basic clinical skills curriculum that occurred universally over the years, with emphasis on the last ten years of curricular steps at Ross University School of Medicine. METHODS: This is article is a literature review. It is a summary of the authors' opinions following review of prior publications and discussions with academic personnel involved in curricular development. RESULTS: Globally, the main methodologies utilized over the years included Apprenticeship, Discipline based, Organ-System Based, Problem-Based Learning and Clinical Presentation-Based models. Several external and internal stimuli have influenced these various teaching methodologies. Being proactive in curricular development is necessary to prevent stunting. CONCLUSIONS: Although each stage of curricular development brought noteworthy improvements in medical education, innovations continue to be necessary for curricular growth. PMID- 29490528 TI - Persistent influence of a narrative educational program on physician attitudes regarding patient care. AB - PURPOSE: Educational approaches involving patient stories aim at enhancing empathy and patient-centered care; however, it is not known whether the influence of such programs on physician attitudes persists beyond medical school. MATERIALS AND METHODS: The Family Centered Experience (FCE) paired preclinical medical students with patient families over two years and engaged students in reflective dialogs about the volunteers' stories. This study examined possible long-term influences on attitudes toward medicine and doctoring. Interviews were conducted with former students at the end of or after post-graduate training. All had completed the FCE between 4 and 10 years before the study. Thematic analysis was informed by a constructivist Grounded Theory approach. RESULTS: Several themes were identified. The FCE made graduates aware of the patients' perspectives and impacted their clinical practice in specific ways, such as developing collaborative partnerships, conducting family meetings, and breaking bad news. The course had influenced career choices and interest in teaching. Finally, the FCE enhanced appreciation of the human dimensions of medicine, which graduates had drawn upon in subsequent years. CONCLUSIONS: A program based on longitudinal interactions with individuals with chronic illness can have persistent influence by stimulating reflection on the patient's perspective and humanistic approaches to patient care. PMID- 29490529 TI - Addressing the hidden curriculum in the clinical workplace: A practical tool for trainees and faculty. AB - INTRODUCTION: The hidden curriculum, commonly described in negative terms, is considered highly influential in medical education, especially in the clinical workplace. Structured approaches to address it are limited in number and scope. METHODS AND RESULTS: This paper presents a practical, value-neutral method called REVIEW (Reflecting & Evaluating Values Implicit in Education in the Workplace), to facilitate reflection and discussion on the hidden curriculum by faculty members and trainees. REVIEW approaches the hidden curriculum as a reflection of the professional microculture of a clinical team. This microculture results from collective problem solving and mutual negotiation when facing different, often conflicting, demands and interests, and their underlying values in daily clinical practice. Using this nonjudgmental conceptual framework, REVIEW employs a series of 50 culture statements that must be prioritized using Q-sort methodology, reflecting how the culture in a particular clinical context (e.g. ward or department) is perceived by faculty members and trainees. This procedure can be done individually or in groups. Most important is the resulting team discussion after the exercise - a discussion about perceptions of actual team culture and the culture desired by the team. DISCUSSION AND CONCLUSIONS: Our early experiences suggest that REVIEW can be a useful tool for addressing the hidden curriculum. PMID- 29490530 TI - Robotic-assisted vs. laparoscopic and abdominal myomectomy for treatment of uterine fibroids: a meta-analysis. AB - Uterine fibroids are extremely common uterine neoplasms. However, whether robotic assisted laparoscopic myomectomy (RALM) is superior to laparoscopic myomectomy (LM) or abdominal myomectomy (AM) is still debatable. Consequently, we aimed to compare the three currently major surgical techniques used in patients with uterine fibroids. We searched the PubMed, the Cochrane Library, MEDLINE, Embase, and Web of Science databases up to April 22, 2017. The meta-analysis included 20 studies involving 2852 patients. The number of complications [odd ratio (OR) 0.52, p = 0.009], estimated blood loss (EBL) [weighted mean difference (WMD) 33.03, p = 0.02], conversions (OR 0.34, p = 0.03), and postoperative bleeding (OR 0.18, p = 0.03) in RALM cases was significantly less than that for LM. The numbers of complications (OR 0.56, p = 0.03), length of hospital stay (WMD -1.74, p < 0.00001), EBL (WMD -77.74, p < 0.00001), and numbers of transfusions (OR 0.25, p < 0.0001) were significantly decreased, and the operative time (WMD 84.88, p < 0.00001) was significantly prolonged in RALM cases when compared to AM cases. Compared with LM and AM, RALM is associated with significantly fewer complications, significantly lower EBL, significantly fewer conversions than both LM and AM, and significantly less bleeding than LM. PMID- 29490531 TI - The development of a pragmatic, clinically driven ultrasound curriculum in a UK medical school. AB - Whether ultrasound (US) should be incorporated into a medical undergraduate curriculum remains a matter of debate within the medical education arena. There are clear potential benefits to its early introduction particularly with respect to the study of living anatomy and physiology in addition to the learning of clinical skills and procedures required for the graduate clinical practice. However, this needs to be balanced against what is perceived as an added value in addition to financial and time constraints which may potentially lead to the sacrifice of other aspects of the curriculum. Several medical schools have already reported their experiences of teaching US either as a standalone course or as a fully integrated vertical curriculum. This article describes and discusses the initial experience of a UK medical school that has taken the steps to develop its own pragmatic vertical US curriculum based on clinical endpoints with the intent of using US to enhance the learning experience of students and equipping them with the skills required for the safe practice as a junior doctor. PMID- 29490532 TI - Aggressive Incidents in Residential Youth Care. AB - It is assumed that group climate can have an effect on aggressive behavior in adolescents living in residential facilities, but it is largely unknown whether there are climate differences between the various types of residential institutions, and whether group climate differently affects aggression incidents among adolescents placed in institutions that differ in levels of security (and openness). In current research, the differences in perception of group climate between open, semi-secure, and secure residential youth care facilities were examined as well as the association between group climate and aggression. In total, 159 adolescents (96 males, 63 females) completed the Prison Group Climate Instrument (PGCI), and (aggressive) incidents were recorded during a period of 3 months. Perception of group climate-including support from staff, group atmosphere among adolescents, possibilities for growth, and repression-did not differ between the various types of residential care, except for possibilities for growth. Adolescents in open and semi-secure institutions experienced more possibilities for growth than their peers in secure institutions. A more positive perception of group climate in open institutions proved to be related to less aggressive incidents at the living group. For semi-secure and secure institutions, no relation between group climate and aggression was found. Also, the longer adolescents stayed in residential youth care, the more aggressive incidents occurred. PMID- 29490533 TI - State-Level Variability in Veteran Reliance on Veterans Health Administration and Potentially Preventable Hospitalizations: A Geospatial Analysis. AB - Most Veterans who use the Veterans Health Administration (VHA) also utilize private-sector health care providers. To better inform local and regional health care planning, we assessed the association between reliance on VHA ambulatory care and total and system-specific preventable hospitalization rates (PHRs) at the state level. We conducted a retrospective dynamic cohort study using Veterans with diabetes mellitus, aged 66 years or older, and dually enrolled in VHA and Medicare parts A and B from 2004 to 2010. While controlling for median age and proportion of males, we measured the association between reliance on VHA ambulatory care and PHRs at the state level using multivariable ordinary least square regression, geographically weighted regression, and generalized additive models. We measured geospatial patterns in PHRs using global Moran's I and univariate local indicator spatial analysis. Approximately 30% of hospitalized Veterans experienced a preventable hospitalization. Reliance on VHA ambulatory care at the state level ranged from 13.92% to 67.78% and was generally not associated with PHRs. Geospatial analysis consistently identified a cluster of western states with low PHRs from 2006 to 2010. Given the generally low reliance on VHA ambulatory care and lack of association between this reliance and PHRs, policy changes to improve Veterans' health care outcomes should address private sector care in addition to VHA care. PMID- 29490534 TI - Defining a framework for medical teachers' competencies to teach ethnic and cultural diversity: Results of a European Delphi study. AB - BACKGROUND: Medical students need to be trained in delivering diversity responsive health care but unknown is what competencies teachers need. The aim of this study was to devise a framework of competencies for diversity teaching. METHODS: An open-ended questionnaire about essential diversity teaching competencies was sent to a panel. This resulted in a list of 74 teaching competencies, which was sent in a second round to the panel for rating. The final framework of competencies was approved by the panel. RESULTS: Thirty-four experts participated. The final framework consisted of 10 competencies that were seen as essential for all medical teachers: (1) ability to critically reflect on own values and beliefs; (2) ability to communicate about individuals in a nondiscriminatory, nonstereotyping way; (3) empathy for patients regardless of ethnicity, race or nationality; (4) awareness of intersectionality; (5) awareness of own ethnic and cultural background; (6) knowledge of ethnic and social determinants of physical and mental health of migrants; (7) ability to reflect with students on the social or cultural context of the patient relevant to the medical encounter; (8) awareness that teachers are role models in the way they talk about patients from different ethnic, cultural and social backgrounds; (9) empathy for students of diverse ethnic, cultural and social background; (10) ability to engage, motivate and let all students participate. CONCLUSIONS: This framework of teaching competencies can be used in faculty development programs to adequately train all medical teachers. PMID- 29490535 TI - Neurofunctional changes after a single mirror therapy intervention in chronic ischemic stroke. AB - BACKGROUND: Mirror therapy (MT) is becoming an alternative rehabilitation strategy for various conditions, including stroke. Although recent studies suggest the positive benefit of MT in chronic stroke motor recovery, little is known about its neural mechanisms. PURPOSE: To identify functional brain changes induced by a single MT intervention in ischemic stroke survivors, assessed by both transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI). MATERIALS AND METHODS: TMS and fMRI were used to investigate 15 stroke survivors immediately before and after a single 30-min MT session. RESULTS: We found statistically significant increase in post-MT motor evoked potential (MEP) amplitude (increased excitability) from the affected primary motor cortex (M1), when compared to pre-MT MEP. Post-MT fMRI maps were associated with a more organized and constrained pattern, with a more focal M1 activity within the affected hemisphere after MT, limited to the cortical area of hand representation. Furthermore, we find a change in the balance of M1 activity toward the affected hemisphere. In addition, significant correlation was found between decreased fMRI beta-values and increased MEP amplitude post-MT, in the affected hemisphere. CONCLUSION: Our study suggests that a single MT intervention in stroke survivors is related to increased MEP of the affected limb, and a more constrained activity of the affected M1, as if activity had become more constrained and limited to the affected hemisphere. PMID- 29490536 TI - Efficacy of infection control interventions, other than decolonization, in reducing the incidence of new MRSA acquisition in a neurosurgical intensive care unit. PMID- 29490537 TI - Meaningful engagement and person-centered residential dementia care: A critical interpretive synthesis. AB - BACKGROUND: People with moderate to advanced dementia living in residential care are at risk of occupational deprivation. Person-centered care has been adopted as a guiding principle in the provision of residential care for older adults with dementia. In this context, there has been shift in occupational therapy practice from addressing occupational performance towards focusing on meaningful engagement. While both meaningful engagement and person-centered care have been well researched the relationship between the two concepts is poorly understood. AIM: A critical interpretative synthesis was conducted to determine how principles of person-centered care inform occupational therapy practice in relation to promotion of meaningful engagement among residents with moderate to advanced dementia. METHODS: A systematic search of research addressing meaningful engagement of people with moderate to advanced dementia identified 26 papers. RESULTS: Papers were classified as theoretical papers and empirical research. Two overarching constructs emerged, namely promoting a culture of collaborative care and understanding the resident as a person with a past, present and future. CONCLUSIONS: Occupational deprivation prevails and person-centered care is not fully addressed if opportunities for growth and engagement for residents with moderate to advanced dementia is not extended beyond their life history. SIGNIFICANCE: Creating continued opportunities for building agency of residents with dementia could promote occupational justice in residential care. PMID- 29490538 TI - How to tell a patient's story? Influence of the case narrative design on the clinical reasoning process in virtual patients. AB - BACKGROUND: Virtual patients (VPs) are narrative-based educational activities to train clinical reasoning in a safe environment. Our aim was to explore the influence of the design of the narrative and level of difficulty on the clinical reasoning process, diagnostic accuracy and time-on-task. METHODS: In a randomized controlled trial, we analyzed the clinical reasoning process of 46 medical students with six VPs in three different variations: (1) patients showing a friendly behavior, (2) patients showing a disruptive behavior and (3) a version without a patient story. RESULTS: For easy VPs, we did not see a significant difference in diagnostic accuracy. For difficult VPs, the diagnostic accuracy was significantly higher for participants who worked on the friendly VPs compared to the other two groups. Independent from VP difficulty, participants identified significantly more problems and tests for disruptive than for friendly VPs; time on task was comparable for these two groups. The extrinsic motivation of participants working on the VPs without a patient story was significantly lower than for the students working on the friendly VPs. CONCLUSIONS: Our results indicate that the measured VP difficulty has a higher influence on the clinical reasoning process and diagnostic accuracy than the variations in the narratives. PMID- 29490539 TI - Activity gains after upper limb surgery for spasticity in patients with spinal cord injury. AB - : Spasticity is a common and increasingly prevalent secondary complication of spinal cord injury. The aim of the study was to evaluate patient-experienced gains in prioritized activities after surgery to reduce the effects of spasticity in upper limbs in tetraplegia. The study includes evaluation of 30 operations for 27 patients performed on hypertonic tetraplegic hands during 2007-2015 using the Canadian Occupational Performance Measure. Activity performance increased at both 6 months and 12 months by a mean of 3.0 and 2.9 points, respectively. Satisfaction increased by 3.3 and 3.4, respectively. All types of activities improved, with wheelchair manoeuvring as one of the highest rated. The intervention increased prioritized activity performance and persisted at least 12 months after surgery. Patients with mild upper limb impairment showed greater improvement after surgery. After operation, patients were able to perform 71% of their prioritized activities, which they could not perform before. Patients' satisfaction with the performance was high. LEVEL OF EVIDENCE: IV. PMID- 29490540 TI - Cerebrospinal fluid lactate as a marker to differentiate between community acquired acute bacterial meningitis and aseptic meningitis/encephalitis in adults: a Danish prospective observational cohort study. AB - BACKGROUND: The ability of cerebrospinal fluid (CSF) lactate to distinguish between acute bacterial meningitis (ABM) and aseptic meningitis/encephalitis (AME) is debated. We assessed the diagnostic value of CSF lactate to discriminate between ABM and AME. METHODS: We included 176 patients from a prospective adult cohort with neuroinfections. In total, 51 ABM and 125 AME patients with clinically and/or microbiologically diagnosed acute meningitis were examined with CSF-lactate and traditional markers for infection. Receiver operating characteristic (ROC) curves were used to assess diagnostic performance. RESULTS: In CSF, lactate, leukocytes, fraction of neutrophils, protein and glucose ratio, were significantly different between the ABM and AME groups. CSF lactate had the best diagnostic value, with an area under the curve (AUC) of 0.976 (95%CI 0.966 0.997) and using a cut-off of 3.5 mmol/L a sensitivity of 96% and specificity of 85%. Antibiotic treatment before lumbar puncture had no significant effect on the AUC of CSF lactate. CONCLUSIONS: Compared to traditional CSF-markers, CSF lactate is more accurate to distinguish between ABM and AME. PMID- 29490541 TI - (Re-)Establishing familiarity: Resumption of occupations by older adults with physical disabilities. AB - BACKGROUND: There is a need for in-depth understanding of how elderly persons resume their occupations while recovering from physical disabilities in their home and community. The aim of this study was to explore and understand how engaging in occupations unfolded over time for some older persons with physical disabilities in Japan. MATERIALS AND METHODS: In this narrative-in-action study four elderly participants were recruited following a mixed purposive and convenience sampling method. Data was gathered at two to three weeks' intervals over six months, with a follow-up visit at nine months. Qualitative interviews and participant-observations were analyzed using narrative analysis. RESULTS: This study identified the central meaning of resuming occupations as reestablishing former and establishing new familiarity. Familiarity was expressed in three features, namely as repertoires of occupations fulfilling needs and meanings, as performing occupations according to expectation, and as a resource for dealing with problems of engaging in occupation. What was experienced as familiar could be adjusted to accommodate ones changing needs or situation. CONCLUSION AND SIGNIFICANCE: (Re-)establishing familiarity is a new concept representing transitions from an occupational perspective. Facilitating familiarity can assist older persons to experience health and well-being, even while transitioning after an illness or injury. PMID- 29490542 TI - Open book examinations: Not a panacea. PMID- 29490543 TI - Novel horizontal and vertical integrated bioethics curriculum for medical courses. AB - Studies conducted by the University of Haifa, Israel in 2001, evaluating the effectiveness of bioethics being taught in medical colleges, suggested that there was a significant lack of translation in clinical care. Analysis also revealed, ineffectiveness with the teaching methodology used, lack of longitudinal integration of bioethics into the undergraduate medical curriculum, and the limited exposure to the technology in decision making when confronting ethical dilemmas. A modern novel bioethics curriculum and innovative methodology for teaching bioethics for the medical course was developed by the UNESCO Chair in Bioethics, Haifa. The horizontal (subject-wise) curriculum was vertically integrated seamlessly through the entire course. An innovative bioethics teaching methodology was employed to implement the curriculum. This new curriculum was piloted in a few medical colleges in India from 2011 to 2015 and the outcomes were evaluated. The evaluation confirmed gains over the earlier identified translation gap with added high student acceptability and satisfaction. This integrated curriculum is now formally implemented in the Indian program's Health Science Universities which is affiliated with over 200 medical schools in India. This article offers insights from the evaluated novel integrated bioethics curriculum and the innovative bioethics teaching methodology that was used in the pilot program. PMID- 29490545 TI - Use of a flexible hollow-core carbon dioxide laser for microsurgical resection of vestibular schwannomas. AB - OBJECTIVE The CO2 laser has been used on an intermittent basis in the microsurgical resection of brain tumors for decades. These lasers were typically cumbersome to use due to the need for a large, bulky design since infrared light cannot be transmitted via fiber-optic cables. Development of the OmniGuide cable, which is hollow and lined with an omnidirectional dielectric mirror, has facilitated the reintroduction of the CO2 laser in surgical use in a number of fields. This device allows for handheld use of the CO2 laser in a much more ergonomically favorable configuration, holding promise for microneurosurgical applications. This device was introduced into the authors' practice for use in the microsurgical resection of skull base tumors, including vestibular schwannomas. METHODS The authors reviewed the initial 41 vestibular schwannomas that were treated using the OmniGuide CO2 laser during an 8-month period from March 2010 to October 2010. The laser was used for all large tumors, and select medium-sized tumors were treated via both the translabyrinthine and retrosigmoid approaches. The estimated time of tumor resection and estimated blood loss were obtained from operating room records. Data regarding complications, facial nerve and hearing outcomes, and further treatment were collected from hospital and clinic records, MRI reports, and direct review of MR images. Time of resection and blood loss were compared to a control group (n = 18) who underwent surgery just prior to use of the laser. RESULTS A total of 41 patients with vestibular schwannomas were surgically treated. The median estimated time of tumor resection was 150 minutes, and the median estimated blood loss was 300 ml. The only operative complication was 1 CSF leak. Thirty-eight patients had normal facial nerve function at late follow-up. The median MRI follow-up was 52 months, and, during that time, only 1 patient required further treatment for regrowth of a residual tumor. CONCLUSIONS The OmniGuide CO2 laser is a useful adjunct in the resection of large vestibular schwannomas. This device was used primarily as a cutting tool rather than for tumor vaporization, and it was found to be of most use for very large and/or firm tumors. There were no laser-associated complications, and the results compared favorably to earlier reports of vestibular schwannoma resection. PMID- 29490544 TI - Influence of motor imagery of isometric flexor hallucis brevis activity on the excitability of spinal neural function. AB - PURPOSE: This study aimed to validate the preliminary steps of motor image voluntary training in patients who are prone to falling as toe flexion muscle strength decreases. MATERIALS AND METHODS: We recorded the F-wave in 30 healthy subjects (20 men, 10 women; mean age, 22.5 +/- 2.1 years). First, in a resting condition, the muscle was relaxed during the F-wave recording. Subsequently, the motion of the left flexor hallucis brevis muscle is photographed. F-waves were recorded immediately and at 5, 10, and 15 min after motor imagery. The amplitude of the F/M ratio and persistence were measured. The intervention group watched the exercise task video used for F-wave measurement daily for 1 month, whereas the non-intervention group did not. The second measurement was performed 1 month later in each group. RESULTS: In the first measurement of the amplitude of the F/M ratio in both intervention and non-intervention groups, the image condition was significantly increased compared with the resting condition, but there was no significant difference in persistence. A significant decrease in the amplitude of the F/M ratio after image conditioning was observed in the second measurement of the intervention group. CONCLUSION: Although spinal nerve function excitement was enhanced during motor imagery, movement suppression was promoted, and spinal nerve excitability was suppressed when repeating the simple task. In the future, gradually upscaling the difficulty level of the toe flexion motor task used in the motor image may be necessary to prevent falls. PMID- 29490546 TI - Keyhole retrosigmoid approach for large vestibular schwannomas: strategies to improve outcomes. AB - OBJECTIVE There are numerous treatment strategies in the management for large vestibular schwannomas, including resection only, staged resections, resections followed by radiosurgery, and radiosurgery only. Recent evidence has pointed toward maximal resection as being the optimum strategy to prevent tumor recurrence; however, durable tumor control through aggressive resection has been shown to occur at the expense of facial nerve function and to risk other approach related complications. Through a retrospective analysis of their single institution series of keyhole neurosurgical approaches for large vestibular schwannomas, the authors aim to report and justify key techniques to maximize tumor resection and reduce surgical morbidity. METHODS A retrospective chart review was performed at the Centre for Minimally Invasive Neurosurgery. All patients who had undergone a keyhole retrosigmoid approach for the resection of large vestibular schwannomas, defined as having a tumor diameter of >= 3.0 cm, were included in this review. Patient demographics, preoperative cranial nerve status, perioperative data, and postoperative follow-up were obtained. A review of the literature for resections of large vestibular schwannomas was also performed. The authors' institutional data were compared with the historical data from the literature. RESULTS Between 2004 and 2017, 45 patients met the inclusion criteria for this retrospective chart review. When compared with findings in a historical cohort in the literature, the authors' minimally invasive, keyhole retrosigmoid technique for the resection of large vestibular schwannomas achieved higher rates of gross-total or near-total resection (100% vs 83%). Moreover, these results compare favorably with the literature in facial nerve preservation (House-Brackmann I-II) at follow-up after gross-total resections (81% vs 47%, p < 0.001) and near-total resections (88% vs 75%, p = 0.028). There were no approach related complications in this series. CONCLUSIONS It is the experience of the senior author that complete or near-complete resection of large vestibular schwannomas can be successfully achieved via a keyhole approach. In this series of 45 large vestibular schwannomas, a greater extent of resection was achieved while demonstrating high rates of facial nerve preservation and low approach related and postoperative complications compared with the literature. PMID- 29490547 TI - Preoperative diffusion tensor imaging-fiber tracking for facial nerve identification in vestibular schwannoma: a systematic review on its evolution and current status with a pooled data analysis of surgical concordance rates. AB - OBJECTIVE Total tumor excision with the preservation of neurological function and quality of life is the goal of modern-day vestibular schwannoma (VS) surgery. Postoperative facial nerve (FN) paralysis is a devastating complication of VS surgery. Determining the course of the FN in relation to a VS preoperatively is invaluable to the neurosurgeon and is likely to enhance surgical safety with respect to FN function. Diffusion tensor imaging-fiber tracking (DTI-FT) technology is slowly gaining traction as a viable tool for preoperative FN visualization in patients with VS. METHODS A systematic review of the literature in the PubMed, Cochrane Library, and Web of Science databases was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines, and those studies that preoperatively localized the FN in relation to a VS using the DTI-FT technique and verified those preoperative FN tracking results by using microscopic observation and electrophysiological monitoring during microsurgery were included. A pooled analysis of studies was performed to calculate the surgical concordance rate (accuracy) of DTI-FT technology for FN localization. RESULTS Fourteen studies included 234 VS patients (male/female ratio 1:1.4, age range 17-75 years) who had undergone preoperative DTI-FT for FN identification. The mean tumor size among the studies ranged from 29 to 41.3 mm. Preoperative DTI-FT could not visualize the FN tract in 8 patients (3.4%) and its findings could not be verified in 3 patients (1.2%), were verified but discordant in 18 patients (7.6%), and were verified and concordant in 205 patients (87.1%). CONCLUSIONS Preoperative DTI-FT for FN identification is a useful adjunct in the surgical planning for large VSs (> 2.5 cm). A pooled analysis showed that DTI-FT successfully identifies the complete FN course in 96.6% of VSs (226 of 234 cases) and that FN identification by DTI-FT is accurate in 90.6% of cases (205 of 226 cases). Larger studies with DTI-FT-integrated neuronavigation are required to look at the direct benefit offered by this specific technique in preserving postoperative FN function. PMID- 29490548 TI - Simultaneous cochlear implantation as a therapeutic option in vestibular schwannoma surgery: case report. AB - Hearing loss is the most common symptom of vestibular schwannomas (VSs). The management of these lesions includes observation, radiosurgery, and microsurgical resection. Hearing preservation and rehabilitation are the major challenges after the tumor treatment. A 43-year-old man with previous left-sided profound hearing loss and tinnitus presented with a 2-mm left-sided intracanalicular VS. The decision was made to perform a simultaneous cochlear implantation (CI) and microsurgical resection of the tumor. The patient did well postoperatively, with significant improvement of tinnitus, sound localization, and speech recognition in noise. Previous reports of simultaneous CI and VS resection in patients with neurofibromatosis type 2 and sporadic VS in the only hearing ear have been described. The role of CI in patients with VS and normal contralateral hearing has been recently described, showing positive outcomes due to the binaural benefits. Tinnitus also can be treated by the implantation of the cochlear device. The simultaneous microsurgical removal of VS and implantation of a cochlear device is a feasible approach in patients with unilateral hearing loss and severe tinnitus. PMID- 29490549 TI - Letter to the Editor. Complications from the use of flow-diverting devices. PMID- 29490550 TI - Endoscope-assisted middle fossa craniotomy for resection of inferior vestibular nerve schwannoma extending lateral to transverse crest. AB - OBJECTIVE The authors describe their results using an endoscope as an adjunct to microsurgical resection of inferior vestibular schwannomas (VSs) with extension into the fundus of the internal auditory canal below the transverse crest. METHODS All patients who had undergone middle fossa craniotomy for VSs performed by the senior author between September 2014 and August 2016 were prospectively enrolled in accordance with IRB policies, and the charts of patients undergoing surgery for inferior vestibular nerve tumors, as determined either on preoperative imaging or as intraoperative findings, were retrospectively reviewed. Age prior to surgery, side of surgery, tumor size, preoperative and postoperative pure-tone average, and speech discrimination scores were recorded. The presence of early and late facial paralysis, nerve of tumor origin, and extent of resection were also recorded. RESULTS Six patients (all women; age range 40-65 years, mean age 57 years) met these criteria during the study period. Five of the 6 patients underwent gross-total resection; 1 patient underwent a near-total resection because of a small amount of tumor that adhered to the facial nerve. Gross-total resection was facilitated using the operative endoscope in 2 patients (33%) who were found to have additional tumor visible only through the endoscope. All patients had a House-Brackmann facial nerve grade of II or better in the immediate postoperative period. Serviceable hearing (American Academy of Otolaryngology-Head and Neck Surgery class A or B) was preserved in 3 of the 6 patients. CONCLUSIONS Endoscope-assisted middle fossa craniotomy for resection of inferior vestibular nerve schwannomas with extension beyond the transverse crest is safe, and hearing preservation is feasible. PMID- 29490551 TI - Introduction. Update on the treatment of acoustic tumors. PMID- 29490552 TI - Minimally invasive endoscopic repair of refractory lateral skull base cerebrospinal fluid rhinorrhea: case report and review of the literature. AB - Cerebrospinal fluid (CSF) leaks occur in approximately 10% of patients undergoing a translabyrinthine, retrosigmoid, or middle fossa approach for vestibular schwannoma resection. Cerebrospinal fluid rhinorrhea also results from trauma, neoplasms, and congenital defects. A high degree of difficulty in repair sometimes requires repetitive microsurgical revisions-a rate of 10% of cases is often cited. This can not only lead to morbidity but is also costly and burdensome to the health care system. In this case-based theoretical analysis, the authors summarize the literature regarding endoscopic endonasal techniques to obliterate the eustachian tube (ET) as well as compare endoscopic endonasal versus open approaches for repair. Given the results of their analysis, they recommend endoscopic endonasal ET obliteration (EEETO) as a first- or second-line technique for the repair of CSF rhinorrhea from a lateral skull base source refractory to spontaneous healing and CSF diversion. They present a case in which EEETO resolved refractory CSF rhinorrhea over a 10-month follow-up after CSF diversions, wound reexploration, revised packing of the ET via a lateral microscopic translabyrinthine approach, and the use of a vascularized flap had failed. They further summarize the literature regarding studies that describe various iterations of EEETO. By its minimally invasive nature, EEETO imposes less morbidity as well as less risk to the patient. It can be readily implemented into algorithms once CSF diversion (for example, lumbar drain) has failed, prior to considering open surgery for repair. Additional studies are warranted to further demonstrate the outcome and cost-saving benefits of EEETO as the data until now have been largely empirical yet very hopeful. The summaries and technical notes described in this paper may serve as a resource for those skull base teams faced with similar challenging and otherwise refractory CSF leaks from a lateral skull base source. PMID- 29490553 TI - Systematic review and meta-analysis of the technique of subtotal resection and stereotactic radiosurgery for large vestibular schwannomas: a "nerve-centered" approach. AB - OBJECTIVE During the last decade, the primary objective for large vestibular schwannoma (VS) management has progressively shifted, from tumor excision to nerve preservation by using a combined microsurgical and radiosurgical approach. The aim of this study was to provide a systematic review and meta-analysis of the available literature regarding the combined strategy of subtotal resection (STR) followed by stereotactic radiosurgery (SRS) for large VSs. METHODS The authors performed a systematic review and meta-analysis in compliance with the PRISMA guidelines for article identification and inclusion using the PubMed, Embase, and Cochrane databases. Established inclusion criteria were used to screen all identified relevant articles published before September 2017 without backward date limit. RESULTS The authors included 9 studies (248 patients). With a weighted mean follow-up of 46 months (range 28-68.8 months), the pooled rate of overall tumor control was 93.9% (95% CI 91.0%-96.8%). Salvage treatment (second STR and/or SRS) was necessary in only 13 (5.24%) of 18 patients who experienced initial treatment failure. According to the House-Brackmann (HB) grading scale, functional facial nerve preservation (HB grade I-II) was achieved in 96.1% of patients (95% CI 93.7%-98.5%). Serviceable hearing after the combined approach was preserved in 59.9% (95% CI 36.5%-83.2%). CONCLUSIONS A combined approach of STR followed by SRS was shown to have excellent clinical and functional outcomes while still achieving a tumor control rate comparable to that obtained with a total resection. Longer-term follow-up and larger patient cohorts are necessary to fully evaluate the rate of tumor control achieved with this approach. PMID- 29490554 TI - Facial nerve outcome and extent of resection in cystic versus solid vestibular schwannomas in radiosurgery era. AB - OBJECTIVE Cystic vestibular schwannomas (CVSs) are a subgroup of vestibular schwannomas (VSs) that are reported to be associated with unpredictable clinical behavior and unfavorable postoperative outcomes. The authors aimed to review their experience with microsurgical treatment of CVSs in terms of extent of resection and postoperative facial nerve (FN) function and compare these outcomes with those of their solid counterparts. METHODS Two hundred-eleven VS patients were treated surgically between 2006 and 2017. Tumors were defined as cystic when preoperative neuroimaging demonstrated cyst formation that was confirmed by intraoperative findings. Solid VS (SVSs) with similar classes were used for comparison. Clinical data of the patients were reviewed retrospectively, including clinical notes and images, as well as operative, pathology, and neuroradiology reports. RESULTS Thirty-two patients (20 males and 12 females) with a mean age of 52.2 years (range 17-77 years) underwent microsurgical resection of 33 CVSs (mean size 3.6 cm, range 1.5-5 cm). Forty-nine patients (26 males and 23 females) with a mean age of 49.9 years (range 21-75 years) underwent microsurgical resection of 49 SVSs (mean size 3 cm, range 2-4.5 cm). All operations were performed via either a retrosigmoid or a translabyrinthine approach. Gross-total resection was achieved in 30 cases in the CVS group (90.9%) and 37 in the SVS group (75.5%). The main reason for subtotal and near-total resection was adherence of the tumor to the brainstem and/or FN in both groups. None of the patients with subtotal or near-total resection in the CVS group demonstrated symptomatic regrowth of the tumor during the mean follow-up period of 41.6 months (range 18-82 months). The FN was anatomically preserved in all patients in both groups. Good FN outcomes were achieved in 15 of CVS (grade I-II; 45.5%) and 35 of SVS (71.4%) surgeries at discharge. Good and fair FN functions were noted in 22 (grade I-II; 81.5%) and 5 (grade III only; 18.5%) of the CVS patients, respectively, at the 1-year follow-up; none of the patients showed poor FN function. CONCLUSIONS Surgery of CVSs does not necessarily result in poor outcomes in terms of the extent of resection and FN function. Special care should be exercised to preserve anatomical continuity of the FN during surgery, since long-term FN function outcomes are much more satisfactory than short-term results. High rates of gross-total resection and good FN outcomes in our study may also suggest that microsurgery stands as the treatment of choice in select cases of large CVSs and SVSs in the era of radiosurgery. PMID- 29490555 TI - Systematic review of interventions to encourage careers in academic medicine. AB - AIMS: Academic medicine is a career route that historically struggles to recruit and retain suitable doctors. The aim of this paper is to review the evidence for interventions to encourage careers in academic medicine by way of a descriptive systematic review. METHODS: Key databases were searched in February 2017. Studies that evaluated interventions to encourage careers in academic medicine and that used a pre-post analysis or included a comparison group were included. Interventions reporting only learner satisfaction were excluded. The review was specific to medical students and graduates. RESULTS: Twenty-four studies were identified for inclusion within the review. The included studies identified interventions across five domains: postgraduate funding, postgraduate training, mentoring, undergraduate interventions, and institutional change. The papers varied in terms of strength of conclusion and method of analysis with broad, structured, well-funded programs having the most palpable results. CONCLUSIONS: The five domains identified offer a framework that can be used by institutions who wish to develop similar programs. It also offers a body of research on which an evidence base can be built. PMID- 29490556 TI - Focus on fertility preservation. PMID- 29490557 TI - Intralesional bleomycin A5 injection for the treatment of nasal polyps through inducing apoptosis. AB - CONCLUSION: An intralesional bleomycin A5 (BLE) injection might be used as an alternative therapy for eosinophilic-type nasal polyps (NPs). BLE-induced apoptosis might play an important role in shrinkage of NPs. OBJECTIVES: The aim of this study is to determine the effect and explore the possible role of apoptosis in shrinkage of NPs. METHODS: Twenty-nine patients with eosinophilic type NPs experienced repeated local injection of BLE. The recurrence rate of this group was obtained. The mechanism of BLE treatment was investigated through an in vitro experiment. Nasal polyp tissues were treated with BLE. The apoptotic activity was detected by the presence of DNA smear and test of terminal deoxynucleotidyl transferase dUTP nick end labeling. The caspase-8 and PARP were examined through immunohistochemistry and Western blotting. RESULTS: After several local injections of BLE, the nasal polyp tissues decreased and then disappeared. During follow-up of 3 years the recurrence rate of this group was significantly lower than another one treated with operation plus medicine treatment. Apoptosis in BLE-treated tissue was prominently detected in the infiltrating inflammatory cells. The expression of PARP and casp-8 were increased in BLE-treated nasal polyp tissue compared with PBS-treated tissue. PMID- 29490558 TI - Primary surgery with or without postoperative radiotherapy in early stage squamous cell carcinoma in the anal canal and anal margin. AB - BACKGROUND: Standard treatment of localized squamous cell carcinoma of the anus (SCCA) is radiotherapy (RT) combined with chemotherapy, that is, chemoradiation (CRT). Primary surgery has a limited role, but is a recommended treatment for small well differentiated SCCA localized in the anal margin, with re-excision or postoperative RT/CRT in case of involved surgical margins. The evidence supporting these strategies is limited. AIM: To study the recurrence patterns and survival outcomes in patients treated with surgery alone compared with surgery followed by postoperative RT/CRT. MATERIAL AND METHODS: From a large Nordic database we identified 93 patients with stage TxT1-2N0M0 SCCA treated with surgery alone (n = 59) or surgery followed by RT/CRT (n = 34). Surgery consisted of local excision in 86 patients and abdominoperineal resection in seven patients, all of them in the surgery alone group. In 38 (41%) of the patients, the tumor was localized merely in the anal margin and in all remaining cases the anal canal was involved. Median RT dose to the tumor bed was 54 (range 46-66) Gy. Adjuvant RT to lymph nodes was given in 75% of the patients. Half of the patients received concomitant chemotherapy, usually 5-fluorouracil and mitomycin C. RESULTS: The locoregional recurrence (LRR) rate was significantly higher after surgery alone compared to surgery followed by adjuvant RT/CRT (36% vs. 9%, p = .006). The 3-year recurrence free survival (RFS) and overall survival (OS) were significantly better in patients who received postoperative RT/CRT than in patients who did not (3-year RFS 84.2% vs. 52.7%, p < .001 and 3-year OS 87.2% vs. 70%, p = .026). CONCLUSIONS: Surgery alone of SCCA was associated with a high LRR rate and poor survival. The addition of postoperative RT/CRT lead to significantly improved locoregional control and survival. PMID- 29490559 TI - Psychometric Properties of the Snaith-Hamilton Pleasure Scale and a Facet-Level Analysis of the Relationship Between Anhedonia and Extraversion in a Nonclinical Sample. AB - The aim of this study is to investigate the psychometric properties of the Snaith Hamilton Pleasure Scale (SHAPS) and look at facets of extraversion as predictors of anhedonia. SHAPS is hypothesized to be multidimensional, stable over time in a nonclinical sample, and related to extraversion on both dimension and facet level. Data collection was conducted at baseline ( N = 362) and at a 10-week follow-up ( N = 94). The structural properties of SHAPS were analyzed using principal component analysis and confirmatory factor analysis. Multiple regression explored facets of extraversion as predictors of anhedonia. The results show that SHAPS is stable across time ( r = .71, p < .001), with high internal consistency (alpha = .89). In the principal component analysis, a two factor model emerged (Social and Physical anhedonia). The confirmatory factor analysis indicated that the two-factor model consisting of Physical anhedonia (alpha = .81) and Social anhedonia (alpha = .87) had a better fit than the one factor model. Higher scores on Gregariousness and Positive emotions at baseline predicted higher scores on the SHAPS total and Social and Physical anhedonia ( p < .05). Lower scores on Assertiveness predicted higher scores on Social anhedonia ( p < .05). These results support the view of anhedonia as a multidimensional concept that should be regarded as a trait, rather than a state or mere bypassing symptom. The relationship between anhedonia and extroversion is best understood by applying a multidimensional approach to anhedonia and by focusing on the facet level of extroversion. PMID- 29490560 TI - Moderate Physical Activity in an Aquatic Environment During Pregnancy (SWEP Study) and Its Influence in Preventing Postpartum Depression. AB - INTRODUCTION: Postpartum depression (PPD) can begin within 6 weeks postpartum (International Classification of Diseases, 10th Revision) and represents a significant health problem for mothers. AIM: To determine whether physical activity during pregnancy alleviates PPD. METHOD: Randomized controlled trial in which the exercise group practiced moderate physical exercise in an aquatic environment (1-hour sessions, 3 days a week), following the recommendations of the SWEP method. RESULTS: The results observed in the Edinburgh Postnatal Depression Scale were significant between the exercise group and the control group ( p < .001). In addition, significant differences were observed according in body mass index between the exercise group and control group in the overweight and obesity categories ( p < .05). CONCLUSION: Women who perform moderate physical exercise in an aquatic environment are at lower risk of PPD than sedentary women. Overweight and obesity among sedentary women during pregnancy are closely associated with positive screening for PPD. PMID- 29490561 TI - Waiting impulsivity: a distinctive feature of ADHD neuropsychology? AB - Impulsivity is a core feature of attention-deficit hyperactivity disorder (ADHD). It has been conceptualized in a number of different ways. In the current article, we examine how the new concept of "waiting impulsivity", which refers to premature responding before a scheduled target appears, adds to our understanding of impulsivity in ADHD. Sixty children (8-12 years old; 30 ADHD; 30 typically developing controls) completed the 4-choice serial reaction time task, a measure of waiting impulsivity, alongside tasks measuring inhibitory control and temporal discounting and questionnaires measuring behavioral disorder symptoms, delay aversion, and various aspects of impulsivity. A multiple logistic regression model was used to explore the contribution of the primary task outcomes to predict group membership. Children with ADHD displayed more waiting impulsivity and less inhibitory control; they did not differ in temporal discounting. There was no correlation between waiting impulsivity and inhibitory control. Waiting impulsivity was correlated with parent-reported ratings of hyperactivity/impulsivity, inattention, oppositional defiant disorder (ODD), and conduct disorder (CD) and with self-reported delay aversion ratings. Only waiting impulsivity was a significant predictor of ADHD status. In conclusion, waiting impulsivity is distinct from inhibitory control deficits and predicts ADHD status independently of it. Future research needs to examine the relationship with delay aversion and ODD/CD more thoroughly. PMID- 29490562 TI - Investigating cardiovascular patients' preferences and expectations regarding the use of social media in health education. AB - BACKGROUND: To reach more people in the community, health educators have considered employing social media alongside traditional health education methods. AIMS: To understand the preferences and expectations of patients with cardiovascular diseases (CVDs) regarding the use of social media in health education. To assess the association between patients' socio-demographics with their preferences and expectations about the use of social media in health education. METHODS: This is a cross-sectional descriptive study, which included 135 subjects with an established diagnosis of CVDs. The subjects were met at three cardiac outpatient clinics and recruited through a convenience sampling technique. They were recruited if they were adults, oriented and diagnosed with the CVDs for at least six months. RESULTS: Most subjects (50.3%) were interested in receiving health education through social media, and 74.8% of them felt that using social media in health education would improve the process and lead to better outcomes. Preference for social media was significantly related to younger age, higher education, lower income, watching health education programmes on television, positive family history of CVDs, and currently has a job. Furthermore, higher positive expectations regarding using social media in health education were significantly related to higher education, watching health education programmes on television, being single, and currently has a job. CONCLUSIONS: Subjects with CVDs are enthusiastic about health education through social media, believing that it will be good for educating them and providing them with the up-to-date information they need to live with their diseases. Findings of this study may positively contribute to the international efforts of improving health education through employing social media to improve accessibility to health education materials, and consequently decrease the burden of CVDs. PMID- 29490563 TI - A Transgenic tdTomato Rat for Cell Migration and Tissue Engineering Applications. AB - The growing deficit in suitable tissues for patients awaiting organ transplants demonstrates the clinical need for engineered tissues as alternative graft sources. Demonstrating safety and efficacy by tracking the migration and fate of implanted cells is a key consideration required for approval of promising engineered tissues. Cells from transgenic animals that express green fluorescent protein (GFP) are commonly used for this purpose. However, GFP can create difficulties in practice due to high levels of green autofluorescence in many musculoskeletal tissues. Tandem-dimer tomato (tdTomato) is a stable, robust red fluorescent protein that is nearly threefold brighter than GFP. Our objective was to create a line of transgenic rats that ubiquitously express tdTomato in all cells, driven by the human ubiquitin C promoter. We sought to determine the rats' utility in tissue engineering applications by fabricating engineered skeletal muscle units (SMUs) from isolated muscle-derived tdTomato cells. These tdTomato SMUs were implanted into a volumetric muscle loss (VML) defect of the tibialis anterior muscle in a rat ubiquitously expressing GFP. We also evaluated a novel method for modularly combining individual SMUs to create a larger engineered tissue. Following a recovery period of 28 days, we found that implantation of the modular SMU led to a significant decrease in the size of the remaining VML deficit. Histological analysis of explanted tissues demonstrated both tdTomato and GFP expression in the repair site, indicating involvement of both implanted and host cells in the regeneration process. These results demonstrate the successful generation of a tdTomato transgenic rat, and the use of these rats in tissue engineering and cell migration applications. Furthermore, this study successfully validated a method for scaling engineered tissues to larger sizes, a factor that will be important for repairing volumetric injuries in more clinically relevant models. PMID- 29490564 TI - Worsening Dual-Task Gait Costs after Concussion and their Association with Subsequent Sport-Related Injury. AB - Prior studies suggest that concussion may lead to an increased risk of a subsequent time-loss sport-related injury, but the mechanisms responsible are unknown. We measured the symptom and dual-task gait outcomes for athletes initially post-concussion and after clinical recovery. Participants then self reported any additional injuries incurred in the year after their concussion. Forty-two athletes (52% female, mean age = 16.8 +/- 3.2 years) completed the study. They underwent a dual-task gait evaluation and symptom inventory within 21 days post-concussion, and again after they were deemed clinically recovered. Approximately one year later, participants documented if they had sustained any subsequent sport-related injuries. The repeated measures analysis of variance (ANOVA) was used to evaluate changes in dual-task gait and symptoms across time and between groups. A significant group*time interaction (p = 0.02) indicated that the group that went on to sustain a subsequent time-loss injury after returning to sports (n = 15) demonstrated significant average walking speed dual task cost worsening across time (-17.9 +/- 9.1% vs. -25.1 +/- 12.5%; p = 0.007). In contrast, the group that did not sustain an additional injury walked with consistent dual-task cost values across time (-25.2 +/- 9.2% vs. -24.6 +/- 8.4%; p = 0.76). Symptoms improved for all participants (main effect of time, p < 0.001; Post-Concussion Symptom Scale [PCSS] = 25.0 +/- 16.9 vs. 2.8 +/- 7.5; p < 0.001), but did not differ between groups (p = 0.77). Significant dual-task gait cost worsening throughout concussion recovery was associated with time-loss injuries during sports in the year after a concussion. These findings indicate that worsening ability to execute a concurrent gait and cognitive task may relate to the risk of incurring an injury during sports after clinical concussion recovery. PMID- 29490565 TI - TLE1 Expression in Malignant Rhabdoid Tumor and Atypical Teratoid/Rhabdoid Tumor. AB - Malignant rhabdoid tumors (MRT; atypical teratoid/rhabdoid tumor [ATRT] in the central nervous system) are aggressive tumors in infants and children which can overlap with other sarcomas, such as synovial sarcoma (SS). The gold standard for SS diagnosis is characterization of the t(X;18) chromosomal translocation. However, stratification of cases for molecular analysis is not always straightforward or feasible. Recent literature suggests transducer-like enhancer of split 1 (TLE1) protein expression may distinguish SS from certain histologic mimics; however, this has not been investigated in MRT and ATRT. We stained whole tissue sections of 18 archived cases of MRT and ATRT with TLE1. Nuclear expression was scored using a 4-tiered (0, 1+, 2+, and 3+) scale describing staining intensity, extent, or combination of both. The majority of MRT and ATRT cases showed some TLE1 immunoreactivity (n = 16; 89% for >=1 + staining); 14 (78%) of total cases showed >=2 + positivity using any of the 3 scoring systems. Over half (n = 10; 56%) of cases showed >=2 + staining; 4 (22%) cases showed 3 + strong and diffuse TLE1 staining measured by all scoring systems in agreement. Although still of potential use, we urge caution in the interpretation of TLE1 when the differential diagnosis includes both SS and MRT or ATRT. PMID- 29490566 TI - Is international junior success a reliable predictor for international senior success in elite combat sports? AB - Currently in the literature, there is a dearth of empirical research that confirms whether international junior success is a reliable predictor for future international senior success. Despite the uncertainty of the junior-senior relationship, federations and coaches still tend to use junior success as a predictor for long-term senior success. A range of former investigations utilising a retrospective lens has merely focused on success that athletes attained at junior level competitions. Success that was achieved at senior-level competitions but at a junior age was relatively ignored. This study explored to what extent international senior success can be predicted based on success that athletes achieved in either international junior level competitions (i.e. junior medalists) or senior competitions at a junior age (i.e. early achievers). The sample contains 4011 international male and female athletes from three combat sports (taekwondo, wrestling and boxing), who were born between 1974 and 1990 and participated in both international junior and senior-level competitions between 1990 and 2016. Gender and sport differences were compared. The results revealed that 61.4% of the junior medalists and 90.4% of the early achievers went on to win international medals at a senior age. Among the early achievers, 92.2% of the taekwondo athletes, 68.4% of the wrestling athletes and 37.9% of the boxing athletes could be reliably "predicted" to win international senior medals. The findings demonstrate that specific to the three combat sports examined, international junior success appears to be an important predictor to long-term international senior success. PMID- 29490567 TI - Sharing stories about medical education in difficult circumstances: Conceptualizing issues, strategies, and solutions. AB - BACKGROUND: Global economic forces, political decisions, and natural disasters are only some of the factors that affect contemporary healthcare education. Given the centrality of health in all settings, the future of healthcare education depends on how we overcome these difficult circumstances. METHODS: Through a series of collaborative activities involving healthcare educators from around the world and their attempts to overcome these difficulties, the authors have developed a conceptual model centered around the people involved, the impact of culture, and organizations and systems. RESULTS: The model can help to frame discussions and develop strategies about how best we, as a community of health professionals and educators, collaborate and share wisdom, experiences and resources to assist colleagues who might be struggling to deliver education. What has clearly emerged from this work is the centrality of leadership and management in effectively challenging and addressing difficult circumstances. CONCLUSIONS: Contemporary health professions' education leadership needs to be inclusive, mindful, compassionate and caring; echoing and role-modeling how we expect our students to be with patients and colleagues. This means being willing to confront unacceptable behaviors and speak out and challenge authority when needed. It also requires awareness and understanding of the complex systems in which healthcare education is provided. PMID- 29490568 TI - The Relationship of Circular RNAs With Ovarian Endometriosis. AB - Circular RNAs (circRNAs) are involved in the pathogenesis of many diseases, although their expression pattern and role in endometriosis remains unknown. Therefore, here, we profiled the expression patterns of circRNAs in ovarian ectopic and paired eutopic endometria as well as constructed a circRNA-miRNA-mRNA network. Circular RNA and messenger RNA (mRNA) expression profiles were assessed by a microarray analysis in 4 patients. Quantitative real-time polymerase chain reaction (qRT-PCR) validation of 8 circRNAs and mRNAs was conducted in another 37 patients. We detected 1258 up- and 1061 downregulated circRNAs as well as 1900 up and 2535 downregulated mRNAs between the ectopic and eutopic endometria. Functional analysis suggested that most differentially expressed mRNAs participate in immune-inflammatory responses and cell cycle regulation. The qRT PCR validation results for 5 circRNAs ( circ_0004712, circ_0002198, circ_0003570, circ_0008951, and circ_0017248) and 8 mRNAs ( SCN3B, ENTPD1, IL16, BACH2, C3, CKS2, G0S2, and PGRMC1) matched the microarray results. On basis of target prediction, we constructed a circRNA-miRNA-mRNA network. This revealed the primary roles of cancer-related, purine metabolism, glycerophospholipid metabolism, and thyroid hormone signaling pathways in endometriosis pathogenesis. This is the first study of circRNA expression patterns in ovarian endometriosis, which suggests that circRNAs are candidate factors in the activation of ovarian endometriosis and are promising diagnostic biomarkers and treatment targets. PMID- 29490569 TI - Synthesis and in vitro evaluation of thermosensitive hydrogel scaffolds based on (PNIPAAm-PCL-PEG-PCL-PNIPAAm)/Gelatin and (PCL-PEG-PCL)/Gelatin for use in cartilage tissue engineering. AB - BACKGROUND: Biodegradable thermosensitive hydrogel scaffolds based on novel three block PCL-PEG-PCL and penta block PNIPAAm-PCL-PEG-PCL-PNIPAAm copolymers blended with gelatin were prepared and examined on functional behavior of chondrocytes. METHODS: In this work, we compared two different thermosensitive hydrogel scaffolds (PNIPAAm-PCL-PEG-PCL-PNIPAAm)/Gelatin and (PCL-PEG-PCL)/Gelatin prepared by TIPS (thermally induced phase separation) method. The feature of copolymers was characterized by FT-IR, 1H NMR. The lower critical solution temperatures (LCSTs) of aqueous solutions of copolymers were measured by cloud point (turbidity) measurements. We also examined water absorption capacity and swelling ratio. Mechanical features of the prepared hydrogels were evaluated by stress-strain measurements. Thereafter, isolated chondrocytes were cultured on each scaffold for a period of 10 days and cell arrangement and morphology studied pre-and post-plating. Cell survival assay was done by using MTT assay. The transcription level of genes Sox-9, Collagen-II, COMP, MMP-13 and oligomeric matrix protein was monitored by real-time PCR assay. The samples were also stained by Toluidine blue method to monitor the synthesis of proteoglycan. RESULTS: Data demonstrated an increased survival rate in cells coated seeded on scaffolds, especially (PNIPAAm-PCL-PEG-PCL-PNIPAAm)/Gelatin as compared to control cells on the plastic surface. (PNIPAAm-PCL-PEG-PCL-PNIPAAm)/Gelatin had potential to increase the expression of genes Sox-6, Collagen-II, COMP and after 10 days in vitro. CONCLUSION: Thermosensitive PCEC/Gel and (PNIPAAm-PCEC PNIPAAm)/Gel hydrogel scaffolds that fabricated by TIPS method possesses useful hydrophilic properties for growth and cell embedding and secretion of extracellular matrix. It can serve as an ideal strategy to promote the formation of cartilage tissue. PMID- 29490570 TI - Visual Occlusion Decreases Motion Sickness in a Flight Simulator. AB - Sensory conflict theories of motion sickness (MS) assert that symptoms may result when incoming sensory inputs (e.g., visual and vestibular) contradict each other. Logic suggests that attenuating input from one sense may reduce conflict and hence lessen MS symptoms. In the current study, it was hypothesized that attenuating visual input by blocking light entering the eye would reduce MS symptoms in a motion provocative environment. Participants sat inside an aircraft cockpit mounted onto a motion platform that simultaneously pitched, rolled, and heaved in two conditions. In the occluded condition, participants wore "blackout" goggles and closed their eyes to block light. In the control condition, participants opened their eyes and had full view of the cockpit's interior. Participants completed separate Simulator Sickness Questionnaires before and after each condition. The posttreatment total Simulator Sickness Questionnaires and subscores for nausea, oculomotor, and disorientation in the control condition were significantly higher than those in the occluded condition. These results suggest that under some conditions attenuating visual input may delay the onset of MS or weaken the severity of symptoms. Eliminating visual input may reduce visual/nonvisual sensory conflict by weakening the influence of the visual channel, which is consistent with the sensory conflict theory of MS. PMID- 29490571 TI - Vulval lichen planus-lichen sclerosus overlap. AB - Vulval lichen planus-lichen sclerosus overlap is an emerging observation. Few clinical reports exist with no reviews of literature. We present a focused update of this phenomenon and discuss a clinical case. We report a 63-year-old woman with a 20-year history of ulcerative vulvo-vaginitis, initially diagnosed as benign mucous membrane (cicatricial) pemphigoid. This led to prolonged treatment with oral corticosteroids with minimal improvement in symptoms. Subsequent complications of long-term use of systemic corticosteroid ensued. A clinico pathological diagnosis of severe erosive lichen planus was made on clinical findings and on non-specific biopsy changes of ulceration and inflammation. Treatment with topical clobetasol propionate 0.05% ointment twice daily led to dramatic improvement of ulceration, easing of discomfort and marked improvement in quality of life. Clinical examination revealed Wickham's striae on the labia majora supporting the diagnosis. Six years after commencement of topical clobetasol, white plaques were noticed on the labia majora, perineum and peri anal region consistent with lichen sclerosus, confirmed by repeat vulval skin biopsy and on vulvectomy. This case highlights the challenge of diagnosis of extensive vulvo-vaginal ulceration and the necessity to re-examine a previous diagnosis if there is poor response to treatment. PMID- 29490572 TI - Modes of HIV transmission among adolescents and young adults aged 10-24 years in Kenya. AB - Understanding how HIV is acquired can inform interventions to prevent infection. We constructed a risk profile of 10-24 year olds participating in the 2012 Kenya AIDS Indicator Survey and classified them as perinatally infected if their biological mother was infected with HIV or had died, or if their father was infected with HIV or had died (for those lacking mother's data). The remaining were classified as sexually infected if they had sex, and the remaining as parenterally infected if they had a blood transfusion. Overall, 84 (1.6%) of the 5298 10-24 year olds tested HIV positive; 9 (11%) were aged 10-14 and 75 (89%) 15 24 years. Five (56%) 10-14 year olds met criteria for perinatal infection; 4 (44%) did not meet perinatal, sexual or parenteral transmission criteria and parental HIV status was not established. Of the 75 HIV-infected, 15 to 24 year olds, 5 (7%) met perinatal transmission, 63 (84%) sexual and 2 (3%) parenteral criteria; 5 (7%) were unclassified. Perinatal transmission likely accounted for 56% and sexual transmission for 84% of infections among 10-14 year olds and 15-24 year olds, respectively. Although our definitions may have introduced some uncertainty, and with the number of infected participants being small, our findings suggest that mixed modes of HIV transmission exist among adolescents and young people. PMID- 29490573 TI - A Comparison of Nursing Education and Workforce Planning Initiatives in the United States and England. AB - Health care systems in England and the United States are under similar pressures to provide higher quality, more efficient care in the face of aging populations, increasing care complexity, and rising costs. In 2010 and 2011, major strategic reports were published in the two countries with recommendations for how to strengthen their respective nursing workforces to address these challenges. In England, it was the 2010 report of the Prime Minister's Commission on the Future of Nursing and Midwifery, Front Line Care: The Future of Nursing and Midwifery in England. In the United States, it was the Institute of Medicine's report The Future of Nursing: Leading Change, Advancing Health. The authors of both reports recommended shifting entry level nursing education to the baccalaureate degree and building capacity within their educational systems to prepare nurses as leaders, educators, and researchers. This article will explore how, with contrasting degrees of success, the nursing education systems in the United States and England have responded to these recommendations and examine how different regulatory and funding structures have hindered or enabled these efforts. PMID- 29490574 TI - Athletes do better after FAI arthroscopic treatment in male population. AB - BACKGROUND: Arthroscopic surgery is becoming popular in the management of hip pathologies. There are numerous studies describing the outcomes of the treatment of athletes with this method. These outcomes are generally found to be excellent. Yet there are little data in the literature with respect to the arthroscopic treatment of nonathletes. The objective of our study is to compare the outcomes of the femoroacetabular impingement (FAI) treatment between athletes and nonathletes using arthroscopy, using two popular scales. METHODS: The study involved a total of 129 male patients operated at our departments between 2009 and 2013. The subjects were divided into two groups: athletes and nonathletes. The results were assessed using the Nonarthritic Hip Score (NAHS) and Modified Harris Hip Score (MHHS). In addition, the length of postoperative hospitalization was evaluated. RESULTS: Analyses revealed that athletes performed better in NAHS over each period under analysis (prior to the operation, 12 and 24 months after the operation). As regards MHHS in these periods, the results in both groups were comparable. In addition, it was found that the length of postoperative hospitalization was similar in athletes and nonathletes. CONCLUSIONS: Arthroscopic treatment of FAI is an effective method producing visible effects in athletes as well as nonathletes but quicker recovery in male athletic population. In the examined population, NAHS was a better measurement tool than MMHS, showing differences between the athlete and nonathlete population. PMID- 29490575 TI - Students' motivation for interprofessional collaboration after their experience on an IPE ward: A qualitative analysis framed by self-determination theory. AB - PURPOSE: Interprofessional Education (IPE) may depend for its success not only on cognitive gains of learners, but also on affective and motivational benefits. According to Self-Determination Theory (SDT), a major motivation theory, autonomy (feeling of choice), competence (feeling of capability), and relatedness (feeling of belonging) drive motivation in a way that can improve performance. We investigated which elements of IPE in a clinical ward potentially influence students' feelings in these three areas. METHODS: We conducted semi-structured interviews with 21 students from medicine, nursing, pharmacy, and physical therapy attending a three-week IPE ward and analyzed the data using a realist approach. Two researchers independently identified meaning units using open coding. Thirteen themes were synthesized. Next, meaning units, expressing autonomy, competence, or relatedness were discerned. RESULTS: Students appeared motivated for an IPE ward, with its authentic situations making them feel responsible to actively contribute to care plans, by understanding how professions differ in their contributions and analytic approach and by informal contact with other professions, enhanced by a dedicated physical space for team meetings. CONCLUSION: Students valued the IPE ward experience and autonomous motivation for IPE was triggered. They mentioned practical ways to incorporate what they learned in future interprofessional collaboration, e.g. in next placements. PMID- 29490576 TI - A contemporary and a historical patient with an ectopic meningioma. AB - INTRODUCTION: Ectopic meningiomas are rare tumors which can be encountered by all surgical specialties. PATIENTS AND METHODS: We report on two different cases, a contemporary one and a historical one, highlighting the diversity of clinical presentations and prognoses of these lesions. Furthermore epidemiological aspects, clinical features, and diagnostic and therapeutic work-up in patients with an ectopic meningioma are reviewed. RESULTS: Typically, ectopic meningiomas present as gradually expanding lesions, causing a variety of symptoms by their mass effect. Diagnosis is based on histological characteristics, which are similar to those of intracranial meningiomas. Treatment is primarily surgical. CONCLUSIONS: The cases we report are at different ends of the clinical and prognostic spectrum. Therapeutic options for different clinical scenarios are discussed. PMID- 29490577 TI - Effects of whey protein in carbohydrate-electrolyte drinks on post-exercise rehydration. AB - The purpose of this study was to examine the effects of different amounts of whey protein in carbohydrate-electrolyte (CE) drinks on post-exercise rehydration. Ten males completed 5 trials in a randomised cross-over design. A 4-h recovery was applied after a 60-min run at 65% VO2peak in each trial. During recovery, the participants ingested a high-carbohydrate CE drink (CE-H), a low-carbohydrate CE drink (CE-L), a high-whey-protein (33 g.L-1) CE drink (CW-H), a medium-whey protein (22 g.L-1) CE drink (CW-M) or a low-whey-protein (15 g.L-1) CE drink (CW L) in a volume equivalent to 150% of their body mass (BM) loss. The drinks were provided in six equal boluses and consumed by the participants within 150 min in each trial. After exercise, a BM loss of 2.15% +/- 0.05% was achieved. Urine production was less in the CW-M and CW-H trials during recovery, which induced a greater fluid retention in the CW-M (51.0% +/- 5.7%) and CW-H (55.4% +/- 3.8%) trials than in any other trial (p < .05). The plasma albumin content was higher in the CW-H trial than in the CE-H and CE-L trials at 2 h (p < .05) and 3 h (p < .01) during recovery. The aldosterone concentration was lower in the CE-H trial than in the CW-M and CW-H trials after recovery (p < .05). It is concluded that the rehydration was improved when whey protein was co-ingested with CE drinks during a 4-h recovery after a 60-min run. However, this additive effect was only observed when whey protein concentration was at least 22 g.L-1 in the current study. PMID- 29490578 TI - Physiological implications of preparing for a natural male bodybuilding competition. AB - This study aimed to describe the body composition and physiological changes which take place during the in-season and recovery periods of a group of natural bodybuilders. Natural male bodybuilders (n = 9) were assessed 16 (PRE16), 8 (PRE8), and 1 (PRE1) week(s) before, and 4 (POST4) weeks after a bodybuilding competition. Assessments included body composition, resting metabolic rate (RMR), serum hormones, and 7-day weighed food and training diaries. Change in parameters was assessed using repeated-measures analysis of variance. Dietary protein intake remained high throughout the study period (2.8-3.1 g kg-1 d-1). Fat mass (FM) was significantly reduced from PRE16 to PRE1 (8.8 +/- 3.1 vs. 5.3 +/- 2.4 kg, P < .01). There was a small decrease in lean mass (LM) from PRE8 to PRE1 (71.8 +/- 9.1 vs. 70.9 +/- 9.1 kg, P < .05). No changes in RMR were observed (P > .05). Large reductions in total and free testosterone (16.4 +/- 4.4 vs. 10.1 +/- 3.6 nmol L-1, P < .05; 229.3 +/- 72.4 vs. 116.8 +/- 76.9 pmol L-1, P < .05), and insulin-like growth factor-1 (IGF-1) (27.0 +/- 7.7 vs. 19.9 +/- 7.6 nmol L-1, P < .05) occurred between PRE16 and PRE1. LM and IGF-1 increased from PRE1 to POST4 (70.9 +/- 9.1 vs. 72.5 +/- 8.5 kg, P < .05; 19.9 +/- 7.6 vs. 25.4 +/- 9.3 nmol L 1, P < .05). Despite substantial reductions in FM, participants maintained almost all of their LM. The reduction in anabolic hormone concentration is likely attributable to the prolonged negative energy balance, despite a high dietary protein intake. PMID- 29490579 TI - Prevalence and Predictors of Diabetes Mellitus and Hypertension in Armenian Americans in Los Angeles. AB - Purpose The purpose of this study was to describe the prevalence of diabetes mellitus (DM) and hypertension (HTN) along with associated risk factors among Armenian Americans living in Los Angeles. Methods After Institutional Review Board approval, a sample of 877 Armenian Americans was collected for 5 consecutive years (2011-2015) at a health fair. Collected data included: sociodemographic variables; cardiometabolic data, including systolic (SBP) and diastolic (DBP) blood pressure, glucose (Glu), and lipids; anthropometric data, including height (Ht), weight (Wt), body mass index (BMI), waist circumference (WC), and hip circumference (HC). Retrospective descriptive correlation, test of significance, and logistic regression analyses were performed. Results Findings showed that about 50% of the participants had abnormal waist/hip ratio and approximately one-quarter of the subjects had glucose levels that were indicative of high risk for DM. Logistic regression analysis revealed that high SBP ( P = .04), above normal WC ( P = .03), and high triglycerides ( P = .04) were significant in predicting DM. Moreover, age ( P =.0001), family history of cardiovascular disease ( P= .01), and above normal WC ( P = .04) were found to be significant predictors of HTN. Conclusion Waist circumference indicated to be a strong predictor for DM and HTN. Early detection and timely interventions are important to prevent DM and HTN and their associated complications. For an underserved population, health fairs become one effective avenue for screening, referral, and evaluation. PMID- 29490580 TI - Branched-chain amino acid (BCAA) supplementation enhances adaptability to exercise training of mice with a muscle-specific defect in the control of BCAA catabolism. AB - Branched-chain alpha-keto acid dehydrogenase (BCKDH) kinase (BDK) suppresses the branched-chain amino acid (BCAA) catabolism by inactivation of the BCKDH complex. The muscle-specific BDK-deficient (BDK-mKO) mice showed accelerated BCAA oxidation in muscle and decreased endurance capacity after training (Xu et al. PLoS One. 12 (2017) e0180989). We here report that BCAA supplementation overcompensated endurance capacity in BDK-mKO mice after training. PMID- 29490581 TI - The Corundum Stone and Crystallographic Chemistry. AB - This article presents a detailed history and exegesis of the 1798 paper of Charles Greville and Jacques-Louis Count de Bournon, "On the Corundum Stone from Asia." This was the first published argument to establish that the mineral corundum was related to, or identical with, the ruby and the sapphire. It was also the first time that the science of crystallography, recently developed in France, was publically introduced to a British scientific audience. Rene Just Hauy's theory of the three-dimensional structure of minerals proposed a new kind of extension of chemistry into the solid state. The story of corundum illustrates the new and sophisticated mineralogy that had emerged in the late eighteenth century and how an increasingly global natural history relied upon extended networks of trade and empire. It shows also how mineralogical debates had begun to move beyond the private and restricted milieux of mining schools and wealthy collectors and into more public scientific fora. PMID- 29490582 TI - Down-regulation of senescence marker protein 30 by iron-specific chelator deferoxamine drives cell senescence. AB - To our knowledge, this is the first study to report down-regulation of senescence marker protein 30 (SMP30) by iron-specific chelator deferoxamine (DFO) on FAO cell senescence, using a DNA microarray. Furthermore, DFO treatment increased senescence marker beta-galactosidase activity, whereas this activity was attenuated by overexpression of SMP30. Our data suggested that down-regulation of SMP30 drives cell senescence in iron-chelated condition. PMID- 29490583 TI - Outcomes of arteriovenous fistula for hemodialysis in octogenarian population. AB - : Introduction Guidelines have been recommending the use of arteriovenous fistula among the hemodialysis population, but no clear conclusion has emerged with regard to the adequate access type in octogenarians. In this paper, the outcomes of arteriovenous fistula in octogenarian cohort were presented for death-censored cumulative patency rate, complications, and patients' survival rate. Methods A retrospective review of 88 consecutive arteriovenous fistula interventions in 70 octogenarian patients were performed at one referral institution between January 2010 and June 2014. The patients' records were analyzed and postoperative complications were documented. Death-censored cumulative arteriovenous fistula patency rates were calculated, and Kaplan-Meier method was used to analyze patient survival for 24 months. FINDINGS: Eighty-eight arteriovenous fistula constructions and six salvage procedures were performed in 70 octogenarians. Fifty-four (61.3%) forearm and 34 (38.7%) upper arm fistulas were created. All types of fistulas had 6-, 12-, 18-, and 24-month death-censored cumulative patency rates of 63.6%, 58.3%, 48.8%, and 41.4%, respectively. The primary failure rate was 40.9%. A total of 15 complications were documented as edema, hematoma/bleeding, infection, distal ischemia, and venous aneurysm, all of which had been treated. Patient survival rates for 12 and 24 months were 68.5% and 58.5%, respectively. DISCUSSION AND CONCLUSION: This analysis regarding arteriovenous fistula in octogenarian end-stage renal disease patients figured out equal death-censored cumulative patency compared to nonelderly, and two-year survival rate was acceptable. This study strengthens the argument that arteriovenous fistula should be the best proper choice in selected octogenarians; older age only should not be considered as an absolute contraindication for arteriovenous fistula creation in octogenarians; and patient-based approach should be applied. PMID- 29490584 TI - Co-occurrence of mycotoxins in commercial formula milk and cereal-based baby food on the Qatar market. AB - The present study was conducted to explore the occurrence of mycotoxins in commercial baby foods in Doha-Qatar. LCMS/MS- and HPLC-based analysis of baby food (n = 67) for 12 mycotoxins confirmed the presence of aflatoxin M1 (AFM1, 33%), ochratoxin A (OTA, 31%), deoxynivalenol (DON, 27%), aflatoxin B1 (AFB1, 22%), fumonisin B2 (FB2, 10%), zearalenone (ZEN, 4%) and T-2 toxin (2%). Noodles exhibited the maximum contamination percentage, with 33% of the samples being contaminated above the EU maximum limits, for at least one mycotoxin. Among the multi-grain flake samples, up to 28% and for the milk and milk-based-cereal samples, 14% contained at least one mycotoxin above the EU maximum limits. From all cereal-based food samples, 22%, 5%, 2% and 2% were concurrently contaminated with 2, 3, 4 and 5 mycotoxins, respectively. The occurrence of toxicological important mycotoxins in Qatari market warrants the implementation of strict regulatory limits to protect human health. PMID- 29490587 TI - Family Nursing Network: Announcement: 14th International Family Nursing Conference. PMID- 29490585 TI - Sharing Genetic Risk Information: Implications for Family Nurses Across the Life Span. AB - Sharing genetic risk information in families can be very challenging. However, the consequences of poor communication can be detrimental to the psychological health and well-being of parents and children in the present and the long term. Family nursing can play an important role in supporting family communication about genetic conditions. This role has several components: Firstly, improved assessment of families affected by or at risk from inherited genetic conditions. Secondly, facilitation of families' discussions of genetic risk, especially between parents and children. Family nurses can use an integrated model of family care to support parents and their children in discussion of genetic risk information throughout the child's development, including provision of assistance specifically for young people, who want to discuss the issues they face with informed nurses. Thirdly there is a role for family nurses in educating other specialist nurses in taking a more family-focused approach when they are caring for patients affected by genetic conditions. If the full benefits of genomic technologies are to be recognized and implemented, it is essential that the relational impact of the science be strengthened to enhance family relationships and support genetic risk information sharing. PMID- 29490588 TI - Guest Editorial: Make Space for the Suffering. PMID- 29490589 TI - School of Medicine of Federal University of Rio Grande Do Norte: A traditional curriculum with innovative trends in medical education. AB - INTRODUCTION: The Medical School of the Federal University of Rio Grande do Norte (UFRN) is one of the biggest public medical schools in Northeast Brazil. In the last decade, significant investment in faculty development, innovative learning methodologies and student engagement has been key milestones in educational improvement at this medical school, harnessed to recent political changes that strengthened community-based and emergency education. This study describes how curriculum changes in UFRN Medical School have been responsible for major improvements in medical education locally and which impacts such transformations may have on the educational community. METHODS: A group of students and teachers revised the new curriculum and established the key changes over the past years that have been responsible for the local enhancement of medical education. This information was compared and contrasted to further educational evidences in order to define patterns that can be reproduced in other institutions. RESULTS: Improvements in faculty development have been fairly observed in the institution, exemplified by the participation of a growing number of faculty members in programs for professional development and also by the creation of a local masters degree in health education. Alongside, strong student engagement in curriculum matters enhanced the teaching-learning process. CONCLUSIONS: Due to a deeper involvement of students and teachers in medical education, it has been possible to implement innovative teaching-learning and assessment strategies over the last ten years and place UFRN Medical School at a privileged position in relation to undergraduate training, educational research and professional development of faculty staff. PMID- 29490590 TI - Effect of Brain-Derived Neurotrophic Factor on the Neurogenesis and Osteogenesis in Bone Engineering. AB - During bone growth, the lack of a neuralized vascular network in the regenerating area can affect subsequent bone quality. This study aimed to investigate if brain derived neurotrophic factor (BDNF) could promote neurogenesis and osteogenesis in human bone mesenchymal stem cells (hBMSCs) to improve bone formation during tissue engineering. Initially, a safe and effective BDNF concentration that facilitated hBMSC proliferation in vitro was determined. Subsequently, examination of mineralized nodule formation and evaluation of alkaline phosphatase (ALP) activity and ALP gene expression revealed that the most effective concentration of BDNF to elicit a response in hBMSCs was 100 ng/mL. In addition, we found out that by binding with TrkB receptor, the downstream Erk1/2 was phosphorylated, which promoted the expression of transcription factors, such as Runx2 and Osterix that are associated with osteoblast differentiation. We also found that by day 7 post-treatment, the neurogenic biomarkers, p75 and s100, were highly expressed in 100 ng/mL BDNF-treated hBMSCs. Finally, the effects of BDNF on osteogenesis and neurogenesis in newly formed tissues were assessed using animal models with a beta-tricalcium phosphate scaffold. This revealed that treatment with 100 ng/mL BDNF promoted the osteogenesis and neurogenesis of hBMSCs in vivo by increasing expression of the osteogenic marker osteocalcin and various neurogenic biomarkers, including microtubule-associated protein 2, glial fibrillary acidic protein, neural/glial antigen 2, and beta-tubulin III. This study has demonstrated that BDNF promotes hBMSC osteogenesis and neurogenesis in vitro and in vivo, and that BDNF may indirectly promote osteogenesis through increased neurogenesis. This further suggests that encouraging neutralization during bone engineering will lead to effective repairing of bone defects. The study may also provide insight into related fields, such as osseoperception and stress feedback regulation after dental implantation. PMID- 29490591 TI - Deep inferior epigastric artery perforator flap harvest after full abdominoplasty. AB - Abdominal scars are no longer a contra-indication for abdominal perforator flap harvesting. Few research data exists about the regeneration potential of the abdominal wall's perforator system. Therefore, previous abdominoplasty with umbilical transposition is an absolute contra-indication for a DIEaP-flap (deep inferior epigastric artery perforator flap). A 50-year-old patient required a breast reconstruction of the right breast, 10 years after an abdominoplasty with undermining of the superior abdomen and umbilical transposition. The patient was scheduled for a free lumbar artery perforator (LaP) flap. The preoperative computed tomography-angiography mapping showed nice lumbar perforators and to our surprise a good-sized DIEa perforator in the peri-umbilical region. The DIEa perforator on the right hemi-abdomen, consisting of two veins and one artery, was pulsatile and found suitable in size. A classical flap harvest and transfer was further performed. This case report is the first in which a dominant perforator is found in the area of undermining after a full abdominoplasty with umbilical repositioning. Further investigations regarding the nature and timing of re permeation or regeneration of perforators after abdominoplasty are to be done. Nevertheless, we are convinced that with appropriate perforator mapping and a suitable plan B, previous abdominoplasty is no longer an absolute but a relative contra-indication for performing DIEaP-flap. PMID- 29490592 TI - Women show similar central and peripheral fatigue to men after half-marathon. AB - Women are known to be less fatigable than men in single-joint exercises, but fatigue induced by running has not been well understood. Here we investigated sex differences in central and peripheral fatigue and in rate of force development (RFD) in the knee extensors after a half-marathon run. Ten male and eight female amateur runners (aged 25-50 years) were evaluated before and immediately after a half-marathon race. Knee extensors forces were obtained under voluntary and electrically evoked isometric contractions. Maximal voluntary isometric contraction (MVC) force and peak RFD were recorded. Electrically doublet stimuli were delivered during the MVC and at rest to calculate the level of voluntary activation and the resting doublet twitch. After the race, decreases in MVC force (males: -11%, effect size [ES] 0.52; females: -11% ES 0.33), voluntary activation (males: -6%, ES 0.87; females: -4%, ES 0.72), and resting doublet twitch (males: 6%, ES 0.34; females: -8%, ES 0.30) were found to be similar between males and females. The decrease in peak RFD was found to be similar between males and females (males: -14%, ES 0.43; females: -15%, ES 0.14). Half-marathon run induced both central and peripheral fatigue, without any difference between men and women. The maximal and explosive strength loss was found similar between sexes. Together, these findings do not support the need of sex-specific training interventions to increase the tolerance to neuromuscular fatigue in half marathoners. PMID- 29490593 TI - Monopolar Radiofrequency Ablation of Thyroid Nodules: A Prospective Austrian Single-Center Study. AB - BACKGROUND: Monopolar radiofrequency ablation is currently deemed an exotic treatment option for benign thyroid nodules in many central European countries. The aim of this study was to evaluate prospectively the safety and efficacy of this method in a large patient cohort following its introduction in Austria. METHODS: Peri- and post-interventional complications were analyzed for 277 patients. Efficacy was determined for 300 and 154 nodules at 3 and 12 months post treatment, respectively. All treatments were performed with an internally cooled 18G radiofrequency electrode using a free-hand, "moving-shot" technique following subcutaneous and local perithyroidal anesthesia. RESULTS: Mean patient age (SD) was 52 +/- 12.9 years (75% female), and overall mean baseline nodule volume (SD) was 13.8 +/- 15.9 mL. Nodules were visible in 62.8% of patients, 40% had a symptom score >=4 on a 10-point visual analogue scale, and 14.4% had hyperthyroidism. Mean overall nodule volume reduction rates (VRR) at 3 and 12 months were 68 +/- 16% and 82 +/- 13%, respectively (p < 0.001). At 12 months, 81% of nodules exhibited a VRR of >=70%, with 10%, 6%, and 2% of nodules showing VRRs of 60-70%, 50-60%, and <=50%, respectively. Subgroup analysis according to baseline nodule size (<=10 mL to >30 mL) or baseline nodule composition (solid, mixed, cystic) revealed significantly higher VRRs for smaller and cystic nodules. Moreover, nodule shrinkage was accompanied by significantly improved symptom and cosmetic scores after 3 and 12 months (p < 0.001). Of 32 hyperthyroid patients, 27 (84%) were euthyroid, four had subclinical hyperthyroidism, and one had subclinical hypothyroidism at last follow-up. Post-procedural complications were absent in 83% of patients, minimal in 12.9%, moderate and reversible in 3.2% (1.8% voice change, 0.7% hyperthyroidism, 0.3% wound infection treated with antibiotics, 0.3% epifascial hematoma), and irreversible in 0.7% (one case with hypothyroidism and one with a wound infection treated by surgery). CONCLUSIONS: It is concluded that a single treatment course with monopolar radiofrequency ablation is both safe and highly effective in terms of nodule volume reduction, relief of local symptoms, and (in patients with hyperthyroidism) restoration of euthyroid function. In no case was a prescription of thyroid medication required among those patients who were euthyroid at baseline. PMID- 29490595 TI - Limiting Prescriptions (and Clinicians) as Systems Grow. PMID- 29490594 TI - Post-activation potentiation (PAP) in endurance sports: A review. AB - While there is strong support of the usefulness of post-activation potentiation (PAP) phenomenon in power demanding sports, the role that PAP could play in endurance sports has received less attention. The aim of this review is to present evidence for a better understanding of PAP in endurance athletes; and to discuss the physiological basis and methodological aspects necessary for better practices and designing further studies. A search for relevant articles on PAP and endurance trained athletes was carried out using Medline and ISI Web of Knowledge databases. Twenty-two studies were included in the review. The current evidence suggests the possible influence of PAP for performance enhancement after appropriate conditioning activities during warm up. Evaluation of PAP responses during testing, training and competition may be also important for athletes monitoring. There are many unresolved questions about the optimum load parameters for benefiting from PAP in both training and competition; and the role that PAP may exert for optimal performance while interacting with central and peripheral factors associated with muscle fatigue. Further studies should elucidate the association between PAP responses and long-term adaptations in endurance athletes. PMID- 29490596 TI - The Doctor Is (Virtually) In: Using Electronic Consultation to Provide Prompt Psychiatric Services. PMID- 29490597 TI - Wellness Benefits of a Social Security Exit Plan. PMID- 29490598 TI - Imaging Helps Guide Physical Therapy Treatment in a Patient With Diffuse Systemic Sclerosis (Scleroderma). AB - A 50-year-old woman with an 8-year history of diffuse systemic sclerosis, a form of scleroderma, was referred by her rheumatologist to physical therapy for decreased finger range of motion (ROM) and pain that adversely affected her dexterity and ability to perform activities of daily living. To determine whether joint mobilization would be appropriate for this patient, posterior-to-anterior and modified lateral radiographs of both hands were requested by the physical therapist. Images showed significant bone loss in the distal phalanges of both thumbs and in the left third and fourth digits, and calcinosis in the tips of both thumbs. Because metacarpophalangeal and interphalangeal joint spaces appeared normal, except for a slight narrowing of the right fifth distal interphalangeal joint, joint mobilization, which would have been contraindicated by bone or joint destruction, was considered appropriate to help increase ROM. J Orthop Sports Phys Ther 2018;48(3):226. doi:10.2519/jospt.2018.7662. PMID- 29490599 TI - The End of an Era? AB - In 1972, American orthopaedic surgeon Charles Neer published his seminal paper, "Anterior Acromioplasty for the Chronic Impingement Syndrome in the Shoulder: A Preliminary Report." It wasn't a robust scientific paper; however, it changed the direction of orthopaedic practice for the next half century. Neer argued that a primary cause of shoulder pain was attrition of the supraspinatus tendon and related structures from the overlying acromion, especially when the arm was elevated. Neer recommended surgical removal to stop the impingement, and over the last half century, it could be argued that millions of people around the globe would have undergone acromioplasty surgery to stop this portion of the bone impinging onto the soft tissues located in the subacromial space. More recently, against the tide of subacromial decompression surgery there has been dissent, and the relationship between the acromion and symptoms has been challenged. J Orthop Sports Phys Ther 2018;48(3):127-129. doi:10.2519/jospt.2018.0102. PMID- 29490600 TI - Scapholunate Dissociation. AB - A 52-year-old man sustained an injury to the right wrist following a fall into a push-up position. Direct-access outpatient physical therapy evaluation was performed 24 hours after the injury. A scaphoid radiograph series, consistent with American College of Radiology guidelines, was obtained based upon examination findings. The radiographs revealed a scapholunate gap of 4 mm and a scapholunate angle of greater than 60 degrees , suggestive of scapholunate dissociation. J Orthop Sports Phys Ther 2018;48(3):225. doi:10.2519/jospt.2018.7774. PMID- 29490601 TI - Posterior Shoulder Tightness: To Treat or Not to Treat? AB - Shoulder pain is a common musculoskeletal complaint that is difficult to treat because of the biomechanical complexity of the shoulder region, the interplay between mobility and stability, and the vital role played by the shoulder in moving, positioning, and providing stability for hand function. Despite advances in biomechanics and pain science, there is still much to learn about how impairments influence shoulder function and health. One impairment, posterior shoulder tightness (PST), is often noted in individuals with shoulder pain and consequently has generated much discussion and debate in recent years. Range-of motion shifts and deficits are the clinical indicators of PST, with 3 tissue alterations potentially contributing to these modifications: (1) increased humeral retrotorsion (retroversion), (2) reduced posterior glenohumeral joint capsule extensibility, and (3) reduced posterior shoulder muscle/tendon extensibility. The significance of each alteration for shoulder function and the interaction among them remain unclear. It is also unknown if, or to what extent, these impairments can be resolved through interventions. This raises a clinically relevant and straightforward question: when PST is present, should we treat or not treat? In this Viewpoint, we will debate this question and propose that physical therapy interventions have the potential to improve only 1 of the 3 tissue alterations contributing to PST. J Orthop Sports Phys Ther 2018;48(3):133 136. doi:10.2519/jospt.2018.0605. PMID- 29490602 TI - If It Doesn't Work, Why Do We Still Do It? The Continuing Use of Subtalar Joint Neutral Theory in the Face of Overpowering Critical Research. AB - The use of subtalar joint neutral (STJN) in the assessment and treatment of foot related musculoskeletal symptomology is common in daily practice and still widely taught. The main pioneer of this theory was Dr Merton L. Root, and it has been labeled with a variety of names: "the foot morphology theory," "the subtalar joint neutral theory," or simply "Rootian theory" or "Root model." The theory's core concepts still underpin a common approach to musculoskeletal assessment of the foot, as well as the consequent design of foot orthoses. The available literature continues to point to Dr Root's theory as the most prevalently utilized. Concurrently, the worth of this theory has been challenged due to its poor reliability and limited external validity. This Viewpoint reviews the main clinical areas of the STJN theory, and concludes with a possible explanation and concerns for its ongoing use. To support our view, we will discuss (1) historical inaccuracies, (2) challenges with reliability, and (3) concerns with validity. J Orthop Sports Phys Ther 2018;48(3):130-132. doi:10.2519/jospt.2018.0604. PMID- 29490603 TI - Harnessing a Novel Inhibitory Role of miR-16 in Osteogenesis by Human Mesenchymal Stem Cells for Advanced Scaffold-Based Bone Tissue Engineering. AB - MicroRNA (miRNA) therapeutics is increasingly being developed to either target bone-related diseases such as osteoporosis and osteoarthritis or as the basis for novel bone tissue engineering strategies. A number of miRNAs have been reported as potential osteo-therapeutics but no consensus has yet been established on the optimal target. miR-16 has been studied extensively in nonosteogenic functions and used as functionality reporter target in the development of nonviral miRNA delivery platforms. This study hypothesized that miR-16 may also play an inhibitory role in osteogenesis due to its ability to directly target Smad5 and AcvR2a. This study thus aimed to assess the potential of miR-16 inhibition to increase osteogenesis in human mesenchymal stem cells (hMSCs) using a previously established miRNA delivery platform composed of nanohydroxyapatite (nHA) particles as nonviral vectors in combination with collagen-nHA scaffolds designed specifically for bone repair. Initial results showed that antagomiR-16 delivery efficiently increased the relative levels of both putative targets and Runx2, the key transcription factor for osteogenesis, while also increasing osteocalcin levels. Furthermore, significant increases in mineral calcium deposition by hMSCs were found in both monolayer and most importantly in scaffold-based osteodifferentiation studies, ultimately demonstrating that miR-16 inhibition further enhances the therapeutic potential of a scaffold with known potential for bone repair applications and thus holds significant therapeutic potential as a novel bone tissue engineering strategy. Furthermore, we suggest that harnessing the additional functions known to miR-16 by incorporating either its enhancers or inhibitors to tissue-specific tailored scaffolds provides exciting opportunities for a diverse range of therapeutic indications. PMID- 29490604 TI - Characterization of In Vitro Reconstructed Human Normotrophic, Hypertrophic, and Keloid Scar Models. AB - To understand scar pathology, develop new drugs, and provide a platform for personalized medicine, physiologically relevant human scar models are required, which are characteristic of different scar pathologies. Hypertrophic scars and keloids are two types of abnormal scar resulting from unknown abnormalities in the wound healing process. While they display different clinical behavior, differentiation between the two can be difficult-which in turn means that it is difficult to develop optimal therapeutic strategies. The aim of this study was to develop in vitro reconstructed human hypertrophic and keloid scar models and compare these to normotrophic scar and normal skin models to identify distinguishing biomarkers. Keratinocytes and fibroblasts from normal skin and scar types (normotrophic, hypertrophic, keloid) were used to reconstruct skin models. All skin models showed a reconstructed differentiated epidermis on a fibroblast populated collagen-elastin matrix. Both abnormal scar types showed increased contraction, dermal thickness, and myofibroblast staining compared to normal skin and normotrophic scar. Notably, the expression of extracellular matrix associated genes showed distinguishing profiles between all scar types and normal skin (hyaluronan synthase-1, matrix-metalloprotease-3), between keloid and normal skin (collagen type IV), between normal scar and keloid (laminin alpha1), and between keloid and hypertrophic scar (matrix-metalloprotease-1, integrin alpha5). Also, inflammatory cytokine and growth factor secretion (CCL5, CXCL1, CXCL8, CCL27, IL-6, HGF) showed differential secretion between scar types. Our results strongly suggest that abnormal scars arise from different pathologies rather than simply being on different ends of the scarring spectrum. Furthermore, such normal skin and scar models together with biomarkers, which distinguish the different scar types, would provide an animal free, physiologically relevant scar diagnostic and drug testing platform for the future. PMID- 29490605 TI - Polyplex System Versus Nucleofection for Human Skin Cell Transfection and Effect of Internal Ribosome Entry Site Sequence. AB - Nonviral transfection has important implications on gene therapy because of its safety. In particular, polyfection and nucleofection are two widely used systems for nonviral gene delivery. Their potential depends on the transfection efficiency achieved, which is influenced in turn by the type of cells transfected and by the plasmid that carries the gene of interest. The efficiency of transfection by polyfection or nucleofection in human fibroblasts and keratinocytes was evaluated in this study. Transfections were performed with plasmids containing a gene of interest (human cathelicidin antimicrobial peptide) and two reporter genes (red or green fluorescent protein) that included or not an internal ribosome entry site (IRES). The efficiency was measured by flow cytometry in terms of percentage of cells expressing the reporter gene; viability of transfected cells was also evaluated. It was found that nucleofection was more efficient than polyplexes for transfecting fibroblasts, while no significant differences were found between both systems of transfection when applied to keratinocytes. Regarding the viability of fibroblasts after transfection, values were high in both systems. In contrast, keratinocytes were more sensitive to nucleofection. It was also noted that both types of cells decreased reporter gene expression when IRES sequence was located upstream of the reporter gene, suggesting a negative effect on the expression of this gene. These results confirm that the transfection efficiency depends on the type of cells and the system used. PMID- 29490606 TI - Identification of novel loci associated with maturity and yield traits in early maturity soybean plant introduction lines. AB - BACKGROUND: To continue to meet the increasing demands of soybean worldwide, it is crucial to identify key genes regulating flowering and maturity to expand the cultivated regions into short season areas. Although four soybean genes have been successfully utilized in early maturity breeding programs, new genes governing maturity are continuously being identified suggesting that there remains as yet undiscovered loci governing agronomic traits of interest. The objective of this study was to identify novel loci and genes involved in a diverse set of early soybean maturity using genome-wide association (GWA) analyses to identify loci governing days to maturity (DTM), flowering (DTF) and pod filling (DTPF), as well as yield and 100 seed weight in Canadian environments. To do so, soybean plant introduction lines varying significantly for maturity, but classified as early varieties, were used. Plants were phenotyped for the five agronomic traits for five site-years and GWA approaches used to identify candidate loci and genes affecting each trait. RESULTS: Genotyping using genotyping-by-sequencing and microarray methods identified 67,594 single nucleotide polymorphisms, of which 31,283 had a linkage disequilibrium < 1 and minor allele frequency > 0.05 and were used for GWA analyses. A total of 9, 6, 4, 5 and 2 loci were detected for GWA analyses for DTM, DTF, DTPF, 100 seed weight and yield, respectively. Regions of interest, including a region surrounding the E1 gene for flowering and maturity, and several novel loci, were identified, with several loci having pleiotropic effects. Novel loci affecting maturity were identified on chromosomes five and 13 and reduced maturity by 7.2 and 3.3 days, respectively. Novel loci for maturity and flowering contained genes orthologous to known Arabidopsis flowering genes, while loci affecting yield and 100 seed weight contained genes known to cause dwarfism. CONCLUSIONS: This study demonstrated substantial variation in soybean agronomic traits of interest, including maturity and flowering dates as well as yield, and the utility of GWA analyses in identifying novel genetic factors underlying important agronomic traits. The loci and candidate genes identified serve as promising targets for future studies examining the mechanisms underlying the related soybean traits. PMID- 29490607 TI - QTL mapping of volatile compound production in Saccharomyces cerevisiae during alcoholic fermentation. AB - BACKGROUND: The volatile metabolites produced by Saccharomyces cerevisiae during alcoholic fermentation, which are mainly esters, higher alcohols and organic acids, play a vital role in the quality and perception of fermented beverages, such as wine. Although the metabolic pathways and genes behind yeast fermentative aroma formation are well described, little is known about the genetic mechanisms underlying variations between strains in the production of these aroma compounds. To increase our knowledge about the links between genetic variation and volatile production, we performed quantitative trait locus (QTL) mapping using 130 F2 meiotic segregants from two S. cerevisiae wine strains. The segregants were individually genotyped by next-generation sequencing and separately phenotyped during wine fermentation. RESULTS: Using different QTL mapping strategies, we were able to identify 65 QTLs in the genome, including 55 that influence the formation of 30 volatile secondary metabolites, 14 with an effect on sugar consumption and central carbon metabolite production, and 7 influencing fermentation parameters. For ethyl lactate, ethyl octanoate and propanol formation, we discovered 2 interacting QTLs each. Within 9 of the detected regions, we validated the contribution of 13 genes in the observed phenotypic variation by reciprocal hemizygosity analysis. These genes are involved in nitrogen uptake and metabolism (AGP1, ALP1, ILV6, LEU9), central carbon metabolism (HXT3, MAE1), fatty acid synthesis (FAS1) and regulation (AGP2, IXR1, NRG1, RGS2, RGT1, SIR2) and explain variations in the production of characteristic sensorial esters (e.g., 2-phenylethyl acetate, 2-metyhlpropyl acetate and ethyl hexanoate), higher alcohols and fatty acids. CONCLUSIONS: The detection of QTLs and their interactions emphasizes the complexity of yeast fermentative aroma formation. The validation of underlying allelic variants increases knowledge about genetic variation impacting metabolic pathways that lead to the synthesis of sensorial important compounds. As a result, this work lays the foundation for tailoring S. cerevisiae strains with optimized volatile metabolite production for fermented beverages and other biotechnological applications. PMID- 29490608 TI - The effects of trastuzumab on HER2-mediated cell signaling in CHO cells expressing human HER2. AB - BACKGROUND: Targeted therapy with trastuzumab has become a mainstay for HER2 positive breast cancer without a clear understanding of the mechanism of its action. While many mechanisms have been suggested for the action of trastuzumab, most of them are not substantiated by experimental data. It has been suggested that trastuzumab functions by inhibiting intracellular signaling initiated by HER2, however, the data are very controversial. A major issue is the different cellular background of various breast cancer cells lines used in these studies. Each breast cancer cell line has a unique expression profile of various HER receptors, which could significantly affect the effects of trastuzumab. METHODS: To overcome this problem, in this research we adopted a cell model that allow us to specifically examine the effects of trastuzumab on a single HER receptor without the influence of other HER receptors. Three CHO cell lines stably expressing only human EGFR (CHO-EGFR), HER2 (CHO-K6), or HER3 (CHO-HER3) were used. Various methods including cytotoxicity assay, immunoblotting, indirect immunofluorescence, cross linking, and antibody-dependent cellular cytotoxicity (ADCC) were employed in this research. RESULTS: We showed that trastuzumab did not bind EGFR and HER3, and thus did not affect the homodimerization and phosphorylation of EGFR and HER3. However, overexpression of HER2 in CHO cells, in the absence of other HER receptors, resulted in the homodimerization of HER2 and the phosphorylation of HER2 at all major pY residues. Trastuzumab bound to HER2 specifically and with high affinity. Trastuzumab inhibited neither the homodimerization of HER2, nor the phosphorylation of HER2 at most phosphotyrosine residues. Moreover, trastuzumab did not inhibit the phosphorylation of ERK and AKT in CHO-K6 cells, and did not inhibit the proliferation of CHO-K6 cells. However, trastuzumab induced strong ADCC in CHO-K6 cells. CONCLUSION: We concluded that, in the absence of other HER receptors, trastuzumab exerts its antitumor activity through the induction of ADCC, rather than the inhibition of HER2-homodimerization and phosphorylation. PMID- 29490610 TI - A randomized approach to speed up the analysis of large-scale read-count data in the application of CNV detection. AB - BACKGROUND: The application of high-throughput sequencing in a broad range of quantitative genomic assays (e.g., DNA-seq, ChIP-seq) has created a high demand for the analysis of large-scale read-count data. Typically, the genome is divided into tiling windows and windowed read-count data is generated for the entire genome from which genomic signals are detected (e.g. copy number changes in DNA seq, enrichment peaks in ChIP-seq). For accurate analysis of read-count data, many state-of-the-art statistical methods use generalized linear models (GLM) coupled with the negative-binomial (NB) distribution by leveraging its ability for simultaneous bias correction and signal detection. However, although statistically powerful, the GLM+NB method has a quadratic computational complexity and therefore suffers from slow running time when applied to large scale windowed read-count data. In this study, we aimed to speed up substantially the GLM+NB method by using a randomized algorithm and we demonstrate here the utility of our approach in the application of detecting copy number variants (CNVs) using a real example. RESULTS: We propose an efficient estimator, the randomized GLM+NB coefficients estimator (RGE), for speeding up the GLM+NB method. RGE samples the read-count data and solves the estimation problem on a smaller scale. We first theoretically validated the consistency and the variance properties of RGE. We then applied RGE to GENSENG, a GLM+NB based method for detecting CNVs. We named the resulting method as "R-GENSENG". Based on extensive evaluation using both simulated and empirical data, we concluded that R-GENSENG is ten times faster than the original GENSENG while maintaining GENSENG's accuracy in CNV detection. CONCLUSIONS: Our results suggest that RGE strategy developed here could be applied to other GLM+NB based read-count analyses, i.e. ChIP-seq data analysis, to substantially improve their computational efficiency while preserving the analytic power. PMID- 29490609 TI - Comparative oesophageal cancer risk assessment of hot beverage consumption (coffee, mate and tea): the margin of exposure of PAH vs very hot temperatures. AB - BACKGROUND: Consumption of very hot (> 65 degrees C) beverages is probably associated with increased risk of oesophageal cancer. First associations were reported for yerba mate and it was initially believed that high content of polycyclic aromatic hydrocarbons (PAH) might explain the risk. Later research on other beverage groups such as tea and coffee, which are also consumed very hot, found associations with increased risk of oesophageal cancer as well. The risk may therefore not be inherent in any compound contained in mate, but due to temperature. The aim of this study was to quantitatively assess the risk of PAH in comparison with the risk of the temperature effect using the margin of exposure (MOE) methodology. METHODS: The human dietary benzo[a]pyrene (BaP) and PAH4 (sum of benzo[a]pyrene, benzo[a]anthracene, chrysene, and benzo[b]fluoranthene) exposure through consumption of coffee, mate, and tea was estimated. The oesophageal cancer risk assessment for both PAH and temperature was conducted using the MOE approach. RESULTS: Considering differences in the transfer of the PAH from the leaves of mate and tea or from the ground coffee to the infusion, and considering the different preparation methods, exposures may vary considerably. The average individual exposure in MUg/kg bw/day arising from consumption of 1 cup (0.2 L) of infusion was highest for mate (2.85E-04 BaP and 7.22E-04 PAH4). The average per capita exposure in MUg/kg bw/day was as follows: coffee (4.21E-04 BaP, 4.15E-03 PAH4), mate (4.26E-03 BaP, 2.45E-02 PAH4), and tea (8.03E-04 BaP, 4.98E-03 PAH4). For all individual and population-based exposure scenarios, the average MOE for BaP and PAH4 was > 100,000 independent of beverage type. MOE values in this magnitude are considered as a very low risk. On the contrary, the MOE for the temperature effect was estimated as < 1 for very hot drinking temperatures, corroborating epidemiological observations about a probable oesophageal cancer risk caused by this behaviour. CONCLUSIONS: The temperature effect but not PAH exposure may pose an oesophageal cancer risk. Consumer education on risks associated with consumption of 'very hot' beverages and policy measures to threshold serving temperatures should be discussed. PMID- 29490611 TI - Large-scale genomic prediction using singular value decomposition of the genotype matrix. AB - BACKGROUND: For marker effect models and genomic animal models, computational requirements increase with the number of loci and the number of genotyped individuals, respectively. In the latter case, the inverse genomic relationship matrix (GRM) is typically needed, which is computationally demanding to compute for large datasets. Thus, there is a great need for dimensionality-reduction methods that can analyze massive genomic data. For this purpose, we developed reduced-dimension singular value decomposition (SVD) based models for genomic prediction. METHODS: Fast SVD is performed by analyzing different chromosomes/genome segments in parallel and/or by restricting SVD to a limited core of genotyped individuals, producing chromosome- or segment-specific principal components (PC). Given a limited effective population size, nearly all the genetic variation can be effectively captured by a limited number of PC. Genomic prediction can then be performed either by PC ridge regression (PCRR) or by genomic animal models using an inverse GRM computed from the chosen PC (PCIG). In the latter case, computation of the inverse GRM will be feasible for any number of genotyped individuals and can be readily produced row- or element-wise. RESULTS: Using simulated data, we show that PCRR and PCIG models, using chromosome-wise SVD of a core sample of individuals, are appropriate for genomic prediction in a larger population, and results in virtually identical predicted breeding values as the original full-dimension genomic model (r = 1.000). Compared with other algorithms (e.g. algorithm for proven and young animals, APY), the (chromosome-wise SVD-based) PCRR and PCIG models were more robust to size of the core sample, giving nearly identical results even down to 500 core individuals. The method was also successfully tested on a large multi-breed dataset. CONCLUSIONS: SVD can be used for dimensionality reduction of large genomic datasets. After SVD, genomic prediction using dense genomic data and many genotyped individuals can be done in a computationally efficient manner. Using this method, the resulting genomic estimated breeding values were virtually identical to those computed from a full-dimension genomic model. PMID- 29490612 TI - Complete genomic sequences of Propionibacterium freudenreichii phages from Swiss cheese reveal greater diversity than Cutibacterium (formerly Propionibacterium) acnes phages. AB - BACKGROUND: A remarkable exception to the large genetic diversity often observed for bacteriophages infecting a specific bacterial host was found for the Cutibacterium acnes (formerly Propionibacterium acnes) phages, which are highly homogeneous. Phages infecting the related species, which is also a member of the Propionibacteriaceae family, Propionibacterium freudenreichii, a bacterium used in production of Swiss-type cheeses, have also been described and are common contaminants of the cheese manufacturing process. However, little is known about their genetic composition and diversity. RESULTS: We obtained seven independently isolated bacteriophages that infect P. freudenreichii from Swiss-type cheese samples, and determined their complete genome sequences. These data revealed that all seven phage isolates are of similar genomic length and GC% content, but their genomes are highly diverse, including genes encoding the capsid, tape measure, and tail proteins. In contrast to C. acnes phages, all P. freudenreichii phage genomes encode a putative integrase protein, suggesting they are capable of lysogenic growth. This is supported by the finding of related prophages in some P. freudenreichii strains. The seven phages could further be distinguished as belonging to two distinct genomic types, or 'clusters', based on nucleotide sequences, and host range analyses conducted on a collection of P. freudenreichii strains show a higher degree of host specificity than is observed for the C. acnes phages. CONCLUSIONS: Overall, our data demonstrate P. freudenreichii bacteriophages are distinct from C. acnes phages, as evidenced by their higher genetic diversity, potential for lysogenic growth, and more restricted host ranges. This suggests substantial differences in the evolution of these related species from the Propionibacteriaceae family and their phages, which is potentially related to their distinct environmental niches. PMID- 29490613 TI - Identification and characterization of microRNAs involved in ascidian larval metamorphosis. AB - BACKGROUND: Metamorphosis takes place within the life cycle of most marine invertebrates. The marine ascidian is a classical model to study complex cellular processes and underlying molecular mechanisms involved in its larval metamorphosis. The detailed molecular signaling pathways remain elusive, though extracellular signal-regulated kinases (ERKs) and c-Jun N-terminal kinase (JNK) have been revealed to regulate cell migration, differentiation, and apoptosis in ascidian larval organ regression and juvenile organ development. MicroRNAs (miRNAs) are small non-coding RNAs that modulate gene expression at the post transcriptional level. Large numbers of miRNAs have been demonstrated to be involved in many developmental and metamorphic processes. However, the identification of miRNAs in ascidian larval metamorphosis has not yet been investigated. RESULTS: Totally, 106 known and 59 novel miRNAs were screened out through RNA-sequencing of three small RNA libraries from 18 to 21-h post fertilization (hpf) tailbud embryos as well as from 42 hpf larvae (after tail regression) in Ciona savignyi. Expression profiling of miRNAs was confirmed by quantitative real-time PCR, showing that the expression levels of csa-miR-4040, csa-miR-4086, csa-miR-4055, csa-miR-4060, csa-miR-216a, csa-miR-216b, csa-miR 217, csa-miR-183, and csa-miR-92c were significantly higher in 42 hpf larvae, whereas those of csa-miR-4018a, csa-miR-4018b, and csa-miR-4000f were higher in 18 and 21 hpf embryos; then, their expression in 42 hpf larvae became significantly low. For these 12 miRNAs, whose expression levels significantly changed, we predicted their target genes through the combination of miRanda and TargetScan. This prediction analysis revealed 332 miRNA-target gene pairs that were associated with the ERK, JNK, and transforming growth factor beta signaling pathways, suggesting that the identified miRNAs are involved in the regulation of C. savignyi larval metamorphosis via controlling the expression of their target genes. Furthermore, we validated the expression of five selected miRNAs by northern blotting. Among the selected miRNAs, the expression patterns of csa-miR 4018a, csa-miR-4018b, and csa-miR-4000f were further examined by whole-mount in situ hybridization. The results showed that all three miRNAs were specifically expressed in a cell population resembling mesenchymal cells at the head and trunk part in swimming larvae but not in metamorphic larvae. Utilizing the luciferase assay, we also confirmed that miR-4000f targeted Mapk1, suggesting that the csa miR-4018a/csa-miR-4018b/csa-miR-4000f cluster regulates larval metamorphosis through the Mapk1-mediated signaling pathway. CONCLUSIONS: Totally, 165 miRNAs, including 59 novel ones, were identified from the embryos and larvae of C. savignyi. Twelve of them showed significant changes in expression before and during metamorphosis. In situ hybridization and northern blotting results revealed that three miRNAs are potentially involved in the signaling regulatory network for the migration and differentiation of mesenchymal cells in larval metamorphosis. Furthermore, the luciferase reporter assay revealed that Mapk1 is a target of csa-miR-4000f. Our results not only present a list and profile of miRNAs involved in Ciona metamorphosis but also provide informative cues to further understand their function in ascidian larval metamorphosis. PMID- 29490614 TI - A cross-syndrome cohort comparison of sleep disturbance in children with Smith Magenis syndrome, Angelman syndrome, autism spectrum disorder and tuberous sclerosis complex. AB - BACKGROUND: Sleep disturbance is common in children with neurodevelopmental disorders, with high rates identified in children with Smith-Magenis syndrome (SMS), Angelman syndrome (AS), autism spectrum disorder (ASD) and tuberous sclerosis complex (TSC). Phenotypic sleep profiles for these groups may implicate different pathways to sleep disturbance. At present, cross-group comparisons that might elucidate putative phenotypic sleep characteristics are limited by measurement differences between studies. In this study, a standardised questionnaire was administered across groups affording comparison of the prevalence and profile of sleep disturbance between groups and contrast to chronologically age-matched typically developing (TD) peers. METHODS: The modified version of Simonds and Parraga's sleep questionnaire, adapted for use in children with intellectual disabilities, was employed to assess sleep disturbance profiles in children aged 2-15 years with SMS (n = 26), AS (n = 70), ASD (n = 30), TSC (n = 20) and a TD contrast group (n = 47). Associations between sleep disturbance and age, obesity, health conditions and overactivity/impulsivity were explored for each neurodevelopmental disorder group. RESULTS: Children with SMS displayed severe night waking (81%) and early morning waking (73%). In contrast, children with ASD experienced difficulties with sleep onset (30%) and sleep maintenance (43%). Fewer children with ASD (43%) and AS (46%) experienced severe night waking compared to children with SMS (both p < .01). Higher sleep disordered breathing scores were identified for children with SMS (p < .001) and AS (p < .001) compared to the TD group. Sleep disturbance in children with AS and TSC was associated with poorer health. Children experiencing symptoms indicative of gastro-oesophageal reflux had significantly higher sleep-disordered breathing scores in the AS, SMS and ASD groups (all p < .01). A number of associations between overactivity, impulsivity, gastro-oesophageal reflux, age and sleep disturbance were found for certain groups. CONCLUSIONS: These data reveal syndrome-specific profiles of sleep disturbance. The divergent associations between sleep parameters and person characteristics, specifically symptoms of gastro-oesophageal reflux, overactivity and impulsivity and age, implicate aetiology-specific mechanisms underpinning sleep disturbance. The differences in prevalence, severity and mechanisms implicated in sleep disturbance between groups support a syndrome-sensitive approach to assessment and treatment of sleep disturbance in children with neurodevelopmental disorders. PMID- 29490615 TI - Salt hypersensitive mutant 9, a nucleolar APUM23 protein, is essential for salt sensitivity in association with the ABA signaling pathway in Arabidopsis. AB - BACKGROUND: Although the nucleolus involves two major functions: pre-rRNA processing and ribosome biogenesis/assembly, increasing evidence indicates that it also plays important roles in response to abiotic stress. However, the possible regulatory mechanisms underlying the nucleolar proteins responsive to abiotic stress are largely unknown. High salinity is one of the major abiotic stresses, which hinders plant growth and productivity. Here, genetic screening approach was used to identify a salt hypersensitive mutant 9 (sahy9) mutant, also known as apum23, in Arabidopsis thaliana. Functional characterization of SAHY9/APUM23 through analyses of gene/protein expression profiles and metabolites was performed to decipher the possible regulatory mechanisms of the nucleolar protein SAHY9/APUM23 in response to salt stress. RESULTS: Seedlings of the sahy9/apum23 mutant displayed postgermination developmental arrest and then became bleached after prolonged culture under various salt stresses. Transcriptomic and proteomic analyses of salt-treated sahy9/apum23 and wild-type seedlings revealed differential expression of genes/proteins that have similar functional categories of biological processes, primarily those involved in cellular and metabolic processes as well as abiotic and biotic stress responses. However, the consistency of differential gene expression at both the transcript and protein levels was low (~ 12%), which suggests the involvement of posttranscriptional processing during the salt response. Furthermore, the altered expression of genes and proteins mediated by SAHY9/APUM23 regarding salt sensitivity involves abscisic acid (ABA) biosynthesis and signaling, abiotic stress responses, and ribosome biogenesis-related genes. Importantly, NCED3, ABI2, PP2CA, and major ABA-responsive marker genes, such as RD20 and RD29B, were down-regulated at both the transcript and protein levels in conjunction with lower contents of ABA and changes in the expression of a subset of LEA proteins in sahy9/apum23 mutants under salt stress. Moreover, the salt hypersensitivity of the sahy9/apum23 mutant was largely rescued by the exogenous application of ABA during salt stress. CONCLUSION: Our results revealed that SAHY9/APUM23 regulated the expression of ribosome biogenesis-related genes and proteins, which further affected the ribosome composition and abundance, and potential posttranscriptional regulation. The salt hypersensitivity of sahy9/apum23 is associated with the ABA-mediated signaling pathway and the downstream stress responsive network of this pathway. PMID- 29490616 TI - Dairy products and colorectal cancer in middle eastern and north African countries: a systematic review. AB - BACKGROUND: This systematic review was conducted to explain the association between dairy products and colorectal cancer (CRC) risk in Middle Eastern and North African countries (MENA). METHODS: The database consulted were PubMed, Clinical Trials, and Cochrane to extract the relevant studies published till the 31stof December 2016, using inclusion and exclusion criteria according to Prisma Protocol. The characteristics of these studies comprised the consumption of all types of dairy products in relation to CRC risk. RESULTS: Seven studies were included in this review. For dairy products overall, no significant association was found. Regarding modern dairy products, included studies found controversial results with OR = 9.88 (95% CI: 3.80-24.65) and ORa = 0.14 (95% CI: 0.02-0.71). A positive association was reported between traditional dairy products and CRC risk, to OR = 18.66 (95% CI: 3.06-113.86) to OR = 24 (95% CI: 1.74-330.82) to ORa = 1.42 (95% CI: 0.62-3.25), ptrend = 0.03. Calcium was inversely associated with the CRC risk with ORa = 0.08 (95% CI: 0.04-0.17). CONCLUSION: This is the first systematic review which illustrated the association between dairy consumption and CRC risk in MENA region. The results were inconsistent and not always homogeneous. Further specified studies may be warranted to address the questions about the association between CRC and dairy products in a specific context of MENA region. PMID- 29490618 TI - Correction to: Rate and determinants of non-adherence to a gluten-free diet and nutritional status assessment in children and adolescents with celiac disease in a tertiary Brazilian referral center: a cross-sectional and retrospective study. AB - CORRECTION: Unfortunately, after publication of this article [1], it was noticed that the names of the second and third authors were incorrectly displayed, respectively, as Glauce Hiromi Yonaminez and Carla Aline Satiro. The correct names are Glauce Hiromi Yonamine and Carla Aline Fernandes Satiro and can be seen in the corrected author list above. The original article has also been updated to correct this error. PMID- 29490619 TI - Correction to: Childhood disability in Malawi: a population based assessment using the key informant method. AB - Following the publication of this article [1] it was brought to our attention that inadvertently the COSECSA Oxford Orthopaedic Link (COOL) programme was not acknowledged for funding this study. PMID- 29490617 TI - Development of a complex intervention to improve participation of nursing home residents with joint contractures: a mixed-method study. AB - BACKGROUND: Joint contractures in nursing home residents limit the capacity to perform daily activities and restrict social participation. The purpose of this study was to develop a complex intervention to improve participation in nursing home residents with joint contractures. METHODS: The development followed the UK Medical Research Council framework using a mixed-methods design with re-analysis of existing interview data using a graphic modelling approach, group discussions with nursing home residents, systematic review of intervention studies, structured 2-day workshop with experts in geriatric, nursing, and rehabilitation, and group discussion with professionals in nursing homes. RESULTS: Graphic modelling identified restrictions in the use of transportation, walking within buildings, memory functions, and using the hands and arms as the central target points for the intervention. Seven group discussions with 33 residents revealed various aspects related to functioning and disability according the International Classification of Functioning, Disability and Health domains body functions, body structures, activities and participation, environmental factors, and personal factors. The systematic review included 17 studies with 992 participants: 16 randomised controlled trials and one controlled trial. The findings could not demonstrate any evidence in favour of an intervention. The structured 2-day expert workshop resulted in a variety of potential intervention components and implementation strategies. The group discussion with the professionals in nursing homes verified the feasibility of the components and the overall concept. The resulting intervention, Participation Enabling CAre in Nursing (PECAN), will be implemented during a 1-day workshop for nurses, a mentoring approach, and supportive material. The intervention addresses nurses and other staff, residents, their informal caregivers, therapists, and general practitioners. CONCLUSIONS: In view of the absence of any robust evidence, the decision to use mixed methods and to closely involve both health professionals and residents proved to be an appropriate means to develop a complex intervention to improve participation of and quality of life in nursing home residents. We will now evaluate the PECAN intervention for its impact and feasibility in a pilot study in preparation for an evaluation of its effectiveness in a definitive trial. TRIAL REGISTRATION: German clinical trials register, reference number DRKS00010037 (12 February 2016). PMID- 29490620 TI - Development of tissue inflammation accompanied by NLRP3 inflammasome activation in rabbits infected with Treponema pallidum strain Nichols. AB - BACKGROUND: The inflammasome responses in Treponema pallidum infection have been poorly understood to date. This study aimed to investigate the expression of the nucleotide-binding leucine-rich receptor protein 3 (NLRP3) inflammasome in the development of tissue inflammation in rabbits infected with T. pallidum. METHODS: Forty-five rabbits were randomly assigned to a blank group or an infection group, and the latter was divided into no benzathine penicillin G (BPG) and BPG treatment subgroups. Rabbits in the infection group were injected intradermally with 0.1 mL of a 107/mL T. pallidum suspension at 10 marked sites along the back, and the blank group was treated with normal saline. The BPG treatment subgroup received 200,000 U of BPG administered intramuscularly twice, at 14 d and 21 d post-infection. The development of lesions was observed, and biopsies of the injection site and various organs, including the kidney, liver, spleen, lung, and testis, were obtained for NLRP3, caspase-1, and interleukin-1beta (IL-1beta) mRNA analysis during infection. Blood was also collected for the determination of IL 1beta concentration. RESULTS: Rabbits infected with T. pallidum (both the BPG treatment and no BPG treatment subgroups), exhibited NLRP3 inflammasome activation and IL-1beta secretion in cutaneous lesions, showing a trend in elevation to decline; NLRP3 mRNA expression reached a peak at 18 d in the BPG treatment subgroup and 21 d in the no BPG treatment subgroup and returned to "normal" levels [vs. the blank group (P > 0.05)] at 42 d post-infection. The trend was similar to the change in cutaneous lesions in the infected rabbits, which reached a peak at 16 d in the BPG treatment subgroup and 18 d in the no BPG treatment subgroup. NLRP3, caspase-1, and IL-1beta mRNA expression levels were slightly different in different organs. NLRP3 inflammasome activation was also observed in the kidney, liver, lung, spleen and testis. IL-1beta expression was observed in the kidney, liver, lung and spleen; however, there was no detectable level of IL-1beta in the testes of the infected rabbits. CONCLUSIONS: This study established a clear link between NLRP3 inflammasome activation and the development of tissue inflammation in rabbits infected with T. pallidum. BPG therapy imperceptibly adjusted syphilitic inflammation. PMID- 29490621 TI - Effect of an vitamin D deficiency on depressive symptoms in child and adolescent psychiatric patients - a randomized controlled trial: study protocol. AB - BACKGROUND: Depression is a significant health and economic burden worldwide affecting not only adults but also children and adolescents. Current treatment options for this group are scarce and show moderate effect sizes. There is emerging evidence that dietary patterns and specific nutritional components might play a role in the risk for developing depression. This study protocol focusses on the role of vitamin D which is for long known to be relevant for calcium and phosphorous homeostasis and bone health but might also impact on mental health. However, the assessment of the vitamin D status of depressed juvenile patients, or supplementation of vitamin D is currently not part of routine treatment. Controlled intervention studies are indispensable to prove whether a vitamin D deficiency ameliorates depressive symptoms. METHODS/DESIGN: This double blinded, randomized controlled trial will enroll 200 inpatients from a child and adolescent psychiatric department with a vitamin D deficiency defined by a 25(OH) vitamin D-level < 30 nmol/l (12 ng/ml) and a Beck Depressions Inventory (BDI-II) score > 13 (indicating at least: mild depression). Upon referral, all patients will be screened, checked for inclusion criteria, and those eligible will be randomized after written consent into a supplementation or placebo group. Both study-arms will receive treatment-as-usual for their psychiatric disorder according to established clinical guidelines. The participants of the vitamin D supplementation group will receive 2640 I.E. vitamin D3 q.d. for 28 days in accordance with best practice in pediatric endocrinology. We hypothesize that delaying supplementation of vitamin D in the placebo arm will affect the treatment success of the depressive symptomatology in comparison to the vitamin D supplementation group. Patients will be enrolled for a period of 28 days based on the mean length of hospitalization of juveniles with depression. DISCUSSION: Randomized controlled trials in children and adolescents with depression are needed to elucidate the role of a vitamin D deficiency for mental disorders and to investigate the relevance of a routine assessment and supplementation of vitamin D deficits. TRIAL REGISTRATION: DRKS00009758, 16/06/2016 (retrospectively registered). PMID- 29490623 TI - Quality of life in hemodialysis diabetic patients: a multicenter cross-sectional study from Palestine. AB - BACKGROUND: Both diabetes and hemodialysis can seriously impair patients' health related quality of life (HRQOL). This study seeks to obtain data which will help to address the factors associated with impaired HRQOL in hemodialysis patients with diabetes in Palestine. METHODS: A cross-sectional study was performed in multiple centers in the period from November 2016 to June 2017. We utilized the Arabic version of EuroQoL 5 Dimensions 5 Levels (EQ-5D-5L) scale and EuroQol visual analogue scale (EQ-VAS) to measure patients' HRQOL. The study was conducted in six dialysis centers in the North of West Bank, Palestine. Descriptive and comparative statistics were used to describe clinical and socio demographic features of patients. Multiple linear regression analysis was used to determine the association between clinical and socio-demographic factors and HRQOL score. RESULTS: One hundred and forty one diabetic patients undergoing hemodialysis were enrolled in our study. Overall, 52.5% of them (74 patients) were males; the patients had a mean age of 60.32 with 52.5% of them aged below 60. The mean +/- standard deviation of EQ-5D-5L index and EQ-VAS score was 0.314 +/- 0.4 and 50.85+/-22.43, respectively. The findings of this study suggest that female patients, uneducated patients, unemployed patients, unmarried patients, and patients with more chronic diseases and comorbidities had a significant poor HRQOL scores (p values <0.05). Variables such as marital status and occupational status were significantly (p < 0.05) associated with the QOL score. More specifically, married status and employed patients positively associated with QOL score (beta = 0.22; p = 0.016 and beta = 0.27; p = 0.013, respectively). CONCLUSIONS: Among diabetic patients undergoing hemodialysis, married status and being employed were associated with modestly higher scores of QOL. We recommend that healthcare providers give more attention to diabetic dialysis patients who are unemployed and unmarried, as they are at a higher risk of having impaired HRQOL. PMID- 29490622 TI - Association of low blood pressure with suicidal ideation: a cross-sectional study of 10,708 adults with normal or low blood pressure in Korea. AB - BACKGROUND: Whether constitutional low blood pressure (BP) causes substantive health problems has been controversial, and subjects with hypotension exhibit a range of symptoms, from mild typical conditions such as tiredness and dizziness to more specific psychological conditions and even cognitive disorders. This study investigated whether low BP is associated with suicidal ideation in the general population. METHODS: Four years of data from the 2010-2013 Korean National Health and Nutrition Examination Survey were used. Among the 23,163 participants, aged 19-101 years, 10,708 with normal or low BP were included in the analysis of the association between low BP and suicidal ideation. The criterion used for low BP was systolic BP (SBP) < 100 mmHg, and in comparative analyses, the criteria used for low BP were SBP < 110, < 95, and < 90 mmHg. The association of prehypertension or hypertension with suicidal ideation was also examined. Suicidal ideation was assessed by a questionnaire. RESULTS: Compared with the normotensive reference group, the odds ratios (ORs) for suicidal ideation were significantly higher in the three hypotensive groups after adjusting for sex, age, body mass index, total cholesterol level, household income, educational level, marital status, current smoking status, alcohol intake, and the interaction between sex and age (OR = 1.29, 95% confidence interval [CI], 1.08 to 1.55; OR = 1.44, 95% CI, 1.14 to 1.82; and OR = 1.71, 95% CI, 1.11 to 2.62 for SBP < 100, SBP < 95, and SBP < 90 mmHg, respectively). Adding the clinical morbidities of diabetes mellitus, stroke, myocardial infarction/angina pectoris, and depression as covariates had little effect on the strength of the associations (OR = 1.25, 95% CI, 1.04 to 1.50; OR = 1.43, 95% CI, 1.13 to 1.81; and OR = 1.74, 95% CI, 1.14 to 2.68 for SBP < 100, < 95, and < 90 mmHg, respectively). CONCLUSIONS: Low SBP showed an association with suicidal ideation in the general Korean population. The association was significant for low BP, defined as a SBP < 100 mmHg, and the strength of the association increased as the criteria for low BP increased in strictness. PMID- 29490624 TI - Curcumin prevents strokes in stroke-prone spontaneously hypertensive rats by improving vascular endothelial function. AB - BACKGROUND: Antioxidants have shown great promise in stroke prevention. Diarylheptanoids (also known as diphenylheptanoids) are a small class of plant secondary metabolites that possess antioxidant activity greater than that of alpha-tocopherol. Curcumin is the best known member and is mainly extracted from turmeric. This study aimed to explore whether curcumin has a preventive effect on stroke. METHODS: Stroke-prone spontaneously hypertensive rats (SHRsp) were randomly divided into control group (n = 10) and curcumin group (n = 10), and saline or curcumin (100 mg/kg/day) was administrated daily. Vascular endothelial function was examined by the relaxation of the artery in response to acetylcholine (ACH). The levels of reactive oxygen species (ROS) and nitric oxide (NO) were measured by using dihydroethidium (DHE) and 4, 5-diaminofluorescein (DAF-2 DA), respectively. The expression of uncoupling protein 2 (UCP2) was examined by RT-PCR and immunoblotting. RESULTS: Administration of curcumin significantly delayed the onset of stroke and increased the survival of SHRsp, which was ascribed to decreased ROS and improved endothelial dependent relaxation of carotid arteries. In the presence of UCP2 inhibitor genipin, both curcumin mediated decrease of ROS and increase of NO production were blocked. CONCLUSION: Our study suggests that curcumin exerts a stroke preventive effect by attenuating oxidative stress to improve vascular endothelial function, which might be associated with UCP2 signaling. PMID- 29490625 TI - Impact of timing of adjuvant chemotherapy on survival in stage III colon cancer: a population-based study. AB - BACKGROUND: There is no consensus regarding the optimal time to initiate adjuvant chemotherapy after surgery for stage III colon cancer, and the relevant postoperative complications that cause delays in adjuvant chemotherapy are unknown. METHODS: Eligible patients aged >=66 years who were diagnosed with stage III colon cancer from 1992 to 2008 were identified using the linked Surveillance, Epidemiology, and End Results-Medicare database. Kaplan-Meier analysis and a Cox proportional hazards model were utilized to evaluate the impact of the timing of adjuvant chemotherapy on overall survival (OS). RESULTS: A total of 18,491 patients were included. Delayed adjuvant chemotherapy was associated with worse OS (9-12 weeks: hazard ratio [HR] = 1.222, 95% confidence interval [CI] = 1.063 1.405; 13-16 weeks: HR = 1.252, 95% CI = 1.041-1.505; >= 17 weeks: HR = 1.969, 95% CI = 1.663-2.331). The efficacies of adjuvant chemotherapy within 5-8 weeks and <=4 weeks were similar (HR = 1.045, 95% CI = 0.921-1.185). Compared with the non-chemotherapy group, chemotherapy initiated at >=21 weeks did not significantly improve OS (HR = 0.882, 95% CI = 0.763-1.018). Patients with postoperative complications, particularly cardiac arrest, ostomy infection, shock, and septicemia, had a significantly higher risk of a 4- to 11-week delay in adjuvant chemotherapy (p < 0.05). CONCLUSIONS: Adjuvant chemotherapy initiated within 8 weeks was acceptable for patients with stage III colon cancer. Delayed adjuvant chemotherapy after 8 weeks was significantly associated with worse OS. However, adjuvant chemotherapy might still be useful even with a delay of approximately 5 months. Moreover, postoperative complications were significantly associated with delayed adjuvant chemotherapy. PMID- 29490626 TI - Cross-cultural generalizability of suicide first aid actions: an analysis of agreement across expert consensus studies from a range of countries and cultures. AB - BACKGROUND: A number of Delphi expert consensus studies have been carried out with different countries and cultural groups to develop guidelines on how a member of the public should provide assistance to a person who is suicidal. The present study aimed to determine whether cross-culturally generalizable suicide first aid actions are possible by comparing agreement across these Delphi studies. METHODS: Data on endorsement rates for items were compared across six Delphi studies. These studies involved panels of professionals and consumer advocates from English-speaking countries, professionals from Sri Lanka, professionals from Japan, professionals from India, professionals from the Philippines, and professionals and consumer advocates in refugee and immigrant mental health. Correlations were calculated between item endorsement rates across panels. RESULTS: There were 18 items that were highly endorsed across all eight of the Delphi panels and an additional 15 items highly endorsed across the panels from the three lower middle-income countries (India, Philippines and Sri Lanka). Correlations across panels in item endorsement rates were all 0.60 or above, but were higher between panels from countries that are socioeconomically similar. CONCLUSIONS: There is broad agreement across the diverse expert panels about what are appropriate suicide first aid actions for members of the public, indicating that cross-cultural generalizability is possible. However, there is also some cultural specificity, indicating the need for local tailoring. PMID- 29490627 TI - Utility of dominant epitopes derived from cell-wall protein LppZ for immunodiagnostic of pulmonary tuberculosis. AB - BACKGROUND: Serological antibodies tests for tuberculosis (TB) are widely used in developing countries. They appear to have some advantages- faster, simple and could be used for extrapulmonary TB. However, most of current commercial TB serological tests are failed to provide sufficient sensitivity and specificity. Improved serological biomarkers were essential. In this study, we present an approach using peptide array to discover new immunodiagnostic biomarkers based on immunodominant epitopes of TB antigens. RESULTS: The Probable conserved lipoprotein LppZ, which is difficult to express and purify in vivo was selected as the model antigen. We use two-step screening for dominant epitope selection. Based on peptide array data from 170 TB patients and 41 control samples, two dominant epitopes were identified to have diagnostic value for TB patients. Truncation assay was used to identify the core reactive sequence. Peptide- based ELISA was used to evaluate the diagnostic ability of pep-LppZ-1 and pep-LppZ-13. Pep-LppZ-1 has a sensitivity of 49.2% and a specificity of 83.3% in TB diagnose. Pep-LppZ-13 has a sensitivity of 43.3% and a specificity of 88.5% in TB diagnose. CONCLUSIONS: Our result demonstrated that peptide array screening would be an advantage strategy of screening TB diagnostic peptides. PMID- 29490628 TI - Variance component analysis to assess protein quantification in biomarker validation: application to selected reaction monitoring-mass spectrometry. AB - BACKGROUND: In the field of biomarker validation with mass spectrometry, controlling the technical variability is a critical issue. In selected reaction monitoring (SRM) measurements, this issue provides the opportunity of using variance component analysis to distinguish various sources of variability. However, in case of unbalanced data (unequal number of observations in all factor combinations), the classical methods cannot correctly estimate the various sources of variability, particularly in presence of interaction. The present paper proposes an extension of the variance component analysis to estimate the various components of the variance, including an interaction component in case of unbalanced data. RESULTS: We applied an experimental design that uses a serial dilution to generate known relative protein concentrations and estimated these concentrations by two processing algorithms, a classical and a more recent one. The extended method allowed estimating the variances explained by the dilution and the technical process by each algorithm in an experiment with 9 proteins: L FABP, 14.3.3 sigma, Calgi, Def.A6, Villin, Calmo, I-FABP, Peroxi-5, and S100A14. Whereas, the recent algorithm gave a higher dilution variance and a lower technical variance than the classical one in two proteins with three peptides (L FABP and Villin), there were no significant difference between the two algorithms on all proteins. CONCLUSIONS: The extension of the variance component analysis was able to estimate correctly the variance components of protein concentration measurement in case of unbalanced design. PMID- 29490629 TI - Study on expression of plasma sCD138 in patients with hemorrhagic fever with renal syndrome. AB - BACKGROUND: Until now, there is non-specific treatment, and exploring early and novel biomarkers to determine the disease severity and prognosis of hemorrhagic fever with renal syndrome (HFRS) would be of importance for clinician to take systematic and timely intervention. This study observed the expression of plasma sCD138, a soluble component shedding from the glycocalyx (GCX) to the circulating blood, and evaluated its predictive value on disease severity and prognosis of HFRS. METHODS: One hundred and seventy-six patients with HFRS who were treated at our center between January 2011 and December 2013 were randomly enrolled in this study. The patients were divided into a mild-type group, a moderate-type group, a severe-type group and a critical-type group according to the HFRS criteria for clinical classification. Thirty-five blood samples from healthy subjects were obtained as the controls. The concentrations of sCD138 were detected using enzyme linked immunosorbent assay (ELISA). The levels of prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (Fib), albumin (ALB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), white blood cells (WBC), platelets (PLT), glucose (GLU), blood urea nitrogen (BUN) and serum creatinine (Scr) in the samples were routinely tested. The levels of sCD138 among the different types were compared; the correlation among sCD138 and the laboratory parameters mentioned above were analyzed. The predictive effectiveness for prognosis of sCD138 was evaluated using the receiver operating characteristic (ROC) curve analysis. RESULTS: Except for the mild-type, the levels of sCD138 in the moderate-, severe- and critical-type patients during the acute stage were significantly higher than that of the convalescent stage and the control (P<0.05). With the aggravation of the disease, the levels of sCD138 during the acute stage had an increasing tendency, while demonstrated no significant difference among the moderate-, severe- and critical-type patients (P>0.05). sCD138 was negatively correlated with Fib, PLT and ALB, and was positively correlated with WBC and AST (P<0.05). sCD138 demonstrated predictive effectiveness for prognosis with the area under the curve (AUC) of 0.778 (P<0.001). CONCLUSION: Dynamic detection of plasma sCD138 might be benefit to evaluating the disease severity and prognosis of the patients with HFRS. PMID- 29490630 TI - ATACseqQC: a Bioconductor package for post-alignment quality assessment of ATAC seq data. AB - BACKGROUND: ATAC-seq (Assays for Transposase-Accessible Chromatin using sequencing) is a recently developed technique for genome-wide analysis of chromatin accessibility. Compared to earlier methods for assaying chromatin accessibility, ATAC-seq is faster and easier to perform, does not require cross linking, has higher signal to noise ratio, and can be performed on small cell numbers. However, to ensure a successful ATAC-seq experiment, step-by-step quality assurance processes, including both wet lab quality control and in silico quality assessment, are essential. While several tools have been developed or adopted for assessing read quality, identifying nucleosome occupancy and accessible regions from ATAC-seq data, none of the tools provide a comprehensive set of functionalities for preprocessing and quality assessment of aligned ATAC seq datasets. RESULTS: We have developed a Bioconductor package, ATACseqQC, for easily generating various diagnostic plots to help researchers quickly assess the quality of their ATAC-seq data. In addition, this package contains functions to preprocess aligned ATAC-seq data for subsequent peak calling. Here we demonstrate the utilities of our package using 25 publicly available ATAC-seq datasets from four studies. We also provide guidelines on what the diagnostic plots should look like for an ideal ATAC-seq dataset. CONCLUSIONS: This software package has been used successfully for preprocessing and assessing several in-house and public ATAC-seq datasets. Diagnostic plots generated by this package will facilitate the quality assessment of ATAC-seq data, and help researchers to evaluate their own ATAC-seq experiments as well as select high-quality ATAC-seq datasets from public repositories such as GEO to avoid generating hypotheses or drawing conclusions from low-quality ATAC-seq experiments. The software, source code, and documentation are freely available as a Bioconductor package at https://bioconductor.org/packages/release/bioc/html/ATACseqQC.html . PMID- 29490631 TI - Medullary unidentified bright objects in Neurofibromatosis type 1: a case series. AB - BACKGROUND: In Neurofibromatosis type 1, cerebral Unidentified Bright Objects are a well-known benign entity that has been extensively reported in the literature. In our case series, we wish to focus on a further possible location of such lesions, the spinal cord, which we have defined as medullary Unidentified Bright Objects. These have been, to our knowledge, scarcely described in previous works. CASE PRESENTATION: We report the cases of 7 patients with medullary Unidentified Bright Objects in Neurofibromatosis type 1 that we have followed for up to 9 years in our Regional Referral Center for Neurofibromatosis. In all of our patients, these lesions were completely asymptomatic and reported on Magnetic Resonance exams the patients underwent for other clinical indications. CONCLUSIONS: The aim of our work is to increase awareness of the possibility of medullary Unidentified Bright Objects in Neurofibromatosis type 1 patients, which can simulate neoplastic lesions, suggesting a more conservative approach in these cases. PMID- 29490632 TI - Clinical decision making in the era of immunotherapy for high grade-glioma: report of four cases. AB - BACKGROUND: Immune checkpoint inhibitors (ICPIs) are being investigated in clinical trials for patients with glioblastoma. While these therapies hold great promise, management of the patients receiving such treatment can be complicated due to the challenges in recognizing immune-related adverse events caused by checkpoint inhibitor treatment. Brain imaging changes that are the consequence of an inflammatory response may be misinterpreted as disease progression leading to inappropriate premature cessation of treatment. The aim of this study was to, by way of a series of cases, underscore the challenges in determining the nature of contrast-enhancing masses that develop during the treatment of patients with glioblastoma treated with ICPIs. CASE PRESENTATION: We reviewed the clinical course and management of 4 patients on ICPIs who developed signs of tumor progression on imaging. These findings were examined in the context of Immunotherapy Response Assessment in Neuro-Oncology (iRANO) guidelines. Although all 4 patients had very similar imaging findings, 2 of the 4 patients were later found to have intense inflammatory changes (pseudoprogression) by pathologic examination. CONCLUSIONS: A high index of suspicion for pseudoprogression needs to be maintained when a patient with brain tumor on immunotherapy presents with worsening in an area of a pre-existing tumor or a new lesion in brain. Our findings strongly suggest that pathological diagnosis remains the gold standard for distinguishing tumor progression from pseudoprogression in patients receiving immunotherapy. There is a large unmet need to develop reliable non-invasive imaging diagnostic techniques. TRIAL REGISTRATION: ClinicalTrials.gov NCT02311920. Registered 8 December 2014. PMID- 29490633 TI - Effect of surgery and radiotherapy on complete blood count, lymphocyte subsets and inflammatory response in patients with advanced oral cancer. AB - BACKGROUND: The immune system has a known role in the aetiology, progression and final treatment outcome of oral squamous cell cancers. The aim of this study was to evaluate the influence of radical surgery and radiotherapy on advanced oral squamous cell carcinoma blood counts, lymphocyte subsets and levels of acute inflammatory response markers. METHODS: Blood samples were obtained from 56 patients 5 days before and 10 days after surgery, 30 days and 1 year after radiotherapy. The whole blood count, lymphocyte subsets and inflammatory response markers (C-reactive protein, erythrocyte sedimentation rate, leukocyte count, expression of index CD64 and index CD163 on neutrophils and monocytes) were measured, statistically analysed and correlated with clinical treatment outcomes. RESULTS: The post-operative period was characterised by the onset of anaemia, thrombocytosis, lymphopenia with reduced B lymphocyte, T helper cell and NK cell counts, and a rise in acute phase reactants. Immediately after radiotherapy, the anaemia improved, the lymphopenia worsened, and thrombocyte levels returned to pre-treatment values. There was a drop in counts across the T and B cell lines, including a reduction in B lymphocytes, naive and memory T cells with reduced CD4+ and CD8+ counts and a decreased CD4/CD8 ratio. One year after radiotherapy all the lymphocyte subsets remained depressed, the only exception being NK cells, whose levels returned to pre-treatment values. CONCLUSIONS: We concluded that surgery resulted in a stronger acute phase response than radiotherapy, while radiotherapy caused a long-lasting reduction in lymphocyte counts. There was no correlation between any of the pre-treatment parameters and the clinical outcome. PMID- 29490635 TI - Correction: expanded HIV pre-exposure prophylaxis (PrEP) implementation in communities in new South Wales, Australia (EPIC-NSW): design of an open label, single arm implementation trial. AB - After publication of the article [1], it has been brought to our attention that one of the members of the EPIC-NSW study group has had their name spelt incorrectly in the acknowledgements. The article mentions "Muhammad Hammoud" when in fact the correct spelling is "Mohamed Hammoud". PMID- 29490634 TI - A novel canine histiocytic sarcoma cell line: initial characterization and utilization for drug screening studies. AB - BACKGROUND: Histiocytic sarcoma is a rare disorder in humans, however it is seen with appreciable frequency in certain breeds of dogs, such as Bernese mountain dog. The purpose of this study was to fully characterize a novel canine histiocytic sarcoma cell line, and utilize it as a tool to screen for potential therapeutic drugs. METHODS: The histiocytic sarcoma cell line was characterized by expression of cellular markers as determined by immunohistochemistry and flow cytometry techniques. The neoplastic cells were also evaluated for their capability of phagocytizing beads particles, and their potential to grow as xenograft in an immunodeficient mouse. We investigated the in vitro cytotoxic activity of a panel of thirteen compounds using the MTS proliferation assay. Inhibitory effects of different drugs were compared using one-way ANOVA, and multiple means were compared using Tukey's test. RESULTS: Neoplastic cells expressed CD11c, CD14, CD18, CD45, CD172a, CD204, MHC I, and vimentin. Expression of MHC II was upregulated after exposure to LPS. Furthermore, the established cell line clearly demonstrated phagocytic activity similar to positive controls of macrophage cell line. The xenograft mouse developed a palpable subcutaneous soft tissue mass after 29 days of inoculation, which histologically resembled the primary neoplasm. Dasatinib, a tyrosine kinase pan-inhibitor, significantly inhibited the growth of the cells in vitro within a clinically achievable and tolerable plasma concentration. The inhibitory response to dasatinib was augmented when combined with doxorubicin. CONCLUSIONS: In the present study we demonstrated that a novel canine histiocytic sarcoma cell line presents a valuable tool to evaluate novel treatment approaches. The neoplastic cell line favorably responded to dasatinib, which represents a promising anticancer strategy for the treatment of this malignancy in dogs and similar disorders in humans. PMID- 29490636 TI - Interventions to reduce the negative effects of alcohol consumption in older adults: a systematic review. AB - BACKGROUND: Older individuals are consuming alcohol more frequently yet there is limited evidence on the effectiveness of current interventions. This systematic review aims to investigate interventions that target alcohol use in individuals aged 55 + . METHODS: CINAHL, ERIC, MEDLINE, Science Direct, PsychInfo, SCOPUS, Web of Science and socINDEX were searched using terms devised from the PICO (Population, Intervention, Comparison and Outcome) tool. Studies using pharmaceutical interventions, or those that investigated comorbidities or the use of other substances were excluded. Peer reviewed empirical studies written in the English language that compared the outcomes of alcohol related interventions to standard care were included in this review. Studies were appraised and assessed for quality using the relevant Critical Appraisal Skills Programme checklist. RESULTS: Seven papers were included in this review. Six were conducted in the United States of America and one in Denmark. The interventions were carried out in primary care centres and in community based groups. The studies included in this review showed varying levels of success. Participants showed improvements in at least one area of alcohol consumption or frequency of consumption however, these did not always reach significance. CONCLUSION: Individuals in this age group appear to respond well to interventions aimed at reducing alcohol consumption. However, included studies had limitations, in particular many did not include a clear intervention description; leaving us unable to fully investigate the components required for success. Further research is needed on the effective components of alcohol interventions targeting older people. PMID- 29490637 TI - Study protocol for a randomised controlled trial of exercise training in pulmonary hypertension (ExTra_PH). AB - BACKGROUND: Exercise training is an integral component of evidence-based management programs for many chronic cardiac and respiratory conditions. Despite this, there are limited high-quality studies available on the significance of exercise training in pulmonary hypertension (PH). The aim of this study is to evaluate the short and long-term effectiveness of exercise training in PH patients in terms of exercise capacity, quality of life, cardiac function and disease progression. METHODS: This randomized control trial will aim to recruit 50 medically stable PH patients categorised as New York Heart Association functional classification II-III. Participants will be randomly allocated to either the supervised exercise training group or usual care group for the 8-week study period. Exercise training will be conducted in an outpatient setting. Measurements at baseline and following the 8-week study period include exercise capacity (6 min walk distance and cardiopulmonary exercise test), cardiac function (exercise cardiac magnetic resonance imaging [CMRI] and echocardiography), health-related quality of life (Cambridge Pulmonary Hypertension Outcome Review), adverse responses to exercise training and time to clinical worsening. In addition, participants will be followed up for a minimum of 2 year period from commencement of the study so as to monitor long-term clinical outcomes i.e. time to clinical worsening. DISCUSSION: This study will determine whether an 8-week outpatient based supervised exercise training program is safe and beneficial for medically stable PH patients in the short and long term. This will be the first study to examine the impact of exercise training on right heart function using exercise CMRI. Results from the study will contribute new knowledge in relation to the impact of exercise training on cardiac function, long-term prognosis and inform clinical practice guidelines for this patient population. Moreover, the study will add to our understanding regarding the efficacy of exercise training in individuals with PH in an outpatient setting. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Registry: ACTRN12616001467426 . Registered 21st October, 2016. PMID- 29490639 TI - Commenting on "Prognostic and diagnostic significance of copeptin in acute exacerbation of chronic obstructive pulmonary disease and acute heart failure: data from ACE 2 study" by Jacob A. Winther and colleagues. AB - We would like to comment on the article entitled "Prognostic and diagnostic significance of copeptin in acute exacerbation of chronic obstructive pulmonary disease and acute heart failure: data from ACE 2 study" by Jacob A. Winther and colleagues, in the light of the results of a multicentric study published in 2014 by Vetrone F. et al., in which 336 patients with dyspnea were enrolled in the Emergency Departments of three University Hospitals in Italy.These two studies confirm the prognostic role of copeptin in patients with dyspnea due to heart failure but, while Winther et al. performed the copeptin measurements only at admission, Vetrone et al. evaluated the time-course of copeptin plasma concentration from the admission to the hospital discharge. The results showed a better performance of copeptin measured at discharge as prognostic biomarker compared to copeptin at hospital admission; similarly, a lower reduction or an increase in copeptin concentration from admission to discharge was a strong prognostic predictor of unfavorable outcome. In our opinion this is a very important result, opening new perspectives for the use of copeptin as prognostic marker in HF patients. PMID- 29490638 TI - Dietary patterns are influenced by socio-demographic conditions of women in childbearing age: a cohort study of pregnant women. AB - BACKGROUND: Women's health during their reproductive years and whilst pregnant has implications for their children's health, both in utero and during childhood. Associations of women's pre-pregnancy dietary patterns (DP) with maternal socio demographic characteristics and nutrient intake were investigated in ProcriAr cohort study in Sao Paulo/Brazil, 2012. METHODS: The DPs of 454 women were investigated by principal component factor analysis, using dietary information from a validated 110-item food frequency questionnaire. Multiple linear regression models identified independent associations between DPs and maternal socio-demographic characteristics and Spearman's correlation determined associations between DPs and nutrients intake. RESULTS: Participants' mean age was 26.1 years (standard deviation = 6.3), 10.3% had more than 8 years of formal education, 30% were migrants from outside of the Southeast of Brazil, 48% were employed, 13% were smokers, and 51% were overweight/obese. Four DPs were derived: 'Lentils, whole grains and soups,' 'Snacks, sandwiches, sweets and soft drinks,' 'Seasoned vegetables and lean meats,' and 'Sweetened juices, bread and butter, rice and beans'. The 'Lentils, whole grains and soups' score was positively related to maternal age, being non-smoker and born in the South, North or Midwest of Brazil. The 'Snacks, sandwiches, sweets and soft drinks' score was positively related to higher maternal education, and negatively related to age, lack of formal work and being born in the Northeast region. The 'Seasoned vegetables and lean meats' score was positively related to higher maternal education. The 'Sweetened juices, bread and butter, rice and beans' score was positively related to unemployment and to no family history of hypertension, and negatively related to maternal overweight and obesity. Dietary intake of fruits and vegetables, foods that require preparation, nutrients from one-carbon metabolism, protein, iron, calcium and vitamin D were correlated with the 'Seasoned vegetables and lean meats'. Dietary intake of sugar-sweetened and alcoholic beverages, industrialized and takeaway foods, and foods rich in sugar, energy, fat, and synthetic folate were correlated with the 'Snacks, sandwiches, sweets and soft drinks'. CONCLUSIONS: Findings from this study add perspectives to be considered in the implementation of health interventions, which could improve women's nutritional status and provide an adequate environment for the developing fetus. PMID- 29490640 TI - The value of facial attractiveness for encouraging fruit and vegetable consumption: analyses from a randomized controlled trial. AB - BACKGROUND: An effect of increased fruit and vegetable (FV) consumption on facial attractiveness has been proposed and recommended as a strategy to promote FV intakes, but no studies to date demonstrate a causal link between FV consumption and perceived attractiveness. This study investigated perceptions of attractiveness before and after the supervised consumption of 2, 5 or 8 FV portions/day for 4 weeks in 30 low FV consumers. Potential mechanisms for change via skin colour and perceived skin healthiness were also investigated. METHODS: Faces were photographed at the start and end of the 4 week intervention in controlled conditions. Seventy-three independent individuals subsequently rated all 60 photographs in a randomized order, for facial attractiveness, facial skin yellowness, redness, healthiness, clarity, and symmetry. RESULTS: Using clustered multiple regression, FV consumption over the previous 4 weeks had no direct effect on attractiveness, but, for female faces, some evidence was found for an indirect impact, via linear and non-linear changes in skin yellowness. Effect sizes, however, were small. No association between FV consumption and skin healthiness was found, but skin healthiness was associated with facial attractiveness. CONCLUSIONS: Controlled and objectively measured increases in FV consumption for 4 weeks resulted indirectly in increased attractiveness in females via increases in skin yellowness, but effects are small and gradually taper as FV consumption increases. Based on the effect sizes from this study, we are hesitant to recommend the use of facial attractiveness to encourage increased FV consumption. TRIAL REGISTRATION: Clinical trial Registration Number NCT01591057 ( www.clinicaltrials.gov ). Registered: 27th April, 2012. PMID- 29490641 TI - "One program that could improve health in this neighbourhood is ____?" using concept mapping to engage communities as part of a health and human services needs assessment. AB - BACKGROUND: This paper presents the findings of a rapid needs assessment conducted at the request of the local health authority responsible for health care services, the Toronto Central Local Health Integration Network (Ontario, Canada), to inform health and social service planning. METHODS: We utilized concept mapping methodology to facilitate engagement with diverse stakeholders more than 300 community members and service providers-with a focus on hard to reach populations. Key informant interviews with service providers were used to augment findings. RESULTS: Participants identified 48 unique services or service approaches they believed would improve the health of residents in the area, including those addressing health care, mental health and addictions, youth, families, people experiencing homelessness, seniors, general social services, and services targeting specific populations. While service providers consistently identified a critical need for mental health and addiction services, community members placed greater importance on the social determinants of health including access to housing, job placement supports and training and service accessibility. Both groups agreed that services and programs for seniors and people experiencing homelessness would be highly important. CONCLUSION: Our study provides a unique example of using concept mapping as a tool to aid a rapid service gap analysis and community engagement in a metropolitan area. The findings also reinforce the importance of working cross-sectorally, using a Health in All Policies approach when planning services for underserved populations. PMID- 29490642 TI - Eating Disorder Quality of Life Scale (EDQLS) in ethnically diverse college women: an exploratory factor analysis. AB - BACKGROUND: Extant research suggests that disordered eating is common in college women and is associated with decreased quality of life. The Eating Disorder Quality of Life Scale (EDQLS) examines impairment to disordered eating-related quality of life, but has not been validated in college women. Accordingly, the purpose of this study was to examine the reliability, validity, and factor structure of the EDQLS in a diverse sample of 971 college women. METHOD: Students from a large United States university completed questionnaires examining disordered eating and the EDQLS online. RESULTS: The EDQLS demonstrated excellent internal consistency and good convergent validity with the Eating Disorder Examination Questionnaire (EDEQ). Contrary to the original 12-domain design of the EDQLS, principal component analyses suggested five factors that mapped onto the following constructs: (1) Positive Emotionality; (2) Body/Weight Dissatisfaction; (3) Disordered Eating Behaviors; (4) Negative Emotionality; and (5) Social Engagement. However, 15 of the 40 items loaded onto multiple factors. CONCLUSIONS: Total scores on the EDQLS are reliable and valid when used with diverse samples of college women, but some revisions are needed to create subscales than can justifiably be used in clinical practice. PMID- 29490643 TI - Delays in seeking and receiving health care services for pneumonia in children under five in the Peruvian Amazon: a mixed-methods study on caregivers' perceptions. AB - BACKGROUND: Delays in receiving adequate care for children suffering from pneumonia can be life threatening and have been described associated with parents' limited education and their difficulties in recognizing the severity of the illness. The "three delays" was a model originally proposed to describe the most common determinants of maternal mortality, but has been adapted to describe delays in the health seeking process for caregivers of children under five. This study aims to explore the caregivers' perceived barriers for seeking and receiving health care services in children under five years old admitted to a referral hospital for community-acquired pneumonia in the Peruvian Amazon Region using the three-delays model framework. METHODS: There were two parts to this mixed-method, cross-sectional, hospital-based study. First, medical charts of 61 children (1 to 60 months old) admitted for pneumonia were reviewed, and clinical characteristics were noted. Second, to examine health care-seeking decisions and actions, as well as associated delays in the process of obtaining health care services, we interviewed 10 of the children's caregivers. RESULTS: Half of the children in our study were 9 months old or less. Main reasons for seeking care at the hospital were cough (93%) and fever (92%). Difficulty breathing and fast breathing were also reported in more than 60% of cases. In the interviews, caregivers reported delays of 1 to 14 days to go to the closest health facility. Factors perceived as causes for delays in deciding to seek care were apparent lack of skills to recognize signs and symptoms and of confidence in the health system, and practicing self-medication. No delays in reaching a health facility were reported. Once the caregivers reached a health facility, they perceived lack of competence of medical staff and inadequate treatment provided by the primary care physicians. CONCLUSION: According to caregivers, the main delays to get health care services for pneumonia among young children were identified in the initial decision of caregivers to seek healthcare and in the health system to provide it. Specific interventions targeted to main barriers may be useful for reducing delays in providing appropriate health care for children with pneumonia. PMID- 29490644 TI - Increased plasma and adipose tissue levels of ANGPTL8/Betatrophin and ANGPTL4 in people with hypertension. AB - BACKGROUND: Hypertension is a risk factor for both cardiovascular diseases (CVDs) and type 2 diabetes (T2D). Angiopoietin-like proteins (ANGPTLs), mainly ANGPTL3, ANGPTL4 and ANGPTL8, are associated with increased plasma lipid content due to their role in regulating the activity of lipoprotein lipase, a key enzyme in metabolism of the lipoprotein in circulation. Dyslipidaemia is a risk factor for hypertension development; however, the roles of ANGPTL3, ANGPTL4 and ANGPTL8 in subjects with hypertension have not yet been established. This study compared the plasma and adipose tissue levels of ANGPTL3, ANGPTL4 and ANGPTL8 in age- and body mass index-matched subjects with and without hypertension. METHODS: A total of 119 subjects, including 69 hypertensive and 50 non-hypertensive subjects, were enrolled. ANGPTL3, ANGPTL4 and ANGPTL8 plasma levels were measured by ELISA, whereas their levels in adipose tissue were assessed via real-time PCR. RESULTS: We found that ANGPTL4 (202.49 +/- 17.44 ng/mL vs. 160.64 +/- 10.36 ng/mL, p = 0.04) and ANGPTL8 levels (2310.96 +/- 194.88 pg/mL vs. 1583.35 +/- 138.27 pg/mL, p = 0.001) were higher in hypertensive subjects than non-hypertensive subjects. However, ANGPTL3 levels were not significantly different between the two populations. Similarly, ANGPTL4 and ANGPTL8 levels were also elevated in subjects with T2D and hypertension than in those with T2D but not hypertension. Additionally, people with highest tertiles of ANGPTL8 had higher odds of having hypertension (odd ratio [OR] = 3.8, 95% confidence interval [CI] = (1.5-9.8), p Value = 0.005. Similar to its plasma levels, ANGPTL4 and ANGPTL8 were higher in adipose tissue. CONCLUSIONS: In conclusion, our data illustrate that ANGPTL4 and ANGPTL8 levels in both plasma and adipose tissues are increased in subjects with hypertension. The elevated levels of ANGPTL4 and ANGPTL8 in hypertensive subjects highlight their potential involvement, their potential role as biomarkers for hypertension and their therapeutic value in hypertension given their roles in regulating lipid metabolism. PMID- 29490645 TI - Apatinib exhibits anti-leukemia activity in preclinical models of acute lymphoblastic leukemia. AB - BACKGROUND: Acute lymphoblastic leukemia (ALL) is a clonal malignant disorder characterized by an uncontrolled proliferation of immature B or T lymphocytes. Extensive studies have suggested an involvement of angiogenesis signaling in ALL progression and resistance to treatment. Thus, targeting angiogenesis with anti angiogenic drugs may be a promising approach for ALL treatment. In this study, we investigated the effectiveness of Apatinib, a novel receptor tyrosine kinase inhibitor selectively targeting VEGFR-2 in ALL cells. METHOD: ALL cell lines were treated with different concentration of Apatinib and then CCK8 assay, flow cytometry were used to determine the IC50 value and cell apoptosis, respectively. The effect of Apatinib against primary ALL cells from 11 adult patients and normal counterparts were also analyzed by apoptosis with flow cytometry. Next, we used western bolting and mass cytometry (CyTOF) assay to explore the underlying mechanism of the cytotoxicity of Apatinib. Finally, the anti-leukemia activity was further evaluated in an in vivo xenograft model of ALL. RESULTS: Our results showed that Apatinib significantly inhibited cell growth and promoted apoptosis in both B and T lineage ALL cell lines in a dose- and time-dependent manner. The IC50 values of Apatinib against Nalm6, Reh, Jurkat and Molt4 for 48 h were 55.76 +/- 13.19, 51.53 +/- 10.74, 32.43 +/- 5.58, 39.91 +/- 9.88 MUmol/L, and for 72 h were 30.34 +/- 2.65, 31.96 +/- 3.92, 17.62 +/- 5.90, and 17.65 +/- 2.17 MUmol/L respectively. Similarly, Apatinib shows cytotoxic activity against primary adult ALL cells while sparing their normal counterparts in vitro. Moreover, Apatinib suppressed ALL growth and progression in an in vivo xenograft model. Mechanistically, Apatinib-induced cytotoxicity was closely associated with inhibition of VEGFR2 and its downstream signaling cascades, including the PI3 K, MAPK and STAT3 pathways. CONCLUSION: Our study indicates that Apatinib exerts its anti-leukemia effect by inducing apoptosis through suppressing the VEGFR2 signaling pathway, supporting a potential role for Apatinib in the treatment of ALL. PMID- 29490646 TI - A bibliometric analysis of the published road traffic injuries research in India, post-1990. AB - BACKGROUND: Globally, road traffic injuries are the leading cause of death among those aged 15-29 years. However, road traffic injury research has not received adequate attention from the scientific community in low- and middle-income countries, including India. The present study aims to provide a bibliometric overview of research assessing road traffic injuries in India. METHODS: We used Scopus to extract relevant research in road traffic injuries published from 1991 to 2017. This study presented the key bibliometric indicators such as trends of annual publications and citations, top 10 authors, journals, institutions and highly cited articles, citation analysis of articles, co-occurrence of keywords, etc. Analysis was performed using Scopus, Microsoft Excel, and VOS-viewer. RESULTS: A total of 242 articles were retrieved with an h-index of 18, excluding self-citations. A steadfast growth of publications was documented in last decade, especially after the year 2010. The h-index of the top 10 authors, institutions, journals and highly cited articles did not surpass single digits. A network visualisation map showed that 'traffic accident', 'male', 'adolescent' and 'child' were the most commonly encountered key terms. The prominent authors were Gururaj G, Dandona R, and Hyder AA, whereas the top journals were the Indian Journal of Forensic Medicine and Toxicology, Medico Legal Update, and the International Journal of Applied Engineering Research and top institutions were the All India Institute of Medical Sciences, New Delhi, the Indian Institute of Technology, Delhi, and the Administrative Staff College of India. CONCLUSION: In India, road traffic injuries research is inadequate in quantity and quality, warranting greater attention from researchers and policy planners to address the burden of road traffic injuries. PMID- 29490647 TI - Disinvestment in healthcare: an overview of HTA agencies and organizations activities at European level. AB - BACKGROUND: In an era of a growing economic pressure for all health systems, the interest for "disinvestment" in healthcare increased. In this context, evidence based approaches such as Health Technology Assessment (HTA) are needed both to invest and to disinvest in health technologies. In order to investigate the extent of application of HTA in this field, methodological projects/frameworks, case studies, dissemination initiatives on disinvestment released by HTA agencies and organizations located in Europe were searched. METHODS: In July 2015, the websites of HTA agencies and organizations belonging to the European network for HTA (EUnetHTA) and the International Network of Agencies for HTA (INAHTA) were accessed and searched through the use of the term "disinvestment". Retrieved deliverables were considered eligible if they reported methodological projects/frameworks, case studies and dissemination initiatives focused on disinvestment in healthcare. RESULTS: 62 HTA agencies/organizations were accessed and eight methodological projects/frameworks, one case study and one dissemination initiative were found starting from 2007. With respect to methodological projects/frameworks, two were delivered in Austria, one in Italy, two in Spain and three in U.K. As for the case study and the dissemination initiative, both came from U.K. The majority of deliverables were aimed at making an overview of existing disinvestment approaches and at identifying challenges in their introduction. CONCLUSIONS: Today, in a healthcare context characterized by resource scarcity and increasing service demand, "disinvestment" from low-value services and reinvestment in high-value ones is a key strategy that may be supported by HTA. The lack of evaluation of technologies in use, in particular at the end of their lifecycle, may be due to the scant availability of frameworks and guidelines for identification and assessment of obsolete technologies that was shown by our work. Although several projects were carried out in different countries, most remain constrained to the field of research. Disinvestment is a relatively new concept in HTA that could pose challenges also from a methodological point of view. To tackle these challenges, it is necessary to construct experiences at international level with the aim to develop new methodological approaches to produce and grow evidence on disinvestment policies and practices. PMID- 29490648 TI - The effectiveness of a stage-based lifestyle modification intervention for obese children. AB - BACKGROUND: Interventions that encompass behavioural modifications of dietary intake and physical activity are essential for the management of obesity in children. This study assessed the effectiveness of a stage-based lifestyle modification intervention for obese children. METHODS: A total of 50 obese children (7-11 years old) were randomized to the intervention group (IG, n = 25) or the control group (CG, n = 25). Data were collected at baseline, at follow-up (every month) and at six months after the end of the intervention. IG received stage-based lifestyle modification intervention based on the Nutrition Practice Guideline for the Management of Childhood Obesity, while CG received standard treatment. Changes in body composition, physical activity and dietary intake were examined in both the intervention and control groups. RESULTS: Both groups had significant increases in weight (IG: 1.5 +/- 0.5 kg; CG: 3.9 +/- 0.6 kg) (p < 0.01) and waist circumference (IG: 0.1 +/- 0.5 cm; CG: 2.2 +/- 0.7 cm) (p < 0.05), but the increases were significantly higher in CG than IG. Body Mass Index (BMI)-for-age z scores decreased significantly in IG (- 0.2 +/- 0.0, p < 0.01) but not in CG. The physical activity of the IG significantly increased (0.44 +/- 0.13) compared with that of CG (- 0.28 +/- 0.18), and the difference in mean change between groups was statistically significant (p < 0.05). Dietary intake was not significantly different between the two groups. However, calorie and carbohydrate intake decreased significantly in both groups. CONCLUSIONS: A stage based intervention that modified dietary and physical activity behaviour may be effective in weight management for obese children. TRIAL REGISTRATION: NCT03429699 retrospectively registered 9 February 2018. PMID- 29490649 TI - Mosquito net coverage in years between mass distributions: a case study of Tanzania, 2013. AB - BACKGROUND: The Government of Tanzania is the main source of long-lasting insecticidal nets (LLINs) for its population. Mosquito nets (treated and untreated) are also available in the commercial market. To sustain investments and health gains in the fight against malaria, it is important for the National Malaria Control Programme to monitor LLIN coverage especially in the years between mass distributions and to understand what households do if their free nets are deemed unusable. The aim of this paper was to assess standard LLIN indicators by wealth status in Tanzania in 2013, 2 years after the last mass campaign in 2011, and extend the analysis to untreated nets (UTNs) to investigate how households adapt when nets are not continuously distributed. METHODS: Between October-December 2013, a household survey was conducted in 3398 households in eight districts in Tanzania. Using the Roll Back Malaria indicators, the study analysed: (1) household net ownership; (2) access to nets; (3) population net use and (4) net use:access ratio. Outcomes were calculated for LLINs and UTNs. Results were analysed by socio-economic quintiles and by district. RESULTS: Only three of the eight districts had household LLIN ownership of more than 80%. In 2013, less than a quarter of the households had one LLIN for every two people and only half of the population had access to an LLIN. Only the wealthier quintiles increased their net ownership and access to levels above 80% through the addition of UTNs. Overall net use of the population was low (LLINs: 32.8%; UTNs: 9.5%) and net use:access ratio was below target level (LLINs: 0.66; UTN: 0.50). Both measures varied significantly by district. CONCLUSIONS: Two years after the last mass campaign, the percentage of households or population with access to LLINs was low. These findings indicate the average rate at which households in Tanzania lose their nets is higher than the rate at which they acquire new nets. The wealthiest households topped up their household net ownership with UTNs. Efforts to make LLINs available through commercial markets should be promoted, so those who can afford to buy nets purchase LLINs rather than UTNs. Net use was low around 40% and mostly explained by lack of access to nets. However, the use:access ratio was poor in Mbozi and Kahama districts warranting further investigations to understand other barriers to net use. PMID- 29490650 TI - Long non-coding RNA Gas5 regulates proliferation and apoptosis in HCS-2/8 cells and growth plate chondrocytes by controlling FGF1 expression via miR-21 regulation. AB - BACKGROUND: LncRNA Gas5 is known to be a key control element during growth, differentiation and development in mammalian species. However, the role and function of Gas5 in growth plate chondrocytes has not been determined. METHODS: The overexpression and knockdown models of Gas5 and miR-21 in cells and animals were constructed. Cell survival was determined by MTT assay and flow cytometry. Animal biochemical indices were measured by enzyme-linked immunosorbent assay, hematoxylin/eosin staining, immunohistochemistry or in situ hybridisation. Dual luciferase reporter gene assay was carried out to study targeting. RESULTS: First, we found the expression levels of fibroblast growth factor 1(FGF1) were up regulated and miR-21 were down-regulated in Gas5 overexpressing model cells. Meanwhile, the expression levels of FGF1 and Gas5 were up-regulated in miR-21 knockdown model cells. Furthermore, cell proliferation was significantly promoted after Gas5 knockdown or miR-21 overexpression. Subsequently, Gas5 promoted apoptosis, while miR-21 suppressed apoptosis. Animal assays demonstrated that both Gas5 and dexamethasone suppressed proliferation and promoted apoptosis of growth plate chondrocytes, up-regulated FGF1 expression but reduced miR-21 expression. Finally, there was a binding relationship between Gas5, miR-21 and FGF1. CONCLUSION: We concluded that Gas5 regulated proliferation and apoptosis in growth plate by controlling FGF1 expression via miR-21 regulation. PMID- 29490651 TI - Fiscal rules, powerful levers for controlling the health budget? Evidence from 32 OECD countries. AB - BACKGROUND: Publicly funded healthcare forms an intricate part of government spending in most Organisation for Economic Co-operation and Development (OECD) countries, because of its reliance on entitlements and dedicated revenue streams. The impact of budgetary rules and procedures on publicly funded health care might thus be different from other spending categories. In this study we focus on the potential of fiscal rules to contain these costs and their design features. METHODS: We assess the relationship between fiscal rules and the level of public health care expenditure of 32 (OECD) countries between 1985 and 2014. Our dataset consists of health care expenditure data of the OECD and data on fiscal rules of the International Monetary Fund (IMF) for that same period. Through a multivariate regression analysis, we estimate the association between fiscal rules and its subcategories and inflation adjusted public health care expenditure. We control for population, Gross Domestic Product (GDP), debt and whether countries received an IMF bailout for the specific period. In all our regressions we include country and year fixed effects. RESULTS: The presence of a fiscal rule on average is associated with a 3 % reduction of public health care expenditure. Supranational balanced budget rules are associated with some 8 % lower expenditure. Health service provision-oriented countries with more passive purchasing structures seem less capable of containing costs through fiscal rules. Fiscal rules demonstrate lagged effectiveness; the potential for expenditure reduction increases after one and two years of fiscal rule implementation. Finally, we find evidence that fiscal frameworks that incorporate multi-year expenditure ceilings show additional potential for cost control. CONCLUSIONS: Our study shows that there seems a clear relationship between the potential of fiscal rules and budgeting health expenses. Using fiscal rules to contain the level of health care expenditure can thus be a necessary precondition for successful strategies for cost control. PMID- 29490652 TI - Assessment of household use of iodized salt and adequacy of salt iodization: a cross-sectional National Study in Saudi Arabia. AB - OBJECTIVES: This study was conducted to assess household coverage with iodized salt in Saudi Arabia, and to determine adequacy of salt iodization. METHODS: A school-based cross-sectional study using WHO 30-cluster survey methodology. RESULTS: Analysis of 4242 salt samples using qualitative rapid test kit (RTK) revealed that 68.7% (95% CI 67.3-70.1%) were iodized with significant regional differences (p < 0.001). The highest iodized salt samples came from Makkah (82.3%), Riyadh (81.1%) and Maddinah (76.2%) regions, while the least iodized salt samples came from Hail (31.3%), Baha (53.0%), and Northern Borders (57.5%) regions. The national weighted proportion of households consuming iodizes salt was 69.8% (95% CI 69.4-71.2), which is below the Universal Salt Iodization (USI) goal (>=90% coverage). For validation, a quantitative iodometric titration method was used to analyze 775 representative salt samples screened iodized by RTK; iodine content of >=15 ppm was found in 95.2% (95% CI 93.9-96.5) of samples with median iodine content 51 ppm (mean 50.4 +/- 21.8). More than 70% of the iodized salt samples contained iodine concentration higher than the recommended national level (15-40 ppm). CONCLUSIONS: The study revealed inadequate consumption of iodized salt among Saudi households and explored marked regional heterogeneity. The majority of iodized salt samples contained iodine concentration more than the recommended level. These findings imply the need to launch a public awareness campaign on use of iodized salt. Legislation to ban production and sale of non iodized salt sale for human consumption might be considered. A well-functioning monitoring system at factory level and surveillance system are crucially needed to ensure proper salt iodization and intake. PMID- 29490653 TI - Renal capsule metastasis from renal pelvic cancer: a case report. AB - BACKGROUND: Metastatic renal cancers are relatively common. Most are metastases to the renal parenchyma via a hematogenous route and are derived from lung, breast, and gastrointestinal cancer, malignant melanoma, and hematologic malignant cancer. However, little is known about renal capsule metastasis from other cancers. CASE PRESENTATION: We report a 71-year-old woman with breast cancer who was treated with endocrine therapy. She presented with gross hematuria and was diagnosed as having right renal pelvic cancer and renal cell cancer. She underwent right laparoscopic radical nephroureterectomy. Pathological findings revealed right pelvic cancer and renal capsule metastasis. CONCLUSION: Renal capsule metastasis derived from renal pelvic cancer is very rare. When diagnosing renal capsule cancer, we believe that renal capsule metastasis should also be taken into consideration. Clinical and radiological differential diagnosis of renal capsule metastasis from renal cell cancer and primary renal capsule cancer is difficult. Assessment of the histopathological findings of the surgical specimens seems to be the only realistic approach to achieving the correct diagnosis. PMID- 29490654 TI - Health care resource use among patients with advanced non-small cell lung cancer: the PIvOTAL retrospective observational study. AB - BACKGROUND: Data are scarce regarding real-world health care resource use (HCRU) for non-small cell lung cancer (NSCLC). An understanding of current clinical practices and HCRU is needed to provide a benchmark for rapidly evolving NSCLC management recommendations and therapeutic options. The objective of this study was to describe real-world HCRU for patients with advanced NSCLC. METHODS: This multinational, retrospective chart review study was conducted at academic and community oncology sites in Italy, Spain, Germany, Australia, Japan, South Korea, Taiwan, and Brazil. Deidentified data were drawn from medical records of 1440 adults (>=18 years old) who initiated systemic therapy (2011 to mid-2013) for a new, confirmed diagnosis of advanced or metastatic (stage IIIB or IV) NSCLC. We summarized HCRU associated with first and subsequent lines of systemic therapy for advanced/metastatic NSCLC. RESULTS: The proportion of patients who were hospitalized at least once varied by country from 24% in Italy to 81% in Japan during first-line therapy and from 22% in Italy to 84% in Japan during second line therapy; overall hospitalization frequency was 2.5-11.1 per 100 patient weeks, depending on country. Emergency visit frequency also varied among countries (overall from 0.3-5.9 per 100 patient-weeks), increasing consistently from first- through third-line therapy in each country. The outpatient setting was the most common setting of resource use. Most patients in the study had multiple outpatient visits in association with each line of therapy (overall from 21.1 to 59.0 outpatient visits per 100 patient-weeks, depending on country). The use of health care resources showed no regular pattern associated with results of tests for activating mutations of the epidermal growth factor receptor (EGFR) gene or anaplastic lymphoma kinase (ALK) gene rearrangements. CONCLUSIONS: HCRU varied across countries. These findings suggest differing approaches to the clinical management of advanced NSCLC among the eight countries. Comparative findings and an understanding of country-specific clinical practices can help to identify areas of need and guide future resource allocation for patients with advanced NSCLC. Further studies evaluating the costs associated with resource use are warranted. PMID- 29490656 TI - Successful joint preservation of distal radius osteosarcoma by en bloc tumor excision and reconstruction using a tumor bearing frozen autograft: a case report. AB - BACKGROUND: The wrist joint is an extremely rare site for osteosarcoma. Joint structure preservation to maintain good limb function is well described in case of knee osteosarcoma, whereas it is not described in case of wrist joint osteosarcoma. In this report, we present the first case of joint preservation surgery to treat distal radius osteosarcoma using a tumor bearing autograft treated with liquid nitrogen. CASE PRESENTATION: A 46-year-old male presented with swelling and pain in the right wrist and was diagnosed with conventional osteosarcoma of the distal radius. The patient responded well to neoadjuvant chemotherapy and the tumor shrank remarkably. Wide tumor excision to preserve the radiocarpal joint and reconstruction with a tumor bearing frozen autograft were performed. Partial bone union was detected 3 months postoperatively and complete bone union was detected 9 months postoperatively. Following the surgery, there was immediate commencement of the range of motion (ROM) training in both the wrist and fingers. At the final postoperative follow-up of 41 months, the patient had normal ROM in the wrist, fingers, and forearms, with a score of 100% in the Musculoskeletal Tumor Society (MSTS) score and was disease free. CONCLUSION: We present the first case in which en bloc tumor excision with joint preservation of the wrist and reconstruction using a tumor bearing frozen autograft were performed. The surgery yielded excellent hand, wrist, and forearm function at the final follow-up. PMID- 29490657 TI - "Never at ease" - family carers within integrated palliative care: a multinational, mixed method study. AB - BACKGROUND: Family carers manage a wide range of responsibilities in the lives and care of patients receiving palliative care. They fulfil multiple roles and perform activities within different settings. This has immediate consequences on family carers' every-day lives. According to literature, family carers in palliative care are both part of the formal and informal care network, but also persons in need of support. This article aims to investigate 1) burdens and rewards associated with family caregiving and 2) what family carers find helpful in their contact with professionals from integrated palliative care initiatives (IPC-i) and other services. METHODS: Family carers looking after patients with cancer, chronic obstructive pulmonary disease or chronic heart failure were purposefully recruited at 22 IPC-i in Belgium, Germany, Hungary, the Netherlands and the United Kingdom in the course of the project "Patient-centred palliative care pathways in advanced cancer and chronic disease" (InSup-C). Semi-structured interviews (n = 156) and 87 quantitative questionnaires (CRA, POS, CANHELP Lite) were conducted with family carers. Interviews were analysed with transnationally agreed thematic codes (MAXQDA or NVivo). Statistical tests (SPSS) were carried out in accordance with the characteristic value of the items and distributions. RESULTS: On average, quantitative data showed moderate burden, but the qualitative findings indicated that this burden might be underrated. There is some evidence that IPC-i with well-developed professional care networks and communication systems relieved family carers' burden by direct and indirect interventions; e.g. provision of night shift nurses or psychological support. Needs of family carers were similar in all participating countries. However, in all countries IPC-i mostly offered one-off events for family carers, lacking systematic or institutionalised support structures. CONCLUSIONS: Data suggest that, most IPC-i did not pay enough attention to the needs of most family carers, and did not offer proactive care and access to supportive resources to them (e.g. training, respite care, access to resources). We recommend recognizing family carers as part of the 'unit of care' and partner in caregiving, to improve their knowledge about, and access to, and the support available. PMID- 29490655 TI - Adaptive designs in clinical trials: why use them, and how to run and report them. AB - Adaptive designs can make clinical trials more flexible by utilising results accumulating in the trial to modify the trial's course in accordance with pre specified rules. Trials with an adaptive design are often more efficient, informative and ethical than trials with a traditional fixed design since they often make better use of resources such as time and money, and might require fewer participants. Adaptive designs can be applied across all phases of clinical research, from early-phase dose escalation to confirmatory trials. The pace of the uptake of adaptive designs in clinical research, however, has remained well behind that of the statistical literature introducing new methods and highlighting their potential advantages. We speculate that one factor contributing to this is that the full range of adaptations available to trial designs, as well as their goals, advantages and limitations, remains unfamiliar to many parts of the clinical community. Additionally, the term adaptive design has been misleadingly used as an all-encompassing label to refer to certain methods that could be deemed controversial or that have been inadequately implemented.We believe that even if the planning and analysis of a trial is undertaken by an expert statistician, it is essential that the investigators understand the implications of using an adaptive design, for example, what the practical challenges are, what can (and cannot) be inferred from the results of such a trial, and how to report and communicate the results. This tutorial paper provides guidance on key aspects of adaptive designs that are relevant to clinical triallists. We explain the basic rationale behind adaptive designs, clarify ambiguous terminology and summarise the utility and pitfalls of adaptive designs. We discuss practical aspects around funding, ethical approval, treatment supply and communication with stakeholders and trial participants. Our focus, however, is on the interpretation and reporting of results from adaptive design trials, which we consider vital for anyone involved in medical research. We emphasise the general principles of transparency and reproducibility and suggest how best to put them into practice. PMID- 29490658 TI - The Cambridge Prognostic Groups for improved prediction of disease mortality at diagnosis in primary non-metastatic prostate cancer: a validation study. AB - BACKGROUND: The purpose of this study is to validate a new five-tiered prognostic classification system to better discriminate cancer-specific mortality in men diagnosed with primary non-metastatic prostate cancer. METHODS: We applied a recently described five-strata model, the Cambridge Prognostic Groups (CPGs 1-5), in two international cohorts and tested prognostic performance against the current standard three-strata classification of low-, intermediate- or high-risk disease. Diagnostic clinico-pathological data for men obtained from the Prostate Cancer data Base Sweden (PCBaSe) and the Singapore Health Study were used. The main outcome measure was prostate cancer mortality (PCM) stratified by age group and treatment modality. RESULTS: The PCBaSe cohort included 72,337 men, of whom 7162 died of prostate cancer. The CPG model successfully classified men with different risks of PCM with competing risk regression confirming significant intergroup distinction (p < 0.0001). The CPGs were significantly better at stratified prediction of PCM compared to the current three-tiered system (concordance index (C-index) 0.81 vs. 0.77, p < 0.0001). This superiority was maintained for every age group division (p < 0.0001). Also in the ethnically different Singapore cohort of 2550 men with 142 prostate cancer deaths, the CPG model outperformed the three strata categories (C-index 0.79 vs. 0.76, p < 0.0001). The model also retained superior prognostic discrimination in the treatment sub-groups: radical prostatectomy (n = 20,586), C-index 0.77 vs. 074; radiotherapy (n = 11,872), C-index 0.73 vs. 0.69; and conservative management (n = 14,950), C-index 0.74 vs. 0.73. The CPG groups that sub-divided the old intermediate-risk (CPG2 vs. CPG3) and high-risk categories (CPG4 vs. CPG5) significantly discriminated PCM outcomes after radical therapy or conservative management (p < 0.0001). CONCLUSIONS: This validation study of nearly 75,000 men confirms that the CPG five-tiered prognostic model has superior discrimination compared to the three-tiered model in predicting prostate cancer death across different age and treatment groups. Crucially, it identifies distinct sub-groups of men within the old intermediate-risk and high-risk criteria who have very different prognostic outcomes. We therefore propose adoption of the CPG model as a simple-to-use but more accurate prognostic stratification tool to help guide management for men with newly diagnosed prostate cancer. PMID- 29490659 TI - Clinical and imaging characteristics in patients undergoing surgery for lumbar epidural lipomatosis. AB - BACKGROUND: Lumbar epidural lipomatosis (LEL) is characterized by abnormal accumulation of unencapsulated adipose tissue in the spinal epidural space. Such accumulation compresses the dural sac and nerve roots, and results in various neurological findings. However, the pathophysiology of LEL remains unclear. This study examined the associations between imaging and clinical findings in detail, and investigated the mechanisms underlying symptom onset by measuring intraoperative epidural pressures in LEL. METHODS: Sixteen patients (all men; mean age, 68.8 years) were enrolled between 2011 and 2015. Mean body mass index was 26.5 kg/m2. Four cases were steroid-induced, and the remaining 12 cases were idiopathic. All patients presented with neurological deficits in the lower extremities. Cauda equina syndrome (CES) alone was seen in 8 patients, radiculopathy alone in 4, and both radiculopathy and CES (mixed CES) in 4. All patients subsequently underwent laminectomy with epidural lipomatosis resection and were followed-up for more than 1 year. We investigated the clinical course and imaging and measured epidural pressures during surgery. RESULTS: Subjective symptoms improved within 1 week after surgery. Mean Japanese Orthopaedic Association (JOA) score was 15.2 +/- 2.8 before surgery, improving to 25.4 +/- 2.5 at 1 year after surgery. On magnetic resonance imaging, all lipomatosis lesions included the L4-5 level. On preoperative computed tomography, saucerization of the laminae was not observed in radiculopathy cases, whereas saucerization of the posterior vertebral body was observed in all radiculopathy or mixed CES cases. Intraoperative epidural pressures were significantly higher than preoperative subarachnoid pressures. The results suggest that high epidural pressure resulting from the proliferation of adipose tissue leads to saucerization of the lumbar spine and subsequent symptoms. CONCLUSIONS: Clinical courses were satisfactory after laminectomy. In LEL, epidural pressure increases and symptoms develop through the abnormal proliferation of adipose tissue. Higher epidural pressures induce saucerization of the laminae and/or posterior vertebral body. Furthermore, the direction of proliferative adipose tissue (i.e., site of saucerization) might be related to the types of neurological symptoms. PMID- 29490660 TI - Identification and validation a TGF-beta-associated long non-coding RNA of head and neck squamous cell carcinoma by bioinformatics method. AB - BACKGROUND: The role of transforming growth factorbeta (TGF-beta)-induced tumor progression in advanced malignancy is well established, but the involvement of long non-coding RNAs (lncRNAs) in TGF-beta signaling remains unclear. This study aimed to identify TGF-beta-associated lncRNAs in head and neck squamous cell carcinoma (HNSCC). METHODS: Expression profiling of lncRNAs was obtained using Gene Expression Omnibus and The Cancer Genome Atlas. Real-time quantitative PCR was used to analyze the expression of EPB41L4A-AS2 in HNSCC cell line. We used bioinformatics resources (DAvID) to conduct Gene Ontology biological processes and KEGG pathways at the significant level. Wound healing assay, cell migration and invasion assays, were used to examine the effects of EPB41L4A-AS2 on tumor cell metastasis in vivo. Protein levels of EPB41L4A-AS2 targets were determined by western blot. RESULTS: A novel TGF-beta-associated lncRNA, EPB41L4A-AS2, was found downregulated by TGF-beta and associated with invasion and metastasis. The relationship of EPB41L4A-AS2 with the clinicopathological features and prognosis of HNSCC patients was evaluated. Bioinformatic analyses revealed that EPB41L4A AS2 may be involved in processes associated with the tumor-associated signaling pathway, especially the TGF-beta signaling pathway. Furthermore, a TGF-beta induced epithelial-to-mesenchymal transition (EMT) model was established. Low EPB41L4A-AS2 expression was determined, and overexpression of this gene inhibited cell migration and invasion in the EMT model. Moreover, EPB41L4A-AS2 suppressed TGFBR1 expression. CONCLUSIONS: EPB41L4A-AS2 might serve as a negative regulator of TGF-beta signaling and as an effective prognostic biomarker and important target in anti-metastasis therapies of HNSCC patients. PMID- 29490661 TI - Effect of tear collection on lacrimal total protein content in dogs and cats: a comparison between Schirmer strips and ophthalmic sponges. AB - BACKGROUND: Quantification of lacrimal total protein content (TPC) is an important tool for clinical scientists to understand disease pathogenesis, identify potential biomarkers and assess response to therapy, among other applications. However, TPC is not only affected by disease state but also by the method used for tear collection. Thus, the purpose of this study is to determine the impact on TPC of two methods of tear collection in dogs and cats: Schirmer strips and polyvinyl acetal (PVA) sponges. METHODS: (i) In vivo - Ten healthy dogs and 10 healthy cats were examined. Each animal underwent two sessions, separated by 10 min, in which a Schirmer strip was placed in one randomly selected eye until the 20-mm mark was reached, while a strip of PVA sponge was placed in the other eye for 1 min. (ii) In vitro - Schirmer strips and PVA sponges were spiked with various volumes of four bovine serum albumin solutions (0.5, 4, 10, and 20 mg/mL). In both experiments, the wetted absorbent materials were centrifuged for 1 min, and the TPC was quantified on the extracted fluid using Direct DetectTM infrared spectroscopy. RESULTS: Lacrimal TPC in dogs and cats ranged from 5.2 to 14.6 mg/mL and from 6.2 to 20.6 mg/mL, respectively. In cats, TPC was significantly lower with Schirmer strips vs. PVA sponges (P < 0.001). In dogs, the volume absorbed by PVA sponges was negatively correlated with TPC (r = - 0.48, P = 0.033). The inter-session coefficient of variation was significantly lower with Schirmer strips vs. PVA sponges in both species (P <= 0.010). In vitro, both absorbent materials resulted in a 'concentrating effect' of the TPC obtained post-centrifugation, which was most pronounced when the volume absorbed was low, especially for Schirmer strips. CONCLUSION: Schirmer strips provide a repeatable method to quantify lacrimal TPC in dogs and cats, although care should be taken to absorb sufficient volumes of tears to minimize the concentrating effect from the absorbent material. PMID- 29490662 TI - Vegetarian-style dietary pattern during adolescence has long-term positive impact on bone from adolescence to young adulthood: a longitudinal study. AB - BACKGROUND: The amount of bone accrued during adolescence is an important determinant of later osteoporosis risk. Little is known about the influence of dietary patterns (DPs) on the bone during adolescence and their potential long term implications into adulthood. We examined the role of adolescent DPs on adolescent and young adult bone and change in DPs from adolescence to young adulthood. METHODS: We recruited participants from the Saskatchewan Pediatric Bone Mineral Accrual Study (1991-2011). Data from 125 participants (53 females) for adolescent analysis (age 12.7 +/- 2 years) and 115 participants (51 females) for adult analysis (age 28.2 +/- 3 years) were included. Bone mineral content (BMC) and areal bone mineral density (aBMD) of total body (TB), femoral neck (FN) and lumbar spine (LS) were measured using dual-energy X-ray absorptiometry. Adolescent dietary intake data from multiple 24-h recalls were summarized into 25 food group intakes and were used in the principal component analysis to derive DPs during adolescence. Associations between adolescent DPs and adolescent or adult BMC/BMD were analyzed using multiple linear regression and multivariate analysis of covariance while adjusting for sex, age, the age of peak height velocity, height, weight, physical activity and total energy intake. Generalized estimating equations were used for tracking DPs. RESULTS: We derived five DPs including "Vegetarian-style", "Western-like", "High-fat, high-protein", "Mixed" and "Snack" DPs. The "Vegetarian-style" DP was a positive independent predictor of adolescent TBBMC, and adult TBBMC, TBaBMD (P < 0.05). Mean adolescent TBaBMD and young adult TBBMC, TBaBMD, FNBMC and FNaBMD were 5%, 8.5%, 6%, 10.6% and 9% higher, respectively, in third quartile of "Vegetarian-style" DP compared to first quartile (P < 0.05). We found a moderate tracking (0.47-0.63, P < 0.001) in DP scores at individual levels from adolescence to adulthood. There were an upward trend in adherence to "Vegetarian-style" DP and an downward trend in adherence to "High-fat, high-protein" DP from adolescence to young adulthood (P < 0.01). CONCLUSION: A "Vegetarian-style" DP rich in dark green vegetables, eggs, non-refined grains, 100% fruit juice, legumes/nuts/seeds, added fats, fruits and low-fat milk during adolescence is positively associated with bone health. PMID- 29490663 TI - Class-modeling analysis reveals T-cell homeostasis disturbances involved in loss of immune control in elite controllers. AB - BACKGROUND: Despite long-lasting HIV replication control, a significant proportion of elite controller (EC) patients may experience CD4 T-cell loss. Discovering perturbations in immunological parameters could help our understanding of the mechanisms that may be operating in those patients experiencing loss of immunological control. METHODS: A case-control study was performed to evaluate if alterations in different T-cell homeostatic parameters can predict CD4 T-cell loss in ECs by comparing data from EC patients showing significant CD4 decline (cases) and EC patients showing stable CD4 counts (controls). The partial least-squares-class modeling (PLS-CM) statistical methodology was employed to discriminate between the two groups of patients, and as a predictive model. RESULTS: Herein, we show that among T-cell homeostatic alterations, lower levels of naive and recent thymic emigrant subsets of CD8 cells and higher levels of effector and senescent subsets of CD8 cells as well as higher levels of exhaustion of CD4 cells, measured prior to CD4 T-cell loss, predict the loss of immunological control. CONCLUSIONS: These data indicate that the parameters of T-cell homeostasis may identify those EC patients with a higher proclivity to CD4 T-cell loss. Our results may open new avenues for understanding the mechanisms underlying immunological progression despite HIV replication control, and eventually, for finding a functional cure through immune-based clinical trials. PMID- 29490664 TI - A systematic review of team-building interventions in non-acute healthcare settings. AB - BACKGROUND: Healthcare is increasingly delivered in a team-based format emphasizing interdisciplinary coordination. While recent reviews have investigated team-building interventions primarily in acute healthcare settings (e.g. emergency or surgery departments), we aimed to systematically review the evidence base for team-building interventions in non-acute settings (e.g. primary care or rehabilitation clinics). METHODS: We conducted a systematic review in PubMed and Embase to identify team-building interventions, and conducted follow up literature searches to identify articles describing empirical studies of those interventions. This process identified 14 team-building interventions for non acute healthcare settings, and 25 manuscripts describing empirical studies of these interventions. We evaluated outcomes in four domains: trainee evaluations, teamwork attitudes/knowledge, team functioning, and patient impact. RESULTS: Trainee evaluations for team-building interventions were generally positive, but only one study associated team-building with statistically significant improvement in teamwork attitudes/knowledge. Similarly mixed results emerged for team functioning and patient impact. CONCLUSIONS: The evidence base for healthcare team-building interventions in non-acute healthcare settings is much less developed than the parallel literature for short-term team function in acute care settings. Only one intervention we identified has been tested in multiple non-acute settings by distinct research teams. Positive findings regarding the utility of team-building interventions are tempered by a lack of control conditions, inconsistency in outcome measures, and high probability of bias. Considering these results alongside the well-recognized costs of poor healthcare teamwork suggests that additional research is sorely needed to develop the evidence base for team-building in non-acute settings. PMID- 29490665 TI - South-south collaboration on HIV/AIDS prevention and treatment research: when birds of a feather rarely flock together. AB - BACKGROUND: South-south collaboration on health and development research is a critical mechanism for social and economic progress. It allows sharing and replicating experiences to find a "southern solution" to meet shared health challenges, such as access to adequate HIV/AIDS prevention and treatment. This study aimed to generate evidence on the dynamics of south-south collaboration in HIV/AIDS research, which could ultimately inform stakeholders on the progress and nature of collaboration towards increased research capacities in low- and middle income countries (LMIC). METHODS: Bibliometric and social network analysis methods were used to assess the 10-year (2006-2015) scientific contribution of LMIC, through the analysis of scientific publications on HIV/AIDS prevention and/or treatment. Five dimensions oriented the study: knowledge production, co authorship analysis, research themes mapping, research types classification and funding sources. RESULTS: Publications involving LMIC have substantially increased overtime, despite small expression of south-south collaboration. Research themes mapping revealed that publication focus varied according to collaborating countries' income categories, from diagnosis, opportunistic infections and laboratory-based research (LMIC single or LMIC-LMIC) to human behavior and healthcare, drug therapy and mother to child transmission (LMIC HIC). The analysis of research types showed that south-south collaborations frequently targeted social sciences issues. Funding agencies acknowledged in south-south collaboration also showed diverse focus: LMIC-based funders tended to support basic biomedical research whereas international/HIC-based funders seem to cover predominantly social sciences-oriented research. CONCLUSIONS: Although the global environment has fostered an increasing participation of LMIC in collaborative learning models, south-south collaboration on HIV/AIDS prevention and/or treatment research seemed to be lower than expected, stressing the need for strategies to foster these partnerships. The evidence presented in this study can be used to strengthen a knowledge platform to inform future policy, planning and funding decisions, contributing to the development of enhanced collaboration and a priority research agenda for LMICs. PMID- 29490666 TI - Differential effect of angiotensin II and blood pressure on hippocampal inflammation in mice. AB - BACKGROUND: Angiotensin II (Ang II), a peptide hormone involved in the development of hypertension, causes systemic and cerebral inflammation, affecting brain regions important for blood pressure control. The cause-and-effect relationship between hypertension and inflammation is two-way, but the role of blood pressure in the induction of cerebral inflammation is less clear. The vulnerability of specific brain regions, particularly those important for memory, is also of interest. METHODS: We used molecular biology approaches, immunohistochemistry, and electron microscopy to examine the interdependence between the hypertensive and pro-inflammatory effects of Ang II. We examined the effect of blood pressure by administering a subpressive (200 ng/kg/min) or a pressive Ang II dose (1000 or 1900 ng/kg/min) with and without hydralazine (150 mg/L) for 1 week and used phenylephrine to increase blood pressure independently of the renin-angiotensin system. RESULTS: Ang II increased ionized calcium binding adaptor molecule 1 (Iba-1) levels (marker of microgliosis) in the whole brain and in the hippocampus in a dose-dependent manner. Pressive Ang II induced specific changes in microglial morphology, indicating differences in functional phenotype. An increase in hippocampal glial fibrillary acidic protein (GFAP) was seen in mice receiving pressive Ang II, while no induction of cerebral gliosis was observed after 7 days of subpressive Ang II infusion. Although phenylephrine led to increased astrogliosis, it did not affect Iba-1 expression. Pressive Ang II stimulated TNF-alpha production in the hippocampus, and daily treatment with hydralazine prevented this increase. Hydralazine also reduced GFAP and Iba-1 levels. With longer perfusion (14 days), subpressive Ang II led to some but not all the inflammatory changes detected with the pressive doses, mainly an increase in CD68 and Iba-1 but not of GFAP or TNF-alpha. CONCLUSIONS: Blood pressure and Ang II differentially contribute to hippocampal inflammation in mice. Control of blood pressure and Ang II levels should prevent or reduce brain inflammation and therefore brain dysfunctions associated with hypertension. PMID- 29490667 TI - Research priorities during infectious disease emergencies in West Africa. AB - OBJECTIVES: This paper presents the results of the consultations conducted with various stakeholders in Africa and other experts to document community perspectives on the types of research to be prioritised in outbreak conditions. The Delphi method was used to distill consensus. RESULTS: Our consultations highlighted as key, the notion that in an infectious disease outbreak situation, the need to establish an evidence base on how to reduce morbidity and mortality in real time takes precedence over the production of generalizable knowledge. Research studies that foster understanding of how disease transmission could be prevented in the future remain important, implementation research that explores how to mitigate the impact of outbreaks in the present should be prioritized. Clinical trials aiming to establish the safety profile of therapeutic interventions should be limited during the acute phase of an epidemic with high fatality-and should preferably use adaptive designs. We concluded that community members have valuable perspectives to share about research priorities during infectious disease emergencies. Well designed consultative processes could help identify these opinions. PMID- 29490668 TI - Extracellular matrix stiffness controls osteogenic differentiation of mesenchymal stem cells mediated by integrin alpha5. AB - BACKGROUND: Human mesenchymal stem cell (hMSC) differentiation into osteoblasts has important clinical significance in treating bone injury, and the stiffness of the extracellular matrix (ECM) has been shown to be an important regulatory factor for hMSC differentiation. The aim of this study was to further delineate how matrix stiffness affects intracellular signaling through integrin alpha5/beta1, FAK, and Wnt signaling, subsequently regulating the osteogenic phenotype of hMSCs. METHODS: hMSCs were cultured on tunable polyacrylamide hydrogels coated with fibronectin with stiffness corresponding to a Young's modulus of 13-16 kPa and 62-68 kPa. After hMSCs were cultured on gels for 1 week, gene expression of alpha-1 type I collagen, BGLAP, and RUNX2 were evaluated by real-time PCR. After hMSCs were cultured on gels for 24 h, signaling molecules relating to integrin alpha5 (FAK, ERK, p-ERK, Akt, p-Akt, GSK-3beta, p-GSK-3beta, and beta-catenin) were evaluated by western blot analysis. RESULTS: Osteogenic differentiation was increased on 62-68 kPa ECM, as evidenced by alpha-1 type I collagen, BGLAP, and RUNX2 gene expression, calcium deposition, and ALP staining. In the process of differentiation, gene and protein expression of integrin alpha5/beta1 increased, together with protein expression of the downstream signaling molecules FAK, p-ERK, p-Akt, GSK-3beta, p-GSK-3beta, and beta-catenin, indicating that these molecules can affect the osteogenic differentiation of hMSCs. An antibody blocking integrin alpha5 suppressed the stiffness-induced expression of all osteoblast markers examined. In particular, alpha-1 type I collagen, RUNX2, and BGLAP were significantly downregulated, indicating that integrin alpha5 regulates hMSC osteogenic differentiation. Downstream expression of FAK, ERK, p-ERK, and beta-catenin protein was unchanged, whereas Akt, p-Akt, GSK-3beta, and p-GSK-3beta were upregulated. Moreover, expression of Akt and p Akt was upregulated with anti-integrin alpha5 antibody, but no difference was observed for FAK, ERK, and p-ERK between the with or without anti-integrin alpha5 antibody groups. At the same time, expression of GSK-3beta and p-GSK-3beta was upregulated and beta-catenin levels showed no difference between the groups with or without anti-integrin alpha5 antibody. Since Akt, p-Akt, GSK-3beta, and p-GSK 3beta displayed the same changes between the groups with or without anti-integrin alpha5 antibody, we then detected the links among them. Expression of p-Akt and p GSK-3beta was reduced effectively in the presence of the Akt inhibitor Triciribine. However, Akt, GSK-3beta, and beta-catenin were unchanged. These results suggested that expression of p-GSK-3beta was regulated by p-Akt on 62-68 kPa ECM. CONCLUSIONS: Taken together, our results provide evidence that matrix stiffness (62-68 kPa) affects the osteogenic outcome of hMSCs through mechanotransduction events that are mediated by integrin alpha5. PMID- 29490669 TI - Thiamine diphosphate reduction strongly correlates with brain glucose hypometabolism in Alzheimer's disease, whereas amyloid deposition does not. AB - BACKGROUND: The underlying mechanism of brain glucose hypometabolism, an invariant neurodegenerative feature that tightly correlates with cognitive impairment and disease progression of Alzheimer's disease (AD), remains elusive. METHODS: Positron emission tomography with 2-[18F]fluoro-2-deoxy-D-glucose (FDG PET) was used to evaluate brain glucose metabolism, presented as the rate of 2 [18F]fluoro-2-deoxy-D-glucose standardized uptake value ratio (FDG SUVR) in patients with AD or control subjects and in mice with or without thiamine deficiency induced by a thiamine-deprived diet. Brain amyloid-beta (Abeta) deposition in patients with clinically diagnosed AD was quantified by performing assays using 11C-Pittsburgh compound B PET. The levels of thiamine metabolites in blood samples of patients with AD and control subjects, as well as in blood and brain samples of mice, were detected by high-performance liquid chromatography with fluorescence detection. RESULTS: FDG SUVRs in frontal, temporal, and parietal cortices of patients with AD were closely correlated with the levels of blood thiamine diphosphate (TDP) and cognitive abilities, but not with brain Abeta deposition. Mice on a thiamine-deprived diet manifested a significant decline of FDG SUVRs in multiple brain regions as compared with those in control mice, with magnitudes highly correlating with both brain and blood TDP levels. There were no significant differences in the changes of FDG SUVRs in observed brain regions between amyloid precursor protein/presenilin-1 and wild-type mice following thiamine deficiency. CONCLUSIONS: We demonstrate, for the first time to our knowledge, in vivo that TDP reduction strongly correlates with brain glucose hypometabolism, whereas amyloid deposition does not. Our study provides new insight into the pathogenesis and therapeutic strategy for AD. PMID- 29490670 TI - Impact of 68Ga-PSMA-PET imaging on target volume definition and guidelines in radiation oncology - a patterns of failure analysis in patients with primary diagnosis of prostate cancer. AB - BACKGROUND: 68Ga-PSMA-PET-imaging has proven to be a highly sensitive and specific diagnostic element for patients with prostate cancer (PC). Does the standard clinical target volume (CTV) cover the majority of 68Ga-PSMA-PET detected lymph nodes (LNs) in a primary setting? METHODS: 25 out of 159 patients with primary PC who underwent 68Ga-PSMA-PET-imaging were analyzed in the process of this study. These 25 high-risk patients had a total of 126 LNs with positive 68Ga-PSMA-ligand uptake. A standard CTV according to the 'Radiation Therapy Oncology Group' consensus was delineated and LNs were judged whether they were in or outside of this target volume. With a Pearson correlation we additionally evaluated whether the Gleason score, the prostate-specific antigen (PSA) value or the risk according to the Roach formula correlate with a higher chance of LNs being outside of the CTV in uncommon LN locations. RESULTS: 81 (64.3%) of 126 LNs were covered by the CTV with a complete coverage of all positive LNs inside the respective radiation volume in 11 of 25 patients (44%). LNs that were not covered by the CTV included (para-aortic,) common-iliac, pre-sacral, obturatoric, para rectal, para-vesical and pre-acetabular locations. In a statistical analysis neither the Gleason score, nor the PSA value, nor the calculated risk with the Roach formula correlated with LNs being inside or outside of the CTV in this patient group. CONCLUSION: 68Ga-PSMA-PET-imaging proves to be a valuable asset for patients and physicians for primary diagnosis and treatment planning. In our study, trusting the RTOG consensus for CTV delineation would have led to up to 35.7% of all LNs not to be included in the clinical radiation volume, which might have resulted in insufficient radiation dose coverage. PMID- 29490671 TI - Implementation between text and work-a qualitative study of a readmission prevention program targeting elderly patients. AB - BACKGROUND: Numerous studies emphasize the importance of context in implementation. Successful implementation across the health care system depends on conditions and requirements that are often presented to health professionals through text-based materials and might present contradictory expectations to the work of health professionals. In this study, we operationalize institutional context as the text-based material, which from the perspective of health professionals, influence health care work. Via the case of a readmission prevention program for elderly patients, we examine the experiences of health professionals that work with implementation, concerning the contradictions that arise between the demands imposed by program implementation and their everyday work routines, and the role of text-based materials in these contradictions. METHOD: We conducted five focus group interviews among health professionals working at different locations in a single administrative region of Denmark. The 24 health professionals in our study included hospital physicians, hospital nurses, medical secretaries, municipal care managers, registered municipal nurses, and general practitioners. All focus group interviews were transcribed verbatim. Inspired by institutional ethnography, we look into text-based materials, such as written guidelines, if health professionals indicate they are important. RESULTS: The health professionals experience that specific demands of the readmission prevention program come into conflict with the existing demands and daily work routines. Professional resistance to control and the existing digital communication tools create tensions with a program requirement for standardized enrollment of patients to the program. In addition, the striving for autonomy among health professionals and the high level of mono-professional working routines create tension with the program requirements for an additional amount of interdisciplinary work. The different demands are widely mediated by text-based materials such as the existing digital communication tools and the instructions on how to use them, and the official agreement of the role and assignment for Danish GPs. CONCLUSION: Successful implementation of the prevention program is affected by various tensions between the program demands and the existing health care work. Text-based materials mediate the different demands of the institutional context in to health care work and influence the process of implementation. PMID- 29490672 TI - "The era of single disease cowboys is out": evaluating the experiences of students, faculty, and collaborators in an interdisciplinary global health training program. AB - BACKGROUND: Global Health is an inherently interdisciplinary field but overseas training in global health, particularly among health science institutions, has been an 'individual' or 'individual discipline' experience. Team-based training is an approach to global health education which is increasing in popularity; research on team-training demonstrates that teams are more productive than individuals. In 2015, the Johns Hopkins Center for Global Health (CGH) developed the Global Established Multidisciplinary Sites (GEMS) program, an interdisciplinary training program which was designed to establish a new norm in global health training by bringing interdisciplinary teams of faculty and students together to identify and solve complex global health challenges. This research aims to evaluate the program's first year and contribute to the literature on interdisciplinary team training. We conducted 22 in-depth interviews with students, faculty, and local collaborators from 3 GEMS project sites. Findings were analyzed for themes through a framework approach. RESULTS: The program exposed students, faculty, and collaborators to a wide range of disciplines in global health. Students' desire to learn how other disciplines contribute to global health solutions was an important motivator for joining GEMS; many participants including faculty and collaborators valued exposure to multiple disciplines. Mentorship and communication were a challenge across all teams in part due to members having distinct "disciplinary languages". Balancing disciplinary representation on teams and establishing work plans were also key challenges. CONCLUSIONS: Based on the data the CGH provides four recommendations for institutions developing global health interdisciplinary teams to optimize team functioning and address challenges in mentorship, language, and roles: 1) address interdisciplinary communication early, 2) develop work plans during group formation, 3) meet as a team prior to travel, and 4) establish regular check ins. This article provides first-hand reflections on interdisciplinary team experiences in a global context and provides a pathway for the development of innovative strategies in global health training. PMID- 29490673 TI - The effect of excess weight on circulating inflammatory cytokines in drug-naive first-episode psychosis individuals. AB - BACKGROUND: Low-grade inflammation has been repeatedly associated with both excess weight and psychosis. However, no previous studies have addressed the direct effect of body mass index (BMI) on basal serum cytokines in individuals with first-episode psychosis (FEP). OBJECTIVES: The aim of this study is to analyze the effect of BMI on basal serum cytokine levels in FEP patients and control subjects, separating the total sample into two groups: normal-weight and overweight individuals. METHODS: This is a prospective and open-label study. We selected 75 FEP patients and 75 healthy controls with similar characteristics to patients according to the following variables: sex, age, and cannabis and tobacco consumption. Both controls and patients were separated into two groups according to their BMI: subjects with a BMI under 25 were considered as normal weight and those with a BMI equal to or more than 25 were considered as overweight. Serum levels of 21 cytokines/chemokines were measured at baseline using the Human High Sensitivity T Cell Magnetic Bead Panel protocol from the Milliplex(r) Map Kit. We compared the basal serum levels of the 21 cytokines between control and patient groups according to their BMI. RESULTS: In the normal-weight group, IL-8 was the only cytokine that was higher in patients than in the control group (p = 0.001), whereas in the overweight group, serum levels of two pro-inflammatory cytokines (IL-6, p = 0.000; IL-1beta, p = 0.003), two chemokines (IL-8, p = 0.001; MIP 1beta, p = 0.001), four Th-1 and Th-2 cytokines (IL-13, p = 0.009; IL-2, p = 0.001; IL-7, p = 0.001; IL-12p70, p = 0.010), and one Type-3 cytokine (IL-23, p = 0.010) were higher in patients than in controls. CONCLUSIONS: Most differences in the basal serum cytokine levels between patients and healthy volunteers were found in the overweight group. These findings suggest that excess weight can alter the homeostasis of the immune system and therefore may have an additive pro inflammatory effect on the one produced by psychosis in the central nervous system. PMID- 29490674 TI - Caudal lumbar spinal cysts in two French Bulldogs. AB - BACKGROUND: Spinal cysts are rare findings in veterinary medicine, but they are increasingly recognized due to the availability of advanced imaging techniques. Extradural meningeal cysts in French Bulldogs have not been reported previously and arachnoid cysts (diverticula) have not been reported at the caudal lumbar (L6 L7) region in dogs. CASE PRESENTATION: Two French Bulldogs, aged 5 and 8 years, were referred for evaluation of lower back pain and bilateral hind limb neurological deficits. Neurologic examination revealed ataxia and postural deficits in both dogs. Magnetic resonance imaging (MRI) showed cauda equina compression due to a cyst-like lesion at the level of L6-L7 in both cases. The dogs underwent dorsal laminectomy and the meningeal cyst was completely removed in one dog and in the other dog the spinal arachnoid diverticula was marsupialized. In Case 1, histopathology of the cysts was performed and MRI was repeated. Both dogs were pain free during follow-up evaluations. CONCLUSIONS: Based on radiological, intra-operative and histopathological findings, the first case was diagnosed as a meningocele connected by a pedicle to the caudal tip of the dural sac forming a dural diverticulum categorized as an extradural spinal cyst type Ib, and Case 2 as a type III intradural arachnoid diverticula. It is concluded that spinal cysts should be included in the differential diagnosis of cauda equina syndrome and lower back pain in French Bulldogs. Results of these cases may be useful for diagnostic and treatment management. PMID- 29490675 TI - A qualitative evaluation of a simplified cardiovascular management program in Tibet, China. AB - BACKGROUND: The simplified cardiovascular management (SimCard Study) program was a cluster randomized controlled trial conducted in Tibet, China to evaluate a multifaceted intervention consisting of appropriate medication prescriptions and lifestyle recommendations delivered by village doctors. The intervention was effective in improving the management of cardiovascular diseases in resource limited settings. The aim of this qualitative study was to examine stakeholder feedback and to inform future research and scaling up. METHOD: A total of 28 face to-face individual interviews were conducted. The interviews were conducted in 6 out of 14 intervention villages by 2 interviewers who speak the local language. Participants included 18 community members at high risk of CVD, 6 village doctors, 2 local project coordinators, and 2 county officials. Interview guides were used to facilitate the interview covering the focus of perceived usefulness and content of the intervention, fidelity to the intervention, and potential scalability of the intervention. Qualitative interviews were coded using thematic analysis. RESULTS: The average age of the participants was 41 years and 70% were female. Our findings showed that the intervention was delivered according to the protocol and was described as a useful program for CVD management by both high risk individuals and village doctors. However, lack of knowledge among high-risk individuals, insufficient availability of healthcare providers, inadequate financial incentive, and incomplete infrastructure such as difficulty in transportation and cell phone signal were identified as the main barriers to successful implementation and scale-up. CONCLUSION: The intervention was implemented in line with the protocol and provided substantial benefits for relevant community members and health professionals. However, multiple health system barriers need to be addressed for successful scale-up in rural China. TRIAL REGISTRATION: Unique identifier: NCT01503814 . Registered 11 December 2011. PMID- 29490676 TI - Pharmacological characterisation of CR6086, a potent prostaglandin E2 receptor 4 antagonist, as a new potential disease-modifying anti-rheumatic drug. AB - BACKGROUND: Prostaglandin E2 (PGE2) acts via its EP4 receptor as a cytokine amplifier (e.g., interleukin [IL]-6) and induces the differentiation and expansion of inflammatory T-helper (Th) lymphocytes. These mechanisms play a key role in the onset and progression of rheumatoid arthritis (RA). We present the pharmacological characterisation of CR6086, a novel EP4 receptor antagonist, and provide evidence for its potential as a disease-modifying anti-rheumatic drug (DMARD). METHODS: CR6086 affinity and pharmacodynamics were studied in EP4 expressing HEK293 cells by radioligand binding and cyclic adenosine monophosphate (cAMP) production, respectively. In immune cells, IL-6 and vascular endothelial growth factor (VEGF) expression were analysed by RT-PCR, and IL-23 and IL-17 release were measured by enzyme-linked immunosorbent assay (ELISA). In collagen induced arthritis (CIA) models, rats or mice were immunised with bovine collagen type II. Drugs were administered orally (etanercept and methotrexate intraperitoneally) starting at disease onset. Arthritis progression was evaluated by oedema, clinical score and histopathology. Anti-collagen II immunoglobulin G antibodies were measured by ELISA. RESULTS: CR6086 showed selectivity and high affinity for the human EP4 receptor (Ki = 16.6 nM) and functioned as a pure antagonist (half-maximal inhibitory concentration, 22 nM) on PGE2-stimulated cAMP production. In models of human immune cells in culture, CR6086 reduced key cytokine players of RA (IL-6 and VEGF expression in macrophages, IL-23 release from dendritic cells, IL-17 release from Th17 cells). In the CIA model of RA in rats and mice, CR6086 significantly improved all features of arthritis: severity, histology, inflammation and pain. In rats, CR6086 was better than the selective cyclooxygenase-2 inhibitor rofecoxib and at least as effective as the Janus kinase inhibitor tofacitinib. In mice, CR6086 and the biologic DMARD etanercept were highly effective, whereas the non-steroidal anti-inflammatory drug naproxen was ineffective. Importantly, in a study of CR6086/methotrexate, combined treatment greatly improved the effect of a fully immunosuppressive dose of methotrexate. CONCLUSIONS: CR6086 is a novel, potent EP4 antagonist showing favourable immunomodulatory properties, striking DMARD effects in rodents, and anti-inflammatory activity targeted to immune-mediated inflammatory diseases and distinct from the general effects of cyclooxygenase inhibitors. These results support the clinical development of CR6086, both as a stand-alone DMARD and as a combination therapy with methotrexate. The proof-of-concept trial in patients with RA is ongoing. PMID- 29490677 TI - Decision-making in the detection and management of patients with sepsis in resource-limited settings: the importance of clinical examination. PMID- 29490678 TI - Locomotor training using an overground robotic exoskeleton in long-term manual wheelchair users with a chronic spinal cord injury living in the community: Lessons learned from a feasibility study in terms of recruitment, attendance, learnability, performance and safety. AB - BACKGROUND: For individuals who sustain a complete motor spinal cord injury (SCI) and rely on a wheelchair as their primary mode of locomotion, overground robotic exoskeletons represent a promising solution to stand and walk again. Although overground robotic exoskeletons have gained tremendous attention over the past decade and are now being transferred from laboratories to clinical settings, their effects remain unclear given the paucity of scientific evidence and the absence of large-scale clinical trials. This study aims to examine the feasibility of a locomotor training program with an overground robotic exoskeleton in terms of recruitment, attendance, and drop-out rates as well as walking performance, learnability, and safety. METHODS: Individuals with a SCI were invited to participate in a 6 to 8-week locomotor training program with a robotic exoskeleton encompassing 18 sessions. Selected participants underwent a comprehensive screening process and completed two familiarization sessions with the robotic exoskeleton. The outcome measures were the rate of recruitment of potential participants, the rate of attendance at training sessions, the rate of drop-outs, the ability to walk with the exoskeleton, and its progression over the program as well as the adverse events. RESULTS: Out of 49 individuals who expressed their interest in participating in the study, only 14 initiated the program (recruitment rate = 28.6%). Of these, 13 individuals completed the program (drop-out rate = 7.1%) and attended 17.6 +/- 1.1 sessions (attendance rate = 97.9%). Their greatest standing time, walking time, and number of steps taken during a session were 64.5 +/- 10.2 min, 47.2 +/- 11.3 min, and 1843 +/- 577 steps, respectively. During the training program, these last three parameters increased by 45.3%, 102.1%, and 248.7%, respectively. At the end of the program, when walking with the exoskeleton, most participants required one therapist (85.7%), needed stand-by or contact-guard assistance (57.1%), used forearm crutches (71.4%), and reached a walking speed of 0.25 +/- 0.05 m/s. Five participants reported training-related pain or stiffness in the upper extremities during the program. One participant sustained bilateral calcaneal fractures and stopped the program. CONCLUSIONS: This study confirms that larger clinical trials investigating the effects of a locomotor training program with an overground robotic exoskeleton are feasible and relatively safe in individuals with complete motor SCI. Moreover, to optimize the recruitment rate and safety in future trials, this study now highlights the need of developing pre-training rehabilitation programs to increase passive lower extremity range of motion and standing tolerance. This study also calls for the development of clinical practice guidelines targeting fragility fracture risk assessment linked to the use of overground robotic exoskeletons. PMID- 29490679 TI - Developmental transcriptomics of the brittle star Amphiura filiformis reveals gene regulatory network rewiring in echinoderm larval skeleton evolution. AB - BACKGROUND: Amongst the echinoderms the class Ophiuroidea is of particular interest for its phylogenetic position, ecological importance and developmental and regenerative biology. However, compared to other echinoderms, notably echinoids (sea urchins), relatively little is known about developmental changes in gene expression in ophiuroids. To address this issue, we have generated and assembled a large RNAseq data set of four key stages of development in the brittle star Amphiura filiformis and a de novo reference transcriptome of comparable quality to that of a model echinoderm-the sea urchin Strongylocentrotus purpuratus. Furthermore, we provide access to the new data via a web interface: http://www.echinonet.eu/shiny/Amphiura_filiformis/ . RESULTS: We have identified highly conserved genes associated with the development of a biomineralised skeleton. We also identify important class-specific characters, including the independent duplication of the msp130 class of genes in different echinoderm classes and the unique occurrence of spicule matrix (sm) genes in echinoids. Using a new quantification pipeline for our de novo transcriptome, validated with other methodologies, we find major differences between brittle stars and sea urchins in the temporal expression of many transcription factor genes. This divergence in developmental regulatory states is more evident in early stages of development when cell specification begins, rather than when cells initiate differentiation. CONCLUSIONS: Our findings indicate that there has been a high degree of gene regulatory network rewiring and clade-specific gene duplication, supporting the hypothesis of a convergent evolution of larval skeleton development in echinoderms. PMID- 29490680 TI - Effect of an exercise-based cardiac rehabilitation program "Baduanjin Eight Silken-Movements with self-efficacy building" for heart failure (BESMILE-HF study): study protocol for a randomized controlled trial. AB - BACKGROUND: Exercise-based cardiac rehabilitation is a beneficial therapy for patients with chronic heart failure. The delivery of exercise-based cardiac rehabilitation should adopt an evidence-based approach, as well as be culturally appropriate and sensitive to individual needs and preferences. The Baduanjin Eight-Silken-Movements with Self-efficacy Building for Heart Failure (BESMILE-HF) program is the first to apply a traditional Chinese exercise, Baduanjin, as the core component in an exercise-based cardiac rehabilitation program. This trial aims to assess the efficacy, safety, and acceptability of the addition of the BESMILE-HF program to usual medications for patients with chronic heart failure. METHODS/DESIGN: The BESMILE-HF study is a mixed-design study. It includes a two group, parallel, randomized controlled trial with 200 chronic heart failure patients, as well as a qualitative component. Patients will be randomized into either an intervention group receiving the 12-week BESMILE-HF program plus usual medications, or a control group receiving only usual medications. The primary outcomes are peak oxygen consumption assessed using a cardiopulmonary exercise test, and disease-specific quality of life using the Minnesota Living with Heart Failure Questionnaire. The secondary outcomes are: exercise performance, exercise self-efficacy, general quality of life, dyspnea and fatigue, depression, cardiac function, prognostic and inflammatory indicator levels, hospitalization, use of medications, and major adverse cardiac events. Assessments will be carried out at baseline, and at the 4th week, 8th week, and 12th week. The qualitative component will include a semi-structure interview describing patients' experiences with the intervention. DISCUSSION: This study can provide evidence for how to deliver a contextually adapted exercise-based cardiac rehabilitation program with the potential to be scaled up throughout China. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03180320 . Registered on 2 June 2017. PMID- 29490681 TI - Retinoic acid enhances germ cell differentiation of mouse skin-derived stem cells. AB - BACKGROUND: Retinoic acid (RA) signaling has been identified as a key driver in male and female gamete development. The presence of RA is a critical step in the initiation of meiosis and is required for the production of competent oocytes from primordial germ cells. Meiosis has been identified as a difficult biological process to recapitulate in vitro, when differentiating stem cells to germ cells. We have previously shown that primordial germ cell-like cells, and more advanced oocyte-like cells (OLCs), can be formed by differentiating mouse skin-derived stem cells. However, the OLCs remain unable to function due to what appears to be failure of meiotic initiation. The aim of this study was to determine the effect of RA treatment, during stem cell differentiation to germ cells, particularly on the initiation of meiosis. RESULTS: Using qPCR we found significant increases in the meiosis markers Stra8 and Sycp3 and a significant reduction in the meiosis inhibitor Nanos2, in the differentiating populations. Furthermore, OLCs from the RA treated group, expressed significantly more of the meiosis regulatory gene Marf1 and the oocyte marker Oct4. At the protein level RA treatment was found to increase the expression of the gap junction protein CX43 and the pluripotency marker OCT4. Moreover, the expression of SYCP3 was significantly upregulated and the localization pattern better matched that of control fetal ovarian cells. RA treatment also improved the structural integrity of the OLCs produced by initiating the expression of all three zona pellucida transcripts (Zp1-3) and improving ZP3 expression levels and localization. Finally, the addition of RA during differentiation led to an almost two-fold increase in the number of OLCs recovered and increased their in vitro growth. CONCLUSION: RA is a key driver in the formation of functioning gametes and its addition during stem cell to germ cell differentiation improves OLCs entry into meiosis. PMID- 29490682 TI - Therapeutic and pharmaco-biological, dose-ranging multicentre trial to determine the optimal dose of TRAnexamic acid to reduce blood loss in haemorrhagic CESarean delivery (TRACES): study protocol for a randomised, double-blind, placebo controlled trial. AB - BACKGROUND: Postpartum haemorrhage (PPH) is the leading cause of maternal death worldwide. Tranexamic acid (TA), an antifibrinolytic drug, reduces bleeding and transfusion need in major surgery and trauma. In ongoing PPH following vaginal delivery, a high dose of TA decreases PPH volume and duration, as well as maternal morbidity, while early fibrinolysis is inhibited. In a large international trial, a TA single dose reduced mortality due to bleeding but not the hysterectomy rate. TA therapeutic dosages vary from 2.5 to 100 mg/kg and seizures, visual disturbances and nausea are observed with the highest dosages. TA efficiency and optimal dosage in haemorrhagic caesarean section (CS) has not been yet determined. We hypothesise large variations in fibrinolytic activity during haemorrhagic caesarean section needing targeted TA doses for clinical and biological efficacy. METHODS/DESIGN: The current study proposal is a blinded, randomised controlled trial with the primary objective of determining superiority of either 1 g of TXA or 0.5 g of TXA, in comparison to placebo, in terms of 30% blood-loss reduction at 6 h after non-emergency haemorrhagic caesarean delivery (active PPH > 800 mL) and to correlate this clinical effect in a pharmacokinetics model with fibrinolysis inhibition measured by an innovative direct plasmin measurement regarding plasmatic TA concentration. A sample size of 342 subjects (114 per group) was calculated, based on the expected difference of 30% reduction of blood loss between the placebo group and the low-dose group, out of which 144 patients will be included blindly in the pharmaco-biological substudy. A non haemorrhagic reference group will include 48 patients in order to give a reference for peak plasmin level. DISCUSSION: TRACES trial is expected to give the first pharmacokinetics data to determinate the optimal dose of tranexamic acid to reduce blood loss and inhibit fibrinolysis in hemorrhagic cesarean section. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02797119 . Registered on 13 June 2016. PMID- 29490683 TI - Exploring determinants predicting response to intra-articular hyaluronic acid treatment in symptomatic knee osteoarthritis: 9-year follow-up data from the Osteoarthritis Initiative. AB - BACKGROUND: The weight of recommendation for intra-articular therapies such as hyaluronic acid injections varies from one set of guidelines to another, and they have not yet reached unanimity with respect to the usefulness of intra-articular hyaluronic acid (IAHA) injections for the symptomatic treatment of knee osteoarthritis (OA). Among the reasons for the controversy is that the current literature provides inconsistent results and conclusions about such treatment. This study aimed at identifying determinants associated with a better response to IAHA treatment in knee OA. METHODS: Subjects were selected from the Osteoarthritis Initiative database. Participants were subjects who had radiographic OA, received one IAHA treatment, and had data on demographics and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores at visits before (T0) and after (T1; within 6 months) treatment. Pain was analyzed for demographic, clinical, and imaging characteristics at T0 and change over time (T0 to T1). Subjects with WOMAC pain > 0 at T0 were subdivided into Low, Moderate, and High pain groups based on tertile analysis. Further analyses were done with the High pain group (score >= 8), which was divided into responders (improvement in pain >= 20%) and nonresponders (unchanged or worsening of pain). RESULTS: Participants (n = 310) received a total of 404 treatments (one per knee). In the Low and Moderate pain groups vs the High pain group, participants had significantly lower score at T0 (p < 0.001), and the Low vs High pain group had significantly lower BMI (p = 0.002), greater joint space width (JSW) (p = 0.010) and knee cartilage volume (p <= 0.009), and smaller synovial effusion (p = 0.033). In the High pain group, responders vs nonresponders were usually younger (p = 0.014), with greater cartilage volume in the medial compartment (p = 0.046), a trend toward greater JSW, and a significant improvement in all WOMAC scores (p < 0.001), while nonresponders showed worsening of symptoms. CONCLUSIONS: This study identified reliable predictive determinants that can distinguish patients who could best benefit from IAHA treatment: high levels of knee pain, younger, and less severe structural damage. These could be implemented in clinical practice as a useful guide for physicians. PMID- 29490684 TI - Transcriptome of Russet Norkotah and its clonal selection, TXNS278. AB - OBJECTIVES: Potato has a large genetic diversity. This diversity is in part due to somaclonal variability that appears within potato selections for which tubers are used as seeds. However, the potato tetraploid genome, as well as the use of tubers for crop propagation, does not allow for easy genetic studies. The objective is to gain knowledge at the genomic level from standard Russet Norkotah and a subclonal Russet Norkotah selection TXNS278. DATA DESCRIPTION: In this report, we used RNA-seq, which allows genome-wide gene expression analysis to sequence the transcriptomes of the subclonal Russet Norkotah selection TXNS278 with standard Russet Norkotah grown in commercial fields. Among the selections, TXNS278 appeared in a multi-year analysis in Texas as a top No 1 yielding variety. Russet Norkotah and TXNS278 leaf and root transcriptomes were sequenced at two time points during growing season. PMID- 29490685 TI - A novel single variant in the MEFV gene causing Mediterranean fever and Behcet's disease: a case report. AB - BACKGROUND: Familial Mediterranean fever is an autoinflammatory disease of unknown etiology, characterized clinically by recurrent attacks of sudden-onset fever with arthralgia and/or thoracoabdominal pain and pathogenetically by autosomal recessive inheritance due to a mutation in the MEFV gene. Behcet's disease is an inflammatory disease characterized by recurrent oral and genital aphthous ulcerations, uveitis, and skin lesions. Preliminarily, our literature review suggested that patients with familial Mediterranean fever who also have Behcet's disease have only a single mutated familial Mediterranean fever gene. The MEFV gene mutation responsible for familial Mediterranean fever is probably a susceptibility factor for Behcet's disease, particularly for patients with vascular involvement, and both disorders can occur concurrently in a patient, as in the present case. CASE PRESENTATION: A 10-year-old girl of Moroccan origin presented to our institution for genetic consultation for genetic testing of the MEFV gene. She had fever associated with abdominal and diffuse joint pain in addition to headache. These symptoms have oriented pediatricians to familial Mediterranean fever. The evolution was marked by Behcet's syndrome symptoms. Sanger sequencing followed by complete exome sequencing analysis of the MEFV gene for the proband mutation revealed a novel variant. We conclude that the novel single variant c.2078 T > A (p.Met693Lys) could be responsible for the association of familial Mediterranean fever and Behcet's disease. CONCLUSION: To the best of our knowledge, this is the first report of a new variant in exon 10 of the MEFV gene in a Moroccan family. This novel variant should be listed in the MEFV sequence variant databases. PMID- 29490686 TI - Redefining mouse transgenesis with CRISPR/Cas9 genome editing technology. AB - The generation of genetically modified alleles in mice using conventional transgenesis technologies is a long and inefficient process. A new study shows that the in situ delivery of CRISPR/Cas9 reagents into pregnant mice results in a high efficiency of editing, and enables the rapid generation of both simple and complex alleles. PMID- 29490687 TI - Genetic ablation of dynactin p150Glued in postnatal neurons causes preferential degeneration of spinal motor neurons in aged mice. AB - BACKGROUND: Dynactin p150Glued, the largest subunit of the dynactin macromolecular complex, binds to both microtubules and tubulin dimers through the N-terminal cytoskeleton-associated protein and glycine-rich (CAP-Gly) and basic domains, and serves as an anti-catastrophe factor in stabilizing microtubules in neurons. P150Glued also initiates dynein-mediated axonal retrograde transport. Multiple missense mutations at the CAP-Gly domain of p150Glued are associated with motor neuron diseases and other neurodegenerative disorders, further supporting the importance of microtubule domains (MTBDs) in p150Glued functions. However, most functional studies were performed in vitro. Whether p150Glued is required for neuronal function and survival in vivo is unknown. METHODS: Using Cre-loxP genetic manipulation, we first generated a line of p150Glued knock-in mice by inserting two LoxP sites flanking the MTBD-coding exons 2 to 4 of p150Glued-encoding Dctn1 gene (Dctn1LoxP/), and then crossbred the resulting Dctn1LoxP/ mice with Thy1-Cre mice to generate the bigenic p150Glued (Dctn1LoxP/LoxP; Thy1-Cre) conditional knockout (cKO) mice for the downstream motor behavioral and neuropathological studies. RESULTS: P150Glued expression was completely abolished in Cre-expressing postnatal neurons, including corticospinal motor neurons (CSMNs) and spinal motor neurons (SMNs), while the MTBD-truncated forms remained. P150Glued ablation did not affect the formation of dynein/dynactin complex in neurons. The p150Glued cKO mice did not show any obvious developmental phenotypes, but exhibited impairments in motor coordination and rearing after 12 months of age. Around 20% loss of SMNs was found in the lumbar spinal cord of 18-month-old cKO mice, in company with increased gliosis, neuromuscular junction (NMJ) disintegration and muscle atrophy. By contrast, no obvious degeneration of CSMNs, striatal neurons, midbrain dopaminergic neurons, cerebellar granule cells or Purkinje cells was observed. Abnormal accumulation of acetylated alpha-tubulin, and autophagosome/lysosome proteins was found in the SMNs of aged cKO mice. Additionally, the total and cell surface levels of glutamate receptors were also substantially elevated in the p150Glued-depleted spinal neurons, in correlation with increased vulnerability to excitotoxicity. CONCLUSION: Overall, our findings demonstrate that p150Glued is particularly required to maintain the function and survival of SMNs during aging. P150Glued may exert its protective function through regulating the transportation of autophagosomes, lysosomes, and postsynaptic glutamate receptors in neurons. PMID- 29490688 TI - The effects of interventions targeting multiple health behaviors on smoking cessation outcomes: a rapid realist review protocol. AB - BACKGROUND: Health behaviors directly impact the health of individuals, and populations. Since individuals tend to engage in multiple unhealthy behaviors such as smoking, excessive alcohol use, physical inactivity, and eating an unhealthy diet simultaneously, many large community-based interventions have been implemented to reduce the burden of disease through the modification of multiple health behaviors. Smoking cessation can be particularly challenging as the odds of becoming dependent on nicotine increase with every unhealthy behavior a smoker exhibits. This paper presents a protocol for a rapid realist review which aims to identify factors associated with effectively changing tobacco use and target two or more additional unhealthy behaviors. METHODS: An electronic literature search will be conducted using the following bibliographic databases: MEDLINE, Embase, PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL), The Cochrane Library, Social Science Abstracts, Social Work Abstracts, and Web of Science. Two reviewers will screen titles and abstracts for relevant research, and the selected full papers will be used to extract data and assess the quality of evidence. Throughout this process, the rapid realist approach proposed by Saul et al., 2013 will be used to refine our initial program theory and identify contextual factors and mechanisms that are associated with successful multiple health behavior change. DISCUSSION: This review will provide evidence-based research on the context and mechanisms that may drive the success or failure of interventions designed to support multiple health behavior change. This information will be used to guide curriculum and program development for a government funded project on improving smoking cessation by addressing multiple health behaviors in people in Canada. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017064430. PMID- 29490689 TI - Metformin improves ovarian follicle dynamics by reducing theca cell proliferation and CYP-17 expression in an androgenized rat model. AB - BACKGROUND: Metformin influences insulin receptor signaling, which might interfere with the proliferation of ovarian follicular structures and steroidogenesis. We hypothesize that reductions in glucose and insulin levels might interfere with CYP-17 expression and histomorphological changes in an androgenized rat model. The aim of this study was to analyze the effect of metformin on CYP-17 expression, follicular dynamics, and proliferative parameters in neonatally androgenized female rats. METHODS: Thirty-six newborn rats were randomly allocated to the following three groups on the third day of life: control (CG, n = 12), androgenized (GA, n = 12), and androgenized + metformin (GAmet, n = 12). The GA and GAmet animals were administered 0.1 mL of testosterone propionate (1.25 mg/animal) diluted in castor oil (vehicle) in a single dose; the CG rats received a subcutaneous injection of the vehicle in the dorsum. After 90 days, gavage treatment was initiated, distilled water was administered to the CG and GA rats, and metformin (150 mg/kg) was administered to the GAmet animals. The treatment was administered daily for six weeks. Following anesthesia, blood was drawn for biochemical measurements, and the ovaries were removed for histological and immunohistochemical analyses of Ki67, VEGFA and CYP17 expression. The glucose and insulin levels were also measured. RESULTS: The comparison of the GA and GAmet animals revealed that metformin decreased the weight as well as the glucose and insulin levels, slowed the proliferation of the theca interna and interstitial cells, as evidenced by Ki-67 and VEGF-A expression, and diminished CYP17 expression in the analyzed ovarian structures. In addition, metformin reduced the number of degenerating follicles and interstitial cells and improved angiogenesis. CONCLUSION: Metformin improves the carbohydrate metabolism, reduces proliferation, and decreases CYP-17 expression in the follicular structures of androgenized rats. PMID- 29490690 TI - TRAnexamic acid in hemorrhagic CESarean section (TRACES) randomized placebo controlled dose-ranging pharmacobiological ancillary trial: study protocol for a randomized controlled trial. AB - BACKGROUND: Evidence increases that a high or a standard dose of tranexamic acid (TA) reduces postpartum bleeding. The TRACES pharmacobiological substudy aims to establish a therapeutic strategy in hemorrhagic (H) Cesarean section (CS) with respect to the intensity of fibrinolysis by using innovative assays. METHOD/DESIGN: The TRACES trial is a multicenter, randomized, double-blind, placebo-controlled, TA dose-ranging study that measures simultaneously plasmatic and uterine and urine TA concentrations and the plasmin peak inhibition tested by a simultaneous thrombin plasmin generation assay described by Van Geffen (novel hemostasis assay [NHA]). Patients undergoing H CS (>800 mL) will receive blindly TA 0.5 g or 1 g or placebo. A non-hemorrhagic (NH) group will be recruited to establish plasmin generation profile. Venous blood will be sampled before, at the end, and then at 30, 60, 120, and 360 min after injection. Uterine bleeding will be sampled after injection. Urine will be sampled 2 h and 6 h after injection. The number of patients entered into the study will be 114 H + 48 NH out of the 390 patients of the TRACES clinical trial. DISCUSSION: To explore the two innovative assays, a preliminary pilot study was conducted. Blood samples were performed repeatedly in patients undergoing either a H (>800 mL) or NH (<800 mL) CS and in non-pregnant women (NP). H patients received TA (0-2 g). Dose-dependent TA plasmatic concentrations were determined by LC-MS/MS quantification. Plasmin generation and its inhibition were tested in vitro and in vivo using the simultaneous thrombin-plasmin generation assay (STPGA). The pilot study included 15 patients in the H group, ten patients in the NH group, and seven patients in the NP group. TA plasmatic concentration showed a dose-dependent variation. STPGA inter-assay variation coefficients were < 20% for all plasmin parameters. Inter individual dispersion of plasmin generation capacity was higher in H and NH groups than in NP group. Profile evolution over time was different between groups. This preliminary technical validation study allows TRACES pharmacobiological trial to be conducted. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02797119. Registered on 13 June 2016. PMID- 29490691 TI - Improving the identification of dementia with Lewy bodies in the context of an Alzheimer's-type dementia. AB - BACKGROUND: Dementia due to Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are the two most common neurodegenerative causes of dementia. They commonly occur together, especially in older people, but clinical identification of these diseases in dementia is difficult in such circumstances. We therefore conducted a study using cases with both comprehensive prospective clinical assessments and complete neuropathological examination to determine if it is possible to identify such mixed cases clinically and to determine features which may identify DLB in the presence of AD dementia. METHODS: At Newcastle Brain Bank we identified subjects who had a clinical diagnosis of dementia and who also had autopsy diagnoses of pure AD, pure DLB, or mixed AD+DLB. All subjects had undergone prospective longitudinal clinical assessments. Mixed AD+DLB patients met neuropathological criteria for both DLB (limbic/neocortical Lewy body disease) and AD (Braak stage V/VI and CERAD B/C). The records of these subjects were carefully reviewed by two specialists in old-age psychiatry blind to autopsy findings to determine baseline and final clinical diagnoses based on these detailed records. The presence of characteristic Lewy body symptoms and other clinical information was also recorded. RESULTS: Of 59 subjects included, 19 were AD, 18 DLB, and 22 mixed AD+DLB. At baseline no subjects were correctly identified as having mixed AD+DLB and by final diagnosis only 23% were identified. The only symptom which helped in identifying the presence of Lewy body disease in the context of a mixed AD+DLB dementia was complex visual hallucinations. CONCLUSIONS: Whilst the identification of DLB in the context of a dementia with an AD pattern is difficult, the emergence of complex visual hallucinations in the context of such a degenerative dementia suggests the presence of Lewy body disease and should encourage a careful assessment. Biomarkers appear likely to be necessary to help improve identification of different disease subtypes underlying dementia. PMID- 29490692 TI - The antibody response in the bovine mammary gland is influenced by the adjuvant and the site of subcutaneous vaccination. AB - Intramammary infections in cattle resulting in mastitis have detrimental effects on cows' well-being, lifespan and milk production. In the host defense against S. aureus mastitis antibodies are thought to play an important role. To explore potential ways to increase antibody titers in the bovine mammary gland the effects of various adjuvants on the magnitude, isotype, and neutralizing capacity of antibodies produced following subcutaneous vaccine administration at different immunization sites were analyzed. In this study, alpha-toxoid was used as a model antigen and formulated in three different alum-based adjuvants: Alum-Saponin, Alum-Oil, and Alum-Saponin-Oil. Vaccines were administered near the suspensory ligament of the udder or in the lateral triangular area of the neck. At both immunization sites, immunization with alpha-toxoid in Alum-Saponin-Oil resulted in higher specific antibody titers in milk and serum as compared with Alum-Oil and Alum-Saponin, without favoring an IgG1, IgG2, or IgA response. Furthermore, the neutralizing capacity of milk serum and serum following immunization near the udder and in the neck was higher when Alum-Saponin-Oil was used as adjuvant compared with Alum-Oil and Alum-Saponin. Prime immunizations near the udder effectively increased both antibody isotype titers and neutralization titers, while prime plus boost immunizations were required to induce similar effects following immunization in the neck. Results indicate that subcutaneous administration of an Alum-Saponin-Oil based vaccine near the udder could be further explored for the development of a one-shot vaccination strategy to efficiently increase intramammary antibody responses. PMID- 29490693 TI - A hypomorphic inherited pathogenic variant in DDX3X causes male intellectual disability with additional neurodevelopmental and neurodegenerative features. AB - BACKGROUND: Intellectual disability (ID) is a common condition with a population prevalence frequency of 1-3% and an enrichment for males, driven in part by the contribution of mutant alleles on the X-chromosome. Among the more than 500 genes associated with ID, DDX3X represents an outlier in sex specificity. Nearly all reported pathogenic variants of DDX3X are de novo, affect mostly females, and appear to be loss of function variants, consistent with the hypothesis that haploinsufficiency at this locus on the X-chromosome is likely to be lethal in males. RESULTS: We evaluated two male siblings with syndromic features characterized by mild-to-moderate ID and progressive spasticity. Quad-based whole exome sequencing revealed a maternally inherited missense variant encoding p.R79K in DDX3X in both siblings and no other apparent pathogenic variants. We assessed its possible relevance to their phenotype using an established functional assay for DDX3X activity in zebrafish embryos and found that this allele causes a partial loss of DDX3X function and thus represents a hypomorphic variant. CONCLUSIONS: Our genetic and functional data suggest that partial loss of function of DDX3X can cause syndromic ID. The p.R79K allele affects a region of the protein outside the critical RNA helicase domain, offering a credible explanation for the observed retention of partial function, viability in hemizygous males, and lack of pathology in females. These findings expand the gender spectrum of pathology of this locus and suggest that analysis for DDX3X variants should be considered relevant for both males and females. PMID- 29490694 TI - Systematic review of ototoxic pre-surgical antiseptic preparations - what is the evidence? AB - OBJECTIVE: There is uncertainty regarding the safety of surgical antiseptic preparations in the ear. A systematic review of the literature was conducted to assess the evidence regarding ototoxicity of surgical antiseptic preparations. METHODS: A literature search was conducted using the PRISMA methods. Key words included "ototoxicity" "hearing loss", "antiseptic", "surgical preparation", "tympanoplasty", "vestibular dysfunction", "chlorhexidine", "iodine", "povidone", "ethanol", and "hydrogen peroxide" using Medline, Embase, Cochrane Library, Scopus and Web of Science. We included peer-reviewed papers that 1) objectively measured ototoxicity in humans or animals through hearing, vestibular function or histologic examination, 2) studied topically applied surgical antiseptic preparations, 3) were either in English or had an English abstract. We excluded papers that were 1) in vitro studies, 2) ear trauma studies, 3) studies of ototoxic ear drops intended for therapy, or 4) case reports. Studies included in the final review were screened using the PRISMA method. Current systematic review registration number pending: 83,675. RESULTS: Fifty-six papers were identified as using PRISMA criteria. After applying our exclusion criteria, 13 papers met overall study criteria. Of these, six papers reported ototoxicity of iodine based solutions, five papers reported ototoxicity of chlorhexidine and ethanol and two papers assessed hydrogen peroxide. All papers reviewed were animal studies. Iodine based solutions show least harm overall, while chlorhexidine and high concentrations of alcohol based solutions showed most harm. The evidence on hydrogen based solutions was inconclusive. CONCLUSIONS: The overall evidence for anyone antiseptic solution is weak. There is some evidence that iodine, chlorhexidine, hydrogen peroxide and alcohol based antiseptics have ototoxicity. Conclusive evidence for human ototoxicity from any solution is not strong. PMID- 29490695 TI - Health disparities monitoring in the U.S.: lessons for monitoring efforts in Israel and other countries. AB - BACKGROUND: Health disparities are a persistent problem in many high-income countries. Health policymakers recognize the need to develop systematic methods for documenting and tracking these disparities in order to reduce them. The experience of the U.S., which has a well-established health disparities monitoring infrastructure, provides useful insights for other countries. MAIN BODY: This article provides an in-depth review of health disparities monitoring in the U.S. Lessons of potential relevance for other countries include: 1) the integration of health disparities monitoring in population health surveillance, 2) the role of political commitment, 3) use of monitoring as a feedback loop to inform future directions, 4) use of monitoring to identify data gaps, 5) development of extensive cross-departmental cooperation, and 6) exploitation of digital tools for monitoring and reporting. Using Israel as a case in point, we provide a brief overview of the healthcare and health disparities landscape in Israel, and examine how the lessons from the U.S. experience might be applied in the Israeli context. CONCLUSION: The U.S. model of health disparities monitoring provides useful lessons for other countries with respect to documentation of health disparities and tracking of progress made towards their elimination. Given the persistence of health disparities both in the U.S. and Israel, there is a need for monitoring systems to expand beyond individual- and healthcare system level factors, to incorporate social and environmental determinants of health as health indicators/outcomes. PMID- 29490696 TI - Imaging features of fibrolamellar hepatocellular carcinoma in gadoxetic acid enhanced MRI. AB - BACKGROUND: Fibrolamellar hepatocellular carcinoma (FLC) is a rare malignancy occurring in young patients without cirrhosis. Objectives of our study were to analyze contrast material uptake in hepatobiliary phase imaging (HBP) in gadoxetic acid-enhanced liver MRI in patients with FLC and to characterize imaging features in sequence techniques other than HBP. METHODS: In this retrospective study on histology-proven FLC, contrast material uptake in HBP was quantitatively assessed by calculating the corrected FLC enhancement index (CEI) using mean signal intensities of FLC and lumbar muscle on pre-contrast imaging and HBP, respectively. Moreover, enhancement patterns in dynamic contrast enhanced MRI and relative signal intensities compared with background liver parenchyma were determined by two radiologists in consensus for HBP, diffusion weighted imaging using high b-values (DWI), and T2 and T1 weighted pre-contrast imaging. RESULTS: In 6 of 13 patients with FLC gadoxetic acid-enhanced liver MRI was available. The CEI suggested presence of HBP contrast material uptake in all FLCs. A mean CEI of 1.35 indicated FLC signal increase of 35% in HBP compared with pre-contrast imaging. All FLCs were hypointense in HBP compared with background liver parenchyma. Three of 6 FLCs had arterial hyperenhancement and venous wash-out. In DWI and T2 weighted imaging, 5 of 6 FLCs were hyperintense. In T1 weighted imaging, 5 of 6 FLCs were hypointense. CONCLUSION: Hepatobiliary uptake of gadoxetic acid was quantitatively measurable in all FLCs investigated in our study. The observation of hypointensity of FLCs in HBP compared with background liver parenchyma emphasizes the role of gadoxetic acid-enhanced liver MRI for non-invasive diagnosis of FLC and its importance in the diagnostic work up of indeterminate liver lesions. PMID- 29490697 TI - "Candidatus Paraporphyromonas polyenzymogenes" encodes multi-modular cellulases linked to the type IX secretion system. AB - BACKGROUND: In nature, obligate herbivorous ruminants have a close symbiotic relationship with their gastrointestinal microbiome, which proficiently deconstructs plant biomass. Despite decades of research, lignocellulose degradation in the rumen has thus far been attributed to a limited number of culturable microorganisms. Here, we combine meta-omics and enzymology to identify and describe a novel Bacteroidetes family ("Candidatus MH11") composed entirely of uncultivated strains that are predominant in ruminants and only distantly related to previously characterized taxa. RESULTS: The first metabolic reconstruction of Ca. MH11-affiliated genome bins, with a particular focus on the provisionally named "Candidatus Paraporphyromonas polyenzymogenes", illustrated their capacity to degrade various lignocellulosic substrates via comprehensive inventories of singular and multi-modular carbohydrate active enzymes (CAZymes). Closer examination revealed an absence of archetypical polysaccharide utilization loci found in human gut microbiota. Instead, we identified many multi-modular CAZymes putatively secreted via the Bacteroidetes-specific type IX secretion system (T9SS). This included cellulases with two or more catalytic domains, which are modular arrangements that are unique to Bacteroidetes species studied to date. Core metabolic proteins from Ca. P. polyenzymogenes were detected in metaproteomic data and were enriched in rumen-incubated plant biomass, indicating that active saccharification and fermentation of complex carbohydrates could be assigned to members of this novel family. Biochemical analysis of selected Ca. P. polyenzymogenes CAZymes further iterated the cellulolytic activity of this hitherto uncultured bacterium towards linear polymers, such as amorphous and crystalline cellulose as well as mixed linkage beta-glucans. CONCLUSION: We propose that Ca. P. polyenzymogene genotypes and other Ca. MH11 members actively degrade plant biomass in the rumen of cows, sheep and most likely other ruminants, utilizing singular and multi-domain catalytic CAZymes secreted through the T9SS. The discovery of a prominent role of multi-modular cellulases in the Gram-negative Bacteroidetes, together with similar findings for Gram-positive cellulosomal bacteria (Ruminococcus flavefaciens) and anaerobic fungi (Orpinomyces sp.), suggests that complex enzymes are essential and have evolved within all major cellulolytic dominions inherent to the rumen. PMID- 29490698 TI - Clinical evaluation of haploidentical hematopoietic combined with human umbilical cord-derived mesenchymal stem cells in severe aplastic anemia. AB - BACKGROUND: This study not only evaluated the clinical effects of treatment using haploidentical hematopoietic stem cells (haplo-HSCs) combined with human umbilical cord mesenchymal stem cells (UC-MSCs) in patients with severe aplastic anemia (SAA), but also investigated the factors related to graft versus host disease (GVHD). METHODS: Cotransplantation of haplo-HSCs and UC-MSCs was performed in 24 SAA patients. The conditioning regimens consisted of rabbit anti human T-lymphocyte immunoglobulin (ATG), cyclophosphamide, and fludarabine with or without busulfan. GVHD was prevented using cyclosporine A, ATG, anti-CD25 monoclonal antibody, and mycophenolate material. RESULTS: The incidence of acute GVHD was 50%. The incidence of severe acute GVHD was not related to gender, age, donor-recipient relations, and patient/donor pair, while patient/donor pair (r = 0.541, P = 0.022) was significantly correlated with incidence of chronic GVHD. Upon follow-up for a median of 13 months, 5 of the 24 patients (20.8%) were dead. The survival rates at 3 and 6 months in all patients were 87.5% (21/24) and 83.3% (20/24), respectively. CONCLUSION: Cotransplantation of haplo-HSCs combined with UC-MSCs was an effective and safe approach for the treatment of patients with SAA. The appropriate conditioning regimen and early treatment for infection also played a critical role in the success of HSCT. PMID- 29490699 TI - An introduction to overviews of reviews: planning a relevant research question and objective for an overview. AB - BACKGROUND: Overviews of systematic reviews are a relatively new approach to synthesising evidence, and research methods and associated guidance are developing. Within this paper we aim to help readers understand key issues which are essential to consider when taking the first steps in planning an overview. These issues relate to the development of clear, relevant research questions and objectives prior to the development of an overview protocol. METHODS: Initial discussions and key concepts for this paper were formed during a workshop on overview methods at the 2016 UK Cochrane Symposium, at which all members of this author group presented work and contributed to wider discussions. Detailed descriptions of the various key features of overviews and their different objectives were created by the author group based upon current evidence (Higgins J, Green S. Cochrane Handbook Syst Rev Interv. 2011;4:5, Pollock M, et al. Sys Rev. 2016;5:190-205, Pollock A, et al. Cochrane overviews of reviews: exploring the methods and challenges. UK and Ireland: Cochrane Symposium; 2016, Pieper D, et al. Res Syn Meth. 2014;5:187-99, Lunny C, et al. Sys Rev. 2016;5:4-12, Hartling L, et al. Comparing multiple treatments: an introduction to overviews of reviews. In 23rd Cochrane Colloquium; 2015, Hartling L, et al. Plos One. 2012;7:1 8, Ballard M, Montgomery P. Res Syn Meth. 2017;8:92-108) and author experiences conducting overviews. RESULTS: Within this paper we introduce different types of overviews and suggest common research questions addressed by these overviews. We briefly reflect on the key features and objectives of the example overviews discussed. CONCLUSIONS: Clear decisions relating to the research questions and objectives are a fundamental first step during the initial planning stages for an overview. Key stakeholders should be involved at the earliest opportunity to ensure that the planned overview is relevant and meaningful to the potential end users of the overview. Following best practice in common with other forms of systematic evidence synthesis, an overview protocol should be published, ensuring transparency and reducing opportunities for introduction of bias in the conduct of the overview. PMID- 29490701 TI - Pylorus drainage procedures in thoracoabdominal esophagectomy - a single-center experience and review of the literature. AB - BACKGROUND: Pylorotomy and pyloroplasty in thoracoabdominal esophagectomy are routinely performed in many high-volume centers to prevent delayed gastric emptying (DGE) due to truncal vagotomy. Currently, controversy remains regarding the need for these practices. The present study aimed to determine the value and role of pyloric drainage procedures in esophagectomy with gastric replacement. METHODS: A retrospective review of prospectively collected data was performed for all consecutive patients who underwent thoracoabdominal resection of the esophagus between January 2009 and December 2016 at the Katharinenhospital in Stuttgart, Germany. Clinicopathologic features and surgical outcomes were evaluated with a focus on postoperative nutrition and gastric emptying. RESULTS: The study group included 170 patients who underwent thoracoabdominal esophageal resection with a gastric conduit using the Ivor Lewis approach. The median age of the patients was 64 years. Most patients were male (81%), and most suffered from adenocarcinoma of the esophagus (75%). The median hospital stay was 20 days, and the 30-day hospital death rate was 2.9%. According to the department standard, pylorotomy, pyloroplasty, or other pyloric drainage procedures were not performed in any of the patients. Overall, 28/170 patients showed clinical signs of DGE (16.5%). CONCLUSIONS: In the literature, the rate of DGE after thoracoabdominal esophagectomy is reported to be approximately 15%, even with the use of pyloric drainage procedures. This rate is comparable to that reported in the present series in which no pyloric drainage procedures were performed. Therefore, we believe that pyloric drainage procedures may be unwarranted in thoracoabdominal esophagectomy. However, future randomized trials are needed to ultimately confirm this supposition. PMID- 29490700 TI - CD74 regulates complexity of tumor cell HLA class II peptidome in brain metastasis and is a positive prognostic marker for patient survival. AB - Despite multidisciplinary local and systemic therapeutic approaches, the prognosis for most patients with brain metastases is still dismal. The role of adaptive and innate anti-tumor response including the Human Leukocyte Antigen (HLA) machinery of antigen presentation is still unclear. We present data on the HLA class II-chaperone molecule CD74 in brain metastases and its impact on the HLA peptidome complexity.We analyzed CD74 and HLA class II expression on tumor cells in a subset of 236 human brain metastases, primary tumors and peripheral metastases of different entities in association with clinical data including overall survival. Additionally, we assessed whole DNA methylome profiles including CD74 promoter methylation and differential methylation in 21 brain metastases. We analyzed the effects of a siRNA mediated CD74 knockdown on HLA expression and HLA peptidome composition in a brain metastatic melanoma cell line.We observed that CD74 expression on tumor cells is a strong positive prognostic marker in brain metastasis patients and positively associated with tumor-infiltrating T-lymphocytes (TILs). Whole DNA methylome analysis suggested that CD74 tumor cell expression might be regulated epigenetically via CD74 promoter methylation. CD74high and TILhigh tumors displayed a differential DNA methylation pattern with highest enrichment scores for antigen processing and presentation. Furthermore, CD74 knockdown in vitro lead to a reduction of HLA class II peptidome complexity, while HLA class I peptidome remained unaffected.In summary, our results demonstrate that a functional HLA class II processing machinery in brain metastatic tumor cells, reflected by a high expression of CD74 and a complex tumor cell HLA peptidome, seems to be crucial for better patient prognosis. PMID- 29490702 TI - Identifying trial recruitment uncertainties using a James Lind Alliance Priority Setting Partnership - the PRioRiTy (Prioritising Recruitment in Randomised Trials) study. AB - BACKGROUND: Despite the problem of inadequate recruitment to randomised trials, there is little evidence to guide researchers on decisions about how people are effectively recruited to take part in trials. The PRioRiTy study aimed to identify and prioritise important unanswered trial recruitment questions for research. The PRioRiTy study - Priority Setting Partnership (PSP) included members of the public approached to take part in a randomised trial or who have represented participants on randomised trial steering committees, health professionals and research staff with experience of recruiting to randomised trials, people who have designed, conducted, analysed or reported on randomised trials and people with experience of randomised trials methodology. METHODS: This partnership was aided by the James Lind Alliance and involved eight stages: (i) identifying a unique, relevant prioritisation area within trial methodology; (ii) establishing a steering group (iii) identifying and engaging with partners and stakeholders; (iv) formulating an initial list of uncertainties; (v) collating the uncertainties into research questions; (vi) confirming that the questions for research are a current recruitment challenge; (vii) shortlisting questions and (viii) final prioritisation through a face-to-face workshop. RESULTS: A total of 790 survey respondents yielded 1693 open-text answers to 6 questions, from which 1880 potential questions for research were identified. After merging duplicates, the number of questions was reduced to 496. Questions were combined further, and those that were submitted by fewer than 15 people and/or fewer than 6 of the 7 stakeholder groups were excluded from the next round of prioritisation resulting in 31 unique questions for research. All 31 questions were confirmed as being unanswered after checking relevant, up-to-date research evidence. The 10 highest priority questions were ranked at a face-to-face workshop. The number 1 ranked question was "How can randomised trials become part of routine care and best utilise current clinical care pathways?" The top 10 research questions can be viewed at www.priorityresearch.ie . CONCLUSION: The prioritised questions call for a collective focus on normalising trials as part of clinical care, enhancing communication, addressing barriers, enablers and motivators around participation and exploring greater public involvement in the research process. PMID- 29490703 TI - Nanostructured surface topographies have an effect on bactericidal activity. AB - BACKGROUND: Due to the increased emergence of antimicrobial resistance, alternatives to minimize the usage of antibiotics become attractive solutions. Biophysical manipulation of material surface topography to prevent bacterial adhesion is one promising approach. To this end, it is essential to understand the relationship between surface topographical features and bactericidal properties in order to develop antibacterial surfaces. RESULTS: In this work a systematic study of topographical effects on bactericidal activity of nanostructured surfaces is presented. Nanostructured Ormostamp polymer surfaces are fabricated by nano-replication technology using nanoporous templates resulting in 80-nm diameter nanopillars. Six Ormostamp surfaces with nanopillar arrays of various nanopillar densities and heights are obtained by modifying the nanoporous template. The surface roughness ranges from 3.1 to 39.1 nm for the different pillar area parameters. A Gram-positive bacterium, Staphylococcus aureus, is used as the model bacterial strain. An average pillar density at ~ 40 pillars MUm-2 with surface roughness of 39.1 nm possesses the highest bactericidal efficiency being close to 100% compared with 20% of the flat control samples. High density structures at ~ 70 pillars MUm-2 and low density structures at < 20 pillars MUm-2 with surface roughness smaller than 20 nm reduce the bactericidal efficiency to almost the level of the control samples. CONCLUSION: The results obtained here suggests that the topographical effects including pillar density and pillar height inhomogeneity may have significant impacts on adhering pattern and stretching degree of bacterial cell membrane. A biophysical model is prepared to interpret the morphological changes of bacteria on these nanostructures. PMID- 29490704 TI - What family doctors know about congenital CMV: a regional survey in Iran. AB - BACKGROUND: Since there is no effective treatment or vaccine against the congenital cytomegalovirus (cCMV) infection, knowledge and awareness of medical doctor's (MDs) especially family doctors are essential for preventive strategies and it also seems to be usually ignored by healthcare providers. Aim of this study was to investigate awareness of MDs about cCMV infection in Iran. METHODS: A single page questionnaire was randomly distributed among 450 MDs including general practitioners, pediatricians, gynecologists, internal and other medical specialists concerning of their knowledge in clinical presentation, diagnosis, prevention, prognosis, epidemiology, transmission, and management of cCMV infection. All statistical analyses were performed using SPSS version 16. RESULTS: More than half of questionnaire recipients refused to take part in any of the questionnaire items. The most of the respondents were agreed for newborn CMV screening tests and mandatory CMV test for women trying to get pregnant, which, are not routinely tested. The knowledge of general practitioners about cCMV was less than usual. The field of expertise had a profound effect in this survey, but age and gender did not. CONCLUSIONS: Our results indicated that the knowledge of cCMV infection, especially among family doctors contains several gaps. Urgent action is required to improve family doctor's knowledge of CMV infection. Surveys to evaluate CMV awareness among MDs, healthcare professionals and women of childbearing age are proposed. PMID- 29490705 TI - Anti-CD74 antibodies have no diagnostic value in early axial spondyloarthritis: data from the spondyloarthritis caught early (SPACE) cohort. AB - BACKGROUND: Anti-CD74 IgG antibodies are reported to be elevated in patients with axial spondyloarthritis (axSpA). This study assessed the diagnostic value of anti CD74 antibodies in patients with early axSpA. METHODS: Anti-CD74 IgG and IgA antibodies were first measured in an exploratory cohort of patients with radiographic axSpA (138 patients with ankylosing spondyloarthritis (AS)) and 57 healthy controls and then were measured in patients with early axSpA (n = 274) and with non-SpA chronic back pain (CBP) (n = 319), participating in the spondyloarthritis caught early (SPACE) prospective cohort study of patients under 45 years old with early back pain (for >= 3 months, but <= 2 years). RESULTS: In the exploratory cohort, anti-CD74 IgG antibodies were present in 79.7% of patients with AS vs. 43.9% of healthy controls (p < 0.001). Anti-CD74 IgA antibodies were present in 28.5% of patients with AS vs. 5.3% of healthy controls (p < 0.001). In the SPACE cohort, anti-CD74 IgG antibody levels were present in 46.4% of the patients with axSpA vs. 47.9% of the patients with CBP (p = 0.71). Anti-CD74 IgA antibodies were present in 54.7% of the patients with axSpA and 37.0% of the patients with CBP (p < 0.001). This resulted in a positive predictive value of 58.8% (compared to a prior probability of 46.2%) and a negative predictive value of 59.1% (compared to a prior probability of 53.8%). In a regression model, total serum IgA was associated with axSpA odds ratio (OR) 1.19, p < 0.001) whereas anti-CD74 IgA was not (OR) 1.01, p = 0.33). Furthermore, anti-CD74 IgA was associated with sacroiliitis on magnetic resonance imaging (MRI) (OR) = 2.50, p = 0.005) and heel enthesitis (OR) = 2.56, p = 0.002). CONCLUSIONS: Albeit anti-CD74 IgA is elevated in patients with early axSpA, this elevation is not sufficiently specific to yield significant diagnostic value in patients under 45 years old presenting with early back pain. PMID- 29490706 TI - Early long-term administration of the CSF1R inhibitor PLX3397 ablates microglia and reduces accumulation of intraneuronal amyloid, neuritic plaque deposition and pre-fibrillar oligomers in 5XFAD mouse model of Alzheimer's disease. AB - BACKGROUND: Besides the two main classical features of amyloid beta aggregation and tau-containing neurofibrillary tangle deposition, neuroinflammation plays an important yet unclear role in the pathophysiology of Alzheimer's disease (AD). Microglia are believed to be key mediators of neuroinflammation during AD and responsible for the regulation of brain homeostasis by balancing neurotoxicity and neuroprotective events. We have previously reported evidence that neuritic plaques are derived from dead neurons that have accumulated intraneuronal amyloid and further recruit Iba1-positive cells, which play a role in either neuronal demise or neuritic plaque maturation or both. METHODS: To study the impact of microglia on neuritic plaque development, we treated two-month-old 5XFAD mice with a selective colony stimulation factor 1 receptor (CSF1R) inhibitor, PLX3397, for a period of 3 months, resulting in a significant ablation of microglia. Directly after this treatment, we analyzed the amount of intraneuronal amyloid and neuritic plaques and performed behavioral studies including Y-maze, fear conditioning and elevated plus maze. RESULTS: We found that early long-term PLX3397 administration results in a dramatic reduction of both intraneuronal amyloid as well as neuritic plaque deposition. PLX3397 treated young 5XFAD mice also displayed a significant decrease of soluble fibrillar amyloid oligomers in brain lysates, a depletion of soluble pre-fibrillar oligomers in plasma and an improvement in cognitive function measured by fear conditioning tests. CONCLUSIONS: Our findings demonstrate that CSF1R signaling, either directly on neurons or mediated by microglia, is crucial for the accumulation of intraneuronal amyloid and formation of neuritic plaques, suggesting that these two events are serially linked in a causal pathway leading to neurodegeneration and neuritic plaque formation. CSF1R inhibitors represent potential preventative or therapeutic approach that target the very earliest stages of the formation of intraneuronal amyloid and neuritic plaques. PMID- 29490707 TI - A pyoderma gangrenous-like cutaneous leishmaniasis in a Libyan woman with rheumatoid arthritis: a case report. AB - BACKGROUND: Several case reports describe diseases presenting with skin ulcerations, which resemble pyoderma gangrenosum especially in immune-compromised patients, often proven on further workup, to have an infective or malignant etiology. However, treatment of pyoderma gangrenosum by systemic steroids or other immunosuppressive agents may worsen the condition. CASE PRESENTATION: We report here, a 45 year-old Libyan woman with rheumatoid arthritis on low dose steroids with pyoderma gangrenosum-like skin lesions and positive pathergy. Slit smear was positive for Leishmania amastigotes and histopathological examination confirmed the diagnosis of cutaneous leishmaniasis. The lesions healed completely by parenteral sodium stibogluconate (Pentostam) 600 mg daily. CONCLUSION: We report for the first time, a rare and unusual presentation of pyoderma gangrenosum like-cutaneous leishmaniasis in a patient with rheumatoid arthritis. Atypical cutaneous leishmaniasis should not be ruled out in the differential diagnosis of unresponsive skin diseases, with slit/smear and a skin biopsy is required. PMID- 29490709 TI - Infectious mononucleosis - not always a benign condition: a case report of infectious mononucleosis-associated acute acalculous cholecystitis. AB - Infectious mononucleosis is typically a self-limited viral infection of adolescence and early adulthood that resolves in a period of weeks, causing no major sequelae. We describe a case of a healthy 18-year-old female diagnosed with infectious mononucleosis who also presented with right upper quadrant abdominal pain, moderate transaminitis, and cholestatic biochemistry. An ultrasound revealed acute acalculous cholecystitis, generally a condition seen in the context of critical illness. Further investigating emergency department patients with infectious mononucleosis is often not indicated, but may be important for those who present atypically. PMID- 29490710 TI - TELE-EXPERTISE SYSTEM BASED ON THE USE OF THE ELECTRONIC PATIENT RECORD TO SUPPORT REAL-TIME ANTIMICROBIAL USE. AB - OBJECTIVES: The aims of this study are (i) to present the design of a tele expertise system, based on the telephone and electronic patient record (EPR), which supports the counseling of the infectious diseases specialist (IDS) for appropriate antimicrobial use, in a French University hospital; and (ii) to assess the diffusion of the system, the users' adherence, and their perceived utility. METHODS: A prospective observational study was conducted to measure (i) the number and patterns of telephone calls for tele-expertise council, the number of initial and secondary assessments from the IDS and multidisciplinary meetings; (ii) the clinicians' adherence rate to therapeutic proposals by the IDS and the number of clinical situations for which the IDS decided to move to bedside; and (iii) the perceived utility of the system by the medical managers of the most demanding departments. RESULTS: The review of patients' records for 1 year period indicates that 87 percent of the therapeutic recommendations were fully followed. The adherence was high, despite the IDS moving to the bedside only in 6 percent of cases. Medical managers of the most demanding departments considered the system to be useful. Moreover, 6,994 tele-expertise notifications have been recorded into the EPR for 48 months. CONCLUSIONS: The tele-expertise system is an original way to design information technology supported antimicrobial stewardship intervention based on the remote access to relevant information by the IDS and on the traceability of the medical counseling for the clinicians. PMID- 29490708 TI - Integrated proteomics and network analysis identifies protein hubs and network alterations in Alzheimer's disease. AB - Although the genetic causes for several rare, familial forms of Alzheimer's disease (AD) have been identified, the etiology of the sporadic form of AD remains unclear. Here, we report a systems-level study of disease-associated proteome changes in human frontal cortex of sporadic AD patients using an integrated approach that combines mass spectrometry-based quantitative proteomics, differential expression analysis, and co-expression network analysis. Our analyses of 16 human brain tissues from AD patients and age-matched controls showed organization of the cortical proteome into a network of 24 biologically meaningful modules of co-expressed proteins. Of these, 5 modules are positively correlated to AD phenotypes with hub proteins that are up-regulated in AD, and 6 modules are negatively correlated to AD phenotypes with hub proteins that are down-regulated in AD. Our study generated a molecular blueprint of altered protein networks in AD brain and uncovered the dysregulation of multiple pathways and processes in AD brain, including altered proteostasis, RNA homeostasis, immune response, neuroinflammation, synaptic transmission, vesicular transport, cell signaling, cellular metabolism, lipid homeostasis, mitochondrial dynamics and function, cytoskeleton organization, and myelin-axon interactions. Our findings provide new insights into AD pathogenesis and suggest novel candidates for future diagnostic and therapeutic development. PMID- 29490711 TI - Ultrasonographic diagnosis of diaphragm paralysis in a neonate during mechanical ventilation after cardiac surgery. AB - Diaphragm excursion method is unsuitable for diagnosis of diaphragm paralysis during positive pressure ventilation. We diagnosed diaphragm paralysis in a neonate, without interrupting positive pressure respiratory support after cardiac surgery, using the diaphragm thickness fraction, which could be evaluated during mechanical ventilation and was unaffected by bowel gases. The diaphragm thickness fraction method can help diagnose diaphragm dysfunction using only echography. PMID- 29490712 TI - Against the Stream: Generalised anxiety disorder (GAD) - a redundant diagnosis. AB - The diagnosis of generalised anxiety disorder is a distraction of no value. It is highly unreliable, co-occurring with many other disorders of firmer diagnostic status, and has intrinsic connections to personality dysfunction. It is argued that classification would be heartily relieved to rid itself of this unnecessary appendage and for the symptom of anxiety to remain as a descriptive term only. Declaration of interest None. PMID- 29490713 TI - Establishment of prophylactic enoxaparin dosing recommendations to achieve targeted anti-factor Xa concentrations in children with CHD. AB - BACKGROUND: Enoxaparin may be used to prevent central venous catheter-related thrombosis in patients with CHD. We aimed to determine whether current enoxaparin dosing regimens effectively achieve anti-factor Xa concentrations within prophylactic goal ranges in this patient population. METHODS: We implemented a formal protocol aimed at reducing central venous catheter-related thrombosis in children with CHD in January, 2016. Standard empiric prophylactic enoxaparin dosing regimens were used - for example, 0.75 mg/kg/dose every 12 hours for patients <2 months of age and 0.5 mg/kg/dose every 12 hours for patients ?2 months of age - with anti-factor Xa goal range of 0.25-0.49 IU/ml. Patients <2 years of age who received enoxaparin and had at least one valid steady-state anti factor Xa measurement between 25 January, 2016 and 31 August, 2016 were retrospectively reviewed. RESULTS: During the study period, 47 patients had 186 anti-factor Xa concentrations measured, of which 20 (11%) were above and 112 (60%) were below the prophylactic goal range. Anti-factor Xa concentrations within the goal range were ultimately achieved in 31 patients. Median dose required to achieve anti-factor Xa concentrations within the prophylactic range was 0.89 mg/kg/dose (25, 75%: 0.75, 1.11) for patients <2 months (n=23 patients) and 0.79 mg/kg/dose (25, 75%: 0.62, 1.11) for patients ?2 months (n=8 patients). CONCLUSIONS: Enoxaparin doses required to achieve prophylactic anti-factor Xa concentrations in young children with CHD were consistently higher than the currently recommended prophylactic dosing regimens. Further study is needed to determine whether dose titration to achieve prophylactic anti-factor Xa concentrations is effective in preventing central venous catheter-related thrombosis. PMID- 29490714 TI - A pulmonary artery sling with a vascular ring in a toddler: an uncommon combination. AB - Pulmonary artery slings and vascular rings are very rare congenital anomalies. It is even rarer to have both anomalies in the same setting. We present a case of a toddler who was diagnosed with a left pulmonary artery sling and a vascular ring as part of the screening process for the VACTERL association - co-occurrence of vertebral, anorectal, cardiac, tracheoesophageal, renal, and limb malformations. He underwent a successful surgical repair via median sternotomy and on cardiopulmonary bypass with an uneventful postoperative course. PMID- 29490715 TI - Preoperative bioelectrical impedance predicts intensive care length of stay in children following cardiac surgery. AB - We have previously shown that children with a bioelectrical impedance spectroscopy phase angle at 50 degrees (PA 50 degrees ) of <2.7 on postoperative day 2 had a four-fold increase in the risk of prolonged paediatric intensive care length of stay. In this study, we demonstrate a relationship between a baseline measure of phase angle 200/5 degrees and postoperative length of stay. PMID- 29490716 TI - Disparities in the management of cardiovascular risk factors in patients with psychiatric disorders: a systematic review and meta-analysis. AB - BACKGROUND: The high cardiovascular (CV) morbidity and mortality reported for patients with psychiatric disorders may possibly be due to a poorer management of CV risk factors (CVRFs). However, these healthcare disparities remain poorly understood. In this paper, studies comparing the management of smoking, diabetes, hypertension and dyslipidaemia, in patients with and without depression, anxiety, schizophrenia, bipolar or personality disorder, were reviewed. METHODS: Prospective studies comparing rates of screening, diagnosis, treatment and control of CVRFs were searched in PubMed, Embase, PsychInfo, Scopus and Web of Science (inception to January 2017). The Meta-analysis of Observational Studies in Epidemiology (MOOSE) criteria were used. Studies were assessed for quality. Wherever possible, meta-analyses were conducted to summarize the findings. RESULTS: Twenty studies, out of the 18 333 references initially identified, were included. Most studies were heterogeneous in design. Two areas permitted meta analyses: the pooled odds ratio for quitting smoking for those with depression was 0.64 (0.49-0.80) p < 0.001; the pooled difference of glycated haemoglobin for patients with type 2 diabetes and depression was 0.18 (0.06-0.31) p = 0.005. Individual studies showed associations between: schizophrenia and lower probability of having smoking habit recorded; schizoid personality disorder and higher probability of remaining non-smokers after quitting; anxiety and poorer control of type I diabetes; depression, anxiety or schizophrenia and lower probability of having a diagnosis of hypertension; schizophrenia or bipolar disorder and lower use of antihypertensive and lipid-lowering drugs. CONCLUSIONS: A proactive clinical management, together with further studies, are needed to reduce the CV morbidity and mortality of patients with psychiatric disorders. PMID- 29490717 TI - Spanish Version of the Satisfaction with Life Scale: Validation and Factorial Invariance Analysis in Chile. AB - The aim of this study is to: (1) examine the psychometric properties of the Spanish version of the Satisfaction with Life scale (SWLS) on a representative sample of the Chilean population (N = 1,500); (2) test the factorial invariance of the SWLS across gender and employment status (henceforth status); and (3) provide normative data of the SWLS for Chile. Results suggest that the Spanish version of the SWLS is a valid and reliable instrument for measuring global life satisfaction in Chile and for comparison across gender and status. Confirmatory factor analysis shows support, across all groups, for a modified single-factor structure of the SWLS that allows error terms of items 1 and 2 to correlate (GFI > .98; RMSEA .99; RMSEA < .06). Metric invariance holds for gender (DeltaCFI = 0; RMSEA = .051) and status (Deltachi2 = 23.93, nonsignificant; ?CFI = 0; RMSEA = .045). Scalar invariance holds for gender and some status combinations; partial scalar invariance holds for the rest. Mean levels of life satisfaction can be compared across gender and status, albeit cautiously for status combinations for which scalar invariance does not hold. PMID- 29490718 TI - Role of Surprise in the Discrimination of the Facial Expression of Fear. AB - The facilitating role of the facial expression of surprise in the discrimination of the facial expression of fear was analyzed. The sample consisted of 202 subjects that undertook a forced-choice test in which they had to decide as quickly as possible whether the facial expression displayed on-screen was one of fear, anger or happiness. Variations were made to the prime expression (neutral expression, or one of surprise); the target expression (facial expression of fear, anger or happiness), and the prime duration (50 ms, 150 ms or 250 ms). The results revealed shorter reaction times in the response to the expression of fear when the prime expression was one of surprise, with a prime duration of 50 ms (p = .009) and 150 ms (p = .001), compared to when the prime expression was a neutral one. By contrast, the reaction times were longer in the discrimination of an expression of fear when the prime expression was one of surprise with a prime duration of 250 ms (p < .0001), compared to when the prime expression was a neutral one. This pattern of results was obtained solely in the discrimination of the expression of fear. The discussion focuses on these findings and the possible functional continuity between surprise and fear. PMID- 29490719 TI - Associations of anabolic-androgenic steroid use with other behavioral disorders: an analysis using directed acyclic graphs. AB - BACKGROUND: Anabolic-androgenic steroid (AAS) use is known to be associated with other psychiatric disorders, such as body image disorders, conduct disorder/sociopathy, and other substance use disorders (SUD) - but the causal pathways among these conditions remain poorly delineated. METHODS: We created a directed acyclic graph to diagram hypothesized relationships among AAS use and dependence, body image disorder (BID), conduct disorder/sociopathy, and other SUD. Using proportional hazards models, we then assessed potentially causal relationships among these variables, using a dataset of 233 male weightlifters, of whom 102 had used AAS. RESULTS: BID and conduct disorder/sociopathy both strongly contributed to the development of AAS use, but did not appear to contribute further to the progression from AAS use to AAS dependence. Other SUD beginning prior to first AAS use - whether broadly defined or restricted only to opioids - failed to show an effect on AAS use or progression to AAS dependence. Conversely, AAS use contributed significantly to the subsequent first-time development of opioid use disorders but did not significantly increase the risk for first-time development of non-opioid SUD, taken as a whole. CONCLUSIONS: Our analysis suggests that AAS use and other SUD are mutually attributable to underlying conduct disorder/sociopathy. SUD do not appear to represent a 'gateway' to subsequent AAS use. AAS use may represent a gateway to subsequent opioid use disorder, but probably not to other SUD. PMID- 29490720 TI - Dog bites in the emergency department: a descriptive analysis. AB - CLINICIAN'S CAPSULE What is known about the topic? Though government statistics exist, there is an overall paucity of data evaluating dog bite injuries. What did this study ask? We aimed to describe the nature of dog bite injuries, their management, and their long-term complications. What did this study find? Of 475 dog bites, large muscular breeds were most frequently implicated. Eleven percent of bites occurred in the head and neck region, three patients were admitted to the hospital, and a 10% infection rate was identified. Why does this study matter to clinicians? Educational programs for dog owners, children, and health care workers may help decrease this common source of morbidity. PMID- 29490721 TI - The efficacy of daily snack replacement with oligofructose-enriched granola bars in overweight and obese adults: a 12-week randomised controlled trial. AB - Oligofructose is a prebiotic dietary fibre obtained from chicory root inulin. Oligofructose supplementation may affect satiety, food intake, body weight and/or body composition. The aim was to examine the efficacy of oligofructose supplemented granola bars on the following weight management outcomes: satiety, energy intake, body weight and body composition in overweight or obese adults. In all, fifty-five adults with overweight or obesity (thirty-six females/nineteen males; age: 41 (sd 12) years; 90.6 (sd 11.8) kg; BMI: 29.4 (sd 2.6) kg/m2) participated in a parallel, triple-blind, placebo-controlled intervention. A total of twenty-nine subjects replaced their snacks twice a day with an equienergetic granola bar supplemented with 8 g of oligofructose (OF-Bar). Subjects in the control group (n 26) replaced their snack with a control granola bar without added oligofructose (Co-Bar). Satiety, 24-h energy intake, body weight and body composition (fat mass and waist circumference) were measured at baseline, weeks 6 and 12. In addition, weekly appetite and gastrointestinal side effects were measured. During the intervention, energy intake, body weight and fat mass remained similar in the Co-Bar and OF-Bar groups (all P>0.05). Both groups lost 0.3 (sd 1.2) kg lean mass (P<0.01) and reduced their waist circumference with -2.2 (sd 3.6) cm (P<0.0001) after 12 weeks. The OF-Bar group reported decreased hunger in later weeks of the intervention (P=0.04), less prospective food consumption (P=0.03) and less thirst (P=0.003). To conclude, replacing daily snacks for 12 weeks with oligofructose-supplemented granola bars does not differentially affect energy intake, body weight and body composition compared with a control bar. However, there was an indication that appetite was lower after oligofructose bar consumption. PMID- 29490748 TI - Engineered Non-Viral Gene Vectors for Combination Cancer Therapy: A Review. AB - Following the US Food and Drug Administration's approval of gene therapy drugs, the great potential of disease gene therapy is once again being taken seriously. However, finding a safe and efficient gene delivery vector remains the biggest challenge to successful gene therapy. To overcome this, engineered non-viral gene delivery vectors are continually being developed, despite their lower efficiencies compared with viral vectors. However, the complex biological barriers and instability caused by charge interactions mean that, no major breakthroughs have been made in the clinical development of these non-viral gene vectors. Nevertheless, the functions of the engineered polymer gene carriers are continuously expanding, and success has been achieved with the combined use of therapeutic molecules and targeted delivery. These polymer gene-carrier vectors offer a broader choice of new treatments for diseases ever before. PMID- 29490749 TI - Microneedles-Based Transdermal Drug Delivery Systems: A Review. AB - A microneedle (MN) is a micron-sized needle with a height of 10-2000 MUm and a width of 10-50 MUm, which can penetrate through the epidermis layer to dermal tissue directly without pain. Microneedles are widely used in transdermal drug delivery systems (TDDS) because they are efficient, safe, convenient and painless. Morphologically, microneedles are divided into four types: solid microneedles, coated microneedles, dissolving microneedles, and hollow microneedles. Different types of microneedles play different roles in different research fields. Microneedles also have different characteristics and applications depending on the materials they are made from. In recent years, microneedles have frequently been used to deliver drugs, genes, proteins, RNA, and vaccines, and have achieved amazing therapeutic effect. Meanwhile, a variety of nano-carriers combined with microneedle delivery systems highlight the application of microneedles. The materials, types, and applications of the microneedles are summarized in this review. Overall, this review aims to serve as a foundational study of microneedles and hopes to promote their clinical application. PMID- 29490750 TI - Recent Progress in Functional Micellar Carriers with Intrinsic Therapeutic Activities for Anticancer Drug Delivery. AB - Polymeric micelles have presented superior delivery properties for poorly water soluble chemotherapeutic agents. However, it remains discouraging that there may be some additional short or long-term toxicities caused by the metabolites of high quantities of carriers. If carriers had simultaneous therapeutic effects with the drug, these issues would not be a concern. For this, carriers not only simply act as drug carriers, but also exert an intrinsic therapeutic effect as a therapeutic agent. The functional micellar carriers would be beneficial to maximize the anticancer effect, overcome the drug resistance and reduce the systemic toxicity. In this review, we aim to summarize the recent progress on the development of functional micellar carriers with intrinsic anticancer activities for the delivery of anticancer drugs. This review focuses on the design strategies, properties of carriers and the drug loading behavior. In addition, the combinational therapeutic effects between carriers and chemotherapeutic agents are also discussed. PMID- 29490751 TI - Performance Evaluation of a Novel Sample In-Answer Out (SIAO) System Based on Magnetic Nanoparticles. AB - In recent years, the prevention, control, diagnosis and treatment of infectious diseases has become a global focus for public health. Traditional methods for pathogen testing have some major disadvantages including the need for highly skilled staff and expensive instrumentation, while procedural aspects are complex and sensitive to the environment. These shortcomings have greatly limited the application of traditional testing in on site pathogen detection. In this paper, we present a new point-of-care-testing (POCT) system based on magnetic nanoparticles that enable sample in-answer out (SIAO) automated real-time testing for pathogens. Various performance tests were conducted on the instrument. Nucleic acid extraction efficiencies of SIAO versus manual systems were 95.49% and 84.33%, respectively. Real-time PCR by two methods (TaqMan-based probe and SYBR green dye) in the SIAO system was achievable, with comparable results to the manual method. Nucleic acid testing with the SIAO system was repeatable and better than with manual testing. The SIAO system had good anti-pollution performance with easy avoidance of inter-assay cross contamination. Finally, use of the SIAO system for adenovirus detection produced similar results to LightCycler2.0 system assay findings. The amplification plots and Ct values suggested similar amplification plots shapes for adenovirus testing with the SIAO system and with real-time fluorescence PCR testing and commercial instrument post manual nucleic acid extraction. Collectively, these findings indicate that testing with the SIAO system is virtually equivalent to that of manual extraction with commercial system testing. PMID- 29490752 TI - Curcumin-Loaded TPGS/F127/P123 Mixed Polymeric Micelles for Cervical Cancer Therapy: Formulation, Characterization, and InVitro and InVivo Evaluation. AB - Cervical cancer is the fourth most common cancer in women worldwide, and existing treatments cause severe side effects and great burdens. Thus, the development of safe, inexpensive therapeutic agents is necessary. Curcumin (Cur), a well-known natural product, exerts promising anti-cancer activities against various cancer types. However, its therapeutic efficacy is severely restrained due to rapid degradation, poor aqueous solubility, and low bioavailability. The objective of this study was to investigate the therapeutic potential of novel curcumin-loaded TPGS/F127/P123 mixed polymeric micelles (Cur@NPT100) for cervical cancer treatment. The Cur@NPT100 exhibited an average size of approximately 19 nm, a zeta potential of around -4 mV, a drug loading of 8.18 +/- 0.36%, and an encapsulation efficiency of 79.38 +/- 4.65%. Unlike free Cur, Cur@NPT100 are readily dispersed in aqueous medium, showing enhanced stability and a sustained release profile over a 6-day period. In vitro cell culture experiments revealed that TPGS/F127/P123 mixed polymeric micelles (NPT100) based nanocarriers substantially promoted the selective cellular uptake of Cur into HeLa cells rather than by non-cancerous NIH3T3 cells, inducing higher cytotoxicity and greater apoptosis and significantly increasing the percentage of cells arrested at the G2/M phase of the cell cycle. Additionally, the Cur@NPT100 facilitated more Cur accumulation in the mitochondria and decreased the mitochondrial membrane potential. In addition, western blot assays demonstrated that Cur@NPT100 were more potent than free Cur at activating the mitochondria-mediated apoptosis pathway. In vivo results further confirmed that Cur@NPT100 exhibited a much higher antitumor efficacy than free Cur and had excellent biocompatibility. In conclusion, Cur@NPT100 might be an effective therapeutic agent for cervical cancer. PMID- 29490753 TI - pH-Responsive Nanoparticles Based on Covalently Grafted Conjugates of Carboxymethyl Chitosan and Daunorubicin for the Delivery of Anti-Cancer Drugs. AB - The drug controlled release responding to tumour microenvironment is a hotspot for cancer therapy research. Herein, pH-sensitive shell-core nanoparticles (NPs) were devised and fabricated for tumour treatment. The detailed characterisations of their structures demonstrated the successful formation of the precursors and NPs. More importantly, the NPs show excellent features, i.e., negative surface potential, narrow size distribution, and suitable dimension for cell penetration. And they have superior stability in pH 7.4 buffer (i.e., blood environment). In addition, owing to the existence of the pH-labile imine bond, a controlled release of drugs from NPs was achieved in drug release test. Confocal laser scanning microscopy (CLSM) and flow cytometry proved the internalization of NPs into HeLa cells and their further translocation into cell nuclei. The cytotoxicity results also revealed a remarkable cytotoxicity of the NPs to HeLa cells. Thus, this type of NP may be potentially useful for the efficient drug delivery. PMID- 29490754 TI - An Injectable, Wound-Adapting, Self-Healing Hydrogel for Fibroblast Growth Factor 2 Delivery System in Tissue Repair Applications. AB - Rapid wound healing is a fundamental health concern and poses a critical challenge for healthcare systems worldwide. Here, we developed an injectable, dynamic, self-healing hydrogel serving as a fibroblast growth factor 2 (FGF2) delivery system for tissue repair applications. Benzaldehyde-terminated polyethylene glycol (BAPEG) was synthesized and cross-linked with N-Succinyl chitosan (SCS) through reversible Schiff-base reaction to form a dynamic self healing hydrogel. Because it can be injected after gelation and self-heal into an integral part, the hydrogel could not only auto-adapt to the irregular wound surface to provide better protection but also encapsulate drugs homogeneously and implant into tissue with a less invasive strategy. As a result, the FGF2-loaded SCS/BAPEG hydrogel is able to significantly promote the process of angiogenesis, collagen deposition, and granulation tissue formation, as well as reduce inflammation. This study opens the door to self-healing hydrogels serving as a drug delivery system for tissue repair applications. PMID- 29490755 TI - Production of Transgenic Mice Through Sperm-Mediated Gene Transfer Using Magnetic Nano-Carriers. AB - Current methods of transgenic animal production suffer from low efficiency, cumbersome operation, and high cost. Magnetic nanoparticles (MagNPs) have several characteristics, such as a high carrying efficiency, non-immunogenicity, and strong targeting inducible via magnetic fields, that make them well-suited for use in the generation of transgenic animals. In this study, we used magnetic nano carriers combined with sperm-mediated gene transfer (SMGT) to generate transgenic mice that harbor the enhanced green fluorescent protein (EGFP) gene. Exogenous plasmid DNA loaded onto Fe3O4 MagNPs were first delivered into mouse sperm cells under a magnetic field. Transfected sperm cells were then incubated with oocytes to complete fertilization, and transgenic mice were successfully generated though embryo transplantation. We demonstrate that this method is exceedingly facile, fast, and cost-effective, with higher transfection efficiency than that of conventional liposome methods. PMID- 29490756 TI - Graded Nano Glass-Zirconia Material for Dental Applications-Part II Biocompatibility Evaluation. AB - A graded glass/graded zirconia (G/Z) system was previously synthesized via the infiltration of a low modulus nanosized glass into a zirconia surface. The bond strength of G/Z to veneering porcelains was demonstrated to be 3-fold higher than in zirconia-based systems. Nevertheless, biocompatibility testing prior to the possible clinical application of G/Z systems is essential. Herein, such biocompatibility testing was performed with L-929 fibroblasts seeded onto G/Z and yttria-stabilized tetragonal zirconia polycrystals (Y-TZP) for 2-72 h. Assessments included an oral mucous membrane irritation test in conjunction with analyses of cell viability, cell morphology, cell cycle, cell apoptosis, oxidative stress responses, inflammatory cytokine expression, and cellular toxicity. Cell viability tests showed no significant decrease in G/Z- and Y-TZP treated cells over 72 h. Fluorescence and SEM images demonstrated that cell spreading on Y-TZP and G/Z was similar; cells were flattened and well-spread. Oxidative stress data for G/Z- and Y-TZP-treated cells showed no significant difference in ROS production. Cellular toxicity results for G/Z did not elicit significant differences in LDH release compared with Y-TZP over 72 h. G/Z and Y TZP had no significant differences in IL-1alpha, IL-8, PGE2, and TNF-alpha expression and elicited significantly increased IL-8 expression compared with that of the untreated control group. Cells that were cultured with G/Z showed no significant changes in cell cycle distribution compared with Y-TZP or the untreated control group. Cells that were cultured with Y-TZP and G/Z showed no apoptosis compared to untreated controls at 24 and 48 h. According to the oral mucous membrane irritation test, scores for the macroscopic and microscopic observations for both G/Z and Y-TZP sides were 0, demonstrating no consequent irritation. Therefore, the excellent biocompatibility of G/Z indicates that it has potential for future clinical applications. PMID- 29490757 TI - Promotion of Propranolol Delivery to Hemangiomas by Using Anti-VEGFR Antibody Conjugated Poly(lactic-co-glycolic acid) Nanoparticles. AB - Infantile hemangiomas are the most common tumors affecting children. Although infantile hemangiomas are benign, they could result in morbidity and mortality. The only US Food and Drug Administration-approved drug for infantile hemangiomas is propranolol hydrochloride (HemangeolTM); however, its adverse effects and high frequency of administration hamper its clinical application. Vascular endothelial growth factor receptor (VEGFR) is crucial to the angiogenesis of infantile hemangiomas, and thus it is considered a valuable therapeutic target for infantile hemangiomas. To reduce the adverse effects and high administration frequency of propranolol, we developed propranolol-loaded nanoparticles conjugated with anti-VEGFR antibody (PNP-VEGFR) as a controlled- and targeted release system to treat infantile hemangiomas. The characteristics, anti hemangioma activity, and mechanisms of PNP-VEGFR were examined in vitro and in vivo. The developed PNP-VEGFR exhibited a small size (~100 nm), drug encapsulation efficiency (~60%), and sustained drug release for 8 days. PNP-VEGFR was efficiently bound to human umbilical vein endothelial cells and human hemangioma endothelial cells in a VEGFR-dependent manner, resulting in enhanced cytotoxic effects and stronger inhibition of VEGF expression, compared to that of the untargeted propranolol-loaded nanoparticles (PNP) and propranolol. Notably, the in vivo therapeutic effects of PNP-VEGFR in infantile hemangiomas were superior to that of propranolol and PNP, as reflected by significantly reduced hemangioma volume, weight, and microvessel density, without any noticeable behavioral changes or weight loss. PNP-VEGFR was shown to provide targeted delivery and sustained release of propranolol to infantile hemangiomas. Therefore, it represents a promising treatment for infantile hemangiomas. PMID- 29490758 TI - Preparation of Hydrogel Based on Poly(ester amine) (PEA) for Bilirubin Removal. AB - Hyperbilirubinemia, caused by the disorders in bilirubin metabolism, could result in neurotoxicity, permanent brain damage and even death. As one of effective bilirubin removal technologies from blood, hemoperfusion had attracted much attention. However, the development of bilirubin adsorbents used in hemoperfusion with excellent adsorption capacity and hemocompatibility still faced great challenges. In this work, the cationic hydrogel was prepared by the photo initiated polymerization of biodegradable poly(ester amine) (PEA) based on PLLA and low molecular weight PEI1800. The PEA hydrogel had favorable swelling behavior and bilirubin adsorption capacity, and the bilirubin adsorption amount could reach up to 374.43 mg/g. The effects of pH value, ionic strength and human serum albumin (HSA) were also studied. Besides, the results of hemolytic test indicated that PEA hydrogel had favorable hemocompatibility. Based on these results, the prepared PEA hydrogel would be quite hopeful as an effective adsorbent for bilirubin removal from blood. PMID- 29490759 TI - In Vivo Study of Mastoid Obliteration Using Hydroxyapatite-Chitosan Patch. AB - Many artificial materials have been used for mastoid cavity obliteration in canal wall down tympanomastoidectomy. Among the artificial materials, hydroxyapatite is most popular material for mastoid cavity obliteration. Hydroxyapatite is biostable and osteoconductive, but it has poor mechanical properties, especially brittleness. To overcome the limitation, hydroxyapatite has been combined with natural chitosan polymer, which is biocompatible and flexible, to produce a hydroxyapatite-chitosan patch via a sublimation-assisted compression process. We evaluated this hydroxyapatite-chitosan patch for tympanic cavity obliteration in a rat model by comparing it with sham surgery group, bone cement and homologous cartilage. The cavity obliteration ratio and new bone formation in tympanic bullae were determined by computed tomography, histological analysis, field emission scanning electron microscopy, and energy-dispersive X-ray spectroscopy. Comparing the hydroxyapatite-chitosan patch with homologous cartilage and bone cement, the tympanic cavity obliteration ratio was superior in the patch group (40.96 +/- 7.79%) than other groups (32.23 +/- 6.93% and 16.07 +/- 6.10%). Even the hydroxyapatite-chitosan patch made no difference in new bone formation ratio ranging from 27.92 +/- 11.08 to 29.17 +/- 10.96% with other groups. In conclusion, hydroxyapatite-chitosan patch for mastoid cavity obliteration showed easy handling, flexibility, favorable osteogenesis and biostability. PMID- 29490760 TI - Aligned Fibers Fabricated by Near-Field Electrospinning Influence the Orientation and Differentiation of hPDLSCs for Periodontal Regeneration. AB - The periodontal ligament (PDL) is a specific connective tissue composed of organized and aligned collagenous fibers that fix the tooth root in the alveolar bone. The alignment of PDL fibers and their function have been neglected in the past, as many studies investigated the regeneration of the periodontium, including alveolar bone and cementum regeneration. In this study, we fabricated biodegradable aligned fibers (epsilon-caprolactone/collagen) by near-field electrospinning (NFE) to control the arrangement of human periodontal ligament stem cells (hPDLSCs), aiming to guide the oriented regeneration of the periodontal ligament. Compared with random electrospun fibers, the in vitro study investigated the effects of nanotopography on stem cell differentiation of hPDLSCs. The hPDLSCs were identified by flow cytometry, and the multipotency of hPDLSCs was confirmed by successful osteogenic induction. The hPDLSCs were co cultured with aligned and random fibers. The cell morphology was observed by confocal micrograph and scanning electron micrograph, which showed that aligned fibers could guide the orientation and elongation of hPDLSCs. The expression of periodontal ligament-related genes was higher when cultured with aligned fibers than when cultured with random fibers. In conclusion, via near-field electrospinning, aligned biodegradable fibers were prepared and guided the orientation arrangement of hPDLSCs, providing a better microenvironment for periodontal ligament regeneration. This technology might be further used in the regeneration of tissues in a given direction. PMID- 29490761 TI - Efficacy of Different Compositions of Cerium Oxide Nanoparticles in Tumor-Stroma Interaction. AB - The biomedical application of cerium oxide nanoparticles (nanoceria) is a focal point of research for a few years. The biochemical effects of nanoceria depend on various factors including particle size, oxidation state of cerium, oxygen vacancies on the surface, use of dispersants or coatings, pH and cell type. Due to their autocatalytic redox-activity, these particles are considered to act as a specific anti-cancer tool with less side effects on healthy cells and tissues, as the particles kill tumor cells, while protecting healthy cells from oxidative damage. In the present study, four different types of nanoceria were investigated with regard to their impact on biochemical parameters in vitro, which play a pivotal role in tumor-stroma interaction. The obtained data and presented in vitro test parameters will be helpful in designing nanoceria compositions, which are ideally suited for anticancer therapy, either as a 'stand alone drug' or in combination with other chemotherapeutics. PMID- 29490762 TI - Table of Contents to Volume 13, Numbers 1-12, 2017. PMID- 29490765 TI - Allergic diseases: A collection of interactive immunologic disorders at the crossroads of genetics, environment, and immunity. PMID- 29490766 TI - Association between urticaria and nematode infections. AB - BACKGROUND: The association between parasites and urticaria was first suggested in the last century. A wide range, 0-75.4%, of the prevalence of parasitic infection has been reported with chronic urticaria (CU). Moreover, urticaria may be detected in patients with parasitosis. Nematodes are a type of helminth that infect hundreds of millions of people throughout the world. OBJECTIVE: The aim of this work was to collect and review the published studies and cases of urticaria associated with nematode infections. METHODS: A search of scientific literature data bases from January 1960 until May 2017 was carried out. RESULTS: Numerous nematode infections have been associated with urticaria and/or angioedema: Anisakis simplex, Ascaris species (spp.), Dirofilaria spp., Enterobius vermicularis, Gnathostoma spp., Loa loa, Mansonella streptocerca; Necator americanus, Onchocerca volvulus, Strongyloides stercoralis, Toxocara spp., Trichinella spp., and Wuchereria bancrofti. The pathogenesis of urticaria in these infections generally remains unexplained. In some cases, skin manifestations were caused by the presence of the worm in the skin (Filaria, Gnathostoma); in other cases, such as A. simplex and S. stercoralis infections, there was a clear immunoglobulin E-mediated mechanism that led to allergic reactions, and infection and allergy coexisted; for other nematodes, the association was anecdotal and only a few cases were reported. CONCLUSION: It is difficult to detect a certain causal effect, except when urticaria improves or disappears after infection treatment. Cases of isolated urticaria not associated with other symptoms rarely may be caused by helminths. In the current guideline for urticaria, parasitosis is considered to be a rare possible cause of CU in developed industrial countries, Therefore, although a routine screening of parasitic infection in CU is not recommended, in our opinion, testing a patient with urticaria for parasites is a physician's choice based on the characteristics of the patient, such as associated symptoms, dietary habit, provenance country and previous travel. PMID- 29490767 TI - Association of alopecia areata with atopic dermatitis and chronic spontaneous urticaria. AB - BACKGROUND: Epidemiologic studies report that alopecia areata (AA) is related to various atopic and autoimmune diseases. The purpose of this study was to identify clinical characteristics and the prevalence of comorbid conditions in Israeli patients with AA. METHODS: This retrospective, matched, case-control study was based on data from an electronic patient record data base. The patients with an electronically documented diagnosis of AA were included in the AA group. The control group was randomly sampled from the remaining subjects, with a case-to control ratio of two controls for each case. Comorbidity was compared between the study groups. RESULTS: A total of 1751 subjects (49.4% men and 50.6% women), ages 34.9 +/- 17.8 years old, were identified. The control group consisted of 3502 age and sex-matched subjects. The AA group was characterized by a higher blood eosinophil count (0.39 +/- 0.12 cells/mm3) than the control group (0.31 +/- 0.14 cells/mm3; p < 0.001). In the AA group, there was a higher prevalence of allergic rhinitis (odds ratio [OR] 2.15 [1.85-2.49]; p < 0.001), asthma (OR 1.57 [1.28 1.93]; p < 0.001), atopic dermatitis (AD) (OR 4.17 [3.18-5.47]; p < 0.001), and food allergy (OR 2.79 [1.58-4.91]; p < 0.001) than in the control group. The prevalence of organ-specific and systemic autoimmune diseases was significantly higher in the AA group than in the control group, with the OR of having any autoimmune disease calculated to be 4.72 (3.99-5.57; p < 0.001). The OR of having chronic spontaneous urticaria (CSU) with AA was 6.15 (4.06-9.32; p < 0.001). In patients with concomitant AA and CSU, allergic rhinitis and AD were more prevalent than in patients with CSU in the control group. CONCLUSION: An estimated prevalence of AA among an Israeli population was ~0.8%. The novel finding of our study was the high prevalence of food allergy and CSU in patients with AA. PMID- 29490768 TI - Association between psoriasis and asthma risk: A meta-analysis. AB - BACKGROUND: Psoriasis has been shown to be related to an increased risk of asthma, although the results remain inconclusive. Therefore, we performed a meta analysis to determine whether psoriasis increases the risk of asthma. METHODS: A comprehensive search of medical literature data bases was conducted through May 2017. The pooled odds ratios (OR) and corresponding 95% confidence intervals (CI) were calculated. RESULTS: A total of six studies with 66,772 psoriasis cases and 577,415 controls were included. Our meta-analysis showed that psoriasis was significantly associated with the increased risk of asthma (OR 1.32 [95% CI, 1.20 1.46]). The older age patients with psoriasis (>=50 years) (OR 1.64 [95% CI, 1.44 1.88]) had a higher risk of asthma susceptibility compared with the younger patients (20-49 years old) (OR 1.25 [95% CI 1.09-1.44]). Subgroup analysis by ethnicity indicated a significant increase in asthma risk in both Asian populations (OR 1.35 [95% CI, 1.18-1.54]) and white populations (OR 1.27 [95% CI, 1.05-1.54]) with psoriasis compared with those without psoriasis. CONCLUSION: Results of this meta-analysis indicated that the patients with psoriasis had a higher risk of asthma susceptibility, especially among the older patients with psoriasis. PMID- 29490769 TI - Safety of a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate in children: A randomized clinical trial. AB - BACKGROUND: The safety of a novel intranasal formulation of azelastine hydrochloride (AZE) and fluticasone propionate (FP) has been established in adults and adolescents with allergic rhinitis but not in children <12 years old. OBJECTIVE: To evaluate the safety and tolerability of an intranasal formulation of AZE and FP in children ages 4-11 years with allergic rhinitis. METHODS: The study was a randomized, 3-month, parallel-group, open-label design. Qualified patients were randomized in a 3:1 ratio to AZE/FP (n = 304) or fluticasone propionate (FP) (n = 101), one spray per nostril twice daily, and to one of three age groups: >=4 to <6 years, >=6 to <9 years, and >=9 to <12 years. Safety was assessed by child- or caregiver-reported adverse events, nasal examinations, vital signs, and laboratory assessments. RESULTS: The incidence of treatment related adverse events (TRAEs) was low in both the AZE/FP (16%) and FP-only (12%) groups after 90 days' continuous use. Epistaxis was the most frequently reported TRAE in both groups (AZE/FP, 9%; FP, 9%), followed by headache (AZE/FP, 3%; FP, 1%). All other TRAEs in the AZE/FP group were reported by <=1% of the children. The majority of TRAEs were of mild intensity and resolved spontaneously. Results of nasal examinations showed an improvement over time in both groups, with no cases of mucosal ulceration or nasal septal perforation. There were no unusual or unexpected changes in laboratory parameters or vital signs. CONCLUSION: The intranasal formulation of AZE and FP was safe and well tolerated after 3 months' continuous use in children with allergic rhinitis.The study was registered on ClinicalTrials.gov (NCT01794741). PMID- 29490770 TI - In vitro induction of T regulatory cells by a methylated CpG DNA sequence in humans: Potential therapeutic applications in allergic and autoimmune diseases. AB - BACKGROUND: Allergic and autoimmune diseases comprise a group of inflammatory disorders caused by aberrant immune responses in which CD25+ Forkhead box P3 positive (FOXP3+) T regulatory (Treg) cells that normally suppress inflammatory events are often poorly functioning. This has stimulated an intensive investigative effort to find ways of increasing Tregs as a method of therapy for these conditions. One such line of investigation includes the study of how ligation of Toll-like receptors (TLRs) by CpG oligonucleotides (ODN) results in an immunostimulatory cascade that leads to induction of T-helper (Th) type 1 and Treg-type immune responses. OBJECTIVE: The present study investigated the mechanisms by which calf thymus mammalian double-stranded DNA (CT-DNA) and a synthetic methylated DNA CpG ODN sequence suppress in vitro lymphoproliferative responses to antigens, mitogens, and alloantigens when measured by [3H]-thymidine incorporation and promote FoxP3 expression in human CD4+ T cells in the presence of transforming growth factor (TGF) beta and interleukin-2 (IL-2). METHODS: Lymphoproliferative responses of peripheral blood mononuclear cells from four healthy subjects or nine subjects with systemic lupus erythematosus to CT-DNA or phytohemagglutinin (PHA) was measured by tritiated thymidine ([3H]-TdR) incorporation expressed as a stimulation index. Mechanisms of immunosuppressive effects of CT-DNA were evaluated by measurement of the degree of inhibition to lymphoproliferative responses to streptokinase-streptodornase, phytohemagglutinin (PHA), concanavalin A (Con A), pokeweed mitogen (PWM), or alloantigens by a Con A suppressor assay. The effects of CpG methylation on induction of FoxP3 expression in human T cells were measured by comparing inhibitory responses of synthetic methylated and nonmethylated 8-mer CpG ODN sequences by using cell sorting, in vitro stimulation, and suppressor assay. RESULTS: Here, we showed that CT-DNA and a synthetic methylated DNA 8-mer sequence could suppress antigen-, mitogen-, and alloantigen-induced lymphoproliferation in vitro when measured by [3H]-thymidine. The synthetic methylated DNA CpG ODN but not an unmethylated CpG ODN sequence was shown to promote FoxP3 expression in human CD4+ T cells in the presence of TGF beta and IL-2. The induction of FoxP3+ suppressor cells is dose dependent and offers a potential clinical therapeutic application in allergic and autoimmune and inflammatory diseases. CONCLUSION: The use of this methylated CpG ODN offers a broad clinical application as a novel therapeutic method for Treg induction and, because of its low cost and small size, should facilitate delivery via nasal, respiratory, gastrointestinal routes, and/or by injection, routes of administration important for vaccine delivery to target sites responsible for respiratory, gastrointestinal, and systemic forms of allergic and autoimmune disease. PMID- 29490771 TI - Interleukin 33 and interleukin 4 regulate interleukin 31 gene expression and secretion from human laboratory of allergic diseases 2 mast cells stimulated by substance P and/or immunoglobulin E. AB - BACKGROUND: Cytokine interleukin (IL) 31 has emerged as an important component of allergic and inflammatory diseases associated with pruritus, such as atopic dermatitis (AD) and mastocytosis. Mast cells (MC) are stimulated by allergic and nonallergic triggers, and play a critical role in such diseases by secreting histamine and tryptase as well as cytokines and chemokines. IL-33 has been reported to augment MC responses, but its effect on secretion of IL-31 is not known. OBJECTIVES: To investigate whether IL-33 can stimulate the secretion of IL 31 from cultured human MCs and whether this response is augmented by either the neuropeptide substance P (SP) or immunoglobulin E (IgE) and anti-IgE in the absence or presence of IL-4. METHODS: Laboratory of Allergic Diseases (LAD2) human MCs were cultured in StemProH-34 SFM medium supplemented by stem cell factor and were stimulated either with IL-33 (10 ng /mL) or SP (2 MUM), or preincubated with IgE (1 MUg/mL) overnight, and then stimulated with anti-IgE (1 MUg/mL) for 24 hours. IL-31 gene expression was measured by quantitative polymerase chain reaction, and protein was measured by enzyme-linked immunosorbent assay. RESULTS: IL-33 (10 ng/mL) induces IL-31 gene expression, synthesis, and secretion from LAD2 cells in the absence of degranulation, whereas SP and IgE on their own have no effect. However, the effect of IL-33 is augmented by SP (2 MUM) and/or IgE and anti-IgE (1 MUg/mL both) and especially their combination. Moreover, this response is significantly further increased when LAD2 cells are cultured in the presence of IL-4. CONCLUSION: These findings provide evidence that IL-33 induced secretion of IL-31 from LAD2 MC, an action augmented by novel neuroimmune interactions that may help in the development of new treatments of allergic and inflammatory diseases, especially AD and mastocytosis. PMID- 29490773 TI - Let the Author Beware: Preventing Publication Remorse. PMID- 29490772 TI - For the Patient. PMID- 29490774 TI - The Fundamental Unity of Knowledge. PMID- 29490775 TI - Potential Adverse Health Outcomes of Digital Textbook Use: Teachers' Perspectives. AB - BACKGROUND AND PURPOSE: The digital textbook (DT) is an appealing new educational medium. The positive effects of DT use include stimulation of interest in learning and stimulation of motivation to learn. Few studies have examined the awareness of classroom-based educational experts about the adverse health outcomes of DT use. The objective of this study was to understand the perspectives of elementary schoolteachers regarding the effects of DT use on students' health. METHODS: The recommended method of focus group discussions was used to clarify teachers' individual and shared views about this topic. The study design included three discussions with three different groups of teachers. RESULTS: The results indicated that the critical health issues identified by the schoolteachers were potential risks to physical health, risks to psychological health, and environmental health risks in the classroom. IMPLICATIONS FOR PRACTICE: Awareness and evaluation of adverse health effects for DT users is an important first step for effective DT implementation in our schools. This study provided fundamental data and results that can be used to understand the effects of DT use on student health and to suggest guidelines to predict and prevent adverse health effects in the users of this technology. PMID- 29490776 TI - Learning Situations in Nursing Education: A Concept Analysis. AB - BACKGROUND AND PURPOSE: The nursing student requires opportunities to learn within authentic contexts so as to enable safe and competent practice. One strategy to facilitate such learning is the creation of learning situations. A lack of studies on the learning situation in nursing and other health care fields has resulted in insufficient knowledge of the characteristics of the learning situation, its antecedents, and consequences. Nurse educators need to have comprehensive and practical knowledge of the definition and characteristics of the learning situation so as to enable their students to achieve enhanced learning outcomes. The aim of this study was to clarify the concept of the learning situation as it relates to the education of nurses and improve understanding of its characteristics, antecedents, and consequences. METHODS: The Bonis method of concept analysis, as derived from the Rodgers' evolutionary method, provided the framework for analysis. Data collection and analysis were undertaken in two phases: "interdisciplinary" and "intra-disciplinary." The data source was a search of the literature, encompassing nursing and allied health care professions, published from 1975 to 2016. RESULTS: No agreement on the conceptual phenomenon was discovered in the international literature. The concept of a learning situation was used generally in two ways and thus classified into the themes of: "formal/informal learning situation" and "biologic/nonbiologic learning situation." Antecedents to the creation of a learning situation included personal and environmental factors. The characteristics of a learning situation were described in terms of being complex, dynamic, and offering potential and effective learning opportunities. Consequences of the learning situation included enhancement of the students' learning, professionalization, and socialization into the professional role. IMPLICATION FOR PRACTICE: The nurse educator, when considering the application of the concept of a learning situation in their educational planning, must acknowledge that the application of this concept will include the student's clinical learning experiences. More studies are required to determine factors influencing the creation of a successful learning situation from the perspectives of nurse educators and nursing students, clinical nurses and patients. PMID- 29490777 TI - Risk Knowledge and Awareness of Coronary Heart Disease, and Health Promotion Behaviors Among Adults in Oman. AB - BACKGROUND AND PURPOSE: The purpose of this study was to assess the relationships between an individual's characteristics and experiences (age, gender, level of education, income, and employment), knowledge of coronary heart disease (CHD) risk factors, perception of health status, awareness of CHD, and health promotion behaviors among adult Omanis. METHODS: Using Pender's health promotion model, a cross-sectional and correlational survey design was employed. A self-administered questionnaire was distributed to 180 participants in Muscat, the capital of Oman. Descriptive and multivariate linear regression analyses were employed. RESULTS: Increasing age was associated with high levels of awareness about CHD. Participants who were employed and knowledgeable about CHD risk factors were more likely to have lower perceptions of health. The regression model showed that knowledge of CHD risk factors and awareness of CHD had positive associations with health promotion behaviors. Meanwhile, employed participants had lower health promotion behaviors scores. IMPLICATIONS FOR PRACTICE: Interventions to increase health promotion behaviors should include application of behavioral change strategies that are suitable for age and employment status. The strategies must focus on providing information to enhance knowledge and awareness about CHD. PMID- 29490778 TI - Physical Activity in Parents of Young African American Children: The Application of Social Cognitive Theory. AB - BACKGROUND: Social cognitive theory (SCT) proposes that personal and environmental factors influence behavior bidirectionally. Research examining the personal and environmental factors of physical activity (PA) among African Americans (AAs) framed by SCT is scarce. PURPOSE: The purpose of this article is to enhance knowledge of SCT as a foundation for health promotion and PA research, in general, and among AAs. Findings from a previous study provide exemplars for key factors and relationships in SCT. IMPLICATIONS FOR RESEARCH AND PRACTICE: The SCT serves as a good framework for researchers studying health promotion and PA in generalamong AA parents. PMID- 29490780 TI - Building to Make a Difference: Advanced Practice Nurses' Experience of Power. AB - Power is necessary for nurses to affect change in patient care and to move the nursing profession forward. Despite the evolving body of nursing research on power, there have been no studies that have investigated the nature of advanced practice nurses' (APNs') power. The purpose of this study was to explore the APNs' lived experience of power. Interpretive phenomenology guided the method and analysis. Eight APNs employed in a single Canadian tertiary care teaching health care organization engaged in in-depth interviews. The overarching theme, building to make a difference, reflected the APNs' perception of power in their practice, which involved a passion to facilitate change in practice to improve patient care. Building to make a difference involved three themes: building on, building with, and building for. The APNs experienced more power-a process they described as power creep-when they used soft power that was shared with others to affect positive change in health care. These findings contribute to our understanding of how power is perceived and manifested in the APN role, thus further enabling organizations to create working conditions to support the APNs' endeavors to empower others. PMID- 29490779 TI - The Effects of Religious and Cultural Beliefs on Muslim Transplant Candidates During the Pretransplant Waiting Period. AB - BACKGROUND: Awaiting organ transplantation can be stressful, and pretransplant candidates' religious and cultural beliefs can influence how they adapt to the stress. While little is known about the effect religious and cultural beliefs have on the pretransplant waiting period, virtually nothing is known regarding whether and how Shia Muslim patients' religious and cultural beliefs facilitate more positive patient outcomes while they await transplantation. Therefore, it is important for nurses and other health care providers to understand transplant candidates' experiences dealing with the stressors that present themselves during the pretransplant waiting period, especially how their religious and cultural beliefs affect their adaptation to the stressors. AIM: The purpose of this study was to explore the lived experience of Shia Muslim organ transplant candidates regarding how their religious and cultural beliefs affect their adaptation to the pretransplant waiting period. SAMPLE: A purposeful sample of 11 Shia Muslim organ transplant candidates who were on an organ transplant waiting list in Iran (kidney, n = 4; heart, n = 4; liver, n = 3) was recruited. METHOD: A qualitative research design using the hermeneutical phenomenological approach was utilized in this study. In-depth unstructured interviews were conducted by one of the authors (ZS) in different locations across Iran. RESULTS: Data analysis led to the development of six themes: "the misty road of organ transplantation," "to accede to organ transplantation despite religious conflict," "one step away from death," "the master key of liberation," "fear of the unknown," and "reliance on God." NURSING IMPLICATIONS: The findings of this study will help nurses understand the religious and cultural meaning associated with stressors experienced by Shia Muslim patients awaiting organ transplant. This information can assist nurses to develop plans of care that include patient-specific interventions that take into consideration the patients' religious and cultural beliefs. CONCLUSION: Shia Muslim patients awaiting organ transplantation experience feelings that are often in conflict with their religious and cultural beliefs. However, the patients' reliance on God during the pretransplant waiting period facilitated healthier attitudes regarding transplantation. PMID- 29490782 TI - Instructions to Authors 2018. PMID- 29490781 TI - CHIMIA News. PMID- 29490783 TI - Editorial. PMID- 29490784 TI - Exzellenz in der Bildung fur eine innovative Schweiz: Die Position des Wirtschaftsdachverbandes Chemie Pharma Biotech. AB - In Switzerland, the chemical, pharma and biotech industries make a substantial and sustained contribution to the Swiss economy. The company members of scienceindustries employ around 70,000 people in Switzerland. Since 1980 value creation and productivity have increased markedly. As a result the share of the Swiss gross value added has grown continually to reach 5.6% in 2015. Exports have also increased. Today the chemical, pharma and biotech industry contributes around 45% of all Swiss exports and is therefore the largest Swiss export industry. This article describes the key requirements from the viewpoint of the chemical-pharma industry in order that Switzerland can continue to compete as an innovative location in global competition. PMID- 29490785 TI - Die SimplyScience Stiftung. AB - SimplyScience is an internet platform for 8 to 18 year olds and their parents and teachers, created by the scienceindustries in 2008. scienceindustries represents the chemical, pharma and biotech industries and is active in the Swiss Federal Department of Economic Affairs, Education and Research's programme 'Promotion of Science, Mathematics and Technology', the so-called 'MINT' subjects. SimplyScience presents articles, videos and podcasts on diverse scientific subjects and has the objective of interesting children and adolescents for science and technology matters and thereby encouraging them to consider a career in one of the MINT subjects. PMID- 29490786 TI - Bildung fur das Lehramt Chemie in Deutschland. Didaktik bereits im Studium. AB - This article describes the training and further education of chemistry teachers in Germany. Specific features are highlighted and, in part, critically examined. PMID- 29490787 TI - Teaching Fundamental Aspects of Natural and Artificial Photosynthesis in Higher Education. AB - Photosynthesis or the storage of solar energy in chemical bonds is a process which, in its essence, goes far beyond a conversion of CO2 and water into dioxygen and glucose or other organic products. Photosynthesis is a process which comprises elementary features of most of the chemical reactions and some physical processes we are looking at in higher education; light absorption, proton transfer, redox reactions and making and breaking of bonds amongst others. Metals and main group elements are involved and the entire process is embedded in a biological environment that involves proteins and membranes. In this article, we will focus on two key aspects of natural photosynthesis, namely the absorption of light (photons) and the separation of the excitons into electrons and holes based on P680 along with the electrochemical energetics. Further, we will present an artificial light driven catalytic process which mimics PSI for the reduction of water to H2, the inorganic congener of nicotinamide adenine dinucleotide phosphate (NADPH). This light-driven reductive process shall show the mechanistic complexity of the 'easy' reaction 2H+ + 2e- -> H2. PMID- 29490789 TI - Chemistry and Art. AB - This review summarizes possibilities of including scientific methods for investigation of art objects into the secondary school chemistry curriculum. We discuss methods such as X-ray radiography, infrared reflectography, neutron activation autoradiography, X-ray fluorescence, and Raman spectroscopy and provide recent examples of their use. The results obtained, especially when combined with modern digital image processing algorithms, are indeed impressive. The second part of the paper is devoted to suggestions for actual use in teaching. The activities in the classroom can be centered around scientific investigation of a single painting, properties and use of a single pigment, or utilizing parallels in the history of Chemistry and history of Art. Finally, scientific methods for detecting art fraud including actual historical examples are especially motivating for the students and various teaching activities can be designed around this aspect. PMID- 29490788 TI - Mehr Licht im Chemieunterricht! Experimentelle Zugange zu Grundkonzepten der Photochemie. AB - On September 8, 2016, the Swiss Chemical Society (SCS) organized a symposium called the 'Future of Chemical Education' with lectures and workshops during the SCS Fall meeting at ETH Zurich. This article is a summary of the lecture and workshop that the author held at this event in which teachers carried out model experiments on photocatalysis and conversion of solar energy into stored chemical energy. PMID- 29490790 TI - Adopting the Chemical Potential in the High School Curriculum: Why not? AB - Discussing some examples involving the equilibrium condition in phase transitions and chemical reac- tions, we show how it is possible to introduce the concept of chemical potential (MU) even at the beginning of high school. This provides the students with a simple way of conceptualizing and managing quantitatively phenomena which, on the surface, are quite different; and it allows them to do this in a way which is both unifying and coherent. PMID- 29490791 TI - Integrating Chemistry: Crossing the Millennium Divide. AB - A personal account of the development of two University level chemistry books is presented. The account focuses on ways to integrate the traditional branches of chemistry into a textbook that captures the imagination of students and relates chemical principles and fundamental topics to environmental, medicinal, biological and industrial applications. The ways in which teaching methods have changed over two decades and how web-based resources can be used to improve the communication of chemical (in particular structural) concepts are highlighted. PMID- 29490792 TI - Apoc Social: A Mobile Interactive and Social Learning Platform for Collaborative Solving of Advanced Problems in Organic Chemistry. AB - Mobile devices such as smartphones are carried in the pockets of university students around the globe and are increasingly cheap to come by. These portable devices have evolved into powerful and interconnected handheld computers, which, among other applications, can be used as advanced learning tools and providers of targeted, curated content. Herein, we describe Apoc Social (Advanced Problems in Organic Chemistry Social), a mobile application that assists both learning and teaching college-level organic chemistry both in the classroom and on the go. With more than 750 chemistry exercises available, Apoc Social facilitates collaborative learning through discussion boards and fosters enthusiasm for complex organic chemistry. PMID- 29490793 TI - Challenges in Creating Online Exercises and Exams in Organic Chemistry. AB - e-Learning has become increasingly important in chemical education and online exams can be an attractive alternative to traditional exams written on paper, particularly in classes with a large number of students. Ten years ago, we began to set up an e-course complementing our lecture courses Organic Chemistry I and II within the open-source e-learning environment Moodle. In this article, we retrace a number of decisions we took over time, thereby illustrating the challenges one faces when creating online exercises and exams in (organic) chemistry. Special emphasis is put on the development of MOSFECCS (MOlecular Structural Formula Editor and Calculator of Canonical SMILES), our new editor for drawing structural formulae and converting them to alphanumeric SMILES codes that can be submitted as answers to e-problems. Convinced that the possibility for structure input is essential to set up sensible chemistry quizzes and exams, and realising that existing tools present major flaws in an educational context, we decided to embark on the implementation of MOSFECCS which takes into account a number of didactic aspects. PMID- 29490794 TI - Educational Tools to Introduce Computer-Aided Drug Design to Students and to the Public at Large. AB - The Drug Design Workshop initiative was put in place in 2015 and consists of a collection of educational tools especially developed to introduce computer-aided drug design to the general public and students of various levels. These presentations, hands-on sessions, physical material and on-line educational tools (http://www.drug-design-workshop.ch) have been used in a variety of settings including classrooms, universities, teacher training sessions and science fairs. The main goal is to inform an audience as broad as possible regarding the processes and challenges for the design, discovery and development of drugs. The present article describes what is presently available and the future direction for new activities currently under development. PMID- 29490795 TI - Chemistry Cube Game - Exploring Basic Principles of Chemistry by Turning Cubes. AB - The Chemistry Cube Game invites students at secondary school level 1 and 2 to explore basic concepts of chemistry in a playful way, either as individuals or in teams. It consists of 15 different cubes, 9 cubes for different acids, their corresponding bases and precursors, and 6 cubes for different reducing and oxidising agents. The cubes can be rotated in those directions indicated. Each 'allowed' vertical or horizontal rotation of 90 degrees stands for a chemical reaction or a physical transition. Two different games and playing modes are presented here: First, redox chemistry is introduced for the formation of salts from elementary metals and non-metals. Second, the speciation of acids and bases at different pH-values is shown. The cubes can be also used for games about environmental chemistry such as the carbon and sulphur cycle, covering the topic of acid rain, or the nitrogen cycle including ammoniac synthesis, nitrification and de-nitrification. PMID- 29490798 TI - Deep Learning Invades Drug Design and Synthesis. PMID- 29490799 TI - Chemtogether 2017 ETH Zurich. PMID- 29490800 TI - "Wanted: Innovative Chemistry of Today, 2030 and Beyond". PMID- 29490801 TI - Meet & Greet of the Alfred Werner Scholarships. PMID- 29490802 TI - TEDD Annual Meeting with 3D Bioprinting Workshop. AB - Bioprinting is the technology of choice for realizing functional tissues such as vascular system, muscle, cartilage and bone. In the future, bioprinting will influence the way we engineer tissues and bring it to a new level of physiological relevance. That was the topic of the 2017 TEDD Annual Meeting at ZHAW Waedenswil on 8th and 9th November. In an exciting workshop, the two companies regenHU Ltd. and CELLINK gave us an insight into highly topical applications and collaborations in this domain. PMID- 29490803 TI - Quo Vadis Point-of-Care Diagnostics? Report II of the SWISS SYMPOSIUM in Point-of Care Diagnostics 2017. AB - U.S. studies show that the global point-of-care (POC) diagnostics market will reach $40.5 bn by 2022, with a compound annual growth rate (CAGR) of 10%. This is one of the reasons why HES-SO Valais-Wallis and CSEM, acting on behalf of the NTN Swiss Biotech thematic platform in vitro Diagnostics (TP IVD), invited interested parties on October 26, 2017 to the SWISS SYMPOSIUM in Point-of-Care Diagnostics (see CHIMIA No. 12/2017). We now bring the second report on the future prospects of POC diagnostics. PMID- 29490828 TI - Honoring the Nature of the Patient. PMID- 29490806 TI - Editorial. PMID- 29490829 TI - Finding Meaning Through Kristen Swanson's Caring Behaviors: A Cornerstone of Healing for Nursing Education. AB - Swanson's (1991) middle range theory of caring has traditionally been used to define the care of patients and family members. Swanson's caring theory outlines five caring processes: knowing, being with, doing for, enabling, and maintaining belief (p. 163). Nurse educators can utilize these caring processes to teach nursing students by cultivating meaningful, healing relationships. This article presents an example of a nursing faculty member's application of this theory to her teaching pedagogy. This account serves to guide therapeutic teaching as well as to encourage further scholarly work examining the relationship between Swanson's caring theory and nursing education. PMID- 29490830 TI - Diversity, Inclusion, and Storying: Connecting Across Cultures to Give Meaning to Patients' Whole Health. AB - Transcultural nursing inspires us for humanness. The breadth of a culture is handed down through stories. Storytelling creates understanding and mutuality within a culture and between cultures. Deeper understanding can lead to better patient outcomes across variances in health, wellness, and social standing. The intentional use of storying by six nurses in a project called Story Care led to more appreciative understanding of the other's culture and raised awareness of self in interaction with another. The nurses, patients, and their families had deliberate opportunities to learn more about another who was culturally different, to understand how historical perspectives influence the dynamics of interactions, and to explore a sense of commonality and mutuality in nurse patient engagements. As we strive for cultural intelligence, diversity, and inclusion in our organizations, transcultural nursing helps nurses connect to and be mindful of cultural ways in which we understand a patient's or population's vulnerability, determination, spirit, and strengths that give meaning to their whole health. PMID- 29490831 TI - Teaching the Meaning of Culture in a Baccalaureate Nursing Curriculum. AB - Because culture affects virtually every aspect of life, including health beliefs, customs, and practices, it is imperative that nursing students recognize and value its critical importance to the people whom they will care for as clients/patients. Hence, the notion of culture must be introduced early on in nursing programs and threaded throughout the entire curriculum. PMID- 29490832 TI - Gifts in Health Crisis: The Use of Health Coaching to Create Opportunity for a More Meaningful Life. AB - The purpose of this article is to explore health coaching as an effective intervention in times of health crisis for patients, families, and health-care staff. The pause that a health crisis creates in the activities of normal life allows for deeper questions about a person's life to emerge. Health coaching provides a safe space for clients to engage with these life questions while facilitating a connection with their sense of personal empowerment and innate inner wisdom. The result is a more meaningful and resilient life despite the outcome of the health crisis. PMID- 29490833 TI - Preferment: A New Meaning in Retirement. AB - This article reviews key trends affecting societal views on aging, examines data on RN retirement, and explores the many opportunities that are open to nurses who are approaching retirement. It describes a new way to think about this phase preferment- along with strategies for preparing for preferment. PMID- 29490834 TI - The Essence of Spiritual Care. AB - Spiritual care is an important component of holistic nursing care. To implement spiritual care, the nurse must assess, diagnose, and respond to the needs of each patient and her or his significant others. Meeting the spiritual care needs of the patient can lead to physical healing, reduction of pain, and personal growth. Nurses providing spiritual care experience lower stress and less burnout. PMID- 29490835 TI - Enhancing Spiritually Based Care Through Gratitude Practices: A Health-Care Improvement Project. AB - BACKGROUND: Addressing spirituality in health care is important as it improves health outcomes; however, several provider barriers exist to providing spiritually based care. Local problem: A chart audit at a multidisciplinary wellness center serving a population with chronic mental health problems identified a need to improve the number of spiritually based interventions provided to clients by the nurse practitioner. DESIGN: A quasi-experimental design and pre- and post-test questionnaire were used to measure outcomes including the number of spiritually based interventions and provider attitudes. INTERVENTION: Providers, including a nutritionist, exercise physiologist, pharmacist, acupuncturist, and nurse practitioner, participated in two, 1-hour interactive educational sessions on providing spiritually based care, emphasizing the use of gratitude practices. RESULTS: The mean number of spiritually based interventions charted per visit by the nurse practitioner increased from 0.4 pre implementation to 1.1 post-implementation (rate ratio = 2.57, with 95% CI [1.75, 3.87]; p < .001). Descriptive statistics from all providers show improvements in attitudes and comfort level in addressing spiritually based care. Several intervention areas documented by the nurse practitioner decreased significantly, including mind/body, which may be related to the study, as many spiritually based interventions are also mind/body interventions. CONCLUSION: Interactive educational sessions on spirituality can improve a health-care team's attitudes, comfort level, and practice of providing spiritually based care. Generalizability is limited to the project site, but the process could be implemented in other facilities to determine if similar results can be achieved. PMID- 29490836 TI - Gray Reflections: Poetry as a Pathway to Nursing Student Empathy and the Creation of Meaning in a Long-Term-Care Clinical Practicum. AB - The unique needs of the aging adult require caregivers who can completely comprehend the experience of this population. Purposefully educating nursing students to enhance development of empathy is crucial for the provision of adequate care. Innovative pedagogical strategies that produce opportunities for nursing students to reflect on patient care experiences are an opportunity for educators to guide the creation of meaning in practice for nursing students. The use of poetry reading and writing enhances the student reflective process in clinical practicum environments and may serve as a strategy to support empathic development in nursing students. PMID- 29490837 TI - The Impact of Caring: Teaching Students Empathy Through the Patient Voice. AB - The purpose of this educational brief is to describe an innovative learning experience focused on teaching students empathy for chronic illness, using patient voices. Panel members of individuals who had experienced acute and chronic illness from either the perspective of the patient or caregiver participated in a one-time session for undergraduate baccalaureate nursing students. Panel members presented their narrative to the students, engaging them in a question-and-answer session about the impact of nursing care on their experience. Both the panelists and the students found the experience meaningful. Over time the panel has varied in format, but has consistently humanized the patient experience, highlighted the importance of empathy, and conveyed the impact that nurses have on their patients and families. This innovative strategy proved to be very beneficial for students transitioning into their first clinical experience. PMID- 29490838 TI - Dying: A Natural Passage. PMID- 29490869 TI - The power of talk and power in talk: a systematic review of Indigenous narratives of culturally safe healthcare communication. AB - The study aimed to explore Indigenous narrative accounts of healthcare access within qualitative research papers, to better understand Indigenous views on culturally safe healthcare and health communication represented in that literature. A systematic literature review of peer-reviewed academic qualitative studies identified 65 papers containing Indigenous respondents' views on accessing healthcare. Analysis included all Indigenous voice (primary quotations) and author findings describing healthcare access across these studies. Healthcare communication, or 'talk', emerged as a key theme. Indigenous clients valued talk within healthcare interactions; it was essential to their experience of care, having the power to foster relationships of trust, strengthen engagement and produce positive outcomes. By mediating the power differentials between health professionals and Indigenous clients, talk could either reinforce powerlessness, through judgmental down-talk, medical jargon or withholding of talk, or empower patients with good talk, delivered on the client's level. Good talk is a critical ingredient to improving Indigenous accessibility and engagement with healthcare services, having the ability to minimise the power differentials between Indigenous clients and the healthcare system. PMID- 29490870 TI - Institutional review of the implementation and use of a Clostridium difficile infection bundle and probiotics in adult trauma patients. AB - BACKGROUND: Clostridium difficile infection (CDI) is a common cause of healthcare associated infections contributing to morbidity and mortality. Our objective was to evaluate the impact of the implementation of a CDI bundle along with probiotic utilization. METHODS: A retrospective review of trauma admissions from 2008 to 2014 was performed. The CDI bundle was implemented in stages from 2009 through 2014 with probiotics initiated in 2010. The bundle included changes in cleaning practices, education, screening, and contact precautions. RESULTS: 4632 (49%) patients received antibiotics with 21% receiving probiotics. Probiotic use was associated with increased age, male sex, more severely injured, and antibiotic use. CDI incidence decreased from 11.2 to 4.8 per 1000 admissions, p = .03. Among patients who received antibiotics CDI incidence decreased from 2.2% to 0.7%, p = .01. CONCLUSIONS: We report the largest series of a CDI bundle implementation including probiotics. During the period of adoption of these interventions, the incidence of CDI decreased significantly. PMID- 29490871 TI - Response to: High-grade squamous intraepithelial lesion (HSIL) of the cervix with bizarre cytological appearances ('pleomorphic HSIL'). PMID- 29490872 TI - Pigmented Paget's disease of the nipple mistaken for melanoma in situ: a diagnostic pitfall for the unwary. PMID- 29490873 TI - h-caldesmon immunoreactivity in atypical fibroxanthoma: implications for the differential diagnosis. PMID- 29490874 TI - Risk factors for the development of incident atrial fibrillation in patients with cardiac implantable electronic devices. AB - INTRODUCTION: Cardiac implantable electronic devices (CIEDs) can detect atrial fibrillation (AF) early and accurately. Risk factors for the development of new onset AF in patients with CIEDs remains uncertain. METHODS: Patients with CIEDs who visited Chiba University Hospital between January 2016 and December 2016 were enrolled. We only included patients without single chamber CIEDs or a known history of AF. RESULTS: Of 371 patients with CIEDs, 78 (21.0%; median age 61.0 years, 65.5% male) developed new-onset AF. Multivariate analysis demonstrated that independent predictors for the development of new or incident AF were age >=65 years (odd ratio [OR] 2.76, 95% confidence interval [CI] 1.54-4.96, P = 0.001), diabetes mellitus (OR 2.24, 95% CI 1.20-4.19, P = 0.011), congestive heart failure (OR 1.94, 95% CI 1.06-3.54, P = 0.031), and left atrial volume index >34 ml/m2 (OR 3.51, 95% CI 1.96-6.25, P < 0.001). Based on these 4 clinical factors (age >= 65, diabetes mellitus, congestive heart failure, left atrial volume index > 34 ml/m2) there was a good predictive ability for new AF development (AUC 0.728) and clinically usefulness using decision curve analysis. CONCLUSIONS: A substantial number of patients with CIEDs develop new-onset AF. Four clinical factors (age >= 65, diabetes mellitus, congestive heart failure, left atrial volume index > 34 ml/m2) independently predicted new-onset AF and may provide an approach to clinically useful risk assessment for incident AF. PMID- 29490876 TI - Migration patterns and HIV prevention in Uganda. PMID- 29490875 TI - Migration and risk of HIV acquisition in Rakai, Uganda: a population-based cohort study. AB - BACKGROUND: In sub-Saharan Africa, migrants typically have higher HIV prevalence than non-migrants; however, whether HIV acquisition typically precedes or follows migration is unknown. We aimed to investigate the risk of HIV after migration in Rakai District, Uganda. METHODS: In a prospective population-based cohort of HIV negative participants aged 15-49 years in Rakai, Uganda, between April 6, 1999, and Jan 30, 2015, we assessed the association between migration and HIV acquisition. Individuals were classified as recent in-migrants (<=2 years in community), non-recent in-migrants (>2 years in community), or permanent residents with no migration history. The primary outcome was incident HIV infection. We used Poisson regression to estimate incidence rate ratios (IRRs) of HIV associated with residence status with adjustment for demographics, sexual behaviours, and time. Data were also stratified and analysed within three periods (1999-2004, 2005-11, and 2011-15) in relation to the introduction of combination HIV prevention (CHP; pre-CHP, early CHP, and late CHP). FINDINGS: Among 26 995 HIV-negative people who participated in the Rakai Community Cohort Study survey, 15 187 (56%) contributed one or more follow-up visits (89 292 person-years of follow-up) and were included in our final analysis. 4451 (29%) were ever in migrants and 10 736 (71%) were permanent residents. 841 incident HIV events occurred, including 243 (29%) among in-migrants. HIV incidence per 100 person years was significantly increased among recent in-migrants compared with permanent residents, for both women (1.92, 95% CI 1.52-2.43 vs 0.93, 0.84-1.04; IRR adjusted for demographics 1.75, 95% CI 1.33-2.33) and men (1.52, 0.99-2.33 vs 0.84, 0.74-0.94; 1.74, 1.12-2.71), but not among non-recent in-migrants (IRR adjusted for demographics 0.94, 95% CI 0.74-1.19 for women and 1.28, 0.94-1.74 for men). Between the pre-CHP and late-CHP periods, HIV incidence declined among permanent resident men (p<0.0001) and women (p=0.002) and non-recent in-migrant men (p=0.031), but was unchanged among non-recent in-migrant women (p=0.13) and recent in-migrants (men p=0.76; women p=0.84) INTERPRETATION: The first 2 years after migration are associated with increased risk of HIV acquisition. Prevention programmes focused on migrants are needed to reduce HIV incidence in sub-Saharan Africa. FUNDING: National Institute of Mental Health, the National Institute of Allergy and Infectious Diseases, the National Institute of Child Health and Development, the National Institute for Allergy and Infectious Diseases Division of Intramural Research, National Institutes of Health; the Centers for Disease Control and Prevention; the Bill & Melinda Gates Foundation; and the Johns Hopkins University Center for AIDS Research. PMID- 29490877 TI - Genomic and phenotypic diversity of Clostridium difficile during long-term sequential recurrences of infection. AB - Infection with the emerging pathogen Clostridioides (Clostridium) difficile might lead to colonization of the gastrointestinal tract of humans and mammals eventually resulting in antibiotic-associated diarrhea, which can be mild to possibly life-threatening. Recurrences after antibiotic treatment have been described in 15-30% of the cases and are either caused by the original (relapse) or by new strains (reinfection). In this study, we describe a patient with ongoing recurrent C. difficile infections over 13 months. During this time, ten C. difficile strains of six different ribotypes could be isolated that were further characterized by phenotypic and genomic analyses including motility and sporulation assays, growth fitness and antibiotic susceptibility as well as whole genome sequencing. PCR ribotyping of the isolates confirmed that the recurrences were a mixture of relapses and reinfections. One recurrence was due to a mixed infection with three different strains of two different ribotypes. Furthermore, genomes were sequenced and multi-locus sequence typing (MLST) was carried out, which identified the strains as members of sequence types (STs) 10, 11, 14 and 76. Comparison of the genomes of isolates of the same ST originating from recurrent CDI (relapses) indicated little within-patient microevolution and some concurrent within-patient diversity of closely related strains. Isolates of ribotype 126 that are binary toxin positive differed from other ribotypes in various phenotypic aspects including motility, sporulation behavior and cell morphology. Ribotype 126 is genetically related to ribotype 078 that has been associated with increased virulence. Isolates of the ribotype 126 exhibited elongated cells and a chaining phenotype, which was confirmed by membrane staining and scanning electron microscopy. Furthermore, this strain exhibits a sinking behavior in liquid medium in stationary growth phase. Taken together, our observation has proven multiple CDI recurrences that were based on a mixture of relapses and reinfections. PMID- 29490878 TI - Commentary for establishing centers of excellence for surgical oncology. PMID- 29490879 TI - Optimization of fecal sample processing for microbiome study - The journey from bathroom to bench. AB - Although great interest has been displayed by researchers in the contribution of gut microbiota to human health, there is still no standard protocol with consensus to guarantee the sample quality of metagenomic analysis. Here we reviewed existing methodology studies and present suggestions for optimizing research pipeline from fecal sample collection to DNA extraction. First, we discuss strategies of clinical metadata collection as common confounders for microbiome research. Second, we propose general principles for freshly collected fecal sample and its storage and share a DIY stool collection kit protocol based on the manual procedure of Human Microbiome Project (HMP). Third, we provide a useful information of collection kit with DNA stabilization buffers and compare their pros and cons for multi-omic study. Fourth, we offer technical strategies as well as information of novel tools for sample aliquoting before long-term storage. Fifth, we discuss the substantial impact of different DNA extraction protocols on technical variations of metagenomic analysis. And lastly, we point out the limitation of current methods and the unmet needs for better quality control of metagenomic analysis. We hope the information provided here will help investigators in this exciting field to advance their studies while avoiding experimental artifacts. PMID- 29490881 TI - Transfusion transmission of hepatitis A virus with fecal shedding in a previously hepatitis A vaccinated recipient. AB - We describe a rare case of hepatitis A virus (HAV) replication in feces despite presence of hepatitis A antibodies in an acute myeloid leukemia (AML) patient after transfusion with HAV contaminated platelets. The patient has been vaccinated against HAV years before the AML diagnosis. Transient infection and reshedding should thus be considered in antibody-positive hematological patients. Transfusion associated HAV transmission is rare, and little evidence exists on the clinical consequences and possible effect of treatment with immunoglobulin. Further reporting on fecal shedding despite antibodies are needed, as HAV antibody levels are used as course of action for post-exposure prophylaxis and infection control. PMID- 29490880 TI - A plant-produced vaccine protects mice against lethal West Nile virus infection without enhancing Zika or dengue virus infectivity. AB - West Nile virus (WNV) has caused multiple global outbreaks with increased frequency of neuroinvasive disease in recent years. Despite many years of research, there are no licensed therapeutics or vaccines available for human use. One of the major impediments of vaccine development against WNV is the potential enhancement of infection by related flaviviruses in vaccinated subjects through the mechanism of antibody-dependent enhancement of infection (ADE). For instance, the recent finding of enhancement of Zika virus (ZIKV) infection by pre-exposure to WNV further complicates the development of WNV vaccines. Epidemics of WNV and the potential risk of ADE by current vaccine candidates demand the development of effective and safe vaccines. We have previously reported that the domain III (DIII) of the WNV envelope protein can be readily expressed in Nicotiana benthamiana leaves, purified to homogeneity, and promote antigen-specific antibody response in mice. Herein, we further investigated the in vivo potency of a plant-made DIII (plant-DIII) in providing protective immunity against WNV infection. Furthermore, we examined if vaccination with plant-DIII would enhance the risk of a subsequent infection by ZIKV and Dengue virus (DENV). Plant-DIII vaccination evoked antigen-specific cellular immune responses as well as humoral responses. DIII-specific antibodies were neutralizing and the neutralization titers met the threshold correlated with protective immunity by vaccines against multiple flaviviruses. Furthermore, passive administration of anti-plant DIII mouse serum provided full protection against a lethal challenge of WNV infection in mice. Notably, plant DIII-induced antibodies did not enhance ZIKV and DENV infection in Fc gamma receptor-expressing cells, addressing the concern of WNV vaccines in inducing cross-reactive antibodies and sensitizing subjects to subsequent infection by heterologous flavivirus. This study provides the first report of a WNV subunit vaccine that induces protective immunity, while circumventing induction of antibodies with enhancing activity for ZIKV and DENV infection. PMID- 29490882 TI - Eosinopenia in women with schizophrenia: Drug-induced or a sign of gender specific difference in pathogenesis? PMID- 29490883 TI - Integrated molecular analysis of the inactivation of a non-enveloped virus, feline calicivirus, by UV-C radiation. AB - UV-C treatment has been shown to be a powerful way to inactivate non-enveloped viruses in water samples. However, little is known about how the viruses were inactivated by UV-C radiation. In this study, we investigated the inactivation mechanism of a single-stranded RNA (ssRNA) non-enveloped virus, feline calicivirus (FCV), as a surrogate for the human norovirus, using UV-C radiation with different wavelengths. Integrated molecular analyses using RT-qPCR, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and mass spectrometry were employed to evaluate the extent of ssRNA genome and protein degradation. UV-C radiation of FCV efficiently impaired the infectivity of FCV in mammalian cells. We also identified degradation of the RNA genome, whose copy numbers decreased from 48% to 56% following UV255 or UV281 radiation. Significant degradation of capsid protein was not observed, whereas oxidation of amino acid residues in the major capsid protein VP-1 was determined. Our results suggest that damage to the RNA genome is primarily responsible for the observed decrease in FCV infectivity of CRFK cells. This study provides not only relevant baseline data but also an overview and possible mechanism for the disinfection of non enveloped ssRNA viruses using UV-C radiation. PMID- 29490884 TI - Repetitive nerve stimulation and jitter measurement with disposable concentric needle electrode in newly diagnosed myasthenia gravis patients. AB - INTRODUCTION: The aim of this study was to define the diagnostic accuracy of concentric needle (CN)-jitter in newly diagnosed myasthenia gravis (MG) patients and to compare CN-jitter with repetitive nerve stimulation. METHODS: In 30 MG patients, repetitive nerve stimulation in 4 muscles (orbicularis oculi, nasalis, trapezius and abductor digiti minimi) and CN-jitter of extensor digitorum (ED) and frontalis muscles were evaluated. RESULTS: Twenty-eight of 30 patients (93%) had high jitter in at least one muscle. Repetitive nerve stimulation was abnormal in 23 of the patients (77%). Eighty-six percent of the patients in whom repetitive nerve stimulation test was negative could be diagnosed with CN-jitter. The most frequent muscle showing abnormal decrement was orbicularis oculi. The results of CN-jitter were similar between patients with different serological groups. Of 13 patients with generalized weakness, all had high jitter in both muscles studied whereas of 17 patients only with ocular weakness, 15 had high jitter in at least one muscle studied. CONCLUSION: Abnormal RNS was present in 77% of newly diagnosed MG patients, being less than CN-jitter (93%) but more than antibody positivity (73.3%). PMID- 29490885 TI - Slow-wave sleep: From the cell to the clinic. AB - In recent decades, increasing evidence has positioned slow-wave sleep (SWS) as a major actor in neurophysiological phenomena such as glucose metabolism, hormone release, immunity and memory. This proposed role for SWS, coupled with observations of impaired SWS in several pathologies as well as in aging, has led some researchers to implement methods that could specifically enhance SWS. This review aims to gather the current knowledge extending from the cell to the clinic, in order to construct an overview of what is currently known about so called SWS. We slowly expand the view from the molecular processes underlying SWS to the cell unit and assembly to cortical manifestations. We then describe its role in physiology and cognition to finally assess its association with clinical aspects. Finally, we address practical considerations for several techniques that could be used to manipulate SWS, in order to improve our understanding of SWS and possibly help the development of treatments for SWS clinical disorders. PMID- 29490886 TI - Osteosarcoma of the jaw: Challenges in the diagnosis and treatment. AB - PURPOSE: Osteosarcomas rarely affect jaw bones. Patients are usually older than those who suffer long bone sarcomas, with a rare incidence of metastasis. This is suggestive of a different pattern of behavior compared with long bone sarcomas. This study aimed to present NCI, Cairo University experience in treating patients diagnosed with osteosarcomas of the jaw, including the diagnostic challenges and treatment outcome. PATIENTS AND METHODS: This is a retrospective case series study of all cases of osteosarcomas of mandible and maxilla that were treated at the NCI, in the period between 2006 and 2013. Patients' data, including demographic data, various clinical presentations, results of investigations, treatment modalities performed and outcomes, were collected from hospital records kept in the Biostatistics Department at NCI. RESULTS: Records showed 21 cases of osteosarcoma of the jaw. The mandible was affected in 15 cases, the maxilla in six. Two cases had sun-ray periosteal reactions. Erroneous biopsy results were found in 4 cases compared with final pathology reports of surgical resections. All cases underwent surgical resections, with 8 cases having positive margins. The median follow-up period was 19.3 months (range 0.3-98.0 months). The cumulative disease-free survival (DFS) was 27.5% and the median DFS was 72 months. The cumulative overall survival at end of the study was 77.4%. CONCLUSIONS: Osteosarcoma of the jaw is challenging both to diagnose and manage. This is due to the high incidence of mistakes in biopsy results, rare specific radiological features and difficulties in proper resection due to proximity to vital structures. PMID- 29490887 TI - Facial restoration by transplantation. AB - Hundred years ago, Sir Harold Gillies laid a foundation to the modern plastic surgery trying to reconstruct facial defects of severely disfigured soldiers of World War I. Some years later, Joseph Murray experimented with rejection of skin grafts aimed for treatment of burned patients who sustained their injuries on battlefields of World War II. In 1954, the acquired expertise and intensive research allowed him to perform the first successful kidney transplantation in the world at Peter Bent Brigham Hospital in Boston. For his achievements in organ transplantation he was awarded Nobel Prize in 1990. The face transplantation appears to be a natural evolution of the work of these two extraordinary plastic surgeons. The first case of partial face transplant from 2005 in France revealed the world that facial restoration by transplantation is superior to conventional reconstruction methods. Since 2009, our team has performed 7 cases of face transplantation at Brigham and Women's Hospital, which is to our best knowledge the largest living single center face transplant cohort in the world. In this article, we want to reflect on the experience with face transplantation at our institution from the past years. We aim to briefly review the key points of the know-how which was given to us from the care of these unique patients. PMID- 29490888 TI - The dark side of tumor-associated endothelial cells. AB - Angiogenesis is a hallmark of cancer and a requisite that tumors must achieve to fulfill their metabolic needs of nutrients and oxygen. As a critical step in cancer progression, the 'angiogenic switch' allows tumor cells to survive and grow, and provides them access to vasculature resulting in metastatic progression and dissemination. Tumor-dependent triggering of the angiogenic switch has critical consequences on tumor progression which extends from an increased nutrient supply and relies instead on the ability of the tumor to hijack the host immune response for the generation of a local immunoprivileged microenvironment. Tumor angiogenic-mediated establishment of endothelial anergy is responsible for this process. However, tumor endothelium can also promote immune tolerance by unbalanced expression of co-stimulatory and co-inhibitory molecules and by releasing soluble factors that restrain T cell function and induce apoptosis. In this review, we discuss the molecular properties of the tumor endothelial barrier and endothelial anergy and discuss the main immunosuppressive mechanisms triggered by the tumor endothelium. Lastly, we describe the current anti angiogenic therapeutic landscape and how targeting tumor angiogenesis can contribute to improve clinical benefits for patients. PMID- 29490889 TI - [Definition of endometriosis expert centres]. AB - OBJECTIVES: The College national des gynecologues obstetriciens francais (CNGOF), in agreement with the Societe de chirurgie gynecologique et pelvienne (SCGP), has set up a commission in 2017 to define endometriosis expert centres, with the aim of optimizing endometriosis care in France. METHODS: The committee included members from university and general hospitals as well as private facilities, representing medical, surgical and radiological aspects of endometriosis care. Opinion of endometriosis patients' associations was obtained prior to writing this work. The final text was presented and unanimously validated by the members of the CNGOF Board of Directors at its meeting of October 13, 2017. RESULTS: Based on analysis of current management of endometriosis and the last ten years opportunities in France, the committee has been able to define the contours of endometriosis expert centres. The objectives, production specifications, mode of operation, missions and funding for these centres were described. The following missions have been specifically defined: territorial organization, global and referral care, communication and teaching as well as research and evaluation. CONCLUSION: Because of its daily impact for women and its economic burden in France, endometriosis justifies launching of expert centres throughout the country with formal accreditation by health authorities, ideally as part of the National Health Plan. PMID- 29490890 TI - [How I do...to study by ultrasonography the foetal mesenteric vasculature]. PMID- 29490891 TI - [How I do... a colpocleisis with hysterectomy for vaginal prolapse (Pitie Salpetriere Hospital, Paris, France)]. PMID- 29490892 TI - The Effect of Doctor-Consumer Interaction on Social Media on Consumers' Health Behaviors: Cross-Sectional Study. AB - BACKGROUND: Both doctors and consumers have engaged in using social media for health purposes. Social media has changed traditional one-to-one communication between doctors and patients to many-to-many communication between doctors and consumers. However, little is known about the effect of doctor-consumer interaction on consumers' health behaviors. OBJECTIVE: The aim of this study was to investigate how doctor-consumer interaction in social media affects consumers' health behaviors. METHODS: On the basis of professional-client interaction theory and social cognitive theory, we propose that doctor-consumer interaction can be divided into instrumental interaction and affective interaction. These two types of interactions influence consumers' health behaviors through declarative knowledge (DK), self-efficacy (SE), and outcome expectancy (OE). To validate our proposed research model, we employed the survey method and developed corresponding measurement instruments for constructs in our research model. A total of 352 valid answers were collected, and partial least square was performed to analyze the data. RESULTS: Instrumental doctor-consumer interaction was found to influence consumers' DK (t294=5.763, P<.001), SE (t294=4.891, P<.001), and OE (t294=7.554, P<.001) significantly, whereas affective doctor-consumer interaction also impacted consumers' DK (t294=4.025, P<.001), SE (t294=4.775, P<.001), and OE (t294=4.855, P<.001). Meanwhile, consumers' DK (t294=3.838, P<.001), SE (t294=3.824, P<.001), and OE (t294=2.985, P<.01) all significantly affected consumers' health behaviors. Our mediation analysis showed that consumers' DK, SE, and OE partially mediated the effect of instrumental interaction on health behaviors, whereas the three mediators fully mediated the effect of affective interaction on health behaviors. CONCLUSIONS: Compared with many intentional intervention programs, doctor-consumer interaction can be treated as a natural cost-effective intervention to promote consumers' health behaviors. Meanwhile, both instrumental and affective interaction should be highlighted for the best interaction results. DK, SE, and OE are working mechanisms of doctor-consumer interaction. PMID- 29490893 TI - Empirical Evidence for the Outcomes of Therapeutic Video Games for Adolescents With Anxiety Disorders: Systematic Review. AB - BACKGROUND: Extant evidence suggests that the proportion of adolescents suffering from anxiety disorders (ADs) has increased by up to 70% since the mid-1980s, with experience of anxiety at this stage associated with significant negative short- and long-term life outcomes. The existing therapeutic interventions (eg, cognitive behavioral therapy, CBT; attention bias modification, ABM) have proven to have clinically measurable benefits in reducing anxiety, but their efficacy is often compromised by social and practical barriers. The growing discrepancy between demand for, and access to, clinical interventions for anxiety has led to the development of a range of eHealth (health care practice supported by electronic processes and communication) and mHealth (versions of eHealth using mobile devices) interventions. One such protocol is therapeutic games, which aim to provide clinical frameworks in dynamic, adaptable, and personalized virtual environments. Although some evidence exists to suggest therapeutic games are associated with reductions in subjective anxiety and observed stress reactivity, there is currently, to our knowledge, no systematic review of the adherence to, and effectiveness of, therapeutic games for adolescent anxiety. OBJECTIVE: The aim of this review was to establish the effectiveness of therapeutic games in making clinically measurable reductions in anxiety symptoms in adolescent samples. METHODS: A systematic search of the existing academic literature published between 1990 and July 2017 was conducted using the databases Journal of Medical Internet Research, Journal Storage, Psychology Articles, Psychology Info, ScienceDIRECT, and Scopus. Records linked to empirical papers on therapeutic games for anxiety using adolescent samples were evaluated. RESULTS: A total of 5 studies (N=410 participants) met the inclusion criteria, and 3 gamified anxiety interventions for adolescents were identified. The papers included a mixture of randomized controlled trials, quasi-experimental studies, and usability studies comprising quantitative and qualitative measures, with varying degrees of mixed methods. Extant evidence shows potential for therapeutic games to create clinically measurable reductions in symptoms of anxiety in adolescent samples, though findings are complicated in some cases by a low sample size, and in other cases by research design and methodological complications, including anxiety reductions in control groups caused by a control-game selection. CONCLUSIONS: Although research in this field appears to be extremely limited, as demonstrated by the small number of papers meeting the inclusion criteria for this review, early findings suggest that therapeutic games have potential in helping to engage adolescents with anxiety and lead to clinically measurable reductions in symptoms. PMID- 29490894 TI - Supporting Accurate Interpretation of Self-Administered Medical Test Results for Mobile Health: Assessment of Design, Demographics, and Health Condition. AB - BACKGROUND: Technological advances in personal informatics allow people to track their own health in a variety of ways, representing a dramatic change in individuals' control of their own wellness. However, research regarding patient interpretation of traditional medical tests highlights the risks in making complex medical data available to a general audience. OBJECTIVE: This study aimed to explore how people interpret medical test results, examined in the context of a mobile blood testing system developed to enable self-care and health management. METHODS: In a preliminary investigation and main study, we presented 27 and 303 adults, respectively, with hypothetical results from several blood tests via one of the several mobile interface designs: a number representing the raw measurement of the tested biomarker, natural language text indicating whether the biomarker's level was low or high, or a one-dimensional chart illustrating this level along a low-healthy axis. We measured respondents' correctness in evaluating these results and their confidence in their interpretations. Participants also told us about any follow-up actions they would take based on the result and how they envisioned, generally, using our proposed personal health system. RESULTS: We find that a majority of participants (242/328, 73.8%) were accurate in their interpretations of their diagnostic results. However, 135 of 328 participants (41.1%) expressed uncertainty and confusion about their ability to correctly interpret these results. We also find that demographics and interface design can impact interpretation accuracy, including false confidence, which we define as a respondent having above average confidence despite interpreting a result inaccurately. Specifically, participants who saw a natural language design were the least likely (421.47 times, P=.02) to exhibit false confidence, and women who saw a graph design were less likely (8.67 times, P=.04) to have false confidence. On the other hand, false confidence was more likely among participants who self-identified as Asian (25.30 times, P=.02), white (13.99 times, P=.01), and Hispanic (6.19 times, P=.04). Finally, with the natural language design, participants who were more educated were, for each one-unit increase in education level, more likely (3.06 times, P=.02) to have false confidence. CONCLUSIONS: Our findings illustrate both promises and challenges of interpreting medical data outside of a clinical setting and suggest instances where personal informatics may be inappropriate. In surfacing these tensions, we outline concrete interface design strategies that are more sensitive to users' capabilities and conditions. PMID- 29490895 TI - Reported Theory Use by Digital Interventions for Hazardous and Harmful Alcohol Consumption, and Association With Effectiveness: Meta-Regression. AB - BACKGROUND: Applying theory to the design and evaluation of interventions is likely to increase effectiveness and improve the evidence base from which future interventions are developed, though few interventions report this. OBJECTIVE: The aim of this paper was to assess how digital interventions to reduce hazardous and harmful alcohol consumption report the use of theory in their development and evaluation, and whether reporting of theory use is associated with intervention effectiveness. METHODS: Randomized controlled trials were extracted from a Cochrane review on digital interventions for reducing hazardous and harmful alcohol consumption. Reporting of theory use within these digital interventions was investigated using the theory coding scheme (TCS). Reported theory use was analyzed by frequency counts and descriptive statistics. Associations were analyzed with meta-regression models. RESULTS: Of 41 trials involving 42 comparisons, half did not mention theory (50% [21/42]), and only 38% (16/42) used theory to select or develop the intervention techniques. Significant heterogeneity existed between studies in the effect of interventions on alcohol reduction (I2=77.6%, P<.001). No significant associations were detected between reporting of theory use and intervention effectiveness in unadjusted models, though the meta-regression was underpowered to detect modest associations. CONCLUSIONS: Digital interventions offer a unique opportunity to refine and develop new dynamic, temporally sensitive theories, yet none of the studies reported refining or developing theory. Clearer selection, application, and reporting of theory use is needed to accurately assess how useful theory is in this field and to advance the field of behavior change theories. PMID- 29490896 TI - Possible Risk Factors for Severe Anemia in Hospitalized Sickle Cell Patients at Muhimbili National Hospital, Tanzania: Protocol for a Cross-Sectional Study. AB - BACKGROUND: Sickle cell disease (SCD) is the most common inherited disorder worldwide, with the highest burden in sub-Saharan Africa. The natural history of SCD is characterized by periods of steady state interspersed by acute episodes. The acute anemic crises may be transient and are precipitated by treatable factors like infections, nutritional deficiencies, and sequestration. Anemia is almost always present, although it occurs at different levels of severity. OBJECTIVE: This paper describes the protocol of a cross-sectional study to determine the prevalence of severe anemia and associated factors among sickle cell patients hospitalized at the Muhimbili National Hospital. METHODS: This is an ongoing, descriptive, cross-sectional, hospital-based study among individuals with SCD, admitted to the Muhimbili National Hospital in Dares Salaam, Tanzania. A minimum sample size of 369 was calculated based on the previous prevalence of hospitalizations due to severe anemia (20%) in the same cohort. We are using a piloted standardized case report form to document clinical and laboratory parameters following informed consent. Data analysis will be performed using Stata software. Severe anemia is defined as Hb<5g/dL. Chi-square or Fisher's exact test will be used to ascertain association between categorical variables, and t-test will be used for numerical variables. Regression models for severe anemia against explanatory and confounding variables will be run, and results will be presented as adjusted odds ratio with 95% confidence intervals. A P value of <.05 will be considered significant. RESULTS: Enrolment commenced in January 2015 and concluded in September 2016. Complete data analysis will begin in February 2018. The study results are expected to be published in May 2018. CONCLUSIONS: This protocol paper will provide a useful and practical model for conducting cross-sectional studies in hospitalized patients that cover a wide ranging of clinical and laboratory variables. PMID- 29490897 TI - Exploring the Influence of a Smartphone App (Young with Diabetes) on Young People's Self-Management: Qualitative Study. AB - BACKGROUND: Adequate self-management is the cornerstone of preventing type 1 diabetes mellitus (T1DM) complications. However, T1DM self-management is challenging for young people, who often struggle during the transition from childhood to adulthood. The mobile health (mHealth) app Young with Diabetes (YWD) was developed in collaboration with young people to enhance their T1DM self management during this transition. OBJECTIVE: The purpose of this study was to explore the influence of YWD on young people's self-management during a 12-month period. METHODS: A qualitative explorative approach was used, comprising a purposive sample of 20 young people (11 females and 9 males, ages 15 to 23 years, with app use of 3 to 64 days) from 3 pediatric and 3 adult departments. Participants were interviewed individually using a semistructured interview guide. Data were collected from January to March 2017 and analyzed using thematic analysis. RESULTS: A total of 5 themes were identified: (1) not feeling alone anymore ("we are in this together"); (2) gaining competence by sharing experiences and practical knowledge ("they know what they are talking about"); (3) feeling safer ("it's just a click away"); (4) breaking the ice by starting to share thoughts and feelings and asking for help ("it is an outstretched hand"); and (5) lack of motivating factors ("done with the app"). Young people reported that YWD promoted self-management by peer-to-peer social support, exchanging messages with health care providers, and sharing YWD with parents. Participants recommended YWD as a supplement to self-management for newly diagnosed young people with T1DM and suggested improvements in app content and functionality. CONCLUSIONS: The mHealth app YWD has the potential to support self-management. In particular, peer-to-peer support reduced feelings of loneliness and helped young people to gain knowledge and skills for managing T1DM. A need exists for alternative ways to train health care providers in using YWD and to support collaboration between young people and their parents to further improve young people's self-management of T1DM. PMID- 29490898 TI - Prehospital Advanced Diagnostics and Treatment of Acute Stroke: Protocol for a Controlled Intervention Study. AB - BACKGROUND: Acute ischemic stroke (AIS) is a medical emergency. The outcome is closely linked to the time elapsing from symptom onset to treatment, and seemingly small delays can mean the difference between full recovery and physical and cognitive dysfunction. Recanalization to allow blood to reenter the affected area is most efficient immediately after symptoms occur, and intravenous thrombolysis must be initiated no later than 4.5 hours after the symptom onset. A liable diagnosis is mandatory to administer the appropriate treatment. Prehospital diagnosis and, in cases where contraindications are ruled out, prehospital initiation of intravenous thrombolysis have been shown to significantly decrease the time from alarm to the treatment. OBJECTIVE: The objective of this paper is to investigate the effectiveness of prehospital thrombolysis as measured by (1) time spent from symptom onset to treatment and (2) the number of patients treated within 4.5 hours. In addition, we want to conduct explorative studies. These will include (1) the use of biomarkers for diagnostic and prognostic use where we will collect blood samples from various time points, including the hyperacute phase and (2) the study of magnetic resonance imaging (MRI) images at day 1 to determine the infarct volume and if the time to thrombolysis has an influence on this. METHODS: This is a prospective controlled intervention study. The intervention will involve a computed tomography (CT) and thrombolysis in a physician-manned ambulance called a mobile stroke unit (MSU). The control will be the conventional pathway where the patient is transported to the hospital for CT, and thrombolysis as per current procedure. RESULTS: Patient inclusion has started and a total of 37 patients are enrolled (control and intervention combined). The estimated time to completed inclusion is 36 months, starting from May 2017. The results of this study will be analyzed and published at the end of the trial. CONCLUSIONS: This trial aims to document the feasibility of saving time for all stroke patients by providing prehospital diagnostics and treatment, as well as transport to appropriate level of care, in a safe environment provided by anesthesiologists trained in prehospital critical care. TRIAL REGISTRATION: ClinicalTrials.gov NCT03158259; https://clinicaltrials.gov/show/NCT03158259 (Archived by WebCite at http://www.webcitation.org/6wxNEUMUD). PMID- 29490900 TI - Limb hypertrophy: a skin vascular malformation and bilateral hydroureteronephrosis in a neonate. AB - The second daughter of two healthy non-consanguineous parents, born at 37 weeks, presented with a large 3*2 cm abdominal angiomatous formation on her left flank, associated with left leg hypertrophy, macrodactyly of both feet with syndactyly of the second and third finger of the right food and left polydactyly (figure 1). Her neurological development and cardiopulmonary function were normal; she had no gastrointestinal or skeletal problems. Her weight was 3195 g (75th-90th centile). edpract;archdischild-2017-314021v2/F1F1F1Figure 1Photos of the lower limbs and the left side of the abdomen reveal bilateral hypertrophy of the limbs, more evident in the left leg, macrodactyly of both feet with syndactyly of the second and third finger of the right foot and left polydactyly and a large abdominal angiomatous formation. QUESTIONS 1: What investigations would you think of in a baby with limb hypertrophy and a vascular malformation? Limb X-rays followed by abdominal and limb CT scanLimb muscles and soft tissues MRIKidney and limb ultrasound followed by abdominal and limb CT scanThigh, leg and abdominal MRI and in second instance brain MRIThigh, leg and abdominal CT scan and brain MRI. QUESTIONS 2: Which overgrowth syndrome includes limb hypertrophy, skin vascular malformations and bilateral hydroureteronephrosis?Neurofibromatosis type ISotos syndromeBeckwith-Wiedemann syndromeMadelung's diseasePIK3CA-related overgrowth spectrum (PROS) disorder. Answers to the questions are on page 02 Answers to the questions on page 1. PMID- 29490899 TI - Cardiac Auscultation Using Smartphones: Pilot Study. AB - BACKGROUND: Cardiac auscultation is a cost-effective, noninvasive screening tool that can provide information about cardiovascular hemodynamics and disease. However, with advances in imaging and laboratory tests, the importance of cardiac auscultation is less appreciated in clinical practice. The widespread use of smartphones provides opportunities for nonmedical expert users to perform self examination before hospital visits. OBJECTIVE: The objective of our study was to assess the feasibility of cardiac auscultation using smartphones with no add-on devices for use at the prehospital stage. METHODS: We performed a pilot study of patients with normal and pathologic heart sounds. Heart sounds were recorded on the skin of the chest wall using 3 smartphones: the Samsung Galaxy S5 and Galaxy S6, and the LG G3. Recorded heart sounds were processed and classified by a diagnostic algorithm using convolutional neural networks. We assessed diagnostic accuracy, as well as sensitivity, specificity, and predictive values. RESULTS: A total of 46 participants underwent heart sound recording. After audio file processing, 30 of 46 (65%) heart sounds were proven interpretable. Atrial fibrillation and diastolic murmur were significantly associated with failure to acquire interpretable heart sounds. The diagnostic algorithm classified the heart sounds into the correct category with high accuracy: Galaxy S5, 90% (95% CI 73% 98%); Galaxy S6, 87% (95% CI 69%-96%); and LG G3, 90% (95% CI 73%-98%). Sensitivity, specificity, positive predictive value, and negative predictive value were also acceptable for the 3 devices. CONCLUSIONS: Cardiac auscultation using smartphones was feasible. Discrimination using convolutional neural networks yielded high diagnostic accuracy. However, using the built-in microphones alone, the acquisition of reproducible and interpretable heart sounds was still a major challenge. TRIAL REGISTRATION: ClinicalTrials.gov NCT03273803; https://clinicaltrials.gov/ct2/show/NCT03273803 (Archived by WebCite at http://www.webcitation.org/6x6g1fHIu). PMID- 29490901 TI - The Productivity Burden of Diabetes at a Population Level. AB - OBJECTIVE: Recent studies suggest that diabetes may impact work productivity. In the current study, we sought to estimate the lifetime and population impact of diabetes on productivity using the novel measure of "productivity-adjusted life years" (PALYs). RESEARCH DESIGN AND METHODS: Using age-specific mortality rates and a productivity index attributable to diabetes (akin to the quality of life index, but which adjusts for reduction in productivity) and life table modeling, we estimated years of life and PALYs lost to diabetes among Australians with diabetes currently aged 20-65 years, with follow-up until 69 years. Life tables were first constructed for the cohort with diabetes and then repeated for the same cohort but with the assumption that they no longer had diabetes. The "nondiabetic" cohort had lower mortality rates and improved productivity. The differences in total years of life lived and PALYs lived between the two cohorts reflected the impact of diabetes. RESULTS: Overall, diabetes reduced total years of life lived by the cohort by 190,219 years or almost 3%. Diabetes reduced PALYs by 11.6% and 10.5% among men and women, respectively. For both sexes, the impact of diabetes on productivity was lowest in those aged 65-69 years and highest in those 20-24 years. Among the latter, PALYs were reduced by 12.2% and 11.0% for men and women, respectively. CONCLUSIONS: Elimination of diabetes can prolong life years lived by the whole population and increase the amount of productive years lived. Employers and government should be aware that having diabetes affects work force productivity and implement prevention programs to reduce the impact of diabetes on the workforce. PMID- 29490902 TI - Prediction of the Effects of Renal Impairment on Clearance for Organic Cation Drugs that Undergo Renal Secretion: A Simulation-Based Study. AB - Renal impairment (RI) is a major health concern with a growing prevalence. RI leads to various physiologic changes, in addition to a decrease in glomerular filtration rate, that impact the pharmacokinetics (PK) and, specifically, the renal clearance (CLR) of compounds, including alterations of drug transporter (DT)/drug-metabolizing enzyme expression and activity, as well as protein binding. The objectives of this study were to use a physiologically based pharmacokinetic modeling platform to 1) assess the impact of alterations in DT expression, toxin-drug interactions (TDIs), and free fraction (fu) on PK predictions for the organic cation transporter 2/multidrug and toxin extrusion protein 1 substrate metformin in RI populations; and 2) use available in vitro data to improve predictions of CLR for two actively secreted substrates, metformin and ranitidine. The goal was to identify changes in parameters other than glomerular filtration rate-namely, fu and DT expression/activity-that are consistent with in vitro and clinical data in RI, and predict the importance of these parameters in the PK of metformin and ranitidine in RI patients. Our results demonstrated that including alterations in DT expression and fu, and including TDIs affecting DT activity, as indicated by in vitro data, improved the simulated predictions of CLR and other PK parameters for both metformin and ranitidine in RI. Our simulations suggest that modifications of DT expression/activity and fu are necessary for improved predictions of CLR in RI for compounds that are actively secreted, and that improvement of PK predictions in RI populations for metformin and ranitidine can be obtained by incorporating in vitro data. PMID- 29490903 TI - Metabolism and Disposition of Verinurad, a Uric Acid Reabsorption Inhibitor, in Humans. AB - Verinurad (RDEA3170) is a second generation selective uric acid reabsorption inhibitor for the treatment of gout and asymptomatic hyperuricemia. Following a single oral solution of 10-mg dose of [14C]verinurad (500 MUCi), verinurad was rapidly absorbed with a median time to occurrence of maximum observed concentration (Tmax) of 0.5 hours and terminal half-life of 15 hours. In plasma, verinurad constituted 21% of total radioactivity. Recovery of radioactivity in urine and feces was 97.1%. Unchanged verinurad was the predominant component in the feces (29.9%), whereas levels were low in the urine (1.2% excreted). Acylglucuronide metabolites M1 (direct glucuronidation) and M8 (glucuronidation of N-oxide) were formed rapidly after absorption of verinurad with terminal half life values of approximately 13 and 18 hours, respectively. M1 and M8 constituted 32% and 31% of total radioactivity in plasma and were equimolar to verinurad on the basis of AUC ratios. M1 and M8 formed in the liver were biliary cleared with complete hydrolysis in the GI tract, as metabolites were not detected in the feces and/or efflux across the sinusoidal membrane; M1 and M8 accounted for 29.2% and 32.5% of the radioactive dose in urine, respectively. In vitro studies demonstrated that CYP3A4 mediated the formation of the N-oxide metabolite (M4), which was further metabolized by glucuronyl transferases (UGTs) to form M8, as M4 was absent in plasma and only trace levels were present in the urine. Several UGTs mediated the formation of M1, which could also be further metabolized by CYP2C8. Overall, the major clearance route of verinurad is metabolism via UGTs and CYP3A4 and CYP2C8. PMID- 29490905 TI - Kaur R, Morris M, Pichichero ME. Epidemiology of Acute Otitis Media in the Postpneumococcal Conjugate Vaccine Era. Pediatrics. 2017;140(3):e20170101. PMID- 29490906 TI - RE: Global Initiatives for Early Childhood Development Should Be Disability Inclusive. PMID- 29490904 TI - Urinary IgG4 and Smad1 Are Specific Biomarkers for Renal Structural and Functional Changes in Early Stages of Diabetic Nephropathy. AB - Diabetic nephropathy (DN) is the major cause of end-stage kidney disease, but early biomarkers of DN risk are limited. Herein we examine urinary IgG4 and Smad1 as additional early DN biomarkers. We recruited 815 patients with type 2 diabetes; 554 patients fulfilled the criteria of an estimated glomerular filtration rate (eGFR) >60 mL/min and no macroalbuminuria at baseline, with follow-up for 5 years. Patients without macroalbuminuria were also recruited for renal biopsies. Urinary IgG4 and Smad1 were determined by enzyme-linked immunoassays using specific antibodies. The specificity, sensitivity, and reproducibility were confirmed for each assay. Increased urinary IgG4 was significantly associated with lower eGFR. The level of urinary IgG4 also significantly correlated with surface density of peripheral glomerular basement membrane (Sv PGBM/Glom), whereas Smad1 was associated with the degree of mesangial expansion-both classic pathological findings in DN. Baseline eGFR did not differ between any groups; however, increases in both urinary IgG4 and Smad1 levels at baseline significantly predicted later development of eGFR decline in patients without macroalbuminuria. These data suggest that urinary IgG4 and Smad1 at relatively early stages of DN reflect underlying DN lesions and are relevant to later clinical outcomes. PMID- 29490908 TI - Tikanmaki et al. Physical Fitness in Young Adults Born Preterm. Pediatrics. 2016;137(1):e20151289. PMID- 29490907 TI - Parents Refusing Dialysis for a 3-Month-Old With Renal Failure. AB - A 3-month-old boy with failure to thrive was referred to a nephrology clinic after a diagnostic workup for failure to thrive revealed a serum urea nitrogen level of 95 mg/dL and creatinine level of 3.6 mg/dL. A renal ultrasound revealed marked bilateral hydronephrosis with little remaining renal cortex in either kidney. A voiding cystourethrogram revealed evidence of posterior urethral valves. The child had no evident comorbidities. Fulguration of the valves was successfully performed but did not lead to improvement in kidney function. The nephrologists recommended the initiation of dialysis with the hope that the child would be able to receive a kidney transplant in the future. After careful consideration, the family stated that they did not want this child to suffer with a lifetime of dialysis and transplant care. They were also concerned about the impact of this child's illness on their other 2 children and their family. They requested that their son be provided with palliative care only. Experts in nephrology, bioethics, and critical care discuss the ethical issues raised by this parental request. PMID- 29490909 TI - Cost-Effectiveness of Supplemental Donor Milk Versus Formula for Very Low Birth Weight Infants. AB - OBJECTIVES: To determine the cost-effectiveness of supplemental donor human milk (DHM) versus preterm formula (PTF) for very low birth weight (VLBW, <1500 g) infants from a societal perspective to 18 months' corrected age. METHODS: This prospective cost-effectiveness analysis of 363 VLBW infants was conducted for a randomized control trial. Infants recruited from October 2010 to December 2012 were fed DHM or PTF whenever mother's milk was unavailable. Formal health care costs for initial hospitalization and readmissions were obtained from standardized cost-accounting systems and physician fees. Informal and nonhealth care sector costs (eg, caregiver transportation, labor market earnings) were calculated from parent reports. RESULTS: Mean infant birth weight was 996 (SD, 272) grams. Incidence of necrotizing enterocolitis (NEC) differed between groups (all stages 3.9% DHM, 11.0% PTF; P = .01). Costs to 18 months did not differ with a mean (95% confidence interval) of 217 624 (197 697-237 551) and 217 245 (196 494-237 995) 2015 Canadian dollars in the DHM and PTF groups. Postdischarge costs were lower in the DHM (46 440 [40 648-52 233]) than PTF group (55 102 [48 269-61 934]) (P = .04), driven by parent lost wages. DHM cost an additional $5328 per case of averted NEC. CONCLUSIONS: In a high mother's milk use setting, total costs from a societal perspective to 18 months of providing supplemental DHM versus PTF to VLBW infants did not differ, although postdischarge costs were lower in the DHM group. Although supplemental DHM was not cost-saving, it reduced NEC supporting its use over PTF. PMID- 29490910 TI - The ethical concerns about transgenic crops. AB - It is generally accepted that transgenesis can improve our knowledge of natural processes, but also leads to agricultural, industrial or socio-economical changes which could affect human society at large and which may, consequently, require regulation. It is often stated that developing countries are most likely to benefit from plant biotechnology and are at the same time most likely to be affected by the deployment of such new technologies. Therefore, ethical questions related to such biotechnology probably also need to be addressed. We first illustrate how consequentialist and nonconsequentialist theories of ethics can be applied to the genetically modified organism debate, namely consequentialism, autonomy/consent ethics (i.e. self-determination of people regarding matters that may have an effect on these people) and virtue ethics (i.e. whether an action is in adequacy with ideal traits). We show that these approaches lead to highly conflicting views. We have then refocused on moral 'imperatives', such as freedom, justice and truth. Doing so does not resolve all conflicting views, but allows a gain in clarity in the sense that the ethical concerns are shifted from a technology (and its use) to the morality or amorality of various stakeholders of this debate. PMID- 29490911 TI - Recent advances in head impulse test findings in central vestibular disorders. AB - The head impulse test (HIT) is used to evaluate the vestibulo-ocular reflex (VOR) during a high-velocity head rotation. Corrective catch-up saccades that occur during or after the HITs usually indicate peripheral vestibular hypofunction, whereas in acute vestibular syndrome, normal clinical (bedside) HITs should prompt a search for a central lesion. However, recent quantitative studies that evaluated HITs using magnetic search coils or video-based techniques have demonstrated that specific patterns of HIT abnormalities are associated with central vestibular disorders. While normal clinical HITs are typical of central lesions, discrepancies have been observed between clinical and quantitative HITs. The horizontal head impulse VOR gains can be significantly reduced unilaterally or bilaterally (positive HITs) in lesions involving the vestibular nucleus, nucleus prepositus hypoglossi, or flocculus. In diffuse cerebellar lesions, the VOR gain during horizontal head impulses may increase (hyperactive) with corrective saccades directed the opposite way. The presence of cross-coupled vertical corrective saccades during horizontal HITs is also suggestive of diffuse cerebellar lesions. Lesions involving the vestibular nucleus, medial longitudinal fasciculus, and cerebellum may show decreased or increased gains of the VOR during vertical HITs. Defining the differences in patterns observed during abnormal HITs may help practitioners localize the responsible lesions in both central and peripheral vestibulopathy. PMID- 29490912 TI - Epilepsy, antiepileptic drugs, and serious transport accidents: A nationwide cohort study. AB - OBJECTIVES: To investigate the association between epilepsy and antiepileptic drugs and serious transport accidents requiring emergency care or resulting in death. METHODS: We identified 29,220 individuals 18 years or older with epilepsy without cerebral palsy or intellectual disability and 267,637 matched controls using Swedish registers. This nationwide cohort was followed from 2006 to 2013 for serious transport accidents. We used Cox regression to analyze the risk of serious transport accidents between individuals with epilepsy and matched controls, and then stratified Cox regression to compare the risk during periods of medication with the risk during nonmedication period within the same individual with epilepsy. We adjusted for civil status, employment, education, living area, psychiatric disorders prior to the start of follow-up, and psychotropic medication. RESULTS: Compared to matched controls, individuals with epilepsy were at increased risk of serious transport accidents (hazard ratio [HR] 1.37; 95% confidence interval [CI] 1.29-1.46). There were increased risks of pedestrian accidents (HR 2.24, 95% CI 1.69-2.97), bicycle accidents (HR 1.68, 95% CI 1.49-1.89) and car accidents (HR 1.31, 95% CI 1.19-1.44). However, among patients with a diagnosis of epilepsy, use of antiepileptic drugs did not influence the risk of serious transport accidents in population-level comparisons (HR 0.97; 95% CI 0.85-1.11) or within-individual comparisons (HR 0.99; 95% CI 0.69-1.42). CONCLUSION: Serious transportation accidents were more common in individuals with epilepsy, but this risk was independent of use of antiepileptic drugs. PMID- 29490914 TI - Epilepsy and transportation: Moving through the confusion. PMID- 29490913 TI - Moderating effect of APOE epsilon4 on the relationship between sleep-wake cycle and brain beta-amyloid. AB - OBJECTIVES: To clarify the relationships between sleep-wake cycle and cerebral beta-amyloid (Abeta) deposition in cognitively normal (CN) older adults, focusing primarily on the moderating effects of the APOE epsilon4 allele. METHODS: The present study included 133 CN older adults who participated in the Korean Brain Aging Study for Early Diagnosis & Prediction of Alzheimer's Disease cohort. All participants underwent [11C] Pittsburgh compound B-PET imaging to quantify Abeta deposition in the brain and blood sampling for APOE genotyping. Sleep and circadian parameters were measured using actigraphy for 8 consecutive days. RESULTS: The APOE epsilon4 allele had moderating effects on the associations of sleep latency (SL), mesor, and acrophase with cerebral Abeta deposition, and the interactions between APOE epsilon4 status and SL and between APOE epsilon4 status and acrophase remained significant after adjusting for multiple comparisons. In APOE epsilon4 noncarriers, shorter SL, higher mesor, and advanced acrophase were associated with Abeta positivity. In contrast, APOE epsilon4 carriers showed a relationship between delayed acrophase and Abeta accumulation that approached but did not reach significance. After the Bonferroni correction, the associations of shorter SL and higher mesor with Abeta positivity remained significant for APOE epsilon4 noncarriers. CONCLUSIONS: Our findings suggest that the APOE epsilon4 allele may act as a moderator in the relationship between the sleep-wake cycle and Abeta accumulation in CN older adults. Thus, APOE epsilon4 status needs to be considered as a key factor when designing related research or interventions. PMID- 29490915 TI - Retinal signs and 20-year cognitive decline in the Atherosclerosis Risk in Communities Study. AB - OBJECTIVE: To test the hypothesis that retinal vascular signs are associated with greater cognitive decline over 20 years in 12,317 men and women 50 to 73 years of age at baseline. METHODS: A composite cognitive score was created with 3 neuropsychological tests measured at 3 time points (1990-1992 to 2011-2013). Retinal signs were measured with fundus photography (1993-1995). Differences in cognitive change by retinal signs status were estimated with linear mixed models. Cognitive scores were imputed for living participants with incomplete cognitive testing. RESULTS: In multivariable-adjusted analyses that controlled for attrition, loss of vascular integrity (retinopathy and its components) was associated with greater 20-year decline (difference in 20-year cognitive change for moderate/severe vs no retinopathy -0.53 SD, 95% confidence interval -0.74 to 0.33). Estimated differences were similar in participants with and without diabetes mellitus and in white and black participants. CONCLUSIONS: Retinopathy was associated with accelerated rates of 20-year cognitive decline. These findings support the exploration of more sensitive measures in the eye such as optical coherence tomography angiography, which may provide surrogate indexes of microvascular lesions relevant to cognitive decline in older adults. PMID- 29490917 TI - High-frequency oscillations in awake patients undergoing brain tumor-related epilepsy surgery. AB - OBJECTIVE: To examine the relationship between high-frequency oscillations (HFOs) and the presence of preoperative seizures, World Health Organization tumor grade, and isocitrate dehydrogenase 1 (IDH1) mutational status in gliomas. METHODS: We retrospectively studied intraoperative electrocorticography recorded in 16 patients with brain tumor (12 presenting with seizures) who underwent awake craniotomy and surgical resection between September 2016 and June 2017. The number and distribution of HFOs were determined and quantified visually and with an automated HFO detector. RESULTS: Five patients had low-grade (1 with grade I and 4 with grade II) and 11 had high-grade (6 with grade III and 5 with grade IV) brain tumors. An IDH1 mutation was found in 6 patients. Patients with a history of preoperative seizures were more likely to have HFOs than those without preoperative seizures (9 of 12 vs 0 of 4, p = 0.02). The rate of HFOs was higher in patients with IDH1 mutant (mean 7.2 per minute) than IDH wild-type (mean 2.3 per minute) genotype (p = 0.03). CONCLUSIONS: HFOs are common in brain tumor related epilepsy, and HFO rate may be a useful measure of epileptogenicity in gliomas. Our findings further support the notion that IDH1 mutant genotype is more epileptogenic than IDH1 wild-type genotype gliomas. PMID- 29490918 TI - Strong control of Southern Ocean cloud reflectivity by ice-nucleating particles. AB - Large biases in climate model simulations of cloud radiative properties over the Southern Ocean cause large errors in modeled sea surface temperatures, atmospheric circulation, and climate sensitivity. Here, we combine cloud resolving model simulations with estimates of the concentration of ice-nucleating particles in this region to show that our simulated Southern Ocean clouds reflect far more radiation than predicted by global models, in agreement with satellite observations. Specifically, we show that the clouds that are most sensitive to the concentration of ice-nucleating particles are low-level mixed-phase clouds in the cold sectors of extratropical cyclones, which have previously been identified as a main contributor to the Southern Ocean radiation bias. The very low ice nucleating particle concentrations that prevail over the Southern Ocean strongly suppress cloud droplet freezing, reduce precipitation, and enhance cloud reflectivity. The results help explain why a strong radiation bias occurs mainly in this remote region away from major sources of ice-nucleating particles. The results present a substantial challenge to climate models to be able to simulate realistic ice-nucleating particle concentrations and their effects under specific meteorological conditions. PMID- 29490921 TI - US public health agency is sued over failure to release emails from Coca-Cola. PMID- 29490919 TI - MLH1-rheMac hereditary nonpolyposis colorectal cancer syndrome in rhesus macaques. AB - Over the past two decades, 33 cases of colonic adenocarcinomas have been diagnosed in rhesus macaques (Macaca mulatta) at the nonhuman primate colony of the Keeling Center for Comparative Medicine and Research at The University of Texas MD Anderson Cancer Center. The distinctive feature in these cases, based on PET/computed tomography (CT) imaging, was the presence of two or three tumor lesions in different locations, including proximal to the ileocecal juncture, proximal to the hepatic flexure, and/or in the sigmoid colon. These colon carcinoma lesions selectively accumulated [18F]fluorodeoxyglucose ([18F]FDG) and [18F]fluoroacetate ([18F]FACE) at high levels, reflecting elevated carbohydrate and fatty acid metabolism in these tumors. In contrast, the accumulation of [18F]fluorothymidine ([18F]FLT) was less significant, reflecting slow proliferative activity in these tumors. The diagnoses of colon carcinomas were confirmed by endoscopy. The expression of MLH1, MSH2, and MSH6 proteins and the degree of microsatellite instability (MSI) was assessed in colon carcinomas. The loss of MLH1 protein expression was observed in all tumors and was associated with a deletion mutation in the MLH1 promoter region and/or multiple single nucleotide polymorphism (SNP) mutations in the MLH1 gene. All tumors exhibited various degrees of MSI. The pedigree analysis of this rhesus macaque population revealed several clusters of affected animals related to each other over several generations, suggesting an autosomal dominant transmission of susceptibility for colon cancer. The newly discovered hereditary nonpolyposis colorectal cancer syndrome in rhesus macaques, termed MLH1-rheMac, may serve as a model for development of novel approaches to diagnosis and therapy of Lynch syndrome in humans. PMID- 29490920 TI - Direct observations of rock moisture, a hidden component of the hydrologic cycle. AB - Recent theory and field observations suggest that a systematically varying weathering zone, that can be tens of meters thick, commonly develops in the bedrock underlying hillslopes. Weathering turns otherwise poorly conductive bedrock into a dynamic water storage reservoir. Infiltrating precipitation typically will pass through unsaturated weathered bedrock before reaching groundwater and running off to streams. This invisible and difficult to access unsaturated zone is virtually unexplored compared with the surface soil mantle. We have proposed the term "rock moisture" to describe the exchangeable water stored in the unsaturated zone in weathered bedrock, purposely choosing a term parallel to, but distinct from, soil moisture, because weathered bedrock is a distinctly different material that is distributed across landscapes independently of soil thickness. Here, we report a multiyear intensive campaign of quantifying rock moisture across a hillslope underlain by a thick weathered bedrock zone using repeat neutron probe measurements in a suite of boreholes. Rock moisture storage accumulates in the wet season, reaches a characteristic upper value, and rapidly passes any additional rainfall downward to groundwater. Hence, rock moisture storage mediates the initiation and magnitude of recharge and runoff. In the dry season, rock moisture storage is gradually depleted by trees for transpiration, leading to a common lower value at the end of the dry season. Up to 27% of the annual rainfall is seasonally stored as rock moisture. Significant rock moisture storage is likely common, and yet it is missing from hydrologic and land-surface models used to predict regional and global climate. PMID- 29490923 TI - Risk of hepatitis B virus reactivation in patients treated with ibrutinib. PMID- 29490922 TI - Living network meta-analysis compared with pairwise meta-analysis in comparative effectiveness research: empirical study. AB - OBJECTIVE: To examine whether the continuous updating of networks of prospectively planned randomised controlled trials (RCTs) ("living" network meta analysis) provides strong evidence against the null hypothesis in comparative effectiveness of medical interventions earlier than the updating of conventional, pairwise meta-analysis. DESIGN: Empirical study of the accumulating evidence about the comparative effectiveness of clinical interventions. DATA SOURCES: Database of network meta-analyses of RCTs identified through searches of Medline, Embase, and the Cochrane Database of Systematic Reviews until 14 April 2015. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Network meta-analyses published after January 2012 that compared at least five treatments and included at least 20 RCTs. Clinical experts were asked to identify in each network the treatment comparison of greatest clinical interest. Comparisons were excluded for which direct and indirect evidence disagreed, based on side, or node, splitting test (P<0.10). OUTCOMES AND ANALYSIS: Cumulative pairwise and network meta-analyses were performed for each selected comparison. Monitoring boundaries of statistical significance were constructed and the evidence against the null hypothesis was considered to be strong when the monitoring boundaries were crossed. A significance level was defined as alpha=5%, power of 90% (beta=10%), and an anticipated treatment effect to detect equal to the final estimate from the network meta-analysis. The frequency and time to strong evidence was compared against the null hypothesis between pairwise and network meta-analyses. RESULTS: 49 comparisons of interest from 44 networks were included; most (n=39, 80%) were between active drugs, mainly from the specialties of cardiology, endocrinology, psychiatry, and rheumatology. 29 comparisons were informed by both direct and indirect evidence (59%), 13 by indirect evidence (27%), and 7 by direct evidence (14%). Both network and pairwise meta-analysis provided strong evidence against the null hypothesis for seven comparisons, but for an additional 10 comparisons only network meta-analysis provided strong evidence against the null hypothesis (P=0.002). The median time to strong evidence against the null hypothesis was 19 years with living network meta-analysis and 23 years with living pairwise meta analysis (hazard ratio 2.78, 95% confidence interval 1.00 to 7.72, P=0.05). Studies directly comparing the treatments of interest continued to be published for eight comparisons after strong evidence had become evident in network meta analysis. CONCLUSIONS: In comparative effectiveness research, prospectively planned living network meta-analyses produced strong evidence against the null hypothesis more often and earlier than conventional, pairwise meta-analyses. PMID- 29490925 TI - Where is the evidence for automated triage apps? PMID- 29490924 TI - Antiphospholipid antibodies and recurrent thrombosis after a first unprovoked venous thromboembolism. AB - It is uncertain whether antiphospholipid antibodies (APAs) increase the risk of recurrence after a first unprovoked venous thromboembolism (VTE). We tested for anticardiolipin antibodies, anti-beta2 glycoprotein 1 antibodies, and lupus anticoagulant on 2 occasions ~6 months apart in 307 patients with a first unprovoked VTE who were part of a prospective cohort study. We then determined if APAs were associated with recurrent thrombosis in the 290 patients who stopped anticoagulant therapy in response to negative D-dimer results. Compared with those without an APA, the hazard ratios for recurrent VTE were 1.8 (95% confidence interval [CI], 0.9-3.7; P = .09) in the 25.9% of patients with an APA on >=1 occasions, 2.7 (95% CI, 1.1-.7; P = .03) in the 9.0% of patients with the same APA on 2 occasions, and 4.5 (95% CI, 1.5-13.0; P = .006) in the 3.8% of patients with 2 or 3 different APA types on either the same or different occasions. There was no association between having an APA and D-dimer levels. We conclude that having the same type of APA on 2 occasions or having >1 type of APA on the same or different occasions is associated with recurrent thrombosis in patients with a first unprovoked VTE who stop anticoagulant therapy in response to negative D-dimer tests. APA and D-dimer levels seem to be independent predictors of recurrence in patients with an unprovoked VTE. This trial was registered at www.clinicaltrials.gov as #NCT00720915. PMID- 29490926 TI - Childhood in Syria. PMID- 29490927 TI - Does personal politics affect attitudes towards the NHS? PMID- 29490928 TI - Jason Leitch: Three chords and the tooth. PMID- 29490929 TI - CCGs try to block expansion of Babylon's GP at Hand service. PMID- 29490930 TI - Shortlisted teams are announced for 10th BMJ Awards. PMID- 29490933 TI - More medicines for children: impact of the EU paediatric regulation. AB - INTRODUCTION: This paper focuses on the authorisation of new medicines, new indications and new pharmaceutical forms or strengths for use in children and also on the availability of paediatric information in the product information of centrally authorised medicinal products following the enforcement of the Paediatric Regulation on 26 January 2007. OBJECTIVES: To investigate whether the Paediatric Regulation has led to more medicines available for children in the European Union (EU) and if more information on paediatric use is now available in the product information of medicines authorised via the centralised procedure. MATERIALS AND METHODS: We retrospectively analysed the centrally authorised medicinal products in the EU that had an approval for an initial marketing authorisation, a type II variation, or a line extension during the years 2004 2006 and 2012-2014. Medicinal products not subjected to the obligations of the Paediatric Regulation were excluded. RESULTS: In 2004-2006, 20 new medicines and 10 new indications were centrally authorised for paediatric use compared with 26 new medicines and 37 new indications in 2012-2014. The number of medicines with a new pharmaceutical form or strength for use in children was eight in 2004-2006 and seven in 2012-2014. There was a huge increase in the number of products with changes of paediatric relevance in the summary of product characteristics in 2012 2014 compared with 2004-2006. CONCLUSIONS: The entry into force of the Paediatric Regulation has had a positive impact on paediatric drug development with more medicines available for children in the EU and substantially more information available for clinicians on paediatric use in the product information. PMID- 29490934 TI - Health status in 1040 adults with disorders of sex development (DSD): a European multicenter study. AB - OBJECTIVE: The knowledge about health status in adults with disorder of sex development (DSD) is scarce. DESIGN AND METHODS: A cross-sectional observational study in 14 European tertiary centers recruited 1040 participants (717 females, 311 males, 12 others) with DSD. Mean age was 32.4 +/- 13.6 year (range 16-75). The cohort was divided into: Turner (n = 301), Klinefelter (n = 224), XY-DSD (n = 222), XX-DSD (excluding congenital adrenal hyperplasia (CAH) and 46,XX males) (n = 21), 46,XX-CAH (n = 226) and 45,X/46,XY (n = 45). Perceived and objective health statuses were measured and compared to European control data. RESULTS: In DSD, fair to very good general health was reported by 91.4% and only 8.6% reported (very) bad general health (controls 94.0% and 6.0%, P < 0.0001). Longstanding health issues other than DSD and feeling limited in daily life were reported in 51.0% and 38.6%, respectively (controls 24.5% and 13.8%, P < 0.0001 both). Any disorder except DSD was present in 84.3% (controls 24.6%, P < 0.0001). Males reported worse health than females. In the subgroup analysis, Klinefelter and 46,XX-DSD patients reported bad general health in 15.7% and 16.7%, respectively (Turner 3.2% and CAH 7.4%). Comorbidities were prevalent in all DSD subgroups but Klinefelter and Turner were most affected. Early diagnosis of DSD and a healthy lifestyle were associated with less comorbidities. CONCLUSIONS: Overall, general health appeared to be good but a number of medical problems were reported, especially in Klinefelter and Turner. Early diagnosis of DSD and a healthy lifestyle seemed to be important. Lifelong follow-up at specialized centers is necessary. PMID- 29490935 TI - Transcatheter valve replacement in congenital heart disease: the present and the future. PMID- 29490932 TI - Emerging Technologies for Molecular Diagnosis of Sepsis. AB - Rapid and accurate profiling of infection-causing pathogens remains a significant challenge in modern health care. Despite advances in molecular diagnostic techniques, blood culture analysis remains the gold standard for diagnosing sepsis. However, this method is too slow and cumbersome to significantly influence the initial management of patients. The swift initiation of precise and targeted antibiotic therapies depends on the ability of a sepsis diagnostic test to capture clinically relevant organisms along with antimicrobial resistance within 1 to 3 h. The administration of appropriate, narrow-spectrum antibiotics demands that such a test be extremely sensitive with a high negative predictive value. In addition, it should utilize small sample volumes and detect polymicrobial infections and contaminants. All of this must be accomplished with a platform that is easily integrated into the clinical workflow. In this review, we outline the limitations of routine blood culture testing and discuss how emerging sepsis technologies are converging on the characteristics of the ideal sepsis diagnostic test. We include seven molecular technologies that have been validated on clinical blood specimens or mock samples using human blood. In addition, we discuss advances in machine learning technologies that use electronic medical record data to provide contextual evaluation support for clinical decision-making. PMID- 29490916 TI - Comparing intracerebral hemorrhages associated with direct oral anticoagulants or warfarin. AB - OBJECTIVES: This cross-sectional survey explored the characteristics and outcomes of direct oral anticoagulant (DOAC)-associated nontraumatic intracerebral hemorrhages (ICHs) by analyzing a large nationwide Japanese discharge database. METHODS: We analyzed data from 2,245 patients who experienced ICHs while taking anticoagulants (DOAC: 227; warfarin: 2,018) and were urgently hospitalized at 621 institutions in Japan between April 2010 and March 2015. We compared the DOAC- and warfarin-treated patients based on their backgrounds, ICH severities, antiplatelet therapies at admission, hematoma removal surgeries, reversal agents, mortality rates, and modified Rankin Scale scores at discharge. RESULTS: DOAC associated ICHs were less likely to cause moderately or severely impaired consciousness (DOAC-associated ICHs: 31.3%; warfarin-associated ICHs: 39.4%; p = 0.002) or require surgical removal (DOAC-associated ICHs: 5.3%; warfarin associated ICHs: 9.9%; p = 0.024) in the univariate analysis. Propensity score analysis revealed that patients with DOAC-associated ICHs also exhibited lower mortality rates within 1 day (odds ratio [OR] 4.96, p = 0.005), within 7 days (OR 2.29, p = 0.037), and during hospitalization (OR 1.96, p = 0.039). CONCLUSIONS: This nationwide study revealed that DOAC-treated patients had less severe ICHs and lower mortality rates than did warfarin-treated patients, probably due to milder hemorrhages at admission and lower hematoma expansion frequencies. PMID- 29490936 TI - STAT-3-independent production of IL-17 by mouse innate-like alphabeta T cells controls ocular infection. AB - Appropriate regulation of IL-17 production in the host can mean the difference between effective control of pathogens and uncontrolled inflammation that causes tissue damage. Investigation of conventional CD4+ T cells (Th17 cells) has yielded invaluable insights into IL-17 function and its regulation. More recently, we and others reported production of IL-17 from innate alphabeta+ T cell populations, which was shown to occur primarily via IL-23R signaling through the transcription factor STAT-3. In our current study, we identify promyelocytic leukemia zinc finger (PLZF)-expressing iNKT, CD4-/CD8+, and CD4-/CD8- (DN) alphabeta+T cells, which produce IL-17 in response to TCR and IL-1 receptor ligation independently of STAT-3 signaling. Notably, this noncanonical pathway of IL-17 production may be important in mucosal defense and is by itself sufficient to control pathogenic Staphylococcus aureus infection at the ocular surface. PMID- 29490937 TI - MANAGEMENT OF ENDOCRINE DISEASE: Pitfalls on the replacement therapy for primary and central hypothyroidism in adults. AB - Hypothyroidism is one of the most common hormone deficiencies in adults. Most of the cases, particularly those of overt hypothyroidism, are easily diagnosed and managed, with excellent outcomes if treated adequately. However, minor alterations of thyroid function determine nonspecific manifestations. Primary hypothyroidism due to chronic autoimmune thyroiditis is largely the most common cause of thyroid hormone deficiency. Central hypothyroidism is a rare and heterogeneous disorder characterized by decreased thyroid hormone secretion by an otherwise normal thyroid gland, due to lack of TSH. The standard treatment of primary and central hypothyroidism is hormone replacement therapy with levothyroxine sodium (LT4). Treatment guidelines of hypothyroidism recommend monotherapy with LT4 due to its efficacy, long-term experience, favorable side effect profile, ease of administration, good intestinal absorption, long serum half-life and low cost. Despite being easily treatable with a daily dose of LT4, many patients remain hypothyroid due to malabsorption syndromes, autoimmune gastritis, pancreatic and liver disorders, drug interactions, polymorphisms in DIO2 (iodothyronine deiodinase 2), high fiber diet, and more frequently, non compliance to LT4 therapy. Compliance to levothyroxine treatment in hypothyroidism is compromised by daily and fasting schedule. Many adult patients remain hypothyroid due to all the above mentioned and many attempts to improve levothyroxine therapy compliance and absorption have been made. PMID- 29490939 TI - LITE microscopy: Tilted light-sheet excitation of model organisms offers high resolution and low photobleaching. AB - Fluorescence microscopy is a powerful approach for studying subcellular dynamics at high spatiotemporal resolution; however, conventional fluorescence microscopy techniques are light-intensive and introduce unnecessary photodamage. Light-sheet fluorescence microscopy (LSFM) mitigates these problems by selectively illuminating the focal plane of the detection objective by using orthogonal excitation. Orthogonal excitation requires geometries that physically limit the detection objective numerical aperture (NA), thereby limiting both light gathering efficiency (brightness) and native spatial resolution. We present a novel live-cell LSFM method, lateral interference tilted excitation (LITE), in which a tilted light sheet illuminates the detection objective focal plane without a sterically limiting illumination scheme. LITE is thus compatible with any detection objective, including oil immersion, without an upper NA limit. LITE combines the low photodamage of LSFM with high resolution, high brightness, and coverslip-based objectives. We demonstrate the utility of LITE for imaging animal, fungal, and plant model organisms over many hours at high spatiotemporal resolution. PMID- 29490938 TI - Lipoxins Regulate the Early Growth Response-1 Network and Reverse Diabetic Kidney Disease. AB - Background The failure of spontaneous resolution underlies chronic inflammatory conditions, including microvascular complications of diabetes such as diabetic kidney disease. The identification of endogenously generated molecules that promote the physiologic resolution of inflammation suggests that these bioactions may have therapeutic potential in the context of chronic inflammation. Lipoxins (LXs) are lipid mediators that promote the resolution of inflammation.Methods We investigated the potential of LXA4 and a synthetic LX analog (Benzo-LXA4) as therapeutics in a murine model of diabetic kidney disease, ApoE-/- mice treated with streptozotocin.Results Intraperitoneal injection of LXs attenuated the development of diabetes-induced albuminuria, mesangial expansion, and collagen deposition. Notably, LXs administered 10 weeks after disease onset also attenuated established kidney disease, with evidence of preserved kidney function. Kidney transcriptome profiling defined a diabetic signature (725 genes; false discovery rate P<=0.05). Comparison of this murine gene signature with that of human diabetic kidney disease identified shared renal proinflammatory/profibrotic signals (TNF-alpha, IL-1beta, NF-kappaB). In diabetic mice, we identified 20 and 51 transcripts regulated by LXA4 and Benzo-LXA4, respectively, and pathway analysis identified established (TGF-beta1, PDGF, TNF alpha, NF-kappaB) and novel (early growth response-1 [EGR-1]) networks activated in diabetes and regulated by LXs. In cultured human renal epithelial cells, treatment with LXs attenuated TNF-alpha-driven Egr-1 activation, and Egr-1 depletion prevented cellular responses to TGF-beta1 and TNF-alphaConclusions These data demonstrate that LXs can reverse established diabetic complications and support a therapeutic paradigm to promote the resolution of inflammation. PMID- 29490941 TI - Olfactory dysfunction is worse in primary ciliary dyskinesia compared with other causes of chronic sinusitis in children. AB - Cilia have multiple functions including olfaction. We hypothesised that olfactory function could be impaired in primary ciliary dyskinesia (PCD). Olfaction, nasal nitric oxide (nNO) and sinus CT were assessed in patients with PCD and non-PCD sinus disease, and healthy controls (no CT scan). PCD and non-PCD patients had similar severity of sinus disease. Despite this, defective olfaction was more common in patients with PCD (P<0.0001) and more severe in patients with PCD with major Transmission Electron Microscopy (TEM) abnormalities. Only in classical PCD did olfaction inversely correlate with sinusitis and nNO. We speculate that defective olfaction in PCD is primary in nature. PMID- 29490940 TI - Ki67 Changes Identify Worse Outcomes in Residual Breast Cancer Tumors After Neoadjuvant Chemotherapy. AB - BACKGROUND: Several breast cancer (BC) trials have adopted pathological complete response (pCR) as a surrogate marker of long-term treatment efficacy. In patients with luminal subtype, pCR seems less important for outcome prediction. BC is a heterogeneous disease, which is evident in residual tumors after neoadjuvant chemotherapy (NAC). This study evaluates changes in Ki67 in relation to disease free survival (DFS) and overall survival (OS) in patients without pCR. SUBJECTS, MATERIALS, AND METHODS: Four hundred thirty-five patients with stage IIA-IIIC BC without pCR after standard NAC with anthracycline and paclitaxel were analyzed. We analyzed the decrease or lack of decrease in the percentage of Ki67-positive cells between core biopsy samples and surgical specimens and correlated this value with outcome. RESULTS: Twenty-five percent of patients presented with luminal A-like tumors, 45% had luminal B-like tumors, 14% had triple-negative BC, 5% had HER2-positive BC, and 11% had triple-positive BC. Patients were predominantly diagnosed with stage III disease (52%) and high-grade tumors (46%). Median Ki67 level was 20% before NAC, which decreased to a median of 10% after NAC. Fifty-seven percent of patients had a decrease in Ki67 percentage. Ki67 decrease significantly correlated with better DFS and OS compared with no decrease, particularly in the luminal B subgroup. Multivariate analysis showed that nonreduction of Ki67 significantly increased the hazard ratio of recurrence and death by 3.39 (95% confidence interval [CI] 1.8-6.37) and 7.03 (95% CI 2.6 18.7), respectively. CONCLUSION: Patients without a decrease in Ki67 in residual tumors after NAC have poor prognosis. This warrants the introduction of new therapeutic strategies in this setting. IMPLICATIONS FOR PRACTICE: This study evaluates the change in Ki67 percentage before and after neoadjuvant chemotherapy (NAC) and its relationship with survival outcomes in patients with breast cancer who did not achieve complete pathological response (pCR). These patients, a heterogeneous group with diverse prognoses that cannot be treated using a single algorithm, pose a challenge to clinicians. This study identified a subgroup of these patients with a poor prognosis, those with luminal B-like tumors without a Ki67 decrease after NAC, thus justifying the introduction of new therapeutic strategies for patients who already present a favorable prognosis (luminal B-like with Ki67 decrease). PMID- 29490942 TI - Zeb1 in Stromal Myofibroblasts Promotes Kras-Driven Development of Pancreatic Cancer. AB - The transcription factor Zeb1 has been identified as a crucial player in Kras dependent oncogenesis. In pancreatic ductal adenocarcinoma (PDAC), Zeb1 is highly expressed in myofibroblasts and correlates with poor prognosis. As Kras mutations are key drivers in PDAC, we aimed here to assess the necessity of Zeb1 for Kras driven PDAC and to define the role of Zeb1-expressing myofibroblasts in PDAC development. Genetically engineered mice with conditional pancreatic KrasG12D and Trp53 mutations (KPC) were crossed with Zeb1 haploinsufficient mice (Z+/-). Extensive PDAC was prominent in all 20-week-old KPC;Z+/+ mice, whereas only low grade precursor lesions were detected in age-matched KPC;Z+/- littermates, with PDAC developing eventually in KPC;Z+/- aged animals. Zeb1 expression in myofibroblasts occurred early in tumorigenesis and Zeb1 haploinsufficiency retarded native expansion of stromal myofibroblasts during precursor-to-cancer progression. Zeb1 downregulation in mPSC repressed their activated gene profile, impaired their migratory and proliferative activity, and attenuated their tumor supporting features. Conditioned media from Z+/+ mouse-activated (myofibroblast like) pancreatic stellate cells (mPSC) boosted Ras activity in pancreatic cancer cells carrying mutant Kras; this effect was not observed when using conditioned media from Z+/- mPSC, revealing a paracrinal cooperative axis between Zeb1 expressing PSC and oncogenic Kras-bearing tumor cells. We conclude that Zeb1 expressing stromal myofibroblasts enable a heterotypic collaboration with the Kras-fated epithelial compartment, thus supporting pancreatic malignancy.Significance: Zeb1 expression in stromal myofibroblasts supports PDAC development via collaboration with the epithelial compartment bearing oncogenic Kras mutations. Cancer Res; 78(10); 2624-37. (c)2018 AACR. PMID- 29490943 TI - Loss of Pax5 Exploits Sca1-BCR-ABLp190 Susceptibility to Confer the Metabolic Shift Essential for pB-ALL. AB - Preleukemic clones carrying BCR-ABLp190 oncogenic lesions are found in neonatal cord blood, where the majority of preleukemic carriers do not convert into precursor B-cell acute lymphoblastic leukemia (pB-ALL). However, the critical question of how these preleukemic cells transform into pB-ALL remains undefined. Here, we model a BCR-ABLp190 preleukemic state and show that limiting BCR-ABLp190 expression to hematopoietic stem/progenitor cells (HS/PC) in mice (Sca1-BCR ABLp190) causes pB-ALL at low penetrance, which resembles the human disease. pB ALL blast cells were BCR-ABL-negative and transcriptionally similar to pro-B/pre B cells, suggesting disease onset upon reduced Pax5 functionality. Consistent with this, double Sca1-BCR-ABLp190+Pax5+/- mice developed pB-ALL with shorter latencies, 90% incidence, and accumulation of genomic alterations in the remaining wild-type Pax5 allele. Mechanistically, the Pax5-deficient leukemic pro B cells exhibited a metabolic switch toward increased glucose utilization and energy metabolism. Transcriptome analysis revealed that metabolic genes (IDH1, G6PC3, GAPDH, PGK1, MYC, ENO1, ACO1) were upregulated in Pax5-deficient leukemic cells, and a similar metabolic signature could be observed in human leukemia. Our studies unveil the first in vivo evidence that the combination between Sca1-BCR ABLp190 and metabolic reprogramming imposed by reduced Pax5 expression is sufficient for pB-ALL development. These findings might help to prevent conversion of BCR-ABLp190 preleukemic cells.Significance: Loss of Pax5 drives metabolic reprogramming, which together with Sca1-restricted BCR-ABL expression enables leukemic transformation. Cancer Res; 78(10); 2669-79. (c)2018 AACR. PMID- 29490945 TI - ERbeta-Mediated Alteration of circATP2B1 and miR-204-3p Signaling Promotes Invasion of Clear Cell Renal Cell Carcinoma. AB - Early studies have indicated that estrogen receptor beta (ERbeta) can influence the progression of clear cell renal cell carcinoma (ccRCC). Here, we report the mechanistic details of ERbeta-mediated progression of ccRCC. ERbeta increased ccRCC cell invasion via suppression of circular RNA ATP2B1 (circATP2B1) expression by binding directly to the 5' promoter region of its host gene ATPase plasma membrane Ca2+ transporting 1 (ATP2B1). ERbeta-suppressed circATP2B1 then led to reduced miR-204-3p, which increased fibronectin 1 (FN1) expression and enhanced ccRCC cell invasion. Targeting ERbeta with shRNA suppressed ccRCC metastasis in a murine model of RCC; adding circATP2B1 shRNA partly reversed this effect. Consistent with these experimental results, ccRCC patient survival data from The Cancer Genome Atlas indicated that a patient with higher ERbeta and FN1 expression had worse overall survival and a patient with higher miR-204-3p expression had significantly better overall survival. Together, these results suggest that ERbeta promotes ccRCC cell invasion by altering the ERbeta/circATP2B1/miR-204-3p/FN1 axis and that therapeutic targeting of this newly identified pathway may better prevent ccRCC progression.Significance: These results identify an ERbeta/circATP2B1/miR-204-3p/FN1 signaling axis in RCC, suggesting ERbeta and circular RNA ATP2B1 as prognostic biomarkers for this disease. Cancer Res; 78(10); 2550-63. (c)2018 AACR. PMID- 29490944 TI - Predictive Gene Signatures Determine Tumor Sensitivity to MDM2 Inhibition. AB - Early clinical trials using murine double minute 2 (MDM2) inhibitors demonstrated proof-of-concept of p53-induced apoptosis by MDM2 inhibition in cancer cells; however, not all wild-type TP53 tumors are sensitive to MDM2 inhibition. Therefore, more potent inhibitors and biomarkers predictive of tumor sensitivity are needed. The novel MDM2 inhibitor DS-3032b is 10-fold more potent than the first-generation inhibitor nutlin-3a. TP53 mutations were predictive of resistance to DS-3032b, and allele frequencies of TP53 mutations were negatively correlated with sensitivity to DS-3032b. However, sensitivity to DS-3032b of TP53 wild-type tumors varied greatly. We thus used two methods to create predictive gene signatures. First, by comparing sensitivity to MDM2 inhibition with basal mRNA expression profiles in 240 cancer cell lines, a 175-gene signature was defined and validated in patient-derived tumor xenograft models and ex vivo human acute myeloid leukemia (AML) cells. Second, an AML-specific 1,532-gene signature was defined by performing random forest analysis with cross-validation using gene expression profiles of 41 primary AML samples. The combination of TP53 mutation status with the two gene signatures provided the best positive predictive values (81% and 82%, compared with 62% for TP53 mutation status alone). In addition, the top-ranked 50 genes selected from the AML-specific 1,532-gene signature conserved high predictive performance, suggesting that a more feasible size of gene signature can be generated through this method for clinical implementation. Our model is being tested in ongoing clinical trials of MDM2 inhibitors.Significance: This study demonstrates that gene expression profiling combined with TP53 mutational status predicts antitumor effects of MDM2 inhibitors in vitro and in vivoCancer Res; 78(10); 2721-31. (c)2018 AACR. PMID- 29490946 TI - TRPM2 Mediates Neutrophil Killing of Disseminated Tumor Cells. AB - Neutrophils play a critical role in cancer, with both protumor and antitumor neutrophil subpopulations reported. The antitumor neutrophil subpopulation has the capacity to kill tumor cells and limit metastatic spread, yet not all tumor cells are equally susceptible to neutrophil cytotoxicity. Because cells that evade neutrophils have greater chances of forming metastases, we explored the mechanism neutrophils use to kill tumor cells. Neutrophil cytotoxicity was previously shown to be mediated by secretion of H2O2 We report here that neutrophil cytotoxicity is Ca2+ dependent and is mediated by TRPM2, a ubiquitously expressed H2O2-dependent Ca2+ channel. Perturbing TRPM2 expression limited tumor cell proliferation, leading to attenuated tumor growth. Concomitantly, cells expressing reduced levels of TRPM2 were protected from neutrophil cytotoxicity and seeded more efficiently in the premetastatic lung.Significance: These findings identify the mechanism utilized by neutrophils to kill disseminated tumor cells and to limit metastatic spread. Cancer Res; 78(10); 2680-90. (c)2018 AACR. PMID- 29490947 TI - Metabolic Determinants of Sensitivity to Phosphatidylinositol 3-Kinase Pathway Inhibitor in Small-Cell Lung Carcinoma. AB - Comprehensive genomic analysis has revealed that the PI3K/AKT/mTOR pathway is a feasible therapeutic target in small-cell lung carcinoma (SCLC). However, biomarkers to identify patients likely to benefit from inhibitors of this pathway have not been identified. Here, we show that metabolic features determine sensitivity to the PI3K/mTOR dual inhibitor gedatolisib in SCLC cells. Substantial phosphatidyl lipid analysis revealed that a specific phosphatidylinositol (3,4,5)-trisphosphate (PIP3) subspecies lipid product PIP3 (38:4) is predictive in assessing sensitivity to PI3K/mTOR dual inhibitor. Notably, we found that higher amounts of purine-related aqueous metabolites such as hypoxanthine, which are characteristic of SCLC biology, lead to resistance to PI3K pathway inhibition. In addition, the levels of the mRNA encoding hypoxanthine phosphoribosyl transferase 1, a key component of the purine salvage pathway, differed significantly between SCLC cells sensitive or resistant to gedatolisib. Moreover, complementation with purine metabolites could reverse the vulnerability to targeting of the PI3K pathway in SCLC cells normally sensitive to gedatolisib. These results indicate that the resistance mechanism of PI3K pathway inhibitors is mediated by the activation of the purine salvage pathway, supplying purine resource to nucleotide biosynthesis. Metabolomics is a powerful approach for finding novel therapeutic biomarkers in SCLC treatment.Significance: These findings identify features that determine sensitivity of SCLC to PI3K pathway inhibition and support metabolomics as a tool for finding novel therapeutic biomarkers. Cancer Res; 78(9); 2179-90. (c)2018 AACR. PMID- 29490948 TI - YAP1-Mediated Suppression of USP31 Enhances NFkappaB Activity to Promote Sarcomagenesis. AB - To date, no consistent oncogenic driver mutations have been identified in most adult soft tissue sarcomas; these tumors are thus generally insensitive to existing targeted therapies. Here we investigated alternate mechanisms underlying sarcomagenesis to identify potential therapeutic interventions. Undifferentiated pleomorphic sarcoma (UPS) is an aggressive tumor frequently found in skeletal muscle where deregulation of the Hippo pathway and aberrant stabilization of its transcriptional effector yes-associated protein 1 (YAP1) increases proliferation and tumorigenesis. However, the downstream mechanisms driving this deregulation are incompletely understood. Using autochthonous mouse models and whole genome analyses, we found that YAP1 was constitutively active in some sarcomas due to epigenetic silencing of its inhibitor angiomotin (AMOT). Epigenetic modulators vorinostat and JQ1 restored AMOT expression and wild-type Hippo pathway signaling, which induced a muscle differentiation program and inhibited sarcomagenesis. YAP1 promoted sarcomagenesis by inhibiting expression of ubiquitin-specific peptidase 31 (USP31), a newly identified upstream negative regulator of NFkappaB signaling. Combined treatment with epigenetic modulators effectively restored USP31 expression, resulting in decreased NFkappaB activity. Our findings highlight a key underlying molecular mechanism in UPS and demonstrate the potential impact of an epigenetic approach to sarcoma treatment.Significance: A new link between Hippo pathway signaling, NFkappaB, and epigenetic reprogramming is highlighted and has the potential for therapeutic intervention in soft tissue sarcomas. Cancer Res; 78(10); 2705-20. (c)2018 AACR. PMID- 29490949 TI - Anti-CD137 Cancer Immunotherapy Suppresses Tumor Growth-Letter. PMID- 29490950 TI - Anti-CD137 Cancer Immunotherapy Suppresses Tumor Growth-Response. PMID- 29490951 TI - Microbiome and Esophageal Adenocarcinoma-Letter. PMID- 29490952 TI - How effective and cost-effective are innovative combinatorial technologies and practices for supporting older people with long-term conditions to remain well in the community? An evaluation protocol for an NHS Test Bed in North West England. AB - INTRODUCTION: The Lancashire and Cumbria Innovation Alliance (LCIA) Test Bed is a partnership between the National Health Service in England, industry (led by Philips) and Lancaster University. Through the implementation of a combination of innovative health technologies and practices, it aims to determine the most effective and cost-effective ways of supporting frail older people with long-term conditions to remain well in the community. Among the Test Bed's objectives are to improve patient activation and the ability of older people to self-care at home, reduce healthcare system utilisation, and deliver increased workforce productivity. METHODS AND ANALYSIS: Patients aged 55 years and over are recruited to four cohorts defined by their risk of hospital admission, with long-term conditions including chronic obstructive pulmonary disease, dementia, diabetes and heart failure. The programme is determined on an individual basis, with a range of technologies available. The evaluation is adopting a two-phase approach: phase 1 includes a bespoke patient survey and a mass matched control analysis; and phase 2 is using observational interviews with patients, and weekly diaries, action learning meetings and focus groups with members of staff and other key stakeholders. Phase 1 data analysis consists of a statistical evaluation of the effectiveness of the programme. A health economic analysis of its costs and associated cost changes will be undertaken. Phase 2 data will be analysed thematically with the aid of Atlas.ti qualitative software. The evaluation is located within a logic model framework, to consider the processes, management and participation that may have implications for the Test Bed's success. ETHICS AND DISSEMINATION: The LCIA Test Bed evaluation has received ethical approval from the Health Research Authority and Lancaster University's Faculty of Health and Medicine Research Ethics Committee. A range of dissemination methods are adopted, including deliberative panels to validate findings and develop outcomes for policy and practice. PMID- 29490953 TI - Budget impact analysis of heparin-bonded polytetrafluoroethylene grafts (Propaten) against standard polytetrafluoroethylene grafts for below-the-knee bypass in patients with critical limb ischaemia in France. AB - OBJECTIVES: To evaluate the budget impact of progressive replacement of standard polytetrafluoroethylene (PTFE) grafts by heparin-bound PTFE (Propaten) for below the-knee (BTK) bypass in patients with critical limb ischaemia (CLI). DESIGN: From a review of the scientific literature, we calculated a theoretical BTK primary patency for Propaten grafts. Using the French hospital expenditure database (PMSI), we retrospectively estimated a rehospitalisation rate for standard PTFE grafts. From these data, a model was created to assess the budget impact of a progressive replacement from standard PTFE grafts to Propaten grafts over a 5-year horizon. We performed an univariate sensitivity analysis to assess the robustness of our results. SETTING: French National Health Insurance (FNHI) perspective. PARTICIPANT: Patients with CLI. MAIN OUTCOME MEASURES: Budget impact analysis. RESULTS: Data extraction from the PMSI revealed that 656 patients were treated with PTFE grafts in 2011 in French public hospitals for a BTK bypass. Assuming a 2-year survival rate of 76.8%, observed reinterventions rate for standard PTFE grafts at 24 months from the PMSI was 35.1%. The mean rehospitalisation cost was ?10 689. The budget impact analysis based on these data found a net cumulative 5-year payer budget reduction of ?112 420 in favour of Propaten, under the assumption of a 75.6% primary patency for Propaten grafts for a projected population of 3215 patients of which 801 received a Propaten graft. CONCLUSIONS: Our budget impact analysis showed a positive impact on the national health insurance budget of the replacement of standard PTFE grafts by Propaten grafts for BTK bypass in patients with CLI in France. This supports the enactment of a reimbursement policy by the FNHI. PMID- 29490954 TI - Socioeconomic inequality in health domains in Tehran: a population-based cross sectional study. AB - OBJECTIVE: Reduction of socioeconomic inequality in health requires appropriate evidence on health and its distribution based on socioeconomic indicators. The objective of this study was to assess socioeconomic inequality in various health domains and self-rated health (SRH). METHODS: This study was conducted using data collected in a survey in 2014 on a random sample of individuals aged 18 and above in the city of Tehran. The standardised World Health Survey Individual Questionnaire was used to assess different health domains. The age-adjusted prevalence of poor health was calculated for each health domain and SRH based on levels of education and wealth quintiles. Furthermore, the Slope Index of Inequality (SII) and the Relative Index of Inequality (RII) were applied to assess socioeconomic inequality in each of the health domains and SRH. RESULTS: The age-adjusted prevalence of poor health was observed in a descending order from the lowest to the highest wealth quintiles, and from the lowest level of education to the highest. RII also showed varying values of inequality among different domains, favouring rich subgroups. The highest wealth-related RII was observed in the 'Mobility' domain with a value of 4.16 (95% CI 2.01 to 8.62), and the highest education-related RII was observed in the 'Interpersonal Activities' domain with a value of 6.40 (95% CI 1.91 to 21.36). CONCLUSIONS: Substantial socioeconomic inequalities were observed in different health domains in favour of groups of better socioeconomic status. Based on these results, policymaking aimed at tackling inequalities should pay attention to different health domains as well as to overall health. PMID- 29490955 TI - Estimating the HIV undiagnosed population in Catalonia, Spain: descriptive and comparative data analysis to identify differences in MSM stratified by migrant and Spanish-born population. AB - OBJECTIVE: Undiagnosed HIV continues to be a hindrance to efforts aimed at reducing incidence of HIV. The objective of this study was to provide an estimate of the HIV undiagnosed population in Catalonia and compare the HIV care cascade with this step included between high-risk populations. METHODS: To estimate HIV incidence, time between infection and diagnosis and the undiagnosed population stratified by CD4 count, we used the ECDC HIV Modelling Tool V.1.2.2. This model uses data on new HIV and AIDS diagnoses from the Catalan HIV/AIDS surveillance system from 2001 to 2013. Data used to estimate the proportion of people enrolled, on ART and virally suppressed in the HIV care cascade were derived from the PISCIS cohort. RESULTS: The total number of people living with HIV (PLHIV) in Catalonia in 2013 was 34 729 (32 740 to 36 827), with 12.3% (11.8 to 18.1) of whom were undiagnosed. By 2013, there were 8458 (8101 to 9079) Spanish-born men who have sex with men (MSM) and 2538 (2334 to 2918) migrant MSM living with HIV in Catalonia. A greater proportion of migrant MSM than local MSM was undiagnosed (32% vs 22%). In the subsequent steps of the HIV care cascade, migrants MSM experience greater losses than the Spanish-born MSM: in retention in care (74% vs 55%), in the proportion on combination antiretroviral treatment (70% vs 50%) and virally suppressed (65% vs 46%). CONCLUSIONS: By the end of 2013, there were an estimated 34 729 PLHIV in Catalonia, of whom 4271 were still undiagnosed. This study shows that the Catalan epidemic of HIV has continued to expand with the key group sustaining HIV transmission being MSM living with undiagnosed HIV. PMID- 29490956 TI - Emergency department presentation and readmission after index psychiatric admission: a data linkage study. AB - OBJECTIVE: To use linked administrative datasets to assess factors associated with emergency department (ED) presentation and psychiatric readmission in three distinctive time intervals after the index psychiatric admission. DESIGN: A retrospective data-linkage study. SETTING: Cohort study using four linked government minimum datasets including acute hospital care from July 2005 to June 2012 in New South Wales, Australia. PARTICIPANTS: People who were alive and aged >=18 years on 1 July 2005 and who had their index admission to a psychiatric ward from 1 July 2007 to 30 June 2010. OUTCOME MEASURES: ORs of factors associated with psychiatric admission and ED presentation were calculated for three intervals: 0-1 month, 2-5 months and 6-24 months after index separation. RESULTS: Index admission was identified in 35 056 individuals (51% -males) with a median age of 42 years. A total of 12 826 (37%) individuals had at least one ED presentation in the 24 months after index admission. Of those, 3608 (28%) presented within 0-1 month, 6350 (50%) within 2-5 months and 10 294 (80%) within 6-24 months after index admission. A total of 14 153 (40%) individuals had at least one psychiatric readmission in the first 24 months. Of those, 6808 (48%) were admitted within 0-1 month, 6433 (45%) within 2-5 months and 7649 (54%) within 6-24 months after index admission. Principal diagnoses and length of stay at index admission, sociodemographic factors, Charlson Comorbidity Index score, drug and alcohol comorbidity, intellectual disability and other inpatient service use were significantly associated with ED presentations and psychiatric readmissions, and these relationships varied somewhat over the intervals studied. CONCLUSION: Social determinants of service use, drug and alcohol intervention, addressing needs of individuals with intellectual disability and recovery oriented whole-person approaches at index admission are key areas for investment to improve trajectories after index admission. PMID- 29490958 TI - Systematic review of clinical practice guidelines to identify recommendations for rehabilitation after stroke and other acquired brain injuries. AB - OBJECTIVES: Rehabilitation clinical practice guidelines (CPGs) contain recommendation statements aimed at optimising care for adults with stroke and other brain injury. The aim of this study was to determine the quality, scope and consistency of CPG recommendations for rehabilitation covering the acquired brain injury populations. DESIGN: Systematic review. INTERVENTIONS: Included CPGs contained recommendations for inpatient rehabilitation or community rehabilitation for adults with an acquired brain injury diagnosis (stroke, traumatic or other non-progressive acquired brain impairments). Electronic databases (n=2), guideline organisations (n=4) and websites of professional societies (n=17) were searched up to November 2017. Two independent reviewers used the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument, and textual syntheses were used to appraise and compare recommendations. RESULTS: From 427 papers screened, 20 guidelines met the inclusion criteria. Only three guidelines were rated high (>75%) across all domains of AGREE-II; highest rated domains were 'scope and purpose' (85.1, SD 18.3) and 'clarity' (76.2%, SD 20.5). Recommendations for assessment and for motor therapies were most commonly reported, however, varied in the level of detail across guidelines. CONCLUSION: Rehabilitation CPGs were consistent in scope, suggesting little difference in rehabilitation approaches between vascular and traumatic brain injury. There was, however, variability in included studies and methodological quality. PROSPERO REGISTRATION NUMBER: CRD42016026936. PMID- 29490957 TI - Do female sex workers have lower uptake of HIV treatment services than non-sex workers? A cross-sectional study from east Zimbabwe. AB - OBJECTIVE: Globally, HIV disproportionately affects female sex workers (FSWs) yet HIV treatment coverage is suboptimal. To improve uptake of HIV services by FSWs, it is important to identify potential inequalities in access and use of care and their determinants. Our aim is to investigate HIV treatment cascades for FSWs and non-sex workers (NSWs) in Manicaland province, Zimbabwe, and to examine the socio demographic characteristics and intermediate determinants that might explain differences in service uptake. METHODS: Data from a household survey conducted in 2009-2011 and a parallel snowball sample survey of FSWs were matched using probability methods to reduce under-reporting of FSWs. HIV treatment cascades were constructed and compared for FSWs (n=174) and NSWs (n=2555). Determinants of service uptake were identified a priori in a theoretical framework and tested using logistic regression. RESULTS: HIV prevalence was higher in FSWs than in NSWs (52.6% vs 19.8%; age-adjusted OR (AOR) 4.0; 95% CI 2.9 to 5.5). In HIV positive women, FSWs were more likely to have been diagnosed (58.2% vs 42.6%; AOR 1.62; 1.02-2.59) and HIV-diagnosed FSWs were more likely to initiate ART (84.9% vs 64.0%; AOR 2.33; 1.03-5.28). No difference was found for antiretroviral treatment (ART) adherence (91.1% vs 90.5%; P=0.9). FSWs' greater uptake of HIV treatment services became non-significant after adjusting for intermediate factors including HIV knowledge and risk perception, travel time to services, physical and mental health, and recent pregnancy. CONCLUSION: FSWs are more likely to take up testing and treatment services and were closer to achieving optimal outcomes along the cascade compared with NSWs. However, ART coverage was low in all women at the time of the survey. FSWs' need for, knowledge of and proximity to HIV testing and treatment facilities appear to increase uptake. PMID- 29490959 TI - Design of a phase IV randomised, double-blind, placebo-controlled trial assessing the ImPact of Residual Inflammation Detected via Imaging TEchniques, Drug Levels and Patient Characteristics on the Outcome of Dose TaperIng of Adalimumab in Clinical Remission Rheumatoid ArThritis (RA) patients (PREDICTRA). AB - INTRODUCTION: The current American College of Rheumatology and European League Against Rheumatism treatment recommendations advise tapering biological disease modifying antirheumatic drug (bDMARD) therapy in patients with rheumatoid arthritis (RA) who achieve stable clinical remission while receiving bDMARDs. However, not all patients maintain remission or low disease activity after tapering or discontinuation of bDMARDs. The aim of the ImPact of Residual Inflammation Detected via Imaging TEchniques, Drug Levels and Patient Characteristics on the Outcome of Dose TaperIng of Adalimumab in Clinical Remission Rheumatoid ArThritis (RA) study, or PREDICTRA, is to generate data on patient and disease characteristics that may predict the clinical course of a fixed dose-tapering regimen with the bDMARD adalimumab. METHODS AND ANALYSIS: PREDICTRA is an ongoing, multicentre, phase IV, randomised, double-blind, parallel-group study of adalimumab dose tapering controlled by withdrawal in participants with RA who achieved stable clinical remission while receiving adalimumab. The study includes a screening period, a 4-week lead-in period with open-label adalimumab 40 mg every other week and a subsequent 36-week double blind period during which participants are randomised 5:1 to adalimumab 40 mg every 3 weeks (taper arm) or placebo (withdrawal arm). The primary explanatory efficacy variables are lead-in baseline hand and wrist MRI-detected synovitis and bone marrow oedema scores, as well as a composite of both scores; the dependent variable is the occurrence of flare up to week 40. Additional efficacy variables, safety, pharmacokinetics, biomarkers and immunogenicity will also be assessed, and an ultrasound substudy will be conducted. ETHICS AND DISSEMINATION: The study is conducted in accordance with the International Conference on Harmonisation guidelines, local laws and the ethical principles of the Declaration of Helsinki. All participants are required to sign a written informed consent statement before the start of any study procedures. TRIAL REGISTRATION NUMBER: EudraCT 2014-001114 26 and NCT02198651; Pre-results. PMID- 29490960 TI - Heritability of glaucoma and glaucoma-related endophenotypes: systematic review and meta-analysis protocol. AB - INTRODUCTION: Glaucoma is the second leading cause of age-related vision loss worldwide; it is an umbrella term that is used to describe a set of complex ocular disorders with a multifactorial aetiology. Both genetic and lifestyle risk factors for glaucoma are well established. Thus far, however, systematic reviews on the heritability of glaucoma have focused on the heritability of primary open angle glaucoma only. No systematic review has comprehensively reviewed or meta analysed the heritability of other types of glaucoma, including glaucoma-related endophenotypes. The aim of this study will be to identify relevant scientific literature regarding the heritability of both glaucoma and related endophenotypes and summarise the evidence by performing a systematic review and meta-analysis. METHODS AND ANALYSIS: This systematic review will follow the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols 2015 checklist, which provides a standardised approach for carrying out systematic reviews. To capture as much literature as possible, a comprehensive step-by-step systematic search will be undertaken in MEDLINE (PubMed), EMBASE, Web of Science and ScienceDirect, and studies published until 31 December 2017 will be included. Two reviewers will independently search the articles for eligibility according to predefined selection criteria. A database will be used for screening of eligible articles. The quality of the included studies will be rated independently by two reviewers, using the National Health Institute Quality Assessment tool for Observational Cohort and Cross-Sectional Studies. A random-effects model will be used for the meta-analysis. This systematic review is registered with the International Prospective Register of Systematic Reviews with a registration number: CRD42017064504. ETHICS AND DISSEMINATION: We will use secondary data from peer reviewed published articles, and hence there is no requirement for ethics approval. The results of this systematic review will be disseminated through publication in a peer-reviewed scientific journal. PMID- 29490961 TI - Extent and cost of inappropriate use of tumour markers in patients with pulmonary disease: a multicentre retrospective study in Shanghai, China. AB - OBJECTIVES: The currently implemented healthcare reform in China requires substantial capital investment. Although overtreatment results in serious waste, inappropriate laboratory use is widespread, and overuse of tumour markers (TMs) has attracted increasing attention. DESIGN: Retrospective study. SETTING: The respiratory, thoracic surgery and oncology departments of three hospitals in Shanghai from 2014 to 2015. PARTICIPANTS: Patients with chronic obstructive pulmonary disease (COPD) and primary bronchogenic lung cancer (PLC). Based on clinical guidelines and physician experience, the criteria of suitability of TM examinations were determined, and the number, cost and proportion of inappropriate TM requests were analysed. RESULTS: The area under the receiver operating characteristic curve for carcinoembryonic antigen+cytokeratin fragment 21-1+squamous cell carcinoma antigen+neuron-specific enolase in patients with COPD and PLC was 0.813, in accordance with the cost-effectiveness principle, indicating good clinical and health economics values. In the 2706 patients, 12 496-16 956 (58.27%-79.06%) of TM requests were inappropriate. Furthermore, the involved expense was 650 200-1 014 156 yuan, accounting for 7.69%-12.00% of examination expenses and 1.35%-2.11% of hospitalisation costs. CONCLUSIONS: We found that the inappropriate use of TMs was widespread for patients with pulmonary disease. Clinicians should use TMs strictly according to the guidelines to effectively manage laboratory resources and control costs. PMID- 29490962 TI - Associations between socioeconomic factors and proinflammatory cytokines in children, adolescents and young adults: a systematic review protocol. AB - INTRODUCTION: There is now substantial evidence of a social gradient in bone health. Social stressors, related to socioeconomic status, are suggested to produce an inflammatory response marked by increased levels of proinflammatory cytokines. Here we focus on the particular role in the years before the achievement of peak bone mass, encompassing childhood, adolescence and young adulthood. An examination of such associations will help explain how social factors such as occupation, level of education and income may affect later-life bone disorders. This paper presents the protocol for a systematic review of existing literature regarding associations between socioeconomic factors and proinflammatory cytokines in those aged 6-30 years. METHODS AND ANALYSIS: We will conduct a systematic search of PubMed, OVID and CINAHL databases to identify articles that examine associations between socioeconomic factors and levels of proinflammatory cytokines, known to influence bone health, during childhood, adolescence or young adulthood. The findings of this review have implications for the equitable development of peak bone mass regardless of socioeconomic factors. Two independent reviewers will determine the eligibility of studies according to predetermined criteria, and studies will be assessed for methodological quality using a published scoring system. Should statistical heterogeneity be non significant, we will conduct a meta-analysis; however, if heterogeneity prevent numerical syntheses, we will undertake a best-evidence analysis to determine whether socioeconomic differences exist in the levels of proinflammatory cytokines from childhood through to young adulthood. ETHICS AND DISSEMINATION: This study will be a systematic review of published data, and thus ethics approval is not required. In addition to peer-reviewed publication, these findings will be presented at professional conferences in national and international arenas. PMID- 29490963 TI - Exploiting science? A systematic analysis of complementary and alternative medicine clinic websites' marketing of stem cell therapies. AB - OBJECTIVE: To identify the frequency and qualitative characteristics of stem cell related marketing claims made on websites of clinics featuring common types of complementary and alternative medicine practitioners. The involvement of complementary and alternative medicine practitioners in the marketing of stem cell therapies and stem cell-related interventions is understudied. This research explores the extent to which they are involved and collaborate with medical professionals. This knowledge will help with identifying and evaluating potential policy responses to this growing market. DESIGN: Systematic website analysis. SETTING: Global. US and English-language bias due to methodology. MAIN OUTCOME MEASURES: Representations made on clinic websites in relation to practitioner types, stem cell therapies and their targets, stem cell-related interventions. Statements about stem cell therapies relating to evidence of inefficacy, limited evidence of efficacy, general procedural risks, risks specific to the mode of therapy, regulatory status, experimental or unproven nature of therapy. Use of hype language (eg, language that exaggerates potential benefits). RESULTS: 243 websites offered stem cell therapies. Many websites advertised stem cell transplantation from multiple sources, such as adipose-derived (112), bone marrow derived (100), blood-derived (28), umbilical cord-derived (26) and others. Plant stem cell-based treatments and products (20) were also advertised. Purposes for and targets of treatment included pain, physical injury, a wide range of diseases and illnesses, cosmetic concerns, non-cosmetic ageing, sexual enhancement and others. Medical doctors (130), chiropractors (53) and naturopaths (44) commonly work in the clinics we found to be offering stem cell therapies. Few clinic websites advertising stem cell therapies included important additional information, including statements about evidence of inefficacy (present on only 12.76% of websites), statements about limited evidence of efficacy (18.93%), statements of general risks (24.69%), statements of risks specific to the mode(s) of therapy (5.76%), statements as to the regulatory status of the therapies (30.86%) and statements that the therapy is experimental or unproven (33.33%). Hype language was noted (31.69%). CONCLUSIONS: Stem cell therapies and related interventions are marketed for a wide breadth of conditions and are being offered by complementary and alternative practitioners, often in conjunction with medical doctors. Consumer protection and truth-in-advertising regulation could play important roles in addressing misleading marketing practices in this area. PMID- 29490964 TI - Mediating effects of metabolic factors on the association between fruit or vegetable intake and cardiovascular disease: the Korean National Health and Nutrition Examination Survey. AB - OBJECTIVE: We assessed the mediating effects of metabolic components on the relationship between fruit or vegetable intake and cardiovascular disease (CVD). DESIGN: Cross-sectional study. SETTING: This study was conducted using data from the 2013-2015 Korean National Health and Nutrition Examination Survey, which is a national representative cross-sectional survey to assess health and nutritional status in the Korean population. METHOD AND ANALYSIS: A total of 9040 subjects (3555 males and 5485 females) aged >=25 years were included in the study. Physician-diagnosed CVD via self-report was used as the outcome. Fruit or vegetable intake was measured via a dish-based semiquantitative food frequency questionnaire and grouped into categories (<1 time/day, 1 time/day, 2 times/day and >=3 times/day). Systolic blood pressure (SBP), cholesterol and fasting glucose were considered metabolic mediators, and the bootstrap method was used to assess mediating effect. RESULTS: About 1.8% of adults aged 25-64 years had CVD. According to the result of 'process' macro, the confounder-adjusted risk for CVD decreased by 14% (OR=0.86, 95% CI 0.74 to 0.98) as fruit, but not vegetable, intake was increased by one unit per day. After additional adjustment for three metabolic factors simultaneously, the OR was attenuated to 0.89 (95% CI 0.77 to 1.03). This result indicates that the indirect effect of three metabolic factors accounted for 21.4% of the relationship between fruit intake and CVD. SBP was a more important metabolic mediator than the other factors. The indirect effect by metabolic factors accounted for 30.0% when body mass index was additionally controlled as a mediator, and SBP still had an independent effect compared with the other mediators. CONCLUSIONS: Our results indicate that controlling SBP may lessen the CVD risk, and a diet rich in fruits can regulate SBP which, in turn, reduces CVD risk. PMID- 29490965 TI - Danish Observational Study of Eldercare work and musculoskeletal disorderS (DOSES): a prospective study at 20 nursing homes in Denmark. AB - PURPOSE: Musculoskeletal disorders (MSDs), sickness absence and premature retirement are highly prevalent among eldercare workers. We conducted a prospective observational workplace study with the main purpose to investigate longitudinal associations between physical and psychosocial working conditions and occurrence of MSD and its consequences (pain-related interference with daily work activities and sickness absence) among Danish eldercare workers. PARTICIPANTS: At 20 Danish nursing homes, a total of 941 eldercare workers employed in day and evening shifts were invited to the study. Of those, 553 participated in the baseline measurements, and 441 completed the total period of 12 months follow-up. FINDINGS TO DATE: Data were collected from September 2013 to January 2016. Physical and psychosocial working conditions were assessed with multiple methods (observations, accelerometer measurements and work schedules), and multiple levels of information (nursing home, ward, resident and eldercare worker) were incorporated in the data collection. MSD and the consequences hereof were assessed monthly during a 1-year follow-up. Study participants and non participants were comparable on most of the 27 sociodemographic, health and working condition characteristics at baseline. The exceptions were higher neck shoulder pain intensity, less sickness absence, more exposure to negative behaviour from residents and a higher percentage of working day shifts and fewer evening shifts among participants compared with non-participants. FUTURE PLANS: The first publications will report on the associations of physical and psychosocial working conditions with occurrence of MSD and its consequences. In addition, the cohort gives the opportunity to investigate the importance of organisational, management and team factors for distribution of physical work demands and development of MSD among the workers. This will provide important knowledge for future workplace interventions to reduce MSD and sickness absence. PMID- 29490966 TI - Empathy, burn-out and the use of gut feeling: a cross-sectional survey of Danish general practitioners. AB - OBJECTIVE: Research has suggested that physicians' gut feelings are associated with parents' concerns for the well-being of their children. Gut feeling is particularly important in diagnosis of serious low-incidence diseases in primary care. Therefore, the aim of this study was to examine whether empathy, that is, the ability to understand what another person is experiencing, relates to general practitioners' (GPs) use of gut feelings. Since empathy is associated with burn out, we also examined whether the hypothesised influence of empathy on gut feeling use is dependent on level of burn-out. DESIGN: Cross-sectional questionnaire survey. Participants completed the Jefferson Scale of Physician Empathy and The Maslach Burnout Inventory. SETTING: Primary care. PARTICIPANTS: 588 active GPs in Central Denmark Region (response rate=70%). PRIMARY OUTCOME MEASURES: Self-reported use of gut feelings in clinical practice. RESULTS: GPs who scored in the highest quartile of the empathy scale had fourfold the odds of increased use of gut feelings compared with GPs in the lowest empathy quartile (OR 3.99, 95% CI 2.51 to 6.34) when adjusting for the influence of possible confounders. Burn-out was not statistically significantly associated with use of gut feelings (OR 1.29, 95% CI 0.90 to 1.83), and no significant interaction effects between empathy and burn-out were revealed. CONCLUSIONS: Physician empathy, but not burn-out, was strongly associated with use of gut feelings in primary care. As preliminary results suggest that gut feelings have diagnostic value, these findings highlight the importance of incorporating empathy and interpersonal skills into medical training to increase sensitivity to patient concern and thereby increase the use and reliability of gut feeling. PMID- 29490967 TI - Effectiveness of postdischarge interventions for reducing the severity of chronic pain after total knee replacement: systematic review of randomised controlled trials. AB - OBJECTIVE: Approximately 20% of patients experience chronic pain after total knee replacement (TKR). The aim of this systematic review was to evaluate the effectiveness of postdischarge interventions commenced in the first 3 months after surgery in reducing the severity of chronic pain after TKR. DESIGN: The protocol for this systematic review was registered on PROSPERO (registration number: CRD42017041382). MEDLINE, Embase, CINAHL, PsycINFO and The Cochrane Library were searched from inception to November 2016. Randomised controlled trials of postdischarge intervention which commenced in the first 3 months after TKR surgery were included. The primary outcome of the review was self-reported pain severity at 12 months or longer after TKR. Risk of bias was assessed using the Cochrane risk-of-bias tool. RESULTS: Seventeen trials with data from 2485 randomised participants were included. The majority of trials evaluated physiotherapy interventions (n=13); other interventions included nurse-led interventions (n=2), neuromuscular electrical stimulation (n=1) and a multidisciplinary intervention (n=1). Opportunities for meta-analysis were limited by heterogeneity. No study found a difference in long-term pain severity between trial arms, with the exception of one trial which found home-based functional exercises aimed at managing kinesiophobia resulted in lower pain severity scores at 12 months postoperatively compared with advice to stay active. CONCLUSION: This systematic review and narrative synthesis found no evidence that one type of physiotherapy intervention is more effective than another at reducing the severity of chronic pain after TKR. Further research is needed to evaluate non-physiotherapy interventions, including the provision of care as part of a stratified and multidisciplinary care package. PROSPERO REGISTRATION NUMBER: CRD42017041382. PMID- 29490968 TI - Spatial distribution of clinical computer systems in primary care in England in 2016 and implications for primary care electronic medical record databases: a cross-sectional population study. AB - OBJECTIVES: UK primary care databases (PCDs) are used by researchers worldwide to inform clinical practice. These databases have been primarily tied to single clinical computer systems, but little is known about the adoption of these systems by primary care practices or their geographical representativeness. We explore the spatial distribution of clinical computing systems and discuss the implications for the longevity and regional representativeness of these resources. DESIGN: Cross-sectional study. SETTING: English primary care clinical computer systems. PARTICIPANTS: 7526 general practices in August 2016. METHODS: Spatial mapping of family practices in England in 2016 by clinical computer system at two geographical levels, the lower Clinical Commissioning Group (CCG, 209 units) and the higher National Health Service regions (14 units). Data for practices included numbers of doctors, nurses and patients, and area deprivation. RESULTS: Of 7526 practices, Egton Medical Information Systems (EMIS) was used in 4199 (56%), SystmOne in 2552 (34%) and Vision in 636 (9%). Great regional variability was observed for all systems, with EMIS having a stronger presence in the West of England, London and the South; SystmOne in the East and some regions in the South; and Vision in London, the South, Greater Manchester and Birmingham. CONCLUSIONS: PCDs based on single clinical computer systems are geographically clustered in England. For example, Clinical Practice Research Datalink and The Health Improvement Network, the most popular primary care databases in terms of research outputs, are based on the Vision clinical computer system, used by <10% of practices and heavily concentrated in three major conurbations and the South. Researchers need to be aware of the analytical challenges posed by clustering, and barriers to accessing alternative PCDs need to be removed. PMID- 29490969 TI - Children's toothache is becoming everybody's business: where do parents go when their children have oral pain in London, England? A cross-sectional analysis. AB - OBJECTIVES: To assess the number of parents who visited community pharmacies in London seeking pain medications for their children's pain and specifically for oral pain, to identify which health services parents contacted before their pharmacy visit and to estimate the cost to the National Health Service (NHS) when children with oral pain who visit pharmacies also see health professionals outside dentistry. DESIGN: A cross-sectional study. SETTING: 1862 pharmacies in London in November 2016-January 2017. PARTICIPANTS: Parents, carers and adolescents purchasing over-the-counter pain medications or collecting pain prescriptions for children (0-19 years). BRIEF INTERVENTION: A survey administered by pharmacy staff to participants and a guidance pack. MAIN OUTCOME MEASURES: The number of parents who visited pharmacies seeking pain medications for their children's pain and oral pain and the number of parents who contacted health professionals outside dentistry before their pharmacy visit. Estimated costs of visits by children with oral pain to health professionals outside dentistry. RESULTS: One in two (951) pharmacies participated collecting information from 6915 parents seeking pain medications for their children. The majority (65%) of parents sought pain medications to relieve their children's oral pain. Only 30% of children with oral pain had seen a dentist before the pharmacy visit, while 28% of children had seen between one and four different health professionals. The cost to the NHS of children contacting health professionals outside dentistry was L36 573, extrapolated to an annual cost of L373 288. Replicating these findings across all pharmacies in England could mean that the NHS spends an estimated L2.3 million annually when children with oral pain inappropriately use multiple health services. CONCLUSION: Most parents who visited pharmacies for children's pain medications in London sought pain medications for children's oral pain. Children's inappropriate contact with multiple health services when they have oral pain adds significant costs to the NHS. PMID- 29490971 TI - Sex Differences in the Association Between Measures of General and Central Adiposity and the Risk of Myocardial Infarction: Results From the UK Biobank. AB - BACKGROUND: There are substantial differences in the distribution of adipose tissue between women and men. We assessed the sex-specific relationships and their differences between measures of general and central adiposity and the risk of incident myocardial infarction (MI). METHODS AND RESULTS: Between 2006 and 2010, the UK Biobank recruited over 500 000 participants aged 40 to 69 years across the United Kingdom. During 7 years of follow-up, 5710 cases of MI (28% women) were recorded among 265 988 women and 213 622 men without a history of cardiovascular disease at baseline. Cox regression models yielded adjusted hazard ratios for MI associated with body mass index, waist circumference, waist-to-hip ratio, and waist-to-height ratio. There was an approximate log-linear relationship between measures of general and central adiposity and the risk of MI in both sexes. A 1-SD higher in body mass index, waist circumference, waist-to hip ratio, and waist-to-height ratio, respectively, were associated with hazard ratios (confidence intervals) for MI of 1.22 (1.17; 1.28), 1.35 (1.28; 1.42), 1.49 (1.39; 1.59), and 1.34 (1.27; 1.40) in women and of 1.28 (1.23; 1.32), 1.28 (1.23; 1.33), 1.36 (1.30; 1.43), and 1.33 (1.28; 1.38) in men. The corresponding women-to-men ratios of hazard ratios were 0.96 (0.91; 1.02), 1.07 (1.00; 1.14), 1.15 (1.06; 1.24), and 1.03 (0.97; 1.09). CONCLUSIONS: Although general and central adiposity measures each have profound deleterious effects on the risk of MI in both sexes, a higher waist circumference and waist-to-hip ratio conferred a greater excess risk of MI in women than in men. Waist-to-hip ratio was more strongly associated with the risk of MI than body mass index in both sexes, especially in women. PMID- 29490970 TI - Identifying primary care patient safety research priorities in the UK: a James Lind Alliance Priority Setting Partnership. AB - OBJECTIVES: To identify the top 10 unanswered research questions for primary care patient safety research. DESIGN: A modified nominal group technique. SETTING: UK. PARTICIPANTS: Anyone with experience of primary care including: patients, carers and healthcare professionals. 341 patients and 86 healthcare professionals submitted questions. MAIN OUTCOMES: A top 10, and top 30, future research questions for primary care patient safety. RESULTS: 443 research questions were submitted by 341 patients and 86 healthcare professionals, through a national survey. After checking for relevance and rephrasing, a total of 173 questions were collated into themes. The themes were largely focused on communication, team and system working, interfaces across primary and secondary care, medication, self-management support and technology. The questions were then prioritised through a national survey, the top 30 questions were taken forward to the final prioritisation workshop. The top 10 research questions focused on the most vulnerable in society, holistic whole-person care, safer communication and coordination between care providers, work intensity, continuity of care, suicide risk, complex care at home and confidentiality. CONCLUSIONS: This study was the first national prioritisation exercise to identify patient and healthcare professional priorities for primary care patient safety research. The research priorities identified a range of important gaps in the existing evidence to inform everyday practice to address primary care patient safety. PMID- 29490972 TI - Left Ventricular Torsion Associated With Aortic Stiffness in Hypertension. AB - BACKGROUND: Left ventricular (LV) torsion plays a key role in cardiac efficiency. In hypertension, aortic stiffening augments cardiac afterload. However, little is known about the links between LV regional contraction and aortic stiffness. We, therefore, investigated these relationships and their contribution to LV diastolic function. METHODS AND RESULTS: The study included normotensive and hypertensive individuals with normal LV ejection. Apical, basal, and global LV rotation rate and LV global longitudinal strain were measured (2-dimensional speckle tracking echocardiography). Aortic stiffness was calculated from carotid femoral pulse wave velocity, and LV relaxation was calculated from early diastolic mitral annulus motion. The ratio of basal or apical untwist/twist rates was calculated to assess relationships between aortic stiffness and LV torsion parameters. LV twist and untwist rates were greater in hypertensive than normotensive individuals because of increased basal twist (P<0.001) and untwist (P<0.001) rates. LV relaxation was reduced (early diastolic mitral annulus motion=7.4+/-1.9 versus 10.4+/-2.3 cm/s; P<0.001). In the whole population, basal untwist rate increased with aortic stiffening (R=0.43; P<0.001) and LV relaxation (R=0.41; P=0.001). The ratio of basal untwist/twist rate was positively correlated with carotid-femoral pulse wave velocity, and in the hypertensive group, was greater than in the control group and positively correlated to carotid femoral pulse wave velocity(P<0.001). Results were independent of age, treatment, mean blood pressure, and indexed LV mass. CONCLUSIONS: In hypertensive individuals, greater basal LV torsion was associated with increased aortic stiffness and improved diastolic function. These changes may compensate for the deleterious effects of aortic stiffening on LV relaxation. PMID- 29490973 TI - Risk Factors for Major Early Adverse Events Related to Cardiac Catheterization in Children and Young Adults With Pulmonary Hypertension: An Analysis of Data From the IMPACT (Improving Adult and Congenital Treatment) Registry. AB - BACKGROUND: Cardiac catheterization is the gold standard for assessment and follow-up of patients with pulmonary hypertension (PH). To date, there are limited data about the factors that influence the risk of catastrophic adverse events after catheterization in this population. METHODS AND RESULTS: A retrospective multicenter cohort study was performed to measure risk of catastrophic adverse outcomes after catheterization in children and young adults with PH and identify risk factors for these outcomes. All catheterizations in children and young adults, aged 0 to 21 years, with PH at hospitals submitting data to the IMPACT (Improving Adult and Congenital Treatment) registry between January 1, 2011, and December 31, 2015, were studied. Using mixed-effects multivariable regression, we assessed the association between prespecified subject-, procedure-, and center-level covariates and the risk of death, cardiac arrest, or mechanical circulatory support during or after cardiac catheterization. A total of 8111 procedures performed in 7729 subjects at 77 centers were studied. The observed risk of the composite outcome was 1.4%, and the risk of death before discharge was 5.2%. Catheterization in prematurely born neonates and nonpremature infants was associated with increased risk of catastrophic adverse event, as was precatheterization treatment with inotropes and lower systemic arterial saturation. Secondary analyses demonstrated the following: (1) increasing volumes of catheterization in patients with PH were associated with reduced risk of composite outcome (odds ratio, 0.8 per 10 procedures; P=0.002) and (2) increasing pulmonary vascular resistance and pulmonary artery pressures were associated with increased risk (P<0.0001 for both). CONCLUSIONS: Young patients with PH are a high-risk population for diagnostic and interventional cardiac catheterization. Hospital experience with PH is associated with reduced risk, independent of total catheterization case volume. PMID- 29490974 TI - Pediatric and Adolescent Pulmonary Hypertension: What Is the Risk of Undergoing Invasive Hemodynamic Testing? PMID- 29490975 TI - Performance on the Nephrology In-Training Examination and ABIM Nephrology Certification Examination Outcomes. AB - BACKGROUND AND OBJECTIVES: Medical specialty and subspecialty fellowship programs administer subject-specific in-training examinations to provide feedback about level of medical knowledge to fellows preparing for subsequent board certification. This study evaluated the association between the American Society of Nephrology In-Training Examination and the American Board of Internal Medicine Nephrology Certification Examination in terms of scores and passing status. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The study included 1684 nephrology fellows who completed the American Society of Nephrology In-Training Examination in their second year of fellowship training between 2009 and 2014. Regression analysis examined the association between In-Training Examination and first-time Nephrology Certification Examination scores as well as passing status relative to other standardized assessments. RESULTS: This cohort included primarily men (62%) and international medical school graduates (62%), and fellows had an average age of 32 years old at the time of first completing the Nephrology Certification Examination. An overwhelming majority (89%) passed the Nephrology Certification on their first attempt. In-Training Examination scores showed the strongest association with first-time Nephrology Certification Examination scores, accounting for approximately 50% of the total explained variance in the model. Each SD increase in In-Training Examination scores was associated with a difference of 30 U (95% confidence interval, 27 to 33) in certification performance. In-Training Examination scores also were significantly associated with passing status on the Nephrology Certification Examination on the first attempt (odds ratio, 3.46 per SD difference in the In-Training Examination; 95% confidence interval, 2.68 to 4.54). An In-Training Examination threshold of 375, approximately 1 SD below the mean, yielded a positive predictive value of 0.92 and a negative predictive value of 0.50. CONCLUSIONS: American Society of Nephrology In-Training Examination performance is significantly associated with American Board of Internal Medicine Nephrology Certification Examination score and passing status. PMID- 29490976 TI - Proximal Tubular Secretory Clearance: A Neglected Partner of Kidney Function. AB - The secretion of small molecules by the proximal tubules of the kidneys represents a vital homeostatic function for rapidly clearing endogenous solutes and medications from the circulation. After filtration at the glomerulus, renal blood flow is directed through a network of peritubular capillaries, where transporters of the proximal tubules actively secrete putative uremic toxins and hundreds of commonly prescribed drugs into the urine, including protein-bound substances that cannot readily cross the glomerular basement membrane. Despite its central physiologic importance, tubular secretory clearance is rarely measured or even estimated in clinical or research settings. Major barriers to estimating tubular solute clearance include uncertainty regarding optimal endogenous secretory markers and a lack of standardized laboratory assays. The creation of new methods to measure tubular secretion could catalyze advances in kidney disease research and clinical care. Differences in secretory clearance relative to the GFR could help distinguish among the causes of CKD, particularly for disorders that primarily affect the tubulointerstitium. As the primary mechanism by which the kidneys excrete medications, tubular secretory clearance offers promise for improving kidney medication dosing, which is currently exclusively on the basis of filtration. The differing metabolic profiles of retained solutes eliminated by secretion versus glomerular filtration suggest that secretory clearance could uniquely inform uremic toxicity, refine existing measures of residual kidney function, and improve prediction of cardiovascular and kidney disease outcomes. Interdisciplinary research across clinical, translational, and laboratory medicine is needed to bring this often neglected kidney function into the limelight. PMID- 29490977 TI - CDA as a predictive marker for life-threatening toxicities in patients with AML treated with cytarabine. AB - Cytarabine (Ara-C) is the backbone of acute myeloid leukemia (AML) chemotherapy. Little is known about possible risk factors predictive for the frequent (ie, up to 16%) life-threatening or lethal toxicities caused by Ara-C. Ara-C is detoxified in the liver by a single enzyme, cytidine deaminase (CDA), coded by a gene known to be highly polymorphic. In this proof-of-concept study, we particularly investigated the role of the CDA poor metabolizer (PM) phenotype in Ara-C toxicities. CDA phenotyping (measurement of CDA residual activity in serum) and genotyping (search for the CDA*2 allelic variant) were performed in 58 adult patients with AML treated with the standard 7+3 (Ara-C + anthracyclines) protocol. Statistically significantly lower CDA activity was observed in patients experiencing severe/lethal toxicities as compared with patients who did not (1.5 +/- 0.7 U/mg vs 3.95 +/- 3.1 U/mg; Student t test P < .001). Subsequent receiver operating characteristic analysis identified a threshold in CDA activity (ie, 2 U/mg) associated with PM syndrome and increased risk of developing severe toxicities. Five percent of patients experienced lethal toxicities, all displaying CDA PM status (1.3 +/- 0.5 U/mg). In terms of efficacy, a trend toward higher response rates and longer progression-free survival and overall survival were observed in patients with low CDA activity. Taken together, the results of this study strongly suggest that CDA is a predictive marker of life-threatening toxicities in patients with AML receiving induction therapy with standard Ara-C. PMID- 29490979 TI - Coffee consumption and gout: a Mendelian randomisation study. PMID- 29490978 TI - Platelet TGF-beta1 deficiency decreases liver fibrosis in a mouse model of liver injury. AB - Transforming growth factor-beta1 (TGF-beta1) signaling in hepatic stellate cells (HSCs) plays a primary role in liver fibrosis, but the source of TGF-beta1 is unclear. Because platelets are rich in TGF-beta1, we examined the role of platelet TGF-beta1 in liver fibrosis by challenging wild-type (WT) mice and mice deficient in platelet TGF-beta1 (PF4CreTgfb1f/f) with carbon tetrachloride (CCl4), an inducer of acute hepatic injury and chronic fibrosis. CCl4 elicited equivalent hepatic injury in WT and PF4CreTgfb1f/f mice based on loss of cytochrome P450 (Cyp2e1) expression, observed at 6 hours and peaking at 3 days after CCl4 challenge; PF4CreTgfb1f/f mice exhibited less liver fibrosis than control mice. Activated platelets were observed during acute liver injury (6 hours), and WT mice with transient platelet depletion (thrombocytopenia) were partially protected from developing fibrosis compared with control mice (P = .01), suggesting an association between platelet activation and fibrosis. Transient increases in TGF-beta1 levels and Smad2 phosphorylation signaling were observed 6 hours and 3 days, respectively, after CCl4 challenge in WT, but not PF4CreTgfb1f/f , mice, suggesting that increased TGF-beta1 levels originated from platelet-released TGF-beta1 during the initial injury. Numbers of collagen producing HSCs and myofibroblasts were higher at 3 days and 36 days, respectively, in WT vs PF4CreTgfb1f/f mice, suggesting that platelet TGF-beta1 may have stimulated HSC transdifferentiation into myofibroblasts. Thus, platelet TGF-beta1 partially contributes to liver fibrosis, most likely by initiating profibrotic signaling in HSCs and collagen synthesis. Further studies are required to evaluate whether blocking platelet and TGF-beta1 activation during acute liver injury prevents liver fibrosis. PMID- 29490980 TI - Are MRI-detected erosions specific for RA? A large explorative cross-sectional study. AB - OBJECTIVES: MRI is recommended in the diagnostic process of rheumatoid arthritis (RA) to detect joint damage early. MRI-detected erosions are also present in symptom-free controls, especially at older age. It is unclear if RA-specific MRI detected erosions can be distinguished from 'physiological' erosions in symptom free individuals. This study compared MRI-detected erosions of patients with RA with healthy controls and with other arthritides. METHODS: 589 newly presenting patients with early arthritis (238 RA, 351 other arthritides) and 193 symptom free controls underwent contrast-enhanced 1.5T MRI of unilateral metacarpophalangeal and metatarsophalangeal (MTP) joints. Total erosion score (according to the Rheumatoid Arthritis MRI Scoring System), number, severity, location of erosions and simultaneous presence of MRI-detected inflammation (synovitis and/or bone marrow oedema) were compared; participants were categorised in three age groups (<40, 40-59, >=60). RESULTS: Patients with RA had statistically significant higher total erosion scores than controls but scores of individual persons largely overlapped. Grade >=2 erosions and MTP5 erosions were specific for RA (specificity 98%-100% and 90%-98% for different age groups). MTP1 erosions were only specific if aged <40 (specificity 98%) and erosions with inflammation if aged <60 (specificity 91%-100%). >=1 of the mentioned erosion characteristics were present in 29% of patients with RA. Comparing patients with RA with other arthritides revealed that grade >=2 erosions and MTP5 erosions remained specific for RA (specificity >=89%) as well as MTP1 erosions if aged <40 (specificity 93%), in contrast to erosions combined with inflammation (specificity 49%-85%). CONCLUSIONS: Total erosion scores of individual persons were largely overlapping. Erosion characteristics specific for RA were identified, but were infrequently present. Caution is needed not to overestimate the value of MRI erosions in the diagnostic process. PMID- 29490981 TI - Adalimumab for childhood onset uveitis. PMID- 29490982 TI - Regulatory integration of Hox factor activity with T-box factors in limb development. AB - In tetrapods, Tbx4, Tbx5 and Hox cluster genes are crucial for forelimb and hindlimb development and mutations in these genes are responsible for congenital limb defects. The molecular basis of their integrated mechanisms of action in the context of limb development remains poorly understood. We studied Tbx4 and Hoxc10 owing to their overlapping loss-of-function phenotypes and colocalized expression in mouse hindlimb buds. We report an extensive overlap between Tbx4 and Hoxc10 genome occupancy and their putative target genes. Tbx4 and Hoxc10 interact directly with each other, have the ability to bind to a previously unrecognized T box-Hox composite DNA motif and show synergistic activity when acting on reporter genes. Pitx1, the master regulator for hindlimb specification, also shows extensive genomic colocalization with Tbx4 and Hoxc10. Genome occupancy by Tbx4 in hindlimb buds is similar to Tbx5 occupancy in forelimbs. By contrast, another Hox factor, Hoxd13, also interacts with Tbx4/Tbx5 but antagonizes Tbx4/Tbx5 dependent transcriptional activity. Collectively, the modulation of Tbx-dependent activity by Hox factors acting on common DNA targets may integrate different developmental processes for the balanced formation of proportionate limbs. PMID- 29490983 TI - The histone acetyltransferase inhibitor Nir regulates epidermis development. AB - In addition to its function as an inhibitor of histone acetyltransferases, Nir (Noc2l) binds to p53 and TAp63 to regulate their activity. Here, we show that epidermis-specific ablation of Nir impairs epidermal stratification and barrier function, resulting in perinatal lethality. Nir-deficient epidermis lacks appendages and remains single layered during embryogenesis. Cell proliferation is inhibited, whereas apoptosis and p53 acetylation are increased, indicating that Nir is controlling cell proliferation by limiting p53 acetylation. Transcriptome analysis revealed that Nir regulates the expression of essential factors in epidermis development, such as keratins, integrins and laminins. Furthermore, Nir binds to and controls the expression of p63 and limits H3K18ac at the p63 promoter. Corroborating the stratification defects, asymmetric cell divisions were virtually absent in Nir-deficient mice, suggesting that Nir is required for correct mitotic spindle orientation. In summary, our data define Nir as a key regulator of skin development. PMID- 29490984 TI - The heart tube forms and elongates through dynamic cell rearrangement coordinated with foregut extension. AB - In the initiation of cardiogenesis, the heart primordia transform from bilateral flat sheets of mesoderm into an elongated midline tube. Here, we discover that this rapid architectural change is driven by actomyosin-based oriented cell rearrangement and resulting dynamic tissue reshaping (convergent extension, CE). By labeling clusters of cells spanning the entire heart primordia, we show that the heart primordia converge toward the midline to form a narrow tube, while extending perpendicularly to rapidly lengthen it. Our data for the first time visualize the process of early heart tube formation from both the medial (second) and lateral (first) heart fields, revealing that both fields form the early heart tube by essentially the same mechanism. Additionally, the adjacent endoderm coordinately forms the foregut through previously unrecognized movements that parallel those of the heart mesoderm and elongates by CE. In conclusion, our data illustrate how initially two-dimensional flat primordia rapidly change their shapes and construct the three-dimensional morphology of emerging organs in coordination with neighboring morphogenesis. PMID- 29490986 TI - Molecular Alterations and Buparlisib Efficacy in Patients with Squamous Cell Carcinoma of the Head and Neck: Biomarker Analysis from BERIL-1. AB - Purpose: The preplanned exploratory analysis of the BERIL-1 trial presented here aimed to identify biomarkers of response to the combination of buparlisib and paclitaxel.Patients and Methods: BERIL-1 was a multicenter, randomized, double blind, placebo-controlled phase II study. Patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) progressing on/after one previous platinum-based chemotherapy regimen in the recurrent or metastatic setting were treated with either buparlisib plus paclitaxel or placebo plus paclitaxel. Archival tumor tissue and ctDNA samples were analyzed for molecular alterations and immune infiltration using next-generation sequencing or immunohistochemistry.Results: Biomarker analyses were performed in randomized patients (n = 158) with available biomarker data. The most frequently (>5%) mutated genes were TP53, FAT1, TET2, KMT2D, PIK3CA, NOTCH1, NFE2L2, NOTCH2, CCND1, and CDKN2A Patients with SCCHN tumors (from various primary sites) having HPV-negative status (HR = 0.51), TP53 alterations (HR = 0.55) or low mutational load (HR = 0.57) derived overall survival (OS) benefit with the combination of buparlisib and paclitaxel. OS benefit with this combination was also increased in patients with presence of intratumoral TILs >=10% (HR = 0.51), stromal TILs >=15% (HR = 0.53), intratumoral CD8-positive cells >=5% (HR = 0.45), stromal CD8 positive cells >=10% (HR = 0.47), or CD8-positive cells in invasive margins >25% (HR = 0.37). A trend for improved progression-free survival with the combination of buparlisib and paclitaxel was also observed in these patients.Conclusions: The BERIL-1 biomarker analyses showed that patients with TP53 alterations, HPV negative status, low mutational load, or high infiltration of TILs or CD8 positive cells derived survival benefit with the combination of buparlisib and paclitaxel. Clin Cancer Res; 24(11); 2505-16. (c)2018 AACR. PMID- 29490985 TI - PER2 regulation of mammary gland development. AB - The molecular clock plays key roles in daily physiological functions, development and cancer. Period 2 (PER2) is a repressive element, which inhibits transcription activated by positive clock elements, resulting in diurnal cycling of genes. However, there are gaps in our understanding of the role of the clock in normal development outside of its time-keeping function. Here, we show that PER2 has a noncircadian function that is crucial to mammalian mammary gland development. Virgin Per2-deficient mice, Per2-/- , have underdeveloped glands, containing fewer bifurcations and terminal ducts than glands of wild-type mice. Using a transplantation model, we show that these changes are intrinsic to the gland and further identify changes in cell fate commitment. Per2-/- mouse mammary glands have a dual luminal/basal phenotypic character in cells of the ductal epithelium. We identified colocalization of E-cadherin and keratin 14 in luminal cells. Similar results were demonstrated using MCF10A and shPER2 MCF10A human cell lines. Collectively this study reveals a crucial noncircadian function of PER2 in mammalian mammary gland development, validates the Per2-/- model, and describes a potential role for PER2 in breast cancer. PMID- 29490987 TI - Discovery and Validation of Circulating Biomarkers of Colorectal Adenoma by High Depth Small RNA Sequencing. AB - Purpose: Colorectal cancer is the third most common cancer worldwide, causing approximately 700,000 deaths each year. The majority of colorectal cancers begin as adenomas. Definitive screening for colorectal adenomas is currently accomplished through colonoscopy but, owing largely to costs and invasiveness, is typically limited to patient groups at higher risk by virtue of age or family history. We sought to determine if blood-based small RNA markers could detect colorectal adenoma.Experimental Design: We applied high-depth small RNA sequencing to plasma from a large (n = 189) cohort of patients, balanced for age, sex, and ancestry. Our analytical methodology allowed for the detection of both microRNAs and other small RNA species. We replicated sequencing results by qPCR on plasma samples from an independent cohort (n = 140).Results: We found several small RNA species with significant associations to colorectal adenoma, including both microRNAs and non-microRNA small RNAs. These associations were robust to correction for patient covariates, including age. Among the adenoma-associated small RNAs, two, a miR-335-5p isoform and an un-annotated small RNA, were validated by qPCR in an independent cohort. A classifier trained on measures of these two RNAs in the discovery cohort yields an AUC of 0.755 (0.775 with age) for adenoma detection in the independent cohort. This classifier accurately detects adenomas in patients under 50 and is robust to sex or ancestry.Conclusions: Circulating small RNAs (including but not limited to miRNAs) discovered by sequencing and validated by qPCR identify patients with colorectal adenomas effectively. Clin Cancer Res; 24(9); 2092-9. (c)2018 AACR. PMID- 29490988 TI - Leveraging the Success of HIV Drug Development Paradigms for Cancer. PMID- 29490989 TI - A Genetic Polymorphism in CTLA-4 Is Associated with Overall Survival in Sunitinib Treated Patients with Clear Cell Metastatic Renal Cell Carcinoma. AB - Purpose: The survival of patients with clear cell metastatic renal cell carcinoma (cc-mRCC) has improved substantially since the introduction of tyrosine kinase inhibitors (TKI). With the fact that TKIs interact with immune responses, we investigated whether polymorphisms of genes involved in immune checkpoints are related to the clinical outcome of cc-mRCC patients treated with sunitinib as first TKI.Experimental Design: Twenty-seven single-nucleotide polymorphisms (SNP) in CD274 (PD-L1), PDCD1 (PD-1), and CTLA-4 were tested for a possible association with progression-free survival (PFS) and overall survival (OS) in a discovery cohort of 550 sunitinib-treated cc-mRCC patients. SNPs with a significant association (P < 0.05) were tested in an independent validation cohort of 138 sunitinib-treated cc-mRCC patients. Finally, data of the discovery and validation cohort were pooled for meta-analysis.Results:CTLA-4 rs231775 and CD274 rs7866740 showed significant associations with OS in the discovery cohort after correction for age, gender, and Heng prognostic risk group [HR, 0.84; 95% confidence interval (CI), 0.72-0.98; P = 0.028, and HR, 0.73; 95% CI, 0.54-0.99; P = 0.047, respectively]. In the validation cohort, the associations of both SNPs with OS did not meet the significance threshold of P < 0.05. After meta-analysis, CTLA-4 rs231775 showed a significant association with OS (HR, 0.83; 95% CI, 0.72-0.95; P = 0.008). Patients with the GG genotype had longer OS (35.1 months) compared with patients with an AG (30.3 months) or AA genotype (24.3 months). No significant associations with PFS were found.Conclusions: The G-allele of rs231775 in the CTLA-4 gene is associated with an improved OS in sunitinib-treated cc-mRCC patients and could potentially be used as a prognostic biomarker. Clin Cancer Res; 24(10); 2350-6. (c)2018 AACR. PMID- 29490991 TI - Targeting Tumor Vasculature with TNF Leads Effector T Cells to the Tumor and Enhances Therapeutic Efficacy of Immune Checkpoint Blockers in Combination with Adoptive Cell Therapy. AB - Purpose: Irregular blood flow and endothelial cell anergy, which characterize many solid tumors, hinder tumor infiltration by cytotoxic T lymphocytes (CTL). This confers resistance to cancer immunotherapy with monoclonal antibodies directed against regulatory pathways in T lymphocytes (i.e., immune checkpoint blockade, ICB). We investigated whether NGR-TNF, a TNF derivative capable of targeting the tumor vasculature, and improving intratumor infiltration by activated CTLs, could sensitize tumors to ICB with antibodies specific for the PD 1 and CTLA-4 receptors.Experimental Design: Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice with autochthonous prostate cancer and C57BL/6 mice with orthotopic B16 melanoma were treated with NGR-TNF, adoptive T-cell therapy (ACT), and ICB, and monitored for immune surveillance and disease progression.Results: The combination of ACT, NGR-TNF, and ICB was the most effective in delaying disease progression, and in improving overall survival of mice bearing ICB-resistant prostate cancer or melanoma. Mechanistically, the therapeutic effects were associated with potent tumor infiltration, especially by endogenous but also by adoptively transferred PD-1+, granzyme B+, and interferon gamma+ CTLs. The therapeutic effects were also associated with favorable T effector/regulatory T cell ratios.Conclusions: Targeting the tumor vasculature with low-dose TNF in association with ACT may represent a novel strategy for enhancing T-cell infiltration in tumors and overcoming resistance to immune checkpoint blockers. Clin Cancer Res; 24(9); 2171-81. (c)2018 AACR. PMID- 29490990 TI - Combinations of Bevacizumab and Erlotinib Show Activity in Colorectal Cancer Independent of RAS Status. AB - Purpose: There is extensive cross-talk between VEGF- and EGFR-pathway signaling in colorectal cancer. However, combinations of VEGF- and EGFR-targeted monoclonal antibodies (mAb) show disappointing activity, in particular for patients with mutant RAS Previous results show that tyrosine kinase inhibitors (TKI) can be active in colorectal cancer models resistant to mAbs. This prompted us to examine whether the activity of bevacizumab can be increased by combination with erlotinib.Experimental Design: The antitumor activity of bevacizumab, erlotinib, and their combination was determined in colorectal cancer models with different RAS status and bevacizumab sensitivity. EGFR/VEGF pathway activation was characterized by immunohistochemistry, Western blot, and ELISA assays. The influence of cetuximab and erlotinib on EGF-mediated migration and the EGFR-EGF ligand feedback loop was established in colorectal cancer cell lines with different RAS status.Results: The addition of erlotinib increased bevacizumab activity in all models independent of RAS status. Bevacizumab exposure was accompanied by marked EGFR activation in tumor cells as well as in tumor associated endothelial cells (TECs) and resulted in strong accumulation of intracellular EGFR, which could be attenuated by erlotinib. In cellular models, erlotinib was able to attenuate EGF-mediated functions in all cell lines independent of RAS status while cetuximab only showed activity in RAS wild-type cells.Conclusions: These results should provide a molecular framework to better understand the increased activity of the bevacizumab-erlotinib combination, compared with bevacizumab alone, in the GERCOR DREAM phase III clinical trial. Differential activity of mAbs and TKIs targeting the same signaling pathway is likely applicable for other tumor types. Clin Cancer Res; 24(11); 2548-58. (c)2018 AACR. PMID- 29490992 TI - Oral Anticoagulation in Very Elderly Patients With Atrial Fibrillation: A Nationwide Cohort Study. AB - BACKGROUND: Stroke prevention with oral anticoagulants (OACs) is the cornerstone for the management of atrial fibrillation (AF). However, data about the use of OACs among patients >=90 years of age are limited. We aimed to investigate the risk of ischemic stroke and intracranial hemorrhage (ICH) and the net clinical benefit of OAC treatment for very elderly patients with AF (>=90 years of age). METHODS: This study used the National Health Insurance Research Database in Taiwan. Risks of ischemic stroke and ICH were compared between 11 064 and 14 658 patients with and without AF >=90 years of age without antithrombotic therapy from 1996 to 2011. Patients with AF (n=15 756) were divided into 3 groups (no treatment, antiplatelet agents, and warfarin), and the risks of stroke and ICH were analyzed. The risks of ischemic stroke and ICH were further compared between patients treated with warfarin and nonvitamin K antagonist OACs (NOACs) from 2012 to 2015 when NOACs were available in Taiwan. RESULTS: Compared with patients without AF, patients with AF had an increased risk of ischemic stroke (event number/patient number, incidence = 742/11 064, 5.75%/y versus 1399/14 658, 3.00%/y; hazard ratio, 1.93; 95% confidence interval, 1.74-2.14) and similar risk of ICH (131/11 064, 0.97%/y versus 206/14 658, 0.54%/y; hazard ratio, 0.85; 95% confidence interval, 0.66-1.09) in competing risk analysis for mortality. Among patients with AF, warfarin use was associated with a lower stroke risk (39/617, 3.83%/y versus 742/11 064, 5.75%/y; hazard ratio, 0.69; 95% confidence interval, 0.49-0.96 in a competing risk model), with no difference in ICH risk compared with nontreatment. When compared with no antithrombotic therapy or antiplatelet drugs, warfarin was associated with a positive net clinical benefit. These findings persisted in propensity-matched analyses. Compared with warfarin, NOACs were associated with a lower risk of ICH (4/978, 0.42%/y versus 19/768, 1.63%/y; hazard ratio, 0.32; 95% confidence interval, 0.10-0.97 in a competing risk model), with no difference in risk of ischemic stroke. CONCLUSIONS: Among patients with AF >=90 years of age, warfarin was associated with a lower risk of ischemic stroke and positive net clinical benefit. Compared with warfarin, NOACs were associated with a lower risk of ICH. Thus, OACs may still be considered as thromboprophylaxis for elderly patients, with NOACs being the more favorable choice. PMID- 29490993 TI - Vascular Smooth Muscle-Specific Progerin Expression Accelerates Atherosclerosis and Death in a Mouse Model of Hutchinson-Gilford Progeria Syndrome. AB - BACKGROUND: Progerin, an aberrant protein that accumulates with age, causes the rare genetic disease Hutchinson-Gilford progeria syndrome (HGPS). Patients who have HGPS exhibit ubiquitous progerin expression, accelerated aging and atherosclerosis, and die in their early teens, mainly of myocardial infarction or stroke. The mechanisms underlying progerin-induced atherosclerosis remain unexplored, in part, because of the lack of appropriate animal models. METHODS: We generated an atherosclerosis-prone model of HGPS by crossing apolipoprotein E deficient (Apoe-/-) mice with LmnaG609G/G609G mice ubiquitously expressing progerin. To induce progerin expression specifically in macrophages or vascular smooth muscle cells (VSMCs), we crossed Apoe-/-LmnaLCS/LCS mice with LysMCre and SM22alphaCre mice, respectively. Progerin expression was evaluated by polymerase chain reaction and immunofluorescence. Cardiovascular alterations were determined by immunofluorescence and histology in male mice fed normal chow or a high-fat diet. In vivo low-density lipoprotein retention was assessed by intravenous injection of fluorescently labeled human low-density lipoprotein. Cardiac electric defects were evaluated by electrocardiography. RESULTS: Apoe-/ LmnaG609G/G609G mice with ubiquitous progerin expression exhibited a premature aging phenotype that included failure to thrive and shortened survival. In addition, high-fat diet-fed Apoe-/-LmnaG609G/G609G mice developed a severe vascular pathology, including medial VSMC loss and lipid retention, adventitial fibrosis, and accelerated atherosclerosis, thus resembling most aspects of cardiovascular disease observed in patients with HGPS. The same vascular alterations were also observed in Apoe-/-LmnaLCS/LCSSM22alphaCre mice expressing progerin specifically in VSMCs, but not in Apoe-/-LmnaLCS/LCSLysMCre mice with macrophage-specific progerin expression. Moreover, Apoe-/-LmnaLCS/LCSSM22alphaCre mice had a shortened lifespan despite the lack of any overt aging phenotype. Aortas of ubiquitously and VSMC-specific progerin-expressing mice exhibited increased retention of fluorescently labeled human low-density lipoprotein, and atheromata in both models showed vulnerable plaque features. Immunohistopathological examination indicated that Apoe-/-LmnaLCS/LCSSM22alphaCre mice, unlike Apoe-/-LmnaG609G/G609G mice, die of atherosclerosis-related causes. CONCLUSIONS: We have generated the first mouse model of progerin-induced atherosclerosis acceleration, and demonstrate that restricting progerin expression to VSMCs is sufficient to accelerate atherosclerosis, trigger plaque vulnerability, and reduce lifespan. Our results identify progerin-induced VSMC death as a major factor triggering atherosclerosis and premature death in HGPS. PMID- 29490995 TI - Discordant Calcium and Parathyroid Hormone with Presumed Epileptic Seizures. PMID- 29490994 TI - Long-Term Outcomes of Hypertrophic Cardiomyopathy Diagnosed During Childhood: Results From a National Population-Based Study. AB - BACKGROUND: Late survival and symptomatic status of children with hypertrophic cardiomyopathy have not been well defined. We examined long-term outcomes for pediatric hypertrophic cardiomyopathy. METHODS: The National Australian Childhood Cardiomyopathy Study is a longitudinal population-based cohort study of children (0-10 years of age) diagnosed with cardiomyopathy between 1987 and 1996. The primary study end point was time to death or cardiac transplantation. RESULTS: There were 80 patients with hypertrophic cardiomyopathy, with a median age at diagnosis of 0.48 (interquartile range, 0.1, 2.5) years. Freedom from death/transplantation was 86% (95% confidence interval [CI], 77.0-92.0) 1 year after presentation, 80% (95% CI, 69.0-87.0) at 10 years, and 78% (95% CI, 67.0 86.0) at 20 years. From multivariable analyses, risk factors for death/transplantation included symmetrical left ventricular hypertrophy at the time of diagnosis (hazard ratio, 4.20; 95% CI, 1.60-11.05; P=0.004), Noonan syndrome (hazard ratio, 2.88; 95% CI, 1.02-8.08; P=0.045), higher posterior wall thickness z score (hazard ratio, 1.45; 95% CI, 1.22-1.73; P<0.001), and lower fractional shortening z score (hazard ratio, 0.84; 95% CI, 0.74-0.95; P=0.005) during follow-up. Nineteen (23%) subjects underwent left ventricular myectomy. At a median of 15.7 years of follow-up, 27 (42%) of 63 survivors were treated with beta-blocker, and 13 (21%) had an implantable cardioverter-defibrillator. CONCLUSIONS: The highest risk of death or transplantation for children with hypertrophic cardiomyopathy is within 1 year after diagnosis, with low attrition rates thereafter. Many subjects receive medical, surgical, or device therapy. PMID- 29490996 TI - Commentary. PMID- 29490997 TI - Commentary. PMID- 29490999 TI - Counterpoint: The Potential Harms of Human Gene Editing Using CRISPR-Cas9. PMID- 29490998 TI - Point: Treating Human Genetic Disease One Base Pair at a Time: The Benefits of Gene Editing. PMID- 29491000 TI - 8-Month-Old Boy with Ataxia after Ingestion of Cow's Milk. PMID- 29491001 TI - Unexpected M-protein in an Anticoagulated Patient. PMID- 29491002 TI - Amino Acids: Riddles from A to Y. PMID- 29491003 TI - Oncoprotein CIP2A promotes the disassembly of primary cilia and inhibits glycolytic metabolism. AB - In most mammalian cells, the primary cilium is a microtubule-enriched protrusion of the plasma membrane and acts as a key coordinator of signaling pathways during development and tissue homeostasis. The primary cilium is generated from the basal body, and cancerous inhibitor of protein phosphatase 2A (CIP2A), the overexpression of which stabilizes c-MYC to support the malignant growth of tumor cells, is localized in the centrosome. Here, we show that CIP2A overexpression induces primary cilia disassembly through the activation of Aurora A kinase, and CIP2A depletion increases ciliated cells and cilia length in retinal pigment epithelium (RPE1) cells. CIP2A depletion also shifts metabolism toward the glycolytic pathway by altering the expression of metabolic genes related to glycolysis. However, glycolytic activation in CIP2A-depleted cells does not depend on cilia assembly, even though enhanced cilia assembly alone activates glycolytic metabolism. Collectively, these data suggest that CIP2A promotes primary cilia disassembly and that CIP2A depletion induces metabolic reprogramming independent of primary cilia. PMID- 29491005 TI - The genesis of a conspiracy theory: Why do people believe in scientific conspiracy theories and how do they spread? PMID- 29491004 TI - HP1 links centromeric heterochromatin to centromere cohesion in mammals. AB - Heterochromatin protein-1 (HP1) is a key component of heterochromatin. Reminiscent of the cohesin complex which mediates sister-chromatid cohesion, most HP1 proteins in mammalian cells are displaced from chromosome arms during mitotic entry, whereas a pool remains at the heterochromatic centromere region. The function of HP1 at mitotic centromeres remains largely elusive. Here, we show that double knockout (DKO) of HP1alpha and HP1gamma causes defective mitosis progression and weakened centromeric cohesion. While mutating the chromoshadow domain (CSD) prevents HP1alpha from protecting sister-chromatid cohesion, centromeric targeting of HP1alpha CSD alone is sufficient to rescue the cohesion defects in HP1 DKO cells. Interestingly, HP1-dependent cohesion protection requires Haspin, an antagonist of the cohesin-releasing factor Wapl. Moreover, HP1alpha CSD directly binds the N-terminal region of Haspin and facilitates its centromeric localization. The need for HP1 in cohesion protection can be bypassed by centromeric targeting of Haspin or inhibiting Wapl activity. Taken together, these results reveal a redundant role for HP1alpha and HP1gamma in the protection of centromeric cohesion through promoting Haspin localization at mitotic centromeres in mammalian cells. PMID- 29491007 TI - Fucosyltransferase Induction during Influenza Virus Infection Is Required for the Generation of Functional Memory CD4+ T Cells. AB - T cells mediating influenza viral control are instructed in lymphoid and nonlymphoid tissues to differentiate into memory T cells that confer protective immunity. The mechanisms by which influenza virus-specific memory CD4+ T cells arise have been attributed to changes in transcription factors, cytokines and cytokine receptors, and metabolic programming. The molecules involved in these biosynthetic pathways, including proteins and lipids, are modified to varying degrees of glycosylation, fucosylation, sialation, and sulfation, which can alter their function. It is currently unknown how the glycome enzymatic machinery regulates CD4+ T cell effector and memory differentiation. In a murine model of influenza virus infection, we found that fucosyltransferase enzymatic activity was induced in effector and memory CD4+ T cells. Using CD4+ T cells deficient in the Fut4/7 enzymes that are expressed only in hematopoietic cells, we found decreased frequencies of effector cells with reduced expression of T-bet and NKG2A/C/E in the lungs during primary infection. Furthermore, Fut4/7-/- effector CD4+ T cells had reduced survival with no difference in proliferation or capacity for effector function. Although Fut4/7-/- CD4+ T cells seeded the memory pool after primary infection, they failed to form tissue-resident cells, were dysfunctional, and were unable to re-expand after secondary infection. Our findings highlight an important regulatory axis mediated by cell-intrinsic fucosyltransferase activity in CD4+ T cell effectors that ensure the development of functional memory CD4+ T cells. PMID- 29491008 TI - Circulating Exosomes with Distinct Properties during Chronic Lung Allograft Rejection. AB - Circulating exosomes containing donor HLA and lung-associated self-antigens (SAg) are thought to play an important role in allograft rejection after human lung transplantation. We characterized exosomes isolated from serum of 10 lung transplant recipients (LTxR) diagnosed with bronchiolitis obliterans syndrome (BOS) and compared them with exosomes isolated from serum of 10 stable LTxR. Lung associated SAg (K-alpha-1-tubulin [Kalpha1T] and collagen V [Col-V]), MHC class II molecules, costimulatory molecules CD40, CD80, and CD86, and transcription factors class II MHC trans-activator, NF-kappaB, hypoxia-inducible factor 1 alpha, IL-1R-associated kinase 1, MyD88, and 20S proteasome were detected in exosomes from BOS, but not stable LTxR. In contrast, adhesion molecules were present in both groups. C57BL/6 mice immunized with exosomes from BOS but not stable LTxR demonstrated Ab to SAg (Col-V, 33.5 +/- 15.7 versus 10.4 +/- 6.4, p = 0.021; Kalpha1T, 925 +/- 403 versus 317 +/- 285, p = 0.044) and HLA (mean fluorescence intensity: BOS, 8450; stable, 632; p < 0.05). Furthermore, splenic lymphocytes demonstrated increased frequency of lung SAg-specific IL-17 (Col-V, 128 +/- 46 versus 31 +/- 21, p = 0.013; Kalpha1T, 194 +/- 47 versus 67 +/- 43, p = 0.014) and IFN-gamma (Col-V, 165 +/- 79 versus 38 +/- 40, p = 0.042; Kalpha1T, 232 +/- 64 versus 118 +/- 39, p = 0.012). Reduced levels of IL-10-producing cells were seen in BOS exosome immunized mice compared with mice immunized with stable exosomes (Col-V, 59 +/- 23 versus 211 +/- 85, p = 0.016; Kalpha1T, 78 +/- 49 versus 295 +/- 104, p = 0.017). Owing to the unique immune-stimulating properties of exosomes induced during rejection, we propose that they play an important role in eliciting both alloantigen- and SAg-specific immunity, leading to chronic rejection after lung transplantation. PMID- 29491006 TI - SIRT5 inhibits peroxisomal ACOX1 to prevent oxidative damage and is downregulated in liver cancer. AB - Peroxisomes account for ~35% of total H2O2 generation in mammalian tissues. Peroxisomal ACOX1 (acyl-CoA oxidase 1) is the first and rate-limiting enzyme in fatty acid beta-oxidation and a major producer of H2O2 ACOX1 dysfunction is linked to peroxisomal disorders and hepatocarcinogenesis. Here, we show that the deacetylase sirtuin 5 (SIRT5) is present in peroxisomes and that ACOX1 is a physiological substrate of SIRT5. Mechanistically, SIRT5-mediated desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation in both cultured cells and mouse livers. Deletion of SIRT5 increases H2O2 production and oxidative DNA damage, which can be alleviated by ACOX1 knockdown. We show that SIRT5 downregulation is associated with increased succinylation and activity of ACOX1 and oxidative DNA damage response in hepatocellular carcinoma (HCC). Our study reveals a novel role of SIRT5 in inhibiting peroxisome-induced oxidative stress, in liver protection, and in suppressing HCC development. PMID- 29491009 TI - IL-15 Promotes Polyfunctional NK Cell Responses to Influenza by Boosting IL-12 Production. AB - IL-15 is a key regulator of NK cell maintenance and proliferation and synergizes with other myeloid cell-derived cytokines to enhance NK cell effector function. At low concentrations, trans-presentation of IL-15 by dendritic cells can activate NK cells, whereas at higher concentrations it can act directly on NK cells, independently of accessory cells. In this study, we investigate the potential for IL-15 to boost responses to influenza virus by promoting accessory cell function. We find that coculture of human PBMCs with inactivated whole influenza virus (A/Victoria/361/2011) in the presence of very low concentrations of IL-15 results in increased production of myeloid cell-derived cytokines, including IL-12, IFN-alpha2, GM-CSF, and IL-1beta, and an increased frequency of polyfunctional NK cells (defined by the expression of two or more of CD107a, IFN gamma, and CD25). Neutralization experiments demonstrate that IL-15-mediated enhancement of NK cell responses is primarily dependent on IL-12 and partially dependent on IFN-alphabetaR1 signaling. Critically, IL-15 boosted the production of IL-12 in influenza-stimulated blood myeloid dendritic cells. IL-15 costimulation also restored the ability of less-differentiated NK cells from human CMV-seropositive individuals to respond to influenza virus. These data suggest that very low concentrations of IL-15 play an important role in boosting accessory cell function to support NK cell effector functions. PMID- 29491010 TI - Maternal and Early Postnatal Immune Activation Produce Dissociable Effects on Neurotransmission in mPFC-Amygdala Circuits. AB - Inflammatory processes may be involved in the pathophysiology of neuropsychiatric illnesses including autism spectrum disorder (ASD). Evidence from studies in rodents indicates that immune activation during early development can produce core features of ASD (social interaction deficits, dysregulation of communication, increases in stereotyped behaviors, and anxiety), although the neural mechanisms of these effects are not thoroughly understood. We treated timed-pregnant mice with polyinosinic:polycytidylic acid (Poly I:C), which simulates a viral infection, or vehicle on gestational day 12.5 to produce maternal immune activation (MIA). Male offspring received either vehicle or lipopolysaccharide, which simulates a bacterial infection, on postnatal day 9 to produce postnatal immune activation (PIA). We then used optogenetics to address the possibility that early developmental immune activation causes persistent alterations in the flow of signals within the mPFC to basolateral amygdala (BLA) pathway, a circuit implicated in ASD. We found that our MIA regimen produced increases in synaptic strength in glutamatergic projections from the mPFC to the BLA. In contrast, our PIA regimen produced decreases in feedforward GABAergic inhibitory postsynaptic responses resulting from activation of local circuit interneurons in the BLA by mPFC-originating fibers. Both effects were seen together when the regimens were combined. Changes in the balance between excitation and inhibition were differentially translated into the modified spike output of BLA neurons. Our findings raise the possibility that prenatal and postnatal immune activation may affect different cellular targets within brain circuits that regulate some of the core behavioral signs of conditions such as ASD.SIGNIFICANCE STATEMENT Immune system activation during prenatal and early postnatal development may contribute to the development of autism spectrum disorder (ASD). Combining optogenetic approaches and behavioral assays that reflect core features of ASD (anxiety, decreased social interactions), we uncovered mechanisms by which the ASD-associated behavioral impairments induced by immune activation could be mediated at the level of interactions within brain circuits implicated in control of emotion and motivation (mPFC and BLA, specifically). Here, we present evidence that prenatal and postnatal immune activation can have different cellular targets in the brain, providing support to the notion that the etiology of ASD may be linked to the excitation/inhibition imbalance in the brain affecting the signal flow within relevant behavior-driving neural microcircuits. PMID- 29491011 TI - Celecoxib Ameliorates Seizure Susceptibility in Autosomal Dominant Lateral Temporal Epilepsy. AB - Autosomal dominant lateral temporal epilepsy (ADLTE) is an inherited syndrome caused by mutations in the leucine-rich glioma inactivated 1 (LGI1) gene. It is known that glutamatergic transmission is altered in LGI1 mutant mice, and seizures can be reduced by restoring LGI1 function. Yet, the mechanism underlying ADLTE is unclear. Here, we propose that seizures in male LGI1-/- mice are due to nonsynaptic epileptiform activity in cortical neurons. We examined the intrinsic excitability of pyramidal neurons in the temporal cortex of male LGI1-/- mice and found that the voltage-gated K+ channel Kv1.2 was significantly downregulated. We also found that cytosolic phospholipase A2 (cPLA2)-cyclooxygenase 2 (Cox2) signaling was enhanced in LGI1-/- mice. Interestingly, Cox2 inhibition effectively restored the dysregulated Kv1.2 and reduced the intrinsic excitability of pyramidal neurons. Moreover, in vivo injection of celecoxib, an FDA-approved nonsteroidal anti-inflammatory drug, rescued the defective Kv1.2 (an ~1.9-fold increase), thereby alleviating the seizure susceptibility and extending the life of LGI1-/- mice by 5 d. In summary, we conclude that LGI1 deficiency dysregulates cPLA2-Cox2 signaling to cause hyperexcitability of cortical pyramidal neurons, and celecoxib is a potential agent to manage human ADLTE.SIGNIFICANCE STATEMENT Haploinsufficiency of the leucine-rich glioma inactivated 1 (LGI1) gene is the major pathogenic basis for ADLTE, an inherited syndrome with no cure to date. Existing studies suggest that altered glutamatergic transmission in the hippocampus causes this disease, but the data are paradoxical. We demonstrate that the loss of LGI1 decreases Kv1.2 expression, enhances intrinsic excitability, and thereby causes epilepsy. Interestingly, for the first time, we show that an FDA-approved drug, celecoxib, rescues the Kv1.2 defect and alleviates seizure susceptibility in LGI1-/- mice, as well as improving their survival. Thus, we suggest that celecoxib is a promising drug for the treatment of ADLTE patients. PMID- 29491012 TI - Cell-Specific Deletion of PGC-1alpha from Medium Spiny Neurons Causes Transcriptional Alterations and Age-Related Motor Impairment. AB - Multiple lines of evidence indicate that a reduction in the expression and function of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) is associated with neurodegeneration in diseases such as Huntington's disease (HD). Polymorphisms in the PGC-1alpha gene modify HD progression and PGC-1alpha expression is reduced in striatal medium spiny neurons (MSNs) of HD patients and mouse models. However, neither the MSN-specific function of PGC-1alpha nor the contribution of PGC 1alpha deficiency to motor dysfunction is known. We identified novel, PGC-1alpha dependent transcripts involved in RNA processing, signal transduction, and neuronal morphology and confirmed reductions in these transcripts in male and female mice lacking PGC-1alpha specifically in MSNs, indicating a cell-autonomous effect in this population. MSN-specific PGC-1alpha deletion caused reductions in previously identified neuronal and metabolic PGC-1alpha-dependent genes without causing striatal vacuolizations. Interestingly, these mice exhibited a hypoactivity with age, similar to several HD animal models. However, these newly identified PGC-1alpha-dependent genes were upregulated with disease severity and age in knock-in HD mouse models independent of changes in PGC-1alpha transcript, contrary to what would be predicted from a loss-of-function etiological mechanism. These data indicate that PGC-1alpha is necessary for MSN transcriptional homeostasis and function with age and that, whereas PGC-1alpha loss in MSNs does not replicate an HD-like phenocopy, its downstream genes are altered in a repeat-length and age-dependent fashion. Understanding the additive effects of PGC-1alpha gene functional variation and mutant huntingtin on transcription in this cell type may provide insight into the selective vulnerability of MSNs in HD.SIGNIFICANCE STATEMENT Reductions in peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha)-mediated transcription have been implicated in the pathogenesis of Huntington's disease (HD). We show that, although PGC-1alpha-dependent transcription is necessary to maintain medium spiny neuron (MSN) function with age, its loss is insufficient to cause striatal atrophy in mice. We also highlight a set of genes that can serve as proxies for PGC-1alpha functional activity in the striatum for target engagement studies. Furthermore, we demonstrate that PGC-1alpha-dependent genes are upregulated in a dose- and age-dependent fashion in HD mouse models, contrary to what would be predicted from a loss-of-function etiological mechanism. However, given this role for PGC-1alpha in MSN transcriptional homeostasis, it is important to consider how genetic variation in PGC-1alpha could contribute to mutant-huntingtin-induced cell death and disease progression. PMID- 29491013 TI - Phylogenetic Characterization of Salmonella enterica Serovar Typhimurium and Its Monophasic Variant Isolated from Food Animals in Japan Revealed Replacement of Major Epidemic Clones in the Last 4 Decades. AB - Salmonella enterica serovar Typhimurium (Salmonella Typhimurium) and its monophasic variant (Salmonella 4,[5],12:i:-) are the major causes of gastroenteritis in both humans and animals. Pulsed-field gel electrophoresis and multilocus variable-number tandem-repeat analysis have been used widely as subtyping methods for these pathogens in molecular epidemiological analyses, but the results do not precisely reflect phylogenetic information. In this study, we performed a phylogenetic analysis of these serovars using whole-genome sequencing data and identified nine distinct genotypic clades. Then, we established an allele-specific PCR-based genotyping method detecting a clade-specific single nucleotide polymorphism to rapidly identify the clade of each isolate. Among a total of 815 isolates obtained from cattle in Japan between 1977 and 2017, clades 1, 7, and 9 contained 77% of isolates. Obvious replacement of the dominant clone was observed five times in this period, and clade 9, which mostly contains Salmonella 4,[5],12:i:-, is currently dominant. Among 140 isolates obtained from swine in Japan between 1976 and 2017, clades 3 and 9 contained 64% of isolates. Clade 9 is the latest clone as is the case in cattle isolates. Clade 9 is similar to an epidemic clone from Europe, which is characterized by sequence type 34 (ST34), chromosomal Salmonella genomic island 3, and a composite transposon containing antimicrobial resistance genes. The increased prevalence of clade 9 among food animals in Japan might be a part of the pandemic of the European Salmonella 4,[5],12:i:- clone. PMID- 29491015 TI - Clostridium scindens Is Present in the Gut Microbiota during Clostridium difficile Infection: a Metagenomic and Culturomic Analysis. PMID- 29491014 TI - Foodborne Outbreak of Group G Streptococcal Pharyngitis in a School Dormitory in Osaka, Japan. AB - In September 2016, 140 patients with primary symptoms of sore throat and fever were identified in a school dormitory in Osaka, Japan. Epidemiological and laboratory investigations determined that these symptomatic conditions were from a foodborne outbreak of group G streptococcus (GGS), with GGS being isolated from samples from patients, cooks, and foods. The strain of GGS was identified as Streptococcus dysgalactiae subsp. equisimilis of two emm types (stG652.0 and stC36.0). The causative food, a broccoli salad, was contaminated with the two types of S. dysgalactiae subsp. equisimilis, totaling 1.3 * 104 CFU/g. Pulsed field gel electrophoresis (PFGE) of samples from patients, cooks, and foods produced similar band patterns among samples with the same emm type. This result suggested the possibility of exposure from the contaminated food. The average onset time was 44.9 h and the prevalence rate was 62%. This is the first report to identify the causative food of a foodborne outbreak by Streptococcus dysgalactiae subsp. equisimilis. PMID- 29491016 TI - Efficacy of Pulsed-Field Gel Electrophoresis and Repetitive Element Sequence Based PCR in Typing of Salmonella Isolates from Assam, India. AB - A total of 12 Salmonella isolates belonging to different serovars, viz, Salmonella enterica serovar Enteritidis (n = 4), Salmonella enterica serovar Weltevreden (n = 4), Salmonella enterica serovar Newport (n = 1), Salmonella enterica serovar Litchifield (n = 1), and untypeable strains (n = 2) were isolated from 332 diarrheic fecal samples collected from animals, birds, and humans. Of the two molecular typing methods applied, viz, repetitive element sequence-based PCR (REP-PCR) and pulsed-field gel electrophoresis (PFGE), PFGE could clearly differentiate the strains belonging to different serovars as well as differentiate between strains of the same serovar with respect to their source of isolation, whereas REP-PCR could not differentiate between strains of the same serovar. Thus, it can be suggested that PFGE is more useful and appropriate for molecular typing of Salmonella isolates during epidemiological investigations than REP-PCR. PMID- 29491017 TI - Surveillance of Circulating Bordetella pertussis Strains in Europe during 1998 to 2015. AB - One reason for increased pertussis incidence is the adaptation of Bordetella pertussis to vaccine-induced immunity by modulating its genomic structure. This study, EUpert IV, includes 265 isolates collected from nine European countries during 2012 to 2015 (n = 265) and compares the results to previous EUpert I to III studies (1998 to 2009). The analyses included genotyping, serotyping, pulsed field gel electrophoresis (PFGE), and multilocus variable-number tandem-repeat analysis (MLVA). Genotyping results showed only small variations among the common virulence genes of B. pertussis The frequencies of serotypes Fim2 and Fim3 varied among the four collections. Genomic analyses showed that MLVA type 27 increased to 80% between the periods of 1998 to 2001 and 2012 to 2015. Two PFGE profiles, BpSR3 (29.4%) and BpSR10 (27.2%), constituted more than 50% of the circulating isolates in the present collection. Our study indicates that the European B. pertussis population is changing and became more homogenous after the introduction of acellular pertussis vaccines. PMID- 29491018 TI - Validation of a Human Papillomavirus (HPV) DNA Cervical Screening Test That Provides Expanded HPV Typing. AB - As cervical cancer screening shifts from cytology to human papillomavirus (HPV) testing, a major question is the clinical value of identifying individual HPV types. We aimed to validate Onclarity (Becton Dickinson Diagnostics, Sparks, MD), a nine-channel HPV test recently approved by the FDA, by assessing (i) the association of Onclarity types/channels with precancer/cancer; (ii) HPV type/channel agreement between the results of Onclarity and cobas (Roche Molecular Systems, Pleasanton, CA), another FDA-approved test; and (iii) Onclarity typing for all types/channels compared to typing results from a research assay (linear array [LA]; Roche). We compared Onclarity to histopathology, cobas, and LA. We tested a stratified random sample (n = 9,701) of discarded routine clinical specimens that had tested positive by Hybrid Capture 2 (HC2; Qiagen, Germantown, MD). A subset had already been tested by cobas and LA (n = 1,965). Cervical histopathology was ascertained from electronic health records. Hierarchical Onclarity channels showed a significant linear association with histological severity. Onclarity and cobas had excellent agreement on partial typing of HPV16, HPV18, and the other 12 types as a pool (sample-weighted kappa value of 0.83); cobas was slightly more sensitive for HPV18 and slightly less sensitive for the pooled high-risk types. Typing by Onclarity showed excellent agreement with types and groups of types identified by LA (kappa values from 0.80 for HPV39/68/35 to 0.97 for HPV16). Onclarity typing results corresponded well to histopathology and to an already validated HPV DNA test and could provide additional clinical typing if such discrimination is determined to be clinically desirable. PMID- 29491019 TI - Nucleotide Sequence Database Comparison for Routine Dermatophyte Identification by Internal Transcribed Spacer 2 Genetic Region DNA Barcoding. AB - Conventional dermatophyte identification is based on morphological features. However, recent studies have proposed to use the nucleotide sequences of the rRNA internal transcribed spacer (ITS) region as an identification barcode of all fungi, including dermatophytes. Several nucleotide databases are available to compare sequences and thus identify isolates; however, these databases often contain mislabeled sequences that impair sequence-based identification. We evaluated five of these databases on a clinical isolate panel. We selected 292 clinical dermatophyte strains that were prospectively subjected to an ITS2 nucleotide sequence analysis. Sequences were analyzed against the databases, and the results were compared to clusters obtained via DNA alignment of sequence segments. The DNA tree served as the identification standard throughout the study. According to the ITS2 sequence identification, the majority of strains (255/292) belonged to the genus Trichophyton, mainly T. rubrum complex (n = 184), T. interdigitale (n = 40), T. tonsurans (n = 26), and T. benhamiae (n = 5). Other genera included Microsporum (e.g., M. canis [n = 21], M. audouinii [n = 10], Nannizzia gypsea [n = 3], and Epidermophyton [n = 3]). Species-level identification of T. rubrum complex isolates was an issue. Overall, ITS DNA sequencing is a reliable tool to identify dermatophyte species given that a comprehensive and correctly labeled database is consulted. Since many inaccurate identification results exist in the DNA databases used for this study, reference databases must be verified frequently and amended in line with the current revisions of fungal taxonomy. Before describing a new species or adding a new DNA reference to the available databases, its position in the phylogenetic tree must be verified. PMID- 29491020 TI - Misidentification of Candida auris by RapID Yeast Plus, a Commercial, Biochemical Enzyme-Based Manual Rapid Identification System. PMID- 29491021 TI - Diagnostic Yield of Laboratory Methods and Value of Viral Genotyping during an Outbreak of Mumps in a Partially Vaccinated Population in British Columbia, Canada. AB - Mumps remains endemic in North America despite routine use of the measles, mumps, and rubella (MMR) vaccine. In 2016, an outbreak of mumps in British Columbia, Canada, provided an opportunity to determine the diagnostic utility of laboratory testing methods. Specimens from patients with clinical mumps were tested for infection using a commercial enzyme-linked immunosorbent assay (ELISA) for antibody detection and an in-house reverse transcriptase PCR (RT-PCR) targeting viral fusion and small hydrophobic (SH) genes. Viral genotyping was performed by SH gene sequencing. Laboratory data was linked with epidemiologic case data. Of the 139 confirmed cases, 94 (68%) had reported or documented history of MMR vaccination. Specimens were typically collected 1 day (for buccal and IgM tests) or 2 days (for urine tests) after symptom onset. Most confirmed cases (69%) were confirmed by buccal swab RT-PCR. Among cases tested by multiple methods, the percent positivity for buccal swab RT-PCR was 90% (96/107) compared to 43% (30/69) for both IgM ELISA and urine RT-PCR. Mumps IgM detection was higher in confirmed cases with no history of vaccination than in those with history (64% versus 34%, P = 0.02). The outbreak strain was identified as genotype G related to MuVi/Sheffield.GBR/1.05 but with conserved variations in five nucleotides within the SH gene that allowed linkage of geographically distinct cases. In conclusion, RT-PCR of buccal specimens had the highest diagnostic yield during a mumps outbreak in a partially vaccinated population. To optimize mumps diagnostic potential, clinicians should collect specimens depending on when the patient presents for care and their immunization history. PMID- 29491022 TI - Evaluation of a PCR Method for Detection of Entamoeba polecki, with an Overview of Its Molecular Epidemiology. AB - Entamoebapolecki is a parasite of human and nonhuman primates, other mammals, and birds. Due to overlapping morphological features, cysts of E. polecki may be confused with those of other Entamoeba species commonly found in human fecal samples, including immature cysts of Entamoeba histolytica Although the presence of E. polecki in human Entamoeba-positive stool samples may be rare, its prevalence is likely underestimated due to such confusion. Here, we give examples of diagnostic approaches applied so far and summarize data on the molecular epidemiology of E. polecki, including host specificity and phylogeography. Moreover, we evaluate a novel diagnostic conventional PCR developed for the screening of fecal samples for E. polecki The assay was highly sensitive and specific when used on genomic DNA extracted directly from stool and Swedish wastewater samples. The PCR enabled the identification of all four subtypes (ST1 to ST4) of E. polecki by PCR product sequencing. Most (23/28) subtyped E. polecki positive samples detected in patients in Sweden between 2002 and 2015 reflected colonization by ST4 and were seen in travelers/foreigners. Two and three human cases of ST2 and ST3, respectively, were also detected. Subtypes 1, 2, and 3 were detected in 3/21 wastewater samples, suggesting local endemicity of these E. polecki subtypes; interestingly, ST4 was not detected in wastewater. In conclusion, the current PCR assay enables simple and cost-effective screening of fecal and wastewater samples for E. polecki Human cases of E. polecki appear to involve primarily ST4, while E. polecki detected in wastewater may be primarily of animal origin. PMID- 29491023 TI - Risso's dolphins plan foraging dives. AB - Humans remember the past and use that information to plan future actions. Lab experiments that test memory for the location of food show that animals have a similar capability to act in anticipation of future needs, but less work has been done on animals foraging in the wild. We hypothesized that planning abilities are critical and common in breath-hold divers who adjust each dive to forage on prey varying in quality, location and predictability within constraints of limited oxygen availability. We equipped Risso's dolphins with sound-and-motion recording tags to reveal where they focus their attention through their externally observable echolocation and how they fine tune search strategies in response to expected and observed prey distribution. The information from the dolphins was integrated with synoptic prey data obtained from echosounders on an underwater vehicle. At the start of the dives, whales adjusted their echolocation inspection ranges in ways that suggest planning to forage at a particular depth. Once entering a productive prey layer, dolphins reduced their search range comparable to the scale of patches within the layer, suggesting that they were using echolocation to select prey within the patch. On ascent, their search range increased, indicating that they decided to stop foraging within that layer and started searching for prey in shallower layers. Information about prey, learned throughout the dive, was used to plan foraging in the next dive. Our results demonstrate that planning for future dives is modulated by spatial memory derived from multi-modal prey sampling (echoic, visual and capture) during earlier dives. PMID- 29491024 TI - The effect of dispersal on rates of cumulative cultural evolution. AB - The ability to develop cultural adaptations to local environments is critical to the biological success of humans. Although overall population size and connectedness are thought to play an important role in increasing the rate of cumulative cultural evolution, the independent effect of dispersal rules on rates of cultural evolution has not been examined. Here, a computational model is used to explore the effect of dispersal on the rate of cultural evolution in traits transmitted patrilineally (from father to son), matrilineally (mother to daughter) and bilineally (through both sexes). Two dispersal conditions are modelled: patrilocality (where females disperse and males stay) and bilocality (where either sex may disperse). The results suggest that when only females disperse, the capacity for cumulative cultural evolution in traits shared only among males is severely constrained. This occurs even though overall rates of dispersal and the number of cultural models available to males and females are identical in both dispersal conditions. The constraints on the evolution of patrilineally inherited traits could be considered to represent a process of 'cultural inbreeding', analogous to genetic inbreeding. PMID- 29491025 TI - Developmental experience with anthropogenic noise hinders adult mate location in an acoustically signalling invertebrate. AB - Phenotypic plasticity facilitates survival and reproduction in rapidly changing and novel environments. Traffic noise spectrally overlaps with (i.e. masks) the sounds used by many acoustically signalling organisms to locate and secure mates. To determine if pre-reproductive exposure to noise improves adult performance in noisy environments, we reared field crickets (Teleogryllus oceanicus) in one of three noise environments: masking traffic noise, traffic noise from which frequencies that spectrally overlap with the crickets' song were removed (non masking), or silence. At reproductive maturity, we tested female mate location ability under one of the same three acoustic conditions. We found that exposure to noise during rearing hindered female location of mates, regardless of the acoustic environment at testing. Females reared in masking noise took 80% longer than females reared in silence to locate a simulated singing male who was less than 1 m away. Impaired mate location ability can be added to a growing list of fitness costs associated with anthropogenic noise, alongside reductions in pairing success, nesting success and offspring survival. PMID- 29491027 TI - Correction to 'Intra-ejaculate sperm selection in female zebra finches'. PMID- 29491026 TI - Local extinction of the Asian tiger mosquito (Aedes albopictus) following rat eradication on Palmyra Atoll. AB - The Asian tiger mosquito, Aedes albopictus, appears to have been extirpated from Palmyra Atoll following rat eradication. Anecdotal biting reports, collection records, and regular captures in black-light traps showed the species was present before rat eradication. Since then, there have been no biting reports and no captures over 2 years of extensive trapping (black-light and scent traps). By contrast, the southern house mosquito, Culex quinquefasciatus, was abundant before and after rat eradication. We hypothesize that mammals were a substantial and preferred blood meal for Aedes, whereas Culex feeds mostly on seabirds. Therefore, after rat eradication, humans and seabirds alone could not support positive population growth or maintenance of Aedes This seems to be the first documented accidental secondary extinction of a mosquito. Furthermore, it suggests that preferred host abundance can limit mosquito populations, opening new directions for controlling important disease vectors that depend on introduced species like rats. PMID- 29491028 TI - Understanding the evolution of personality requires the study of mechanisms behind the development and life history of personality traits. AB - Research on animal personality explains the coexistence of distinct behavioural phenotypes within a species and demonstrates limits to individual plasticity. However, the mechanisms guiding the lifelong development of personality should receive more attention, because many elements of personality are emergent properties of interactions between the environment and an individual's genetic background. In these interactions, mechanisms (e.g. genetic regulatory networks, epigenetic processes and neuroendocrine regulation) influencing personality may be modified. An approach integrating proximate mechanisms with a view of lifelong personality development will crucially improve understanding stability, plasticity and inter-individual variability of personalities and clarify the effects of selection on the phenomenon. PMID- 29491029 TI - Narrow anthropogenic corridors direct the movement of a generalist boreal butterfly. AB - Ecological and anthropogenic corridors are becoming more common worldwide, but little is known about how corridor size (width) affects species' movements, and thus their effects. Here we investigated whether 4- and 8-m wide anthropogenic corridors (seismic lines) cleared for petroleum (oil sands) exploration in boreal forests in Alberta, Canada, act on altering the behaviour of a habitat generalist butterfly, the Arctic fritillary (Boloria chariclea). Specifically, we captured 539 Arctic fritillaries and released them in seismic line corridor or control sites with no structural directionality (i.e. forests and clearings), and recorded both their initial direction (along the seismic line or not) and persistence in directional movements. Arctic fritillaries moved inside these lines twice as often as they left them, and maintained their initial direction more often, regardless of line size and independently of forest structure or sex of individuals. Thus, anthropogenic corridors as narrow as 4 m can affect insect movements. Given the vast area of boreal forests disturbed from seismic assessments, investigating if the effects of these dense, localized lines affect population dynamics and species interactions would provide important insights to managing this ecosystem and identifying restoration actions. PMID- 29491030 TI - Bone resorption: supporting immunometabolism. AB - Activation of the immune system is associated with an increase in the breakdown of various peripheral tissues, including bone. Despite the widely appreciated role of inflammatory mediators in promoting bone resorption, the functional value behind this process is not completely understood. Recent advances in the field of immunometabolism have highlighted the metabolic reprogramming that takes place in activated immune cells. It is now believed that the breakdown of peripheral tissue provides metabolic substrates to fuel metabolic anabolism in activated immune cells. We argue that phosphate, liberated by bone resorption, plays an indispensable role in sustaining immune cell metabolism. The liberated phosphate is then incorporated into macromolecules such as nucleotides and phospholipids, and is also used for the phosphorylation of metabolites (e.g. glycolytic intermediates). In addition, magnesium, also liberated during the breakdown of bone, is an essential cofactor required by various metabolic enzymes which are upregulated in activated immune cells. Finally, calcium activates various additional molecules involved in immune cell migration. Taken together, these factors suggest a key role for bone resorption during infection. PMID- 29491031 TI - State-dependent judgement bias in Drosophila: evidence for evolutionarily primitive affective processes. AB - Affective states influence decision-making under ambiguity in humans and other animals. Individuals in a negative state tend to interpret ambiguous cues more negatively than individuals in a positive state. We demonstrate that the fruit fly, Drosophila melanogaster, also exhibits state-dependent changes in cue interpretation. Drosophila were trained on a Go/Go task to approach a positive (P) odour associated with a sugar reward and actively avoid a negative (N) odour associated with shock. Trained flies were then either shaken to induce a purported negative state or left undisturbed (control), and given a choice between: air or P; air or N; air or ambiguous odour (1 : 1 blend of P : N). Shaken flies were significantly less likely to approach the ambiguous odour than control flies. This 'judgement bias' may be mediated by changes in neural activity that reflect evolutionarily primitive affective states. We cannot say whether such states are consciously experienced, but use of this model organism's versatile experimental tool kit may facilitate elucidation of their neural and genetic basis. PMID- 29491032 TI - First detection of bee viruses in hoverfly (syrphid) pollinators. AB - Global declines of insect pollinators jeopardize the delivery of pollination services in both agricultural and natural ecosystems. The importance of infectious diseases has been documented in honeybees, but there is little information on the extent to which these diseases are shared with other pollinator orders. Here, we establish for the first time the presence of three important bee viruses in hoverfly pollinators (Diptera: Syrphidae): black queen cell virus (BQCV), sacbrood virus (SBV) and deformed wing virus strain B (DWV-B). These viruses were detected in two Eristalis species, which are behavioural and morphological bee mimics and share a foraging niche with honeybees. Nucleotide sequences of viruses isolated from the Eristalis species and Apis mellifera were up to 99 and 100% identical for the two viruses, suggesting that these pathogens are being shared freely between bees and hoverflies. Interestingly, while replicative intermediates (negative strand virus) were not detected in the hoverflies, viral titres of SBV were similar to those found in A. mellifera These results suggest that syrphid pollinators may play an important but previously unexplored role in pollinator disease dynamics. PMID- 29491033 TI - A Nonsense Variant in the ACADVL Gene in German Hunting Terriers with Exercise Induced Metabolic Myopathy. AB - Several enzymes are involved in fatty acid oxidation, which is a key process in mitochondrial energy production. Inherited defects affecting any step of fatty acid oxidation can result in clinical disease. We present here an extended family of German Hunting Terriers with 10 dogs affected by clinical signs of exercise induced weakness, muscle pain, and suspected rhabdomyolysis. The combination of clinical signs, muscle histopathology and acylcarnitine analysis with an elevated tetradecenoylcarnitine (C14:1) peak suggested a possible diagnosis of acyl-CoA dehydrogenase very long chain deficiency (ACADVLD). Whole genome sequence analysis of one affected dog and 191 controls revealed a nonsense variant in the ACADVL gene encoding acyl-CoA dehydrogenase very long chain, c.1728C>A or p.(Tyr576*). The variant showed perfect association with the phenotype in the 10 affected and more than 500 control dogs of various breeds. Pathogenic variants in the ACADVL gene have been reported in humans with similar myopathic phenotypes. We therefore considered the detected variant to be the most likely candidate causative variant for the observed exercise induced myopathy. To our knowledge, this is the first description of this disease in dogs, which we propose to name exercise induced metabolic myopathy (EIMM), and the identification of the first canine pathogenic ACADVL variant. Our findings provide a large animal model for a known human disease and will enable genetic testing to avoid the unintentional breeding of affected offspring. PMID- 29491035 TI - Paediatric lung imaging: the times they are a-changin'. AB - Until recently, functional tests were the most important tools for the diagnosis and monitoring of lung diseases in the paediatric population. Chest imaging has gained considerable importance for paediatric pulmonology as a diagnostic and monitoring tool to evaluate lung structure over the past decade. Since January 2016, a large number of papers have been published on innovations in chest computed tomography (CT) and/or magnetic resonance imaging (MRI) technology, acquisition techniques, image analysis strategies and their application in different disease areas. Together, these papers underline the importance and potential of chest imaging and image analysis for today's paediatric pulmonology practice. The focus of this review is chest CT and MRI, as these are, and will be, the modalities that will be increasingly used by most practices. Special attention is given to standardisation of image acquisition, image analysis and novel applications in chest MRI. The publications discussed underline the need for the paediatric pulmonology community to implement and integrate state-of-the art imaging and image analysis modalities into their structure-function laboratory for the benefit of their patients. PMID- 29491036 TI - Immunological and toxicological risk assessment of e-cigarettes. AB - Knowledge of the long-term toxicological and immunological effects of e-cigarette (e-cig) aerosols remains elusive due to the relatively short existence of vaping. Therefore, we performed a systematic search of articles published in public databases and analysed the research evidence in order to provide critical information regarding e-cig safety. Electronic nicotine delivery systems (or e cigs) are an alternative to traditional cigarettes for the delivery of nicotine and are typically filled with glycerol or propylene glycol-based solutions known as e-liquids. Though present in lower quantities, e-cig aerosols are known to contain many of the harmful chemicals found in tobacco smoke. However, due to the paucity of experimental data and contradictory evidence, it is difficult to draw conclusive outcomes regarding toxicological, immunological and clinical impacts of e-cig aerosols. Excessive vaping has been reported to induce inflammatory responses including mitogen-activated protein kinase, Janus tyrosine kinase/signal transducer and activator of transcription and nuclear factor-kappaB signalling, similar to that induced by tobacco smoke. Based on recent evidence, prolonged exposure to some constituents of e-cig aerosols might result in respiratory complications such as asthma, chronic obstructive pulmonary disease and inflammation. Future studies are warranted that focus on establishing correlations between e-cig types, generations and e-liquid flavours and immunological and toxicological profiles to broaden our understanding about the effects of vaping. PMID- 29491037 TI - Unclassifiable interstitial lung disease: a pathologist's perspective. AB - Classifying pulmonary fibrotic disease into various diagnostic categories provides the clinician with expectations for both prognosis and proper treatment. Despite years of experience with histological, radiological and clinical guidelines, a group of patients remains with unclassifiable interstitial lung disease. In this article, the possible barriers to classification will be explored, and some strategies will be discussed to aid in overcoming these barriers. PMID- 29491034 TI - Tuberculosis and lung damage: from epidemiology to pathophysiology. AB - A past history of pulmonary tuberculosis (TB) is a risk factor for long-term respiratory impairment. Post-TB lung dysfunction often goes unrecognised, despite its relatively high prevalence and its association with reduced quality of life. Importantly, specific host and pathogen factors causing lung impairment remain unclear. Host immune responses probably play a dominant role in lung damage, as excessive inflammation and elevated expression of lung matrix-degrading proteases are common during TB. Variability in host genes that modulate these immune responses may determine the severity of lung impairment, but this hypothesis remains largely untested. In this review, we provide an overview of the epidemiological literature on post-TB lung impairment and link it to data on the pathogenesis of lung injury from the perspective of dysregulated immune responses and immunogenetics. PMID- 29491038 TI - Preclinical Efficacy and Safety of the Novel Antidiabetic, Antiobesity MetAP2 Inhibitor ZGN-1061. AB - Methionine aminopeptidase 2 (MetAP2) inhibition is a promising approach to treating diabetes, obesity, and associated metabolic disorders. Beloranib, a MetAP2 inhibitor previously investigated for treatment of Prader-Willi syndrome, was associated with venous thrombotic adverse events likely resulting from drug effects on vascular endothelial cells (ECs). Here, we report the pharmacological characterization of ZGN-1061, a novel MetAP2 inhibitor being investigated for treatment of diabetes and obesity. Four weeks of subcutaneous administration of ZGN-1061 to diet-induced obese (DIO) insulin-resistant mice produced a 25% reduction in body weight, primarily due to reduced fat mass, that was comparable to beloranib. ZGN-1061 also produced improvements in metabolic parameters, including plasma glucose and insulin, and, in HepG2 cells, initiated gene changes similar to beloranib that support observed in vivo pharmacodynamics. In vitro studies in ECs demonstrated that ZGN-1061 effects on EC proliferation and coagulation proteins were greatly attenuated, or absent, relative to beloranib, due to lower intracellular drug concentrations, shorter half-life of inhibitor bound MetAP2 complex, and reduced cellular enzyme inhibition. In dogs, ZGN-1061 was more rapidly absorbed and cleared, with a shorter half-life than beloranib. Unlike beloranib, ZGN-1061 did not increase coagulation markers in dogs, and ZGN 1061 had a greatly improved safety profile in rats relative to beloranib. In conclusion, ZGN-1061 and beloranib demonstrated similar efficacy in a mouse model of obesity, while ZGN-1061 had a markedly improved safety profile in multiple in vitro and in vivo models. The lower duration of exposure characteristic of ZGN 1061 is expected to provide a meaningfully enhanced clinical safety profile. PMID- 29491039 TI - The N54-alphas Mutant Has Decreased Affinity for betagamma and Suggests a Mechanism for Coupling Heterotrimeric G Protein Nucleotide Exchange with Subunit Dissociation. AB - Ser54 of Gsalpha binds guanine nucleotide and Mg2+ as part of a conserved sequence motif in GTP binding proteins. Mutating the homologous residue in small and heterotrimeric G proteins generates dominant-negative proteins, but by protein-specific mechanisms. For alphai/o, this results from persistent binding of alpha to betagamma, whereas for small GTP binding proteins and alphas this results from persistent binding to guanine nucleotide exchange factor or receptor. This work examined the role of betagamma interactions in mediating the properties of the Ser54-like mutants of Galpha subunits. Unexpectedly, WT-alphas or N54-alphas coexpressed with alpha1B-adrenergic receptor in human embryonic kidney 293 cells decreased receptor stimulation of IP3 production by a cAMP independent mechanism, but WT-alphas was more effective than the mutant. One explanation for this result would be that alphas, like Ser47 alphai/o, blocks receptor activation by sequestering betagamma; implying that N54-alphaS has reduced affinity for betagamma since it was less effective at blocking IP3 production. This possibility was more directly supported by the observation that WT-alphas was more effective than the mutant in inhibiting betagamma activation of phospholipase Cbeta2. Further, in vitro synthesized N54-alphas bound biotinylated-betagamma with lower apparent affinity than did WT-alphas The Cys54 mutation also decreased betagamma binding but less effectively than N54-alphas Substitution of the conserved Ser in alphao with Cys or Asn increased betagamma binding, with the Cys mutant being more effective. This suggests that Ser54 of alphas is involved in coupling changes in nucleotide binding with altered subunit interactions, and has important implications for how receptors activate G proteins. PMID- 29491040 TI - Impact of Infection Status and Cyclosporine on Voriconazole Pharmacokinetics in an Experimental Model of Cerebral Scedosporiosis. AB - Cerebral Scedosporium infections usually occur in lung transplant recipients as well as in immunocompetent patients in the context of near drowning. Voriconazole is the first-line treatment. The diffusion of voriconazole through the blood brain barrier in the context of cerebral infection and cyclosporine administration is crucial and remains a matter of debate. To address this issue, the pharmacokinetics of voriconazole was assessed in the plasma, cerebrospinal fluid (CSF), and brain in an experimental model of cerebral scedosporiosis in rats receiving or not receiving cyclosporine. A single dose of voriconazole (30 mg/kg, i.v.) was administered to six groups of rats randomized according to the infection status and the cyclosporine dosing regimen (no cyclosporine, a single dose, or three doses; 15 mg/kg each). Voriconazole concentrations in plasma, CSF, and brain samples were quantified using ultra-performance liquid chromatography tandem mass spectrometry and high-performance liquid chromatography UV methods and were documented up to 48 hours after administration. Pharmacokinetic parameters were estimated using a noncompartmental approach. Voriconazole pharmacokinetic profiles were similar for plasma, CSF, and brain in all groups studied. The voriconazole Cmax and area under the curve (AUC) (AUC0 >= 48 hours) values were significantly higher in plasma than in CSF [CSF/plasma ratio, median (range) = 0.5 (0.39-0.55) for AUC0 >= 48 hours and 0.47 (0.35 and 0.75) for Cmax]. Cyclosporine administration was significantly associated with an increase in voriconazole exposure in the plasma, CSF, and brain. In the plasma, but not in the brain, an interaction between the infection and cyclosporine administration reduced the positive impact of cyclosporine on voriconazole exposure. Together, these results emphasize the impact of cyclosporine on brain voriconazole exposure. PMID- 29491041 TI - Cerebral organoids: ethical issues and consciousness assessment. AB - Organoids are three-dimensional biological structures grown in vitro from different kinds of stem cells that self-organise mimicking real organs with organ specific cell types. Recently, researchers have managed to produce human organoids which have structural and functional properties very similar to those of different organs, such as the retina, the intestines, the kidneys, the pancreas, the liver and the inner ear. Organoids are considered a great resource for biomedical research, as they allow for a detailed study of the development and pathologies of human cells; they also make it possible to test new molecules on human tissue. Furthermore, organoids have helped research take a step forward in the field of personalised medicine and transplants. However, some ethical issues have arisen concerning the origin of the cells that are used to produce organoids (ie, human embryos) and their properties. In particular, there are new, relevant and so-far overlooked ethical questions concerning cerebral organoids. Scientists have created so-called mini-brains as developed as a few-months-old fetus, albeit smaller and with many structural and functional differences. However, cerebral organoids exhibit neural connections and electrical activity, raising the question whether they are or (which is more likely) will one day be somewhat sentient. In principle, this can be measured with some techniques that are already available (the Perturbational Complexity Index, a metric that is directly inspired by the main postulate of the Integrated Information Theory of consciousness), which are used for brain-injured non-communicating patients. If brain organoids were to show a glimpse of sensibility, an ethical discussion on their use in clinical research and practice would be necessary. PMID- 29491042 TI - Lesbian motherhood and mitochondrial replacement techniques: reproductive freedom and genetic kinship. AB - In this paper, we argue that lesbian couples who wish to have children who are genetically related to both of them should be allowed access to mitochondrial replacement techniques (MRTs). First, we provide a brief explanation of mitochondrial diseases and MRTs. We then present the reasons why MRTs are not, by nature, therapeutic. The upshot of the view that MRTs are non-therapeutic techniques is that their therapeutic potential cannot be invoked for restricting their use only to those cases where a mitochondrial DNA disease could be 'cured'. We then argue that a positive case for MRTs is justified by an appeal to reproductive freedom, and that the criteria to access these techniques should hence be extended to include lesbian couples who wish to share genetic parenthood. Finally, we consider a potential objection to our argument: that the desire to have genetically related kin is not a morally sufficient reason to allow lesbian couples to access MRTs. PMID- 29491043 TI - Publishing in an ASPET Journal - What's in It for You? PMID- 29491044 TI - Postoperative Hypofractionated Radiation Therapy in Prostate Carcinoma: A Systematic Review. AB - BACKGROUND/AIM: A systematic review on toxicity, local control (LC), overall survival (OS), and biochemical relapse-free survival (bRFS) after postoperative hypofractionated radiotherapy (HFRT) on prostate cancer (PCa) was performed. MATERIALS AND METHODS: Based on the PRISMA methodology, studies reporting clinical results after adjuvant or salvage HFRT were included. RESULTS: A total of 1,208 patients from 17 eligible studies were included. Median follow-up was 30 months. No case of severe acute gastrointestinal (GI) toxicity was recorded. Grade >=3 acute genitourinary (GU) toxicity ranged between 0% and 3%. Different rates of grade >=2 late GI (range=0-8.7%) and GU (range=0-66%) toxicity were recorded. Encouraging results on LC, OS, and bRFS were reported. CONCLUSION: Acute toxicity does not seem to be increased in patients receiving postoperative HFRT, but the results of late-GU toxicity are conflicting. Further prospective studies are needed before including postoperative HFRT in clinical practice. PMID- 29491045 TI - Stereotactic Body Radiation Therapy for Patients with Early-stage Prostate Cancer. AB - AIM: Stereotactic body radiation therapy (SBRT) is emerging as a new treatment option for early-stage prostate cancer, theoretically providing clinical and economic benefits compared to conventionally fractionated external-beam radiation therapy (CF-EBRT). This review aimed to evaluate available published data to determine if the proposed theoretical benefits translate clinically. MATERIALS AND METHODS: A systematic search strategy was employed across three databases using predefined search terms, inclusion and exclusion criteria to identify relevant articles. RESULTS: Sixteen articles were included. Biochemical progression-free survival rates of 77.1-100% were reported in SBRT studies compared to 55-98% in CF-EBRT studies. Incidence of acute grade 1, 2, and 3 genitourinary toxicities were reported in the range of 13.3-71%, 12-25% and 0-3%, respectively, in the SBRT cohort in comparison to 28.7-51.9%, 15.6-41.4%. and 1.1 8.1%, respectively, in the CF-EBRT cohort. Incidence of acute grade 1, 2, and 3 gastrointestinal toxicities were reported in the range of 13-67%, 1-27% and 0-9%, respectively, of the SBRT cohort compared to 16.1- 51.1%, 6.3-20.7% and 0-3%, respectively, of the CF-EBRT cohort. Mean treatment costs estimates associated with SBRT ranged from $22,152 to $24,873 and $33,068 to $35,431 for CF-EBRT. CONCLUSION: Available data support the hypothesis of lower rates of acute toxicity and reduced economic burden associated with SBRT compared to CF-EBRT, however, randomised data with longer follow-up are needed to determine whether SBRT is clinically more effective than CF-EBRT. PMID- 29491046 TI - Centrosomal Abnormalities in Pancreatic Cancer: Molecular Mechanisms and Clinical Implications. AB - The centrosome is the main microtubule-organizing center in human cells. It regulates normal cell-cycle progression and cell division. Aberrations in the number, structure and function of centrosomes have been found to drive genomic instability and tumorigenesis. Pancreatic cancer frequently displays centrosomal aberrations. Supernumerary and abnormal centrosomes are observed in the earliest stages of pancreatic tumor development, and the p53 pathway acts as an initial barrier to the proliferation of cells with extra centrosomes. In this review, we summarize recent advances in the understanding of centrosomal aberrations in pancreatic cancer, focusing on regulatory mechanisms and prospects for future anticancer treatment. PMID- 29491047 TI - Radiation Therapy for Angiosarcoma of the Scalp: Total Scalp Irradiation and Local Irradiation. AB - Angiosarcoma, a rare cutaneous malignancy, frequently arises in the scalp of older individuals. Because it characteristically initially mimics benign disease, such as a bruise, definitive diagnosis in the early stages is difficult. Angiosarcoma of the scalp is highly malignant and often accompanied by lung metastases that cause hemopneumothorax. Although surgery has been the standard and most reliable curative treatment for angiosarcoma of the scalp, there is a high probability of local recurrence, even after wide surgical excision. Therefore, postoperative radiation therapy has been administered in an attempt to minimize local recurrence. However, surgery is contraindicated in many older patients because of severe comorbidities or age. Definitive radiation therapy has been administered to such patients and has achieved good local control. In particular, total scalp irradiation may be a promising option for curative treatment of angiosarcoma of the scalp. Recent reports suggest that chemotherapy, particularly with taxanes, can prolong survival by reducing the rate of distant failure after radiation therapy. Thus, radiation therapy along with chemotherapy is now recommended for curative treatment of patients with inoperable disease and even some patients with operable disease. Technological developments in radiation therapy, such as intensity-modulated radiation therapy, will contribute to enhanced efficacy and reduced toxicities in the treatment of patients with angiosarcoma of the scalp. PMID- 29491048 TI - Gastric Cancer Cells in Peritoneal Lavage Fluid: A Systematic Review Comparing Cytological with Molecular Detection for Diagnosis of Peritoneal Metastases and Prediction of Peritoneal Recurrences. AB - BACKGROUND/AIM: Detecting free tumor cells in the peritoneal lavage fluid of gastric cancer patients permits to assess a more accurate prognosis, predict peritoneal recurrence and select cases for a more aggressive treatment. Currently, cytology and molecular biology comprise the two most popular methods of detection that are under constant study by researchers. MATERIALS AND METHODS: We burrowed into the available literature comparing cytological with molecular detection of free intraperitoneal gastric cancer cells. PubMed, Science Direct, Scopus and Google Scholar were the search engines investigated. RESULTS: As of 2017, 51 dedicated studies have been published. Messenger RNA of carcinoembryonic antigen was the genetic target most frequently described. The genetic technique is usually superior to cytology in sensitivity (38-100% vs. 12.3-67% respectively), whereas cytological examination tends to show a slight pre eminence in specificity (approximately 100%). CONCLUSION: So far, given the imperfection of each method, employment of both cytology and molecular examination seem to be mandatory. PMID- 29491049 TI - Is Adjuvant Endocrine Therapy Indicated for DCIS Patients After Complete Surgical Excision? AB - Data derived from pathological analysis, natural history, radiological characteristics, genomic profiling, and clinical outcome indicate that ductal carcinoma in situ (DCIS) is a heterogeneous disease; meaning that no single therapeutic strategy is best, but rather that treatment should be personalised and entail a rigorous multidisciplinary approach. The role of adjuvant endocrine therapy after surgical excision has been the subject of scientific debate in view of the in situ nature of this neoplasm. We reviewed the literature and summarised the evidence regarding the need for adjuvant endocrine therapy following complete surgical excision of DCIS through the identification of the most important outcomes, evaluation of quality of evidence, and assessment of the trade-offs involved. There is no scientific evidence that adjuvant endocrine therapy reduces the incidence of ipsilateral breast invasive recurrence or breast cancer mortality in the context of adequate local treatment of DCIS in the form of breast conserving surgery with clear surgical margins plus adjuvant radiotherapy or total mastectomy. Therefore, its routine use is not indicated. However, adjuvant endocrine therapy can be considered after a rigorous multidisciplinary discussion and patient counselling in a carefully selected subgroup of patients with high-risk estrogen receptor-positive DCIS. PMID- 29491050 TI - Update on Surgical Management of Small Bowel Neuroendocrine Tumors. AB - The widespread use of endoscopy and imaging in combination with the continuous update of the staging systems for neuroendocrine tumors has led to an increase in the incidence of small intestinal neuroendocrine tumors (si-NENs) globally. Despite high survival rates, severe complications may occur even in early stages due to the anatomic location of the primary site and the desmoplastic reaction. Surgery plays a central role in the management of patients with si-NENs. Excision of locoregional disease along with extensive lymph node dissection should be performed in fit patients, even in the presence of metastases. Multimodality treatment of liver metastases includes hepatectomy, ablative techniques and liver transplantation. Hormone therapy with somatostatine analogs is of high importance for symptomatic control; special caution should be exercised both pre- and intra operatively. A multidisciplinary approach is essential in order to provide personalized therapeutics for patients with si-NENs. Clinical research and specialization in this field should be further encouraged. PMID- 29491051 TI - Detection of Distinct Changes in Gene-expression Profiles in Specimens of Tumors and Transition Zones of Tenascin-positive/-negative Head and Neck Squamous Cell Carcinoma. AB - BACKGROUND/AIM: Having previously initiated genome-wide expression profiling in head and neck squamous cell carcinoma (HNSCC) for regions of the tumor, the margin of surgical resecate (MSR) and normal mucosa (NM), we here proceed with respective analysis of cases after stratification according to the expression status of tenascin (Ten). MATERIALS AND METHODS: Tissue specimens of each anatomical site were analyzed by immunofluorescent detection of Ten, fibronectin (Fn) and galectin-1 (Gal-1) as well as by microarrays. RESULTS: Histopathological examination demonstrated that Ten+Fn+Gal-1+ co-expression occurs more frequently in samples of HNSCC (55%) than in NM (9%; p<0.01). Contrary, the Ten-Fn+Gal-1- (45%) and Ten-Fn-Gal-1- (39%) status occurred with significantly (p<0.01) higher frequency than in HNSCC (3% and 4%, respectively). In MSRs, different immunophenotypes were distributed rather equally (Ten+Fn+Gal-1+=24%; Ten-Fn+Gal-1 =36%; Ten-Fn-Gal-1-=33%), differing to the results in tumors (p<0.05). Absence/presence of Ten was used for stratification of patients into cohorts without a difference in prognosis, to comparatively examine gene-activity signatures. Microarray analysis revealed i) expression of several tumor progression-associated genes in Ten+ HNSCC tumors and ii) a strong up-regulation of gene expression assigned to lipid metabolism in MSRs of Ten- tumors, while NM profiles remained similar. CONCLUSION: The presented data reveal marked and specific changes in tumors and MSR specimens of HNSCC without a separation based on prognosis. PMID- 29491052 TI - Modulation of Tumor Cell Metabolism by Laser Photochemotherapy with Cisplatin or Zoledronic Acid In Vitro. AB - BACKGROUND/AIM: Laser photochemotherapy is a new approach in cancer treatment using low-level laser therapy (LLLT) to enhance the effect of chemotherapy. MATERIALS AND METHODS: In order to evaluate the effect of LLLT on tumor cells, HeLa cells were treated with cisplatin or zoledronic acid (ZA) followed by LLLT. Cell viability was evaluated with 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H tetrazolium-5-carboxanilide assay. Oxidative phosphorylation and glycolysis were measured using extracellular flux analysis. Immunocytochemistry of heat-shock protein 70 (HSP70) and western blot analysis were performed. RESULTS: LLLT alone increased viability and was associated with lower oxidative phosphorylation but higher glycolysis rates. Cisplatin and ZA alone lowered cell viability, glycolysis and oxidative phosphorylation. This effect was significantly enhanced in conjunction with LLLT and was accompanied by reduced oxidative phosphorylation and collapse of glycolysis. CONCLUSION: Our observations indicate that LLLT may raise the cytotoxicity of cisplatin and ZA by modulating cellular metabolism, pointing to a possible application in cancer treatment. PMID- 29491053 TI - Combination Treatment of Polo-Like Kinase 1 and Tankyrase-1 Inhibitors Enhances Anticancer Effect in Triple-negative Breast Cancer Cells. AB - BACKGROUND/AIM: Breast cancer is the most common malignant cancer type in women, and triple-negative breast cancer (TNBC) is an extremely aggressive subtype of breast cancer with poor prognosis rates. The present study investigated the antitumor effect of polo-like kinase 1 (PLK1) inhibitor in combination with the tankyrase-1 (TNKS1) inhibitor on TNBC cells. MATERIALS AND METHODS: We evaluated the antitumor effects of combination therapy with PLK1 and TNKS1 inhibitor using cell viability analysis, apoptosis assay and transwell assay for cell invasion and migration in TNBC cells. RESULTS: Combination treatment with PLK1 and TNKS1 inhibitors not only inhibited the invasion and migration capacity of TNBC cells, but also increased the apoptosis and cell death of TNBC cells. The viability of TNBC cells with low expression of beta-catenin and high expression of PLK1 was not affected by treatment with PLK1 inhibitor. However, the combination treatment with the TNKS1 inhibitor significantly decreased cell invasion and migration and increased apoptosis. CONCLUSION: Combination therapy of PLK1 and TNKS1 inhibitors may improve the therapeutic efficacy of the current treatment for TNBC. PMID- 29491054 TI - Chemotherapeutic Effect of CD147 Antibody-labeled Micelles Encapsulating Doxorubicin Conjugate Targeting CD147-Expressing Carcinoma Cells. AB - BACKGROUND: CD147 (basigin/emmprin) is expressed on the surface of carcinoma cells. MATERIALS AND METHODS: For studying the efficacy of CD147-targeting medicine on CD147-expressing cells, we studied the effect of anti-CD147-labeled polymeric micelles (CD147ab micelles) that encapsulated a conjugate of doxorubicin with glutathione (GSH-DXR), with specific accumulation and cytotoxicity against CD147-expressing A431 human epidermoid carcinoma cells, Ishikawa human endometrial adenocarcinoma cells, and PC3 human prostate carcinoma cells. RESULTS: By treatment of each cell type with CD147ab micelles for 1 h, a specific accumulation of CD147ab micelles in CD147-expressing cells was observed. In addition, the cytotoxicity of GSH-DXR-encapsulated micelles against each cell type was measured by treatment of the micelles for 1 h. The cytotoxic effect of CD147ab micelles carrying GSH-DXR was 3- to 10-fold higher for these cells than that of micelles without GSH-DXR. CONCLUSION: These results suggest that GSH-DXR encapsulated CD147ab micelles could serve as an effective drug delivery system to CD147-expressing carcinoma cells. PMID- 29491056 TI - Glucans and Cancer: Comparison of Commercially Available beta-glucans - Part IV. AB - BACKGROUND/AIM: beta-Glucans are well-established immunomodulators with strong effects across all immune reactions. Due to the extensive amount of studies, glucans are steadily progressing from a non-specific immunomodulator to a licensed drug. However, direct comparisons of higher numbers of different glucans are rare. MATERIALS AND METHODS: In this study, we used 16 different glucans isolated from yeasts, mushroom, algae, and oat and compared their effects on phagocytosis, IL-2 production, antibody secretion, and inhibition of three experimental cancer models. RESULTS: Our results showed significant differences among tested glucans, showing that despite the fact that glucans in general have strong stimulating effects on most aspects of the immune system, it is necessary to choose the right glucan. CONCLUSION: Based on our studies, we can conclude that highly purified and active glucans have significant pleiotropic effects. PMID- 29491055 TI - Mutational and Functional Analysis of FANCB as a Candidate Gene for Sporadic Head and Neck Squamous Cell Carcinomas. AB - BACKGROUND/AIM: Head and neck squamous cell carcinomas (HNSCCs) form a heterogeneous tumor entity located throughout the oral cavity, pharynx and larynx that is caused predominantly by chemically or virally induced carcinogenesis. Heterozygous germline mutations in cancer susceptibility genes might also lead to increased incidence of HNSCCs. As DNA stability is typically impaired in HNSCC cells and genes of the Fanconi anemia/BRCA DNA repair pathway can be mutated or down-regulated in HNSCCs, we investigated here whether germline mutations occur in the X-chromosomal FANCB as candidate gene. MATERIALS AND METHODS: Germline DNA of 85 consecutive HNSCC patients was sequenced. Missense alterations in FANCB were functionally tested in reference cells. RESULTS AND CONCLUSION: Four single nucleotide polymorphisms were identified, three of which were located in untranslated regions of FANCB (rs2188383, rs2375729, rs2905223) and predicted to be associated with normal function. One missense alteration, c.1004G>A resulting in p.G335E (rs41309679), in exon 4 was detected in five men in homozygous and in five women in heterozygous state. Four in silico prediction programs uniformally predicted p.G335E to be associated with loss-of-function of the protein. To clarify these predictions, we expressed the FANCB p.G335E protein in primary human FANCB deficient fibroblasts. Cell cycle analysis of these fibroblasts established that the FANCB p.G335E was functionally indistinguishable from the wildtype FANCB protein. Thus, functional studies in genetically defined cells showed that the p.G335E germline alteration in FANCB is not associated with impaired function. PMID- 29491057 TI - BRAF Inhibitors and Radiation Do Not Act Synergistically to Inhibit WT and V600E BRAF Human Melanoma. AB - BACKGROUND/AIM: Recent evidence suggests that melanoma patients treated with BRAF inhibitors experience radiosensitization with an increased frequency of side effects. This could also imply increased effectiveness when treating melanoma. MATERIALS AND METHODS: To test whether the BRAF inhibitors dabrafenib and vemurafenib together with ionizing radiation more effectively inhibit melanoma cells, primary human melanoma tumor cell lines expressing wild-type (WT) or mutant V600E BRAF were analyzed by cell survival, cell death, and cell-cycle testing. RESULTS: All melanoma cell lines examined were radioresistant in these assays. BRAF inhibitor treatment alone suppressed cell survival more effectively than radiation in all the mutant V600E BRAF cell lines, and vemurafenib, but not dabrafenib, also inhibited cell survival in the WT BRAF cell lines at clinically relevant concentrations. However, when cells were treated with BRAF inhibitor followed by radiation, there was no increased effect on the suppression of cell survival. Vemurafenib induced more necrosis than radiation in most melanoma cell lines, irrespective of BRAF status, but this effect was not additive with the combination treatment. BRAF inhibitors and radiation had variable, but independent effects on the induction of cell-cycle arrest. CONCLUSION: These results suggest that BRAF inhibitors and ionizing radiation do not act synergistically to inhibit the growth of primary human melanoma cells. PMID- 29491058 TI - Squamous Cell Carcinoma Antigen-encoding Genes SERPINB3/B4 as Potentially Useful Markers for the Stratification of HNSCC Tumours. AB - BACKGROUND/AIM: The squamous cell carcinoma antigen (SCCA), encoded by the genes SERPINB3/B4, is a tumour marker produced by head and neck squamous cell carcinoma (HNSCC). We aimed to examine SERPINB3/B4 mRNA levels and its clinical significance in the therapeutic context. MATERIALS AND METHODS: We retrieved mRNA expression levels, clinical, pathological and genomic data for 520 HNSCC from The Cancer Genome Atlas (TCGA). RESULTS: HNSCC tumours express high levels of SERPINB3/B4 mRNA. SERPINB3 expression differs depending on Human papillomavirus (HPV) infection status, primary tumour location, grade and differentiation, extension to lymph nodes and extracapsular spread. Interestingly, we observed an association between SERPINB3/B4 and the presence of tumour immune infiltrate as well as the expression of the immune checkpoint regulators PD-L1/PD-L2 that depended on HPV status. CONCLUSION: Our findings point to potential interest of SERPINB3/B4 for the stratification of HNSCC patients in the therapeutic context. PMID- 29491059 TI - Inhibition of Asparagine-linked Glycosylation Participates in Hypoxia-induced Down-regulation of Cell-surface MICA Expression. AB - BACKGROUND/AIM: Hypoxia down-regulates the expression of cell surface major histocompatibility class I-related chain molecule A (MICA) without increasing its shedding. Recently, the inhibition of N-linked glycosylation was also shown to reduce the cell-surface expression of MICA. We investigated the participation of asparagine (Asn)-linked glycosylation in hypoxia-induced down-regulation of cell surface MICA using osteosarcoma cells. MATERIALS AND METHODS: The cell-surface expression and Asn-N-glycosylation of MICA were estimated by flow cytometry, and western blot analyses, respectively. RESULTS: Hypoxia reduced the expression of N linked glycosylated MICA, as well as the ratio of N-linked glycosylated to non glycosylated MICA. 2-Deoxy-D-glucose, which inhibits N-linked glycosylation, reduced the cell-surface expression of MICA under normoxia, while D-Mannose increased N-glycosylated MICA, increasing cell-surface MICA under hypoxia. Cells transfected with wild-type MICA expression vector expressed cell surface MICA more than those transfected with mutant MICA expression vectors designed for abrogation of N-linked glycosylation. CONCLUSION: The inhibition of Asn-N-linked glycosylation participates in hypoxia-induced down-regulation of cell-surface expression of MICA. PMID- 29491060 TI - Expression of Sphingosine Kinase-1 Is Associated with Invasiveness and Poor Prognosis of Oral Squamous Cell Carcinoma. AB - BACKGROUND/AIM: The expression of sphingosine kinase-1 (SphK1) has been reported in several cancers. However, the exact roles of SphK1 in cancer progression still remain unknown. The aim of the present study was to investigate SphK1 expression in oral squamous cell carcinoma (OSCC) and clarify the involvement of SphK1 in the proliferation and invasiveness of OSCC and its prognostic implications. MATERIALS AND METHODS: Expression of SphK1, E-cadherin, vimentin, and Ki-67 were examined in 69 OSCC tissues immunohistochemically, as well as by western blot, and correlations between their expression and relationships with tumor invasiveness and prognosis were analyzed. RESULTS: SphK1 was expressed in the tumor cells of 38 of 69 OSCCs, particularly at the invasion front. Patients with OSCCs with high SphK1 expression showed higher invasive grades and unfavorable survival rates. SphK1 expression correlated with acquisition of vimentin expression and loss of E-cadherin expression; there was no significant difference in Ki-67 labeling indices between OSCCs with high and low SphK1 expression. CONCLUSION: These results demonstrate the involvement of SphK1 in the invasiveness of OSCC and in unfavorable prognosis, indicating its role in the epithelial-mesenchymal transition of OSCC cells. PMID- 29491061 TI - Impact of Methadone on Cisplatin Treatment of Bladder Cancer Cells. AB - BACKGROUND: Cisplatin-based chemotherapy is the treatment of choice for advanced bladder cancer. Since many tumor cells show inherent or acquired cisplatin resistance, research is needed to improve the therapeutic efficacy. Since the analgesic methadone is discussed as being a sensitizer for chemotherapy, we tested its effects on the cisplatin treatment of bladder cancer cells. MATERIALS AND METHODS: T24 and HT-1376 bladder cancer cells were incubated with cisplatin in combination with methadone. Cytotoxicity was examined using the WST-1 viability assay and induction of apoptosis was analyzed via phase-contrast microscopy, flow cytometry, and western blot analysis. RESULTS: Methadone was shown to enhance the cytotoxic effects of cisplatin on T24 cells based on the induction of apoptosis. In contrast, HT-1376 cells were identified as non responders to methadone. CONCLUSION: Methadone could act as a chemosensitizer in the future treatment of advanced bladder cancer. Further research is needed to identify the underlying molecular mechanisms. PMID- 29491062 TI - Galangin Induces p53-independent S-phase Arrest and Apoptosis in Human Nasopharyngeal Carcinoma Cells Through Inhibiting PI3K-AKT Signaling Pathway. AB - BACKGROUND/AIM: Anti-cancer activity of 3,5,7-trihydroxyflavone (galangin) has been documented in a variety of cancer types; however, its effect on human nasopharyngeal carcinoma (NPC) cells remains undetermined. MATERIALS AND METHODS: Human NPC cell lines were treated with galangin. Apoptosis was analyzed by assessing nuclear condensation, cleavage of pro-caspase-3 and poly ADP-ribose polymerase (PARP), and DNA fragmentation. Short hairpin RNA-mediated silencing of p53 was used for characterizing the role of p53 in the anti-cancer activity of galangin. Phosphatidylinositol 3-kinase (PI3K) inhibitor, protein kinase B (AKT) inhibitor, and ectopic expression of wild type p85alpha or p85alpha mutant lacking p110alpha-binding ability were utilized to confirm the involvement of PI3K/AKT inactivation in galangin-induced apoptosis. RESULTS: Galangin induces apoptosis and S-phase arrest by attenuating the PI3K/AKT signaling pathway. Silencing of p53 did not block the anti-cancer activity of galangin on NPC cells. CONCLUSION: Galangin effects on apoptosis and S-phase arrest in NPC cells are mediated via interfering with the PI3K-AKT signaling pathway in a p53-independent manner. PMID- 29491063 TI - Suppressive Effect of Delta-Tocotrienol on Hypoxia Adaptation of Prostate Cancer Stem-like Cells. AB - BACKGROUND/AIM: A hallmark of the progression of prostate cancer to advanced disease is the acquisition of androgen-independent growth. This malignant phenotype is characterized by resistance to conventional treatments and predisposes to formation of hypoxic regions containing stem-like cancer cells. Unfortunately, an effective therapy to target prostate cancer stem cells under hypoxia has not yet been established. In this report, we studied whether delta tocotrienol (T3), a vitamin E family member that has exhibited the most potent anti-cancer activity, could suppress the survival of prostate cancer stem-like cells. MATERIALS AND METHODS: PC3 stem-like cells were isolated from PC3 parental cells using a three-dimensional culture system. The stemness of the isolated PC3 stem-like cells was confirmed by evaluation of resistance to an anticancer agent (docetaxel) and tumor formation capacity in a xenograft model. The effects of delta-T3 on PC3 stem-like cells under a hypoxia condition were examined by WST-8 (cell viability), real-time reverse transcription-polymerase chain reaction (PCR) and western blotting. RESULTS: delta-T3 demonstrated a cytotoxic effect on prostate cancer stem-like cells in a dose dependent manner and a reduction in the protein levels of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha. Additionally, a specific inhibitor toward HIF-1alpha induced cytotoxicity on PC3 cells, but selective inhibition of HIF-2alpha had no effect. CONCLUSION: Overall, these results suggest that delta-T3 could inhibit the survival of prostate cancer stem-like cells under hypoxia, primarily through the inactivation of HIF-1alpha signaling. PMID- 29491064 TI - Reduced Tumour Proportion Scores for Programmed Cell Death Ligand 1 in Stored Paraffin Tissue Sections. AB - BACKGROUND/AIM: We evaluated the effects of storage of formalin-fixed, paraffin embedded (FFPE) sections on the tumour proportion score (TPS) for programmed cell death ligand 1 (PD-L1), as indicator in non-small cell lung cancer (NSCLC) tissues of treatment efficacy. MATERIALS AND METHODS: NSCLC postoperative specimens with PD-L1 TPS >=50% were obtained and cut into five serial sections. One section was stained immediately, and four were stored at 4 degrees C for 2, 4, 6, or 8 weeks. Slides were subjected to PD-L1 immunohistochemistry using the anti-PD-L1 clone 28-8. PD-L1 TPS were blindly evaluated by two independent pathologists. RESULTS: Twelve specimens (60 slides) were evaluated. After slide storage for 2, 4, 6, and 8 weeks, a TPS of <50% was obtained in five (41%), four (33%), seven (58%), and eight (67%) patients, respectively. CONCLUSION: TPS values for PD-L1 were reduced by long-term slide storage of FFPE specimens. Sectioned slides should be stained for PD-L1 without delay. PMID- 29491065 TI - Vitamins C and K3: A Powerful Redox System for Sensitizing Leukemia Lymphocytes to Everolimus and Barasertib. AB - BACKGROUND/AIM: Recent studies provided convincing evidence for the anticancer activity of combined application of vitamin C and pro-vitamin K3 (menadione). The molecular pathways underlying this process are still not well established. The present study aimed to investigate the effect of the combination of vitamin C plus pro-vitamin K3 on the redox status of leukemia and normal lymphocytes, as well as their sensitizing effect for a variety of anticancer drugs. MATERIALS AND METHODS: Cytotoxicity of the substances was analyzed by trypan blue staining and automated counting of live and dead cells. Apoptosis was analyzed by fluorescein isothiocyanate-annexin V test. Oxidative stress was evaluated by the intracellular levels of reactive oxygen and nitrogen species and protein-carbonyl products. RESULTS: Combined administration of 300 MUM vitamin C plus 3 MUM pro vitamin K3 reduced the viability of leukemia lymphocytes by ~20%, but did not influence the viability of normal lymphocytes. All combinations of anticancer drug plus vitamins C and K3 were characterized by synergistic cytotoxicity towards Jurkat cells, compared to cells treated with drug alone for 24 h. In the case of barasertib and everolimus, this synergistic cytotoxicity increased within 72 hours. It was accompanied by strong induction of apoptosis, but a reduction of level of hydroperoxides and moderately increased protein-carbonyl products in leukemia cells. CONCLUSION: Leukemia lymphocytes were more sensitive to combined administration of anticancer drug (everolimus or barasertib) plus vitamins C and K3, compared to normal lymphocytes. The combination of vitamin C plus K3 seems to be a powerful redox system that could specifically influence redox homeostasis of leukemia cells and sensitize them to conventional chemotherapy. PMID- 29491066 TI - The Comparison Between Molecular Tumour Profiling in Microdissected and Surgical Tissue Samples. AB - BACKGROUND/AIM: Laser capture microdissection (LCM) is one of the most important tools in molecular and histopathological tissue analysis. We compared the expression level of protein phosphatase genes in LCM and surgical colorectal cancer samples to evaluate whether there is a significant difference in molecular profiling. MATERIALS AND METHODS: The expression levels of 99 protein phosphatase and 15 control genes were analysed in 104 microdissected, 81 surgical colorectal cancer and 25 control samples. Microarray expression data were obtained from the GEO Database of the National Center for Biotechnology Information. RESULTS: The analysis revealed that over 60% of expression results were in agreement with LCM and surgically obtained samples while 32% of non-matched results belonged to the group where no effect was observed in LCM samples and down-regulation- or overexpression was reported in surgical samples. CONCLUSION: Generally, it is more likely to find critical genetic alterations in surgically obtained than in LCM samples. PMID- 29491067 TI - Clinicopathological and Prognostic Significance of Epithelial Gremlin1 Expression in Gastric Cancer. AB - BACKGROUND/AIM: Gastric cancer (GC) is one of the most common malignancies worldwide. Gremlin1 is an antagonist of bone morphogenetic proteins that plays a critical role in several biological processes including cancer biology. MATERIALS AND METHODS: We immunohistochemically examined the expression and distribution of Gremlin1 in non-neoplastic gastric mucosa in a series of 159 GC cases. RESULTS: Among 159 GC primary tumors, 59 (37%) were positive for Gremlin1. Gremlin1 negative GC cases showed significantly more advanced clinicopathologic factors and a trend toward intestinal-type GC. Gremlin1 expression was also frequently observed in MUC5AC-positive and G-type GC cases. Gremlin1-negative GCs had a poorer survival rate than Gremlin1-positive GCs (p=0.002). Univariate and multivariate analyses revealed that Gremlin1 expression is an independent predictor of survival in GCs. CONCLUSION: These results indicate that Gremlin1 could be involved in GC progression and may be a good marker of long-term survival in GC. PMID- 29491068 TI - Pre-exposure to Fluorouracil Increased Trifluridine Incorporation and Enhanced its Anti-tumor Effect for Colorectal Cancer. AB - BACKGROUND/AIM: Trifluridine/tipiracil (FTD/TPI) is used for metastatic colorectal cancer, that is refractory to 5-fluorouracil (5-FU)-based therapies. However, the impact of pre-exposure to 5-FU on the anti-cancer effect of FTD, which is a key component of FTD/TPI, is unclear. MATERIALS AND METHODS: The incorporation into DNA and anti-cancer activity of FTD were analyzed in several cancer cell lines under response to FTD treatment with or without 5-FU pre exposure. The volumes of tumors in xenografted nude mice were examined among groups that were either untreated or treated with S-1, FTD/TPI or FTD/TPI with pre-exposure to S-1. RESULTS: Pre-exposure to 5-FU significantly increased FTD incorporation into DNA and enhanced its anti-cancer effect for viability and proliferation of cancer cells. In the xenograft nude mouse model, the tumor volumes in the FTD/TPI-treated and S-1-pre-exposed group were lower than those in the FTD/TPI-only-treated group. Although both FTD dose and exposure time in the FTD/TPI-treated and S-1-pre-exposed mice were smaller than those in the FTD/TPI only-treated mice, the incorporated FTD in the tumors in the former group was 86.5% of that in the latter group. CONCLUSION: Pre-exposure to 5-FU enhanced the incorporation into DNA and the anti-cancer effect of FTD in the context of colorectal cancer. Our data indicate the potential for a new sequential therapy using S-1 and FTD/TPI to improve prognosis of colorectal cancer. PMID- 29491069 TI - Clinical Implications of CD4+CD25+Foxp3+Regulatory T Cell Frequencies After CHP MAGE-A4 Cancer Vaccination. AB - BACKGROUND/AIM: The aim of this study was to explore whether the treatment effect or immune response to a cancer vaccine can be predicted by the percentage of CD4+CD25+Foxp3+ regulatory T cells (Tregs) in peripheral blood mononuclear cells (PBMCs) after vaccination. PATIENTS AND METHODS: Sixteen patients (9 men, 7 women; median age 61.5 years) enrolled in the CHP-MAGE-A4 cancer vaccine clinical trial who had a fixed dose (300 MUg of CHP-MAGE-A4 cancer vaccine and 0.5 Klinische Einheit (KE) of OK432 and received at least four vaccinations were investigated. Safety, immune response, and clinical effects were assessed before and after the cancer vaccination. RESULTS: Treg ratios that remained low both before and after vaccination were associated with a good prognosis, and a low Treg/CD4 lymphocyte ratio 7-weeks after the initial vaccination was correlated with a better prognosis. CONCLUSION: The Treg ratio following vaccination appears to have some utility for predicting patient prognosis. PMID- 29491070 TI - AZD8055 Exerts Antitumor Effects on Colon Cancer Cells by Inhibiting mTOR and Cell-cycle Progression. AB - BACKGROUND/AIM: AZD8055 is an inhibitor of mammalian target of rapamycin (mTOR) that can suppress both mTOR complex 1 (mTORC1) and mTORC2. This study investigated the antitumor effects of AZD8055 on colon cancer. MATERIALS AND METHODS: The effects of AZD8055 on proliferation, apoptosis, and cell cycle of colon cancer cells, and tumor growth in a mouse colon cancer model were studied. RESULTS: AZD8055 significantly inhibited proliferation and induced apoptosis of colon cancer cells (p<0.05). The phosphorylation of both AKT and S6 kinase 1 (S6K1) was suppressed by AZD8055. AZD8055 also induced G0/G1 cell-cycle arrest, reduced cyclin D1 and increased p27 expression, and suppressed the levels of phospho-cyclin-dependent kinase 2 and phospho-retinoblastoma. Compared to the control, oral administration of AZD8055 significantly suppressed tumor growth in mice (p<0.05). CONCLUSION: AZD8055 induces cytotoxicity, apoptosis, and cell cycle arrest of colon cancer cells, and exerts an antitumor effect in mice. It also inhibits the mTOR signaling pathway and mTOR-dependent cell-cycle progression. PMID- 29491071 TI - Polymorphisms of ABCB1, CYP3A4 and CYP3A5 Genes in Ovarian Cancer and Treatment Response in Poles. AB - BACKGROUND/AIM: Ovarian cancer is a lethal gynecological malignancy, with 5-year survival of only about one third of patients. The ABCB1 gene encodes the P glycoprotein which is one of the multidrug efflux pumps. Its decreased activity may result in multidrug resistance of cancer cells. Drug-metabolizing enzymes Cyp3A4 and Cyp3A5 may affect success of chemotherapy. In this study we attempted to examine the effects of 12 single nucleotide polymorphisms (SNPs) of the ABCB1 gene and one SNP in each of CYP3A4 and CYP3A5 genes on the incidence of ovarian cancer in Polish women and their response to treatment. MATERIALS AND METHODS: Our study included 276 patients and 369 healthy control women. RESULTS: The results showed no significant differences between patients and controls in allele frequencies of the tested SNPs, with one exception: rs2157926T allele decreased cancer risk by 99.4% (odds ratio, 0.006). Moreover, rs2032582T increased fourfold the risk of metastasis. Finally, rs1128503CC genotype prolonged survival (p=0.024778). CONCLUSION: These findings may contribute to a better prediction of therapy outcome. PMID- 29491072 TI - Curcumin and Rutin Down-regulate Cyclooxygenase-2 and Reduce Tumor-associated Inflammation in HPV16-Transgenic Mice. AB - AIM: Cyclo-oxygenase-2 (COX2) plays a prominent role in carcinogenesis. This study addresses the effects of two nutraceutical compounds on the expression of COX2 and tumor-associated inflammation in human papillomavirus type 16 (HPV16) transgenic mice. MATERIALS AND METHODS: Six-week-old FVB/n mice were supplemented with rutin or curcumin for 24 weeks: HPV16-/- no treatment, n=12; HPV16+/- no treatment, n=13; HPV16+/- rutin, n=12; HPV16+/- curcumin, n=13. HPV16-induced skin lesions and their inflammatory infiltrates were studied histologically. COX2 expression was assessed immunohistochemically. RESULTS: Rutin reduced COX2 expression in the dermis (immunostaining score 7.83 versus 11.25 in untreated HPV16-transgenic mice) and epidermis (4.5 versus 10.0). Curcumin led to dermal and epidermal scores of 10.5 and 4.5. Both compounds reduced leukocytic infiltration, but neither prevented epidermal dysplasia. CONCLUSION: COX2 expression in HPV16-induced lesions may be modulated by nutraceuticals, reducing tumor-associated inflammation. However, this was not sufficient to block carcinogenesis, calling for additional studies focused on combination therapies. PMID- 29491073 TI - Combined Oocyte Retrieval and Robot-assisted Hysterectomy in a Super Morbidly Obese Patient with Endometrial Carcinoma. AB - AIM: To report on the unique, innovative management of a super morbidly obese patient presenting for fertility preservation in the setting of Grade 2 endometrioid endometrial adenocarcinoma. CASE REPORT: A back-to-back oocyte retrieval and robot-assisted total laparoscopic hysterectomy (RA-TLH) with bilateral salpingo-oophorectomy (BSO) was performed in a 37-year-old nulligravid woman with super morbid obesity (BMI 63 kg/m2) with endometrial cancer. MAIN OUTCOME MEASURE: the successful retrieval of oocytes for fertility preservation and oncologic intervention via RA-TLH with BSO in the same operative and anesthetic episode. RESULTS: This combined procedure strategy was successful in our case and is a feasible option for similar high-risk patients in the future. CONCLUSION: Identifying safe and effective approaches for oocyte retrieval in morbidly obese patients represents a pressing need as obesity rates rise among reproductive-aged women. Back-to-back oocyte retrieval and RA-TLH with BSO are not only feasible, but could also decrease significant anesthetic risks for morbidly obese patients. PMID- 29491074 TI - A Panel of Biomarkers for Diagnosis of Prostate Cancer Using Urine Samples. AB - BACKGROUND/AIM: Prostate cancer (PCa) diagnosis using patient urine samples represents a non-invasive and more convenient method than the conventional biopsy and prostate-specific antigen (PSA) test. This study intended to identify a biomarker panel to distinguish PCa from benign prostate using urine samples. MATERIALS AND METHODS: We identified six biomarkers with differential gene expression in 154 PCa and benign prostate specimens. We then determined mRNA expression signature and the diagnostic performance of the 6-biomarker panel in 156 urine samples from patients with PCa and benign disease. RESULTS: The 6 biomarker panel distinguished PCa from benign prostate cases with sensitivity of 80.6%, specificity of 62.9% and area under the curve (AUC) of 0.803 (p<0.0001), whereas serum PSA at 4 ng/ml cutoff had sensitivity of 95.5%, specificity of 20.2% and AUC of 0.521 (p<0.0001). CONCLUSION: The 6-biomarker panel for use in urine samples was able to distinguish PCa from benign prostate with higher specificity and accuracy than PSA and may be useful in clinical settings. PMID- 29491075 TI - Clear Cell Sarcoma-like Tumor of the Gastrointestinal Tract: Clinical Outcome and Pathologic Features of a Molecularly Characterized Tertiary Center Case Series. AB - BACKGROUND/AIM: Clear cell sarcoma-like tumor of the gastrointestinal tract (CCSLTGT) is a very rare and relatively recently characterized mesenchymal neoplasm arising within the wall of the small bowel, stomach, or large bowel, predominantly in adolescents and young adults. Only few anecdotal reports or small series have been published and a consensus on treatment has not been formulated. Complete resection remains the only curative option for localized disease, but despite optimal surgery, CCSLTGT typically shows highly aggressive behavior with a high rate of local recurrence, metastases, and death from disease. The hallmark of CCSLTGT is the presence of EWSR1-CREB1 or EWSR1-ATF1 gene fusions, detectable with reverse transcription-polymerase chain reaction (PCR). The aim of this study was to assess all referred cases of CCSLTGT, and document the pathological features, treatment and outcome of these patients. PATIENTS AND METHODS: We retrospectively reviewed all cases of histologically- and molecularly-confirmed CCSLTGT with EWSR1-CREB1 or EWSR1-ATF1 fusions at our tertiary sarcoma center, between 2009 and 2016. RESULTS: We assessed six patients diagnosed with CCSLTGT. In a median follow-up of 8 months, all patients received surgery, and additionally one patient was treated with chemotherapy and had progressive disease. Five of six patients experienced recurrence or progression of disease and 4 of 6 patients died of disease. CONCLUSION: Our study confirms that CCSLTGT is a very rare aggressive sarcoma subtype with a very poor outcome. Greater international collaboration is required to obtain a better understanding of this disease. PMID- 29491076 TI - COX2/PTGS2 Expression Is Predictive of Response to Neoadjuvant Celecoxib in HER2 negative Breast Cancer Patients. AB - BACKGROUND: The prognostic and predictive role of cyclo-oxygenase-2 (COX2) in breast cancer is still debated, and in particular, its role as a target of COX2 inhibitor (celecoxib) in neoadjuvant setting. MATERIALS AND METHODS: We analyzed a series of 156 breast cancer samples from patients of the COX2 inhibitor-treated arm included in the REMAGUS-02 randomized phase II trial. COX2 gene expression was assessed by reverse transcription and quantitative polymerase chain reaction using ribonucleic acid from frozen biopsies. Pathological complete response (pCR) was the surrogate end-point. RESULTS: Significantly higher rates of grade 3, and estrogen and progesterone receptor negativity were observed in tumors with the highest expression of COX2. pCR rates were significantly higher in COX2 overexpressing tumors in patients receiving celecoxib. The test for interaction between COX2 gene expression and the celecoxib effect was statistically significant (p<0.01), but was not retained in the multivariate analysis. CONCLUSION: COX2 overexpression is predictive of pCR in patients with celecoxib treated tumors. The efficacy of celecoxib in breast cancer might be improved by quantification of COX2 gene expression. PMID- 29491077 TI - Serum C-reactive Protein and Neutrophil/Lymphocyte Ratio After Neoadjuvant Radiotherapy in Soft Tissue Sarcoma. AB - BACKGROUND/AIM: The predictive value of serum C-reactive protein (CRP) and neutrophil/lymphocyte (N/L) ratio in soft tissue sarcoma (STS) patients receiving neoadjuvant radiotherapy (RT) has not been analyzed. PATIENTS AND METHODS: From 2007 to 2015, we identified 98 STS patients from a prospective database. Using multivariate analysis, we analyzed CRP and N/L ratios as predictors of overall survival (OS). RESULTS: Mean age of patients was 59 years, 46% were female, and 55% of tumors were located at the extremity. A total of 15 histologies were represented. Fifty percent received preoperative RT. Except for extremity location, characteristics were similar between the preoperative RT and upfront surgery cohorts, including baseline CRP levels and N/L ratios. Multivariate analysis of upfront surgery revealed histological grade, tumor size, and baseline N/L ratio to be predictors of OS, while for preoperative RT, baseline CRP and N/L ratio were not predictive. CONCLUSION: Baseline CRP and N/L ratio did not predict poor clinical outcome in STS patients receiving neoadjuvant RT. PMID- 29491078 TI - Expression of Progesterone and Androgen Receptors in the Breast of Premenopausal Women, Considering Menstrual Phase. AB - BACKGROUND: Progesterone and androgens are important for normal development and tumorigenesis of the breast. PATIENTS AND METHODS: Breast tissue samples from 49 premenopausal women were obtained. The progesterone receptors (PRA, PRB, PGRMC1 and PGRMC2) and the androgen receptor (AR) were determined in malignant and benign breast tumors and control tissues. RESULTS: The PRB and AR mRNA levels were highest in tumors. PGRMC1 and PGRMC2 mRNA levels were higher in malignant tumors compared to their paired normal tissues. PRA protein showed most immunostaining in benign tumors. PRB immunostaining varied according to menstrual phase. AR immunostaining was highest in the glands of malignant tumors. CONCLUSION: Progesterone and androgen receptors are differently regulated in tumors compared to normal breast tissues. A malignant breast tumor could appear PR-negative if collected in the luteal phase, but positive in the follicular phase. This finding may have clinical implications. PMID- 29491079 TI - Dose-function Histogram Evaluation Using 99mTc-GSA SPECT/CT Images for Stereotactic Body Radiation Therapy Planning for Hepatocellular Carcinoma Patients: A Dosimetric Parameter Comparison. AB - BACKGROUND/AIM: We evaluated the influence of previous treatments on the parametric discrepancies between dose-volume histograms (DVHs) and dose-function histograms (DFHs) generated based on 99mTc-GSA SPECT images of hepatocellular carcinoma (HCC) patients treated with stereotactic body radiation therapy (SBRT). PATIENTS AND METHODS: Twelve patients underwent SBRT at 30-40 Gy. Registration between planning CT and SPECT/CT images was performed, and DFH parameters were calculated as follows: Fx=(sum of the counts within the liver volume receiving a dose of more than x Gy/sum of the counts within the whole liver volume) *100. The discrepancy between Fx and Vx (Dx) was also calculated. RESULTS: The number of previous treatments for lesions other than SBRT-treated lesions (>=2 vs. <2) exhibited a significant influence on the absolute values of D10, D15, and D20 (p<0.05). CONCLUSION: Previous treatment significantly influences the parametric discrepancy between DFH and DVH. PMID- 29491080 TI - Transitory Stoma at the Time of Complete Cytoreductive Surgery Affects Survival for Patients with Advanced-stage Ovarian Cancer. AB - AIM: To evaluate the influence on relapse-free survival (RFS) and overall survival (OS) of a transitory protective stoma (TPS) at the time of complete cytoreductive surgery for advanced-stage ovarian cancer. PATIENTS AND METHODS: From our Institution, we retrospectively selected patients from 2006 to 2011 with ovarian cancer with the following criteria: stage IIIB to IVA (pleural effusion) according to the International Federation of Gynaecology and Obstetrics classification; complete cytoreductive surgery (CC0 according to Sugarbaker's classification); and a low anterior resection. We evaluated the influence on relapse-free survival (RFS) and overall survival (OS) of a transitory protective stoma (TPS). RESULTS: Nine patients were identified with and 90 without TPS. We found no difference between these two groups in terms of age, body mass index, histological subtype, grade, initial cancer antigen 125 level, type of surgery, Peritoneal Cancer Index score and the interval between surgery and adjuvant chemotherapy. Two out of the nine patients (22%) in the TPS group had adhered to the chemotherapy schedule versus 52/90 (58%) in the no-TPS group (p<0.05). Eight out of the nine patients with a TPS had undergone stomal closure with a median delay of 25 weeks (5-40 weeks). In the univariate analysis using the log-rank test, undergoing an ileostomy at the time of cytoreductive surgery was significantly associated with decreased OS (p=0.003) and RFS (p=0.001). In the multivariate analysis, a TPS was associated with a higher risk of recurrence (p=0.002). CONCLUSION: An ileostomy at the time of complete CRS negatively affects survival in patients with advanced-stage ovarian cancer. PMID- 29491081 TI - Surveillance Imaging in HPV-related Oropharyngeal Cancer. AB - BACKGROUND/AIM: Current guidelines derived from a pre-human papilloma virus (HPV) era in oropharyngeal cancer do not recommend routine surveillance imaging. We aimed to analyze the method of recurrence detection in HPV+ disease to determine a role for follow-up imaging. PATIENTS AND METHODS: All HPV+ and HPV- oropharyngeal cancer patients treated at our institution from 2005-2016 with biopsy-proven recurrence were identified and their method of recurrence detection was analyzed. RESULTS: A total of 16 HPV+ oropharyngeal cancer patients were identified to have recurrence, 12 (75%) of which experienced distant recurrence and 13 (81.3%) were detected asymptomatically with imaging at a median time of 19.7 months after initial treatment and verifying no residual disease. Twelve (75%) detections were with PET-CT. While HPV- patients (17 patients) also have a high rate of asymptomatic detection (16 patients, 94.1%), their 3-year post recurrence survival was significantly lower at 6.5% compared to 83.6% for the HPV+ group (p<0.01). CONCLUSION: In HPV+ patients, a large proportion of failures are asymptomatic distant metastases, which occur beyond 6 months following treatment completion, and are detected with whole body imaging alone. In light of long term post-recurrence survival observed, this preliminary data suggests that routine surveillance imaging should be further studied for HPV+ disease. PMID- 29491082 TI - Synthesis and Binding of a Novel PSMA-specific Conjugate. AB - BACKGROUND/AIM: Prostate-specific membrane antigen (PSMA) is emerging as a target for treatment of castration-resistant prostate cancer (CRPC) while its up regulated in the majority of CRPC tumors. The most common approach is targeted radionuclide therapy. MATERIALS AND METHODS: The PSMA binding pharmacophore Glu Urea-Lysine (GUL) and lysine were conjugated to oxidized dextran with reductive amination and subsequently labelled with fluorosceinisothiocyanate (FITC). Three prostate cancer cell lines were used for binding studies, 22Rv1 (PSMA positive), DU145 (PSMA negative) and PC3 (PSMA negative). Binding images were obtained by fluorescence microscopy. RESULTS: PDC binding was recorded on the 22Rv1 cell line while the negative cell lines showed no or slight background binding. PDC binding could be inhibited by pre-incubation with a molar excess of unlabelled PDC. CONCLUSION: This is a novel template for PSMA targeted CRPC therapy, either using cytostatics or radionuclides. PMID- 29491083 TI - Characterization and Management of Borderline Ovarian Tumors - Results of a Retrospective, Single-center Study of Patients Treated at the Department of Gynecology and Obstetrics of the University Medicine Greifswald. AB - BACKGROUND/AIM: Borderline ovarian tumors (BOT) are malignant epithelial ovarian tumors with a very low incidence, therefore lacking sufficient clinical experience in diagnostics and treatment. This study characterized the histology, clinical features, diagnostics and therapy of BOT including patients treated at the Department of Gynecology and Obstetrics of the University Medicine Greifswald. MATERIALS AND METHODS: In this retrospective, single-center study, patients with BOT treated between 1990 and 2010 were analyzed according to their histological and clinical reports. RESULTS: A total of 54 patients were enrolled. The median age was 54.6 (range=23-83) years. Distribution of histological subtypes was: serous in 31 patients (57.4 %) and mucinous in 23 patients (42.6%). All patients underwent surgery. Eight patients (14.8%) were treated according to actual therapy recommendations during the initial surgery. Eight patients (14.8%) received adjuvant chemotherapy contrary to treatment recommendations. In the case of 36 patients (66.7%), a frozen section was taken intraoperatively, which matched the definitive histological result in 88.9%. During average follow-up of 70.3 months (range=0-231 months), two patients (3.7%) developed tumor recurrence after 9 and 29 months, respectively, two patients (3.7%) died of causes other than BOT. CONCLUSION: Our study critically demonstrated that until a few years ago, BOTs were not usually treated according to international therapy recommendations. Nevertheless, the rate of tumor recurrence was very low. PMID- 29491084 TI - Functionality of the Tumor Suppressor microRNA-1 in Malignant Tissue and Cell Line Cells of Uterine Leiomyosarcoma. AB - BACKGROUND/AIM: Uterine leiomyosarcoma (uLMS) is a very rare mesenchymal tumor showing an aggressive clinical course and poor prognosis for patients. Due to the low incidence, little is known about molecular tumor biology and biomarkers of uLMS. Micro-RNA-1 (miR-1) has been identified as a pivotal tumor suppressor in numerous entities being suited as a molecular marker for tumor progression. MATERIALS AND METHODS: uLMS patient samples were analyzed regarding their miR-1 expression levels. Furthermore, miR-1 growth inhibitory and target regulatory properties were examined in transfected uLMS cells SK-UT-1. RESULTS: miR-1 was strongly suppressed in uLMS tumor tissue compared to adjacent healthy tissue. In vitro studies, however, failed to detect growth inhibitory properties of miR-1 in SK-UT-1 cells. The expression of the cell survival and MAP kinases Erk-1/2 and p38 was not targeted by miR-1. CONCLUSION: Tumor suppressive mechanisms of miR-1, seem to be inhibited in uLMS SK-UT-1 cells, maybe as part of the malignant transformation process. Regardless of the microRNA's cellular functionality, miR 1 may represent a promising biomarker of diagnosis in uLMS therapy. PMID- 29491085 TI - The Prognostic Significance of Hsp70/Hsp90 Expression in Breast Cancer: A Systematic Review and Meta-analysis. AB - BACKGROUND/AIM: Studies have focused on heat shock protein (Hsp) inhibitors as potential treatment agents in breast cancer, with controversial results. Adopting a pathophysiological perspective, this systematic review aims to synthesize the evidence examining the association between Hsp70/Hsp90 expression and breast cancer prognosis, as well as prognosis-related clinicopathological indices. Secondarily, changes in Hsp70/Hsp90 expression in the continuum of breast neoplasia were assessed. MATERIALS AND METHODS: Hsp70/Hsp90 expression was approached globally, quantified by means of immunohistochemistry, western blot or PCR. This study was performed in accordance with the PRISMA guidelines. Relevant studies were sought in PubMed, up to December 31, 2015. RESULTS: A total of 23 eligible studies were identified (7,288 breast cancer cases). High Hsp90 expre s sion was associated with worse overall survival (pooled RR=1.48, 95%CI=1.21-1.82) and marginally with worse disease-free survival. High Hsp70 expression also correlated with worse disease-free survival (pooled RR=1.77, 95%CI=1.71-2.82). Hsp70 intense expression correlated with ER positivity (pooled OR=3.51, 95%CI=1.31-9.40) and PR positivity (pooled OR=2.48, 95%CI=1.39-4.44). No significant associations were noted between Hsp70/Hsp90 expression and clinicopathological variables including histological grade, tumor size, nodal metastasis or patient age at diagnosis. No clear pattern emerged for Hsp70/Hsp90 expression along the breast neoplasia continuum. CONCLUSION: This systematic review and meta-analysis highlights the prognostic role of Hsp90 and Hsp70 expression in breast cancer. Further high-quality studies, with detailed reporting are needed to provide epidemiological evidence complementing the findings of ongoing clinical trials on Hsp inhibitors. PMID- 29491086 TI - A Strategy for Using Intraoperative Nerve Monitoring During Esophagectomy to Prevent Recurrent Laryngeal Nerve Palsy. AB - BACKGROUND: There have been only sporadic reports on intraoperative nerve monitoring (IONM) during esophageal cancer surgery. We aimed to establish a strategy for the use of IONM during esophagectomy. PATIENTS AND METHODS: Forty one cases enrolled in this study. The IONM was performed before and after lymph node dissection in the thoracic cavity and cervical area. Occurrence of recurrent laryngeal nerve (RLN) palsy was assessed on the seventh postoperative day. RESULTS: The identification of nerves using IONM was possible in all cases. The positive and negative predictive values of IOMN were 80% and 92%, respectively. Loss of response was observed during the thoracic procedure in 14 out of 16 cases, with the predominance of left RLN palsy (n=12). CONCLUSION: In esophageal cancer surgery, identification of the RLN using IONM can be carried out safely, simply, and promptly. Using IONM systematically, the prediction of RLN palsy and detection of nerve injury point seems feasible. PMID- 29491087 TI - Number of Resected Lymph Nodes and Survival of Patients with Locally Advanced Esophageal Squamous Cell Carcinoma Receiving Preoperative Chemoradiotherapy. AB - BACKGROUND: The association of extended lymph node (LN) dissection with improved outcomes in patients with locally advanced esophageal squamous cell carcinoma (ESCC) who received preoperative chemoradiotherapy (CRT) followed by surgery is debatable. PATIENTS AND METHODS: We reviewed data from patients with esophageal cancer enrolled in three phase II clinical trials of preoperative paclitaxel and cisplatin-based CRT during 2000-2012. Patients with ESCC who underwent planned esophagectomy were enrolled. The number of resected LNs and other clinicopathological factors were analyzed regarding their impact on progression free (PFS) and overall (OS) survival using Cox proportional hazards model. RESULTS: In total, 139 patients were included. The median PFS and OS were 24.4 and 31.8 months, respectively. The median number of resected and positive LNs were 19 (range=2-96) and 0 (range=0-9), respectively. The mean number of positive LNs did not differ significantly among quartile groups of total resected LNs (quartile 1: 2-12, 2: 13-19, 3: 20-29, and 4: 30-96). The resected LN number analyzed as dichotomies divided by the median or as continuous variables was not associated with PFS or OS. However, in an exploratory analysis, patients of quartiles 2 and 3 had longer PFS and OS than those with quartiles of 1 and 4 in multivariate analysis (p=0.019 and 0.005, respectively). CONCLUSION: Although extensive LN dissection was not associated with improved survival, resection of 13-29 LNs was associated with improved survival in patients with locally advanced ESCC receiving preoperative paclitaxel and cisplatin-based CRT. PMID- 29491088 TI - Impact of Visceral Metastasis on Efficacy of Fulvestrant in Patients with Hormone Receptor-positive Recurrent Breast Cancer. AB - BACKGROUND: Previous studies have suggested that the presence of visceral metastasis is a parameter useful in predicting the treatment efficacy of fulvestrant in patients with advanced breast cancer. PATIENTS AND METHODS: We retrospectively examined the association between treatment efficacy and presence of visceral metastasis in 75 patients with hormone receptor-positive recurrent breast cancer who were treated with fulvestrant or no more than five lines of other endocrine monotherapy after recurrence. RESULTS: Nineteen patients received fulvestrant, 10 of whom had visceral metastasis. The median time to progression was 4 months for the overall study population; it was significantly longer for patients with non-visceral metastasis (5.4 months; 95% confidence interval=3.7 11.2 months) than for those with visceral metastasis (3.3 months; 95% confidence interval, 0.4-5.3 months; p=0.01). No differences in time to progression were found between the groups of patients with visceral metastasis and non-visceral metastasis who underwent other endocrine therapies. CONCLUSION: Fulvestrant is more effective for patients with non-visceral metastasis of recurrent breast cancer with than for those with visceral metastasis. PMID- 29491089 TI - Is Mistletoe Treatment Beneficial in Invasive Breast Cancer? A New Approach to an Unresolved Problem. AB - BACKGROUND/AIM: In this retrospective study, we compared breast cancer patients treated with and without mistletoe lectin I (ML-I) in addition to standard breast cancer treatment in order to determine a possible effect of this complementary treatment. PATIENTS AND METHODS: This study included 18,528 patients with invasive breast cancer. Data on additional ML-I treatments were reported for 164 patients. We developed a "similar case" method with a distance measure retrieved from the beta variable in Cox regression to compare these patients, after stage adjustment, with their non-ML-1 treated counterparts in order to answer three hypotheses concerning overall survival, recurrence free survival and life quality. RESULTS: Raw data analysis of an additional ML-I treatment yielded a worse outcome (p=0.02) for patients with ML treatment, possibly due to a bias inherent in the ML-I-treated patients. Using the "similar case" method (a case based reasoning approach) we could not confirm this harm for patients using ML-I. Analysis of life quality data did not demonstrate reliable differences between patients treated with ML-I treatment and those without proven ML-I treatment. CONCLUSION: Based on a "similar case" model we did not observe any differences in the overall survival (OS), recurrence-free survival (RFS), and quality of life data between breast cancer patients with standard treatment and those who in addition to standard treatment received ML-I treatment. PMID- 29491090 TI - A Case of 15-Year Recurrence-free Survival After Microwave Coagulation Therapy for Liver Metastasis from Gastric Cancer. AB - A 70-year-old man with a growing liver tumor had undergone subtotal gastrectomy with pancreaticoduodenectomy for gastric cancer (T4b P0 H0 N1, Stage IIIB) 30 months before admission to our hospital. Enhanced computed tomography revealed two hypervascular nodules in segments 4 and 8. After histological diagnosis of small liver metastases from gastric cancer in segment 8, the patient underwent open microwave coagulation therapy (MCT) for the tumor (diameter: 30 mm) in segment 4. MCT was performed by using 1.5-cm and 3-cm monopolar needle electrodes with 22 times of puncture under the condition of 100 W * 60 sec. Liver abscess developed at the MCT site; however, it was decreased with percutaneous drainage. The patient is alive, without tumor recurrence even after 15 years since the MCT. This successful case proves that appropriate MCT is a promising treatment for patients with gastric liver metastases. PMID- 29491091 TI - Clinical Burden of Modified Glasgow Prognostic Scale in Colorectal Cancer. AB - BACKGROUND/AIM: This study aimed to clarify the potential of modified Glasgow Prognostic Score (mGPS) as a prognostic biomarker and reveal the significance of fish oil (FO)-enriched nutrition in colorectal cancer (CRC). PATIENTS AND METHODS: A total of 738 CRC patients from three different patient cohorts, including 670 patients in the biomarker study and 68 patients in the nutrition intervention study, were analyzed. RESULTS: High preoperative mGPS was significantly correlated with well-recognized disease progression factors and advanced UICC stage classification. In addition, high mGPS was an independent prognostic factor in both cohorts, especially in stage III and IV patients. These statuses were maintained in postoperative course and correlated with sarcopenia. Furthermore, FO-enriched nutrition suppressed systemic inflammatory reaction and improved skeletal muscle mass and prognosis, especially in CRC patients with mGPS 1 or 2. CONCLUSION: Assessment of mGPS could identify patients with high-risk CRC, who might be candidates for FO-enriched nutrition. PMID- 29491092 TI - A New Scoring-system for Estimating Overall Survival After Radiotherapy of Recurrent Head and Neck Cancers. AB - BACKGROUND/AIM: Locoregional recurrences of head and neck cancers are often associated with a poor overall survival (OS). Outcomes may be improved with individualized treatments considering a patient's lifespan. A specific scoring system for estimating OS prognoses is presented. PATIENTS AND METHODS: In a preceding study of these 60 patients, Eastern Cooperative Oncology Group performance score (ECOG 0-1 versus 2, p=0.002) and N-stage (N0-1 versus N2, p=0.004) were identified as independent predictors of OS. RESULTS: In the current study, the following scoring points were assigned: ECOG performance score 2=0 points, ECOG performance score 0-1=1 point, N2=0 points, N0-1=1 point. Patient scores were 0, 1 or 2 points with 3-year OS rates of 0%, 46% and 83%, respectively (p<0.0001). On multivariable analysis, differences remained significant (p<0.0001). CONCLUSION: This new scoring system includes three groups of patients with significantly different OS prognoses and can assist physicians when designing individualized therapy for locoregional recurrences of head and neck cancer. PMID- 29491093 TI - An Exploratory Study of Radiation Dermatitis in Breast Cancer Patients. AB - BACKGROUND/AIM: Radiation dermatitis is observed in 95% of breast cancer patients receiving radiotherapy. The aim of this study was to explore the correlation between protein expression in tumor cells and the risk of developing radiation dermatitis. PATIENTS AND METHODS: Breast cancer patients receiving postoperative radiotherapy were included in this study. Tumor specimens from 122 patients were examined by immunohistochemistry for the expression of Ki67, ataxia telangiectasia mutated (ATM) kinase, hypoxia-inducible factor-1-alpha (HIF-1a), inducible nitric oxide synthase (iNOS), and a-glucosidase (aGluc). The findings were correlated with the occurrence and severity of radiation dermatitis (Radiation therapy oncology group-RTOG grading scale), taking into consideration body weight and skin type (Fitzpatrick system). Data were explored further via pathway and network analyses. RESULTS: Correlation of radiation dermatitis (RTOG scale) with the observed increased expression of Ki67, ATM, iNOS, HIF-1a and aGluc, failed to reach statistical significance when skin type and/or body weight were considered. Network interactions of proteins involved in tumor growth (Ki67, ATM) and/or affect the oxidation state of the cell (HIF-1a, iNOS, aGluc) were revealed, that may contribute to the risk of developing acute radiation dermatitis. CONCLUSION: Correlation of the increased expression of the studied proteins and the occurrence and severity of radiation dermatitis in women undergoing postoperative radiotherapy, failed to reach statistical significance. Pathway and network analyses predicted that vasodilation and angiogenesis may contribute to radiation-induced dermatitis via mechanisms that need to be further explored. Our strategy serves as a paradigm for coupling histopathological data to molecular findings and network analyses for risk assessment in the clinic. PMID- 29491094 TI - mTORC1 and mTORC2 Expression Levels in Oral Squamous Cell Carcinoma: An Immunohistochemical and Clinicopathological Study. AB - BACKGROUND/AIM: Mammalian target of rapamycin (mTOR) plays a critical role in the regulation of tumor cell motility, invasion and cancer cell metastasis. mTOR consists of two separate multi-protein complexes, mTOR complex (mTORC) 1 and mTORC2. MATERIALS AND METHODS: We investigated the expression levels of mTORC1 and mTORC2 immunohistochemically in oral squamous cell carcinoma (OSCC). RESULTS: mTORC1 and mTORC2 were more highly expressed in tumors than in normal oral mucosa. mTORC1 expression was correlated with T classification, N classification, and survival rate (p<0.05), whereas mTORC2 expression was only correlated with T classification (p<0.05). Histologically, the expression levels of mTORC1 and mTORC2 correlated with cancer cell invasion and the expression of proliferating cell nuclear antigen (p<0.05), respectively. Expression levels of vascular endothelial growth factors and hypoxia-inducible factor 1 in the mTORC1 (-)/ mTORC2 (+) group were significantly lower than those in other groups. CONCLUSION: These findings suggested that mTORC1 and mTORC2 could be promising anti-tumor targets in OSCC, and mTORC1 (-)/mTORC2 (+) may have a correlation with the malignant potential of OSCC. PMID- 29491095 TI - Expression of Class III Beta-tubulin Predicts Prognosis in Patients with Cisplatin-resistant Bladder Cancer Receiving Paclitaxel-based Second-line Chemotherapy. AB - BACKGROUND/AIM: Class III beta-tubulin (TUBB3) expression is recognized as a predictive marker for chemosensitivity to cisplatin- and taxane-based chemotherapies in various malignancies. The aim of this study was to clarify the predictive value of TUBB3 expression for the anticancer effects of first-line cisplatin-based chemotherapy and second-line paclitaxel-based chemotherapy in patients with urothelial cancer (UC). PATIENTS AND METHODS: We reviewed 116 patients with UC (90 with bladder cancer and 27 with upper urinary tract cancer) treated with first-line cisplatin-based chemotherapy. Among them, 42 patients received a paclitaxel-based regimen as second-line chemotherapy for advanced cisplatin-resistant UC. TUBB3 expression was evaluated using immunohistochemistry, and survival analyses were performed using Kaplan-Meier survival curves and multivariate Cox proportional hazard analysis. RESULTS: TUBB3 was mainly detected in the cytoplasm of cancer cells, and 64 patients (55.2%) were judged as having positive TUBB3 expression. TUBB3 expression was significantly associated with tumour grade (p<0.001). TUBB3 expression was not associated with time to progression after first-line cisplatin-based chemotherapy. However, positive expression of TUBB3 was significantly associated with unfavourable overall survival in patients receiving second-line paclitaxel based chemotherapy (p=0.021). In addition, a multivariate analysis model including T-stage and metastasis at the beginning of second-line therapy and regimen showed that TUBB3 expression was an independent predictor of poorer survival (hazard ratio(HR)=3.44, 95% confidential interval(CI)=1.15-10.33, p=0.027). CONCLUSION: TUBB3 expression was identified as a useful predictive factor for survival after second-line paclitaxel-based therapy in patients with cisplatin-resistant UC. Our results are useful for determining treatment strategies for such patients. PMID- 29491096 TI - Associations Between Histogram Analysis DCE MRI Parameters and Complex 18F-FDG PET Values in Head and Neck Squamous Cell Carcinoma. AB - AIM: To analyze associations between parameters of positron-emission tomography (PET) and histogram analysis values of dynamic contrast-enhanced (DCE) imaging in patients with head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: Overall, 28 patients with primary HNSCC of different localizations were involved. 18F-FDG-PET/CT and DCE MR imaging were performed for all patients. Histogram analysis parameters of DCE MRI were calculated. Spearman's correlation coefficient was used to analyze the associations between investigated parameters. RESULTS: In the overall cohort, SUVmax correlated with Kep P10 (rho=0.43, p=0.027), Kep P25 (0.40, p=0.035), and had a tendency to correlate with median Kep (rho=0.33, p=0.098). TLG tended to correlate with Kep P25 (0.33, p=0.09) and P10 Ktrans (rho=0.35, p=0.07). In G1/2 tumors, SUVmax correlated with Kep P10 (rho=0.645, p=0.032), and tended to correlate with Ktrans mean (rho=0.54, p=0.089), Ktrans min (rho=0.58, p=0.06), Ktrans P10 (rho=0.56, p=0.07), Ktrans P25 (rho=0.59, p=0.056), and Ktrans median (rho=0.054, p=0.089), as well with Kep min (rho=0.56, p=0.07). SUVmean tended to correlate with Kep kurtosis (rho=0.56, p=0.07). In G3 tumors, no tendencies or statistically significant correlations between the PET and DCE MRI parameters were identified. CONCLUSION: Tumor metabolism and perfusion show complex associations in HNSCC. These associations depend on tumor grading. PMID- 29491097 TI - Lenvatinib in Advanced Radioiodine-refractory Thyroid Cancer: A Snapshot of Real life Clinical Practice. AB - BACKGROUND: We retrospectively analyzed the efficacy and safety of lenvatinib in 12 patients with advanced radioiodine-refractory thyroid cancer in the setting of daily clinical practice. PATIENTS AND METHODS: The starting daily dose of lenvatinib was 24 mg, tapered in the case of adverse events. Disease status was periodically evaluated by a single radiologist and safety assessment was regularly performed. RESULTS: After a median follow-up of 13.3 months, 6- and 12 month progression-free survival rates were 63.6% and 54.6%, respectively. Overall survival at 6 and 12 months was 83.3% and 75.0%. Partial response was observed in five patients, while two showed stable disease as their best response. Conversely, progressive disease at first radiological assessment was detected in four patients. All patients experienced at least one adverse event, including systemic and gastrointestinal toxicity, high blood pressure and hand-foot syndrome. In order to manage toxicity, transient drug interruption and dose reduction were required in 10 and 9 cases, respectively. CONCLUSION: Our data confirm lenvatinib efficacy in patients with advanced thyroid cancer, despite an important toxic profile. PMID- 29491098 TI - National Practice Patterns for Clinical T1N0 Nasopharyngeal Cancer in the Elderly: A National Cancer Data Base Analysis. AB - BACKGROUND: The standard of care for T1N0 nasopharyngeal cancer (NPC) is definitive radiation therapy (RT). However, practice patterns in the elderly may not necessarily follow national guidelines. Herein, we investigated national practice patterns for T1N0 NPC. MATERIALS AND METHODS: The National Cancer Data Base (NCDB) was queried for clinical T1N0 primary NPC cases (2004-2013) in patients >=70 years old. Patient, tumor, and treatment parameters were extracted. Kaplan-Meier analysis was used to compare overall survival (OS) between patients receiving RT versus those under observation. Logistic regression was used to examine variables associated with receipt of RT. Cox proportional hazards modeling determined variables associated with OS. Landmark analysis of patients surviving 1 year or more was performed to assess survival differences between groups. RESULTS: In total, data of 147 patients were analyzed. RT was delivered to 89 patients (61%), whereas 58 (39%) patients underwent observation. On multivariable analysis, older patients were less likely to receive RT (p=0.003), but there were no differences between groups in terms of Charlson-Deyo comorbidity index. Median and 5-year OS in patients receiving RT versus those under observation were 71 and 33 months, and 59% and 48% (p=0.011), respectively. For patients surviving 1 year or more (n=96), there was a strong trend showing that receipt of RT was associated with better median and 5-year OS. CONCLUSION: This National Data Base analysis shows that observation is relatively common for T1N0 NPC in the elderly, but is associated with poorer survival. PMID- 29491099 TI - Upper Abdominal Resection for Isolated Metastatic Lesions in Recurrent Cervical Cancer. AB - Upper abdominal involvement in recurrent cervical cancer usually occurs as part of systemic disease and is most often amenable to palliative chemotherapy. However, in certain cases in which oligometastatic disease is proven, surgery might be considered. We present a case series of six patients submitted to surgery for upper abdominal oligometastases with cervical origin. The main surgical procedures performed included atypical hepatectomy (in five cases) and splenectomy (in one case). In all cases, the cervical origin of the lesions was revealed by histopathological studies. After a median follow-up period of 1 year, there was no evidence of recurrent disease in five cases, while the sixth case was diagnosed with disseminated lesions and is under palliative chemotherapy. In conclusion, upper abdominal resection for oligometastatic disease from cervical cancer can improve the long-term survival in selected cases. PMID- 29491100 TI - A Retrospective Multicenter Study of Carbon Ion Radiotherapy for Locally Advanced Olfactory Neuroblastomas. AB - The purpose was to evaluate efficacy and safety of carbon ion radiotherapy (C-ion RT) in patients with locally advanced olfactory neuroblastomas (ONBs). This study was a sub-analysis of the Japan Carbon-Ion Radiation Oncology Study Group Study (1402 HN, UMIN000024473). Clinical data of T4 ONBs treated with C-ion RT at four Institutions between November 2003 and December 2014 were retrospectively reviewed. Twenty-one patients underwent C-ion RT. Seven patients had T4a and 14 had T4b tumours without cervical node metastases. The median follow-up period was 39 (range=5-111) months. The 3-year overall survival and local control rates were 88.4% and 83.0%, respectively. Grade 4 late toxicity was observed in three patients, including ipsilateral optic nerve disorder (n=2) and ipsilateral retinopathy (n=1). C-Ion RT is effective and can be a curative modality for T4 ONBs. Prospective multicenter studies are warranted to confirm these findings. PMID- 29491101 TI - Moderate Hypofractionation in Patients with Low-risk Prostate Cancer: Long-term Outcomes. AB - BACKGROUND/AIM: To evaluate outcomes in patients with low-risk prostate cancer treated with hypofractionated radiotherapy (HyRT). PATIENTS AND METHODS: Between April 2004 and December 2015, 175 patients with low-risk prostate cancer were treated with HyRT 60 Gy in 20 fractions with or without image guidance and reduction of margin from clinical target volume to planning target volume. RESULTS: The median follow-up was 66 months. The 8-year overall survival for the whole patient cohort was 88.9%. The 8-year biochemical no evidence of disease was higher in patients treated with image-guided HyRT (98.8% vs. 88%, p=0.023). During treatment, patients treated with image-guided HyRT presented a lower rate of grade 1-2 gastrointestinal toxicity (25.3% vs. 42.2%, p=0.001). At the last follow-up, the grade 1 Gastro-intestinal toxicity rate was 4.0% and the grade 1-2 genito-urinary toxicity rate was 25.1%. CONCLUSION: Our study demonstrated the efficacy of the schedule used with a low rate of acute and late toxicities. Therefore, reduction of margins with image-guided HyRT is safe. PMID- 29491102 TI - Evaluation of Optimal Lymph Node Dissection in Remnant Gastric Cancer Based on Initial Distal Gastrectomy. AB - BACKGROUND/AIM: The purpose of this study was to reveal the optimal lymph node (LN) dissection in remnant gastric cancer (RGC) patients. PATIENTS AND METHODS: We retrospectively analyzed 46 RGC patients divided into two groups: patients who underwent initial gastrectomy for benign (group B) and malignant (group M) diseases. RESULTS: Metastasis was more frequently observed at the left (nos. 2, 4sa, 4sb, 10, and 11p/d) and right (nos. 1, 3, 4d, 7, 8a, and 12a) side LNs of RGC in groups M and B. Modified IEBLD scores (frequency of LN metastasis by median survival time of patients with metastatic LNs) were high at station nos. 10 (4.7), 11p/d (4.3/9.9), and 16 (4.3) in group M and nos. 1 (2.1), 7 (1.9) and mesojejunal (3.0) in group B. CONCLUSION: After lymphadenectomy for initial gastric cancer, lymphatic flow toward the splenic artery was predominant. Therefore, splenectomy with para-aortic LN dissection is an option. PMID- 29491103 TI - Prognostic Significance of High EphA1-4 Expression Levels in Locally Advanced Gastric Cancer. AB - BACKGROUND/AIM: Erythropoietin-producing hepatocellular carcinoma receptor A (EphA) is associated with angiogenesis and invasive tumor progression. In this study, we evaluated the EphA1-4 expression levels in advanced gastric cancer. PATIENTS AND METHODS: Tumor tissues obtained from 114 patients with advanced gastric adenocarcinoma who underwent gastrectomy were analyzed. In addition, the impact of EPHA 1-4 mRNA expression on survival was analyzed using the Kaplan Meier plotter database on the website. RESULTS: High EphA 1, 2, and 4 expression levels were significantly related to recurrence (p<0.01, p=0.04, and p<0.01). Both high EphA 1 and 4 expression levels were independent predictors of relapse free interval (hazard ratio [HR]=2.0, p=0.03; HR=2.4, p=0.03) and disease specific survival (HR=2.0, 95% p=0.03; HR=2.5, p=0.02) on multivariate analysis. In the Kaplan-Meier plotter database, high EPHA2 mRNA expression was significantly associated with poor survival in patients with gastric cancer (p=0.0098), and high expression levels of EPHA1 and 4 tended to be associated with poor survival (p=0.050, p=0.052). CONCLUSION: EphA 1, 2, and 4 may play key roles in recurrence and survival in patients with advanced gastric cancer. PMID- 29491104 TI - Rates, Sites and Times of Recurrence and Clinical Outcome of Endometrial Cancer Patients with Histologically-positive Nodes: An Italian Two-center Retrospective Study. AB - BACKGROUND/AIM: To assess the patterns of recurrence of node-positive endometrial cancer patients. PATIENTS AND METHODS: This investigation assessed 82 patients who received different postoperative treatments. RESULTS: Recurrence developed in 36 patients after a median time of 13.5 months, and involved the vagina, pelvic nodes, para-aortic nodes and distant sites in 5, 8, 16 and 17 patients, respectively. Five-year progression-free survival (PFS) and 5-year overall survival (OS) were 51.1% and 59.8%. PFS and OS were significantly better for endometrioid than for non-endometrioid tumors. There was a trend towards a better outcome for patients who underwent chemotherapy+/-radiotherapy compared to those who received radiotherapy alone. Among the former, there was a better 5-year PFS (65.8% versus 33.7%, p=0.038) in patients who received platinum/paclitaxel-based regimens compared to those who received platinum-based chemotherapy. CONCLUSION: Disease recurred in 43.9% of patients, and platinum/paclitaxel-based chemotherapy plus radiotherapy appeared to be the best adjuvant treatment. PMID- 29491105 TI - Contribution of Patient-reported Symptoms Before Palliative Radiotherapy to Development of Multivariable Prognostic Models. AB - BACKGROUND/AIM: Typically, prognostic scores predicting survival in patients with metastatic cancer are based on disease- and patient-related factors, such as extent of metastases, age and performance status. Patient-reported symptoms have been included less often. Our group has assessed all patients with the Edmonton Symptom Assessment System (ESAS, a one-sheet questionnaire addressing 11 major symptoms and wellbeing on a numeric scale of 0-10) before palliative radiotherapy (PRT) since 2012. Therefore, we were able to analyze the prognostic impact of baseline ESAS symptom severity. PATIENTS AND METHODS: We performed a retrospective review of 102 patients treated with PRT between 2012 and 2015. All ESAS items were analyzed by two different methods, dichotomized by median score and by score <4 vs. >=4. Uni- and multivariable analyses were performed to identify prognostic factors for survival, and from these a 4-tiered score was developed. RESULTS: The most common tumor types were prostate, breast and non small cell lung cancer, predominantly with distant metastases. Despite differences between the two methods of ESAS data handling, the final multivariable models were strikingly similar. Therefore, the better reproducible cut-off was chosen, i.e. a score >=4. Multivariable analyses resulted in 4 significant prognostic factors, which contributed equally to the 4-tiered survival score (performance status, more than one cancer diagnosis, progressive disease outside the PRT target volume(s), ESAS appetite). Estimated median survival for different point sums was 24.5 months (0), 8.4 months (1), 4.7 months (2) and 3.0 months (3), p=0.0001. CONCLUSION: This score identified patients with different survival outcomes, including a good prognostic group with median survival of approximately 2 years. The results may be useful to inform PRT fractionation. PMID- 29491106 TI - Case Report: CEA Elevation Can Be a Marker of Increased Inflammation During Treatment with Oxaliplatin. AB - Oxaliplatin is a platinum-based chemotherapy that is an integral part of several regimens for colorectal cancer. We present the case of a patient, a 58-year-old male, who had initially presented aged 56 years with rectal bleeding for several months. His serum carcinoembryonic antigen (CEA) level at the time of diagnosis was 4.6 ng/ml. His CEA level increased significantly during oxaliplatin-based chemotherapy and declined to a near normal level after completion of therapy. There was no evidence of disease during this time and he remains disease-free. Oxaliplatin has been shown to cause an inflammatory response which appears to be one of the mechanisms of toxicity and high CEA levels have been correlated with increased inflammation. We postulate that this patient's rising CEA level was secondary to an inflammatory response to oxaliplatin-based therapy, which is further supported by the subsequent decrease after completion of chemotherapy. To our knowledge, this is the first published case of oxaliplatin-induced rising CEA level. PMID- 29491107 TI - Safety of Simultaneous Bilateral Pulmonary Resection for Metastatic Lung Tumors. AB - AIM: We investigated the safety of simultaneous bilateral lung resection for lung metastases. PATIENTS AND METHODS: We retrospectively analyzed 185 patients with pulmonary metastases who underwent unilateral or bilateral pulmonary resection from August 2009 to December 2016 at a single institution. RESULTS: Single-stage bilateral lung resection was undertaken in 19 patients, and the other 166 patients underwent unilateral pulmonary resection, including 20 patients who underwent repeated resections for synchronous or metachronous metastases. Operative time and drainage days in the bilateral group were significantly longer than those in the unilateral group (220+/-20 vs. 152+/-6.9 min: p<0.01, and 2.79+/-0.3 vs. 2.08+/-0.1 days: p<0.01). Incidence of postoperative complications and postoperative in-hospital days did not differ between the two groups (p=0.33 and 0.66, respectively). The bilateral group was further divided into two groups, namely, those who underwent wedge resection on both sides (WW) and those who underwent wedge resection on one side and segmentectomy or lobectomy on an opposite side (WSL). Operative time in the WSL group was significantly longer than that in the WW group (260+/-19 vs. 201+/-18 min: p=0.03). However, there was no significant difference in duration of chest tube use and postoperative hospital days between the two groups (p=0.26 and p=0.89). No severe postoperative complications occurred in either group. CONCLUSION: One-stage bilateral pulmonary metastasectomy appears to be safe as long as only wedge resection is performed on at least one side. PMID- 29491108 TI - Laparoscopy-assisted Distal Gastrectomy for Gastric Cancer in Elderly Patients: Surgical Outcomes and Prognosis. AB - BACKGROUND/AIM: Elderly patients usually have various comorbidities. Laparoscopic gastrectomy as a minimally-invasive treatment might be feasible for these patients. The aim of this study was to evaluate the safety and efficacy of laparoscopy-assisted distal gastrectomy (LADG) in elderly patients with gastric cancer by comparing the surgical outcomes and prognosis. PATIENTS AND METHODS: We analyzed 136 patients who had undergone LADG between January 2013 and December 2014. We compared elderly patients (75 years old or more) with non-elderly patients. RESULTS: The incidence of all postoperative complications did not differ between groups, and there were no significant differences in the time to first oral intake or the duration of postoperative hospital stay. The 3-year overall and recurrence-free survival rates were not significantly different between the groups. CONCLUSION: LADG is a safe and less invasive treatment for gastric cancer in elderly patients, who have a greater incidence of comorbidity. PMID- 29491109 TI - Barriers to Organized Mammography Screening Programs in Hungary: A Questionnaire based Study of 3,313 Women. AB - BACKGROUND/AIM: Despite well-organized Hungarian invitational mammography screening, participation rates have never reached 50%. This is similar to rates in Central Eastern Europe. In order to reduce breast cancer mortality, the participation rate should be at least 70%. This questionnaire-based study assessed the barriers associated with low adherence rates. MATERIALS AND METHODS: Women 45-65 years of age were interviewed by questionnaire containing 15 structured questions focused on socioeconomic status and barriers to screening. RESULTS: A total of 3,313 women completed the questionnaire. The main reasons for avoiding screening were work absenteeism (18.9%), fear of painful examination (18.39%), and poor understanding of mammography screening (14.94%). CONCLUSION: Education is required to increase awareness among women about the utility and availability of breast screening services. This report provides information on the appropriate level of intervention needed to increase screening participation in Hungary and other developing countries in Central Eastern Europe to reduce breast cancer-related mortality. PMID- 29491110 TI - Ki-67 and Survivin as Predictive Factors for Rectal Cancer Treated with Preoperative Chemoradiotherapy. AB - AIM: To evaluate the usefulness of Ki-67 index and survivin as predictive prognostic factors for rectal cancer treated with preoperative chemoradiotherapy. PATIENTS AND METHODS: The Ki-67 index and survivin expression were examined in patients with stage II/III rectal cancer (n=46) by immunohistochemistry. Patients were divided into a high-group and a low-group for the Ki-67 index, and positive and negative groups for survivin expression. Overall and disease-free survival were compared between the groups, and the correlation between Ki-67 index and survivin expression was assessed. RESULTS: The 5-year disease-free survival rate of the group with high Ki-67 index was significantly lower than that of the group with low Ki-67 index (53% and 88%, p=0.03), as was the 5-year overall survival rate (68% and 100%, p=0.03). Findings for survivin were not significant. CONCLUSION: Ki-67 index and survivin may be useful biomarkers for rectal cancer with preoperative CRT. PMID- 29491112 TI - Self-expandable Metallic Stents Contribute to Reducing Perioperative Complications in Colorectal Cancer Patients with Acute Obstruction. AB - BACKGROUND/AIM: The self-expandable metallic stent (SEMS) is an excellent non invasive tool for emergent bowel obstruction. This study was designed to evaluate the clinical usefulness of the SEMS for avoiding perioperative complications. PATIENTS AND METHODS: We analyzed a total of 47 consecutive patients who had a bowel obstruction due to colorectal cancer at initial diagnosis between 2012 and 2017 from hospital records. RESULTS: Perioperative complications occurred in 30% (14/47) of patients. Univariate and multivariate logistic regression analyses identified an age of more than 75 years [p=0.037, OR=6.84 (95% CI=1.11-41.6)] and the absence of an SEMS treatment [p=0.028, OR=18.5 (95% CI=1.36-250.0)] as independent risk factors for perioperative complications. Pneumonia (12.7% (6/47)) was the most common complication. There were no pneumonia patients (0% (0/15)) who were treated with the SEMS. In contrast to patients with the non-SEMS treatment, 18.7% (6/32) of all patients and 35.7% (5/14) of elderly patients had pneumonia. CONCLUSION: The SEMS is a safe and effective treatment for avoiding perioperative complications, particularly pneumonia, and may be a crucial strategy in elderly patients with acute obstruction due to colorectal cancer. PMID- 29491111 TI - A Feasibility Study of Capecitabine and Oxaliplatin for Patients with Stage II/III Colon Cancer -ACTOR Study. AB - BACKGROUND/AIM: Past studies have suggested that adjuvant capecitabine and oxaliplatin (CAPOX) provides decreased tumor relapse and longer survival in patients with curatively resected colon cancer. We report the first evidence of the feasibility of adjuvant CAPOX in Japanese patients with early colon cancer. PATIENTS AND METHODS: Eligible patients had histologically-confirmed stage II/III colon cancer and received curative resection. The primary endpoint was completion rate of treatment after 8 cycles of adjuvant CAPOX. RESULTS: Thirty-six patients were enrolled in this study. The completion rate of CAPOX and oxaliplatin were 77.8% and 61.1%, respectively. The incidence of grade >=3 adverse events was neutropenia (n=6), thrombocytopenia (n=3), nausea (n=5), hand-foot syndrome (n=1) and peripheral sensory neuropathy (n=1). Three-year disease-free survival for stage II patients and stage III patients were 100% and 79.3%, respectively. CONCLUSION: Adjuvant CAPOX can be safely administered to Japanese patients with stage II/III colon cancer. PMID- 29491113 TI - The Modified Glasgow Prognostic Score in Patients with Gemcitabine-refractory Biliary Tract Cancer. AB - BACKGROUND: No standard second-line chemotherapy has been yet established for gemcitabine-refractory biliary tract cancer (BTC). PATIENTS AND METHODS: We conducted multivariable Cox regression analysis to examine the prognostic factors for overall survival (OS) in patients who had received gemcitabine-based treatment. RESULTS: Forty-six patients received second-line chemotherapy. The median serum carbohydrate antigen 19-9 (CA 19-9) value was 487 U/ml. The modified Glasgow prognostic score (mGPS) was: 0 (n=24), 1 (n=10), or 2 (n=10). The second line chemotherapy included: S-1 in 20 patients, gemcitabine-based in 20, and tyrosine kinase inhibitors in five. The median OS was 8.3 months, and the median progression-free survival was 3.0 months. Multivariate analysis identified serum CA 19-9 >=500 U/ml, mGPS >=1, and presence of liver metastasis as significant prognostic factors for OS. CONCLUSION: Second-line chemotherapy for gemcitabine refractory BTC remains inadequate. Randomized trials with appropriate stratification criteria are required. PMID- 29491114 TI - Preoperative Stating of Pelvic Lymph Nodes in Prostate Cancer Patients via Endorectal Magnetic Resonance Imaging. AB - BACKGROUND/AIM: The aim of this study was to evaluate the diagnostic sensitivity, specificity and accuracy of endorectal magnetic resonance imaging (e-MRI), as a preoperative staging modality in the diagnosis of lymph node metastasis (LNM) in patients with prostate cancer (PCa). PATIENTS AND METHODS: Retrospectively, we analyzed data from N=168 patients who underwent radical prostatectomy (RP) between 2004 and 2013 at two tertiary medical centres. Prior to RP all patients underwent an e-MRI. Inclusion criteria were: PSA levels >20 ng/ml or Gleason score >7. Examinations were performed on a closed 1.0-T system combined with an endorectal body phased-array coil, imaging results were correlated with histopathology. RESULTS: 10.7% (N=18 patients) had histologically-proven LNM. e MRI was true-positive in N=6 (33.3%) and false-negative N=12 patients (66.6%). N=150 (89.3%) patients without LNM e-MRI were true-negative in 96% and false positive in 4%. Sensitivity was 96%, specificity was 33%, accuracy was 64.5%. CONCLUSION: e-MRI can be considered a useful preoperative staging modality in diagnosis of LNM. PMID- 29491115 TI - Clinicopathological Characteristics of High-grade Squamous Intraepithelial Lesions Involving Condyloma Acuminatum. AB - BACKGROUND/AIM: Severe nuclear atypia can be associated with condyloma acuminatum. In this study, we investigated nine cases of perianal condyloma acuminatum with severe nuclear atypia and determined whether severe nuclear atypia is sufficient for the diagnosis of high-grade squamous intraepithelial lesion (HSIL). MATERIALS AND METHODS: The clinical data and pathological features of the nine patients were collected. p16 Immunostaining and human papillomavirus genotyping were also performed. RESULTS: The resected specimens of six men infected with human immunodeficiency virus showed features suggestive of HSIL, including the expansion of basaloid cells, severe nuclear pleomorphism in the lower one-third, bizarre nuclei, mitotic figure in the upper two-thirds, atypical mitosis, block positivity for p16, and high-risk human papillomavirus infection. In contrast, the resected specimens of the remaining three patients did not show any of those HSIL features, even though there were several microscopic foci showing severe nuclear atypia in the upper two-thirds of the papillomatous epithelium. CONCLUSION: Our observation regarding the occurrence of HSIL involving perianal condyloma acuminatum in human immunodeficiency virus-infected patients suggests that active, complete surgical excision of perianal condyloma acuminatum and a thorough histopathological examination are necessary. The diagnosis of severe nuclear atypia involving the upper two-thirds of the epithelium should be made with great caution. PMID- 29491116 TI - Tumor Hypoxia Detected by 18F-fluoromisonidazole Positron Emission Tomography (FMISO PET) as a Prognostic Indicator of Radiotherapy (RT). AB - BACKGROUND/AIM: 18F-misonidazole positron emission tomography (FMISO PET)/computed tomography (CT) obtained before and during radiotherapy (RT) was analyzed as to whether it could predict clinical outcome. PATIENTS AND METHODS: Twenty-two patients were included. FMISO PET/ CT was performed twice before RT and at a dose of approximately 20 Gy/10 fractions. FMISO maximum standardized uptake values (SUVmax), the tumor-to-muscle ratios (T/M), and hypoxic volume (HV) in gross target volumes were measured. RESULTS: Of the 22 tumors, 18 had hypoxic areas (SUVmax >=1.60) before RT. SUVmax, T/M, and HV on the first PET/CT were significantly correlated with initial tumor response, although the values during RT were not related to the response. The overall survival and loco-regional control rates of patients below cut-off values were significantly better than those above the cut-off values. CONCLUSION: Tumor hypoxia detected by FMISO PET/CT before RT may predict clinical outcome. PMID- 29491117 TI - Skin Rash Can Be a Useful Marker for Afatinib Efficacy. AB - BACKGROUND/AIM: Although afatinib has a strong efficacy, it can be toxic; hence, we aimed to determine markers of response to afatinib in order to assess prognosis. PATIENTS AND METHODS: Information on clinical background, therapeutic effects, and adverse events was collected retrospectively at one Institution from patients treated with afatinib as initial epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). We examined the relationship between different adverse events and their effects on prognosis. RESULTS: Afatinib was used in 32 patients as the initial EGFR-TKI. Adverse events of grade 3 or higher including diarrhoea (12.5%), paronychia (6.3%), and stomatitis (3.1%) were experienced by patients. The median progression-free survival (PFS) was 15.4 months. A relationship between skin rash severity and PFS was observed. CONCLUSION: Grade 2 or higher skin rash might be a marker for long-term efficacy of afatinib when administered as a first-line treatment. PMID- 29491118 TI - Defunctioning Ileostomy Is a Key Risk Factor for Small Bowel Obstruction After Colorectal Cancer Resection. AB - BACKGROUND/AIM: Early postoperative small bowel obstruction (EPSBO) prolongs hospital stays after surgery. This study aimed to evaluate the risk factors for EPSBO associated with colorectal cancer resection. PATIENTS AND METHODS: We retrospectively compared the clinical variables of patients with EPSBO (n=37) and those without (n=812) after primary tumor resection for colorectal cancer at our hospital between January 2010 and December 2015. RESULTS: In multivariate analysis, significant differences between the two groups was found in male sex, open surgery, and defunctioning ileostomy (DI) placement (p=0.024, p<0.0001, and p=0.023, respectively), but not for colostomy placement. Of 16 patients with DI who developed EPSBO, 13 (81.3%) cases resulted from obstruction of the stomal outlet. CONCLUSION: Male sex, open surgery, and DI placement are risk factors for EPSBO after colorectal cancer resection. For patients with placement of DI, obstruction of the stomal outlet should be carefully considered. PMID- 29491119 TI - Spatiotemporal Analysis of Breast Cancer Incidence: A Study in Southern Portugal Between 2005 and 2012. AB - AIM: To characterize the spatiotemporal patterns of breast cancer (BC) incidence in females in the area with the highest incidence rate (IR) of the country in 2005-2012. MATERIALS AND METHODS: The BC-IR was studied using mapping techniques, analysis of spatiotemporal clusters and analysis of spatial variations in temporal trends. RESULTS: The overall BC-IR was 119.13/105 inhabitants. The annual BC-IRs were 17.7, 156.9, 213.3 and 232.9/105 inhabitants for women diagnosed at <40, 40-49, 50-64 and >=65 years of age. This IR increased overall (by 4.113%/year) and for the four age groups (by 5.935, 3.833, 4.114 and 2.194%/year, respectively). In patients with locoregional and metastatic disease, the IRs were 93.6 and 7.4/105 inhabitants, increasing by 6.976 and 0.303%/year, respectively. Several spatiotemporal clusters and two spatial-variations in temporal trends were detected. The Lisbon region showed high IR clusters for most groups. CONCLUSION: This study identified critical areas of high IR and increasing trends for female BC-IR, providing evidence of heterogeneities in this area. PMID- 29491120 TI - Clinical Value of Serum p53 Antibody in the Diagnosis and Prognosis of Esophageal Squamous Cell Carcinoma. AB - BACKGROUND/AIM: Identifying useful biomarkers is central to selecting optimal therapeutic strategies for esophageal squamous cell carcinoma (ESCC). Serum p53 antibody (S-p53Ab), squamous cell carcinoma antigen (SCC-Ag), and carcinoembryonic antigen (CEA) were investigated to evaluate the significance of single and combined tumor markers in determining the diagnosis and prognosis of ESCC. MATERIALS AND METHODS: Serum samples were obtained preoperatively from 133 patients with histologically-confirmed ESCC, including 32 patients with stage I (24.1%). Levels of S-p53Ab were assessed by enzyme-linked immunosorbent assay, using a new version of a highly specific, quantitative kit. The cut-off value for S-p53Ab was 1.3 U/ml. RESULTS: S-p53Ab was detected in 39.1% (52 out of 133) of patients with ESCC, including 40.0% (20 out of 50) of patients with early-stage ESCC. Positive rates for S-p53Ab, CEA, and SCC-Ag among patients with stage I ESCC (n=32) were 40.6%, 12.5%, and 31.3%, respectively. Positivity for S-p53Ab was not associated with positivity for CEA or SCC-Ag (p=0.249 and 0.747, respectively). The positive rate for diagnosis of ESCC increased from 39.1% to 65.4% when S-p53Ab was combined with SCC-Ag in this study. We found no significant correlation between the presence of S-p53Ab in ESCC and overall survival. Conversely, Cox regression analysis revealed that the International Union Against Cancer/TNM classification and systemic inflammation score were independent prognostic factors for ESCC in this series (hazard ratio(HR)=3.811, 95% confidence interval(CI)=1.548-9.378, p=0.004; and HR=2.218; 95% CI=1.087 4.523, p=0.029, respectively). Kaplan-Meier analysis revealed significant differences between patients with elevated S-p53Ab and SCC-Ag and patients with elevated levels of only one or neither of these factors (p=0.009). CONCLUSION: The diagnostic rate with S-p53Ab was better than that with SCC-Ag and CEA in patients with early-stage ESCC. Combined detection of S-p53Ab and SCC-Ag can markedly improve diagnostic sensitivity and may permit more accurate stratification of patients with ESCC. PMID- 29491121 TI - Outcome of Trimodal Therapy in Elderly Patients with Esophageal Cancer: Prognostic Value of the Charlson Comorbidity Index. AB - BACKGROUND: In the real-world setting outside clinical trials, neoadjuvant chemoradiation therapy followed by esophagectomy may represent overtreatment in some elderly individuals with multiple comorbidities. PATIENTS AND METHODS: Through an observational cohort study, consecutive patients with esophageal cancer treated with the protocol of the Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) were compared to patients of similar age who underwent upfront surgery during the same study period. RESULTS: Fifty consecutive patients treated between 2010 and 2017 were enrolled. Thirty-two (64%) were older than 65 years and three (9.4%) were octogenarians. Eleven patients dropped-out of the protocol. Sixty-four patients undergoing upfront surgery served as controls. Compared to those who dropped out, patients who completed the protocol were younger (p=0.002) and had a lower Charlson Comorbidity Index (CCI) (p=0.003); the CCI was also lower (p=0.006) in the group treated with upfront surgery. The American Society of Anesthesiologists score did not discriminate between those who dropped out and patients who completed the protocol (p=0.178). CONCLUSION: Routine use of the CCI may help in the pretreatment risk stratification of elderly patients with esophageal carcinoma. PMID- 29491122 TI - High Frequency of Spread Through Air Spaces in Resected Small Cell Lung Cancer. AB - BACKGROUND/AIM: Spread through air spaces (STAS) is a novel invasive pattern of lung cancer, especially adenocarcinoma and squamous cell carcinoma. However, its frequency and significance in patients with resected small cell lung cancer (SCLC) remains unclear. PATIENTS AND METHODS: A total of 30 patients with resected SCLC were analyzed for STAS. STAS was classified as either no STAS, low STAS (1-4 single cells or clusters of STAS), or high STAS (>=5 single cells or clusters of STAS). We evaluated the association between STAS and clinicopathological characteristics and postoperative survivals. RESULTS: Among 30 patients, 5 (17%), 6 (20%) and 19 (63%) were classified as having no, low and high STAS, respectively. Fisher's exact test demonstrated no significant associations between the positivity for STAS and clinicopathological characteristics. No significant differences were observed in recurrence-free and overall survival between STAS-negative/low and STAS-high patients. CONCLUSION: STAS was frequently observed in patients with resected SCLC. PMID- 29491126 TI - Can we forecast induction failure in acute myeloid leukemia? PMID- 29491124 TI - Effect of cariporide on ram sperm pH regulation and motility: possible role of NHE1. AB - Sperm motility, a feature essential for in vivo fertilization, is influenced by intracellular pH (pHi) homeostasis. Several mechanisms are involved in pHi regulation, among which sodium-hydrogen exchangers (NHEs), a family of integral transmembrane proteins that catalyze the exchange of Na+ for H+ across lipid bilayers. A preliminary characterization of NHE activity and kinetic parameters, followed by analysis of the expression and localization of the protein in ram spermatozoa was performed. NHE activity showed an apparent Km for external Na+ of 17.61 mM. Immunoblotting revealed a molecular mass of 85 kDa. Immunolocalization pattern showed some species-specific aspects, such as positive labeling at the equatorial region of the sperm head. Cariporide, a selective NHE1 inhibitor, significantly reduced pHi recovery (85%). Similarly, exposure to cariporide significantly inhibited different motility parameters, including those related to sperm capacitation. In vitro fertilization (IVF) was not affected by cariporide, possibly due to the non-dramatic, although significant, drop in motility and velocity parameters or due to prolonged exposure during IVF, which may have caused progressive loss of its inhibitory effect. In conclusion, this is the first study documenting, in a large animal model (sheep) of well-known translational relevance, a direct functional role of NHE on sperm pHi and motility. The postulated specificity of cariporide toward isoform 1 of the Na+/H+ exchanger seems to suggest that NHE1 may contribute to the observed effects on sperm cell functionality. PMID- 29491127 TI - Bortezomib for prevention of acute graft-versus-host disease: a conclusion reached. PMID- 29491123 TI - The role of renal dipeptidyl peptidase-4 in kidney disease: renal effects of dipeptidyl peptidase-4 inhibitors with a focus on linagliptin. AB - Emerging evidence suggests that dipeptidyl peptidase-4 (DPP-4) inhibitors used to treat type 2 diabetes may have nephroprotective effects beyond the reduced renal risk conferred by glycemic control. DPP-4 is a ubiquitous protein with exopeptidase activity that exists in cell membrane-bound and soluble forms. The kidneys contain the highest levels of DPP-4, which is increased in diabetic nephropathy. DPP-4 inhibitors are a chemically heterogeneous class of drugs with important pharmacological differences. Of the globally marketed DPP-4 inhibitors, linagliptin is of particular interest for diabetic nephropathy as it is the only compound that is not predominantly excreted in the urine. Linagliptin is also the most potent DPP-4 inhibitor, has the highest affinity for this protein, and has the largest volume of distribution; these properties allow linagliptin to penetrate kidney tissue and tightly bind resident DPP-4. In animal models of kidney disease, linagliptin elicited multiple renoprotective effects, including reducing albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis, independent of changes in glucagon-like peptide-1 (GLP-1) and glucose levels. At the molecular level, linagliptin prevented the pro-fibrotic endothelial-to mesenchymal transition by disrupting the interaction between membrane-bound DPP-4 and integrin beta1 that enhances signaling by transforming growth factor-beta1 and vascular endothelial growth factor receptor-1. Linagliptin also increased stromal cell derived factor-1 levels, ameliorated endothelial dysfunction, and displayed unique antioxidant effects. Although the nephroprotective effects of linagliptin are yet to be translated to the clinical setting, the ongoing Cardiovascular and Renal Microvascular Outcome Study with Linagliptin in Patients with Type 2 Diabetes Mellitus (CARMELINA(r)) study will definitively assess the renal effects of this DPP-4 inhibitor. CARMELINA(r) is the only clinical trial of a DPP-4 inhibitor powered to evaluate kidney outcomes. PMID- 29491128 TI - Use of desmopressin in the treatment of hemophilia A: towards a golden jubilee. PMID- 29491129 TI - Comment on "MEK inhibition with trametinib and tyrosine kinase inhibition with imatinib in multifocal histiocytic sarcoma". PMID- 29491130 TI - Acquired thrombotic thrombocytopenic purpura in a child: rituximab to prevent relapse. A pediatric report and literature review. PMID- 29491131 TI - Plasma ghrelin is probably not a useful biomarker for risk prediction or early detection of colorectal cancer. PMID- 29491132 TI - SNPing away at mutant p53 activities. AB - A delicate balance in the levels of proteins that regulate the p53 tumor suppressor pathway exists such that subtle changes alter p53 tumor suppressor activity and cancer risk. Many single-nucleotide polymorphisms (SNPs) in the p53 pathway alter p53 transcriptional activity and are associated with cancer risk. In addition, some SNPs influence the gain-of-function (GOF) activities of mutant p53 through unknown mechanisms. In this issue of Genes & Development, Basu and colleagues (pp. 230-243) provide direct evidence that the presence of an R72 polymorphism enhances the GOF invasive and metastatic properties of mutant p53 by regulating interactions with PGC-1alpha, an important regulator of mitochondrial biogenesis and oxidative phosphorylation. The study culminates with evidence that R72 is associated with worse outcomes in human breast cancer. PMID- 29491133 TI - Neuronal regulation of longevity by staying cool. AB - Aging is fundamental to life and reflects functional declines in different tissues at the organismal level. As a systematic process, aging can be influenced by the interplay between genetic and environmental factors, and the nervous system plays a crucial role in this regulation. Environmental inputs can be sensed by the nervous system, which consequently triggers signaling outputs toward peripheral tissues to regulate gene expression systematically. Thus, understanding the underlying molecular mechanisms behind environmentally triggered neuron-periphery cross-talk is crucial for the promotion of an organism's health and longevity. PMID- 29491134 TI - A rADAR defense against RNAi. AB - Adenosine deaminases that act on RNA (ADARs) convert adenosines (A) to inosines (I) in stretches of dsRNA. The biological purpose of these editing events for the vast majority of ADAR substrates is largely unknown. In this issue of Genes & Development, Reich and colleagues (pp. 271-282) demonstrate that in Caenorhabditis elegans, A-to-I editing in double-stranded regions of protein coding transcripts protects these RNAs from targeting by the RNAi pathway. Disruption of this safeguard through loss of ADAR activity coupled with enhanced RNAi results in developmental abnormalities and profound changes in gene expression that suggest aberrant induction of an antiviral response. Thus, editing of cellular dsRNA by ADAR helps prevent host RNA silencing and inadvertent antiviral activity. PMID- 29491138 TI - A Role for Cellular Prion Protein in Late-Onset Alzheimer's Disease: Evidence from Preclinical Studies. PMID- 29491136 TI - Brain-gut communications via distinct neuroendocrine signals bidirectionally regulate longevity in C. elegans. AB - Tissue-tissue communications are integral to organismal aging, orchestrating a body-wide aging process. The brain plays a key role in this process by detecting and processing signals from the environment and then communicating them to distal tissues such as the gut to regulate longevity. How this is achieved, however, is poorly understood. Here, using Caenorhabditis elegans as a model, we identified two distinct neuroendocrine signaling circuits by which the worm nervous system senses cool and warm environmental temperatures through cool- and warm-sensitive neurons and then signals the gut to extend and shorten life span, respectively. The prolongevity "cool" circuit uses the small neurotransmitters glutamate and serotonin, whereas the anti-longevity "warm" circuit is mediated by insulin-like neuropeptides. Both types of neuroendocrine signals converge on the gut through their cognate receptors to differentially regulate the transcription factor DAF 16/FOXO, leading to opposing outcomes in longevity. Our study illustrates how the brain detects and processes environmental signals to bidirectionally regulate longevity by signaling the gut. PMID- 29491137 TI - The cryo-EM structure of the SF3b spliceosome complex bound to a splicing modulator reveals a pre-mRNA substrate competitive mechanism of action. AB - Somatic mutations in spliceosome proteins lead to dysregulated RNA splicing and are observed in a variety of cancers. These genetic aberrations may offer a potential intervention point for targeted therapeutics. SF3B1, part of the U2 small nuclear RNP (snRNP), is targeted by splicing modulators, including E7107, the first to enter clinical trials, and, more recently, H3B-8800. Modulating splicing represents a first-in-class opportunity in drug discovery, and elucidating the structural basis for the mode of action opens up new possibilities for structure-based drug design. Here, we present the cryogenic electron microscopy (cryo-EM) structure of the SF3b subcomplex (SF3B1, SF3B3, PHF5A, and SF3B5) bound to E7107 at 3.95 A. This structure shows that E7107 binds in the branch point adenosine-binding pocket, forming close contacts with key residues that confer resistance upon mutation: SF3B1R1074H and PHF5AY36C The structure suggests a model in which splicing modulators interfere with branch point adenosine recognition and supports a substrate competitive mechanism of action (MOA). Using several related chemical probes, we validate the pose of the compound and support their substrate competitive MOA by comparing their activity against both strong and weak pre-mRNA substrates. Finally, we present functional data and structure-activity relationship (SAR) on the PHF5AR38C mutation that sensitizes cells to some chemical probes but not others. Developing small molecule splicing modulators represents a promising therapeutic approach for a variety of diseases, and this work provides a significant step in enabling structure-based drug design for these elaborate natural products. Importantly, this work also demonstrates that the utilization of cryo-EM in drug discovery is coming of age. PMID- 29491139 TI - Optical Coherence Tomography: Future Applications in Cerebrovascular Imaging. PMID- 29491140 TI - Geographic Modeling to Quantify the Impact of Primary and Comprehensive Stroke Center Destination Policies. AB - BACKGROUND AND PURPOSE: We evaluated the impact of a primary stroke center (PSC) destination policy in a major metropolitan city and used geographic modeling to evaluate expected changes for a comprehensive stroke center policy. METHODS: We identified suspected stroke emergency medical services encounters from 1/1/2004 to 12/31/2013 in Philadelphia, PA. Transport times were compared before and after initiation of a PSC destination policy on 10/3/2011. Geographic modeling estimated the impact of bypassing the closest hospital for the closest PSC and for the closest comprehensive stroke center. RESULTS: There were 2 326 943 emergency medical services runs during the study period, of which 15 099 had a provider diagnosis of stroke. Bypassing the closest hospital for a PSC was common before the official policy and increased steadily over time. Geographic modeling suggested that bypassing the closest hospital in favor of the closest PSC adds a median of 3.1 minutes to transport time. Bypassing to the closest comprehensive stroke center would add a median of 8.3 minutes. CONCLUSIONS: Within a large metropolitan area, the time cost of routing patients preferentially to PSCs and comprehensive stroke centers is low. PMID- 29491141 TI - Two zinc-binding domains in the transporter AdcA from Streptococcus pyogenes facilitate high-affinity binding and fast transport of zinc. AB - Zinc is an essential metal in bacteria. One important bacterial zinc transporter is AdcA, and most bacteria possess AdcA homologs that are single-domain small proteins due to better efficiency of protein biogenesis. However, a double-domain AdcA with two zinc-binding sites is significantly overrepresented in Streptococcus species, many of which are major human pathogens. Using molecular simulation and experimental validations of AdcA from Streptococcus pyogenes, we found here that the two AdcA domains sequentially stabilize the structure upon zinc binding, indicating an organization required for both increased zinc affinity and transfer speed. This structural organization appears to endow Streptococcus species with distinct advantages in zinc-depleted environments, which would not be achieved by each single AdcA domain alone. This enhanced zinc transport mechanism sheds light on the significance of the evolution of the AdcA domain fusion, provides new insights into double-domain transporter proteins with two binding sites for the same ion, and indicates a potential target of antimicrobial drugs against pathogenic Streptococcus species. PMID- 29491135 TI - Assessing sufficiency and necessity of enhancer activities for gene expression and the mechanisms of transcription activation. AB - Enhancers are important genomic regulatory elements directing cell type-specific transcription. They assume a key role during development and disease, and their identification and functional characterization have long been the focus of scientific interest. The advent of next-generation sequencing and clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-based genome editing has revolutionized the means by which we study enhancer biology. In this review, we cover recent developments in the prediction of enhancers based on chromatin characteristics and their identification by functional reporter assays and endogenous DNA perturbations. We discuss that the two latter approaches provide different and complementary insights, especially in assessing enhancer sufficiency and necessity for transcription activation. Furthermore, we discuss recent insights into mechanistic aspects of enhancer function, including findings about cofactor requirements and the role of post-translational histone modifications such as monomethylation of histone H3 Lys4 (H3K4me1). Finally, we survey how these approaches advance our understanding of transcription regulation with respect to promoter specificity and transcriptional bursting and provide an outlook covering open questions and promising developments. PMID- 29491142 TI - Aspartyl proteases in Candida glabrata are required for suppression of the host innate immune response. AB - A family of 11 cell surface-associated aspartyl proteases (CgYps1-11), also referred as yapsins, is a key virulence factor in the pathogenic yeast Candida glabrata However, the mechanism by which CgYapsins modulate immune response and facilitate survival in the mammalian host remains to be identified. Here, using RNA-Seq analysis, we report that genes involved in cell wall metabolism are differentially regulated in the Cgyps1-11Delta mutant. Consistently, the mutant contained lower beta-glucan and mannan levels and exhibited increased chitin content in the cell wall. As cell wall components are known to regulate the innate immune response, we next determined the macrophage transcriptional response to C. glabrata infection and observed differential expression of genes implicated in inflammation, chemotaxis, ion transport, and the tumor necrosis factor signaling cascade. Importantly, the Cgyps1-11Delta mutant evoked a different immune response, resulting in an enhanced release of the pro inflammatory cytokine IL-1beta in THP-1 macrophages. Further, Cgyps1-11Delta induced IL-1beta production adversely affected intracellular proliferation of co infected WT cells and depended on activation of spleen tyrosine kinase (Syk) signaling in the host cells. Accordingly, the Syk inhibitor R406 augmented intracellular survival of the Cgyps1-11Delta mutant. Finally, we demonstrate that C. glabrata infection triggers elevated IL-1beta production in mouse organs and that the CgYPS genes are required for organ colonization and dissemination in the murine model of systemic infection. Altogether, our results uncover the basis for macrophage-mediated killing of Cgyps1-11Delta cells and provide the first evidence that aspartyl proteases in C. glabrata are required for suppression of IL-1beta production in macrophages. PMID- 29491143 TI - Hairy and enhancer of split 1 (HES1) protects cells from endoplasmic reticulum stress-induced apoptosis through repression of GADD34. AB - Disruption in endoplasmic reticulum (ER) function, termed ER stress, occurs in many diseases, including neurodegenerative disorders, diabetes, and cancer. Cells respond to ER stress with the unfolded protein response (UPR), which triggers a broad transcriptional program to restore and enhance ER function. Here, we found that ER stress up-regulates the mRNA encoding the developmentally regulated transcriptional repressor hairy and enhancer of split 1 (HES1), in a variety cell types. Depletion of HES1 increased cell death in response to ER stress in mouse and human cells, in a manner that depended on the pro-apoptotic gene growth arrest and DNA damage-inducible protein GADD34 (also known as Protein phosphatase 1 regulatory subunit 15A, or MyD116). Furthermore, HES1 bound to the GADD34 promoter, and its depletion led to an up-regulation of GADD34 expression during ER stress. Our results identify HES1 as a repressor of GADD34 expression, and reveal that HES1 contributes to cell fate determination in response to ER stress. PMID- 29491144 TI - Post-translational modification of type IV collagen with 3-hydroxyproline affects its interactions with glycoprotein VI and nidogens 1 and 2. AB - Type IV collagen is a major component of the basement membrane and interacts with numerous other basement membrane proteins. Many of these interactions are poorly characterized. Type IV collagen is abundantly post-translationally modified with 3-hydroxyproline (3-Hyp), but 3-Hyp's biochemical role in type IV collagen's interactions with other proteins is not well established. In this work, we present binding data consistent with a major role of 3-Hyp in interactions of collagen IV with glycoprotein VI and nidogens 1 and 2. The increased binding interaction between type IV collagen without 3-Hyp and glycoprotein VI has been the subject of some controversy, which we sought to explore, whereas the lack of binding of nidogens to type IV collagen without 3-Hyp is novel. Using tandem MS, we show that the putative glycoprotein VI-binding site is 3-Hyp-modified in WT PFHR-9 type IV collagen, but not in PFHR-9 cells in which prolyl-3-hydroxylase 2 (P3H2) has been knocked out (KO). Moreover, we observed altered 3-Hyp occupancy across many other sites. Using amino acid analysis of type IV collagen from the WT and P3H2 KO cell lines, we confirm that P3H2 is the major, but not the only 3 Hyp-modifying enzyme of type IV collagen. These findings underscore the importance of post-translational modifications of type IV collagen for interactions with other proteins. PMID- 29491145 TI - Disulfide isomerase activity of the dynamic, trimeric Proteus mirabilis ScsC protein is primed by the tandem immunoglobulin-fold domain of ScsB. AB - Correct disulfide bond formation is essential for proper folding of many proteins, including bacterial virulence factors. The suppressor of copper sensitivity (Scs) proteins have roles in dithiol/disulfide interchange and the bacterial response to copper stress. Encoded in a four-gene cassette (ScsABCD) present in many Gram-negative bacteria, the Scs proteins are enigmatic and poorly characterized. Here, we show that the periplasmic alpha-domain of the membrane protein ScsB in the Gram-negative bacterium Proteus mirabilis forms a redox relay with the soluble periplasmic protein PmScsC. We also found that the periplasmic alpha-domain is sufficient to activate the disulfide isomerase activity of PmScsC. The crystal structure of PmScsBalpha at a resolution of 1.54 A revealed that it comprises two structurally similar immunoglobulin-like folds, one of which includes a putative redox-active site with the sequence CXXXC. We confirmed the importance of these cysteine residues for PmScsBalpha function, and in addition, we engineered cysteine variants that produced a stable complex between PmScsC and PmScsBalpha. Using small-angle X-ray and neutron scattering analyses with contrast variation, we determined a low-resolution structure of the PmScsC PmScsBalpha complex. The structural model of this complex suggested that PmScsBalpha uses both of its immunoglobulin-like folds to interact with PmScsC and revealed that the highly dynamic PmScsC becomes ordered upon PmScsBalpha binding. These findings add to our understanding of the poorly characterized Scs proteins. PMID- 29491147 TI - Publishing in an ASPET Journal - What's in It for You? PMID- 29491148 TI - Correction to "Nitric Oxide-Donating Nonsteroidal Anti-Inflammatory Drugs Inhibit the Growth of Various Cultured Human Cancer Cells: Evidence of a Tissue Type Independent Effect". PMID- 29491146 TI - Mice lacking ARV1 have reduced signs of metabolic syndrome and non-alcoholic fatty liver disease. AB - Metabolic syndrome (MetS) is a term used to characterize individuals having at least three of the following diseases: obesity, dyslipidemia, hyperglycemia, insulin resistance, hypertension, and nonalcoholic fatty liver disease (NAFLD). It is widespread, and the number of individuals with MetS is increasing. However, the events leading to the manifestation of MetS are not well-understood. Here, we show that loss of murine ARV1 (mARV1) results in resistance to acquiring diseases associated with MetS. Arv1-/- animals fed a high-fat diet were resistant to diet induced obesity, had lower blood cholesterol and triglyceride levels, and retained glucose tolerance and insulin sensitivity. Livers showed no gross morphological changes, contained lower levels of cholesterol, triglycerides, and fatty acids, and showed fewer signs of NAFLD. Knockout animals had elevated levels of liver farnesol X receptor (FXR) protein and its target, small heterodimer protein (SHP). They also had decreased levels of CYP7alpha1, CYP8beta1, and mature SREBP1 protein, evidence suggesting that liver FXR signaling was activated. Strengthening this hypothesis was the fact that peroxisome proliferator-activating receptor alpha (PPARalpha) protein was elevated, along with its target, fibroblast growth factor 21 (FGF21). Arv1-/- animals excreted more fecal cholesterol, free fatty acids, and bile acids. Their small intestines had 1) changes in bile acid composition, 2) an increase in the level of the intestinal FXR antagonist, tauromuricholic acid, and 3) showed signs of attenuated FXR signaling. Overall, we believe that ARV1 function is deleterious when consuming a high-fat diet. We further hypothesize that ARV1 is critical for initiating events required for the progression of diseases associated with MetS and NAFLD. PMID- 29491149 TI - Targeted Doxorubicin-Loaded Bacterially Derived Nano-Cells for the Treatment of Neuroblastoma. AB - Advanced stage neuroblastoma is an aggressive disease with limited treatment options for patients with drug-resistant tumors. Targeted delivery of chemotherapy for pediatric cancers offers promise to improve treatment efficacy and reduce toxicity associated with systemic chemotherapy. The EnGeneIC Dream Vector (EDVTM) is a nanocell, which can package chemotherapeutic drugs and target tumors via attachment of bispecific proteins to the surface of the nanocell. Phase I trials in adults with refractory tumors have shown an acceptable safety profile. Herein we investigated the activity of EGFR-targeted and doxorubicin loaded EDVTM (EGFREDVTMDox) for the treatment of neuroblastoma. Two independent neuroblastoma cell lines with variable expression of EGFR protein [SK-N-BE(2), high; SH-SY-5Y, low] were used. EGFREDVTMDox induced apoptosis in these cells compared to control, doxorubicin, or non-doxorubicin loaded EGFREDVTM In three dimensional tumor spheroids, imaging and fluorescence life-time microscopy revealed that EGFREDVTMDox had a marked enhancement of doxorubicin penetration compared to doxorubicin alone, and improved penetration compared to non-EGFR targeted EDVTMDox, with enhanced spheroid penetration leading to increased apoptosis. In two independent orthotopic human neuroblastoma xenograft models, short-term studies (28 days) of tumor-bearing mice led to a significant decrease in tumor size in EGFREDVTMDox-treated animals compared to control, doxorubicin, or non-EGFR EDVTMDox There was increased TUNEL staining of tumors at day 28 compared to control, doxorubicin, or non-EGFR EDVTMDox Moreover, overall survival was increased in neuroblastoma mice treated with EGFREDVTMDox (P < 0007) compared to control. Drug-loaded bispecific-antibody targeted EDVsTM offer a highly promising approach for the treatment of aggressive pediatric malignancies such as neuroblastoma. Mol Cancer Ther; 17(5); 1012-23. (c)2018 AACR. PMID- 29491150 TI - ELKS active zone proteins as multitasking scaffolds for secretion. AB - Synaptic vesicle exocytosis relies on the tethering of release ready vesicles close to voltage-gated Ca2+ channels and specific lipids at the future site of fusion. This enables rapid and efficient neurotransmitter secretion during presynaptic depolarization by an action potential. Extensive research has revealed that this tethering is mediated by an active zone, a protein dense structure that is attached to the presynaptic plasma membrane and opposed to postsynaptic receptors. Although roles of individual active zone proteins in exocytosis are in part understood, the molecular mechanisms that hold the protein scaffold at the active zone together and link it to the presynaptic plasma membrane have remained unknown. This is largely due to redundancy within and across scaffolding protein families at the active zone. Recent studies, however, have uncovered that ELKS proteins, also called ERC, Rab6IP2 or CAST, act as active zone scaffolds redundant with RIMs. This redundancy has led to diverse synaptic phenotypes in studies of ELKS knockout mice, perhaps because different synapses rely to a variable extent on scaffolding redundancy. In this review, we first evaluate the need for presynaptic scaffolding, and we then discuss how the diverse synaptic and non-synaptic functional roles of ELKS support the hypothesis that ELKS provides molecular scaffolding for organizing vesicle traffic at the presynaptic active zone and in other cellular compartments. PMID- 29491151 TI - Unique Phenotypic Characteristics of Recently Transmitted HIV-1 Subtype C Envelope Glycoprotein gp120: Use of CXCR6 Coreceptor by Transmitted Founder Viruses. AB - Adequate information on the precise molecular and biological composition of the viral strains that establish HIV infection in the human host will provide effective means of immunization against HIV infection. In an attempt to identify the transmitted founder (TF) virus and differentiate the biological properties and infectious potential of the TF virus from those of the population of the early transmitted viruses, 250 patient-derived gp120 envelope glycoproteins were cloned in pMN-K7-Luc-IRESs-NefDeltagp120 to obtain chimeric viruses. Samples were obtained from eight infants who had recently become infected with HIV through mother-to-child transmission (MTCT) and two adults who acquired infection through the heterosexual route and were in the chronic stage of infection. Among the 250 clones tested, 65 chimeric viruses were infectious, and all belonged to HIV-1 subtype C. The 65 clones were analyzed for molecular features of the envelope, per-infectious-particle infectivity, coreceptor tropism, drug sensitivity, and sensitivity to broadly neutralizing antibodies. Based on genotypic and phenotypic analysis of the viral clones, we identified 10 TF viruses from the eight infants. The TF viruses were characterized by shorter V1V2 regions, a reduced number of potential N-linked glycosylation sites, and a higher infectivity titer compared to the virus variants from the adults in the chronic stage of infection. CXCR6 coreceptor usage, in addition to that of the CCR5 coreceptor, which was used by all 65 chimeric viruses, was identified in 13 viruses. The sensitivity of the TF variants to maraviroc and a standard panel of neutralizing monoclonal antibodies (VRC01, PG09, PG16, and PGT121) was found to be much lower than that of the virus variants from the adults in the chronic stage of infection.IMPORTANCE Tremendous progress has been made during the last three and half decades of HIV research, but some significant gaps continue to exist. One of the frontier areas of HIV research which has not seen a breakthrough yet is vaccine research, which is because of the enormous genetic diversity of HIV-1 and the unique infectious fitness of the virus. Among the repertoire of viral variants, the virus that establishes successful infection (transmitted founder [TF] virus) has not been well characterized yet. An insight into the salient features of the TF virus would go a long way toward helping with the design of an effective vaccine against HIV. Here we studied the biological properties of recently transmitted viruses isolated from infants who acquired infection from the mother and have come up with unique characterizations for the TF virus that establishes infection in the human host. PMID- 29491152 TI - An M2 Rather than a TH2 Response Contributes to Better Protection against Latency Reactivation following Ocular Infection of Naive Mice with a Recombinant Herpes Simplex Virus 1 Expressing Murine Interleukin-4. AB - We found previously that altering macrophage polarization toward M2 responses by injection of colony-stimulating factor 1 (CSF-1) was more effective in reducing both primary and latent infections in mice ocularly infected with herpes simplex virus 1 (HSV-1) than M1 polarization by gamma interferon (IFN-gamma) injection. Cytokines can coordinately regulate macrophage and T helper (TH) responses, with interleukin-4 (IL-4) inducing type 2 TH (TH2) as well as M2 responses and IFN gamma inducing TH1 as well as M1 responses. We have now differentiated the contributions of these immune compartments to protection against latency reactivation and corneal scarring by comparing the effects of infection with recombinant HSV-1 in which the latency-associated transcript (LAT) gene was replaced with either the IL-4 (HSV-IL-4) or IFN-gamma (HSV-IFN-gamma) gene using infection with the parental (LAT-negative) virus as a control. Analysis of peritoneal macrophages in vitro established that the replacement of LAT with the IL-4 or IFN-gamma gene did not affect virus infectivity and promoted polarization appropriately. Protection against corneal scarring was significantly higher in mice ocularly infected with HSV-IL-4 than in those infected with HSV-IFN-gamma or parental virus. Levels of primary virus replication in the eyes and trigeminal ganglia (TG) were similar in the three groups of mice, but the numbers of gC+ cells were lower on day 5 postinfection in the eyes of HSV-IL-4-infected mice than in those infected with HSV-IFN-gamma or parental virus. Latency and explant reactivation were lower in both HSV-IL-4- and HSV-IFN-gamma-infected mice than in those infected with parental virus, with the lowest level of latency being associated with HSV-IL-4 infection. Higher latency correlated with higher levels of CD8, PD-1, and IFN-gamma mRNA, while reduced latency and T-cell exhaustion correlated with lower gC+ expression in the TG. Depletion of macrophages increased the levels of latency in all ocularly infected mice compared with their undepleted counterparts, with macrophage depletion increasing latency in the HSV IL-4 group greater than 3,000-fold. Our results suggest that shifting the innate macrophage immune responses toward M2, rather than M1, responses in HSV-1 infection would improve protection against establishment of latency, reactivation, and eye disease.IMPORTANCE Ocular HSV-1 infections are among the most frequent serious viral eye infections in the United States and a major cause of virus-induced blindness. As establishment of a latent infection in the trigeminal ganglia results in recurrent infection and is associated with corneal scarring, prevention of latency reactivation is a major therapeutic goal. It is well established that absence of latency-associated transcripts (LATs) reduces latency reactivation. Here we demonstrate that recombinant HSV-1 expressing IL-4 (an inducer of TH2/M2 responses) or IFN-gamma (an inducer of TH1/M1 responses) in place of LAT further reduced latency, with HSV-IL-4 showing the highest overall protective efficacy. In naive mice, this higher protective efficacy was mediated by innate rather than adaptive immune responses. Although both M1 and M2 macrophage responses were protective, shifting macrophages toward an M2 response through expression of IL-4 was more effective in curtailing ocular HSV-1 latency reactivation. PMID- 29491153 TI - Mechanisms of Host IFI16, PML, and Daxx Protein Restriction of Herpes Simplex Virus 1 Replication. AB - The initial events after DNA virus infection involve a race between epigenetic silencing of the incoming viral DNA by host cell factors and expression of viral genes. Several host gene products, including the nuclear domain 10 (ND10) components PML (promyelocytic leukemia) and Daxx (death domain-associated protein 6), as well as IFI16 (interferon-inducible protein 16), have been shown to restrict herpes simplex virus 1 (HSV-1) replication. Whether IFI16 and ND10 components work together or separately to restrict HSV-1 replication is not known. To determine the combinatorial effects of IFI16 and ND10 proteins on viral infection, we depleted Daxx or PML in primary human foreskin fibroblasts (HFFs) in the presence or absence of IFI16. Daxx or IFI16 depletion resulted in higher ICP0 mutant viral yields, and the effects were additive. Surprisingly, small interfering RNA (siRNA) depletion of PML in the HFF cells led to decreased ICP0 null virus replication, while short hairpin RNA (shRNA) depletion led to increased ICP0-null virus replication, arguing that different PML isoforms or PML related proteins may have restrictive or proviral functions. In normal human cells, viral DNA replication increases expression of all classes of HSV-1 genes. We observed that IFI16 repressed transcription from both parental and progeny DNA genomes. Taken together, our results show that the mechanisms of action of IFI16 and ND10 proteins are independent, at least in part, and that IFI16 exerts restrictive effects on both input and replicated viral genomes. These results raise the potential for distinct mechanisms of action of IFI16 on parental and progeny viral DNA molecules.IMPORTANCE Many human DNA viruses transcribe their genomes and replicate in the nucleus of a host cell, where they exploit the host cell nuclear machinery for their own replication. Host factors attempt to restrict viral replication by blocking such events, and viruses have evolved mechanisms to neutralize the host restriction factors. In this study, we provide information about the mechanisms of action of three host cell factors that restrict replication of herpes simplex virus (HSV). We found that these factors function independently and that one acts to restrict viral transcription from parental and progeny viral DNA genomes. These results provide new information about how cells counter DNA virus replication in the nucleus and provide possible approaches to enhance the ability of human cells to resist HSV infection. PMID- 29491154 TI - Caspase-Dependent Apoptosis Induction via Viral Protein ORF4 of Porcine Circovirus 2 Binding to Mitochondrial Adenine Nucleotide Translocase 3. AB - Apoptosis is an essential strategy of host defense responses and is used by viruses to maintain their life cycles. However, the apoptotic signals involved in virus replication are poorly known. In the present study, we report the molecular mechanism of apoptotic induction by the viral protein ORF4, a newly identified viral protein of porcine circovirus type 2 (PCV2). Apoptosis detection revealed not only that the activity of caspase-3 and -9 is increased in PCV2-infected and ORF4-transfected cells but also that cytochrome c release from the mitochondria to the cytosol is upregulated. Subsequently, ORF4 protein colocalization with adenine nucleotide translocase 3 (ANT3) was observed using structured illumination microscopy. Moreover, coimmunoprecipitation and pulldown analyses confirmed that the ORF4 protein interacts directly with mitochondrial ANT3 (mtANT3). Binding domain analysis further confirmed that N-terminal residues 1 to 30 of the ORF4 protein, comprising a mitochondrial targeting signal, are essential for the interaction with ANT3. Knockdown of ANT3 markedly inhibited the apoptotic induction of both ORF4 protein and PCV2, indicating that ANT3 plays an important role in ORF4 protein-induced apoptosis during PCV2 infection. Taken together, these data indicate that the ORF4 protein is a mitochondrial targeting protein that induces apoptosis by interacting with ANT3 through the mitochondrial pathway.IMPORTANCE The porcine circovirus type 2 (PCV2) protein ORF4 is a newly identified viral protein; however, little is known about its functions. Apoptosis is an essential strategy of the host defense response and is used by viruses to maintain their life cycles. In the present study, we report the molecular mechanism of the apoptosis induced by the ORF4 protein. The ORF4 protein contains a mitochondrial targeting signal and is an unstable protein that is degraded by the proteasome-dependent pathway. Viral protein ORF4 triggers caspase-3- and -9 dependent cellular apoptosis in mitochondria by directly binding to ANT3. We conclude that the ORF4 protein is a mitochondrial targeting protein and reveal a mechanism whereby circovirus recruits ANT3 to induce apoptosis. PMID- 29491155 TI - Copy Number Heterogeneity, Large Origin Tandem Repeats, and Interspecies Recombination in Human Herpesvirus 6A (HHV-6A) and HHV-6B Reference Strains. AB - Quantitative PCR is a diagnostic pillar for clinical virology testing, and reference materials are necessary for accurate, comparable quantitation between clinical laboratories. Accurate quantitation of human herpesvirus 6A/B (HHV-6A/B) is important for detection of viral reactivation and inherited chromosomally integrated HHV-6A/B in immunocompromised patients. Reference materials in clinical virology commonly consist of laboratory-adapted viral strains that may be affected by the culture process. We performed next-generation sequencing to make relative copy number measurements at single nucleotide resolution of eight candidate HHV-6A and seven HHV-6B reference strains and DNA materials from the HHV-6 Foundation and Advanced Biotechnologies Inc. Eleven of 17 (65%) HHV-6A/B candidate reference materials showed multiple copies of the origin of replication upstream of the U41 gene by next-generation sequencing. These large tandem repeats arose independently in culture-adapted HHV-6A and HHV-6B strains, measuring 1,254 bp and 983 bp, respectively. The average copy number measured was between 5 and 10 times the number of copies of the rest of the genome. We also report the first interspecies recombinant HHV-6A/B strain with a HHV-6A backbone and a >5.5-kb region from HHV-6B, from U41 to U43, that covered the origin tandem repeat. Specific HHV-6A reference strains demonstrated duplication of regions at U1/U2, U87, and U89, as well as deletion in the U12-to-U24 region and the U94/U95 genes. HHV-6A/B strains derived from cord blood mononuclear cells from different laboratories on different continents with fewer passages revealed no copy number differences throughout the viral genome. These data indicate that large origin tandem duplications are an adaptation of both HHV-6A and HHV-6B in culture and show interspecies recombination is possible within the Betaherpesvirinae.IMPORTANCE Anything in science that needs to be quantitated requires a standard unit of measurement. This includes viruses, for which quantitation increasingly determines definitions of pathology and guidelines for treatment. However, the act of making standard or reference material in virology can alter its very accuracy through genomic duplications, insertions, and rearrangements. We used deep sequencing to examine candidate reference strains for HHV-6, a ubiquitous human virus that can reactivate in the immunocompromised population and is integrated into the human genome in every cell of the body for 1% of people worldwide. We found large tandem repeats in the origin of replication for both HHV-6A and HHV-6B that are selected for in culture. We also found the first interspecies recombinant between HHV-6A and HHV-6B, a phenomenon that is well known in alphaherpesviruses but to date has not been seen in betaherpesviruses. These data critically inform HHV-6A/B biology and the standard selection process. PMID- 29491157 TI - Intragastric administration of Lactobacillus plantarum and AT-2-inactivated SIV does not protect Indian rhesus macaques from intra-rectal SIV challenge nor reduce virus replication after transmission. AB - A major obstacle to development of an effective AIDS vaccine is that along with intended beneficial responses, immunization regimen may activate CD4+ T cells that can facilitate acquisition of HIV by serving as target cells for the virus. Lu et al. reported that intra-gastric administration of chemically inactivated SIVmac239 (iSIV) and Lactobacillus plantarum (LP) (iSIV+LP) protected 15/16 Chinese-origin rhesus macaques (RMs) from high-dose intra-rectal SIVmac239 challenge at three months post-immunization. They attributed the observed protection to induction of immune tolerance, mediated by "MHC-Ib/E-restricted CD8+ regulatory T cells that suppressed SIV-harboring CD4+ T cell activation and ex vivo SIV replication in 15/16 animals without inducing SIV-specific antibodies or cytotoxic T". Andrieu et al subsequently reported protection from infection in 23/24 RM immunized intragastrically or intravaginally with iSIV and BCG, LP or Lactobacillus rhamnosus, which they ascribed to the same tolerogenic mechanism. Using vaccine materials obtained from our co-authors, we conducted an immunization and challenge experiment in 54 Indian RMs, and included control groups receiving iSIV only or LP only, as well as unvaccinated animals. Intra rectal challenge with SIVmac239 resulted in rapid infection in all groups of vaccinated RMs as well as unvaccinated controls. iSIV+LP vaccinated animals that became SIV infected showed viral loads similar to those observed in animals receiving iSIV only, LP only, and unvaccinated controls. The protection from SIV transmission conferred by intra-gastric iSIV+LP administration reported previously for Chinese origin RMs was not observed when the same experiment was conducted in a larger cohort of Indian-origin animals.IMPORTANCE: Despite increased understanding in immune responses against HIV, a safe and effective AIDS vaccine is not yet available. One obstacle is that immunization may activate CD4+ T cells that could act as target cells for acquisition of HIV. An alternative strategy could involve induction of a tolerizing response that limits the availability of activated CD4+ T cells, thus limiting the ability of virus to establish infection. In this regard, exciting results were obtained in Chinese origin rhesus macaques by using a "tolerogenic" vaccine consisting of intra gastric administration of Lactobacillus plantarum and AT-2-inactivated SIV (iSIV+LP) which showed highly significant protection from virus transmission. Here, we administered iSIV+LP immunizations to Indian-origin rhesus macaques, and failed to observe any protective effect from virus acquisition in this experimental setting. This work is important as it contributes to the overall assessment of the clinical potential of a new candidate AIDS vaccine platform based on the iSIV+LP. PMID- 29491156 TI - Asymmetric Modification of Hepatitis B Virus (HBV) Genomes by an Endogenous Cytidine Deaminase inside HBV Cores Informs a Model of Reverse Transcription. AB - Cytidine deaminases inhibit replication of a broad range of DNA viruses by deaminating cytidines on single-stranded DNA (ssDNA) to generate uracil. While several lines of evidence have revealed hepatitis B virus (HBV) genome editing by deamination, it is still unclear which nucleic acid intermediate of HBV is modified. Hepatitis B virus has a relaxed circular double-stranded DNA (rcDNA) genome that is reverse transcribed within virus cores from a RNA template. The HBV genome also persists as covalently closed circular DNA (cccDNA) in the nucleus of an infected cell. In the present study, we found that in HBV-producing HepAD38 and HepG2.2.15 cell lines, endogenous cytidine deaminases edited 10 to 25% of HBV rcDNA genomes, asymmetrically with almost all mutations on the 5' half of the minus strand. This region corresponds to the last half of the minus strand to be protected by plus-strand synthesis. Within this half of the genome, the number of mutations peaks in the middle. Overexpressed APOBEC3A and APOBEC3G could be packaged in HBV capsids but did not change the amount or distribution of mutations. We found no deamination on pregenomic RNA (pgRNA), indicating that an intact genome is encapsidated and deaminated during or after reverse transcription. The deamination pattern suggests a model of rcDNA synthesis in which pgRNA and then newly synthesized minus-sense single-stranded DNA are protected from deaminase by interaction with the virus capsid; during plus-strand synthesis, when enough dsDNA has been synthesized to displace the remaining minus strand from the capsid surface, the single-stranded DNA becomes deaminase sensitive.IMPORTANCE Host-induced mutation of the HBV genome by APOBEC proteins may be a path to clearing the virus. We examined cytidine-to-thymidine mutations in the genomes of HBV particles grown in the presence or absence of overexpressed APOBEC proteins. We found that genomes were subjected to deamination activity during reverse transcription, which takes place within the virus capsid. These observations provide a direct insight into the mechanics of reverse transcription, suggesting that newly synthesized dsDNA displaces ssDNA from the capsid walls, making the ssDNA accessible to deaminase activity. PMID- 29491158 TI - Virulent poxviruses inhibit DNA sensing by preventing STING activation. AB - Cytosolic recognition of DNA has emerged as a critical cellular mechanism of host immune activation upon pathogen invasion. The central cytosolic DNA sensor cGAS activates STING, which is phosphorylated, dimerises and translocates from the ER to a perinuclear region to mediate IRF-3 activation. Poxviruses are dsDNA viruses replicating in the cytosol and hence likely to trigger cytosolic DNA sensing. Here we investigated the activation of innate immune signalling by 4 different strains of the prototypic poxvirus vaccinia virus (VACV) in a cell line proficient in DNA sensing. Infection with the attenuated VACV strain MVA activated IRF-3 via cGAS and STING, and accordingly STING dimerised and was phosphorylated during MVA infection. Conversely, VACV strains Copenhagen and Western Reserve inhibited STING dimerisation and phosphorylation during infection and in response to transfected DNA and cGAMP, thus efficiently suppressing DNA sensing and IRF-3 activation. A VACV deletion mutant lacking protein C16, thought to be the only viral DNA sensing inhibitor acting upstream of STING, retained the ability to block STING activation. Similar inhibition of DNA-induced STING activation was also observed for cowpox and ectromelia viruses. Our data demonstrate that virulent poxviruses possess mechanisms for targeting DNA sensing at the level of the cGAS-STING axis and that these mechanisms do not operate in replication-defective strains such as MVA. These findings shed light on the role of cellular DNA sensing in poxvirus-host interactions and will open new avenues to determine its impact on VACV immunogenicity and virulence.IMPORTANCE Poxviruses are dsDNA viruses infecting a wide range of vertebrates and include the causative agent of smallpox (variola virus) and its vaccine vaccinia virus (VACV). Despite smallpox eradication VACV remains of interest as a therapeutic. Attenuated strains are popular vaccine candidates, whereas replication-competent strains are emerging as efficient oncolytics in virotherapy. The successful therapeutic use of VACV depends on a detailed understanding of its ability to modulate host innate immune responses. DNA sensing is a critical cellular mechanism for pathogen detection and activation of innate immunity that is centrally coordinated by the ER-resident protein STING. Here STING is shown to mediate immune activation in response to MVA, but not to virulent VACV strains or other virulent poxviruses, which prevent STING activation and DNA sensing during infection and after DNA transfection. These results provide new insights into poxvirus immune evasion and have implications in the rational design of VACV based therapeutics. PMID- 29491159 TI - Identification of Piperazinylbenzenesulfonamides as New Inhibitors of Claudin-1 Trafficking and Hepatitis C Virus Entry. AB - Hepatitis C virus (HCV) infection causes 500,000 deaths annually, in association with end-stage liver diseases. Investigations of the HCV life cycle have widened the knowledge of virology, and here we discovered that two piperazinylbenzenesulfonamides inhibit HCV entry into liver cells. The entry of HCV into host cells is a complex process that is not fully understood but is characterized by multiple spatially and temporally regulated steps involving several known host factors. Through a high-content virus infection screening analysis with a library of 1,120 biologically active chemical compounds, we identified SB258585, an antagonist of serotonin receptor 6 (5-HT6), as a new inhibitor of HCV entry in liver-derived cell lines as well as primary hepatocytes. A functional characterization suggested a role for this compound and the compound SB399885, which share similar structures, as inhibitors of a late HCV entry step, modulating the localization of the coreceptor tight junction protein claudin-1 (CLDN1) in a 5-HT6-independent manner. Both chemical compounds induced an intracellular accumulation of CLDN1, reflecting export impairment. This regulation correlated with the modulation of protein kinase A (PKA) activity. The PKA inhibitor H89 fully reproduced these phenotypes. Furthermore, PKA activation resulted in increased CLDN1 accumulation at the cell surface. Interestingly, an increase of CLDN1 recycling did not correlate with an increased interaction with CD81 or HCV entry. These findings reinforce the hypothesis of a common pathway, shared by several viruses, which involves G-protein-coupled receptor-dependent signaling in late steps of viral entry.IMPORTANCE The HCV entry process is highly complex, and important details of this structured event are poorly understood. By screening a library of biologically active chemical compounds, we identified two piperazinylbenzenesulfonamides as inhibitors of HCV entry. The mechanism of inhibition was not through the previously described activity of these inhibitors as antagonists of serotonin receptor 6 but instead through modulation of PKA activity in a 5-HT6-independent manner, as proven by the lack of 5-HT6 in the liver. We thus highlighted the involvement of the PKA pathway in modulating HCV entry at a postbinding step and in the recycling of the tight junction protein claudin-1 (CLDN1) toward the cell surface. Our work underscores once more the complexity of HCV entry steps and suggests a role for the PKA pathway as a regulator of CLDN1 recycling, with impacts on both cell biology and virology. PMID- 29491160 TI - Enhanced Human-Type Receptor Binding by Ferret-Transmissible H5N1 with a K193T Mutation. AB - All human influenza pandemics have originated from avian influenza viruses. Although multiple changes are needed for an avian virus to be able to transmit between humans, binding to human-type receptors is essential. Several research groups have reported mutations in H5N1 viruses that exhibit specificity for human type receptors and promote respiratory droplet transmission between ferrets. Upon detailed analysis, we have found that these mutants exhibit significant differences in fine receptor specificity compared to human H1N1 and H3N2 and retain avian-type receptor binding. We have recently shown that human influenza viruses preferentially bind to alpha2-6-sialylated branched N-linked glycans, where the sialic acids on each branch can bind to receptor sites on two protomers of the same hemagglutinin (HA) trimer. In this binding mode, the glycan projects over the 190 helix at the top of the receptor-binding pocket, which in H5N1 would create a stearic clash with lysine at position 193. Thus, we hypothesized that a K193T mutation would improve binding to branched N-linked receptors. Indeed, the addition of the K193T mutation to the H5 HA of a respiratory-droplet transmissible virus dramatically improves both binding to human trachea epithelial cells and specificity for extended alpha2-6-sialylated N-linked glycans recognized by human influenza viruses.IMPORTANCE Infections by avian H5N1 viruses are associated with a high mortality rate in several species, including humans. Fortunately, H5N1 viruses do not transmit between humans because they do not bind to human-type receptors. In 2012, three seminal papers have shown how these viruses can be engineered to transmit between ferrets, the human model for influenza virus infection. Receptor binding, among others, was changed, and the viruses now bind to human-type receptors. Receptor specificity was still markedly different compared to that of human influenza viruses. Here we report an additional mutation in ferret-transmissible H5N1 that increases human-type receptor binding. K193T seems to be a common receptor specificity determinant, as it increases human-type receptor binding in multiple subtypes. The K193T mutation can now be used as a marker during surveillance of emerging viruses to assess potential pandemic risk. PMID- 29491162 TI - Long Noncoding RNA uc002yug.2 Activates HIV-1 Latency through Regulation of mRNA Levels of Various RUNX1 Isoforms and Increased Tat Expression. AB - The HIV-1 reservoir is a major obstacle to complete eradication of the virus. Although many proteins and RNAs have been characterized as regulators in HIV 1/AIDS pathogenesis and latency, only a few long noncoding RNAs (lncRNAs) have been shown to be closely associated with HIV-1 replication and latency. In this study, we demonstrated that lncRNA uc002yug.2 plays a key role in HIV-1 replication and latency. uc002yug.2 potentially enhances HIV-1 replication, long terminal repeat (LTR) activity, and the activation of latent HIV-1 in both cell lines and CD4+ T cells from patients. Further investigation revealed that uc002yug.2 activates latent HIV-1 through downregulating RUNX1b and -1c and upregulating Tat protein expression. The accumulated evidence supports our model that the Tat protein has the key role in the uc002yug.2-mediated regulatory effect on HIV-1 reactivation. Moreover, uc002yug.2 showed an ability to activate HIV-1 similar to that of suberoylanilide hydroxamic acid or phorbol 12-myristate 13-acetate using latently infected cell models. These findings improve our understanding of lncRNA regulation of HIV-1 replication and latency, providing new insights into potential targeted therapeutic interventions.IMPORTANCE The latent viral reservoir is the primary obstacle to curing HIV-1 disease. To date, only a few lncRNAs, which play major roles in various biological processes, including viral infection, have been identified as regulators in HIV-1 latency. In this study, we demonstrated that lncRNA uc002yug.2 is important for both HIV-1 replication and activation of latent viruses. Moreover, uc002yug.2 was shown to activate latent HIV-1 through regulating alternative splicing of RUNX1 and increasing the expression of Tat protein. These findings highlight the potential merit of targeting lncRNA uc002yug.2 as an activating agent for latent HIV-1. PMID- 29491161 TI - Relative Abundance of Integrant-Derived Viral RNAs in Infected Tissues Harvested from Chronic Hepatitis B Virus Carriers. AB - Five matching sets of nonmalignant liver tissues and hepatocellular carcinoma (HCC) samples from individuals chronically infected with hepatitis B virus (HBV) were examined. The HBV genomic sequences were determined by using overlapping PCR amplicons covering the entire viral genome. Four pairs of tissues were infected with HBV genotype C, while one pair was infected with HBV genotype B. HBV replication markers were found in all tissues. In the majority of HCC samples, the levels of pregenomic/precore RNA (pgRNA) and covalently closed circular DNA (cccDNA) were lower than those in liver tissue counterparts. Regardless of the presence of HBV replication markers, (i) integrant-derived HBV RNAs (id-RNAs) were found in all tissues by reverse transcription-PCR (RT-PCR) analysis and were considerably abundant or predominant in 6/10 tissue samples (2 liver and 4 HCC samples), (ii) RNAs that were polyadenylated using the cryptic HBV polyadenylation signal and therefore could be produced by HBV replication or derived from integrated HBV DNA were found in 5/10 samples (3 liver and 2 HCC samples) and were considerably abundant species in 3/10 tissues (2 livers and 1 HCC), and (iii) cccDNA-transcribed RNAs polyadenylated near position 1931 were not abundant in 7/10 tissues (2 liver and 5 HCC samples) and were predominant in only two liver samples. Subsequent RNA sequencing analysis of selected liver/HCC samples also showed relative abundance of id-RNAs in most of the examined tissues. Our findings suggesting that id-RNAs could represent a significant source of HBV envelope proteins, which is independent of viral replication, are discussed in the context of the possible contribution of id-RNAs to the HBV life cycle.IMPORTANCE The relative abundance of integrant-derived HBV RNAs (id-RNAs) in chronically infected tissues suggest that id-RNAs coding for the envelope proteins may facilitate the production of a considerable fraction of surface antigens (HBsAg) in infected cells bearing HBV integrants. If the same cells support HBV replication, then a significant fraction of assembled HBV virions could bear id-RNA-derived HBsAg as a major component of their envelopes. Therefore, the infectivity of these HBV virions and their ability to facilitate virus cell-to-cell spread could be determined mainly by the properties of id-RNA derived envelope proteins and not by the properties of replication-derived HBsAg. These interpretations suggest that id-RNAs may play a role in the maintenance of chronic HBV infection and therefore contribute to the HBV life cycle. Furthermore, the production of HBsAg from id-RNAs independently of viral replication may explain at least in part why treatment with interferon or nucleos(t)ides in most cases fails to achieve a loss of serum HBsAg. PMID- 29491163 TI - Alpha/Beta Interferon (IFN-alpha/beta) Signaling in Astrocytes Mediates Protection against Viral Encephalomyelitis and Regulates IFN-gamma-Dependent Responses. AB - The contribution of distinct central nervous system (CNS) resident cells to protective alpha/beta interferon (IFN-alpha/beta) function following viral infections is poorly understood. Based on numerous immune regulatory functions of astrocytes, we evaluated the contribution of astrocyte IFN-alpha/beta signaling toward protection against the nonlethal glia- and neuronotropic mouse hepatitis virus (MHV) strain A59. Analysis of gene expression associated with IFN alpha/beta function, e.g., pattern recognition receptors (PRRs) and interferon stimulated genes (ISGs), revealed lower basal mRNA levels in brain-derived astrocytes than in microglia. Although astrocytes poorly induced Ifnbeta mRNA following infection, they upregulated various mRNAs in the IFN-alpha/beta pathway to a higher extent than microglia, supporting effective IFN-alpha/beta responsiveness. Ablation of the IFN-alpha/beta receptor (IFNAR) in astrocytes using mGFAPcre IFNARfl/fl mice resulted in severe encephalomyelitis and mortality, coincident with uncontrolled virus replication. Further, virus spread was not restricted to astrocytes but also affected microglia and neurons, despite increased and sustained Ifnalpha/beta and ISG mRNA levels within the CNS. IFN gamma, a crucial mediator for MHV control, was not impaired in infected mGFAPcre IFNARfl/fl mice despite reduced T cell CNS infiltration. Unexpectedly however, poor induction of IFN-gamma-dependent major histocompatibility complex (MHC) class II expression on microglia supported that defective IFN-gamma signaling contributes to uncontrolled virus replication. A link between sustained elevated IFN-alpha/beta and impaired responsiveness to IFN-gamma supports the novel concept that temporally limited early IFN-alpha/beta responses are critical for effective antiviral IFN-gamma function. Overall, our results imply that IFN alpha/beta signaling in astrocytes is not only critical in limiting early CNS viral spread but also promotes protective antiviral IFN-gamma function.IMPORTANCE An antiviral state established by IFN-alpha/beta contains initial viral spread as adaptive immunity develops. While it is apparent that the CNS lacks professional IFN-alpha/beta producers and that resident cells have distinct abilities to elicit innate IFN-alpha/beta responses, protective interactions between inducer and responder cells require further investigation. Infection with a glia- and neuronotropic coronavirus demonstrates that astrocytes mount a delayed but more robust response to infection than microglia, despite their lower basal mRNA levels of IFN-alpha/beta-inducing components. Lethal, uncontrolled viral dissemination following ablation of astrocyte IFN-alpha/beta signaling revealed the importance of IFN-alpha/beta responses in a single cell type for protection. Sustained global IFN-alpha/beta expression associated with uncontrolled virus did not suffice to protect neurons and further impaired responsiveness to protective IFN-gamma. The results support astrocytes as critical contributors to innate immunity and the concept that limited IFN-alpha/beta responses are critical for effective subsequent antiviral IFN-gamma function. PMID- 29491164 TI - Euphyllophyte Paleoviruses Illuminate Hidden Diversity and Macroevolutionary Mode of Caulimoviridae. AB - Endogenous viral elements (paleoviruses) provide "molecular fossils" for studying the deep history and macroevolution of viruses. Endogenous plant pararetroviruses (EPRVs) are widespread in angiosperms, but little is known about EPRVs in earlier branching plants. Here we use a large-scale phylogenomic approach to investigate the diversity and macroevolution of plant pararetroviruses (formally known as Caulimoviridae). We uncover an unprecedented and unappreciated diversity of EPRVs within the genomes of gymnosperms and ferns. The known angiosperm viruses constitute only a minor part of the Caulimoviridae diversity. By characterizing the distribution of EPRVs, we show that no major euphyllophyte lineages escape the activity of Caulimoviridae, raising the possibility that many exogenous Caulimoviridae remain to be discovered in euphyllophytes. We find that the copy numbers of EPRVs are generally high, suggesting that EPRVs might define a unique group of repetitive elements and represent important components of euphyllophyte genomes. Evolutionary analyses suggest an ancient origin of Caulimoviridae and at least three independent origins of Caulimoviridae in angiosperms. Our findings reveal the remarkable diversity of Caulimoviridae and have important implications for understanding the origin and macroevolution of plant pararetroviruses.IMPORTANCE Few viruses have been documented in plants outside angiosperms. Viruses can occasionally integrate into host genomes, forming endogenous viral elements (EVEs). Endogenous plant pararetroviruses (EPRVs) are widespread in angiosperms. In this study, we performed comprehensive comparative and phylogenetic analyses of EPRVs and found that EPRVs are present in the genomes of gymnosperms and ferns. We identified numerous EPRVs in gymnosperm and fern genomes, revealing an unprecedented depth in the diversity of plant pararetroviruses. Plant pararetroviruses mainly underwent cross-species transmission, and angiosperm pararetroviruses arose at least three times. Our study provides novel insights into the diversity and macroevolution of plant pararetroviruses. PMID- 29491165 TI - Tunneling Nanotubes as a Novel Route of Cell-to-Cell Spread of Herpesviruses. AB - Various types of intercellular connections that are essential for communication between cells are often utilized by pathogens. Recently, a new type of cellular connection, consisting of long, thin, actin-rich membrane extensions named tunneling nanotubes (TNTs), has been shown to play an important role in cell-to cell spread of HIV and influenza virus. In the present report, we show that TNTs are frequently formed by cells infected by an alphaherpesvirus, bovine herpesvirus 1 (BoHV-1). Viral proteins, such as envelope glycoprotein E (gE), capsid protein VP26, and tegument protein Us3, as well as cellular organelles (mitochondria) were detected by immunofluorescence and live-cell imaging of nanotubes formed by bovine primary fibroblasts and oropharynx cells (KOP cells). Time-lapse confocal studies of live cells infected with fluorescently labeled viruses showed that viral particles were transmitted via TNTs. This transfer also occurred in the presence of neutralizing antibodies, which prevented free entry of BoHV-1. We conclude that TNT formation contributes to successful cell-to-cell spread of BoHV-1 and demonstrate for the first time the participation of membrane nanotubes in intercellular transfer of a herpesvirus in live cells.IMPORTANCE Efficient transmission of viral particles between cells is an important factor in successful infection by herpesviruses. Herpesviruses can spread by the free-entry mode or direct cell-to-cell transfer via cell junctions and long extensions of neuronal cells. In this report, we show for the first time that an alphaherpesvirus can also spread between various types of cells using tunneling nanotubes, intercellular connections that are utilized by HIV and other viruses. Live-cell monitoring revealed that viral transmission occurs between the cells of the same type as well as between epithelial cells and fibroblasts. This newly discovered route of herpesviruses spread may contribute to efficient transmission despite the presence of host immune responses, especially after reactivation from latency that developed after primary infection. Long-range communication provided by TNTs may facilitate the spread of herpesviruses between many tissues and organs of an infected organism. PMID- 29491166 TI - Annexin A2 Mediates the Localization of Measles Virus Matrix Protein at the Plasma Membrane. AB - Annexins are a family of structurally related proteins that bind negatively charged membrane phospholipids in a Ca2+-dependent manner. Annexin A2 (AnxA2), a member of the family, has been implicated in a variety of cellular functions including the organization of membrane domains, vesicular trafficking and cell cell adhesion. AnxA2 generally forms the heterotetrameric complex with a small Ca2+-binding protein S100A10. Measles virus (MV), a member of the family Paramyxoviridae, is an enveloped virus with a nonsegmented negative strand RNA genome. Knockdown of AnxA2 greatly reduced MV growth in cells, without affecting its entry and viral RNA production. In MV-infected, AnxA2-knockdown cells, the expression level of the matrix (M) protein, but not other viral proteins, was reduced compared with that in control cells, and the distribution of the M protein at the plasma membrane was decreased. The M protein lines the inner surface of the envelope and plays an important role in virus assembly by connecting the nucleocapsid to the envelope proteins. The M protein bound to AnxA2 independently of AnxA2's phosphorylation or its association with S100A10, and was co-localized with AnxA2 within cells. Truncation of the N-terminal 10 amino acid residues, but not the N-terminal 5 residues, compromised the ability of the M protein to interact with AnxA2 and localize at the plasma membrane. These results indicate that AnxA2 mediates the localization of the MV M protein at the plasma membrane by interacting with its N-terminal region (especially residues at positions 6-10), thereby aiding in MV assembly.IMPORTANCE Measles virus (MV) is an important human pathogen, still claiming ~ 100,000 lives per year despite the presence of effective vaccines, and causes occasional outbreaks even in developed countries. Replication of viruses largely relies on the functions of host cells. Our study revealed that the reduction of the host protein annexin A2 compromises the replication of MV within the cell. Further studies demonstrated that annexin A2 interacts with the MV matrix (M) protein and mediates the localization of the M protein at the plasma membrane where MV particles are formed. The M protein lines the inner surface of the MV envelope membrane and plays a role in MV particle formation. Our results provide useful information for the understanding of the MV replication process and potential development of anti-viral agents. PMID- 29491168 TI - Integrating morphology and kinematics in the scaling of hummingbird hovering metabolic rate and efficiency. AB - Wing kinematics and morphology are influential upon the aerodynamics of flight. However, there is a lack of studies linking these variables to metabolic costs, particularly in the context of morphological adaptation to body size. Furthermore, the conversion efficiency from chemical energy into movement by the muscles (mechanochemical efficiency) scales with mass in terrestrial quadrupeds, but this scaling relationship has not been demonstrated within flying vertebrates. Positive scaling of efficiency with body size may reduce the metabolic costs of flight for relatively larger species. Here, we assembled a dataset of morphological, kinematic, and metabolic data on hovering hummingbirds to explore the influence of wing morphology, efficiency, and mass on hovering metabolic rate (HMR). We hypothesize that HMR would decline with increasing wing size, after accounting for mass. Furthermore, we hypothesize that efficiency will increase with mass, similarly to other forms of locomotion. We do not find a relationship between relative wing size and HMR, and instead find that the cost of each wingbeat increases hyperallometrically while wingbeat frequency declines with increasing mass. This suggests that increasing wing size is metabolically favourable over cycle frequency with increasing mass. Further benefits are offered to larger hummingbirds owing to the positive scaling of efficiency. PMID- 29491169 TI - Biomechanics of Tetrahymena escaping from a dead end. AB - Understanding the behaviours of swimming microorganisms in various environments is important for understanding cell distribution and growth in nature and industry. However, cell behaviour in complex geometries is largely unknown. In this study, we used Tetrahymena thermophila as a model microorganism and experimentally investigated cell behaviour between two flat plates with a small angle. In this configuration, the geometry provided a 'dead end' line where the two flat plates made contact. The results showed that cells tended to escape from the dead end line more by hydrodynamics than by a biological reaction. In the case of hydrodynamic escape, the cell trajectories were symmetric as they swam to and from the dead end line. Near the dead end line, T. thermophila cells were compressed between the two flat plates while cilia kept beating with reduced frequency; those cells again showed symmetric trajectories, although the swimming velocity decreased. These behaviours were well reproduced by our computational model based on biomechanics. The mechanism of hydrodynamic escape can be understood in terms of the torque balance induced by lubrication flow. We therefore conclude that a cell's escape from the dead end was assisted by hydrodynamics. These findings pave the way for understanding cell behaviour and distribution in complex geometries. PMID- 29491167 TI - Mutations in the Basic Region of the Mason-Pfizer Monkey Virus Nucleocapsid Protein Affect Reverse Transcription, Genomic RNA Packaging, and the Virus Assembly Site. AB - In addition to specific RNA-binding zinc finger domains, the retroviral Gag polyprotein contains clusters of basic amino acid residues that are thought to support Gag-viral genomic RNA (gRNA) interactions. One of these clusters is the basic K16NK18EK20 region, located upstream of the first zinc finger of the Mason Pfizer monkey virus (M-PMV) nucleocapsid (NC) protein. To investigate the role of this basic region in the M-PMV life cycle, we used a combination of in vivo and in vitro methods to study a series of mutants in which the overall charge of this region was more positive (RNRER), more negative (AEAEA), or neutral (AAAAA). The mutations markedly affected gRNA incorporation and the onset of reverse transcription. The introduction of a more negative charge (AEAEA) significantly reduced the incorporation of M-PMV gRNA into nascent particles. Moreover, the assembly of immature particles of the AEAEA Gag mutant was relocated from the perinuclear region to the plasma membrane. In contrast, an enhancement of the basicity of this region of M-PMV NC (RNRER) caused a substantially more efficient incorporation of gRNA, subsequently resulting in an increase in M-PMV RNRER infectivity. Nevertheless, despite the larger amount of gRNA packaged by the RNRER mutant, the onset of reverse transcription was delayed in comparison to that of the wild type. Our data clearly show the requirement for certain positively charged amino acid residues upstream of the first zinc finger for proper gRNA incorporation, assembly of immature particles, and proceeding of reverse transcription.IMPORTANCE We identified a short sequence within the Gag polyprotein that, together with the zinc finger domains and the previously identified RKK motif, contributes to the packaging of genomic RNA (gRNA) of Mason Pfizer monkey virus (M-PMV). Importantly, in addition to gRNA incorporation, this basic region (KNKEK) at the N terminus of the nucleocapsid protein is crucial for the onset of reverse transcription. Mutations that change the positive charge of the region to a negative one significantly reduced specific gRNA packaging. The assembly of immature particles of this mutant was reoriented from the perinuclear region to the plasma membrane. On the contrary, an enhancement of the basic character of this region increased both the efficiency of gRNA packaging and the infectivity of the virus. However, the onset of reverse transcription was delayed even in this mutant. In summary, the basic region in M-PMV Gag plays a key role in the packaging of genomic RNA and, consequently, in assembly and reverse transcription. PMID- 29491170 TI - Expression profiling across wild and cultivated tomatoes supports the relevance of early miR482/2118 suppression for Phytophthora resistance. AB - Plants possess a battery of specific pathogen resistance (R-)genes. Precise R gene regulation is important in the presence and absence of a pathogen. Recently, a microRNA family, miR482/2118, was shown to regulate the expression of a major class of R-genes, nucleotide-binding site leucine-rich repeats (NBS-LRRs). Furthermore, RNA silencing suppressor proteins, secreted by pathogens, prevent the accumulation of miR482/2118, leading to an upregulation of R-genes. Despite this transcriptional release of R-genes, RNA silencing suppressors positively contribute to the virulence of some pathogens. To investigate this paradox, we analysed how the regulation of NBS-LRRs by miR482/2118 has been shaped by the coevolution between Phytophthora infestans and cultivated and wild tomatoes. We used degradome analyses and qRT-PCR to evaluate and quantify the co-expression of miR482/2118 and their NBS-LRR targets. Our data show that miR482/2118-mediated targeting contributes to the regulation of NBS-LRRs in Solanum lycopersicum. Based on miR482/2118 expression profiling in two additional tomato species-with different coevolutionary histories with P. infestans-we hypothesize that pathogen mediated RNA silencing suppression is most effective in the interaction between S. lycopersicum and P. infestans Furthermore, an upregulation of miR482/2118 early in the infection may increase susceptibility to P. infestans. PMID- 29491171 TI - Restoration and repair of Earth's damaged ecosystems. AB - Given that few ecosystems on the Earth have been unaffected by humans, restoring them holds great promise for stemming the biodiversity crisis and ensuring ecosystem services are provided to humanity. Nonetheless, few studies have documented the recovery of ecosystems globally or the rates at which ecosystems recover. Even fewer have addressed the added benefit of actively restoring ecosystems versus allowing them to recover without human intervention following the cessation of a disturbance. Our meta-analysis of 400 studies worldwide that document recovery from large-scale disturbances, such as oil spills, agriculture and logging, suggests that though ecosystems are progressing towards recovery following disturbances, they rarely recover completely. This result reinforces conservation of intact ecosystems as a key strategy for protecting biodiversity. Recovery rates slowed down with time since the disturbance ended, suggesting that the final stages of recovery are the most challenging to achieve. Active restoration did not result in faster or more complete recovery than simply ending the disturbances ecosystems face. Our results on the added benefit of restoration must be interpreted cautiously, because few studies directly compared different restoration actions in the same location after the same disturbance. The lack of consistent value added of active restoration following disturbance suggests that passive recovery should be considered as a first option; if recovery is slow, then active restoration actions should be better tailored to overcome specific obstacles to recovery and achieve restoration goals. We call for a more strategic investment of limited restoration resources into innovative collaborative efforts between scientists, local communities and practitioners to develop restoration techniques that are ecologically, economically and socially viable. PMID- 29491172 TI - Strong linkages between depth, longevity and demographic stability across marine sessile species. AB - Understanding the role of the environment in shaping the evolution of life histories remains a major challenge in ecology and evolution. We synthesize longevity patterns of marine sessile species and find strong positive relationships between depth and maximum lifespan across multiple sessile marine taxa, including corals, bivalves, sponges and macroalgae. Using long-term demographic data on marine sessile and terrestrial plant species, we show that extreme longevity leads to strongly dampened population dynamics. We also used detailed analyses of Mediterranean red coral, with a maximum lifespan of 532 years, to explore the life-history patterns of long-lived taxa and the vulnerability to external mortality sources that these characteristics can create. Depth-related environmental gradients-including light, food availability, temperature and disturbance intensity-drive highly predictable distributions of life histories that, in turn, have predictable ecological consequences for the dynamics of natural populations. PMID- 29491173 TI - Human echolocators adjust loudness and number of clicks for detection of reflectors at various azimuth angles. AB - In bats it has been shown that they adjust their emissions to situational demands. Here we report similar findings for human echolocation. We asked eight blind expert echolocators to detect reflectors positioned at various azimuth angles. The same 17.5 cm diameter circular reflector placed at 100 cm distance at 0 degrees , 45 degrees or 90 degrees with respect to straight ahead was detected with 100% accuracy, but performance dropped to approximately 80% when it was placed at 135 degrees (i.e. somewhat behind) and to chance levels (50%) when placed at 180 degrees (i.e. right behind). This can be explained based on poorer target ensonification owing to the beam pattern of human mouth clicks. Importantly, analyses of sound recordings show that echolocators increased loudness and numbers of clicks for reflectors at farther angles. Echolocators were able to reliably detect reflectors when level differences between echo and emission were as low as -27 dB, which is much lower than expected based on previous work. Increasing intensity and numbers of clicks improves signal-to noise ratio and in this way compensates for weaker target reflections. Our results are, to our knowledge, the first to show that human echolocation experts adjust their emissions to improve sensory sampling. An implication from our findings is that human echolocators accumulate information from multiple samples. PMID- 29491174 TI - Vocal contagion of emotions in non-human animals. AB - Communicating emotions to conspecifics (emotion expression) allows the regulation of social interactions (e.g. approach and avoidance). Moreover, when emotions are transmitted from one individual to the next, leading to state matching (emotional contagion), information transfer and coordination between group members are facilitated. Despite the high potential for vocalizations to influence the affective state of surrounding individuals, vocal contagion of emotions has been largely unexplored in non-human animals. In this paper, I review the evidence for discrimination of vocal expression of emotions, which is a necessary step for emotional contagion to occur. I then describe possible proximate mechanisms underlying vocal contagion of emotions, propose criteria to assess this phenomenon and review the existing evidence. The literature so far shows that non human animals are able to discriminate and be affected by conspecific and also potentially heterospecific (e.g. human) vocal expression of emotions. Since humans heavily rely on vocalizations to communicate (speech), I suggest that studying vocal contagion of emotions in non-human animals can lead to a better understanding of the evolution of emotional contagion and empathy. PMID- 29491175 TI - Meta-analysis reveals weak associations between intrinsic state and personality. AB - Individual differences in behaviour characterize humans and animals alike. A hot field in behavioural ecology asks why this variation in 'personality' evolved. Theory posits that selection favours the integration of 'intrinsic state' and behaviour. Metabolism, hormones, energetic reserves and structural size have particularly been proposed as states covarying with behaviour among-individuals, either genetically or through plasticity integration. We conducted a meta analysis estimating the amount of among-individual variation in behaviour attributable to variation in state. Our literature search showed that only 22% of the studies claiming to estimate individual-level associations between state and behaviour actually did so. Our meta-analysis revealed that relatively aggressive, bold, explorative and/or active individuals had relatively high metabolic rates, hormone levels, body weights and/or body sizes. The proportion of among individual variation common to state and behaviour was nevertheless small (approx. 5%). This means that (i) adaptive explanations involving intrinsic states fail to explain much individual variation in behaviour, (ii) empiricists should consider nonlinear, additive or interactive effects of (multiple) intrinsic states, (iii) explanations not involving intrinsic states might be important, or (iv) empirical tests of state-dependent personality theory were inappropriate. Our meta-analysis highlights the importance of feedback between empiricists and theoreticians in the study of adaptive behavioural variation. PMID- 29491176 TI - The combined impacts of experimental defaunation and logging on seedling traits and diversity. AB - Animals can have both positive (e.g. via seed dispersal) and negative (e.g. via herbivory) impacts on plants. The net effects of these interactions remain difficult to predict and may be affected by overhunting and habitat disturbance, two widespread threats to tropical forests. Recent studies have documented their separate effects on plant recruitment but our understanding of how defaunation and logging interact to influence tropical tree communities is limited. From 2013 to 2016, we followed the fate of marked tree seedlings (n = 1489) from 81 genera in and outside experimental plots. Our plots differentially excluded small, medium and large-bodied mammal herbivores in logged and unlogged forest in Malaysian Borneo. We assessed the effects of experimental defaunation and logging on taxonomic diversity and plant trait (wood density, specific leaf area, fruit size) composition of seedling communities. Although seedling mortality was highest in the presence of all mammal herbivores (44%), defaunation alone did not alter taxonomic diversity nor plant trait composition. However, herbivores (across all body sizes) significantly reduced mean fruit size across the seedling community over time (95% confidence interval (CI): -0.09 to -0.01), particularly in logged forest (95% CI: -0.12 to -0.003). Our findings suggest that impacts of mammal herbivores on plant communities may be greater in forests with a history of disturbance and could subsequently affect plant functional traits and ecological processes associated with forest regeneration. PMID- 29491177 TI - Diversity-dependent evolutionary rates in early Palaeozoic zooplankton. AB - The extent to which biological diversity affects rates of diversification is central to understanding macroevolutionary dynamics, yet no consensus has emerged on the importance of diversity-dependence of evolutionary rates. Here, we analyse the species-level fossil record of early Palaeozoic graptoloids, documented with high temporal resolution, to test directly whether rates of diversification were influenced by levels of standing diversity within this major clade of marine zooplankton. To circumvent the statistical regression-to-the-mean artefact, whereby higher- and lower-than-average values of diversity tend to be followed by negative and positive diversification rates, we construct a non-parametric, empirically scaled, diversity-independent null model by randomizing the observed diversification rates with respect to time. Comparing observed correlations between diversity and diversification rate to those expected from this diversity independent model, we find evidence for negative diversity-dependence, accounting for up to 12% of the variance in diversification rate, with maximal correlation at a temporal lag of approximately 1 Myr. Diversity-dependence persists throughout the Ordovician and Silurian, despite a major increase in the strength and frequency of extinction and speciation pulses in the Silurian. By contrast to some previous work, we find that diversity-dependence affects rates of speciation and extinction nearly equally on average, although subtle differences emerge when we compare the Ordovician and Silurian. PMID- 29491178 TI - Physico-chemical characteristics of evaporating respiratory fluid droplets. AB - The detailed physico-chemical characteristics of respiratory droplets in ambient air, where they are subject to evaporation, are poorly understood. Changes in the concentration and phase of major components in a droplet-salt (NaCl), protein (mucin) and surfactant (dipalmitoylphosphatidylcholine)-may affect the viability of any pathogens contained within it and thus may affect the efficiency of transmission of infectious disease by droplets and aerosols. The objective of this study is to investigate the effect of relative humidity (RH) on the physico chemical characteristics of evaporating droplets of model respiratory fluids. We labelled these components in model respiratory fluids and observed evaporating droplets suspended on a superhydrophobic surface using optical and fluorescence microscopy. When exposed to continuously decreasing RH, droplets of different model respiratory fluids assumed different morphologies. Loss of water induced phase separation as well as indication of a decrease in pH. The presence of surfactant inhibited the rapid rehydration of the non-volatile components. An enveloped virus, phi6, that has been proposed as a surrogate for influenza virus appeared to be homogeneously distributed throughout the dried droplet. We hypothesize that the increasing acidity and salinity in evaporating respiratory droplets may affect the structure of the virus, although at low enough RH, crystallization of the droplet components may eliminate their harmful effects. PMID- 29491179 TI - Spatially extended hybrid methods: a review. AB - Many biological and physical systems exhibit behaviour at multiple spatial, temporal or population scales. Multiscale processes provide challenges when they are to be simulated using numerical techniques. While coarser methods such as partial differential equations are typically fast to simulate, they lack the individual-level detail that may be required in regions of low concentration or small spatial scale. However, to simulate at such an individual level throughout a domain and in regions where concentrations are high can be computationally expensive. Spatially coupled hybrid methods provide a bridge, allowing for multiple representations of the same species in one spatial domain by partitioning space into distinct modelling subdomains. Over the past 20 years, such hybrid methods have risen to prominence, leading to what is now a very active research area across multiple disciplines including chemistry, physics and mathematics. There are three main motivations for undertaking this review. Firstly, we have collated a large number of spatially extended hybrid methods and presented them in a single coherent document, while comparing and contrasting them, so that anyone who requires a multiscale hybrid method will be able to find the most appropriate one for their need. Secondly, we have provided canonical examples with algorithms and accompanying code, serving to demonstrate how these types of methods work in practice. Finally, we have presented papers that employ these methods on real biological and physical problems, demonstrating their utility. We also consider some open research questions in the area of hybrid method development and the future directions for the field. PMID- 29491180 TI - Model-based estimation of superinfection prevalence from limited datasets. AB - Humans can be infected sequentially by different strains of the same virus. Estimating the prevalence of so-called 'superinfection' for a particular pathogen is vital because superinfection implies a failure of immunologic memory against a given virus despite past exposure, which may signal challenges for future vaccine development. Increasingly, viral deep sequencing and phylogenetic inference can discriminate distinct strains within a host. Yet, a population-level study may misrepresent the true prevalence of superinfection for several reasons. First, certain infections such as herpes simplex virus (HSV-2) only reactivate single strains, making multiple samples necessary to detect superinfection. Second, the number of samples collected in a study may be fewer than the actual number of independently acquired strains within a single person. Third, detecting strains that are relatively less abundant can be difficult, even for other infections such as HIV-1 where deep sequencing may identify multiple strains simultaneously. Here we develop a model of superinfection inspired by ecology. We define an infected individual's richness as the number of infecting strains and use ecological evenness to quantify the relative strain abundances. The model uses an EM methodology to infer the true prevalence of superinfection from limited clinical datasets. Simulation studies with known true prevalence are used to contrast our EM method to a standard (naive) calculation. While varying richness, evenness and sampling we quantify the accuracy and precision of our method. The EM method outperforms in all cases, particularly when sampling is low, and richness or unevenness is high. Here, sensitivity to our assumptions about clinical data is considered. The simulation studies also provide insight into optimal study designs; estimates of prevalence improve equally by enrolling more participants or gathering more samples per person. Finally, we apply our method to data from published studies of HSV-2 and HIV-1 superinfection. PMID- 29491181 TI - Primordial sex facilitates the emergence of evolution. AB - Compartments are ubiquitous throughout biology, and they have very likely played a crucial role at the origin of life. Here we assume that a protocell, which is a compartment enclosing functional components, requires N such components in order to be evolvable. We calculate the timescale in which a minimal evolvable protocell is produced. We show that when protocells fuse and share information, the timescales polynomially in N By contrast, in the absence of fusion, the worst case scenario is exponential in N We discuss the implications of this result for the origin of life and other biological processes. PMID- 29491182 TI - An update on smart biocatalysts for industrial and biomedical applications. AB - Recently, smart biocatalysts, where enzymes are conjugated to stimuli-responsive (smart) polymers, have gained significant attention. Based on the presence or absence of external stimuli, the polymer attached to the enzyme changes its conformation to protect the enzyme from the external environment and regulate the enzyme activity, thus acting as a molecular switch. Owing to this behaviour, smart biocatalysts can be separated easily from a reaction mixture and re-used several times. Several such smart polymer-based biocatalysts have been developed for industrial and biomedical applications. In addition, they have been used in biosensors, biometrics and nano-electronic devices. This review article covers recent advances in developing different kinds of stimuli-responsive enzyme bioconjugates, including conjugation strategies, and their applications. PMID- 29491183 TI - Fast direct neuronal signaling via the IL-4 receptor as therapeutic target in neuroinflammation. AB - Ongoing axonal degeneration is thought to underlie disability in chronic neuroinflammation, such as multiple sclerosis (MS), especially during its progressive phase. Upon inflammatory attack, axons undergo pathological swelling, which can be reversible. Because we had evidence for beneficial effects of T helper 2 lymphocytes in experimental neurotrauma and discovered interleukin-4 receptor (IL-4R) expressed on axons in MS lesions, we aimed at unraveling the effects of IL-4 on neuroinflammatory axon injury. We demonstrate that intrathecal IL-4 treatment during the chronic phase of several experimental autoimmune encephalomyelitis models reversed disease progression without affecting inflammation. Amelioration of disability was abrogated upon neuronal deletion of IL-4R. We discovered direct neuronal signaling via the IRS1-PI3K-PKC pathway underlying cytoskeletal remodeling and axonal repair. Nasal IL-4 application, suitable for clinical translation, was equally effective in improving clinical outcome. Targeting neuronal IL-4 signaling may offer new therapeutic strategies to halt disability progression in MS and possibly also neurodegenerative conditions. PMID- 29491184 TI - Constitutive and TNFalpha-inducible expression of chondroitin sulfate proteoglycan 4 in glioblastoma and neurospheres: Implications for CAR-T cell therapy. AB - The heterogeneous expression of tumor-associated antigens limits the efficacy of chimeric antigen receptor (CAR)-redirected T cells (CAR-Ts) for the treatment of glioblastoma (GBM). We have found that chondroitin sulfate proteoglycan 4 (CSPG4) is highly expressed in 67% of the GBM specimens with limited heterogeneity. CSPG4 is also expressed on primary GBM-derived cells, grown in vitro as neurospheres (GBM-NS), which recapitulate the histopathology and molecular characteristics of primary GBM. CSPG4.CAR-Ts efficiently controlled the growth of GBM-NS in vitro and in vivo upon intracranial tumor inoculation. Moreover, CSPG4.CAR-Ts were also effective against GBM-NS with moderate to low expression of CSPG4. This effect was mediated by the in vivo up-regulation of CSPG4 on tumor cells, induced by tumor necrosis factor-alpha (TNFalpha) released by the microglia surrounding the tumor. Overall, the constitutive and TNFalpha-inducible expression of CSPG4 in GBM may greatly reduce the risk of tumor cell escape observed when targeted antigens are heterogeneously expressed on tumor cells. PMID- 29491185 TI - Mechanical circulatory support device-heart hysteretic interaction can predict left ventricular end diastolic pressure. AB - The full potential of mechanical circulatory systems in the treatment of cardiogenic shock is impeded by the lack of accurate measures of cardiac function to guide clinicians in determining when to initiate and how to optimally titrate support. The left ventricular end diastolic pressure (LVEDP) is an established metric of cardiac function that refers to the pressure in the left ventricle at the end of ventricular filling and immediately before ventricular contraction. In clinical practice, LVEDP is typically only inferred from, and poorly correlates with, the pulmonary capillary wedge pressure (PCWP). We leveraged the position of an indwelling percutaneous ventricular assist device and advanced data analysis methods to obtain LVEDP from the hysteretic operating metrics of the device. We validated our hysteresis-derived LVEDP measurement using mock flow loops, an animal model of cardiac dysfunction, and data from a patient in cardiogenic shock to show greater measurement precision and correlation with actual pressures than traditional inferences via PCWP. Delineation of the nonlinear relationship between device and heart adds insight into the interaction between ventricular support devices and the native heart, paving the way for continuous assessment of underlying cardiac state, metrics of cardiac function, potential closed-loop automated control, and rational design of future innovations in mechanical circulatory support systems. PMID- 29491186 TI - Toward achieving precision health. AB - Health care systems primarily focus on patients after they present with disease, not before. The emerging field of precision health encourages disease prevention and earlier detection by monitoring health and disease based on an individual's risk. Active participation in health care can be encouraged with continuous health-monitoring devices, providing a higher-resolution picture of human health and disease. However, the development of monitoring technologies must prioritize the collection of actionable data and long-term user engagement. PMID- 29491187 TI - Rapid detection of Mycobacterium tuberculosis in sputum with a solvatochromic trehalose probe. AB - Tuberculosis (TB) is the leading cause of death from an infectious bacterial disease. Poor diagnostic tools to detect active disease plague TB control programs and affect patient care. Accurate detection of live Mycobacterium tuberculosis (Mtb), the causative agent of TB, could improve TB diagnosis and patient treatment. We report that mycobacteria and other corynebacteria can be specifically detected with a fluorogenic trehalose analog. We designed a 4-N,N dimethylamino-1,8-naphthalimide-conjugated trehalose (DMN-Tre) probe that undergoes >700-fold increase in fluorescence intensity when transitioned from aqueous to hydrophobic environments. This enhancement occurs upon metabolic conversion of DMN-Tre to trehalose monomycolate and incorporation into the mycomembrane of Actinobacteria. DMN-Tre labeling enabled the rapid, no-wash visualization of mycobacterial and corynebacterial species without nonspecific labeling of Gram-positive or Gram-negative bacteria. DMN-Tre labeling was detected within minutes and was inhibited by heat killing of mycobacteria. Furthermore, DMN-Tre labeling was reduced by treatment with TB drugs, unlike the clinically used auramine stain. Lastly, DMN-Tre labeled Mtb in TB-positive human sputum samples comparably to auramine staining, suggesting that this operationally simple method may be deployable for TB diagnosis. PMID- 29491189 TI - Accurate motor mapping in awake common marmosets using micro electrocorticographical stimulation and stochastic threshold estimation. AB - OBJECTIVE: Motor map has been widely used as an indicator of motor skills and learning, cortical injury, plasticity, and functional recovery. Cortical stimulation mapping using epidural electrodes is recently adopted for animal studies. However, several technical limitations still remain. Test-retest reliability of epidural cortical stimulation (ECS) mapping has not been examined in detail. Many previous studies defined evoked movements and motor thresholds by visual inspection, and thus, lacked quantitative measurements. A reliable and quantitative motor map is important to elucidate the mechanisms of motor cortical reorganization. The objective of the current study was to perform reliable ECS mapping of motor representations based on the motor thresholds, which were stochastically estimated by motor evoked potentials and chronically implanted micro-electrocorticographical (uECoG) electrode arrays, in common marmosets. APPROACH: ECS was applied using the implanted uECoG electrode arrays in three adult common marmosets under awake conditions. Motor evoked potentials were recorded through electromyographical electrodes implanted in upper limb muscles. The motor threshold was calculated through a modified maximum likelihood threshold-hunting algorithm fitted with the recorded data from marmosets. Further, a computer simulation confirmed reliability of the algorithm. MAIN RESULTS: Computer simulation suggested that the modified maximum likelihood threshold-hunting algorithm enabled to estimate motor threshold with acceptable precision. In vivo ECS mapping showed high test-retest reliability with respect to the excitability and location of the cortical forelimb motor representations. SIGNIFICANCE: Using implanted uECoG electrode arrays and a modified motor threshold-hunting algorithm, we were able to achieve reliable motor mapping in common marmosets with the ECS system. PMID- 29491188 TI - HIV latency in isolated patient CD4+ T cells may be due to blocks in HIV transcriptional elongation, completion, and splicing. AB - Latently infected CD4+ T cells are the main barrier to complete clearance of HIV infection, but it is unclear what mechanisms govern latent HIV infection in vivo. To address this question, we developed a new panel of reverse transcription droplet digital polymerase chain reaction (RT-ddPCR) assays specific for different HIV transcripts that define distinct blocks to transcription. We applied this panel of assays to CD4+ T cells freshly isolated from HIV-infected patients on suppressive antiretroviral therapy (ART) to quantify the degree to which different mechanisms inhibit HIV transcription. In addition, we measured the degree to which these transcriptional blocks could be reversed ex vivo by T cell activation (using anti-CD3/CD28 antibodies) or latency-reversing agents. We found that the main reversible block to HIV RNA transcription was not inhibition of transcriptional initiation but rather a series of blocks to proximal elongation, distal transcription/polyadenylation (completion), and multiple splicing. Cell dilution experiments suggested that these mechanisms operated in most of the HIV-infected CD4+ T cells examined. Latency-reversing agents exerted differential effects on the three blocks to HIV transcription, suggesting that these blocks may be governed by different mechanisms. PMID- 29491190 TI - Protective effects of glutamine on human melanocyte oxidative stress model. AB - Background: Vitiligo is a disorder caused by the loss of the melanocyte activity on melanin pigment generation. Studies show that oxidative-stress induced apoptosis in melanocytes is closely related to the pathogenesis of vitiligo. Glutamine is a well known antioxidant with anti-apoptotic effects, and is used in a variety of diseases. However, it is unclear whether glutamine has an antioxidant or anti-apoptotic effect on melanocytes. Aims: The aim of this study was to investigate the protective effects of glutamine on a human melanocyte oxidative stress model. Methods: The oxidative stress model was established on human melanocytes using hydrogen peroxide. The morphology and viability of melanocytes, levels of oxidants [reactive oxygen species and malondialdehyde], levels of antioxidants [superoxide dismutase and glutathione-S-transferase], and apoptosis-related indicators (caspase-3, bax and bcl-2) were examined after glutamine exposure at various concentrations. Expressions of nuclear factor-E2 related factor 2, heme oxygenase-1, and heat shock protein 70 were detected using western blot technique after glutamine exposure at various concentrations. Results: Our results demonstrate that pre-treatment and post-treatment with glutamine promoted melanocyte viability, increased levels of superoxide dismutase, glutathione-S-transferase and bcl-2, decreased levels of reactive oxygen species, malondialdehyde, bax and caspase-3, and enhanced nuclear factor E2-related factor 2, heme oxygenase-1, and heat shock protein 70 expression in a dose dependent manner. The effect of pre-treatment was more significant than post treatment, at the same concentration. Limitations: The mechanisms of glutamine activated nuclear factor-E2-related factor 2 antioxidant responsive element signaling pathway need further investigation. Conclusions: Glutamine enhances the antioxidant and anti-apoptotic capabilities of melanocytes and protects them against oxidative stress. PMID- 29491191 TI - A cross-sectional study of variations in the biophysical parameters of skin among healthy volunteers. AB - Background: Biophysical parameters of skin such as trans-epidermal water loss (TEWL), hydration, elasticity, pH, and sebum reflects it functional integrity. Advances in technology have made it possible to measure these parameters by non invasive methods. These parameters are useful for the prediction of disease and its prognosis. It also helps in developing new skin care products according to various skin types, and to evaluate, modify, or compare the effects of existing products. Aim: The aim of the study was to measure, evaluate, and analyze variations in biophysical parameters at pre-selected skin sites in healthy Indian volunteers, across different age groups and gender. Methods: The study was conducted among 500 healthy Indian volunteers, between 5 and 70 years of age, in the outpatient department of dermatology at Sir T. Hospital, Bhavnagar. Biophysical parameters such as TEWL, hydration, elasticity, and sebum content was measured on four pre-selected body sites by a Dermalab instrument (Cortex Technology, Denmark). The skin pH was measured with a sensitive pH probe (BEPL 2100). Results: All parameters were higher in males compared to females, except for sebum content, which was equal in both genders. Transepidermal water loss and hydration was lower in middle and older age groups. The skin pH showed no statistically significant difference with age. Sebum content was higher in middle and older age groups. The nose had the highest sebum content across all age groups. The forehead showed higher median values of TEWL and hydration compared to other sites. Though elasticity has highest value on forearm, only leg region showed statistically significant value. Limitations: The present study was confined to a single geographical area, so the effect of environment changes could not be judged accurately. Seasonal variations were not studied as it was a cross-sectional study. Conclusion: Skin properties vary with age, gender, and location on the body. This knowledge will help to create a database of these parameters in the Indian population. It would assist in the diagnosis of various clinical conditions and monitor therapeutic response. PMID- 29491192 TI - Crusted nipple and areola: A new aetiology of secondary hyperkeratosis of the nipple and areola. AB - Hyperkeratosis of the nipple and areola is a rare condition first described by Tauber in 1923. Less than 100 cases have been reported in the literature. Hyperkeratosis of the nipple and areola presents as hyperkeratotic, hyperpigmented plaques on the nipple and areola. It is more common in females. An 18-year-old female patient presented with hyperkeratotic, plaque-like, hard crusts on both nipples and areolas. The examining physician could successfully remove this crust using his finger. The crust had accumulated as a result of the patient's reluctance to touch or clean the breast area due to psychological issues. A crusted nipple and areola may occur as a secondary condition due to a patient's reluctance to touch or clean their breasts. PMID- 29491193 TI - Localized unilateral basaloid follicular hamartoma along Blaschko's lines on face. AB - Basaloid follicular hamartoma (BFH) is a rare hamartoma of hair follicle. Clinical presentations may vary but are united by the same histopathological features in the form of folliculocentric basaloid or squamoid cell proliferation in the superficial dermis, which represents malformed and distorted hair follicles. It is important to recognize this entity as its simulant is basal cell carcinoma, a low-grade malignancy. Here, we report a case of localized unilateral BFH in a Blaschkoid distribution on the face of a 14-year-old female. PMID- 29491195 TI - Ruptured Abdominal Aortic Aneurysm Treated by Double-Balloon Technique and Endovascular Strategy: Case Series. AB - PURPOSE: Mortality in patients with ruptured abdominal aortic aneurysms (rAAAs) has remained high despite advances in interventions. Endovascular aneurysm repair (EVAR) was recently developed for treatment of rAAAs. In this study, we assessed our endovascular strategy including a double-balloon technique for rAAA. METHODS: We analyzed 12 consecutive patients with rAAAs who were treated by our double balloon technique and endovascular strategy from March 2013 to July 2016. RESULTS: The 30-day and 1-year mortality rates were both 17%. The mean times from admission to arrival at the hybrid operating room, from admission to aortic occlusion, and from admission to completion of EVAR were 46.8, 63.5, and 110.0 minutes, respectively. CONCLUSION: This study indicates that the herein-described double-balloon endovascular technique is feasible for use in the management of rAAA. PMID- 29491194 TI - Is there a correlation of serum and tissue T helper-1 and -2 cytokine profiles with psoriasis activity and severity? A cross-sectional study. AB - Background: Previous studies correlating Th1 and Th2 cytokine profiles with psoriasis activity provided inconsistent results. Correlation of tissue cytokine levels with psoriasis severity has not been studied till now. Objective: To compare serum and tissue Th1 and Th2 cytokine profiles of patients with active and stable psoriasis as well as healthy controls, and to correlate them with psoriasis severity. Methodology: This was a cross-sectional study involving adult patients with 'active' psoriasis (untreated progressive chronic plaque psoriasis, guttate psoriasis, and erythrodermic psoriasis), 'stable' psoriasis (stable plaque psoriasis or those with completely resolved lesions) and healthy subjects with non-inflammatory skin lesions as controls. Mean levels of Th1 and Th2 cytokines in serum [interleukin 2 (IL-2), interferon-gamma (IFN-gamma), IL-4, IL 10] and tissue mRNA expression (IFN-gamma, IL-4) were compared among these three groups. Results: There were 30 patients each in active and stable psoriasis groups, and 15 in the control group. Mean serum IL-2, IFN-gamma, and IL-10 levels of patients with psoriasis patients were significantly higher than the controls (P < 0.001 for both active and stable psoriasis), whereas mean serum IL-4 level of patients was significantly lower than the controls (P < 0.001). However, there was no statistically significant difference of serum cytokine levels between active and stable psoriasis groups. Mean quantitative tissue mRNA expression of IFN-gamma and IL-4 of patients with active and stable psoriasis were significantly lower than the controls (P < 0.001 and <0.01, respectively), but were not significantly different between active and stable psoriasis groups. Serum and tissue cytokines showed weak correlation with psoriasis area and severity index. Limitations: Small sample size and heterogenous nature of patients with psoriasis in terms of disease activity, morphology and treatment are limitations of this study. Conclusions: There is no significant change in the serum or tissue levels of Th1 and Th2 cytokines with activity or severity of psoriasis. PMID- 29491197 TI - Early Surgical Reconstruction of Sternum with Longitudinal Rigid Polymer Plating after Acute Chest Trauma. AB - PURPOSE: The surgical management of the patients with traumatic sternal fractures remains controversial. The aim of this study was to evaluate the effectiveness of an early surgical reconstruction of a displaced sternal fracture utilizing longitudinal rigid polymer fixation in the settings of an acute chest trauma. METHODS: To perform the sternal fixation, we utilized a longitudinal rigid plating system. The plate is made of polyether ether ketone (PEEK), an organic thermoplastic polymer. RESULTS: We used the entire length of the plate on each side of the fracture, secured in multiple places with 6-8 screws. Once the plates have been fully secured we tighten all the screws with a screwdriver. We demonstrated that the method minimizes pain and prevents the development of pulmonary complications. CONCLUSION: This technique provides cosmetically acceptable results, minimizing risk of sternal nonunion, and decreases length of hospitalization. PMID- 29491196 TI - Strategy for Porcelain Ascending Aorta in Cardiac Surgery. PMID- 29491198 TI - A modified shark-fin test simulating the single-step/double-mix technique: A comparison of three groups of elastomers. AB - The shark-fin test was modified to convey the clinical application of a single step/double-mix technique assessing the behavior of two viscosities applied at one point in time. A medium and light body polyether (PE), a medium and light body polyvinylsiloxane (PVS), and a medium as well as heavy and light body vinyl polyether silicone (PVXE) impression material were analyzed solely, and in a layered mixture of 1:1 and 3:1 at working times of 50, 80, and 120 s. The fin heights were measured with a digital ruler. The wettability was measured 50 and 80 s after mixing by drop shape analysis. The results showed a synergistic effect of the medium and light body PE. This was not observed in PVXE and PVS. Interestingly, PVXE showed an antagonistic flow behavior in 3:1 mixture with medium body. PVXE was more hydrophilic than PE and PVS. Future rheological studies should clarify the detected flow effects. PMID- 29491199 TI - Inhibitory effect of curcuminoid pretreatments on endogenous dentin proteases. AB - The aim of this study was to evaluate the effect of curcuminoids on the dentin endogenous protease activity. Demineralized dentin were pretreated with 50 or 100 uM of three different curcuminoids for 60 s and incubated up to 3 months. Untreated beams served as controls. Dry dentin mass was measured after incubation. Aliquots were analyzed for the quantity of ICTP and CTX releases for MMP and cathepsin-K mediated degradation, respectively. The effect of curcuminoids on matrix-bound MMP and soluble rhMMP-9 were measured using an activity assay. Data were subjected to repeated-measures-ANOVA (alpha=0.05). Gelatinolytic activity was analyzed using zymography. ICTP and CTX release and dry mass loss of curcuminoid-treated groups were significantly lower than the control. Inhibition of rhMMP-9 varied from 29-49% among curcumonoid-treated groups, whereas no inhibition was observed at untreated control (p>0.05). Results were confirmed by zymography. The study showed that the pretreatment of dentin matrices by curcuminoids decreases endogenous protease activity-mediated degradation in dentin. PMID- 29491200 TI - The strategies used for curing universal adhesives affect the micro-bond strength of resin cement used to lute indirect resin composites to human dentin. AB - We evaluated the effect of different curing strategies for universal adhesives on micro-tensile bond strength (MUTBS) between resin cement and dentin and/or between resin cement and indirect resin composite. Flat coronal dentin surfaces and composite resin disks were pretreated with silane-containing universal adhesives, with or without light-curing on the dentin-side and/or composite resin disk-side. Resin disks were luted onto the pretreated dentin surfaces with the corresponding dual-cure adhesive resin cements and light-cured, and cut into beams after 24-h water storage. After 0 or 10,000 thermocycles (5oC/55oC) in a water bath, the MUTBS of the composite resin disk-dentin beam was tested. The MUTBS was highest when universal adhesives were applied to both the dentin- and the indirect composite resin disk-side, followed by light-curing. Thermocycling decreased MUTBS in all but the Scotchbond Universaltreated group, with light curing on both sides. The effect of curing strategies is dependent upon the materials. PMID- 29491201 TI - Evaluation of water absorption properties and fabrication of hollow obturator model using 3D digital dentistry. AB - Fluid accumulation in the hollow spaces of obturator is a continuing problem when fabricating hollow obturator prostheses using the conventional method. To address this problem, the three-dimensional (3D) digital technology was used to evaluate water absorption in the inner hollow obturator spaces. Solid and hollow obturator specimens were fabricated using a 3D printer with photocurable resin. Then, the hermeticity was examined by leak testing. These specimens were immersed in distilled water at 37 degrees C. Each specimen was weighed every 24 h for 120 days, and weight changes between each group were compared. Water accumulation in the hollow obturator was not visually observed. Although water absorption was significantly higher in solid specimens, the weight increase rate was also significantly higher in hollow specimens. Applying a laminating 3D photo fabrication made the fabrication of a completely unified hollow obturator model possible. PMID- 29491202 TI - Surface modification of porous alpha-tricalcium phosphate granules with heparin enhanced their early osteogenic capability in a rat calvarial defect model. AB - Heparin binds to and modulates various growth factors, potentially augmenting the bone-forming capability of biomaterials. Here, alpha-tricalcium phosphate (alpha TCP) granules were modified with peptide containing the marine mussel-derived adhesive sequence, which reacts with alpha-TCP surface, and cationic sequence, which binds to heparin (alpha-Ph). alpha-Ph retained the alpha-TCP phase and intergranule spaces after the surface modification. The existence of heparin on alpha-Ph granules was confirmed using X-ray photoelectron spectroscopy. Granules of alpha-TCP and alpha-Ph were implanted into critical-size defects in rat calvaria for 4 weeks. Micro-computed tomography, histological evaluation, and Alcian blue staining revealed that alpha-Ph induced superior bone formation compared with alpha-TCP. Newly formed bone on alpha-Ph was preferentially in contact with the Alcian blue-stained surfaces of granules. These results suggested that heparinization enhanced the early osteogenic capacity of alpha TCP, possibly by modulating the secretion of Alcian blue-stained extracellular matrixes. PMID- 29491204 TI - Morphological Control of Microtubule-Encapsulating Giant Vesicles by Changing Hydrostatic Pressure. AB - For the development of artificial cell-like machinery, liposomes encapsulating cytoskeletons have drawn much recent attention. However, there has been no report showing isothermally reversible morphological changes of liposomes containing cytoskeletons. We succeeded in reversibly changing the shape of cell-sized giant vesicles by controlling the polymerization/depolymerization state of cytoskeletal microtubules that were encapsulated in the vesicles using pressure changes. The result indicates that it is possible to manipulate artificial cell models composed of molecules such as lipids and proteins. The findings obtained in this study will be helpful in clarifying the details of cooperation between cytoskeletal dynamics and morphogenesis of biological membranes and in improving the design and construction of further advanced artificial cell-like machinery, such as drug-delivery systems. In addition, the experimental system used in this study can be applied to research to elucidate the adaptive strategy of living organisms to external stimuli and extreme conditions such as osmotic stress and high-pressure environments like the deep sea. PMID- 29491205 TI - Bio-inspired Multiblock Molecules for Membrane Functionalization. AB - A multipass transmembrane (MTM) structure is prevalent in membrane proteins for a wide range of functions. Typically, the MTM structure is constructed of bundled multiple alpha-helices spanning the membrane which are connected by flexible domains. One characteristic feature of MTM proteins is dynamic functions such as stimuli responses and conformational changes. In this review, the development of synthetic molecules forming an MTM structure in membranes is highlighted. The MTM folded structure is developed using an amphiphilic molecular design with a multiblock strategy between rigid hydrophobic components and flexible hydrophilic units. Such synthetic amphiphiles not only form the MTM structure by folding but also self-assemble to construct supramolecular ion channels. An elaborated molecular design of the MTM structure with a ligand-binding pocket allows for ligand-gated regulation of ion transport. Light-triggered membrane deformation for vesicle budding is also demonstrated. PMID- 29491206 TI - Lipid Bilayers Manipulated through Monolayer Technologies for Studies of Channel Membrane Interplay. AB - Fluidity and mosaicity are two critical features of biomembranes, by which membrane proteins function through chemical and physical interactions within a bilayer. To understand this complex and dynamic system, artificial lipid bilayer membranes have served as unprecedented tools for experimental examination, in which some aspects of biomembrane features have been extracted, and to which various methodologies have been applied. Among the lipid bilayers involving liposomes, planar lipid bilayers and nanodiscs, recent developments of lipid bilayer methods and the results of our channel studies are reviewed herein. Principles and techniques of bilayer formation are summarized, which have been extended to the current techniques, where a bilayer is formed from lipid-coated water-in-oil droplets (water-in-oil bilayer). In our newly developed method, termed the contact bubble bilayer (CBB) method, a water bubble is blown from a pipette into a bulk oil phase, and monolayer-lined bubbles are docked to form a bilayer through manipulation by pipette. An asymmetric bilayer can be readily formed, and changes in composition in one leaflet were possible. Taking advantage of the topological configuration of the CBB, such that the membrane's hydrophobic interior is contiguous with the surrounding bulk organic phase, oil-dissolved substances such as cholesterol were delivered directly to the bilayer interior to perfuse around the membrane-embedded channels (membrane perfusion), and current recordings in the single-channel allowed detection of immediate changes in the channels' response to cholesterol. Chemical and mechanical manipulation in each monolayer (monolayer technology) allows the examination of dynamic channel membrane interplay. PMID- 29491207 TI - Method for Prediction of Efficacy of Sugammadex Administered to Recover from Rocuronium-Induced Neuromuscular Blockade in Gynecological Laparoscopic Surgery Cases. AB - Sugammadex (SDX), a neuromuscular blocking-reversal agent, quickly reverses neuromuscular blockade induced by rocuronium (RCR). SDX dosage is set according to the state of neuromuscular blockade determined with a neuromuscular monitoring device. However, in clinical situations, such a devise is not frequently used. Here, we report construction of a method for theoretically setting SDX dose by which the optimum reverse time (RT) can be obtained for individual patients even when the device is not available. The subjects were 42 adult female patients who underwent laparoscopic surgery from 1 August 2015 to 31 March 2016, during which RCR and SDX were administered. We formulated an equation for theoretically calculating the RCR residual ratio (RR) in blood after SDX administration. Furthermore, we examined the relationship between RR and RT. Based on the results obtained, we developed a method for predicting RT using RR. We excluded 1 subject as the RT value was detected as an outlier in our analysis. Multiple regression analysis was performed using standard body weight, serum creatinine, total bilirubin, and RR as explanatory variables. The number of subjects with a prediction error of RT within +/-1 min was 36 (87.8%) of 41 in multiple regression analysis. We could predict RT following SDX administration by using the RT prediction expression with RR obtained for subjects administered RCR during the surgery. Furthermore, our results suggest that the SDX dose able to achieve optimum RT may be set prior to surgery on the basis of the present methodology. PMID- 29491208 TI - Effects of the Nonsteroidal Anti-inflammatory Drug Celecoxib on Mitochondrial Function. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat inflammation and pain. In the present study, we examined the effects of celecoxib, a cyclooxygenase-2 (COX-2)-selective NSAID, on rat liver mitochondrial function. Celecoxib dose-dependently induced mitochondria swelling, which was not suppressed by cyclosporine A (CsA). The oxygen consumption rate in mitochondria suspended solution was facilitated by the addition of celecoxib, and its uncoupling activity was observed. Celecoxib also suppressed SF6847-induced uncoupling, and appeared to exert inhibitory effects on the electron transport chain. Celecoxib suppressed the state 3 oxygen consumption rate in the presence of ADP. Protein release from the mitochondrial matrix was detected following the addition of celecoxib, and aldehyde dehydrogenase 2 (ALDH2) and hydroxymethylglutaryl-CoA (HMG-CoA) synthase 2 (HMGCS2) bands were confirmed in a Western blot analysis. On the other hand, protein release of cytochrome C (CytC), which is an inducer of apoptosis, from the intermembrane space was not observed. Celecoxib enhanced the membrane permeability of human erythrocytes and synthesized liposomes dose-dependently. It then induced the membrane-involving mitochondrial swelling and suppressed mitochondrial function. PMID- 29491209 TI - Pharmacokinetics and Metabolism of Streptochlorin and Its Synthetic Derivative, 5 Hydroxy-2'-isobutyl Streptochlorin, in Mice. AB - The purpose of this study was to investigate the pharmacokinetics and metabolism of streptochlorin and its derivative 5-hydroxy-2'-isobutyl streptochlorin (HIS) in mice. Plasma concentration of streptochlorin declined rapidly resulting in a high sustemic plasma clearance (CLp) (5.8+/-1.7 L/h/kg), a large volume of distribution (Vss) (1.4+/-0.9 L/kg) and a short half-life (t1/2) (0.4+/-0.1 h) after a single intravenous administration (5 mg/kg). Oral bioavailability (F) was 10.3+/-3.4% after a single oral administration (10 mg/kg). HIS also showed a rapid plasma decline with a high CLp (11.3+/-8.8 L/h/kg), a high Vss (0.8+/-1.0 L/kg) and a short t1/2 (0.070+/-0.004 h) following intravenous administration. It was not detected in plasma after oral administration. Metabolic stability studies using mouse liver microsomes and S9 fractions predicted a high hepatic clearance for both compounds, consistent with the in vivo data. Metabolite identification studies revealed three metabolic pathways for streptochlorin: monooxygenation, glucuronidation of the indole moiety and oxidative opening of the 4-chlorooxazole ring. HIS was metabolized via monooxygenation of the isobutyl chain and glucuronidation of the indole ring. These results may aid in structural optimization to mitigate the metabolic liability of streptochlorin. PMID- 29491210 TI - Assembly of Taurine Transporter (Slc6a6) with Na+-H+ Exchanger Regulatory Factor 1 (Slc9a3r1) Improves GABA Transport Activity by Increasing the Maximum Transport Velocity. AB - Regulating gamma-aminobutyric acid (GABA) uptake transport on the plasma membranes is required for its efficient clearance from the brain interstitial fluid. The purpose of this study was to clarify the assembly of taurine transporter (TauT/Slc6a6) and PSD-95/Disc-large/Zo-1 (PDZ) domain of Na+-H+ exchanger regulatory factor 1 (NHERF1) as a regulatory mechanism of TauT-mediated GABA transport activity. In vitro glutathione S-transferase (GST)-pull down assay and immunoblotting with anti-NHERF1 antibody revealed that NHERF1 protein was present in rat brain lysates as the binding protein of the GST-fusion TauT C terminal protein with the PDZ-binding ETMM motif but not its corresponding deletion mutant lacking the motif. [3H]GABA uptake by TauT-NHERF1-coexpressing oocytes and TauT-singly expressing oocytes exhibited saturable kinetics with Michaelis-Menten constant values of 0.835+/-0.288 and 0.982+/-0.569 mM and a maximal transport velocity of 206+/-37 and 283+/-28 pmol/(h.oocyte), respectively. These results suggest that the assembly of TauT PDZ-binding motif and NHERF1 increases the maximal transport velocity of GABA rather than changes the affinity. PMID- 29491211 TI - Splenic Delivery System of pDNA through Complexes Electrostatically Constructed with Protamine and Chondroitin Sulfate. AB - We developed and optimized a novel gene delivery vector constructed electrostatically with an anionic biological component and a cationic biological component. Cationic binary complexes of plasmid DNA (pDNA) with novo-protamine sulfate as a medical product (PRT complexes) demonstrated high gene expression with minimal cytotoxicity, likely related with its total cationic charge. Subsequently, anionic compounds were added to the PRT complexes to form ternary complexes with neutral or anionic charges. Among the anionic compounds examined, chondroitin sulfate sodium (CS) as a medical product encapsulated the PRT complexes to produce stable ternary complexes (CS complexes) at charge ratios of >=4 with pDNA. CS complexes exhibited high gene expression without cytotoxicity in mouse melanoma cell line, B16-F10 cells, in vitro. An inhibition study with endocytosis inhibitors suggested that PRT complexes were mainly taken up by caveolae-mediated endocytosis, and CS complexes were mainly taken up by clathrin mediated endocytosis in B16-F10 cells. We found that CS complexes including pDNA encoding Oplophorus gracilirostris luciferase induced selective gene expression in the spleen after intravenous administration into ddY male mice. Thus, we successfully constructed useful gene vectors with biological components as medical products. PMID- 29491212 TI - Association of DNA Repair and Drug Transporter in Relation to Chemosensitivity in Primary Culture of Thai Gastric Cancer Patients. AB - Acquired resistance is a major reason for poor clinical outcomes in cancer chemotherapy patients. The aim of this study was to determine the sensitivity to anticancer drugs and to identify the alterations of DNA repair and drug transporter in a model of primary culture obtained from pre- and post-platinum based anticancer treatments in nine Thai gastric cancer patients. Ex vivo sensitivity to anti-cancer drugs (cisplatin, oxaliplatin, 5-fluorouracil (5-FU) and irinotecan) was analysed using 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. The expression of the drug transporter (multidrug resistance-associated protein 1 (MRP1), P-glycoprotein (P-gp)) and DNA repair (X-ray cross-complementing gene 1 (XRCC1) and excision repair cross complementing 1 (ERCC1)) were examined by RT-PCR. The IC50 to cisplatin and oxaliplatin of the cells obtained from gastric cancer patients after clinical drug treatments were administered to five patients (55.5%) revealed a significant increase when compared with prior treatments. The basal expression values of XRCC1, ERCC1 and MRP1 obtained from the treated patients were in correlation with those of IC50. Ex vivo platinum drug treatment of the primary culture obtained from naive patients over seven days also revealed a significant increase in MRP1 (7/9), XRCC1 (4/9) and ERCC1 (4/9). These observations have also been observed in the KATOIII cell line. Clinical treatment by platinum-based anti-cancer drug can develop acquired drug resistance in Thai gastric cancer patients through upregulation in the expression of drug transporter MRP1 and DNA repair XRCC1 and ERCC1. In cell culture model, cisplatin-resistant gastric cancer cell line KATOIII/diamminedichloroplatinum (KATOIII/DDP) significantly increased the expression level of these genes when compared to its parental cells (KATOIII). PMID- 29491213 TI - A New Approach for Quantifying Radio-Biological Effects Using the Time Course of Mouse Leg Contracture. AB - A digitization approach to the time course of radiation-induced mouse leg contracture was proposed for quantifying the radiation effect on an individual living mouse. The shortening of the mouse leg length can be easily measured with a caliper/ruler to offer a very simple digitalized index of the radiation effect. Left hind legs of mice were irradiated with single dose of 32 Gy of 290 MeV carbon-ion beam using 0, 50, or 117 mm binary filter (BF). The right legs were used as a control. The lengths of both hind legs of the mice were measured using a digital caliper before irradiation and every week after irradiation. The degree of leg contracture, DeltaSt, at the time point t was estimated by subtraction of the left irradiated leg length from the right control leg length. Equation was fitted on the daily time course of DeltaSt, and two parameters, DeltaSmax and Ts, were estimated. DeltaSt=DeltaSmax*(1-exp(t/Ts)), where DeltaSmax is the maximum degree of leg contracture, and Ts is time of leg contracture. The effect of carbon-ion irradiation on a living mouse was quantified by DeltaSmax and Ts of the leg contracture, and then compared to that of X-rays. By 32 Gy irradiation, DeltaSmax was largest for the BF117 experiment, followed by X-ray~BF50>BF0. Ts was shortest for the BF50 experiment, while other irradiation conditions give similar Ts. A logarithmic function was successfully repurposed for the evaluation of radio-biological response. PMID- 29491214 TI - Bisphenol A and Its Derivatives Induce Degradation of HIF-1alpha via the Lysosomal Pathway in Human Hepatocarcinoma Cell Line, Hep3B. AB - Bisphenol A (BPA, 2,2-bis(4-hydroxyphenyl)propane), one of the phenolic compounds widely used in the manufacture of plastic and epoxy resins, is known as an endocrine disruptor. In a previous study, we found that BPA induced hypoxia inducible factor-1alpha (HIF-1alpha) degradation by dissociation from heat shock protein 90 (Hsp90). In this study, to investigate the structural requirements for degradation of HIF-1alpha, we estimated the effect of BPA derivatives (BPE, BPF, BPB, Dimethyl butylidene diphenol (DMBDP), Ethyl hexylidene diphenol (EHDP), Bishydroxyphenyl cyclohexane (BHCH), and Methyl benzylidene bisphenol (MBBP)) on HIF-1alpha protein degradation, using human hepatocarcinoma cell line, Hep3B. BPB, DMBDP, BHCH, and MBBP decreased HIF-1alpha protein levels more efficiently than BPA, but BPE, BPF, and EHDP did not affect HIF-1alpha protein levels. BPA degraded HIF-1alpha even in the presence of MG132, a proteasome inhibitor. In this study, we found that ammonium chloride (NH4Cl), a lysosomal enzyme inhibitor, efficiently restored the decrease in HIF-1alpha protein levels by BPA. Recent studies indicated that HIF-1alpha is degraded by the lysosomal pathway as well as the proteasomal pathway. Therefore, we investigated the levels of heat shock cognate 70 kDa protein (HSC70) protein after treatment with BPA. We found that BPA induced HSC70 protein and overexpression of HSC70 enhanced HIF-1alpha degradation in Hep3B cells. These results suggested that BPA causes the degradation of HIF-1alpha by induction of HSC70, leading lysosomal degradation of HIF-1alpha. PMID- 29491215 TI - Cigarette Smoke Extract Disrupts Transcriptional Activities Mediated by Thyroid Hormones and Its Receptors. AB - Cigarette smoke contains over 4800 compounds, including at least 200 toxicants or endocrine disruptors. Currently, effects of cigarette smoke on thyroid hormone (TH) levels remains to be clarified. Here, we demonstrate that cigarette smoke extract (CSE) possesses thyroid hormone properties and acts synergistically as a partial agonist for thyroid hormone receptors (TRs) in the presence of TH. In transient gene expression experiments, CSE stimulated transcriptional activity with TH in a dose-dependent manner. Stimulatory effects were observed with physiological TH concentrations, although CSE did not activate TRs without TH. CSE (5%) dissolved in phosphate-buffered saline (PBS) supplemented with 1 nM TH was approximately comparable to 3.2+/-0.1 and 2.3+/-0.2 nM of TRalpha1 and TRbeta1, respectively. To illustrate probable mechanisms of the CSE agonistic activity, effects on TR mediated transcriptional functions with cofactors were investigated. With a mammalian two-hybrid assay, CSE recruited the nuclear coactivators glucocorticoid receptor interacting protein 1 (GRIP1) and steroid receptor coactivator 1 (SRC1) to the TR. Unsaturated carbonyl compounds, acrolein, crotonaldehyde, and methyl vinyl ketone, representative constituents of CSE, retained such agonistic properties and possibly contributed to stimulatory effects. The results suggest that CSE recruits a transcriptional activator and may reinforce TH binding to the TR additively, resulting in gene expression. CSE partially agonizes TH action and may disturb the function of various nuclear hormone receptor types and their cofactors to disrupt the physiological processes. PMID- 29491216 TI - Selective Androgen Receptor Modulator, YK11, Up-Regulates Osteoblastic Proliferation and Differentiation in MC3T3-E1 Cells. AB - Androgens are key regulators that play a critical role in the male reproductive system and have anabolic effects on bone mineral density and skeletal muscle mass. We have previously reported that YK11 is a novel selective androgen receptor modulator (SARM) and induces myogenic differentiation and selective gene regulation. In this study, we show that treatment of YK11 and dihydrotestosterone (DHT) accelerated cell proliferation and mineralization in MC3T3-E1 mouse osteoblast cells. Further, YK11-treated cells increased osteoblast specific differentiation markers, such as osteoprotegerin and osteocalcin, compared to untreated cells. These observations were attenuated by androgen receptor (AR) antagonist treatment. To clarify the effect of YK11, we investigated rapid non genomic signaling by AR. The phosphorylated Akt protein level was increased by YK11 and DHT treatment, suggesting that YK11 activates Akt-signaling via non genomic signaling of AR. Because it is known Akt-signaling is a key regulator of androgen-mediated osteoblast differentiation, YK11 has osteogenic activity as well as androgen. PMID- 29491217 TI - Nelumbo nucifera Seed Extract Promotes Sleep in Drosophila melanogaster. AB - The sleep-promoting effects of the water extract of Nelumbo nucifera seeds (NNE) were investigated in an invertebrate model. The effects of NNE on the subjective nighttime activity, sleep episodes, and sleep time were determined using Drosophila melanogaster and locomotor activity monitoring systems in basal and caffeine-induced arousal conditions. The movements of fruit flies were analyzed using the Noldus EthoVision-XT system, and the levels of neuromodulators were analyzed using HPLC. Expression of neuromodulator receptors was analyzed using real-time PCR. NNE was shown to contain neurotransmission-related components; gamma-aminobutyric acid (GABA) (2.33+/-0.22 mg/g), tryptophan (2.00+/-0.06 mg/g), quinidine (0.55+/-0.33 mg/g), and neferine (0.16+/-0.01 mg/g). The total activity of flies during nighttime was decreased by 52% with 1.0% NNE treatment. In the individual and collective conditions, the subjective nighttime activities (45/38%) and sleep bouts (20/14%) of flies was significantly decreased with NNE treatment, while total sleep times (10/27%) were significantly increased. This sleep-promoting effect is more pronounced in caffeine-treated conditions; the nighttime activity of flies was reduced by 53%, but total sleep time was increased by 60%. Our video-tracking analysis showed a significant decrease of the moving distance and velocity of flies by NNE. This NNE-mediated sleep promoting effect was associated with up-regulation of GABAA/GABAB and serotonin receptors. The NNE-mediated increase of GABA content was identified in flies. These results demonstrate that NNE effectively promotes sleep in flies by regulating the GABAergic/serotonergic neuromodulators, and could be an alternative agent for sleep promotion. PMID- 29491218 TI - The Impact of One-Dose Package of Medicines on Patient Waiting Time in Dispensing Pharmacy: Application of a Discrete Event Simulation Model. AB - Improvement in patient waiting time in dispensing pharmacies is an important element for patient and pharmacists. The One-Dose Package (ODP) of medicines was implemented in Japan to support medicine adherence among elderly patients; however, it also contributed to increase in patient waiting times. Given the projected increase in ODP patients in the near future owing to rapid population aging, development of improved strategies is a key imperative. We conducted a cross-sectional survey at a single dispensing pharmacy to clarify the impact of ODP on patient waiting time. Further, we propose an improvement strategy developed with use of a discrete event simulation (DES) model. A total of 673 patients received pharmacy services during the study period. A two-fold difference in mean waiting time was observed between ODP and non-ODP patients (22.6 and 11.2 min, respectively). The DES model was constructed with input parameters estimated from observed data. Introduction of fully automated ODP (A ODP) system was projected to reduce the waiting time for ODP patient by 0.5 times (from 23.1 to 11.5 min). Furthermore, assuming that 40% of non-ODP patients would transfer to ODP, the waiting time was predicted to increase to 56.8 min; however, introduction of the A-ODP system decreased the waiting time to 20.4 min. Our findings indicate that ODP is one of the elements that increases the waiting time and that it might become longer in the future. Introduction of the A-ODP system may be an effective strategy to improve waiting time. PMID- 29491219 TI - SKF83959 Has Protective Effects in the Scopolamine Model of Dementia. AB - Patients with Alzheimer's disease (AD) always have cognitive impairments. In this study we investigated whether 6-chloro-7,8-dihydroxy-3-methyl-1-(3-methylphenyl) 2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959) has improvements on cognitive dysfunction. The scopolamine model of dementia was used to investigate the anti amnesic activities of SKF83959, and then, Western blotting and pharmacological inhibitor were used to assay the anti-amnesic mechanisms of SKF83959. It was found that SKF83959 administration significantly improved the scopolamine-induced memory impairments in the passive avoidance task, Y-maze test, and Morris water maze task. Moreover, SKF83959 treatment significantly antagonized the down regulating effects of scopolamine on brain-derived neurotrophic factor (BDNF) signaling cascade in the hippocampus, but not cortex. Importantly, the usage of K252a, a selective inhibitor of tyrosine kinase B (TrkB), significantly attenuated the protective effects of SKF83959 in the scopolamine model. Collectively, this study shows that SKF83959 has beneficial effects in the scopolamine model of dementia by modulation of hippocampal BDNF signaling, implying a novel and potential therapeutic agent for treating dementia in AD. PMID- 29491220 TI - Induction of Growth Differentiation Factor 15 in Skeletal Muscle of Old Taurine Transporter Knockout Mouse. AB - It has been identified that skeletal muscle is an endocrine tissue. Since skeletal muscle aging affects not only to muscle strength and function but to systemic aging and lifespan, myokines secreted from skeletal muscle may be crucial factors for intertissue communication during aging. In the present study, we investigated the expression of myokines associated with skeletal muscle aging in taurine transporter knockout (TauTKO) mice, which exhibit the accelerated skeletal muscle aging. Among transforming growth factor (TGF)-beta family genes, only growth and differentiation factor 15 (GDF15) was markedly higher (>3-fold) in skeletal muscle of old TauTKO mice compared with that of either young TauTKO mice or old wild-type mice. Circulating levels of GDF15 were also elevated in old TauTKO mice. An elevation in circulating GDF15 was also observed in very old (30 month-old) wild-type mice, while skeletal GDF15 levels were normal. The treatment of cultured mouse C2C12 myotubular cells with aging-related factors that mediate cellular stresses, such as oxidative stress (hydrogen peroxide) and endoplasmic reticulum stress (tunicamycin and thapsigargin), leads to an increase in GDF15 secretion. In conclusion, GDF15 is a myokine secreted by aging-related stress and may control aging phenotype. PMID- 29491221 TI - Development of a New Conditionally Immortalized Human Liver Sinusoidal Endothelial Cells. AB - Liver sinusoidal endothelial cells (LSECs), which are specialized endothelial cells that line liver sinusoids, have been reported to participate in a variety of liver functions, such as blood macromolecule clearance and factor VIII production. In addition, LSECs play crucial roles in liver regeneration following acute liver injury, as well as the development and progression of liver diseases or drug-induced hepatotoxicity. However, the molecular mechanisms underlying their roles remain mostly unknown. Therefore, in order to contribute to the clarification of those mechanisms, herein we report on the development of a new immortalized human LSEC (HLSEC) line. To produce this cell line, two immortalized genes were introduced into the primary HLSECs, which eventually resulted in the establishment of the HLSEC/conditionally immortalized, clone-J (HLSEC/ciJ). Consistent with the two-immortalized gene expression, HLSEC/ciJ showed excellent proliferation activity. Additionally, the results of gene expression analyses showed that several LSEC (as well as pan-endothelial) marker mRNAs and proteins were clearly expressed in HLSEC/ciJ. Furthermore, we found that adherence junction proteins were localized at the cell border in the HLSEC/ciJ monolayer, and that the cells exhibited a tube-like structure formation property. Taken together, the results obtained thus far indicate that we have successfully immortalized HLSECs, resulting in creation of HLSEC/ciJ, a cell line that possesses infinite proliferation ability while retaining possession of at least some HLSEC features. We believe that the HLSEC/ciJ have the potential to provide a valuable and unlimited alternative source of HLSECs for use in liver/LSEC physiology/pathophysiology, pharmacology, and toxicology studies. PMID- 29491223 TI - Errata for Biological and Pharmaceutical Bulletin. PMID- 29491222 TI - Cancer-Type OATP1B3 mRNA in Extracellular Vesicles as a Promising Candidate for a Serum-Based Colorectal Cancer Biomarker. AB - Cancer-type organic anion transporting polypeptide 1B3 (Ct-OATP1B3) mRNA is a variant isoform of the liver-type OATP1B3. Because Ct-OATP1B3 mRNA shows an excellent cancer-specific expression profile in colorectal cancer (CRC), and that its expression levels are associated with CRC prognosis, it holds the potential to become a useful CRC detection and diagnosis biomarker. While the potential is currently justified only at the tissue level, if existence of Ct-OATP1B3 mRNA in CRC-derived extracellular vesicles (EVs) is validated, the findings could enhance its translational potential as a CRC detection and diagnosis biomarker. Therefore, this study aims at proving that Ct-OATP1B3 mRNA exists in CRC-derived EVs, and can be detected using serum specimens. To examine the possibility of Ct OATP1B3 mRNA being existed in extracellular milieu, we isolated EVs from the human CRC (HCT116, HT-29, and SW480) cell lines, and prepared their cDNAs. The RT PCR results showed that Ct-OATP1B3 mRNA was clearly present in EVs derived from the human CRC cell lines. Then, in order to further explore the possibility that Ct-OATP1B3 mRNA in CRC-derived EVs can be detected in serum, we isolated serum EVs derived from human CRC xenograft mice, and then performed RT-PCR. The results showed that Ct-OATP1B3 mRNA could be found in all serum EV and CRC tissue samples of the mice examined. Collectively, our findings, which show that Ct-OATP1B3 mRNA exists in EVs and can be detected in (at least) mouse serum, strengthen the potential use of Ct-OATP1B3 mRNA as a serum-based CRC biomarker. PMID- 29491224 TI - Divergent patterns of genic copy number variation in KCNIP1 gene reveal risk locus of type 2 diabetes in Chinese population. AB - Copy number variation (CNV) has emerged as another important genetic marker in addition to SNP for understanding etiology of complex disease. Kv channel interacting protein 1 (KCNIP1) is a Ca2+-dependent transcriptional modulator that contributes to the regulation of insulin secretion. Previous genome-wide CNV assay identified the KCNIP1 gene encompassing a CNV region, however, its further effect and risk rate on type 2 diabetes (T2D) have rarely been addressed, especially in Chinese population. The current study aims to detect and excavate genetic distribution profile of KCNIP1 CNV in Chinese T2D and control populations, and further to investigate the associations with clinical characteristics. Divergent patterns of the KCNIP1 CNV were identified (p < 0.01), in which the copy number gain was predominant in T2D, while the copy number normal accounted for the most in control group. Consistently, the individuals with copy number gain showed significant risk on T2D (OR = 4.550, p < 0.01). The KCNIP1 copy numbers presented significantly positive correlations with fasting plasma glucose and glycated hemoglobin in T2D. For OGTT test, the T2D patients with copy number gain had remarkably elevated glucose contents (60, 120, 180-min, p < 0.05 or p < 0.01) and diminished insulin levels (60, 120-min, p < 0.05) than those with copy number loss and normal, which suggested that the KCNIP1 CNV was correlated with the glucose and insulin action. This is the first CNV association study of the KCNIP1 gene in Chinese population, and these data indicated that KCNIP1 might function as a T2D-susceptibility gene whose dysregulation alters insulin production. PMID- 29491225 TI - Increased secreted frizzled-related protein 4 and ficolin-3 levels in gestational diabetes mellitus women. AB - By biochemical and epidemiological similarity with type 2 diabetes mellitus (T2DM), gestational diabetes mellitus (GDM) has some overlap between prediction markers and risk factors of T2DM. The present study aimed to establish that secreted frizzled-related protein 4 (SFRP4) and ficolin-3 levels, which have been linked to insulin resistance and the development of T2DM, are elevated in GDM women. A longitudinal prospective cohort study of 86 GDM and 273 normal glucose tolerant (NGT) pregnant women was performed. The clinical parameters, lipid profiles, and serum SFRP4 and ficolin-3 levels were tested during the early and late second-trimester and third-trimester of pregnancy. Both SFRP4 and ficolin-3 levels were significantly higher in GDM women as compared to the NGT participants at three test points (p < 0.01). Spearman's correlation analysis showed that serum SFRP4 levels were significantly positively correlated with ficolin-3 during the early and late second-trimester and third-trimester of pregnancy. The elevated SFRP4 and ficolin-3 concentrations at 16-18 weeks gestation significantly associated with GDM were conformed using binary logistic regression analysis after controlling for other variables [odds ratios (OR) with 95% confidence intervals (CI) for SFRP4: 2.84 (1.78-4.53), p < 0.01; for ficolin-3: 2.45 (1.55-3.88), p < 0.01]. In Conclusions, increased SFRP4 and ficolin-3 levels are significantly associated with GDM development and might be important risk factors for this pregnancy complication. PMID- 29491226 TI - Rapid detection and differentiation of avian infectious bronchitis virus: an application of Mass genotype by melting temperature analysis in RT-qPCR using SYBR Green I. AB - A method based on Melting Temperature analysis of Hypervariable regions (HVR) of S1 gene within a RT-qPCR was developed to detect different genotypes of avian infectious bronchitis virus (IBV) and identify the Mass genotype. The method was able to rapidly identify the Mass genotype among IBV field isolates, vaccine attenuated strains and reference M41 strain in allantoic liquid and also directly in tissues. The RT-qPCR developed detected the virus in both tracheal and pulmonary samples from M41-infected or H120-infected birds, in a larger post infection period compared to detection by standard method of virus isolation. RT qPCR method tested provided a sensitivity and rapid approach for screening on IBV detection and Mass genotyping from IBV isolates. PMID- 29491227 TI - Pathophysiological Significance of Velocity-Based Microvascular Resistance at Maximal Hyperemia in Peripheral Artery Disease. AB - AIM: Maximal hyperemic response, leading to examination of microvascular resistance in lower-limb lesions is not well understood. This study aimed to investigate the infrainguinal arterial physiological response through a hyperemic condition and the pathophysiological significance of microvascular resistance in peripheral artery disease. METHODS: Sixteen limbs with focal stenosis of the superficial femoral artery (SFA) and 16 control limbs were analyzed. We assessed the fractional flow reserve (FFR), vascular flow reserve (VFR), and hyperemic microvascular resistance (h-MR) of the SFA with a pressure/Doppler flow sensor tipped combination guidewire before and after endovascular therapy (EVT). Skin perfusion pressure (SPP) on both the dorsal and the plantar sides of the foot was measured at baseline before and after the endovascular procedures. RESULTS: FFR (p<0.05) and VFR (p<0.05), but not h-MR, improved after EVT. There was no association between h-MR and FFR or VFR before EVT. h-MR was negatively correlated with the dorsal SPP before EVT (r=-0.589, p<0.05). h-MR in patients with high h-MR before EVT significantly decreased after EVT (p<0.05). Patients with high, but not those with low, h-MR before EVT exhibited a significant increase in dorsal and plantar SPP after EVT (p<0.05, each). CONCLUSION: EVT for SFA stenosis improved FFR and VFR comprehensively, with no apparent change in h MR. However, high h-MR before EVT may play a predictive role for limb perfusion improvement associated with h-MR reduction after EVT. PMID- 29491228 TI - Comparative toxicity of dinophysistoxin-1 and okadaic acid in mice. AB - The mouse bioassay for diarrhetic shellfish poisoning toxins has been used worldwide. In this study, dinophysistoxin-1 (DTX-1) and okadaic acid (OA) were compared for toxicity. The lethality rate increased and the median survival time decreased in a dose-dependent manner in both DTX-1 and OA. The median lethal dose value was 150.4 ug/kg (95% confidence interval=130.1-171.2 ug/kg) for DTX-1 and 185.6 ug/kg (95% confidence interval=161.2-209.6 ug/kg) for OA. The toxicity equivalent factor 1:1 has been used for OA and DTX-1 in the EU and Japan. Thus, it may be considered that toxicity potential of DTX-1 has remained underestimated as compared to that of OA and DTX-1 might be more toxic than OA. PMID- 29491231 TI - A Case of Imported Taenia asiatica Infection in Japan. PMID- 29491232 TI - Molecular Epidemiology of Trichophyton tonsurans, the Causative Dermatophyte of the Tinea Gladiatorum Epidemic in Japan between 2011 and 2015. AB - Trichophyton tonsurans, a major pathogen causing tinea capitis and tinea corporis, has been isolated from contact sports-players in Japan. The molecular types of 208 strains isolated between 2011 and 2015 were determined to understand the contemporary Japanese epidemic. Of these, 142 were isolated from practitioners of judo, 28 from wrestlers, 7 from sumo wrestlers, and 31 from individuals with unknown backgrounds. Based on length polymorphisms of the non transcribed spacer (NTS) region of the ribosomal RNA gene, these 208 strains were divided into 3 subtypes: NTS I (204; 98.1%), II (3; 1.4%), and III (1; 0.5%). Single nucleotide polymorphisms (SNPs) and deletion/insertion profiles in the NTS region, length polymorphisms of the alkaline protease 1 gene, and a SNP in the carboxypeptidase Y gene were identified in 50 NTS I strains isolated between 2011 and 2015, and in 10 strains isolated before 2005. All 60 strains were classified as the same molecular type, with a profile identical to that of type Ib, a major type in the United States of America. These results indicate that NTS I strains isolated in Japan are clonal and independent of the type of sports activity. PMID- 29491233 TI - Characterization of In Vitro Expanded Virus-Specific T cells for Adoptive Immunotherapy against Virus Infection. AB - Adoptive transfer of virus-specific T cells has emerged as a promising therapeutic approach for treatment of virus infections in immunocompromised hosts. Characterization of virus-specific T cells provides essential information about the curative mechanism of the treatment. In this study, we developed a T cell epitope mapping system for 718 overlapping peptides spanning 6 proteins of 3 viruses (pp65 and IE1 from cytomegalovirus; LMP1, EBNA1, and BZLF1 from Epstein Barr virus; Penton from adenovirus). Peripheral blood mononuclear cells (PBMCs) from 33 healthy Japanese donors were stimulated with these peptides and virus specific CD4+ and CD8+ T cells were expanded in vitro in the presence of interleukin (IL) 4 and IL7. A median of 13 (minimum-maximum, 2-46) peptides was recognized in the cohort. Both fresh and cryopreserved PBMCs were used for in vitro expansion. The expansion and breadth of T cell responses were not significantly different between the 2 PBMC sets. We assessed viral regions frequently recognized by T cells in a Japanese cohort that could become pivotal T cell targets for immunotherapy in Japan. We tested epitope prediction for CD8+ T cell responses against a common target region using a freely available online tool. Some epitopes were considered to be predictive. PMID- 29491234 TI - Clinical Evaluation of Hepatocarcinogenesis and Outcome Using a Novel Glycobiomarker Wisteria floribunda Agglutinin-Positive Mac-2 Binding Protein (WFA+-M2BP) in Chronic Hepatitis C with Advanced Fibrosis. AB - This study aimed to assess the association between the serum glycobiomarker Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+-M2BP) for liver fibrosis and outcomes and carcinogenesis of hepatocellular carcinoma (HCC) in chronic hepatitis C (CHC) patients with advanced fibrosis. Serum WFA+-M2BP levels were measured in 128 consecutive CHC patients including 49 with HCC histopathologically diagnosed with advanced fibrosis (44 with fibrosis stage F3 and 84 with fibrosis stage F4) in our hospital. The median WFA+-M2BP level was significantly higher in F4 than in F3 patients (6.9 vs. 2.3 cutoff index [COI], respectively; p<0.001). The difference in WFA+-M2BP levels between patients with and without HCC was not significant. The respective 5-/8-yr survival rates of patients without HCC at enrollment with high (>=4 COI, n=39), intermediate (1-4 COI, n=33), and low WFA+-M2BP (<1 COI, n=7) levels were 78%/48%, 100%/82%, and 100%/100%, respectively. The differences in survival rates between groups were significant (p=0.0041). Patients with high WFA+-M2BP levels had a significantly higher incidence of HCC than those with low WFA+-M2BP levels (p=0.0019). Cumulative 5-yr carcinogenesis rates in patients with high, intermediate, and low WFA+-M2BP levels were 48.7%, 16.9%, and 0%, respectively; the differences between groups were significant (p=0.002). Serum WFA+-M2BP levels might allow the prediction of carcinogenesis and outcome in CHC patients with advanced fibrosis. PMID- 29491235 TI - Infection Control Following an Outbreak of Extended-Spectrum Beta-Lactamase Producing Klebsiella pneumoniae Isolated from Catheter-Associated Urinary Tract Infection. AB - We present our experience with controlling an outbreak of extended-spectrum beta lactamase (ESBL)-producing bacteria in catheter-associated urinary tract infection and the measures taken to prevent future outbreaks. In June 2015, 9 out of 44 hospitalized patients in the same ward tested positive for antibiotic resistant bacteria in urine cultures, including ESBL-producing Klebsiella pneumoniae. Since these bacteria belonged to the same cluster, we concluded this was a localized outbreak. Seven out of 10 environmental tests detected resistant strains at 1,000 colony forming units/cm2 or more. After an outbreak, we undertook periodic monitoring by active surveillance culture (ASC) every 2 months, along with environmental wipe testing. Cleaning regimen was performed through alcohol disinfection 5 or 7 times a day, then changed to complex-type chlorine-based disinfectant cleaner once a day that includes potassium peroxymonosulfate. ASC revealed only one positive case of antibiotic-resistant strain after incorporating new infection controls. Only a few environmental tests were positive for the bacteria after the new cleaning regimen, suggesting this cleaner might be effective for inhibiting outbreaks. Our control measures successfully prevented further outbreak and inhibited the recurrence. PMID- 29491236 TI - Case of Human Infection with Anaplasma phagocytophilum in Inner Mongolia, China. AB - Anaplasma phagocytophilum is an obligate intracellular bacterium that causes febrile illness in humans and livestock. A 49-year-old woman was suffering from feverish symptoms, fatigue, arthralgia, general body pain, and anorexia for 2 weeks. Later, she visited the Bayannur Centers for Disease Control and Prevention Hospital in Inner Mongolia, China. Molecular-based diagnostic analysis of the patient's blood revealed that A. phagocytophilum p44 DNA was positive, but Brucella omp31, spotted fever group Rickettsia gltA, Orientia tsutsugamushi 16S rDNA, and Ehrlichia p28 were negative. The amino acid sequences of 9 A. phagocytophilum p44 clones obtained from the patient shared 44-100% similarity among them and were closely related to those of previously identified p44 clones from Canis familiaris (accession no. KJV64194) and from Ixodes persulcatus tick (no. BAN28309). Serological tests using the patient's serum showed that immunoglobulin M (IgM) and IgG titers to A. phagocytophilum antigens were 160 and 20, respectively, determined using indirect immunofluorescence assay, and the reaction to recombinant P44 proteins (rP44-1, rP44-18ES, and/or rP44-47) was confirmed using Western blot analysis. Thus, the results obtained in this study strongly suggest that the patient was infected with A. phagocytophilum. To our knowledge, this is the first case of human anaplasmosis infection in the Inner Mongolia Autonomous Region. PMID- 29491237 TI - Venom and Antivenom of the Redback Spider (Latrodectus hasseltii) in Japan. Part I. Venom Extraction, Preparation, and Laboratory Testing. AB - The redback spider (Latrodectus hasseltii Thorell) reportedly invaded Japan in September 1995. To date, 84 redback spider bite cases have been reported; 7 of these cases employed the antivenom. Antivenom has been imported from Australia in the past, but because of restrictions on exportation it was evident that nearly all of the antivenom present in Japan would expire during 2014. In 2014, a plan was proposed to experimentally manufacture and stockpile a horse antiserum for ourselves, using redback spiders indigenous to Japan. A total of 11,403 female spiders were captured alive: 1,217 from the vicinity of Nishinomiya City, Hyogo prefecture, and 10,186 from Osaka prefecture. Of these, 10,007 females were dissected, and the venom was extracted from the venom glands of individuals and subjected to crude purification to yield 4 lots, of which the majority was alpha latrotoxin. Among them, a large amount of single lots with an estimated protein content of 236 mg is subsequently scheduled to be used for immunizing horses. We also determined lethal toxicity of the venom (LD50: 9.17 MUg per mouse), and established the assay for the determination of an anti-lethal titer of antivenom in mice. PMID- 29491238 TI - Isolation Rate of Neisseria meningitidis in Japanese Children with Respiratory Tract Infections. AB - Although invasive meningococcal disease is rare in Japan (0.028 cases per 100,000 population), its incidence is 10 times greater in many other countries. Colonization is a prerequisite for invasive meningococcal disease. However, no study in Japan has involved specifically analyzing the carriage rate of Neisseria meningitidis in children. During 5 months in 2015, the respiratory tract specimens of patients who presented to 3 hospitals with respiratory symptoms were cultured. The bacteria were identified in selective media using a meningococcal detection kit and the serogroup was identified using polymerase chain reaction analysis. In 389 patients aged <=15 years with respiratory symptoms, the N. meningitidis isolation rate was 0.26% (1/389). The serogroup of the only child who tested positive was Y. In this study, we detected a low meningococcal isolation rate in pediatric patients. Due to increasing globalization, the risk of invasive meningococcal disease is likely increasing in Japan. Accordingly, invasive meningococcal diseases should be continuously monitored in Japan. Future large-scale studies should assess meningococcal isolation rates and corresponding serogroups. PMID- 29491239 TI - Trends of Human Coronaviruses in Yamagata, Japan in 2015-2016 Focusing on the OC43 Outbreak of June 2016. PMID- 29491240 TI - A Food Poisoning Outbreak Due to Food Handler-Associated Contamination with the Human Norovirus GII.P16-GII.2 Variant Strain in Italian Cuisine in Tokyo during the 2016/17 Winter Season. PMID- 29491241 TI - Surgically Treated Community-Acquired Brain Abscess: Bacteriological Analysis Based on Predisposing Infections. AB - Community-acquired brain abscesses are still encountered in clinical practice and cause considerable complications, despite improvements in hygiene in modernized societies. This study aimed to identify potential risk factors pertaining to predisposing infections and microorganisms to facilitate the effective treatment of brain abscesses. Of 121 surgically treated patients with brain abscesses, the most frequent predisposing condition was odontogenic infections (49/121 patients, 40.5%) followed by sinusitis (14/121, 11.6%). Of 121 patients, 51 (42.1%) had no identifiable predisposing infection. Viridans group streptococci (VGS) were the most frequently identified (47%) bacteria in all patients, and anaerobes were more frequently isolated in patients with odontogenic infections (36.7%, p=0.001) than aerobes. Among the patients with no identifiable predisposing infection, the most commonly isolated pathogen was VGS (38.3%); anaerobes occurred significantly less frequently (p=0.045), and old pulmonary tuberculosis was significantly more common (p=0.001) than in the group with identified predisposing infections. There was only one case of staphylococcal infection in 121 patients. The present study indicates that VGS should be the first target for antibiotic treatment when predisposing infections are not identifiable in patients with brain abscesses. Additionally, the association of old tuberculosis with community-acquired brain abscesses is common in these patients. PMID- 29491242 TI - First Molecular Evidence of Anaplasma phagocytophilum in Rodent Populations of Nanchang, China. AB - In this study, systematic surveillance of rodent populations in Nanchang of China and determination of Anaplasma phagocytophilum infection in rodents were performed. Between 2011 and 2015, 110,084 rodent snap traps were set in 4 counties and in the city center of Nanchang, China. Finally, 942 rodents were captured, with a relative density of 0.86%. The densities varied considerably by geographical area with Anyi being the most rodent-infested County. Frequently captured rodents were sewer rats (Rattus norvegicus), house mice (Mus musculus), and Rattus flavipectus. The Anaplasma genera were investigated by PCR in 19 live rodents trapped by welded cages in Anyi, 6 rodents were assessed as positive based on amplification of 16S rRNA. Sequence analysis revealed 3 variants of A. phagocytophilum in Nanchang. PCR analysis of the gltA (citrate synthase) gene found 1 sample that was positive for A. phagocytophilum infection. The sequence of A. phagocytophilum gltA gene formed a clade with and showed 99% identity to A. phagocytophilum that has been previously described in rodents from South-Eastern China. Taken together, our research indicated that commensal rodents are potential hosts for A. phagocytophilum and controlling the rodent population may facilitate subsequent prevention of human granulocytic anaplasmosis in Nanchang, China, in the future. PMID- 29491243 TI - An Outbreak of Foodborne Infection Caused by Shigella sonnei in West Bengal, India. AB - A foodborne acute gastroenteritis outbreak due to Shigella sonnei infection occurred in a household after eating foods in a housewarming party at Pakapol Village, South 24 Parganas District of West Bengal, an Indian state, in November 2016. Here, we report the epidemiological and microbiological findings of this outbreak. Thirty-four people attended the party on November 23, 2016, and had lunch together. The median incubation period from the time of food consumption to the development of acute gastroenteritis was 18.5 h (interquartile range, 16.5-22 h). The overall attack rate was 73% (25/34), and 76% (19/25) of them required hospitalization. All age groups were affected with 100% recovery rate. One served food item was significantly associated with the illness, i.e., tomato salad (risk ratio, 4.14; 95% confidence interval, 1.21-14.13). Among the 12 stool specimens tested, 8 (67%; 8/12) were positive for S. sonnei. All S. sonnei strains were completely resistant to nalidixic acid, norfloxacin, ciprofloxacin, ofloxacin, and erythromycin, and partially resistant to tetracycline, doxycycline, streptomycin, and trimethoprim/sulfamethoxazole. Pulsed-field gel electrophoresis analysis showed that the recent outbreak strains of S. sonnei were clonally related with the locally circulating strains in Kolkata. PMID- 29491244 TI - Geographic Spread of Influenza under the Influence of Community Population Size, Which Differed from That of Measles and Rubella. AB - The influenza season is defined as the period from week 36 of the year to week 20 of the subsequent year in this report. The population size of prefectures (x) and number of patients per prefecture (y) were initially uncorrelated, but a correlation developed as the season advanced. The correlation with correlation coefficient >0.7 emerged increasingly earlier over time; it developed in week 5 of the subsequent year in 2001/2002, but in week 47 of the same year in 2014/2015. Once x and y were correlated, plots of y on the vertical axis against x on the horizontal axis resulted in a straight line, y = Cxs, where s was the slope of the plot and C was a constant. The slope was high (s>1) initially, but decreased (s<1) later, indicating that influenza first spread to populated prefectures and then nationwide, involving less populated prefectures. This spread pattern was the same for the seasonal influenza and AH1pdm2009, although the progression of the latter was much faster. For measles and rubella epidemics, the number of patients per prefecture was proportional to the square of the population size from the start to the end of the season. PMID- 29491245 TI - Detection of Viruses and Mycoplasma pneumoniae in Hospitalized Patients with Severe Acute Respiratory Infection in Northern China, 2015-2016. AB - Severe acute respiratory infection (SARI) presents a huge disease and economic burden worldwide. The present study described the frequency and types of different infectious etiologies among hospitalized patients with SARI in Tianjin, China, during 2015 and 2016. Basic information, in addition to a throat or serum sample, was collected from SARI patients. Nine viruses were detected using reverse transcription polymerase chain reaction, and Mycoplasma pneumoniae was detected using the Serodia Myco II gelatin particle agglutination test. A total of 585 specimens from 2,290 SARI cases were collected. The most common infection (19.66%, 115/585) was M. pneumoniae, followed by influenza virus A/B (6.15%, 36/585), and respiratory syncytial virus (4.96%, 29/585). Identification of viral or M. pneumoniae infections was the highest in the pediatric medicine ward (74.84%, 119/159), followed by the intensive care unit (37.04%, 80/216) and respiratory medicine ward (34.29%, 72/210). M. pneumoniae was highest (38.71%, 24/62) in the 5-14-year age group. Influenza was the main infection in January 2015 and March 2016. The correlation coefficient for the proportion of hospitalized cases of SARI and the positive detection rate within the same week was 0.25. M. pneumoniae and influenza were the leading pathogens among hospitalized SARI patients. A continued surveillance of hospitalized cases of SARI can detect emerging diseases, such as avian influenza A (H7N9) virus and other respiratory disease outbreaks. PMID- 29491246 TI - The Second Candida auris Isolate from Aural Discharge in Japan. PMID- 29491248 TI - Improvement of bilirubin oxidase productivity of Myrothecium verrucaria and studies on the enzyme overproduced by the mutant strain in the solid-state fermentation. AB - Bilirubin oxidase has applications in the health and environmental sectors. Hence, several attempts have been made to increase enzyme yields. However, improvements were not very high. We report here the development of a mutant strain of Myrothecium verrucaria by using UV-rays, which produced 28.8 times more enzyme compared with the parent and was higher than the yields reported in earlier submerged cultures. The mutant strain produced 35.6 times more enzyme than the parent in solid-state fermentation, which is better than that previously reported for a solid-state fermentation process. The specific activity of the enzyme produced by the mutant was higher than that of the parental enzyme. Bilirubin oxidase from both strains showed an optimum activity at pH 7 and 40 degrees C. However, the time required to inactivate half of the initial enzyme activity at 60 degrees C was much higher in the case of the enzyme obtained from the mutant compared with the parental enzyme. The improved thermostability of the enzyme from the mutant strain could be due to the point mutations induced during the UV irradiation, since there was no change in the mass of the enzyme compared with the parental enzyme. The bilirubin oxidase of the mutant strain degraded the bilirubin faster than the enzyme obtained from the parent under similar conditions. Faster activity of the enzyme obtained from the mutant strain could be due to its lower Km (79.4 MUM) compared with that of the parental enzyme (184 MUM). Hence, the mutant enzyme showed a better functionality and thermostability, which will be beneficial for industrial applications. PMID- 29491249 TI - Marker-free insertion of a series of C-terminal epitopes based on the 50:50 method in Saccharomyces cerevisiae. PMID- 29491247 TI - Differential Distribution of Salmonella Serovars and Campylobacter spp. Isolates in Free-Living Crows and Broiler Chickens in Aomori, Japan. AB - Salmonella and Campylobacter cause foodborne enteritis mainly via the consumption of raw/undercooked contaminated poultry meat and products. Broiler flocks are primarily colonized with these bacteria; however, the underlying etiology remains unclear. The present study was conducted in order to obtain further information on the prevalence and genotypic distribution of Salmonella and Campylobacter in free-living crows and broiler flocks in a region for 2 years, thereby facilitating estimations of the potential risk of transmission of C. jejuni from crows to broiler flocks. Salmonella serovars Bredeney and Derby were isolated from 8 and 3 out of 123 captured crows, respectively, both of which are not common in broiler chickens. Campylobacter were isolated from all 89 crows tested and C. jejuni was prevalent (85 crows). Pulsed field gel electrophoresis showed broad diversity in the crow isolates of C. jejuni. However, 3 crow isolates and 2 broiler isolates showing similar banding patterns were assigned to different sequence types in multi-locus sequence typing. These results indicate that crows do not share Salmonella serovars with broilers, and harbor various genotypes of C. jejuni that differ from those of broiler flocks. Thus, our results indicate that crows are not a potential vector of these bacteria to broiler flocks in this region. PMID- 29491250 TI - Saccharomyces cerevisiae lipid droplet associated enzyme Ypr147cp shows both TAG lipase and ester hydrolase activities. AB - Saccharomyces cerevisiae Ypr147cp was found localized to lipid droplets but the physiological role of Ypr147cp remains unknown. Sequence analysis of Ypr147cp revealed an alpha/beta hydrolase domain along with the conserved GXSXG lipase motif. Recombinant Ypr147cp showed both triacylglycerol lipase and ester hydrolase activities. Knock out of YPR147C led to accumulation of TAG in ypr147cDelta when compared to wild type (WT). In addition, transmission electron microscopic analysis of ypr147cDelta cells revealed a greater number of lipid bodies, justifying the increase in TAG content, and the phenotype was rescued upon overexpression of YPR147C in ypr147cDelta. Moreover, the lipid profiling confirmed the accumulation of fatty acids derived from neutral and phospholipids in ypr147cDelta cells. Based on these results, Ypr147cp is identified as a lipid droplet associated triacylglycerol lipase along with an ester hydrolyzing capacity. PMID- 29491251 TI - Investigation of the key determinants of Asian nurses' quality of life. AB - The study aimed to compare nurses' quality of life and investigate key determinants among Asian countries with different economic status. A cross sectional survey was conducted across five Asian countries (Japan, Singapore, Malaysia, Thailand, and Bhutan). Quality of life (WHOQOL-BREF), job stress (National Institute of Occupational Safety and Health questionnaire), and demographic data were assessed. Stepwise multivariate linear regression analysis was performed to identify the key determinants of quality of life. Participants were 3,829 nurses (response rate: 82%) with a mean age of 33 +/- 10 yr and majority were women (92%). Regarding quality of life, Bhutan yielded the highest scores, followed by Malaysia, Thailand, Singapore, and Japan, and these results were statistically significant. The key determinants that were significantly related to quality of life were "stress coping ability," "life satisfaction," "Japan," "social support," "job stress," and "Singapore" (adjusted R2=0.46). In conclusion, nurses' quality of life differs across Asian countries and is not linked to the country's economic development. To maintain a good quality of life for nurses, an international exchange program like international nursing conferences for work environment and staff coping strategies is recommended to broaden institution' minds and share experiences and exchange views to be able to realize their own problems and discover global solutions to them. PMID- 29491253 TI - Dengue Virus and Its Inhibitors: A Brief Review. AB - The global occurrence of viral infectious diseases poses a significant threat to human health. Dengue virus (DENV) infection is one of the most noteworthy of these infections. According to a WHO survey, approximately 400 million people are infected annually; symptoms deteriorate in approximately one percent of cases. Numerous foundational and clinical investigations on viral epidemiology, structure and function analysis, infection source and route, therapeutic targets, vaccines, and therapeutic drugs have been conducted by both academic and industrial researchers. At present, CYD-TDV or Dengvaxia(r) is the only approved vaccine, but potent inhibitors are currently under development. In this review, an overview of the viral life circle and the history of DENVs is presented, and the most recently reported antiviral candidates and newly discovered promising targets are focused and summarized. We believe that these successes and failures have enabled progress in anti-DENV drug discovery and hope that our review will stimulate further innovation in this area. PMID- 29491254 TI - Supramolecular Pharmaceutical Sciences: A Novel Concept Combining Pharmaceutical Sciences and Supramolecular Chemistry with a Focus on Cyclodextrin-Based Supermolecules. AB - Supramolecular chemistry is an extremely useful and important domain for understanding pharmaceutical sciences because various physiological reactions and drug activities are based on supramolecular chemistry. However, it is not a major domain in the pharmaceutical field. In this review, we propose a new concept in pharmaceutical sciences termed "supramolecular pharmaceutical sciences," which combines pharmaceutical sciences and supramolecular chemistry. This concept could be useful for developing new ideas, methods, hypotheses, strategies, materials, and mechanisms in pharmaceutical sciences. Herein, we focus on cyclodextrin (CyD) based supermolecules, because CyDs have been used not only as pharmaceutical excipients or active pharmaceutical ingredients but also as components of supermolecules. PMID- 29491255 TI - A Novel Approach to the Treatment of Plasma Protein Deficiency: Ex Vivo Manipulated Adipocytes for Sustained Secretion of Therapeutic Proteins. AB - Despite the critical need for lifelong treatment of inherited and genetic diseases, there are no developmental efforts for most such diseases due to their rarity. Recent progress in gene therapy, including the approvals of two products (Glybera and Strimvelis) that may provide patients with sustained effects, has shed light on the development of gene therapy products. Most gene therapy products are based on either adeno-associated virus-mediated in vivo gene transfer to target tissues or administration of ex vivo gene-transduced hematopoietic cells. In such circumstances, there is room for different approaches to provide clinicians with other therapeutic options through a variety of principles based on studies not only to gain an understanding of the pathological mechanisms of diseases, but also to understand the physiological functions of target tissues and cells. In this review, we summarize recent progress in gene therapy-mediated enzyme replacement and introduce a different approach using adipocytes to enable lifelong treatment for intractable plasma protein deficiencies. PMID- 29491256 TI - Establishment of a Patient-Derived Tumor Xenograft Model and Application for Precision Cancer Medicine. AB - Patient-derived xenograft (PDX) models can be created with the transplantation of cancerous cells or tissues from patients' primary tumors into immunodeficient mice. PDXs are now in the spotlight as more accurate human cancer models compared with mouse tumor and human cancer cell lines transplanted into mice. PDX technology leads to breakthroughs with the introduction of novel, highly immunodeficient mice such as NOG (NOD/Scid/IL2Rgammanull), NSG (NOD/Scid/IL2Rgammanull), and NOJ (NOD/Scid/Jak3null) mice. Xenograft efficiency differs by type of tumor, site of implantation, and tumor aggressiveness. Subcutaneous implantation is a standard method for PDX, and renal capsule or orthotropic implantation improves the efficiency. Despite positive test results in animal cancer models, significant numbers of novel drug candidates fail in clinical trials because conventional animal models such as murine tumor and human cancer cell line transplantation models do not always reflect the nature of human cancers. Since PDXs conserve the original tumor characteristics such as heterogeneous histology, clinical biomolecular signatures, malignant phenotypes and genotypes, tumor architecture, and tumor vasculature, they are currently believed to offer relevant predictive insights into clinical outcomes when evaluating the efficacy of novel cancer therapies. PDX banks with integrated genomic signatures are now established in many organizations including pharmaceutical companies. These PDX databases are becoming powerful tools for advancing precision cancer medicine. PMID- 29491257 TI - Dihydroorotate Dehydrogenase as a Target for the Development of Novel Helicobacter pylori-Specific Antimicrobials. AB - Helicobacter pylori (H. pylori) infection is the world's most common bacterial infection, affecting approximately 50% of the global population. H. pylori is the strongest known risk factor for stomach diseases, including cancer. Hence, treatment for H. pylori infection can help reduce the risk of these diseases. However, the emergence of drug-resistant strains of H. pylori and the occurrence of adverse effects resulting from current therapies have complicated the successful eradication of H. pylori infection. Although various antibiotics that target several bacterial enzymes have been discovered, dihydroorotate dehydrogenase (DHODH) may hold potential for the development of novel anti-H. pylori agents with reduced toxicity and side effects. Here we review the existing literature that has focused on strategies for developing novel therapeutic agents that target the DHODH of H. pylori. PMID- 29491258 TI - Discovery of 2-[(E)-2-(7-Fluoro-3-methylquinoxalin-2-yl)vinyl]-6-pyrrolidin-1-yl N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine Hydrochloride as a Highly Selective PDE10A Inhibitor. AB - Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms. Therefore PDE10A inhibitor is expected as a therapeutic method for psychosis disease such as schizophrenia. Avanafil (1) is a PDE5 inhibitor (treatment for erectile dysfunction) discovered by our company. We paid attention to the homology of PDE10A and PDE5 and took advantage of PDE5 inhibitor library to discover PDE10A inhibitors, and found a series of compounds that exhibit higher potency for PDE10A than PDE5. We transformed the afforded derivatives, which had weak inhibitory activity against PDE10A, and discovered stilbene as a PDE10A inhibitor. Brain penetration of this compound was improved by further conversion of N-containing heterocycles and their substituents. The afforded dimethylaminopyrimidine was effective for rat conditioned avoidance response (CAR) test; however, it did not exhibit good brain penetration. We performed in depth optimization focusing on substituents of the quinoxaline ring, and produced 3-methyl-7-fluoro quinoxaline. This compound was the most effective in rat CAR test due to its strong PDE10A inhibitory activity and good pharmacokinetics. PMID- 29491259 TI - Discovery of N-{2-Methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-N' [2-(propane-2-sulfonyl)phenyl]-1,3,5-triazine-2,4-diamine (ASP3026), a Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor. AB - Anaplastic lymphoma kinase (ALK) is a validated therapeutic target for treating echinoderm microtubule-associated protein-like 4 (EML4)-ALK positive non-small cell lung cancer (NSCLC). We synthesized a series of 1,3,5-triazine derivatives and identified ASP3026 (14a) as a potent and selective ALK inhibitor. In mice xenografted with NCI-H2228 cells expressing EML4-ALK, once-daily oral administration of 14a demonstrated dose-dependent antitumor activity. Here, syntheses and structure-activity relationship (SAR) studies of 1,3,5-triazine derivatives are described. PMID- 29491260 TI - The Effect of Compaction Force on the Transition to Hydrate of Anhydrous Aripiprazole. AB - Aripiprazole (APZ) is used to treat schizophrenia and is administered as a tablet containing the anhydrous form of APZ. In this study, the effect of compaction force on the crystal form transition was investigated. The crystalline state was observed by X-ray diffraction (XRD). APZ Anhydrous Form II was compacted into tablets. The XRD intensity of anhydrous APZ became lower with higher compressive force. The degree of crystallinity decreased with the compaction force. The powder and the compacted tablets of anhydrous APZ were stored for one week under 60 degrees C and 75% relative humidity. The powder showed no crystal form transition after storage. For the tablets, however, XRD peaks of APZ hydrate were observed after storage. The tablets compacted with higher force showed the higher XRD diffraction intensity of hydrate form. We concluded that the crystallinity reduction of APZ Anhydrous Form II by compaction caused and accelerated the transition to hydrate under high temperature and humidity conditions. In order to manufacture crystallographically stable tablets containing anhydrous APZ, it is important to prevent this crystallinity reduction during compaction. PMID- 29491261 TI - Fragment-Based Discovery of Pyrimido[1,2-b]indazole PDE10A Inhibitors. AB - In this study, we report the identification of potent pyrimidoindazoles as phosphodiesterase10A (PDE10A) inhibitors by using the method of fragment-based drug discovery (FBDD). The pyrazolopyridine derivative 2 was found to be a fragment hit compound which could occupy a part of the binding site of PDE10A enzyme by using the method of the X-ray co-crystal structure analysis. On the basis of the crystal structure of compound 2 and PDE10A protein, a number of compounds were synthesized and evaluated, by means of structure-activity relationship (SAR) studies, which culminated in the discovery of a novel pyrimidoindazole derivative 13 having good physicochemical properties. PMID- 29491262 TI - Biomass Potential of Virgin and Calcined Tapioca (Cassava Starch) for the Removal of Sr(II) and Cs(I) from Aqueous Solutions. AB - In this study, we prepared novel adsorbents containing virgin and calcined tapioca products for removing strontium (Sr(II)) and cesium (Cs(I)) from aqueous solutions. The characteristics of tapioca, along with its capacity to adsorb Sr(II) and Cs(I), were evaluated. Multiple tapioca products were prepared and tested. The adsorbent prepared by boiling the tapioca followed by calcination at 300 degrees C (BTP300) was the most effective. In addition, adsorption was affected by the adsorbent's surface properties. The Sr(II) and Cs(I) adsorbed onto BTP300 could be recovered through desorption by hydrochloric acid at different concentrations, which indicates that BTP300 can be used several times for adsorption/desorption. The results of this study suggest that BTP300, which was produced from tapioca biomass, can remove Sr(II) and Cs(I) from aqueous solutions. PMID- 29491263 TI - Development of Triazine-Based Benzylating Reagents Possessing t-Butyl Group on the Triazine Core: Thermally Controllable Reagents for the Initiation of Reaction. AB - Benzylating reagents, 4-(4,6-di-t-butyl-1,3,5-triazin-2-yl)-4-benzylmorpholinium triflate, and related derivatives have been developed. The reagents release benzyl triflate as a benzyl cation equivalent upon heating the solution to 40 degrees C under neutral conditions. The O-benzylation of alcohols using a stoichiometric amount of these reagents afforded corresponding benzyl ethers in good to high yields. This was due to the presence of a bulky t-butyl group on the triazine ring of these reagents that prevents the consumption of benzyl triflate via a side reaction with a morpholinotriazine derivative. PMID- 29491264 TI - Synthesis of Novel Thiophene, Thiazole and Coumarin Derivatives Based on Benzimidazole Nucleus and Their Cytotoxicity and Toxicity Evaluations. AB - The reactivity of compounds 2-(1-(2-chloroacetyl)-1H-benzo[d]imidazol-2 yl)acetonitrile 2 and 3-(1-(2-chloroacetyl)-1H-benzo[d]imidazol-2-yl)-2H-chromen 2-one 8 towards different chemical reagents were studied and a series of novel benzimidazole derivatives were obtained (2-6a-d and 8-12a-d). Moreover, in vitro growth inhibitory effect of the newly synthesized compounds were evaluated in term of [IC50 uM] against the six cancer cell lines, human lung carcinoma (A549), lung cancer (H460), human colorectal (HT29), gasteric cancer cell (MKN-45), glioma cell line (U87MG) and cellosaurus cell line (SMMC-7721) where foretinib was used as standard reference. The results showed that compounds 2 (only for A549 cell line), 3a, 4, 6c, 6d, 8, 9a, 9e and 9f were the most active compounds towards the six cancer cell lines. On the other hand, the toxicity of these most potent compounds against shrimp larvae indicated that compounds 3a, 4, 6d, 9e and 9f were non toxic while compounds 6c and 8 were very toxic and compounds 2 and 9a were harmful against the tested organisms. PMID- 29491265 TI - Design of a Topically Applied Gel Spray Formulation with Ivermectin Using a Novel Low Molecular Weight Gelling Agent, Palmitoyl-Glycine-Histidine, to Treat Scabies. AB - Palmitoyl-glycine-histidine (Pal-GH) is a new low molecular weight gelling agent. It exhibits thixotropic behavior, low viscosity, and high dissolving properties for a wide range of hydrophilic to lipophilic drugs. Orally administered ivermectin (IVM) is used to treat scabies. However, this treatment is associated with well-known side effects, thus a study is awaited to search for alternative routes of administration. Although a topical formulation of IVM could be a candidate, it requires whole body application except the head and face for several hours on a daily basis. Therefore, in this study, we prepared a gel spray formulation containing IVM as an approach for application to large skin areas with a single spray application without further contact with the applied formulation. Pal-GH gel spray formulations were prepared from its aqueous solution by a heating and cooling method. Rheological behavior and physical appearance (spraying, spreading ability, volume of spraying, and homogeneity) of the prepared formulations were evaluated. Pal-GH gel with propylene glycol demonstrated impressive rheological properties (typical thixotropic behavior) with high hysteresis area among all the tested Pal-GH gels and spreading ability. The obtained IVM concentration in the skin after topical application of 0.1% IVM containing Pal-GH formulation onto hairless rats was much higher than the reported therapeutic concentration obtained from oral administration in humans. These results suggested that topical application of IVM using a Pal-GH gel spray formulation could be an alternative to the conventional oral forms for the scabies treatment. PMID- 29491266 TI - Synthesis of 3beta-tert-Butyldimethylsiloxy-22-phenylthio-23,24-bisnorchola 5,9(11)-diene and Reductive Nucleophilic Attack on a Branched Aliphatic Aldehyde. AB - 3beta-tert-Butyldimethylsiloxy-22-phenylthio-23,24-bisnorchola-5,9(11)-diene, which has a double bond between C-9 and C-11 and a phenylsulfenyl group on the terminus of the side chain, is a potential synthetic intermediate for steroids with 9,11-unsaturation or 9,11-seco skeletons. We describe here the synthesis of the title compound from 17-ethylenedioxy-3-acetoxyandrosta-3,5-dien-11-one. The introduction of an ethylene unit to 3beta-tert-butyldimethylsiloxyandrosta 5,9(11)-dien-17-one by the action of ethyltriphenylphosphonium bromide under basic conditions resulted in an inseparable mixture of two stereoisomeric products (5 : 1). However, in the subsequent step, only the (Z)-isomer was susceptible to the Lewis acid-catalyzed ene reaction with formaldehyde, giving a stereochemically pure product with the desired configuration. Within three steps, the ene-product was derivatized to the title compound, with a total yield of 53% over seven steps. Reductive terminal anion formation by treatment with lithium di tert-butylbiphenyl (LiDBB) and subsequent nucleophilic attack on a branched aliphatic aldehyde was demonstrated, with an eye toward the introduction of side chains, especially for steroids with oxygen functionality at C-23. PMID- 29491267 TI - Absorption Mechanisms of Iron, Copper, and Zinc: An Overview. AB - Essential trace elements play pivotal roles in numerous structural and catalytic functions of proteins. Adequate intake of essential trace elements from the daily diet is indispensable to the maintenance of health, and their deficiency leads to a variety of conditions. However, excessive amounts of these trace elements may be highly toxic, and in some cases, may cause damage by the production of harmful reactive oxygen species. Homeostatic dysregulation of their metabolism increases the risk of developing diseases. Specific transport proteins that facilitate influx or efflux of trace elements play key roles in maintaining the homeostasis. Recent elucidation of their crucial functions significantly facilitated our understanding of the molecular mechanisms of iron (Fe), copper (Cu), and zinc (Zn) absorption in the small intestine. This paper summarizes their absorption mechanisms, with a focus on indispensable functions of the molecules involved in it, and briefly discusses the mechanisms of homeostatic control of each element at the cellular and systemic levels. PMID- 29491268 TI - Parathyroid Hormone Levels Are Independently Associated with eGFR and Albuminuria: The Dong-gu Study. AB - Increased parathyroid hormone (PTH) was associated with cardiovascular mortality and morbidity in CKD patients. Our aim was to investigate the associations among estimated glomerular filtration rate (eGFR), albumin/creatinine ratio (ACR) and PTH independent of 25-hydroxyvitamin D (25(OH)D). This study included 9,162 individuals who completed the baseline survey of the Dong-gu Study, which was conducted in Korea from 2007 to 2010. The eGFR, ACR, PTH and 25(OH)D were measured in participants who met the detailed inclusion criteria. After being adjusting for covariates (sex, age, waist circumference, smoking, alcohol intake, physical activity, hypertension medications, diabetes medication, total cholesterol, triglyceride, HDL cholesterol) and log-ACR, the PTH value stratified by 25(OH)D level significantly decreased with increasing eGFR levels in each 25(OH)D stratum. Moreover, after adjustment for the same covariates and log-eGFR, the PTH value stratified by 25(OH)D level significantly increased with increasing ACR levels in each 25(OH)D stratum. In conclusion, the PTH values significantly decreased with increasing eGFR levels and increased with increasing ACR levels independently of 25(OH)D in an adult Korean population >=50 y of age. PMID- 29491269 TI - Folic Acid Promotes Wound Healing in Diabetic Mice by Suppression of Oxidative Stress. AB - The aim of this study was to investigate the effects of folic acid on impaired wound healing in diabetic mice. Male mice were divided into three groups: group 1, the non-diabetic mice (control); group 2, the streptozotocin (STZ)-induced type 1 diabetic mice; and group 3, the diabetic mice that received a daily dose of 3 mg/kg folic acid via oral gavage. Full-thickness excision wounds were created with 8-mm skin biopsy punches. Each wound closure was continuously evaluated until the wound healed up. Wound healing was delayed in diabetic mice compared with the non-diabetic mice. There were significantly reduced levels of hydroxyproline content (indicator of collagen deposition) and glutathione in diabetic wounds, whereas levels of lipid peroxidation and protein nitrotyrosination were increased. Daily supplementation with folic acid restored diabetes-induced healing delay. Histopathology showed that folic acid supplementation accelerated granulation tissue formation, proliferation of fibroblasts, and tissue regeneration in diabetic mice. Interestingly, folic acid alleviated diabetes-induced impaired collagen deposition in wounds. Moreover, folic acid significantly decreased levels of lipid peroxidation, protein nitrotyrosination and glutathione depletion in diabetic wounds. In conclusion, our results indicate that folic acid supplementation may improve impaired wound healing via suppressing oxidative stress in diabetic mice. PMID- 29491270 TI - Effects of Parenteral Amino Acid Administration on the Postoperative Nutritional Status and Wound Healing of Protein-Malnourished Rats. AB - In Japan, parenteral nutrition (PN) solutions are frequently administered to patients in the postoperative short-term period. In these cases, amino acid containing peripheral parenteral nutrition (PPN) solutions, amino acid-free maintenance solutions or combinations of the two are used. However, consensus regarding the most beneficial solution for these patients is lacking. Here, we examined the nutritional status and wound healing outcomes in protein malnourished rats receiving postoperative administrations of PPN solution, maintenance solution or combinations of the two solutions. Protein malnutrition was induced in Sprague-Dawley rats by feeding an AIN-93G-based low-protein diet (5% casein) for 2 wk. After laparotomy, dorsal skin incision, and placement of a jugular vein catheter, the rats were divided into 3 groups. Each group was administered 113 kcal/kg/d, with group A receiving maintenance solutions without amino acid, group B receiving PPN with 1.5% amino acid, and group C receiving PPN with 3% amino acid. After 5 d post-operative administration, we measured the tensile strength of the wound area, skeletal muscle weights, and nutritional parameters. Significantly higher plasma nutritional parameters and gastrocnemius and extensor digitorum longus (EDL) muscle weights were observed in groups B and C than in group A. Group C exhibited significantly elevated tensile strength of the wound area along with up-regulation of type I collagen mRNA expression compared to group A. These findings demonstrate the nutritional status and wound healing benefits of short-term postoperative administration of PPN solutions containing amino acids in protein-malnourished rats. PMID- 29491271 TI - Effects of Pediococcus acidilactici R037 on Serum Triglyceride Levels in Mice and Rats after Oral Administration. AB - The biological effects of heat-killed Pediococcus acidilactici R037 (R037) were evaluated when orally administered in mice and rats. Oral R037 administration at a daily dose of 10 and 100 mg/kg for 3 wk dose-dependently reduced fasting and non-fasting serum triglyceride concentrations in KK-Ay/TaJcl mice, a model of type II diabetes, obesity, hypercholesterolemia, and hypertriglyceridemia. Serum levels of free fatty acids in the 100 mg/kg group tended to decrease (not statistically significant), and total cholesterol levels remained unchanged. Treatment with R037 resulted in a significant decrease in blood glucose (at 100 mg/kg) and liver weight (at 10 and 100 mg/kg), and a small body weight gain (at 100 mg/kg) as compared to those in control mice. In addition, oral R037 administration at 100, 200, and 400 mg/kg/d for 1 wk dose-dependently suppressed the increase in serum triglyceride levels in Wistar rats after oral fat loading. Moreover, intraduodenal injection of 120 mg of R037 in Wistar rats suppressed gastric vagal nerve activity (GVNA) indicating suppression of intestinal digestion and absorption of food, and suppression of appetite. The R037 injection potentiated epididymal white adipose tissue sympathetic nerve activity (WAT-SNA) and tended to potentiate pancreatic sympathetic nerve activity (PSNA), suggesting that R037 activated lipolysis. Taken together, these findings indicate that R037 lowers serum triglycerides, possibly through suppressing intestinal absorption and potentiating lipolytic pathways. R037 may be useful for primary prevention of coronary artery diseases in subjects with mild or borderline dyslipidemia in combination with lifestyle changes. PMID- 29491272 TI - Oral Glucose Tolerance and Tryptophan Metabolism in Non-Obese and Non-Insulin Dependent Diabetic Goto-Kakizaki Rats Fed High-Tryptophan Diets. AB - We investigated oral glucose tolerance and tryptophan (Trp) metabolism in non obese and non-insulin-dependent diabetic Goto-Kakizaki (GK) rats fed high-Trp diets. Five-week-old male Wistar and GK rats were fed a 20% casein diet (control diet) or the same diet supplemented with 1%, 2%, 3%, or 5% Trp for 58 d. Oral glucose tolerance tests were performed on Days 14 and 28 of the experimental period. Urine as well as livers and blood were collected on the last day of the experiment. The glucose concentration and the amount of Trp metabolites were measured. On Day 14 of the experiment, the incremental blood glucose concentrations integrated over a period of 2 h (DeltaAUC0-2h) of blood glucose in rats fed the 3% and 5% Trp diets had decreased by 13% and 18%, respectively, compared with that of the control-GK rats. However, no significant differences were found in the rats fed +1% or +2% Trp diets compared with control-GK rats. On Day 28, there were no significant differences found in the DeltaAUC0-2h of blood glucose levels in any group including the control-GK group. On the last day, the concentrations of plasma glucose, total cholesterol, and triglyceride did not show differences in any group. There were no specific phenomena observed in the metabolism of Trp in GK rats even when fed an excess of Trp, compared with that of Wistar rats. Oral Trp administration and its continuous use may not improve blood glucose levels in type 2 diabetic rats. PMID- 29491273 TI - Antihypertensive Effect of gamma-Aminobutyric Acid-Enriched Brown Rice on Spontaneously Hypertensive Rats. AB - 'Haiibuki' is a giant embryo rice cultivar that contains abundant gamma aminobutyric acid (GABA) compared with conventional rice cultivars. Here, we performed a functional evaluation of 'GABA-enriched brown rice' (GEBR) prepared by modifying the 'Haiibuki' cultivar to contain more GABA. Study 1: Spontaneously hypertensive rats were divided into three groups [control (cornstarch), normal brown rice, and GEBR] and fed an orally administered diet for 4 wk. A significant blood pressure elevation-inhibitory effect was observed in the GEBR group as compared with the other groups. Study 2: Rats were divided into two groups and fed ad libitum for 12 wk. The two groups were control (commercial feed with 5% cornstarch) and GEBR (commercial feed with 5% GEBR). Body weight, blood pressure, food consumption, and water intake were measured during the study period, and blood chemistry was analyzed after the study. Plasma 8-hydroxy-2'-deoxyguanosine (8-OHdG) and urinary isoprostane were measured 12 and 10 wk after the start of the study, respectively. A significant blood pressure elevation-inhibitory effect was observed in the GEBR group. The 8-OHdG and isoprostane levels were significantly lower in the GEBR group than in the control group, demonstrating an oxidative stress-reducing effect. Therefore, GEBR exhibited a blood pressure elevation-inhibitory effect under the conditions of this study. The antioxidative action may occur secondarily to the antihypertensive action of GABA, suggesting that the long-term ad libitum ingestion of GEBR prevents hypertension. A reduction in oxidative stress could reduce the chances of complications in cardiovascular diseases. PMID- 29491274 TI - The Impairment of Trans Fatty Acids on Learning, Memory and Brain Amino Acid Neurotransmitters in Mice. AB - The aim of the study was to demonstrate the impairment of trans fatty acids (TFAs) in neurological disorders in mice. Forty-eight male Kunming mice were randomly divided into four groups with twelve in each group, namely a control group (corn oil group), and TFA groups with low, middle and high dosages. The tested chemicals were given by gavage, once a day, for 12 wk in total, with the volume of the intragastric liquid as 0.1 mL/10 g of body weight. The mice in the control group were given corn oil only. The mice in the TFA groups were given TFA solution (doses were 25, 50 and 100 mg/kg of body weight, respectively). The Morris circle water maze was used to test learning and memory of mice. The activity of acetylcholinesterase (AChE), nitric oxide synthase (NOS) and the level of brain amino acid neurotransmitters were tested. In the Morris water maze task, and compared to the control group, TFAs showed no obvious effect on learning or memory. TFA intake led to a significant decrease of AChE in all TFA groups, and the increase in levels of NOS in the high-dose group. Meanwhile, intake of TFAs increased the levels of Asp, Glu, Gly, and Tau in all TFA groups. The results suggest that long-term intake of TFAs probably impairs learning, memory and brain neurotransmitters in mice. PMID- 29491275 TI - Identification of Functional Food Factors as beta2-Adrenergic Receptor Agonists and Their Potential Roles in Skeletal Muscle. AB - Maintaining skeletal muscle functions by controlling muscle metabolism is of utmost importance. beta2-Adrenergic receptor (beta2-AR), which is expressed in skeletal muscle, is a member of the G-protein-coupled receptor family that plays a critical role in the maintenance of muscle mass. In the present study, using luciferase reporter assays in beta2-AR-expressing HEK293 cells, we discovered several food factors that exhibited agonistic activity at mouse or human beta2 AR. Osthole, gramine, and hordenine were identified as both mouse and human beta2 AR agonists, whereas berberine was identified as a mouse beta2-AR agonist only. Additionally, intramuscular injection of gramine or hordenine in mice facilitated gene expression of several cAMP response element binding protein targets, which is thought to result in increased skeletal muscle protein synthesis. This study provides evidence that several food factors might exert potential health effects on skeletal muscle by enhancing cAMP signaling through the activation of beta2 AR. PMID- 29491276 TI - Effect of Passion Fruit Seed Extract Rich in Piceatannol on the Skin of Women: A Randomized, Placebo-Controlled, Double-Blind Trial. AB - Piceatannol has been reported to have a wide variety of effects on the skin, including promoting collagen production, inhibiting melanin synthesis, inducing the antioxidant glutathione, and eliminating reactive oxygen species. In this study, a randomized, placebo-controlled, double-blind trial was conducted to clinically evaluate the effects of piceatannol-rich passion fruit seed extract on the skin of healthy Japanese women (age, 35-54 y). Thirty-two women with dry skin received either passion fruit seed extract (5 mg piceatannol) or a placebo (dextrin) for 8 wk. Skin hydration and other parameters on the face were assessed at 0, 4, and 8 wk by using specialized equipment. Furthermore, questionnaire interviews were conducted regarding the physical condition of subjects at 0, 4, and 8 wk. The results showed that consumption of passion fruit seed extract led to significant increases in the moisture content of human skin after 4 and 8 wk compared with that before the trial. The amount of transepidermal water loss decreased over time, although the differences were not significant. Moreover, a stratified analysis of subjects with moisture values of <=200 MUS revealed increased moisture content in the passion fruit seed extract group as compared with the placebo group. Furthermore, the results of questionnaires showed significant reductions in "perspiration" and "fatigue" in the passion fruit seed extract group as compared with the placebo group. These results indicate that oral intake of passion fruit seed extract that is rich in piceatannol could improve the moisture of dry skin and reduce fatigue. PMID- 29491277 TI - beta-Glucan in Foods and Its Physiological Functions. AB - beta-Glucans are a class of polysaccharides consisting of D-glucose units that are polymerized primarily via the beta-1,3 glycosidic bonds, in addition to the beta-1,4 and/or beta-1,6 bonds. They are present in various food products such as cereals, mushrooms, and seaweeds and are known for their numerous effects on the human body, depending on their structures, which are diverse. The major physicochemical properties of beta-glucans include their antioxidant property, which is responsible for the scavenging of reactive oxygen species, and their role as dietary fiber for preventing the absorption of cholesterol, for promoting egestion, and for producing short-chain fatty acids in the intestine. Dietary beta-glucans also exert immunostimulatory and antitumor effects by activation of cells of the mucosal immune system via beta-glucan receptors, such as dectin-1. In this review, we elaborate upon the diversity of the structures and functions of beta-glucans present in food, along with discussing their proposed mechanisms of action. In addition to the traditional beta-glucan-containing foods, recent progress in the commercial mass cultivation and supply of an algal species, Euglena gracilis, as a food material is briefly described. Mass production has enabled consumption of paramylon, a Euglena-specific novel beta-glucan source. The biological effects of paramylon are discussed and compared with those of other beta-glucans. PMID- 29491278 TI - Revival of Historical Kana Orthography in a Patient with Allographic Agraphia. AB - Japanese people born before World War II learned Japanese kana (Japanese syllabograms) writing in a style that is not currently used. These individuals had to learn the current style of kana orthography after the war. An 85-year-old man was taken to our hospital by his family who were surprised by his diary. It was written with kanji (Japanese ideograms) and katakana using the prewar style. A neuropsychological examination revealed impaired recall of hiragana. Neuroimaging studies revealed atrophy of the left fronto-parietal lobe and hypoperfusion of the left frontal lobe. His allographic agraphia might have resulted from the disturbance of the current style of kana orthography. PMID- 29491279 TI - Dedifferentiated Liposarcoma Occurring in the Right Pulmonary Hilum. PMID- 29491280 TI - The Prevalence and Findings of Subclinical Influenza-associated Cardiac Abnormalities among Japanese Patients. AB - Objective Although life-threatening cardiac complications in influenza infection are rare, subclinical influenza-associated cardiac abnormalities may occur more frequently. We investigated the prevalence of subclinical cardiac findings. Methods After obtaining their written informed consent, 102 subjects were enrolled in the present study. The study subjects underwent a first set of examinations, which included electrocardiography (ECG), echocardiography, and the measurement of their cardiac enzyme levels. Those with one or more abnormal findings among these examinations were encouraged to undergo a repeat examination 2 weeks later. Results Among the 102 subjects enrolled, 22 (21.6%) were judged to have cardiac findings, including ST-T abnormalities, pericardial effusion, diastolic dysfunction, and cardiac enzyme elevation. Eighteen of these 20 subjects underwent a second screening at a median of 14 days later, and it was found that 11 of the 18 subjects were free from cardiac findings on this second examination. This suggested that the abnormalities were only transient and they therefore might have been associated with influenza. Approximately 20% of the influenza patients enrolled had cardiac findings, including ST-T segment abnormalities, pericardial effusion, and cardiac enzyme elevation. Conclusion Among the 102 patients who were studied, the cardiac findings were only mild and transient; however, physicians should be aware of influenza infection-associated cardiac abnormalities because such abnormalities may not be rare. PMID- 29491281 TI - Interstitial Lung Disease Is a Possible Manifestation of Anti-signal Recognition Particle Antibody Syndrome. PMID- 29491282 TI - Manifestation of Central Diabetes Insipidus in a Patient with Thyroid Storm. AB - We herein report a case of central diabetes insipidus complicated with thyroid storm. A middle-aged woman who was receiving treatment for Graves' disease suddenly complained of polydipsia, polyuria and general fatigue. Laboratory tests showed hyperthyroidism, hypernatremia, hypoosmolar urine and a decreased plasma vasopressin level. The occurrence of central diabetes insipidus with hyperthyroidism was revealed on the basis of pituitary magnetic resonance imaging, a water deprivation test and a desmopressin test. The clinical co existence of diabetes insipidus and hyperthyroidism is very rare; however, the complication should be considered when hypernatremia and/or dehydration progress in patients with Graves's disease as a common autoimmune-related etiology. PMID- 29491283 TI - An HIV-infected Patient with Confirmed Overlapping Complications of Severe Amebic Colitis and CMV Enteritis. AB - We herein report a case of simultaneous amebic colitis and cytomegalovirus (CMV) enteritis in an HIV-infected patient. The patient was a 40-year-old man who developed bloody stool and diarrhea. We diagnosed him with severe amebic colitis associated with HIV infection and administered metronidazole. While his symptoms began to improve, the patient then developed CMV enteritis. We administered ganciclovir, and his symptoms improved. However, despite control of the infection, stenosis of the descending colon caused intestinal obstruction, and colostomy was performed. This case shows the importance of considering the possibility of simultaneous infection when gastrointestinal symptoms appear in people infected with HIV. PMID- 29491284 TI - Pneumothorax Secondary to an Ingested Fish Bone. PMID- 29491285 TI - A Gastric Follicular Lymphoma Presenting as a Submucosal Tumor with a Diagnosis Determined by Endoscopic Resection. AB - We herein report the case of 74-year-old man with gastric follicular lymphoma resected by endoscopic submucosal dissection (ESD). A submucosal tumor 7 mm in diameter was detected at the gastric middle body. Endoscopic ultrasonography showed a homogenous hypoechoic tumor localized in the submucosa. The tumor was removed by ESD immediately, before further tumor growth would preclude endoscopic resection. The pathological findings indicated follicular lymphoma (FL) with negative horizontal and vertical margins. The clinical stage of FL was confirmed to be stage I by extensive work-up procedures, including contrast-enhanced computed tomography, fluorodeoxyglucose-positron emission tomography, esophagogastroduodenoscopy, and colonoscopy. The patient remains in complete remission without any treatment. PMID- 29491286 TI - Gastrocnemius Myalgia as a Rare Initial Manifestation of Crohn's Disease. AB - The initial symptoms of Crohn's disease (CD) sometimes present as extraintestinal lesions, which can be a diagnostic challenge for physicians. Painful legs, known as "gastrocnemius myalgia syndrome", are rare complications that often precede abdominal manifestations. We herein report the case of a 38-year-old man who presented with bilateral leg myalgia lasting for 4 months. Magnetic resonance imaging showed abnormal intensity, and a muscle biopsy revealed inflammatory cell infiltration. Abdominal symptoms appeared three months after the myalgia onset, and the diagnosis of CD was confirmed later by endoscopic and radiological findings. To our knowledge, this is the first description of gastrocnemius myalgia syndrome in Japan. PMID- 29491287 TI - Reply to "The Effects of Tranilast on Cardiomyopathy in Becker Muscular Dystrophy Requires Profound Cardiac and Neurologic Evaluations". PMID- 29491288 TI - A Patient with Non-alcoholic Steatohepatitis Complicated by Multiple Myeloma. AB - A 68-year-old woman with liver dysfunction was diagnosed with nonalcoholic steatohepatitis (NASH) stage 1. Three years later, she showed massive ascites and jaundice. A trans-jugular liver biopsy confirmed advanced cirrhosis, suggesting that her liver fibrosis had progressed rapidly. At the same time, she was diagnosed with multiple myeloma (MM). In this case, the plasma levels of osteopontin (OPN), a proinflammatory cytokine that promotes liver fibrosis progression through the hedgehog pathway and is increased in patients with MM, were increased. This increased OPN expression was accompanied by the upregulation of the hedgehog pathway in this patient, suggesting that the MM-associated increase in OPN had promoted the progression of liver fibrosis through the hedgehog pathway. The progression of liver fibrosis should be monitored in patients with NASH if other diseases, such as MM, are present. PMID- 29491291 TI - Left Main Bronchial Stenosis due to Schwannoma. PMID- 29491289 TI - Concurrent Autoimmune Neutropenia and Idiopathic Thrombocytopenic Purpura Associated with IgG4-related Diease. AB - IgG4-related disease (IgG4RD) is a multi-organ disorder characterized by an elevated serum IgG4 level and IgG4-positive plasma cell infiltration of the affected organs, accompanied by tissue fibrosis and sclerosis. Although it can affect any organ, to our knowledge, no cases involving concurrent autoimmune neutropenia and thrombocytopenia have been reported. A 62-year-old man visited our hospital and was diagnosed with IgG4RD accompanied by interstitial pneumonitis, lymphadenopathy, and interstitial nephritis. During his clinical course, he developed autoimmune neutropenia and idiopathic thrombocytopenic purpura. Our case, invoving multiple hematological abnormalities, might help deepen our understanding of the pathophysiology of IgG4RD. PMID- 29491290 TI - Optimizing Hemodynamics with Transcatheter Arterial Embolization in Adrenal Pheochromocytoma Rupture. AB - Pheochromocytoma rupture is rare, and emergent adrenalectomy is associated with a high mortality. We herein report a patient with pheochromocytoma rupture who was stabilized by transcatheter arterial embolization (TAE) and subsequently underwent elective surgery. A 45-year-old man presented with the sudden onset of left lateral abdominal pain, headache, chest discomfort, high blood pressure, and adrenal hemorrhaging on enhanced abdominal computed tomography. TAE was performed under a provisional diagnosis of pheochromocytoma rupture. Following oral doxazosin, he underwent elective left adrenalectomy four and a half months after TAE. Stabilizing the hemodynamic status by TAE before adrenalectomy is a viable option for treating pheochromocytoma rupture. PMID- 29491292 TI - The Differential Diagnosis of Acute Onset Truncal Ataxia: The Importance of Dysgeusia in Miller Fisher Syndrome. AB - Miller Fisher syndrome (MFS) can be difficult to diagnose, particularly in mild cases where some of the standard triad of symptoms (external ophthalmoplegia, ataxia, and loss of deep tendon reflex) are absent. We herein report a case of the incomplete form of MFS diagnosed in a 54-year-old Japanese man who presented only with ataxia symptoms and was positive for the anti-GQ1b antibody. However, the patient also suffered from dysgeusia, a significant impairment of taste perception. We propose that dysgeusia in acute-onset ataxia cases may constitute an important clinical feature to aid in the diagnosis of the incomplete form of MFS. PMID- 29491294 TI - LIG4 Syndrome Associated with Hypocellular Myeloid Dysplasia. PMID- 29491293 TI - Restoration of a Conduction Block after the Long-term Treatment of CIDP with Anti neurofascin 155 Antibodies: Follow-up of a Case over 23 Years. AB - We herein report a woman with chronic inflammatory demyelinating polyneuropathy (CIDP) in whom positivity for anti-neurofascin 155 antibodies was revealed 23 years after the onset of neuropathy. The patient initially reported numbness in the face at 50 years of age and subsequently manifested features compatible to typical CIDP. Steroid administration initiated at 54 years of age ameliorated her neuropathic symptoms. Although the nerve conduction indices at 59 years of age deteriorated, those at 68, 72, and 73 years of age showed a gradual recovery. The deterioration and subsequent restoration of compound muscle action potential amplitudes was the most dramatic, suggesting that a conduction block can be reversed earlier than other electrophysiological indices. PMID- 29491295 TI - Portal-systemic Encephalopathy due to Complicated Spleno-renal Shunt Successfully Treated with Balloon-occluded Retrograde Transvenous Obliteration Using a Double Coaxial Balloon Catheter System and Shape-memory Coils. AB - A 70-year-old woman with hepatitis C cirrhosis underwent balloon-occluded retrograde transvenous obliteration for hepatic encephalopathy due to spleno renal shunt. Because the shunt was thick, long, and winding, we used a coaxial and double interruption system, which enables the effective occlusion of the drainage route, and shape-memory coils, which are more physically stable than conventional metallic coils because they form three-dimensional loops. The patient was successfully treated with the combined usage of these devices, resulting in a normal serum ammonia level. Thereafter, the patient was treated with direct-acting antivirals, and a sustained virological response was achieved. PMID- 29491296 TI - Treatment of Class IV Lupus Nephritis with Mycophenolate Mofetil Monotherapy. AB - Lupus nephritis (LN) occurs in up to 60% of systemic lupus erythematosus patients. Combination therapy involving a corticosteroid and cyclophosphamide or mycophenolate mofetil (MMF) has been a standard therapy for LN. However, clinicians generally prefer to minimize steroid use in LN treatment. We herein report the case of a Japanese man with LN whose severe chronic heart failure prevented us from using steroid therapy. Instead, his LN was successfully treated with MMF monotherapy. Based on our experience with this case, we suggest that MMF monotherapy may represent a feasible LN treatment option in patients who cannot tolerate steroid therapy. PMID- 29491297 TI - Clinically Amyopathic Dermatomyositis with Interstitial Pneumonia That Was Successfully Treated with Plasma Exchange. AB - Patients with clinically amyopathic dermatomyositis (CADM), a subset of dermatomyositis characterized by a lack of muscle involvement, frequently develop rapidly progressive and treatment-resistant interstitial lung disease. We report the case of a 49-year-old man who was diagnosed with CADM. He developed interstitial pneumonia, which did not respond to combination therapy with methylprednisolone pulse therapy, cyclophosphamide, and cyclosporine. We therefore attempted plasma exchange. After 7 courses of therapeutic plasma exchange, the interstitial pneumonia gradually improved. This case suggests that plasma exchange might be an effective therapeutic option for patients with progressive interstitial lung disease in steroid- and immunosuppressive therapy refractive CADM. PMID- 29491298 TI - Development of Necrotizing Myopathy Following Interstitial Lung Disease with Anti signal Recognition Particle Antibody. AB - A 72-year-old man was admitted due to dyspnea on exertion with interstitial shadows and elevated serum creatinine kinase (CK). Despite a close examination, which included magnetic resonance imaging (MRI), we could not diagnose myopathy. Prednisolone was administered and gradually tapered. One year later, anti-signal recognition particle (SRP) antibody was confirmed and he was re-admitted for hypoxemia with elevated CK. MRI revealed muscle edema and a histopathological examination of a muscle biopsy specimen showed necrotizing myopathy. Prednisolone, cyclosporine, and intravenous immunoglobulin were administered. Physicians should carefully monitor muscle symptoms and serum CK levels in cases of interstitial lung disease with anti-SRP antibodies. PMID- 29491299 TI - Adult T-cell Leukemia/Lymphoma as a Methotrexate-associated Lymphoproliferative Disorder in a Patient with Rheumatoid Arthritis. AB - The patient was a 74-year-old Japanese woman with rheumatoid arthritis (RA) who developed generalized lymphadenopathy with elevated levels of lactase dehydrogenase (LD), and soluble IL-2 receptor (sIL-2R). She was found to be positive for anti-human T-cell leukemia virus type 1 (HTLV-1) antibodies. Her symptoms and laboratory abnormalities spontaneously regressed after the cessation of methotrexate (MTX), suggesting that she had an MTX-associated lymphoproliferative disorder; however, her lymphadenopathy appeared again approximately 14 months later with LD and sIL-2R elevation. A histopathological analysis and Southern blotting of a lymph node biopsy specimen for HTLV-1 provirus supported the diagnosis of adult T-cell leukemia/lymphoma (ATL) (lymphoma type). These data confirmed that an HTLV-1 positive RA patient may develop ATL. PMID- 29491300 TI - Emergence of Carbapenem Non-susceptible Campylobacter coli after Long-term Treatment against Recurrent Bacteremia in a Patient with X-linked Agammaglobulinemia. AB - We herein report a case of recurrent Campylobacter coli bacteremia in a 37-year old Japanese man with X-linked agammaglobulinemia (XLA). The patient experienced seven episodes of C. coli bacteremia over one year, with an erythematous rash intermittently emerged on the lower limbs. Although hospitalization for intravenous treatment was repeatedly recommended, he obstinately declined it. Following long-term oral antibiotic treatment with tebipenem and faropenem for the persistent infection, C. coli showed elevated minimum inhibitory concentrations to meropenem, a key drug for severe campylobacteriosis. Physicians should note that the overuse of antibiotics can lead to the emergence of carbapenem-non-susceptible Campylobacter strains. PMID- 29491301 TI - Cerebral Infarction with Leriche Syndrome. PMID- 29491302 TI - Severe and Recurrent Hypoglycemia Caused by Garenoxacin in a Patient not Taking Hypoglycemic Drugs. AB - Quinolones are known to induce hypoglycemia, although there is no written report of garenoxacin-induced hypoglycemia. We herein report a case of garenoxacin induced hypoglycemia in a patient not taking hypoglycemic drugs. An 89-year-old Japanese woman with type 2 diabetes and chronic renal insufficiency requiring hemodialysis was admitted to the emergency department in a comatose state. Her serum glucose measured 1 mg/dL on arrival. The patient had not taken any hypoglycemic drugs recently and had never experienced a hypoglycemic episode. She had received a four-day course of garenoxacin treatment before the emergency admission. Clinicians should therefore recognize the potential risk of hypoglycemia during garenoxacin therapy. PMID- 29491304 TI - Ischemic Duodenitis with Delayed Elevation of Pancreatic Enzymes. PMID- 29491303 TI - Stenotic Ischemic Enteritis with Concomitant Hepatic Portal Venous Gas and Pneumatosis Cystoides Intestinalis. AB - A 69-year-old man was admitted to a hospital with complaints of abdominal pain. Computed tomography showed hepatic portal venous gas and pneumatosis cystoides intestinalis. Conservative treatment was effective; however, after discharge, he developed complaints of vomiting. Fluoroscopic enteroclysis revealed a stricture in the jejunum necessitating admission to our hospital. Transoral balloon assisted enteroscopy showed a circumferential ulcer with a stricture. The stricture was surgically resected, and a histopathological examination was consistent with ischemic enteritis. Stenotic ischemic enteritis should be considered among the differential diagnoses in a patient presenting with hepatic portal venous gas and pneumatosis cystoides intestinalis showing small intestinal obstruction. PMID- 29491305 TI - Adrenal Lymphoma Presenting with the CT Angiogram Sign. PMID- 29491306 TI - Transmitral Doppler Flow Pattern in Left Atrial Myxoma. PMID- 29491307 TI - An Advanced Well-differentiated Pancreatic Neuroendocrine Carcinoma (NET-G3) Associated with Von Hippel-Lindau Disease. AB - A 45-year old woman who underwent several surgeries for tumors associated with von Hippel-Lindau disease (VHL) was referred to our hospital due to a pancreatic tumor and liver tumors. She was diagnosed with pancreatic neuroendocrine tumor (NET) with a Ki67 index of 40% based on the examination of a biopsy specimen of the liver tumors. She was treated with everolimus for 6 months and sunitinib for 6 weeks as first- and second-line therapies. She survived for 13 months. At autopsy the diagnosis of pancreatic neuroendocrine tumor (NET)-G3 was confirmed. We herein report an aggressive clinical course of VHL-related NET G3. The further accumulation of cases is required to reach a consensus on treatment for this disease. PMID- 29491309 TI - Portal Venous Gas Due to Decompression Sickness. PMID- 29491308 TI - The Clinical Significance of Low Serum Arachidonic Acid in Sepsis Patients with Hypoalbuminemia. AB - Objectives Fatty acids (FAs) have various roles in pro-inflammatory and anti inflammatory functions. Hypoalbuminemia is often observed in sepsis patients. An imbalance among these compounds formed from FAs caused by hypoalbuminemia may be related to increased mortality in sepsis patients. The purpose of this study was to investigate the correlations between serum albumin and FAs in sepsis and the outcome. Methods This study was an observational investigation. The clinical and laboratory data of sepsis patients were recorded and the Sequential Organ Failure Assessment (SOFA) score was calculated at admission. The serum arachidonic acid (AA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and dihomo-gamma linolenic acid (DHLA) levels were also measured as FAs. The body mass index (BMI) was used to determine the general nutrition status. Results Two hundred sepsis patients were enrolled during the study period. No significant correlations were observed between the BMI and the SOFA score or the serum albumin level at admission. The FA levels of the non-survivors were significantly lower, but there were no significant differences in the EPA/AA levels of the survivors and non survivors. A low serum albumin level was closely related to low AA (p<0.0001), EPA (p<0.0001), DHA (p=0.0003), and DHLA levels (p<0.0001). A multiple logistic regression analysis revealed that a high SOFA score [adjusted odds ratio, 1.19; 95% confidence interval (CI), 1.02-1.39, p=0.026] and low AA (adjusted odds ratio, 0.98; 95% CI, 0.978-0.994, p=0.041) were associated with a poor outcome. Conclusion A lower AA level was an important determinant of the outcome of patients with sepsis. These findings are consistent with the findings of previous studies, which reported that hypoalbuminemia might alter the AA metabolism in sepsis patients. PMID- 29491310 TI - Fulminant Type 1 Diabetes Mellitus Accompanied by Positive Conversion of Anti insulin Antibody after the Administration of Anti-CTLA-4 Antibody Following the Discontinuation of Anti-PD-1 Antibody. AB - An 80-year-old woman with malignant melanoma received 20 cycles of anti programmed death 1 (PD-1) antibody (nivolumab) treatment and showed normal glucose tolerance. Three weeks after switching to anti-cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) antibody (ipilimumab), her plasma glucose level was elevated to 639 mg/dL, her HbA1c was 7.7%, and her fastening serum C-peptide immunoreactivity was undetectable. Anti-glutamic acid decarboxylase and insulinoma-associated protein-2 antibodies were negative. She was diagnosed with fulminant type 1 diabetes mellitus (F1DM). Remarkably, her anti-insulin antibody was positively converted, and her Sialylated Carbohydrate Antigen, Krebs von den Lungen-6 levels increased after ipilimumab therapy. She possessed F1DM susceptible Human Leukocyte Antigen-DR4. A fluorescence activated cell sorting analysis showed an altered T-cell population. This case of F1DM highlights specific mechanisms underlying pancreatic beta cell immunity. PMID- 29491311 TI - The Effects of Tranilast on Cardiomyopathy in Becker Muscular Dystrophy Requires Profound Cardiac and Neurologic Evaluations. PMID- 29491312 TI - Acute Massive Gastric Dilatation in a Patient with an Eating Disorder. PMID- 29491313 TI - Asymmetric Magnetic Resonance Imaging Findings in Metronidazole-induced Encephalopathy. PMID- 29491314 TI - Stroke-like Migraine Attacks after Radiation Therapy (SMART) Syndrome Followed by Cerebral Infarction. AB - A 36-year-old man with a history of irradiation for acute lymphoblastic leukemia developed headache with cortical dysfunction lasting for 4 weeks. The clinical features were consistent with stroke-like migraine attacks after radiation therapy (SMART) syndrome. Six months later, he developed cerebral infarction due to occlusions of the left anterior and middle cerebral arteries. This is the first case report describing SMART syndrome followed by severe cerebral infarction. Although an association between the two episodes was not assumed, this case indicates that protective therapies against infarction might need to be considered for patients with SMART syndrome. PMID- 29491315 TI - The Clinical Findings Useful for Driving Safety Advice for Parkinson's Disease Patients. AB - Objective We conducted a study to obtain information that could be used to provide Parkinson's disease (PD) patients with appropriate advice on safe driving. Methods Consecutive PD patients who visited our office were studied. Among these patients, those who had experienced driving after being diagnosed with PD were interviewed by neurologists and a trained nurse to investigate their previous car accidents, motor function, cognitive function, sleepiness, levodopa equivalent dose (LED), and emotional dysregulation. The rates of major car accidents before and after the onset of PD were compared. Results Fifteen patients had experienced a major car accident resulting in human injury or serious property damage since the onset of PD. When the rates of major car accidents before and after the onset of PD were compared, the ratio was 4.3 [95% confidence interval (CI) 1.9-9.7]. The incidence of accidents after the onset of PD was correlated with age, disease duration, LED, the cognitive function Mini Mental Scale Examination (MMSE), Japanese translation of the Montreal Cognitive Assessment (MoCA-J), but not the motor symptom score [Unified Pankinson's disease rating scale (UPDRS) part III at the time of the study]. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP) score was also higher in patients with major car accidents. Conclusion The severity of symptoms (Hoehn-Yahr classification), cognitive function, and disease duration were expected to be risk factors for car accidents. However, the motor symptom score (UPDRS part III) was not associated with the incidence of major car accidents. In addition to a low cognitive function and the severity of symptoms, the QUIP score might be an independent factor that can be referenced when advising PD patients to refrain from driving. PMID- 29491316 TI - A Novel p.L145Q Mutation in the HNF1B Gene in a Case of Maturity-onset Diabetes of the Young Type 5 (MODY5). AB - Maturity-onset diabetes of the young (MODY) is an autosomal dominant form of early onset diabetes. The hepatocyte nuclear factor-1-beta (HNF1B) gene is responsible for MODY type 5 (MODY5) with distinctive clinical features, including pancreatic atrophy and renal disease. We herein report a Japanese case of young onset diabetes with typical phenotypes of MODY5 and a novel heterozygous missense mutation (p.L145Q) in the HNF1B gene. The mutation was located in the Pit-Oct-Unc (POU)-specific domain, and the amino acid residue L145 was highly conserved among species. It is strongly suggested that this mutation explains the phenotypes of MODY5. PMID- 29491317 TI - Neurogenic Pulmonary Edema without Norepinephrine Elevation. PMID- 29491319 TI - Skeletal Muscle Pump Function Is Associated With Exercise Capacity in Patients With Heart Failure. AB - BACKGROUND: Skeletal muscle pump function may play a key role in maintaining cardiac output (CO), because of the lack of cardiac contractility reserve during incremental exercise in heart failure (HF) patients. We aimed to investigate the relationship between lower leg pump function and surrogate measures of CO during cardiopulmonary exercise testing (CPX) in HF patients.Methods and Results:Consecutive cardiac patients referred for CPX had their lower leg ejection fraction (LgEF) measured using strain gauge plethysmography as a marker of skeletal muscle pump function. We analyzed 88 patients, including 65 HF patients and 23 control subjects. Unlike the control subjects, LgEF correlated with peak oxygen consumption (VO2) and peak oxygen (O2) pulse (peak VO2: r=0.280, P=0.024; peak O2 pulse: r=0.540, P<0.001) in HF patients. Significant relationships among LgEF, peak VO2, and peak O2 pulse were observed in HF patients with reduced EF (peak VO2: r=0.367, P=0.026; peak O2 pulse: r=0.658, P<0.001), whereas LgEF in HF patients with preserved EF showed a weak correlation only with peak O2 pulse (r=0.407, P=0.032). LgEF was selected as an independent determinant of peak VO2 (beta=0.187, P=0.036) and peak O2 pulse (beta=0.520, P<0.001) in HF patients. CONCLUSIONS: Lower leg skeletal muscle function may contribute to exercise capacity through an indirect mechanism on cardiac function in HF. PMID- 29491318 TI - The Anticipated Renoprotective Effects of Sodium-glucose Cotransporter 2 Inhibitors. AB - Sodium-glucose cotransporter 2 (SGLT2), which is specifically expressed on the apical side of proximal tubular cells, is involved in the reabsorption of most of the glucose filtered by the glomeruli, and its inhibitors are gaining publicity as potent antihyperglycemic drugs. In some clinical trials, SGLT2 inhibitors exerted cardiovascular and kidney protective effects, which appeared to be partly independent of the original glucose-lowering effect. SGLT2 inhibitors have both direct and indirect renoprotective effects. The direct effects involve the suppression of hyperplasia/hypertrophy, inflammation, and fibrosis in the proximal tubular cells, utilization of ketone bodies, restored tubuloglomerular feedback, decreased oxygen consumption, improvement in anemia, and preconditioning against ischemia/reperfusion. The indirect effects involve a reduction in insulin levels and resistance, uric acid concentration, body weight, and blood pressure. However, safety concerns remain, including consequences of an enhanced glucose load in the lower nephron, leg amputation, bone fractures, and therapeutic efficacy in patients with advanced chronic kidney disease. PMID- 29491321 TI - Comparison of Peak-area Ratios and Percentage Peak Area Derived from HPLC evaporative Light Scattering and Refractive Index Detectors for Palm Oil and its Fractions. AB - High-Performance Liquid Chromatography (HPLC) methods via evaporative light scattering (ELS) and refractive index (RI) detectors are used by the local palm oil industry to monitor the TAG profiles of palm oil and its fractions. The quantitation method used is based on area normalization of the TAG components and expressed as percentage area. Although not frequently used, peak-area ratios based on TAG profiles are a possible qualitative method for characterizing the TAG of palm oil and its fractions. This paper aims to compare these two detectors in terms of peak-area ratio, percentage peak area composition, and TAG elution profiles. The triacylglycerol (TAG) composition for palm oil and its fractions were analysed under similar HPLC conditions i.e. mobile phase and column. However, different sample concentrations were used for the detectors while remaining within the linearity limits of the detectors. These concentrations also gave a good baseline resolved separation for all the TAGs components. The results of the ELSD method's percentage area composition for the TAGs of palm oil and its fractions differed from those of RID. This indicates an unequal response of TAGs for palm oil and its fractions using the ELSD, also affecting the peak area ratios. They were found not to be equivalent to those obtained using the HPLC RID. The ELSD method showed a better baseline separation for the TAGs components, with a more stable baseline as compared with the corresponding HPLC-RID. In conclusion, the percentage area compositions and peak-area ratios for palm oil and its fractions as derived from HPLC-ELSD and RID were not equivalent due to different responses of TAG components to the ELSD detector. The HPLC-RID has a better accuracy for percentage area composition and peak-area ratio because the TAG components response equally to the detector. PMID- 29491322 TI - An Improved Method for Determination of Cyanide Content in Bitter Almond Oil. AB - An improved colorimetric method for determination of cyanide content in bitter almond oil was developed. The optimal determination parameters were as follows: volume ratio of hydrochloric acid to bitter almond oil (v/v), 1.5:1; holding time for hydrolysis, 120 min; and volume ratio of distillation solution to bitter almond oil (v/v), 8:1. Analytical results showed that the relative standard deviations (SDs) of determinations were less than 10%, which satisfies the test requirements. The results of high-performance liquid chromatography and measurements exhibited a significant correlation (R = 0.9888, SD = 0.2015). Therefore, the improved colorimetric method can be used to determine cyanide content in bitter almond oil. PMID- 29491323 TI - Effect of Various Factors on Orange II Decoloration Reaction by Horseradish Peroxidase in the Presence of Detergent Enzymes. AB - The effects of four detergent enzymes on the Orange II decoloration reaction by horseradish peroxidase (HRP) were investigated. Stainzyme, Lipex, Celluclean, and Savinase did not affect the decoloration reaction up to a concentration of 0.1% Under weak alkaline to alkaline conditions, the presence of four enzymes did not affect the decoloration reaction, but affected the decoloration reaction under neutral to acidic conditions. The effect of Ca2+ and Mg2+ concentrations on Orange II decoloration reactions in the presence of four enzymes was also investigated. Ca2+ and Mg2+ did not affect the decoloration reaction up to 500 ppm. PMID- 29491320 TI - Impact of B-Type Natriuretic Peptide Level on Risk Stratification of Thromboembolism and Death in Patients With Nonvalvular Atrial Fibrillation - The Hokuriku-Plus AF Registry. AB - BACKGROUND: B-type natriuretic peptide (BNP) may be a predictor of stroke risk in patients with nonvalvular atrial fibrillation (NVAF); because heart failure is associated with the incidence of stroke in AF patients. However, limited data exist regarding the association between BNP at baseline and risks of thromboembolic events (TE) and death in NVAF patients. Methods and Results: We prospectively studied 1,013 NVAF patients (725 men, 72.8+/-9.7 years old) from the Hokuriku-plus AF Registry to determine the relationship between BNP at baseline and prognosis among Japanese NVAF patients. During the follow-up period (median, 751 days); 31 patients experienced TE and there were 81 cases of TE/all cause death. For each endpoint we constructed receiver-operating characteristic curves that gave cutoff points of BNP for TE (170 pg/mL) and TE/all-cause death (147 pg/mL). Multivariate analysis with the Cox-proportional hazards model indicated that high BNP was significantly associated with risks of TE (hazard ratio [HR] 3.86; 95% confidence interval [CI] 1.83-8.67; P=0.0003) and TE/all cause death (HR 2.27; 95% CI 1.45-3.56; P=0.0003). Based on the C-index and net reclassification improvement, the addition of BNP to CHA2DS2-VASc statistically improved the prediction of TE. CONCLUSIONS: In a real-world cohort of Japanese NVAF patients, high BNP was significantly associated with TE and death. Plasma BNP might be a useful biomarker for these adverse clinical events. PMID- 29491324 TI - Endogenous Adenosine May Be Related to Left Ventricular Dysfunction, Dilation, and Wall Thinning in Patients With Heart Disease. AB - BACKGROUND: The role of endogenous adenosine in cardiac patients is still unclear, so we investigated the relationship between the plasma adenosine concentration and left ventricular (LV) function, LV dilation and LV wall thinning in cardiac patients.Methods and Results:In 97 cardiac patients, with angina pectoris, old myocardial infarction, dilated or hypertrophic cardiomyopathy, and valvular heart disease, plasma adenosine concentrations were measured using the LC-MS/MS system, and the LV function, LV end-diastolic dimension (LVDd), LV posterior wall thickness (LVPWth), and interventricular septum thickness (IVSth) were assessed by echocardiography. The plasma adenosine concentration was significantly higher in patients with a LV ejection fraction (EF), an indicator of the LV systolic function, <47% compared with those with LVEF >=47% (P=0.027). There was no difference between the plasma adenosine concentration and E/e', an indicator of LV diastolic function. The plasma adenosine concentration was significantly higher in patients with LVDd >=50 mm than in those with LVDd <50 mm (P=0.030). The plasma adenosine concentration was inversely correlated with IVSth (P=0.003) and LVPWth (P=0.0007). The plasma adenosine concentration was significantly higher in patients with IVSth <8 mm than in those with IVSth >=8 mm (P=0.015), and was significantly higher in patients with LVPWth <8 mm than in those with LVPWth >=8 mm (P=0.020). CONCLUSIONS: Endogenous adenosine may be related to LV dysfunction, dilation, and wall thinning in cardiac patients. PMID- 29491325 TI - Protective Effects of Topiroxostat on an Ischemia-Reperfusion Model of Rat Hearts. AB - BACKGROUND: Ischemia/reperfusion (I/R) injury triggers cardiac dysfunctions via creating reactive oxygen species (ROS). Because xanthine oxidase (XO) is one of the major enzymes that generate ROS, inhibition of XO is expected to suppress ROS induced I/R injury. However, it remains unclear whether XO inhibition really yields cardioprotection during I/R. The protective effects of the XO inhibitors, topiroxostat and allopurinol, on cardiac I/R injury were evaluated.Methods and Results:Using isolated rat hearts, ventricular functions, occurrence of arrhythmias, XO activities and thiobarbituric acid reactive substances (TBARS) productions and myocardial levels of adenine nucleotides before and after I/R, and cardiomyocyte death markers during reperfusion, were evaluated. Topiroxostat prevented left ventricular dysfunctions and facilitated recovery from arrhythmias during I/R. Allopurinol and the antioxidant, N-acetylcysteine (NAC), exhibited similar effects at higher concentrations. Topiroxostat inhibited myocardial XO activities and TBARS productions after I/R. I/R decreased myocardial levels of ATP, ADP and AMP, but increased that of xanthine. While topiroxostat, allopurinol or NAC did not change myocardial levels of ATP, ADP or AMP after I/R, all of the agents decreased the level of xanthine. They also decreased releases of CPK and LDH during reperfusion. CONCLUSIONS: Topiroxostat showed protective effects against I/R injury with higher potency than allopurinol or NAC. It dramatically inhibited XO activity and TBARS production, suggesting suppression of ROS generation. PMID- 29491326 TI - Relationship Between Cotinine-Verified Smoking Status and Incidence of Hypertension in 74,743 Korean Adults. AB - BACKGROUND: The relationship between chronic smoking and hypertension (HTN) is inconclusive in previous studies, which were mainly based on self-reported smoking status. The aim of this study was to evaluate the association of cotinine verified smoking status with incident HTN.Methods and Results:A total of 74,743 participants (43,104 men; age 38+/-5.4 years) were included in the study, with a mean follow-up period of 29 months. Individuals were divided into 4 groups on the basis of their cotinine-verified smoking status at baseline and at follow-up (never-smoking, new-smoking, former-smoking, and sustained-smoking). The incidence rate of HTN in the never-smoking, new-smoking, former-smoking, and sustained-smoking groups was 8.2%, 7.6%, 10.1%, and 8.7% for men and 1.8%, 2.5%, 1.5%, and 2.2% for women, respectively. In a multivariate Cox-hazard regression analysis adjusted for the variables with a univariate relationship, new-smoking and sustained-smoking had decreased relative risks (RRs) for incident HTN compared with never-smoking (RR [95% CI], 0.75 [0.58, 0.96] for new-smoking and 0.82 [0.74, 0.90] for sustained-smoking). Cotinine-verified current smoking at baseline was also inversely associated with incident HTN compared with cotinine verified never-smoking at baseline (0.91 [0.84, 0.98]). These results remained significant only in men, although there was no sex interaction. CONCLUSIONS: This longitudinal study showed that cotinine-verified new-smoking and sustained smoking decreased the risk for incident HTN, especially in men, compared with never-smoking. PMID- 29491327 TI - Effects of Statin Intensity on Clinical Outcome in Acute Myocardial Infarction Patients. AB - BACKGROUND: There has been debate regarding the added benefit of high-intensity statins compared with low-moderate-intensity statins, especially in patients with acute myocardial infarction (AMI).Methods and Results:The Korea Acute Myocardial Infarction Registry-National Institutes of Health consecutively enrolled 13,104 AMI patients. Of these, a total of 12,182 patients, who completed 1-year follow up, were included in this study, and all patients were classified into 3 groups (no statin; low-moderate-intensity statin; and high-intensity statin). The primary outcome was major adverse cardiac event (MACE) including cardiac death, non-fatal MI, and repeat revascularization at 1 year. Both low-moderate-intensity and high-intensity statin significantly reduced low-density lipoprotein cholesterol (LDL-C; all P<0.001). Compared with the no statin group, both statin groups had significantly lower risk of MACE (low-moderate intensity: HR, 0.506; 95% CI: 0.413-0.619, P<0.001; high intensity: HR, 0.464; 95% CI: 0.352-0.611, P<0.001). The risk of MACE, however, was similar between the low-moderate- and high-intensity statin groups (HR, 0.917; 95% CI: 0.760-1.107, P=0.368). Multivariable adjustment, propensity score matching, and inverse probability weighted analysis also produced the same results. CONCLUSIONS: When adequate LDL C level is achieved, patients on a low-moderate-intensity statin dose have similar cardiovascular outcomes to those on high-intensity statins. PMID- 29491329 TI - [An early history of Japanese amyotrophic lateral sclerosis (ALS)-related diseases and the current development]. AB - The present review focuses an early history of Japanese amyotrophic lateral sclerosis (ALS)-related diseases and the current development. In relation to foreign previous reports, five topics are introduced and discussed on ALS with dementia, ALS/Parkinsonism dementia complex (ALS/PDC), familial ALS (FALS), spinal bulbar muscular atrophy (SBMA), and multisystem involvement especially in cerebellar system of ALS including ALS/SCA (spinocerebellar ataxia) crossroad mutation Asidan. This review found the great contribution of Japanese reports on the above five topics, and confirmed the great development of ALS-related diseases over the past 120 years. PMID- 29491328 TI - [Improvement of human T-lymphotropic virus type 1 associated demyelinating neuropathy with corticosteroid therapy]. AB - The patient was a 58-year-old man, who was hospitalized with progressive bilateral leg weakness, and sensory impairment in all four extremities. Chronic inflammatory demyelinating polyneuropathy (CIDP) was suspected based on an electrophysiological examination, and intravenous immunoglobulin therapy (IVIg) was initiated. However, his symptoms progressed. The serum and cerebrospinal fluid were positive for human T-lymphotropic virus type 1 (HTLV-1) antibodies; hence the patient was diagnosed as having HTLV-1 associated neuropathy. After administration of corticosteroid, muscle strength markedly improved. Thus, our findings suggest that rather than IVIg, corticosteroid therapy is recommended for the treatment of CIDP like neuropathy in HTLV-1 infected patients. PMID- 29491330 TI - [Paradoxical embolism due to right superior vena cava draining into the left atrium]. AB - We report a forty-six-year-old man with a past history of brain abscess managed by surgical drainage and recurrent ischemic strokes. After treatment of brain abscess, he had been on medication for symptomatic epilepsy, but had ceased medication by his judgment. He was taken to a hospital in an ambulance for an epileptic seizure. In the hospital he suffered from drug-induced renal dysfunction caused by the intravenous anti-epileptic drug, and right hemiparesis due to ischemic stroke occurred on the third hospitalization day. He was transferred to our hospital to get a treatment for renal failure. His renal function improved gradually by hemodialysis, but an ischemic stroke recurred in the right cerebellar hemisphere. Closer examinations on the mechanisms of his strokes revealed the draining of right superior vena cava (RSVC) directly into the left atrium (LA), persistent left superior vena cava (PLSVC) and atrial septal defect (ASD). He had a rare anomaly of the systemic venous return. It seemed that his repeated strokes were caused by paradoxical embolism through the draining of RSVC to LA, and air or thrombi in the infusion lines other than intravenous thrombi was thought to be an embolic cause in this case. PMID- 29491331 TI - [A case of short-lasting unilateral neuralgiform headache with conjunctival injection and tearing triggered by mumps meningitis in a patient with recurrent primary stabbing headache]. AB - A 32-year-old man with a 16-year history of recurrent primary stabbing headache was admitted to our hospital, owing to mumps meningitis. On day 2 of admission, he began experiencing episodes of unbearable intermittent stabbing pain, each lasting few seconds, with conjunctival injection and tearing, on the temporal side of the left orbit. We suspected trigeminal autonomic cephalgias, and administered non-steroidal anti-inflammatory drugs (NSAIDs), oxygen, and sumatriptan; however, the pain episodes persisted. Subsequently, after the start of intravenous lidocaine administration, the pain episodes stopped. We diagnosed a short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), triggered by mumps meningitis. This is a valuable case report, involving a patient with a history of primary stabbing headache who was diagnosed with SUNCT triggered by mumps meningitis. PMID- 29491332 TI - [A case of Alexander disease with dropped head syndrome]. AB - A 51-year-old woman presented with progressive weakness of the neck extensor muscles and gait disturbances since the past 6 years. In addition, she presented with symptoms such as dysarthria, dysphagia, bladder, and rectal disturbances. Bilateral plantar reflex was positive. Her gait was short-stepped-spastic. Brain and cervical MRI showed atrophy of the medulla and spinal cord. As these imaging features were suggestive of Alexander disease (AxD), we sequenced the GFAP gene. We identified a heterozygous c.368T>C missense mutation of the GFAP gene in the patient. This was the first case of the mutation in Japanese patients, and subsequently, she was diagnosed with AxD type 2. There are a few studies which reported that patients with AxD complained of dropped head syndrome. Dropped head syndrome can be the initial manifestation of AxD. PMID- 29491333 TI - [Cerebral infarction related to varicella zoster virus vasculopathy]. AB - A 14-year-old girl developed transient disturbance of consciousness, dysarthria, and clumsiness of the right upper limb 4 months after herpes zoster ophthalmicus. Brain MRI showed acute cerebral infarction in the left middle cerebral artery (MCA) territory. CT angiography demonstrated mild stenosis in the top of the left internal carotid artery and the proximal side of the MCA. Cerebrospinal fluid (CSF) examination showed slightly mononuclear pleocytosis (6/MUl). Titer of the anti-varicella zoster virus (VZV) IgG antibodies in CSF was increased, and gadolinium-enhanced brain MRI (T1-weighted imaging) revealed enhancement of the vessel walls at the stenotic lesions. Based on the diagnosis of VZV vasculopathy, methylprednisolone and valacicrovir were administered, followed by acyclovir, in addition to antithrombotic therapy using aspirin and warfarin. After these treatment, her right upper clumsiness was resolved and gadolinium-enhancement of the vessel walls was disappeared on MRI. VZV vasculopathy may cause ischemic stroke in young patients, especially in children. A careful history-taking about herpes is necessary to detect the disease as a potential cause in young stroke patients. PMID- 29491334 TI - [Triptan-responsive migraine-like headache caused by cavernous sinus dural arteriovenous fistula in a 69-year-old woman with a history of migraine without aura]. AB - A 69-year-old woman with a previous history of migraine without aura developed throbbing headache in the right frontal region accompanied by nausea, lasting more than 4 hours a day. The headache intensity was more severe than that of usual her migraine headaches. Administration of eletriptan in the previous hospital improved her headaches. However, one month later the patient experienced more intense headaches in the same region and then was referred to our hospital. MR angiography showed abnormal signal intensities in the cavernous sinus. Cerebral angiography revealed blood reflux to the cavernous sinus, leading to diagnosis of cavernous sinus dural arteriovenous fistula. Transvenous embolization of cavernous sinus dural arteriovenous fistula was performed, which resulted in resolution of the patient's headache. We should be aware that patients with cavernous sinus dural arteriovenous fistula can manifest migraine like headaches without being accompanied by cranial nerve palsies. PMID- 29491335 TI - [Cerebrospinal fluid leakage and abducens nerve palsy caused by bowling activity]. AB - Cerebrospinal fluid leakage can develop due to traffic trauma or lumbar puncture; however, in many cases, it develops spontaneously without any obvious cause. This report describes a case of cerebrospinal fluid leakage caused by bowling activity. A 57-year-old woman adjusted her bowling form, which led to the development of an orthostatic headache and double vision. Cerebrospinal fluid leakage and right abducens nerve palsy was diagnosed, which was resistant to conservative treatment. An epidural blood patch was performed, leading to an improvement in the headache and abducens nerve palsy. The hypotension and nerve palsy may have been caused by small amounts of cerebrospinal fluid leakage due to repeated traction of the brachial plexus and nerve root resulting from an irregular bowling form. To the best of our knowledge, there are no reported cases of cerebrospinal fluid leakage caused by bowling; therefore, this is a valuable case to investigate the mechanism of onset. Similar mechanisms may have remained undiscovered in other cases of spontaneous intracranial hypotension. PMID- 29491336 TI - [Dropped head syndrome as first manifestation of primary hyperparathyroid myopathy]. AB - 75 years old woman presented with 6-month history of progressive dropped head syndrome. Neurological examination revealed moderate weakness of flexor and extensor of neck and mild weakness of proximal appendicular muscles with normal deep tendon reflexes. The needle electromyography showed short duration and low amplitude motor unit potential. No fibrillation potentials or positive sharp waves were seen. Biopsy of deltoid muscle was normal. Laboratory studies showed elevated levels of serum calcium (11.8 mg/dl, upper limit of normal 10.1) and intact parathyroid hormone (104 pg/ml, upper limit of normal 65), and decreased level of serum phosphorus (2.3 mg/dl, lower limit of normal 2.7). Ultrasonography and enhanced computed tomography revealed a parathyroid tumor. The tumor was removed surgically. Pathological examination proved tumor to be parathyroid adenoma. Dropped head and weakness of muscles were dramatically improved within a week after the operation. Although hyperparathyroidism is a rare cause of dropped head syndrome, neurologists must recognize hyperparathyroidism as a treatable cause of dropped head syndrome. PMID- 29491337 TI - [Ultrastructural Patterns of Interactions between Murine Lung Macrophages and Yeast Cells of Cryptococcus neoformans Strains with Different Virulence]. AB - This article presents the ultrastructural patterns of interactions between the murine lung macrophages and cells of low- (RKPGY-881, -1165, -1178) and high virulence (RKPGY-1090, -1095, -1106) strains of Cryptococcus neoformans at the seventh post-experimental day. It was found that if macrophages ingest living yeast cells, the latter can: 1) become completely free from polysaccharide capsules, after that their contents undergo lysis, and cell wall debris are extruded from the macrophage (first scenario); 2) become partly free from their capsules, destroy the phagosomal plasma membrane and induce destructive processes inside the macrophage causing their death (second scenario); or 3) not lose their capsules and localize inside macrophage in latent state (third scenario). Macrophages can also ingest senescent and dead C. neoformans cells surrounded by capsules that are lost at the ingesting and phagosome stages (fourth scenario). The study revealed the dependence of cell-mediated immunity on the stage of development of ingested C. neoformans yeast cells. Here we describe a new mechanism of capsular polysaccharide elimination of C. neoformans yeast cells by murine macrophages. PMID- 29491338 TI - [National Trends in the Distribution of Candida Species Causing Candidemia in Japan from 2003 to 2014]. AB - The Epidemiological Investigation Committee for Human Mycoses in Japan performed a retrospective epidemiological survey of candidemia and causative Candida species. Data from 2003 to 2014 were collected from 10 Japanese university hospitals. A total of 328,318 blood cultures were included. The prevalence of fungi in all cultures and in positive cultures were 0.58+/-0.09% and 4.46+/ 0.66%, respectively. Among the results that were positive for Candida species (N=1,921), Candida albicans was the most common species (39.5%) and was followed by Candida parapsilosis (23.3%), Candida glabrata (13.2%), Candida tropicalis (7.1%), Candida krusei (3.2%), and others (13.7%). During the last 6 years, the frequency of C. albicans has significantly decreased in Japan, while that of C. glabrata has increased. Additional surveys are needed to continuously monitor the trends in the distribution of candidemia. PMID- 29491340 TI - [Inquiry about the Dermatopyte Test Strip]. PMID- 29491341 TI - [Erratum]. PMID- 29491339 TI - [Histopathological Diagnosis of Invasive Fungal Infections in Formalin-Fixed and Paraffin-Embedded Tissues in Conjunction with Molecular Methods]. AB - The main objective of this study was to evaluate the relationship between histopathology, polymerase chain reaction (PCR), and in situ hybridization (ISH) for the identification of causative fungi in formalin-fixed and paraffin-embedded (FFPE) tissue specimens. Since pathogenic fungi in tissue specimens can be difficult to identify morphologically, PCR and ISH have been usually employed as auxiliary procedures. However, little comparison has been made on the sensitivity and specificity of PCR and ISH using FFPE specimens. Therefore, to compare and clarify the reproducibility and usefulness of PCR and ISH as auxiliary procedures for histological identification, we performed histopathological review, PCR assays, and ISH to identify pathogenic fungi in 59 FFPE tissue specimens obtained from 49 autopsies. The following are the main findings for this retrospective review: i) even for cases classified as "mold not otherwise specified" (MNOS), two cases could be identified as Aspergillus species by molecular methods; ii) all cases classified as non-zygomycetes mold (NZM) were Aspergillus species and were not identified by molecular methods as other fungi; iii) all 3 cases classified as zygomycetes mold (ZM) could be identified by molecular methods as Mucorales; iv) except for 1 case identified by molecular methods as Trichosporon spp., 5 cases were originally identified as dimorphic yeast (DY). As a measure of nucleic acid integrity, PCR and ISH successfully detected human and fungal nucleic acids in approximately 60% of the specimens. Detection of Aspergillus DNA by nested PCR assay and by ISH against the A. fumigatus ALP gene were similarly sensitive and significant (p<0.01). Thus, our findings demonstrated the potential risk of error in the classification of fungi based on pathological diagnosis. Combining molecular methods such as ISH and PCR on FFPE specimens with pathological diagnosis should improve diagnostic accuracy of fungal infection. PMID- 29491343 TI - [Term 17]. PMID- 29491342 TI - [Reply to Comments on My Article]. PMID- 29491344 TI - Intracardiac Abscess and Pacemaker Lead Infection Secondary to Hematogenous Dissemination of Methicillin-Sensitive Staphylococcus Aureus from a Prior Diabetic Foot Ulcer and Osteomyelitis. AB - BACKGROUND Intracardiac abscesses are an unusual occurrence in developed countries. With the increase in use of implantable cardiac devices, the increase use of and advancements in antibiotics, and the longevity of patients with cardiac devices, one may expect an increase in such infections; however, case reports are rare. We are presenting a case in which hematogenous dissemination of methicillin-sensitive Staphylococcus aureus (MSSA) infection from a lower extremity diabetic ulcer propagated into an infected pacemaker lead and ultimately an intracardiac abscess of the right atrium. CASE REPORT A 77-year-old male with a history of MSSA diabetic foot infection complicated by osteomyelitis presented with fever, syncope, and wide complex tachycardia, and he was found to have an intracardiac abscess and fibrinous lead vegetations. The patient was deemed too ill for invasive surgical intervention given his comorbidities, pacemaker generator replacement requirement, and intermittent ventricular tachycardia. The patient was subsequently sent home with oral antibiotics and home hospice per patient and family wishes. CONCLUSIONS This case demonstrated how hematogenous dissemination of MSSA infections from a diabetic foot ulcer and osteomyelitis can seed pacemaker hardware resulting in an intracardiac abscess. Unfortunately, our patient was too ill to undergo all procedures required to eradicate the abscess and infected pacemaker hardware. The standard of care would be complete hardware removal. Conservative management would include indefinite or prolonged antibiotic therapy, with the notion that intracardiac abscesses cannot be cured with antibiotics alone. This conservative management approach would be deemed necessary in a select population that cannot undergo surgical intervention. PMID- 29491345 TI - Glutamine Enhances the Hypoglycemic Effect of Insulin in L6 Cells via Phosphatidylinositol-3-Kinase (PI3K)/Protein Kinase B (AKT)/Glucose Transporter 4 (GLUT4) Signaling Pathway. AB - BACKGROUND Diabetes mellitus (DM) is characterized by a decreased blood level of glutamine (Gln), which may contribute to the disturbance in the effect of insulin on skeletal muscle. Therefore, it is crucial to study how to improve the effect of insulin on skeletal muscle by increasing Gln. In the present study, we investigated the effect of Gln on the hypoglycemic action of insulin in skeletal muscle L6 cells at high glucose levels through the insulin signaling pathway and glycogen synthesis pathway. MATERIAL AND METHODS The L6 cells were cultured in and stimulated by Gln and insulin. The glutamine analogue, L-Gamma-Glutamyl-p nitroanilide (GPNA), was used for verifying the effect of Gln. The expression of insulin signaling molecules, including phosphatidylinositol-3-kinase (PI3K), 3 phosphoinositide-dependent protein kinase-1 (PDK1), protein kinase B (AKT), protein kinase C zeta (PKCz), and glucose transporter 4 (GLUT4), were detected by real-time PCR and Western blot analysis, GLUT4 translocation was observed by immunofluorescence staining, glycogen synthase kinase (GSK) was analyzed by Western blotting, and glucose uptake was measured by glucose oxidase method (GOD). RESULTS The results demonstrated that Gln combined with insulin remarkably up-regulated PI3K and PDK1 and also increased AKT and PKCz phosphorylation. The present study shows that Gln enhanced the impact of insulin on GLUT4 and its translocation. The results of glucose uptake and GSK phosphorylation further confirmed the hypoglycemic effect of Gln accompanied with insulin. The hypoglycemic effect of Gln was reversed by GPNA. CONCLUSIONS These findings suggest that Gln enhances the hypoglycemic role of insulin through the PI3K/AKT/GLUT4 signaling pathway and glycogen synthesis pathway. PMID- 29491346 TI - Implication of liver enzymes on incident cardiovascular diseases and mortality: A nationwide population-based cohort study. AB - Although liver enzymes, such as gamma-glutamyltransferase (GGT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), have recently been suggested as risk factors for cardiovascular diseases (CVD), impact on mortality after myocardial infarction (MI) or ischemic stroke (IS) was not previously examined. Using a population-based, nationwide cohort database, we explored the implication of GGT and aminotransferases on the development of CVD and all-cause mortality during a median 9.1 years of follow-up. Among 16,624,006 Korean adults, both GGT and aminotransferases exhibited a positive relationship with MI, IS, and mortality in a multivariate adjusted model. ALT and AST showed U-shaped associations with mortality, whereas GGT showed a positive linear relationship with mortality. The risk of 1-year mortality after MI or IS was significantly higher in the highest quartile of GGT compared to the lowest quartile (HR, 1.46; 95% CI, 1.40-1.52). The implication of GGT on MI, IS, and mortality persisted regardless of traditional cardiovascular risk parameters. This study demonstrated the unique pattern of association of ALT, AST, and GGT with the development of CVD and all-cause mortality in the Korean population. In particular, GGT showed the most robust linear relationship with mortality before and after cardiovascular events independent of risk factors. PMID- 29491347 TI - Author Correction: Low frequency transcranial electrical stimulation does not entrain sleep rhythms measured by human intracranial recordings. AB - It has come to our attention that we did not specify whether the stimulation magnitudes we report in this Article are peak amplitudes or peak-to-peak. All references to intensity given in mA in the manuscript refer to peak-to-peak amplitudes, except in Fig. 2, where the model is calibrated to 1 mA peak amplitude, as stated. In the original version of the paper we incorrectly calibrated the computational models to 1 mA peak-to-peak, rather than 1 mA peak amplitude. This means that we divided by a value twice as large as we should have. The correct estimated fields are therefore twice as large as shown in the original Fig. 2 and Supplementary Figure 11. The corrected figures are now properly calibrated to 1 mA peak amplitude. Furthermore, the sentence in the first paragraph of the Results section 'Intensity ranged from 0.5 to 2.5 mA (current density 0.125-0.625 mA mA/cm2), which is stronger than in previous reports', should have read 'Intensity ranged from 0.5 to 2.5 mA peak to peak (peak current density 0.0625-0.3125 mA/cm2), which is stronger than in previous reports.' These errors do not affect any of the Article's conclusions. PMID- 29491348 TI - Molecular Dynamics Simulation of Water Confinement in Disordered Aluminosilicate Subnanopores. AB - The porous structure and mass transport characteristics of disordered silicate porous media were investigated via a geometry based analysis of water confined in the pores. Disordered silicate porous media were constructed to mimic the dissolution behavior of an alkali aluminoborosilicate glass, i.e., soluble Na and B were removed from the bulk glass, and then water molecules and Na were introduced into the pores to provide a complex porous structure filled with water. This modelling approach revealed large surface areas of disordered porous media. In addition, a number of isolated water molecules were observed in the pores, despite accessible porous connectivity. As the fraction of mobile water was approximately 1%, the main water dynamics corresponded to vibrational motion in a confined space. This significantly reduced water mobility was due to strong hydrogen-bonding water-surface interactions resulting from the large surface area. This original approach provides a method for predicting the porous structure and water transport characteristics of disordered silicate porous media. PMID- 29491349 TI - The circadian regulator BMAL1 programmes responses to parasitic worm infection via a dendritic cell clock. AB - Resistance to the intestinal parasitic helminth Trichuris muris requires T-helper 2 (TH2) cellular and associated IgG1 responses, with expulsion typically taking up to 4 weeks in mice. Here, we show that the time-of-day of the initial infection affects efficiency of worm expulsion, with strong TH2 bias and early expulsion in morning-infected mice. Conversely, mice infected at the start of the night show delayed resistance to infection, and this is associated with feeding driven metabolic cues, such that feeding restriction to the day-time in normally nocturnal-feeding mice disrupts parasitic expulsion kinetics. We deleted the circadian regulator BMAL1 in antigen-presenting dendritic cells (DCs) in vivo and found a loss of time-of-day dependency of helminth expulsion. RNAseq analyses revealed that IL-12 responses to worm antigen by circadian-synchronised DCs were dependent on BMAL1. Therefore, we find that circadian machinery in DCs contributes to the TH1/TH2 balance, and that environmental, or genetic perturbation of the DC clock results in altered parasite expulsion kinetics. PMID- 29491350 TI - Egr2-dependent microRNA-138 is dispensable for peripheral nerve myelination. AB - Recent studies have elucidated the crucial role for microRNAs in peripheral nerve myelination by ablating components of the microRNA synthesis machinery. Few studies have focused on the role of individual microRNAs. To fill this gap, we focused this study on miR-138, which was shown to be drastically reduced in Dicer1 and Dgcr8 knockout mice with hypomyelinating phenotypes and to potentially target the negative regulators of Schwann cell differentiation. Here, we show that of two miR-138 encoding loci, mir-138-1 is the predominant locus transcribed in Schwann cells. mir-138-1 is transcriptionally upregulated during myelination and downregulated upon nerve injury. EGR2 is required for mir-138-1 transcription during development, and both SOX10 and EGR2 bind to an active enhancer near the mir-138-1 locus. Based on expression analyses, we hypothesized that miR-138 facilitates the transition between undifferentiated Schwann cells and myelinating Schwann cells. However, in conditional knockouts, we could not detect significant changes in Schwann cell proliferation, cell cycle exit, or myelination. Overall, our results demonstrate that miR-138 is an Egr2-dependent microRNA but is dispensable for Schwann cell myelination. PMID- 29491351 TI - Expanding biological space coverage enhances the prediction of drug adverse effects in human using in vitro activity profiles. AB - In vitro assay data have recently emerged as a potential alternative to traditional animal toxicity studies to aid in the prediction of adverse effects of chemicals on humans. Here we evaluate the data generated from a battery of quantitative high-throughput screening (qHTS) assays applied to a large and diverse collection of chemicals, including approved drugs, for their capacity in predicting human toxicity. Models were built with animal in vivo toxicity data, in vitro human cell-based assay data, as well as in combination with chemical structure and/or drug-target information to predict adverse effects observed for drugs in humans. Interestingly, we found that the models built with the human cell-based assay data performed close to those of the models based on animal in vivo toxicity data. Furthermore, expanding the biological space coverage of assays by including additional drug-target annotations was shown to significantly improve model performance. We identified a small set of targets, which, when added to the current suite of in vitro human cell-based assay data, result in models that greatly outperform those built with the existing animal toxicity data. Assays can be developed for this set of targets to screen compounds for construction of robust models for human toxicity prediction. PMID- 29491352 TI - Pathways of cellular internalisation of liposomes delivered siRNA and effects on siRNA engagement with target mRNA and silencing in cancer cells. AB - Design of an efficient delivery system is a generally recognised bottleneck in translation of siRNA technology into clinic. Despite research efforts, cellular processes that determine efficiency of siRNA silencing achieved by different delivery formulations remain unclear. Here, we investigated the mechanism(s) of cellular internalisation of a model siRNA-loaded liposome system in a correlation to the engagement of delivered siRNA with its target and consequent silencing by adopting siRNA molecular beacon technology. Probing of cellular internalisation pathways by a panel of pharmacological inhibitors indicated that clathrin mediated (dynamin-dependent) endocytosis, macropinocytosis (dynamine independent), and cell membrane cholesterol dependent process(es) (clathrin and caveolea-independent) all play a role in the siRNA-liposomes internalization. The inhibition of either of these entry routes was, in general, mirrored by a reduction in the level of siRNA engagement with its target mRNA, as well as in a reduction of the target gene silencing. A dramatic increase in siRNA engagement with its target RNA was observed on disruption of endosomal membrane (by chloroquine), accompanied with an increased silencing. The work thus illustrates that employing molecular beacon siRNA technology one can start to assess the target RNA engagement - a stage between initial cellular internalization and final gene silencing of siRNA delivery systems. PMID- 29491353 TI - Prevalence of hyperlipidemia in Shanxi Province, China and application of Bayesian networks to analyse its related factors. AB - This study aimed to obtain the prevalence of hyperlipidemia and its related factors in Shanxi Province, China using multivariate logistic regression analysis and tabu search-based Bayesian networks (BNs). A multi-stage stratified random sampling method was adopted to obtain samples among the general population aged 18 years or above. The prevalence of hyperlipidemia in Shanxi Province was 42.6%. Multivariate logistic regression analysis indicated that gender, age, region, occupation, vegetable intake level, physical activity, body mass index, central obesity, hypertension, and diabetes mellitus are associated with hyperlipidemia. BNs were used to find connections between those related factors and hyperlipidemia, which were established by a complex network structure. The results showed that BNs can not only be used to find out the correlative factors of hyperlipidemia but also to analyse how these factors affect hyperlipidemia and their interrelationships, which is consistent with practical theory, is superior to logistic regression and has better application prospects. PMID- 29491354 TI - Biodegradation of 17beta-estradiol by Bacterial Co-culture Isolated from Manure. AB - Animal wastes are potential sources of natural and steroidal estrogen hormones into the environment. These hormones can be removed by microorganisms with induced enzymes. Two strains of 17beta-estradiol-degrading bacteria (LM1 and LY1) were isolated from animal wastes. Based on biochemical characteristics and 16 S rDNA gene sequences, we identified strains LM1 and LY1 as belonging to the genus of Acinetobacter and Pseudomonas, respectively. Bacterial co-culture containing LM1 and LY1 bacterial strains could rapidly remove approximately 98% of E2 (5 mg L-1) within 7 days. However, strains LM1 and LY1 degraded 77% and 68% of E2 when they were incubated alone, respectively. More than 90% of 17beta-estradiol (E2, <= 20 mg L-1) could be removed by bacterial co-culture. Low C/N ratio (1:35) was more suitable for bacterial growth and E2 degradation. The optimal pH for bacterial co-culture to degrade E2 ranged from 7.00 to 9.00. Coexisting sodium acetate, glucose and sodium citrate decreased E2 degradation in the first 4 days, but more E2 was removed when they were depleted. The growth of the bacterial co culture was not significantly decreased by Ni, Pb, Cd or Cu at or below 0.8, 1.2, 1.6 or 0.8 mg L-1, respectively. These data highlight the usefulness of bacterial co-culture in the bioremediation of estrogen-contaminated environments. PMID- 29491356 TI - Experimental demonstration of conformal phased array antenna via transformation optics. AB - Transformation Optics has been proven a versatile technique for designing novel electromagnetic devices and it has much wider applicability in many subject areas related to general wave equations. Among them, quasi-conformal transformation optics (QCTO) can be applied to minimize anisotropy of transformed media and has opened up the possibility to the design of broadband antennas with arbitrary geometries. In this work, a wide-angle scanning conformal phased array based on all-dielectric QCTO lens is designed and experimentally demonstrated. Excited by the same current distribution as such in a conventional planar array, the conformal system in presence of QCTO lens can preserve the same radiation characteristics of a planar array with wide-angle beam-scanning and low side lobe level (SLL). Laplace's equation subject to Dirichlet-Neumann boundary conditions is adopted to construct the mapping between the virtual and physical spaces. The isotropic lens with graded refractive index is realized by all-dielectric holey structure after an effective parameter approximation. The measurements of the fabricated system agree well with the simulated results, which demonstrate its excellent wide-angle beam scanning performance. Such demonstration paves the way to a robust but efficient array synthesis, as well as multi-beam and beam forming realization of conformal arrays via transformation optics. PMID- 29491355 TI - Mitofusin 2: from functions to disease. AB - Mitochondria are highly dynamic organelles whose functions are essential for cell viability. Within the cell, the mitochondrial network is continuously remodeled through the balance between fusion and fission events. Moreover, it dynamically contacts other organelles, particularly the endoplasmic reticulum, with which it enterprises an important functional relationship able to modulate several cellular pathways. Being mitochondria key bioenergetics organelles, they have to be transported to all the specific high-energy demanding sites within the cell and, when damaged, they have to be efficiently removed. Among other proteins, Mitofusin 2 represents a key player in all these mitochondrial activities (fusion, trafficking, turnover, contacts with other organelles), the balance of which results in the appropriate mitochondrial shape, function, and distribution within the cell. Here we review the structural and functional properties of Mitofusin 2, highlighting its crucial role in several cell pathways, as well as in the pathogenesis of neurodegenerative diseases, metabolic disorders, cardiomyopathies, and cancer. PMID- 29491357 TI - Ectomesenchymal chondromyxoid tumor: a comprehensive updated review of the literature and case report. AB - Prompted by a unique case of an ectomesenchymal chondromyxoid tumor (ECT) of the palate in a 54-year-old female, we reviewed the English and German literature on this entity until the end of 2016 using PubMed. The search produced 74 lingual cases with a nearly equal sex distribution and a mean age of 39.3 years, and two extra-lingual cases sharing histological and immunohistological features including nodular growth, round, fusiform or spindle-shaped cellular architecture, and chondromyxoid stroma. Immunophenotyping showed the majority of cases to be positive for glial fibrillary acidic protein (GFAP), S-100 protein, glycoprotein CD57, pancytokeratin (AE1/AE3), and smooth muscle actin (SMA); in isolated cases there was molecular-genetic rearrangement or gain of Ewing sarcoma breakpoint region 1 (EWSR1) but no rearrangement of pleomorphic adenoma gene 1 (PLAG1). At present, ectomesenchymal cells that migrate from the neural crest are considered to play a pivotal role in tumor origin. All cases had a benign course, although there were three recurrences. Because of the rarity of this tumor and the need for differential diagnostic differentiation from myoepithelioma and pleomorphic adenoma, both oral surgeons and pathologists should be aware of this entity. PMID- 29491358 TI - To respond or not to respond - a personal perspective of intestinal tolerance. AB - For many years, the intestine was one of the poor relations of the immunology world, being a realm inhabited mostly by specialists and those interested in unusual phenomena. However, this has changed dramatically in recent years with the realization of how important the microbiota is in shaping immune function throughout the body, and almost every major immunology institution now includes the intestine as an area of interest. One of the most important aspects of the intestinal immune system is how it discriminates carefully between harmless and harmful antigens, in particular, its ability to generate active tolerance to materials such as commensal bacteria and food proteins. This phenomenon has been recognized for more than 100 years, and it is essential for preventing inflammatory disease in the intestine, but its basis remains enigmatic. Here, I discuss the progress that has been made in understanding oral tolerance during my 40 years in the field and highlight the topics that will be the focus of future research. PMID- 29491359 TI - Depression: Bursting with depression. PMID- 29491360 TI - Genetic tagging of active neurons in auditory cortex reveals maternal plasticity of coding ultrasonic vocalizations. AB - Cortical neurons are often functionally heterogeneous even for molecularly defined subtypes. In sensory cortices, physiological responses to natural stimuli can be sparse and vary widely even for neighboring neurons. It is thus difficult to parse out circuits that encode specific stimuli for further experimentation. Here, we report the development of a Cre-reporter mouse that allows recombination for cellular labeling and genetic manipulation, and use it with an activity dependent Fos-CreERT2 driver to identify functionally active circuits in the auditory cortex. In vivo targeted patch recordings validate our method for neurons responding to physiologically relevant natural sounds such as pup wriggling calls and ultrasonic vocalizations (USVs). Using this system to investigate cortical responses in postpartum mothers, we find a transient recruitment of neurons highly responsive to USVs. This subpopulation of neurons has distinct physiological properties that improve the coding efficiency for pup USV calls, implicating it as a unique signature in parental plasticity. PMID- 29491361 TI - Aggregating sequences that occur in many proteins constitute weak spots of bacterial proteostasis. AB - Aggregation is a sequence-specific process, nucleated by short aggregation-prone regions (APRs) that can be exploited to induce aggregation of proteins containing the same APR. Here, we find that most APRs are unique within a proteome, but that a small minority of APRs occur in many proteins. When aggregation is nucleated in bacteria by such frequently occurring APRs, it leads to massive and lethal inclusion body formation containing a large number of proteins. Buildup of bacterial resistance against these peptides is slow. In addition, the approach is effective against drug-resistant clinical isolates of Escherichia coli and Acinetobacter baumannii, reducing bacterial load in a murine bladder infection model. Our results indicate that redundant APRs are weak points of bacterial protein homeostasis and that targeting these may be an attractive antibacterial strategy. PMID- 29491362 TI - A quantum light-emitting diode for the standard telecom window around 1,550 nm. AB - Single photons and entangled photon pairs are a key resource of many quantum secure communication and quantum computation protocols, and non-Poissonian sources emitting in the low-loss wavelength region around 1,550 nm are essential for the development of fibre-based quantum network infrastructure. However, reaching this wavelength window has been challenging for semiconductor-based quantum light sources. Here we show that quantum dot devices based on indium phosphide are capable of electrically injected single photon emission in this wavelength region. Using the biexciton cascade mechanism, they also produce entangled photons with a fidelity of 87 +/- 4%, sufficient for the application of one-way error correction protocols. The material system further allows for entangled photon generation up to an operating temperature of 93 K. Our quantum photon source can be directly integrated with existing long distance quantum communication and cryptography systems, and provides a promising material platform for developing future quantum network hardware. PMID- 29491363 TI - Quantitative account of social interactions in a mental health care ecosystem: cooperation, trust and collective action. AB - Mental disorders have an enormous impact in our society, both in personal terms and in the economic costs associated with their treatment. In order to scale up services and bring down costs, administrations are starting to promote social interactions as key to care provision. We analyze quantitatively the importance of communities for effective mental health care, considering all community members involved. By means of citizen science practices, we have designed a suite of games that allow to probe into different behavioral traits of the role groups of the ecosystem. The evidence reinforces the idea of community social capital, with caregivers and professionals playing a leading role. Yet, the cost of collective action is mainly supported by individuals with a mental condition - which unveils their vulnerability. The results are in general agreement with previous findings but, since we broaden the perspective of previous studies, we are also able to find marked differences in the social behavior of certain groups of mental disorders. We finally point to the conditions under which cooperation among members of the ecosystem is better sustained, suggesting how virtuous cycles of inclusion and participation can be promoted in a 'care in the community' framework. PMID- 29491364 TI - Psychogenic itch. AB - Psychogenic itch can be defined as "an itch disorder where itch is at the center of the symptomatology and where psychological factors play an evident role in the triggering, intensity, aggravation, or persistence of the pruritus." The disorder is poorly known by both psychiatrists and dermatologists and this review summarizes data on psychogenic itch. Because differential diagnosis is difficult, the frequency is poorly known. The burden is huge for people suffering from this disorder but a management associating psychological and pharmacological approach could be very helpful. Classification, psychopathology, and physiopathology are still debating. New data from brain imaging could be very helpful. Psychological factors are known to modulate itch in all patients, but there is a specific diagnosis of psychogenic itch that must be proposed cautiously. Neurophysiological and psychological theories are not mutually exclusive and can be used to better understand this disorder. Itch can be mentally induced. Opioids and other neurotransmitters, such as acetylcholine and dopamine, are probably involved in this phenomenon. PMID- 29491365 TI - Comprehensive Review of Genetic Association Studies and Meta-Analysis on polymorphisms in microRNAs and Urological Neoplasms Risk. AB - Gene expression is negatively regulated by microRNAs (miRNAs), which commonly act as tumor oncogenes or suppressors. Previous results were inconsistent concerning the relationship between polymorphisms in miRNAs and risk of urological neoplasms. Here, we conducted a comprehensive literature research on diverse databases aiming at enrolling all eligible studies up to August 31, 2016. A total of 13 publications comprising 29 case-control studies were enrolled for three polymorphisms in three miRNAs. Overall analyses suggested significant associations between miR-146a rs2910164 polymorphism and urological neoplasms risk in allelic, homozygote and recessive models. In the stratified analysis by ethnicity, we uncovered a significant association between rs2910164 polymorphism and risk of urological neoplasms in Asian populations in allelic, homozygote and recessive models. Highlighted, when stratified analysis was conducted by cancer type, rs2910164 polymorphism was also significantly associated with an increased risk of bladder cancer in allelic, homozygote and recessive models. Although for rs11614913 and rs3746444 polymorphisms, overall analyses suggested negative results, for rs11614913 polymorphism, when subgroup analysis was conducted by cancer type, a significantly decreased risk of renal cell cancer was identified in recessive model. In brief, current work indicated that miR-146a rs2910164 polymorphism is a risk factor for urological neoplasms, particularly for bladder cancer. PMID- 29491366 TI - Bacterial reduction in sealed caries lesions is strain- and material-specific. AB - Sealing can arrest caries lesions. We aimed to evaluate if sealing effects and kinetics are bacterial-strain and sealing-material specific. Human dentin discs were mounted in a dual-chamber device. Caries lesions were induced chemically and contaminated with either Lactobacillus rhamnosus (LR) or Streptococcus sobrinus (SS). For (1) kinetics assessment, the initial bacterial load and the sealing period were varied, and lesions sealed using a self-etch adhesive and composite. For (2) comparing materials, six sealing protocols (#1-#6) were evaluated: 1# Self-etch adhesive plus composite placed without a liner, or #2 calcium hydroxide, or #3 mineral trioxide aggregate, or #4 Biodentine liners; #5 antibacterial adhesive plus composite; #6 glass ionomer cement. Pulpal fluid flow was simulated during sealing. The outcome was the number of surviving bacteria (CFU) per g dentin. For LR, bacterial survival increased significantly with increasing initial bacterial load and decreased with longer sealing periods. The relative reduction followed a first-order kinetics. More LR survived under calcium hydroxide or MTA than other materials (p < 0.001). For SS, nearly no bacteria survived sealing regardless of sealing period, initial bacterial load or sealing material. In conclusion, sealing effects and kinetics were strain- and material-specific. PMID- 29491367 TI - Redox crosstalk at endoplasmic reticulum (ER) membrane contact sites (MCS) uses toxic waste to deliver messages. AB - Many cellular redox reactions housed within mitochondria, peroxisomes and the endoplasmic reticulum (ER) generate hydrogen peroxide (H2O2) and other reactive oxygen species (ROS). The contribution of each organelle to the total cellular ROS production is considerable, but varies between cell types and also over time. Redox-regulatory enzymes are thought to assemble at a "redox triangle" formed by mitochondria, peroxisomes and the ER, assembling "redoxosomes" that sense ROS accumulations and redox imbalances. The redoxosome enzymes use ROS, potentially toxic by-products made by some redoxosome members themselves, to transmit inter compartmental signals via chemical modifications of downstream proteins and lipids. Interestingly, important components of the redoxosome are ER chaperones and oxidoreductases, identifying ER oxidative protein folding as a key ROS producer and controller of the tri-organellar membrane contact sites (MCS) formed at the redox triangle. At these MCS, ROS accumulations could directly facilitate inter-organellar signal transmission, using ROS transporters. In addition, ROS influence the flux of Ca2+ ions, since many Ca2+ handling proteins, including inositol 1,4,5 trisphosphate receptors (IP3Rs), SERCA pumps or regulators of the mitochondrial Ca2+ uniporter (MCU) are redox-sensitive. Fine-tuning of these redox and ion signaling pathways might be difficult in older organisms, suggesting a dysfunctional redox triangle may accompany the aging process. PMID- 29491368 TI - Targeting glucocorticoid receptors prevents the effects of early life stress on amyloid pathology and cognitive performance in APP/PS1 mice. AB - Exposure to chronic stress or elevated glucocorticoid hormone levels in adult life has been associated with cognitive deficits and an increased risk for Alzheimer's disease (AD). Since exposure to stress during early life enhances stress-responsiveness and lastingly affects cognition in adult life, we here investigated; (i) whether chronic early life stress (ELS) affects AD pathology and cognition in middle-aged APPswe/PS1dE9 mice, and (ii) whether it is still possible to rescue these late effects by briefly blocking glucocorticoid receptors (GRs) at a translationally relevant, middle age. Transgenic APPswe/PS1dE9 mice were subjected to ELS by housing dams and pups with limited nesting and bedding material from postnatal days 2-9 only. In 6- and 12-month-old offspring, this resulted in enhanced hippocampal amyloid-beta (Abeta)-40 and -42 levels, and in reduced cognitive flexibility, that correlated well with the Abeta42 levels. In parallel, CORT levels and BACE1 levels were significantly elevated. Surprisingly, blocking GRs for only 3 days at 12 months of age reduced CORT levels, reduced hippocampal Abeta40 and -42, and beta-site APP-cleaving enzyme 1 (BACE1) levels, and notably rescued the cognitive deficits in 12-month old APPswe/PS1dE9 mice. These mouse data demonstrate that exposure to stress during the sensitive period early in life influences later amyloid pathology and cognition in genetically predisposed, mutant mice, and as such, may increase AD vulnerability. The fact that a short treatment with a GR antagonist at middle age lastingly reduced Abeta levels and rescued the cognitive deficits after ELS, highlights the therapeutic potential of this drug for reducing amyloid pathology. PMID- 29491370 TI - Stable N-doped & FeNi-decorated graphene non-precious electrocatalyst for Oxygen Reduction Reaction in Acid Medium. AB - NiFe nanoparticles-decorated & N-doped graphene is introduced as an effective and stable non-precious electrocatalyst for ORR in the acid medium. Compared to conventional Pt/C electrodes under the same conditions, the proposed nanocatalyst shows closer onset potential and current density. Typically, the observed onset potentials and current densities for the synthesized and Pt/C electrodes are 825 and 910 mV (vs. NHE) and -3.65 and -4.31 mA.cm-2 (at 5 mV.s-1), respectively. However, the most important advantage of the introduced metallic alloy-decorated graphene is its distinct stability in acid medium; the retention in the electrocatalytic performance after 1,000 successive cycles is approximately 98%. This finding is attributed to the high corrosion resistance of the NiFe alloy. The kinetic study indicates that the number of the transferred electrons is 3.46 and 3.89 for the introduced and Pt/C (20 wt%) electrodes, respectively which concludes a high activity for the proposed nanocomposite. The suggested decorated graphene can be synthesized using a multi-thermal method. Typically, nickel acetate, iron acetate, graphene oxide and urea are subjected to MW heating. Then, sintering with melamine in an Argon atmosphere at 750 degrees C is required to produce the final electrocatalyst. Overall, the introduced NiFe@ N-doped Gr nanocomposite shows remarkable electrochemical activity in the acid medium with long-term stability. PMID- 29491371 TI - 3D printing of robotic soft actuators with programmable bioinspired architectures. AB - Soft actuation allows robots to interact safely with humans, other machines, and their surroundings. Full exploitation of the potential of soft actuators has, however, been hindered by the lack of simple manufacturing routes to generate multimaterial parts with intricate shapes and architectures. Here, we report a 3D printing platform for the seamless digital fabrication of pneumatic silicone actuators exhibiting programmable bioinspired architectures and motions. The actuators comprise an elastomeric body whose surface is decorated with reinforcing stripes at a well-defined lead angle. Similar to the fibrous architectures found in muscular hydrostats, the lead angle can be altered to achieve elongation, contraction, or twisting motions. Using a quantitative model based on lamination theory, we establish design principles for the digital fabrication of silicone-based soft actuators whose functional response is programmed within the material's properties and architecture. Exploring such programmability enables 3D printing of a broad range of soft morphing structures. PMID- 29491369 TI - Endoplasmic reticulum and mitochondria in diseases of motor and sensory neurons: a broken relationship? AB - Recent progress in the understanding of neurodegenerative diseases revealed that multiple molecular mechanisms contribute to pathological changes in neurons. A large fraction of these alterations can be linked to dysfunction in the endoplasmic reticulum (ER) and mitochondria, affecting metabolism and secretion of lipids and proteins, calcium homeostasis, and energy production. Remarkably, these organelles are interacting with each other at specialized domains on the ER called mitochondria-associated membranes (MAMs). These membrane structures rely on the interaction of several complexes of proteins localized either at the mitochondria or at the ER interface and serve as an exchange platform of calcium, metabolites, and lipids, which are critical for the function of both organelles. In addition, recent evidence indicates that MAMs also play a role in the control of mitochondria dynamics and autophagy. MAMs thus start to emerge as a key element connecting many changes observed in neurodegenerative diseases. This review will focus on the role of MAMs in amyotrophic lateral sclerosis (ALS) and hereditary motor and sensory neuropathy, two neurodegenerative diseases particularly affecting neurons with long projecting axons. We will discuss how defects in MAM signaling may impair neuronal calcium homeostasis, mitochondrial dynamics, ER function, and autophagy, leading eventually to axonal degeneration. The possible impact of MAM dysfunction in glial cells, which may affect the capacity to support neurons and/or axons, will also be described. Finally, the possible role of MAMs as an interesting target for development of therapeutic interventions aiming at delaying or preventing neurodegeneration will be highlighted. PMID- 29491372 TI - I-AbACUS: a Reliable Software Tool for the Semi-Automatic Analysis of Invasion and Migration Transwell Assays. AB - The quantification of invasion and migration is an important aspect of cancer research, used both in the study of the molecular processes involved in this collection of diseases and the evaluation of the efficacy of new potential treatments. The transwell assay, while being one of the most widely used techniques for the evaluation of these characteristics, shows a high dependence on the operator's ability to correctly identify the cells and a low protocol standardization. Here we present I-AbACUS, a software tool specifically designed to aid the analysis of transwell assays that automatically and specifically recognizes cells in images of stained membranes and provides the user with a suggested cell count. A complete description of this instrument, together with its validation against the standard analysis technique for this assay is presented. Furthermore, we show that I-AbACUS is versatile and able to elaborate images containing cells with different morphologies and that the obtained results are less dependent on the operator and their experience. We anticipate that this instrument, freely available (Gnu Public Licence GPL v2) at www.marilisacortesi.com as a standalone application, could significantly improve the quantification of invasion and migration of cancer cells. PMID- 29491373 TI - Super anticorrosion of aluminized steel by a controlled Mg supply. AB - The current anticorrosion strategy makes use of coatings to passively protect the steel, which faces increasing challenge due to the tightened environmental regulations and high cost. This paper reports a new method for achieving a super anticorrosion function in Al-Si alloys through Mg nano-metallurgy, which was characterized by real-time synchrotron measurements. The unique function is based on the formation of an amorphous and self-charge-compensated MgAl2O4-SiO2 phase between the grain boundaries to help prevent the penetration of oxygen species through the grain boundaries. Through this, the corrosion resistance of pristine aluminized steel could be improved almost 20 fold. An analysis of the phases, microstructures of the Mg-coated aluminized layer and corrosion products consistently supported the proposed mechanism. This charge-compensated corrosion resistance mechanism provides novel insight into corrosion resistance. PMID- 29491374 TI - Chloroquine modulates antitumor immune response by resetting tumor-associated macrophages toward M1 phenotype. AB - Resetting tumor-associated macrophages (TAMs) is a promising strategy to ameliorate the immunosuppressive tumor microenvironment and improve innate and adaptive antitumor immunity. Here we show that chloroquine (CQ), a proven anti malarial drug, can function as an antitumor immune modulator that switches TAMs from M2 to tumor-killing M1 phenotype. Mechanistically, CQ increases macrophage lysosomal pH, causing Ca2+ release via the lysosomal Ca2+ channel mucolipin-1 (Mcoln1), which induces the activation of p38 and NF-kappaB, thus polarizing TAMs to M1 phenotype. In parallel, the released Ca2+ activates transcription factor EB (TFEB), which reprograms the metabolism of TAMs from oxidative phosphorylation to glycolysis. As a result, CQ-reset macrophages ameliorate tumor immune microenvironment by decreasing immunosuppressive infiltration of myeloid-derived suppressor cells and Treg cells, thus enhancing antitumor T-cell immunity. These data illuminate a previously unrecognized antitumor mechanism of CQ, suggesting a potential new macrophage-based tumor immunotherapeutic modality. PMID- 29491375 TI - Methylphenidate enhances neuronal differentiation and reduces proliferation concomitant to activation of Wnt signal transduction pathways. AB - Methylphenidate (Ritalin) is the most commonly prescribed drug in the treatment of attention-deficit hyperactivity disorder. It is suggested that in vivo, methylphenidate treatment supports cortical maturation, however, the molecular and cellular mechanisms are not well understood. This study aimed to explore the potential effect of methylphenidate on cell proliferation and maturation in various cellular models, hypothesizing its interaction with the Wnt-signaling. The termination of cell proliferation concomitant to neuronal maturation following methylphenidate treatment was observed in all of the cell-models tested: murine neural stem-, rat PC12- and the human SH-SY5Y-cells. Inhibition of Wnt-signaling in SH-SY5Y cells with Dkk1 30 min before methylphenidate treatment suppressed neuronal differentiation but enhanced proliferation. The possible involvement of the dopamine-transporter in cell differentiation was discounted following the observation of opposing results after GBR-12909 treatment. Moreover, Wnt-activation via methylphenidate was confirmed in Wnt-luciferase reporter assay. These findings reveal a new mechanism of action of methylphenidate that might explain long-term effects. PMID- 29491377 TI - Characterizing the replicability of cell types defined by single cell RNA sequencing data using MetaNeighbor. AB - Single-cell RNA-sequencing (scRNA-seq) technology provides a new avenue to discover and characterize cell types; however, the experiment-specific technical biases and analytic variability inherent to current pipelines may undermine its replicability. Meta-analysis is further hampered by the use of ad hoc naming conventions. Here we demonstrate our replication framework, MetaNeighbor, that quantifies the degree to which cell types replicate across datasets, and enables rapid identification of clusters with high similarity. We first measure the replicability of neuronal identity, comparing results across eight technically and biologically diverse datasets to define best practices for more complex assessments. We then apply this to novel interneuron subtypes, finding that 24/45 subtypes have evidence of replication, which enables the identification of robust candidate marker genes. Across tasks we find that large sets of variably expressed genes can identify replicable cell types with high accuracy, suggesting a general route forward for large-scale evaluation of scRNA-seq data. PMID- 29491376 TI - PAN-cancer analysis of S-phase enriched lncRNAs identifies oncogenic drivers and biomarkers. AB - Despite improvement in our understanding of long noncoding RNAs (lncRNAs) role in cancer, efforts to find clinically relevant cancer-associated lncRNAs are still lacking. Here, using nascent RNA capture sequencing, we identify 1145 temporally expressed S-phase-enriched lncRNAs. Among these, 570 lncRNAs show significant differential expression in at least one tumor type across TCGA data sets. Systematic clinical investigation of 14 Pan-Cancer data sets identified 633 independent prognostic markers. Silencing of the top differentially expressed and clinically relevant S-phase-enriched lncRNAs in several cancer models affects crucial cancer cell hallmarks. Mechanistic investigations on SCAT7 in multiple cancer types reveal that it interacts with hnRNPK/YBX1 complex and affects cancer cell hallmarks through the regulation of FGF/FGFR and its downstream PI3K/AKT and MAPK pathways. We also implement a LNA-antisense oligo-based strategy to treat cancer cell line and patient-derived tumor (PDX) xenografts. Thus, this study provides a comprehensive list of lncRNA-based oncogenic drivers with potential prognostic value. PMID- 29491379 TI - Electrically controlled transformation of memristive titanates into mesoporous titanium oxides via incongruent sublimation. AB - Perovskites such as SrTiO3, BaTiO3, and CaTiO3 have become key materials for future energy-efficient memristive data storage and logic applications due to their ability to switch their resistance reversibly upon application of an external voltage. This resistance switching effect is based on the evolution of nanoscale conducting filaments with different stoichiometry and structure than the original oxide. In order to design and optimize memristive devices, a fundamental understanding of the interaction between electrochemical stress, stoichiometry changes and phase transformations is needed. Here, we follow the approach of investigating these effects in a macroscopic model system. We show that by applying a DC voltage under reducing conditions on a perovskite slab it is possible to induce stoichiometry polarization allowing for a controlled decomposition related to incongruent sublimation of the alkaline earth metal starting in the surface region. This way, self-formed mesoporous layers can be generated which are fully depleted by Sr (or Ba, Ca) but consist of titanium oxides including TiO and Ti3O with tens of micrometre thickness. This illustrates that phase transformations can be induced easily by electrochemical driving forces. PMID- 29491378 TI - Nanodroplet processing platform for deep and quantitative proteome profiling of 10-100 mammalian cells. AB - Nanoscale or single-cell technologies are critical for biomedical applications. However, current mass spectrometry (MS)-based proteomic approaches require samples comprising a minimum of thousands of cells to provide in-depth profiling. Here, we report the development of a nanoPOTS (nanodroplet processing in one pot for trace samples) platform for small cell population proteomics analysis. NanoPOTS enhances the efficiency and recovery of sample processing by downscaling processing volumes to <200 nL to minimize surface losses. When combined with ultrasensitive liquid chromatography-MS, nanoPOTS allows identification of ~1500 to ~3000 proteins from ~10 to ~140 cells, respectively. By incorporating the Match Between Runs algorithm of MaxQuant, >3000 proteins are consistently identified from as few as 10 cells. Furthermore, we demonstrate quantification of ~2400 proteins from single human pancreatic islet thin sections from type 1 diabetic and control donors, illustrating the application of nanoPOTS for spatially resolved proteome measurements from clinical tissues. PMID- 29491380 TI - Accuracy of Combined Computed Tomography Colonography and Dual Energy Iiodine Map Imaging for Detecting Colorectal masses using High-pitch Dual-source CT. AB - To evaluate the diagnostic accuracy of combined computed tomography colonography (CTC) and dual-energy iodine map imaging for detecting colorectal masses using high-pitch dual-source CT, compared with optical colonography (OC) and histopathologic findings. Twenty-eight consecutive patients were prospectively enrolled in this study. All patients were underwent contrast-enhanced CTC acquisition using dual-energy mode and OC and pathologic examination. The size of the space-occupied mass, the CT value after contrast enhancement, and the iodine value were measured and statistically compared. The sensitivity, specificity, accuracy rate, and positive predictive and negative predictive values of dual energy contrast-enhanced CTC were calculated and compared between conventional CTC and dual-energy iodine images. The iodine value of stool was significantly lower than the colonic neoplasia (P < 0.01). The sensitivity of conventional CTC was 95.6% (95% CI = 77.9%-99.2%), combined CTC and dual-energy iodine maps imaging was 95.6% (95% CI = 77.9%-99.2%). The specificity of the two methods was 42.8% (95% CI = 15.4%-93.5%) and 100% (95% CI = 47.9%-100%; P = 0.02), respectively. Compared with optical colonography and histopathology, combined CTC and dual-energy iodine maps imaging can distinguish stool and colonic neoplasia, distinguish between benign and malignant tumors initially and improve the diagnostic accuracy of CTC for colorectal cancer screening. PMID- 29491381 TI - Interleukin-10 produced by myeloid-derived suppressor cells is critical for the induction of Tregs and attenuation of rheumatoid inflammation in mice. AB - Myeloid-derived suppressor cells (MDSCs) are heterogenous populations of immature myeloid progenitor cells with immunoregulatory function. MDSCs play critical roles in controlling the processes of autoimmunity but their roles in rheumatoid arthritis (RA) are controversial. The present study was undertaken to investigate whether MDSCs have therapeutic impact in mice with collagen-induced arthritis (CIA), an animal model of RA. We also examined the mechanisms underlying the anti arthritic effect of MDSCs. In vitro treatment with MDSCs repressed IL-17 but increased FOXP3 in CD4+ T cells in mice. In vivo infusion of MDSCs markedly ameliorated inflammatory arthritis. Th17 cells and Th1 cells were decreased while Tregs were increased in the spleens of MDSCs-treated mice. MDSCs profoundly inhibited T cell proliferation. Addition of anti-IL-10 almost completely blocked the anti-proliferative effects of MDSCs on T cells. Anti-IL-10 blocked the expansion of Tregs by MDSCs. However, infusion of MDSCs from IL-10 KO mice failed to suppress inflammatory arthritis. MDSCs could reciprocally regulate Th17/Treg cells and suppress CIA via IL-10, suggesting that MDSCs might be a promising therapeutic strategy for T cell mediated autoimmune diseases including RA. PMID- 29491382 TI - Role of iRhom2 in intestinal ischemia-reperfusion-mediated acute lung injury. AB - Intestinal ischemia-reperfusion (I/R) may cause acute systemic and lung inflammation. However, the detailed mechanism of this inflammatory cascade has not been fully elucidated. Inactive rhomboid protein 2 (iRhom2) is essential for the maturation of TNF-alpha converting enzyme (TACE), which is required for TNF alpha secretion. We evaluated the role of iRhom2 in a mouse model of intestinal I/R using iRhom2 knockout (KO) and wild-type (WT) mice. Lung injury following intestinal I/R was significantly attenuated in iRhom2 KO mice compared with WT mice. After intestinal I/R, lungs from iRhom2 KO mice showed significantly lower myeloperoxidase (MPO) activity and markedly reduced cell apoptosis associated with a decreased level of active caspase 3 and decreased TUNEL staining compared with lungs from WT mice. TNF-alpha levels were elevated in the serum and lungs of WT mice with intestinal I/R and significantly reduced in iRhom2 KO mice with intestinal I/R. iRhom2 may play a critical role in the pathogenesis of acute lung injury (ALI) after intestinal I/R and thus may be a novel therapeutic target for ALI after intestinal I/R injury. PMID- 29491383 TI - Cognitive control over memory - individual differences in memory performance for emotional and neutral material. AB - It is widely accepted that people differ in memory performance. The ability to control one's memory depends on multiple factors, including the emotional properties of the memorized material. While it was widely demonstrated that emotion can facilitate memory, it is unclear how emotion modifies our ability to suppress memory. One of the reasons for the lack of consensus among researchers is that individual differences in memory performance were largely neglected in previous studies. We used the directed forgetting paradigm in an fMRI study, in which subjects viewed neutral and emotional words, which they were instructed to remember or to forget. Subsequently, subjects' memory of these words was tested. Finally, they assessed the words on scales of valence, arousal, sadness and fear. We found that memory performance depended on instruction as reflected in the engagement of the lateral prefrontal cortex (lateral PFC), irrespective of emotional properties of words. While the lateral PFC engagement did not differ between neutral and emotional conditions, it correlated with behavioural performance when emotional - as opposed to neutral - words were presented. A deeper understanding of the underlying brain mechanisms is likely to require a study of individual differences in cognitive abilities to suppress memory. PMID- 29491384 TI - Uniform two-dimensional square assemblies from conjugated block copolymers driven by pi-pi interactions with controllable sizes. AB - Two-dimensional (2-D) micro- and nano-architectures are attractive because of their unique properties. However, the formation of 2-D supramolecular highly symmetrical structures with considerable control is still a major challenge. Here we present a simple approach for the preparation of regular and homogeneous 2-D fluorescent square non-crystallization micelles with conjugated diblock copolymers PPV12-b-P2VP n through a process of dissolving-cooling-aging. The scale of the formed micelles can be controlled by the ratio of PPV/P2VP blocks and the concentration of the solution. The results reveal that the micelles of PPV12-b-P2VP n initially form 1-D structures and then grow into 2-D structures in solution, and the growth is driven by intermolecular pi-pi interactions with the PPV12 blocks. The formation of 2-D square micelles is induced by herringbone arrangement of the molecules, which is closely related to the presence of the branched alkyl chains attached to conjugated PPV12 cores. PMID- 29491385 TI - Mitochondria-associated membranes in aging and senescence: structure, function, and dynamics. AB - Sites of close contact between mitochondria and the endoplasmic reticulum (ER) are known as mitochondria-associated membranes (MAM) or mitochondria-ER contacts (MERCs), and play an important role in both cell physiology and pathology. A growing body of evidence indicates that changes observed in the molecular composition of MAM and in the number of MERCs predisposes MAM to be considered a dynamic structure. Its involvement in processes such as lipid biosynthesis and trafficking, calcium homeostasis, reactive oxygen species production, and autophagy has been experimentally confirmed. Recently, MAM have also been studied in the context of different pathologies, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, type 2 diabetes mellitus and GM1-gangliosidosis. An underappreciated amount of data links MAM with aging or senescence processes. In the present review, we summarize the current knowledge of basic MAM biology, composition and action, and discuss the potential connections supporting the idea that MAM are significant players in longevity. PMID- 29491386 TI - Mitochondria-associated membranes (MAMs) and inflammation. AB - The endoplasmic reticulum (ER) and mitochondria are tightly associated with very dynamic platforms termed mitochondria-associated membranes (MAMs). MAMs provide an excellent scaffold for crosstalk between the ER and mitochondria and play a pivotal role in different signaling pathways that allow rapid exchange of biological molecules to maintain cellular health. However, dysfunctions in the ER mitochondria architecture are associated with pathological conditions and human diseases. Inflammation has emerged as one of the various pathways that MAMs control. Inflammasome components and other inflammatory factors promote the release of pro-inflammatory cytokines that sustain pathological conditions. In this review, we summarize the critical role of MAMs in initiating inflammation in the cellular defense against pathogenic infections and the association of MAMs with inflammation-mediated diseases. PMID- 29491387 TI - Understanding the Structure, Multimerization, Subcellular Localization and mC Selectivity of a Genomic Mutator and Anti-HIV Factor APOBEC3H. AB - APOBEC3H (A3H) is a member of the APOBEC3 subfamily of DNA cytosine deaminases that are important for innate immune defense and have been implicated in cancer biogenesis. To understand the structural basis for A3H biochemical function, we determined a high-resolution structure of human A3H and performed extensive biochemical analysis. The 2.49 A crystal structure reveals a uniquely long C terminal helix 6 (h6), a disrupted beta5 strand of the canonical five-stranded beta-sheet core, and a long loop 1 around the Zn-active center. Mutation of a loop 7 residue, W115, disrupted the RNA-mediated dimerization of A3H yielding an RNA-free monomeric form that still possessed nucleic acid binding and deaminase activity. A3H expressed in HEK293T cells showed RNA dependent HMW complex formation and RNase A-dependent deaminase activity. A3H has a highly positively charged surface surrounding the Zn-active center, and multiple positively charged residues within this charged surface play an important role in the RNA-mediated HMW formation and deaminase inhibition. Furthermore, these positively charged residues affect subcellular localization of A3H between the nucleus and cytosol. Finally, we have identified multiple residues of loop 1 and 7 that contribute to the overall deaminase activity and the methylcytosine selectivity. PMID- 29491388 TI - Development and Evaluation of Novel Statistical Methods in Urine Biomarker-Based Hepatocellular Carcinoma Screening. AB - Hepatocellular carcinoma is one of the fastest growing cancers in the US and has a low survival rate, partly due to difficulties in early detection. Because of HCC's high heterogeneity, it has been suggested that multiple biomarkers would be needed to develop a sensitive HCC screening test. This study applied random forest (RF), a machine learning technique, and proposed two novel models, fixed sequential (FS) and two-step (TS), for comparison with two commonly used statistical techniques, logistic regression (LR) and classification and regression trees (CART), in combining multiple urine DNA biomarkers for HCC screening using biomarker values obtained from 137 HCC and 431 non-HCC (224 hepatitis and 207 cirrhosis) subjects. The sensitivity, specificity, area under the receiver operating curve, and variability were estimated through repeated 10 fold cross-validation to compare the models' performances in accuracy and robustness. We show that RF and TS have higher accuracy and stability; specifically, they reach 90% specificity and 86%/87% sensitivity respectively along with 15% higher sensitivity and 10% higher specificity than LR in cross validation. The potential of RF and TS to develop a panel of multiple biomarkers and the possibility for self-training, cloud-based models for HCC screening are discussed. PMID- 29491389 TI - Rapid Detection of Zika Virus in Urine Samples and Infected Mosquitos by Reverse Transcription-Loop-Mediated Isothermal Amplification. AB - Infection with Zika virus (ZIKV) is of growing concern since infection is associated with the development of congenital neurological disease. Quantitative reverse transcription PCR (qRT-PCR) has been the standard for ZIKV detection; however, Reverse Transcription Loop-Mediated Isothermal Amplification (RT-LAMP) may allow for faster and cheaper testing. Studies have suggested that ZIKV detection in urine is more sensitive and has a longer window of detection compared to serum and saliva. The objective of this study was to develop a urine diagnostic test that could be completed in under 30 minutes. Urine samples spiked with ZIKV or dengue virus were tested using RT-LAMP as well as by conventional quantitative qRT-PCR. These techniques were then validated using crude lysates made from ZIKV infected mosquitoes in addition to urine and serum samples from ZIKV infected patients. RT-LAMP specifically detected ZIKV in urine and serum for ZIKV infected patients and crude mosquito lysates. This test was performed in under 30 minutes and did not require RNA extraction from urine nor mosquitos. This approach could be used for monitoring of exposed individuals, especially pregnant women, couples wanting to conceive, or individuals with suspicious symptoms as well as surveillance of mosquito populations. PMID- 29491390 TI - Acquired Enamel Pellicle Engineered Peptides: Effects on Hydroxyapatite Crystal Growth. AB - The aim of this study was to test the hypothesis that duplication/hybridization of functional domains of naturally occurring pellicle peptides amplified the inhibitory effect of hydroxyapatite crystal growth, which is related to enamel remineralization and dental calculus formation. Histatin 3, statherin, their functional domains (RR14 and DR9), and engineered peptides (DR9-DR9 and DR9-RR14) were tested at seven different concentrations to evaluate the effect on hydroxyapatite crystal growth inhibition. A microplate colorimetric assay was used to quantify hydroxyapatite crystal growth. The half-maximal inhibitory concentration (IC50) was determined for each group. ANOVA and Student-Newman Keuls pairwise comparisons were used to compare the groups. DR9-DR9 increased the inhibitory effect of hydroxyapatite crystal growth compared to single DR9 (p < 0.05), indicating that functional domain multiplication represented a strong protein evolution pathway. Interestingly, the hybrid peptide DR9-RR14 had an intermediate inhibitory effect compared to DR9 and DR9-DR9. This study used an engineered peptide approach to investigate a potential evolution protein pathway related to duplication/hybridization of acquired enamel pellicle's natural peptide constituents, contributing to the development of synthetic peptides for therapeutic use against dental caries and periodontal disease. PMID- 29491391 TI - Disruption of the open conductance in the beta-tongue mutants of Cytolysin A. AB - Cytolysin A (ClyA) is a water-soluble alpha pore-forming toxin that assembles to form an oligomeric pore on host cell membranes. The ClyA monomer possesses an alpha-helical bundle with a beta-sheet subdomain (the beta-tongue) previously believed to be critical for pore assembly and/or insertion. Oligomerization of ClyA pores transforms the beta-tongue into a helix-turn-helix that embeds into the lipid bilayer. Here, we show that mutations of the beta-tongue did not prevent oligomerization or transmembrane insertion. Instead, beta-tongue substitution mutants yielded pores with decreased conductance while a deletion mutation resulted in pores that rapidly closed following membrane association. Our results suggest that the beta-tongue may play an essential structural role in stabilizing the open conformation of the transmembrane domain. PMID- 29491393 TI - Endoscopic score vs. fecal biomarkers for predicting relapse in patients with ulcerative colitis after clinical remission and mucosal healing. AB - Objectives: Achieving endoscopic remission or decreasing the level of fecal biomarkers as an ideal therapeutic goal in ulcerative colitis has not been determined. This prospective study was to compare the clinical relevance of endoscopic score with fecal biomarkers for predicting relapse after clinical remission and mucosal healing (MH). Methods: One hundred and sixty-four patients who achieved clinical remission and MH (Mayo endoscopic subscore (MES) 0 or 1) were included. At entry, fecal samples were collected for the measurement of calprotectin, lactoferrin, and hemoglobin. Thereafter patients received masalamine maintenance therapy, and were followed for 12 months. Results: During the 12-month study, 46 patients (28%) relapsed. The relapse rate was not significantly higher in 27/80 patients (34%) with MES 1 than in 19/84 patients (23%) with MES 0 (P = 0.16). The median fecal calprotectin, lactoferrin, and hemoglobin were significantly higher in patients with relapse than those in remission (calprotectin, 182 vs. 94 MUg/g; lactoferrin, 185.5 vs. 111 MUg/g; hemoglobin, 168 vs. 104 ng/mL; all P < 0.0001). A cutoff value of 115 ug/g calprotectin had 83% sensitivity and 81% specificity to predict relapse, whereas lactoferrin, 145 ug/g had 70% sensitivity and 79% specificity, and hemoglobin, 135 ng/mL showed 74% sensitivity and 73% specificity. The accuracy was significantly lower for hemoglobin as compared with calprotectin and lactoferrin. Conclusions: Fecal calprotectin, lactoferrin, and to a lesser degree fecal hemoglobin appeared to be objective biomarkers for predicting future relapse after achieving clinical remission and MH. The predictive value of these biomarkers was higher than with MES. PMID- 29491392 TI - Disruption of ER-mitochondria signalling in fronto-temporal dementia and related amyotrophic lateral sclerosis. AB - Fronto-temporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two related and incurable neurodegenerative diseases. Features of these diseases include pathological protein inclusions in affected neurons with TAR DNA-binding protein 43 (TDP-43), dipeptide repeat proteins derived from the C9ORF72 gene, and fused in sarcoma (FUS) representing major constituent proteins in these inclusions. Mutations in C9ORF72 and the genes encoding TDP-43 and FUS cause familial forms of FTD/ALS which provides evidence to link the pathology and genetics of these diseases. A large number of seemingly disparate physiological functions are damaged in FTD/ALS. However, many of these damaged functions are regulated by signalling between the endoplasmic reticulum and mitochondria, and this has stimulated investigations into the role of endoplasmic reticulum mitochondria signalling in FTD/ALS disease processes. Here, we review progress on this topic. PMID- 29491394 TI - Chimeric peptide EP45 as a dual agonist at GLP-1 and NPY2R receptors. AB - We report the design and target validation of chimeric peptide EP45, a novel 45 amino acid monomeric dual agonist peptide that contains amino acid sequence motifs present within the blood glucose-lowering agent exendin-4 (Ex-4) and the appetite-suppressing agent PYY(3-36). In a new high-throughput FRET assay that provides real-time kinetic information concerning levels of cAMP in living cells, EP45 recapitulates the action of Ex-4 to stimulate cAMP production via the glucagon-like peptide-1 receptor (GLP-1R), while also recapitulating the action of PYY(3-36) to inhibit cAMP production via the neuropeptide Y2 receptor (NPY2R). EP45 fails to activate glucagon or GIP receptors, whereas for cells that co express NPY2R and adenosine A2B receptors, EP45 acts in an NPY2R-mediated manner to suppress stimulatory effects of adenosine on cAMP production. Collectively, such findings are remarkable in that they suggest a new strategy in which the co existing metabolic disorders of type 2 diabetes and obesity will be treatable using a single peptide such as EP45 that lowers levels of blood glucose by virtue of its GLP-1R-mediated effect, while simultaneously suppressing appetite by virtue of its NPY2R-mediated effect. PMID- 29491395 TI - Highly stretchable carbon aerogels. AB - Carbon aerogels demonstrate wide applications for their ultralow density, rich porosity, and multifunctionalities. Their compressive elasticity has been achieved by different carbons. However, reversibly high stretchability of neat carbon aerogels is still a great challenge owing to their extremely dilute brittle interconnections and poorly ductile cells. Here we report highly stretchable neat carbon aerogels with a retractable 200% elongation through hierarchical synergistic assembly. The hierarchical buckled structures and synergistic reinforcement between graphene and carbon nanotubes enable a temperature-invariable, recoverable stretching elasticity with small energy dissipation (~0.1, 100% strain) and high fatigue resistance more than 106 cycles. The ultralight carbon aerogels with both stretchability and compressibility were designed as strain sensors for logic identification of sophisticated shape conversions. Our methodology paves the way to highly stretchable carbon and neat inorganic materials with extensive applications in aerospace, smart robots, and wearable devices. PMID- 29491396 TI - A key role for MAM in mediating mitochondrial dysfunction in Alzheimer disease. AB - In the last few years, increased emphasis has been devoted to understanding the contribution of mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) to human pathology in general, and neurodegenerative diseases in particular. A major reason for this is the central role that this subdomain of the ER plays in metabolic regulation and in mitochondrial biology. As such, aberrant MAM function may help explain the seemingly unrelated metabolic abnormalities often seen in neurodegeneration. In the specific case of Alzheimer disease (AD), besides perturbations in calcium and lipid homeostasis, there are numerous documented alterations in mitochondrial behavior and function, including reduced respiratory chain activity and oxidative phosphorylation, increased free radical production, and altered organellar morphology, dynamics, and positioning (especially perinuclear mitochondria). However, whether these alterations are primary events causative of the disease, or are secondary downstream events that are the result of some other, more fundamental problem, is still unclear. In support of the former possibility, we recently reported that C99, the C-terminal processing product of the amyloid precursor protein (APP) derived from its cleavage by beta-secretase, is present in MAM, that its level is increased in AD, and that this increase reduces mitochondrial respiration, likely via a C99 induced alteration in cellular sphingolipid homeostasis. Thus, the metabolic disturbances seen in AD likely arise from increased ER-mitochondrial communication that is driven by an increase in the levels of C99 at the MAM. PMID- 29491397 TI - Single cell polarity in liquid phase facilitates tumour metastasis. AB - Dynamic polarisation of tumour cells is essential for metastasis. While the role of polarisation during dedifferentiation and migration is well established, polarisation of metastasising tumour cells during phases of detachment has not been investigated. Here we identify and characterise a type of polarisation maintained by single cells in liquid phase termed single-cell (sc) polarity and investigate its role during metastasis. We demonstrate that sc polarity is an inherent feature of cells from different tumour entities that is observed in circulating tumour cells in patients. Functionally, we propose that the sc pole is directly involved in early attachment, thereby affecting adhesion, transmigration and metastasis. In vivo, the metastatic capacity of cell lines correlates with the extent of sc polarisation. By manipulating sc polarity regulators and by generic depolarisation, we show that sc polarity prior to migration affects transmigration and metastasis in vitro and in vivo. PMID- 29491399 TI - Barrett's esophagus is associated with a distinct oral microbiome. AB - OBJECTIVES: The esophageal microbiome is composed of predominantly oral flora and is altered in reflux-related conditions including Barrett's esophagus (BE). Changes to the esophageal microbiome may be reflected in the oral cavity. Assessing the oral microbiome thus represents a potential non-invasive method to identify patients with BE. METHODS: Patients with and without BE undergoing upper endoscopy were prospectively enrolled. Demographics, clinical data, medications, and dietary intake were assessed. 16S rRNA gene sequencing was performed on saliva samples collected prior to endoscopy. Taxonomic differences between groups were assessed via linear discriminant analysis effect size (LEfSe). Logit models were used to develop microbiome signatures to distinguish BE from non-BE, assessed by area under the receiver operating curve (AUROC). RESULTS: A total of 49 patients were enrolled (control = 17, BE = 32). There was no significant difference in alpha diversity comparing all BE patients vs. CONTROLS: At the phylum level, the oral microbiome in BE patients had significantly increased relative abundance of Firmicutes (p = 0.005) and decreased Proteobacteria (p = 0.02). There were numerous taxonomic differences in the oral microbiome between BE and controls. A model including relative abundance of Lautropia, Streptococcus, and a genus in the order Bacteroidales distinguished BE from controls with an AUROC 0.94 (95% CI: 0.85-1.00). The optimal cutoff identified BE patients with 96.9% sensitivity and 88.2% specificity. CONCLUSIONS: The oral microbiome in BE patients was markedly altered and distinguished BE with relatively high accuracy. The oral microbiome represents a potential screening marker for BE, and validation studies in larger and distinct populations are warranted. PMID- 29491400 TI - Estimating the nutrient thresholds of a typical tributary in the Liao River basin, Northeast China. AB - Estimating regional nutrient criteria for streams and rivers is a key step toward protecting river water quality and restoring the health of aquatic ecosystems. Using a multivariable statistical analysis technique, nutrients were identified as the main factor influencing the degradation of the benthic macroinvertebrate community. Three chemical methods (the reference stream distribution approach, all-streams distribution approach and Y-intercept approach) and one biological method (the stress-response approach) were applied to evaluate the nutrient thresholds in the Qing River basin. The reference stream distribution approach and all-streams distribution approach were based on calculating a predetermined percentile of reference streams and all-streams water quality data set, respectively. The Y-intercept approach was based on determining the influence of human activity on water quality by linear regression models. The biological method was based on the response of the benthic macroinvertebrate community structure to changes in water quality. The chemical thresholds were 0.750-1.288 mg/L for total nitrogen (TN) and 0.035-0.046 mg/L for total phosphorus (TP); the biological thresholds were 1.050-1.655 for TN and 0.052-0.101 for TP. The results from the chemical approaches were verified using the biological method, resulting in preliminarily recommended thresholds of 1.000 mg/L TN and 0.040 mg/L TP in the Qing River system. PMID- 29491401 TI - Gut microbial composition in patients with psoriasis. AB - Since the last 5-10 years the relevance of the gut microbiome on different intestinal illnesses has been revealed. Recent findings indicate the effect of gut microbiome on certain dermatological diseases such as atopic dermatitis. However, data on other skin diseases such as psoriasis are limited. This is the first time attempting to reveal the gut microbiome composition of psoriatic patients with a prospective study including a group of patients with plaque psoriasis, analyzing their gut microbiome and the relationship between the microbiome composition and bacterial translocation. The microbiome of a cohort of 52 psoriatic patients (PASI score >=6) was obtained by 16s rRNA massive sequencing with MiSeq platform (Illumina inc, San Diego) with an average of 85,000 sequences per sample. The study of the gut microbiome and enterotype shows from the first time a specific "psoriatic core intestinal microbiome" that clearly differs from the one present in healthy population. In addition, those psoriatic patients classified as belonging to enterotype 2 tended to experience more frequent bacterial translocation and higher inflammatory status (71%) than patients with other enterotypes (16% for enterotype 1; and 21% for enterotype 3). PMID- 29491398 TI - The role of the mitochondria and the endoplasmic reticulum contact sites in the development of the immune responses. AB - Mitochondria and endoplasmic reticulum (ER) contact sites (MERCs) are dynamic modules enriched in subset of lipids and specialized proteins that determine their structure and functions. The MERCs regulate lipid transfer, autophagosome formation, mitochondrial fission, Ca2+ homeostasis and apoptosis. Since these functions are essential for cell biology, it is therefore not surprising that MERCs also play a critical role in organ physiology among which the immune system stands by its critical host defense function. This defense system must discriminate and tolerate host cells and beneficial commensal microorganisms while eliminating pathogenic ones in order to preserve normal homeostasis. To meet this goal, the immune system has two lines of defense. First, the fast acting but unspecific innate immune system relies on anatomical physical barriers and subsets of hematopoietically derived cells expressing germline-encoded receptors called pattern recognition receptors (PRR) recognizing conserved motifs on the pathogens. Second, the slower but very specific adaptive immune response is added to complement innate immunity. Adaptive immunity relies on another set of specialized cells, the lymphocytes, harboring receptors requiring somatic recombination to be expressed. Both innate and adaptive immune cells must be activated to phagocytose and process pathogens, migrate, proliferate, release soluble factors and destroy infected cells. Some of these functions are strongly dependent on lipid transfer, autophagosome formation, mitochondrial fission, and Ca2+ flux; this indicates that MERCs could regulate immunity. PMID- 29491403 TI - Electrochemical Sensor for Detection of miRs Based on the Differential Effect of Competitive Structures in The p19 Function. AB - The present study aim to design a liposomal electrochemical sensor using 1, 2 dioleoyl-3-trimethylammoniumpropane (DOTAP) and dioleoylphosphatidylethanolamine(DOPE), chimeric probes and p19, it has been considered as a caliper molecule as well. Also the competitor structural hybrid (RNA) was used to detect three types of miRs in one screen printed electrode modified by gold nanoparticle (SCPE/GNP). In this purpose, the sensor signal stabilized when the cationic DOTAP-DOPE with hybrids of the chimeric probes (Stem, M-linear) sandwiched in order to detect 221-124a miRs. Given the lack of accessibility to RNA-miRs segments of chimeric probes, p19 inhibited the electrochemical reaction and shifted signal to off. After that p19 connected with the free hybrid of T-linear/21miR (just RNA) as competing for structure and the signal was shifted to ON, again. In this study, the electrochemical measurements were performed between the potentials at -0.4 V and +0.4 V with 1 mM [Fe(CN)6]-3 /4 which DOTAP-DOPE acted as an enhancer layer in the electrostatically reaction. This sensor determines as low as 0.4 fM of miRNA with high selectivity and specificity for sequential analysis of 124a-221-21 miRs in just 2 h. PMID- 29491404 TI - Eye movement patterns in infants suggest illusory motion perception induced by stationary gradation. AB - Infants less than 1 year old are known to preferentially look at pictures of motion illusion induced by luminance gradation. However, the mechanisms underlying infant's perception of motion illusion remain unclear. The current study analyzed the eye movement patterns of infants perceiving a motion illusion induced by stationary luminance gradations (a derivative of the Fraser-Wilcox illusion). Infants produced the same movement patterns that increase the magnitude of illusory motion in adults. We conclude that infants and adults similarly perceive motion illusion. PMID- 29491402 TI - Mitochondria-associated ER membranes (MAMs) and lysosomal storage diseases. AB - Lysosomal storage diseases (LSDs) comprise a large group of disorders of catabolism, mostly due to deficiency of a single glycan-cleaving hydrolase. The consequent endo-lysosomal accumulation of undigested or partially digested substrates in cells of virtually all organs, including the nervous system, is diagnostic of these diseases and underlies pathogenesis. A subgroup of LSDs, the glycosphingolipidoses, are caused by deficiency of glycosidases that process/degrade sphingolipids and glycosphingolipids (GSLs). GSLs are among the lipid constituents of mammalian membranes, where they orderly distribute and, together with a plethora of membrane proteins, contribute to the formation of discrete membrane microdomains or lipid rafts. The composition of intracellular membranes enclosing organelles reflects that at the plasma membrane (PM). Organelles have the tendencies to tether to one another and to the PM at specific membrane contact sites that, owing to their lipid and protein content, resemble PM lipid rafts. The focus of this review is on the MAMs, mitochondria associated ER membranes, sites of juxtaposition between ER and mitochondria that function as biological hubs for the exchange of molecules and ions, and control the functional status of the reciprocal organelles. We will focus on the lipid components of the MAMs, and highlight how failure to digest or process the sialylated GSL, GM1 ganglioside, in lysosomes alters the lipid conformation and functional properties of the MAMs and leads to neuronal cell death and neurodegeneration. PMID- 29491405 TI - Deep Residual Network Predicts Cortical Representation and Organization of Visual Features for Rapid Categorization. AB - The brain represents visual objects with topographic cortical patterns. To address how distributed visual representations enable object categorization, we established predictive encoding models based on a deep residual network, and trained them to predict cortical responses to natural movies. Using this predictive model, we mapped human cortical representations to 64,000 visual objects from 80 categories with high throughput and accuracy. Such representations covered both the ventral and dorsal pathways, reflected multiple levels of object features, and preserved semantic relationships between categories. In the entire visual cortex, object representations were organized into three clusters of categories: biological objects, non-biological objects, and background scenes. In a finer scale specific to each cluster, object representations revealed sub-clusters for further categorization. Such hierarchical clustering of category representations was mostly contributed by cortical representations of object features from middle to high levels. In summary, this study demonstrates a useful computational strategy to characterize the cortical organization and representations of visual features for rapid categorization. PMID- 29491406 TI - FcalphaRI co-stimulation converts human intestinal CD103+ dendritic cells into pro-inflammatory cells through glycolytic reprogramming. AB - CD103+ dendritic cells (DC) are crucial for regulation of intestinal tolerance in humans. However, upon infection of the lamina propria this tolerogenic response is converted to an inflammatory response. Here we show that immunoglobulin A (IgA) immune complexes (IgA-IC), which are present after bacterial infection of the lamina propria, are important for the induction of inflammation by the human CD103+SIRPalpha+ DC subset. IgA-IC, by recognition through FcalphaRI, selectively amplify the production of proinflammatory cytokines TNF, IL-1beta and IL-23 by human CD103+ DCs. These cells then enhance inflammation by promoting Th17 responses and activating human intestinal innate lymphoid cells 3. Moreover, FcalphaRI-induced cytokine production is orchestrated via upregulation of cytokine translation and caspase-1 activation, which is dependent on glycolytic reprogramming mediated by kinases Syk, PI3K and TBK1-IKKepsilon. Our data suggest that the formation of IgA-IC in the human intestine provides an environmental cue for the conversion of a tolerogenic to an inflammatory response. PMID- 29491407 TI - Cell-based glycan arrays for probing glycan-glycan binding protein interactions. AB - Glycan microarrays provide a high-throughput means of profiling the interactions of glycan-binding proteins with their ligands. However, the construction of current glycan microarray platforms is time consuming and expensive. Here, we report a fast and cost-effective method for the assembly of cell-based glycan arrays to probe glycan-glycan-binding protein interactions directly on the cell surface. Chinese hamster ovary cell mutants with a narrow and relatively homogeneous repertoire of glycoforms serve as the foundation platforms to develop these arrays. Using recombinant glycosyltransferases, sialic acid, fucose, and analogs thereof are installed on cell-surface glycans to form cell-based arrays displaying diverse glycan epitopes that can be probed with glycan-binding proteins by flow cytometry. Using this platform, high-affinity glycan ligands are discovered for Siglec-15-a sialic acid-binding lectin involved in osteoclast differentiation. Incubating human osteoprogenitor cells with cells displaying a high-affinity Siglec-15 ligand impairs osteoclast differentiation, demonstrating the utility of this cell-based glycan array technology. PMID- 29491408 TI - Nox4 is a Target for Tuberin Deficiency Syndrome. AB - The mechanism by which TSC2 inactivation or deficiency contributes to the pathology of tuberous sclerosis complex (TSC) is not fully clear. We show that renal angiomyolipomas from TSC patients and kidney cortex from Tsc2+/- mice exhibit elevated levels of reactive oxygen species (ROS). Downregulation of tuberin (protein encoded by TSC2 gene) in renal proximal tubular epithelial cells significantly increased ROS concomitant with enhanced Nox4. Similarly, we found elevated levels of Nox4 in the renal cortex of Tsc2+/- mice and in the renal angiomyolipomas from TSC patients. Tuberin deficiency is associated with activation of mTORC1. Rapamycin, shRNAs targeting raptor, or inhibition of S6 kinase significantly inhibited the expression of Nox4, resulting in attenuation of production of ROS in tuberin-downregulated proximal tubular epithelial cells. In contrast, activation of mTORC1 increased Nox4 and ROS. These results indicate that Nox4 may be a potential target for tuberin-deficiency-derived diseases. Using a xenograft model from tuberin-null tubular cells in nude mice, both anti sense Nox4 and GKT137831, a specific inhibitor of Nox1/4, significantly inhibited the tumor growth. Thus, our results demonstrate the presence of an antagonistic relationship between tuberin and Nox4 to drive oncogenesis in the tuberin deficiency syndrome and identify Nox4 as a target to develop a therapy for TSC. PMID- 29491409 TI - Post-epizootic salamander persistence in a disease-free refugium suggests poor dispersal ability of Batrachochytrium salamandrivorans. AB - Lack of disease spill-over between adjacent populations has been associated with habitat fragmentation and the absence of population connectivity. We here present a case which describes the absence of the spill-over of the chytrid fungus Batrachochytrium salamandrivorans (Bsal) between two connected subpopulations of fire salamanders (Salamandra salamandra). Based on neutrally evolving microsatellite loci, both subpopulations were shown to form a single genetic cluster, suggesting a shared origin and/or recent gene flow. Alpine newts (Ichthyosaura alpestris) and fire salamanders were found in the landscape matrix between the two sites, which are also connected by a stream and separated by no obvious physical barriers. Performing a laboratory trial using alpine newts, we confirmed that Bsal is unable to disperse autonomously. Vector-mediated dispersal may have been impeded by a combination of sub-optimal connectivity, limited dispersal ability of infected hosts and a lack of suitable dispersers following the rapid, Bsal-driven collapse of susceptible hosts at the source site. Although the exact cause remains unclear, the aggregate evidence suggests that Bsal may be a poorer disperser than previously hypothesized. The lack of Bsal dispersal between neighbouring salamander populations opens perspectives for disease management and stresses the necessity of implementing biosecurity measures preventing human-mediated spread. PMID- 29491410 TI - Varying temperature and silicon content in nanodiamond growth: effects on silicon vacancy centres. AB - Nanodidamonds containing colour centres open up many applications in quantum information processing, metrology, and quantum sensing. However, controlling the synthesis of nanodiamonds containing silicon vacancy (SiV) centres is still not well understood. Here we study nanodiamonds produced by a high-pressure high temperature method without catalyst metals, focusing on two samples with clear SiV signatures. Different growth temperatures and relative content of silicon in the initial compound between the samples altered their nanodiamond size distributions and abundance of SiV centres. Our results show that nanodiamond growth can be controlled and optimised for different applications. PMID- 29491411 TI - Recent progress and perspectives of space electric propulsion systems based on smart nanomaterials. AB - Drastic miniaturization of electronics and ingression of next-generation nanomaterials into space technology have provoked a renaissance in interplanetary flights and near-Earth space exploration using small unmanned satellites and systems. As the next stage, the NASA's 2015 Nanotechnology Roadmap initiative called for new design paradigms that integrate nanotechnology and conceptually new materials to build advanced, deep-space-capable, adaptive spacecraft. This review examines the cutting edge and discusses the opportunities for integration of nanomaterials into the most advanced types of electric propulsion devices that take advantage of their unique features and boost their efficiency and service life. Finally, we propose a concept of an adaptive thruster. PMID- 29491412 TI - The novel BET bromodomain inhibitor BI 894999 represses super-enhancer-associated transcription and synergizes with CDK9 inhibition in AML. AB - Bromodomain and extra-terminal (BET) protein inhibitors have been reported as treatment options for acute myeloid leukemia (AML) in preclinical models and are currently being evaluated in clinical trials. This work presents a novel potent and selective BET inhibitor (BI 894999), which has recently entered clinical trials (NCT02516553). In preclinical studies, this compound is highly active in AML cell lines, primary patient samples, and xenografts. HEXIM1 is described as an excellent pharmacodynamic biomarker for target engagement in tumors as well as in blood. Mechanistic studies show that BI 894999 targets super-enhancer regulated oncogenes and other lineage-specific factors, which are involved in the maintenance of the disease state. BI 894999 is active as monotherapy in AML xenografts, and in addition leads to strongly enhanced antitumor effects in combination with CDK9 inhibitors. This treatment combination results in a marked decrease of global p-Ser2 RNA polymerase II levels and leads to rapid induction of apoptosis in vitro and in vivo. Together, these data provide a strong rationale for the clinical evaluation of BI 894999 in AML. PMID- 29491413 TI - Coupling between intra- and intermolecular motions in liquid water revealed by two-dimensional terahertz-infrared-visible spectroscopy. AB - The interaction between intramolecular and intermolecular degrees of freedom in liquid water underlies fundamental chemical and physical phenomena such as energy dissipation and proton transfer. Yet, it has been challenging to elucidate the coupling between these different types of modes. Here, we report on the direct observation and quantification of the coupling between intermolecular and intramolecular coordinates using two-dimensional, ultra-broadband, terahertz infrared-visible (2D TIRV) spectroscopy and molecular dynamics calculations. Our study reveals strong coupling of the O-H stretch vibration, independent of the degree of delocalization of this high-frequency mode, to low-frequency intermolecular motions over a wide frequency range from 50 to 250 cm-1, corresponding to both the intermolecular hydrogen bond bending (~ 60 cm-1) and stretching (~ 180 cm-1) modes. Our results provide mechanistic insights into the coupling of the O-H stretch vibration to collective, delocalized intermolecular modes. PMID- 29491414 TI - Monovalent manganese based anodes and co-solvent electrolyte for stable low-cost high-rate sodium-ion batteries. AB - The demand of sustainable power supply requires high-performance cost-effective energy storage technologies. Here we report a high-rate long-life low-cost sodium ion battery full-cell system by innovating both the anode and the electrolyte. The redox couple of manganese(I/II) in Prussian blue analogs enables a high-rate and stable anode. Soft X-ray absorption spectroscopy and resonant inelastic X-ray scattering provide direct evidence suggesting the existence of monovalent manganese in the charged anode. There is a strong hybridization between cyano ligands and manganese-3d states, which benefits the electronic property for improving rate performance. Additionally, we employ an organic-aqueous cosolvent electrolyte to solve the long-standing solubility issue of Prussian blue analogs. A full-cell sodium-ion battery with low-cost Prussian blue analogs in both electrodes and co-solvent electrolyte retains 95% of its initial discharge capacity after 1000 cycles at 1C and 95% depth of discharge. The revealed manganese(I/II) redox couple inspires conceptual innovations of batteries based on atypical oxidation states. PMID- 29491416 TI - Dual properties of a hydrogen oxidation Ni-catalyst entrapped within a polymer promote self-defense against oxygen. AB - The Ni(P2N2)2 catalysts are among the most efficient non-noble-metal based molecular catalysts for H2 cycling. However, these catalysts are O2 sensitive and lack long term stability under operating conditions. Here, we show that in a redox silent polymer matrix the catalyst is dispersed into two functionally different reaction layers. Close to the electrode surface is the "active" layer where the catalyst oxidizes H2 and exchanges electrons with the electrode generating a current. At the outer film boundary, insulation of the catalyst from the electrode forms a "protection" layer in which H2 is used by the catalyst to convert O2 to H2O, thereby providing the "active" layer with a barrier against O2. This simple but efficient polymer-based electrode design solves one of the biggest limitations of these otherwise very efficient catalysts enhancing its stability for catalytic H2 oxidation as well as O2 tolerance. PMID- 29491417 TI - Clinical significance of an elevated ankle-brachial index differs depending on the amount of appendicular muscle mass: the J-SHIPP and Nagahama studies. AB - Clinical implication of a high ankle-brachial index (ABI) is not well known. Based on our previous study, we suspected that body composition may be a determinant of a high ABI and may consequently modulate the clinical significance of a high ABI. Datasets of two studies with independent cohorts, the anti-aging study cohort (n = 1765) and the Nagahama study cohort (n = 8,039), were analyzed in this study, in which appendicular muscle mass was measured by computed tomography and bioelectrical impedance analysis, respectively. Brachial and ankle blood pressures were measured using a cuff-oscillometric method. In the anti aging study cohort, thigh muscle area (beta = 0.387, p < 0.001), but not fat area, showed a strong positive association with the ABI independent of the body mass index (p = 0.662) and other possible covariates, including systolic brachial blood pressure (p = 0.054), carotid hypertrophy (p = 0.559), and arterial stiffness (beta = 0.102, p = 0.001). This positive association was replicated in the Nagahama cohort. When the subjects were subdivided by the 75th percentiles of the ABI and appendicular muscle mass, multinomial logistic regression analysis identified insulin resistance as an independent determinant of an elevated ABI in subjects with normal muscle mass (coefficient = 0.134, p = 0.010), whereas insulin resistance was inversely associated with an elevated ABI in subjects with high muscle mass (coefficient = -0.268, p = 0.001). Appendicular muscle mass was a strong determinant of the ABI. The clinical background, particularly insulin resistance, of individuals with an elevated ABI may differ based on the amount of muscle mass. PMID- 29491415 TI - Rational design of a trispecific antibody targeting the HIV-1 Env with elevated anti-viral activity. AB - HIV-1 broadly neutralizing antibodies (bNAbs) are being explored as passively administered therapeutic and preventative agents. However, the extensively diversified HIV-1 envelope glycoproteins (Env) rapidly acquire mutations to evade individual bNAbs in monotherapy regimens. The use of a "single" agent to simultaneously target distinct Env epitopes is desirable to overcome viral diversity. Here, we report the use of tandem single-chain variable fragment (ScFv) domains of two bNAbs, specific for the CD4-binding site and V3 glycan patch, to form anti-HIV-1 bispecific ScFvs (Bi-ScFvs). The optimal Bi-ScFv crosslinks adjacent protomers within one HIV-1 Env spike and has greater neutralization breadth than its parental bNAbs. Furthermore, the combination of this Bi-ScFv with a third bNAb recognizing the Env membrane proximal external region (MPER) results in a trispecific bNAb, which has nearly pan-isolate neutralization breadth and high potency. Thus, multispecific antibodies combining functional moieties of bNAbs could achieve outstanding neutralization capacity with augmented avidity. PMID- 29491418 TI - Two distinct domains contribute to the substrate acyl chain length selectivity of plant acyl-ACP thioesterase. AB - The substrate specificity of acyl-ACP thioesterase (TE) plays an essential role in controlling the fatty acid profile produced by type II fatty acid synthases. Here we identify two groups of residues that synergistically determine different substrate specificities of two acyl-ACP TEs from Cuphea viscosissima (CvFatB1 and CvFatB2). One group (V194, V217, N223, R226, R227, and I268 in CvFatB2) is critical in determining the structure and depth of a hydrophobic cavity in the N terminal hotdog domain that binds the substrate's acyl moiety. The other group (255-RKLSKI-260 and 285-RKLPKL-289 in CvFatB2) defines positively charged surface patches that may facilitate binding of the ACP moiety. Mutagenesis of residues within these two groups results in distinct synthetic acyl-ACP TEs that efficiently hydrolyze substrates with even shorter chains (C4- to C8-ACPs). These insights into structural determinants of acyl-ACP TE substrate specificity are useful in modifying this enzyme for tailored fatty acid production in engineered organisms. PMID- 29491420 TI - Femtosecond Laser Mass Spectrometry and High Harmonic Spectroscopy of Xylene Isomers. AB - Structural isomers, molecules having the same chemical formula but with atoms bonded in different order, are hard to identify using conventional spectroscopy and mass spectrometry. They exhibit virtually indistinguishable mass spectra when ionized by electrons. Laser mass spectrometry based on photoionization of the isomers has emerged as a promising alternative but requires shaped ultrafast laser pulses. Here we use transform limited femtosecond pulses to distinguish the isomers using two methods. First, we probe doubly charged parent ions with circularly polarized light. We show that the yield of doubly charged ortho-xylene decreases while para-xylene increases over a range of laser intensities when the laser polarization is changed from linear to circular. Second, we probe high harmonic generation from randomly oriented isomer molecules subjected to an intense laser field. We show that the yield of high-order harmonics varies with the positioning of the methyl group in xylene isomers (ortho-, para- and meta-) and is due to differences in the strength of tunnel ionization and the overlap between the angular peaks of ionization and photo-recombination. PMID- 29491419 TI - Assembly of 913 microbial genomes from metagenomic sequencing of the cow rumen. AB - The cow rumen is adapted for the breakdown of plant material into energy and nutrients, a task largely performed by enzymes encoded by the rumen microbiome. Here we present 913 draft bacterial and archaeal genomes assembled from over 800 Gb of rumen metagenomic sequence data derived from 43 Scottish cattle, using both metagenomic binning and Hi-C-based proximity-guided assembly. Most of these genomes represent previously unsequenced strains and species. The draft genomes contain over 69,000 proteins predicted to be involved in carbohydrate metabolism, over 90% of which do not have a good match in public databases. Inclusion of the 913 genomes presented here improves metagenomic read classification by sevenfold against our own data, and by fivefold against other publicly available rumen datasets. Thus, our dataset substantially improves the coverage of rumen microbial genomes in the public databases and represents a valuable resource for biomass-degrading enzyme discovery and studies of the rumen microbiome. PMID- 29491422 TI - Identification, expression, and endocrine-disruption of three ecdysone-responsive genes in the sentinel species Gammarus fossarum. AB - Taking advantage of a large transcriptomic dataset recently obtained in the sentinel crustacean amphipod Gammarus fossarum, we developed an approach based on sequence similarity and phylogenetic reconstruction to identify key players involved in the endocrine regulation of G. fossarum. Our work identified three genes of interest: the nuclear receptors RXR and E75, and the regulator broad complex (BR). Their involvement in the regulation of molting and reproduction, along with their sensitivity to chemical contamination were experimentally assessed by studying gene expression during the female reproductive cycle, and after laboratory exposure to model endocrine disrupting compounds (EDCs): pyriproxyfen, tebufenozide and piperonyl butoxide. RXR expression suggested a role of this gene in ecdysis and post-molting processes. E75 presented two expression peaks that suggested a role in vitellogenesis, and molting. BR expression showed no variation during molting/reproductive cycle. After exposure to the three EDCs, a strong inhibition of the inter-molt E75 peak was observed with tebufenozide, and an induction of RXR after exposure to pyriproxyfen and piperonyl butoxide. These results confirm the implication of RXR and E75 in hormonal regulation of female reproductive cycles in G. fossarum and their sensitivity towards EDCs opens the possibility of using them as specific endocrine disruption biomarkers. PMID- 29491421 TI - Sheep genome functional annotation reveals proximal regulatory elements contributed to the evolution of modern breeds. AB - Domestication fundamentally reshaped animal morphology, physiology and behaviour, offering the opportunity to investigate the molecular processes driving evolutionary change. Here we assess sheep domestication and artificial selection by comparing genome sequence from 43 modern breeds (Ovis aries) and their Asian mouflon ancestor (O. orientalis) to identify selection sweeps. Next, we provide a comparative functional annotation of the sheep genome, validated using experimental ChIP-Seq of sheep tissue. Using these annotations, we evaluate the impact of selection and domestication on regulatory sequences and find that sweeps are significantly enriched for protein coding genes, proximal regulatory elements of genes and genome features associated with active transcription. Finally, we find individual sites displaying strong allele frequency divergence are enriched for the same regulatory features. Our data demonstrate that remodelling of gene expression is likely to have been one of the evolutionary forces that drove phenotypic diversification of this common livestock species. PMID- 29491423 TI - Spatial specificity of auxin responses coordinates wood formation. AB - Spatial organization of signalling events of the phytohormone auxin is fundamental for maintaining a dynamic transition from plant stem cells to differentiated descendants. The cambium, the stem cell niche mediating wood formation, fundamentally depends on auxin signalling but its exact role and spatial organization is obscure. Here we show that, while auxin signalling levels increase in differentiating cambium descendants, a moderate level of signalling in cambial stem cells is essential for cambium activity. We identify the auxin dependent transcription factor ARF5/MONOPTEROS to cell-autonomously restrict the number of stem cells by directly attenuating the activity of the stem cell promoting WOX4 gene. In contrast, ARF3 and ARF4 function as cambium activators in a redundant fashion from outside of WOX4-expressing cells. Our results reveal an influence of auxin signalling on distinct cambium features by specific signalling components and allow the conceptual integration of plant stem cell systems with distinct anatomies. PMID- 29491425 TI - The mitochondrial nucleoside diphosphate kinase (NDPK-D/NME4), a moonlighting protein for cell homeostasis. AB - Mitochondrial nucleoside diphosphate kinase (NDPK-D; synonyms: NME4, NM23-H4) represents the major mitochondrial NDP kinase. The homohexameric complex emerged as a protein with multiple functions in bioenergetics and phospholipid signaling. It occurs at different but precise mitochondrial locations and can affect among other mitochondrial shapes and dynamics, as well as the specific elimination of defective mitochondria or cells via mitophagy or apoptosis. With these various functions in cell homeostasis, NDPK-D/NME4 adds to the group of so-called moonlighting (or gene sharing) proteins. PMID- 29491424 TI - ASC- and caspase-8-dependent apoptotic pathway diverges from the NLRC4 inflammasome in macrophages. AB - The NLRC4 inflammasome recognizes bacterial flagellin and components of the type III secretion apparatus. NLRC4 stimulation leads to caspase-1 activation followed by a rapid lytic cell death known as pyroptosis. NLRC4 is linked to pathogen-free auto-inflammatory diseases, suggesting a role for NLRC4 in sterile inflammation. Here, we show that NLRC4 activates an alternative cell death program morphologically similar to apoptosis in caspase-1-deficient BMDMs. By performing an unbiased genome-wide CRISPR/Cas9 screen with subsequent validation studies in gene-targeted mice, we highlight a critical role for caspase-8 and ASC adaptor in an alternative apoptotic pathway downstream of NLRC4. Furthermore, caspase-1 catalytically dead knock-in (Casp1 C284A KI) BMDMs genetically segregate pyroptosis and apoptosis, and confirm that caspase-1 does not functionally compete with ASC for NLRC4 interactions. We show that NLRC4/caspase-8-mediated apoptotic cells eventually undergo plasma cell membrane damage in vitro, suggesting that this pathway can lead to secondary necrosis. Unexpectedly, we found that DFNA5/GSDME, a member of the pore-forming gasdermin family, is dispensable for the secondary necrosis that follows NLRC4-mediated apoptosis in macrophages. Together, our data confirm the existence of an alternative caspase-8 activation pathway diverging from the NLRC4 inflammasome in primary macrophages. PMID- 29491426 TI - The extracellular domain of Her2 in serum as a biomarker of breast cancer. AB - Breast cancer is a major health problem worldwide. In ~15% of breast cancers, the epidermal growth factor receptor HER2, a transmembrane protein, is overexpressed. This HER2 overexpression is associated with an aggressive form of the disease and a poor clinical prognosis. The extracellular domain (ECD) of HER2 is released into the blood by a proteolytic mechanism known as "ECD shedding". This proteolytic shedding leaves a constitutively active truncated receptor in the membrane that is 10-100-fold more oncogenic than the full-length receptor and promotes the growth and survival of cancer cells. Shedding of the HER2 ECD is increased during metastasis: whereas 15% of primary breast cancer patients have elevated levels of serum HER2 ECD (sHER2 ECD), the levels reach 45% in patients with metastatic disease. Thus, sHER2 ECD has been proposed as a promising biomarker for cancer recurrence and for monitoring the disease status of patients overexpressing HER2. Nevertheless, in 2016, the American Society of Clinical Oncology advises clinicians not to use soluble HER2 levels to guide their choice of adjuvant therapy for patients with HER2-positive breast cancer, because the evidence was considered not strong enough. Currently, biomarkers such as carcinoembryonic antigen and cancer antigen 15-3 are widely used to monitor metastatic breast cancer disease even if the level of evidence of clinical impact of this monitoring is poor. In this article, we review the evidence that sHER2 ECD might be used in some situations as a biomarker for breast cancer. Although this serum biomarker will not replace the direct measurement of tumor HER2 status for diagnosis of early-stage tumors; it might be especially useful in metastatic disease for prognosis, as an indicator of cancer progression and of therapy response, particularly to anti-HER2 therapies. Owing to these data, sHER2 ECD should be considered as a promising biomarker to detect cancer recurrence and metastasis. PMID- 29491427 TI - Simulation of solute transport through heterogeneous networks: analysis using the method of moments and the statistics of local transport characteristics. AB - We used a time domain random walk approach to simulate passive solute transport in networks. In individual pores, solute transport was modeled as a combination of Poiseuille flow and Taylor dispersion. The solute plume data were interpreted via the method of moments. Analysis of the first and second moments showed that the longitudinal dispersivity increased with increasing coefficient of variation of the pore radii CV and decreasing pore coordination number Z. The third moment was negative and its magnitude grew linearly with time, meaning that the simulated dispersion was intrinsically non-Fickian. The statistics of the Eulerian mean fluid velocities [Formula: see text], the Taylor dispersion coefficients [Formula: see text] and the transit times [Formula: see text] were very complex and strongly affected by CV and Z. In particular, the probability of occurrence of negative velocities grew with increasing CV and decreasing Z. Hence, backward and forward transit times had to be distinguished. The high-tau branch of the transit-times probability curves had a power law form associated to non-Fickian behavior. However, the exponent was insensitive to pore connectivity, although variations of Z affected the third moment growth. Thus, we conclude that both the low- and high-tau branches played a role in generating the observed non Fickian behavior. PMID- 29491428 TI - Secondary forest regeneration benefits old-growth specialist bats in a fragmented tropical landscape. AB - Tropical forest loss and fragmentation are due to increase in coming decades. Understanding how matrix dynamics, especially secondary forest regrowth, can lessen fragmentation impacts is key to understanding species persistence in modified landscapes. Here, we use a whole-ecosystem fragmentation experiment to investigate how bat assemblages are influenced by the regeneration of the secondary forest matrix. We surveyed bats in continuous forest, forest fragments and secondary forest matrix habitats, ~15 and ~30 years after forest clearance, to investigate temporal changes in the occupancy and abundance of old-growth specialist and habitat generalist species. The regeneration of the second growth matrix had overall positive effects on the occupancy and abundance of specialists across all sampled habitats. Conversely, effects on generalist species were negligible for forest fragments and negative for secondary forest. Our results show that the conservation potential of secondary forests for reverting faunal declines in fragmented tropical landscapes increases with secondary forest age and that old-growth specialists, which are often of most conservation concern, are the greatest beneficiaries of secondary forest maturation. Our findings emphasize that the transposition of patterns of biodiversity persistence in island ecosystems to fragmented terrestrial settings can be hampered by the dynamic nature of human-dominated landscapes. PMID- 29491430 TI - Dual-band transmission polarization converter based on planar-dipole pair frequency selective surface. AB - A novel linear polarization converter operating in C- and X-bands with high polarization conversion ratio is described and demonstrated based on frequency selective surface. The building element is a planar-dipole pair, which is orthogonally printed on a double-layer substrate and vertically connected by a pair of through-via holes functioning as a quasi-two-wire transmission line coupler. A perforated metal shielding layer is sandwiched between the double layer structure to only support a transverse electric and magnetic (TEM) mode coupling between the top and bottom dipolar components. The front dipole responds to the incident transverse electric (TE) wave, and sends the induced current into the two-wire transmission line to feed the bottom dipole. The bottom dipole is orthogonal or oriented at an arbitrary angle with respect to the top one, and a resultant outgoing transverse magnetic (TM) wave or arbitrary orientation polarized wave can be achieved. In addition, a bidirectional orthogonal polarization converter is realized by using double orthogonally arranged planar dipole pairs, which are also printed on the same double-layer substrate. PMID- 29491429 TI - Simulated microgravity inhibits cell focal adhesions leading to reduced melanoma cell proliferation and metastasis via FAK/RhoA-regulated mTORC1 and AMPK pathways. AB - Simulated microgravity (SMG) was reported to affect tumor cell proliferation and metastasis. However, the underlying mechanism is elusive. In this study, we demonstrate that clinostat-modelled SMG reduces BL6-10 melanoma cell proliferation, adhesion and invasiveness in vitro and decreases tumor lung metastasis in vivo. It down-regulates metastasis-related integrin alpha6beta4, MMP9 and Met72 molecules. SMG significantly reduces formation of focal adhesions and activation of focal adhesion kinase (FAK) and Rho family proteins (RhoA, Rac1 and Cdc42) and of mTORC1 kinase, but activates AMPK and ULK1 kinases. We demonstrate that SMG inhibits NADH induction and glycolysis, but induces mitochondrial biogenesis. Interestingly, administration of a RhoA activator, the cytotoxic necrotizing factor-1 (CNF1) effectively converts SMG-triggered alterations and effects on mitochondria biogenesis or glycolysis. CNF1 also converts the SMG-altered cell proliferation and tumor metastasis. In contrast, mTORC inhibitor, rapamycin, produces opposite responses and mimics SMG-induced effects in cells at normal gravity. Taken together, our observations indicate that SMG inhibits focal adhesions, leading to inhibition of signaling FAK and RhoA, and the mTORC1 pathway, which results in activation of the AMPK pathway and reduced melanoma cell proliferation and metastasis. Overall, our findings shed a new light on effects of microgravity on cell biology and human health. PMID- 29491431 TI - Adult mouse eIF2Bepsilon Arg191His astrocytes display a normal integrated stress response in vitro. AB - Vanishing white matter (VWM) is a genetic childhood white matter disorder, characterized by chronic as well as episodic, stress provoked, neurological deterioration. Treatment is unavailable and patients often die within a few years after onset. VWM is caused by recessive mutations in the eukaryotic initiation factor 2B (eIF2B). eIF2B regulates protein synthesis rates in every cell of the body. In normal cells, various types of cellular stress inhibit eIF2B activity and induce the integrated stress response (ISR). We have developed a VWM mouse model homozygous for the pathogenic Arg191His mutation in eIF2Bepsilon (2b5 ho ), representative of the human disease. Neuropathological examination of VWM patient and mouse brain tissue suggests that astrocytes are primarily affected. We hypothesized that VWM astrocytes are selectively hypersensitive to ISR induction, resulting in a heightened response. We cultured astrocytes from wildtype and VWM mice and investigated the ISR in assays that measure transcriptional induction of stress genes, protein synthesis rates and cell viability. We investigated the effects of short- and long-term stress as well as stress recovery. We detected congruent results amongst the various assays and did not detect a hyperactive ISR in VWM mouse astrocytes. PMID- 29491432 TI - A symbolic network-based nonlinear theory for dynamical systems observability. AB - When the state of the whole reaction network can be inferred by just measuring the dynamics of a limited set of nodes the system is said to be fully observable. However, as the number of all possible combinations of measured variables and time derivatives spanning the reconstructed state of the system exponentially increases with its dimension, the observability becomes a computationally prohibitive task. Our approach consists in computing the observability coefficients from a symbolic Jacobian matrix whose elements encode the linear, nonlinear polynomial or rational nature of the interaction among the variables. The novelty we introduce in this paper, required for treating large-dimensional systems, is to identify from the symbolic Jacobian matrix the minimal set of variables (together with their time derivatives) candidate to be measured for completing the state space reconstruction. Then symbolic observability coefficients are computed from the symbolic observability matrix. Our results are in agreement with the analytical computations, evidencing the correctness of our approach. Its application to efficiently exploring the dynamics of real world complex systems such as power grids, socioeconomic networks or biological networks is quite promising. PMID- 29491434 TI - TRPV4-mediates oscillatory fluid shear mechanotransduction in mesenchymal stem cells in part via the primary cilium. AB - Skeletal homeostasis requires the continued replenishment of the bone forming osteoblast from a mesenchymal stem cell (MSC) population, a process that has been shown to be mechanically regulated. However, the mechanisms by which a biophysical stimulus can induce a change in biochemical signaling, mechanotransduction, is poorly understood. As a precursor to loading-induced bone formation, deciphering the molecular mechanisms of MSC osteogenesis is a critical step in developing novel anabolic therapies. Therefore, in this study we characterize the expression of the mechanosensitive calcium channel Transient Receptor Potential subfamily V member 4 (TRPV4) in MSCs and demonstrate that TRPV4 localizes to areas of high strain, specifically the primary cilium. We demonstrate that TRPV4 is required for MSC mechanotransduction, mediating oscillatory fluid shear induced calcium signaling and early osteogenic gene expression. Furthermore, we demonstrate that TRPV4 can be activated pharmacologically eliciting a response that mirrors that seen with mechanical stimulation. Lastly, we show that TRPV4 localization to the primary cilium is functionally significant, with MSCs with defective primary cilia exhibiting an inhibited osteogenic response to TRPV4 activation. Collectively, this data demonstrates a novel mechanism of stem cell mechanotransduction, which can be targeted therapeutically, and further highlights the critical role of the primary cilium in MSC biology. PMID- 29491433 TI - Emerging molecular mechanisms in chemotherapy: Ca2+ signaling at the mitochondria associated endoplasmic reticulum membranes. AB - Inter-organellar communication often takes the form of Ca2+ signals. These Ca2+ signals originate from the endoplasmic reticulum (ER) and regulate different cellular processes like metabolism, fertilization, migration, and cell fate. A prime target for Ca2+ signals are the mitochondria. ER-mitochondrial Ca2+ transfer is possible through the existence of mitochondria-associated ER membranes (MAMs), ER structures that are in the proximity of the mitochondria. This creates a micro-domain in which the Ca2+ concentrations are manifold higher than in the cytosol, allowing for rapid mitochondrial Ca2+ uptake. In the mitochondria, the Ca2+ signal is decoded differentially depending on its spatiotemporal characteristics. While Ca2+ oscillations stimulate metabolism and constitute pro-survival signaling, mitochondrial Ca2+ overload results in apoptosis. Many chemotherapeutics depend on efficient ER-mitochondrial Ca2+ signaling to exert their function. However, several oncogenes and tumor suppressors present in the MAMs can alter Ca2+ signaling in cancer cells, rendering chemotherapeutics ineffective. In this review, we will discuss recent studies that connect ER-mitochondrial Ca2+ transfer, tumor suppressors and oncogenes at the MAMs, and chemotherapy. PMID- 29491435 TI - Explaining combinatorial effects of mycotoxins Deoxynivalenol and Zearalenone in mice with urinary metabolomic profiling. AB - Urine metabolic profiling of mice was conducted utilizing gas chromatography-mass spectrometry (GC-MS) to investigate the combinatory effect of mycotoxins deoxynivalenol (DON) and zearalenone (ZEN) on the metabolism of the mice. Experiments were conducted by means of five-week-old mice which were individually exposed to 2 mg/kg DON, 20 mg/kg ZEN and the mixture of DON and ZEN (2 mg/kg and 20 mg/kg, respectively). The intragastric administration was applied for three weeks and urine samples were collected for metabolic analysis. Univariate and multivariate analysis were applied to data matrix processing along with respective pathway analysis by MetaMapp and CytoScape. The results showed that the combined DON and ZEN administration resulted in lower significant changes, compared to the individual mycotoxin treated groups verified by heatmap. Metabolic pathways network mapping indicated that the combined mycotoxins treated groups showed a little effect on the metabolites in most pathways, especially in glucose metabolism and its downstream amino acid metabolism. In glucose metabolism, the content of galactose, mannitol, galactonic acid, myo-inositol, tagatose was drastically down-regulated. Furthermore, the organic acids, pyruvate, and amino acids metabolism displayed the same phenomenon. In conclusion, the combined DON/ZEN administration might lead to an "antagonistic effect" in mice metabolism. PMID- 29491436 TI - Unattached kinetochores drive their own capturing by sequestering a CLASP. AB - Kinetochores that are not attached to microtubules prevent chromosome missegregation via the spindle assembly checkpoint. We show that they also promote their own capturing. Similar to what governs the localization of spindle assembly checkpoint proteins, the phosphorylation of Spc105 by Mps1 allows unattached kinetochores to sequester Stu1 in cooperation with Slk19. The withdrawal of Stu1, a CLASP essential for spindle integrity, from microtubules and attached kinetochores disrupts the organization of the spindle and thus allows the enhanced formation of dynamic random microtubules that span the nucleus and are ideal to capture unattached kinetochores. The enhanced formation of nuclear random microtubules does not occur if Stu1 sequestering to unattached kinetochores fails and the spindle remains uncompromised. Consequently, these cells exhibit a severely decreased capturing efficiency. After the capturing event, Stu1 is relocated to the capturing microtubule and prevents precocious microtubule depolymerization as long as kinetochores are laterally or incompletely end-on attached. PMID- 29491437 TI - Estimating apple tree canopy chlorophyll content based on Sentinel-2A remote sensing imaging. AB - The remote sensing technology provides a new means for the determination of chlorophyll content in apple trees that includes a rapid analysis, low cost and large monitoring area. The Back-Propagation Neural Network (BPNN) and the Supported Vector Machine Regression (SVMR) methods were both frequently used method to construct estimation model based on remote sensing imaging. The aim of this study was to find out which estimation model of apple tree canopy chlorophyll content based on the vegetation indices constructed with visible, red edge and near-infrared bands of the sensor of Sentinel-2 was more accurate and stabler. The results were as follows: The calibration set coefficient of determination (R2) value of 0.729 and validation set R2 value of 0.667 of the model using the SVMR method based on the vegetation indices (NDVIgreen + NDVIred + NDVIre) were higher than those of the model using the BPNN method by 8.2% and 11.0%, respectively. The calibration set root mean square error (RMSE) of 0.159 and validation set RMSE of 0.178 of the model using the SVMR method based on the vegetation indices (NDVIgreen + NDVIred + NDVIre) were lower than those of the model using the BPNN method by 5.9% and 3.8%, respectively. PMID- 29491438 TI - Environmental factors driving fungal distribution in freshwater lake sediments across the Headwater Region of the Yellow River, China. AB - Dispersal limitation and environmental filtering are two primary processes involved in shaping microbial community structure. The pristine environmental and geographical relatively isolation of small lakes distributed in the Headwater Region of Yellow River (HRYR) offer a unique opportunity to test the relative roles of these two processes on fungal communities. Here, we investigated the fungal community in sediment samples from 10 lakes located in the HRYR using high throughput sequencing. The results showed that the fungal community was dominated by Sordariomycetes, Leotiomycetes, Dothideomycetes, Pezizomycetes and Agaricomycetes. The results revealed that altitude, mean annual temperature, C/N ration, dissolve organic carbon and total nitrogen were the best predictors for shaping fungal community structure in these lakes. Significant spatial and environmental distance decay relationships in the fungal community were detected. The partial Mantel test indicated that the fungal community structure was significantly correlated with environmental distance but not with geographic distance. Overall, environmental filtering plays a more important role than dispersal limitation in fungal community structure at a local scale in such an pristine and isolated region. PMID- 29491439 TI - 'Cyclical Bias' in Microbiome Research Revealed by A Portable Germ-Free Housing System Using Nested Isolation. AB - Germ-Free (GF) research has required highly technical pressurized HEPA ventilation anchored systems for decades. Herein, we validated a GF system that can be easily implemented and portable using Nested Isolation (NesTiso). GF standards can be achieved housing mice in non-HEPA-static cages, which only need to be nested 'one-cage-inside-another' resembling 'Russian dolls'. After 2 years of monitoring ~100,000 GF-mouse-days, NesTiso showed mice can be maintained GF for life (>1.3 years), with low animal daily-contamination-probability risk (1 every 867 days), allowing the expansion of GF research with unprecedented freedom and mobility. At the cage level, with 23,360 GF cage-days, the probability of having a cage contamination in NesTiso cages opened in biosafety hoods was statistically identical to that of opening cages inside (the 'gold standard') multi-cage pressurized GF isolators. When validating the benefits of using NesTiso in mouse microbiome research, our experiments unexpectedly revealed that the mouse fecal microbiota composition within the 'bedding material' of conventional SPF-cages suffers cyclical selection bias as moist/feces/diet/organic content ('soiledness') increases over time (e.g., favoring microbiome abundances of Bacillales, Burkholderiales, Pseudomonadales; and cultivable Enterococcus faecalis over Lactobacillus murinus and Escherichia coli), which in turn cyclically influences the gut microbiome dynamics of caged mice. Culture 'co-streaking' assays showed that cohoused mice exhibiting different fecal microbiota/hemolytic profiles in clean bedding (high-within-cage individual diversity) 'cyclically and transiently appear identical' (less diverse) as bedding soiledness increases, and recurs. Strategies are proposed to minimize this novel functional form of cyclical bedding-dependent microbiome selection bias. PMID- 29491440 TI - Social content and emotional valence modulate gaze fixations in dynamic scenes. AB - Previous research has shown that low-level visual features (i.e., low-level visual saliency) as well as socially relevant information predict gaze allocation in free viewing conditions. However, these studies mainly used static and highly controlled stimulus material, thus revealing little about the robustness of attentional processes across diverging situations. Secondly, the influence of affective stimulus characteristics on visual exploration patterns remains poorly understood. Participants in the present study freely viewed a set of naturalistic, contextually rich video clips from a variety of settings that were capable of eliciting different moods. Using recordings of eye movements, we quantified to what degree social information, emotional valence and low-level visual features influenced gaze allocation using generalized linear mixed models. We found substantial and similarly large regression weights for low-level saliency and social information, affirming the importance of both predictor classes under ecologically more valid dynamic stimulation conditions. Differences in predictor strength between individuals were large and highly stable across videos. Additionally, low-level saliency was less important for fixation selection in videos containing persons than in videos not containing persons, and less important for videos perceived as negative. We discuss the generalizability of these findings and the feasibility of applying this research paradigm to patient groups. PMID- 29491441 TI - Multimorbidity patterns in relation to polypharmacy and dosage frequency: a nationwide, cross-sectional study in a Japanese population. AB - In the present study, we aimed to identify multimorbidity patterns in a Japanese population and investigate whether these patterns have differing effects on polypharmacy and dosage frequency. Data was collected on 17 chronic health conditions via nationwide cross-sectional survey of 3,256 adult Japanese residents. Factor analysis was performed to identify multimorbidity patterns, and associations were determined with excessive polypharmacy [concurrent use of >= 10 prescription or over-the-counter (OTC) medications] and higher dosage frequency ( >= 3 doses per day). Secondary outcomes were the number of concurrent prescription medications and the number of concurrent OTC medications. We used a generalized linear model to adjust for individual sociodemographic characteristics. Five multimorbidity patterns were identified: cardiovascular/renal/metabolic, neuropsychiatric, skeletal/articular/digestive, respiratory/dermal, and malignant/digestive/urologic. Among these patterns, malignant/digestive/urologic and cardiovascular/renal/metabolic patterns showed the strongest associations with excessive polypharmacy and the number of concurrent OTC medications. Malignant/digestive/urologic, respiratory/dermal, and skeletal/articular/digestive patterns were also associated with higher dosage frequency. Multimorbidity patterns have differing effects on excessive polypharmacy and dosage frequency. Malignant/digestive/urologic pattern may be at higher risk of impaired medication safety and increased treatment burden, than other patterns. Continued study is warranted to determine how to incorporate multimorbidity patterns into risk assessments of polypharmacy and overall treatment burden. PMID- 29491442 TI - JMJD-1.2 controls multiple histone post-translational modifications in germ cells and protects the genome from replication stress. AB - Post-translational modifications of histones, constitutive components of chromatin, regulate chromatin compaction and control all DNA-based cellular processes. C. elegans JMJD-1.2, a member of the KDM7 family, is a demethylase active towards several lysine residues on Histone 3 (H3), but its contribution in regulating histone methylation in germ cells has not been fully investigated. Here, we show that jmjd-1.2 is expressed abundantly in the germline where it controls the level of histone 3 lysine 9, lysine 23 and lysine 27 di-methylation (H3K9/K23/K27me2) both in mitotic and meiotic cells. Loss of jmjd-1.2 is not associated with major defects in the germ cells in animals grown under normal conditions or after DNA damage induced by UV or ionizing irradiation. However, jmjd-1.2 mutants are more sensitive to replication stress and the progeny of mutant animals exposed to hydroxyurea show increased embryonic lethality and mutational rate, compared to wild-type. Thus, our results suggest a role for jmjd 1.2 in the maintenance of genome integrity after replication stress and emphasize the relevance of the regulation of histone methylation in genomic stability. PMID- 29491443 TI - Long-term optical brain imaging in live adult fruit flies. AB - Time-lapse in vivo microscopy studies of cellular morphology and physiology are crucial toward understanding brain function but have been infeasible in the fruit fly, a key model species. Here we use laser microsurgery to create a chronic fly preparation for repeated imaging of neural architecture and dynamics for up to 50 days. In fly mushroom body neurons, we track axonal boutons for 10 days and record odor-evoked calcium transients over 7 weeks. Further, by using voltage imaging to resolve individual action potentials, we monitor spiking plasticity in dopamine neurons of flies undergoing mechanical stress. After 24 h of stress, PPL1-alpha'3 but not PPL1-alpha'2alpha2 dopamine neurons have elevated spike rates. Overall, our chronic preparation is compatible with a broad range of optical techniques and enables longitudinal studies of many biological questions that could not be addressed before in live flies. PMID- 29491444 TI - Morphological characterization of the progenies of pure and reciprocal crosses of Pangasianodon hypophthalmus (Sauvage, 1878) and Clarias gariepinus (Burchell, 1822). AB - Twenty-five traditional and thirty-four geometric morphometric comparisons were carried out on pure and reciprocal crosses of Pangasianodon hypophthalmus (Sauvage, 1878) and Clarias gariepinus (Burchell, 1822). Thirty fish samples each of the C. gariepinus (CH), P. hypophthalmus (PH), Pangapinus (?PH * ?CG) and the two distinct morphotypes of the Clariothalmus (?CG * ?PH) (Clarias-like and Panga like) between the ages of four and six months were used for this study. Phenotypically, the Clarias-like Clariothalmus and the Pangapinus progenies were indistinguishable from their maternal parents while the Panga-like Clariothalmus was a phenotypic intermediary of the putative parents but looks more closely to the paternal parent. Hence, both univariate proportion and multivariate analysis of the collected data successfully separated the different fishes into three multivariate spaces. The analysis of the dendrogram with complete linkage and Euclidean distance further showed the close relationship of the isolated Panga like Clariothalmus progenies to the paternal parent, however, Clarias-like Clariothalmus and the Pangapinus were completely intermingled with their maternal parents. The most important index of discrimination of these fishes into different multivariate spaces was the fin characteristic which showed 100% exclusive ranges for the individual groups in many cases. PMID- 29491445 TI - Nozzle Shape Guided Filler Orientation in 3D Printed Photo-curable Nanocomposites. AB - Here, we report guided orientation of silver nanowires (AgNWs) in extruded patterns with photo-curable 3D printing technology. A printable conductive composite material composed of polymer matrix and silver nanowires shows significantly varied electrical properties depending on the cross-sectional shape of printing nozzles: flat or circular. The composite is designed to have highly conductive AgNWs and a dielectric polymer matrix like photo-curable methacrylate resin. The dielectric permittivity of photo-curable composite resin with 1.6 vol. % of AgNWs printed through a circular nozzle showed 27. However, the same resin showed much lower permittivity with 20 when it is printed with a flat nozzle. The cross-sectional sample morphology shows that AgNWs printed with a circular nozzle are aligned, and AgNWs printed with a flat nozzle are randomly distributed. A computational simulation of paste extrusion with two different nozzle shapes showed clearly different fluidic velocities at the nozzle exit, which contributes to different fiber orientation in printed samples. A radio frequency identification sensor is fabricated with 3D printed composite using a flat nozzle for the demonstration of AgNW based 3D printed conductor. PMID- 29491446 TI - Visual stimulation-induced mild stress enhances cognitive behavior in cynomolgus monkey. AB - Cortisol is a well-known endogenous glucocorticoid that serves as a stress indicator. It is normally released under stressful condition to warn about imminent danger and thus is critical for survival of the species. However, it is unclear how cortisol relates to cognitive process under physiological condition in high-order primates such as non-human primates (NHP). Here, we report that a slight but significant increase in blood cortisol level by mild stress is positively correlated with the cognitive function in cynomolgus monkey. We stimulated 3 groups of monkeys by viewing consecutive series of pictures of monkeys, pictures of humans, or animation still pictures. We first found that the blood cortisol level was significantly higher during the stimulation session and returned to normal after stimulation session. Among the three types of pictures, the monkeys which were stimulated with monkey pictures showed the most significant increase in cortisol level during stimulation. Furthermore, the monkeys showed significantly enhanced manipulation, suggesting that cortisol affected cognitive processes. Overall, our study demonstrates that visual stimulation both increases blood cortisol and enhances manipulating behavior. Therefore, unlike the common notion that cortisol is a stress indicator, our data supports that a mild increase of cortisol enhances cognition in NHP. PMID- 29491448 TI - Nestedness patterns and the role of morphodynamics and spatial distance on sandy beach fauna: ecological hypotheses and conservation strategies. AB - Sandy beach fauna is hypothesized to be mainly structured by environmental variables. As such, it is expected that morphodynamic characteristics are limiting factors, and the species pool inhabiting harsher reflective beaches would be a subset of (i.e., nested in) the fauna of nearby dissipative beaches. We investigated the existence of a nestedness pattern in sandy beach assemblages, as well as the contribution of environmental and spatial variables (i.e., factors that potentially affect an assemblage regardless of environmental conditions - typically related to distance between sites and dispersal of organisms) on sandy beach macrobenthic fauna. Dissipative beaches had higher species richness than reflective beaches but we found no nestedness pattern. Furthermore, almost every beach showed exclusive species. Spatial variables exerted stronger influence on macrobenthic assemblages than local environmental variables. Our results therefore suggest that local and small-scale recruitment is the predominant process structuring macrobenthic assemblages. These results bring important implications for sandy beach conservation: given that spatial distance is an important factor structuring macrobenthic fauna and different sandy beaches harbor different pools of species, conservation programs need to focus on sandy beaches across large spatial scales and with varied morphodynamic characteristics in order to preserve coastal biodiversity. PMID- 29491447 TI - Absence of Claudin 11 in CNS Myelin Perturbs Behavior and Neurotransmitter Levels in Mice. AB - Neuronal origins of behavioral disorders have been examined for decades to construct frameworks for understanding psychiatric diseases and developing useful therapeutic strategies with clinical application. Despite abundant anecdotal evidence for white matter etiologies, including altered tractography in neuroimaging and diminished oligodendrocyte-specific gene expression in autopsy studies, mechanistic data demonstrating that dysfunctional myelin sheaths can cause behavioral deficits and perturb neurotransmitter biochemistry have not been forthcoming. At least in part, this impasse stems from difficulties in identifying model systems free of degenerative pathology to enable unambiguous assessment of neuron biology and behavior in a background of myelin dysfunction. Herein we examine myelin mutant mice lacking expression of the Claudin11 gene in oligodendrocytes and characterize two behavioral endophenotypes: perturbed auditory processing and reduced anxiety/avoidance. Importantly, these behaviors are associated with increased transmission time along myelinated fibers as well as glutamate and GABA neurotransmitter imbalances in auditory brainstem and amygdala, in the absence of neurodegeneration. Thus, our findings broaden the etiology of neuropsychiatric disease to include dysfunctional myelin, and identify a preclinical model for the development of novel disease-modifying therapies. PMID- 29491449 TI - Chronic helminth infection burden differentially affects haematopoietic cell development while ageing selectively impairs adaptive responses to infection. AB - Throughout the lifespan of an individual, the immune system undergoes complex changes while facing novel and chronic infections. Helminths, which infect over one billion people and impose heavy livestock productivity losses, typically cause chronic infections by avoiding and suppressing host immunity. Yet, how age affects immune responses to lifelong parasitic infection is poorly understood. To disentangle the processes involved, we employed supervised statistical learning techniques to identify which factors among haematopoietic stem and progenitor cells (HSPC), and both innate and adaptive responses regulate parasite burdens and how they are affected by host age. Older mice harboured greater numbers of the parasites' offspring than younger mice. Protective immune responses that did not vary with age were dominated by HSPC, while ageing specifically eroded adaptive immunity, with reduced numbers of naive T cells, poor T cell responsiveness to parasites, and impaired antibody production. We identified immune factors consistent with previously-reported immune responses to helminths, and also revealed novel interactions between helminths and HSPC maturation. Our approach thus allowed disentangling the concurrent effects of ageing and infection across the full maturation cycle of the immune response and highlights the potential of such approaches to improve understanding of the immune system within the whole organism. PMID- 29491450 TI - Fluorescent Holographic Fringes with a Surface Relief Structure Based on Merocyanine Aggregation Driven by Blue-violet Laser. AB - Stability and integration are the goals for developing photonic devices. Spirooxazines have the property of photoinduced merocyanine-aggregation in polymer matrix, which can be applied to fluorescence emission and stable information storage. Although visible light coherent radiation with UV-assist has been used to achieve polarization-modulated holographic memory in spirooxazine doped PMMA films, the complexity of optical systems is increased and the aggregation ability of merocyanine is decreased. Here, we report that fluorescent holographic gratings with a surface relief structure can be inscribed in the film via sole irradiation of 403.4 nm. Time-dependent photo-anisotropy and holographic dynamics were both investigated with different power densities of the near-UV laser. The non-exponential photokinetics was explained by the sequential formation of mono- and aggregate-merocyanine molecules. The appearance of merocyanine aggregates is found to be beneficial to the long-term holographic memory with fluorescent emission. This work provides a research strategy for the integrity of storage, display and micro-fabrication of organic functional devices. PMID- 29491451 TI - All-optical control and super-resolution imaging of quantum emitters in layered materials. AB - Layered van der Waals materials are emerging as compelling two-dimensional platforms for nanophotonics, polaritonics, valleytronics and spintronics, and have the potential to transform applications in sensing, imaging and quantum information processing. Among these, hexagonal boron nitride (hBN) is known to host ultra-bright, room-temperature quantum emitters, whose nature is yet to be fully understood. Here we present a set of measurements that give unique insight into the photophysical properties and level structure of hBN quantum emitters. Specifically, we report the existence of a class of hBN quantum emitters with a fast-decaying intermediate and a long-lived metastable state accessible from the first excited electronic state. Furthermore, by means of a two-laser repumping scheme, we show an enhanced photoluminescence and emission intensity, which can be utilized to realize a new modality of far-field super-resolution imaging. Our findings expand current understanding of quantum emitters in hBN and show new potential ways of harnessing their nonlinear optical properties in sub diffraction nanoscopy. PMID- 29491452 TI - Bioprocessing strategies for cost-effective large-scale biogenic synthesis of nano-MgO from endophytic Streptomyces coelicolor strain E72 as an anti-multidrug resistant pathogens agent. AB - In this report, the local nano-MgO synthesizer strain has been isolated from Ocimum sanctum plant and deposited in GenBank as endophytic Streptomyces coelicolor strain E72. Its intracellular metabolic fraction that contains 7.2 MUg/MUl of carbohydrate, 6.3 g/l of protein and 5.2 nmol/hr/ml of nitrate reductase used to produce multi-surface shaped nano-MgO with diameter ~25 nm. To the best of our knowledge, this is the first report using statistical nanobiotechnological strategies (Plackett -Burman, Box-Behnken and Taguchi experimental designs) to study and evaluate the endophytic S. coelicolor biomass production (123.3 g/l) and extract the highest bioactive metabolites that used for biogenic synthesis of nano-MgO (320 g/l) through exponential sucrose pulses feeding fermentation strategy after 192 hr in semi industrial scale bioreactor (7 L). Purified nano-MgO applied in vitro against multi-drug resistant human pathogens and the large inhibition zone recorded against Shigella flexneri (108 +/- 10.53 mm). The average of MICs was recorded as 25 ug/ml that inhibited 90% of the pathogenic living cells and compared with 100 mg/ml ampicilin/sulbactam solution that killed 40% of the same pathogen. These results are expected to gather sufficient knowledge to discover and develop a new cheap and eco-friendly nano-MgO as an extremely strong antimicrobial agent used in biomedical applications. PMID- 29491453 TI - New thin-film surface electrode array enables brain mapping with high spatial acuity in rodents. AB - In neuroscience, single-shank penetrating multi-electrode arrays are standard for sequentially sampling several cortical sites with high spatial and temporal resolution, with the disadvantage of neuronal damage. Non-penetrating surface grids used in electrocorticography (ECoG) permit simultaneous recording of multiple cortical sites, with limited spatial resolution, due to distance to neuronal tissue, large contact size and high impedances. Here we compared new thin-film parylene C ECoG grids, covering the guinea pig primary auditory cortex, with simultaneous recordings from penetrating electrode array (PEAs), inserted through openings in the grid material. ECoG grid local field potentials (LFP) showed higher response thresholds and amplitudes compared to PEAs. They enabled, however, fast and reliable tonotopic mapping of the auditory cortex (place frequency slope: 0.7 mm/octave), with tuning widths similar to PEAs. The ECoG signal correlated best with supragranular layers, exponentially decreasing with cortical depth. The grids also enabled recording of multi-unit activity (MUA), yielding several advantages over LFP recordings, including sharper frequency tunings. ECoG first spike latency showed highest similarity to superficial PEA contacts and MUA traces maximally correlated with PEA recordings from the granular layer. These results confirm high quality of the ECoG grid recordings and the possibility to collect LFP and MUA simultaneously. PMID- 29491454 TI - The right inferior frontal gyrus processes nested non-local dependencies in music. AB - Complex auditory sequences known as music have often been described as hierarchically structured. This permits the existence of non-local dependencies, which relate elements of a sequence beyond their temporal sequential order. Previous studies in music have reported differential activity in the inferior frontal gyrus (IFG) when comparing regular and irregular chord-transitions based on theories in Western tonal harmony. However, it is unclear if the observed activity reflects the interpretation of hierarchical structure as the effects are confounded by local irregularity. Using functional magnetic resonance imaging (fMRI), we found that violations to non-local dependencies in nested sequences of three-tone musical motifs in musicians elicited increased activity in the right IFG. This is in contrast to similar studies in language which typically report the left IFG in processing grammatical syntax. Effects of increasing auditory working demands are moreover reflected by distributed activity in frontal and parietal regions. Our study therefore demonstrates the role of the right IFG in processing non-local dependencies in music, and suggests that hierarchical processing in different cognitive domains relies on similar mechanisms that are subserved by domain-selective neuronal subpopulations. PMID- 29491455 TI - Hematopoietic lineage distribution and evolutionary dynamics of clonal hematopoiesis. AB - Clonal hematopoiesis of indeterminate potential (CHIP) occurs in an age-related manner and associates with an increased risk of hematologic cancer, atherosclerotic disease, and shorter overall survival. Little is known about the cell of origin, repartition patterns of clonal mutations within the hematopoietic differentiation tree, and its dynamics under evolutionary pressure. Using targeted sequencing, CHIP was identified in 121 out of 437 elderly individuals (27.7%). Variant allele frequencies (VAFs) of 91 mutations were studied in six peripheral blood cell fractions. VAFs were significantly higher in monocytes, granulocytes, and NK-cells compared to B- or T cells. In all cases with available bone marrow material, mutations could be identified in Lin-CD34+CD38- HSCs with subsequent expansion to myeloid primed progenitors. In 22 patients with solid cancer receiving (radio-)chemotherapy, longitudinal study of 32 mutations at 121 time points identified relative VAF changes of at least 50% in 13/32 mutations. VAFs of DNMT3A, were stable in 12/13 cases (P < .001). Cancer patients with a clonal mutation other than DNMT3A required more often red blood cell transfusions and dose reductions. Our results provide novel insights into cellular distribution of clonal mutations, their dynamics under chemotherapy, and advocate for systematic analyses for CHIP in cancer patients. PMID- 29491456 TI - Genetic heterogeneity of primary lesion and metastasis in small intestine neuroendocrine tumors. AB - Data on intratumoral heterogeneity of small intestine neuroendocrine tumors (SI NETs) and related liver metastasis are limited. The aim of this study was to characterize genetic heterogeneity of 5 patients with SI-NETs. Therefore, formalin-fixed, paraffin-embedded tissue samples of primary and metastatic lesions as well as benign liver of five patients with synchronously metastasized, well differentiated SI-NETs were analyzed with whole exome sequencing. For one patient, chip based 850k whole DNA methylome analysis was performed of primary and metastatic tumor tissue as well as control tissue. Thereby, 156 single nucleotide variants (SNVs) in 150 genes were identified and amount of mutations per sample ranged from 9-34 (mean 22). The degree of common (0-94%) and private mutations per sample was strongly varying (6-100%). In all patients, copy number variations (CNV) were found and the degree of intratumoral heterogeneity of CNVs corresponded to SNV analysis. DNA methylation analysis of a patient without common SNVs revealed a large overlap of common methylated CpG sites. In conclusion, SI-NET primary and metastatic lesions show a highly varying degree of intratumoral heterogeneity. Driver events might not be detectable with exome analysis only, and further comprehensive studies including whole genome and epigenetic analyses are warranted. PMID- 29491457 TI - Towards in cellulo virus crystallography. AB - Viruses are a significant threat to both human health and the economy, and there is an urgent need for novel anti-viral drugs and vaccines. High-resolution viral structures inform our understanding of the virosphere, and inspire novel therapies. Here we present a method of obtaining such structural information that avoids potentially disruptive handling, by collecting diffraction data from intact infected cells. We identify a suitable combination of cell type and virus to accumulate particles in the cells, establish a suitable time point where most cells contain virus condensates and use electron microscopy to demonstrate that these are ordered crystalline arrays of empty capsids. We then use an X-ray free electron laser to provide extremely bright illumination of sub-micron intracellular condensates of bacteriophage phiX174 inside living Escherichia coli at room temperature. We have been able to collect low resolution diffraction data. Despite the limited resolution and completeness of these initial data, due to a far from optimal experimental setup, we have used novel methodology to determine a putative space group, unit cell dimensions, particle packing and likely maturation state of the particles. PMID- 29491458 TI - Current-induced magnetic switching with spin-orbit torque in an interlayer coupled junction with a Ta spacer layer. AB - Spin-orbit torque has attracted considerable attention as a means to overcome limits of devices based on spin-transfer torque. However, a small magnetic field that is collinear to the current flow must be applied to break symmetry and induce deterministic current-induced magnetization switching. Recently, a junction utilizing interlayer coupling mediated by a Ru spacer layer between two CoFe layers was designed for symmetry breaking and exhibited current-induced magnetization switching without a magnetic field. Here, we demonstrate zero-field current-induced switching of the perpendicular magnetization of a Co layer that is indirectly coupled with a CoFe layer via a Ta spacer. The weak interlayer coupling exhibited by Ta allows the layer thickness to be relatively small (~0.5 nm), enabling appropriate interlayer coupling to induce spin-orbit torque for current-induced magnetic switching. External magnetic field effects on switching characteristics show that the current switching process is quite stable against external environments. PMID- 29491459 TI - Cytomegalovirus-specific T-cells are associated with immune senescence, but not with systemic inflammation, in people living with HIV. AB - In people living with HIV (PLWHIV), coinfection with cytomegalovirus (CMV) has been associated with inflammation, immunological ageing, and increased risk of severe non-AIDS related comorbidity. The effect of CMV-specific immune responses on systemic inflammation, immune activation and T-cell senescence was evaluated in 53 PLWHIV treated with combination antiretroviral therapy (cART). Activated-, terminally differentiated-, naive-, and senescent T-cells were assessed by flow cytometry, and plasma levels of CMV IgG, interleukin-6, tumor necrosis factor alpha, high-sensitivity C-reactive protein and soluble-CD14 were measured. In PLWHIV, expression of interleukin-2, tumor necrosis factor-alpha and interferon gamma was measured by intracellular-cytokine-staining after stimulation of T cells with CMV-pp65, CMV-IE1, and CMV-gB. Increased CMV-specific T-cell responses were associated with a higher ratio of terminally differentiated/naive CD8+ T cells and with increased proportions of senescent CD8+ T-cells, but not with systemic inflammation or sCD14. Increased CMV-specific CD4+ T-cell responses were associated with increased proportions of activated CD8+ T-cells. In PLWHIV with expansion of CMV-specific T-cells or increased T-cell senescence, CMV-specific polyfunctionality was maintained. That the magnitude of the CMV-specific T-cell response was associated with a senescent immune phenotype, suggests that a dysregulated immune response against CMV may contribute to the immunological ageing often described in PLWHIV despite stable cART. PMID- 29491460 TI - High capacity in G protein-coupled receptor signaling. AB - G protein-coupled receptors (GPCRs) constitute a large family of receptors that activate intracellular signaling pathways upon detecting specific extracellular ligands. While many aspects of GPCR signaling have been uncovered through decades of studies, some fundamental properties, like its channel capacity-a measure of how much information a given transmission system can reliably transduce-are still debated. Previous studies concluded that GPCRs in individual cells could transmit around one bit of information about the concentration of the ligands, allowing only for a reliable on or off response. Using muscarinic receptor-induced calcium response measured in individual cells upon repeated stimulation, we show that GPCR signaling systems possess a significantly higher capacity. We estimate the channel capacity of this system to be above two, implying that at least four concentration levels of the agonist can be distinguished reliably. These findings shed light on the basic principles of GPCR signaling. PMID- 29491461 TI - Clinical and biological implications of mutational spectrum in acute myeloid leukemia of FAB subtypes M4 and M5. AB - The mutational spectrum and molecular characteristics of acute myelomonocytic lineage leukemia, namely acute myeloid leukemia (AML) French-American-British (FAB) subtypes M4 and M5, are largely unknown. In order to explore the mutational spectrum and prognostic factors of FAB-M4 and -M5, next-generation sequencing (NGS) was performed to screen for mutated genes and fusion genes relevant to the pathogenesis of AML. Of the 63 patients enrolled in the study, 60% had more than three mutated genes. NPM1 had the highest mutation frequency, followed by DNMT3A, FLT3, NRAS, RUNX1, and TET2. Univariate analysis suggested that age >=60 years was an independent factor for both poor event-free survival (EFS) and overall survival (OS, P = 0.009, 0.002, respectively), MYH11-CBFbeta was associated with better EFS and OS (P = 0.029, 0.016, respectively). However, multivariate analysis was not able to identify any independent risk factor for survival in the cohort of FAB-M4 and -M5 patients, including peripheral white blood cell count, bone marrow blast percentage, MYH11-CBFbeta, FLT3-ITD, mutations in NPM1 and DNMT3A, and allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our study provided new insight into the mutational spectrum and molecular characteristics of FAB-M4 and -M5. The clinical implications of the genetic signature of FAB-M4 and -M5 need to be further elucidated by larger studies. PMID- 29491462 TI - Gene expression models based on a reference laboratory strain are poor predictors of Mycobacterium tuberculosis complex transcriptional diversity. AB - Every year, species of the Mycobacterium tuberculosis complex (MTBC) kill more people than any other infectious disease caused by a single agent. As a consequence of its global distribution and parallel evolution with the human host the bacteria is not genetically homogeneous. The observed genetic heterogeneity has relevance at different phenotypic levels, from gene expression to epidemiological dynamics. However, current systems biology datasets have focused on the laboratory reference strain H37Rv. By using large expression datasets testing the role of almost two hundred transcription factors, we have constructed computational models to grab the expression dynamics of Mycobacterium tuberculosis H37Rv genes. However, we have found that many of those transcription factors are deleted or likely dysfunctional across strains of the MTBC. As a result, we failed to predict expression changes in strains with a different genetic background when compared with experimental data. These results highlight the importance of designing systems biology approaches that take into account the genetic diversity of tubercle bacilli, or any other pathogen, if we want to identify universal targets for vaccines, diagnostics and treatments. PMID- 29491463 TI - Target delivery of doxorubicin tethered with PVP stabilized gold nanoparticles for effective treatment of lung cancer. AB - Development of drug delivery system conjugated with doxorubicin (dox) on the surface of AuNPs with polyvinylpyrrolidone (Dox@PVP-AuNPs), we have demonstrated that human lung cancer cells can significantly overcome by the combination of highly effective cellular entry and responsive intracellular release of doxorubicin from Dox@PVP-AuNPs complex. Previously drug release from doxorubicin conjugated AuNPs was confirmed by the recovered fluorescence of doxorubicin from quenching due to the nanosurface energy transfer between doxorubicinyl groups and AuNPs. Dox@PVP-AuNPs achieved enhanced inhibition of lung cancer cells growth than free Doxorubicin and PVP-AuNPs. The in vitro cytotoxic effect of PVP-AuNPs, free Dox and Dox@PVP-AuNPs inhibited the proliferation of human lung cancer cells with IC50 concentration. Compared with control cells, PVP-AuNPs and free Dox, Dox@PVP-AuNPs can increases ROS generation, sensitize mitochondrial membrane potential and induces both early and late apoptosis in lung cancer cells. Moreover, Dox@PVP-AuNPs highly upregulates the expression of tumor suppressor genes than free Dox and PVP-AuNPs and induces intrinsic apoptosis in lung cancer cells. From the results, Dox@PVP-AuNPs can be considered as an potential drug delivery system for effective treatment of human lung cancer. PMID- 29491464 TI - Is there expert consensus on expert consensus? PMID- 29491465 TI - Gut decontamination during allogeneic hematopoietic stem cell transplantation and the risk of acute graft-versus-host disease. PMID- 29491466 TI - Characterization of Exosomal SLC22A5 (OCTN2) carnitine transporter. AB - Exosomes are extracellular vesicles involved in cell-to-cell communication. Previous large scale proteomics revealed that they contain SLC proteins. However, no data on the function of exosomal SLCs is available, so far. An SLC localized in exosomes was here characterized for the first time: the carnitine transporter OCTN2 (SLC22A5). The protein was detected by Western Blot analysis in HEK293 exosomes. To investigate the functional properties of the exosomal OCTN2, the proteins extracted from vesicles were reconstituted into proteolipsomes and the transport function was measured as uptake of 3H-carnitine. Transport was stimulated by sodium and was dependent on pH. 3H-carnitine uptake was inhibited by Acetyl-carnitine, but not by Asn, Gln and Arg thus excluding interference by ATB0,+, an amino acid transporter which also recognizes carnitine. Cardiolipin failed to stimulate transport, excluding the activity of the mitochondrial Carnitine/acylcarnitine transporter. Increased level of exosomal OCTN2 was induced by treatment of HEK293 with the pro-inflammatory cytokine INFgamma. All data concurred to demonstrate that OCTN2 present in exosomes is fully functional and is in its native conformation. Functional OCTN2 was detected also in human urinary exosomes, thus suggesting the OCTN2 exosomal protein as a candidate biomarker for inflammation related pathologies. PMID- 29491467 TI - Lack of spatial structure for phenotypic and genetic variation despite high self fertilization in Aquilegia canadensis (Ranunculaceae). AB - By reducing genetically effective population size and gene flow, self fertilization should lead to strong spatial genetic structure (SGS). Although the short-lived plant Aquilegia canadensis produces large, complex, nectar-rich flowers, 75% of seed, on average, are self-fertilized. Previous experimental results are consistent with the fine-scale SGS expected in selfing populations. In contrast, key floral traits show no evidence of SGS, despite a significant genetic basis to phenotypic variation within populations. In this study, we attempt to resolve these contradictory results by hierarchically sampling plants from two plots nested within each of seven rock outcrops distributed over several km, and comparing the spatial pattern of phenotypic variation in four floral traits with neutral genetic variation at 10 microsatellite loci. For both floral and microsatellite variation, we detected only weak hierarchical structuring and no isolation by distance. The spatial pattern of variation in floral traits was on par with microsatellite polymorphisms. These results suggest regular long distance gene flow via pollen. At much finer spatial scales within plots, estimates of relatedness were higher (albeit very low) between nearest neighbors than random plants, and declined with increasing distance between neighbors, which is consistent with highly localized seed dispersal. High selfing should yield SGS, but strong inbreeding depression in A. canadensis likely erodes SGS so that reproductive plants exhibit weak structure typical of outcrossers, especially given that outcrossing and consequent gene flow in this species are mediated by strong-flying hummingbirds and bumble bees. PMID- 29491468 TI - Evaluation of a Pretargeting Strategy for Molecular Imaging of the Prostate Stem Cell Antigen with a Single Chain Antibody. AB - In pretargeted radio-immunotherapy, the gradual administration of a non radioactive tumor antigen-addressing antibody-construct and the subsequent application of a radioactive labeled, low molecular weight substance enable a highly effective and selective targeting of tumor tissue. We evaluated this concept in prostate stem cell antigen (PSCA)-positive cancers using the antigen specific, biotinylated single chain antibody scFv(AM1)-P-BAP conjugated with tetrameric neutravidin. To visualize the systemic biodistribution, a radiolabeled biotin was injected to interact with scFv(AM1)-P-BAP/neutravidin conjugate. Biotin derivatives conjugated with different chelators for complexation of radioactive metal ions and a polyethylene glycol linker (n = 45) were successfully synthesized and evaluated in vitro and in a mouse xenograft model. In vivo, the scFv(AM1)-P-BAP showed highly PSCA-specific tumor retention with a PSCA+ tumor/PSCA- tumor accumulation ratio of ten. PEGylation of radiolabeled biotin resulted in lower liver uptake improving the tumor to background ratio. PMID- 29491470 TI - Dietary n-3 and n-6 polyunsaturated fatty acids, the FADS gene, and the risk of gastric cancer in a Korean population. AB - n-3 polyunsaturated fatty acids (PUFAs) and n-6 PUFAs are reported to have immunomodulatory effects, but few studies have examined these functions. Thus, we examined whether dietary n-3 and n-6 PUFAs are associated with the risk of gastric cancer and further investigated whether fatty acid desaturases 1 and 2 (FADS1 and FADS2) modify this association. In a case-control study, 1,464 participants (402 cases and 1,062 controls) were enrolled. A semi-quantitative food frequency questionnaire was utilized to measure dietary PUFA intake. Genotyping was performed using the Axiom(r) Exome 319 Array. Multivariable logistic models were established after adjusting for confounding variables. The risk of gastric cancer was significantly decreased among participants who had the highest tertile intake of docosahexaenoic acid (DHA), an n-3 PUFA, even after adjusting for covariates [odds ratios (OR) = 0.72, 95% confidence intervals (95% CIs) = 0.53-0.99]. However, no significant interaction according to FADS1 rs174546 or FADS2 rs174583 was observed. In conclusion, we observed a significant inverse association between dietary DHA and the risk of gastric cancer but found that FADS1 rs174546 and FADS2 rs174583 did not modify the association between dietary n-3 or n-6 PUFAs and gastric cancer risk. PMID- 29491471 TI - Molecular-genetic characterization of common, noncoding UBASH3A variants associated with type 1 diabetes. AB - Genome-wide association and fine-mapping studies have identified over 40 susceptibility regions for type 1 diabetes (T1D), a common autoimmune disease; however, most of the disease-associated variants are noncoding, and it remains a challenge to understand their biological contributions to T1D pathogenesis. One identified T1D risk locus is located at chromosome 21q22.3 where the most likely candidate gene is UBASH3A, a negative regulator of NF-kappaB signaling. Various noncoding variants in UBASH3A have been shown to be associated with T1D or other autoimmune diseases. Here we investigated four such SNPs-rs11203202, rs80054410, rs11203203, and rs1893592. We discovered a novel role for rs1893592 in T1D and showed that its minor allele protects against T1D. Our haplotype analysis identified three T1D-associated UBASH3A haplotypes, and revealed that risk for T1D is affected by additive effects of these four UBASH3A variants. In human primary CD4+ T cells, upon T-cell receptor stimulation, the minor allele of rs1893592 was associated with both a significant reduction in the overall mRNA levels of UBASH3A, and an increase in the proportion of a normally occurring, but low-abundant, UBASH3A transcript that retains intron-9 sequences and cannot produce full-length UBASH3A protein. This reduction in UBASH3A, as a consequence of the minor allele at rs1893592, resulted in increased secretion of IL-2, a key cytokine that is required for T-cell activation and function but is deficient in some T1D subjects. Our study provides new mechanistic insights into how rs1893592 affects T1D and autoimmunity, and how interactions between multiple T1D associated, noncoding variants influence the disease risk. PMID- 29491469 TI - Heritable DNA methylation marks associated with susceptibility to breast cancer. AB - Mendelian-like inheritance of germline DNA methylation in cancer susceptibility genes has been previously reported. We aimed to scan the genome for heritable methylation marks associated with breast cancer susceptibility by studying 25 Australian multiple-case breast cancer families. Here we report genome-wide DNA methylation measured in 210 peripheral blood DNA samples provided by family members using the Infinium HumanMethylation450. We develop and apply a new statistical method to identify heritable methylation marks based on complex segregation analysis. We estimate carrier probabilities for the 1000 most heritable methylation marks based on family structure, and we use Cox proportional hazards survival analysis to identify 24 methylation marks with corresponding carrier probabilities significantly associated with breast cancer. We replicate an association with breast cancer risk for four of the 24 marks using an independent nested case-control study. Here, we report a novel approach for identifying heritable DNA methylation marks associated with breast cancer risk. PMID- 29491472 TI - Integrative functional analysis of super enhancer SNPs for coronary artery disease. AB - Clinical research in coronary artery disease (CAD) primarily focused on genetic variants located in protein-coding regions. Recently, mutations fall within non coding regions have been suggested to be essential to the pathogenesis of human complex disease. Super enhancer is a densely spaced cluster of transcriptional enhancers located in non-coding regions, which is critical for regulating cell type specific gene expression. However, the underlying mechanism of the super enhancer single-nucleotide polymorphisms (SNPs) affecting the risk of CAD remains unclear. By integrating genome-wide association study (GWAS) meta-analysis of CAD and cell/tissue-specific histone modification data set, we identified 366 potential CAD-associated super enhancer SNPs in 67 loci, including 94 SNPs that are involved in regulating chromatin interactive and/or affecting the transcription factors binding affinity. Interestingly, we found 7 novel functional loci (CBFA2T3, ZMIZ1, DIP2B, SCNN1D/ACAP3, TMEM105, CAMK2G, and MAPK1) that CAD-associated super enhancer SNPs were clustered into the same or neighboring super enhancers. Pathway analysis showed a significant enrichment in several well-known signaling and regulatory processes, e.g., cAMP signaling pathway and ErbB signaling pathway, which play a key role in CAD metabolism. Our results highlight the potential functional importance of CAD-associated super enhancer SNPs and provide the targets for further insights on the pathogenesis of CAD. PMID- 29491473 TI - A novel missense SNAP25b mutation in two affected siblings from an Israeli family showing seizures and cerebellar ataxia. AB - SNAP25 is a core component of the soluble N-ethylmaleimide-sensitive factor attachment receptor complex, which plays a critical role in synaptic vesicle exocytosis. To date, six de novo SNAP25 mutations have been reported in patients with neurological features including seizures, intellectual disability, severe speech delay, and cerebellar ataxia. Here, we analyzed an Israeli family with two affected siblings showing seizures and cerebellar dysfunction by whole-exome sequencing, and identified a novel missense SNAP25 mutation (c.176G > C, p.Arg59Pro) inherited from their unaffected father. Two SNAP25 isoforms are known, SNAP25a and SNAP25b, which each contain a different exon 5. The c.176G > C mutation found in this study was specific to SNAP25b, while five previously reported mutations were identified in exons common to both isoforms. Another was previously reported to be specific to SNAP25b. Comparing clinical features of reported patients with SNAP25 mutations, the current patients demonstrated apparently milder clinical features with normal intelligence, and no magnetic resonance imaging abnormality or facial dysmorphism. Our results expand the clinical spectrum of SNAP25 mutations. PMID- 29491474 TI - Associative properties of structural plasticity based on firing rate homeostasis in recurrent neuronal networks. AB - Correlation-based Hebbian plasticity is thought to shape neuronal connectivity during development and learning, whereas homeostatic plasticity would stabilize network activity. Here we investigate another, new aspect of this dichotomy: Can Hebbian associative properties also emerge as a network effect from a plasticity rule based on homeostatic principles on the neuronal level? To address this question, we simulated a recurrent network of leaky integrate-and-fire neurons, in which excitatory connections are subject to a structural plasticity rule based on firing rate homeostasis. We show that a subgroup of neurons develop stronger within-group connectivity as a consequence of receiving stronger external stimulation. In an experimentally well-documented scenario we show that feature specific connectivity, similar to what has been observed in rodent visual cortex, can emerge from such a plasticity rule. The experience-dependent structural changes triggered by stimulation are long-lasting and decay only slowly when the neurons are exposed again to unspecific external inputs. PMID- 29491475 TI - A Functional Signature Ontology (FUSION) screen detects an AMPK inhibitor with selective toxicity toward human colon tumor cells. AB - AMPK is a serine threonine kinase composed of a heterotrimer of a catalytic, kinase-containing alpha and regulatory beta and gamma subunits. Here we show that individual AMPK subunit expression and requirement for survival varies across colon cancer cell lines. While AMPKalpha1 expression is relatively consistent across colon cancer cell lines, AMPKalpha1 depletion does not induce cell death. Conversely, AMPKalpha2 is expressed at variable levels in colon cancer cells. In high expressing SW480 and moderate expressing HCT116 colon cancer cells, siRNA mediated depletion induces cell death. These data suggest that AMPK kinase inhibition may be a useful component of future therapeutic strategies. We used Functional Signature Ontology (FUSION) to screen a natural product library to identify compounds that were inhibitors of AMPK to test its potential for detecting small molecules with preferential toxicity toward human colon tumor cells. FUSION identified 5'-hydroxy-staurosporine, which competitively inhibits AMPK. Human colon cancer cell lines are notably more sensitive to 5'-hydroxy staurosporine than are non-transformed human colon epithelial cells. This study serves as proof-of-concept for unbiased FUSION-based detection of small molecule inhibitors of therapeutic targets and highlights its potential to identify novel compounds for cancer therapy development. PMID- 29491476 TI - Stromal C-type lectin receptor COLEC12 integrates H. pylori, PGE2-EP2/4 axis and innate immunity in gastric diseases. AB - Tissue stroma is known to be important in regulating Hp-mediated inflammation, but its interaction with Hp and dendritic cells (DCs) remains to be determined. To this end, the potential crosstalk between H. pylori (Hp) infected gastric stromal cells (Hp-GSCs) and DCs was investigated. Primary GSCs from cancerous and adjacent normal tissues were generated from gastric cancer patients, and monocyte derived DCs were obtained from healthy individuals. Levels of cytokines and prostaglandin E2 (PGE2) were measured by ELISA, and C-type lectin expression in GSCs was assessed by flow cytometry and immunohistochemistry. In a trans-well co culture system, significantly upregulated DC-derived IL-23 expression was found when DCs were co-cultured with Hp-infected GSCs (Hp-GSCs). Further, PGE2 from Hp GSCs was discovered to possess the priming effect, which could be inhibited by anti-COLEC12 (Collectin subfamily member 12) Abs, COLEC12 knockdown or when alpha3-fucosyltransferase-null (futB; HP0651) strain of Hp was used. Also, the expression of COLEC12 was co-localized with CD90+ stromal cells in cancerous tissues. Hp-GSCs-conditioned DCs were able to induce the expression of IL-17 from CD4+ T cells, which could be inhibited by IL-23-neutralizing Abs. These results suggested the importance of COLEC12 as a receptor involved in Hp-stromal cell interaction and its subsequent conditioning effect on DCs. PMID- 29491477 TI - Comprehensive detection of pathogens in immunocompromised children with bloodstream infections by next-generation sequencing. AB - Bloodstream infection (BSI) is a severe complication in immunocompromised patients. Next-generation sequencing (NGS) allows us to analyze comprehensively and quantitatively all microorganisms present in a clinical sample. Thirty-five pediatric patients (12 with BSI and 23 with suspected BSI/negative blood culture) were enrolled. Plasma/serum samples were used for sequencing and the results were compared with those from blood culture. Sequencing reads of bacteria isolated in blood culture were identified by NGS in all plasma/serum samples at disease onset. Bacteria isolated in blood culture were identical to the dominant bacteria by NGS in 8 of 12 patients. Bacterial reads per million reads of the sequence depth (BR) > 200 and relative importance values of the dominant bacteria (P1) > 0.5 were employed to determine causative pathogens. Causative pathogens were detected using these criteria in 7 of 12 patients with BSI. Additionally, causative bacteria were detected in the plasma/serum at 7 days before disease onset in two patients with catheter-related BSI. Causative pathogens, including virus, were identified in three patients with suspected BSI. Lastly, a total of 62 resistance genes were detected by NGS. In conclusion, NGS is a new method to identify causative microorganisms in BSI and may predict BSI in some patients. PMID- 29491478 TI - AxonDeepSeg: automatic axon and myelin segmentation from microscopy data using convolutional neural networks. AB - Segmentation of axon and myelin from microscopy images of the nervous system provides useful quantitative information about the tissue microstructure, such as axon density and myelin thickness. This could be used for instance to document cell morphometry across species, or to validate novel non-invasive quantitative magnetic resonance imaging techniques. Most currently-available segmentation algorithms are based on standard image processing and usually require multiple processing steps and/or parameter tuning by the user to adapt to different modalities. Moreover, only a few methods are publicly available. We introduce AxonDeepSeg, an open-source software that performs axon and myelin segmentation of microscopic images using deep learning. AxonDeepSeg features: (i) a convolutional neural network architecture; (ii) an easy training procedure to generate new models based on manually-labelled data and (iii) two ready-to-use models trained from scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Results show high pixel-wise accuracy across various species: 85% on rat SEM, 81% on human SEM, 95% on mice TEM and 84% on macaque TEM. Segmentation of a full rat spinal cord slice is computed and morphological metrics are extracted and compared against the literature. AxonDeepSeg is freely available at https://github.com/neuropoly/axondeepseg . PMID- 29491479 TI - Collision sensitive niche profile of the worst affected bird-groups at wind turbine structures in the Federal State of Brandenburg, Germany. AB - Biodiversity-related impacts at wind energy facilities have increasingly become a cause of conservation concern, central issue being the collision of birds. Utilizing spatial information of their carcass detections at wind turbines (WTs), we quantified the detections in relation to the metric distances of the respective turbines to different land-use types. We used ecological niche factor analysis (ENFA) to identify combinations of land-use distances with respect to the spatial allocation of WTs that led to higher proportions of collisions among the worst affected bird-groups: Buntings, Crows, Larks, Pigeons and Raptors. We also assessed their respective similarities to the collision phenomenon by checking for overlaps amongst their distance combinations. Crows and Larks showed the narrowest "collision sensitive niche"; a part of ecological niche under higher risk of collisions with turbines, followed by that of Buntings and Pigeons. Raptors had the broadest niche showing significant overlaps with the collision sensitive niches of the other groups. This can probably be attributed to their larger home range combined with their hunting affinities to open landscapes. Identification of collision sensitive niches could be a powerful tool for landscape planning; helping avoid regions with higher risks of collisions for turbine allocations and thus protecting sensitive bird populations. PMID- 29491480 TI - Osteoarthritis: Targeting gp130 aids cartilage repair. PMID- 29491483 TI - Dynamical Casimir Effect for Gaussian Boson Sampling. AB - We show that the Dynamical Casimir Effect (DCE), realized on two multimode coplanar waveg-uide resonators, implements a gaussian boson sampler (GBS). The appropriate choice of the mirror acceleration that couples both resonators translates into the desired initial gaussian state and many-boson interference in a boson sampling network. In particular, we show that the proposed quantum simulator naturally performs a classically hard task, known as scattershot boson sampling. Our result unveils an unprecedented computational power of DCE, and paves the way for using DCE as a resource for quantum simulation. PMID- 29491482 TI - A New Pleistocene Hominin Tracksite from the Cape South Coast, South Africa. AB - A Late Pleistocene hominin tracksite has been identified in coastal aeolianite rocks on the Cape south coast of South Africa, an area of great significance for the emergence of modern humans. The tracks are in the form of natural casts and occur on the ceiling and side walls of a ten-metre long cave. Preservation of tracks is of variable quality. Up to forty hominin tracks are evident. Up to thirty-five hominin tracks occur on a single bedding plane, with potential for the exposure of further tracks. Five tracks are apparent on a second hominin track-bearing bedding plane. A number of individuals made the tracks while moving down a dune surface. A geological investigation at the site and stratigraphic comparison to published geochronological studies from this area suggest that the tracks are ~90 ka in age. If this is the case, the shoreline at the time would have been approximately 2 km distant. This is the first reported hominin tracksite from this time period. It adds to the relatively sparse global record of early hominin tracks, and represents the largest and best preserved archive of Late Pleistocene hominin tracks found to date. The tracks were probably made by Homo sapiens. PMID- 29491484 TI - Salivary and serum androgens with anti-Mullerian hormone measurement for the diagnosis of polycystic ovary syndrome. AB - To determine the predictive value of a raised androgen level with an elevated anti-Mullerian hormone (AMH) for the diagnosis or exclusion of polycystic ovary syndrome (PCOS), a prospective cross-sectional study of 170 women (105 with PCOS type A and 65 normal) was undertaken. AMH was combined with one of, total serum testosterone (T); calculated free androgen index; salivary testosterone (salT); serum androstenedione (A); salivary androstenedione (salA). The diagnostic sensitivity and specificity of AMH (>35 pmol/l) alone for PCOS were 55% and 79% respectively. The diagnostic sensitivity and specificity of AMH (>35 pmol/l) with either an elevated T or raised FAI level for PCOS showed 100% specificity and a 100% positive predictive value. Conversely, diagnostic exclusion of PCOS was shown by an AMH <35 pmol/l with a normal T or FAI salivary testosterone giving 100% specificity and 100% positive predictive value. AMH with an elevated A or elevated salA level gave specificities of 87% and 94%, and positive predictive values 80% and 94%, respectively. Therefore, the combination of an AMH with a cut off of 35 pmol/l combined with a raised T and/or a FAI will confirm PCOS whilst a normal AMH with a normal T and/or FAI will exclude PCOS, thus addressing diagnostic uncertainty. PMID- 29491481 TI - The Spanish version of Face-Name Associative Memory Exam (S-FNAME) performance is related to amyloid burden in Subjective Cognitive Decline. AB - The Face-Name Associative Memory Exam (FNAME) is a paired associative memory test created to detect memory deficits in individuals with preclinical Alzheimer's disease (AD). Worse performance on FNAME in cognitively healthy individuals were found related to higher amyloid beta (Abeta) burden measured with Positron Emission-Tomography using 11C-PiB (PiB-PET). We previously reported normative data of a Spanish version of FNAME (S-FNAME) in cognitively healthy Spanish speaking subjects. The aim of the present study was to determine whether performance on S-FNAME was associated with Abeta burden in subjective cognitive decline (SCD) individuals. 200 SCD subjects received neurological and neuropsychological assessments, including the S-FNAME and the Word List task from the Wechsler-Memory-Scale-III (WMS-III). Moreover, they received an MRI and (18)F Florbetaben Positron-Emission-Tomography (FBB-PET) to measure Abeta burden. Three cognitive factor composites were derived for the episodic memory measures (face name [SFN-N], face-occupation [SFN-O] and WMS-III) to determine whether episodic memory performance was related to Abeta deposition. Higher global Abeta deposition was significantly related to worse performance on SFN-N but not with SFN-O or WMS-III Composite. Moreover, worse SFN-N performance was significantly related to higher Abeta deposition in bilateral Posterior Cingulate Cortex. The S-FNAME may be a promising neuropsychological tool for detecting SCD individuals with preclinical AD. PMID- 29491485 TI - Difference of uveal parameters between the acute primary angle closure eyes and the fellow eyes. AB - PURPOSE: To measure the anterior and posterior ocular biometric characteristics concurrently and to explore the relationship between iris, ciliary body and choroid in acute primary angle closure eyes (APAC) and fellow eyes. METHODS: It is a prospective, cross-sectional study. Thirty patients with recent APAC were finally enroled in it. Anterior and posterior uveal parameters were measured simultaneously by anterior segment optical coherence tomography (AS-OCT), swept source optical coherence tomography (SS-OCT) and ultrasound biomicroscopy (UBM). The parameters were measured including: pupil diameter (PD); iris thickness, curvature (ICURV), area (IAREA); anterior chamber depth (ACD), width (ACW), area (ACA), volume (ACV); lens vault (LV); choroidal thickness and retinal thickness; maximum ciliary body thickness (CBTmax); ciliary body thickness at the point of the scleral spur (CBT0) and 1000 mm away (CBT1000); anterior placement of the ciliary body (APCB); and trabecular-ciliary angle (TCA). RESULTS: Compared with fellow eyes, APAC eyes had narrower anterior biometric parameters and presented with smaller anterior segment parameters (including ACD and ACW); (p < 0.01)), smaller IAREA and ICURV (p < 0.001), larger LV (p = 0.035), thinner ciliary body and less anterior ciliary process (p < 0.01). After adjustment for potential confounders (axial length, spherical equivalent and PD), APCB was positive correlated with choroidal thickness and CBT, and CBT was positive correlated with choroidal thickness. CONCLUSIONS: Compared with fellow eyes, APAC eyes had narrower anterior biometric parameters, thinner ciliary body and smaller iris area and curvature. APCB, CBT and choroidal thickness were positively correlated. However, further studies are required before these conclusions are generalised. PMID- 29491486 TI - Low nocturnal diastolic ocular perfusion pressure as a risk factor for NTG progression: a 5-year prospective study. AB - OBJECTIVE: To assess the relationship between baseline intraocular pressure (IOP), blood pressure (BP) and ocular perfusion pressure (OPP), and the 5-year visual field progression in normal-tension glaucoma (NTG) patients. DESIGN: Prospective, longitudinal study. METHODS: Sixty-five NTG patients who were followed up for 5 years are included in this study. All the enrolled patients underwent baseline 24-h IOP and BP monitoring via 2-hourly measurements in their habitual position and were followed up for over 5 years with reliable VF tests. Modified Anderson criteria were used to assess VF progression. Univariable and multivariable analyses using Cox's proportional hazards model were used to identify the systemic and clinical risk factors that predict progression. Kaplan Meier survival analyses were used to compare the time elapsed to confirmed VF progression in the presence or absence of each potential risk factor. RESULTS: At 5-year follow-up, 35.4% of the enrolled patients demonstrated visual field progression. There were statistically significant differences in the mean diastolic blood pressure (p < 0.05) and diastolic OPP (p < 0.05) between the progressing and the non-progressing group. There was no association between IOP parameters and NTG progression. Multivariable analysis identified low nocturnal DOPP at baseline as a significant predictive risk factor for glaucomatous visual field progression at 5 years. An mmHg decrease in nocturnal DOPP increases the hazard of progression by 1.4 times. Patients with DOPP < 35 mmHg have 2.3-fold higher probability of progressing compared to the patients with DOPP > 43.7 mmHg (log rank = 0.018). CONCLUSION: Diastolic parameters of BP and OPP were significantly lower in the NTG patients who progressed after 5 years. Low nocturnal DOPP is an independent predictor of glaucomatous visual field progression in NTG patients. PMID- 29491487 TI - Prevalence of reticular pseudodrusen in an elderly UK Caucasian population-The Bridlington Eye Assessment Project (BEAP): a cross-sectional study (2002-2006). AB - AIMS: To determine prevalence, associations, and risk factors for reticular pseudodrusen (RPD) in a UK population. METHODS: Cross-sectional study of Bridlington residents aged >=65 years. Masked grading of colour fundus photographs from 3549 participants. RPD presence, phenotype, and topography were recorded, demographic details were analysed, and prevalence was calculated. RESULTS: RPD was detected in 281 eyes (176 individuals) of 3476 participants (5.06%) with gradable images, and bilateral in 76.6%. Digital enhancement increased detection by 15.7%. Prevalence increased significantly with age from 1.18% (65-69 years) to 27.27% (>=90 years) (mean age 81.1, SD 6.01; OR 1.18, 95% CI 1.15-1.21, p value <0.001), was higher in females (5.9% vs 4.0%; OR 1.52, 95% CI 1.09-2.13, p = 0.014), and associated with diabetes (OR 1.97, CI 1.20-3.17, p = 0.005). History of antihypertension treatment appeared protective (OR 0.64, 95% CI 0.46-0.90, p = 0.009). RPD subtypes were dot in 18.5%, ribbon in 36.7%, and mixed in 36.3%. RPD were located outside the ETDRS grid in 88%, and most commonly in the outer superior subfield. Central grid involvement occurred in 12.1% of right and 14.3% of left eyes. RPD occurred in 25.9% of participants with grade 4 AMD in at least one eye. RPD was associated with visual dissatisfaction after controlling for age (OR 0.63, 95% CI 0.45-0.88, p = 0.007). CONCLUSION: RPD occur more commonly than previously reported, most frequently in the upper-outer macular subfield, but also within the central subfield, albeit with reduced frequency and altered morphology. RPD may be associated with visual dissatisfaction and diabetes, but are less frequent in persons receiving antihypertension therapy. PMID- 29491488 TI - Changes in optical coherence tomography measurements after orbital wall decompression in dysthyroid optic neuropathy. AB - PURPOSE: The purpose of our study was to assess changes in peripapillary retinal nerve fiber layer (RNFL) thickness after orbital wall decompression in eyes with dysthyroid optic neuropathy (DON). METHODS: We analyzed peripapillary optical coherence tomography (OCT) images (Cirrus HD-OCT) from controls and patients with DON before and 1 and 6 months after orbital wall decompression. RESULTS: There was no significant difference in mean preoperative peripapillary retinal nerve fiber layer thickness between eyes with DON and controls. The superior and inferior peripapillary RNFL thickness decreased significantly 1 month after decompression surgery compared to preoperative values (p = 0.043 and p = 0.022, respectively). The global average, superior, temporal, and inferior peripapillary RNFL thickness decreased significantly 6 months after decompression surgery compared to preoperative values (p = 0.015, p = 0.028, p = 0.009, and p = 0.006, respectively). Patients with greater preoperative inferior peripapillary RNFL thickness tended to have better postoperative visual acuity at the last visit (p = 0.024, OR = 0.926). CONCLUSIONS: Our data revealed a significant decrease in peripapillary RNFL thickness postoperatively after orbital decompression surgery in patients with DON. We also found that greater preoperative inferior peripapillary RNFL thickness was associated with better visual outcomes. We suggest that RNFL thickness can be used as a prognostic factor for DON before decompression surgery. PMID- 29491489 TI - Genome-wide analysis revealed that DZNep reduces tubulointerstitial fibrosis via down-regulation of pro-fibrotic genes. AB - Tubulointerstitial fibrosis has been recently reported to be caused by the collapse of the epigenetic regulation of kidney diseases. We examined whether pharmacological inhibition of histone modification is effective against renal fibrosis. DZNep (3-deazaneplanocin A) was originally developed as an anti-cancer drug to inhibit the repressive histone mark, H3K27me3. We used a model of chronic tubulointerstitial fibrosis induced by unilateral ischaemia/reperfusion and administered DZNep intravenously to the mice for 8 weeks. We found DZNep contributes to the reduction of tubulointerstitial fibrosis. We selected only tubular cells from in vivo samples using laser-capture microdissection because epigenetic regulation is specific to the cell types, and we focused on the changes in the tubular cells. We performed a genome-wide analysis of tubular cells using high-throughput sequencing (RNA-seq) to identify novel epigenetic factors associated with renal fibrosis. We found that pro-fibrotic genes such as COL3A1 (collagen type 3a1) and TIMP2 (tissue inhibitor of metalloproteinase 2) were suppressed by DZNep in vivo. In addition, pro-fibrotic genes such as COL4A1 (collagen type 4a1), TIMP2 and MMP14 were down-regulated by DZNep in vitro. In conclusion, we found that pharmacological epigenetic modification by DZNep decreased the expression levels of fibrogenic genes in tubular cells and inhibited tubulointerstitial fibrosis. PMID- 29491490 TI - Obesity-related acetylcholinesterase elevation is reversed following laparoscopic sleeve gastrectomy. AB - BACKGROUND: Impaired sympathetic/parasympathetic response, expressed by elevated Acetylcholinesterase (AChE) is associated with obesity, metabolic syndrome and inflammation. However, the association between morbid obesity and AChE and the changes in cholinergic tone following bariatric laparoscopic sleeve gastrectomy (LSG) surgery-induced weight reduction were never analyzed. METHODS: Two studies are presented; the first (the "apparently healthy cohort") was a cross-sectional study and the second (the "LSG cohort") was a prospective-cohort study with 12 months of follow-up. The "apparently healthy cohort" included 1450 apparently healthy participants who volunteered to the Tel-Aviv Medical Center Inflammation Survey (TAMCIS) during a routine annual checkup visit. The "LSG cohort" included 77 morbid obese patients before and at 3, 6, and 12 months following LSG surgery. Main outcomes included anthropometric measurements, Hemoglobin A1c (HbA1C), serum AChE, insulin test and Homeostasis Model Assessment (HOMA). RESULTS: Among the TAMCIS participants, serum AChE activity increased with BMI in a dose-dependent manner until it reached a peak level at BMI of 30-35 kg/m2, followed by a plateau. Following LSG, a significant decrease in AChE activity between baseline and 12 months post-surgery was found for men, but not for women (-122.2 +/- 135.3, P < 0.001 vs. -21.8 +/- 120.5, P = 0.258 nmol substrate hydrolyzed/min per ml, respectively). The reduction in AChE activity was negatively correlated with %excess weight loss (EWL) and positively correlated with %body fat reduction at 12 months post-surgery among women (r = -0.329, P = 0.034 and r = 0.350, P = 0.023, respectively). In men, AChE activity reduction was positively correlated with the HOMA reduction (r = 0.358, P = 0.048). CONCLUSIONS: Obesity-related AChE resistance phenotype may be reversed following LSG and correlates with metabolic outcomes. Further long-term studies will be needed to validate and evaluate the beneficial effect of AChE reduction post bariatric surgery. PMID- 29491491 TI - Skinfold thickness measurements and mortality in white males during 27.7 years of follow-up. AB - INTRODUCTION: Obesity is a major risk factor for mortality from a range of causes. We investigated whether skinfold measurements were associated with mortality independently of variation in body mass index (BMI). METHODS: A prospective analysis of mortality in 870 apparently healthy adult Caucasian men participating in an occupational health cohort was undertaken. At baseline, skinfold measurements were taken at biceps, triceps, iliac and subscapular sites. Derived measurements included the sum of all four skinfolds and subscapular to triceps, subscapular to iliac and BMI to iliac ratios. All-cause mortality was analysed by Cox proportional hazards modelling and death in specific mortality subcategories by competing risks analysis. RESULTS: During a mean of 27.7 years follow up, there were 303 deaths (119 cancer, 101 arteriovascular, 40 infection, 43 other). In univariable analysis, BMI was associated with all-cause, cancer, arteriovascular and other mortality and subscapular skinfold with all-cause and arteriovascular mortality. On bivariable analysis, with inclusion of BMI, subscapular skinfold ceased to be a associated with mortality but iliac skinfold emerged as strongly, negatively associated with all-cause and arteriovascular mortality. In multivariable analysis, with inclusion of age, BMI, smoking, alcohol and exercise, iliac skinfold was negatively associated with all-cause (Hazard ratio HR 0.77, 95% confidence interval CI 0.66-0.90, p = 0.002), arteriovascular (HR 0.75, 95%CI 0.58,0.97, p = 0.02) and infection (HR 0.63, 95%CI 0.42,0.94, p = 0.02) death. Among obese participants (BMI >= 30 kg/m2), iliac skinfold of <=9.7 mm was associated with a six-fold increase in all-cause mortality risk. CONCLUSION: Low iliac skinfold thickness is an independent risk factor for all-cause mortality in adult white males with risk apparently concentrated among people who are obese. PMID- 29491492 TI - Decomposer food web in a deciduous forest shows high share of generalist microorganisms and importance of microbial biomass recycling. AB - Forest soils represent important terrestrial carbon (C) pools where C is primarily fixed in the plant-derived biomass but it flows further through the biomass of fungi and bacteria before it is lost from the ecosystem as CO2 or immobilized in recalcitrant organic matter. Microorganisms are the main drivers of C flow in forests and play critical roles in the C balance through the decomposition of dead biomass of different origins. Here, we track the path of C that enters forest soil by following respiration, microbial biomass production, and C accumulation by individual microbial taxa in soil microcosms upon the addition of 13C-labeled biomass of plant, fungal, and bacterial origin. We demonstrate that both fungi and bacteria are involved in the assimilation and mineralization of C from the major complex sources existing in soil. Decomposer fungi are, however, better suited to utilize plant biomass compounds, whereas the ability to utilize fungal and bacterial biomass is more frequent among bacteria. Due to the ability of microorganisms to recycle microbial biomass, we suggest that the decomposer food web in forest soil displays a network structure with loops between and within individual pools. These results question the present paradigms describing food webs as hierarchical structures with unidirectional flow of C and assumptions about the dominance of fungi in the decomposition of complex organic matter. PMID- 29491493 TI - Competition-colonization tradeoffs structure fungal diversity. AB - Findings of immense microbial diversity are at odds with observed functional redundancy, as competitive exclusion should hinder coexistence. Tradeoffs between dispersal and competitive ability could resolve this contradiction, but the extent to which they influence microbial community assembly is unclear. Because fungi influence the biogeochemical cycles upon which life on earth depends, understanding the mechanisms that maintain the richness of their communities is critically important. Here, we focus on ectomycorrhizal fungi, which are microbial plant mutualists that significantly affect global carbon dynamics and the ecology of host plants. Synthesizing theory with a decade of empirical research at our study site, we show that competition-colonization tradeoffs structure diversity in situ and that models calibrated only with empirically derived competition-colonization tradeoffs can accurately predict species-area relationships in this group of key eukaryotic microbes. These findings provide evidence that competition-colonization tradeoffs can sustain the landscape-scale diversity of microbes that compete for a single limiting resource. PMID- 29491495 TI - Comparison of StrengthsQuest Signature Themes in Student Pharmacists and Other Health Care Profession Students. AB - Objective. To determine whether there is a distinctive pattern of StrengthsQuest Signature Themes or leadership domains for Doctor of Pharmacy students compared to students in other health care professional programs. Methods. Students in Doctor of Pharmacy (PharmD), Master of Physician Assistant (PA), Doctor of Physical Therapy (DPT), and Doctor of Osteopathic Medicine (DO) programs at Campbell University completed the online Clifton StrengthsQuest assessment and received their Signature Themes. The frequency of individual themes and the leadership domains into which they are sorted by Gallup was analyzed for each program. Results were compared between programs and with national frequencies among undergraduate students. Results. The most common themes in the total population were Learner, Relator, Responsibility, Harmony, and Achiever. Learner and Relator were among the five most frequent themes for all four individual programs while Responsibility and Harmony were among the top five for three programs. The most frequently reported themes in PharmD and PA students (39% and 38% of all themes, respectively) are grouped by Gallup into the executing domain, and into the relationship-building domain for DO and DPT students (35% and 33% of all themes, respectively). The least frequent themes in PharmD, DO and PA students were those grouped into the influencing domain, reported by 10% or fewer students. Conclusion. Numerous similarities were found in theme frequencies among students in four different health care professions, suggesting there is not a distinctive Doctor of Pharmacy Signature Theme profile. PMID- 29491494 TI - Transcriptional patterns identify resource controls on the diazotroph Trichodesmium in the Atlantic and Pacific oceans. AB - The N2-fixing cyanobacterium Trichodesmium is intensely studied because of the control this organism exerts over the cycling of carbon and nitrogen in the low nutrient ocean gyres. Although iron (Fe) and phosphorus (P) bioavailability are thought to be major drivers of Trichodesmium distributions and activities, identifying resource controls on Trichodesmium is challenging, as Fe and P are often organically complexed and their bioavailability to a single species in a mixed community is difficult to constrain. Further, Fe and P geochemistries are linked through the activities of metalloenzymes, such as the alkaline phosphatases (APs) PhoX and PhoA, which are used by microbes to access dissolved organic P (DOP). Here we identified significant correlations between Trichodesmium-specific transcriptional patterns in the North Atlantic (NASG) and North Pacific Subtropical Gyres (NPSG) and patterns in Fe and P biogeochemistry, with the relative enrichment of Fe stress markers in the NPSG, and P stress markers in the NASG. We also observed the differential enrichment of Fe-requiring PhoX transcripts in the NASG and Fe-insensitive PhoA transcripts in the NPSG, suggesting that metalloenzyme switching may be used to mitigate Fe limitation of DOP metabolism in Trichodesmium. This trait may underpin Trichodesmium success across disparate ecosystems. PMID- 29491496 TI - Identifying the Presence of Cognitive Apprenticeship in the Layered Learning Practice Model. AB - Objective. To identify the presence of cognitive apprenticeship themes in the layered learning practice model (LLPM). Methods. Attending pharmacists who had implemented an LLPM completed an individual 90-minute face-to-face semi structured interview. Three researchers independently reviewed transcripts to identify cognitive apprenticeship themes according to the framework's dimensions and sub-dimensions. Results. Of 25 eligible attending pharmacists, 24 (96%) agreed to participate. All core dimensions of the cognitive apprenticeship framework emerged during the interviews; however, preceptors varied in how they used the framework in the training of pharmacy learners at different levels. This variability was especially apparent within the sub-dimensions of the content and method domains. Conclusion. This study demonstrates that all four cognitive apprenticeship principles are being used in the clinical environments operationalizing the LLPM. These findings suggest that cognitive apprenticeship is an applicable and relevant educational framework when engaging multiple learners in clinical education environments. PMID- 29491497 TI - Assessing Students' Impressions of the Cultural Awareness of Pharmacy Faculty and Students. AB - Objective. To determine pharmacy students' impressions of their faculty's interactions with diverse student and patient populations. Methods. Three student focus groups were convened. Eighty-four page transcripts were coded, and emergent themes were identified by qualitative analysis. Results. Students defined diversity as multidimensional beyond traditional categories. Emergent themes were faculty awareness or lack of awareness of cultural diversity, disparate cultural perspectives and preferences within student groups, teaching/learning approaches to prepare students to be more culturally competent, and student group dynamics. First- and second-year students emphasized student-to-student interactions, while third- and fourth-year students emphasized a lack of preparation for the realities of contemporary practice based on instructional methods. Conclusion. Students perceived the majority of their pharmacy faculty to be culturally sensitive and aware, but microaggression and discrimination from faculty and student peers were experienced. Study implications can potentially improve curricular offerings, cultural awareness of faculty and students, and care to diverse patient populations. PMID- 29491498 TI - Team-Based Learning Experiences of Fourth-Year Pharmacy Students in a South African University. AB - Objective. To determine fourth-year pharmacy students' learning experiences with team-based learning (TBL) at a South African university. Methods. A survey composed of biographical data and quantitative questions focusing on student learning experiences was sent to students. There were 183 (91.5%) students who completed the survey. Results. Students had a positive experience with TBL and found it valuable and more worthwhile than traditional lecture methods, regardless of their initial negative perception of TBL. Students enjoyed working in multi-cultural, mixed gender teams. Conclusion. TBL is an effective teaching strategy to simulate the reality of health professions where practitioners are required to work in a team. TBL should be offered in more courses in health professions curriculum in South Africa to strengthen and promote efficient health care delivery. PMID- 29491499 TI - Impact of Spacing of Practice on Learning Brand Name and Generic Drugs. AB - Objective. To test the impact of schedules of retrieval practice on learning brand and generic name drug information in a self-paced course. Methods. Students completed weekly quizzes on brand and generic name conversions for 100 commonly prescribed drugs. Each student completed part of the drug list on a schedule of equal, expanding, or contracting spacing, one practice (massed) or study only in a partial block design. Results. On measures of long-term retention, the contracting spacing schedule led to superior retention (67%) compared to the massed practice (50%) and study-only condition (46%); contracting practice also was significantly higher than expanding practice (58%,) or equal practice (59%). Overall performance decreased by almost 50% (final exam 95%, long-term retention 55%) over a 6-week period. Conclusion. A contracting spacing schedule was the most effective schedule of practice, and all spacing schedules were superior to massed practice or study-only conditions. PMID- 29491500 TI - Integration of a Community Pharmacy Simulation Program into a Therapeutics Course. AB - Objective. To demonstrate the feasibility of integrating the computer simulation, MyDispense, into a therapeutics course and to measure its effects on student perception and learning. Methods. We conducted a prospective study with an experimental phase and an implementation phase. In the first phase, students were randomized to complete a therapeutics case using MyDispense or traditional paper methods in class. In the second phase, all students completed two therapeutic cases using MyDispense in class with the option to complete four additional outside-of-class cases using MyDispense. Students completed pre- and post-tests in class and three surveys. Results. In the experimental phase, mean test scores increased from pre- to post-test for both MyDispense and traditional paper groups, but the difference between the groups was not statistically significant. Students in the traditional paper group reported statistically significant gains in confidence compared to the MyDispense group. In the implementation phase, mean test scores again increased, however, student perception of the use of MyDispense for therapeutics was negative. Completing the optional outside-of-class cases, however, was positively and significantly correlated with the midterm and final examination scores. Conclusion. Implementation of MyDispense in therapeutics may be feasible and has positive effects (eg, correlation with exam scores, capacity for immediate feedback, and potential for effective self-study). With short-term use and in the absence of assessment methods that also require seeking information from patients, students prefer to learn via traditional paper cases. PMID- 29491501 TI - Student Perceptions of the Pharmacist's Approach Across the Varying Levels of Medication Therapy Management Services. AB - Objective. To explore third-year pharmacy (P3) student perceptions of medication therapy management (MTM) after an introduction to the various levels of MTM services within an MTM course. Methods. A qualitative survey was conducted of 158 P3 students. Open-ended questions were used to explore students' thoughts, feelings, and perceptions related to the pharmacist's approach in MTM following a lecture establishing differences in roles and responsibilities between the varying levels of MTM. Emphasis was placed on the pharmacist's role when providing comprehensive medication management (CMM). CMM is a higher-level direct patient care service with a whole-patient focus that goes beyond medication or disease specific focuses of either a comprehensive medication review (CMR) or targeted medication review (TMR). Thematic analysis was performed and an inductive approach to data analysis was used. Results. The following five themes were identified: misperceptions entering the course, efficient delivery of MTM depends on understanding the differences between services, doctor of pharmacy education is a factor in confused MTM role expectations, role limitations exist and referrals to other providers, and the CMR meets unmet needs. Conclusion. Students noted initial confusion between their roles and responsibilities during a CMM versus a CMR. Pharmacy educators should address the varying roles and responsibility differences across MTM services within their curriculum. PMID- 29491502 TI - Third-Party Onboarding Organizations as Gatekeepers for Student Placement Decisions. AB - Health system human resource departments are putting new requirements, paperwork, and processes in place to meet new Joint Commission standards for treating students like employees who onboard at the beginning of employment. These processes have significantly increased the workload of experiential education offices and present an additional burden to students. In an attempt to streamline these processes, health systems are contracting with third-party tracking and placement organizations. Converting this process to an electronic one (such as what third-party organizations offer) could present advantages; however, there are many concerns about going through a third-party organization that could control placement decisions. This commentary describes these concerns and provides guidance to schools should they choose to work with one of these organizations. PMID- 29491503 TI - Using Hand Signs to Teach HIV Medications. AB - Objective. To describe an innovative active learning strategy that uses students' hands to facilitate learning and retention of major concepts related to nucleotide/nucleoside reverse transcriptase inhibitors (NRTIs). Methods. Students wrote the names of the NRTIs on their fingers, then an interactive activity used a variety of hand signs to teach the drugs. Focus groups were conducted with a total of 20 students one year after being exposed to the new teaching strategy. Students were asked five knowledge-based questions related to the subject matter to assess retention of the material. Results. On average, students answered 64% of the questions correctly. Most students (95%) used their hands to answer the knowledge-based questions. There was a statistically significant association between using hands to answer the question and answering the question correctly. When asked which active learning method was most effective, 14 (70%) participants reported "hands." Conclusion. Using students' hands was well received by this cohort of students. More research is needed to determine if this active learning method could be considered for use in other disease states to help students learn complex medications with many nuances. PMID- 29491504 TI - We're All In This Together. PMID- 29491505 TI - Flexner, Educational Reform, Social Accountability and Meta-Curriculum. PMID- 29491506 TI - Response to We're All In This Together. PMID- 29491507 TI - Advocating for Patient Care Literacy. AB - The value of the arts and humanities in becoming an "educated" pharmacist is reviewed in this commentary. The term "patient care literacy" is defined as becoming a more humane pharmacist. This implies not only using heads but HARTSS (humanities, arts and social sciences) for developing the necessary skills. A conceptual framework for curricular reform that focuses on using the arts and humanities is proposed for advancing patient care literacy. Methods for enhancing use of arts and humanities for developing pharmacy graduates is specifically proposed. The need for more empiric research to demonstrate the value of the arts and humanities in developing a patient care literate professional is highlighted. PMID- 29491508 TI - Response to Flexner, Educational Reform, Social Accountability and Meta Curriculum. PMID- 29491509 TI - Teaching Scholar Resolutions for 2018. PMID- 29491511 TI - 'Other Spaces' for the Dangerous Dead of Provincial England, c.1752-1832. AB - The Murder Act (1752) decreed that homicide perpetrators should be hanged and sent for post-execution punishment. This article explores the event management of criminal dissections by penal surgeons in situ. It reveals that the punishment parade of the condemned did not stop at the scaffold, contrary to the impression in many standard historical accounts. Instead, ordinary people accompanied criminal corpses to many different types of dissection venues. Penal surgeons hand-picked these performance spaces that were socially produced for legal and practical reasons. They had to be able to process large numbers of people who wanted to be part of the consumption of post-mortem 'harm' in English communities. Event management on location had to have emotional and visual appeal, moral coherence, be timed appropriately, and, if successful, would enhance the deterrence value of the capital code. Yet, managing the 'dangerous dead' involved a great deal of discretionary justice with unpredictable outcomes. It often happened in 'counter-sites' of punishment in the community and involved a great deal of immersive theatre. Some events worked well, others threatened the social order. In 'Other Spaces' the 'Dangerous Dead' was hence a fascinating feature of the Murder Act outside the Metropolis from 1752 to 1832. PMID- 29491510 TI - Total Solid-Phase Synthesis of Biologically Active Drosophila Insulin-Like Peptide 2 (DILP2). AB - In the fruit fly Drosophila melanogaster, there are eight insulin-like peptides (DILPs) with DILPs 1-7 interacting with a sole insulin-like receptor tyrosine kinase (DInR) while DILP8 interacts with a single G protein-coupled receptor (GPCR), Lgr3. Loss-of-function dilp mutation studies show that the neuropeptide DILP2 has a key role in carbohydrate and lipid metabolism as well as longevity and reproduction. A better understanding of the processes whereby DILP2 mediates its specific actions is required. Consequently we undertook to prepare DILP2 as part of a larger, detailed structure-function relationship study. Use of our well established insulin-like peptide synthesis protocol that entails separate solid phase assembly of each of the A- and B-chains with selective cysteine S protection followed by sequential S-deprotection and simultaneous disulfide bond formation produced DILP2 in good overall yield and high purity. The synthetic DILP2 was shown to induce significant DInR phosphorylation and downstream signalling, with it being more potent than human insulin. This peptide will be a valuable tool to provide further insights into its binding to the insulin receptor, the subsequent cell signalling and role in insect metabolism. PMID- 29491512 TI - Performance of the Indian Journal of Anaesthesia in 2017: How did we do and where do we go from here? PMID- 29491514 TI - Comparison of the ProSeal laryngeal mask airway with the I-GelTM in the different head-and-neck positions in anaesthetised paralysed children: A randomised controlled trial. AB - Background and Aims: Head and neck movements alter the shape of the pharynx, resulting in changes in the oropharyngeal leaking pressures and ventilation with supragottic airway devices. We compared the effect of the different head-and-neck positions on the oropharyngeal leak pressures and ventilation with the I-GelTM and ProSealTM laryngeal mask airway (PLMA) in anaesthetised paralysed children. Methods: A total of 70 children were randomly assigned to receive PLMA (n = 35) or I-GelTM (n = 35) for airway management. Oropharyngeal leak pressure in maximum flexion, maximum extension and the neutral position was taken as the primary outcome. Peak inspiratory pressures (PIPs), expired tidal volume, ventilation score and fibreoptic grading were also assessed. Results: No significant difference was noted in oropharyngeal leak pressures of PLMA and I-GelTM during neutral (P = 0.34), flexion (P = 0.46) or extension (P = 0.18). PIPs mean (standard deviation [SD]) were significantly higher (17.7 [4.03] vs. 14.6 [2.4] cm H2O, P = 0.002) and expired tidal volume mean [SD] was significantly lower (5.5 [1.6] vs. 6.9 [2] ml/kg, P = 0.0017) with I-GelTM compared to PLMA. Fibreoptic grading and ventilation score were comparable in both the groups in all the three head-and-neck positions. Conclusion: PLMA and I-GelTM, both recorded similar oropharyngeal leaking pressures in all the three head-and-neck positions. However, higher peak pressures and lower expired tidal volume in maximum flexion of the neck while ventilating with I-Gel may warrant caution and future evaluation. PMID- 29491513 TI - Advances in regional anaesthesia: A review of current practice, newer techniques and outcomes. AB - Advances in ultrasound guided regional anaesthesia and introduction of newer long acting local anaesthetics have given clinicians an opportunity to apply novel approaches to block peripheral nerves with ease. Consequently, improvements in outcomes such as quality of analgesia, early rehabilitation and patient satisfaction have been observed. In this article we will review some of the newer regional anaesthetic techniques, long acting local anaesthetics and adjuvants, and discuss evidence for key outcomes such as cancer recurrence and safety with ultrasound guidance. PMID- 29491515 TI - A prospective randomised controlled study for evaluation of high-volume low concentration intraperitoneal bupivacaine for post-laparoscopic cholecystectomy analgesia. AB - Background and Aims: Low-volume high-concentration bupivacaine irrigation of the peritoneal cavity has been reported to be ineffective for short-term analgesia after laparoscopic cholecystectomy (LC). This study was conducted to evaluate the effectiveness of intraperitoneal instillation of high-volume low-concentration bupivacaine for post-operative analgesia in LC. Methods: Sixty patients undergoing LC were included in this prospective, double-blind, randomised study. Patients were divided into two (n = 30) groups. In Group S, intraperitoneal irrigation was done with 500 ml of normal saline. In Group B, 20 ml of 0.5% (100 mg) bupivacaine was added to 480 ml of normal saline for intraperitoneal irrigation during and after surgery. Post-operative pain was assessed by numeric pain rating scale (NRS) at fixed time intervals. Duration of analgesia (DOA), total rescue analgesic requirement (intravenous tramadol), presence of shoulder pain, nausea and vomiting were recorded for the initial 24 h post-operatively. Results: Mean DOA in Group S was 0.06 +/- 0.172 h (3.6 +/- 10.32 min) and that in Group B was 19.35 +/- 8.64 h (P = 0.000). Cumulative requirement of rescue analgesic in 24 h in Group S was 123.33 +/- 43.01 mg and that in Group B was 23.33 +/- 43.01 mg (P = 0.000). There was no significant difference in incidence of shoulder pain, nausea and vomiting between the groups. Conclusion: High-volume low-concentration of intraperitoneal bupivacaine significantly increases post operative DOA and reduces opioid requirement after LC. PMID- 29491516 TI - Airway management in the presence of cervical spine instability: A cross sectional survey of the members of the Indian Society of Neuroanaesthesiology and Critical Care. AB - Background and Aims: There is a paucity of clinical practice guidelines for the ideal approach to airway management in patients with cervical spine instability (CSI). The aim of this survey was to evaluate preferences, perceptions and practices regarding airway management in patients with CSI among neuroanaesthesiologists practicing in India. Methods: A 25-item questionnaire was circulated for cross-sectional survey to 378 members of the Indian Society of Neuroanaesthesiology and Critical Care (ISNACC) by E-mail. We sent four reminders and again submitted our survey to non-responders during the 2017 annual ISNACC meeting. Apart from demographic information, the survey captured preferred methods of intubation and airway management for patients with CSI and their justification. Regression analysis was used to identify factors associated with the use of indirect technique for intubation. Results: Only 122 out of the 378 anaesthesiologists responded to our survey. Most respondents were senior consultants, working in training hospitals, and performed >=25 intubations per year for CSI patients. The majority of neuroanaesthesiologists (78.7%; n = 96) preferred indirect techniques for elective intubation. However, 45 anaesthesiologists (36.9%) preferred indirect techniques for emergency intubation. In an adjusted analysis, preference for patients to be conscious during intubation was significantly associated with the use of indirect techniques (odds ratio = 3.79; confidence interval = 1.52-9.49, P < 0.01). Conclusions: Among ISNACC members, indirect techniques are preferred for elective intubation of patients with CSI, while direct laryngoscopy is preferred for emergency intubation. PMID- 29491517 TI - Comparison of different doses of intravenous lignocaine on etomidate-induced myoclonus: A prospective randomised and placebo-controlled study. AB - Background and Aims: Etomidate-induced myoclonus (EM) is observed in 50%-80% of unpremedicated patients. Low-dose lignocaine has been shown to attenuate but not abolish the EM. The aim of this prospective, randomised controlled study was to compare the different doses of lignocaine on the incidence and severity of EM. Methods: Two hundred adult patients were randomly assigned into four groups to receive saline placebo (Group I) or IV lignocaine 0.5 mg/kg (Group II), 1 mg/kg (Group III) or 1.5 mg/kg (Group IV) 2 min before injection etomidate 0.3 mg/kg IV. The patients were assessed for the EM using a four-point intensity scoring system. Our primary outcome was the incidence of myoclonus at 2 min (EM2). The incidence of myoclonus at 1 min (EM1) and severity of myoclonus constituted the secondary outcomes. ANOVA and Pearson Chi-square test were used for statistical analysis and P < 0.05 was considered as statistically significant. Results: The incidence of EM was significantly reduced in Groups III [(EM1: 32% vs. 60%, P = 0.009); (EM2: 42% vs. 76%, P = 0.001)] and IV (EM2: 54% vs. 76%, P = 0.035) compared with Group I. Lignocaine 1 mg/kg and 1.5 mg/kg significantly reduced the incidence of severe myoclonus at 2 min (14% each) compared to Groups I (42%, P = 0.003) and II (32%, P = 0.032). Conclusion: Lignocaine 1 mg/kg and 1.5 mg/kg IV pretreatment significantly reduces the incidence of EM, with maximum attenuation observed with 1 mg/kg. PMID- 29491518 TI - Fast tracking in adult living donor liver transplantation: A case series of 15 patients. AB - Background and Aims: Fast tracking (FT) for more efficacious use of resources may be difficult after living donor liver transplantation (LDLT) due to a partial liver graft, complex vascular anastomoses and longer operating time. Our study was aimed at reporting our experience with FT (on table extubation) in LDLT recipients. A secondary objective of our study was to look at defining a subgroup of patients who could be prospectively planned for FT. Methods: We studied the demographics and outcomes of 15 LDLT recipients extubated immediately in the operating suite based on an uneventful intraoperative course, haemodynamic stability after graft reperfusion and improvement of metabolic parameters post implantation and vascular anastomoses. Results: Twelve recipients were males, and mean age, body mass index (BMI) and Model for End Stage Liver Disease (MELD) score were 43 +/- 12 years, 23 +/- 3 kg/m2 and 15.5 +/- 6, respectively, most were Child-Turcotte-Pugh Class B. Diabetes and hypothyroidism were present in 1 and 2 patients, respectively. Post-extubation, none required immediate re intubation and one patient needed non-invasive ventilation for 2 h. Conclusion: Fast tracked recipients were young, with a low BMI, low MELD scores, minimal comorbidities and good immediate graft function post-reperfusion. PMID- 29491519 TI - Pulmonary hypertension and post-operative outcome in renal transplant: A retrospective analysis of 170 patients. AB - Background and Aims: Renal transplant is the best possible treatment for patients suffering with end-stage renal disease (ESRD). Cardiovascular events are the commonest factors contributing to perioperative morbidity and mortality in this population. These patients have a high incidence (up to 60%) of pulmonary hypertension (PH) and that may affect the perioperative outcome. Methods: In this study, we aimed to study the impact of PH on perioperative outcome after renal transplant. PH was defined as patients with pulmonary artery systolic pressure >=35 mmHg on pre-operative echocardiography. Medical records of 170 patients who had undergone renal transplantation in the past 3 years were reviewed. Primary outcome was delayed graft functioning and secondary outcomes were perioperative complications such as hypotension, arrhythmias, need of post-operative mechanical ventilation, atelectasis and pulmonary oedema. Results: We observed 46.5% incidence of PH in ESRD patients. Compared to patients without PH, more patients with PH had postoperative hypotension (26.58% vs. 9.89%, P = 0.004) and delayed graft functioning (8.8% vs. 1.1%, P = 0.026). On multivariate analysis, however, PH was not an independent predictor of delayed graft functioning. Conclusion: In ESRD patients, although PH is not an independent predictor of delayed graft functioning, patients having PH are more prone for perioperative hypotension and delayed graft functioning after renal transplant. PMID- 29491520 TI - Anaesthetic management of an infant posted for ventricular septal defect closure with right-sided eventration of diaphragm. AB - Eventration of the diaphragm is a rare entity, characterised by abnormal elevation of a dome of diaphragm. In this condition, the diaphragm is composed of fibrous tissue with few or no interspersed muscle fibres. Eventration can be congenital or acquired. Congenital eventration results from inadequate development of muscles or absence of phrenic nerve. The common cause of acquired eventration is injury to the phrenic nerve from traumatic birth injury or surgery for heart disease. The perioperative anaesthetic management of diaphragmatic eventration along with ventricular septal defect with severe pulmonary hypertension makes this case both challenging and unique. PMID- 29491521 TI - Erector spinae plane block may aid weaning from mechanical ventilation in patients with multiple rib fractures: Case report of two cases. AB - Uncontrolled pain in patients with rib fracture leads to atelectasis and impaired cough which can progress to pneumonia and respiratory failure necessitating mechanical ventilation. Of the various pain modalities, regional anaesthesia (epidural and paravertebral) is better than systemic and oral analgesics. The erector spinae plane block (ESPB) is a new modality in the armamentarium for the management of pain in multiple rib fractures, which is simple to perform and without major complications. We report a case series where ESPB helped in weaning the patients from mechanical ventilation. Further randomised controlled studies are warranted in comparing their efficacy in relation to other regional anaesthetic techniques. PMID- 29491522 TI - Fluoroscopic-guided paramedian approach to subarachnoid block in patients with ankylosing spondylitis: A case series. PMID- 29491523 TI - Airway challenges in laryngotracheoplasty with Montgomery T-tube for subglottic stenosis. PMID- 29491524 TI - Should end-tidal carbon dioxide monitoring be mandatory for surgeries under spinal anaesthesia? PMID- 29491525 TI - Erector spinae plane block an effective block for post-operative analgesia in modified radical mastectomy. PMID- 29491526 TI - Paediatric Endobronchial Ultrasound-guided Transbronchial Needle Aspiration: Anaesthetic and procedural considerations. PMID- 29491527 TI - Jet insufflation options for the cannot intubate-cannot ventilate situation. PMID- 29491528 TI - Reply to Grocott HP, regarding their comment on 'Jet insufflator for cannot intubate cannot ventilate situation: An Indian Jugaad'. PMID- 29491529 TI - Anaesthetic management of patients with Brugada syndrome. PMID- 29491530 TI - The baffling issues of Brugada electrocardiogram pattern for anaesthesiologist! PMID- 29491531 TI - Dextrose for post-operative nausea and vomiting prophylaxis. PMID- 29491532 TI - Gender Ideologies in Europe: A Multidimensional Framework. AB - The authors argue, in line with recent research, that operationalizing gender ideology as a unidimensional construct ranging from traditional to egalitarian is problematic and propose an alternative framework that takes the multidimensionality of gender ideologies into account. Using latent class analysis, they operationalize their gender ideology framework based on data from the 2008 European Values Study, of which eight European countries reflecting the spectrum of current work-family policies were selected. The authors examine the form in which gender ideologies cluster in the various countries. Five ideology profiles were identified: egalitarian, egalitarian essentialism, intensive parenting, moderate traditional, and traditional. The five ideology profiles were found in all countries, but with pronounced variation in size. Ideologies mixing gender essentialist and egalitarian views appear to have replaced traditional ideologies, even in countries offering some institutional support for gendered separate spheres. PMID- 29491533 TI - Tuftsin-phosphorylcholine treatment of autoimmune diseases - a benefit and a message from helminths? PMID- 29491534 TI - Curcumin modulation of the activation of PYK2 in peripheral blood mononuclear cells from patients with lupus nephritis. AB - Introduction: Proline-rich tyrosine kinase 2 (PYK2) provides important signals during the activation of lymphocytes, which is essential in autoimmune diseases. Systemic lupus erythematosus (SLE) is a representative autoimmune disease, and lupus nephritis (LN) is one of its most severe complications. Although glucocorticoid-binding immuno-suppression is the first-line therapy for patients with LN, the common and severe side effects of such treatment call for new strategies to improve long-term prognosis and life quality for these patients. Curcumin has been used to treat autoimmune disease with good curative effect, but little is known about the effect of curcumin on LN patients. Our aim was to investigate the mechanism of curcumin for management of LN, specifically regarding the PYK2 pathways. Material and methods: Freshly isolated peripheral blood mononuclear cells (PBMCs) from 20 LN patients and 20 healthy individuals were cultured and stimulated with either PMA, PMA+TyrA9 (PYK2 specific inhibitor), or PMA+Curcumin, and with PBS as control. After 48 hours of incubation, cells were harvested and the expression of PYK2, p-PYK2, CD40L, CTLA 4, and PBMCs proliferation were measured. Then the expression and activation of PYK2 was evaluated using Western blot, the expression of costimulatory molecules CD40L and CTLA-4 protein was evaluated using flow cytometry, and PBMC proliferation was assessed using a [3H]-thymidine incorporation assay. Results: Curcumin inhibited the expression and activation of PYK2 in PBMCs in patients with LN in vitro. The inhibition rate of curcumin was negatively correlated with the level of serum complement, but positively correlated with 24-h proteinuria. Curcumin also suppressed the expression of costimulatory molecules CD40L and CTLA 4, as well as PBMC proliferation. Interestingly, these effects were not reproduced on PBMC cultures of healthy subjects. Conclusions: The inhibition of PYK2 signalling protein may be one of the mechanisms underlying the action of curcumin in LN treatment. PMID- 29491535 TI - Cytokines and integrins related to inflammation of joint and gut in patients with spondyloarthritis and inflammatory bowel disease. AB - Objectives: Inflammatory bowel disease (IBD) and spondyloarthritis (SpA) have some overlapping clinical features, i.e. gut and joint inflammation. Cytokines of interleukin 17(IL-17)/IL-23 axis play a pathogenic role in both diseases. Integrins (ITGs) regulate migration of immune cells to inflamed tissues (ITGbeta7 into gut, ITGbeta2 into gut and also to other tissues). In this study, we search for differences in the serum concentrations of these cytokines and integrins between patients suffering from SpA or IBD with and without overlapping symptoms. Material and methods: Patients with SpA (n = 30), IBD (n = 68), and healthy volunteers (n = 28) were included in the study. Fourteen SpA patients reported symptoms characteristic for IBD. Spondyloarthritis symptoms were diagnosed in 50% of IBD patients, while other patients of this group reported arthralgia only. Serum concentrations of IL-17, IL-22, IL-23, ITGbeta2, and ITGbeta7 were measured by specific enzyme-linked immunosorbent assay using commercially available sets. The Mann-Whitney and Spearman's rank tests were used for intergroup comparison and correlation assessment, respectively. Results: Comparison of patient groups showed significantly higher serum concentrations of IL-17, IL-22, and ITGbeta7 in SpA, and up-regulated levels of IL-23 in IBD patients. Similar differences were observed between patient subgroups, both with and without overlapping symptoms. In SpA but not in IBD patients, serum concentrations of ITGbeta7 inversely correlated (r = -0.552) with C-reactive protein. Conclusions: Patients with SpA and IBD differ in the circulating concentrations of IL-17/IL-23 axis cytokines and ITGbeta7, irrespectively of the presence or absence of overlapping symptoms. Therefore, we conclude that observed differences are attributed rather to underlying than concurrent disease. PMID- 29491536 TI - Drug-free remission: the goal of the future in management of patients with rheumatoid arthritis. AB - Management of patients with rheumatoid arthritis according to the "treat-to target" strategy requires achievement of remission or low disease activity when remission cannot be achieved (mostly in patients with advanced disease). The assessment of remission and low disease activity is based on a number of definitions depending on the applied instruments which do not always correspond to one another. The role of biomarkers and imaging techniques (ultrasound and magnetic resonance imaging) in predicting the risk for disease relapse after achieving remission and tapering disease-modifying antirheumatic drugs treatment are presented. The concept of achieving the full control of inflammation including residua synovial inflammation and drug free-remission is discussed. PMID- 29491537 TI - Status of etoricoxib in the treatment of rheumatic diseases. Expert panel opinion. AB - Pain is one of the most disabling symptoms of rheumatoid diseases. Patients with pain secondary to osteoarthritis (OA), rheumatoid arthritis (RA), ankylosing spondylitis (AS) or gout require effective analgesic treatment, and the physician's task is to select a drug that is best suited for an individual patient. The choice of pharmacotherapy should be based both on drug potency and clinical efficacy, and its safety profile, particularly in the elderly population, as the number of comorbidities (and hence the risk of treatment complications and drug interactions) rises with age. In cases involving a high risk of gastrointestinal complications or concerns about hepatotoxicity, with a low cardiovascular risk, the first-line nonsteroidal anti-inflammatory drugs to consider should be coxibs including etoricoxib. PMID- 29491538 TI - Antinuclear antibodies in autoimmune and allergic diseases. AB - Antinuclear antibodies (ANA) are primarily significant in the diagnosis of systemic connective tissue diseases. The relationship between their occurrence in allergic diseases is poorly documented. However, the mechanism of allergic and autoimmune diseases has a common thread. In both cases, an increased production of IgE antibodies and presence of ANA in selected disease entities is observed. Equally important is the activation of basophils secreting proinflammatory factors and affecting the differentiation of TH17 lymphocytes. Both autoimmune and allergic diseases have complex multi-pathogenesis and often occur in genetically predisposed individuals. The presence of antinuclear antibodies was confirmed in many systemic connective tissue diseases and some allergic diseases. Examples include atopic dermatitis, non-allergic asthma, and pollen allergy. Co occurring allergic and autoimmune disorders induce further search for mechanisms involved in the aetiopathogenesis of both groups of diseases. PMID- 29491539 TI - Morphea - selected local treatment methods and their effectiveness. AB - Localised scleroderma is an uncommon connective tissue disease of multifactorial aetiology occurring in the paediatric and adult population. It is relatively difficult to conduct any research on the subject of this disease entity treatment due to the low number of patients suffering from morphea, a tendency of the disease to remit spontaneously, and not yet well recognised aetiology. Hence, there has been developed no causal treatment of well-proven effectiveness, and schedules of symptomatic therapy are not yet clearly determined. The paper depicts most widely used topical treatment methods in morphea therapy, which due to minor risk of systemic adverse effects seem to be a beneficial therapeutic alternative. The main aim of this article was to analyse different topical treatment options used in localised scleroderma therapy and to indicate the most appropriate, safe, and effective one. PMID- 29491540 TI - Organising pneumonia - the first manifestation of rheumatoid arthritis. AB - Organising pneumonia (OP) is a distinct type of interstitial lung disease, because it can also be seen in association with several conditions such as infections, drugs, and connective tissue diseases. An association of OP with rheumatoid arthritis (RA) has also been described. Joint manifestations of RA usually precede lung involvements by several years; however, in less than 10% of cases of RA, interstitial lung disease may be the initial feature of RA. Organising pneumonia as the initial manifestation or developed simultaneously of RA is extremely rare, and its clinical features remain unknown. We present a 56 year-old woman with OP as the first manifestation of RA. PMID- 29491541 TI - Hepatic involvement in granulomatosis with polyangiitis - diagnostic difficulties. AB - We report the case of a 57-year-old Caucasian man who presented with dry cough, haemoptysis, fever, lung nodules, erythrocyturia, and acute hepatitis. After a lung biopsy, the patient was diagnosed with granulomatosis with polyangiitis. The diagnosis was supported by the presence of anti-proteinase-3 anti-neutrophil cytoplasmic antibodies. The most common causes of liver damage are excluded. The patient was treated with prednisone and cyclophosphamide, which resulted in remission of chest CT findings and improvement in liver function tests. During the flare, new lung infiltrations as well as elevation of liver enzymes were present. Treatment with rituximab resulted in complete clinical and radiological remission and normalisation of liver function tests. What makes this case worth reporting is the rare liver involvement in the GPA. After exclusion of coexistence of autoimmune liver disease and drug-induced liver lesion, organ involvement was supported by the reversion of abnormal LFT after the immunosuppression of GPA. PMID- 29491543 TI - Professor Stefan H. Mackiewicz. PMID- 29491542 TI - A child with subcorneal pustular dermatosis responded to IVIG treatment (Sneddon Wilkinson disease). AB - Subcorneal pustular dermatosis (SPD) is a rare, chronic, recurrent dermatosis characterised by sterile pustules. It develops mainly in middle-aged or elder women, but is also rarely seen in children. The exact aetiology of the disease is unknown. In literature, cases associated with IgA gammopathy have been reported. In this article; we report a case of a five-year-old girl who was diagnosed as SPD by clinical features, histopathological characteristics, and direct immunofluorescence analysis results. IgA was high, and IgG-IgM and CD19+ B cell were low. We noticed that during IVIG treatment for immunodeficiency, dermatological symptoms were recovered rapidly. Clinical profile of SPD and its association with systemic diseases may provide early detection of immune dysfunction. PMID- 29491544 TI - Statistical Properties of Ribbon Evolution and Reconnection Electric Fields in Eruptive and Confined Flares. AB - : A statistical study of the chromospheric ribbon evolution in H[Formula: see text] two-ribbon flares was performed. The data set consists of 50 confined (62%) and eruptive (38%) flares that occurred from June 2000 to June 2015. The flares were selected homogeneously over the H[Formula: see text] and Geostationary Operational Environmental Satellite (GOES) classes, with an emphasis on including powerful confined flares and weak eruptive flares. H[Formula: see text] filtergrams from the Kanzelhohe Observatory in combination with Michelson Doppler Imager (MDI) and Helioseismic and Magnetic Imager (HMI) magnetograms were used to derive the ribbon separation, the ribbon-separation velocity, the magnetic-field strength, and the reconnection electric field. We find that eruptive flares reveal statistically larger ribbon separation and higher ribbon-separation velocities than confined flares. In addition, the ribbon separation of eruptive flares correlates with the GOES SXR flux, whereas no clear dependence was found for confined flares. The maximum ribbon-separation velocity is not correlated with the GOES flux, but eruptive flares reveal on average a higher ribbon separation velocity (by ~ 10 km s-1). The local reconnection electric field of confined ([Formula: see text]) and eruptive ([Formula: see text]) flares correlates with the GOES flux, indicating that more powerful flares involve stronger reconnection electric fields. In addition, eruptive flares with higher electric-field strengths tend to be accompanied by faster coronal mass ejections. Electronic Supplementary Material: The online version of this article (10.1007/s11207-018-1253-1) contains supplementary material, which is available to authorized users. PMID- 29491545 TI - Journal peer review: a bar or bridge? An analysis of a paper's revision history and turnaround time, and the effect on citation. AB - Journal peer review lies at the heart of academic quality control. This article explores the journal peer review process and seeks to examine how the reviewing process might itself contribute to papers, leading them to be more highly cited and to achieve greater recognition. Our work builds on previous observations and views expressed in the literature about (a) the role of actors involved in the research and publication process that suggest that peer review is inherent in the research process and (b) on the contribution reviewers themselves might make to the content and increased citation of papers. Using data from the journal peer review process of a single journal in the Social Sciences field (Business, Management and Accounting), we examine the effects of peer review on papers submitted to that journal including the effect upon citation, a novel step in the study of the outcome of peer review. Our detailed analysis suggests, contrary to initial assumptions, that it is not the time taken to revise papers but the actual number of revisions that leads to greater recognition for papers in terms of citation impact. Our study provides evidence, albeit limited to the case of a single journal, that the peer review process may constitute a form of knowledge production and is not the simple correction of errors contained in submitted papers. PMID- 29491546 TI - Country-specific determinants of world university rankings. AB - This paper examines country-specific factors that affect the three most influential world university rankings (the Academic Ranking of World Universities, the QS World University Ranking, and the Times Higher Education World University Ranking). We run a cross sectional regression that covers 42-71 countries (depending on the ranking and data availability). We show that the position of universities from a country in the ranking is determined by the following country-specific variables: economic potential of the country, research and development expenditure, long-term political stability (freedom from war, occupation, coups and major changes in the political system), and institutional variables, including government effectiveness. PMID- 29491547 TI - Tracking the follow-up of work in progress papers. AB - Academic conferences offer numerous submission tracks to support the inclusion of a variety of researchers and topics. Work in progress papers are one such submission type where authors present preliminary results in a poster session. They have recently gained popularity in the area of Human Computer Interaction (HCI) as a relatively easier pathway to attending the conference due to their higher acceptance rate as compared to the main tracks. However, it is not clear if these work in progress papers are further extended or transitioned into more complete and thorough full papers or are simply one-off pieces of research. In order to answer this we explore self-citation patterns of four work in progress editions in two popular HCI conferences (CHI2010, CHI2011, HRI2010 and HRI2011). Our results show that almost 50% of the work in progress papers do not have any self-citations and approximately only half of the self-citations can be considered as true extensions of the original work in progress paper. Specific conferences dominate as the preferred venue where extensions of these work in progress papers are published. Furthermore, the rate of self-citations peaks in the immediate year after publication and gradually tails off. By tracing author publication records, we also delve into possible reasons of work in progress papers not being cited in follow up publications. In conclusion, we speculate on the main trends observed and what they may mean looking ahead for the work in progress track of premier HCI conferences. PMID- 29491548 TI - Trends in local public child welfare agencies 1999-2009. AB - US public child welfare agencies have faced increasing pressure in the first decade of this century to demonstrate efficiency and accountability, even as the Great Recession increased pressures on millions of families and undermined human service funding. This paper reports on analyses of the two cohorts of local public child welfare agencies from the National Survey of Child and Adolescent Well-Being to identify changes in their structure and practice. Local agency adaptations have included some structural integration and apparently increased use of subcontracting, including investigations. Collectively, these trends appear to be fostering a tighter coupling of local child welfare agencies with other service providers. Some of these connections may improve families' access to a range of services. However, the increased reliance on private providers may also undermine accountability and flexibility to respond to changing needs. PMID- 29491549 TI - Extra-pair parentage and personality in a cooperatively breeding bird. AB - Abstract: Why so much variation in extra-pair parentage occurs within and among populations remains unclear. Often the fitness costs and benefits of extra-pair parentage are hypothesised to explain its occurrence; therefore, linking extra pair parentage with traits such as personality (behavioural traits that can be heritable and affect reproductive behaviour) may help our understanding. Here, we investigate whether reproductive outcomes and success are associated with exploratory behaviour in a natural population of cooperatively breeding Seychelles warblers (Acrocephalus sechellensis) on Cousin Island. Exploratory behaviour correlates positively with traits such as risk-taking behaviour and activity in other wild bird species and might promote extra-pair mating by increasing the rate at which potential extra-pair partners are encountered. We therefore predicted that fast-exploring individuals would have more extra-pair offspring. There is also a potential trade-off between pursuing extra-pair parentage and mate guarding in males. We therefore also predicted that fast exploring males would be more likely to pursue extra-pair parentage and that this would increase the propensity of their mate to gain extra-pair parentage. We found that neither the total number of offspring nor the number of extra-pair offspring were associated with a male's or female's exploratory behaviour. However, there was a small but significant propensity for females to have extra pair fertilisations in pairs that were behaviourally disassortative. Overall, we conclude that, due to the small effect size, the association between exploratory behaviour and extra-pair paternity is unlikely to be biologically relevant. Significance statement: True genetic monogamy is rare, even in socially monogamous systems, and multiple factors, such as behaviour, social structure, morphology and physiology, determined by the biological system can cause variation in extra-pair parentage (EPP). Therefore, investigating the inherent differences in these factors among individuals could be informative. We investigated whether reproductive outcomes/success are associated with differences in the propensity to explore novel environments/objects in a promiscuous, island-dwelling cooperatively breeding bird, the Seychelles warbler. Our results showed that exploratory behaviour was not associated with the number of offspring produced by an individual, and thus the long-term fitness consequences of different exploratory tendencies did not differ. We also found that the propensity to engage in EPP in females was higher in dissimilar behavioural pairs, but due to the small effect size, we hesitate to conclude that there are personality-dependent mating outcomes in the population. PMID- 29491550 TI - Controlling for Prior Attainment Reduces the Positive Influence that Single Gender Classroom Initiatives Exert on High School Students' Scholastic Achievements. AB - Research points to the positive impact that gender-segregated schooling and classroom initiatives exert on academic attainment. An evaluation of these studies which reveal positive effects highlights, however, that students are typically selectively assigned to single- or mixed-gender instructional settings, presenting a methodological confound. The current study controls for students' prior attainment to appraise the efficacy of a single-gender classroom initiative implemented in a co-educational high school in the United Kingdom. Secondary data analysis (using archived data) was performed on 266 middle-ability, 11-12 year old students' standardized test scores in Languages (English, foreign language), STEM-related (Mathematics, Science, Information and Communication Technology), and Non-STEM subjects (art, music, drama). Ninety-eight students (54, 55% female) were taught in single-gender and 168 (69, 41% female) in mixed-gender classrooms. Students undertook identical tests irrespective of classroom type, which were graded in accordance with U.K national curriculum guidelines. Controlling for students' prior attainment, findings indicate that students do not appear to benefit from being taught in single-gender relative to mixed-gender classrooms in Language and STEM-related subjects. Young women benefitted from being taught in mixed-gender relative to single-gender classes for Non-STEM subjects. However, when prior ability is not controlled for, the intervention appears to be effective for all school subjects, highlighting the confounding influence of selective admissions. These findings suggest that gender-segregated classroom initiatives may not bolster students' grades. It is argued that studies that do not control for selection effects may tell us little about the effectiveness of such interventions on scholastic achievement. PMID- 29491551 TI - Time to Move Beyond the Big Five? PMID- 29491553 TI - Incidence of amphistome infection in sheep from Mhow, Madhya Pradesh. AB - A total of 445 faecal samples and 128 rumens of sheep collected from Slaughter house, Mhow (Madhya Pradesh) were examined for a period of 1 year from February 2011 to January 2012. Faecal sample examination based, incidence of amphistomes was found to be 23.37% from the study area. The incidence of amphistomes was significantly higher (p < 0.01) during summer (36.75%) than winter (27.74%) and monsoon (3.52%). Age-wise, non-significantly higher infection was observed in >=1 year-old animals (23.61%) than <1 year-old animals (23.11%). Non-significantly higher rate of infection was recorded in case of females (25.63%) than that of males (19.64%). Out of 128, 49 (38.28%) rumens were found positive for amphistomes. The prevalence of Paramphistomum cervi (27.34%) was found to be significantly (p < 0.01) higher than Gastrothylax crumenifer (10.94%). PMID- 29491554 TI - Antimalarial activity of Artemisia nilagirica against Plasmodium falciparum. AB - Malaria is one of the most prevalent vector borne infectious disease and a serious global health problem in the world. Treatment for malaria is commonly inadequate due to the lack of quality assured limited number of effective drugs, underline how important it is to discover new antimalarial plants from number of natural sources. In the present study, the efficacy of antimalarial activity was studied by taking six various (n-hexane, chloroform, petroleum ether, ethanol, methanol and aqueous) organic leaf extracts of Artemisia nilagirica (Clarke) Pamp. against malarial parasite Plasmodium falciparum. Promising antiplasmodial activity was found in all tested extracts; however, maximum 50% inhibitory concentration (IC50) values were noticed after 32 h of incubation, which is 5.76 +/- 0.82, 7.09 +/- 1.09, 9.88 +/- 1.13, 10.24 +/- 1.52, 11.37 +/- 1.77 and 50.15 +/- 6.16 ug/ml in methanol, chloroform, n-hexane, petroleum ether, ethanol and aqueous extracts, respectively. In conclusion, A. nilagirica leaf extract possesses antiplasmodial activity which may be used as a potent plant-based antimalarial drug in the future by investigating the hidden phytochemical/(s). PMID- 29491552 TI - The fauna and perspective of rodentia ectoparasites in Iran relying on their roles within public health and veterinary characteristics. AB - Historically, rodents-ectoparasites are responsible for many diseases in human and domestic animal communities because they are well-adapted to the environment and nutritional resources. In addition, ectoparasites can affect the reproductive rates, ecological fitness and the dispersal pattern of their hosts. Data was compiled through all publications relating to ectoparasites fauna from Iranian rodents. Host specificity, rodent-parasites interaction, geographical distribution, ecological trends as well as the medical or veterinary importance of ectoparasites are considered in this review. Also, results compared with other equal global findings. According to the obtained information, the genus Hyalomma considered being the major vector of Crimean-Congo hemorrhagic fever. Sistan Balouchistan, Isfahan, Fars and Khuzestan are endemic provinces of this disease in Iran. Ixodes ticks (especially Hyalomma spp.) commonly existed throughout the months but had high activity in spring and late autumn seasons. Muridae as the most diversified rodent family was more reiterated exploited host by all parasites in this knowledge. Tatera indica confirmed as a positive host for Francisella tularensis by serological test but the definitive reservoir is still unclear in Iran. Meriones persicus as a nocturnal jird has been permanently presented in semi-desert areas except Dasht-e Kavir desert. This rodent was the frequent host for Pulicid fleas followed by Mus musculus and Cricetulus migratorius (Cricetidae). Rattus norvegicus was specialized host for Polyplax spinulosa (spiny rat louse). Pulex irritans from Pulicidae was spread in particularly west of Iran which known as an endemic focus of plague. Mites were high diversity than other taxa. The domestic vertebrates (sheep, goat and cattle) were primitive hosts and rodents were discovered as auxiliary hosts for ticks in Iran apparently. The available data suggested that lice had a type of model of host specificity due to their morphological traits. Meanwhile, Alborz and Zagros mountains ranges provided the specialized habitats for animals which have been surrounded by northern and western regions. Perhaps these mountainous areas can prevent gene flow between local mammalian populations. Notably, the genealogy of parasite genome can orient toward the evolutionary process into speciation point. In general, more researches are needed to decipher the whole sights of host parasite association and the role of ectoparasites within zoonosis diseases. PMID- 29491555 TI - Genomic analysis of Blastocystis hominis isolates in patients with HIV-positive using locus SSU-rDNA. AB - Blastocystis hominis (B. hominis) is a protozoan zoonosis which clinical signs of infection with this parasite has been reported to be more severe in patients with weakened immune systems than healthy controls. So, the aim of the study was to evaluate genomic analysis of B. hominis isolates obtained from patients with HIV positive using locus SSU-rDNA. At first, 268 stool samples were randomly collected from patients with HIV-positive referred to health centers of Khuzestan province, southwest of Iran. Formol-ether and direct smear techniques were used for the detection of parasitic agents. After extracting DNA, the samples were analyzed by the PCR method. Finally, the subtypes were determined by the sequencing and PCR methods. New samples were used for the preparation of positive control sample; they were cultured in coagulant-serum biphasic cultivation media. Of 268 stool samples, 33 (12.3%) cases were detected positive for B. hominis using Formol-Ether technique but 51 (19%) cases were positive using molecular method. The most common isolates were related to the subtype III with 29 positive cases (56.8%), then, genotype I with 11 (21.6%) cases, 6 cases (11.8%) with genotype II, 3 (5.9%) combined cases with genotypes I and III as well as 2 cases (3.9%) with genotype VI. There was a significant difference between two groups of HIV-positive patients (infected with the parasite and/or without the parasite) in the term of the mean of TCD4-positive cells. The results indicated a relatively high prevalence of B. hominis in HIV-positive patients as well as our findings may represent that the number reduction of TCD4-positive cells has an effective role in the increased risk of the parasitic infection in HIV-positive patients. PMID- 29491556 TI - Acaricidal potency of polyherbal spray against Rhipicephalus microplus and Hyalomma anatolicum infestation in cattle. AB - Acaricidal potential of polyherbal spray (Andropogon citrates, Cymbopogon citratus, Ocimum sanctum, Pinus longifoia, Calotropis procera, Datura stramonium, Aegle marmelos, Ricinus communis, Azadirachta indica, Allium sativum, Carica papaya, Annona squamosa and Pongamia glabra) was assessed against tick infestation in cattle on the basis of measurement of tick count, complete blood count and plasma glucose, total protein, albumin and globulin before treatment and 21 days after treatment. Single application of polyherbal spray over body of 20 randomly selected tick infested cattle revealed significant reduction in mean tick count starting from 3 days post treatment till 21 days post treatment. Highly significant (P < 0.01) increase in total erythrocyte count and packed cell volume was observed in treated cows 21 days after application of spray compared to pre-treatment values indicating the reduction in blood loss due to heavy tick infestation before treatment. Plasma biochemical parameters revealed no significant changes in pre-treatment and post treatment values. The results of present study imply the clinical and haematological improvement in tick infested cattle treated with polyherbal spray and it could be potential product for use in livestock as acaricide. PMID- 29491557 TI - A note on mixed coccidian and Capillaria infection in pigeons. AB - Two adult pigeons were presented to the Teaching Veterinary Hospital (TVH), GADVASU, Ludhiana, Punjab with the history of weakness, anorexia, ruffled feathers and intermittent diarrhoea. Coproscopic examination revealed the presence of coccidian oocysts alongside eggs of Capillaria spp. Based on the morphological characters the eggs were designated as C. obsignata. Sporulation studies on the coccidian oocysts revealed mixed infection of Eimeria columbae and E. columbarum. PMID- 29491558 TI - Geographic and ecological features of phlebotomine sand flies (Diptera: Psychodidae) as leishmaniasis in Central Iran. AB - Phlebotomine sand flies occur throughout the tropics and subtropics, as well as in temperate regions of the world. They are vectors of human and canine leishmaniasis and sand fly fevers caused by phleboviruses. This study was aimed to determine the geographic and ecological characteristics of phlebotomine sand flies as vectors of leishmaniasis and to prepare a checklist of phlebotomine sand flies. The study was conducted in Qom province, central Iran, between April and November 2016. Qom is located in latitude 34.6399 degrees N and longitude 50.8759 degrees E with average annual minimum and maximum temperatures of 16.5 and 49 degrees C, annual rainfall of 150 mm and relative humidity of 84 and 28%, respectively. Sand flies were collected by sticky paper traps from Qom city and its six districts. The sand flies collected were separated from the sticky paper traps using an insulin syringe and kept in 70% ethanol for species identification using taxonomic keys. Also, a literature review was performed using all published reports on phlebotomine sand flies in this province during 1999-2015. A total of 28,410 sand flies from two genera and 14 species were collected. Phlebotomus papatasi, the main vector of zoonotic cutaneous leishmaniasis and arboviruses, and Phlebotomus sergenti, the vector of anthroponotic cutaneous leishmaniasis, were the predominant species followed by Phlebotomus kandelakii, P. major and P. alexandri. Fourteen species from two genera mostly from wet and mountainous areas were identified in the study area. Kahak and Markazi districts were identified as high-risk foci with numerous leishmaniasis vectors species; we recommend intensifying and strengthening of vector control programme in the area of study. PMID- 29491559 TI - Tick infestation in human beings in the Nilgiris and Kancheepuram district of Tamil Nadu, India. AB - Thirteen human beings were infested with ticks at Sandynallah and Gudalur of the Nilgiris district and Mottur Suruvakkam of Kancheepuram district of Tamil Nadu from January 2016 to December 2016. The collected ticks were identified as Rhipicephalus haemaphysaloides, Otobius megnini and Hyalomma isaaci. The tick infestation was observed more on the persons working with animals (sheep and goats) than those working in tea estate. The person infested with R. haemaphysaloides revealed erythematous papule (2 mm size) and inflammatory lesion up to 16 days whereas, the people infested with H. isaaci showed continuous itching and irritation for > 6 months and wound formation (0.5 cm) at the biting site. The people infested with O. megnini showed irritation, vomiting sensation and fever. PMID- 29491560 TI - Standardization of a latex agglutination test for coproantigen detection of Fasciola sp. in bovine cattle stool. AB - Fasciolosis is a zoonotic parasitic disease, which affects humans and animals; diagnosed through noncommercial immunoassay tests that cannot be used on the field. Thereby, establishing the optimal conditions to develop a latex agglutination technique with IgG and IgM antibodies directed against excretion/secretion antigens of Fasciola sp. is a priority. Latex particles were sensitized with IgG and IgM antibodies directed against excretion/secretion antigens of Fasciola sp. The specificity of the antibodies was determined against antigens of different helminths and protozoa; the sensitivity and specificity of the test was evaluated against a previously standardized direct ELISA. The coupling rates of the IgG and IgM antibodies were 85.77 and 100%, respectively. The minimum detectable concentration of Fasciola sp. excretion/secretion antigens, diluted in a phosphate-buffered saline, was 1.589 mg/mL(IgG) and 0.158 mg/mL(IgM) and for the antigens incorporated in the bovine cattle stool it was 3.178 mg/mL(IgG) and 1.589 mg/mL(IgM). The test showed crossed reaction against Giardia sp., and Cryptosporidium sp. antigens. Agreement of the IgG and IgM latex test against the ELISA test was of 78.78 and 96.96%, respectively; the specificity found was of 100% for both tests and sensitivity was 78.79% (IgG) and 96.97% (IgM). This work standardized the latex agglutination technique to detect Fasciola sp. antigens in bovine cattle stool. PMID- 29491561 TI - Knowledge, attitude and practice (KAP) on malaria, from high malaria burden rural communities, southeastern Iran. AB - Nowadays, community based control strategies are considered efficient in reaching the malaria elimination goal. For this reason, this study was conducted to access the knowledge, attitude and practice of people on malaria from rural areas with high malaria incidence. In this descriptive-analytic study, a total of 200 rural residents of southeastern Iran were recruited. They were selected based on cluster and simple random sampling methods. Data collection was done using questionnaire with reliability confirmation by Cronbach's alpha and data was analyzed using SPSS. Mosquito's bite was answered as the main route of malaria transmission. Also, majority of the participants correctly expressed most important symptoms of malaria. Most of them believed that malaria is preventable and the best strategy for its control is indoor residual spraying. Very few number of the respondents mentioned sleeping under insecticide treated bed net as a method for controlling the transmission of malaria. Chi square test shows significant difference between the level of education and usage of mosquito nets, but there was no significant difference between the use of bed nets and time of usage. Another significant relationship was seen between malaria infection, use of mosquito nets and place of sleeping at nights during summer. The current study showed the appropriate level of KAP among rural communities in southeast of Iran. Alongside of people's knowledge and attitudes, their practice about malaria should be increased as an effective factor for achieving to great goal of malaria elimination. PMID- 29491563 TI - Studies on prevalence and histomorphology of Sarcocystis species infecting cattle in Andhra Pradesh, India. AB - The present study was carried out to determine the prevalence of bovine sarcocystosis and identify the different species of Sarcocystis cysts in cattle in different regions of Chittoor district, Andhra Pradesh. A total of 150 slaughtered cattle over a period of 1 year were examined both macroscopically and microscopically for the presence of Sarcocystis infection. Out of 150 slaughtered cattle examined, macroscopic sarcocysts were observed in nine cattle and were exclusively found in oesophagus. Examination of tissue samples collected from different predilection sites from each of 150 cattle by pepsin-HCl digestion method revealed presence of live banana shaped bradyzoites under light microscopy in 134 cattle. Six cattle that were positive by macroscopic examination were also positive by microscopic examination of tissues. The overall prevalence of Sarcocystis infection in cattle of Chittoor district was 91.33%. The prevalence of macroscopic and microscopic sarcocysts was 6.57 and 93.43% respectively. Statistically a significant relationship between the prevalence of infection among different age groups (P < 0.001) and no significant relationship (P > 0.001) between the prevalence of Sarcocystis infection in male (91.76%) and female (90.76%) cattle was observed. In both male and females the prevalence of Sarcocystis infection increased with age. Microscopically sections of tissues from cattle that were positive by tissue digestion technique revealed thin walled cysts (4.5 +/- 0.5 um) in 131 samples and thick walled cysts (0.5 +/- 0.12 um) in six cattle. PMID- 29491562 TI - Antiplasmodial activity of two medicinal plants against clinical isolates of Plasmodium falciparum and Plasmodium berghei infected mice. AB - Malaria is an infectious and deadly parasitic disease, associated with fever, anaemia and other ailments. Unfortunately the upsurge of plasmodium multidrug resistant constrained researchers to look for new effective drugs. Medicinal plants seem to be an unquenchable source of bioactive principles in the treatment of various diseases. The aim of this study was to assess the antiplasmodial activity of two Ivorian medicinal plants. The in vitro activity was evaluated against clinical isolates and Plasmodium falciparum K1 multidrug resistant strain using the fluorescence based SYBR green I assay. The in vivo bioassay was carried out using the classical 4 day suppressive and curative tests on Plasmodium berghei infected mice. Results showed that the in vitro bioassay of both plant extracts were found to exhibit a promising and moderate antiparasitic effects on clinical isolates (5 ug/mL < IC50 < 15 ug/mL) and Plasmodium falciparum multidrug resistant K1 strain (15 ug/mL < IC50 < 50 ug/mL). Furthermore, the in vivo antiplasmodial screening of both extracts showed a significant decrease in parasitemia, which was dose-dependent. Body temperature in mice treated with both extracts at experimental doses increased, compared to the negative control group and was dose-dependent. As for mice body weight a significant decrease (p < 0.001) was noticed in the negative control group compared to tested groups of animals. The hydroethanolic stem bark extract of Anthocleista djalonensis A Chev and leaves extract of Ziziphus mauritiana Lam exhibited anti-malarial activities. Therefore, the bioactive compounds of both plant extracts need to be investigated. PMID- 29491564 TI - Molecular diagnosis of microsporidia strains in slaughtered cows of southwest of Iran. AB - Microsporidia is often considered as an opportunistic infection in patients with impaired immune systems such as patients with acquired immune deficiency syndrome, transplant recipients, children and old people. Due to the ability of the parasite to transmit from animals to human as well as the increasing prevalence of parasitic infections and immune deficiency diseases; therefore, the aim of this study was to evaluate molecular diagnosis of microsporidia strains in slaughtered cows of southwest of Iran. Initially, 256 stool samples of cows were collected from 5 regions of Khuzestan province, southwest of Iran and stained by modified trichrome (weber). Then, the parasite spores were examined by optical microscope. Total DNA was extracted from samples using DNA extraction kit for stool (Bioneer) and evaluated by multiplex/nested PCR method. The products of nested-PCR were explored by RFLP method using restriction enzyme MnlI. For genotyping, positive samples of RFLP were sequenced. Of 256, 21 and 48 samples were found positive by the staining and nested PCR tests, respectively. Of 48, 36 samples were Enterocytozoon bieneusi with genotype frequency D (22), J (9) and M (5). Also 9 were detected as Encephalitozoon species among which 2 were E. cuniculi, 6 were E. intestinalis and 1 was E. hellem Eventually, 3 samples were found positive for both Enterocytozoon and Encephalitozoon. The results showed that cows can be a source of microsporidia infections. Due to the zoonotic importance of this parasite and its ability to transmit from animals to humans; the detection and species determination of the parasite seems essential. The highest risk of infection is for individuals with impaired immune systems. PMID- 29491566 TI - Description of Pleurogenoides cyanophlycti n. sp. (Digenea: Pleurogenidae) infecting Euphlyctis cyanophlyctis from the Western Ghats, India. AB - Pleurogenoides cyanophlycti n. sp. (Digenea, Pleurogenidae) from the intestine of the water skipper, Euphlyctis cyanophlyctis (Anura, Dicroglossidae), inhabiting the Western Ghats, India is described and illustrated. Pleurogenoides cyanophlycti n. sp. is new to the genus and is separated from its congeners on the basis of differences in morphology and morphometry. It is named after the host, E. cyanophlyctis. PMID- 29491565 TI - Preparation and characterization of excretory and secretory antigen of Cotylophoron cotylophorum and Gastrothylax crumenifer. AB - Excretory and secretory antigen of adult Cotylophoron cotylophorum and Gastrothylax crumenifer was prepared and characterized by SDS-PAGE. Adult paramphistomes were collected in PBS from rumen of sheep slaughtered at Perambur and Villivakkam slaughter houses, Chennai, Tamil Nadu. Excretory/Secretory (E/S) antigens of G. crumenifer and C. cotylophorum were prepared by incubating in PBS at 28.3 degrees C overnight in a shaking incubator and centrifuged. The culture supernatant was used as antigen. The protein concentration of E/S antigens of C. cotylophorum and G. crumenifer ranged from 0.4 to 7.1 mg/ml and 3.3 to 5.9 mg/ml, respectively. SDS-PAGE analysis of E/S antigen of C. cotylophorum revealed two polypeptide bands from the range of 32 and 40 kDa. Whereas, SDS-PAGE analysis of E/S antigen of G. crumenifer revealed only one polypeptide band of 35 kDa. Excretory/secretory antigen may be used for serodiagnosis of paramphistomosis infection in sheep. PMID- 29491567 TI - A study on prevalence and molecular characterization of trypanosomal species infecting equines in Lahore region, Pakistan. AB - Trypanosomiasis is an important protozoal disease with a diverse range of susceptible host including human. In the current study, molecular characterization of prevalent species was done through a pan-trypanosome polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP). A total of three hundred (n = 300) equines including horses, donkeys and mules (100 each) were randomly selected and the equine blood samples were subjected to screening for trypanosomes through microhaematocrit centrifuge technique (MHCT), conventional PCR, semi-nested PCR and RFLP. Overall prevalence of trypanosomal species was 8% (24/300) as revealed by MHCT and species wise prevalence in horses, donkeys and mules was 4.33% (13/300), 1.33% (4/300) and 2.33% (7/300), respectively. Conventional and semi-nested PCR depicted an overall prevalence of 21% (63/300) and species wise prevalence in horses, donkeys and mules was 12% (36/300), 3.67% (11/300) and 5.33% (16/300), respectively. RFLP analysis of the semi-nested products, using Msp1 and Eco571 enzymes, negated the presence of T. congolense, T. brucei, T. vivax, T. theileri, and T. vivax in the positive samples and revealed that the animals might be suffering from T. evansi infection as the enzymes used were not able to detect this species. This hypothesis was further confirmed by using T. evansi specific primers which depicted all of the 63 samples were positive for T. evansi. It is inferred that T. evansi is the major trypanosome species prevalent in equines. Furthermore, PCR is more sensitive as compared to microscopic examination and the pan-trypanosome PCR-RFLP assay is suitable for carrying out laboratory diagnosis of field samples and epidemiological studies. Further studies on the possibilities of use of other restriction enzymes may help to improve the species specificity of the assay. PMID- 29491569 TI - First molecular characterization of Sarcocystis spp. in cattle in Qena Governorate, Upper Egypt. AB - Cattle are intermediate hosts for several Sarcocystis species with different definitive hosts. The present study, to our knowledge, is the first to determine the prevalence of Sarcocystis infection and morphologically and molecularly identify Sarcocystis species in cattle in Qena Governorate, Upper Egypt. The samples were collected from the heart and oesophagus muscles of 84 slaughtered cattle (76 males and 8 females) aged between 11 months and 3 years from slaughterhouses in different localities in Qena Governorate, Upper Egypt. The samples were macroscopically and histologically examined, and the molecular identification of the species was performed using 18S ribosomal subunit DNA through PCR and DNA sequencing. Infection was detected in 72 out of 84 animals (85.7%) and was more prevalent in males (76.2%) than in females (9.5). Using light microscopy, the microscopic sarcocysts were observed to be thin-walled. Sequencing and genotyping revealed one isolate that had 99 and 100% identity, respectively, to Sarcocystis cruzi, while another isolate had 95 and 99% identity to Sarcocystis hjorti. The present study is the first to identify Sarcocystis infection in cattle in Qena Governorate, Upper Egypt both morphologically and molecularly. Sarcocystis cruzi and S. hjorti species were isolated from cattle, which is of veterinary importance and indicates that morphologically similar Sarcocystis species are genetically distinct. Additionally, the results show that Sarcocystis species are not host-specific. PMID- 29491570 TI - Prevalence and risk factors associated with Giardia duodenalis infection in dairy cattle of Chitwan, Nepal. AB - Livestock farming has been an integral part of Nepalese agriculture systems since time immemorial. Giardia duodenalis is a cosmopolitan intestinal parasite present in a wide range of hosts. Very little or no information is reported on the prevalence of giardiasis in livestock of Nepal. This study was done during Jan 18 to July 19, 2014 to determine the prevalence and associated risk factors of Giardia duodenalis infection in dairy cattle of Chitwan, Nepal. A total of 96 fresh fecal samples were collected from various dairy pocket areas and were transferred to collection bottles with 10% formalin. Wet smears of the samples were prepared, stained with lugol's iodine and then viewed under microscope at 400* magnification. The overall prevalence was found to be 44.79% (43/96). Based on the risk factors assessment survey, age was found to be significantly associated with the prevalence of Giardia duodenalis. The prevalence was found significantly (P < 0.05) higher in 1-6 months age group compared to > 3 years. Similarly, higher prevalence was found in diarrheic animals compared to their counterparts (P < 0.05). Though higher prevalence was recorded in unhygienically housed animals, it was statistically non-significant (P < 0.05). Giardiasis should be considered as an important cause of diarrhea and further advanced diagnostic approaches should be employed for the confirmation of giardiasis in dairy cattle. PMID- 29491568 TI - Assessment of spiramycin-loaded chitosan nanoparticles treatment on acute and chronic toxoplasmosis in mice. AB - Toxoplasmosis is a zoonotic parasitic disease with worldwide distribution. Chitosan is a natural polymer which is commonly used in the production of nanomedicines. It is known to enable higher drug permeation, being biocompatible and has very low toxicity, besides its antimicrobial effects. Our study aimed to assess the effect of spiramycin-loaded chitosan nanoparticles (SLCNs) in treatment of acute and chronic toxoplasmosis in mice. 200 male Swiss albino mice were included in our study, divided to two main groups; Toxoplasma gondii RH strain infected group and ME49 strain infected group, each main group was subdivided into four subgroups; subgroup I: infected control, subgroup II: infected and received chitosan nanoparticles (CS NPs); 20 ug of CS NPs in 100 ul of PBS/mouse/dose, subgroup III: infected and treated with spiramycin (Rovamycin); 100 mg/kg/day, subgroup IV: infected and treated with 100 mg/kg/day spiramycin-loaded chitosan nanoparticles. Effect of treatment was assessed parasitologically and histopathologically. It was noticed that SLCNs significantly decreased the mortality rate of infected mice with both strains compared to high mortality rate of mice in the infected control subgroups. Moreover, there was a significant decrease in the number of organisms of SLCNs treated subgroup as compared to the other subgroups. Histopathological studies showed a marked improvement of the pathological pictures of brain, liver, spleen and eye in the subgroup received SLCNs as opposed to other groups. In conclusion, the present study revealed that loading of spiramycin on chitosan nanoparticles increased its antiparasitic effect on acute and chronic T. gondii infection. PMID- 29491571 TI - Tick infestation on sheep, goat, horse and wild hare in Tamil Nadu. AB - The prevalence of tick infestation and their predilection sites on sheep, goat, horse and wild hare were studied at various places of Tamil Nadu, India. The prevalence of tick infestation in Madras red sheep, Tellicherry goat and horse was 77.11, 78.21 and 13.33%, respectively. Sheep were heavily infested with Haemaphysalis bispinosa followed by Hyalomma isaaci, Rhipicephalus haemaphysaloides and H. anatolicum. The ticks from goats were identified as H. bispinosa, R. haemaphysaloides, H. isaaci and R. sanguineus. Horses were infested with Otobus megnini and R. sanguineus. The ticks on wild hare (Lepus nigricollis) were identified as R. haemaphysaloides and H. bispinosa. Wild hare acts as a source of infestation to the sheep and goats since these animals shared the same field. PMID- 29491572 TI - Two new species of Pleurogenoides (Luhe, 1901) Travassos, 1921 (Digenea: Pleurogenidae) infecting two species of frogs of the Western Ghats, India. AB - Two new species of digenetic trematodes of the genus Pleurogenoides infecting the freshwater frogs, Euphlyctis cyanophlyctis and Hoplobatrachus tigerinus inhabiting the Western Ghats, India are described and illustrated. Pleurogenoides euphlycti n. sp. and P. wayanadensis n. sp. are separated from their congeners on the basis of differences in the morphology and morphometry. The prevalence of infection of P. euphlycti n. sp. in E. cyanophlyctis is 8.99% and in H. tigerinus 12.5% and the intensity is 6.5 and 7.0 respectively. Prevelance of P. wayanadensis n. sp. in E. cyanophlyctis is 4.49% and in H. tigerinus 6.25% and the intensity is 11.25 and 6 respectively. Since trematode parasites have complex life cycles, with multiple hosts that follow trophic level transfer, the parasite larvae may serve as reliable indicators of species diversity in an ecosystem. PMID- 29491573 TI - Histopathology of gill, muscle, intestine, kidney, and liver on Myxobolus sp. infected Koi carp (Cyprinus carpio). AB - This research aims to investigate the clinical symptoms of Myxobolus sp.-infected Koi carp (Cyprinus carpio) and to observe fish histopathology including histological alteration in the intestine, kidney, and liver organs. Descriptive method was employed in this research. The fish sample was obtained from Fish Farmer Group at Nglegok Village in Blitar City. The main observed parameters were the alteration of intestine, kidney, and liver of Koi infected with Myxobolus sp. parasite. The observation result of the histopathology of the parasite-infected fish indicated that necrosis and cyst occurred in the intestine. Necrosis also occurred in kidney, while hyaline degeneration occurred in tubule cells. Furthermore, necrosis and inflammation were also found in liver. It is obvious from the result that Myxobolus sp. infection resulted in the damage of Koi carp vital organs. PMID- 29491574 TI - In vitro and in vivo anthelmintic efficacy of two pentacyclic triterpenoids, ursolic acid and betulinic acid against mice pinworm, Syphacia obvelata. AB - Pinworm infections are one of the common problems in laboratory rodents and man. At present there are only few drugs against intestinal helminths, and new drugs are urgently needed to cope up any future risk of drug resistance. Interest in plant secondary metabolites (PSMs) has risen considerably in the recent years for the discovery and development of new drugs. In the present study, we explored the in vitro and in vivo anthelmintic potentials of two pentacyclic triterpenoids, ursolic acid (UA) and betulinic acid (BA), the important PSMs of many medicinal plants, against Syphacia obvelata (Nematoda: Oxyuridae), a common pinworm of mice. The results of this study indicated that in both, in vitro and in vivo assays, BA showed comparatively better anthelmintic effects than UA. In the in vitro assay, 1.00 mg/ml concentration of BA showed paralysis and mortality of worms in 1.20 +/- 0.04 and 2.30 +/- 0.03 h, respectively. In the in vivo assay, a single 10.00 mg/kg dose of BA, administered for 5 days, revealed 68.78% reduction in egg counts and 84.08% reduction in worm counts of infected mice. The present study suggests that BA holds a great promise to be pursued further for detailed testing against some other representative group of helminth parasites. PMID- 29491575 TI - Retraction Note to: Comparative karyological analysis of three species of Bothriocephalus Rudolphi 1808 (Cestoda:Pseudophyllidea) from Schizothorax species of Kashmir valley. AB - [This retracts the article DOI: 10.1007/s12639-012-0185-1.]. PMID- 29491576 TI - Pilot Translation of the Social Skills Improvement System Questionnaire Among Indian Children. AB - Background: Many developmental and mental disorders significantly impair the ability of children and adolescents to successfully function in society. Among several scales evaluating social performance, the Social Skills Improvement System by Gresham and Elliot evaluates the social functioning of children from ages 3 to 18 years. It has three forms per child - to be filled in by the child himself/herself, by the parent and the teacher. Each form has 75, 79, and 83 items, respectively, assessed on a four-point system. Methodology: The present study aimed at translating and validating this scale on a small pilot sample of parents and child only (n = 21). The Cronbach alpha of the Hindi forms was estimated. Intraclass correlation between each item of the original and translated versions of the scale was examined. Results: For the parent form, Cronbach alpha was 0.9, and for the student form, it was 0.8. The maximum correlation was present in the parent form (40% of items). Self-scoring forms by children correlated 23% of the time between the Hindi and English versions. Conclusion: Significant correlation was not seen between the original and translated versions. Possible reasons are discussed. PMID- 29491577 TI - Are the grapes sour...? PMID- 29491578 TI - Right time to highlight the canvass of our speciality amongst the members. PMID- 29491579 TI - A critique on nuclear factor-kappa B and signal transducer and activator of transcription 3: The key transcription factors in periodontal pathogenesis. AB - Periodontal disease is initiated by microorganisms in dental plaque, and host immunoinflammatory response to the microbial challenge helps in disease progression. Conventional periodontal therapy was mainly targeted on the elimination of microbial component. However, a better understanding of molecular aspects in host response will enable the clinicians to formulate effective host modulation therapy (HMT) for the periodontal management. Inflammatory mediators were the main targets for HMT in the past. Transcription factors can regulate the production of multiple mediators simultaneously, and inhibition of these factors will be more beneficial than blocking individual molecule. Two important transcription factors implicated in chronic inflammatory diseases are nuclear factor kappa B (NF-kappaB) and signal transducers and activators of transcription 3. The role of these factors in periodontal disease is a less explored area. This comprehensive review is aimed at unveiling the critical role of NF-kappaB and signal transducers and activators of transcription 3 in periodontal pathogenesis. An online search was performed using MEDLINE/PubMed database. All publications till 2016 related to NF-kappaB, signal transducer and activator of transcription 3 (STAT3), and inflammation were included in writing this review. A total of 27,390 references were published based on the search terms used. Out of these, 507 were related to the periodontal research published in English till 2016. Relevant papers were chosen after carefully reading the abstract. This review has attempted to comprehend the existing knowledge regarding the role of transcription factors NF-kappaB and STAT3 in periodontal disease. Moreover, it also provides a connecting molecular link for the periodontal medicine concept. PMID- 29491580 TI - Preliminary studies on the inhibition potential of Indian domestic curd against coliforms, an emerging periodontal pathogen. AB - Background: Coliforms colonize in dental plaques via oral route and may lead to systemic complications. Escherichia coli and its lipopolysaccharide-induced periodontitis is an emerging threat. Clinical management necessitates antibiotic regimens with risk of resistance and upsetting the gut. There is urgent need for better, sustainable, and economical alternative. Aim: To investigate the inhibition of coliforms, a potential periodontopathogen directly by Indian domestic curd (IDC) "in situ". Materials and Methods: Coliforms from natural habitat (Municipal sewage in Agartala, Tripura), a source of infection through food and water, were used as target organism. Domestically prepared curd without any fortification is used to explore its true inhibition potential. Assays of agar well diffusion performed with IDC (ultraviolet sterilized and pH adjusted 6.5) against isolated pure cultures of coliforms. The study protocol nullified effect of organic acids, volatile compounds, bacteriophages, and peroxides in IDC. Peptide nature of inhibitory ingredient was studied by Sodium Dodecyle Sulphate Polyacrylamide Gel Electrophoresis (SDS-PAGE), urea treatment. Computational phylogenetics revealed structural features of inhibitory ingredient. Statistical comparisons were done by analysis of variance. Second order polynomial regression was done to evaluate the effect of IDC dilution on coliform inhibition. Mann-Whitney U-test performed to analyze different sample treatments. Results: Agar well diffusion (sealed bottom wells) shows inhibition of catalase-negative coliforms (confirmed by Gram staining and triple sugar iron agar assay) in pure culture (MacConkey agar). Activity diminished in urea, potentiated in ethylene diamine tetra acetic acid, remains unchanged by heat treatment (121 degrees C, 15 min). SDS-PAGE revealed three distinct peptides (>10 15KDa). Hence, thermostable inhibitory peptides attached to target cell lead to observed activity (titer up to 1204.82 AU/ml with minimum 8 mm inhibition). Conclusions: IDC adequately inhibits sewage coliforms and may prevent dental plaques coliform colonization and its associated risks. PMID- 29491581 TI - Assessment of postgraduate dental students using mini-clinical examination tool in periodontology and implantology. AB - Introduction: Mini-clinical examination (mini-CEX) is a new assessment tool that observes the student using a standard rating form. The aim of this study was to evaluate the feasibility and usefulness of the mini-CEX as an assessment and feedback tool in the postgraduate setting in periodontology. Materials and Methods: Eight postgraduate students and two evaluators were included in this study carried out for 4 months during which the students were made to appear for four encounters evaluated on a standardized nine-point Likert scale. Feedback was obtained from the students about this assessment after the fourth encounter. Results: Sixty-three percent of the students felt that mini-CEX is better than the conventional assessment tools. Seventy-five percent of the students felt that this type of mini-CEX assessment helped improve the student-teacher relationship and student-patient relationship. Sixty-three percent of the students were satisfied with this assessment pattern and were willing to face more encounters as it helped them improve their competencies. Seventy-five percent of the students agreed that they felt anxious on being observed while taking cases. Conclusion: The training and assessment of a wide range of procedures make dentistry unique. Good communication skills and counseling can allay patient's fear and anxiety. This structured way of assessment of clinical skills and feedback provides good clinical care and helps improve the quality of the resulting information which would induce confidence, improve clinical competencies, and alleviate the fear of examination among the students. PMID- 29491582 TI - Indagation of serum and salivary reactive oxygen metabolite and cortisol levels in chronic periodontitis and stress-induced chronic periodontitis patients. AB - Background: Periodontal disease is not a conventional bacterial infection but is an inflammatory disease initiated by immune response against a group of microorganisms in susceptible hosts. There are many intriguing researches that unfold the secrets of chronic periodontitis. The current researches in chronic periodontitis are directed toward an approach that respects the scientific relationship between the various risk factors, the genetic factors, and the progression of the disease. Aim: This study aims to evaluate the cortisol and reactive oxygen metabolites (ROM) concentration in serum and to find out their association in periodontal health and disease. Materials and Methods: In this study, totally thirty patients have been taken and divided into two groups of chronic periodontitis (Group I) and stress-induced chronic periodontitis (Group II) and evaluated the correlation between the ROM and cortisol levels in them. This is the first study, where both the levels of ROM and cortisol are checked in the serum and saliva. The analysis is done to check the association between them. Statistical Analysis: The data were statistically analyzed using software program (SPSSV 16), Pearson correlation, and paired t-test. Results: Comparison of the mean ROM levels in Group I and Group II showed that mean ROM level in Group II is highly significant than Group I. Conclusion: Our study suggests that stress can have a role in the progression of periodontal disease by increasing the cortisol and ROM levels. PMID- 29491583 TI - The association between receptor activator of nuclear factor kappa-beta ligand and clinical attachment level among waterpipe smoker. AB - Background: Higher levels of receptor activator of nuclear factor kappa-beta ligand, i.e., RANKL, were reported among periodontitis patients compared with their healthy peers. This study aimed to measure the salivary level of RANKL among waterpipe smokers and to find the possible correlation between salivary level of RANKL and clinical periodontal parameters. Materials and Methods: This study is a cross-sectional study involving 89 (49 waterpipe smokers and 40 nonsmokers) participants. The whole unstimulated saliva samples were collected for quantitative determination of RNAKL using a human RANKL enzyme-linked immunosorbent assay kit. Plaque index, gingival index, bleeding on probing, periodontal pocket depth (PPD), and clinical attachment level (CAL) were recorded for each participant. Mann-Whitney U-test was used to detect any difference between groups at P < 0.05. Spearman correlation coefficient test was used to test the association between variables. Linear regression was used to investigate the cause-and-effect relationship between the associated variables. Results: In a comparison, RANKL, PPD, and CAL showed statistical differences (P < 0.05) between waterpipe smokers and nonsmokers. RANKL was found to be positively associated with CAL, and approximately 62.8% of CAL in this study sample could be explained by RANKL. The regression equation was CAL = 1.744 + 0.004 (RANKL). Conclusions: The salivary level of RANKL was positively related to CAL in this study sample. PMID- 29491584 TI - High risk human papillomavirus in the periodontium : A case control study. AB - Background: Human papilloma viruses (HPVs) are small DNA viruses that have been identified in periodontal pocket as well as gingival sulcus. High risk HPVs are also associated with a subset of head and neck carcinomas. It is thought that the periodontium could be a reservoir for HPV. Aims: 1. Detection of Human Papilloma virus (HPV) in periodontal pocket as well as gingival of patients having localized chronic periodontitis and gingival sulcus of periodontally healthy subjects. 2. Quantitative estimation of E6 and E7 mRNA in subjects showing presence of HPV3. To assess whether periodontal pocket is a reservoir for HPV. Settings and Design: This case-control study included 30 subjects with localized chronic Periodontitis (cases) and 30 periodontally healthy subjects (controls). Two samples were taken from cases, one from periodontal pocket and one from gingival sulcus and one sample was taken from controls. Methods and Materials: Samples were collected in the form of pocket scrapings and gingival sulcus scrapings from cases and controls respectively. These samples were sent in storage media for identification and estimation of E6/E7 mRNA of HPV using in situ hybridization and flow cytometry. Statistical analysis: Statistical analysis was done by using, mean, percentage and Chi Square test. A statistical package SPSS version 13.0 was used to analyze the data. P value < 0.05 was considered as statistically significant. Results: pocket samples as well as sulcus samples for both cases and controls were found to contain HPV E6/E7 mRNAInterpretation and. Conclusion: Presence of HPV E6/E7 mRNA in periodontium supports the hypothesis that periodontal tissues serve as a reservoir for latent HPV and there may be a synergy between oral cancer, periodontitis and HPV. However prospective studies are required to further explore this link. PMID- 29491585 TI - Evaluation of dietary supplementation of omega-3 polyunsaturated fatty acids as an adjunct to scaling and root planing on salivary interleukin-1beta levels in patients with chronic periodontitis: A clinico-immunological study. AB - Context: Host modulation with omega-3 polyunsaturated fatty acids (omega-3 PUFAs) has anti-inflammatory and pro-resolution actions through replacing and inhibiting metabolism of arachidonic acid (AA). Aim: This study was aimed at evaluating clinical parameters and salivary levels of interleukin-1 beta (IL-1beta) after scaling and root planing (SRP) in chronic periodontitis patients, with and without dietary supplementation of omega-3 PUFAs. Settings and Design: Forty otherwise healthy participants with severe chronic periodontitis were included. Full-mouth periodontal examination and scaling and root planing were done for test and control group (20 participants each). Materials and Methods: The control group received SRP alone while test group received daily dose of 700 mg omega-3 PUFA capsules for 3 months. All clinical parameters were checked at baseline, 1 month, and 3 months' duration, whereas levels of IL-1beta were checked in saliva at baseline and 3 months after therapy. Statistical Analysis Used: T-test and repeated measure analysis of variance were used with Statistical Package for the Social Science Windows software. Results: Improvements in all clinical outcomes were similar in both groups over 3 months. Improvements in clinical parameters were not statistically significant on intergroup comparison, except for improvement in Bleeding Index and reduction in levels of IL-1beta, which were statistically significant in test group as compared to control group (P < 0.05). Conclusion: Even though adjunct therapy with omega-3 PUFAs can modulate cytokine levels and show proresolution properties, its importance on clinical outcomes may be controversial. Thus, this may be used as an adjunctive management of chronic periodontitis. PMID- 29491586 TI - Comparative clinical evaluation of gallium-aluminum-arsenide diode laser and potassium nitrate in treating dentinal hypersensitivity. AB - Context: Dentinal hypersensitivity (DH) is a chronic disorder in which patients report sharp and acute pain to a variety of stimuli. Till date, a standardized procedure to treat DH is missing, though several alternative treatment strategies have been designed, including laser therapies. Aim: The aim of the study was to treat DH with minimum chemical concentration and least laser energy level with longer follow-up period. Materials and Methods: One hundred and twenty patients were randomly divided into four groups: (i) Group 1-5% potassium nitrate (KNO3); (ii) Group 2 - gallium-aluminum-arsenide diode laser (62.2 J/cm2, wavelength - 980 nm, noncontact pulse mode, and power wattage - 0.5 W); (iii) Group 3 - combined 5% KNO3 and the diode laser; and (iv) Group 4 - placebo (control). The visual analog scale (VAS) scores were recorded, analyzed, and compared to tactile stimuli, cold water, and air blast tests at different intervals for 6 weeks. Results: Synergistic use of 5% KNO3 and diode laser (Group 3) significantly reduced the DH pain, which was almost negligible after 6th week (97%-99% of the pain was reported to be relieved) and showed promising results than any other studied groups. Further, the diode laser (Group 2) showed better results than 5% KNO3 (Group 1). One-way ANOVA and Bonferroni correction post hoc test revealed the combination of groups with significant differences in the mean VAS scores at the different interval of time (P < 0.01). Conclusions: Convincingly, the combined application of 5% KNO3 with the diode laser can be recommended for treating DH patients. PMID- 29491587 TI - Awareness, Attitude, and Prevalence of usage of magnification devices among the dental practitioners in the state of Andhra Pradesh - A questionnaire-based study. AB - Background: Dentistry, dealing with teeth and supporting tissues in the oral cavity is not only an ever-evolving science but also an art combined with good eye-hand coordination. It not only encompasses clinical and theoretical skills which play a crucial role in the success of therapy but also a lot of intrinsic work is accomplished in dentistry. In a journey to fulfill the above accomplishments and for facilitating early diagnosis of pathologies which usually go unnoticed, a clearer and magnified field of vision are also essential. The purpose of this study is to evaluate the awareness, attitude, and prevalence of the usage of magnification devices among the dental practitioners in the state of Andhra Pradesh. Materials and Methods: A questionnaire-based study was conducted to assess the awareness, attitude, and prevalence of magnification devices among the 370 dental practitioners in Andhra Pradesh. All the participants were provided with a prestructured questionnaire comprising of 24 questions and answering was completely self-based. Results: Among the participants, majority were aware about magnification in dentistry (91.1%), and also of the different types of magnification devices available (90.5%). On the other hand, when the reason for not using magnification devices was taken into consideration, 32.7% attributed that they have not experienced the devices and 32.4% felt that devices were too expensive. Moreover, when regarding the usage of devices was taken into account, only 23.8% of the total participants were exposed to the usage of magnification aids. Conclusion: Among the selected group of participants, even though majority were aware of magnification in dentistry its application in practice was very less. PMID- 29491588 TI - Awareness and knowledge of periodontal disease among Saudi primary school teachers in Aseer region. AB - Background: The consequences of periodontal disease are not limited to the oral cavity. As schools are considered to be one of the principal systems in preventive oral health, teachers' knowledge pertaining to the periodontal disease, their awareness with regard to its implications and their role in increasing the awareness of the students regarding this disease comprises only one aspect with respect to the prevention of the periodontal disease. Therefore, the aim of this study is to investigate the baseline awareness and knowledge of Saudi primary school teachers regarding the periodontal disease. Materials and Methods: For this purpose, a questionnaire was distributed among the participants of the study. Results: It was observed that 91.4% of the participants reported that the periodontal disease does not need any treatment although 70% of the participants believed that it could result in tooth loss, and 95% considered the periodontal disease to be a preventable disease. Moreover, social media (44%) and television advertisements (39%) were the main sources from where they acquired information about the periodontal disease. Conclusions: Most participants have heard about the importance of periodontal health but are not sufficiently aware of its consequences and negative effects on their body. They are used to receiving information about periodontal diseases from nondental clinics and unreliable sources. This creates misconceptions. Although the participants were keen to attend educational events on periodontal health, the lack of medical communication between the health practitioners and the general public is evident. Mostly, investigated areas and individuals do not have any educational means to be aware of periodontal health. PMID- 29491589 TI - Drug-induced atypical hyperplasia enveloping salivary gland malignancy. AB - Gingival enlargement is a very common side effect associated with the administration of several drugs, mainly anticonvulsants, calcium channel blockers (CCBs), and immunosuppressants. Amlodipine (a CCB) is a safe antihypertensive drug with a longer duration of action. Gingival enlargement induced by amlodipine is less prevalent among CCBs. Since the pathogenesis is not well understood, it is still a challenge for clinicians to diagnose and manage cases effectively. This case presents an atypical unilateral palatal gingival enlargement in a 61 year-old hypertensive female taking amlodipine. Difficulty for a pathologist in diagnosing in spite of repeated sample submission from the lesion and repeated failure for the operator to reach the underlying pathology due to amlodipine induced hyperplasia have also been discussed in this case report. PMID- 29491590 TI - Dimorphic anemia and mental depression as a result of systemic manifestations of generalized aggressive periodontitis: A pioneer case report. AB - Generalized aggressive periodontitis (GAP) is a rare form of periodontitis resulting in early loss of teeth. Most of the clinical evidence available in literature focuses on the diagnosis and management aspects of GAP. Systemic manifestations of GAP have been reported infrequently. To the best of our knowledge, the present case report is the first-ever evidence providing a possible mechanism and link between GAP, dimorphic anemia, and mental depression suggesting that dimorphic anemia and mental depression are probable systemic manifestations of GAP. A young female reported with her father to the hospital with a complaint of pain in her oral cavity and lack of desire to eat. On thorough examination, GAP with dimorphic anemia and mental depression were diagnosed. Periodontal treatment along with nutritional supplements was prescribed. An improvement was noticed in the patient's condition after a follow up period of 6 months. Systemic manifestations of GAP should include the diagnoses of dimorphic anemia and mental depression and should be treated accordingly. PMID- 29491591 TI - Horizontal alveolar ridge expansion followed by immediate placement of implants and rehabilitation with zirconia prosthesis. AB - In recent years, there have been a growing number of procedures involving dental implants. Most cases, though, are characterized by bone atrophy, especially horizontal atrophy. This clinical case aims to report a technique for the expansion of the horizontal alveolar ridge. A longitudinal fracture was created in the alveolar ridge to expand the bone, followed by immediate insertion of dental implants along with a particulate allogeneic bone graft. Eight implants were placed in the maxilla, and after 12 months, a surgical reopening was performed, along with rehabilitation with a protocol-type prosthesis, for which a zirconia infrastructure was made. The patient was observed during a 10-month follow-up period in which an effective osseointegration of all implants was achieved as a result of such a technique. The split-crest technique followed by the immediate placement of implants and a particulate allogeneic bone graft proved to be effective, with a predictable osseointegration. PMID- 29491592 TI - Piezosurgery(r)-assisted periodontally accelerated osteogenic orthodontics. AB - Periodontally accelerated osteogenic orthodontic procedure has become useful adjunct to reduce orthodontic treatment time as compared with conventional orthodontics. This case demonstrates the use of Piezosurgery(r) to facilitate rapid tooth movement with relatively shorter treatment time. A 23-year-old male with Angles Class I malocclusion having spaced anterior teeth and protrusion requested orthodontic treatment with reduced time period. Before surgery, presurgical orthodontic treatment was done to do initial alignment of the teeth. This was followed by piezosurgical corticotomy and final space closure was achieved by active orthodontic tooth movement. The total treatment time required to complete the orthodontic treatment was 5 months. 1-year follow-up revealed no evidence of any adverse periodontal effects or relapse. Thus, Piezosurgery(r) assisted corticotomy may prove to be a noble and effective treatment approach to decrease the orthodontic treatment time. PMID- 29491593 TI - Fibrotic encapsulation of orthodontic appliance in palate. AB - Iatrogenic trauma though not serious is very common in dental practice. Orthodontic treatment can inflict such injuries as they are prolonged over a long period of time. Ill-fabricated orthodontic appliances, such as wires and brackets, or the patients' habits such as application of constant pressure over the appliance can traumatize the adjacent oral soft tissues. In rare cases, these appliances can get embedded into the mucosa and gingival tissues. This case report describes one such case of iatrogenic trauma to the palatal mucosa due to entrapment of a tongue spike appliance and its surgical management. PMID- 29491594 TI - From the Editor's Desk. PMID- 29491595 TI - Odontogenic myxoma: A causality dilemma - Report of a nonpareil case and review of literature. AB - Odontogenic myxoma is a benign locally aggressive neoplasm with a sparse prevalence and incertitude histogenesis. They constitute 3%-6% of odontogenic tumors in gnathic bones. It is ubiquitously seen between vicenarian to early quadragenarian group with female proclivity and fondness to the mandibular jaws. They are silent lesions clinically and show myxoid stroma amidst fibrous background. This report highlights central odontogenic myxoma in a 43-year-old male patient and focuses on concepts, differential diagnosis, molecular concepts and treatment aspect. PMID- 29491596 TI - Ameloblastoma arising in the wall of dentigerous cyst: Report of a rare entity. AB - Dentigerous cyst (DC) is a developmental odontogenic cyst that encloses the crown of an unerupted tooth by expansion of its follicle with accumulation of fluid between the reduced enamel epithelium and the tooth crown and is attached to the neck of the tooth. The lining of DCs shows a potential for neoplastic transformation to ameloblastoma, squamous cell carcinoma, and mucoepidermoid carcinoma. Here, we report a rare case of an ameloblastoma arising in the wall of a DC. PMID- 29491597 TI - Aggressive adenomatoid odontogenic tumor of the mandible: A rare case report and review of the literature. AB - Adenomatoid odontogenic tumor (AOT) is a relatively rare and distinct odontogenic tumor that is exclusively odontogenic epithelium in origin. Although considerable numbers of reports are available with regard to the clinical and histological spectrum of AOT, very few have highlighted its rare aggressive nature. This article focuses on an AOT causing jaw swelling in the mandibular anterior region with cortical plate expansion and perforation, root resorption and paresthesia. The present case had remarkably unusual clinical and radiographic features that distinguished it from most conventional AOTs and supported its neoplastic nature. PMID- 29491598 TI - A curious case of central odontogenic fibroma: A novel perspective. AB - We appraise a case of central odontogenic fibroma (COF) with unusual histologic features of entrapped neural elements and mast cells. The presence of mast cells attributed to the release of stem cell factor, the principal growth and activating factor of mast cells. A putative role for C-kit and mast cells in the pathogenesis of COF is described. PMID- 29491599 TI - Orthokeratinized odontogenic cyst with calcification: A rare case report of a distinct entity. AB - Orthokeratinized odontogenic cyst (OOC) is a relatively rare odontogenic cyst, distinct from odontogenic keratocyst (OKC). In the 4th edition of WHO Classification of Head and Neck Tumors (2017), OOC has been included as a separate entity in the category of developmental odontogenic cysts. It presents as a unilocular radiolucent lesion in the posterior mandible and is frequently related to impacted teeth, thus mimicking dentigerous cyst. Due to low local aggressiveness and no association with nevoid basal cell carcinoma syndrome, it does not show tendency to recur. When compared to OKC, OOC exhibits substantial number of differences with respect to clinical, pathological and behavioral features and treatment modalities. Hence, recognizing OOC as unique lesion is mandatory to avoid unnecessary overtreatment. This paper aims to report a rare case of OOC associated with impacted tooth, showing calcifications and emphasizes its differences from OKC. Furthermore, the recent concepts about OKC and OOC are discussed. PMID- 29491600 TI - Hemangiomatous ameloblastoma: Case report with a brief review. AB - Ameloblastoma is a benign epithelial odontogenic tumor with many histological variants. Hemangiomatous ameloblastoma (HA) is a very rare variant which shows unique histopathological features varying from conventional ameloblastoma. We present a case of a 35-year-old female patient with a swelling over right lower back region of jaw, showing mixed radiolucent-opacity. Incisional biopsy showed microscopic features of desmoplastic ameloblastoma showing extensive desmoplasia and compressed odontogenic epithelial islands. Excisional biopsy revealed ameloblastomatous areas with extensive vascular component microscopically. Based on these findings, a diagnosis of HA was made. PMID- 29491601 TI - A mixed odontogenic sarcoma: A challenging histopathologic case and brief review of the literature. AB - Ameloblastic fibro-odontosarcoma (AFOS) is an extremely rare malignant mixed odontogenic tumor. The ectomesenchymal part of the neoplasm shows malignancy, whereas the epithelial component is rather benign. In addition, small areas with deposition of enamel matrix and dentine material are seen. The rarity of this neoplasm and microscopic similarities with other malignant and benign tumors can lead to diagnostic problems. Here, we describe the histopathologic features of a new case of AFOS of the mandible in a 34-year-old female patient. It is essential for oral pathologists to be familiar with the microscopic features of this rare neoplasm to have a proper diagnosis. This is also the first reported case of AFOS that closely resembles osteosarcoma in some areas. PMID- 29491602 TI - Chondrosarcoma of maxilla. AB - Chondrosarcoma is a rare malignant cartilaginous tumor of the head and neck region. It is a slow-growing tumor and is mostly detected in the anterior maxilla and the base of the skull. We report a case of "Grade II Chondrosarcoma" of the posterior right side of the palate invading maxillary sinus and perforating the floor of the orbit. PMID- 29491603 TI - Metastatic renal cell carcinoma presenting as maxillary lesion: Report of two rare cases. AB - Oral cavity is not a usual site for metastasis, accounting about 1% of all oral tumors. The majority site for metastasis is the mandible and less common the maxilla followed by intraoral soft tissue. These tumors may be the first clinical manifestation of the primary lesion. One of the most important sites of the primary neoplasm that metastasizes to the jaws is kidney. Therefore, considering to this fact that the metastatic tumors always are not seen in a typical site, it is necessary to rule out the metastatic carcinomas to jaws. We presented two cases of metastatic renal cell carcinoma to maxilla with two different clinical features, one of them with an intraosseous lytic lesion and the other one with a large exophytic mass. PMID- 29491604 TI - Melanotic neuroectodermal tumor of infancy: A rare case report. AB - Melanotic neuroectodermal tumor of infancy is a rare benign but locally aggressive neoplasm of neural crest origin with a high recurrence rate. It usually affects infants of < 1 year of age. Involvement of maxilla of an infant is the most common presentation although cases outside this setting have been reported. We report the case of a 6-month-old male child presenting with intraoral swelling. Radiologically, a tumor was detected in the right maxilla, and wide local excision was done. Histological examination revealed typical biphasic population of cells with deposits of melanin pigment. Immunohistochemistry study was done confirming the diagnosis. PMID- 29491605 TI - Aggressive high-grade Ewing's sarcoma of maxilla: A rare case report. AB - Ewing's sarcoma (ES) is an uncommon malignancy of childhood and adults that constitutes 6%-8% of all primary malignant tumors and the third-most common tumor after osteosarcoma and chondrosarcoma, frequently involves the mandible among jaw bones. This article presents a rare case of ES of maxilla in a 22-year-old male patient showing extensive lesion into skull base which was confirmed with computed tomography, dilemmatic histopathologic features in H and E which is not a frequent presentation. Histopathologic features showed monotonous round cells with hypo- and hyper-cellular areas, intralesional hemorrhage and necrosis with lesional cells positive for CD99. Although the prognosis is poor, early diagnosis and long-term follow-up can improve the survival. The diagnosis was confirmed by immunohistochemistry where lesional cells were positive for CD 99 and vimentin. ES of maxilla is a rare and aggressive tumor. Hence, early diagnosis, combined therapy, and long-term follow-up are suggested in such cases. PMID- 29491606 TI - Adenoid cystic carcinoma of alveolar mucosa: A rare case report. AB - Adenoid cystic carcinomas are rare epithelial malignancies of salivary glands that show slow growth and local invasion with recurrences seen many years after diagnosis. Upto 50% of tumors occur in intraoral minor salivary glands usually in the hard palate. Tumors on the alveolar mucosa are extremely rare. We present a case of adenoid cystic carcinoma on the right alveolar mucosa in a 35 year old female. The case is been presented for its rarity. PMID- 29491607 TI - Sialolipoma of parotid gland in a 1-year-old male child: A case report and review of literature. AB - Sialolipoma is a recently described rare histological variant of lipoma, characterized by well-demarcated proliferation of mature adipocytes with secondary entrapment of salivary gland elements. Less than forty cases of sialolipoma have been reported in English literature. This tumor has been reported both in major and minor salivary glands, with the parotid gland being the most common site. Age incidence in this tumor varies from 0 month to 84 years. However, the occurrence of this tumor in an infant is very rare. In the published literature, the size of this tumor varied from 1 to 7 cm. In the present case, the tumor size was >7 cm. To the best of our knowledge, congenital sialolipoma >7 cm has been rarely reported earlier. Hence, this case is presented because of its rarity and unusual gross appearance. PMID- 29491608 TI - Polymorphous adenocarcinoma of the oral cavity: A skeptical case mimicking lobular carcinoma of breast and gastric carcinoma. AB - Polymorphous adenocarcinoma (PAC) is a distinctive salivary gland neoplasm that predominantly occurs in the minor salivary glands. The tumor is characterized by cytological uniformity, morphological diversity, an infiltrative growth pattern and low metastatic potential. It presents as an asymptomatic, slow- growing mass within the oral cavity. This salivary gland tumor is difficult to diagnose both clinically and histopathologically due to its indolent presentation and diverse architectural pattern which includes various microscopic patterns namely- solid, ductal-tubular, cribriform, trabecular and single-file growth. Hence, Immunohistochemistry plays a very important role in diagnosing this tumor. We hereby report a rare case of PAC occurring in a 50yr old female patient presenting with a lesion in right upper posterior part of alveolus extending to the hard palate. PMID- 29491609 TI - Adenoid cystic carcinoma of palate: Report of a solid variant. AB - Adenoid cystic carcinomas (ADCCs) are uncommon tumors, comprising < 1% of all head-and-neck cancers and 20%-25% of all salivary cancers. The most common presenting symptom of the lesion is a slowly growing mass followed by pain due to the propensity of these tumors for perineural invasion. The tumor is most often clinically deceptive by its small size and slow growth, which actually overlies its extensive subclinical invasion and marked ability for early metastasis making the prognosis questionable, aptly referred as "wolf in sheep's clothing." Cribriform, tubular and solid are the three recognized histopathological patterns. In ADCC, one of the important prognostic factors is the histological grade determined by the percentage of solid component in the tumor, which in the present study comprise more than 30% of the entire lesion rendering it an unfavorable prognosis. PMID- 29491610 TI - Keratinizing pleomorphic adenoma: An unusual case report. AB - Pleomorphic adenoma (PA) is the most common benign tumor of major or minor salivary glands. PA exhibits a great histological diversity, such as differentiation into oncocytic, sebaceous, mucinous, squamous, chondroid, osseous or adipose cells. Squamous metaplasia rarely results in the formation of extensive keratin-filled cyst lined by squamous epithelium. Extensive squamous metaplasia can be mistaken for malignancy, including mucoepidermoid carcinoma and squamous cell carcinoma. Here, we report a case of slowly enlarging PA with extensive squamous metaplasia and keratin cyst formations in a minor salivary gland in hard palate and discuss its microscopic features. PMID- 29491611 TI - Juvenile primary extranasopharyngeal angiofibroma, presenting as cheek swelling. AB - Angiofibroma is a locally advancing immensely vascular tumor that essentially arises from the nasopharynx. The clinical characteristics of extranasopharyngeal angiofibroma (ENA) do not accord to that of nasopharyngeal angiofibroma and can present a diagnostic confront. We describe a case of primary juvenile ENA in a 19 year-old patient who presented with a rapidly enlarging mass of the cheek region. The case is unusual because of its anatomic location. The diagnostic and management particulars are sketched. PMID- 29491612 TI - Leukemic gingival enlargement: A case report and review of literature. AB - The oral cavity manifests signs of various systemic diseases. This entails thorough examination of the oral mucosa, gingiva, teeth, tongue and other oral tissues. Occasionally, oral signs can be an expression of systemic conditions such as endocrine imbalance, nutritional deficiencies and blood disorders. Leukemia is a malignancy of white blood cells, which may result in significant morbidity and mortality. Oral changes maybe the first and only presenting features in leukemia patients, making it imperative for the dentist to diagnose the disease accurately. PMID- 29491613 TI - Proliferative endophytic lesion of the maxilla: A diagnostic challenge. AB - Carcinoma cuniculatum (CC) is an extremely rare neoplasm of the oral cavity. It is essentially a well-differentiated variety of squamous cell carcinoma and shows lower metastasis risk. The histological features of CC can mimic that of papillary squamous cell carcinoma or verrucous carcinoma. CC commonly affects the plantar region of the foot, and very few cases have been described in the oral cavity. The classical histological characteristics noted are infiltration of underlying connective tissue by squamous epithelium with keratin cores and keratin-filled crypts. Herewith, we present a case of CC of the right maxilla in a young Dravidian male patient who works in a battery factory. The case presented a diagnostic challenge both clinically and histopathologically before it was completely resected using a total maxillectomy technique. The case delineates the diagnostic challenge and management of the disease. PMID- 29491614 TI - Cutaneous horn: A mask to underlying malignancy. AB - Cutaneous horns (cornu cutaneum) are uncommon lesions consisting of keratotic material resembling that of an animal horn. It is a conical- or cylindrical shaped excessive hyperkeratosis of variable size ranging from few millimeters to several centimeters with a variable in size and shape, such as cylindrical, conical, pointed, transversely or longitudinally corrugated, or curved like a ram's horn. The lesions typically occur in sun-exposed areas, particularly the face, ear, nose, forearms and dorsum of hands. Even though 60% of the cutaneous horns are benign in nature, the possibility of skin cancer should always be kept in mind. The clinical diagnosis includes various benign and malignant lesions at its base. Lesions associated with cutaneous horn are keratosis, sebaceous molluscum, verruca, trichilemmal, Bowen's disease, epidermoid carcinoma, malignant melanoma and basal cell carcinoma. Herewith, we report a case of cutaneous horn on the upper lip vermillion masking the underlying malignancy at its base. PMID- 29491615 TI - Benign lymphoepithelial cyst of parotid gland: Review and case report. AB - Benign lymphoepithelial cyst (BLC), also known as branchial cyst, is an infrequent lesion usually occurs in the parotid gland or the lateral cervical area including lymph nodes. It occurs due to the process of lymphocyte-induced cystic ductular dilatation and is always diagnosed postoperatively by histopathological examination (HPE). These dysontogenetic lesions are usually found in the lateral neck but can also be located in the salivary glands, mostly in the parotids. A 35-year-old male reported to Government Dental College, Indore, before 3 years, with a soft, nontender, gradually increasing, compressible diffuse swelling involving the left parotid gland for the last 9-10 months of size 3.5 cm * 2.5 cm * 4.5 cm at the time of presentation with normal Stensen's duct and facial nerve function. ELISA test was negative, biochemistry indicated high protein content of aspirated fluid and magnetic resonance imaging showed hypertense cystic fluid in both T1- and T2-weighted images, suggesting high protein or hemorrhage and negating a solid lesion. Superficial parotidectomy was done with nonincidental healing. HPE of excisional tissue revealed it to be BLC. PMID- 29491616 TI - Papillary carcinoma of thyroid in a thyroglossal cyst. AB - Thyroglossal duct cyst (TDC) is the most common congenital anomaly of the thyroid gland and the most common congenital cervical abnormality in childhood. Carcinoma arising from a TDC is rare, which composes only 1% of TDC cases. Here, we are reporting a case of 50-year-old male with a swelling in the upper left neck region which was progressively increasing in size over 5 years. Ultrasonography report showed a large lobulated cystic mass. Internal echoes with calcification and there were no neck nodes. Thyroid gland was normal. In the present study, the Sistrunk procedure was used to excise a TDC. Papillary carcinoma was confirmed with the histopathological examination following the surgery. The patient was treated with radioactive iodide and thyroid suppression therapy was given as adjuvant treatment. The patient has been following for 2 years without any metastasis. PMID- 29491617 TI - Renal cell carcinoma metastatic to the maxillary gingiva: A case report and review of the literature. AB - Tumor metastasis to the oral cavity is rare and is usually an indication of late stage disease and poor prognosis. While, there are reports of renal cell carcinoma (RCC) metastatic to oral cavity, vast majority of them are to the jaw. Herein, we present a case of a 78-year-old woman with RCC metastasis limited to the oral soft tissue without any bone involvement. As the lesion solely involved maxillary gingiva, it clinically mimicked that of a pyogenic granuloma, which is a reactive, nonneoplastic condition. This case was further complicated as the patient was unaware of primary cancer and appeared to be in good physical health. Her oral metastasis marked the initial manifestation of an otherwise silent primary renal cancer. PMID- 29491618 TI - Oral lymphangiomas - clinical and histopathological relations: An immunohistochemically analyzed case series of varied clinical presentations. AB - Lymphangiomas are benign malformations that represent hamartoma of malformed lymphatics and are composed of cystically dilated lymphatic channels which do not communicate or drain into other lymphatic channels or veins leading to accumulation of lymph. They are congenital malformations with rare occurrence in oral cavity within which tongue dorsum is the most affected site. Venous malformations are often difficult to differentiate from lymphatic malformations leading to the development of several lymphatic markers like D2-40 which seems to be useful for distinguishing vascular from lymphatic vessels. The most effective treatment is surgery having good prognosis for most of the patients but depending on their location (neck/tongue) and size (large size) they may cause airway obstruction causing death. Herewith, we present the rare cases of oral lymphangiomas of tongue, palate and buccal mucosa with varied and characteristic clinical presentations. PMID- 29491619 TI - Mucormycosis in immunocompetent patient resulting in extensive maxillary sequestration. AB - Mucormycosis or zygomycosis, also called phycomycosis, is an uncommon, invasive, potentially lethal and an aggressive fungal infection of the order Mucorales that usually affects patients with alteration of their immunological system. From its initial description (Paltauf, 1885), this entity still has a high mortality. Imaging techniques are not usually diagnostic, and cultures are not totally reliable. Definitive diagnosis is exclusively obtained by means of histopathological examination. Early recognition and aggressive treatment are of paramount importance and have reduced the mortality and morbidity. We present here a case report of oral mucormycosis in a 32-year-old male, immunocompetent individual resulting in extensive maxillary sequestration. PMID- 29491620 TI - Cervicofacial infection in a 3-year-old child with regional odontodysplasia: A case report and literature review. AB - Regional odontodysplasia (RO) also known as ghost teeth is a rare developmental anomaly affecting the mesodermal and ectodermal components of teeth with characteristic clinical and radiographic findings. The enamel and dentin are hypomineralized and hypocalcified with short roots and open apices. The affected teeth have an abnormal morphology, meaning they are fragile and thin and liable to fracture and decay. Radiographically, there is a marked reduction in radiodensity with little distinction between the enamel and dentin, hence the term "ghost teeth." RO generally affects one particular segment in one or both arches of the maxilla or mandible and can affect both the primary and permanent dentition. We report a unique case of a 3-year-old female who presented to Alder Hey Children's Hospital acutely unwell with a left-sided cervicofacial swelling from RO affecting the entire portion of the left maxilla. PMID- 29491621 TI - Leprosy of the hard palate: A rare case report. AB - Leprosy is a chronic granulomatous infection caused by Mycobacterium leprae, a bacillus that presents a peculiar tropism for the skin and peripheral nerves. Leprosy instigates various types of clinical presentation and exerts influence on the patient's immune response. The clinical gamut of leprosy ranges from the tuberculoid form (TT) to the disseminative and progressive lepromatous form (LL). Oral lesions are uncommon but, when present, occur in the lepromatous form and are broadly divided into nonspecific and specific lesions. In this article, we present a case of leprosy of the hard palate in a 25-year-old male. The case is been presented for its rarity. PMID- 29491622 TI - Tuberculosis of the maxillary sinus masquerading as a facial abscess, a unique occurrence. AB - The incidence of tuberculosis is a frequent finding especially in developing countries owing to a significant population of the people belonging to the lower socioeconomic strata with poor hygiene and nutrition. Tubercular involvement of the paranasal sinuses is usually asymptomatic until it reaches an advanced state and when it involves the maxillary sinus, this initial period of quiescence often mimics the clinical presentation of a chronic sinus infection, which often leads to a diagnostic dilemma. Symptoms commonly reported are chronic sinusitis and rhinorrhea, both of which being nonspecific in nature leading to a quandary. We herewith present a 50-year-old patient who presented with symptoms of an odontogenic infection involving the right maxillary molars. Primary management did not yield to the resolution of presenting symptoms. On biopsy, through an endoscopic approach and subsequent histopathological examination, the diagnosis of tuberculosis was arrived at. The patient responded well to antitubercular drug therapy. PMID- 29491623 TI - Fusion of maxillary central incisors with mesiodens. AB - Fusion and gemination are developmental anomalies which are quite similar to each other but can be distinguished from each other if properly assessed. Fusion and gemination have been described as a result of developmental anomalies of dental tissues. The exact etiology is still unknown, but a genetic predisposition is suggested. This article highlights the importance of clinical and radiographic correlation in arriving at a definitive diagnosis. PMID- 29491624 TI - Trigeminal neuralgia induced by odontogenic keratocyst associated with impacted supernumerary teeth: A rare case report. AB - Odontogenic keratocyst(OKC)is a cyst oftooth origin with an aggressive behavior including a high recurrence rate, it has been rechristened to keratocystic odontogenic tumor(KCOT) as it be the reflects its neoplastic nature. We report a case of KCOT in association with an impacted supernumerary tooth along with Trigeminal Neuralgia, that subsided by itself after removal of the cyst. PMID- 29491625 TI - Zerumbone Suppresses Angiogenesis in HepG2 Cells through Inhibition of Matrix Metalloproteinase-9, Vascular Endothelial Growth Factor, and Vascular Endothelial Growth Factor Receptor Expressions. AB - Context: Due to increase in the number of patients with impaired immunity, the incidence of liver cancer has increased considerably. Aims: The aim of this study is the investigation the in vitro anticancer effect of zerumbone (ZER) on hepatocellular carcinoma (HCC). Materials and Methods: The anticancer mechanism of ZER was determined by the rat aortic ring, human umbilical vein endothelial cells (HUVECs) proliferation, chorioallantoic membrane, cell migration, and proliferation inhibition assays. Results: Our results showed that ZER reduced tube formation by HUVECs effectively inhibits new blood vessel and tissue matrix formation. Western blot analysis revealed that ZER significantly (P < 0.05) decreased expression of molecular effectors of angiogenesis, the matrix metalloproteinase-9, vascular endothelial growth factor (VEGF), and VEGF receptor proteins. We found that ZER inhibited the proliferation and suppressed migration of HepG2 cell in dose-dependent manner. Statistical Analysis Used: Statistical analyses were performed according to the Statistical Package for Social Science (SPSS) version 17.0. The data were expressed as the mean +/- standard deviation and analyzed using a one-way analysis of variance. A P < 0.05 was considered statistically significant. Conclusion: The study for the first time showed that ZER is an inhibitor angiogenesis, tumor growth, and spread, which is suggested to be the mechanisms for its anti-HCC effect. SUMMARY: Tumor angiogenesis has currently become an important research area for the control of cancer growth and metastasis. The current study determined the effect of zerumbone on factors associated with angiogenesis that occurs in tumor formation. Abbreviations used: ZER: Zerumbone, MMP-9: Matrix metalloproteinase-9, VEGF: Vascular endothelial growth factor, VEGFR: Vascular endothelial growth factor receptor, HUVECs: Human umbilical vein endothelial cells, HCC: Hepatocellular carcinoma, HIFCS: Heat inactivated fetal calf serum, DMSO: Dimethyl sulfoxide, EDTA: Ethyldiaminetetraacetic acid, Ig: Immunoglobulin, CAM: Chorioallantoic membrane, HRP: Horseradish peroxidase, NIH: National Institutes of Health, MTT: Microtetrazolium, SPSS: Statistical Package for Social Science. PMID- 29491626 TI - Cerebroprotective Actions of Triticum aestivum Linn Powder and Bauhinia purpurea Flower Powder in Surgically Induced Cerebral Infraction in Rats. AB - Objective: The prime objective of this study is to evaluate the cerebroprotective actions of Triticum aestivum (wheatgrass) powder and Bauhinia purpurea flower (dev kanchan) powder against the experimentally induced global ischemia reperfusion injury in rats. Materials and Methods: In the first phase of the studies, 1 h before the surgical procedure, the Wistar rats were orally served with varied doses of wheatgrass powder (5, 10, 30, and 100 MUg/kg) and Bauhinia flower powder (30, 100, 200, and 300 MUg/kg), respectively. The ischemia was induced by 30-min bilateral carotid artery occlusion in succession to reperfusion for 4 h. It was proved that the wheatgrass powder and Bauhinia flower powder yielded a significant, dose-dependent cerebroprotection in terms of reduction in cerebral infarct size when compared with the control group. Coming to the second phase of the studies, a certain potential dose of 10 MUg/kg of wheatgrass and 200 MUg/kg of Bauhinia flower powders was selected keeping the protective action in view, and the animals were treated for 15 days. Results: The major findings of the study are that wheatgrass and Bauhinia flower powders significantly augmented the magnitude of the antioxidant enzymes, viz., super oxide dismutase and catalase, and further reduced the levels of lipid peroxidation. Conclusions: The present study clearly showed that the wheatgrass powder and Bauhinia flower powder possess significant antioxidant properties that may act as a key ingredient in various ayurvedic preparations for the treatment of various diseases like cerebral ischemic reperfusion injury. SUMMARY: The wheat grass contains high amount of bioflavonoids, alkaloids, SOD etc which are responsible for anti oxidant activity.The Bauhinia purpurea contains glycosides, flavonoids and also plays a major role in DPPH activity which is responsible for anti oxidant activity.The wheat grass (10 mg/kg) and bauhinia (200 mg/kg) significantly(P < 0.0001) reduced the percentage of infract size when compared to Ischemia reperfusion control group.The wheat grass (10 mg/kg) and bauhinia (200 mg/kg) significantly (P <0.0001) reduced the lipid peroxidation (MDA) and increased SOD and Catalase. Abbreviations used: BCAO: Bilateral Carotid Artery Occlusion, MCA: middle cerebral artery, ROS: reactive oxygen species, SCMC: Sodium carboxy methyl cellulose, p.o: Per oral route, T.T.C: Triphenyl tetrazolium chloride, MDA: Malondialdehyde, SOD: Super oxide dismutase. PMID- 29491627 TI - Identification of Inhibitors against Metastasis Protein "Survivin:" In silico Discovery Using Virtual Screening and Molecular Docking Studies. AB - Background: In experimental therapy of cancer, survivin is considered to be one of the well-established targets. Studies have found that it is overexpression in most of the human tumors, but it is rarely found in normal tissues. It is having varied structural and functional role. It controls cell division and cellular stress response and also regulates metastasis and migration of cancerous cells. It has also been recognized as a biomarker which makes it unconventional drug target. In spite of being one of the centrally active components in metastasis and invasion, their clinical use is minimal. To increase the therapeutic efficiency of cancer and its various stages, it is important to survey novel reagents targeting the pathways and mechanism involving survivin. Objective: The aim of this study was to identify novel survivin inhibitor candidates using in silico screening. Materials and Methods: In this course of work, virtual screening on a dataset of natural compounds retrieved from ZINC and other libraries were performed. Comparative analysis of the protein was done by studying the binding affinity of inhibitors that are already available. The best interacting complex was set for molecular dynamics simulation for 25 ns to validate the stability of system. These molecules were checked for their toxicity and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties using OSIRIS and pre-ADMET tools. Results: We discovered ten such candidates with better binding efficiency with survivin in comparison to marketed chemical against the same. Furthermore, these inhibitor candidates did not induce cell toxicity. Binding affinity of reference molecules was varied from -6.8 to 8.5 kcal/mol while that of top scoring compound ZINC00689728 is -9.3 kcal/mol binding energy. Good placement and strong bond formation of selected molecule was observed during course of work. It is also having permissible ADMET property. Conclusion: Considering all the parameters, the screened molecule can be considered as a potential lead compound for designing new drug against survivin. Further investigation and testing will be required to make it to the final stage. SUMMARY: Survivin is one of the important protein of metastasis. Inhibiting survivin might led to the increased therapeutic efficiency of cancer. In this work we are screening library of natural compounds in view of finding some potent inhibitor against survivin. Abbreviations used: MD: Molecular dynamics, LogS: Aqueous solubility, Acceptor HB: Hydrogen bond acceptor, Donor HB: Donor hydrogen bond donor, ADMET: Absorption, distribution, metabolism, excretion, and toxicity, RCSB: Research Collaboratory for Structural Bioinformatics, OPLS: Optimized potentials for liquid simulations, RMSD: Root-mean-square deviation. PMID- 29491628 TI - Taxifolin Inhibits 7,12-Dimethylbenz(a)anthracene-induced Breast Carcinogenesis by Regulating AhR/CYP1A1 Signaling Pathway. AB - Background: Breast cancer (BC), because of its invasive characteristics, is one of the most common and deadliest cancers among the female population around the world. Research has demonstrated that AhR signaling also plays a vital role in BC initiation and development as well. Therefore, blocking this pathway to natural interferences paves a new channel for the prevention of BC. Several natural compounds such as flavonoids possess the anticancer activities against different cancers. Objective: The present study has been designed to estimate the chemotherapeutic potential of taxifolin (TAX) against 7,12 dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma in Sprague-Dawley rats. Materials and Methods: Initially, the molecular docking analysis of AhR and cytochrome P450s (CYPs) (CYP1A1 and CYP1B1) was performed using MAESTRO tool, in an attempt to rationalize the activity of TAX, based on their CYP1-binding potential. The in vitro CYP1A1 activity was determined by luciferase assay with CYP1A1 substrate luciferin CEE. The in vivo analysis was performed by administrating TAX at 10, 20, 40 mg/kg BW for 28 days intragastrically in DMBA induced (25 mg/animal dose) at 55 days of age Sprague-Dawley (SD) rats. BC initiates after 90 days of tumor induction phase. The molecular mechanism of TAX on Ahr and CYPs was also examined through the mRNA and protein expressions using reverse transcription-quantitative polymerase chain reaction and Western blotting analysis. Results: Furthermore, TAX altered the energy regulation on DMBA-induced BC in SD rats by considerably restoring the cancer-induced modulations in tumor growth. Our results showed that TAX reduced the expressions of CYP1A1 and CYP1B1 in DMBA-induced mammary carcinoma by downregulating the AhR signaling pathway. Conclusion: This study revealed that TAX might be able to act as a chemotherapeutic agent against CYP1A1- and CYP1B1-mediated cancer and the inhibition of the DMBA-induced mammary carcinogenesis in a rat model.Abbreviations used: CYPs: Cytochrome P450s; PAH: polycyclic aromatic hydrocarbons; HRP- Horseradish peroxidase; BSA: Bovine serum albumin; DTTP: Deoxythymidine Triphosphate (nucleotide); RT-qPCR: Real Time quantitative polymerase chain reaction; CADD: Computer Aided Drug Drafting. PMID- 29491629 TI - In vitro Cytotoxicity and Apoptotic Assay in HT-29 Cell Line Using Ficus hispida Linn: Leaves Extract. AB - Background: Ficus hispida Linn. (Family Moraceae), well-known beneficial medicinal shrub, has been traditionally used for the treatment of various diseases such as leukoderma. Objective: The aim of the present study is to investigate the efficacy of F. hispida ethanolic leaves extract for antiproliferative, apoptotic, cell cycle blockade, and wound healing. Materials and Methods: F. hispida leaves extract was treated with colorectal adenocarcinoma cancer cell line HT29 for 24 h with control. The cells were treated at varying concentration ranges of 15, 31, 62, 125, and 250 MUg/ml each The cytotoxicity effect of leaves extract was studied by 3-[4, 5-dimethylthiazol-2-yl]-2, 5 diphenyltetrazolium bromide assay and their anticancer activity was further evaluated using cell cycle analysis and wound scratch assay. Results: The end antiproliferative result showed that HT-29 cell viability decreases in a concentration-dependent manner and the growth inhibitory effect (IC50) values are obtained at a concentration of 125 MUg. The increase in number of apoptotic cell was observed after treating HT-29 cells with the sample in double-staining methods. G0/G1 phase of the cell cycle was significantly blocked by the test sample followed by the G2/M phase in a negligible manner. In vitro cell wound closure or contracture was not significant when compared the sample against control group. Conclusion: F. hispida Linn. ethanolic leaves extract had shown to possess excellent cytotoxic effect through inducing apoptosis, especially causing cell cycle arrest at the G0/G1 phase. SUMMARY: The experiment tries to evaluate the effectiveness of F. hispida leaves extract as an antiproliferative, apoptotic, cell cycle inhibitor and wound healing agent. Results showed that F. hispida Linn extract own cytotoxic property by inducing apoptosis through cell cycle arrest. Abbreviations used: HT 29: Human adenocarcinoma colorectal cell line; PBS: Phosphate Buffered Saline; FBS: Fetal Bovine Serum; DMEM: Dulbecco's Modified Eagles Medium; MTT: 3 [4, 5 dimethylthiazol 2 yl] 2, 5 diphenyltetrazolium bromide; NCCS: National Centre for Cell Sciences; DMSO: DiMethyl SulfOxide; PI: Propidium Iodide; AO: Acridine Orange;EB: Ethidium Bromide; IC: Inhibitory Concentration. PMID- 29491630 TI - Safety Profile Investigations of Meyna spinosa (Roxb.) and Oroxylum indicum (Linn.) Extracts Collected from Northeast India. AB - Background: Meyna spinosa (M.S) (Roxb.) ex Link and Oroxylum indicum (O.I) (Linn.) Vent, widely used traditional Northeast Indian medicinal plant used for various purposes, have not yet explored for safety profile. Objective: To investigate the safety profile of M.S (Roxb.) ex Link leaves and O.I (Linn.) Vent stem bark extracts collected from Northeast region of India. Materials and Methods: In this study, mutagenic, cytotoxic, and genotoxic and/or nontoxic potential of these two plant extracts using various toxicological investigations, as per the regulatory test guidelines, were evaluated. The mutagenic, cytotoxic, and genotoxic potential of these two plants were assayed using Ames test, 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, comet assay, and micronucleus test in the bone marrow cells. Results: The results demonstrated that the tested doses of M.S (Roxb.) ex Link leaves extract showed mutagenic, cytotoxic, and genotoxic effects, whereas O.I (Linn.) Vent stem bark extracts showed nonmutagenic, noncytotoxic, and nongenotoxic effects. Conclusion: The stem bark extracts of O.I (Linn.) Vent has no mutagenic, cytotoxic, and genotoxic or clastogenic effects in our experimental conditions. However, M.S (Roxb.) ex Link leaves extract caused a significant increase in DNA damage as compared with the positive control, i.e., cyclophosphamide. Thus, the present study revealed that M.S (Roxb.) ex Link leaves extract is toxic, while O.I (Linn.) Vent stem bark extract was found to be safe. SUMMARY: For the first time, we reported the safety performance of these two plants.The absence of toxicity in Oroxylum indicum (O.I) plant extracts was observed at various doses in animals.Interestingly, our result indicated that Meyna spinosa (M.S) extract shows toxicological effect.Therefore, O.I plant extracts was considered as safer plant extract as compared to M.S. Abbreviations used: MS: Meyna spinosa; OI: Oroxylum indicum. PMID- 29491632 TI - Biochemical Characterization of Fungus Isolated during In vitro Propagation of Bambusa balcooa. AB - Background: Bambusa balcooa (Poaceae: Bambusoideae) is a multipurpose bamboo species, which is native of the Indian subcontinent. B. balcooa is regarded as one of the best species for scaffolding and building purposes because of its strong culm. Other uses include paper pulp, handicrafts, and products of the wood chip industry. Due to these various uses in industries, this species has been identified as one of the priority bamboos by the National Bamboo Mission. Objective: This study is designed to analyze the identification of fungus and develop the strategy to eliminate the contamination during in vitro establishment of B. balcooa through nodal part. Fungus contamination is a problem which is encountered during in vitro establishment of B. balcooa cultures. Materials and Methods: In the present study, fungus contamination from in vitro cultured plant has been isolated and subjected to partial sequence analysis of the 18S rRNA gene to identify the fungus strain. Experiments were designed to develop a strategy for removal of the fungus contamination with the help of antifungal compounds and commercial antimicrobial supplement supplied by HiMedia. Results: Fusarium equiseti was identified as endophytic fungus. It was observed that antimicrobial supplement at concentration of 500 MUl/l was more effective concentration to remove fungus contamination and not showed any detrimental effect on growth parameters of shoot. Conclusion: This experiment would help in identification and to get rid of fungal contamination and improve the in vitro establishment of B. balcooa cultures for large-scale propagation. SUMMARY: Endogenous fungus was isolated from contaminated culture of B. balcooa, and it was identified as Fusarium equiseti and submitted to NCBI under accession no. KP274872. The endophytic fungus had shown substantial production of amylase, cellulase, and protease media. Gibberellic acid (GA3) production by F. equiseti was maximum on the 7th day on inoculation. Abbreviations used:B. balcooa: Bambusa balcooa, F. equiseti: Fusarium equiseti, PDA: Potato dextrose agar, PCR: Polymerase chain reaction, MS: Murashige and Skoog's, BAP: 6-Benzylaminopurine, ITS1/4: Internal transcribed spacer region 1/4, GA3: Gibberellic acid. PMID- 29491631 TI - Black Tea (Camellia sinensis) Extract Induced Prenatal and Postnatal Toxicity in Experimental Albino rats. AB - Background: Tea (Camellia sinensis) being the most widely drank beverage and despite having numerous beneficial role toward health and disease, its safety evaluation during pregnancy and prenatal, postnatal developmental period need to be monitored. Objective: This study was to evaluate the toxicity of black tea extract (BTE) in experimental pregnant rats and on their pups during prenatal and postnatal developmental periods. Materials and Methods: Pregnant female (120 +/- 10 g) Wister albino rats were chosen for this study. Group 1 was control group where pregnant female rats were treated with saline. Group 2 and Group 3 were pregnant female rats treated with 50 mg and 100 mg BTE/kg/day, respectively, throughout prenatal and postnatal periods. All three groups of rats were provided food and drinking water ad libitum. Animals were examined through their urinary and serum parameters, histopathological studies, and biomorphometric studies in pups. All data were expressed as mean +/- standard deviation with significance between the controls and the treated groups (n = 6). Collected data were subjected to the analysis of variance and Tukey test; P < 0.05 was considered as statistically significant. Results: BTE produced significant alterations in urinary calcium, creatinine, and urea during prenatal period; exhibited proteinuria, ketonuria, and histology showed nephrotoxicity during postnatal period, and BTE also showed a significant increase in serum proinflammatory cytokines and decreased anti-inflammatory cytokines level compared to control group. BTE caused significant changes in biomorphometric parameters in the pups as compared with pups of control mothers. Conclusion: This study confirmed the BTE-induced toxicity in pregnant rats and their pups. SUMMARY: Black tea (Camellia sinensis) is the most widely drank beverage. This study was to evaluate the toxicity BTE in experimental pregnant rats and on their pups during prenatal and postnatal developmental periods. Animals were examined through their urinary and serum parameters, histopathological studies, and biomorphometric studies in pups. BTE.induced toxicity in pregnant rats and their pups. Abbreviations used: BTE: Black tea extract, IL-1alpha: Interleukin 1 alpha, IL-1 beta: Interleukin 1 beta, IL-6: Interleukin 6, IL-10: Interleukin 10, TNF-alpha: Tumor necrosis factor alpha. PMID- 29491633 TI - Computational Breakthrough of Natural Lead Hits from the Genus of Arisaema against Human Respiratory Syncytial Virus. AB - Background: To date, efforts for the prevention and treatment of human respiratory syncytial virus (RSV) infection have been still vain, and there is no safe and effective clinical accepted vaccine. Arisaema genus has claimed for various traditional bioactivities, but scientific assessments are quite limited. Objective: This encouraged us to carry out our present study on around 60 phytoconstituents of different Arisaema species as a natural inhibitor against the human RSV. Materials and Methods: Selected 60 phytochemical entities were evaluated on the docking behavior of human RSV receptor (PDB: 4UCC) using Maestro 9.3 (Schrodinger, LLC, Cambridge, USA). Furthermore, kinetic properties and toxicity nature of top graded ligands were analyzed through QikProp and ProTox tools. Results: Notably, rutin (glide score: -8.49), schaftoside (glide score: 8.18) and apigenin-6,8-di-C-beta-D-galactoside (glide score - 7.29) have resulted in hopeful natural lead hits with an ideal range of kinetic descriptors values. ProTox tool (oral rodent toxicity) has resulted in likely toxicity targets of apex-graded tested ligands. Conclusion: Finally, the whole efforts can be explored further as a model to confirm its anti-human RSV potential with wet laboratory experiments. SUMMARY: Rutin, schaftoside, and apigenin-6,8-di-C-beta-D galactoside showed promising top hits docking profile against human respiratory syncytial virusMoreover, absorption, distribution, metabolism, excretion properties (QikProp) of top hits resulted within an ideal range of kinetic descriptorsProTox tool highlighted toxicity class ranges, LD50 values, and possible toxicity targets of apex-graded tested ligands. Abbreviations used: RSV: Respiratory syncytial virus, PRRSV: Porcine respiratory and reproductive syndrome virus, ADME-T: Absorption, distribution, metabolism, excretion, and toxicity. PMID- 29491634 TI - In silico Prediction and Wet Lab Validation of Arisaema tortuosum (Wall.) Schott Extracts as Antioxidant and Anti-breast Cancer Source: A Comparative Study. AB - Background: Globally, reactive oxygen species have served as an alarm predecessor toward pathogenesis of copious oxidative stress-related diseases. The researchers have turned their attention toward plant-derived herbal goods due to their promising therapeutic applications with minimal side effects. Arisaema tortuosum (Wall.) Schott (ATWS) is used in the traditional medicine since ancient years, but scientific assessments are relatively inadequate and need to be unlocked. Objective: Our aim was designed to validate the ATWS tuber and leaf extracts as an inhibitor of oxidative stress using computational approach. Materials and Methods: The reported chief chemical entities of ATWS were docked using Maestro 9.3 (Schrodinger, LLC, Cambridge, USA) tool and further ATWS extracts (tubers and leaves) were validated with 2,2'-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS), ferric-reducing ability of plasma (FRAP), and sulforhodamine B assays experimentally. Results: In silico results showed notable binding affinity of ATWS phytoconstituents with the receptor (PDB: 3ERT). Experimentally, butanolic tuber fraction confirmed promising antioxidant potential (ABTS: IC50: 271.67 MUg/ml; DPPH: IC50: 723.41 MUg/ml) with a noteworthy amount of FRAP (195.96 MUg/mg), total phenolic content (0.087 MUg/mg), and total flavonoid content (7.5 MUg/mg) while chloroform fraction (leaves) showed considerable reduction in the cell viability of MCF-7 cell line. Conclusion: The current findings may act as a precious tool to further unlock novel potential therapeutic agents against oxidative stress. SUMMARY: Quercetin showed top.ranked glide score with notable binding toward 3ERT receptorAmong extracts, butanolic tubers confirmed as promising antioxidant with remarkable amount of TPC and TFCIn addition, chloroform fraction (leaves) revealed considerable decline in the cell viability of MCF-7 cell line. Abbreviations used: ATWS: Arisaema tortuosum (Wall.) Schott, DPPH: 2,2'-diphenyl 1-picrylhydrazyl, ABTS: 2,2'-Azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt, FRAP: Ferric-reducing ability of plasma, TPC: Total phenolic content, TFC: Total flavonoid content, SRB: Sulforhodamine B. PMID- 29491635 TI - Phytochemical Study of Aegle marmelos: Chromatographic Elucidation of Polyphenolics and Assessment of Antioxidant and Cytotoxic Potential. AB - Background: The antioxidant potential of medicinal plants has been illustrated through many reports clearly depicting that plants are a rich source of antioxidants, making them a great resource of novel drugs and health-care products. Objectives: The current study is, therefore, focused toward the assessment of antioxidant properties along with the presence of phytochemicals in leaves of 18 varieties/accessions of Aegle marmelos. Materials and Methods: The antioxidant activities were initially measured using superoxide radical scavenging method, 2, 2-diphenyl-1-picrylhydrazyl (DPPH), and ferric-reducing ability of plasma assays. Further, thin-layer chromatography (TLC), high performance TLC, and column chromatography were performed to isolate the potentially active fraction and anti-inflammatory activity of crude, and the isolated fraction was tested on J774 macrophage cell line. Results: The maximum inhibition of superoxide anions was shown by Pant Aparna. Additionally, Pant Aparna extract was most efficient, exhibiting 92.0% inhibition in scavenging the DPPH radicals. The content of total carotenoids was found to be higher in Pant Aparna among all the varieties/accessions. Furthermore, the crude extract and the fraction A. marmelos methanolic fraction 21 (AMMF21) were found to be nontoxic and significant reactive oxygen species, and NO inhibition was observed in a concentration-dependent manner. Moreover, the methanolic extract of variety Pant Aparna showed promising in vitro antioxidant activity, indicating its potency for therapeutic applications. Conclusion: In brief, this is the first ever report on Pant Aparna as the best variety in terms of phytocompounds and identification of potential antioxidant activity. In addition, the AMMF21 fraction of methanolic extract possessing best antioxidant activity on macrophage cells indicates its use as a novel phytotherapeutic agent. SUMMARY: Our study identifies the best variety/accession of Aegle marmelos possessing the potential antioxidant and reactive oxygen species scavenging activity possessed by the methanolic crude extract of variety Pant Aparna along with the fraction A. marmelos methanolic fraction 21 isolated through column chromatography on J774 murine macrophage cell lineThe high-performance thin-layer chromatography fingerprinting profile obtained acts as a diagnostic tool to identify and determine the quality and purity of this extract and fraction in future studiesOn the basis of the results obtained, the above variety should be taken further to exploit its immense potential for other biological activities of medicinal importancePant Aparna is an outstanding variety of A. marmelos and should be extensively studied for isolation of a novel and potential therapeutic agent. Abbreviations used: AMMF21: Aegle marmelos methanolic fraction 21, DPPH: (2, 2-diphenyl-1-picrylhydrazyl), FRAP: Ferric-reducing ability of plasma, HP-TLC: High-performance-thin-layer chromatography, TLC: Thin-layer chromatography, TCA: Trichloroacetic acid, TPTZ: 2,4,6-Tripyridyl-s-triazine, DNPH: 2,4-dinitrophenyl hydrazine, NBT: Nitroblue tetrazolium, NADH: Nicotinamide adenine dinucleotide, PMS: Phenazine metho sulfate, DMEM: Dulbecco's modified Eagle medium; MTT: (3-(4,5-dimethythiazol-2 yl)-2,5-diphenyl tetrazolium bromide, DCFDA: 2',7'-dichlorofluorescein diacetate, LPS: Lipopolysaccharide, NED: N-(1-Naphthyl) ethylenediamine. PMID- 29491636 TI - Viwithan, a Standardized Withania somnifera Root Extract Induces Apoptosis in Murine Melanoma Cells. AB - Background: Withania somnifera is an Indian medicinal herb known for the multipotential ability to cure various therapeutic ailments as described in the ayurvedic system of medicine. Objective: In the present study, we have evaluated the antiproliferative activity of a standardized W. somnifera root extract (Viwithan) against different human and murine cancer cell lines. Materials and Methods: The cytotoxicity of Viwithan was determined using thiazolyl blue tetrazolium blue assay and crystal violet staining. The apoptotic changes in B16F1 cells following treatment with Viwithan were observed by acridine orange/ethidium bromide (AO/EB) staining and DNA fragmentation assay. The binding affinity of withanolides in Viwithan with antiapoptotic proteins B-cell lymphoma 2, B-cell lymphoma-extra large, and myeloid cell leukemia 1 (MCL-1) were studied using in silico approach. Results: The half maximal inhibitory concentration (IC50) values of Viwithan against liver hepatocellular carcinoma, Henrietta Lacks cervical carcinoma cells, human colorectal carcinoma cell line, and Ehrlich ascites carcinoma cells were 1830, 968, 2715, and 633 MUg/ml, respectively. Interestingly, Viwithan was highly effective against B16F1 cells with an IC50 value of 220 MUg/ml after 24 h treatment. The morphological alterations of apoptotic cell death were clearly observed in the AO/EB-stained cells after treatment with Viwithan. Viwithan induced late apoptotic changes in treated B16F1 cells as evident by the ladder formation of fragmented DNA in a time-dependent manner. The findings of molecular docking showed that withanolides present in Viwithan have a more binding affinity with the antiapoptotic proteins, particularly MCL-1. Conclusion: We have reported for the first time that Viwithan with 5% withanolides has a potent cytotoxic effect, particularly against B16F1 murine melanoma cells among the different cancer cell lines tested. SUMMARY: The present study reports for the first time that Viwithan, a standardized 5% Withania somnifera root extract, has potent cytotoxicity against B16F1 murine melanoma cellsWe have investigated the in vitro cytotoxicity of Viwithan in different human and murine cancer cells. Interestingly, we found that Viwithan was particularly very effective against B16F1 melanoma cells with a half maximal inhibitory concentration value of 220 MUg/mlThe microscopic observations following acridine orange/ethidium bromide staining and DNA fragmentation assays clearly indicated that Viwithan might initiate late apoptosis in B16F1 cellsThe binding affinity of withanolides in Viwithan with antiapoptotic proteins of B cell lymphoma 2 family was predicted using AutoDock tool. The results from in silico studies indicated a plausible synergistic effect of withanolides attributing to the Viwithan-induced apoptosis through suppression of intrinsic pathway for carcinogenesis. Abbreviations used: MTT: Thiazolyl blue tetrazolium blue; DMSO: Dimethyl sulfoxide; BSA: Bovine serum albumin; DMEM: Dulbecco's minimum essential medium; NCCS: National Centre for Cell Science; PBS: Phosphate Buffered Saline; HepG2: Liver hepatocellular carcinoma; HeLa: Henrietta Lacks cervical carcinoma cells; HCT-116: Human colorectal carcinoma cell line; EAC: Ehrlich ascites carcinoma cells; IC50: Half maximal inhibitory concentration; AO/EB: Acridine orange/Ethidium bromide; BCL-2: B-cell lymphoma 2; BCL-XL: B-cell lymphoma-extra large; MCL-1: Myeloid cell leukemia 1; PDB: Protein Data Bank; ANOVA: Analysis of variance. PMID- 29491637 TI - Protective Effect of Exacum lawii on Cisplatin-induced Oxidative Renal Damage in Rats. AB - Background: Exacum lawii (Gentianaceae), a bitter herb conventionally used in kidney diseases and eye problems, endemic to the Western coast and Southern part of India. Aim: Folklore reports encourage the author to explore the nephroprotective effect of the standardized ethanolic extract of E. lawii against cisplatin-induced renal toxicity in the rat to scientifically validate its traditional use. Materials and Methods: Ethanolic extract of the whole plant of E. lawii was standardized with swertiamarin (secoiridoid glycoside) using high performance liquid chromatography and tested for subacute toxicity according to the OECD guidelines. Nephroprotective potential at different doses of extract was evaluated against cisplatin (6 mg/kg, intraperitoneal) in experimental rats. The changes in serum renal toxicity markers, renal tissue oxidative stress biomarkers, and proinflammatory cytokines level were measured. To estimate the change in oxidative status of renal tissues, DNA and single viable cells were isolated from treated rat kidney, DNA fragmentation assay and flow cytometric analysis of reactive oxygen species (ROS) were performed. Histopathology of renal tissues was also examined. Results: Swertiamerin was found to be 119.59 mg/g of extract. Administration of E. lawii extract (ELE) restored the biochemical parameters. It also decreases the elevated proinflammatory cytokines level in kidney tissues and protected rat kidneys from oxidative stress in rats. Nephroprotective activity was validated by estimating ROS production in kidney live cells and DNA damage in kidney tissue. The histological architecture was also conserved. Conclusion: ELE showed significant renal protection against cisplatin through reducing oxidative stress and inflammation. SUMMARY: High performance liquid chromatography standardisation of Exacum lawii extract with Swertiamerin and its subacute toxicity studyNephroprotective activity of Exacum lawii extract and Swertiamerin was evaluated in cisplatin-induced model and justified by various biochemical parameters and histopathological studyRole of oxidative stress in cisplatin-induced nephrotoxicity was confirmed by measuring levels of antioxidant markers and proinflammatory cytokines in rat renal tissues, ROS estimation by flow cytometry and DNA fragmentation assay by gel electrophoresis in renal cells. Abbreviations used: ELE: Exacum lawii ethanolic extract; WHO: World Health Organization; SOD: Superoxide dismutase; CAT: Catalase; MDA: Malondialdehyde; HPTLC: High performance thin layer chromatography; p.o.: Per oral; i.p.: Intraperitoneal; TNF-alpha: Tumor necrosis factor alpha; IL-1beta: Interleukin 1 beta; IL-6: Interleukin 6; ROS: Reactive oxygen species. PMID- 29491638 TI - Rhinacanthins-rich Extract Enhances Glucose Uptake and Inhibits Adipogenesis in 3T3-L1 Adipocytes and L6 Myotubes. AB - Background: Obesity is one of the imperative dynamics in the incidence and intensification of type 2 diabetes mellitus (T2DM). Rhinacanthus nasutus leaf extracts are previously reported for their antidiabetic and antiobesity potential. Objective: The present study was performed to evaluate glucose uptake stimulatory and antiadipogenic activities of a standardized rhinacanthins-rich extract (RRE) and its marker compounds namely rhinacanthin-C (RC), rhinacanthin-D (RD), and rhinacanthin-N (RN) in 3T3-L1 and L6 cells. Materials and Methods: RRE was prepared by a green extraction process, and the marker compounds (RC, RD, and RN) were isolated from the RRE using a silica gel column chromatography. Glucose uptake stimulation in both 3T3-L1 and L6 cells was performed by quantification of residual glucose in the media using glucose oxidase kit. Antiadipogenic activity in 3T3-L1 adipocytes was performed by intracellular lipids quantification using oil red O dye. Results: At the highest effective dose, RRE (20 MUg/mL) exhibited satisfactory glucose uptake stimulatory effect in 3T3-L1 adipocytes that equivalent to RN (20 MUg/mL) and the positive control insulin (0.58 MUg/mL) but higher than RC (20 MUg/mL) and RD (20 MUg/mL). In addition, treatments of L6 myotubes showed that RRE (2.5 MUg/mL) exhibited potent and equivalent glucose uptake stimulation (>80%) to RC (2.5 MUg/mL) and the standard drugs, insulin (2.90 MUg/mL) and metformin (219.5 MUg/mL), but higher than RD (2.5 MUg/mL) and RN (2.5 MUg/mL). Furthermore, RRE (20 MUg/mL) exhibited potent antiadipogenic effect in 3T3-L1 adipocytes, which equivalent to RC (20 MUg/mL) but higher than RD (20 MUg/mL) and RN (20 MUg/mL). Conclusions: The undertaken study suggests that RRE could be used as an effective remedy in the treatment of obesity associated T2DM. SUMMARY: Rhinacanthins-rich extract and its marker compounds showed potent glucose uptake stimulatory activity in 3T3-L1 adipocytes and L6 myotubesRhinacanthins-rich extract and rhinacanthin-C showed comparable antiadipogenic effect in 3T3-L1 adipocytesRRE could be used as an effective remedy in the treatment of obesity-associated T2DM. Abbreviations used: T2DM: Type-2 diabetes mellitus; RRE: Rhinacanthins-rich extract; RC: Rhinacanthin-C; RD: Rhinacanthin-D; RN: Rhinacanthin-N; alpha-MEM: alpha-Minimum essential medium; DMEM: Dulbecco's modified Eagle's medium; HS: Horse serum; FBS: Fetal bovine serum; BSA: Bovine serum albumin; IBMX: 3-isobutyl-1-methylxanthine; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; GO: Glucose oxidase; NMR: Nuclear magnetic resonance; HPLC: High-performance liquid chromatography. PMID- 29491639 TI - Expression of Hepatic Cytochrome P450s in Rats Administered with Guibi-tang, a Traditional Herbal Formula. AB - Objective: The aim of this study was to investigate the possible herb-drug interactions between the traditional herbal formula Guibi-tang (GBT; Guipi-tang, Kihi-to) and conventional drugs. Materials and Methods: GBT was orally administered to either male or female Sprague Dawley (SD) rats once daily at doses of 1000, 2000, or 5000 mg/kg/day for 13 weeks. The messenger ribonucleic acid (mRNA) expression of drug-metabolizing enzyme cytochrome P450 isozymes (cytochrome P450s; CYP1A1, 1A2, 2B1/2, 2C11, 2E1, 3A1, 3A2, and 4A1) was analyzed in hepatic tissues by reverse transcription-polymerase chain reaction. Results: Repeated oral administration of GBT did not significantly influence the mRNA expression of hepatic CYP1A1, 1A2, 2B1/2, 2C11, 2E1, 3A1, 3A2, and 4A1 in male rats. By contrast, in female rats, the mRNA expression of hepatic CYP1A2 and 2B1/2 was significantly increased by repeated GBT treatment. Conclusion: Our findings indicate that caution is required in females when GBT is taken concomitantly with conventional drugs metabolized by CYP1A2 or 2B1/2. Our results provide information regarding the safety and effectiveness of GBT for clinical use. SUMMARY: Repeated oral administration of Guibi-tang (GBT) for 13 weeks did not affect the messenger ribonucleic acid (mRNA) expression of hepatic CYP1A1, 1A2, 2B1/2, 2C11, 2E1, 3A1, 3A2, and 4A1 in male ratsRepeated oral administration of GBT for 13 weeks induced mRNA expression of hepatic CYP1A2 and 2B1/2 but not for CYP1A1, 2C11, 2E1, 3A1, 3A2, and 4A1 in female rats. Abbreviations used: CYP450: Cytochrome P450s, GBT: Guibi-tang, SD: Sprague Dawley, HPLC: High performance liquid chromatography, OECD: Organization for Economic Cooperation and Development, RNA: Ribonucleic acid, RT-PCR: Reverse transcription-polymerase chain reaction, GADPH: Glyceraldehyde-3-phosphate dehydrogenase. PMID- 29491640 TI - Antibacterial Synergy of Silver Nanoparticles with Gentamicin and Chloramphenicol against Enterococcus faecalis. AB - Background: Enterococcus faecalis (Ef) is a multidrug-resistant pathogenic bacteria associated with hospital-acquired infections. Ef is involved in a number of infectious diseases. It generally infects patients with the weekend immune system, i.e. a person mostly acquires Ef infections in the hospital, especially in intensive care units and thus, is more likely to be resistant to many antibiotics. Development of resistance against various antibiotics and emergence of drug-resistant strains is a growing global concern. Objective: Due to the unselective use of antibiotics for a long time multidrug resistant bacteria and extensively drug-resistant, which is now posing a new challenge to the medical community. To treat infections caused by Ef, the synergistic effect of different antibiotics with silver nanoparticles (AgNPs) was tested against Ef. Materials and Methods: In the present study, synthesis of AgNPs was carried out from the cell-free supernatant of Klebsiella pneumoniae. AgNPs were characterized using various techniques, namely, ultraviolet-visible spectrophotometry, transmission electron microscopy, and Fourier transform infrared spectroscopy. Moreover, process optimization was done for enhanced production of AgNPs. In addition, antimicrobial activity of the nanoparticles was also tested. Furthermore, the nanoparticles were evaluated for their antimicrobial activities in combination with gentamicin and chloramphenicol, against Ef. Results: The results showed that the combination of gentamicin and chloramphenicol with AgNPs has a better antibacterial effect. To add to this, hemolytic activity of AgNPs was evaluated against human red blood corpuscles (RBCs). AgNPs were found to be nontoxic to RBCs. Conclusion: The collective effect of AgNps with Gentamicin and Chloramphenicol was more as compared to AgNps alone which indicate the synergistic effect of these components. These observations show the potential of AgNPs in combination with above-stated antibiotics against Ef infections. SUMMARY: Enterococcus faecalis (Ef) is a multidrug-resistant bacteria with is resistant to wide range of antibioticsDue to this increasing resistance, there is a need to find a new approach to overcome the infections caused by EfThe combined effect of silver nanoparticles (AgNPs) with gentamicin and chloramphenicol was notably seen against EfFurthermore, the AgNPs were nontoxic to the human red blood corpuscles which confirm its nontoxic nature. Abbreviations used: Ef: Enterococcus faecalis, MDR: Multidrug resistance, AgNPs: Silver nanoparticles, Kp: Klebsiella pneumoniae, RBCs: Red blood corpuscles, ENPs: Engineered nanoparticles, FTIR: Fourier transform infrared spectroscopy, TEM: Transmission electron microscopy, AgNO3: Silver nitrate, EDTA: Ethylenediaminetetraacetic acid, PBS: Phosphate-buffered saline. PMID- 29491641 TI - Triphala, Regulates Adipogenesis through Modulation of Expression of Adipogenic Genes in 3T3-L1 Cell Line. AB - Background: Triphala, an Ayurvedic polyherbal formulation, is used for the treatment of various diseases including obesity. Objective: The present study was planned to evaluate the anti-adipogenic potential of aqueous extract of Triphala (TPaq) using 3T3-L1 adipocyte cell line model. Methods: The effect of aqueous extract of Triphala (TPaq) was tested on the viability of 3T3- L1 cells by MTT assay. The cells were treated with a cocktail of dexamethasone (DEX), isobutylmethylxanthine (IBMX) and insulin to induce adipogenesis. The cells were treated either with the induction cocktail or with the cocktail containing different concentrations (1, 10 and100 MUg/ml) of TPaq. Intracellular lipid content was analyzed using Oil O Red stain and was quantified after extracting with isopropanol at 500 nm wavelength. The expression of early (PPAR-gamma and C/EBP-alpha) and late (GLUT4 and FAS) phase adipogenic genes was studied by real time PCR. Results: TPaq did not affect the viability of 3T3-L1 cell line. Interestingly, TPaq induced a concentration dependant decrease in the intracellular lipid content and expression of both early and late phase adipogenic genes. This decrease was statistically significant compared to cells treated with only induction cocktail. Conclusion: These results suggested that Triphala regulated lipid accumulation by down regulating expression of adipogenic genes, resulting into prevention of adipogenesis. SUMMARY: The purpose of this study was to evaluate the effect of an ayurvedic polyherbal drug Triphala on adipogenesis using 3T3-L1 cell line. The results suggested that Triphala regulated lipid accumulation by downregulating expression of adipogenic genes, resulting into the prevention of adipogenesis. Abbreviations used: TPaq: Aqueous extract of Triphala; DMEM: Dulbecco's Modified Eagle's medium; FBS: Fetal Bovine Serum; IBMX: Isobutyl methylxanthine; DMX: Dexamethasone; MTT: [3-(4, 5 dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide] assay; PPARgamma: Peroxisome proliferator-activated receptor; C/EBP:Enhancer binding protein alpha, FAS:Fatty acid synthase; Glut-4: Glucose phosphate transporter 4. PMID- 29491642 TI - Green Synthesis of Silver Nanoparticles Using Leaf Extract of Common Arrowhead Houseplant and Its Anticandidal Activity. AB - Background: Silver nanoparticles have excellent medical and nonmedical properties and application compared with other metallic nanoparticles. In the present study, fresh leaves of Syngonium podophyllum have been used for synthesis of silver nanoparticles. Objectives: In this study, we evaluated the anticandidal activity of S. podophyllum and the synthesized nanoparticles. Materials and Methods: In this study, simple and economical procedure was adopted for silver nanoparticles synthesis. S. podophyllum leaf was processed to obtain aqueous extract as a biological material for nanoparticles production. Synthesized nanoparticles were characterized by ultraviolet (UV) spectroscopy, X-ray diffraction (XRD), and atomic force microscopy. Results: The progress of silver nanoparticles biosynthesis from leaf extract of S. podophyllum was observed by UV-visible spectroscopy. The peaks maxima were observed at 455 nm for silver nanoparticles synthesized from the leaf extracts of S. podophyllum. XRD diffractogram showing Bragg peaks of face-centered cubic crystalline elemental silver confirming the formation of silver nanoparticles. The minimal inhibitory concentration values of aqueous extracts of S. podophyllum leaf were estimated by broth dilution method and found that the extracts exhibited antifungal activity against Candida albicans. The antifungal activity was also determined using disk diffusion method by measuring the diameter for zone of inhibition. Conclusion: S. podophyllum leaf extract shows strong antifungal activity against C. albicans. S. podophyllum could be applied in the fields of medical and pharmaceuticals for formulation of new drugs. SUMMARY: The synthesis, characterization, and antifungal activities of silver nanoparticle from Common arrowhead house plant.The silver nanoparticles were confirmed to be spherical in shape.The antifungal activities of the confirmed their therapeutic potential. Abbreviation used: AgNO3: Silver nitrate, MIC: Minimum inhibitory concentration, MTCC: Microbial type culture collection, SPR: Surface plasmon resonance, UV: Ultraviolet, XRD: X-ray diffraction. PMID- 29491643 TI - A New Highly Selective and Specific Anti-puerarin polyclonal Antibody for Determination of Puerarin Using a Mannich Reaction Hapten Conjugate. AB - Background: Puerarin (PUE) is a phytoestrogen found in Pueraria candollei and Pueraria lobata. These plants are substantial for traditional medicine in various Asian countries. PUE is a key marker that can be found only in the Pueraria species. Objective: To establish the method for determination of PUE content which is required for quality control of pharmaceutical products. Materials and Methods: PUE-cationized bovine serum albumin conjugate was created via Mannich reaction. After the rabbit immunization, the obtain anti-PUE polyclonal antibody (PAb) was used to develop an enzyme-linked immunosorbent assay (ELISA). Results: An anti-PUE PAb possess a great sensitivity and specificity. The cross-reactivity analysis shows no cross-reaction of an established antibody against other substances. In addition, we successfully developed an indirect competitive ELISA (icELISA) for the quantitative analysis of PUE. The result of method validation conforms to acceptance criteria and correlates with high-performance liquid chromatography, the reference method. The icELISA was applied to determine PUE content in Pueraria spp. plant samples and its derived pharmaceutical products. Conclusion: This highly specific immunogen was created from the Mannich reaction. An icELISA can also be applied to other research propose in the further studies. SUMMARY: The new immunogen conjugated (puerarin-cBSA) via Mannich reaction was successfully in rising of antibody against puerarin (PUE)The obtained anti-PUE polyclonal antibody (PAb) was high sensitivity and specificity to PUEAn indirect competitive enzyme-linked immunosorbent assay (icELISA) was developed and validated using anti-PUE PAbThe established icELISA was applied to determine PUE content in various tuberous root of Pueraria sppMoreover, icELISA method can be applicable in Pueraria spp. derived products. Abbreviations used: PUE: Puerarin; PAb: Polyclonal antibody; ELISA: Enzyme-linked immunosorbent assay; icELISA: Indirect competitive ELISA; cBSA: Cationized bovine serum albumin. PMID- 29491644 TI - Mechanistic In vitro Evaluation of Prosopis farcta Roots Potential as an Antidiabetic Folk Medicinal Plant. AB - Objective: Prosopis farcta has been used as a traditional herbal medicine for treating Diabetes mellitus. The aim of this study is to investigate the antidiabetic mechanisms of infusion (INF) extract of P. farcta and discovering the active extract for the first time. Materials and Methods: Six different extracts of P. farcta were prepared using five different solvents (ethanol, n hexane, acetone, ethanol:water (1:1 v/v), and water). Cytotoxicity and cell proliferation assays were performed on mouse pancreatic beta-cells (beta-TC3) using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium method. The effects of P. farcta on glucose metabolism (in a hepatocellular carcinoma cell line [HepG2]) and glucose diffusion across a dialysis membrane (as a model of cellular glucose absorption) were evaluated. The protective effect of various P. farcta extracts on cytotoxicity, mitochondrial membrane potential (MMP), and streptozotocin (STZ)-induced apoptosis in beta-TC3 cells was investigated. Results: Cytotoxicity study indicated that extracts were safe on beta-TC3 and HepG2 (<=0.5 mg/ml). INF protected beta-TC3 cells from apoptosis induced by STZ and improved cell viability for 20% and significantly decrease depolarization of MMP (P < 0.005). The results showed that INF inhabited breaking/streaking the DNA. Proliferation study showed no significant increase in the number of cells either at single or multiple doses. In moderate hyperglycemia (11.1 mmol/l), a significant glucose-lowering effect was observed but glucose diffusion was not the probable mechanism of extracts antidiabetic effect. In conclusion, only INF, the traditionally used extract, has an antidiabetic potential by attenuating the death and apoptosis induced by STZ in beta-TC3 cells and increase glucose consumption. Conclusion: The present study demonstrates that only INF extract have an antidiabetic potential by attenuating the death and apoptosis induced by STZ in beta-TC3 cells and increase glucose consumption. SUMMARY: Six different extracts from P. farcta were prepared using five different solvents [ethanol, n hexane, acetone, ethanol: water (1:1 v/v), and water]The protective effect of various P. farcta extracts on cytotoxicity, mitochondrial membrane potential (MMP), and Streptozotocin-induced apoptosis in beta-TC3 cells were investigated.Infusion has an antidiabetic potential by attenuating the death and apoptosis induced by STZ in beta-TC3 cells and increase glucose consumptionThe effect of infusion extract on glucose consumption in hepatocellular carcinoma cell line cells (a) and effect of infusion extract on glucose consumption in hepatocellular carcinoma cell line cells adjusted by optical density MTT (b). Significance was calculated by analysis of variance (*P <= 0.05). MTT: 3 (4,5 dimethylthiazol 2 yl) 2,5 diphenyltetrazolium. Abbreviations used: AC: Acetone extract; ANOVA: Analysis of variance; BSA: Bovine serum albumin; beta-TC3: Mouse pancreatic beta-cells; DMEM: Dulbecco modified Eagle medium; DMSO: Dimethyl sulfoxide; ETH: Ethyl acetate extract; FBS: Fetal bovine serum; HDETH: Hydroethanolic extract; HepG2: Hepatocellular carcinoma cell line; HEX: Hexane extract; INF: Infusion; KUMS: Kermanshah University of Medical Sciences; MMP: Mitochondrial membrane potential; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium; NaCl: Natrium chloride; OD: Optical density; spp: Species; STZ: Streptozotocin; Tag: T-antigen; USA: United States of America. PMID- 29491646 TI - The Natural Compound Dansameum Reduces foam Cell Formation by Downregulating CD36 and Peroxisome Proliferator-activated Receptor-gamma; Expression. AB - Background: Atherosclerosis-induced vascular disorders are major causes of death in most western countries. During the development of atherosclerotic lesions, foam cell formation is essential and formed through the expression of CD36 and the peroxisome proliferator-activated receptor gamma (PPAR-gamma). Objective: To investigate whether dansameum extract (DSE) could show anti-atherosclerotic effect through down-regulating cellular redox state including CD36 and PARP-gamma expression in oxidative low-density lipoprotein (oxLDL)-treated RAW264.7 cells and on differentiated foam cells in ApoE Knockout (ApoE-/-) mice. Materials and Methods: The Korean polyherbal medicine DSE was prepared from three plants in the following proportions: 40 g of Salvia miltiorrhiza root, 4 g of Amomumxanthioides fruit, and 4 g of Santalum album lignum. The immunohistochemistry and reverse transcription-polymerase chain reaction was used for analysis of protein and mRNA involved in foam cell formation. Results: We first showed that effects of DSE on foam cell formation in both oxLDL-induced RAW264.7 cells and in blood vessels from apolipoprotein E deficientApoE-/- mice with high fat diet-fed. DSE treatment significantly reduced the expression of CD36 and PPAR-gamma in oxLDL-stimulated RAW264.7 cells and ApoE-/-mice, in the latter case by regulating heme oxygenase 1. Furthermore, DSE treatment also reduced cellular lipid content in vitro and in vivo experiments. Conclusion: Our data suggest that DSE may have anti atherosclerotic properties through regulating foam cell formation. SUMMARY: Dansameum extract (DSE) Regulates the expression of CD36 and peroxisome proliferator-activated receptor gamma in oxidative low-density lipoprotein stimulated RAW264.7 Cells and ApoE Knockout (ApoE Knockout [ApoE-/-]) miceDSE Regulates Cholesterol Levels in the Serum of ApoE-deficient (ApoE-/-) miceDSE Reduced the Formation of Foam Cells by Regulating heme oxygenase-1 in ApoE-/- mice with high fat diet-fed. Abbreviations used: DSE: Dansameum extract, PPAR gamma: Peroxisome proliferator-activated receptor gamma, HO-1: Heme oxygenase-1, CVD: Cardiovascular diseases. PMID- 29491645 TI - Hepatoprotective Effects of Nonpolar Extracts from Inflorescences of Thistles Cirsium vulgare and Cirsium ehrenbergii on Acute Liver Damage in Rat. AB - Background: Drugs for the treatment of liver diseases are scarce and not effective enough. Some species of the genus Cirsium possess hepatoprotective activity. There are no studies on the hepatoprotective effects of nonpolar extracts from inflorescences of thistles Cirsium vulgare and Cirsium ehrenbergii, and there are few reports on their chemical composition. Objective: The aim is to obtain the hexane extract from inflorescences of both thistles and to identify preliminarily their main chemical component, and to evaluate the hepatoprotective properties of the extracts. Materials and Methods: Hexane extracts were obtained using a Soxhlet apparatus. The chemical composition was analyzed using infrared spectra and gas chromatography-mass spectrometry. Two doses (250 and 500 mg/kg, p.o.) of both extracts were administered to assess their hepatoprotective effect on acute carbon tetrachloride (TC)-induced liver damage in rats using biochemical markers of necrosis, cholestasis, functionality, oxidative stress, and histological analysis. Results: Extracts were shown to have a very similar chemical profile. Their major constituent seems to be lupeol acetate. The two doses of both extracts demonstrated comparable hepatoprotective properties because they significantly diminished all the liver injury indicators (P < 0.05) and were corroborated using histopathology. Conclusion: This is the first study on the hepatoprotective effects of nonpolar extracts from inflorescences of thistles C. vulgare and C. ehrenbergii. Hexane extracts administration totally prevented the acute TC-induced liver damage. The preliminary chemical analysis strongly suggests the lupeol acetate as their major constituent. Lupeol and its derivatives have been previously reported as antiinflammatory and hepatoprotective agents. SUMMARY: Hexane extracts of both thistles kept normal liver functionality and glycogen store in carbon tetrachloride-induced acute liver damageHexane extracts of both thistles showed anti-necrotic and anti cholestatic effects, also diminished the lipid peroxidation and nitric oxide levels on the carbon tetrachloride-induced acute liver damageThe two doses of hexane extracts administered (250 and 500 mg/kg) prevented the liver injury in a very similar extentBoth nonpolar extracts are chemically very similar and their main compound seems to be lupeol acetate. Abbreviations used: TC: Carbon tetrachloride; FT-IR: Fourier transform Infrared spectroscopy; GC-MS: Gas chromatography - Mass spectrometry; V: Vehicle; E: Extract; Ecv: Extract of Cirsium vulgare; Ece: Extract of Cirsium ehrenbergii; AP: Alkaline phosphatase; GGTP: gamma-Glutamyl transpeptidase; ALT: Alanine aminotransferase; DB: Direct bilirubin; TB: Total bilirubin; LP: Lipid peroxidation; MDA: Malondialdehyde; NO: Nitric oxide; TNF-alpha: Tumor necrosis factor-alpha. PMID- 29491647 TI - Antioxidant Activity of the Essential Oil and its Major Terpenes of Satureja macrostema (Moc. and Sesse ex Benth.) Briq. AB - Background: The aim of this study was to investigate the in vitro antioxidant activity of Satureja macrostema (Moc. and Sesse ex Benth.) Briq. (Lamiaceae) essential oil, a Mexican medicinal plant known as nurite. Materials and Methods: Fresh aerial parts of S. macrostema plants cultivated in greenhouse for 3 months were subjected to hydrodistillation in a Clevenger apparatus to obtain essential oil. Volatile compounds were identified by gas chromatography (GC) and GC/mass spectrometry. Antioxidant effectiveness of essential oil and its major terpenes of S. macrostema was examined by three different radical scavenging methods: 2,2 diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azinobis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS), and total antioxidant capacity (TAC). The concentrations tested were 0.001, 0.01, 0.1, and 1 mg/mL. Results: The major volatile compounds were caryophyllene, limonene, linalool, pulegone, menthone, and thymol. S. macrostema essential oil showed the highest free radical scavenging activity with DPPH and ABTS methods (53.10% and 92.12%, respectively) at 1 mg/mL and 98% with TAC method at 0.1 mg/mL. Thymol exerted the highest antioxidant capacity with 0.1 mg/mL, reaching 83.38%, 96.96%, and 98.57% by DPPH, ABTS, and TAC methods. Caryophyllene, limonene, linalool, pulegone, and menthone exhibited an antioxidant capacity <25% with the DPPH and ABTS methods; however, limonene showed a TAC of 85.41% with 0.01 mg/mL. Conclusion: The essential oil of S. macrostema and thymol showed a free radical scavenging activity close to that of the synthetic butylated hydroxytoluene. SUMMARY: The major volatile compounds of essential oil of Satureja macrostema were caryophyllene, limonene, linalool, pulegone, menthone and thymolThe essential oil of S. macrostema showed a high free radical scavengingThymol exerted the highest antioxidant capacity by DPPH, ABTS and TAC methods. Abbreviations used: GC: Gas Chromatography; DPPH: 2,2 diphenyl-1-picrylhydrazyl; ABTS: 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid; TAC: Total antioxidant capacity. PMID- 29491648 TI - Simultaneous Quantification of Forskolin and Iso-Forskolin in Coleus forskohlii (Wild.) Briq. and Identification of Elite Chemotype, Collected from Eastern Ghats (India). AB - Background: Coleus forskohlii is a well-known industrially important medicinal plant, for its high forskolin content. Objective: A simple, selective, and sensitive high-performance thin layer chromatography (HPTLC) method was developed and validated for simultaneous quantification of forskolin and iso-forskolin in C. forskohlii germplasm collected from the Eastern Ghats, India. Materials and Methods: Chromatographic separation of the targeted marker(s) was obtained on precoated silica plates using toluene: ethyl acetate: methanol (90:30:0.5, v/v/v) as the mobile phase. Results: Densitometric quantification of forskolin and iso forskolin was carried out at 545 nm. Forskolin and iso-forskolin were identified by comparing the ultraviolet spectra of standard and sample track at Rf of 0.64 +/- 0.02 and 0.36 +/- 0.01, after derivatization with anisaldehyde sulfuric acid reagent. The linearity of both the analytes was obtained in the range of 300-1200 ng/spot with the regression coefficient (R2) of 0.991 and 0.986. Recovery of analyte (s) at three levels, namely, 100, 150, and 200 ng/spot was found to be 100.46% +/- 0.29%, 99.64% +/- 0.33%, 100.02% +/- 0.76% and 99.76% +/- 0.62%, 99.56% +/- 0.35%, 100.02% +/- 0.22%, respectively, for forskolin and iso forskolin. The content of forskolin and iso-forskolin varies from 0.046% to 0.187% and 0.002% to 0.077%, respectively (dry weight basis), the maximum content of both the markers was found in NBC-31, from Thakurwada, Maharashtra. Conclusion: The developed HPTLC method was linear, accurate, and reliable as per the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines. The study aids in the identification of elite chemotype for commercial prospection of industrially viable medicinal crop. SUMMARY: 12 Samples are collected from different locations of the eastern ghat regionsQuantification of two major marker forskolin and iso forskolinThe maximum content of both the markers was found in NBC -31, from Thakurwada, MaharashtraIdentification of elite chemotype of collected samples may be useful for commercial prospection in industries. PMID- 29491649 TI - Methyl Jasmonate and Salicylic Acid Enhanced the Production of Ursolic and Oleanolic Acid in Callus Cultures of Lepechinia Caulescens. AB - Background: The production of triterpenes from plants for pharmacological purposes varies in concentration, due to genetic and environmental factors. In vitro culture enables the control and increase of these bioactive molecules. Objective: To evaluate the effect of plant growth regulators and elicitors in the induction of calli and the production of ursolic acid (UA) and oleanolic acid (OA) in Lepechinia caulescens. Materials and Methods: Leaf explants were exposed for the induction of calli at different concentrations and combinations of 2,4 dichlorophenoxyacetic acid (2,4-D) and 6-benzylaminopurine (BAP). Methyl jasmonate (MJ) and salicylic acid were used as elicitors. High-performance liquid chromatography method was used to quantify UA and OA content in each treatment. Results: Treatment with 3.0 mg/L of 2,4-D and 0.1 mg/L of BAP produced the best results for calli induction and production of UA (1.57 mg/g dry weight [DW]) and OA (1.13 mg/g DW). Both elicitors facilitated the accumulation of triterpenes. Conclusion: The combination of auxins and cytokinins showed favorable results for the induction of calli. Variation concerning the accumulation of UA and OA was observed between treatments. MJ increased the production of triterpenes five times after 8 h of exposure, compared to control treatment. There is a greater accumulation of UA (16.58 mg/g DW) and OA (1.94 mg/g DW) in leaves of wild plants. SUMMARY: Callus cultures of Lepechinia caulescens were obtained from leaf explants treated with 2,4-dichlorophenoxyacetic acid and 6 bencylaminopurineResulting cultures were elicited with methyl jasmonate (MJ) and salicylic acid to increase the production of the triterpenes, ursolic acid (UA), and oleanolic acid (OA)The cultures elicited with MJ increased the production of UA and OA five times, as compared to the control. Abbreviations used: 2,4-D: 2,4 dichlorophenoxyacetic acid, BAP: 6-benzylaminopurine, DW: Dry weight, MJ: Methyl jasmonate, OA: Oleanolic acid, PGRs: Plant growth regulators, UA: Ursolic acid, SA: Salicylic acid. PMID- 29491650 TI - Liquid Chromatography Mass Spectrometry Analysis and Cytotoxicity of Asparagus adscendens Roots against Human Cancer Cell Lines. AB - Background: Asparagus adscendens Roxb. (Asparagaceae), is native to the Himalayas. This plant has been used in the prevention and effective treatment of various forms of cancers. Objective: This paper reports, for the first time, on the cytotoxicity of the methanol (MeOH) extract of the roots of A. adscendens and its solid-phase extraction (SPE) fractions against four human carcinoma cell lines and LC-ESI-QTOF-MS analysis of the SPE fractions. Materials and Methods: Finely powdered roots of A. adscendens were macerated in methanol and extracted through SPE using gradient solvent system (water: methanol) proceeded for analysis on LC-ESI-QTOF-MS and cytotoxicity against four human carcinoma cell lines: breast (MCF7), liver (HEPG2), lung (A549), and urinary bladder (EJ138), using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assay. Results: The MeOH extract and four SPE fractions exhibited cytotoxicity against all cell lines with the IC50 values ranging from 6 to 79 MUg/mL. As observed in other Asparagus species, the presence of saponins and sapogenins in the SPE fractions was evident in the liquid chromatography-mass spectrometry data. Conclusion: It is reasonable to assume that the cytotoxicity of the MeOH extract of the roots of A. adscendens and its SPE fractions, at least partly, due to the presence of saponins and their aglycones. This suggests that A. adscendens could be exploited as a potential source of cytotoxic compounds with putative anticancer potential. SUMMARY: The MeOH extract and all solid-phase extraction (SPE) fractions exhibited various levels of cytotoxicity against all cell lines with the IC50 values ranging from 6 to 79 MUg/mLThe presence of saponins and sapogenins in the SPE fractions was evident in the Liquid chromatography-mass spectrometry dataDue to the presence of saponins and their aglycones, suggest that A. adscendens could be exploited as a potential source of cytotoxic compounds with putative anticancer potential. Abbreviation used: SPE: Solid-phase extraction, MCF7: Breast cancer cell line, HEPG2: Liver cancer cell line, A549: Lung liver cancer cell line, EJ138: Urinary bladder cancer cell line, MTT: 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide, LC-MS: Liquid chromatography-mass spectrometry. PMID- 29491651 TI - Studying the Inhibitory Effect of Quercetin and Thymoquinone on Human Cytochrome P450 Enzyme Activities. AB - Background: Quercetin (QR) and thymoquinone (TQ) are herbal remedies that are currently extensively used by the general population to prevent and treat various chronic conditions. Therefore, investigating the potential of pharmacokinetic interactions caused by the concomitant use of these herbal remedies and conventional medicine is warranted to ensure patient safety. Purpose of the Study: This study was conducted to determine the inhibitory effect of QR and TQ, two commonly used remedies, on the activities of selected cytochrome P450 (CYP) enzymes that play an important role in drug metabolism and/or toxicology. Materials and Methods: The in vitro studies were conducted using fluorescence based high throughput assays using human c-DNA baculovirus expressed CYP enzymes. For measuring CYP2E1 activity, a validated High-performance liquid chromatography (HPLC) assay was utilized to measure the formation of 6-hydroxychlorzoxazone. Results: The obtained half-maximum inhibitory concentration values with known positive control inhibitors of this study were comparable to the published values indicating accurate experimental techniques. Although QR did not show any significant effect on CYP1A2 and CYP2E1, it exhibited a strong inhibitory effect against CYP2D6 and a moderate effect against CYP2C19 and CYP3A4. On the other hand, TQ demonstrated a strong and a moderate inhibitory effect against CYP3A4 and CYP2C19, respectively. Conclusions: The findings of this study may indicate that consumption of QR or TQ, in the form of food or dietary supplements, with drugs that are metabolized by CYP2C19, CYP2D6, or CYP3A4 may cause significant herb-drug interactions. SUMMARY: Neither QR nor TQ has any significant inhibitory effect on the activity of CYP1A2 or CYP2E1 enzymesBoth QR and TQ have a moderate to strong inhibitory effect on CYP3A4 activityQR has a moderate inhibitory effect on CYP2C19 and a strong inhibitory effect on CYP2D6Both QR and TQ are moderate inhibitors of the CYP2C9 activity. Abbreviations used: ABT: Aminobenztriazole, BZF: 7,8 Benzoflavone, CYP: Cytochrome P450, GB: Gingko Biloba, IC50: Half maximum inhibitory concentration, KTZ: Ketoconazole, QND: Quinidine, QR: Quercetin, TCP: Tranylcypromine, TQ: Thymoquinone. PMID- 29491652 TI - Umbilicus Reconstruction After Melanoma Excision. AB - An 81-year-old woman was admitted with a nodular cutaneous melanoma of the abdominal wall involving the umbilicus. After performing wide excision with 2 cm margin of the melanoma, umbilical reconstruction and defect closure were planned. After careful consideration, we decided to use an island pedicle flap which allowed closure of the defect and reconstruction of the umbilicus. PMID- 29491653 TI - Standard Guidelines of Care: Performing Procedures in Patients on or Recently Administered with Isotretinoin. AB - Background: Currently, the standard protocol regarding the performance of procedures on patients receiving or having recently received isotretinoin (13-cis retinoic acid) states that the procedures should not be performed. The recommendations in standard books and drug insert require discontinuation of isotretinoin for 6 months before performing cosmetic procedures, including waxing, dermabrasion, chemical peels, laser procedures, or incisional and excisional cold-steel surgery. These recommendations have been followed for over two decades despite little evidence for the stated increased risk of scarring. Objective: The Association of Cutaneous Surgeons (I) constituted a task force to review the evidence and to recommend consensus guidelines regarding the safety of skin procedures, including resurfacing, energy-device treatments, and dermatosurgical procedures in patients with concurrent or recent isotretinoin administration. Materials and Methods: Data were extracted from the literature through a PubMed search using the keywords "isotretinoin," "safety," "scarring," "keloids," "hypertrophic scarring," and "pigmentation." The evidence was then labeled and circulated to all members of task force for review. Results: The task force is of the opinion that there is insufficient evidence to support the current protocol of avoiding and delaying treatments in the patient group under consideration and recommends that the current practice should be discontinued. The task force concludes that performing procedures such as laser hair removal, fractional lasers for aging and acne scarring, lasers for pigmented skin lesions, fractional radio-frequency microneedling, superficial and medium-depth peels, microdermabrasion, dermaroller, biopsies, radio-frequency ablation, and superficial excisions is safe in patients with concurrent or recent isotretinoin administration. PMID- 29491654 TI - Decoding Facial Esthetics to Recreate an Esthetic Hairline: A Method Which Includes Forehead Curvature. AB - Context: The evidence suggests that our perception of physical beauty is based on how closely the features of one's face reflect phi (the golden ratio) in their proportions. By that extension, it must certainly be possible to use a mathematical parameter to design an anterior hairline in all faces. Aim: To establish a user-friendly method to design an anterior hairline in cases of male pattern alopecia. Materials and Methods: We need a flexible measuring tape and skin marker. A reference point A (glabella) is taken in between eyebrows. Mark point E, near the lateral canthus, 8 cm horizontal on either side from the central point A. A mid-frontal point (point B) is marked 8 cm from point A on the forehead in a mid-vertical plane. The frontotemporal points (C and C') are marked on the frontotemporal area, 8 cm in a horizontal plane from point B and 8 cm in a vertical plane from point E. The temporal peak points (D and D') are marked on the line joining the frontotemporal point C to the lateral canthus point E, slightly more than halfway toward lateral canthus, usually 5 cm from the frontotemporal point C. This line makes an anterior border of the temporal triangle. Result: We have conducted a study with 431 cases of male pattern alopecia. The average distance of the mid-frontal point from glabella was 7.9 cm. The patient satisfaction reported was 94.7%. Conclusion: Our method gives a skeletal frame of the anterior hairline with minimal criteria, with no need of visual imagination and experience of the surgeon. It automatically takes care of the curvature of the forehead and is easy to use for a novice surgeon. PMID- 29491655 TI - Follicular Unit Grafting in Chronic Nonhealing Leg Ulcers: A Clinical Study. AB - Introduction and Objectives: The restoration of the epithelium after injury takes place by migration of epithelial cells adjoining a wound or by centrifugal migration from hair follicles. To evaluate the feasibility and potential healing capacity of scalp follicular unit grafts transplanted into the wound bed of chronic leg ulcers. Materials and Methods: Patients with chronic nonhealing ulcers of more than 6 weeks duration were selected for the study. Those with infected ulcers and uncontrolled diabetes were excluded from the study. Fifteen patients were included in the study. Follicular unit grafts were harvested under local anesthesia using small-diameter (1 mm) circular punches. A density of 5 follicular grafts/cm2 was implanted into the ulcer bed. The ulcer was dressed with Vaseline gauze and elastic bandage for 24 h. The wound area and volume were calculated by length * width * 0.7854 and length * width * depth * 0.7854, respectively. The treatment outcome was defined as the percentage in change of area and volume of the ulcer, 18 weeks after intervention. Results: A total of 15 patients with 17 ulcers were treated with the above method. Of these 17 ulcers, 11 were venous ulcers, 2 were pyoderma gangrenosum associated with varicose veins, 2 were traumatic ulcers, and 2 were trophic ulcers. The baseline mean area of the ulcer was 6.72 cm2 (SD 5.65) and baseline volume was 2.87 cm3 (SD 2.9). The final area of the ulcer at the end of 18 weeks after the procedure was 3.84 cm2 (SD 5.43) and the final volume was 1.21 cm3 (SD 2.45), which was statistically significant. The mean percentage improvement in the area and volume of the ulcer was 48.8% and 71.98%, respectively. Two patients did not respond to the treatment. There were no adverse events after the procedure. Conclusion: We conclude that follicular unit grafting into wound beds is feasible and represents a promising therapeutic alternative for managing nonhealing chronic leg ulcers. PMID- 29491656 TI - Safety and Early Satisfaction Assessment of Patients Seeking Nonsurgical Rhinoplasty with Filler. AB - Background: Nonsurgical aesthetic treatments are usually preferred by patients because their effects are visible immediately after the treatment and patients can return to their normal activities on the same day. Although many studies have indicated safety and efficacy of filler injection to improve facial appearance, it is not absolutely confirmed for nose reshaping. Objectives: To assess the safety and early satisfaction of 52 consecutive patients underwent nonsurgical rhinoplasty with an injection of a 20-mg/mL smooth, cohesive, and viscous hyaluronic acid (HA) filler. Materials and Methods: Fifty-two consecutive healthy patients, dissatisfied with the appearance of their nose, were treated with HA injections between November 2014 and November 2016. Complications and side effects were documented. Aesthetic outcomes were scored subjectively on a scale of 1-4 represented by four emoticons. Results: Among patients, 96.15% affirmed to be "very satisfied" at the end of the procedure (50 patients over 52 treated). No major complications and side effects occurred. Conclusions: Outcomes of this study, with the limitation of a non-comparative open-label study, show that surgical remodeling of the nose, with the use of a 20-mg/mL smooth, cohesive, and viscous HA filler, is a safe and predictable technique, with a high degree of satisfaction for the patients. PMID- 29491657 TI - Langerhans Cell Histiocytosis - A Challenge for the Dental Professional. AB - Langerhans cell histiocytosis (LCH) is a group of rare disorders histologically characterized by the proliferation of LC, involving multiple organs and systems. Typically, there is bone involvement and, less frequently, lesions may be found in the lungs, liver, lymph nodes, skin, and mucosae. Oral soft tissue lesions without bone involvement are rare. Antigenic markers that react with CD1a glycoprotein, cytoplasmatic protein S100 detected by immunoperoxidase staining, and/or presence of Birbeck granules on electron microscopic examination are required for a definitive diagnosis of LCH. In this article, we report a case of LCH, which had presented with multiple oral lesions without any other systemic signs and symptoms. Management of such children with periodontal manifestations should include hematological and, if possible, immunological investigations at an early stage. Careful clinical examination, good diagnostic skill, and awareness of characteristic cytological features of LCH can lead to earlier diagnosis and treatment with minimal deformity. PMID- 29491658 TI - Lip Repositioning: A Boon in Smile Enhancement. AB - This clinical report describes the successful use of lip repositioning technique for the reduction of excessive gingival display. The lip repositioning technique was performed with the main objective of reducing gummy smile by limiting the retraction of elevator muscles (e.g., zygomaticus minor, levator anguli, orbicularis oris, and levator labii superioris). This technique includes removing a strip of mucosa from the maxillary buccal vestibule, creating a partial thickness flap between mucogingival junction and upper lip musculature, and suturing the lip mucosa with mucogingival junction, resulting in a narrow vestibule and restricted muscle pull, thereby reducing gingival display. PMID- 29491659 TI - Multiple Asymptomatic Juxta-Articular Nodules Mimicking Tuberous-Xanthoma-A Unusual Presentation of Tophaceous Gout. AB - Asymptomatic, juxta-articular nodules are an uncommon morphology, which is usually diagnosed as xanthomas, calcinosis cutis or rheumatoid nodules. This study was represented as a case of gout, which is a disorder of purine metabolism resulting in elevation of serum uric acid and deposition of monosodium urate crystals within and around joints and manifests clinically as inflammatory arthritis. Urate crystal deposits have also been found in tendons, ligaments, viscera, and the skin, with the term "tophi" being used for the non-articular deposits. In the chronic stage, the lesion can be asymptomatic lesions and is often misdiagnosed. PMID- 29491660 TI - Clearance of Recalcitrant Onychomycosis Following Q-switched Nd-Yag Laser. PMID- 29491661 TI - Thread Lift in Breast Ptosis. PMID- 29491662 TI - Radiofrequency-Assisted Body Piercing. AB - The art of body piercing is ancient; however, nowadays it has evolved into a fashion statement. In the Indian subcontinent, ear and nose piercing hold religious and cultural significance in addition to being done for aesthetic reasons. Body piercing is routinely performed by railroading technique or by piercing guns; many modifications of the technique have emerged. Irrespective of the technique used, the main complications associated are intraoperative bleeding and postoperative infection. To overcome these problems, we describe a novel and simple technique of ear and nose piercing using the radio frequency cautery. PMID- 29491663 TI - My Experience with the ACSI Fellowship Program at CUTIS Institute of Dermatology. PMID- 29491664 TI - Plagiarism: An issue of concern. PMID- 29491665 TI - The rights of patients as consumers: An ancient view. AB - As far as the rights of consumers are concerned, the International Organization of Consumer's Union (IOCU) in 1983 has specified about the eight rights of a consumer. The Consumer Protection Act (CPA), 1986 then prescribed six "Rights of Consumers," which are protected under the act. However, these rights can be observed in the ancient Indian texts such as Brihat-trayee, Narad Smruti, and Kautilya Arthashastra., in the form of rights given to patients. For the purpose of present study, the implemented methodology includes - (1) study of the consumer rights described by IOCU and CPA, (2) detailed review of literature for observance of replication of these consumer rights in the ancient Indian texts and (3) a comparative study of the present consumer rights with the rights of patients observed in ancient Indian texts. This study shows that the substance of consumer rights is not a recent evolution, but the foundation of these rights has been laid well beforehand in the ancient times, which were provided to the patients by medical profession as well as by the rulers. The current scenario of protection of consumer rights is the replication of this ancient practice only. PMID- 29491666 TI - Tantraguna - The ancient criteria for scientific writing. AB - The scientific paper has been developed over the past three centuries into a tool to communicate the results of scientific inquiry. Scientific writing must have of a high standard because it is related with the process of gaining knowledge for the learned as well as new learners. In ancient era, specific writing methodology was adopted by the scientists to prepare standard and highly-scientific manuscripts in the field. Tools such as Tantrayukti (techniques for writing/decoding treatise), Tachchhilya (inclinations), Kalpana (compositions), etc., have been described in the classics to maintain the quality standards of scientific literature. Due to well-established writing methods, scientific literatures such as Samhita (Ayurvedic texts), Samgraha-grantha (compendia), Nighantu (lexicons), etc., were written uniformly and good quality literature was generated. The characteristics of good scientific writing for Shastra (treatise) have been described in the Vimanasthana of Charaka Samhita which is known as Tantraguna. The Tantraguna covers the key points of the writing such as language, order, length, method, etc. After reviewing and analyzing these Tantraguna, it can be concluded that the ancient writing method can be compared with some aspect to current introduction, methods, results and discussion structure of scientific writing. This analysis may help to empower and strengthen the current standards of scientific writing by editing new aspects of ancient writing method. PMID- 29491667 TI - Ayurvedic preparations for the management of Iron Deficiency Anemia: A systematic review. AB - Iron deficiency anemia (IDA) is a global public health crisis, so also in India. As per the World Health Organization's report, half of the total anemia is IDA. Ayurveda offers several formulations for the management of IDA. Given in this context, a systematic review was carried out to understand the role of Ayurvedic formulations for the management of IDA. For this purpose, articles were obtained from PubMed and through hand search process. Of the 37 articles identified, 10 articles were finally selected for the review. Of the 10 studies identified, 3 studies were (n = 10) exclusively focused on pregnant women, 2 studies (n = 10) were exclusively focused on pediatric age group, 1 study (n = 10) was exclusively focused on geriatric anemia and 4 studies (n = 10) were focused on general population. The response of most of the Ayurvedic formulations was better than Allopathic formulations and there was no untoward effect as observed with iron salts. Statistically significant results were obtained in favor of most of the Ayurvedic formulations in subjective and hematological parameters. Among six different formulations, Sarva-Jvara-Hara Lauha is suggested as the drug of choice for IDA as the Hb regeneration with this drug is highest- 0.16 g/dl/day, as reported by one of the studies. In addition, Punarnavadi Mandura is currently used as an anemia correcting agent at the community level promoted by the National Rural Health Mission and is included in the Accredited Social Health Activist's drugs kit. As most of these Ayurvedic formulations are found effective against IDA, their usage should be fostered at all level in addition to modern allopathic medicines. PMID- 29491668 TI - Effect of Vishamashana on health: A survey study. AB - Introduction: Ayurveda has a novel concept of Vishamashana. Vishamashana means taking food irregularly or without following a particular time. Aims: In the present era, due to the competitiveness in each and every field of life, today's individual does not get sufficient time for taking food and to maintain its quantity and quality. Vishamashana became a very common habit and trend in the modern developed era. As per the Ayurvedic Siddhanta, Vishamashana aggravates all the three Doshas and it is also said to be an important cause of vitiating the Agni. Hence, present survay was conducted to assess the effect of Vishamashana on health. Material and Methods: survey study has been done on 100 persons having habit of Vishamashana. Persons were divided into two groups: Group A for volunteers and Group B for patients. A special proforma was prepared for the assessment of health status based on Swastha Lakshanas of Charaka Samhita and Kashyapa Samhita. Results: In the survey study, majority of patients of Group B were found to have Avara health status and Group A had Madhyama health Status. PMID- 29491669 TI - Lifestyle related factors associated with Sthaulya (obesity) - A cross-sectional survey study. AB - Introduction: The burden of lifestyle disorders is rapidly increasing worldwide. Modernization, affluence, science and technological development lead to still more sedentary life styles. By exposing oneself to all these factors human being unknowingly invited a number of diseases, out of which Sthaulya (obesity) is one which disturbs physical, mental and social health of an individual. Aims and Objectives: To identify the main lifestyle related Aharatmaka (dietary factors), Viharatmaka (physical activities) and Manasika (psychological) factors associated with Sthaulya (obesity) among the patient aged in between 20-60 years. Material and Methods: Cross-sectional survey study was done among 250 patients of Sthaulya (obesity) visiting outpatient department of the Institute from the period May 2013 to June 2014. The patients were selected using simple random sampling method. Ethical clearance was obtained from the Institute and Lifestyle related questionnaire was used for survey study which was based on the etiological factors mentioned in the Ayurvedic classics. Observations and Conclusions: The survey study revealed that intake of Guru and Snigdha Ahara (heavy fatty food), Avyayama (lack of involvement in physical activities), Divasvapna (day sleep) and psychological distress are the main lifestyle related factors strongly associated with the Sthaulya (Obesity). PMID- 29491670 TI - Effect of Ekakala Bhojana in patients of Agnimandya. AB - Background: Though Sushruta Samhita is considered as the chief surgical treatise, Maharshi Sushruta has also emphasized on the preventive and curative aspects of diet. Dwadasha Ashana Pravichara is one of the unique concepts of Sushruta Samhita which can be considered as the root of diet therapy. In Dwadasha Ashana Pravichara, diet pattern is described for both healthy and diseased people. Aim: This study aimed to assess the effect of Ekakala Bhojana in Agnimandya patients. Materials and Methods: Patients fulfilling the criteria of selection were selected for the present study and were divided into two groups using simple random sampling method. Patients were treated for 10 days. The patients in Group A were treated with Trikatu tablet and those in Group B were given Ekakala Bhojana and placebo tablet. Effect of therapy was assessed on the basis of Abhyavaharana and Jarana Shakti. Results: Group B (Ekakala Bhojana) shows better results than Group A in the parameters of Abhyavaharana and Jarana Shakti except in Udgarashuddhi. Group B (65.19%) shows better result in Ahara shakti than that of Group A (55.76%). Conclusion: Agnimadya may be treated at primary level without the use of any medicine and only by reducing frequency of meal to Ekakala Bhojana. PMID- 29491671 TI - Evaluation of the effect of Kanchnara Guggulu and Tankana-Madhu Pratisarana in the management of Tundikeri (tonsillitis) in children. AB - Introduction: Tonsillitis is a common illness in the childhood period. There are about 7,455,494 cases of tonsillitis in India per year. Tonsillitis can be compared with Tundikeri in Ayurveda. In the present study, Kanchnara Guggulu tablets and Pratisarana of Tankana-Madhu were selected. Aim: To evaluate the effect of Kanchnar Guggulu and Tankana-Madhu Pratisarana in the management of Tundikeri in children. Materials and Methods: In the present study, a total of 31 patients aged between 5 and 16 years attending the outpatient department of Kaumarbhritya Department and Shalakya Tantra Department were registered. Among them, 26 patients completed the treatment. Kanchnara Guggulu tablets were administered orally in Group A and in Group B, Pratisarana with Tankana-Madhu was done along with the oral administration of Kanchnara Guggulu tablets. Results: The results showed that in Group A, 21.43% of patients got complete remission, 42.86% of patients got marked improvement and 35.71% of patients got moderate improvement. In Group B, 25% of patients got complete remission, 58.33% of patients got marked improvement and 16.67% of patients got moderate improvement. Conclusion: Both the groups showed highly significant results in all cardinal and associated features of Tundikeri. Kanchnara Guggulu and Tankana-Madhu Pratisarana are a safe and effective modality for the treatment of Tundikeri. PMID- 29491672 TI - Evaluation of Gandhakadi Yoga as an adjuvant therapy in the management of Beejadushtijanya Pandu (thalassemia major). AB - Introduction: Thalassemia major is a malignant type of genetic disorder and iron overload is the main complication of the disease which results due to frequent blood transfusions. Gandhakadi Yoga has been proved effective against iron overload in experimental studies and pilot voluntary study, hence, taken for clinical evaluation in the present study. Aim: The aim of this study is to evaluate the efficacy of Gandhakadi Yoga as an adjuvant therapy in the management of thalassemia major. Materials and Methods: A total of 46 patients of age group 2-12 years were registered and randomly divided into two groups. Group A (trial group-Gandhakadi Yoga with blood transfision (BT)) and Group B (control Group with BT and iron chelation therapy). The assessment was done based on the subjective and objective parameters after12 weeks of treatment, with a follow-up of 12 weeks. The data obtained in clinical study was analyzed using Student's "t" test. Results: Trial drug provided highly significant result (P < 0.001) in most of the subjective parameters and BT interval was prolonged. In Group A, the maximum improvement was found in three patients (13.04%); moderate improvement in 15 patients (65.22%) and mild improvement in five patients (21.74%). No adverse drug reaction was reported during the clinical study. Conclusion: Gandhakadi Yoga provided better results than control in subjective and objective parameters, BT interval and general health status, hence, has an effective role as an adjuvant in the management of thalassemia major. PMID- 29491673 TI - Clinical validation of efficacy and safety of herbal cough formulation "Honitus syrup" for symptomatic relief of acute non-productive cough and throat irritation. AB - Background: Acute cough represents the most common illness evaluated in the outpatient settings. Available remedies for its management are generally allopathic combinations of antihistamines and decongestants that achieve antitussive activity, but often with unpleasant side effects prompting the need to explore safer and effective options. Honitus is an Ayurvedic proprietary herbal cough syrup with benefits of honey, intended to provide relief in acute nonproductive cough and throat irritation without causing drowsiness. This study investigated the safety and efficacy of Honitus in reducing acute nonproductive cough and throat irritation in comparison to a standard marketed allopathic cough syrup intended for use in similar conditions. Materials and Methods: This was a randomized double-blind study conducted in 105 individuals who received orally 2 tsp (10 ml) of either Honitus or marketed cough syrup (MCS) four times a day for 3 days. Response to treatment was evaluated from baseline to the end of treatment period on the basis of changes in day and night frequencies of cough, throat irritation and development of adverse events (AEs). Results: Honitus was found safe and effective in reducing symptoms of acute nonproductive cough, throat irritation, and comparable to MCS in reducing day and night frequencies of cough, the time to relief from cough and throat irritation and the Physician's Global Assessment of cough. Honitus showed comparably better results than MCS on throat irritation, the duration of relief from cough and throat irritation without causing drowsiness. No AEs related to study or study products were reported. Conclusion: Honitus Syrup is safe and effective in reducing the symptoms of acute nonproductive cough and throat irritation without causing drowsiness. PMID- 29491674 TI - Manasa prakrti inventory": A pilot survey study based tool to evaluate personality. AB - Background: Science is not a mere conglomeration of facts, but the systematic arrangement of facts ascertained through observations and interpretations. Surveys are based on observation which helps in the comprehensive examination of an area or population for a particular purpose. Surveys help in the evaluation and revalidation of existing facts or principles and also in finding out new facts. Ayurveda, the time-tested medical system of India also expanded the horizon of its knowledge by means of keen observation and surveys. Ayurveda visualizes health and disease through a psychosomatic approach. Dosa prakrti mentioned in Ayurveda incorporates both somatic as well as psychic features. Thus, it represents the total psychosomatic constitution of the person. Besides, physical, sensual, intellectual, or moral characteristics and attributes can be understood under the broad heading of Triguna. Ayurveda has elaborated the psychic dispositions of a person based on Manasa prakrti. Hence, each and every person has all the three qualities of mind all the time, but there is a relative variation of these in different persons and this determines the three separate Manasa prakrti, namely, Satvika, Rajasika, and Tamasika which is also known as Mahaprakrti. Aim: This article aims at an overview on the formation of an inventory for the gross assessment of Manasa prakrti. Methods and Materials: Initially Manasa prakrti inventory comprising of fifty statements has been developed based on literature. The inventory was later subjected for face validation method. There after it was used for pilot survey study. Results: One hundred volunteers were easily categorized under Satva- Rajasadhika (32%), Rajasa Tamasadhika (24%), Satva- Tamasadhika (24%), Rajasadhika (18%), Tamasadhika (4%) and Satvika Prakrti (2%). Conclusion: Hence, this Manasa prakrti inventory was effective as an effective applicable test to assess psychic disposition of an individual. PMID- 29491675 TI - Experimental and histopathological observation scoring methods for evaluation of wound healing properties of Jatyadi Ghrita. AB - Introduction: Jatyadi ghrita is a classical Ayurvedic formulation indicated in the treatment of various types of ulcers. Aim: The study was designed to explore the wound healing properties of Jatyadi Ghrita in diabetes - induced rats. Materials and Methods: In the present study, diabetes mellitus was induced to 6 to 8-week-old male Wistar rats by injecting streptozotocin cut 65 mg/kg body weight intravenously by 15 min prior to the administration of Nicotinamide at 230 mg/kg body weight intraperitoneally. Animals having diabetes were used for grouping namely, diabetic control (DC), Ghrita control (GC), positive control (PC), i.e., mupirocin HCl, Jatyadi Ghrita treatment and one group of non-DC. Full thickness excision wound was created and diameter was recorded. Daily clinical observations were recorded. A wound scoring method was developed. Wound diameter and score were recorded on days 1, 2, 3, 5, 7, 9, 12, 14 and 15. Photographs were taken at the same time interval points. Body weight and feed consumption were recorded weekly. Animals were sacrificed at regular intervals to collect the wound area tissue for histopathology analysis. Obtained data was analyzed statistically. Results and Observation: It was observed that there was no significant difference in diameter and percent change in wound healing as compared to any control. However, clinical score and histopathological changes in Jatyadi Ghrita group were improved from the second day of the study as compared to control. Conclusion: This indicates that the drug has similar wound healing activity as compared to the modern drug mupirocin HCl. PMID- 29491676 TI - Physicochemical characterization of Shadguna Balijarita Makaradhwaja: A preliminary study. AB - Background: Makaradhwaja, a herbomineral preparation, is a popular aphrodisiac and rejuvenator in traditional medicine. It is prepared from purified gold, mercury, and sulphur in different proportions by the application of gradually increasing heat in modified electrical muffle furnace (Valuka Yantra). To find out major and minor trace elements and structural composition of Makaradhwaja, its chemical characterization is needed. Aim: This study aims to develop preliminary physicochemical profile of Shadguna Balijarita Makaradhwaja (SBM). Materials and Methods: Physicochemical characterization of Shadguna Balijarita Makaradhwaja was carried out by adopting various techniques, viz. X-ray diffraction, inductively coupled plasma optical emission spectrometry (ICP-OES), and Fourier transform infrared spectroscopy to determine structure and contents. Results and Conclusion: Shadguna Balijarita Makaradhwaja contains 12131 ppm of gold in inductively coupled plasma optical emission spectrometry study. FTIR study revealed few organic compounds. Structurally, it is a mercuric sulfide having an empirical formula HgS. PMID- 29491677 TI - Acute toxicity and antihyperlipidemic activity of rhizome of Tectaria coadunata (Kukkutnakhi): A folklore herb. AB - Background: Tectaria coadunata (Wall. Ex Hook and Grev.) C. Chr (Kukkutnakhi) is a pteridophyte fern which is found in Western Ghats, Kerala Ghats, and Mahendragiri forest region. It is used by many Vaidyas in hyperlipidemic conditions and obesity. Aim: This study aimed to evaluate the acute toxicity and antihyperlipidemic activity of T. coadunata in experimental animals. Materials and Methods: Oral acute toxicity study was carried out in female Wistar rats as per OECD 425 guideline. Antihyperlipidemic activity of powder of T. coadunata (540 mg/kg) was carried out in high-fat diet-induced hyperlipidemia in Wistar albino rats. Results: T. coadunata rhizome powder at the dose of 2000 mg/kg did not produce any mortality and toxic effects during acute toxicity study in female rats. Test drug produced highly significant (P < 0.001) reversal in the triglycerides and very-low-density lipoprotein (VLDL)-cholesterol along with nonsignificant decrease in the cholesterol level in rats fed with hyperlipidemic diet. Further, T. coadunata has shown nonsignificant decrease in serum urea, serum glutamic pyruvic transaminase, alkaline phosphatase, and bilirubin direct while statistically significant decrease in bilirubin total in comparison to cholesterol control group. Histopathological study has shown reversal of adverse changes induced by hyperlipidemic diet in heart, liver, and kidney. Conclusion: It is concluded that drug is safe up to the dose level of 2000 mg/kg in rats. Rhizome of T. coadunata has shown antihyperlipidemic activity in rats, which suggest its potential role in hyperlipidemia and associated conditions. PMID- 29491678 TI - Phytochemical, pharmacological evaluation of Morinda pubescens J.E.Sm. bark extract for nephroprotective activity. AB - Background: Morinda pubescens J.E.Sm. (Rubiaceae) is an important medicinal plant used in indigenous system of medicine i.e., Ayurveda, Siddha and Unani. Objective: The aim of this study is to evaluate the nephroprotective effect of M. pubescens in gentamicin induced acute renal failure in rats. Methods: Nephrotoxicity was induced in male Wistar rats by administration of gentamicin (100 mg/kg, i.p.) once daily for 10 days. Simultaneously, the treatment was conducted with water extract bark of M. pubescens (200 mg/kg, p.o.) and its ethyl acetate fractions (100 mg/kg, p.o.) once daily for ten days. Silymarin (50 mg/kg, p.o.) is used as standard drug. Using renal biochemical markers creatinine, urea, uric acid, BUN, albumin, protein, and other parameters are kidney weight, body weight, urine volume and histopathology of the kidney. Statistical analysis was performed by using one - way ANOVA followed by Dunnett's test. Results: It was observed that the water extract and its ethyl acetate fractions bark of M. pubescens has brought back the altered levels of biochemical markers and other parameters to the near normal levels. Histopathological study revealed treatment groups also shows the normal texture of kidney. Conclusions: The present study possessed nephroprotective activity but ethyl acetate fraction was found to exhibit greater nephroprotective activity than the water extract. PMID- 29491679 TI - An ayurvedic proprietary herbal preparation, Calci-7, prevents ovariectomy induced osteoporosis in rats. AB - Introduction: CALCI-7 (CA) is an ayurvedic proprietary medicine, used to treat osteoporosis in postmenopausal women. However, scientific proof for its anti osteoporotic effect and mechanism of action remain unclear due to which present study was under taken. Materials and Methods: Ovariectomy was performed to induce osteoporosis. Rats were given CA 100 mg/kg, p.o. and estrogen 0.0563 mg/kg, i.m. once a day from day 1 to day 42. Animals were weighed weekly for body weight variation. At the end of 42 days treatment, urine and the blood samples were collected for analysis of calcium, phosphorus and alkaline phosphatase. Immediately, after sample collection, the uterus was carefully removed and weighed. Results were analysed using ANOVA. Results: CA treatment to ovariectyomized (OVX) rats showed significant improvement in body weight, increased levels of calcium and phosphorus levels in serum while levels were found to be decreased in urine as compared to OVX group. The significant increase in uterine weight and femur length were observed in treatment groups. In the histopathological examination bone structure showed a normal structure with lacuna and various lamellae without any damage or porosity in bone in the formulation and estrogen-treated group. Conclusion: The present findings are strongly suggestive that CA possesses comparable efficacy to estrogen and thus can be useful in the postmenopausal osteoporosis. PMID- 29491680 TI - Evaluation of antitussive and anti-asthmatic activity of Tabernaemontana divaricata(L.) R. Br. Ex Roem. and Schult. AB - Background: The study was aimed to investigate the antitussive and anti-asthmatic activities of ethanolic extract of Tabernaemontana divaricata (TDEE) leaves by in vivo and in vitro models. Recently, indole alkaloids (monoterpenoid indole alkaloids) have been approved as investigational new drug for clinical trial in respiratory diseases, and T. divaricata has already proven its potential for the presence of indole alkaloids. Materials and Methods: Acute toxicity studies of TDEE were performed in accordance with the Organization for Economic Cooperation and Development guidelines no. 425. The sensitized guinea pigs were screened out and divided into control, standard, and TDEE-treated groups. Anti-asthmatic activity of TDEE was assessed by in vitro guinea pig tracheal chain method and in vivo bronchoprotective test method using aminophylline as a standard drug. Taken codeine as standard, antitussive activity was evaluated by in vivo citric acid induced tussive response. Results: TDEE was found to be safe up to 2000 mg/kg, body weight. TDEE exhibits maximum bronchi relaxation of 91.66% and 92.83% against acetylcholine and histamine-induced contraction, respectively. TDEE exhibited maximum and significant (P < 0.001) bronchoprotection of 42.28% at the dose level of 200 mg/kg, body weight. TDEE at aerosolic dose of 6% (w/v) exhibited decreased average cough frequency (4.83 +/- 0.30) which is quite significant (P < 0.001) and effective as compared to standard drug codeine. Based on the histopathological evidences, TDEE-treated groups showed reduced inflammatory cell infiltration and had restored epithelial damage. Conclusion: The results of the study revealed the potent antitussive and anti-asthmatic activities of T. divaricata, which support its further implication for the treatment of cough-associated complications such as cough variant asthma. PMID- 29491681 TI - Regulation of the intestinal immune system by flavonoids and its utility in chronic inflammatory bowel disease. AB - Flavonoids are phytochemicals which can regulate the activity of the intestinal immune system. In patients with chronic inflammatory bowel disease (IBD) there is an overexpression and imbalance of the components of the inflammatory immune reactions which are chronically activated. Suppression of inflammation can be achieved by anti-inflammatory drugs which are used in clinical medicine but these can cause serious side effects. Flavonoids can have natural immunosuppressive properties and inhibit the activation of immune cells and its effectors (chemokines, TNF-, cytokines). Phytochemicals such as flavonoids bind to the nuclear Ah (aryl hydrocarbon) -receptor thereby stimulating protective enzyme activities. As shown by clinical evidence in patients and by experimental work some flavonoids (apigenin, epigallocatechin gallate) were effective in the inhibition of inflammation. Instead of or additionally to anti-inflammatory drugs flavonoids can be used in IBD patients to treat the over-reactive immunologic system. This is accomplished by upregulation of the Ah-receptor. Flavonoids interact with toll-like receptors expressing on the surface of immune cells, then they were internalized to the cytosol and transferred into the nucleus, where they were attached to the Ah-receptor. The Ah-receptor binds to the Ah-R nuclear translocator and via Ah response element beneficial protective enzymes and cytokines are induced, leading to upregulation of the anti-inflammatory system. PMID- 29491682 TI - Relaxin influences ileal muscular activity through a dual signaling pathway in mice. AB - AIM: To investigate the signaling pathways involved in the relaxin (RLX) effects on ileal preparations from mice through mechanical and electrophysiological experiments. METHODS: For mechanical experiments, ileal preparations from female mice were mounted in organ baths containing Krebs-Henseleit solution. The mechanical activity was recorded via force-displacement transducers, which were coupled to a polygraph for continuous recording of isometric tension. Electrophysiological measurements were performed in current- and voltage-clamp conditions by a microelectrode inserted in a single smooth muscle cell (SMC) of the ileal longitudinal layer. Both the membrane passive properties and inward voltage-dependent L-type Ca2+ currents were recorded using suitable solutions and voltage stimulation protocols. RESULTS: Mechanical experiments showed that RLX induced a decay of the basal tension and a reduction in amplitude of the spontaneous contractions. The effects of RLX were partially reduced by 1H [1,2,4]oxadiazolo[4,3-a]-quinoxalin-1-one (ODQ) or 9-cyclopentyladenine mesylate (9CPA), inhibitors of guanylate cyclase (GC) and adenylate cyclase (AC), respectively, and were abolished in the concomitant presence of both drugs. Electrophysiological experiments demonstrated that RLX directly influenced the biophysical properties of ileal SMCs, decreasing the membrane conductance, hyperpolarizing the resting membrane potential, reducing the L-type calcium current amplitude and affecting its kinetics. The voltage dependence of the current activation and inactivation time constant was significantly speeded by RLX. Each electrophysiological effect of RLX was reduced by ODQ or 9CPA, and abolished in the concomitant presence of both drugs as observed in mechanical experiments. CONCLUSION: Our new findings demonstrate that RLX influences ileal muscle through a dual mechanism involving both GC and AC. PMID- 29491683 TI - Gas chromatography/mass spectrometry based metabolomic study in a murine model of irritable bowel syndrome. AB - AIM: To study the role of microbial metabolites in the modulation of biochemical and physiological processes in irritable bowel syndrome (IBS). METHODS: In the current study, using a metabolomic approach, we analyzed the key metabolites differentially excreted in the feces of control mice and mice with IBS, with or without Clostridium butyricum (C. butyricum) treatment. C57BL/6 mice were divided into control, IBS, and IBS + C. butyricum groups. In the IBS and IBS + C. butyricum groups, the mice were subjected to water avoidance stress (WAS) for 1 h/d for ten days. Gas chromatography/mass spectrometry (GC-MS) together with multivariate analysis was employed to compare the fecal samples between groups. RESULTS: WAS exposure established an appropriate model of IBS in mice, with symptoms of visceral hyperalgesia and diarrhea. The differences in the metabolite profiles between the control group and IBS group significantly changed with the progression of IBS (days 0, 5, 10, and 17). A total of 14 differentially excreted metabolites were identified between the control and IBS groups, and phenylethylamine was a major metabolite induced by stress. In addition, phenylalanine metabolism was found to be the most relevant metabolic pathway. Between the IBS group and IBS + C. butyricum group, 10 differentially excreted metabolites were identified. Among these, pantothenate and coenzyme A (CoA) biosynthesis metabolites, as well as steroid hormone biosynthesis metabolites were identified as significantly relevant metabolic pathways. CONCLUSION: The metabolic profile of IBS mice is significantly altered compared to control mice. Supplementation with C. butyricum to IBS mice may provide a considerable benefit by modulating host metabolism. PMID- 29491684 TI - Colonoscopy surveillance for high risk polyps does not always prevent colorectal cancer. AB - AIM: To determine the frequency and risk factors for colorectal cancer (CRC) development among individuals with resected advanced adenoma (AA)/traditional serrated adenoma (TSA)/advanced sessile serrated adenoma (ASSA). METHODS: Data was collected from medical records of 14663 subjects found to have AA, TSA, or ASSA at screening or surveillance colonoscopy. Patients with inflammatory bowel disease or known genetic predisposition for CRC were excluded from the study. Factors associated with CRC developing after endoscopic management of high risk polyps were calculated in 4610 such patients who had at least one surveillance colonoscopy within 10 years following the original polypectomy of the incident advanced polyp. RESULTS: 84/4610 (1.8%) patients developed CRC at the polypectomy site within a median of 4.2 years (mean 4.89 years), and 1.2% (54/4610) developed CRC in a region distinct from the AA/TSA/ASSA resection site within a median of 5.1 years (mean 6.67 years). Approximately, 30% (25/84) of patients who developed CRC at the AA/TSA/ASSA site and 27.8% (15/54) of patients who developed CRC at another site had colonoscopy at recommended surveillance intervals. Increasing age; polyp size; male sex; right-sided location; high degree of dysplasia; higher number of polyps resected; and piecemeal removal were associated with an increased risk for CRC development at the same site as the index polyp. Increasing age; right-sided location; higher number of polyps resected and sessile endoscopic appearance of the index AA/TSA/ASSA were significantly associated with an increased risk for CRC development at a different site. CONCLUSION: Recognition that CRC may develop following AA/TSA/ASSA removal is one step toward improving our practice efficiency and preventing a portion of CRC related morbidity and mortality. PMID- 29491685 TI - Nationwide cohort study suggests that nucleos(t)ide analogue therapy decreases dialysis risk in Taiwanese chronic kidney disease patients acquiring hepatitis B virus infection. AB - AIM: To investigate the risk of end-stage renal disease (ESRD) in hepatitis B virus (HBV)-infected patients with chronic kidney disease (CKD) with and without nucleos(t)ide analogue (NA) therapy. METHODS: This nationwide cohort study included 103444 Taiwanese CKD adults without hepatitis C virus infection from the Taiwan Longitudinal Health Insurance Database 2005 between 1997 and 2012. We identified 2916 CKD patients who acquired HBV infection and did not receive NAs (untreated cohort), and they were propensity-matched 1:4 with 11664 uninfected counterparts. We also identified 442 CKD patients who acquired HBV infection and received NAs (treated cohort), and they were propensity-matched 1:3 with 1326 untreated counterparts. The association between HBV infection, NA use, and ESRD was analyzed using competing risk analysis. RESULTS: Multivariable Cox regression analysis showed a 1.67-fold higher risk (P < 0.0001) of ESRD in the untreated cohort (16-year cumulative incidence, 10.1%) than in the matched uninfected cohort (16-year cumulative incidence, 6.6%), which was independent of cirrhosis or diabetes. The treated cohort (16-year cumulative incidence, 2.2%) had an 87% lower ESRD risk (P < 0.0001) compared with the matched untreated cohort (16-year cumulative incidence, 11.9%). The number needed to treat for one fewer ESRD after NA use at 12 years was 12. Multivariable stratified analyses verified these associations in all subgroups. CONCLUSION: This study suggests that untreated HBV infection and NA therapy are associated with increased and decreased risk of ESRD, respectively, in CKD patients. Identification of HBV status and targeted monitoring for ESRD development are important in CKD patients living in HBV endemic areas. PMID- 29491687 TI - Comparison of TPMT and NUDT15 polymorphisms in Chinese patients with inflammatory bowel disease. AB - AIM: To observe gene polymorphisms of TPMT and NUDT15, and compare their predictive value for azathioprine (AZA)-induced leukopenia in inflammatory bowel disease (IBD). METHODS: This study enrolled 219 patients diagnosed with IBD in Xiangya Hospital, Central South University, Changsha, China from February 2016 to November 2017. Peripheral blood of all patients was collected to detect their genotypes of TPMT and NUDT15 by pyrosequencing at the Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital. Eighty patients were treated with AZA according to the disease condition. During the first month, patients who received AZA underwent routine blood tests and liver function tests once a week. The endpoint of the study was leukopenia induced by AZA. By analyzing patient characteristics, genotypes and leukopenia induced by drug use, we found the risk factors associated with AZA-induced leukopenia. RESULTS: There were 219 patients with IBD (160 men and 59 women), including 39 who were confirmed with ulcerative colitis (UC), 176 with Crohn's disease (CD) and 4 with undetermined IBD (UIBD). There were 44 patients (20.1%) with mutant genotype of NUDT15 (C/T); among them, 16 received AZA, and 8 (50%) developed leukopenia. There were 175 patients (79.7%) with wild genotype of NUDT15 (C/C); among them, 64 received AZA, and 11 (17.2%) developed leukopenia. A significant difference was found between NUDT15 C/T and its wild-type C/C (P = 0.004). There were only 3 patients with TPMT mutant genotype of A/G (1.4%) who participated in the research, and 1 of them was treated with AZA and developed leukopenia. The remaining 216 patients (98.6%) were found to bear the wild genotype of TPMT (A/A); among them, 79 patients received AZA, and 18 (22.8%) developed leukopenia, and there was no significant difference from those with A/G (P = 0.071). The frequency of TPMT mutation was 1.4%, and NUDT15 mutation rate was significantly higher and reached 20.1% (P = 0.000). Therefore, NUDT15 gene polymorphism was obviously a better biomarker than TPMT gene polymorphism in the prediction of AZA induced leukopenia. CONCLUSION: Mutation rate of NUDT15 in Chinese IBD patients is higher than that of TPMT. NUDT15 polymorphism is a better predictor for AZA induced leukopenia than TPMT polymorphism. PMID- 29491686 TI - Intravoxel incoherent motion diffusion-weighted magnetic resonance imaging for predicting histological grade of hepatocellular carcinoma: Comparison with conventional diffusion-weighted imaging. AB - AIM: To compare intravoxel incoherent motion (IVIM)-derived parameters with conventional diffusion-weighted imaging (DWI) parameters in predicting the histological grade of hepatocellular carcinoma (HCC) and to evaluate the correlation between the parameters and the histological grades. METHODS: A retrospective study was performed. Sixty-two patients with surgically confirmed HCCs underwent diffusion-weighted magnetic resonance imaging with twelve b values (10-1200 s/mm2). The apparent diffusion coefficient (ADC), pure diffusion coefficient (D), pseudo-diffusion coefficient (D*), and perfusion fraction (f) were calculated by two radiologists. The IVIM and conventional DWI parameters were compared among the different grades by using analysis of variance (ANOVA) and the Kruskal-Wallis test. Receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic efficiency of distinguishing between low grade (grade 1, G1) and high-grade (grades 2 and 3, G2 and G3) HCC. The correlation between the parameters and the histological grades was assessed by using the Spearman correlation test. Bland-Altman analysis was used to evaluate the reproducibility of the two radiologists' measurements. RESULTS: The differences in the ADC and D values among the groups with G1, G2, and G3 histological grades of HCCs were statistically significant (P < 0.001). The D* and f values had no significant differences among the different histological grades of HCC (P > 0.05). The ROC analyses demonstrated that the D and ADC values had better diagnostic performance in differentiating the low-grade HCC from the high-grade HCC, with areas under the curve (AUCs) of 0.909 and 0.843, respectively, measured by radiologist 1 and of 0.911 and 0.852, respectively, measured by radiologist 2. The following significant correlations were obtained between the ADC, D, and D* values and the histological grades: r = -0.619 (P < 0.001), r = -0.628 (P < 0.001), and r = -0.299 (P = 0.018), respectively, as measured by radiologist 1; r = -0.622 (P < 0.001), r = -0.633 (P < 0.001), and r = -0.303 (P = 0.017), respectively, as measured by radiologist 2. The intra-class correlation coefficient (ICC) values between the two observers were 0.996 for ADC, 0.997 for D, 0.996 for D*, and 0.992 for f values, which indicated excellent inter-observer agreement in the measurements between the two observers. CONCLUSION: The IVIM-derived D and ADC values show better diagnostic performance in differentiating high-grade HCC from low-grade HCC, and there is a moderate to good correlation between the ADC and D values and the histological grades. PMID- 29491689 TI - On a reverse Mulholland's inequality in the whole plane. AB - By introducing multi-parameters, applying the weight coefficients and Hermite Hadamard's inequality, we give a reverse of the extended Mulholland inequality in the whole plane with the best possible constant factor. The equivalent forms and a few particular cases are also considered. PMID- 29491688 TI - Detection of fusion gene in cell-free DNA of a gastric synovial sarcoma. AB - Synovial sarcoma (SS) is genetically characterized by chromosomal translocation, which generates SYT-SSX fusion transcripts. Although SS can occur in any body part, primary gastric SS is substantially rare. Here we describe a detection of the fusion gene sequence of gastric SS in plasma cell-free DNA (cfDNA). A gastric submucosal tumor was detected in the stomach of a 27-year-old woman and diagnosed as SS. Candidate intronic primers were designed to detect the intronic fusion breakpoint and this fusion sequence was confirmed in intron 10 of SYT and intron 5 of SSX2 by genomic polymerase chain reaction (PCR) and direct sequencing. A locked nucleic acid (LNA) probe specific to the fusion sequence was designed for detecting the fusion sequence in plasma and the fusion sequence was detected in preoperative plasma cfDNA, while not detected in postoperative plasma cfDNA. This technique will be useful for monitoring translocation-derived diseases such as SS. PMID- 29491690 TI - Inequalities between degree- and distance-based graph invariants. AB - Inequalities provide a way to study topological indices relatively. There are two major classes of topological indices: degree-based and distance-based indices. In this paper we provide a relative study of these classes and derive inequalities between degree-based indices such as Randic connectivity, GA, ABC, and harmonic indices and distance-based indices such as eccentric connectivity, connective eccentric, augmented eccentric connectivity, Wiener, and third ABC indices. PMID- 29491691 TI - Key Vulnerabilities in the Surgical Environment: Container Mix-Ups And Syringe Swaps. AB - Container mix-ups and syringe swaps in the surgical environment. PMID- 29491693 TI - Drug and Device News. AB - Approvals, new indications, regulatory activities, and more. PMID- 29491692 TI - NIH Starts to Spend $4.8 Billion in "Extra" Cures Drug Research Money. AB - NIH starts to spend billions in Cures drug research money. PMID- 29491694 TI - Pharmaceutical Approval Update. AB - Zoster vaccine recombinant, adjuvanted (Shingrix) for the prevention of shingles in adults; angiotensin II injection (Giapreza) to increase blood pressure in adults with septic or other distributive shock; and glycopyrrolate inhalation solution (Lonhala Magnair) for the maintenance treatment of chronic obstructive pulmonary disease. PMID- 29491695 TI - Oritavancin (Orbactiv): A New-Generation Lipoglycopeptide for the Treatment Of Acute Bacterial Skin and Skin Structure Infections. AB - Oritavancin (Orbactiv): a new-generation lipoglycopeptide for the treatment of acute bacterial skin and skin structure infections. PMID- 29491697 TI - Time- and Temperature-Controlled Transport: Supply Chain Challenges and Solutions. AB - The author reviews the latest improvements and advancements in the pharmaceutical supply chain, including those in packaging, monitoring, warehousing, and regulation. PMID- 29491696 TI - The 21st Century Cures Act: FDA Implementation One Year Later: Some Action, Some Results, Some Questions. AB - The Food and Drug Administration has made significant progress implementing some of the 60 provisions of the 21st Century Cures Act passed in 2016. The author discusses the successes and shortcomings of the agency's regulatory activities. PMID- 29491698 TI - Current Practice Patterns in the Management Of Alcohol Withdrawal Syndrome. AB - Objective: The aim of this study was to examine current practice patterns surrounding the management of alcohol withdrawal syndrome (AWS) in the Northeast region of the United States. Methods: A survey questionnaire with several treatment options related to current practice in the management of AWS was developed. All hospitals with 100 beds or more located in the Northeast region were selected, and 512 surveys were mailed to pharmacy directors of those hospitals. Results: Responses from 90 hospitals in nine states were included in the analyses. For the treatment of mild, moderate, and severe AWS, most institutions utilized protocols or guidelines (66%, 73%, and 67%, respectively). However, two-thirds of the hospitals indicated that guidelines or protocols were not in place to treat benzodiazepine (BZD)-refractory AWS. A BZD-only treatment strategy was selected as the first choice for mild and moderate AWS (74% and 54%, respectively), whereas a BZD regimen in combination with a variety of other agents, including haloperidol, dexmedetomidine, phenobarbital, or propofol, was frequently used in the treatment of severe and BZD-refractory AWS. Conclusion: The findings suggest that considerable heterogeneity exists, particularly in the treatment of severe and BZD-refractory AWS, among hospitals in the Northeast. Given that current guidelines focus mainly on BZD therapy, the results of this survey highlight the need for updated practice guidelines utilizing other treatment strategies. PMID- 29491699 TI - Expediting Formulary Standardization in a Multihospital Health System Using Layered Learners. AB - Drug formularies are a necessary part of medication management in hospitals and health systems. The system-level P&T committee at BJC HealthCare, a multihospital health system in St. Louis, Missouri, developed an approach to standardization of a system-wide formulary using available layered learners to complete the work in an expedited manner before implementation of a system-wide electronic medical record. The formulary standardization work was allocated to reviewers-including pharmacy students, residents, clinical pharmacy specialists, and pharmacy leadership-according to the complexity of the drug class under review, and a pharmacist was assigned to oversee and support the learner (student or resident) as class reviews were performed. The reviewer prepared a review of the drug class, developed recommendations for formulary agents and therapeutic interchanges, and presented recommendations to key stakeholder groups in the organization before a final decision by the system P&T committee. Using this approach, 27 therapeutic class reviews were conducted in 15 months, and 153 of 346 individual agents reviewed (44%) were retained on the formulary. The alignment of formulary medications and interchanges in the 27 classes resulted in an estimated $1.185 million savings in supply costs in the 12 months after implementing the changes. Standardization of the formulary and therapeutic interchanges can be expedited by using a layered learner model, and this model can be used in other health systems to accelerate the formulary review process. PMID- 29491700 TI - Price-Performance Ratio Analysis Of Enteral Vitamin K Formulations. AB - Background: Vitamin K compounded oral solution costs significantly less on a per milligram basis compared with tablet formulations. Current literature has shown that international normalized ratio (INR) lowering in the reversal of vitamin K antagonists (VKAs) occurs to a similar degree when using vitamin K oral solution compared with tablet formulations. Objective: To compare drug spending on vitamin K oral solution versus tablet using a price-performance ratio (PPR). Methods: A retrospective chart review was conducted at a tertiary care academic medical center to compare INR reversal of VKA-induced coagulopathy on a price basis for vitamin K oral solution versus tablet. The price of the oral solution accounted for supplies and labor. A PPR was calculated based upon the following formula: vitamin K formulation cost divided by the hourly percent change in INR following vitamin K administration. Results: The PPR for vitamin K tablets was 27.0 compared with 5.8 for the oral solution (P = 0.006). Conclusions: Utilization of vitamin K solution resulted in a significantly reduced cost per INR-lowering effect relative to commercially available tablets. Utilization of a compounded vitamin K solution represents an enticing means of cost-savings in the hospital setting. PMID- 29491701 TI - ASCO Gastrointestinal Cancers Symposium And San Antonio Breast Cancer Symposium. AB - We present sessions on hepatocellular carcinoma and colorectal and pancreatic cancers from ASCO GI. Key sessions from SABCS covered dose intensification, new trial data, and ovarian suppression to preserve fertility. PMID- 29491702 TI - Research Briefs. PMID- 29491703 TI - Father Involvement and Behavior Problems among Preadolescents at Risk of Maltreatment. AB - Although there is a well-established connection between father involvement and children's positive behavioral development in general, this relation has been understudied in more vulnerable and high-risk populations. The aims of this study were to examine how the quantity (i.e., the amount of shared activities) and quality (i.e., perceived quality of the father-child relationship) of father involvement are differently related to internalizing and externalizing behavior problems among preadolescents at risk of maltreatment and test if these associations are moderated by father type and child maltreatment. A secondary data analysis was conducted using data from the Longitudinal Studies of Child Abuse and Neglect (LONGSCAN). Generalized estimating equations analysis was performed on a sample of 499 preadolescents aged 12 years. The results indicated that higher quality of father involvement was associated with lower levels of internalizing and externalizing behavior problems whereas greater quantity of father involvement was associated with higher levels of internalizing and externalizing behavior problems. The positive association between the quantity of father involvement and behavior problems was stronger in adolescents who were physically abused by their father. The association between father involvement and behavior problems did not differ by the type of father co-residing in the home. The findings suggest that policies and interventions aimed at improving the quality of fathers' relationships and involvement with their children may be helpful in reducing behavior problems in adolescents at risk of maltreatment. PMID- 29491704 TI - Hybrid wide-angle viewing-endoscopic vitrectomy using a 3D visualization system. AB - Purpose: To introduce a hybrid wide-angle viewing-endoscopic vitrectomy, which we have reported, using a 3D visualization system developed recently. Subjects and methods: We report a single center, retrospective, consecutive surgical case series of 113 eyes that underwent 25 G vitrectomy (rhegmatogenous retinal detachment or proliferative vitreoretinopathy, 49 eyes; epiretinal membrane, 18 eyes; proliferative diabetic retinopathy, 17 eyes; vitreous opacity or vitreous hemorrhage, 11 eyes; macular hole, 11 eyes; vitreomacular traction syndrome, 4 eyes; and luxation of intraocular lens, 3 eyes). Results: This system was successfully used to perform hybrid vitrectomy in the difficult cases, such as proliferative vitreoretinopathy and proliferative diabetic retinopathy. Conclusion: Hybrid wide-angle viewing-endoscopic vitrectomy using a 3D visualization system appears to be a valuable and promising method for managing various types of vitreo-retinal disease. PMID- 29491705 TI - A retrospective analysis of the use of loteprednol etabonate ophthalmic suspension 0.5% following canaloplasty. AB - Background: While loteprednol etabonate (LE) suspension 0.5% is approved for the treatment of postoperative ocular inflammation, there have been no reported studies of its use in glaucoma patients undergoing canaloplasty. Methods: This was a retrospective medical chart review conducted at a single US center. Data were collected on patients with glaucoma who underwent canaloplasty with or without cataract surgery, and were prescribed LE suspension 0.5% postoperatively. Outcomes evaluated included postsurgical inflammation (anterior chamber [AC] cells and flare), intraocular pressure (IOP), number of IOP-lowering medications, and postsurgical complications. Results: Data were collected on 204 patients (262 eyes) with a mean (SD) age of 71.6 (11.3) years. The most frequent LE dosing regimens at day 1, week 1, and month 1 postsurgery were QID (92.3%; 241/261), TID (52.6%; 133/253), and QD (65.5%; 78/119), respectively. Inflammation (AC flare and cells), mostly mild, was noted in 33.2% (86/259) of eyes on postoperative day 1 and 8.6% (21/244) of eyes at month 1. Mean IOP and mean number of IOP-lowering medications were significantly reduced from baseline (P<0.001) at all time points postoperatively. Complete (no IOP-lowering medication) or qualified (use of <=2 IOP-lowering medications) surgical success was achieved in 78.8% and 90.6% of eyes, respectively, at month 6 and 63.4% and 92.7% of eyes at month 36. The most frequently observed postoperative complication was hyphema in 48.7% (126/259) eyes at day 1, which decreased to 0.4% (1/244) of eyes by month 1. IOP >=30 mmHg was noted in 13 (5.3%) eyes at postoperative week 1 and rarely thereafter, and no patient discontinued therapy because of an IOP increase. Conclusion: These real world data suggest that canaloplasty with or without cataract surgery managed postoperatively with LE suspension 0.5% is effective and safe in the glaucoma patient. PMID- 29491706 TI - Berberine nanoparticles with enhanced in vitro bioavailability: characterization and antimicrobial activity. AB - Background: Berberine is an isoquinoline alkaloid widely used in Ayurveda and traditional Chinese medicine to treat illnesses such as hypertension and inflammatory conditions, and as an anticancer and hepato-protective agent. Berberine has low oral bioavailability due to poor aqueous solubility and insufficient dissolution rate, which can reduce the efficacy of drugs taken orally. In this study, evaporative precipitation of nanosuspension (EPN) and anti solvent precipitation with a syringe pump (APSP) were used to address the problems of solubility, dissolution rate and bioavailability of berberine. Methods: Semi-crystalline nanoparticles (NPs) of 90-110 nm diameter for APSP and 65-75 nm diameter for EPN were prepared and then characterized using differential scanning calorimetry (DSC) and X-ray powder diffractometry (XRD). Thereafter, drug content solubility and dissolution studies were undertaken. Berberine and its NPs were evaluated for their antibacterial activity. Results: The results indicate that the NPs have significantly increased solubility and dissolution rate due to conversion of the crystalline structure to a semi-crystalline form. Conclusion: Berberine NPs produced by both APSP and EPN methods have shown promising activities against Gram-positive and Gram-negative bacteria, and yeasts, with NPs prepared through the EPN method showing superior results compared to those made with the APSP method and the unprocessed drug. PMID- 29491707 TI - Functional intercalated nanocomposites with chitosan-glutathione-glycylsarcosine and layered double hydroxides for topical ocular drug delivery. AB - Background: To enhance ocular bioavailability, the traditional strategies have focused on prolonging precorneal retention and improving corneal permeability by nano-carriers with positive charge, thiolated polymer, absorption enhancer and so on. Glycylsarcosine (GS) as an active target ligand of the peptide tranpsporter-1 (PepT-1), could specific interact with the PepT-1 on the cornea and guide the nanoparticles to the treating site. Purpose: The objective of the study was to explore the active targeting intercalated nanocomposites based on chitosan glutathione-glycylsarcosine (CG-GS) and layered double hydroxides (LDH) as novel carriers for the treatment of mid-posterior diseases. Materials and methods: CG GS-LDH intercalated nanocomposites were prepared by the coprecipitation hydrothermal method. In vivo precorneal retention study, ex vivo fluorescence images, in vivo experiment for distribution and irritation were studied in rabbits. The cytotoxicity and cellular uptake were studied in human corneal epithelial primary cells (HCEpiC). Results: CG-GS-LDH nanocomposites were prepared successfully and characterized by FTIR and XRD. Experiments with rabbits showed longer precorneal retention and higher distribution of fluorescence probe/model drug. In vitro cytological study, CG-GS-LDH nanocomposites exhibited enhanced cellular uptake compared to pure drug solution. Furthermore, the investigation of cellular uptake mechanisms demonstrated that both the active transport by PepT-1 and clathrin-mediated endocytosis were involved in the internalization of CG-GS-LDH intercalated nanocomposites. An ocular irritation study and a cytotoxicity test indicated that these nanocomposites produced no significant irritant effects. Conclusions: The active targeting intercalated nanocomposites could have great potential for topical ocular drug delivery due to the capacity for prolonging the retention on the ocular surface, enhancing the drug permeability through the cornea, and efficiently delivering the drug to the targeted site. PMID- 29491708 TI - Redox-sensitive micelles composed of disulfide-linked Pluronic-linoleic acid for enhanced anticancer efficiency of brusatol. AB - Brusatol (Bru) exhibits promising anticancer effects, with both proliferation inhibition and chemoresistance amelioration activity. However, the poor solubility and insufficient intracellular delivery of Bru greatly restrict its application. Herein, to simultaneously utilize the advantages of Pluronics as drug carriers and tumor microenvironment-responsive drug release profiles, a flexible amphiphilic copolymer with a polymer skeleton, that is, Pluronic(r) F68 grafting with linoleic acid moieties by redox-reducible disulfide bonds (F68-SS LA), was synthesized. After characterization by 1H-nuclear magnetic resonance and Fourier transform infrared spectroscopy, the redox-sensitive F68-SS-LA micelles were self-assembled in a much lower critical micelle concentration than that of the unmodified F68 copolymer. Bru was loaded in micelles (Bru/SS-M) with high loading efficiency, narrow size distribution, and excellent storage stability. The redox-sensitive Bru/SS-M exhibited rapid particle dissociation and drug release in response to a redox environment. Based on the enhanced cellular internalization, Bru/SS-M achieved higher cytotoxicity in both Bel-7402 and MCF-7 cells compared with free Bru and nonreducible micelles. The improved anticancer effect was attributed to the remarkably decreased mitochondrial membrane potential and increased reactive oxygen species level as well as apoptotic rate. These results demonstrated that F68-SS-LA micelles possess great potential as an efficient delivery vehicle for Bru to promote its anticancer efficiency via an oxidation pathway. PMID- 29491709 TI - Investigation of antitumor activities of trastuzumab delivered by PLGA nanoparticles. AB - Background: We report the development of an efficient antibody delivery system for the incorporation of trastuzumab (TZ) into poly(lactic-co-glycolic) acid nanoparticles (PLGA NPs). The aim of the work was to overcome the current limitations in the clinical use of therapeutic antibodies, including immunogenicity, poor pharmacokinetics, low tumor penetration and safety issues. Materials and methods: Trastuzumab-loaded PLGA NPs (PLGA-TZ) were synthesized according to a double emulsion method. The same protocol was used to produce control batches of nonspecific IgG-loaded NPs and empty PLGA NPs. After release of TZ from PLGA NPs, the effects on the main biological activities of the antibody were evaluated on SKBR3 (human epidermal growth factor receptor 2 [HER2] positive breast cancer cell line), including specific binding to HER2, phosphorylation of HER2 (Y1248), degradation of HER2 protein and antibody dependent cell-mediated cytotoxicity (ADCC) mechanism. In addition, an MTT assay was performed for treating SKBR3 cells with PLGA NPs loaded with TZ and doxorubicin to evaluate the cytotoxic activity of the combined treatment. Results and discussion: TZ was gradually released in a prolonged way over 30 days. The physical characterization performed with circular dichroism, Fourier transform infrared and fluorescence spectroscopy of TZ after release demonstrated that no structural alterations occurred compared to the native antibody. In vitro experiments using SKBR3 cells showed that TZ released from PLGA NPs maintained the same biological activity of native TZ. PLGA NPs allowed a good co encapsulation efficiency of TZ and doxorubicin resulting in improved therapy. Conclusion: With the TZ case study, we demonstrate that the distinctive features of therapeutic monoclonal antibodies, including molecular targeting efficiency, capability to inhibit or properly affect the regulatory signaling pathways of cancer cells and stimulation of the ADCC, are fully preserved after loading into and release from PLGA NPs. In addition, PLGA NPs are shown to allow for the simultaneous incorporation of TZ and conventional chemotherapeutics, resulting in a potent antitumor nanodrug well suited for in situ combination and neoadjuvant therapy. PMID- 29491710 TI - Corpus callosum infarction with cognitive dysfunction: two case reports and literature review. AB - Introduction: The incidence of corpus callosum infarction is low, and sudden cognitive dysfunction caused by corpus callosum infarction is very rare. We report two cases of acute corpus callosum infarction with sudden cognitive impairment, and the related basis, clinical manifestations, diagnosis, differential diagnosis, treatment, and prognosis of this disease are reviewed. Cases presentation: The two patients had sudden and severe memory impairment and spatial orientation disorder. Their cognitive function scores were significantly lower, and their MRI demonstrated clear corpus callosum infarction. Through treatment, the symptoms improved significantly. Discussion: This paper reports two cases with corpus callosum infarction with sudden cognitive impairment, and its relevant background is also reviewed, which will help doctors with the classification diagnosis of cerebral infarction and understanding of corpus callosum infarction. PMID- 29491711 TI - Prospective interepisodal mood monitoring in patients with affective disorders: a feasibility study. AB - Objectives: Our primary objective was to assess the feasibility of interepisodal telephonic mood monitoring in patients with affective disorders in a low-resource setting. Secondary objectives included gathering data on longitudinal mood trajectories and assessing patient acceptance of mood monitoring. Methods: Inpatients with a primary mood or anxiety disorder were recruited predischarge. Assessment at intake included demographic information, the Life Events Checklist, and the Childhood Trauma Questionnaire. Participants telephonically completed the Altman Self-Rating Mania Scale (ASRM) and Quick Inventory of Depressive Symptomatology (QIDS), weekly, for 26 weeks. Units of alcohol consumed and life events were recorded. Semi-structured interviews were conducted midway through the mood monitoring protocol. Results: Of the 61 eligible participants (77% female; mean age =35.3 years), 28 completed 26 weeks of telephonic mood monitoring. Thirty-three participants (54.1%) withdrew prematurely or were lost to follow-up. Males were more likely to terminate study participation prematurely. Despite the significant decline in depression scores over 26 weeks, participants endorsed persistent mild-to-moderate depressive symptoms. Statistically, participants who were married/in a relationship had higher mean depression scores throughout the study compared to participants who were single. Throughout the study, ASRM scores were not indicative of significant mania. Suicidality (as measured by QIDS item 12) was highest at Week 3 and Week 12 postdischarge for those who completed 26 weeks of monitoring. Conclusion: Despite the high attrition rate, interepisodal telephonic mood monitoring was deemed to be feasible and it can provide useful information to track progress, encourage medication adherence, and manage early warning signs of relapse. Further research is required to determine the benefit of weekly mood monitoring on mood fluctuations and to examine strategies that enhance retention. PMID- 29491712 TI - Dietary black-grained wheat intake improves glycemic control and inflammatory profile in patients with type 2 diabetes: a randomized controlled trial. AB - Introduction: Although black-grained wheat (BGW) is recognized as a nutritional food for humans in China, it has yet to be utilized well for industrial applications, which can be attributed to the limited research data available on its health benefits. Thus, the hypothesis was tested that a daily substitution of BGW for a partial staple food would improve glycemia and inflammatory profile of type 2 diabetes mellitus (T2DM) patients by a randomized controlled trial. Materials and methods: A total of 120 patients were randomly divided between control group (diet control and nutritional education) and BGW group (daily substitution of BGW for a partial staple food). Results: Based on the significant difference between BGW and control groups (P<0.05), the primary outcomes were that BGW treatment in diet resulted in a significant lowering of glycated albumin (GA, 18.05 to 16.06 mmol/L) level in T2DM patients after a 5-week intervention, and this treatment regimen was much more efficient than the strategy of diet control alone. In addition, BGW supplementation prevented the increase in tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 induced by T2DM. There were no significant differences in blood glucose, glycated hemoglobin or insulin levels between the 2 groups. The subgroup analyses of the BGW daily intake showed that, except the TNF-alpha, significant improvements in GA and IL-6 were observed when the BGW intake dose was >69 g/day. Conclusion: These findings support the hypothesis that BGW may improve glycemia and the inflammatory profile in T2DM patients. PMID- 29491714 TI - Hospital medicine beyond the United States. AB - Hospital medicine is the fastest growing specialty in the United States. An interesting aspect of the rapid expansion of hospital medicine is the expansion of the field beyond the United States. Although the health care systems, regulations, and cultural norms in these nations differ, there are striking similarities in the profession's development. We performed a literature review to better understand the factors contributing to the growth of hospital medicine internationally. In this article, we describe some of the drivers for expansion of hospital medicine outside the United States and the challenges faced by these groups. We also discuss the role the United States could play in the continued growth of hospital medicine internationally. PMID- 29491713 TI - Effect of MRSA on CYP450: dynamic changes of cytokines, oxidative stress, and drug-metabolizing enzymes in mice infected with MRSA. AB - Background: Methicillin-resistant Staphylococcus aureus (MRSA) is a very damaging and widespread pathogen, which is associated with many diseases and causes serious infections. MRSA infection can modulate the effects of drugs, which may occur through an influence on cytochrome P450 (CYP450), the drug-metabolizing enzyme in the liver. In this study, we evaluated the underlying mechanism of drug failure or poisoning in MRSA infection. Materials and methods: Mice were infected with three different doses of MRSA and the changes in CYP450 expression, cytokines, and oxidative stress markers were evaluated. Results: The administration of an attack dose of MRSA caused serious symptoms of infection and resulted in a 40% mortality rate in the mice. MRSA induced strong inflammation and oxidative stress in the mice, predominantly caused by significant increases in interleukin (IL)-1beta, IL-4, IL-6, macrophage inflammatory protein, glutathione S-transferase (GST), and malondialdehyde, and decreases in oxygen radical absorbance capacity and glutathione levels in the liver. The expression of IL-2, tumor necrosis factor-alpha, and GST was briefly suppressed, but increased on days 3 and 7. The increased inflammation and oxidative stress further induced a significant decrease in the mRNA levels and activities of CYP450 1A2, 2D22, 2E1, and 3A1 in MRSA-infected mice within the first day of infection. Conclusion: These results show that MRSA infection leads to inflammation and oxidative stress, and reduces the expression levels and activities of drug metabolism enzymes, which decreased drug metabolism in patients infected with MRSA. Therefore, to avoid a drug overdose, the plasma concentration of patients with MRSA infection should be continuously monitored. PMID- 29491715 TI - A video depicting resuscitation did not impact upon patients' decision-making. AB - Background: Previous studies have demonstrated that video of and scripted information about cardiopulmonary resuscitation (CPR) can be deployed during clinician-patient end-of-life discussions. Few studies, however, examine whether video adds to verbal information-sharing. We hypothesized that video augments script-only decision-making. Methods: Patients aged >65 years admitted to hospital wards were randomized to receive evidence-based information ("script") vs. script plus video of simulated CPR and intubation. Patients' decisions registered in the hospital record, by hospital discharge were compared for the two groups. Results: Fifty script-only intervention patients averaging 77.7 years were compared to 50 script+video patients with a mean age of 74.7 years. Eleven of 50 (22%) in each group declined CPR; and an additional three (script) vs. four (script+video) refused intubation for respiratory failure. There were no differences in sex, self-reported health trajectory, functional limitations, length of stay, or mortality associated with decisions. Conclusion: The rate at which verbally informed hospitalized elders opted out of resuscitation was not impacted by adding a video depiction of CPR. PMID- 29491716 TI - Psychiatric and physical comorbidities and pain in patients with multiple sclerosis. AB - Background: It has been observed that patients with multiple sclerosis (MS), who have psychiatric and physical comorbidities such as depression and COPD, have an increased risk of experiencing more pain. In this study, we have distinguished between pain intensity and pain affect, as the latter, particularly, requires treatment. Furthermore, while pain and comorbidities have been assessed using questionnaires, this is possibly a less reliable method for those who are cognitively vulnerable. Objective: The aim of this study was to determine whether psychiatric and physical comorbidities can predict pain intensity and pain affect in MS patients, susceptible to cognitive impairment. Methods: Ninety-four patients with MS and 80 control participants participated in this cross-sectional study. Besides depression and anxiety, 47 additional comorbidities were extracted from patients' medical records. Depression and anxiety were assessed using the Beck Depression Inventory and the Symptom Check List-90. Pain was assessed using the Number of Words Chosen Affective, Coloured Analog Scale, and the Faces Pain Scale. Cognitive functions, for example, memory and executive functions, were assessed using several neuropsychological tests. Results: The main findings indicate that psychiatric comorbidities (depression and anxiety) predict both pain intensity and pain affect and that total physical comorbidity predicts only pain affect in MS patients, susceptible to cognitive impairment. Conclusion: Both psychiatric and physical comorbidities predict pain affect. All three clinical outcomes enhance MS patients' suffering. PMID- 29491717 TI - Projector-based virtual reality dome environment for procedural pain and anxiety in young children with burn injuries: a pilot study. AB - Background: Virtual reality (VR) is a non-pharmacological method to distract from pain during painful procedures. However, it was never tested in young children with burn injuries undergoing wound care. Aim: We aimed to assess the feasibility and acceptability of the study process and the use of VR for procedural pain management. Methods: From June 2016 to January 2017, we recruited children from 2 months to 10 years of age with burn injuries requiring a hydrotherapy session in a pediatric university teaching hospital in Montreal. Each child received the projector-based VR intervention in addition to the standard pharmacological treatment. Data on intervention and study feasibility and acceptability in addition to measures on pain (Face, Legs, Activity, Cry, Consolability scale), baseline (Modified Smith Scale) and procedural (Procedure Behavior Check List) anxiety, comfort (OCCEB-BECCO [behavioral observational scale of comfort level for child burn victims]), and sedation (Ramsay Sedation Scale) were collected before, during, and after the procedure. Data analyses included descriptive and non-parametric inferential statistics. Results: We recruited 15 children with a mean age of 2.2+/-2.1 years and a mean total body surface area of 5% (+/-4). Mean pain score during the procedure was low (2.9/10, +/-3), as was the discomfort level (2.9/10, +/-2.8). Most children were cooperative, oriented, and calm. Assessing anxiety was not feasible with our sample of participants. The prototype did not interfere with the procedure and was considered useful for procedural pain management by most health care professionals. Conclusion: The projector based VR is a feasible and acceptable intervention for procedural pain management in young children with burn injuries. A larger trial with a control group is required to assess its efficacy. PMID- 29491718 TI - Prevalence of and risk factors for Modic change in patients with symptomatic cervical spondylosis: an observational study. AB - Background: The aim of this study was to assess the prevalence of cervical Modic change (MC) in patients with cervical spondylosis and to develop a better understanding of the possible risk factors for the prevalence of MC. Methods: Between January 2014 and April 2017, patients with cervical spondylosis were included in our study. All patients underwent magnetic resonance imaging (MRI) to evaluate the presence of MC. The MC was classified into three types according to the Modic classification. Potential risk factors were collected from demographic data, lifestyle variables, laboratory tests, and radiographic images. Both univariate and multivariate analysis were used to detect factors associated with MC. We further compared several variables related to fat metabolism between patients with Type 1 and Type 2 MC. Results: The prevalence of MC in patients with cervical spondylosis was 9.24%. The MC was most frequent at C5-6, followed by C6-7, C4-5, and C3-4. The proportion of Type 1 MC in patients with neck pain was significantly higher than that in patients without neck pain (46.2% vs 13.6%, P=0.027). However, none of the variables associated with fat metabolism showed a significant difference between Type 1 and Type 2 MC. Multivariate logistic analysis showed that age >=55 years (odds ratio [OR], 1.91; 95% confidence interval [CI], 1.22-2.98) and body mass index (BMI) >=25 kg/m2 (OR, 2.41; 95% CI, 1.62-3.59) were two significant independent factors that are associated with cervical MC in patients with cervical spondylosis (P<0.05). Conclusion: It appears that advanced age and high BMI were two factors that may be responsible for cervical MC. Type 1 MC is associated with the prevalence of neck pain. However, we cannot confirm that Type 2 MC is correlated with fat metabolism. PMID- 29491720 TI - Husbands' perceptions of their wives' breast cancer coping efficacy: testing congruence models of adjustment. AB - Introduction: Recent reviews have reinforced the notion that having a supportive spouse can help with the process of coping with and adjusting to cancer. Congruence between spouses' perspectives has been proposed as one mechanism in that process, yet alternative models of congruence have not been examined closely. This study assessed alternative models of congruence in perceptions of coping and their mediating effects on adjustment to breast cancer. Methods: Seventy-two women in treatment for breast cancer and their husbands completed measures of marital adjustment, self-efficacy for coping, and adjustment to cancer. Karnofsky Performance Status was obtained from medical records. Wives completed a measure of self-efficacy for coping (wives' ratings of self-efficacy for coping [WSEC]) and husbands completed a measure of self-efficacy for coping (husbands' ratings of wives' self-efficacy for coping [HSEC]) based on their perceptions of their wives' coping efficacy. Results: Interestingly, the correlation between WSEC and HSEC was only 0.207; thus, they are relatively independent perspectives. The following three models were tested to determine the nature of the relationship between WSEC and HSEC: discrepancy model (WSEC - HSEC), additive model (WSEC + HSEC), and multiplicative model (WSEC * HSEC). The discrepancy model was not related to wives' adjustment; however, the additive (B=0.205, P<0.001) and multiplicative (B=0.001, P<0.001) models were significantly related to wives' adjustment. Also, the additive model mediated the relationship between performance status and adjustment. Discussion: Husbands' perception of their wives' coping efficacy contributed marginally to their wives' adjustment, and the combination of WSEC and HSEC mediated the relationship between functional status and wives' adjustment, thus positively impacting wives' adjustment to cancer. Future research is needed to determine the quality of the differences between HSEC and WSEC in order to develop interventions to optimize the impact of these two relatively independent perspectives on cancer outcomes. PMID- 29491719 TI - Coprescribing proton-pump inhibitors with nonsteroidal anti-inflammatory drugs: risks versus benefits. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are often coadministered with proton-pump inhibitors (PPIs) to reduce NSAID-induced gastrointestinal (GI) adverse events. This coadministration is generally regarded as safe, and is included in many of the guidelines on NSAID prescription. However, recent evidence indicates that the GI risks associated with NSAIDs can be potentiated when they are combined with PPIs. This review discusses the GI effects and complications of NSAIDs and how PPIs may potentiate these effects, options for prevention of GI side effects, and appropriate use of PPIs in combination with NSAIDs. PMID- 29491722 TI - The dome technique: a new surgical technique to enhance soft-tissue margins and emergence profiles around implants placed in the esthetic zone. AB - Achieving symmetry of the soft-tissue margins between anterior maxillary dental implant restorations and adjacent teeth is a therapeutic challenge for both the implant surgeon and the restorative dentist. This article describes a modified procedure utilizing autogenous connective-tissue grafts to improve primarily buccal soft-tissue margins and secondarily inter-proximal tissues around tooth bound single dental implants. This technique has the advantage of allowing for coronal augmentation of the peri-implant soft tissue while maximizing the blood supply to the area by using tunneling-technique principles. A detailed description of the technique and a case with a stable result over 24 months after crown placement is presented. PMID- 29491721 TI - Combination of CRP and NLR: a better predictor of postoperative survival in patients with gastric cancer. AB - Objectives: C-reactive protein (CRP) and neutrophil to lymphocyte ratio (NLR) were independent predictive factors for gastric cancer (GC). Our study was designed to prove the prognostic value of the combination of CRP and NLR (COC NLR) in GC patients. Materials and methods: A total of 1,058 GC patients who underwent D2 resection from Sun Yat-Sen University Cancer Center between 2003 and 2013 were included. They were divided into three groups (low: NLR <=2.5, CRP <=6.1; medium: NLR >2.5, CRP <=4.5; high: NLR >2.5, CRP >4.5 or NLR <=2.5, CRP >6.1) by the random forest method. Survival analysis stratified by COC-NLR groups was performed. Results: The mean survival time for each group was: for the low group 75.44 months (95% CI: 72.48-78.40), the medium group 56.50 months (95% CI: 50.68-62.31), and the high group 38.65 months (95% CI: 34.51-42.97). The low group showed obviously better overall survival (OS) than other two groups (p<0.001). Survival analysis showed that COC-NLR had statistical significance in both univariate and multivariate analyses (p<0.01). Conclusion: This study showed that COC-NLR could work as an independent prognostic factor in GC and provide more accurate prediction than single NLR or CRP. PMID- 29491723 TI - Comorbidity in US patients with multiple sclerosis. AB - Objective: To assess the trends in the prevalence of comorbidities in US patients with multiple sclerosis (MS), and the association of demographic characteristics with the presence of comorbidities. Study design: A retrospective analysis was conducted from a sample of 5 million patients from the IMS Health Real World Data Adjudicated Claims - US database. Methods: Comorbidity in patients with MS was assessed by year (2006-2014), and logistic regression models evaluated the association of age, sex, and region with select comorbidities. Results: The most common comorbidities from 2006 to 2014 were hyperlipidemia and hypertension (25.9%-29.7% of patients within an individual year), followed by gastrointestinal disease (18.4%-21.2% of patients) and thyroid disease (12.9%-17.1% of patients). The proportion with a claim for hyperlipidemia increased from 2006 to 2009, was stable from 2009 to 2011, and then declined from 2011 to 2014. The proportion with a claim for hypertension generally increased from 2006 to 2013, then declined from 2013 to 2014. The proportion with a claim for gastrointestinal disease, thyroid disease, and anxiety generally increased from 2006 to 2014. Claims for comorbidities were statistically significantly more likely among older age groups (p<0.05), with the exception of anxiety and alcohol abuse, which were statistically significantly less likely among older age groups. Claims for gastrointestinal disease (OR=0.75), thyroid disease (OR=0.36), chronic lung disease (OR=0.76), arthritis (OR=0.71), anxiety (OR=0.63), and depression (OR=0.69) were statistically significantly less likely among males versus females (all p<0.05). Claims for hyperlipidemia (OR=1.39), hypertension (OR=1.25), diabetes (OR=1.31), and alcohol abuse (OR=2.41) were significantly more likely among males (p<0.05). Many comorbidity claims were statistically significantly more likely in the Northeast and South compared with the Midwest and West. Conclusion: This study provides select comorbidity claims estimates in US patients with MS, and thus highlights the importance of comprehensive patient care approaches. PMID- 29491724 TI - Tobacco use and misuse among Indigenous children and youth in Canada. AB - While tobacco is sacred in many Indigenous cultures, the recreational misuse of commercial tobacco is highly addictive and harmful. Tobacco misuse is the leading preventable cause of premature death in the world. Smoking rates among Canadian Indigenous youth are at least three times higher than for their non-Aboriginal peers, an alarming statistic on many levels. The tolls on health from extensive tobacco use range from disproportionately high individual mortality and morbidity to heavy socioeconomic burdens on Indigenous communities. Paediatric health care providers are uniquely positioned to collaborate with community stakeholders to prevent and treat tobacco misuse in young people and their families, while understanding the cultural value of tobacco for many Indigenous peoples. Targeted interventions can positively impact length and quality of life, improve overall health and decrease the immense social and human costs of tobacco misuse. PMID- 29491725 TI - Energy and sports drinks in children and adolescents. AB - Sports drinks and caffeinated energy drinks (CEDs) are commonly consumed by youth. Both sports drinks and CEDs pose potential risks for the health of children and adolescents and may contribute to obesity. Sports drinks are generally unnecessary for children engaged in routine or play-based physical activity. CEDs may affect children and adolescents more than adults because they weigh less and thus experience greater exposure to stimulant ingredients per kilogram of body weight. Paediatricians need to recognize and educate patients and families on the differences between sport drinks and CEDs. Screening for the consumption of CEDs, especially when mixed with alcohol, should be done routinely. The combination of CEDs and alcohol may be a marker for higher risk of substance use or abuse and for other health-compromising behaviours. PMID- 29491727 TI - Editorial: Genomics and Functional Genomics of Stress-mediated Signaling in Plants: Volume II. PMID- 29491726 TI - Multienvironment genomic variance decomposition analysis of open-pollinated Interior spruce (Picea glauca x engelmannii). AB - The advantages of open-pollinated (OP) family testing over controlled crossing (i.e., structured pedigree) are the potential to screen and rank a large number of parents and offspring with minimal cost and efforts; however, the method produces inflated genetic parameters as the actual sibling relatedness within OP families rarely meets the half-sib relatedness assumption. Here, we demonstrate the unsurpassed utility of OP testing after shifting the analytical mode from pedigree- (ABLUP) to genomic-based (GBLUP) relationship using phenotypic tree height (HT) and wood density (WD) and genotypic (30k SNPs) data for 1126 38-year old Interior spruce (Picea glauca (Moench) Voss x P. engelmannii Parry ex Engelm.) trees, representing 25 OP families, growing on three sites in Interior British Columbia, Canada. The use of the genomic realized relationship permitted genetic variance decomposition to additive, dominance, and epistatic genetic variances, and their interactions with the environment, producing more accurate narrow-sense heritability and breeding value estimates as compared to the pedigree-based counterpart. The impact of retaining (random folding) vs. removing (family folding) genetic similarity between the training and validation populations on the predictive accuracy of genomic selection was illustrated and highlighted the former caveats and latter advantages. Moreover, GBLUP models allowed breeding value prediction for individuals from families that were not included in the developed models, which was not possible with the ABLUP. Response to selection differences between the ABLUP and GBLUP models indicated the presence of systematic genetic gain overestimation of 35 and 63% for HT and WD, respectively, mainly caused by the inflated estimates of additive genetic variance and individuals' breeding values given by the ABLUP models. Extending the OP genomic-based models from single to multisite made the analysis applicable to existing OP testing programs. PMID- 29491728 TI - Transcriptome Analysis of ABA/JA-Dual Responsive Genes in Rice Shoot and Root. AB - The phytohormone abscisic acid (ABA) enables plants to adapt to adverse environmental conditions through the modulation of metabolic pathways and of growth and developmental programs. We used comparative microarray analysis to identify genes exhibiting ABA-dependent expression and other hormone-dependent expression among them in Oryza sativa shoot and root. We identified 854 genes as significantly up- or down-regulated in root or shoot under ABA treatment condition. Most of these genes had similar expression profiles in root and shoot under ABA treatment condition, whereas 86 genes displayed opposite expression responses in root and shoot. To examine the crosstalk between ABA and other hormones, we compared the expression profiles of the ABA-dependently regulated genes under several different hormone treatment conditions. Interestingly, around half of the ABA-dependently expressed genes were also regulated by jasmonic acid based on microarray data analysis. We searched the promoter regions of these genes for cis-elements that could be responsible for their responsiveness to both hormones, and found that ABRE and MYC2 elements, among others, were common to the promoters of genes that were regulated by both ABA and JA. These results show that ABA and JA might have common gene expression regulation system and might explain why the JA could function for both abiotic and biotic stress tolerance. PMID- 29491729 TI - Genome-wide Analysis of Alternative Splicing in An Inbred Cabbage (Brassica oleracea L.) Line 'HO' in Response to Heat Stress. AB - Introduction: High-throughput RNA sequencing (RNA-Seq) studies demonstrate that Alter-native Splicing (AS) is a widespread mechanism that enhances transcriptome diversity, particularly in plants exposed to environmental stress. In an attempt to determine the transcriptome and AS patterns of cabbage inbred line "HO" under Heat Stress (HS), RNA-Seq was carried out using HS-treated and con-trol samples. Genome-wide analysis indicated that AS is differentially regulated in response to HS. The number of AS events markedly increased in HS-treated samples compared to the control. Conclusion: We identified 1,864 genes, including Heat shock transcription factor (Hsf) and heat shock protein (Hsp) genes, that exhibited >4 fold changes in expression upon exposure to HS. The enriched Gene Ontology (GO) terms of the 1,864 genes included 'response to stress/abiotic stimulus/chemical stimulus', among, which the genes most highly induced by HS encode small Hsps and Hsf proteins. The heat-induced genes also showed an increased number of AS events under HS conditions. In addi-tion, the distribution of AS types was altered under HS conditions, as the level of Intron Retention (IR) decreased, whereas other types of AS increased, under these conditions. Severe HS-induced AS was al-so observed in Hsfs and Hsps, which play crucial roles in regulating heat tolerance. Our results support the notion that AS of HS-related genes, such as HsfA2 and HsfB2a, are important for heat stress adapta-tion in cabbage. PMID- 29491730 TI - Mapping the microRNA Expression Profiles in Glyoxalase Over-expressing Salinity Tolerant Rice. AB - In the recent years, glyoxalase pathway has been an active area of research in both human and plants. This pathway is reported to confer stress tolerance in plants, by modulating the glutathione homeostasis to achieve detoxification of a potent cytotoxic and mutagenic compound, methylglyoxal. The microRNAs (miRNAs) are also reported to play significant role in stress tolerance for plants. However, the cross-talk of miRNAs with the metabolism regulated by glyoxalase in the salinity-tolerance is unexplored. We therefore investigated whether expression profiles of miRNAs are altered in response to glyoxalase overexpression, and if any of these are also responsible for modulating the stress responses of plants. In this study, the Next Generation Sequencing (NGS) was employed to profile miRNA expression levels from glyoxalase overexpressing transgenic lines. The associated targets of differentially expressed miRNAs were predicted and their functional annotation was carried out using Gene Ontology (GO) and KEGG Orthology (KO), which showed their involvement in several crucial biological pathways. The analysis of NGS datasets also identified other isoforms or isomiRs of selected miRNAs, which may have an active role in developing tolerance against salt stress. Different aspects of miRNA modifications were also studied in glyoxalase overexpressing lines. PMID- 29491731 TI - Impact of Glyphosate on the Rhizosphere Microbial Communities of An EPSPS Transgenic Soybean Line ZUTS31 by Metagenome Sequencing. AB - Background: The worldwide use of glyphosate has dramatically increased, but also has been raising concern over its impact on mineral nutrition, plant pathogen, and soil microbiota. To date, the bulk of previous studies still have shown different results on the effect of glyphosate application on soil rhizosphere microbial communities. Objective: This study aimed to clarify whether glyphosate has impact on nitrogen-fixation, pathogen or disease suppression, and rhizosphere microbial community of a soybean EPSPS-transgenic line ZUTS31 in one growth season. Method: Comparative analysis of the soil rhizosphere microbial communities was performed by 16S rRNA gene amplicons sequencing and shotgun metagenome sequencing analysis between the soybean line ZUTS31 foliar sprayed with diluted glyphosate solution and those sprayed with water only in seed filling stage. Results: There were no significant differences of alpha diversity but with small and insignificant difference of beta diversity of soybean rhizosphere bacteria after glyphosate treatment. The significantly enriched Gene Ontology (GO) terms were cellular, metabolic, and single-organism of biological process together with binding, catalytic activity of molecular function. The hits and gene abundances of some functional genes being involved in Plant Growth Promoting Traits (PGPT), especially most of nitrogen fixation genes, significantly decreased in the rhizosphere after glyphosate treatment. Conclusion: Our present study indicated that the formulation of glyphosate isopropylamine salt did not significantly affect the alpha and beta diversity of the rhizobacterial community of the soybean line ZUTS31, whereas it significantly influenced some functional genes involved in PGPT in the rhizosphere during the single growth season. PMID- 29491732 TI - OsCBSCBSPB4 is a Two Cystathionine-beta-Synthase Domain-containing Protein from Rice that Functions in Abiotic Stress Tolerance. AB - Cystathionine beta-synthase (CBS) domains have been identified in a wide range of proteins of unrelated functions such as, metabolic enzymes, kinases and channels, and usually occur as tandem re-peats, often in combination with other domains. In plants, CBS Domain-Containing Proteins (CDCPs) form a multi-gene family and only a few are so far been reported to have a role in development via regu-lation of thioredoxin system as well as in abiotic and biotic stress response. However, the function of majority of CDCPs still remains to be elucidated in plants. Here, we report the cloning, characterization and functional validation of a CBS domain containing protein, OsCBSCBSPB4 from rice, which pos-sesses two CBS domains and one PB1 domain. We show that OsCBSCBSPB4 encodes a nucleo-cytoplasmic protein whose expression is induced in response to various abiotic stress conditions in salt-sensitive IR64 and salt-tolerant Pokkali rice cultivars. Further, heterologous expression of OsCBSCB-SPB4 in E. coli and tobacco confers marked tolerance against various abiotic stresses. Transgenic tobac-co seedlings over expressing OsCBSCBSPB4 were found to exhibit better growth in terms of delayed leaf senescence, profuse root growth and increased biomass in contrast to the wild-type seedlings when subjected to salinity, dehydration, oxidative and extreme temperature treatments. Yeast-two hybrid stud-ies revealed that OsCBSCBSPB4 interacts with various proteins. Of these, some are known to be in volved in abiotic stress tolerance. Our results suggest that OsCBSCBSPB4 is involved in abiotic stress response and is a potential candidate for raising multiple abiotic stress tolerant plants. PMID- 29491733 TI - A Salt Overly Sensitive Pathway Member from Brassica juncea BjSOS3 Can Functionally Complement DeltaAtsos3 in Arabidopsis. AB - Background: Salt Overly Sensitive (SOS) pathway is a well-known pathway in arabidopsis, essential for maintenance of ion homeostasis and thus conferring salt stress tolerance. In arabidopsis, the Ca2+ activated SOS3 interacts with SOS2 which further activates SOS1, a Na+/H+ antiporter, responsible for removing toxic sodium ions from the cells. In the present study, we have shown that these three components of SOS pathway, BjSOS1, BjSOS2 and BjSOS3 genes exhibit differential expression pattern in response to salinity and ABA stress in contrasting cultivars of Brassica. It is also noticed that constitutive expression of all the three SOS genes is higher in the tolerant cultivar B. juncea as compared to the sensitive B. nigra. In silico interaction of BjSOS2 and BjSOS3 has been reported recently and here we demonstrate in vivo interaction of these two proteins in onion epidermal peel cells. Further, overexpression of BjSOS3 in corresponding arabidopsis mutant DeltaAtsos3 was able to rescue the mutant phenotype and exhibit higher tolerance towards salinity stress at the seedling stage. Conclusion: Taken together, these findings demonstrate that the B. juncea SOS3 (BjSOS3) protein is a functional ortholog of its arabidopsis counterpart and thus show a strong functional conservation of SOS pathway responsible for salt stress signalling between arabidopsis and Brassica species. PMID- 29491734 TI - Identification of a Missense Mutation in the alpha-galactosidase A Gene in a Chinese Family with Fabry Disease. AB - Introduction: Fabry Disease (FD), the second most common lysosomal storage disorder after Gaucher disease, is characterized by variable clinical manifestations, including angiokeratoma, corneal dystrophy, recurrent episodes of extremity pain, renal impairment, cardiac complications and cerebrovascular manifestations. It is caused by mutations in the alpha-galactosidase A gene (gene symbol GLA) on chromosome Xq22, which leads to deficiency of lysosomal alpha galactosidase A (alpha-Gal A), and subsequent accumulation of glycosphingolipids in various tissues and organs. The aim of this study is to identify the disease causing mutation in a five-generation Chinese family with FD. A c.782G>T transversion (p.G261V) in the GLA gene was identified in four patients and two asymptomatic carriers by direct sequencing, and it co-segregated with the disease in the family. The variant is predicted to be disease-causing mutation and result in seriously abnormal function of alpha-Gal A. Four patients in this family present with classic phenotype of FD, including acroparesthesias, hypohidrosis, angiokeratomas and intermittent burning pain in extremity. Conclusion: The disease severity is similar among male and female patients. Our study extends the genotype-phenotype relationship between mutations in the GLA gene and clinical findings of FD, which may be helpful in the genetic counseling of patients with FD. PMID- 29491735 TI - Editorial:New Insights into the Genomes of Kinetoplastid Parasites. PMID- 29491736 TI - High-throughput Methods for Dissection of Trypanosome Gene Regulatory Networks. AB - : From synthesis to decay, mRNA associates with RNA-binding proteins (RBPs) establishing dynamic ribonucleoprotein particles (RNPs). Understanding the composition and function of RNPs is fundamental to understanding how eukaryotic mRNAs are controlled. This is especially relevant for trypanosomes and related kinetoplastid parasites, which mostly rely on post-transcriptional mechanisms to control gene expression. Crucial for trypanosome differentiation, development, or even response to heat shock, RBPs are known to be essential modulators of diverse molecular processes. The recent application of large-scale quantitative methods, such as Next-Generation Sequencing (NGS) and quantitative mass spectrometry, has revealed new exciting features about the parasite RNA-related metabolism. Novel proteins carrying RNA-binding activity, including many proteins without RNA related ontology were discovered setting a necessary groundwork to get in insights into RNA biology. CONCLUSION: This review aims to give the reader an understanding of current trypanosome RNP research, highlighting the progress made using high-throughput approaches. PMID- 29491737 TI - Gene and Chromosomal Copy Number Variations as an Adaptive Mechanism Towards a Parasitic Lifestyle in Trypanosomatids. AB - Trypanosomatids are a group of kinetoplastid parasites including some of great public health importance, causing debilitating and life-long lasting diseases that affect more than 24 million people worldwide. Among the trypanosomatids, Trypanosoma cruzi, Trypanosoma brucei and species from the Leishmania genus are the most well studied parasites, due to their high prevalence in human infections. These parasites have an extreme genomic and phenotypic variability, with a massive expansion in the copy number of species-specific multigene families enrolled in host-parasite interactions that mediate cellular invasion and immune evasion processes. As most trypanosomatids are heteroxenous, and therefore their lifecycles involve the transition between different hosts, these parasites have developed several strategies to ensure a rapid adaptation to changing environments. Among these strategies, a rapid shift in the repertoire of expressed genes, genetic variability and genome plasticity are key mechanisms. Trypanosomatid genomes are organized into large directional gene clusters that are transcribed polycistronically, where genes derived from the same polycistron may have very distinct mRNA levels. This particular mode of transcription implies that the control of gene expression operates mainly at post-transcriptional level. In this sense, gene duplications/losses were already associated with changes in mRNA levels in these parasites. Gene duplications also allow the generation of sequence variability, as the newly formed copy can diverge without loss of function of the original copy. Recently, aneuploidies have been shown to occur in several Leishmania species and T. cruzi strains. Although aneuploidies are usually associated with debilitating phenotypes in superior eukaryotes, recent data shows that it could also provide increased fitness in stress conditions and generate drug resistance in unicellular eukaryotes. In this review, we will focus on gene and chromosomal copy number variations and their relevance to the evolution of trypanosomatid parasites. PMID- 29491739 TI - Biology of Trypanosoma cruzi Retrotransposons: From an Enzymatic to a Structural Point of View. AB - Introduction: An important portion of the Trypanosoma cruzi genome is composed of mobile genetic elements, which are interspersed with genes on all chromosomes. The L1Tc non-LTR retrotransposon and its truncated version NARTc are the most highly represented and best studied of these elements. L1Tc is actively transcribed in all three forms of the Trypanosoma parasite and encodes the proteins that enable it to autonomously mobilize. This mini review discusses the enzymatic properties of L1Tc that enable its mobilization and possibly the mobilization of other non-autonomous retrotransposons in Trypanosoma. We also briefly review the Hepatitis Delta Virus-like autocatalytic and 2A self-cleaving viral-like sequences contained in L1Tc that regulate post-transcriptional properties such as relative protein abundance and mRNA stability. Special emphasis is placed on the Pr77 dual system, which is based on the RNA pol II dependent internal promoter of L1Tc and NARTc and the HDV-like ribozyme activity encoded by the first 77 nucleotides of the element's DNA and RNA. The high degree of conservation of the Pr77 sequence, referred to as the "Pr77-hallmark", among different trypanosomatid retroelements suggests that these mobile elements are responsible for the distribution of regulatory sequences within the genome they inhabit. Conclusion: We also discuss how the involvement of L1Tc and NARTc in the gene regulatory processes of these parasites could justify their domestication and long-term coexistence in these ancient organisms. PMID- 29491738 TI - Conservation and Variation in Strategies for DNA Replication of Kinetoplastid Nuclear Genomes. AB - Introduction: Understanding how the nuclear genome of kinetoplastid parasites is replicated received experimental stimulus from sequencing of the Leishmania major, Trypanosoma brucei and Trypanosoma cruzi genomes around 10 years ago. Gene annotations suggested key players in DNA replication initiation could not be found in these organisms, despite considerable conservation amongst characterised eukaryotes. Initial studies that indicated trypanosomatids might possess an archaeal-like Origin Recognition Complex (ORC), composed of only a single factor termed ORC1/CDC6, have been supplanted by the more recent identification of an ORC in T. brucei. However, the constituent subunits of T. brucei ORC are highly diverged relative to other eukaryotic ORCs and the activity of the complex appears subject to novel, positive regulation. The availability of whole genome sequences has also allowed the deployment of genome-wide strategies to map DNA replication dynamics, to date in T. brucei and Leishmania. ORC1/CDC6 binding and function in T. brucei displays pronounced overlap with the unconventional organisation of gene expression in the genome. Moreover, mapping of sites of replication initiation suggests pronounced differences in replication dynamics in Leishmania relative to T. brucei. Conclusion: Here we discuss what implications these emerging data may have for parasite and eukaryotic biology of DNA replication. PMID- 29491740 TI - Transcriptional Regulation of Telomeric Expression Sites and Antigenic Variation in Trypanosomes. AB - Introduction: Trypanosoma brucei uses antigenic variation to evade the host antibody clearance by periodically changing its Variant Surface Glycoprotein (VSGs) coat. T. brucei encode over 2,500 VSG genes and pseudogenes, however they transcribe only one VSG gene at time from one of the 20 telomeric Expression Sites (ESs). VSGs are transcribed in a monoallelic fashion by RNA polymerase I from an extranucleolar site named ES body. VSG antigenic switching occurs by transcriptional switching between telomeric ESs or by recombination of the VSG gene expressed. VSG expression is developmentally regulated and its transcription is controlled by epigenetic mechanisms and influenced by a telomere position effect. Conclusion: Here, we discuss 1) the molecular basis underlying transcription of telomeric ESs and VSG antigenic switching; 2) the current knowledge of VSG monoallelic expression; 3) the role of inositol phosphate pathway in the regulation of VSG expression and switching; and 4) the developmental regulation of Pol I transcription of procyclin and VSG genes. PMID- 29491741 TI - Introgression of the Kinetoplast DNA: An Unusual Evolutionary Journey in Trypanosoma cruzi. AB - Introduction: Phylogenetic relationships between different lineages of Trypanosoma cruzi, the agent of Chagas disease, have been controversial for several years. However, recent phylogenetic and phylogenomic analyses clarified the nuclear relationships among such lineages. However, incongruence between nuclear and kinetoplast DNA phylogenies has emerged as a new challenge. This incongruence implies several events of mitochondrial introgression at evolutionary level. However, the mechanism that gave origin to introgressed lineages is unknown. Here, I will review and discuss how maxicircles of the kinetoplast were horizontally and vertically transferred between different lineages of T. cruzi. Conclusion: Finally, I will discuss what we know - and what we don't - about the kDNA transference and inheritance in the context of sexual reproduction in this parasite. PMID- 29491743 TI - Leptomonas pyrrhocoris: Genomic insight into Parasite's Physiology. AB - Background: Leptomonas pyrrhocoris is a parasite of the firebug Pyrrhocoris apterus. This flagellate has been recently proposed as a model species for studying different aspects of the biology of monoxenous trypanosomatids, including host - parasite interactions. During its life cycle L. pyrrhocoris never tightly attaches to the epithelium of the insect gut. In contrast, its dixenous relatives (Leishmania spp.) establish a stable infection via attachment to the intestinal walls of their insect hosts. Material and Methods: This process is mediated by chemical modifications of the cell surface lipophosphoglycans. In our study we tested whether the inability of L. pyrrhocoris to attach to the firebug's midgut is associated with the absence of these glycoconjugates. We also analyzed evolution of the proteins involved in proper lipophosphoglycan assembly, cell attachment and establishment of a stable infection in L. pyrrhocoris, L. seymouri, and Leishmania spp. Our comparative analysis demonstrated differences in SCG/L/R repertoire between the two parasite subgenera, Leishmania and Viannia, which may be related to distinct life strategies in various Leishmania spp. The genome of L. pyrrhocoris encodes 6 SCG genes, all of which are quite divergent from their orthologs in the genus Leishmania. Using direct probing with an antibody recognizing the beta-Gal side chains of lipophosphoglycans, we confirmed that these structures are not synthesized in L. pyrrhocoris. Conclusion: We conclude that either the SCG enzymes are not active in this species (similarly to SCG5/7 in L. major), or they possess a different biochemical activity. PMID- 29491742 TI - Epigenetic Regulation of Transcription in Trypanosomatid Protozoa. AB - The Trypanosomatid family includes flagellated parasites that cause fatal human diseases. Remarkably, protein-coding genes in these organisms are positioned in long tandem arrays that are transcribed polycistronically. However, the knowledge about regulation of transcription initiation and termination in trypanosomatids is scarce. The importance of epigenetic regulation in these processes has become evident in the last years, as distinctive histone modifications and histone variants have been found in transcription initiation and termination regions. Moreover, multiple chromatin-related proteins have been identified and characterized in trypanosomatids, including histone-modifying enzymes, effector complexes, chromatin-remodelling enzymes and histone chaperones. Notably, base J, a modified thymine residue present in the nuclear DNA of trypanosomatids, has been implicated in transcriptional regulation. Here we review the current knowledge on epigenetic control of transcription by all three RNA polymerases in this group of early-diverged eukaryotes. PMID- 29491744 TI - Synthesis of Trifluoroacetyl-Substituted Cyclopropanes Using Onium Ylides. AB - The use of carbonyl-stabilized ammonium- and sulfonium ylides allows for the synthesis of highly-functionalized trifluoroacetyl-substituted cyclopropanes. It turned out that the diastereoselectivities strongly depend on the nature of the chosen ylide and the employed base. The products could be obtained in good yields under operationally simple conditions. PMID- 29491746 TI - Profiling the interactome of protein kinase C zeta by proteomics and bioinformatics. AB - Background: Protein kinase C zeta (PKCzeta), an isoform of the atypical protein kinase C, is a pivotal regulator in cancer. However, the molecular and cellular mechanisms whereby PKCzeta regulates tumorigenesis and metastasis are still not fully understood. In this study, proteomics and bioinformatics analyses were performed to establish a protein-protein interaction (PPI) network associated with PKCzeta, laying a stepping stone to further understand the diverse biological roles of PKCzeta. Methods: Protein complexes associated with PKCzeta were purified by co-immunoprecipitation from breast cancer cell MDA-MB-231 and identified by LC-MS/MS. Two biological replicates and two technical replicates were analyzed. The observed proteins were filtered using the CRAPome database to eliminate the potential false positives. The proteomics identification results were combined with PPI database search to construct the interactome network. Gene ontology (GO) and pathway analysis were performed by PANTHER database and DAVID. Next, the interaction between PKCzeta and protein phosphatase 2 catalytic subunit alpha (PPP2CA) was validated by co-immunoprecipitation, Western blotting and immunofluorescence. Furthermore, the TCGA database and the COSMIC database were used to analyze the expressions of these two proteins in clinical samples. Results: The PKCzeta centered PPI network containing 178 nodes and 1225 connections was built. Network analysis showed that the identified proteins were significantly associated with several key signaling pathways regulating cancer related cellular processes. Conclusions: Through combining the proteomics and bioinformatics analyses, a PKCzeta centered PPI network was constructed, providing a more complete picture regarding the biological roles of PKCzeta in both cancer regulation and other aspects of cellular biology. PMID- 29491747 TI - Considerations for Providing Ambulatory Pharmacy Services for Pediatric Patients. AB - Pediatric clinical pharmacists are an integral part of the health care team. By practicing in an ambulatory care clinic, they can reduce the risk of medication errors, improve health outcomes, and enhance patient care. Unfortunately, because of limited data, misconceptions surrounding the role of pharmacists, and reimbursement challenges, there may be difficulty in establishing or expanding pediatric clinical pharmacy services to an ambulatory care setting. The purpose of this paper is to provide an overview of considerations for establishing or expanding pharmacy services in a pediatric ambulatory care clinic. The primer will discuss general and pediatric-specific pharmacy practice information, as well as potential barriers, and recommendations for identifying a practice site, creating a business plan, and integrating these services into a clinic setting. PMID- 29491745 TI - Lessons learnt in recruiting disadvantaged families to a birth cohort study. AB - Background: Dental decay in early childhood can be prevented by a model based on shared care utilising members of primary care team such as Child and Family Health Nurses (CFHNs) in health promotion and early intervention. The aims of this study were to identify the facilitators and barriers faced by CFHNs in recruiting research participants from disadvantaged backgrounds to a birth cohort study in South Western Sydney, Australia. Methods: Child and Family Health Nurses recruited mothers-infants dyads (n = 1036) at the first post-natal home visit as part of Healthy Smiles Healthy Kids Study, an ongoing birth cohort study in South Western Sydney. The nurses (n = 19) were purposively selected and approached for a phone based in-depth semi-structured interview to identify the challenges faced by them during the recruitment process. Interviews were audio-recorded, subsequently transcribed verbatim and analysed by thematic analysis. Results: The nurses found the early phase of parenting was an overwhelming stage for parents as they are pre-occupied with more immediate issues such as settling and feeding a newborn. They highlighted some key time-points such as during pregnancy and/or around the time of infant teething may be more appropriate for recruiting families to dental research projects. However, they found it easier to secure the family's attention by offering incentives, gifts and invitations for free oral health services. The use of web-based approaches and maintaining regular contact with the participants was deemed crucial for long-term research. Cultural and linguistic barriers were seen as an obstacle in recruiting ethnic minority populations and the need for cultural insiders in the research team was deemed important to resolve the challenges associated with conducting research with diverse cultures. Finally, nurses identified the importance of inter-professional collaboration to provide easier access to recruiting research participants. Conclusions: This study highlighted the need for multiple time-points and incentives to facilitate recruitment and retention of disadvantaged communities in longitudinal research. The need for cultural insiders and inter-professional collaboration in research team are important to improve research participation. PMID- 29491748 TI - Use of Electronic Health Record Tools to Facilitate and Audit Infliximab Prescribing. AB - OBJECTIVES: The objective of this project was to assess a pediatric institution's use of infliximab and develop and evaluate electronic health record tools to improve safety and efficiency of infliximab ordering through auditing and improved communication. METHODS: Best use of infliximab was defined through a literature review, analysis of baseline use of infliximab at our institution, and distribution and analysis of a national survey. Auditing and order communication were optimized through implementation of mandatory indications in the infliximab orderable and creation of an interactive flowsheet that collects discrete and free-text data. The value of the implemented electronic health record tools was assessed at the conclusion of the project. RESULTS: Baseline analysis determined that 93.8% of orders were dosed appropriately according to the findings of a literature review. After implementation of the flowsheet and indications, the time to perform an audit of use was reduced from 60 minutes to 5 minutes per month. Four months post implementation, data were entered by 60% of the pediatric gastroenterologists at our institution on 15.3% of all encounters for infliximab. Users were surveyed on the value of the tools, with 100% planning to continue using the workflow, and 82% stating the tools frequently improve the efficiency and safety of infliximab prescribing. CONCLUSIONS: Creation of a standard workflow by using an interactive flowsheet has improved auditing ability and facilitated the communication of important order information surrounding infliximab. Providers and pharmacists feel these tools improve the safety and efficiency of infliximab ordering, and auditing data reveal that the tools are being used. PMID- 29491750 TI - Sedation Protocol During Bevacizumab Intravitreal Injection in Preterm Infants With Retinopathy of Prematurity. AB - OBJECTIVES: This study describes outcomes of intravenous (IV) analgesics and sedatives for bedside intravitreal bevacizumab injections for retinopathy of prematurity. METHODS: This retrospective study included infants receiving intravitreal bevacizumab injections between January 2012 and May 2016. Infants were excluded if bevacizumab was administered under general anesthesia or for incomplete records. Data collection included demographics, sedation and analgesia regimen, and cardiopulmonary adverse events (AEs). The primary objective was to identify the median doses of the IV analgesics and sedatives. The secondary objectives included the number of patients with cardiopulmonary AEs and those with procedure success, defined as procedure completion without interruption and absence of interventions. RESULTS: Fifteen infants were included. Fourteen (93.3%) were initiated on a fentanyl infusion at a median of 2 mcg/kg/hr (IQR, 2 3.6), and 12 (80%) received midazolam infusions at a median of 0.06 mg/kg/hr. All patients received at least 1 IV neuromuscular blocker dose just prior to the procedure. Only 2 patients (13.3%) required an increase in their fentanyl or midazolam infusions. Procedure success was achieved in 13 patients (86.7%). Five patients (33.3%) experienced 1 cardiopulmonary AE. One patient (6.7%) had a delay in the procedure, and 1 patient (6.7%) required naloxone. Despite this, the procedure was completed in all patients. CONCLUSIONS: Most received fentanyl and midazolam infusions with a dose of vecuronium just prior to the procedure. Thirteen (86.7%) met the criteria for procedure success. One-third experienced a cardiopulmonary AE. Future studies are needed to identify the optimal agents and route of administration for this procedure. PMID- 29491749 TI - Impact of Early Versus Late Diuretic Exposure on Metabolic Bone Disease and Growth in Premature Neonates. AB - OBJECTIVES: This study aimed to determine whether there are differences in the incidence of metabolic bone disease (MBD) between preterm neonates first exposed to diuretics prior to 2 weeks of life versus those exposed after 2 weeks. METHODS: This study was a retrospective analysis of premature neonates born at a tertiary care center between 2011 and 2015 who received either furosemide or chlorothiazide. The primary outcome was incidence of MBD. Secondary outcomes included growth, electrolyte disturbances, oxygen requirement, and length of stay. RESULTS: A total of 147 patients were included. Early initiation (n = 90) and late initiation (n = 57) arms were balanced with respect to birth weight and gestational age. There was no difference in incidence of MBD in the early group (76%) versus the late group (65%; p = 0.164). Stratification by cumulative dose showed incidence of 85% in patients receiving >=8 mg/kg of furosemide, compared with 68% and 64% of those in the <4 mg/kg and 4 to 7.9 mg/kg strata, respectively (p = 0.06). The early group experienced greater reductions in length-for-age growth during diuretic therapy (-70% versus -40%; p = 0.009). Electrolyte abnormalities were more prevalent in the early group. Although there was no difference in duration of mechanical ventilation, duration of supplemental oxygen requirement was reduced in the late group (75 versus 89 days; p = 0.003). CONCLUSIONS: Timing of diuretic initiation did not affect incidence of MBD. Increased cumulative furosemide exposure may be associated with higher incidence. Patients first exposed to diuretics within 2 weeks of life are at higher risk for electrolyte abnormalities and reduced growth velocity. PMID- 29491751 TI - Infantile Gastroesophageal Reflux: Adherence to Treatment Guidelines in the Hospital Setting. AB - OBJECTIVES: Recent guidelines defined and differentiated the management of gastroesophageal reflux (GER) and gastroesophageal reflux disease (GERD). The guidelines recommend against using empiric acid suppression therapy for infantile GER. The primary objective of this study was to assess inpatient guideline adherence regarding management of infantile GER through the perspective of pharmacists. Secondary objectives included assessing pharmacist comfort level with differentiation between GER and GERD, observing current trends in practice relating to the primary objective, and determining the availability of institution-specific guidelines that address the management of infantile GER. METHODS: An institutional review board-approved, national, online survey of pharmacists with inpatient pediatric experience was conducted. Pediatric pharmacy membership directories were used to create the listserv of eligible pharmacists. The 2009 NASPGHAN/ESPGHAN (North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition/European Society for Pediatric Gastroenterology, Hepatology, and Nutrition) Pediatric Gastroesophageal Reflux Clinical Practice Guideline was used to develop the survey and to define both GER and GERD. Demographic data was also collected regarding the institutional setting and pharmacists responding. RESULTS: The overall response rate was 14.8% (n = 149). Although 29.7% of pharmacists stated empiric acid suppression trials were not used for infantile GER at their institution, 44.6% responded that these trials are initiated 1 to 2 times per week in their hospitals. In addition, 19.6% responded that these empiric trials were initiated 3 to 5 times per week. A smaller percentage of responders reported even higher frequencies per week at their institutions. CONCLUSIONS: From the results of the survey, infants continue to receive empiric acid suppression trials for GER in the inpatient setting, which is not adherent to the current guideline recommendation. PMID- 29491752 TI - Preliminary Indications for the Use of Sugammadex After Its Addition to a Formulary at a Tertiary Care Children's Hospital. AB - OBJECTIVES: Neuromuscular blocking agents (NMBAs) are administered to facilitate endotracheal intubation and provide skeletal muscle relaxation in surgical procedures. Sugammadex (Bridion) recently received approval by the United States Food and Drug Administration for reversal of rocuronium and vecuronium-induced neuromuscular blockade thereby providing an alternative to acetylcholinesterase inhibitors such as neostigmine. This quality improvement analysis sought to investigate the clinical reasons and common clinical perceptions for choosing sugammadex over neostigmine to reverse NMBAs. METHODS: One hundred cases were reviewed where sugammadex was used for neuromuscular blockade reversal in the operating room. Cases were identified from electronic medical record reports. Anesthesia providers responsible for administering sugammadex were interviewed to obtain rationales for sugammadex use in the perioperative setting. Responses were reviewed to identify distinct reasons for using sugammadex. Two independent raters ranked the reasons according to prevalence. The study was exempt from Institutional Review Board approval as a quality improvement (QI) project. RESULTS: Forty-two anesthesia providers (15 Certified Registered Nurse Anesthetists, 5 anesthesiology trainees, and 22 attending anesthesiologists) were interviewed to identify reasons why sugammadex was administered intraoperatively in 100 surgical cases (69/31 male/female patients, age 9.4 +/- 6.5 years). The author identified the top 19 common reasons respondents chose to use sugammadex for each case, and independent raters reviewed the response summaries for those 19 primary reasons sugammadex was used. The most common reasons for choosing sugammadex were: 1) beneficial pharmacokinetics of the agent; 2) sugammadex's perceived superior efficacy over neostigmine; and 3) concerns regarding adverse effects of neostigmine and/or the anticholinergic agent. CONCLUSIONS: Sugammadex has recently been introduced for clinical use to reverse NMBAs at our institution. Primary reasons and perceptions for its use over neostigmine included a limited adverse effect profile, a greater sense of control and predictability of patients' response, and a limited incidence of residual neuromuscular blockade. PMID- 29491753 TI - Voriconazole: Poor Oral Bioavailability and Possible Renal Toxicity in an Infant With Invasive Aspergillosis. AB - Voriconazole is the recommended agent of choice for treatment of invasive aspergillosis; however, achieving therapeutic serum concentrations while avoiding toxicity, both with intravenous and oral formulations, is challenging in infants. We report the case of an infant with confirmed invasive aspergillosis who developed renal toxicity possibly associated with IV voriconazole. Renal function improved upon withdrawal of the IV agent and switch to the oral formulation. The infant subsequently required large oral weight-based dosing to achieve therapeutic voriconazole serum concentrations. This case illustrates a rare side effect associated with voriconazole as well as the issues surrounding the pharmacokinetic profile of voriconazole in a pediatric patient. PMID- 29491754 TI - Gabapentin Improves Oral Feeding in Neurologically Intact Infants With Abdominal Disorders. AB - Feeding intolerance, poor oral feeding skills, and retching are common symptoms seen in medically complex infants with a history of abdominal disorders and surgical interventions, such as gastrostomy tube placement and Nissen fundoplication. Visceral hyperalgesia may play a role in the underlying pathophysiology. We report the use of orally administered gabapentin in 3 infants with presumed visceral hyperalgesia presenting as poor tolerance of enteral and oral feeds. Retching and outward discomfort associated with feeds was resolved within 2 to 3 days of initiation of therapy. Full oral feeds were obtained in all 3 patients within 3 to 4 months of starting gabapentin without changing adjunctive medications or therapies. After attainment of full oral feeds, all patients were successfully weaned off gabapentin over a month, with no notable side effects, signs of withdrawal, or impact on ability to feed by mouth. PMID- 29491756 TI - Pain Management. PMID- 29491755 TI - Significant Hyperbilirubinemia and Acute Hepatocellular Jaundice in a Pediatric Patient Receiving Deferasirox: A Case Report. AB - Despite a boxed warning, postmarketing reports of deferasirox-associated hepatic injury in patients with chronic transfusions are not well described. Hepatic impairment, including failure, has been reported to occur more frequently in patients older than 55 years and in those with significant comorbidities, including liver cirrhosis and multiorgan failure. In this case report, we describe significant hyperbilirubinemia and acute hepatocellular jaundice related to deferasirox in a 7-year-old female being treated for iron overload secondary to chronic transfusions. This report outlines a unique case without preexisting risk factors in which other causes of liver injury are excluded as defined by the Roussel Uclaf Causality Assessment Method, which indicates a probable score of deferasirox causing the injury. PMID- 29491757 TI - Serrated Colorectal Lesions in Patients With Inflammatory Bowel Disease. AB - The serrated neoplasia pathway is thought to account for up to 30% of sporadic colorectal cancer, but its role in inflammatory bowel disease (IBD)-related colorectal cancer is still not well elucidated. Hyperplastic polyps are not thought to impart an increased risk of colorectal cancer; however, sessile serrated adenomas/polyps and traditional serrated adenomas may have malignant potential. From the limited research currently available, this appears to hold true for IBD patients as well. IBD patients do not seem to be at a higher risk of typical serrated colorectal lesions than the general population, but it is still not known if they have a quicker progression to colorectal cancer. Serrated epithelial change is a newly described finding in patients with longstanding colitis that may increase the risk of colorectal cancer in IBD patients. Overall, serrated lesions are not uncommon in the IBD population, and further research is needed to understand the role that serrated lesions play in the development of colorectal cancer. PMID- 29491758 TI - Variable Use of Disaccharidase Assays When Evaluating Abdominal Pain. AB - Background and Aims: Patients with a disaccharidase deficiency typically present with abdominal discomfort and often with diarrhea. However, disaccharidase deficiency is often overlooked as a cause of these complaints. Therefore, we sought to determine the prevalence of lactase and sucrase deficiencies in a pediatric population undergoing diagnostic esophagogastroduodenoscopy (EGD) and to describe disaccharidase testing practices among pediatric gastroenterologists. Methods: Endoscopic records from patients undergoing diagnostic EGD and disaccharidase analysis (DA) were retrospectively reviewed. Diagnostic EGDs performed over a 5-year period (2010 through 2014) at a freestanding endoscopy center serving 13 pediatric gastroenterologists were assessed. Demographic and clinical data on patients were collected and grouped; patients with primary sucrase-isomaltase deficiency (SID) were the main focus. The data were stratified by the physician performing the procedures. Results: Over the 5-year study period, 5368 EGDs were performed, with abdominal pain as the primary indication in 3235 cases (60.2%). DAs were performed on 963 patients (17.9% of the total cohort; 29.8% of those with abdominal pain). Lactase deficiencies, sucrase deficiencies, and primary SID were found in 44.7%, 7.6%, and 3.5% of DAs, respectively. The number of DAs performed varied widely among physicians, ranging from 1.6% to 64.5% of EGDs evaluating patients with abdominal pain. Univariate regression analysis revealed significant correlations between the number of DAs performed and the number of SID and lactase deficiencies found (P<.001 for both). Conclusion: Rates of DAs vary widely among pediatric gastroenterologists performing diagnostic EGDs in children with abdominal pain. Physician education and clinical practice guidelines regarding the use of DAs are warranted. PMID- 29491760 TI - Update on Relative Value Units and the Cognitive Physician Visit. PMID- 29491759 TI - Hepatitis B Virus Infection and Organ Transplantation. AB - Hepatitis B virus (HBV) infection remains an important cause of liver disease and continues to present several unique challenges in organ transplantation despite the availability of an effective vaccine to prevent HBV infection and the introduction of oral therapy to treat HBV infection over 20 years ago. HBV recurrence following liver transplantation can now be prevented with antiviral therapy, although controversy persists as to whether immunoprophylaxis with hepatitis B immunoglobulin is also necessary. HBV reactivation following organ transplantation can occur even in recipients with absent hepatitis B surface antigen at the time of transplantation and remains an important cause of morbidity and mortality. Expansion of the donor pool by using organs from hepatitis B core antibody-positive donors can result in HBV infection in the recipient. Another challenge is severe HBV reactivation leading to liver failure in HBV-infected patients receiving immunomodulatory agents, which are increasingly being used for a variety of nonneoplastic indications. PMID- 29491762 TI - Emerging Therapeutic Targets for Hepatitis Delta Virus Infection. PMID- 29491761 TI - The Role of Gut-Brain Interactions in Influencing Symptoms of Irritable Bowel Syndrome. PMID- 29491763 TI - Endoscopic Mucosal Resection Vs Endoscopic Submucosal Dissection for Colon Polyps. PMID- 29491764 TI - Pain Management in Patients With Inflammatory Bowel Disease. PMID- 29491765 TI - GASTRO-HEP News. PMID- 29491766 TI - Experiences of Professional Helping Relations by Persons with Co-occurring Mental Health and Substance Use Disorders. AB - Recovery in co-occurring mental health and substance use disorders often involves relationships with professional helpers, yet little is known about how these are experienced by service users. The aim of this study was to explore and describe behaviour and attributes of professional helpers that support recovery, as experienced by persons with co-occurring disorders. Within a collaborative approach, in-depth individual interviews with eight persons with lived experience of co-occurring disorders were analysed using systematic text condensation. The analysis yielded four categories of recovery-supporting behaviour and attributes of professional helpers and the ability to build trust cuts across all of them: Building trust through (a) hopefulness and loving concern, (b) commitment, (c) direct honesty and expectation and (d) action and courage. Services should allow for flexibility and continuity, and training should recognise the importance of establishing trust in order to reach out to this group. PMID- 29491767 TI - Co-occurring Mental Disorders in Substance Abuse Treatment: the Current Health Care Situation in Germany. AB - Aim of this study was to investigate the current health care situation for patients with co-occurring mental disorders in addiction treatment. Therefore, data from the German Substance Abuse Treatment System (N = 194,406) was analysed with regard to the prevalence of comorbid mental disorders, treatment characteristics and outcomes of patients with comorbid psychiatric diagnosis. In outpatient setting, the prevalence of comorbid diagnoses was considerably lower (4.6%) than in inpatient setting (50.7%), but mood and anxiety disorders were the most prevalent additional diagnoses in both settings. In the treatment of patients with these comorbid disorders, we found higher rates of complementary internal and external (psychiatric) treatment, more co-operations and referrals after treatment, and positive treatment process outcomes. Findings indicate that the knowledge of an additional diagnosis influences the health care provision of affected patients and can therefore be seen as the essential precondition for providing adequate and comprehensive treatment. This highlights the importance of a sufficient consideration and diagnostic assessment of mental disorders in addiction treatment to further improve the health care situation of comorbid patients. PMID- 29491768 TI - Alcohol Drinking and Low Nutritional Value Food Eating Behavior of Sports Bettors in Gambling Advertisements. AB - The prevalence of sports betting advertising has become a major concern for gambling regulators, particularly since the legalization of online gambling in many European jurisdictions. Although the composition of gambling advertisement narratives has received some limited attention, nothing is known regarding how betting advertisements (often referred to as "adverts" or "commercials") might be associating gambling with other potentially risky behaviors. The present paper examines the representation of alcohol drinking and low nutritional value food eating in sports betting advertising. By means of a mixed-methods approach to content analysis, a sample of British and Spanish soccer betting adverts was analyzed (N = 135). The results suggest that betting advertising aligns drinking alcohol with sports culture and significantly associates emotionally charged sporting situations such as watching live games or celebrating goals with alcohol. Additionally, alcohol drinking is more frequent in betting adverts with a higher number of characters, linking friendship bonding and alcohol drinking (especially beer) in the context of sports gambling. PMID- 29491769 TI - Substance Use and Psychological Disorders Among Art and Non-art University Students: an Empirical Self-Report Survey. AB - Media stories often suggest that those working in the creative arts appear to use and abuse psychoactive substances. The aim of the present study was to analyze the relationship between the use of psychoactive substances and the presence of psychological disorders among art and non-art students. Questionnaires related to these two areas were completed by 182 art students in higher education and a control group of 704 non-art university students. To assess psychoactive substance use, a structured questionnaire including the Cannabis Abuse Screening Test (CAST) and the Alcohol Use Disorders Identification Test (AUDIT) was administered to participants. Psychological disorders were assessed using the Hungarian version of the Brief Symptom Inventory (BSI) and the Global Severity Index (GSI). After analyzing the data, significant differences were found between the two groups regarding their first use of psychoactive substances. Art students' current substance use was found to be significantly more frequent compared to the control group. In relation to psychological disorders, art students scored significantly higher on three scales of the BSI (i.e., psychoticism, hostility, and phobic anxiety). Overall, a significantly higher proportion of artists were labeled as "problematic" using the GSI. The results suggest that artists have a higher risk of both substance use and experiencing psychological disorders. PMID- 29491770 TI - A Pilot Evaluation of a Tutorial to Teach Clients and Clinicians About Gambling Game Design. AB - This paper describes the pilot evaluation of an Internet-based intervention, designed to teach counselors and problem gamblers about how electronic gambling machines (EGMs) work. This study evaluated the tutorial using assessment tools, such as rating scales and test of knowledge about EGMs and random chance. The study results are based on a number of samples, including problem gambling counselors (n = 25) and problem gamblers (n = 26). The interactive tutorial was positively rated by both clients and counselors. In addition, we found a significant improvement in scores on a content test about EGM games for both clients and counselors. An analysis of the specific items suggests that the effects of the tutorial were mainly on those items that were most directly related to the content of the tutorial and did not always generalize to other items. This tutorial is available for use with clients and for education counselors. The data also suggest that the tutorial is equally effective in group settings and in individual settings. These results are promising and illustrate that the tool can be used to teach counselors and clients about game design. Furthermore, research is needed to evaluate its impact on gambling behavior. PMID- 29491771 TI - "Internet Addiction": a Conceptual Minefield. AB - With Internet connectivity and technological advancement increasing dramatically in recent years, "Internet addiction" (IA) is emerging as a global concern. However, the use of the term 'addiction' has been considered controversial, with debate surfacing as to whether IA merits classification as a psychiatric disorder as its own entity, or whether IA occurs in relation to specific online activities through manifestation of other underlying disorders. Additionally, the changing landscape of Internet mobility and the contextual variations Internet access can hold has further implications towards its conceptualisation and measurement. Without official recognition and agreement on the concept of IA, this can lead to difficulties in efficacy of diagnosis and treatment. This paper therefore provides a critical commentary on the numerous issues of the concept of "Internet addiction", with implications for the efficacy of its measurement and diagnosticity. PMID- 29491772 TI - Conceptual Issues Concerning Internet Addiction and Internet Gaming Disorder: Further Critique on Ryding and Kaye (2017). AB - The recent commentary paper by Ryding and Kaye Journal of Mental Health and Addiction (doi 10.1007/s11469-017-9811-6, 2017) rightly claimed that "internet addiction" (IA) is a conceptual minefield and raised some important issues for researchers and treatment providers working in the online addiction field. In the present commentary paper, some of the assertions made by Ryding and Kaye are briefly critiqued and extended. More specifically, the present paper (i) examines IA and Internet-based addictions and argues that IA is now a misnomer, (ii) examines IA and its relationship to Internet Gaming Disorder (IGD) and argues IA and IGD are two completely different constructs, and that IGD is a sub-type of gaming disorder rather than a sub-type of IA, (iii) argues that the time spent engaging in online activities is not a good criterion for assessing online addictions and that the context of use is far more important criterion, and (iv) argues that those researchers working in the IA field can learn a lot from the problem gambling field in collecting robust data. More specifically, one of the innovative ways forward could be to build strategic partnerships with commercial online companies to analyze their behavioral tracking data. PMID- 29491773 TI - Digital Traces of Behaviour Within Addiction: Response to Griffiths (2017). AB - Griffiths' (2017) response to the recent commentary piece by Ryding and Kaye (2017) on "Internet Addiction: A conceptual minefield" provided a useful critique and extension of some key issues. We take this opportunity to further build upon on one of these issues to provide some further insight into how the field of "internet addiction" (IA) or technological addictions more generally, may benefit from capitalising on behavioural data. As such, this response extends Griffiths' (2007) points surrounding the efficacy of behavioural data previously used in studies on problematic gambling, to consider its merit for future research on IA or associated topics such as Internet Gaming Disorder (IGD) or "Smartphone addiction". Within this, we highlight the challenges associated with utilising behavioural data but provide some practical solutions which may support researchers and practitioners in this field. These recent developments could, in turn, advance our understanding and potentially validate such concepts by establishing behavioural correlates, conditions and contexts. Indeed, corroborating behavioural metrics alongside self-report measures presents a key opportunity if scholars and practitioners are to move the field forward. PMID- 29491774 TI - pH responsive alginate polymeric rafts for controlled drug release by using box behnken response surface design. AB - Aim of the present work was to develop alginate raft forming tablets for controlled release pantoprazole sodium sesquihydrate (PSS). Box behnken design was used to optimize 15 formulations with three independent and three dependent variables. Physical tests of all formulations were within pharmacopoeial limits. Raft was characterized by their strength, thickness, resilience, acid neutralizing capacity, floating lag time and total floating time. Raft strength, thickness and resilience of optimized formulation AR9 were 7.43 +/- 0.019 g, 5.8 +/- 0.245 cm and greater than 480 min, respectively. Buffering and neutralizing capacity were 11.2 +/- 1.01 and 6.5 +/- 0.56 meq, respectively. Dissolution studies were performed by using simulated gastric fluid pH 1.2 and cumulative percentage release of optimized formulation AR9 was found 98%. First order release kinetics were followed and non-fickian diffusion was observed as value of n was greater than 0.45 in korsmeyer-peppas model. PSS, polymers, tablets and rafts were further characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffractometry (XRD) and differential scanning calorimetry (DSC). FTIR spectra of PSS, polymers and raft of optimized formulation AR9 showed peaks at 3223.09, 1688.17, 1586.67, 1302.64 and 1027.74 cm-1 due to -OH stretching, ester carbonyl group (C=O) stretching, existence of water and carboxylic group in raft, C-N stretching and -OH bending vibration showed no interaction between them. XRD showed diffraction lines indicates crystalline nature of PSS. DSC thermogram showed endothermic peaks at 250 degrees C for PSS. The developed raft was suitable for controlled release delivery of PSS. PMID- 29491775 TI - Hybrid networks based on epoxidized camelina oil. AB - Lately, renewable resources received great attention in the macromolecular compounds area, regarding the design of the monomers and polymers with different applications. In this study the capacity of several modified vegetable oil-based monomers to build competitive hybrid networks was investigate, taking into account thermal and mechanical behavior of the designed materials. In order to synthesize such competitive nanocomposites, the selected renewable raw material, camelina oil, was employed due to the non-toxicity and biodegradability behavior. General properties of epoxidized camelina oil-based materials were improved by loading of different types of organic-inorganic hybrid compounds - polyhedral oligomeric silsesquioxane (POSS) bearing one (POSS1Ep) or eight (POSS8Ep) epoxy rings on the cages. In order to identify the chemical changes occurring after the thermal curing reactions, FT-IR spectrometry was employed. The new synthesized nanocomposites based on epoxidized camelina oil (ECO) were characterized by dynamic mechanical analyze and thermogravimetric analyze. The morphology of the ECO-based materials was investigate by scanning electron microscopy and supplementary information regarding the presence of the POSS compounds were establish by energy dispersive X-ray analysis and X-ray photoelectron spectroscopy. The smooth materials without any separation phase indicates a well dispersion of the Si-O-Si cages within the organic matrix and the incorporation of this hybrid compounds into the ECO network demonstrates to be a well strategy to improve the thermal and mechanical properties, simultaneously. PMID- 29491776 TI - Dynamic release of gentamicin sulfate (GS) from alginate dialdehyde (AD) crosslinked casein (CAS) films for antimicrobial applications. AB - In the present work, antibiotic drug gentamicin sulfate (GS) has been loaded into alginate dialdehyde-crosslinked casein (CAS) films for wound dressing applications. The films have been characterized by Fourier transform infrared spectroscopy, X-ray diffraction analysis and scanning electron microscopy. The dynamic release of model drug GS has been investigated in the physiological fluid at 37 degrees C. The drug release data has been interpreted in the terms of various kinetic models such as Power function model, first order model and Schott model. The release data was found to be well fitted by Schott model. The various diffusion coefficients are also evaluated. The adsorption of model therapeutic protein BSA on the film has been investigated. The maximum adsorption is found to be 5.7 mg/cm2.The films were tested for their antibacterial and anti-fungal action. Finally, the in vivo wound healing study was carried out on Albino wistar rats. PMID- 29491777 TI - One-step grafting of temperature-and pH-sensitive (N-vinylcaprolactam-co-4 vinylpyridine) onto silicone rubber for drug delivery. AB - A one-step method was implemented to graft N-vinylcaprolactam (NVCL) and 4 vinylpyridine (4VP) onto silicone rubber (SR) films using gamma radiation in order to endow the silicone surface with temperature- and pH-responsiveness, and give it the ability to host and release diclofenac in a controlled manner and thus prevent bacterial adhesion. The effects of radiation conditions (e.g., dose and monomers concentration) on the grafting percentage were evaluated, and the modified films were characterized by means of FTIR-ATR, Raman spectroscopy, calorimetry techniques (DSC and TGA) and contact angle measurements. The films responsiveness to stimuli was evaluated by recording the swelling degree of pristine and modified SR in buffer solutions (critical pH point) and as a function of changes in temperature (Upper Critical Solution Temperature, UCST). The graft copolymers of SR-g-(NVCL-co-4VP) showed good cytocompatibility against fibroblast cells for prolonged times, could host diclofenac and release it in a sustained manner for up to 24 h, and exhibited bacteriostatic activity when challenged against Escherichia coli. PMID- 29491778 TI - Synthesis of well-defined bisbenzoin end-functionalized poly(epsilon caprolactone) macrophotoinitiator by combination of ROP and click chemistry and its use in the synthesis of star copolymers by photoinduced free radical promoted cationic polymerization. AB - A new well-defined bisbenzoin group end-functionalized poly(epsilon-caprolactone) macrophotoinitiator (PCL-(PI)2) was synthesized by combination of ring opening polymerization (ROP) and click chemistry. The ROP of epsilon-CL monomer in bulk at 110 degrees C, by means of a hydroxyl functional initiator namely, 3 cyclohexene-1-methanol in conjunction with stannous-2-ethylhexanoate, (Sn(Oct)2), yielded a well-defined PCL with a cyclohexene end-chain group (PCL-CH). The bromination and subsequent azidation of the cyclohexene end-chain group gave bisazido functionalized poly(epsilon-caprolactone) (PCL-(N3)2). Separately, an acetylene functionalized benzoin photoinitiator (PI-alkyne) was synthesized by using benzoin and propargyl bromide. Then the click reaction between PCL-(N3)2 and PI-alkyne was performed by Cu(I) catalysis. The spectroscopic studies revealed that poly(epsilon-caprolactone) with bisbenzoin photoactive functional group at the chain end (PCL-(PI)2) with controlled chain length and low polydispersity was obtained. This PCL-(PI)2 macrophotoinitiator was used as a precursor in photoinduced free radical promoted cationic polymerization to synthesize an AB2-type miktoarm star copolymer consisting of poly(epsilon caprolactone) (PCL, as A block) and poly(cyclohexene oxide) (PCHO, as B block), namely PCL(PCHO)2. PMID- 29491779 TI - Effect of sulfonation degree on molecular weight, thermal stability, and proton conductivity of poly(arylene ether sulfone)s membrane. AB - Direct copolymerization of sulfonated and non-sulfonated difluorodiphenyl sulfones as dihalide monomers with hydroquinone and also 4,4'-(4,4'-sulfonylbis (1,4-phenylene)bis(oxy)) diphenol as diols led to preparation of two series of poly(arylene ether sulfone)s. Copolymers with different degrees of sulfonation (40, 50 and 60%) were synthesized in order to evaluate their potential for fuel cell application. 1H-NMR, FT-IR, and mass spectroscopy were used for characterization of prepared monomers and copolymers. Differential scanning calorimetry and thermogravimetric analysis were applied for investigation and comparison of the thermal properties of copolymers. Laser light scattering (LLS) was employed to calculate zeta potential, conductivity, and molecular weight of copolymers. Copolymers were obtained in high and sufficient molecular weight that was basic need to reach reasonable physical and thermal properties for applications as fuel cell membrane. The effect of similar structural repeating units with different sizes on the final properties of sulfonated poly(ether sulfone)s was investigated to compare their potential in fuel cell membrane. PMID- 29491780 TI - Anionic polymerization of p-(2,2'-diphenylethyl)styrene and applications to graft copolymers. AB - Well-controlled anionic polymerization of an initiator-functionalized monomer, p (2,2'-diphenylethyl)styrene (DPES), was achieved for the first time. The polymerization was performed in a mixed solvent of cyclohexane and tetrahydrofuran (THF) at 40 degrees C with n-BuLi as initiator. When the volume ratio of cyclohexane to THF was 20, the anionic polymerization of DPES showed living polymerization characteristics, and well-defined block copolymer PDPES-b PS was successfully synthesized. Furthermore, radical polymerization of methyl methacrylate in the presence of PDPES effectively afforded a graft copolymer composed of a polystyrene backbone and poly(methyl methacrylate) branches. The designation of analogous monomers and polymers was of great significance to synthesize a variety of sophisticated copolymer and functionalize polymer materials. PMID- 29491781 TI - Liquid phase synthesis of aromatic poly(azomethine)s, their physicochemical properties, and measurement of ex situ electrical conductivity of pelletized powdered samples. AB - Aromatic bis-aldehydes have been used as building blocks in the synthesis of polyazomethines (a class of conjugated Schiff bases) and their physicochemical properties have been studied. Six dialdehydes have been synthesized, 3a-3f, via etherification reaction between aromatic diols (2a-2f) and 4-fluorobenzaldehyde (1) (see Scheme 1), and then polymerized with 1,4-phenylenediamine (4a) and 4,4' oxydianiline (4b) (see Scheme 2). The chemical structures of the bis-aldehydes were elucidated by FTIR, 1H NMR and 13C NMR spectroscopic studies, elemental analysis and single crystal whereas the polymers were studied by FTIR and NMR spectroscopy. Their physicochemical properties were examined by their inherent viscosity, organosolubility, differential scanning calorimetry, X-ray powder diffraction, thermogravimetric analysis, solvatochromism, and photoluminescence. We report the electrical conductivity of each polymer measured by the four probe method. The results indicate that the electrical conductivity of polymers lies in range 0.019-0.051 mScm-1 which is reasonably higher than any reported value. PMID- 29491782 TI - Preparation of single-site tin(IV) compounds and their use in the polymerization of epsilon-caprolactone. AB - Butyltin(IV) carboxylate compounds were obtained by reactions of butyltrichlorotin(IV) with potassium pivalate, perfluoroheptanoate, methacrylate, 2,6-pyridinedicarboxylate, and phthalate. The synthesized complexes were fully characterized by nuclear magnetic resonance (1H-, 13C-NMR), Fourier transform infrared (FTIR), mass spectroscopies (MS) and elemental analysis. These tin complexes were used as catalysts for the ring opening polymerization of epsilon caplolactone and the conversion of monomers to polymers was completed in just 1 h. The structures of polymers were characterized by a combination of spectroscopic techniques (NMR, FTIR, MS), differential scanning calorimeter (DSC) and gel permeation chromatography. In this study, the epsilon-caplolactone polymers with different average molecular weights between 5000 and 40,000 Da having a regular structure were obtained. PMID- 29491783 TI - Synthesis and characterization of novel polyimides derived from 4,4'-bis(5-amino 2-pyridinoxy)benzophenone: effect of pyridine and ketone units in the main. AB - A diamine monomer, 4,4'-bis(5-amino-2-pyridinoxy)benzophenone, was designed and synthesized, and used to react with commercially different kinds of aromatic dianhydrides to prepare a series of polyimides containing pyridine and ketone units via the classical two-step procedure. Glass transition temperatures (Tg) of the resultant polyimides PI-(1-5) derived from 4,4'-bis(5-amino-2-pyridinoxy) benzophenone with various dianhydrides ranged from 201 to 310 degrees C measured by differential scanning calorimetry. The temperatures for 5%wt loss of the resultant polyimides in nitrogen atmosphere obtained from the thermogravimetric analysis curves fell in the range of 472-501 degrees C. The temperatures for 10%wt loss of the resultant polyimides in nitrogen atmosphere fell in the range of 491-537 degrees C. Meanwhile, the char yields at 800 degrees C were in the range of 55.3-60.8%. Moreover, the moisture absorption of polyimide films was measured in the range of 0.37-2.09%. The thin films showed outstanding mechanical properties with tensile strengths of 103-145 MPa, an elongation at break of 12.9 15.2%, and a tensile modulus of 1.20-1.88 Gpa, respectively. The coefficients of thermal expansion of the resultant polyimides were obtained among 26-62 ppm degrees C-1. To sum up, this series of polyimides had a good combination of properties applied for high-performance materials and showed promising potential applications in the fields of optoelectronic devices. PMID- 29491785 TI - Synthesis and characterization of fluorinated polyacrylate latex emulsified with novel surfactants. AB - The fluorinated polyacrylate latex were successfully prepared with semi- continuous seeded emulsion polymerization of butyl acrylate (BA), methyl methacrylate (MMA) and hexafluorobutyl methacrylate (HFMA) which was initiated with potassium persulfate (KPS) initiator and emulsified with the novel mixed surfactants of sodium lauryl glutamate (SLG) and alkylphenol ethoxylates (OP-10). The structure of the resultant latex was confirmed by Fourier transform infrared spectroscopy (FTIR). The particle size of the latex was measured by Zetatrac dynamic light scattering detector. The film of latex was tested by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and contact angle (CA). The optimum conditions of preparing the novel fluorinated polyacrylate latex are optimized and the results are as follows: the amount of emulsifiers is 4.0%; mass ratio of SLG to OP-10 is 1:1, the amount of the initiator is 0.6%. The mass ratio of MMA to BA is 1:1 and the amount of HFMA is 7.0%. In this case, the conversion is high and the polymerization stability is good. In addition, the water resistance and thermal properties of the latex films were improved significantly in comparison with the film of the latex prepared without the fluorinated monomer. PMID- 29491784 TI - Monomers for adhesive polymers, 18. Synthesis, photopolymerization and adhesive properties of polymerizable alpha-phosphonooxy phosphonic acids. AB - Four polymerizable alpha-phosphonooxy phosphonic acids 7a, 7b, 9 and 16 were synthesized in seven steps. They were characterized by 1H, 13C and 31P NMR spectroscopy and by high-resolution mass spectroscopy. The copolymerization of acidic monomers 7a, 7b, 9 and 16 with 2-hydroxyethyl methacrylate was studied using a differential scanning calorimeter. Due to the presence of two acidic groups, those monomers are significantly more reactive than 10 methacryloyloxydecylphosphonic acid (MDPA) and 10-methacryloyloxydecyl dihydrogen phosphate (MDP). Self-etch adhesives based on monomers 7a, 7b, 9 and 16 were formulated and used to mediate a bond between a dental composite and the dental hard tissues (dentin and enamel). These adhesives exhibit excellent performances and provide significantly higher dentin and enamel shear bond strength than adhesives based on MDP or MDPA. PMID- 29491786 TI - Design and UV-curable behaviour of boron based reactive diluent for epoxy acrylate oligomer used for flame retardant wood coating. AB - Difunctional boron-containing reactive flame retardant for UV-curable epoxy acrylate oligomer was synthesized from phenyl boronic acid and glycidyl methacrylate. The synthesized reactive diluent was utilized to formulate ultraviolet (UV)-curable wood coatings. The weight fractions of reactive diluent in coatings formulation was varied from 5 to 25 wt % with constant photoinitiator concentration. The molecular structure of reactive flame retardant was confirmed by Fourier-transform infrared, Nuclear magnetic resonance (NMR) and 11B NMR spectral analysis. Further, the efficacy of flame retardant behaviour of coatings was evaluated using limiting oxygen index and UL-94 vertical burning test. Thermal stability of cured coatings films were estimated from thermogravimetric and differential scanning calorimetry analysis. The effects of varying concentration of reactive diluent on the viscosity of coatings formulation along with optical, mechanical and chemical resistance properties of coatings were also evaluated. The coatings gel content, water absorption behaviour, contact angle analysis and stain resistance were also studied. PMID- 29491787 TI - Concentration effects in the base-catalyzed hydrolysis of oligo(ethylene glycol)- and amine-containing methacrylic monomers. AB - Concentration effects in the base-catalyzed hydrolysis of water-soluble methacrylates (3-(N,N-dimethylaminoethyl) methacrylate (DMAEMA), 2-hydroxyethyl methacrylate (HEMA) and oligo(ethylene glycol) methacrylates (OEGMAs)) have been studied. These monomers are rapidly hydrolyzed in the presence of bases at the room temperature in dilute aqueous solutions, but the reaction rate decreases sharply in highly concentrated solutions. A clear correlation was found between a form of the viscosity isotherm for DMAEMA solutions and the concentration dependence of the autocatalytic hydrolysis rate which indicates the connection of process kinetics with the structure of solutions. These data should be considered when carrying out homo- and copolymerization of the previously mentioned monomers in aqueous solutions. PMID- 29491788 TI - Synthesis of G0 aminopolyol and aminosugar dendrimers, controlled by NMR and MALDI TOF mass spectrometry. AB - Organic compounds designed to serve as stable dendrimer cores were developed. A series of aminosugar and amino polyol containing G0 dendrimers were synthesized. The reaction mixture composition was checked by MALDI TOF mass spectrometry, while that of purified products - by 1H and 13C NMR combined with 2D NMR spectroscopy as well as MALDI TOF MSMS mass spectra. Mass spectrometric fragmentation experiments were performed in positive ion mode in order to determine common fragmentation patterns of [M+H]+ ions. PMID- 29491790 TI - A new initiating system based on [(SiMes)Ru(PPh3)(Ind)Cl2] combined with azo-bis isobutyronitrile in the polymerization and copolymerization of styrene and methyl methacrylate. AB - The homopolymerization and copolymerization of styrene and methyl methacrylate, initiated for the first time by the combination of azo-bis-isobutyronitrile (AIBN) with [(SiMes)Ru(PPh3)(Ind)Cl2] complex. The reactions were successfully carried out, on a large scale, in presence this complex at 80 degrees C. It was concluded from the data obtained that the association of AIBN with the ruthenium complex reduces considerably the transfer reactions and leads to the controlled radical polymerization and the well-defined polymers. PMID- 29491789 TI - Sugar-based bicyclic monomers for aliphatic polyesters: a comparative appraisal of acetalized alditols and isosorbide. AB - Three series of polyalkanoates (adipates, suberates and sebacates) were synthesized using as monomers three sugar-based bicyclic diols derived from D glucose (Glux-diol and isosorbide) and D-mannose (Manx-diol). Polycondensations were conducted in the melt applying similar reaction conditions for all cases. The aim was to compare the three bicyclic diols regarding their suitability to render aliphatic polyesters with enhanced thermal and mechanical properties. The ensuing polyesters had molecular weights (Mw) in the 25,000-50,000 g mol-1 range with highest values being attained for Glux-diol. All the polyesters started to decompose above 300 degrees C and most of them did not display perceivable crystallinity. On the contrary, they had glass transition temperatures much higher than usually found in homologous polyesters made of alkanediols, and showed a stress-strain behavior consistent with their Tg values. Glux-diol was particularly effective in increasing the Tg and to render therefore polyesters with high elastic modulus and considerable mechanical strength. PMID- 29491791 TI - Designing of cardanol based polyol and its curing kinetics with melamine formaldehyde resin. AB - Commercially used industrial baking enamels consist of alkyd or polyester resin with melamine formaldehyde. These resins are mainly derived from fossil resources. Considering growing environmental legislation regarding use of petroleum based raw materials, utilization of renewable resources to synthesize various chemistries can be the only obvious option as far as academia and industries are concerns. The present work deals with exploration of one of the natural resources (Cardanol) for polyol synthesis, its characterization (FTIR and NMR) and its curing behavior with melamine formaldehyde resin by differential scanning calorimetry (DSC). The optimized formulations from DSC study were further evaluated for general coating properties to study the suitability of developed polyol for industrial coating application. The experimental studies revealed that melamine content in the curing mixtures and thereby developed crosslinking density played an important role in deciding the coatings properties. PMID- 29491792 TI - Novel 'schizophrenic' diblock copolymer synthesized via RAFT polymerization: poly(2-succinyloxyethyl methacrylate)-b-poly[(N-4-vinylbenzyl),N,N-diethylamine]. AB - This article describes the synthesis and characterization of a novel 'schizophrenic' diblock copolymer [poly(2-succinyloxyethyl methacrylate)-b poly[(N-4-vinylbenzyl),N,N-diethylamine)]; PSEMA-b-PVEA] via reversible addition of fragmentation chain transfer (RAFT) polymerization technique. The chemical structures of all samples as representatives were characterized by means of Fourier transform infrared (FTIR), and 1H nuclear magnetic resonance (NMR) spectroscopies. The molecular weights of PHEMA and PVEA segments were calculated to be 9770 and 12,630 gmol-1, respectively, from 1H NMR spectroscopy. The self assembly behavior of the synthesized PSEMA-b-PVEA diblock copolymer was investigated by means of 1H NMR spectroscopy, dynamic light scattering (DLS) measurements, and transmission electron microscopy (TEM) observation. The average sizes of the PSEMA-b-PVEA micelles at pHs 3.0, 6.0, and 10.0 were obtained to be 294, 237, and 201 nm, respectively, from DLS analysis. The zeta potential measurements at various pHs demonstrated that the synthesized PSEMA-b-PVEA diblock copolymer has zwitterionic properties, and the range of isoelectric point's (IEP's) was determined as 5.8-7.3. It is expected that the synthesized PSEMA-b-PVEA diblock copolymer considered as a prospective candidate in nanomedicine applications such as drug delivery, mainly due to its excellent 'schizophrenic' micellization behavior. PMID- 29491793 TI - Preparation and characterization of monodisperse molecularly imprinted polymer microspheres by precipitation polymerization for kaempferol. AB - A new kind of molecularly imprinted polymer (MIP) microspheres for the selective extraction of kaempferol was prepared by precipitation polymerization using 4 vinylpridine (4-VP) and ethylene glycol dimethacrylate (EDMA) as functional monomer and cross-linker respectively. The synthesis conditions, such as ratios of 4-VP/EDMA and polymerization time were discussed in detail. Results showed that the 2% was the optimal concentration of co-monomers to obtain monodisperse MIP microspheres, the best ratio of 4-VP/EDMA was 1:2, and 24 h was considered as the proper polymerization time. Compared with the MIP agglomeration or coagulum particles, monodisperse MIP microspheres showed the better adsorption capacity: the saturated adsorption capacity of monodisperse MIP microspheres was 7.47 mg g 1, the adsorption equilibrium could be obtained in 30 min. Finally, the adsorption performances of the optimal MIP microspheres were evaluated by kinetic adsorption, adsorption isotherm, and selective adsorption experiments, which indicated that the adsorption mechanism were chemical single layer adsorption and the separation factor was up to 3.91 by comparing with the structure similar compound (quercetin). The MIP microspheres exhibit prospects in the kaempferol efficient and selective separation. PMID- 29491794 TI - Bi-diketopyrrolopyrrole (Bi-DPP) as a novel electron accepting compound in low band gap pi-conjugated donor-acceptor copolymers/oligomers. AB - The synthesis and characterization of a novel 2,5-diketopyrrolo[3,4 c]pyrrole(DPP)-based accepting building block with the scheme DPP-neutral small linker-DPP (Bi-DPP) is presented, which was utilized as electron accepting moiety for low band gap pi-conjugated donor-acceptor copolymers as well as for a donor acceptor small molecule. The electron accepting moiety Bi-DPP was prepared via a novel synthetic pathway by building up two DPP moieties step by step simultaneously starting from a neutral phenyl core unit. Characterization of the synthesized oligomeric and polymeric materials via cyclic voltammetry afford LUMO energy levels from -3.49 to -3.59 eV as well as HOMO energy levels from -5.07 to 5.34 eV resulting in low energy band gaps from 1.52 to 1.81 eV. Spin coating of the prepared donor-acceptor oligomers/polymers resulted in well-defined films. Moreover, UV-vis measurements of the investigated donor-acceptor systems showed a broad absorption over the whole visible region. It is demonstrated that Bi-DPP as an electron accepting moiety in donor-acceptor systems offer potential properties for organic solar cell devices. PMID- 29491795 TI - New biosourced AA and AB monomers from 1,4:3,6-dianhydrohexitols, Isosorbide, Isomannide, and Isoidide. AB - In the present work, we propose the synthesis of a new family of sugar derived 1,4:3,6-dianhydrohexitol based AA/AB-type monomers. Unprecedented diacids based on Isomannide and Isoidide were elaborated with high yields and showed interestingly high melting point ranges (240-375 degrees C). Optimization of reaction conditions (temperature, time of reaction, and reactant ratios) has been investigated to synthesize the key intermediate of a set of AB monomers with acid, ester, and acid chloride functionalities. Isosorbide based ether benzoic acid AB monomer was polymerized and characterized by NMR and DSC techniques. The results show a semicrystalline behavior of the obtained polymer thanks to the controlled stereoregular arrangement of the AB starting monomer. PMID- 29491796 TI - Investigation of aggregation induced emission in 4-hydroxy-3-methoxybenzaldehyde azine and polyazine towards application in (opto) electronics: synthesis, characterization, photophysical and electrical properties. AB - An azine monomer 4-hydroxy-3-methoxybenzaldehyde azine was synthesized by refluxing with ethanolic solution of vanillin with hydrazine hydrate. It was then converted into polyazine by oxidative polymerization. The structure of azine and polyazine was characterized by FT-IR, UV-visible, 1H-NMR and 13C-NMR. Spectral results suggest the formation of polymer, through C-C and C-O-C coupling of the phenylene and oxyphenylene. The relationship between the structures and photophysical properties of azine and polyazine was studied. Both azine and polyazine show, aggregation induced emission with increase in concentration in DMSO solution. The single crystal structure of azine suggesting the various inter and intra molecular interactions rigidify the conformation and locked the intramolecular rotations of the phenyl rings in the molecule. The inhibition of intramolecular rotation, J- aggregation and increase of conjugation impart the fluorescence in aggregated state. Additionally, the electronic properties namely orbital energies and resulting energy gap calculated theoretically by density functional theory (DFT). PMID- 29491797 TI - Controlled grafting of vinylic monomers on polyolefins: a robust mathematical modeling approach. AB - Experimental and mathematical modeling analyses were used for controlling melt free-radical grafting of vinylic monomers on polyolefins and, thereby, reducing the disturbance of undesired cross-linking of polyolefins. Response surface, desirability function, and artificial intelligence methodologies were blended to modeling/optimization of grafting reaction in terms of vinylic monomer content, peroxide initiator concentration, and melt-processing time. An in-house code was developed based on artificial neural network that learns and mimics processing torque and grafting of glycidyl methacrylate (GMA) typical vinylic monomer on high-density polyethylene (HDPE). Application of response surface and desirability function enabled concurrent optimization of processing torque and GMA grafting on HDPE, through which we quantified for the first time competition between parallel reactions taking place during melt processing: (i) desirable grafting of GMA on HDPE; (ii) undesirable cross-linking of HDPE. The proposed robust mathematical modeling approach can precisely learn the behavior of grafting reaction of vinylic monomers on polyolefins and be placed into practice in finding exact operating condition needed for efficient grafting of reactive monomers on polyolefins. PMID- 29491798 TI - Design and synthesis of bio-based UV curable PU acrylate resin from itaconic acid for coating applications. AB - UV curable PUA resin was successfully synthesized from polyol based on sustainable resource originated from itaconic acid (IA), isophorone diisocyanate (IPDI) and 2-hydroxyethyl methacrylate (HEMA). A polyol was synthesized by condensation reaction of IA with 16-hexanediol in the presence of p Toluenesulfonic acid (pTSA). The synthesized PUA resin was characterized for its structural elucidation by using Fourier Transform Infrared Spectrophotometer (FTIR), 1H and 13C NMR spectroscopy. The synthesized UV curable PUA resin was incorporated in varying concentrations in conventional PUA coating system. The effects of varying concentration of synthesized UV curable PUA resin on rheology, crystallinity, thermal and coating properties were evaluated. The rheological behavior of the resins were evaluated at variable stress and result showed decrease in viscosity of resin as concentration of synthesized UV curable PUA resin increases in conventional PUA resin. The cured coatings have been evaluated for glass transition temperature (Tg) and thermal behavior by differential scanning calorimeter and thermogravimetric analysis respectively. The degree of crystallinity of the coatings was determined from X-ray diffraction patterns using the PFM program. It was found that increase in the mass proportion of IA based PUA in coatings, the coating becomes more rigid and crystalline. The synthesized UV curable PUA coatings showed interesting mechanical, chemical, solvent and thermal properties as compared to the conventional PUA. Further, cured coatings were also evaluated for gel content and water absorption. PMID- 29491799 TI - Convenient syntheses of fullerynes for 'clicking' into fullerene polymers. AB - Alkyne-functionalized fullerenes (fullerynes) were designed and conveniently synthesized via Bingel reaction in one step with high yields. They were used to react with azido-functionalized polystyrene (PS) via Huisgen [3 + 2] cycloaddition 'click' chemistry to form two fullerene polymers: one with C60 tethered to the end of a PS chain (C60-1PS) and the other with C60 tethered at the junction point of two PS chains of identical molecular weight (C60-2PS). The fullerene polymers were characterized by 1H NMR, 13C NMR, FT-IR, MALDI-TOF mass spectrometry and SEC. The results showed that the fullerene polymers are well defined with narrow polydispersity and high fullerene functionality. Besides, aggregation of C60 in THF was observed in the SEC traces. The optical properties of the fullerene polymers were studied by UV-Vis absorption spectroscopy, and the results suggested that the PS chain(s) on the fullerene core has no remarkable effect on the optic property of C60. The thermal properties of the fullerene polymers were studied by TGA and DSC, and the results indicated that the two fullerene polymers with different C60 content and distinct molecular topology may have different self-assemble architectures in the solid state. The well-defined fullerene polymers can be used as model compounds to study the self-assemble architecture of shape amphiphiles based on polymer-tethered molecular nanoparticles. PMID- 29491801 TI - Facile preparation of a novel nickel-containing metallopolymer via RAFT polymerization. AB - While the metallocene polymers were comprehensively studied, other metallopolymers are rarely explored. The major challenge is the lack of a synthetic platform for the preparation of metal coordinated derivatives, monomers, and polymers. Therefore, the development of a facile synthesis of new metal coordinated monomers and polymers is critically needed. A novel successfully synthesized methacrylate-containing nickel complex is reported in this communication. Controlled RAFT polymerizations are further carried out to prepare a series of side-chain nickel containing polymers with different molecular weight and narrow Polydispersity Index (PDI). This new metallopolymer performs specific electrochemical and excellent thermal properties. This study provides a novel and convenient strategy to prepare metallopolymer with controllable molecular weight, which has potential applications in assembled, catalytic and magnetic materials. PMID- 29491800 TI - Synthesis of self-curable polysulfone containing pendant benzoxazine units via CuAAC click chemistry. AB - Synthesis, characterization, and properties of new thermally curable polysulfone containing benzoxazine moieties in the side chain were investigated. First, chloromethylation and subsequent azidation processes were performed to form polysulfone containing pendant clickable azide groups. Independently, antagonist 3,4-dihydro-3-(prop-2-ynyl)-2H-benzoxazine was prepared by using paraformaldehyde, phenol and propargylamine. The following copper(I) catalyzed azide-alkyne cycloaddition click reaction was applied to obtain self-curable polysulfone with pendant benzoxazine units. The polymer and intermediates at various stages were characterized by 1H-NMR, 13C-NMR and FT-IR spectroscopies. The thermal properties and curing behavior of final polymer were investigated by differential scanning calorimetry and thermal gravimetric analysis. Compared to the neat polysulfone, the obtained polymers exhibited thermally more stable polymers. PMID- 29491802 TI - The structural, morphological and thermal properties of grafted pH-sensitive interpenetrating highly porous polymeric composites of sodium alginate/acrylic acid copolymers for controlled delivery of diclofenac potassium. AB - In present investigation new formulations of Sodium Alginate/Acrylic acid hydrogels with high porous structure were synthesized by free radical polymerization technique for the controlled drug delivery of analgesic agent to colon. Many structural parameters like molecular weight between crosslinks (Mc ), crosslink density (Mr ), volume interaction parameter (v2,s ), Flory Huggins water interaction parameter and diffusion coefficient (Q) were calculated. Water uptake studies was conducted in different USP phosphate buffer solutions. All samples showed higher swelling ratio with increasing pH values because of ionization of carboxylic groups at higher pH values. Porosity and gel fraction of all the samples were calculated. New selected samples were loaded with the model drug (diclofenac potassium).The amount of drug loaded and released was determined and it was found that all the samples showed higher release of drug at higher pH values. Release of diclofenac potassium was found to be dependent on the ratio of sodium alginate/acrylic acid, EGDMA and pH of the medium. Experimental data was fitted to various model equations and corresponding parameters were calculated to study the release mechanism. The Structural, Morphological and Thermal Properties of interpenetrating hydrogels were studied by FTIR, XRD, DSC, and SEM. PMID- 29491803 TI - Novel functionalized monomers based on kojic acid: snythesis, characterization, polymerization and evalution of antimicrobial activity. AB - Two novel acrylate monomers, [5-(benzyloxy)-4-oxo-4H-pyran-2-yl]methyl acrylate and {1-[(5-(benzyloxy)-4-oxo-4H-pyran-2-yl)methyl]-1,2,3-triazol-4-yl}methyl acrylate were synthesized by the reaction of 5-benzyloxy-2-(hydroxymethyl)-4H pyran-4-one and 5-(benzyloxy)-2-{[4-(hydroxymethyl)-1,2,3-triazol-1-yl]methyl}-4H pyran-4-one with acryloyl chloride in the presence of triethylamine, respectively. These monomers were polymerized using 2,2'-azobisisobutyronitrile (AIBN) as the initiator in N,N-dimethylformamide:14-dioxane (10:1) solution. The thermal behavior of the polymers was investigated by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). The synthesized compounds were evaluated for their antibacterial and antifungal activites aganist bacteria and fungi using the disk diffusion method. The results indicated that some of these compounds demonstrated moderate to good antibacterial and antifungal activities. PMID- 29491804 TI - Tailoring of energetic groups in acroyloyl polymers. AB - Acryloyl based novel energetic monomers having nitro acrylates and nitro triazole acrylates were synthesized and further used for polymerization. Due to scavanging properties of nitro groups, syntheses of nitro aromatic polymers are not facile at normal conditions. In this regard, we report a simple protocol to synthesize these energetic group embeded acroloyl polymers. These polymers were characterized by FTIR, and NMR spectroscopic techniques. gel permeation chromatography (GPC) technique was employed in order to understand molecular mass of these polymers along with average molecular weight, number average weight and poly dispersity index. Glass transition temperature (Tg) was determined by using DSC analysis. It was observed that with increase in nitro groups in polymers there is a decrease in glass transition temperature. Two steps degradation were depicted in the TGA thermograph in nitro containing polymers. Heat release during this reaction was found up to 951 J/g. Increase in nitrogen content in polymer unit enhanced the heat release of polymers. PMID- 29491805 TI - Hypercrosslinked porous polyporphyrin by metal-free protocol: characterization, uptake performance, and heterogeneous catalysis. AB - Through metal-free protocol, hypercrosslinked porous polyporphyrin with permanent porosity was obatined via the Friedel-Crafts alkylation of tetracarbazolylporphyrin using formaldehyde dimethyl acetal as an external cross linker. Its chemical structure and porosity was well characterized and confirmed. The BET specific surface area value of HCP-TCPP is 1050 m2 g-1 and related dominant pore size is centered at 0.63 nm. The adsorption amount of methanol by HCP-TCPP is high up to 800 mg g-1 (about 25.0 mmol g-1) at its saturated vapor pressure, which is higher than that of toluene (600 mg g-1, 6.5 mmol g-1). Further study indicates that polymer HCP-TCPP, possessing the high BET specific surface area and total pore volume, exhibits good hydrogen uptake of 3.44 wt % (77 K) and high carbon dioxide uptake of 41.1 wt % (298 K) at 18.0 bar. Besides, the obtained porous polymer can also be used as an effective heterogeneous catalyst for the Knoevenagel condensation between various aldehydes and malononitrile. PMID- 29491806 TI - The effects of different amounts of drug microspheres on the vivo and vitro performance of the PLGA/beta-TCP scaffold. AB - OIC-A006 (BMPs osteogenesis compounds), can stimulate bone marrow mesenchymal stem cells ALP, OPN, OC, Cbfal expression. To stimulate new bone formation in the body. We postulate different amounts of drug microspheres on the PLGA/beta-CPT scaffold can produce the effects on performance and sustained release characteristics. In this paper, through adding different amount of carrier drug microsphere, three concentrations scaffolds which are 12.5, 18.75 and 25 MUmol/L are prepared by adding different amounts of drug-loaded microspheres. Hereafter called OICM/CPT-200, OICM/CPT-300, OICM/CPT-400. We implant them in rat femur diameter 3 mm depth of 3 mm hole for eight weeks. The degradation, microsphere, delivery properties, with X-ray, micro-CT and histology are tested. Results show that the contain carrier drug microsphere scaffolds become radiopaque, and the gaps between the scaffold and radial cut ends are often invisible. This preliminary study reveals that different carrier drug microsphere has a corresponding effect the performance of stent body, OICM/CPT - 200 scaffolds induction effect is best. Illustrates that the low concentration load OIC-A006 microspheres can promote bone healing, and high concentration of OIC-A006 micro ball is played a inhibitory effect on bone healing process. PMID- 29491807 TI - A CO2-switchable amidine monomer: synthesis and characterization. AB - Smart system employed CO2 gas as new trigger has been attracting enormous attention in recent years, but few monomers that are capable of switching their hydrophobicity/hydrophility upon CO2 stimulation have been reported. A novel CO2 responsive monomer, 4-vinylbenzyl amidine, is designed and synthesized in this work with N,N-dimethylacetamide dimethyl acetal and 4-vinylbenzyl amine that is prepared through the Gabriel reaction. In bi-phase solvent of n-hexane and water, the monomer dissolves in n-hexane first and then transforms into water upon the CO2 treatment, indicating a hydrophobic to hydrophilic transition. This transformation is demonstrated as reversible by monitoring the conductivity variation of its wet dimethyl formamide solution during alternate bubbling/removing CO2. The protonation of 4-vinylbenzyl amidine upon CO2 treatment is demonstrated by 1H NMR which also accounts for the dissolubility change. The reversible addition-fragmentation chain-transfer polymerization of this monomer is also performed, finding the reaction only occurs in glacial acetic acid. The reason can be ascribed to the different radical structure produced in different solvent. PMID- 29491808 TI - Processable dodecylbenzene sulfonic acid (DBSA) doped poly(N-vinyl carbazole) poly(pyrrole) for optoelectronic applications. AB - A soluble poly (n-vinyl carbazole)-polypyrrole (PNVC-Ppy) copolymer was prepared through oxidative chemical polymerization wherein dodecyl benzene sulfonic acid (DBSA) was used as a dopant to facilitate polymer-organic solvent interaction and ammonium persulfate (APS) was used as an oxidant. Compared with undoped PNVC-Ppy, the DBSA-doped PNVC-Ppy copolymer showed higher solubility in some selected organic solvents. The composition and structural characteristics of the DBSA doped PNVC-Ppy were determined by Fourier transform infrared, ultraviolet visible, and X-ray diffraction spectroscopic methods. Field emission scanning electron microscopic method was employed to observe the morphology of the DBSA doped PNVC-Ppy copolymer. The electrical conductivity of the DBSA-doped PNVC-Ppy copolymer was measured at room temperature. The conductivity increased with increasing concentration of APS oxidant, and the highest conductivity was recorded at 0.004 mol/dm3 APS at a polymerization temperature of -5 degrees C. The increased conductivity can be explained by the extended half-life of pyrrole free radical at a lower temperature and a gradual increase in chain length over a prolonged time due to the slow addition of APS. Furthermore, the obtained soluble copolymer exhibits unique optical and thermal properties different from those of PNVC and Ppy. PMID- 29491809 TI - The synthesis of poly(vinyl chloride) nanocomposite films containing ZrO2 nanoparticles modified with vitamin B1 with the aim of improving the mechanical, thermal and optical properties. AB - In the present investigation, solution casting method was used for the preparation of nanocomposite (NC) films. At first, the surface of ZrO2 nanoparticles (NPs) was modified with vitamin B1 (VB1) as a bioactive coupling agent to achieve a better dispersion and compatibility of NPs within the poly(vinyl chloride) (PVC) matrix. The grafting of modifier on the surface of ZrO2 was confirmed by Fourier transform infrared spectroscopy and thermogravimetric analysis (TGA). Finally, the resulting modified ZrO2 (ZrO2 VB1), was used as a nano-filler and incorporated into the PVC matrix to improve its mechanical and thermal properties. These processes were carried out under ultrasonic irradiation conditions, which is an economical and eco-friendly method. The effect of ZrO2-VB1 on the properties and morphology of the PVC matrix was characterized by various techniques. Field emission scanning electron microscopy and transmission electron microscopy analyses showed a good dispersion of fillers into the PVC matrix with the average diameter of 37-40 nm. UV-Vis spectroscopy was used to study optical behavior of the obtained NC films. TGA analysis has confirmed the presence of about 7 wt% VB1 on the surface of ZrO2. Also, the data indicated that the thermal and mechanical properties of the NC films were enhanced. PMID- 29491810 TI - Synthesis of novel cross-linked s-triazine-containing poly(aryl ether)s nanoparticles for biological fluorescent labeling. AB - A blue-fluorescence 2,4,6-tris(4-fluorophenyl)-1,3,5-triazine (TFPT) monomer was synthesized with high yield and high purity under mild reaction conditions. The TFPT, which had three active fluoric groups, was facilely incorporated into stable cross-linked fluorescent polymeric nanoparticles (FCPNs) via precipitation polymerization with 6-(4-hydroxyphenyl)pyridazin-3(2H)-one (HPZ). The FCPNs were highly dispersible in water and showed uniform size, intense blue fluorescence, and excellent biocompatibility, making them promising for live cell imaging label applications. This work has the potential to promote the exploitation of novel s triazine monomers, and to provide a new view of functional crossing-linked polymers based on such monomers. PMID- 29491811 TI - Linear-dendritic block copolymers as a green scale inhibitor for calcium carbonate in cooling water systems. AB - Water-soluble monomer APEG-PG-(OH)n were produced and the Structure of APEG-PG (OH)5 were identified by 1H-NMR. APEG-PG-(OH)n were copolymerized with maleic anhydride (MA) to synthesize no phosphate and nitrogen free calcium carbonate inhibitor MA/APEG-PG-(OH)n. The structure and thermal property of MA/APEG-PG (OH)5 were characterized and measured by 1H-NMR, GPC and TGA. The observation shows that the dosage and n value of MA/APEG-PG-(OH)n plays an important role on CaCO3 inhibition. MA/APEG-PG-(OH)5 displays superior ability to inhibit the precipitation of calcium carbonate, with approximately 97% inhibition at a level of 8 mg/L. The effect on formation of CaCO3 was investigated with combination of SEM and XRD analysis. PMID- 29491812 TI - Synthesis of sharply thermo and PH responsive PMA-b-PNIPAM-b-PEG-b-PNIPAM-b-PMA by RAFT radical polymerization and its schizophrenic micellization in aqueous solutions. AB - Sharply thermo- and pH-responsive pentablock terpolymer with a core-shell-corona structure was prepared by RAFT polymerization of N-isopropylacrylamide and methacrylic acid monomers using PEG-based benzoate-type of RAFT agent. The PEG based RAFT agent could be easily synthesized by dihydroxyl-capped PEG with 4 cyano-4-(thiobenzoyl) sulfanylpentanoic acids, using esterification reaction. This pentablock terpolymer was characterized by 1H NMR, FT-IR, and GPC. The PDI was obtained by GPC, indicating that the molecular weight distribution was narrow and the polymerization was well controlled. The thermo- and pH-responsive micellization of the pentablock terpolymer in aqueous solution was investigated using fluorescence spectroscopy technique, UV-vis transmittance, and TEM. The LCST of pentablock terpolymer increased (over 50 degrees C) compared to the NIPAM homopolymer (~32 degrees C), due to the incorporation of the hydrophilic PEG and PMA blocks in pentablock terpolymer (PNIPAM block as the core, PEG the block and the hydrophilic PMA block as the shell and the corona). Also, pH dependent phase transition behavior shows at a pH value of about ~5.8, according to pKa of MAA. Thus, in acidic solution at room temperature, the pentablock terpolymer self-assembled to form core-shell-corona micelles, with the hydrophobic PMA block as the core, the PNIPAM block and the hydrophilic PEG block as the shell and the corona, respectively. PMID- 29491813 TI - Enhanced gastric retention and drug release via development of novel floating microspheres based on Eudragit E100 and polycaprolactone: synthesis and in vitro evaluation. AB - Eudragit E 100 and polycaprolactone (PCL) floating microspheres for enhanced gastric retention and drug release were successfully prepared by oil in water solvent evaporation method. Metronidazole benzoate, an anti-protozoal drug, was used as a model drug. Polyvinyl alcohol was used as an emulsifier. The prepared microspheres were observed for % recovery, % degree of hydration, % water uptake, % drug loading, % buoyancy and % drug release. The physico-chemical properties of the microspheres were studied by calculating encapsulation efficiency of microspheres and drug release kinetics. Drug release characteristics of microspheres were studied in simulated gastric fluid and simulated intestinal fluid i.e., at pH 1.2 and 7.4 respectively. Fourier transform infrared spectroscopy was used to reveal the chemical interaction between drug and polymers. Scanning electron microscopy was conducted to study the morphology of the synthesized microspheres. PMID- 29491814 TI - A novel catalyst system for the synthesis of N,N'-Methylenebisacrylamide from acrylamide. AB - N,N'-Methylenebisacrylamide (MBAA), which is an important raw material in a widely industrial area, was synthesized using convenient catalysts. The synthesized monomer was fully characterized by the elemental analysis, fourier transform infrared (FT-IR) spectroscopy, thermogravimetric analysis (TGA), 1H NMR, 13C-NMR, GC/MS, and high performance liquid chromatography (HPLC) analysis. Six different homogeneous and heterogeneous catalysts were used to obtain maximum monomer yield. The MBAA was obtained with 95% yield by using Cu(II) catalyst containing carboxylate groups ligands. PMID- 29491815 TI - Synthesis of imine bond containing insoluble polymeric ligand and its transition metal complexes, structural characterization and catalytic activity on esterification reaction. AB - In this study, synthesis of insoluble polymeric ligand (L) and its transition metal complexes [Cu(L)Cl2].2H2O (1), [Co(L)Cl2(H2O)2] (2) and [Ni(L)Cl2(H2O)2] (3), having the azomethine groups, were synthesized by the condensation reactions of the diamines and dialdehydes. The structural properties were characterized by the analytical and spectroscopic methods using by elemental analysis, Fourier Transform Infrared, Thermo Gravimetric Analysis, Powder X-ray Diffraction, magnetic susceptibility and Inductively Coupled Plasma. The solubilities of the synthesized polymeric materials were also investigated and found as insoluble some organic and inorganic solvents. Additionally, their catalytic performance was carried out for the esterification reaction of acetic acid and butyl acetate. The highest conversion rate is 75.75% by using catalyst 1. The esterification of butanol gave butyl acetate with 100% selectivity. PMID- 29491816 TI - Highly optical transparency and thermally stable polyimides containing pyridine and phenyl pendant. AB - In order to obtain highly optical transparency polyimides, two novel aromatic diamine monomers containing pyridine and kinky structures, 1,1-bis[4-(5-amino-2 pyridinoxy)phenyl]diphenylmethane (BAPDBP) and 1,1-bis[4-(5-amino-2 pyridinoxy)phenyl]-1-phenylethane (BAPDAP), were designed and synthesized. Polyimides based on BAPDBP, BAPDAP, 2,2-bis[4-(5-amino-2 pyridinoxy)phenyl]propane (BAPDP) with various commercial dianhydrides were prepared for comparison and structure-property relationships study. The structures of the polyimides were characterized by Fourier transform infrared (FT IR) spectrometer, wide-angle X-ray diffractograms (XRD) and elemental analysis. Film properties including solubility, optical transparency, water uptake, thermal and mechanical properties were also evaluated. The introduction of pyridine and kinky structure into the backbones that polyimides presented good optical properties with 91-97% transparent at 500 nm and a low cut-off wavelength at 353 398 nm. Moreover, phenyl pendant groups of the polyimides showed high glass transition temperatures (Tg ) in the range of 257-281 degrees C. These results suggest that the incorporating pyridine, kinky and bulky substituents to polymer backbone can improve the optical transparency effectively without sacrificing the thermal properties. PMID- 29491818 TI - Study on initiating approach of (3-(tert-butylperoxy)propyl) trimethoxysilane on the polymerization of acrylonitrile as an initiator. AB - (3-(tert-butylperoxy)propyl) trimethoxysilane (TBPT), is a tailor-made new style silane coupling agent with peroxide group, which have ability of initiating polymerization. This study used TBPT to generate free radical, and initiated the polymerization of acrylonitrile (AN), thereby forming polyacrylonitrile (PAN) in two approaches, thermal initiation system and redox initiation system. Meanwhile this study bonded TBPT onto nano-TiO2 to get modified nano-TiO2 by means of the coupling function of TBPT, and then made the peroxide group of the modified nano TiO2 decompose and initiate the polymerization of AN in thermal initiation system and redox initiation system respectively. The products were investigated and analyzed by FTIR, XPS and TG. The result showed that on one hand, in the products of the thermal initiation there was PAN, which both attached and unattached to the modified nano-TiO2; on the other hand, in the products of the redox initiation system the PAN unattached to the modified nano-TiO2 was produced, while the PAN attached to the modified nano-TiO2 was not. PMID- 29491817 TI - Synthesis and characterization of hyperbranched poly(ester-amine) by Michael addition polymerization. AB - A series of tertiary amine-based hyperbranched poly(amine-ester)s have been synthesized by Michael addition polymerization of trifunctional monomer, TMEA and difunctional monomer, diacylates in chloroform, and the resultant polymers were subsequently treated with mercaptoethenol or 1-dodecanethiol for improving stability in storage. The caption efficiency of mercaptoethanol is much better than that of 1-dodecanthiol. Kinetic study reveals that the thiol group is consumed faster than the acrylate group when the polymerization with feed molar ratio of diacrylate/TMEA = 2/1 was carried out. At initial polymerization, monomer conversion increases fast, but the molecular weights increase slowly and sharp increase of the molecular weight occurs at the final polymerization. The hyperbranched polymers were well characterized by 1H NMR spectra and TD-SEC, and DBs of the polymers obtained are between 0.6 and 0.82, as well as the molar ratios of diacrylate/TMEA in the hyperbranched polymers are between 1.60 and 1.82. The fluorescence efficiency and quantum yields of HypET20, HypHT24 and HypDT24 has the following sequence: HypET20 > HypHT24 > HypDT24. PMID- 29491819 TI - Synthesis of hypergrafted poly[4-(N,N-diphenylamino)methylstyrene] through tandem anionic-radical polymerization of radical-inimer. AB - In this paper, we present a tandem anionic-radical approach for synthesizing hypergrafted polymers. We prepared 4-(N,N-diphenylamino)methylstyrene (DPAMS) as a new radical-based inimer. Linear PDPAMS was prepared through anionic polymerization. Hypergrafted PDPAMS was synthesized through the self-condensing vinyl polymerization of DPAMS with linear PDPAMS. The linear backbone of PDPAMS, which incorporated latent radical initiating sites, served as a 'hyperlinker' to link hyperbranched side chains. The molecular weights of hypergrafted polymers increased as the length of the linear backbone chain increased. The hypergrafted structure of the resulting polymer was confirmed using a conventional gel permeation chromatograph apparatus equipped with a multiangle light scattering detector, nuclear magnetic resonance, differential scanning calorimetry, and thermogravimetric analysis. This strategy can be applied to synthesize other complex architectures based on hyperbranched polymers by changing the structure of a polymer backbone through anionic polymerization. PMID- 29491821 TI - Preparation and performance of crosslinked poly(arylene ether)s containing azobenzene chromophores. AB - A series of novel poly(arylene ether)s with crosslinked groups and different azobenzene chromophores contents (azo-CPAEs: PAE-allyl20%-azo20%, PAE-allyl20% azo40%, PAE-allyl20%-azo60%) were synthesized from a new bisfluoro monomer, (2,6 difluorophenyl)-(4-hydroxyphenyl)methanone. Their chemical structures were characterized by means of UV-vis and FI-IR. The thermal properties of the polymers were investigated by TGA and DSC, indicating the polymers had high glass transition temperatures (Tg > 147 degrees C) and good thermal stability (Td5 > 360 degrees C) even when the contents of azobenzene chromophores was high to 60%. And the influence of thermal crosslinking on the performance of PAE-allyl20% azo20%, a typical one of the series, was investigated. Tg of PAE-allyl20%-azo20% increased with the increase of heating time when heat-treated at 250 degrees C for 20, 40 and 60 min, indicating the crosslink degree of the polymer increased. After heat-treated for 60 min, Tg of PAE-allyl20%-azo20% increased to 175 degrees C from 147 degrees C before thermal crosslinking. Upon irradiation with a 532 nm neodymium doped yttrium aluminum garnet (Nd:YAG) laser beam, the remnant value of the polymer PAE-allyl20%-azo20% before and after the thermal crosslinking were 81 and 96%, respectively, meaning that the PAE-allyl20%-azo20% after thermal crosslink showed more stable photoinduced alignment than that before thermal crosslinking. PMID- 29491820 TI - Preparation and characterization of pH sensitive crosslinked Linseed polysaccharides-co-acrylic acid/methacrylic acid hydrogels for controlled delivery of ketoprofen. AB - Some pH responsive polymeric matrix of Linseed (Linum usitatissimum), L. hydrogel (LSH) was prepared by free radical polymerization using potassium persulfate (KPS) as an initiator, N,N-methylene bisacrylamide (MBA) as a crosslinker, acrylic acid (AA) and methacrylic acid (MAA) as monomers; while ketoprofen was used as a model drug. Different formulations of LSH-co-AA and LSH-co-MAA were formulated by varying the concentration of crosslinker and monomers. Structures obtained were thoroughly characterized using Fourier transforms infrared (FTIR) spectroscopy, XRD analysis and Scanning electron microscopy. Sol-gel fractions, porosity of the materials and ketoprofen loading capacity were also measured. Swelling and in vitro drug release studies were conducted at simulated gastric fluids, i.e., pH 1.2 and 7.4. FTIR evaluation confirmed successful grafting of AA and MAA to LSH backbone. XRD studies showed retention of crystalline structure of ketoprofen in LSH-co-AA and its amorphous dispersion in LSH-co-MAA. Gel content was increased by increasing MBA and monomer content; whereas porosity of hydrogel was increased by increasing monomer concentration and decreased by increasing MBA content. Swelling of copolymer hydrogels was high at pH 7.4 and low at pH 1.2. Ketoprofen release showed an increasing trend by increasing monomer content; however it was decreased with increasing MBA content. Sustained release of ketoprofen was noted from copolymers and release followed Korsmeyer-Peppas model. PMID- 29491822 TI - High performances of dual network PVA hydrogel modified by PVP using borax as the structure-forming accelerator. AB - A dual network hydrogel made up of polyvinylalcohol (PVA) crosslinked by borax and polyvinylpyrrolidone (PVP) was prepared by means of freezing-thawing circles. Here PVP was incorporated by linking with PVA to form a network structure, while the introduction of borax played the role of crosslinking PVA chains to accelerate the formation of a dual network structure in PVA/PVP composite hydrogel, thus endowing the hydrogel with high mechanical properties. The effects of both PVP and borax on the hydrogels were evaluated by comparing the two systems of PVA/PVP/borax and PVA/borax hydrogels. In the former system, adding 4.0% PVP not only increased the water content and the storage modulus but also enhanced the mechanical strength of the final hydrogel. But an overdose of PVP just as more than 4.0% tended to undermine the structure of hydrogels, and thus deteriorated hydrogels' properties because of the weakened secondary interaction between PVP and PVA. Likewise, increasing borax could promote the gel crosslinking degree, thus making gels show a decrease in water content and swelling ratio, meanwhile shrinking the pores inside the hydrogels and finally enhancing the mechanical strength of hydrogels prominently. The developed hydrogel with high performances holds great potential for applications in biomedical and industrial fields. PMID- 29491823 TI - UV induced reversible chain extension of 1-(2-anthryl)-1-phenylethylene functionalized polyisobutylene. AB - The synthesis of novel 1-(2-anthryl)-1-phenylethylene (APE) di-telechelic polyisobutylenes is described. Utilization of a difunctional cationic initiator and the in situ addition of the non-homopolymerizable APE lead to the formation of di-anthryl telechelic polyisobutylenes. Products were characterized by 1H NMR spectroscopy and Size Exclusion Chromatography. The polymers were UV irradiated at 365 and 254 nm and the reversible photocycloaddition of anthryl moieties was investigated. The chain extension of di-anthryl telechelic PIBs through photocoupling at 365 nm produced higher molecular weight products from low molecular weight precursors. The effect of precursor polymer concentration on the degree of chain extension was investigated, and intermolecular interactions leading to the formation of tetramers was observed. The photocoupled products were UV irradiated at 254 nm to induce the reversal of photocycloaddition of anthryl groups and to follow the consequent photoscission of polymers. PMID- 29491824 TI - The production of high efficiency Ziegler-Natta catalyst with dual active sites nature using cyclohexyl chloride as promoter with super activity and produced superior polyethylene with controllable molecular weight distribution. AB - In the previous studies, the several halocarbons (HC) were tested as promoters for a Ti-based Ziegler-Natta (ZN) catalyst at different polymerization conditions. The Results showed that chloro cyclohexane has the best operation in catalyst activity, polymer particle size growth, hydrogen responsibility and wax reduction too. For the first time in this study, the effect of Al/Ti ratio on the optimum HC/Ti ratio has been considered and the results showed that the optimum HC/Ti ratio depends on the Al/Ti ratio directly. In the optimum HC/Ti ratio, the catalyst activity and hydrogen responsibility ratio of the catalyst increase up to 125 and 55% respectively. The acceptable growth of polymer powder up to 46%, lower flow rate ratio (FRR) up to 19% and decrease of wax amount up to 12%, completed the promotion results. Furthermore, in the next part of this study and as key note, a little dose of halocarbon was used in the catalyst preparation to produce the special catalysts with dual active sites. In the catalyst preparation, the concentration of each active sites depends on the halocarbon amount and it can control the molecular weight distribution of the produced polyethylene; because each active sites have different response to hydrogen. The halocarbon based catalysts showed the remarkable effect on the catalyst activity, the molecular weight and especially molecular weight distribution (MWD). The flow rate ratio and MWD could be increased up to 77 and 88% respectively as the main result of halocarbon addition during the catalyst preparation. PMID- 29491825 TI - Modified polyether-sulfone membrane: a mini review. AB - Polyethersulfone has been widely used as a promising material in medical applications and waste-treatment membranes since it provides excellent mechanical and thermal properties. Hydrophobicity of polyethersulfone is considered one main disadvantage of using this material because hydrophobic surface causes biofouling effects to the membrane which is always thought to be a serious limitation to the use of polyethersulfone in membrane technology. Chemical modification to the material is a promising solution to this problem. More specifically surface modification is an excellent technique to introduce hydrophilic properties and functional groups to the polyethersulfone membrane surface. This review covers chemical modifications of the polyethersulfone and covers different methods used to enhance the hydrophilicity of polyethersulfone membrane. In particular, the addition of amino functional groups to polyethersulfone is used as a fundamental method either to introduce hydrophilic properties or introduce nanomaterials to the surface of polyethersulfone membrane. This work reviews also previous research reports explored the use of amino functionalized polyethersulfone with different nanomaterials to induce biological activity and reduce fouling effects of the fabricated membrane. PMID- 29491826 TI - Microwave-assisted synthesis of isosorbide-derived diols for the preparation of thermally stable thermoplastic polyurethane. AB - In order to prepare thermally stable isosorbide-derived thermoplastic polyurethane, the synthesis of two new chiral exo-exo configured diols, prepared from isosorbide, and two types of diphenols (bisphenol A and thiodiphenol) was described. The synthesis conditions were optimized under conventional heating and microwave irradiations. To prove their suitability in polymerization, these monomers were successfully polymerized using 4,4'-diphenylmethane diisocyanate (MDI) and hexamethylene diisocyanate (HDI). Both monomers and polymers have been studied by NMR, FT-IR, TGA, DSC; intrinsic viscosity of polymers has also been determined. The results showed the effectiveness of the synthetic strategy proposed; moreover, a dramatic reduction of the reaction time and an important improvement of the monomers yield using microwave irradiation have been demonstrated. The monomers, as well as the polymers, showed excellent thermal stability both in air and nitrogen. It was also shown that the introduction of sulphur in the polyurethane backbone was effective in delaying the onset of degradation as well as the degradation rate. PMID- 29491827 TI - Radical polymerization approach for ring opened oxanorbornene anhydride based macromonomers. AB - In this work, we synthesized end group functionalization of the cis-Norbornene-5 6-endo-dicarboxylic anhydride species via the ring-opening metathesis polymerization (ROMP) of oxanorbornene derivatives generated a chiseled poly(cis Norbornene-5-6-endo-Dicarboxylic anhydride) acrylate macromonomer. Further, acrylate oxanorbornene based macromonomer further polymerized via reversible addition fragmentation chain transfer (RAFT) polymerization technique. Chain transfer is exhibited in the structure during the radical polymerizations so that free radical polymerization could also be used to comb structure copolymers with a PDI value below 1.2 with the help of acrylate oxanorbornene. Atomic force microscopy reveals the comb shape of branched polymer brushes structure. This method involves polymerizable end-group attachment to a macromonomer, and the backbone of the comb polymer is created in a second step of the polymerization. We believe that this kind of comb structured polymers can be considered for different biological applications. PMID- 29491828 TI - Synthesis and characterization of epoxy resin of 9,9'-bis-(3,5-dibromo-4 hydroxyphenyl) anthrone-10 and its jute composite. AB - Epoxy resin of 9,9'-bis-(3,5-dibromo-4-hydroxyphenyl) anthrone-10 (EANBr, EEW 490) was synthesized and was characterized by IR and 1HNMR . EANBr and EPK3251 cured resin (EANBrC) were characterized by DSC and TGA at 10 degrees Cmin-1 under nitrogen atmosphere. Broad DSC endothermic transitions of EANBr (265.3 degrees C) and EANBrC (291.4 degrees C) are due to some physical change and further confirmed by no weight loss in their TG thermograms. EANBr and EANBrC are thermally stable up to 340 degrees C and 310 degrees C, respectively. EANBr has followed single step degradation kinetics, while EANBrC has followed two step degradation kinetics. EANBr followed apparently zero order kinetics, while EANBrC followed apparently second order (1.80) and first order (0.89) degradation kinetics, respectively. Ea and A values of EANBrC (299.7 kJmol-1 and 6.32 * 1020 s-1) were found higher than that of EANBr (201 kJmol-1 and 2.45 * 1013 s-1) due to more rigid nature of EANBrC. The DeltaS* value of the first step degradation of EANBrC (146.3 JK-1 mol-1) was found much more than that of EANBr (4.6 JK-1 mol 1). Jute - EANBr composite (J-EANBr) was prepared by compression molding technique at 120 degrees C for 5 h and under 20 Bar pressure. The observed tensile strength, flexural strength, electric strength and volume resistivity of J-EANBr are 24.7 MPa, 19.0 MPa, 1.8 kVmm-1 and 3.5 * 1012 ohm cm, respectively. Water absorption in J-EANBr was carried out at 30 +/- 2 degrees C against distilled water, 10% NaCl, 10% HCl, 10% HNO3, 10% H2SO4, 10% NaOH, and 10% KOH and also in boiling water. The equilibrium time and equilibrium water content for J-EANBr in different environments are 384-432 h; 12.7-15.2%, respectively. The observed equilibrium water content and diffusivity trends of J-EANBr are KOH>H2SO4>HCl>NaOH>H2O>NaCl and H2O>NaCl>NaOH>H2SO4>HCl>KOH, respectively. Good thermo-mechanical, electrical properties and excellent hydrolytic stability of J EANBr may be useful for high temperature applications in diverse fields. PMID- 29491829 TI - The Burden of Systemic Adiposity on Pancreatic Disease: Acute Pancreatitis, Non Alcoholic Fatty Pancreas Disease, and Pancreatic Cancer. AB - Obesity is a global epidemic as recognized by the World Health Organization. Obesity and its related comorbid conditions were recognized to have an important role in a multitude of acute, chronic, and critical illnesses including acute pancreatitis, nonalcoholic fatty pancreas disease, and pancreatic cancer. This review summarizes the impact of adiposity on a spectrum of pancreatic diseases. PMID- 29491830 TI - Gastrocnemius Myoelectric Control of a Robotic Hip Exoskeleton Can Reduce the User's Lower-Limb Muscle Activities at Push Off. AB - We present a novel assistive control strategy for a robotic hip exoskeleton for assisting hip flexion/extension, based on a proportional Electromyography (EMG) strategy. The novelty of the proposed controller relies on the use of the Gastrocnemius Medialis (GM) EMG signal instead of a hip flexor muscle, to control the hip flexion torque. This strategy has two main advantages: first, avoiding the placement of the EMG electrodes at the human-robot interface can reduce discomfort issues for the user and motion artifacts of the recorded signals; second, using a powerful signal for control, such as the GM, could improve the reliability of the control system. The control strategy has been tested on eight healthy subjects, walking with the robotic hip exoskeleton on the treadmill. We evaluated the controller performance and the effect of the assistance on muscle activities. The tuning of the assistance timing in the controller was subject dependent and varied across subjects. Two muscles could benefit more from the assistive strategy, namely the Rectus Femoris (directly assisted) and the Tibialis Anterior (indirectly assisted). A significant correlation was found between the timing of the delivered assistance (i.e., synchronism with the biological hip torque), and reduction of the hip flexors muscular activity during walking; instead, no significant correlations were found for peak torque and peak power. Results suggest that the timing of the assistance is the most significant parameter influencing the effectiveness of the control strategy. The findings of this work could be important for future studies aimed at developing assistive strategies for walking assistance exoskeletons. PMID- 29491831 TI - Species-Specific 5 mC and 5 hmC Genomic Landscapes Indicate Epigenetic Contribution to Human Brain Evolution. AB - Human evolution from non-human primates has seen substantial change in the central nervous system, with the molecular mechanisms underlying human brain evolution remaining largely unknown. Methylation of cytosine at the fifth carbon (5-methylcytosine; 5 mC) is an essential epigenetic mark linked to neurodevelopment, as well as neurological disease. The emergence of another modified form of cytosine (5-hydroxymethylcytosine; 5 hmC) that is enriched in the brain further substantiates a role for these epigenetic marks in neurodevelopment, yet little is known about the evolutionary importance of these marks in brain development. Here, human and monkey brain tissue were profiled, identifying 5,516 and 4,070 loci that were differentially methylated and hydroxymethylated, respectively, between the species. Annotation of these loci to the human genome revealed genes critical for the development of the nervous system and that are associated with intelligence and higher cognitive functioning, such as RELN and GNAS. Moreover, ontological analyses of these differentially methylated and hydroxymethylated genes revealed a significant enrichment of neuronal/immunological-related processes, including neurogenesis and axon development. Finally, the sequences flanking the differentially methylated/hydroxymethylated loci contained a significant enrichment of binding sites for neurodevelopmentally important transcription factors (e.g., OTX1 and PITX1), suggesting that DNA methylation may regulate gene expression by mediating transcription factor binding on these transcripts. Together, these data support dynamic species-specific epigenetic contributions in the evolution and development of the human brain from non-human primates. PMID- 29491832 TI - Neural Damage in Experimental Trypanosoma brucei gambiense Infection: The Suprachiasmatic Nucleus. AB - Trypanosoma brucei (T. b.) gambiense is the parasite subspecies responsible for most reported cases of human African trypanosomiasis (HAT) or sleeping sickness. This severe infection leads to characteristic disruption of the sleep-wake cycle, recalling attention on the circadian timing system. Most animal models of the disease have been hitherto based on infection of laboratory rodents with the T. b. brucei subspecies, which is not infectious to humans. In these animal models, functional, rather than structural, alterations of the master circadian pacemaker, the hypothalamic suprachiasmatic nucleus (SCN), have been reported. Information on the SCN after infection with the human pathogenic T. b. gambiense is instead lacking. The present study was aimed at the examination of the SCN after T. b. gambiense infection of a susceptible rodent, the multimammate mouse, Mastomys natalensis, compared with T. b. brucei infection of the same host species. The animals were examined at 4 and 8 weeks post-infection, when parasites (T. b. gambiense or T. b. brucei) were detected in the brain parenchyma, indicating that the disease was in the encephalitic stage. Neuron and astrocyte changes were examined with Nissl staining, immunophenotyping and quantitative analyses. Interestingly, significant neuronal loss (about 30% reduction) was documented in the SCN during the progression of T. b. gambiense infection. No significant neuronal density changes were found in the SCN of T. b. brucei-infected animals. Neuronal cell counts in the hippocampal dentate gyrus of T. b. gambiense-infected M. natalensis did not point out significant changes, indicating that no widespread neuron loss had occurred in the brain. Marked activation of astrocytes was detected in the SCN after both T. b. gambiense and T. b. brucei infections. Altogether the findings reveal that neurons of the biological clock are highly susceptible to the infection caused by human pathogenic African trypanosomes, which have the capacity to cause permanent partial damage of this structure. PMID- 29491833 TI - Plasma Amyloid Is Associated with White Matter and Subcortical Alterations and Is Modulated by Age and Seasonal Rhythms in Mouse Lemur Primates. AB - Accumulation of amyloid-beta (Abeta) peptides in the brain is a critical early event in the pathogenesis of Alzheimer's disease (AD), the most common age related neurodegenerative disorder. There is increasing interest in measuring levels of plasma Abeta since this could help in diagnosis of brain pathology. However, the value of plasma Abeta in such a diagnosis is still controversial and factors modulating its levels are still poorly understood. The mouse lemur (Microcebus murinus) is a primate model of cerebral aging which can also present with amyloid plaques and whose Abeta is highly homologous to humans'. In an attempt to characterize this primate model and to evaluate the potential of plasma Abeta as a biomarker for brain alterations, we measured plasma Abeta40 concentration in 21 animals aged from 5 to 9.5 years. We observed an age-related increase in plasma Abeta40 levels. We then evaluated the relationships between plasma Abeta40 levels and cerebral atrophy in these mouse lemurs. Voxel-based analysis of cerebral MR images (adjusted for the age/sex/brain size of the animals), showed that low Abeta40 levels are associated with atrophy of several white matter and subcortical brain regions. These results suggest that low Abeta40 levels in middle-aged/old animals are associated with brain deterioration. One special feature of mouse lemurs is that their metabolic and physiological parameters follow seasonal changes strictly controlled by illumination. We evaluated seasonal-related variations of plasma Abeta40 levels and found a strong effect, with higher plasma Abeta40 concentrations in winter conditions compared to summer. This question of seasonal modulation of Abeta plasma levels should be addressed in clinical studies. We also focused on the amplitude of the difference between plasma Abeta40 levels during the two seasons and found that this amplitude increases with age. Possible mechanisms leading to these seasonal changes are discussed. PMID- 29491834 TI - From Chemotherapy to Combined Targeted Therapeutics: In Vitro and in Vivo Models to Decipher Intra-tumor Heterogeneity. AB - Recent advances in next-generation sequencing and other omics technologies capable to map cell fate provide increasing evidence on the crucial role of intra tumor heterogeneity (ITH) for cancer progression. The different facets of ITH, from genomic to microenvironmental heterogeneity and the hierarchical cellular architecture originating from the cancer stem cell compartment, contribute to the range of tumor phenotypes. Decoding these complex data resulting from the analysis of tumor tissue complexity poses a challenge for developing novel therapeutic strategies that can counteract tumor evolution and cellular plasticity. To achieve this aim, the development of in vitro and in vivo cancer models that resemble the complexity of ITH is crucial in understanding the interplay of cells and their (micro)environment and, consequently, in testing the efficacy of new targeted treatments and novel strategies of tailoring combinations of treatments to the individual composition of the tumor. This challenging approach may be an important cornerstone in overcoming the development of pharmaco-resistances during multiple lines of treatment. In this paper, we report the latest advances in patient-derived 3D (PD3D) cell cultures and patient-derived tumor xenografts (PDX) as in vitro and in vivo models that can retain the genetic and phenotypic heterogeneity of the tumor tissue. PMID- 29491835 TI - Sex Differences in the Effects of a Kappa Opioid Receptor Antagonist in the Forced Swim Test. AB - There is growing evidence that kappa opioid receptor (KOR) antagonists could be a useful class of therapeutics for treating depression and anxiety. However, the overwhelming majority of preclinical investigations examining the behavioral effects of KOR antagonists have been in male rodents. Here, we examined the effects of the long-acting KOR antagonist nor-binaltophimine (norBNI) on immobility in the forced swim test in males and females of two different rodent species (C57Bl/6J and California mice). Consistent with previous reports, norBNI (10 mg/kg) decreased immobility in the forced swim test for male C57Bl/6J and California mice. Surprisingly, dose-response studies in female C57Bl/6J and California mice showed that norBNI did not reduce immobility. Pharmacokinetic analyses showed that metabolism and brain concentrations of norBNI were similar in male and female C57Bl/6J. In the nucleus accumbens of male but not female C57Bl/6J, norBNI increased phosphorylation of c-Jun N-terminal kinase (pJNK), a putative mechanism for norBNI action. However, no differences in pJNK were observed in male or female California mice. Together, these results suggest that immobility in the forced swim test is less dependent on endogenous KOR signaling in female rodents and highlight the importance of examining the effects of possible therapeutic agents in both males and females. PMID- 29491836 TI - Inhibition of Protein Glycation by Tiger Milk Mushroom [Lignosus rhinocerus (Cooke) Ryvarden] and Search for Potential Anti-diabetic Activity-Related Metabolic Pathways by Genomic and Transcriptomic Data Mining. AB - Naturally occurring anti-glycation compounds have drawn much interest in recent years as they show potential in reducing or preventing the risk of chronic complications for diabetic patients. In this study, annotation of the genome transcriptome data from tiger milk mushroom (Lignosus rhinocerus, syn. Lignosus rhinocerotis) to PlantCyc enzymes database identified transcripts that are related to anti-diabetic properties, and these include genes that are involved in carotenoid and abscisic acid biosynthesis as well as genes that code for glyoxalase I, catalase-peroxidases, and superoxide dismutases. The existence of these genes suggests that L. rhinocerus may contain bioactive compound(s) with anti-glycation properties that can be exploited for management of diabetic complications. A medium-molecular-weight (MMW) fraction which was obtained from a combination of cold water extraction and Sephadex(r) G-50 (fine) gel filtration chromatography of L. rhinocerus sclerotia powder was demonstrated to exhibit potent anti-glycation activity. The fraction specifically inhibited the formation of N??-(carboxymethyl)lysine, pentosidine, and other advanced glycation end product (AGE) structures in a human serum albumin-glucose system, with an IC50 value of 0.001 mg/ml, almost 520 times lower than that of the positive control, aminoguanidine hydrochloride (IC50 = 0.52 mg/ml). Its ability to suppress protein glycation may be partly associated with its strong superoxide anion radical scavenging activity (10.16 +/- 0.12 mmol TE/g). Our results suggest that the MMW fraction of L. rhinocerus shows potential to be developed into a potent glycation inhibitor for preventing AGE-mediated diabetic complications. PMID- 29491837 TI - A Mechanistic Overview of Triptolide and Celastrol, Natural Products from Tripterygium wilfordii Hook F. AB - Triptolide and celastrol are predominantly active natural products isolated from the medicinal plant Tripterygium wilfordii Hook F. These compounds exhibit similar pharmacological activities, including anti-cancer, anti-inflammation, anti-obesity, and anti-diabetic activities. Triptolide and celastrol also provide neuroprotection and prevent cardiovascular and metabolic diseases. However, toxicity restricts the further development of triptolide and celastrol. In this review, we comprehensively review therapeutic targets and mechanisms of action, and translational study of triptolide and celastrol. We systemically discuss the structure-activity-relationship of triptolide, celastrol, and their derivatives. Furthermore, we propose the use of structural derivatives, targeted therapy, and combination treatment as possible solutions to reduce toxicity and increase therapeutic window of these potent natural products from T. wilfordii Hook F. PMID- 29491839 TI - Aging Decreases Hand Volume Expansion with Water Immersion. AB - Hands may show early signs of aging with altered skin texture, skin permeability and vascular properties. In clinics, a hand volumeter is used to measure swelling of hands due to edema, carpal tunnel syndrome or drug interventions. The hand volume measurements are generally taken without taking age into consideration. We hypothesized that age affects hand volumeter measurements and that the younger age group (<=40 years) records a greater change in hand volume as compared to the older group (>40 years). Four volumetric measurements were taken at 5 min intervals during 20 min of water immersion using a clinically-approved hand volumeter. After 20 min of immersion, the hand volume changes of the younger age group were significantly higher than the older age group (p < 0.001). Specifically, the right-hand volume of the younger age group (<=40 years, n = 30) increased by 4.3 +/- 2%, and the left hand increased by 3.4 +/- 2.1%. Conversely, the right-hand volume of the older age group (>40 years, n = 10) increased by 2.2 +/- 2.0%, and the left hand decreased by 0.6 +/- 2.4% after 20 min of water immersion. The data are presented as Mean +/- SD. Hand volume changes were not correlated with body mass index (BMI) or gender, and furthermore, neither of these two variables affected the relationship between age and hand volume changes with water immersion. We conclude that the younger age group has a higher increase in hand volume with water immersion as compared to the older age group. PMID- 29491841 TI - Signal Quality Evaluation of Emerging EEG Devices. AB - Electroencephalogram (EEG) registration as a direct measure of brain activity has unique potentials. It is one of the most reliable and predicative indicators when studying human cognition, evaluating a subject's health condition, or monitoring their mental state. Unfortunately, standard signal acquisition procedures limit the usability of EEG devices and narrow their application outside the lab. Emerging sensor technology allows gel-free EEG registration and wireless signal transmission. Thus, it enables quick and easy application of EEG devices by users themselves. Although a main requirement for the interpretation of an EEG is good signal quality, there is a lack of research on this topic in relation to new devices. In our work, we compared the signal quality of six very different EEG devices. On six consecutive days, 24 subjects wore each device for 60 min and completed tasks and games on the computer. The registered signals were evaluated in the time and frequency domains. In the time domain, we examined the percentage of artifact-contaminated EEG segments and the signal-to-noise ratios. In the frequency domain, we focused on the band power variation in relation to task demands. The results indicated that the signal quality of a mobile, gel-based EEG system could not be surpassed by that of a gel-free system. However, some of the mobile dry-electrode devices offered signals that were almost comparable and were very promising. This study provided a differentiated view of the signal quality of emerging mobile and gel-free EEG recording technology and allowed an assessment of the functionality of the new devices. Hence, it provided a crucial prerequisite for their general application, while simultaneously supporting their further development. PMID- 29491842 TI - Higher Impulsivity As a Distinctive Trait of Severe Cocaine Addiction among Individuals Treated for Cocaine or Alcohol Use Disorders. AB - Aims: Despite alcohol being the most often used addictive substance among addicted patients, use of other substances such as cocaine has increased over recent years, and the combination of both drugs aggravates health impairment and complicates clinical assessment. The aim of this study is to identify and characterize heterogeneous subgroups of cocaine- and alcohol-addicted patients with common characteristics based on substance use disorders, psychiatric comorbidity and impulsivity. Methods: A total of 214 subjects with cocaine and/or alcohol use disorders were recruited from outpatient treatment programs and clinically assessed. A latent class analysis was used to establish phenotypic categories according to diagnosis of cocaine and alcohol use disorders, mental disorders, and impulsivity scores. Relevant variables were examined in the latent classes (LCs) using correlation and analyses of variance and covariance. Results: Four LCs of addicted patients were identified: Class 1 (45.3%) formed by alcohol dependent patients exhibiting lifetime mood disorder diagnosis and mild impulsivity; Class 2 (14%) formed mainly by lifetime cocaine use disorder patients with low probability of comorbid mental disorders and mild impulsivity; Class 3 (10.7%) formed by cocaine use disorder patients with elevated probability to course with lifetime anxiety, early and personality disorders, and greater impulsivity scores; and Class 4 (29.9%) formed mainly by patients with alcohol and cocaine use disorders, with elevated probability in early and personality disorders and elevated impulsivity. Furthermore, there were significant differences among classes in terms of Diagnostic and Statistical Manual of Mental Disorders-4th Edition-Text Revision criteria for abuse and dependence: Class 3 showed more criteria for cocaine use disorders than other classes, while Class 1 and Class 4 showed more criteria for alcohol use disorders. Conclusion: Cocaine- and alcohol-addicted patients who were grouped according to diagnosis of substance use disorders, psychiatric comorbidity, and impulsivity show different clinical and sociodemographic variables. Whereas mood and anxiety disorders are more prevalent in alcohol-addicted patients, personality disorders are associated with cocaine use disorders and diagnosis of comorbid substance use disorders. Notably, increased impulsivity is a distinctive characteristic of patients with severe cocaine use disorder and comorbid personality disorders. Psychiatric disorders and impulsivity should be considered for improving the stratification of addicted patients with shared clinical and sociodemographic characteristics to select more appropriate treatments. PMID- 29491843 TI - Type and Timing of Negative Life Events Are Associated with Adolescent Depression. AB - Previous studies have demonstrated an association between negative life events (NLEs) in childhood and resilience/posttraumatic growth (PTG) with regard to the pathogenesis of major depressive disorder. We hypothesized that the type and timing of NLEs interact to influence mental health in the general youth population. Therefore, the present study aimed to examine the effects of NLE timing and intensity on current depressive symptoms, and to determine the direct and indirect effects of NLEs/resilience on PTG and depression among non-clinical adolescents. Data were collected from 1,038 high-school students across seven high schools in Fukui, Japan, during their freshman and sophomore years (648 boys and 390 girls, mean age = 15.71, SD = 0.524). Respondents completed a set of questionnaires designed to evaluate the type and timing of NLEs, depressive and traumatic symptoms, and PTG. Cluster analysis was used to divide participants into three groups based on outcomes: "cluster 1" (n = 631), for whom depressive scores were significantly lower than other two subgroups (p < 0.05, for both); "cluster 2" (n = 52), for whom levels of current and past perceived stress associated with NLEs were significantly higher than those of the other two subgroups (p < 0.05, for both); "cluster 3" (n = 374), for whom perceived stress at the time of NLE was significantly higher than that of participants in the cluster 1 (p < 0.05) group, but not the cluster 2 group. Our findings indicated that exposure to NLEs at a younger age resulted in stronger negative outcomes and that NLE timing and intensity were associated with PTG and current symptoms of depression. Furthermore, path analysis demonstrated that associations between perceived stress at the time of NLEs were direct and indirect predictors of current depression via PTG and that posttraumatic stress symptom and PTG mediate the association between NLEs/trait-resiliency and current depression. In conclusion, our findings suggest that event intensity, NLE timing, and gender may play a role in emotional vulnerability during adolescence. PMID- 29491840 TI - Neuropathic Pain: Delving into the Oxidative Origin and the Possible Implication of Transient Receptor Potential Channels. AB - Currently, neuropathic pain is an underestimated socioeconomic health problem affecting millions of people worldwide, which incidence may increase in the next years due to chronification of several diseases, such as cancer and diabetes. Growing evidence links neuropathic pain present in several disorders [i.e., spinal cord injury (SCI), cancer, diabetes and alcoholism] to central sensitization, as a global result of mitochondrial dysfunction induced by oxidative and nitrosative stress. Additionally, inflammatory signals and the overload in intracellular calcium ion could be also implicated in this complex network that has not yet been elucidated. Recently, calcium channels namely transient receptor potential (TRP) superfamily, including members of the subfamilies A (TRAP1), M (TRPM2 and 7), and V (TRPV1 and 4), have demonstrated to play a role in the nociception mediated by sensory neurons. Therefore, as neuropathic pain could be a consequence of the imbalance between reactive oxygen species and endogen antioxidants, antioxidant supplementation may be a treatment option. This kind of therapy would exert its beneficial action through antioxidant and immunoregulatory functions, optimizing mitochondrial function and even increasing the biogenesis of this vital organelle; on balance, antioxidant supplementation would improve the patient's quality of life. This review seeks to deepen on current knowledge about neuropathic pain, summarizing clinical conditions and probable causes, the relationship existing between oxidative stress, mitochondrial dysfunction and TRP channels activation, and scientific evidence related to antioxidant supplementation. PMID- 29491844 TI - Mood As Cumulative Expectation Mismatch: A Test of Theory Based on Data from Non verbal Cognitive Bias Tests. AB - Affective states are known to influence behavior and cognitive processes. To assess mood (moderately long-term affective states), the cognitive judgment bias test was developed and has been widely used in various animal species. However, little is known about how mood changes, how mood can be experimentally manipulated, and how mood then feeds back into cognitive judgment. A recent theory argues that mood reflects the cumulative impact of differences between obtained outcomes and expectations. Here expectations refer to an established context. Situations in which an established context fails to match an outcome are then perceived as mismatches of expectation and outcome. We take advantage of the large number of studies published on non-verbal cognitive bias tests in recent years (95 studies with a total of 162 independent tests) to test whether cumulative mismatch could indeed have led to the observed mood changes. Based on a criteria list, we assessed whether mismatch had occurred with the experimental procedure used to induce mood (mood induction mismatch), or in the context of the non-verbal cognitive bias procedure (testing mismatch). For the mood induction mismatch, we scored the mismatch between the subjects' potential expectations and the manipulations conducted for inducing mood whereas, for the testing mismatch, we scored mismatches that may have occurred during the actual testing. We then investigated whether these two types of mismatch can predict the actual outcome of the cognitive bias study. The present evaluation shows that mood induction mismatch cannot well predict the success of a cognitive bias test. On the other hand, testing mismatch can modulate or even inverse the expected outcome. We think, cognitive bias studies should more specifically aim at creating expectation mismatch while inducing mood states to test the cumulative mismatch theory more properly. Furthermore, testing mismatch should be avoided as much as possible because it can reverse the affective state of animals as measured in a cognitive judgment bias paradigm. PMID- 29491845 TI - Symbolic Number Comparison Is Not Processed by the Analog Number System: Different Symbolic and Non-symbolic Numerical Distance and Size Effects. AB - HIGHLIGHTS We test whether symbolic number comparison is handled by an analog noisy system.Analog system model has systematic biases in describing symbolic number comparison.This suggests that symbolic and non-symbolic numbers are processed by different systems. Dominant numerical cognition models suppose that both symbolic and non-symbolic numbers are processed by the Analog Number System (ANS) working according to Weber's law. It was proposed that in a number comparison task the numerical distance and size effects reflect a ratio-based performance which is the sign of the ANS activation. However, increasing number of findings and alternative models propose that symbolic and non-symbolic numbers might be processed by different representations. Importantly, alternative explanations may offer similar predictions to the ANS prediction, therefore, former evidence usually utilizing only the goodness of fit of the ANS prediction is not sufficient to support the ANS account. To test the ANS model more rigorously, a more extensive test is offered here. Several properties of the ANS predictions for the error rates, reaction times, and diffusion model drift rates were systematically analyzed in both non-symbolic dot comparison and symbolic Indo-Arabic comparison tasks. It was consistently found that while the ANS model's prediction is relatively good for the non-symbolic dot comparison, its prediction is poorer and systematically biased for the symbolic Indo-Arabic comparison. We conclude that only non-symbolic comparison is supported by the ANS, and symbolic number comparisons are processed by other representation. PMID- 29491838 TI - Iron Sulfur and Molybdenum Cofactor Enzymes Regulate the Drosophila Life Cycle by Controlling Cell Metabolism. AB - Iron sulfur (Fe-S) clusters and the molybdenum cofactor (Moco) are present at enzyme sites, where the active metal facilitates electron transfer. Such enzyme systems are soluble in the mitochondrial matrix, cytosol and nucleus, or embedded in the inner mitochondrial membrane, but virtually absent from the cell secretory pathway. They are of ancient evolutionary origin supporting respiration, DNA replication, transcription, translation, the biosynthesis of steroids, heme, catabolism of purines, hydroxylation of xenobiotics, and cellular sulfur metabolism. Here, Fe-S cluster and Moco biosynthesis in Drosophila melanogaster is reviewed and the multiple biochemical and physiological functions of known Fe S and Moco enzymes are described. We show that RNA interference of Mocs3 disrupts Moco biosynthesis and the circadian clock. Fe-S-dependent mitochondrial respiration is discussed in the context of germ line and somatic development, stem cell differentiation and aging. The subcellular compartmentalization of the Fe-S and Moco assembly machinery components and their connections to iron sensing mechanisms and intermediary metabolism are emphasized. A biochemically active Fe S core complex of heterologously expressed fly Nfs1, Isd11, IscU, and human frataxin is presented. Based on the recent demonstration that copper displaces the Fe-S cluster of yeast and human ferredoxin, an explanation for why high dietary copper leads to cytoplasmic iron deficiency in flies is proposed. Another proposal that exosomes contribute to the transport of xanthine dehydrogenase from peripheral tissues to the eye pigment cells is put forward, where the Vps16a subunit of the HOPS complex may have a specialized role in concentrating this enzyme within pigment granules. Finally, we formulate a hypothesis that (i) mitochondrial superoxide mobilizes iron from the Fe-S clusters in aconitase and succinate dehydrogenase; (ii) increased iron transiently displaces manganese on superoxide dismutase, which may function as a mitochondrial iron sensor since it is inactivated by iron; (iii) with the Krebs cycle thus disrupted, citrate is exported to the cytosol for fatty acid synthesis, while succinyl-CoA and the iron are used for heme biosynthesis; (iv) as iron is used for heme biosynthesis its concentration in the matrix drops allowing for manganese to reactivate superoxide dismutase and Fe-S cluster biosynthesis to reestablish the Krebs cycle. PMID- 29491846 TI - Learning and Recall of Medical Treatment-Related Information in Older Adults Using the Differential Outcomes Procedure. AB - It has recently been reported that the differential outcomes procedure (DOP) might be one of the therapeutical techniques focused at promoting autonomy in the elderly to deal with their medical issues. Molina et al. (2015) found that a group of healthy young adults improved their learning and long-term retention of six disorder/pill associations when each relationship to be learned was associated with a particular reinforcer (the differential outcomes condition) compared to when they were randomly administered (the non-differential outcomes condition). In the present study, we extend these findings to older adults who usually show difficulties to remember to take their medications as prescribed. Participants were asked to learn the association between three pills and the specific time at the day when they had to take each medication. Two memory tests were also performed 1 h and 1 week after completing the training phase. Results showed a faster learning of the task and long-term retention of the previously learned associations (pill/time of day) when differential outcomes were used. Furthermore, the older adults' performance in the learning and memory phases did not differ from that of the younger adults in the DOP condition. These findings demonstrate that this procedure can help elderly people to ameliorate not only their learning, but also their long-term memory difficulties, suggesting the potential for the DOP to promote adherence to treatment in this population. PMID- 29491847 TI - Oenococcus oeni in Chilean Red Wines: Technological and Genomic Characterization. AB - The presence and load of species of LAB at the end of the malolactic fermentation (MLF) were investigated in 16 wineries from the different Chilean valleys (Limari, Casablanca, Maipo, Rapel, and Maule Valleys) during 2012 and 2013, using PCR-RFLP and qPCR. Oenococcus oeni was observed in 80% of the samples collected. Dominance of O. oeni was reflected in the bacterial load (O. oeni/total bacteria) measured by qPCR, corresponding to >85% in most of the samples. A total of 178 LAB isolates were identified after sequencing molecular markers, 95 of them corresponded to O. oeni. Further genetic analyses were performed using MLST (7 genes) including 10 commercial strains; the results indicated that commercial strains were grouped together, while autochthonous strains distributed among different genetic clusters. To pre-select some autochthonous O. oeni, these isolates were also characterized based on technological tests such as ethanol tolerance (12 and 15%), SO2 resistance (0 and 80 mg l-1), and pH (3.1 and 3.6) and malic acid transformation (1.5 and 4 g l-1). For comparison purposes, commercial strain VP41 was also tested. Based on their technological performance, only 3 isolates were selected for further examination (genome analysis) and they were able to reduce malic acid concentration, to grow at low pH 3.1, 15% ethanol and 80 mg l-1 SO2. The genome analyses of three selected isolates were examined and compared to PSU-1 and VP41 strains to study their potential contribution to the organoleptic properties of the final product. The presence and homology of genes potentially related to aromatic profile were compared among those strains. The results indicated high conservation of malolactic enzyme (>99%) and the absence of some genes related to odor such as phenolic acid decarboxylase, in autochthonous strains. Genomic analysis also revealed that these strains shared 470 genes with VP41 and PSU-1 and that autochthonous strains harbor an interesting number of unique genes (>21). Altogether these results reveal the presence of local strains distinguishable from commercial strains at the genetic/genomic level and also having genomic traits that enforce their potential use as starter cultures. PMID- 29491849 TI - Study of the Metatranscriptome of Eight Social and Solitary Wild Bee Species Reveals Novel Viruses and Bee Parasites. AB - Bees are associated with a remarkable diversity of microorganisms, including unicellular parasites, bacteria, fungi, and viruses. The application of next generation sequencing approaches enables the identification of this rich species composition as well as the discovery of previously unknown associations. Using high-throughput polyadenylated ribonucleic acid (RNA) sequencing, we investigated the metatranscriptome of eight wild bee species (Andrena cineraria, Andrena fulva, Andrena haemorrhoa, Bombus terrestris, Bombus cryptarum, Bombus pascuorum, Osmia bicornis, and Osmia cornuta) sampled from four different localities in Belgium. Across the RNA sequencing libraries, 88-99% of the taxonomically informative reads were of the host transcriptome. Four viruses with homology to insect pathogens were found including two RNA viruses (belonging to the families Iflaviridae and Tymoviridae that harbor already viruses of honey bees), a double stranded DNA virus (family Nudiviridae) and a single stranded DNA virus (family Parvoviridae). In addition, we found genomic sequences of 11 unclassified arthropod viruses (related to negeviruses, sobemoviruses, totiviruses, rhabdoviruses, and mononegaviruses), seven plant pathogenic viruses, and one fungal virus. Interestingly, nege-like viruses appear to be widespread, host specific, and capable of attaining high copy numbers inside bees. Next to viruses, three novel parasite associations were discovered in wild bees, including Crithidia pragensis and a tubulinosematid and a neogregarine parasite. Yeasts of the genus Metschnikowia were identified in solitary bees. This study gives a glimpse of the microorganisms and viruses associated with social and solitary wild bees and demonstrates that their diversity exceeds by far the subset of species first discovered in honey bees. PMID- 29491850 TI - The Composition and Structure of Biofilms Developed by Propionibacterium acnes Isolated from Cardiac Pacemaker Devices. AB - The present study aimed to understand the biofilm formation mechanism of Propionibacterium acnes by analyzing the components and structure of the biofilms. P. acnes strains were isolated from the surface of explanted cardiac pacemaker devices that exhibited no clinical signs of infection. Culture tests using a simple stamp culture method (pressing pacemakers against the surface of agar plates) revealed frequent P. acnes colonization on the surface of cardiac pacemaker devices. P. acnes was isolated from 7/31 devices, and the isolates were categorized by multilocus sequence typing into five different sequence types (STs): ST4 (JK18.2), ST53 (JK17.1), ST69 (JK12.2 and JK13.1), ST124 (JK5.3), ST125 (JK6.2), and unknown ST (JK19.3). An in vitro biofilm formation assay using microtiter plates demonstrated that 5/7 isolates formed biofilms. Inhibitory effects of DNase I and proteinase K on biofilm formation varied among isolates. In contrast, dispersin B showed no inhibitory activity against all isolates. Three-dimensional live/dead imaging of P. acnes biofilms with different biochemical properties using confocal laser microscopy demonstrated different distributions and proportions of living and dead cells. Additionally, it was suggested that extracellular DNA (eDNA) plays a role in the formation of biofilms containing living cells. Ultrastructural analysis of P. acnes biofilms using a transmission electron microscope and atmospheric scanning electron microscope revealed leakage of cytoplasmic components along with cell lysis and fibrous structures of eDNA connecting cells. In conclusion, the biochemical properties and structures of the biofilms differed among P. acnes isolates. These findings may provide clues for establishing countermeasures against biofilm-associated infection by P. acnes. PMID- 29491851 TI - Pantoea ananatis Genetic Diversity Analysis Reveals Limited Genomic Diversity as Well as Accessory Genes Correlated with Onion Pathogenicity. AB - Pantoea ananatis is a member of the family Enterobacteriaceae and an enigmatic plant pathogen with a broad host range. Although P. ananatis strains can be aggressive on onion causing foliar necrosis and onion center rot, previous genomic analysis has shown that P. ananatis lacks the primary virulence secretion systems associated with other plant pathogens. We assessed a collection of fifty P. ananatis strains collected from Georgia over three decades to determine genetic factors that correlated with onion pathogenic potential. Previous genetic analysis studies have compared strains isolated from different hosts with varying diseases potential and isolation sources. Strains varied greatly in their pathogenic potential and aggressiveness on different cultivated Allium species like onion, leek, shallot, and chive. Using multi-locus sequence analysis (MLSA) and repetitive extragenic palindrome repeat (rep)-PCR techniques, we did not observe any correlation between onion pathogenic potential and genetic diversity among strains. Whole genome sequencing and pan-genomic analysis of a sub-set of 10 strains aided in the identification of a novel series of genetic regions, likely plasmid borne, and correlating with onion pathogenicity observed on single contigs of the genetic assemblies. We named these loci Onion Virulence Regions (OVR) A-D. The OVR loci contain genes involved in redox regulation as well as pectate lyase and rhamnogalacturonase genes. Previous studies have not identified distinct genetic loci or plasmids correlating with onion foliar pathogenicity or pathogenicity on a single host pathosystem. The lack of focus on a single host system for this phytopathgenic disease necessitates the pan-genomic analysis performed in this study. PMID- 29491852 TI - Alterations in the Spectrum of Spontaneous Rifampicin-Resistance Mutations in the Bacillus subtilis rpoB Gene after Cultivation in the Human Spaceflight Environment. AB - The effect of Bacillus subtilis exposure to the human spaceflight environment on growth, mutagenic frequency, and spectrum of mutations to rifampicin resistance (RifR) was investigated. B. subtilis cells were cultivated in Biological Research in Canister-Petri Dish Fixation Units (BRIC-PDFUs) on two separate missions to the International Space Station (ISS), dubbed BRIC-18 and BRIC-21, with matching asynchronous ground controls. No statistically significant difference in either growth or in the frequency of mutation to RifR was found in either experiment. However, nucleotide sequencing of the RifR regions of the rpoB gene from RifR mutants revealed dramatic differences in the spectrum of mutations between flight (FL) and ground control (GC) samples, including two newly discovered rpoB alleles in the FL samples (Q137R and L489S). The results strengthen the idea that exposure to the human spaceflight environment causes unique stresses on bacteria, leading to alterations in their mutagenic potential. PMID- 29491848 TI - Surfaceome and Proteosurfaceome in Parietal Monoderm Bacteria: Focus on Protein Cell-Surface Display. AB - The cell envelope of parietal monoderm bacteria (archetypal Gram-positive bacteria) is formed of a cytoplasmic membrane (CM) and a cell wall (CW). While the CM is composed of phospholipids, the CW is composed at least of peptidoglycan (PG) covalently linked to other biopolymers, such as teichoic acids, polysaccharides, and/or polyglutamate. Considering the CW is a porous structure with low selective permeability contrary to the CM, the bacterial cell surface hugs the molecular figure of the CW components as a well of the external side of the CM. While the surfaceome corresponds to the totality of the molecules found at the bacterial cell surface, the proteinaceous complement of the surfaceome is the proteosurfaceome. Once translocated across the CM, secreted proteins can either be released in the extracellular milieu or exposed at the cell surface by associating to the CM or the CW. Following the gene ontology (GO) for cellular components, cell-surface proteins at the CM can either be integral (GO: 0031226), i.e., the integral membrane proteins, or anchored to the membrane (GO: 0046658), i.e., the lipoproteins. At the CW (GO: 0009275), cell-surface proteins can be covalently bound, i.e., the LPXTG-proteins, or bound through weak interactions to the PG or wall polysaccharides, i.e., the cell wall binding proteins. Besides monopolypeptides, some proteins can associate to each other to form supramolecular protein structures of high molecular weight, namely the S-layer, pili, flagella, and cellulosomes. After reviewing the cell envelope components and the different molecular mechanisms involved in protein attachment to the cell envelope, perspectives in investigating the proteosurfaceome in parietal monoderm bacteria are further discussed. PMID- 29491854 TI - Protein Engineering for Nicotinamide Coenzyme Specificity in Oxidoreductases: Attempts and Challenges. AB - Oxidoreductases are ubiquitous enzymes that catalyze an extensive range of chemical reactions with great specificity, efficiency, and selectivity. Most oxidoreductases are nicotinamide cofactor-dependent enzymes with a strong preference for NADP or NAD. Because these coenzymes differ in stability, bioavailability and costs, the enzyme preference for a specific coenzyme is an important issue for practical applications. Different approaches for the manipulation of coenzyme specificity have been reported, with different degrees of success. Here we present various attempts for the switching of nicotinamide coenzyme preference in oxidoreductases by protein engineering. This review covers 103 enzyme engineering studies from 82 articles and evaluates the accomplishments in terms of coenzyme specificity and catalytic efficiency compared to wild type enzymes of different classes. We analyzed different protein engineering strategies and related them with the degree of success in inverting the cofactor specificity. In general, catalytic activity is compromised when coenzyme specificity is reversed, however when switching from NAD to NADP, better results are obtained. In most of the cases, rational strategies were used, predominantly with loop exchange generating the best results. In general, the tendency of removing acidic residues and incorporating basic residues is the strategy of choice when trying to change specificity from NAD to NADP, and vice versa. Computational strategies and algorithms are also covered as helpful tools to guide protein engineering strategies. This mini review aims to give a general introduction to the topic, giving an overview of tools and information to work in protein engineering for the reversal of coenzyme specificity. PMID- 29491853 TI - Cultivation and Genomic Analysis of "Candidatus Nitrosocaldus islandicus," an Obligately Thermophilic, Ammonia-Oxidizing Thaumarchaeon from a Hot Spring Biofilm in Graendalur Valley, Iceland. AB - Ammonia-oxidizing archaea (AOA) within the phylum Thaumarchaeota are the only known aerobic ammonia oxidizers in geothermal environments. Although molecular data indicate the presence of phylogenetically diverse AOA from the Nitrosocaldus clade, group 1.1b and group 1.1a Thaumarchaeota in terrestrial high-temperature habitats, only one enrichment culture of an AOA thriving above 50 degrees C has been reported and functionally analyzed. In this study, we physiologically and genomically characterized a newly discovered thaumarchaeon from the deep branching Nitrosocaldaceae family of which we have obtained a high (~85%) enrichment from biofilm of an Icelandic hot spring (73 degrees C). This AOA, which we provisionally refer to as "Candidatus Nitrosocaldus islandicus," is an obligately thermophilic, aerobic chemolithoautotrophic ammonia oxidizer, which stoichiometrically converts ammonia to nitrite at temperatures between 50 and 70 degrees C. "Ca. N. islandicus" encodes the expected repertoire of enzymes proposed to be required for archaeal ammonia oxidation, but unexpectedly lacks a nirK gene and also possesses no identifiable other enzyme for nitric oxide (NO) generation. Nevertheless, ammonia oxidation by this AOA appears to be NO dependent as "Ca. N. islandicus" is, like all other tested AOA, inhibited by the addition of an NO scavenger. Furthermore, comparative genomics revealed that "Ca. N. islandicus" has the potential for aromatic amino acid fermentation as its genome encodes an indolepyruvate oxidoreductase (iorAB) as well as a type 3b hydrogenase, which are not present in any other sequenced AOA. A further surprising genomic feature of this thermophilic ammonia oxidizer is the absence of DNA polymerase D genes - one of the predominant replicative DNA polymerases in all other ammonia-oxidizing Thaumarchaeota. Collectively, our findings suggest that metabolic versatility and DNA replication might differ substantially between obligately thermophilic and other AOA. PMID- 29491855 TI - Prevalence of Genetic Determinants and Phenotypic Resistance to Ciprofloxacin in Campylobacter jejuni from Lithuania. AB - Recently, the number of reports on isolation of ciprofloxacin resistant Campylobacter jejuni has increased worldwide. The aim of this study was to determine the prevalence of resistance to ciprofloxacin and its genetic determinants among C. jejuni isolated from humans (n = 100), poultry products (n = 96) and wild birds (n = 96) in Lithuania. 91.4% of the C. jejuni isolates were phenotypically resistant to ciprofloxacin. DNA sequence analyses of the gyrA gene from 292 isolates revealed that a change in amino acid sequence, Thr86Ile, was the main substition conferring resistance to ciprofloxacin. This change was significantly associated with isolates from poultry products (P < 0.05) and humans (P < 0.05). A total of 26.7% of C. jejuni isolates from human (n = 47), poultry products (n = 30) and wild bird (n = 1), had a mutation from Ser at position 22, and six had an additional mutation from Ala at position 39. Eight isolates from poultry and two isolates from human, corresponding to 67.0% of isolates with MICs >=128 MUg/ml, showed missense mutations Thr86Ile (ACA -> ATA) and Ser22Gly (AGT -> GGT) together, whereas isolates without these mutations showed lower MIC values (from 4 to 64 MUg/ml). Two hundred forty-five C. jejuni isolates showed one or more silent mutations, and 32.4% of examined isolates possessed six silent mutations. In addition to the ciprofloxacin resistant isolates harboring only Thr86Ile point mutation (110 isolates), the current study identified resistant isolates (n = 101) harboring additional point mutations (Ser22Gly, Ala39Ser, Arg48Lys, Thr85Ala Ala122Ser, Glu136Asp, Vall49Ile), and strains (n = 57) having only Glu136Asp point mutation. The study highlight the potential public health problem with elevated ciprofloxacin resistance in Campylobacters from poultry meat, wild birds and humans, and the need for extensive surveillance enabling to follow changes of antimicrobial resistance development in this species. PMID- 29491856 TI - Functional Characterization of ABCC Proteins from Trypanosoma cruzi and Their Involvement with Thiol Transport. AB - Chagas disease is a neglected disease caused by the protozoan Trypanosoma cruzi and affects 8 million people worldwide. The main chemotherapy is based on benznidazole. The efficacy in the treatment depends on factors such as the parasite strain, which may present different sensitivity to treatment. In this context, the expression of ABC transporters has been related to chemotherapy failure. ABC transporters share a well-conserved ABC domain, responsible for ATP binding and hydrolysis, whose the energy released is coupled to transport of molecules through membranes. The most known ABC transporters are ABCB1 and ABCC1, involved in the multidrug resistance phenotype in cancer, given their participation in cellular detoxification. In T. cruzi, 27 ABC genes were identified in the genome. Nonetheless, only four ABC genes were characterized: ABCA3, involved in vesicular trafficking; ABCG1, overexpressed in strains naturally resistant to benznidazole, and P-glycoprotein 1 and 2, whose participation in drug resistance is controversial. Considering P-glycoprotein genes are related to ABCC subfamily in T. cruzi according to the demonstration using BLASTP alignment, we evaluated both ABCB1-like and ABCC-like activities in epimastigote and trypomastigote forms of the Y strain. The transport activities were evaluated by the efflux of the fluorescent dyes Rhodamine 123 and Carboxyfluorescein in a flow cytometer. Results indicated that there was no ABCB1 like activity in both T. cruzi forms. Conversely, results demonstrated ABCC-like activity in both epimastigote and trypomastigote forms of T. cruzi. This activity was inhibited by ABCC transport modulators (probenecid, indomethacin, and MK 571), by ATP-depleting agents (sodium azide and iodoacetic acid) and by the thiol depleting agent N-ethylmaleimide. Additionally, the presence of ABCC-like activity was supported by direct inhibition of the thiol-conjugated compound efflux with indomethacin, characteristic of ABCC subfamily members. Taken together, the results provide the first description of native ABCC-like activity in T. cruzi epimastigote and trypomastigote forms, indicating that the study of the biological role for that thiol transporter is crucial to reveal new molecular mechanisms for therapeutic approaches in the Chagas disease. PMID- 29491857 TI - Body Mass Index and Sex Affect Diverse Microbial Niches within the Gut. AB - Gut microbiota is considered a separate organ with endocrine capabilities, actively contributing to tissue homeostasis. It consists of at least two separate microbial populations, the lumen-associated (LAM) and the mucosa-associated microbiota (MAM). In the present study, we compared LAM and MAM, by collecting stools and sigmoid brush samples of forty adults without large-bowel symptoms, and through a 16S rRNA gene next-generation sequencing (NGS) approach. MAM sample analysis revealed enrichment in aerotolerant Proteobacteria, probably selected by a gradient of oxygen that decreases from tissue to lumen, and in Streptococcus and Clostridium spp., highly fermenting bacteria. On the other hand, LAM microbiota showed an increased abundance in Bacteroides, Prevotella, and Oscillospira, genera able to digest and to degrade biopolymers in the large intestine. Predicted metagenomic analysis showed LAM to be enriched in genes encoding enzymes mostly involved in energy extraction from carbohydrates and lipids, whereas MAM in amino acid and vitamin metabolism. Moreover, LAM and MAM communities seemed to be influenced by different host factors, such as diet and sex. LAM is affected by body mass index (BMI) status. Indeed, BMI negatively correlates with Faecalibacterium prausnitzii and Flavonifractor plautii abundance, putative biomarkers of healthy status. In contrast, MAM microbial population showed a significant grouping according to sex. Female MAM was enriched in Actinobacteria (with an increased trend of the genus Bifidobacterium), and a significant depletion in Veillonellaceae. Interestingly, we found the species Gemmiger formicilis to be associated with male and Bifidobacterium adolescentis, with female MAM samples. In conclusion, our results suggest that gut harbors microbial niches that differ in both composition and host factor susceptibility, and their richness and diversity may be overlooked evaluating only fecal samples. PMID- 29491858 TI - Characterization of Asymptomatic Bacteriuria Escherichia coli Isolates in Search of Alternative Strains for Efficient Bacterial Interference against Uropathogens. AB - Asymptomatic bacterial colonization of the urinary bladder (asymptomatic bacteriuria, ABU) can prevent bladder colonization by uropathogens and thus symptomatic urinary tract infection (UTI). Deliberate bladder colonization with Escherichia coli ABU isolate 83972 has been shown to outcompete uropathogens and prevent symptomatic UTI by bacterial interference. Many ABU isolates evolved from uropathogenic ancestors and, although attenuated, may still be able to express virulence-associated factors. Our aim was to screen for efficient and safe candidate strains that could be used as alternatives to E. coli 83972 for preventive and therapeutic bladder colonization. To identify ABU E. coli strains with minimal virulence potential but maximal interference efficiency, we compared nine ABU isolates from diabetic patients regarding their virulence- and fitness associated phenotypes in vitro, their virulence in a murine model of sepsis and their genome content. We identified strains in competitive growth experiments, which successfully interfere with colonization of ABU isolate 83972 or uropathogenic E. coli strain 536. Six isolates were able to outcompete E. coli 83972 and two of them also outcompeted UPEC 536 during growth in urine. Superior competitiveness was not simply a result of better growth abilities in urine, but seems also to involve expression of antagonistic factors. Competitiveness in urine did not correlate with the prevalence of determinants coding for adhesins, iron uptake, toxins, and antagonistic factors. Three ABU strains (isolates 61, 106, and 123) with superior competitiveness relative to ABU model strain 83972 display low in vivo virulence in a murine sepsis model, and susceptibility to antibiotics. They belong to different phylogroups and differ in the presence of ExPEC virulence- and fitness-associated genes. Importantly, they all lack marked cytotoxic activity and exhibit a high LD50 value in the sepsis model. These strains represent promising candidates for a more detailed assessment of relevant fitness traits in urine and their suitability for therapeutic bladder colonization. PMID- 29491859 TI - Elucidating Duramycin's Bacterial Selectivity and Mode of Action on the Bacterial Cell Envelope. AB - The use of naturally occurring antimicrobial peptides provides a promising route to selectively target pathogenic agents and to shape microbiome structure. Lantibiotics, such as duramycin, are one class of bacterially produced peptidic natural products that can selectively inhibit the growth of other bacteria. However, despite longstanding characterization efforts, the microbial selectivity and mode of action of duramycin are still obscure. We describe here a suite of biological, chemical, and physical characterizations that shed new light on the selective and mechanistic aspects of duramycin activity. Bacterial screening assays have been performed using duramycin and Populus-derived bacterial isolates to determine species selectivity. Lipidomic profiles of selected resistant and sensitive strains show that the sensitivity of Gram-positive bacteria depends on the presence of phosphatidylethanolamine (PE) in the cell membrane. Further the surface and interface morphology were studied by high resolution atomic force microscopy and showed a progression of cellular changes in the cell envelope after treatment with duramycin for the susceptible bacterial strains. Together, these molecular and cellular level analyses provide insight into duramycin's mode of action and a better understanding of its selectivity. PMID- 29491860 TI - Characterization of Two Endo-beta-1, 4-Xylanases from Myceliophthora thermophila and Their Saccharification Efficiencies, Synergistic with Commercial Cellulase. AB - The xylanases with high specific activity and resistance to harsh conditions are of high practical value for biomass utilization. In the present study, two new GH11 xylanase genes, MYCTH_56237 and MYCTH_49824, have been cloned from thermophilic fungus Myceliophthora thermophila and expressed in Pichia pastoris. The specific activities of purified xylanases reach approximately 1,533.7 and 1,412.5 U/mg, respectively. Based on multiple template-based homology modeling, the structures of their catalytic domains are predicted. Enzyme activity was more effective in 7.5 L fermentor, yielding 2,010.4 and 2,004.2 U/mL, respectively. Both enzymes exhibit optimal activity at 60 degrees C with pH of 6.0 and 7.0, respectively. Their activities are not affected by EDTA and an array of metal ions. The kinetic constants have been determined for MYCTH_56237 (Km = 8.80 mg/mL, Vmax = 2,380 U/mg) and MYCTH_49824 (Km = 5.67 mg/mL, Vmax = 1,750 U/mg). More importantly, both xylanases significantly cooperate with the commercial cellulase Celluclast 1.5 L in terms of the saccharification efficiency. All these biochemical properties of the xylanases offer practical potential for future applications. PMID- 29491861 TI - Oligopeptide Targeting Sortase A as Potential Anti-infective Therapy for Staphylococcus aureus. AB - Sortase A (SrtA)-catalyzed anchorage of surface proteins in most Gram-positive bacteria is indispensable for their virulence, suggesting that this transpeptidase is a promising target for antivirulence therapy. Here, an oligopeptide, LPRDA, was identified as an effective inhibitor of SrtA via virtual screening based on the LPXTG substrate sequence, and it was found to inhibit SrtA activity in vitro and in vivo (IC50 = 10.61 MUM) by competitively occupying the active site of SrtA. Further, the oligopeptide treatment had no anti Staphylococcus aureus activity, but it provided protection against S. aureus induced mastitis in a mouse model. These findings indicate that the oligopeptide could be used as an effective anti-infective agent for the treatment of infection caused by S. aureus or other Gram-positive bacteria via the targeting of SrtA. PMID- 29491862 TI - Development of a 2-Nitrobenzoate-Sensing Bioreporter Based on an Inducible Gene Cluster. AB - Based on the sole information of structural genes of the 2-nitrobenzoate (2NBA) utilizing catabolic gene cluster (onbX1X2FCAR1EHJIGDBX3), 2NBA-sensing bioreporters were constructed by incorporating egfp into the onb gene cluster of Cupriavidus sp. strain ST-14. Incorporation of reporter gene in proximal to the hypothesized promoter region in conjunction with the disruption of the gene encoding inducer-metabolizing enzyme was turned out to be advantageous in reporter gene expression at low inducer concentration. The bioreporter strain was capable of expressing EGFP from the very 1st hour of induction and could detect 2NBA at (sub) nanomolar level exhibiting a strict specificity toward 2NBA, displaying no response to EGFP expression from its meta- and para-isomers as well as from a number of structurally related compounds. The present study is a successful demonstration of the development of a 2NBA-sensing bioreporter with respect to ease of construction, inducer specificity, and sensitivity, without prior knowledge of the associated inducer-responsive promoter-regulator elements. The present approach can be used as a model for the development of bioreporters for other environmental pollutants. PMID- 29491863 TI - Corrigendum: Genome-Based Taxonomic Classification of Bacteroidetes. AB - [This corrects the article on p. 2003 in vol. 7, PMID: 28066339.]. PMID- 29491864 TI - Preterm Life in Sterile Conditions: A Study on Preterm, Germ-Free Piglets. AB - Preterm infants born with immature organ systems, which can impede normal development, can also be highly sensitive to different biological and/or environmental factors. Animal models could aid in investigating and understanding the effects of different conditions on the health of these immunocompromised infants. The epitheliochorial placentation of the pig prevents the prenatal transfer of protective colostral immunoglobulins. Surgical colostrum-deprived piglets are free of maternal immunoglobulins, and the cells that are normally provided via colostrum. We bred preterm germ-free piglets in sterile conditions and compared them with their term counterparts. Enterocyte development and intestinal morphology, tight junction proteins claudin-1 and occludin, pattern recognizing receptors, adaptor molecules and coreceptors (RAGE, TLR2, TLR4, TLR9, MyD88, TRIF, MD2, and CD14), and inflammasome NLRP3 transcription were all evaluated. The production of inflammatory mediators IFN-alpha, IL-4, IL-6, IL-8, IL-10, IL-12/23 p40, TNF-alpha, IFN-gamma, and high mobility group box 1 (HMGB1) in the intestine of germ-free piglets was also assessed. In the preterm germ-free piglets, the ileum showed decreased lamina propria cellularity, reduced villous height, and thinner and less distinct stratification - especially muscle layer, in comparison with their term counterparts. Claudin-1 transcription increased in the intestine of the preterm piglets. The transcription levels of pattern recognizing receptors and adaptor molecules showed ambiguous trends between the groups. The levels of IL-6, IL-8, IL-10, and TNF-alpha were increased in the preterm ileum numerically (though not significantly), with statistically significant increases in the colon. Additionally, IL-12/23 p40 and IFN-gamma were statistically significantly higher in the preterm colon. Both blood plasma and intestinal HMGB1 levels were nonsignificantly higher in the preterm group. We propose that the intestine of the preterm germ-free piglets showed "mild inflammation in sterile conditions." This model, which establishes preterm, hysterectomy-derived germ-free piglets, without protective maternal immunoglobulins, can be used to study influences of microbiota, nutrition, and therapeutic interventions on the development and health of vulnerable immunocompromised preterm infants. PMID- 29491865 TI - Altered Toll-Like Receptor-4 Response to Lipopolysaccharides in Infants Exposed to HIV-1 and Its Preventive Therapy. AB - Pathogen sensing and recognition through pattern recognition receptors, and subsequent production of pro-inflammatory cytokines, is the cornerstone of the innate immune system. Despite the fact that HIV-exposed uninfected (HEU) infants are prone to serious bacterial infections, no study has focused on the functionality of their bacteria recognition system. This is the first study to investigate baseline levels of three critically important immune response molecules in this population: complement component (C)-3, toll-like receptor (TLR)-4, and C-reactive protein (CRP). We enrolled 16 HEU and 6 HIV-unexposed (HU) infants. TLR4 function was investigated by stimulating whole blood with increasing concentrations of TLR4-agonist ultrapure lipopolysaccharides. TLR4/TLR4-agonist dose response were assessed by measuring IL-6 secretion. Complement C3 and CRP were measured by photo spectrometry. Data showed no significant differences in baseline concentration of CRP between HEU and HU infants. Complement C3 was significantly higher in HEU infants than HU infants. TLR4 anergy was observed in 7 of 12 HEU infants, whereas the rest of HEU infants (n = 4) and the control HU infants tested (n = 3) showed responsive TLR4. None of the HEU infants investigated in this study had severe infections in the year after their birth. In conclusion, TLR4 anergy can occur in HEU infants without necessarily translating to increased vulnerability to infectious diseases. PMID- 29491866 TI - Phosphatidylserine-Liposomes Promote Tolerogenic Features on Dendritic Cells in Human Type 1 Diabetes by Apoptotic Mimicry. AB - Type 1 diabetes (T1D) is a metabolic disease caused by the autoimmune destruction of insulin-producing beta-cells. With its incidence increasing worldwide, to find a safe approach to permanently cease autoimmunity and allow beta-cell recovery has become vital. Relying on the inherent ability of apoptotic cells to induce immunological tolerance, we demonstrated that liposomes mimicking apoptotic beta cells arrested autoimmunity to beta-cells and prevented experimental T1D through tolerogenic dendritic cell (DC) generation. These liposomes contained phosphatidylserine (PS)-the main signal of the apoptotic cell membrane-and beta cell autoantigens. To move toward a clinical application, PS-liposomes with optimum size and composition for phagocytosis were loaded with human insulin peptides and tested on DCs from patients with T1D and control age-related subjects. PS accelerated phagocytosis of liposomes with a dynamic typical of apoptotic cell clearance, preserving DCs viability. After PS-liposomes phagocytosis, the expression pattern of molecules involved in efferocytosis, antigen presentation, immunoregulation, and activation in DCs concurred with a tolerogenic functionality, both in patients and control subjects. Furthermore, DCs exposed to PS-liposomes displayed decreased ability to stimulate autologous T cell proliferation. Moreover, transcriptional changes in DCs from patients with T1D after PS-liposomes phagocytosis pointed to an immunoregulatory prolife. Bioinformatics analysis showed 233 differentially expressed genes. Genes involved in antigen presentation were downregulated, whereas genes pertaining to tolerogenic/anti-inflammatory pathways were mostly upregulated. In conclusion, PS liposomes phagocytosis mimics efferocytosis and leads to phenotypic and functional changes in human DCs, which are accountable for tolerance induction. The herein reported results reinforce the potential of this novel immunotherapy to re-establish immunological tolerance, opening the door to new therapeutic approaches in the field of autoimmunity. PMID- 29491868 TI - Phytohormone Interaction Modulating Fruit Responses to Photooxidative and Heat Stress on Apple (Malus domestica Borkh.). AB - Sun-related physiological disorders such as sun damage on apples (Malus domestica Borkh) are caused by cumulative photooxidative and heat stress during their growing season triggering morphological, physiological, and biochemical changes in fruit tissues not only while it is on the tree but also after it has been harvested. The objective of the work was to establish the interaction of auxin (indole-3-acetic acid; IAA), abscisic acid (ABA), jasmonic acid (JA), salicylic acid (SA), and ethylene (ET) and its precursor ACC (free and conjugated, MACC) during development of sun-injury-related disorders pre- and post-harvest on apples. Peel tissue was extracted from fruit growing under different sun exposures (Non-exposed, NE; Exposed, EX) and with sun injury symptoms (Moderate, Mod). Sampling was carried out every 15 days from 75 days after full bloom (DAFB) until 120 days post-harvest in cold storage (1 degrees C, > 90%RH). Concentrations of IAA, ABA, JA, SA, were determined using UHPLC mass spectrometry, and ET and ACC (free and conjugated MACC) using gas chromatography. IAA was found not to be related directly to sun injury development, but it decreased 60% in sun exposed tissue, and during fruit development. ABA, JA, SA, and ethylene concentrations were significantly higher (P <= 0.05) in Mod tissue, but their concentration, except for ethylene, were not affected by sun exposure. ACC and MACC concentrations increased until 105 DAFB in all sun exposure categories. During post-harvest, ethylene climacteric peak was delayed on EX compared to Mod. ABA and SA concentrations remained stable throughout storage in both tissue. JA dramatically increased post-harvest in both EX and Mod tissue, and orchards, confirming its role in low temperature tolerance. The results suggest that ABA, JA, and SA together with ethylene are modulating some of the abiotic stress defense responses on sun-exposed fruit during photooxidative and heat stress on the tree. PMID- 29491867 TI - Acquired Natural Killer Cell Dysfunction in the Tumor Microenvironment of Classic Hodgkin Lymphoma. AB - An understanding of interactions within the tumor microenvironment (TME) of classic Hodgkin lymphoma (cHL) has helped pave the way to novel immunotherapies that have enabled dormant and tumor-tolerant immune cells to be reactivated. The immunosuppressive nature of the TME in cHL specifically inhibits the proliferation and activity of natural killer (NK) cells, which contributes to tumor immune-escape mechanisms. This deficiency of NK cells begins at the tumor site and progresses systemically in patients with advanced disease or adverse prognostic factors. Several facets of cHL account for this effect on NK cells. Locally, malignant Reed-Sternberg cells and cells from the TME express ligands for inhibitory receptors on NK cells, including HLA-E, HLA-G, and programmed death-ligand 1. The secretion of chemokines and cytokines, including soluble IL-2 receptor (sCD25), Transforming Growth Factor-beta, IL-10, CXCL9, and CXCL10, mediates the systemic immunosuppression. This review also discusses the potential reversibility of quantitative and functional NK cell deficiencies in cHL that are likely to lead to novel treatments. PMID- 29491869 TI - Development of Molecular Markers Linked to Powdery Mildew Resistance Gene Pm4b by Combining SNP Discovery from Transcriptome Sequencing Data with Bulked Segregant Analysis (BSR-Seq) in Wheat. AB - Powdery mildew resistance gene Pm4b, originating from Triticum persicum, is effective against the prevalent Blumeria graminis f. sp. tritici (Bgt) isolates from certain regions of wheat production in China. The lack of tightly linked molecular markers with the target gene prevents the precise identification of Pm4b during the application of molecular marker-assisted selection (MAS). The strategy that combines the RNA-Seq technique and the bulked segregant analysis (BSR-Seq) was applied in an F2:3 mapping population (237 families) derived from a pair of isogenic lines VPM1/7*Bainong 3217 F4 (carrying Pm4b) and Bainong 3217 to develop more closely linked molecular markers. RNA-Seq analysis of the two phenotypically contrasting RNA bulks prepared from the representative F2:3 families generated 20,745,939 and 25,867,480 high-quality read pairs, and 82.8 and 80.2% of them were uniquely mapped to the wheat whole genome draft assembly for the resistant and susceptible RNA bulks, respectively. Variant calling identified 283,866 raw single nucleotide polymorphisms (SNPs) and InDels between the two bulks. The SNPs that were closely associated with the powdery mildew resistance were concentrated on chromosome 2AL. Among the 84 variants that were potentially associated with the disease resistance trait, 46 variants were enriched in an about 25 Mb region at the distal end of chromosome arm 2AL. Four Pm4b-linked SNP markers were developed from these variants. Based on the sequences of Chinese Spring where these polymorphic SNPs were located, 98 SSR primer pairs were designed to develop distal markers flanking the Pm4b gene. Three SSR markers, Xics13, Xics43, and Xics76, were incorporated in the new genetic linkage map, which located Pm4b in a 3.0 cM genetic interval spanning a 6.7 Mb physical genomic region. This region had a collinear relationship with Brachypodium distachyon chromosome 5, rice chromosome 4, and sorghum chromosome 6. Seven genes associated with disease resistance were predicted in this collinear genomic region, which included C2 domain protein, peroxidase activity protein, protein kinases of PKc_like super family, Mlo family protein, and catalytic domain of the serine/threonine kinases (STKc_IRAK like super family). The markers developed in the present study facilitate identification of Pm4b during its MAS practice. PMID- 29491870 TI - Overexpression of PvGF14c from Phyllostachys violascens Delays Flowering Time in Transgenic Arabidopsis. AB - 14-3-3 Proteins are a family of highly conserved regulatory molecules expressed in all eukaryotic cells and regulate a diverse set of biological responses in plants. However, their functions in flowering of Phyllostachys violascens are poorly understood. In this study, four non-?? Pv14-3-3 genes from P. violascens were identified and named PvGF14b, PvGF14c, PvGF14e, and PvGF14f. qRT-PCR analyses revealed that PvGF14b and PvGF14e exhibited widely expressed in all tested bamboo tissues. PvGF14b was highest expression in root and lowest in immature leaf. Whereas PvGF14c and PvGF14f showed tissue-specific expression. PvGF14c was mainly expressed in immature and mature leaves. PvGF14f was highest expression in mature leaves. These four genes were not significantly differentially expressed in mature leaf before bamboo flowering and during flower development. PvGF14b and PvGF14c were not induced by circadian rhythm. PvGF14c displayed subcellular localization in the cytoplasm and PvFT in nucleus and cytoplasm. Yeast two-hybrid screening and bimolecular fluorescence complementation confirmed the interaction between PvGF14c and PvFT. The overexpression of PvGF14b, PvGF14c, and PvGF14e significantly delayed flowering time in transgenic Arabidopsis under long-day condition. These findings suggested that at least three PvGF14 genes are involved in flowering and may act as a negative regulator of flowering by interacting with PvFT in bamboo. PMID- 29491871 TI - Optimization of an RNA-Seq Differential Gene Expression Analysis Depending on Biological Replicate Number and Library Size. AB - RNA-Seq is a widely used technology that allows an efficient genome-wide quantification of gene expressions for, for example, differential expression (DE) analysis. After a brief review of the main issues, methods and tools related to the DE analysis of RNA-Seq data, this article focuses on the impact of both the replicate number and library size in such analyses. While the main drawback of previous relevant studies is the lack of generality, we conducted both an analysis of a two-condition experiment (with eight biological replicates per condition) to compare the results with previous benchmark studies, and a meta analysis of 17 experiments with up to 18 biological conditions, eight biological replicates and 100 million (M) reads per sample. As a global trend, we concluded that the replicate number has a larger impact than the library size on the power of the DE analysis, except for low-expressed genes, for which both parameters seem to have the same impact. Our study also provides new insights for practitioners aiming to enhance their experimental designs. For instance, by analyzing both the sensitivity and specificity of the DE analysis, we showed that the optimal threshold to control the false discovery rate (FDR) is approximately 2-r, where r is the replicate number. Furthermore, we showed that the false positive rate (FPR) is rather well controlled by all three studied R packages: DESeq, DESeq2, and edgeR. We also analyzed the impact of both the replicate number and library size on gene ontology (GO) enrichment analysis. Interestingly, we concluded that increases in the replicate number and library size tend to enhance the sensitivity and specificity, respectively, of the GO analysis. Finally, we recommend to RNA-Seq practitioners the production of a pilot data set to strictly analyze the power of their experimental design, or the use of a public data set, which should be similar to the data set they will obtain. For individuals working on tomato research, on the basis of the meta-analysis, we recommend at least four biological replicates per condition and 20 M reads per sample to be almost sure of obtaining about 1000 DE genes if they exist. PMID- 29491872 TI - The Cell Cycle Checkpoint Regulator ATR Is Required for Internal Aluminum Toxicity-Mediated Root Growth Inhibition in Arabidopsis. AB - Aluminum (Al) can target multiple sites of root cells for toxicity, including the cell wall, the plasma membrane and symplastic components. Previous work revealed that the cell cycle checkpoint regulator (ATR) Ataxia Telangiectasia-mutated and Rad3-related is required for Al toxicity-induced root growth inhibition in als3 and that the symplastic component DNA is an important target site of Al for the toxicity. However, whether monitoring DNA integrity through ATR-regulated pathway is required for Al-induced root growth inhibition in other Al-sensitive mutants remains unknown. In this study, we demonstrated that the atr mutation could also rescue the Al hypersensitivity and Al-induced cell cycle arrest in star1, which supports the hypothesis that ALS3 and STAR1 function together to be involved in the detoxification of Al in Arabidopsis. However, mutation of ATR could not rescue the Al-sensitive phenotype of almt1 or stop1, both of which are defective in external detoxification mechanisms of Al. We further showed that the Al hypersensitivity and Al-induced quiescent center (QC) differentiation in als1 could also be rescued by the atr mutation. Therefore, our results suggest that ATR-regulated pathway is involved in the modulation of internal Al toxicity mediated root growth inhibition in Arabidopsis. PMID- 29491873 TI - Low-Light Dependence of the Magnetic Field Effect on Cryptochromes: Possible Relevance to Plant Ecology. AB - Various responses to static magnetic fields (MF) have been reported in plants, and it has been suggested that the geomagnetic field influences plant physiology. Accordingly, diverse mechanisms have been proposed to mediate MF effects in plants. The currently most probable sensor candidates are cryptochromes (Cry) which are sensitive to submillitesla MF. Here, we propose a quantitative approach of the MF effect on Cry depending on light intensity, and try to link it to a possible functional role for magnetic sensitivity in plants. Based on a theoretical evaluation and on a review of relevant data on Arabidopsis thaliana Cry 1, we point out that the MF effect on the signaling state of Cry, as well as the possible consequences of that effect on certain phenotypes (growth in particular) show parallel dependences on light intensity, being most prominent at low light levels. Based on these findings, we propose that Cry magnetosensitivity in plants could represent an ecological adaptation which regulates the amount of Cry signaling state under low light conditions. That hypothesis would preferentially be tested by studying sensitive and specific endpoints, such as the expression of clock proteins that are downregulated by Cry, but under light intensities lower than those used so far. Finally, we highlight that the low light dependence of the MF effect described here could also apply to light dependent functions of animal Cry, in particular magnetoreception which, from the present evaluation, would be based on the magnetic sensitivity of the photoreduction reaction, like in plants. PMID- 29491874 TI - Dehydrins Impart Protection against Oxidative Stress in Transgenic Tobacco Plants. AB - Environmental stresses generate reactive oxygen species (ROS) which might be detrimental to the plants when produced in an uncontrolled way. However, the plants ameliorate such stresses by synthesizing antioxidants and enzymes responsible for the dismutation of ROS. Additionally, the dehydrins were also able to protect the inactivation of the enzyme lactate dehydrogenase against hydroxyl radicals (OH?) generated during Fenton's reaction. SbDhn1 and SbDhn2 overexpressing transgenic tobacco plants were able to protect against oxidative damage. Transgenic tobacco lines showed better photosynthetic efficiency along with high chlorophyll content, soluble sugar and proline. However, the malonyl dialdehyde (MDA) content was significantly lower in transgenic lines. Experimental evidence demonstrates the protective effect of dehydrins on electron transport chain in isolated chloroplast upon methyl viologen (MV) treatment. The transgenic tobacco plants showed significantly lower superoxide radical generation () upon MV treatment. The accumulation of the H2O2 was also lower in the transgenic plants. Furthermore, in the transgenic plants the expression of ROS scavenging enzymes was higher compared to non-transformed (NT) or vector transformed (VT) plants. Taken together these data, during oxidative stress dehydrins function by scavenging the () directly and also by rendering protection to the enzymes responsible for the dismutation of () thereby significantly reducing the amount of hydrogen peroxides formed. Increase in proline content along with other antioxidants might also play a significant role in stress amelioration. Dehydrins thus function co-operatively with other protective mechanisms under oxidative stress conditions rendering protection in stress environment. PMID- 29491875 TI - A Systems Biology Study in Tomato Fruit Reveals Correlations between the Ascorbate Pool and Genes Involved in Ribosome Biogenesis, Translation, and the Heat-Shock Response. AB - Changing the balance between ascorbate, monodehydroascorbate, and dehydroascorbate in plant cells by manipulating the activity of enzymes involved in ascorbate synthesis or recycling of oxidized and reduced forms leads to multiple phenotypes. A systems biology approach including network analysis of the transcriptome, proteome and metabolites of RNAi lines for ascorbate oxidase, monodehydroascorbate reductase and galactonolactone dehydrogenase has been carried out in orange fruit pericarp of tomato (Solanum lycopersicum). The transcriptome of the RNAi ascorbate oxidase lines is inversed compared to the monodehydroascorbate reductase and galactonolactone dehydrogenase lines. Differentially expressed genes are involved in ribosome biogenesis and translation. This transcriptome inversion is also seen in response to different stresses in Arabidopsis. The transcriptome response is not well correlated with the proteome which, with the metabolites, are correlated to the activity of the ascorbate redox enzymes-ascorbate oxidase and monodehydroascorbate reductase. Differentially accumulated proteins include metacaspase, protein disulphide isomerase, chaperone DnaK and carbonic anhydrase and the metabolites chlorogenic acid, dehydroascorbate and alanine. The hub genes identified from the network analysis are involved in signaling, the heat-shock response and ribosome biogenesis. The results from this study therefore reveal one or several putative signals from the ascorbate pool which modify the transcriptional response and elements downstream. PMID- 29491876 TI - Genome-Wide Association Mapping for Tolerance to Preharvest Sprouting and Low Falling Numbers in Wheat. AB - Preharvest sprouting (PHS), the germination of grain on the mother plant under cool and wet conditions, is a recurring problem for wheat farmers worldwide. alpha-amylase enzyme produced during PHS degrades starch resulting in baked good with poor end-use quality. The Hagberg-Perten Falling Number (FN) test is used to measure this problem in the wheat industry, and determines how much a farmer's wheat is discounted for PHS damage. PHS tolerance is associated with higher grain dormancy. Thus, breeding programs use germination-based assays such as the spike wetting test to measure PHS susceptibility. Association mapping identified loci associated with PHS tolerance in U.S. Pacific Northwest germplasm based both on FN and on spike-wetting test data. The study was performed using a panel of 469 white winter wheat cultivars and elite breeding lines grown in six Washington state environments, and genotyped for 15,229 polymorphic markers using the 90k SNP Illumina iSelect array. Marker-trait associations were identified using the FarmCPU R package. Principal component analysis was directly and a kinship matrix was indirectly used to account for population structure. Nine loci were associated with FN and 34 loci associated with PHS based on sprouting scores. None of the QFN.wsu loci were detected in multiple environments, whereas six of the 34 QPHS.wsu loci were detected in two of the five environments. There was no overlap between the QTN detected based on FN and PHS, and there was little correlation between the two traits. However, both traits appear to be PHS-related since 19 of the 34 QPHS.wsu loci and four of the nine QFN.wsu loci co-localized with previously published dormancy and PHS QTL. Identification of these loci will lead to a better understanding of the genetic architecture of PHS and will help with the future development of genomic selection models. PMID- 29491877 TI - Corrigendum: Divisions of labor in the thiamin biosynthetic pathway among organs of maize. AB - [This corrects the article on p. 370 in vol. 5, PMID: 25136345.]. PMID- 29491878 TI - SHI/STY Genes Affect Pre- and Post-meiotic Anther Processes in Auxin Sensing Domains in Arabidopsis. AB - In flowering plants, mature sperm cells are enclosed in pollen grains formed in structures called anthers. Several cell layers surrounding the central sporogenous cells of the anther are essential for directing the developmental processes that lead to meiosis, pollen formation, and the subsequent pollen release. The specification and function of these tissues are regulated by a large number of genetic factors. Additionally, the plant hormone auxin has previously been shown to play important roles in the later phases of anther development. Using the R2D2 auxin sensor system we here show that auxin is sensed also in the early phases of anther cell layer development, suggesting that spatiotemporal regulation of auxin levels is important for early anther morphogenesis. Members of the SHI/STY transcription factor family acting as direct regulators of YUC auxin biosynthesis genes have previously been demonstrated to affect early anther patterning. Using reporter constructs we show that SHI/STY genes are dynamically active throughout anther development and their expression overlaps with those of three additional downstream targets, PAO5, EOD3 and PGL1. Characterization of anthers carrying mutations in five SHI/STY genes clearly suggests that SHI/STY transcription factors affect anther organ identity. In addition, their activity is important to repress periclinal cell divisions as well as premature entrance into programmed cell death and cell wall lignification, which directly influences the timing of anther dehiscence and the pollen viability. The SHI/STY proteins also prevent premature pollen germination suggesting that they may play a role in the induction or maintenance of pollen dormancy. PMID- 29491879 TI - Mapping of a Major QTL for Ceratocystis Wilt Disease in an F1 Population of Theobroma cacao. AB - Cacao is an important crop, its beans are key raw materials for the chocolate and cosmetic industries. Ceratocystis wilt of cacao (CWC) caused by Ceratocystis cacaofunesta is a lethal disease for the crop. Therefore, the selection of resistant cacao varieties is one of the viable ways to minimize losses in cacao production. In this paper, we described the identification of a major QTL associated with CWC in an F1 mapping population from a cross between a resistant, "TSH 1188," and a susceptible genotype, "CCN 51." A set of 266 trees were genotyped using 3,526 single nucleotide polymorphic markers and then multiple QTL mapping analyses were performed. Two QTLs were identified on chromosomes IV and VI. The major QTL was located at 20 cM from the top position of chromosome VI, accounting for more than 60% of the phenotypic variation. The favorable allele T1, with haplotype GTT, came from the "TSH 1188" parent. It was evident that the haplotype combination T1C2 on chromosome VI was the most significant for resistance, since 93% of resistant trees had this haplotype. The major QTL converged to a genomic region of 739.4 kb that harbored nine candidate genes, including two major classes of resistance genes, which would make them the primary candidates involved in the resistance to CWC. The haplotypes detected are now used to improve the efficiency and precision of the selection of resistant trees in cacao breeding. PMID- 29491880 TI - Unlikely Nomads: Settlement, Establishment, and Dislodgement Processes of Vegetative Seagrass Fragments. AB - The dispersal of seagrasses is important to promoting the resilience and long term survival of populations. Most of the research on long-distance dispersal to date has focused on sexual propagules while the dispersal of vegetative fragments has been largely overlooked, despite the important role this mechanism might play. In this study, we proposed a conceptual model that categorizes vegetative fragment dispersal into seven fundamental steps: i.e., (i) fragment formation, (ii) transport, (iii) decay, (iv) substrate contact, (v) settlement, (vi) establishment, and (vii) dislodgement. We present two experiments focusing on the final steps of the model from substrate contact to dislodgement in four tropical seagrass species (Cymodocea rotundata, Halophila ovalis, Halodule uninervis, and Thalassia hemprichii), which are critical for dispersed vegetative fragments to colonize new areas. We first conducted a mesocosm experiment to investigate the effect of fragment age and species on settlement (i.e., remains on the substrate in a rising tide) and subsequently establishment (i.e., rooting in substrate) rates. To determine dislodgement resistance of settled fragments, we also subjected fragments under different burial treatments to wave and currents in a flume. We found that both initial settlement and subsequent establishment rates increased with fragment age. H. ovalis was the only species that successfully established within the study period. After settlement, dislodgement resistance depended primarily on burial conditions. Smaller species H. ovalis and H. uninervis were also able to settle more successfully, and withstand higher bed shear stress before being dislodged, compared to the larger species T. hemprichii and C. rotundata. However, the ordinal logistic regressions did not reveal relationships between the tested plant morphometrics and the energy needed for dislodgement (with the exception of C. rotundata), indicating that there are potentially some untested species-specific traits that enable certain species to withstand dislodgement better. We discuss the implication our findings have on the dispersal potential for different species and the conservation of seagrasses. This study represents the first effort toward generating parameters for a bio physical model to predict vegetative fragment dispersal. PMID- 29491881 TI - Detection of Bacterial Infection in Melon Plants by Classification Methods Based on Imaging Data. AB - The bacterium Dickeya dadantii is responsible of important economic losses in crop yield worldwide. In melon leaves, D. dadantii produced multiple necrotic spots surrounded by a chlorotic halo, followed by necrosis of the whole infiltrated area and chlorosis in the surrounding tissues. The extent of these symptoms, as well as the day of appearance, was dose-dependent. Several imaging techniques (variable chlorophyll fluorescence, multicolor fluorescence, and thermography) provided spatial and temporal information about alterations in the primary and secondary metabolism, as well as the stomatal activity in the infected leaves. Detection of diseased leaves was carried out by using machine learning on the numerical data provided by these imaging techniques. Mathematical algorithms based on data from infiltrated areas offered 96.5 to 99.1% accuracy when classifying them as mock vs. bacteria-infiltrated. These algorithms also showed a high performance of classification of whole leaves, providing accuracy values of up to 96%. Thus, the detection of disease on whole leaves by a model trained on infiltrated areas appears as a reliable method that could be scaled-up for use in plant breeding programs or precision agriculture. PMID- 29491884 TI - Do coyotes Canis latrans influence occupancy of prey in suburban forest fragments? AB - With the extirpation of apex predators from many North American systems, coyotes Canis latrans have become the de facto top predator and are ubiquitous members of most ecosystems. Keystone predators aid in maintaining ecosystem function by regulating the mammal community through direct predation and instilling the landscape of fear, yet the value of coyotes regulating systems to this capacity is understudied and likely variable across environments. Since coyotes are common in the Midwestern United States, we utilized camera traps and occupancy analyses to assess their role in regulating the distribution of mammalian herbivores in a fragmented suburban ecosystem. Forest cover was a strong positive predictor of white-tailed deer Odocoileus virginianus detection, while coyote occurrence had a negative effect. Coyotes exerted a negative effect on squirrel (Sciurus spp.) and eastern cottontail rabbit Sylvilagus floridanus occurrence, while urban cover was a positive predictor for the prey species' occurrence. These results suggest all 3 species behaviorally avoid coyotes whereby deer seek denser forest cover and squirrels and cottontails mitigate risk by increasing use of urban areas. Although previous studies reveal limited influence of coyote on the rest of the carnivore guild in suburban systems, we suggest coyotes play an important role in regulating the herbivorous mammals and hence may provide similar ecological benefits in urban/suburban forest fragments through trophic cascades. Furthermore, since hunting may not be allowed in urban and suburban habitats, coyotes might also serve as the primary regulator of nuisance species occurring at high abundance such as white-tailed deer and squirrels. PMID- 29491885 TI - The road to opportunities: landscape change promotes body-size divergence in a highly mobile species. AB - Landscape change provides a suitable framework for investigating population-level responses to novel ecological pressures. However, relatively little attention has been paid to examine the potential influence of landscape change on the geographic scale of population differentiation. Here, we tested for morphological differentiation of red-necked nightjars Caprimulgus ruficollis breeding in a managed property and a natural reserve situated less than 10 km apart. At both sites, we also estimated site fidelity over 5 years and quantified the potential foraging opportunities for nightjars. Breeding birds in the managed habitat were significantly larger in size-as indexed by keel length-than those in the natural one. However, there were no significant differences in wing or tail length. Immigration from neighboring areas was almost negligible and, furthermore, no individual (out of 1130 captures overall) exchanged habitats between years, indicating strong site fidelity. Food supply for nightjars was equally abundant in both habitats, but the availability of foraging sites was remarkably higher in the managed property. As a result, nightjars-particularly fledglings-in the latter habitat benefited from increased foraging opportunities in relation to those in the natural site. It seems likely that the fine-scale variation in nightjar morphology reflects a phenotypic response to unequal local conditions, since non-random dispersal or differential mortality had been determined not to be influential. High site fidelity appears to contribute to the maintenance of body-size differences between the two habitats. Results from this nightjar population highlight the potential of human-induced landscape change to promote population-level responses at exceedingly small geographic scales. PMID- 29491882 TI - A Comprehensive Atlas of E3 Ubiquitin Ligase Mutations in Neurological Disorders. AB - Protein ubiquitination is a posttranslational modification that plays an integral part in mediating diverse cellular functions. The process of protein ubiquitination requires an enzymatic cascade that consists of a ubiquitin activating enzyme (E1), ubiquitin conjugating enzyme (E2) and an E3 ubiquitin ligase (E3). There are an estimated 600-700 E3 ligase genes representing ~5% of the human genome. Not surprisingly, mutations in E3 ligase genes have been observed in multiple neurological conditions. We constructed a comprehensive atlas of disrupted E3 ligase genes in common (CND) and rare neurological diseases (RND). Of the predicted and known human E3 ligase genes, we found ~13% were mutated in a neurological disorder with 83 total genes representing 70 different types of neurological diseases. Of the E3 ligase genes identified, 51 were associated with an RND. Here, we provide an updated list of neurological disorders associated with E3 ligase gene disruption. We further highlight research in these neurological disorders and discuss the advanced technologies used to support these findings. PMID- 29491883 TI - Role of MicroRNA in Proliferation Phase of Wound Healing. AB - Wound healing is a complex biological process that is generally composed of four phases: hemostasis, inflammation, proliferation, and remodeling. The proliferation phase is crucial for effective healing compared to other phases. Many critical events occur during this phase, i.e., migration of fibroblasts, re epithelialization, angiogenesis and wound contraction. Chronic wounds are common and are considered a major public health problem. Therefore, there is the increasing need to discover new therapeutic strategies. MicroRNA (miRNA) research in the field of wound healing is in its early phase, but the knowledge of the recent discoveries is essential for developing effective therapies for the treatment of chronic wounds. In this review, we focused on recently discovered miRNAs which are involved in the proliferation phase of wound healing in the past few years and their role in wound healing. PMID- 29491886 TI - Emblematic forest dwellers reintroduced into cities: resource selection by translocated juvenile kaka. AB - Urbanization and exotic species are major threats to the conservation of forest dependent wildlife species. Some emblematic species, indicators of habitat quality for the conservation of other species, might successfully be reintroduced within cities when habitat restoration and pest management programs are combined. We studied the landscape resource selection of juvenile kaka Nestor meridionalis tracked with Global Positioning System (GPS) units and released into the predator free reserve of Zealandia in Wellington city, New Zealand. Kaka moved beyond the predator exclusion fence into urban suburbs. The home range size and areas of high use estimated using local convex hull (a-LoCoH) ranged from 20 to 240 ha and 2 to 21 ha, respectively. Using resource selection functions and model selection we found that native forest patches and urban areas close to the reserve were selected by kaka to establish their home ranges. At a lower scale of selection (i.e., selection of habitats within home ranges), kaka selected the same habitat, but not necessarily those close to the reserve. Native forest patches throughout the city can facilitate the dispersal of individuals, while the reserve provides protection and opportunities for supplementary feeding. Urban areas might have been selected due to the placement of feeders in private backyards. Survival of forest-dwelling species in cities requires careful urban planning and management to provide the necessary habitat patches, refugia, and food sources. PMID- 29491887 TI - The dynamics of color signals in male threespine sticklebacks Gasterosteus aculeatus. AB - Body coloration and color patterns are ubiquitous throughout the animal kingdom and vary between and within species. Recent studies have dealt with individual dynamics of various aspects of coloration, as it is in many cases a flexible trait and changes in color expression may be context-dependent. During the reproductive phase, temporal changes of coloration in the visible spectral range (400-700 nm) have been shown for many animals but corresponding changes in the ultraviolet (UV) waveband (300-400 nm) have rarely been studied. Threespine stickleback Gasterosteus aculeatus males develop conspicuous orange-red breeding coloration combined with UV reflectance in the cheek region. We investigated dynamics of color patterns including UV throughout a male breeding cycle, as well as short-term changes in coloration in response to a computer-animated rival using reflectance spectrophotometry and visual modeling, to estimate how colors would be perceived by conspecifics. We found the orange-red component of coloration to vary during the breeding cycle with respect to hue (theta/R50) and intensity (achieved chroma/red chroma). Furthermore, color intensity in the orange-red spectral part (achieved chroma) tended to be increased after the presentation of an artificial rival. Dynamic changes in specific measures of hue and intensity in the UV waveband were not found. In general, the orange-red component of the signal seems to be dynamic with respect to color intensity and hue. This accounts in particular for color changes during the breeding cycle, presumably to signal reproductive status, and with limitations as well in the intrasexual context, most likely to signal dominance or inferiority. PMID- 29491888 TI - Postconflict behavior among Rhinopithecus roxellana leader males in the Qinling Mountains, China. AB - Since reconciliation was first described more than 20 years ago, a large number of postconflict behaviors have been observed among females in many polygynous primate species. However, few studies have been conducted among males, perhaps due to the rarity with which they maintain friendly relationships with one another and their aggressive competition for resources. Although this is true for many primate males, Sichuan snub-nosed monkeys Rhinopithecus roxellana represent a potential exception as male cooperation has been known to occur. In this study, using postconflict/matched-control(PC-MC) and time-rule methods, we analyzed postconflict behavior among males and the possible occurrence of bystander affiliation or reconciliation. A total of 246 PC-MC pairs among leader males were obtained. On average, each leader male exhibited only 0.04 aggressive behaviors per observation hour, and conciliation among leader males occurred at a low rate (2.03%) relative to other primate species. The occurrence of consolation affiliation interactions between focal males and group members other than former opponents differed significantly between PCs and MCs, which is the first time this has been confirmed among R. roxellana males. We discuss the results in light of recent theories concerning consolation in primates. The patterns of postconflict contact demonstrated that R. roxellana may be a unique species among colobines. PMID- 29491889 TI - Spearfishing-induced behavioral changes of an unharvested species inside and outside a marine protected area. AB - By prohibiting fishing, marine protected areas (MPAs) provide a refuge for harvested species. Humans are often perceived as predators by prey and therefore respond fearfully to humans. Thus, fish responses to humans inside and outside of an MPA can provide insights into their perception of humans as a predatory threat. Previous studies have found differences in the distance that harvested species of fish initiate flight (flight initiation distance-FID) from humans inside and outside an MPA, but less is known about unharvested species. We focused on whether the lined bristletooth Ctenochaetus striatus, an unharvested surgeonfish, can discriminate between a snorkeler and a snorkeler with a spear gun inside and outside of a no-take MPA in Mo'orea, French Polynesia. Additionally, we incorporated starting distance (the distance between the person and prey at the start of an experimental approach), a variable that has been found to be important in assessing prey escape decisions in terrestrial species, but that has not been extensively studied in aquatic systems. Lined bristletooth FID was significantly greater in the presence of a spear gun and varied depending on if the spear gun encounter was inside or outside of the MPA. These results imply a degree of sophistication of fish antipredator behavior, generate questions as to how a nontargeted species of fish could acquire fear of humans, and demonstrate that behavioral surveys can provide insights about antipredator behavior. PMID- 29491890 TI - Responses to threat in a freshwater invader: longitudinal data reveal personality, habituation, and robustness to changing water temperatures in the "killer shrimp" Dikerogammarus villosus (Crustacea: Amphipoda). AB - Freshwater biodiversity and ecosystem integrity are under threat from biological invasions. The "killer shrimp" Dikerogammarus villosus is a highly predatory amphipod that has spread readily across Central Europe and recently the UK and its arrival has been associated with the significant loss of resident species. Despite this, studies of its behavioral ecology are sparse, even though its behavior may contribute to its invasion success. For the first time, we investigated antipredator "fleeing" behavior in D. villosus and how this changed with water temperature. Three key patterns emerged from our analysis. First, within a particular temperature condition there are moderate but consistent among individual differences in behavior. These are driven by a combination of mean level among-individual differences and within-individual relative consistency in behavior, and provide the key marker for animal personalities. Second, the fleeing responses were not influenced by temperature and third, regardless of temperature, all individuals appeared to habituate to a repeated nondangerous stimulus, indicating a capacity for individual learning. We suggest that the antipredator behavior of D. villosus contributes to its rapid spread and that consistent among-individual differences in behavior may promote biological invasions across heterogeneous conditions. Robustness to changing water temperatures may also be potentially advantageous, particularly in an era of global climate change, where average temperatures could be elevated and less predictable. PMID- 29491891 TI - Effects of historically familiar and novel predator odors on the physiology of an introduced prey. AB - Predator odors can elicit fear responses in prey and predator odor recognition is generally associated with physiological responses. Prey species are often more likely to respond to the odor of familiar rather than alien predators. However, predator naivety in an introduced prey species has rarely been investigated. We examined the physiological response, as shown by changes in ventilatory variables, of an introduced terrestrial herbivore, the European rabbit Oryctolagus cuniculus, in Australia, to the odor of potential predators and to control odors (distilled water and horse), to explore if responses were limited to historical (cat and fox) predators, or extended to historically novel predators (snake and quoll). All odors except distilled water elicited a response, with rabbits showing long-term higher respiratory frequencies and lower tidal volumes after introduction of the odors, indicating an increase in alertness. However, the intensity of the rabbits' reaction could not be directly linked to any pattern of response with respect to the history of predator-prey relationships. Rabbits exhibited significantly stronger reactions in response to both cat and quoll odors than they did to distilled water, but responses to horse, fox, and snake odor were similar to that of water. Our results show that the introduced rabbit can respond to both historical and novel predators in Australia, and suggest that shared evolutionary history is not necessarily a prerequisite to predator odor recognition. PMID- 29491892 TI - Newt life after fish introduction: extirpation of paedomorphosis in a mountain fish lake and newt use of satellite pools. AB - Fish introduction is one of the main causes of amphibian decline worldwide. It affects particularly rare aquatic phenotypes such as paedomorphs, which retain gills during the adult stage. In this context, we determined whether small wetlands, such as pools surrounding fished and fishless lakes, could sustain paedomorphic and metamorphic newts. To this end, we surveyed lakes known historically to sustain Alpine newts Ichthyosaura alpestris as well as 35 nearby pools. On the basis of the published records, the only known population exhibiting paedomorphosis in the Swiss Alps was found to be extirpated by salmonid introductions. However, the metamorphs persisted in peripheral pools, paedomorphosis was discovered at a new locality, and overwintering larvae were still present in one of the lakes. These results show the importance of conserving varied aquatic habitats such as pools in mountainous environments where the main resources can become unsuitable for amphibians because of fish introductions. Pools may also function as reservoirs in maintaining newt populations until programs to remove fish from lakes can be carried out. It is not known if paedomorphs could reappear after fish removal. However, the combined resilience of amphibians after fish removal and the genetic basis for paedomorphosis highlighted in other taxa by previous studies suggest that there is the potential to maintain this intraspecific case of diversity even after its disappearance. PMID- 29491893 TI - Genetic basis for body size variation between an anadromous and two derived lacustrine populations of threespine stickleback Gasterosteus aculeatus in southwest Alaska. AB - Body size is a highly variable trait among geographically separated populations. Size-assortative reproductive isolation has been linked to recent adaptive radiations of threespine stickleback (Gasterosteus aculeatus) into freshwater, but the genetic basis of the commonly found size difference between anadromous and derived lacustrine sticklebacks has not been tested. We studied the genetic basis of size differences between recently diverging stickleback lineages in southwest Alaska using a common environment experiment. We crossed stickleback within one anadromous (Naknek River) and one lake (Pringle Lake) population and between the anadromous and two lake populations (Pringle and JoJo Lakes), and raised them in a salinity of 4-6 ppt. The F1 anadromous and freshwater forms differed significantly in size, whereas hybrids were intermediate or exhibited dominance toward the anadromous form. Additionally, the size of freshwater F1s differed from their wild counterparts, with within-population F1s from Pringle Lake growing larger than their wild counterparts, while there was no size difference between lab-raised and wild anadromous fish. Sexual dimorphism was always present in anadromous fish, but not in freshwater, and not always in the hybrid crosses. These results, along with parallel changes among anadromous and freshwater forms in other regions, suggest that this heritable trait is both plastic and may be under divergent and/or sexual selection. PMID- 29491894 TI - Reproduction and survival in the city: which fitness components drive urban colonization in a reed-nesting waterbird? AB - Processes of adaptation to urban environments are well described for relatively few avian taxa, mainly passerines, but selective forces responsible for urban colonization in ecologically different groups of birds remain mostly unrecognized. The aim of this article is to identify drivers of recent urban colonization (Lodz, central Poland) by a reed-nesting waterbird, the Eurasian coot Fulica atra. Urban colonizers were found to adopt a distinct reproductive strategy by maximizing the number of offspring (carryover effects of higher clutch size), whereas suburban individuals invested more in the quality of the progeny (higher egg volume), which could reflect differences in predatory pressure between 2 habitats. In fact, reduced predation rate was strongly suggested by elevated hatching success in highly urbanized areas, where probability of hatching at least 1 chick was higher by 30% than in suburban natural-like habitats. Coots nesting in highly urbanized landscape had considerably higher annual reproductive success in comparison to suburban pairs, and the difference was 4-fold between the most and least urbanized areas. There was also a constant increase in size-adjusted body mass and hemoglobin concentration of breeding coots from the suburbs to the city centre. Urban colonization yielded no survival benefits for adult birds and urban individuals showed higher site fidelity than suburban conspecifics. The results suggest that the recent urban colonization by Eurasian coots was primary driven by considerable reproductive benefits which may be primarily attributed to: (1) reduced predation resulting from an exclusion of most native predators from highly urbanized zones; (2) increased condition of urban-dwelling birds resulting from enhanced food availability. PMID- 29491895 TI - Wind effects on the migration routes of trans-Saharan soaring raptors: geographical, seasonal, and interspecific variation. AB - Wind is among the most important environmental factors shaping birds' migration patterns. Birds must deal with the displacement caused by crosswinds and their behavior can vary according to different factors such as flight mode, migratory season, experience, and distance to goal areas. Here we analyze the relationship between wind and migratory movements of three raptor species which migrate by soaring-gliding flight: Egyptian vulture Neophron percnopterus, booted eagle Aquila pennata, and short-toed snake eagle Circaetus gallicus. We analyzed daily migratory segments (i.e., the path joining consecutive roosting locations) using data recorded by GPS satellite telemetry. Daily movements of Egyptian vultures and booted eagles were significantly affected by tailwinds during both autumn and spring migrations. In contrast, daily movements of short-toed eagles were only significantly affected by tailwinds during autumn migration. The effect of crosswinds was significant in all cases. Interestingly, Egyptian vultures and booted eagles showed latitudinal differences in their behavior: both species compensated more frequently at the onset of autumn migration and, at the end of the season when reaching their wintering areas, the proportion of drift segments was higher. In contrast, there was a higher drift at the onset of spring migration and a higher compensation at the end. Our results highlight the effect of wind patterns on the migratory routes of soaring raptors, with different outcomes in relation to species, season, and latitude, ultimately shaping the loop migration patterns that current tracking techniques are showing to be widespread in many long distance migrants. PMID- 29491896 TI - Low-ranking female Japanese macaques make efforts for social grooming. AB - Grooming is essential to build social relationships in primates. Its importance is universal among animals from different ranks; however, rank-related differences in feeding patterns can lead to conflicts between feeding and grooming in low-ranking animals. Unifying the effects of dominance rank on feeding and grooming behaviors contributes to revealing the importance of grooming. Here, I tested whether the grooming behavior of low-ranking females were similar to that of high-ranking females despite differences in their feeding patterns. I followed 9 Japanese macaques Macaca fuscata fuscata adult females from the Arashiyama group, and analyzed the feeding patterns and grooming behaviors of low- and high-ranking females. Low-ranking females fed on natural foods away from the provisioning site, whereas high-ranking females obtained more provisioned food at the site. Due to these differences in feeding patterns, low ranking females spent less time grooming than high-ranking females. However, both low- and high-ranking females performed grooming around the provisioning site, which was linked to the number of neighboring individuals for low-ranking females and feeding on provisioned foods at the site for high-ranking females. The similarity in grooming area led to a range and diversity of grooming partners that did not differ with rank. Thus, low-ranking females can obtain small amounts of provisioned foods and perform grooming with as many partners around the provisioning site as high-ranking females. These results highlight the efforts made by low-ranking females to perform grooming and suggest the importance of grooming behavior in group-living primates. PMID- 29491897 TI - Does boldness explain vulnerability to angling in Eurasian perch Perca fluviatilis? AB - Consistent individual differences (CIDs) in behavior are of interest to both basic and applied research, because any selection acting on them could induce evolution of animal behavior. It has been suggested that CIDs in the behavior of fish might explain individual differences in vulnerability to fishing. If so, fishing could impose selection on fish behavior. In this study, we assessed boldness-indicating behaviors of Eurasian perch Perca fluviatilis using individually conducted experiments measuring the time taken to explore a novel arena containing predator (burbot, Lota lota) cues. We studied if individual differences in boldness would explain vulnerability of individually tagged perch to experimental angling in outdoor ponds, or if fishing would impose selection on boldness-indicating behavior. Perch expressed repeatable individual differences in boldness-indicating behavior but the individual boldness-score (the first principal component) obtained using principal component analysis combining all the measured behavioral responses did not explain vulnerability to experimental angling. Instead, large body size appeared as the only statistically significant predictor of capture probability. Our results suggest that angling is selective for large size, but not always selective for high boldness. PMID- 29491898 TI - Predator-prey distance and latency to flee from an immobile predator: functional relationship and importance. AB - When an immobile prey has detected an immobile predator nearby, predation risk is greater when the predator is closer. Consequently, prey flee with shorter latency as standing distance (predator-prey distance when both are still) decreases. Since it was first reported in 2009, this relationship has been confirmed in the few species studied. However, little is known about the functional relationship between standing distance and latency to flee (LF). We hypothesized that LF increases as standing distance increases at short distances, but reaches a plateau at longer distances where prey can escape reliably if attacked. We simulated immobile predators by moving slowly into positions near striped plateau lizards Sceloporus virgatus, stopping and then remaining immobile, and recording LF from the stopping time. LF increased from shorter to longer standing distances in a decelerating manner. The relationship was concave downward, and LF was indistinguishable among the longer standing distance groups. Latency to flee appears to reach a plateau or approach an asymptotic value as standing distance increases. The effect size of standing distance was large, indicating that S. virgatus sensitively adjusts LF to the level of risk associated with standing distance. Relationships between risk assessment and theoretical zones associated with risk, its assessment by prey, and escape decisions are discussed. Effect sizes of standing distance were substantial to large in all studies to date, indicating that standing distance is an important predation risk factor when both predator and prey are immobile. PMID- 29491899 TI - Time till death affects spider mobility and web-building behavior during web construction in an orb-web spider. AB - It is well known that age influences organism mobility. This was demonstrated in vertebrates (such as mammals and birds) but has been less studied in invertebrates with the exception of Drosophila and the nematode Caenorhabditis elegans. Here we studied the influence of age on the mobility of the orb-weaving spider Zygiella x-notata during web construction. The orb-web is a good model because it has a characteristic geometrical structure and video tracking can be used to easily follow the spider's movements during web building. We investigated the influence of age (specifically chronological age, life span, and time till death) on different parameters of spider mobility during the construction of the capture spiral (distance traveled, duration of construction, spider velocity, spider movement, and spider inactivity) with a generalized linear model (GLM) procedure adjusted for the spider mass. The results showed that neither chronological age, nor life span affected the mobility parameters. However, when the time till death decreased, there was a decrease in the distance traveled, the duration of the construction of the capture spiral, and the spider movement. The spider velocity and the time of inactivity were not affected. These results could be correlated with a decrease in the length of the silky thread deposited for the construction of the capture spiral. Spiders with a shorter time till death built smaller web using less silk. Thus, our study suggests strongly that time till death affects spider mobility during web construction but not the chronological age and thus may be a good indicator of senescence. PMID- 29491900 TI - Reconciling concepts, theory, and empirical patterns surrounding cascade reinforcement. PMID- 29491901 TI - Reinforcement's incidental effects on reproductive isolation between conspecifics. AB - Reinforcement-the process whereby maladaptive hybridization leads to the strengthening of prezygotic isolation between species-has a long history in the study of speciation. Because reinforcement affects traits involved in mate choice and fertility, it can have indirect effects on reproductive isolation between populations within species. Here we review examples of these "cascading effects of reinforcement" (CER) and discuss different mechanisms through which they can arise. We discuss three factors that are predicted to influence the potential occurrence of CER: rates of gene flow among populations, the strength of selection acting on the traits involved in reinforcement, and the genetic basis of those traits. We suggest that CER is likely if (1) the rate of gene flow between conspecific populations is low; (2) divergent selection acts on phenotypes involved in reinforcement between sympatric and allopatric populations; and (3) the genetic response to reinforcement differs among conspecific populations subject to parallel reinforcing selection. Future work continuing to address gene flow, selection, and the genetic basis of the traits involved in the reinforcement will help develop a better understanding of reinforcement as a process driving the production of species diversity, both directly and incidentally. PMID- 29491902 TI - Reinforcement as an initiator of population divergence and speciation. AB - When hybridization results in reduced fitness, natural selection is expected to favor the evolution of traits that minimize the likelihood of hybridizing in the first place. This process, termed reinforcement (or, more generally, reproductive character displacement), thereby contributes to the evolution of enhanced reproductive isolation between hybridizing groups. By enhancing reproductive isolation in this way, reinforcement plays an important role in the final stages of speciation. However, reinforcement can also contribute to the early stages of speciation. Specifically, because selection to avoid hybridization occurs only in sympatric populations, the unfolding of reinforcement can lead to the evolution of traits in sympatric populations that reduce reproduction between conspecifics in sympatry versus those in allopatry. Thus, reinforcement between species can lead to reproductive isolation-and possibly speciation-between populations in sympatry versus those in allopatry or among different sympatric populations. Here, I describe how this process can occur, the conditions under which it is most likely to occur, and the empirical data needed to evaluate the hypothesis that reinforcement can initiate speciation. PMID- 29491903 TI - Is cascade reinforcement likely when sympatric and allopatric populations exchange migrants? AB - When partially reproductively isolated species come back into secondary contact, these taxa may diverge in mating preferences and sexual cues to avoid maladaptive hybridization, a process known as reinforcement. This phenomenon often leads to reproductive character displacement (RCD) between sympatric and allopatric populations of reinforcing species that differ in their exposure to hybridization. Recent discussions have reinvigorated the idea that RCD may give rise to additional speciation between conspecific sympatric and allopatric populations, dubbing the concept "cascade reinforcement." Despite some empirical studies supporting cascade reinforcement, we still know very little about the conditions for its evolution. In the present article, we address this question by developing an individual-based population genetic model that explicitly simulates cascade reinforcement when one of the hybridizing species is split into sympatric and allopatric populations. Our results show that when sympatric and allopatric populations reside in the same environment and only differ in their exposure to maladaptive hybridization, migration between them generally inhibits the evolution of cascade by spreading the reinforcement alleles from sympatry into allopatry and erasing RCD. Under these conditions, cascade reinforcement only evolved when migration rate between sympatric and allopatric populations was very low. This indicates that stabilizing sexual selection in allopatry is generally ineffective in preventing the spread of reinforcement alleles. Only when sympatric and allopatric populations experienced divergent ecological selection did cascade reinforcement evolve in the presence of substantial migration. These predictions clarify the conditions for cascade reinforcement and facilitate our understanding of existing cases in nature. PMID- 29491904 TI - Assortative mating and self-fertilization differ in their contributions to reinforcement, cascade speciation, and diversification. AB - Cascade speciation and reinforcement can evolve rapidly when traits are pleiotropic and act as both signal/cue in nonrandom mating. Here, we examine the contribution of two key traits-assortative mating and self-fertilization-to reinforcement and (by extension) cascade speciation. First, using a population genetic model of reinforcement we find that both assortative mating and self fertilization can make independent contributions to increased reproductive isolation, consistent with reinforcement. Self-fertilization primarily evolves due to its 2-fold transmission advantage when inbreeding depression (d) is lower (d < 0.45) but evolves as a function of the cost of hybridization under higher inbreeding depression (0.45 < d < 0.48). When both traits can evolve simultaneously, increased self-fertilization often prohibits the evolution of assortative mating. We infer that, under specific conditions, mating system transitions are more likely to lead to increased reproductive isolation and initiate cascade speciation, than assortative mating. Based on the results of our simulations, we hypothesized that transitions to self-fertilization could contribute to clade-wide diversification if reinforcement or cascade speciation is common. We tested this hypothesis with comparative data from two different groups. Consistent with our hypothesis, there was a trend towards uniparental reproduction being associated with increased diversification rate in the Nematode phylum. For the plant genus Mimulus, however, self-fertilization was associated with reduced diversification. Reinforcement driving speciation via transitions to self-fertilization might be short lived or unsustainable across macroevolutionary scales in some systems (some plants), but not others (such as nematodes), potentially due to differences in susceptibility to inbreeding depression and/or the ability to transition between reproductive modes. PMID- 29491905 TI - Patterns of reproductive isolation in the Drosophila subquinaria complex: can reinforced premating isolation cascade to other species? AB - The reinforcement of premating barriers due to reduced hybrid fitness in sympatry may cause secondary sexual isolation within a species as a by-product. Consistent with this, in the fly Drosophila subquinaria, females that are sympatric with D. recens mate at very low rates not only with D. recens, but also with conspecific D. subquinaria males from allopatry. Here, we ask if these effects of reinforcement cascade more broadly to affect sexual isolation with other closely related species. We assay reproductive isolation of these species with D. transversa and find that choosy D. subquinaria females from the region sympatric with D. recens discriminate strongly against male D. transversa, whereas D. subquinaria from the allopatric region do not. This increased sexual isolation cannot be explained by natural selection to avoid mating with this species, as they are allopatric in geographic range and we do not identify any intrinsic postzygotic isolation between D. subquinaria and D. transversa. Variation in epicuticular hydrocarbons, which are used as mating signals in D. subquinaria, follow patterns of premating isolation: D. transversa and allopatric D. subquinaria are most similar to each other and differ from sympatric D. subquinaria, and those of D. recens are distinct from the other two species. We suggest that the secondary effects of reinforcement may cascade to strengthen reproductive isolation with other species that were not a target of selection. These effects may enhance the divergence that occurs in allopatry to help explain why some species are already sexually isolated upon secondary contact. PMID- 29491906 TI - Population differentiation at a regional scale in spadefoot toads: contributions of distance and divergent selective environments. AB - The causes of population differentiation can provide insight into the origins of early barriers to gene flow. Two key drivers of population differentiation are geographic distance and local adaptation to divergent selective environments. When reproductive isolation arises because some populations of a species are under selection to avoid hybridization while others are not, population differentiation and even speciation can result. Spadefoot toad populations Spea multiplicata that are sympatric with a congener have undergone reinforcement. This reinforcement has resulted not only in increased reproductive isolation from the congener, but also in the evolution of reproductive isolation from nearby and distant conspecific allopatric populations. We used multiple approaches to evaluate the contributions of geographic distance and divergent selective environments to population structure across this regional scale in S. multiplicata, based on genotypes from six nuclear microsatellite markers. We compared groups of populations varying in both geographic location and in the presence of a congener. Hierarchical F-statistics and results from cluster analyses and discriminant analyses of principal components all indicate that geographic distance is the stronger contributor to genetic differentiation among S. multiplicata populations at a regional scale. However, we found evidence that adaptation to divergent selective environments also contributes to population structure. Our findings highlight how variation in the balance of evolutionary forces acting across a species' range can lead to variation in the relative contributions of geographic distance and local adaptation to population differentiation across different spatial scales. PMID- 29491907 TI - Exploration of unpredictable environments by networked groups. AB - Information sharing is a critical task for group-living animals. The pattern of sharing can be modeled as a network whose structure can affect the decision making performance of individual members as well as that of the group as a whole. A fully connected network, in which each member can directly transfer information to all other members, ensures rapid sharing of important information, such as a promising foraging location. However, it can also impose costs by amplifying the spread of inaccurate information (if, for example the foraging location is actually not profitable). Thus, an optimal network structure should balance effective sharing of current knowledge with opportunities to discover new information. We used a computer simulation to measure how well groups characterized by different network structures (fully connected, small world, lattice, and random) find and exploit resource peaks in a variable environment. We found that a fully connected network outperformed other structures when resource quality was predictable. When resource quality showed random variation, however, the small world network was better than the fully connected one at avoiding extremely poor outcomes. These results suggest that animal groups may benefit by adjusting their information-sharing network structures depending on the noisiness of their environment. PMID- 29491908 TI - Asiatic Callosciurus squirrels as seed dispersers of exotic plants in the Pampas. AB - Seed dispersal by exotic mammals exemplifies mutualistic interactions that can modify the habitat by facilitating the establishment of certain species. We examined the potential for endozoochoric dispersal of exotic plants by Callosciurus erythraeus introduced in the Pampas Region of Argentina. We identified and characterized entire and damaged seeds found in squirrel faeces and evaluated the germination capacity and viability of entire seeds in laboratory assays. We collected 120 samples of squirrel faeces that contained 883 pellets in seasonal surveys conducted between July 2011 and June 2012 at 3 study sites within the main invasion focus of C. erythraeus in Argentina. We found 226 entire seeds in 21% of the samples belonging to 4 species of exotic trees and shrubs. Germination in laboratory assays was recorded for Morus alba and Casuarina sp.; however, germination percentage and rate was higher for seeds obtained from the fruits than for seeds obtained from the faeces. The largest size of entire seeds found in the faeces was 4.2 * 4.0 mm, whereas the damaged seeds had at least 1 dimension >= 4.7 mm. Our results indicated that C. erythraeus can disperse viable seeds of at least 2 species of exotic trees. C. erythraeus predated seeds of other naturalized species in the region. The morphometric description suggested a restriction on the maximum size for the passage of entire seeds through the digestive tract of squirrels, which provides useful information to predict its role as a potential disperser or predator of other species in other invaded communities. PMID- 29491909 TI - Interactive effects of reproductive assets and ambient predation risk on the threat-sensitive decisions of Trinidadian guppies. AB - Threat-sensitive behavioral trade-offs allow prey animals to balance the conflicting demands of successful predator detection and avoidance and a suite of fitness-related activities such as foraging, mating, and territorial defense. Here, we test the hypothesis that background predation level and reproductive status interact to determine the form and intensity of threat-sensitive behavioral decisions of wild-caught female Trinidadian guppies Poecilia reticulata. Gravid and nongravid guppies collected from high- and low-predation pressure populations were exposed to serial dilutions of conspecific chemical alarm cues. Our results demonstrate that there was 'no effect of reproductive status on the response of females originating from a low-predation population, with both gravid and nongravid guppies exhibiting strong anti-predator responses to the lowest concentration of alarm cues tested. Increasing cue concentrations did not result in increases in response intensity. Conversely, we found a significant effect of reproductive status among guppies from a high-predation population. Nongravid females from the high-predation population exhibited a strong graded (proportional) response to increasing concentrations of alarm cue. Gravid females from the same high-predation population, however, shifted to a nongraded response. Together, these results demonstrate that accrued reproductive assets influence the threat-sensitive behavioral decisions of prey, but only under conditions of high-ambient predation risk. PMID- 29491910 TI - Lack of functional link in the tadpole morphology induced by predators. AB - Most studies of predator-induced plasticity have focused on documenting how prey species respond to predators by modifying phenotypic traits and how traits correlate with fitness. We have previously shown that Pleurodema thaul tadpoles exposed to the dragonfly Rhionaeschna variegata responded strongly by showing morphological changes, less activity, and better survival than non-exposed tadpoles. Here, we tested whether there is a functional link between morphological plasticity and increased survival in the presence of predators. Tadpoles that experienced predation risk were smaller, less developed, and much less active than tadpoles without this experience. Burst speed did not correlate significantly with morphological changes and predator-induced deeper tails did not act as a lure to divert predator strikes away from the head. Although we have previously found that tadpoles with predator-induced morphology survive better under a direct predator threat, our results on the functional link between morphology and fitness are not conclusive. Our results suggest that in P. thaul tadpoles (1) burst speed is not important to evade predators, (2) those exposed to predators reduce their activity, and (3) morphological changes do not divert predator attacks away from areas that compromise tadpole survivalEE. Our results show that morphological changes in P. thaul tadpoles do not explain burst speed or lure attraction, although there was a clear reduction of activity, which itself reduces predation. We propose that changes in tadpole activity could be further analyzed from another perspective, with morphological change as an indirect product of behavior mediated by physiological mechanisms. PMID- 29491912 TI - The role of monoamines in modulating behavior. PMID- 29491911 TI - Biochemical regulation of pigment motility in vertebrate chromatophores: a review of physiological color change mechanisms. AB - The fundamental unit of rapid, physiological color change in vertebrates is the dermal chromatophore unit. This unit, comprised of cellular associations between different chromatophore types, is relatively conserved across the fish, amphibian, and reptilian species capable of physiological color change and numerous attempts have been made to understand the nature of the four major chromatophore types (melanophores, erythrophores, xanthophores, and iridophores) and their biochemical regulation. In this review, we attempt to describe the current state of knowledge regarding what classifies a pigment cell as a dynamic chromatophore, the unique characteristics of each chromatophore type, and how different hormones, neurotransmitters, or other signals direct pigment reorganization in a variety of vertebrate taxa. PMID- 29491913 TI - Assessment strategies and fighting patterns in animal contests: a role for serotonin? AB - Accurate assessment of the probability of success in an aggressive confrontation with a conspecific is critical to the survival and fitness of the individuals. Various game theory models have examined these assessment strategies under the assumption that contests should favor the animal with the greater resource holding potential (RHP), body size typically being the proxy. Mutual assessment asserts that an individual can assess their own RHP relative to their opponent, allowing the inferior animal the chance to flee before incurring unnecessary costs. The model of self-determined persistence, however, assumes that an individual will fight to a set personal threshold, independent of their opponent's RHP. Both models have been repeatedly tested using size as a proxy for RHP, with neither receiving unambiguous support. Here we present both morphological and neurophysiological data from size-matched and mismatched stalk eyed fly fights. We discovered differing fighting strategies between winners and losers. Winners readily escalated encounters to higher intensity and physical contact and engaged in less low-intensity, posturing behaviors compared with losers. Although these fighting strategies were largely independent of size, they were associated with elevated levels of 5-HT. Understanding the neurophysiological factors responsible for mediating the motivational state of opponents could help resolve the inconsistencies seen in current game theory models. Therefore, we contend that current studies using only size as a proxy for RHP may be inadequate in determining the intricacies of fighting ability and that future studies investigating assessment strategies and contest outcome should include neurophysiological data. PMID- 29491914 TI - Controlling the decision to fight or flee: the roles of biogenic amines and nitric oxide in the cricket. AB - Aggression is a common behavioral strategy employed by animals to secure limited resources, but must be applied with restraint to limit potential costs including injury. How animals make the adaptive decision to fight or flee is barely known. Here, we review our work on crickets that reveals the roles of biogenic amines, primarily octopamine (the insect analog of noradrenaline) and nitric oxide (NO). Using aminergic drugs, we found that amines are not essential for actually initiating aggression. However, octopamine is necessary for mediating the aggression-promoting effects of potentially rewarding experiences including stimulation with a male antenna, physical exertion, winning, and resource possession. Hence, octopamine can be considered as the motivational component of aggression. Imposed handicaps that impede aggressive signaling revealed that the agonistic actions of an opponent perceived during fighting act to reduce aggression, and that crickets make the decision to flee the moment the accumulated sum of such aversive experiences exceeds some critical level. Treatment with nitridergic drugs revealed that the impact of the opponent's aggressive actions is mediated by NO. NO acts to suppress aggression by promoting the tendency to flee and is primarily responsible for the depressed aggressiveness of subordinates after social defeat. Octopamine and dopamine can each restore aggression in subordinates, but only dopamine is necessary for normal recovery. The role of serotonin remains unclear, and is discussed. We conclude that octopamine and NO control the decision to fight or flee by mediating the effects of potentially rewarding and aversive experiences, respectively. PMID- 29491915 TI - The organization of societal conflicts by pavement ants Tetramorium caespitum: an agent-based model of amine-mediated decision making. AB - Ant colonies self-organize to solve complex problems despite the simplicity of an individual ant's brain. Pavement ant Tetramorium caespitum colonies must solve the problem of defending the territory that they patrol in search of energetically rich forage. When members of 2 colonies randomly interact at the territory boundary a decision to fight occurs when: 1) there is a mismatch in nestmate recognition cues and 2) each ant has a recent history of high interaction rates with nestmate ants. Instead of fighting, some ants will decide to recruit more workers from the nest to the fighting location, and in this way a positive feedback mediates the development of colony wide wars. In ants, the monoamines serotonin (5-HT) and octopamine (OA) modulate many behaviors associated with colony organization and in particular behaviors associated with nestmate recognition and aggression. In this article, we develop and explore an agent-based model that conceptualizes how individual changes in brain concentrations of 5-HT and OA, paired with a simple threshold-based decision rule, can lead to the development of colony wide warfare. Model simulations do lead to the development of warfare with 91% of ants fighting at the end of 1 h. When conducting a sensitivity analysis, we determined that uncertainty in monoamine concentration signal decay influences the behavior of the model more than uncertainty in the decision-making rule or density. We conclude that pavement ant behavior is consistent with the detection of interaction rate through a single timed interval rather than integration of multiple interactions. PMID- 29491916 TI - Biparental behavior in the burying beetle Nicrophorus orbicollis: a role for dopamine? AB - Burying beetles Nicrophorus orbicollis exhibit facultative biparental care of young. To reproduce, a male-female burying beetle pair bury and prepare a small vertebrate carcass as food for its altricial young. During a breeding bout, male and female behavior changes synchronously at appropriate times and is coordinated to provide effective care for offspring. Although the ecological and evolutionary factors that shape this remarkable reproductive plasticity are well characterized, the neuromodulation of parental behavior is poorly understood. Juvenile hormone levels rise dramatically at the time beetle parents accept and feed larvae, remain highly elevated during the stages of most active care and fall abruptly when care is terminated. However, hormonal fluctuations alone cannot account for this elaborate control of reproduction. The biogenic amines octopamine (OA), dopamine (DA), and serotonin (5-HT) mediate a diversity of insect reproductive and social behaviors. In this study, we measured whole brain monoamine levels in individual male and female burying beetles and compared OA, DA, and 5-HT profiles between breeding (parental) and nonbreeding, unmated beetles. Remarkably, after 24 h of care, when parental feeding rates begin to peak, DA brain levels increase in breeding beetles when compared to nonbreeding controls. In contrast, brain OA and 5-HT levels did not change significantly. These results provide the first evidence for a potential role of DA in the modulation of burying beetle parental behavior. PMID- 29491918 TI - A dopamine and noradrenaline reuptake inhibitor (bupropion) does not alter exercise performance of bank voles. AB - Physical performance is determined both by biophysical and physiological limitations and behavioral characteristic, specifically motivation. We applied an experimental evolution approach combined with pharmacological manipulation to test the hypothesis that evolution of increased aerobic exercise performance can be triggered by evolution of motivation to undertake physical activity. We used a unique model system: bank voles from A lines, selected for high swim-induced aerobic metabolism (VO2swim), which achieved a 61% higher mass-adjusted VO2swim than those from unselected C lines. Because the voles could float on the water surface with only a minimum activity, the maximum rate of metabolism achieved in that test depended not only on their aerobic capacity, but also on motivation to undertake intensive activity. Therefore, we hypothesized that signaling of neurotransmitters putatively involved in regulating physical activity (dopamine and noradrenaline) had changed in response to selection. We measured VO2swim after intraperitoneal injections of saline or the norepinephrine and dopamine reuptake inhibitor bupropion (20 mg/kg or 30 mg/kg). Additionally, we measured forced-exercise VO2 (VO2max). In C lines, VO2swim (mass-adjusted mean +/- standard error (SE): 4.0 +/- 0.1 mLO2/min) was lower than VO2max (5.0 +/- 0.1 mLO2/min), but in A lines VO2swim (6.0 +/- 0.1 mLO2/min) was as high as VO2max (6.0 +/- 0.1 mLO2/min). Thus, the selection effectively changed both the physiological-physical performance limit and mechanisms responsible for the willingness to undertake vigorous locomotor activity. Surprisingly, the drug had no effect on the achieved level of VO2swim. Thus, the results did not allow firm conclusions concerning involvement of these neurotransmitters in evolution of increased aerobic exercise performance in the experimental evolution model system. PMID- 29491919 TI - Role of brain serotonin in modulating fish behavior. AB - The organization of the brain serotonergic system appears to have been highly conserved across the vertebrate subphylum. In fish as well as in other vertebrates, brain serotonin (5-HT), mainly acts as a neuromodulator with complex effects on multiple functions. It is becoming increasingly clear that acute and chronic increase in brain 5-HT neurotransmission have very different effects. An acute 5-HT activation, which is seen in both winners and losers of agonistic interactions, could be related to a general arousal effect, whereas the chronic activation observed in subordinate fish is clearly linked to the behavioral inhibition displayed by these individuals. Fish displaying divergent stress coping styles (proactive vs. reactive) differ in 5-HT functions. In teleost fish, brain monoaminergic function is also related to life history traits. PMID- 29491920 TI - Oxidative stress favours herpes virus infection in vertebrates: a meta-analysis. AB - Herpes viruses are responsible for a variety of pathological effects in humans and in both wild and domestic animals. One mechanism that has been proposed to facilitate replication and activity of herpes viruses is oxidative stress (OS). We used meta-analytical techniques to test the hypotheses that (1) herpes virus infection causes OS and (2) supplementation of antioxidants reduces virus load, indicating that replication is favoured by a state of OS. Results based on studies on mammals, including humans, and birds show that (1) OS is indeed increased by herpes virus infection across multiple tissues and species, (2) biomarkers of OS may change differently between tissues, and (3) the effect size does not differ among different virus strains. In addition, the increase of oxidative damage in blood (tissue commonly available in ecological studies) was similar to that in the tissues most sensitive to the herpes virus. Our results also show that administration of antioxidants reduces virus yield, indicating that a condition of OS is favorable for the viral replication. In addition, some antioxidants may be more efficient than others in reducing herpes virus yield. Our results point to a potential mechanism linking herpes virus infection to individual health status. PMID- 29491921 TI - Giant pandas use odor cues to discriminate kin from nonkin. AB - Sociality is an important factor in both the mechanism and function of kin recognition, yet it is little explored in solitary species. While there may be future opportunities for nepotistic functions of kin discrimination among solitary species, the ability to discriminate kin from nonkin may still have important roles in social regulation. The solitary giant panda Ailuropoda melanoleuca offers a good model system to explore kin discrimination in a solitary mammal. As kin discrimination in many other mammals is olfactorily mediated, we investigated whether giant pandas are able to discriminate odor cues from daughters even after months and years of separation. Our results indicate that giant pandas are capable of discriminating between kin and nonkin using odor cues available in urine and body odor. Daughters preferentially investigated the odors of unrelated adult female pandas over the odors of their mothers, and mothers spent more time investigating the odors of unrelated age-matched female pandas over those from their daughters. Because these studies were conducted months or years after the mother-daughter period of dependency ended, it is still unclear what mechanism is used for recognition. Long-term olfactory memories and phenotype matching should both be considered, and further studies are required for such determination. PMID- 29491922 TI - GPS tracking of non-breeding ravens reveals the importance of anthropogenic food sources during their dispersal in the Eastern Alps. AB - In many songbirds, the space use of breeders is well studied but poorly understood for non-breeders. In common ravens, some studies of non-breeders indicate high vagrancy with large individual differences in home range size, whereas others show that up to 40% of marked non-breeders can be regularly observed at the same anthropogenic food source over months to years. The aim of this study was to provide new insights on ravens' behavior during dispersal in the Eastern Alps. We deployed Global Positioning System (GPS) loggers on 10 individuals to gather accurate spatial and temporal information on their movements to quantify: 1) the dimension of the birds' space use (home range size with seasonal effects and daily/long-term travel distances), 2) how long they stayed in a dispersal stage of wandering as opposed to settling temporarily, and 3) their destination of movements. We recorded movements of up to 40 km per hour, more than 160 km within 1 day and more than 11,000 km within 20 months, indicating high vagrancy. Switching frequently between temporarily settling and travelling large distances in short time intervals leads to extensive home ranges, which also explains and combines the different findings in the literature. The destinations are rich anthropogenic food sources, where the birds spent on average 75% of their time. We discuss how ravens may find these "feeding hot spots" and which factors may influence their decision to stay/leave a site. The strong dependence on anthropogenic resources found in this population may have implications for site management and conservation issues. PMID- 29491917 TI - Central monoaminergic systems are a site of convergence of signals conveying the experience of exercise to brain circuits involved in cognition and emotional behavior. AB - Physical activity can enhance cognitive function and increase resistance against deleterious effects of stress on mental health. Enhanced cognitive function and stress resistance produced by exercise are conserved among vertebrates, suggesting that ubiquitous mechanisms may underlie beneficial effects of exercise. In the current review, we summarize the beneficial effects of exercise on cognitive function and stress resistance and discuss central and peripheral signaling factors that may be critical for conferring the effects of physical activity to brain circuits involved in cognitive function and stress. Additionally, it is suggested that norepinephrine and serotonin, highly conserved monoamines that are sensitive to exercise and able to modulate behavior in multiple species, could represent a convergence between peripheral and central exercise signals that mediate the beneficial effects of exercise. Finally, we offer the novel hypothesis that thermoregulation during exercise could contribute to the emotional effects of exercise by activating a subset of temperature sensitive serotonergic neurons in the dorsal raphe nucleus that convey anxiolytic and stress-protective signals to forebrain regions. Throughout the review, we discuss limitations to current approaches and offer strategies for future research in exercise neuroscience. PMID- 29491923 TI - Foraging ecology and occurrence of 7 sympatric babbler species (Timaliidae) in the lowland rainforest of Borneo and peninsular Malaysia. AB - Understanding foraging strategies of birds is essential to understanding mechanisms of their community assembly. To provide such information on a key Southeast Asian rainforest family, the babblers (Timaliidae), we evaluated foraging behavior and abundance in 7 morphologically and behaviorally similar sympatric species (Cyanoderma erythropterum, C. rufifrons, Stachyris maculata, S. nigricollis, S. poliocephala, Macronus ptilosus, and Mixornis gularis) in 5 habitats defined by structural complexity: (1) continuous native rainforest, (2) logged native rainforest fragments, (3) mature industrial tree plantation, (4) young industrial plantation, and (5) oil palm plantation. Enough data were obtained to compare abundance in all 7 species and foraging behavior in 5. All species were common in forest fragments and mature industrial tree plantations and less so in continuous rainforest and young industrial plantations; only M. gularis occurred in oil palm. In terms of foraging, M. gularis was the greatest generalist; C. rufifrons foraged mainly on live leaves in the forest midstory; and S. maculata, C. erythropterum, and M. ptilosus foraged mainly on dead leaves suspended in understory vegetation at significantly different heights. The dead leaf substrate depends on a rich supply of falling leaves and extensive understory structure, conditions most common in native forest and old industrial plantations, and less so in mature forest, young plantations, and oil palm. Because of the importance of foraging data to understanding and managing biodiversity, we encourage the development of foraging fields in eBird (ebird.org), so that birdwatchers may help collect these relatively rare data. PMID- 29491924 TI - Habitat preferences of two sparrow species are modified by abundances of other birds in an urban environment. AB - Every species has certain habitat requirements, which may be altered by interactions with other co-occurring species. These interactions are mostly ignored in predictive models trying to identify key habitat variables correlated with species population abundance/occurrence. We investigated how the structure of the urban landscape, food resources, potential competitors, predators, and interaction between these factors influence the abundance of house sparrow Passer domesticus and the tree sparrow P. montanus in sixty 25 ha plots distributed randomly across residential areas of the city of Poznan (Poland). The abundance of the house sparrow was positively correlated with the abundance of pigeons but negatively correlated with human-related food resources. There were significant interaction terms between abundances of other urban species and habitat variables in statistical models. For example, the abundance of house sparrow was negatively correlated with the abundance of corvids and tree sparrows but only when food resources were low. The abundance of tree sparrows positively correlated with density of streets and the distance from the city center. The abundance of this species positively correlated with the abundance of corvids when food resources were low but negatively correlated at low covers of green area. Our study indicates that associations between food resources, habitat covers, and the relative abundance of two sparrow species are altered by the abundance of other urban species. Competition, niche separation and social facilitation may be responsible for these interactive effects. Thus, biotic interactions should be included not only as an additive effect but also as an interaction term between abundance and habitat variables in statistical models predicting species abundance and occurrence. PMID- 29491925 TI - Effects of absolute fasting on reproduction and survival of the invasive apple snail Pomacea canaliculata in its native range. AB - A South American freshwater gastropod, the apple snail Pomacea canaliculata, has become a driver of ecosystemic changes in wetlands and an important rice pest after its introduction to various parts of the world, mainly Asia. The objective of this study was to study the effect of an abrupt interruption in food availability in the short term (up to 4 weeks) and long term (up to 8 months) on survival and reproductive activity. The main results indicate that short-term fasting mainly affects the survival of males, but only when they are raised together with females, probably due to a greater mate-searching activity that increases mortality in the individuals with lower reserves. The number of copulating snails or egg-laying females shows an abrupt drop when fasting and a rapid recovery after the food supply is restored. The strategy of discontinuing reproductive activity prioritizes energy conservation for the survival of the females. Interpopulation variation in resistance to starvation was observed in adults, which can be explained to some extent by the food availability that they experienced in their natural environment. No interpopulational differences in survival were seen in hatchlings. The mean maximum values of survival under starvation were 52.6 days in hatchlings and the 3.3% of adults survive over than 200 days, which may be a relevant trait in dispersal and establishment in new habitats. PMID- 29491926 TI - Cuticular bacteria appear detrimental to social spiders in mixed but not monoculture exposure. AB - Much of an animal's health status, life history, and behavior are dictated by interactions with its endogenous and exogenous bacterial communities. Unfortunately, interactions between hosts and members of their resident bacterial community are often ignored in animal behavior and behavioral ecology. Here, we aim to identify the nature of host-microbe interactions in a nonmodel organism, the African social spider Stegodyphus dumicola. We collected and identified bacteria from the cuticles of spiders in situ and then exposed spiders to bacterial monocultures cultures via topical application or injection. We also topically inoculated spiders with a concomitant "cocktail" of bacteria and measured the behavior of spiders daily for 24 days after inoculation. Lastly, we collected and identified bacteria from the cuticles of prey items in the capture webs of spiders, and then fed spiders domestic crickets which had been injected with these bacteria. We also injected 1 species of prey-borne bacteria into the hemolymph of spiders. Only Bacillus thuringiensis caused increased mortality when injected into the hemolymph of spiders, whereas no bacterial monocultures caused increased mortality when applied topically, relative to control solutions. However, a bacterial cocktail of cuticular bacteria caused weight loss and mortality when applied topically, yet did not detectibly alter spider behavior. Consuming prey injected with prey-borne bacteria was associated with an elongated lifespan in spiders. Thus, indirect evidence from multiple experiments suggests that the effects of these bacteria on spider survivorship appear contingent on their mode of colonization and whether they are applied in monoculture or within a mixed cocktail. We urge that follow-up studies should test these host-microbe interactions across different social contexts to determine the role that microbes play in colony performance. PMID- 29491927 TI - Hand preference during bimanual coordinated task in northern pig-tailed macaques Macaca leonina. AB - In humans, handedness is one defining characteristic regardless of cultures and ethnicity. Population-level right handedness is considered to be related with the evolution of left hemisphere for manual control and language. In order to further understand evolutionary origins of human cerebral lateralization and its behavioral adaptation, standardized measures on hand preference are required to make reliable comparison in nonhuman primate species. In this study, we present the first evidence on hand preference during bimanual coordinated tasks in northern pig-tailed macaques Macaca leonina. The classical TUBE task was applied to examine hand preference among nine individuals from Tianjin Zoo of China. We recorded and made analysis on both frequency and bout data on manual laterality. The results consistently show that subjects displayed strong individual hand preferences, whereas no significant group-level handedness was found. There were no sex and age significant differences on both direction and strength of hand preference. The M. leonina preferred to use the index finger to extract the baited food inside the tube. Our findings fill the knowledge gap on primate handedness, and efficiently affirm the robustness of the TUBE task as one efficient measure of hand preference in primates. PMID- 29491928 TI - Phylogenetic framework for coevolutionary studies: a compass for exploring jungles of tangled trees. AB - Phylogenetics is used to detect past evolutionary events, from how species originated to how their ecological interactions with other species arose, which can mirror cophylogenetic patterns. Cophylogenetic reconstructions uncover past ecological relationships between taxa through inferred coevolutionary events on trees, for example, codivergence, duplication, host-switching, and loss. These events can be detected by cophylogenetic analyses based on nodes and the length and branching pattern of the phylogenetic trees of symbiotic associations, for example, host-parasite. In the past 2 decades, algorithms have been developed for cophylogetenic analyses and implemented in different software, for example, statistical congruence index and event-based methods. Based on the combination of these approaches, it is possible to integrate temporal information into cophylogenetical inference, such as estimates of lineage divergence times between 2 taxa, for example, hosts and parasites. Additionally, the advances in phylogenetic biogeography applying methods based on parametric process models and combined Bayesian approaches, can be useful for interpreting coevolutionary histories in a scenario of biogeographical area connectivity through time. This article briefly reviews the basics of parasitology and provides an overview of software packages in cophylogenetic methods. Thus, the objective here is to present a phylogenetic framework for coevolutionary studies, with special emphasis on groups of parasitic organisms. Researchers wishing to undertake phylogeny-based coevolutionary studies can use this review as a "compass" when "walking" through jungles of tangled phylogenetic trees. PMID- 29491929 TI - Differential introgression suggests candidate beneficial and barrier loci between two parapatric subspecies of Pearson's horseshoe bat Rhinolophus pearsoni. AB - Observations that rates of introgression between taxa can vary across loci are increasingly common. Here, we test for differential locus-wise introgression in 2 parapatric subspecies of Pearson's horseshoe bat (Rhinolophus pearsoni chinensis and R. p. pearsoni). To efficiently identify putative speciation genes and/or beneficial genes in our current system, we used a candidate gene approach by including loci from X chromosome that are suggested to be more likely involved in reproductive isolation in other organisms and loci underlying hearing that have been suggested to spread across the hybrid zone in another congeneric species. Phylogenetic and coalescent analyses were performed at 2 X-linked, 4 hearing genes, as well as 2 other autosomal loci individually. Likelihood ratio tests could not reject the model of zero gene flow at 2 X-linked and 2 autosomal genes. In contrast, gene flow was supported at 3 of 4 hearing genes. While this introgression could be adaptive, we cannot rule out stochastic processes. Our results highlight the utility of the candidate gene approach in searching for speciation genes and/or beneficial genes across the species boundary in natural populations. PMID- 29491930 TI - Impact of anthropogenic pressure on the formation of population structure and genetic diversity of raccoon dog Nyctereutes procyonoides. AB - The raccoon dog Nyctereutes procyonoides experienced an active introduction and acclimatization in the European part of Russia followed by its migration to and colonization in the neighboring countries. Eventually, it has spread rapidly into many European countries. N. procyonoides probably invaded Lithuania from the neighboring countries of Belarus and Latvia where the species was introduced. However, the data on genetic diversity and population structure of the raccoon dogs in the recently invaded territories are still scarce. The objectives of this study were to investigate genetic diversity of N. procyonoides in Lithuania after acclimatization, and to assess the impact of anthropogenic pressure on the formation of population structure. A total of 147 N. procyonoides individuals collected from different regions of Lithuania were genotyped using 17 microsatellite markers. The microsatellite analysis of raccoon dogs indicated high levels of genetic diversity within the population. The Bayesian clustering analysis in STRUCTURE identified 4 genetic clusters among sampled raccoon dogs that could not reveal a clear separation between subpopulations. The widespread distribution of raccoon dogs in Lithuania, high level of genetic variation observed within subpopulations, and low level of variation portioned among subpopulations suggest migration and gene flow among locations. The significant correlation between genetic and geographic distances indicated isolation that reflected the distance between locations. The fencing of highways and very intensive traffic could be barriers to gene flow between the western and eastern sampling areas of raccoon dogs. PMID- 29491931 TI - Mammals and habitat disturbance: the case of brown hare and wildfire. AB - Ecosystem disturbances, such as wildfires, are driving forces that determine ecology and conservation measures. Species respond differentially to wildfires, having diverse post-fire population evolution. This study reports, for first time, the responses of brown hare (Lepus europaeus Pallas, 1778) to wildfires. Hare relative abundance, age ratio, diet quality, body condition, and diseases were studied. Fire influence on vegetation was calculated at a micro-scale level. Hare abundance was lower the first year after wildfires in burned relative to unburned areas. The reverse was found in the second year when hare abundance was higher in burned areas. Hare abundance in burned areas was also higher in the third and fourth years. In the fifth and sixth years after wildfire no significant difference was found in abundance. At a micro-scale level, higher numbers of hare feces were counted in places with greater wildfire influence on vegetation. Age ratio analysis revealed more juveniles in burned areas, but the same number of neonates in burned and unburned areas, indicating lower mortality of juveniles in burned areas. Reduced predation in burned areas provides the most plausible explanation for our findings. PMID- 29491932 TI - Exaggerated male pheromones in rats may increase predation cost. AB - Male animals with more conspicuous visual and acoustic signals increase their mating success, but also increase the risk of being attacked by eavesdropping predators. In rodents, males with richer sex pheromones often have higher attractiveness to females, but whether or not the males are also at higher predation risk is poorly known. Here, we used 2 laboratory inbred strains of the rat Rattus norvegicus, Brown Norway (BN) and Lewis (LEW), and wild-captured rats as odor donors to assess the relationship between the pheromone levels in male rats and attractiveness to domestic cats Felis catus. LEW rats had significantly higher levels of male pheromones (e.g., 4-heptanone, 2-heptanone, and 9-hydroxy-2 nonanone) than BN rats. Simultaneously, wild-captured male rats were selectively assigned to 2 groups (HIGH or LOW) based on pheromone content as determined by gas chromatography-mass spectrometry (GC-MS). Binary choice tests were carried out during the night in the test room. We found that cats spent more time investigating male bedding and urine of LEW rats than the counterpart of BN rats. Likewise, cats also preferred bedding and urine odor of the HIGH wild rats compared with the counterparts of LOW wild rats. Adding synthetic analogs of the 3 pheromone ketones into the urine of either BN rats or LOW wild rats significantly increased their attractiveness to cats. Our data suggest that the rats with exaggerated male pheromones more strongly attracted predators and thus as a consequence may suffer from elevated predation risk. PMID- 29491933 TI - Antipredatory reaction of the leopard gecko Eublepharis macularius to snake predators. AB - Ability to recognize a risk of predation and react with adaptive antipredatory behavior can enhance fitness, but has some costs as well. Animals can either specifically react on the most dangerous predators (threat-sensitive avoidance) or they have safe but costly general wariness avoiding all potential predators. The level of threat may depend on the predator's foraging ecology and distribution with the prey with sympatric and specialist species being the most dangerous. We used 2 choice trials to investigate antipredatory behavior of captive born and wild-caught leopard geckos confronted with different snake predators from 2 families (Colubridae, Boidae) varying in foraging ecology and sympatric/allopatric distribution with the geckos. Predator-naive subadult individuals have general wariness, explore both chemically and visually, and perform antipredatory postures toward a majority of snake predators regardless of their sympatry/allopatry or food specialization. The most exaggerated antipredatory postures in both subadult and adult geckos were toward 2 sympatric snake species, the spotted whip snake Hemorrhois ravergieri, an active forager, and the red sand boa Eryx johnii, a subterranean snake with a sit-and-wait strategy. In contrast, also subterranean but allopatric the Kenyan sand boa Eryx colubrinus did not elicit any antipredatory reaction. We conclude that the leopard gecko possesses an innate general antipredatory reaction to different species of snake predators, while a specific reaction to 2 particular sympatric species can be observed. Moreover, adult wild caught geckos show lower reactivity compared with the captive born ones, presumably due to an experience of a real predation event that can hardly be simulated under laboratory conditions. PMID- 29491934 TI - Mismatching between nest volume and clutch volume reduces egg survival and fledgling success in black-tailed gulls. AB - A longstanding suggestion posits that parents prefer to match nest volume and clutch size (clutch volume), but few studies have tested this in colonial seabirds that nest in the open. Here, we demonstrate the effects of nest-clutch volume matching on egg survival, hatching, and fledgling success in black-tailed gulls Larus crassirostris on Hongdo Island, Korea. We show that the volume mismatch, defined as the difference between nest volume and total egg volume (the sum of all eggs' volume in the clutch), was positively related to egg and chick mortality caused by predation, but was not significantly related to hatching success incurred by insulation during the incubation period. Although nest volume was negatively related to laying date, we found that the mismatch was positively related to laying date. Our results support the claim that well-matched nest clutch volume may contribute to survival of eggs and chicks, and ultimately breeding success. PMID- 29491935 TI - Local predation risk shapes spatial and foraging neophobia patterns in Trinidadian guppies. AB - The "dangerous niche" hypothesis posits that neophobia functions to reduce the cost of habitat use among animals exposed to unknown risks. For example, more dangerous foraging or higher competition may lead to increased spatial neophobia. Likewise, elevated ambient predation threats have been shown to induce phenotypically plastic neophobic predator avoidance. In both cases, neophobia is argued to reduce the cost of living associated with ecological uncertainty. Here, we test the hypothesis that ambient predation shapes both neophobic predator avoidance and spatial and foraging neophobia in Trinidadian guppies. Guppies were exposed to a novel foraging arena paired with a known cue (conspecific alarm cue), a novel cue (lemon odor), or a stream water control in three streams differing in ambient predation risk. We demonstrate that guppies from a high predation-risk stream exhibited risk-averse foraging patterns regardless of the chemical stimulus presented (high spatial neophobia) and that those from a low predation-risk stream were only risk-averse when the foraging arenas were paired with conspecific alarm cue (lower spatial neophobia). Those tested in the intermediate-predation-risk stream were consistently intermediate to the high risk vs. low-risk populations. Our study suggests that ambient predation risk shapes both neophobic predator avoidance and space-use patterns and that neophobia may function as a "generalized" response to ecological uncertainty. PMID- 29491936 TI - Expanding the phenotypic plasticity paradigm to broader views of trait space and ecological function. AB - Foundational concepts of trait spaces, including phenotypic plasticity and function of traits, should be expanded and better integrated with ecological theory. This article addresses two areas where plasticity theory can become further integrated with ecological, evolutionary, and developmental thinking. First is the idea that not only trait means within environments and plasticity of trait means across environments is optimized by selection, but that the entire shape of phenotype distributions such as variance or skew should be optimized within and across environments. In order for trait distribution shape to evolve into adaptations, there must be a genetic basis for and selection upon variation in distribution shapes and their plasticities. I present published and new data demonstrating genetic control and selection for higher moments of phenotype distributions; though, plasticity in these values has not yet been tested. Genetic control of phenotype distribution moments is shown for Neurospora crassa ascospore size and shape. Selection on trait distribution moments is shown for Eurosta solidaginis gall size. Second, there is a tradition in modeling plasticity as an adaptive strategy that pits it as an alternative to ecological specialization or generalization. However, these strategies need not be considered alternatives. Rather, with environmental fluctuation within generations plasticity may produce additive or non-additive intermediate (generalist) phenotypes, or something new altogether. I present published and new data on the snail Physa virgata and fish Gambusia affinis that show plasticity produces partly intermediate (generalist) and partly unique phenotypic elements in mixed and fluctuating environments. Plasticity can thus be viewed in the context of a broader trait space and as having broader ecological roles than currently is conceived. PMID- 29491937 TI - The evolution of phenotypic plasticity in fish swimming. AB - Fish have a remarkable amount of variation in their swimming performance, from within species differences to diversity among major taxonomic groups. Fish swimming is a complex, integrative phenotype and has the ability to plastically respond to a myriad of environmental changes. The plasticity of fish swimming has been observed on whole-organismal traits such as burst speed or critical swimming speed, as well as underlying phenotypes such as muscle fiber types, kinematics, cardiovascular system, and neuronal processes. Whether the plastic responses of fish swimming are beneficial seems to depend on the environmental variable that is changing. For example, because of the effects of temperature on biochemical processes, alterations of fish swimming in response to temperature do not seem to be beneficial. In contrast, changes in fish swimming in response to variation in flow may benefit the fish to maintain position in the water column. In this paper, we examine how this plasticity in fish swimming might evolve, focusing on environmental variables that have received the most attention: temperature, habitat, dissolved oxygen, and carbon dioxide variation. Using examples from previous research, we highlight many of the ways fish swimming can plastically respond to environmental variation and discuss potential avenues of future research aimed at understanding how plasticity of fish swimming might evolve. We consider the direct and indirect effects of environmental variation on swimming performance, including changes in swimming kinematics and suborganismal traits thought to predict swimming performance. We also discuss the role of the evolution of plasticity in shaping macroevolutionary patterns of diversity in fish swimming. PMID- 29491939 TI - Predation changes the shape of thermal performance curves for population growth rate. AB - Ectotherms generally demonstrate nonlinear changes in performance (e.g., movement speed, individual growth, population growth) as a function of temperature that are characterized by thermal performance curves (TPC). Predation risk elicits phenotypic and behavioral changes that likewise impact performance measures. We tested whether exposure to predation Orthocyclops modestus impacts the maximum population growth rate (rmax) TPC of the protist Paramecium aurelia. We fit predator and non-predator exposed P. aurelia population growth rates to a function previously shown to best describe Paramecium population growth rate TPC's (Lactin-2) and compared subsequent parameter estimates between curves. For Paramecium exposed to predation risk, maximum population growth increased more rapidly as temperatures rose and decreased more rapidly as temperatures fell compared to the initial temperature. The area under each TPC curve remained approximately the same, consistent with the idea of a trade-off in performance across temperatures. Our results indicate TPCs are flexible given variation in food web context and that trophic interactions may play an important role in shaping TPCs. Furthermore, this and other studies illustrate the need for a mechanistic model of TPCs with parameters tied to biologically meaningful properties. PMID- 29491938 TI - The importance of trans-generational effects in Lepidoptera. AB - The importance of trans-generational effects in shaping an individuals' phenotype and fitness, and consequently even impacting population dynamics is increasingly apparent. Most of the research on trans-generational effects still focuses on plants, mammals, and birds. In the past few years, however, increasing number of studies, especially on maternal effects, have highlighted their importance also in many insect systems. Lepidoptera, specifically butterflies, have been used as model systems for studying the role of phenotypic plasticity within generations. As ectotherms, they are highly sensitive to environmental variation, and indeed many butterflies show adaptive phenotypic plasticity in response to environmental conditions. Here, we synthesize what is known about trans-generational effects in Lepidoptera, compile evidence for different environmental cues that are important drivers of trans-generational effects, and point out which offspring traits are mainly impacted. Finally, we emphasize directions for future research that are needed for better understanding of the adaptive nature of trans-generational effects in Lepidoptera in particular, but potentially also in other organisms. PMID- 29491940 TI - Speciation along a shared evolutionary trajectory. AB - Groups of organisms-whether multiple species or populations of a single species can differ in several non-exclusive ways. For example, groups may have diverged phenotypically, genetically, or in the evolutionary responses available to them. We tested for the latter of these-response divergence-between 2 species of woodrats: Neotoma fuscipes and Neotoma macrotis. Based on random skewers analyses we found that, despite being well differentiated both phenotypically and genetically, N. fuscipes and N. macrotis appear to be diverging along a shared evolutionary trajectory (r degrees = 0.895, P = 0.114). Because these species are currently in secondary contact, their phenotypic evolution being along a shared evolutionary axis has important implications. In particular, that their response to selection arising from interspecific interactions will be constrained along the same evolutionary trajectory may reduce the potential for reinforcing selection to maintain species boundaries. PMID- 29491941 TI - Sexual dimorphism across 3 stages of development in polygynous Artiodactyls is not affected by maternal care. AB - In polygynous mammals, mature males are usually much heavier than females. Competition for females is intense, and few males reproduce. Given the importance of the male's body size for the reproduction and social life of these species, levels of sexual dimorphism were studied in 27 species of polygynous terrestrial cetartiodactyls at the 3 most significant stages of development: birth, 6 months of age, and adulthood. Overall, there were 3 different types of changes in male to-female (M/F) mass ratios between birth and adulthood, corresponding to the 3 categories of adult dimorphism. The change in mass ratio between birth and 6 months of age was inversely correlated to the degree of dimorphism at birth. Most adult dimorphism was acquired after weaning. On the whole, postnatal maternal care seems to have no or even an inverse effect on the evolution of dimorphism, which is apparently not consistent with the assumption of greater maternal investment in male than in female offspring among polygynous mammals. PMID- 29491942 TI - Scale dependency of Liolaemus lizards' home range in response to different environmental variables. AB - Animal habitat-use patterns cannot be isolated from scale issues. Consequently, multi-scale studies provide a complete characterization of ecological patterns that can further explain the observed variation. Liolaemus constitutes the world's second most speciose lizard genus. In this study, we assessed the relationships between home range size and environmental variables at 3 different spatial scales. The study at a local and regional scale was focused on the habitat specialist Liolaemus multimaculatus. The lizard's home range was calculated using the minimum convex polygon method in populations from grassland sites of the coastal sand dunes of the Argentinean Pampas under 2 different conditions, with or without forestations of Acacia longifolia. On the other hand, at a geographical scale we considered the evolutionary implications of 20 species of Liolaemus. Home range size, phylogeny, ecological, environmental, and climatic data were obtained from the literature and remote sensing. L. multimaculatus home range varied from 12.66 to 570.00 m. Regionally, this species had smaller home ranges in forested habitats ([Formula: see text]: 94.02 m2) compared with the non forested sites ([Formula: see text]: 219.78 m2). Habitat structure, vegetation types, and food availability would explain the space use at finer scales. When the 20 species of Liolaemus were considered, high mean air temperature and broad thermal amplitudes showed an inverse relationship with home range size. Neither net primary productivity nor phylogeny was good predictors for home range variation at geographical scale. This study highlights the scale dependence of the explicative capability of a set of environmental and intrinsic variables on home range patterns. PMID- 29491943 TI - Red River barrier and Pleistocene climatic fluctuations shaped the genetic structure of Microhyla fissipes complex (Anura: Microhylidae) in southern China and Indochina. AB - South China and Indochina host striking species diversity and endemism. Complex tectonic and climatic evolutions appear to be the main drivers of the biogeographic patterns. In this study, based on the geologic history of this region, we test 2 hypotheses using the evolutionary history of Microhyla fissipes species complex. Using DNA sequence data from both mitochondrial and nuclear genes, we first test the hypothesis that the Red River is a barrier to gene flow and dispersal. Second, we test the hypothesis that Pleistocene climatic cycling affected the genetic structure and population history of these frogs. We detect 2 major genetic splits that associate with the Red River. Time estimation suggests that late Miocene tectonic movement associated with the Red River drove their diversification. Species distribution modeling (SDM) resolves significant ecological differences between sides of the Red River. Thus, ecological divergence also probably promoted and maintained the diversification. Genogeography, historical demography, and SDM associate patterns in southern China with climate changes of the last glacial maximum (LGM), but not Indochina. Differences in geography and climate between the 2 areas best explain the discovery. Responses to the Pleistocene glacial-interglacial cycling vary among species and regions. PMID- 29491944 TI - Dedicated population genomics for the silent world: the specific questions of marine population genetics. PMID- 29491945 TI - Current hypotheses to explain genetic chaos under the sea. AB - Chaotic genetic patchiness (CGP) refers to surprising patterns of spatial and temporal genetic structure observed in some marine species at a scale where genetic variation should be efficiently homogenized by gene flow via larval dispersal. Here we review and discuss 4 mechanisms that could generate such unexpected patterns: selection, sweepstakes reproductive success, collective dispersal, and temporal shifts in local population dynamics. First, we review examples where genetic differentiation at specific loci was driven by diversifying selection, which was historically the first process invoked to explain CGP. Second, we turn to neutral demographic processes that may drive genome-wide effects, and whose effects on CGP may be enhanced when they act together. We discuss how sweepstakes reproductive success accelerates genetic drift and can thus generate genetic structure, provided that gene flow is not too strong. Collective dispersal is another mechanism whereby genetic structure can be maintained regardless of dispersal intensity, because it may prevent larval cohorts from becoming entirely mixed. Theoretical analyses of both the sweepstakes and the collective dispersal ideas are presented. Finally, we discuss an idea that has received less attention than the other ones just mentioned, namely temporal shifts in local population dynamics. PMID- 29491946 TI - Genetic load in marine animals: a review. AB - Marine invertebrates and fish are well known for their remarkable genetic diversity, which is commonly explained by large population size and the characteristic dispersive nature of their early, planktonic life history. Other potential sources of diversity in marine animals, such as a higher mutation rate, have been much less considered, though evidence for a high genetic load in marine bivalves has been accumulating for nearly half a century. In this review, I examine evidence for a higher genetic load in marine animals from studies of molecular marker segregation and linkage over the last 40 years, and survey recent work examining mutational load with molecular evolution approaches. Overall, marine animals appear to have higher genetic load than terrestrial animals (higher dn/ds ratios, inbreeding load, and segregation dis'tortion), though results are mixed for marine fish and data are lacking for many marine animal groups. Bivalves (oysters) have the highest loads observed among marine animals, comparable only to long-lived plants; however, more data is needed from other bivalves and more marine invertebrate taxa generally. For oysters, a higher load may be related to a chronically lower effective population size that, in concert with a higher mutational rate, elevate the number of deleterious mutations observed. I suggest that future studies use high-throughput sequencing approaches to examine (1) polymorphism in genome-scale datasets across a wider range of marine animals at the population level and (2) intergenerational mutational changes between parents and offspring in crosses of aquaculture species to quantify mutation rates. PMID- 29491947 TI - Navigating the currents of seascape genomics: how spatial analyses can augment population genomic studies. AB - Population genomic approaches are making rapid inroads in the study of non-model organisms, including marine taxa. To date, these marine studies have predominantly focused on rudimentary metrics describing the spatial and environmental context of their study region (e.g., geographical distance, average sea surface temperature, average salinity). We contend that a more nuanced and considered approach to quantifying seascape dynamics and patterns can strengthen population genomic investigations and help identify spatial, temporal, and environmental factors associated with differing selective regimes or demographic histories. Nevertheless, approaches for quantifying marine landscapes are complicated. Characteristic features of the marine environment, including pelagic living in flowing water (experienced by most marine taxa at some point in their life cycle), require a well-designed spatial-temporal sampling strategy and analysis. Many genetic summary statistics used to describe populations may be inappropriate for marine species with large population sizes, large species ranges, stochastic recruitment, and asymmetrical gene flow. Finally, statistical approaches for testing associations between seascapes and population genomic patterns are still maturing with no single approach able to capture all relevant considerations. None of these issues are completely unique to marine systems and therefore similar issues and solutions will be shared for many organisms regardless of habitat. Here, we outline goals and spatial approaches for landscape genomics with an emphasis on marine systems and review the growing empirical literature on seascape genomics. We review established tools and approaches and highlight promising new strategies to overcome select issues including a strategy to spatially optimize sampling. Despite the many challenges, we argue that marine systems may be especially well suited for identifying candidate genomic regions under environmentally mediated selection and that seascape genomic approaches are especially useful for identifying robust locus-by environment associations. PMID- 29491948 TI - Detecting polygenic selection in marine populations by combining population genomics and quantitative genetics approaches. AB - Highly fecund marine species with dispersive life-history stages often display large population sizes and wide geographic distribution ranges. Consequently, they are expected to experience reduced genetic drift, efficient selection fueled by frequent adaptive mutations, and high migration loads. This has important consequences for understanding how local adaptation proceeds in the sea. A key issue in this regard, relates to the genetic architecture underlying fitness traits. Theory predicts that adaptation may involve many genes but with a high variance in effect size. Therefore, the effect of selection on allele frequencies may be substantial for the largest effect size loci, but insignificant for small effect genes. In such a context, the performance of population genomic methods to unravel the genetic basis of adaptation depends on the fraction of adaptive genetic variance explained by the cumulative effect of outlier loci. Here, we address some methodological challenges associated with the detection of local adaptation using molecular approaches. We provide an overview of genome scan methods to detect selection, including those assuming complex demographic models that better describe spatial population structure. We then focus on quantitative genetics approaches that search for genotype-phenotype associations at different genomic scales, including genome-wide methods evaluating the cumulative effect of variants. We argue that the limited power of single locus tests can be alleviated by the use of polygenic scores to estimate the joint contribution of candidate variants to phenotypic variation. PMID- 29491949 TI - Evaluating the Ryman-Laikre effect for marine stock enhancement and aquaculture. AB - The Ryman-Laikre (R-L) effect is an increase in inbreeding and a reduction in total effective population size (NeT ) in a combined captive-wild system, which arises when a few captive parents produce large numbers of offspring. To facilitate evaluation of the R-L effect for scenarios that are relevant to marine stock enhancement and aquaculture, we extended the original R-L formula to explicitly account for several key factors that determine NeT , including the numbers of captive and wild adults, the ratio of captive to wild Ne/N (beta), productivity of captive and wild breeders, and removal of individuals from the wild for captive breeding. We show how to provide quantitative answers to questions such as: What scenarios lead to no loss of effective size? What is the maximum effective size that can be achieved? and What scenarios insure that NeT will be no smaller than a specified value? Important results include the following: (1) For large marine populations, the value of beta becomes increasingly important as the captive contribution increases. Captive propagation will sharply reduce NeT unless the captive contribution is very small or beta is very large (~103 or higher). (2) Very large values of beta are only possible if wild Ne/N is tiny. Therefore, large wild populations undergoing captive enhancement at even modest levels will suffer major reductions in effective size unless wild Ne is a tiny fraction of the census size (about 10-4 or lower). PMID- 29491950 TI - Marine invasions enter the genomic era: three lessons from the past, and the way forward. AB - The expanding scale and increasing rate of marine biological invasions have been documented since the early 20th century. Besides their global ecological and economic impacts, non-indigenous species (NIS) also have attracted much attention as opportunities to explore important eco-evolutionary processes such as rapid adaptation, long-distance dispersal and range expansion, and secondary contacts between divergent evolutionary lineages. In this context, genetic tools have been extensively used in the past 20 years. Three important issues appear to have emerged from such studies. First, the study of NIS has revealed unexpected cryptic diversity in what had previously been assumed homogeneous entities. Second, there has been surprisingly little evidence of strong founder events accompanying marine introductions, a pattern possibly driven by large propagule loads. Third, the evolutionary processes leading to successful invasion have been difficult to ascertain due to faint genetic signals. Here we explore the potential of novel tools associated with high-throughput sequencing (HTS) to address these still pressing issues. Dramatic increase in the number of loci accessible via HTS has the potential to radically increase the power of analyses aimed at species delineation, exploring the population genomic consequences of range expansions, and examining evolutionary processes such as admixture, introgression, and adaptation. Nevertheless, the value of this new wealth of genomic data will ultimately depend on the ability to couple it with expanded "traditional" efforts, including exhaustive sampling of marine populations over large geographic scales, integrated taxonomic analyses, and population level exploration of quantitative trait differentiation through common-garden and other laboratory experiments. PMID- 29491952 TI - The evolutionary consequences of selfish genetic elements. PMID- 29491951 TI - Studying the genetic basis of speciation in high gene flow marine invertebrates. AB - A growing number of genes responsible for reproductive incompatibilities between species (barrier loci) exhibit the signals of positive selection. However, the possibility that genes experiencing positive selection diverge early in speciation and commonly cause reproductive incompatibilities has not been systematically investigated on a genome-wide scale. Here, I outline a research program for studying the genetic basis of speciation in broadcast spawning marine invertebrates that uses a priori genome-wide information on a large, unbiased sample of genes tested for positive selection. A targeted sequence capture approach is proposed that scores single-nucleotide polymorphisms (SNPs) in widely separated species populations at an early stage of allopatric divergence. The targeted capture of both coding and non-coding sequences enables SNPs to be characterized at known locations across the genome and at genes with known selective or neutral histories. The neutral coding and non-coding SNPs provide robust background distributions for identifying FST-outliers within genes that can, in principle, identify specific mutations experiencing diversifying selection. If natural hybridization occurs between species, the neutral coding and non-coding SNPs can provide a neutral admixture model for genomic clines analyses aimed at finding genes exhibiting strong blocks to introgression. Strongylocentrotid sea urchins are used as a model system to outline the approach but it can be used for any group that has a complete reference genome available. PMID- 29491953 TI - Selfish genetic elements and the gene's-eye view of evolution. AB - During the last few decades, we have seen an explosion in the influx of details about the biology of selfish genetic elements. Ever since the early days of the field, the gene's-eye view of Richard Dawkins, George Williams, and others, has been instrumental to make sense of new empirical observations and to the generation of new hypotheses. However, the close association between selfish genetic elements and the gene's-eye view has not been without critics and several other conceptual frameworks have been suggested. In particular, proponents of multilevel selection models have used selfish genetic elements to criticize the gene's-eye view. In this paper, I first trace the intertwined histories of the study of selfish genetic elements and the gene's-eye view and then discuss how their association holds up when compared with other proposed frameworks. Next, using examples from transposable elements and the major transitions, I argue that different models highlight separate aspects of the evolution of selfish genetic elements and that the productive way forward is to maintain a plurality of perspectives. Finally, I discuss how the empirical study of selfish genetic elements has implications for other conceptual issues associated with the gene's eye view, such as agential thinking, adaptationism, and the role of fitness maximizing models in evolution. PMID- 29491954 TI - Rare horizontal transmission does not hide long-term inheritance of SINE highly conserved domains in the metazoan evolution. AB - Transposable elements (TEs) are self-replicating, mobile DNA sequences which constitute a significant fraction of eukaryotic genomes. They are generally considered selfish DNA, as their replication and random insertion may have deleterious effects on genome functionalities, although some beneficial effects and evolutionary potential have been recognized. Short interspersed elements (SINEs) are non-autonomous TEs with a modular structure: a small RNA-related head, a body, and a long interspersed element-related tail. Despite their high turnover rate and de novo emergence, the body may retain highly conserved domains (HCDs) shared among divergent SINE families: in metazoans, at least nine HCD SINEs have been recognized. Data mining on public molecular databases allowed the retrieval of 16 new HCD-SINE families from cnidarian, molluscs, arthropods, and vertebrates. Tracking the ancestry of HCDs on the metazoan phylogeny revealed that some of them date back to the Radiata-Bilateria split. Moreover, phylogenetic and age versus divergence analyses of the most ancient HCDs suggested that long-term vertical inheritance is the rule, with few horizontal transfer events. We suggest that the evolutionary conservation of HCDs may be linked to their potential to serve as recombination hotspots. This indirectly affects host genomes by maintaining active and diverse SINE lineages, whose insertions may impact (either positively or negatively) on the evolution of the genome. PMID- 29491955 TI - No evidence for female discrimination against male house mice carrying a selfish genetic element. AB - Meiotic drivers distort transmission to the next generation in their favor, with detrimental effects on the fitness of their homologues and the rest of the genome. Male carriers of meiotic drivers commonly inflict costs on their mates through genetic incompatibility, reduced fecundity, or biased brood sex ratios. Given these costs, evidence for female discrimination against male carriers is surprisingly rare. One of few examples is the t haplotype in house mice, a meiotic driver that shows strong transmission distortion in males and is typically homozygote lethal. As a consequence, mating between 2 t heterozygous (+/t) mice leads to high embryo mortality. Previous experiments showing that +/t females avoid this incompatibility cost by preferring +/+ versus +/t males have inferred preference based on olfactory cues or brief social interactions. Evidence from mating contexts in laboratory settings and semi-natural populations has been inconclusive. Here, we investigated female choice from a large number of no-choice mating trials. We found no evidence for discrimination against +/t males based on mating, remating, and copulatory behavior. Further, we found no evidence for avoidance of incompatibility through selective interactions between gametes. The likelihood of mating showed significant effects of female weight and genotype, suggesting that our test paradigm enabled females to exhibit mate choice. We discuss the strengths and limitations of our approach. By explicitly considering selection at both the individual and gene level, we argue why precopulatory female discrimination by +/t females may be less evolutionarily stable than discrimination by all females based on postcopulatory mechanisms. PMID- 29491957 TI - Virtual is the new reality. PMID- 29491956 TI - Mitochondrial selfish elements and the evolution of biological novelties. AB - We report the present knowledge about RPHM21, a novel male-specific mitochondrial protein with a putative role in the paternal inheritance of sperm mitochondria in the Manila clam Ruditapes philippinarum, a species with doubly uniparental inheritance of mitochondria (DUI). We review all the available data on rphm21 transcription and translation, analyze in detail its female counterpart, RPHF22, discuss the homology with RPHM21, the putative function and origin, and analyze their polymorphism. The available evidence is compatible with a viral origin of RPHM21 and supports its activity during spermatogenesis. RPHM21 is progressively accumulated in mitochondria and nuclei of spermatogenic cells, and we hypothesize it can influence mitochondrial inheritance and sexual differentiation. We propose a testable model that describes how the acquisition of selfish features by a mitochondrial lineage might have been responsible for the emergence of DUI, and for the evolution of separate sexes (gonochorism) from hermaphroditism. The appearance of DUI most likely entailed the invasion of at least 1 selfish element, and the extant DUI systems can be seen as resolved conflicts. It was proposed that hermaphroditism was the ancestral condition of bivalves, and a correlation between DUI and gonochorism was documented. We hypothesize that DUI might have driven the shift from hermaphroditism to gonochorism, with androdioecy as transition state. The invasion of sex-ratio distorters and the evolution of suppressors can prompt rapid changes among sex-determination mechanisms, and DUI might have been responsible for one of such changes in some bivalve species. If true, DUI would represent the first animal sex-determination system involving mtDNA-encoded proteins. PMID- 29491960 TI - Using RGB displays to portray color realistic imagery to animal eyes. AB - RGB displays effectively simulate millions of colors in the eyes of humans by modulating the relative amount of light emitted by 3 differently colored juxtaposed lights (red, green, and blue). The relationship between the ratio of red, green, and blue light and the perceptual experience of that light has been well defined by psychophysical experiments in humans, but is unknown in animals. The perceptual experience of an animal looking at an RGB display of imagery designed for humans is likely to poorly represent an animal's experience of the same stimulus in the real world. This is due, in part, to the fact that many animals have different numbers of photoreceptor classes than humans do and that their photoreceptor classes have peak sensitivities centered over different parts of the ultraviolet and visible spectrum. However, it is sometimes possible to generate videos that accurately mimic natural stimuli in the eyes of another animal, even if that animal's sensitivity extends into the ultraviolet portion of the spectrum. How independently each RGB phosphor stimulates each of an animal's photoreceptor classes determines the range of colors that can be simulated for that animal. What is required to determine optimal color rendering for another animal is a device capable of measuring absolute or relative quanta of light across the portion of the spectrum visible to the animal (i.e., a spectrometer), and data on the spectral sensitivities of the animal's photoreceptor classes. In this article, we outline how to use such equipment and information to generate video stimuli that mimic, as closely as possible, an animal's color perceptual experience of real-world objects. Key words: color vision, computer animation, perception, video playback, virtual reality. PMID- 29491959 TI - What artifice can and cannot tell us about animal behavior. AB - Artifice-the manipulation of social and environmental stimuli-is fundamental to research in animal behavior. State-of-the-art techniques have been developed to generate and present complex visual stimuli. These techniques have unique strengths and limitations. However, many of the issues with synthetic animation and virtual reality are common to playback experiments in general, including those using unmanipulated video or auditory stimuli. Playback experiments, in turn, fall into the broader category of experiments that artificially manipulate the array of stimuli experienced by a subject. We argue that the challenges of designing and interpreting experiments using virtual reality or synthetic animations are largely comparable to those of studies using older technologies or addressing other modalities, and that technology alone is unlikely to solve these challenges. We suggest that appropriate experimental designs are the key to validating behavioral responses to artificial stimuli and to interpreting all studies using artifice, including those that present complex visual displays. PMID- 29491958 TI - Technical and conceptual considerations for using animated stimuli in studies of animal behavior. AB - Rapid technical advances in the field of computer animation (CA) and virtual reality (VR) have opened new avenues in animal behavior research. Animated stimuli are powerful tools as they offer standardization, repeatability, and complete control over the stimulus presented, thereby "reducing" and "replacing" the animals used, and "refining" the experimental design in line with the 3Rs. However, appropriate use of these technologies raises conceptual and technical questions. In this review, we offer guidelines for common technical and conceptual considerations related to the use of animated stimuli in animal behavior research. Following the steps required to create an animated stimulus, we discuss (I) the creation, (II) the presentation, and (III) the validation of CAs and VRs. Although our review is geared toward computer-graphically designed stimuli, considerations on presentation and validation also apply to video playbacks. CA and VR allow both new behavioral questions to be addressed and existing questions to be addressed in new ways, thus we expect a rich future for these methods in both ultimate and proximate studies of animal behavior. PMID- 29491961 TI - Animated images in the analysis of zebrafish behavior. AB - This invited review is based upon a recent oral paper I presented at the Virtual Reality Symposium of the 34th International Ethological Conference (2015, Cairns, Australia), and as such it describes studies conducted mainly in my own laboratory. It reviews how we utilized visual stimuli for inducing behavioral responses in the zebrafish with a focus on shoaling, group forming behavior. The zebrafish is gaining increasing popularity in neuroscience. With this interest, its behavior is also more frequently studied. One of the many advantages of the zebrafish over traditional laboratory rodents is that this species is diurnal, and it relies heavily upon its visual system. Thus, similarly to our own species, zebrafish respond to visual stimuli in a robust and easily quantifiable manner. For the past decade, we have been exploring how to use such visual stimuli, and have developed numerous paradigms with which we can induce and quantify a variety of behavioral responses, including shoaling. This review summarizes some of these studies, and discusses questions including whether one should use live fish as stimulus, whether and how one could present animated (moving images) of fish, and how one could optimize a range of stimulus presentation parameters to elicit the most robust responses in zebrafish. Although the zebrafish is a relative newcomer in ethology and behavioral neuroscience, and although many of our findings only represent the first steps in this research, our results suggest that the behavioral analysis of the zebrafish will have an important place in biomedical research. PMID- 29491962 TI - Computer animations of color markings reveal the function of visual threat signals in Neolamprologus pulcher. AB - Visual signals, including changes in coloration and color patterns, are frequently used by animals to convey information. During contests, body coloration and its changes can be used to assess an opponent's state or motivation. Communication of aggressive propensity is particularly important in group-living animals with a stable dominance hierarchy, as the outcome of aggressive interactions determines the social rank of group members. Neolamprologus pulcher is a cooperatively breeding cichlid showing frequent within-group aggression. Both sexes exhibit two vertical black stripes on the operculum that vary naturally in shape and darkness. During frontal threat displays these patterns are actively exposed to the opponent, suggesting a signaling function. To investigate the role of operculum stripes during contests we manipulated their darkness in computer animated pictures of the fish. We recorded the responses in behavior and stripe darkness of test subjects to which these animated pictures were presented. Individuals with initially darker stripes were more aggressive against the animations and showed more operculum threat displays. Operculum stripes of test subjects became darker after exposure to an animation exhibiting a pale operculum than after exposure to a dark operculum animation, highlighting the role of the darkness of this color pattern in opponent assessment. We conclude that (i) the black stripes on the operculum of N. pulcher are a reliable signal of aggression and dominance, (ii) these markings play an important role in opponent assessment, and (iii) 2D computer animations are well suited to elicit biologically meaningful short-term aggressive responses in this widely used model system of social evolution. PMID- 29491963 TI - The virtual lover: variable and easily guided 3D fish animations as an innovative tool in mate-choice experiments with sailfin mollies-I. Design and implementation. AB - Animal behavior researchers often face problems regarding standardization and reproducibility of their experiments. This has led to the partial substitution of live animals with artificial virtual stimuli. In addition to standardization and reproducibility, virtual stimuli open new options for researchers since they are easily changeable in morphology and appearance, and their behavior can be defined. In this article, a novel toolchain to conduct behavior experiments with fish is presented by a case study in sailfin mollies Poecilia latipinna. As the toolchain holds many different and novel features, it offers new possibilities for studies in behavioral animal research and promotes the standardization of experiments. The presented method includes options to design, animate, and present virtual stimuli to live fish. The designing tool offers an easy and user friendly way to define size, coloration, and morphology of stimuli and moreover it is able to configure virtual stimuli randomly without any user influence. Furthermore, the toolchain brings a novel method to animate stimuli in a semiautomatic way with the help of a game controller. These created swimming paths can be applied to different stimuli in real time. A presentation tool combines models and swimming paths regarding formerly defined playlists, and presents the stimuli onto 2 screens. Experiments with live sailfin mollies validated the usage of the created virtual 3D fish models in mate-choice experiments. PMID- 29491964 TI - The virtual lover: variable and easily guided 3D fish animations as an innovative tool in mate-choice experiments with sailfin mollies-II. Validation. AB - The use of computer animation in behavioral research is a state-of-the-art method for designing and presenting animated animals to live test animals. The major advantages of computer animations are: (1) the creation of animated animal stimuli with high variability of morphology and even behavior; (2) animated stimuli provide highly standardized, controlled and repeatable testing procedures; and (3) they allow a reduction in the number of live test animals regarding the 3Rs principle. But the use of animated animals should be attended by a thorough validation for each test species to verify that behavior measured with live animals toward virtual animals can also be expected with natural stimuli. Here we present results on the validation of a custom-made simulation for animated 3D sailfin mollies Poecilia latipinna and show that responses of live test females were as strong to an animated fish as to a video or a live male fish. Movement of an animated stimulus was important but female response was stronger toward a swimming 3D fish stimulus than to a "swimming" box. Moreover, male test fish were able to discriminate between animated male and female stimuli; hence, rendering the animated 3D fish a useful tool in mate-choice experiments with sailfin mollies. PMID- 29491965 TI - Computer-animated stimuli to measure motion sensitivity: constraints on signal design in the Jacky dragon. AB - Identifying perceptual thresholds is critical for understanding the mechanisms that underlie signal evolution. Using computer-animated stimuli, we examined visual speed sensitivity in the Jacky dragon Amphibolurus muricatus, a species that makes extensive use of rapid motor patterns in social communication. First, focal lizards were tested in discrimination trials using random-dot kinematograms displaying combinations of speed, coherence, and direction. Second, we measured subject lizards' ability to predict the appearance of a secondary reinforcer (1 of 3 different computer-generated animations of invertebrates: cricket, spider, and mite) based on the direction of movement of a field of drifting dots by following a set of behavioural responses (e.g., orienting response, latency to respond) to our virtual stimuli. We found an effect of both speed and coherence, as well as an interaction between these 2 factors on the perception of moving stimuli. Overall, our results showed that Jacky dragons have acute sensitivity to high speeds. We then employed an optic flow analysis to match the performance to ecologically relevant motion. Our results suggest that the Jacky dragon visual system may have been shaped to detect fast motion. This pre-existing sensitivity may have constrained the evolution of conspecific displays. In contrast, Jacky dragons may have difficulty in detecting the movement of ambush predators, such as snakes and of some invertebrate prey. Our study also demonstrates the potential of the computer-animated stimuli technique for conducting nonintrusive tests to explore motion range and sensitivity in a visually mediated species. PMID- 29491966 TI - Social interactivity in pigeon courtship behavior. AB - A closed-loop teleprompter system was used to isolate and manipulate social interactivity in the natural courtship interactions of pigeons Columbia livia. In Experiment 1, a live face-to-face real-time interaction between 2 courting pigeons (Live) was compared to a played back version of the video stimulus recorded during the pairs Live interaction. We found that pigeons were behaving interactively; their behavior depended on the relationships between their own signals and those of their partner. In Experiment 2, we tested whether social interactivity relies on spatial cues present in the facing direction of a partner's display. By moving the teleprompter camera 90 degrees away from its original location, the partner's display was manipulated to appear as if it is directed 90 degrees away from the subject. We found no effect of spatial offset on the pigeon's behavioral response. In Experiment 3, 3 time delays, 1 s, 3 s, and 9 s, a Live condition, and a playback condition were chosen to investigate the importance of temporal contiguity in social interactivity. Furthermore, both opposite-sex (courtship) and same-sex (rivalry) pairs were studied to investigate whether social-context affects social interactivity sensitivity. Our results showed that pigeon courtship behavior is sensitive to temporal contiguity. Behavior declined in the 9 s and Playback conditions as compared to Live condition and the shorter time delays. For males only, courtship behavior also increased in the 3-s delay condition. The effect of social interactivity and time delay was not observed in rivalry interactions, suggesting that social interactivity may be specific to courtship. PMID- 29491967 TI - Technology advancing the study of animal cognition: using virtual reality to present virtually simulated environments to investigate nonhuman primate spatial cognition. AB - Virtual simulated environments provide multiple ways of testing cognitive function and evaluating problem solving with humans (e.g., Woollett et al. 2009). The use of such interactive technology has increasingly become an essential part of modern life (e.g., autonomously driving vehicles, global positioning systems (GPS), and touchscreen computers; Chinn and Fairlie 2007; Brown 2011). While many nonhuman animals have their own forms of "technology", such as chimpanzees who create and use tools, in captive animal environments the opportunity to actively participate with interactive technology is not often made available. Exceptions can be found in some state-of-the-art zoos and laboratory facilities (e.g., Mallavarapu and Kuhar 2005). When interactive technology is available, captive animals often selectively choose to engage with it. This enhances the animal's sense of control over their immediate surroundings (e.g., Clay et al. 2011; Ackerman 2012). Such self-efficacy may help to fulfill basic requirements in a species' daily activities using problem solving that can involve foraging and other goal-oriented behaviors. It also assists in fulfilling the strong underlying motivation for contrafreeloading and exploration expressed behaviorally by many species in captivity (Young 1999). Moreover, being able to present nonhuman primates virtual reality environments under experimental conditions provides the opportunity to gain insight into their navigational abilities and spatial cognition. It allows for insight into the generation and application of internal mental representations of landmarks and environments under multiple conditions (e.g., small- and large-scale space) and subsequent spatial behavior. This paper reviews methods using virtual reality developed to investigate the spatial cognitive abilities of nonhuman primates, and great apes in particular, in comparison with that of humans of multiple age groups. We make recommendations about training, best practices, and also pitfalls to avoid. PMID- 29491969 TI - Influence of free water availability on a desert carnivore and herbivore. AB - Anthropogenic manipulation of finite resources on the landscape to benefit individual species or communities is commonly employed by conservation and management agencies. One such action in arid regions is the construction and maintenance of water developments (i.e., wildlife guzzlers) adding free water on the landscape to buttress local populations, influence animal movements, or affect distributions of certain species of interest. Despite their prevalence, the utility of wildlife guzzlers remains largely untested. We employed a before after control-impact (BACI) design over a 4-year period on the US Army Dugway Proving Ground, Utah, USA, to determine whether water availability at wildlife guzzlers influenced relative abundance of black-tailed jackrabbits Lepus californicus and relative use of areas near that resource by coyotes Canis latrans, and whether coyote visitations to guzzlers would decrease following elimination of water. Eliminating water availability at guzzlers did not influence jackrabbit relative abundance. Coyote relative use was impacted by water availability, with elimination of water reducing use in areas associated with our treatment, but not with areas associated with our control. Visitations of radio-collared coyotes to guzzlers declined nearly 3-fold following elimination of water. Our study provides the first evidence of a potential direct effect of water sources on a mammalian carnivore in an arid environment, but the ecological relevance of our finding is debatable. Future investigations aimed at determining water effects on terrestrial mammals could expand on our findings by incorporating manipulations of water availability, obtaining absolute estimates of population parameters and vital rates and incorporating fine-scale spatiotemporal data. PMID- 29491968 TI - Virtual reality systems for rodents. AB - Over the last decade virtual reality (VR) setups for rodents have been developed and utilized to investigate the neural foundations of behavior. Such VR systems became very popular since they allow the use of state-of-the-art techniques to measure neural activity in behaving rodents that cannot be easily used with classical behavior setups. Here, we provide an overview of rodent VR technologies and review recent results from related research. We discuss commonalities and differences as well as merits and issues of different approaches. A special focus is given to experimental (behavioral) paradigms in use. Finally we comment on possible use cases that may further exploit the potential of VR in rodent research and hence inspire future studies. PMID- 29491970 TI - Topographic heterogeneity and temperature amplitude explain species richness patterns of birds in the Qinghai-Tibetan Plateau. AB - Large-scale patterns of species richness have gained much attention in recent years; however, the factors that drive high species richness are still controversial in local regions, especially in highly diversified montane regions. The Qinghai-Tibetan Plateau (QTP) and the surrounding mountains are biodiversity hot spots due to a high number of endemic montane species. Here, we explored the factors underlying this high level of diversity by studying the relationship between species richness and environmental variables. The richness patterns of 758 resident bird species were summarized at the scale of 1 degrees *1 degrees grid cell at different taxonomic levels (order, family, genus, and species) and in different taxonomic groups (Passeriformes, Galliformes, Falconiformes, and Columbiformes). These richness patterns were subsequently analyzed against habitat heterogeneity (topographical heterogeneity and land cover), temperature amplitude (annual temperature, annual precipitation, precipitation seasonality, and temperature seasonality) and a vegetation index (net primary productivity). Our results showed that the highest richness was found in the southeastern part of the QTP, the eastern Himalayas. The lowest richness was observed in the central plateau of the QTP. Topographical heterogeneity and temperature amplitude are the primary factors that explain overall patterns of species richness in the QTP, although the specific effect of each environmental variable varies between the different taxonomic groups depending on their own evolutionary histories and ecological requirements. High species richness in the southeastern QTP is mostly due to highly diversified habitat types and temperature zones along elevation gradients, whereas the low species richness in the central plateau of the QTP may be due to environmental and energetic constraints, as the central plateau is harsh environment. PMID- 29491971 TI - Habitat selection of woodchat shrikes Lanius senator during spring stopover is related to foraging strategy. AB - Every spring a huge number of passerines cross the Sahara Desert and the Mediterranean Sea on their way to their breeding grounds. Stopover sites after such extended barriers where birds can rest, refuel, and find shelter from adverse weather, are of crucial importance for the outcome of their migration. Stopover habitat selection used by migrating birds depends on landscape context, habitat patch characteristics, as well as on the particular energetic conditions and needs of individual birds, but it is still poorly investigated. We focused on a long-distance migrating passerine, the woodchat shrike, in order to investigate for the first time the species' habitat selection at a spring stopover site (island of Antikythira, Greece) after the crossing of the Sahara Desert and Mediterranean Sea. We implemented radio-tracking, color-ringing, and visual behavioral observations to collect data on microhabitat use. Generalized Linear Mixed Models were developed to identify the species' most preferred microhabitat during its stopover on this low human disturbed island. We found that high maquis vegetation surrounded by low vegetation was chosen as perches for hunting. Moreover, high maquis vegetation appeared to facilitate hunting attempts toward the ground, the most frequently observed foraging strategy. Finally, we discuss our findings in the context of conservation practices for the woodchat shrike and their stopover sites on Mediterranean islands. PMID- 29491972 TI - Increased population density reduces body growth and female investment in a simultaneous hermaphrodite. AB - Sex allocation theory applied to hermaphrodites assumes that there is a trade off between the allocation of resources to male and female functions, within a fixed reproductive resource budget. Charnov's classic resource allocation model predicts a more female-biased sex allocation when competition among different sperm donors is low due to diminishing fitness returns for male investment. By manipulating the social group size, one automatically changes the population density at which individuals live. Increasing population density may affect reproductive allocation, leading to resource competition and/or to increased concentration of harmful metabolites. This could lead to an over- or underestimation of the individual adjustment of sex allocation responses to mating opportunities. In this article, we tested the effects of density and social group size separately on female investment and body growth (considered as proxy of the overall energy budget) in the simultaneously hermaphroditic polychaete worm Ophryotrocha diadema. We manipulated social group size (i.e., monogamous and promiscuous regimes) and density (i.e., 4 levels) using a full factorial design, to identify the underlying factor affecting female allocation (in terms of egg production) and body growth. In contrast to findings of previous experiments, we found that an increase in population density reduced body growth and egg production of hermaphrodites irrespective of social group size. We advance the hypothesis that the increase of catabolites and oxygen consumption in high-density conditions reduces the overall resource budget and this could obscure group size effects on female fecundity. PMID- 29491973 TI - Balancing past and present: how experience influences boldness over time in Eurasian perch. AB - Adapting to fluctuating predation conditions is a challenge for prey. By learning through experience, animals may adjust their anti-predator behavior to better reflect current predation risk. Although many studies show experience of predation to alter prey behavior, little is known about how prey rely on such experience over time. By comparing boldness over different temporal scales between individuals of Eurasian perch, either experienced or naive of predators, we examine how risk is traded based on past and present experience. Differences in predator exposure during the first year of life were found to lead to differences in risk-taking behavior, even after the perch been kept in a predator free environment for 9 months. However, the response to a potential predator was quickly readjusted after increased experience of current conditions. The results highlight how prey have to balance past experiences of predators against current threat levels. PMID- 29491974 TI - On the identification of paedomorphic and overwintering larval newts based on cloacal shape: review and guidelines. AB - Paedomorphosis is an alternative process to metamorphosis in which adults retain larval traits at the adult stage. It is frequent in newts and salamanders, where larvae reach sexual maturity without losing their gills. However, in some populations, larvae overwinter in water, while remaining immature. These alternative ontogenetic processes are of particular interest in various research fields, but have different causes and consequences, as only paedomorphosis allows metamorphosis to be bypassed before maturity. It is thus relevant to efficiently identify paedomorphs versus overwintering larvae. In this context, the aim of this article was 3-fold: firstly, to perform a meta-analysis of the identification procedures carried out in the literature; secondly, to determine the effectiveness of body size to make inferences about adulthood by surveying natural newt populations of Lissotriton helveticus and Ichthyosaura alpestris, and thirdly, to propose easy guidelines for an accurate distinction between large larvae and paedomorphs based on an external sexual trait, which is essential for reproduction-the cloaca. More than half of the studies in the literature do not mention the diagnostic criteria used for determining adulthood. The criteria mentioned were the presence of mature gonads (10%), eggs laid (4%), courtship behavior (10%), and external morphological sexual traits (39%) including the cloaca (24%). Body-size thresholds should not be used as a proxy for paedomorphosis, because overwintering larvae can reach a larger size than paedomorphs within the same populations. In contrast, diagnosis based on cloacal external morphology is recommended, as it can be processed by the rapid visual assessment of all caught specimens, thus providing straightforward data at the individual level for both sexes. PMID- 29491975 TI - Temperature modifies activity, inter-individual relationships and group structure in a fish. AB - A host of abiotic factors modify fish social behavior. However, few studies have characterized the effects of temperature on behavior. In this study, brown trout Salmo trutta fry were reared at 5 different temperatures (4 degrees C, 6 degrees C, 8 degrees C, 10 degrees C, and 12 degrees C). In order to characterize group structure, 3 behavioral parameters were investigated: group social structure (based on inter-individual distances), inter-individual relationships (based on physical contacts), and individual activity. These behavioral parameters were studied at the emergence stage, which corresponds to a switch from a social gregarious life in the gravel to a solitary one in the water column. Data analysis showed that the inter-individual distances increased with increasing temperature, particularly the nearest neighbor distance. The mean number of physical contacts between fry increased at both low and high temperatures. At high temperatures, most fry moved apart from each other after a physical contact. Swimming activity decreased at both the lower and upper temperatures (18% of activity at 4 degrees C, 38% at 8 degrees C, and 12% at 12 degrees C). This study showed that temperature modifies brown trout fry activity, inter-individual relationships, and social behavior, which all affect group cohesion before emergence and can influence their survival and dispersal. PMID- 29491976 TI - Integrative behavioral ecotoxicology: bringing together fields to establish new insight to behavioral ecology, toxicology, and conservation. AB - The fields of behavioral ecology, conservation science, and environmental toxicology individually aim to protect and manage the conservation of wildlife in response to anthropogenic stressors, including widespread anthropogenic pollution. Although great emphasis in the field of toxicology has been placed on understanding how single pollutants affect survival, a comprehensive, interdisciplinary approach that includes behavioral ecology is essential to address how anthropogenic compounds are a risk for the survival of species and populations in an increasingly polluted world. We provide an integrative framework for behavioral ecotoxicology using Tinbergen's four postulates (causation and mechanism, development and ontogeny, function and fitness, and evolutionary history and phylogenetic patterns). The aims of this review are: 1) to promote an integrative view and re-define the field of integrative behavioral ecotoxicology; 2) to demonstrate how studying ecotoxicology can promote behavior research; and 3) to identify areas of behavioral ecotoxicology that require further attention to promote the integration and growth of the field. PMID- 29491977 TI - Asymmetrical positive assortative mating induced by developmental lead (Pb2+) exposure in a model system, Drosophila melanogaster. AB - Anthropogenic pollutants have the potential to disrupt reproductive strategies. Little is known about how lead (Pb2+) exposure disrupts individual-level responses in reproductive behaviors, which are important for fitness. Drosophila melanogaster was used as a model system to determine the effects of: 1) developmental lead exposure on pre-mating reproductive behaviors (i.e., mate preference), and 2) lead exposure and mating preferences on fitness in the F0 parental generation and F1 un-exposed offspring. Wild-type strains of D. melanogaster were reared from egg stage to adulthood in control or leaded medium (250 MUM PbAc) and tested for differences in: mate preference, male song performance, sex pheromone expression, fecundity, mortality, and body weight. F0 leaded females preferentially mated with leaded males (i.e., asymmetrical positive assortative mating) in 2-choice tests. This positive assortative mating was mediated by the females (and not the males) and was dependent upon context and developmental exposure to Pb. Neither the courtship song nor the sex pheromone profile expressed by control and leaded males mediated the positive assortative mating in leaded females. Leaded females did not incur a fitness cost in terms of reduced fecundity, increased mortality, or decreased body weight by mating with leaded males. These results suggest that sublethal exposure to lead during development can alter mate preferences in adults, but not fitness measures once lead exposure has been removed. We suggest that changes in mate preference may induce fitness costs, as well as long-term population and multi-generational implications, if pollution is persistent in the environment. PMID- 29491978 TI - Urban health and ecology: the promise of an avian biomonitoring tool. AB - Urban-dwelling birds have the potential to serve as powerful biomonitors that reveal the impact of environmental change due to urbanization. Specifically, urban bird populations can be used to survey cities for factors that may pose both public and wildlife health concerns. Here, we review evidence supporting the use of avian biomonitors to identify threats associated with urbanization, including bioaccumulation of toxicants and the dysregulation of behavior and physiology by related stressors. In addition, we consider the use of birds to examine how factors in the urban environment can impact immunity against communicable pathogens. By studying the behavior, physiology, and ecology of urban bird populations, we can elucidate not only how avian populations are responding to environmental change, but also how unintended consequences of urbanization affect the well-being of human and non-human inhabitants. PMID- 29491979 TI - Exposure to dietary mercury alters cognition and behavior of zebra finches. AB - Environmental stressors can negatively affect avian cognitive abilities, potentially reducing fitness, for example by altering response to predators, display to mates, or memory of locations of food. We expand on current knowledge by investigating the effects of dietary mercury, a ubiquitous environmental pollutant and known neurotoxin, on avian cognition. Zebra finches Taeniopygia guttata were dosed for their entire lives with sub-lethal levels of mercury, at the environmentally relevant dose of 1.2 parts per million. In our first study, we compared the dosed birds with controls of the same age using tests of three cognitive abilities: spatial memory, inhibitory control, and color association. In the spatial memory assay, birds were tested on their ability to learn and remember the location of hidden food in their cage. The inhibitory control assay measured their ability to ignore visible but inaccessible food in favor of a learned behavior that provided the same reward. Finally, the color association task tested each bird's ability to associate a specific color with the presence of hidden food. Dietary mercury negatively affected spatial memory ability but not inhibitory control or color association. Our second study focused on three behavioral assays not tied to a specific skill or problem-solving: activity level, neophobia, and social dominance. Zebra finches exposed to dietary mercury throughout their lives were subordinate to, and more active than, control birds. We found no evidence that mercury exposure influenced our metric of neophobia. Together, these results suggest that sub-lethal exposure to environmental mercury selectively harms neurological pathways that control different cognitive abilities, with complex effects on behavior and fitness. PMID- 29491980 TI - Developmental exposure to heavy metals alters visually-guided behaviors in zebrafish. AB - This laboratory-based study determined the consequences of heavy metal exposure using zebrafish Danio rerio. Embryos were transiently exposed to environmentally relevant concentrations of cadmium or nickel until 72 h postfertilization (hpf), then they were returned to system water and allowed to grow until 7, 9, and 11 days postfertilization (dpf), when they were examined morphologically and behaviorally. Morphological measures of notochord length, eye diameter, and inter eye distance were not different across treatments; however, significant differences in optomotor responses were observed in treated larvae at all ages tested. These results suggest that initial developmental exposure to cadmium and nickel significantly impacts visually-guided larval behavior. The absence of significant differences in gross morphology suggests that the effects of these metals are subtle and may occur at the cellular level. By using this ecologically relevant model and pollutant type, this study has broad application and implications with regard to safe levels of contaminant in drinking water and freshwater ecosystems. PMID- 29491981 TI - Interbirth intervals are associated with age of the mother, but not with infant mortality in Indian rhinoceroses. AB - Rhinoceroses are among the most endangered mammals in the world. Despite a recent increase in numbers in most wild populations, poaching or political instability may exterminate large populations very quickly. Therefore, captive or ex situ rhinoceros populations can play an important role in their conservation. Previous studies identified infant mortality and interbirth intervals among the main parameters affecting the viability and survival of rhinoceros populations. In our study, we tested the recently suggested prediction that in captive Indian rhinoceros Rhinoceros unicornis, longer interbirth intervals may result in higher infant mortality. We also examined the factors that are the main predictors of infant mortality and interbith intervals using the studbook data on Indian rhinoceros born in zoos worldwide as well as data from Dudhwa National Park, India, where rhinoceroses were successfully reintroduced. We found no association between interbirth intervals and infant mortality. In both populations, the main predictor of infant mortality was mother's parity, with higher mortality in calves born to primiparous mothers. In addition, we found that the interbirth intervals were shorter in zoos than in Dudhwa and that they increased with increase in age of the mother, which was the only factor affecting interbirth interval in both populations. Our results show that the same factors affect both parameters in both populations and thus illustrate that the reproduction and infant survival of Indian rhinoceros in zoos reflect the natural pattern. Furthermore, we suggest that in captivity, the interbirth intervals could be slightly prolonged to approach the situation in the wild. PMID- 29491982 TI - Smelling fit: scent marking exposes parasitic infection status in the banded mongoose. AB - Preference for uninfected mates is presumed beneficial as it minimizes one's risk of contracting an infection and infecting one's offspring. In avian systems, visual ornaments are often used to indicate parasite burdens and facilitate mate choice. However, in mammals, olfactory cues have been proposed to act as a mechanism allowing potential mates to be discriminated by infection status. The effect of infection upon mammalian mate choice is mainly studied in captive rodents where experimental trials support preference for the odors of uninfected mates and some data suggest scent marking is reduced in individuals with high infection burdens. Nevertheless, whether such effects occur in nonmodel and wild systems remains poorly understood. Here, we investigate the interplay between parasite load (estimated using fecal egg counts) and scent marking behavior in a wild population of banded mongooses Mungos mungo. Focusing on a costly protozoan parasite of the genus Isospora and the nematode worm Toxocara, we first show that banded mongooses that engage in frequent, intensive scent marking have lower Isospora loads, suggesting marking behavior may be an indicator trait regarding infection status. We then use odor presentations to demonstrate that banded mongooses mark less in response to odors of opposite sexed individuals with high Isospora and Toxocara loads. As both of these parasites are known to have detrimental effects upon the health of preweaned young in other species, they would appear key targets to avoid during mate choice. Results provide support for scent as an important ornament and mechanism for advertising parasitic infection within wild mammals. PMID- 29491983 TI - Facing different predators: adaptiveness of behavioral and morphological traits under predation. AB - Predation is thought to be one of the main structuring forces in animal communities. However, selective predation is often measured on isolated traits in response to a single predatory species, but only rarely are selective forces on several traits quantified or even compared between different predators naturally occurring in the same system. In the present study, we therefore measured behavioral and morphological traits in young-of-the-year Eurasian perch Perca fluviatilis and compared their selective values in response to the 2 most common predators, adult perch and pike Esox lucius. Using mixed effects models and model averaging to analyze our data, we quantified and compared the selectivity of the 2 predators on the different morphological and behavioral traits. We found that selection on the behavioral traits was higher than on morphological traits and perch predators preyed overall more selectively than pike predators. Pike tended to positively select shallow bodied and nonvigilant individuals (i.e. individuals not performing predator inspection). In contrast, perch predators selected mainly for bolder juvenile perch (i.e. individuals spending more time in the open, more active), which was most important. Our results are to the best of our knowledge the first that analyzed behavioral and morphological adaptations of juvenile perch facing 2 different predation strategies. We found that relative specific predation intensity for the divergent traits differed between the predators, providing some additional ideas why juvenile perch display such a high degree of phenotypic plasticity. PMID- 29491984 TI - Do predator energy demands or previous exposure influence protection by aposematic coloration of prey? AB - Growing evidence exists that aposematic and toxic prey may be included in a predator's diet when the predator experiences physiological stress. The tree sparrow Passer montanus is known to have a significant portion of aposematic and toxic ladybirds in its natural diet. Here, we present experiments testing the attack and eating rate of the tree sparrow toward the invasive aposematic harlequin ladybird Harmonia axyridis. We wondered whether the sparrow's ability to prey on native ladybirds predisposes them to also prey on harlequin ladybirds. We compared the attack and eating rates of tree sparrows of particular age and/or experience classes to test for any changes during ontogeny (hand-reared * young wild-caught *adult wild-caught) and with differing perceived levels of physiological stress (summer adult * winter adult). Winter adult tree sparrows commonly attacked and ate the offered ladybirds with no evidence of disgust or metabolic difficulties after ingestion. Naive and wild immature tree sparrows attacked the ladybirds but hesitated to eat them. Adult tree sparrows caught in the summer avoided attacking the ladybirds. These results suggest that tree sparrows are able to cope with chemicals ingested along with the ladybirds. This pre-adaptation enables them to include ladybirds in their diet; though they commonly do this only in times of shortage in insect availability (winter). Young sparrows showed avoidance toward the chemical protection of the ladybirds. PMID- 29491985 TI - Network approach to understanding the organization of and the consequence of targeted leader removal on an end-oriented task. AB - Relocation is an important event in the lives of several social insects whereby all colony members have to be transferred to a new nest when conditions in the old nest become unfavorable. In the current study, network tools were used to examine the organization of this goal-oriented task in the Indian queenless ant Diacamma indicum which relocate their colonies by means of tandem running. Individual ants were used as nodes and tandem runs as directed edges to construct unweighted networks. Network parameters were characterized in control relocations (CRs) and in relocations where the node with the highest outdegree, that is, the Maximum tandem leader (Max TL) was experimentally removed. These were then compared to 1) randomized networks, 2) simulated networks in which Max TL was removed, and 3) simulated networks with removal of a random leader. Not only was there complete recovery of the task, but the manner in which it was organized when Max TL was removed was comparable to CRs. The results obtained from our empirical study were significantly different from the results predicted by simulations of leader removal. At an individual level, the Max TL had a significantly higher outdegree than expected by chance alone and in her absence the substitute Max TL did comparable work. In addition, the position of the Max TL in the pathway of information flow was conserved in control and experimentally manipulated conditions. Understanding the organization of this critical event as more than the sum of individual interactions using network parameters allows us to appreciate the dynamic response of groups to perturbations. PMID- 29491986 TI - The seasonal role of field characteristics on seed-eating bird abundances in agricultural landscapes. AB - In temperate agroecosystems, avian responses in abundance and distribution to landscape attributes may be exacerbated by the coupling of natural seasons and farming practices. We assessed the seasonal roles of field type, field use in the surroundings, and distance from a field to the nearest woodlot on the abundance of seed-eating birds in a 225,000 km2 study area in the Pampas of central Argentina. During spring-summer and autumn of 2011-2013, we randomly selected 392 fields and used transect samples to collect data on abundance and presence of seed-eating bird species. We recorded a total of 11,579 individuals belonging to 15 seed-eating bird species. We used generalized lineal mixed models to relate bird abundance to field type, field use in the surroundings, and distance to the nearest woodlot. In spring-summer (breeding season) most bird responses were associated with their nesting requirements. Species that build their nests in trees, such as eared doves Zenaida auriculata, picazuro pigeons Patagioenas picazuro, and monk parakeets Myiopsitta monachus, were more abundant in fields closer to woodlots, whereas grassland yellow-finches Sicalis luteola, which nest at areas with tall grasses, were more abundant in fields with livestock use patches in the field surroundings. In autumn (non-breeding season), most bird responses were associated with foraging and refuge needs. The high abundance of eared doves in crop stubbles and the association of pigeons at field surroundings dominated by croplands or at crop stubbles surrounded by livestock use fields revealed the intimate association of these species to sites with high availability of food resources. In addition, both picazuro pigeons and spot winged pigeons Patagioenas maculosa were associated with woodlots, which provide suitable roosting sites. Our results show that in temperate agroecosystems, the relationships between field characteristics and seed-eating bird abundances vary with season. PMID- 29491987 TI - The effect of fasting and body reserves on cold tolerance in 2 pit-building insect predators. AB - Pit-building antlions and wormlions are 2 distantly-related insect species, whose larvae construct pits in loose soil to trap small arthropod prey. This convergent evolution of natural histories has led to additional similarities in their natural history and ecology, and thus, these 2 species encounter similar abiotic stress (such as periodic starvation) in their natural habitat. Here, we measured the cold tolerance of the 2 species and examined whether recent feeding or food deprivation, as well as body composition (body mass and lipid content) and condition (quantified as mass-to-size residuals) affect their cold tolerance. In contrast to other insects, in which food deprivation either enhanced or impaired cold tolerance, prolonged fasting had no effect on the cold tolerance of either species, which had similar cold tolerance. The 2 species differed, however, in how cold tolerance related to body mass and lipid content: although body mass was positively correlated with the wormlion cold tolerance, lipid content was a more reliable predictor of cold tolerance in the antlions. Cold tolerance also underwent greater change with ontogeny in wormlions than in antlions. We discuss possible reasons for this lack of effect of food deprivation on both species' cold tolerance, such as their high starvation tolerance (being sit-and-wait predators). PMID- 29491988 TI - Introduction to the special column: communication, cooperation, and cognition in predators. PMID- 29491989 TI - An assessment of African lion Panthera leo sociality via social network analysis: prerelease monitoring for an ex situ reintroduction program. AB - The wild population of the African lion Panthera leo continues to decline, requiring alternate conservation programs to be considered. One such program is ex situ reintroduction. Prior to release, long-term monitoring and assessment of behavior is required to determine whether prides and coalitions behave naturally and are sufficiently adapted to a wild environment. Social network analysis (SNA) can be used to provide insight into how the pride as a whole and individuals within it, function. Our study was conducted upon 2 captive-origin prides who are part of an ex situ reintroduction program, and 1 wild pride of African lion. Social interactions were collected at all occurrence for each pride and categorized into greet, social grooming, play, and aggression. Betweenness centrality showed that offspring in each pride were central to the play network, whereas degree indicated that adults received (indegree) the greatest number of overall social interactions, and the adult males of each pride were least likely to initiate (outdegree) any interactions. Through the assessment of individual centrality and degree values, a social keystone adult female was identified for each pride. Social network results indicated that the 2 captive-origin prides had formed cohesive social units and possessed relationships and behaviors comparable with the wild pride for the studied behaviors. This study provided the first SNA comparison between captive-bred origin and a wild pride of lions, providing valuable information on individual and pride sociality, critical for determining the success of prides within an ex situ reintroduction program. PMID- 29491990 TI - Lions, hyenas and mobs (oh my!). AB - Understanding the factors that facilitate the emergence of cooperation among organisms is central to the study of social evolution. Spotted hyenas Crocuta crocuta frequently cooperate to mob lions Panthera leo, approaching the lions as a tightknit group while vocalizing loudly in an attempt to overwhelm them and drive them away. Whereas cooperative mobbing behavior has been well documented in birds and some mammals, to our knowledge it has never been described during interactions between 2 apex predators. Using a 27-year dataset, we characterize lion-hyena encounters, assess rates of mobbing behavior observed during these interactions, and inquire whether mobbing results in successful acquisition of food. Lions and hyenas interacted most often at fresh kills, especially as prey size and the number of hyenas present increased. Possession of food at the beginning of an interaction positively affected retention of that food by each predator species. The presence of male lions increased the probability of an interspecific interaction but decreased the likelihood of hyenas obtaining or retaining possession of the food. Hyena mobbing rates were highest at fresh kills, but lower when adult male lions were present. The occurrence of mobbing was predicted by an increase in the number of hyenas present. Whether or not mobbing resulted in acquisition of food from lions was predicted by an increase in the number of mobs formed by the hyenas present, suggesting that cooperation among hyenas enhances their fitness. PMID- 29491991 TI - Do females use their sexual status to gain resource access? Investigating food for-sex in wolves and dogs. AB - While food sharing among related individuals can be explained by kin selection, food sharing between unrelated individuals has been more of an evolutionary puzzle. The food-for-sex hypothesis provides an explanation for the occurrence of food sharing among nonkin. However, little is known about the socio-ecological factors that can promote such a commodity exchange. A species mating system is a factor potentially influencing food-for-sex patterns of behavior. Here, we compared wolves, which form pair-bonds, with dogs, which are typically promiscuous in free-ranging contexts, to investigate the effect of reproductive stages on the behavior around a food source in 2 different contexts. Furthermore, we considered the roles of both the males and the females in the potential food for-sex exchange. Results indicate that in both species and for both sexes the breeding period promotes decreased aggression. Additionally, females were more persistent in their attempts to access the food and were able to monopolize the resource more when in heat as compared to outside the breeding period. Finally, in dogs, but not wolves, females spent more time in proximity to the male's bone and had a shorter latency to start eating it when in heat. Overall, this study demonstrates that the food-for-sex hypothesis plays a part in intersexual food sharing in canids, and highlights the role of females in the interaction. These effects were especially the case in dogs, suggesting a potential effect of mating system on food-for-sex responses. PMID- 29491992 TI - Visual classification of feral cat Felis silvestris catus vocalizations. AB - Cat vocal behavior, in particular, the vocal and social behavior of feral cats, is poorly understood, as are the differences between feral and fully domestic cats. The relationship between feral cat social and vocal behavior is important because of the markedly different ecology of feral and domestic cats, and enhanced comprehension of the repertoire and potential information content of feral cat calls can provide both better understanding of the domestication and socialization process, and improved welfare for feral cats undergoing adoption. Previous studies have used conflicting classification schemes for cat vocalizations, often relying on onomatopoeic or popular descriptions of call types (e.g., "miow"). We studied the vocalizations of 13 unaltered domestic cats that complied with our behavioral definition used to distinguish feral cats from domestic. A total of 71 acoustic units were extracted and visually analyzed for the construction of a hierarchical classification of vocal sounds, based on acoustic properties. We identified 3 major categories (tonal, pulse, and broadband) that further breakdown into 8 subcategories, and show a high degree of reliability when sounds are classified blindly by independent observers (Fleiss' Kappa K = 0.863). Due to the limited behavioral contexts in this study, additional subcategories of cat vocalizations may be identified in the future, but our hierarchical classification system allows for the addition of new categories and new subcategories as they are described. This study shows that cat vocalizations are diverse and complex, and provides an objective and reliable classification system that can be used in future studies. PMID- 29491993 TI - Howl variation across Himalayan, North African, Indian, and Holarctic wolf clades: tracing divergence in the world's oldest wolf lineages using acoustics. AB - Vocal divergence within species often corresponds to morphological, environmental, and genetic differences between populations. Wolf howls are long range signals that encode individual, group, and subspecies differences, yet the factors that may drive this variation are poorly understood. Furthermore, the taxonomic division within the Canis genus remains contended and additional data are required to clarify the position of the Himalayan, North African, and Indian wolves within Canis lupus. We recorded 451 howls from the 3 most basal wolf lineages-Himalayan C. lupus chanco-Himalayan haplotype, North African C. lupus lupaster, and Indian C. lupus pallipes wolves-and present a howl acoustic description within each clade. With an additional 619 howls from 7 Holarctic subspecies, we used a random forest classifier and principal component analysis on 9 acoustic parameters to assess whether Himalayan, North African, and Indian wolf howls exhibit acoustic differences compared to each other and Holarctic wolf howls. Generally, both the North African and Indian wolf howls exhibited high mean fundamental frequency (F0) and short duration compared to the Holarctic clade. In contrast, the Himalayan wolf howls typically had lower mean F0, unmodulated frequencies, and short howls compared to Holarctic wolf howls. The Himalayan and North African wolves had the most acoustically distinct howls and differed significantly from each other and to the Holarctic wolves. Along with the influence of body size and environmental differences, these results suggest that genetic divergence and/or geographic distance may play an important role in understanding howl variation across subspecies. PMID- 29491994 TI - Adult meerkats modify close call rate in the presence of pups. AB - In animals, signaling behavior is often context-dependent, with variation in the probability of emitting certain signals dependent on fitness advantages. Senders may adjust signaling rate depending on receiver identity, presence of audiences, or noise masking the signal, all of which can affect the benefits and costs of signal production. In the cooperative breeding meerkat Suricata suricatta, group members emit soft contact calls, termed as "close calls", while foraging in order to maintain group cohesion. Here, we investigated how the close calling rate during foraging was affected by the presence of pups, that produce continuous, noisy begging calls as they follow older group members. Adults decreased their overall close call rate substantially when pups were foraging with the group in comparison to periods when no pups were present. We suggest this decrease was likely due to a masking effect of the loud begging calls, which makes the close call function of maintaining group cohesion partly redundant as the centrally located begging calls can be used instead to maintain cohesion. There was some support that adults use close calls strategically to attract specific pups based on fitness advantages, that is, as the philopatric sex, females should call more than males and more to female pups than male pups. Dominant females called more than dominant males when a pup was in close proximity, while subordinates showed no sex-based differences. The sex of the nearest pup did not affect the calling rate of adults. The study shows that meerkats modify their close call production depending on benefits gained from calling and provides an example of the flexible use of one calling system in the presence of another, here contact calls versus begging calls, within the same species. PMID- 29491995 TI - Social interactions in a solitary carnivore. AB - In total, 177 of 245 terrestrial carnivores are described as solitary, and much of carnivore ecology is built on the assumptions that interactions between adult solitary carnivores are rare. We employed Global Positioning System (GPS) technology and motion-triggered cameras to test predictions of land-tenure territoriality and the resource dispersion hypothesis in a territorial carnivore, the puma Puma concolor. We documented 89 independent GPS interactions, 60% of which occurred at puma kills (n = 53), 59 camera interactions, 11 (17%) of which captured courtship behaviors, and 5 other interactions (1 F-F, 3 M-F, and 1 M-M). Mean minimum weekly contact rates were 5.5 times higher in winter, the season when elk Cervus elaphus were aggregated at lower elevations and during which puma courtship primarily occurred. In winter, contacts rates were 0.6 +/- 0.3 (standard deviation (SD)) interactions/week vs. 0.1 +/- 0.1 (SD) interactions/week during summer. The preponderance of interactions at food sources supported the resource dispersion hypothesis, which predicts that resource fluxes can explain temporary social behaviors that do not result in any apparent benefits for the individuals involved. Conspecific tolerance is logical when a prey is so large that the predator that killed it cannot consume it entirely, and thus, the costs of tolerating a conspecific sharing the kill are less than the potential costs associated with defending it and being injured. Puma aggregations at kills numbered as high as 9, emphasizing the need for future research on what explains tolerance among solitary carnivores. PMID- 29491996 TI - Spatially biased dispersal of acorns by a scatter-hoarding corvid may accelerate passive restoration of oak habitat on California's largest island. AB - Scatter hoarding by corvids (crows, jays, magpies, and nutcrackers) provides seed dispersal for many large-seeded plants, including oaks and pines. When hoarding seeds, corvids often choose nonrandom locations throughout the landscape, resulting in differential survival of seeds. In the context of habitat restoration, such disproportional storing of seeds in areas suitable for germination and establishment can accelerate expansion and recovery of large seeded tree populations and their associated ecosystems. Here, we investigate the spatial preferences of island scrub jays Aphelocoma insularis during scatter hoarding of acorns (Quercus spp.) on Santa Cruz Island. We use a large behavioral data set on the birds' behavior in combination with seedling surveys and spatial analysis to determine whether 1) island scrub jays disproportionally cache seeds in specific habitat types, and 2) whether the preferred habitat type is suitable for oak regeneration. Our results show that the jays nonrandomly cache acorns across the landscape; they use chaparral and coastal sage scrub disproportionally while avoiding open and grassy areas. The areas used most often for caching were also the areas with the highest oak seedling densities. We discuss the potential role of these findings for the recovery of Santa Cruz Island's oak habitat since the 1980s. PMID- 29491997 TI - Predator-induced phenotypic plasticity of shape and behavior: parallel and unique patterns across sexes and species. AB - Phenotypic plasticity is often an adaptation of organisms to cope with temporally or spatially heterogenous landscapes. Like other adaptations, one would predict that different species, populations, or sexes might thus show some degree of parallel evolution of plasticity, in the form of parallel reaction norms, when exposed to analogous environmental gradients. Indeed, one might even expect parallelism of plasticity to repeatedly evolve in multiple traits responding to the same gradient, resulting in integrated parallelism of plasticity. In this study, we experimentally tested for parallel patterns of predator-mediated plasticity of size, shape, and behavior of 2 species and sexes of mosquitofish. Examination of behavioral trials indicated that the 2 species showed unique patterns of behavioral plasticity, whereas the 2 sexes in each species showed parallel responses. Fish shape showed parallel patterns of plasticity for both sexes and species, albeit males showed evidence of unique plasticity related to reproductive anatomy. Moreover, patterns of shape plasticity due to predator exposure were broadly parallel to what has been depicted for predator-mediated population divergence in other studies (slender bodies, expanded caudal regions, ventrally located eyes, and reduced male gonopodia). We did not find evidence of phenotypic plasticity in fish size for either species or sex. Hence, our findings support broadly integrated parallelism of plasticity for sexes within species and less integrated parallelism for species. We interpret these findings with respect to their potential broader implications for the interacting roles of adaptation and constraint in the evolutionary origins of parallelism of plasticity in general. PMID- 29491998 TI - A longitudinal network analysis of social dynamics in rooks corvus frugilegus: repeated group modifications do not affect social network in captive rooks. AB - Numerous studies have investigated the remarkable variation of social features and the resulting structures across species. Indeed, relationships are dynamic and vary in time according to various factors such as environmental conditions or individuals attributes. However, few studies have investigated the processes that stabilize the structures within a given species, and the behavioral mechanisms that ensure their coherence and continuity across time. Here, we used a dynamic actor-based model, RSiena, to investigate the consistency of the temporal dynamic of relationships of a group of captive rooks facing recurrent modifications in group composition (i.e., the loss and introduction of individuals). We found that changes in relationships (i.e., formation and removal) followed consistent patterns regardless of group composition and sex-ratio. Rooks preferentially interacted with paired congeners (i.e., unpopular attachment) and were more likely to form relationships with individuals bonded to a current social partner (i.e., "friends of friends", or triadic closure). The sex of individuals had no effect on the dynamic of relationships. This robust behavioral mechanisms formed the basis of inter-connected networks, composed of sub-structures of individuals emerging from the enmeshment of dyadic and triadic motifs. Overall, the present study reveals crucial aspects of the behavioral mechanisms shaping rooks social structure, suggesting that rooks live in a well-integrated society, going far beyond the unique monogamous pair-bond. PMID- 29491999 TI - Phenotypic plasticity can explain evolution of sympatric polymorphism in the hairy snail Trochulus hispidus (Linnaeus, 1758). AB - Morphological variation of snails from the genus Trochulus is so huge that their taxonomy is unclear. The greatest variability concerns forms hispidus and sericeus/plebeius, which are often considered as separate species. To evidence the species barriers, we carried out crossbreeding experiments between these two sympatric morphs. Moreover, we compared the shell morphology of laboratory-bred offspring with their wild parents to test if the variation can be explained by the phenotypic plasticity model. We found that the two Trochulus morphs show no reproductive barriers. The fecundity rates, the mean clutch size, and F1 viability observed for all crosses were not significantly different. In hybrid crosses (in F2 generation), we also recorded reproduction compatibility, similar fecundity, and hatching success as in their parents. Accordingly, phylogenetic analyses revealed the significant grouping of sequences from these different morphs and supported no constrains in reproduction between them. Comparison of shell morphology between wild and laboratory samples showed that various characters appeared highly plastic. The average shell shape of the hispidus morph changed significantly from flat with wide umbilicus to elevated with narrower umbilicus such as in the sericeus/plebeius morph. All these findings indicate that the examined morphs do not represent separate biological species and the evolutionary process is not advanced enough to separate their genetic pool. Therefore, phenotypic plasticity has played a significant role in the evolution of Trochulus shell polymorphism. The two morphs can evolve independently in separate phylogenetic lineages under the influence of local environmental conditions. PMID- 29492000 TI - Orbit orientation in didelphid marsupials (Didelphimorphia: Didelphidae). AB - Usually considered a morphologically conservative group, didelphid marsupials present considerable variation in ecology and body size, some of which were shown to relate to morphological structures. Thus, changes on orbit morphology are likely and could be related to that variation. We calculated orbit orientation in 873 specimens of 16 Didelphidae genera yielding estimates of orbits convergence (their position relative to midsagittal line) and verticality (their position relative to frontal plane). We then compared similarities in these variables across taxa to ecological, morphological and phylogenetic data to evaluate the influencing factors on orbit orientation in didelphids. We found an inverse relation between convergence and verticality. Didelphids orbits have low verticality but are highly convergent, yet orbit orientation differs significantly between taxa, and that variation is related to morphological aspects of the cranium. Rostral variables are the only morphological features correlated with orbit orientation: increasing snout length yields more convergent orbits, whereas increase on snout breadth imply in more vertical orbits. Size and encephalization quotients are uncorrelated with orbit orientation. Among ecological data, diet showed significant correlation whereas locomotion is the factor that less affects the position of orbits. Phylogeny is uncorrelated to any orbital parameters measured. Ecological factors seemingly play a more important role on orbit orientation than previously expected, and differentiation on orbit orientation seems to be more functional than inherited. Thus, despite the apparent homogeneity on didelphid morphology, there is subtle morphological variability that may be directly related to feeding behavior. PMID- 29492001 TI - Animal vocal communication: function, structures, and production mechanisms. PMID- 29492002 TI - Affairs happen-to whom? A study on extrapair paternity in common nightingales. AB - Most birds engage in extrapair copulations despite great differences across and within species. Besides cost and benefit considerations of the two sex environmental factors have been found to alter mating strategies within or between populations and/or over time. For socially monogamous species, the main advantage that females might gain from mating with multiple males is probably increasing their offspring's genetic fitness. Since male (genetic) quality is mostly not directly measurable for female birds, (extrapair) mate choice is based on male secondary traits. In passerines male song is such a sexual ornament indicating male phenotypic and/or genetic quality and song repertoires seem to affect female mate choice in a number of species. Yet their role in extrapair mating behavior is not well understood. In this study, we investigated the proportion of extrapair paternity (EPP) in a population of common nightingales Luscinia megarhynchos. We found that EPP rate was rather high (21.5% of all offspring tested) for a species without sexual dimorphism and high levels of paternal care. Furthermore, the occurrence of EPP was strongly related to the spatial distribution of male territories with males settling in densely occupied areas having higher proportions of extrapair young within their own brood. Also, song repertoire size affected EPP: here larger repertoires of social mates were negatively related to the probability of being cuckolded. When directly comparing repertoires sizes of social and extrapair mates, extrapair mates tended to have larger repertoires. We finally discuss our results as a hint for a flexible mating strategy in nightingales where several factors-including ecological as well as male song features-need to be considered when studying reproductive behavior in monogamous species with complex song. PMID- 29492003 TI - Calling underwater is a costly signal: size-related differences in the call rates of Antarctic leopard seals. AB - It is proposed that where sexually selected vocal communication is an honest signal, the call production rate is predicted to change throughout the breeding season. Male leopard seals call underwater for many hours each day over their three- to four-month breeding season, and it is hypothesized that a decrease in calling rate would be associated with the declining body condition of smaller males. The calling rates of leopard seals were measured (N = 49 recordings) and compared between seals of different size classes throughout the breeding season. Male leopard seals produce their calls at more stable rates as they become larger. In this study, larger male leopard seals adopted a strategy of consistent underwater calling throughout the breeding season, whereas there was a breakdown in the calling stereotypy of the smaller males at its height. Toward the end of the breeding season, the smaller seals produced fewer calls in shortened calling bouts, and they took more rest periods. Therefore, underwater calling may represent an honest signal in the leopard seal. For marine mammals that call underwater, the production of repetitive sequences advertises the breath-holding ability of the caller to the listeners, and this ability may be related to male stamina and endurance, thus representing an honest signal that could be widespread in other species. PMID- 29492004 TI - Humans identify negative (but not positive) arousal in silver fox vocalizations: implications for the adaptive value of interspecific eavesdropping. AB - The ability to identify emotional arousal in heterospecific vocalizations may facilitate behaviors that increase survival opportunities. Crucially, this ability may orient inter-species interactions, particularly between humans and other species. Research shows that humans identify emotional arousal in vocalizations across multiple species, such as cats, dogs, and piglets. However, no previous study has addressed humans' ability to identify emotional arousal in silver foxes. Here, we adopted low- and high-arousal calls emitted by three strains of silver fox-Tame, Aggressive, and Unselected-in response to human approach. Tame and Aggressive foxes are genetically selected for friendly and attacking behaviors toward humans, respectively. Unselected foxes show aggressive and fearful behaviors toward humans. These three strains show similar levels of emotional arousal, but different levels of emotional valence in relation to humans. This emotional information is reflected in the acoustic features of the calls. Our data suggest that humans can identify high-arousal calls of Aggressive and Unselected foxes, but not of Tame foxes. Further analyses revealed that, although within each strain different acoustic parameters affect human accuracy in identifying high-arousal calls, spectral center of gravity, harmonic-to-noise ratio, and F0 best predict humans' ability to discriminate high-arousal calls across all strains. Furthermore, we identified in spectral center of gravity and F0 the best predictors for humans' absolute ratings of arousal in each call. Implications for research on the adaptive value of inter-specific eavesdropping are discussed. PMID- 29492005 TI - How small could a pup sound? The physical bases of signaling body size in harbor seals. AB - Vocal communication is a crucial aspect of animal behavior. The mechanism which most mammals use to vocalize relies on three anatomical components. First, air overpressure is generated inside the lower vocal tract. Second, as the airstream goes through the glottis, sound is produced via vocal fold vibration. Third, this sound is further filtered by the geometry and length of the upper vocal tract. Evidence from mammalian anatomy and bioacoustics suggests that some of these three components may covary with an animal's body size. The framework provided by acoustic allometry suggests that, because vocal tract length (VTL) is more strongly constrained by the growth of the body than vocal fold length (VFL), VTL generates more reliable acoustic cues to an animal's size. This hypothesis is often tested acoustically but rarely anatomically, especially in pinnipeds. Here, we test the anatomical bases of the acoustic allometry hypothesis in harbor seal pups Phoca vitulina. We dissected and measured vocal tract, vocal folds, and other anatomical features of 15 harbor seals post-mortem. We found that, while VTL correlates with body size, VFL does not. This suggests that, while body growth puts anatomical constraints on how vocalizations are filtered by harbor seals' vocal tract, no such constraints appear to exist on vocal folds, at least during puppyhood. It is particularly interesting to find anatomical constraints on harbor seals' vocal tracts, the same anatomical region partially enabling pups to produce individually distinctive vocalizations. PMID- 29492006 TI - Modeling individual vocal differences in group-living lemurs using vocal tract morphology. AB - Vocal individuality is widespread in social animals. Individual variation in vocalizations is a prerequisite for discriminating among conspecifics and may have facilitated the evolution of large complex societies. Ring-tailed lemurs Lemur catta live in relatively large social groups, have conspicuous vocal repertoires, and their species-specific utterances can be interpreted in light of source-filter theory of vocal production. Indeed, their utterances allow individual discrimination and even recognition thanks to the resonance frequencies of the vocal tract. The purpose of this study is to determine which distinctive vocal features can be derived from the morphology of the upper vocal tract. To accomplish this, we built computational models derived from anatomical measurements collected on lemur cadavers and compared the results with the spectrographic output of vocalizations recorded from ex situ live individuals. Our results demonstrate that the morphological variation of the ring-tailed lemur vocal tract explains individual distinctiveness of their species-specific utterances. We also provide further evidence that vocal tract modeling is a powerful tool for studying the vocal output of non-human primates. PMID- 29492007 TI - Candidate genes have sex-specific effects on timing of spring migration and moult speed in a long-distance migratory bird. AB - The timing of major life-history events, such as migration and moult, is set by endogenous circadian and circannual clocks, that have been well characterized at the molecular level. Conversely, the genetic sources of variation in phenology and in other behavioral traits have been sparsely addressed. It has been proposed that inter-individual variability in the timing of seasonal events may arise from allelic polymorphism at phenological candidate genes involved in the signaling cascade of the endogenous clocks. In this study of a long-distance migratory passerine bird, the willow warbler Phylloscopus trochilus, we investigated whether allelic variation at 5 polymorphic loci of 4 candidate genes (Adcyap1, Clock, Creb1, and Npas2), predicted 2 major components of the annual schedule, namely timing of spring migration across the central Mediterranean sea and moult speed, the latter gauged from ptilochronological analyses of tail feathers moulted in the African winter quarters. We identified a novel Clock gene locus (Clock region 3) showing polyQ polymorphism, which was however not significantly associated with any phenotypic trait. Npas2 allele size predicted male (but not female) spring migration date, with males bearing longer alleles migrating significantly earlier than those bearing shorter alleles. Creb1 allele size significantly predicted male (but not female) moult speed, longer alleles being associated with faster moult. All other genotype-phenotype associations were statistically non-significant. These findings provide new evidence for a role of candidate genes in modulating the phenology of different circannual activities in long-distance migratory birds, and for the occurrence of sex-specific candidate gene effects. PMID- 29492008 TI - Limited proteomic response in the marine snail Melarhaphe neritoides after long term emersion. AB - Rocky intertidal organisms are commonly exposed to environmental gradients, promoting adaptations to these conditions. Emersion time varies along the intertidal range and in the supralittoral zone is frequently larger than a single tidal cycle, even lasting for weeks. The planktonic-dispersing gastropod Melarhaphe neritoides is a common species of the high shore, adapted to reduce water loss in order to survive during long-term emersion. In this study, we investigated the molecular response, at the proteome level, of M. neritoides collected in high-shore tide pools to a series of emersion periods, from 8 to 24 days, in laboratory conditions. We compared this response to individuals maintained submerged during this period, because this was their original habitat. We also included a reversion treatment in the study, in which emersed individuals were returned to the submerged conditions. Although we detected an increase in overall protein concentration with longer emersion periods, contrary to general expectation, the two dimensional electrophoresis (2DE)-based proteomic analysis did not show significant differences between the treatments at the level of individual protein spots, even after an emersion period of 24 days. Our results suggest that the metabolism remains unaltered independent of the treatment carried out or the changes are very subtle and therefore difficult to detect with our experimental design. We conclude that M. neritoides could be equally adapted to emersion and submersion without drastic physiological changes. PMID- 29492009 TI - The endemic Patagonian vespertilionid assemblage is a depauperate ecomorphological vicariant of species-rich neotropical assemblages. AB - Vespertilionidae is the most diverse chiropteran family, and its diversity is concentrated in warm regions of the World; however, due to physiological and behavioral adaptations, these bats also dominate bat faunas in temperate regions. Here we performed a comparative study of vespertilionid assemblages from two broad regions of the New World, the cold and harsh Patagonia, versus the remaining temperate-to-subtropical, extra-Patagonian eco-regions of the South American Southern Cone. We took an ecomorphological approach and analyzed the craniodental morphological structure of these assemblages within a phylogenetic framework. We measured 17 craniodental linear variables from 447 specimens of 22 currently recognized vespertilionid species of the study regions. We performed a multivariate analysis to define the morphofunctional space, and calculated the pattern and degree of species packing for each assemblage. We assessed the importance of phylogeny and biogeography, and their impact on depauperate (Patagonian) versus rich (extra-Patagonian) vespertilionid assemblages as determinants of morphospace structuring. We implemented a sensitivity analysis associated to small samples of rare species. The morphological patterns were determined chiefly by the evolutionary history of the family. The Patagonian assemblage can be described as a structurally similar but comparatively depauperate ecomorphological version of those assemblages from neighboring extra Patagonian eco-regions. The Patagonian assemblage seems to have formed by successively adding populations from Northern regions that eventually speciated in the region, leaving corresponding sisters (vicariants) in extra-Patagonian eco regions that continued to be characteristically richer. Despite being structurally akin, degree of species packing in Patagonia was comparatively very low, which may reflect the effect of limited dispersal success into a harsh region for bat survival. PMID- 29492010 TI - Factors influencing wild boar damage to agricultural crops in Sardinia (Italy). AB - Crop damage by wildlife is a frequent source of human-wildlife conflict. Understanding which factors increase the risk of damage is crucial to the development of effective management strategies. The aims of this study were to provide a general description of agricultural damage caused by wild boar Sus scrofa meridionalis over a 7-year period in North-eastern Sardinia (Mediterranean Italy), and to formulate a predictive model of damage risk. We recorded a total of 221 cases of wild boar damage, with economic losses amounting to 483,982 Euros. Damage events mostly involved vineyards, meadows and oat fields, and were characterized by a peak incidence in summer and early autumn, and a minimum in spring. Damaged fields were characterized by an increasing presence of permanent crops, a decreasing presence of woodlands, maquis and urban areas, and a reduced distance from shelter areas (forests and shrublands). The analysis of spatiotemporal variation of boar-induced damage and the identification of factors that augment the risk of damage provides essential information for contributing to the development of a more effective plan for managing wild boar populations. PMID- 29492011 TI - Long-term data from a small mammal community reveal loss of diversity and potential effects of local climate change. AB - Climate change affects distribution and persistence of species. However, forecasting species' responses to these changes requires long-term data series that are often lacking in ecological studies. We used 15 years of small mammal trapping data collected between 1978 and 2015 in 3 areas at Donana National Park (southwest Spain) to (i) describe changes in species composition and (ii) test the association between local climate conditions and size of small mammal populations. Overall, 5 species were captured: wood mouse Apodemus sylvaticus, algerian mouse Mus spretus, greater white-toothed shrew Crocidura russula, garden dormouse Eliomys quercinus, and black rat Rattus rattus. The temporal pattern in the proportion of captures of each species suggests that the small mammal diversity declined with time. Although the larger species (e.g., E. quercinus), better adapted to colder climate, have disappeared from our trapping records, M. spretus, a small species inhabiting southwest Europe and the Mediterranean coast of Africa, currently is almost the only trapped species. We used 2-level hierarchical models to separate changes in abundance from changes in probability of capture using records of A. sylvaticus in all 3 areas and of M. spretus in 1. We found that heavy rainfall and low temperatures were positively related to abundance of A. sylvaticus, and that the number of extremely hot days was negatively related to abundance of M. spretus. Despite other mechanisms are likely to be involved, our findings support the importance of climate for the distribution and persistence of these species and raise conservation concerns about potential cascading effects in the Donana ecosystem. PMID- 29492012 TI - Historical relationships of areas of endemism of the Brazilian Atlantic rain forest: a cladistic biogeographic analysis of harvestman taxa (Arachnida: Opiliones). AB - Based on a cladistic biogeographic analysis of 6 species-level phylogenies of harvestman taxa, we searched for congruence in the historical relationships of 12 areas of endemism of the Brazilian Atlantic Rain Forest. We constructed general area cladograms using Primary Brooks Parsimony Analysis (BPA), BPA of nodes, and paralogy-free subtree analysis. These analyses resulted in 6 general area cladograms, that allow to infer a general pattern of the relationships among areas of endemism from the Brazilian Atlantic Rain Forest. Northern areas resulted related basally showing main disjunctions at the Doce River Valley and Todos os Santos Bay/Sao Francisco River Valley. The remaining areas of endemism were included in a southern and a southeastern block, separated by the Ribeira do Iguape Valley. Incongruence Length Differences tests showed no significant incongruence among the resulting cladograms and other matrix partitions. We concluded that tectonism and ancient marine transgressions were the probable processes responsible for the main disjunctions, whereas Neogene refugia seem to have caused the more recent disjunctions. The general pattern and redundancy in area relationships suggest a model of main reiterative barriers in diversification at multiple times for the evolution of the Atlantic Rain Forest. The renewal of cladistic biogeography and the search for common biogeographic patterns are discussed. PMID- 29492013 TI - Physical separation from the mate diminishes male's attentiveness towards other females: a study in monogamous prairie voles Microtus ochrogaster. AB - We tested whether continuous cohabitation in monogamous voles affects the mated male's attentiveness to his breeding partner versus another female. Each male was housed in a 3-chamber apparatus with a Focal female (FF) and a Control female (CF) for 13 days then placed in a T-maze to assess his attentiveness to and memory of those females. The Distal male remained physically separated from both females, but received their distal cues. The Separate male cohabited with the FF for 3 days then remained physically separated from both females. The Disrupt male's continuous cohabitation with the FF was disrupted by having him physically separated from her after 10 days and placed with the CF for the last 3 days. The Continuous male cohabited continuously with the FF for 13 days. With females in the T-maze, the Separate and Disrupt males spent more time near the FF's box and the Disrupt males spent more time manipulating the FF's box than the CF's box. The Separate males groomed themselves more when near the FF's box than the CF's box. The Distal and Continuous males' attentiveness to the two females did not differ. Results suggest that physical distance from the partner may reduce male's attentiveness toward other potential mates. Prairie voles might be similar to socially monogamous primates in using tactile cues as a signal for maintaining their social bonds. PMID- 29492014 TI - Females choose gentle, but not healthy or macho males in Campbell dwarf hamsters (Phodopus campbelli Thomas 1905). AB - Androgen-dependent male sexual traits (STs) as well as immunocompetence are theoretically assumed to be key indicators of a male's quality for the mate choosing female. We studied mate choice by sexually motivated (SM) females of Campbell's dwarf hamsters. Females chose between 2 tethered male siblings that differed in expression of STs. Males were unrelated to the female and able to contact and copulate with her. In both males, we measured sex-related morphology of body mass, mid-ventral specific skin gland, ano-genital distance, and external testicular diameter. We also estimated levels of blood testosterone and cortisol, specific T- and B-cell immune responses to antigens, as well as aggressive and sexual dominance in sibling males through additional encounter experiments with another SM female (male sibs could freely compete for the female). We found that SM females chose a partner among 2 male sibs and spent over 80% of their time on average with the preferred male compared with the non-preferred one. Her choice was not associated with the first visit of the chosen male, with a higher expression of sex-related traits, higher levels of blood testosterone, or with aggressive dominance. The choice was not associated with the intensity of T-cell immune response to phitohemagglutinin (PHA). Instead there was a tendency for a negative relationship with the expression of STs and B-cell response to the antigen challenge. The only character that unambiguously influenced female choice was the non-aggressive male to female grooming during sexual contact. There was no difference in breeding success between preferred and non-preferred males paired with virgin females. PMID- 29492015 TI - Active explorers show low learning performance in a social insect. AB - An intriguing question in behavioral biology is whether consistent individual differences (called animal personalities) relate to variation in cognitive performance because commonly measured personality traits may be associated with risk-reward trade-offs. Social insects, whose learning abilities have been extensively characterized, show consistent behavioral variability, both at colony and at individual level. We investigated the possible link between personality traits and learning performance in the carpenter ant Camponotus aethiops. Exploratory activity, sociability, and aggression were assessed twice in ant foragers. Behaviors differed among individuals, they were partly repeatable across time and exploratory activity correlated positively with aggression. Learning abilities were quantified by differential conditioning of the maxilla labium extension response, a task that requires cue perception and information storage. We found that exploratory activity of individual ants significantly predicted learning performance: "active-explorers" were slower in learning the task than "inactive-explorers". The results suggest for the first time a link between a personality trait and cognitive performance in eusocial insects, and that the underlying individual variability could affect colony performance and success. PMID- 29492016 TI - Experimental manipulation of size and shape of tail spots and sexual selection in barn swallows. AB - Barn swallows Hirundo rustica have white spots on their tail feathers, and they have been hypothesized to be a handicap because white spots are prone to feather breakage, ectoparasites are disproportionately common in white spots, and size of white spots increases with tail length. Here I test for attractiveness of narrow and long tail spots by manipulation of their shape while using complete painting of spots and an absence of treatment as a control. Female barn swallows are known to differentially invest in reproduction when mated to attractive males. Spot manipulation took place during laying of the first clutch, and there were no effects of treatment on clutch size or brood size of first or second broods. In contrast, the incidence of second clutches and the total number of eggs and fledglings produced during the breeding season was larger in males with painting of the side of tail spots rather than painting of the tip of spots, painting of entire spots, or no treatment. These findings are consistent with the hypothesis that it is the shape rather than the size of tail spots that affects differential reproductive effort by female barn swallows. PMID- 29492017 TI - Male reproductive suppression: not a social affair. AB - In the animal kingdom there are countless strategies via which males optimize their reproductive success when faced with male-male competition. These male strategies typically fall into two main categories: pre- and post-copulatory competition. Within these 2 categories, a set of behaviors, referred to as reproductive suppression, is known to cause inhibition of reproductive physiology and/or reproductive behavior in an otherwise fertile individual. What becomes evident when considering examples of reproductive suppression is that these strategies conventionally encompass reproductive interference strategies that occur between members of a hierarchical social group. However, mechanisms aimed at impairing a competitor's reproductive output are also present in non-social animals. Yet, current thinking emphasizes the importance of sociality as the primary driving force of reproductive suppression. Therefore, the question arises as to whether there is an actual difference between reproductive suppression strategies in social animals and equivalent pre-copulatory competition strategies in non-social animals. In this perspective paper we explore a broad taxonomic range of species whose individuals do not repeatedly interact with the same individuals in networks and yet, depress the fitness of rivals. Examples like alteration of male reproductive physiology, female mimicry, rival spermatophore destruction, and cementing the rival's genital region in non-social animals, highlight that male pre-copulatory reproductive suppression and male pre copulatory competition overlap. Finally, we highlight that a distinction between male reproductive interference in animals with and without a social hierarchy might obscure important similarities and does not help to elucidate why different proximate mechanisms evolved. We therefore emphasize that male reproductive suppression need not be restricted to social animals. PMID- 29492018 TI - Invasive rats strengthen predation pressure on bird eggs in a South Pacific island rainforest. AB - Invasive rats (Rattus spp.) are known to have pervasive impacts on island birds, particularly on their nesting success. To conserve or restore bird populations, numerous invasive rat control or eradication projects are undertaken on islands worldwide. However, such projects represent a huge investment and the decision making process requires proper assessment of rat impacts. Here, we assessed the influence of two sympatric invasive rats (Rattus rattus and R. exulans) on native bird eggs in a New Caledonian rainforest, using artificial bird-nest monitoring. A total of 178 artificial nests containing two eggs of three different sizes were placed either on the ground or 1.5 m high and monitored at the start of the birds' breeding season. Overall, 12.4% of the nests were depredated during the first 7 days. At site 1, where nests were monitored during 16 days, 41.8% of the nests were depredated. The main predator was the native crow Corvus moneduloides, responsible for 62.9% of the overall predation events. Rats were responsible for only 22.9% of the events, and ate only small and medium eggs at both heights. Our experiment suggests that in New Caledonia, predation pressure by rats strengthens overall bird-nest predation, adding to that by native predators. Experimental rat control operations may allow reduced predation pressure on nests as well as the recording of biodiversity responses after rat population reduction. PMID- 29492019 TI - Prey reduce risk-taking and abundance in the proximity of predators. AB - Prey have evolved anti-predator defences that reduce or eliminate the risk of predation. Predators often reproduce at specific sites over many years causing permanent threats to local prey species. Such prey may respond by moving elsewhere thereby reducing local population abundance, or they may stay put and adjust their behavior to the presence of predators. We tested these predictions by analyzing population abundance and anti-predator behavior within 100 m of and 500 m away from nests of sparrowhawks Accipiter nisus and goshawks A. gentilis for 80 species of birds. Population abundance of prey was reduced by 11% near goshawk nests and by 15% near sparrowhawk nests when compared with nearby control sites in similar habitats. Flight initiation distance (FID) of prey, estimated as the distance at which birds took flight when approached by a human, increased by 50% in the presence of hawk nests, providing evidence of adjustment of anti predator behavior to prevailing risks of predation. Susceptibility to predation was estimated as log transformed abundance of the observed number of prey items obtained from prey remains collected around nests minus log transformed expected number of prey according to point counts of breeding birds. FID increased from 10 to 46 m with increasing susceptibility of prey species to predation by the goshawk and from 12 to 15 m with increasing susceptibility of prey species to predation by the sparrowhawk. These findings suggest that prey adjust their distribution and anti-predator behavior to the risk of predation. PMID- 29492020 TI - Nesting tree characteristics of heronry birds of urban ecosystems in peninsular India: implications for habitat management. AB - Wetland ecosystems, particularly the mangrove forest, are the primary wild habitat of heronry birds. However, urban ecosystems have become a favorite breeding habitat of these birds. To provide inputs into the habitat management for conservation of these birds, we investigated the quantitative and qualitative characteristics of nesting trees of heronry birds in the urban environment of the North Kerala region of peninsular India. Census on nesting trees was done in 3 major microhabitats of the urban ecosystem: avenues of national highways and towns, nonresidential plots, and residential areas apart from the mangrove islets in the peri-urban locality. The study found that 174 trees of 22 species hosted 1,928 heronry bird nests in the urban habitats; mangrove forests, although plentiful in the study area, hosted only about 20% of the total nests encountered in the study. Rain trees Samanea saman (43.7%) were the most available nesting tree. The greatest number of nests and nesting trees were encountered on the roads of urban areas, followed by nonresidential areas and residential areas. The differences in the observed frequencies of nesting trees in 3 microhabitats and in 3 types of roads (national highways > state highways > small pocket road) were significant. Canopy spread, girth size, and quality of the trees predicted the tree selection of the heronry birds in urban environments. Therefore, we recommend proper management and notification of the identified nesting trees as protected sites for the conservation of herorny birds. PMID- 29492021 TI - Loss of largest and oldest individuals of the Montpellier snake correlates with recent warming in the southeastern Iberian Peninsula. AB - The effects of climate change on organisms are now being extensively studied in many different taxa. However, the variation in body size, usually shrinkage in response to increasing temperature, has received little attention regarding to reptiles. During past periods of global warming, many organisms shrank in size, and current evidence and experiments manipulating temperature have shown a biomass decrease in some organisms with increasing temperatures. Here we test whether the body size of the Montpellier snake Malpolon monspessulanus from the southeastern Iberian Peninsula is changing and correlated with the increasing temperature in this region during a 39-year period (1976-2014). We measured the snout-vent length (SVL) of vouchers in scientific collections to check for trends in adult body size at the population level in relation with temperature, while controlling for the age of the individuals (estimated by skeletochronology, n =141). Given the great ontogenetic variation in body size of the study species, we categorized age in 3 classes: "young adults" (under 5 years old), "intermediate adults" (from 5 to 7 years old), and "old adults" (from 8 to 14 years old). By means of linear mixed models, we found a negative relationship between SVL of "old adults" and average annual temperature in the region during the lifetime of each individual. Our results indicate that largest and oldest individuals of the Montpellier Snake, that is, males because of strong sexual size dimorphism in this species, disappeared from the study population, and suggest that it occurred in response to rising environmental temperature. PMID- 29492022 TI - The origin of invasion of an alien frog species in Tibet, China. AB - Identifying the origins of alien species has important implications for effectively controlling the spread of alien species. The black-spotted frog Pelophylax nigromaculatus, originally from East Asia, has become an alien species on the Tibetan Plateau (TP). In this study, we collected 300 individuals of P. nigromaculatus from 13 native regions and 2 invasive regions (including Nyingchi and Lhasa) on the TP. To identify the source region of the TP introductions, we sequenced portions of the mitochondrial cyt b gene. We sequenced a ~600-bp portion of the mitochondrial cyt b gene to identify 69 haplotypes (124 polymorphic sites) in all sampled populations. According to the network results, we suggest that the P. nigromaculatus found on the TP was most likely originated from Chongqing by human introduction. Furthermore, we found that the genetic diversity was significantly lower for invasive than for native sites due to founder effects. Our study provides genetic evidence that this alien species invaded the cold environment of high elevations and expanded the distribution of P. nigromaculatus in China. PMID- 29492023 TI - Islands conserve high species richness and areas of endemism of Hormaphidinae aphids. AB - Patterns of biodiversity and endemism are important and form the foundation for biogeography and conservation studies. Hormaphidinae is an aphid group mainly distributed in the Sino-Japanese, Oriental, and Nearctic zoogeographic realms. To infer the areas of endemism of Hormaphidinae aphids in the Sino-Japanese and Oriental realms, we employed a geographical distribution dataset covering all 225 species in subfamily Hormaphidinae. In total, 1,245 distribution occurrence records for all species were analyzed in addition to the number of species in a certain grid cell to calculate species richness. Two methods (parsimony analysis of endemicity (PAE) and the use of an optimization criterion-NDM/VNDM) using a total of 6 grid sizes were applied to detect possible areas of endemism and to assess the probable effects of the 2 different methods and 6 grid sizes on the results of the patterns of the areas of endemism. The results revealed that islands presented most of the areas with high species richness and endemic species, particularly Japan, Taiwan Island, Java Island, the Malaysian Peninsula, southeast Himalaya, and the Hengduan Mountains. Most of these areas of endemism were located on islands or a peninsula. Islands were therefore shown to play an essential role in facilitating the formation of high species richness and endemism. Different grid sizes directly determined the regions of the areas of endemism, with small grid sizes tending to detect small and discrete areas of endemism and large grid sizes identifying continuous areas of endemism. In terms of the two methods, NDM/VNDM was found to identify more areas of endemism than PAE. PMID- 29492024 TI - Smaller and bolder prey snails have higher survival in staged encounters with the sea star Pisaster giganteus. AB - Temporally consistent individual differences in behavior, also known as animal personality, can have large impacts on individual fitness. Here, we explore the degree to which individual differences in anti-predator response (or boldness) influence survival rates in groups of snails Chlorostoma funebralis when they encounter a predatory sea star Pisaster giganteus. The snail C. funebralis shows consistent individual variation in predator response where some fearful snails actively flee bodies of water occupied by predators whereas bolder snails consistently do not. We show here that bold snails are significantly more likely to survive encounters with a predatory sea star and, somewhat counterintuitively, fearful snails actually suffer higher mortality rates. We also found that smaller snails and those occurring at higher experimental densities experienced higher per capita survival rates. Positive effects of prey boldness on survival are not uncommonly reported in the animal personality literature; however, such results are inconsistent with classic animal personality theory borrowed from the optimal foraging literature. The findings herein add to the growing body of evidence that consistent individual differences in behavior can impact predator-prey interactions and that boldness is potentially under positive predator-driven selection in some systems. PMID- 29492025 TI - Does social context affect boldness in juveniles? AB - Differences in boldness are common between populations or between related species and are discussed as part of individual coping style, personality, or behavioral syndrome. Boldness has been found to be dependent on experience, social, and environmental contexts. The major aim of the present study was to establish an experimental environment that would allow analyzing the risk-taking behavior of 2 competing invasive goby species. Neogobius melanostomus was more active in the absence of a predator Sander lucioperca than N. fluviatilis and clearly spent more time "swimming" and "feeding" than N. fluviatilis. In addition, N. melanostomus was always faster than N. fluviatilis both when leaving the shelter and reaching offered food. Based on the different behaviors recorded, species specific boldness scores were established using a principal component analysis. Although there was no overall difference in boldness scores between the 2 species, both competitive conditions and the effect of the predator played significant roles as factors influencing boldness. Neogobius melanostomus was more affected by the presence/absence of the predator than the social circumstances. Neogobius fluviatilis, on the other hand, was more active and bolder in competitive situations. However, when alone, N. fluviatilis was rather inactive and displayed altogether shy behavior, independent of the presence/absence of the predator. Thus, the study confirms the prediction that there are differences in behavior and behavioral plasticity, and therein predator avoidance strategies, between ecologically similar species of goby living in sympatry. We argue that these differences may be related to differential habitat use of both invasive species that presently dominate the fish community in the Lower Rhine. PMID- 29492026 TI - Group dynamics and relocation decisions of a trap-building predator are differentially affected by biotic and abiotic factors. AB - Most habitats in nature are heterogeneous, incorporating favorable and unfavorable microhabitats for different animals, based on their ecological niche. Unsuitable microhabitats have negative consequences for individual growth and survival. Animals, therefore, should fine-tune their location within the habitat by dispersing away from such microhabitats. We studied the suitability of different constant microhabitat conditions for wormlion larvae, a trap-building predator, tested in groups under laboratory conditions. Wormlions construct pit traps in loose soil and capture small arthropod prey. As wormlions occur in high densities in nature, testing in groups is thus more indicative of their natural behavior than testing individuals. Wormlions responded strongly to biotic conditions-high conspecific density, starvation, and large body mass of conspecifics-by either increasing pit-relocation events or moving away from the microhabitat center to the periphery of the arena, probably opting for a way out. In other instances, individuals increased their distance to the nearest neighbor, thereby changing the spatial pattern toward a more regular pattern, potentially indicating interference competition. The only abiotic condition apparently perceived by wormlions as unsuitable was shallow sand, which led to frequent relocations. The two other abiotic factors-illumination and sand particle size had no observable effect on behavior, although wormlions in nature always occur under shade in fine sand, and prefer both shade and fine sand particle size under laboratory conditions when given a choice. Under the fine spatial scale of the present experiment, biotic factors appear to be more influential than abiotic ones. PMID- 29492027 TI - Inter- and intra-population variability of the protein content of femoral gland secretions from a lacertid lizard. AB - Femoral glands of male lizards produce waxy secretions that are involved in inter and intraspecific chemical communication. The main components of these secretions are proteins and lipids, the latter having been extensively studied and already associated to male quality. On the opposite, the composition and role of proteins are nearly unknown, the only available information coming from few studies on iguanids. These studies got the conclusion that proteins might have a communicative function, notably they could signal individual identity. A generalization of these findings requires the extension of protein analysis to other lizard families, and the primary detection of some patterns of individual variability. Using the common wall lizard Podarcis muralis as a model species, the protein fraction of the femoral pore secretions was investigated to provide the first characterization of this component in a lacertid lizard and to explore its source of variability, as a first step to support the hypothesized communicative role. Samples of proteins from femoral secretions were collected from 6 Italian populations and subjected to 1-dimensional electrophoresis. The binary vector of the band presence/absence was used to define the individual profiles. Protein fraction is found to have a structured pattern, with both an individual and a population component. Although the former supports the potential communicative role of proteins, the latter offers a double interpretation, phylogenetic or environmental, even though the phylogenetic effect seems more likely given the climatic resemblance of the considered sites. Further studies are necessary to shed light on both these issues. PMID- 29492028 TI - Using accelerometry to compare costs of extended migration in an arctic herbivore. AB - Understanding how individuals manage costs during the migration period is challenging because individuals are difficult to follow between sites; the advent of hybrid Global Positioning System-acceleration (ACC) tracking devices enables researchers to link spatial and temporal attributes of avian migration with behavior for the first time ever. We fitted these devices on male Greenland white fronted geese Anser albifrons flavirostris wintering at 2 sites (Loch Ken, Scotland and Wexford, Ireland) to understand whether birds migrating further during spring fed more on wintering and staging areas in advance of migration episodes. Although Irish birds flew significantly further (ca. 300 km) than Scottish birds during spring, their cumulative hours of migratory flight, flight speed during migration, and overall dynamic body ACC (i.e., a proxy for energy expenditure) were not significantly different. Further, Irish birds did not feed significantly more or expend significantly more energy in advance of migration episodes. These results suggest broad individual plasticity in this species, although Scottish birds arriving on breeding areas in Greenland with greater energy stores (because they migrated less) may be better prepared for food scarcity, which might increase their reproductive success. PMID- 29492029 TI - Evolutionary computation in zoology and ecology. AB - Evolutionary computational methods have adopted attributes of natural selection and evolution to solve problems in computer science, engineering, and other fields. The method is growing in use in zoology and ecology. Evolutionary principles may be merged with an agent-based modeling perspective to have individual animals or other agents compete. Four main categories are discussed: genetic algorithms, evolutionary programming, genetic programming, and evolutionary strategies. In evolutionary computation, a population is represented in a way that allows for an objective function to be assessed that is relevant to the problem of interest. The poorest performing members are removed from the population, and remaining members reproduce and may be mutated. The fitness of the members is again assessed, and the cycle continues until a stopping condition is met. Case studies include optimizing: egg shape given different clutch sizes, mate selection, migration of wildebeest, birds, and elk, vulture foraging behavior, algal bloom prediction, and species richness given energy constraints. Other case studies simulate the evolution of species and a means to project shifts in species ranges in response to a changing climate that includes competition and phenotypic plasticity. This introduction concludes by citing other uses of evolutionary computation and a review of the flexibility of the methods. For example, representing species' niche spaces subject to selective pressure allows studies on cladistics, the taxon cycle, neutral versus niche paradigms, fundamental versus realized niches, community structure and order of colonization, invasiveness, and responses to a changing climate. PMID- 29492030 TI - Restricted dispersal determines fine-scale spatial genetic structure of Mongolian gerbils. AB - Restricted gene flow may cause positive spatial genetic autocorrelation of animal populations at fine spatial scales. The Mongolian gerbil Meriones unguiculatus is a territorial, social rodent. Territoriality may create social fences to restrict dispersal or gene flow of Mongolian gerbils to a short distance. Restricted dispersal may differentiate fine-scale spatial genetic structure of populations with increasing distances (i.e., isolation by distance [IBD]). Competition for mates and inbreeding avoidance may result in equal dispersal propensity and subsequently similar spatial genetic autocorrelation between males and females of monogamous gerbils. We genotyped 327 gerbils, live captured from 26 burrow systems on a 9-ha plot in northcentral Inner Mongolia, China, using seven microsatellite loci. Spatial genetic autocorrelation was positive within 80 m and became negative from 80 m to 200 m, suggesting restricted gene flow. Inter-group genetic and geographic distances were related positively, supporting the IBD model. Live trapping data demonstrated equal dispersal propensities of male and female gerbils. Restricted dispersal and social organization may determine fine scale spatial population genetic structure of social rodents. PMID- 29492031 TI - Effects of study area size on home range estimates of common bottlenose dolphins Tursiops truncatus. AB - Knowledge of an animal's home range is a crucial component in making informed management decisions. However, many home range studies are limited by study area size, and therefore may underestimate the size of the home range. In many cases, individuals have been shown to travel outside of the study area and utilize a larger area than estimated by the study design. In this study, data collected by multiple research groups studying bottlenose dolphins on the east coast of Florida were combined to determine how home range estimates increased with increasing study area size. Home range analyses utilized photo-identification data collected from 6 study areas throughout the St Johns River (SJR; Jacksonville, FL, USA) and adjacent waterways, extending a total of 253 km to the southern end of Mosquito Lagoon in the Indian River Lagoon Estuarine System. Univariate kernel density estimates (KDEs) were computed for individuals with 10 or more sightings (n = 20). Kernels were calculated for the primary study area (SJR) first, then additional kernels were calculated by combining the SJR and the next adjacent waterway; this continued in an additive fashion until all study areas were included. The 95% and 50% KDEs calculated for the SJR alone ranged from 21 to 35 km and 4 to 19 km, respectively. The 95% and 50% KDEs calculated for all combined study areas ranged from 116 to 217 km and 9 to 70 km, respectively. This study illustrates the degree to which home range may be underestimated by the use of limited study areas and demonstrates the benefits of conducting collaborative science. PMID- 29492032 TI - Restricted cross-scale habitat selection by American beavers. AB - Animal habitat selection, among other ecological phenomena, is spatially scale dependent. Habitat selection by American beavers Castor canadensis (hereafter, beaver) has been studied at singular spatial scales, but to date no research addresses multi-scale selection. Our objectives were to determine if beaver habitat selection was specialized to semiaquatic habitats and if variables explaining habitat selection are consistent between landscape and fine spatial scales. We built maximum entropy (MaxEnt) models to relate landscape-scale presence-only data to landscape variables, and used generalized linear mixed models to evaluate fine spatial scale habitat selection using global positioning system (GPS) relocation data. Explanatory variables between the landscape and fine spatial scale were compared for consistency. Our findings suggested that beaver habitat selection at coarse (study area) and fine (within home range) scales was congruent, and was influenced by increasing amounts of woody wetland edge density and shrub edge density, and decreasing amounts of open water edge density. Habitat suitability at the landscape scale also increased with decreasing amounts of grass frequency. As territorial, central-place foragers, beavers likely trade-off open water edge density (i.e., smaller non-forested wetlands or lodges closer to banks) for defense and shorter distances to forage and obtain construction material. Woody plants along edges and expanses of open water for predator avoidance may limit beaver fitness and subsequently determine beaver habitat selection. PMID- 29492033 TI - Meta-analysis reveals that reproductive strategies are associated with sexual differences in oxidative balance across vertebrates. AB - Oxidative stress is a key physiological mechanism underlying life-history tradeoffs. Here, I use meta-analytic techniques to test whether sexual differences in oxidative balance are common in vertebrates and to identify which factors are associated with such differences. The dataset included 732 effect size estimates from 100 articles (82 species). Larger unsigned effect size (meaning larger sexual differences in a given marker) occurred in: reptiles and fish; those species that do not provide parental care; and oviparous species. Estimates of signed effect size (positive values meaning higher oxidative stress in males) indicated that females were less resistant to oxidative stress than males in: reptiles while males and females were similar in fish, birds, and mammals; those species that do not provide parental care; and oviparous species. There was no evidence for a significant sexual differentiation in oxidative balance in fish, birds, and mammals. Effect size was not associated with: the number of offspring; whether the experimental animals were reproducing or not; biomarker (oxidative damage, non-enzymatic, or enzymatic antioxidant), the species body mass; the strain (wild vs. domestic); or the study environment (wild vs. captivity). Oxidative stress tended to be higher in females than males across most of the tissues analyzed. Levels of residual heterogeneity were high in all models tested. The findings of this meta-analysis indicate that diversification of reproductive strategies might be associated with sexual differences in oxidative balance. This explorative meta-analysis offers a starting platform for future research to investigate the relationship between sex and oxidative balance further. PMID- 29492034 TI - Genetic variation in foundation species governs the dynamics of trophic interactions. AB - Various studies have demonstrated that the foundation species genetic diversity can have direct effects that extend beyond the individual or population level, affecting the dependent communities. Additionally, these effects may be indirectly extended to higher trophic levels throughout the entire community. Quercus castanea is an oak species with characteristics of foundation species beyond presenting a wide geographical distribution and being a dominant element of Mexican temperate forests. In this study, we analyzed the influence of population (He) and individual (HL) genetic diversity of Q. castanea on its canopy endophagous insect community and associated parasitoids. Specifically, we studied the composition, richness (S) and density of leaf-mining moths (Lepidoptera: Tischeridae, Citheraniidae), gall-forming wasps (Hymenoptera: Cynipidae), and canopy parasitoids of Q. castanea. We sampled 120 trees belonging to six populations (20/site) through the previously recognized gradient of genetic diversity. In total, 22 endophagous insect species belonging to three orders (Hymenoptera, Lepidoptera, and Diptera) and 20 parasitoid species belonging to 13 families were identified. In general, we observed that the individual genetic diversity of the host plant (HL) has a significant positive effect on the S and density of the canopy endophagous insect communities. In contrast, He has a significant negative effect on the S of endophagous insects. Additionally, indirect effects of HL were observed, affecting the S and density of parasitoid insects. Our results suggest that genetic variation in foundation species can be one of the most important factors governing the dynamics of tritrophic interactions that involve oaks, herbivores, and parasitoids. PMID- 29492035 TI - Context-dependent regulation of pectoralis myostatin and lipid transporters by temperature and photoperiod in dark-eyed juncos. AB - A prominent example of seasonal phenotypic flexibility is the winter increase in thermogenic capacity (=summit metabolism, [Formula: see text]) in small birds, which is often accompanied by increases in pectoralis muscle mass and lipid catabolic capacity. Temperature or photoperiod may be drivers of the winter phenotype, but their relative impacts on muscle remodeling or lipid transport pathways are little known. We examined photoperiod and temperature effects on pectoralis muscle expression of myostatin, a muscle growth inhibitor, and its tolloid-like protein activators (TLL-1 and TLL-2), and sarcolemmal and intracellular lipid transporters in dark-eyed juncos Junco hyemalis. We acclimated winter juncos to four temperature (3 degrees C or 24 degrees C) and photoperiod [short-day (SD) = 8L:16D; long-day (LD) = 16L:8D] treatments. We found that myostatin, TLL-1, TLL-2, and lipid transporter mRNA expression and myostatin protein expression did not differ among treatments, but treatments interacted to influence lipid transporter protein expression. Fatty acid translocase (FAT/CD36) levels were higher for cold SD than for other treatments. Membrane-bound fatty acid binding protein (FABPpm) levels, however, were higher for the cold LD treatment than for cold SD and warm LD treatments. Cytosolic fatty acid binding protein (FABPc) levels were higher on LD than on SD at 3 degrees C, but higher on SD than on LD at 24 degrees C. Cold temperature groups showed upregulation of these lipid transporters, which could contribute to elevated Msum compared to warm groups on the same photoperiod. However, interactions of temperature or photoperiod effects on muscle remodeling and lipid transport pathways suggest that these effects are context-dependent. PMID- 29492036 TI - Basal metabolic rate in free-living tropical birds: the influence of phylogenetic, behavioral, and ecological factors. AB - The majority of our knowledge of avian energetics is based on studies of birds from temperate and high latitudes. Using the largest existing sample of wild caught Old World tropical species, we showed that birds from Southern Vietnam had lower basal metabolic rate (BMR) than temperate species. The strongest dissimilarity between tropical and temperate species was the low scaling exponent in the allometric relation between BMR and body mass in tropical birds (the regression slope was 0.573). The passerine migrants to temperate and high latitudes had higher BMR than tropical sedentary passerines. Body mass alone accounted for 93% of the variation in BMR (body mass ranged from 5 to 252 g). Contrary to some other studies, we did not find evidence besides the above mentioned that phylogeny, taxonomy, behavior, or ecology have a significant influence on BMR variation among tropical birds. PMID- 29492037 TI - Polistes metricus queens exhibit personality variation and behavioral syndromes. AB - Consistent differences in behavior between individuals, otherwise known as animal personalities, have become a staple in behavioral ecology due to their ability to explain a wide range of phenomena. Social organisms are especially serviceable to animal personality techniques because they can be used to explore behavioral variation at both the individual and group level. Despite the success of personality research in social organisms generally, and social Hymenoptera in particular, social wasps (Vespidae) have received little to no attention in the personality literature. In the present study, we test Polistes metricus (Vespidae; Polistinae) paper wasp queens for the presence of repeatable variation in, and correlations ("behavioral syndromes") between, several commonly used personality metrics: boldness, aggressiveness, exploration, and activity. Our results indicate that P. metricus queens exhibit personalities for all measured traits and correlations between different behavioral measures. Given that paper wasps have served as a model organism for a wide range of phenomena such as kin selection, dominance hierarchies, mate choice, facial recognition, social parasitism, and chemical recognition, we hope that our results will motivate researchers to explore whether, or to what degree, queen personality is important in their research programs. PMID- 29492038 TI - Happy together? Avoidance of conspecifics by gregarious mussels. AB - Zebra mussel Dreissena polymorpha is a Ponto-Caspian species invasive in Europe and North America, with great environmental impact. It lives byssally attached to hard substrata in large aggregations, which is often explained by its preferences for conspecifics, though direct evidence for such preferences has been rather limited so far. We studied the reactions of zebra mussels to conspecifics, hypothesizing that they may either be attracted to one another or form aggregations only in the absence of alternative attachment sites. In Experiment 1, we tested mussel tendency to detach from existing druses depending on druse size (2-25 individuals) and substratum type (soft: sand; hard: glass). Mussels detached significantly more often on the hard substratum and from larger druses compared to soft substratum and smaller druses, respectively. This indicates that mussels tended to avoid conspecifics at high density, particularly when alternative substratum was available. In Experiment 2, we tested the responses of single mussels to distant (3 or 15 cm) conspecifics (0, 3, 15 individuals per 2.5 l tank) on the sandy substratum. The presence of conspecifics, regardless of their distance and density, resulted in single unattached mussels staying more often in their initial positions. Mussels did not move preferentially towards or away from the conspecifics. Thus, even on unsuitable substratum mussels were not attracted by conspecifics and probably exhibited an avoidance reaction by reducing their movement. This suggests that dense mussel aggregations are formed due to the lack of available alternative attachment sites rather than due to their preferences for conspecifics. PMID- 29492039 TI - Taste responsiveness to two steviol glycosides in three species of nonhuman primates. AB - Primates have been found to differ widely in their taste perception and studies suggest that a co-evolution between plant species bearing a certain taste substance and primate species feeding on these plants may contribute to such between-species differences. Considering that only platyrrhine primates, but not catarrhine or prosimian primates, share an evolutionary history with the neotropical plant Stevia rebaudiana, we assessed whether members of these three primate taxa differ in their ability to perceive and/or in their sensitivity to its two quantitatively predominant sweet-tasting substances. We found that not only neotropical black-handed spider monkeys, but also paleotropical black-and white ruffed lemurs and Western chimpanzees are clearly able to perceive stevioside and rebaudioside A. Using a two-bottle preference test of short duration, we found that Ateles geoffroyi preferred concentrations as low as 0.05 mM stevioside and 0.01 mM rebaudioside A over tap water. Taste preference thresholds of Pan troglodytes were similar to those of the spider monkeys, with 0.05 mM for stevioside and 0.03 mM for rebaudioside A, whereas Varecia variegata was slightly less sensitive with a threshold value of 0.1 mM for both substances. Thus, all three primate species are, similar to human subjects, clearly more sensitive to both steviol glycosides compared to sucrose. Only the spider monkeys displayed concentration-response curves with both stevioside and rebaudioside A which can best be described as an inverted U-shaped function suggesting that Ateles geoffroyi, similar to human subjects, may perceive a bitter side taste at higher concentrations of these substances. Taken together, the results of the present study do not support the notion that a co-evolution between plant and primate species may account for between-species differences in taste perception of steviol glycosides. PMID- 29492040 TI - Male competition and speciation: expanding our framework for speciation by sexual selection. PMID- 29492041 TI - Interspecific competition, hybridization, and reproductive isolation in secondary contact: missing perspectives on males and females. AB - Research on sexual selection and hybridization has focused on female mate choice and male-male competition. While the evolutionary outcomes of interspecific female preference have been well explored, we are now gaining a better understanding of the processes by which male-male competition between species in secondary contact promotes reproductive isolation versus hybridization. What is relatively unexplored is the interaction between female choice and male competition, as they can oppose one another or align with similar outcomes for reproductive isolation. The role of female-female competition in hybridization is also not well understood, but could operate similarly to male-male competition in polyandrous and other systems where costs to heterospecific mating are low for females. Reproductive competition between either sex of sympatric species can cause the divergence and/or convergence of sexual signals and recognition, which in turn influences the likelihood for interspecific mating. Future work on species interactions in secondary contact should test the relative influences of both mate choice and competition for mates on hybridization outcomes, and should not ignore the possibilities that females can compete over mating resources, and males can exercise mate choice. PMID- 29492042 TI - How does male-male competition generate negative frequency-dependent selection and disruptive selection during speciation? AB - Natural selection has been shown to drive population differentiation and speciation. The role of sexual selection in this process is controversial; however, most of the work has centered on mate choice while the role of male-male competition in speciation is relatively understudied. Here, we outline how male male competition can be a source of diversifying selection on male competitive phenotypes, and how this can contribute to the evolution of reproductive isolation. We highlight how negative frequency-dependent selection (advantage of rare phenotype arising from stronger male-male competition between similar male phenotypes compared with dissimilar male phenotypes) and disruptive selection (advantage of extreme phenotypes) drives the evolution of diversity in competitive traits such as weapon size, nuptial coloration, or aggressiveness. We underscore that male-male competition interacts with other life-history functions and that variable male competitive phenotypes may represent alternative adaptive options. In addition to competition for mates, aggressive interference competition for ecological resources can exert selection on competitor signals. We call for a better integration of male-male competition with ecological interference competition since both can influence the process of speciation via comparable but distinct mechanisms. Altogether, we present a more comprehensive framework for studying the role of male-male competition in speciation, and emphasize the need for better integration of insights gained from other fields studying the evolutionary, behavioral, and physiological consequences of agonistic interactions. PMID- 29492043 TI - Male-driven reproductive and agonistic character displacement in darters and its implications for speciation in allopatry. AB - Selection against hybridization can cause mating traits to diverge between species in sympatry via reproductive character displacement (RCD). Additionally, selection against interspecific fighting can cause aggressive traits to diverge between sympatric species via agonistic character displacement (ACD). By directly affecting conspecific recognition traits, RCD and ACD between species can also incidentally cause divergence in mating and fighting traits among populations within a species [termed cascade RCD (CRCD) and cascade ACD]. Here, we demonstrate patterns consistent with male-driven RCD and ACD in 2 groups of darters (orangethroat darter clade Ceasia and rainbow darter Etheostoma caeruleum). In both groups, males that occur in sympatry (between Ceasia and E. caeruleum) have higher levels of preference for mating and fighting with conspecifics over heterospecifics than do males from allopatry. This is consistent with RCD and ACD. We also found patterns consistent with CRCD and cascade ACD among species of Ceasia. Ceasia males that are sympatric to E. caeruleum (but allopatric to one another) also have heightened preferences for mating and fighting with conspecific versus heterospecific Ceasia. In contrast, Ceasia males that are allopatric to E. caeruleum readily mate and fight with heterospecific Ceasia. We suggest that RCD and ACD between Ceasia and E. caeruleum has incidentally led to divergence in mating and fighting traits among Ceasia species. This study is unique in that male preferences evolve via both RCD (male preference for conspecific females) and ACD (male preference to fight conspecific males) which leads to subsequent divergence among allopatric lineages. PMID- 29492044 TI - Color and behavior differently predict competitive outcomes for divergent stickleback color morphs. AB - Our knowledge of how male competition contributes to speciation is dominated by investigations of competition between within-species morphs or closely related species that differ in conspicuous traits expressed during the breeding season (e.g. color, song). In such studies, it is important to consider the manner in which putatively sexually selected traits influence the outcome of competitive interactions within and between types because these traits can communicate information about competitor quality and may not be utilized by homotypic and heterotypic receivers in the same way. We studied the roles of breeding color and aggressive behaviors in competition within and between two divergent threespine stickleback Gasterosteus aculeatus color types. Our previous work in this system showed that the switch from red to black breeding coloration is associated with changes in male competition biases. Here, we find that red and black males also use different currencies in competition. Winners of both color types performed more aggressive behaviors than losers, regardless of whether the competitor was of the same or opposite color type. But breeding color differently predicted competitive outcomes for red and black males. Males who were redder at the start of competition were more likely to win when paired with homotypic competitors and less likely to win when paired with heterotypic competitors. In contrast, black color, though expressed in the breeding season and condition dependent, was unrelated to competitive outcomes. Placing questions about the role of male competition in speciation in a sexual signal evolution framework may provide insight into the "why and how" of aggression biases and asymmetries in competitive ability between closely related morphs and species. PMID- 29492045 TI - Intrasexual competition enhances reproductive isolation between locally adapted populations. AB - During adaptation to different habitat types, both morphological and behavioral traits can undergo divergent selection. Males often fight for status in dominance hierarchies and rank positions predict reproductive success. Ecotypes with reduced fighting abilities should have low reproductive success when migrating into habitats that harbor ecotypes with superior fighting abilities. Livebearing fishes in the Poecilia mexicana-species complex inhabit not only regular freshwater environments, but also independently colonized sulfidic (H2S containing) habitats in three river drainages. In the current study, we found fighting intensities in staged contests to be considerably lower in some but not all sulfidic surface ecotypes and the sulfidic cave ecotype compared with populations from non-sulfidic surface sites. This is perhaps due to selection imposed by H2S, which hampers oxygen uptake and transport, as well as cellular respiration. Furthermore, migrants from sulfidic habitats may lose fights even if they do not show overall reduced aggressiveness, as physiological performance is likely to be challenged in the non-sulfidic environment to which they are not adapted. To test this hypothesis, we simulated migration of H2S-adapted males into H2S-free waters, as well as H2S-adapted cave-dwelling males into sulfidic surface waters. We found that intruders established dominance less often than resident males, independent of whether or not they showed reduced aggressiveness overall. Our study shows that divergent evolution of male aggressive behavior may also contribute to the maintenance of genetic differentiation in this system and we call for more careful evaluation of male fighting abilities in studies on ecological speciation. PMID- 29492046 TI - The roles of inter- and intra-sexual selection in behavioral isolation between native and invasive pupfishes. AB - Male-male competition and female mate choice may both play important roles in driving and maintaining reproductive isolation between species. When previously allopatric species come into secondary contact with each other due to introductions, they provide an opportunity to evaluate the identity and strength of reproductive isolating mechanisms. If reproductive isolation is not maintained, hybridization may occur. We examined how reproductive isolating mechanisms mediate hybridization between endemic populations of the Red River pupfish Cyprinodon rubrofluviatilis and the recently introduced sheepshead minnow C. variegatus. In lab-based dominance trials, males of both species won the same number of competitions. However, male C. rubrofluviatilis that won competitions were more aggressive than C. variegatus winners, and more aggression was needed to win against competitor C. variagatus than allopatric C. rubrofluviatilis. Duration of fights also differed based on the relatedness of the competitor. In dichotomous mate choice trials, there were no conspecific or heterospecific preferences expressed by females of either species. Our findings that male-male aggression differs between closely and distantly related groups, but female choice does not suggest that male-male competition may be the more likely mechanism to impede gene flow in this system. PMID- 29492047 TI - Accreditation System and Standards for Medical Education in Pakistan: It's time we raise the bar. PMID- 29492048 TI - Spectrum of Celiac disease in Paediatric population: Experience of Tertiary Care Center from Pakistan. AB - Objective: To determine clinical features and relevant laboratory investigations of patient with celiac disease (CD) and comparing classical celiac disease (CCD) with Non-diarrheal celiac disease (NDCD). Methods: This is a five years retrospective study conducted at The Aga Khan University Hospital Karachi, Pakistan from January 2010 to December 2015, enrolling children from one year to 15 years of either gender diagnosed as celiac disease in accordance with revised ESPGHAN criteria. Biopsy samples with grade 2 or more on Modified Marsh Classification were considered as consistent with celiac disease. Celiac patients were categorized into Classical celiac disease (with Chronic Diarrhea) and non diarrheal celiac disease (Atypical celiac) and their clinical features and relevant laboratory investigations were documented. Results: Total 66 patients were selected with celiac disease according to inclusion criteria, 39 (59.09%) patients were labeled as CCD and 27 (40.91%) patients were labeled as NDCD. Marsh grading 3a and above were more marked in CCD as compared to NDCD. Mean titer for Tissue transglutaminase antibodies (TTG) were higher in CCD group in comparison to NDCD group. In CCD, the most common clinical presentations were abdominal distension whereas in NDCD, the most remarkable features were recurrent abdominal pain (62.9%). Frequency of failure to thrive is significantly high in CCD (82.05%) but patients merely with short stature were more common in NDCD (33.3%). Refractory anemia was present in 66.6% patients in NDCD group and 41.1% patients in CCD group. 74.3% patients in CCD group were vitamin D deficient whereas 85% patient had vitamin D deficiency in NDCD group (p= 0.03). Conclusion: NDCD is not uncommon in our population. Recurrent abdominal pain, failure to thrive or patients only with short stature and refractory anemia are prominent features in NCDC group whereas abdominal distension, failure to thrive and recurrent abdominal pain were noticeable features in CCD. High grade histopathology and raised antibodies titer is hallmark of CCD. Vitamin D deficiency is almost equally present in both groups. PMID- 29492049 TI - Comparison of corneal morphological characteristics between diabetic and non diabetic population. AB - Objective: To compare corneal morphological parameters between diabetics and age matched non-diabetic control subjects and to evaluate the correlation of these parameters in relation to duration of diabetes mellitus (DM), glycemic status and severity of diabetic retinopathy.(DR). Methods: This cross sectional comparative study was conducted at the Department of Ophthalmology, PNS Shifa Karachi from February 2016 to January 2017. Patients with ages between 10 to 80 years of either gender who were diagnosed to have DM were recruited in the study. Control group comprised of age matched healthy volunteers who did not have DM. Corneal morphological parameters (CED, Average cell size, CV of cell size and hexagonality) was evaluated in each subject with non-contact specular microscope and findings were endorsed on a pre devised proforma. Results: Data of 298 eyes (149 diabetic patients and 149 healthy controls) was evaluated. Mean corneal endothelial cell density (CED) of diabetic population was 2494.47 +/- 394.10 cells/mm2, while mean CED of control group was 2574.46 +/- 279.97 cells/mm2 [p = 0.04]. Between group differences in mean average cell size, CV of cell size and hexagonality was statistically not significant. Analysis of corneal endothelial parameters among subgroups of patients with no DR, with NPDR and PDR did not show statistically significant difference. Moreover, patients with diabetes of more than 10 years duration had significantly lower CED (p <0.01) and larger average cell size (p= 0.03). Duration of DM was significantly correlated with type of DR, HbA1c level, CED, polymegethism and hexagonality. Conclusion: Mean corneal endothelial cell density (CED) was found to be significantly lower in diabetic population as compared to healthy controls. PMID- 29492050 TI - Analyzing communication skills of Pediatric Postgraduate Residents in Clinical Encounter by using video recordings. AB - Objective: To analyze communication skills of pediatric postgraduate residents in clinical encounter by using video recordings. Methods: This qualitative exploratory research was conducted through video recording at The Children's Hospital Lahore, Pakistan. Residents who had attended the mandatory communication skills workshop offered by CPSP were included. The video recording of clinical encounter was done by a trained audiovisual person while the resident was interacting with the patient in the clinical encounter. Data was analyzed by thematic analysis. Results: Initially on open coding 36 codes emerged and then through axial and selective coding these were condensed to 17 subthemes. Out of these four main themes emerged: (1) Courteous and polite attitude, (2) Marginal nonverbal communication skills, (3) Power game/Ignoring child participation and (4) Patient as medical object/Instrumental behaviour. All residents treated the patient as a medical object to reach a right diagnosis and ignored them as a human being. There was dominant role of doctors and marginal nonverbal communication skills were displayed by the residents in the form of lack of social touch, and appropriate eye contact due to documenting notes. A brief non medical interaction for rapport building at the beginning of interaction was missing and there was lack of child involvement. Conclusion: Paediatric postgraduate residents were polite while communicating with parents and child but lacking in good nonverbal communication skills. Communication pattern in our study was mostly one-way showing doctor's instrumental behaviour and ignoring the child participation. PMID- 29492051 TI - Frequency of depression among patients with Type-I diabetes in a developing country, Pakistan. AB - Objective: To determine the frequency of depressive symptoms among young people with Type-I diabetes. Methods: This cross sectional study was conducted at Baqai Institute of Diabetology & Endocrinology, Karachi, Pakistan from February to December 2015. All People aged between 12-20 years with Type-I diabetes for at least 1 year attending the OPD were included in the study. Information about participants' demographic characteristics, co morbidities and Complications, current treatment and medications were obtained. Acylated hemoglobin (HbA1C) levels were checked in all People. The Center for Epidemiologic Studies Depression (CES-D) scale was used to assess the depressive symptoms in the study participants. A cut off value of >= 16 was used to screen for depression. SPSS 19 was used to analyze the results. Results: Out of 104 people with Type-I diabetes, depressive symptoms were observed in 44 (42.3%) participants. Depressive symptoms were more frequent in females (28/55, 50.9%). Depressed people had more episodes of DKA (11/44, 25%), hypoglycemia (12/44, 27.3%) or hospitalization (7/44, 15.9%) in the last six months which were not statistically significant. Conclusion: Depressive symptoms are quite common in people with Type-I diabetes. Health care professionals should consider screening youth with diabetes for depression regularly. Further large scale studies are needed to validate our findings. PMID- 29492052 TI - Combined Detection of Urinary Micro Albumin, alpha1-microglobulin and N-acetyl beta-D-glucosaminidase in the Early Diagnosis of Diabetic Nephropathy. AB - Objective: To analyze the values of combined detection of urinary micro albumin (mAlb), alpha1-microglobulin (alpha1-MG) and N-acetyl-beta-D-glucosaminidase (NAG) in the early diagnosis of diabetic nephropathy (DN). Methods: Ninety-four patients with early DN who were admitted to the hospital between April 2015 and April 2016 were selected and set as a DN group. Moreover, seventy-six patients with diabetes who were admitted to the hospital in the same period were selected and set as a diabetes group, and sixty-four healthy people were selected as set as a control group. The urinary mAlb, alpha1-MG and NAG of the three groups were detected. Moreover, the patients were divided into a favorable blood glucose control group and a poor blood glucose control group according to the blood glucose control condition of the patients. The detection results of the three groups were compared and statistically analyzed. Results: The urinary mAlb, alpha1-MG and NAG levels of the DN group were significantly higher than those of the diabetes group and control group, and the differences had statistical significance (P<0.05). The detection indicator values of the favorable blood glucose control group were much lower than those of the poor blood glucose control group, and the difference was statistically significant (P<0.05). The positive rate of the combined detection of mAlb, alpha1-MG and NAG levels was 90.2%, which was much higher than that of single indicator (P<0.05). Conclusion: Combined detection of urinary mAlb, alpha1-MG and NAG is sensitive in diagnosing early renal damages in DN patients. PMID- 29492053 TI - Fundus fluorescence Angiography in diagnosing diabetic retinopathy. AB - Objective: To investigate the manifestation characteristics of fundus fluorescence angiography (FFA) and its values in diagnosing diabetic retinopathy through comparing direct ophthalmoscopy. Methods: Two hundred fifty patients (500 eyes) who were suspected as diabetic retinopathy and admitted to the hospital between February 2015 and December 2016 were selected. They underwent direct ophthalmoscopy and FFA. The manifestation characteristics of FFA in the diagnosis of diabetic retinopathy were summarized. The two examination methods were compared. Results: In the diagnosis with direct ophthalmoscopy, 375 eyes out of 500 eyes were diagnosed as diabetic retinopathy (75%); there were 74 eyes at stage I, 88 eyes at stage II, 92 eyes at stage III, 83 eyes of stage IV, 28 eyes of stage V and 10 eyes of stage VI. In the diagnosis with FFA, 465 eyes out of 500 eyes were diagnosed as diabetic retinopathy (93%); there were 94 eyes at stage I, 110 eyes at stage II, 112 at stage III, 92 eyes at stage IV, 41 eyes at stage V and 16 eyes at stage VI. The detection rate of diabetic retinopathy using FFA was significantly higher than that using direct ophthalmoscopy (P<0.05). FFA found that 316 eyes had non-proliferative retinopathy (67.96%), 75 eyes had pre proliferative lesions (16.13%), 149 eyes had proliferative lesions (32.04%), 135 eyes had diabetic maculopathy (29.03%) and 31 eyes had diabetic optic disc lesions (6.67%). Conclusion: The detection rate of diabetic retinopathy using FFA is higher than that using direct ophthalmoscopy. FFA could accurately determine clinical stage. Therefore, it is an important approach in treatment efficacy evaluation and treatment guidance, suggesting a significant application value. PMID- 29492054 TI - A randomized controlled trial of intermittent Cervical Traction in sitting Vs. Supine position for the management of Cervical Radiculopathy. AB - Objective: To compare the effectiveness of intermittent cervical Traction in sitting vs. supine position for the management of cervical radiculopathy. Methods: A randomized clinical trial was done to compare pain and disability modification of cervical radiculopathy patients by using cervical traction in sitting and supine positions. Forty patients (males and females aged between 18 60 years with chronic cervical radiculopathy) were recruited for the trial. Participants were randomized into two homogeneous groups by dice method. The Group-A (n=20) received 3-weeks of intermittent cervical traction in sitting position along with Transcutaneous Electric Nerve Stimulation (TENS) and hot pack. The Group-B (n=20) received the same treatment except the intermittent cervical traction that was applied in supine position. Participants were assessed two times: at baseline (week 0) and at the termination of rehabilitation (week 3). Neck disability index was used to collect the data before and after the treatment. Results: The mean age of the patients was 43.15+/-8.99 vs. 48.80+/ 6.89 years in Group-A vs. Group-B respectively. Mean (+/-S.D.) weight of the patients was 74.75+/-12.11 vs. 74.60+/-11.24 kg in Group-A vs. Group-B respectively. Mean Neck Disability Index score at start of treatment was 30.30+/ 7.46 vs. 30.75+/-7.85 in Group-A and Group-B respectively. There was a significant difference in Group-A and Group-B regarding aggregate NDI score at the end of treatment (19.45+/-7.12 vs. 11.05+/-4.40; p<0.0001). Conclusion: Supine position is better choice for applying cervical traction as compared to sitting position for the management of cervical radiculopathy comparing post interventional NDI score. PMID- 29492055 TI - Effectiveness of Test-Enhanced Learning (TEL) in lectures for undergraduate medical students. AB - Objective: To determine the effectiveness of Test-Enhanced learning as a learning tool in lectures for undergraduate medical students. Method: This quantitative, randomized controlled trial included eighty-four students of 4th year MBBS from Yusra Medical & Dental College, Islamabad. The duration of study was from March 2016 to August 2016. After obtaining the informed consent; participants were equally assigned to interventional and non-interventional study groups through stratified randomization. Single best answer MCQs of special pathology were used as data collection instrument after validation. A pre- and post-test was taken from both groups, before and after the intervention, respectively and their results were compared using SPSS version 21. Results: There were 13 male (31%) and 29 female (69%) participants in each study group who showed an equivalent baseline performance on pre-test (p=0.95). Statistically significant difference was found among mean scores of interventional and non-interventional study groups at exit exam (p=0.00). Interventional group also showed a significant improvement in their post-test scores (mean: 17.17+/-1.59) as compared to pre-test scores (mean: 6.19+/-1.81). Conclusions: Test-enhanced learning has significant effect on improving the learning of course content delivered to undergraduate medical students through lectures. PMID- 29492056 TI - Symptoms of Depression and Anxiety among Women attending Primary Health Care in Gilgit-Baltistan (GB), Pakistan. AB - Objective: To assess symptoms of anxiety and depression among women reporting to primary health care (PHC women) in Gilgit Baltistan (GB), Pakistan. Methods: This was a cross-sectional study conducted on PHC women belonging GB including other three provinces of Pakistan. PHQ-9 and GAD-7 were used to assess anxiety and depression. Descriptive and inferential statistical techniques were applied to analyze the collected data. Results: PHC women from GB reported higher level of depressive symptoms (t=7.58, p=0.00) and lower level of anxiety symptoms (t=8.3, p=0.00) when compared with cut-off score. Insignificant differences were found in depressive (t=1.5, p>.05) and anxiety (t=1.2, p>.05) scores between GB women and women from rest of Pakistan. However, inter-province differences in depressive (F=5.78, p= 00) and anxiety (F=4.5, p=0.00) symptoms were significant. Increasing age and lack of education were found significant risk factors for GB PHC women's depressive and anxiety symptoms. Conclusions: PHC women from GB have higher level of depressive and lower level of anxiety symptoms like women from other provinces of Pakistan. Their demographics should be considered while addressing their emotional problems. PMID- 29492057 TI - Association of vitamin D deficiency and VDBP gene polymorphism with the risk of AMI in a Pakistani population. AB - Objective: To investigate the relationship of vitamin D deficiency and risk of AMI in a Pakistani population, and to find out any association between vitamin D binding protein (VDBP) genotypes and risk of AMI in this population. Methods: In a comparative cross-sectional study, 246 patients (age: 20-70 years; 171 males and 75 females) with first AMI were enrolled with informed consent. Similarly, 345 healthy adults (230 males and 115 females) were enrolled as controls. Their fasting serum samples were analyzed for 25 (OH) vitamin D, lipids and other biomarkers using kit methods, while DNA was analyzed for VDBP genotypes using PCR RFLP based methods. Chi-squared test and logistic regression were used for association of vitamin D deficiency and VDBP genotypes with AMI. Results: Mean serum concentration of 25(OH) vitamin D was significantly lower in AMI patients compared to healthy subjects (p=0.015) and percent vitamin D deficiency was higher in AMI patients compared to healthy subjects (p=0.003). VDBP IF-IF genotype was positively associated with the risk of AMI in subject above 45 years after adjusting for potential confounders [OR = 9.86; 95% CI=1.16 to 83.43]. Conclusion: Vitamin D deficiency and VDBP IF-IF genotype are associated with AMI in Pakistani adults. PMID- 29492058 TI - Lateral mass screw fixation in cervical spine injury. AB - Objective: To determine clinical outcome in patients with cervical injury after lateral mass screws fixation in a tertiary care hospital. Methods: This study included 88 patients, with cervical injury confirmed radiologically. Patients <12 or >70 years, with traumatic discs, cord compression without subluxation and previously operated on cervical spine were excluded from this study. All patients underwent fixation with lateral mass screws through posterior approach under fluoroscopic guidance. Frankel grading was used to assess the clinical status of these patients pre-operatively & post-operatively. Results: There were 60(68.18%) males and 28(31.8%) females. The ages varied from 18 to 55 years with a mean of 32 yrs +/- 8 yrs. The most common level of injury was C5-C6 in 46(52%) patients. According to Frankel grading system, 35 (39.8%) patients were placed in Grade A, 15(17.05%) in Grade B, 22(25%) in Grade C, 12 (13.6%) in Grade D, four (4.5%) in Grade E on admission. Postoperatively, 16 (18.2%) patients were placed in Grade A, 23 (26.1%) in Grade B, eight (9.1%) in Grade C, nine (10.2%) in Grade D and 26(29.6%) patients in Grade E with an overall improvement in neurological function in 51(58%) and power in 37(42%) patients. The major complications encountered were respiratory infections in 10(11.36%) and wound infection in four (4.5%) while eight (9.1%) patients expired. Conclusion: Lateral mass screws technique is a safe and effective method for cervical fixation after proper reduction. PMID- 29492059 TI - Effect of fibrin vs cellulose based haemostatic agents with traditional haemostatic procedures in thyroid surgery. AB - Objective: To compare the efficacy of fibrin-based hemostat and cellulose-based hemostat with traditional procedures in patients undergoing thyroid surgery. Methods: Between January 2012 and December 2016, 255 patients were scheduled to undergo total thyroidectomy at Surgical Clinic Nis. The patients were randomized to: Group-I use of classic surgical procedures to achieve hemostasis, Group-II use Surgicel and Group-III use Beriplas. Results: A statistically significant reduction of surgical time was found for Group-I compared with Group-II and III (p<=0.01 for both groups). Statistically significant reduction of intraoperative blood loss was found for Group-I compared with Group-II from 102.3mL vs. 86.1mL (p<=0.01) as well as compared to Group-III (mean 77.4mL, p<=0.01). Removal of the wound drain occurred sooner in the Group-II and III compared with Group-I (mean 37.1h vs. 40.1h, p<=0.05; mean 31.2h vs. 40.1h, p<=0.01). There were no significant differences in terms of postoperative morbidity among the groups. Conclusions: Fibrin based haemostat seems to be an effective hemostatic agent for patients undergoing thyroid surgery. We suggest that, where appropriate, this fibrin-based haemostat should be used as a first line hemostatic agent in thyroidectomy in combination with conventional surgical means of hemostasis. PMID- 29492060 TI - Neutrophil lymphocyte ratio (NLR): A well assessment tool of glycemic control in type 2 diabetic patients. AB - Background and Objective: Increased neutrophil lymphocyte ratio (NLR) is a marker as well as predictor of various cardiac and non cardiac disorders. Our aim was to assess the relationship between NLR and different level of glycemic control in type 2 diabetic patients. Methods: An observational study was conducted at diabetic clinic of Sheikh Zayed Medical College/Hospital, Rahim Yar Khan from September 2016 to February 2017 in which 330 type 2 diabetic patients were randomly divided in to three groups based upon diabetes control according to ADA criteria. Patients in group A with HbA1c <= 7% (excellent control), group B HbA1c 7.0-9.0 % (poor control) and group C HbA1c >= 9 %(worst control). Patients were assessed in terms of complete blood count and C - reactive protein. Results: As compared to excellent control (Group A) patients with worst control (Group C)showed a high leukocyte count (p.001), high neutrophil count (P.003) and lower lymphocyte count (P 0.44) while patients in poor control (Group B)did not differ significantly. Similarly value of NLR was also significantly higher in worst control (Group C) as compared to poor control(Group B) and excellent control (Group A) diabetes (4.3+/-2.8, 2.7+/-1.0 and2.0+/-0.5(p.001). NLR were found independent predictor of worst diabetes control (OR: 1.809, 95% CI: 1.459-2.401) along with fasting blood sugar (OR: 0.938, 95% CI: 0.995-0.982) and CRP (OR: 1.020, 95% CI: 1.003-1.028). Conclusion: Increased NLR level is associated with elevated HbA1c and poor glycemic control in patients of type 2 diabetes mellitus. It can be used as a disease monitoring tool during the follow up of diabetic patients. PMID- 29492061 TI - Correlation between Serum Uric Acid Level and Microalbuminuria in Type-2 Diabetic Nephropathy. AB - Objective: To measure the correlation between microalbuminuria and serum uric acid level in Type-2 diabetic nephropathy. Methods: This cross-sectional study was done in department of Medicine, Mayo hospital Lahore from August 2014 to February 2015. A total of 200 patients with Type-2 diabetic nephropathy were enrolled in the study. Demographic data and contact details were obtained. Serum Uric acid and microalbuminuria by albumin to creatinine ratio (ACR) in random urine sample was measured at the time of inclusion of patients. All the information was collected through a pre-defined proforma. Pearson correlation coefficient and t-test were used to assess correlation and significance respectively. Results: Out of 200 cases, 29%(n=58) were between 16-40 years of age while 71%(n=142) were between 41-65 years of age, Mean +/- SD was calculated as 48.1+/-10.26 years, 48.5%(n=97) were male and 51.5%(n=103) were females, Mean serum uric acid level was calculated as 6.99+/-1.01 mg/dL while microalbuminuria was calculated as 5.63+/-1.08 mg/mmol, r value was 0.0838 which is a positive correlation. Conclusion: The results of our study concluded that level of serum uric acid and microalbuminuria are significantly correlated to nephropathy in patients having Type-2 diabetes mellitus. PMID- 29492062 TI - Diagnostic utility of C-kit protein (CD117) expression in differentiating adenoid cystic carcinoma and polymorphous low grade Adenocarcinoma. AB - Background & Objective: To evaluate usefulness of immunohistochemical marker C kit (CD117) in differentiating Adenoid cystic carcinoma (AdCC) from Polymorphous low-grade adenocarcinoma (PLGA) in patients of salivary gland carcinomas. AdCC is a malignant salivary gland neoplasm with poor prognosis. PLGA is a salivary gland malignancy with indolent growth pattern. Differentiating between the two entities is a diagnostic challenge. We evaluated the role of C-kit in differentiating the two. Methods: This is a Cross sectional study. Samples of 19 tumors including 12 AdCC and 4 PLGA was evaluated at Department of Histopathology, Armed Forces Institute of Pathology, Rawalpindi from December 2015 to August 2016. Immunohistochemical techniques were used to analyze the level of c-kit expression in AdCC (n = 12), polymorphous low-grade adenocarcinoma (PLGA) (n = 6). Samples were stained using monoclonal antibody against C-kit. Statistical analysis of the data was done using SPSS version 21. Results: Strong diffuse cytoplasmic reactivity was observed in more than 50% of the tumor cells of AdCC whereas less than 20% of cells showed negative to weak positivity in PLGA. Hence, the difference in the expression of c-kit between AdCC and PLGA was statistically significant (p value <0.002). Conclusions: CD117 expression itself can be used as a marker in differential diagnosis of salivary gland neoplasms. However, the percentage of the CD117 immunoreactive cells and the staining intensities appeared to be important factors in distinguishing AdCC from PLGA. PMID- 29492063 TI - Risk factors associated with diabetes in periurban community, Lahore Pakistan. AB - Objectives: To identify factors (sociodemographic characteristic, behavioural factors, health care advice and physical measurements like weight, height, waist and hip circumferences) associated with diabetes. Methods: This study was conducted in the Nain Sukh which is a peri-urban area near Lahore between January till August 2016. A sum of 1080 households of both gender with age between 15-69 years were interviewed through a structured questionnaire and necessary measurements were taken. The data analysis was done by using SPSS version 17. All the recommended ethical clearance both institutional as well as individual levels were duly taken. Result: The mean age of the participants was 34 years +/- 14SD with female predominance. Total prevalence of diabetes was found to be 9.8% out of which 83% were females between age of 45-69 years (p<0.00). Diabetes was significantly associated with obesity with 33% participants were overweight while 42% were obese (p<0.00). Diabetes was also significantly associated with central obesity, positive family history (p<0.000). Almost 45% of the households were advised to reduce weight and take special diet (p<0.000). Conclusion: The diabetes is significantly associated with positive family history and deranged BMI both overweight and obesity along with central obesity. This can only be prevented by health education and life style modifications. PMID- 29492064 TI - Difference of efficacy between Laparoscopic Modified Soave operation and Open Radical Resection in the treatment of Hirschsprung's disease. AB - Objective: To analyze and compare the efficacy of laparoscopic modified Soave operation and open radical resection in the treatment of Hirschsprung's disease. Methods: Two hundred and sixteen children who suffered from Hirschsprung's disease and were admitted into the hospital from June 2015 to December 2016 were selected as research subjects. They were grouped into an observation group in which patients were treated by laparoscopic modified Soave operation and open radical resection and a control group in which patients were treated by open radical resection. The clinical efficacy and complications of the two groups were observed, and the defecation function was also evaluated. Results: Operation indicators such as the operation time, time to recovery of intestine peristalsis, intraoperative blood loss and pain score of the observation group were superior to those of the control group, and the difference had statistical significance (P<0.05). The mean arterial pressure (MAP) and heart rate (HR) of the observation group were lower than those of the control group at all time points after operation, and the difference suggested statistical significance (P<0.05). The postoperative complications of the observation group were less than those of the control group. The follow-up results demonstrated that the excellent and good rate of Kelly score of the observation group was 81.5%, higher than 61.1% in the control group. Conclusion: Laparoscopic modified Soave operation has definite efficacy in the treatment of Hirschsprung's disease, and the treatment is featured by high safety and few complications, which is beneficial to the recovery of defecation function; hence laparoscopic modified Soave operation is worth clinical promotion. PMID- 29492065 TI - Comparing neonatal respiratory morbidity in neonates delivered after 34 weeks of gestation with and without antenatal corticosteroid. AB - Objective: To investigate the effect of antenatal corticosteroid prophylaxis on neonatal respiratory morbidity between 34 and 37 weeks of gestation. Methods: This retrospective study evaluated the neonatal respiratory complications of 683 low risk singleton pregnancies delivered at 34-37 weeks of gestation in a tertiary care center between Jan 2012 and Sept 2015. Group-I (n=294) comprised data of woman who did not receive betamethasone and Group-II(n=396) comprised those who received betamethasone after 34 weeks of gestation for cases at risk of preterm birth. Primary outcome was neonatal respiratory morbidity (NRM). NRM was defined as any respiratory disease that required medical support including supplemental oxygen, nasal continuous positive airway pressure, endotracheal intubation, or exogenous surfactant, with more than 25% oxygen for > 10 minute to maintain neonate oxygen saturation >90% Demographic characteristics, mode of delivery, fetal birth weight and neonatal respiratory complications was compared between the two groups. Results: There was no statistically significant difference for neonatal respiratory morbidity development rate between patients who received betamethasone or those who did not receive it. The incidence of neonatal respiratory morbidity was similar (15.3% in the control group and 14.9% in the intervention group; p=0.88). Conclusion: We found no improvement with betamethasone administration empirically in late preterm birth as regards prevention of Neonatal Respiratory Morbidity(NRM). PMID- 29492066 TI - Comparison of three formulae for estimation of glomerular filtration rate in severely malnourished children at tertiary care facility. AB - Objectives: First objective was to compare eGFR by Updated Schwartz (US) and Simple Height Independent (SHID) formula with Original Schwartz (OS) in children with Severe Acute Malnutrition (SAM). The second objective was to compare eGFR in children below and above two years. Methods: This analytic study on estimation of GFR was based on retrospective data collected from 78 children with SAM at Nutritional Rehabilitation Unit from October 2014 - March 2015. Glomerular filtration rate was calculated using serum creatinine (S. Cr) and height in Original Schwartz, US and by age in SHID equation and compared with OS as standard. Data was analyzed using descriptive statistics. Results: There were 78 children in this study. Males were 39(50%). Mean age of patients was 18+/-15.53 months with 62(79.48%) <=24 months. Mean weight, height and Mid Upper Arm Cir cumference was 5.69+/-2.42kg, 68.52+13.59 cm and 10+/-1.57 cm respectively. Mean eGFR by OS, US and SHID formula was 71.45+/-49.89, 58.06+/-3.91 and 59.33+/ 3.73ml/min/1.73m2 respectively. There was significant difference (0.001) in mean eGFR calculated by three different formulae. Majority of children (73%) had subnormal GFR (<90 ml/min /1.73 m2). There was a significant difference in GFR >=90ml calculated by US compared to OS (0.025) and by SHID with OS (0.04) in children below two years and no difference in children above two years. But there was no difference in other categories of eGFR calculated by either of formula in both age groups. Conclusion: We found a significant difference in eGFR in ranges above 90 ml/min/1.73 m2 by US compared to OS as well as by SHID with OS in children below two years and no difference in children above two years. Also, there was no difference in GFR categories below 90 ml/min /1.73 m2 calculated by either of formula in both age groups. So, we may conclude that either of formula can be used in clinical practice for eGFR in mild to severe renal dysfunction in severely malnour-ished children. PMID- 29492067 TI - Impact of maternal education, employment and family size on nutritional status of children. AB - Objective: To determine the impact of maternal education, employment, and family size on nutritional status of children. Methods: It was case control study conducted at OPD of children Hospital Lahore, from September 2015 to April 2017. Total 340 children (170 cases and 170 controls) with age range of six months to five years along with their mothers were included. Anthropometric measurements were plotted against WHO growth Charts. 170 wasted (<-2 SD) were matched with 170 controls (>= -2 SD). Maternal education, employment and family size were compared between the cases and control. Confounding variables noted and dichotomized. Univariate analysis was carried out for factors under consideration i.e.; Maternal Education, employment and family size to study the association of each factor. Logistic regression analysis was applied to study the independent association. Results: Maternal education had significant association with growth parameters; OR of 1.32 with confidence interval of (CI= 1.1 to 1.623). Employment status of mothers had OR of 1.132 with insignificant confidence interval of (CI=0.725 to 1.768). Family size had OR of one with insignificant confidence interval (CI=0.8 -1.21). Association remained same after applying bivariate logistic regression analysis. Conclusion: Maternal education has definite and significant effect on nutritional status of children. This is the key factor to be addressed for prevention or improvement of childhood malnutrition. For this it is imperative to launch sustainable programs at national and regional level to uplift women educational status to combat this ever increasing burden of malnutrition. PMID- 29492068 TI - Clinical analysis of Primary Gastrointestinal Non-Hodgkin's Lymphoma. AB - Objective: To study the clinical characteristics and prognostic factors of survival for patients with primary gastrointestinal non-Hodgkin's lymphoma (PGI NHL). Methods: A retrospective analysis was performed for 104 PGI-NHL patients who were admitted in Baoding First Central Hospital from July 2003 to January 2014. Results: There were 58 males and 46 females. The median age of onset was 53 (15-83) years old. In terms of pathogenic sites, there were 51 gastric cases (49.00%) and 53 intestinal cases (51.00%), with the median survival of 35 (1-130) months. The 1-, 3- and 5-year overall survival (OS) rates were 88.40%, 80.70% and 78.80%, respectively. The factors influencing the progression-free survival (PFS) and OS rates were studied by univariate and multivariate analyses. The PFS and OS rates of patients with B-cell PGI-NHL were significantly higher than those of patients with T-cell PGI-NHL (P<0.05). The PFS and OS rates of patients with primary gastric lymphoma were significantly higher than those of patients with primary intestinal lymphoma (P<0.05), but the data were not associated with Ann Arbor stage or LDH level (P>0.05). Compared with non-surgical patients, only patients with intestinal lymphoma benefited from surgery (P<0.05). Conclusion: The pathogenic site and pathological type are risk factors that affect the survival of PGI-NHL patients, and chemotherapy should be given the first priority for patients with primary gastric lymphoma. PMID- 29492069 TI - Change in central corneal thickness, corneal endothelial cell density, anterior chamber depth and axial length after repair of rhegmatogenous retinal detachment. AB - Objective: To compare the effects of Pars Plana Vitrectomy (PPV) and Scleral Buckling (SB) with reference to Central Corneal Thickness (CCT), Corneal Endothelial-Cell Density (CED), Anterior Chamber Depth (ACD) and Axial Length (AL) in repair of Rhegmatogenous Retinal Detachment (RRD). Methods: This comparative cross sectional analytical study was conducted at Armed Forces Institute of Ophthalmology (AFIO), Rawalpindi from July 2013 to July 2015. A total of 69 eyes of 69 patients which underwent repair of RRD by either PPV or SB were analyzed to compare mean change in CCT, CED, ACD and AL between two groups. Results: Mean age of patients was 56.23+/-5.22 years. Mean pre-operative CCT, CED, ACD and AL in PPV group was 533.06+/-13.28um, 2231.67+/-164.57Cells/mm2, 3.37+/-0.18mm and 23.66+/-0.76mm respectively. Mean post-operative CCT, CED, ACD and AL in PPV group was 534.81+/-11.83um, 2037.19+/-167.83 Cells/mm2, 3.24+/ 0.13mm and 23.88+/-0.80mm respectively. Change in CED, ACD and AL from pre operative value after PPV was statistically significant (p<0.001). Mean pre operative CCT, CED, ACD and AL in SB group was 530.73+/-12.59 um, 2161.79+/ 161.96 Cells/mm2, 3.343+/-0.14mm and 23.67+/-0.82mm respectively. Mean post operative CCT, CED, ACD and AL in SB group was 532.76+/-7.74 um, 2158.27+/-156.58 Cells/mm2, 3.24+/-0.10mmand 25.71+/-0.86mm respectively. Change in ACD and AL from pre-operative value after SB was statistically significant (p<0.001). Mean change of CED, ACD and AL between two groups was also statistically significant (p<0.001). Conclusion: Rhegmatogenous retinal detachment repair causes ocular changes, with significantly more decrease in corneal endothelial cell density after pars plana vitrectomy, and more increase in anterior chamber depth and axial length after scleral buckling. PMID- 29492070 TI - Examination of short and long term complications of thermocautery, plastic clamping, and surgical circumcision techniques. AB - Objective: In this study, thermocautery, plastic clamping, and conventional (open surgical) circumcision techniques were compared in terms of their complications. Methods: Male patients who underwent circumcisions between May 2014 and May 2015 in two separate pediatric surgery clinics were retrospectively analyzed using the hospital registry system. These patients were evaluated in terms of age, accompanying pathologies, anesthesia techniques, complication rates, duration of surgery, and circumcision techniques. A statistical analysis of the data was performed, with a P<0.05 considered to be statistically significant. Results: The patients were divided into three groups according to the circumcision method: conventional surgical circumcision (n=833), thermocautery (n=1011), and plastic clamp (n=218). Complications were observed in 21 cases (1%): bleeding (11), infection (2), trapped penis (6), meatitis (1), and scrotal injury (1). There were significantly fewer complications in the thermocautery technique when compared to the clamping and surgical circumcision techniques. The plastic clamping and thermocautery techniques were superior to a surgical circumcision in terms of the operation time. Conclusion: The thermocautery circumcision technique can be used easily in both the operating theatre and in designated circumcision rooms, with a lower complication rate, when compared to plastic clamping and surgical circumcisions. PMID- 29492071 TI - Flipped classroom instructional approach in undergraduate medical education. AB - Objective: In this study we implemented the "flipped classroom" model to enhance active learning in medical students taking neurosciences module at Aga Khan University, Karachi. Methods: Ninety eight undergraduate medical students participated in this study. The study was conducted from January till March 2017. Study material was provided to students in form of video lecture and reading material for the non-face to face sitting, while face to face time was spent on activities such as case solving, group discussions, and quizzes to consolidate learning under the supervision of faculty. To ensure deeper learning, we used pre and post-class quizzes, work sheets and blog posts for each session. Student feedback was recorded via a likert scale survey. Results: Eighty four percent students gave positive responses towards utility of flipped classroom in terms of being highly interactive, thought provoking and activity lead learning. Seventy five percent of the class completed the pre-session preparation. Students reported that their queries and misconceptions were cleared in a much better way in the face-to-face session as compared to the traditional setting (4.09 +/ 1.04). Conclusion: Flipped classroom(FCR) teaching and learning pedagogy is an effective way of enhancing student engagement and active learning. Thus, this pedagogy can be used as an effective tool in medical schools. PMID- 29492072 TI - Correlation of dual-source computed tomography/dual-energy imaging with pathological grading of lung adenocarcinoma and its clinical value. AB - Objective: To explore the correlation of dual-source computed tomography (DSCT)/dual-energy imaging with pathological grading of lung adenocarcinoma. Methods: A total of 47 patients with lung adenocarcinoma were selected. Tissues were histopathologically confirmed by routine DSCT scanning and dual-energy enhanced scanning. Arterial-phase and venous-phase iodine distribution images and single-energy images at 40-190 keV were obtained. The region of interest was outlined to obtain CT values. The iodine concentrations of each tumor in two phases were recorded to calculate normalized iodine concentrations (NICs). Results: The maximum diameter and minimum diameter of tumors in low differentiation (LD) group were significantly higher than those of high differentiation (HD) group (P<0.05). In LD group, 70.8% of margins were lobulated, which significantly exceeded that of HD group (30.4%) (P<0.05). Besides, 26.1% of patients in HD group were complicated with ground-glass opacity, which was significantly higher than that of LD group (4.2%) (P<0.05). In venous phase, there were significant differences between the two groups at low energy levels (40-70 keV) (P<0.05). At high energy levels (80-190 keV), the CT values of LD group were slightly higher than those of HD group. In arterial and venous phases, NICs of HD group were lower than those of LD group (P>0.05). Conclusion: HD and LD groups could be predictably distinguished by single-energy images at low energy levels (40-70 keV) in the venous phase. Quantitative analysis of NIC in the venous phase is also valuable for predicting the pathological grade of lung adenocarcinoma. PMID- 29492073 TI - Validation of serum C-reactive protein for the diagnosis and monitoring of antibiotic therapy in neonatal sepsis. AB - Objective: To evaluate the adequacy of serum C-reactive protein (CRP) in diagnosing neonatal sepsis and role of CRP in determining the duration of antibiotic treatment in neonatal sepsis. Methods: In this validation study, we included 135 neonates with suspected diagnosis of sepsis within duration of nine months from September 2016 to May2017 in Children Hospital Multan. Blood samples were drawn from every neonate for culture sensitivity and measurement of serum C reactive proteins. In all suspected neonates, empirical antibiotics e.g. Gentamycin or Ampicillin were started after taking blood samples. Serum CRP levels >5 mg/dl were marked as positive results. 2nd blood samples for measurement of serum CRP were taken after 72 hours of the first sample. There were two primary endpoints; one to determine the sensitivity and specificity of CRP against blood culture and second was to determine the negative predictive value of CRP in determining the duration of anti-biotic in neonates presenting with sepsis. Results: Out of these 135 babies, 102 (75.5%) were confirmed to have sepsis using blood culture reports. CRP results were Positive in 85 (62.9%) neonates on first baseline measurement and were positive in 103 (76.29%) neonates after 72 hours of admission. The sensitivity of CRP in diagnosing sepsis was 98.03%, specificity was 91.0%, positive predictive value (PPV) was 97% and negative predictive value (NPV) was 93.7%. The mean duration of antibiotic treatment in CRP guided group was 5.03 days versus 7.02 days in standard treatment duration group (p-value <0.001). The NPV of CRP in determining the duration of antibiotics was 100.0%. Conclusion: Serum CRP level is a reliable test in establishing the diagnosis of neonatal sepsis. It accurately monitors the duration of antibiotic therapy and results in significant reduction in the treatment duration of neonatal sepsis. PMID- 29492074 TI - Retinal and Choroidal Thickness in Patients with High Myopia without Maculopathy. AB - Objective: To evaluate macular choroidal thickness (CT) and retinal thickness in Turkish patients with high myopia without maculopathy and in normal subjects and to examine the association with age, axial length (AL), best corrected visual acuity (BCVA), cycloplegic refraction, and spherical equivalent (SE). Methods: This prospective study was performed between January 2015 and June 2016 in the Department of Ophthalmology, Duzce University Medical Faculty. It had 65 individuals (30 patients with high myopia, 35 healthy subjects). Retinal and choroidal images were obtained using spectral-domain optical coherence tomography (OCT). Measurements (one subfoveal, three temporal, three nasal) were taken at 500 MUm intervals up to 1,500 MUm using the caliper system. Only the right eye was used for subsequent analysis. Results: The mean age was 29.5 +/- 14.5 years and 25.6 +/- 7.0 in the high myopia and control groups, respectively. The subfoveal CT was significantly lower in the high myopia group (mean, 218.3 +/- 102.25 mm) than the control group (mean, 331.83 +/- 99.06 mm; p < 0.001). In both groups, the choroid was thinnest at the nasal 1,500 MUm location, being 158.40 +/ 90.8 MUm and 301 +/- 103.59 MUm, respectively. Retinal thickness in both groups was thickest at the nasal 1,500 MUm location and thinnest in the subfoveal region. In patients with high myopia, CT was negatively correlated with AL (r= 0.490, p=0.006) and age (r=-0.455, p=0.012). Conclusions: Highly myopic eyes have a thinner choroid, which may be secondary to longer AL but is not an independent factor. Further studies in the field of OCT are important to exploring the pathology of high myopia. PMID- 29492075 TI - Application of BiPAP through Endotracheal Tube in Comatose Patients with COPD Exacerbation. AB - Objective: To evaluate the effectiveness and safety of using BiPAP through endotracheal tube in comatose Chronic Obstructive Pulmonary Disease (COPD) patients with hypercapnic respiratory failure. Methods: This is a prospective study done at Department of Chest Medicine, Jinnah Postgraduate Medical Centre, Karachi, during March to June 2017. It included all comatose COPD patients with hypercapnic respiratory failure who had a poor functional status prior to the illness and who did not meet the criteria to be kept on mechanical ventilator. Patients with apnea and other causes of coma were excluded. These patients were applied BiPAP through endotracheal tube and its response on blood gases and neurological status was evaluated. Results: The success rate of BiPAP through endotracheal tube was 70.5% (31/44). Improvement in Glasgow Coma Scale (GCS) score (p<0.01), pH (p<0.01), and PaCO2 (<0.01) was observed among the responders following two hours and 24 hours of therapy. No significant difference was found in response with regards to gender, smoking status, prior use of noninvasive ventilation or duration of disease. No complications were observed during the therapy. Conclusion: In resource poor settings, the use of BiPAP through endotracheal tube can be an effective and safe intervention for comatose COPD patients with hypercapnic respiratory failure. PMID- 29492077 TI - CNS relapse of diffuse large B cell Lymphoma A single centre experience. AB - Background and Objective: Central nervous system (CNS) relapse of diffuse large B cell lymphoma (DLBCL) is relatively uncommon and nearly fatal. Two years CNS relapse risk is 0.8% in low, 3.9% in intermediate and 12% in high risk patients. Our aim was to study, the baseline characteristics and outcome in term of median survival of DLBCL patients with CNS relapse. Methods: This is a retrospective analysis. All patients of DLBCL with CNS relapse from 2006 to 2014 were included. Data were collected from computerized Hospital Information System and analyzed for characteristics and median survival. Results: Out of twenty one patients included in the study, 14(66.3%) males and 7(33.7%) were females. On initial diagnosis of DLBCL, median age was 37.4 years (27-47). Ann Arbor stage of I-IV was in 3 (14.3%), 2(9.5%), 4(19%) and 12(57.1%) patients, respectively. Extra nodal involvement was noted in 16(76.2%), high LDH in 18(85.7%), bone marrow involvement in 8(38.1%) and bulky disease in 5(23.8%) patients. International Prognostic Index (IPI) score was 1 in 4(19%), 2 in 9(42.9%), 3 in 8(38.1%) patients. Extra-nodal sites were gut in 2(9.1%) while 1(4.5%) patient of each of following organs involvement was seen: cervix, gluteal muscle, iliac bone, liver, ovaries, pancreas, parotid gland and testes. Chemotherapy CHOP was given to 16(76.2%) and RCHOP in 5(23.8%) patients. Prophylactic intrathecal methotrexate was given to 10(47.6%) patients. Complete response was in 10 (47.6%), partial response was in 3 (14.3%) and disease progression was in 8 (38.1%) patients. CNS relapse occurred in 17 (81%) patients within six months after completion of therapy. CNS relapse along with systemic disease was in 14(66.6%) patients. Isolated CNS relapse was noted in 7(33.3%) patients. Second line chemotherapy regimens were HDMTX 5(23.8%), HDMTX/TRIO IT 3(14.2%), HDMTX/HDAC 2(9.5%), HCVAD 3(14.2%), ICE 4(19.4%), DHAP 1(4.7%), ICE/HDMTX 1(4.7%), none 2(9.5%). Overall median survival of CNS relapsed patients was 54 days. Conclusion: Patients with DLBCL who had advanced stage, high LDH and extra-nodal involvement at initial presentation are at high risk for CNS relapse. About half of the patients had CNS relapse despite primary CNS prophylaxis. Once relapsed in CNS, these patients have very poor prognosis. PMID- 29492078 TI - Smoking Cessation with Medication and Behaviour Therapy. AB - Background and Objective: Smoking Cessation Clinics (SCCs) involve the use of cognitive behavior therapy and effective medications provided by specialists. Our objective was to report socio-demographic data, investigative services provided, and determine the smoking cessation success. Methods: Data from all hospitals affiliated with the Beyoglu Public Hospitals Union were obtained between January 1, 2015 and December 31, 2015. Data from Sisli Hamidiye Etfal Training and Research Hospital were reviewed via retrospective chart review in the same period. Frequency and average values were determined using statistical software. In the evaluation of related factors, chi-square and student t tests were applied; p <= 0.05 was considered statistically significant. Results: The mean admission age was 38.72 +/- 12.20 years (min 13; max 94). Women tended to be older than men at the time of admission but men started smoking younger than women. Less than the high school educated subjects started smoking at early ages. The smoking cessation rate was 39.3% (n = 219) when treated with medication and behavioral therapy. Conclusion: About 48% smokers stopped smoking after treatment with medications and behaviour therapy. Most of the smokers were between 30-50 years of age. More Smoking Cessation Clinics should be established to allow access to more highly educated patients to smoking cessation resources. PMID- 29492076 TI - Analysis of the surgical treatment of fracture in HIV positive patients: A clinical study. AB - Objective: To evaluate the incidence of postoperative infection and fracture nonunion as well as the risk factors for postoperative infection in human immunodeficiency virus (HIV) positive patients. Methods: From May 2013 to March 2016, the HIV positive fracture patients treated surgically in orthopaedics department of our hospital were analyzed retrospectively, and fifty HIV negative fracture patients during the same period were selected as control. The clinical data of included patients were reviewed. The incidence of postoperative infection and fracture nonunion were compared between the two groups, and the risk factors for postoperative infection in HIV positive patients were evaluated. Results: The incidence of poor wound healing and incision infection in HIV positive group was higher than that in HIV negative group, but there were no significant differences between the two groups (p>0.05). Multivariable regression analysis demonstrated that HIV clinical category (p<0.05), CD4+T-lymphocyte category (p<0.01) and open fracture (p<0.05) were independent risk factors for postoperative wound infections, but age, gender, operation time, incision type, emergency operation, albumin and lymphocyte count were not (p>0.05). There was no significant difference in the rate of nonunion between the two groups (p>0.05). Conclusion: The incision can be healed, and fracture can be united normally in most of HIV positive patients with fracture, and postoperative wound infections were significantly associated with HIV clinical category, CD4+T-lymphocyte category and open fracture. PMID- 29492079 TI - Is Political Activism on Social Media an initiator of Psychological Stress? AB - Objective: To find out the association of psychological stress with political activism on social networking sites (SNS) in adults. To find association of psychological stress and political activism with age, gender and occupational status. Methods: A descriptive cross-sectional study of 8 months (Aug 2014 to March 2015) was conducted on young adults between age group of 20-40 years of different universities of Rawalpindi, Pakistan. Closed ended standardized questionnaires (i.e. Cohen Perceived Stress-10) were distributed via non probability convenient sampling among a total sample size of 237. Sample size was calculated using WHO sample size calculator and data was analyzed in STATA version 12. Results: The mean age of participants was 21.06+/-1.425 years. Out of the 237 participants, 150 (63.3%) were males and 87 (36.7%) females. Regarding their occupation, 13 (51.9%) were military cadets, 8 (3.4%) were consultant, 47 (19.8%) medical officer, 3 (1.3%) PG students and 56 (23.6%) MBBS students. Significant association of occupation was established with both political activism and psychological stress (p=0.4 and p=0.002 respectively). Among 237 individuals, 91 (38.4%) were stressed out and 146 (61.6%) were not. Among whole sample, political activists on SNS were found to be 23 (9.7%). Out of these 23 individuals who were politically active, 15 (65.2%) were stressed out and 8 (34.7%) were not. A significant association between stress and political activism was established (p=0.005). Conclusion: Political activism via social networking sites is playing significant role on adult person's mental health in terms of stress among different occupation. PMID- 29492080 TI - Therapeutic effects of Pulpotomy and Pulpectomy on deciduous molars with deep caries. AB - Objective: To evaluate the therapeutic effects of pulpotomy and pulpectomy on deciduous molars with deep caries. Methods: A total of 124 children (192 molars) with deep caries treated from February 2014 to February 2015 were selected. They each had at least one molar with deep caries. MTA pulpotomy (101 molars) and Vitapex pulpectomy (91 molars) as well as prefabricated metal crown repair were conducted. The patients were followed up for 18 months after surgery, and the therapeutic effects were evaluated through clinical and X-ray examinations. Results: The proportion of molars without lesions was 80.20% in pulpotomy group, which significantly exceeded that of pulpectomy group (72.53%). The pulpotomy group with good clinical manifestations underwent spontaneous pain in four molars during follow-up, and five molars gradually underwent pain and gingival redness and swelling. The pulpectomy group suffered from occlusion discomfort in nine molars and gingival fistula in seven molars during follow-up. The postoperative morbidity of pulpectomy group was significantly higher than that of pulpotomy group (chi2=4.50, P=0.04). The 18-month tooth survival rates of pulpotomy and pulpectomy groups were 90% and 79% respectively, which were significantly different (chi2=4.645, P=0.031). Conclusion: The postoperative outcomes of pulpotomy are superior to those of pulpectomy. PMID- 29492081 TI - Impact of network aided platforms as educational tools on academic performance and attitude of pharmacology students. AB - Objective: This cross-sectional study aimed to examine the impact of learning management system and WhatsApp application as educational tools on students' academic achievement and attitude. Methods: The sample population was the students of six medical colleges of Riyadh, Saudi Arabia attending Medical Pharmacology's semester course in Bachelor of Medicine, Bachelor of Surgery (MBBS) program from September 2016 to January 2017. An exploratory approach was adopted based on a comparison between students exposed to only in-class lectures (Group-N), in-class lectures together with WhatsApp platform to disseminate the lecture slides (Group-W) and students group with in-class lectures facility blended with Learning Management System (LMS) and WhatsApp platform (Group-WL). The students' grades were assessed using unified multiple choice questions at the end of the semester. Data were analyzed using descriptive statistics and Pearson correlation (p<0.01). Results: Using learning management system (LMS) and/or WhatsApp messenger tool showed a significant positive correlation in improving students' grades. Additionally, use of WhatsApp enhances students' in-class attendance though statistically insignificant. Conclusion: The results are pivotal for a paradigm shift of in-class lectures and discussion to mobile learning (M-learning). M-learning through WhatsApp may be as an alternative, innovative, and collaborative tool in achieving the required goals in medical education. PMID- 29492082 TI - Association between body mass index and activities of daily living in homecare patients. AB - Objective: Overweight or obesity may cause many chronic illnesses. Furthermore, several studies have shown that high body mass index is associated with mortality and morbidity among the elderly. Therefore, obesity or being overweight could adversely affect the performance of activities of daily living. In this study our aim was to investigate the association between Body Mass Index and Activity of Daily Living in Homecare Patients. Method: The records of 2016 from the homecare unit of Sisli Hamidiye Etfal Training and Research Hospital were retrospectively reviewed. During this period, 1105 patients visited this facility. Unconscious or bedridden patients (hemiplegia, hemiparesia, and tetraparesis) and patients with incomplete data were excluded from the study. Therefore, the survey was completed with 250 files, which included all the data needed for our research. Age, gender, Body Mass Index and Barthel Index scores were recorded to the statistical program; p<=0.05 was considered as statistically significant. Results: One hundred fifty one (60.4%) were women, and 99 (39.6%) were men. The relations between gender and age, weight, and Barthel index scores were not statistically significant. There was a significant positive correlation between weight and Barthel index scores as well as between Body Mass Index and Barthel index scores (r = 0.190; p = 0.003). The patients were divided into two groups: Group-I (underweight and normal weight) and Group-II (overweight and obese). Group-II exhibited a much higher ability to perform Activity of Daily Living than Group-I (p = 0.002). Conclusion: Some studies report that obesity is protective against Activity of Daily Living, but the opposite is reported in some others. Our study showed increased values of Body Mass Index and Activity of Daily Living ability, which are indicative of protective effects. The relationship between Body Mass Index and physical disability is not yet proven to be linear. PMID- 29492083 TI - Recognition of sentinel lymph nodes in patients with papillary thyroid cancer by nano-carbon and methylene blue. AB - Objective: To compare the accuracy and feasibility of methylene blue and nano carbon in clinical tracing of sentinel lymph nodes (SLNs) in patients with papillary thyroid cancer (PTC). Methods: Ninety-six PTC patients were selected and randomly divided into a methylene blue group and a nano-carbon group (n=48). During surgery, tracer agent was injected around the tumor, and SLNs were resected and subjected to frozen pathological examination. The results were compared with those of routine pathological examination after surgery. Results: Latent lymph node metastasis (level VI and lateral neck) was detected in both groups, with neck distribution of SLNs. There was no significant difference in the detection rate or accuracy of SLNs between two groups (P>0.05). The incorrect resection rate of parathyroid gland and incidence of temporary hypoparathyroidism in the methylene blue group were significantly higher than those of the nano carbon group (t=4.137, P<0.05). Conclusions: The state of PTC lymph nodes can be well evaluated by SLN biopsy using both methylene blue and nano-carbon as tracers, but using nano-carbon has a lower incidence rate of parathyroid injury, with great clinical prospects accordingly. PMID- 29492084 TI - Determinants of health expenditure in OECD countries: A decision tree model. AB - Objective: This study aimed to identify the major variables in the estimation of health expenditure in OECD member countries with the decision tree method and to categorize the member countries by health expenditure. Methods: The study population comprised the 2014 data of the 35 OECD countries. In the study, health expenditure as a share of gross domestic product was the dependent variable while gross domestic product per capita, percentage of total population covered by public and private insurance, out-of-pocket health expenditure as percentage of total expenditure on health, age dependency ratio, life expectancy at birth, number of hospitals per million population, number of physicians per 1000 population/head counts, pharmaceutical sales and perceived health status were designated as independent variables. The decision tree model was constructed with the CART algorithm using the Orange data mining software package. Results: In the study, GDP per capita, life expectancy at birth, age dependency ratio, number of hospitals and percentage of the population with a bad perceived health status were identified as the major variables in the estimation of health expenditure. OECD countries were categorized in 6 groups according to the decision tree model. According to the CART algorithm used in the model, the classification accuracy rate and the precision of estimation were computed as 80.56% and 81.25%, respectively. Conclusion: The study results revealed that the most important determinant for estimating the share of GDP allocated to health expenditure was GDP per capita. Future studies should be conducted with the inclusion of different variables in the model. PMID- 29492085 TI - Clinical relationship between auditory neuropathy and nervous system diseases. AB - Objective: To explore the clinical relationship between auditory neuropathy (AN) and nervous system diseases. Methods: A total of 134 AN patients who were treated in our hospital from December 2011 to April 2016 were selected. Then 120 cases (240 ears) with complete data of pure tone audiometry and acoustic immittance test were selected as an AN1 group, which was compared with 30 patients (49 ears) with general sensorineural hearing loss (SHL) in regard to the results of pure tone audiometry and acoustic immittance test. On the other hand, 79 cases (158 ears) of the 134 patients with complete data of DP otoacoustic emission test were selected as an AN2 group, which was compared with 30 normal subjects (60 ears) regarding the results of DP otoacoustic emission test. Results: Increases in the pure-tone hearing threshold by air conduction of AN1 group significantly exceeded those of SHL group at 0.125 and 0.25 kHz (low frequency) (P<0.05). The former group had significantly lower values at 1.0, 2.0 kHz (moderate frequency) and 4.0, 8.0 kHz (high frequency) (P<0.05). Of 134 patients, 14 (19 ears) had evoked V wave upon auditory brainstem response, whereas no waves after I wave were evoked in other tested ears. Distortion product (DP) otoacoustic emissions could all be evoked. AN2 group had significantly higher amplitudes of DP-gram than those of normal control group at 0.5 and 0.7 kHz (low frequency) (P<0.05). Except for three cases of unsteady walking and 10 of dizziness, others did not suffer from typical symptoms of vertigo attack. As to caloric test-induced electronystagmograms, there were 30 bilaterally normal cases (75.0%), one case of left-side semicircular canal paresis (25%) and nine cases of bilateral semicircular canal paresis (22.5%). Four patients with other nervous system diseases were complicated with AN. Other nervous system disorders included three cases of optic nerve atrophy and 7 of lower limb nerve damage. Conclusion: According to characteristic hearing dysfunction, AN may occur in the afferent pathway of acoustic nerve, probably accompanied by the pathological changes of efferent nerve in the olivocochlear system inside the brainstem. PMID- 29492086 TI - Multidisciplinary team (MDT) meeting and Radiologist workload, a prospective review in a tertiary care hospital. AB - Objective: To quantify the increase in workload associated with multidisciplinary team meetings for radiologists in a tertiary care hospital over a period of 15 months. Methods: Data was collected prospectively regarding number of multidisciplinary team meetings, number of clinical cases discussed, number of individual imaging studies reviewed, and preparation time of residents, senior registrar and consultants and the delivery time of meeting. Results: Total 223 meetings were held over 15 months (April 2014 to June 2015) for 12 clinical specialty areas. There were 1120 clinical case discussions and a total of 2759 documented individual imaging studies reviewed. Resident's preparation time was 74.6 hours/month, senior registrar's preparation time was 47.93 hours/month, consultant's preparation time was 18.67 hours/month and the total duration time for meetings was 18 hours/month. Conclusion: Multidisciplinary team meetings now represent a significant workload of radiology and has reduced the time for other academic activities within the department. PMID- 29492087 TI - Atorvastatin as an adjuvant with betamethasone valerate reduces disease severity and cardiovascular risks in Psoriasis. AB - Objectives: To evaluate the effect of Atorvastatin as an adjuvant with betamethasone valerate on disease severity and cardiovascular risks in chronic plaque type psoriatic patients. Methods: It is an interventional study conducted in Pharmacology Department of BMSI, JPMC with the collaboration of Dermatology Department of JPMC, Karachi. The duration of study was from June 2013 to June 2016. Seventy five psoriatic patients were prescribed Tablet Atorvastatin 40-20 mg/day (40mg for first three months twice daily followed by 20mg once daily for the next three month) plus topical Betamethasone Valerate 0.1% once daily for 6 months (three week apply than one week interval). The efficacy and safety profile of drugs was measured by PASI, DLQI, hsCRP, LFTS and Lipid profile. Results: The percentage change of PASI is 86.749+/-0.547, DLQI is 82.697+/-.2.61 and hsCRP is 40.371+/-8.505, which showed highly significant improvement in patient at the end of last follow up. LFTs and CPK for safety profile of therapy showed non significant results. Conclusion: Atorvastatin used as an adjuvant therapy with currently existing standard therapy (topical betamethasone) in patients having mild to moderate plaque type psoriasis reduces disease severity and cardiovascular risks. PMID- 29492089 TI - How to run a successful Journal. AB - Publishing and successfully running a good quality peer reviewed biomedical scientific journal is not an easy task. Some of the pre-requisites include a competent experienced editor supported by a team. Long term sustainability of a journal will depend on good quality manuscripts, active editorial board, good quality of reviewers, workable business model to ensure financial support, increased visibility which will ensure increased submissions, indexation in various important databases, online availability and easy to use website. This manuscript outlines the logistics and technical issues which need to be resolved before starting a new journal and ensuring sustainability of a good quality peer reviewed journal. PMID- 29492088 TI - AAA Syndrome, Case Report of a Rare Disease. AB - Triple A (Allgrove) syndrome, an autosomal recessive disease is characterized by achalasia, alacrimia and ACTH-resistant adrenal failure with progressive neurological syndrome including central, peripheral and autonomic nervous system impairment, and mild mental retardation. The triple A syndrome gene, designated AAAS, localized on chromosome 12q 13 encodes for a 546 amino acid protein called ALADIN (Alacrimia-Achlasia-Adrenal Insufficiency and Neurologic disorder). This report relates to two sisters, aged 8 and 12 years, who had vomiting, muscle weakness, alacrimia, excessive fatigue and dysphagia. Abdominal sonography, esophago-gastroduodenoscopy, barium swallow, esophageal manometry, CT scan abdomen and brain, biochemical profiles, as well as neurologic and ophthalmic evaluations were consistent with Allgrove's syndrome. Management consisted of pneumatic balloon dilatation for achalasia and initiation of cortisone therapy with successful resolution of dysphagia and other symptoms. PMID- 29492090 TI - A Study on Catalase Gene Promoter Polymorphism -21 A/T (rs7943316) in Healthy Pakistani population. AB - Background & Objective: Catalase (CAT) is an important endogenous antioxidant enzyme that detoxifies H2O2 into water and oxygen, consequently limiting the deleterious effects of reactive oxygen species. It has suggested that CAT-21A/T (rs7943316) OMIM: 115500 gene promoter polymorphism is predominantly associated with different human disorders such as hypertension, cancers, diabetes, nephropathy, and other diseases accompanied by oxidative stress. This study was designed to investigate the prevalence of mutant T allele frequency in healthy individuals. Methods: The study group consisted of 110 healthy individuals were enrolled from Baqai Institute of Diabetology and Endocrinology (BIDE), Karachi, Pakistan, during the period of April 2010 to May 2013. DNA was isolated from leukocytes. Genotyping of CAT-21A/T (rs7943316) gene promoter polymorphism was carried out using thermal cycler followed by RFLP. Blast N analysis was performed for the confirmation of gene sequences. Results: In CAT-21A/T (rs7943316) gene promoter polymorphism, wild type genotype (AA) was observed in 18.26% and alterered genotype (AT/TT) found in 81.74% cases. Conclusions: Data demonstrates that frequency and distribution of mutant T allele was more prevalent as compared to wild type A allele in the study group. PMID- 29492091 TI - Micro-Feedback Training:Learning the art of effective feedback. AB - Multiple attributes are expected of postgraduate research supervisors. Provision of timely and effective face-to-face feedback is one such skill that carries enormous significance in supervisee's professional development. Feedback allows the supervisees to improve upon their performances. Unfortunately, both supervisors and supervisees have contrasting approaches towards the ongoing feedback practices. This incongruence is attributed, in part, to a lack of structured pedagogic training among the medical professionals. A standardized schema is therefore required to acquire and harmonize this pedagogical skill. One such systemized way is a training method called microteaching. Microteaching has long been used to enhance and incorporate old and new undergraduate teaching skills, respectively. Here we propose a similar structured approach of micro feedback to inculcate effective feedback skills among postgraduate research supervisors using feedback-based scenarios, simulated students, standardized checklists and audiovisual aids. Thus, micro-feedback exercise may prove to be quite promising in improving feedback practices of postgraduate research supervisors. PMID- 29492092 TI - Determination of patients requiring elective surgery following successful endoscopic detorsion in sigmoid volvulus. AB - Sigmoid volvulus (SV) is an unusual type of colonic obstruction, in which the sigmoid colon wraps around itself. As a rule, SV is decompressed via endoscopy in uncomplicated cases, while surgery is required in complicated cases. However, the recurrence rate following endoscopic detorsion is relatively high, with a relatively high mortality rate. Consequently, as a prophylactic procedure to prevent recurrence, elective surgery is suggested in some patients. Nevertheless, the selection criteria are open to questioning. In this report, we evaluate those criteria based on the broad experience of our clinic, and suggest elective surgery in patients in ASA classes I-III. PMID- 29492093 TI - Un-ruptured Non-Coronary Sinus of Valsalva Aneurysm with Complete Heart Block. AB - Sinus of Valsalva aneurysm is a rare cardiac anomaly with wide spectrum of clinical presentation ranging from asymptomatic state to dreadful complications due to compression of vital surrounding structures or aortic dissection. There are only few reported cases of sinus of Valsalva aneurysm presented with cardiac arrhythmias including complete heart block. We herein, present a case of a 50 year male who presented with complete heart block. A large noncoronary sinus of Valsalva aneurysm compressing the surrounding atrioventricular junctional tissue was detected incidentally during echocardiographic study, which was considered to be the cause of patient's complete heart block. This case report implies the importance of clinical suspicion of secondary causes like sinus of Valsalva aneurysm in patients with complete heart block and utility of echocardiography in the evaluation of heart block patients. PMID- 29492094 TI - Dealing a Neonate with CHARGE Syndrome:Anaesthesia perspective of perioperative care. AB - CHARGE syndrome is a condition that can disturb numerous areas of human body. As an abbreviation CHARGE stands for: coloboma, heart defects, atresia choanae, and retardation of growth, genital, and ear abnormalities. The configuration of malformations differs among individuals with this disorder, and the various health issues can be life-threatening during infancy and childhood. Affected individuals typically have several main features or a combination of major and minor appearances. Here we are presenting a case report of a neonate with CHARGE syndrome who underwent successful repair of choanal atresia under general anaesthesia with invasive monitoring. PMID- 29492095 TI - Evaluation of eczema, asthma, allergic rhinitis and allergies among the Grade-1 children of Iqaluit. AB - Background: Little is known about the prevalence of asthma, allergic rhinitis, eczema and allergies among Canadian Inuit children, especially those living in the arctic and subarctic areas. Methods: A cross-sectional study among Grade 1 students attending schools in Iqaluit, the capital of Nunavut, was conducted during the 2015/2016 school year. We used the International Study of Allergy and Asthma in Children questionnaire with added questions relevant to the population. In addition, skin prick tests were conducted to test for sensitization to common food and environmental allergens. Results: The prevalence of current asthma was 15.9% (> 2:1 males) with the highest prevalence among those with any non-Inuit heritage at 38.5%. The prevalence of current and past allergic rhinitis was 6.8%, also predominant among males, with the lowest prevalence among the mixed ethnicity. Home crowdedness was inversely related to past asthma. Being ever outside Nunavut was associated with higher prevalence of current and past asthma. No statistically significant relationship was found with passive smoking or exclusive breast feeding during the first 4 months of life. The current eczema prevalence was 20.5%, with the highest prevalence recorded among the Inuit at 25% compared to 15.4% among the mixed ethnicity and 14.3% among the non-Inuit. We noted a high rate of sensitization to cat at 26.7% while absent sensitization to other common inhalant allergens. Conclusion: Variations in the prevalence and risk factors of asthma, allergic rhinitis and eczema among different ethnicities living at the same subarctic environment may be related to genetic, gene environment interaction and/or lifestyle factors that require further investigation. PMID- 29492096 TI - Total antioxidant capacity of the diet modulates the association between habitual nitrate intake and cardiovascular events: A longitudinal follow-up in Tehran Lipid and Glucose Study. AB - Background: Considering the lack of data on the association between habitual dietary intakes of nitrate (NO3-) and nitrite (NO2-) and cardiovascular events, we assessed possible effects of dietary NO3- and NO2-, in the context of total antioxidant capacity (TAC) of the diet, with the risk of cardiovascular (CVD) outcomes. Methods: Adult men and women without CVD (n = 2369) were recruited from the Tehran Lipid and Glucose Study and were followed for a mean of 6.7 years. Dietary NO3- and NO2- intakes, as well as dietary TAC and nitric oxide (NO) index were assessed at baseline (2006-2008). Multivariable-adjusted Cox proportional hazards regression models were used to estimate risk of CVD above and below median of dietary intakes of NO3-/NO2- and dietary TAC and NO index. Due to a significant interaction between NO3-/NO2- intake and TAC, stratified analyses were done for < and >= median dietary TAC. Results: Daily mean (SD) dietary NO3- and NO2- intakes were 460 (195) and 9.5 (3.9) mg; mean (SD) dietary TAC and NO index was 1406 (740) and 338 (197) MUmol trolox equivalent (TE)/100 g. In subjects with lower dietary TAC, higher intake of NO3- (>= 430 mg/d) was accompanied with an increased risk of CVD (HR = 3.28, 95% CI = 1.54-6.99). There were no significant associations between dietary intakes of NO2-, TAC of the diet and NO index with the occurrence of CVD events during the study follow-up. Conclusion: High habitual intake of NO3-, in the context of low TAC of the food, may be associated with the risk of CVD outcomes. PMID- 29492097 TI - Active Aging and Elderly's Quality of Life: Comparing the Impact on Literature of Projects Funded by the European Union and USA. AB - Background: The objective of this research is to verify whether European projects on Active Aging (AA) and Elderly Quality of Life (Qol) funded by the Seventh Framework Programme (FP7) produce an impact on literature similar to projects funded by the National Health Institute (NHI) of the United States on international literature using well-known bibliometric indicators. This effort may be useful in developing standardized and replicable procedures. Methods: Fifteen randomly selected projects on AA and Elderly Qol concluded in August 2017 and funded by FP7 were compared to similar projects funded by the US NHI with reference to papers published (Scopus and Scholar), papers published in Q1 journals, and the number of citations of the papers linked to the projects. Results: In all the indicators considered, the European projects showed no difference with the US NHI projects. Conclusions: The EU-funded AA and Qol Elderly projects have an impact on scientific literature comparable to projects funded in the United States by the NHI Agency.Our results are consistent with the data on general medical research, which indicates that, European research remains at a high level of competitiveness.In this experimental study, our methodology appeared to be convincing and reliable and it could be applied to the extent of the impact of more extensive research areas.Our research did not evaluate the relationship between funding required by research and scientific productivity. PMID- 29492098 TI - Development of models for classification of action between heat-clearing herbs and blood-activating stasis-resolving herbs based on theory of traditional Chinese medicine. AB - Background: Action ("gongxiao" in Chinese) of traditional Chinese medicine (TCM) is the high recapitulation for therapeutic and health-preserving effects under the guidance of TCM theory. TCM-defined herbal properties ("yaoxing" in Chinese) had been used in this research. TCM herbal property (TCM-HP) is the high generalization and summary for actions, both of which come from long-term effective clinical practice in two thousands of years in China. However, the specific relationship between TCM-HP and action of TCM is complex and unclear from a scientific perspective. The research about this is conducive to expound the connotation of TCM-HP theory and is of important significance for the development of the TCM-HP theory. Methods: One hundred and thirty-three herbs including 88 heat-clearing herbs (HCHs) and 45 blood-activating stasis-resolving herbs (BAHRHs) were collected from reputable TCM literatures, and their corresponding TCM-HPs/actions information were collected from Chinese pharmacopoeia (2015 edition). The Kennard-Stone (K-S) algorithm was used to split 133 herbs into 100 calibration samples and 33 validation samples. Then, machine learning methods including supported vector machine (SVM), k-nearest neighbor (kNN) and deep learning methods including deep belief network (DBN), convolutional neutral network (CNN) were adopted to develop action classification models based on TCM-HP theory, respectively. In order to ensure robustness, these four classification methods were evaluated by using the method of tenfold cross validation and 20 external validation samples for prediction. Results: As results, 72.7-100% of 33 validation samples including 17 HCHs and 16 BASRHs were correctly predicted by these four types of methods. Both of the DBN and CNN methods gave out the best results and their sensitivity, specificity, precision, accuracy were all 100.00%. Especially, the predicted results of external validation set showed that the performance of deep learning methods (DBN, CNN) were better than traditional machine learning methods (kNN, SVM) in terms of their sensitivity, specificity, precision, accuracy. Moreover, the distribution patterns of TCM-HPs of HCHs and BASRHs were also analyzed to detect the featured TCM-HPs of these two types of herbs. The result showed that the featured TCM-HPs of HCHs were cold, bitter, liver and stomach meridians entered, while those of BASRHs were warm, bitter and pungent, liver meridian entered. Conclusions: The performance on validation set and external validation set of deep learning methods (DBN, CNN) were better than machine learning models (kNN, SVM) in sensitivity, specificity, precision, accuracy when predicting the actions of heat clearing and blood-activating stasis-resolving based on TCM-HP theory. The deep learning classification methods owned better generalization ability and accuracy when predicting the actions of heat-clearing and blood-activating stasis resolving based on TCM-HP theory. Besides, the methods of deep learning would help us to improve our understanding about the relationship between herbal property and action, as well as to enrich and develop the theory of TCM-HP scientifically. PMID- 29492099 TI - Diagnostic validity of fine-needle capillary cytology in palpable tumours at the Oncology Institute of Peru. AB - Objective: To evaluate the diagnostic validity of fine-needle capillary cytology (FNCC) in palpable tumours. Material and methods: A retrospective, single-tray, cross-sectional diagnostic test study was carried out. We reviewed the cytological reports of the case files of the Cytology Unit of the Northern Regional Institute of Neoplastic Diseases (IREN) from January 2012 to December 2016. Results: A total of 332 patients were selected, with an average age of 54.77 years (range 13-90 years); 61.4% of patients were female. The most frequent anatomical sites were lymph nodes (49.7%), thyroid (13.3%), breast (12.3%) and soft tissues (11.4%). Twenty-five cytologies did not have a histological correlation and six showed an atypical result. In the lymph node study, the most frequent pathology was metastatic carcinoma (49.7%), followed by lymphoma (13.3%). The FNCC had a sensitivity of 99.55%, a specificity of 98.77%, a positive predictive value of 99.55% and a negative predictive value of 98.77%. The positive likelihood ratio was 80.63%. Conclusions: FNCC is a useful, safe, reliable and economical ambulatory technique with minimal complications and high diagnostic accuracy. PMID- 29492100 TI - Knowledge and attitude of women regarding breast cancer screening tests in Eastern Iran. AB - Introduction: According to recent statistics, there has been a rapid growth of breast cancer in developing countries. Thus, early detection is essential. This study is based on the perception of people in the Northeast of Iran regarding breast cancer screening. Methods: In a cross-sectional study, 1469 women were selected randomly in the period from April to November 2016. The study population consisted of women or their companions referring to outpatient clinics or people in public urban areas who filled out a breast cancer screening questionnaire in an interview. Results: The patients' age was in the range of 14 to 84 years (mean = 38.8). More than 84% of interviewees were not informed of breast cancer and screening tests. The main reasons mentioned by patients for their failure to do screening tests was 'absence of any symptom or problem' and 'they did not think it was necessary'.There was not a significant difference between income level, marital status and knowledge of people about breast cancer screening tests (P > 0.05). However, employment, education level and family history had a positive effect on people's awareness of breast cancer and its screening tests (P < 0.05). Conclusion: The lack of knowledge in people from low socio-economic classes was the main barrier to breast cancer screening. In this regard, organizing training programs by physicians and the media can help raise screening rates. PMID- 29492101 TI - InforMD: a new initiative to raise public awareness about breast density. AB - On a mammogram, breast density (also known as mammographic density) is shown as white and bright regions and is associated with reduced sensitivity in cancer detection and increased breast cancer risk. However, many Australian women are unaware of the significance of breast density as it is not routinely reported or discussed. In order to address this lack of knowledge, Australian breast cancer researchers with expertise in mammographic density formed the InforMD alliance (INformation FORum on Mammographic Density) in 2016. The alliance is working to raise awareness of breast density with the goal of improving breast cancer diagnosis and health outcomes for women. The InforMD website (www.InforMD.org.au) was launched in October 2016, coinciding with a major nationwide public awareness campaign by the alliance during breast cancer awareness month. The website contains unbiased, accurate, updated information on breast density. The website also provides summaries of major research articles in layperson language, recent news items related to breast density, links to relevant information for health professionals, events, and feature articles. Members of the public and health professionals can also subscribe for news updates. The interactive online Forum section facilitates discussion between health professionals, scientists and members of the public. To increase online traffic to the website, Facebook (www.facebook.com/BeInforMD) and Twitter (https://twitter.com/BeInforMD_) pages were launched in December 2016. Since its launch, InforMD has generated considerable interest. The public awareness campaign reached over 7 million Australians through a combination of newspaper, TV, radio, and online news. The website has attracted 13,058 unique visitors and 30,353 page views (data as of 19/12/2017). Breast cancer researchers have a significant role to play in disseminating information to the public on breast density. A combination of mainstream and social media, together with a well-informed and updated website, has laid the groundwork for the InforMD alliance to reach a wide audience. PMID- 29492102 TI - Radical en bloc peritonectomy in advanced ovarian cancer. AB - In order to reach cytoreduction in advanced ovarian cancer, peritonectomy and diaphragmatic stripping are procedures required to remove the disease in the upper abdomen. Diaphragm involvement is estimated in up to 40% of cases. Nevertheless, in some of these patients, the tumour volume may constitute a limitation of the technique due to the association with abdominal wall involvement, bulky tumour at the Morrison's pouch or liver infiltration. Extensive upper abdominal procedures should represent a basic resource for the gynaecologic oncologist in order to reach an optimal cytoreduction. A radical peritonectomy with en bloc resection for treating advanced ovarian cancer with extensive widespread diaphragmatic peritoneal carcinomatosis is showed in this surgical film. PMID- 29492103 TI - Awareness and compliance with pharmacovigilance requirements amongst UK oncology healthcare professionals. AB - Since 2013, once a medicine receives marketing authorisation in the European Union, it is labelled with an inverted black triangle indicating all adverse reactions should be reported. Our aim was to explore understanding of the black triangle and compliance with adverse event (AE) reporting requirements by UK oncology healthcare professionals (HCPs). A questionnaire was electronically distributed to oncology pharmacists (P) via the British Oncology Pharmacy Association, to oncologists (O) through the Association of Cancer Physicians and also to nurses (N) via the UK Oncology Nursing Society. Overall, 125 (42 O, 61 P, 22 N) clinicians participated. The purpose of the black triangle was unknown by 26% (55% O, 5% P, 28% N) and 54% did not alter their AE reporting in the presence of a black triangle. Once the black triangle was removed, only 38% were aware which AEs should be reported, 46% did not report all serious AEs for established medicines, including life-threatening or disabling AEs. Reasons for non-reporting were decision making on what to report (45%); time consumed by reporting (41%); AEs perceived as not serious enough (35%) and follow-up process (23%). Understanding of the pharmacovigilance framework among respondent groups was variable. Across all groups, AEs appear substantially under-reported. Reasons identified in the study include the time consuming nature of AE reporting and a lack of understanding around the black triangle and AE reporting process. There is a need to further support HCP education on AE reporting coupled with a review of the current reporting process to ensure maximal engagement. PMID- 29492104 TI - Secondary breast cancer after Hodgkin lymphoma: a case report and literature review. AB - The occurrence of secondary breast cancers in women previously exposed to chest irradiation for Hodgkin lymphoma (HL) is considered as a major issue for the quality of life of these long-term survivors as well as a challenge for clinical management. This study reports a case of a woman treated for HL at the age of 24 years, who developed breast cancer after an interval of 20 years. This case highlights once again the importance of awareness among HL survivors about their increased breast cancer risk and re-launches the debate about the efficacy of adoption of breast screening guidelines. PMID- 29492105 TI - Direct and highly productive conversion of cyanobacteria Arthrospira platensis to ethanol with CaCl2 addition. AB - Background: The cyanobacterium Arthrospira platensis shows promise as a carbohydrate feedstock for biofuel production. The glycogen accumulated in A. platensis can be extracted by lysozyme-degrading the peptidoglycan layer of the bacterial cell walls. The extracted glycogen can be converted to ethanol through hydrolysis by amylolytic enzymes and fermentation by the yeast Saccharomyces cerevisiae. Thus, in the presence of lysozyme, a recombinant yeast expressing alpha-amylase and glucoamylase can convert A. platensis directly to ethanol, which would simplify the procedure for ethanol production. However, the ethanol titer and productivity in this process are lower than in ethanol production from cyanobacteria and green algae in previous reports. Results: To increase the ethanol titer, a high concentration of A. platensis biomass was employed as the carbon source for the ethanol production using a recombinant amylase-expressing yeast. The addition of lysozyme to the fermentation medium increased the ethanol titer, but not the ethanol productivity. The addition of CaCl2 increased both the ethanol titer and productivity by causing the delamination of polysaccharide layer on the cell surface of A. platensis. In the presence of lysozyme and CaCl2, ethanol titer, yield, and productivity improved to 48 g L-1, 93% of theoretical yield, and 1.0 g L-1 h-1 from A. platensis, corresponding to 90 g L-1 of glycogen. Conclusions: We developed an ethanol conversion process using a recombinant amylase-expressing yeast from A. platensis with a high titer, yield, and productivity by adding both lysozyme and CaCl2. The direct and highly productive conversion process from A. platensis via yeast fermentation could be applied to multiple industrial bulk chemicals. PMID- 29492106 TI - The structural and functional contributions of beta-glucosidase-producing microbial communities to cellulose degradation in composting. AB - Background: Compost habitats sustain a vast ensemble of microbes that engender the degradation of cellulose, which is an important part of global carbon cycle. beta-Glucosidase is the rate-limiting enzyme of degradation of cellulose. Thus, analysis of regulation of beta-glucosidase gene expression in composting is beneficial to a better understanding of cellulose degradation mechanism. Genetic diversity and expression of beta-glucosidase-producing microbial communities, and relationships of cellulose degradation, metabolic products and the relative enzyme activity during natural composting and inoculated composting were evaluated. Results: Compared with natural composting, adding inoculation agent effectively improved the degradation of cellulose, and maintained high level of the carboxymethyl cellulose (CMCase) and beta-glucosidase activities in thermophilic phase. Gene expression analysis showed that glycoside hydrolase family 1 (GH1) family of beta-glucosidase genes contributed more to beta glucosidase activity in the later thermophilic phase in inoculated compost. In the cooling phase of natural compost, glycoside hydrolase family 3 (GH3) family of beta-glucosidase genes contributed more to beta-glucosidase activity. Intracellular beta-glucosidase activity played a crucial role in the regulation of beta-glucosidase gene expression, and upregulation or downregulation was also determined by extracellular concentration of glucose. At sufficiently high glucose concentrations, the functional microbial community in compost was altered, which may contribute to maintaining beta-glucosidase activity despite the high glucose content. Conclusion: This research provides an ecological functional map of microorganisms involved in carbon metabolism in cattle manure rice straw composting. The performance of the functional microbial groups in the two composting treatments is different, which is related to the cellulase activity and cellulose degradation, respectively. PMID- 29492107 TI - Multimodal analysis of pretreated biomass species highlights generic markers of lignocellulose recalcitrance. AB - Background: Biomass recalcitrance to enzymatic hydrolysis has been assigned to several structural and chemical factors. However, their relative importance remains challenging to evaluate. Three representative biomass species (wheat straw, poplar and miscanthus) were submitted to four standard pretreatments (dilute acid, hot water, ionic liquid and sodium chlorite) in order to generate a set of contrasted samples. A large array of techniques, including wet chemistry analysis, porosity measurements using NMR spectroscopy, electron and fluorescence microscopy, were used in order to determine possible generic factors of biomass recalcitrance. Results: The pretreatment conditions selected allowed obtaining samples displaying different susceptibility to enzymatic hydrolysis (from 3 up to 98% of the initial glucose content released after 96 h of saccharification). Generic correlation coefficients were calculated between the measured chemical and structural features and the final saccharification rates. Increases in porosity displayed overall strong positive correlations with saccharification efficiency, but different porosity ranges were concerned depending on the considered biomass. Lignin-related factors displayed highly negative coefficients for all biomasses. Lignin content, which is likely involved in the correlations observed for porosity, was less detrimental to enzymatic hydrolysis than lignin composition. Lignin influence was highlighted by the strong negative correlation with fluorescence intensity which mainly originates from monolignols in mature tissues. Conclusions: Our results provide a better understanding of the factors responsible for biomass recalcitrance that can reasonably be considered as generic. The correlations with specific porosity ranges are biomass species dependent, meaning that enzymes cocktails with fitted enzyme size are likely to be needed to optimise saccharification depending on the biomass origin. Lignin composition, which probably influences its structure, is the most important parameter to overcome to enhance enzymes access to the polysaccharides. Accordingly, fluorescence intensity was found to be a rapid and simple method to assess recalcitrance after pretreatment. PMID- 29492108 TI - Human ring chromosome registry for cases in the Chinese population: re emphasizing Cytogenomic and clinical heterogeneity and reviewing diagnostic and treatment strategies. AB - Background: Constitutional ring chromosomes are rare orphan chromosomal disorders. Ring chromosome syndrome featuring growth retardation and mild to intermediate intellectual disability is likely caused by the dynamic behavior of ring chromosome through cell cycles. Chromosomal and regional specific phenotypes likely result from segmental losses and gains during the ring formation. Although recent applications of genomic copy number and sequencing analyses revealed various ring chromosome structures from an increasing number of case studies, there was no organized effort for compilating and curating cytogenomic and clinical finding for ring chromosomes. Methods: A web-based interactive 'Human Ring Chromosome Registry' using Microsoft Access based relational database was developed to present genetic and phenotypic findings of ring chromosome cases. Chinese ring chromosome cases reported in the literature was reviewed and compiled as a testing data set to validate this registry. Results: A total of 113 cases of ring chromosomes were retrieved in all chromosomes except for chromosomes 16, 17 and 19. The most frequently seen ring chromosomes by a decreasing order of relative frequencies were ring 13 (14%), X (12%), 22 (10%), 15 (9%), 14 (7%), and 18 (7%). Genomic imbalances were detected in 18 out of 19 cases analyzed by microarray or sequencing. Variable clinical manifestations of developmental delay, dysmorphic facial features, intellectual disability, microcephaly, and hypotonia were noted in most autosomal rings. Chromosomal specific syndromic phenotypes included Wolf-Hirschhorn syndrome in a ring chromosome 4, cri-du-chat syndrome in a ring chromosome 5, epilepsy in ring chromosomes 14 and 20, Turner syndrome in ring chromosome X, and infertility in ring chromosomes 13, 21, 22 and Y. Effective growth hormone supplemental treatment for growth retardation in a ring chromosome 18 was noted. Conclusions: Based on findings from these Chinese ring chromosome cases, guidelines for cytogenomic diagnosis and criteria for case registration were proposed. Further research to define underlying mechanisms of ring chromosome formation and dynamic mosaicism, to delineate the genotype-phenotype correlations, and to develop chromosome therapy for ring chromosomes were discussed. PMID- 29492109 TI - Higher frequency of hamstring injuries in elite track and field athletes who had a previous injury to the ankle - a 17 years observational cohort study. AB - Background: Inversion injury to the ankle and hamstring injuries are common problems in most sports. It is not known whether these injuries constitute a predisposing factor or a precursor of injury or re-injury of these anatomical locations. Therefore, we wished to test the hypothesis that a previous inversion ankle injury exerted a significant effect on the chance of an athlete suffering from a subsequent ipsilateral hamstring injury and vice versa. Methods: In an observational cohort study over 17 years (1998-2015), 367 elite track and field athletes, were grouped according to their first traumatic isolated ankle or hamstring injury. Fifty athletes experienced both injuries. The Mann-Whitney U and Chi-square tests (p < 0.05) were performed to test possible associations of ankle and hamstring injury with age, gender, athletics discipline, grade, and type of antecedent injury. Results: Athletes with a preceding ankle injury had a statistically significantly higher chance of experiencing a subsequent hamstring injury compared with athletes who had experienced a hamstring injury as their first traumatic event (x2 = 4.245, p = 0.039). The proportion of both ankle and hamstring injury events was not statistically different between female (18%) and male (11%) athletes. Age and grade of injury did not influence the proportion of ankle and/or hamstring injury events. Conclusion: There is a statistically significantly higher frequency of hamstring injuries in elite track and field athletes having experienced a previous ankle ligament injury. PMID- 29492110 TI - Spectrum of cardiovascular diseases in six main referral hospitals of Ethiopia. AB - Background: The spectrum of cardiovascular diseases varies between and within countries, depending on the stage of epidemiological transition and risk factor profiles. Understanding this spectrum requires regional and national data for each region or country. This study was designed to determine the spectrum of cardiovascular diseases in six university hospitals in Ethiopia. Methods: This is a cross-sectional study of the spectrum of cardiovascular diseases in six main referral/teaching hospitals located in different parts of the country. Consecutive patients visiting the follow-up cardiac clinics of these hospitals from 1 January to 30 June 2015 were included in the study. Data were collected on a pretested questionnaire. Results: A total of 6275 patients (58.5% females) were included in the study. Nearly 61% of the patients were from urban areas. The median age was 33 years (IQR 14-55 years). Valvular heart disease was the most common diagnosis, accounting for 40.5% of the cases. Of 2541 patents with valvular heart disease, 2184 (86%) were cases of chronic rheumatic heart disease. Conclusion: Our study shows that chronic rheumatic valvular heart disease is the most common cardiovascular diagnosis among patients seen at cardiology clinics of six referral/teaching hospitals in the country, followed by congenital heart diseases. Hypertensive and ischaemic heart diseases also accounted for a significant proportion of the cases. Therefore, strategies directed towards primary and secondary prevention of acute rheumatic fever as well as prevention of risk factors for hypertension and ischaemic heart disease may need to be strengthened. PMID- 29492111 TI - Efficacy and safety of sarilumab in patients with active rheumatoid arthritis. AB - The mainstay of rheumatoid arthritis (RA) treatment involves the use of medications that slow disease progression and reduce inflammation. Inadequate treatment responses and intolerances to conventional RA treatment have led to the development of biologic agents for the management of moderate-to-severe disease activity. Interleukin-6 (IL-6) inhibition is one of the targets for biologic activity in RA treatment. IL-6 is found in excess in the synovial fluid and contributes to joint erosion through its action on osteoclast cells. Sarilumab is a new IL-6 inhibitor indicated for the treatment of moderate-to-severe RA as monotherapy or in combination with conventional therapies in patients with an inadequate response to previous RA treatment. PMID- 29492112 TI - Azlactone-Functionalized Polymers as Reactive Platforms for the Design of Advanced Materials: Progress in the Last Ten Years. AB - Polymers functionalized with azlactone (or oxazolone) functionality have become increasingly useful for the rapid and modular design of functional materials. Because azlactones can react via ring-opening reactions with a variety of different nucleophilic species (e.g., primary amines, hydroxyl groups, and thiol functionality), azlactone-functionalized materials can serve as convenient 'reactive' platforms for the post-synthesis or post-fabrication introduction of a broad range of chemical functionality to soluble polymers, insoluble supports, and surfaces/interfaces. The last decade has seen an increase in both the number and the variety of reports that exploit the properties and the reactivities of azlactone-functionalized polymers. Here, we highlight recent work from several different laboratories, including our own, toward the design and characterization of azlactone-functionalized polymers, with a particular emphasis on: (i) new synthetic approaches for the preparation of well-defined azlactone-functionalized polymers using living/controlled methods of polymerization, (ii) the design and modular synthesis of side-chain functionalized polymers and block copolymers via post-polymerization modification of azlactone-functionalized polymers, (iii) the development of reactive polymeric supports useful in the contexts of separations and catalysis, and (iv) methods for the fabrication of reactive thin films and other approaches to the immobilization of azlactone functionality on surfaces and interfaces. Examples discussed herein reveal a growing awareness of azlactone functionality as a useful tool for polymer chemists, and highlight several ways that the unique reactivity of these materials can both complement and provide useful alternatives to other reactive polymers currently used to design functional materials. PMID- 29492113 TI - Review of Surgical Anatomy of the Tumors Involving Cavernous Sinus. AB - The lesions involving cavernous sinus (CS) and lateral sellar region includes tumors, vascular lesions, infection, inflammation, and trauma. Tumors associated with CS cause significant distortion of the microanatomy posing an additional surgical challenge to the neurosurgeons. The surgical approach and microsurgical anatomy with respect to the origin and growth of the tumor within the CS region have not been comprehensively described in recent years. We conducted a review of literature concerning CS and associated tumors, complied through MEDLINE/OVID and using cross-references of articles on PubMed with the keywords cavernous sinus, CS tumors, pituitary adenoma, meningioma, schwannoma, chordoma, CS hemangiomas, extradural, interdural, intradural, skull base, gamma knife radiosurgery, endoscopic endonasal approach. Based on the tumor origin and growth pattern, the tumors associated with CS can be classified into three categories: Type-I: tumor originating from CS, Type-II: originating from lateral wall of CS, and Type-III: extraneous origin and occupying CS. The review focuses on approach to a tumor within each type of tumor in the CS region. The emphasis is that the tumor growth pattern and significant distortion of the CS anatomy caused by the tumor growth should be considered while planning the optimal surgical approach for tumors in this region to ensure complete tumor resection with minimal neurovascular morbidity. PMID- 29492114 TI - Direct Cerebral Revascularization: Extracranial-intracranial Bypass. AB - In 1967, the first extracranial to intracranial (EC-IC) arterial anastomosis was performed. Since that time, EC-IC bypass surgery has become a widely accepted surgical treatment for patients with IC stenotic or occlusive atherosclerotic lesions. This article will discuss the history, indications, types, surgical methods, and complications of the EC-IC bypass. PMID- 29492115 TI - Is Mechanical Ventilation Mandatory for the Management of Severe Head Injury? Outcome in 53 Medically Managed Severe Head Injury Patients, Without Ventilatory Support: A Prospective Study. AB - Background: Severe head injury (SHI) is a major cause of mortality and morbidity across the world. The current paradigm of management of SHI involves admission in Intensive Care Unit (ICU), mechanical ventilation (MV), and intracranial pressure (ICP) monitoring. Such resources are expensive and often unavailable in the developing world. Objective: MV or ICP monitoring was unavailable for our patients due to the scarcity of resources. Hence, other alternatives were considered to prevent secondary brain injury due to hypoxia. This study assessed the outcome after SHI when managed with an early tracheostomy (ET). Methods: This prospective observational study over 13 months included all medically managed SHI patients without MV or ICP monitoring. The Glasgow outcome scale (GOS) was assessed at discharge and compared with published historical data reported after treatment in an ICU environment. Results: Our study included 53 unoperated patients with SHI among 1862 patients with traumatic brain injury. Overall mortality was 24.5% (13/53) and compared favorably with reported mortality of 25% 40% reported from centers using intensive management. At discharge, the favorable outcome with a GOS of 4 or 5 was seen in 39.6% (21/53). Conclusion: With ET, the results of management of SHI in our patients were comparable to results reported after MV in an ICU environment. Hence, ET is a cost-effective alternative when resources are scarce. MV should be used if hypoxia persists after tracheostomy. Although MV effectively prevents hypoxia, it has complications. We conclude that although MV was unavailable for our patients, they did not have the complications associated with it. PMID- 29492116 TI - Cerebral Contusion: An Investigation of Etiology, Risk Factors, Related Diagnoses, and the Surgical Management at a Major Government Hospital in Cambodia. AB - Introduction: Cerebral contusions are a common type of injury among the Cambodian population, mostly due to road traffic accidents. This article aims to assess various aspects around brain contusion focusing on the condition at admission, residing province, mechanism and time of injury, age and sex distribution with differing helmet wearing, and alcohol consumption patterns. Hospitalization related data such as treatment and outcome were analyzed. Methods: This was a retrospective analysis of 406 cases who have been admitted during the period between May 2013 and May 2016. Results: Two hundred and ninety-five (75.51%) of the patients came from rural areas, 312 (76.84%) were male (mean age 31.17 +/- 12.90 years for males and 38.5 +/- 16.29 years for females). The average hospital stay amounted to 10.51 +/- 6.67 days. One hundred and eight two cases (52.29%) happened between 4.00 and 11.00 p.m. Three hundred and nineteen (79%) of the injured patients were motorcycle drivers and 18% pedestrians. Male patients had an alcohol involvement in 135 (49.45%) (females in 5 [6.25%]) cases and 26 (10%) wore a helmet (females in 5 [6.25%]). Surgery was performed in 82 cases, specifically craniotomy and craniectomy +/- elevation of a depressed skull fracture. Two hundred and ninety-six (73.09%) patients showed related second diagnosis, mostly subdural hematoma in 96 (32.43%) and epidural hematoma in 63 (21.28%) cases. Fifty patients (13.16%) had a Glasgow Coma Scale of 3-8. 92 (24.21%) of 9-12 and 238 (62.63%) of 13-15 on admission. Most of the patients were discharged with an improved status 324 (91.52%) according to the Glasgow Outcome Scale 4 or 5. Conclusion: The severity and resulting neurologic impairment of cerebral contusions show the importance of more in-depth research and prevention programs. PMID- 29492117 TI - The Effect of Hand Exercise on Reducing the Symptoms in Hemodialysis Patients with Carpal Tunnel Syndrome. AB - Context: Carpal tunnel syndrome (CTS) is one of the most common peripheral neuropathies, and there is no consensus on the preferred method of treatment. Aims: The aim of this study is to determine the effects of hand exercise performed with a ball on symptoms and to evaluate the results in hemodialysis (HD) patients with CTS. Settings and Design: This study was conducted in patients with HD who were treated in dialysis centers and state hospitals in Turkey between 2011 and 2012. Subjects and Methods: This study included 19 patients (28 hands) that were diagnosed as CTS. For exercise treatment, a hand and finger exercise ball that consists of two parts: a foam body and flexible rubber cords was used. Patients placed their fingers through each cord, squeezed it for 1 s, and then opened their fingers against the cord for 1 s. Patients repeated this exercise for 30 s to 1 min/day. Statistical Analysis Used: The McNemar, Friedman ANOVA, and the Wilcoxon test with a Bonferroni correction were used on SPSS 20.0 software package program. P < 0.05 was considered statistically significant. Results: Results showed that recovery was performed from physical examination results, grip strength, and Boston questionnaire scores. About 21.4% of patients' electrophysiological results were negative at the end of the 1st month and 32.1% of them at the end of the 3rd month. Conclusion: Due to the slowed progress of CTS and detection of slight improvement in evaluation parameters, this self applicable and practical exercise can be used as an alternative treatment of mild CTS in patients with HD. PMID- 29492118 TI - Etanercept Prevents Histopathological Damage after Spinal Cord Injury in Rats. AB - Background: The aim of our study is to assess the neuroprotective effects of the tumor necrosis factor alpha (TNF-alpha) inhibitor etanercept (ETA) on histopathological and biochemical changes following spinal cord injury (SCI). Patients and Methods: Fifty-four male Wistar albino rats were randomly assigned into three main groups: The sham, trauma, and ETA group (n = 18 per group). Each of these groups was further divided into three subgroups (n = 6 per subgroup) based on the different tissue sampling times postinjury: 1 h, 6 h, and 24 h. Clip compression model was used for SCI. Rats in the ETA group were treated with 5 mg/kg of ETA immediately after the clip was removed. After 1, 6, and 24 h, the spinal cord was totally removed between the levels T8-T10. Sample tissue was immediately harvested and fixed for histopathological and electron microscopic examination and were analyzed for TNF-alpha, interleukin-1beta (IL-1beta), superoxide dismutase (SOD), adenosine deaminase, catalase (CAT), and malondialdehyde levels in both the tissue and serum. Results: The serum and tissue levels of cytokines and enzymes were seen to change after SCI between hyperacute, acute, and subacute stages. Treatment with ETA selectively inhibited TNF-alpha, and IL-1beta expression together with increased levels of antioxidative enzymes (SOD, CAT). Conclusion: Early administration of ETA after SCI may remarkably attenuate neuronal injury by decreasing tissue and serum TNF alpha and IL-1beta levels, while increasing antioxidative enzymes such as SOD and CAT in subacute and acute stages, respectively. PMID- 29492120 TI - Aneurysm of Anterior Inferior Cerebellar Artery-posterior Inferior Cerebellar Artery Variant. AB - Aneurysms arising from anterior inferior cerebellar artery-posterior inferior cerebellar artery (AICA-PICA) variant are extremely rare. They usually present with subarachnoid hemorrhage. This is probably the second case report of a large thrombosed AICA-PICA variant aneurysm presenting as a cerebellopontine angle mass lesion with cranial nerve palsy, managed successfully by surgical clipping. PMID- 29492119 TI - Significant Effect of Anti-tyrosine Kinase Inhibitor (Gefitinib) on Overall Survival of the Glioblastoma Multiforme Patients in the Backdrop of Mutational Status of Epidermal Growth Factor Receptor and PTEN Genes. AB - Introduction: We aimed to assess the effect of anti-tyrosine kinase inhibitors (TKIs) (gefitinib) in overall survival (OS) of the glioblastoma multiforme (GBM) patients in the backdrop of mutational status of epidermal growth factor receptor (EGFR) and PTEN genes. Materials and Methods: All the patients subjected to resection or biopsies were put on gefitinib, and radiotherapy was delivered as per the hospital protocol. EGFR and PTEN mutational spectrum was performed by single-strand conformation polymorphism followed by DNA sequencing. Results: In total, 50% GBM tumors had mutation either in EGFR or PTEN. Median progression free survival (PFS) and OS observed in patients with EGFR +ve/PTEN -ve were significantly favorable (P < 0.05) which aggregated to 9(7, 11) months and 20 (16, 24) months, respectively, than 6 (4, 8) months and 13 (7, 19) months in patients with PTEN +ve/EGFR -ve. Patients positive for both EGFR/PTEN had lower disease-free survival and OS of 6 and 9 months as compared to 6 (5, 7) and 14 (12, 24) months for those negative for both EGFR/PTEN. Conclusions: We conclude that EGFR gene alterations with wild-type PTEN are associated with significantly better PFS and OS in patients treated with anti-TKIs (gefitinib). Combined EGFR and PTEN gene mutation is associated with significantly poor response to gefitinib in terms of median OS. PMID- 29492121 TI - Fatal Intracranial Hemorrhage in a Patient with Severe Dengue Fever. AB - Dengue fever has been a major cause of morbidity and mortality in subtropical and tropical countries. We report a rare case of severe dengue with spontaneous intracranial hemorrhage. A search of literature through PubMed revealed that the largest series analyzed so far only included five cases. A 47-year-old man presented with 7 days history of fever, headache, myalgia, and vomiting with hematemesis. On the day of presentation, he had reduced consciousness and an episode of generalized tonic-clonic seizure. His Glasgow Coma Scale was E1V1M3 with anisocoria. Postresuscitation computed tomography of the brain revealed a right subdural and left thalamic hemorrhage. His blood investigations revealed thrombocytopenia, dengue virus type 1 nonstructural protein antigen test was positive, dengue IgM negative, and dengue IgG positive. A right decompressive craniectomy was done. Unfortunately, the patient died soon after. Spontaneous intracranial hemorrhage in patients with dengue fever is an uncommon entity but usually carry a grave prognosis. To date, there has been no clear management guideline for such cases, as both operative and nonoperative approaches have their own inherent risks. PMID- 29492122 TI - Misdiagnosed Case of Scalp Arteriovenous Malformation. AB - Scalp arteriovenous malformations (AVMs) are abnormal vascular lesions that can be treated safely and effectively, with surgical or endovascular approaches. Because of their complex vascularity, the detailed preoperative evaluation must be carefully performed. Here, we present a case of scalp AVM that required two operations as a result of a misdiagnosis because of inadequate preoperative assessment. PMID- 29492123 TI - De novo Craniopharyngioma of the Fourth Ventricle: Case Report and Review of Literature. AB - Craniopharyngiomas usually involve the sella and suprasellar space. Their occurrence in the posterior fossa without extension to the suprasellar region is uncommon with only 16 cases reported in the literature. We report a case of a primary posterior fossa craniopharyngioma that was managed by complete excision with a good recovery. Our case was unique in that the craniopharyngioma occurred in the fourth ventricle and extended downward to the level of C1, a manifestation that was reported only twice in the past. The literature on the topic is reviewed. PMID- 29492124 TI - Posttraumatic Cervicovertebral Junction Acute Subdural Hematoma and Cisterna Magna Subarachnoid Hemorrhage Presenting with Progressive Hydrocephalus. AB - Herein, we discuss a rare case of posttraumatic cervicovertebral junction subdural hematoma and associated cisterna magna subarachnoid hemorrhage. Due to progression in the hydrocephalus, he has undergone midline suboccipital craniectomy and evacuation of the hematoma. The patient made an uneventful recovery. PMID- 29492125 TI - Falcine Myxoid Chondrosarcoma: A Rare Aggressive Case. AB - Chondrosarcoma is the second most common primary malignancy of bone after osteosarcoma. Cranial primary chondrosarcomas mostly originate from the skull base cartilage formation zones. Parasagittal falcine origin is very rare for primary extra-skeletal intracranial chondrosarcomas. We report a rare case of primary myxoid chondrosarcoma at falx cerebri. The patient was a 35-year-old lady with right arm and leg weakness. Her brain magnetic resonance imaging depicted a left parasagittal mass lesion attached to the falx cerebri. En bloc resection via left frontal craniotomy was performed. Three more local recurrences occurred in 9 months' time since the index surgery, which were all managed with re-surgeries and/or adjuvant stereotactic radiosurgeries. This is the second case of myxoid type parasagittal chondrosarcoma but with the most protracted disease course. Even though surgery remains the mainstay of treatment for parasagittal chondrosarcomas, adjuvant therapy might be necessary in aggressive ones. PMID- 29492126 TI - Pure Tethered Cervical Cord and Review of Literature. AB - Tethering of the spinal cord in the lumbosacral region with myelomeningocele is a well-known phenomenon. Only sporadic cases of tethering along the rest of the neuraxis, including the hindbrain, cervical, and thoracic spinal cord have been documented, always along with some associated congenital malformations (hydrocephalus, Chiari malformation, myelomeningocele, meningocele, hamartomatous stalk, spina bifida occulta, intramedullary lipoma, intradural fibrous adhesions, the fusion of the sixth and seventh cervical vertebrae, split cord malformation, or low-lying cord). In this report, 14-year-old male developed symptoms related to tethering of the cervical spinal cord, but without any associated congenital malformations, that is the pure tethered cervical cord. This causes his moribund status and makes the manuscript unique and contributes to the hitherto literature. The authors discuss the diagnosis, treatment, and postoperative course of this entity. The uniqueness in treatment is that we have operated the case without the help of intraoperative somatosensory evoked potentials and motor evoked potential from posterolateral approach under local anesthesia. PMID- 29492127 TI - Endotracheal Intubation for Penetrating Neck Trauma. AB - Tracheal intubation is performed as part of daily routine in the operating room, rarely with complications. However, management of airway for cases such as a penetrating neck trauma case might constitute exceptions, in which cases the stabilization of the neck to prevent any further neural damage is a significant source of concern for the anesthesiologist. Generally, intubation techniques for penetrating neck trauma were planned according to the initial position of patients. To our knowledge, this is the first case report of alterated the position of the patient during the anesthesia induction for direct laryngoscopy. We report a case of successful airway management of a patient with penetrating neck trauma, by endotracheal intubation with direct laryngoscopy (DL) technique. PMID- 29492128 TI - A Rare Case of Concurrent Herpes Simplex Encephalitis and Glioblastoma Multiforme. AB - Herpes encephalitis superimposed on an intracranial malignancy has previously been described mainly in the context of malignancy imitating infection or in the postoperative setting after neurosurgical intervention. We report a rare case of de novo presentation of concurrent herpes encephalitis and glioblastoma. A 63 year-old man presented with status epilepticus and subsequent magnetic resonance imaging (MRI) brain showed a right temporal enhancing lesion with mass effect. He underwent a craniotomy and debulking of this lesion, which on subsequent histology was positive for herpes simplex virus (HSV) antigens and HSV DNA was confirmed by polymerase chain reaction analysis. The sample however also had some hypercellular areas with atypical astrocytes. Our patient recovered well from surgery and was eventually commenced on acyclovir albeit with a delay of 3 weeks due to the initial diagnostic dilemma. However, he re-presented with lethargy and confusion a further 3 weeks later and an MRI scan showed recurrence of the temporal lesion with MR spectroscopy more suggestive of high-grade glioma. He, therefore, underwent a further debulking surgery and the histology revealed a WHO Grade 4 glioblastoma with some residual areas of inflammation. A diagnosis of 2 co-existing pathologies namely HSV encephalitis and glioblastoma was thus reached. Unfortunately, due to poor performance status, he could not undergo chemo-radiotherapy and died 8 months after presentation. Immuno-modulators, expressed locally and globally in glioma patients, are likely to render them susceptible to infections. There are an increasing number of reports of HSV encephalitis in the glioma setting postoperatively. However, we report a de novo presentation which has only been recognized once before in the 1970s. Recognition of HSV encephalitis in glioma patients in the de novo and also the postoperative context is important for commencing early treatment and preventing poor outcomes. PMID- 29492129 TI - A Rare Primary Dumbbell Lipoblastoma. AB - Lipomas and lipoblastomas are benign tumors of mesenchymal origin in contrast to liposarcoma that is a malignant tumor. Atypical lipomatous lesion arising from embryonal fat cells is termed as lipoblastoma. In the present case report 9-month old male presented to us with painless, rapidly progressing mass over back, power was normal in all four limbs, fine needle aspiration cytology was suggestive of cellular tissue, magnetic resonance imaging suggestive of well-defined enhancing mass in paravertebral location, extending from D3 to D10 vertebrae with intraspinal extension, communicating through neural foramina at level of D7. Intraoperatively, it was dumbbell-shaped, looked like neurofiboma based on the gross findings and it was adherent to dorsal nerve root also. Single level laminectomy with complete surgical excision of lesion done with sacrifice of dorsal nerve root. Histopathology was suggestive of lipoblastoma. Postoperative recovery was uneventful. PMID- 29492130 TI - Diagnosis, Treatment, and Management Strategy of Meningioma during Pregnancy. AB - The most common benign tumor of the brain is meningiomas. Usually diagnosed between the ages of 40-60, they are more common in women. Studies have shown a strong relationship between hormones and malignancies. Although meningiomas are slow-growing tumors of the brain, pregnancy seems to induce its growth speed. Studies concerning meningiomas and hormone relationship may explain the reason why symptoms during pregnancy flare. More specifically, the estrogen and progesterone receptor may take an active role through signal transduction in inducing the growth of the tumor. Thus, the dilemma of pregnancy + meningioma arises. In this case, a 21-year-old pregnant with a giant meningioma diagnosed on the symptom of loss of sight is reported. Her pregnancy was terminated, and the tumor was excised. Her vision improved and the histopathological examination showed a progesterone receptor positive meningioma. It is a challenging decision to be made by the physician, the patient and the family when deciding if and when pregnancy should be terminated once an intracranial meningioma is diagnosed. PMID- 29492131 TI - Chronic Subdural Hematoma Associated with Fahr Syndrome: A Clinical Association or Just a Simple Coincidence? AB - The Fahr syndrome (FS) is a rare degenerative neurological disorder (its prevalence is <0.5%). FS is distinguished by the presence of abnormal bilateral intracranial calcifications with a predilection for the basal ganglia, also presented by movement disorders such as parkinsonism, paresis, and speech disorders. Chronic subdural hematoma (CSH), which is typically the result of mild head trauma, is a regularly encountered condition in elderly. A 63-year-old man has referred to our clinic from another hospital with a history of mild head trauma approximately a month ago. At the time of admission, the patient's Glasgow Coma Scale point was 15 points. In the history, there was only mild ataxia and right-sided hemiparesis. The laboratory examination revealed no electrolytes level abnormalities and normal endocrinal test examinations. Computed tomography revealed bilateral calcifications of basal ganglia, dentate nuclei which were misinterpreted as intracerebral contusion; with CSH of left temporal and parietal region. The hematoma was evacuated by burr-hole drainage. The patient was discharged 5 days after the surgery. The pathophysiology of FS is still unrevealed. There are some suggestions such as secondary to local disturbance of blood-brain barrier or a calcium neuronal metabolism disorder. However, on the other hand, local blood-brain barrier disturbance would also take part in CSH pathology. We hypostasized that patients with the history of FS, who had mild head traumas, might prone to subdural collections. On the other hand, FS and CSH coexistence is very unusual. Neurosurgeons might keep in mind FS when bilateral calcifications are seen in a patient. PMID- 29492132 TI - Pituitary Apoplexy during Treatment of Prolactinoma with Cabergoline. AB - Pituitary apoplexy is a rare clinical presentation caused by infarction of the pituitary gland or adenoma with or without hemorrhage. Although pituitary apoplexy is usually spontaneous, one of the predisposing factors is treatment with dopamine agonists, especially bromocriptine. The occurrence of apoplexy during cabergoline therapy is reported much less frequently. In this article, we report a 34-year-old man with macroprolactinomas who developed sudden visual deterioration due to pituitary apoplexy 1 year after initiation of cabergoline therapy. He was treated via endoscopic trans-sphenoidal surgery and his visual status recovered dramatically. PMID- 29492133 TI - Subcutaneous Schwannoma in the Head Region. AB - Schwannoma is a benign neural tumor derived from Schwann cells surrounding the nerves. It occurs primarily in subcutaneous tissues and muscles with a tendency for distal extremities, head, and neck area. Treatment of schwannoma is surgical excision. Lipomas are the most common soft-tissue lesions. A case is presented to increase awareness on differential diagnosis of head and neck subcutaneous masses. PMID- 29492134 TI - Isolated Extracranial Intraosseous Metastasis of an Intracranial Meningioma following Bevacizumab Therapy: Case Report and Review of the Literature. AB - Meningiomas account for a significant proportion of all primary intracranial tumors; distant metastasis is quite rare. We report a patient with resected, atypical meningioma. The patient's clinical course over 5 years included two craniotomies, a course of radiation, and a shortened course of bevacizumab. Only 5 months after starting bevacizumab, the patient developed an isolated left clavicular pathological fracture attributable to metastatic anaplastic meningioma. This constitutes the first report of meningioma with isolated extracranial intraosseous metastasis in the modern English literature and highlights concerns associated with the use of anti-angiogenic agents in promoting more invasive tumor phenotypes upon disease recurrence. PMID- 29492135 TI - Intractable Yawning as a Predominant Symptom of Temporal Lobe Ganglioglioma: Case Report and Review of Literature. AB - Yawning, a physiologic reflex exhibited by vertebrates, is seldom noticed as a symptom of a disease. Not too often is a patient aware of it as a symptom, unless it is of such a distressing nature to seek attention. In this situation, to distinguish between normal and abnormal behavior would pose a diagnostic dilemma for the attending physician. Intractable yawning has been a presenting symptom of many pathologic states such as stroke, epilepsy, and migraine. Literature is sparse regarding intractable yawning caused by tumors of the brain. Most of the time, the etiology cited is the infratentorial location of these tumors causing compression of the brainstem and the centers responsible for yawning. Intractable yawning as a predominant symptom of supratentorial tumor is rare. We present a case of an 18-year-old girl who presented with abnormal yawning. On evaluation, magnetic resonance imaging revealed a tumor in the posterior part of the inferior temporal gyrus. There was no significant compression of the brainstem structures to suggest this as a cause for her symptom. She underwent a craniotomy and total excision of lesion. Postoperatively, her symptoms improved and her salvos of yawns ceased. The histopathological examination revealed a ganglioglioma of the temporal lobe. The present case is unique as it is the only case reported in the literature of a supratentorial tumor causing abnormal yawning. PMID- 29492136 TI - Adult Supratentorial Extraventricular Anaplastic Ependymoma: Therapeutic Approach and Clinical Review. AB - We report a 69-year-old patient with left paresthesia and hemiparesis. Magnetic resonance imaging revealed a right frontoparietal cystic tumor. A subtotal surgical resection was performed, and an Ommaya reservoir was left in place. The pathological diagnosis was supratentorial extraventricular anaplastic ependymoma. Radiation therapy was administered, and Ommaya reservoir drainages were performed. Four months after, her clinical status deteriorated after a reservoir drainage and image revealed an acute hemorrhage. An additional resection was carried out, and chemotherapy was undergone. One month later the tumor relapsed and the patient died 18 months after initial diagnosis. Some poor prognostic factors have been suggested in the literature: Young age, incomplete tumor resection - eloquent area location, histological anaplasia, supratentorial, and extraventricular locations. Ommaya reservoirs may be used in cystic lesions as a temporary measure only. Surgery is the mainstay of therapy with adjuvant radiotherapy and/or chemotherapy. PMID- 29492137 TI - Primary Type I Cutaneous Meningioma of the Scalp: Cytohistological and Immunohistochemical Features of a Rare Neoplasm. AB - Primary cutaneous meningioma of scalp is a rare lesion and often clinically misdiagnosed. As clinical features are nonspecific, the diagnosis is often perplexing in this exceptional site. We report a case of a 7-year-old girl presenting with a nodule over occipital region of scalp since birth. No bony defect was noted on X-ray. On fine needle aspiration cytology, smears were cellular consisting mostly cohesive clusters of cells having pale pink granular cytoplasm, round to oval nuclei with unassuming nucleoli along with psammomatous calcification suggestive of cutaneous meningioma. Histology and immunohistochemistry with epithelial membrane antigen (EMA) confirmed the diagnosis. Histological sections revealed a proliferation of a spindle-shaped cell in the dermis, arranged in whorls or individually amid collagen fibers and psammoma bodies. Immunohistochemical study revealed positivity for EMA. A diagnosis of Type I cutaneous meningioma was finally rendered based on characteristic clinical, intraoperative, morphological, and immunohistochemical observations. PMID- 29492138 TI - Ruptured Distal Middle Cerebral Artery Mycotic Aneurysm: A Rare, First Presentation of Infective Endocarditis. AB - Mycotic cerebral aneurysms are rare inflammatory aneurysms associated with high mortality and morbidity reaching up to 80% after rupture. We report a case of incidentally diagnosed infective endocarditis presenting with rupture of distal middle cerebral artery mycotic aneurysm and intracerebral hematoma. Aneurysmectomy with clip ligation of the terminal cortical branch and hematoma evacuation was done with good surgical outcome. PMID- 29492139 TI - Nontraumatic Subdural Hematoma and Intracystic Hemorrhage Associated with a Middle Fossa Arachnoid Cyst. AB - Intracranial arachnoid cysts (ACs) are relatively common findings that can be seen in up to 2% of patients. They are generally found incidentally with a benign clinical course and can be usually managed by observation. We report an unusual case of a middle fossa AC presenting with spontaneous intracystic hemorrhage along with subdural hematoma (SDH) causing significant mass effect and midline shift requiring surgical treatment. Even though the risk of hemorrhage in patients with AC is very low, the presence of AC is a known risk factor for SDH. Fortunately, the clinical outcome of patients who present with hemorrhage associated with AC is generally favorable with early recognition and prompt surgical treatment. Our case highlights the fact that both intracystic hemorrhage and SDH can occur in association with AC even in the absence of trauma and should be kept in mind when counseling patients with incidental AC about the natural history of these lesions. PMID- 29492140 TI - Use of Detachable Coils Without the Need of a Double Marker Microcatheter: Technical Note. AB - When using detachable coils for cerebral aneurysm embolization, it is necessary to place a microcatheter with radiopaque markers at 2 sites (tip and 3 cm proximal from the tip) in most cases. Detachable coils that can be positioned independently from the proximal marker may facilitate new applications utilizing their characteristics. Herein, we report 2 cases that were treated with new applications. Detachable coils that function to electrically detect the moment they come out of the microcatheter were used. In one patient with a large aneurysm with an irregular shape, coil embolization was applied by advancing the catheter more than 3 cm from the aneurysm neck to the caudally protruded compartment near the proximal end of the neck, which was difficult to reach with the coil. In the other patient with cerebral arteriovenous malformation (AVM), microcatheters for AVM without a proximal marker were used for coil embolization before Onyx injection: Coil embolization was applied through one microcatheter to a site more proximal than the tip of the other microcatheter, followed by Onyx injection through the distal catheter, by which the nidus was continuously penetrated from the initiation of injection, obtaining an effect similar to that of the plug and push technique. Through the use of detachable coils, which are not dependent on the visibility of the proximal marker, the limitation of catheter positioning is reduced and the applicable types of catheter increase, which may facilitate to enable its use for new clinical indications. PMID- 29492142 TI - Importance of Calvaria in Cerebrospinal Fluid Dynamics: A Case of Ventriculomegaly and Sinking Flap Syndrome after Decompressive Craniectomy. AB - Sinking flap syndrome and hydrocephalus are well-known complications of decompressive craniectomy. The underlying pathogenesis and management of these complications are still unclear. We present a case of hydrocephalus and recurrent sinking flap syndrome following decompressive craniectomy. We highlight the pivotal role of calvaria in the management of these complications. PMID- 29492141 TI - Management of Obstructive Hydrocephalus in Pregnant Patient. AB - De novo obstructive hydrocephalus is a rare event during pregnancy. There are only case reports presented in literature. We aimed to discuss the pathophysiological basis and management options with an exemplary case presentation and review of the current literature. A 28-year-old G2P1 patient presented to our clinic with headache, vomiting, and deteriorated vision at the 8th week of gestation. She had no history of central nervous system infection or trauma. A brain magnetic resonance imaging was obtained. There was hydrocephalus due to cerebral aqueduct stenosis (Evan's index of 58%). She was managed conservatively with bed rest and diuretics; however, she got no relief. A ventriculoperitoneal shunt was inserted at the 13th week of gestation. At the 38th week, she had cesarean section (C/S) due to previous history of C/S in the first pregnancy and present cord entanglement of the fetus. C/S was conducted under epidural anesthesia after conforming she had no increased intra cranial pressure findings. Delivery was uneventful with a healthy newborn. Obstructive hydrocephalus is a very rare complication during pregnancy. Hydrocephalus becomes obvious and necessitates treatment, before the third trimester of pregnancy. Timely diagnosis, especially differentiation from preeclampsia, is a life-saving step. If no complication happens during intervention for hydrocephalus, spontaneous vaginal delivery is a safe way of delivery for both mother's and newborn's well-being. C/S should be saved for obstetrical indications and can be conducted under epidural anesthesia if intracranial pressure is kept under control. Interdisciplinary approach of neurosurgeons and anesthesiologists is pivotal for delicate care of the patient and the baby. PMID- 29492143 TI - Brown-Sequard Syndrome Caused by Blunt Cervical Trauma with Radiographic Correlation. AB - Brown-Sequard syndrome, while uncommon, is a neurological condition that classically results from the hemisection of the spinal cord as a result of a penetrating injury to the spinal cord. We present a reported case of blunt trauma causing a high-energy cervical burst fracture/dislocation with a significant cord signal change producing Brown-Sequard syndrome. In this case, the burst fracture at the level of C5 obtained from the motor vehicle accident led to the damage of the left-sided lateral spinal thalamic tract, descending lateral cortical spinal tracts, and ascending dorsal column. This is a unique case of blunt nonpenetrating trauma leading to a high-energy cervical burst fracture/dislocation causing significant cord signal change on T2-weighted magnetic resonance imaging (MRI). These physical changes produced symptoms of neurologic impairment commonly seen in those patients with Brown-Sequard syndrome. PMID- 29492144 TI - Bow Hunter's Syndrome in a Patient with a Right Hypoplastic Vertebral Artery and a Dynamically Compressible Left Vertebral Artery. AB - This is a case report of a 48-year-old man with multiple transient ischemic attacks and a known hypoplastic right vertebral artery (VA) who presented after a syncopal event while turning his head to the left. The objective of this study is to demonstrate the necessity of proper diagnosis and management of cerebrovascular pathology including imaging and surgical intervention in patients with known anatomical anomalies. This study was conducted at Massachusetts, United States of America. Our patient's history was significant for a hypoplastic right VA and a stenotic segment of the right VA at the C3-C4 junction. There was also degeneration of the C3-C4 facet on the left, with osteophyte formation compressing the VA, and a fusion of the C2-C3 segment. Imaging demonstrated obliteration of the left VA flow with head rotation to the left and subsequent reconstitution of flow in the neutral position. After consultation, the patient decided to proceed with surgical management with an anterior cervical discectomy and fusion at the level of C3-C4. Symptoms of vertebrobasilar insufficiency including syncopal episodes resolved after treatment. VA anomalies, although uncommon, are important to understand. Our patient presented with an anomalous right VA, as well as severe degenerative changes to the C2/C3 vertebrae that contributed to the development of Bow Hunter's syndrome. It is essential that proper monitoring and follow-up has to be carried out in patients with abnormal cerebral vasculature to minimize the occurrence of Bow Hunter's syndrome. PMID- 29492145 TI - Single Stage Complete Removal of Dumbbell Trigeminal Schwannoma in a Child by Skull Base Approach. AB - Trigeminal schwannomas (TSs) are extremely rare tumors in childhood, particularly in the absence of neurofibromatosis. Although multi-staged surgical strategies have been reported in the literature, safe and single stage microsurgical removal is possible. We report a rare case of dumbbell TS, in a 9-year-old girl in whom single stage complete removal was done using fronto-temporo-orbito-zygomatic craniotomy and sub temporal approach. PMID- 29492146 TI - Mature Cystic Teratoma of Dorsal Spinal Cord in Adult: An Unusual Lesion. AB - Teratomas are a type of multipotential cell tumor that contain a mixture of multiple germinal layers formed by normal organogenesis and reproductive tissues the incidence of intracranial teratomas is low, approximately 0.5-2.2% of all intracranial tumors. The occurrence of teratomas in the spine is extremely rare. Except for in the sacrococcygeal region, teratomas constitute <0.5% of all intraspinal tumors. According to the literature this is only 8th case of dorsal spinal mature cystic teratoma reported till date. PMID- 29492147 TI - Pediatric Isolated Cortical (Ectopic) Anaplastic Ependymoma. AB - Ependymomas are tumors derived from ependymal cells lining the ventricles or from the central canal of the spinal cord. It usually arises in the ventricles with extra ventricular extension. Less than 15 cases of purely cortical ependymomas are reported. We report a rare case of purely cortical anaplastic ependymoma in a pediatric patient, which is rarely reported. PMID- 29492148 TI - Case of an Intracranial Malignant Peripheral Nerve Sheath Tumor in the Setting of Pacer-dependent Heart Block. AB - Intracranial malignant peripheral nerve sheath tumors (MPNSTs) are an extremely rare entity with only a handful of cases reported in the literature. MPNSTs typically occur in the extremities and the trunk. The treatment algorithm includes, when possible, gross-total resection as these tumors are extremely aggressive. When these tumors occur intracranially, they are termed malignant intracerebral nerve sheath tumors. The diagnosis hinges on immunohistochemistry and pathological features and often the diagnosis can be delayed for this reason. In this setting, it is critical to utilize intraoperative navigation, thus necessitating the use of fine-cut magnetic resonance imaging (MRI). This report presents a patient who presented with symptoms of obstructive hydrocephalus secondary to an intracranial mass. The patient underwent a full and extensive metastatic workup that was ultimately negative. To complicate things, the patient was fully pacemaker dependent. In this report, we review the literature surrounding this type of tumor, along with a detailed presentation of the case mentioned including the difficulties of cardiac pacing in the setting of MRI. PMID- 29492149 TI - En-bloc Resection of a Giant Cell Tumor Causing Cervical Vertebral Collapse. AB - Giant cell tumors (GCTs) are rare, benign, and locally aggressive primary bone neoplasms. Spine is seldom affected, especially above the level of sacrum. In this report, we describe a case with GCT of the cervical vertebrae which causes collapse of the corpus. A 32-year-old female presented with gradual neck pain and abrupt paresthesia of the left hand. Computed tomography scan showed C6 vertebral collapse and magnetic resonance imaging demonstrated vertebral plana of C6 by a low signal intensity lesion on T1- and T2-weighted images. Emergent surgical intervention was taken due to the possibility of spinal injury. The tumor was removed by en-bloc resection and histopathological investigation confirmed GCT. In most of the cases, en-bloc resection of GCTs of the spine is not feasible. Despite the location and close contact of the lesion with spinal cord, later approach was successful for our case; thus, appropriate differential diagnosis for vertebral column lesions as well as selecting an optimum treatment is mandatory. PMID- 29492150 TI - Isolated Intramedullary Spinal Cysticercosis: A Case Report with Review of Literature of a Rare Presentation. AB - A number of parasitic infections can involve the central nervous system of which neurocysticercosis (NCC) is the most common one in developing countries. Most often the brain is involved, spine and spinal cord involvement is very rare and intramedullary involvement is rarer still. Here, we report a 30-year-old male patient, with intramedullary NCC of dorsal spinal cord. PMID- 29492151 TI - Primary Giant Sphenotemporal Intradiploic Meningioma. AB - Intradiploic meningioma is a rare subset of meningioma accounting for 1% of all cases. Authors report a rare case of giant sphenotemporal intradiploic meningioma with orbital extension in a 27-year-old female. It was managed successfully with complete surgical excision and bony reconstruction using autologous split thickness bone graft. PMID- 29492152 TI - Combined Retrosigmoid-paramedian Supracerebellar Transtentorial Approach as an Alternative to Classical Transtemporal Approaches: A Technical Note. AB - Epidermoid tumors are rare benign neoplasms. They commonly occur in the parasellar region and the cerebellopontine angle but may sometimes present in the so-called petroclival region, or beyond the boundaries of this location. For those that are localized in multiple compartments, staged surgeries, extensive transtemporal approaches, or somewhat limited extended middle fossa approach are generally performed. Although a good resection can be achieved by these approaches, they carry relatively high morbidity and mortality. We report a case of epidermoid tumor with infra- and supratentorial extensions, and propose a combined retrosigmoid-paramedian supracerebellar transtentorial approach as an alternative to classical transtemporal approaches. PMID- 29492153 TI - Contralateral Radiculopathy: A Kernohan-Woltman Notch-like Phenomenon. AB - Lumbar disc herniation is the most common cause of radiculopathy. In most cases, the chief complaint is associated with radicular pain due to nerve compression on the herniated side. However, a radicular pain contralateral to the herniation side is an unusual finding rarely reported in the literature. Here, a case of right lower limb radicular pain in the presence of left extruded L4-L5 disc herniation is reported. Management of the patient is discussed in addition to a review of the literature regarding hypotheses on the mechanism of this unusual situation. PMID- 29492154 TI - A Unique Case of Primary Intracranial Melanoma. AB - Primary intracranial melanoma is an uncommon entity and only case reports have been published in the literature. We report a case of an elderly male who was operated with a preliminary diagnosis of meningioma, but it proved to be a histological surprise as it came out to be melanoma with no primary anywhere in the body. PMID- 29492155 TI - Solitary Intraspinal Juvenile Xanthogranuloma in an Infant. AB - Juvenile xanthogranuloma (JXG) is a benign, non-Langerhans cell histiocytic proliferative disorder. We report a case of solitary JXG in an infant presenting as an intraspinal mass. Awareness of this mode of presentation is very important as subsequent prognosis differs from other tumors at the same location. JXG is a self-limiting dermatologic disorder usually occurring in first two decades of life. On rare occasion, it has been reported at extra-cutaneous sites such as central nervous system (CNS), eyes, liver, spleen, lungs and kidneys, and in other age groups. Isolated CNS involvement is extremely rare, especially in the spinal cord. PMID- 29492157 TI - Pure Endoscopic Management of Fourth Ventricle Arachnoid Cyst: Case Report and Literature Review. AB - Arachnoid cysts (ACs) within the fourth ventricle are rare, and only a few cases have been reported in the literature. These are benign lesions within the arachnoid membrane, and they have been reported to occur in almost all locations where arachnoid is present. Different procedures have been performed to restore a normal cerebrospinal fluid dynamic and/or pressure, including shunting and partial or complete excision of the cyst by open microsurgery or endoscopic fenestration. We report the case of a fourth ventricle AC successfully treated using only endoscopic anterior trans-frontal cyst fenestration/marsupialization and standard third ventriculostomy. Clinical and technical features are discussed, along with the pertinent literature. PMID- 29492156 TI - Widespread Intra-abdominal Carcinomatosis from a Rhabdoid Meningioma after Placement of a Ventriculoperitoneal Shunt: A Case Report and Review of the Literature. AB - Intra-abdominal metastasis (IAM) of central nervous system (CNS) tumors via ventriculoperitoneal shunt (VPS) is rare but has been previously reported (e.g., germinomas and medulloblastomas). However, there has been no previous report in the literature involving meningiomas. A case of primary rhabdoid meningioma with widespread intra-abdominal carcinomatosis after placement of a VPS in a 36-year old man is described. The patient underwent preoperative angioembolization of the tumor, craniotomy, and surgical excision, followed by postoperative gamma knife radiosurgery. Five months later, he underwent a decompressive craniectomy and surgical excision for tumor recurrence causing raised intracranial pressure and communicating hydrocephalus, necessitating placement of a VPS. One month after placement of the VPS, the patient developed abdominal distension and confusion. He was treated for a VPS infection, and the shunt was explanted. He continued to deteriorate with high output from the peritoneal drain placed at the time of shunt explantation. An exploratory laparotomy revealed multiple diffuse peritoneal and omental nodules which had the same histopathological and immunohistochemical morphology as the primary tumor. We reviewed the current literature on IAM of primary CNS tumors via VPS, which revealed that patients belonging in the pediatric age group, of the male gender, and with a primary intracranial germinoma or medulloblastoma have a higher incidence of IAM. Majority of IAM occurred within 2 years of VPS placement, and patients most commonly present with abdominal distension and ascites. Treatment after diagnosis is varied and the prognosis is poor, with more than half of the patients dying within a year. It is vital for clinicians to maintain a high index of suspicion for similar patients, as early intervention could potentially improve patient outcomes and patient expectations managed more effectively. PMID- 29492158 TI - Thoracic Intramedullary Lipoma in a 3-year-old Child: Spontaneous Decrease in the Size Following Incomplete Resection. AB - Nondysraphic intramedullary spinal cord lipomas are even rarer. We present a thoracic intramedullary lipoma which spontaneously decreased in size following surgical debulking. A 3-year-old girl was admitted to our department with complaints of back pain since 1 year and progressive difficulty in walking since 6 months. Her magnetic resonance imaging (MRI) revealed T8-9 intramedullary mass showing increased signal intensity in both T1- and T2-weighted images. The patient was operated with a T8-9 laminoplasty and debulking, and internal decompression of the tumor was made. Histologically, the tumor was uniformly composed of mature adipose tissue revealing a lipoma. First-month control MRI revealed the rest mass almost the half volume of the preoperative mass. The 2nd year MRI revealed the size of the lipoma was spontaneously decreased to almost half of postoperative size and 3rd year was the same as the 2nd year with a mild kyphosis. Decompression and debulking with or without duraplasty is the most appropriate treatment for symptomatic patients. Dietary measures with control of fat intake and long-term follow-up are also suggested. PMID- 29492159 TI - Ectopic Choroid Plexus Papilloma. AB - Choroid plexus papilloma is a rare intracranial neoplasm. These lesions most commonly present in the fourth ventricle in adults and lateral ventricle in children. Herein, we report a case of a 57-year-old male with complaint of backache of few weeks duration. Magnetic resonance imaging revealed an intradural and extramedullary space occupying lesion at D8 level. Histology showed multiple free-floating papillae with a central fibrovascular core. The cells showed immunoreactivity for vimentin, glial fibrillary acidic protein, synaptophysin, S 100 protein, and cytokeratins (CK, CK7). PMID- 29492160 TI - Unusual Case of Cerebellopontine Angle Epidermoid Causing Cerebellar Atrophy. PMID- 29492161 TI - Scrotal Complications of Ventriculoperitoneal Shunt. PMID- 29492162 TI - Intraventricular Hemorrhage: A Rare Complication Secondary to Traumatic Lumbar Puncture. PMID- 29492163 TI - Commentary for Radiation Induced Sphenoid Wing Meningioma. PMID- 29492164 TI - Positive Orientation-a Common Base for Hedonistic and Eudemonistic Happiness? AB - Positive orientation (PO) is proposed as a common base for hedonistic and eudemonistic senses of happiness. PO involves a tendency to formulate positive judgments concerning the self, one's personal life, and the future. Previously, PO had been investigated in the context of the hedonistic approach to well-being. In this article, we tested a broader understanding of PO, which is conceptualized, here, as a latent factor underlying variables that exemplify hedonistic and eudemonistic view on happiness. Using two samples (N = 159 and N = 200), we tested three models of PO extended to include various measures of meaning of life. The extended models fitted the data well. Results suggest that PO can be a general factor that is the basis for integrating two aspects of well being: searching for positivity and pleasure, as well as striving for meaning. PMID- 29492165 TI - Daniel T.L. Shek: Pioneer in Chinese Quality of Life Research. PMID- 29492166 TI - Amine Containing Analogs of Sulindac for Cancer Prevention. AB - Background: Sulindac belongs to the chemically diverse family of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) that effectively prevent adenomatous colorectal polyps and colon cancer, especially in patients with familial adenomatous polyposis. Sulindac sulfide amide (SSA), an amide analog of sulindac sulfide, shows insignificant COX-related activity and toxicity while enhancing anticancer activity in vitro and demonstrating in vivo xenograft activity. Objective: Develop structure-activity relationships in the sulindac amine series and identify analogs with promising anticancer activities. Method: A series of sulindac amine analogs were designed and synthesized and then further modified in a "libraries from libraries" approach to produce amide, sulfonamide and N,N disubstituted sulindac amine sub-libraries. All analogs were screened against three cancer cell lines (prostate, colon and breast). Results: Several active compounds were identified viain vitro cancer cell line screening with the most potent compound (26) in the nanomolar range. Conclusion: Compound 26 and analogs showing the most potent inhibitory activity may be considered for further design and optimization efforts as anticancer hit scaffolds. PMID- 29492167 TI - Oxidation of Hydroxy- and Dihydroxybenzoic Acids Under the Udenfriend's Conditions. An HPLC Study. AB - Background: Non-enzymatic hydroxylation of aromatic compounds to the respective phenolic derivatives is a possible metabolic pathway of xenobiotics. The formed metabolites can undergo consecutive oxidative reactions with free radicals to form potential toxic molecules. Objective: Development of HPLC methods to separate, identify and quantitate the main products formed from salicylic acid, 2,3-dihydroxybenzoic acid and 2,5-dihydroxybenzoic acid under in vitro hydroxylation conditions (Udenfriend's system). Method: An RP-HPLC-UV-Vis method was developed to separate salicylic acid and isomeric dihydroxybenzoic acids formed in the Udenfriend's system. Confirmation of structures of the oxidized products of salicylic acid, 2,3-dihydroxybenzoic acid and 2,5-dihydroxybenzoic acid was performed by HPLC-ESI-MS/MS method. Results: The HPLC-UV-Vis method was evaluated for a number of validation characteristics (selectivity, repeatability and intermediate precision, LOD, LOQ and calibration range). It was found that oxidation of salicylic acid resulted in the formation of 2,3- and 2,5 dihydroxybenzoic acids. Furthermore, the hydroxylated metabolites can be further metabolized under the Udenfriend's conditions. Conclusion: The results give evidence for possible involvement of the oxidized metabolites of salicylic acid in the development of biological action of salicylates at the site of inflammation, where high hydroxyl radical level can be detected. PMID- 29492168 TI - Histomorphometric Analysis of Bone Density in Relation to Tactile Sense of the Surgeon During Dental Implant Placement. AB - Introduction: A correct diagnosis and optimal treatment planning is essential for success in implant dentistry. Proper diagnosis of bone quality is an important part of the diagnostic procedure. Objective: The purpose of this study was to correlate the tactile sense of the surgeon in the assessment of bone density to the histomorphometric analysis of bone quality. Methods: In this study, 56 bone samples from 33 patients were harvested from implant sites with trephine drills. The samples were analyzed with Image J software. In the samples following parameters were measured: BV/TV, superficial cortical plate thickness, the number and thickness of haversian canals in cortical bone and the number, thickness and distance of trabecules in cancellous bone. The clinical hardness of bone during drilling was evaluated by surgeon according to Misch. GEE analysis with exchangeable correlation structure and linear model was used to evaluate the relationship between the tactile sense of the surgeon and histomorphometric parameters and all analysis was adjusted for two confounding variables: gender and location. Results: There were 51.79% implants in D2 samples and 48.21% in D3. Bone classification according to Misch was significantly correlated to distance of trabecules in cancellous bone (P-value=0.05), and shown marginally significant correlation with mean superficial cortical bone thickness (P-value =0.07) and number of haversian canals (P-value =0.005) in cortical bone. Discussion: There were differences between our results and others. The authors believed that these differences mainly are because of confounding factors, that in this study were eliminated. The clinical finding during surgery can approximately explain the histologic properties of bone. Conclusion: It is concluded that tactile sense of the surgeon can exhibit the histologic properties of the bone, and we are able to estimate the healing prognosis of the bone in implant placement. PMID- 29492170 TI - Digital Dentistry: The Revolution has Begun. PMID- 29492169 TI - Neurological Assessment Using a Quantitative Sensory Test in Patients with Chronic Unilateral Orofacial Pain. AB - Background: Quantitative Sensory Testing (QST) has been used in clinical and experimental settings to establish sensory assessment for different types of pains, and may be a useful tool for the assessment of orofacial pain, but this premise needs to be tested. Objective: The aim of the study was to evaluate responses to thermal stimuli between painful and non-painful facial sites in subjects with orofacial pain using QST. Methods: A total of 60 participants (5o females: 28-83 years; 10 males: 44-81 years) with unilateral orofacial pain were recruited from the Orofacial Pain Clinic at the Pain Management and Research Centre, Royal North Shore Hospital, Sydney, Australia. The study followed the methods of limits of the German Research Network testing four modalities of thermal thresholds, the Warm Sensation, the Cold Sensation, the Heat Pain and the Cold Pain using a TSA-II Neurosensory Analyser. The results were compared to the results from the unaffected side of the same patient on the same area and a single t test statistical analysis was performed, where a p value of less than 0.05 was considered significant. Results: The Mean Difference for Cold Sensation between the pain side and the non-pain side was 0.48 degrees C +/- 1.5 (t= 2.466, p=0.017), 0.68 degrees C +/- 2.04 for Warm Sensation (t= -2.573, p= 0.013), 2.56 degrees C +/- 2.74 for Cold Pain (t= 7.238, p<0.001) and -1.21 degrees C +/- 2.59 for Hot Pain (t= -3.639, p=0.001). Conclusion: The study showed that QST methods using thermal stimuli could be used to evaluate sensory dysfunction in orofacial pain patients using the specific parameters of cool and warm sensation, and cold and hot pain. PMID- 29492171 TI - Comparison of 3D Scanning Versus 2D Photography for the Identification of Facial Soft-Tissue Landmarks. AB - Background: Three dimensional facial scanning is an innovation that provides opportunity for digital data acquisition, smile analysis and communication of treatment plan and outcome with patients. Objectives: To assess the applicability of 3D facial scanning as compared to 2D clinical photography. Materials & Methods: Sample consisted of thirty Caucasians aged between 25 and 50 years old, without any dentofacial deformities. Fifteen soft-tissue facial landmarks were identified twice by 3 observers on 2D and 3D images of the 30 subjects. Five linear proportions and nine angular measurements were established in the orbital, nasal and oral regions. These data were compared to anthropometric norms of young Caucasians. Furthermore, a questionnaire was completed by 14 other observers, according to their personal judgment of the 2D and 3D images. Results: Quantitatively, proportions linking the three facial regions in 3D were closer to the clinical standard (for 2D 3.3% and for 3D 1.8% error rate). Qualitatively, in 67% of the cases, observers were as confident about 3D as they were about 2D. Intra-observer Correlation Coefficient (ICC) revealed a better agreement between observers in 3D for the questions related to facial form, lip step and chin posture. Conclusion: The laser facial scanning could be a useful and reliable tool to analyze the circumoral region for orthodontic and orthognathic treatments as well as for plastic surgery planning and outcome. PMID- 29492172 TI - Evaluation of Dimensional Changes of 3D Printed Models After Sterilization: A Pilot Study. AB - Objectives: To assess the effect of two of the most commonly used sterilization techniques on 3D printed clinical objects. Materials & Methods: The two sterilization methods used in our hospital and investigated in this paper are: Steam heat and Gas plasma. Three objects were printed and tested in this study: a tooth replica, an orthognathic final splint, a surgical cutting guide for the purpose of mandible reconstruction. For each of the 3 objects, 4 copies were made: one original STL object, one copy of the object pre-sterilization, one copy of post-steam heat sterilization, and one copy of post-gas plasma sterilization. Each printed object was scanned using a high resolution CBCT protocol and the compared (morphologically and volumetrically). Results: At the level of volumetric changes, no difference was found between pre and post-sterilization for both methods evaluated. As for the morphological changes, only differences were noticed with the orthognathic splint object indicating deformation of the printed splints after sterilization. Larger differences were observed with heat sterilization, making it less reliable. Conclusion: Sterilization of dental objects to be used in a clinical setting may lead to deformation of the printed model, especially for heat sterilization. Further investigations are needed to confirm these findings. PMID- 29492173 TI - Guided Implant Surgery to Reduce Morbidity in Von Willebrand Disease Patients: A Case Report. AB - Introduction: Von Willebrand Disease is the most common inherited bleeding disorder. In the general population, 1/8000 patients are affected. Primary hemostasis (platelet adhesion) and coagulation (protection of Factor VIII) are altered. Among several bleeding symptoms, these patients suffer from excessive bleeding of oral mucosa and dental management requires a close collaboration between haematologists and oral surgeons. Materials & Methods: Guided implant surgery can be used to increase the accuracy of implant placement and to reduce the overall morbidity of this surgical procedure by using a flapless surgery technique. Case Report: We report the case of a 49 years old woman having a Type 2A von Willebrand disease and who presented to replace tooth #.46 because of interradicular fracture and peri-apical infection. After planning the implant surgery using Codiagnostix(r) software, a surgical guide was prepared. The patient received 4 injections of von Willebrand factor (Willfactin(r)) for this particular surgical procedure. The implant was placed immediately after tooth removal and local haemostasis was performed. Discussion: The follow-up was uneventful and the implant was restored by a crown 4 months later. Two cases of implant placement in haemophiliac patients have been reported before in the literature. Conclusion: As far as we know, this is the first case report of implant placement in a patient having a von Willebrand disease. The use of guided surgery allowed to perform a mini-invasive procedure and thus contributed to prevent bleeding complications in this patient. PMID- 29492174 TI - Ultralow Dose MSCT Imaging in Dental Implantology. AB - Introduction: The Council Directive 2013/59 Euratom has a clear commitment for keeping medical radiation exposure as low as reasonably achievable and demands a regular review and use of diagnostic reference levels. Methods: In dental implantology, the range of effective doses for cone beam computed tomography (CBCT) shows a broad overlap with multislice computed tomography (MSCT). More recently, ultralow dose imaging with new generations of MSCT scanners may impart radiation doses equal to or lower than CBCT. Dose reductions in MSCT have been further facilitated by the introduction of iterative image reconstruction technology (IRT), which provides substantial noise reduction over the current standard of filtered backward projection (FBP). Aim: The aim of this article is to review the available literature on ultralow dose CT imaging and IRTs in dental implantology imaging and to summarize their influence on spatial and contrast resolution, image noise, tissue density measurements, and validity of linear measurements of the jaws. Conclusion: Application of ultralow dose MSCT with IRT technology in dental implantology offers the potential for very large dose reductions compared with standard dose imaging. Yet, evaluation of various diagnostic tasks related to dental implantology is still needed to confirm the results obtained with various IRTs and ultra-low doses so far. PMID- 29492175 TI - Impact of Cone Beam Computed Tomography Dose in Pre-Surgical Implant Analysis. AB - Objectives: Cone-Beam Computed Tomography (CBCT) produces vital information required for the accurate and prudent placement of dental implants. Lack of standardization between CBCT machines may result in unsafe patient exposure to harmful radiation; higher doses are not necessarily associated with improved image quality. Aim: The study aimed to assess the influence of low- and high-dose milliamperage settings on CBCT images for objective and subjective implant planning. Methods: Two dry skulls (4 hemi-maxillary segments of the maxilla and 4 hemi-maxillary segments of the mandible) were scanned under low (2 mA) and high (6.3 mA) dosage settings using a CBCT (Carestream CS 9300). Cross-sectional slices of both image qualities were evaluated by five expert clinicians, for image quality for implant planning and objective bone measurements. Results: There were no significant differences in bone measurements taken on high or low dose images (p > 0.05). In qualitative image assessments, assessment and image quality for almost all observers were independent of each other. For planning posterior mandibular implant placement, increased dosage improved concordance and kappa values between low and high dose images. Conclusion: Reduction in milliamperage did not affect diagnostic image quality for objective bone measurements and produced sufficient intra-rater reliability for qualitative assessment; therefore dose reduction can be achieved without compromising diagnostic decision- making. PMID- 29492176 TI - Digital Dynamic 3D Monitoring of Lower Incisors Intrusion in Lingual Orthodontics. AB - Objective: The aim of the present study is to propose a 3-dimensional evaluation of lower intrusion obtained with lingual orthodontics considering not only the crowns but also dental roots. Methods: 9 adult patients underwent fixed lingual orthodontic treatment with i-TTya lingual brackets system for the correction of crowding in the lower arch associated with a deep overbite. Initial records, consisting of photos, CBCTs and intraoral scans were collected. Threshold segmentation of the CBCT was performed to generate a three-dimensional virtual model of each the teeth of the lower arch, superimposed with the crown of the same teeth obtained by intraoral scan models to generate a complete set of digital composite lower arch The same procedure was performed to monitor one key step of the i-TTYA technique consisting in lower incisors intrusion (T2). T1-T2 three-dimensional superimposition and color displacement maps were generated to measure and evaluate the movements obtained at the lower arch. Results: The root displacement of the incisors during their intrusion in the early stage was totally "bone-safe" in the 88.9% (8 of 9) of the cases observed. No significant extrusion of the premolars used as anchorage unit was measured. Conclusion: This method has proved to be an accurate and reliable approach to dynamically visualize the 3-dimensional positions of the teeth, including their roots, with no additional radiation for in-progress treatment monitoring. The 3-dimensional evaluation showed that the employed lingual appliance allowed to obtain significant lower incisors intrusion with negligible undesired extrusion of premolars employed as anchorage teeth. PMID- 29492177 TI - Conventional Vs Digital Impressions: Acceptability, Treatment Comfort and Stress Among Young Orthodontic Patients. AB - Objective: The objective of the present study was to compare patients' acceptability, comfort and stress with conventional and digital impressions. Materials and Methods: Thirty young orthodontic patients (15 males and 15 females) who had no previous experience of impressions were enrolled in this study. Conventional impressions for orthodontic study models of the dental arches were taken using an alginate impression material (Hydrogum(r), Zhermack Spa, Badia Polesine, Rovigo, Italy). Fifteen days later, digital impressions of both arches were acquired using an intraoral scanner (CS3600(r), Carestream Dental, Rochester, NY, USA). Immediately after impression taking, patients' acceptability, comfort and stress were measured using two questionnaires and the State anxiety scale. Results: Data showed no difference in terms of anxiety and stress; however, patients preferred the use of digital impressions systems instead of conventional impression techniques. Alginate impressions resulted as fast as digital impressions. Conclusions: Digital impressions resulted the most accepted and comfortable impression technique in young orthodontic patients, when compared to conventional techniques. PMID- 29492178 TI - The Micromorphological Research of the Internal Structure of Chairside CAD/CAM Materials by the Method of Scanning Impulse Acoustic Microscopy (SIAM). AB - Aim: The aim of the present work was to compare the elastic properties and internal structure of 4 different CAD/CAM chairside materials, by the method of Scanning Impulse Acoustic Microscopy (SIAM). Methods: Four chairside CAD/CAM materials with different structures from hybrid ceramic (VITA Enamic, VITA Zahnfabrik), feldspatic ceramic (VITABlocs Mark II, VITA Zahnfabrik), leucite glass-ceramic (IPS Empress CAD, Ivoclar Vivadent) and PMMA (Telio CAD, Ivoclar Vivadent) were examined by Scanning Impulse Acoustic Microscope (SIAM). Results: The results of micromorphological research of CAD/CAM chairside materials using SIAM method showed differences between the internal structures of these materials. The internal structure of feldspatic and glass-ceramic samples revealed the presence of pores with different sizes, from 10 to 100 microns; the structure of polymer materials rendered some isolated defects, while in the structure of hybrid material, defects were not found. Conclusion: Based on the results obtained from the present study, in cases of chairside production of dental crowns, it would be advisable to give preference to the blocks of hybrid ceramics. Such ceramics devoid of quite large porosity, glazing for CAD/CAM crowns made from leucite glass-ceramic and feldspatic ceramic may be an option. For these purposes, commercially available special muffle furnace for clinical and laboratory individualization and glazing of ceramic prostheses were provided. Further studies are needed to confirm the evidence emerging from the present research. PMID- 29492179 TI - Exploring Receipt of HIV PEP Counseling Among Women Sexually Assaulted by an Intimate Partner. AB - Among 136 women sexually assaulted by a current or former male intimate partner presenting to hospital-based violence treatment centers, 58 (42.6%) received HIV post-exposure prophylaxis (HIV PEP) counseling by a specially trained sexual assault nurse. We identified factors that were associated with receipt of HIV PEP counseling. Those who received counseling were more likely to have been younger than 25 years of age, single, a student, vaginally penetrated, and have received various other services (e.g., STI prophylaxis). They were less likely to have been unemployed. Hospital-based violence treatment centers need to be aware that not all women sexually assaulted by an intimate partner will have the same risk of acquisition of HIV and care needs. PMID- 29492180 TI - Structural Determinants of Workforce Participation after Retirement in Poland. AB - In this paper, we aim to analyse selected structural determinants of workforce participation after retirement in Poland. By structural determinants we mean characteristics of one's socio-economic position that (a) result from the interplay of social conditions (mechanisms of power, differentiated access to resources) and individual agency, and (b) restrict or facilitate individuals' choices. We conceptualise workforce participation as engaging in either part- or full-time paid employment despite receiving the old-age pension. Our general hypothesis is that working in older age is not only a matter of motivation or psychological traits but also a complex interplay of structural characteristics, accumulated by individuals during their life course. In the paper, we test a number of hypotheses about the role of specific components of socio-economic status (SES), i.e. occupational prestige, education, and wealth, for workforce participation among retirees. We argue that, in case of retirees, the prestige of the last job before retirement is a more reliable measure of the social position than education. Hence, we conduct a more detailed analysis of the role of occupational prestige for the chances of being employed after retirement. The analysis was based on data gathered in the years 2013-2014 within the sixth wave of the Polish Panel Survey POLPAN (www.polpan.org). We extracted a subsample of retirees from this dataset and used logistic regression to test the hypotheses described above. We found that both occupational prestige of the last job before retirement and educational attainments are strong predictors of being in paid work after retirement, however the impact of occupational prestige varies across the groups with the lowest and higher level of retirement pension. We also found that there are horizontal differences in the occupational structure of the chances for workforce participation after retirement and additionally found that being a farm owner increases the propensity to engage in economic activity after retirement. The paper contributes to the field of studies on the relationship between SES and workforce participation after retirement in line with the cumulative advantage/disadvantage theory and shows that resources that individuals have accumulated during the life course can determine their chances of working after retirement just as individual motivations or organisational characteristics do. PMID- 29492181 TI - Frequency of BRCA1 and BRCA2 causative founder variants in ovarian cancer patients in South-East Poland. AB - Background: Causative variants in BRCA1 and BRCA2 are well-established risk factors for breast and ovarian cancer. In Poland, the causative founder variants in the BRCA1 are responsible for a significant proportion of ovarian cancer cases, however, regional differences in the frequencies of various mutations may exist. The spectrum and frequency of BRCA1/2 mutations between ovarian cancer patients have not yet been studied in the region of South-East Poland. Methods: We examined 158 consecutive unselected cases of ovarian cancer patients from the region of Podkarpacie. We studied 13 Polish causative founder variants in BRCA1 (c.5266dupC, c.4035delA, c.5251C > T, c.181 T > G, c.676delT, c.68_69delAG, c.3700_3704delGTAAA, c.1687C > T, c.3756_3759delGTCT) and in BRCA2 (c.658_659delGT, c.7910_7914delCCTTT, c.3847_3848delGT, c.5946delT). Results: A BRCA1 causative founder variants were detected in 10 of the 158 (6.3%) ovarian cancer cases. BRCA2 causative founder variants were not observed. The c.5266dupC mutation was detected in 6 patients, c.181 T > G mutation in 3 patients and the c.676delT mutation in 1 patient. The median age of diagnosis of the 10 hereditary ovarian cancers was 55.5 years of age. Conclusions: The frequency of 13 causative founder variants in Podkarpacie was lower than in other regions of Poland. Testing of three BRCA1 mutations (c.5266dupC, c.181 T > G, c.676delT) should be considered a sensitive test panel. PMID- 29492182 TI - Atomic-Scale Structure of the Hematite alpha-Fe2O3(1102) "R-Cut" Surface. AB - The alpha-Fe2O3(1102) surface (also known as the hematite r-cut or (012) surface) was studied using low-energy electron diffraction (LEED), X-ray photoelectron spectroscopy (XPS), ultraviolet photoelectron spectroscopy (UPS), scanning tunneling microscopy (STM), noncontact atomic force microscopy (nc-AFM), and ab initio density functional theory (DFT)+U calculations. Two surface structures are stable under ultrahigh vacuum (UHV) conditions; a stoichiometric (1 * 1) surface can be prepared by annealing at 450 degrees C in ~10-6 mbar O2, and a reduced (2 * 1) reconstruction is formed by UHV annealing at 540 degrees C. The (1 * 1) surface is close to an ideal bulk termination, and the undercoordinated surface Fe atoms reduce the surface bandgap by ~0.2 eV with respect to the bulk. The work function is measured to be 5.7 +/- 0.2 eV, and the VBM is located 1.5 +/- 0.1 eV below EF. The images obtained from the (2 * 1) reconstruction cannot be reconciled with previously proposed models, and a new "alternating trench" structure is proposed based on an ordered removal of lattice oxygen atoms. DFT+U calculations show that this surface is favored in reducing conditions and that 4 fold-coordinated Fe2+ cations at the surface introduce gap states approximately 1 eV below EF. The work function on the (2 * 1) termination is 5.4 +/- 0.2 eV. PMID- 29492184 TI - Compressive Sensing Based Q-Space Resampling for Handling Fast Bulk Motion in Hardi Acquisitions. AB - Diffusion-weighted (DW) MRI has become a widely adopted imaging modality to reveal the underlying brain connectivity. Long acquisition times and/or non cooperative patients increase the chances of motion-related artifacts. Whereas slow bulk motion results in inter-gradient misalignment which can be handled via retrospective motion correction algorithms, fast bulk motion usually affects data during the application of a single diffusion gradient causing signal dropout artifacts. Common practices opt to discard gradients bearing signal attenuation due to the difficulty of their retrospective correction, with the disadvantage to lose full gradients for further processing. Nonetheless, such attenuation might only affect limited number of slices within a gradient volume. Q-space resampling has recently been proposed to recover corrupted slices while saving gradients for subsequent reconstruction. However, few corrupted gradients are implicitly assumed which might not hold in case of scanning unsedated infants or patients in pain. In this paper, we propose to adopt recent advances in compressive sensing based reconstruction of the diffusion orientation distribution functions (ODF) with under sampled measurements to resample corrupted slices. We make use of Simple Harmonic Oscillator based Reconstruction and Estimation (SHORE) basis functions which can analytically model ODF from arbitrary sampled signals. We demonstrate the impact of the proposed resampling strategy compared to state-of art resampling and gradient exclusion on simulated intra-gradient motion as well as samples from real DWI data. PMID- 29492185 TI - Dolichocolon revisited: An inborn anatomic variant with redundancies causing constipation and volvulus. AB - The objective of this review is to examine whether a redundant colon gives rise to symptoms like constipation and volvulus. In 1820, Monterossi made drawings of colons with displacements and elongation of the colon found during autopsy. In 1912, Kienboeck first visualized a redundant colon using bismuth, and Lardennois and Auborg named the anatomic variant dolichocolon in 1914. The criteria were later: A sigmoid loop rising over the line between the iliac crests, a transverse colon below the same line and extra loops at the flexures. The incidence of dolichocolon is 1.9%-28.5%. Dolichocolon seems to be congenital, as fetuses, newborns, and infants exhibit colonic redundancies. Studies have identified a triade of constipation, abdominal pain, and distension. Colon transit time was recently shown to increase significantly with increased number of redundancies, which increases abdominal pain, bloating and infrequent defecation. The diagnosis of dolichocolon is established by barium enema or CT-colonography. Treatment is conservative, or surgical in case of volvulus or refractory constipation. PMID- 29492183 TI - Honey as a Potential Natural Antioxidant Medicine: An Insight into Its Molecular Mechanisms of Action. AB - Honey clasps several medicinal and health effects as a natural food supplement. It has been established as a potential therapeutic antioxidant agent for various biodiverse ailments. Data report that it exhibits strong wound healing, antibacterial, anti-inflammatory, antifungal, antiviral, and antidiabetic effects. It also retains immunomodulatory, estrogenic regulatory, antimutagenic, anticancer, and numerous other vigor effects. Data also show that honey, as a conventional therapy, might be a novel antioxidant to abate many of the diseases directly or indirectly associated with oxidative stress. In this review, these wholesome effects have been thoroughly reviewed to underscore the mode of action of honey exploring various possible mechanisms. Evidence-based research intends that honey acts through a modulatory road of multiple signaling pathways and molecular targets. This road contemplates through various pathways such as induction of caspases in apoptosis; stimulation of TNF-alpha, IL-1beta, IFN gamma, IFNGR1, and p53; inhibition of cell proliferation and cell cycle arrest; inhibition of lipoprotein oxidation, IL-1, IL-10, COX-2, and LOXs; and modulation of other diverse targets. The review highlights the research done as well as the apertures to be investigated. The literature suggests that honey administered alone or as adjuvant therapy might be a potential natural antioxidant medicinal agent warranting further experimental and clinical research. PMID- 29492188 TI - Pulling the BAX trigger for tumor cell death. PMID- 29492187 TI - Perioperative liver and spleen elastography in patients without chronic liver disease. AB - AIM: To investigate changes in hepatic and splenic stiffness in patients without chronic liver disease during liver resection for hepatic tumors. METHODS: Patients scheduled for liver resection for hepatic tumors were considered for enrollment. Tissue stiffness measurements on liver and spleen were conducted before and two days after liver resection using point shear-wave elastography. Histological analysis of the resected liver specimen was conducted in all patients and patients with marked liver fibrosis were excluded from further study analysis. Patients were divided into groups depending on size of resection and whether they had received preoperative chemotherapy or not. The relation between tissue stiffness and postoperative biochemistry was investigated. RESULTS: Results are presented as median (interquartile range). 35 patients were included. The liver stiffness increased in patients undergoing a major resection from 1.41 (1.24-1.63) m/s to 2.20 (1.72-2.44) m/s (P = 0.001). No change in liver stiffness in patients undergoing a minor resection was found [1.31 (1.15-1.52) m/s vs 1.37 (1.12-1.77) m/s, P = 0.438]. A major resection resulted in a 16% (7%-33%) increase in spleen stiffness, more (P = 0.047) than after a minor resection [2 ( 1-13) %]. Patients who underwent preoperative chemotherapy (n = 20) did not differ from others in preoperative right liver lobe [1.31 (1.16-1.50) vs 1.38 (1.12-1.56) m/s, P = 0.569] or spleen [2.79 (2.33-3.11) vs 2.71 (2.37-2.86) m/s, P = 0.515] stiffness. Remnant liver stiffness on the second postoperative day did not show strong correlations with maximum postoperative increase in bilirubin (R2 = 0.154, Pearson's r = 0.392, P = 0.032) and international normalized ratio (R2 = 0.285, Pearson's r = 0.534, P = 0.003). CONCLUSION: Liver and spleen stiffness increase after a major liver resection for hepatic tumors in patients without chronic liver disease. PMID- 29492186 TI - Transcutaneous electroacupuncture alleviates postoperative ileus after gastrectomy: A randomized clinical trial. AB - AIM: To investigate the efficacy and safety of transcutaneous electroacupuncture (TEA) to alleviate postoperative ileus (POI) after gastrectomy. METHODS: From April 2014 to February 2017, 63 gastric cancer patients were recruited from the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. After gastrectomy, the patients were randomly allocated to the TEA (n = 33) or control (n = 30) group. The patients in the TEA group received 1 h TEA on Neiguan (ST36) and Zusanli (PC6) twice daily in the morning and afternoon until they passed flatus. The main outcomes were hours to the first flatus or bowel movement, time to nasogastric tube removal, time to liquid and semi-liquid diet, and hospital stay. The secondary outcomes included postoperative symptom assessment and complications. RESULTS: Time to first flatus in the TEA group was significantly shorter than in the control group (73.19 +/- 15.61 vs 82.82 +/- 20.25 h, P = 0.038), especially for open gastrectomy (76.53 +/- 14.29 vs 87.23 +/ 20.75 h, P = 0.048). Bowel sounds on day 2 in the TEA group were significantly greater than in the control group (2.30 +/- 2.61/min vs 1.05 +/- 1.26/min, P = 0.017). Time to nasogastric tube removal in the TEA group was earlier than in the control group (4.22 +/- 1.01 vs 4.97 +/- 1.67 d, P = 0.049), as well as the time to liquid diet (5.0 +/- 1.34 vs 5.83 +/- 2.10 d, P = 0.039). Hospital stay in the TEA group was significantly shorter than in the control group (8.06 +/- 1.75 vs 9.40 +/- 3.09 d, P = 0.041). No significant differences in postoperative symptom assessment and complications were found between the groups. There was no severe adverse event related to TEA. CONCLUSION: TEA accelerated bowel movements and alleviated POI after open gastrectomy and shortened hospital stay. PMID- 29492189 TI - Distinct histone modifications denote early stress-induced drug tolerance in cancer. AB - Besides somatic mutations or drug efflux, epigenetic reprogramming can lead to acquired drug resistance. We recently have identified early stress-induced multi drug tolerant cancer cells termed induced drug-tolerant cells (IDTCs). Here, IDTCs were generated using different types of cancer cell lines; melanoma, lung, breast and colon cancer. A common loss of the H3K4me3 and H3K27me3 and gain of H3K9me3 mark was observed as a significant response to drug exposure or nutrient starvation in IDTCs. These epigenetic changes were reversible upon drug holidays. Microarray, qRT-PCR and protein expression data confirmed the up-regulation of histone methyltransferases (SETDB1 and SETDB2) which contribute to the accumulation of H3K9me3 concomitantly in the different cancer types. Genome-wide studies suggest that transcriptional repression of genes is due to concordant loss of H3K4me3 and regional increment of H3K9me3. Conversely, genome-wide CpG site-specific DNA methylation showed no common changes at the IDTC state. This suggests that distinct histone methylation patterns rather than DNA methylation are driving the transition from parental to IDTCs. In addition, silencing of SETDB1/2 reversed multi drug tolerance. Alterations of histone marks in early multi-drug tolerance with an increment in H3K9me3 and loss of H3K4me3/H3K27me3 is neither exclusive for any particular stress response nor cancer type specific but rather a generic response. PMID- 29492191 TI - Local injection of high-molecular hyaluronan promotes wound healing in old rats by increasing angiogenesis. AB - Impaired angiogenesis contributes to delayed wound healing in aging. Hyaluronan (HA) has a close relationship with angiogenesis and wound healing. However, HA content decreases with age. In this study, we used high molecular weight HA (HMW HA) (1650 kDa), and investigated its effects on wound healing in old rats by local injection. We found that HMW-HA significantly increases proliferation, migration and tube formation in endothelial cells, and protects endothelial cells against apoptosis. Local injection of HMW-HA promotes wound healing by increasing angiogenesis in old rats. HMW-HA increases the phosphorylation of Src, ERK and AKT, leading to increased angiogenesis, suggesting that local injection of HMW-HA promotes wound healing in elderly patients. PMID- 29492190 TI - Targeting ovarian cancer and endothelium with an allosteric PTP4A3 phosphatase inhibitor. AB - Overexpression of protein tyrosine phosphatase PTP4A oncoproteins is common in many human cancers and is associated with poor patient prognosis and survival. We observed elevated levels of PTP4A3 phosphatase in 79% of human ovarian tumor samples, with significant overexpression in tumor endothelium and pericytes. Furthermore, PTP4A phosphatases appear to regulate several key malignant processes, such as invasion, migration, and angiogenesis, suggesting a pivotal regulatory role in cancer and endothelial signaling pathways. While phosphatases are attractive therapeutic targets, they have been poorly investigated because of a lack of potent and selective chemical probes. In this study, we disclose that a potent, selective, reversible, and noncompetitive PTP4A inhibitor, JMS-053, markedly enhanced microvascular barrier function after exposure of endothelial cells to vascular endothelial growth factor or lipopolysaccharide. JMS-053 also blocked the concomitant increase in RhoA activation and loss of Rac1. In human ovarian cancer cells, JMS-053 impeded migration, disrupted spheroid growth, and decreased RhoA activity. Importantly, JMS-053 displayed anticancer activity in a murine xenograft model of drug resistant human ovarian cancer. These data demonstrate that PTP4A phosphatases can be targeted in both endothelial and ovarian cancer cells, and confirm that RhoA signaling cascades are regulated by the PTP4A family. PMID- 29492192 TI - Octogenarians with EGFR-mutated non-small cell lung cancer treated by tyrosine kinase inhibitor: a multicentric real-world study assessing tolerance and efficacy (OCTOMUT study). AB - Objective: To assess efficacy and tolerance of EGFR tyrosine-kinase inhibitors (TKIs) for advanced EGFR-mutated non-small cell lung cancer (NSCLC) in octogenarians. Patients and methods: Patients aged 80 years or older with EGFR mutated NSCLC treated by EGFR TKI between January 2011 and March 2015 whatever the line of treatment were retrospectively selected. Results: 20 centers retrospectively included 114 patients (women, 77.2%; Caucasians, 98.3%; mean age, 83.9 years). A performance status of 0-1 or 2-3 at diagnosis was reported for 71.6% and 28.4% of patients, respectively. Overall, 95.6% of patients had adenocarcinomas and histological stage at diagnosis was stage IV for 79.8% of patients. EGFR mutations were identified mainly on exon 19 (46.5%) and exon 21 (40.4%). A geriatric assessment was performed in 35.1% of patients. TKI treatment was administered to 97.3% of patients as first or second line of treatment. Overall response rate and disease control rate were 63.3% (69/109) and 78.9% (86/109), respectively. Median progression-free survival was 11.9 months (95% confidence interval [CI], 8.6-14.7) and median overall survival was 20.9 months (95% CI, 14.3-27.1). After progression, 36/95 (37.9%) patients received a new line of chemotherapy. Main toxicities were cutaneous for 66.7% of patients (grade 3-4, 10%), diarrhea for 56.0% (grade 3-4, 15%; grade 5, 2%) and others for 25.7% (grade 3-4, 41%). Conclusions: Octogenarians with EGFR-mutated NSCLC treated by EGFR TKI had clinical outcomes and toxicity profile comparable to younger patients. Geriatric assessment appeared to be underused in this population. PMID- 29492193 TI - Preclinical evaluation of the PI3K/Akt/mTOR pathway in animal models of multiple sclerosis. AB - The PI3K/AKT/mTOR pathway is an intracellular signalling pathway that regulates cell activation. proliferation, metabolism and apoptosis. Increasing body of data suggests that alterations in the PI3K/AKT/mTOR pathway may result in an enhanced susceptibility to autoimmunity. Multiple Sclerosis (MS) is one of the most common chronic inflammatory diseases of the central nervous system leading to demyelination and neurodegeneration. In the current study, we have firstly evaluated in silico the involvement of the mTOR network on the generation and progression of MS and on oligodendrocyte function, making use of currently available whole-genome transcriptomic data. Then, the data generated in silico were subjected to an ex-vivo evaluation. To this aim, the involvement of mTOR was validated on a well-known animal model of MS and in vitro on Th17 cells. Our data indicate that there is a significant involvement of the mTOR network in the etiopathogenesis of MS and that Rapamycin treatment may represent a useful therapeutic approach in this clinical setting. On the other hand, our data showed that a significant involvement of the mTOR network could be observed only in the early phases of oligodendrocyte maturation, but not in the maturation process of adult oligodendrocytes and in the process of remyelination following demyelinating injury. Overall, our study suggests that targeting the PI3K/mTOR pathway, although it may not be a useful therapeutic approach to promote remyelination in MS patients, it can be exploited to exert immunomodulation, preventing/delaying relapses, and to treat MS patients in order to slow down the progression of disability. PMID- 29492194 TI - Expression of the mRNA stability regulator Tristetraprolin is required for lactation maintenance in the mouse mammary gland. AB - Tristetraprolin (TTP), an mRNA-binding protein that negatively controls levels of inflammatory factors, is highly expressed in the lactating mouse mammary gland. To determine the biological relevance of this expression profile, we developed bi transgenic mice in which this protein is specifically down-regulated in the secretory mammary epithelium in the secretory mammary epithelium during lactation. Our data show that TTP conditional KO mice produced underweight litters, possibly due to massive mammary cell death induced during lactation without the requirement of additional stimuli. This effect was linked to overexpression of inflammatory cytokines, activation of STAT3 and down-regulation of AKT phosphorylation. Importantly, blocking TNFalpha activity in the lactating conditional TTP KO mice inhibited cell death and similar effects were observed when this treatment was applied to wild-type animals during 48 h after weaning. Therefore, our results demonstrate that during lactation TTP wards off early involution by preventing the increase of local inflammatory factors. In addition, our data reveal the relevance of locally secreted TNFalpha for triggering programmed cell death after weaning. PMID- 29492195 TI - Peroxiredoxin-1 promotes cell proliferation and metastasis through enhancing Akt/mTOR in human osteosarcoma cells. AB - Osteosarcoma is characterized by high propensity for metastasis, especially to the lung, which is the main cause of death. Peroxiredoxin-1 (PRDX1) plays significant roles in multiple processes of initiation and progression of tumorogenesis. However, whether PRDX1 participates in metastasis of osteosarcoma remains unknown. Here, we demonstrate that PRDX1 overexpressed in osteosarcoma tissues comparing to adjacent non-tumor tissues. Two independent cohorts of patients showed high level of PRDX1 correlated with clinicopathological features such as larger tumor size and advanced tumor metastasis stage. While patients with high PRDX1 level have poor prognosis. Notably, expression level of PRDX1 especially increased in lung lesion of osteosarcoma patients, indicating that PRDX1 may promote lung metastasis. Ectopic expression of PRDX1 promotes osteosarcoma cell migration and metastasis in vitro and in vivo, whereas knockdown of PRDX1 expression suppresses cell metastatic behaviors such as invasion and migration. Furthermore, we found that PRDX1 promotes cells metastasis through enhancing Akt/mTOR signal pathway. Taken together, our findings prove the important role of PRDX1 in the molecular etiology of osteosarcoma and suggest that PRDX1 may be a novel prognostic biomarker and therapeutic target for osteosarcoma. PMID- 29492196 TI - Inhibition of STAT1 sensitizes radioresistant nasopharyngeal carcinoma cell line CNE-2R to radiotherapy. AB - Radioresistance remains a major obstacle for clinicians in the treatment of nasopharyngeal carcinoma (NPC). Others and we have reported that signal transducer and activator of transcription 1 (STAT1) may be as an important gene for resistance to radiation. However, the relationship between STAT1 and radioresistance is still elusive. In this study, by constitutive silencing STAT1 in human radioresistant nasopharyngeal carcinoma CNE-2R cell line, we showed that inhibition of STAT1 enhanced radiosensitivity of CNE-2R. Furthermore, knockdown of STAT1 led to growth suppression and apoptosis promotion in vitro and in vivo. Moreover, cells with low STAT1 expression increased G2/M phase and decreased S phase at 2Gy. These result revealed that knockdown of stat1 expression could sensitizes the CNE-2R to radiotherapy, But the exact mechanism needs to be further clarified. PMID- 29492197 TI - Development of risk prediction models for glioma based on genome-wide association study findings and comprehensive evaluation of predictive performances. AB - Over 14 common single nucleotide polymorphisms (SNP) have been consistently identified from genome-wide association studies (GWAS) as associated with glioma risk in European background. The extent to which and how these genetic variants can improve the prediction of glioma risk has was not been investigated. In this study, we employed three independent case-control datasets in Chinese populations, tested GWAS signals in dataset1, validated association results in dataset2, developed prediction models in dataset2 for the consistently replicated SNPs, refined the consistently replicated SNPs in dataset3 and developed tailored models for Chinese populations. For model construction, we aggregated the contribution of multiple SNPs into genetic risk scores (count GRS and weighed GRS) or predicted risks from logistic regression analyses (PRFLR). In dataset2, the area under receiver operating characteristic curves (AUC) of the 5 consistently replicated SNPs by PRFLR(SNPs) was 0.615, higher than those of all GRSs(ranging from 0.607 to 0.611, all P>0.05). The AUC of genetic profile significantly exceeded that of family history (fmc) alone (AUC=0.535, all P<0.001). The best model in our study comprised "PRURA +fmc" (AUC=0.646) in dataset3. Further model assessment analyses provided additional evidence. This study indicates that genetic markers have potential value for risk prediction of glioma. PMID- 29492198 TI - UBASH3B promotes tamoxifen resistance and could be negatively regulated by ESR1. AB - Purpose: To explore the prognostic value of UBASH3B in ER+ breast cancer patients and explore potential molecular mechanisms. Materials and Methods: Datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were re-analyzed to explore the association between UBASH3B and the progression of ER+ breast cancer. Kaplan-Meier plot analysis with a total of 734 ER+ samples and Gene Set Enrichment Analysis with 632 samples were used in the study. Results: High expression of UBASH3B is negatively correlated with distant metastasis free survival (DMFS, P = 0.01, P = 0.045, P = 0.04 in 2 independent datasets and a merged dataset, respectively), disease specific survival (DSS, P = 0.028) and disease free survival (DFS, P = 0.0052, P = 0.011, P = 0.016 in 3 independent datasets, respectively) in ER+ breast cancer patients. Subset analysis found that UBASH3B also has prognostic value on both lymph node positive and negative sub populations with ER+ breast cancer. This study also demonstrates that UBASH3B expression is tightly associated with tamoxifen resistance and TP53 mutation, which explains the association between UBASH3B and poor prognosis of ER+ breast cancer. Further analyses show that the expression of UBASH3B is affected by promoter methylation and copy number loss. Besides, UBASH3B is inversely correlated with ER and down-regulated by ER. Importantly, we find cisplatin could be a therapeutic option targeting on UBASH3B in clinical settings. Conclusions: UBASH3B is negatively regulated by ER and confers poor outcome in ER+ breast cancer patients. Cisplatin is a potential therapeutic option for the management of breast cancer patients with high expression of UBASH3B. PMID- 29492199 TI - The mutational landscape of MYCN, Lin28b and ALKF1174L driven murine neuroblastoma mimics human disease. AB - Genetically engineered mouse models have proven to be essential tools for unraveling fundamental aspects of cancer biology and for testing novel therapeutic strategies. To optimally serve these goals, it is essential that the mouse model faithfully recapitulates the human disease. Recently, novel mouse models for neuroblastoma have been developed. Here, we report on the further genomic characterization through exome sequencing and DNA copy number analysis of four of the currently available murine neuroblastoma model systems (ALK, Th-MYCN, Dbh-MYCN and Lin28b). The murine tumors revealed a low number of genomic alterations - in keeping with human neuroblastoma - and a positive correlation of the number of genetic lesions with the time to onset of tumor formation was observed. Gene copy number alterations are the hallmark of both murine and human disease and frequently affect syntenic genomic regions. Despite low mutational load, the genes mutated in murine disease were found to be enriched for genes mutated in human disease. Taken together, our study further supports the validity of the tested mouse models for mechanistic and preclinical studies of human neuroblastoma. PMID- 29492200 TI - Proteomic analysis of chicken embryo fibroblast cells infected with recombinant H5N1 avian influenza viruses with and without NS1 eIF4GI binding domain. AB - Non-structural 1 (NS1) protein is a key virulence factor that regulates replication of influenza virus. A recombinant H5N1 virus lacking the eIF4GI binding domain of NS1 (rNS1-SD30) exhibits significantly lower pathogenicity than H5N1 virus with an intact eIF4GI-binding domain (rNS1-wt). To further investigate this phenomenon, we performed comparative proteomics analyses to profile host proteins in chicken embryo fibroblasts (CEFs) infected with rNS1-wt and rNS1-SD30 viruses. In total, 81 differentially expressed (DE) proteins were identified at 12, 24, and 36 h post-infection. These proteins are mainly involved in the cytoskeletal, apoptotic and stress responses, transcription regulation, transport and metabolic processes, mRNA processing and splicing, and cellular signal transduction. Overexpression of DE proteins revealed that ANXA7 suppresses propagation of rNS1-SD30, but not rNS1-wt viruses. Moreover, ALDH7A1, ANXA7, and DCTN2 strongly enhanced IFN-beta promoter activity induced by chicken MDA5 (chMDA5), and in the case of ANXA7, also by the rNS1-SD30 viral strain. NS1-wt co transfection suppressed the ANXA7-mediated increase in IFN-beta promoter activity induced by chMDA5. These findings highlight the role of NS1 eIF4GI binding domain in H5N1 pathogenicity, and may contribute to the design of antiviral strategies to reduce the high morbidity and mortality associated with this pathogen. PMID- 29492201 TI - TrkAIII signals endoplasmic reticulum stress to the mitochondria in neuroblastoma cells, resulting in glycolytic metabolic adaptation. AB - Alternative TrkAIII splicing characterises advanced stage metastatic disease and post-therapeutic relapse in neuroblastoma (NB), and in NB models TrkAIII exhibits oncogenic activity. In this study, we report a novel role for TrkAIII in signaling ER stress to the mitochondria in SH-SY5Y NB cells that results in glycolytic metabolic adaptation. The ER stress-inducing agents DTT, A23187 and thapsigargin activated the ER stress-response in control pcDNA SH-SY5Y and TrkAIII expressing SH-SY5Y cells and in TrkAIII SH-SY5Y cells increased TrkAIII targeting to mitochondria and internalisation into inner-mitochondrial membranes. Within inner-mitochondrial membranes, TrkAIII was subjected to Omi/HtrA2 dependent cleavage to tyrosine phosphorylated 45-48kDa carboxyl terminal active fragments, localised predominantly in tyrosine kinase-domain mitochondrial matrix orientation. This stress-induced activation of mitochondrial TrkAIII was associated with increased ROS production, prevented by the ROS scavenger Resveratrol and underpinned by changes in Ca2+ movement, implicating ROS/Ca2+ interplay in overcoming the mitochondrial TrkAIII activation threshold. Stress induced, cleavage-activation of mitochondrial TrkAIII resulted in mitochondrial PDHK1 tyrosine phosphorylation, leading to glycolytic metabolic adaptation. This novel mitochondrial role for TrkAIII provides a potential self-perpetuating, drug reversible way through which tumour microenvironmental stress may maintain the metastasis promoting "Warburg effect" in TrkAIII expressing NBs. PMID- 29492202 TI - Evaluating vacquinol-1 in rats carrying glioblastoma models RG2 and NS1. AB - Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor, and available experimental and routine therapies result in limited survival benefits. A vulnerability of GBM cells to catastrophic vacuolization and cell death, a process termed methuosis, induced by Vacquinol-1 (VQ-1) has been described earlier. In the present study, we investigate the efficacy of VQ-1 treatment in two syngeneic rat GBM models, RG2 and NS1. VQ-1 treatment affected growth of both RG2 and NS1 cells in vitro. Intracranially, significant reduction in RG2 tumor size was observed, although no effect was seen on overall survival. No survival advantage or effect on tumor size was seen in animals carrying the NS1 models compared to untreated controls. Furthermore, immunological staining of FOXP3, CD4 and CD8 showed no marked difference in immune cell infiltrate in tumor environment following treatment. Taken together, a survival advantage of VQ-1 treatment alone could not be demonstrated here, even though some effect upon tumor size was seen. Staining for immune cell markers did not indicate that VQ-1 either reduced or increased host anti-tumor immune response. PMID- 29492203 TI - Protein biosynthesis, a target of sorafenib, interferes with the unfolded protein response (UPR) and ferroptosis in hepatocellular carcinoma cells. AB - Sorafenib is the first line treatment for advanced hepatocellular carcinoma (HCC). We explored its impact on the proteostasis of cancer cells, i.e. the processes that regulate the synthesis, maturation and turn-over of cellular proteins. We observed that sorafenib inhibits the production of the tumour marker alpha-foetoprotein (AFP) in two different HCC cell lines, an effect that correlated with a radical inhibition of protein biosynthesis. This effect was observed at clinically relevant concentrations of sorafenib and was not related to the effect of sorafenib on the transport of amino acids across the plasma membrane or the induction of the unfolded protein response (UPR). Instead, we observed that sorafenib inhibits translation initiation and the mechanistic target of rapamycin (mTOR) signaling cascade, as shown by the analysis of phosphorylation levels of the protein 4EBP1 (eukaryotic translation initiation factor 4E binding protein 1). We explored the consequences of this inhibition in HCC cells. We observed that overall sorafenib is a weak inducer of the UPR that can paradoxically prevent the UPR induced by tunicamycin. We also found no direct synergistic anticancer effect between sorafenib and various strategies that inhibit the UPR. In agreement with the possibility that translation inhibition might be an adaptive stress response in HCC cells, we noted that it protects cancer cell from ferroptosis, a form of oxidative necrosis. Our findings point to the modulation of protein biosynthesis and mTOR signaling as being important, yet complex determinants of the response of HCC cells to sorafenib. PMID- 29492204 TI - Stromal versus tumoral inflammation differentially contribute to metastasis and poor survival in laryngeal squamous cell carcinoma. AB - In solid tumors the biology and clinical course are strongly influenced by the interaction of tumor cells and infiltrating stromal host cells. The aim of this study was to assess the relative importance of stromal vs. tumoral inflammation for metastasis and survival in patients with laryngeal squamous cell carcinoma (LSCC). In 110 patients with tissues from histologically proven LSCC the expression of CD45, CD11b, CD3, MMP-9 and COX-2 was semiquantitatively analyzed in stromal regions and tumor nests. CD45, CD11b, CD3 and MMP-9 positive cells were more abundant in stroma whereas COX-2 was predominantly expressed in epithelial tumor nests. High expression of stromal CD45 and CD11b on immune cells in tumor regions correlated with COX-2 expression on tumor cells. High levels of CD45 in stroma as well as CD11b and COX-2 in tumor nests were associated with increased metastasis. In contrast, high frequencies of CD3 cells in the tumor core area were associated with reduced metastasis. Overall survival was reduced in patients with high stromal CD45, high tumoral CD11b and high tumoral COX-2 expression. This is the first study which separately analyzes peritumoral stroma and tumor core area in laryngeal squamous cell carcinoma in terms of CD45, CD11b, CD3, MMP-9 and COX-2 expression. Our results indicate that stroma and tumor islands need to be considered as two separate compartments in the inflammatory tumor microenvironment. Inflammatory stromal leukocytes, abundant myeloid cells in tumor regions and high expression of COX-2 on tumor cells are linked to metastatic disease and poor overall survival. PMID- 29492206 TI - Mixed phenotype acute leukemia contains heterogeneous genetic mutations by next generation sequencing. AB - Mixed phenotype acute leukemia (MPAL) is an uncommon manifestation of acute leukemia. The aim of this study is to further characterize the genetic landscape of de novo cases of MPAL that fulfill the 2016 World Health Organization (WHO) classification criteria for this entity. We identified 14 cases examined by next generation sequencing (NGS) using 28 (n = 10), 53 (n = 3) or 81 (n = 1) gene panels: 7 cases with a B-cell/myeloid (B/My) immunophenotype, 6 T-cell/myeloid (T/My) immunophenotype, and 1 B-cell/T-cell (B/T) immunophenotype. A total of 25 distinct mutations were identified in 15 different genes in 9/14 (64%) patients. FLT3-ITD was the only recurrent mutation in 2 patients. B/My MPAL cases less commonly harbored mutations compared with T/My MPAL cases (43% vs. 100%, p = 0.07). In contrast, B/My MPALs more commonly showed a complex karyotype compared to T/My MPALs (71% vs. 17%, p = 0.1). With NGS and karyotype combined, most (93%) MPAL cases had mutations or cytogenetic abnormalities. With a median follow-up of 12.5 months, there were no significant differences in median overall survival (OS) between patients with B/My or T/My MPAL (17.8 and 6.5 months, respectively, p = 0.81) or between patients with MPAL with versus without gene mutations (6.5 and 13.3 months, respectively, p = 0.86). Our data suggest that the distinguishing cases of MPAL according to immunophenotype has value because the underlying mechanisms of leukemogenesis might differ between B/My and T/My MPAL. PMID- 29492205 TI - Resveratrol ameliorates autophagic flux to promote functional recovery in rats after spinal cord injury. AB - Resveratrol is known to improve functional recovery after spinal cord injury, but the exact mechanism involved is yet unclear. The aim of this study was to clarify whether resveratrol can exert neuroprotective effects via activating neuronal autophagic flux, in view of the underlying role of the autophagic flux mediated by resveratrol on neuronal apoptosis after spinal cord injury, and identify the role of the liver kinase B1(LKB1)/adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/ p70 ribosomal protein S6 kinase (p70s6k) signal pathway in the autophagic flux mediated by resveratrol. The results obtained strongly indicate that resveratrol improved functional recovery in Sprague-Dawley rats after acute spinal cord injury, preserved their motor neurons, alleviated the neuronal apoptosis, and ameliorated neuronal autophagic flux. After blocking the autophagic flux, the neuroprotective effects of resveratrol were eliminated. Furthermore, it was proved that resveratrol can activate the LKB1/AMPK/mTOR/p70s6k pathway in vivo and in vitro, and the LKB1/AMPK/mTOR/p70s6k pathway plays a vital role in activating the autophagic flux mediated by resveratrol in PC12 cells. Thus, resveratrol enables to ameliorate neuronal autophagic flux via the LKB1/AMPK/mTOR/p70s6k pathway to alleviate apoptosis, and finally ameliorating functional recovery after acute SCI in SD rats. PMID- 29492207 TI - Evaluation of vascular events in patients with myeloproliferative syndromes and mutations of either the januskinase-2 or calreticulin gene at the university hospital Krems from 2008 to 2015. AB - Myeloproliferative neoplasms (MPN), classified as polycythemia vera (PV), essential thrombocytosis (ET) and myelofibrosis (MF) are stem-cell derived disorders. Mutations in either the januskinase-2 (JAK-2) or the calreticulin (CALR) gene are characteristic for MPN and may result in enhanced proliferation of red blood cells, white blood cells and platelets, and thus increase the risk for vascular events. This study is a retrospective and descriptive analysis of records of patients, who underwent treatment for myeloproliferative syndromes at the Department of Hemato-Oncology of the University hospital Krems from 2008 to the end of 2015. Out of 250 patients, who were suspected for MPN, 51 patients displayed a JAK-2 V617F mutation. These were analyzed with regard to their blood values, gender, age at diagnosis, therapy and vascular events before and after diagnosis (during therapy). Of the 51 patients diagnosed with MPN and a JAK-2 V617F mutation, 33 suffered from PV, 15 from ET and 3 from MF. More men than women were diagnosed with MPN and the median age at diagnosis was 72 years. Acetylsalicylic acid, phlebotomy and Hydroxyurea were the most frequent therapies applied. In our study cohort, the most common vascular events were acute coronary syndrome and transitory ischemic attack. Thromboembolic events were effectively reduced by MPN therapy while no elevation in bleeding events could be observed. PMID- 29492208 TI - Zinc ion dyshomeostasis increases resistance of prostate cancer cells to oxidative stress via upregulation of HIF1alpha. AB - Zinc ions (Zn2+) are known to influence cell survival and proliferation. However the homeostatic regulation of Zn2+ and their role in prostate cancer (PC) progression is poorly understood. Therefore the subcellular distribution and uptake of Zn2+ in PC cells were investigated. Inductively coupled plasma mass spectroscopy and fluorescent microscopy with the Zn2+-specific fluorescent probe FluoZin-3 were used to quantify total and free Zn2+, respectively, in the normal prostate epithelial cell line (PNT1A) and three human PC cell lines (PC3, DU145 and LNCaP). The effects of Zn2+ treatment on proliferation and survival were measured in vitro using MTT assays and in vivo using mouse xenografts. The ability of Zn2+ to protect against oxidative stress via a HIF1alpha-dependent mechanism was investigated using a HIF1alpha knock-down PC3 model. Our results demonstrate that the total Zn2+ concentration in normal PNT1A and PC cells is similar, but PC3 cells contain significantly higher free Zn2+ than PNT1A cells (p < 0.01). PNT1A cells can survive better in the presence of high concentrations of Zn2+ than PC3 cells. Exposure to 10 uM Zn2+ over 72 hours significantly reduces PC3 cell proliferation in vitro but not in vivo. Zn2+ increases PC3 cell survival up to 2.3-fold under oxidative stress, and this protective effect is not seen in PNT1A cells or in a HIF1alpha-KD PC3 cell model. A state of Zn2+ dyshomeostasis exists in PC. HIF1alpha is an integral component of a Zn2+-dependent protective mechanism present in PC3 cells. This pathway may be clinically significant through its contribution to castrate-resistant PC survival. PMID- 29492209 TI - EGFR is involved in dermatofibrosarcoma protuberans progression to high grade sarcoma. AB - Dermatofibrosarcoma protuberans (DFSP), amounting to 6% of all soft tissue sarcomas, has a slow growth rate, contrasting with a likelihood for local recurrence and a 10-20% evolution to higher-grade sarcoma, or "transformed DFSP" (DFSP-T). At molecular level, the characteristic COL1A1-PDGFB rearrangement, leading to sustained PDGFR signaling, is not linked to the evolutive potential. Here, we studied EGFR, another tyrosine kinase receptor, using laser microdissection to select the different histologic components of DFSP (DFSP center, DFSP infiltrative periphery, DFSP-T higher-grade sarcoma), in 22 patients followed over 3 to 156 months. EGFR protein and mRNA were expressed in 13/22 patients with DFSP or DFSP-T, and increased with tumor progression, both in microdissected areas of higher-grade sarcomas and in microdissected areas of local extension. No cancer-associated EGFR gene mutation or copy-number variation, nor any KRAS, BRAF, NRAS hotspot mutations were found in any microdissected area. Among epithelial-mesenchymal transition factors tested, SNAIL 1/2 had the same expression pattern as EGFR while ZEB1/2 or TWIST1/2 did not. Using a proteome profiler phospho-kinase array on 3 DFSP and 3 DFSP-T cryopreserved tissue samples, EGFR phosphorylation was detected in each case. Among EGFR downstream pathways, we found positive correlations between phosphorylation levels of EGFR and STAT5a/b (r = 0.87, p < 0.05) and TOR (r = 0.95, p < 0.01), but not ERK in the MAPK pathway (r = -0.18, p > 0.70). We thus demonstrated that in DFSP evolution to high grade sarcoma, EGFR and SNAIL were involved, with EGFR activation and signaling through TOR and STAT5a/b downstream effectors, which could lead on to new therapies for advanced DFSP. PMID- 29492210 TI - Pentraxin 3 deficiency enhances features of chronic rejection in a mouse orthotopic lung transplantation model. AB - Chronic lung allograft dysfunction (CLAD) is a serious complication after lung transplantation and thought to represent chronic rejection. Increased expression of Pentraxin 3 (PTX3), an acute phase protein, was associated with worse outcome in lung transplant patients. To determine the role of recipient PTX3 in development of chronic rejection, we used a minor alloantigen-mismatched murine orthotopic single lung transplant model. Male C57BL/10 mice were used as donors. Male PTX3 knockout (KO) mice and their wild type (WT) littermates on 129/SvEv/C57BL6/J background were used as recipients. In KO recipients, 7/13 grafted lungs were consolidated without volume recovery on CT scan, while only 2/9 WT mice showed similar graft consolidation. For grafts where lung volume could be reliably analyzed by CT scan, the lung volume recovery was significantly reduced in KO mice compared to WT. Interstitial inflammation, parenchymal fibrosis and bronchiolitis obliterans scores were significantly higher in KO mice. Presence of myofibroblasts and lymphoid aggregation was significantly enhanced in the grafts of PTX3 KO recipients. Recipient PTX3 deficiency enhanced chronic rejection-like lesions by promoting a fibrotic process in the airways and lung parenchyma. The underlying mechanisms and potential protective role of exogenous PTX3 as a therapy should be further explored. PMID- 29492211 TI - Serum complement factor I is associated with disease activity of systemic lupus erythematosus. AB - Although aberrant complement activation is involved in the pathogenesis of systemic lupus erythematosus (SLE), the role of complement regulatory proteins in disease activity of SLE remains limited. We enrolled the pediatric-onset SLE patients from our cohort study over 10 years. The clinical and laboratory data including SLEDAI disease activity score, and serum complement factor H (CFH), CFI, CD46, C5a, and C5b-9 in the active and remission phases were determined. Glomerular C5b-9 deposition as a complement activity marker was also examined. Forty patients (35 female and 5 male, aged 13.9 +/- 3.8 years) met the criteria of investigation were assessed. Fever and kidney were the most common symptom and organ involved, respectively. Mean SLEDAI in the active and remission phases were 12.6 vs 1.7, respectively. All patients exhibited lower serum C3, C4, CFH and CFI and higher serum anti-dsDNA and CD46 in the active pahse. There was a significant difference in serum CFH, CFI and CD46 between active and remissive phases. Serum CFI but not CFH and CD46 level was negatively correlated with SLEDAI score in active phase. Compared to classical activity markers, serum CFI was superior to C4 and anti-dsDNA in reflecting disease activity and also significantly correlated with white blood count and hemoglobin. Glomerular C5b-9 depositions were detected in patients with nephritis during active phase but not in disease controls. Serum CFI level may not only be a promising biomarker for disease activity of SLE, but also reflects the hematological features of SLE. PMID- 29492212 TI - Clinical significance of primary tumor score determined by tumor depth and size in patients with resectable gastric cancer. AB - Although postoperative management of gastric cancer is determined by pathological stage based on the tumor-node-metastasis classification, predicting disease recurrence and prognosis in patients undergoing gastrectomy is clinically difficult. We investigated the depth of tumor invasion and tumor size in resected specimens from patients with gastric cancer and assessed the clinical utility of primary tumor score (PTS) calculated by tumor depth and size as a prognostic marker. We classified 247 patients with gastric cancer into three groups based on cut-off values for deeper tumor invasion (pT2-T4) and larger tumor size (>= 45 mm) as a PTS of 2 (both abnormalities), 1 (one abnormality), or 0 (neither abnormality). PTS correlated significantly with lymph node metastasis, lymphovascular invasion, and stage (P < 0.0001 each). Survival differences among groups based on PTS were significant (P < 0.0001). Multivariate analysis identified PTS alone as an independent prognostic factor (P = 0.0363). PTS derived from primary tumor information alone is a potentially useful marker for predicting tumor progression and prognosis in postoperative patients with gastric cancer. PMID- 29492213 TI - Low salt and low calorie diet does not reduce more body fat than same calorie diet: a randomized controlled study. AB - Background: Recent several observational studies have reported that high salt intake is associated with obesity. But it is unclear whether salt intake itself induce obesity or low salt diet can reduce body fat mass. We investigated whether a low salt diet can reduce body weight and fat amount. Matrials and Methods: The randomized, open-label pilot trial was conducted at a single institution. A total of 85 obese people were enrolled. All participants were served meals three times a day, and provided either a low salt diet or control diet with same calorie. Visceral fat was measured with abdominal computer tomography, while body fat mass and total body water was measured with bio-impedance. Results: Reductions in body weight (-6.3% vs. -5.0%, p = 0.05) and BMI (-6.6% vs. -5.1%, p = 0.03) were greater in the low salt group than in the control group. Extracellular water and total body water were significantly reduced in the low salt group compared to the control group. However, changes in body fat mass, visceral fat area, and skeletal muscle mass did not differ between the two groups. Changes in lipid profile, fasting glucose, and HOMA-IR did not differ between the two groups. Conclusions: A two-month low salt diet was accompanied by reduction of body mass index. However, the observed decrease of body weight was caused by reduction of total body water, not by reduction of body fat mass or visceral fat mass. PMID- 29492214 TI - Genetic alterations in main candidate genes during melanoma progression. AB - Cutaneous melanoma is a common and aggressive human skin cancers. Much is actually known about the molecular mechanisms underlying melanoma pathogenesis. The aim of the study was to evaluate any possible correlation between mutations in main growth-controlling genes (BRAF, NRAS, CDKN2A) and copy number variations in frequently amplified candidate genes (MITF, EGFR, CCND1, cMET, and cKIT) during melanoma initiation and progression. A large series of primary and secondary melanoma tissue samples (N = 274) from 232 consecutively-collected patients of Italian origin as well as 32 tumor cell lines derived from primary and metastatic melanomas underwent mutation screening and fluorescence in situ hybridization (FISH) analysis. Overall, BRAF, NRAS, and CDKN2A were found mutated in 62.5%, 12.5% and 59% cell lines and in 47%, 16%, 12% tumor tissues, respectively. Quite identical mutation patterns between primary tumors and metastatic lesions were found for BRAF and NRAS genes; mutations of CDKN2A gene appeared to be instead selected during tumor progression. In cell lines, high rates of gene amplifications were observed (varying from 12.5% for cKIT to 50% for MITF); vast majority of cell lines (75%) presented at least one amplified gene. Conversely, prevalence of gene amplification was significantly and progressively decreasing in melanoma metastases (12%) and primary melanomas (4%). Our findings suggest that gene amplifications may be acquired during the late phases of melanoma evolution and mostly act as "passenger" or "non-causative" alterations. PMID- 29492215 TI - MiR-153 regulates expression of hypoxia-inducible factor-1alpha in refractory epilepsy. AB - Mesial temporal lobe epilepsy (mTLE), the most common type of temporal lobe epilepsy (TLE), is particularly relevant due to its high frequency of therapeutic resistance of anti-epileptic therapies. MicroRNAs (miRNAs) have been shown to be dysregulated in epilepsy and neurodegenerative diseases, and we hypothesized that miRNAs could be involved in the pathogenesis of MTLE. The present study aimed to explore the expression and functions of miRNA-153 in mTLE. The expression levels of miRNA-153 in refractory TLE patients were evaluated. The bioinformatics analysis showed that the potential target genes of miR-153 were involved in biological processes, molecular functions, and cellular components. miRNA-153 is significantly dysregulated in temporal cortex and plasma of mTLE patients. We identify HIF-1alpha as a direct target of miRNA-153, and luciferase reporter assays demonstrated that miR-153 could regulate the HIF-1alphaexpression via 3' UTR pairing. These data suggest that miR-153 might represent a useful biomarker and treatment target for patients with mTLE. PMID- 29492216 TI - Cell mass-dependent expression of an anticancer protein drug by tumor-targeted Salmonella. AB - Bacterial cancer therapy relies on the properties of certain bacterial species capable of targeting and proliferating within solid malignancies. If these bacteria could be loaded with antitumor proteins, the efficacy of this approach could be greatly increased. However, because most antitumor proteins are also toxic to normal tissue, they must be expressed by bacteria that specifically target and exclusively localize to tumor tissue. As a strategy for treating solid malignancies, we recently evaluated L-asparaginase (L-ASNase) delivered by tumor targeted Salmonella. In this system, L-ASNase was expressed under the control of the araBAD promoter (PBAD) of the E. coli arabinose operon, which is induced by injection of L-arabinose. Here, we further improved the performance of recombinant Salmonella in cancer therapy by exploiting the quorum-sensing (QS) system, which uses cell mass-dependent auto-induction logic. This approach obviates the necessity of monitoring intratumoral bacterial status and inducing cargo protein expression by administration of an exogenous compound. Recombinant Salmonella in tumors expressed and secreted active L-ASNase in a cell mass dependent manner, yielding significant anticancer effects. These results suggest that expression of a therapeutic protein under the control of the QS system represents a promising engineering platform for the production of recombinant proteins in vivo. PMID- 29492217 TI - Cyclic trans-phosphorylation in a homodimer as the predominant mechanism of EGFRvIII action and regulation. AB - Despite intensive research no therapies targeted against the oncogenic EGFRvIII are present in the clinic. One of the reasons is the elusive nature of the molecular structure and activity of the truncated receptor. The recent publications indicate the EGF-bound wild-type EGFR to trans-phosphorylate the EGFRvIII initiating aberrant signaling cascade. The elevated stability of the mutant receptor contributes towards oncogenic potential, preventing termination of signaling by receptor degradation. Here, we show that inhibition of phosphatases leads to a marked increase in phosphorylation of wild-type EGFR and EGFRvIII, indicating that both undergo cyclic rounds of phosphorylation and dephosphorylation on all investigated tyrosine residues, including Tyr1045. Still, we observe elevated stability of the mutant receptor, suggesting phosphorylation as insufficient to cause degradation. Hyperphosphorylation of EGFRvIII was hindered only by EGFR tyrosine kinase inhibitors. Co immunoprecipitation as well as semi-native Western blotting structural analyses together with functional investigation of EGFRvIII's phosphorylation following depletion of wild-type EGFR by shRNA or EGF-mediated degradation indicated homodimerization as the predominant quaternary structure of the mutant receptor. Dimers were observed only under non-reducing conditions, suggesting that homodimerization is mediated by covalent bonds. Previous reports indicated cysteine at position 16 to mediate covalent homodimerization. Upon its substitution to serine, we have observed impaired formation of dimers and lower phosphorylation levels of the mutated oncogene. Based on the obtained results we propose that EGFRvIII is predominantly regulated dynamically by phosphatases that counteract the process of trans-phosphorylation occurring within the homodimers. PMID- 29492218 TI - Cav3.1 overexpression is associated with negative characteristics and prognosis in non-small cell lung cancer. AB - Introduction: Voltage-gated calcium channels (VGCC) have been found to be differentially expressed in several different tumor types, but their role in tumor growth, malignant invasion, metastases and impact on clinical outcomes has not been clarified. Materials and Methods: From a cohort database of 193 patients with early-stage NSCLC, 163 formalin-fixed paraffin-embedded specimens were available for analysis to construct tissue microarrays. Cav3.1 protein expression was detected using fluorescence immunohistochemistry, and quantified using automated image acquisition and analysis. Results: Among the cohort of 193 NSCLC patients, adenocarcinoma (53.9%) and squamous cell carcinoma (SCC) (30.1%) were the most common histologies. There was no difference between SCC and non-SCC subtypes in overall survival (OS) or relapse-free survival (RFS); 74.2 vs 90.1 months (p = 0.543) and 48.8 vs 52.6 months (p = 0.766), respectively. T-type VGCC 3.1 (Cav3.1) overexpression was assessed by tissue microarray immunohistochemistry analysis from 163 available patient samples. Eighteen (11.0%) NSCLC primaries were found to have Cav3.1 overexpression levels, and were significantly associated with SCC histology (p < 0.001), larger tumor size (p < 0.001) and later stage disease at diagnosis (p = 0.019). Median OS was 48.6 vs 106.7 months for Cav3.1 overexpressing and non-overexpressing patients, respectively (p = 0.032). Regression analysis revealed a significantly negative effect for Cav3.1 overexpression on RFS (Hazard ratio [HR] = 2.02, p = 0.048). Conclusions: Cav3.1 overexpression is a potential biomarker for poorer patient outcomes. These results bring supportive evidence for calcium channels inducing an aggressive phenotype in NSCLC and potentially may serve as a therapeutic target in overexpressing tumors. PMID- 29492219 TI - PD-L1 expression in colorectal cancer defines three subsets of tumor immune microenvironments. AB - Objectives: We investigated the PD-L1 expression in colorectal cancer (CRC) and in its microenvironment. Results: PD-L1 was expressed in neoplastic cells (NCs) and tumor-infiltrating immune cells (IICs). All samples PD-L1+ on NCs were also on IICs. Three types of cancers could be grouped: group A(NCs-/ IICs-); group B (NCs-/ IICs+); group C (NCs+/IICs+). To group A belong tumors characterized by poorly immunogenic competence, poor immune response but massive granulocyte infiltrate, justifying the absence of PD-L1 as an immunoinhibitor receptor. To Group B probably belong more immunogenic CRCs, justifying the strong IICs mediated immune response, and up-regulation of PD-L1 expression only on IICs. To group C belong CRCs probably characterized by a large amount of tumor neoantigens resulting in a marked infiltration of lymphocytes and PD-L1 upregulation also in NCs. Materials and Methods: Sixty-three colorectal cancer specimens from a cohort of 61 patients were retrospectively reviewed. Thirty-seven MSS and 26 MSI-H CRCs enrolled in this study. Immunohistochemical staining to PD-L1 was performed by using MAb E1L3N. Conclusions: Our study calls attention to the importance to assess PD-L1 expression in tumor microenvironment also evaluating type and density of infiltrating immune cells to better stratify CRCs with different immunological patterns. PMID- 29492220 TI - RNA sequencing reveals widespread transcriptome changes in a renal carcinoma cell line. AB - We used RNA sequencing (RNA-Seq) technology to investigate changes in the transcriptome profile in the Caki-1 clear cell renal cell carcinoma (ccRCC) cells, which overexpress monocyte chemoattractant protein-induced protein 1 (MCPIP1). RNA-Seq data showed changes in 11.6% and 41.8% of the global transcriptome of Caki-1 cells overexpressing wild-type MCPIP1 or its D141N mutant, respectively. Gene ontology and KEGG pathway functional analyses showed that these transcripts encoded proteins involved in cell cycle progression, protein folding in the endoplasmic reticulum, hypoxia response and cell signalling. We identified 219 downregulated transcripts in MCPIP1-expressing cells that were either unchanged or upregulated in D141N-expressing cells. We validated downregulation of 15 transcripts belonging to different functional pathways by qRT-PCR. The growth and viability of MCPIP1-expressing cells was reduced because of elevated p21Cip1 levels. MCPIP1-expressing cells also showed reduced levels of DDB1 transcript that encodes component of the E3 ubiquitin ligase that degrades p21Cip1. These results demonstrate that MCPIP1 influences the growth and viability of ccRCC cells by increasing or decreasing the transcript levels for proteins involved in cell cycle progression, protein folding, hypoxia response, and cell signaling. PMID- 29492222 TI - Caspase-3 over-expression is associated with poor overall survival and clinicopathological parameters in breast cancer: a meta-analysis of 3091 cases. AB - Caspase-3 is a vital executioner molecule during the apoptotic process. Numerous studies have revealed the close association of caspase-3 expression and breast cancer. Nevertheless, the prognostic value of caspase-3 expression for patients with breast cancer remains uncertain. To thoroughly analyze the prognostic effect of caspase-3 expression on the clinicopathological features and survival of breast cancer, we conducted this meta-analysis. With various search strategies, electronic databases were comprehensively searched. A total of 3091 patients from 21 studies were ultimately obtained. The analysis results indicated that increased expression of caspase-3 had a negative influence on the overall survival (OS) of breast cancer (HR = 1.73, 95%CI 1.12-2.67, P = 0.014). Subgroup analyses based on race revealed that the value of caspase-3 for evaluating patients' OS was more useful in Asian patients (HR = 3.16, 95%CI 1.20-8.15, P = 0.020), and subgroup analyses based on study analytical methods revealed that caspase-3 was a risk factor for breast cancer patients in multivariate overall survival analyses (HR = 1.67, 95%CI 1.02-2.75, P = 0.044). As for the relationship between caspase-3 expression and breast cancer subtype as well as progression, caspase-3 might serve as a risk factor for the progestogen receptor (PR) and human epidermal growth factor receptor-2 (HER-2) subtypes (OR = 1.44, 95%CI 1.09-1.89, P = 0.010; OR = 1.76, 95%CI 1.18-2.62, P = 0.050, respectively) of breast cancer. However, no evidence showed that increased expression of caspase-3 was statistically correlated with tumor differentiation state (low/moderate or high), tumor TNM stage (I-II/III-IV) or lymph node metastasis ( /+). In conclusion, this meta-analysis revealed that increased caspase-3 expression was significantly associated with worse prognosis and two subtypes of breast cancer. More prospective studies are urgently needed to define the prognostic value of caspase-3 expression in patients with breast cancer. PMID- 29492221 TI - The role of neoadjuvant chemotherapy followed by interval debulking surgery in advanced ovarian cancer: a systematic review and meta-analysis of randomized controlled trials and observational studies. AB - Objective: We aimed to performed a meta-analysis and systematic review on the role of neoadjuvant chemotherapy followed by interval debulking surgery (NACT IDS) in advanced ovarian cancer (AOC) patients. Materials and Methods: We searched PubMed, EMBASE, and the Cochrane Library for relevant articles. All statistical analyses were performed in Review Manager 5.3.5. Results: In two randomized controlled trials (RCTs), there was no significant difference in overall survival (OS) (HR = 0.93, 95% CI: 0.81-1.06) or progression-free survival (PFS) (HR = 0.97, 95% CI: 0.86-1.09). Few adverse events (HR = 0.37, 95% CI: 0.19 0.72) and a high optimal debulking surgery rate (HR = 1.69, 95% CI: 1.50-1.91) were observed with NACT. In 22 observational studies, primary debulking surgery (PDS) yielded better OS (HR = 1.38, 95% CI: 1.19-1.60) but not progression-free survival (PFS) (HR = 1.03, 95% CI: 0.86-1.23). An increased optimal cytoreduction rate (HR = 1.17, 95% CI: 1.12-1.22) was observed with NACT. Irrespective of the degree of residual disease, OS was longer in the PDS group than that in the NACT group. Patients with FIGO stage III (HR = 1.43, 95% CI: 1.05-1.95) and IV (HR = 1.14, 95% CI: 1.06-1.23) disease had better survival with PDS. Conclusions: Treatment with NACT-IDS improves perioperative outcomes and optimal cytoreduction rates, but it may not improve OS. NACT-IDS is not inferior to PDS-CT in terms of survival outcomes in selected AOC patients. Future studies should focus on candidate selection for NACT. PMID- 29492223 TI - The diagnostic role of DNA methylation in sporadic endometrial cancer: a systematic review and meta-analysis. AB - Background: Although increasing numbers of methylated genes have been identified as biomarkers for endometrial cancer, the results have been inconsistent. We therefore carried out a systematic review and meta-analysis to evaluate the diagnostic accuracy of methylated genes as markers for sporadic endometrial cancer. Results: A total of 22 studies including 1930 participants (sporadic endometrial cancer patients and normal individuals) met our eligibility criteria. The pooled sensitivity and specificity were 0.93 (95% confidence interval: 0.91 0.94) and 0.48 (95% confidence interval: 0.46-0.50), respectively. The area under the summary receiver operating characteristic curve was 0.8834. The presence of DNA methylation was significantly associated with lymph node metastasis of endometrial cancer (pooled odds ratio: 0.28, 95% confidence interval: 0.15-0.52, p < 0.001). Materials and Methods: We searched the relevant literature systematically using the PubMed and Web of Science databases up to April 2017. Diagnostic accuracy variables were pooled and analyzed using Meta-DiSc software. Sensitivity analysis and publication bias were evaluated using Review Manager. Conclusions: This meta-analysis suggests that the detection of DNA methylation is associated with lymph node metastasis, with high sensitivity but relatively low specificity for the diagnosis of sporadic endometrial cancer. PMID- 29492224 TI - Remote ischemic conditioning improves myocardial parameters and clinical outcomes during primary percutaneous coronary intervention: a meta-analysis of randomized controlled trials. AB - We conducted a systematic review and meta-analysis to evaluate the effects of remote ischemic conditioning on myocardial parameters and clinical outcomes in ST segment elevation acute myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention. Ten eligible randomized controlled trials with 1006 STEMI patients were identified. Compared with controls, remote ischemic conditioning reduced the myocardial enzyme levels (standardized mean difference = 0.86; 95% CI: -1.44 to -0.28; P = 0.004; I2 = 94.5%), and increased the incidence of complete ST-segment resolution [odds ratio (OR) = 1.74; 95% CI: 1.09 to 2.77; P = 0.02; I2 = 47.9%]. Remote ischemic conditioning patients had a lower risk of all-cause mortality (OR = 0.27; 95% CI: 0.12 to 0.62; P = 0.002; I2 = 0.0%) and lower major adverse cardiovascular and cerebrovascular events rate (OR=0.45; 95% CI: 0.27 to 0.75; P = 0.002; I2 = 0.0%). Meta-analysis suggested that remote ischemic conditioning conferred cardioprotection by reducing myocardial enzymes and increasing the incidence of complete ST-segment resolution in patients after STEMI. As a result, clinical outcomes were improved in terms of mortality and incidence of major adverse cardiovascular and cerebrovascular events. PMID- 29492225 TI - Association between homocysteine levels and calcific aortic valve disease: a systematic review and meta-analysis. AB - Previous studies have reported inconsistent results regarding the association between homocysteine (Hcy) levels and calcific aortic valve disease (CAVD). We investigate the association between Hcy levels in patients with CAVD and controls by conducting a systematic review and meta-analysis. We conducted a systematic search of studies published prior to the end of March 2017 in the PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials and the Chinese Biomedical Literature databases. Eligible studies evaluating plasma Hcy levels in CAVD patients and controls were identified by two independent investigators. Standardized mean difference (SMD) and the corresponding 95% confidence intervals (95% CIs) were estimated using the random-effects model. Ten studies involving 6349 participants were included. Pooled analysis demonstrated that Hcy levels were significantly elevated in patients with CAVD compared with controls (pooled SMD: 0.57, 95% CI: 0.36-0.79). This elevation was more obvious in American and Asian populations than in Turkish populations. Furthermore, Hcy levels were significantly elevated in patients with mild-to-moderate CAVD and severe CAVD. Our results demonstrate that CAVD is associated with elevated Hcy levels. PMID- 29492226 TI - Associations between apparent diffusion coefficient (ADC) and KI 67 in different tumors: a meta-analysis. Part 2: ADCmin. AB - The purpose of this part of the meta-analysis was to summarize data regarding associations between minimum apparent diffusion coefficient (ADCmin) and KI 67 in different tumors. MEDLINE library was screened for associations between ADCmin and KI 67 in different tumors up to April 2017. Overall, 23 studies with 944 patients were identified. Associations between ADC and KI 67 were analyzed by Spearman's correlation coefficient. The pooled correlation coefficient between ADCmin and KI 67 for all included tumors was rho = -0.47. In detail, the correlation coefficients for separate tumors were as follows: cerebral lymphoma: rho = -0.61 (95% CI = [-0.82; -0.41]); cervical cancer: rho = -0.56 (95% CI = [ 0.68;-0.43]); pituitary adenoma: rho = -0.55 (95% CI = [-1.31; 0.22]); glioma: rho = -0.40 (95% CI = [-0.55; -0.24]); breast cancer: rho = -0.37 (95% CI = [ 0.74; -0.01]); meningioma, rho = -0.15 (95% CI = [-0.38; 0.07]). PMID- 29492227 TI - The association between BRCA1 gene polymorphism and cancer risk: a meta-analysis. AB - Many studies have reported that BRCA1 polymorphisms are associated with cancer risk, but the results remain controversial. The purpose of this meta-analysis is to evaluate the relationship between BRCA1 polymorphisms (rs799917, rs1799950, rs1799966, or rs16941) and cancer risk. Relevant studies were identified via a systematic search of the PubMed, Embase, and Web of Science databases up to July 31, 2017. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to examine the strength of the associations. Thirty-five studies published in 19 publications involving 28,094 cases and 50,657 controls were included in this meta-analysis. There was no obvious association between rs799917, rs1799966, or rs16941 polymorphisms and overall cancer risk in any genetic models. However, subgroup analyses revealed that the rs799917 polymorphism could decrease the risk of cervical cancer, esophageal squamous cell carcinoma (ESCC), gastric cancer, and non-Hodgkin lymphoma (NHL) among Asian populations in one or more genetic models and that rs16941 could increase overall cancer risk among Caucasian populations in the homozygote and recessive models. Our meta-analysis also indicated that rs1799950 could decrease the breast cancer (BC) risk among Caucasian populations in the homozygote and recessive models. In summary, our results suggest that BRCA1 polymorphisms may play an important role in the etiology of cancer. However, due to the limited number of studies, these findings should be confirmed by new studies with larger sample sizes that address various types of cancer. PMID- 29492228 TI - Polymorphisms in four microRNAs and risk of oral squamous cell cancer: a meta analysis. AB - Objectives: Single nucleotide polymorphisms in microRNAs (microRNA-196a2 rs11614913, microRNA-146a rs2910164, microRNA-149 rs2292832 and microRNA-499 rs3746444) have been inconsistently associated with risk for oral squamous cell cancer (OSCC). This meta-analysis aimed to assess the correlation between microRNA polymorphisms and susceptibility to OSCC. Materials and Methods: Free words were used to search for the relevant studies without language limitations in electronic databases including PubMed, Embase, Web of Science and SCOPUS through June 15, 2017. Odds ratios (ORs) were calculated to investigate the effects of microRNA polymorphisms on oral cancer risk. Results: Eleven studies were included. Analysis under the recessive model of microRNA-146a (CC vs GG+CG) showed significant differences (ORs = 0.874, P = 0.041). The G allele and the GG genotype of microRNA-499 were associated with OSCC risk (ORs >1, P < 0.05). MicroRNA-196a2 rs11614913 and microRNA-149 polymorphisms appeared to have no relationship with OSCC risk (P > 0.05). In the sensitivity analysis, there was a significant association between the TT genotype of microRNA-196a2 and OSCC risk (TT vs TC + CC, ORs < 1, P < 0.05). Conclusions: There may be no significant relationship between microRNA-149 polymorphisms and OSCC risk, and the CC genotype of microRNA-146a may have protective effects against oral cancer. However, the G allele and the GG genotype of microRNA-499 may increase OSCC risk. PMID- 29492229 TI - Analysis of response rate with ANTI PD1/PD-L1 monoclonal antibodies in advanced solid tumors: a meta-analysis of randomized clinical trials. AB - Background: Anti-PD1/PD-L1 monoclonal antibodies (mAbs) increase overall survival compared to standard of care (SOC) in different tumors. However, a proportion of patients (pts) will have progressive disease (PD) as best response. We conducted a meta-analysis to study the rates of response comparing these antibodies with SOC. Methods: A search of published trials in MEDLINE and EMBASE analyzing anti PD1/PD-L1mAbs monotherapy compared to SOC. Relative risk (RR) with 95% confidence interval (CI) of response rates between groups was estimated. Subgroup analyses for location of primary tumor, number of previous treatment lines, selected population by PD-L1 expression and type of radiological assessment were made. Results: Twelve studies accounting for 6,700 pts were included (anti-PD1/PD-L1 mAbs: 3,451 pts; SOC: 3,249 pts [2,823 pts: chemotherapy, 426 pts: targeted therapy]). Adjusted response rates were (N, %): Complete Response (CR) (69/3153, 2.19%), Partial Response (PR) (596/3153, 18.90%), Stable Disease (SD) (632/2463, 25.66%) and PD (1027/2463, 41.70%); and CR (16/2955, 0.54%), PR (263/2955, 8.90%), SD (835/2269, 36.80%) and PD (834/2269, 36.76%) with anti-PD1/PD-L1 mAbs and SOC, respectively. Anti-PD1/PD-L1 mAbs improved CR rate (RR 3.48) and PR rate (RR 2.27). There were no differences in the PD rate between groups (RR 1.10). Subgroup analyses showed an improvement in clinical benefit with anti-PD1/PD-L1 mAbs for melanoma (RR 1.59; 1.37-1.84 95% CI) and those treated in the first line setting (RR 1.57; 1.27-1.95 95% CI). Conclusions: Anti-PD1/PD-L1 mAbs increase overall response rate compared to SOC without an increase in PD rate. Melanoma and pts treated in first line setting seem to have greater benefit with anti PD1/PD-L1 mAbs. Findings: In this systematic meta-analysis, anti-PD1/PD-L1 mAbs were associated with a greater overall response rate. Patients with melanoma and those managed in the first line setting seem to have an additional benefit with anti-PD1/PD-L1 mAbs. PMID- 29492230 TI - Comparing single oral contrast-enhanced ultrasonography and double contrast enhanced ultrasonography in the preoperative Borrmann classification of advanced gastric cancer. AB - Objectives: To evaluate the accuracy of double contrast-enhanced ultrasonography (DCEUS) in preoperative Borrmann classification of advanced gastric cancer (AGC). Materials and Methods: A total of 162 patients histologically confirmed AGC were enrolled into this study. Single oral contrast-enhanced ultrasonography (SOCEUS) were performed in 80 patients and DCEUS (intravenous microbubbles combined with oral contrast-enhanced ultrasound) were performed in 82 patients preoperatively. The findings of the histopathologic examination of resected specimens after surgery were considered as gold standard. The accuracy of SOCEUS was compared with the accuracy of DCEUS in determining Borrmann classification. Interobserver agreement between two sonographyers of SOCEUS and DCEUS had also been assessed. Results: The accuracy of SOCEUS and DCEUS in Borrmann classification of advanced gastric cancer were 78.75% and 91.46% respectively. There was a significant difference between two methods (chi2 = 5.186, P < 0.05). The interobserver agreement of two methods was both excellent for assessing the Borrmann classification with a Kappa value of 0.777 by SOCEUS and 0.844 by DCEUS. Conclusions: DCEUS is a valuable method for Borrmann classification with its high accuracy preoperatively. It should be used widely. PMID- 29492231 TI - Potential delay in the diagnosis of vulvar cancer and associated risk factors in women treated in German gynecological practices. AB - The goal of this study was to estimate a potential delay in the diagnosis of vulvar cancer and identify associated risk factors in women treated in gynecological practices in Germany. The current study sample included 1,652 women from 218 gynecological practices who received an initial diagnosis of vulvar cancer (ICD 10: C51) between January 2000 and December 2015 (index date). After applying several exclusion criteria, 505 non-cancer controls were matched (1:1) to 505 vulvar cancer cases based on age, health insurance status, and index date. The primary outcome was the delay in vulvar cancer diagnosis in women who had received an initial diagnosis of diseases of Bartholin's gland, inflammation of vagina and vulva, or other specified noninflammatory disorders of vulva, including atrophy, hypertrophy, and cyst. A logistic regression model was used to estimate the association between vulvar cancer and pre-defined diagnoses. The mean age was 60.8 years (SD = 15.6 years), and 4.8% of women had private health insurance coverage. Inflammation of vagina and vulva was diagnosed 328 days (SD = 95 days) prior to the detection of vulvar cancer. This delay was 186 days (SD = 196 days) in patients affected by diseases of Bartholin's gland and 300 days (SD = 116 days) in those with other specified noninflammatory disorders of vulva including atrophy, hypertrophy, and cyst. The risk of vulvar cancer was positively associated with inflammation of vagina and vulva (OR = 2.28) and other specified noninflammatory disorders of vulva (OR = 5.39). The mean potential delay of vulvar cancer diagnosis ranged from 186 to 328 days. PMID- 29492232 TI - The risk of cirrhosis in non-alcohol drinkers is greater in female than male betel nut chewers. AB - Background and Aim: The association of betel nut with liver cirrhosis among alcohol drinkers has been clearly shown. However, very few studies have shown such an association among non-alcohol drinkers. The aim of this study was to assess the relationship between betel nut chewing and cirrhosis among non-alcohol drinkers. Materials and Methods: This study retrospectively analyzed data retrieved from the 2012 Adult Preventive Medical Services and the National Health Insurance Research Datasets in Taiwan. Participants' information included physical examination and lifestyle, alongside laboratory tests. Betel nut chewers were grouped into three categories: never, occasional and frequent. Diseases were diagnosed using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). Initially, 1573024 adults aged 40 years and above who engaged in the free adult preventive medical services in 2012 were recruited. However, only 1065246 of them were included in the analysis. Chi square test and logistic regression were used for the analyses. Results: After multivariable adjustments, there were significant relationships between cirrhosis and betel nut chewing in both sexes (P-trend < 0.0001). The risk of cirrhosis was greater in females than males. The odds ratios of cirrhosis in occasional and frequent female chewers were respectively 2.91; 95% C.I: 1.75-4.83 and 3.06; 95% C.I: 1.69-5. However, they were respectively 1.76; 95% C.I: 1.47-2.10 and 2.32; 95% C.I: 1.90-2.85 in occasional and frequent male chewers. Conclusions: This study demonstrated significant relationships between betel nut chewing and cirrhosis in both male and female non-alcohol drinkers. The risk of cirrhosis was greater in female than male chewers. PMID- 29492233 TI - Hyperuricemia is associated with decreased changes in heart rate variability after hemodialysis in non-diabetic patients. AB - Hyperuricemia has been associated with low heart rate variability (HRV), however whether there is an association between uric acid (UA) and HRV changes after hemodialysis (HD) is unknown. The aim of this study was to investigate the role of UA in HRV changes before and after HD in non-diabetic patients. Ninety-six non diabetic patients under maintenance HD were enrolled. HRV was examined to assess changes before and after HD. A change in HRV (DeltaHRV) was calculated as post-HD HRV minus pre-HD HRV. Compared to the patients with a UA level ? 7 mg/dL, those with a UA level > 7 mg/dL had lower ?high frequency (HF)% (p = 0.027). UA was negatively associated with ?HF% (r = -0.247, p = 0.015) and ?low frequency (LF)/HF (r = -0.236, p = 0.021) in the non-diabetic patients undergoing HD. Furthermore, in multivariate analysis after adjustments for demographic, clinical, and biochemical characteristics and medications, UA was independently associated with ?HF% (per 1 mg/dL, unstandardized coefficient beta = -2.892; 95% CI, -5.066 to -0.717; p = 0.010) and ?LF/HF (per 1 mg/dL, unstandardized coefficient beta = -0.165; 95% CI, -0.291 to -0.038; p = 0.011). Hyperuricemia contributed to lesser HF% and LF/HF increase after HD in the non-diabetic patients, reflecting a state of impaired sympatho-vagal equilibrium in non diabetic HD patients with hyperuricemia. Lowering UA levels may have the potential to improve increased HRV in non-diabetic HD patients. PMID- 29492234 TI - Detecting asymptomatic recurrence after radical nephroureterectomy contributes to better prognosis in patients with upper urinary tract urothelial carcinoma. AB - Background: The prognostic benefit of regular follow-up to detect asymptomatic recurrence after radical nephroureterectomy (RNU) remains unclear. We aimed to assess whether regular follow-up to detect asymptomatic recurrence after RNU improves patient survival. Materials and Methods: We retrospectively analysed 415 patients who underwent RNU for upper tract urothelial carcinoma at four hospitals between January 1995 and February 2017. All patients had regular follow-up examinations after RNU including urine cytology, blood biochemical tests, and computed tomography. We investigated the first site and date of tumor recurrence. Overall survivals of patients who developed recurrence, stratified by mode of recurrence (asymptomatic vs. symptomatic group), were estimated using the Kaplan Meier method with the log-rank test. Cox proportional hazards regression analysis was performed using inverse probability of treatment weighting (IPTW) to evaluate the impact of the mode of recurrence on survival. Results: Of the 415 patients, 108 (26%) experienced disease recurrences after RNU. Of these, 62 (57%) were asymptomatic and 46 (43%) were symptomatic at the time of diagnosis. The most common recurrence site and symptom were lymph nodes and pain, respectively. Overall survival after RNU and time from recurrence to death in the asymptomatic group were significantly longer than that in the symptomatic group. Multivariate Cox regression analysis showed that symptomatic recurrence was an independent risk factor for overall survival after RNU and survival from recurrence to death. Conclusions: Routine oncological follow-up for detection of asymptomatic recurrence contributes to a better prognosis after RNU. PMID- 29492235 TI - Coronary artery disease risk in young women with polycystic ovary syndrome. AB - Women with polycystic ovary syndrome are characterized by obesity, menstruation irregularity, hirsutism and infertility, and prevalent with cardiometabolic comorbidities, but population-based studies on the risk of developing coronary artery disease are limited. From claims data of the Taiwan National Health Insurance, we identified 8048 women with polycystic ovary syndrome aged 15-49 years newly diagnosed in 1998-2013, and 32192 women without the syndrome and CAD as controls, frequency matched by age and diagnosis date. By the end of 2013, after a mean follow-up period of 5.9 years, the overall incidence of coronary artery disease was 63% higher in women with polycystic ovary syndrome than in controls (2.25 vs. 1.38 per 1000 person-years). The adjusted hazard ratio [aHR] of coronary artery disease was 1.44 (95% confidence interval (CI) = 1.14-1.81) for women with polycystic ovary syndrome, compared with controls. Hazards of coronary artery disease were significant during follow-up periods of 3-4 years (aHR = 1.52, 95% CI = 1.00-2.30) and of 5-9 years (aHR = 1.58, 95% CI = 1.07 2.32). The incidence of coronary artery disease increased further in those with cardiometabolic comorbidities. Among women with polycystic ovary syndrome, those with comorbid diabetes had an incidence of 35.2 per 1000 person-years, 20-fold greater than those without cardiometabolic comorbidities. In conclusion, women with polycystic ovary syndrome are at an elevated risk of coronary artery disease. Preventive interventions should be provided to them, particularly for those with the comorbidity of metabolism symptom. PMID- 29492236 TI - Monoinstitutional real world experience in management of Vinflunine as second line therapy for transitional cell carcinoma of the urothelium. AB - Vinflunine is the only cytotoxic agent tested as a second line therapy in transitional cell carcinoma of the urothelium in a phase III trial. It is not largely employed in clinical practice because of the high incidence of grade 3-4 toxicity. We evaluated efficacy and safety of Vinflunine at the dose of 280 mg/m2 every 3 weeks associated with primary prophylaxis with granulocyte growth factors and laxatives for patients progressed after platinum + Gemcitabine. Overall survival was 8.5 months, progression-free survival 4.33 months and response rate 25%, with disease control rate 57.2%. Grade III-IV neutropenia occurred in 10.7% of the patients, grade III-IV anemia and grade III thrombocytopenia in 10.7% and 7.2%, respectively. Among non haematological toxicity, grade I-II constipation was reported in 14.2% of the patients, without grade III-IV adverse events. No discontinuation for toxicity was observed. This study underlines that Vinfluinine at a dose of 280 mg/m2 associated with primary prophylaxis for neutropenia and constipation is effective and with a favorable toxicity profile. PMID- 29492239 TI - Comparison of Cameriere's and Demirjian's methods of age estimation among children in Kerala: a pilot study. AB - The aim was to compare age estimation using Cameriere's and Demirjian's methods to chronologic age in children with mixed dentition in a rural population of Kerala. The present study comprised of 10 subjects of age range 7-12 years. Dental age was assessed using Cameriere's and Demirjian's methods and was compared to the chronologic age. Panoramic radiographs were used for assessment of dental age. Data were analysed using paired t-test. The mean of difference obtained was 0.92 and the pvalue was 0.172 which showed insignificant difference between the two methods. Cameriere's method showed a positive linear correlation (0.6393) with chronologic age and was statistically significant (P=0.0171), whereas Demirjian's method showed a negative correlation (-0.7598) and was statistically insignificant (P=0.9967). The present study indicated that Cameriere's method is reliable for age estimation in our population and is more accurate than Demirjian's method. PMID- 29492237 TI - Senescence and cell death in chronic liver injury: roles and mechanisms underlying hepatocarcinogenesis. AB - Chronic liver injury (CLI) is a complex pathological process typically characterized by progressive destruction and regeneration of liver parenchymal cells due to diverse risk factors such as alcohol abuse, drug toxicity, viral infection, and genetic metabolic disorders. When the damage to hepatocytes is mild, the liver can regenerate itself and restore to the normal state; when the damage is irreparable, hepatocytes would undergo senescence or various forms of death including apoptosis, necrosis and necroptosis. These pathological changes not only promote the progression of the existing hepatopathies via various underlying mechanisms but are closely associated with hepatocarcinogenesis. In this review, we discuss the pathological changes that hepatocytes undergo during CLI, and their roles and mechanisms in the progression of hepatopathies and hepatocarcinogenesis. We also give a brief introduction about some animal models currently used for the research of CLI and progress in the research of CLI. PMID- 29492240 TI - Accidental local infiltration of formalin into the buccal mucosa: A case report and review of the literature. AB - Formalin is a hazardous chemical, yet it is the choice of fixative for diagnostic pathology. Dental surgeons routinely use formalin for preservation of oral biopsy specimens. Literature search revealed that during regular biopsy procedures, unintentional injection with formalin has occurred, and such rare seven cases have been reported till date. In addition to the literature review, the present article describes first case of accidental local infiltration with formalin into the buccal mucosa during a biopsy procedure, its damaging effect on the oral tissues, subsequent judicious management of the patient and successful tissue reconstruction with collagen membrane. PMID- 29492241 TI - Objective measurement of head movement differences in children with and without autism spectrum disorder. AB - Background: Deficits in motor movement in children with autism spectrum disorder (ASD) have typically been characterized qualitatively by human observers. Although clinicians have noted the importance of atypical head positioning (e.g. social peering and repetitive head banging) when diagnosing children with ASD, a quantitative understanding of head movement in ASD is lacking. Here, we conduct a quantitative comparison of head movement dynamics in children with and without ASD using automated, person-independent computer-vision based head tracking (Zface). Because children with ASD often exhibit preferential attention to nonsocial versus social stimuli, we investigated whether children with and without ASD differed in their head movement dynamics depending on stimulus sociality. Methods: The current study examined differences in head movement dynamics in children with (n = 21) and without ASD (n = 21). Children were video recorded while watching a 16-min video of social and nonsocial stimuli. Three dimensions of rigid head movement-pitch (head nods), yaw (head turns), and roll (lateral head inclinations)-were tracked using Zface. The root mean square of pitch, yaw, and roll was calculated to index the magnitude of head angular displacement (quantity of head movement) and angular velocity (speed). Results: Compared with children without ASD, children with ASD exhibited greater yaw displacement, indicating greater head turning, and greater velocity of yaw and roll, indicating faster head turning and inclination. Follow-up analyses indicated that differences in head movement dynamics were specific to the social rather than the nonsocial stimulus condition. Conclusions: Head movement dynamics (displacement and velocity) were greater in children with ASD than in children without ASD, providing a quantitative foundation for previous clinical reports. Head movement differences were evident in lateral (yaw and roll) but not vertical (pitch) movement and were specific to a social rather than nonsocial condition. When presented with social stimuli, children with ASD had higher levels of head movement and moved their heads more quickly than children without ASD. Children with ASD may use head movement to modulate their perception of social scenes. PMID- 29492242 TI - Molecular evidence for asymmetric hybridization in three closely related sympatric species. AB - Natural hybridization is common in plants and results in different evolutionary consequences to hybridizing species. Pre- and post-zygotic reproductive isolating barriers can impede hybridization between closely related species to maintain their species integrity. In Northwest Yunnan, three Ligularia species (Ligularia cyathiceps, L. duciformis and L. yunnanensis) and four types of morphologically intermediate individuals were discovered growing together in an area subject to human disturbance. In this study, we used three low-copy nuclear loci to test the natural hybridization hypothesis and the hybridization direction was ascertained by three chloroplast DNA fragments. The results indicated there were two hybridization groups at the study site, L. cyathiceps * L. duciformis and L. duciformis * L. yunnanensis, and two types of morphologically intermediate individuals were produced by L. cyathiceps and L. duciformis, and another two types were produced by L. duciformis and L. yunnanensis, while no hybrids between L. cyathiceps and L. yunnanensis were observed. Both hybridizing groups showed bidirectional but asymmetric hybridization and the factors influencing the symmetry are discussed. Most hybrids produced by the two hybridization groups seemed to be F1 generation. Hybrids with different morphologies within the same hybridization group showed similar genetic components. The results suggest that although human disturbance may promote natural hybridization among the three Ligularia species bringing them together, hybrids are limited to F1s and therefore species boundaries might be maintained. PMID- 29492243 TI - A review of the new GLP-1 receptor agonist/basal insulin fixed-ratio combination products. AB - There have been several new treatment approaches established for the management of hyperglycemia in type 2 diabetes (T2D), with treatment guidelines listing both glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and basal insulin therapies as considerations for patients who have failed to control their blood glucose with oral antidiabetic agents. New studies have highlighted the importance of initiating combination therapy earlier in the T2D disease process to avoid clinical inertia and prevent the long-term complications arising from uncontrolled diabetes. Until recently, both GLP-1 RAs and basal insulin therapies were only available as single agents, but there are now two combination pen devices that deliver both a GLP-1 RA and basal insulin simultaneously. This article reviews the current clinical evidence evaluating the use of these combination GLP-1 RA/basal insulin preparations to treat T2D, presents both potential benefits as well as possible downsides with the use of these agents, and discusses the current place in therapy these products represent in the management of T2D. PMID- 29492238 TI - Anorectal mucosal melanoma. AB - Anorectal melanoma is an uncommon and aggressive mucosal melanocytic malignancy. Due to its rarity, the pre-operative diagnosis remains difficult. The first symptoms are non-specific such as anal bleeding, anal mass or pain. Although anorectal melanoma carries a poor prognosis; optimal therapeutics strategies are unclear. Surgical resection remains the mainstay of treatment. The optimal surgical procedure for primary tumours is controversial and can vary from wide local excision or endoscopic mucosal resection (EMR) to an abdomino-perineal resection. A high degree of uncertainly exists regarding the benefit of radiation therapy or chemotherapy. The treatment of advanced melanoma is evolving rapidly with better understanding of the disease biology and immunology. Considerable effort has been devoted to the identification of molecular determinants of response to target therapies and immunotherapy. PMID- 29492245 TI - Can supporting health literacy reduce medication-related harm in older adults? PMID- 29492244 TI - Antidiabetic phytoconstituents and their mode of action on metabolic pathways. AB - Diabetes Mellitus, characterized by persistent hyperglycaemia, is a heterogeneous group of disorders of multiple aetiologies. It affects the human body at multiple organ levels thus making it difficult to follow a particular line of the treatment protocol and requires a multimodal approach. The increasing medical burden on patients with diabetes-related complications results in an enormous economic burden, which could severely impair global economic growth in the near future. This shows that today's healthcare system has conventionally been poorly equipped towards confronting the mounting impact of diabetes on a global scale and demands an urgent need for newer and better options. The overall challenge of this field of diabetes treatment is to identify the individualized factors that can lead to improved glycaemic control. Plants are traditionally used worldwide as remedies for diabetes healing. They synthesize a diverse array of biologically active compounds having antidiabetic properties. This review is an endeavour to document the present armamentarium of antidiabetic herbal drug discovery and developments, highlighting mechanism-based antidiabetic properties of over 300 different phytoconstituents of various chemical categories from about 100 different plants modulating different metabolic pathways such as glycolysis, Krebs cycle, gluconeogenesis, glycogen synthesis and degradation, cholesterol synthesis, carbohydrate metabolism as well as peroxisome proliferator activated receptor activation, dipeptidyl peptidase inhibition and free radical scavenging action. The aim is to provide a rich reservoir of pharmacologically established antidiabetic phytoconstituents with specific references to the novel, cost effective interventions, which might be of relevance to other low-income and middle-income countries of the world. PMID- 29492246 TI - An update on the safety of current therapies for Alzheimer's disease: focus on rivastigmine. AB - Alzheimer's disease (AD) is the most common cause of major neurocognitive disorders worldwide. Despite all research efforts, therapeutic options for AD are still limited to two drug classes: cholinesterase inhibitors (ChEIs) and the NMDA receptor antagonist memantine. Donepezil, rivastigmine and galantamine are the three ChEIs FDA-approved as first-line treatment for AD. Although they share the same mode of action, they differ in terms of their pharmacologic characteristics and route of administration, which can impact their safety and tolerability profile. Rivastigmine, available in both oral and transdermal patch formulations, is a slowly reversible dual inhibitor of acetyl and butyryl cholinesterase, selective for the G1 isoform of acetylcholinesterase, without hepatic metabolism by the CYP-450 system. Despite its unique features, it has been associated with a higher incidence of adverse events in comparison to other ChEIs. The oral form, approved for the treatment of mild to moderate AD, is associated with a higher incidence of gastrointestinal side effects. The transdermal patch formulation approved for use across all stages of AD has been shown to have a better tolerability profile in comparison to both the oral form and even other ChEIs. One important tolerability concern is adverse dermatologic reactions, which are mostly benign, and can be either preventable or manageable. One important safety concern is the risk of treatment overdose by administering multiple patches at the same time, potentially leading to fatal outcomes. This can be prevented by educating patients and caregivers about the proper use of the patch. The goal for the future would be to optimize the patch formulation to increase both efficacy and safety. PMID- 29492247 TI - Likelihood of reporting medication errors in hospitalized children: a survey of nurses and physicians. AB - Background: Hospitalized children are at risk of medication errors (MEs) due to complex dosage calculations and preparations. Incident reporting systems may facilitate prevention of MEs but underreporting potentially undermines this system. We aimed to examine whether scenarios involving medications should be reported to a national mandatory incident reporting system and the likelihood of self- and peer-reporting these scenarios among paediatric nurses and physicians. Methods: Participants' reporting of MEs was explored through a questionnaire involving 20 medication scenarios. The scenarios represented different steps in the medication process, types of error, patient outcomes and medications. Reporting rates and odds ratios with 95% confidence interval [OR, (95% CI)] were calculated. Barriers to and enablers of reporting were identified through content analysis of participants' comments. Results: The response rate was 42% (291/689). Overall, 61% of participants reported that scenarios should be reported. The likelihood of reporting was 60% for self-reporting and 37% for peer-reporting. Nurses versus physicians, and healthcare professionals with versus without patient safety responsibilities assessed to a larger extent that the scenarios should be reported [OR = 1.34 (1.05-1.70) and OR = 1.41 (1.12-1.78), respectively]; were more likely to self-report, [OR = 2.81 (1.71-4.62) and OR = 2.93 (1.47-5.84), respectively]; and were more likely to peer-report [OR = 1.89 (1.36-2.63) and OR = 3.61 (2.57-5.06), respectively].Healthcare professionals with versus without management responsibilities were more likely to peer-report [OR = 5.16 (3.44-7.72)]. Participants reported that scenarios resulting in actual injury or incidents considered to have a learning potential should be reported. Conclusion: The likelihood of underreporting scenarios was high among paediatric nurses and physicians. Nurses and staff with patient safety responsibilities were more likely to assess that scenarios should be reported and to report. Incidents with actual injury or learning potential were more likely to be reported. The potential for improving reporting rates involving MEs seems high. PMID- 29492249 TI - Robot-assisted repair of diaphragmatic hernias following ventricular assist device implantation. AB - Use of ventricular assist devices (VADs) is increasingly common, as is the need for surgeons to be familiar with the management of common complications in this population. Nonetheless, repair of diaphragmatic hernias which commonly develop following VAD implantation remains technically challenging due to intra-abdominal adhesions and the proximity of vital structures. Despite the potential benefits of improved dexterity and visualization, robotic approaches have thus far not been used to address this. We present the first two described cases of robot assisted repair of diaphragmatic hernias in the setting of prior or current VAD placement. PMID- 29492248 TI - Toxic association between an intestinal myxoma and a mesenteric lipoma in a child: a case report. AB - Intestinal myxoma is among the rarest presentations of this benign tumour. Moreover, the association of an intestinal myxoma and a mesenteric lipoma is even more surprising. Intestinal tumours are often diagnosed inadvertently: a routine physical exam may identify these tumours or an abdominal computed tomography scan or abdominal ultrasound for another indication. Acute intestinal obstruction is rare. We hereby report the case of a 6-year-old boy who presented in the emergency room of our institution with acute intestinal obstruction and the management of this case. PMID- 29492250 TI - Gastrointestinal stromal tumour as a rare association with neurofibromatosis type 1. AB - Gastrointestinal stromal tumours (GIST) are rare tumours of mesenchymal origin. These can be associated with neurofibromatosis type 1 (NF1), which is an autosomal dominant disorder. The prevalence of GIST in NF1 is estimated at 3.9 25%. This paper describes the presentation of a GIST arising from the jejenum in a 75-year-old lady with NF1, who presented with gastrointestinal bleeding. This was diagnosed by CT angiography. She was managed with laparotomy, with resection of small bowel, and an ischaemic segment of large bowel with two primary anastomoses. Pathology showed GIST of spindle cell type (Figs 3 and 4), 90 mm in size, with complete local excision. The patient was discharged on the eighth post operative day and is currently undergoing regular clinic follow-up after multidisciplinary team meeting discussion. PMID- 29492251 TI - Transanal minimally invasive surgery for resection of retrorectal cyst. AB - Tailgut cysts are benign retrorectal embryological remnants, often found incidentally or when evaluating a patient for pelvic symptoms. Transanal minimally invasive surgery (TAMIS) offers patients a low morbidity surgical approach for resection of a variety of low rectal lesions. This is a case report of resection of a tailgut cyst using TAMIS, including images and description of the steps of the procedure. PMID- 29492252 TI - Primary hyperparathyroidism presenting as acute psychosis secondary to hypercalcaemia requiring curative parathyroidectomy. AB - Primary hyperparathyroidism (PHPT) can cause hypercalcaemia secondary to a pathologically high secretion of parathyroid hormone. Rarely this can first manifest as acute psychosis. It is imperative to exclude organic causes of psychosis before labelling the psychosis as primarily psychological. If hypercalcaemia is revealed, investigation is required to elucidate the underlying cause whilst instigating treatment to lower serum calcium levels. If PHPT is the underlying pathology, subsequent treatment involves surgical exploration and resection of the parathyroid adenoma or hyperplasia. PMID- 29492253 TI - Case report of a ruptured endobutton used in medial patellofemoral ligament reconstruction causing patellofemoral impingement. AB - The medial patellofemoral ligament (MPFL) is a key soft tissue stabilizer of the medial patella, with deficiency proven to be a key contributor to patellar dislocation. Reconstruction of this ligament has become a widely employed procedure in managing patients with recurrent patellar dislocation, and is also gaining popularity in the setting of primary dislocation. A wide variety of techniques have been described, differing in the type of graft used, sites for fixation and fixation technique. A number of complications have also been reported in the literature, including post-operative stiffness, apprehension, patellar fracture and recurrence of instability and dislocation. Here we report a case of an endobutton used in MPFL reconstruction becoming displaced after minimal trauma in a young female patient, subsequently causing patellofemoral irritation, patellar cartilaginous damage and functional limitation. This complication has not been previously reported to our knowledge and is one that surgeons must be aware of. PMID- 29492255 TI - An intrapancreatic accessory spleen presenting as a rapidly growing pancreatic mass after splenectomy in a patient with hereditary spherocytosis: a case report and literature review. AB - The case of a 16-year-old boy with an intrapancreatic accessory spleen presenting as a rapidly growing pancreatic mass after splenectomy for splenomegaly due to hereditary spherocytosis is reported herein. When he was 15 years old, the patient visited at a hospital due to jaundice and radiological examinations showed a huge spleen with a 2-cm mass near or in the pancreatic tail. Sonazoid enhanced ultrasonography showed hypervascularity in the mass located near the pancreatic tail, which was suspicious for an accessory spleen. During splenectomy by laparotomy, the mass could not be found by inspection or intraoperative ultrasonography. One year after the splenectomy, the mass grew rapidly to 4 cm. Laparoscopic surgery was performed to aid in the differential diagnosis of the mass, and a laparoscopic ultrasonogram revealed that the mass was located in the pancreatic tail. The patient underwent laparoscopic distal pancreatectomy and was discharged uneventfully on the 11th postoperative day. PMID- 29492254 TI - Laparoscopic treatment of a patent ductus venosus and the use of indocyanine green to monitor perioperative hepatic function. AB - Patent ductus venosus (PDV) is an uncommon but important congenital portocaval shunt that can lead to numerous complications if untreated. This case describes the successful management of a 17-year-old male with symptomatic PDV. Doppler ultrasonography and contrast-enhanced computed tomography (CT) confirmed a large communication between the left portal vein and the inferior vena cava. Angiography demonstrated a large and high flow PDV which precluded its therapeutic embolization. Based on these findings, laparoscopic closure of the PDV was elected and successfully performed. Perioperative indocyanine green (ICG) clearance was performed and marked improvement was observed following the occlusion of the PDV. The patient showed immediate resolution of symptoms post operatively and remains asymptomatic 2 years after his surgery. Laparoscopic approach to the management of PDV is feasible. ICG clearance, for the first time, was demonstrated in this setting to be a useful and rapid bedside test for the real-time assessment of liver function. PMID- 29492256 TI - A case report of squamous cell carcinoma in a suprapubic urinary catheter tract: surgical excision and simultaneous colostomy formation. AB - Squamous cell carcinoma (SCC) arising from a suprapubic cystostomy tract is a rare complication of long-term suprapubic catheterization (SPC). A 53-year-old man with paraplegia secondary to spina bifida presented with a painful granulomatous lesion around his SPC site that was being treated with silver nitrate cauterization in the community. Consequently, he developed a sacral pressure sore due to reduced mobility from the pain. He also had increasing difficulties with defaecation secondary to his spina bifida. His sacral pressure sore was secondary to a cryptoglandular fistula with coccygeal osteomylelitis. Post-operative pathology revealed infiltrative SCC involving full thickness of the specimen from skin to the bladder wall with clear surgical margins. We describe the first case requiring a simultaneous suprapubic tract SCC excision and colostomy formation. We recommend early investigation of lesions arising from a long-term suprapubic tract especially in patients with spinal cord injuries or congenital defects. PMID- 29492257 TI - Alternatives to ketamine in depression: state-of-the-art and future perspectives. PMID- 29492258 TI - Benzodiazepine prescription in Ontario residents aged 65 and over: a population based study from 1998 to 2013. AB - Background: Although commonly used in anxiety and insomnia, recent guidelines recommend caution when prescribing benzodiazepines in the elderly. Here we examined rates of benzodiazepine prescribing to older adults in Ontario, Canada from 1998 to 2013 and impact of legislation that made prescribing regulations more strict. Method: Annual benzodiazepine prescription rates for Ontario residents aged 65 and over were examined using the Ontario Drug Benefit database which captures all publicly funded prescriptions. Since most drugs, including benzodiazepines, are funded for residents aged ?65, data are essentially population-based. Weighted least squares regression methods were used to examine trends in prescribing rates (all benzodiazepines, anxiolytics, hypnotics, short- and long-acting drugs and individual drugs) from 1998 to 2013 for all Ontario residents aged ?65 and by sex and 5-year age bands. Impact on monthly prescribing rates of legislative changes (November 2011) which aimed to promote appropriate prescribing and dispensing practices for controlled substances, including requiring prescribers to record specified information, was assessed by constructing an interrupted time-series model. Results: Benzodiazepines were prescribed to 23.2% of the 1,412,638 Ontario residents aged ?65 in 1998, declining to 14.9% of 2,057,899 residents aged ?65 in 2013 (p < 0.001 for trend). Rates were significantly greater throughout in older age bands (p < 0.001) and 1.54-1.62 times greater in females than males (p < 0.001). Lorazepam was the most prescribed benzodiazepine throughout, but rates declined from 11.4% in 1998 to 8.5% in 2013. Diazepam rates fell from 2.3% to 0.7%. However, clonazepam prescription rates increased until 2011, 1.7-fold overall. After the November 2011 legal changes, downward shifts were observed in total benzodiazepine prescription rates and for each drug individually. The step function, conditional on covariates, suggested benzodiazepine rates after November 2011 were 2.89 per 1000 (p < 0.001) below rates observed previously, representing a relative reduction of 4.8% compared to the year before the intervention. Conclusion: Benzodiazepine prescribing rates declined markedly in this population from 1998 to 2013. Targeted legislation may have reduced rates, but the effect, although statistically significant, was small. PMID- 29492259 TI - Long non-coding RNA CASC2 improved acute lung injury by regulating miR-144 3p/AQP1 axis to reduce lung epithelial cell apoptosis. AB - Background and objective: Apoptosis of lung epithelial cell is implicated in the pathogenesis of acute lung injury (ALI). To study the protective effect and mechanism of cancer susceptibility candidate 2 (CASC2) on reducing lung epithelial cell apoptosis after LPS inducing acute lung injury in mice. Methods and results: The ALI mice model was performed by intratracheally instilling with lipopolysaccharide (LPS). The CASC2 expression detected by quantitative real-time polymerase chain reaction was significantly decreased in LPS-induced A549 cell and ALI mice model. LPS induced A549 cell apoptosis, while transfection with pcDNA-CASC2 reversed the increased cell apoptosis, suggesting overexpression of CASC2 inhibited LPS-induced A549 cell apoptosis. In addition, we found that miR 144-3p expression were opposite to CASC2, while Aquaporin-1 (AQP1) expression was opposite to miR-144-3p in LPS-induced A549 cell and ALI mice model. The RNA immunoprecipitation and RNA pull-down assay demonstrated that CASC2 could function as a miR-144-3p decoy. The luciferase reporter assay revealed that AQP1 was a target of miR-144-3p in A549 cell. And then, further in vitro studied showed that CASC2 controlled AQP1 expression by regulating miR-144-3p, and LPS induced A549 cell apoptosis by regulating CASC2/miR-144-3p/AQP1 axis. At last, after injection with lentivirus-expressing CASC2 or control lentivirus, the mice were intratracheally instilled with LPS. Comparing to the mice injected with pcDNA, the mice injected with pcDNA-CASC2 had a significantly reduced lung wet dry weight ratio. Conclusions: Long non-coding RNA CASC2 improved acute lung injury by regulating miR-144-3p/AQP1 axis to reduce lung epithelial cell apoptosis. PMID- 29167739 TI - Measuring evolutionary rates of proteins in a structural context. AB - We describe how to measure site-specific rates of evolution in protein-coding genes and how to correlate these rates with structural features of the expressed protein, such as relative solvent accessibility, secondary structure, or weighted contact number. We present two alternative approaches to rate calculations: One based on relative amino-acid rates, and the other based on site-specific codon rates measured as dN/ dS. We additionally provide a code repository containing scripts to facilitate the specific analysis protocols we recommend. PMID- 29492261 TI - Economic evaluations and their use in infection prevention and control: a narrative review. AB - Background: The objective of this review is to provide a comprehensive overview of the different types of economic evaluations that can be utilized by Infection Prevention and Control practitioners with a particular focus on the use of the quality adjusted life year, and its associated challenges. We also highlight existing economic evaluations published within Infection Prevention and Control, research gaps and future directions. Design: Narrative Review. Conclusions: To date the majority of economic evaluations within Infection Prevention and Control are considered partial economic evaluations. Acknowledging the challenges, which include variable utilities within infection prevention and control, a lack of randomized controlled trials, and difficulty in modelling infectious diseases in general, future economic evaluation studies should strive to be consistent with published guidelines for economic evaluations. This includes the use of quality adjusted life years. Further research is required to estimate utility scores of relevance within Infection Prevention and Control. PMID- 29492262 TI - VIM-positive Pseudomonas aeruginosa in a large tertiary care hospital: matched case-control studies and a network analysis. AB - Background: Emergence of multidrug-resistant Pseudomonas aeruginosa is of global concern. We aimed to identify epidemiological relationships, the most common way of transmission, and risk factors for presence of Verona Integron-encoded Metallo beta-lactamase (VIM)-positive P. aeruginosa (VIM-PA). Methods: We conducted a network analysis and matched case-control studies (1:2:2). Controls were hospital based and matched with cases for ward, day of admission (control group 1 and 2) and time between admission and the identification of VIM-PA (control group 1). The network was visualized using Cytoscape, and risk factors were determined using conditional logistic regression. Results: Between August 2003 and April 2015, 144 case patients and 576 control patients were recruited. We identified 307 relationships in 114 out of these 144 patients, with most relationships (84.7%) identified at the same department < 3 months after a previous case patient was discharged. In the multivariable model, having undergone >=1 gastroscopy (odds ratio [OR] = 4.40, 95% confidence interval [CI] = 2.00 to 9.65 and OR = 2.47; 95% CI = 1.12 to 5.49), > 10 day use of selective digestive tract decontamination (SDD) (OR = 2.97; 95% CI = 1.02 to 8.68 and OR = 4.61; 95% CI = 1.22 to 17.37), and use of quinolones (OR = 3.29; 95% CI = 1.34 to 8.10 and OR = 3.95; 95% CI = 1.13 to 13.83 and OR = 4.47; 95% CI = 1.75 to 11.43) were identified as risk factors when using both control groups. Conclusions: The network analysis indicated that the majority of transmissions occurred on the wards, but through unidentified and presumably persistent sources, which are most likely in the innate hospital environment. Previous use of certain antibiotic regimens made patients prone to VIM-PA carriage. Additionally, gastroscopy could be considered as a high-risk procedure in patients with risk factors. Our results add to the growing body of evidence that infection control measures targeting VIM PA should be focused on reducing antibiotics and eliminating sources in the environment. PMID- 29492263 TI - A roadmap for 'core concepts' in evolutionary medicine. PMID- 29492264 TI - The importance of Evolutionary Medicine in developing countries: A case for Pakistan's medical schools. AB - Evolutionary Medicine (EM) is a fundamental science exploring why our bodies are plagued with disease and hindered by limitations. EM views the body as an assortment of benefits, mistakes, and compromises molded over millennia. It highlights the role of evolution in numerous diseases encountered in community and family medicine clinics of developing countries. It enables us to ask informed questions and develop novel responses to global health problems. An understanding of the field is thus crucial for budding doctors, but its study is currently limited to a handful of medical schools in high-income countries. For the developing world, Pakistan's medical schools may be excellent starting posts as the country is beset with communicable and non-communicable diseases that are shaped by evolution. Remarkably, Pakistani medical students are open to studying and incorporating EM into their training. Understanding the principles of EM could empower them to tackle growing health problems in the country. Additionally, some difficulties that western medical schools face in integrating EM into their curriculum may not be a hindrance in Pakistan. We propose solutions for the remaining challenges, including obstinate religious sentiments. Herein, we make the case that incorporating EM is particularly important in developing countries such as Pakistan and that it is achievable in its medical student body. PMID- 29492265 TI - An evolutionary account of vigilance in grief. AB - Grief is characterized by a number of cardinal cognitive symptoms, including preoccupation with thoughts of the deceased and vigilance toward indications that the deceased is in the environment. Compared with emotional symptoms, little attention has been paid to the ultimate function of vigilance in grief. Drawing on signal-detection theory, we propose that the ultimate function of vigilance is to facilitate the reunification (where possible) with a viable relationship partner following separation. Preoccupation with thoughts about the missing person creates the cognitive conditions necessary to maintain a low baseline threshold for the detection of the agent-any information associated with the agent is highly salient, and attention is correspondingly readily deployed toward such cues. These patterns are adaptive in cases of an absent but living partner, but maladaptive in cases of the death of a partner. That they occur in the latter likely reflects the intersection of error-management considerations and the kludge-like configuration of the mind. We discuss results from two previous studies designed to test predictions concerning input conditions and individual differences based on this account, and consider the implications of these findings for mainstream bereavement theories and practices. PMID- 29492267 TI - Malignant pleural mesothelioma presenting with remitting-relapsing pleural effusions: report of two cases. AB - Pleural effusions are common and are associated with malignancy in one sixth of cases. Malignant pleural effusion (MPE) is typically persistent and progressive, prompting further investigations if the initial tests are not diagnostic. A spontaneously remitting effusion is commonly presumed to be benign, and further investigations may not be performed. We present two cases in which the presenting pleural effusion spontaneously resolved but recurred (in one case, multiple times), leading to further investigations that revealed an underlying malignant pleural epithelioid mesothelioma. These cases demonstrate the need for clinicians to be aware that remitting effusions can occur in the context of pleural malignancy and should be kept under observation, with a low threshold for further investigation if relapse occurs. PMID- 29492268 TI - Pericardial effusion as an atypical initial presentation of extra-gonadal nonseminomatous germ cell tumor: a case report and literature review. AB - Extra gonadal germ cell tumors have variable clinical presentations and locations. We report a case of an extra-gonadal germ cell tumor in a 26-year-old male who presented with chest pain. Imaging revealed a large pericardial effusion with underlying mass invading the pericardium. Pericardial effusion is an extremely rare initial site of diagnosis or site of metastasis for malignancy. This case illustrates the importance of a thorough history and physical examination, broad differential diagnosis, and to keep in mind serious complications from rare presentations of disease. PMID- 29492269 TI - Mammalian meat allergy following a tick bite: a case report. AB - The alpha-gal allergy is an emerging IgE-mediated reaction against the galactose alpha-1,3-galactose carbohydrate found in mammalian meats. Patients with this condition will develop anaphylactic symptoms 3-6 h after the ingestion of mammalian meat food products such as beef, pork or lamb. The prevalence of this allergy is drastically increasing and severe reactions including anaphylactic shock have been reported, yet many patients experience symptoms for years before a diagnosis is made. We describe the presentation, diagnosis and management of a patient with the alpha-gal allergy in attempt to improve early recognition and management of patients with this condition. PMID- 29492270 TI - Chronic urticaria and thyroid autoimmunity: a perplexing association. AB - Chronic urticaria has long been thought to be associated with autoimmune conditions, in particular autoimmune thyroid disease (AITD). We detail an unusual case of a 49-year-old patient presenting with urticaria distributed on both shins and hands, with no known associated triggers, and subsequently diagnosed with AITD. The urticaria resolved upon treatment of the AITD. We also summarize the currently postulated pathophysiological links between the two diseases. This case highlights that physicians should have a low threshold for investigating autoimmune conditions in cases of chronic urticaria, with particular attention given to AITD. PMID- 29492271 TI - Ruptured hepatic aneurysm as first presenting symptom of polyarteritis nodosa. AB - Polyarteritis nodosa (PAN) is an inflammatory vasculitis that creates regions of stenosis and aneurysm formation. The authors describe a 66-year-old female with hepatic artery rupture as the first presentation of undiagnosed PAN, presenting with abdominal pain followed by hemorrhagic shock. This aneurysm was suture ligated with a successful outcome. A mesenteric arteriogram demonstrated lesions consistent with PAN including aneurysms of the left gastric branches, right and left hepatic arteries, and beaded appearance of the iliac artery. However, she developed massive pulmonary embolism from which she did not recover after discharge. Postmortem examination confirmed left hepatic artery aneurysm rupture and changes consistent with PAN on gross anatomical examination and histology. This report provides a unique overview of the disease process through imaging, gross anatomic specimen and pathology. Life-threatening hepatic artery aneurysm rupture is an uncommon presentation of PAN which may benefit readers in creating a more robust differential diagnosis. PMID- 29492266 TI - Why monkeys do not get multiple sclerosis (spontaneously): An evolutionary approach. AB - The goal of this review is to apply an evolutionary lens to understanding the origins of multiple sclerosis (MS), integrating three broad observations. First, only humans are known to develop MS spontaneously. Second, humans have evolved large brains, with characteristically large amounts of metabolically costly myelin. This myelin is generated over long periods of neurologic development-and peak MS onset coincides with the end of myelination. Third, over the past century there has been a disproportionate increase in the rate of MS in young women of childbearing age, paralleling increasing westernization and urbanization, indicating sexually specific susceptibility in response to changing exposures. From these three observations about MS, a life history approach leads us to hypothesize that MS arises in humans from disruption of the normal homeostatic mechanisms of myelin production and maintenance, during our uniquely long myelination period. This review will highlight under-explored areas of homeostasis in brain development, that are likely to shed new light on the origins of MS and to raise further questions about the interactions between our ancestral genes and modern environments. PMID- 29492272 TI - Mirror therapy for an adult with central post-stroke pain: a case report. AB - Background: Treatment of central post-stroke pain (CPSP) after a thalamic capsular stroke is generally based on pharmacological approach as it is low responsive to physiotherapy. In this case report, the use of mirror therapy (MT) for the reduction of CPSP in a subject after a stroke involving thalamus is presented. Case presentation: Five years after a right lenticular-capsular thalamic stroke, despite a good recovery of voluntary movement that guaranteed independence in daily life activities, a 50-year-old woman presented with mild weakness and spasticity, an important sensory loss and a burning pain in the left upper limb. MT for reducing arm pain was administered in 45-min sessions, five days a week, for two consecutive weeks. MT consisted in performing symmetrical movements of both forearms and hands while watching the image of the sound limb reflected by a parasagittal mirror superimposed to the affected limb. Pain severity was assessed using visual analogue scale (VAS) before and after the intervention and at one-year follow-up. After the two weeks of MT, the patient demonstrated 4.5 points reduction in VAS pain score of the hand at rest and 3.9 points during a maximal squeeze left hand contraction. At one-year follow-up, pain reduction was maintained and also extended to the shoulder. Conclusion: This case report shows the successful application of a motor training with a sensory confounding condition (MT) in reducing CPSP in a patient with a chronic thalamic stroke. PMID- 29492274 TI - Successive occurrence of recombinant infectious bronchitis virus strains in restricted area of Middle East. AB - Routine molecular diagnostic testing by our laboratory, based on using a primer pair with conservative binding sites on the spike glycoprotein coding sequence, has indicated the recurring of a unique phylogenetic cluster of chicken infectious bronchitis viruses (IBV) in the Middle East since 2010. The nearly full-length S1 subunit of the spike gene phylogeny of selected strains, however, split up this grouping, suggesting potential recombination in the S1 gene. In order to clarify this, various bioinformatic analyses of the strains were carried out, which confirmed this supposition. Two patterns of recombination were found among the strains, one of which could also be identified in GenBank-deposited IBV sequences from the region. These findings demonstrate that IBV strains of different recombinant patterns occur simultaneously in the same geographic region and could circulate for an extended period of time, thus contributing to the knowledge on IBV evolution. PMID- 29492273 TI - Rapid Sequencing of Complete env Genes from Primary HIV-1 Samples. AB - The ability to study rapidly evolving viral populations has been constrained by the read length of next-generation sequencing approaches and the sampling depth of single-genome amplification methods. Here, we develop and characterize a method using Pacific Biosciences' Single Molecule, Real-Time (SMRT(r)) sequencing technology to sequence multiple, intact full-length human immunodeficiency virus 1 env genes amplified from viral RNA populations circulating in blood, and provide computational tools for analyzing and visualizing these data. PMID- 29492276 TI - Diversity and comparative genomics of chimeric viruses in Sphagnum-dominated peatlands. AB - A new group of viruses carrying naturally chimeric single-stranded (ss) DNA genomes that encompass genes derived from eukaryotic ssRNA and ssDNA viruses has been recently identified by metagenomic studies. The host range, genomic diversity, and abundance of these chimeric viruses, referred to as cruciviruses, remain largely unknown. In this article, we assembled and analyzed thirty-seven new crucivirus genomes from twelve peat viromes, representing twenty-four distinct genome organizations, and nearly tripling the number of available genomes for this group. All genomes possess the two characteristic genes encoding for the conserved capsid protein (CP) and a replication protein. Additional ORFs were conserved only in nearly identical genomes with no detectable similarity to known genes. Two cruciviruses possess putative introns in their replication associated genes. Sequence and phylogenetic analyses of the replication proteins revealed intra-gene chimerism in at least eight chimeric genomes. This highlights the large extent of horizontal gene transfer and recombination events in the evolution of ssDNA viruses, as previously suggested. Read mapping analysis revealed that members of the 'Cruciviridae' group are particularly prevalent in peat viromes. Sequences matching the CP ranged from 0.6 up to 10.9 percent in the twelve peat viromes. In contrast, from sixty-nine available viromes derived from other environments, only twenty-four contained cruciviruses, which on average accounted for merely 0.2 percent of sequences. Overall, this study provides new genome information and insights into the diversity of chimeric viruses, a necessary first step in progressing toward an accurate quantification and host range identification of these new viruses. PMID- 29492275 TI - Challenges in the analysis of viral metagenomes. AB - Genome sequencing technologies continue to develop with remarkable pace, yet analytical approaches for reconstructing and classifying viral genomes from mixed samples remain limited in their performance and usability. Existing solutions generally target expert users and often have unclear scope, making it challenging to critically evaluate their performance. There is a growing need for intuitive analytical tooling for researchers lacking specialist computing expertise and that is applicable in diverse experimental circumstances. Notable technical challenges have impeded progress; for example, fragments of viral genomes are typically orders of magnitude less abundant than those of host, bacteria, and/or other organisms in clinical and environmental metagenomes; observed viral genomes often deviate considerably from reference genomes demanding use of exhaustive alignment approaches; high intrapopulation viral diversity can lead to ambiguous sequence reconstruction; and finally, the relatively few documented viral reference genomes compared to the estimated number of distinct viral taxa renders classification problematic. Various software tools have been developed to accommodate the unique challenges and use cases associated with characterizing viral sequences; however, the quality of these tools varies, and their use often necessitates computing expertise or access to powerful computers, thus limiting their usefulness to many researchers. In this review, we consider the general and application-specific challenges posed by viral sequencing and analysis, outline the landscape of available tools and methodologies, and propose ways of overcoming the current barriers to effective analysis. PMID- 29492278 TI - Geography and host species shape the evolutionary dynamics of U genogroup infectious hematopoietic necrosis virus. AB - Infectious hematopoietic necrosis virus (IHNV) is a negative-sense RNA virus that infects wild and cultured salmonids throughout the Pacific Coastal United States and Canada, from California to Alaska. Although infection of adult fish is usually asymptomatic, juvenile infections can result in high mortality events that impact salmon hatchery programs and commercial aquaculture. We used epidemiological case data and genetic sequence data from a 303 nt portion of the viral glycoprotein gene to study the evolutionary dynamics of U genogroup IHNV in the Pacific Northwestern United States from 1971 to 2013. We identified 114 unique genotypes among 1,219 U genogroup IHNV isolates representing 619 virus detection events. We found evidence for two previously unidentified, broad subgroups within the U genogroup, which we designated 'UC' and 'UP'. Epidemiologic records indicated that UP viruses were detected more frequently in sockeye salmon (Oncorhynchus nerka) and in coastal waters of Washington and Oregon, whereas UC viruses were detected primarily in Chinook salmon (Oncorhynchus tshawytscha) and steelhead trout (Oncorhynchus mykiss) in the Columbia River Basin, which is a large, complex watershed extending throughout much of interior Washington, Oregon, and Idaho. These findings were supported by phylogenetic analysis and by FST. Ancestral state reconstruction indicated that early UC viruses in the Columbia River Basin initially infected sockeye salmon but then emerged via host shifts into Chinook salmon and steelhead trout sometime during the 1980s. We postulate that the development of these subgroups within U genogroup was driven by selection pressure for viral adaptation to Chinook salmon and steelhead trout within the Columbia River Basin. PMID- 29492279 TI - Environmental Epigenetics. PMID- 29492277 TI - Evolution of HIV virulence in response to widespread scale up of antiretroviral therapy: a modeling study. AB - There are global increases in the use of HIV antiretroviral therapy (ART), guided by clinical benefits of early ART initiation and the efficacy of treatment as prevention of transmission. Separately, it has been shown theoretically and empirically that HIV virulence can evolve over time; observed virulence levels may reflect an adaptive balance between infected lifespan and per-contact transmission rate. However, the potential effects of widespread ART usage on HIV virulence are unknown. To predict these effects, we used an agent-based stochastic model to simulate evolutionary trends in HIV virulence, using set point viral load as a proxy for virulence. We calibrated our model to prevalence and incidence trends of South Africa. We explored two distinct ART scenarios: (1) ART initiation based on HIV-infected individuals reaching a CD4 count threshold; and (2) ART initiation based on individual time elapsed since HIV infection (a scenario that mimics "universal testing and treatment" (UTT) aspirations). In each case, we considered a range in population uptake of ART. We found that HIV virulence is generally unchanged in scenarios of CD4-based initiation. However, with ART initiation based on time since infection, virulence can increase moderately within several years of ART rollout, under high coverage levels and early treatment initiation (albeit within the context of epidemics that are rapidly decreasing in size). Sensitivity analyses suggested the impact of ART on virulence is relatively insensitive to model calibration. Our modeling study suggests that increasing HIV virulence driven by UTT is likely not a major public health concern, but should be monitored in sentinel surveillance, in a manner similar to transmitted resistance to antiretroviral drugs. PMID- 29492280 TI - Variable directionality of gene expression changes across generations does not constitute negative evidence of epigenetic inheritance. AB - Transgenerational epigenetic inheritance in mammals has been controversial due to inherent difficulties in its experimental demonstration. A recent report has, however, opened a new front in the ongoing debate by claiming that endocrine disrupting chemicals, contrary to previous findings, do not cause effects across generations. This claim is based on the observation that gene expression changes induced by these chemicals in the exposed and unexposed generations are mainly in the opposite direction. This analysis shows that the pattern of gene expression reported in the two generations is not expected by chance and is suggestive of transmission across generations. A meta-analysis of diverse data sets related to endocrine disruptor-induced transgenerational gene expression alterations, including the data provided in the said report, further suggests that effects of endocrine disrupting chemicals persist in unexposed generations. Based on the prior evidence of phenotypic variability and gene expression alterations in opposite direction between generations, it is argued here that calling evidence of mismatched directionality in gene expression in experiments testing potential of environmental agents in inducing epigenetic inheritance of phenotypic traits as negative is untenable. This is expected to settle the newly raised doubts over epigenetic inheritance in mammals. PMID- 29492281 TI - Prenatal lead exposure is associated with decreased cord blood DNA methylation of the glycoprotein VI gene involved in platelet activation and thrombus formation. AB - Early-life lead exposure impairs neurodevelopment and later exposure affects the cardiovascular system. Lead has been associated with reduced global 5 methylcytosine DNA methylation, suggesting that lead toxicity acts through epigenetic mechanisms. The objective of this study is to clarify how early-life lead exposure alters DNA methylation of specific genes, using an epigenomic approach. We measured lead concentrations in urine [gestational week (GW), 8] and erythrocytes (GW 14), using inductively coupled plasma mass spectrometry, for 127 pregnant mothers recruited in the MINIMat food and supplementation cohort in rural Bangladesh. Cord blood DNA methylation was analyzed with the Infinium HumanMethylation450K BeadChip, and top sites were validated by methylation sensitive high-resolution melt curve analysis. Maternal urinary lead concentrations (divided into quartiles) showed significant (after adjustment for false discovery rate) inverse associations with methylation at nine CpGs. Three of these sites were in the 5'-end, including the promoter, of glycoprotein IV (GP6); cg18355337 (q = 0.029, beta = -0.30), cg25818583 (q = 0.041, beta = 0.18), and cg23796967 (q = 0.047, beta = -0.17). The methylation in another CpG site in GP6 was close to significant (cg05374025, q = 0.057, beta = - 0.23). The erythrocyte lead concentrations (divided into quartiles) were also inversely associated with CpG methylation in GP6, although this was not statistically significant after false discovery rate adjustments. Eight CpG sites in GP6 constituted a differentially methylated region in relation to urinary lead (P = 0.005, q = 0.48) and erythrocyte lead (P = 0.007, q = 0.46). In conclusion, we found that moderate prenatal lead exposure appears to epigenetically affect GP6, a key component of platelet aggregation and thrombus formation, suggesting a novel link between early lead exposure and cardiovascular disease later in life. PMID- 29492282 TI - Medaka as a model for studying environmentally induced epigenetic transgenerational inheritance of phenotypes. AB - Ability of environmental stressors to induce transgenerational diseases has been experimentally demonstrated in plants, worms, fish, and mammals, indicating that exposures affect not only human health but also fish and ecosystem health. Small aquarium fish have been reliable model to study genetic and epigenetic basis of development and disease. Additionally, fish can also provide better, economic opportunity to study transgenerational inheritance of adverse health and epigenetic mechanisms. Molecular mechanisms underlying germ cell development in fish are comparable to those in mammals and humans. This review will provide a short overview of long-term effects of environmental chemical contaminant exposure in various models, associated epigenetic mechanisms, and a perspective on fish as model to study environmentally induced transgenerational inheritance of altered phenotypes. PMID- 29492283 TI - The role of non-genetic inheritance in evolutionary rescue: epigenetic buffering, heritable bet hedging and epigenetic traps. AB - Rapid environmental change is predicted to compromise population survival, and the resulting strong selective pressure can erode genetic variation, making evolutionary rescue unlikely. Non-genetic inheritance may provide a solution to this problem and help explain the current lack of fit between purely genetic evolutionary models and empirical data. We hypothesize that epigenetic modifications can facilitate evolutionary rescue through 'epigenetic buffering'. By facilitating the inheritance of novel phenotypic variants that are generated by environmental change-a strategy we call 'heritable bet hedging'-epigenetic modifications could maintain and increase the evolutionary potential of a population. This process may facilitate genetic adaptation by preserving existing genetic variation, releasing cryptic genetic variation and/or facilitating mutations in functional loci. Although we show that examples of non-genetic inheritance are often maladaptive in the short term, accounting for phenotypic variance and non-adaptive plasticity may reveal important evolutionary implications over longer time scales. We also discuss the possibility that maladaptive epigenetic responses may be due to 'epigenetic traps', whereby evolutionarily novel factors (e.g. endocrine disruptors) hack into the existing epigenetic machinery. We stress that more ecologically relevant work on transgenerational epigenetic inheritance is required. Researchers conducting studies on transgenerational environmental effects should report measures of phenotypic variance, so that the possibility of both bet hedging and heritable bet hedging can be assessed. Future empirical and theoretical work is required to assess the relative importance of genetic and epigenetic variation, and their interaction, for evolutionary rescue. PMID- 29492284 TI - Probing the germline-dependence of epigenetic inheritance using artificial insemination in mice. AB - We developed a simple, noninvasive artificial insemination technique to study epigenetic germline inheritance in mice. This technique avoids interfering factors introduced by superovulation, surgery, in vitro culture or mating that can confound the transmission of acquired epigenetic information through the germline. Using a stress model, we demonstrate that our method is suited to test the causal involvement of the male germline in transmitting acquired information from father to offspring. PMID- 29492286 TI - Erratum: Ancestral vinclozolin exposure alters the epigenetic transgenerational inheritance of sperm small noncoding RNAs. AB - [This corrects the article DOI: 10.1093/eep/dvw001.]. PMID- 29492285 TI - Transgenerational plasticity is sex-dependent and persistent in yellow monkeyflower (Mimulus guttatus). AB - Transgenerational phenotypic plasticity, whereby environmental cues experienced by parents alter the phenotype of their progeny, has now been documented in diverse organisms. Transmission of environmentally determined responses is known to occur through both maternal and paternal gametes, but the underlying mechanisms have rarely been compared. In addition, the persistence of induction over multiple generations appears to vary widely, but has been characterized for relatively few systems. Yellow monkeyflower (Mimulus guttatus) is known to exhibit transgenerational induction of increased glandular trichome production in response to simulated insect damage. Here, we test for differences between maternal and paternal transmission of this response and examine its persistence over five generations following damage. Maternal and paternal damage resulted in similar and apparently additive increases in progeny trichome production. Treatment of germinating seeds with the genome-wide demethylating agent 5 azacytidine erased the effect of maternal but not paternal damage. The number of glandular trichomes remained elevated for three generations following damage. These results indicate that transgenerational transmission occurs through both maternal and paternal germ lines, but that they differ in the proximate mechanism of epigenetic inheritance. Our results also indicate that a wounding response can persist for multiple generations in the absence of subsequent damage. PMID- 29492287 TI - Particulate matter, the newborn methylome, and cardio-respiratory health outcomes in childhood. AB - Ambient air pollution is associated with adverse health outcomes including cardio respiratory diseases. Epigenetic mechanisms such as DNA methylation may play a role in driving such associations. We investigated the effects of prenatal particulate matter (PM) exposure on DNA methylation of 178,309 promoter regions in 240 newborns using the Infinium HumanMethylation450 BeadChip, using a generalized linear regression model with a quasi-binomial link family, adjusted for gender, plate, and cell types. PM-associated CpG loci were then investigated for their associations with childhood asthma, carotid intima-media thickness (CIMT), and blood pressure (BP) using logistic or linear regression. Thirty-one loci were associated with either PM10 or PM2.5 using FDR-corrected p-values of less than 0.15. Two loci were evaluated for replication in a separate population of 280 Children's Health Study (CHS) subjects using Pyrosequencing, of which one successfully replicated (COLEC11 cg03579365). Three of the 31 loci were also associated with physician-diagnosed asthma at 6 years old, two were associated with CIMT and one with systolic BP at 10 years old. A higher methylation level in TM9SF2 (cg02015529) and UBE2S (cg00035623), respectively, was associated with a 2SD increase in prenatal PM and was also associated with 36% and 98% increased odds of asthma; whereas methylation of TDRD6 (cg22329831) was negatively associated with PM and a 24% decreased odds of asthma. Prenatal PM exposure was associated with altered DNA methylation in newborn blood in a small number of gene promoters, some of which were also associated with cardio-respiratory health outcomes later in childhood. Keywords: methylation, particulate matter, air pollution, asthma, cardiovascular. PMID- 29492288 TI - Epigenetic response to environmental change: DNA methylation varies with invasion status. AB - Epigenetic mechanisms may be important for a native species' response to rapid environmental change. Red Imported Fire Ants (Solenopsis invicta Santschi, 1916) were recently introduced to areas occupied by the Eastern Fence Lizard (Sceloporus undulatus Bosc & Daudin, 1801). Behavioral, morphological and physiological phenotypes of the Eastern Fence Lizard have changed following invasion, creating a natural biological system to investigate environmentally induced epigenetic changes. We tested for variation in DNA methylation patterns in Eastern Fence Lizard populations associated with different histories of invasion by Red Imported Fire Ants. At methylation sensitive amplified fragment length polymorphism loci, we detected a higher diversity of methylation in Eastern Fence Lizard populations from Fire Ant uninvaded versus invaded sites, and uninvaded sites had higher methylation. Our results suggest that invasive species may alter methylation frequencies and the pattern of methylation among native individuals. While our data indicate a high level of intrinsic variability in DNA methylation, DNA methylation at some genomic loci may underlie observed phenotypic changes in Eastern Fence Lizard populations in response to invasion of Red Imported Fire Ants. This process may be important in facilitating adaptation of native species to novel pressures imposed by a rapidly changing environment. PMID- 29492289 TI - Transcriptomic data reanalysis allows for a contribution of embryonic transcriptional change-induced gene expression reprogramming in transgenerational epigenetic inheritance. AB - A recent study investigated sperm-mediated inheritance of diet induced metabolic phenotypes, reported underlying regulation of the target genes of the endogenous retroelement MERVL and the ribosomal protein genes in embryos, and suggested that the altered regulation observed may cause placentation defects which can secondarily result in abnormal metabolism. A reanalysis of available transcriptomic data however shows that MERVL targets and the developmentally altered genes are themselves enriched for metabolic pathways, thus connecting embryonic gene expression with offspring phenotypes, and providing an alternative interpretation of the reported findings. This is consistent with a similar study suggesting a contribution of embryonic transcriptional change-induced gene expression reprogramming in altered offspring metabolism. PMID- 29492290 TI - Can imprinting play a role in the response of Tetrahymena pyriformis to toxic substance exposure? AB - Among protozoa, Tetrahymena pyriformis is the most commonly ciliated model used for laboratory research. All living organisms need to adapt to ever changing adverse conditions in order to survive. This article focuses on the phenomenon that exposure to toxic doses of the toxicants protects against a normally harmful dose of the same stressor. This first encounter by toxicant provokes the phenomenon of epigenetical imprinting, by which the reaction of the cell is quantitatively modified. This modification is transmitted to the progeny generations. The experiments demonstrate the possibility of epigenetic effects at a unicellular level and call attention to the possibility that the character of unicellular organisms has changed through to the present day due to an enormous amount of non-physiological imprinter substances in their environment. The results point to the validity of epigenetic imprinting effects throughout the animal world. Imprinting in Tetrahymena was likely the first epigenetic phenomenon which was justified at cellular level. It is very useful for the unicellular organisms, as it helps to avoid dangerous molecules more easily or to find useful ones and by this contributes to the permanence of the population's life. PMID- 29492291 TI - Epigenetics in disease and well-being. AB - The research education seminar 'Epigenetics in disease and well-being' organized by and held at Linkoping University, Linkoping, Sweden earlier this year, aimed to discuss the interaction between environmental factors and epigenetic modifications and its consequences for human and animal health. A selection of presented papers is hereby presented which highlighted the mechanisms by which environmental stressors challenge homeostasis to such an extent that the effects can become transgenerational but also proposed the development of epigenomic based pre-emptive medicine. PMID- 29492292 TI - Molecular carriers of acquired inheritance: absence of evidence is not evidence of absence. AB - In utero exposure to environmental endocrine disruptors can cause transgenerational effects in the males of subsequent generations. DNA methylation (5 mC) was suggested, but being challenged as the molecular carrier of such epigenetic information. In a recent study, Schuster et al. show a changed small RNA profile changed in the sperm of F3 generation after F0 in utero vinclozolin exposure, suggesting additional transgenerational epigenetic carriers for endocrine disruptor effects, other than DNA methylation. PMID- 29492294 TI - Environmental enrichment as an intervention for adverse health outcomes of prenatal stress. AB - Prenatal stress (PS) has complex neurological, behavioural and physiological consequences for the developing offspring. The phenotype linked to PS usually lasts into adulthood and may even propagate to subsequent generations. The often uncontrollable exposure to maternal stress and the lasting consequences emphasize the urgent need for treatment strategies that effectively reverse stress programming. Exposure to complex beneficial experiences, such as environmental enrichment (EE), is one of the most powerful therapies to promote neuroplasticity and behavioural performance at any time in life. A small number of studies have previously used EE to postnatally treat consequences of PS in the attempt to reverse deficits that were primarily induced in utero . This review discusses the available data on postnatal EE exposure in prenatally stressed individuals. The goal is to determine if EE is a suitable treatment option that reverses adverse consequences of stress programming and enhances stress resiliency. Moreover, this review discusses data with respect to relevant hypotheses including the cumulative stress and the mismatch hypotheses. The articles included in this review emphasize that EE reverses most behavioural, physiological and neural deficits associated with PS. Differing responses may be dependent on the timing and variability of stress and EE, exercise, and potentially vulnerable and resilient phenotypes of PS. Results from this study suggest that enrichment may provide an effective therapy for clinical populations suffering from the effects of PS or early life trauma. PMID- 29492293 TI - Maternal stress and diet may influence affective behavior and stress-response in offspring via epigenetic regulation of central peptidergic function. AB - It has been shown that maternal stress and malnutrition, or experience of other adverse events, during the perinatal period may alter susceptibility in the adult offspring in a time-of-exposure dependent manner. The mechanism underlying this may be epigenetic in nature. Here, we summarize some recent findings on the effects on gene-regulation following maternal malnutrition, focusing on epigenetic regulation of peptidergic activity. Numerous neuropeptides within the central nervous system are crucial components in regulation of homeostatic energy balance, as well as affective health (i.e. health events related to affective disorders, psychiatric disorders also referred to as mood disorders). It is becoming evident that expression, and function, of these neuropeptides can be regulated via epigenetic mechanisms during fetal development, thereby contributing to the development of the adult phenotype and, possibly, modulating disease susceptibility. Here, we focus on two such neuropeptides, neuropeptide Y (NPY) and corticotropin-releasing hormone (CRH), both involved in regulation of endocrine function, energy homeostasis, as well as affective health. While a number of published studies indicate the involvement of epigenetic mechanisms in CRH-dependent regulation of the offspring adult phenotype, NPY has been much less studied in this context and needs further work. PMID- 29492295 TI - Stress-induced transposon reactivation: a mediator or an estimator of allostatic load? AB - Transposons are playing an important role in the evolution of eukaryotic genomes. These endogenous virus-like elements often amplify within their host genomes in a species specific manner. Today we have limited understanding when and how these amplification events happens. What we do know is that cells have evolved multiple line of defenses to keep these potentially invasive elements under control, often involving epigenetic mechanisms such as DNA-methylation and histone modifications. Emerging evidence shows a strong link between transposon activity and human aging and diseases, as well as a role for transposons in normal brain development. Controlling transposon activity may therefore uphold the fine balance between health and disease. In this article we investigate this balance, and sets it in relation to allostatic load, which conceptualize the link between stress and the "wear and tear" of the organism that leads to aging and disease. We hypothesize that stress-induced retrotransposon reactivation in humans may be used to estimate allostatic load, and may be a possible mechanism in which transposons amplify within species genomes. PMID- 29492296 TI - Epigenetic mechanisms involved in the effects of stress exposure: focus on 5 hydroxymethylcytosine. AB - 5-hydroxymethylcytosine (5hmC) is a recently re-discovered transient intermediate in the active demethylation pathway that also appears to play an independent role in modulating gene function. Epigenetic marks, particularly 5-methylcytosine, have been widely studied in relation to stress-related disorders given the long lasting effect that stress has on these marks. 5hmC is a good candidate for involvement in the etiology of these disorders given its elevated concentration in mammalian neurons, its dynamic regulation during development of the central nervous system, and its high variability among individuals. Although we are unaware of any studies published to date examining 5 hmC profiles in human subjects who have developed a psychiatric disorder after a life stressor, there is emerging evidence from the animal literature that 5hmC profiles are altered in the context of fear-conditioning paradigms and stress exposure, suggesting a possible role for 5hmC in the biological underpinnings of stress-related disorders. In this review, the authors examine the available approaches for profiling 5hmC and describe their advantages and disadvantages as well as discuss the studies published thus far investigating 5hmC in the context of fear-related learning and stress exposure in animals. The authors also highlight the global versus locus-specific regulation of 5hmC in these studies. Finally, the limitations of the current studies and their implications are discussed. PMID- 29492297 TI - Epigenetic alterations induced by environmental stress associated with metabolic and neurodevelopmental disorders. AB - Epigenetics is a gene regulation mechanism that does not depend on genomic DNA sequences but depends on chemical modification of genomic DNA and histone proteins around which DNA is wrapped. The failure of epigenetic mechanisms is known to cause various congenital disorders. It is also known that the failures of epigenetic mechanisms causes various acquired disorders since epigenetic modifications of the genome (i.e., "epigenome") are more vulnerable to environmental stress, such as malnutrition, environmental chemicals, and mental stress, than the "genome," especially during the early period of life. However, the epigenome has a reversible property since it is based on removable residues on genomic DNA. Thus, environmentally induced epigenomic alterations can be potentially restored. In fact, some medicines, especially for psychiatric diseases, are known to restore an altered epigenome, resulting in the correction of gene expression. Several lines of evidence suggest that environmentally induced epigenomic alterations are not erased completely during gametogenesis, but are transmitted to subsequent generations with disease phenotypes. In accordance with these understandings, I would like to propose the development of epigenomic-based preemptive medicine that consists of the early detection of the developmental origins of diseases using epigenomic signatures and the early intervention that take advantages of the use of epigenomic reversibility. PMID- 29492298 TI - Adolescent epigenetic profiles and environmental exposures from early life through peri-adolescence. AB - Epigenetic perturbations induced by environmental exposures at susceptible lifestages contribute to disease development. Even so, the influence of early life and ongoing exposures on the adolescent epigenome is rarely examined. We examined the association of exposure biomarkers for lead (Pb), bisphenol A (BPA), and nine phthalates metabolites with blood leukocyte DNA methylation at LINE-1 repetitive elements and environmentally responsive genes ( IGF2 , H19 , and HSD11B2 ) in peri-adolescents. Participants ( n = 247) from the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) birth cohorts were followed-up once between the ages of 8 and 14 years, and concurrent exposures were measured in biospecimen collected at that time (blood Pb, urinary BPA, and phthalate metabolites). Prenatal and childhood exposures to Pb were previously approximated using maternal and child samples. BPA and phthalate metabolites were measured in third trimester maternal urine samples. Significant associations ( P < 0.05) were observed between DNA methylation and exposure biomarkers that were gene and biomarker specific. For example, Pb was only associated with LINE-1 hypomethylation during pregnancy ( P = 0.04), while early childhood Pb was instead associated with H19 hypermethylation ( P = 0.04). Concurrent urinary mono (2-ethylhexyl) phthalate (MEHP) was associated with HSD11B2 hypermethylation ( P = 0.005). Sex-specific associations, particularly among males, were also observed. In addition to single exposure models, principal component analysis was employed to examine exposure mixtures. This method largely corroborated the findings of the single exposure models. This study along with others in the field suggests that environment-epigenetic relationships vary by chemical, exposure timing, and sex. PMID- 29492299 TI - Bisphenol-A and metabolic diseases: epigenetic, developmental and transgenerational basis. AB - Exposure to environmental toxicants is now accepted as a factor contributing to the increasing incidence of obesity and metabolic diseases around the world. Such environmental compounds are known as 'obesogens'. Among them, bisphenol-A (BPA) is the most widespread and ubiquitous compound affecting humans and animals. Laboratory animal work has provided conclusive evidence that early-life exposure to BPA is particularly effective in predisposing individuals to weight gain. Embryonic exposure to BPA is reported to generate metabolic disturbances later in life, such as obesity and diabetes. When BPA administration is combined with a high-fat diet, there is an exacerbation in the development of metabolic disorders. Remarkably, upon BPA exposure of gestating females, metabolic disturbances have been found both in the offspring and later in life in the mothers themselves. When considering the metabolic effects generated by an early developmental exposure to BPA, one of the questions that arises is the role of precursor cells in the etiology of metabolic disorders. Current evidence shows that BPA and other endocrine disruptors have the ability to alter fat tissue development and growth by affecting the capacity to generate functional adipocytes, as well as their rate of differentiation to specific cell types. Epigenetic mechanisms seem to be involved in the BPA-induced effects related to obesity, as they have been described in both in vitro and in vivo models. Moreover, recent reports also show that developmental exposure to BPA generates abnormalities that can be transmitted to future generations, in a process called as transgenerational epigenetic inheritance. PMID- 29492300 TI - Perinatal maternal alcohol consumption and methylation of the dopamine receptor DRD4 in the offspring: the Triple B study. AB - Maternal alcohol use during the perinatal period is a major public health issue, the higher ends of which are associated with foetal alcohol spectrum disorder and a range of adverse health outcomes in the progeny. The underlying molecular mechanisms remain largely unknown but may include the epigenetic disruption of gene activity during development. Alcohol directly activates the neurotransmitter dopamine, which plays an essential role in neurodevelopment. To investigate whether antenatal and early postnatal alcohol consumption were associated with differential dopamine receptor DRD4 promoter methylation in infants (n = 844). Data were drawn from the large population based Triple B pregnancy cohort study, with detailed information on maternal alcohol consumption in each trimester of pregnancy and early postpartum. DNA was extracted from infant buccal swabs collected at 8-weeks. DRD4 promoter DNA methylation was analysed by Sequenom MassARRAY. No strong evidence was found for an association between alcohol consumption during pregnancy and infant DRD4 methylation at 8-weeks postpartum. However, maternal alcohol consumption assessed contemporaneously at 8-weeks postpartum was associated with increased methylation at 13 of 19 CpG units examined (largest Delta + 3.20%, 95%Confidence Interval:1.66,4.75%, P = 0.0001 at CpG.6). This association was strongest in women who breastfeed, suggesting the possibility of a direct effect of alcohol exposure via breast milk. The findings of this study could influence public health guidelines around alcohol consumption for breastfeeding mothers; however, further research is required to confirm these novel findings. PMID- 29492302 TI - Meeting summary: the inaugural meeting of the US DOHaD society. AB - The US chapter of the International Developmental Origins of Health and Disease (DOHaD) Society recently held its inaugural meeting in Detroit, MI. US-based DOHaD researchers gathered both to create this new society chapter and share their latest research. The US DOHaD Society will provide a much-needed domestic forum for a broad range of DOHaD topics including nutrition, toxicology, stress, epidemiology, epigenetics, and more. PMID- 29492301 TI - Fractionated low-dose exposure to ionizing radiation leads to DNA damage, epigenetic dysregulation, and behavioral impairment. AB - Studies of Fractionated Exposure to Low Doses of Ionizing Radiation (FELDIR) has become of increasing importance to clinical interventions. Its consequences on DNA damage, physical, and mental health have been insufficiently investigated, however. The goal of this study was to determine the effects of FELDIR on the brain using a mouse model. We addressed the levels of DNA damage, global genomic methylation, and DNA methylation machinery in cerebellum, frontal lobe, olfactory bulb and hippocampal tissues, as well as behavioral changes linked to FELDIR exposure. The results reveal increased levels of DNA damage, as reflected by increased occurrence of DNA Strand Breaks (SBs) and dysregulation of stress response kinase p38. FELDIR also resulted in initial loss of global genomic methylation and altered expression of methyltransferases DNMT1 (down-regulation) and DNMT3a (up-regulation), as well as methyl-binding protein MeCP2 (up regulation). FELDIR-associated behavioral changes included impaired skilled limb placement on a ladder rung task, increased rearing activity in an open field, and elevated anxiety-like behaviors. The said alterations showed significant dose and tissue specificity. Thus, FELDIR represents a critical impact on DNA integrity and behavioral outcomes that need to be considered in the design of clinical intervention studies. PMID- 29492303 TI - Association between DNA methylation profiles in leukocytes and serum levels of persistent organic pollutants in Dutch men. AB - Consumption of polluted fish may lead to high levels of persistent organic pollutants (POPs) in humans, potentially causing adverse health effects. Altered DNA methylation has been suggested as a possible contributor to a variety of adverse health effects. The aim of this study was to evaluate the relationship between serum POP levels (dioxins, polychlorobiphenyls, and perfluoroctane sulphonate) and DNA methylation. We recruited a total of 80 Dutch men who regularly consumed eel from either low- or high-polluted areas, and subsequently had normal or elevated POP levels. Clinical parameters related to e.g. hormone levels and liver enzymes were measured as biomarkers for adverse health effects. The Infinium 450K BeadChip was used to assess DNA methylation in a representative subset of 34 men. We identified multiple genes with differentially methylated regions (DMRs; false discovery rate <0.05) related to POP levels. Several of these genes are involved in carcinogenesis (e.g. BRCA1, MAGEE2, HOXA5), the immune system (e.g. RNF39, HLA-DQB1), retinol homeostasis (DHRS4L2), or in metabolism (CYP1A1). The DMRs in these genes show mean methylation differences up to 7.4% when comparing low- and high-exposed men, with a mean difference up to 14.4% for single positions within a DMR. Clinical parameters were not significantly associated with serum POP levels. This is the first explorative study investigating extensive DNA methylation in relation to serum POP levels among men. We observed that elevated POP levels are associated with aberrant DNA methylation profiles in adult men who consumed high-polluted eel. These preliminary findings warrant further confirmation in other populations. PMID- 29492304 TI - Facilitation of environmental adaptation and evolution by epigenetic phenotype variation: insights from clonal, invasive, polyploid, and domesticated animals. AB - There is increasing evidence, particularly from plants, that epigenetic mechanisms can contribute to environmental adaptation and evolution. The present article provides an overview on this topic for animals and highlights the special suitability of clonal, invasive, hybrid, polyploid, and domesticated species for environmental and evolutionary epigenetics. Laboratory and field studies with asexually reproducing animals have shown that epigenetically diverse phenotypes can be produced from the same genome either by developmental stochasticity or environmental induction. The analysis of invasions revealed that epigenetic phenotype variation may help to overcome genetic barriers typically associated with invasions such as bottlenecks and inbreeding. Research with hybrids and polyploids established that epigenetic mechanisms are involved in consolidation of speciation by contributing to reproductive isolation and restructuring of the genome in the neo-species. Epigenetic mechanisms may even have the potential to trigger speciation but evidence is still meager. The comparison of domesticated animals and their wild ancestors demonstrated heritability and selectability of phenotype modulating DNA methylation patterns. Hypotheses, model predictions, and empirical results are presented to explain how epigenetic phenotype variation could facilitate adaptation and speciation. Clonal laboratory lineages, monoclonal invaders, and adaptive radiations of different evolutionary age seem particularly suitable to empirically test the proposed ideas. A respective research agenda is presented. PMID- 29492305 TI - Human exposure to flame-retardants is associated with aberrant DNA methylation at imprinted genes in sperm. AB - Emerging evidence suggests that early exposure to endocrine disrupting chemicals has long-term consequences that can influence disease risk in offspring. During gametogenesis, imprinted genes are reasonable epigenetic targets with the ability to retain and transfer environmental messages. We hypothesized that exposures to organophosphate (OP) flame-retardants can alter DNA methylation in human sperm cells affecting offspring's health. Sperm and urine samples were collected from 67 men in North Carolina, USA. Urinary metabolites of a chlorinated OP, tris(1,3 dichloro-2-propyl) phosphate, and two non-chlorinated OPs, triphenyl phosphate and mono-isopropylphenyl diphenyl phosphate, were measured using liquid chromatography tandem mass-spectrometry. Sperm DNA methylation at multiple CpG sites of the regulatory differentially methylated regions (DMRs) of imprinted genes GRB10, H19, IGF2, MEG3, NDN, NNAT, PEG1/MEST, PEG3, PLAGL1, SNRPN, and SGCE/PEG10 was quantified using bisulfite pyrosequencing. Regression models were used to determine potential associations between OP concentrations and DNA methylation. We found that men with higher concentrations of urinary OP metabolites, known to originate from flame-retardants, have a slightly higher fraction of sperm cells that are aberrantly methylated. After adjusting for age, obesity-status and multiple testing, exposure to mono-isopropylphenyl diphenyl phosphate was significantly related to hypermethylation at the MEG3, NDN, SNRPN DMRs. Exposure to triphenyl phosphate was associated with hypermethylation at the GRB10 DMR; and tris(1,3-dichloro-2-propyl) phosphate exposure was associated with altered methylation at the MEG3 and H19 DMRs. Although measured methylation differences were small, implications for public health can be substantial. Interestingly, our data indicated that a multiplicity of OPs in the human body is associated with increased DNA methylation aberrancies in sperm, compared to exposure to few OPs. Further research is required in larger study populations to determine if our findings can be generalized. PMID- 29492306 TI - Effects of a parental exposure to diuron on Pacific oyster spat methylome. AB - Environmental epigenetic is an emerging field that studies the cause-effect relationship between environmental factors and heritable trait via an alteration in epigenetic marks. This field has received much attentions since the impact of environmental factors on different epigenetic marks have been shown to be associated with a broad range of phenotypic disorders in natural ecosystems. Chemical pollutants have been shown to affect immediate epigenetic information carriers of several aquatic species but the heritability of the chromatin marks and the consequences for long term adaptation remain open questions. In this work, we investigated the impact of the diuron herbicide on the DNA methylation pattern of spat from exposed Crassotrea gigas genitors. This oyster is one of the most important mollusk species produced worldwide and a key coastal economic resource in France. The whole genome bisulfite sequencing (WGBS, BS-Seq) was applied to obtain a methylome at single nucleotide resolution on DNA extracted from spat issued from diuron exposed genitors comparatively to control spat. We showed that the parental diuron exposure has an impact on the DNA methylation pattern of its progeny. Most of the differentially methylated regions occurred within coding sequences and we showed that this change in methylation level correlates with RNA level only in a very small group of genes. Although the DNA methylation profile is variable between individuals, we showed conserved DNA methylation patterns in response to parental diuron exposure. This relevant result opens perspectives for the setting of new markers based on epimutations as early indicators of marine pollutions. PMID- 29492307 TI - Pesticide use and LINE-1 methylation among male private pesticide applicators in the Agricultural Health Study. AB - Cancer risk may be associated with DNA methylation (DNAm) levels in Long Interspersed Nucleotide Element 1 (LINE-1), a surrogate for global DNAm. Exposure to certain pesticides may increase risk of particular cancers, perhaps mediated in part through global DNAm alterations. To date, human data on pesticide exposure and global DNAm alterations are limited. The goal of this study was to evaluate alterations of LINE-1 DNAm by pesticides in a variety of classes. Data from 596 cancer-free male participants enrolled in the Agricultural Health Study (AHS) were used to examine associations between use of 57 pesticides and LINE-1 DNAm measured via Pyrosequencing in peripheral blood leucocytes. Participants provided information on pesticide use at three contacts between 1993 and 2010. Associations of ever/never pesticide use and lifetime days of application (years of use * days per year) and LINE-1 DNAm level were assessed using linear regression, adjusting for potential confounders (race, age at blood draw, and frequency of drinking alcohol) and other moderately correlated pesticides. After adjustment, ever application of 10 pesticides was positively associated and ever application of eight pesticides was negatively associated with LINE-1 DNAm. In dose-response analyses, increases in five pesticides (imazethapyr, fenthion, EPTC, butylate, and heptachlor) were associated with increasing LINE-1 DNAm (ptrend < 0.05) and increases in three pesticides (carbaryl, chlordane, and paraquat) were associated with decreasing LINE-1 DNAm (ptrend < 0.05). This study provides some mechanistic insight into the pesticide-cancer relationship, which may be mediated in part by epigenetics. PMID- 29492308 TI - Cadmium exposure and age-associated DNA methylation changes in non-smoking women from northern Thailand. AB - DNA methylation changes with age, and may serve as a biomarker of aging. Cadmium (Cd) modifies cellular processes that promote aging and disrupts methylation globally. Whether Cd modifies aging processes by influencing establishment of age associated methylation marks is currently unknown. In this pilot study, we characterized methylation profiles in > 450 000 CpG sites in 40 non-smoking women (age 40-80) differentially exposed to environmental Cd from Thailand. Based on specific gravity adjusted urinary Cd, we classified them as high (HE) and low (LE) exposed and age-matched within 5 years. Urinary Cd was defined as below 2 ug/l in the LE group. We predicted epigenetic age (DNAm-age) using two published methods by Horvath and Hannum and examined the difference between epigenetic age and chronologic age (Deltaage). We assessed differences by Cd exposure using linear mixed models adjusted for estimated white blood cell proportions, BMI, and urinary creatinine. We identified 213 age-associated CpG sites in our population (P < 10-4). Counterintuitively, the mean Deltaage was smaller in HE vs. LE (Hannum: 3.6 vs. 7.6 years, P = 0.0093; Horvath: 2.4 vs. 4.5 years, P = 0.1308). The Cd exposed group was associated with changes in methylation (P < 0.05) at 12, 8, and 20 age-associated sites identified in our population, Hannum, and Horvath. From the results of this pilot study, elevated Cd exposure is associated with methylation changes at age-associated sites and smaller differences between DNAm age and chronologic age, in contrast to expected age-accelerating effects. Cd may modify epigenetic aging, and biomarkers of aging warrant further investigation when examining Cd and its relationship with chronic disease and mortality. PMID- 29492309 TI - Low maternal adherence to a Mediterranean diet is associated with increase in methylation at the MEG3-IG differentially methylated region in female infants. AB - Diet is dictated by the surrounding environment, as food access and availability may change depending on where one lives. Maternal diet during pregnancy is an important part of the in utero environment, and may affect the epigenome. Studies looking at overall diet pattern in relation to DNA methylation have been lacking. The Mediterranean diet is known for its health benefits, including decreased inflammation, weight loss, and management of chronic diseases. This study assesses the association between maternal adherence to a Mediterranean diet pattern during pregnancy and infant DNA methylation at birth. Mediterranean diet adherence in early pregnancy was measured in 390 women enrolled in the Newborn Epigenetic Study, and DNA methylation was assessed in their infants at birth. Multinomial logistic regression was used to assess the association between adherence to a Mediterranean diet and infant methylation at the MEG3, MEG3-IG, pleiomorphic adenoma gene-like 1, insulin-like growth factor 2 gene, H19, mesoderm-specific transcript, neuronatin, paternally expressed gene 3, sarcoglycan and paternally expressed gene 10 regions, measured by pyrosequencing. Infants of mothers with a low adherence to a Mediterranean diet had a greater odds of hypo-methylation at the MEG3-IG differentially methylated region (DMR). Sex-stratified models showed that this association was present in girls only. This study provides early evidence on the association between overall diet pattern and methylation at the 9 DMRs included in this study, and suggests that maternal diet can have a sex-specific impact on infant DNA methylation at specific imprinted DMRs. PMID- 29492312 TI - Exposure to phthalate esters induces an autophagic response in male germ cells. AB - Phthalate esters are plasticizers that impart flexibility to polvinylchloride plastics. As they are not covalently bound, they can leach from a wide range of products, including food containers, medical devices, clothing, and toys, leading to widespread environmental exposure. Phthalate toxicity has been linked to male infertility by disrupting testosterone production and testis development. Phthalates also impair proliferation and viability of spermatogonial stem cells (SSC), the role of which is to support lifelong spermatogenesis. To elucidate cellular mechanisms in spermatogonia affected by long-term phthalate exposure, we grafted primate testis tissue into mice. Grafts treated with di-n-butyl phthalate showed an increase in autophagy compared to controls. Short term in vitro exposure of porcine germ cells to mono(2-ethylhexyl) phthalate, also resulted in an increase in autophagy. Viability was lower in cells exposed to phthalates, but treatment with rapamycin to induce autophagy significantly increased viability. The data suggests autophagy is triggered in spermatogonia as a response to a toxic insult, which may constitute a survival mechanism in spermatogonia. PMID- 29492311 TI - An emerging role for epigenetic regulation of Pgc-1alpha expression in environmentally stimulated brown adipose thermogenesis. AB - Metabolic disease is a leading cause of death worldwide, and obesity, a central risk factor, is reaching epidemic proportions. Energy expenditure and brown adipose tissue (BAT) thermogenesis are implicated in metabolic disease, and it is becoming evident that impaired BAT activity is regulated by gene/environment interactions. Peroxisome proliferator-activated receptor gamma coactivator 1alpha (Pgc-1alpha) is a critical regulator of BAT thermogenesis, which is highly inducible by environmental stimuli such as cold and diet. This review focuses on the environmentally mediated epigenetic and transcriptional regulation of Pgc 1alpha gene expression during BAT thermogenesis. We illustrate interactions between histone modifications and transcription factors at the Pgc-1alpha promoter that cause BAT Pgc-1alpha transcription in response to cold. Histone modifications also modulate BAT Pgc-1alpha transcription in response to nutrients though diet has been less characterized than cold with respect to regulation of Pgc-1alpha transcription. Pgc-1alpha DNA methylation and RNA expression were also correlated to indicators of adiposity and glucose homeostasis across numerous human tissues. Although post-translational modification of Pgc-1alpha protein has been well-characterized across diverse tissues and environments, comparatively little is known of the epigenetic mechanisms regulating Pgc-1alpha transcription, particularly in BAT thermogenesis. PMID- 29492310 TI - DNA methylation alterations in Alzheimer's disease. AB - The observation that Alzheimer's disease (AD) patients with similar and even identical genetic backgrounds often present with heterogeneous pathologies has prompted the hypothesis that epigenetics may contribute to AD. While the study of epigenetics encompasses a variety of modifications including histone modifications and non-coding RNAs, much of the research on how epigenetics might impact AD pathology has been focused on DNA methylation. To this end, several studies have characterized DNA methylation alterations in various brain regions of individuals with AD, with conflicting results. This review examines the results of studies analyzing both global and gene-specific DNA methylation changes in AD and also assesses the results of studies analyzing DNA hydroxymethylation in patients with AD. PMID- 29492313 TI - Transgenerational epigenetics and environmental justice. AB - Human transmission to offspring and future generations of acquired epigenetic modifications has not been definitively established, although there are several environmental exposures with suggestive evidence. This article uses three examples of hazardous substances with greater exposures in vulnerable populations: pesticides, lead, and diesel exhaust. It then considers whether, if there were scientific evidence of transgenerational epigenetic inheritance, there would be greater attention given to concerns about environmental justice in environmental laws, regulations, and policies at all levels of government. To provide a broader perspective on environmental justice the article discusses two of the most commonly cited approaches to environmental justice. John Rawls's theory of justice as fairness, a form of egalitarianism, is frequently invoked for the principle that differential treatment of individuals is justified only if actions are designed to benefit those with the greatest need. Another theory, the capabilities approach of Amartya Sen and Martha Nussbaum, focuses on whether essential capabilities of society, such as life and health, are made available to all individuals. In applying principles of environmental justice the article considers whether there is a heightened societal obligation to protect the most vulnerable individuals from hazardous exposures that could adversely affect their offspring through epigenetic mechanisms. It concludes that unless there were compelling evidence of transgenerational epigenetic harms, it is unlikely that there would be a significant impetus to adopt new policies to prevent epigenetic harms by invoking principles of environmental justice. PMID- 29492316 TI - Environment, epigenetics and reproduction. AB - A conference summary of the third biannual Kenya Africa Conference "Environment, Epigenetics and Reproduction" is provided. A partial special Environmental Epigenetics issue containing a number of papers in Volume 3, Issue 3 and 4 are discussed. PMID- 29492314 TI - An overview of a Sertoli cell transplantation model to study testis morphogenesis and the role of the Sertoli cells in immune privilege. AB - Advanced testicular germ cells, expressing novel cell surface and intracellular proteins, appear after the establishment of central tolerance and thus are auto immunogenic. However, due to testis immune privilege these germ cells normally do not evoke a detrimental immune response. The Sertoli cell (SC) barrier (also known as the blood-testis barrier) creates a unique microenvironment required for the completion of spermatogenesis and sequesters the majority of the advanced germ cells from the immune system. Given that an intact SC barrier is necessary for spermatogenesis and that disruption of the SC barrier results in loss of advanced germ cells independent of an immune response, this dual role of the SC barrier makes it difficult to directly test the importance of the SC barrier in immune privilege. The ability of SCs to survive and protect co-grafted cells when transplanted ectopically (outside the testis) across immunological barriers is well-documented. Here, we will discuss the use of a SC transplantation model to investigate the role of SC and the SC barrier in immune privilege. Additionally, the formation of cord/tubule like structures in this model, containing both SCs and myoid cells, further extends its application to study testis morphogenesis. We will also discuss the potential use of this model to study the effects of drugs/environmental toxins on testis morphogenesis, tight junction formation and SC-myoid cell interactions. PMID- 29492315 TI - Maintenance of Mest imprinted methylation in blastocyst-stage mouse embryos is less stable than other imprinted loci following superovulation or embryo culture. AB - Assisted reproductive technologies are fertility treatments used by subfertile couples to conceive their biological child. Although generally considered safe, these pregnancies have been linked to genomic imprinting disorders, including Beckwith-Wiedemann and Silver-Russell Syndromes. Silver-Russell Syndrome is a growth disorder characterized by pre- and post-natal growth retardation. The Mest imprinted domain is one candidate region on chromosome 7 implicated in Silver Russell Syndrome. We have previously shown that maintenance of imprinted methylation was disrupted by superovulation or embryo culture during pre implantation mouse development. For superovulation, this disruption did not originate in oogenesis as a methylation acquisition defect. However, in comparison to other genes, Mest exhibits late methylation acquisition kinetics, possibly making Mest more vulnerable to perturbation by environmental insult. In this study, we present a comprehensive evaluation of the effects of superovulation and in vitro culture on genomic imprinting at the Mest gene. Superovulation resulted in disruption of imprinted methylation at the maternal Mest allele in blastocysts with an equal frequency of embryos having methylation errors following low or high hormone treatment. This disruption was not due to a failure of imprinted methylation acquisition at Mest in oocytes. For cultured embryos, both the Fast and Slow culture groups experienced a significant loss of maternal Mest methylation compared to in vivo-derived controls. This loss of methylation was independent of development rates in culture. These results indicate that Mest is more susceptible to imprinted methylation maintenance errors compared to other imprinted genes. PMID- 29492317 TI - Multigenerational analysis of sex-specific phenotypic differences at midgestation caused by abnormal folate metabolism. AB - The exposure to adverse environmental conditions (e.g. poor nutrition) may lead to increased disease risk in an individual and their descendants. In some cases, the results may be sexually dimorphic. A range of phenotypes has been associated with deficiency in or defective metabolism of the vitamin folate. However, the molecular mechanism linking folate metabolism to development is still not well defined nor is it clear whether phenotypes are sex-specific. The enzyme methionine synthase reductase (MTRR) is required for the progression of folate metabolism and the utilization of methyl groups from the folate cycle. Previously, we showed that the hypomorphic Mtrrgt mutation in mice results in metabolic disruption, epigenetic instability, and a wide spectrum of developmental phenotypes (e.g. growth defects, congenital malformations) at midgestation that appear in subsequent wild-type generations. This transgenerational effect only occurs through the maternal lineage. Here, we explore whether the phenotypes that result from either intrinsic or ancestral Mtrr deficiency are sexually dimorphic. We found that no sexual dimorphism is apparent in either situation when the phenotypes were broadly or specifically defined. However, when we focused on the group of phenotypically normal conceptuses derived from maternal grandparental Mtrr deficiency, we observed an apparent increase in placental efficiency in each subsequent generation leading to F4 generation female embryos that weigh more than controls. These data suggest that ancestral abnormal folate metabolism may lead to male grandprogeny that are less able to adapt or female grandprogeny that are programmed to become more sensitive to folate availability in subsequent generations. PMID- 29492319 TI - Macrophage Targeted Nanoparticles for Antiretroviral (ARV) Delivery. AB - Objective: To reduce the amount of the antiretroviral (ARV) nevirapine necessary to achieve therapeutic concentrations using macrophage targeted nanoparticles. Methods: Core-shell nanoparticles were prepared from FDA approved, biodegradable and biocompatible polymers, with poly(lactic-co-glycolic) acid (PLGA) as the core and chitosan (CS) as the shell using a water/oil/water method. Nevirapine was encapsulated in the core of the nanoparticles. beta-glucan (GLU) was adsorbed to the surface of the nanoparticle. Macrophage uptake and intracellular nevirapine concentrations were determined by fluorescence imaging and ultra-performance liquid chromatography/mass spectroscopy (UPLC-MS). Optical imaging was employed to characterize the biodistribution of nanoparticles following intravenous injection in CD-1 mice. Results: We synthesized spherical shaped 190 nm GLU-CS PLGA nanoparticles that provide controlled release of nevirapine. In THP-1 macrophage the uptake of PLGA and CS- PLGA nanoparticles was less compared to targeted GLU-CS-PLGA nanoparticles. THP-1 macrophage were dosed with free nevirapine (10 MUg/well) and GLU-CS- PLGA nanoparticles containing 1/10 the concentration of free nevirapine (1 MUg nevirapine/well). The intracellular concentration of nevirapine was the same for both nanoparticles and free nevirapine at 2 and 24 hrs. No significant change in THP-1 macrophage viability was observed in the presence of nanoparticles relative to the control. Ex vivo imaging demonstrates that nanoparticles are predominantly found in the liver and kidney and at 24 hr there is still a large amount of nanoparticles in the body. Conclusion: These data demonstrate that the total dose of nevirapine delivered by GLU-CS-PLGA nanoparticles can be greatly reduced, to limit side effects, while still providing maximal ARV activity in a known cellular reservoir. PMID- 29492318 TI - A 'phenotypic hangover': the predictive adaptive response and multigenerational effects of altered nutrition on the transcriptome of Drosophila melanogaster. AB - The Developmental Origins of Health and Disease hypothesis predicts that early life environmental exposures can be detrimental to later-life health and that mismatch between the pre- and post-natal environment may contribute to the growing non-communicable disease epidemic. Within this is an increasingly recognized role for epigenetic mechanisms; for example, epigenetic modifications can be influenced by nutrition and can alter gene expression in mothers and offspring. Currently, there are few whole-genome transcriptional studies of response to nutritional alteration. Thus, we sought to explore how nutrition affects the expression of genes involved in epigenetic processes in Drosophila melanogaster. We manipulated Drosophila food macronutrient composition at the F0 generation, mismatched F1 offspring back to a standard diet and analysed the transcriptome of the F0-F3 generations by RNA sequencing. At F0, the altered (high-protein, low-carbohydrate) diet increased expression of genes classified as having roles in epigenetic processes, with co-ordinated down-regulation of genes involved in immunity, neurotransmission and neurodevelopment, oxidative stress and metabolism. Upon reversion to standard nutrition, mismatched F1 and F2 generations displayed multigenerational inheritance of altered gene expression. By the F3 generation, gene expression had reverted to F0 (matched) levels. These nutritionally induced gene expression changes demonstrate that dietary alterations can up-regulate epigenetic genes, which may influence the expression of genes with broad biological functions. Furthermore, the multigenerational inheritance of the gene expression changes in F1 and F2 mismatched generations suggests a predictive adaptive response to maternal nutrition, aiding the understanding of the interaction between maternal diet and offspring health, with direct implications for the current non-communicable disease epidemic. PMID- 29492320 TI - Klippel-Feil Syndrome with Sprengel Deformity and Extensive Upper Extremity Deformity: A Case Report and Literature Review. AB - Introduction: Klippel-Feil syndrome (KFS) is a congenital anomaly resulting from fusion of cervical vertebral bodies secondary to the dysregulation of signaling pathways during somite development. It is commonly associated with scoliosis and Sprengel deformity. We present a case of KFS with commonly associated abnormalities as well as deformities that have not yet been reported in the literature. Case Presentation: A 3-year-old girl presented for further evaluation of a left upper extremity deformity following a negative genetic workup. Upon physical exam and radiographic imaging, the patient was diagnosed with KFS and associated abnormalities including cervical scoliosis, Sprengel deformity, and congenital deformity of the left upper extremity. Deformities of the left upper extremity include radioulnar synostosis, a four-rayed hand, and absent thenar musculature. The Sprengel deformity was corrected surgically with a Woodward procedure. Discussion: Congenital musculoskeletal deformities can be differentiated based upon spinal and limb embryology. The presence of extraspinal abnormalities not originating from somite differentiation may suggest a severe form of KFS. Important considerations in the workup of the KFS patient include looking for deformities of the shoulder girdle and upper extremities to identify abnormalities for intervention at a young age. PMID- 29492321 TI - Top 100 Cited Articles in Recent Tobacco Research. AB - Background: The total citations that a peer-reviewed manuscript has is often used to measure the impact that a publication has in its respective field of study. Both the citation count and total number of publications are often used as measures of academic productivity and success. This issue has been previously investigated in the field of tobacco control research. Given the changing landscape in the field of tobacco research since 2004, we sought to re-examine this issue. The study purpose was to identify the 100 top-cited tobacco-related articles published since 2005, and to categorize and describe the fields of study represented in these articles. Methods: We searched the Scopus library database to determine the citations of the top 100 tobacco-related articles. Information was gathered on: title, number of authors, publication year, journal name and impact factor, country of origin, article type and subject category. Articles were selected and analyzed by two independent investigators. Results: We identified the 100 top-cited articles published in 58 journals, led by The New England Journal of Medicine (8) and Lancet (6), between 2005 and 2014. The United States was the most common country of origin for the highly-cited articles. The top article types were observation (27%), basic science (26%), and review articles (24%). The most common article subject area was medicine (74%). A statistically significant association was found between the journal impact factor and the number of top 100 cited articles (p = 0.03). Conclusions: This review may be helpful to identify articles that may be contributing to the conduct of current and future tobacco research. The analysis can be used as a reference to review and evaluate the publications that are making a high impact in the field of tobacco research. PMID- 29492322 TI - Chronic subdural hematoma of the posterior fossa treated by suboccipital craniotomy. AB - Background: Chronic subdural hematoma (CSDH) of the posterior fossa is uncommon in adults. Only a few cases have been reported, and most of these were secondary to head injury or anticoagulant therapy. We herein describe a case of successful surgical treatment of CSDH in the posterior fossa after surgical removal of a large supratentorial and infratentorial dermoid cyst. Case Description: A 71-year old woman underwent removal of a left supratentorial and infratentorial dermoid cyst via a left transzygomatic approach. Three years, 6 months after surgery, screening computed tomography revealed CSDH in the supratentorial and infratentorial regions. Four months later, the patient was transferred to the emergency department with cerebellar ataxia, vomiting, and deterioration of consciousness. Two hematomas, one in the supratentorial region and one in the infratentorial region, were greatly compressing the brain, and seemed to be separate lesions. It was difficult to judge on computed tomography whether there was communication between these two hematoma cavities. The patient underwent hematoma removal via suboccipital craniotomy for the posterior fossa CSDH to resolve brain stem compression. Burr-hole irrigation was used for the supratentorial CSDH to avoid upper herniation. The patient recovered uneventfully and was discharged with no neurological deficits. Conclusion: Although the optimal treatment for CSDH of the posterior fossa remains unclear because of the limited number of previous reports, direct decompression of the posterior fossa via suboccipital craniotomy should be considered, especially when CSDH exists primarily at the cerebellopontine angle and strongly compresses the brain stem. PMID- 29492323 TI - Commentary on: Neuropathic pain in low back-related leg pain patients: What is the evidence of prevalence, characteristics, and prognosis in primary care? A systematic review of the literature. PMID- 29492324 TI - The integral neurosurgeon: A tribute. PMID- 29492325 TI - Management of concomitant metabolic encephalopathy and meningioma with vasogenic edema and impending herniation. AB - Background: Altered mental status describes impaired mental functioning ranging from confusion to coma and indicates an illness, either metabolic or structural in nature. Metabolic causes include hypothyroidism, hyperuremia, hypo/hyperglycemia, hypo/hypernatremia, and encephalopathy. The structural causes include tumors, brain hemorrhage, infection, and stroke. To our knowledge, this is the first case in which a patient presented with altered mental status from both metabolic (myxedema coma) and structural diseases (frontal meningioma) with vasogenic edema and midline shift. Case Description: A 55-year-old female presented with progressive coma. The clinical features included bradycardia and hypothermia. The imaging demonstrated a large frontal meningioma with a significant midline shift with laboratory findings suggestive of severe hypothyroidism and myxedema coma. Hypothyroidism was treated aggressively with intravenous T3 and T4 with close neurosurgical observation. Osmodiuretics and steroids were administered as temporizing agents prior to craniotomy. Craniotomy was successfully undertaken after using these appropriate pre-emptive measures. Conclusions: Management of concomitant metabolic encephalopathy and meningioma with vasogenic edema and impending herniation can be challenging. Correction of the encephalopathy is crucial to minimize perioperative morbidity and mortality. Awareness of metabolic causes of acute decompensation is critical for perioperative management, so a high index of clinical suspicion can make an important timely diagnosis for treatment initiation. Severely hypothyroid patients are sensitive to anesthetic agents and are at a high risk for perioperative complications. Prompt treatment prior to surgical intervention can help minimize perioperative complications. PMID- 29492326 TI - Diagnosis of demyelinating brain lesion simulating brain tumors on fast imaging employing steady-state acquisition magnetic resonance imaging. AB - Background: A single inflammatory demyelinating brain lesion sometimes mimics a brain tumor on conventional magnetic resonance imaging (MRI), and thus poses a considerable diagnostic challenge. We assessed the usefulness of a new MRI technique, fast imaging employing steady-state acquisition (FIESTA), for the diagnosis of inflammatory demyelinating disease (IDD). Methods: Three patients (2 males, 1 female) with a histopathologically proven inflammatory demyelinating brain lesion which mimicked a brain tumor on MRI were evaluated with a post contrast three-dimensional FIESTA sequence before biopsy and treatment. Those images were compared with the images of intra-axial brain tumors (n = 147). Results: Preoperative FIESTA showed an iso- or slightly hyperintense distinct intralesional structure that appeared reticulate or broad-line in patients with IDD. These structures traversed a hyperintense demyelinating lesion in the deep grey matter (DGM) and were connected to the surrounding extralesional area, which appeared to be dense fibers between DGM. Such distinct intralesional structures were not observed in most brain tumors. Conclusion: Reticulate or broad-line-like intralesional structures on FIESTA may, therefore, be suggestive of IDD rather than indicate a brain tumor. PMID- 29492327 TI - Is it time to perform the first human head transplant? Comment on the CSA (cephalosomatic anastomosis) paper by Ren, Canavero, and colleagues. PMID- 29492328 TI - Is it time to perform the first human head transplant? Comment on the CSA (CephaloSomatic Ansatomisis) paper by Ren, Canavero, and colleagues. PMID- 29492329 TI - Intrauterine Herpes Simplex Virus Infection Presenting as a Zosteriform Eruption in a Newborn. AB - There is significant morbidity and mortality associated with the transmission of herpes simplex virus (HSV) from pregnant women to their fetus or newborn. Although most commonly transmitted in the peripartum period, in rare cases HSV can lead to intrauterine infection. Cutaneous lesions are the most common manifestation of intrauterine HSV, and have a wide spectrum of presentation. We present a rare case of intrauterine HSV-2 infection presenting with a zosteriform eruption mimicking congenital varicella syndrome in a newborn. PMID- 29492330 TI - A microbial survey of the International Space Station (ISS). AB - Background: Modern advances in sequencing technology have enabled the census of microbial members of many natural ecosystems. Recently, attention is increasingly being paid to the microbial residents of human-made, built ecosystems, both private (homes) and public (subways, office buildings, and hospitals). Here, we report results of the characterization of the microbial ecology of a singular built environment, the International Space Station (ISS). This ISS sampling involved the collection and microbial analysis (via 16S rDNA PCR) of 15 surfaces sampled by swabs onboard the ISS. This sampling was a component of Project MERCCURI (Microbial Ecology Research Combining Citizen and University Researchers on ISS). Learning more about the microbial inhabitants of the "buildings" in which we travel through space will take on increasing importance, as plans for human exploration continue, with the possibility of colonization of other planets and moons. Results: Sterile swabs were used to sample 15 surfaces onboard the ISS. The sites sampled were designed to be analogous to samples collected for (1) the Wildlife of Our Homes project and (2) a study of cell phones and shoes that were concurrently being collected for another component of Project MERCCURI. Sequencing of the 16S rDNA genes amplified from DNA extracted from each swab was used to produce a census of the microbes present on each surface sampled. We compared the microbes found on the ISS swabs to those from both homes on Earth and data from the Human Microbiome Project. Conclusions: While significantly different from homes on Earth and the Human Microbiome Project samples analyzed here, the microbial community composition on the ISS was more similar to home surfaces than to the human microbiome samples. The ISS surfaces are species-rich with 1,036-4,294 operational taxonomic units (OTUs per sample). There was no discernible biogeography of microbes on the 15 ISS surfaces, although this may be a reflection of the small sample size we were able to obtain. PMID- 29492331 TI - Quantifying the effectiveness of shoreline armoring removal on coastal biota of Puget Sound. AB - Shoreline armoring is prevalent around the world with unprecedented human population growth and urbanization along coastal habitats. Armoring structures, such as riprap and bulkheads, that are built to prevent beach erosion and protect coastal infrastructure from storms and flooding can cause deterioration of habitats for migratory fish species, disrupt aquatic-terrestrial connectivity, and reduce overall coastal ecosystem health. Relative to armored shorelines, natural shorelines retain valuable habitats for macroinvertebrates and other coastal biota. One question is whether the impacts of armoring are reversible, allowing restoration via armoring removal and related actions of sediment nourishment and replanting of native riparian vegetation. Armoring removal is targeted as a viable option for restoring some habitat functions, but few assessments of coastal biota response exist. Here, we use opportunistic sampling of pre- and post-restoration data for five biotic measures (wrack % cover, saltmarsh % cover, number of logs, and macroinvertebrate abundance and richness) from a set of six restored sites in Puget Sound, WA, USA. This broad suite of ecosystem metrics responded strongly and positively to armor removal, and these results were evident after less than one year. Restoration responses remained positive and statistically significant across different shoreline elevations and temporal trajectories. This analysis shows that removing shoreline armoring is effective for restoration projects aimed at improving the health and productivity of coastal ecosystems, and these results may be widely applicable. PMID- 29492332 TI - Evolutionary radiation of earless frogs in the Andes: molecular phylogenetics and habitat shifts in high-elevation terrestrial breeding frogs. AB - The loss of hearing structures and loss of advertisement calls in many terrestrial breeding frogs (Strabomantidae) living at high elevations in South America are common and intriguing phenomena. The Andean frog genus Phrynopus Peters, 1873 has undergone an evolutionary radiation in which most species lack the tympanic membrane and tympanic annulus, yet the phylogenetic relationships among species in this group remain largely unknown. Here, we present an expanded molecular phylogeny of Phrynopus that includes 24 nominal species. Our phylogeny includes Phrynopus peruanus, the type species of the genus, and 10 other species for which genetic data were previously unavailable. We found strong support for monophyly of Phrynopus, and that two nominal species-Phrynopus curator and Phrynopus nicoleae-are junior synonyms of Phrynopus tribulosus. Using X-ray computed tomography (CT) imaging, we demonstrate that the absence of external hearing structures is associated with complete loss of the auditory skeletal elements (columella) in at least one member of the genus. We mapped the tympanum condition on to a species tree to infer whether the loss of hearing structures took place once or multiple times. We also assessed whether tympanum condition, body size, and body shape are associated with the elevational distribution and habitat use. We identified a single evolutionary transition that involved the loss of both the tympanic membrane and tympanic annulus, which in turn is correlated with the absence of advertisement calls. We also identified several species pairs where one species inhabits the Andean grassland and the other montane forest. When accounting for phylogenetic relatedness among species, we detected a significant pattern of increasing body size with increasing elevation. Additionally, species at higher elevations tend to develop shorter limbs, shorter head, and shorter snout than species living at lower elevations. Our findings strongly suggest a link between ecological divergence and morphological diversity of terrestrial breeding frogs living in montane gradients. PMID- 29492333 TI - Bacterial identification of the vaginal microbiota in Ecuadorian pregnant teenagers: an exploratory analysis. AB - Background: Bacterial vaginosis (BV) is a microbial imbalance (i.e., dysbiosis) that can produce serious medical effects in women at childbearing age. Little is known, however, about the incidence of BV or vaginal microbiota dysbiosis in pregnant teenagers in low and middle-income countries such as Ecuador. The scope of this exploratory analysis was to study the relationship between epidemiologic and microbial risk factors. Among the microbiology risk factors this study investigated five Lactobacillus species, two of them know in preview studies as microbiology risk factors for BV development (Lactobacillus acidophilus and Lactobacillus iners), and the last three known for being associated with a healthy vaginal tract (Lactobacillus crispatus, Lactobacillus gasseri and Lactobacillus jensenii). In addition, fastidious anaerobes known to be microbial risk factors for BV development in pregnant teenagers were searched as well, more exactly, Gardnerella vaginalis, Atopobium vaginae and Mobiluncus mulieris. Methods: Ninety-five healthy adolescent pregnant women, visiting a secondary level hospital in Quito, Ecuador, were enrolled into the study in 2015. The enrolled patients were between 10 to 13 weeks of pregnancy. Four epidemiological risk factors were collected in a survey: age, civil status, sexual partners and condom use. Also, vaginal pH was measured as a health risk factor. DNA was extracted from endocervical and exocervical epithelia from all the patients' samples. PCR analysis was performed in order to characterize the presence of the eight bacterial species known as risk factors for BV development, targeting three anaerobes and five Lactobacillus species. Univariate and multivariate analysis were performed to identify associated factors for the presence of anaerobic species using logistic regression. Results: The 95 vaginal microflora samples of these teenagers were analyzed. Two of the bacterial species known to cause BV: A. vaginae (100%) and G. vaginalis (93.7%) were found in high prevalence. Moreover, the most predominant bacterial Lactobacillus species found in the pregnant teenagers' vaginal tract were L. crispatus (92.6%), L. iners (89.5%) and L. acidophilus (87.4%). In addition, the average vaginal pH measured in the study population was 5.2, and high pH was associated with the presence of the three anaerobic species (p = 0.001). Finally, L. jensenii's presence in the study decreased in 72% the occupation of the three anaerobes. Discussion: This work identified a high pH as a risk factor for BV anaerobes' presence in adolescent pregnant women. Moreover, this study identified L. crispatus, L. iners and L. acidophilus to be the most abundant species in our study population. From all fastidious anaerobes analyzed in this study, A. vaginae was present in all pregnant teenagers. To conclude, L. jensenii could be a potential healthy vaginal microbiota candidate in pregnant teenagers and should be further analyzed in future studies. PMID- 29492334 TI - Comparing the awareness of and beliefs in sexually transmitted infections among university students in Madagascar and the United States of America. AB - Young adults have a higher risk of contracting sexually transmitted infections (STIs) than other age groups. This risk may be mediated by their social and cultural setting which can impact young adults' awareness of, beliefs in, and risk of contracting STIs (including HIV/AIDS). In order to understand how these factors vary among young adults of different cultures, it is important to study these issues on a cross-cultural scale. This study aimed to increase understanding of the relationship between the culture of a place of study and: (1) STI awareness; (2) belief in STIs; and (3) self-reported STI prevalence in the study population. Survey data were collected from university students in Madagascar (n = 242 surveys in 2013) and the United States of America (n = 199 surveys in 2015). Compared to students at the American university, students at the Malagasy university: (1) did not appear to have a conclusively lower awareness of STIs; (2) did not differ in rates of belief in the existence of gonorrhea and syphilis, but had higher rates of disbelief in HIV/AIDS; and (3) were more likely to report having been infected with syphilis and gonorrhea, but not with HIV/AIDS. Students at the Malagasy university also listed different reasons than the students at the American university for why they believed in the existence of STIs. These findings highlight the need for further cross-cultural research to better adapt intervention strategies to different cultural settings. PMID- 29492335 TI - MIA-Clustering: a novel method for segmentation of paleontological material. AB - Paleontological research increasingly uses high-resolution micro-computed tomography (MUCT) to study the inner architecture of modern and fossil bone material to answer important questions regarding vertebrate evolution. This non destructive method allows for the measurement of otherwise inaccessible morphology. Digital measurement is predicated on the accurate segmentation of modern or fossilized bone from other structures imaged in MUCT scans, as errors in segmentation can result in inaccurate calculations of structural parameters. Several approaches to image segmentation have been proposed with varying degrees of automation, ranging from completely manual segmentation, to the selection of input parameters required for computational algorithms. Many of these segmentation algorithms provide speed and reproducibility at the cost of flexibility that manual segmentation provides. In particular, the segmentation of modern and fossil bone in the presence of materials such as desiccated soft tissue, soil matrix or precipitated crystalline material can be difficult. Here we present a free open-source segmentation algorithm application capable of segmenting modern and fossil bone, which also reduces subjective user decisions to a minimum. We compare the effectiveness of this algorithm with another leading method by using both to measure the parameters of a known dimension reference object, as well as to segment an example problematic fossil scan. The results demonstrate that the medical image analysis-clustering method produces accurate segmentations and offers more flexibility than those of equivalent precision. Its free availability, flexibility to deal with non-bone inclusions and limited need for user input give it broad applicability in anthropological, anatomical, and paleontological contexts. PMID- 29492336 TI - A new ICA-based fingerprint method for the automatic removal of physiological artifacts from EEG recordings. AB - Background: EEG may be affected by artefacts hindering the analysis of brain signals. Data-driven methods like independent component analysis (ICA) are successful approaches to remove artefacts from the EEG. However, the ICA-based methods developed so far are often affected by limitations, such as: the need for visual inspection of the separated independent components (subjectivity problem) and, in some cases, for the independent and simultaneous recording of the inspected artefacts to identify the artefactual independent components; a potentially heavy manipulation of the EEG signals; the use of linear classification methods; the use of simulated artefacts to validate the methods; no testing in dry electrode or high-density EEG datasets; applications limited to specific conditions and electrode layouts. Methods: Our fingerprint method automatically identifies EEG ICs containing eyeblinks, eye movements, myogenic artefacts and cardiac interference by evaluating 14 temporal, spatial, spectral, and statistical features composing the IC fingerprint. Sixty-two real EEG datasets containing cued artefacts are recorded with wet and dry electrodes (128 wet and 97 dry channels). For each artefact, 10 nonlinear SVM classifiers are trained on fingerprints of expert-classified ICs. Training groups include randomly chosen wet and dry datasets decomposed in 80 ICs. The classifiers are tested on the IC-fingerprints of different datasets decomposed into 20, 50, or 80 ICs. The SVM performance is assessed in terms of accuracy, False Omission Rate (FOR), Hit Rate (HR), False Alarm Rate (FAR), and sensitivity (p). For each artefact, the quality of the artefact-free EEG reconstructed using the classification of the best SVM is assessed by visual inspection and SNR. Results: The best SVM classifier for each artefact type achieved average accuracy of 1 (eyeblink), 0.98 (cardiac interference), and 0.97 (eye movement and myogenic artefact). Average classification sensitivity (p) was 1 (eyeblink), 0.997 (myogenic artefact), 0.98 (eye movement), and 0.48 (cardiac interference). Average artefact reduction ranged from a maximum of 82% for eyeblinks to a minimum of 33% for cardiac interference, depending on the effectiveness of the proposed method and the amplitude of the removed artefact. The performance of the SVM classifiers did not depend on the electrode type, whereas it was better for lower decomposition levels (50 and 20 ICs). Discussion: Apart from cardiac interference, SVM performance and average artefact reduction indicate that the fingerprint method has an excellent overall performance in the automatic detection of eyeblinks, eye movements and myogenic artefacts, which is comparable to that of existing methods. Being also independent from simultaneous artefact recording, electrode number, type and layout, and decomposition level, the proposed fingerprint method can have useful applications in clinical and experimental EEG settings. PMID- 29492337 TI - 16S rRNA gene sequencing reveals effects of photoperiod on cecal microbiota of broiler roosters. AB - Photoperiod is an important factor in stimulating broiler performance in commercial poultry practice. However, the mechanism by which photoperiod affects the performance of broiler chickens has not been adequately explored. The current study evaluated the effects of three different photoperiod regimes (short day (LD) = 8 h light, control (CTR) = 12.5 h light, and long day (SD) = 16 h light) on the cecal microbiota of broiler roosters by sequencing bacterial 16S rRNA genes. At the phylum level, the dominant bacteria were Firmicutes (CTR: 68%, SD: 69%, LD: 67%) and Bacteroidetes (CTR: 25%, SD: 26%, and LD: 28%). There was a greater abundance of Proteobacteria (p < 0.01) and Cyanobacteria (p < 0.05) in chickens in the LD group than in those in the CTR group. A significantly greater abundance of Actinobacteria was observed in CTR chickens than in SD and LD chickens (p < 0.01). The abundance of Deferribacteres was significantly higher in LD chickens than in SD chickens (p < 0.01). Fusobacteria and Proteobacteria were more abundant in SD chickens than in CTR and LD chickens. The predicted functional properties indicate that cellular processes may be influenced by photoperiod. Conversely, carbohydrate metabolism was enhanced in CTR chickens as compared to that in SD and LD chickens. The current results indicate that different photoperiod regimes may influence the abundance of specific bacterial populations and then contribute to differences in the functional properties of gut microbiota of broiler roosters. PMID- 29492338 TI - Genome-Enhanced Detection and Identification (GEDI) of plant pathogens. AB - Plant diseases caused by fungi and Oomycetes represent worldwide threats to crops and forest ecosystems. Effective prevention and appropriate management of emerging diseases rely on rapid detection and identification of the causal pathogens. The increase in genomic resources makes it possible to generate novel genome-enhanced DNA detection assays that can exploit whole genomes to discover candidate genes for pathogen detection. A pipeline was developed to identify genome regions that discriminate taxa or groups of taxa and can be converted into PCR assays. The modular pipeline is comprised of four components: (1) selection and genome sequencing of phylogenetically related taxa, (2) identification of clusters of orthologous genes, (3) elimination of false positives by filtering, and (4) assay design. This pipeline was applied to some of the most important plant pathogens across three broad taxonomic groups: Phytophthoras (Stramenopiles, Oomycota), Dothideomycetes (Fungi, Ascomycota) and Pucciniales (Fungi, Basidiomycota). Comparison of 73 fungal and Oomycete genomes led the discovery of 5,939 gene clusters that were unique to the targeted taxa and an additional 535 that were common at higher taxonomic levels. Approximately 28% of the 299 tested were converted into qPCR assays that met our set of specificity criteria. This work demonstrates that a genome-wide approach can efficiently identify multiple taxon-specific genome regions that can be converted into highly specific PCR assays. The possibility to easily obtain multiple alternative regions to design highly specific qPCR assays should be of great help in tackling challenging cases for which higher taxon-resolution is needed. PMID- 29492339 TI - In silico structural and functional prediction of African swine fever virus protein-B263R reveals features of a TATA-binding protein. AB - African swine fever virus (ASFV) is the etiological agent of ASF, a fatal hemorrhagic fever that affects domestic pigs. There is currently no vaccine against ASFV, making it a significant threat to the pork industry. The ASFV genome sequence has been published; however, about half of ASFV open reading frames have not been characterized in terms of their structure and function despite being essential for our understanding of ASFV pathogenicity. The present study reports the three-dimensional structure and function of uncharacterized protein, pB263R (NP_042780.1), an open reading frame found in all ASFV strains. Sequence-based profiling and hidden Markov model search methods were used to identify remote pB263R homologs. Iterative Threading ASSEmbly Refinement (I TASSER) was used to model the three-dimensional structure of pB263R. The posterior probability of fold family assignment was calculated using TM-fold, and biological function was assigned using TM-site, RaptorXBinding, Gene Ontology, and TM-align. Our results suggests that pB263R has the features of a TATA-binding protein and is thus likely to be involved in viral gene transcription. PMID- 29492340 TI - Repeatability of glucocorticoid hormones in vertebrates: a meta-analysis. AB - We often expect that investigations of the patterns, causes, and consequences of among-individual variation in a trait of interest will reveal how selective pressures or ecological conditions influence that trait. However, many endocrine traits, such as concentrations of glucocorticoid (GC) hormones, exhibit adaptive plasticity and, therefore, do not necessarily respond to these pressures as predicted by among-individual phenotypic correlations. To improve our interpretations of among-individual variation in GC concentrations, we need more information about the repeatability of these traits within individuals. Many studies have already estimated the repeatability of baseline, stress-induced, and integrated GC measures, which provides an opportunity to use meta-analytic techniques to investigate (1) whether GC titers are generally repeatable across taxa, and (2) which biological or methodological factors may impact these estimates. From an intensive search of the literature, we collected 91 GC repeatability estimates from 47 studies. Overall, we found evidence that GC levels are repeatable, with mean repeatability estimates across studies ranging from 0.230 for baseline levels to 0.386 for stress-induced levels. We also noted several factors that predicted the magnitude of these estimates, including taxon, sampling season, and lab technique. Amphibians had significantly higher repeatability in baseline and stress-induced GCs than birds, mammals, reptiles, or bony fish. The repeatability of stress-induced GCs was higher when measured within, rather than across, life history stages. Finally, estimates of repeatability in stress-induced and integrated GC measures tended to be lower when GC concentrations were quantified using commercial kit assays rather than in house assays. The extent to which among-individual variation in GCs may explain variation in organismal performance or fitness (and thereby inform our understanding of the ecological and evolutionary processes driving that variation) depends on whether measures of GC titers accurately reflect how individuals differ overall. Our findings suggest that while GC titers can reflect some degree of consistent differences among individuals, they frequently may not. We discuss how our findings contribute to interpretations of variation in GCs, and suggest routes for the design and analysis of future research. PMID- 29492341 TI - A simple method of equine limb force vector analysis and its potential applications. AB - Background: Ground reaction forces (GRF) measured during equine gait analysis are typically evaluated by analyzing discrete values obtained from continuous force time data for the vertical, longitudinal and transverse GRF components. This paper describes a simple, temporo-spatial method of displaying and analyzing sagittal plane GRF vectors. In addition, the application of statistical parametric mapping (SPM) is introduced to analyse differences between contra lateral fore and hindlimb force-time curves throughout the stance phase. The overall aim of the study was to demonstrate alternative methods of evaluating functional (a)symmetry within horses. Methods: GRF and kinematic data were collected from 10 horses trotting over a series of four force plates (120 Hz). The kinematic data were used to determine clean hoof contacts. The stance phase of each hoof was determined using a 50 N threshold. Vertical and longitudinal GRF for each stance phase were plotted both as force-time curves and as force vector diagrams in which vectors originating at the centre of pressure on the force plate were drawn at intervals of 8.3 ms for the duration of stance. Visual evaluation was facilitated by overlay of the vector diagrams for different limbs. Summary vectors representing the magnitude (VecMag) and direction (VecAng) of the mean force over the entire stance phase were superimposed on the force vector diagram. Typical measurements extracted from the force-time curves (peak forces, impulses) were compared with VecMag and VecAng using partial correlation (controlling for speed). Paired samples t-tests (left v. right diagonal pair comparison and high v. low vertical force diagonal pair comparison) were performed on discrete and vector variables using traditional methods and Hotelling's T2 tests on normalized stance phase data using SPM. Results: Evidence from traditional statistical tests suggested that VecMag is more influenced by the vertical force and impulse, whereas VecAng is more influenced by the longitudinal force and impulse. When used to evaluate mean data from the group of ten sound horses, SPM did not identify differences between the left and right contralateral limb pairs or between limb pairs classified according to directional asymmetry. When evaluating a single horse, three periods were identified during which differences in the forces between the left and right forelimbs exceeded the critical threshold (p < .01). Discussion: Traditional statistical analysis of 2D GRF peak values, summary vector variables and visual evaluation of force vector diagrams gave harmonious results and both methods identified the same inter-limb asymmetries. As alpha was more tightly controlled using SPM, significance was only found in the individual horse although T2 plots followed the same trends as discrete analysis for the group. Conclusions: The techniques of force vector analysis and SPM hold promise for investigations of sidedness and asymmetry in horses. PMID- 29492342 TI - Conservative treatment for patients with subacromial impingement: Changes in clinical core outcomes and their relation to specific rehabilitation parameters. AB - Background: Impaired patient-reported shoulder function and pain, external rotation strength, abduction strength, and abduction range-of-motion (ROM) is reported in patients with subacromial impingement (SIS). However, it is unknown how much strength and ROM improves in real-life practice settings with current care. Furthermore, outcomes of treatment might depend on specific rehabilitation parameters, such as the time spent on exercises (exercise-time), number of physiotherapy sessions (physio-sessions) and number of corticosteroid injections, respectively. However, this has not previously been investigated. The purpose of this study was to describe changes in shoulder strength, ROM, patient-reported function and pain, in real-life practice settings, and explore the association between changes in clinical core outcomes and specific rehabilitation parameters. Methods: Patients diagnosed with SIS at initial assessment at an outpatient hospital clinic using predefined criteria's, who had not undergone surgery after 6 months, were included in this prospective cohort study. After initial assessment (baseline), all patients underwent treatment as usual, with no interference from the investigators. The outcomes Shoulder Pain and Disability Index (SPADI:0-100), average pain (NRS:0-10), external rotation strength, abduction strength and abduction ROM, pain during each test (NRS:0-10), were collected at baseline and at six month follow-up. Amount of exercise-time, physio sessions and steroid-injections was recorded at follow-up. Changes in outcomes were analyzed using Wilcoxon Signed-Rank test, and the corresponding effect sizes (ES) were estimated. The associations between changes in outcomes and rehabilitation parameters were explored using multiple regression analyses. Results: Sixty-three patients completed both baseline and follow-up testing. Significant improvements were seen in SPADI (19 points, ES:0.53, p < 0.001) and all pain variables (median 1-1.5 points, ES:0.26-0.39, p < 0.01), but not in strength and ROM (ES:0.9-0.12, p > 0.2). A higher number of physio-sessions was significantly associated with larger improvements in external rotation strength (0.7 Newton/session, p = 0.046), and higher exercise-time was significantly associated with decrease in average pain (-0.2 points/1,000 min, p = 0.048). Discussion: Patient-reported function and pain improved after six months of current care, but strength and ROM did not improve. This is interesting, as strengthening exercises is part of most current interventions. While two significant associations were identified between self-reported rehabilitation parameters and outcomes, the small gains per physio-session or 1,000 min of exercise-time reduces the clinical relevance of these relationships. Collectively, the findings from this study indicate room for improvement of the current rehabilitation of SIS, especially with regard to core clinical outcomes, such as strength and range of motion. PMID- 29492343 TI - Diversity in root growth responses to moisture deficit in young faba bean (Vicia faba L.) plants. AB - Background: Soil moisture deficiency causes yield reduction and instability in faba bean (Vicia faba L.) production. The extent of sensitivity to drought stress varies across accessions originating from diverse moisture regimes of the world. Hence, we conducted successive greenhouse experiments in pots and rhizotrons to explore diversity in root responses to soil water deficit. Methods: A set of 89 accessions from wet and dry growing regions of the world was defined according to the Focused Identification of Germplasm Strategy and screened in a perlite-sand medium under well watered conditions in a greenhouse experiment. Stomatal conductance, canopy temperature, chlorophyll concentration, and root and shoot dry weights were recorded during the fifth week of growth. Eight accessions representing the range of responses were selected for further investigation. Starting five days after germination, they were subjected to a root phenotyping experiment using the automated phenotyping platform GROWSCREEN-Rhizo. The rhizotrons were filled with peat-soil under well watered and water limited conditions. Root architectural traits were recorded five, 12, and 19 days after the treatment (DAT) began. Results: In the germplasm survey, accessions from dry regions showed significantly higher values of chlorophyll concentration, shoot and root dry weights than those from wet regions. Root and shoot dry weight as well as seed weight, and chlorophyll concentration were positively correlated with each other. Accession DS70622 combined higher values of root and shoot dry weight than the rest. The experiment in GROWSCREEN-Rhizo showed large differences in root response to water deficit. The accession by treatment interactions in taproot and second order lateral root lengths were significant at 12 and 19 DAT, and the taproot length was reduced up to 57% by drought. The longest and deepest root systems under both treatment conditions were recorded by DS70622 and DS11320, and total root length of DS70622 was three times longer than that of WS99501, the shortest rooted accession. The maximum horizontal distribution of a root system and root surface coverage were positively correlated with taproot and total root lengths and root system depth. DS70622 and WS99501 combined maximum and minimum values of these traits, respectively. Thus, roots of DS70622 and DS11320, from dry regions, showed drought-avoidance characteristics whereas those of WS99501 and Melodie/2, from wet regions, showed the opposite. Discussion: The combination of the germplasm survey and use of GROWSCREEN-Rhizo allowed exploring of adaptive traits and detection of root phenotypic markers for potential drought avoidance. The greater root system depth and root surface coverage, exemplified by DS70622 and DS11320, can now be tested as new sources of drought tolerance. PMID- 29492344 TI - Deficit irrigation and fertilization strategies to improve soil quality and alfalfa yield in arid and semi-arid areas of northern China. AB - Background: In the arid and semi-arid areas of northern China, overexploitation of fertilizers and extensive irrigation with brackish groundwater have led to soil degradation and large areas of farmland have been abandoned. In order to improve the soil quality of abandoned farmland and make reasonable use of brackish groundwater, we conducted field trials in 2013 and 2014. Methods: In our study, we used three fertilization modes (CF, chemical fertilizer; OM, organic manure and chemical fertilizer; NF, no fertilizer) and three deficit irrigation levels (I0: 0 mm; I75: 75 mm; I150: 150 mm). Results: The results showed that the activities of soil urease, alkaline phosphatase, invertase, catalase, and dehydrogenase in the OM treatment were significantly improved compared with those in the CF and NF treatments under the three deficit irrigation levels. Compared with NF, the OM treatment significantly increased soil organic carbon (SOC), water-soluble carbon (WSC), total nitrogen, microbial biomass carbon and nitrogen (MBC and MBN), and soil respiration rate, and significantly decreased soil C:N and MBC:MBN ratios and the metabolic quotient, thus improving the soil quality of abandoned farmland. Furthermore, the OM treatment increased alfalfa plant height, leaf area index, leaf chlorophyll content, and biomass yield. Under the CF and OM fertilization modes, the activities of urease and catalase in I150 were significantly higher than those in I0, whereas irrigating without fertilizer did not significantly increase the activity of these two enzymes. Regardless of fertilization, alkaline phosphatase activity increased with an increase in irrigation amount, whereas invertase activity decreased. Discussion: The results showed that deficit irrigation with brackish groundwater under the OM treatment can improve soil quality. Over the two years of the study, maximum SOC, total nitrogen, WSC, MBC, and MBN were observed under the OM-I150 treatment, and the alfalfa biomass yield of this treatment was also significantly higher than that of the OM-I0 treatment. Therefore, the OM-I150 treatment could be used as a suitable measure not only to improve the quality of abandoned farmland soil but also to increase the alfalfa biomass yield in arid and semi-arid areas of northern China. PMID- 29492345 TI - Assessment of three risk evaluation systems for patients aged >=70 in East China: performance of SinoSCORE, EuroSCORE II and the STS risk evaluation system. AB - Objectives: To assess and compare the predictive ability of three risk evaluation systems (SinoSCORE, EuroSCORE II and the STS risk evaluation system) in patients aged >=70, and who underwent coronary artery bypass grafting (CABG) in East China. Methods: Three risk evaluation systems were applied to 1,946 consecutive patients who underwent isolated CABG from January 2004 to September 2016 in two hospitals. Patients were divided into two subsets according to their age: elderly group (age >=70) with a younger group (age <70) used for comparison. The outcome of interest in this study was in-hospital mortality. The entire cohort and subsets of patients were analyzed. The calibration and discrimination in total and in subsets were assessed by the Hosmer-Lemeshow and the C statistics respectively. Results: Institutional overall mortality was 2.52%. The expected mortality rates of SinoSCORE, EuroSCORE II and the STS risk evaluation system were 0.78(0.64)%, 1.43(1.14)% and 0.78(0.77)%, respectively. SinoSCORE achieved the best discrimination (the area under the receiver operating characteristic curve (AUC) = 0.829), followed by the STS risk evaluation system (AUC = 0.790) and EuroSCORE II (AUC = 0.769) in the entire cohort. In the elderly group, the observed mortality rate was 4.82% while it was 1.38% in the younger group. SinoSCORE (AUC = .829) also achieved the best discrimination in the elderly group, followed by the STS risk evaluation system (AUC = .730) and EuroSCORE II (AUC = 0.640) while all three risk evaluation systems all had good performances in the younger group. SinoSCORE, EuroSCORE II and the STS risk evaluation system all achieved positive calibrations in the entire cohort and subsets. Conclusion: The performance of the three risk evaluation systems was not ideal in the entire cohort. In the elderly group, SinoSCORE appeared to achieve better predictive efficiency than EuroSCORE II and the STS risk evaluation system. PMID- 29492346 TI - Fruit and vegetable consumption and anemia among adult non-pregnant women: Ghana Demographic and Health Survey. AB - Background: Anemia is the most widely prevalent form of micronutrient deficiency that affects over a quarter of the global population. Evidence suggests that the burden of anemia is higher in the developing countries with women of reproductive age and children being the most at-risk groups. The most common causes are believed to be malnutrition and low bioavailability of micronutrients, which usually result from poor dietary habits and inadequate intake of food rich in micronutrients such as fresh fruits and vegetables. Regular consumption of F&V was shown to have protective effect against NCDs; however, evidence on this protective effect against micronutrient deficiency diseases are limited. Objectives: (1) To measure the prevalence of anemia among adult non-pregnant women in Ghana, and (2) to investigate if there is any cross-sectional relationship between F&V consumption and anemia. Methods: This is a cross sectional study based on data extracted from the Ghana Demographic and Health Survey, 2008. Subjects were 4,290 non-pregnant women aged between 15 and 49 years. Hemoglobin levels were measured by HemoCue(r) hemoglobin-meter. Association between anemia and F&V consumption was assessed by multivariable regression methods. Results: Findings indicate that well over half (57.9%) of the women were suffering from anemia of some level. The percentage of women consuming at least five servings of fruits and vegetables a day were 5.4% and 2.5% respectively. Results of multivariable analysis indicated that among urban women, consumption of <5 servings fruits/day was associated with significantly higher odds of severe [AOR = 9.27; 95% CI [5.15-16.70]] and moderate anemia [AOR = 6.63; 95% CI [4.21-10.44]], and consumption of <5 servings of vegetables/day was associated with higher odds of moderate anemia [AOR = 2.39; 95% CI [1.14-5.02]] compared with those who consumed >5 servings/day. Conclusion: The findings indicate that urban women who did not maintain WHO recommended level of F&V consumption bear a significantly higher likelihood of being moderate to severely anemic. PMID- 29492347 TI - Kompetitive Allele Specific PCR (KASPTM) genotyping of 48 polymorphisms at different caprine loci in French Alpine and Saanen goat breeds and their association with milk composition. AB - Using a novel and fast genotyping method called Kompetitive Allele Specific PCR (KASPTM), we carried out a pilot study on 48 single nucleotide polymorphisms (SNPs) belonging to 40 genes in French Alpine (n = 24) and Saanen (n = 25) goats reared in Romania. Furthermore, the associations of the 13 polymorphic genetic variants with milk production and composition were investigated. Thirty-five SNPs did not show polymorphism in the studied populations. Polymorphic SNPs were detected in the following genes: CAST, CLEC4E, DES, GHRHR, HSP90AA1, IL15RA, IL1RN, IL8, MITF, PPRC1, SOCS3, TNF and TNFSF13. The studied Alpine population was in Hardy-Weinberg disequilibrium at the g.62894878A>G locus (rs671391101) (P < 0.05). The results showed that four SNPs rs671391101 (GHRHR), rs640582069 (IL1RN) rs635583012 (SOCS3) and rs635969404 (IL15RA) out of the 13 polymorphic markers were significantly associated with milk production, protein, fat and lactose content in the Alpine breed. However, no significant effect was recorded in the Saanen population regarding milk yield or milk chemical composition. The current results provide new insights for the development of SNP marker-assisted selection technology in the goat industry and confirm the potential of using SNPs for the GHRHR, IL1RN, SOCS3, and IL15RA genes as candidate genes for selection, highlighting the direct implications of such genes for farm production outputs. The results from this study are relevant for future goat genomic studies and the inclusion of the associated traits into up-to-date selection schemes. PMID- 29492349 TI - A Reversible Cause of Complete Heart Block Causing Chest Pain and Syncope. AB - Vasospastic angina (VSA), also known as variant or Prinzmetal's angina, is a relatively uncommon cause of retrosternal chest pain with transient ST segment elevation, mainly due to vasospasm in the coronary arteries. This is a case of 37 year-old female who presented with chest pain and syncope. Her initial workup, including echocardiogram, was negative. Subsequently, she was sent home with an event monitor. During the next two weeks, she continued to have recurrent episodes of similar chest pains and presented to her cardiology appointment with a heart rate of 45 bpm and blood pressure of 100/60 mmHg and was taken to hospital emergency department. Event monitor review showed intermittent complete heart block. In the hospital, the electrocardiogram (EKG) showed complete heart block and inferior lead ST elevations concomitantly with the chest pains. Although suspicious for vasospastic angina, coronary artery disease had to be ruled out for which patient underwent coronary angiography without evidence of significant obstructive disease. Immediately thereafter, the patient underwent permanent pacemaker placement without recurrence of syncopal episodes. This case signifies complete heart block as one of the rare complications of vasospastic angina which otherwise can also lead to symptoms such as dizziness, shortness of breath, syncope, cardiac arrest, and sudden cardiac death. PMID- 29492348 TI - Functional outcomes and quality of life after a 6-month early intervention program for oral cancer survivors: a single-arm clinical trial. AB - Background: Advanced treatment of oral cancer increases survival rates; however, it also increases the risk of developing shoulder dysfunction, dysphagia, oral dysfunction, donor site morbidity and psychological issues. This single-arm preliminary pilot study aims to explore the effects of a six-month early intervention program following reconstructive surgery in oral cancer survivors. Methods: A total of 65 participants were analyzed following reconstructive surgery. Outcome measurements were taken during the first visit, and at one, three and six months after reconstructive surgery. Results: Scapular muscle strength and shoulder range of motion progressively improved during the 6-month follow-up. The mean Disability of the Arms, Shoulder and Hand (DASH) score showed significant improvement at 1 month (p < .001). Health related QoL showed significant differences between baseline and 6-months post-surgery scores on global health and on most of the function and symptom scales. The predicted return-to-work rate was 80% at one year after the operation. Return-to-work rate differs in different vocational types, with a higher rate of return in the skilled or semi-skilled (87.5%) and self-employed (86.7%). Conclusions: We suggest that early integrated intervention program with a follow-up of at least six months following reconstructive surgery may help develop and identify intervention guidelines and goals in the initial six months of treatment following neck dissection in oral cancer survivors. PMID- 29492350 TI - Scabies Surrepticius: Scabies Masquerading as Pityriasis Rosea. AB - Scabies, a mite infestation caused by 'Sarcoptes scabiei', most commonly presents as pruritic linear burrows where the mite has invaded the skin. Scabies variant such as bullous, crusted, hidden, incognito, nodular and scalp-mimic the other conditions. In addition, atypical presentations of scabies can masquerade as dermatitis herpetiformis, ecchymosis, Langerhans cell histiocytosis, systemic lupus erythematosus, urticaria, and urticaria pigmentosa. A 59-year-old male presented with non-pruritic papulosquamous plaques on his chest, abdomen, and back resembling lesions of pityriasis rosea in morphology and distribution. The complete cutaneous examination also demonstrated burrows on his finger webs. A mineral oil preparation of skin scrapings showed scabies mites, ova, and scybala. His infestation resolved after the treatment with topical permethrin 5% cream and oral ivermectin 15 mg on days one and eight. In conclusion, scabies surrepticius is a term that has recently been established to unify not only the numerous variants but also the atypical presentations of scabies. The inaccurate diagnosis of scabies infestation can lead to increased medical costs and the side effects of unnecessary tests and the treatment. Pityriasis rosea-like scabies can be added to the list of atypical presentations that are included under the unifying designation scabies surrepticius. PMID- 29492351 TI - Multilevel Contiguous Osteoporotic Lumbar Compression Fractures: The Relationship of Scoliosis to the Development of Cascading Fractures. AB - Osteoporotic patients can present with either single or multiple fractures secondary to repeated falls and progressive osteoporosis. Multiple fractures often lead to additional spinal deformity and are a sign of more severe osteoporosis. In the thoracic spine, multiple fractures are associated with the development of gradual thoracic kyphosis but neurologic deficits are uncommon. In the lumbar spine, patients with multiple lumbar fractures have more constant lumbar pain, may have symptoms related to concurrent lumbar stenosis or degenerative scoliosis, and may present with radiculopathy, especially with fractures at L4 and L5. In a review of a series of patients with recurrent multiple lumbar fractures or 'cascading' fractures, it was found that all the patients were female, had severe osteoporosis, often untreated, had a previous history of multiple previous thoracic and lumbar fractures, and all had associated scoliotic spinal deformities ranging from 6o to 50o. It was found that if the curve progressed and the greater the degree of curvature, the more frequently subsequent multiple fractures developed, leading to recurrent acute episodes of pain. Forty percent also had additional sacral insufficiency fractures, an unusually high percentage. Biomechanically, the lumbar spine is both more mobile and supports a larger portion of the spinal load compared to the thoracic spine. The existence or worsening of a lumbar spinal deformity from degenerative lumbar scoliosis shifts the mechanical forces more to one side on already weakened osteoporotic lumbar vertebrae and sacrum, leading to an increased incidence of these fractures. Because of the chronic and uneven lower lumbar spinal load with severe vertebral osteoporosis in certain patients with repeat lumbar fractures and worsening degenerative lumbar scoliosis, there may be a rationale to add preventive vertebroplasty at adjacent vertebral endplates when treating acute recurrent lumbar fractures to decrease the incidence of recurrence in other vertebrae. PMID- 29492352 TI - Life-Threatening Thrombocytopenia Secondary to Trimethoprim/Sulfamethoxazole. AB - Thrombocytopenia is an uncommon side effect of trimethoprim/sulfamethoxazole (TMP/SMX) when given in the usual recommended adult dosage. We report a case of severe and possibly life-threatening thrombocytopenia associated with TMP/SMX therapy. A 92-year-old female presented after a mechanical fall and subsequent intractable bleeding from a laceration on her left leg. She had a history of cellulitis of the lower extremities treated with a 10-day course of TMP/SMX. Her last dose was two days before the visit. The physical examination was significant for a small laceration on her left shin, with persistent oozing of blood. Her blood work was notable for white blood cells (WBC) 9.4*10^9/L (9.4*10^3/mm^3), hemoglobin 125g/L (12.5 g/dL) and platelets 5*10^9/L (5*10^3/mm^3). A repeat platelet count was 4*10^9/L. Prothrombin time was 11 seconds and the international normalized ratio (INR) was one. The TMP/SMX was discontinued and one unit of platelets was transfused. Her platelet count subsequently increased to 108*10^9/L. Severe thrombocytopenia with a platelet count of <=10*10^9/Lmay rarely result in the catastrophic spontaneous bleeding. Thus, low platelet counts associated with TMP/SMX carry potential life-threatening complications. The clinicians should be aware of this adverse effect of TMP/SMX, which appears to be dose/duration independent. We suggest careful monitoring of complete blood cell count, especially platelet count, before and during TMP/SMX therapy. PMID- 29492353 TI - The Importance of Writing and Publishing Case Reports During Medical Training. AB - Case reports are valuable resources of unusual information that may lead to new research and advances in clinical practice. Many journals and medical databases recognize the time-honored importance of case reports as a valuable source of new ideas and information in clinical medicine. There are published editorials available on the continued importance of open-access case reports in our modern information-flowing world. Writing case reports is an academic duty with an artistic element. Unfortunately, few physicians-in-training receive formal education on what constitutes a publishable case report. This article emphasizes that the medical education community, specially the graduate medical education community, should be aware of the importance of writing and publishing good quality case reports. PMID- 29492354 TI - Spectral Analysis Methods Based on Background Subtraction and Curvature Calculation Used in the Detection or Quantification of Hemolysis and Icterus in Blood-derived Clinical Samples. AB - Objective We aimed to find new methods to detect and quantify hemolysis and icterus which may cause assay biases. These methods need to determine each of these interferents in the presence of various other interferents. They also need to have less stringent requirements in development and implementation than those conventional analyzers currently must satisfy. Design and methods We developed two spectral analysis methods that obtain absorption signals of interest by background subtraction or by calculating the spectral curvatures near the peaks of interest. We optimized and tested the performance of these methods using a plasma sample set with permutations of the levels of hemolysis, icterus, and lipemia (using 510 samples in total). Results The processed signals correlated well with concentrations of hemoglobin and bilirubin, indicators of hemolysis and icterus, respectively. Through iterations of randomly splitting the samples for calibration and testing, the two new methods performed as well as those used on conventional analyzers. We demonstrated that the two methods can lessen the application requirements of 1) prior knowledge of the absorption spectra of individual interferents, 2) calibration over a wide concentration range for each interferent, and 3) the need for full-range spectrophotometers spanning most of the ultraviolet/visible spectrum. We also proposed a hardware setup to detect and quantify hemolysis or icterus with a camera and two optical filters. Conclusions This work indicates that new methods of spectral analysis can reduce practical constraints in the development of interference screening systems. These methods could also benefit other assays that rely on reading spectral signals. PMID- 29492355 TI - Efficacy of Stereotactic Radiosurgery in Patients with Multiple Metastases: Importance of Volume Rather Than Number of Lesions. AB - The role of stereotactic radiosurgery (SRS) in the treatment of multiple brain metastases is controversial. While whole brain radiation therapy (WBRT) has historically been the mainstay of treatment, its value is increasingly being questioned as emerging data supports that SRS alone can provide comparable therapeutic outcomes for limited (one to three) intracranial metastases with fewer adverse effects, including neurocognitive decline. Multiple recent studies have also demonstrated that patients with multiple (> 3) intracranial metastases with a low overall tumor volume have a favorable therapeutic response to SRS, with no significant difference compared to patients with limited metastases. Herein, we present a patient with previously controlled breast cancer who presented with multiple recurrences of intracranial metastases but low total intracranial tumor volume each time. This patient underwent SRS alone for a total of 40 metastatic lesions over three separate procedures with good local control and without any significant cognitive toxicity. The patient eventually opted for enrollment in the NRG-CC001 clinical trial after multiple cranial recurrences. She received conventional WBRT with six months of memantine and developed significant neurocognitive side effects. This case highlights the growing body of literature supporting the role of SRS alone in the management of multiple brain metastases and the importance of maximizing neurocognition as advances in systemic therapies prolong survival in Stage IV cancer. PMID- 29492356 TI - Streptococcus Pneumoniae Causing Intra-abdominal and Pelvic Infection: A Case Series. AB - Streptococcus pneumoniae is a pathogen known to cause pneumonia, sinusitis, meningitis, and otitis media, but is overlooked as a pathogen causing gastrointestinal illness. We report four cases of Streptococcus pneumoniae causing intra-abdominal and pelvic infection. Streptococcus pneumoniae should be considered in the setting of intra-abdominal infection, especially in patients with risk factors for invasive pneumococcal disease or with a concomitant respiratory infection at presentation. PMID- 29492357 TI - Adequate Neutrophil Responses and Non-Inferior Clinical Outcomes Can Be Achieved by a Two-Day Course of Low-Dose Filgrastim: A Retrospective Single Institution Experience. AB - Background Filgrastim is used in the setting of chemotherapy-induced neutropenia to stimulate recovery of bone marrow, which allows for further chemotherapy administration without delay. The recommended dose is 5 ug/kg. The commercially available vials of the drug come in two strengths; 300 ug and 480 ug. Due to these limitations in dosage formulations, it is a frequent occurrence to administer a lower dosage to patients weighing more than 60 kg, in whom the ideal dose would have been more than 300 ug but less than 480 ug. It is also a frequent practice to administer the drug for two consecutive days as it often leads to adequate response that will render patients eligible for their next cycle administration. Objective To determine whether a course of 300 ug of filgrastim administered daily for two consecutive days was as successful at reducing chemotherapy-induced neutropenia-related complications in patients with a higher weight (>60 kg) and hence receiving suboptimal dose as compared to those with weight less than 60 kg who are receiving the recommended dose. Methods We identified 91 patients from our facility with chemotherapy-induced neutropenia treated with 300 ug of filgrastim daily for two consecutive days, and we separated them into low, medium, and high weight groups. Multivariate logistic regression models examined correlations between outcomes (e.g., increases in absolute neutrophil count) and predictors (e.g., weight groups). Results The vast majority of encounters demonstrated rises in white blood cell (WBC) and absolute neutrophil count (ANC). Infection rates were not significantly different between low and medium weight groups (5% vs 0%; p = 0.1658), but the high weight group's infection rate was significantly higher than the medium weight group (5% vs 33%; p = 0.001). The high weight group did have an increased rate of febrile neutropenia as compared to medium and low weight groups, but these differences were not significant. Incidences of chemotherapy delay and dose reduction were comparable across the three weight groups. Limitations Retrospective study, small sample size, heterogeneous cancer sites and different chemotherapy regimens administered limit generalizability of findings. Conclusion Patients with weights <85 kg receiving a two-day course of 300 ug of filgrastim have similar neutropenia-related complication rates with a potential percent cost-savings of roughly 43%. PMID- 29492358 TI - Culture Shift: Building an Awareness of Our Mortality. AB - The end of life discussions can often be difficult for a multitude of reasons. Our culture is pervasive with ideas of mortality, and that medicine can avert this human constant. Medicine, as a field, must embrace our limitations so that we can engage in honest discussions with the families and the patients regarding the end of life care. PMID- 29492359 TI - Excellent Outcomes in a Geriatric Patient with Multiple Brain Metastases Undergoing Surgical Resection with Cesium-131 Implantation and Stereotactic Radiosurgery. AB - Stereotactic radiosurgery (SRS) is a minimally invasive, focal treatment option for brain metastases. Multiple studies support its use in various settings as an effective, comparable alternative to surgery and whole-brain radiation therapy (WBRT). Here, we present excellent outcomes in a 90-year-old patient who underwent SRS after initially presenting at age 84 with multiple brain metastases of an unknown primary, as well as undergoing SRS to a site of tumor recurrence that was initially treated with surgical resection and intraoperative cesium-131 (Cs-131) brachytherapy. To our knowledge, this is one of the first reports describing the effective use of both intraoperative brachytherapy and SRS in the management of multiple brain metastases. PMID- 29492360 TI - Developing a Knowledge Test for a Neonatal Ethics Teaching Program. AB - Objective The innovative Neonatal-Perinatal Medicine (NPM) Ethics Teaching Program at the University of Ottawa provides NPM trainees with vital foundational knowledge required to manage ethically contentious clinical scenarios frequently encountered in practice. In this study, our aim was to develop a knowledge test to assess the impact of the NPM Ethics Teaching Program on trainees' knowledge about ethics. Study design Using an iterative four-step process, we developed a test for assessing pre- and post-training knowledge of NPM ethics. We first created a blueprint of the test, identifying its purpose, length, and format. We then weighted the learning outcomes of the NPM Ethics Teaching Program sessions to determine the number of questions that would be asked to assess to each learning outcome. Next, we populated the question bank and constructed a draft test. We obtained feedback from content experts on the draft test and piloted the draft test with former trainees from the NPM Ethics Teaching Program. Results We developed a pre- and post-knowledge test in NPM ethics consisting of 44 multiple choice questions (MCQs), each with five response options. The test takes approximately 60 minutes to complete. It took roughly 15 months to design and pilot the NPM ethics test. Conclusions This test can aid in the assessment of the amount of NPM ethics gained by trainees and contribute to the identification of areas for improvement in teaching and in the overall ethics program. Further iterations of the test will allow for additional assessment of its validity and the efficacy of the teaching program. Given the lack of structured evaluative ethics teaching programs in NPM nationally, this project will act as another step towards the introduction of our NPM Ethics Teaching Program to other Canadian NPM residencies. PMID- 29492361 TI - Non-Islet Cell Tumor Hypoglycemia: A Rare Cause of Hypoglycemia in Pulmonary Sarcomatoid Cancer. AB - Non-islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic condition caused most commonly by metastatic mesenchymal tumors. A 74-year-old non-diabetic male with an eight-year history of metastatic sarcomatoid lung cancer presented with altered mental status. His previous treatment included a lobectomy and radiation. Laboratory investigations were significant for blood glucose of 28 mg/dL, confirming hypoglycemia. He was hypokalemic, a condition seen in approximately 50% of patients with NICTH, at 2.8 mEq/L of potassium (normal 3.5 5.2 mEq/dL) and his urine toxicology screen was negative. A computed tomography (CT) of the head was negative for any acute events. His tumor burden had progressed as compared to previous CTs. Administration of dextrose resolved his symptoms. Laboratory studies during subsequent hypoglycemic events measured his insulin-like growth factor-I (IGF-I) at 51 ng/mL, insulin-like growth factor-II (IGF-II) at 290 ng/mL, growth hormone (GH) at 0.6 ng/mL, C-peptide at 0.16 ng/mL (low), and insulin levels at <1 uIU/mL. 'Big' IGF-II, the gold standard for the diagnosis of NICTH, was not available at our facility. Based on these results, NITCH was diagnosed clinically. NICTH is a rare condition with episodes of recurrent hypoglycemic episodes in the setting of metastatic cancer. Ideal therapy for NICTH is tumor resection or debulking. In cases of inoperable tumors, glucocorticoids or recombinant human growth hormone (rGH) maintain euglycemia, with glucagon rescue in case of an emergency. PMID- 29492362 TI - Clozapine: Improvement of Negative Symptoms of Schizophrenia. AB - We report five cases of treatment-resistant schizophrenia that presented with prominent negative and positive symptoms. They fulfill the criteria of diagnosis of schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5). They showed lack of response despite receiving multiple trials of first and second generation psychotropic agents. We decided to give these patients a trial of clozapine to improve their negative and positive symptoms as well as their quality of life. The patients showed various responses to the treatment. Two patients had a robust response to clozapine, two had a moderate response, and treatment was discontinued for one patient due to a side effect of eosinophilia with clozapine, with an eosinophil count increased to 40,000/mm3 (40%). Clozapine has been established to be more beneficial than conventional antipsychotics in patients with treatment-resistant schizophrenia and apparently more useful, based on existing evidence, in managing the negative symptoms of schizophrenia. We suspect that the improvement in negative symptoms will be associated with an improvement in positive symptoms as well as the compound has a direct action on neuronal pathways responsible for the negative symptoms. Five treatment-refractory schizophrenic patients were given a trial of clozapine for 24 weeks and observed. Overall, two patients showed modest improvement in psychotic and negative symptoms including insight and judgment improvement in disorganization. Two patients demonstrated robust response with significant improvement in negative symptoms including insight, judgment, affect, avolition, and disorganization and also an improvement in psychotic symptoms. We monitored complete blood chemistry (CBC) including the absolute neutrophil count on a weekly basis. Before initiation of the treatment, four patients had all the routine labs performed including glycated hemoglobin (HbA1C), thyroid panel, CBC, comprehensive metabolic panel and fasting lipid profile; all were within normal reference ranges. One patient had type 2 diabetes mellitus (DM) for the past eight years, and his HbA1c was 6.7; that remained stable through the treatment. We managed the symptoms of his type 2 DM with oral hypoglycemic agents and long acting insulin to control blood sugar and performed a yearly urine analysis for proteinuria to monitor organ damage. His other routine labs were within normal range. PMID- 29492363 TI - The Case of an Obstructed Stone at the Distal Urethra. AB - This report highlights a presentation of urinary calculus impacted at the urethral meatus and bedside extraction after evaluation with point-of-care ultrasound (POCUS). Visualization of a stone at the urethral meatus prompted a point-of-care ultrasound of the penile shaft and glans. The ultrasound ruled out anatomic variations such as urethral diverticula and as a result bedside removal was expedited. The stone was successfully removed with traction and intraurethral lidocaine gel without urethral lesions or injury to the meatus. Bedside ultrasound is readily available in the emergency department and can be used to characterize urethral foreign bodies, evaluate urethral anatomy, and assess the likelihood of bedside removal. PMID- 29492364 TI - Spontaneous Rupture of a Hepatic Adenoma: Diagnostic Nuances and the Necessity of Followup. AB - We present the case of a young female on oral contraceptives (OCs) who was diagnosed with focal nodular hyperplasia (FNH) and remained on oral contraceptives. Months later, the patient presented with acute abdominal pain and intratumoral hemorrhage in the liver. The patient was taken to the operating room (OR) and was diagnosed with a ruptured hepatic adenoma (HA). We review the key diagnostic features of FNH and HA, the different management guidelines including use of OCs, and potential surgical indications. HA compared to FNH has a significantly higher rate of sequelae despite being a benign lesion, thus providers must accurately distinguish between the two diagnoses to prevent potential morbidity and mortality. PMID- 29492365 TI - Cryptic but Deadly: A Serious Killer in Patients with Advanced Liver Disease that Should Not Be Missed. AB - Cryptococcal peritonitis is an under-recognized disease that is an important cause of mortality in end-stage liver disease. We report a 43-year old male with decompensated cirrhosis secondary to refractory autoimmune hepatitis on immunosuppression with hepatocellular carcinoma who developed cryptococcal peritonitis. The patient subsequently developed ischemic bowel and multisystem organ failure secondary to abdominal compartment syndrome, leading to rapid deterioration and death. Frequently, these patients experience delays in diagnosis and treatment, which leads to a rapid and high mortality. This case report synthesizes data regarding the optimal approach for screening and managing patients with cryptococcal peritonitis and proposes a pathogenic mechanism of mortality with implications for improved treatment in the future. PMID- 29492367 TI - Isolated Homocysteinemia Leading to Thromboembolism in Young Male with Normal Vitamin B12 and Folate Levels. AB - Pulmonary embolism (PE) with isolated homocysteinemia is a rare disease. The diagnosis demands a proper clinical workup. Timely diagnosis can prevent complications and provide a better quality of life for the patient. We present a young man with homocysteinemia with deep vein thrombosis (DVT), pulmonary embolism, and normal vitamin B12 and folate levels despite being treated with rivaroxaban. PMID- 29492366 TI - Association of Psychiatric Illness or Psychotropic Medication Usage with Calcaneus Fracture. AB - Background There is a noticeable lack of studies examining the connection between psychiatric illness and orthopaedic injury. The goal of this study is to determine if a relationship exists between calcaneus fracture and psychiatric illness or use of psychotropic medication. Methods A retrospective review was undertaken of calcaneus fracture patients at our institution from January 2011 through January 2014, and those with a diagnosis of psychiatric illness or history of psychotropic medication usage were identified. Medication records were analyzed along with medical histories taken during the initial encounter. If the patient was admitted, hospital notes for the hospitalization were reviewed to determine if any information was missed during the initial encounter. The date of injury, age, sex, insurance status at the time of initial encounter, psychiatric diagnoses or psychotropic medication use, and mechanism of injury were recorded. Any specific psychiatric diagnoses were collected from the patient charts, as was the presence of any specific prescribed psychotropic medications. After completion of the data collection, an attending psychiatrist verified the recorded data to ensure an accurate psychiatric assessment. Results A total of 85 calcaneus fractures met the inclusion criteria. In the population, there were 71 males and 14 females. The average age of the patients was 41.74 years, with 24% of patients having a diagnosis of psychiatric illness at the time of injury. The relative risk of a psychiatric illness in males compared to females was 0.31 (p = 0.009) while the relative risk of using psychotropic medication in males compared to females was 0.17 (p = 0.0007). Males were less likely to undergo operative intervention than females (p = 0.0001). The average age of a patient who either had a diagnosis or took medication for a psychiatric illness was 48.4 years, as compared to 39.7 years in those who did not (p = 0.014). Conclusion Males were less likely to have a psychiatric illness or be currently treated with psychotropic medications. A dedicated review of psychiatric history and prior medication may be useful during preoperative, perioperative, and postoperative treatment planning. Level of Clinical Evidence: 4. PMID- 29492368 TI - An Excellent Clinical Outcome with Stereotactic Radiosurgery in a Geriatric Patient with Multiple and Recurrent Brain Metastases. AB - The incidence of brain metastases range from 10 to 20% of all adult patients with cancer and lung cancer is associated with one of the highest incidences of brain metastases. In geriatric patients, who already have limited cognitive function, whole brain radiation therapy (WBRT) can be a problem. Stereotactic radiosurgery (SRS) is a one day, outpatient treatment with minimal effect to normal brain and could particularly be useful in elderly patients. We report the case of a geriatric patient with metastatic lung adenocarcinoma who had multiple brain metastases and recurrences, who responded well to the stereotactic radiosurgery (six sessions) with acceptable tumor control. PMID- 29492369 TI - Two-year Outcomes from a Single Surgeon's Learning Curve Experience of Oblique Lateral Interbody Fusion without Intraoperative Neuromonitoring. AB - Introduction Oblique lumbar interbody fusion (OLIF) is a newer procedure that avoids the psoas and lumbosacral plexus due to its oblique trajectory into the retroperitoneal space. While early experience with OLIF is reassuring, the longer term clinical efficacy has not been well established. The purpose of this study was to describe two-year clinical outcomes with OLIF performed by a single surgeon during the learning curve without the aid of the neuromonitoring. Materials and methods Chart review was performed for the consecutive patients who underwent OLIF by a single surgeon. Back pain severity on a visual analog scale (VAS) and Oswestry Disability Index (ODI) were collected preoperatively and postoperatively at six weeks, three months, six months, one year and two years. Results A total of 21 patients (38 levels) were included in this study. The indications for surgery were degenerative disc disease (n=10, 47.6%), spondylolisthesis (n=9, 42.9%) and spinal stenosis (n=6, 28.6%). The median operating room time was 351 minutes (interquartile range (IQR): 279-406 minutes), blood loss was 40 ml (IQR: 30-150 ml), and hospital stay was 2.0 days (IQR: 1.0 3.5 days). The complication rate was 9.5%, both venous injuries. There were no other perioperative complications. Back pain severity decreased by 70%, on average, over two years (p <0.001). A total of 17 (81%) patients reported at least a two-point decrease from the baseline. The ODI scores decreased by 55%, on average, over two years (p <0.001), with 16 (76%) patients reporting at least a 15-point decrease from the baseline. Over two years, no symptomatic pseudarthrosis, hardware failure, reoperations, or additional complications were reported. Conclusions The oblique lateral interbody fusion performed without the intraoperative neuromonitoring was safe and clinically efficacious for up to two years. The complication rate in this cohort is similar to other published OLIF series and appears acceptable when compared to the lateral lumbar interbody fusion (LLIF) and the anterior lumbar interbody fusion (ALIF). No motor or sensory deficits were observed in this study, supporting the premise that the neuromonitoring is unnecessary in OLIF. PMID- 29492370 TI - Diatoms as an indicator for tile drainage flow in a German lowland catchment. AB - Background: The separation of runoff components within a model simulation is of great importance for a successful implementation of management measures. Diatoms could be a promising indicator for tile drainage flow due to their diverse preferences to different aquatic habitats. In this study, we collected diatom samples of 9 sites (4 tile drainage, TD, and 5 river sites, Ri) in a German lowland catchment at a weekly or biweekly time step from March to July 2013 with the aim of testing the suitability of diatoms for tile drainage flow, which is typical for lowland catchment. Results: Planothidium lanceolatum, Ulnaria biceps, and Navicula gregaria dominated in TD sites with relative abundances of 22.2, 21.5, and 10.9%, respectively. For Ri sites, the most abundant species was Navicula lanceolata (20.5%), followed by Ulnaria biceps (12.9%), Cyclotella meneghiniana (9.5%), and Planothidium lanceolatum (9.3%). Compared with Ri sites, TD had a lower diatom density, biomass, species richness, and percentage of Aquatic/Riparian diatoms (AqRi%). However, the proportion of Riparian diatoms (RiZo%) increased at TD. Indicator value method (IndVal) revealed that the two groups (Ri and TD) were characterized by different indicator species. Fifteen taxa, including Cocconeis placentula, Cyclotella meneghiniana, N. lanceolata, and U. biceps, were significant indicators for Ri sites. Planothidium lanceolatum, Achnanthidium minutissimum, and Navicula gregaria were significant indicators for TD sites. Conclusion: A pronounced variation was found in the species lists of diatom community between Ri and TD water body types associated with different indicator species. With respect to hydrograph separation, these findings highlight the suitability of diatoms as an indicator for tile drainage flow. However, spatial and temporal variations of diatoms should be considered in future surveys. PMID- 29492371 TI - Optimization of extraction parameters of pentacyclic triterpenoids from Swertia chirata stem using response surface methodology. AB - In the present investigation, pentacyclic triterpenoids were extracted from different parts of Swertia chirata by solid-liquid reflux extraction methods. The total pentacyclic triterpenoids (UA, OA, and BA) in extracted samples were determined by HPTLC method. Preliminary studies showed that stem part contains the maximum pentacyclic triterpenoid and was chosen for further studies. Response surface methodology (RSM) has been employed successfully by solid-liquid reflux extraction methods for the optimization of different extraction variables viz., temperature (X1 35-70 degrees C), extraction time (X2 30-60 min), solvent composition (X3 20-80%), solvent-to-solid ratio (X4 30-60 mlg-1), and particle size (X5 3-6 mm) on maximum recovery of triterpenoid from stem parts of Swertia chirata. A Plackett-Burman design has been used initially to screen out the three extraction factors viz., particle size, temperature, and solvent composition on yield of triterpenoid. Moreover, central composite design (CCD) was implemented to optimize the significant extraction parameters for maximum triterpenoid yield. Three extraction parameters viz., mean particle size (3 mm), temperature (65 degrees C), and methanol-ethyl acetate solvent composition (45%) can be considered as significant for the better yield of triterpenoid A second-order polynomial model satisfactorily fitted the experimental data with the R2 values of 0.98 for the triterpenoid yield (p < 0.001), implying good agreement between the experimental triterpenoid yield (3.71%) to the predicted value (3.79%). PMID- 29492373 TI - Indigenous plant growth-promoting bacteria enhance plant growth, biomass, and nutrient uptake in degraded forest plants. AB - The present study was aimed to isolate indigenous plant growth-promoting bacteria (PGPB) from Nanmangalam reserve forest, India and to analyze their positive impact on nursery plant species. In total, 160 isolates were obtained from different nitrogen-free Media (LGI, JMV, NFB). Amongst these, 12 isolates were shown positive for 5-8% of ammonia production nif H positive and then isolates were further tested for their plant growth-promoting (PGP) activity. Based on their PGP activity, nine isolates were selected, and applied in nurseries of twelve native plant species, along with organic manure and inorganic fertilizer. All the isolates were shown positive effects when compared to control. In that, five of these bacterial isolates, Paenibacillus sp. RRB2, Azospirillum brasilense RRAK5, Bacillus subtilis subsp. subtilis RRD8, Burholdria kururiensis RRAK1, and Pseudomonas stutzeri RRAN2, enhanced biomass production in several trees. PMID- 29492372 TI - The use of Agrobacterium-mediated insertional mutagenesis sequencing to identify novel genes of Humicola insolens involved in cellulase production. AB - A transfer DNA (T-DNA)-tagged mutant library of Humicola insolens was screened for mutants with altered cellulase production using the plate-clearing zone assay. Three selected mutants (5-A7, 5-C6, and 13-B7) exhibited significantly depressed FPase, CMCase and xylanase activities compared with the wild-type strain upon shake-flask fermentation, while the pNPCase and pNPGase activities of the three mutants were relatively higher than those of the parental strain. Combined with the results of SDS-PAGE and mass spectrometry, we suggest that expression of the CMCases Cel6B, Cel7B, CMC3, and XynA/B/C was reduced in the mutant strains. Twelve putative T-DNA insertion sites were identified in the three mutants via Agrobacterium-mediated insertional mutagenesis sequencing (AIM Seq). Bioinformatics analysis suggested that a putative dolichyl pyrophosphate phosphatase, two hypothetical proteins encoding genes of unknown function, and/or nine intergenic fragments may be involved in cellulase and hemicellulase production by H. insolens. This provides promising new candidate genes relevant to cellulase production by the fungus, which will be crucial not only for our understanding of the molecular mechanism underlying cellulase production, but also for strain improvement. PMID- 29492374 TI - Surface functionalization dependent subcellular localization of Superparamagnetic nanoparticle in plasma membrane and endosome. AB - In this article, we elaborate the application of thermal decomposition based synthesis of Fe3O4 superparamagnetic nanoparticle (SPMNP) in subcellular fractionation context. Here, we performed surface functionalization of SPMNP with phospholipids and dimercaptosuccinic acid. Surprisingly, we observed surface functionalization dependent SPMNP localization in subcellular compartments such as plasma membrane, endosomes and lysosomes. By using SPMNP based subcellular localization with pulse-chase methodology, we could use SPMNP for high pure-high yield organelle (plasma membrane, endosomes and lysosome) fractionation. Further, SPMNP that are distinctly localized in subcellular compartments can be used as technology for subcellular fractionation that can complement existing tools for cell biology research. As a future perspective, isolated magnetic organelles can be extended to protein/protein complex purification for biochemical and structural biology studies. PMID- 29492375 TI - Is a matrix exponential specification suitable for the modeling of spatial correlation structures? AB - This paper investigates the adequacy of the matrix exponential spatial specifications (MESS) as an alternative to the widely used spatial autoregressive models (SAR). To provide as complete a picture as possible, we extend the analysis to all the main spatial models governed by matrix exponentials comparing them with their spatial autoregressive counterparts. We propose a new implementation of Bayesian parameter estimation for the MESS model with vague prior distributions, which is shown to be precise and computationally efficient. Our implementations also account for spatially lagged regressors. We further allow for location-specific heterogeneity, which we model by including spatial splines. We conclude by comparing the performances of the different model specifications in applications to a real data set and by running simulations. Both the applications and the simulations suggest that the spatial splines are a flexible and efficient way to account for spatial heterogeneities governed by unknown mechanisms. PMID- 29492377 TI - Guest Editor Introduction. PMID- 29492376 TI - Practical application of spatial ecosystem service models to aid decision support. AB - Ecosystem service (ES) spatial modelling is a key component of the integrated assessments designed to support policies and management practices aiming at environmental sustainability. ESTIMAP ("Ecosystem Service Mapping Tool") is a collection of spatially explicit models, originally developed to support policies at a European scale. We based our analysis on 10 case studies, and 3 ES models. Each case study applied at least one model at a local scale. We analyzed the applications with respect to: the adaptation process; the "precision differential" which we define as the variation generated in the model between the degree of spatial variation within the spatial distribution of ES and what the model captures; the stakeholders' opinions on the usefulness of models. We propose a protocol for adapting ESTIMAP to the local conditions. We present the precision differential as a means of assessing how the type of model and level of model adaptation generate variation among model outputs. We then present the opinion of stakeholders; that in general considered the approach useful for stimulating discussion and supporting communication. Major constraints identified were the lack of spatial data with sufficient level of detail, and the level of expertise needed to set up and compute the models. PMID- 29492378 TI - Back to the future. PMID- 29492379 TI - Heart transplantation versus left ventricular assist devices as destination therapy or bridge to transplantation for 1-year mortality: a systematic review and meta-analysis. AB - Background: The optimal treatment for advanced heart failure (HF) patients with regards to mortality remains unknown. Heart transplantation (HTx) and left ventricular assist devices (LVAD) used either as a bridge to transplant (BTT) or destination therapy (DT) have been compared in a number of studies, without definite conclusions with regards to mortality benefit. We sought to systematically review the pertinent literature and perform a meta-analysis of all the available studies presenting head-to-head comparisons between HTx and LVAD BTT or LVAD DT for late (>6 months) all-cause mortality. Methods: We performed a systematic search of Medline and Cochrane Central databases in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We conducted a meta-analysis of late mortality comparing HTx vs. BTT LVAD and HTx vs. DT LVAD using a random effects model. Results: Eight studies were included in our meta-analysis, reporting data on 7,957 patients in total. Although the available studies are of high quality [8 stars in Newcastle-Ottawa Scale (NOS) on average], there is paucity of mortality data. Specifically, seven studies compared HTx with BTT and five studies compared HTx with DT for 1-year mortality. Our pooled estimates showed that there was no difference in late mortality among these strategies. Conclusions: Our meta-analysis highlights the small number and the heterogeneity of available studies referring to the optimal invasive management of advanced HF, and shows that there are no differences between HTx and LVAD for these patients with regards to late mortality. PMID- 29492380 TI - Outcomes and survival following heart retransplantation for cardiac allograft failure: a systematic review and meta-analysis. AB - Background: Long-term efficacy of heart retransplantation (RTx) for end-stage cardiac allograft failure remains unclear given the limited worldwide experience and is an important question to elucidate given the shortage of donor organs. The aim of this systematic review was to examine the outcomes of RTx in patients with cardiac allograft failure. Methods: Electronic search was performed to identify all studies in the English literature assessing RTx for cardiac allograft failure. All identified articles were systematically assessed for inclusion and exclusion criteria. Results: Eleven studies were included for analysis, with a total of 7,791 patients. A total of 7,446 patients underwent primary heart transplantation (HTx) whereas 345 patients underwent RTx with average time from primary HTx to RTx interval of 5.03 years (95% CI: 3.13-6.94 years). There were 35.2% of patients received RTx within 30 days of primary transplant. Early mortality was significantly higher among RTx patients (RTx 28.2% vs. HTx 11.2%, P<0.001) whereas survival was significantly higher among HTx patients when compared to RTx patients at 1 year (HTx 81.8% vs. RTx 59.1%, P<0.001), 2 years (HTx 77.9% vs. RTx 53.6%, P<0.001), 3 years (HTx 76.1% vs. RTx 49.8%, P<0.001), 5 years (HTx 68.8% vs. RTx 41.4%, P<0.001) and 10 years (HTx 53.9% vs. RTx 31.7%, P<0.001). There were no significant differences between HTx and RTx in terms of freedom from rejection at 1 year (HTx 61.0% vs. RTx 53.7%, P=0.43), 2 years (HTx 63.8% vs. RTx 53.7%, P=0.26), 3 years (HTx 62.9% vs. RTx 51.9%, P=0.30) and 5 years (HTx 61.0% vs. RTx 51.9%, P=0.36). Conclusions: Patients who underwent heart RTx had a significant lower survival when compared to those who only underwent primary HTx. There were no significant differences in post transplantation freedom from rejection. Careful patient selection and perioperative care can make heart RTx a viable option for selected recipients. PMID- 29492381 TI - Percutaneous coronary intervention versus coronary artery bypass grafting in heart transplant recipients with coronary allograft vasculopathy: a systematic review and meta-analysis of 1,520 patients. AB - Background: Transplant coronary artery vasculopathy (TCAV) is the major cause of late allograft failure and death in heart transplant recipients. The aim of this systematic review was to examine the outcomes of percutaneous coronary interventions (PCIs) as compared to coronary artery bypass grafting (CABG) surgery in the management of TCAV. Our secondary objective was to compare the use and outcomes of drug eluting stents (DES) as compared to bare metal stents (BMS) in this patient population. Methods: Electronic search was performed to identify all studies in the English literature examining PCI as compared to CABG for TCAV in heart transplant recipients. All identified articles were systematically assessed for inclusion and exclusion criteria. Results: Of the 4,989 studies identified, 29 studies were included. Among 1,520 patients who developed TCAV, 1,470 patients underwent PCI and 50 patients underwent CABG. There were no significant differences in baseline demographics and comorbidities among the PCI and CABG cohorts. Compared to the PCI cohort, patients who underwent CABG had a higher early mortality (CABG 36.4% vs. PCI 4.3%, P<0.001) and overall mortality (CABG 42.3% vs. PCI 21.4%, P=0.049). When comparing DES versus BMS cohorts, there were no significant differences in the rate of in-stent stenosis (DES 14.5% vs. BMS 24.4%, P=0.476), overall mortality (DES 17.4% vs. BMS 30.8%, P=0.302) or cardiac related mortality (DES 7.7% vs. BMS 21.8%, P=0.415). Conclusions: CABG and PCI are both feasible modalities for revascularization in patients with TCAV where PCI is associated with lower mortality. There were no differences in outcomes among patients who underwent PCI with DES as compared to BMS. Potential bias may exist due to heterogeneity in available data. Further studies are needed to delineate evidence-based guidelines to tailor the appropriate therapy, CABG or PCI, to the appropriate patient. PMID- 29492382 TI - Current state of pediatric cardiac transplantation. AB - Pediatric heart transplantation is standard of care for children with end-stage heart failure. The diverse age range, diagnoses, and practice variations continue to challenge the development of evidence-based practices and new technologies. Outcomes in the most recent era are excellent, especially with the more widespread use of ventricular assist devices (VADs). Waitlist mortality remains high and knowledge of risk factors for death while waiting and following transplantation contributes to decision-making around transplant candidacy and timing of listing. The biggest gap impacting both waitlist and overall survival remains mechanical support options for infants and patients with single ventricle physiology. Though acute rejection has decreased progressively, both diagnosis and management of antibody-mediated rejection has become increasingly challenging and complex, as has the ability to understand the implication of anti-HLA antibodies detected both pre- and post-transplantation-including when and how to intervene. Trends in immunosuppression protocols include more use of induction therapy and steroid avoidance or withdrawal protocols. Common long-term morbidities include renal insufficiency, which can be mitigated with surveillance and renal-sparing strategies, and infections. Functional outcomes are excellent, but significant psychosocial challenges exist in relation to neurodevelopment, non-adherence, and transition from child-centered to adult-centered care. Cardiac allograft vasculopathy (CAV) remains a barrier to long-term survival, though it is more apparent that objective evidence of an impact on the allograft is important with regards to impact on outcomes. Retransplantation is rare in pediatric heart transplant recipients. Pediatric heart transplantation continues to evolve in order to address the challenges of the diverse group of patients that reach end-stage heart failure during childhood. PMID- 29492384 TI - Current approaches in retrieval and heart preservation. AB - Fifty years after the first successful heart transplantation, despite multiple advances in the treatment of advanced acute and chronic heart failure, there is still no equivalent to heart transplantation as a long-term treatment for end stage heart failure. Transplantation is, however, limited by the scarcity and quality of heart allografts. Donors are nowadays significantly older, particularly in European countries, and traumatic head injury as the cause of death has been replaced by intracerebral hemorrhage or hypoxic brain damage in the majority of cases. In addition, many donors have undergone extensive resuscitation efforts. Recipient characteristics have progressively changed too within the last couple of decades; recipients are older, often with comorbidities and nearly half of them are bridged to transplant with a wide variety of mechanical circulatory support devices. These developments have resulted in heart transplant surgery becoming significantly more challenging with longer more complex surgery and increased ischemia times for organs that were previously considered to be borderline or non-transplantable in many cases. To address this, several options have been explored within the last years and as a result, novel strategies have been developed and tested in order to optimize graft preservation and potentially increase the donor pool. The two notable developments are the ability to procure hearts from donors after circulatory death and the advent of ex-vivo perfusion of hearts. This technology has made the transplantation of extended criteria organs, including those from circulatory determined death (DCD) donors possible, and allow for out of body time of more than 12 hours in heart transplantation. In this review, we set out the basis of the current practices in organ procurement, and the opportunities for the future as demands for organ transplantation continue to increase. PMID- 29492383 TI - Current indications for transplantation: stratification of severe heart failure and shared decision-making. AB - Heart failure (HF) is a complex clinical syndrome that results from structural or functional cardiovascular disorders causing a mismatch between demand and supply of oxygenated blood and consecutive failure of the body's organs. For those patients with stage D HF, advanced therapies, such as mechanical circulatory support (MCS) or heart transplantation (HTx), are potentially life-saving options. The role of risk stratification of patients with stage D HF in a value based healthcare framework is to predict which subset might benefit from advanced HF (AdHF) therapies, to improve outcomes related to the individual patient including mortality, morbidity and patient experience as well as to optimize health care delivery system outcomes such as cost-effectiveness. Risk stratification and subsequent outcome prediction as well as therapeutic recommendation-making need to be based on the comparative survival benefit rationale. A robust model needs to (I) have the power to discriminate (i.e., to correctly risk stratify patients); (II) calibrate (i.e., to show agreement between the predicted and observed risk); (III) to be applicable to the general population; and (IV) provide good external validation. The Seattle Heart Failure Model (SHFM) and the Heart Failure Survival Score (HFSS) are two of the most widely utilized scores. However, outcomes for patients with HF are highly variable which make clinical predictions challenging. Despite our clinical expertise and current prediction tools, the best short- and long-term survival for the individual patient, particularly the sickest patient, is not easy to identify because among the most severely ill, elderly and frail patients, most preoperative prediction tools have the tendency to be imprecise in estimating risk. They should be used as a guide in a clinical encounter grounded in a culture of shared decision-making, with the expert healthcare professional team as consultants and the patient as an empowered decision-maker in a trustful safe therapeutic relationship. PMID- 29492385 TI - Heart transplantation from donation after circulatory determined death. AB - Fifty years since the first successful human heart transplant from a non-heart beating donor, this concept of heart transplantation from donation after circulatory determined death (DCD) promises to be one of the most exciting developments in heart transplantation. Heart transplantation has established itself as the best therapeutic option for patients with end-stage heart failure, with the opportunity to provide these patients with a near-normal quality of life. However, this treatment is severely limited by the availability of suitable donor hearts. In recent times, heart transplantation has been limited to using donor hearts from donors following brain stem death. The use of donor hearts from DCD had been thought to be associated with high risk and poor outcomes until recent developments in organ perfusion and retrieval techniques have shown that this valuable resource may provide an answer to the global shortage of suitable donor hearts. With established DCD heart transplant programmes reporting encouraging results, this technique has been shown to be comparable to the current gold standard of donation after brain death (DBD) heart transplantation. PMID- 29492386 TI - Role of paediatric assist device in bridge to transplant. AB - Background: While heart transplantation has gained recognition as the gold standard therapy for advanced heart failure, the scarcity of donor organs has become an important concern. The evolution of surgical alternatives such as ventricular assist devices (VADs), allow for recovery of the myocardium and ensure patient survival until heart transplantation becomes possible. This report elaborates the role of VADs as a bridge to heart transplantation in infants and children (<=18 years old) with end-stage heart failure. Methods: A retrospective review of the medical records of 201 heart transplant recipients between May 1986 and September 2014 identified 78 children [38.8%; mean age 7.2 (7.8+/-6.0) years old; IQR: 2.6-11.8 years] with advanced heart failure who were supported with a VAD [left VAD (LVAD) =21; biventricular VAD (BVAD) =57] as a bridge to heart transplantation. Fourteen (17.9%) patients were less than 1 year old; 15 (19.2%) children had a cardiac arrest and underwent cardiopulmonary resuscitation, with 7 of these patients also requiring extracorporeal membrane oxygenation (ECMO) support prior to implantation of a VAD. The aetiology of heart failure was primarily cardiomyopathy (dilative, restrictive from endocardial fibrosis, idiopathic or toxic-induced), reported in 56 (71.8%) patients. The VADs employed were primarily Berlin Heart EXCOR(r) (n=63), HeartWare (n=13), Berlin Heart INCOR(r) (n=1), and Toyobo (n=1). Results: Mean duration of VAD support was 59 (133.37+/-191.57) days (range, 1-945 days; IQR: 23-133 days) before a donor heart became available. The primary complication encountered while patients were being bridged to transplant was mediastinal bleeding (7.8%). The main indication for pump exchanges was thrombus formation in the valves. There was no incidence of technical failure of the blood pump or driving system components. Skin infections around the cannulae occurred in 2.5%. Adverse neurological symptoms (thromboembolism 11.1%, cerebral haemorrhage 3.6%) that occurred did not have any permanent neurological sequelae that could be detected on clinical examination in this study. Mean duration of follow-up was 9.4 (10.3+/-7.6) years (IQR: 3.74 15.14 years). Cumulative survival rates of patients bridged to transplantation with VAD were 93.6%+/-2.8%, 84.6%+/-4.1%, 79.1%+/-4.7%, 63.8%+/-6.2%, 61.6%+/ 7.1%, and 52.1%+/-9.3% at 30 days, 1, 5, 10, 15 and 20 years, respectively. There was no statistically significant difference (P=0.79) in survival rates of patients bridged to heart transplantation with VAD compared to those who underwent primary heart transplantation. Post-transplant survival rates stratified according to the type of VAD implanted and number of ventricles supported were not statistically different (P=0.93 and 0.73, respectively). In addition, post-transplant survival rates were not significantly different when age, gender and diagnosis were adjusted for. Furthermore, no statistically significant difference was found when post-transplant survival rates of children who had episodes of rejection were compared to those who did not have episodes of rejection. Conclusions: The results in this series demonstrate that VADs satisfactorily support paediatric patients with advanced heart failure from a variety of aetiologies until heart transplantation. The data further suggests that patients bridged with VADs have comparable long-term post-transplant survival as those undergoing primary heart transplantation. PMID- 29492387 TI - The cardioprotective effect of interleukin-11 against ischemia-reperfusion injury in a heart donor model. AB - Background: Previously, we have demonstrated the cardioprotective effect of interleukin (IL)-11 in animal models of acute coronary syndrome. In this study, we sought to evaluate its cardioprotective potential during prolonged hypothermic global ischemia and subsequent reperfusion using a rat heart donor model. Methods: IL-11 was administered intravenously 10 minutes before harvesting the rat heart. The hearts were preserved in cold (4 degrees C) Krebs-Henseleit buffer for 6 hours, and then attached to a Langendorff perfusion apparatus and reperfused with an oxygenated Krebs-Henseleit solution containing IL-11. Normal saline was used instead of IL-11 in the control group. Functional recovery of the reperfused heart was observed by using a left ventricular balloon. Myocardial cell injury was quantified by measuring the biomarkers collected from the coronary effluent. Apoptotic cells were identified and counted using the terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) staining technique. Results: IL-11 administration improved myocardial function after 6 hours of cold ischemia. Although there were no significant differences in any of the baseline-measured values between the two groups, left ventricular developed pressure (LVDP) and changes in left ventricular pressures (dP/dt) were significantly higher in the IL-11 group at 120-minute reperfusion. The number of TUNEL-labeled cardiomyocytes was also significantly smaller in the IL-11 group. Conclusions: The administration of IL-11 showed a significant recovery of cardiac contractile function after 6 hours of cold ischemia. Our data suggest that it may have significant therapeutic potential for maintaining the functional viability of the heart exposed to prolonged hypothermic global ischemia. PMID- 29492388 TI - How to obtain and maintain favorable results after heart transplantation: keys to success? AB - We compared survival in our heart recipients with survival rates reported by the International Society of Heart and Lung Transplantation (ISHLT) Registry. As recipient and donor characteristics are changing over time, we studied four different eras. In order to differentiate between short- and long-term survival, we analyzed both overall survival and survival at one year. Obviously, this exercise is only relevant when baseline donor and recipient characteristics are comparable, as these differences may affect the outcome in opposite directions. To overcome this potential bias as much as possible, we calculated the Index for Mortality Prediction After Cardiac Transplantation (IMPACT)-scores and the Donor Risk Index (DRI). Looking to our results, we found that our DRIs in the different eras are almost equal to those obtained from the United Network for Organ Sharing database in the very same eras. Our IMPACT-scores, on the other hand, seem higher than those reported by ISHLT. Survival after transplantation and conditional on 1 year survival was higher than the outcome reported by the ISHLT Registry. As our operation technique and post-transplant immunosuppressive schedule did not differ from most centers, we speculated on potential factors that might contribute to our positive results. Patient selection and a relatively short waiting time are important contributors to the overall survival benefit. Our centralized follow-up may also have played an important role. Finally, the indefinite compulsory health insurance coverage in our country and easy access to different screening programs might also have influenced our outcome in a positive way. We are well aware that with challenges like donor organ shortage, more and more patients on mechanical circulatory support (MCS) will affect outcomes in the future. PMID- 29492389 TI - Neonatal heart transplantation. AB - Neonatal heart transplantation was developed and established in the 1980's as a durable modality of therapy for complex-uncorrectable heart disease. Patients transplanted in the neonatal period have experienced unparalleled long-term survival, better than for any other form of solid-organ transplantation. However, the limited availability of neonatal and young infant donors has restricted the indications and applicability of heart transplantation among newborns in the current era. Indications for heart transplantation include congenital heart disease not amenable to other forms of surgical palliation, and cardiomyopathy, including some primary tumors. Use of ABO-incompatible transplants, and organs with prolonged cold ischemic time or marginal function have all been associated with good outcomes in infants. These extended strategies to increase the donor pool may also someday include donation after determination of circulatory death and the use of anencephalic donors. The operative techniques for donors and recipients of neonatal heart transplantation are unique and have been well described. Immunosuppression protocols for neonates need not include induction and are largely steroid-free. Newborn and young infant transplant recipients have fewer episodes of rejection, less coronary allograft vasculopathy, less post transplant lymphoproliferative disease and less renal dysfunction than their older counterparts. Long-term outcomes have been very encouraging in terms of graft survival, patient survival, and quality of life. Our review highlights the history, current indications, techniques and outcomes of heart transplantation in this immunologically-privileged subset of patients. PMID- 29492390 TI - Donor selection in the modern era. AB - The growing disparity between the supply of donor hearts for transplantation and the demand for such organs has led to liberalization of the criteria for donor heart acceptance over the past few decades. The upper age limit and size restrictions for donor heart acceptance continue to be revised and hearts are being routinely used from donors with left ventricular dysfunction, left ventricular hypertrophy (LVH), cocaine use, multiple medical co-morbidities and after cardiopulmonary resuscitation. This article reviews recent data for use of such "expanded criteria" donor hearts and suggests ways to further increase the donor pool, including use of hearts from donors with hepatitis C and after circulatory determination of death. Donor biomarkers and risk scores may eventually aid in heart acceptance decisions, while ethical issues surrounding information sharing with transplant recipients remain a topic of great debate. PMID- 29492391 TI - The future of cardiac transplantation. AB - The first human-to-human heart transplant was performed 50 years ago in 1967. Heart transplantation has now entered an era of tremendous growth and innovation. The future of heart transplantation is bright with the advent of newer immunosuppressive medications and strategies that may even result in tolerance. Much of this progress in heart transplant medicine is predicated on a better understanding of acute and chronic rejection pathways through basic science studies. The future will also include personalized medicine where genomics and molecular science will dictate customized treatment for optimal outcomes. The introduction of mechanical circulatory support (MCS) devices has changed the landscape for patients with severe heart failure to stabilize the most ill patient and make them better candidates for heart transplant. As ex vivo preservation takes hold, we may witness an expansion of the donor pool through the use of donation after cardiac death (DCD) donors. In addition, further geographical donor heart sharing through ex vivo preservation may further decrease waitlist mortality by enabling longer distance donor hearts to be allocated for the sickest waitlist patient. It is no doubt an exciting time to be involved in the field of heart transplantation. In this perspective, we will summarize the present state of heart transplantation and discuss various innovations that are being pursued. PMID- 29492392 TI - Overview of adult congenital heart transplants. AB - Transplantation for adult patients with congenital heart disease (ACHD) is a growing clinical endeavor in the transplant community. Understanding the results and defining potential high-risk patient subsets will allow optimization of patient outcomes. This review summarizes the scope of ACHD transplantation, the mechanisms of late ventricular dysfunction, the ACHD population at risk of developing heart failure, the indications and potential contraindications for transplant, surgical considerations, and post-transplant outcomes. The findings reveal that 3.3% of adult heart transplants occur in ACHD patients. The potential mechanisms for the development of late ventricular dysfunction include a morphologic systemic right ventricle, altered coronary perfusion, and ventricular noncompaction. The indications for transplant in ACHD patients include systemic ventricular failure refractory medical therapy, Fontan patients failing from chronic passive pulmonary circulation, and progressive cyanosis leading to functional decline. Transplantation in ACHD patients can be quite complex and may require extensive reconstruction of the branch pulmonary arteries, systemic veins, or the aorta. Vasoplegia, bleeding, and graft right ventricular dysfunction can complicate the immediate post-transplant period. The post transplant operative mortality ranges between 14% and 39%. The majority of early mortality occurs in ACHD patients with univentricular congenital heart disease. However, there has been improvement in operative survival in more contemporary studies. In conclusion, the experience with cardiac transplantation for ACHD patients with end-stage heart failure is growing, and high-risk patient subsets have been defined. Significant strides have been made in developing evidence based guidelines of indications for transplant, and the intraoperative management of complex reconstruction has evolved. With proper patient selection, more aggressive use of mechanical circulatory support, and earlier referral of patients with failing Fontan physiology, outcomes should continue to improve. PMID- 29492394 TI - Pre-transplant ventricular assist device explant. AB - Explantation of a left ventricular assist device (LVAD) may be challenging even in the most experienced hands. We aim to describe the technique for explantation of an LVAD together with the heart as applicable to all contemporary implantable mechanical assist devices. In order to ensure safe explantation, particular care must be taken at three distinct stages: at the time of LVAD implantation, at pre transplant assessment and at the time of heart transplantation. The preparation for a safe explantation at LVAD implantation includes positioning the driveline and the outflow graft away from the back of the sternum to ensure protection from injury during re-entry into the chest. At transplant assessment, essential investigations include computed tomography (CT) of the chest and ultrasound imaging of femoral vessels. At the time of heart transplantation, the site of peripheral access should be prepared and vessels exposed in case of a need for emergency bypass. We advise careful dissection starting from the lower aspect of the under surface of the sternum, moving as proximally as possible before attempting to use the oscillating saw. Much of the dissection of the heart is done off-pump. Cardiopulmonary bypass may be established either through peripheral vessels or the outflow graft in an emergency. Central direct cannulation is then established. After the heart and major vessels are isolated, explantation of the heart may begin either en-bloc or after splitting the ventricles in a sagittal plane. The basal regions of both ventricles and both atria are removed, leaving generous cuffs for anastomosis of the left atrium, pulmonary artery, aorta, inferior and superior vena cava (SVC). The apex of the heart is then removed with the device taking care not to injure the phrenic nerve. PMID- 29492393 TI - Transplantation in the single ventricle population. AB - The single ventricle patient population comprises the most complex cohort presenting to the cardiac transplant team, in terms of demographics, anatomic substrate, and unique physiology. It is also the most rapidly growing diagnostic group presenting for heart transplantation. In this manuscript, we aim to describe the changing landscape of transplantation in single ventricle conditions through reflection on our own institution's practice and experience, alongside contemporary literature review. Single ventricle patients are heterogeneous in terms of age, anatomic diagnosis and physiology according to surgical stage of repair. Progress in surgical palliative strategies has impacted upon the present composition of the population, with growing numbers of hypoplastic left heart syndrome patients and those with late physiology failure following Fontan completion. Multiple prior surgeries, immunological sensitivity and multi-organ involvement impart high peri-operative risk but can be mitigated in part by careful pre-operative planning by a dedicated multi-disciplinary team addressing issues such as planning of concurrent reconstructive surgery, minimizing the post operative effect of collaterals, timely harvesting, oversizing of donor organs to minimize graft failure, and strategies to address anticipated post-operative elevation in pulmonary vascular resistance. Determining optimal timing for transplant in these patients remains unclear, but understanding the risk of alternative surgical options can help guide decision making with regards to listing. PMID- 29492395 TI - Standard orthotopic heart transplantation. PMID- 29492396 TI - Heart transplantation. PMID- 29492397 TI - Risk factors and mortality associated with multimorbidity in people with stroke or transient ischaemic attack: a study of 8,751 UK Biobank participants. AB - Background: Multimorbidity is common in stroke, but the risk factors and effects on mortality remain poorly understood. Objective: To examine multimorbidity and its associations with sociodemographic/lifestyle risk factors and all-cause mortality in UK Biobank participants with stroke or transient ischaemic attack (TIA). Design: Data were obtained from an anonymized community cohort aged 40-72 years. Overall, 42 comorbidities were self-reported by those with stroke or TIA. Relative risk ratios demonstrated associations between participant characteristics and number of comorbidities. Hazard ratios demonstrated associations between the number and type of comorbidities and all-cause mortality. Results were adjusted for age, sex, socioeconomic status, smoking, and alcohol intake. Data were linked to national mortality data. Median follow-up was 7 years. Results: Of 8,751 participants (mean age 60.9+/-6.7 years) with stroke or TIA, the all-cause mortality rate over 7 years was 8.4%. Over 85% reported >=1 comorbidities. Age, socioeconomic deprivation, smoking and less frequent alcohol intake were associated with higher levels of multimorbidity. Increasing multimorbidity was associated with higher all-cause mortality. Mortality risk was double for those with >=5 comorbidities compared to those with none. Having cancer, coronary heart disease, diabetes, or chronic obstructive pulmonary disease significantly increased mortality risk. Presence of any cardiometabolic comorbidity significantly increased mortality risk, as did any non cardiometabolic comorbidity. Conclusions: In stroke survivors, the number of comorbidities may be a more helpful predictor of mortality than type of condition. Stroke guidelines should take greater account of comorbidities, and interventions are needed that improve outcomes for people with multimorbidity and stroke. PMID- 29492398 TI - Prostatic artery embolization versus transurethral resection of the prostate in the treatment of benign prostatic hyperplasia: protocol for a non-inferiority clinical trial. AB - Background: Benign prostatic hyperplasia (BPH) is a prevalent disease associated with lower urinary tract symptoms (LUTS). The standard of care for moderate-to severe LUTS unresponsive to pharmacological treatment is the transurethral resection of the prostate (TURP). However, this intervention is not exempt from complications. Prostatic artery embolization (PAE) has been described as a new, effective and safe procedure for the treatment of LUTS secondary to BPH. To date, only one clinical trial has been published on the use of PAE for LUTS, but the study was methodologically flawed in terms of safety monitoring. Therefore, well designed clinical studies are required to compare the efficacy and safety of both techniques in the treatment of LUTS secondary to BPH. Methods and design: This was a prospective, randomized, non-inferiority clinical trial comparing efficacy and safety of PAE and TURP in the treatment of BPH-related LUTS. A total of 60 patients diagnosed with BPH with obstructive moderate or severe LUTS refractory to medical therapy and candidates for TURP were randomized to either PAE or TURP. The presence and severity of LUTS were assessed using the validated Spanish version of the International Prostate Symptom Score (IPSS). Primary end points included improvement in maximum urinary flow rate (Qmax) as measured at baseline and 1 year after the intervention. Improvement in IPSS as measured at baseline and after the intervention, reduction in prostate volume, no deterioration or improvement of sexual function (International Index of Erectile Function [IIEF]), reduction in PSA and PVR, satisfaction of the patient with the operation and adverse events occurring during the study were secondary outcome measures. Discussion: The aim of this clinical study was to investigate whether PAE is a valid therapeutic option for LUTS that is not inferior to TURP in terms of efficacy and safety. This study also helped to define the profile of candidates for PAE and analyzed the benefits and complications associated with this new technique. PMID- 29492399 TI - Efficacy of Paracetamol in Closure of Ductus Arteriosus in Infants under 32 Weeks of Gestation. AB - Background: Standard medical treatment for patent ductus arteriosus (PDA) closure has been indomethacin/ibuprofen or surgical ligation. Up to date, new strategies have been reported with paracetamol. The aim of this study was to present our experience with intravenous paracetamol for closing PDA in preterm neonates presenting contraindication to ibuprofen or ibuprofen had failed and no candidates for surgical ligation because of huge instability. Materials and methods: We conducted a retrospective case series study in a neonatal intensive care unit from a tertiary hospital. 9 preterm infants <=32 weeks of gestational age with hemodynamically significant PDA (hsPDA) were enrolled. They received 15 mg/kg/6h intravenous paracetamol for ductal closure. Demographic data and transaminase levels before and after treatment were collected. Results: 30 preterm babies were diagnosed of hsPDA. 11/30 received ibuprofen with closure in 81.1%. 9 received intravenous paracetamol mainly due to bleeding disorders or thrombocytopenia. Successful closure on paracetamol was achieved in seven of nine babies (77.7%). There was a significant increase in transaminase levels in two patients. They required no treatment for normalization. Conclusion: Paracetamol is an effective option in closure PDA. It should be a first-line therapeutic option when there are contraindications for ibuprofen treatment. Transaminases must be checked during treatment. PMID- 29492400 TI - A Protocol for a Feasibility and Acceptability Study of a Participatory, Multi Level, Dynamic Intervention in Urban Outreach Centers to Improve the Oral Health of Low-Income Chinese Americans. AB - Introduction: While the US health care system has the capability to provide amazing treatment of a wide array of conditions, this care is not uniformly available to all population groups. Oral health care is one of the dimensions of the US health care delivery system in which striking disparities exist. More than half of the population does not visit a dentist each year. Improving access to oral health care is a critical and necessary first step to improving oral health outcomes and reducing disparities. Fluoride has contributed profoundly to the improved dental health of populations worldwide and is needed regularly throughout the life course to protect teeth against dental caries. To ensure additional gains in oral health, fluoride toothpaste should be used routinely at all ages. Evidence-based guidelines for annual dental visits and brushing teeth with fluoride toothpaste form the basis of this implementation science project that is intended to bridge the care gap for underserved Asian American populations by improving access to quality oral health care and enhancing effective oral health promotion strategies. The ultimate goal of this study is to provide information for the design and implementation of a randomized controlled trial of a participatory, multi-level, partnered (i.e., with community stakeholders) intervention to improve the oral and general health of low-income Chinese American adults. Methods: This study will evaluate the feasibility and acceptability of implementing a partnered intervention using remote data entry into an electronic health record (EHR) to improve access to oral health care and promote oral health. The research staff will survey a sample of Chinese American patients (planned n = 90) screened at three outreach centers about their satisfaction with the partnered intervention. Providers (dentists and community health workers), research staff, administrators, site directors, and community advisory board members will participate in structured interviews about the partnered intervention. The remote EHR evaluation will include group adaptation sessions and workflow analyses via multiple recorded sessions with research staff, administrators, outreach site directors, and providers. The study will also model knowledge held by non-patient participants to evaluate and enhance the partnered intervention for use in future implementations. PMID- 29492401 TI - Formation and Accumulation of Acetaldehyde and Strecker Aldehydes during Red Wine Oxidation. AB - The main aim of the present work is to study the accumulation of acetaldehyde and Strecker aldehydes (isobutyraldehyde, 2-methylbutanal, isovaleraldehyde, methional, phenylacetaldehyde) during the oxidation of red wines, and to relate the patterns of accumulation to the wine chemical composition. For that, eight different wines, extensively chemically characterized, were subjected at 25 degrees C to three different controlled O2 exposure conditions: low (10 mg L-1) and medium or high (the stoichiometrically required amount to oxidize all wine total SO2 plus 18 or 32 mg L-1, respectively). Levels of volatile aldehydes and carbonyls were then determined and processed by different statistical techniques. Results showed that young wines (<2 years-old bottled wines) hardly accumulate any acetaldehyde regardless of the O2 consumed. In contrast, aged wines (>3 years old bottled wines) accumulated acetaldehyde while their content in SO2 was not null, and the aged wine containing lowest polyphenols accumulated it throughout the whole process. Models suggest that the ability of a wine to accumulate acetaldehyde is positively related to its content in combined SO2, in epigallocatechin and to the mean degree of polymerization, and negatively to its content in Aldehyde Reactive Polyphenols (ARPs) which, attending to our models, are anthocyanins and small tannins. The accumulation of Strecker aldehydes is directly proportional to the wine content in the amino acid precursor, being the proportionality factor much higher for aged wines, except for phenylacetaldehyde, for which the opposite pattern was observed. Models suggest that non-aromatic Strecker aldehydes share with acetaldehyde a strong affinity toward ARPs and that the specific pattern of phenylacetaldehyde is likely due to a much reduced reactivity toward ARPs, to the possibility that diacetyl induces Strecker degradation of phenyl alanine and to the potential higher reactivity of this amino acid to some quinones derived from catechin. All this makes that this aldehyde accumulates with intensity, particularly in young wines, shortly after wine SO2 is depleted. PMID- 29492402 TI - Structure Based Virtual Screening Studies to Identify Novel Potential Compounds for GPR142 and Their Relative Dynamic Analysis for Study of Type 2 Diabetes. AB - GPR142 (G protein receptor 142) is a novel orphan GPCR (G protein coupled receptor) belonging to "Class A" of GPCR family and expressed in beta cells of pancreas. In this study, we reported the structure based virtual screening to identify the hit compounds which can be developed as leads for potential agonists. The results were validated through induced fit docking, pharmacophore modeling, and system biology approaches. Since, there is no solved crystal structure of GPR142, we attempted to predict the 3D structure followed by validation and then identification of active site using threading and ab initio methods. Also, structure based virtual screening was performed against a total of 1171519 compounds from different libraries and only top 20 best hit compounds were screened and analyzed. Moreover, the biochemical pathway of GPR142 complex with screened compound2 was also designed and compared with experimental data. Interestingly, compound2 showed an increase in insulin production via Gq mediated signaling pathway suggesting the possible role of novel GPR142 agonists in therapy against type 2 diabetes. PMID- 29492403 TI - The Biological Role of Nestin(+)-Cells in Physiological and Pathological Cardiovascular Remodeling. AB - The intermediate filament protein nestin was identified in diverse populations of cells implicated in cardiovascular remodeling. Cardiac resident neural progenitor/stem cells constitutively express nestin and following an ischemic insult migrate to the infarct region and participate in angiogenesis and neurogenesis. A modest number of normal adult ventricular fibroblasts express nestin and the intermediate filament protein is upregulated during the progression of reparative and reactive fibrosis. Nestin depletion attenuates cell cycle re-entry suggesting that increased expression of the intermediate filament protein in ventricular fibroblasts may represent an activated phenotype accelerating the biological impact during fibrosis. Nestin immunoreactivity is absent in normal adult rodent ventricular cardiomyocytes. Following ischemic damage, the intermediate filament protein is induced in a modest population of pre-existing adult ventricular cardiomyocytes bordering the peri-infarct/infarct region and nestin(+)-ventricular cardiomyocytes were identified in the infarcted human heart. The appearance of nestin(+)-ventricular cardiomyocytes post myocardial infarction (MI) recapitulates an embryonic phenotype and depletion of the intermediate filament protein inhibits cell cycle re-entry. Recruitment of the serine/threonine kinase p38 MAPK secondary to an overt inflammatory response after an ischemic insult may represent a seminal event limiting the appearance of nestin(+)-ventricular cardiomyocytes and concomitantly suppressing cell cycle re entry. Endothelial and vascular smooth muscle cells (VSMCs) express nestin and upregulation of the intermediate filament protein may directly contribute to vascular remodeling. This review will highlight the biological role of nestin(+) cells during physiological and pathological remodeling of the heart and vasculature and discuss the phenotypic advantage attributed to the intermediate filament protein. PMID- 29492406 TI - Effect of cladribine therapy on lung cysts in pulmonary Langerhans cell histiocytosis. AB - Cladribine therapy may be beneficial in advanced forms of pulmonary Langerhans cell histiocytosis, even that with multiple cystic changes http://ow.ly/yeLr30i0Tt6. PMID- 29492404 TI - Direct Reprogramming of Spiral Ganglion Non-neuronal Cells into Neurons: Toward Ameliorating Sensorineural Hearing Loss by Gene Therapy. AB - Primary auditory neurons (PANs) play a critical role in hearing by transmitting sound information from the inner ear to the brain. Their progressive degeneration is associated with excessive noise, disease and aging. The loss of PANs leads to permanent hearing impairment since they are incapable of regenerating. Spiral ganglion non-neuronal cells (SGNNCs), comprised mainly of glia, are resident within the modiolus and continue to survive after PAN loss. These attributes make SGNNCs an excellent target for replacing damaged PANs through cellular reprogramming. We used the neurogenic pioneer transcription factor Ascl1 and the auditory neuron differentiation factor NeuroD1 to reprogram SGNNCs into induced neurons (iNs). The overexpression of both Ascl1 and NeuroD1 in vitro generated iNs at high efficiency. Transcriptome analyses revealed that iNs displayed a transcriptome profile resembling that of endogenous PANs, including expression of several key markers of neuronal identity: Tubb3, Map2, Prph, Snap25, and Prox1. Pathway analyses indicated that essential pathways in neuronal growth and maturation were activated in cells upon neuronal induction. Furthermore, iNs extended projections toward cochlear hair cells and cochlear nucleus neurons when cultured with each respective tissue. Taken together, our study demonstrates that PAN-like neurons can be generated from endogenous SGNNCs. This work suggests that gene therapy can be a viable strategy to treat sensorineural hearing loss caused by degeneration of PANs. PMID- 29492407 TI - Reproducibility of hypercapnic ventilatory response measurements with steady state and rebreathing methods. AB - In this study, the hypercapnic ventilatory response (HCVR) was measured, defined as the ventilation response to carbon dioxide tension (PCO2 ). We investigated which method, rebreathing or steady-state, is most suitable for measurement of the HCVR in healthy subjects, primarily based on reproducibility. Secondary outcome parameters were subject experience and duration. 20 healthy adults performed a rebreathing and steady-state HCVR measurement on two separate days. Subject experience was assessed using numeric rating scales (NRS). The intraclass correlation coefficient (ICCs) of the sensitivity to carbon dioxide above the ventilatory recruitment threshold and the projected apnoea threshold were calculated to determine the reproducibility of both methods. The ICCs of sensitivity were 0.89 (rebreathing) and 0.56 (steady-state). The ICCs of the projected apnoea threshold were 0.84 (rebreathing) and 0.25 (steady-state). The steady-state measurement was preferred by 16 out of 20 subjects; the differences in NRS scores were small. The hypercapnic ventilatory response measured using the rebreathing setup provided reproducible results, while the steady-state method did not. This may be explained by high variability in end-tidal PCO2 . Differences in subject experience between the methods are small. PMID- 29492408 TI - Learning models of Human-Robot Interaction from small data. AB - This paper offers a new approach to learning discrete models for human-robot interaction (HRI) from small data. In the motivating application, HRI is an integral part of a pediatric rehabilitation paradigm that involves a play-based, social environment aiming at improving mobility for infants with mobility impairments. Designing interfaces in this setting is challenging, because in order to harness, and eventually automate, the social interaction between children and robots, a behavioral model capturing the causality between robot actions and child reactions is needed. The paper adopts a Markov decision process (MDP) as such a model, and selects the transition probabilities through an empirical approximation procedure called smoothing. Smoothing has been successfully applied in natural language processing (NLP) and identification where, similarly to the current paradigm, learning from small data sets is crucial. The goal of this paper is two-fold: (i) to describe our application of HRI, and (ii) to provide evidence that supports the application of smoothing for small data sets. PMID- 29492409 TI - The Effect of CuO Nanoparticles on Antimicrobial Effects and Shear Bond Strength of Orthodontic Adhesives. AB - Statement of the Problem: Orthodontic appliances facilitate microbial plaque accumulation and increase the chance of white spot lesions. There is a need for new plaque control methods independent of patient's cooperation. Purpose: The aim of this study was to determine the effects of incorporating copper oxide (CuO) nanoparticles on antimicrobial properties and bond strength of orthodontic adhesive. Materials and Method: CuO nanoparticles were added to the composite transbond XT at concentrations of 0.01, 0.5 and 1 wt.%. To evaluate the antimicrobial properties of composites containing nanoparticles, the disk agar diffusion test was used. For this purpose, 10 discs from each concentration of nano-composites (totally 30 discs) and 10 discs from conventional composite (as the control group) were prepared. Then the diameter of streptococcus mutans growth inhibition around each disc was determined in blood agar medium. To evaluate the shear bond strength, with each concentration of nano-composites as well as the control group (conventional composite), 10 metal brackets were bonded to the human premolars and shear bond strength was determined using a universal testing machine. Results: Nano-composites in all three concentrations showed significant antimicrobial effect compared to the control group (p< 0.001). With increasing concentration of nanoparticles, antimicrobial effect showed an upward trend, although statistically was not significant. There was no significant difference between the shear bond strength of nano-composites compared to control group (p= 0.695). Conclusion: Incorporating CuO nanoparticles into adhesive in all three studied concentrations added antimicrobial effects to the adhesive with no adverse effects on shear bond strength. PMID- 29492410 TI - Low Lymphatic Vessel Density Correlates with Lymph Node Metastasis in Oral Squamous Cell Carcinoma. AB - Statement of the Problem: Regional lymph nodes are the nodes draining lymph from region around the tumor and presence of metastatic tumor in regional lymph nodes is the most important prognostic factor for malignant tumors of epithelial origin. Lymphangiogenesis is associated with an increased incidence of regional lymph nodes metastasis and is possibly an essential step for metastasis. Tumor cells secrete lymphangiogenic cytokines, which results in formation of lymphatic vessels within and around the tumor and act as portals for tumor spread. Purpose: The present study aims to investigate and quantify lymphatic vessel density (LVD) in oral squamous cell carcinoma (OSCC) and determine whether LVD can predict the risk of sentinel lymph node metastasis. Material and Method: 50 specimens of OSCC, without and with lymph node metastasis (25 each) along with 25 specimens of normal oral mucosa were assessed and LVD was quantified by D2-40 immunostaining. Discrete hotspots of intratumoral lymphatics were identified in superficial and deep areas in all carcinomas to calculate LVD. Results: When compared to normal mucosa, LVD decreased in the superficial intratumoral areas and decreased further in deep areas. In addition, LVD in the superficial and deep areas of OSCC without nodal metastasis was significantly higher than that in OSCC with nodal metastasis. Conclusion: Our study provides evidence that lymphangiogenesis varies within the tumor. Lymphatic vessels are either compressed, collapsed, destroyed or absent in deep intratumoral region. Decrease in LVD predicts cervical lymph node metastasis both in superficial and deep areas. Lymphatics in superficial areas are probably major conduit for nodal metastasis in OSCCs. PMID- 29492411 TI - Cone Beam CT Study of Temporal Crest Canal. AB - Statement of the Problem: It is crucial for clinicians to be certain about the location of mandibular canal and determine any anatomical variants relevant to it. The temporal crest canal (TCC) is a rare anatomical variant of mandibular canal that lack of awareness about its presence can complicate surgical procedures. Purpose: This study investigated the anatomical characteristics and prevalence of the TCC using CBCT. Materials and Method: This descriptive cross section study evaluated 327 CBCTs (654 sides) from all the patients with various problems. TCC on sagittal and axial plans were identified and then classified into two types based on their configuration. The prevalence of TCC was calculated amongst men and women. Results: Six TCC (0.91%) were observed in 654 sides. We observed all 6 TCCs in females. One case (0.30%) was bilateral TCC, and the remaining four (1.22%) cases were unilateral TCC (two on the left and two on the right side). Considering the classification of TCC, five sides had presentation of type I and one case was type II based on Kawai et al. study. Conclusion: Three dimensional images of CBCT data are useful in confirming the presence of TCC. TCC is considered as a clinically significant structure; therefore, this variation should be carefully investigated using reconstructed CBCT images. PMID- 29492412 TI - The Impact of Calcium Hydroxide on the Osteoinductive Capacity of Demineralized Freeze-Dried Bone Allograft: an In-Vitro Study. AB - Statement of the Problem: A great challenge in periodontal therapy is the regeneration enhancement of osseous defects through applying osteoinductive materials. Demineralized freeze-dried bone allograft (DFDBA) has already been introduced as an allograft with osteoconductive and variable osteoinductive properties. Calcium hydroxide [Ca(OH)2] is an available well-known material in dentistry, which induces hard tissue formation. Purpose: This study evaluated the efficiency of combination of DFDBA and Ca(OH)2 in improving the quality of osteoinduction of DFDBA. Materials and Method: Human bone marrow-derived mesenchymal stem cells were taken from volunteers' iliac crest. Cell proliferation was determined by MTT test at 18, 24 and 48 hours post-culture in 10 groups. The employed material were 0.5, 1.0 mg/ml Ca(OH)2 in two forms of suspension and pH-adjusted solution, 10mg/ml DFDBA per se and in combination with 0.5 and 1.0 mg/ml Ca(OH)2. Mineralization was assessed by Alizarin red staining in 10 mg/ml DFDBA, DFDBA+ 0.5 and 1 mg/ml Ca(OH)2 in solution and suspension forms. The data were statistically analyzed by using one-way ANOVA and Tukey's post-hoc test (p< 0.05). Results: The pH-adjusted solutions exhibited better cell proliferation compared with the suspension groups. The combination of 0.5mg/ml Ca(OH)2 solution and DFDBA increased the cell proliferation and mineralization compared with DFDBA per se (p= 0.033). Conclusion: The combination of Ca(OH)2 with DFDBA improved the osteoinductivity of DFDBA. PMID- 29492405 TI - Biofortified Crops Generated by Breeding, Agronomy, and Transgenic Approaches Are Improving Lives of Millions of People around the World. AB - Biofortification is an upcoming, promising, cost-effective, and sustainable technique of delivering micronutrients to a population that has limited access to diverse diets and other micronutrient interventions. Unfortunately, major food crops are poor sources of micronutrients required for normal human growth. The manuscript deals in all aspects of crop biofortification which includes-breeding, agronomy, and genetic modification. It tries to summarize all the biofortification research that has been conducted on different crops. Success stories of biofortification include lysine and tryptophan rich quality protein maize (World food prize 2000), Vitamin A rich orange sweet potato (World food prize 2016); generated by crop breeding, oleic acid, and stearidonic acid soybean enrichment; through genetic transformation and selenium, iodine, and zinc supplementation. The biofortified food crops, especially cereals, legumes, vegetables, and fruits, are providing sufficient levels of micronutrients to targeted populations. Although a greater emphasis is being laid on transgenic research, the success rate and acceptability of breeding is much higher. Besides the challenges biofortified crops hold a bright future to address the malnutrition challenge. PMID- 29492413 TI - Efficiency of Castor Oil as a Storage Medium for Avulsed Teeth in Maintaining the Viability of Periodontal Ligament Cells. AB - Statement of the Problem: Researchers always seek a new storage medium for avulsed teeth. Castor oil is a vegetable oil with several advantages such as antimicrobial and antioxidant properties, low toxicity, and glutathione preservation capability, low cost, and high availability. Purpose: The purpose of this study was to evaluate and compare the capacity of castor oil as a new storage medium in preserving the viability of periodontal ligament (PDL) cells compared to Hank's balanced salt solution (HBSS) and milk. Materials and Method: Forty freshly extracted human teeth were divided into 3 experimental and 2 control groups. The experimental teeth were stored dry for 30 min and then immersed for 45 min in one of the following media; castor oil, HBSS, and milk. The positive and negative control groups were exposed to 0 min and 2 h of dry time respectively with no immersion in any storage medium. The teeth were then treated with dispase grade II and collagenase and the number of viable PDL cells were counted. Data were analyzed using Kruskal- Wallis test. Results: The percentage of viable cells treated with castor oil, HBSS and milk counted immediately after removal from these media were 46.93, 51.02 and 55.10 % respectively. The statistical analysis revealed that the value for castor oil was significantly lower than HBSS and milk (p> 0.05). Conclusion: Within the parameters of this study, it appears that castor oil cannot be served as an ideal medium for storage of avulsed tooth. More investigations under in vivo conditions are required to justify the results of this study. PMID- 29492414 TI - Comparison the Pain Relief of Amitriptyline Mouthwash with Benzydamine in Oral Mucositis. AB - Statement of the Problem: A significant proportion of patients undergoing chemotherapy or radiotherapy suffer from mucositis. The first symptom of oral mucositis is pain. Severe pain, burning sensation, and discomfort in the oral cavity make it difficult to continue treatment and even continue living in these patients. Purpose: The aim of this study was to evaluate and compare the effect of amitriptyline mouthwash (in two forms of simple and niosomal) as a local anesthetic agent with benzydamine HCl mouthwash in oral mucositis after radiotherapy or chemotherapy. Materials and Method: This double-blind study was performed on 60 patients with oral mucositis caused by radiotherapy and chemotherapy. The severity of mucositis was determined based on patient judgment; then dental examination was performed and recorded in a checklist. Three groups were assigned based on using either benzydamine HCL, amitriptyline, or niosomal form of amitriptyline. Pain and burning sensation were evaluated with VAS at different time intervals: before use and one, five, ten, and thirty minutes and one hour after using mouthwash. T-test was used to compare the intensity of pain between the two groups. ANOVA and Tukey test were used to compare the intensity of pain between groups. Results: Statistical analyses showed the maximum reduction in pain intensity at two different time intervals (p= 0.04). Ten minutes after the use of niosomal form of amitriptyline, a 95% decrease in pain was observed. A 99% reduction in pain occurred after the use of simple form of amitriptyline (p= 0.04). Conclusion: Use of amitriptyline mouthwash had local anesthetic effects in oral mucositis without systemic side effects. Decrease in the severity of pain with the use of amitriptyline mouthwash was more than that of benzydamine HCL mouthwash. PMID- 29492415 TI - Evaluation of Infraorbital Canal in Cone Beam Computed Tomography of Maxillary Sinus. AB - Statement of the Problem: Ignoring anatomic variations may lead to iatrogenic injuries by surgeons. Purpose: The aim of this study was to examine the relationship between the course of infraorbital canal and maxillary sinus using cone beam computed tomography scans (CBCT). Materials and Method: One hundred and ninety two CBCT scans were reviewed for 384 infraorbital canals. The anatomic variants of infraorbital canals were classified into three types based on the protrusion degree of the infraorbital nerve from the maxillary roof into the sinus. Measurements were made on infraorbital canal as vertical distance from the infraorbital rim to the infraorbital foramen, the maximum horizontal distance from the infraorbital canal to the canine root, the maximum diagonal length of the nerve protruded in sinus, the maximum vertical distance from the center of the nerve to the sinus roof. Results: 26.5% of infraorbital canals were entirely contained within the sinus roof. 50.3% of infraorbital canals were located below the roof but remaining juxtaposed to it. In 23.2%, the nerve canal descended into the sinus. The prevalence of type3 of infraorbital canal significantly increased from 14.8% in cases without an ipsilateral Haller cell to 29.1% when a Haller cell was present. The average distance between the infraorbital foramen and the infraorbital rim were increased proportionally to the degree of protrusion of the nerve course into the maxillary sinus (ANOVA p< 0.001). Conclusion: The infraorbital canal protrusion into the sinus is a common variation that must be considered during surgical procedures to avoid iatrogenic injury. PMID- 29492416 TI - Effects of Universal and Conventional MDP Primers on the Shear Bond Strength of Zirconia Ceramic and Nanofilled Composite Resin. AB - Statement of the Problem: The clinical success of ceramic depends on the quality of the bond between the zirconia and resin cement. Purpose: In the present study, the effects of universal and conventional MDP-containing primers were evaluated on the shear bond strength of zirconia ceramic and nanofilled composite resin. Materials and Method: Thirty blocks of zirconia ceramic (6mm*2mm) were prepared. Then the inner surfaces were air-abraded and divided into three groups (n= 10) as follows: untreated with primer (control group, I); All- Bond Universal (group II) and Z-Prime Plus (group III). The specimens in each group were bonded with Variolink N cement to cylinders of composite resin Z350XT. After 24 hour water storage, the shear bond strength test was performed with a universal testing machine at a crosshead speed of 1mm/ min and bond strength values (MPa) were calculated and analyzed with one-way ANOVA and post hoc Tukey tests (p< 0.05). The failure mode of each specimen was evaluated under a stereomicroscope and representative specimens were analyzed by scanning electron microscopy (SEM). Results: The mean shear bond strength values (MPa) were 7.58+/-1.62, 17.51+/-1.34 and 22.45+/-3.60 in groups I, II and III, respectively. These results indicated that the shear bond strength were significantly higher in groups II and III compared to the control group (p< 0.001). Chemical pre-treatment of zirconia with Z- Prime Plus revealed significantly higher bond strength than the All-Bond Universal adhesive (p< 0.002). All the failure modes were adhesive in the control group (I) and when using primer treatment, mixed failures occurred in 40% and 50% of specimens in groups II and III, respectively. Conclusion: Treatment with both primers resulted in higher bond strength values compared to the control group. The use of Z-Prime Plus treatment in combination with air-abrasion procedure resulted in the highest bond strength. PMID- 29492417 TI - Pain Perception Due to Dental Injection by Smartject: Split Mouth Design Study. AB - Statement of the Problem: Dental injection is one of the most fearful procedures in dental setting, especially for children. Many researchers have attempted to find a painless method. As computer controlled local anesthesia delivery system devices (CCLADs) allow the speed rate and pressure of injection solution to be controlled, they may cause less pain during injection in comparison to the conventional method. Purpose: The aim of this study was to compare pain perception in dental injection by Smartject with conventional technique. Materials and Method: The present study was a randomized single-blind crossover clinical trial. The participants consisted of 50 healthy volunteer dental students. They received a topical anesthetic agent plus injection in maxillary premolar buccal mucosa via conventional technique on one side (control) and a topical anesthetics agent plus injection in maxillary premolar buccal mucosa by Smartject on the other side (experimental). The first injection method was chosen based on block randomization table. A blind person recorded the subjects' pain perception of injection based on the visual analogue scale (VAS) in the two groups. Repeated measure test, independent Student t-test and Student paired t- test were used. Statistical significance was defined at p< 0.05. Results: There was statistically significant difference in VAS score between Smartject and the conventional technique. The mean of VAS scores for Smartject and the conventional technique were 14.5+/-7.4 and 24+/-12.1, respectively. Conclusion: It is suggested, needle penetration is not the main reason of pain during injection. Inconsistent fluid pressure created by injected anesthetic solution on nerve fibers is more impressive in pain development. Hence, Smartject as a CCLAD can be considered as an appropriate device for dental injection. PMID- 29492418 TI - Diagnostic Efficacy of Deeper Sections in Routine Oral Histopathology Practice: a Retrospective Study. AB - Statement of the Problem: Histopathology is a gold standard diagnostic tool for oral lesions. Nonspecific and overlapping microscopic features often pose diagnostic challenges in routine practice. In such conditions, deeper sections have utility to enhance the sensitivity and accuracy of the diagnosis. Purpose: To analyze the percentage of deeper sections requested and to evaluate the diagnostic efficacy of these deeper sections in routine oral histopathology practice. Additionally, the utility of deeper sections in specific oral lesions have also been evaluated. Materials and Method: A total of 850 cases from the archives of Department of Oral Pathology and Microbiology, were analyzed, and 106 cases with deeper sections were selected. Out of 106, 82 cases were accepted for our analysis and 24 were rejected as deeper sections were done due to staining errors or folding of tissue. The present retrospective study involves comparison of initial histological findings with those seen in deeper sections of same specimen. Results: Deeper sections improved the diagnosis of 48 cases (58.54%). Remaining 31 cases (38%) showed the same histological features, whereas in 3 cases (3.66%), initial sections were good as compared to deeper sections. Out of 22 cases of provisional hyperkeratotic/ dysplastic lesion, 16 (72.72%) showed change in diagnosis, i.e. from mild to severe dysplasia or from dysplasia to carcinoma. A total 12 out of 17 (70.59%) cases of odontogenic lesions were non- diagnostic or showed minimal characteristic features on initial sections, but their deeper sections revealed clearly identifiable features and some of them also showed cystic lesion turning into tumor pathology. Conclusion: This study highlights the diagnostic efficacy of deeper sections and their contribution towards providing accurate and more descriptive features. PMID- 29492419 TI - Adenoid Squamous Cell Carcinoma of Oral Cavity: a Case Report. AB - Adenoid squamous cell carcinoma is a rare variant of squamous cell carcinoma with features of adenoid pattern. It has been reported to originate in the sun- exposed skin of the head and neck region. Although rare, there are cases documented within the oral cavity and nasopharynx. The clinical behaviour and the prognosis are variable. We report a case of adenoid squamous cell carcinoma in a 63-year-old female patient presented with a large mass in the left mandibular alveolar ridge. Histologically, the lesion showed areas of conventional squamous cell carcinoma along with atypical epithelial cells forming a glandular pattern. However, there is no evidence of glandular differentiation, secretory activity or its products. Adenoid squamous cell carcinoma must be differentiated from adenosquamous carcinoma in which adenocarcinoma elements are positive for mucins. There are few cases reported to establish biological behaviour and prognosis. PMID- 29492420 TI - Piezopuncture-Assisted Canine Distalization in Orthodontic Patients: Two Case Reports. AB - With the increasing number of young adults seeking orthodontic treatment to improve their smile esthetics or oral function, the time spent wearing brackets is one of the biggest challenges for these patients. Various surgical techniques have been developed over the years to accelerate tooth movement and reduce the total treatment time. A newly introduced, minimally invasive procedure namely piezopuncture, which uses a piezosurgical tool to create multiple cortical punctures through the gingiva, is presented in this report of two extraction cases. PMID- 29492421 TI - Satisfactory spinal anesthesia with a total of 1.5 mg of bupivacaine for transurethral resection of bladder tumor in an elderly patient. AB - Spinal anesthesia is popular for endoscopic urological surgery. Many patients undergoing urological surgery are elderly. It is important to limit the dose to reduce any resultant hemodynamic effect. We present a case in which incremental administration of 0.1 % bupivacaine up to 1.5 mg was sufficient to produce satisfactory spinal anesthesia for transurethral resection of bladder tumor (TURBT). PMID- 29492422 TI - Remifentanil-induced alterations in neutrophil numbers after surgery. AB - Background: Neutrophils are the first line of defense against invasive microorganisms during and after surgery. There is a possibility that different opioid analgesics used during surgery have different effects on the leucocyte count. We retrospectively analyzed the numbers of leucocytes, neutrophils, and lymphocytes just after surgery in patients who received remifentanil-based anesthesia and those who received fentanyl-based anesthesia.In female patients who underwent modified mastectomy or simple mastectomy with resection of a lymph node(s) or with biopsy of a sentinel lymph node(s) between January 2010 and December 2013 (n = 83), propensity score pairwise matching was performed according to the patient's age and procedure, and forty patients (Remifentanil group and Fentanyl group; n = 20 each) were analyzed. Findings: Postoperative numbers of leucocytes and neutrophils were significantly lower in patients who received remifentanil-based anesthesia than in those who received fentanyl-based anesthesia (p = 0.03, p = 0.014; leucocytes and neutrophils, respectively). The increases in the numbers of leucocytes and neutrophils were significantly lower in the patients in the remifentanil group (p = 0.009, p = 0.0046; increase in leucocytes and neutrophils, respectively). Conclusions: In conclusion, remifentanil-based anesthesia attenuates postoperative leucocyte and neutrophil counts. It is unknown whether this phenomenon indicates the possibility of immunosuppression. Further studies are required. PMID- 29492423 TI - Rocuronium-sugammadex use for electroconvulsive therapy in a hemodialysis patient: a case report. AB - Background: Recently, rocuronium with subsequent use of sugammadex was proposed for electroconvulsive therapy (ECT) as an alternative to succinylcholine. Because sugammadex is cleared via the kidney with no metabolism, it is unknown that rocuronium-sugammadex use is safe in hemodialysis patients who received ECT. Case presentation: In this case report, we used rocuronium with subsequent administration of sugammadex in a 69-year-old female, hemodialysis patient, scheduled for ten ECT sessions for severe major depression. In the initial eight sessions, we tested the feasibility of rocuronium-sugammadex use for ECT. During the series of four ECT sessions, we measured plasma concentrations for the sum of sugammadex and sugammadex-rocuronium complex and observed whether possible residual sugammadex affected muscle relaxation during subsequent sessions of ECT. The results showed the feasibility of rocuronium-sugammadex use as muscle relaxants for ECT in patients undergoing hemodialysis. However, an accumulation of sugammadex did occur even after two sessions of hemodialysis, and residual sugammadex decreased the effect of the rocuronium given in the subsequent ECT sessions. Rocuronium-sugammadex was successfully utilized as muscle relaxants for ECT in this patient. Conclusions: Our experience in this case may indicate that if succinylcholine is contraindicated, rocuronium-sugammadex can be an alternative method for muscle relaxation during ECT in patients undergoing hemodialysis. When this rocuronium-sugammadex procedure is used, the effect of residual sugammadex after hemodialysis on the subsequently administered rocuronium should be considered. PMID- 29492424 TI - Efficacy of intraoperative transesophageal echocardiography in a case of protamine shock during transcatheter aortic valve implantation. AB - Here, we report the case of a patient who developed protamine shock during a transcatheter aortic valve implant (TAVI) procedure, which was diagnosed by intraoperative transesophageal echocardiography (TEE). A 77-year-old man with symptomatic severe aortic stenosis and reduced left ventricular (LV) function underwent TAVI under general anesthesia. During the procedure, a transcatheter heart valve (THV) was deployed via the transfemoral approach, without any other major complications. The entire device system was then removed, and protamine sulfate was administered intravenously in 2 min. Two minutes after the protamine administration, severe hypotension occurred. TEE did not reveal THV malfunction or any other major complications. However, comparison of the TEE image obtained before protamine administration and that obtained 2 min after protamine administration showed right ventricular (RV) dilatation, RV free wall motion abnormality, and LV volume reduction, without any electrocardiographic changes. We diagnosed this as protamine shock and bolus infusions of phenylephrine and norepinephrine were administered, and chest compressions were initiated immediately. After 1 min, hypotension as well as the right and left ventricular size and dysfunction immediately reverted to baseline. The severe systemic hypotension resolved as well. Thereafter, he recovered from anesthesia without other complications. This case showed the clinical features of protamine shock with acute pulmonary hypertension. The TEE images, in this case, should be a reminder for all doctors who perform intraoperative TEE for patient monitoring when they perform procedures to treat structural heart diseases. PMID- 29492425 TI - Anesthetic management of a patient with factor VII deficiency undergoing laparoscopic colectomy: a case report. AB - Background: Congenital factor VII (FVII) deficiency is a rare autosomal recessive coagulation disorder that is characterized by prolongation of prothrombin time. Recombinant activated FVII (rFVIIa) is widely used in the management of bleeding in patients with congenital FVII deficiency. We experienced anesthetic management of a patient with congenital FVII deficiency who was scheduled for laparoscopic colectomy using rFVIIa. Case presentation: We report a 67-year-old man with rectal cancer who was diagnosed with congenital FVII deficiency. He was scheduled for laparoscopic colectomy. General anesthesia was performed with propofol, remifentanil, and rocuronium without epidural anesthesia. For coagulation management, 1 mg of rFVIIa was intravenously administered before starting surgery. During surgery, FVII activity and prothrombin time-international normalized ratio (PT-INR) were maintained to be above 10 % and within the normal range (0.8-1.2), respectively. The surgery was uneventfully completed. Conclusions: We reported successful management of a patient with congenital FVII deficiency undergoing laparoscopic colectomy with monitoring of FVII activity and/or PT-INR. PMID- 29492427 TI - Relation between fentanyl dose and patient state index during spinal anesthesia for elective cesarean section. AB - Background: In spinal anesthesia for cesarean section, the addition of fentanyl to the local anesthetic has been reported to improve perioperative analgesia. However, there is only limited knowledge on sedative effects of the added fentanyl. We examined whether the patient state index(r) (PSI) can detect and present the light sedated level with patients undergoing cesarean section. Findings: We measured respiratory rate (RR), SpO2, and PSI values. Between child delivery and the completion of the operation, the proportions of time with the PSI values <90 and 80 were calculated. RR <8 breaths/min or SpO2 <95 % was defined as respiratory depression. Respiratory depression was not observed in any patient. At fentanyl doses of 10, 15, and 20 MUg, the proportions of time with the PSI <90 were 14.5 +/- 20.8, 49.4 +/- 35.3, and 71.1 +/- 22.9 %, respectively (P < 0.01). There were significant differences between 10 and 15 MUg (P < 0.05), and 10 and 20 MUg (P < 0.01). Similarly, the proportions of time with the PSI values <80 were 0.5 +/- 1.8, 21.1 +/- 24.1, and 31.8 +/- 32.2 %, respectively (P < 0.05). There was a significant difference between 10 and 20 MUg (P < 0.05). Conclusions: The PSI values decreased in a dose-dependent manner with increasing dose of fentanyl, but no respiratory depression was observed. The PSI values decreased to less than 90, when fentanyl was administered more than 15 MUg. Furthermore, the PSI values decreased to less than 80, when fentanyl was administered 20 MUg. PMID- 29492428 TI - Blood pressure shifts resulting from a concealed arteriovenous fistula associated with an iliac aneurysm: a case report. AB - Background: A solitary iliac aneurysm (SIA) is more uncommon than an abdominal aortic aneurysm. The aneurysm is located in the deep pelvis and is diagnosed when it reaches a large size with symptoms of compression around adjacent structures and organs or when it ruptures. A definite diagnosis of an arteriovenous fistula (AVF) associated with a SIA is difficult preoperatively because there might not be enough symptoms and time for diagnosis. Here, we present a patient with asymptomatic rupture of SIA into the common iliac vein with characteristic blood pressure shifts. Case presentation: A 41-year-old man with a huge SIA underwent aortobifemoral graft replacement. Preoperatively, his blood pressure showed characteristic shifts for one or two heartbeats out of five beats, indicating that an AVF was present and that the shunt was about to having a high flow. During surgery, an AVF associated with the SIA was found to be concealed owing to compression from the huge iliac artery aneurysm, and the shunt showed a high flow, resulting in shock during the surgery. No complications were noted after aortobifemoral graft replacement. Postoperatively, we noted an enhanced paravertebral vein on computed tomography (CT), which indicated the presence of an AVF. Conclusions: Definite diagnosis of an AVF offers advantages in surgical and anesthetic management. We emphasize that a large SIA can push the iliac vein and occlude an AVF laceration, concealing the enhancement of the veins in the arterial phase on CT. Blood pressure shifts might predict the existence of a concealed AVF that has a large shunt. Even if the vena cava and the iliac veins are not enhanced on CT, anesthesiologists should carefully determine whether their distal branches are enhanced. PMID- 29492426 TI - Therapeutic plasma exchange in heart transplantation: role of coagulation assessment with thromboelastometry. AB - Therapeutic plasma exchange (TPE) is a potentially life-saving procedure which effectively removes donor-specific human leukocyte antigen (HLA) antibodies from the bloodstream, allowing critically ill heart transplant recipients to receive a donor organ with less wait time, and reducing the risk of acute organ rejection. The bulk of coagulation factors is initially removed from the blood during TPE using albumin and is later replaced with allogeneic plasma. Coagulopathy may develop during TPE and then can persist due to intraoperative blood loss and hemodilution during surgery and cardiopulmonary bypass. We hereby describe the utility of rotational thromboelastometry to assess rapid coagulation changes during TPE and subsequent heart transplant (HT) surgery. PMID- 29492429 TI - Successful clavicle fracture surgery performed under selective supraclavicular nerve block using the new subclavian approach. AB - Objectives: Cervical nerves block cannot be performed on some patients because of the risk of phrenic nerve paralysis. To overcome this limitation, we discovered the site of selective only supraclavicular nerve block at the subclavian site. Case report: We present the case of a 62-year-old woman with clavicular fracture. We performed a selective block of the supraclavicular nerve and the fifth and sixth cervical nerves for the clavicle fracture surgery. Conclusions: We can perform selective supraclavicular nerve blocks for clavicular fracture surgery of patients who have bilateral pneumothorax. PMID- 29492430 TI - Emergency cardiac surgery and heparin resistance in a patient with essential thrombocythemia. AB - A 66-year-old man with thrombocytosis was brought to our hospital to undergo removal of a left ventricular thrombus. He had developed cerebral infarction 6 days before presenting to the hospital and suffered from right incomplete hemiparalysis. Blood tests on admission revealed his platelet count to be 124.3 * 104/MUl. The urgent removal operation was performed under general anesthesia. For carrying out extracorporeal circulation (ECC), approximately three times as much heparin as expected was needed, as well as antithrombin III (AT III) administration. This met the definition of heparin resistance. The thrombus was removed and surgical left ventricular reconstruction was performed. Aspirin and warfarin were initiated on postoperative day 5. A bone marrow biopsy was performed on postoperative day 8, which revealed hypercellular marrow with megakaryocyte proliferation, and the patient was diagnosed as having essential thrombocythemia (ET). Although hydroxycarbamide administration started on postoperative day 10, his platelet count increased to 290.7 * 104/MUl on postoperative day 13. The counts descended gradually, and on postoperative day 34, his platelet count reached the normal range and he was discharged from the hospital. In the perioperative period, his new neurologic abnormality did not appear. Addition of heparin, administration of AT III, and coating the cardiopulmonary bypass circuit with heparin or macromolecular polymer prevented clot formation and enabled safe ECC in a patient with ET and a high platelet count. PMID- 29492431 TI - Successful airway management using a MultiViewScope handle with a stylet scope in a patient with Schwartz-Jampel syndrome. AB - Schwartz-Jampel syndrome (SJS) is a rare disorder characterized by micrognathia, kyphoscoliosis, and myotonia. The greatest challenge in the anesthetic management of patients with SJS is performing tracheal intubation. The MultiViewScope (MVS) is a video laryngoscope system in which the video monitor handle can be attached to a stylet scope, laryngoscope blade, or fiberscope. We report a 21-month-old boy with SJS who required general anesthesia. Direct laryngoscopy was impossible because of his limited mouth opening; however, his trachea was easily intubated using an MVS handle with a stylet scope. The MVS is useful for managing difficult airways associated with SJS. PMID- 29492432 TI - Rapid development of a spinal epidural hematoma following thoracic epidural catheter removal in an esophageal carcinoma surgical patient: a case report. AB - Background: The occurrence of spinal epidural hematomas associated with the use of epidural catheters is relatively rare. Furthermore, it is unusual for hematoma associated neurological symptoms to occur within 15 min of removing a catheter. Here, we report our experience with an esophageal carcinoma surgical patient who developed an epidural hematoma almost immediately after catheter removal, resulting in paralysis of his lower extremities. The patient achieved full neurological recovery following prompt diagnosis and surgical intervention. Case presentation: A 68-year-old man was admitted with esophageal carcinoma and underwent video-assisted thoracoscopic esophagectomy followed by posterior mediastinal gastric tube reconstruction. During surgery, the patient was administered both general and epidural anesthesia. The epidural catheter was inserted approximately 5 cm into the epidural space at the Th6-7 level. The patient was extubated the following day in the general intensive care unit. Two days after surgery, the d-dimer level was high at 36.9 MUg/mL (reference range 0 0.9 MUg/mL), and we decided to administer an anticoagulant (enoxaparin sodium) to prevent thrombosis. The epidural catheter was removed 2 h prior to the scheduled administration of enoxaparin sodium. However, the patient reported a complete lack of strength in his lower extremities 15 min after catheter removal. Upon examination, the manual muscle testing score was 1 out of 5, and the patient experienced impaired touch sensation and cold sensation below Th4. An emergency magnetic resonance imaging scan was performed 2 h after catheter removal, which revealed a possible spinal epidural hematoma spreading from Th3 to Th6. Three hours after catheter removal, we began emergency surgery to evacuate the hematoma, which had spread to Th7. After surgery, the patient showed improvements in touch sensation, cold sensation, and motor function. The patient was able to walk 2 days after hematoma removal. Conclusions: It is highly unusual for a spinal epidural hematoma to develop so rapidly after the removal of an epidural catheter. This case emphasizes the need for vigilant patient monitoring, rapid diagnosis, and prompt surgery to ensure adequate neurological recovery in these patients. PMID- 29492433 TI - Perioperative posterior reversible encephalopathy syndrome in a patient with no history of hypertension: a case report. AB - Background: Posterior reversible encephalopathy syndrome is characterized by reversible neurological symptoms with leukoencephalopathy detectable by computed tomography (CT) and magnetic resonance (MR) imaging. Case presentation: We here present a patient with no history of hypertension who, after being transferred back to the ward after undergoing total hysterectomy under general anesthesia, had several seizures and lost consciousness. Posterior reversible encephalopathy syndrome was suspected on the basis of brain CT images and clinical findings. She was treated with respiratory support, sedative drugs, and anticonvulsants, and MR imaging confirmed a diagnosis of posterior reversible encephalopathy syndrome. She regained consciousness and responsiveness the following day. Conclusions: Clinically, posterior reversible encephalopathy syndrome resembles cerebral infarction or intracranial hemorrhage; MR imaging is useful for differentiating it from these conditions. Including this condition in the differential diagnosis and instituting appropriate treatment is important in minimizing the risk of development of irreversible neurological damage during the perioperative period. PMID- 29492434 TI - Lactate level during cardiopulmonary bypass as a predictor of postoperative outcomes in adult patients undergoing cardiac surgery. AB - Background: It has been reported that prolonged intensive care unit (ICU) stay after cardiac surgery is associated with poor patient outcome. In addition, prolonged stay can block the efficient use of ICU beds with an increase in expenditure of health-care costs. The aim of the present study was to retrospectively determine which pre- and intra-operative factors could significantly affect ICU-free survival days (IFSD) which has been suggested to reflect postoperative patients' outcome, as well as variables significantly associated with the main predictors of IFSD. Findings: We reviewed anesthesia charts and medical records of 145 patients undergoing cardiac surgery under cardiopulmonary bypass (CPB) in our hospital from January 2014 to October 2015, and 72 patients' records were finally used for the analysis. IFSD was a median of 25 days (95% CI 24-26). The multiple regression analysis indicated that preoperative estimated glomerular filtration rate, differences between preoperative mean arterial pressure and mean CPB pressure, and blood lactate level at 2 h after CPB (CPB-2 h) were independently associated with IFSD (beta regression coefficients 0.086, -0.083, and -3.601, respectively). Conclusion: In addition to preoperative renal function and differences between preoperative MAP and CPB pressure, the lactate level at CPB-2 h could be a major predictor of postoperative outcome in patients undergoing cardiac surgery. PMID- 29492435 TI - Surgery cancellations after entering the operating room. AB - Background: Surgery cancellation results in unavailability of the operating room and loss time. We identified the frequency of and reasons for operation cancellations after patients entered the operating room and assessed the preventability of such cancellations. Findings: A retrospective chart review of all scheduled surgical procedures proposed under general anesthesia in a period spanning 2008 to 2016 was performed, and the reasons for cancellation were assessed.A total of 30 surgery procedures were cancelled after the patient had entered the operation room and preparation for general anesthesia had been completed. Ten of 18 cases (55.6%) that were cancelled before general anesthesia induction could have been prevented, accounting for 36.7% of the overall cancellations. The majority of the cancellations after anesthesia were due to the patients' health status. Conclusions: Improving the systems for checking patients' medical problems and performing preoperative evaluations can reduce the number of cancellations after the patient has entered the operating room. PMID- 29492436 TI - A case of a giant cell myocarditis that developed massive left ventricular thrombus during percutaneous cardiopulmonary support. AB - Background: Giant cell myocarditis, characterized by infiltration of multinucleated giant cells in the myocardium, is a rare type of myocarditis. It often progresses rapidly into fulminant heart failure and indicates a poor prognosis. When a patient with giant cell myocarditis develops into severe myocarditis presenting with a cardiogenic shock, we should use a percutaneous cardiopulmonary support (PCPS), which could occur complications. We experienced a patient with giant cell myocarditis, who developed left ventricular thrombus formations during the circulation support therapy with PCPS for cardiogenic shock. Case presentation: A 60-year-old man who developed a cardiogenic shock was transferred to our hospital. After the admission, inotropic agents were increased and an intra-aortic balloon pumping was started. But these therapies did not improve his hemodynamic status. He was placed PCPS. Then, he underwent endomyocardial biopsy and was diagnosed with giant cell myocarditis. On the next morning, he developed complete atrioventricular block, and subsequently, thrombus formations occurred in his left ventricular outlet tract and Valsalva sinus despite an anticoagulant therapy. Thereafter, we intensified the anticoagulant therapy to prevent further thrombus formation, but he developed an intracranial hemorrhage. He did not recover from heart failure and died 16 days after the admission. Conclusions: We present a patient with giant cell myocarditis who developed widespread thrombosis in the left ventricle during the circulatory support with PCPS, despite anticoagulant therapy. In this case, decreased left myocardial contractility caused by giant cell myocarditis and increased left ventricular afterload by the retrograde perfusion from the PCPS induced the thrombotic tendency and congestion in the left ventricle. In addition, he developed complete atrioventricular block, which reduced the left ventricular ejection and enhanced the thrombus formation. Because patients with giant cell myocarditis have a low probability of spontaneous recovery, heart transplantation or ventricular assist device implantation may be required for circulatory support. We should establish mechanical circulatory support rapidly to improve the prognosis of patients with giant cell myocarditis. Moreover, a ventricular assist device, which can prevent both ventricular congestion and retrograde blood flow, might be suitable to prevent complications as this case. PMID- 29492437 TI - Anesthetic management of a patient with esophageal penetration of a tracheal stent: a case report. AB - Background: Tracheal stent is a good way to maintain a patent airway in case of stenosis. Although anesthesia techniques for the placement of a stent in the trachea of patients with tracheal stenosis have been reported, the management of general anesthesia in patients with a tracheal stent is not well established. Case presentation: We report the anesthetic management in the patient with a partly fractured tracheal stent. A 65-year-old man with colon cancer was scheduled for colectomy under general anesthesia. Eight years ago, a tracheal stent was placed because of lung cancer. Preoperative evaluation revealed that a part of the tracheal stent had penetrated the esophagus. We induced general epidural anesthesia via spontaneous breathing through a laryngeal mask airway to avoid mediastinal emphysema caused by positive pressure ventilation. The patient has been followed up for 2 years without any respiratory complications. Conclusion: General anesthesia can be safely induced under spontaneous ventilation through a laryngeal mask airway in a patient with a fractured tracheal stent. PMID- 29492438 TI - Peripheral nerve block with a high concentration of tetracaine dissolved in bupivacaine for intractable post-herpetic itch: a case report. AB - Background: Post-herpetic itch (PHI) is a neuropathic itch syndrome following herpes zoster. It has been reported that PHI is occasionally sufficiently severe to compromise patients' quality of life and frequently refractory to treatment. Here, we present a case of severe chronic PHI successfully treated with supraorbital nerve block using a high concentration of tetracaine dissolved in bupivacaine. Case presentation: An 82-year-old man presented with severe chronic itching in the ophthalmic branch of the left trigeminal nerve dermatome, following acute herpes zoster. The patient's itching was unresponsive to usual medical treatments for PHI including antiepileptic drugs, topical capsaicin cream, and supraorbital nerve radiofrequency thermo-coagulation. Topical lidocaine cream could relieve the itching, but could not provide long-term relief of itching and thus failed to achieve a satisfactory result. After these conventional treatments, left supraorbital nerve block using 4% tetracaine dissolved with 0.5% bupivacaine was conducted. Afterwards, the patient experienced long-lasting resolution of the itching with improvement of sleep disturbance. A transient, mild edema of the eyelids occurred, but there were no other complications. Conclusions: Peripheral nerve block using 4% tetracaine dissolved with 0.5% bupivacaine was beneficial in relieving PHI in the ophthalmic division of the trigeminal nerve. PMID- 29492439 TI - Bridging bronchus, type six, as a new rare case of a bronchial anomaly. AB - In 1976, Gonzales-Crussi et al. (Am. J. Dis. Child. 130:1015-18, 1976) introduced the first case of bridging bronchus as a rare bronchial branching anomaly; since then, only 14 worldwide cases was described. We suggest our case might be number 15 and could be the first case of type six of this bronchial anomaly. We present a case of a 10-month-old infant with bridging bronchus, congenital tracheal stenosis, and double outlet right ventricle who underwent major laparoscopic surgery for repair of gastrointestinal anomalies to raise awareness of this rare underdiagnosed congenital anomaly and a thorough discussion of the tracheobronchial anomalies and its clinical implications. PMID- 29492440 TI - Effect of arginine vasopressin on systemic and pulmonary arterial pressure in a patient with pulmonary hypertension secondary to pulmonary emphysema: a case report. AB - Although data from several studies support the use of arginine vasopressin (AVP) for the treatment of hypotension concomitant with pulmonary hypertension (PH) in the cardiac surgery setting, to our knowledge, no previous studies have reported the effect of AVP on the systemic and pulmonary circulation of patients with PH secondary to lung diseases. In this report, we present the hemodynamic responses to bolus administrations of AVP and noradrenaline in a patient with PH secondary to pulmonary emphysema. The patient showed low systemic vascular resistance hypotension during off-pump single-lung transplantation. The bolus administration of AVP (0.5 U) increased systemic arterial pressure by 35.2%, with a minimal change in pulmonary arterial pressure, resulting in a significant decrease in the pulmonary arterial pressure/systemic arterial pressure ratio. In contrast, the bolus administration of noradrenaline (10 or 20 MUg) increased both systemic and pulmonary arterial pressures by 14.8 and 6.7%, respectively. In summary, the bolus administration of AVP effectively increased systemic arterial pressure with a minimal effect on pulmonary arterial pressure in a patient with PH secondary to pulmonary emphysema. This case highlights the potential utility of AVP to treat low systemic vascular resistance hypotension in patients with PH secondary to lung diseases. PMID- 29492441 TI - Transforaminal epidural blood patch for intractable spontaneous cerebrospinal fluid leak: a case report. AB - Background: Epidural blood patch (EBP) is a recognized treatment for spontaneous cerebrospinal fluid leak (SCFL) and is typically administered by the interlaminar approach. Here, we report a case of a patient in whom SCFL failed to resolve after three applications of interlaminar EBPs before finally being successfully treated with transforaminal EBP. Case presentation: We report a case of a 41-year old female with a definitive diagnosis of SCFL according to computed tomography (CT) myelography. A fluoroscopy-guided interlaminar EBP was applied three times without resolution of her orthostatic headache. A second myelography was therefore performed demonstrating a leak point on the ventral side of the dura mater. To close the ruptured ventral dura mater, it was necessary to fill the ventral epidural space with blood. Therefore, transforaminal EBP was performed. On spinal CT performed immediately after treatment, the ventral epidural space was observed to be filled with injected blood. Her headache improved the following day, and her symptoms completely subsided after 5 days. Conclusion: Transforaminal epidural blood patch is appropriate for patients with intractable cerebrospinal fluid leak. Patients with cerebrospinal fluid leakage due to rupture of the ventral side of the dura mater may be particularly good candidates for this procedure. PMID- 29492442 TI - Rebound hyperkalemia after cessation of ritodrine in a parturient undergoing cesarean section. AB - A 36-year-old parturient with a suspicion of placenta accreta under tocolytic therapy with ritodrine infusion underwent emergency cesarean section under general anesthesia with propofol, ketamine, and remifentanil because massive bleeding was anticipated. The ritodrine infusion was discontinued 1 h before cesarean section. The baby was delivered 6 min after induction of anesthesia. However, after the manual removal of the placenta from the uterus, the bleeding was massive and uncontrollable. We rapidly transfused crystalloid, colloid, and red blood cells through potassium removal filter. Hyperkalemia (5.8 mmol/L) was detected just before blood transfusion. One hour later, hemostasis was still difficult, and hyperkalemia was promoted (6.1 mmol/L). Thus, glucose insulin therapy started with intravenous furosemide to treat hyperkalemia. Gynecologists decided to induce the Bakri balloon tamponade for the treatment of postpartum hemorrhage. At the end of surgery, plasma potassium level also reduced to 5.5 mmol/L. In the ICU, the bleeding still continued, and then radiologists performed bilateral internal iliac artery embolization for full hemostasis. Postoperative plasma potassium level was stable and 3.3 mmol/L in the next morning. Although one of the common adverse reactions of ritodrine is hypokalemia, we should also beware of a rebound hyperkalemia after its cessation. PMID- 29492443 TI - Breakage and retention of thoracic paravertebral catheter: a case report. AB - Background: Paravertebral catheters are generally inserted and removed without complications. However, catheter breakage occurs rarely. This is the first report describing breakage of a thoracic paravertebral catheter and retention of the catheter fragment within the patient. Case presentation: A 65-year-old female patient complained of an unusual sensation in her back during postoperative chemotherapy for lung cancer. A catheter fragment was identified in the soft tissues of the back on computed tomography. The paravertebral catheter had been placed 2 years prior left lower lobectomy. The patient had neither neurological symptoms nor infection signs around the fragment. However, the potential side effects of chemotherapy, including coagulopathy and immunosuppression, increased the risk of late-onset hematoma and abscess formation around the fragment. Therefore, we surgically removed the catheter fragment. Analysis of the fragment revealed that the catheter had been severed by the cutting edge of the Tuohy needle or the suture needle. Conclusion: In this report, a paravertebral catheter fragment was retained in the posterior mediastinum for 2 years. The catheter was likely damaged during the insertion procedure. We suggest that catheters should not be withdrawn through the Tuohy needle, but be withdrawn together with the Tuohy needle. Although secure fixation of the catheter can be achieved with sutures, to reduce the risk of damage to the catheter, alternative methods, such as surgical tapes or skin glue should be considered. After removal of a catheter, its tip should be checked to ensure that the entire catheter has been completely removed. If a catheter fragment is retained within the patient, removal of the fragment should be considered according to the patient's condition and risks. PMID- 29492445 TI - Interference with pulse oximetry by the Stealth StationTM Image Guidance System. AB - Background: A pulse oximeter is one of the most important monitors to save patients undergoing anesthesia and monitored sedation. The authors report a case of orthopedic surgery, in which interference of pulse oximetry occurred when using a Stealth StationTM navigation system (Medtronic Sofamor Danek, Memphis, TN). Applying a black plastic shield (Masimo Ambient Shield: Masimo Corporation, Irvine, CA) completely eliminated the interference. Case presentation: A 37-year old male patient with a giant cell tumor of the left femur was scheduled to undergo curettage of the femur using an intraoperative CT three-dimensional imaging system (O-armTM) and Stealth StationTM navigation system. During the surgery, the SpO2 value, which was maintained between 97 and 99% until the time, disappeared suddenly with abnormal pulse wave. Because a distortion in the SpO2 value was reproduced by repeated movement of cameras on the head of the Stealth StationTM navigation system, we recognized that the interference signal was coming from the navigation system. To eliminate the infrared light, the pulse oximetry probe was covered with a black plastic shield and the interference was completely eliminated. Conclusions: The Stealth StationTM navigation system was found to interfere with the SpO2 value, and a black plastic shield was useful for eliminating the interfering signal. Anesthesiologists should understand the risk of interference by the neuro-navigation system and know how to solve the problem. PMID- 29492444 TI - Does preoperative patient's estimated acceptable pain affect the satisfaction with postoperative pain management? AB - Background: Patient satisfaction with postoperative pain management is an important quality indicator in patient health care, but its determinants are poorly understood. Here, we examined the contribution of the discrepancy between an individual's estimated acceptable and actual postoperative pain scores to the overall satisfaction with pain treatment. Findings: A total of 93 surgical patients were included in this study. Preoperatively, the subjects were asked to rate their estimated acceptable postoperative pain using a numerical rating scale (NRS). One day after the surgery, the patients were again asked to give NRS ratings of the overall actual pain intensity they had experienced, as well as their satisfaction with the provided pain treatment. The median estimated acceptable and actual NRS values for postoperative pain were 4.0 (3.0-5.0) and 4.0 (2.0-5.0), respectively. Although there was no correlation between the degree of patient satisfaction and preoperative estimated acceptable pain intensity, there was a significant negative correlation between the degree of patient satisfaction and postoperative actual pain intensity. When the preoperative estimated acceptable NRS value was compared with the postoperative actual value for each individual, postoperative NRS was greater in 34 cases (36.6%), less in 43 cases (46.2%), and equal in 16 cases (17.2%). The degree of patient satisfaction was not significantly correlated with the magnitude of difference between preoperative estimated acceptable NRS and postoperative actual NRS. Conclusions: Our findings suggest that inquiring about the estimated acceptable pain before surgery may not help anesthesiologists to understand the patient's goal of pain management for improving patient satisfaction. PMID- 29492446 TI - A case of laparotomic cholecystectomy in a patient with biventricular assist devices. AB - We describe a patient with biventricular assist devices who had systemic inflammation because of cholecystitis that required open cholecystectomy, and we discuss the anesthetics and monitors that should be used in unstable patients with ventricular assist devices (VADs) who are undergoing major surgery. The patient was a 40-year-old man in the dilated phase of hypertrophic obstructive cardiomyopathy, who was implanted with an internal left VAD and external right VAD. We anesthetized the patient with a combination of a low dose of sevoflurane and ketamine to minimize vasodilation. We chose ketamine because we expected it to have a postoperative analgesic effect. An INVOSTM (Medtronic) monitor was beneficial, especially since the pulse oximeter did not work because of a pulse deficit. The FloTrachTM (Edwards Lifesciences) failed to measure the stroke volume and its variability. The left VAD, the Jarvik2000, did not show its flow rate. However, we were able to estimate that the flow was stabilized, because the flow rate of the right VAD was stable, and there was no significant change in both ventricles and septa, as shown on transesophageal echocardiography. PMID- 29492447 TI - Anesthetic management of a child with phosphomannomutase-2 congenital disorder of glycosylation (PMM2-CDG). AB - Background: Glycosylation is one of the major posttranslational modifications of proteins and it is essential for proteins to obtain normal biological functions. Congenital disorders of glycosylation (CDGs) are very rare genetic disorders that lack enzymes needed for glycosylation. Phosphomannomutase-2 (PMM2)-CDG is the most common type of CDG. CDGs can cause a wide variety of clinical symptoms in almost every organ system. Muscular hypotonia is often present in patients with CDGs and is one of the most notable problems for anesthetic management because the susceptibility to nondepolarizing neuromuscular blocking agents (NMBAs) in patients with CDGs is unknown. Case presentation: The patient was a 17-month-old boy who weighed 6.5 kg and was 71 cm tall. He presented for strabismus surgery. He had muscular hypotonia, mental retardation, hepatic dysfunction, mild cerebellar hypoplasia, and some dysmorphic features including inverted nipples and abnormal subcutaneous fat distribution of the hips. Gene analysis revealed a compound heterozygous mutation in the gene encoding PMM2 and the patient was diagnosed as having PMM2-CDG. General anesthesia was performed with sevoflurane, nitrous oxide, and rocuronium. Neuromuscular monitoring was performed during anesthesia using train-of-four (TOF)-Watch(r) (MSD, Japan). As postoperative analgesia, the surgeon performed sub-Tenon's anesthesia. We did not use any intravenous analgesic. After completion of the operation, residual rocuronium was competed by administration of sugammadex. The patient gained consciousness and spontaneous breathing was established shortly thereafter, and the trachea was smoothly extubated. He was transported to an inpatient ward and was discharged to his home the next day without any complication. Conclusions: We performed safe anesthetic management in a 17-month-old boy with PMM2-CDG using rocuronium under neuromuscular monitoring.A patient with PMM2-CDG may show nearly normal susceptibility to nondepolarizing NMBAs. PMID- 29492448 TI - Lipid emulsion injection-induced reversal of cardiac toxicity and acceleration of emergence from general anesthesia after scalp infiltration of a local anesthetic: a case report. AB - Background: A scalp block or wound infiltration of local anesthetic is thought to effectively control post-craniotomy pain. However, it can result in local anesthetic toxicity (LAST), which is difficult to distinguish from brain damage due to the surgical procedure when emergence from general anesthesia is delayed. Lipid rescue (infusion of a lipid emulsion) is a widely accepted treatment for LAST. Case presentation: A 64-year-old man underwent surgical resection of a glioma in the brainstem. While still under general anesthesia, and before suturing of the wound, he received a 20-mL scalp infusion of ropivacaine 0.75%. His emergence from anesthesia was delayed, his respiration was suppressed, and premature ventricular contractions occurred; all of which are symptoms of LAST. Injection of a 20% lipid emulsion rapidly alleviated these symptoms. Interestingly, the blood concentration of ropivacaine increased after lipid rescue. Conclusions: The increase in ropivacaine concentration in the blood after lipid rescue suggests that the intravenously administered lipid emulsion absorbed the ropivacaine from the intoxicated brain and heart tissue. This finding is consistent with the lipid sink theory as a mechanistic explanation of lipid rescue. PMID- 29492449 TI - Difficult tracheal intubation and post-extubation airway stenosis in an 11-month old patient with unrecognized subglottic stenosis: a case report. AB - Background: Subglottic stenosis can lead to life-threatening difficult tracheal intubation during general anesthesia. We report a case of difficult tracheal intubation in an 11-month-old female who had unrecognized subglottic stenosis. Case presentation: The patient was scheduled for elective correction of a right accessory auricle. She was suspected of having first and second branchial arch syndrome. Preoperative physical examination was normal. Anesthesia was induced uneventfully using sevoflurane. It was not possible to pass size 4.0, 3.5, or 3.0 cuffed endotracheal tubes due to an advanced subglottic lesion. Subsequent successful intubation was achieved using a 3.0 uncuffed tube. Stridor was audible after extubation, and the patient required several days' treatment with dexamethasone to address respiratory distress. Conclusions: We encountered unrecognized subglottic stenosis that led to difficult tracheal intubation and post-extubation airway stenosis. PMID- 29492450 TI - A case report of intracranial hemorrhage after spinal anesthesia. AB - Background: Chronic subdural hematoma (CSDH) after spinal anesthesia is a rare complication. We experienced a patient who developed CSDH after postdural puncture headache (PDPH) following combined spinal and epidural anesthesia (CSE). Case presentation: A 38-week-gestation parturient with a history of previous cesarean delivery underwent elective cesarean section under CSE. She had been receiving aspirin therapy for Kawasaki disease for many years. She developed a symptom of PDPH 1 day after the surgery. Fluid administration and analgesics were started. Although the headache was relatively severe and persistent, it suddenly disappeared on the third postoperative day. Aspirin administration was restarted on the third postoperative day, and the patient was discharged 1 week after the surgery. 2 weeks after being discharged, she was readmitted to our hospital for severe headache and was diagnosed as having CSDH. An epidural blood patch was performed, resulting in resolution of the hematoma. Conclusions: We experienced a case of CSDH after PDPH in a patient who was receiving aspirin therapy. Aspirin therapy should be restarted after confirmation of the absence of headache. We should consider the possibility of unexpected disappearance of PDPH in the postoperative period may be due to the development of CSDH. PMID- 29492451 TI - Preventative management against thromboembolism using fresh frozen plasma in a coronary artery bypass graft patient with protein S deficiency: a case report. AB - Protein S deficiency patient is characterized by recurrent thrombosis, and its risk is higher intraoperatively, especially in cardiac surgery involving cardiopulmonary bypass. Two heparin cessation periods are defined in cardiac surgery. One is the period between the cessation of heparin 4 to 5 h before surgery and the heparinization prior to cardiopulmonary bypass. The other is the period between protamine administration and resumption of heparin postoperatively. Because the risk of thromboembolism is high during the period of heparin cessation, other anticoagulants are necessary. Although fresh frozen plasma, rich in protein S, is often used in cardiac surgery for protein S deficiency patients, the most appropriate times and volume of its administration to prevent thromboembolism remain poorly understood. We herein report a case of on-pump coronary artery bypass grafting in a patient with protein S deficiency who received fresh frozen plasma targeting the two heparin cessation periods. Some qualitative measurements to identify the effect of fresh frozen plasma on the protein S level are desirable to evaluate whether our present administration strategy has any beneficial effects on protein S deficiency patients. PMID- 29492453 TI - Synchrotron x-ray imaging visualization study of capillary-induced flow and critical heat flux on surfaces with engineered micropillars. AB - Over the last several decades, phenomena related to critical heat flux (CHF) on structured surfaces have received a large amount of attention from the research community. The purpose of such research has been to enhance the safety and efficiency of a variety of thermal systems. A number of theories have been put forward to explain the key CHF enhancement mechanisms on structured surfaces. However, these theories have not been confirmed experimentally because of limitations in the available visualization techniques and the complexity of the phenomena. To overcome these limitations and elucidate the CHF enhancement mechanism on the structured surfaces, we introduce synchrotron x-ray imaging with high spatial (~2 MUm) and temporal (~20,000 Hz) resolutions. This technique has enabled us to confirm that capillary-induced flow is the key CHF enhancement mechanism on structured surfaces. PMID- 29492452 TI - The Neural Dynamics of Facial Identity Processing: Insights from EEG-Based Pattern Analysis and Image Reconstruction. AB - Uncovering the neural dynamics of facial identity processing along with its representational basis outlines a major endeavor in the study of visual processing. To this end, here, we record human electroencephalography (EEG) data associated with viewing face stimuli; then, we exploit spatiotemporal EEG information to determine the neural correlates of facial identity representations and to reconstruct the appearance of the corresponding stimuli. Our findings indicate that multiple temporal intervals support: facial identity classification, face space estimation, visual feature extraction and image reconstruction. In particular, we note that both classification and reconstruction accuracy peak in the proximity of the N170 component. Further, aggregate data from a larger interval (50-650 ms after stimulus onset) support robust reconstruction results, consistent with the availability of distinct visual information over time. Thus, theoretically, our findings shed light on the time course of face processing while, methodologically, they demonstrate the feasibility of EEG-based image reconstruction. PMID- 29492454 TI - A minimal RNA ligand for potent RIG-I activation in living mice. AB - We have developed highly potent synthetic activators of the vertebrate immune system that specifically target the RIG-I receptor. When introduced into mice, a family of short, triphosphorylated stem-loop RNAs (SLRs) induces a potent interferon response and the activation of specific genes essential for antiviral defense. Using RNA sequencing, we provide the first in vivo genome-wide view of the expression networks that are initiated upon RIG-I activation. We observe that SLRs specifically induce type I interferons, subsets of interferon-stimulated genes (ISGs), and cellular remodeling factors. By contrast, polyinosinic:polycytidylic acid [poly(I:C)], which binds and activates multiple RNA sensors, induces type III interferons and several unique ISGs. The short length (10 to 14 base pairs) and robust function of SLRs in mice demonstrate that RIG-I forms active signaling complexes without oligomerizing on RNA. These findings demonstrate that SLRs are potent therapeutic and investigative tools for targeted modulation of the innate immune system. PMID- 29492455 TI - The ancestral retinoic acid receptor was a low-affinity sensor triggering neuronal differentiation. AB - Retinoic acid (RA) is an important intercellular signaling molecule in vertebrate development, with a well-established role in the regulation of hox genes during hindbrain patterning and in neurogenesis. However, the evolutionary origin of the RA signaling pathway remains elusive. To elucidate the evolution of the RA signaling system, we characterized RA metabolism and signaling in the marine annelid Platynereis dumerilii, a powerful model for evolution, development, and neurobiology. Binding assays and crystal structure analyses show that the annelid retinoic acid receptor (RAR) binds RA and activates transcription just as vertebrate RARs, yet with a different ligand-binding pocket and lower binding affinity, suggesting a permissive rather than instructive role of RA signaling. RAR knockdown and RA treatment of swimming annelid larvae further reveal that the RA signal is locally received in the medial neuroectoderm, where it controls neurogenesis and axon outgrowth, whereas the spatial colinear hox gene expression in the neuroectoderm remains unaffected. These findings suggest that one early role of the new RAR in bilaterian evolution was to control the spatially restricted onset of motor and interneuron differentiation in the developing ventral nerve cord and to indicate that the regulation of hox-controlled anterior posterior patterning arose only at the base of the chordates, concomitant with a high-affinity RAR needed for the interpretation of a complex RA gradient. PMID- 29492456 TI - Quantum valence criticality in a correlated metal. AB - A valence critical end point existing near the absolute zero provides a unique case for the study of a quantum version of the strong density fluctuation at the Widom line in the supercritical fluids. Although singular charge and orbital dynamics are suggested theoretically to alter the electronic structure significantly, breaking down the standard quasi-particle picture, this has never been confirmed experimentally to date. We provide the first empirical evidence that the proximity to quantum valence criticality leads to a clear breakdown of Fermi liquid behavior. Our detailed study of the mixed valence compound alpha YbAlB4 reveals that a small chemical substitution induces a sharp valence crossover, accompanied by a pronounced non-Fermi liquid behavior characterized by a divergent effective mass and unusual T/B scaling in the magnetization. PMID- 29492457 TI - Observation of symmetry-protected topological band with ultracold fermions. AB - Symmetry plays a fundamental role in understanding complex quantum matter, particularly in classifying topological quantum phases, which have attracted great interests in the recent decade. An outstanding example is the time-reversal invariant topological insulator, a symmetry-protected topological (SPT) phase in the symplectic class of the Altland-Zirnbauer classification. We report the observation for ultracold atoms of a noninteracting SPT band in a one-dimensional optical lattice and study quench dynamics between topologically distinct regimes. The observed SPT band can be protected by a magnetic group and a nonlocal chiral symmetry, with the band topology being measured via Bloch states at symmetric momenta. The topology also resides in far-from-equilibrium spin dynamics, which are predicted and observed in experiment to exhibit qualitatively distinct behaviors in quenching to trivial and nontrivial regimes, revealing two fundamental types of spin-relaxation dynamics related to bulk topology. This work opens the way to expanding the scope of SPT physics with ultracold atoms and studying nonequilibrium quantum dynamics in these exotic systems. PMID- 29492458 TI - A surface-display biohybrid approach to light-driven hydrogen production in air. AB - Solar-to-chemical production by artificial and bioinspired photosynthetic systems is of tremendous interest to help solve current global energy and environmental problems. We developed a bioinorganic hybrid system for photocatalytic hydrogen production under aerobic conditions by combining light-harvesting semiconductors, hydrogenase catalysis, and self-aggregation of whole bacterial cells. We induced hydrogen production via self-photosynthesis in engineered Escherichia coli cells, which were originally designed for bioremediation, with in situ biosynthesis of biocompatible cadmium sulfide nanoparticles using a surface-display system. We also introduced a biomimetic silica encapsulation strategy into the engineered E. coli cells, enabling this hybrid system to continuously produce hydrogen for 96 hours, even under natural aerobic conditions. This biohybrid catalytic approach may serve as a general strategy for solar-to-chemical production. PMID- 29492460 TI - Amazon Tipping Point. PMID- 29492459 TI - Tunable Weyl and Dirac states in the nonsymmorphic compound CeSbTe. AB - Recent interest in topological semimetals has led to the proposal of many new topological phases that can be realized in real materials. Next to Dirac and Weyl systems, these include more exotic phases based on manifold band degeneracies in the bulk electronic structure. The exotic states in topological semimetals are usually protected by some sort of crystal symmetry, and the introduction of magnetic order can influence these states by breaking time-reversal symmetry. We show that we can realize a rich variety of different topological semimetal states in a single material, CeSbTe. This compound can exhibit different types of magnetic order that can be accessed easily by applying a small field. Therefore, it allows for tuning the electronic structure and can drive it through a manifold of topologically distinct phases, such as the first nonsymmorphic magnetic topological phase with an eightfold band crossing at a high-symmetry point. Our experimental results are backed by a full magnetic group theory analysis and ab initio calculations. This discovery introduces a realistic and promising platform for studying the interplay of magnetism and topology. We also show that we can generally expand the numbers of space groups that allow for high-order band degeneracies by introducing antiferromagnetic order. PMID- 29492461 TI - Secondary Lingular Sleeve Resection to Avoid Pneumonectomy Following Bronchial Anastomotic Dehiscence after Left Lower Lobe Sleeve Resection for Destroyed Lung Syndrome. AB - Bronchial sleeve resections are technically demanding procedures compared with lobectomies. In case of bronchial anastomotic dehiscence, secondary pneumonectomy is the treatment of choice. However, a secondary pneumonectomy is usually associated with high morbidity and mortality. Here, we first report, to the best of our knowledge, a secondary lingular sleeve resection following bronchial anastomotic dehiscence after left lower lobe sleeve resection in a patient with a destroyed lobe syndrome due to a pseudotumor. This approach enabled the avoidance of secondary pneumonectomy, hence reducing the possible pneumonectomy-associated complications. PMID- 29492462 TI - Open access: Is there a predator at the door? PMID- 29492463 TI - Health-related quality of life and economic burden of vestibular loss in older adults. AB - Objectives: Vestibular loss is a debilitating condition, and despite its high prevalence in older adults, the quality of life (QoL) burden of vestibular loss in older individuals has not been well-studied. This report quantifies the impact on overall QoL and identifies domains of health most affected. We hypothesize vestibular loss will be associated with impairment in diverse domains of health related QoL. Study Design: Prospective, case-control study. Methods: A convenience sample of 27 patients age >=60 years with vestibular physiologic loss was recruited from an academic neurotology clinic. The patients did not have any identifiable cause of their vestibular loss other than aging. The convenience sample was compared to an age-matched cross-sectional sample of the general US population (n = 1266). The main outcome was QoL measured by the Ontario Health Utilities Index Mark III (HUI3). Results: Compared to the general population, patients with vestibular loss had significantly lower overall unadjusted HUI3 scores (-0.32, p < 0.001). Multivariate regression analysis showed vestibular loss was significantly associated with poorer performance in vision (-0.11 p < 0.0001), speech (-0.15, p < 0.0001), dexterity (-0.13, p < 0.0001), and emotion ( 0.07, p = 0.0065). Adjusted aggregate HUI3 was also significantly lower for vestibular loss (-0.15, p = 0.0105). These QoL decrements resulted in an average loss of 1.30 Quality-Adjusted Life Years (QALYs). When using a $50,000/QALY willingness-to-pay threshold, vestibular loss was associated with a $64,929 lifetime economic burden per affected older adult, resulting in a total lifetime societal burden of $227 billion for the US population >=60 years of age. Conclusions: Loss of vestibular function with aging significantly decreases quality of life across multiple domains of well-being. These QoL reductions are responsible for heavy societal economic burdens of vestibular loss, which reveal potential benefits of prompt diagnosis and treatment of this condition. Level of Evidence: 3. PMID- 29492464 TI - A retrospective analysis on patients at high-risk for obstructive sleep apnea undergoing ear, nose, and throat surgeries. AB - Background: Obstructive sleep apnea (OSA) may be related to episodes of oxygen de saturation, hypercapnia, cardiovascular dysfunction, cor-pulmonale, and pulmonary hypertension. STOP-BANG is an acronym for eight specific questions used to assess the likelihood of OSA. If the individual exhibits three or more of these indicators, he/she should be considered to be at high risk for OSA complications. Therefore, the decision of proceeding with inpatient versus outpatient ENT surgery still remains controversial. The primary objective of the study was to identify and correlate desaturation (SPO2 <90%) episodes and risk factors. Methods: We conducted a single-center retrospective study between October 1, 2011 and August 31, 2014 in order to identify postoperative complications during the first 24 hours that justify postoperative monitoring and hospital admission. A total of 292 subjects were included for data analysis. Patients were divided into two groups based on the number of OSA risk factors: group A with 3-4 risk factors (n = 166), and group B with >=5 risk factors (n = 126). The following information was collected: demographics, ASA, preoperative STOP-BANG score, length of surgery, intraoperative complications, opioid consumption, post anesthesia care unit (PACU) and overall length of stay, supplemental oxygen requirement, oxygen desaturation, and postoperative opioid consumption. Results: No statistically significant difference was found when comparing demographic variables between both groups. All STOP-BANG variables showed statistical significance. PACU and inpatient variables were similar among both groups, with the exception of length of hospital stay (longer stay in group B when compared to group A [p = 0.003]). Desaturation differences between both groups during PACU were statistically significant (p = 0.008). A post-hoc analysis showed a 0% incidence of overall desaturation in the group with three STOP-BANG indicators. Conclusions: Our retrospective analysis concluded that patients diagnosed with three STOP-BANG risk factors did not experience postoperative complications and hospital admission was not justified. Level of Evidence: 4. PMID- 29492465 TI - Current and future management of recurrent respiratory papillomatosis. AB - Objectives: Recurrent respiratory papillomatosis (RRP) is a chronic disease of the respiratory tract that occurs in both children and adults. It is caused by the human papillomavirus (HPV), in particular low-risk HPV6 and HPV11, and aggressiveness varies among patients. RRP remains a chronic disease that is difficult to manage. This review provides perspectives on current and future management of RRP. Results: The current standard of care is surgical excision, with adjuvant therapies as needed. Surgical management of RRP has evolved with the introduction of microdebriders and photoangiolytic lasers; the latter can now be used in the office setting. Numerous adjuvant pharmacologic therapies have been utilized with some success. Also, exciting preliminary data show that HPV vaccines may prolong the time to recurrence in the RRP population. There is also optimism that wide-spread HPV vaccination could reduce RRP incidence indirectly by preventing vertical HPV transmission to newborns. Conclusion: To date, the biology of RRP is not well understood, although it has been noted to become more aggressive in the setting of immune suppression. Additional research is needed to better understand immune system dysfunction in RRP such that immunomodulatory approaches may be developed for RRP management. Level of Evidence: 4. PMID- 29492467 TI - Completion lymphadenectomy for sentinel node positive cutaneous head & neck melanoma. AB - : The application and utility of melanoma sentinel lymph node biopsy (SLNB) has evolved significantly since its inception over two decades ago. The current focus has shifted from a staging modality to potentially a therapeutic intervention. Recent research to include large multi-institutional randomized trials have attempted to answer the question: is a completion lymph node dissection (CLND) required following a positive SLNB? This review provides an evidence-based, contemporary review of the utility of CLND for SLNB positive head and neck cutaneous melanoma patients. Level of Evidence: NA. PMID- 29492466 TI - Olfactory epithelium: Cells, clinical disorders, and insights from an adult stem cell niche. AB - : Disorders causing a loss of the sense of smell remain a therapeutic challenge. Basic research has, however, greatly expanded our knowledge of the organization and function of the olfactory system. This review describes advances in our understanding of the cellular components of the peripheral olfactory system, specifically the olfactory epithelium in the nose. The article discusses recent findings regarding the mechanisms involved in regeneration and cellular renewal from basal stem cells in the adult olfactory epithelium, considering the strategies involved in embryonic olfactory development and insights from research on other stem cell niches. In the context of clinical conditions causing anosmia, the current view of adult olfactory neurogenesis, tissue homeostasis, and failures in these processes is considered, along with current and future treatment strategies. Level of Evidence: NA. PMID- 29492468 TI - Systematic review of the diagnostic value of magnetic resonance imaging for early glottic carcinoma. AB - Objective: In early glottic cancer, accurate assessment of tumor extension, including depth infiltration, is of great importance for both staging, therapeutic approach and systematic comparison of data. Our goal was to assess the diagnostic value of MRI in pre-therapeutic staging of primary early stage (T1 and T2) glottic carcinoma. Study design: Systematic review of literature. Methods: We conducted a systematic search in Pubmed, Embase, and Scopus up to September 23, 2016. Included studies were selected and critically appraised for relevance and validity. Results: Seven out of 938 unique articles were selected, including 64 cases. MRI over-staged 6% and under-staged 13% of cT1 and cT2 tumors. However, available data is heterogeneous, very limited and mainly based on subanalysis of a small amount of patients. Reported MRI protocols appear to be suboptimal for small laryngeal lesions. Diagnostic value of MRI for subtle depth infiltration or laryngeal anatomical subsites (eg, laryngeal ventricle, vocal cord, etc.) could not be assessed. Conclusions: More studies are needed to assess the diagnostic value of MRI for small glottic tumors. PMID- 29492471 TI - Ion channel gene expressions in infertile men: A case-control study. AB - Background: Infertility is described as not receiving pregnancy despite unprotected and regular sexual intercourse in a 1 yr period. It is detected by 15% of the couples. Male and female factor in the etiology may be detected in similar rates. Objective: The present study aims to investigate ion channel gene expression in semen samples of infertile male compared with fertile men. Materials and Methods: A total of 150 men who applied to the urology clinic due to infertility were divided into five equal groups: asthenozoospermia, oligozoospermia, oligoasthenoteratozoospermia, teratozoospermia, and normozoospermia (control). All paticipants were evaluated with Cation Channel Spermia (CatSper) 1, 2, 3, 4, Proton Voltage Gated Ion Channel1 (Hv1), Potassium Channel Subfamily U1 (KCNU1), and transmembrane protein (TMEM16A) gene expression in semen samples. Results: "CatSper1, 4, HV1, KCNU1, and TMEM16A gene expression were detected higher in the oligozoospermia group compared to the controls. CatSper1, 2, 3, 4, KCNU1, and TMEM16A gene expression in the asthenozoospermia group and CatSper1, 2, 3, 4, KCNU1, and TMEM16A gene expression in the teratozoospermia group were detected lower compared to the controls. CatSper1, 4, HV1, and TMEM16A gen expression were higher in the oligoasthenoteratozoospermia men than the controls while CatSper3 gen expression was detected as lower." Conclusion: It was detected that these ion channels have an effect on sperm progressive motility and morphology. It may be considered that mutations in these ion channels may result in infertility. PMID- 29492469 TI - Genomics of mucoepidermoid and adenoid cystic carcinomas. AB - Objective: To report on the current state of the literature on the genetics of mucoepidermoid and adenoid cystic carcinomas of the salivary glands with a focus on genomic screens and recently discovered genetic translocations. Methods: A PubMed based literature review was performed to query for genetics related basic science and preclinical studies about mucoepidermoid and adenoid cystic carcinomas of the salivary glands. Results and conclusions: Genetic translocations between CRTC1 and MAML2 in mucoepidermoid carcinoma and between MYB and NFIB in adenoid cystic carcinoma have been recently discovered and have therapeutic implications. Key signaling pathways such as the EGFR pathway in mucoepidermoid carcinoma and the Notch pathway, chromatin regulation, and c-kit mediated epithelial-mesenchymal transitions in adenoid cystic carcinoma have recently been elucidated, pointing to possible therapeutic targets in both cancers. PMID- 29492470 TI - Systemic Sclerosis Trial Design Moving Forward. AB - The 2013 ACR-EULAR classification criteria for systemic sclerosis (SSc) have shifted the construct of SSc. The new reality is that patients recruited for trials may not be so severe and not so advanced. We can now look for therapeutics that might stop disease evolution and/or prevent organ involvement. This article highlights recent advances in research methodology, and broadens the potential range of design and analytic considerations when planning a SSc trial. PMID- 29492472 TI - In vitro fertilization outcome in frozen versus fresh embryo transfer in women with elevated progesterone level on the day of HCG injection: An RCT. AB - Background: The effect of elevated progesterone level on human chorionic gonadotropin (HCG) day in in vitro fertilization cycles is controversial. Some suppose that rise in progesterone level seems to have a negative impact on implantation and pregnancy by desynchronizing the endometrium, while others disagree. Objective: To evaluate the superiority of the frozen cycle over fresh cycle on live birth in patients with elevated progesterone level on HCG day. Materials and Methods: In this double-blind, randomized clinical trial, 72 women undergoing assisted reproductive technology with elevated progesterone level (>=1.8 ng/dl) on HCG day were included. The participants were grouped by fresh versus frozen embryo transfer, randomly. Finally, the clinical pregnancy and live birth rate were compared. Results: The implantation rate was 21.51%. The clinical pregnancy rate was 47.22% in fresh embryo transfer group (17/36) and 41.66% in frozen group (15/36) (p=0. 40). The live birth rate was not significantly difference between two groups (p=0.56). Conclusion: None of the fresh and frozen cycles are superior to the other and we recommend individualizing the decision for each patient. The frozen cycle may impose more emotional stress on patients. PMID- 29492473 TI - Comparison the diagnostic value of serological and molecular methods for screening and detecting Chlamydia trachomatis in semen of infertile men: A cross sectional study. AB - Background: Chlamydia trachomatis (CT) with damaging effects on sperm quality parameters can often cause infertility in men. Objective: The main objective of this study was to determine the diagnostic value of polymerase chain reaction (PCR) and enzyme linked immuno sorbent assay (ELISA) for screening and detecting CT in semen samples of infertile men. Materials and Methods: In this cross sectional study, 465 men referring to the clinical laboratory of Royan Institute were chosen for primary screening and detection of the presence of CT. 93 samples were normozoospermia with normal sperm parameters i.e. sperm number, motility and morphology (Asymptomatic) and 372 had abnormal sperm parameters (Symptomatic) in semen analysis. ELISA test was performed as the screening test. Samples with optical density (OD) >0.200 were selected as the case and asymptomatic samples with OD <0.200 were selected as the control group for the confirmatory test. PCR assay was used to confirm the serological results. Results: In the case groups (n=62), 4 out of 32 symptomatic samples (12.5%), and 1 out of 30 asymptomatic samples (3.3%) revealed positive results in PCR. No PCR positive sample was observed in the control group (n=34). The final results revealed that considering OD >0.400 as the ELISA positive, the diagnostic value of CT-ELISA positive in symptomatic and asymptomatic infertile patients were 0.019 (7 of 372) and 0.021 (2 of 93), respectively. There was no relationship between the presence of CT infection and different sperm abnormalities. Conclusion: The anti-CT IgA ELISA test may be introduced as an appropriate tool for screening purpose in the seminal plasma to select suspicious samples for PCR confirmatory tests. PMID- 29492474 TI - Religious teachings and sexuality of women living in Rafsanjan: A qualiattive inquiry. AB - Background: Islamic doctrine and related teachings play a seminal role in constructing the sexual performance of followers, women in particular. Objective: The aim was to explore women's understandings of Islamic Shiite principles related to their sexuality. Materials and Methods: In a qualitative content analysis approach, four individual interviews and seven focus groups conducted in Rafsanjan, a big city in Kerman province in Iran. Content analysis was used to extract meanings and themes. Results: Three major themes were emerged describing the sexual concepts and religious-related teachings concerning women's sexual understandings and performances: "unconditional sexual submission" (Tamkin), "paradox between virtue and unconditional sexual submission" and "misconceptions". Conclusion: Religious teachings have a basic and comprehensive role in sexuality construction and sexual health of women. However, occasional inconsistency between beliefs, learning and sexual expectations, practices, and situations would lead to jeopardize the psychological and somatic health of women. Religious-related misconceptions have essential role in creating sexual problems. PMID- 29492475 TI - Supplementation of L-carnitine during in vitro maturation of mouse oocytes affects expression of genes involved in oocyte and embryo competence: An experimental study. AB - Background: Oocyte developmental competence is one of the key factors for determining the success rate of assisted reproductive technique. Objective: The aim of the current study was to investigate the effect of L-carnitine (LC) supplementation during in vitro maturation (IVM), on preimplantation embryo development and expression of genes involved in embryo competence derived from oocytes selected with brilliant cresyl blue (BCB) test. Materials and Methods: Cumulus-oocyte complexes (COCs) were obtained from NMRI mice ovaries. COCs were stained with BCB and then BCB+ (colored cytoplasm) oocytes cultured in IVM medium supplemented with 0.3 or 0.6 mg/ml LC. COCs untreated with LC were used as control. Fertilization rate and blastocyst development rate were determined after in vitro fertilization. In addition, quantitative reverse transcriptase polymerase chain reaction was used to measure relative genes expression related with development (Ccnb1, Mos, Ces5, and Dppa2) and apoptosis (Bax and Bcl-xL) in oocytes and embryos. Results: Oocytes treated with both LC concentrations showed higher blastocyst development rate compared with untreated oocytes (p<0.01). Moreover, fertilization rate was increased in oocytes treated with 0.6 mg/ml LC (p<0.01). Treatment of oocytes with both LC concentrations increased (p<0.01) the level of Ccnb1 mRNA in MII oocytes. The two-cell stage embryos and blastocysts derived from LC-treated oocytes (0.6 mg/ml) showed increased the expression levels of Dppa2 and Bcl-xl mRNA, respectively (p<0.01). Conclusion: The results of the present study show that adding of LC to the IVM medium of BCB+ oocytes can ameliorate reproductive success following in vitro fertilization. PMID- 29492476 TI - Does laparoscopy still has a role in modern fertility practice? AB - Background: More than 3 decades after the introduction of in vitro fertilization (IVF) and despite the improved success rates of assisted reproductive technologies, the argument for performing laparoscopy as a part of the infertility workup still stands. Objective: To evaluate the role of laparoscopy+/ hysteroscopy in diagnosis and management of infertility in our setting in view of modern fertility practice. Materials and Methods: This case control study was carried out on 600 infertile women subjected to laparoscopy or combined laparoscopy and hysteroscopy at endoscopy unit in Minia University Hospital, Egypt during the period from January 2012 to December 2014. Results: The causes of infertility as identified by laparoscopy+/-hysteroscopy were polycystic ovary syndrome (25.1%), tubal factor (30%), uterine cause (4%), and endometriosis (2.7%). No cause was identified in 38.2% of cases. Based on operative findings, women were treated with different options. Expectant management was used in 92 cases (15.3%). Ovulation induction with anti-estrogens or gonadotropins was used in 372 cases (62%). Sixty cases (10%) had intrauterine insemination and sixty four cases (10.7%) underwent in vitro fertilization (IVF) / intracytoplasmic sperm injection (ICSI) treatment. Within 1 yr after laparoscopy, 180 cases achieved pregnancy (30%). The most favorable outcome was recorded in women with unexplained infertility (36.7% of cases got pregnant) followed by women with polycystic ovary syndrome (27.8%). Participants with uterine and tubal infertility factor achieved pregnancy in 25% and 22.8% of cases, respectively. The worst outcome was recorded in women with endometriosis. Conclusion: Laparoscopy still has an important role in the diagnosis and treatment of infertility. PMID- 29492477 TI - Evaluation of the effect of follicular stimulating hormone on the in vitro bovine spermatogonial stem cells self-renewal: An experimental study. AB - Background: Spermatogonial stem cells (SSCs) are undifferentiated cells which are highly reproducible and expandable. Several studies have been conducted to reproduce these cells in culture. They used growth factors, hormones and different feeder cells to improve survival and proliferation of SSCs. Objective: This study was conducted to evaluate the effects of follicular stimulating hormone (FSH) on gene expression of fibroblast growth factor (FGF2) and glial cell-derived neurotrophic factor (GDNF) in Sertoli cells. Materials and Methods: Sertoli cells and SSCs were isolated from 3-5 month-old calves. Bovine testicular cells were cultured for 15 days with or without FSH. Identification of these cells was confirmed by immunocytochemistry analysis. Colony formation of SSCs was evaluated using an inverted microscope. The gene expression of FGF2 and GDNF and the gene markers bcl6b, thy-1, and C-kit were evaluated using the quantitative RT PCR technique. Results: The results indicated that FSH increased colonization of SSCs. the expression of GDNF, FGF2, and markers of undifferentiated spermatogonia was increased following culture in control and FSH groups (p<0.05), this increase was more in FSH group. Conversely, the expression of C-kit was decreased in both groups (p<0.05). Conclusion: The results showed that FSH can increase the self renewal of SSCs in vitro via upregulation of GDNF and FGF2 expression in Sertoli cells. PMID- 29492479 TI - Deserts in the Deluge: TerraPopulus and Big Human-Environment Data. AB - Terra Populus, or TerraPop, is a cyberinfrastructure project that integrates, preserves, and disseminates massive data collections describing characteristics of the human population and environment over the last six decades. TerraPop has made a number of GIScience advances in the handling of big spatial data to make information interoperable between formats and across scientific communities. In this paper, we describe challenges of these data, or 'deserts in the deluge' of data, that are common to spatial big data more broadly, and explore computational solutions specific to microdata, raster, and vector data models. PMID- 29492478 TI - Successful pregnancy and live birth after intrauterine administration of autologous platelet-rich plasma in a woman with recurrent implantation failure: A case report. AB - Background: Platelets contain a significant amount of growth factors that have positive effects on local tissue repair and endometrial receptivity. Case: Here we present a 45-yr-old woman with primary infertility and two failed in vitro fertilization (IVF) cycles who was candidate to receive donor eggs. Five consecutive frozen-thawed embryo transfer cycles with good quality embryos were performed within 2 yr. With the diagnosis of recurrent implantation failure (RIF), the patient was treated for improving endometrial receptivity with intrauterine administration of autologous platelet-rich plasma (PRP), 24 hr before embryo transfer. The patient gave birth to a healthy baby boy weighing 2350 gr in the cesarean section. Conclusion: Extensive literature search suggests that this is the first successful pregnancy after administration of PRP in a woman with RIF. Local administration of PRP before embryo transfer may play a vital role in successful implantation . PMID- 29492480 TI - Efficient simulation method for nano-patterned charged surfaces in an electrolyte solution. AB - We present a method to efficiently simulate nano-patterned charged surfaces inside an electrolyte solution. Simulations are performed in the grand canonical ensemble and are used to calculate the force between surfaces with various charge patterns. The electric field produced by the surfaces is calculated analytically and is used as an external potential. To treat the long range Coulomb interaction between the ions we use a modified 3d Ewald summation method. The force between the surfaces is found to depend strongly on the specific charge pattern, on the surface alignment and separation. PMID- 29492481 TI - Visualization and intracellular dynamic tracking of exosomes and exosomal miRNAs using single molecule localization microscopy. AB - Exosomes are small membrane vesicles secreted by a wide variety of cells. Studies have demonstrated that exosomal miRNAs can influence the biological processes of recipient cells. Therefore, direct imaging and tracking of exosomal miRNAs in living recipient cells are essential for exosome functional analysis. However, the moderate spatial resolution of conventional fluorescence microscopy limits the precise imaging and tracking of exosomes considering their relatively small size (<100 nm). Here, we took advantage of single molecule localization microscopy (SMLM) to realize the visualization and dynamic tracking of exosomes and exosomal miRNAs in living cells. First, we demonstrated simultaneous SMLM imaging of HeLa-derived exosomes and two kinds of exosomal miRNAs (mir-21 and mir 31) and tracked their movement after cellular uptake. The motion of exosomes within the intercellular filamentous structures was observed successfully. Moreover, dual-color SMLM based dynamic tracking revealed that as one kind of natural carrier of cellular cargoes, exosomes can encapsulate mir-21 inside to prevent enzyme degradation during transfer and then release them into recipient cells. These findings can provide new insights into the pathway of intercellular communication and affirm that SMLM is a powerful technique to track the motion of exosomes and exosomal contents in recipient cells. PMID- 29492482 TI - Symmetry strategies for high performance lanthanide-based single-molecule magnets. AB - Toward promising candidates of quantum information processing, the rapid development of lanthanide-based single-molecule magnets (Ln-SMMs) highlights design strategies in consideration of the local symmetry of lanthanide ions. In this review, crystal-field theory is employed to demonstrate the electronic structures according to the semiquantitative electrostatic model. Then, specific symmetry elements are analysed for the elimination of transverse crystal fields and quantum tunnelling of magnetization (QTM). In this way, high-performance Ln SMMs can be designed to enable extremely slow relaxation of magnetization, namely magnetic blocking; however, their practical magnetic characterization becomes increasingly challenging. Therefore, we will attempt to interpret the experimental behaviours and clarify some issues in detail. Finally, representative Ln-SMMs with specific local symmetries are summarized in combination with the discussion on the symmetry strategies, and some of the underlying questions are put forward. PMID- 29492483 TI - Synthetic polyprenol-pyrophosphate linked oligosaccharides are efficient substrates for mycobacterial galactan biosynthetic enzymes. AB - Mycobacteria, including the human pathogen Mycobacterium tuberculosis, produce a complex cell wall that is critical for their survival. The largest structural component of the cell wall, the mycolyl-arabinogalactan-peptidoglycan complex, has at its core a galactan domain composed of d-galactofuranose residues. Mycobacterial galactan biosynthesis has been proposed to involve two glycosyltransferases, GlfT1 and GlfT2, which elongate polyprenol-pyrophosphate linked glycosyl acceptor substrates using UDP-galactofuranose as the donor substrate. We here report the first chemical synthesis of GlfT1 and GlfT2 acceptor substrates containing pyrophosphate and polyprenol moieties (compounds 3, 4, 22 and 23). The approach involves chemical synthesis of an oligosaccharide, subsequent phosphorylation at the reducing end and coupling to a polyprenol phosphate. These compounds were shown to be substrates for either GlfT1 (22 and 23) or GlfT2 (3 and 4) and all were substantially more active than the corresponding alkyl glycoside substrates reported previously. Mass spectrometric analysis of the products formed from the reaction of 3, 4, 22 and 23 with the respective cognate enzyme and UDP-galactofuranose provide additional evidence for the galactan biosynthetic model in which GlfT1 adds the first two galactofuranose residues with the remainder being installed via GlfT2. Overall, these results highlight the importance of the pyrophosphate motif in recognition of acceptor substrates by both enzymes and demonstrate a straightforward route for the preparation of such compounds. The work also provides additional support for the process by which this important glycan is biosynthesized using, for the first time, close structural analogs to the natural substrates. PMID- 29492484 TI - Associative behaviour and effect of functional groups on the fluorescence of graphene oxide. AB - We have juxtaposed the structural, vibrational and emission properties of graphene oxide (GO) with various degrees of reduction with and without a model dispersant, unveiling a strong associative behavior between GO sheets and the influence of H-bonds. The interlayer spacings are ~0.84 and 0.78 nm for the as prepared and reduced samples. -OH groups are predominantly effected by the photo thermal reduction. Also we note some regeneration of [double bond splayed left]C[double bond, length as m-dash]O and -COOH groups in reduced samples. Clear changes to the phonon density of states indicated the doping effects due to H bonds via the oxygeneous groups. Importantly, the defect related Raman bands are rather prone to the effect of dispersant, unveiling their intrinsic nature. In the context of fluorescence, internal vibration relaxation mediated by CC stretch vibrations emphasized the localized nature of sp2 domains of relatively smaller size. Fluorescence consists of 6 components, where the higher energy components are more influenced due to H-bonds than those of the lower energy regime, attributed to their associative behavior and chemical functionality, respectively. Excitation dependent fluorescence measurements indicated a range of optical gaps from ~3.5 to 2 eV. The associative behavior of GO and rGO with and without a dispersant provides crucial insights into the fundamental understanding of various molecular processes. PMID- 29492485 TI - Evidence of transboundary mercury and other pollutants in the Puyango-Tumbes River basin, Ecuador-Peru. AB - In Portovelo in southern Ecuador, 87 gold processing centers along the Puyango Tumbes River produce an estimated 6 tonnes of gold per annum using a combination of mercury amalgamation and/or cyanidation and processing poly-metallic ores. We analysed total Hg, Hg isotopes, total arsenic, cadmium, copper, lead and zinc in water and sediment along the Puyango in 2012-2014. The highest total mercury (THg) concentrations in sediments were found within a 40 km stretch downriver from the processing plants, with levels varying between 0.78-30.8 mg kg-1 during the dry season and 1.80-70.7 mg kg-1 during the wet season, with most concentrations above the CCME (Canadian Council of Ministers of the Environment) Probable Effect Level (PEL) of 0.5 mg kg-1. Data from mercury isotopic analyses support the conclusion that mercury use during gold processing in Portovelo is the source of Hg pollution found downstream in the Tumbes Delta in Peru, 160 km away. The majority of the water and sediment samples collected from the Puyango Tumbes River had elevated concentrations of, arsenic, cadmium, copper, lead and zinc exceeding the CCME thresholds for the Protection of Aquatic Life. At monitoring points immediately below the processing plants, total dissolved concentrations of these metals exceeded the thresholds by 156-3567 times in surface waters and by 19-740 times in sediment. The results illustrate a significant transboundary pollution problem involving Hg and other toxic metals, amplified by the fact that the Puyango-Tumbes River is the only available water source in the semi-arid region of northern Peru. PMID- 29492486 TI - A molecular quantum switch based on tunneling in meta-d-phenol C6H4DOH. AB - We introduce the concept of a molecular quantum switch and demonstrate it with the example of meta-d-phenol, based on recent theoretical and high-resolution spectroscopic results for this molecule. We show that in the regime of tunneling switching with localized low-energy states and delocalized high-energy states the molecular quantum switch can be operated in two different ways: (i) a quasiclassical switching by coherent infrared radiation between the two isomeric structures syn- and anti-m-d-phenol; and (ii) a highly nonclassical switching making use of bistructural quantum superposition states of the syn and anti structures, which can be observed by their time-dependent spectra after preparation. PMID- 29492487 TI - The precipitation, growth and stability of mercury sulfide nanoparticles formed in the presence of marine dissolved organic matter. AB - The methylation of mercury is known to depend on the chemical forms of mercury (Hg) present in the environment and the methylating bacterial activity. In sulfidic sediments, under conditions of supersaturation with respect to metacinnabar, recent research has shown that mercury precipitates as beta-HgS(s) nanoparticles (beta-HgS(s)nano). Few studies have examined the precipitation of beta-HgS(s)nano in the presence of marine dissolved organic matter (DOM). In this work, we used dynamic light scattering (DLS) coupled with UV-Vis spectroscopy and transmission electron microscopy (TEM) to investigate the formation and fate of beta-HgS(s)nano formed in association with marine DOM extracted from the east and west of Long Island Sound, and at the shelf break of the North Atlantic Ocean, as well as with low molecular weight thiols. We found that while the beta-HgS(s)nano formed in the presence of oceanic DOM doubled in size after 5 weeks, those forming in solutions with coastal DOM did not grow over time. In addition, when the HgII : DOM ratio was varied, beta-HgS(s)nano only rapidly aggregated at high ratios (>41 MUmol HgII per mg C) where the concentration of thiol groups was determined to be substantially low relative to HgII. This suggests that functional groups other than thiols could be involved in the stabilization of beta-HgS(s)nano. Furthermore, we showed that beta-HgS(s)nano forming under anoxic conditions remained stable and could therefore persist in the environment sufficiently to impact the methylation potential. Exposure of beta-HgS(s)nano to sunlit and oxic environments, however, caused rapid aggregation and sedimentation of the nanoparticles, suggesting that photo-induced changes or oxidation of organic matter adsorbed on the surface of beta-HgS(s)nano affected their stability in surface waters. PMID- 29492488 TI - Hierarchical Fe-doped Ni3Se4 ultrathin nanosheets as an efficient electrocatalyst for oxygen evolution reaction. AB - Developing highly efficient oxygen evolution reaction (OER) electrocatalysts is critical to the cost-effective generation of clean fuels. Transition-metal selenides have been proposed to be OER catalyst alternatives to noble metal based catalysts, but generally exhibit limited electrocatalytic activity. We here report hierarchical Fe-doped Ni3Se4 ((Ni,Fe)3Se4) ultrathin nanosheets as an efficient electrocatalyst for OER in alkaline electrolytes. The preparation involves a solvothermal synthesis and a topotactic conversion process. The prepared hierarchical (Ni,Fe)3Se4 ultrathin nanosheets show abundant and accessible catalytically active sites, facile charge transfer and a high specific surface area. Relative to the Ni3Se4 nanosheets, the as-prepared (Ni,Fe)3Se4 ultrathin nanosheets show a higher current density and a lower Tafel slope towards the OER. Remarkably, hierarchical (Ni,Fe)3Se4 ultrathin nanosheets supported on Ni foam exhibit an electrocatalytic OER with a current density of 10 mA cm-2 at a low overpotential of 225 mV and a small Tafel slope of about 41 mV dec-1. This study establishes (Ni,Fe)3Se4 ultrathin nanosheets as an efficient electrocatalyst for the OER that can be used in the fields of metal-air batteries and water splitting for hydrogen production. PMID- 29492490 TI - Electroosmosis near surfactant laden liquid-air interfaces. AB - Generation of an electroosmostic (EO) flow near a liquid-gas interface covered with ionic surfactants is experimentally investigated. A combination of microscopic flow measurements with a molecular characterization of the interface by second harmonic generation (SHG) shows that under an electrical forcing, although a liquid flow is generated below the free surface, the surfactants remain immobile. The zeta potential was then determined and compared to the surfactant surface coverage. This combination of experimental techniques opens the route to simultaneously probe the liquid flow near a soapy interface and the corresponding surfactant repartition affecting the hydrodynamic boundary condition. PMID- 29492489 TI - Chlorinated cobalt alkyne complexes derived from acetylsalicylic acid as new specific antitumor agents. AB - [(Prop-2-ynyl)-2-acetoxybenzoate]dicobalthexacarbonyl (Co-ASS), an organometallic derivative of the irreversible cyclooxygenase-1/2 (COX-1/2) inhibitor acetylsalicylic acid (ASS), demonstrated high growth-inhibitory potential against various tumor cell lines and inhibition of both COX isoenzymes. With the objective of increasing the selectivity for COX-2, we introduced a chlorine substituent in position 3, 4, 5, or 6 of the ASS moiety, respectively. Increased COX-2 selectivity is desirable as this isoenzyme is predominantly related to the development of cancer and abnormal tissue growth. The new compounds were investigated in comprehensive cellular biological assays to identify the impact of the chlorine substitution at the complex on COX-1/2 inhibition, antiproliferative activity, apoptosis, metabolic activity, cell-based COX inhibition, and cellular uptake. Chlorination distinctly reduced the effects at isolated COX-1 (about 25% inhibition at 10 MUM; Co-ASS: 82.7%), while those at COX-2 remained almost unchanged (about 65% inhibition at 10 MUM; Co-ASS: 78.5%). In cellular systems, with exception of the 6-Cl derivative, all compounds showed notable antitumor activity in COX-1/2 expressing tumor cells (HT-29 (IC50 = 1.5 2.7 MUM), MDA-MB-231 (IC50 = 5.2-8.0 MUM)), but were distinctly less active in the COX-1/2-negative MCF-7 breast cancer cell line (IC50 = 15.2-22.9 MUM). All complexes possess high selectivity for tumor cells, because they did not influence the growth of the non-tumorigenic, human bone marrow stromal cell line HS-5. These findings clearly demonstrate that the interference with the COX-1/2 cascade contributes to the mode of anticancer action of the cobalt alkyne complexes. PMID- 29492491 TI - Barbituric acid-modified graphitic carbon nitride nanosheets for ratiometric fluorescent detection of Cu2. AB - In this work, barbituric acid-modified graphitic carbon nitride (BCN) nanosheets with blue-green fluorescence were prepared by a copolymerization of dicyandiamide with barbituric acid and then by a chemical oxidation process. A ratiometric fluorescent sensor for Cu2+ was designed by using BCN nanosheets as the report probe and Ru(bpy)3Cl2 as the reference probe. In the presence of different concentrations of Cu2+, the blue-green fluorescence of BCN nanosheets was drastically quenched, while the red fluorescence of Ru(bpy)3Cl2 remained constant. The color of the sensor changed from blue-green to red, resulting in ratiometric and visual detection of Cu2+ ions. The detection limit for Cu2+ was estimated to be 70 nM, and as low as 5 MUM Cu2+ was distinguished with the naked eye. Additionally, this sensor was also applied for the detection of Cu2+ in tap water samples. PMID- 29492492 TI - Negative effective Li transference numbers in Li salt/ionic liquid mixtures: does Li drift in the "Wrong" direction? AB - The electrophoretic mobilities MU of all ion species in the lithium salt/ionic liquid mixtures LiTFSA/EmimTFSA and LiBF4/EmimBF4 are determined by 1H, 19F and 7Li electrophoretic NMR. The average drift direction of Li is identical to that of the anions TFSA- or BF4-. This proves a correlated ion motion of Li with the anions in negatively charged Li-containing clusters in both systems. The effective charge of these clusters is determined as -1, or -2 in the system with TFSA or BF4, respectively, pointing at the existence of [Li(TFSA)2]- or [Li(BF4)3]2-. This behavior is described by a negative effective transference number of Li, resulting in a negative contribution of Li ions to the overall conductivity. Li effective transference numbers are in the range of -0.04 to 0.02, depending on Li salt concentration and anion type. Transference numbers thus clearly deviate from apparent transference numbers estimated from diffusion coefficients, as an effect of a vehicular transport mechanism. This has important implications for the mechanism of Li mass transport in Li ion batteries as the drift of charged clusters has to be overcompensated by diffusive mass transport of neutral, Li-containing aggregates. PMID- 29492493 TI - Encapsulation of metal nanostructures into metal-organic frameworks. AB - Metal-organic frameworks (MOFs) have been demonstrated to be excellent hosts for metal nanostructures. Herein, a perspective of recent development achieved to control the location, composition, shape, and structure of the encapsulated metal nanostructures is provided. The interesting properties and potential applications of the designed metal@MOF composites as well as future challenges and opportunities in this field are also discussed. PMID- 29492494 TI - Controlled doping of transition metal dichalcogenides by metal work function tuning in phthalocyanine compounds. AB - We explored surface charge transfer interaction between a family of phthalocyanine (Pc) compounds and transition metal dichalcogenides (TMDs). Comparing the device characteristics of TMD field-effect transistors (FETs), we demonstrate both p-type and n-type doping of TMDs by tuning the work function of the metal substitution in the Pc compound. Our findings suggest a near linear correlation between the metal work function and doping level. Such doping predictability has yet to be achieved whereas we provide here the first report of its kind. PMID- 29492495 TI - Comment on "Methanol dimer formation drastically enhances hydrogen abstraction from methanol by OH at low temperature" by W. Siebrand, Z. Smedarchina, E. Martinez-Nunez and A. Fernandez-Ramos, Phys. Chem. Chem. Phys., 2016, 18, 22712. AB - The article "Methanol dimer formation drastically enhances hydrogen abstraction from methanol by OH at low temperature" proposes a dimer mediated mechanism in order to explain the large low temperature rate coefficients for the OH + methanol reaction measured by several groups. It is demonstrated here theoretically that under the conditions of these low temperature experiments, there are insufficient dimers formed for the proposed new mechanism to apply. Experimental evidence is also presented to show that dimerization of the methanol reagent does not influence the rate coefficients reported under the conditions of methanol concentration used for the kinetics studies. It is also emphasised that the low temperature experiments have been performed using both the Laval nozzle expansion and flow-tube methods, with good agreement found for the rate coefficients measured using these two distinct techniques. PMID- 29492496 TI - Singlet and triplet energy transfer dynamics in self-assembled axial porphyrin anthracene complexes: towards supra-molecular structures for photon upconversion. AB - Energy and electron transfer reactions are central to many different processes and research fields, from photosynthesis and solar energy harvesting to biological and medical applications. Herein we report a comprehensive study of the singlet and triplet energy transfer dynamics in porphyrin-anthracene coordination complexes. Seven newly synthesized pyridine functionalized anthracene ligands, five with various bridge lengths and two dendrimer structures containing three and seven anthracene units, were prepared. We found that triplet energy transfer from ruthenium octaethylporphyrin to an axially coordinated anthracene is possible, and is in some cases followed by back triplet energy transfer to the porphyrin. The triplet energy transfer follows an exponential distance dependence with an attenuation factor, beta, of 0.64 A-1. Further, singlet energy transfer from anthracene to the ruthenium porphyrin appears to follow a R6 Forster distance dependence. Porphyrin-anthracene complexes are also used as triplet sensitizers for triplet-triplet annihilation (TTA) based photon upconversion, demonstrating their potential for photophysical and photochemical applications. The triplet lifetime of the complex is extended by the anthracene ligands, resulting in a threefold increase in the upconversion efficiency, PhiUC to 4.5%, compared to the corresponding ruthenium porphyrin-pyridine complex. Based on the results herein we discuss the future design of supra-molecular structures for TTA upconversion. PMID- 29492497 TI - Reversible light-mediated compositional and structural transitions between CsPbBr3 and CsPb2Br5 nanosheets. AB - This communication describes a new method to achieve reversible light-induced chemical composition and phase structural transitions from polyvinylpyrrolidone capped orthorhombic CsPbBr3 to tetragonal CsPb2Br5 nanosheets or vice versa. This work will deepen our understanding of the controlled synthesis, post-processing, and decomposition pathway of cesium lead halide perovskite nanocrystals. PMID- 29492498 TI - Interspecies differences in the cytochrome P450 activity of hepatocytes exposed to PLGA and silica nanoparticles: an in vitro and in vivo investigation. AB - Nanomedicines represent a promising approach in the treatment and diagnosis of numerous disorders. The majority of the injected dose of nanoparticles (NPs) is sequestrated in the liver. Despite this hepatic tropism, the interaction of NPs with the detoxification function of the liver remains unclear. The present study consists of evaluating the impact of biodegradable poly(lactide-co-glycolide) (PLGA) and silica NPs on cytochrome P450 (CYP) activities. The effects of NPs were evaluated in vitro on human and rat hepatocytes in primary cultures and in vivo by intravenous injections in healthy rats. More than the physicochemical properties, the composition of NPs (organic, inorganic) dramatically influenced the detoxification function of the liver. Silica NPs modulated the CYP activity both in rat and human hepatocytes, in contrast to PLGA NPs. A CYP isoform dependent effect was reported and the modulation of the metabolic hepatic activity was species-dependent. Human hepatocytes were sensitive to an exposure to PLGA NPs, whereas no marked effect was detected in rat hepatocytes. The in vitro data obtained in rat hepatocytes were correlated with the in vivo data. This study emphasizes the interest to set up relevant in vitro models using human hepatic cells to evaluate the hepatotoxicity of nanomedicines. PMID- 29492499 TI - Synthesis of silyl iron hydride via Si-H activation and its dual catalytic application in the hydrosilylation of carbonyl compounds and dehydration of benzamides. AB - The hydrido silyl iron complex (o-Ph2PC6H4SiMe2)Fe(PMe3)3H (2) was obtained via the activation of the Si-H bond of the bidentate silyl ligand o-Ph2P(C6H4)SiMe2H (1) by Fe(PMe3)4. 2 showed good to excellent catalytic activity in both the reduction of aldehydes/ketones and the dehydration of benzamide. In addition, with complex 2 as a catalyst, alpha,beta-unsaturated carbonyls could be selectively reduced to the corresponding alpha,beta-unsaturated alcohols. The mechanisms of the formation of 2 and the catalytic dehydration process are proposed and partly experimentally verified. PMID- 29492500 TI - Ultra-fast dynamics in the nonlinear optical response of silver nanoprism ordered arrays. AB - In this work we present the study of the ultra-fast dynamics of the nonlinear optical response of a honeycomb array of silver triangular nanoprisms, performed using a femtosecond pulsed laser tuned with the dipolar surface plasmon resonance of the nanoarray. Nonlinear absorption and refraction, and their time-dependence, were explored using the z-scan and time-resolved excite-probe techniques. Nonlinear absorption is shown to change sign with the input irradiance and the behavior was explained on the basis of a three-level model. The response time was determined to be in the picosecond regime. A technique based on a variable frequency chopper was also used in order to discriminate the thermal and electronic contributions to the nonlinearity, which were found to have opposite signs. All these findings propel the investigated nanoprism arrays as good candidates for applications in advanced ultra-fast nonlinear nanophotonic devices. PMID- 29492502 TI - Electrochemical nanoarchitectonics through polyaminobenzylamine-dodecyl phosphate complexes: redox activity and mesoscopic organization in self-assembled nanofilms. AB - Molecular design and preparation of redox active films displaying mesoscopic levels of organization represents one of the most actively pursued research areas in nanochemistry. These mesostructured materials are not only of great interest at the fundamental level because of their unique properties but they can also be employed for a wide range of applications such as electrocatalysts, electronic devices, and electrochemical energy conversion and storage. Herein, we introduce a simple and straightforward strategy to chemically modify electrode surfaces with self-assembled electroactive polyelectrolyte-surfactant complexes. These assemblies are composed of amino-appended polyaniline and monododecyl phosphate. The complexes were deposited by spin-coating and the films were characterized by spectroscopic and X-ray-based techniques: XRR, GISAXS, WAXS, and XPS. The films presented a well-defined lamellar structure, directed by the strong interaction between the phosphate groups and the positively charged amine groups in the polyelectrolyte. These films also displayed intrinsic electroactivity in both acidic and neutral solutions, showing that the polymer remains electroactive and ionic transport is still possible through the stratified and hydrophobic coatings. The stability and enhanced electroactivity in neutral solutions make these assembled films promising building blocks for the construction of nanostructured electrochemical platforms. PMID- 29492501 TI - Polymer tube nanoreactors via DNA-origami templated synthesis. AB - We describe the stepwise synthesis of precise polymeric objects programmed by a 3D DNA tube transformed from a common 2D DNA tile as a precise biotemplate for atom transfer radical polymerization. The catalytic interior space of the DNA tube was utilized for synthesizing a bio-inspired polymer, polydopamine. PMID- 29492503 TI - Bioinks for 3D bioprinting: an overview. AB - Bioprinting is an emerging technology with various applications in making functional tissue constructs to replace injured or diseased tissues. It is a relatively new approach that provides high reproducibility and precise control over the fabricated constructs in an automated manner, potentially enabling high throughput production. During the bioprinting process, a solution of a biomaterial or a mixture of several biomaterials in the hydrogel form, usually encapsulating the desired cell types, termed the bioink, is used for creating tissue constructs. This bioink can be cross-linked or stabilized during or immediately after bioprinting to generate the final shape, structure, and architecture of the designed construct. Bioinks may be made from natural or synthetic biomaterials alone, or a combination of the two as hybrid materials. In certain cases, cell aggregates without any additional biomaterials can also be adopted for use as a bioink for bioprinting processes. An ideal bioink should possess proper mechanical, rheological, and biological properties of the target tissues, which are essential to ensure correct functionality of the bioprinted tissues and organs. In this review, we provide an in-depth discussion of the different bioinks currently employed for bioprinting, and outline some future perspectives in their further development. PMID- 29492504 TI - Interfacial electrostatics of poly(vinylamine hydrochloride), poly(diallyldimethylammonium chloride), poly-l-lysine, and poly-l-arginine interacting with lipid bilayers. AB - Charge densities of cationic polymers adsorbed to lipid bilayers are estimated from second harmonic generation (SHG) spectroscopy and quartz crystal microbalance with dissipation monitoring (QCM-D) measurements. The systems surveyed included poly(vinylamine hydrochloride) (PVAm), poly(diallyldimethylammonium chloride) (PDADMAC), poly-l-lysine (PLL), and poly-l arginine (PLR), as well as polyalcohol controls. Upon accounting for the number of positive charges associated with each polyelectrolyte, the binding constants and apparent free energies of adsorption as estimated from SHG data are comparable despite differences in molecular masses and molecular structure, with DeltaGads values of -61 +/- 2, -58 +/- 2, -57 +/- 1, -52 +/- 2, -52 +/- 1 kJ mol 1 for PDADMAC400, PDADMAC100, PVAm, PLL, and PLR, respectively. Moreover, we find charge densities for polymer adlayers of approximately 0.3 C m-2 for poly(diallyldimethylammonium chloride) while those of poly(vinylamine) hydrochloride, poly-l-lysine, and poly-l-arginine are approximately 0.2 C m-2. Time-dependent studies indicate that polycation adsorption to supported lipid bilayers is only partially reversible for most of the polymers explored. Poly(diallyldimethylammonium chloride) does not demonstrate reversible binding even over long timescales (>8 hours). PMID- 29492505 TI - Water desorption from a confined biopolymer. AB - We study desorption of water from a confined biopolymer (chitosan thin films) by employing temperature dependent specular X-ray reflectivity and spectroscopic ellipsometry. The water desorption is found to occur via three distinct stages with significantly different desorption rates. The distinct rates of water desorption are attributed to the presence of different kinds of water with disparate mobilities inside the biopolymer film. We identify two characteristic temperatures (Tc1 and Tc2) at which the water desorption rate changes abruptly. Interestingly, the characteristic temperatures decrease with decreasing the film thickness. The thickness dependence of the characteristic temperature is interpreted in the context of a higher mobility of polymer chains at the free surface for polymers under one-dimensional confinement. PMID- 29492506 TI - Trapping of transient, heavy pnictogen-centred biradicals. AB - Since the heavy biradicals [E(MU-NTer)]2 (E = Sb, Bi) are only of fleeting existence in solution, they were generated in situ and trapped by [2 + 2] addition reactions utilizing alkynes such as tolan (Ph-C[triple bond, length as m dash]C-Ph). The structure, biradical character and bonding of [E(MU-NTer)]2 biradicals as well as their addition products are discussed on the basis of computations and experimental data. PMID- 29492507 TI - Optical spectroscopy of isolated flavins: photodissociation of protonated lumichrome. AB - The optical properties of flavins strongly depend on the charge and oxidation states as well as the environment. Herein, the electronic spectrum of cold protonated lumichrome, the smallest flavin molecule, is recorded by means of photodissociation in the visible range (VISPD) in a cryogenic ion trap tandem mass spectrometer coupled to an electrospray ionization source. The vibronic spectrum is assigned to the S1 <- S0 (pipi*) transition of the most stable N5 protonated isomer by comparison with quantum chemical calculations at the PBE0/cc pVDZ level in combination with multidimensional Franck-Condon simulations. Analysis of the geometric and electronic structures of neutral and protonated lumichrome explains the large red shift of the band origin upon protonation (DeltaS1 ~ -6000 cm-1), which corresponds to the increase in proton affinity upon S1 excitation as a result of charge transfer. N5 protonation greatly modifies the structure of the central pyrazine ring of the chromophore. The orbitals involved in S1 <- S0 excitation include an important fraction of the probability at the central ring and they are, hence, largely influenced by the positive charge of the attached proton. The rich vibronic spectrum indicates the large geometry change upon S1 excitation. This combined experimental and computational approach is shown to be suitable to determine the optical properties of flavins as a function of oxidation, protonation, metalation, and microsolvation state. PMID- 29492508 TI - RNA-binding protein HuR regulates hsa-let-7c expression by its RNA recognition motif. AB - MicroRNAs (miRNAs) are small noncoding RNAs that control diverse cellular and developmental events through repression of large sets of target mRNAs. miRNAs expressions were mainly regulated at two levels: transcriptional and post transcriptional. Transcriptional regulation of miRNA-encoding genes produce specific expression patterns of individual miRNA. However, the mechanism of post transcriptional regulation of miRNAs remains largely unknown. The present study was aimed to clarify whether HuR, an evolutionary conserved AU-rich binding protein, could regulate miRNAs expressions. By means of a computational screen for AUUUA motifs within pri-miRNAs, we found that the downstream of hsa-let-7c but not hsa-miR-21 was enriched of AUUUA motifs. Then we transfected HuR and mutant HuR lacking RNA recognition motif 3 (RRM3) respectively into HEK293T cells. And HuR protein and miRNAs expressions were detected by Western blot and real-time PCR, respectively. The results showed that the overexpression of HuR promoted mature hsa-let-7c expression but not hsa-miR-21 expression. Furthermore, overexpression of HuR deletion mutant lacking RRM3 did not promote hsa-let-7c expression. These results suggest that RRM3 is crucial for HuR mediating mature hsa-let-7c expression. Collectively, these findings proposed a novel role of HuR in biogenesis of miRNAs, possibly by way of post-transcriptional regulation of miRNAs. PMID- 29492509 TI - [Functional plasticity of trigeminal motor nucleus in unilateral mastication model rats]. AB - To observe the plasticity changes of trigeminal motor nucleus (Mo5) and masseter H-reflex in unilateral mastication model rats and explore the possible mechanism of functional plasticity in motor center involved in unilateral mastication, 54 adult male Wistar rats were randomly divided into 1-month (n = 10), 3-month (n = 10), and 16-month (n = 7) model groups and their corresponding control groups, respectively. Unilateral mastication model rats were prepared by intermittent removal of clinical crowns of left teeth (model side). Rats were anesthetized (20% urethane, i.p.), and bilateral Mo5 were chosen to conduct extracellular recordings, while bilateral electromyography (EMG) of masseter muscle and its H reflex were simultaneously recorded by a polygraph. It was observed that the firing rate of Mo5 neurons in model sides was significantly lower than that of right sides in 3 model groups, and that of left sides in their control groups. The response latency of Mo5, which was evoked by electrical stimulation of masseter nerve in model sides of 1-month and 3-month model groups, was significantly longer than that of left sides in their control groups. Moreover, the amplitude of H-wave in model sides of 3-month and 16-month model groups was lower than that of left sides in their control groups when H-reflex was evoked by electrical stimulation of left masseter nerve. These results suggest that unilateral mastication in model rats decreases the Mo5 neuron excitability, and this may be one of the functional plasticity mechanisms in motor center involved in unilateral mastication. PMID- 29492510 TI - [Effect of different concentrations of calcitonin gene-related peptide on the long-term potentiation in hippocampus of mice]. AB - The purpose of this study was to explore the effects of different concentrations of calcitonin gene-related peptide (CGRP) on long-term potentiation (LTP) in the hippocampus of mice. C57BL/6J mice (30 days old) were randomly divided into control group, three CGRP groups, and CGRP + CGRP8-37 group (10 mice for each group). Different concentrations of CGRP (50, 100 and 200 nmol/L) were given to the hippocampal slices of mice. The presynaptic release of neurotransmitters and the induction of LTP were measured by extracellular field recording techniques. The result showed that different concentrations of CGRP did not affect the presynaptic release of neurotransmitters, but 100 and 200 nmol/L CGRP increased the amplitude of LTP induced in the hippocampus of mice. This facilitation effect of CGRP was blocked by its specific antagonist CGRP8-37. These results suggest that CGRP dose-dependently facilitates the induction of LTP in the hippocampus of mice through its specific receptor. PMID- 29492511 TI - [Macrophages depletion impairs skeletal muscle regeneration by regulating inflammation and oxidative stress levels]. AB - The objective of this study was to explore the roles of macrophages in the regeneration of injured skeletal muscle and the mechanisms involved. Mice were randomly divided into the following groups: muscle contusion (S), muscle contusion control (SCon), macrophages depleted (T) and macrophages depleted control (TCon) groups. Muscle contusion model was created by high-energy blunt injury. Macrophages depletion model was constructed by injection of clodronate liposomes. Their gastrocnemius muscles were harvested at the time points of 1, 3, 7 and 14 d post-injury. The changes in skeletal muscle morphology were assessed by hematoxylin-eosin (HE) staining and Masson's trichrome staining. The mRNA and protein levels of inflammatory cytokines, chemokines and oxidative stress factors were analyzed by real-time polymerase chain reaction (RCR) and Western blotting, respectively. HE staining results showed that a small amount of regenerating myofibers were observed in the S group (14 d post-injury), whereas a large number of regenerating muscle fibers were observed in the T group. Quantitative analyses showed that the sizes of regenerating myofibers were significantly smaller in the T group as compared with the S group at 14 d post-injury (P < 0.05). At the same time, Masson staining results showed that macrophage depletion significantly increased the area of fibrosis as compared with the S group at 14 d post-injury (P < 0.01). The expression levels of inflammatory cytokines, chemokines, and oxidative stress factors were increased significantly after muscle injury. Moreover, macrophage depletion increased the expressions of inflammatory cytokines, chemokines and oxidative stress factors as compared with the S group during the later stage of injury (7-14 d post-injury). These results suggest that macrophages depletion can aggravate fibrosis and impair muscle regeneration, and inflammatory cytokines, chemokines and oxidative stress factors may be involved in this process. PMID- 29492512 TI - [Acetylcholine suppresses microglial inflammatory response in rats via acting on microglial alpha7nAChR]. AB - Microglia are the main immune cells in the central nervous system. In the present study, the mechanism for acetylcholine (ACh) inhibiting microglial inflammatory response was investigated. Primary culture of microglia was isolated from cerebral cortex of Sprague-Dawley (SD) rats. Lipopolysaccharide (LPS) was used to activate the microglia to induce inflammatory response, and then the microglia were treated with ACh for 24 h. Protein expressions of several inflammatory factors, insulin-like growth factor 1 (IGF-1) and alpha7 nicotinic acetylcholine receptor (alpha7nAChR) were detected by Western blot. Release of inflammatory factors and IGF-1 into media was detected by ELISA. After alpha7nAChR gene silence was achieved by lentivirus-transfection of alpha7nAChR-shRNA, the change of ACh effect was observed. The results showed that LPS induced microglial activation, up-regulated inducible nitric oxide synthase (iNOS) protein expression, increased the expressions and release of IL-1beta and TNF-alpha, and decreased the expression and release of the neurotrophic factor, IGF-1. ACh could reverse these effects of LPS. Meanwhile, LPS reduced the protein expression of alpha7nAChR on the microglial cells, whereas ACh could reverse the effect. Silencing of alpha7nAChR gene in microglia abolished the ability of ACh to inhibit LPS-induced inflammatory responses. These results suggest that ACh exerts its protection against LPS-induced microglial inflammation via acting on alpha7nAChR on microglia, which may provide a novel target for the treatment of neuro-inflammatory diseases. PMID- 29492513 TI - [Hirsutine induces apoptosis of human breast cancer MDA-MB-231 cells through mitochondrial pathway]. AB - The aim of this study was to investigate the effects of hirsutine on apoptosis of breast cancer cells and its possible mechanism. The MCF-10A, MCF-7 and MDA-MB-231 cells were treated with hirsutine at different concentrations for 48 h or incubated with 160 MUmol/L hirsutine for 24, 48, and 72 h. The MCF-10A cell line is a non-tumorigenic epithelial cell line, and the MCF-7 and MDA-MB-231 are human breast adenocarcinoma cell lines. CCK-8 assay was employed to detect the cell viability. Flow cytometry was used to assay the apoptosis and mitochondrial membrane potential (MMP). The protein expressions of Bcl-2, Bax, cleaved-caspase 9, cleaved-caspase 3 and cytochrome C (Cyt C) in the MDA-MB-231 cells were detected by Western blotting. The results showed that hirsutine remarkably reduced the viability of MCF-7 and MDA-MB-231 cells in a time- and dose-dependent manner (P < 0.05) with IC50 values of 447.79 and 179.06 MUmol/L, respectively. In the MDA-MB-231 cells, hirsutine induced apoptosis and depolarization of MMP (P < 0.05), released Cyt C from mitochondria (P < 0.05), and activated caspase 9 and caspase 3 (P < 0.05). However, these effects induced by hirsutine were all inhibited by cyclosporin A (CsA) (P < 0.05), a specific inhibitor of mitochondrial permeability transition pore (MPTP). In addition, hirsutine down regulated the protein level of Bcl-2 and up-regulated the protein level of Bax (P < 0.05). These results suggest that hirsutine may induce apoptosis of human breast cancer MDA-MB-231 cells through decreasing the ratio of Bcl-2 to Bax, opening MPTP, releasing Cyt C from mitochondria, and activating caspase 9 and caspase 3. PMID- 29492514 TI - [An improved method for in vivo electroporation of morpholinos into the adult zebrafish retina]. AB - In vivo electroporation of morpholinos (MOs) into the retina of adult zebrafish is an efficient method to study gene function related to retinal disease and regeneration. However, the currently reported methods are complicated with low MO transfer efficiency and high probability to cause collateral damage. The present study was aimed to optimize the existing MO electroporation methods. Two major changes were made to MO electroporation procedure in zebrafish retina. One was to coat the inner side of the electrode with ultrasonic gel. The other was to replace the commonly used round electrode with novel rectangular one. The results showed that the use of ultrasonic gel reduced collateral damage caused by retinal electroporation and simplified the experimental procedure. The rectangular electrode significantly increased transfection efficiency of MO electroporation. In particular, knocking down the expression of Ascl1a in the retina by using our method significantly inhibited the generation of retinal progenitor cells. These results suggest our method is the optimization of the current MO electroporation methods and may be a better alternative for relevant researchers. PMID- 29492515 TI - [The glymphatic system: concept, function and research progresses]. AB - The glymphatic system is a cerebrospinal fluid-interstitial fluid exchange system dependent on the water channel aquaporin-4 polarized on astrocyte endfeet, which is proposed to account for the clearance of abnormal proteins (e.g. beta-amyloid) and metabolites (e.g. lactate) from the brain. Accumulating studies have revealed that glymphatic activity during sleep and general anesthesia is dramatically enhanced, while its function is significantly damaged during aging, traumatic brain injury, Alzheimer's disease, stroke, and diabetes. The glymphatic hypothesis is a breakthrough in the field of neuroscience recently, which would considerably enhance our comprehension on the cerebrospinal fluid circulation and its role in the maintenance of brain homeostasis. In this review, we briefly introduced the conceptualization of glymphatic system, summarized the recent progresses, and prospected its future investigation and potential clinical application. PMID- 29492516 TI - [Insulin and cardiovascular protection: from bench to bedside]. AB - Insulin resistance is "common soil" of many major cardiovascular diseases, such as diabetes, coronary heart disease, hypertension and heart failure. Recent studies have revealed that, in addition to metabolic modulation, insulin exerts direct cardiovascular protective effects. This article reviews the current progresses in the pathogenesis and cardiovascular protection strategies of metabolic cardiovascular diseases, and highlights the mechanism of actions of insulin in cardiovascular protection. PMID- 29492517 TI - [Advances in neurobiological mechanisms of comorbid depression and gastrointestinal disease]. AB - Depression is a common mood disorder, which is harmful to public health critically. Gastrointestinal diseases are a series of diseases with both dynamic changes and organic disease, including functional gastrointestinal disease, gastroesophageal reflux disease, gastritis, and gastric ulcer. In recent years, the phenomena of comorbid depression and gastrointestinal disease have become common, however, most patients were diagnosed as unilateral depression or gastrointestinal disease in the clinical treatment process, resulting in delayed treatment or even invalid. The present review focuses on some of the clinical symptoms of comorbid depression and gastrointestinal disease, and begins to explore the possible pathogenesis, so as to find out the potential neurobiological pathways of comorbidity. Consequently, the more attention on comorbid depression and gastrointestinal disease will be paid, and the clinical and basic research of comorbidity and the drug development will be provided. PMID- 29492518 TI - [Superior colliculus-pulvinar-amygdala subcortical visual pathway and its biological significance]. AB - Superior colliculus-pulvinar-amygdala pathway is one of the subcortical visual pathways in mammalian brain. Some recent studies suggest that this pathway is involved in processing emotion-related visual information. This review discusses the possibility that this pathway is more related to visual alert rather than simply the early visual information processing. The biological significance of this pathway is also discussed. Instead of detecting "where" or "what" the visual target is, the task of this early visual stage is to send out a warning signal, i.e., "something appears", so that the brain can be set up in a state of alert, which is important for the survival of animals. Thus, in the early visual information process, detection of new object "emerging" or "disappearing" takes priority over the acquisition of its feature information of "texture" and "shape", etc. The subcortical pathway may provide the neural basis of early visual warning in topological perception, a biological significance critical for animal survival. PMID- 29492519 TI - [Research advances on anti-inflammatory, antioxidant and anti-apoptotic biological effects of methane]. AB - Methane (CH4) is the simplest hydrocarbons and endogenous CH4 has been thought only to be generated by methanogens in the oral cavity and gastrointestinal tract of the mammals. However, recent animal studies have shown that endogenous CH4 can also be generated from choline and its metabolites in the mammals to protect the plasma membrane from reactive oxygen species attack and repair the membrane. In addition, exogenous CH4 can ameliorate the oxidative stress injury of multiple tissues and organs through its anti-inflammatory, antioxidant and anti-apoptosis effects. This paper reviews the recent researches about CH4 synthetic metabolism and biological functions, and highlights its potential of wide application in the prevention and treatment of oxidative stress related diseases and the significance for the development of gas medicine. PMID- 29492520 TI - [Pyroptosis and stroke]. AB - Pyroptosis is a form of inflammatory programmed cell death activated by caspase-1 and caspase-4/5/11, and involves in the pathogenesis of infectious diseases and nervous system diseases. Pyroptosis is mediated by canonical inflammasome pathway and non-canonical inflammasome pathway. The canonical inflammasome pathway is activated in stroke and aggravates brain injury. Inhibition of inflammasome, caspase-1, IL-1beta and IL-18 ameliorates brain injury. These studies indicate that canonical inflammasome pathway contributes to post-stroke brain injury, therefore, pyroptosis has become a potential therapeutic target for preventing excessive cell death during stroke. We reviewed the relationship between pyroptosis and stroke to provide some perspectives on future researches in this field. PMID- 29492521 TI - Cerebral Perfusion Pressure Variability Between Patients and Between Centres. AB - INTRODUCTION: The aim of this analysis was to investigate to what extent median cerebral perfusion pressure (CPP) differs between severe traumatic brain injury (TBI) patients and between centres, and whether the 2007 change in CPP threshold in the Brain Trauma Foundation guidelines is reflected in patient data collected at several centres over different time periods. METHODS: Data were collected from the Brain-IT database, a multi-centre project between 2003 and 2005, and from a recent project in four centres between 2009 and 2013. For patients nursed with their head up at 30 degrees and with the blood pressure transducer at atrium level, CPP was corrected by 10 mmHg. Median CPP, interquartile ranges and total CPP ranges over the monitoring time were calculated per patient and per centre. RESULTS: Per-centre medians pre-2007 were situated between 50 and 70 mmHg in 6 out of 16 centres, while 10 centres had medians above 70 mmHg and 4 above 80 mmHg. Post-2007, three out of four centres had medians between 60 and 70 mmHg and one above 80 mmHg. One out of two centres with data pre- and post-2007 shifted from a median CPP of 76 mmHg to 60 mmHg, while the other remained at 68-67 mmHg. CONCLUSIONS: CPP data are characterised by a high inter-individual variability, but the data also suggest differences in CPP policies between centres. The 2007 guideline change may have affected policies towards lower CPP in some centres. Deviations from the guidelines occur in the direction of CPP > 70 mmHg. PMID- 29492522 TI - Pre-hospital Predictors of Impaired ICP Trends in Continuous Monitoring of Paediatric Traumatic Brain Injury Patients. AB - OBJECTIVE: Although secondary insults such as raised intracranial pressure (ICP) or cardiovascular compromise strongly contribute to morbidity, a growing interest can be noticed in how the pre-hospital management can affect outcomes after traumatic brain injury (TBI). The objective of this study was to determine whether pre-hospital co-morbidity has influence on patterns of continuously measured waveforms of intracranial physiology after paediatric TBI. MATERIALS AND METHODS: Thirty-nine patients (mean age, 10 years; range, 0.5-15) admitted between 2002 and 2015 were used for the current analysis. Pre-hospital motor score, pupil reactivity, pre-hospital hypoxia (SpO2 < 90%) and hypotension (mean arterial pressure < 70 mmHg) were documented. ICP and arterial blood pressure (ABP) were monitored continuously with an intraparenchymal microtransducer and an indwelling arterial line. Pressure monitors were connected to bedside computers running ICM+ software. Pressure reactivity was determined as the moving correlation between 30 10-s averages of ABP and ICP (PRx). The mean ICP and PRx were calculated for the whole monitoring period for each patient. RESULTS: Those with pre-hospital hypotension were susceptible to higher ICP [20 (IQR 8) vs 13 (IQR 6) mmHg; p = 0.01] and more frequent ICP plateau waves [median = 0 (IQR 1), median = 4 (IQR 9); p = 0.001], despite having similar MAP, CPP and PRx during monitoring. Those with unreactive pupils tended to have higher ICP than those with reactive pupils (18 vs 14 mmHg, p = 0.08). Pre-hospital hypoxia, motor score and pupillary reactivity were not related to subsequent monitored intracranial or systemic physiology. CONCLUSION: In paediatric TBI, pre-hospital hypotension is associated with increased ICP in the intensive care unit. PMID- 29492523 TI - Prognosis of Severe Traumatic Brain Injury Outcomes in Children. AB - OBJECTIVES: We aimed to determine prognostic factors that can influence the outcome of severe traumatic brain injury (TBI) in children. MATERIALS AND METHODS: One hundred and sixty-nine patients with severe TBI were included. Consciousness was evaluated using the Glasgow Coma Scale (GCS). Severity of concomitant injuries was evaluated using the Injury Severity Score (ISS). Computer tomography (CT) scanning was used on admission and later. Intracranial injuries were classified using the Marshall CT scale. Intracranial pressure (ICP) monitoring took place in 80 cases. Serum samples of 65 patients were tested for S 100beta protein and of 43 patients for neuron specific enolase (NSE). Outcomes were evaluated 6 months after trauma using the Glasgow Outcome Scale (GOS). Statistical and mathematical analysis was conducted. The accuracy of our prognostic model was defined in another group of patients (n = 118). RESULTS: GCS, pupil size and photoreaction, ISS, hypotension and hypoxia are significant predictors of outcome of severe TBI in children. CT results complement the forecast significantly. The accuracy of surviving prognosis came to 76% (0.76) in case of S-100beta protein level <= 0.25 MUg/l and NSE level < 19 MUg/l. A mathematical model of outcome prognosis was based on discriminant function analysis. The model of prognosis was tested on the control group. The accuracy of prognosis was 86%. CONCLUSIONS: A personalised prognostic model makes it possible to predict the outcome of severe TBI in children on the first day after trauma. PMID- 29492524 TI - Do ICP-Derived Parameters Differ in Vegetative State from Other Outcome Groups After Traumatic Brain Injury? AB - OBJECTIVE: In nearly 1,000 traumatic brain injury (TBI) patients monitored in the years 1992-2014, we identified 18 vegetative state (VS) cases. Our database provided access to continuous computer-recorded signals, which we used to compare primary signals, intracranial pressure (ICP)-derived indices and demographic data between VS patients, patients who survived but who were not VS (S), and patients who died (D). METHOD: Mean values of ICP, arterial blood pressure (ABP) and cerebral perfusion pressure (CPP) from the whole monitoring periods were compared between the different outcome groups. Secondary indices included pressure reactivity index (PRx), the magnitude of slow ICP vasogenic waves, the pulse amplitude of the first harmonic component of the ICP waveform and heart rate (HR). RESULTS: Mean blood pressure was lowest in the VS group-significantly in comparison to those who died (p = 0.02) and almost significantly (p = 0.1) in comparison to the patients who survived. Mean ICP in VS patients was lower than those who died (VS, 13 +/- 5 mmHg; D, 22 +/- 14 mmHg; p < 0.001), but not significantly different from those who survived (p > 0.05). The magnitude of slow vasogenic ICP waves was the same in VS patients and those who died, but significantly lower than in those who survived (S, 1.04 +/- 0.57 mmHg; VS, 0.74 +/- 0.45; p = 0.01). CONCLUSION: Patients who progress to a VS differ from non-VS survivors in displaying decreased power of slow vasogenic waves and from those who die by not experiencing as high a burden of intracranial hypertension. PMID- 29492525 TI - Cerebral Arterial Compliance in Traumatic Brain Injury. AB - OBJECTIVE: The main role of the cerebral arterial compliance (cAC) is to maintain the stiffness of vessels and protect downstream vessels when changing cerebral perfusion pressure. The aim was to examine the flexibility of the cerebral arterial bed based on the assessment of the cAC in patients with traumatic brain injury (TBI) in groups with and without intracranial hematomas (IHs). MATERIALS AND METHODS: We examined 80 patients with TBI (mean age, 35.7 +/- 12.8 years; 42 men, 38 women). Group 1 included 41 patients without IH and group 2 included 39 polytraumatized patients with brain compression by IH. Dynamic electrocardiography (ECG)-gated computed tomography angiography (DHCTA) was performed 1-14 days after trauma in group 1 and 2-8 days after surgical evacuation of the hematoma in group 2. Amplitude of arterial blood pressure (ABP), as well as systole and diastole duration were measured noninvasively. Transcranial Doppler was measured simultaneously with DHCTA. The cAC was calculated by the formula proposed by Avezaat. RESULTS: The cAC was significantly decreased (p < 0.001) in both groups 1 and 2 compared with normal data. The cAC in group 2 was significantly decreased compared with group 1, both on the side of the former hematoma (r = 0.017). CONCLUSION: The cAC in TBI gets significantly lower compared with the conditional norm (p < 0.001). After removal of the intracranial hematomas, compliance in the perifocal zone remains much lower (r = 0.017) compared with compliance of the other brain hemisphere. PMID- 29492526 TI - The Cerebrovascular Resistance in Combined Traumatic Brain Injury with Intracranial Hematomas. AB - OBJECTIVE: The aim was to evaluate changes in cerebrovascular resistance (CVR) in combined traumatic brain injury (CTBI) in groups with and without intracranial hematomas (IH). MATERIALS AND METHODS: Treatment outcomes in 70 patients with CTBI (42 males and 28 females) were studied. Mean age was 35.5 +/- 14.8 years (range, 15-73). The patients were divided into two groups: group 1 included 34 CTBI patients without hematomas; group 2 comprised 36 patients with CTBI and IH. The severity according to the Glasgow Coma Scale averaged 10.4 +/- 2.6 in group 1, and 10.6 +/- 2.8 in group 2. All patients underwent perfusion computed tomography (CT) and transcranial Doppler of both middle cerebral arteries. Cerebral perfusion pressure and CVR were calculated. RESULTS: The mean CVR values in each group (both with and without hematomas) appeared to be statistically significantly higher than the mean normal value. Intergroup comparison of CVR values showed statistically significant increase in the CVR level in group 2 on the side of the removed hematoma (r = 0.037). CVR in the perifocal zone of the removed hematoma remained significantly higher compared with the symmetrical zone in the contralateral hemisphere (p = 0.0009). CONCLUSION: CVR in patients with CTBI is significantly increased compared to the normal value and remains elevated after evacuation of hematoma in the perifocal zone compared to the symmetrical zone in the contralateral hemisphere. This is indicative of certain correlation between the mechanisms of cerebral blood flow autoregulation and maintaining CVR. PMID- 29492527 TI - Computed Tomography Indicators of Deranged Intracranial Physiology in Paediatric Traumatic Brain Injury. AB - OBJECTIVE: Computed tomography (CT) of the brain can allow rapid assessment of intracranial pathology after traumatic brain injury (TBI). Frequently in paediatric TBI, CT imaging can fail to display the classical features of severe brain injury with raised intracranial pressure. The objective of this study was to determine early CT brain features that influence intracranial or systemic physiological trends following paediatric TBI. MATERIALS AND METHODS: Thirty three patients (mean age, 10 years; range, 0.5-16) admitted between 2002 and 2015 were used for the current analysis. Presence of petechial haemorrhages, basal cistern compression, subarachnoid blood, midline shift and extra-axial masses on the initial trauma CT head were assessed. ICP and arterial blood pressure (ABP) were then monitored continuously with an intraparenchymal microtransducer and an indwelling arterial line. Pressure monitors were connected to bedside computers running ICM+ software. Pressure reactivity was determined as the moving correlation between 30, 10-s averages of ABP and ICP (PRx). The mean ICP, ABP, cerebral perfusion pressure (CPP; ABP minus ICP) and PRx were calculated for the whole monitoring period for each patient. RESULTS: The presence of subarachnoid blood was related to higher ICP, higher ABP and a trend toward higher PRx. Smaller basal cisterns were related to increased ICP (R = -0.42, p = 0.02), impaired PRx (R = -0.5, p = 0.003). The presence of an extra-axial mass was associated with deranged PRx (-0.02 vs. 0.41, p = 0.003) and a trend toward higher ICP (14 vs. 40, p = 0.07). Interestingly the degree of midline shift was not related to ICP or PRx. CONCLUSIONS: The size of the basal cisterns, the presence of subarachnoid blood or an extra-axial mass are all related to disturbed ICP and pressure reactivity in this paediatric TBI cohort. Patients with these features are ideal candidates for invasive multimodal monitoring. PMID- 29492528 TI - Mean Square Deviation of ICP in Prognosis of Severe TBI Outcomes in Children. AB - OBJECTIVES: Prognostic value of intracranial pressure (ICP) is discussed in the recent literature. The aim of our study was to find the parameter that could be representative of ICP variations and might become a good predictor of severe traumatic brain injury (TBI) outcomes in children. MATERIALS AND METHODS: The study included 81 patients with severe TBI (2004-2014). INCLUSION CRITERIA: GCS <= 8, age > 3 years old, admission time to our clinic <24 h from the time of injury. Mean daily values of ICP were used as a predictor, Glasgow outcome scale value was used as a grouping variable. Outcomes were assessed 6 months after injury. RESULTS: Total mortality was 27%. We have entered the indicator "energy ICP" (E 2), which describes the dynamics of the process and energy. E 2 value in the group of survivors was <500 mmHg2; the probability of accurate forecasting was 91%. Sensitivity, 0.9; specificity; 0.94. CONCLUSIONS: The proposed method is accessible and easy to perform. This method has high specificity in the prediction of severe traumatic brain injury outcome and can be a reliable tool for ICP control. PMID- 29492529 TI - KidsBrainIT: A New Multi-centre, Multi-disciplinary, Multi-national Paediatric Brain Monitoring Collaboration. AB - OBJECTIVES: Validated optimal cerebral perfusion pressure (CPP) treatment thresholds in children do not exist. To improve the intensive care unit (ICU) management of the paediatric traumatic brain injury (TBI) population, we are forming a new paediatric multi-centre collaboration to recruit standardised ICU data for running and reporting upon models for assessing autoregulation and optimal CCP (CPPopt). MATERIALS AND METHODS: We are adapting the adult BrainIT group's approach to develop a new Paediatric Brain Monitoring and Information Technology Group (KidsBrainIT), which will include a repository to store prospectively collected high-resolution physiological, clinical, and outcome data. In the first phase of this project there are 7 UK Paediatric Intensive Care Units, 1 Spanish, 1 Belgium, and 1 Romanian Centre interested in participating. In subsequent phases, we plan to open recruitment to other centres both within Europe, US and abroad. We are collaborating with the Leuven Group and plan to use their LAx (low-frequency autoregulation index), DATACAR (dynamic adaptive target of active cerebral autoregulation), CPPopt and visualisation methodologies. We also plan to use the continuous diffuse optical monitoring and tomography technology developed in Barcelona as an acute surrogate end-point for optimising brain perfusion. This technology allows non-invasive continuous monitoring of deep tissue perfusion and oxygenation in adults but its clinical application in infants and children with TBI has not been studied previously. RESULTS: We report on the current status of setting up this new collaboration and also on pilot analyses in two centres which are the basis of our rationale for the need for a prospective validation study of CPPopt in children. Specifically, we demonstrated that CPPopt varied with time for each patient during their paediatric intensive care unit (PICU) stay, and the median overall CPPopt levels for children aged 2-6 years, 7-11 years and 12-16 years were 68.83, 68.09, and 72.17 mmHg respectively. Among survivors and patients with favourable outcome (GOS 4 and 5), there were significantly higher proportions with CPP monitoring time within CPPopt (p = 0.04 and p = 0.01 respectively). CONCLUSIONS: There is a need and an interest in forming a multi-centre PICU collaboration for acquiring data and performing analyses for determining validated CPPopt thresholds in the paediatric TBI population. KidsBrainIT is being formed to meet that need. PMID- 29492530 TI - Increased ICP and Its Cerebral Haemodynamic Sequelae. AB - OBJECTIVES: Increased intracranial pressure (ICP) is a pathological feature of many neurological diseases; however, the local and systemic sequelae of raised ICP are incompletely understood. Using an experimental paradigm, we aimed to describe the cerebrovascular consequences of acute increases in ICP. MATERIALS AND METHODS: We assessed cerebral haemodynamics [mean arterial blood pressure (MAP), ICP, laser Doppler flowmetry (LDF), basilar artery Doppler flow velocity (Fv) and estimated vascular wall tension (WT)] in 27 basilar artery-dependent rabbits during experimental (artificial lumbar CSF infusion) intracranial hypertension. WT was estimated as the difference between critical closing pressure and ICP. RESULTS: From baseline (~9 mmHg) to moderate increases in ICP (~41 mmHg), cortical LDF decreased (from 100 to 39.1%, p < 0.001), while mean global Fv was unchanged (from 47 to 45 cm/s, p = 0.38). In addition, MAP increased (from 88.8 to 94.2 mmHg, p < 0.01 and WT decreased (from 19.3 to 9.8 mmHg, p < 0.001). From moderate to high ICP (~75 mmHg), both global Fv and cortical LDF decreased (Fv, from 45 to 31.3 cm/s, p < 0.001; LDF, from 39.1 to 13.3%, p < 0.001) while MAP increased further (94.2 to 114.5 mmHg, p < 0.001) and estimated WT was unchanged (from 9.7 to 9.6 mmHg, p = 0.35). CONCLUSION: In this analysis, we demonstrate a cortical vulnerability to increases in ICP and two ICP dependent cerebro-protective mechanisms: with moderate increases in ICP, WT decreases and MAP increases to buffer cerebral perfusion, while with severe increases of ICP, an increased MAP predominates. PMID- 29492531 TI - What Determines Outcome in Patients That Suffer Raised Intracranial Pressure After Traumatic Brain Injury? AB - INTRODUCTION: Episodes of raised intracranial pressure (ICP) after traumatic brain injury (TBI) are responsible for the majority of secondary brain injury events and thereby strongly affect long-term outcome. However, not all patients with major episodes of raised ICP suffer a poor outcome. The aim of the current analysis was to identify variables contributing to good outcome in patients suffering episodes of high ICP. METHODS: Retrospective analysis of 20 severe TBI patients admitted to the University Hospitals Leuven between 2010 and 2014. All patients had at least one episode of ICP > 30 mmHg for more than 3 min in succession. Outcome was assessed by the extended Glasgow Outcome Scale at 6 months. Partial least squares (PLS) regression was used to derive factors determining outcome. Pressure reactivity index (PRx) was calculated as an index for cerebrovascular autoregulation capacity. RESULTS: Both outcome groups did not differ for age, Glasgow Coma Score, pupil reactivity, computed tomography Marshall classification, glycaemia, haemoglobin and CRASH and IMPACT scores on admission. Significant differences were found for mean ICP, number of episodes of ICP > 30 mmHg, number and duration of longest PRx episodes. The number of episodes of ICP > 30 mmHg correlated significantly with the number and duration of longest PRx episodes. PLS regression indicates that episodes of impaired autoregulation contributed equally to explaining outcome compared to episodes of raised ICP. CONCLUSIONS: Prolonged episodes of disturbed dynamic cerebral autoregulation contribute to detrimental outcome in patients with increased ICP. Autoregulation seems to have an important protective role in tolerating episodes of raised ICP. PMID- 29492532 TI - Visualisation of the 'Optimal Cerebral Perfusion' Landscape in Severe Traumatic Brain Injury Patients. AB - OBJECTIVE: An 'optimal' cerebral perfusion pressure (CPPopt) can be defined as the point on the CPP scale corresponding to the greatest autoregulatory capacity. This can be established by examining the pressure reactivity index PRx-CPP relationship, which is approximately U-shaped but suffers from noise and missing data. In this paper, we present a method for plotting the whole PRx-CPP relationship curve against time in the form of a colour-coded map depicting the 'landscape' of that relationship extending back for several hours and to display this robustly at the bedside.This is a short version of a full paper recently published in Critical Care Medicine (2016) containing some new insights and details of a novel bedside implementation based on a presentation during Intracranial Pressure 2016 Symposium in Boston. METHODS: Recordings from routine monitoring of traumatic brain injury patients were processed using ICM+. Time averaged means for arterial blood pressure, intracranial pressure, cerebral perfusion pressure (CPP) and pressure reactivity index (PRx) were calculated and stored with time resolution of 1 min. ICM+ functions have been extended to include not just an algorithm of automatic calculation of CPPopt but also the 'CPPopt landscape' chart. RESULTS: Examining the 'CPPopt landscape' allows the clinician to differentiate periods where the autoregulatory range is narrow and needs to be targeted from periods when the patient is generally haemodynamically stable, allowing for more relaxed CPP management. This information would not have been conveyed using the original visualisation approaches. CONCLUSIONS: We describe here a natural extension to the concept of autoregulatory assessment, providing the retrospective 'landscape' of the PRx-CPP relationship extending over the past several hours. We have incorporated such visualisation techniques online in ICM+. The proposed visualisation may facilitate clinical evaluation and use of autoregulation-guided therapy. PMID- 29492533 TI - Is There a Relationship Between Optimal Cerebral Perfusion Pressure-Guided Management and PaO2/FiO2 Ratio After Severe Traumatic Brain Injury? AB - OBJECTIVE: Severe traumatic brain injury (TBI) management has been associated with adult respiratory distress syndrome (ARDS) in previous literature. We aimed to investigate the relationships between optimal CPP-guided management, ventilation parameters over time and outcome after severe TBI. MATERIALS AND METHODS: We performed retrospective analysis of recorded data from 38 patients admitted to the NCCU after severe TBI, managed with optimal cerebral perfusion pressure (CPPopt)-guided therapy, calculated using pressure reactivity index (PRx). All patients were sedated and ventilated with lung protective criteria (Peep > 5, tidal volume 6-8 ml/kg and airway pressure < 30 cmH2O). RESULTS: Daily mean CPPopt varied between a minimum of 84 mmHg and a maximum of 91 mmHg with an all period mean value of 88 mmHg. The mean value for the difference between CPP and CPPopt was -1.9 mmHg. Daily mean P/F ratio decreased and varied between 253 and 387 with an all-period mean of 294 mmHg. During the 10 days of recording data, five patients (13%) developed criteria of severe ARDS, but only two patients died due to severe ARDS (5%). PaO2/FiO2 (P/F) ratio did not correlate with CPPopt, but showed a strong correlation with tidal volume (p = 0.000) and driving pressure (p = 0.000). CONCLUSIONS: Although CPPopt-guided therapy may induce a decrease in P/F ratio over time during the first 10 days, we could not find an association with worst outcome, which may be influenced by lung protective ventilation strategies and preservation of cerebral autoregulation. PMID- 29492534 TI - Cognitive Outcomes of Patients with Traumatic Bifrontal Contusions. AB - OBJECTIVES: We aimed to investigate the prevalence and pattern of cognitive dysfunction in patients with traumatic bifrontal contusions and their association with functional outcome. MATERIALS AND METHODS: We prospectively recruited patients with bifrontal contusions in a regional neurosurgical center in Hong Kong over a 2-year period. Functional outcome was assessed by modified Rankin Scale (mRS), and cognitive outcomes were assessed by Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and a comprehensive neuropsychological battery. RESULTS: We recruited 34 patients with traumatic bifrontal contusions over a 2-year period. Nine (26%) patients had craniotomy for evacuation of left or right frontal contusions. Functional outcome using mRS was significantly correlated with cognitive outcomes using MMSE or MoCA. The effect of cognitive outcome using MMSE or MoCA persisted after adjustments of age, sex, admission Glasgow Coma Scale, and surgery. In patients who completed the comprehensive neuropsychological assessments, cognitive impairment in at least one of the neuropsychological tests was noted in 73% of them. CONCLUSIONS: Cognitive dysfunction had a significant impact on functional outcome, and treatment strategy should be developed to minimize them. PMID- 29492535 TI - Non-invasive Intracranial Pressure Assessment in Brain Injured Patients Using Ultrasound-Based Methods. AB - BACKGROUND: Non-invasive measurement of intracranial pressure (ICP) can be invaluable in the management of critically ill patients. Invasive measurement of ICP remains the "gold standard" and should be performed when clinical indications are met, but it is invasive and brings some risks. In this project, we aim to validate the non-invasive ICP (nICP) assessment models based on arterious and venous transcranial Doppler ultrasonography (TCD) and optic nerve sheath diameter (ONSD). METHODS: We included brain injured patients requiring invasive ICP monitoring (intraparenchymal or intraventricular). We assessed the concordance between ICP measured non-invasively with arterious [flow velocity diastolic formula (ICPFVd) and pulsatility index (PI)], venous TCD (vPI) and ICP derived from ONSD (nICPONSD) compared to invasive ICP measurement. RESULTS: Linear regression showed a positive relationship between nICP and ICP for all the methods, except PIv. ICPONSD showed the strongest correlation with invasive ICP (r = 0.61) compared to the other methods (ICPFVd, r = 0.26, p value = 0.0015; PI, r = 0.19, p value = 0.02, vPI, r = 0.056, p value = 0.510). The ability to predict intracranial hypertension was highest for ICPONSD (AUC = 0.91; 95% CI, 0.85-0.97 at ICP > 20 mmHg), with a sensitivity and specificity of 85%, followed by ICPFVd (AUC = 0.67; 95% CI, 0.54-0.79). CONCLUSIONS: Our results demonstrate that among the non-invasive methods studied, ONSD showed the best accuracy in the detection of ICP. PMID- 29492536 TI - Analysis of a Minimally Invasive Intracranial Pressure Signals During Infusion at the Subarachnoid Spinal Space of Pigs. AB - OBJECTIVE: We developed a new minimally invasive method for intracranial pressure monitoring (ICPMI). The objective of this project is to verify the similarities between the ICPMI and the invasive method (ICPInv), for different components of the intracranial pressure signal-namely, the mean value (trend) as well as its pulsatile component. MATERIALS AND METHODS: A 9 kg anesthetized pig was used for simultaneous ICP monitoring with both methods. ICP was increased by performing ten infusions of 6 ml 0.9% saline into the spinal subarachnoid space, using a catheter implanted in the lumbar region. For correlation analysis, the signals were decomposed into two components-trend and pulsatile signals. Pearson correlation coefficient was calculated between ICPInv and ICPMI. RESULTS: During the infusions, the correlation between the pulsatile components of the signals was above 0.5 for most of the time. The signal trends showed a good agreement (correlation above 0.5) for most of the time during infusions. CONCLUSIONS: The ICPMI signal trends showed a good linear agreement with the signal obtained invasively. Based on the waveform analysis of the pulsatile component of ICP, our results indicate the possibility of using the minimally invasive method for assessing the neuroclinical state of the patient. PMID- 29492537 TI - Comparison of Different Calibration Methods in a Non-invasive ICP Assessment Model. AB - OBJECTIVE: Previously we described the method of continuous intracranial pressure (ICP) estimation using arterial blood pressure (ABP) and cerebral blood flow velocity (CBFV). The model was constructed using reference patient data. Various individual calibration strategies were used in the current attempt to improve the accuracy of this non-invasive ICP (nICP) assessment tool. MATERIALS AND METHODS: Forty-one patients (mean, 52 years; range, 18-77 years) with severe brain injuries were studied. CBFV in the middle cerebral artery (MCA), ABP and invasively assessed ICP were simultaneously recorded for 1 h. Recording was repeated at days 2, 4 and 7. In the first recording, invasively assessed ICP was recorded to calibrate the nICP procedure by means of either a constant shift of nICP (snICP), a constant shift of nICP/ABP ratio (anICP) or by including this recording for a model reconstruction (cnICP). At follow-up days, the calibrated nICP procedures were applied and the results compared to the original nICP. RESULTS: In 76 follow-up recordings, the mean differences (Bias), the SD and the mean absolute differences (DeltaICP) between ICP and the nICP methods were (in mmHg): nICP, -5.6 +/- 5.72, 6.5; snICP, +0.7 +/- 6.98, 5.5, n.s.; anICP, +1.0 +/- 7.22, 5.6, n.s.; cnICP, -3.4 +/- 5.68, 5.4, p < 0.001. In patients with craniotomy (n = 19), the nICP was generally higher than ICP. This overestimation could be reduced by cnICP calibration, but not completely avoided. DISCUSSION: Constant shift calibrations (snICP, anICP) decrease the Bias to ICP, but increase SD and, therefore, increase the 95% confidence interval (CI = 2 * SD). This calibration method cannot be recommended. Compared to nICP, the cnICP method reduced the Bias and slightly reduced SD, and showed significantly decreased DeltaICP. Compared to snICP and anICP, the Bias was higher. This effect was probably caused by the patients with craniotomy. CONCLUSION: The cnICP calibration method using initial recordings for model reconstruction showed the best results. PMID- 29492538 TI - An Embedded Device for Real-Time Noninvasive Intracranial Pressure Estimation. AB - OBJECTIVE: The monitoring of intracranial pressure (ICP) is indicated for diagnosing and guiding therapy in many neurological conditions. Current monitoring methods, however, are highly invasive, limiting their use to the most critically ill patients only. Our goal is to develop and test an embedded device that performs all necessary mathematical operations in real-time for noninvasive ICP (nICP) estimation based on a previously developed model-based approach that uses cerebral blood flow velocity (CBFV) and arterial blood pressure (ABP) waveforms. MATERIALS AND METHODS: The nICP estimation algorithm along with the required preprocessing steps were implemented on an NXP LPC4337 microcontroller unit (MCU). A prototype device using the MCU was also developed, complete with display, recording functionality, and peripheral interfaces for ABP and CBFV monitoring hardware. RESULTS: The device produces an estimate of mean ICP once per minute and performs the necessary computations in 410 ms, on average. Real time nICP estimates differed from the original batch-mode MATLAB implementation of theestimation algorithm by 0.63 mmHg (root-mean-square error). CONCLUSIONS: We have demonstrated that real-time nICP estimation is possible on a microprocessor platform, which offers the advantages of low cost, small size, and product modularity over a general-purpose computer. These attributes take a step toward the goal of real-time nICP estimation at the patient's bedside in a variety of clinical settings. PMID- 29492539 TI - Transcranial Bioimpedance Measurement as a Non-invasive Estimate of Intracranial Pressure. AB - OBJECTIVES: We have previously demonstrated a relationship between transcranial bioimpedance (TCB) measurements and intracranial pressure (ICP) in an animal model of raised ICP. The primary objective of this study was to explore the relationship between non-invasive bioelectrical impedance measurements of the brain and skull and ICP in traumatic brain injury (TBI) patients. MATERIALS AND METHODS: Included patients were adults admitted to the Neurological Intensive Care Unit with TBI and undergoing invasive ICP monitoring as part of their routine clinical care. Multi-frequency TCB measurements were performed hourly through bi-temporal electrodes. The bioimpedance parameters of Z c (impedance at the characteristic frequency) and R 0 (resistance to a direct current) were then modelled against ICP using unadjusted and adjusted linear models. RESULTS: One hundred and sixty-eight TCB measurements were available from ten study participants. Using an unadjusted linear modelling approach, there was no significant relationship between measured ICP and Zc or R0. The most significant relationship between ICP and TCB parameters was found by adjusting for multiple patient specific variables and using Zc and R0 normalised per patient (p < 0.0001, r 2 = 0.32). CONCLUSIONS: These pilot results confirm some degree of relationship between TCB parameters and invasively measured ICP. The magnitude of this relationship is small and, on the basis of the current study, TCB is unlikely to provide a clinically useful estimate of ICP in patients admitted with TBI. PMID- 29492541 TI - Volumetric Ophthalmic Ultrasound for Inflight Monitoring of Visual Impairment and Intracranial Pressure. AB - OBJECTIVE: The objective is enhanced ophthalmic ultrasound imaging to monitor ocular structure and intracranial dynamics changes related to visual impairment and intracranial pressure (ICP) induced by microgravity. The goals are to improve the ease of use and reduce operator variability by automatically rendering improved views of the anatomy and deriving new metrics of the morphology and dynamics. MATERIALS AND METHODS: A prototype three-dimensional (3-D) probe was integrated onto a portable ultrasound scanner. Image analysis algorithms were developed to automatically detect the ocular anatomy and simultaneously render views of the optic nerve with improved sheath definition. Curvature metrics were calculated from 3-D retinal surfaces to quantify posterior globe flattening, and tissue velocity waveforms of the optic nerve were analyzed to assess intracranial dynamics. RESULTS: New 3-D structural measurements were evaluated in a head-down tilt study. The response of optic nerve sheath and globe flattening metrics were quantified in 11 healthy volunteers from baseline to moderately elevated ICP. The optic nerve measurements showed good correlation with existing two-dimensional (2 D) methods and an acute response to increased ICP, while globe flattening did not show an acute response. The tissue velocities were evaluated in a porcine model from baseline to significantly elevated ICP and correlated with invasive ICP readings in four animals. CONCLUSIONS: Volumetric ophthalmic imaging was demonstrated on a portable ultrasound system and structural measurements validated with existing methods. New 3-D structural measurements and dynamic measurements were evaluation during in vivo studies. Further investigations are needed to evaluate improvements in performance for non-experts and application to clinically relevant conditions. PMID- 29492540 TI - Pulsed Electromagnetic Field (PEMF) Mitigates High Intracranial Pressure (ICP) Induced Microvascular Shunting (MVS) in Rats. AB - OBJECTIVE: High-frequency pulsed electromagnetic field (PEMF) stimulation is an emerging noninvasive therapy that we have shown increases cerebral blood flow (CBF) and tissue oxygenation in the healthy rat brain. In this work, we tested the effect of PEMF on the brain at high intracranial pressure (ICP). We previously showed that high ICP in rats caused a transition from capillary (CAP) to non-nutritive microvascular shunt (MVS) flow, tissue hypoxia and increased blood brain barrier (BBB) permeability. METHODS: Using in vivo two-photon laser scanning microscopy (2PLSM) over the rat parietal cortex, and studied the effects of PEMF on microvascular blood flow velocity, tissue oxygenation (NADH autofluorescence), BBB permeability and neuronal necrosis during 4 h of elevated ICP to 30 mmHg. RESULTS: PEMF significantly dilated arterioles, increased capillary blood flow velocity and reduced MVS/capillary ratio compared to sham treated animals. These effects led to a significant decrease in tissue hypoxia, BBB degradation and neuronal necrosis. CONCLUSIONS: PEMF attenuates high ICP induced pathological microcirculatory changes, tissue hypoxia, BBB degradation and neuronal necrosis. PMID- 29492542 TI - Does the Variability of Evoked Tympanic Membrane Displacement Data (V m) Increase as the Magnitude of the Pulse Amplitude Increases? AB - OBJECTIVES: Evoked tympanic membrane displacement (TMD) measurements, quantified by V m, record small volume changes in the ear canal following stimulation of the acoustic reflex. V m shows a correlation with intracranial pressure (ICP) and has been proposed as an option to non-invasively measure ICP. The spontaneous pulsing of the tympanic membrane, driven by the cardiovascular pulse, may contaminate the recordings and contribute to high measurement variability in some subjects. This study hypothesised that the larger the spontaneous vascular pulse, the larger the variability in V m. MATERIALS AND METHODS: Spontaneous and evoked TMD data from each ear in the sitting and supine position were recorded from 100 healthy volunteers using the MMS-14 CCFP analyser. ECG was also recorded to identify each heartbeat. Using bespoke software written in Matlab, spontaneous data were analysed to produce average pulse amplitude (PA) waveforms and evoked data were analysed to calculate average V m and its standard deviation. Averaged spontaneous PA was plotted against V m variability and Pearson's correlation coefficient was calculated to test for a significant linear relationship. RESULTS: There was a strong positive correlation between PA and V m variability in all conditions: left sitting, r = 0.758; left supine, r = 0.665; right sitting, r = 0.755; right supine, r = 0.513. All were significant at p < 0.001. CONCLUSION: This study shows that large V m variability is associated with a large spontaneous vascular pulse. This suggests that efforts to reduce vascular pulsing from recordings, either by a subtraction technique during post-processing or ECG-gating of the evoking stimulus, may improve reliability of the V m measurement. PMID- 29492544 TI - A Wearable Transcranial Doppler Ultrasound Phased Array System. AB - OBJECTIVE: Practical deficiencies related to conventional transcranial Doppler (TCD) sonography have restricted its use and applicability. This work seeks to mitigate several such constraints through the development of a wearable, electronically steered TCD velocimetry system, which enables noninvasive measurement of cerebral blood flow velocity (CBFV) for monitoring applications with limited operator interaction. MATERIALS AND METHODS: A highly-compact, discrete prototype system was designed and experimentally validated through flow phantom and preliminary human subject testing. The prototype system incorporates a custom two-dimensional transducer array and multi-channel transceiver electronics, thereby facilitating acoustic beamformation via phased array operation. Electronic steering of acoustic energy enables algorithmic system controls to map Doppler power throughout the tissue volume of interest and localize regions of maximal flow. Multi-focal reception permits dynamic vessel position tracking and simultaneous flow velocimetry over the time-course of monitoring. RESULTS: Experimental flow phantom testing yielded high correlation with concurrent flowmeter recordings across the expected range of physiological flow velocities. Doppler power mapping has been validated in both flow phantom and preliminary human subject testing, resulting in average vessel location mapping times <14 s. Dynamic vessel tracking has been realized in both flow phantom and preliminary human subject testing. CONCLUSIONS: A wearable prototype CBFV measurement system capable of autonomous vessel search and tracking has been presented. Although flow phantom and preliminary human validation show promise, further human subject testing is necessary to compare velocimetry data against existing commercial TCD systems. Additional human subject testing must also verify acceptable vessel search and tracking performance under a variety of subject populations and motion dynamics-such as head movement and ambulation. PMID- 29492543 TI - Analysis of a Non-invasive Intracranial Pressure Monitoring Method in Patients with Traumatic Brain Injury. AB - OBJECTIVE: We aimed to compare the invasive (iICP) and a non-invasive intracranial pressure (nICP) monitoring methods in patients with traumatic brain injury, based on the similarities of the signals' power spectral densities. MATERIALS AND METHODS: We recorded the intracranial pressure of seven patients with traumatic brain injury admitted to Hospital Sao Joao, Portugal, using two different methods: a standard intraparenchymal (iICP) and a new nICP method based on mechanical extensometers. The similarity between the two monitoring signals was inferred from the Euclidean distance between the non-linear projection in a lower dimensional space (ISOMAP) of the windowed power spectral densities of the respective signals. About 337 h of acquisitions were used out of a total of 608 h. The only data exclusion criterion was the absence of any of the signals of interest. RESULTS: The averaged distance between iICP and nICP, and between arterial blood pressure (ABP) and nICP projections in the embedded space are statistically different for all seven patients analysed (Mann-Whitney U, p < 0.05). CONCLUSIONS: The similarity between the iICP and nICP monitoring methods was higher than the similarity between the nICP and the recordings of the radial ABP for all seven patients. Despite the possible differences between the shape of the ABP waveform at radial and parietal arteries, the results indicate-based on the similarities of iICP and nICP as functions of time-that the nICP method can be applied as an alternative method for ICP monitoring. PMID- 29492545 TI - Quantification of Macrocirculation and Microcirculation in Brain Using Ultrasound Perfusion Imaging. AB - OBJECTIVE: The aim of this study was to investigate the feasibility of simultaneous visualization of the cerebral macrocirculation and microcirculation, using ultrasound perfusion imaging (UPI). In addition, we studied the sensitivity of this technique for detecting changes in cerebral blood flow (CBF). MATERIALS AND METHODS: We performed an observational study in ten healthy volunteers. Ultrasound contrast was used for UPI measurements during normoventilation and hyperventilation. For the data analysis of the UPI measurements, an in-house algorithm was used to visualize the DICOM files, calculate parameter images and select regions of interest (ROIs). Next, time intensity curves (TIC) were extracted and perfusion parameters calculated. RESULTS: Both volume- and velocity related perfusion parameters were significantly different between the macrocirculation and the parenchymal areas. Hyperventilation-induced decreases in CBF were detectable by UPI in both the macrocirculation and microcirculation, most consistently by the volume-related parameters. The method was safe, with no adverse effects in our population. CONCLUSIONS: Bedside quantification of CBF seems feasible and the technique has a favourable safety profile. Adjustment of current method is required to improve its diagnostic accuracy. Validation studies using a 'gold standard' are needed to determine the added value of UPI in neurocritical care monitoring. PMID- 29492546 TI - HDF5-Based Data Format for Archiving Complex Neuro-monitoring Data in Traumatic Brain Injury Patients. AB - OBJECTIVES: Modern neuro-critical care units generate high volumes of data. These data originate from a multitude of devices in various formats and levels of granularity. We present a new data format intended to store these data in an ordered and homogenous way. MATERIAL AND METHODS: The adopted data format was based on the hierarchical model, HDF5, which is capable of dealing with a mixture of small and very large datasets with equal ease. It is possible to access and manipulate individual data elements directly within a single file, and this is extensible and versatile. RESULTS: The file structure that was agreed divided the patient data into four different groups: 'Annotations' for clinical events and sporadic observations, 'Numerics' for all the low-frequency data, 'Waves' for all the high-frequency data and 'Summaries' for the trend data and calculated parameters. The addition of attributes to every group and dataset makes the file self-described. More than 200 files have been successfully collected and stored using this format. CONCLUSION: The new file format was implemented in ICM+ software and validated as part of a collaboration with participating centres across Europe. PMID- 29492547 TI - Are Slow Waves of Intracranial Pressure Suppressed by General Anaesthesia? AB - OBJECTIVES: Slow waves of intracranial pressure (ICP) are spontaneous oscillations with a frequency of 0.3-4 cycles/min. They are often associated with pathological conditions, following vasomotor activity in the cranial enclosure. This study quantifies the effects of general anaesthesia (GA) on the magnitude of B-waves compared with natural sleep and the conscious state. MATERIALS AND METHODS: Four groups of 30 patients each were formed to assess the magnitude of slow waves. Group A and group B consisted of normal pressure hydrocephalus (NPH) patients, each undergoing cerebrospinal fluid (CSF) infusion studies, conscious and under GA respectively. Group C comprised conscious, naturally asleep hydrocephalic patients undergoing overnight ICP monitoring; group D, which included deeply sedated head injury patients monitored in the intensive care unit (ICU), was compared with group C. RESULTS: The average amplitude for group A patients was higher (0.23 +/- 0.10 mmHg) than that of group B (0.15 +/- 0.10 mmHg; p = 0.01). Overnight magnitude of slow waves was higher in group C (0.20 +/ 0.13 mmHg) than in group D (0.11 +/- 0.09 mmHg; p = 0.002). CONCLUSION: Slow waves of ICP are suppressed by GA and deep sedation. When using slow waves in clinical decision-making, it is important to consider the patients' level of consciousness to avoid incorrect therapeutic and management decisions. PMID- 29492548 TI - Critical Closing Pressure During a Controlled Increase in Intracranial Pressure. AB - OBJECTIVES: The objectives were to compare three methods of estimating critical closing pressure (CrCP) in a scenario of a controlled increase in intracranial pressure (ICP) induced during an infusion test in patients with suspected normal pressure hydrocephalus (NPH). METHODS: We retrospectively analyzed data from 37 NPH patients who underwent infusion tests. Computer recordings of directly measured intracranial pressure (ICP), arterial blood pressure (ABP) and transcranial Doppler cerebral blood flow velocity (CBFV) were used. The CrCP was calculated using three methods: first harmonics ratio of the pulse waveforms of ABP and CBFV (CrCPA) and two methods based on a model of cerebrovascular impedance, as a function of cerebral perfusion pressure (CrCPinv), and as a function of ABP (CrCPninv). RESULTS: There is good agreement among the three methods of CrCP calculation, with correlation coefficients being greater than 0.8 (p < 0.0001). For the CrCPA method, negative values were found for about 20% of all results. Negative values of CrCP were not observed in estimators based on cerebrovascular impedance. During the controlled rise of ICP, all three estimators of CrCP increased significantly (p < 0.05). The strongest correlation between ICP and CrCP was found for CrCPinv (median R = 0.41). CONCLUSION: Invasive CrCP is most sensitive to variations in ICP and can be used as an indicator of the status of the cerebrovascular system during infusion tests. PMID- 29492549 TI - Effect of Mild Hypocapnia on Critical Closing Pressure and Other Mechanoelastic Parameters of the Cerebrospinal System. AB - OBJECTIVE: Brain arterial critical closing pressure (CrCP) has been studied in several diseases such as traumatic brain injury (TBI), subarachnoid haemorrhage, hydrocephalus, and in various physiological scenarios: intracranial hypertension, decreased cerebral perfusion pressure, hypercapnia, etc. Little or nothing so far has been demonstrated to characterise change in CrCP during mild hypocapnia. METHOD: We retrospectively analysed recordings of intracranial pressure (ICP), arterial blood pressure (ABP) and blood flow velocity from 27 severe TBI patients (mean 39.5 +/- 3.4 years, 6 women) in whom a ventilation increase (20% increase in respiratory minute volume) was performed over 50 min as part of a standard clinical CO2 reactivity test. CrCP was calculated using the Windkessel model of cerebral arterial flow. Arteriolar wall tension (WT) was calculated as a difference between CrCP and ICP. The compartmental compliances arterial (C a ) and cerebrospinal fluid space (C i ) were also evaluated. RESULTS: During hypocapnia, ICP decreased from 17+/-6.8 to 13.2+/-6.6 mmHg (p < 0.000001). Wall tension increased from 14.5 +/- 9.9 to 21.7+/-9.1 mmHg (p < 0.0002). CrCP, being a sum of WT + ICP, changed significantly from 31.5 +/- 11.9 mmHg to 34.9+/-11.1 mmHg (p < 0.002), and the closing margin (ABP-CrCP) remained constant at an average value of 60 mmHg. C a decreased significantly during hypocapnia by 30% (p < 0.00001) and C i increased by 26% (p < 0.003). CONCLUSION: During hypocapnia in TBI patients, ICP decreases and WT increases. CrCP increases slightly as the rise in wall tension outweighs the decrease in ICP. The closing margin remained unchanged, suggesting that the risk of hypocapnia-induced ischemia might not be increased. PMID- 29492550 TI - Occurrence of CPPopt Values in Uncorrelated ICP and ABP Time Series. AB - OBJECTIVES: Optimal cerebral perfusion pressure (CPPopt) is a concept that uses the pressure reactivity (PRx)-CPP relationship over a given period to find a value of CPP at which PRx shows best autoregulation. It has been proposed that this relationship be modelled by a U-shaped curve, where the minimum is interpreted as being the CPP value that corresponds to the strongest autoregulation. Owing to the nature of the calculation and the signals involved in it, the occurrence of CPPopt curves generated by non-physiological variations of intracranial pressure (ICP) and arterial blood pressure (ABP), termed here "false positives", is possible. Such random occurrences would artificially increase the yield of CPPopt values and decrease the reliability of the methodology.In this work, we studied the probability of the random occurrence of false-positives and we compared the effect of the parameters used for CPPopt calculation on this probability. MATERIALS AND METHODS: To simulate the occurrence of false-positives, uncorrelated ICP and ABP time series were generated by destroying the relationship between the waves in real recordings. The CPPopt algorithm was then applied to these new series and the number of false positives was counted for different values of the algorithm's parameters. RESULTS: The percentage of CPPopt curves generated from uncorrelated data was demonstrated to be 11.5%. CONCLUSION: This value can be minimised by tuning some of the calculation parameters, such as increasing the calculation window and increasing the minimum PRx span accepted on the curve. PMID- 29492551 TI - Simultaneous Transients of Intracranial Pressure and Heart Rate in Traumatic Brain Injury: Methods of Analysis. AB - OBJECTIVES: The detection of increasing intracranial pressure (ICP) is important in preventing secondary brain injuries. Before mean ICP increases critically, transient ICP elevations may be observed. We have observed ICP transients of less than 10 min duration ,which occurred simultaneously with transient increases in heart rate (HR). These simultaneous events in HR and ICP suggest a direct interaction or communication between the heart and the brain. METHODS: This chapter describes four mathematical methods and their applicability in detecting the above heart-brain cross-talk events during long-term monitoring of ICP. RESULTS: Recurrence plots, cross-correlation function and wavelet analysis confirmed the relationship between ICP and HR time series. Using the peaks detection algorithm with a sliding window approach we found an average of 37 cross-talk events (+/- SD 39). The number of events detected varied among patients, from 1 to more than 150 events. CONCLUSION: Our analysis suggested that the peaks detection algorithm based on a sliding window approach is feasible for detecting simultaneous peaks, e.g. cross-talk events in the ICP and HR signals. PMID- 29492552 TI - Increasing the Contrast-to-Noise Ratio of MRI Signals for Regional Assessment of Dynamic Cerebral Autoregulation. AB - OBJECTIVE: To devise an appropriate measure of the quality of a magnetic resonance imaging (MRI) signal for the assessment of dynamic cerebral autoregulation, and propose simple strategies to improve its quality. MATERIALS AND METHODS: Magnetic resonance images of 11 healthy subjects were scanned during a transient decrease in arterial blood pressure (BP). Mean signals were extracted from non-overlapping brain regions for each image. An ad-hoc contrast-to-noise ratio (CNR) was used to evaluate the quality of these regional signals. Global mean signals were obtained by averaging the set of regional signals resulting after applying a Hampel filter and discarding a proportion of the lower quality component signals. RESULTS: Significant improvements in CNR values of global mean signals were obtained, whilst maintaining significant correlation with the original ones. A Hampel filter with a small moving window and a low rejection threshold combined with a selection of the 50% component signals seems a recommendable option. CONCLUSIONS: This work has demonstrated the possibility of improving the quality of MRI signals acquired during transient drops in BP. This approach needs validation at a voxel level, which could help to consolidate MRI as a technological alternative to the standard techniques for the study of cerebral autoregulation. PMID- 29492553 TI - Comparing Models of Spontaneous Variations, Maneuvers and Indexes to Assess Dynamic Cerebral Autoregulation. AB - OBJECTIVE: We analyzed the performance of linear and nonlinear models to assess dynamic cerebral autoregulation (dCA) from spontaneous variations in healthy subjects and compared it with the use of two known maneuvers to abruptly change arterial blood pressure (BP): thigh cuffs and sit-to-stand. MATERIALS AND METHODS: Cerebral blood flow velocity and BP were measured simultaneously at rest and while the maneuvers were performed in 20 healthy subjects. To analyze the spontaneous variations, we implemented two types of models using support vector machine (SVM): linear and nonlinear finite impulse response models. The classic autoregulation index (ARI) and the more recently proposed model-free ARI (mfARI) were used as measures of dCA. An ANOVA analysis was applied to compare the different methods and the coefficient of variation was calculated to evaluate their variability. RESULTS: There are differences between indexes, but not between models and maneuvers. The mfARI index with the sit-to-stand maneuver shows the least variability. CONCLUSIONS: Support vector machine modeling of spontaneous variation with the mfARI index could be used for the assessment of dCA as an alternative to maneuvers to introduce large BP fluctuations. PMID- 29492554 TI - ICP and Antihypertensive Drugs. AB - OBJECTIVES: Arterial hypertension is among the leading risks for mortality. This burden requires in hypertensive patients the use of single, double or more antihypertensive drugs. The relationship between intracranial pressure (ICP) and arterial blood pressure is complex and still under debate. The impact of antihypertensive drugs on ICP is unknown. We wanted to understand whether the use of antihypertensive drugs has a significant influence on ICP and cerebrospinal fluid (CSF)/brain related parameters. MATERIALS AND METHODS: In a cohort of 95 patients with suspected normal pressure hydrocephalus, we prospectively collected drug details according to the Anatomical Therapeutic Chemical (ATC) classification. Lumbar infusion studies were performed. Using ICM+ software, we calculated at baseline and plateau ICP and pulse amplitude, resistance to CSF outflow, elastance, and pressure in the sagittal sinus and CSF production rate. We studied the influence of the administration of 1, 2, 3 or more antihypertensive drugs on ICP-derived parameters. We compared the data using Student's and Mann-Whitney tests or Chi-squared and Fisher's exact test. RESULTS: Elastance is significantly higher in patients with at least one antihypertensive drug compared with patients without medication. On the contrary, pressure volume index (PVI) is significantly decreased in patients with antihypertensive drugs compared with patients not on these medications. However, the number of antihypertensive drugs does not seem to influence other ICP parameters. CONCLUSIONS: Patients on antihypertensive drugs seem to have a stiffer brain than those not on them. PMID- 29492555 TI - ICP: From Correlation to Causation. AB - Intracranial pressure (ICP) is a complex modality in the sense that it largely interconnects various systemic and intra-cranial variables such as cerebral blood flow and volume, cerebrospinal fluid flow and absoption, craniospinal container. In this context, although empirical correlation is an interesting tool for establishing relations between pairs of observed variables, it may be limited to establishing causation relations. For instance, if variables X and Y are mainly influenced by variable Z, their correlation is strong, but does not mean that X has a causation relation with Y or vice versa. In this work, we explore the use of the statistical concept of partial correlation to ICP and other derived measures to apprehend the interplay between correlation and causation. PMID- 29492556 TI - A Waveform Archiving System for the GE Solar 8000i Bedside Monitor. AB - OBJECTIVES: Our objective was to develop, deploy, and test a data-acquisition system for the reliable and robust archiving of high-resolution physiological waveform data from a variety of bedside monitoring devices, including the GE Solar 8000i patient monitor, and for the logging of ancillary clinical and demographic information. MATERIALS AND METHODS: The data-acquisition system consists of a computer-based archiving unit and a GE Tram Rac 4A that connects to the GE Solar 8000i monitor. Standard physiological front-end sensors connect directly to the Tram Rac, which serves as a port replicator for the GE monitor and provides access to these waveform signals through an analog data interface. Together with the GE monitoring data streams, we simultaneously collect the cerebral blood flow velocity envelope from a transcranial Doppler ultrasound system and a non-invasive arterial blood pressure waveform along a common time axis. All waveform signals are digitized and archived through a LabView controlled interface that also allows for the logging of relevant meta-data such as clinical and patient demographic information. RESULTS: The acquisition system was certified for hospital use by the clinical engineering team at Boston Medical Center, Boston, MA, USA. Over a 12-month period, we collected 57 datasets from 11 neuro-ICU patients. The system provided reliable and failure-free waveform archiving. We measured an average temporal drift between waveforms from different monitoring devices of 1 ms every 66 min of recorded data. CONCLUSIONS: The waveform acquisition system allows for robust real-time data acquisition, processing, and archiving of waveforms. The temporal drift between waveforms archived from different devices is entirely negligible, even for long-term recording. PMID- 29492557 TI - Deriving the PRx and CPPopt from 0.2-Hz Data: Establishing Generalizability to Bedmaster Users. AB - OBJECTIVE: The objective was to explore the validity of industry-parameterized vital signs in the generation of pressure reactivity index (PRx) and optimal cerebral perfusion pressure (CPPopt) values. MATERIALS AND METHODS: Ten patients with intracranial pressure (ICP) monitors from 2008 to 2013 in a tertiary care hospital were included. Arterial blood pressure (ABP) and ICP were sampled at 240 Hz (of waveform data) and 0.2 Hz (of parameterized data produced by heuristic industry proprietary algorithms). 240-Hz ABP were filtered for pulse pressure and diastolic ABP within the limits of 20-150 mmHg. The PRx was calculated as Pearson's correlation coefficient using 10-s averages of ICP and ABP over a 5-min moving window with 80% overlap. For ease of comparison, we used the naming convention of BMx for PRx values derived from 0.2-Hz data. A 5-min median cerebral perfusion pressure (CPP) trend was calculated, PRx or BMx values divided and averaged into CPP bins spanning 5 mmHg. The minimum Y value (PRx or BMx) of the parabolic function fit to the resulting XY plot of 4 h of data was obtained, and updated every 1 min. Pearson's R correlations were calculated for each patient. Linear mixed-effects models were used with a random intercept to assess the overall correlation between the PRx (outcome) and the BMx (fixed effect) or the CPPopt-PRx (outcome) and the CPPopt-BMx (fixed effect). RESULTS: The overall correlation between the PRx and BMx was 0.78 based on the linear mixed effects models (p < 0.0001), and the overall correlation for the CPPopt-PRx and CPPopt BMx based on the linear mixed effects models was 0.76 (p < 0.0001). One patient had low correlation of CPPopts derived from the PRx vs the BMx; this patient had the least number of hours of CPPopt data to compare. CONCLUSIONS: The BMx shows promise in CPPopt derivation against the validated PRx measure. If further developed, it could expand the capability of centers to derive CPPopt goals for use in clinical trials. PMID- 29492558 TI - Medical Waveform Format Encoding Rules Representation of Neurointensive Care Waveform Data. AB - OBJECTIVE: Technology in neurointensive care units can collect and store vast amounts of complex patient data. The CHART-ADAPT project is aimed at developing technology that will allow for the collection, analysis and use of these big data at the patient's bedside in neurointensive care units. A requirement of this project is to automatically extract and transfer high-frequency waveform data (e.g. ICP) from monitoring equipment to high performance computing infrastructure for analysis. Currently, no agreed data standard exists in neurointensive care for the description of this type of data. In this pilot study, we investigated the use of Medical Waveform Format Encoding Rules (MFER- www.mfer.org-ISO 11073 92001) as a possible data standard for neurointensive care waveform data. MATERIALS AND METHODS: Several waveform formats were explored (e.g. XML, DICOM waveform) and evaluated for suitability given existing computing infrastructure constraints, e.g. NHS network capacity and the processing capabilities of existing integration software. Key requirements of the format included a compact data size and the use of a recognised standard. The MFER waveform format (ISO/TS 11073-92001) met both requirements. To evaluate the practicality of the MFER waveform format, seven waveform signals (ICP, ECG, ART, CVP, EtCO2, Pleth, Resp) collected over a period of 8 h from a patient at the Institute of Neurological Sciences in Glasgow were converted into MFER waveform format. RESULTS: The MFER waveform format has two main components: sampling information and frame information. Sampling information describes the frequency of the data sampling and the resolution of the data. Frame information describes the data itself; it consists of three elements: data block (the actual data), channel (each type of waveform data occupies a channel) and sequence (the repetition of the data). All seven waveform signals were automatically and successfully converted into the MFER waveform format. One MFER file was created for each minute of data (total of 479 files, 181 KB each). CONCLUSIONS: The MFER waveform format has potential as a lightweight standard for representing high-frequency neurointensive care waveform data. Further work will include a comparison with other waveform data formats and a live trial of using the MFER waveform format to stream patient data over a longer period. PMID- 29492559 TI - Multi-Scale Peak and Trough Detection Optimised for Periodic and Quasi-Periodic Neuroscience Data. AB - OBJECTIVES: The reliable detection of peaks and troughs in physiological signals is essential to many investigative techniques in medicine and computational biology. Analysis of the intracranial pressure (ICP) waveform is a particular challenge due to multi-scale features, a changing morphology over time and signal to-noise limitations. Here we present an efficient peak and trough detection algorithm that extends the scalogram approach of Scholkmann et al., and results in greatly improved algorithm runtime performance. MATERIALS AND METHODS: Our improved algorithm (modified Scholkmann) was developed and analysed in MATLAB R2015b. Synthesised waveforms (periodic, quasi-periodic and chirp sinusoids) were degraded with white Gaussian noise to achieve signal-to-noise ratios down to 5 dB and were used to compare the performance of the original Scholkmann and modified Scholkmann algorithms. RESULTS: The modified Scholkmann algorithm has false positive (0%) and false-negative (0%) detection rates identical to the original Scholkmann when applied to our test suite. Actual compute time for a 200-run Monte Carlo simulation over a multicomponent noisy test signal was 40.96 +/- 0.020 s (mean +/- 95%CI) for the original Scholkmann and 1.81 +/- 0.003 s (mean +/- 95%CI) for the modified Scholkmann, demonstrating the expected improvement in runtime complexity from [Formula: see text] to [Formula: see text]. CONCLUSIONS: The accurate interpretation of waveform data to identify peaks and troughs is crucial in signal parameterisation, feature extraction and waveform identification tasks. Modification of a standard scalogram technique has produced a robust algorithm with linear computational complexity that is particularly suited to the challenges presented by large, noisy physiological datasets. The algorithm is optimised through a single parameter and can identify sub-waveform features with minimal additional overhead, and is easily adapted to run in real time on commodity hardware. PMID- 29492560 TI - Room Air Readings of Brain Tissue Oxygenation Probes. AB - OBJECTIVE: Brain tissue oxygenation (pbtO2) monitoring with microprobes is increasingly used as an important parameter in addition to intracranial pressure in acutely brain-injured patients. Data on accuracy and long-term drift after use are scarce. We investigated room air readings of used pbtO2 probes for their relationship with the duration of monitoring, geographic location of the center, and manufacturer type. METHODS: After finishing clinically indicated monitoring in patients, pbtO2 probes used in two centers in Berlin and Munich were explanted and cleaned to avoid blood contamination. Immediately afterward, room air readings of partial oxygen pressure (pairO2) from 44 Licox(r) and 10 Raumedic (r) pbtO2 probes were recorded. Assumed height above sea level was 42 m for Berlin and 485 m for Munich; this resulted in assumed theoretical pairO2 readings of 157.8 mmHg in Berlin and 149.9 mmHg in Munich. RESULTS: Licox (r) probes in Berlin showed a mean pairO2 of 160.5 (SD 14.4) mmHg and of 147.8 (11.9) mmHg in Munich. Raumedic (r) probes in Berlin showed a mean pairO2 of 170.5 (12.2) mmHg and the single Raumedic (r) probe used in Munich 155 mmHg. No significant drift was found over time for probes with up to 14 days of monitoring. Prolonged use of up to 20 days showed a clinically negligible drift of 1.2 mmHg per day of use for Licox(r) probes.Mean absolute deviation for pairO2 from expected values was 6.4% for Licox (r) and 9.7% for Raumedic (r) probes. CONCLUSION: Room air partial oxygen pressure pairO2 may be utilized to assess the proper function of a pbtO2 probe. It provides a tool for quality control which is easy to implement. Probe readings are stable in the clinically relevant range, even after prolonged use. PMID- 29492561 TI - What Do We Mean by Cerebral Perfusion Pressure? AB - INTRODUCTION: No consensus exists on the exact method for measuring mean arterial blood pressure (MAP) in the definition of cerebral perfusion pressure (CPP). The aim of the current study is to investigate how different MAP measurement methods have influenced the CPP recommendations in the Brain Trauma Foundation (BTF) guidelines. METHODS: All papers on which the chapter on CPP thresholds in the 2007 version of the BTF guidelines is based, were reviewed. If accurate descriptions of head of bed elevation and arterial pressure transducer height were lacking, the authors were emailed for clarification. Additionally, the effect of choosing the radial artery for MAP measurement and the potential effect of gravity were studied in the literature. RESULTS: Thresholds of CPP in the BTF guidelines are based on 11 studies. Head of bed elevation at 30 degrees was part of the protocol in 5 studies, patients were nursed flat in 1 study, and this variable remained unknown for 5 studies. The arterial pressure transducer was at heart level in 5 studies, at ear level in 3 studies, and height was unknown in 3 studies. Measuring MAP in the radial artery underestimates carotid artery MAP by approximately 10 mmHg in the flat position, and in a nonflat position gravity influences MAP of the internal carotid artery. CONCLUSION: There is no uniform definition for CPP, which may affect conclusions on proposed CPP targets in severe traumatic brain injury by +/-10 mmHg. PMID- 29492562 TI - Investigation of the Relationship Between the Burden of Raised ICP and the Length of Stay in a Neuro-Intensive Care Unit. AB - OBJECTIVES: Raised intracranial pressure (ICP) is well known to be indicative of a poor outcome in traumatic brain injury (TBI). This phenomenon was quantified using a pressure time index (PTI) model of raised ICP burden in a paediatric population. Using the PTI methodology, this pilot study is aimed at investigating the relationship between raised ICP and length of stay (LOS) in adults admitted to a neurological intensive care unit (neuro-ICU). MATERIALS AND METHODS: In 10 patients admitted to the neuro-ICU following TBI, ICP was measured and data from the first 24 h were analysed. The PTI is a bounded area under the curve, where the bound is the threshold limit of interest for the signal. The upper bound of 20 mmHg for ICP is commonly used in clinical practice. To fully investigate the relationship between ICP and LOS, further bounds from 1 to 40 mmHg were used during the PTI calculations. A backwards step Poisson regression model with a log link function was used to find the important thresholds for the prediction of full LOS, measured in hours, in the neuro-ICU. RESULTS: The fit was assessed using a Chi-squared deviance goodness of fit method, which showed a non significant p value of 0.97, indicating a correctly specified model. The backwards step strategy, minimising the model's Akaike information criteria (AIC) at each change, found that levels 13-16, 18 and 20-21 combined were the most predictive. From this model it can be shown that for every 1 mmHg/h increase in burden, as measured by the PTI, the LOS has a base exponential increase of approximately 2 h, with the largest increases in the LOS given at the 20-mmHg threshold level. CONCLUSIONS: This model demonstrates that increased duration of raised ICP in the early monitoring period is associated with a prolonged LOS in the neuro-ICU. Further validation of the PTI model in a larger cohort is currently underway as part of the CHART-ADAPT project. Second, further adjustment with known predictors of outcome, such as severity of injury, would help to improve the fit and validate the current combination of predictors. PMID- 29492563 TI - Pressure Reactivity-Based Optimal Cerebral Perfusion Pressure in a Traumatic Brain Injury Cohort. AB - OBJECTIVES: Retrospective data from patients with severe traumatic brain injury (TBI) indicate that deviation from the continuously calculated pressure reactivity-based "optimal" cerebral perfusion pressure (CPPopt) is associated with worse patient outcome. The objective of this study was to assess the relationship between prospectively collected CPPopt data and patient outcome after TBI. METHODS: We prospectively collected intracranial pressure (ICP) monitoring data from 231 patients with severe TBI at Addenbrooke's Hospital, UK. Uncleaned arterial blood pressure and ICP signals were recording using ICM+(r) software on dedicated bedside computers. CPPopt was determined using an automatic curve fitting procedure of the relationship between pressure reactivity index (PRx) and CPP using a 4-h window, as previously described. The difference between an instantaneous CPP value and its corresponding CPPopt value was denoted every minute as DeltaCPPopt. A negative DeltaCPPopt that was associated with impaired PRx (>+0.15) was denoted as being below the lower limit of reactivity (LLR). Glasgow Outcome Scale (GOS) score was assessed at 6 months post-ictus. RESULTS: When DeltaCPPopt was plotted against PRx and stratified by GOS groupings, data belonging to patients with a more unfavourable outcome had a U-shaped curve that shifted upwards. More time spent with a DeltaCPPopt value below the LLR was positively associated with mortality (area under the receiver operating characteristic curve = 0.76 [0.68-0.84]). CONCLUSIONS: In a recent cohort of patients with severe TBI, the time spent with a CPP below the CPPopt-derived LLR is related to mortality. Despite aggressive CPP- and ICP-oriented therapies, TBI patients with a fatal outcome spend a significant amount of time with a CPP below their individualised CPPopt, indicating a possible therapeutic target. PMID- 29492564 TI - Spaceflight-Induced Visual Impairment and Globe Deformations in Astronauts Are Linked to Orbital Cerebrospinal Fluid Volume Increase. AB - OBJECTIVE: Most of the astronauts onboard the International Space Station (ISS) develop visual impairment and ocular structural changes that are not fully reversible upon return to earth. Current understanding assumes that the so-called visual impairments/intracranial pressure (VIIP) syndrome is caused by cephalad vascular fluid shift. This study assesses the roles of cerebrospinal fluid (CSF) and intracranial pressure (ICP) in VIIP. MATERIALS AND METHODS: Seventeen astronauts, 9 who flew a short-duration mission on the space shuttle (14.1 days [SD 1.6]) and 7 who flew a long-duration mission on the ISS (188 days [SD 22]) underwent MRI of the brain and orbits to assess the pre-to-post spaceflight changes in four categories: VIIP severity measures: globe flattening and nerve protrusion; orbital and ventricular CSF volumes; cortical gray and white matter volumes; and MR-derived ICP (MRICP). RESULTS: Significant pre-to-post-flight increase in globe flattening and optic nerve protrusion occurred only in the long duration cohort (0.031 [SD 0.019] vs -0.001 [SD 0.006], and 0.025 [SD 0.013] vs 0.001 [SD 0.006]; p < 0.00002 respectively). The increased globe deformations were associated with significant increases in orbital and ventricular CSF volumes, but not with increased tissue vascular fluid content. Additionally, a moderate increase in MRICP of 6 mmHg was observed in only two ISS astronauts with large ocular structure changes. CONCLUSIONS: These findings are evidence for the primary role of CSF and a lesser role for intracranial cephalad fluid-shift in the formation of VIIP. VIIP is caused by a prolonged increase in orbital CSF spaces that compress the globes' posterior pole, even without a large increase in ICP. PMID- 29492565 TI - Ventriculomegaly in the Elderly: Who Needs a Shunt? A MRI Study on 90 Patients. AB - OBJECTIVE: In the case of ventriculomegaly in the elderly, it is often difficult to differentiate between communicating chronic hydrocephalus (CCH) and brain atrophy. The aim of this study is to describe the MRI criteria of CCH, defined by a symptomatic patient with ventriculomegaly and that improved after shunt placement. MATERIALS AND METHODS: Magnetic resonance imaging was prospectively evaluated in 90 patients with ventriculomegaly. Patients were classified into three groups: patients without clinical signs of CCH (control, n = 47), patients with CCH treated by shunt placement with clinical improvement (responders, n = 36), and patients with CCH treated using a shunt without clinical improvement (nonresponders, n = 7). MRI parameters of the two groups of interest (responders vs. controls) were compared. RESULTS: Compared with controls, Evans' index (p = 0.029), ventricular area (p < 0.01), and volume (p = 0.0001) were higher in the responders. In this group, the callosal angle was smaller (p <= 0.0001) and the aqueductal stroke volume (SVa) of CSF was higher (p <= 0.0001) than in controls. On the ROC curves, the optimal cut-off values for differentiating between responders and controls were a ventricular area >33.5 cm2, a callosal angle <90.8 degrees and a SVa > 136.5 MUL/R-R. In multivariate analysis, responders remained associated with SVa and callosal angle, with a c-statistic of 0.90 (95%CI, 0.83 0.98). CONCLUSION: On suspicion of CCH, a large ventricular area, a small callosal angle, and an increased aqueductal stroke volume are important MRI arguments that can be associated with the clinical evaluation and dynamic testing of CSF to confirm the indication for a shunt. PMID- 29492566 TI - Is There a Link Between ICP-Derived Infusion Test Parameters and Outcome After Shunting in Normal Pressure Hydrocephalus? AB - OBJECTIVE: The term "hydrocephalus" encompasses a range of disorders characterised by clinical symptoms, abnormal brain imaging and derangement of cerebrospinal fluid (CSF) dynamics. The ability to elucidate which patients would benefit from CSF diversion (a shunt or third ventriculostomy) is often unclear. Similar difficulties are encountered in shunted patients to predict the scope for improvement by shunt re-adjustment or revision. MATERIALS AND METHODS: We compared retrospective pre-shunting infusion test results performed in 310 adult patients diagnosed with normal pressure hydrocephalus (NPH) and their improvement after shunting. RESULTS: Resistance to CSF outflow correlated significantly with improvement (p < 0.05). Other markers known from the literature, such as amplitude in CSF pulse pressure, the slope of the amplitude-pressure regression line, or elasticity did not show any correlation with outcome. CONCLUSION: Outcome following shunting in adult NPH is associated with resistance to CSF outflow; however, the latter cannot be taken as an absolute predictor of shunt response. PMID- 29492567 TI - Mathematical Modelling of CSF Pulsatile Flow in Aqueduct Cerebri. AB - OBJECTIVE: The phase-contrast MRI technique permits the non-invasive assessment of CSF movements in cerebrospinal fluid cavities of the central nervous system. Of particular interest is pulsatile cerebrospinal fluid (CSF) flow through the aqueduct cerebri. It is allegedly increased in hydrocephalus, having potential diagnostic value, although not all scientific reports contain unequivocally positive conclusions. METHODS: For the mathematical simulation of CSF flow, we used a computational model of cerebrospinal blood/fluid circulation designed by a former student as his PhD project. With this model, cerebral blood flow and CSF may be simulated in various vessels using a system of non-linear differential equations as time-varying signals. RESULTS: The amplitude of CSF flow seems to be positively related to the amplitude of pulse waveforms of intracranial pressure (ICP) in situations where mean ICP increases, such as during simulated infusion tests and following step increases of resistance to CSF outflow. An additional positive association between the pulse amplitude of ICP and CSF flow can be seen during simulated increases in the amplitude of arterial pulses (without changes in mean arterial pressure, MAP). The opposite effect can be observed during step increases in the resistance of the aqueduct cerebri and with decreasing elasticity of the system, where the CSF flow amplitude and the ICP pulse amplitude are related inversely. Vasodilatation caused by both gradual decreases in MAP and by increases in PaCO2 provokes an elevation in the observed amplitude of pulsatile CSF flow. CONCLUSIONS: Preliminary results indicate that the pulsations of CSF flow may carry information about both CSF-circulatory and cerebral vasogenic components. In most cases, the pulsations of CSF flow are positively related to the pulse amplitudes of both arterial pressure and ICP and to a degree of cerebrovascular dilatation. PMID- 29492568 TI - Cerebrospinal Fluid and Cerebral Blood Flows in Idiopathic Intracranial Hypertension. AB - OBJECTIVES: Cerebrospinal fluid (CSF) and blood flows have a strong relationship during a cardiac cycle. Idiopathic intracranial hypertension (IIH) is a pathology that seems to present hemodynamic and hydrodynamic disturbance. The aim of this study was to establish CSF and blood interaction in IIH. MATERIAL AND METHODS: We retrospectively studied cerebral hydrodynamic and hemodynamic flows by phase contrast MRI (PCMRI) in 13 IIH subjects (according Dandy's criteria) and 16 controls. We analyzed arterial peak flow, pulsatility index, and resistive index in arterial and venous compartments (PFart, PIart, RIart, PFvein, PIvein, RIvein) and measured arteriovenous and CSF peak flow and stroke volume (PFav, SVVASC, PFCSF, SVCSF). RESULTS: We found no significant difference between IIH and control groups in arterial and venous parameters. Arteriovenous flow analysis showed higher PFav and SVVASC in the IIH group than in the control group (respectively 369 +/- 27 mL/min and 286 +/- 47 mL/min, p = 0.02; and 1085 +/- 265 MUL/cardiac cycle and 801 +/- 226 MUL/cardiac cycle, p = 0.007). PFCSF and SVCSF were higher in the IIH group than in the control group (respectively 206 +/- 50 mL/min and 126.6 +/- 24.8 mL/min, p = 0.04; and 570 +/- 190 MUL/cardiac cycle and 430 +/- 100 MUL/cardiac cycle, p = 0.0007). CONCLUSION: Although no significant change was found in arterial and venous flows, we showed that a small phase shift of venous outflow might cause an increase in the arteriovenous pulsatility and an increasing brain expansion during the cardiac cycle. This arteriovenous flow increase would result in an increase of CSF flushing through the foramen magnum and an increased ICP. PMID- 29492569 TI - Significant Association of Slow Vasogenic ICP Waves with Normal Pressure Hydrocephalus Diagnosis. AB - OBJECTIVE: We aimed to test whether there is an association of slow vasogenic wave (SVW) occurrence with positive response to external lumbar drainage (ELD) and ventriculoperitoneal shunting and to design a method for the recognition and quantification of SVWs in the intracranial pressure (ICP) signal. MATERIALS AND METHODS: We constructed SVW templates using normalized sine waves. We calculated the cross-correlation between the respective SVW template and the ICP signal. This was followed by shifting the templates forward and performing the cross correlation analysis again until the end of the recording. Cross-correlation values above a threshold were considered to be indicative of SVWs. This threshold was previously determined and validated on a sample of ICP records of six patients. We calculated the root mean square of the recognized SVW periods as a measure of signal strength. Time-averaged signal strength was calculated over the full recording time (ICPSmean) and over the wave periods (ICPS). RESULTS: We determined ICPS and ICPSmean in recordings of 2 groups of patients presenting with Hakim's triad: 26 normal pressure hydrocephalus (NPH) patients and 20 non NPH patients. We then tested whether there was an association between ICPS or ICPSmean and the respective diagnosis using a Mann-Whitney test. We found significant association between ICPS (p = 0.014) and ICPSmean (p = 0.022) and the diagnoses. CONCLUSIONS: The described method based on pattern recognition in the time domain is suitable for the detection and quantification of SVWs in ICP signals. We found a significant association between the occurrence of SVWs and independent NPH diagnosis. PMID- 29492570 TI - ICP Monitoring and Phase-Contrast MRI to Investigate Intracranial Compliance. AB - OBJECTIVE: The amplitude of intracranial pressure (ICP) can be measured by ICP monitoring. Phase-contrast magnetic resonance imaging (PCMRI) can quantify blood and cerebrospinal fluid (CSF) flows. The aim of this work was to investigate intracranial compliance at rest by combining baseline ICP monitoring and PCMRI in hydrocephalus patients. MATERIALS AND METHODS: ICP monitoring was performed before infusion testing to quantify DeltaICP_rest at the basal condition in 33 suspected hydrocephalus patients (74 years). The day before, patients had had a PCMRI to assess total cerebral blood flow (tCBF), intracranial blood volume change (stroke volume SVblood), and cervical CSF volume change (the stroke volume CSV). Global (blood and CSF) intracranial volume change (DeltaIVC) during each cardiac cycle (CC) was calculated. Finally, Compliance: C_rest = DeltaIVC/DeltaICP_rest was calculated. The data set was postprocessed by two operators according to blind analysis. RESULTS: Bland-Altman plots showed that measurements presented no significant difference between the two operators. DeltaICP_rest = 2.41 +/- 1.21 mmHg, tCBF = 469.89 +/- 127.54 mL/min, SVblood = 0.82 +/- 0.32 mL/cc, CSV = 0.50 +/- 0.22 mL/cc, DeltaIVC = 0.44 +/- 0.22 mL, and C_rest = 0.23 +/- 0.15 mL/mmHg. There are significant relations between SVblood and CSV and also SVblood and tCBF. CONCLUSIONS: During "basal" condition, the compliance amplitude of the intracranial compartment is heterogeneous in suspected hydrocephalus patients, and its value is lower than expected! This new parameter could represent new information, complementary to conventional infusion tests. We hope that this information can be applied to improve the selection of patients for shunt surgery. PMID- 29492572 TI - Differential Systolic and Diastolic Regulation of the Cerebral Pressure-Flow Relationship During Squat-Stand Manoeuvres. AB - OBJECTIVE: Cerebral pressure-flow dynamics are typically reported between mean arterial pressure and mean cerebral blood velocity. However, by reporting only mean responses, potential differential regulatory properties associated with systole and diastole may have been overlooked. MATERIALS AND METHODS: Twenty young adults (16 male, age: 26.7 +/- 6.6 years, BMI: 24.9 +/- 3.0 kg/m2) were recruited for this study. Middle cerebral artery velocity was indexed via transcranial Doppler. Cerebral pressure-flow dynamics were assessed using transfer function analysis at both 0.05 and 0.10 Hz using squat-stand manoeuvres. This method provides robust and reliable measures for coherence (correlation index), phase (timing buffer) and gain (amplitude buffer) metrics. RESULTS: There were main effects for both cardiac cycle and frequency for phase and gain metrics (p < 0.001). The systolic phase (mean +/- SD) was elevated at 0.05 (1.07 +/- 0.51 radians) and 0.10 Hz (0.70 +/- 0.46 radians) compared to the diastolic phase (0.05 Hz: 0.59 +/- 0.14 radians; 0.10 Hz: 0.33 +/- 0.11 radians). Conversely, the systolic normalized gain was reduced (0.05 Hz: 0.49 +/- 0.12%/%; 0.10 Hz: 0.66 +/ 0.20%/%) compared to the diastolic normalized gain (0.05 Hz: 1.46 +/- 0.43%/%; 0.10 Hz: 1.97 +/- 0.48%/%). CONCLUSIONS: These findings indicate there are differential systolic and diastolic aspects of the cerebral pressure-flow relationship. The oscillations associated with systole are extensively buffered within the cerebrovasculature, whereas diastolic oscillations are relatively unaltered. This indicates that the brain is adapted to protect itself against large increases in systolic blood pressure, likely as a mechanism to prevent cerebral haemorrhages. PMID- 29492571 TI - Numerical Cerebrospinal System Modeling in Fluid-Structure Interaction. AB - OBJECTIVE: Cerebrospinal fluid (CSF) stroke volume in the aqueduct is widely used to evaluate CSF dynamics disorders. In a healthy population, aqueduct stroke volume represents around 10% of the spinal stroke volume while intracranial subarachnoid space stroke volume represents 90%. The amplitude of the CSF oscillations through the different compartments of the cerebrospinal system is a function of the geometry and the compliances of each compartment, but we suspect that it could also be impacted be the cardiac cycle frequency. To study this CSF distribution, we have developed a numerical model of the cerebrospinal system taking into account cerebral ventricles, intracranial subarachnoid spaces, spinal canal and brain tissue in fluid-structure interactions. MATERIALS AND METHODS: A numerical fluid-structure interaction model is implemented using a finite-element method library to model the cerebrospinal system and its interaction with the brain based on fluid mechanics equations and linear elasticity equations coupled in a monolithic formulation. The model geometry, simplified in a first approach, is designed in accordance with realistic volume ratios of the different compartments: a thin tube is used to mimic the high flow resistance of the aqueduct. CSF velocity and pressure and brain displacements are obtained as simulation results, and CSF flow and stroke volume are calculated from these results. RESULTS: Simulation results show a significant variability of aqueduct stroke volume and intracranial subarachnoid space stroke volume in the physiological range of cardiac frequencies. CONCLUSIONS: Fluid-structure interactions are numerous in the cerebrospinal system and difficult to understand in the rigid skull. The presented model highlights significant variations of stroke volumes under cardiac frequency variations only. PMID- 29492573 TI - Normative Ranges of Transcranial Doppler Metrics. AB - OBJECTIVE: To determine normal ranges for traditional transcranial Doppler (TCD) measurements for two age groups (14-19 and 20-29 years) and compare to existing literature results. The development of a normal range for TCD measurements will be required for the development of diagnostic and prognostic tests in the future. MATERIALS AND METHODS: We performed TCD on the middle cerebral artery on 147 healthy subjects aged 18.9 years (SD = 2.1) and calculated mean cerebral blood flow velocity (mCBFV) and pulsatility index (PI). The study population was divided into two age populations (14-19 and 20-29 years). RESULTS: There was a significant decrease in PI (p = 0.015) for the older age group with no difference in mCBFV. CONCLUSION: Age-related, normal data are a prerequisite for TCD to continue to gain clinical acceptance. Our correlation of age-related TCD findings with previously published results as the generally accepted "gold standard" underlines the validity and sensitivity of this ultrasound method. PMID- 29492574 TI - Autoregulating Cerebral Tissue Selfishly Exploits Collateral Flow Routes Through the Circle of Willis. AB - OBJECTIVE: Ischemic stroke is a leading cause of death and disability. Autoregulation and collateral blood flow through the circle of Willis both play a role in preventing tissue infarction. A steady-state model of the cerebral arterial network was used to investigate the interaction of these mechanisms when autoregulation is impaired ipsilateral to an occluded artery. MATERIALS AND METHODS: Twelve structural variants of the circle of Willis were modelled with left internal carotid artery occlusion and coupled with (1) a passive model of the cerebral vascular bed, (2) a steady-state model of an autoregulating cerebral vascular bed, and (3) a model in which the contralateral hemisphere autoregulates and the ipsilateral hemisphere does not. RESULTS: Results showed that if the autoregulatory response is impaired ipsilaterally, then, in the autoregulating hemisphere, cerebral flows are preserved at the expense of those on the ipsilateral side. CONCLUSIONS: Thus, although autoregulation is an essential facilitator of collateral flow through the circle of Willis, contralateral autoregulation can exacerbate flow reductions if not balanced by the same response in the vascular beds on the ipsilateral side. The status of the autoregulatory response in both hemispheres can strongly influence cerebral blood flows and tissue survival and should, therefore, be monitored in stroke. PMID- 29492575 TI - ICP Monitoring by Open Extraventricular Drainage: Common Practice but Not Suitable for Advanced Neuromonitoring and Prone to False Negativity. AB - OBJECTIVE: A drawback in the use of an external ventricular drain (EVD) originates in the fact that draining cerebrospinal fluid (CSF) (open system) and intracranial pressure (ICP) monitoring can be done at the same time but is considered to be unreliable regarding the ICP trace. Furthermore, with the more widespread use of autoregulation monitoring using blood pressure and ICP signals, the question arises of whether an ICP signal from an open EVD can be used for this purpose. Using an EVD system with an integrated parenchymal ICP probe we compared the different traces of an ICP signal and their derived parameters under opened and closed CSF drainage. METHODS: Twenty patients with either subarachnoid or intraventricular hemorrhage and indication for ventriculostomy plus ICP monitoring received an EVD in combination with an air-pouch-based ICP probe. ICP was monitored via an open ventricular catheter (ICP_evd) and ICP probe (ICP_probe) simultaneously. Neuromonitoring data (ICP, arterial blood pressure, cerebral perfusion pressure, pressure reactivity index (PRx)) were recorded by ICM+ software for the time of ICU intensive care treatment. Routinely (at least every 4 h) ICP was recorded with a closed CSF drainage system for at least 15 min. ICP, ICP amplitude, and the autoregulation parameters (PRx_probe, PRx_evd) were evaluated for every episode with closed CSF drainage and during the 3 h prior with an open drainage system. RESULTS: One hundred and forty-four episodes with open/closed drainage were evaluated. During open drainage, overall mean ICP_evd levels were nonsignificantly different from those of ICP_probe, with 9.8 + 3.3 versus 8.2 + 3.2 mmHg, respectively. Limits of agreement ranged between 5.2 and -8.3 mmHg. However, 51 increases of ICP >20 mmHg with a duration of 3-30 min were missed by ICP_evd, and in 101 episodes the difference between ICPs was greater than 10 mmHg. After closure of the EVD, ICP increased moderately using both methods. Mean PRx_evd was significantly higher (falsely indicating impaired autoregulation) and more subjected to fluctuations than PRx_probe. CONCLUSION: The general practice of draining CSF and monitoring ICP via a (usually open) EVD plus frequently performed catheter closure for ICP reading is feasible for assessment of overall ICP trends. However, it does have clinically relevant drawbacks, namely, a significant amount of undetected increases in ICP above thresholds, and continuous assessment of cerebrovascular autoregulation is less reliable. In conclusion, all patients who need CSF drainage plus ICP monitoring due to the severity of their brain insult need either an EVD with integrated ICP probe or an EVD line plus a separate ICP probe. PMID- 29492576 TI - Comparison of Intracranial Pressure and Pressure Reactivity Index Obtained Through Pressure Measurements in the Ventricle and in the Parenchyma During and Outside Cerebrospinal Fluid Drainage Episodes in a Manipulation-Free Patient Setting. AB - OBJECTIVE: We investigated the effect of cerebrospinal fluid (CSF) drainage on the intracranial pressure (ICP) signal measured in the parenchyma and the ventricle as well as the effect on the pressure reactivity index (PRx) calculated from both signals. METHODS: Ten patients were included in this prospective study. All patients received a parenchymal ICP sensor and an external ventricular drain (EVD) for CSF drainage. ICP signals (ICP-p and ICP-evd) were captured. Part of the study was a period of 90 min during which the patient was free from any manipulation, consisting of 30 min of drainage (O1), 30 min EVD closed (C) and 30 min of drainage (O2). RESULTS: Mean ICP-evd and mean AMP-evd increased (3.03 and 0.46 mmHg) from O1 to C and decreased (2.12 and 0.43 mmHg) from C to O2. ICP-p and AMP-p changes were less pronounced (closing EVD: +0.81 mmHg/+0.22 mmHg; opening EVD: -0.22 mmHg/-0.05 mmHg). Mean difference between PRx-evd and PRx-p was 0.12 for O1, 0.02 for C and -0.02 for O2. The intraclass correlation coefficient for absolute agreement of single measures was 0.66 for O1, 0.77 for C and 0.69 for O2. Mean PRx differences demonstrated a significant difference between O1 versus C and O1 versus O2 but not between C versus O2. CONCLUSION: Drainage of CSF reduces ICP magnitude and amplitude through the EVD. This effect was only marginal in parenchymal ICP measurements. In manipulation-free circumstances, agreement of PRx obtained through parenchymal and ventricular measurements was moderate to good, depending on the statistical method, and was not necessarily influenced by drainage. PMID- 29492578 TI - Assessing Cerebral Hemodynamic Stability After Brain Injury. AB - OBJECTIVE: Following brain injury, unstable cerebral hemodynamics can be characterized by abnormal rises in intracranial pressure (ICP). This behavior has been quantified by the RAP index: the correlation (R) between ICP pulse amplitude (A) and mean (P). While RAP could be a valuable indicator of autoregulatory processes, its prognostic ability is not well established and its validity has been questioned due to potential errors in measurement. Here, we test (1) whether RAP is a consistent measure of intracranial hemodynamics and (2) whether RAP has prognostic value in predicting hemodynamic instability following brain injury. MATERIALS AND METHODS: RAP was tested in seven brain injured patients treated in a surgical intensive care unit. A sample of ICP data was randomly chosen and segmented into 1 hour periods. Hours were then categorized as either stable, which contained no sharp rises in ICP, or unstable, which contained >=1 sharp rise-where a sharp rise is defined as ICP exceeding a mean slope of 0.15 mmHg/s. Equal numbers of stable and unstable segments were then selected for each patient. RAP was calculated as the Pearson's correlation coefficient between ICP pulse amplitude (AMP) and mean (mICP), determined in 6 second windows, according to established methods. RESULTS: Results showed that (1) average AMP and ICP levels were similar between stable and unstable periods and (2) unstable periods were identified by RAP values exceeding 0.6 with an average positive predictive value of 74%. CONCLUSIONS: We conclude that RAP can provide a valid measure of ICP dynamics, is not affected by sensor drift, and can better distinguish periods of instability than ICP or AMP alone. PMID- 29492577 TI - Visualizing Cerebrovascular Autoregulation Insults and Their Association with Outcome in Adult and Paediatric Traumatic Brain Injury. AB - OBJECTIVE: The aim of this study is to assess visually the impact of duration and intensity of cerebrovascular autoregulation insults on 6-month neurological outcome in severe traumatic brain injury. MATERIAL AND METHODS: Retrospective analysis of prospectively collected minute-by-minute intracranial pressure (ICP) and mean arterial blood pressure data of 259 adult and 99 paediatric traumatic brain injury (TBI) patients from multiple European centres. The relationship of the 6-month Glasgow Outcome Scale with cerebrovascular autoregulation insults (defined as the low-frequency autoregulation index above a certain threshold during a certain time) was visualized in a colour-coded plot. The analysis was performed separately for autoregulation insults occurring with cerebral perfusion pressure (CPP) below 50 mmHg, with ICP above 25 mmHg and for the subset of adult patients that did not undergo decompressive craniectomy. RESULTS: The colour coded plots showed a time-intensity-dependent association with outcome for cerebrovascular autoregulation insults in adult and paediatric TBI patients. Insults with a low-frequency autoregulation index above 0.2 were associated with worse outcomes and below -0.6 with better outcomes, with and approximately exponentially decreasing transition curve between the two intensity thresholds. All insults were associated with worse outcomes when CPP was below 50 mmHg or ICP was above 25 mmHg. CONCLUSIONS: The colour-coded plots indicate that cerebrovascular autoregulation is disturbed in a dynamic manner, such that duration and intensity play a role in the determination of a zone associated with better neurological outcome. PMID- 29492579 TI - Systolic and Diastolic Regulation of the Cerebral Pressure-Flow Relationship Differentially Affected by Acute Sport-Related Concussion. AB - OBJECTIVE: To determine whether acute sports-related concussion (SRC) exerts differential effects on cerebral autoregulatory properties during systole versus diastole. MATERIALS AND METHODS: One hundred and thirty-six contact-sport athletes tested preseason; 14 sustained a concussion and completed follow-up testing at 72 hours, 2 weeks, and 1 month post-injury. Five minutes of repetitive squat-stand maneuvers induced blood pressure (BP) oscillations at both 0.05 and 0.10 Hz. Beat-by-beat peak-systolic and end-diastolic BP (sysBP/ diasBP) and middle cerebral artery blood velocity (sysMCAv/diasMCAv) were recorded using finger photoplethysmography and transcranial Doppler ultrasound, respectively. Relationships between sysBP-sysMCAv and diasBP-diasMCAv were quantified using transfer function analysis to estimate coherence (correlation), gain (response magnitude), and phase (response latency). RESULTS: Significant main effects of the cardiac cycle were observed across all outcome metrics. A significant main effect of SRC was observed for 0.10 Hz phase: systolic and diastolic phases were reduced at 72 h (21.8 +/- 5.2%) and 2 weeks (22.7 +/- 7.1%) compared to preseason but recovered by 1 month. Concussion significantly impaired diastolic, but not systolic, gain: 0.10 Hz diastolic gain was increased (27.2 +/- 7.7%) at 2 weeks, recovering by 1 month. CONCLUSIONS: Impairments in autoregulatory capacity, observed for a transient period following SRC that persist beyond symptom resolution and clinical recovery, appear to be differentially affected across the cardiac cycle. Similar patterns of impairment were observed for systolic and diastolic phases (response latency); however, normalized gain (response magnitude) impairments were identified only in diastole. These findings may explain the increased cerebral vulnerability as well as exercise-induced symptom exacerbation observed post-SRC. PMID- 29492580 TI - Induced Dynamic Intracranial Pressure and Cerebrovascular Reactivity Assessment of Cerebrovascular Autoregulation After Traumatic Brain Injury with High Intracranial Pressure in Rats. AB - OBJECTIVE: In previous work we showed that high intracranial pressure (ICP) in the rat brain induces a transition from capillary (CAP) to pathological microvascular shunt (MVS) flow, resulting in brain hypoxia, edema, and blood brain barrier (BBB) damage. This transition was correlated with a loss of cerebral blood flow (CBF) autoregulation undetected by static autoregulatory curves but identified by induced dynamic ICP (iPRx) and cerebrovascular (iCVRx) reactivity. We hypothesized that loss of CBF autoregulation as correlated with MVS flow would be identified by iPRx and iCVRx in traumatic brain injury (TBI) with elevated ICP. METHODS: TBI was induced by lateral fluid percussion (LFP) using a gas-driven device in rats. Using in vivo two-photon laser scanning microscopy, cortical microcirculation, tissue oxygenation (NADH autofluoresence), and BBB permeability (fluorescein dye extravasation) were measured before and for 4 h after TBI. Laser Doppler cortical flux, rectal and brain temperature, ICP and mean arterial pressure (MAP), blood gases, and electrolytes were monitored. Every 30 min, a transient 10 mmHg rise in MAP was induced by i.v. bolus of dopamine. iPRx = DeltaICP/DeltaMAP and iCVRx = DeltaCBF/DeltaMAP. RESULTS: We demonstrated that iPRx and iCVRx correctly identified more severe loss of CBF autoregulation correlated with a transition of blood flow to MVS after TBI with high ICP compared to TBI without an increase in ICP. CONCLUSIONS: In TBI with high ICP, high-velocity MVS flow is responsible for the loss of CBF autoregulation identified by iPRx and iCVRx. PMID- 29492581 TI - Prediction of the Time to Syncope Occurrence in Patients Diagnosed with Vasovagal Syncope. AB - OBJECTIVE: In this study we aimed to predict the time to syncope occurrence (TSO) in patients with vasovagal syncope (VVS), solely based on measurements recorded during the supine position of the head-up tilt (HUT) testing protocol. METHODS: We extracted various time and frequency domain features related to morphological aspects of arterial blood pressure (ABP) and the electrocardiogram (ECG) raw signals as well as to dynamic interactions between beat-to-beat ABP, heart rate, and cerebral blood flow velocity. From these we identified the most predictive features related to TSO. RESULTS: Specifically, when no orthostatic stress is involved, TSO in VVS patients can be predicted with high accuracy from a set of only five ECG features. PMID- 29492582 TI - Statistical Signal Properties of the Pressure-Reactivity Index (PRx). AB - OBJECTIVES: The pressure-reactivity index (PRx) is defined in terms of the moving correlation coefficient between intracranial pressure (ICP) and mean arterial pressure (MAP) and is a measure of cerebral autoregulation ability. Plots of PRx against cerebral perfusion pressure (CPP) show a U-shaped behaviour: the minimum reflecting optimal cerebral autoregulation (CPPopt). However U-shaped behaviour may also occur by chance. To date there has been no evaluation of the statistical properties of these signals. MATERIALS AND METHODS: We simulated PRx/CPP distributions using synthetic ICP and MAP signals from Gaussian noise with known cross-correlation and calculated the statistical distribution of extrema in the PRx/CPP relationship. RESULTS: The calculation of PRx on random data is statistically biased to show a U-shaped behaviour when the signals are positively cross-correlated (equivalent to PRx > 0). For PRx < 0, the bias is towards an inverse U-shaped behaviour. We demonstrate that this bias is eliminated by Fisher transforming the PRx data before CPPopt analysis. CONCLUSIONS: Cross-correlated signals are biased to show a U-shaped distribution. A CPPopt-like behaviour will be observed more often than not even from random ICP and MAP signals that do not exhibit autoregulation, unless PRx is Fisher transformed. Care must be taken in interpreting CPPopt in terms of physiology calculated from untransformed data. PMID- 29492583 TI - Validation of the current eligibility criteria for focal therapy in men with localized prostate cancer and the role of MRI. AB - PURPOSE: To validate current eligibility criteria for focal therapy (FT) in prostate cancer men undergoing radical prostatectomy (RP) and to assess the role of magnetic resonance imaging (MRI). METHODS: Retrospective analysis of 217 RP patients (2009-2016) with preoperative MRI (almost all in external institutions) and fulfillment of different FT eligibility criteria: unilateral tumor, clinical tumor stage <= cT2a, prostate volume <= 60 mL and either biopsy Gleason 3 + 3 or <= 3 + 4 and PSA <= 10 or <= 15 ng/mL. Multivariable logistic regression analyses (MVA) assessed the role of MRI to predict the presence of significant contralateral tumor or extracapsular extension (ECE), including seminal vesicle invasion. To quantify model accuracy, Receiver Operating Characteristics-derived area under the curve (AUC) was used. RESULTS: Of 217 patients fulfilling widest biopsy criteria and 113 fulfilling additional MRI criteria, 64 (29.7%) and 37 (32.7%) remained eligible for FT according to histopathological results. In MVA, fulfillment of MRI criteria reached independent predictor status for prediction of contralateral tumor but not for ECE. Addition of MRI resulted in AUC gain (57.5-64.6%). Sensitivity, specificity, PPV and NPV for MRI to predict contralateral tumor were: 41.8, 71.6, 70.9 and 42.6%, respectively. Virtually the same results were recorded for Gleason 3 + 3 and/or PSA <= 10 ng/mL. CONCLUSIONS: Patient eligibility criteria for FT using biopsy criteria remained insufficient with respect to contralateral tumor disease. Although, MRI improves accuracy, it cannot safely exclude or minimize chance of significant cancer on contralateral prostate side. To date, stricter eligibility criteria are needed to provide more diagnostic reliability. PMID- 29492584 TI - Penoscrotal versus minimally invasive infrapubic approach for inflatable penile prosthesis placement: a single-center matched-pair analysis. AB - PURPOSE: To compare perioperative results, safety and efficacy profile in patients receiving inflatable penile prosthesis (IPP) via penoscrotal (PS) or minimally invasive infrapubic (MII) approach for erectile dysfunction. METHODS: A matched-pair analysis was performed including 42 patients undergoing IPP implantation via PS (n = 21) or MII (n = 21) between 2011 and 2016. Clinical and surgical data were prospectively collected. Patients' and partners' outcomes were assessed by the International Index of Erectile Function (IIEF), Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) and Quality of Life and Sexuality with Penile Prosthesis (QoLSPP) questionnaires. RESULTS: Mean (SD) operative time was 128 (40.6) min in group PS and 91 (43.0) min in group MII (p = 0.041). Complications occurred in 3/21 (14%) and 2/21 (10%) patients in groups PS and MII (p = 0.832). Overall, no differences were observed concerning the device utilisation (p = 0.275). However, in group MII 4/21 (19%) patients were able to resume sexual activity prior to 4 postoperative weeks, while in group PS no patient was (p = 0.012). Mean (SD) scores for questionnaires were similar between groups PS and MII: IIEF [20.9 (7.3) vs. 20.7 (4.8); p = 0.132], patient EDITS [76.0 (25.6) vs. 74.7 (20.8); p = 0.256] and partner EDITS [72.5 (29.1) vs. 73.1 (21.4); p = 0.114]. Similarly, QoLSPP showed comparable results among the groups PS and MII: functional domain [3.9 (1.4) vs. 4.0 (1.2); p = 0.390], personal [4.0 (1.2) vs. 4.1 (1.0); p = 0.512], relational [3.7 (1.5) vs. 3.9 (1.2); p = 0.462] and social [4.0 (1.2) vs. 3.9 (1.2); p = 0.766]. CONCLUSIONS: PS and MII demonstrated to be safe and efficient techniques, leading to high level of both patients and partners satisfaction. Additionally, the minimally invasive infrapubic approach showed a shorter operative time and a tendency for a faster return to sexual activity. PMID- 29492585 TI - YRNA expression in prostate cancer patients: diagnostic and prognostic implications. AB - OBJECTIVE: To study the expression of YRNAs (Ro-associated Y), a novel class of non-coding RNAs, in prostate cancer (PCA) patients. METHODS: The expression of all four YRNAs (RNY1, RNY3, RNY4, RNY5) was determined in archival PCA (prostate adenocarcinoma, n = 56), normal (n = 36) and benign prostatic hyperplasia (BPH; n = 28) tissues using quantitative real-time PCR. Associations with clinicopathological parameters and prognostic role for biochemical recurrence free survival were analysed. RESULTS: All YRNAs were significantly downregulated in PCA tissue compared to normal tissue (all YRNAs) and to BPH tissue (RNY4 and RNY5; RNY1 and RNY3 as trend). Among tumor ISUP grade groups, the most prominent differences in the expression were evident between groups 1 and 2 (RNY1, RNY3 und RNY4; all p < 0.05). Discrimination ability for normal/BPH tissue versus tumor tissue in ROC analysis (area under curve) was ranging from 0.658 (RNY1) to 0.739 (RNY4). Higher RNY5 expression was associated with poor prognosis (biochemical recurrence-free survival). CONCLUSION: The expression of YRNAs is altered in PCA and associated with poor prognosis (RNY5). Possible diagnostic role of YRNAs in prostate cancer should be investigated in further studies. PMID- 29492588 TI - Anticipatory coarticulation in non-speeded arm movements can be motor-equivalent, carry-over coarticulation always is. AB - In a sequence of arm movements, any given segment could be influenced by its predecessors (carry-over coarticulation) and by its successor (anticipatory coarticulation). To study the interdependence of movement segments, we asked participants to move an object from an initial position to a first and then on to a second target location. The task involved ten joint angles controlling the three-dimensional spatial path of the object and hand. We applied the principle of the uncontrolled manifold (UCM) to analyze the difference between joint trajectories that either affect (non-motor equivalent) or do not affect (motor equivalent) the hand's trajectory in space. We found evidence for anticipatory coarticulation that was distributed equally in the two directions in joint space. We also found strong carry-over coarticulation, which showed clear structure in joint space: More of the difference between joint configurations observed for different preceding movements lies in directions in joint space that leaves the hand's path in space invariant than in orthogonal directions in joint space that varies the hand's path in space. We argue that the findings are consistent with anticipatory coarticulation reflecting processes of movement planning that lie at the level of the hand's trajectory in space. Carry-over coarticulation may reflect primarily processes of motor control that are governed by the principle of the UCM, according to which changes that do not affect the hand's trajectory in space are not actively delimited. Two follow-up experiments zoomed in on anticipatory coarticulation. These experiments strengthened evidence for anticipatory coarticulation. Anticipatory coarticulation was motor-equivalent when visual information supported the steering of the object to its first target, but was not motor equivalent when that information was removed. The experiments showed that visual updating of the hand's path in space when the object approaches the first target only affected the component of the joint difference vector orthogonal to the UCM, consistent with the UCM principle. PMID- 29492587 TI - Protein O-mannosyltransferases are required for sterigmatocystin production and developmental processes in Aspergillus nidulans. AB - Aspergillus nidulans produces sterigmatocystin (ST), a precursor of a carcinogenic secondary metabolite aflatoxin (AF), during its developmental process. ST biosynthesis has been shown to be affected by various regulatory factors. In this study, we investigated the involvement of O-mannosyltransferases (PmtA, PmtB, PmtC), in ST production and morphological development. Deletion of pmtA (DeltapmtA), pmtB (DeltapmtB) or pmtC (DeltapmtC) caused no spore production and a significant decline of vegetative growth. A tremendous decline of ST level was observed in all Deltapmt mutants at the third day after inoculation. By extending the growth period, ST production of DeltapmtA and DeltapmtB increased to the wild-type level 7 days after inoculation. On the other hand, ST was not detected from 7- or 14-day cultures in DeltapmtC. Expression levels of aflR gene, an essential regulator of the ST biosynthesis pathway, were also down-regulated in the Deltapmt strains. By introducing the aflR overexpression cassette, ST production in the DeltapmtA and DeltapmtB significantly increased to levels comparable to the wild type. However, the presence of the aflR overexpression cassette could not improve ST production in the DeltapmtC mutant. These data suggest that the PMT family is a new endogenous factor that is required for ST biosynthesis in A. nidulans. These findings provide better understanding of the regulatory mechanisms of AF/ST biosynthesis, which can ultimately contribute to our ability to control aflatoxin contamination. PMID- 29492590 TI - Multiple Vertebral Fractures Following Denosumab Discontinuation: Are We Exaggerating? PMID- 29492586 TI - From blood coagulation to innate and adaptive immunity: the role of platelets in the physiology and pathology of autoimmune disorders. AB - Thrombosis and cardiovascular complications are common manifestations of a variety of pathological conditions, including infections and chronic inflammatory diseases. Hence, there is great interest in determining the hitherto unforeseen immune role of the main blood coagulation executor-the platelet. Platelets store and release a plethora of immunoactive molecules, generate microparticles, and interact with cells classically belonging to the immune system. The observed effects of platelet involvement in immune processes, especially in autoimmune diseases, are conflicting-from inciting inflammation to mediating its resolution. An in-depth understanding of the role of platelets in inflammation and immunity could open new therapeutic pathways for patients with autoimmune disorders. This review aims to summarize the current knowledge on the role of platelets in the patomechanisms of autoimmune disorders and suggests directions for future research. PMID- 29492589 TI - [Foot and ankle tumours : Part II: Malignant bone tumours and soft tissue tumours of the foot with differential diagnostic hints]. AB - CLINICAL ISSUE: Both benign and malignant tumours are encountered in the foot and ankle. Due to their rarity, however, diagnosis is often uncertain. Usual criteria such as tumour size, invasiveness or pain fail to differentiate benign from malignant neoplasias. STANDARD RADIOLOGICAL METHODS: Plain radiography and-due to the complex foot anatomy-CT are important in the diagnostic evaluation of primary bone tumours. In the case of soft tissue tumours, ultrasonography is used to identify ganglion cysts. Tumour evaluation and staging are then performed using MRI. Nuclear imaging comes into play when multifocal, metastatic or systemic spread of the disease is suspected or if a biopsy procedure is planned. METHODICAL INNOVATIONS: For the role of dual-energy CT, please refer to part I. Whether dual-energy CT is suitable to assess bone marrow oedema patterns is still debated. SPECIAL FEATURES OF FOOT AND ANKLE TUMOURS: Primary bone tumours generally present in the ankle or the hindfoot. Malignant bone tumours, e. g. chondrosarcoma, are primarily found in the latter. On the other hand, soft tissue tumours generally present in the mid- and forefoot regions. ACHIEVEMENTS: While the radiologic diagnostic evaluation of pedal bone tumours is quite reliable, caution is urgently needed in the case of soft tissue tumours because there are many confusing differential diagnoses. PRACTICAL RECOMMENDATIONS: Proper X-ray examination of the foot (at least in two plains) or with special views according to bony pathology is needed. All soft tissue masses that are not cysts should be evaluated further. MRI remains the diagnostic modality of choice but never stands alone! Caution: Size and well-defined margins of pedal soft tissue tumours are not considered criteria regarding whether a tumour is malignant or not. PMID- 29492591 TI - Uric acid stones increase the risk of chronic kidney disease. AB - The aim of this study was to compare the clinical characteristics of uric acid stones and their potential risk for chronic kidney disease (CKD). A total of 401 patients (196 with uric acid stone and 205 without) were enrolled from our database of patients with urolithiasis. We analyzed the clinical demographic features, stone location, urine chemistries, and renal function. There was a significant difference (p < 0.001) between the two groups in terms of age, with the higher mean age in the uric acid group. Patients with uric acid stones had much lower pH of urine (p < 0.001) and higher serum uric acid level (p = 0.002). Notably, those with uric acid stones had worse eGFR than those with non-uric acid stones. Multivariate analysis confirmed that age over 60 years (ORs = 9.19; 95% CI 3.5-24.3), female sex (ORs = 4.01; 95% CI 1.8-9.0), hyperuricemia (ORs = 8.47; 95% CI 1.6-43.5), and uric acid stone (OR = 2.86; 95% CI 1.2-6.7) were the independent predictors of poor prognoses in CKD. Therefore, an association exists between uric acid stones and higher prevalence of CKD. Patients with uric acid stones may need close monitoring of renal function during follow-up. PMID- 29492592 TI - Cross-modality deep learning-based prediction of TAP binding and naturally processed peptide. AB - Epitopes presented on MHC class I molecules pass multiple processing stages before their presentation on MHC molecules, the main ones being proteasomal cleavage and TAP binding. Transporter associated with antigen processing (TAP) binding is a necessary stage for most, but not all, MHC-I-binding peptides. The molecular determinants of TAP-binding peptides can be experimentally estimated from binding experiments and from the properties of peptides inducing a CD8 T cell response. We here propose novel optimization formalisms to combine binding and activation experimental results to produce a classifier for TAP binding using dual-output kernel and deep learning approaches. The application of these algorithms to the human and murine TAP binding leads to predictors that are much more precise than current state of the art methods. Moreover, the computed score is highly correlated with the observed binding energy. The new predictors show that TAP binding may be much more selective than previously assumed in humans and mice and sensitive to the properties of most positions of the peptides. Beyond the improved precision for TAP binding, we propose that the same approach holds in most molecular binding problems, where functional and binding measures are simultaneously available, and can be used to significantly improve the precision of binding prediction algorithms in general and immune system molecules specifically. PMID- 29492593 TI - Novel biallelic ATM mutations coexist with a mosaic form of triple X syndrome in an 11-year-old girl at remission after T cell acute leukemia. AB - Ataxia-telangiectasia (AT) is a rare neurodegenerative disease characterized by an early onset ataxia, oculocutaneous telangiectasia, immunodeficiency, recurrent infections, radio-sensitivity, and a predisposition to malignancy. We present the case of a child with coexistent AT and trisomy X (47,XXX). We used fluorescent in situ hybridization (FISH) to confirm that this person had 47,XXX karyotype in blood cells, bone marrow, fibroblasts, and buccal smear. Standard cytogenetic studies (not banded) were conducted on blood cells. G-banding analysis was performed on bone marrow cells at the time of the leukemia diagnosis. Flow cytometric investigation of lymphocytes and Sanger sequencing of the ATM gene were used for diagnosis confirmation and description. We report the case of an 11 year-old girl at remission after having T cell acute leukemia for 7 years with progressive signs of ataxia-telangiectasia and with additional X chromosome since birth. At the age of 2 years and 7 months, she was diagnosed with pre-T acute leukemia. From the age of four, she had gait abnormalities. AT was established at the age of seven based on clinical signs and laboratory findings (increased alpha fetoprotein-AFP [227]) and confirmed by detecting compound heterozygous truncating mutations in the ATM gene (p.Y705X and p.L2312I). These genetic findings have not been previously reported in AT and our "double hit" case demonstrates the value of careful clinical evaluation of children with an established genetic diagnosis. Measurement of AFP levels should be considered in patients with neurologic abnormalities after leukemia treatment. PMID- 29492594 TI - A Crispy Diet: Grazers of Achromatium oxaliferum in Lake Stechlin Sediments. AB - Achromatium is the largest freshwater bacterium known to date and easily recognised by conspicuous calcite bodies filling the cell volume. Members of this genus are highly abundant in diverse aquatic sediments and may account for up to 90% of the bacterial biovolume in the oxic-anoxic interfaces. The high abundance implies that Achromatium is either rapidly growing or hardly prone to predation. As Achromatium is still uncultivated and does not appear to grow fast, one could assume that the cells might escape predation by their unusual shape and composition. However, we observed various members of the meiofauna grazing or parasitizing on Achromatium. By microphotography, we documented amoebae, ciliates, oligochetes and plathelminthes having Achromatium cells ingested. Some Achromatium cells harboured structures resembling sporangia of parasitic fungi (chytrids) that could be stained with the chitin-specific dye Calcofluor White. Many Achromatia carried prokaryotic epibionts in the slime layer surrounding the cells. Their regular distribution over the cell might indicate that they are commensalistic rather than harming their hosts. In conclusion, we report on various interactions of Achromatium with the sediment community and show that although Achromatium cells are a crispy diet, full of calcite bodies, predators do not spare them. PMID- 29492596 TI - [Cartilage, bones, chorda : Molecular pathology]. PMID- 29492595 TI - Links Between Heathland Fungal Biomass Mineralization, Melanization, and Hydrophobicity. AB - Comprehending the decomposition process is crucial for our understanding of the mechanisms of carbon (C) sequestration in soils. The decomposition of plant biomass has been extensively studied. It revealed that extrinsic biomass properties that restrict its access to decomposers influence decomposition more than intrinsic ones that are only related to its chemical structure. Fungal biomass has been much less investigated, even though it contributes to a large extent to soil organic matter, and is characterized by specific biochemical properties. In this study, we investigated the extent to which decomposition of heathland fungal biomass was affected by its hydrophobicity (extrinsic property) and melanin content (intrinsic property). We hypothesized that, as for plant biomass, hydrophobicity would have a greater impact on decomposition than melanin content. Mineralization was determined as the mineralization of soil organic carbon (SOC) into CO2 by headspace GC/MS after inoculation by a heathland soil microbial community. Results show that decomposition was not affected by hydrophobicity, but was negatively correlated with melanin content. We argue that it may indicate that either melanin content is both an intrinsic and extrinsic property, or that some soil decomposers evolved the ability to use surfactants to access to hydrophobic biomass. In the latter case, biomass hydrophobicity should not be considered as a crucial extrinsic factor. We also explored the ecology of decomposition, melanin content, and hydrophobicity, among heathland soil fungal guilds. Ascomycete black yeasts had the highest melanin content, and hyaline Basidiomycete yeasts the lowest. Hydrophobicity was an all-or-nothing trait, with most isolates being hydrophobic. PMID- 29492597 TI - Preoperative Watchful-Waiting Time and Surgical Outcome of Patients with Non small Cell Lung Cancer Found by Chest Low-Dose CT Screening. AB - BACKGROUNDS: Chest low-dose CT screening (LDCTS) has been finding unprecedented numbers of peripheral non-small cell lung cancers (NSCLC) at an early stage and increased the number of patients with surgical indication. It is important to explore the influence of preoperative watchful-waiting time (WWT) on surgical outcomes. Objective is to clarify relationship between WWT and surgical outcomes of LDCTS-finding NSCLC from the view point of treatment delay. METHODS: Total 283 cases of NSCLC, found by LDCTS and consecutively resected, were surveyed for preoperative WWT and surgical outcomes. Validity of the present guideline for management of pulmonary nodules detected by LDCTS was verified whether WWT before surgery was suitable for eradication of NSCLC. RESULTS: The median value of WWT was 4.0 months in total, and the distribution of WWT exhibited long-tail-type pattern. That was 5.0 months in the group of pure ground-glass nodule (pGGN), 4.0 months in the group of part-solid nodule (PSN), and 1.7 months in the group of solid nodule (SON). During long-term postoperative observation time (median 79 months), 10-year progression-free survival rates were 100% in pGGN, 96% in PSN, and 72% in SON (P < .0001). They decreased significantly depending on enlargement of size: 91% or higher in size of 2 cm or smaller, and 71% or lower in size of larger than 2 cm (P < .0001). CONCLUSIONS: Limited to LDCTS-finding nodules, surgical outcome will depend mainly on some malignant potential of NSCLC per se, rather than on duration of WWT or treatment delay. PMID- 29492598 TI - Are growth patterns on MRI in small (< 4 cm) solid renal masses useful for predicting benign histology? AB - PURPOSE: To evaluate previously described growth patterns in < 4 cm solid renal masses. MATERIALS AND METHODS: With IRB approval, 63 renal cell carcinomas (RCC; clear cell n = 22, papillary n = 28, chromophobe n = 13) and 36 benign masses [minimal-fat (mf) angiomyolipoma (AML) n = 13, oncocytoma n = 23) from a single institution were independently evaluated by two blinded radiologists (R1/R2) using T2-weighted MRI for (1) the angular interface sign (AIS), (2) bubble-over sign (BOS), (3) percentage (%) exophytic growth and (4) long-to-short axis ratio. Comparisons were performed using ANOVA, chi-square and multi-variate regression. RESULTS: AIS was present in 11.1% (7/63) -9.5% (6/63) R1/R2 RCC compared to 13.9% (5/36) -19.4% (7/36) R1/R2 benign masses (p = 0.68 and 0.16). BOS was present in 11.1% (7/63) -3.2% (2/63) R1/R2 RCC compared to 16.7% (6/36) -8.3% (3/36) R1/R2 benign masses (p = 0.432 and 0.261). Agreement was moderate (K = 0.50 and 0.55). mf-AML [66 +/- 32% (range 0-100%)] and oncocytoma [53 +/- 26% (0-90%)] had larger % exophytic growth compared to RCC [32 +/- 23% (0-80%)] (p < 0.001). No RCC had 90-100% exophytic growth, present in 38.5% (5/13) mf-AMLs and 17.4% (4/23) oncocytomas. The long-to-short axis did not differ between groups (p = 0.053). CONCLUSIONS: Benign masses show greater % exophytic growth whereas other growth patterns are not useful. Future studies evaluating % exophytic growth using multi variate MR analysis in renal masses are required. KEY POINTS: * Greater exophytic growth is associated with benignity among solid renal masses. * Only minimal fat AMLs and oncocytomas had 90-100% exophytic growth. * The angular interface sign was not useful to differentiate benign masses from RCC. * The bubble-over sign was not useful to differentiate benign masses from RCC. * Subjective analysis of growth patterns had fair-to-moderate agreement. PMID- 29492601 TI - "Inverted Figure 3" sign of periampullary carcinoma. PMID- 29492600 TI - Lymphoma-like monoclonal B cell lymphocytosis in a patient population: biology, natural evolution, and differences from CLL-like clones. AB - High-count monoclonal B cell lymphocytosis (MBL) with a chronic lymphocytic leukemia (CLL) phenotype is a well-known entity, featuring 1-4% annual risk of progression towards CLL requiring treatment. Lymphoma-like MBL (L-MBL), on the other hand, remains poorly defined and data regarding outcome are lacking. We retrospectively evaluated 33 L-MBL cases within our hospital population and compared them to 95 subjects with CLL-like MBL (C-MBL). Diagnoses of L-MBL were based on asymptomatic B cell clones with Matutes score < 3, B cells < 5.0 * 103/MUl, and negative computerized tomography scans. We found that median B cell counts were considerably lower compared to C-MBL (0.6 vs 2.3 * 103/MUl) and remained stable over time. Based on immunophenotyping and immunogenetic profiling, most L-MBL clones did not correspond to known lymphoma entities. A strikingly high occurrence of paraproteinemia (48%), hypogammaglobulinemia (45%), and biclonality (21%) was seen; these incidences being significantly higher than in C-MBL (17, 21, and 5%, respectively). Unrelated monoclonal gammopathy of undetermined significance was a frequent feature, as the light chain type of 5/12 paraproteins detected was different from the clonal surface immunoglobulin. After 46-month median follow-up, 2/24 patients (8%) had progressed towards indolent lymphoma requiring no treatment. In contrast, 41% of C-MBL cases evolved to CLL and 17% required treatment. We conclude that clinical L-MBL is characterized by pronounced immune dysregulation and very slow or absent progression, clearly separating it from its CLL-like counterpart. PMID- 29492599 TI - European Society of Urogenital Radiology (ESUR) Guidelines: MR Imaging of Leiomyomas. AB - OBJECTIVE: The aim of the Female Pelvic Imaging Working Group of the European Society of Urogenital Radiology (ESUR) was to develop imaging guidelines for MR work-up in patients with known or suspected uterine leiomyomas. METHODS: Guidelines for imaging uterine leiomyomas were defined based on a survey distributed to all members of the working group, an expert consensus meeting at European Congress of Radiology (ECR) 2017 and a critical review of the literature. RESULTS: The 25 returned questionnaires as well as the expert consensus meeting have shown reasonable homogeneity of practice among institutions. Expert consensus and literature review lead to an optimized MRI protocol to image uterine leiomyomas. Recommendations include indications for imaging, patient preparation, MR protocols and reporting criteria. The incremental value of functional imaging (DWI, DCE) is highlighted and the role of MR angiography discussed. CONCLUSIONS: MRI offers an outstanding and reproducible map of the size, site and distribution of leiomyomas. A standardised imaging protocol and method of reporting ensures that the salient features are recognised. These imaging guidelines are based on the current practice among expert radiologists in the field of female pelvic imaging and also incorporate essentials of the current published MR literature of uterine leiomyomas. KEY POINTS: * MRI allows comprehensive mapping of size and distribution of leiomyomas. * Basic MRI comprise T2W and T1W sequences centered to the uterus. * Standardized reporting ensures pivotal information on leiomyomas, the uterus and differential diagnosis. * MRI aids in differentiation of leiomyomas from other benign and malignant entities, including leiomyosarcoma. PMID- 29492602 TI - Computed tomography findings after radiofrequency ablation in locally advanced pancreatic cancer. AB - PURPOSE: The purpose of the study was to provide a systematic evaluation of the computed tomography(CT) findings after radiofrequency ablation (RFA) in locally advanced pancreatic cancer(LAPC). METHODS: Eighteen patients with intra-operative RFA-treated LAPC were included in a prospective case series. All CT-scans performed prior to RFA and 1 week and 3 months of post-RFA, according to standard regimen, were assessed by two radiologists in consensus, using standardized radiological scoring lists. RESULTS: 51 CT-scans were assessed. One week after RFA, the ablation zone was visible in all patients as a (partially) sharply defined (83%), heterogeneous area (94%). At 3 months of follow-up, the ablation zone was completely invaded by tumor in 67% of patients and still present, but decreased in 33%. In two patients (11%), local thrombosis and/or occlusion of the superior mesenteric vein occurred. The occlusions persisted without clinical consequences and the thrombosis disappeared. A peripancreatic fluid collection was visible 1 week after RFA in 3 patients, wherein the ablation zone extended ventrally outside of the pancreas. CONCLUSIONS: Directly after RFA for LAPC, a well-defined ablation zone is visible on CT-imaging. This ablation zone is usually replaced by tumor ingrowth after 3 months. Moreover, the ablation zone regularly included vascular structures, with rare asymptomatic venous occlusion or thrombosis and without adverse effects on arteries. PMID- 29492603 TI - Combined transarterial chemoembolization of the right inferior phrenic artery and radiofrequency ablation for small hepatocellular carcinoma near the diaphragm: its efficacy and safety. AB - PURPOSE: The purpose of the study is to report the efficacy and safety of combined transarterial chemoembolization (TACE) of the right inferior phrenic artery (IPA) and radiofrequency ablation (RFA) for small hepatocellular carcinoma (HCC) near the diaphragm supplied by the right IPA. METHODS: From July 2009 through April 2015, 11 patients with small (<= 3 cm) HCC near the diaphragm, which was infeasible for ultrasound-guided RFA and supplied by the right IPA, received TACE of the right IPA and subsequent RFA in one session. The safety and therapeutic efficacy, including technique effectiveness and local tumor progression (LTP), were evaluated. RESULTS: Technique effectiveness was achieved in all the 11 patients (100%). During average follow-up period of 39.2 months (range 13-89 months), LTP occurred in none of the 11 patients. There were twelve minor complications in eight patients, including right shoulder pain (n = 4), right pleural effusion (n = 2), diaphragmatic thickening (n = 2), transient lung change (n = 2), subsegmental intrahepatic bile duct stricture (n = 1), and subsegmental hepatic infarction (n = 1). No major complications were encountered CONCLUSION: Combined TACE of the right IPA and RFA can be a safe and effective treatment for small HCC near the diaphragm that is supplied by the right IPA. PMID- 29492604 TI - Computed tomography findings of small bowel gastrointestinal stromal tumors with different histologic risks of progression. AB - PURPOSE: The purpose of the study was to assess the dynamic contrast-enhanced computed tomography features of small bowel gastrointestinal stromal tumors with different risks of progression. METHODS: Forty-two patients with SB GISTs underwent dynamic contrast-enhanced CT scan. All CT features of tumors with different risks were analyzed. The correlation of CT attenuation value in different enhancement phases with different risks was analyzed. RESULTS: In 22 patients, the tumor was in the jejunum, 14 in the ileum, and six in the duodenum. The maximum diameter of the tumors ranged from 1.4 to 21.0 cm (median 8.2 cm). Histologic risk degree was defined according to pathologic findings (three cases were very low risk, 13 cases were low risk, two cases were intermediate risk, and 24 cases were high risk). For all the risk degrees, there were statistical differences in tumor size, heterogeneity, and presence of necrosis (p < 0.05). However, there were no statistical differences in tumor location, presence of calcification, or cystic degeneration (p > 0.05). The CT attenuation value of every risk degree was statistically different in venous phase and delayed phase (p < 0.05). CONCLUSION: Features on dynamic contrast-enhanced CT can correlate with SB GISTs of different risk categories which may be helpful for preoperative diagnosis and prognosis evaluation. PMID- 29492606 TI - Ex vivo MR imaging of colorectal carcinoma before and after formalin fixation: correlation with histopathologic findings. AB - PURPOSE: We aimed to assess and compare ex vivo MRI of resected colorectal carcinoma before and after formalin fixation. METHODS: We enrolled 45 consecutive patients (47 carcinomas) who underwent colorectal carcinoma surgery. Specimens underwent two MR scans at 1.5 T (after resection and 24 h after formalin fixation). Two radiologists evaluated all MR images independently regarding T staging and the subserosal linear architecture. T-stage accuracy and frequency of linear architecture were calculated. A third radiologist measured vertical tumor distance and contrast-to-noise ratio (CNR) of the mucosa, submucosa, muscularis propria, subserosa, and tumor. RESULTS: T-stage accuracy compared to histopathology by the two readers was 91.5% and 87.2% before fixation and 91.5% and 85.1% after fixation, respectively. Linear architecture was observed in 11.1% of T2 tumors and 100% of T3 tumors by both readers. The vertical tumor distance between histopathological and MRI findings was well correlated before and after fixation. The measurement error of the vertical tumor distance between before and after fixation was within 3 mm. CNR of the tumor was significantly lower than those of the submucosa and subserosa before and after fixation (p < 0.05). CNRs of the tumor and muscularis propria were decreased after formalin fixation (p < 0.05). CONCLUSIONS: Subserosal linear architecture represented fibrosis with tumoral invasion, suggesting a T3-4 tumor. The submucosa and subserosa showed high intensity and the mucosa and muscularis propria showed low intensity compared with tumor. CNRs of the tumor and muscularis propria were decreased by formalin fixation. PMID- 29492605 TI - Machine learning for medical ultrasound: status, methods, and future opportunities. AB - Ultrasound (US) imaging is the most commonly performed cross-sectional diagnostic imaging modality in the practice of medicine. It is low-cost, non-ionizing, portable, and capable of real-time image acquisition and display. US is a rapidly evolving technology with significant challenges and opportunities. Challenges include high inter- and intra-operator variability and limited image quality control. Tremendous opportunities have arisen in the last decade as a result of exponential growth in available computational power coupled with progressive miniaturization of US devices. As US devices become smaller, enhanced computational capability can contribute significantly to decreasing variability through advanced image processing. In this paper, we review leading machine learning (ML) approaches and research directions in US, with an emphasis on recent ML advances. We also present our outlook on future opportunities for ML techniques to further improve clinical workflow and US-based disease diagnosis and characterization. PMID- 29492608 TI - Traumatic abdominal aortic injury: clinical considerations for the diagnostic radiologist. AB - Traumatic abdominal aortic injury (TAAI) is a severe complication of penetrating and blunt trauma with significant morbidity and mortality, particularly if diagnosis is delayed. In patients with life-threatening injuries, accurate and prompt diagnosis of TAAI can be made with computed tomography (CT). Once the diagnosis of TAAI is made, the radiologist should provide an accurate description of the aortic lesion and the extent of injury in order to guide management whether it be non-operative, open aortic repair, or endoluminal stent repair. The purpose of this article is to review the key imaging aspects of TAAI and to discuss how the key CT imaging findings affect clinical management. PMID- 29492607 TI - Intrahepatic cholangiocarcinoma: can imaging phenotypes predict survival and tumor genetics? AB - PURPOSE: On computed tomography (CT), intrahepatic cholangiocarcinomas (ICC) are a visibly heterogeneous group of tumors. The purpose of this study was to investigate the associations between CT imaging phenotypes, patient survival, and known genetic markers. METHODS: A retrospective study was performed with 66 patients with surgically resected ICC. Pre-surgical CT images of ICC were assessed by radiologists blinded to tumor genetics and patient clinical data. Associations between qualitative imaging features and overall survival (OS) and disease-free survival (DFS) were performed with Cox proportional hazards regression and visualized with Kaplan-Meier plots. Associations between radiographic features and genetic pathways (IDH1, Chromatin and RAS-MAPK) were assessed with Fisher's Exact test and the Wilcoxon Rank sum test where appropriate and corrected for multiple comparisons within each pathway using the False Discovery Rate correction. RESULTS: Three imaging features were significantly associated with a higher risk of death: necrosis (hazard ratio (HR) 2.95 95% CI 1.44-6.04, p = 0.029), satellite nodules (HR 3.29, 95% CI:1.35-8.02, p = 0.029), and vascular encasement (HR 2.63, 95% CI 1.28-5.41, p = 0.029). Additionally, with each increase in axial size, the risk of death increased (HR 1.14, 95% CI 1.03-1.26, p = 0.029). Similar to findings for OS, satellite nodules (HR 3.81, 95% CI 1.88-7.71, p = 0.002) and vascular encasement (HR 2.25, 95% CI 1.24-4.06, p = 0.019) were associated with increased risk of recurrence/death. No significant associations were found between radiographic features and genes in the IDH1, Chromatin or RAS-MAPK pathways (p = 0.63-84). CONCLUSION: This preliminary analysis of resected ICC suggests associations between CT imaging features and OS and DFS. No association was identified between imaging features and currently known genetic pathways. PMID- 29492609 TI - Acute non-traumatic disease of the abdominal aorta. AB - Acute pathology in the abdominal aorta is associated with significant morbidity and mortality. The most feared complication of abdominal aortic disease is acute rupture in the setting of atherosclerotic abdominal aortic aneurysm. Although frank rupture often is easily diagnosed on CT, other findings such as a hyperattenuating crescent, discontinuous intimal calcium, and draping of the aorta are subtle signs of aneurysm instability. A true aneurysm should be distinguished from a rapidly growing, saccular pseudoaneurysm in the setting of infectious aortitis, as treatment strategy differs. Acute aortic syndrome involving the abdominal aorta, such as dissection and intramural hematoma, often is an extension of thoracic aortic disease, whereas penetrating atherosclerotic ulcers occasionally involve only the abdominal aorta. The goal of treating acute aortic pathology is to repair and prevent rupture, as well as restore and maintain perfusion of the lower extremities, kidneys, and mesentery. However, both open and endovascular repair of the abdominal aorta may become acutely complicated, resulting in compromise of these goals. Examples include aortoenteric fistula, endoleak, anastomotic pseudoaneurysm, graft infection, and thrombosis or kinking of a stent graft resulting in ischemia of the limbs and mesentery. PMID- 29492610 TI - Treatment of the aneurysmal bone cyst by percutaneous intracystic sclerotherapy using ethanol ninety five percent in children. AB - INTRODUCTION: Aneurysmal bone cyst (ABC) is a benign intraosseous lesion filled with blood that can determine a blowout distension of the bone. The purpose of this study is to evaluate the efficacy of sclerotherapy by percutaneous intralesional administration of ethanol 96% for the treatment of this pathology in paediatric patients. METHOD: The retrospective study includes 17 paediatric patients with ABC who were treated by repeated intracystic injection with ethanol 96%, 1 ml/kg, in our clinic between December 2015 and July 2017. Fluoroscopic guidance was used to inject the cyst with contrast agent. The mean follow-up period was 11 months. RESULTS AND DISCUSSION: All cysts are healed or are in the healing process. The mean age was 11 years old. Seven patients needed three repeated injections and ten patients needed two injections until healing. We observed a mean reduction in the size of the lesions, measured on plain X-rays, of 68%. The complications that were observed included the following: dizziness after injection, skin pigmentation at the injection site, local inflammatory reaction, and pain after injection. The current study approves the importance of this minimally invasive treatment with no recurrence after a follow-up of 19 months. The healing rate was 100%. A limitation of this study consists in the small number of patients. CONCLUSION: Sclerotherapy with ethanol 96% is a useful method for the treatment of ABC. It is a minimally invasive method, with no major complications, which lowers the risks of open surgical intervention and has a good rate of success. PMID- 29492611 TI - What is the best glenoid configuration in onlay reverse shoulder arthroplasty? AB - PURPOSE: The purpose of this study was to analyze the effect of different glenoid configurations on arm position and range of motion (ROM) following reverse shoulder arthroplasty (RSA). The hypothesis was that different glenoid configurations would lead to changes in humeral offset, acromio-humeral distance (AHD), ROM, and rotator cuff muscle length. METHODS: Using a three-dimensional (3D) computer model, implantation of an RSA was simulated with a 145 degrees onlay humeral stem combined with five different glenoid configurations which varied in diameter and centre of rotation. Glenoid offset, the AHD, ROM, and muscle length were evaluated for each configuration. RESULTS: Changing glenoid design led to up to a 10 mm change in offset and a 3 mm change in the AHD. There was 7 degrees of improvement in abduction and flexion between the different glenoid designs. Two of the configurations, the 36 mm centered and the BIO-RSA, had an adduction deficit. In extension and external rotation arm with the arm at side, the eccentric 36 mm glenosphere was the best configuration while the centered 36 mm glenosphere was the worst configuration. The 42 mm glenosphere limited external rotation at 90 degrees of abduction. CONCLUSIONS: Varying the glenosphere configurations leads to ROM and muscle length changes following RSA. With a 145 degrees onlay humeral stem, a 36 eccentric glenosphere theoretically optimizes ROM while limiting scapular notching. PMID- 29492612 TI - Efficacy of oral tranexamic acid on blood loss in primary total hip arthroplasty using a direct anterior approach: a prospective randomized controlled trial. AB - BACKGROUND: Tranexamic acid (TXA), delivered intravenously or topically, has been shown to reduce blood loss, the need for transfusion, and relevant healthcare costs when administered in primary standard total hip arthroplasty (THA). Whether the same is true of oral TXA is unclear, the purpose of this study was to determine if oral tranexamic acid is equivalent to intravenous TXA in the case of patients undergoing THA via the direct anterior approach. METHODS: In this prospective randomized controlled trial, 120 patients undergoing primary THA by the direct anterior approach were randomized to receive oral TXA (two doses of 20 mg/kg), intravenous TXA (two doses of 15 mg/kg), or no TXA. Primary outcomes were haemoglobin drop, haematocrit levels, total blood loss, intra-operative blood loss, need for transfusion, and volume transfused. Secondary outcomes included thromboembolic events, wound complications, the length of post-operative hospital stay, and 30-day readmission. RESULTS: Demographic characteristics were similar among the three patient groups (p > 0.05, n = 40 per group). Haemoglobin drop, haematocrit levels, total blood loss, and intra-operative blood loss were similar in the oral and intravenous groups (p > 0.05), and significantly smaller than in the control group (p < 0.05). Transfusions were given to significantly fewer patients in the oral group (3%) and intravenous group (6%) than in the control group (27%, p = 0.01). Costs of TXA and transfusions were significantly lower in the oral group than the intravenous group (p < 0.05). The three groups were similar in thromboembolic events, wound complications, the length of post operative hospital stay, and 30-day readmission (p > 0.05). CONCLUSION: Oral TXA shows similar efficacy and safety as intravenous TXA for reducing haemoglobin drop, haematocrit levels, total blood loss, and transfusion rate following THA by the direct anterior approach. Therefore, the much less-expensive oral formulation may be superior to the intravenous form. PMID- 29492613 TI - A moderate dose of alcohol selectively reduces empathic accuracy. AB - RATIONALE: Drinking alcohol is associated with various interpersonal effects, including effects on cognitive empathy. Empathic accuracy (EA) is a form of cognitive empathy concerned with perceivers' accuracy in inferring a target's thoughts and feelings. The effects of alcohol on EA have not previously been studied. OBJECTIVES: We examined the effect of a moderate alcohol dose on EA in social drinkers. METHODS: Fifty-four men with varying levels of hazardous drinking according to the Alcohol Use Disorders Identification Test (AUDIT) participated in a randomized, double-blind, between-group study. The alcohol group received 0.56 g/kg alcohol in a vodka and tonic-mixed drink. The placebo group received tonic, with 4 ml of vodka sprayed on top. All participants performed an EA task that involved watching 16 videos of people narrating positive and negative emotional autobiographical events and continuously rating how targets felt while narrating. RESULTS: There were no significant main effects of beverage condition on the EA task. There was an effect of the condition by AUDIT interaction for EA on the positive videos. Post-hoc simple contrasts revealed that in participants with lower AUDIT scores, the alcohol condition had lower EA for positive videos than the placebo condition. No significant main effect for condition occurred in the participants with higher AUDIT scores. CONCLUSIONS: The effect of condition in participants with lower AUDIT scores indicates alcohol selectively reduced EA in individuals low on hazardous drinking. This suggests either alcohol-induced impairments of EA for positive events or a positivity bias in men at low risk for alcohol dependency. PMID- 29492614 TI - The kappa-opioid receptor antagonist JDTic decreases ethanol intake in alcohol preferring AA rats. AB - RATIONALE: Studies suggest that the kappa-opioidergic system becomes overactivated as ethanol use disorders develop. Nalmefene, a currently approved treatment for ethanol use disorders, may also elicit some of its main effects via the kappa-opioidergic system. However, the exact role of kappa-opioid receptors on regulating ethanol intake and contribution to the development of ethanol addiction remains to be elucidated. OBJECTIVES: The aim of the present study was to clarify the role of accumbal kappa-opioid receptors in controlling ethanol intake in alcohol-preferring Alko Alcohol (AA) rats. METHODS: Microinfusions of the long-acting and selective kappa-opioid receptor antagonist JDTic (1-15 MUg/site) were administered bilaterally into the nucleus accumbens shell of AA rats voluntarily consuming 10% ethanol solution in the intermittent, time restricted two-bottle choice access paradigm. JDTic (10 mg/kg) was also administered subcutaneously. Both the acute and long-term effects of the treatment on ethanol intake were examined. As a reference, nor-BNI (3 MUg/site) was administered intra-accumbally. RESULTS: Systemically administered JDTic decreased ethanol intake significantly 2 days and showed a similar trend 4 days after administration. Furthermore, intra-accumbally administered JDTic showed a weak decreasing effect on ethanol intake long-term but had no acute effects. Intra-accumbal administration of nor-BNI tended to decrease ethanol intake. CONCLUSIONS: The results provide further evidence that kappa-opioid receptors play a role in controlling ethanol intake and that accumbal kappa-opioid receptors participate in the modulation of the reinforcing effects of ethanol. Furthermore, the results suggest that kappa-opioid receptor antagonists may be a valuable adjunct in the pharmacotherapy of ethanol use disorders. PMID- 29492615 TI - GR3027 reversal of neurosteroid-induced, GABA-A receptor-mediated inhibition of human brain function: an allopregnanolone challenge study. AB - RATIONALE: GR3027 is a novel small molecule GABA-A receptor-modulating steroid antagonist, which in non-clinical studies has shown promise for treatment of human disorders due to allosteric over-activation of GABA-A receptors by neurosteroids, such as allopregnanolone. We here studied its safety, pharmacokinetics, and ability to inhibit allopregnanolone effects in humans. METHODS: Safety and pharmacokinetics were studied in healthy adult males receiving ascending single or multiple oral GR3027 vs. placebo. GR3027-mediated reversal of allopregnanolone effect on maximal saccadic eye velocity (SEV), and self-rated somnolence was studied in a double-blind, placebo-controlled, three part cross-over study in which 3 or 30 mg oral GR3027 preceded 0.05 mg/kg of i.v. allopregnanolone. RESULTS: GR3027 was well tolerated, adverse events were generally mild and transient, and no dose-limiting toxicity or grade 3 adverse events were observed up to the highest single (200 mg) or multiple (100 mg every 12 h for 5 days) doses. The maximum concentration (Cmax) and systemic exposure (area under the plasma concentration-time curve from dose extrapolated to infinity [AUC0-infinity] and/or AUC during the dosing interval [AUCtau]) varied linearly with dose; with dose-dependent accumulation ratios of 1.3-1.6. Allopregnanolone decreased SEV and induced somnolence in most, but not all subjects. By predefined analyses, 30 mg GR3027 significantly inhibited allopregnanolone-induced decrease in SEV (p = 0.03); 3 and 30 mg GR3027 non significantly inhibited allopregnanolone-induced sedation. By post hoc analyses restricted to subjects with allopregnanolone-induced changes and the time period over which they occurred, GR3027 dose dependently inhibited allopregnanolone induced decrease in SEV (p = 0.04 at 30 mg, non-significant at 3 mg) and allopregnanolone-induced sedation (p = 0.01/0.05 at 3/30 mg doses). CONCLUSION: Oral GR3027 mitigates inhibition of brain function induced by allopregnanolone at doses which are clinically well tolerated and associated with linear pharmacokinetics. PMID- 29492616 TI - Intra-hippocampal D-cycloserine rescues decreased social memory, spatial learning reversal, and synaptophysin levels in aged rats. AB - RATIONALE: Aging is characterized by a decrease in N-methyl-D-aspartate receptors (NMDARs) in the hippocampus, which might be one of the factors involved in the age-dependent cognitive decline. D-Cycloserine (DCS), a partial agonist of the NMDAR glycine recognition site, could improve memory deficits associated to neurodegenerative disorders and cognitive deficits observed in normal aging. OBJECTIVES AND METHODS: The aim of the present study was to explore whether DCS would reverse age-dependent memory deficits and decreases in NMDA receptor subunits (GluN1, GluN2A, and GluN2B) and the presynaptic protein synaptophysin in Wistar rats. We investigated the effects of pre-training infusions of DCS (10 MUg/hemisphere) in the ventral hippocampus on two hippocampal-dependent learning tasks, the social transmission of food preference (STFP), and the Morris water maze (MWM). RESULTS: The results revealed that infusions of DCS administered before the acquisition sessions rescued deficits in the STFP retention and MWM reversal learning in old rats. DCS also significantly increased the hippocampal levels of synaptophysin in old rats, which correlated with STFP and MWM performance in all tests. Moreover, although the levels of the GluN1 subunit correlated with the MWM acquisition and reversal, DCS did not enhance the expression of such synaptic protein. CONCLUSIONS: The present behavioral results support the role of DCS as a cognitive enhancer and suggest that enhancing the function of NMDARs and synaptic plasticity in the hippocampus may be related to improvement in social memory and spatial learning reversal in aged animals. PMID- 29492618 TI - Patterns of genomic variation in Chinese maize inbred lines and implications for genetic improvement. AB - KEY MESSAGE: Genetic relationships among Chinese maize germplasms reveal historical trends in heterotic patterns from Chinese breeding programs and identify line Dan340 as a potential genome donor for elite inbred line Zheng58. The characterization of the genetic relationships, heterotic patterns and breeding history of lines in maize breeding programs allows breeders to efficiently use maize germplasm for line improvement over time. In this study, 269 temperate inbred lines, most of which have been widely used in Chinese maize breeding programs since the 1970s, were genotyped using the Illumina MaizeSNP50 BeadChip, which contains 56,110 single-nucleotide polymorphisms. The STRUCTURE analysis, cluster analysis and principal coordinate analysis results consistently revealed seven groups, of which five were consistent with known heterotic groups within the Chinese maize germplasm-Domestic Reid, Lancaster, Zi330, Tang SPT and Tem-tropic I (also known as "P"). These genetic relationships also allowed us to determine the historical trends in heterotic patterns during the three decades from 1970 to 2000, represented by Mo17 from Lancaster, HuangZaoSi (HZS) from Tang SPT, Ye478 from Domestic Reid and P178 from Tem-tropic I heterotic groups. Mo17 related commercial hybrids were widely used in the 1970s and 1980s, followed by the release of HZS- and Ye478-related commercial hybrids in the 1980s and 1990s, and the introduction of Tem-tropic I group in the 1990s and 2000s. Additionally, we identified inbred line Dan340 as a potential genome donor for Zheng58, which is the female parent of the most widely grown commercial hybrid ZhengDan958 in China. We also reconstructed the recombination events of elite line HZS and its 14 derived lines. These findings provide useful information to direct future maize breeding efforts. PMID- 29492617 TI - Combined fine mapping, genetic diversity, and transcriptome profiling reveals that the auxin transporter gene ns plays an important role in cucumber fruit spine development. AB - KEY MESSAGE: Map-based cloning was used to identify the ns gene, which was involved in the formation of cucumber numerous fruit spines together with other genes under regulation by plant hormone signal transduction. The cucumber (Cucumis sativus) fruit spine density has an important impact on the commercial value. However, little is known about the regulatory mechanism for the fruit spine formation. Here, we identified NUMEROUS SPINES (NS), which regulate fruit spine development by modulating the Auxin signaling pathway. We fine-mapped the ns using a 2513 F2 population derived from NCG122 (numerous fruit spines line) and NCG121 (few fruit spines line), and showed that NS encoded auxin transporter like protein 3. Genetic diversity analysis of the NS gene in natural populations revealed that one SNP and one InDel in the coding region of ns are co-segregated with the fruit spine density. The NS protein sequence was highly conserved among plants, but its regulation of fruit spine development in cucumber seems to be a novel function. Transcriptome profiling indicated that the plant hormone signal transduction-related genes were highly enriched in the up-regulated genes in NCG122 versus NCG121. Moreover, expression pattern analysis of the auxin signal pathway-related genes in NCG122 versus NCG121 showed that upstream genes of the pathway (like ns candidate gene Csa2M264590) are down-regulated, while the downstream genes are up-regulated. Quantitative reverse transcription PCR confirmed the differential expression during the fruit spine development. Therefore, reduced expression of ns may promote the fruit spine formation. Our findings provide a valuable framework for dissecting the regulatory mechanism for the fruit spine development. PMID- 29492619 TI - Single-molecule force spectroscopy study of interactions between angiotensin II type 1 receptor and different biased ligands in living cells. AB - Angiotensin II type 1 receptor (AT1R), a typical G protein-coupled receptor, plays a key role in regulating many cardiovascular functions. Different ligands can bind with AT1R to selectively activate either G protein (Gq) or beta-arrestin (beta-arr) pathway, or both pathways, but the molecular mechanism is not clear yet. In this work, we used, for the first time, atomic force microscopy-based single molecule force spectroscopy (SMFS) to study the interactions of AT1R with three types of ligands, balanced ligand, Gq-biased ligand, and beta-arr-biased ligand, in living cells. The results revealed their difference in binding force and binding stability. The complex of the Gq-biased ligand-AT1R overcame two energy barriers with an intermediate state during dissociation, whereas that of beta-arr-biased ligand-AT1R complex overcame one energy barrier. This indicated that AT1R had different ligand-binding conformational substates and underwent different structural changes to activate downstream signaling pathways with variable agonist efficacies. Quantitative analysis of AT1R-ligand binding in living cells at the single-molecule level offers a new tool to study the molecular mechanism of AT1R biased activation. Graphical Abstract Single-molecule force measurement on the living cell expressing AT1R-eGFP with a ligand modified AFM tip (left), the dynamic force spectra of beta-arrestin biased ligands-AT1R (middle), and Gq-biased ligands-AT1R (right). The complexes of beta-arr-biased ligand-AT1R overcame one energy barrier, with one linear region in the spectra, whereas the Gq-biased ligand-AT1R complexes overcame two energy barriers with two linear regions. PMID- 29492620 TI - Phase identification of individual crystalline particles by combining EDX and EBSD: application to workplace aerosols. AB - This paper discusses the combined use of electron backscatter diffraction (EBSD) and energy dispersive X-ray microanalysis (EDX) to identify unknown phases in particulate matter from different workplace aerosols. Particles of alpha-silicon carbide (alpha-SiC), manganese oxide (MnO) and alpha-quartz (alpha-SiO2) were used to test the method. Phase identification of spherical manganese oxide particles from ferromanganese production, with diameter less than 200 nm, was unambiguous, and phases of both MnO and Mn3O4 were identified in the same agglomerate. The same phases were identified by selected area electron diffraction (SAED) in transmission electron microscopy (TEM). The method was also used to identify the phases of different SiC fibres, and both beta-SiC and alpha SiC fibres were found. Our results clearly demonstrate that EBSD combined with EDX can be successfully applied to the characterisation of workplace aerosols. Graphical abstract Secondary electron image of an agglomerate of manganese oxide particles collected at a ferromanganese smelter (a). EDX spectrum of the particle highlighted by an arrow (b). Indexed patterns after dynamic background subtraction from three particles shown with numbers in a PMID- 29492621 TI - Quantification of cardiac troponin I in human plasma by immunoaffinity enrichment and targeted mass spectrometry. AB - Quantification of cardiac troponin I (cTnI), a protein biomarker used for diagnosing myocardial infarction, has been achieved in native patient plasma based on an immunoaffinity enrichment strategy and isotope dilution (ID) liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The key steps in the workflow involved isolating cTnI from plasma using anti-cTnI antibody coupled to magnetic nanoparticles, followed by an enzymatic digestion with trypsin. Three tryptic peptides from cTnI were monitored and used for quantification by ID-LC MS/MS via multiple reaction monitoring (MRM). Measurements were performed using a matrix-matched calibration system. NIST SRM 2921 Human Cardiac Troponin Complex acted as the calibrant and a full-length isotopically labeled protein analog of cTnI was used as an internal standard. The method was successfully demonstrated on five patient plasma samples, with cTnI concentrations measuring between 4.86 MUg/L and 11.3 MUg/L (signifying moderate myocardial infarctions). LC-MS/MS measurement precision was validated by three unique peptides from cTnI and two MRM transitions per peptide. Relative standard deviation (CV) from the five plasma samples was determined to be <=14.3%. This study has demonstrated that quantification of cTnI in native plasma from myocardial infarction patients can be achieved based on an ID-LC-MS/MS method. The development of an ID-LC-MS/MS method for cTnI in plasma is a first step for future certification of matrix based reference materials, which may be used to help harmonize discordant cTnI clinical assays. Graphical abstract A schematic of the workflow for measuring cardiac troponin I (cTnI), a low-abundant protein biomarker used for diagnosing myocardial infarction, in human plasma by isotope-dilution LC-MS/MS analysis. PMID- 29492622 TI - Capacitive hysteresis at the 1-ethyl-3-methylimidazolium tris(pentafluoroethyl) trifluorophosphate-polycrystalline gold interface. AB - We report potential-dependent capacitance curves over a 2-V potential range for the 1-ethyl-3-methylimidazolium tris(pentafluoroethyl)-trifluorophosphate (Emim FAP)-polycrystalline gold interface, and examine the effect of potential scan direction on results. We find very small levels of capacitive hysteresis in the Emim FAP-polycrystalline Au electrochemical system, where capacitance curves show minor dependence on the potential scan direction employed. This is a considerably different response than that reported for the Emim FAP-Au(111) interface where significant hysteresis is observed based on the potential scan direction (Druschler et al. in J Phys Chem C 115 (14):6802-6808, 2011). Hysteresis effects have previously been suggested to be a general feature of an ionic liquid (IL) at electrified interfaces due to slow interfacial processes and has been demonstrated for numerous electrochemical systems. We provide new evidence that the experimental procedure used to acquire capacitance data and data workup could also have implications on capacitance-potential relationships in ILs. This work serves to progress our understanding of the nature of capacitive hysteresis at the IL-electrode interface. Graphical abstract Subtle changes in experimental methods can lead to significantly different capacitance measurements in ionic liquids. Which is the best approach? PMID- 29492623 TI - Development and validation of a rapid, selective, and sensitive LC-MS/MS method for simultaneous determination of D- and L-amino acids in human serum: application to the study of hepatocellular carcinoma. AB - A validated liquid chromatography-tandem mass spectrometry method was developed for the simultaneous determination of D- and L-amino acids in human serum. Under the optimum conditions, except for DL-proline, L-glutamine, and D-lysine, the enantioseparation of the other 19 enantiomeric pairs of proteinogenic amino acids and nonchiral glycine was achieved with a CROWNPAK CR-I(+) chiral column within 13 min. The lower limits of quantitation for L-amino acids (including glycine) and D-amino acids were 5-56.25 MUM and 0.625-500 nM, respectively, in human serum. The intraday precision and interday precision for all the analytes were less than 15%, and the accuracy ranged from -12.84% to 12.37% at three quality control levels. The proposed method, exhibiting high rapidity, enantioresolution, and sensitivity, was successfully applied to the quantification of D- and L-amino acid levels in serum from hepatocellular carcinoma patients and healthy individuals. The serum concentrations of L-arginine, L-isoleucine, L-aspartate, L tryptophan, L-alanine, L-methionine, L-serine, glycine, L-valine, L-leucine, L phenylalanine, L-threonine, D-isoleucine, D-alanine, D-glutamate, D-glutamine, D methionine, and D-threonine were significantly reduced in the hepatocellular carcinoma patients compared with the healthy individuals (P < 0.01). D-Glutamate and D-glutamine were identified as the most downregulated serum markers (fold change greater than 1.5), which deserves further attention in hepatocellular carcinoma research. Graphical abstract Simultaneous determination of D- and L amino acids in human serum from hepatocellular carcinoma patients and healthy individuals. AA amino acid, HCC hepatocellular carcinoma, LC liquid chromatography, MS/MS tandem mass spectrometry, NC normal control, TIC total ion chromatogram. PMID- 29492624 TI - Case report: Electron microscopic evaluation of bone from a patient treated with cinacalcet hydrochloride, maxacalcitol, and alfacalcidol for hyperparathyroid bone disease with secondary hyperparathyroidism. AB - Evaluation of bone is of great importance in chronic kidney disease patients, as these patients are at an increased risk for fractures. We treated a hemodialysis patient suffering from hyperparathyroid bone disease with cinacalcet hydrochloride and concurrent administration of maxacalcitol and alfacalcidol for a year. Hyperparathyroid bone disease is characterized by cortical thinning, increased cortical porosity, reduced trabecular bone volume, and increased hypomineralized matrix volume, and there is little information to date about the effects of treatment with cinacalcet hydrochloride on the bone fragility in patients with hyperparathyroid bone disease. In the present study, histological and backscattered electron microscopic evaluation of this combination treatment revealed an excellent improvement of both bone volume and bone morphology. This treatment improved cortical thinning, cortical porosity, and trabecular thinning. Furthermore, the treatment also reduced hypomineralized matrix volume, indicative of improved mineralization by osteocytes. We speculate that the intermittent maxacalcitol administration may have effectively stimulated the vitamin D receptors expressed on osteocytes and osteoblasts, resulting in increased mineralization. Our approach for evaluating the bone in patients with chronic kidney disease by backscattered electron microscopy is novel. PMID- 29492625 TI - A Double Lane for a Better Circulation: Percutaneous Duplication of the Thoracic Aorta in a Child. AB - Aortic arch interruption or atresia consists in a complete loss of anatomical and luminal continuity between the ascending and descending thoracic aorta. It is usually diagnosed in newborn babies but may also be present in young children, adolescents, adults and elderly patients. In these cases, it can be congenital or more frequently acquired. This latter type of aortic arch atresia is a challenge, and surgery is usually the treatment of choice. Percutaneous approaches are also possible today. We describe a case of percutaneous aortic arch reconstruction in a 9-year-old boy. PMID- 29492626 TI - Regarding "Endovascular Stent-Graft Repair of Spontaneous Isolated Dissection of the Superior Mesenteric Artery". PMID- 29492627 TI - Endolymphatic Optical Coherence Tomography Facilitates Evaluation of the Thoracic Duct Prior to Embolization. PMID- 29492628 TI - Tri-axial Biopsy Needle Cauterization During Splenic Biopsy. PMID- 29492629 TI - MELD Score Does Not Underestimate Short-Term Mortality Risk in Women Versus Men After TIPS Creation. PMID- 29492630 TI - Comparison of Covered Versus Uncovered Stents for Benign Superior Vena Cava (SVC) Obstruction. AB - PURPOSE: To identify whether long-term symptom relief and stent patency vary with the use of covered versus uncovered stents for the treatment of benign SVC obstruction. METHODS AND MATERIALS: We retrospectively identified all patients with benign SVC syndrome treated to stent placement between January 2003 and December 2015 (n = 59). Only cases with both clinical and imaging follow-up were included (n = 47). In 33 (70%) of the patients, the obstruction was due to a central line or pacemaker wires, and in 14 (30%), the cause was fibrosing mediastinitis. Covered stents were placed in 17 (36%) of the patients, and 30 (64%) patients had an uncovered stent. Clinical and treatment outcomes, complications, and the percent stenosis of each stent were evaluated. RESULTS: Technical success was achieved in all cases at first attempt. Average clinical and imaging follow-up in years was 2.7 (range 0.1-11.1) (covered) and 1.7 (range 0.2-10.5) (uncovered), respectively. There was a significant difference (p = 0.044) in the number of patients who reported a return of symptoms between the covered (5/17 or 29.4%) and uncovered (18/30 or 60%) groups. There was also a significant difference (p = < 0.001) in the mean percent stenosis after stent placement between the covered [17.9% (range 0-100) +/- 26.2] and uncovered [48.3% (range 6.8-100) +/- 33.5] groups. No significant difference (p = 0.227) was found in the time (days) between the date of the procedure and the date of clinical follow-up where a return of symptoms was reported [covered: 426.6 (range 28-1554) +/- 633.9 and uncovered 778.1 (range 23-3851) +/- 1066.8]. One patient in the uncovered group had non-endovascular surgical intervention (innominate to right atrial bypass), while none in the covered group required surgical intervention. One major complication (SIR grade C) occurred that consisted of a pericardial hemorrhagic effusion after angioplasty that required covered stent placement. There were no procedure-related deaths. CONCLUSION: Both covered and uncovered stents can be used for treating benign SVC syndrome. Covered stents, however, may be a more effective option at providing symptom relief and maintaining stent patency if validated by further studies. PMID- 29492631 TI - Outcome Measures After Sclerotherapy of Venous Malformations: A Systematic Review. AB - OBJECTIVE: Sclerotherapy has become an important treatment option in the management of vascular malformations. However, little is known about success rate for treatment of venous malformations. This systematic review assesses the available published literature on outcome measures of sclerotherapy for venous malformations. DATA SOURCE: PubMed and EMBASE. REVIEW METHOD: A systematic search was conducted, and studies from March 2008 to October 2016 were included. Based on the identified search results, study selection, data extraction, and assessment of study quality were, according to PRISMA, undertaken independently by two reviewers. RESULTS: One randomized controlled trial and 44 cohort studies were included. The most frequently used measuring methods were subjective measurements, objective measurements, imaging like MRI and ultrasound, and finally patient reported outcome measure survey. Approximately 60% of the studies used more than one measuring method. Outcome measures were pain, swelling, disfigurement, cosmetic complains, patient satisfaction, physical difficulties, volume, diameter, mass, color, shape, size, venous flow, occlusion of venous space, blood pool ratio, and radioisotope uptake. CONCLUSIONS: The published literature over the past 10 years shows no clear method to evaluate the effect of sclerotherapy for venous malformation. We suggest that a standard set of outcome measures should be defined. PMID- 29492632 TI - The Female Threat. PMID- 29492633 TI - Physical Properties of Venous Stents: An Experimental Comparison. AB - PURPOSE: Iliocaval obstruction is a substantial contributor to chronic venous insufficiency and is increasingly being treated endovascularly with angioplasty and stent placement. Utilization of an appropriate stent for treatment is pivotal; however, until today, mechanical properties of venous stents remain unknown. MATERIALS AND METHODS: We analyzed the radial resistive force, the chronic outward force, as well as the crush resistance of seven stent models [Zilver Vena (Cook, Bjaeverskov, Denmark), Sinus Venous, Sinus Obliquus and Sinus XL Flex (Optimed, Ettlingen, Germany), Vici (Veniti; St. Louis, USA), Wallstent (Boston Scientific, Marlborough, USA), and Venovo (Bard, Tempe, USA)] in vitro using a radial force testing machine (RX-650, Machine Solutions Inc., Flagstaff, AZ, USA) and a hardness testing machine (zwickiLine, Zwick Roell, Ulm, Germany). RESULTS: The Sinus Obliquus revealed the highest radial resistive force (19.41 N/cm) and the highest chronic outward force at 50 and 30% nominal diameter (7.93 N/cm at 50%, 16.97 N/cm at 30%) while the Venovo revealed the highest chronic outward force at 90 and 80% nominal diameter (4.83 N/cm at 90%, 5.37 N/cm at 80%). The radial resistive force and the chronic outward force of the Wallstent greatly depended on whether the stent ends were fixated. The Wallstent revealed the highest crush resistance at nominal diameters of 90% (0.46 N/cm) to 60% (1.16 N/cm). The Sinus Obliquus revealed the highest crush resistance at a nominal diameter of 50% (1.41 N/cm). CONCLUSION: Venous stents greatly differ regarding their mechanical properties. These results should be considered when choosing an appropriate stent for the treatment of venous obstruction. PMID- 29492635 TI - [Treatment of nocturia in men with desmopressin]. PMID- 29492634 TI - A Novel CT to Cone-Beam CT Registration Method Enables Immediate Real-Time Intraprocedural Three-Dimensional Assessment of Ablative Treatments of Liver Malignancies. AB - AIM: To evaluate a novel contrast-enhanced cone-beam computed tomography (CE CBCT) registration method for accurate immediate assessment of ablation outcomes. MATERIALS AND METHODS: Contrast-enhanced computed tomography (CECT) was registered with CE-CBCT by applying semiautomatic landmark registration followed by automatic affine and non-rigid registration to correct for respiratory phase differences and liver deformation. This scheme was retrospectively applied to 30 patients who underwent 38 percutaneous microwave liver ablations. Three datasets were obtained for each case: (1) conventional CECT scans 24 h before ablation, (2) intraprocedural CE-CBCT scans, and (3) CECT scans 24 h post-ablation. Using a five-point scale, two experienced radiologists qualitatively assessed registration quality, equivalence of CE-CBCT assessment of ablation outcome to 24 h post-ablation CECT, and perceived increase of confidence using the fusion method to CBCT alone. Additionally, residual post-ablation tumor volumes were measured at both CE-CBCT and 24 h CECT and compared to the pre-CECT. RESULTS: Registration quality was high for both radiologists (R1: 4.3 +/- 0.6, R2: 4.4 +/- 0.5; p = 0.87). Comparisons between the registration of pre-ablation CECT with CE CBCT versus post-ablation CECT regarding the position of the ablated area to the treated target (R1: 4.4 +/- 0.6, R2: 4.6 +/- 0.4) and treatment outcome (R1: 4.5 +/- 0.5, R2: 4.6 +/- 0.4) were equivalent (p > 0.35). Increased confidence was noted when using fusion (R1: 4.6 +/- 0.4, R2: 4.6 +/- 0.4; p = 0.84). Moreover, in 6 ablations (15.8%) the intraprocedural registered CBCT showed residual tumor precisely where identified on the 24 h post-ablation CECT. CONCLUSIONS: Combined CE-CBCT holds the potential to change the current workflow of mini-invasive cancer local treatments. Given earlier visual identification of residual tumor post-ablation, this includes potentially eliminating the need for some additional treatments. PMID- 29492636 TI - [Duodenum-preserving pancreatic head resection in chronic pancreatitis : Limitations of the Heidelberg multicenter ChroPac study]. AB - The data published in Der Chirurg and The Lancet on the results of the multicenter ChroPac study comparing results of 115 patients in the duodenum preserving pancreatic head resection (DPPHR) group with 111 patients in the pancreaticoduodenectomy (PD) group, recommend partial PD as the first line procedure for chronic pancreatitis (CP). This is based on the significantly higher frequency of rehospitalization assigned to CP in the DPPHR group and data derived from post hoc meta-analysis about higher frequency of reoperations in the DPPHR group. Based on the presented data of the intention-to-treat analysis it is difficult to support the authors' recommendation of PD as the first line procedure for CP. The critical points are substantial heterogeneity of the different surgical procedures in the DPPHR group (20%) and PD group (13.5%) and a heterogeneity with respect to the number of patients with very advanced CP in the DPPHR group but not in the PD group. The data on the new onset of diabetes and endocrine insufficiency after surgery are not the result of measuring the preoperative and postoperative status of glucose metabolism and degree of exocrine dysfunction but are based on patient records. The advantages and/or disadvantages of the local parenchyma-sparing pancreatic head resection for CP compared to PD results of the published monocentric randomized controlled studies (RCT) more closely verify the clinical evidence than those of the ChroPac trial. PMID- 29492637 TI - Fibre supplementation for the prevention of type 2 diabetes and improvement of glucose metabolism: the randomised controlled Optimal Fibre Trial (OptiFiT). AB - AIMS/HYPOTHESIS: Insoluble cereal fibres have been shown in large prospective cohort studies to be highly effective in preventing type 2 diabetes, but there is a lack of interventional data. Our 2 year randomised double-blind prospective intervention study compared the effect of an insoluble oat fibre extract with that of placebo on glucose metabolism and incidence of diabetes. METHODS: A total of 180 participants with impaired glucose tolerance underwent a modified version of the 1 year lifestyle training programme PREvention of DIAbetes Self-management (PREDIAS) and were randomised to receive a fibre supplement (n = 89; 7.5 g of insoluble fibre per serving) or placebo (n = 91; 0.8 g of insoluble fibre per serving) twice daily for 2 years. Eligible participants were men and women, were at least 18 years old and did not report corticosteroid or other intensive anti inflammatory treatment, fibre intolerance or any of the following disorders: overt diabetes, chronic or malignant disease, or severe cardiopulmonary, endocrine, psychiatric, gastrointestinal, autoimmune or eating disorder. Participants were recruited at two clinical wards in Berlin and Nuthetal. The allocation was blinded to participants and study caregivers (physicians, dietitians, study nurses). Randomisation was conducted by non-clinical staff, providing neutrally numbered supplement tins. Both supplements were similar in their visual, olfactory and gustatory appearance. Intention-to-treat analysis was applied to all individuals. RESULTS: After 1 year, 2 h OGTT levels decreased significantly in both groups but without a significant difference between the groups (fibre -0.78 +/- 1.88 mmol/l [p <= 0.001] vs placebo -0.46 +/- 1.80 mmol/l [p = 0.020]; total difference 0.32 +/- 0.29 mmol/l; not significant). The 2 year incidence of diabetes was 9/89 (fibre group) compared with 16/91 (placebo group; difference not significant). As secondary outcomes, the change in HbA1c level was significantly different between the two groups (-0.2 +/- 4.6 mmol/mol [-0.0 +/- 0.0%; not significant] vs +1.2 +/- 5.2 mmol/mol [+0.1 +/- 0.0%; not significant]; total difference 1.4 +/- 0.7 mmol/mol [0.1 + 0.0%]); p = 0.018); insulin sensitivity and hepatic insulin clearance increased in both groups. After 2 years, improved insulin sensitivity was still present in both groups, although the effect size had diminished. Separate analysis of the sexes revealed a significantly greater reduction in 2 h glucose levels for women in the fibre group (-0.88 +/- 1.59 mmol/l [p <= 0.001] vs -0.22 +/- 1.52 mmol/l [p = 0.311]; total difference 0.67 +/- 0.31 mmol/l; p = 0.015). Levels of fasting glucose, adipokines and inflammatory markers remained unchanged in the two groups. Significantly increased fibre intake was restricted to the fibre group, despite dietary counselling for both groups. No severe side effects occurred. CONCLUSIONS/INTERPRETATION: We cannot currently provide strong evidence for a beneficial effect of insoluble cereal fibre on glycaemic metabolism, although further studies may support minor effects of fibre supplementation in reducing glucose levels, insulin resistance and the incidence of type 2 diabetes. TRIAL REGISTRATION: clinicaltrials.gov NCT01681173 Funding: German Diabetes Foundation (grant no. 232/11/08). PMID- 29492638 TI - Long-term BMI and growth profiles in offspring of women with gestational diabetes. AB - AIMS/HYPOTHESIS: Gestational diabetes mellitus (GDM) is reported to be associated with childhood obesity, however the magnitude of this association and relation to intrauterine growth is uncertain. We, therefore, aimed to assess whether the growth trajectories of large for gestational age (LGA) and non-LGA offspring of mothers with GDM (OGDM) are different until early adolescence. We also aimed to explore whether growth trajectories of OGDM differ from those of offspring of mothers with type 1 or 2 diabetes (ODM1, ODM2). METHODS: We studied height and BMI standard deviation score (SDS) of the OGDM group, up to the age of 14 years, with subgroup analysis comparing LGA with non-LGA at birth as a reflection of the intrauterine environment. All mothers with GDM who delivered at the University Medical Center Utrecht between 1990 and 2006 were contacted to participate; informed consent was received for 104 OGDM of 93 mothers. Offspring data were collected through Dutch infant welfare centres. Recorded height and weight were converted to BMI and age- and sex-specific SDS values for Dutch children. Additionally, we compared the OGDM group with ODM1 and ODM2 groups in order to identify those offspring with the highest risk of becoming overweight. Growth trajectories were compared between non-LGA and LGA OGDM and between OGDM, ODM1 and ODM2, using a random-effects model. In the longitudinal follow-up a mean of 7.4 +/- 2 measurements per infant were available. RESULTS: Mothers had a prepregnancy BMI of 25.8 kg/m2 and 24% of their infants were LGA at birth. Heights of OGDM were no different from those of the Dutch Growth Study. Non-LGA OGDM showed a BMI SDS comparable with that of the reference population, with a slight increase in early adolescence. LGA OGDM had a higher BMI SDS trajectory than non-LGA OGDM and the reference population, which plateaued at around 10 years of age. Comparison of growth trajectories of OGDM, ODM1 and ODM2 showed ODM2 to have the highest trajectory followed by ODM1 and OGDM, with the LGA counterparts of all three offspring groups in the highest BMI SDS ranges. CONCLUSIONS/INTERPRETATION: Until early adolescence, OGDM have a BMI that is 0.5 SDS higher than that of the Dutch background population. LGA OGDM appear to be at particularly higher risk of being overweight in adolescence compared with non-LGA OGDM, putting them also at a higher lifetime risk of being overweight and developing obesity. ODM2 showed the highest BMI SDS values and had an average BMI SDS of +1.6 until the age of 14, when it became +2 SD. These results emphasize the importance of adequate recognition and timely treatment of maternal gestational diabetes to prevent fetal macrosomia in obstetrics. PMID- 29492639 TI - Biological conversion of methane to chemicals and fuels: technical challenges and issues. AB - Methane is a promising next-generation carbon feedstock for industrial biotechnology due to its low price and huge availability. Biological conversion of methane to valuable products can mitigate methane-induced global warming as greenhouse gas. There have been challenges for the conversion of methane into various chemicals and fuels using engineered non-native hosts with synthetic methanotrophy or methanotrophs with the reconstruction of synthetic pathways for target products. Herein, we analyze the technical challenges and issues of potent methane bioconversion technology. Pros and cons of metabolic engineering of methanotrophs for methane bioconversion, and perspectives on the bioconversion of methane to chemicals and liquid fuels are discussed. PMID- 29492640 TI - A lab-scale model system for cocoa bean fermentation. AB - Lab-scale systems modelling the spontaneous cocoa bean fermentation process are useful tools to research the influence of process parameters on the fermentation and the final bean quality. In this study in Honduras, a 1-kg lab-scale fermentation (LS-F) was compared to a 300-kg on-farm fermentation (OF-F) in a multiphasic approach, analysing microbial counts, microbial species diversity, physico-chemical parameters, and final dried bean quality. Yeast and total aerobic counts of up to 8 log CFU/g during the LS-F were comparable to the OF-F, while counts for lactic acid bacteria and acetic acid bacteria were up to 3 log CFU/g lower during the LS-F than during the OF-F. While species of the genera Hansenia, Saccharomyces, and Acetobacter dominated most of the fermentation processes, the genera dominating the drying phases were Pichia, Trichosporon, Pediococcus, and Acetobacter. Dried beans resulting from the LS-F, compared to the OF-F, were similar in contents of acetic acid, 6 times lower in lactic acid, up to 4 times higher in residual sugars, and 3-12 times higher in polyphenols. Dried beans processed at LS showed a similar flavour profile in terms of astringency, bitterness, acidity, and brown, fine, and cocoa flavours, but 2 units higher off-flavours than OF processed beans. With 81%, the share of well fermented beans from the LS-F complied with industrial standards, whereas 7% over fermented beans were above the threshold. Conclusively, the 5-day model fermentation and subsequent drying successfully mimicked the on-farm process, providing a high-throughput method to screen microbial strains to be used as starter cultures. PMID- 29492641 TI - The impact of Torulaspora delbrueckii yeast in winemaking. AB - Commercial Saccharomyces strains are usually inoculated to ferment alcoholic beverages due to their ability to convert all fermentable sugars into ethanol. However, modern trends in winemaking have turned toward less known, non Saccharomyces yeast species. These species perform the first stages of natural spontaneous fermentation and play important roles in wine variety. New alcoholic fermentation trends have begun to consider objectives other than alcohol production to improve flavor diversity. This review explores the influence of the most used and commercialized non-Saccharomyces yeast, Torulaspora delbrueckii, on fermentation quality parameters, such as ethanol, glycerol, volatile acidity, volatile profile, succinic acid, mannoproteins, polysaccharides, color, anthocyanins, amino acids, and sensory perception. PMID- 29492643 TI - Do arousal and valence have separable influences on attention across time? AB - Previous research has shown that emotions differentially influence attention across time, especially when the valence of the attended stimuli is congruent with the emotion of observer. Sadness produces a larger attentional blink while fear and happiness produce smaller attentional blinks. We report on four dual task rapid serial visual presentation experiments in which participant emotion and the affective features of the first target (T1) were systematically varied to determine whether arousal and valence have unique and consistent influences on attention performance. All T1s connoted affect. Results showed that the emotional experience of negative affect with high arousal led to better second target (T2) detection than negative affect with low arousal. In conditions where positive affect was the experienced emotion, low arousal resulted in better T2 detection than high arousal. When participant arousal was held constant at a low level there were no differences in performance. When participant arousal was high, a cross-over effect was observed in which negative affect produced better performance than positive affect at early positions and negative affect produced better performance at late. The first targets in these experiments varied in arousal and valence to test for emotion congruent effects, but none were found. It was concluded that the experience of varied levels of arousal and types of valence do not have separable influences on attention across time. Rather, their influence is more consistent with emotion-specific mechanisms. PMID- 29492642 TI - Meniscus repair with simultaneous ACL reconstruction demonstrated similar clinical outcomes as isolated ACL repair: a result not seen with meniscus resection. AB - PURPOSE: To compare Knee Injury and Osteoarthritis Outcome Score (KOOS) and EuroQol-5D (EQ-5D) subscale scores at 2-year follow-up for patients with primary isolated ACL reconstruction with patients undergoing ACL reconstruction and simultaneous meniscal treatment in terms of either resection or repair in the Swedish National Knee Ligament Register (SNKLR). METHODS: All ACL reconstruction patients within the SNKLR at 2-year follow-up were reviewed. The KOOS and EQ-5D subscales were assessed in four distinct patient groups: isolated ACL reconstruction, ACL reconstruction + medial meniscus resection, ACL reconstruction + lateral meniscus resection, ACL reconstruction + medial meniscus repair, and ACL reconstruction + lateral meniscus repair. The primary analysis was conducted using linear regression with isolated ACL reconstruction designated as the reference group, and was adjusted for patient age, gender, and time from injury to surgery. RESULTS: The included patients consisted of 10,001 (65.0%) individuals with an isolated ACL injury, 588 (3.8%) with ACL injury plus treated with medial meniscus repair, 2307 (15.0%) with ACL injury plus treated with medial meniscus resection, 323 (2.1%) with ACL injury plus treated with lateral meniscus repair, and 2173 (14.1%) with ACL injury plus treated with lateral meniscus resection. Meniscus resection demonstrated significantly worse results with respect to the KOOS Symptoms subscale for both the medial and lateral meniscus resection groups. Medial meniscus resection also demonstrated worse results for the KOOS quality of life (QoL) subscale, while lateral meniscus resection only approached significance. Outcomes were not different between the isolated ACL reconstruction group and the meniscus repair groups. CONCLUSION: Meniscus resection in addition to ACL reconstruction resulted in worse clinical outcomes than isolated ACL reconstruction patients; a result not seen within the meniscus repair group. This suggests that, when possible, meniscus repair may provide greater clinical outcomes over resection when treating a reparable meniscal tear that presents along with an ACL tear. Clinicians should consider and implement these findings for the management of future meniscus tear patients within their clinical practice. LEVEL OF EVIDENCE: Level III. PMID- 29492644 TI - Preoperative [18F]FDG PET/CT tumour heterogeneity index in patients with uterine leiomyosarcoma: a multicentre retrospective study. AB - PURPOSE: We investigated the prognostic value of the tumour heterogeneity index determined on preoperative [18F]FDG PET/CT in patients with uterine leiomyosarcoma (LMS). METHODS: We retrospectively reviewed patients with uterine LMS who underwent preoperative [18F]FDG PET/CT scans at three tertiary referral hospitals. The PET/CT parameters maximum standardized uptake value of the primary tumour (SUVmax), metabolic tumour volume (MTV) and total lesion glycolysis were assessed. The negative values of the MTV linear regression slope (nMLRS) according to the SUV thresholds of 2.5 and 3.0 were determined as the tumour heterogeneity index. The value of PET/CT-derived parameters in predicting progression-free survival (PFS) and overall survival (OS) were determined in regression analyses. RESULTS: Clinicopathological and PET/CT data from 16 patients were reviewed. The median postsurgical follow-up was 21 months (range 4 82 months), and 12 patients (75.0%) experienced recurrence. Tumour size (P = 0.017), SUVmax (P = 0.019), MTV (P = 0.016) and nMLRS (P = 0.008) were significant prognostic factors for recurrence. MTV (P = 0.048) and nMLRS (P = 0.045) were significant prognostic factors for patient survival. nMLRS was correlated with clinicopathological parameters including tumour size (Pearson's correlation coefficient gamma = 0.825, P < 0.001) and lymph node metastasis (gamma = 0.721, P = 0.004). Patient groups categorized according to the nMLRS cut off value showed significant differences in PFS (P = 0.033) and OS (P = 0.044). CONCLUSION: The preoperative tumour heterogeneity index obtained using the MTV linear regression slope may be a novel and useful prognostic marker in uterine LMS. PMID- 29492647 TI - Integrating child and adolescent psychiatry and the field of early childhood development. PMID- 29492646 TI - The impact of psychological problems and adverse life events on suicidal ideation among adolescents using nationwide data of a school-based mental health screening test in Korea. AB - The aim of this study was to investigate the risk factors for suicidal ideation in adolescents by gender and age. This study used 2013 nationwide school-based mental health screening test data from 591,303 seventh grade students and 618,271 tenth grade students in Korea. Suicidal ideation, four psychological problems, and three adverse life events were evaluated using the Adolescents Mental Health and Problem Behavior Screening Questionnaire-II. Of all students, 12.9-14.7% of the boys and 17.1-23.2% of the girls had suicidal ideation. Mood had the greatest impact on the risk for suicidal ideation and other factors also significantly increased the risk of suicidal ideation. Distractibility was positively related to suicidal ideation only in seventh grade students and behavioral problems increased suicidal ideation more in girls than in boys. Violence constituted the most powerful factor for suicidal ideation among the events; however, bullying constituted the most important event that increased suicidal ideation in seventh grade girls. All factors except 'Distractibility' increased the risk of severe suicidal ideation. The risk factors for suicidal ideation in adolescents differed by gender and age. Interventions should be made according to these characteristics to reduce suicidal ideation in adolescents. PMID- 29492648 TI - [Unclear loss of vision following Descemet membrane endothelial keratoplasty]. PMID- 29492645 TI - The role of zinc and its compounds in leukemia. AB - Zinc is one of the most important microelements necessary for normal body functioning. Zinc is marked in numerous diseases and, hence, its properties and behavior in the body have long been a subject of extensive study. This review considers trends in the assessment of the role of zinc and its compounds in the past decade. It becomes evident that redox-inactive zinc is the main supervisor in the conformation of the most important molecules in all body organs and tissues. We placed emphasis on the variety of zinc-binding sites and the role of zinc in the genesis and progress of different forms of leukemia. The importance of some families of transcription factors in the development and prognosis of treatment of various leukemia forms is examined; new directions of these studies are shown. PMID- 29492649 TI - Porostereum sp., Associated with Saffron (Crocus sativus L.), is a Latent Pathogen Capable of Producing Phytotoxic Chlorinated Aromatic Compounds. AB - Saffron (Crocus sativus L.) is one of the most expensive spices in the world due to its medicinal and aromatic value. However, saffron production is severely affected by the corm rot disease throughout the saffron producing countries. In this study, we report a basidiomycetous latent pathogen of saffron, designated as CSE26, capable of producing phytotoxic compounds. CSE26 is a highly odorous basidiomycete with monomitic hyphal system. Molecular phylogeny of ITS and 28S ribosomal gene sequence of CSE26 assigned it as Porostereum spadiceum. It was found to produce corm rot in C. sativus under in vivo and field conditions, with a disease severity index of 0.7 and 0.5, respectively. CSE26 was found to produce chlorinated aromatic compounds (CAMs) having phytotoxic activity against Arabidopsis plants. Therefore, these compounds may be acting as pathogenic determinants of CSE26. However, there is a need to study the level of production of these CAMs by this fungus in the natural environment and their effects on plant health. PMID- 29492650 TI - Inter- and intra-ventricular dyssynchrony in the systemic right ventricle is a surrogate marker of major cardiac events in mildly symptomatic patients. AB - The aim of the study was to evaluate systemic right ventricular (RV) dyssynchrony in patients with congenitally corrected transposition of the great arteries (CCTGA) and transposition of the great arteries (TGA) with New York Heart Association functional class (NYHA FC) < III. We used cardiac magnetic resonance (CMR) to evaluate the dyssynchrony and assessed whether RV dyssynchrony can be predictive of major cardiac events in their early stages in these patients. We enrolled 71 consecutive, NYHA FC < III patients with systemic RV who underwent CMR between April 1995 and December 2016. We measured intra- and inter ventricular dyssynchrony using a feature-tracking method of cine magnetic resonance imaging. The predictors of major cardiac events were analyzed using the Cox hazard analysis. The data from 36 patients with CCTGA and 35 patients with TGA after an atrial switch were analyzed. Seven (19.4%) patients with CCTGA and 6 (17.1%) patients with TGA showed a QRS duration of >= 130 ms. There were significant intra- and inter-dyssynchrony in the systemic RV groups, compared to healthy controls. The average follow-up period was 5.1 +/- 3.9 years. From among patients with CCTGA, 9 (25.0%) had major cardiac events. The parameters including NYHA FC, indexed RV volume, longitudinal early diastolic strain rate, and intra- and inter-ventricular dyssynchrony were predictive of major cardiac events. From among patients with TGA, 12 (34.3%) had major cardiac events. Age, NYHA FC, QRS duration, RV volume, RV mass index, LV volume, global longitudinal/circumferential strain and intraventricular dyssynchrony, were all predictive of major cardiac events. Systemic RV in NYHA FC < III patients with CCTGA and TGA, have obvious intra- and inter-dyssynchrony, suggesting ineffective wall motion and potential RV dysfunction. Intraventricular dyssynchrony can be an adjunct predictor of major cardiac events in mildly symptomatic patients with both CCTGA and TGA. PMID- 29492651 TI - Are visual functions diagnostic signs of the minimally conscious state? an integrative review. AB - Visual pursuit (VP) and visual fixation (VF) have been recognized as the first signs of emerging consciousness and, therefore, are considered indicative of the minimally conscious state (MCS). However, debate exists about their status as they are considered either conscious reactions or reflexes. The aim of this study is to review the evidence of the definition, operationalization, and assessment of VP and VF in unconscious patients. PubMed and EMBASE were searched for relevant papers between May 26, 1994 and October 1, 2016. In addition, an internet search was done to identify other relevant papers, reports and manuals of assessment methods. Papers were included if the definition, operationalization, or assessment method of VP and VF was discussed in patients with disorders of consciousness. We identified 2364 articles, of which 38 were included. No uniform definitions of VP and VF were found. VP and VF were operationalized differently, depending on which scale was used. The Coma Recovery Scale-revised and the Sensory Tool to Assess Responsiveness were the only diagnostic scales found; the other scales were developed to monitor DOC patients. The use of a mirror was the most sensitive method for detecting VP and VF. The literature about the importance VP and VF in relation with consciousness is controversial. This integrative review shows a lack of consensus regarding the definition, operationalization, and assessment of VP and VF. International consensus development about the definition, operationalization, and assessment of VP and VF is recommended. PMID- 29492652 TI - Cortico-spinal excitability and hand motor recovery in stroke: a longitudinal study. AB - OBJECTIVE: To describe the relationship between changes of cortico-spinal excitability and motor recovery of the affected hand after stroke. METHODS: Eighteen hemiparetic stroke patients with a severe-to-mild upper limb motor impairment were randomized. Cortico-spinal excitability measures (resting motor thresholds and motor evoked potentials) obtained from a distal (abductor pollicis brevis) and proximal (biceps brachii) upper limb muscle were assessed for both hemispheres. Motor function of the affected hand was tested by the Wolf Motor Function and Action Research Arm tests. The evaluations were performed at baseline and weekly over 7 weeks of in-patient neurological rehabilitation. RESULTS: Severe hand dysfunction was associated with a strong suppression of ipsilesional cortico-spinal excitability and a shift of excitability towards the contralesional hemisphere. Mild hand impairment was associated with a shift of cortico-spinal excitability towards the ipsilesional hemisphere. Favorable motor recovery correlated with an increase of ipsilesional cortico-spinal excitability. PMID- 29492653 TI - A new virus, classifiable in the family Tombusviridae, found infecting Solanum tuberosum in the UK. AB - A novel virus was discovered in a freeze-dried collection held at SASA, UK, originating from potato (Solanum tuberosum) cv. Nadine. The complete sequence of the viral RNA was determined to be 3674 nucleotides in length encoding five predicted proteins. Based on the deduced genome organization and phylogenetic analysis, this virus represents a putative new member of the genus Alphanecrovirus, family Tombusviridae, most closely related to isolates of Olive mild mosaic virus. The virus was easily transmitted to indicator plants with symptoms that were slower to develop and less severe than those of related viruses. To distinguish this virus, the clearest symptom differences occurred with Nicotiana debneyi, Chenopodium amaranticolor and Ch. quinoa. The virus was detected with antisera to the related viruses tobacco necrosis virus A and tobacco necrosis virus D. The close association to the tobacco necrosis viruses would suggest this virus is not a new introduction to potato but in the past has been misidentified as one of these viruses. The virus isolate has been named potato necrosis virus. PMID- 29492655 TI - Awake craniotomy for vestibular schwannoma. Is it a novel or a first report? PMID- 29492654 TI - Multiple roles of Sonic Hedgehog in the developing human cortex are suggested by its widespread distribution. AB - Sonic Hedgehog (Shh) plays an instrumental role in brain development, fine-tuning processes such as cell proliferation, patterning, and fate specification. Although, mutations in the SHH pathway in humans are associated with various neurodevelopmental disorders, ranging from holoprosencephaly to schizophrenia, its expression pattern in the developing human brain is not well established. We now determined the previously not reported wide expression of SHH in the human fetal cerebral cortex during most of the gestation period (10-40 gestational weeks). This spatiotemporal distribution puts Shh in a position to influence the fundamental processes involved in corticogenesis. SHH expression increased during development, shifting from progenitor cells in the proliferative zones to neurons, both glutamatergic and GABAergic, and astrocytes in upper cortical compartments. Importantly, the expression of its downstream effectors and complementary receptors revealed evolutionary differences in SHH-pathway gene expression between humans and rodents. PMID- 29492656 TI - Upfront Gamma Knife surgery for facial nerve schwannomas: retrospective case series analysis and systematic review. AB - INTRODUCTION: Facial nerve schwannomas are rare tumors and account for less than 2% of intracranial neurinomas, despite being the most common tumors of the facial nerve. The optimal management is currently under debate and includes observation, microsurgical resection, radiosurgery (RS), and fractionated radiotherapy. Radiosurgery might be a valuable alternative, as a minimally invasive technique, in symptomatic patients and/or presenting tumor growth. METHODS: We review our series of four consecutive cases, treated with Gamma Knife surgery (GKS) between July 2010 and July 2017 in Lausanne University Hospital, Switzerland. Clinical and dosimetric parameters were assessed. Radiosurgery was performed using Leksell Gamma Knife Perfexion. We additionally performed a systematic review, which included 23 articles and 193 treated patients from the current literrature. RESULTS: The mean age at the time of the GKS was 44.25 years (median 43.5, range 34-56). Mean follow-up period was 31.8 months (median 36, range 3-60). Two cases presented with facial palsy and other two with hemifacial spasm. Pretherapeutically, House-Brackmann (HB) grade was II for one case, III for two, and VI for one. The mean gross tumor volume (GTV) was 0.406 ml (median 0.470 ml, range 0.030-0.638 ml). The mean marginal prescribed dose was 12 Gy at the mean 54% isodose line (median 50%, range 50-70). The mean prescription isodose volume (PIV) was 0.510 ml (median 0.596 ml, range 0.052-0.805 ml). The mean dose received by the cochlea was 4.2 Gy (median 4.1 Gy, range 0.1-10). One patient benefited from a staged-volume GKS. At last follow-up, tumor volume was stable in one and decreased in three cases. Facial palsy remained stable in two patients (one HB II and one HB III) and improved in two (from HB III to II and from HB VI to HB III). Regarding hemifacial spasm, both patients presenting one pretherapeutically had a decrease in its frequency and intensity after GKS. All patients kept stable Gardner-Robertson class 1 at last follow-up. CONCLUSION: In our experience, RS and particularly GKS, using standard, yet low doses of radiation, appear to be a safe and effective therapeutic option in the management of these rare tumors. The results as from our systematic review are also encouraging with satisfactory rates of clinical stabilization and/or improvement and high rate of tumor control. Complications are infrequent and mostly transient. PMID- 29492657 TI - Surgical recurrence in Crohn's disease: a comparison between different types of bowel resections. AB - PURPOSE: To compare recurrence frequency and location between different types of bowel resections in Crohn's disease patients. METHODS: This was a retrospective study of consecutive patients undergoing bowel resection for Crohn's disease between 2006 and 2016. Type of primary operation was recorded and grouped as ileocolic resection, small bowel resection, segmental colon resection with colocolic anastomosis or colorectal anastomosis, colectomy with ileorectal anastomosis, or end stoma operation. Binary logistic regression was used to compare surgical recurrence frequency between groups. We also investigated how Crohn's disease location at reoperations was related to the primary bowel resection type. RESULTS: Altogether, 218 patients with a median follow-up of 4.7 years were included in our study. Reoperation was performed in 42 (19.3%) patients. The risk of reoperation using the ileocolic resection group as reference was the following: small bowel resection (odds ratio (OR) 2.95, 95% confidence interval (CI) 1.01-8.66; P = 0.049), segmental colon resection with colocolic or colorectal anastomosis (OR 6.20, 95% CI 2.04-18.87; P = 0.001), colectomy with ileorectal anastomosis (OR 26.57, 95% CI 2.59-273.01; P = 0.006), and end stoma operation (OR 4.62, 95% CI 1.90-11.26; P = 0.001). In case of surgical recurrence, the reoperation type and location correlated with the primary bowel resection type. CONCLUSIONS: Reoperation frequency in Crohn's disease is lower after ileocolic resection than after other types of bowel resections. Surgical recurrence in Crohn's disease tends to maintain the disease location of the primary operation. One third of Crohn's patients undergoing an end stoma operation will still need new bowel resections due to recurrence. PMID- 29492658 TI - The association of short-term memory and cognitive impairment with ghrelin, leptin, and cortisol levels in non-diabetic and diabetic elderly individuals. AB - AIMS: This study assessed short-term memory and biochemical indicators with the levels of ghrelin, leptin, and cortisol between cognitive impairment and normal older adults with or without diabetes. METHODS: We enrolled 286 older adults (aged 65-85 years) with or without diabetes from the local community. Short-term memory was assessed using pictures of common objects; cognitive functioning was assessed using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). The physiological indexes assessed were plasma levels of fasting ghrelin and leptin, ghrelin level at 2_h after breakfast, 24-h urinary cortisol value, body mass index, and plasma cortisol levels at 8:00 a.m., 4:00 p.m., and 12:00 p.m. RESULTS: In both non-diabetic and diabetic subjects, short-term memory was significantly lower in the impaired cognition group (5.99 +/- 2.90 in non-diabetic subjects and 4.71 +/- 2.14 in diabetic subjects) than in the normal cognition group (8.14 +/- 2.23 in non-diabetic subjects and 7.82 +/- 3.37 in diabetic subjects). Baseline ghrelin level was significantly lower in the impaired cognition group (9.07 +/- 1.13 ng/mL in non-diabetic subjects and 7.76 +/- 1.34 ng/mL in diabetic subjects) than in the normal cognition group (10.94 +/ 1.53 ng/mL in non-diabetic subjects and 9.93 +/- 1.76 ng/mL in diabetic subjects); plasma cortisol levels at 8:00 a.m., 4:00 p.m., and 12:00 p.m. were significantly higher in the impaired cognition group than in the normal cognition group, while no significant difference was observed in plasma levels of fasting leptin between different groups. CONCLUSIONS: Fasting plasma ghrelin and cortisol levels may be markers of cognitive decline and memory loss. It is possible that adjusting their levels may have a therapeutic effect, and this should be investigated in future studies. PMID- 29492659 TI - Forensic parameters and admixture in Mestizos from five geographic regions of Mexico based on 20 autosomal STRs (Powerplex 21 system). AB - We analyzed Mestizo (admixed) population samples from different geographic regions of Mexico (n = 1283) with 20 autosomal STRs (PowerPlex(r) 21, Promega Corp.). Allele frequencies and forensic parameters from the Northwest, Northeast, West, Center, and Southeast regions are reported, as well as from the pooled Mexican population sample. The combined PD and PE for this 20 STR system were > 0.9999999999 and > 0.99999996593% in all five population samples, respectively. Analysis of molecular variance (AMOVA) of these Mexican population samples, plus Monterrey (Northeast) and Mexico (Center) Cities, showed low but significant differences among Mexican-Mestizos from the seven populations (Fst = 0.20%; p = 0.0000). Structure analysis showed the highest proportion of Native American ancestry in Mexico City, Center, and Southeast regions, respectively, which was in agreement with the estimated genetic distances represented in a MDS plot and a NJ tree. The best fit of population clusters (K = 4) obtained with the Structure software indicates that Mexican-Mestizos are mainly composed by European, African, and two Native American ancestries. The European and Native American ancestries displayed a contrary gradient, increasing toward the North-West and South-Southeast, respectively. These 20 autosomal STR loci improved the admixture estimation regarding previous studies with the 13 CODIS-STRs, as supported by the higher similarity with previous estimates based on genome-wide SNP. In brief, this study validates the confident use of the PowerPlex(r) 21 system for human identification purposes in Mestizo populations throughout the Mexican territory. PMID- 29492660 TI - Biological and molecular features of Nosema rachiplusiae sp. n., a microsporidium isolated from the neotropical moth Rachiplusia nu (Guenee) (Lepidoptera: Noctuidae). AB - Light, electron microscopy and DNA analyses were performed to characterize a microsporidium infecting Rachiplusia nu larvae from a laboratory rearing in Argentina. Diplokaryotic spores were oval and measured 3.61 +/- 0.29 * 1.61 +/- 0.14 MUM (fresh). The spore wall was composed of an electron-dense exospore and an electron-lucent endospore, ca. 30 nm and 100-120 nm thick, respectively. The polar filament was arranged in a single rank of 10-12 coils (typically 11). Microsporidian cells were found in the cytoplasm, next to the endoplasmic reticulum (especially the prespore stages) and generally surrounded by electron lucent spaces. The infection was polyorganotropic; the fat body appeared as the most heavily invaded tissue, followed by tracheal matrix and epidermis. A molecular phylogeny based on the small (SSU) and large subunit (LSU) ribosomal RNA genes clearly placed the new isolate within the "Nosema bombycis clade". Considering both SSU and LSU concatenated partial sequences, the microsporidium from R. nu showed 99.5% nucleotide similarity with N. bombycis and 99.8% with its closest relative, a microsporidium isolated from Philosamia cynthia. According to its genetic and biological features, the R. nu isolate is proposed as the new species Nosema rachiplusiae sp. n., expanding the limited knowledge on microsporidia associated to endemic South-American moths. PMID- 29492661 TI - Mortality in Robin sequence: identification of risk factors. AB - : Although Robin sequence (RS) is a well-known phenomenon, it is still associated with considerable morbidity and even mortality. The purposes of this study were to gain greater insight into the mortality rate and identify risk factors associated with mortality in RS. We retrospectively reviewed all RS infants followed at the Wilhelmina Children's Hospital from 1995 to 2016. Outcome measurements were death and causes of death. The authors identified 103 consecutive RS infants with a median follow-up of 8.6 years (range 0.1-21.9 years). Ten of the 103 infants (10%) died at a median age of 0.8 years (range 0.1 5.9 years). Nine of these ten infants (90%) were diagnosed with an associated syndrome. Of these, seven infants died of respiratory insufficiency due to various causes (two related to upper airway obstruction). The other two syndromic RS infants died of arrhythmia due to hypernatremia and of West syndrome with status epilepticus. One isolated RS infant died of brain ischemia after MDO surgery. Cardiac anomalies were observed in 41% and neurological anomalies in 36%. The presence of a neurological anomaly was associated with a mortality rate of 40% versus 7% in infants with no neurological anomaly (p = 0.016), with an odds ratio of 8.3 (95% CI 1.4-49.0) for neurological anomaly versus no neurological anomaly. Mortality was 15% in infants with syndromic RS versus 2% in infants with isolated RS (p = 0.044). Mortality was not significantly associated with the presence of a cardiac anomaly, surgical treatment for severe respiratory distress in the neonatal period, or prematurity. CONCLUSION: RS represents a heterogeneous patient population and is associated with a high level of underlying syndromes. The present study reports a mortality rate of 10% significantly associated with syndromic RS and the presence of neurological anomalies. A multidisciplinary approach in all infants born with RS, including genetic testing and examination of neurological anomalies in a standardized way, is crucial to identify infants with underlying syndromes potentially associated with increased mortality. What is Known: * Reported mortality rates in Robin sequence vary from 2% to 26%. * Clinicians mainly focus on the morbidity of Robin sequence that includes respiratory complications due to upper airway obstruction in the period after birth. * Robin sequence represents a heterogeneous patient population and is associated with a high level of underlying syndromes. What is New: * The present study reports a mortality rate of 10% significantly associated with syndromic Robin sequence and the presence of neurological anomalies. * A multidisciplinary approach in all infants born with Robin sequence, including genetic evaluation and standardized workup for neurological anomalies, is crucial to identify infants with underlying syndromes potentially associated with increased mortality. PMID- 29492662 TI - Synaptic plasticity and levodopa-induced dyskinesia: electrophysiological and structural abnormalities. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive degeneration of dopaminergic neurons located in the midbrain. The gold-standard therapy for PD is the restoration of dopamine (DA) levels through the chronic administration of the DA precursor levodopa (L-DOPA). Although levodopa therapy is the main therapeutic approach for PD, its use is limited by the development of very disabling dyskinetic movements, mainly due to the fluctuation of DA cerebral content. Experimental animal models of PD identified in DA D1/ERK-signaling pathway aberrant activation, occurring in striatal projection neurons, coupled with structural spines abnormalities, the molecular and neuronal basis of L-DOPA-induced dyskinesia (LIDs) occurrence. Different electrophysiological approaches allowed the identification of the alteration of homeostatic structural and synaptic changes, the neuronal bases of LIDs either in vivo in parkinsonian patients or in vitro in experimental animals. Here, we report the most recent studies showing electrophysiological and morphological evidence of aberrant synaptic plasticity in parkinsonian patients during LIDs in different basal ganglia nuclei and also in cortical transmission, accounting for the complexity of the synaptic changes during dyskinesias. All together, these studies suggest that LIDs are associated with a loss of homeostatic synaptic mechanisms. PMID- 29492664 TI - Predictive factors of a beneficial quality of life outcome in patients undergoing primary sinonasal surgery: a population-based prospective cohort study. AB - PURPOSE: To assess predictive factors of a beneficial quality of life (QoL) outcome after primary sinonasal surgery. METHODS: A population-based prospective cohort study among 160 adult patients undergoing primary sinonasal surgery (76 septoplasties, SP; 84 endoscopic sinus surgeries, ESS) was conducted. We collected QoL data using the Sinonasal Outcome Test-22 (SNOT-22) before and after surgery. A beneficial QoL outcome was defined as a SNOT-22 score change >= 9 points 12 months after surgery. Various demographic, clinical and symptom-related factors predicting a beneficial QoL outcome were sought using binary logistic regression analysis. RESULTS: The mean age of the patients was 39 years (range 18 61) and 82 (51%) were males. The SNOT-22 score change varied markedly after SP (range - 17 to + 80) and ESS (range - 20 to + 58), but on average it improved (median + 15 after SP and + 16 after ESS). 41 patients (64%) achieved beneficial QoL outcome after SP and 46 (66%) after ESS. In a multivariate analysis, poor QoL before surgery (preoperative SNOT-22 >= 20 points) predicted a beneficial QoL outcome after SP and ESS (adjusted odds ratio 10; 95% confidence interval 1.6-64 and 12; 2.5-55, respectively) and a senior surgeon operating after SP (9.9; 1.5 67). On receiver operating characteristic curve analysis, the integer threshold value for the preoperative SNOT-22 score that gave the highest sensitivity (74%) and specificity (70%) was 30. CONCLUSIONS: QoL change after primary SP and ESS varies. A preoperative SNOT-22 score of at least 30 best predicted a beneficial QoL outcome after both procedures. PMID- 29492663 TI - The striatal cholinergic system in L-dopa-induced dyskinesias. AB - Cholinergic signaling plays a key role in regulating striatal function. The principal source of acetylcholine in the striatum is the cholinergic interneurons which, although low in number, densely arborize to modulate striatal neurotransmission. This modulation occurs via strategically positioned nicotinic and muscarinic acetylcholine receptors that influence striatal dopamine, GABA and other neurotransmitter release. Cholinergic interneurons integrate multiple striatal synaptic inputs and outputs to regulate motor activity under normal physiological conditions. Consequently, an imbalance between these systems is associated with basal ganglia disorders. Here, we provide an overview of how striatal cholinergic interneurons modulate striatal activity under normal and pathological conditions. Numerous studies show that nigrostriatal damage such as that occurs with Parkinson's disease affects cholinergic receptor-mediated striatal activity. This altered cholinergic signaling is an important contributor to Parkinson's disease as well as to the dyskinesias that develop with L-dopa therapy, the gold standard for treatment. Indeed, multiple preclinical studies show that cholinergic receptor drugs may be beneficial for the treatment of L dopa-induced dyskinesias. In this review, we discuss the evidence indicating that therapeutic modulation of the cholinergic system, particularly targeting of nicotinic cholinergic receptors, may offer a novel approach to manage this debilitating side effect of dopamine replacement therapy for Parkinson's disease. PMID- 29492665 TI - Feasibility of the clinical dynamic visual acuity test in typically developing preschoolers. AB - OBJECTIVES: To determine the feasibility of the dynamic visual acuity test (DVA) in children who are preschoolers. METHODS: Thirty-three preschoolers [3 years old (n = 11), 4 years old (n = 6), 5 years old (n = 8), and 6 years old (n = 8)], performed a static visual acuity test (SVA), a passive horizontal DVA (hDVA) at 1 and 2 Hz, and a DVA on treadmill at three age-specific walking speeds (slow/medium/high). The DVA scores, the difference between SVA and hDVA, were used to determine false positive results. RESULTS: The SVA was performed by 31/33 children, the hDVA and DVA on treadmill at slow and medium speed by 27/33 and the DVA on treadmill at high speed by 25/33. Except for one 5 years old, all drop outs were 3 years old. The hDVA at 2 Hz was administered in only six children because of difficulties with focusing on reading the symbols at this frequency. False positive results for the hDVA at 1 Hz were found in 3/27 children, all 3 years old, and 2/6 for the hDVA at 2 Hz. CONCLUSIONS: The DVA on treadmill seems useful for preschoolers from age 5, but this should be further investigated in children with underlying pathologies. PMID- 29492667 TI - Correction to: Microbial community differentiation between active and inactive sulfide chimneys of the Kolumbo submarine volcano, Hellenic Volcanic Arc. AB - In the original publication there is a mistake in the supplementary material. The correct supplementary material is provided in this correction article. PMID- 29492666 TI - Draft genome sequences of bacteria isolated from the Deschampsia antarctica phyllosphere. AB - Genome analyses are being used to characterize plant growth-promoting (PGP) bacteria living in different plant compartiments. In this context, we have recently isolated bacteria from the phyllosphere of an Antarctic plant (Deschampsia antarctica) showing ice recrystallization inhibition (IRI), an activity related to the presence of antifreeze proteins (AFPs). In this study, the draft genomes of six phyllospheric bacteria showing IRI activity were sequenced and annotated according to their functional gene categories. Genome sizes ranged from 5.6 to 6.3 Mbp, and based on sequence analysis of the 16S rRNA genes, five strains were identified as Pseudomonas and one as Janthinobacterium. Interestingly, most strains showed genes associated with PGP traits, such as nutrient uptake (ammonia assimilation, nitrogen fixing, phosphatases, and organic acid production), bioactive metabolites (indole acetic acid and 1 aminocyclopropane-1-carboxylate deaminase), and antimicrobial compounds (hydrogen cyanide and pyoverdine). In relation with IRI activity, a search of putative AFPs using current bioinformatic tools was also carried out. Despite that genes associated with reported AFPs were not found in these genomes, genes connected to ice-nucleation proteins (InaA) were found in all Pseudomonas strains, but not in the Janthinobacterium strain. PMID- 29492669 TI - Alport syndrome and pregnancy: a case series and literature review. AB - PURPOSE: To assess pregnancy outcome in women with Alport syndrome and the impact of pregnancy on the disease progression. METHODS: We describe one of the largest series of pregnancies in Alport syndrome. Seven pregnancies of six women were monitored by a multidisciplinary team of nephrologists and gynecologists. After delivery, patients were followed for at least 3 years. We compare our results with those in the literature. RESULTS: Pregnancy course was uneventful in the patient with isolated microscopic hematuria. In the other cases, all presenting mild proteinuria at conception, some complications occurred. Proteinuria worsened during the last trimester, reaching nephrotic ranges in five out of six pregnancies and was associated with fluid overload leading to hospitalizations and early delivery. The majority of the newborns had a low birth weight. The two patients with arterial hypertension at conception and twin pregnancy developed pre-eclampsia and renal function deterioration persisted after delivery. The one with pre-pregnancy renal dysfunction reached end-stage renal disease. In the other patients, in which renal function and blood pressure were and remained normal, proteinuria improved after delivery and no signs of disease progression were recorded at last observation. CONCLUSIONS: Our observations suggest that Alport syndrome should be considered a potential risk factor for pregnancy in proteinuric patients due to the development of pre-eclampsia, renal function deterioration, and/or full-blown nephrotic syndrome that results in anasarca, slowing of fetal growth and pre-term delivery. Thus, all women with Alport syndrome should receive pre-conceptional counseling and be kept in close follow up during pregnancy. PMID- 29492670 TI - Reply to letter by Dr. G. Corso. PMID- 29492668 TI - De novo transcriptomics reveal distinct phototransduction signaling components in the retina and skin of a color-changing vertebrate, the hogfish (Lachnolaimus maximus). AB - Across diverse taxa, an increasing number of photoreceptive systems are being discovered in tissues outside of the eye, such as in the skin. Dermal photoreception is believed to serve a variety of functions, including rapid color change via specialized cells called chromatophores. In vitro studies of this system among color-changing fish have suggested the use of a phototransduction signaling cascade that fundamentally differs from that of the retina. Thus, the goal of this study was to identify phototransduction genes and compare their expression in the retina and skin of a color-changing fish, the hogfish Lachnolaimus maximus. De novo transcriptomics revealed the expression of genes that may underlie distinct, yet complete phototransduction cascades in L. maximus retina and skin. In contrast to the five visual opsin genes and cGMP-dependent phototransduction components expressed in the retina of L. maximus, only a single short-wavelength sensitive opsin (SWS1) and putative cAMP-dependent phototransduction components were expressed in the skin. These data suggest a separate evolutionary history of phototransduction in the retina and skin of certain vertebrates and, for the first time, indicate an expression repertoire of genes that underlie a non-retinal phototransduction pathway in the skin of a color-changing fish. PMID- 29492671 TI - Ameliorative effects of taurine against diabetes: a review. AB - Diets in rats and humans have shown promising results. Taurine improved glucagon activity, promoted glycemic stability, modified glucose levels, successfully addressed hyperglycemia via advanced glycation end-product control, improved insulin secretion and had a beneficial effect on insulin resistance. Taurine treatment performed well against oxidative stress in brain, increased the secretion of required hormones and protected against neuropathy, retinopathy and nephropathy in diabetes compared with the control. Taurine has been observed to be effective in treatments against diabetic hepatotoxicity, vascular problems and heart injury in diabetes. Taurine was shown to be effective against oxidative stress. The mechanism of action of taurine cannot be explained by one pathway, as it has many effects. Several of the pathways are the advanced glycation end product pathway, PI3-kinase/AKT pathway and mitochondrial apoptosis pathway. The worldwide threat of diabetes underscores the urgent need for novel therapeutic measures against this disorder. Taurine (2-aminoethane sulfonic acid) is a natural compound that has been studied in diabetes and diabetes-induced complications. PMID- 29492672 TI - Enlargement of Frontal Sinus, Case Report. AB - INTRODUCTION: Frontal sinus enlargement has been classified into hypersinus, pneumosinus dilatans and pneumocele. CASE REPORT: A young male presented with aesthetic concerns regarding his forehead swelling. The patient had no functional disturbances. Radiographic assessment proved expansion of the frontal sinus with extreme thinning of the frontal bone. DISCUSSION: The causes of frontal sinus expansion have been listed along with a proposed management plan for each type. If blockage is suspected, functional endoscopic sinus surgery can alleviate the blockage. Open surgery is indicated when the element presents as an aesthetic concern. Obliteration of the sinus is indicated with NF obstruction. And reshaping of the anterior table is the mainstay to correct the enlargement. CONCLUSION: Frontal sinus enlargement regardless of the cause can be tackled using well known principles. We believe that every plastic surgeon should have a basic understanding of frontal sinus enlargement and its management. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29492673 TI - The first hour refill index: a promising marker of volume overload in children and young adults on chronic hemodialysis. AB - BACKGROUND: Volume overload is a known risk factor for cardiovascular complications in children on hemodialysis (HD), but a measurable index of volume overload is still lacking. METHODS: We propose a novel index of pre-HD volume overload based on blood volume (BV) monitoring, the first hour refill index (RI), calculated as the ratio between the ultrafiltration rate indexed for body weight during the first HD hour and the percent BV change at the first hour of the treatment. This parameter was retrospectively calculated in 121 sessions in 11 oligoanuric children and young adults on chronic HD, with median age 14.3 years (range 5.4-22.4), and its association with left-ventricular mass index, pre-HD blood pressure, and number of antihypertensive medications was evaluated. RESULTS: The median RI was 2.07 ml/kg/h/%. There was a significant correlation between RI and median LVMI (r 0.66, p = 0.028), which was 53.4 g/m2.7 (45.7-64) in patients with a median RI > 2, and 36.6 g/m2.7 (24.9-47) in those with a median RI < 2 ml/kg/h/% (p = 0.01). The number of antihypertensive drugs per patient was significantly higher in patients with a RI > 2 than in those with a RI < 2 ml/kg/h/% (three vs one per patient; p = 0.02) while blood pressure was not significantly different between the two groups. CONCLUSIONS: The ratio between the ultrafiltration rate per body weight and the BV change during the first hour of a HD session could be a promising index of refill capacity and pre HD volume overload in children and young adults on chronic HD. PMID- 29492674 TI - Urinary CD80: a biomarker for a favorable response to corticosteroids in minimal change disease. AB - Minimal Change Disease (MCD) is the most common type of nephrotic syndrome in children. The etiology has remained unknown, although it is commonly thought to be due to an unknown circulating factor that triggers podocyte dysfunction. To date, several changes in podocytes have been reported in MCD, of which one is the expression of CD80, also known as B7.1, which is a costimulatory molecule that is normally expressed on antigen -presenting cells. Some studies suggest that subjects with steroid-sensitive MCD may express CD80 in their podocytes during relapse and that this expression is associated with high urinary levels of CD80. Indeed, subjects with MCD in remission, or subjects with other glomerular diseases, such as focal segmental glomerulosclerosis, have substantially lower levels of urinary CD80 excretion. A recent study has now reported that high levels of urinary CD80 may be a sensitive marker for steroid-sensitivity and that their presence is also associated with long-term preservation of renal function. Thus, urinary CD80 is emerging as a potential biomarker for steroid responsiveness in children presenting with primary nephrotic syndrome. PMID- 29492675 TI - The role of inserted polymers in polymeric insulation materials: insights from QM/MD simulations. AB - In this study, we performed a quantum chemical molecular dynamics (QM/MD) simulation to investigate the space charge accumulation process in copolymers of polyethylene (PE) with ethylene acrylic acid (EAA), ethylene vinyl acetate (EVA), styrene-ethylene-butadiene-styrene (SEBS), and black carbon (BC). We predicted that BC, especially branched BC, would possess the highest electron affinity and is identified as the most promising filler in power cable insulation. Following incorporations of 0-4 high-energy electrons into the composites, branched BC exhibited the highest stability and almost all electrons were trapped by it. Therefore, PE was protected efficiently and BC can be considered as an efficient filler for high voltage cables and an inhibitor of tree formation. On the contrary, although EAA, EVA, and SEBS can trap high-energy electrons, the latter can be supersaturated in composites of EAA, EVA, and SEBS with PE. The inserted polymers was unavoidably destroyed following C-H and C-O bond cleavage, which results from the interactions and charge transfer between PE and inserted polymers. The content effects of -COOH, benzene, and -OCOCH3 groups on the electron trapping, mobility and stability of PE were also investigated systematically. We hope this knowledge gained from this work will be helpful in understanding the role of inserted polymers and the growth mechanisms of electrical treeing in high voltage cable insulation. PMID- 29492676 TI - Primary Osteosarcoma in the Elderly Revisited: Current Concepts in Diagnosis and Treatment. AB - PURPOSE OF REVIEW: Osteosarcoma is mostly seen in bones of children and young adults. When it occurs in older persons, the tumor is considered secondary usually complicating Paget disease or irradiated bone. However, there is a second incidence peak of primary osteosarcoma later in life when these tumors occur de novo. This article describes the clinical, imaging, and treatment of POS in older patients, including demographic data of patients from our institution. FINDINGS: We present our experience with 920 cases of osteosarcoma that were seen between 1984 and 2003 at the University of Texas MD Anderson Cancer Center in Houston, TX, USA. Among the 868 primary osteosarcoma of bones, there were 100 (11.52%), which comprised 69% of the tumors in patients over the age of 50 years. Older patients with primary osteosarcoma tend to have relatively more common axial skeleton involvement, have more distant disease, and are difficult to treat because of concomitant comorbidities. Despite that, most adult patients treated with chemotherapy have shown good results with longer disease-free survival. A lytic bone lesion seen in radiographs of elderly patients should include primary osteosarcoma among differential diagnoses. Radical surgery and chemotherapy seem to ensure long-term disease-free survival in most cases. The elderly patients with POS in pelvis, spine, and upper extremities and those with distant disease (metastases) have worse prognosis. PMID- 29492678 TI - Computational modeling of the effective Young's modulus values of fullerene molecules: a combined molecular dynamics simulation and continuum shell model. AB - Estimating the Young's modulus of a structure in the nanometer size range is a difficult task. The reliable determination of this parameter is, however, important in both basic and applied research. In this study, by combining molecular dynamics (MD) simulations and continuum shell theory, we designed a new approach to determining the Young's modulus values of different spherical fullerenes. The results indicate that the Young's modulus values of fullerene molecules decrease nonlinearly with increasing molecule size and understandably tend to the Young's modulus of an ideal flat graphene sheet at large molecular radii. To the best of our knowledge, this is first time that a combined atomistic continuum method which can predict the Young's modulus values of fullerene molecules with high precision has been reported. PMID- 29492677 TI - Contemporary Treatment Approaches to Sinonasal Mucosal Melanoma. AB - Sinonasal mucosal melanoma (SNMM) is a rare oncological entity that comprises most head and neck mucosal melanomas. SNMM has distinctive genetic background, different from cutaneous melanoma. Survival outcomes among SNMM patients are poor; while there is no clear consensus on the optimal management of SNMM, the primary treatment modality is generally considered to be wide surgical excision, and radiation therapy (RT) is often used in the postoperative adjuvant setting to improve locoregional control. Systemic therapies have demonstrated little or no survival benefit, and most SNMM patients die of distant metastatic disease. Owing to the rarity of the disease, the literature describing treatment approaches for SNMM is lacking and largely limited to isolated case reports and retrospective series. Here, we describe contemporary diagnostic and therapeutic approaches to SNMM based on the most recent molecular and outcome data. PMID- 29492679 TI - Archaeal community compositions in tilapia pond systems and their influencing factors. AB - Archaea, like the bacterial communities are gradually being realized as key players in the biogeochemical progress of water ecosystems. In this study, tilapia aquaculture ponds were used for an in-depth understanding of archaeal community compositions in water and surface sediment. Some of the main functions, as well as the communities' response patterns, to time variations, pond differences and some physio-chemical parameters were investigated. The results revealed the dominant phylum in both the water and surface sediment, as Euryarchaeota, while, the most abundant classes were: Halobacteria and Methanomicrobia respectively. Significant differences in the archaeal community compositions in the water and surface sediment, were observed in the early stages of cultivation, which became minimal at the later stage of the GIFT tilapia cultivation. Additionally to the differences in the most abundant classes, more OTUs were observed in water samples than in surface sediment samples. The methane generation could be attributed to the large proportion of methanogens found in both pond water and in the surface sediment. Furthermore, the archaeal community compositions in water and the surface sediment were shaped mainly by temporal variations and pond differences respectively. In the pond water, the archaeal community compositions were highly co-related to the concentration changes of ammonia, sulfate and total nitrogen; while in the surface sediment, the correlation to the content changes was significant in total phosphorus. The archaeal community compositions in surface sediment should be considered as an indicator for future environmental capacity studies in aquaculture. PMID- 29492680 TI - Formulation Stabilization and Disaggregation of Bevacizumab, Ranibizumab and Aflibercept in Dilute Solutions. AB - PURPOSE: Studies were conducted to investigate dilute solutions of the monoclonal antibody (mAb) bevacizumab, mAb fragment ranibizumab and fusion protein aflibercept, develop common procedures for formulation of low concentration mAbs and identify a stabilizing formulation for anti-VEGF mAbs for use in in vitro permeation studies. METHODS: Excipient substitutions were screened. The most stabilizing formulation was chosen. Standard dilutions of bevacizumab, ranibizumab and aflibercept were prepared in PBS, manufacturer's formulation, and the new formulation. Analysis was by SE-HPLC and ELISA. Stability, disaggregation and pre-exposure tests were studied. RESULTS: When Avastin, Lucentis and Eylea are diluted in PBS or manufacturer's formulation, there is a 40-50% loss of monomer concentration and drug activity. A formulation containing 0.3% NaCl, 7.5% trehalose, 10 mM arginine and 0.04% Tween 80 at a pH of 6.78 stabilized the mAbs and minimized the drug loss. The formulation also disaggregates mAb aggregation while preserving the activity. Degassing the formulation increases recovery. CONCLUSIONS: We developed a novel formulation that significantly stabilizes mAbs under unfavorable conditions such as low concentration or body temperature. The formulation allows for tissue permeation experimentation. The formulation also exhibits a disaggregating effect on mAbs, which can be applied to the manufacture/packaging of mAbs and bioassay reagents. PMID- 29492681 TI - Clinical Management of Episodic Memory Changes in Dementia. AB - PURPOSE OF REVIEW: The purpose of this review was to discuss therapeutic options available for the treatment of memory difficulties in dementia. RECENT FINDINGS: Because of the lack of progress in the availability of new medications, there has been an increased interest in focusing on non-pharmacological means to management cognitive symptoms related to dementia. The clinical management of memory loss should focus both on pharmacological and non-pharmacological approaches. Treatment with medications should usually begin with a cholinesterase inhibitor and then followed by addition of memantine if there is a decline. In addition to medication management, emphasis should be placed on the importance of maintaining a healthy lifestyle that encompasses physical activities, cognitive stimulation, and a healthy diet. PMID- 29492682 TI - Updates on Primary Central Nervous System Lymphoma. AB - PURPOSE OF REVIEW: Primary central nervous system lymphoma (PCNSL) is an aggressive malignancy confined to the brain, spinal cord, leptomeninges, and eyes. Due to its rarity, there is a paucity of randomized trials and a varied approach to its management in the oncologic community. This review summarizes recent literature guiding current clinical practice. RECENT FINDINGS: The presentation, work up, and management of PCNSL are discussed. Induction therapy incorporates a methotrexate-based chemotherapy regimen and is generally followed by a consolidation regimen including high dose chemotherapy (with or without autologous stem cell rescue). Whole brain radiation therapy (WBRT) is a potential additional consolidation strategy. Management of relapsed and refractory disease poses a special challenge due to poor outcomes. Immunotherapy and targeted treatments are promising novel strategies for recurrent/refractory patients. Currently, there is little consensus in the management of PCNSL. Treatment recommendations should be tailored to the individual patient, with consideration for risk of neurotoxicity. New, exciting strategies are in development and when feasible, enrollment in a clinical trial should be considered. PMID- 29492683 TI - The Cure of Chronic Myeloid Leukemia: Are We There Yet? AB - PURPOSE OF REVIEW: A large number of chronic myeloid leukemia (CML) patients receiving tyrosine kinase inhibitors (TKIs) can now enjoy a deep molecular control of the disease and the life span could be approaching that of normal population. The purpose of the review is to evaluate current evidence and if we can talk of a cure. RECENT FINDINGS: The revolution in the treatment of CML was apparent since the exquisite efficacy of imatinib mesylate, a tyrosine kinase inhibitor, was proven and received approval for newly diagnosed cases in 2001. Subsequent development of second-generation TKIs, nilotinib and dasatinib, has increased our armamentarium. These TKIs, because of their safety and efficacy, are now offered as first-line therapy, thus relegating use of allogeneic transplant to the second line or beyond. It has also been possible to stop TKIs in selected subsets in whom leukemia burden became undetectable and ~ 40% of them remain drug-free for a number of years-treatment-free remission (TFR). Nevertheless, much work needs to be done to eradicate leukemia stem cells as current TKIs appear unable to eradicate leukemia stem cells (LSC). Effective treatment of more advanced phase CML remains elusive. Further efforts to develop newer molecules targeting BCR-ABL and beyond must be continued. Although TKIs have revolutionized treatment of chronic phase CML, longer follow-up is necessary to realize their curative potential. Equally important is to explore newer targets and development of more potent small molecules for eradication of leukemia clone in all patients. PMID- 29492684 TI - Non-incisional pleurectomy-decortication for malignant pleural mesothelioma. AB - Pleurectomy-decortication (P/D) is lung-sparing surgery with curative intent for malignant pleural mesothelioma (MPM). Visceral pleurectomy is the most challenging step in this procedure. At the beginning of pleurectomy, a sharp pleural incision through the tumor is usually made to create the dissection plane between the visceral pleura and the lung parenchyma, which may cause the spread of tumor cells into the operation field. Here, we describe a sophisticated surgical technique of P/D without any pleural incision ("non-incisional P/D") to achieve en bloc removal of the entire pleura and tumor, which may improve postoperative survival by preventing tumor spread. PMID- 29492686 TI - Combining an In Vitro Kinetic Model with a Physiologically-Based Pharmacokinetic Model to Assess the Potential In Vivo Fate of Polyvinyl Pyrrolidone-Vinyl Acetate Copolymers. AB - PURPOSE: To understand hydrolysis and alcoholysis of polyvinylpyrrolidone-co vinylacetate (PVPVA) during formulation and storage, elucidate the reaction mechanism, establish an intrinsic kinetic model, and apply this model coupled with GastroPlusTM modeling to predict the amount of PVPVA degradation in vivo. METHODS: The experimental approach includes the detection of the polymer reaction by solution nuclear magnetic resonance (NMR) and the measurement of reaction product concentration via gas chromatography (GC). The theoretical approach includes the establishment of the intrinsic kinetic model and the application of GastroPlusTM to predict the degree of PVPVA degradation. RESULTS: The kinetic model established is a first order reaction between PVPVA and 2-propanol (IPA) or water under an acidic condition. The application of this kinetic model shows that between 1.7 and 6.8 mg of degradant is formed in the GI tract for a 850 mg dose of PVPVA. CONCLUSIONS: The results from this application provide valuable input for process development and the risk analysis of the degradation of PVPVA. PMID- 29492685 TI - Association of textile industry effluent with mutagenicity and its toxic health implications upon acute and sub-chronic exposure. AB - Complex industrial discharges pose certain risks to the ecosystem. This study was aimed at identifying acute and sub-chronic toxicological effects of the textile industry wastewater. The textile wastewater was evaluated for the metals and organic pollutants by atomic absorption spectrophotometer and GC-MS respectively. In vitro genotoxicity and mutagenicity were assessed by Comet assay in peripheral lymphocytes isolated from Ovis aries and Ames test in Salmonella typhimurium strains TA-100 and 102 respectively. Physiological and behavioral changes along with systemic toxicity were determined in Rattus norvegicus albinus following acute and sub-chronic exposure. High amount of heavy metals such as Cr, Pb, Hg, As, and Cd were detected in textile wastewater. Organic pollutants such as 25 deacetoxy cucurbitacin-b, E-14-Hexadecenal, 11-Tricosene, and phthalates were also found. In vitro genotoxicity assessment in lymphocytes showed statistically significant DNA damaging potential of textile wastewater. Textile wastewater also showed significantly higher (p? 0.05) mutagenic potential in Salmonella TA-100 and TA-102 strains than sodium azide and 2-amino anthracycline. Acute exposure of textile wastewater to Rattus norvegicus was associated with several physiological changes and behavioral symptoms. Sub-chronic exposure of textile wastewater in Rattus norvegicus instigated the degeneration and necrosis of epithelial cells in renal tubules, hydropic degeneration and necrosis of hepatocytes, peri bronchiolar infiltration and emphysema of the alveoli, and the degradation of myocardial cells. This study concludes that the textile wastewater may cause genotoxicity and mutagenicity, result in physiological and behavioral changes upon acute exposure, and inflict various pathological lesions upon sub-chronic exposure. PMID- 29492687 TI - Comparison of conventional color fundus photography and multicolor imaging in choroidal or retinal lesions. AB - PURPOSE: Our purpose was to compare the characteristics of the retinal and choroidal lesions including choroidal nevus, choroidal melanoma and congenital hypertrophy of the retina pigment epithelium using conventional color fundus photography (CFP) and multicolor imaging (MCI). METHODS: The paired images of patients with retinal or choroidal lesions were assessed for the visibility of lesion's border, halo and drusen using a grading scale (0-2). The area of the lesion was measured on both imaging modalities. The same grading was also done on the individual color channels of MCI for a further evaluation. RESULTS: Thirty three eyes of 33 patients were included. There were no significant differences in the mean border, drusen and halo visibility scores between the two imaging modalities (p = 0.12, p = 0.70, p = 0.35). However, the mean area of the lesion was significantly smaller on MCI than that on CFP (14.9+/-3.3 versus 18.7+/-3.4 mm2, p = 0.01). CONCLUSION: The appearance of choroidal and/ or retinal lesions on MCI may be different than that on CFP. Though MCI can provide similar information with CFP for the features of retinal and/ or choroidal lesions including border, halo and drusen; the infrared light reflection on MCI underestimates the extent of the choroidal lesion by 33%. PMID- 29492688 TI - Effect of prolonged supine position on the intraocular pressure in patients with obstructive sleep apnea syndrome. AB - PURPOSE: Obstructive sleep apnea syndrome (OSAS) patients are at risk of glaucoma but the risk increases if they have higher intraocular pressure (IOP) while sleeping. We aim to evaluate the postural effect of upright and prolong supine positions on IOP in these patients. METHODS: This is a cross-sectional study involving 27 patients with symptoms of OSAS seen at a tertiary institutional center and 25 normal controls performed between June 2015 and June 2016. All patients and controls underwent a polysomnography (PSG) test and were diagnosed with OSAS based on the apnea-hypopnea index (AHI). Patients are those with OSAS symptoms and had AHI > 5, whereas controls are staffs from the ophthalmology clinic without clinical criteria for OSAS and had PSG result of AHI < 5. IOP was measured 10 min after sitting, immediately and at 30 min on supine position and immediately after resuming sitting position. The main outcome measures were the changes in mean IOP in different positions. RESULTS: The increase in mean IOP when changing from sitting to supine position was significantly higher in OSAS patients in both the right eye (RE) (1.01 +/- 1.14 vs 0.44 +/- 0.41 mmHg, p = 0.033) and left eye (LE) (1.20 +/- 1.26 vs 0.48 +/- 0.62 mmHg, p = 0.044). After 30 min supine, the IOP in OSAS patients showed a further increase in IOP than controls (RE 1.20 +/- 1.79 vs 0.12 +/- 0.66 mmHg, p = 0.001 and LE 0.59 +/- 2.00 vs 0.15 +/- 0.78 mmHg, p = 0.246). Higher IOP when sitting post supine is associated with higher IOP on supine position. CONCLUSION: IOP increase is significantly more in OSAS patients on prolong supine position. PMID- 29492689 TI - Effects of intravitreal injection of ranibizumab on choroidal structure and blood flow in eyes with diabetic macular edema. AB - PURPOSE: To determine the effects of an intravitreal injection of ranibizumab (IVR) on the choroidal structure and blood flow in eyes with diabetic macular edema (DME). METHODS: Twenty-eight consecutive patients with DME who received an IVR and 20 non-diabetic, age-matched controls were followed for 1 month. The eyes with DME were divided into those with prior panretinal photocoagulation (PRP, n = 16) and those without prior PRP (no-PRP, n = 12). The enhanced depth imaging optical coherence tomography (EDI-OCT) scans and Niblack's image binarization were performed to determine the choroidal structure. The choroidal blood flow was determined by laser speckle flowgraphy. RESULTS: The subfoveal choroidal thickness at the baseline was significantly thicker in the no-PRP group than in the PRP-treated group. After IVR, the best-corrected visual acuity (BCVA) and central retinal thickness in eyes with DME were significantly improved compared to the baseline values. There were significant differences in the choroidal thickness, total choroidal area, and choroidal vascularity index between the groups after IVR. Choroidal vascular index and choroidal blood flow were significantly reduced only in the no-PRP group and not in the PRP-treated group. In addition, the correlation between the central retinal thickness and the choroidal blood flow was significant in the no-PRP group (r = 0.47, P < 0.05). CONCLUSIONS: A single IVR will reduce the central retinal thickness and improve the BCVA in eyes with DME in both the no-PRP and PRP-treated group. IVR affected the choroidal vasculature and blood flow significantly, and a significant correlation was found between the central retinal thickness and the choroidal blood flow in eyes without PRP. PMID- 29492690 TI - Both plant genotype and herbivory shape aspen endophyte communities. AB - Salicinoid phenolic glycosides are common defence substances in salicaceous trees and specialist leaf beetles use these compounds for their own defence against predators. Salicinoids vary qualitatively and qualitatively in aspen (Populus tremula) and this variation has a genetic basis. The foliar endophyte mycobiome is plentiful and we hypothesised that it is related to plant genotype, potentially mediated by salicinoid composition, and that interactions with the leaf beetle Chrysomela tremula may alter this relationship. We studied these three-way interactions in controlled greenhouse experiments. Endophytic fungi were isolated from sterilised leaf tissues with and without beetle damage, and from beetles. We confirmed that endophyte composition was influenced by host genotype. Beetle activity added generalist morphs to the mycobiome that overrode the initial host association. Yeast-like genera (Cryptococcus and Rhodotorula) were isolated only from beetle-damaged tissues and from beetles, whereas fast growing filamentous fungi dominated beetle-free control plants. Competition experiments between filamentous fungi of plant origin and beetle-related yeasts suggested interaction of both stimulating and inhibiting modes of action amongst the fungi. As a result, we detected examples of amensalism, commensalism, parasitism and competition between the morphs tested, but we found no evidence of mutualism, and consequently no co-evolutionary relationship could be demonstrated, between yeasts carried by beetles, host genotype and associated filamentous morphs. Endophyte studies are method-dependent and high-throughput sequencing technology best define the fungal mycobiome, culturing however continues to be a cheap way to provide fundamental ecological insights and it is also required for experimental studies. PMID- 29492691 TI - Domestic honeybees affect the performance of pre-dispersal seed predators in an alpine meadow. AB - Flowering plants interact simultaneously with mutualistic pollinators and antagonistic herbivores such that plant-mediated interactions between pollinators and herbivores must exist. Although the effects of herbivores on pollinator behavior have been investigated extensively, the effect of pollinators on herbivore performance has seldom been explored. We hypothesized that insect pollinators could improve the survival and growth of pre-dispersal seed predators by increasing seed production. We tested this hypothesis along three transects radiating from well-established apiaries in an alpine meadow by supplementing pollination in sites close to and distant from apiaries and subsequently examining seed production of the dominant nectariferous plant species Saussurea nigrescens (Asteraceae) and the performance of three dominant pre-dispersal seed predators (tephritid fly species). Pollen supplementation (1) significantly increased seed set and mass of developed seed per capitulum (i.e., flowerhead) in the distant but not the close sites, (2) did not change the survival and growth rates of the smaller-bodied species (Tephritis femoralis and Campiglossa nigricauda) at either site, but (3) improved the performance of the larger-bodied seed predator (Terellia megalopyge) at distant sites but not close sites. In addition, the larger-bodied tephritid fly showed higher infestation rates and relative abundance in the close sites than in the distant sites, whereas the smaller-bodied species had lower relative abundances in the close sites and similar infestation rates in both site types. These observations demonstrate contrasting effects of plant mutualists on the performance of antagonists with potential consequences for population sizes of insect herbivores. PMID- 29492692 TI - The interacting effects of forestry and climate change on the demography of a group-living bird population. AB - Anthropogenic degradation of natural habitats is a global driver of wildlife population declines. Local population responses to such environmental perturbations are generally well understood, but in socially structured populations, interactions between environmental and social factors may influence population responses. Thus, understanding how habitat degradation affects the dynamics of these populations requires simultaneous consideration of social and environmental mechanisms underlying demographic responses. Here we investigated the effect of habitat degradation through commercial forestry on spatiotemporal dynamics of a group-living bird, the Siberian jay, Perisoreus infaustus, in boreal forests of northern Sweden. We assessed the interacting effects of forestry, climate and population density on stage-specific, seasonal life-history rates and population dynamics, using long-term, individual-based demographic data from 70 territories in natural and managed forests. Stage-specific survival and reproductive rates, and consequently population growth, were lower in managed forests than in natural forests. Population growth was most sensitive to breeder survival and was more sensitive to early dispersing juveniles than those delaying dispersal. Forestry decreased population growth in managed forests by reducing reproductive success and breeder survival. Increased snow depth improved winter survival, and warmer spring temperatures enhanced reproductive success, particularly in natural forests. Population growth was stable in natural forests but it was declining in managed forests, and this difference accelerated under forecasted climate scenarios. Thus, climatic change could exacerbate the rate of forestry-induced population decline through reduced snow cover in our study species, and in other species with similar life-history characteristics and habitat requirements. PMID- 29492693 TI - Exotic plant species receive adequate pollinator service despite variable integration into plant-pollinator networks. AB - Both exotic and native plant species rely on insect pollinators for reproductive success, and yet few studies have evaluated whether and how exotic plant species receive services from native pollinators for successful reproduction in their introduced range. Plant species are expected to successfully reproduce in their exotic range if they have low reliance on animal pollinators or if they successfully integrate themselves into resident plant-pollinator networks. Here, we quantify the breeding system, network integration, and pollen limitation for ten focal exotic plant species in North America. Most exotic plant species relied on animal pollinators for reproduction, and these species varied in their network integration. However, plant reproduction was limited by pollen receipt for only one plant species. Our results demonstrate that even poorly integrated exotic plant species can still have high pollination service and high reproductive success. The comprehensive framework considered here provides a method to consider the contribution of plant breeding systems and the pollinator community to pollen limitation, and can be applied to future studies to provide a more synthetic understanding of the factors that determine reproductive success of exotic plant species. PMID- 29492695 TI - 3D Interconnected V6O13 Nanosheets Grown on Carbonized Textile via a Seed Assisted Hydrothermal Process as High-Performance Flexible Cathodes for Lithium Ion Batteries. AB - Three-dimensional (3D) free-standing nanostructured materials have been proven to be one of the most promising electrodes for energy storage due to their enhanced electrochemical performance. And they are also widely studied for the wearable energy storage systems. In this work, interconnected V6O13 nanosheets were grown on the flexible carbonized textile (c-textile) via a seed-assisted hydrothermal method to form a 3D free-standing electrode for lithium-ion batteries (LIBs). The electrode exhibited a specific capacity of 170 mA h g-1 at a specific current of 300 mA g-1. With carbon nanotube (CNT) coating, its specific capacities further increased 12-40% at the various current rates. It could retain a reversible capacity of 130 mA h g-1, 74% of the initial capacity after 300 cycles at the specific current of 300 mA g-1. It outperformed most of the mixed-valence vanadium oxides. The improved electrochemical performance was ascribed to the synergistic effect of the 3D nanostructure of V6O13 for feasible Li+ diffusion and transport and highly conductive hierarchical conductive network formed by CNT and carbon fiber in c-textile. PMID- 29492694 TI - The inhibition of invasion of human melanoma cells through N-cadherin knock-down. AB - N-cadherin seems to promote cell migration and invasion in many types of cancers. The object of this study is recognition of the possible role of N-cadherin and selected downstream protein kinases: PI3K, ERK1/2, and mTOR in cell invasion in malignant melanoma. Melanoma cells were transfected with the small interfering RNA (siRNA) that targets human N-cadherin gene (CDH2). Inhibitors LY294002 (PI3K), U0126 (ERK1/2), and everolimus (mTOR) were used to inhibit selected kinases of signalling pathways. In vitro cell invasion was studied using Matrigel and an analysis of matrix metalloproteinases MMP-2 and MMP-9 activity by gelatinase zymogram assay. Treatment of melanoma cell with either siRNA against N cadherin or protein kinase inhibitors led to significantly decreased MMPs expression and activity, as well as diminished invasion. Both the current and the former results suggest that activation of PI3/AKT, mTOR, and ERK kinase, following N-cadherin expression, contributes not only to increased proliferation but also invasive potential of melanoma cells. The results also indicate that N cadherin, as well as the studied kinases, should be considered as a potential target in melanoma therapy. PMID- 29492696 TI - The 2014 updated version of the Confusion Assessment Method for the Intensive Care Unit compared to the 5th version of the Diagnostic and Statistical Manual of Mental Disorders and other current methods used by intensivists. AB - BACKGROUND: One third of patients admitted to an intensive care unit (ICU) will develop delirium. However, delirium is under-recognized by bedside clinicians without the use of delirium screening tools, such as the Intensive Care Delirium Screening Checklist (ICDSC) or the Confusion Assessment Method for the ICU (CAM ICU). The CAM-ICU was updated in 2014 to improve its use by clinicians throughout the world. It has never been validated compared to the new reference standard, the Diagnostic and Statistical Manual of Mental Disorders 5th version (DSM-5). METHODS: We made a prospective psychometric study in a 16-bed medical-surgical ICU of a French academic hospital, to measure the diagnostic performance of the 2014 updated CAM-ICU compared to the DSM-5 as the reference standard. We included consecutive adult patients with a Richmond Agitation Sedation Scale (RASS) >= -3, without preexisting cognitive disorders, psychosis or cerebral injury. Delirium was independently assessed by neuropsychological experts using an operationalized approach to DSM-5, by investigators using the CAM-ICU and the ICDSC, by bedside clinicians and by ICU patients. The sensitivity, specificity, positive and negative predictive values were calculated considering neuropsychologist DSM-5 assessments as the reference standard (primary endpoint). CAM-ICU inter-observer agreement, as well as that between delirium diagnosis methods and the reference standard, was summarized using kappa coefficients, which were subsequently compared using the Z-test. RESULTS: Delirium was diagnosed by experts in 38% of the 108 patients included for analysis. The CAM-ICU had a sensitivity of 83%, a specificity of 100%, a positive predictive value of 100% and a negative predictive value of 91%. Compared to the reference standard, the CAM-ICU had a significantly (p < 0.05) higher agreement (kappa = 0.86 +/- 0.05) than the physicians,' residents' and nurses' diagnoses (kappa = 0.65 +/- 0.09; 0.63 +/- 0.09; 0.61 +/- 0.09, respectively), as well as the patient's own impression of feeling delirious (kappa = 0.02 +/- 0.11). Differences between the ICDSC (kappa = 0.69 +/- 0.07) and CAM-ICU were not significant (p = 0.054). The CAM-ICU demonstrated a high reliability for inter-observer agreement (kappa = 0.87 +/- 0.06). CONCLUSIONS: The 2014 updated version of the CAM-ICU is valid according to DSM-5 criteria and reliable regarding inter-observer agreement in a research setting. Delirium remains under-recognized by bedside clinicians. PMID- 29492698 TI - Synthesis and Characterization of Modified BiOCl and Their Application in Adsorption of Low-Concentration Dyes from Aqueous Solution. AB - The synthesis and characterization of BiOCl and Fe3+-grafted BiOCl (Fe/BiOCl) is reported that are developed as efficient adsorbents for the removal of cationic dyes rhodamine B (RhB) and methylene blue (MB) as well as anionic dyes methyl orange (MO) and acid orange (AO) from aqueous solutions with low concentration of 0.01~0.04 mmol/L. Characterizations by various techniques indicate that Fe3+ grafting induced more open porous structure and higher specific surface area. Both BiOCl and Fe/BiOCl with negatively charged surfaces showed excellent adsorption efficiency toward cationic dyes, which could sharply reach 99.6 and nearly 100% within 3 min on BiOCl and 97.0 and 98.0% within 10 min on Fe/BiOCl for removing RhB and MB, respectively. However, Fe/BiOCl showed higher adsorption capacity than BiOCl toward ionic dyes. The influence of initial dye concentration, temperature, and pH value on the adsorption capacity is comprehensively studied. The adsorption process of RhB conforms to Langmuir adsorption isotherm and pseudo-second-order kinetic feature. The excellent adsorption capacities of as-prepared adsorbents toward cationic dyes are rationalized on the basis of electrostatic attraction as well as open porous structure and high specific surface area. In comparison with Fe/BiOCl, BiOCl displays higher selective efficiency toward cationic dyes in mixed dye solutions. PMID- 29492697 TI - Gene editing by CRISPR/Cas9 in the obligatory outcrossing Medicago sativa. AB - MAIN CONCLUSION: The CRISPR/Cas9 technique was successfully used to edit the genome of the obligatory outcrossing plant species Medicago sativa L. (alfalfa). RNA-guided genome engineering using Clustered Regularly Interspersed Short Palindromic Repeats (CRISPR)/Cas9 technology enables a variety of applications in plants. Successful application and validation of the CRISPR technique in a multiplex genome, such as that of M. sativa (alfalfa) will ultimately lead to major advances in the improvement of this crop. We used CRISPR/Cas9 technique to mutate squamosa promoter binding protein like 9 (SPL9) gene in alfalfa. Because of the complex features of the alfalfa genome, we first used droplet digital PCR (ddPCR) for high-throughput screening of large populations of CRISPR-modified plants. Based on the results of genome editing rates obtained from the ddPCR screening, plants with relatively high rates were subjected to further analysis by restriction enzyme digestion/PCR amplification analyses. PCR products encompassing the respective small guided RNA target locus were then sub-cloned and sequenced to verify genome editing. In summary, we successfully applied the CRISPR/Cas9 technique to edit the SPL9 gene in a multiplex genome, providing some insights into opportunities to apply this technology in future alfalfa breeding. The overall efficiency in the polyploid alfalfa genome was lower compared to other less-complex plant genomes. Further refinement of the CRISPR technology system will thus be required for more efficient genome editing in this plant. PMID- 29492699 TI - Isolated iliopsoas paresis due to traumatic cortical hemorrhage. PMID- 29492700 TI - Circulating antithyroid antibodies contribute to the decrease of glomerular filtration rate in lithium-treated patients: a longitudinal study. AB - BACKGROUND: Concerns about the adverse effects of long-term treatment with lithium include reduced renal function. In the present study, we examined comorbidities which may be associated with chronic kidney disease in a cohort of patients treated with lithium for up to 41 years. METHODS: We studied 394 patients who were treated with lithium for >= 5 years. The potential role of comorbidities (diabetes, concurrent antihypertensive medication, treatment with L thyroxine, and presence of antithyroid peroxidase/microsomes, anti-thyroglobulin, and/or anti-thyrotropin-receptor antibodies) was analysed. We focused on the categories of patients with an estimated glomerular filtration rate (eGFR) lower than 60 or 45 mL/min/1.73 m2 as calculated from serum creatinine according to the Modification of Diet in Renal Disease Study Group. We applied multivariate regression analysis and Cox survival analysis to study the effects exerted by sex, age, duration of lithium treatment, and comorbidities using eGFR categories as the dependent variable. Kaplan-Meier curves were generated to measure the time to decline to an eGFR lower than 45 mL/min/1.73 m2 in patients with positive or negative thyroid antibodies. RESULTS: Age was associated with a decline to an eGFR lower than 60 mL/min/1.73 m2 after controlling for sex, duration of lithium treatment, and comorbidities. Circulating thyroid antibodies were associated with a decline to an eGFR lower than 45 mL/min/1.73 m2. CONCLUSIONS: The present study is the first to suggest a potential role of circulating thyroid antibodies in the severe decline of eGFR in lithium-treated patients. PMID- 29492701 TI - Correction to: Blood platelets and sepsis pathophysiology: A new therapeutic prospect in critically ill patients? AB - Upon publication of the original article [1], it was noticed that the title was incorrect. Instead of 'critical', it should read 'critically', and therefore, the correct title should be. PMID- 29492702 TI - Correction to: Prognostic impact of baseline glucose levels in acute myocardial infarction complicated by cardiogenic shock-a substudy of the IABP-SHOCK II trial. AB - The title of this article was rendered incorrectly; the correct title is as follows. PMID- 29492703 TI - Safety and efficacy of persistent atrial fibrillation ablation using the second generation cryoballoon. AB - BACKGROUND: The second-generation cryoballoon (CB) is increasingly used for treatment of persistent atrial fibrillation (AF). Data regarding the clinical outcome and mechanism of arrhythmia recurrence following persistent AF ablation using CB is sparse. In this study, we aimed to assess the efficacy of CB and mechanisms of atrial tachyarrhythmia (ATA) recurrence in patients with persistent AF. METHODS AND RESULTS: A total of 133 patients (66 +/- 10 years, 60% male) with symptomatic persistent AF, who were scheduled for PVI using the second-generation CB were enrolled. Follow-up included 24 h Holter recording at 3, 6 and 12 months. Any documented episode of ATA lasting more than 30 s was considered as a recurrent arrhythmic event. All targeted veins were isolated (100%). Phrenic nerve palsy with recovery during follow-up occurred in six patients (4.5%), no patient experienced tamponade or a cerebrovascular event. During 12.6 +/- 5.4 months of follow-up, 89/133 (67%) patients were free of ATA recurrences. Multivariable analysis revealed recurrence in the blanking period (HR 11.46, 0.95 CI 3.92-33.49, p < 0.001), presence of cardiomyopathy (HR 2.75, 0.95 CI 1.09 6.96, p = 0.032) and PV abnormality (HR 3.56, 0.95 CI 1.21-10.43, p = 0.021) as predictors for late recurrence. CONCLUSION: In patients with persistent AF, second-generation cryoballoon use is associated with an excellent safety profile and favorable outcomes. Arrhythmia recurrence during the blanking period, presence of cardiomyopathy and PV abnormality were independent predictors of long term AF recurrence. PMID- 29492704 TI - Enhanced 2-keto-L-gulonic acid production by applying L-sorbose-tolerant helper strain in the co-culture system. AB - 2-Keto-L-gulonic acid (the precursor of vitamin C) is bio-converted from L sorbose by mixed fermentation of Ketogulonicigenium vulgare and a helper strain. The helper strain promotes the conversion of 2-KLG by enhancing the growth of K. vulgare, but its growth is greatly inhibited by high concentration of L-sorbose, which consequently influence the 2-KLG production. The aim of this study is to obtain L-sorbose-tolerant helper strain (LHS) by experimental evolution for reduced L-sorbose-inhibition-effect and enhanced 2-KLG productivity in high concentration of L-sorbose. After three steps screening by using our devised screening strategy, three strains (i.e., Bc 21, Bc 47, Bc 50) with high resistance to high concentration of L-sorbose were obtained. The fermentation tests by co-culturing Bc 21 and K. vulgare 418 showed that the production of 2 KLG was increased by 17.9% in 11% L-sorbose medium than that in 8% after 55 h of fermentation and the conversion rate was 89.5%. The results suggested that Bc 21 could be an ideal helper strain for 2-KLG production under high concentration of L-sorbose and demonstrated the feasibility of using experimental evolution to breed LHS for vitamin C production. PMID- 29492705 TI - Advances and Barriers for Clinical Neuroimaging in Late-Life Mood and Anxiety Disorders. AB - PURPOSE OF REVIEW: Mood and anxiety disorders are very commonly experienced by older adults and are becoming a growing concern due to the rapidly aging global population. Recent advances in neuroimaging may help in improving outcomes in late-life mood and anxiety disorders. The elucidation of mechanisms contributing to late-life mental health disorders may ultimately lead to the identification of novel therapeutic interventions. Alternatively, clinically validated imaging biomarkers may allow for the prediction of treatment response and identification of better therapeutic approaches in late-life mood and anxiety disorders. RECENT FINDINGS: In community samples, late-life depression and late-life generalized anxiety disorder occur up to 38 and 15%, respectively, while late-life bipolar disorder is less common and occur in approximately 0.5% of the population. There are significant challenges in treating and improving outcome in late-life mood and anxiety disorders. Time to treatment response and treatment resistance are increased in older adults. Novel neuroimaging techniques have the potential to improve diagnostic and therapeutic outcome in late-life mood and anxiety disorders either through "personalized pharmacotherapy" or through identifying dysfunction regions/networks to be subsequently used for direct interventions such as transcranial magnetic stimulation. This review will provide an overview of recent literature that substantiates the potential role of neuroimaging in clinical practice, as well as the barriers that must be overcome prior to clinical translation. PMID- 29492707 TI - Implementation of mini gastric bypass in the Netherlands: early and midterm results from a high-volume unit. AB - BACKGROUND: Mini gastric bypass (MGB) is a promising and attractive alternative bariatric procedure. In 2011, we introduced MGB in our high-volume bariatric unit. Subsequently, we evaluated short- and midterm results of this procedure. METHODS: A prospective cohort of patients who underwent MGB between 2012 and 2013 was retrospectively evaluated. RESULTS: From 2012 to 2013, primary MGB was performed in 287 patients with a mean BMI of 42 kg/m2 (range 32-76 kg/m2). The mean operation time was 50 min (range 25-120 min). The mortality rate was 0%. Serious complications, such as leakage, pulmonary embolism, or bleeding, occurred in 3.1% of patients; anastomotic leaks occurred in 1.4% of patients. Conversion to Roux-en-Y gastric bypass for biliary reflux or other indications occurred in six patients (2%). During our initial learning phase, biliary reflux rates were higher due to an overly short pouch. Surgical revision for malnutrition was performed in one patient. Percent excess weight loss and percent total body weight loss were 85 and 35%, respectively, after 1 year; 88 and 36.6%, respectively, after 2 years; and 83 and 34.3%, respectively, after 3 years. Follow-up rates after 1, 2, and 3 years were 96% (277/287), 72% (208/287), and 66% (190/287), respectively. CONCLUSIONS: As a primary bariatric procedure, MGB is associated with good early and midterm results. MGB has the potential to become a significant alternative bariatric procedure. Correct technique is of extreme importance when performing MGB; therefore, the appointment of an experienced MGB surgeon as a guide when beginning to utilize this technique is advised. PMID- 29492706 TI - Hyperkalemia in the Hypertensive Patient. AB - PURPOSE OF REVIEW: Hyperkalemia develops in a patient with systemic arterial hypertension (HTN) if one or more risk factors are present, namely chronic kidney disease (CKD) (especially severe stage 4-5 CKD), diabetes mellitus (DM), heart failure (HF), or pharmacological therapies that interfere with potassium homeostasis, mainly through renin-angiotensin-aldosterone inhibition (RAASi). Hyperkalemia is a considerable reason of morbidity (emergency department (ED) visits and hospitalizations) and portends a higher mortality risk in patients at risk; for instance, hyperkalemia increases the risk of mortality within 1 day of a hyperkalemic event. This review aims to identify the risk factors for high serum potassium, highlight the risk versus benefit of RAASi in certain patient populations, and outline preventive as well as therapeutic strategies for hyperkalemia. RECENT FINDINGS: A growing body of evidence supports the safety and efficacy of cation-exchange resins, patiromer, or sodium zirconium cyclosilicate, in patients with a compelling indication for RAASi, yet in whom such therapy was complicated by hyperkalemia, allowing these patients to benefit from continued RAASi therapy. In summary, novel cation exchange polymers present the clinician with a new and safe strategy to address hyperkalemia in patients with a compelling indication for ongoing RAASi therapy instead of withdrawal of such therapy. PMID- 29492708 TI - Does coagulopathy, anticoagulant or antithrombotic therapy matter in incisional hernia repair? Data from the Herniamed Registry. AB - BACKGROUND: A considerable number of patients undergoing incisional hernia repair are on anticoagulant or antiplatelet therapy or have existing coagulopathy which may put them at higher risk for postoperative bleeding complications. Data about the optimal treatment of these patients are sparse. This analysis attempts to determine the rate of postoperative bleeding complications following incisional hernia repair and the consecutive rate of reoperation among patients with coagulopathy or receiving antiplatelet and anticoagulant therapy (higher risk group) compared to patients who do not have a higher risk (normal risk group). METHODS: Out of the 43,101 patients documented in the Herniamed Registry who had an incisional hernia repair, 6668 (15.5%) were on anticoagulant or antithrombotic therapy or had existing coagulopathy. The implication of that higher risk profile for onset of postoperative bleeding was investigated in multivariable analysis. Hence, other influential variables were identified. RESULTS: The rate of postoperative bleeding in the higher risk group was 3.9% (n = 261) and significantly higher compared to the normal risk group at 1.6% (n = 564) (OR 2.001 [1.699; 2.356]; p < 0.001). Additionally, male gender, use of drains, larger defect size, open incisional hernia repair, lower BMI, and higher ASA score significantly increased the risk of postoperative bleeding. The rate of reoperations due to postoperative bleeding was significantly increased in the higher risk group compared to the normal risk group (2.4 vs. 1.0%; OR 1.217 [1.071; 1.382]; p = 0.003). Likewise, the postoperative general complication rate (6.04 vs. 3.66%; p < 0.001) as well as the mortality rate (0.46 vs. 0.17%; p < 0.001) were significantly higher in the higher risk group. CONCLUSIONS: Patients with anticoagulant or antiplatelet therapy or existing coagulopathy who undergo incisional hernia repair have a significantly higher risk for onset of postoperative bleeding. The risk of bleeding complications and complication related reoperations seems to be lower after laparoscopic intraperitoneal onlay mesh. PMID- 29492709 TI - Modified endoscopic gastroplasty for the treatment of obesity. AB - BACKGROUND: Endoscopic sleeve gastroplasty is a safe and feasible treatment for obesity. This study is focused on our technique modification which suggests a different suturing pattern in order to distribute suture tension more evenly. METHODS: A retrospective study of 148 patients (121 women) who underwent this procedure and were monitored for 12 months was conducted. The average age was 41.53 +/- 10 years. The average BMI was 35.11 +/- 5.5 kg/m2 with the average initial weight being 98.7 +/- 17 kg. A subgroup of the first 72 patients (60 women) were monitored for 18 months. A new running "Z" stitch pattern was used to provide gastric cavity reduction by means of 4 parallel suture rows. The stitch pattern was intended to provide a homogenous distribution of the disruptive force on the suture among all stitch points. RESULTS: %TWL was 17.53 +/- 7.57 in 12 months and 18.5 +/- 9% in 18 months indicating durability of the procedure. Patients with a BMI < 35 benefited most from an endoscopic gastroplasty. Leptin did not predict a response to endoscopic gastroplasty and decreased in all patients. In just one case there was a mild bleeding (0.67%) at the insertion point of the helix, which was resolved by sclerotherapy. CONCLUSIONS: Endoscopic gastroplasty offers a real choice for obese patients. This single-center experience with a modified suturing pattern provides a successful technique for weight loss. PMID- 29492710 TI - The Fabrication and High-Efficiency Electromagnetic Wave Absorption Performance of CoFe/C Core-Shell Structured Nanocomposites. AB - CoFe/C core-shell structured nanocomposites (CoFe@C) have been fabricated through the thermal decomposition of acetylene with CoFe2O4 as precursor. The as-prepared CoFe@C was characterized by X-ray powder diffraction, X-ray photoelectron spectroscopy, Raman spectroscopy, transmission electron microscopy, and thermogravimetric analysis. The results demonstrate that the carbon shell in CoFe@C has a poor crystallization with a thickness about 5-30 nm and a content approximately 48.5 wt.%. Due to a good combination between intrinsic magnetic properties and high-electrical conductivity, the CoFe@C exhibits not only excellent absorption intensity but also wide frequency bandwidth. The minimum RL value of CoFe@C can reach - 44 dB at a thickness of 4.0 mm, and RL values below - 10 dB is up to 4.3 GHz at a thickness of 2.5 mm. The present CoFe@C may be a potential candidate for microwave absorption application. PMID- 29492711 TI - A Benefit of Being Heavier Is Being Strong: a Cross-Sectional Study in Young Adults. AB - BACKGROUND: In this study, the main hypothesis is that heavier people enjoy strength exercises more than normal-weight people, mediated by fat-free mass and muscle strength. Further, it is hypothesized that heavier people are better in strength exercises and enjoy strength exercises more compared to aerobic exercises. METHODS: In a cross-sectional study, height, weight, body composition (i.e., fat mass and fat-free mass by underwater weighing), muscle strength (i.e., one-repetition maximal strength for the leg press and chest press), maximal aerobic exertion (VO2max) during cycle ergometry, and psychological determinants (i.e., attitudes, intentions, and self-determined motivations for strength exercises and aerobic exercises using questionnaires) were measured in 68 participants (18-30 years). RESULTS: Significant correlations between weight/BMI and fat-free mass (index) (r values = .70-.80, p values < .001), fat-free mass and muscle strength (r values = .35-.55, p values < .05), and muscle strength and attitudes, intentions, and motivation for strength exercises were found (r values = .29-.43, p values < .05); BMI was related to psychological determinants via fat free mass and muscle strength. Furthermore, participants with a higher BMI are significantly better in strength exercises, more intrinsically motivated, and less motivated to do strength exercises compared to aerobic exercises (all p values < .05). Trends in the same direction were found for the following variables: instrumental attitude, experiential attitude, and intention (p values < .1). CONCLUSIONS: Strength exercises could be more appropriate for heavier people and might therefore be a valuable component in physical activity programs for people who are overweight or obese. PMID- 29492712 TI - In vitro outlook of gold nanoparticles in photo-thermal therapy: a literature review. AB - Hyperthermia is an anti-cancer treatment in which the temperature of the malignant tumor is increased more than other adjacent normal tissues. Microwave, ultrasound, laser, and radiofrequency sources have been used for hyperthermia of cancerous tissues. In the past decade, near-infrared (NIR) laser for cancer therapy, known as photo-thermal therapy (PTT), was expanded in which the photo sensitizer agent converts the light photon energy to heat. The heat following PTT can destroy cancer cells. There are some photo-sensitizer agents which have been used for PTT; however, owing to recent advances in nanotechnology, noble metal nanoparticles like gold (Au) nanoparticles (GNPs) have been used successfully in PTT. GNPs have some desirable specifications, including simple and controlled synthesis, small size, high level of biocompatibility, and surface plasmon resonance (SPR). The SPR effect of the GNPs increases the radiative properties like absorption and scattering; therefore, they can be used in PTT. In this article, we reviewed recent in vitro studies of PTT using GNPs in literature. At first, we focus on the physical properties of GNPs, their interaction with infrared radiation, and physical parameters governing the interaction of infrared radiation with the GNPs. Then, we review the passive and active targeting of GNPs using the different coating to induce the thermal damage in cancer cells using low-level laser PPT. The GNPs' cellular internalization into cancer cells is a challenge which is consequently considered. In this review, we also summarize the results of synergistic cancer therapy studies on the combination of radiation therapy as a routine cancer treatment and PTT: in which significant improvement occurs in treatment efficacy. PMID- 29492714 TI - Schiff base complexes that form sandwich compounds. AB - In this article, we explore the capacity of formed Schiff base complexes to trap metal atoms or ions, using their aromatic ends. The intrinsic geometry of each complex defines the process of substitution. Two cases were studied; one involving a trans Schiff base complex and the other considering how a salen ligand, with nickel systems traps chromium. We also assessed the nature of the new bonds and the frontier molecular orbitals. Graphical abstract Two salen nickel compounds are joint by a Cr(0) atom forming an organometallic interaction. PMID- 29492713 TI - Fractional CO2 laser for genitourinary syndrome of menopause in breast cancer survivors: clinical, immunological, and microbiological aspects. AB - The composition of vaginal microbiome in menopause and cancer survivor women changes dramatically leading to genitourinary syndrome of menopause (GSM) in up to 70% of patients. Recent reports suggest that laser therapy may be valuable as a not hormonal therapeutic modality. The aim of the present study was to evaluate the effects of fractional CO2 laser treatment on the vaginal secretory pathway of a large panel of immune mediators, usually implicated in tissue remodeling and inflammation, and on microbiome composition in postmenopausal breast cancer survivors. The Ion Torrent PGM platform and the Luminex Bio-Plex platform were used for microbiome and immune factor analysis. The significant reduction of clinical symptoms and the non-significant changes in vaginal microbiome support the efficacy and safety of laser treatment. Moreover, the high remodeling status in vaginal epithelium is demonstrated by the significant changes in inflammatory and modulatory cytokine patterns. Laser therapy can be used for the treatment of GSM symptoms and does not show any adverse effects. However, further studies will be needed to clarify its long-term efficacy and other effects. PMID- 29492715 TI - Mast cells and angiogenesis in pancreatic ductal adenocarcinoma. AB - Mast cells are recognized as critical components of the tumor stromal microenvironment in several solid and hematological malignancies, promoting angiogenesis and tumor growth. A correlation between mast cells infiltration, angiogenesis and tumor progression has been reported for pancreatic ductal adenocarcinoma as well. Mast cells contribute to the aggressiveness of the pancreatic ductal carcinoma enhancing the expression of several pro-angiogenic factors such as vascular endothelial growth factor, fibroblast growth factor-2, platelet-derived growth factor and angiopoietin-1 as well as stimulating the pancreatic cancer cells proliferation by IL-13 and tryptase. The disruption of this pro-angiogenic and proliferative stimulation by inhibiting the mast cells migration and degranulation is under investigation as a potential therapeutic approach in pancreatic ductal adenocarcinoma patients. This review will summarize the literature concerning the mast cells infiltration in the pancreatic ductal adenocarcinoma analyzing its role in angiogenesis and tumor progression. PMID- 29492716 TI - Granulomatosis with polyangiitis: clinical course and outcome of 60 patients from a single center in South India. AB - Granulomatosis with polyangiitis (GPA) previously known as Wegener's granulomatosis is one of the forms of idiopathic systemic vasculitis. There is very scanty data available on GPA in Asian and Indian population. We studied data of 60 patients from southern India, diagnosed with GPA to describe the physical characteristics, the treatment, and outcome. Patients who fulfilled any two of the four criteria proposed by the American College of Rheumatology, and those with clinical features of GPA with ANCA positivity and histopathological confirmation, were included in the study. Disease activity and damage were assessed by Birmingham Vasculitis Activity Score v. 3 (BVAS v. 3) and Vasculitis Damage Index (VDI), respectively. Relapses were defined as recurrence of GPA of sufficient severity to require treatment or increase in the dose of treatment on a patient who was previously stable. Out of 60 patients, initial BVAS evaluation showed that 57 (95%) patients had severe disease and 3 (5%) patients had limited disease where median BVAS was 21.5 (range 17-44). Follow-up BVAS evaluation for severe disease showed that 13 (22.8%) patients continued with severe disease of which 9 patients did not survive, 24 (42.3%) had remission, 11 (19.2%) had persistent disease, and 9 (15.7%) were lost to follow-up. The mean VDI score was 2.5 +/- 2. Renal involvement was established in 42 (70%) patients. Upper and lower respiratory involvement was seen in 38 (63%) patients. Nervous system involvement was noted in the 15 (25%) patients. Articular manifestations were seen in 16 (27%) patients. Diverse clinical manifestation delay early diagnosis and treatment of this potentially treatable vasculitis. Focused approach could expedite early diagnosis and can reduce the mortality. PMID- 29492717 TI - The Global Spine Care Initiative: a systematic review for the assessment of spine related complaints in populations with limited resources and in low- and middle income communities. AB - PURPOSE: The purpose of this systematic literature review was to develop recommendations for the assessment of spine-related complaints in medically underserved areas with limited resources. METHODS: We conducted a systematic review and best evidence synthesis of guidelines on the assessment of spine related complaints. Independent reviewers critically appraised eligible guidelines using the Appraisal of Guidelines for Research and Evaluation-II criteria. Low risk of bias clinical practice guidelines was used to develop recommendations. In accordance with the mandate of the Global Spinal Care Initiative (GSCI), recommendations were selected that could be applied to medically underserved areas and low- and middle-income countries by considering the limited access and costs of diagnostic technologies. RESULTS: We screened 3069 citations; 20 guidelines were eligible for critical appraisal. We used 13 that had a low risk of bias that targeted neck and back pain. CONCLUSIONS: When assessing patients with spine-related complaints in medically underserved areas and low- and middle-income countries, we recommend that clinicians should: (1) take a clinical history to determine signs or symptoms suggesting serious pathology (red flags) and psychological factors (yellow flags); (2) perform a physical examination (musculoskeletal and neurological); (3) do not routinely obtain diagnostic imaging; (4) obtain diagnostic imaging and/or laboratory tests when serious pathologies are suspected, and/or presence of progressive neurologic deficits, and/or disabling persistent pain; (5) do not perform electromyography or nerve conduction studies for diagnosis of intervertebral disc disease with radiculopathy; and (6) do not perform discography for the assessment of spinal disorders. This information can be used to inform the GSCI care pathway and model of care. These slides can be retrieved under Electronic Supplementary Material. PMID- 29492718 TI - Comparable clinical and radiological outcomes between skipped-level and all-level plating for open-door laminoplasty. AB - PURPOSE: To compare the clinical and radiological outcomes between skipped-level and all-level plating for cervical laminoplasty. METHODS: Patients with cervical spondylotic myelopathy (CSM) treated by open-door laminoplasty with minimum 2 year postoperative follow-up were included. All patients had opening from C3-6 or C3-7 and were divided into skipped-level or all-level plating groups. Japanese Orthopaedic Association (JOA) scores and canal measurements were obtained preoperatively, immediate (within 1 week) postoperatively, and at 2, 6 weeks, 3, 6 and 12 months postoperatively. Paired t test was used for comparative analysis. Receiver operating characteristic analysis was used to determine the canal expansion cutoff for spring-back closure. RESULTS: A total of 74 subjects were included with mean age of 66.1 +/- 11.3 years at surgery. Of these, 32 underwent skipped-level plating and 42 underwent all-level plating. No significant differences were noted between the two groups at baseline and follow-up. Spring back closure was observed in up to 50% of the non-plated levels within 3 months postoperatively. The cutoff for developing spring-back closure was 7 mm canal expansion for C3-6. No differences were observed in JOA scores and recovery rates between the two groups. None of the patients with spring-back required reoperation. CONCLUSIONS: There were no significant differences between skipped level and all-level plating in terms of JOA or recovery rate, and canal diameter differences. This has tremendous impact on saving costs in CSM management as up to two plates per patient undergoing a standard C3-6 laminoplasty may be omitted instead of four plates to every level to achieve similar clinical and radiological outcomes. LEVEL OF EVIDENCE: III. These slides can be retrieved under Electronic Supplementary Material. PMID- 29492719 TI - Cervical hemivertebra resection and torticollis correction: report on two cases and literature review. AB - PURPOSE: Hemivertebra of the cervical spine is a rare but complex spinal malformation. To our knowledge, only one publication describes excision of an upper-middle cervical (between C2 and C4) hemivertebra. We present our experience with two cases of C3 hemivertebra resection and torticollis correction via a combined anterior-posterior-anterior surgical approach and short segment fixation. METHODS: Two 12-year-old patients with torticollis due to congenital C3 hemivertebra underwent surgery consisting of combined anterior vertebral body osteotomy, posterior element resection with segment instrumentation and deformity correction, and iliac bone graft reconstruction and fixation via an anterior approach. During the osteotomies, the transverse process accompanied with the vertebral artery was disconnected and freed away from the spinal column. Then the deformity was corrected without touching the vertebral artery, which made the procedure safe and comfortable. The details of this technique are presented. Pre- and postoperative radiographic features, as well as clinical outcomes were evaluated. RESULTS: The treatment process was uneventful. The patients had satisfactory clinical outcomes at a mean of 1.5 years follow-up. Head tilt and chin rotation were corrected completely. Radiographs showed favorable deformity correction, well-balanced coronal and sagittal alignment, and solid bony fusion. CONCLUSION: Combined anterior-posterior-anterior hemivertebra resection with short segment instrumentation is a reasonable option for the treatment of congenital cervical hemivertebra, which provided satisfactory deformity correction and good clinical outcomes. LEVEL OF EVIDENCE: 4. PMID- 29492720 TI - Eosinophilic Esophagitis in Children: Endoscopic Findings at Diagnosis and Post intervention. AB - PURPOSE OF REVIEW: The goal of this review is to present and summarize studies on endoscopic findings in eosinophilic esophagitis (EoE), at diagnosis and in response to treatment, utilizing rigorous peer-reviewed literature in children wherever possible and to introduce a recently proposed standardized endoscopic evaluation system. RECENT FINDINGS: Gold standard of diagnosis and assessment of response to therapy in EoE requires multiple endoscopies with biopsies for histology, which allows for observation of the esophageal mucosa. Typical endoscopic findings in patients with EoE include edema, exudate, furrowing, concentric rings, and strictures. Endoscopic findings have been broadly characterized into inflammatory features (edema, exudate, furrowing) and fibro stenotic features (rings, stricture), in order to better reflect their underlying pathophysiology. Recent studies suggest strong correlations between endoscopic findings, through composite scoring systems, and histology, and therefore may be helpful as part of disease surveillance. The EoE Endoscopic Reference Score (EREFS) classification system was proposed in 2013 as an outcome metric for standardization in reporting endoscopic signs of EoE. Subsequent studies support utility of composite scoring, which utility has similarly been seen in pediatric treatment trials. Endoscopy in children provides insight into the natural history of EoE, with progressively more fibro-stenotic features occurring over time, giving an additional perspective into esophageal remodeling and response to treatment. Recognition of typical endoscopic findings at diagnosis and upon repeat endoscopy has allowed a clinician to monitor visual changes in esophageal mucosal health. Further studies to assess the role of composite scoring in disease management are needed. PMID- 29492721 TI - Involvement of Alveolar Macrophages and Neutrophils in Acute Lung Injury After Scorpion Envenomation: New Pharmacological Targets. AB - Androctonus australis hector (Aah) scorpion venom is well known to induce a systemic inflammatory response associated with cell infiltration in lung and edema formation. The present study investigate (i) in vivo the evolution of lung and systemic inflammation triggered by Aah venom and (ii) analyze in vitro the signaling cascade, upstream of inflammatory cytokine expression after Aah venom stimulated mouse alveolar macrophage (MH-S), the main resident immune cells in the lung. The inflammation induced by Aah venom was assessed in mice through inflammatory cell count, nitric oxide metabolite, and lactate dehydrogenase (LDH) activity in blood, concordantly with neutrophil sequestration in tissue and lung histology. In the in vitro study, MH-S cells are stimulated with Aah venom in the presence of signaling pathway inhibitors, NG25 an inhibitor of transforming growth factor beta-activated kinase (TAK1), PD184352 MAP kinase (MKK)1/2 inhibitor, BI605906 an inhibitor of IKkappa-beta (inhibitor of nuclear factor kappa B), and BIRB0796 an inhibitor of p38 MAPK. Obtained results showed that leukocyte transmigration is important in some area of the lung and is closely associated with systemic increase of nitric oxide and LDH. The in vitro study showed that Aah venom induce significantly an increase of the expression of TNF alpha, IL-1beta, and MIP-2 in MH-S cells. The pretreatment with inhibitors showed that cytokine increase involves TAK1, IKkappa-beta, and ERK1/2 pathways, similarly to Toll-like receptor activation. These findings highlight the contribution of alveolar macrophage and their secretory products to tissue damage and made of TAK1 and ERK1/2, an interesting target in scorpion envenomation. PMID- 29492722 TI - A preliminary molecular phylogeny shows Japanese and Austrian populations of the red mite Balaustium murorum (Acari: Trombidiformes: Erythraeidae) to be closely related. AB - The red mite Balaustium murorum (Hermann) inhabits the Western Palaearctic realm and is well adapted to man-made structures. In Japan, B. murorum had been reported more frequently after the 1980s. A molecular phylogeny based on the nuclear 18S rRNA and mitochondrial COI genes, and including B. murorum individuals from Japan and Austria and representatives of related species from Japan showed four Balaustium species-level lineages in Japan (B. murorum, Balaustium sp. 1, Balaustium sp. 2, Balaustium sp. 3). The B. murorum lineage shared identical 18S sequence and COI haplotype with the Austrian population. Balaustium sp. 1 was detected from the Tokyo and Misaki area (Honshu Island) and was the sister group to B. murorum; the other two lineages inhabited coastal environments of Erimo, Hokkaido Island (Balaustium sp. 2) and Ainan, Shikoku Island (Balaustium sp. 3). The high genetic distances among these four lineages indicate that each lineage is a distinct species, with three of the lineages representing undescribed species. Our results are compatible with the conclusion that B. murorum was introduced to Japan from Europe, although our study did not resolve the polarity or timing of migration events. PMID- 29492725 TI - Erratum to: Role of PD-1 in Immunity and Diseases. PMID- 29492723 TI - Fungal Competitors Affect Production of Antimicrobial Lipopeptides in Bacillus subtilis Strain B9-5. AB - Bacillus subtilis has shown success in antagonizing plant pathogens where strains of the bacterium produce antimicrobial cyclic lipopeptides (CLPs) in response to microbial competitors in their ecological niche. To gain insight into the inhibitory role of these CLPs, B. subtilis strain B9-5 was co-cultured with three pathogenic fungi. Inhibition of mycelial growth and spore germination was assessed and CLPs produced by B. subtilis B9-5 were quantified over the entire period of microbial interaction. B. subtilis B9-5 significantly inhibited mycelial growth and spore germination of Fusarium sambucinum and Verticillium dahliae, but not Rhizopus stolonifer. LC-MS analysis revealed that B. subtilis differentially produced fengycin and surfactin homologs depending on the competitor. CLP quantification suggested that the presence of Verticillium dahliae, a fungus highly sensitive to the compounds, caused an increase followed by a decrease in CLP production by the bacterium. In co-cultures with Fusarium sambucinum, a moderately sensitive fungus, CLP production increased more gradually, possibly because of its slower rate of spore germination. With co cultures of the tolerant fungus Rhizopus stolonifer, B. subtilis produced high amounts of CLPs (per bacterial cell) for the duration of the interaction. Variations in CLP production could be explained, in part, by the pathogens' overall sensitivities to the bacterial lipopeptides and/or the relative growth rates between the plant pathogen and B. subtilis. CLP production varied substantially temporally depending on the targeted fungus, which provides valuable insight concerning the effectiveness of B. subtilis B9-5 protecting its ecological niche against the ingress of these pathogens. PMID- 29492724 TI - Direct and inverse identification of constitutive parameters from the structure of soft tissues. Part 1: micro- and nanostructure of collagen fibers. AB - Soft tissues are characterized by a nonlinear mechanical response, highly affected by the multiscale structure of collagen fibers. The effectiveness and the calibration of constitutive models play a major role on the reliability and the applicability of computational models in biomechanics. This paper presents a procedure for the identification of the relationship between collagen-related structural features in soft tissues with model parameters of classical polynomial and exponential-based constitutive models. Histological features at microscale, as well as biochemical and biophysical properties at nanoscale, are addressed by employing a multiscale structural description of soft tissue mechanics as benchmark data set. Both the direct (from structure to parameters) and the inverse (from parameters to structure) problem are addressed. Suitable optimization problems are introduced for accurate numerical and approximated analytical direct relationships. The inverse identification has been addressed by providing also a measure of the reliability of the computed estimates. Results show the effectiveness of the proposed strategies and allow to discuss the fitting capabilities of classical constitutive approaches in terms of parameters identification. PMID- 29492726 TI - Efficient iterative virtual screening with Apache Spark and conformal prediction. AB - BACKGROUND: Docking and scoring large libraries of ligands against target proteins forms the basis of structure-based virtual screening. The problem is trivially parallelizable, and calculations are generally carried out on computer clusters or on large workstations in a brute force manner, by docking and scoring all available ligands. CONTRIBUTION: In this study we propose a strategy that is based on iteratively docking a set of ligands to form a training set, training a ligand-based model on this set, and predicting the remainder of the ligands to exclude those predicted as 'low-scoring' ligands. Then, another set of ligands are docked, the model is retrained and the process is repeated until a certain model efficiency level is reached. Thereafter, the remaining ligands are docked or excluded based on this model. We use SVM and conformal prediction to deliver valid prediction intervals for ranking the predicted ligands, and Apache Spark to parallelize both the docking and the modeling. RESULTS: We show on 4 different targets that conformal prediction based virtual screening (CPVS) is able to reduce the number of docked molecules by 62.61% while retaining an accuracy for the top 30 hits of 94% on average and a speedup of 3.7. The implementation is available as open source via GitHub ( https://github.com/laeeq80/spark-cpvs ) and can be run on high-performance computers as well as on cloud resources. PMID- 29492727 TI - Retinal vessel diameter obtained by optical coherence tomography is spared in Parkinson's disease. AB - PURPOSE: To define the alterations in retinal vessel diameter in Parkinson's disease (PD) by optical coherence tomography (OCT). METHODS: This is a case control study including 41 eyes of 41 patients with diagnosis of PD and 35 eyes of 35 age- and sex-matched control subjects. All subjects underwent complete neurological and ophthalmological examinations before measurements. Retinal vessel diameters and peripapillary retinal nerve fiber layer (pRNFL) thicknesses were evaluated with spectral domain OCT (SD-OCT) with a circular scan centered at the optic disc. The diameters of the superior nasal and temporal arteries and veins, and inferior nasal and temporal arteries and veins were measured and then compared between the groups. Correlations with the duration of the disease, usage of levodopa, and pRNFL thicknesses between retinal vessel diameters were examined with Pearson and Spearman correlation analysis. RESULTS: Average pRNFL thickness is significantly decreased in PD compared to age- and sex-matched controls (p < 0.05). At all measurement points, retinal artery diameter measurements were decreased in the PD group compared to controls, but the differences did not reach statistical significance. Diameters of the retinal veins also did not show any significant difference in the PD and control groups. Superior temporal artery diameter was significantly decreased in patients using levodopa compared to nonusers (p = 0.022). There were no statistically significant correlations between pRNFL thicknesses or disease duration with retinal vessel diameters in PD group. CONCLUSIONS: Parkinson's disease does not seem to have an impact on the retinal vessel diameters obtained by SD-OCT. PMID- 29492728 TI - Factors associated with corneal epithelial defects after pars plana vitrectomy. PMID- 29492729 TI - Mirror image of familial exudative vitreoretinopathy in identical twins. AB - PURPOSE: To report the identical twins who had mirror fundus and angiographic images of familial exudative vitreoretinopathy (FEVR). CASE PRESENTATION: A pair of 16 year old female twins presented with mirror-image asymmetry of monocular decreased vision. The twins were born full term with normal weights. Neither twin revealed any medical disorders during childhood and there was no known family history of ocular disorders. On ocular examination, the best corrected visual acuity (BCVA) was 20/20 in OD and 20/63 in OS for twin 1. For the twin 2, the BCVAs were 20/63 and 20/20 for OD and OS, respectively. Intraocular pressures were within normal limits and anterior segment examinations were unremarkable for both twins. Dilated fundus examinations and angiographic images revealed characteristics FEVR appearance with mirror image phenomenon in the twins. CONCLUSION: This is the first report describing identical twins with mirror images of FEVR. This report may confirm a strong underlying genetic inheritance in the pathogenesis of FEVR. PMID- 29492730 TI - Stable isotope labeling approaches for NMR characterization of glycoproteins using eukaryotic expression systems. AB - Glycoproteins are characterized by the heterogeneous and dynamic nature of their glycan moieties, which hamper crystallographic analysis. NMR spectroscopy provides potential advantages in dealing with such complicated systems, given that the target molecules can be isotopically labeled. Methods of metabolic isotope labeling in recombinant glycoproteins have been developed recently using a variety of eukaryotic production vehicles, including mammalian, yeast, insect, and plant cells, each of which has a distinct N-glycan diversification pathway. Yeast genetic engineering has enabled the overexpression of homogeneous high mannose-type oligosaccharides with 13C labeling for NMR characterization of their conformational dynamics. The utility of stable isotope-assisted NMR spectroscopy has also been demonstrated using the Fc fragment of immunoglobulin G (IgG) as a model glycoprotein, providing useful information regarding intramolecular carbohydrate-protein interactions. Transverse relaxation optimization of intact IgG with a molecular mass of 150 kDa has been achieved by tailored deuteration of selected amino acid residues using a mammalian expression system. This offers a useful probe for the characterization of molecular interaction networks in multimolecular crowded systems typified by serum. Perspectives regarding the development of techniques for tailoring glycoform designs and isotope labeling of recombinant glycoproteins are also discussed. PMID- 29492732 TI - Surgical Management of Adult Acquired Buried Penis. AB - PURPOSE OF REVIEW: Adult acquired buried penis is a morbid condition characterized by complete entrapment of the phallus as a result of morbid obesity, post-surgical cicatrix formation, or primary genital lymphedema. Hygienic voiding is not possible and urinary dribbling is frequent with accompanying inflammation, skin breakdown, and infection from the chronic moisture. The end result is penile skin fibrosis resulting in permanent functional loss. Herein, we describe the etiology of adult acquired buried penis, advances in its surgical management, and quality of life outcomes with treatment. RECENT FINDINGS: Adult acquired buried penis is increasing in incidence as morbid obesity becomes more prevalent. Frequently comorbid conditions affect treatment including those affecting wound healing such a diabetes mellitus. Functional and cosmetic surgical outcomes are being published in greater volume in recent years leading to more refined treatment algorithms. Patient quality of life is greatly improved by definitive surgical management. Adult acquired buried penis is a morbid condition that is increasing in incidence as obesity becomes more commonplace. Surgical management often necessitates surgical lipectomy of the suprapubic fat pad, scrotoplasty, and penile split thickness skin graft. Substantial quality of life improvements have been consistently reported after surgical treatment. PMID- 29492731 TI - 13C APSY-NMR for sequential assignment of intrinsically disordered proteins. AB - The increasingly recognized biological relevance of intrinsically disordered proteins requires a continuous expansion of the tools for their characterization via NMR spectroscopy, the only technique so far able to provide atomic-resolution information on these highly mobile macromolecules. Here we present the implementation of projection spectroscopy in 13C-direct detected NMR experiments to achieve the sequence specific assignment of IDPs. The approach was used to obtain the complete backbone assignment at high temperature of alpha-synuclein, a paradigmatic intrinsically disordered protein. PMID- 29492733 TI - Effects of Prosodic and Semantic Cues on Facial Emotion Recognition in Relation to Autism-Like Traits. AB - The current study investigated whether those with higher levels of autism-like traits process emotional information from speech differently to those with lower levels of autism-like traits. Neurotypical adults completed the autism-spectrum quotient and an emotional priming task. Vocal primes with varied emotional prosody, semantics, or a combination, preceded emotional target faces. Prime target pairs were congruent or incongruent in their emotional content. Overall, congruency effects were found for combined prosody-semantic primes, however no congruency effects were found for semantic or prosodic primes alone. Further, those with higher levels of autism-like traits were not influenced by the prime stimuli. These results suggest that failure to integrate emotional information across modalities may be characteristic of the broader autism phenotype. PMID- 29492734 TI - Conformational analysis of macrocyclic frankincense (Boswellia) diterpenoids. AB - Frankincense oleoresin has been used in traditional medicine for more than 5000 years. The phytochemistry of frankincense (Boswellia spp.) resins includes triterpenoids (including boswellic acids and their derivatives), diterpenoids (cembrenoids and cneorubenoids), and essential oils. The macrocyclic cembrene diterpenoids may play a part in the biological activities of frankincense resin, but neither the biological targets nor the modes of interaction with the targets are currently known. How these macrocycles interact with biological macromolecules likely depends on what conformation(s) are energetically available to them. In this work, a conformational analysis of 15 Boswellia cembrene diterpenoids and 1 verticillane diterpenoid was carried out at the B3LYP/6-31G* and M06-2X/6-31G* levels of theory, including the SM8 aqueous solvation model. The lowest-energy conformations of boscartin B and incensole oxide were the same as the previously reported X-ray crystal structures, while the lowest-energy conformations of boscartins A and C were very similar to the crystal structures. Boscartins D-H and isoincensole oxide showed only one low-energy conformation for each compound and are predicted to be conformationally locked. Incensole, isoincensolol, and serratol are predicted to be conformationally mobile with several low-energy forms. The conformational mobility of Boswellia cembrenoid diterpenoids depends largely on the degree of epoxidation, either oxirane or tetrahydrofuran rings. PMID- 29492736 TI - Human papillomavirus vaccine: Urgent need to promote gender parity. PMID- 29492735 TI - The risk of cardiovascular disease following breast cancer by Framingham risk score. AB - OBJECTIVES: This study evaluates the risk of cardiovascular disease (CVD) following breast cancer, accounting for baseline CVD risk. METHODS: Within the EPIC-NL (Dutch part of the European Prospective Investigation into Nutrition and Cancer) cohort, 1103 women were diagnosed with breast cancer. For every breast cancer patient, 3-4 women without breast cancer (n = 4328) were selected matched for age, year, and time since cohort enrollment. Based on CVD risk factors at cohort enrollment, 10-year risk of CVD was calculated and categorized: low (< 10%), intermediate (10-20%), high (> 20%). Cox proportional hazard models assessed the risk of CVD events (hospitalization or mortality) and CVD mortality of women with versus without breast cancer, adjusted for baseline CVD risk. RESULTS: After median follow-up of 5 and 6 years, 92 (8.3%) and 325 (7.5%) CVD events occurred in women with and without breast cancer, respectively. In the low CVD risk group, women with breast cancer had 1.44 (95% CI 1.00-2.06) times higher risk of CVD events than women without breast cancer. In the intermediate and high CVD risk categories, risk of CVD events was similar in women with and without breast cancer. Overall, women with breast cancer had 1.77 (95% CI 1.10-2.86) times higher risk of CVD mortality than women without breast cancer. CONCLUSIONS: Among women with low CVD risk, women with breast cancer have a higher risk of CVD event than women without breast cancer. Overall, women with breast cancer have a higher risk of CVD mortality than women without breast cancer. PMID- 29492738 TI - African-American women's Upward Economic Mobility and Small for Gestational Age Births: A Population-Based Study. AB - Background The relationship between African-American women's upward economic mobility and small for gestational age (weight for gestational < 10th percentile, SGA) rates is incompletely understood. Objective To ascertain the extent to which African-American women's upward economic mobility from early-life impoverishment is coupled with reduced SGA rates. Methods Stratified and multilevel logistic regression analyses were completed on the Illinois transgenerational dataset of African-American infants (1989-1991) and their Chicago-born mothers (1956-1976) with linked U.S. census income information. Results Impoverished-born (defined as lowest quartile of neighborhood income distribution) African-American women (n = 4891) who remained impoverished by the time of delivery had a SGA rate of 19.7%. Individuals who achieved low (n = 5827), modest (n = 2254), or high (n = 732) upward economic mobility by adulthood had lower SGA rates of 17.2, 14.8, and 13.7%, respectively; RR = 0.9 (0.8-0.9), 0.8 (0.7-0.8), and 0.7 (0.6-0.8), respectively. In adjusted (controlling for traditional individual-level risk factors) multilevel regression models, there was a decreasing linear trend in SGA rates with increasing levels of upward economic mobility; the adjusted RR of SGA birth for impoverished-born African-American women who experienced low, modest, of high (compared to no) upward mobility equaled 0.95 (0.91, 0.99), 0.90 (0.83, 0.98), and 0.86 (0.75, 0.98), respectively, p < 0.05. Conclusions African American women's upward economic mobility from early-life residence in poor urban communities is associated with lower SGA rates independent of adulthood risk status. PMID- 29492737 TI - Treatment of Tuberculous Meningitis and Its Complications in Adults. AB - PURPOSE OF REVIEW: Tuberculous meningitis (TBM) is a global health problem. In this review, we systematically evaluate the evidence for current and emerging antimicrobials, host-directed therapies and supportive managements. RECENT FINDINGS: Current antimicrobial regimes do not factor the differing ability of drugs to cross the blood-brain barrier. Rifampicin may be more effective at higher doses yet the most recent clinical trial failed to demonstrate survival benefit at 15 mg/kg/day. Dose finding studies suggest that higher doses still may be safe and more effective. Fluoroquinolones are currently listed as important second-line agents in drug-resistant TBM; however, a survival benefit as a first line agent has yet to be shown. Linezolid may be a promising antimicrobial with good central nervous system penetrance. Dexamethasone reduces mortality in HIV uninfected individuals yet evidence for its use in HIV co-infection is lacking. Aspirin has anti-inflammatory and anti-thrombotic properties. Small studies have demonstrated efficacy in reducing stroke but further research is required to better understand its effect on controlling the host inflammatory response. Discovery of genetic polymorphisms may direct individualized immune therapies and mediators of the innate immune response may provide targets for the development of novel therapies. There is at present no significant evidence base to guide management of hydrocephalus in HIV co-infection. Further clinical trial data is required to improve treatment outcomes in TBM in particularly in regard to the value of high-dose rifampicin, newer antimicrobials with improved central nervous system penetration and host-directed therapies. Supportive measures in particular the management of hydrocephalus in HIV co-infection should be an area for future research. PMID- 29492739 TI - Maternal Obesity and Risk of Preterm Birth and Low Birthweight in Hawaii PRAMS, 2000-2011. AB - Objective Maternal obesity is a risk factor for preterm birth, a leading cause of infant morbidity and mortality. Native Hawaiian and other Pacific Islanders (NHOPI) have high rates of poor birth outcomes. Despite the high rates of obesity in NHOPI in Hawaii, the association with preterm birth has not been examined in this population. Methods We performed a retrospective cohort study of 20,061 women using data collected by Hawaii's Pregnancy Risk Assessment Monitoring System (PRAMS) from 2000 to 2011. We investigated the contribution of maternal age, pre-pregnancy BMI, gestational diabetes, hypertension, race, socioeconomic status, and smoking to our primary outcomes of preterm birth and low birthweight using multivariable logistic regression, stratified by NHOPI versus non-NHOPI race. Results Pre-pregnancy obesity was more common in NHOPI than non-NHOPI women (23.9 and 10.5%, respectively; p < 0.01). Overall, the risk for preterm birth increased with maternal obesity (BMI >= 30.0; aOR = 1.24, 95% CI 1.06-1.45, p < 0.01), compared with normal weight women. Among NHOPI women, the prevalence of preterm birth was elevated compared with non-NHOPI women although the prevalence of low birth weight was lower. After adjusting for confounders, risk for preterm birth and low birth weight were elevated in NHOPI women compared with White women. Maternal obesity did not significantly affect the risk of prematurity within the NHOPI group. Conclusions for Practice Our study demonstrates an association between maternal pre-pregnancy obesity and preterm deliveries in Hawaii. NHOPI have high rates of pre-pregnancy obesity as well as increased risk of both preterm delivery and low birthweight when compared to White women. Further data are needed to assess interactions between race, maternal health, and neonatal morbidity, and to identify ways to improve birth outcomes for minority populations in the state of Hawaii. PMID- 29492740 TI - Factors Influencing the Successful Implementation of HIV Linkage and Retention Interventions in Healthcare Agencies Across New York State. AB - As part of the System Linkages and Access to Care Initiative, 12 HIV service delivery organizations in New York implemented one of the following three interventions to improve linkage to and retention in HIV care at their site: Peer Support, Appointment Procedures, and Anti-Retroviral Treatment and Access to Services. Aggregate process measure data describing intervention delivery, in conjunction with qualitative findings to help explain barriers and facilitators to achieving full implementation were examined. Process data from the interventions showed shortcomings in the percentage of eligible patients who went on to be enrolled, and the number of enrollees who ultimately received the components of the interventions. Factors identified in qualitative interviews that facilitated implementation and intervention delivery included: concerted buy in and coordination of staff, building upon existing infrastructure including ensuring sufficient staff capacity, and allowing adaptability of certain parts of the intervention to better fit patient needs and clinical settings. PMID- 29492741 TI - Smoking Predicts Food Insecurity Severity among Persons Living with HIV. AB - Food insecurity is a key social and health issue among persons living with HIV (PLHIV). Food insecurity oftentimes co-occurs with substance use, but little is known about the relationship between tobacco use and food insecurity particularly among PLHIV. In this study, we prospectively examined the association of cigarette smoking with food insecurity in a cohort of 108 individuals seeking vocational rehabilitation services. Over the 12-month study period, smokers at baseline reported consistently higher levels of food insecurity compared to non smokers. Smoking remained an independent risk factor for greater food insecurity, controlling for sociodemographic characteristics and known confounders (e.g., substance use, depression). Food insecurity is a key structural and socioeconomic barrier that may partially explain HIV-related health disparities observed among smokers. Further research is needed to characterize the bio-behavioral mechanisms linking smoking and food insecurity as well as test whether smoking cessation can reduce food insecurity in PLHIV who smoke. PMID- 29492742 TI - Family Communication About Genetic Risk of Hereditary Cardiomyopathies and Arrhythmias: an Integrative Review. AB - Screening for hereditary cardiomyopathies and arrhythmias (HCA) may enable early detection, treatment, targeted surveillance, and result in effective prevention of debilitating complications and sudden cardiac death. Screening at-risk family members for HCA is conducted through cascade screening. Only half of at-risk family members are screened for HCA. To participate in screening, at-risk family members must be aware of their risk. This often relies on communication from diagnosed individuals to their relatives. However, family communication is not well understood and is ripe for developing interventions to improve screening rates. Until very recently, family communication of genetic risk has been mostly studied in non-cardiac disease. Using this non-cardiac literature, we developed the family communication of genetic risk (FCGR) conceptual framework. The FCGR has four main elements of the communication process: influential factors, communication strategies, communication occurrence, and reaction to communication. Using the FCGR, we conducted an integrated review of the available literature on genetic risk communication in HCA families. Descriptive analysis of 12 articles resulted in the development of categories describing details of the FCGR elements in the context of HCA. This review synthesizes what is known about influential factors, communication strategies, communication occurrence, and outcomes of communication in the context of HCA. PMID- 29492743 TI - Health state utilities and subjective well-being among psoriasis vulgaris patients in mainland China. AB - PURPOSE: To investigate the validity of direct and indirect health state utility (HSU) and subjective well-being measures in psoriasis vulgaris patients. METHODS: A convenience sampling framework was used to successively recruit patients with psoriasis vulgaris from the outpatient clinics of a tertiary hospital in Changsha, Central South China. Participants completed time trade-off (TTO), standard gamble (SG), the five-level EQ-5D (EQ-5D-5L), the WHO-5 well-being index, and the psoriasis disability index (PDI). The concurrent and known-groups validity of HSUs and well-being index in psoriasis patients were firstly studied. The agreements among HSUs and the relationship between HSU and well-being measures were further explored. RESULTS: A valid sample of 343 patients was analyzed. Mean HSU and well-being scores elicited from the EQ-5D-5L/TTO/SG and WHO-5 were 0.90/0.85/0.88 and 13.69, respectively. The Spearman correlation (concurrent validity) was the strongest between PDI and WHO-5 (r = 0.45), followed by with EQ-5D-5L (0.38), SG (r = 0.20), and the TTO (r = 0.18). The pairwise intraclass correlation coefficients among the three HSU measures were < 0.30. The known-groups validity was evident in all measures except for the SG. Exploratory factor analysis further suggests a complementary relationship between the EQ-5D-5L and WHO-5. CONCLUSIONS: There is a poor agreement between direct and indirect methods on measuring HSU with psoriasis vulgaris. Results from this study recommend that the EQ-5D-5L is the most preferred method to elicit HSU from psoriasis vulgaris patients in mainland China. It is important to further analyze the subjective well-being in addition to the HSU to fully understand the impact of psoriasis. PMID- 29492744 TI - Painful or Mild-Pain Constipation? A Clinically Useful Alternative to Classification as Irritable Bowel Syndrome with Constipation Versus Functional Constipation. AB - PURPOSE: Abdominal pain is not used to characterize constipated patients. This study aimed to compare clinical, psychological, and physiological features in patients with IBS-constipation (IBS-C) with those in patients with functional constipation (FC) according to the intensity of abdominal pain. METHODS: All patients filled a standard Rome III questionnaire. In addition, they indicated the intensity of constipation, diarrhea, bloating, and abdominal pain on a 10 point Likert scale, and their stool form with the Bristol Stool Form Scale. Anxiety and depression were assessed with the Beck Depression Inventory and the State-Trait Anxiety Inventory. Physiological evaluation included anorectal manometry and total and segmental colonic transit time. MAIN RESULTS: A total of 546 consecutive patients, 245 with IBS-C and 301 with FC, were included. Painful constipation (PFC) was found by cluster analysis and subsequently defined as having a value over four on the Likert scale for abdominal pain. PFC was found in 67% of IBS-C patients and in 22% of FC patients. PFC patients have digestive disorders with greater frequency and report higher levels of constipation and bloating, despite similar stool form. They have higher scores of depression, state and trait anxiety, and shorter terminal transit time than mild-pain constipated patients. Compared to IBS-C patients, PFC patients report higher levels of abdominal pain (P < 0.001). Psychological and physiological parameters were similar in PFC and IBS-C patients. CONCLUSION: Painful constipation and mild pain constipation could be an alternative way to identify constipated patients than using the diagnosis of IBS-C and FC for clinical evaluation and drug studies. PMID- 29492745 TI - IMportance of an Irregular Z Line: Is Barrett's in the Eye of the Beholder? PMID- 29492746 TI - Improved precision in the analysis of randomized trials with survival outcomes, without assuming proportional hazards. AB - We present a new estimator of the restricted mean survival time in randomized trials where there is right censoring that may depend on treatment and baseline variables. The proposed estimator leverages prognostic baseline variables to obtain equal or better asymptotic precision compared to traditional estimators. Under regularity conditions and random censoring within strata of treatment and baseline variables, the proposed estimator has the following features: (i) it is interpretable under violations of the proportional hazards assumption; (ii) it is consistent and at least as precise as the Kaplan-Meier and inverse probability weighted estimators, under identifiability conditions; (iii) it remains consistent under violations of independent censoring (unlike the Kaplan-Meier estimator) when either the censoring or survival distributions, conditional on covariates, are estimated consistently; and (iv) it achieves the nonparametric efficiency bound when both of these distributions are consistently estimated. We illustrate the performance of our method using simulations based on resampling data from a completed, phase 3 randomized clinical trial of a new surgical treatment for stroke; the proposed estimator achieves a 12% gain in relative efficiency compared to the Kaplan-Meier estimator. The proposed estimator has potential advantages over existing approaches for randomized trials with time-to event outcomes, since existing methods either rely on model assumptions that are untenable in many applications, or lack some of the efficiency and consistency properties (i)-(iv). We focus on estimation of the restricted mean survival time, but our methods may be adapted to estimate any treatment effect measure defined as a smooth contrast between the survival curves for each study arm. We provide R code to implement the estimator. PMID- 29492747 TI - Biosimilars in the Treatment of Inflammatory Bowel Disease: Supporting Evidence in 2017. AB - PURPOSE OF REVIEW: Monoclonal antibodies targeting tumor necrosis factor-alpha, integrin molecules, and interleukin-12/23 have become backbone therapies for Crohn's disease and ulcerative colitis. While clinically effective, these biologic therapies come with significant expense, contributing to overall healthcare spending in the USA. Biosimilars have the potential to significantly reduce expenditures secondary to the use of biologic medications such as infliximab and adalimumab, though their complicated manufacturing process results in inherent differences in structure when compared to the originator compounds. In this article, we review the available literature regarding biosimilars in IBD. RECENT FINDINGS: Several biosimilar agents to infliximab and adalimumab are currently FDA-approved, with many more currently in development. Initial clinical trials for approval have been conducted in one of the original indications for each originator biologic. There are growing data demonstrating similar clinical efficacy, immunogenicity, and safety of each of the approved infliximab and adalimumab biosimilars, both through indication extrapolation from other diseases such as rheumatoid arthritis and ankylosing spondylitis, as well observational data in patients with inflammatory bowel disease. Further research is ongoing regarding the efficacy and safety of substitution and interchangeability of biosimilars, as well as therapeutic drug monitoring for biosimilar agents. Research to date supports the utilization of reference biologics and biosimilars for new initiators, while additional data are being accrued regarding the interchangeability between these agents. PMID- 29492748 TI - Cytoplasmic Hu-Antigen R (HuR) Expression is Associated with Poor Survival in Patients with Surgically Resected Cholangiocarcinoma Treated with Adjuvant Gemcitabine-Based Chemotherapy. AB - BACKGROUND: Hu-antigen R (HuR) is an RNA-binding protein that regulates the stability, translation, and nucleus-to-cytoplasm translocation of messenger RNAs (mRNAs). OBJECTIVE: The aim of this study was to investigate the prognostic significance of HuR in cholangiocarcinoma patients who received adjuvant gemcitabine-based chemotherapy (AGC) after surgical resection. METHODS: Nuclear and cytoplasmic HuR expression was investigated immunohistochemically in 131 patients with resected cholangiocarcinoma, including 91 patients administered AGC and 40 patients who did not receive adjuvant chemotherapy. The correlation between HuR expression and survival was evaluated by statistical analysis. RESULTS: High nuclear and cytoplasmic HuR expression was observed in 67 (51%) and 45 (34%) patients, respectively. Cytoplasmic HuR expression was significantly associated with lymph node metastasis (p < 0.01), while high cytoplasmic HuR expression was significantly associated with poor disease-free survival [DFS] (p = 0.03) and overall survival [OS] (p = 0.001) in the 91 patients who received AGC, but not in the 40 patients who did not receive AGC (DFS p = 0.17; OS p = 0.07). In the multivariate analysis of patients who received AGC, high cytoplasmic HuR expression was an independent predictor of poor DFS (hazard ratio [HR] 1.77; p = 0.04) and OS (HR 2.09; p = 0.02). Nuclear HuR expression did not affect the survival of enrolled patients. CONCLUSIONS: High cytoplasmic HuR expression was closely associated with the efficacy of AGC in patients with cholangiocarcinoma. The current findings warrant further investigations to optimize adjuvant chemotherapy regimens for resectable cholangiocarcinoma. PMID- 29492750 TI - Progressive microstructural changes of the occipital cortex in Huntington's disease. AB - In this study we longitudinally investigated the rate of microstructural alterations in the occipital cortex in different stages of Huntington's disease (HD) by applying an automated atlas-based approach to diffusion MRI data. Twenty two premanifest (preHD), 10 early manifest HD (early HD) and 24 healthy control subjects completed baseline and two year follow-up scans. The preHD group was stratified based on the predicted years to disease onset into a far (preHD-A) and near (preHD-B) to disease onset group. Clinical and behavioral measures were collected per assessment time point. An automated atlas-based DTI analysis approach was used to obtain the mean, axial and radial diffusivities of the occipital cortex. We found that the longitudinal rate of diffusivity change in the superior occipital gyrus (SOG), middle occipital gyrus (MOG), and inferior occipital gyrus (IOG) was significantly higher in early HD compared to both preHD and controls (all p's <= 0.005), which can be interpreted as an increased rate of microstructural degeneration. Furthermore, the change rate in the diffusivity of the MOG could significantly discriminate between preHD-B compared to preHD-A and the other groups (all p's <= 0.04). Finally, we found an inverse correlation between the Stroop Word Reading task and diffusivities in the SOG and MOG (all p's <= 0.01). These findings suggest that measures obtained from the occipital cortex can serve as sensitive longitudinal biomarkers for disease progression in preHD-B and early HD. These could in turn be used to assess potential effects of proposed disease modifying therapies. PMID- 29492751 TI - Pain Control After Bariatric Surgery: We Still Need More Answers. PMID- 29492749 TI - Comparative Transcriptome Analysis Reveals Growth-Related Genes in Juvenile Chinese Sea Cucumber, Russian Sea Cucumber, and Their Hybrids. AB - Heterosis is important for sea cucumber breeding, but its molecular mechanism remains largely unexplored. In this study, parental lines of Apostichopus japonicus from Russia (R) and China (C) were used to construct hybrids (CR and RC) by reciprocal crossing. We examined the transcriptional profiles of the hybrids (CR and RC) and the purebreds (CC and RR) at different developmental times. A total of 60.27 Gb of clean data was obtained, and 176,649 unigenes were identified, of which 50,312 unigenes were annotated. A total of 414,536 SNPs were identified. A total of 7011 differentially expressed genes (DEGs) were obtained between the purebreds and hybrids at 45 days after fertilization (DAF), and a total of 8218 DEGs were obtained between the purebreds and hybrids at 75 DAF. In addition, a total of 7652 DEGs were obtained between 45 DAF and 75 DAF. The significant DEGs were mainly involved in the MAPK and FOXO signaling pathways, especially in the Ras-Raf-MEK1/2-ERK module, which may be a key regulator of development and growth in juvenile A. japonicus. In addition, we also identified key growth-related genes, such as fgfs, igfs, megfs and hgfs, which were upregulated in the hybrids (RC and CR); these genes may play important roles in heterosis in A. japonicus. Our study provides fundamental information on the molecular mechanisms underlying heterosis in sea cucumber and might suggest strategies for the selection of rapidly growing strains of sea cucumber in aquaculture. PMID- 29492752 TI - Variability in Bariatric Surgical Care Among Various Centers: a Survey of All Bariatric Surgeons in the Province of Quebec, Canada. AB - BACKGROUND: Despite an increase in bariatric surgery across Quebec, Canada, access is still limited. Furthermore, there are differences in resources and multidisciplinary capabilities of providing centers that may impact quality of care and outcomes. METHODS: We performed an online survey of all bariatric surgeons in the province of Quebec, Canada, using the LimeSurvey software. RESULTS: Forty-six surgeons from 15 centers were surveyed. Response rate was 87% (n = 40). Only 13 (35%) surgeons have any formal fellowship training in bariatric surgery and 74% perform > 50 cases/year. All surgeons perform sleeve gastrectomy, 34% do duodenal switch, and 44% provide major revisions. Thirty-one surgeons (77%) identified access to operating room as the main cause for surgical delays. While most surgeons (52%) considered < 6 months as an acceptable wait-time, only 33% achieved this in their practice. Majority (70%) favored a centralized provincial referral system. Patient's geographical convenience, procedural choice, and multidisciplinary capabilities of providing centers are identified as important determinants for centralized referrals (93, 78, and 55%, respectively). Virtually, all supported accreditation/designation of centers and creation of Quebec Bariatric Network for quality control and research (85 and 98%, respectively). CONCLUSION: Bariatric surgical patterns vary among designated centers in Quebec, Canada. Access to multidisciplinary care and surgeon's fellowship training may be contributing factors for the observed variability. Wait-lists are long and timely access to surgery remains an issue. There is near consensus for establishing a centralized referral system, designation of referral vs. primary centers, and creating Quebec Bariatric Network for research and quality control. PMID- 29492753 TI - Use of a web-based app to improve breast cancer symptom management and adherence for aromatase inhibitors: a randomized controlled feasibility trial. AB - PURPOSE: For postmenopausal women with hormone receptor-positive breast cancer, long-term use of aromatase inhibitors (AIs) significantly reduces the risk of cancer recurrence and improves survival. Still, many patients are nonadherent due to adverse side effects. We conducted a pilot randomized controlled trial to test the use of a web-based application (app) designed with and without weekly reminders for patients to report real-time symptoms and AI use outside of clinic visits with built-in alerts to patients' oncology providers. Our goal was to improve symptom burden and medication adherence. METHODS: Forty-four women with early-stage breast cancer and a new AI prescription were randomized to either an App+Reminder (weekly reminders to use app) or an App (no reminders) group. Pre- and post-assessment data were collected from all participants. RESULTS: Participants in the App+Reminder group had higher weekly app usage rate (74 vs. 38%, p < 0.05) during the intervention and reported higher AI adherence at 8 weeks (100 vs. 72%, p < 0.05). Symptom burden increase was higher for the App group compared to the App+Reminder group but did not reach statistical significance. CONCLUSIONS: Weekly reminders to use a web-based app to report AI adherence and treatment-related symptoms demonstrated feasibility and improved short-term AI adherence, which may reduce symptom burden for women with breast cancer and a new AI prescription. IMPLICATIONS FOR CANCER SURVIVORS: If short term gains in adherence persist, this low-cost intervention could improve survival outcomes for women with breast cancer. A larger, long-term study should examine if AI adherence and symptom burden improvements persist for a 5-year treatment period. PMID- 29492754 TI - Associations between physical activity and comorbidities in Korean cancer survivors. AB - PURPOSE: To examine the associations between physical activity, metabolic risk factors, and comorbidities in Korean cancer survivors. METHODS: We used multiple cross-sectional data sets from the 2007-2013 Korean National Health and Nutrition Examination Surveys (KNHANES) that included 1225 cancer survivors. Physical activity and comorbidities were self-reported. Metabolic risk factors were measured via blood analyses and included fasting glucose, insulin, total cholesterol, triglycerides, and blood pressure. RESULTS: The sample was 38.4% male with a mean age of 59.9 +/- 12.4 years. The most common cancers were stomach (22.5%), cervical (14.6%), breast (14.4%), and colorectal (11.8%). Cancer survivors meeting aerobic physical activity guidelines, compared to those completely inactive, had significantly lower fasting glucose (p = .001), HbA1c (p = .006), and systolic blood pressure (p = .001), and significantly lower risks of hypertension (odds ratio [OR] = 0.55, 95% confidential interval [CI] = 0.32 to 0.93), diabetes (OR = 0.64, 95% CI = 0.43 to 0.95), and arthritis (OR = 0.64, 95% CI = 0.41 to 0.99). Moreover, cancer survivors meeting strength exercise guidelines, compared to those not meeting guidelines, had significantly lower levels of fasting glucose (p = .001), HbA1c (p < .001), and total cholesterol (p = .031), and significantly lower risks of arthritis (OR = 0.42, 95% CI = 0.25 to 0.85) and back pain (OR = 0.50, 95% CI = 0.30 to 0.83). CONCLUSION: Aerobic physical activity and strength exercise were significantly associated with lower risks of metabolic disturbances and comorbidities in Korean cancer survivors. IMPLICATIONS FOR CANCER SURVIVORS: Cancer survivors should engage in at least 150 min/week of aerobic exercise and at least 2 days/week of strength exercise to lower their risk of metabolic disturbances and comorbidities. PMID- 29492755 TI - Profound Interfacial Effects in CoFe2O4/Fe3O4 and Fe3O4/CoFe2O4 Core/Shell Nanoparticles. AB - Two sets of core/shell magnetic nanoparticles, CoFe2O4/Fe3O4 and Fe3O4/CoFe2O4, with a fixed diameter of the core (~ 4.1 and ~ 6.3 nm for the former and latter sets, respectively) and thickness of shells up to 2.5 nm were synthesized from metal chlorides in a diethylene glycol solution. The nanoparticles were characterized by X-ray diffraction, transmission electron microscopy, and magnetic measurements. The analysis of the results of magnetic measurements shows that coating of magnetic nanoparticles with the shells results in two simultaneous effects: first, it modifies the parameters of the core-shell interface, and second, it makes the particles acquire combined features of the core and the shell. The first effect becomes especially prominent when the parameters of core and shell strongly differ from each other. The results obtained are useful for optimizing and tailoring the parameters of core/shell spinel ferrite magnetic nanoparticles for their use in various technological and biomedical applications. PMID- 29492756 TI - The Standard Account of Moral Distress and Why We Should Keep It. AB - In the last three decades, considerable theoretical and empirical research has been undertaken on the topic of moral distress among health professionals. Understood as a psychological and emotional response to the experience of moral wrongdoing, there is evidence to suggest that-if unaddressed-it contributes to staff demoralization, desensitization and burnout and, ultimately, to lower standards of patient safety and quality of care. However, more recently, the concept of moral distress has been subjected to important criticisms. Specifically, some authors argue that the standard account of moral distress elucidated by Jameton (AWHONN's Clin Issues Perinat Women's Health 4(4):542-551, 1984) does not refer to a discrete phenomenon and/or that it is not sufficiently broad and that this makes measuring its prevalence among health professionals, and other groups of workers, difficult if not impossible. In this paper, we defend the standard account of moral distress. We understand it as a concept that draws attention to the social, political and contextual determinants of moral agency and brings the emotional landscape of the moral realm to the fore. Given the increasing pressure on health professionals worldwide to meet efficiency, financial and corporate targets and reported adverse effects of these for the quality and safety of patient care, we believe that further empirical research that deploys the standard account moral distress is timely and important. PMID- 29492757 TI - Glibenclamide Prevents Water Diffusion Abnormality in the Brain After Cardiac Arrest in Rats. AB - BACKGROUND: Glibenclamide (GBC) improves neurological outcome after cardiac arrest (CA) in rats. In this study, we sought to elucidate the mechanism responsible for the neuroprotective effects of GBC by using a high-field MRI system. METHODS: Male Sprague-Dawley rats were subjected to 10-min asphyxial CA followed by cardiopulmonary resuscitation (CPR). Diffusion-weighted imaging (DWI) as well as conventional T2-weighted imaging was conducted prior to CA and at 24, 48, and 72 h after resuscitation. Afterward, histological examination was performed. RESULTS: Twelve rats were randomized to receive GBC (n = 6) or vehicle (n = 6) at 15 min after return of spontaneous circulation, while four rats were set as sham control. Rats that underwent CA/CPR and received vehicle exhibited distinct neurological deficit, which was alleviated by GBC treatment. Marked water diffusion abnormality as demonstrated by hyperintense DWI in vulnerable regions of the brain was detected after CA/CPR, with the most prominent hyperintense DWI observed in the hippocampal CA1 region at 72 h. Consistently, histological examination revealed neuronal swelling, dendritic injury, and activation of astrocytes and microglia in the hippocampal CA1 region in vehicle treated rats. Correlation analysis revealed that the ADC values in the hippocampus were significantly correlated with the histological findings (all p < 0.05). CONCLUSION: These results suggest that the neuroprotective effects of GBC after CA was exerted, as least in part, through prevention of water diffusion abnormality, namely brain edema. PMID- 29492759 TI - Perceptual sensitivity to spectral properties of earlier sounds during speech categorization. AB - : Speech perception is heavily influenced by surrounding sounds. When spectral properties differ between earlier (context) and later (target) sounds, this can produce spectral contrast effects (SCEs) that bias perception of later sounds. For example, when context sounds have more energy in low-F1 frequency regions, listeners report more high-F1 responses to a target vowel, and vice versa. SCEs have been reported using various approaches for a wide range of stimuli, but most often, large spectral peaks were added to the context to bias speech categorization. This obscures the lower limit of perceptual sensitivity to spectral properties of earlier sounds, i.e., when SCEs begin to bias speech categorization. Listeners categorized vowels (/i/-/E/, Experiment 1) or consonants (/d/-/g/, Experiment 2) following a context sentence with little spectral amplification (+1 to +4 dB) in frequency regions known to produce SCEs. In both experiments, +3 and +4 dB amplification in key frequency regions of the context produced SCEs, but lesser amplification was insufficient to bias performance. This establishes a lower limit of perceptual sensitivity where spectral differences across sounds can bias subsequent speech categorization. These results are consistent with proposed adaptation-based mechanisms that potentially underlie SCEs in auditory perception. SIGNIFICANCE STATEMENT: Recent sounds can change what speech sounds we hear later. This can occur when the average frequency composition of earlier sounds differs from that of later sounds, biasing how they are perceived. These "spectral contrast effects" are widely observed when sounds' frequency compositions differ substantially. We reveal the lower limit of these effects, as +3 dB amplification of key frequency regions in earlier sounds was enough to bias categorization of the following vowel or consonant sound. Speech categorization being biased by very small spectral differences across sounds suggests that spectral contrast effects occur frequently in everyday speech perception. PMID- 29492758 TI - Hemodynamic, Biochemical, and Ventilatory Parameters are Independently Associated with Outcome after Cardiac Arrest. AB - BACKGROUND: Hypotension, hyperglycemia, dysoxia, and dyscarbia may contribute to reperfusion injury, and each is independently associated with poor outcome (PO) after cardiac arrest. We investigated whether the combined effects of these physiological derangements are associated with cardiac arrest outcomes. METHODS: This institutional review board-approved retrospective cohort study included consecutive resuscitated cardiac arrest patients that received targeted temperature management at Maine Medical Center from 2013 to 2015. We abstracted demographics, intra-arrest factors, and physiological parameters. The primary outcome was dichotomized cerebral performance category (CPC 1-2 vs 3-5) at hospital discharge. After comparing demographics, clinical factors, and persistent post-arrest physiological derangements in patients with good and PO, we constructed a logistic regression model comprised of clinical and demographic factors separately associated with severity, and physiology variables, attempting to evaluate the independent effects of persistent physiological derangements on outcome. RESULTS: Sixty-eight of 222 (31%) patients had CPC 1-2 (good outcome [GO]) at discharge. In bivariate analysis, factors associated with PO included increased time from collapse to resuscitation, non-shockable rhythm, and age combined Charlson comorbidity index. In multivariate analysis, each persistent physiological derangement incrementally decreased the likelihood of GO [OR GO per derangement 0.71 (interquartile range [IQR] 0.51-0.99), p = 0.042, area under the curve (AUC) for final model 0.769]. CONCLUSIONS: Uncorrected physiological derangements in the first 24 h after cardiac arrest are independently associated with PO. Although causality cannot be established, these findings support preclinical models suggesting that aggressive normalization of physiology after resuscitation may be a reasonable strategy to decrease reperfusion injury. PMID- 29492760 TI - The Relationship Between Exclusions from Gambling Arcades and Accessibility: Evidence from a Newly Introduced Exclusion Program in Hesse, Germany. AB - An exclusion system for gambling arcades has been introduced recently in the state of Hesse. The aim of this paper is to identify significant predictors that are useful in explaining the variation of exclusions between different Hessian communities. Next to socio-demographic factors, we control for three different accessibility variables in two models: the number of electronic gambling machines (EGMs) in model I, and the number of locations and density of gambling machines at a location in model II. We disentangle the association between EGMs and exclusions of model I into a location and a clustering effect. Considering the socio-demographic variables, the explanatory power of our cross-sectional models is rather low. Only the age group of the 30-39 years old and those who are not in a partnership (in model I) yield significant results. As self-exclusion systems reduce availability for the group of vulnerable players, this analysis provides evidence for the assumption that the two groups-pathological gamblers and vulnerable players-seem to have little overlap concerning sociodemographic characteristics. The accessibility variables, on the other hand, turn out to be significantly associated with the number of exclusions. All three of them are statistically significant and their association is positive. The results of model II show that the location effect is more pronounced then the clustering effect of EGMs, i.e. the effect of an additional single-licensed arcade on the number of exclusions is stronger than the increase in the number of license at one location. PMID- 29492761 TI - Laparoscopic pancreatic resections in two medium-sized medical centres. AB - To analyze the clinical outcomes of patients undergoing minimally invasive surgery for pancreatic neoplasms, in two medium-volume centers in Northern Italy, a retrospective chart review was performed in the operative registries, searching for patients who had undergone pancreatic surgery via laparoscopy, irrespective of the final pathological nature of the resected neoplasm. For each case, a standard data extraction form was completed and the following data was extracted: age and sex, type of resection, estimated blood loss, length of the operation, number of harvested nodes, post-operative pancreatic fistula, major post operative complications, mortality and final pathological diagnosis. The systematic literature research was also undertaken and the reported results were analyzed. A total of 55 cases were recorded, including 39 distal pancreatectomies and 16 pancreaticoduodenectomies. The most frequent indications leading to surgery were ductal adenocarcinoma (26 pts) and cystic neoplasm (22 pts). No post operative death occurred in this series; pancreatic fistula occurred in 64% of distal pancreatectomies and 22% of pancreaticoduodenectomies. The mean operating times were 178' and 572', respectively. Both distal pancreatectomy and pancreaticoduodenectomy proved to be feasible and were safely performed by laparoscopy, in two centers with medium-volume pancreatic caseload. PMID- 29492762 TI - Cabozantinib Versus Standard-of-Care Comparators in the Treatment of Advanced/Metastatic Renal Cell Carcinoma in Treatment-naive Patients: a Systematic Review and Network Meta-Analysis. AB - BACKGROUND: Cabozantinib has recently been evaluated as a first-line treatment in advanced renal cell carcinoma (aRCC). OBJECTIVE: To indirectly assess efficacy of cabozantinib versus standard-of-care (SoC) comparators in the first-line treatment of aRCC. METHODS: We conducted a systematic literature review (SLR) to identify randomized controlled studies in the first-line setting for aRCC. The outcomes analyzed were overall survival (OS) and progression-free survival (PFS). A network meta-analysis (NMA) was conducted comparing OS and PFS hazard ratios (HRs). RESULTS: Thirteen studies were identified in the SLR to be eligible for inclusion in the NMA. The overall study populations were heterogeneous in terms of risk groups; some studies included favorable risk patients. In intermediate risk patients, HRs (95% confidence interval) for PFS were 0.52 (0.33, 0.82), 0.46 (0.26, 0.80), 0.20 (0.12, 0.36), and 0.37 (0.20, 0.68) when cabozantinib was compared with sunitinib, sorafenib, interferon (IFN), or bevacizumab plus IFN, respectively. In poor-risk patients, the NMA also demonstrated significant superiority in terms of PFS for cabozantinib; HRs were 0.31 (0.11, 0.90), 0.22 (0.06, 0.87), 0.16 (0.04, 0.64), and 0.20 (0.05, 0.88), when cabozantinib was compared with sunitinib, temsirolimus, IFN, or bevacizumab plus IFN, respectively. When the overall study populations were compared, the results were similar to the subgroup analyses. OS HRs in all analyses favored cabozantinib, but were not statistically significant. CONCLUSIONS: The results suggest that cabozantinib significantly increases PFS in intermediate-, and poor-risk subgroups when compared to standard-of-care comparators. Although overall populations included favorable risk patients in some studies, the results seen were consistent with the subgroup analyses. PMID- 29492763 TI - Clinical forensic aspects of self-inflicted neck injuries. AB - The distinction between self-inflicted injuries and other types of injuries is crucial in forensic medicine, and relevant features of wounds should be identified by pathologists, even when they are observed at atypical sites. Herein we report two cases of self-inflicted injuries of the neck involving two young women who had reported being attacked by men. PMID- 29492764 TI - Fatal air embolism in hospital confirmed by autopsy and postmortem computed tomography. AB - Vascular air embolism is caused by penetration of air into veins or arteries through a surgical wound or other connection between the external and internal aspects of the body. Vascular air embolism has various causes, and iatrogenic air embolisms are the most frequently described. We report a case of fatal air embolism in an 83-year-old woman who was admitted to hospital. At the time of the incident, she was alone in her ward receiving an intravenous infusion of antibiotics via a peripheral line in her right forearm. She was also inhaling air through a mask, which was connected via a tubing system to a compressed air connection in the wall behind her bed. Autopsy and postmortem computed tomography (PMCT) findings are presented. The case illustrates the high diagnostic value of PMCT, which is an effective procedure for detecting the presence of air or gas. PMID- 29492765 TI - Emerging ICT for Citizens' Veillance: Theoretical and Practical Insights. AB - In ubiquitous surveillance societies, individuals are subjected to observation and control by authorities, institutions, and corporations. Sometimes, citizens contribute their own knowledge and other resources to their own surveillance. In addition, some of "the watched" observe "the watchers" "through" sous-veillant activities, and various forms of self-surveillance for different purposes. However, information and communication technologies are also increasingly used for social initiatives with a bottom up structure where citizens themselves define the goals, shape the outcomes and profit from the benefits of watching activities. This model, which we define as citizens' veillance and explore in this special issue, may present opportunities for individuals and collectives to be more prepared to meet the challenges they face in various domains including environment, health, planning and emergency response. PMID- 29492768 TI - A Systematic Review and Meta-Analysis of Disparities in the Prevalence of Suicide Ideation and Attempt Among Bisexual Populations. AB - Sexual minorities are at increased risk of suicide; however, it is unclear whether there are within-sexual minority differences in risk across specific sexual identities-notably between bisexual and lesbian/gay subgroups. We therefore conducted a systematic review and meta-analysis to quantify associations between bisexual identity and self-reported suicide ideation and attempt and the moderation of these associations by gender/sex, age, sampling strategy, and measurement of sexuality. Abstracts and full texts were independently screened by two reviewers, resulting in a total of 46 studies that met inclusion criteria and reported 12-month or lifetime prevalence estimates for suicide ideation or attempt. A consistent gradient was observed across all four outcomes, whereby bisexual respondents reported the highest proportion of suicide ideation or attempt, lesbian/gay respondents the next highest proportion, and heterosexual respondents the lowest proportion. Random-effects meta-analysis comparing bisexual individuals with lesbian/gay individuals yielded odds ratios (ORs) ranging between 1.22-1.52 across the four outcomes examined. Between-study variability in ORs was large. Thirty-one percent of heterogeneity was explained by sample type (e.g., probability vs. non-probability) and 17% by gender/sex. ORs were consistently larger for women (range: 1.48-1.95, all statistically significant at p < .05) than for men (range: 1.00-1.48, all p > .05), suggesting that gender/sex moderates the association between bisexual identity and suicide risk. Within-sexual minority differences in suicide risk may be attributed to structural and interpersonal experiences of monosexism, bisexual erasure and invisibility, or lack of bisexual-affirming social support, each of which may be experienced differently across gender/sex identities. PMID- 29492767 TI - Surgical treatment of large vestibular schwannomas in patients with neurofibromatosis type 2: outcomes on facial nerve function and hearing preservation. AB - Surgical treatment of vestibular schwannoma (VS) in patients with neurofibromatosis type 2 (NF2) along with functional preservation of cranial nerves is challenging. The aim of this study was to analyze the outcomes of hearing and facial nerve function in patients with NF2 who underwent large-size VS (> 2 cm) surgery. From 2006 to 2016, one hundred and forty NF2 patients were included with 149 large-size VS resections using retrosigmoid approach. Hearing function was classified according to the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) criteria. Preoperative and one-year postoperative facial nerve function were both assessed using the House-Brackmann (H-B) grading scale. A multivariate logistic regression was performed to identify preoperative predictors for facial function outcomes. No operative death we noted. Total tumor removal was achieved in 82.6% of the operated VSs. The anatomical integrity of the facial nerve was preserved in 67.8% of surgeries. Good facial nerve function (H-B Grades I-III) was maintained in 49.6% of patients at 12 months after surgery. Tumor size larger than 3 cm and preoperative facial weakness related with worse outcome of facial nerve function (P < 0.001; for both). Hearing preservation surgeries were attempted in 31 ears. Class B or C hearing according to the AAO-HNS criteria was maintained in 7 ears (22.5%), and measurable hearing was maintained 11 ears (35.5%). It is challenging to maintain hearing and facial nerve function in NF2 patients with large VSs. Early surgical intervention is an appropriate choice to decrease the risk of neurological functions deficit. PMID- 29492769 TI - Indole acetic acid overproduction transformants of the rhizobacterium Pseudomonas sp. UW4. AB - The plant growth-promoting rhizobacterium Pseudomonas sp. UW4 was transformed to increase the biosynthesis of the auxin, indole-3-acetic acid (IAA). Four native IAA biosynthesis genes from strain UW4 were individually cloned into an expression vector and introduced back into the wild-type strain. Quantitative real-time polymerase chain reaction analysis revealed that the introduced genes ami, nit, nthAB and phe were all overexpressed in these transformants. A significant increase in the production of IAA was observed for all modified strains. Canola plants inoculated with the modified strains showed enhanced root elongation under gnotobiotic conditions. The growth rate and 1-aminocyclopropane 1-carboxylate deaminase activity of transformant strains was lower compared to the wild-type. The indoleacetic acid biosynthesis pathways and the role of this phytohormone in the mechanism of plant growth stimulation by Pseudomonas sp. UW4 is discussed. PMID- 29492766 TI - Protective Effects of Cornel Iridoid Glycoside in Rats After Traumatic Brain Injury. AB - Cornel iridoid glycoside (CIG) is the active ingredient extracted from Cornus officinalis. Our previous studies showed that CIG had protective effects on several brain injury models. In the present study, we aimed to examine the effects and elucidate the mechanisms of CIG against traumatic brain injury (TBI). TBI was induced in the right cerebral cortex of male adult rats. The neurological and cognitive functions were evaluated by modified neurological severity score (mNSS) and object recognition test (ORT), respectively. The level of serum S100beta was measured by an ELISA method. Nissl staining was used to estimate the neuron survival in the brain. The expression of proteins was determined by western blot and/or immunohistochemical staining. We found that intragastric administration of CIG in TBI rats ameliorated the neurological defects and cognitive impairment, and alleviated the neuronal loss in the injured brain. In the acute stage of TBI (24-72 h), CIG decreased the level of S100beta in the serum and brain, increased the ratio of Bcl-2/Bax and decreased the expression of caspase-3 in the injured cortex. Moreover, the treatment with CIG for 30 days increased the levels of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), enhanced the expression of synapsin I, synaptophysin and postsynaptic density protein 95 (PSD-95), and inhibited the apoptosis-regulating factors in the chronic stage of TBI. The present study demonstrated that CIG had neuroprotective effects against TBI through inhibiting apoptosis in the acute stage and promoting neurorestoration in the chronic stage. The results suggest that CIG may be beneficial to TBI therapy. PMID- 29492771 TI - Corrosion of bare carbon steel as a passive sensor to assess moisture availability for biological activity in Atacama Desert soils. AB - Here we consider that the corrosion of polished bared metal coupons can be used as a passive sensor to detect or identify the lower limit of water availability suitable for biological activity in Atacama Desert soils or solid substrates. For this purpose, carbon steel coupons were deposited at selected sites along a west east transect and removed at predetermined times for morphological inspection. The advantage of this procedure is that the attributes of the oxide layer (corrosion extent, morphology and oxide phases) can be considered as a fingerprint of the atmospheric moisture history at a given time interval. Two types of coupons were used, long rectangular shaped ones that were half-buried in a vertical position, and square shaped ones that were deposited on the soil surface. The morphological attributes observed by SEM inspection were found to correlate to the so-called humectation time which is determined from local meteorological parameters. The main finding was that the decreasing trend of atmospheric moisture along the transect was closely related to corrosion behaviour and water soil penetration. For instance, at the coastal site oxide phases formed on the coupon surface rapidly evolve into well-crystallized species, while at the driest inland site Lomas Bayas only amorphous oxide was observed on the coupons. PMID- 29492770 TI - Assessing bat droppings and predatory bird pellets for vector-borne bacteria: molecular evidence of bat-associated Neorickettsia sp. in Europe. AB - In Europe, several species of bats, owls and kestrels exemplify highly urbanised, flying vertebrates, which may get close to humans or domestic animals. Bat droppings and bird pellets may have epidemiological, as well as diagnostic significance from the point of view of pathogens. In this work 221 bat faecal and 118 bird pellet samples were screened for a broad range of vector-borne bacteria using PCR-based methods. Rickettsia DNA was detected in 13 bat faecal DNA extracts, including the sequence of a rickettsial insect endosymbiont, a novel Rickettsia genotype and Rickettsia helvetica. Faecal samples of the pond bat (Myotis dasycneme) were positive for a Neorickettsia sp. and for haemoplasmas of the haemofelis group. In addition, two bird pellets (collected from a Long-eared Owl, Asio otus, and from a Common Kestrel, Falco tinnunculus) contained the DNA of a Rickettsia sp. and Anaplasma phagocytophilum, respectively. In both of these bird pellets the bones of Microtus arvalis were identified. All samples were negative for Borrelia burgdorferi s.l., Francisella tularensis, Coxiella burnetii and Chlamydiales. In conclusion, bats were shown to pass rickettsia and haemoplasma DNA in their faeces. Molecular evidence is provided for the presence of Neorickettsia sp. in bat faeces in Europe. In the evaluated regions bat faeces and owl/kestrel pellets do not appear to pose epidemiological risk from the point of view of F. tularensis, C. burnetii and Chlamydiales. Testing of bird pellets may provide an alternative approach to trapping for assessing the local occurrence of vector-borne bacteria in small mammals. PMID- 29492772 TI - Thermogravimetric analysis, kinetic study, and pyrolysis-GC/MS analysis of 1,1' azobis-1,2,3-triazole and 4,4'-azobis-1,2,4-triazole. AB - BACKGROUND: In general, the greater the number of directly linked nitrogen atoms in a molecule, the better its energetic performance, while the stability will be accordingly lower. But 1,1'-azobis-1,2,3-triazole (1) and 4,4'-azobis-1,2,4 triazole (2) show remarkable properties, such as high enthalpies of formation, high melting points, and relatively high stabilities. In order to rationalize this unexpected behavior of the two compounds, it is necessary to study their thermal decompositions and pyrolyses. Although a great deal of research has been focused on the synthesis and characterization of energetic materials with 1 and 2 as the backbone, a complete report on their fundamental thermodynamic parameters and thermal decomposition properties has not been published. METHODS: Thermogravimetric-differential scanning calorimetry were used to obtain the thermal decomposition data of the title compounds. Kissinger and Ozawa-Doyle methods, the two selected non-isothermal methods, are presented for analysis of the solid-state kinetic data. Pyrolysis-gas chromatography/mass spectrometry was used to study the pyrolysis process of the title compounds. RESULTS: The DSC curves show that the thermal decompositions of 1 and 2 are at different heating rates involved a single exothermic process. The TG curves provide insight into the total weight losses from the compounds associated with this process. At different pyrolysis temperatures, the compositions and types of the pyrolysis products differ greatly and the pyrolysis reaction at 500 degrees C is more thorough than 400 degrees C. CONCLUSIONS: Apparent activation energies (E) and pre-exponential factors (lnA/s-1) are 291.4 kJ mol-1 and 75.53 for 1; 396.2 kJ mol-1 and 80.98 for 2 (Kissinger). The values of E are 284.5 kJ mol-1 for 1 and 386.1 kJ mol-1 for 2 (Ozawa-Doyle). The critical temperature of thermal explosion (T b ) is evaluated as 187.01 degrees C for 1 and 282.78 degrees C for 2. The title compounds were broken into small fragment ions under the pyrolysis conditions, which then might undergo a multitude of collisions and numerous other reactions, resulting in the formation of C2N2 (m/z 52), etc., before being analyzed by the GC/MS system. PMID- 29492773 TI - Electron Transfer Dissociation and Collision-Induced Dissociation of Underivatized Metallated Oligosaccharides. AB - Electron transfer dissociation (ETD) and collision-induced dissociation (CID) were used to investigate underivatized, metal-cationized oligosaccharides formed via electrospray ionization (ESI). Reducing and non-reducing sugars were studied including the tetrasaccharides maltotetraose, 3alpha,4beta,3alpha galactotetraose, stachyose, nystose, and a heptasaccharide, maltoheptaose. Univalent alkali, divalent alkaline earth, divalent and trivalent transition metal ions, and a boron group trivalent metal ion were adducted to the non permethylated oligosaccharides. ESI generated [M + Met]+, [M + 2Met]2+, [M + Met]2+, [M + Met - H]+, and [M + Met - 2H]+ most intensely along with low intensity nitrate adducts, depending on the metal and sugar ionized. The ability of these metal ions to produce oligosaccharide adduct ions by ESI had the general trend: Ca(II) > Mg(II) > Ni(II) > Co(II) > Zn(II) > Cu(II) > Na(I) > K(I) > Al(III) ~ Fe(III) ~ Cr(III). Although trivalent metals were utilized, no triply charged ions were formed. Metal cations allowed for high ESI signal intensity without permethylation. ETD and CID on [M + Met]2+ produced various glycosidic and cross-ring cleavages, with ETD producing more cross-ring and internal ions, which are useful for structural analysis. Product ion intensities varied based on glycosidic-bond linkage and identity of monosaccharide sub-unit, and metal adducts. ETD and CID showed high fragmentation efficiency, often with complete precursor dissociation, depending on the identity of the adducted metal ion. Loss of water was occasionally observed, but elimination of small neutral molecules was not prevalent. For both ETD and CID, [M + Co]2+ produced the most uniform structurally informative dissociation with all oligosaccharides studied. The ETD and CID spectra were complementary. Graphical Abstract ?. PMID- 29492774 TI - Left and right ventricular parameters corrected with threshold-based quantification method in a normal cohort analyzed by three independent observers with various training-degree. AB - While cardiac magnetic resonance (CMR) is the reference method to evaluate left and right ventricular functions, volumes and masses, there is no widely accepted method for the quantitative analysis of trabeculae and papillary muscles (TPM). The aim of this study was to investigate the effect of TPM quantification on left and right ventricular CMR values in a normal cohort and to investigate interobserver variability of threshold-based (TB) analysis by three independent observers with variant experience in CMR. At our clinic, 60 healthy volunteers (30 males, mean age 25.6 +/- 4.7 years) underwent CMR scan performed on a 1.5T Philips Achieva MR machine. On short-axis cine images, endo- and epicardial contours were detected by three independent observers with variable experience in CMR (low- ca. 120, mid- > 800, high-experienced > 5000 original CMR cases). Using Conv and TB methods (Medis 7.6 QMass software Leiden, The Netherland), we measured LV and RV ejection fractions, end-diastolic, end-systolic, stroke volumes and masses. We used TB method for quantifying TPM in ventricles using epicardial contour layers. Interobserver variability was evaluated, and the observer's experience as an impact on variability of each investigated parameters was assessed. Comparing Conv and TB quantification methods' significant difference were detected for all LV and RV parameters in case of all observers (H, M and L p < 0.0001). The global intraclass correlation coefficient (G-ICC) representing interobserver agreement for all investigated parameters was lower with Conv method (G-ICCConv vs. G-ICCTB 0.86 vs. 0.92 p < 0.0001). The ICC of LV parameters was higher using TB quantification (LV-ICCConv vs. LV-ICCTB 0.92 vs. 0.96 p < 0.0001), and for the evaluation of RV values, the TB method also had significantly higher interobserver agreement (RV-ICCConv vs. RV-ICCTB 0.80 vs. 0.89 p < 0.0001). The TB algorithm could be a consistent method to assess LV and RV CMR values, and to measure trabeculae and papillary muscles quantitatively in various level of experience in CMR. PMID- 29492775 TI - Healing score of the Xinsorb scaffold in the treatment of de novo lesions: 6 month imaging outcomes. AB - The objectives of this study are to assess the healing score (HS) and neointimal thickness of the Xinsorb scaffold, and explore the relationships between the implanted patterns, neointimal thickness, and HS. The Xinsorb bioresorbable sirolimus-eluting scaffold is the first domestically designed and fabricated bioresorbable scaffold in China. The 6-month follow-up found it to be safe and effective in the treatment of single de novo coronary lesions. The Xinsorb scaffolds were implanted in 30 patients with symptomatic ischemic coronary disease. A 6-month follow-up was performed in a subset of 19 patients; the HS and neointimal thickness were evaluated by optical coherence tomography. Struts were classified as ApposedCovered, ApposedUncovered, MalapposedCovered, MalapposedUncovered, jailing and presence of intraluminal masses. The implanted pressure, implanted duration, and post-expansion pressure were recorded during the operation. We evaluated the relationship between the HS or neointimal thickness and the implanted pressure, holding time, and post-expansion pressure. The device and procedure success rates were both 100%. No major adverse cardiac or scaffold-thrombus related events occurred. At 6 months, 12,295 struts were analyzed to determine the HS (6.23) and neointimal thickness (0.1021 +/- 0.05718 mm) in the Xinsorb scaffolds. There was a strong negative relationship between the HS and the implantation duration (Pearson r = - 0.518, p = 0.023). A significant negative relationship also existed between the HS and post-dilatation (Pearson r = - 0.631, p = 0.004). The Xinsorb scaffold HS appears negative correlated with the implanted duration and post-dilatation. We will further evaluate the HS of randomized controlled trial of the Xissorb scaffold. PMID- 29492776 TI - Modulation of microbial consortia enriched from different polluted environments during petroleum biodegradation. AB - Environmental microbial communities are key players in the bioremediation of hydrocarbon pollutants. Here we assessed changes in bacterial abundance and diversity during the degradation of Tunisian Zarzatine oil by four indigenous bacterial consortia enriched from a petroleum station soil, a refinery reservoir soil, a harbor sediment and seawater. The four consortia were found to efficiently degrade up to 92.0% of total petroleum hydrocarbons after 2 months of incubation. Illumina 16S rRNA gene sequencing revealed that the consortia enriched from soil and sediments were dominated by species belonging to Pseudomonas and Acinetobacter genera, while in the seawater-derived consortia Dietzia, Fusobacterium and Mycoplana emerged as dominant genera. We identified a number of species whose relative abundances bloomed from small to high percentages: Dietzia daqingensis in the seawater microcosms, and three OTUs classified as Acinetobacter venetianus in all two soils and sediment derived microcosms. Functional analyses on degrading genes were conducted by comparing PCR results of the degrading genes alkB, ndoB, cat23, xylA and nidA1 with inferences obtained by PICRUSt analysis of 16S amplicon data: the two data sets were partly in agreement and suggest a relationship between the catabolic genes detected and the rate of biodegradation obtained. The work provides detailed insights about the modulation of bacterial communities involved in petroleum biodegradation and can provide useful information for in situ bioremediation of oil-related pollution. PMID- 29492777 TI - Contaminant concentration versus flow velocity: drivers of biodegradation and microbial growth in groundwater model systems. AB - Aromatic hydrocarbons belong to the most abundant contaminants in groundwater systems. They can serve as carbon and energy source for a multitude of indigenous microorganisms. Predictions of contaminant biodegradation and microbial growth in contaminated aquifers are often vague because the parameters of microbial activity in the mathematical models used for predictions are typically derived from batch experiments, which don't represent conditions in the field. In order to improve our understanding of key drivers of natural attenuation and the accuracy of predictive models, we conducted comparative experiments in batch and sediment flow-through systems with varying concentrations of contaminant in the inflow and flow velocities applying the aerobic Pseudomonas putida strain F1 and the denitrifying Aromatoleum aromaticum strain EbN1. We followed toluene degradation and bacterial growth by measuring toluene and oxygen concentrations and by direct cell counts. In the sediment columns, the total amount of toluene degraded by P. putida F1 increased with increasing source concentration and flow velocity, while toluene removal efficiency gradually decreased. Results point at mass transfer limitation being an important process controlling toluene biodegradation that cannot be assessed with batch experiments. We also observed a decrease in the maximum specific growth rate with increasing source concentration and flow velocity. At low toluene concentrations, the efficiencies in carbon assimilation within the flow-through systems exceeded those in the batch systems. In all column experiments the number of attached cells plateaued after an initial growth phase indicating a specific "carrying capacity" depending on contaminant concentration and flow velocity. Moreover, in all cases, cells attached to the sediment dominated over those in suspension, and toluene degradation was performed practically by attached cells only. The observed effects of varying contaminant inflow concentration and flow velocity on biodegradation could be captured by a reactive-transport model. By monitoring both attached and suspended cells we could quantify the release of new-grown cells from the sediments to the mobile aqueous phase. Studying flow velocity and contaminant concentrations as key drivers of contaminant transformation in sediment flow-through microcosms improves our system understanding and eventually the prediction of microbial biodegradation at contaminated sites. PMID- 29492778 TI - Transposable elements and the multidimensional genome. PMID- 29492780 TI - Combatting Opioid Overdoses in Ohio: Emergency Department Physicians' Prescribing Patterns and Perceptions of Naloxone. PMID- 29492779 TI - Activating Autophagy as a Therapeutic Strategy for Parkinson's Disease. AB - Parkinson's disease is a progressive neurodegenerative disease characterized by Lewy body pathology of which the primary constituent is aggregated misfolded alpha-synuclein protein. Currently, there are no clinical therapies for treatment of the underlying alpha-synuclein dysfunction and accumulation, and the standard of care for patients with Parkinson's disease focuses only on symptom management, creating an immense therapeutic gap that needs to be filled. Defects in autophagy have been strongly implicated in Parkinson's disease. Here, we review evidence from human, mouse, and cell culture studies to briefly explain these defects in autophagy in Parkinson's disease and the necessity for autophagy to be carefully and precisely tuned to maintain neuron survival. We summarize recent experimental agents for treating alpha-synuclein accumulation in alpha-synuclein Parkinson's disease and related synucleinopathies. Most of the efforts for developing experimental agents have focused on immunotherapeutic strategies, but we discuss why those efforts are misplaced. Finally, we emphasize why increasing autophagy flux for alpha-synuclein clearance is the most promising therapeutic strategy. Activating autophagy has been successful in preclinical models of Parkinson's disease and yields promising results in clinical trials. PMID- 29492781 TI - Purification and Analytical Application of Vigna mungo Chitinase for Determination of Total Fungal Load of Stored Cereals. AB - A novel chitinase from urd bean (Vigna mungo) seeds was purified up to homogeneity and optimized with respect to its optimum working conditions of pH, temperature, and substrate concentration. Overall, 145-fold purification with 70% yield of the purified chitinase was achieved. The notable features of the purified enzyme were its appreciative substrate affinity as well as catalytic efficiency, high thermo stability (70% retention of initial activity at 70 degrees C after 60 min of continuous exposure), and pretty good storage stability (half-life of 45 days at 5 degrees C). The enzyme was used for determination of total chitin contents of the stored cereals that in the absence of any insect infestation, were considered to be directly proportional to the total fungal load of the tested samples. The method was linear up to 7.0 mM with 0.04 mM as the limit of detection. Percent recoveries of added chitin were < 90.0% and within day and between-day coefficients of variations were > 3.0% for all the samples. Chitin values in stored cereal samples obtained by the present method and the popular DNS method showed good correlation, the value for coefficient of determination (R2) being < 0.98. Overall, the method yielded acceptable sensitivity, reproducibility, and accuracy. Graphical Abstract ?. PMID- 29492782 TI - Biokinetic and dosimetric aspects of 64CuCl2 in human prostate cancer: possible theranostic implications. AB - BACKGROUND: The aim of the present study is to evaluate the kinetics and dosimetry of 64CuCl2 in human prostate cancer (PCa) lesions. We prospectively evaluated 50 PCa patients with biochemical relapse after surgery or external beam radiation therapy. All patients underwent 64CuCl2-PET/CT to detect PCa recurrence/metastases. Volumes of interest were manually drawn for each 64CuCl2 avid PCa lesion with a diameter > 1 cm on mpMRI in each patient. Time-activity curves for all lesions were obtained. The effective and biological half-life and the standard uptake values (SUVs) were calculated. Tumour/background ratio (TBR) curves as a function of time were considered. Finally, the absorbed dose per lesion was estimated. RESULTS: The mean effective half-life of 64CuCl2 calculated in the lymph nodes (10.2 +/- 1.7 h) was significantly higher than in local relapses (8.8 +/- 1.1 h) and similar to that seen in bone metastases (9.0 +/- 0.4 h). The mean 64CuCl2 SUVmax calculated 1 h after tracer injection was significantly higher in the lymph nodes (6.8 +/- 4.3) and bone metastases (6.8 +/ 2.9) than in local relapses (4.7 +/- 2.4). TBR mean curve of 64CuCl2 revealed that the calculated TBRmax value was 5.0, 7.0, and 6.2 in local relapse and lymph node and bone metastases, respectively, and it was achieved about 1 h after 64CuCl2 injection. The mean absorbed dose of the PCa lesions per administrated activity was 6.00E-2 +/- 4.74E-2mGy/MBq. Indeed, for an administered activity of 3.7 GBq, the mean dose absorbed by the lesion would be 0.22 Gy. CONCLUSIONS: Dosimetry showed that the dose absorbed by PCa recurrences/metastases per administrated activity was low. The dosimetric study performed does not take into account the possible therapeutic effect of the Auger electrons. Clinical trials are needed to evaluate 64Cu internalization in the cell nucleus that seems related to the therapeutic effectiveness reported in preclinical studies. PMID- 29492783 TI - Altered gut microbiome promotes proteinuria in mice induced by Adriamycin. AB - Inflammation has recently been attributed to dysbiosis of the gut microbiome, which has been linked to proteinuria in chronic kidney disease. Since Adriamycin(r) (ADR) is widely used to induce proteinuria in mouse models, the aim of this study was to explore the potential effect of gut microbiome on this process. Both ADR resistant (C57BL/6) and susceptible (BALB/C) strains were part of the induced nephropathy with ADR injection. BALB/C mice significantly presented increased urinary albumin/creatinine ratio (UACR) with renal lesions in pathology, but C57BL/6 mice were absent from kidney damage. Species and genus level resolution analysis showed a shift in gut microbial profile between BALB/C and C57BL/6 mice. ADR further altered the stool microbiome in BALB/C mice, particularly with enrichment of Odoribacter and depletion of Turicibacter, Marvinbryantia and Rikenella. Moreover, the level of UACR in BALB/C mice was marked related to the abundance of Marvinbryantia, Odoribacter and Turicibacter in stool. Meanwhile, ADR remarkably increased the serum levels of interleukin (IL)-2 in BALB/C mice, but not in C57BL/6 mice. It is suggested that the favorably altered stools as shown in the microbiome might promote the inflammation and proteinuria in ADR-sensitive mice, which provides a new insight on the pathogenicity of chronic kidney disease. PMID- 29492784 TI - The efficacy of cognitive-behavioral therapy for older adults with ADHD: a randomized controlled trial. AB - Older adults with ADHD exhibit significant functional impairment, yet there is little research to guide clinicians in evidence-based care of these adults. This study examined response to treatment in older adults who participated in a previous study of the efficacy of cognitive-behavioral treatment (CBT) in adult ADHD. It was hypothesized that older adults would respond less well to CBT than younger adults, given the cognitive demands of the treatment. As described in the original publication, 88 adults who met DSM-IV criteria for ADHD were randomized to receive either a manualized 12-week CBT group intervention targeting executive dysfunction or a parallel Support group. In the current study, outcomes for 26 adults, aged 50 or older, were compared with those of 55 younger adults with respect to inattentive symptoms assessed on a structured interview by a blind clinician, as well as on ratings by self and/or collateral on measures of attention, executive dysfunction, and comorbidity. Contrary to the hypothesis, older and younger adults were equally responsive to CBT on measures of attention. The older adults also responded as well to Support as to CBT on several outcome measures. The results provide preliminary evidence that CBT is an effective intervention for older adults with ADHD. The unexpected response to support highlights a possible age-specificity of effective therapeutic intervention that requires further investigation. PMID- 29492785 TI - Comparing cognition by integrating concept learning, proactive interference, and list memory. AB - This article describes an approach for training a variety of species to learn the abstract concept of same/different, which in turn forms the basis for testing proactive interference and list memory. The stimulus set for concept-learning training was progressively doubled from 8, 16, 32, 64, 128 . . . to 1,024 different pictures with novel-stimulus transfer following learning. All species fully learned the same/different abstract concept: capuchin and rhesus monkeys learned more readily than pigeons; nutcrackers and magpies were at least equivalent to monkeys and transferred somewhat better following initial training sets. A similar task using the 1,024-picture set plus delays was used to test proactive interference on occasional trials. Pigeons revealed greater interference with 10-s than with 1-s delays, whereas delay time had no effect on rhesus monkeys, suggesting that the monkeys' interference was event based. This same single-item same/different task was expanded to a 4-item list memory task to test animal list memory. Humans were tested similarly with lists of kaleidoscope pictures. Delays between the list and test were manipulated, resulting in strong initial recency effects (i.e., strong 4th-item memory) at short delays and changing to a strong primacy effect (i.e., strong 1st-item memory) at long delays (pigeons 0-s to 10-s delays; monkeys 0-s to 30-s delays; humans 0-s to 100-s delays). Results and findings are discussed in terms of these species' cognition and memory comparisons, evolutionary implications, and future directions for testing other species in these synergistically related tasks. PMID- 29492786 TI - Functional coupling between adenosine A1 receptors and G-proteins in rat and postmortem human brain membranes determined with conventional guanosine-5'-O-(3 [35S]thio)triphosphate ([35S]GTPgammaS) binding or [35S]GTPgammaS/immunoprecipitation assay. AB - Adenosine signaling plays a complex role in multiple physiological processes in the brain, and its dysfunction has been implicated in pathophysiology of neuropsychiatric diseases such as schizophrenia and affective disorders. In the present study, the coupling between adenosine A1 receptor and G-protein was assessed by means of two [35S]GTPgammaS binding assays, i.e., conventional filtration method and [35S]GTPgammaS binding/immunoprecipitation in rat and human brain membranes. The latter method provides information about adenosine A1 receptor-mediated Galphai-3 activation in rat as well as human brain membranes. On the other hand, adenosine-stimulated [35S]GTPgammaS binding determined with conventional assay derives from functional activation of Galphai/o proteins (not restricted only to Galphai-3) coupled to adenosine A1 receptors. The determination of adenosine concentrations in the samples used in the present study indicates the possibility that the assay mixture under our experimental conditions contains residual endogenous adenosine at nanomolar concentrations, which was also suggested by the results on the effects of adenosine receptor antagonists on basal [35S]GTPgammaS binding level. The effects of adenosine deaminase (ADA) on basal binding also support the presence of adenosine. Nevertheless, the varied patterns of ADA discouraged us from adding ADA into assay medium routinely. The concentration-dependent increases elicited by adenosine were determined in 40 subjects without any neuropsychiatric disorders. The increases in %Emax values determined by conventional assay according to aging and postmortem delay should be taken into account in future studies focusing on the effects of psychiatric disorders on adenosine A1 receptor/G-protein interaction in postmortem human brain tissue. PMID- 29492787 TI - Performance evaluation of a novel brain-dedicated SPECT system. PMID- 29492788 TI - Characterization of an Insecticidal Protein from Withania somnifera Against Lepidopteran and Hemipteran Pest. AB - Lectins are carbohydrate-binding proteins with wide array of functions including plant defense against pathogens and insect pests. In the present study, a putative mannose-binding lectin (WsMBP1) of 1124 bp was isolated from leaves of Withania somnifera. The gene was expressed in E. coli, and the recombinant WsMBP1 with a predicted molecular weight of 31 kDa was tested for its insecticidal properties against Hyblaea puera (Lepidoptera: Hyblaeidae) and Probergrothius sanguinolens (Hemiptera: Pyrrhocoridae). Delay in growth and metamorphosis, decreased larval body mass and increased mortality was recorded in recombinant WsMBP1-fed larvae. Histological studies on the midgut of lectin-treated insects showed disrupted and diffused secretory cells surrounding the gut lumen in larvae of H. puera and P. sanguinolens, implicating its role in disruption of the digestive process and nutrient assimilation in the studied insect pests. The present study indicates that WsMBP1 can act as a potential gene resource in future transformation programs for incorporating insect pest tolerance in susceptible plant genotypes. PMID- 29492789 TI - Use of ultrasonic scalpel and monopolar electrocautery for skin incisions in neck dissection: a prospective randomized trial. AB - PURPOSE: Ultrasonic scalpel (UC) and monopolar electrocautery (ME) are standard equipment for soft tissue surgery. The aim of the present study was to compare intraoperative and postoperative patterns of patients using either UC or ME for skin incisions in neck dissection. MATERIAL AND METHODS: In a prospective randomized study of 30 patients, the thermal effects of UC (n = 15) and ME (n = 15) were examined using real-time infrared thermographic imaging. Additionally, tissue damage was evaluated histopathologically. The other measured variables were operation and bleeding time, postoperative pain score (only neck incision area), in-patient time, and complications. RESULTS: UC significantly reduces the thermal effects, compared to ME (p < 0.001). The mean depth of tissue damage (i.e., necrosis) was 272.7 MUm for UC and 284.7 MUm for ME with no significant difference (p = 0.285). From the third postoperative day, patients treated using UC had noticeably less pain in the neck incision area (t3 p = 0.010; t4 p < 0.001; t5 p < 0.005). Cutting time was reduced for ME by 36.1 s (p < 0.001) and the bleeding time was decreased by 40.9 s for UC (p < 0.001). The total preparation time was the same (p = 0.402). When comparing in-patient time (p = 0.723), as well as complications, no significant differences were seen. CONCLUSION: UC results in less postoperative pain and less bleeding in the neck incision area. Accordingly, UC is superior to ME for skin incisions in neck dissection. PMID- 29492791 TI - Involvement of the autophagic pathway in the progression of AMD-like retinopathy in senescence-accelerated OXYS rats. AB - Age-related macular degeneration (AMD) is a complex neurodegenerative disease resulting in a loss of central vision in the elderly. It is currently assumed that impairment of autophagy may be one of the key mechanisms leading to AMD. Here we estimated the influence of age-related autophagy alterations in the retina on the development of AMD-like retinopathy in senescence-accelerated OXYS rats. Significant changes in the expression of the autophagy proteins were absent at the age preceding the development of retinopathy (age 20 days). We found increased levels of LC3A/B, Atg7, and Atg12-Atg5 conjugated proteins in the OXYS retina during manifestation of this retinopathy at the age of 3 months. By contrast, in the retina of 18-month-old OXYS rats with a progressive stage of retinopathy, we revealed significantly decreased protein levels of Atg7 and Atg12 Atg5 as compared to age-matched Wistar rats. Simultaneously with perturbation of the autophagic response, the necrosome subunits Ripk1 and Ripk3 were detected in the OXYS retina. The downregulation of autophagy markers coincided with amyloid beta accumulation (Moab-2) in the retinal pigment epithelium and choroid. Using high-throughput RNA sequencing, we found a missense single-nucleotide polymorphism (SNP) in the Pik3c2b gene associated with autophagy regulation. This SNP was predicted to significantly affect protein structure. Our data prove participation of the autophagic pathway in the progression of AMD-like retinopathy. PMID- 29492792 TI - A virus-derived short hairpin RNA confers resistance against sugarcane mosaic virus in transgenic sugarcane. AB - RNA interference (RNAi) is commonly used to produce virus tolerant transgenic plants. The objective of the current study was to generate transgenic sugarcane plants expressing a short hairpin RNAs (shRNA) targeting the coat protein (CP) gene of sugarcane mosaic virus (SCMV). Based on multiple sequence alignment, including genomic sequences of four SCMV strains, a conserved region of ~ 456 bp coat protein (CP) gene was selected as target gene and amplified through polymerase chain reaction (PCR). Subsequently, siRNAs2 and siRNA4 were engineered as stable short hairpin (shRNA) transgenes of 110 bp with stem and loop sequences derived from microRNA (sof-MIR168a; an active regulatory miRNA in sugarcane). These transgenes were cloned in independent RNAi constructs under the control of the polyubiquitin promoter. The RNAi constructs were delivered into two sugarcane cultivars 'SPF-234 and NSG-311 in independent experiments using particle bombardment. Molecular identification through PCR and Southern blot revealed anti SCMV positive transgenic lines. Upon mechanical inoculation of transgenic and non transgenic sugarcane lines with SCMV, the degree of resistance was found variable among the two sugarcane cultivars. For sugarcane cultivar NSG-311, the mRNA expression of the CP-SCMV was reduced to 10% in shRNA2-transgenic lines and 80% in shRNA4-transgenic lines. In sugarcane cultivar SPF-234, the mRNA expression of the CP-SCMV was reduced to 20% in shRNA2-transgenic lines and 90% in shRNA4 transgenic lines, revealing that transgenic plants expressing shRNA4 were almost immune to SCMV infection. PMID- 29492790 TI - Gene expression hallmarks of cellular ageing. AB - Ageing leads to dramatic changes in the physiology of many different tissues resulting in a spectrum of pathology. Nonetheless, many lines of evidence suggest that ageing is driven by highly conserved cell intrinsic processes, and a set of unifying hallmarks of ageing has been defined. Here, we survey reports of age linked changes in basal gene expression across eukaryotes from yeast to human and identify six gene expression hallmarks of cellular ageing: downregulation of genes encoding mitochondrial proteins; downregulation of the protein synthesis machinery; dysregulation of immune system genes; reduced growth factor signalling; constitutive responses to stress and DNA damage; dysregulation of gene expression and mRNA processing. These encompass widely reported features of ageing such as increased senescence and inflammation, reduced electron transport chain activity and reduced ribosome synthesis, but also reveal a surprising lack of gene expression responses to known age-linked cellular stresses. We discuss how the existence of conserved transcriptomic hallmarks relates to genome-wide epigenetic differences underlying ageing clocks, and how the changing transcriptome results in proteomic alterations where data is available and to variations in cell physiology characteristic of ageing. Identification of gene expression events that occur during ageing across distant organisms should be informative as to conserved underlying mechanisms of ageing, and provide additional biomarkers to assess the effects of diet and other environmental factors on the rate of ageing. PMID- 29492793 TI - Risk of second malignancies among survivors of pediatric thyroid cancer. AB - BACKGROUND: Thyroid carcinoma is a very rare tumor in the pediatric age group, accounting for only 1.5-3% of childhood carcinomas in the United States and Europe. We aimed to identify the risk of a second malignancy among pediatric thyroid cancer survivors. METHODS: The cohort analysis consisted of pediatric cancer patients aged less than 20 years, diagnosed with a primary thyroid cancer, identified by site code ICD-0-3: C739, and reported to the SEER 9 database between 1973 and 2013. They were followed up until December 31, 2013; the end of the study period, or up to death if earlier. RESULTS: Out of 1769 patients diagnosed primarily with thyroid carcinoma, 42 patients had a total of 45 incidences of subsequent malignancies. The mean age of patients at the initial diagnosis of thyroid cancer was 16 years. Females (90.5%) had a significantly higher incidence of second malignancies (SM) than males (9.5%). The overall Standardized Incidence Ratio (SIR) of SM in the study patients was higher than expected (SIR = 1.48). Some specific sites showed significantly higher incidences: the salivary glands (SIR = 33.95), the gum and other parts of the mouth [excluding the lips, tongue, salivary glands and floor of the mouth] (SIR = 24.53)*** and the kidneys (SIR = 5.72). The overall risk of SM in patients who had received radioactive iodine was higher than expected (SIR = 4.41). The cumulative incidence of SM after treatment of thyroid cancer in children increases steadily over 40 years (11.92%). CONCLUSIONS: Race, gender, histological subtypes, and radioactive iodine are potentially significant prognostic factors for the development of SM among pediatric thyroid cancer survivors. Identification of underlying mechanisms that raise the risk of SM is important for both treatment and follow-up strategies. PMID- 29492794 TI - Sociodemographic Influences of Emergency Department Care for Anxiety Disorders. AB - This study examines variations in content of care for anxiety-related emergency department (ED) visits in the USA across various sociodemographic strata. The 2009-2012 National Hospital Ambulatory Medical Care Survey was used to identify all visits to general hospital EDs in which an anxiety diagnosis was recorded (n = 1930). Content and equitability of care was assessed utilizing logistic regression models. There were an estimated 1,856,000 ED visits with anxiety related discharge diagnoses in the USA annually. Content of care and disposition varied by age, race/ethnicity, and insurance status. Visits by Medicaid patients were more likely than visits by privately insured patients to include a toxicology screen (OR = 1.67, p < .05) and visits by patients with either Medicaid or Medicare were less likely to include an EKG (OR = 0.53, p < .05 and OR = 0.52, p < .05, respectively). Understanding variations in ED care for anxiety can identify opportunities for intervention, both in the ED and upstream in appropriate healthcare settings. PMID- 29492797 TI - Primary androgen deprivation therapy as monotherapy in unfavourable intermediate- and high-risk localised prostate cancer: a Singaporean single-centre perspective. AB - PURPOSE: Primary ADT (pADT) monotherapy is used significantly for patients with clinically localised disease in Asia and is acceptable even by guidelines, especially in intermediate- and high-risk disease. This occurs despite controversy in the West and data suggesting association with adverse effects, notably cardiovascular events. We therefore sought to assess the impact of pADT on all-cause mortality and prostate cancer-specific mortality (PCSM) in Asian men with high-risk and unfavourable intermediate-risk PCa. METHODS: With cancer registry data, men from a single centre in Singapore with clinically localised high-risk/unfavourable intermediate-risk PCa diagnosed between 2004 and 2014 and either treated conservatively with no therapy or started on pADT within 1 year of diagnosis were followed up through January 2017. Patients with non-localised PCa (clinical stage T4, regional/distant lymph node involvement, metastases), or receipt of local therapy (radical prostatectomy/radiotherapy) were excluded. The primary outcomes of all-cause mortality and PCSM were analysed with Cox proportional hazards regression models. RESULTS: Three hundred and forty Asian men were analysed, and 177 (52.1%) were started on pADT, with mean age of 77 (49 98) years. There were 119 deaths in the cohort, and 68 (38.4%) occurred in patients treated with pADT (median follow-up, 4.4 years). After adjusting for comorbidities and clinical characteristics, pADT did not provide benefit to all cause mortality, PCSM or cardiovascular mortality. CONCLUSION: For clinically localised unfavourable intermediate-risk and high-risk PCa, starting pADT within 12 months of diagnosis is not associated with improved 5-year all-cause mortality or PCSM compared to patients treated conservatively with no therapy and should be discouraged due to lack of mortality benefit. PMID- 29492795 TI - The coagulome and the oncomir: impact of cancer-associated haemostatic dysregulation on the risk of metastasis. AB - Patients with cancer are at high risk of both thromboembolic and haemorrhagic events during the course of their disease. The pathogenesis of haemostatic dysfunction in cancer is complex and involves the interplay of multiple factors. There is growing evidence that interactions between malignancies and the coagulation system are not random but can represent coordinated and clinically significant adaptations that enhance tumour cell survival, proliferation and metastatic potential. A detailed understanding of the interactions between the haemostatic systems and the pathophysiology of metastasis may not only provide insight into strategies that could potentially reduce the incidence of thrombohaemorrhagic events and complications, but could also help design strategies that are capable of modifying tumour biology, progression and metastatic potential in ways that could enhance anticancer therapies and thereby improve overall survival. PMID- 29492798 TI - Residential Mobility Across Early Childhood and Children's Kindergarten Readiness. AB - Understanding residential mobility in early childhood is important for contextualizing family, school, and neighborhood influences on child well-being. We examined the consequences of residential mobility for socioemotional and cognitive kindergarten readiness using the Early Childhood Longitudinal Study Birth Cohort, a nationally representative longitudinal survey that followed U.S. children born in 2001 from infancy to kindergarten. We described individual, household, and neighborhood characteristics associated with residential mobility for children aged 0-5. Our residential mobility indicators examined frequency of moves, nonlinearities in move frequency, quality of moves, comparisons between moving houses and moving neighborhoods, and heterogeneity in the consequences of residential mobility. Nearly three-quarters of children moved by kindergarten start. Mobility did not predict cognitive scores. More moves, particularly at relatively high frequencies, predicted lower kindergarten behavior scores. Moves from socioeconomically advantaged to disadvantaged neighborhoods were especially problematic, whereas moves within a ZIP code were not. The implications of moves were similar across socioeconomic status. The behavior findings largely support an instability perspective that highlights potential disruptions from frequent or problematic moves. Our study contributes to literature emphasizing the importance of contextualizing residential mobility. The high prevalence and distinct implications of early childhood moves support the need for further research. PMID- 29492799 TI - Males' Later-Life Mortality Consequences of Coresidence With Paternal Grandparents: Evidence From Northeast China, 1789-1909. AB - In this study, we investigate the effect of early-life coresidence with paternal grandparents on male mortality risks in adulthood and older age in northeast China from 1789 to 1909. Despite growing interest in the influence of grandparents on child outcomes, few studies have examined the effect of coresidence with grandparents in early life on mortality in later life. We find that coresidence with paternal grandmothers in childhood is associated with higher mortality risks for males in adulthood. This may reflect the long-term effects of conflicts between mothers and their mothers-in-law. These results suggest that in extended families, patterns of coresidence in childhood may have long-term consequences for mortality, above and beyond the effects of common environmental and genetic factors, even when effects on childhood mortality are not readily apparent. PMID- 29492800 TI - Rise Up, Get Tested, and Live: an Arts-Based Colorectal Cancer Educational Program in a Faith-Based Setting. AB - Engaging community members in efforts to reduce cancer-related health disparities through community mini-grant programs has been shown to have meaningful impact. A predominantly African-American church in South Carolina was awarded a community mini-grant to increase awareness about colorectal cancer (CRC) screening among disproportionally high-risk African-American communities through culturally appropriate arts-based cancer education. The church's pastor, health and wellness ministry, and drama ministry created a theatrical production called Rise Up, Get Tested, and Live. Over 100 attendees viewed the play. A pre/post-test evaluation design assessed the effectiveness of the production in increasing participants' knowledge about CRC and examined their intentions to be screened. Results showed increased knowledge about CRC, increased awareness and understanding about the importance of CRC screening, and favorable intentions about CRC screening. Findings suggest that arts-based cancer education may be an effective tool for the dissemination of information about CRC screening. PMID- 29492801 TI - Leadership Roles and Activities Among Alumni Receiving Postdoctoral Fellowship Training in Cancer Prevention. AB - This study was conducted in 2016-2017 to better understand formal and informal leadership roles and activities of alumni from postdoctoral research training programs in cancer prevention. Data were obtained from surveys of 254 employed scientists who completed cancer prevention postdoctoral training within the National Cancer Institute (NCI) Cancer Prevention Fellowship Program, or at US research institutions through NCI-sponsored National Research Service Award (NRSA) individual postdoctoral fellowship (F32) grants, from 1987 to 2011. Fifteen questions categorized under Organizational Leadership, Research Leadership, Professional Society/Conference Leadership, and Broader Scientific/Health Community Leadership domains were analyzed. About 75% of respondents had at least one organizational leadership role or activity during their careers, and 13-34% reported some type of research, professional society/conference, or broader scientific/health community leadership within the past 5 years. Characteristics independently associated with leadership from regression models were being in earlier postdoctoral cohorts (8 items, range for statistically significant ORs = 2.8 to 10.8) and employment sector (8 items, range for statistically significant ORs = 0.4 to 11.7). Scientists whose race/ethnicity was other than white were less likely to report organizational leadership or management responsibilities (OR = 0.4, 95% CI 0.2-0.9). Here, many alumni from NCI-supported cancer prevention postdoctoral programs were involved in leadership, with postdoctoral cohort and employment sector being the factors most often associated with leadership roles and activities. Currently, there is relatively little research on leadership roles of biomedical scientists in general, or in cancer prevention specifically. This study begins to address this gap and provide a basis for more extensive studies of leadership roles and training of scientists. PMID- 29492802 TI - Enzyme linked immunosorbent assay for total potent estrogenic miroestrol and deoxymiroestrol of Pueraria candollei, a Thai herb for menopause remedy. AB - Miroestrol and deoxymiroestrol are the most potent phytoestrogens of Pueraria candollei var. mirifica, having been proved as an effective herb for menopausal symptoms in folk medicines and clinical trials. To ensure efficacy and safety of P. candollei var. mirifica involved in nutraceutical products being available worldwide, the content of potent phytoestrogens as active ingredients should be specified. Therefore, in this study, we produced a monoclonal antibody for total analysis of potent estrogenic miroestrol and deoxymiroestrol, for which an analytical method was developed using a procedure for an indirect competitive enzyme-linked immunosorbent assay. The antibody exhibited equal reactivity against miroestrol and deoxymiroestrol. The sensitivity of determination was in the range of 31.3-500 ng/ml with high precision. The analytical parameters, such as accuracy (99.6-106% recovery) and high correlation with a HPLC-UV method, indicated the reliability of analysis. This method is of high performance, and it is cheap to control optimal miroestrol and deoxymiroestrol doses of P. candollei var. mirifica nutraceutical products. PMID- 29492804 TI - Coal-derived compounds and their potential impact on groundwater quality during coalbed methane production. AB - Coalbed methane (CBM) is an important unconventional energy source and accounts for a substantial portion of the overall natural gas production in the USA. The extraction of CBM generates significant amounts of produced water, where the withdrawal of groundwater may disturb the subsurface environment and aquifers. The release of toxic recalcitrant compounds from the coal seam is of great concern for those who use groundwater for irrigation and potable water sources. Experiments were conducted that determined a small fraction of coal carbon can be extracted and solubilized in water during the CBM formation and production. These soluble components included long-chain alkanes, aromatic hydrocarbons, and humic compounds. Biometer flask assays demonstrated that these compounds are bioamenable and can be potentially degraded by microorganisms to produce methane and carbon dioxide, where these biodegradation processes may further impact groundwater quality in the coal seam. PMID- 29492803 TI - Concentrations of mercury (Hg) and selenium (Se) in afterbirth and their relations with various factors. AB - The aim of the study was to evaluate Hg and Se concentrations and Se:Hg molar ratios in the placenta, umbilical cord and fetal membranes, and to examine the relationship between the concentrations of the elements and selected factors. The study material consisted of the placenta, umbilical cord and fetal membranes obtained from 91 healthy women from northwestern and central Poland. In our study mean Hg and Se concentrations in afterbirth were ~ 0.01 mg/kg dry weight (dw) and <= 0.5 mg/kg dw, respectively. Correlation analysis showed negative relationships between placenta weight and Se concentration in the placenta and umbilical cord, as well as between placenta length and Se levels in the umbilical cord. We found negative correlations between THg concentration in the placenta and birth weight and between Se concentration in the placenta and umbilical cord and the morphological parameters of the placenta. Furthermore, we noted new types of interactions in specific parts of the afterbirth. In our study, Se:THg molar ratios ranged from 5 to 626; these values indicate protection against Hg toxicity. PMID- 29492805 TI - Boric acid as reference substance for ecotoxicity tests in tropical artificial soil. AB - Reference substances are recommended to evaluate the quality of laboratory test species and the reliability of ecotoxicity data. Boric acid (BA) has been recommended as reference substance in some standardized tests in OECD soil, but no data are available for Tropical Artificial Soil (TAS). For this purpose, avoidance tests with Eisenia andrei, lethality tests with E. andrei and Folsomia candida, and reproduction tests with E. andrei, Enchytraeus crypticus and F. candida were carried out in TAS (5% organic matter), following ISO guidelines, and compared between two laboratories. Collembolans were more sensitive than earthworms in lethality tests (LC50 = 342 and > 1000 mg kg-1, respectively). For both laboratories, the EC50 values were similar for reproduction of oligochaeta species (165 mg kg-1 for E. crypticus; 242 and 281 mg kg-1 for E. andrei), but significantly different for reproduction of F. candida (96 and 198 mg kg-1). Present results suggest that boric acid could replace the current pesticides recommended by ISO guidelines as reference substances on reproduction tests with soil invertebrates in TAS. Concerning avoidance tests, additional investigations should be performed with other substances that cause no neurotoxic effects on soil organisms. PMID- 29492806 TI - Validity of fish, birds and mammals as surrogates for amphibians and reptiles in pesticide toxicity assessment. AB - Amphibians and reptiles are the two most endangered groups of vertebrates. Environmental pollution by pesticides is recognised as one of the major factors threatening populations of these groups. However, the effects of pesticides on amphibians and reptiles have been studied for few substances, which is partly related to the fact that these animals are not included in the mandatory toxicity testing conducted as part of environmental risk assessments of pesticides. Whether risks of pesticides to amphibians and reptiles are addressed by surrogate taxa used in risk assessment is currently under debate. In order to develop a scientifically sound and robust risk assessment scheme, information needs to be gathered to examine whether fish, birds and mammals are valid surrogates for amphibians and reptiles. We updated a systematic review of scientific literature that was recently published compiling toxicity data on amphibians and reptiles. The outcome of this review was analysed with the purposes to (1) compare endpoints from amphibians and reptiles with the available information from fish, birds and mammals, and (2) develop species sensitivity distributions (SSDs) for those substances tested in at least six amphibian species (no substances were found tested in at least six reptile species) to identify a candidate amphibian model species to be used as surrogate in risk assessment. A positive correlation was found between toxicity recorded on fish and amphibians, the former revealing, in general, to be more sensitive than the latter to waterborne pollutants. In the terrestrial environment, although birds and mammals were more sensitive than amphibians and reptiles to at least 60% of tested substances, just a few weak significant correlations were observed. As a general rule, homoeothermic vertebrates are not good surrogates for reptiles and terrestrial amphibians in pesticide risk assessment. However, some chemical-dependent trends were detected, with pyrethroids and organochlorine insecticides being more toxic to amphibians or reptiles than to birds or mammals. These trends could ultimately help in decisions about protection provided by surrogate taxa for specific groups of substances, and also to determine when risk assessment of pesticides needs to pay special consideration to amphibians and reptiles. The outcome of this review reflects that there is still much information needed to reduce uncertainties and extract relevant conclusions on the overall protection of amphibians and reptiles by surrogate vertebrates. PMID- 29492807 TI - Increased healthcare utilization associated with complete atrioventricular block in pacemaker patients. AB - PURPOSE: The purpose of the current study is to characterize and quantify the impact of complete atrioventricular block (cAVB) on heart failure hospitalization (HFH) and healthcare utilization in pacemaker (PM) patients. METHODS: Patients >= 18 years implanted with a dual-chamber PM from April 2008 to March 2014 were selected from the MarketScan(r) Commercial and Medicare Supplemental claims databases. Patients with <= 1-year continuous MarketScan enrollment prior to and post-implant, and those with prior HF diagnosis were excluded. Patients were dichotomized into those with cAVB, defined as a 3rd degree AVB diagnosis or AV node ablation in the year prior to PM implant, versus those without any AVB (noAVB). Post-implant HFH and associated costs were compared based on inpatient claims. RESULTS: The study cohort included 21,202 patients, of which 14,208 had no AVB and 6994 had cAVB, followed for 2.39 and 2.27 years, respectively. Patients with cAVB were associated with a significantly increased risk of cumulative HFH (HR 1.59 [95% CI 1.35-1.86] p < 0.001) and significantly higher costs ($636 [609-697] vs $369 [353-405] per pt-year, p < 0.001) compared to those with no AVB. CONCLUSIONS: Among dual-chamber PM patients without prior HF, cAVB is associated with a significantly increased risk of HFH and greater HF-related healthcare utilization. Identifying patients at high risk for HF in the setting of RV pacing, and potentially earlier use of biventricular or selective conduction system pacing, may reduce HF-related healthcare utilization. PMID- 29492808 TI - Immunogenicity of adenovirus and DNA vaccines co-expressing P39 and lumazine synthase proteins of Brucella abortus in BALB/c mice. AB - Brucella poses a great threat to animal and human health. Vaccination is the most promising strategy in the effort to control Brucella abortus (B. abortus) infection, but the currently used live vaccines interfere with diagnostic tests and could potentially result in disease outbreak. Therefore, new subunit vaccines and combined immunization strategies are currently under investigation. In this study, immunogenicity and protection ability of a recombinant adenovirus and plasmid DNA vaccine co-expressing P39 and lumazine synthase proteins of B. abortus were evaluated based on the construction of the two molecular vaccines. Four immunization strategies (single adenovirus, single DNA, adenovirus/DNA, DNA/adenovirus) were investigated. The results showed that the immunization strategy of DNA priming followed by adenovirus boosting induced robust humoral and cellular immune responses, and it significantly reduced the numbers of B. abortus in a mouse model. These results suggest that it could be a potential antigen candidate for development of a new subunit vaccine against B. abortus infection. PMID- 29492811 TI - Evaluating gas chromatography with a halogen-specific detector for the determination of disinfection by-products in drinking water. AB - The occurrence of disinfection by-products (DBPs) in drinking water has become an issue of concern during the past decades. The DBPs pose health risks and are suspected to cause various cancer forms, be genotoxic, and have negative developmental effects. The vast chemical diversity of DBPs makes comprehensive monitoring challenging. Only few of the DBPs are regulated and included in analytical protocols. In this study, a method for simultaneous measurement of 20 DBPs from five different structural classes (both regulated and non-regulated) was investigated and further developed for 11 DBPs using solid-phase extraction and gas chromatography coupled with a halogen-specific detector (XSD). The XSD was highly selective towards halogenated DBPs, providing chromatograms with little noise. The method allowed detection down to 0.05 MUg L-1 and showed promising results for the simultaneous determination of a range of neutral DBP classes. Compounds from two classes of emerging DBPs, more cytotoxic than the "traditional" regulated DBPs, were successfully determined using this method. However, haloacetic acids (HAAs) should be analyzed separately as some HAA methyl esters may degrade giving false positives of trihalomethanes (THMs). The method was tested on real water samples from two municipal waterworks where the target DBP concentrations were found below the regulatory limits of Sweden. PMID- 29492810 TI - Comparison of choline influx from dynamic 18F-Choline PET/CT and clinicopathological parameters in prostate cancer initial assessment. AB - AIM: The aim of the study was to compare the kinetic analysis of 18F-labeled choline (FCH) uptake with static analysis and clinicopathological parameters in patients with newly diagnosed prostate cancer (PC). MATERIALS AND METHODS: Sixty one patients were included. PSA was performed few days before FCH PET/CT. Gleason scoring (GS) was collected from systematic sextant biopsies. FCH PET/CT consisted in a dual phase: early pelvic list-mode acquisition (from 0 to10 min post injection) and late whole-body acquisition (60 min post-injection). PC volume of interest was drawn using an adaptative thresholding (40% of the maximal uptake) on the late acquisition and projected onto an early static frame of 10 min and each of the 20 reconstructed frames of 30 s. Kinetic analysis was performed using an imaging-derived plasma input function. Early kinetic parameter (K1 as influx) and static parameters (early SUVmean, late SUVmean, and retention index) were extracted and compared to clinicopathological parameters. RESULTS: K1 was significantly, but moderately correlated with early SUVmean (r = 0.57, p < 0.001) and late SUVmean (r = 0.43, p < 0.001). K1, early SUVmean, and late SUVmean were moderately correlated with PSA level (respectively, r = 0.36, p = 0.004; r = 0.67, p < 0.001; r = 0.51, p < 0.001). Concerning GS, K1 was higher for patients with GS >= 4 + 3 than for patients with GS < 4 + 3 (median value 0.409 vs 0.272 min- 1, p < 0.001). No significant difference was observed for static parameters. CONCLUSIONS: FCH influx index K1 seems to be related to GS and could be a non invasive tool to gain further information concerning tumor aggressiveness. PMID- 29492812 TI - Enhanced algae removal by Ti-based coagulant: comparison with conventional Al- and Fe-based coagulants. AB - The water eutrophication caused by cyanobacteria seasonally proliferates, which is a hot potato to be resolved for water treatment plants. This study firstly investigated coagulation performance of titanium tetrachloride (TiCl4) for Microcystis aeruginosa synthetic water treatment. Results show complete algal cell removal by TiCl4 coagulation without damage to cell membrane integrity even under harsh conditions; 60 mg/L TiCl4 was effective in removing the microcystins up to 85%. Furthermore, besides having stronger UV254 removal capability and the higher removal of fluorescent substances over Al- and Fe-based coagulants, TiCl4 coagulant required more compact coagulation and sedimentation tanks due to its significantly improved floc growth and sedimentation speed. Meanwhile, its' short hydraulic retention time avoided algal cell breakage and subsequent algal organic matter release. Microcystin concentrations were kept at a low level during sludge storage period, indicating that the TiCl4 flocs could prevent algal cells from natural lysis. To facilitate water recycling without secondary contamination, the algae-containing sludge after TiCl4 coagulation ought to be disposed within 12 days at 20 degrees C and 8 days at 35 degrees C. PMID- 29492813 TI - Anoxic conditions are beneficial for abiotic diclofenac removal from water with manganese oxide (MnO2). AB - This is the first study examining pharmaceutical removal under anoxic conditions with MnO2. This study compares the abiotic removal of seven pharmaceuticals with reactive MnO2 particles in the presence of oxygen (oxic conditions) and in the absence of oxygen (anoxic conditions). Due to the novelty of pharmaceutical removal under anoxic conditions, the influence of phosphate buffer, pH, and MnO2 morphologies is also examined. Results show that over 90% of diclofenac is removed under anoxic conditions. Additionally, we found that (1) anoxic conditions are beneficial for diclofenac removal with MnO2, (2) phosphate buffer affects the pharmaceutical removal efficiencies, (3) higher pharmaceutical removal is obtained at acidic pH compared to that at neutral or alkaline conditions, and (4) amorphous MnO2 removes pharmaceuticals better than crystalline MnO2. The pharmaceutical molecular structure and properties, MnO2 properties especially reactive sites of the MnO2 surface, are important for degradation kinetics. This study provides a fundamental basis towards understanding pharmaceutical degradation with MnO2 under anoxic conditions, and development of a cost-effective, sustainable technology for removal of pharmaceuticals from water. PMID- 29492814 TI - Source apportionments of PM2.5 organic carbon during the elevated pollution episodes in the Ordos region, Inner Mongolia, China. AB - The Ordos region in the southwestern part of Inner Mongolia experiences frequent PM concentrations in excess of the national PM2.5 air quality standards. In order to determine the key sources of PM2.5 contributing to these pollution episodes, the main sources of PM2.5 OC during elevated PM episodes in the Inner Mongolia were analyzed and compared with non-polluted days. This will provide insight to the main sources of particulate matter pollution during the high-pollution episodes and the effective seasonal strategies to control sources of particulate matter during months and with the highest PM concentrations that need to be controlled. The PMF source contributions to OC demonstrated that the industrial/coal combustion (4762.77 +/- 1061.54 versus 2726.49 +/- 469.75 ng/m3; p < 0.001) and mobile source factors (4651.14 +/- 681.82 versus 2605.55 +/- 276.50 ng/m3; p value < 0.001) showed greater contributions to the elevated concentrations during the episode. The spatial analysis of secondary organic carbon (SOC) factors, regional biomass burning, and biogenic sources did not show significant difference in the pollution episodes and the non-polluted months. In addition, the bivariate polar plots and CWT maps of the industrial/coal combustion and mobile illustrated a regional long-range transport patterns from the external sources to the study area, however, adjacent areas were mostly controlling the contributions of these factors during the PM elevated episodes. The SOC sources, regional biomass burning, and biogenic sources illustrated a regional long-range transport with similar locations found during the elevated pollution episodes compared to the normal situations. PMID- 29492816 TI - Polychlorinated biphenyls in the Yellow River of Henan section: occurrence, composition, and impact factors. AB - The levels, spatial variation, congener profiles, impact factors, and ecological risk of polychlorinated biphenyls (PCBs) in the sediment from the Yellow River of Henan section, China, were investigated in this paper. Total concentration of 31 PCBs and seven indicator PCBs varied from ND to 1015 pg g-1 and ND to 423 pg g-1, respectively. Compared with other aquatic environments around China, PCB levels in the studied area were relatively low. Spatial variations revealed that tributaries possessed higher PCB levels, in comparison to mainstream, which acted as input sources of PCBs in the mainstream. The homolog profiles were dominated by lighter PCBs (Tri-PentaCBs), contributing above 70% of total PCBs. Correlation analysis between PCB concentrations and total organic carbon indicated that local input or atmospheric deposition was the primary controls of spatial variation of PCBs. According to simple sediment quality guidelines (SQG), the risks posed by PCBs in the sediments might be negligible. PMID- 29492815 TI - Behavioral and neurochemical consequences of perinatal exposure to lead in adult male Wistar rats: protective effect by Centella asiatica. AB - The present study evaluated the protective effects of Centella asiatica (CA) leaf extract on behavioral deficits and neurotoxicity in adult rat exposed to lead during perinatal period. Adult Wistar rats were exposed to 0.15% lead acetate (Pb) from gestation day 6 through drinking water and the pups were exposed lactationally to Pb till weaning. Significant perturbations in locomotor activity and exploratory behavior were observed in rats exposed to Pb during perinatal period. The levels of lipid peroxidation increased significantly with a reduction in levels of glutathione and activity levels of acetylcholinesterase and antioxidant enzymes in hippocampus, cerebrum, cerebellum, and medulla of brains excised from Pb-exposed rats. Oral supplementation of CA during postweaning period provided significant protection against Pb-induced behavioral impairments and neurotoxicity, without chelating tissue Pb levels. The possible neuroprotective efficacy of CA may be due to its antioxidant potential but not by lowering effects of brain Pb content. PMID- 29492817 TI - Reduction of N-nitrosodimethylamine formation from ranitidine by ozonation preceding chloramination: influencing factors and mechanisms. AB - Formation of toxic N-nitrosodimethylamine (NDMA) by chloramination of ranitidine, a drug to block histamine, was still an ongoing issue and posed a risk to human health. In this study, the effect of ozonation prior to chloramination on NDMA formation and the transformation pathway were determined. Influencing factors, including ozone dosages, pH, hydroxyl radical scavenger, bromide, and NOM, were studied. The results demonstrated that small ozone dosage (0.5 mg/L) could effectively control NDMA formation from subsequent chloramination (from 40 to 0.8%). The NDMA molar conversion was not only influenced by pH but also by ozone dosages at various pre-ozonation pH (reached the highest value of 5% at pH 8 with 0.5 mg/L O3 but decreased with the increasing pH with 1 mg/L O3). The NDMA molar yield by chloramination of ranitidine without pre-ozonation was reduced by the presence of bromide ion due to the decomposition of disinfectant. However, due to the formation of brominated intermediate substances (i.e., dimethylamine (DMA), dimethyl-aminomethyl furfuryl alcohol (DFUR)) with higher NDMA molar yield than their parent substances, more NDMA was formed than that without bromide ion upon ozonation. Natural organic matter (NOM) and hydroxyl radical scavenger (tert butyl alcohol, tBA) enhanced NDMA generation because of the competition of ozone and more ranitidine left. The NDMA reduction mechanism by pre-ozonation during chloramination of ranitidine may be due to the production of oxidation products with less NDMA yield (such as DMA) than parent compound. Based on the result of Q TOF and GC-MS/MS analysis, three possible transformation pathways were proposed. Different influences of oxidation conditions and water quality parameters suggest that strategies to reduce NDMA formation should vary with drinking water sources and choose optimal ozone dosage. PMID- 29492818 TI - Assessment and identification of nitrogen pollution sources in the Cheongmi River with intensive livestock farming areas, Korea. AB - This study aimed to develop methods for assessing and identifying nitrogen sources in the Cheongmi River, Korea, that has intensive livestock farming areas (ILFA) in its watershed. The assessment focused on the feasibility of the simultaneous use of stable isotopic compositions of ammonium (delta15NNH4) and nitrate (delta15NNO3) for identifying the main nitrogen pollution sources in the Cheongmi River watershed. Our results suggested that the organic nitrogen (Org-N) to total nitrogen (T-N) ratio could be used as an indicator for assessing the effect of livestock excreta on waterways in ILFA. We observed that the T-N concentration was much more strongly affected by livestock excreta than the T-P concentration in the mainstream of the Cheongmi River. The positive correlation was more significant between delta15NNH4 and NH4-N than that between delta15NNO3 and NO3-N for river water samples. Furthermore, the use of delta15NNH4 was more effective than that of delta15NNO3 in evaluating nitrogen variations between May and August in the Cheongmi River because the differences in delta15NNH4 between May and August were more remarkable compared to those in delta15NNO3. Finally, the simultaneous use of delta15NNH4 and delta15NNO3 showed that the dominant nitrogen source at sites M3, M4, M5, and M6, specifically in May, was livestock excreta in the Cheongmi River. The results of this study could be used for sustainable water quality management in the Cheongmi River watershed. PMID- 29492819 TI - Removing polycyclic aromatic hydrocarbons from water using granular activated carbon: kinetic and equilibrium adsorption studies. AB - Polycyclic aromatic hydrocarbons (PAHs) constitute a group of highly persistent, toxic and widespread environmental micropollutants that are increasingly found in water. A study was conducted in removing five PAHs, specifically naphthalene, acenaphthylene, acenaphthene, fluorene and phenanthrene, from water by adsorption onto granular activated carbon (GAC). The pseudo-first-order (PFO) model satisfactorily described the kinetics of adsorption of the PAHs. The Weber and Morris diffusion model's fit to the data showed that there were faster and slower rates of intra-particle diffusion probably into the mesopores and micropores of the GAC, respectively. These rates were negatively related to the molar volumes of the PAHs. Batch equilibrium adsorption data fitted well to the Langmuir, Freundlich and Dubinin-Radushkevich models, of which the Freundlich model exhibited the best fit. The adsorption affinities were related to the hydrophobicity of the PAHs as determined by the log Kow values. Free energies of adsorption calculated from the Dubinin-Radushkevich model and the satisfactory kinetic data fitting to the PFO model suggested physical adsorption of the PAHs. Adsorption of naphthalene, acenaphthylene and acenaphthene in fixed-bed columns containing a mixture of GAC (0.5 g) + sand (24.5 g) was satisfactorily simulated by the Thomas model. PMID- 29492820 TI - Fabrication and characterization of beta-cypermethrin-loaded PLA microcapsules prepared by emulsion-solvent evaporation: loading and release properties. AB - Microcapsulses can be designed to effectively encapsulate, protect, and control the release of pesticides. In this study, emulsion-solvent evaporation method was used to fabricate microcapsules using dichloromethane as the solvent, polylactic acid (PLA) as the carrier materials, poly(vinyl alcohol) as the emulsifier, and beta-cypermethrin as the entrapped pesticide. The effects of process parameters on the microcapsules characteristics (size, loading content, and encapsulation efficiency) were investigated. Also, the release behavior of the beta cypermethrin was measured experimentally and modeled mathematically. Kinetic analysis indicated that release mechanism of beta-cypermethrin was compatible to Fickian diffusion. By optimizing the process parameters, beta-cypermethrin-loaded microcapsules were successfully produced with spherical shape, smooth surface, high encapsulation efficiency (> 80%), and a range of pesticide contents. These parameters could be adjusted to achieve delivery systems with desirable release profiles. The results are beneficial to develop delivery systems for rational and effective usage of pesticides. PMID- 29492821 TI - Cumulative effects of cascade hydropower stations on total dissolved gas supersaturation. AB - Elevated levels of total dissolved gas (TDG) may occur downstream of dams during the spill process. These high levels would increase the incidence of gas bubble disease in fish and cause severe environmental impacts. With increasing numbers of cascade hydropower stations being built or planned, the cumulative effects of TDG supersaturation are becoming increasingly prominent. The TDG saturation distribution in the downstream reaches of the Jinsha River was studied to investigate the cumulative effects of TDG supersaturation resulting from the cascade hydropower stations. A comparison of the effects of the joint operation and the single operation of two hydropower stations (XLD and XJB) was performed to analyze the risk degree to fish posed by TDG supersaturation. The results showed that water with supersaturated TDG generated at the upstream cascade can be transported to the downstream power station, leading to cumulative TDG supersaturation effects. Compared with the single operation of XJB, the joint operation of both stations produced a much higher TDG saturation downstream of XJB, especially during the non-flood discharge period. Moreover, the duration of high TDG saturation and the lengths of the lethal and sub-lethal areas were much higher in the joint operation scenario, posing a greater threat to fish and severely damaging the environment. This work provides a scientific basis for strategies to reduce TDG supersaturation to the permissible level and minimize the potential risk of supersaturated TDG. PMID- 29492822 TI - Experimental investigation on emission reduction in neem oil biodiesel using selective catalytic reduction and catalytic converter techniques. AB - In the present study, non-edible seed oil namely raw neem oil was converted into biodiesel using transesterification process. In the experimentation, two biodiesel blends were prepared namely B25 (25% neem oil methyl ester with 75% of diesel) and B50 (50% neem oil methyl ester with 50% diesel). Urea-based selective catalytic reduction (SCR) technique with catalytic converter (CC) was fixed in the exhaust tail pipe of the engine for the reduction of engine exhaust emissions. Initially, the engine was operated with diesel as a working fluid and followed by refilling of biodiesel blends B25 and B50 to obtain the baseline readings without SCR and CC. Then, the same procedure was repeated with SCR and CC technique for emission reduction measurement in diesel, B25 and B50 sample. The experimental results revealed that the B25 blend showed higher break thermal efficiency (BTE) and exhaust gas temperature (EGT) with lower break-specific fuel consumption (BSFC) than B50 blend at all loads. On comparing with biodiesel blends, diesel experiences increased BTE of 31.9% with reduced BSFC of 0.29 kg/kWh at full load. A notable emission reduction was noticed for all test fuels in SCR and CC setup. At full load, B25 showed lower carbon monoxide (CO) of 0.09% volume, hydrocarbon (HC) of 24 ppm, and smoke of 14 HSU and oxides of nitrogen (NOx) of 735 ppm than diesel and B50 in SCR and CC setup. On the whole, the engine with SCR and CC setup showed better performance and emission characteristics than standard engine operation. PMID- 29492823 TI - Impact of military on biofuels consumption and GHG emissions: the evidence from G7 countries. AB - It was aimed to test the relation among the greenhouse gases emissions, economic growth, biofuels consumption, and militarization in G7 countries during the 1985 2015 period by Pedroni 1995 and panel Johansen tests and two long-run estimators dynamic OLS and fully modified OLS. Long-run estimators found that economic growth and militarization have statistically significant positive impact on CO2 emission of G7 countries. Furthermore, the panel causality tests were applied: Dumitrescu and Hurlin (Econ Model 29(4):1450-1460, 2012) and panel Granger causality. These tests determined the causal relationship between the variables. The results of this paper implied that economic growth and biofuels consumption depend on militarization, and economic growth and militarization are granger causes of the greenhouse gases emissions. PMID- 29492825 TI - Heads Up, Phones Down: A Pedestrian Safety Intervention on Distracted Crosswalk Behavior. AB - Cell phone use has been implicated in driver distraction and motor vehicle crashes, and more recently has been associated with distracted pedestrians. There are limited data on interventions aimed at this important public health issue. We hypothesized that the use of a visual intervention near street crossings would decrease the frequency of distracted behaviors of pedestrians. We performed a prospective observational cohort study examining painted sidewalk stencils reading, "Heads Up, Phones Down" as an intervention to decrease cell phone distractions amongst pedestrians. These stenciled messages were placed at a children's hospital, middle school, and high school in Los Angeles County. Anonymous observations of pedestrian distractions (texting, talking on a phone, headphone use, and other) were conducted before, 1 week after, and 4 months after the intervention. Distractions were compared before and after intervention using Chi square tests. A total of 11,533 pedestrians were observed, with 71% children and 29% adults. Total distractions decreased from 23% pre-intervention to 17% 1 week after stencil placement (p < 0.01), but this was not sustained at 4 months (23%, p = 0.4). A sustained decrease was observed only for texting at 4 months post-intervention (8.5% vs. 6.8%, p < 0.01). A simple visual intervention reduced distracted cell phone usage in pedestrians crossing the street, but this was most effective early after the intervention. Future studies are warranted to determine how to sustain this effect over time and how to minimize other types of distractions. PMID- 29492826 TI - Treatment of complex regional pain syndrome: an updated systematic review and narrative synthesis. AB - PURPOSE: Although multiple treatments have been advocated for complex regional pain syndrome (CRPS), the levels of supportive evidence are variable and sometimes limited. The purpose of this updated review is to provide a critical analysis of the evidence pertaining to the treatment of CRPS derived from recent randomized-controlled trials (RCTs). SOURCE: The MEDLINE, EMBASE, Psychinfo, and CINAHL databases were searched to identify relevant RCTs conducted on human subjects and published in English between 1 May 2009 and 24 August 2017. PRINCIPAL FINDINGS: The search yielded 35 RCTs of variable quality pertaining to the treatment of CRPS. Published trials continue to support the use of bisphosphonates and short courses of oral steroids in the setting of CRPS. Although emerging evidence suggests a therapeutic role for ketamine, memantine, intravenous immunoglobulin, epidural clonidine, intrathecal clonidine/baclofen/adenosine, aerobic exercise, mirror therapy, virtual body swapping, and dorsal root ganglion stimulation, further confirmatory RCTs are warranted. Similarly, trials also suggest an expanding role for peripheral sympathetic blockade (i.e., lumbar/thoracic sympathetic, stellate ganglion, and brachial plexus blocks). CONCLUSIONS: Since our prior systematic review article (published in 2010), 35 RCTs related to CRPS have been reported. Nevertheless, the quality of trials remains variable. Therefore, further research is required to continue investigating possible treatments for CRPS. PMID- 29492824 TI - Inflammasome Activation by Methamphetamine Potentiates Lipopolysaccharide Stimulation of IL-1beta Production in Microglia. AB - Methamphetamine (Meth) is an addictive psychostimulant abused worldwide. Ample evidence indicate that chronic abuse of Meth induces neurotoxicity via microglia associated neuroinflammation and the activated microglia present in both Meth administered animals and human abusers. The development of anti-neuroinflammation as a therapeutic strategy against Meth dependence promotes research to identify inflammatory pathways that are specifically tied to Meth-induced neurotoxicity. Currently, the exact mechanisms for Meth-induced microglia activation are largely unknown. NLRP3 is a well-studied cytosolic pattern recognition receptor (PRR), which promotes the assembly of the inflammasome in response to the danger associated molecular patterns (DAMPs). It is our hypothesis that Meth activates NLRP3 inflammasome in microglia and promotes the processing and release of interleukin (IL)-1beta, resulting in neurotoxic activity. To test this hypothesis, we studied the effects of Meth on IL-1beta maturation and release from rat cortical microglial cultures. Incubation of microglia with physiologically relevant concentrations of Meth after lipopolysaccharide (LPS) priming produced an enhancement on IL-1beta maturation and release. Meth treatment potentiated aggregation of inflammasome adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), induced activation of the IL-1beta converting enzyme caspase-1 and produced lysosomal and mitochondrial impairment. Blockade of capase-1 activity, lysosomal cathepsin B activity or mitochondrial ROS production by their specific inhibitors reversed the effects of Meth, demonstrating an involvement of inflammasome in Meth-induced microglia activation. Taken together, our results suggest that Meth triggers microglial inflammasome activation in a manner dependent on both mitochondrial and lysosomal danger-signaling pathways. PMID- 29492827 TI - Use of protein-based biomarkers of exfoliated cervical cells for primary screening of cervical cancer. AB - There has been no attempt to apply protein-based markers of exfoliated cervical cells (ECCs) for primary screening of cervical cancer. In the present study, the levels of six tumor-associated protein [TAPs: Sialyl Lewis A (SLeA), Cancer Antigen 15-3 (CA 15-3), p53, heat shock protein (Hsp)70, Hsp27 and squamous cervical carcinoma antigen (SCCA)]and of two human papillomavirus (HPV) viral proteins (HPV16 E7 and HPV16 L1) of ECCs lysates were evaluated by enzyme-linked immunosorbent assays (ELISAs).The wells of 96-well plates were coated with the ECCs lysates from normal, cervical intraepithelial neoplasia (CIN) I, CIN II, CIN III and cancer groups, and candidate proteins were detected by relevant antibodies. SLeA level decreased with increasing severity of lesions, whereas the levels of other candidate proteins increased. SLeA, HPV16 L1 and p53 levels appeared more useful for detecting cervical lesions than the other candidates. The combination of ELISA-SLeA and ELISA-HPV16 L1 could efficiently detect cervical lesions from normal. The combination of ELISA-SLeA and ELISA-p53 could powerfully discriminate cancer from normal with 91.3% sensitivity and 96.7% specificity. The protein levels of ECCs have great potential as biomarkers for primary screening of cervical cancer. PMID- 29492828 TI - Initial validation of symptom scores derived from the orthostatic discriminant and severity scale. AB - OBJECTIVE: To develop a scale to quantify and discriminate orthostatic from non orthostatic symptoms. In the current study, we present validation and reliability of orthostatic and non-orthostatic symptom scores taken from the orthostatic discriminate and severity scale (ODSS). METHODS: Validity and reliability were assessed in participants with and without orthostatic intolerance. Convergent validity was assessed by correlating symptoms scores with previously validated tools [autonomic symptom profile (ASP) and the orthostatic hypotension questionnaire (OHQ)]. Clinical validity was assessed by correlating scores against standardized autonomic testing. Test-retest reliability was calculated using an intra-class correlation coefficient. RESULTS: Convergent validity: orthostatic (OS) and non-orthostatic (NS) symptom scores from 77 controls and 67 patients with orthostatic intolerance were highly correlated with both the orthostatic intolerance index of the ASP (OS: r = 0.903; NS: r = 0.651; p < 0.001) and the composite score of the OHQ: (OS: r = 0.800; NS: r = 0.574; p < 0.001). Clinical validity: symptom scores were significantly correlated with the total composite autonomic severity score (OS: r = 0.458; NS: r = 0.315; p < 0.001), and the systolic blood pressure change during head-up tilt (OS: r = - 0.445; NS: r = - 0.354; p < 0.001). In addition, patients with orthostatic intolerance had significantly higher symptom scores compared to controls (OS: 66.5 +/- 18.1 vs. 17.4 +/- 12.9; NS: 19.9 +/- 11.3 vs. 10.2 +/- 6.8; p < 0.001, respectively). Test-retest reliability: Both orthostatic and non-orthostatic symptom scores were highly reliable (OS: r = 0.956 and NS: r = 0.574, respectively; p < 0.001) with an internal consistency of 0.978 and 0.729, respectively. INTERPRETATION: Our initial results demonstrate that the ODSS is capable of producing valid and reliable orthostatic and non-orthostatic symptom scores. Further studies are ongoing to test sensitivity, specificity and symptom severity. PMID- 29492829 TI - Two-patch model for the spread of West Nile virus. AB - A two-patch model for the spread of West Nile virus between two discrete geographic regions is established to incorporate a mobility process which describes how contact transmission occurs between individuals from and between two regions. In the mobility process, we assume that the host birds can migrate between regions, but not the mosquitoes. The basic reproduction number [Formula: see text] is computed by the next generation matrix method. We prove that if [Formula: see text], then the disease-free equilibrium is globally asymptotically stable. If [Formula: see text], the endemic equilibrium is globally asymptotically stable for any nonnegative nontrivial initial data. Using the perturbation theory, we obtain the concrete expression of the endemic equilibrium of the model with a mild restriction of the birds movement rate between patches. Finally, numerical simulations demonstrate that the disease becomes endemic in both patches when birds move back and forth between the two regions. Some numerical simulations for [Formula: see text] in terms of the birds movement rate are performed which show that the impacts could be very complicated. PMID- 29492831 TI - Correction to: Transanal hemorrhoidal dearterialization (THD) for hemorrhoidal disease: a single-center study on 1000 consecutive cases and a review of the literature. AB - The article "Transanal hemorrhoidal dearterialization (THD) for hemorrhoidal disease: a single-center study on 1000 consecutive cases and a review of the literature" written by C. Ratto et al. was originally published Online First without open access. PMID- 29492830 TI - The genetic backgrounds in nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to hepatocellular carcinoma (HCC) and hepatic failure. The development and progression of NAFLD are determined by environmental and genetic factors. The effect of genetic factors has been demonstrated by familial studies, twin studies and several cross-sectional studies. In the past 10 years, genome-wide association studies have revealed several single nucleotide polymorphisms (SNPs) associated with the pathology of NAFLD. Among them, the Patatin-like phospholipase domain-containing 3 (PNPLA3) gene variant I148M showed a strong relationship with the development and progression of NAFLD, NASH, and NAFLD related HCC. The transmembrane 6 superfamily member 2 (TM6SF2) gene variant E167 K was also associated with NAFLD, and it has a relationship with cardiovascular disease. Furthermore, several genes have been proposed as candidate genes to be associated with NAFLD based on case-control studies. We conducted a comprehensive literature search and review on the genetic background of NAFLD. PMID- 29492832 TI - Current status and progress of lymphoma research in East Asian countries: Introduction and planning. PMID- 29492833 TI - Competency-based Suicide Prevention Education: Implementation of a Pilot Course for Undergraduate Health Professions Students. PMID- 29492834 TI - Effect of joint line preservation on mobile-type bearing unicompartmental knee arthroplasty: finite element analysis. AB - In this study, we performed a virtual mobile-bearing unicompartmental knee arthroplasty (UKA) on the contact pressure in the tibial insert and articular cartilage by using finite element (FE) analysis to understand clinical observations and elaborate on the potential risks associated with a joint line preservation such as wear on tibial insert and osteoarthritis on other compartment. Neutral position of the knee joint was defined in 0 mm joint line, and contact pressure between tibial insert and articular cartilage varies with respect to changes of joint line. Therefore, evaluation of contact pressure may provide the degree of joint line preservation. The FE model for the joint line was developed using a perpendicular projection line from the medial tibial plateau to the anatomical axis. Seven FE models for joint lines in cases corresponding to +/- 6, +/- 4, +/- 2, and 0 mm were modeled and analyzed in normal level walking conditions. The maximum contact pressure on the superior and inferior surfaces of the polyethylene insert increased when the joint line became positive while the maximum contact pressure on the articular cartilage increased when the joint line became negative. The increase in the maximum contact pressure in the positive joint line exceeded that in the negative joint line, and this lead to an unsymmetrical maximum contact pressure distribution with respect to the joint line from a 0 reference. The joint line elevation was sensitive to increases or decreases in maximum contact pressures in the mobile-bearing UKA. The findings of the study determined that postoperative joint line preservation is important in mobile-type bearing UKA. PMID- 29492835 TI - Transcatheter aortic valve implantation: a safe and efficient procedure to treat an aortic valve stenosis before lung cancer resection. AB - A 75 year old man presented with left upper lobe squamous cell carcinoma. Severe aortic stenosis has been discovered during preoperative assessment. In this situation, two therapeutic strategies are described: concomitant or two-staged procedures. The debate has not yet led to the conclusion on whether preferably performing one or the other. Furthermore, in an oncologic context, using cardiopulmonary bypass is still controversial. So, thoracic and cardiac surgeons jointly proposed to the patient a transcatheter aortic valve implantation followed, 72 h later, by lung cancer resection. This case report describes a way to treat both diseases avoiding cardiopulmonary bypass adverse effects and without delaying lung cancer treatment. PMID- 29492836 TI - Correction to: Effect of Chromium Nanoparticles on Physiological Stress Induced by Exogenous Dexamethasone in Japanese Quails. AB - The original version of this article contained a mistake: The author name Shokoufe Ghazanfari was incorrectly written as Shekofeh Ghazanfari. PMID- 29492837 TI - Reversed redistribution in SPECT images from spontaneous coronary vasospasm. PMID- 29492838 TI - Prevalence and variability in reporting of clinically actionable incidental findings on attenuation-correction CT scans in a veteran population. AB - BACKGROUND: Myocardial perfusion imaging (MPI) often employs attenuation correction computed tomography (CTAC) to reduce attenuation artifacts and improve specificity. While there is no specific guideline on how they should be reported, incidental noncardiac findings identified on these scans may be clinically significant. The prevalence of these findings in veterans is not currently known. In addition, variability in reporting these findings may depend on the interpreting physician's specialty. METHODS: To guide future decision-making, CTACs in veterans referred for MPI were prospectively evaluated in a quality control project for a set of prespecified actionable incidental findings by cardiologists and a radiologist. RESULTS: On the 771 scans performed over eight months, 285 incidental noncardiac findings were identified by the interpreting cardiologists and 378 were identified by the interpreting radiologist. Pulmonary nodules were the most common occurring in 20% of studies read by the radiologist. Interreader agreements between cardiologists and the radiologist were poor for pulmonary nodules >= 10 mm and hiatal hernias; fair for pulmonary nodules < 10 mm, extracardiac masses, and aortic aneurysms; and moderate for pleural plaques. CONCLUSION: Incidental noncardiac findings on CTACs are common in our veteran population. Overall interobserver agreement in identifying these findings between cardiologists and radiologists is fair. Specific guidelines are needed on how CTACs should be read and reported. PMID- 29492839 TI - Olfactory-ensheathing cells promote physiological repair of injured recurrent laryngeal nerves and functional recovery of glottises in dogs. AB - The aim of this study was to investigate whether the transplantation of olfactory ensheathing cells (OECs) could physiologically repair severely injured recurrent laryngeal nerve (RLN) in dogs. Adult Beagle dogs were surgically introduced with a 10-mm defect in the left RLN and transplanted with a nerve guide (NEUROLAC) containing dog olfactory mucosa-olfactory-ensheathing cells (OM-OECs) in matrigel. The effects of OM-OECs on the morphology, histology, and electrophysiology of the injured RLNs, glottis movement, and voice acoustics were comparatively studied. Two months after transplantation, the normal dogs (group N) had intact left RLNs that contained axons well organized as bundles, transmitted action potentials of high amplitudes without latent phases, and modulated glottis movement to produce normal voices. The RLN-damaged dogs transplanted with OM-OECs (group CTT) had pieces of nerves regenerated in the place of the defects, which contained fewer axons scattered in the internal nerve membrane and wrapped peripherally by the connective tissue, prevented the distal trunk of the defected RLN from shrinking, transmitted action potentials of lower amplitudes with latent phases, and modulated a slightly impaired glottis movement to produce voices with slight differences compared to the N dogs. The RLN-damaged dogs without OM-OECs (group NC) had no nerves generated at the defective or the damaged area, leading to a shrinkage in the enervated distal nerve trunks; a blockage in nerve pulse transit; a paralysis of the left vocal cords; an impaired glottis movement; and abnormal voices. Transplantation of OM-OECs promoted nerve regeneration, and the recoveries of glottises and voices in dogs with RLN injury. PMID- 29492840 TI - Ultrasonographic evaluation of the second stage of labor. Predictive parameters for a successful vaginal delivery with or without neuraxial analgesia: a pilot study. AB - PURPOSE: The aim of the study was to evaluate the progression and rotation of the fetal head during the second stage of labor using translabial ultrasound and to compare ultrasonographic data obtained in nulliparous women both receiving and not receiving neuraxial analgesia. METHODS: The 49 patients enrolled in the study were divided into two groups according to receiving or not receiving neuraxial analgesia. Every half hour from full dilation to delivery, the ultrasonographic translabial parameters of Angle of Progression, Head Symphysis Distance, and Midline Angle were obtained and recorded by a single operator. Then, these records were compared between the two groups of patients. RESULTS: Patients that underwent neuraxial analgesia presented with increased duration of the second stage of labor, with mean values of Angle of Progression significantly higher and of Midline Angle significantly lower for each time interval studied compared to patients without analgesia. A borderline significant relationship was found between administration of neuraxial analgesia and Head Symphysis Distance. CONCLUSIONS: In this study, we demonstrated that combined spinal-epidural analgesia influences the duration of the second stage of labor and the initial progression and rotation of the fetal head through the birth canal, but not the kind of delivery. A correlation between Angle of Progression values and success in the application of a vacuum has been reported by other authors and confirmed in our study. PMID- 29492841 TI - A survey of ocular ultrasound abnormalities in horse: 145 cases. AB - PURPOSE: To describe the association of clinical and ultrasonographic (US) findings in horses affected by visual impairments, to estimate the most frequent ultrasonographic alteration as well importance and limits of US as a part of ophthalmic evaluation in equine patients. METHODS: One-hundred-forty-five horses referred to the Veterinary Teaching Hospitals of the University of Perugia and Camerino for ocular problems were submitted to ophthalmic examination and ocular ultrasound. The following group of abnormalities was established: corneal alteration, cataract, synechiae, iris prolapse, anterior chamber alterations, vitreous opacities, globe reduction, globe enlargement, retinal detachment, lens subluxation/luxation, lens rupture, intraocular masses, retrobulbar masses. Specificity, sensitivity, positive and negative predictive value and related 95% confidence interval were calculated. Kappa value was estimated for concordance evaluation. RESULTS: A total of 384 clinical alterations were observed during ophthalmological examination, while 357 were found by ultrasound investigation. A very good agreement was found for lens subluxation/luxation, intraocular masses, iris prolapse, globe enlargement, lens rupture, vitreous opacities and cataract. Moderate agreement was found for retinal detachment, anterior chamber alterations and synechiae. Corneal alteration and globe reduction resulted in a fair and poor agreement, respectively. CONCLUSIONS: Ultrasonography affords the benefit of providing a complete cross-sectional view of the eyeball, facilitating the identification of ocular diseases in cases of loss of transparency of ocular media. It also represents an indispensable aid whenever anterior opacification precludes the use of ophthalmoscopic or biomicroscopic examination techniques. PMID- 29492842 TI - Genome-Wide Pathway Analysis of Microarray Data Identifies Risk Pathways Related to Salt Stress in Arabidopsis Thaliana. AB - Salt stress is a common abiotic stress in agricultural production, which is affected by multiple genes and environmental factors. Although transcriptome analyses have detected some salt-related genes in Arabidopsis thaliana, these genes are often major genes and can not adequately explain the molecular mechanism of salt tolerance. Some genes related to salt stress, but does not reach significant threshold in gene expression analysis (called modest effect genes), are often ignored. Therefore, we took full account of the role of modest effect genes and performed a pathway-based analysis of three gene microarray datasets to identify the pathways related to salt stress. We also compared these results with the pathways identified by major genes. Finally, three pathways were identified as salt-related pathways, some of which were previously reported to be related to salt stress in plants, while others are novel. These findings will help us to study the molecular mechanism of salt stress, but also provide a new perspective for the study of salt tolerance in Arabidopsis thaliana. PMID- 29492844 TI - Influence of thyroid function on glomerular filtration rate and other estimates of kidney function in two pediatric patients. AB - To determine the optimal method of evaluating kidney function in patients with thyroid dysfunction, this study compared the estimated glomerular filtration rate derived from serum creatinine, cystatin C, or beta2-microglobulin with inulin or creatinine clearance in two pediatric patients, one with hypothyroidism and the other with hyperthyroidism. It was observed that the kidney function decreased in a hypothyroid child and enhanced in a hyperthyroid child, with their kidney function becoming normalized by treatment with drugs, which normalized their thyroid function. Kidney function cannot be accurately evaluated using cystatin C based or beta2-microglobulin-based estimated glomerular filtration rate in patients with thyroid dysfunction, as these tests overestimated glomerular filtration rate in a patient with hypothyroidism and underestimated glomerular filtration rate in a patient with hyperthyroidism, perhaps through a metabolic rate-mediated mechanism. In both our patients, 24-h urinary creatinine secretion was identical before and after treatment, suggesting that creatinine production is not altered in patients with thyroid dysfunction. Therefore, kidney function in patients with thyroid dysfunction should be evaluated using creatinine-based estimated glomerular filtration rate. PMID- 29492843 TI - The Burden of Illness of Idiopathic Pulmonary Fibrosis: A Comprehensive Evidence Review. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a debilitating condition with significant morbidity and poor survival. Since 2010, there has been increased activity in the development of treatments that aim to delay progression of the disease. OBJECTIVE: Our study involves a comprehensive review of the literature for evidence on health-related quality of life (HRQoL), healthcare resource use (HCRU) and costs, and an assessment of the burden of illness of the condition. METHODS: We carried out a systematic literature review (SLR) to identify economic evaluations and HRQoL studies. We searched EMBASE, MEDLINE and MEDLINE In Process for relevant studies from database origins to April 2017. Alongside the presentation of the study characteristics and the available evidence, we carried out a qualitative comparison using reference population estimates for HRQoL and national health expenditure for costs. RESULTS: Our search identified a total of 3241 records. After removing duplicates and not relevant articles, we analysed 124 publications referring to 88 studies published between 2000 and 2017. Sixty studies were HRQoL and 28 were studies on costs or HCRU. We observed an exponential growth of publications in the last 3-5 years, with the majority of the studies conducted in Europe and North America. Among the HRQoL studies, and despite regional differences, there was some agreement between estimates on the absolute and relative level of HRQoL for patients with IPF compared with the general population. Regarding costs, after adjustments for the cost years and currency, the suggested annual per capita cost of patients with IPF in North America was estimated around US$20,000, 2.5-3.5 times higher than the national healthcare expenditure. Additionally, studies that analysed patients with IPF alongside a matched control cohort suggested a significant increase in resource use and cost. CONCLUSION: The reviewed evidence indicates that IPF has considerable impact on HRQoL, relative to the general population levels. Furthermore, in studies of cost and resource use, most estimates of the burden were consistent in suggesting an excess cost for patients with IPF compared with a control cohort or the national health expenditure. This confirms IPF as a growing threat for public health worldwide, with considerable impact to the patients and healthcare providers. PMID- 29492845 TI - QTL for tuber morphology traits in diploid potato. AB - A diploid, potato mapping population consisting of 149 individuals was assessed in three consecutive years for important agronomic and quality traits: tuber shape, regularity of tuber shape, eye depth, mean tuber weight, and tuber flesh color. Analysis of variance showed that the genotype had the largest influence on the phenotypic scores but effect of the genotype * year interactions was also strong. Using this data and an existing genetic map, a quantitative trait loci (QTL) analysis was conducted. From four to seven QTL were detected for each trait except tuber flesh color, which was determined by a major QTL on chromosome III explaining 76.8% of the trait variance. Additionally, a minor QTL for flesh color was localized on chromosome II. For the other traits, significant QTL were detected: for tuber shape on chromosome X, for regularity of tuber shape on chromosome III, for eye depth on chromosome IV, and for tuber weight on chromosome I. Some detected QTL confirmed previous studies, but new ones were also identified. PMID- 29492846 TI - KATP Channel Expression and Genetic Polymorphisms Associated with Progression and Survival in Amyotrophic Lateral Sclerosis. AB - The ATP-sensitive potassium (KATP) channel directly regulates the microglia mediated inflammatory response following CNS injury. To determine the putative role of the KATP channel in amyotrophic lateral sclerosis (ALS) pathology, we investigated whether ALS induces changes in KATP channel expression in the spinal cord and motor cortex. We also characterized new functional variants of human ABCC8, ABCC9, KCNJ8, and KCNJ11 genes encoding for the KATP channel and analyzed their association with ALS risk, rate of progression, and survival in a Spanish ALS cohort. The expression of ABCC8 and KCNJ8 genes was enhanced in the spinal cord of ALS samples, and KCNJ11 increased in motor cortex of ALS samples, as determined by real-time polymerase chain reaction. We then sequenced the exons and regulatory regions of KATP channel genes from a subset of 28 ALS patients and identified 50 new genetic variants. For the case-control association analysis, we genotyped five selected polymorphisms with predicted functional relevance in 185 Spanish ALS (134 spinal ALS and 51 bulbar ALS) patients and 493 controls. We found that bulbar ALS patients presenting the G/G genotype of the rs4148646 variant of ABCC8 and the T/T genotype of the rs5219 variant of KCNJ11 survived longer than other ALS patients presenting other genotypes. Also, the C/C genotype of the rs4148642 variant of ABCC8 and the T/C genotype of the rs148416760 variant of ABCC9 modified the progression rate in spinal ALS patients. Our results suggest that the KATP channel plays a role in the pathophysiological mechanisms of ALS. PMID- 29492847 TI - High-Fructose Consumption Impairs the Redox System and Protein Quality Control in the Brain of Syrian Hamsters: Therapeutic Effects of Melatonin. AB - Although numerous studies have demonstrated the harmful effect of excessive fructose consumption at the systemic level, there is little information on its effects in the central nervous system. The purpose of the present work was to study the cellular alterations related to oxidative stress and protein quality control systems induced by a high-fructose diet in the brain of Syrian hamsters and their possible attenuation by exogenous melatonin. High-fructose intake induced type II diabetes together with oxidative damage, led to alterations of the unfolded protein response by activating the eIF2alpha branch, and impaired the macroautophagic machinery in the brain, favoring the accumulation of aggregates labeled for selective degradation and neurodegeneration markers such as beta-amyloid (1-42), tau-p-S199, and tau-p-S404. Melatonin attenuated the manifestation of type II diabetes and reduced oxidative stress, deactivated eIF2alpha, and decreased tau-p-S404 levels in the brain of animals fed a high fructose diet. PMID- 29492848 TI - SLAB51 Probiotic Formulation Activates SIRT1 Pathway Promoting Antioxidant and Neuroprotective Effects in an AD Mouse Model. AB - The gut-brain axis is a bidirectional communication network functionally linking the gut and the central nervous system (CNS). Based on this, the rational manipulation of intestinal microbiota represents a novel attractive therapeutic strategy for the treatment of CNS-associated disorders. In this study, we explored the properties of a probiotic formulation (namely SLAB51) in counteracting brain oxidative damages associated with Alzheimer's disease (AD). Specifically, transgenic AD mice (3xTg-AD) were treated with SLAB51 and the effects on protein oxidation, neuronal antioxidant defence and repair systems were monitored, with the particular focus on the role of SIRT1-related pathways. We demonstrated that SLAB51 markedly reduced oxidative stress in AD mice brain by activating SIRT1-dependent mechanisms, thus representing a promising therapeutic adjuvant in AD treatment. PMID- 29492851 TI - A 'Real-World' Analysis of Persistence on and Adherence to Glipizide GITS, Glipizide IR and Glibenclamide in Managed Care among Patients with Type 2 Diabetes Mellitus. AB - OBJECTIVE: This study compared persistence on and adherence to therapy with glipizide gastrointestinal therapeutic system (GITS), glipizide immediate release (IR) and glibenclamide (glyburide) in commercially insured patients newly treated for type 2 diabetes mellitus. The objective of the study was to determine if there were differences in persistence and adherence between the three second generation sulphonylureas. STUDY DESIGN: This was a retrospective longitudinal claims data analysis for commercial enrollees in eight independent practice model health plans. Study subjects were 25 years of age or older with a first prescription for a study drug from 1 January 1996 through 31 December 1999. All subjects were newly treated with medication for diabetes mellitus, and were initiated on monotherapy. To be included in the study, subjects had to be continuously enrolled in their health plan 6 months prior to their index claim and at least 30 days following the index claim. METHODS AND SUBJECTS: Persistence was defined as the total days from the index prescription fill date until termination, switch or augmentation of therapy. Adherence was defined as the ratio of days supplied to total days in the treatment period. The treatment period for the measurement of adherence was defined as the period from index prescription fill date to run-out of days supplied of the last filled prescription for the index drug. Cox proportional hazards analysis was used to compare differences in persistence, and multivariate regression was used to assess differences in adherence. Of the 24 311 subjects, 35% filled a first prescription for glipizide GITS, 15% for glipizide IR, and 50% for glibenclamide. Over one-half of study subjects were male, and the average age was between 51 years for the glipizide GITS cohort and 53 years for the glibenclamide cohort. MAIN OUTCOMES AND RESULTS: By the end of the study, 79% of subjects had terminated therapy with their index drug. Cox proportional hazards analysis showed that patients taking glipizide IR were 1.33 times more likely to experience treatment change [95% confidence interval (CI) 1.25 to 1.42], and patients taking glibenclamide were 1.16 times more likely to change therapy (95% CI 1.11 to 1.22) compared with patients taking glipizide GITS in the first 90 days following initiation of therapy. Similar results were found upon subsequent analysis in the 1620 days following the index prescription. The analysis of adherence showed that patients taking glipizide IR or glibenclamide were less adherent to therapy compared with patients taking glipizide GITS (p < 0.001). CONCLUSIONS: Glipizide GITS appears to have an advantage in persistence on and adherence to therapy compared with glipizide IR and glibenclamide. These differences may be related to administration frequency. Lack of persistence and adherence has potential clinical and economic consequences. PMID- 29492849 TI - Physiological Concentration of Prostaglandin E2 Exerts Anti-inflammatory Effects by Inhibiting Microglial Production of Superoxide Through a Novel Pathway. AB - This study investigated the physiological regulation of brain immune homeostasis in rat primary neuron-glial cultures by sub-nanomolar concentrations of prostaglandin E2 (PGE2). We demonstrated that 0.01 to 10 nM PGE2 protected dopaminergic neurons against LPS-induced neurotoxicity through a reduction of microglial release of pro-inflammatory factors in a dose-dependent manner. Mechanistically, neuroprotective effects elicited by PGE2 were mediated by the inhibition of microglial NOX2, a major superoxide-producing enzyme. This conclusion was supported by (1) the close relationship between inhibition of superoxide and PGE2-induced neuroprotective effects; (2) the mediation of PGE2 induced reduction of superoxide and neuroprotection via direct inhibition of the catalytic subunit of NOX2, gp91phox, rather than through the inhibition of conventional prostaglandin E2 receptors; and (3) abolishment of the neuroprotective effect of PGE2 in NOX2-deficient cultures. In summary, this study revealed a potential physiological role of PGE2 in maintaining brain immune homeostasis and protecting neurons via an EP receptor-independent mechanism. PMID- 29492850 TI - RETRACTED ARTICLE: Combination Antiemetic Regimens for Prevention of Postoperative Nausea and Vomiting : Focus on High-Risk Patients. AB - None of the available antiemetics is entirely effective, perhaps because most of them act through the blockade of one receptor. There is a possibility that a combination of antiemetics with different sites of activity would be more effective than one drug alone for prophylaxis against postoperative nausea and vomiting (PONV).The clinical use of combined traditional antiemetics, including antihistamines (e.g. diphenhydramine), butyrophenones (e.g. droperidol) and benzamides (e.g. metoclopramide), for the prevention of PONV is limited because of the possibility of additive central nervous system toxicity, such as delayed emergence, drowsiness and extrapyramidal reactions. The efficacy of a combination of a serotonin 5-HT3 receptor antagonist (ondansetron, granisetron or tropisetron) and dexamethasone is superior to that of 5-HT3 receptor antagonists alone for the prevention of PONV, suggesting that dexamethasone enhances the antiemetic efficacy of 5-HT3 receptor antagonists. The combination of a 5-HT3 receptor antagonist with a traditional antiemetic (droperidol, metoclopramide or promethazine) acting at a different emetogenic receptor is more effective in reducing the incidence of PONV than each antiemetic alone acting at one receptor site. The risk of undesirable adverse effects does not increase with the combination of a 5-HT3 receptor antagonist and a traditional antiemetic at the doses commonly used for PONV, because of the absence of drug interactions. The combination of a 5-HT3 receptor antagonist (ondansetron) with other agents (propofol and CP-122721) reduces the incidence of PONV to a greater degree than monotherapy. However, no data are available for the combination of 5-HT3 receptor antagonists and small doses of propofol for the prevention of PONV.Further studies are needed to evaluate the efficacy and safety of combination antiemetic regimens for PONV. Knowledge regarding combinations of these antiemetic drugs may be necessary to completely prevent PONV. PMID- 29492852 TI - Multiple-Dose Studies can be a More Sensitive Assessment for Bioequivalence than Single-Dose Studies : The Case with Omeprazole. AB - OBJECTIVE: To evaluate the bioequivalence of two enteric-coated formulations of omeprazole, Losec(r) (reference) and Omepradex(r) (test). It is hypothesised that formulation differences may be accentuated following multiple-dose administration, and that testing after multiple administration may therefore provide a more sensitive assessment of bioequivalence. STUDY PARTICIPANTS AND DESIGN: The study comprised two parts: an in vitro dissolution test and an in vivo bioavailability study. The latter was a randomised, two-way crossover comparative study after a single dose and after multiple doses in healthy volunteers. Forty subjects were randomly allocated to receive either test or reference product, once daily in the morning, and blood samples were taken on days 1 and 5. Standard pharmacokinetic analyses were performed, and analysis of variance (ANOVA) was used to compare the log-transformed variables in a model including terms for treatment, subject and period. RESULTS: Although both products meet the formal requirements specified by the United States Pharmacopoeia (USP) for enteric-coated articles, the in vitro dissolution experiments revealed widely differing properties for the two tested products. Less than 10% of the drug content was recovered from the Omepradex(r) formulation following a pre-exposure to pH 3 or 4, compared with over 90% recovered from the Losec(r) formulation. These findings were in agreement with the results of the in vivo bioavailability study, which showed that the two products differed in both their rate and extent of absorption after a single dose and following multiple doses. The products failed the bioequivalence test for area under the plasma concentration-time curve (AUC) and maximum plasma drug concentration (Cmax) after a single dose [AUC: test/reference ratio 0.85, 90% confidence interval (0.76 0.95); Cmax: test/reference ratio 0.85, 90% confidence interval (0.75-0.95)], and the difference between the formulations was even more pronounced after multiple doses [AUC: test/reference ratio 0.73, 90% confidence interval (0.65-0.83); Cmax: test/reference ratio 0.71, 90% confidence interval (0.63-0.81)]. CONCLUSIONS: These data suggest that bioequivalence studies on enteric-coated proton pump inhibitors should include both single- and multiple-dose elements to be fully decisive. The two omeprazole products failed to show bioequivalence, with the observed differences being even more apparent after multiple doses, as postulated. Based on this study, the two products may not be considered either therapeutically equivalent or interchangeable. PMID- 29492854 TI - Evolution of Antibiotic Use and Cost in Patients with Community-Acquired Pneumonia. AB - OBJECTIVE: To investigate the evolution and efficiency of the clinical management (particularly shift therapy) of patients with community-acquired pneumonia (CAP) in a hospital setting. STUDY DESIGN AND METHODS: This was a retrospective analysis of 120 hospitalised patients who were treated with antibiotics for CAP in the first semesters of 1999 (50 patients), 2000 (39 patients) and 2001 (31 patients). We evaluated the prescribed daily dose and the average hospitalisation and treatment periods for each drug. Pareto curves were used to examine relative costs and quantities of drugs administered. Total therapy costs and average cost for an antibiotic were also calculated. RESULTS: Over the 3 years, the drugs most commonly used were ceftriaxone and ciprofloxacin; levofloxacin, introduced in 2001, allowed for shorter average treatment periods. Twenty-one of 39 (53.8%) patients seen in the first semester of 2000 were discharged early compared with 29 of 31 (93.54%) in 2001. Therapy was continued at home (shift therapy) with ciprofloxacin (n = 8), ceftriaxone (n = 5) and cotrimoxazole (n = 2) in 2000 and with ceftriaxone (n = 15), oral ciprofloxacin (n = 7) and oral levofloxacin (n = 7) in 2001. CONCLUSIONS: Shift therapy using either oral or injectable antibiotics is possible in patients with CAP and allowed us to realise significant savings in management. Selection of route of administration of shift therapy should be made on an individual basis. PMID- 29492853 TI - Beat-to-Beat Measurement of Cardiovascular Effects of a Single Subcutaneous Dose of Terbutaline in Healthy Subjects. AB - OBJECTIVE: To evaluate the cardiovascular effects over time of a single subcutaneous (SC) dose of terbutaline 0.75mg in young healthy volunteers using continuous, beat-to-beat monitoring of cardiovascular effects. DESIGN AND METHODS: Nine healthy young volunteers were administered a SC dose of terbutaline sulphate 0.75mg. Cardiovascular effects were continuously monitored over 2 hours using Finapres and Modelflow technology. Blood was drawn at several timepoints for determination of the plasma terbutaline concentration. RESULTS: The peak plasma concentration of terbutaline was 17.3 +/- 4.5 (ug/L at 28.9 +/- 12.5 minutes after SC administration. Changes in cardiovascular parameters were observed very quickly, with increases in stroke volume (16.7 +/-8.9%), cardiac output (46.0 +/- 22.6%), systolic blood pressure (15.1 +/- 11.6%) and heart rate (48.1 +/- 15.7%) at 9.3 +/- 3.8, 16.9 +/- 4.8, 21.3 +/- 8.9 and 49.7 +/- 16.4 minutes, respectively. In five of eight subjects a very rapid (at 9.6 +/- 3.7 minutes) drop in diastolic blood pressure (9.8 +/- 5.1 %) was observed, while total peripheral resistance decreased maximally by 33.5 +/- 7.9% at 18.9 +/- 7.1 minutes. CONCLUSIONS: The magnitude of the cardiovascular effects again stresses the need for cautious use of SC terbutaline in patients with a history of cardiovascular disease. The time-course of some of the cardiovascular effects of a SC dose of terbutaline in relation to terbutaline plasma concentrations was unexpected and suggests direct beta2-adrenoreceptor-mediated effects on the heart. Further investigations using both selective and nonselective beta-receptor antagonists are needed to unravel the complex interactions of beta2-receptor mediated terbutaline-induced effects and cardiovascular reflex mechanisms. PMID- 29492855 TI - Frequency of Extrapyramidal Adverse Reactions in Schizophrenic Outpatients Treated with Risperidone, Olanzapine, Quetiapine or Haloperidol : Results of the EIRE Study. AB - OBJECTIVE: The EIRE (Estudio de Investigacion de Resultados en Esquizofrenia - Outcomes Research Study in Schizophrenia) study was initiated in order to assess the frequency of adverse reactions [extrapyramidal symptoms (EPS), hyperprolactinaemia, sexual dysfunction and weight gain] caused by atypical antipsychotics and haloperidol in patients with schizophrenia during routine treatment in clinical practice. This paper presents the results of the assessment of extrapyramidal adverse reactions. PATIENTS AND STUDY DESIGN: Outpatients diagnosed with schizophrenia according to the Diagnostic and Statistical Manual of mental disorders, 4th edition (DSM-IV), criteria and receiving a single antipsychotic (risperidone, olanzapine, quetiapine or haloperidol) for at least 4 weeks were consecutively recruited. In this cross-sectional and non interventional study data were collected in a single visit; this included demographic and clinical characteristics, current antipsychotic and concomitant treatment, and data on several adverse effects listed in a modified version of the UKU (Udvalg for Kliniske Undersogelser - Committee on Clinical Investigations) scale. For paired comparisons of the frequency of adverse reactions between treatments the Chi-squared (chi2) test was used. For estimation of the risk of a given adverse reaction with a given treatment a logistic regression method was used. RESULTS: 636 evaluable patients (of 669 recruited) were assessed. The frequency of EPS with haloperidol (78.3% of the cases) was higher than with risperidone (55.1%), quetiapine (39.5%) and olanzapine (35.8%) [chi2: p < 0.05], and the difference between risperidone and olanzapine was also statistically significant (chi2: p < 0.05). Very similar results were obtained in the individualised analysis of the items as regards the occurrence of akathisia, which was also more frequent in the haloperidol (36.8%) and risperidone (19.7%) groups than in the olanzapine (11.4%) and quetiapine (2.6%) groups (chi2: p < 0.05). Olanzapine, quetiapine and risperidone also showed a lower risk of EPS than haloperidol when adjusting by dose. CONCLUSION: Our results suggest that the atypical antipsychotics studied are less likely to induce extrapyramidal adverse reactions compared with haloperidol in stabilised patients, although these reactions are still common. PMID- 29492856 TI - Randomised Trial of Two Different Daily Doses of Interferon-alpha versus Classical Therapy in Treatment-Naive Patients with Chronic Hepatitis C. AB - OBJECTIVE: To evaluate the efficacy and tolerability of two different daily doses of interferon-alpha (lymphoblastoid-IFNalpha-N1, Wellferon(r)) [IFNalpha] for 2 months, followed by the same dose on alternate days for up to 1 year, versus administration on alternate days for 1 year. PATIENTS AND METHODS: A non-blind, randomised study of outpatients with chronic hepatitis C at five centres in Sicily, Italy. Ninety-seven consecutive treatment-naive patients [72 patients with hepatitis C virus (HCV) genotype 1b infection] with histological chronic hepatitis C were included in the study and randomised to receive IFNalpha subcutaneously: 5 million international units (MIU) daily for 2 months, followed by the same dose on alternate days for up to 1 year (n = 33, group A); 3 MIU for 2 months, followed by the same dose on alternate days for up to 1 year (32, group B); 5 MIU on alternate days for 12 months (32, group C). Adverse effects were monitored through interviews and by clinical and biochemical check-ups at 1-month intervals. RESULTS: There were no significant differences between the three groups with regard to age, gender, HCV genotype distribution, or severity of histological findings. Seven patients dropped out of the study because of severe adverse effects: three from group A, two from group B, and three from group C. Approximately 30% of the 97 patients, equally distributed between the three groups, had a 'flu-like syndrome of mild-to-moderate intensity. Dosage reduction of IFNalpha from 5 MIU to 3 MIU daily was necessary in two patients in group A during the first month of treatment. Overall, 88 patients completed treatment as scheduled. After the induction phase, HCV was eradicated from the bloodstream in 27 patients (81.8%) from group A versus 15 (46.9%) from group B (p < 0.001) and 15 (46.9%) from group C (p < 0.001). The switch to maintenance dosages caused some infection breakthroughs, with the result that at the end of treatment 16 patients in group A, 12 in group B and 14 in group C had undetectable serum levels of HCV-RNA. After treatment discontinuation, however, five patients in group A, four in group B and six in group C became HCV-RNA positive. Thus, at the end of follow-up, 11 patients in group A, eight in group B and eight in group C had a sustained virological response. CONCLUSION: The present study shows that induction therapy with 5 MIU of IFNalpha administered daily for 2 months is well tolerated and that the percentage of patients with viral eradication at the end of this phase is higher than the percentage obtained with traditional therapy. Unfortunately, this good initial response decreases as treatment continues with conventional therapy, thus nullifying the benefits of the induction phase. PMID- 29492857 TI - Acceptability of Liquid Human Growth Hormone (hGH) [Norditropin Simple Xx(r)] in Adults and Children with GH Deficiency and Children with Chronic Renal Disease. AB - OBJECTIVE: Human growth hormone (GH) is well established as a treatment for growth hormone deficiency. Recently, a new liquid GH formulation (Norditropin SimpleXx(r)) has become available that does not require reconstitution before subcutaneous self-administration with a new delivery system (NordiPenTM) and an optional auto-injector (NordiPenmateTM). In this study the acceptability and tolerability of and compliance with the liquid formulation were investigated DESIGN AND PATIENTS: An open 6-week multicentre trial in 53 patients, including adults and children, was performed in The Netherlands. Acceptability and tolerability of the liquid GH formulation were assessed by questionnaires and compliance by both questionnaires and re-collection of GH cartridges MAIN OUTCOME MEASURES AND RESULTS: The mean daily dosage of GH was 0.24 mg/m2 (0.03 to 0.82 mg/m2) in adults and 1.13 mg/m2 (0.65 to 1.77 mg/m2) in children. Most patients (91% of adults and 89% of children) preferred to continue on the new GH formulation rather than the previously used formulation. This was mainly due to the easier and less time-consuming procedure and the good tolerance of the drug. Self-reported compliance also improved, but this could not be proven due to poor return of study cartridges CONCLUSIONS: The use of the liquid GH formulation Norditropin SimpleXx(r) with the NordiPenTM device and optional use of the NordiPenmateTM device was well accepted by both adults and children. This was mainly due to the avoidance of reconstitution and the ease of handling of the injection device. PMID- 29492858 TI - Rationale for Increasing the Starting Dose of Simvastatin. PMID- 29492859 TI - Muscarinics for Xerostomia in Patients with Sjogren's Syndrome. PMID- 29492861 TI - Analysis of Housekeeping Genes for Accurate Normalization of qPCR Data During Early Postnatal Brain Development. AB - Maturation of the neocortex during the first three postnatal weeks is a complex process that is characterized by different time courses of maturation of different areas of the neocortex. Analysis of gene expression using quantitative PCR after reverse transcription during this period of ontogeny and comparison of different cortical areas require optimal selection of reference genes for correct normalization of the data. Here, we compared expression of nine reference genes in the somatosensory and visual areas of the neocortex at the age of 5, 8, 10, 13, and 20 days. Using widely used GeNorm and NormFinder applications, as well as a novel approach, we compared stability of expression of GAPDH, YWHAZ, TFR1, RPS18, Rn18S, HPRT1, KIF5C, OSBP, and UQCRFS1. We found that, in both neocortical areas studied, YWHAZ and UQCRFS1 are the best reference genes whereas GAPDH and TFR1 are also stably expressed in the somatosensory cortex and OSBP is stable in the visual cortex. Additionally, analysis of stability of expression of these genes by a novel approach showed that the expression of these genes is stable during the entire period from the 5th to the 20th postnatal days. PMID- 29492860 TI - The obesity paradox in cancer: clinical insights and perspectives. AB - A series of evidence demonstrated that obesity represents an established risk factor for an increase in the incidence of multiple cancer types and for poor cancer survival. Nevertheless, recent studies suggested that, in a series of cancers, patients with a normal body mass index (BMI) have worse outcomes than obese patients. This phenomenon, named 'obesity paradox' or 'reverse epidemiology' in cancer, is not well understood and presents controversial aspects. Therefore, this review aims to explore the available studies concerning the relationship between obesity and cancer incidence or survival and to highlight the hypothetical explanations and the methodological framework. In this regard, we underline the limits of BMI as a potential marker of adiposity and the relevance to assessing body composition, beyond the body size. Further studies are needed to define the impact of obesity in cancer patients, to tailor weight management after cancer diagnosis and to hopefully improve overall clinical outcome. PMID- 29492862 TI - Differential Prescribing of Antimuscarinic Agents in Older Adults with Cognitive Impairment. AB - BACKGROUND: Oral oxybutynin has been associated with the development of cognitive impairment. OBJECTIVE: The objective of this study was to describe the use of oral oxybutynin versus other antimuscarinics (e.g., tolterodine, darifenacin, solifenacin, trospium, fesoterodine, transdermal oxybutynin) in older adults with documented cognitive impairment. METHODS: This is a population-based retrospective analysis of antimuscarinic new users aged >= 66 years from January 2008 to December 2011 (n = 42,886) using a 5% random sample of Medicare claims linked with Part D data. Cognitive impairment was defined as a diagnosis of mild cognitive impairment, dementia, use of antidementia medication, and memory loss/drug-induced cognitive conditions in the year prior to the initial antimuscarinic claim. We used multivariable generalized linear models to assess indicators of cognitive impairment associated with initiation of oral oxybutynin versus other antimuscarinics after adjusting for comorbid conditions. RESULTS: In total, 33% received oral oxybutynin as initial therapy. Cognitive impairment was documented in 10,259 (23.9%) patients prior to antimuscarinic therapy. Patients with cognitive impairment were 5% more likely to initiate another antimuscarinic versus oral oxybutynin (relative risk [RR] 1.05; 95% confidence interval [CI] 1.03-1.06). The proportion of patients with cognitive impairment initiated on oral oxybutynin increased from 24.1% in 2008 to 41.1% in 2011. The total cost of oral oxybutynin, in $US, year 2011 values, decreased by 10.5%, whereas the total cost of other antimuscarinics increased by 50.3% from 2008 to 2011. CONCLUSION: Our findings suggest opportunities for quality improvement of antimuscarinic prescribing in older adults, but this may be hampered by cost and formulary restrictions. PMID- 29492863 TI - Safety of Injectable HPbetaCD-Diclofenac in Older Patients with Acute Moderate-to Severe Postoperative Pain: A Pooled Analysis of Three Phase III Trials. AB - BACKGROUND: Hydroxypropyl-beta-cyclodextrin-diclofenac (HPbetaCD-diclofenac) is an NSAID used to treat acute moderate-to-severe postoperative pain. This post hoc analysis investigated the safety of HPbetaCD-diclofenac in patients aged >= 65 years. METHODS: Data from three phase III trials of HPbetaCD-diclofenac in adult patients with acute moderate-to-severe postoperative pain were pooled (NCT00448110, NCT00507026, and NCT00726388). Patients who received one or more dose of HPbetaCD-diclofenac or placebo were included and stratified according to age: < 65, 65-74, or >= 75 years. Numerical and categorical variables were compared across the groups using ANOVA and Cochran-Mantel-Haenszel tests, respectively. Cochran-Mantel-Haenszel relative risks compared with placebo were calculated, adjusted by study. RESULTS: Overall, 1289 patients were included: 878, 282, and 129 in the < 65, 65-74, and >= 75-years groups, respectively. Overall incidence of treatment-emergent adverse events (TEAEs) was similar in the three groups (p = 0.4360). Incidences of postoperative anemia (p < 0.0001), constipation (p = 0.0017), and hypotension (p = 0.0003) increased significantly across the age groups, whereas headache (p = 0.0008) and flatulence (p = 0.0118) decreased significantly. Relative risks for all System Organ Class categories and preferred terms investigated were similar among the groups and similar to placebo. CONCLUSIONS: Overall incidence of TEAEs in patients aged 65-74 or >= 75 years was similar to patients aged < 65 years. The groups displayed similar relative risks for the most frequent TEAEs, which were all similar to placebo. The TEAE profiles of the groups showed differences, all of which may be anticipated due to age-related differences in susceptibility and the types of surgery most commonly performed in each group. CLINICALTRIALS. GOV IDENTIFIERS: NCT00448110, NCT00507026, and NCT00726388. PMID- 29492864 TI - The crystal structure of methanol dehydrogenase, a quinoprotein from the marine methylotrophic bacterium Methylophaga aminisulfidivorans MPT. AB - The first crystal structure of a pyrroloquinoline quinone (PQQ)-dependent methanol dehydrogenase (MDH) from a marine methylotrophic bacterium, Methylophaga aminisulfidivorans MPT (MDH Mas ), was determined at 1.7 A resolution. The active form of MDH Mas (or MDHI Mas ) is a heterotetrameric alpha2beta2, where each beta subunit assembles on one side of each of the alpha-subunits, in a symmetrical fashion, so that two beta-subunits surround the two PQQ-binding pockets on the alpha-subunits. The active site consists of a PQQ molecule surrounded by a beta propeller fold for each alpha-subunit. Interestingly, the PQQ molecules are coordinated by a Mg2+ ion, instead of the Ca2+ ion that is commonly found in the terrestrial MDHI, indicating the efficiency of osmotic balance regulation in the high salt environment. The overall interaction of the beta-subunits with the alpha-subunits appears tighter than that of terrestrial homologues, suggesting the efficient maintenance of MDHI Mas integrity in the sea water environment to provide a firm basis for complex formation with MxaJ Mas or Cyt cL. With the help of the features mentioned above, our research may enable the elucidation of the full molecular mechanism of methanol oxidation by taking advantage of marine bacterium-originated proteins in the methanol oxidizing system (mox), including MxaJ, as the attainment of these proteins from terrestrial bacteria for structural studies has not been successful. PMID- 29492865 TI - Proteome analysis reveals global response to deletion of mrflbA in Monascus ruber. AB - Monascus spp. are commonly used for a wide variety of applications in the food and pharmaceutical industries. In previous studies, the knock-out of mrflbA (a putative regulator of the G protein alpha subunit) in M. ruber led to autolysis of the mycelia, decreased pigmentation and lowered mycotoxin production. Therefore, we aimed to obtain a comprehensive overview of the underlying mechanism of mrflbA deletion at the proteome level. A two-dimensional gel electrophoresis analysis of mycelial proteins indicated that the abundance of 178 proteins was altered in the DeltamrflbA strain, 33 of which were identified with high confidence. The identified proteins are involved in a range of activities, including carbohydrate and amino acid metabolism, hyphal development and the oxidative stress response, protein modification, and the regulation of cell signaling. Consistent with these findings, the activity of antioxidative enzymes and chitinase was elevated in the supernatant of the DeltamrflbA strain. Furthermore, deletion of mrflbA resulted in the transcriptional reduction of secondary metabolites (pigment and mycotoxin). In short, the mutant phenotypes induced by the deletion of mrflbA were consistent with changes in the expression levels of associated proteins, providing direct evidence of the regulatory functions mediated by mrflbA in M. ruber. PMID- 29492866 TI - Bacillus spongiae sp. nov., isolated from sponge of Jeju Island. AB - A Gram-reaction-positive, strictly aerobic, motile, endospore- forming, and rod shaped bacterial strain designated 135PIL107-10T was isolated from a sponge on Jeju Island, and its taxonomic position was investigated using a polyphasic approach. Strain 135PIL107-10T grew at 20-37 degrees C (optimum temperature, 25 degrees C) and pH 6.0-10.0 (optimum pH, 6.0) on marine and R2A agars. Based on 16S rRNA gene phylogeny analysis, the novel strain formed a new branch within the genus Bacillus of the family Bacillaceae, and formed clusters with Bacillus thaohiensis NHI-38T (96.8%), Bacillus fengqiuensis NPK15T (96.7%), and Bacillus songklensis CAU 1033T (96.7%). Lower sequence similarities (97.0%) were found with the type strains of all other recognized members of the genus Bacillus (95.6 96.8% similarity). The G + C content of the genomic DNA was 43.6 mol%. The predominant respiratory quinone was menaquinone-7 and the major fatty acids were iso-C15:0 and iso-C17:1omega10c. The overall polar lipid patterns were diphosphatidylglycerol, phosphatidylglycerol, and phosphatidylethanolamine. The diagnostic diamino acid in the cell-wall peptidoglycan was meso-diaminopimelic acid. The isolate therefore represents a novel species, for which the name Bacillus spongiae sp. nov. is proposed, with the type strain 135PIL107-10T (= KACC 19275T = LMG 30080T). PMID- 29492868 TI - Rapid and robust MALDI-TOF MS techniques for microbial identification: a brief overview of their diverse applications. AB - in mass spectrometry have enabled the investigation of various biological systems by directly analyzing diverse sets of biomolecules (i.e., proteins, lipids, and carbohydrates), thus making a significant impact on the life sciences field. Over the past decade, matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) has been widely utilized as a rapid and reliable method for the identification of microorganisms. MALDI-TOF MS has come into widespread use despite its relatively low resolving power (full width at half maximum, FWHM: < 5,000) and its incompatibility with tandem MS analysis, features with which other high-resolution mass spectrometers are equipped. Microbial identification is achieved by searching databases containing mass spectra of peptides and proteins extracted from microorganisms of interest, using scoring algorithms to match analyzed spectra with reference spectra. In this paper, we give a brief overview of the diverse applications of rapid and robust MALDI-TOF MS-based techniques for microbial identification in a variety of fields, such as clinical diagnosis and environmental and food monitoring. We also describe the fundamental principles of MALDI-TOF MS. The general specifications of the two major MS-based microbial identification systems available in the global market (BioTyper(r) and VITEK(r) MS Plus) and the distribution of these instruments in Republic of Korea are also discussed. The current review provides an understanding of this emerging microbial identification and classification technology and will help bacteriologists and cell biologists take advantage of this powerful technique. PMID- 29492869 TI - UBCG: Up-to-date bacterial core gene set and pipeline for phylogenomic tree reconstruction. AB - Genome-based phylogeny plays a central role in the future taxonomy and phylogenetics of Bacteria and Archaea by replacing 16S rRNA gene phylogeny. The concatenated core gene alignments are frequently used for such a purpose. The bacterial core genes are defined as single-copy, homologous genes that are present in most of the known bacterial species. There have been several studies describing such a gene set, but the number of species considered was rather small. Here we present the up-to-date bacterial core gene set, named UBCG, and software suites to accommodate necessary steps to generate and evaluate phylogenetic trees. The method was successfully used to infer phylogenomic relationship of Escherichia and related taxa and can be used for the set of genomes at any taxonomic ranks of Bacteria. The UBCG pipeline and file viewer are freely available at https://www.ezbiocloud.net/tools/ubcg and https://www.ezbiocloud.net/tools/ubcg_viewer , respectively. PMID- 29492867 TI - Hydrogen sulfide inhibits the growth of Escherichia coli through oxidative damage. AB - Many studies have shown that hydrogen sulfide (H2S) is both detrimental and beneficial to animals and plants, whereas its effect on bacteria is not fully understood. Here, we report that H2S, released by sodium hydrosulfide (NaHS), significantly inhibits the growth of Escherichia coli in a dose-dependent manner. Further studies have shown that H2S treatment stimulates the production of reactive oxygen species (ROS) and decreases glutathione (GSH) levels in E. coli, resulting in lipid peroxidation and DNA damage. H2S also inhibits the antioxidative enzyme activities of superoxide dismutase (SOD), catalase (CAT) and glutathione reductase (GR) and induces the response of the SoxRS and OxyR regulons in E. coli. Moreover, pretreatment with the antioxidant ascorbic acid (AsA) could effectively prevent H2S-induced toxicity in E. coli. Taken together, our results indicate that H2S exhibits an antibacterial effect on E. coli through oxidative damage and suggest a possible application for H2S in water and food processing. PMID- 29492870 TI - Trajectories of Identity Formation Modes and Their Personality Context in Adolescence. AB - Identity formation is a dynamic process during adolescence. Trajectories of identity formation were assessed longitudinally in early and middle adolescents, taking into account the personality underpinnings of this process. Identity formation was conceptualized according to the circumplex of identity formation modes. The model distinguishes basic modes rooted in Marcia's categories of exploration and commitment. Plasticity and stability, the two higher order Big Five meta-traits, were used to assess personality underpinnings. This study includes five measurement waves over 1.5 years and involves 1,839 Polish participants; 914 early adolescents (53.9% girls) and 925 middle adolescents (63.8% girls). The results suggest that (1) the four identity formation modes change dynamically, showing linear and curvilinear growth and that (2) identity formation mode trajectories are more dynamic in middle adolescence than in early adolescence. The results also showed that, in the conditional model, (3) the higher-order personality factors and gender affect the growth factors of identity formation modes. Overall, trajectories of identity formation modes are more linear during early adolescence and more curvilinear during middle adolescence. The initial levels in identity trajectories are influenced by the personality metatraits but only plasticity is related to change among early adolescents. PMID- 29492871 TI - Gut microbiomes and their metabolites shape human and animal health. AB - The host genetic background, complex surrounding environments, and gut microbiome are very closely linked to human and animal health and disease. Although significant correlations between gut microbiota and human and animal health have been revealed, the specific roles of each gut bacterium in shaping human and animal health and disease remain unclear. However, recent omics-based studies using experimental animals and surveys of gut microbiota from unhealthy humans have provided insights into the relationships among microbial community, their metabolites, and human and animal health. This editorial introduces six review papers that provide new discoveries of disease-associated microbiomes and suggest possible microbiome-based therapeutic approaches to human disease. PMID- 29492872 TI - Intestinal microbiota and the immune system in metabolic diseases. AB - The intestinal microbiota is comprised of millions of microorganisms that reside in the gastrointestinal tract and consistently interact with the host. Host factors such as diet and disease status affect the composition of the microbiota, while the microbiota itself produces metabolites that can further manipulate host physiology. Dysbiosis of the intestinal microbiota has been characterized in patients with certain metabolic diseases, some of which involve damage to the host intestinal epithelial barrier and alterations in the immune system. In this review, we will discuss the consequences of dietdependent bacterial dysbiosis in the gastrointestinal tract, and how the associated interaction with epithelial and immune cells impacts metabolic diseases. PMID- 29492873 TI - Type 3 regulatory T cells at the interface of symbiosis. AB - The mammalian gastrointestinal tract accommodates trillions of bacteria, many of which provide beneficial effects to the host, including protection from pathogenic microorganisms and essential metabolites. However, the intestinal immune system needs to adapt to the constantly fluctuating microbial environment at mucosal surfaces in order to maintain homeostasis. In particular, the gut microbiota induces the differentiation of effector Th17 cells and regulatory T cells (Tregs) that express RORgammat, the master regulator of antimicrobial type 3 immunity. RORgammat+ Tregs constitute a major population of colonic Tregs that is distinct from thymusderived Tregs and require bacterial antigens for differentiation. The balance between Th17 cells and RORgammat+ Tregs, that is, the tone of the local type 3 immune response, is regulated by the vitamin A metabolite retinoic acid produced by the host. Furthermore, Th17 cells and RORgammat+ Tregs regulate intestinal type 2 immune responses, explaining how bacteria block allergic reactions. Here, we review the cellular and molecular mechanisms involved in the differentiation, regulation and function of RORgammat+ (type 3) Tregs, and discuss the multiple equilibria that exist between effector T cells and Tregs, as well as between different types of immune responses, which are necessary to maintain homeostasis and health. PMID- 29492874 TI - Mind-altering with the gut: Modulation of the gut-brain axis with probiotics. AB - It is increasingly evident that bidirectional interactions exist among the gastrointestinal tract, the enteric nervous system, and the central nervous system. Recent preclinical and clinical trials have shown that gut microbiota plays an important role in these gut-brain interactions. Furthermore, alterations in gut microbiota composition may be associated with pathogenesis of various neurological disorders, including stress, autism, depression, Parkinson's disease, and Alzheimer's disease. Therefore, the concepts of the microbiota-gut brain axis is emerging. Here, we review the role of gut microbiota in bidirectional interactions between the gut and the brain, including neural, immune-mediated, and metabolic mechanisms. We highlight recent advances in the understanding of probiotic modulation of neurological and neuropsychiatric disorders via the gut-brain axis. PMID- 29492875 TI - Targeting friend and foe: Emerging therapeutics in the age of gut microbiome and disease. AB - Mucosal surfaces that line our gastrointestinal tract are continuously exposed to trillions of bacteria that form a symbiotic relationship and impact host health and disease. It is only beginning to be understood that the cross-talk between the host and microbiome involve dynamic changes in commensal bacterial population, secretion, and absorption of metabolites between the host and microbiome. As emerging evidence implicates dysbiosis of gut microbiota in the pathology and progression of various diseases such as inflammatory bowel disease, obesity, and allergy, conventional treatments that either overlook the microbiome in the mechanism of action, or eliminate vast populations of microbes via wide spectrum antibiotics need to be reconsidered. It is also becoming clear the microbiome can influence the body's response to therapeutic treatments for cancers. As such, targeting the microbiome as treatment has garnered much recent attention and excitement from numerous research labs and biotechnology companies. Treatments range from fecal microbial transplantation to precision-guided molecular approaches. Here, we survey recent progress in the development of innovative therapeutics that target the microbiome to treat disease, and highlight key findings in the interplay between host microbes and therapy. PMID- 29492876 TI - Current understanding of microbiota- and dietary-therapies for treating inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) is a result of chronic inflammation caused, in some part, by dysbiosis of intestinal microbiota, mainly commensal bacteria. Gut dysbiosis can be caused by multiple factors, including abnormal immune responses which might be related to genetic susceptibility, infection, western dietary habits, and administration of antibiotics. Consequently, the disease itself is characterized as having multiple causes, etiologies, and severities. Recent studies have identified >200 IBD risk loci in the host. It has been postulated that gut microbiota interact with these risk loci resulting in dysbiosis, and this subsequently leads to the development of IBD. Typical gut microbiota in IBD patients are characterized with decrease in species richness and many of the commensal, and beneficial, fecal bacteria such as Firmicutes and Bacteroidetes and an increase or bloom of Proteobacteria. However, at this time, cause and effect relationships have not been rigorously established. While treatments of IBD usually includes medications such as corticosteroids, 5-aminosalicylates, antibiotics, immunomodulators, and anti-TNF agents, restoration of gut dysbiosis seems to be a safer and more sustainable approach. Bacteriotherapies (now called microbiota therapies) and dietary interventions are effective way to modulate gut microbiota. In this review, we summarize factors involved in IBD and studies attempted to treat IBD with probiotics. We also discuss the potential use of microbiota therapies as one promising approach in treating IBD. As therapies based on the modulation of gut microbiota becomes more common, future studies should include individual gut microbiota differences to develop personalized therapy for IBD. PMID- 29492878 TI - Liver Safety of Fasiglifam (TAK-875) in Patients with Type 2 Diabetes: Review of the Global Clinical Trial Experience. AB - INTRODUCTION: Fasiglifam (TAK-875) is a G protein-coupled receptor 40 agonist that was being investigated for treatment of type 2 diabetes mellitus (T2DM). A development program was terminated late in phase III clinical trials due to liver safety concerns. METHODS: The liver safety of fasiglifam was assessed from data based on six phase II and nine phase III double-blind studies and two open-label studies with emphasis on pooled data from 15 double-blind studies from both global and Japanese development programs. Taking into consideration different daily doses of fasiglifam administered in clinical studies, the primary comparisons were between all patients exposed to fasiglifam (any dose) versus placebo, and, where applicable, versus the two active comparators, sitagliptin or glimepiride. A Liver Safety Evaluation Committee consisting of hepatologists blinded to treatment assignments evaluated hepatic adverse events (AEs) and serious AEs (SAEs) for causal relationship to study drug. RESULTS: The analysis included data from 9139 patients with T2DM in 15 double-blind controlled studies who received either fasiglifam (n = 5359, fasiglifam group), fasiglifam and sitagliptin (n = 123), or a comparator agent (n = 3657, non-exposed group consisting of placebo and other antidiabetic agents). Exposure to treatment for more than 1 year ranged from 249 patients in the placebo arm, to 370 patients in the glimepiride arm and 617 patients in the fasiglifam 50 mg arm. The primary focus of the analysis was on the hepatic safety of fasiglifam. The overall safety profile based on treatment-emergent AEs (TEAEs), SAEs, deaths, and withdrawal due to AEs was similar between fasiglifam and placebo (excluding liver test abnormalities). However, there was an increased incidence rate of serum alanine aminotransferase (ALT) elevations > 3 * upper limit of normal (ULN), 5 * ULN, and 10 * ULN in fasiglifam-treated patients compared with those treated with placebo or active comparators. ALT elevations > 3 * ULN for fasiglifam were 2.7% compared with 0.8 and 0.5% for the active comparators and placebo. There did not appear to be a clear dose response in incidence of ALT elevations between patients receiving 25 or 50 mg daily. The cumulative incidence of elevations in serum ALT > 3 * ULN was higher in the first 6 months of treatment with fasiglifam compared with both placebo and the active comparators, but the rate of new ALT elevations appeared to be similar across all treatment groups thereafter. No demographic or baseline patient characteristics were identified to predict elevations exceeding ALT > 3 * ULN in fasiglifam-treated patients. The pattern of liver injury with fasiglifam was hepatocellular, and there were no reports of liver-related deaths, liver failure or life-threatening liver injury. Most fasiglifam-associated ALT elevations were asymptomatic and resolved promptly upon discontinuing treatment, but in two patients the recovery was prolonged. Importantly, three important serious liver injury cases were identified among fasiglifam-treated patients; one case was adjudicated to be a clear Hy's Law case and the two remaining cases were considered to closely approximate Hy's Law cases. CONCLUSIONS: Although the incidence of overall AEs, SAEs, and deaths was similar between fasiglifam and placebo, a liver signal was identified based primarily on the difference in liver chemistry values in the fasiglifam group compared with the placebo and active comparator groups. Three serious liver injuries were attributed to fasiglifam treatment. Clinical development of fasiglifam was halted due to these liver safety concerns. PMID- 29492877 TI - The Ruminococci: key symbionts of the gut ecosystem. AB - Mammalian gut microbial communities form intricate mutualisms with their hosts, which have profound implications on overall health. One group of important gut microbial mutualists are bacteria in the genus Ruminococcus, which serve to degrade and convert complex polysaccharides into a variety of nutrients for their hosts. Isolated decades ago from the bovine rumen, ruminococci have since been cultured from other ruminant and non-ruminant sources, and next-generation sequencing has further shown their distribution to be widespread in a diversity of animal hosts. While most ruminococci that have been studied are those capable of degrading cellulose, much less is known about non-cellulolytic, nonruminant associated species, such as those found in humans. Furthermore, a mechanistic understanding of the role of Ruminococcus spp. in their respective hosts is still a work in progress. This review highlights the broad work done on species within the genus Ruminococcus with respect to their physiology, phylogenetic relatedness, and their potential impact on host health. PMID- 29492879 TI - Metabolic Coupling Between Bone Marrow Adipose Tissue and Hematopoiesis. AB - PURPOSE OF REVIEW: Mesenchymal stem cells (MSCs) located in the bone marrow have the capacity to differentiate into multiple cell lineages, including osteoblast and adipocyte. Adipocyte density within marrow is inversely associated with bone mass during aging and in some pathological conditions, contributing to the prevailing view that marrow adipocytes play a largely negative role in bone metabolism. However, a negative association between marrow adipocytes and bone balance is not universal. Although MAT levels appear tightly regulated, establishing the precise physiological significance of MAT has proven elusive. Here, we review recent literature aimed at delineating the function of MAT. RECENT FINDINGS: An important physiological function of MAT may be to provide an expandable/contractible fat depot, which is critical for minimization of energy requirements for sustaining optimal hematopoiesis. Because the energy requirements for storing fat are negligible compared to those required to maintain hematopoiesis, even small reductions in hematopoietic tissue volume to match a reduced requirement for hematopoiesis could represent an important reduction in energy cost. Such a physiological function would require tight coupling between hematopoietic stem cells and MSCs to regulate the balance between MAT and hematopoiesis. Kit-ligand, an important regulator of proliferation, differentiation, and survival of hematopoietic cells, may function as a prototypic factor coupling MAT and hematopoiesis. Crosstalk between hematopoietic and mesenchymal cells in the bone marrow may contribute to establishing the balance between MAT levels and hematopoiesis. PMID- 29492881 TI - Laparoscopic ultrasound manipulator with a spring-based elastic mechanism. AB - PURPOSE: Image guidance is a key technology that can improve the outcome of laparoscopic surgery. However, due to the large deformation caused by digestive organs, a computer-aided navigation system based on preoperative imaging data cannot indicate the correct target position of the lesion (e.g., liver tumors and vessels invisible from the organ surface). To overcome this issue, we developed a laparoscopic ultrasound manipulator with two motorized degrees of freedom at the tip, allowing for the performance of a dexterous ultrasound scan in a confined laparoscopic surgical area. METHOD: The developed manipulator consists of a compact and elastic structure using springs, enabling a safe ultrasound scan and avoiding excess force on the inspected organs. The manipulator is a handheld device equipped with four buttons at the handle, which the surgeon directly grasps to send a motion command to the tip structure. The developed prototype realizes two motorized degree-of-freedom motion at the tip. The size of prototype is 15.0 mm in diameter that is usable in conventional laparoscopy. The tip of the manipulator was carefully designed by considering the kinematic model and the results of the finite element analysis. RESULTS: To assess the prototype, accuracy and rigidity were measured by using a motion processing microscope. The accuracy test showed that the proposed device has a fairly accurate characteristic as a handheld device. This was supposedly caused by the nature of compliant mechanism, which does not have mechanical play in motion. In addition, the intrinsic elastic structure (approximately 2.0 N/mm in most of the range of motion) allowed the ultrasound probe to adequately fit on the curved organ surface without extra effort of manipulation during the inspection. In the in vivo experiment, the yaw motion was found to be effective for investigating the vascular network because the manipulator allows the probe to be rotated while maintaining the same position. CONCLUSION: The mechanical evaluation and in vivo test results showed high feasibility of the prototype. We are currently working on further mechanical improvement for commercialization and development of a real time navigation system that can perform three-dimensional reconstruction of ultrasonographic images by implementing a magnetic position sensor at the tip of the manipulator. PMID- 29492882 TI - Host-Associated Bacteriophage Isolation and Preparation for Viral Metagenomics. AB - Prokaryotic viruses, or bacteriophages, are viruses that infect bacteria and archaea. These viruses have been known to associate with host systems for decades, yet only recently have their influence on the regulation of host associated bacteria been appreciated. These studies have been conducted in many host systems, from the base of animal life in the Cnidarian phylum to mammals. These prokaryotic viruses are useful for regulating the number of bacteria in a host ecosystem and for regulating the strains of bacteria useful for the microbiome. These viruses are likely selected by the host to maintain bacterial populations. Viral metagenomics allows researchers to profile the communities of viruses associating with animal hosts, and importantly helps to determine the functional role these viruses play. Further, viral metagenomics show the sphere of viral involvement in gene flow and gene shuffling in an ever-changing host environment. The influence of prokaryotic viruses could, therefore, have a clear impact on host health. PMID- 29492883 TI - Small RNA Isolation from Tissues of Grapevine and Woody Plants. AB - A protocol is described to purify small (s)RNA molecules from tissues of grapevine and other woody plants. The protocol has been specifically developed to analyze sRNA populations by high-throughput sequencing. It has been widely used on species of the genera Prunus and Vitis particularly rich in polyphenols and other enzyme-inhibiting compounds. The high quality of the sRNAs extracted from leaf or phloem tissues makes them suitable for all molecular biology reactions, in particular for next-generation sequencing library preparation. PMID- 29492880 TI - Multistage segmentation model and SVM-ensemble for precise lung nodule detection. AB - PURPOSE: Lung cancer detection at its initial stages increases the survival chances of patients. Automatic detection of lung nodules facilitates radiologists during the diagnosis. However, there is a challenge of false positives in automated systems which may lead to wrong findings. Precise segmentation facilitates to accurately extract nodules from lung CT images in order to improve performance of the diagnostic method. METHODS: A multistage segmentation model is presented in this study. The lung region is extracted by applying corner-seeded region growing combined with differential evolution-based optimal thresholding. In addition to this, morphological operations are applied in boundary smoothing, hole filling and juxtavascular nodule extraction. Geometric properties along with 3D edge information are applied to extract nodule candidates. Geometric texture features descriptor (GTFD) followed by support vector machine-based ensemble classification is employed to distinguish actual nodules from the candidate set. RESULTS: A publicly available dataset, namely lung image database consortium and image database resource initiative, is used to evaluate performance of the proposed method. The classification is performed over GTFD feature vector and the results show 99% accuracy, 98.6% sensitivity and 98.2% specificity with 3.4 false positives per scan (FPs/scan). CONCLUSION: A lung nodule detection method is presented to facilitate radiologists in accurately diagnosing cancer from CT images. Results indicate that the proposed method has not only reduced FPs/scan but also significantly improved sensitivity as compared to related studies. PMID- 29492884 TI - Double-Stranded RNA-Enriched Preparations to Identify Viroids by Next-Generation Sequencing. AB - Approaches based on next-generation sequencing (NGS) coupled with bioinformatics tools have been developed for detecting viruses and viroids infecting herbaceous and woody plants. Here we describe a protocol to extract nucleic acids from citrus bark and enrich them in double-stranded RNAs. These preparations can be efficiently used for generating cDNA libraries that, after pair-end sequencing and bioinformatics analyses, allow efficient identification of the viroids infecting the source plant. PMID- 29492885 TI - Viral Double-Stranded RNAs (dsRNAs) from Plants: Alternative Nucleic Acid Substrates for High-Throughput Sequencing. AB - High-throughput sequencing (or next-generation sequencing-NGS) is an emerging technology that allows the detection of plant viruses without any prior knowledge. Various sequencing techniques and various templates can be used as substrate for NGS. This chapter describes an optimized protocol for the extraction of double-stranded RNAs (dsRNAs) from a wide range of plants and for their random amplification prior to NGS sequencing. PMID- 29492886 TI - Workup of Human Blood Samples for Deep Sequencing of HIV-1 Genomes. AB - We describe a detailed protocol for the manual workup of blood (plasma/serum) samples from individuals infected with the human immunodeficiency virus type 1 (HIV-1) for deep sequence analysis of the viral genome. The study optimizing the assay was performed in the context of the BEEHIVE (Bridging the Evolution and Epidemiology of HIV in Europe) project, which analyzes complete viral genomes from more than 3000 HIV-1-infected Europeans with high-throughput deep sequencing techniques. The goal of the BEEHIVE project is to determine the contribution of viral genetics to virulence. Recently we performed a pilot experiment with 125 patient plasma samples to identify the method that is most suitable for isolation of HIV-1 viral RNA for subsequent long-amplicon deep sequencing. We reported that manual isolation with the QIAamp Viral RNA Mini Kit (Qiagen) provides superior results over robotically extracted RNA. The latter approach used the MagNA Pure 96 System in combination with the MagNA Pure 96 Instrument (Roche Diagnostics), the QIAcube robotic system (Qiagen), or the mSample Preparation Systems RNA kit with automated extraction by the m2000sp system (Abbott Molecular). Here we present a detailed protocol for the labor-intensive manual extraction method that yielded the best results. PMID- 29492887 TI - Monolith Chromatography as Sample Preparation Step in Virome Studies of Water Samples. AB - Viruses exist in aquatic media and many of them use this media as transmission route. Next-generation sequencing (NGS) technologies have opened new doors in virus research, allowing also to reveal a hidden diversity of viral species in aquatic environments. Not surprisingly, many of the newly discovered viruses are found in environmental fresh and marine waters. One of the problems in virome research can be the low amount of viral nucleic acids present in the sample in contrast to the background ones (host, eukaryotic, prokaryotic, environmental). Therefore, virus enrichment prior to NGS is necessary in many cases. In water samples, an added problem resides in the low concentration of viruses typically present in aquatic media. Different concentration strategies have been used to overcome such limitations. CIM monoliths are a new generation of chromatographic supports that due to their particular structural characteristics are very efficient in concentration and purification of viruses. In this chapter, we describe the use of CIM monolithic chromatography for sample preparation step in NGS studies targeting viruses in fresh or marine water. The step-by-step protocol will include a case study where CIM concentration was used to study the virome of a wastewater sample using NGS. PMID- 29492888 TI - Viral Metagenomics Approaches for High-Resolution Screening of Multiplexed Arthropod and Plant Viral Communities. AB - Viral metagenomic approaches have become essential for culture-independent and sequence-independent viral detection and characterization. This chapter describes an accurate and efficient approach to (1) concentrate viral particles from arthropods and plants, (2) remove contaminating non-encapsidated nucleic acids, (3) extract and amplify both viral DNA and RNA, and (4) analyze high-throughput sequencing (HTS) data by bioinformatics. Using this approach, up to 96 arthropod or plant samples can be multiplexed in a single HTS library. PMID- 29492889 TI - Different Approaches to Discover Mycovirus Associated to Marine Organisms. AB - Here we describe the protocols to characterize the virome associated to fungi isolated from marine organisms assessed on the seagrass Posidonia oceanica and on the marine animal Holothuria poli. We provide detailed protocols for fungal isolation, fungal growth, and total RNA extraction. Ribosomal RNA depletion, cDNA library synthesis and normalization, and sequencing runs on different platforms are part of the protocols that are generally outsourced and therefore are not described in this chapter. We describe, instead, how raw reads are assembled into contigs and how to search for putative viral sequences. Furthermore, we detail qualitative checks to infer the existence of the virus as a replicative biological entity. PMID- 29492890 TI - Use of siRNAs for Diagnosis of Viruses Associated to Woody Plants in Nurseries and Stock Collections. AB - Woody perennial plants like grapevine and fruit trees can be infected by several viruses even as multiple infections. Since they are propagated vegetatively, the phytosanitary status of the propagation material (both the rootstock and the variety) can have a profound effect on the lifetime and health of the new plantations. The fast evolution of sequencing techniques provides a new opportunity for metagenomics-based viral diagnostics. Viral derived small RNAs produced by the host immune system during viral infection can be sequenced by next-generation techniques and analyzed for the presence of viruses, revealing the presence of all known viral pathogens in the sample. This method is based on Illumina sequencing of short RNAs and bioinformatics analysis of virus-derived small RNAs in the host. Here we describe a protocol for this challenging technique step by step with notes, in order to ensure success for every user. PMID- 29492891 TI - The Use of High-Throughput Sequencing for the Study and Diagnosis of Plant Viruses and Viroids in Pollen. AB - This protocol details the wet lab preparation, extraction of fruit pollen samples, and analysis of the sequencing data following Illumina NextSeq small and total RNA sequencing. The protocol was developed for virus and viroid detection using NGS sequencing and was based on the results of a comparison between different extraction methods followed by yield, RNA purity, and integrity assessment. Moreover, the advantage of an additional ribosomal (r)RNA depletion step to the total RNA extraction protocol was evaluated. The smallRNA procedure is the preferred method of choice. If the total RNA protocol is chosen, the use of the mirVana kit followed by an rRNA depletion step is the best option. The library preparation and sequencing steps were outsourced. As a final step in the data analysis, the VirusDetect software was used to detect the viruses and viroids in the pollen samples. PMID- 29492892 TI - High-Resolution Screening of Viral Communities and Identification of New Pathogens in Fish Using Next-Generation Sequencing. AB - Discovery of viral genomes in fish has historically been based on viral enrichment, random priming, cloning, and Sanger sequencing. However, the development of next-generation sequencing has enabled the possibility to sequence the entire virome of a tissue sample. This has led to an enormous increase in discovery of new viruses. In this chapter, we describe a simple and rapid method for viral discovery in fish. The method is based on Illumina sequencing of total RNA from diseased tissue or cell culture and in silico removal of host RNA. PMID- 29492893 TI - Metagenomic Analyses of the Viruses Detected in Mycorrhizal Fungi and Their Host Orchid. AB - In nature, mycorrhizal association with soilborne fungi is indispensable for orchid families. Fungal structures from compatible endo-mycorrhizal fungi in orchid cells are digested in cells to be supplied to orchids as nutrition. Because orchid seeds lack the reserves for germination, they keep receiving nutrition through mycorrhizal formation from seed germination until shoots develop (leaves) and become photoautotrophic. Seeds of all orchid species surely geminate with the help of their own fungal partners, and this specific partnership has been acquired for a long evolutional history between orchids and fungi.We have studied the interactions between orchids and mycorrhizal fungi and recently conducted transcriptome analyses (RNAseq) by a next-generation sequencing (NGS) approach. It is possible that orchid RNA isolated form naturally grown plants is contaminated with RNAs derived from mycorrhizal fungi in the orchid cells. To avoid such contamination, we here prepared aseptically germinated orchid plants (i.e., fungus-free plants) together with a pure-cultured fungal isolate and field-growing orchid samples. In the cDNA library prepared from orchid and fungal tissues, we found that partitivirus-like sequences were common in an orchid and its mycorrhizal fungus. These partitivirus-like sequences were closely related by a phylogenetic analysis, suggesting that transmission of an ancestor virus between the two organisms occurred through the specific relation of the orchid and its associated fungus. PMID- 29492894 TI - DNA Multiple Sequence Alignment Guided by Protein Domains: The MSA-PAD 2.0 Method. AB - Multiple sequence alignment (MSA) is a fundamental component in many DNA sequence analyses including metagenomics studies and phylogeny inference. When guided by protein profiles, DNA multiple alignments assume a higher precision and robustness. Here we present details of the use of the upgraded version of MSA-PAD (2.0), which is a DNA multiple sequence alignment framework able to align DNA sequences coding for single/multiple protein domains guided by PFAM or user defined annotations. MSA-PAD has two alignment strategies, called "Gene" and "Genome," accounting for coding domains order and genomic rearrangements, respectively. Novel options were added to the present version, where the MSA can be guided by protein profiles provided by the user. This allows MSA-PAD 2.0 to run faster and to add custom protein profiles sometimes not present in PFAM database according to the user's interest. MSA-PAD 2.0 is currently freely available as a Web application at https://recasgateway.cloud.ba.infn.it/ . PMID- 29492895 TI - From Whole-Genome Shotgun Sequencing to Viral Community Profiling: The ViromeScan Tool. AB - ViromeScan is an innovative metagenomic analysis tool that allows the viral community characterization in terms of taxonomy from raw data of metagenomics sequencing. It efficiently denoises samples from reads of other microorganisms. Users can adopt the same shotgun metagenomic sequencing data to fully characterize complex microbial ecosystems, including bacteria and viruses. Here we apply ViromeScan pipeline to some examples, thus illustrating the processes computed from raw data to the final output. PMID- 29492896 TI - Shannon Entropy to Evaluate Substitution Rate Variation Among Viral Nucleotide Positions in Datasets of Viral siRNAs. AB - Next-generation sequencing has opened the door to the reconstruction of viral populations and examination of the composition of mutant spectra in infected cells, tissues, and host organisms. In this chapter we present details on the use of the Shannon entropy method to estimate the site-specific nucleotide relative variability of turnip crinkle virus, a positive (+) stranded RNA plant virus, in a large dataset of short RNAs of Cicer arietinum L., a natural reservoir of the virus. We propose this method as a viral metagenomics tool to provide a more detailed description of the viral quasispecies in infected plant tissue. Viral replicative fitness relates to an optimal composition of variants that provide the molecular basis of virus behavior in the complex environment of natural infections. A complete description of viral quasispecies may have implications in determining fitness landscapes for host-virus coexistence and help to design specific diagnostic protocols and antiviral strategies. PMID- 29492897 TI - Insect Virus Discovery by Metagenomic and Cell Culture-Based Approaches. AB - Insects are the most abundant and diverse group of animals on earth, but our knowledge of their viruses is biased toward insect-borne viruses that cause disease in plants, animals, or humans. Recent metagenomic studies and systematic surveys of viruses in wild-caught insects have identified an unanticipated large repertoire of novel viruses and viral sequences. These include new members of existing clades, new clades, and even entirely new virus families. These studies greatly expand the known virosphere in insects, provide opportunities to study virus-host interactions, and generate new insights into virus evolution. In this chapter, we discuss the methods used to identify novel viruses in insects and highlight some notable surprises arising from these studies. PMID- 29492898 TI - Stem Cells Application in Thoracic Surgery: Current Perspective and Future Directions. AB - Two main fields of clinical applications of stem cells in thoracic surgery have been explored: (a) regenerative medicine, that is a branch of translational research in tissue engineering and molecular biology dealing with the replacement, engineering or regeneration of cells, tissues and organs to restore normal function; (b) drug loading and delivery, that is an emerging field proposing stem cells as vectors to deliver anti-cancer agents for targeted therapies.Bronchopleural fistula is a pathological connection between the bronchus and the pleural cavity that may develop after lung resection, thus causing pleural empyema due to colonization by resident airway bacteria; stem cells and regenerative medicine approach can effectively contribute to impaired bronchial healing, thus preventive a septic and ventilator catastrophe.In the field of thoracic oncology, MSC are probably one of the best choice for anticancer drug delivery, emerging as potential experimental approach to malignant mesothelioma treatment.The goal of this review is to focus on clinical applications of stem cell technologies in thoracic surgery, emphasizing regenerative medicine aspects as well as drug loading and delivery in thoracic oncology. PMID- 29492899 TI - MicroRNA-9 and Cell Proliferation in Lipopolysaccharide and Dexamethasone-Treated Naive and Desialylated A549 Cells Grown in Cigarette Smoke Conditioned Medium. AB - In this study we assessed microRNA-9 (miR-9) levels (RT-PCR) and cell proliferation (flow cytometry) in naive and desialylated human alveolar epithelial cells (A549 cells), grown for 24 h in cigarette smoke-conditioned medium. Cells were additionally treated with lipopolysaccharide (LPS) and/or dexamethasone. Proliferation positively correlated with miR-9 levels in both naive and desialylated cells. Cigarette smoke decreased miR-9 levels in both cell types by about three-fold but there was no significant correlation between both parameters. Dexamethasone was without substantial effect on cigarette smoke induced changes in proliferation of naive cells, but some normalization was observed in desialylated cells. Dexamethasone increased miR-9 levels in both cell types grown in cigarette smoke-medium but the effect was stronger in desialylated cells. LPS increased cell proliferation and miR-9 by more than six-fold only in naive cells, while correlation coefficient for both parameters in cigarette smoke LPS group was 0.41. Herein we identify miR-9 as the cigarette smoke (decrease) and LPS-responsive but dexamethasone-unresponsive microRNA. It is possible that increased miR-9 levels in naive A549 cells treated with LPS may be related to the activation of Toll-like receptor 4. Moreover, differences in cell response (both miR-9 and proliferation) to dexamethasone in naive and desialylated cells may point to non-genomic dexamethasone effects. PMID- 29492900 TI - A HIF-independent, CD133-mediated mechanism of cisplatin resistance in glioblastoma cells. AB - PURPOSE: Glioblastoma (GBM) is the commonest brain tumour in adults. A sub population of cells within these tumours, known as cancer stem cells (CSCs), is thought to mediate their chemo-/radiotherapy resistance. CD133 is a cell surface marker that is used to identify and isolate GBM CSCs. However, its functional significance, as well as the relevant microenvironment in which to study CD133, have so far remained unknown. Here, we examined the effect of hypoxia on the expression of CD133 and on that of the hypoxia-related factors HIF-1alpha and HIF 2alpha, and the potential functional significance of CD133 expression on the acquisition of chemo-resistance by GBM cells. METHODS: CD133, HIF-1alpha, HIF 2alpha, VEFG and (control) HPRT mRNA expression analyses were carried out on GBM cells (U251, U87 and SNB19; 2D or 3D cultures) under both normoxic and hypoxic conditions, using qRT-PCR. siRNA was used to downregulate CD133, HIF-1alpha and HIF-2alpha expression in the GBM cells, which was confirmed by flow cytometry and qRT-PCR, respectively. Drug sensitivity-related IC50 values were established using an Alamar Blue cell viability assay in conjunction with the Graphpad prism software tool. RESULTS: We found that the expression of CD133 was upregulated under hypoxic conditions in both the 2D and 3D GBM cell culture models. In addition, an increased resistance to cisplatin, temozolomide and etoposide was observed in the GBM cells cultured under hypoxic conditions compared to normoxic conditions. siRNA-mediated knockdown of either HIF-1alpha or HIF-2alpha resulted in a reduced CD133 expression, with HIF-2alpha having a more long-term effect. We also found that HIF-2alpha downregulation sensitized the GBM cells to cisplatin to a greater extent than HIF-1alpha, whereas CD133 knockdown had a more marked effect on cisplatin sensitisation than knockdown of either one of the HIFs, suggesting the existence of a HIF-independent cisplatin resistance mechanism mediated by CD133. This same mechanism does not seem to be involved in temozolomide resistance, since we found that HIF-1alpha downregulation, but not HIF-2alpha or CD133 downregulation, sensitized GBM cells to temozolomide. CONCLUSIONS: From our data we conclude that the mechanisms underlying hypoxia induced CD133-mediated cisplatin resistance may be instrumental for the design of new GBM treatment strategies. PMID- 29492902 TI - Screening of Ready-to-Eat Meat Products for Hepatitis E Virus in Switzerland. AB - Seroprevalence data for pig herds suggested that there must be a relevant reservoir for hepatitis E virus (HEV) in Switzerland. To know more about the viral presence in ready-to-eat meat products, we screened pork liver sausages and raw meat sausages from the Swiss retail market for the presence of HEV. Testing was performed with a detection method where the virus extraction step was optimized. As for the performance of the improved method, the mean recovery rate for the mengovirus process control was 24.4%, whereas for HEV-inoculated sample matrices between 10.4 and 100% were achieved. The limit of detection was about 1.56 * 103 and 1.56 * 102 genome copies per gram for liver sausages and raw meat sausages, respectively. In the screening programme, HEV-RNA was detected in 10 of total 90 (11.1%) meat products, 7 of 37 (18.9%) liver sausages, and 3 of 53 (5.7%) raw meat sausages. Virus loads of up to 5.54 log10 HEV genome copies per gram were measured. All sequences retrieved from positive samples belonged to HEV genotype 3. The significance of the presented work was a current overview of the HEV prevalence in ready-to-eat meat products on the Swiss retail marked and an improvement of the extraction efficiency of the HEV detection method. PMID- 29492901 TI - Inhibition of autophagy enhances DENSpm-induced apoptosis in human colon cancer cells in a p53 independent manner. AB - PURPOSE: One of the recently developed polyamine (PA) analogues, N 1 ,N11 diethylnorspermine (DENSpm), has been found to act as an apoptotic inducer in melanoma, breast, prostate and colon cancer cells. Also, its potential to induce autophagy has been established. Unfolded protein responses and starvation of amino acids are known to trigger autophagy. As yet, however, the molecular mechanism underlying PA deficiency-induced autophagy is not fully clarified. Here, we aimed to determine the apoptotic effect of DENSpm after autophagy inhibition by 3-methyladenine (3-MA) or siRNA-mediated Beclin-1 silencing in colon cancer cells. METHODS: The apoptotic effects of DENSpm after 3-MA treatment or Beclin-1 silencing were determined by PI and AnnexinV/PI staining in conjunction with flow cytometry. Intracellular PA levels were measured by HPLC, whereas autophagy and the expression profiles of PA key players were determined in HCT116, SW480 and HT29 colon cancer cells by Western blotting. RESULTS: We found that DENSpm-induced autophagy was inhibited by 3-MA treatment and Beclin-1 silencing, and that apoptotic cell death was increased by PA depletion and spermidine/spermine N1-acetyltransferase (SSAT) upregulation. We also found that autophagy inhibition led to DENSpm-induced apoptosis through Atg5 down regulation, p62 degradation and LC3 lipidation in both HCT116 and SW480 cells. p53 deficiency did not alter the response of the colon cancer cells to DENSpm induced apoptotic cell death under autophagy suppression conditions. CONCLUSIONS: From our results we conclude that DENSpm-induced apoptotic cell death is increased when autophagy is inhibited by 3-MA or Beclin-1 siRNA through PA depletion and PA catabolic activation in colon cancer cells, regardless p53 mutation status. PMID- 29492903 TI - Accounting for Scale Heterogeneity in Healthcare-Related Discrete Choice Experiments when Comparing Stated Preferences: A Systematic Review. AB - BACKGROUND: Scale heterogeneity, or differences in the error variance of choices, may account for a significant amount of the observed variation in the results of discrete choice experiments (DCEs) when comparing preferences between different groups of respondents. OBJECTIVE: The aim of this study was to identify if, and how, scale heterogeneity has been addressed in healthcare DCEs that compare the preferences of different groups. METHODS: A systematic review identified all healthcare DCEs published between 1990 and February 2016. The full-text of each DCE was then screened to identify studies that compared preferences using data generated from multiple groups. Data were extracted and tabulated on year of publication, samples compared, tests for scale heterogeneity, and analytical methods to account for scale heterogeneity. Narrative analysis was used to describe if, and how, scale heterogeneity was accounted for when preferences were compared. RESULTS: A total of 626 healthcare DCEs were identified. Of these 199 (32%) aimed to compare the preferences of different groups specified at the design stage, while 79 (13%) compared the preferences of groups identified at the analysis stage. Of the 278 included papers, 49 (18%) discussed potential scale issues, 18 (7%) used a formal method of analysis to account for scale between groups, and 2 (1%) accounted for scale differences between preference groups at the analysis stage. Scale heterogeneity was present in 65% (n = 13) of studies that tested for it. Analytical methods to test for scale heterogeneity included coefficient plots (n = 5, 2%), heteroscedastic conditional logit models (n = 6, 2%), Swait and Louviere tests (n = 4, 1%), generalised multinomial logit models (n = 5, 2%), and scale-adjusted latent class analysis (n = 2, 1%). CONCLUSIONS: Scale heterogeneity is a prevalent issue in healthcare DCEs. Despite this, few published DCEs have discussed such issues, and fewer still have used formal methods to identify and account for the impact of scale heterogeneity. The use of formal methods to test for scale heterogeneity should be used, otherwise the results of DCEs potentially risk producing biased and potentially misleading conclusions regarding preferences for aspects of healthcare. PMID- 29492904 TI - The associations of metabolic syndrome with incident hypertension, type 2 diabetes mellitus and chronic kidney disease: a cohort study. AB - PURPOSE: Metabolic syndrome (MetS) has been extensively studied for its long-term health effects, typically through conventional Cox proportional hazards regression modeling of the overall association of MetS with a single outcome. Such an approach neglects the inherent links between MetS-related disease outcomes and fails to provide sufficient insights into the impact of each component of MetS over time. METHODS: We therefore conducted a retrospective cohort study of 63,680 individuals who received health check-ups at the MJ Health Screening Center in Taiwan from 1997-2005 to study the subsequent risks of hypertension, type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) simultaneously for MetS and its components. Multivariate-adjusted hazard ratios (HRs) were calculated using Cox models for multiple failure outcomes. RESULTS: At baseline, MetS was identified in 7835 participants. Over a median follow-up of 3 years, 8252, 1634, and 6714 participants developed hypertension, T2DM and CKD, respectively. The HR for MetS was 2.41 (95% CI 2.29-2.53) for hypertension, 5.17 (95% CI 4.68-5.71) for T2DM and 1.22 (95% CI 1.15-1.31) for CKD. Three MetS components showed the strongest association with each of the outcomes: elevated blood pressure with hypertension (HR = 3.62, 95% CI 3.46-3.79), raised fasting plasma glucose with T2DM (HR = 8.89, 95% CI 7.86-10.06) and elevated triglycerides with CKD (HR = 1.14, 95% CI 1.08-1.21). CONCLUSIONS: MetS may help identify individuals with metabolic profiles that confer incremental risks for multiple diseases. Additionally, several components of the syndrome should be considered by clinicians, as they show stronger associations with specific diseases than MetS. PMID- 29492906 TI - Correction to: Epoetin Biosimilars in the Treatment of Chemotherapy-Induced Anemia: 10 Years' Experience Gained. AB - Figure 1, HX575 column, 5th box down, which previously read "SC HX575 vs. Eprex(r)/Erypo(r) 417 patients with CKD-related anemia" as shown here. PMID- 29492905 TI - Tenofovir-Associated Bone Adverse Outcomes among a US National Historical Cohort of HIV-Infected Veterans: Risk Modification by Concomitant Antiretrovirals. AB - INTRODUCTION: Tenofovir disoproxil fumarate (TDF) has been associated with greater incidences of bone complications, which might be modified by some concomitantly administered antiretrovirals, possibly by their effect on tenofovir concentrations. We compared bone adverse outcomes among treatment-naive HIV infected US veterans initiating efavirenz (EFV)-containing TDF/emtricitabine (FTC) regimens versus those initiating non-EFV-containing TDF/FTC regimens. METHODS: Using national Veterans Health Administration clinical and administrative data sets, we identified a cohort of treatment-naive HIV-infected veterans without bone disease who initiated therapy with TDF/FTC plus EFV, rilpivirine, elvitegravir/cobicistat, or ritonavir-boosted protease inhibitors in 2003-2015. The primary composite adverse bone outcome was the unadjusted incidence rate (IR) of osteoporosis, osteopenia, or fragility fracture (any hip, wrist, or spine fracture). To account for selection bias and confounding, we used inverse probability of treatment-weighted Cox proportional hazards regression models to calculate adjusted hazard ratios (HRs) for each outcome associated with EFV + TDF/FTC versus each non-EFV-containing TDF/FTC regimen. RESULTS: Of 33,048 HIV-positive veterans, 7161 initiated a TDF/FTC-containing regimen (mean age, 50 years; baseline CD4 < 200 cells/mm3, 33.3%; HIV-1 RNA > 100,000 copies/ml, 22.3%; mean follow-up, 13.0 months). Of these, 4137 initiated EFV- and 3024 non-EFV containing regimens. Veterans initiating EFV- versus non-EFV-containing TDF/FTC regimens had a lower IR of the composite bone outcome (29.3 vs. 41.4 per 1000 patient-years), with significant risk reductions for this outcome [HR, 0.69; 95% confidence interval (CI), 0.58-0.83] and fragility fracture (HR, 0.59; 95% CI, 0.44-0.78). CONCLUSION: EFV + TDF/FTC is associated with a lower risk of adverse bone outcomes compared with other TDF-containing regimens in the VHA. FUNDING: Bristol-Myers Squibb. PMID- 29492907 TI - [Clinical research status of laparoscopic total gastrectomy in China]. AB - Many retrospective and cohort studies have shown that laparoscopic total gastrectomy(LTG) has advantages of less trauma, quicker recovery and better incision than open total gastrectomy, and is not inferior to laparotomy in safety and the short- and long-term outcomes, so it has been widely applied. However there is still a lack of high level evidence-based basis. At present, several prospective multicenter clinical studies are being carried out in China, Japan and South Korea which have high incidence of gastric cancer to demonstrate the safety and feasibility of LTG and evaluate its long-term outcomes as well. A multicenter randomized controlled clinical trial comparing the safety of laparoscopic and open radical gastrectomy(CLASS-02 Research) conducted by Professor Sun Yihong, Zhongshan Hospital of Fudan University, is under way. The subjects of this study were the patients with clinical stage I(, the lesion locating in the gastric body, gastric fundus, or the esophagogastric junction (not involving the cardia dentate line), who were expected to be treated with total gastrectomy. The primary outcome measures were early operative morbidity and mortality and the secondary outcome measures were early postoperative recovery course and postoperative hospital stay. It is believed that results of the study will provide a high level evidence-based basis for the safety of LTG. The ongoing JCOG-1401 study in Japan aims to assess the feasibility and safety of LTG and LAPG for the treatment of early gastric cancer. LTG (Roux-en-Y reconstruction) or LAPG (double-tract or jejunal interposition reconstruction) will be performed in patients with clinical stage I( gastric cancer in this study. The primary endpoint of the study is the incidence of anastomotic leakage, and the secondary endpoints are proportion of patients converted to open surgery, the time to the first flatus, analgesic requirement, postoperative body temperature, the overall survival and relapse-free survival. The follow-up time is at least 5 years, and the results will also effectively evaluate the long-term efficacy of LTG and LAPG in the treatment for early gastric cancer. No.10 lymph nodes dissection of D2 total gastrectomy is a major difficulty in LTG. Japanese JCOG-0110 study has showed that for proximal gastric cancer patients without involvement of the greater curvature of the stomach, routine splenectomy for No.10 lymph nodes dissection is not recommended. In this regard, Professor Huang Changming, Union Hospital of Fujian Medical University, led the ongoing CLASS-04 study to evaluate the safety, feasibility and clinical efficacy of laparoscopic No.10 lymph node dissection with spleen preservation for patients with locally advanced gastric cancer locating in the upper part of the stomach. The ongoing CLASS-02 and JCOG-1401 studies will answer whether LTG is suitable for the treatment of early gastric cancer. We believe that in the absence of high level evidence-based basis, LTG should be applied cautiously to advanced gastric cancer, and LTG for early gastric cancer patients should also be operated by experienced surgeons. PMID- 29492908 TI - [Clinical research status of laparoscopic gastric cancer surgery in China, Japan and South Korea]. AB - Laparoscopic surgery has its unique minimally invasive advantages, however, taking the complex and difficult D2 lymph node dissection for advanced gastric cancer into consideration, laparoscopic gastrectomy was only applied in the treatment of early gastric cancer at its preliminary stage. With the development of more than a decade, many multicenter clinical data have confirmed the safety, feasibility and effectiveness of laparoscopic radical gastrectomy for early gastric cancer. Based on high-quality evidence-based medicine evidence, laparoscopic gastrectomy has been recommended as an optional treatment for stage I( gastric cancer by the Japanese Gastric Cancer Treatment Guidelines 2014(ver.4). However, the safety and effectiveness of laparoscopic gastrectomy for advanced gastric cancer remains controversial due to the lack of high-level evidence-based clinical evidence. Currently, China, Japan and South Korea are trying to clarify its safety and effectiveness by conducting well-designed multicenter prospective randomized controlled trials. To date, CLASS-01 trial in China, whose secondary endpoint indicated that laparoscopic gastrectomy with D2 lymphadenectomy for advanced gastric cancer can be safely performed by experienced surgeons, has provided the highest level evidence for the controversy in the world. At ASCO 2016, the safety reports from Korea's KLASS-02 trial also presented the similar conclusion. The long-term oncologic outcomes of the both researches were particularly promising. Retrospecting the whole development of gastric cancer surgery, it is not difficult to find that its mainstream direction is gradually shifted from "extended and standardized surgical resection" to "individual and precise surgery" for the safety and postoperative quality of life. The new concept of minimally invasive surgery built on laparoscopic surgery emphasizes more than shortening the surgical incision, but minimizing tissue trauma and maximizing functional preservation. On the ground of this new minimally invasive concept, surgeons have appreciated to select the most rational treatment for an individual patient. Thus, techniques focusing on further assisting laparoscopic gastrectomy with reducing trauma and preserving function, such as sentinel node navigation surgery and related fluorescence molecular imaging techniques, are increasingly being applied in gastric cancer surgery. At present, a series of researches about the feasibility of sentinel node navigation surgery and function preserving surgery associated with gastric cancer surgery are actively conducted or prepared. Results of these researches may further promote the development of laparoscopic gastrectomy and achieve the qualitative change in minimally invasive surgery in the new era. PMID- 29492909 TI - [Current status and understandings in function-preserving gastrectomy under the concept of minimally invasive surgery in China, South Korea and Japan]. AB - In the past few years, the early detection of gastric cancer has increased in China. The surgical treatment for early gastric cancer has gradually transformed from conventional gastrectomy with D2 lymphadenectomy to function-preserving gastrectomy which maximally preserves the anatomy and physiology of stomach to maintain the quality of life of the patient. Driven by minimally invasive techniques, function-preserving gastrectomies, including pylorus-preserving gastrectomy, proximal gastrectomy, sentinel node navigation surgery, etc. have already gained great attention especially in Japan and Korea. Although there are still many unsolved problems that need to be further discussed and explored, understanding of the clinical features of early gastric cancer and definition of gastric function preservation, launching clinical trials for solving practical problems, and emphasis of individualized and precision treatment will be the best strategies to improve the efficacy of early gastric cancer. PMID- 29492910 TI - [Laparoscopic gastrectomy combined with neoadjuvant chemotherapy for gastric cancer patients: from the view of the CLASS-03a trial]. AB - Neoadjuvant chemotherapy combined with radical gastrectomy is one of the most important parts of the multimodality therapy strategies for locally advanced gastric cancer. With the development of laparoscopic technique in recent decades, laparoscopic technique plays a more and more important role in the surgical treatment of gastric cancer. Neoadjuvant chemotherapy, as a part of comprehensive treatment of gastric cancer, has gained more and more clinical supports and been recommended for guidelines. With the development of laparoscopic technique and clinical evidence, laparoscopic operation for advanced gastric cancer has been applied more and more widely. However, the safety and efficacy of laparoscopic resection following neoadjuvant chemotherapy, as a new treatment modality, still needs prospectively high-level researches to verify. Therefore, we will discuss some key points of laparoscopic gastrectomy after neoadjuvant chemotherapy based on the CLASS 03a trial, which is led by the Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, the Department of Gastrointestinal Surgery, Peking University Cancer Hospital and Institute, and Chinese Laparoscopic Gastric Surgery Study Group. The CLASS 03a trial aims to confirm surgical and oncological safety of laparoscopy distal D2 radical gastrectomy for locally advanced stage gastric cancer patients (cT3~4a, N-/+, M0) who completed neoadjuvant chemotherapy. On the base of CLASS 03a trial, this article elucidates the choice of neoadjuvant chemotherapy for gastric cancer and proposes some associated problems about neoadjuvant chemotherapy combined with laparoscopic gastric cancer operation. PMID- 29492911 TI - [Technical points of laparoscopic splenic hilar lymph node dissection--The original intention of CLASS-04 research design]. AB - According to Japanese gastric cancer treatment guidelines, the standard operation for locally advanced upper third gastric cancer is the total gastrectomy with D2 lymphadenectomy, which includes the dissection of the splenic hilar lymph nodes. With the development of minimally invasive ideas and surgical techniques, laparoscopic spleen-preserving splenic hilar lymph node dissection is gradually accepted. It needs high technical requirements and should be carried out by surgeons with rich experience of open operation and skilled laparoscopic techniques. Based on being familiar with the anatomy of splenic hilum, we should choose a reasonable surgical approach and standardized operating procedure. A favorable left-sided approach is used to perform the laparoscopic spleen preserving splenic hilar lymph node dissection in Department of Gastric Surgery, Fujian Medical University Union Hospital. This means that the membrane of the pancreas is separated at the superior border of the pancreatic tail in order to reach the posterior pancreatic space, revealing the end of the splenic vessels' trunk. The short gastric vessels are severed at their roots. This enables complete removal of the splenic hilar lymph nodes and stomach. At the same time, based on the rich clinical practice of laparoscopic gastric cancer surgery, we have summarized an effective operating procedure called Huang's three-step maneuver. The first step is the dissection of the lymph nodes in the inferior pole region of the spleen. The second step is the dissection of the lymph nodes in the trunk of splenic artery region. The third step is the dissection of the lymph nodes in the superior pole region of the spleen. It simplifies the procedure, reduces the difficulty of the operation, improves the efficiency of the operation, and ensures the safety of the operation. To further explore the safety of laparoscopic spleen-preserving splenic hilar lymph node dissection for locally advanced upper third gastric cancer, in 2016, we launched a multicenter phase II( trial of safety and feasibility of laparoscopic spleen-preserving No.10 lymph node dissection for locally advanced upper third gastric cancer (CLASS-04). Through the multicenter prospective study, we try to provide scientific theoretical basis and clinical experience for the promotion and application of the operation, and also to standardize and popularize the laparoscopic spleen preserving splenic hilar lymph node dissection to promote its development. At present, the enrollment of the study has been completed, and the preliminary results also suggested that laparoscopic spleen-preserving No.10 lymph node dissection for locally advanced upper third gastric cancer was safe and feasible. We believe that with the improvement of standardized operation training system, the progress of laparoscopic technology and the promotion of Huang's three-step maneuver, laparoscopic spleen-preserving splenic hilar lymph node dissection will also become one of the standard treatments for locally advanced upper third gastric cancer. PMID- 29492912 TI - [Function-preserving gastrectomy for early gastric cancer based on Japanese researches]. AB - In the past, people only focused on surgical resection of gastric cancer to obtain satisfactory therapeutic effect, while the concept of function-preserving in gastric cancer surgery has not been emphasized. Gastric function-preserving surgery was originally performed by Japanese doctor Maki for surgical treatment of gastroduodenal ulcer. With the definition of early gastric cancer being accepted, the pylorus-preserving gastrectomy can be used continuously in the treatment of gastric cancer. Because of high incidence of early gastric cancer in Japan, a variety of application and research about function-preserving gastrectomy in other areas for treatment of early gastric cancer, such as proximal gastrectomy and jejunal interposition, segmental gastrectomy, gastric local resection and laparoscopic and endoscopic cooperative surgery (LECS) at the same time, and regional or sentinel lymph node dissection were performed for the purpose of radical cure. Function-preserving gastrectomy for the treatment of early gastric cancer should include four important factors: (1) decrease of the scope of gastrectomy; (2)retaining pylorus; (3)retaining vagus nerve; (4)regional or sentinel lymph node dissection. The technique of sentinel lymph node can reduce the extent of gastric resection, avoid distal gastrectomy or total gastrectomy, and make gastric resection more suitable for laparoscopic partial gastrectomy, segmental resection, pylorus-preserving gastrectomy and proximal gastrectomy. Function-preserving gastrectomy has the advantage of improving the quality of life and has great potential in the treatment of early gastric cancer. However, the various treatment methods including LECS need strict technical standardization for confirmation of oncology safety. We need careful design, prospective multicenter randomized controlled trials to provide theoretical and technical support. PMID- 29492913 TI - [Clinical trials of laparoscopic gastric cancer surgery in South Korea: review and prospect]. AB - Laparoscopic technology is gradually accepted in gastric cancer surgery, whose efficacy has been demonstrated by some clinical researches. Randomized controlled trials (RCT) are considered as the most important evidence to prove clinical outcomes of laparoscopic surgery for gastric cancer. Korean gastric surgeons have made great contributions to RCT in laparoscopic gastric cancer surgery. KLASS (Korean Laparoscopic Gastrointestinal Surgery Study Group) is one of the most important forerunner and global leader of clinical trials of gastric cancer treatment. KLASS series clinical trials are attracting global attention because of the significant value of surgical treatment for gastric cancer. The RCTs in Korea involve in many aspects of laparoscopic gastrectomy for gastric cancer, including laparoscopy application in early gastric cancer (KLASS-01, KLASS-03 and KLASS-07), advanced gastric cancer (KLASS-02 and KLASS-06), function-preserving gastrectomy (KLASS-04,KLASS-05) and sentinel node navigation surgery (SENORITA trial). In order to share some informations of these RCTs, we review and prospect some important clinical trials of laparoscopic gastric cancer surgery in Korea. With the experience of Korean gastric surgeons, we can make more progress in our own clinical trials of laparoscopic gastric cancer surgery. PMID- 29492914 TI - [Updates and interpretation on NCCN clinical practice guidelines for gastric cancer 2017 version 5]. AB - The National Comprehensive Cancer Network (NCCN) issued the clinical practice guidelines for gastric cancer 2017 edition version 5, which has been fully updated for the treatment of gastric cancer, including systematic treatment, surgery and radiotherapy. This article review and summarize the updated NCCN clinical practice guidelines for gastric cancer in 2017 and try to interpret it. (1)Biomarkers: mismatch repair defect (dMMR) or high microsatellite instability (MSI-H), programmed death ligand 1 (PD-L1) and tumor Epstein Barr virus (EBV) status should be considered for patients with gastric cancer. (2)Treatment of advanced gastric cancer: the major update is the application of immunotherapy (Pembrolizumab, Nivolumab combined with Ipilimumab). (3)Adjuvant therapy after D2 resection and perioperative treatment: the guidelines recommended Capecitabine combined with Oxaliplatin as adjuvant therapy after radical operation, updated from category 2A to 1; although the 2017 edition of the NCCN guidelines have not yet been adopted, Docetaxel-based FLOT scheme has certain potential in adjuvant therapy for gastric cancer. (4) Radiotherapy: a more detailed definition of radiotherapy for gastric cancer in different locations, especially in high-risk lymphatic drainage areas, was updated. (5) Genetic risk assessment: the guidelines recommended genetic screening for gastric cancer, including hereditary diffuse gastric cancer (HDGC), Lynch syndrome, juvenile polyposis (JPS), Peutz Jephers syndrome (PJS) and familial adenomatous polyposis (FAP). The NCCN guidelines continue to update based on new evidences, which is the embodiment of precision medicine in the treatment of gastric cancer. The biggest change in the 2017 gastric cancer guidelines is the updates of immunotherapy, which also suggests that the direction of the gastric cancer treatment began to turn to immunotherapy. PMID- 29492915 TI - [Current status of diagnosis and treatment of early gastric cancer in China--Data from China Gastrointestinal Cancer Surgery Union]. AB - OBJECTIVE: To investigate the current status of diagnosis and treatment of early gastric cancer in China, based on the nationwide survey by China Gastrointestinal Cancer Surgery Union. METHODS: The union sent questionnaires on basic diagnosis and treatment data of gastric and colorectal cancer to all the centers of the union. Different centers collected and summarized their data by year and sent back the questionnaires to the e-mail of theunion(gi_union@foxmail.com) for summary. RESULTS: From 2014 to 2016, the union collected 285 questionnaires from 85 centers all over China. In these 3 years, a total of 88 340 cases of gastric cancer were summarized and there were 17 187 cases of early gastric cancer (part of the data was not available in some centers). The proportion of early gastric cancer varied from 19.5%(5711/29290) in 2014 to 19.0%(6081/32050) in 2015 and 20.0%(5395/27000) in 2016. Significant difference was found among them (chi2=9.553, P=0.008). Significant differences existed not only in the proportion of early gastric cancer between the south (20.9%, 7618/ 36518) and the north (18.5%, 9569/51822) of China (chi2=78.468, P=0.000), but also between the general (20.4%, 11991/58672) and the specialized (17.5%, 5196/29668) hospitals(chi2=107.473, P=0.000). Ultrasonic endoscope was used as routine practice in 10(17.5%, 10/57) general hospitals and 9(56.2%,9/16) specialized hospitals, and significant difference was found between them (chi2=9.721, P=0.002). A total of 4555 early gastric cancer patients received endoscopic therapy. The proportion of patients receiving endoscopic therapy was significantly different between the hospitals in the first-tier cities (36.0%, 2243/6233) and the other cities (21.1%, 2312/10954) (chi2=451.526, P=0.000), and between the hospitals with more than 800 gastric cancer patients per year (28.9%, 3434/11884) and those with less than 800 gastric cancer patients (21.1%, 1121/5303)(chi2=113.270, P=0.000). 37.1%(5270/14186) of early gastric cancer patients received laparoscopic surgery. The proportion of patients receiving laparoscopic surgery was 39.4%(3807/9651) in general hospitals and 32.3%(1463/4535) in specialized hospitals, whose difference was significant (chi2=68.244, P=0.000). The proportion of patients receiving laparoscopic surgery was 29.3%(1269/4328) in the first-tier cities and 40.6%(4001/9858) in the other cities, whose difference was significant as well(chi2=163.480, P=0.000). The proportion of patients receiving laparoscopic surgery was significantly different between the hospitals with more than 800 gastric cancer patients per year(34.5%, 3425/9929) and those with less than 800 gastric cancer patients (43.3%, 1845/4257) (chi2=100.057, P=0.000), and between the hospitals in the south (42.4%, 2552/6016) and those in the north (33.3%, 2718/8170) of China (chi2=124.296, P=0.000). 48.5%(6975) of early gastric cancer patients staged pT1a and 51.5%(7402) staged pT1b. Lymph node metastasis was found in 12.7%(1825/14377) of early gastric cancer. The lymph node metastasis rate of pT1a and pT1b was 5.7%(399/6975) and 19.3%(1426/7402), respectively. The lymph node metastasis rate of early gastric cancer varied from 12.7%(510/4017) in 2014 to 12.2%(668/5494) in 2015 and 13.3%(647/4866) in 2016. CONCLUSION: The data report of China Gastrointestinal Cancer Surgery Union partly reflects the epidemiologic characteristics, current status of diagnosis and treatment of early gastric in China. PMID- 29492916 TI - [Effect of lymphatic vascular invasion on the prognosis of stage I( gastric cancer patients after radical gastrectomy]. AB - OBJECTIVE: To investigate the prognostic value of lymphatic vascular invasion (LVI) for stage I( gastric cancer patients after radical gastrectomy. METHODS: Clinicopathological and intact follow-up data of 469 stage I( gastric cancer patients who underwent radical gastrectomy with R0 resection and were pathologically proven as gastric adenocarcinoma without other malignancy at the Department of Digestive Surgery, The First Affiliated Hospital, The Fourth Military Medical University between February 2009 and December 2012 were retrospectively collected. Chi square test was used to examine the relationship between LVI and clinicopathological data; Log-rank test was used for survival analysis; Cox proportional hazards model was used for univariate and multivariate analysis to explore the prognostic influence of LVI on stage I( gastric cancer patients. RESULTS: A total of 469 patients were enrolled, including 360 male (76.8%) and 109 female patients (23.2%). Median age was 58(25-82) years. There were 114 T1a cases (24.3%), 195 T1b cases (41.6%), and 160 T2 cases (34.1%). There were 439 (93.6%) cases without lymph node metastasis and 30 cases with lymph node metastasis. Presence of LVI was found in 52 patients (11.1%). LVI was closely associated with tumor grade, depth of invasion and status of lymph node metastasis (all P<0.05), rather than gender, age, tumor location and tumor diameter (all P>0.05). LVI detection rate was higher in poorly differentiated and undifferentiated group (14.3%, 32/223) than that in moderately and well differentiated group (8.1%, 20/246) (chi2=4.590, P=0.032). LVI detection rate was higher in T2 (14.4%, 23/160) and T1b (13.3%, 26/195) group than that in T1a group (2.6%,3/114)(chi2=11.020, P=0.004). LVI detection rate was higher in patients with lymph node metastasis (30.0%, 9/30) compared to those without lymph node metastasis (9.8%, 43/439) (chi2=11.629, P=0.001). Median follow-up time was 63(3 74) months. There were totally 46 deaths (9.8%). The 5-year overall survival rate was 90.2%. The 5-year overall survival rate was 82.7% in patients with LVI and 91.1% without LVI, which was significantly different (P=0.039). Univariate analysis showed that age (P=0.012), AJCC T stage (8th edition) (P=0.011), and LVI (P=0.043) were closely associated with the prognosis of gastric cancer patients, while gender, tumor location, tumor diameter, tumor grade, lymph node metastasis or postoperative chemotherapy were not associated to the prognosis (all P>0.05). Multivariate analysis revealed that only age(HR=2.038, 95%CI:1.126 to 3.686, P=0.019) and advanced T stage (T1b: HR=1.427, 95%CI:0.554 to 3.678; T2: HR=2.926, 95%CI:1.199 to 7.140; P=0.017) were independent prognostic factors of stage I( gastric cancer patients (both P<0.05). CONCLUSIONS: LVI is not an independent prognostic factor of stage I( gastric cancer patients. In clinical practice, we should consider adjuvant chemotherapy prudently for stage I( gastric cancer patients with LVI. PMID- 29492917 TI - [Clinical significance of prognostic nutritional index in patients with advanced gastric cancer]. AB - OBJECTIVE: To investigate the relationship of prognostic nutritional index (PNI) with clinicopathological factors and the clinical significance of PNI in predicting the survival in patients with advanced gastric cancer. METHODS: Clinicopathological and follow-up data of 1150 patients with advanced gastric cancer who underwent radical gastrectomy from January 2007 to December 2010 at the Department of Gastrointestinal Surgery, Harbin Medical University Cancer Hospital were analyzed retrospectively. The PNI value was calculated [PNI=absolute value of lymphocyte(109/L)*5 + serum albumin (g/L)] and was grouped according to the mean value of PNI. Relationships of PNI with gender, age, tumor size, depth of invasion, tumor differentiation, tumor stage, tumor location, lymph node metastasis and tumor marker detection level were analyzed. At the same time, for the survival analysis of patients, log-rank method was used for univariate analysis, and Cox method was used for multivariate analysis. RESULTS: Of 1150 cases, 846 were males and 304 were females with an average age of 62 (24 to 88) years. The average maximum diameter of tumor was 5.4(1.0 to 20.0) cm. Tumor of 159 cases located in the gastric fundus, 221 cases in the gastric body, 705 cases in the gastric antrum and 65 cases in the whole stomach. Well differentiated tumors were found in 198 cases and poorly differentiated tumors in 952 cases. As for depth of tumor invasion, 165 cases were T2, 343 cases were T3 and 642 cases were T4. According to TNM stage, 53 cases were stage I(, 397 cases were stage II( and 700 cases were stage III(. The average lymph node metastasis rate was 25.0%, meanwhile lymph node metastasis was N0 in 296 cases, N1 in 246 cases, N2 in 277 cases and N3 in 331 cases. Blood examination showed hemoglobin <=130 g/L in 544 cases and >130 g/L in 606 cases; carcinoembryonic antigen <=5 MUg/L in 903 cases and >5 MUg /L in 247 cases; carbohydrate antigen 19-9 <=37 kU/L in 927 cases and >37 kU/L in 223 cases. In whole patients, the mean value of PNI was 51.81(24.5 to 80.4), PNI <=51.81 group had 563 cases, and PNI >51.81 group had 587 cases. Between PNI <=51.81 group and PNI >51.81 group, age (chi2=22.661, P=0.000), tumor location (chi2=8.979, P=0.030), tumor size (chi2=34.509, P=0.000), tumor stage (chi2=11.644, P=0.003), depth of tumor invasion (chi2=21.681, P=0.000) and hemoglobin (chi2=112.262, P=0.000) were significantly different. Patients were followed up for an average of 45.1 months (4 to 108). The 5-year survival rate was 37.7% in PNI <=51.81 group, while it was 47.0% in PNI >51.81 group, whose difference was statistically significant (chi2=8.326, P=0.004). Univariate analysis showed that patients with PNI <=51.81(P=0.004), deeper tumor invasion (P=0.000), more metastatic lymph nodes (P=0.000), later TNM stage (P=0.000), lymph node metastasis rate >25.02%(P=0.000), hemoglobin <=130 g/L(P=0.011), the maximum tumor diameter >5.4 cm (P=0.000), tumor undifferentiated (P=0.001), CEA >5 MUg /L (P=0.000), CA199 >37 kU/L(P=0.000) and tumors locating in whole stomach (P=0.000) had poorer prognosis. Multivariate analysis showed that the age (HR=1.195, 95%CI: 1.019 to 1.401, P=0.028), the depth of tumor invasion(HR=1.429, 95%CI: 1.231 to 1.658, P=0.000), the number of metastatic lymph node (HR=1.536, 95%CI:1.330 to 1.774, P=0.000), the lymph node metastasis rate (HR=1.376, 95%CI:1.102 to 1.717, P=0.005), tumor TNM stage (HR=1.387, 95%CI: 1.026 to 1.876, P=0.033) and tumor size(HR=1.182, 95%CI: 1.005 to 1.390, P=0.043) were independent prognostic factors of gastric cancer patients, while PNI (HR=0.913, 95%CI: 0.774 to 1.076, P=0.278) was not an independent risk prognostic factor of gastric cancer patients. CONCLUSIONS: Although the PNI is not an independent risk factor of overall survival in patients with advanced gastric cancer, it is still an indicator of survival in patients with gastric cancer. Improving preoperative nutritional status in patients with gastric cancer may contribute to a better prognosis. PMID- 29492918 TI - [Surgical treatment and prognosis of Borrmann type IIII( gastric cancer involving the whole stomach]. AB - OBJECTIVE: To explore the surgical treatment and prognosis of Borrmann type IIII( gastric cancer involving the whole stomach. METHODS: Clinicopathological characteristics and survival data of 223 patients with Borrmann type IIII( gastric cancer involving the whole stomach (defined as the tumor infiltrating 3 regions of the stomach) receiving surgical treatment at the Department of Abdominal Surgery of Zhejiang Cancer Hospital between January 2002 and December 2015 were analyzed retrospectively. The survival time of patients with different clinicopathological features and different treatment methods was compared. Cox regression was used to analyze the independent prognostic factors. RESULTS: Two hundred and twenty-three patients with Borrmann type IIII( gastric cancer involving the whole stomach accounted for 24.0% (223/930) of all Borrmann type IIII( gastric cancer cases undergoing surgical resection at the same period. There were 147 males and 76 females with an average age of 57.8 years. All the patients underwent total gastrectomy. Of these patients, radical resection was performed in 149 cases(66.8%) and palliative resection in 74 cases (33.2%). Combined organ resection was performed in 43 patients (19.3%), including 25 splenectomies, 6 pancreatic body and tail plus spleen and transverse colon resections, 2 transverse colon plus spleen resections, 2 right colon resections, 2 transverse colon resections, 2 ovariectomies, 1 partial jejunal resection, 1 pancreatoduodenectomy, 1 pancreatic tail plus transverse colon resection, and 1 partial pancreatectomy. Postoperative complications occurred in 28 patients(12.6%), including 10 patients with combined organ resection. Esophagojejunal fistula was the most frequent complication, accounting for 39.3%(11/28). Perioperative mortality occurred in 3 patients (1.3%). Thirty-nine patients underwent preoperative adjuvant chemotherapy (clinical stage: cT4aN0M0 in 1 patient, cT4bN1-2M0 in 12 patients, cT4aN1-2M0 in 20 patients, and cT4aN3M0 in 6 patients). Among these 39 patients, post-chemotherapeutic degenerative response was detected in 25 postoperative pathological specimens (64.1%), radical resection was performed in 21 patients (53.8%), distant metastasis was observed in 7 patients (17.9%) and peritoneal metastasis was found in 17 patients (43.6%) during operation. The average maximal tumor diameter was 13.2 cm (range from 6 to 22). Histological types included 23 moderate-poorly differentiated adenocarcinomas (10.3%), 146 poorly differentiated adenocarcinomas (65.5%), 41 signet ring cell carcinomas (18.4%), 11 mucinous adenocarcinomas(4.9%), 1 squamous cell carcinoma (0.4%) and 1 undifferentiated carcinoma (0.4%). Tumor infiltrating duodenum was found in 57 patients (25.6%) and tumor-infiltrating esophagus in 132 patients (59.2%). The positive margin was found in 66 patients (29.6%): upper margin in 35 patients (15.7%), lower margin in 22 patients (9.9%), and both margins in 9 patients(4.0%). Immunohistochemical positive HER2(3+) was detected in 4 patients (1.8%). Tumor infiltrating into serosa(T4a) was found in 197 patients (88.3%) and infiltrating into adjacent organ (T4b) in 26 patients(11.7%). One hundred and forty-three cases (64.1%) had lymphatic or venous invasion, 187 (83.9%) had neural invasion, and 35 (15.7%) had cancer nodules. Of 149 patients undergoing radical resection, 5 patients were stage II(b, 9 patients were III(a, 20 patients were III(b and 115 patients were III(c. Of 145 patients(65.0%) undergoing postoperative chemotherapy, the average cycles of chemotherapy was 3.6 (median 3 cycles) and only 69 patients (47.6%) completed 4 cycles or more. Patients were followed up for 1-102 months (average 17.3 months). The median overall survival time was 13.8 months and the 1-, 3-, and 5 year survival rate was 57.9%, 14.1% and 6.8% respectively. The median survival time of the 149 cases with radical resection was 16.7 months and the 1-, 3- and 5 year survival rate was 67.5%, 16.5% and 8.4% respectively; the median survival time of the 74 cases with palliative resection was 10.3 months and the 1-, 3- and 5-year survival rate was 42.6%, 8.5% and 1.7% respectively, whose differences were statistically significant (all P=0.000). Multivariate analysis showed that tumor staging (P=0.005), radical resection (P=0.009), lymphatic or venous invasion (P=0.017) and postoperative chemotherapy (P=0.001) were independent prognostic factors. CONCLUSIONS: Surgical treatment for Borrmann type IIII( gastric cancer involving the whole stomach is safe. Radical resection can improve the prognosis though the overall survival is poor. PMID- 29492919 TI - [Efficacy comparison between surgical resection and endoscopic submucosal dissection of early gastric cancer in a domestic single center]. AB - OBJECTIVE: To compare the clinical efficacy of endoscopic submucosal dissection (ESD) and surgical resection for early gastric cancer (EGC). Method The retrospective case-control study was conducted. Clinical and pathological data of 246 patients who were diagnosed as early gastric cancer and received ESD or surgery for EGC at Peking University First Hospital from 2010 to 2015 were collected, including 171 males and 75 females with average age of (63.6+/-10.8) years. Eighty-one patients received ESD according to the following indications: no peritoneal lymph node metastasis in preoperative CT; differentiated mucosal cancer without ulcer findings, irrespective of tumor size; differentiated mucosal cancer with diameter <=30 mm and ulcer; differentiated minimal submucosal invasive cancer (<=500 MUm from the muscularis mucosa) with diameter <=30 mm and without ulcer; undifferentiated mucosal cancer with diameter <=20 mm and without ulcer; high grade intraepithelial neoplasia with diameter >20 mm; mucous lesion recurrence after EMR without chance of EMR again. One-hundred and sixty-five cases received surgery according to the findings of peritoneal lymph node metastasis in preoperative CT or the growth of carcinoma beyond the expanding criteria of ESD (surgery group). En block resection rate (removing all the lesion at once) and curative resection rate [standard: negative horizontal and vertical surgical margins; negative vessel carcinoma embolus; pT1a and pT1b (SM1); lesion diameter <3 cm with differentiated type, pT1a with ulcer or pT1b(SM1); lesion diameter <2 cm with undifferentiated type, pT1a without ulcer] were compared between two groups. According to pathological results, including tumor location, macrographic type, size, pathological type, differentiated type, invasive depth, surgical margin, vessel carcinoma embolus and lymph node metastasis, all the patients meeting the ESD curative resection criteria in both groups were subgrouped in order to compare the baseline information, surgical conditions, postoperative complications, recovery, follow-up and survival. The end of follow up was December 2016. RESULTS: The en block resection rate was 93.8%(76/81), while curative resection rate was 91.4% (74/81) in ESD group. The en block resection rate and curative resection rate was both 100% in surgery group. According to the pathological results, 170 cases were confirmed to be in accordance with the curative resection standard, including 74 cases in ESD group and 96 cases in surgery group. Subgroup analysis showed that ESD group had older cases (t=2.939, P=0.004) and more cases with lesion in upper 1/3 of stomach (chi2=8.992, P=0.011), while no significant differences in tumor size, invasion depth, degree of differentiation (t=1.875, 2.393, 3.074, all P>0.05) were observed. Compared to surgery group, ESD group had significantly shorter operative time [(76.4+/-46.3) minutes vs. (271.9+/-92.6) minutes, t=17.950, P=0.000], shorter fasting period [(3.2+/-1.4) days vs. (8.8+/-5.4) days, t=9.801, P=0.000], shorter hospital stay [(9.0+/-5.8) days vs. (22.1+/-9.1) days, t=11.471, P=0.000], less costs [(2.6+/-2.2) ten thousand yuan vs (7.4+/-3.0) ten thousand yuan, t=12.235, P=0.000] and lower morbidity of early-stage postoperative complication [1.4%(1/74) vs. 20.8%(20/96), chi2=14.502, P=0.013]. One-hundred and sixty-two of 170 patients (95.3%) were followed up for median time of 28 months (range, 11 to 84 months). The recurrence rate was 2.7% (2/74) in ESD group and 4.2% (4/96) in surgery group respectively without significant difference(chi2=1.787, P=0.409). Five-year overall survival rate was 97.5% and 96.5% respectively without significant difference as well (chi2=0.115, P=0.735). CONCLUSIONS: ESD is an effective and safe treatment of early gastric cancer. It can be used as the first protocol for well-differentiated mucosal or SM1 EGC without ulcer as well as undifferentiated mucosal EGC with diameter less than 2 cm. PMID- 29492920 TI - [D2 radical resection of omental bursa and No.12p and No.8p for gastric carcinoma: a retrospectively analysis from a single center in China]. AB - OBJECTIVE: To evaluate the safty and feasibility of the D2 radical resection of omental bursa and No.12p and No.8p for gastric carcinoma (GC). METHODS: Clinical data of 1801 GC patients undergoing D2 radical resection of omental bursa and No.12p and No.8p at Fujian Medical University Cancer Hospital from January 2000 to January 2010 were analyzed retrospectively. Inclusion case criteria: (1)age of 18 to 90 years;(2)pathologically diagnosed as GC and receiving D2 radical resection of omental bursa and No.12p and No.8p;(3)complete clinical, pathological and follow-up data; (4)operation performed by same leading surgeon;(5)exclusion of other gastric malignancies, postoperative relapse of GC, and other simultaneous or heterochronous primary malignancies. Surgical procedure points: (1)The outer part of the peritoneum of duodenum descending was cut; the serosa was migrated to the anterior leaf of the gastrointestinal ligament. (2)The posterior lobe of the gastrocolic ligament and the transverse mesocolon were separated bluntly from left side to reach the omentum attaching to the colon portion; incision was made at the edge of the omentum attaching to the transverse colon behind the gastrocolic ligament; the leaves were turned to the anterior mesenteric anterior leaflets, and the entire anterior leaflet of the transverse mesentery was free.(3)The pancreas was separated, and resection of the posterior wall of the omentum sac continued up so that the entire retinal capsule was free; along the edge of the liver the attachment of the omentum was cut to reach the front of esophagus, and transverse incision was made in abdominal peritoneal layer of the esophagus, and then turned to the spleen on the pole; from the obturator to the esophagus incision was performed behind the peritoneum for the net; the uppermost edge of the resection of the capsule was performed as the posterior peritoneal incision to the right edge of the esophagus and was connected with the posterior parietal lobe of the previous resection; the posterior peritoneum was attached along the right edge of the esophagus and descended to the celiac artery; the posterior wall of the omental sac was removed. In the meantime, the liver duodenum ligament was cut, and the portal vein, hepatic artery trilocular was formed. Then the ligament lymph nodes were cleared.(4)The lymph nodes of celiac artery and its major branches were cleared; the envelope in front of pancreas and the part of the pancreas in posterior abdomen were resected; spleen and part of the pancreas tail were free. RESULTS: A total of 1801 cases were enrolled, including 1292 males and 509 females with a ratio of 2.54 with a mean age of(58.9+/-11.5)(18 to 89) years. The proportion of cases with T1a, T1b, T2, T3, T4a and T4b was 4.8% (87 cases), 6.6% (118 cases), 10.7% (193 cases), 17.5% (315 cases), 55.7% (1003 cases) and 4.7%(85 cases) respectively. All the patients completed operations successfully. The mean number of harvested lymph node was 28.5+/-13.7(10 to 85). Lymph node metastasis was found in 1439 cases (79.9%), including 180 cases (10.0%) in No.12p and 232 cases(12.9%) in No.8p respectively. Subgroup analysis showed that in T1a, T1b, T2, T3, T4a and T4b stage, the proportion of No.12p was 0, 1.7% (2/118), 5.2%(10/193), 10.5% (33/315), 12.4% (124/1003) and 12.9%(11/85) respectively, and the proportion of No.8p was 0, 0.8%(1/118), 2.1%(4/193), 4.8%(15/315), 18.9%(190/1003), and 25.9%(22/85) respectively. Postoperative complications were found in 195 patients (10.8%), including 63 cases(3.5%) of peritoneal infection, 52 cases (2.9%) of pulmonary infection, 33 cases(1.8%) of pancreatic leakage, 37 cases (2.1%) of anastomotic fistula, 45 cases (2.5%) of intestinal obstruction and 13 cases(0.7%) of gastroplesia. The 5-year overall survival rate was 53.6%. CONCLUSION: D2 radical resection of omental bursa and No.12p and No.8p is safe and feasible in the treatment of gastric cancer. PMID- 29492921 TI - [Comparison of the application between circular stapler and linear stapler in Billroth II( anastomosis of distal gastrectomy]. AB - OBJECTIVE: To compare the safety and effectiveness of circular stapler and linear stapler in Billroth II( anastomosis following distal gastrectomy for gastric cancer patients. METHODS: Clinical data of gastric adenocarcinoma patients who received distal gastrectomy with Billroth II( anastomosis at Ward IIII( of Gastrointestinal Cancer Center of Peking University Cancer Hospital from January 2013 to April 2017 were collected retrospectively. EXCLUSION CRITERIA: (1) patients identified as stage IIII( gastric cancer by preoperative clinical and postoperative pathological staging. (2) patients undergoing emergency operation due to perforation, obstruction, or bleeding of digestive tract. (3) patients receiving chemotherapy before operation. (4) patients undergoing combined organ resection due to tumor involving other organs. (5) patients complicating with other malignancies. A total of 116 cases were enrolled and divided into circular stapler (CS, 61 cases) group and linear stapler (LS, 55 cases) group according to the application of mechanical stapler. Clinicopathological characteristics, operative conditions and postoperative recovery were compared between two groups. RESULTS: Differences in baseline data, such as tumor size, Lauren classification, differentiation grade, and pathologic stage, between two groups were not statistically significant (all P>0.05). The mean operative time (230 min vs. 234 min), median intra-operative blood loss (50.0 ml vs. 50.0 ml), median number of harvested lymph node (28.0 vs. 26.0) and median number of positive lymph node (1.0 vs. 2.0) between LS group and CS group were not significantly different (all P>0.05) As compared to CS group, LS group presented shorter median time to the first flatus (3.0 days vs. 4.0 days, P=0.038), shorter median time to the first liquid diet (7.0 days vs. 8.0 days, P=0.000), shorter median time to remove the first abdominal drainage tube (7.0 days vs. 9.0 days, P=0.000) and shorter median time of postoperative hospital stay (8.0 days vs. 10.0 days, P=0.000). The morbidity of postoperative complication was 11.5% and 1.8% in CS group and LS group respectively without significant difference (P=0.092). In CS group, 1 case (1.6%) developed anastomotic hemorrhage, 3 cases (4.9%) gastric emptying disorder and 3 cases (4.9%) abdominal infection after operation, who all were cured by conservative treatment without duodenal stump fistula and re-operation. In LS group, only 1 case (1.8%) developed duodenal stump fistula and was cured by re operation. CONCLUSION: In distal gastrectomy with Billroth II( anastomosis for gastric cancer, the application of linear stapler results in faster recovery of gastrointestinal function and shorter hospital stay, indicating more advantages. PMID- 29492922 TI - [Safety evaluation on initial 100 consecutive procedures of self-pulling and latter transected esophagojejunostomy]. AB - OBJECTIVE: To evaluate the feasibility and the short-term safety of self-pulling and latter transected esophagojejunostomy(SPLT) in totally laparoscopic total gastrectomy (TLTG). METHODS: One hundred patients with gastric cancer received TLTG-SPLT at General Surgery Department of Huashan Hospital (Fudan University) from June 2014 to January 2017(SPLT group). The clinicopathologic characteristics, surgical and postoperative outcomes were collected retrospectively and compared with the conventional group undergoing TLTG plus overlap or functional end-to-end anastomosis from October 2013 to December 2015. D2 lymph node dissection was regularly performed for all the patients. In SPLT group, a sterile hemp rope was held to ligate and drag down the esophagus to maintain "self-pulling" after the duodenum was transected by the first stapler, allowing the detachment of the posterior mediastinum. Then a hole 2-3 cm above the ligature rope was made on the right-posterior wall of the esophagus. When the mesenteric tension was checked, another hole was made at the anti-mesenteric border of the jejunum 20 cm distal to the ligament of Treitz. A side-to-side esophagojejunostomy (E-J) was then performed between the right-posterior wall of esophagus and the anti-mesenteric wall of the jejunum with the second linear stapler, forming an entry hole. The "latter transection" was applied with the third stapler inserted from the assistant's Trocar, which facilitated the esophagus and the afferent loop jejunum to be simultaneously transected above the level of the entry hole. After that, a side-to-side jejunojejunostomy(J-J) with another 2 staplers was carried out between the afferent loop stump and the Roux limb 40 cm below E-J, in which the E-J entry hole could also work as the entrance for the stapler. The TLTG-SPLT was therefore completed and the specimen was removed through the incision from the umbilical Trocar site. RESULTS: There were 66 male and 34 female patients in the SPLT group with median age of 64 years. The clinicopathologic baseline data of two groups were comparable(all P>0.05). All the patients underwent operations successfully, and none was converted to open surgery. No positive margin was found in either group. Mean operation duration was (178.2+/-35.9) minute in SPLT group, including (22.9+/-7.1) minute of reconstruction, which both were significantly shorter than those in conventional group [(204.4+/-55.8) minute, P=0.003; (30.5+/-7.2) minute, P=0.000]. Less blood loss [(74.3+/-72.5) ml vs. (104.2+/-71.6) ml, P=0.017] and earlier time to the first flatus [(1.9+/-1.6) days vs. (2.7+/-1.3) days, P=0.001] were observed in SPLT group. There were no significant differences in postoperative hospital stay and pathological findings between the two groups(all P>0.05). Postoperative operation-associated complications were found in 7 cases of SPLT group. Of these 7 patients, 1 case developed gastrointestinal bleeding, 3 pancreatic leakage, 2 chyle leakage, who all were discovered within postoperative 1 week and were cured by conservative treatment, while the other 1 case developed anastomotic fistula complicated with peritoneal infection who received laparoscopic exploration and peritoneal scavenge and drainage, then discharged 34 days later. Six patients in conventional group developed postoperative operation-associated complications, including 1 case of anastomotic bleeding, 3 cases of pancreatic leakage, 1 case of chyle leakage and 1 case of peritoneal infection. Morbidity of postoperative operation-associated complication was not significantly different between two groups [7.0%(7/100) vs. 11.5%(6/52), chi2=0.414, P=0.520]. Fifty patients from two groups underwent endoscopic examination at postoperative 6-month and 12 month, and no obvious anastomotic stenosis and esophageal reflux were observed. CONCLUSION: SPLT is a safe procedure with feasibibility in intracorporeal esophagojejunostomy. PMID- 29492923 TI - [Research progress of the clinically uncommon gastric carcinoma]. AB - Gastric cancer is one of the most important diseases that endangers people's health. Beside gastric adenocarcinoma, gastric carcinoma also includes the following types: adenosquamous carcinoma, squamous carcinoma, gastric neuroendocrine tumor, gastric hepatoid adenocarcinoma, AFP-producing gastric cancer, EBV-associated gastric cancer, lymphoepithelioma-like carcinoma, undifferentiated-type gastric cancer, gastric carcinosarcoma and so on. The adenosquamous carcinoma, squamous carcinoma of stomach, gastric hepatoid adenocarcinoma, AFP-producing gastric cancer and gastric carcinosarcoma mainly occurred in old men, while the linitisplastica gastric cancer was common in young women. It refers to the gastric cancers that are clinically rare and have lower incidence, unique histological and pathological features, however, without obviously clinical manifestations. The clinically uncommon gastric cancers are easy to be misdiagnosed or missed, and further to miss the optimal opportunity for treatment due to the unclearly specific pathogenesis and disease progression. With the development of studies on the clinically uncommon gastric carcinoma, although people have a further knowledge of its pathologic features, methods of diagnosis and treatment, the diagnosis and treatment standards for the clinically uncommon gastric cancer has not yet been established and unified. The therapeutic principle of the clinically uncommon gastric cancers is also the radical surgery, radiotherapy and chemotherapy as the main comprehensive treatment supplemented by individualized treatment. With lucubrating the pathogenesis of them, specific diagnostic methods and treatment measures are new hope for improving the diagnosis and treatment of the clinically uncommon gastric cancers. So, the further researches on the clinically uncommon gastric cancers and exploring their etiology, pathogenesis, histological and pathological features have important significance to their diagnosis and treatment. This article makes a summary of the clinically uncommon gastric cancers with the aspects of epidemiology, histology, pathology, diagnosis, treatment, to provide reference to clinical diagnosis and scientific studies. PMID- 29492924 TI - [Current status and research progress of lymph node dissection in advanced upper gastric cancer]. AB - In recent years, the incidence of gastric cancer has shown a decreasing trend. However, the incidence of advanced upper gastric cancer in China is steadily increasing. Nowadays, surgery is the only way to cure advanced gastric cancer, and lymph node dissection is the key of operation. Since lymph node metastasis is the main metastatic route of gastric cancer, it is critical for surgeons to be aware of this when performing lymph node dissection during operation. At present, the only possible cure for advanced gastric cancer is surgery. The key to a successful operation is to completely dissect the lymph nodes, which has a direct influence on the patient's postoperative survival rate. The lymph node metastasis rate is one of the important predictors of postoperative prognosis in patients with gastric cancer, which is related to the tumor size and especially the depth of invasion. Generally speaking, the deeper the tumor depth and/or the larger the tumor diameter, the relatively higher the lymph node metastasis rate will be. The lymph node metastasis rate determines the extent of lymph node dissection in advanced upper gastric cancer. As D2 lymphadenectomy can bring about a more thorough clearance for the perigastric metastatic lymph nodes and can improve the survival rate of patients with advanced gastric cancer, it has become the standard surgery for advanced gastric cancer. However, during treating advanced upper gastric cancer, since there are multiple and intricate ways for upper gastric cancer to metastasize through lymphatic route, there are still controversials on the necessity to perform mediastinal lymphadenectomy, para aortic lymphadenectomy or dissection for lymph nodes around superior mesenteric vein remains controversial, as well as the necessity for splenectomy while doing splenic hilar lymphadenectomy or the necessity for distal gastric lymphadenectomy when the tumor diameter is less than 4 cm. In order to avoid postoperative pathological staging bias and to guide the further treatment after surgery, the number of dissected lymph nodes in advanced upper gastric cancer is currently required for no less than 15, but it is still controversial on the specific number of lymph node dissected that will improve the prognosis and prolong the survival time. In this paper, the current status and research progress of lymph node dissection in advanced upper gastric cancer are reviewed, in order to provide relevant bases and references for performing lymph node dissection in treating upper gastric cancer. PMID- 29492925 TI - Predictive factors of urinary incontinence after radical prostatectomy: Systematic review. AB - PURPOSE: To determine the predictive factors of urinary incontinence (UI) after radical prostatectomy (RP) for localized prostate cancer. METHODS: Review of the French and English literature between 1996 and 2015 treating risk factors of UI after RP. RESULTS: We identified 46 articles to be analyzed. Preoperative risk factors of UI were age, BMI, prostate surgery history, the sphincter deficit, bladder instability, the quality of the surgical technique (preservation of neuro vacsulaire strips, blood loss) The morphology of the prostate on MRI and the importance of the loss of urine after the removal of the bladder catheter. CONCLUSION: Several risk factors have been implicated clinical order (age, obesity, prostate surgery history, preoperative ED), urodynamics, radiological (the shape of the prostatic apex) and other depending in the surgical technique. PMID- 29492926 TI - Theses defended at Tunis Faculty of Medecine from 2004 to 2005: Scientific become and predictive factors of publications. AB - INTRODUCTION: Several theses are supported, every year, in the Faculty of Medicine of Tunis but their scientific become is this day unknown. The most part of specialities have not bibliometric data. OBJECTIVES: This work had for objectives to study the still unknown future of theses of Tunis Faculty of Medecine during 2004-2005, in terms of publication in indexed reviews and to determine the predictive factors of their publication. METHODS: This was a descriptive bibliometric study of theses supported at the Tunis Faculty of Medicine between January 1st, 2004 and december 31st, 2005. The data collected concerned :number of theses, involved specialities, discipline, type of theses, type of study, number of studied cases (<25 ou ? 25), methodology of the work, identity of the student, the director as well as the number and the rank of one or several directors. The productivity of the various specialities was estimated by two indicators: Ratio thesis-teacher and index of becoming theses. The publication of the theses has been sought in engines "Medline" and "scopus. Predictive factors for publication were sought. RESULTS: Six hundred and thirteen theses were supported, including 57.7% belonged to the medical disciplines. The attributed mention was "very honorable with the congratulations of the jury" in 71,0% of cases and "very honorable with the congratulations of the jury and the proposal at the price of thesis " in 24,0% of the cases. Thirteen comma four pourcent (13.4%) was the rate of publication. These theses were published when the attributed mention was "very honorable with the congratulations of the jury and the proposal at the price of thesis "(p=0.05), when the discipline was community (p <10-3), and when the study was of epidemiological type (p=0.05).The ratio theses-teacher- year was lower than 1 in 70% of cases and the index of becoming theses varied from 0 and 18.7 across all disciplines. The thesis were published in half of the cases in the the review"La Tunisie Medicale". The median of citation was 2 [0-66 citations]. The publication was found thanks to the name of the student which appeared as author in 61.0% of the theses. The student was first author in 12 cases (24.5%). CONCLUSION: The rate of publication of theses of Tunis Faculty of Medecine during 2004-2005 aws little raised by 13.4%. This rate should be considered as a basic figure with regard to wich will be compared the future impact of courses made at present in our Faculty. PMID- 29492927 TI - The implantable cardioverter defibrillator: Indications and follow-up. AB - INTRODUCTION: Sudden cardiac death (SCD) is a public health problem. In most cases, it is the consequence of ventricular arrhythmias. The only treatment of proven effectiveness is the implantable cardioverter defibrillator (ICD). AIM: To describe indications for ICD implantation according to the underlying heart disease and report it's short and long-term results. METHODS: We report a retrospective and descriptive study involving 90 patients implanted with an ICD in our facility collected between January 2003 and December 2014. RESULTS: The average age of our population was 49 +/- 15 years (14-76). A male predominance was noted (sex ratio: 6). Ischemic heart disease was the most common underlying heart disease found in 37% of cases. The average left ventricular ejection fraction was 43.5 +/- 17.7%. A slight predominance of primary prevention was noted in our series (52%). Single, dual and triple chamber ICD were used in respectively 34%, 36% and 30% of cases. The use of triple chamber ICD was more frequent in cardiomyopathies and ischemic heart disease. Early complications were observed in 9 patients (10%). No deaths directly related to the ICD implantation procedure was observed in our series. The mean follow-up was 39.7 months (3-136). We recorded 14 deaths. The main cause of death was refractory heart failure. During follow-up, 16 patients (18%) received appropriate ICD shocks. The only predictor of appropriate therapies was the indication of ICD for secondary prevention (p=0,002). Twenty one patients (23%) had complications inherent to the implantation of ICD. The main complication was inappropriate shocks found in 11 patients (12%). The main cause of these shocks was supraventricular arrhythmias 68%). Ischemic heart disease (p = 0.001) and secondary prevention (p = 0.048) were significantly associated with the occurrence of inappropriate ICD shocks. The ICD was explanted after varying delays in 4 patients (4.4%). CONCLUSION: The results of our study were comparable to major ICD studies and registries particularly in terms of procedural, late complications and the occurrence of appropriate ICD therapies. PMID- 29492928 TI - How to adapt first trimester ultrasound education to Tunisian trainees. AB - OBJECTIVES: To evaluate the impact of a targeted training program on the quality of NT measures performed by OBST/GYN trainees. METHODS: Prospective study. Step1: each trainee achieved 10 T1US . All were evaluated by 2 experts. Step 2: interactive training session where participants received a detailed feedback report. Step3: each candidate performed again 10 T1US. The results obtained before and after the training session were compared. RESULTS: Step1: Herman score was 4.1 with 38% of unacceptable exams. There was no correlation between the score and the level of the training curriculum. Main difficulty was about obtaining sagittal plane. Step2: self-assigned score before the session overestimated image quality (4.5 Vs. 4.1, p=0.03). At the end of the session, It decreased to 3.1. Step3: a significant improvement of technical settings, mean score (5.4 Vs. 4.1; p <0.001) , percentage of acceptable images (85% Vs. 62%, p = 0.002) and sagittal plane (6.4% Vs. 2.9%; p = 0.003). Only 37% had significantly improved their scores. CONCLUSION: The training program evaluated in this study guides the trainee in his daily self-evaluation. This preliminary study can already open discussion on the education and quality control of the T1US in our country. PMID- 29492929 TI - Aeromonas spp. Human Infection: Retrospective Study in the region of Sousse, 2011 - 2015. AB - OBJECTIVE: To present the clinical and bacteriological characteristics of human Aeromonas infections in the central region of Tunisia from January 2011 to September 2015. METHODS: Retrospective study concerning all Aeromonas spp strains isolated at our laboratory during a period of 5 years (2011-2015). Following data were collected: gender, age, hospital department, co-morbidities, site of infection, date, the Aeromonas species and susceptibility phenotype. Identification was based on conventional criteria and antibiotic susceptibility was performed according to the recommendations of "the Committee of the French Society of Microbiology. RESULTS: Thirty six strains of Aeromonas spp were collected during our study period. Mean age was 24 years old with a sex ratio of 1.1. The samples mainly provided from internal medicine (30,5%), neonatology (19,4%). Digestive tract (33%), blood stream (33%), skin and soft tissues (17%) and urinary tract (3%) were the sites of infection. Five infections (14%) were nosocomial, associated with biomaterials. The quart of patients was immuno compromised. The seasonal distribution showed a summer-autumn peak. We noted 2 species: A. hydrophila (83%) and A. veronii biovar sobria (17%). All strains were resistant to amoxicillin and amoxicillin-clavulanic acid whereas we noted effectiveness of third-generation cephalosporins (C3G), fluoroquinolones and aminoglycosids.All patients received antibiotic treatment: 93% an association. Four deaths occured not directly linked to Aeromonas infection. CONCLUSION: In our area, Aeromonas infections must be mentioned in case of diarrhea, especially during summer-autumn or sepsis particularly in immunocompromised patients. A. hydrophila remains the most frequent species at our patients. Due to their resistance to aminopenicillins, a probabilistic treatment including either a fluoroquinolone or a C3G, evently associated with an aminoglycoside, should be conducted. PMID- 29492930 TI - Autoimmune gastritis: assessment of OLGA and OLGIM staging systems. AB - BACKGROUND: Autoimmune gastritis present a risk of cancer related to atrophy and intestinal metaplasia. Two recent classifications OLGA (Operative Link on Gastritis Assessment) and OLGIM (Operative Link on Gastritic Intestinal Metaplasia assessment) have been proposed to reveal the high progressive risk forms (stages III and IV). AIM: To evaluate the OLGA and OLGIM staging systems in chronic autoimmune gastritis. METHODS: A descriptive single institution study of 30 cases of autoimmune gastritis. was performed over a 4-year period. The revaluation of atrophy and intestinal metaplasia, of gastric antrum and corpus, allowed to identify respectively the stages of OLGA and OLGIM systems. RESULTS: Our autoimmune gastritis were at high-risk stages in 26,5% of cases according to two classifications. 95% of low-risk gastritis acoording to OLGA staging presented moderete to severe corpus atrophy. A significant association was present between high-risk gastritis according to OLGA staging and neuroendocrine hyperplasia. Both OLGA and OLGIM systems showed a highly significant positive correlation between them with a mismatch at 2%. CONCLUSIONS: The OLGA and OLGIM staging systems in autoimmune gastritis, allow probably selection of high risk forms of chronic gastritis requiring convenable care. PMID- 29492931 TI - Device-vigilance and environment of the medical practice. AB - INTRODUCTION: The Device-vigilance (DV) manages incidents or risk of incidents related to the use of medical devices (MD). In Tunisia, absence of a regulatory framework organizing DV is the major obstacle to caregivers' involvement in this system. OBJECTIVE: 1/Compare knowledge, attitudes and practices of our UHC's physicians regarding the establishment of DV system (medical versus surgical) and 2/Detect effect of healthcare's environment on risk's perception linked to the use of MD. METHODS: It is a descriptive cross-sectional and comparative study type knowledge, attitudes and practices; among all physicians of our UHC who are users of MD during their practice. A self-administered pre-established pre-tested questionnaire has been established. Data seizure and analyzing was performed using SPSS software20.0. Test adopted was the X2 (Pearson)(p<0.05) with correction using Yates or exact test Fischer. RESULTS: A statistically significant difference in favor of physicians exercising in medical services is reported for the knowledge of standardized reporting form's existence(p=0.04). Physicians practicing in surgical services report incidences and risk of incidences regarding MD use significantly more than their colleague of medical services. For attitudes, surgical physicians perceive the responsible of the reporting as any caregiver (p=0.007).As for the practices, they are for the presence of MD's organized management in the service of exercise(P<10-4). CONCLUSION: At any healthcare environment, lack of knowledge, inadequacy of the attitudes and readjustment of practices among our physicians must be filled. The promulgation of regulatory texts is necessary in order to promote DV's sector of and to ensure the safety of both patients and caregivers. PMID- 29492932 TI - Spontaneous pneumothorax secondary to tuberculosis. AB - INTRODUCTION: Spontaneous pneumothorax (SP) is a frequent complication of pulmonary tuberculosis (TB) and a severe form of the disease. In spite of the fact that TB is a common cause of pneumothorax, a very few series, have been reported. METHODS: We retrospectively analysed the experience of SP secondary to TB in patients who were hospitalized in our department between 2005 and 2015. RESULTS: The mean age of patients was 38,5+/-19 years. Two patients had a history of pulmonary tuberculosis. The chest x-ray showed a pneumothorax in 5 cases, a hydropneumothorax in 5 cases and cavitary lesions accompanying SP in 5 cases. Acido-alcoolo-resistant bacilli were isolated in the expectorations in all patients. Treatment associated antitubercular chemotherapy in compliance with the national plan of struggle against tuberculosis, chest drainage and respiratory physiotherapy. The average duration of chest tube drainage was 23 days. Two patients underwent surgery. The course was favourable in 5 cases. A delay (>1month) to bacilli negativation was noticed in 2 patients and pachypleuritis requiring surgical pleural decortications in 2 patients. CONCLUSION: In our study, tubercular pneumothorax was always associated with active cavitated tuberculosis. The course was most of the time favourable with antitubercular chemotherapy and chest drainage. However, pleural sequelae such as pachypleuritis persisted sometimes. PMID- 29492933 TI - Screening for Depression using the PHQ-9 questionnaire: a study for Tunisian individuals consulting in the primary health care centers. AB - INTRODUCTION: Depression is considered a global public health problem especially in the developed countries, where depression is the leading cause of morbidity. OBJECTIVES: To determine the point prevalence and the severity of depression in primary health care, to define the profile of patients suffering from depression and consulting in primary health care. To identify risk factors for depression, in particular chronic co-morbid conditions. METHODS: Our study was a descriptive and analytical cross-sectional study of 1000 patients aged over 18 years consulting in ten primary care structures. It took place during a period of six successive days from 8 to 13 April 2012. Depression was assessed by the 9-item Patient Health Questionnaire (PHQ-9). RESULTS: In our sample, the average age was 42,4 years ranging from 18 to 89 years. Females were predominant with 66,6 %. According to the PHQ-9, the prevalence of major depressive episode (MDE) was 12,1 %. It was higher among women (13,5%) compared with men (9,3%) with an odds ratio of 1,5. The highest prevalence of MDE (19%) was noted in the age group of 45-54 years. The most prevalent clinical signs found in our population were sleep disorders (29,7%) and suicidal ideation (28,4%). Among patients with MDE, only 10% were followed up for depression. Major depressive disorder was significantly associated with comorbid chronic diseases (p < 0,001), especially diabetes (p = 0,043, OR = 2,1), musculoskeletal diseases (p = 0,028, OR = 2,1) and pulmonary diseases (p = 0,001 , OR = 5,5). Having one comorbid chronic condition multiplied the risk of having a MDE by 2,2. This risk was 3,2 for two or more comorbid chronic conditions. CONCLUSION: Depression in primary care remains a largely underdiagnosed and undertreated condition. Patients with chronic disorders are particularly vulnerable. PMID- 29492934 TI - Ketoprofen versus Diclofenac sodium in the treatment of renal colic. AB - INTRODUCTION: Adult renal colic is a frequent lombo-abdominal painful syndrome in emergencies. Treatment is based on nonsteroidal anti-inflammatory drug (NSAID) but the choice between different NSAIDs remains a subject of controversy. Our aim was to compare the efficacy and the safety of two intramuscularly NSAIDs in renal colic. METHODS: We conducted a 32-week, randomized, double-blind, single-center study . Patients who had renal colic with a visual analogue scale (VAS) >= 5 were randomly assigned to receive, by intramuscularly injection, 100 mg of Ketoprofen (GK) or 75 mg of diclofenac (GD). If VAS > 3 after 40 minute, 1 g of paracetamol was administered as rescue analgesia. Primary endpoint was successful treatment. Secondary outcome was the occurrence of side effects. RESULTS: We have included 80 patients. the average age was 39 +/- 13 years for GK versus 43 +/- 14 years for GD. The mean VAS on admission was also similar in both arms. We objectified a therapeutic success rate of 92% in both groups. This success was similar in both arms. The use of rescue medication was 32.5% in the GK versus 47.5% in the GD (P=0.17). We have observed in 46% (n =37) of the study population side effects. These effects were only minor and no major intolerance expression was registered. CONCLUSION: the efficacy and tolerance of NSAIDs in the treatment of renal colic was the same for diclofenac and ketoprofen. PMID- 29492935 TI - Trends in infective endocarditis. AB - INTRODUCTION: Infectious endocarditis (IE) is a rare disease with a high mortality. In 2009, the European society of cardiology restricted antibiotic prophylaxis to a smaller number of cardiac conditions with very high risk for IE. Did these changes in the guidelines have an impact on the epidemiological and bacteriological profile of IE? AIM: The main aim of our work was to study the evolution of the microbiological profile of IE from 1991 to 2016. METHODS: We realized an analytic retrospective study comparing two groups: group 1 included patients admitted for a certain IE before September 2009 and group 2 those admitted after that date. RESULTS: Patients mean age was 46 +/- 13 years and sex ratio was of 1.5. Forty percent of the patients were at high risk of IE. Blood cultures were positive in 19 cases. The most frequently isolated germ was Staphylococcus (10 patients). Serology was performed in six patients and was positive for Chlamydia Trachomatis in two cases. Forty-two patients had surgical treatment, 17 had a valve culture that was positive in 3 cases only. Clinical and paraclinic characteristics were comparable among the two groups. Negative blood cultures rates decreased from 72% to 68% between group 1 and 2 (p = 0.789). Staphylococcus positive blood cultures increased from 13% to 21% (p = 0.49). In contrast, Streptococcal positive blood cultures decreased from 11% to 5% in 2009 (p = 0.69). CONCLUSION: Our data suggest that there has been no change in the bacteriological profile of IE after the reduction in antibiotic prophylaxis. PMID- 29492936 TI - Alkalin phosphatase is a predictive factor of unresecability in ampullary and periampullary tumors. AB - BACKGROUND: Patients with malignant obstructive jaundice should undergo surgery on the basis of results of preoperative imaging. However, about half of patients are found to be unsuitable forresection during surgical exploration. Our study aimed to determine the clinicobiologicalcharacteristics that predict the resecability of ampullary and periampullary tumors. METHODS: We retrospectively reviewed the medical records of 49 patients (45% men and 55% women) who had malignant obstructive jaundice collected in the Department B of generalsurgery, Charles Nicolle hospital between July 1, 2008 and December 31, 2013. Predictivevariables of unresecability in malignant obstructive jaundice were identified using univariate andmultivariate analysis. RESULTS: 49 patients were included in the study. The mean age was 66,3+/-12,9 years. Twenty patients underwent surgery. Radical resection was performed in 12 patients and surgical palliation by biliary bypass was performed in 8 patients. Twenty-nine patients unfit for surgery underwent endoscopic stenting and chemotherapy. At univariate analysis, age (p=0,016), body mass index (p=0,033), worse general health status (p=0,037), locally advanced disease (p<0,001), serum conjugated bilirubin level (p=0,055), and serum level alkaline phosphatase (ALP) (p=0,014) were associated with unresectableampullary and periampullary tumors. At multivariate analysis serum level ALP was identify as an independent factor of unresecability in malignant obstructive jaundice [OR=0,996; IC a 95% (0,992-1,000) ;p=0,048]. The area under the ROC curve was 0,745 (p=0,016). CONCLUSION: Serum level of ALP can predict resecability in malignant obstructive jaundice. Further studies are needed to identify other factors predicting resecability and prognosis of ampullary and periampullary tumors. PMID- 29492937 TI - Appendiceal duplication: a new case. AB - Duplication of the vermiform appendix is a rare malformation. Few than 100 cases have been reported worldwide. It is usually diagnosed incidentally during emergency appendectomies due to inflammatory processes in the cecal appendix. We report a case of a woman presented with clinical features typical of acute appendicitis and surgical exploration revealed a double appendix. The operating surgeon should be vigilant of these rare anomalies to avoid serious clinical and medico legal consequences. PMID- 29492938 TI - Diaphragmatic hydatid disease: a diagnostic challenge for the radiologist. AB - Primitive hydatid disease of diaphragm is very rare. The preoperative diagnosis of this hydatid location represents a challenge for the radiologist. We reported a case of primitive hydatid cyst of the diaphragm not associated with other hydatid localizations which was diagnosed preoperatively. A 70 year-old woman with no previous medical history, complained of abdominal pain in the right upper quadrant for 7 months. The physical exam and the laboratory tests were unremarkable. Abdominal ultrasound showed multiloculated cystic lesion which appeared to be located in the hepatic dome suggestive of hydatid cyst of the liver. However, computed tomography showed findings but in favour of the diaphragmatic origin of the cyst which was confirmed peroperatively. Since the exploration of cysts lying between the thorax and the abdomen is difficult by ultrasound, computed tomography with multiplanar reconstruction appears to be indispensable in the preoperative assessment of hydatid cysts in contact with the diaphragm. PMID- 29492939 TI - Laparoscopic treatment of a cephalic pancreatic leiomyoma. AB - BACKGROUND: Leiomyoma of the pancreas is very rare. Symptoms and signs are not specific. It has the clinical presentation of a pancreatic mass. The preoperative clinical and radiological assessments are fundamental to establish a therapeutic schema. The curative treatment is surgical resection. A methodical histological examination is required to confirm the final diagnosis of Leiomyoma. CASE REPORT: A 52-year-old female patient presented with a mass of the head of the pancreas. After preoperative assessment, the patient had laparoscopic enucleation. Postoperative course was no remarkable for complications. Pathology examination concluded to leiomyoma. CONCLUSION: Preoperative diagnosis of pancreatic leiomyoma is difficult. It has the features of a pancreatic mass. The preoperative assessment aims to identify signs of malignancy. In its absence, laparoscopy is feasible and safe. Enucleation, if indicated, is a surgical option for a benign disease sparing the patient a pancreatic resection. PMID- 29492940 TI - Adult Henoch-Schonlein purpura and pulmonary tuberculosis. PMID- 29492941 TI - An unusual case of primary colonic dedifferentiated liposarcoma with confusing presentation. PMID- 29492942 TI - Coronary-subclavian steal syndrome presenting with stable angina. PMID- 29492943 TI - Spinal peripheral primitive neuroectodermal tumors: A radiological study of ten cases. AB - AIM: To summarize the imaging features of spinal peripheral primitive neuroectodermal tumor (spPNET) patients. MATERIAL AND METHODS: The computed tomography (CT) and magnetic resonance imaging (MRI) features of ten spPNET patients were retrospectively analyzed, and the clinicopathological data were reviewed. RESULTS: Four men and six women with a mean age of 24.7 years (range, 3 44 years) were included. A total of ten spPNET lesions were found in the ten patients, including six extradural and four intradural extramedullary lesions. Radiologically, spPNET usually presented as heterogeneous iso-intense lesions with a heterogeneously enhanced pattern. A "vault wall-like growth" pattern, a linear enhancement pattern, and vertebral bone involvement tended to be found in extradural lesions, and a ring enhancement pattern was found in extramedullary intradural lesions. Positive Ki-67 expression might be related to necrosis, bone destruction, and hemorrhage. CONCLUSION: A well-defined spinal mass showing iso intensity/attenuation with heterogeneous enhancement accompanied by other imaging features may be suggestive of spPNET and should be added to the list of differential diagnosis symptoms. PMID- 29492944 TI - A Tribute to Jimmie C. Holland, MD. PMID- 29492945 TI - Management of Triple-Negative Breast Cancer in Older Patients: How Is It Different? AB - Triple-negative breast cancer, which affects about 10% of older women with breast cancer, represents a major treatment challenge in this population. Treatment decisions for these patients can best be made based on geriatric assessment, estimated life expectancy, whether the treatment goal is prolonged survival or palliation, the potential benefits and toxicities of a specific treatment, and the patient's personal goals for treatment. Treatment outcomes for healthy older and younger women are similar, but great challenges exist in managing the vulnerable and frail patient. The cornerstone of therapy for early-stage triple negative breast cancer is local therapy (surgery and radiation) and, for most patients, adjuvant chemotherapy. In the management of metastatic triple-negative breast cancer, all therapy is palliative and chemotherapy is the treatment of choice. Since all treatment modalities in older patients-especially chemotherapy can affect physical and mental function, a geriatric assessment is key in selecting the most appropriate treatment strategy. Many older patients (older than 70 years) are poor candidates for state-of-the-art therapy, and some who have substantial comorbidities not related to breast cancer may opt for palliative and hospice care. In this review, we will discuss the role of geriatric assessment, alternative treatment modalities for older women with triple-negative breast cancer, and other special considerations for this patient population. PMID- 29492946 TI - Is This Patient With Metastatic Bladder Cancer a Candidate for Second-Line Immunotherapy Treatment? PMID- 29492947 TI - Point: Is There Still a Role for Intraperitoneal Platinum Therapy in Ovarian Cancer? Yes--IP Platinum Most Definitely Still Has a Place in the Treatment of Ovarian Cancer. PMID- 29492948 TI - Counterpoint: Is There Still a Role for Intraperitoneal Platinum Therapy in Ovarian Cancer? There Is No Role for IP Chemotherapy in Ovarian Cancer. PMID- 29492949 TI - Primary Central Nervous System Lymphoma-PART 2: Modern Therapeutic Management and Future Directions. AB - Primary central nervous system (CNS) lymphoma, a rare CNS neoplasm associated with high mortality, is responsive to therapeutic interventions. In Part 1 of our two-part coverage of this entity, we provided an overview of the epidemiology of primary CNS lymphoma, followed by a discussion of the diagnostic and staging evaluation, and a review of current prognostication systems. In Part 2, we discuss the management of primary CNS lymphoma, focusing in particular on systemic therapies and radiation. With respect to systemic therapies, we provide details of a variety of regimens built around a backbone of high-dose methotrexate. Future directions for the treatment of primary CNS lymphoma are reviewed as well. These include optimization of consolidation regimens and the pursuit of novel agents. PMID- 29492950 TI - Wedding Rigorous Scientific Methodology and Ancient Herbal Wisdom to Benefit Cancer Patients: The Development of PHY906. AB - Our research group has extensively characterized the preclinical and clinical activities of PHY906, a traditional Chinese herbal medicine, as a modulator of irinotecan-based chemotherapy for the treatment of colorectal cancer. This article reviews the critical issues of quality control and standardization of PHY906 and highlights the importance of high-quality material for the conduct of preclinical and clinical studies. Studies to investigate the potential biological mechanisms of action using a systems biology approach play a pivotal role in providing the preclinical rationale to move forward with clinical studies. For early-phase clinical studies, translational biomarkers should be incorporated to characterize the biological effects of the herbal medicine. These biomarkers include tumor mutational load, cytokine/chemokine expression, metabolomic profiling, and the presence of key herbal metabolites. Sophisticated bioinformatic approaches are critical for mining the data and identifying those biomarkers that can define the subset of patients who will benefit from PHY906 or any other herbal medicine, in terms of reduced treatment toxicity, improved quality of life, and/or enhanced clinical activity of treatment. PMID- 29492951 TI - Immunotherapy Plus Stereotactic Radiosurgery: Building on the Promise of Precision Medicine for CNS Malignancies-PART 1: Principles of Combined Treatment. AB - The role of systemic therapy in the treatment of intracranial metastases has traditionally been limited by the blood-brain barrier, and radiation therapy either with whole-brain treatment or stereotactic radiosurgery-has remained a primary treatment modality. Recent evidence has demonstrated that antigens released in the brain can inform the systemic immune system, and systemic antibodies can traverse into the brain. This has led to a renewed interest in investigating novel immunotherapy agents to treat both systemic and intracranial disease. Currently, several trials of immunotherapy, with or without sequential or concurrent radiation, have been performed in patients with brain metastases to evaluate the safety and efficacy of combined treatment. Combined use of stereotactic radiosurgery and checkpoint inhibitors appears safe and effective in the treatment of various brain metastases. Future studies will evaluate the optimal sequencing of radiosurgery and immunotherapy and assess the radiation doses and fractionations that will provide the best tumor response. PMID- 29492952 TI - Discrimination of papillary thyroid cancer from non-cancerous thyroid tissue based on lipid profiling by mass spectrometry imaging. AB - INTRODUCTION: The distinction of papillary thyroid carcinomas from benign thyroid lesions has important implication for clinical man-agement. Classification based on histopathological features can be supported by molecular biomarkers, including lipidomic signatures, identified with the use of high-throughput mass spectrometry techniques. Formalin fixation is a standard procedure for stabilization and preservation of tissue samples, therefore this type of samples constitute highly valuable source of clinical material for retrospective molecular studies. In this study we used mass spectrometry imaging to detect lipids discriminating papillary cancer from not cancerous thyroid directly in formalin-fixed tissue sections. MATERIAL AND METHODS: For this purpose imaging and profiling of lipids present in non-malignant and cancerous thyroid tissue specimens were conducted. High resolution MALDI-Q-Ion Mobility-TOF-MS technique was used for lipidomic analysis of formalin fixed thyroid tissue samples. Lipids were identified by the comparison of the exact molecular masses and fragmentation pathways of the protonated molecule ions, recorded during the MS/MS experiments, with LIPID MAPS database. RESULTS: Several phosphatidylcholines (32:0, 32:1, 34:1 and 36:3), sphingomyelins (34:1 and 36:1) and phosphatidic acids (36:2 and 36:3) were detected and their abundances were significantly higher in cancerous tissue compared to non-cancerous tissue. The same lipid species were detected in formalin-fixed as in fresh-frozen tissue, but [M + Na]+ ions were the most abundant in formalin fixed whereas [M + K]+ ions were predominant in fresh tissue. CONCLUSIONS: Our results prove the viability of MALDI-MSI for analysis of lipid distribution directly in formalin-fixed tissue, and the potential for their use in the classification of thyroid diseases. PMID- 29492953 TI - Food Insecurity in Older Adults in an Integrated Health Care System. AB - OBJECTIVES: To estimate food insecurity prevalence and develop a statistical prediction model for food insecurity. DESIGN: Retrospective cohort study. SETTING: Kaiser Permanente Colorado. PARTICIPANTS: Adult members who completed a pre-Medicare Annual Wellness Visit survey. MEASUREMENTS: Food insecurity was assessed using a single screening question. Sociodemographic and clinical characteristics from electronic health records and self-reported characteristics from the survey were used to develop the prediction model. RESULTS: Of 130,208 older adult members between January 2012 and December 2015, 50,097 (38.5%) completed food insecurity screening, 2,859 of whom (5.7% of respondents) reported food insecurity. The prevalence of food insecurity was 10.0% or greater among individuals who were black or Hispanic, had less than high school education, had Medicaid insurance, were extremely obese, had poor health status or quality of life, had depression or anxiety, had impairments in specific activities of daily living, had other nutritional risk factors, or were socially isolated (all p<.001). A multivariable model based on these and other characteristics showed moderate discrimination (c-statistic = 0.74) between individuals with food insecurity and those without and 14.3% of individuals in the highest quintile of risk reported food insecurity. CONCLUSION: Food insecurity is prevalent even in older adults with private-sector healthcare coverage. Specific individual characteristics, and a model based on those characteristics, can identify older adults at higher risk of food insecurity. System-level interventions will be necessary to connect older adults with community-based food resources. PMID- 29492954 TI - Accuracy of near-patient vs. inbuilt spirometry for monitoring tidal volumes in an in-vitro paediatric lung model. AB - Spirometric monitoring provides precise measurement and delivery of tidal volumes within a narrow range, which is essential for lung-protective strategies that aim to reduce morbidity and mortality in mechanically-ventilated patients. Conventional anaesthesia ventilators include inbuilt spirometry to monitor inspiratory and expiratory tidal volumes. The GE Aisys CS2 anaesthesia ventilator allows additional near-patient spirometry via a sensor interposed between the proximal end of the tracheal tube and the respiratory tubing. Near-patient and inbuilt spirometry of two different GE Aisys CS2 anaesthesia ventilators were compared in an in-vitro study. Assessments were made of accuracy and variability in inspiratory and expiratory tidal volume measurements during ventilation of six simulated paediatric lung models using the ASL 5000 test lung. A total of 9240 breaths were recorded and analysed. Differences between inspiratory tidal volumes measured with near-patient and inbuilt spirometry were most significant in the newborn setting (p < 0.001), and became less significant with increasing age and weight. During expiration, tidal volume measurements with near-patient spirometry were consistently more accurate than with inbuilt spirometry for all lung models (p < 0.001). Overall, the variability in measured tidal volumes decreased with increasing tidal volumes, and was smaller with near-patient than with inbuilt spirometry. The variability in measured tidal volumes was higher during expiration, especially with inbuilt spirometry. In conclusion, the present in vitro study shows that measurements with near-patient spirometry are more accurate and less variable than with inbuilt spirometry. Differences between measurement methods were most significant in the smallest patients. We therefore recommend near-patient spirometry, especially for neonatal and paediatric patients. PMID- 29492955 TI - An approximate joint model for multiple paired longitudinal outcomes and time-to event data. AB - Joint modeling of multivariate paired longitudinal data and time-to-event data presents computational challenges that supersede full likelihood estimation due to the large dimensional random effects vector needed to capture correlation due to clustering with respect to pairs, subjects, and outcomes. We propose an alternative, computationally simpler approach to estimation of complex shared parameter models where missing data is imputed based on the Posterior Predictive Distribution from a Conditional Linear Model (CLM) approximation. Existing methods for complete data are then implemented to obtain estimates of the event time model parameters. Our method is applied to examine the effects of discordant growth in anthropometric measures of longitudinal fetal growth in twin fetuses and the timing of birth. Simulation results are presented to show that our method performs relatively well with moderate measurement errors under certain CLM approximations. PMID- 29492956 TI - Married, unmarried, divorced, and widowed and the risk of stroke. AB - OBJECTIVES: Most studies report that marriage carries a lower risk of stroke than single living. Whether the marriage advantage is applicable with respect to all other marital status categories (unmarried, divorced, widow) remains unclear. We studied marital status and its association with incident stroke. MATERIAL AND METHODS: We included all patients > 40 years of age admitted to hospital for stroke in Denmark during 2003-2012 and compared marital status to the general Danish population (5.5 millions). Relative risks (RR) for stroke were estimated in log-linear Poisson regression models adjusting for age, sex, calendar year, income, and length of education. RESULTS: A total of 58 847 patients with incident stroke were included. Crude incidence rates of stroke (per 1000 per year) among the four marital status categories were as follows: 1.96 (married), 1.52 (unmarried), 2.36 (divorced), and 5.43 (widowed). Compared to married persons, adjusted risk of stroke was significantly increased for divorced (RR 1.23; CI 1.19-1.27) and unmarried men (RR 1.07; CI 1.03-1.11) but not for widowed men (RR 1.02; CI 0.98-1.06); risk was slightly increased for divorced women (RR 1.10; CI 1.06-1.15) while not for widowed (RR 1.0; CI 0.97-1.03) and unmarried women (RR 0.97; CI 0.97-1.03). CONCLUSIONS: Divorce was associated with higher risk of stroke, especially in men. Living in marriage or as unmarried or widower had only little or no impact on the risk of stroke. PMID- 29492957 TI - EMPOWERing Hospitalized Older Adults to Deprescribe Sedative Hypnotics: A Pilot Study. AB - OBJECTIVES: To distribute the EMPOWER patient education brochure and use hospitalization as an opportunity to reduce inappropriate sedatives. DESIGN: Participants were sequentially recruited until we achieved 30-day follow-up telephone and pharmacy records for 50 individuals. The proportion meeting the primary outcome was compared with that of a control cohort and with rates of cessation achieved in the community. SETTING: Fifty-two-bed medical clinical teaching unit in Montreal, Canada. PARTICIPANTS: Inpatients aged 65 and older who were chronic, regular sedative users. MEASUREMENTS: The primary outcome was short term sustained cessation 30-days after discharge. As a secondary outcome, we compared self-reported sleep disturbance before and after the intervention. RESULTS: Sedatives were deprescribed in 32 of 50 (64%) participants who received the EMPOWER brochure, which was significantly higher than our historical rate of 21% (p<.001). Participants did not report significant worsening in their quality of sleep after sedative cessation. CONCLUSION: Hospitalized individuals are willing to deprescribe, and contact with the healthcare system provides the opportunity to initiate the process with educational brochures. This type of intervention requires few resources and is feasible and inexpensive. PMID- 29492958 TI - Targeting liver sinusoidal endothelial cells with miR-20a-loaded nanoparticles reduces murine colon cancer metastasis to the liver. AB - Phenotypic transformation of liver sinusoidal endothelial cells is one of the most important stages of liver metastasis progression. The miRNA effects on liver sinusoidal endothelial cells during liver metastasis have not yet been studied. Herein, whole genome analysis of miRNA expression in these cells during colorectal liver metastasis revealed repressed expression of microRNA-20a. Importantly, downregulation of miR-20a occurs in parallel with upregulation of its known protein targets. To restore normal miR-20a levels in liver sinusoidal endothelial cells, we developed chondroitin sulfate-sorbitan ester nanoparticles conjugated with miR-20a in a delivery system that specifically targets liver sinusoidal endothelial cells. The restoration of normal mir-20a levels in these cells induced downregulation of the expression of its protein targets, and this also resulted in a reduction of in vitro LSEC migration and a reduction of in vivo activation and tumor-infiltrating capacity and ability of the tumor decreased by ~80% in a murine liver metastasis model. PMID- 29492959 TI - Technology, Incentives, or Both? Factors Related to Level of Hospital Health Information Exchange. AB - OBJECTIVE: To assess whether the level of health information exchange (HIE) in U.S. hospitals is related to technology capabilities, incentives to exchange, or both. STUDY SETTING: A total of 1,812 hospitals attesting to stage 2 of Medicare's Meaningful Use Incentive Program through April 2016. STUDY DESIGN: Hospital-level, multivariate OLS regression with state fixed effects was used to analyze the relationship between technology capability and incentives measures, and percent of care transitions with summary of care records (SCRs) sent electronically to subsequent providers. PRINCIPAL FINDINGS: Stage 2 hospitals reported sending SCRs electronically for an average of 41 percent (median = 33 percent) of transitions. HIE level is related to four capability measures, one incentive measure, and one measure that is related to both capability and incentive. Percent of transitions with SCRs sent electronically was 3 percentage points higher (95 percent CI: 0.1-5.1) for hospitals with a third-party HIE vendor, 3 percentage points higher (95 percent CI: 0.5-5.4) for hospitals with an EHR vendor as their HIE vendor, and 3 percentage points higher (95 percent CI: 0.4-5.4) for hospitals that automatically alert primary care providers. The direction and statistical significance of the relationships between specific EHR vendor and electronic SCR transmission level varied by vendor. Nonprofits and government hospitals performed 5 percentage points higher (95 percent CI: 1.5 9.1) and 8 percentage points higher (95 percent CI: 3.4-12.3) than for-profits. Hospitals in systems performed 3 percentage points higher (95 percent CI: 0.8 6.1). CONCLUSION: The overall level of HIE is low, with hospitals sending an SCR electronically for less than half of patient transitions. Specific hospital characteristics related to both technology capabilities and incentives were associated with higher levels of HIE. PMID- 29492961 TI - Understanding Menstrual Migraine. AB - PREMISE: Menstrual-related migraine is very prevalent, very disabling, yet very easy to manage given a good understanding of its cause. POSSIBLE SOLUTION: This article is intended to help with that understanding and to enable headache specialists to prescribe or create effective hormonal preventives of menstrual related migraine. PMID- 29492960 TI - Clinical correlates of augmentation/combination treatment strategies in major depressive disorder. AB - OBJECTIVE: This multicenter, multinational, cross-sectional study aimed to investigate clinical characteristics and treatment outcomes associated with augmentation/combination treatment strategies in major depressive disorder (MDD). METHOD: Sociodemographic, clinical, and treatment features of 1410 adult MDD patients were compared between MDD patients treated with monotherapy and augmentation/combination medication using descriptive statistics, analyses of covariance (ancova), and Spearman's correlation analyses. RESULTS: 60.64% of all participants received augmentation and/or combination strategies with a mean number of 2.18 +/- 1.22 simultaneously prescribed psychiatric drugs. We found male gender, older age, Caucasian descent, higher weight, low educational status, absence of occupation, psychotic symptoms, melancholic and atypical features, suicide risk, in-patient treatment, longer duration of hospitalization, some psychiatric comorbidities (panic disorder, agoraphobia, obsessive-compulsive disorder, and bulimia nervosa), comorbid somatic comorbidity in general and concurrent hypertension, thyroid dysfunction, diabetes, and heart disease in particular, higher current and retrospective Montgomery and Asberg Depression Rating Scale total scores, treatment resistance, and higher antidepressant dosing to be significantly associated with augmentation/combination treatment. These findings were corroborated when examining the number of concurrently administered psychiatric drugs in the statistical analyses. CONCLUSION: Our findings suggest a clear association between augmentation/combination strategies and treatment resistant/difficult-to-treat MDD conditions characterized by severe symptomatology and high amount of psychiatric and somatic comorbidities. PMID- 29492962 TI - Neck function in early hominins and suspensory primates: Insights from the uncinate process. AB - OBJECTIVES: Uncinate processes are protuberances on the cranial surface of subaxial cervical vertebrae that assist in stabilizing and guiding spinal motion. Shallow uncinate processes reduce cervical stability but confer an increased range of motion in clinical studies. Here we assess uncinate processes among extant primates and model cervical kinematics in early fossil hominins. MATERIALS AND METHODS: We compare six fossil hominin vertebrae with 48 Homo sapiens and 99 nonhuman primates across 20 genera. We quantify uncinate morphology via geometric morphometric methods to understand how uncinate process shape relates to allometry, taxonomy, and mode of locomotion. RESULTS: Across primates, allometry explains roughly 50% of shape variation, as small, narrow vertebrae feature the relatively tallest, most pronounced uncinate processes, whereas larger, wider vertebrae typically feature reduced uncinates. Taxonomy only weakly explains the residual variation, however, the association between Uncinate Shape and mode of locomotion is robust, as bipeds and suspensory primates occupy opposite extremes of the morphological continuum and are distinguished from arboreal generalists. Like humans, Australopithecus afarensis and Homo erectus exhibit shallow uncinate processes, whereas A. sediba resembles more arboreal taxa, but not fully suspensory primates. DISCUSSION: Suspensory primates exhibit the most pronounced uncinates, likely to maintain visual field stabilization. East African hominins exhibit reduced uncinate processes compared with African apes and A. sediba, likely signaling different degrees of neck motility and modes of locomotion. Although soft tissues constrain neck flexibility beyond limits suggested by osteology alone, this study may assist in modeling cervical kinematics and positional behaviors in extinct taxa. PMID- 29492963 TI - Efficacy of systemic antibiotics in nonsurgical periodontal therapy for diabetic subjects: a systematic review and meta-analysis. AB - OBJECTIVES: To evaluate the effects of systemic antibiotics as adjuncts to nonsurgical periodontal treatment (NSPT), as opposed to using NSPT alone, on periodontal clinical parameters of diabetic patients with periodontitis. MATERIALS AND METHODS: Randomised controlled trials with a follow-up of 3 months or more, assessing the effects of NSPT in combination with antibiotics, in diabetic patients with periodontitis were included. Trials published up to August 2016 were identified from MEDLINE, EMBASE and LILACS databases. Meta-analyses were conducted to determine changes in clinical attachment level (CAL), probing pocket depth (PPD), bleeding on probing (BOP) and gingival index (GI). Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed in this review. RESULTS: Of the 164 papers potentially admissible to this systematic review, 15 articles on 11 randomised clinical trials were considered as eligible. The results of the meta-analyses presented a modest additional benefit of 0.14 mm (95% confidence interval: 0.08-0.20) in reducing PPD but no further benefit in CAL gain. CONCLUSION: When the data for all antibiotic protocols were considered together for the treatment of periodontitis patients with DM, a significant, albeit small, reduction of PPD and no improvement in CAL gain was observed. When the antibiotic protocols were analysed separately, the combination of amoxicillin plus metronidazole yielded the best results for PPD. PMID- 29492964 TI - Interaction analysis between germline susceptibility loci and somatic alterations in lung cancer. AB - Emerging evidence indicates that germline variations may interact with somatic events in carcinogenesis. However, the germline-somatic interaction in lung cancer remains largely unknown. We investigated whether lung cancer driver genes (CDGs) were more likely to locate within cancer susceptibility regions. Pathway analysis was performed to identify common pathways underlying CDGs and cancer susceptibility genes (CSGs). Next, we analyzed the associations between lung cancer risk SNPs and somatic alterations, including mutations and copy number alterations, in the level of genes, pathways, and overall burden of alterations. Enrichment analysis showed that lung CDGs are more likely to locate within cancer susceptibility regions (p = 8.40 * 10-3 ). Both of lung CSGs and CDGs showed significant enrichment in pathways such as cell cycle and p53 signaling pathway. Gene-based analysis showed that rs36600 (22q12.2) was associated with somatic mutations within ARID1A (OR = 2.45, 95%CI: 1.47-4.08, p = 5.78 * 10-4 ). Pathway based analysis of somatic truncation mutations identified rs2395185 and rs3817963 at 6p22.1 was associated with cell cycle pathway (OR = 1.56, p = 3.61 * 10-4 for rs2395185; OR = 1.58, p = 4.15 * 10-4 for rs3817963), and rs3817963 was also associated with MAPK signaling pathway (OR = 1.54, p = 8.58 * 10-4 ). Further analysis associated rs2395185 at 6p22.1 (HLA class II genes) with increased APOBEC3A expression (p = 9.50 * 10-3 ) and elevated APOBEC mutagenesis (p = 3.58 * 10-3 ). These results indicate germline-somatic interactions in lung tumorigenesis, and help to uncover the molecular mechanisms underlying lung cancer risk SNPs. PMID- 29492965 TI - A clinicopathological study and prognostic factor analysis of 177 salivary duct carcinoma patients from The Netherlands. AB - Salivary duct carcinoma (SDC) is a subtype of salivary gland cancer with a dismal prognosis and a need for better prognostication and novel treatments. The aim of this national cohort study was to investigate clinical outcome, prognostic factors, androgen receptor (AR) and human epidermal growth factor receptor 2 (HER2) expression. SDC patients diagnosed between 1990 and 2014 were identified by the Nationwide Network and Registry of Histo- and Cytopathology in the Netherlands (PALGA). Subsequently, medical records were evaluated and pathological diagnoses reviewed. Data were analyzed for overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS) and prognostic factors. AR was evaluated by immunohistochemistry (IHC), HER2 by IHC and fluorescent in-situ hybridization. A total of 177 patients were included. The median age was 65 years, 75% were male. At diagnosis, 68% presented with lymph node metastases and 6% with distant metastases. Median OS, DFS and DMFS were 51, 23 and 26 months, respectively. In patients presenting without distant metastases, the absolute number of positive lymph nodes was associated with poor OS and DMFS in a multivariable analysis. AR and HER2 were positive in 161/168 (96%) and 44/153 (29%) tumors, respectively, and were not prognostic factors. SDC has a dismal prognosis with primary lymph node involvement in the majority of patients. The absolute number of lymph node metastases was found to be the only prognostic factor for DMFS and OS. AR expression and-to a lesser extent-HER2 expression hold promise for systemic treatment in the metastatic and eventually adjuvant setting. PMID- 29492967 TI - The Solace of an Uncertain Future: Acute Illness, the Self, and Self-Care. AB - "Take care of yourself" may be one of the most ubiquitous phrases spoken to people who are ill or to their caretakers. Yet few people who offer it as a balm consider what the self experience is of the person to whom the injunction is offered. We unravel some of the paradoxes inherent in the phrase, illustrating complexities that arise in the context of a life-threatening diagnosis. To illustrate the relational nature of the self, we analyze a partial transcript of an interview conducted in 1988 with the authors-a family therapist mother who had recently undergone surgery for breast cancer and her then 9-year-old daughter. We also examine the role of time in the interview. We propose that unlike PTSD when the past invades the present, in life-threatening illness the future is foreclosed, leading to distortions in current perception and behavior. The second author presents a follow-up to the interview and relates it to her current experience as a mother with chronic health issues. We close with suggestions for clinicians. PMID- 29492966 TI - The genetic assimilation in language borrowing inferred from Jing People. AB - OBJECTIVES: The Jing people are a recognized ethnic group in Guangxi, southwest China, who are the immigrants from Vietnam during the 16th century. They speak Vietnamese but with lots of language borrowings from Cantonese, Zhuang, and Mandarin. However, it's unclear if there is large-scale gene flow from surrounding populations into Jing people during their language change due to the very limited genetic information of this population. MATERIALS AND METHODS: We collected blood samples from 37 Jing and 3 Han Chinese individuals from Wanwei, Shanxin, and Wutou islands in Guangxi and genotyped about 600,000 genome-wide single nucleotide polymorphisms (SNPs). We used Principal Component Analysis (PCA), ADMIXTURE analysis, f statistics, qpWave and qpAdm to infer the population genetic structure and admixture. RESULTS: Our data revealed that the Jing people are genetically similar to the populations in southwest China and mainland Southeast Asia. But compared with Vietnamese, they show significant evidence of gene flow from surrounding East Asians. The admixture proportion is estimated to be around 35-42% in different Jing groups using southern Han Chinese as a proxy. The majority of the paternal lineages of Jing people are most likely from surrounding East Asians. DISCUSSION: We conclude that the formation and language change of present-day Jing people have involved genetic assimilation of surrounding East Asian populations. The language borrowing, in this case, is not only a cultural phenomenon but has involved demic diffusion. PMID- 29492968 TI - The composition of precarity: 'emerging' composers' experiences of opportunity culture in contemporary classical music. AB - This paper examines the precarious working lives of 'emerging' composers attempting to build a career in the world of new classical music in the UK. This topic is approached by considering the 'composition opportunity', success in which is seen as an important element in 'making it' in this sphere. We argue that such schemes in fact manifest a crucial tension in the nature of artistic labour, and are, at the very least, problematic in their function as conduits towards full professional identity. They may instead act to maintain the precarious working situation of composers in a neoliberal age. The working lives of artists are all too rarely illuminated, and new music composers are no exception; this survey of 47 emerging composers is the largest study of such individuals in the UK. PMID- 29492971 TI - Pro-inflammatory and anti-inflammatory compounds exert similar effects on P glycoprotein in blood-brain barrier endothelial cells. AB - OBJECTIVES: The effects of anti-inflammatory glucocorticoids dexamethasone (DX) and hydrocortisone (HC), pro-inflammatory cytokine interleukin-1beta (IL-1beta) and dietary long-chain polyunsaturated fatty acids (PUFAs) on expression and activity of the ATP-binding cassette transporter P-glycoprotein (P-GP) were studied in porcine brain endothelial cells (PBECs). METHODS: Primary PBECs were treated for 24 h with glucocorticoids, IL-1beta and long-chain PUFAs. P-GP activity was determined by measuring intracellular calcein accumulation and P-GP expression by Western blotting. The effect of PUFAs on membrane fluidity was assessed by fluorescence recovery after photobleaching (FRAP). KEY FINDINGS: Dexamethasone, HC and IL-1beta significantly increased P-GP expression and activity. The effect of IL-1beta was attenuated by the IL-1 receptor antagonist (IL-1RA). This is the first report of the combined actions of IL-1beta and IL-1RA on P-GP expression and the first evidence of glucocorticoid-mediated P-GP up regulation in PBECs. Arachidonic acid (AA), docosahexaenoic acid (DHA) and eicosapentenoic acid (EPA) significantly decreased P-GP activity without affecting expression or membrane fluidity. AA, DHA and EPA counteracted IL-1beta mediated increases in P-GP activity, while AA and EPA, but not DHA, counteracted glucocorticoid-mediated increase in P-GP activity. CONCLUSIONS: While glucocorticoids and IL-1beta possess opposing actions in inflammation, they demonstrate functional consistency by increasing P-GP expression and activity in PBECs. PMID- 29492969 TI - Etiology of hormone receptor positive breast cancer differs by levels of histologic grade and proliferation. AB - Limited epidemiological evidence suggests that the etiology of hormone receptor positive (HR+) breast cancer may differ by levels of histologic grade and proliferation. We pooled risk factor and pathology data on 5,905 HR+ breast cancer cases and 26,281 controls from 11 epidemiological studies. Proliferation was determined by centralized automated measures of KI67 in tissue microarrays. Odds ratios (OR), 95% confidence intervals (CI) and p-values for case-case and case-control comparisons for risk factors in relation to levels of grade and quartiles (Q1-Q4) of KI67 were estimated using polytomous logistic regression models. Case-case comparisons showed associations between nulliparity and high KI67 [OR (95% CI) for Q4 vs. Q1 = 1.54 (1.22, 1.95)]; obesity and high grade [grade 3 vs. 1 = 1.68 (1.31, 2.16)] and current use of combined hormone therapy (HT) and low grade [grade 3 vs. 1 = 0.27 (0.16, 0.44)] tumors. In case-control comparisons, nulliparity was associated with elevated risk of tumors with high but not low levels of proliferation [1.43 (1.14, 1.81) for KI67 Q4 vs. 0.83 (0.60, 1.14) for KI67 Q1]; obesity among women >=50 years with high but not low grade tumors [1.55 (1.17, 2.06) for grade 3 vs. 0.88 (0.66, 1.16) for grade 1] and HT with low but not high grade tumors [3.07 (2.22, 4.23) for grade 1 vs. 0.85 (0.55, 1.30) for grade 3]. Menarcheal age and family history were similarly associated with HR+ tumors of different grade or KI67 levels. These findings provide insights into the etiologic heterogeneity of HR+ tumors. PMID- 29492972 TI - Integrated genetic and morphological data support eco-evolutionary divergence of Angolan and South African populations of Diplodus hottentotus. AB - The genus Diplodus presents multiple cases of taxonomic conjecture. Among these the D. cervinus complex was previously described as comprising three subspecies that are now regarded as separate species: Diplodus cervinus, Diplodus hottentotus and Diplodus omanensis. Diplodus hottentotus exhibits a clear break in its distribution around the Benguela Current system, prompting speculation that Angolan and South African populations flanking this area may be isolated and warrant formal taxonomic distinction. This study reports the first integrated genetic [mitochondrial (mt)DNA and nuclear microsatellite] and morphological (morphometric, meristic and colouration) study to assess patterns of divergence between populations in the two regions. High levels of cytonuclear divergence between the populations support a prolonged period of genetic isolation, with the sharing of only one mtDNA haplotype (12 haplotypes were fully sorted between regions) attributed to retention of ancestral polymorphism. Fish from the two regions were significantly differentiated at a number of morphometric (69.5%) and meristic (46%) characters. In addition, Angolan and South African fish exhibited reciprocally diagnostic colouration patterns that were more similar to Mediterranean and Indian Ocean congeners, respectively. Based on the congruent genetic and phenotypic diversity we suggest that the use of hottentotus, whether for full species or subspecies status, should be restricted to South African D. cervinus to reflect their status as a distinct species-like unit, while the relationship between Angolan and Atlantic-Mediterranean D. cervinus will require further demo-genetic analysis. This study highlights the utility of integrated genetic and morphological approaches to assess taxonomic diversity within the biogeographically dynamic Benguela Current region. PMID- 29492970 TI - National Association of Medical Examiners position paper: Recommendations for the investigation and certification of deaths in people with epilepsy. AB - Sudden unexpected death of an individual with epilepsy can pose a challenge to death investigators, as most deaths are unwitnessed, and the individual is commonly found dead in bed. Anatomic findings (eg, tongue/lip bite) are commonly absent and of varying specificity, thereby limiting the evidence to implicate epilepsy as a cause of or contributor to death. Thus it is likely that death certificates significantly underrepresent the true number of deaths in which epilepsy was a factor. To address this, members of the National Association of Medical Examiners, North American SUDEP Registry, Epilepsy Foundation SUDEP Institute, American Epilepsy Society, and the Centers for Disease Control and Prevention constituted an expert panel to generate evidence-based recommendations for the practice of death investigation and autopsy, toxicological analysis, interpretation of autopsy and toxicology findings, and death certification to improve the precision of death certificate data available for public health surveillance of epilepsy-related deaths. The recommendations provided in this paper are intended to assist medical examiners, coroners, and death investigators when a sudden unexpected death in a person with epilepsy is encountered. PMID- 29492973 TI - Assessing ecological and molecular divergence between the closely related species Hydrolagus pallidus and H. affinis (Chimaeridae). AB - This study investigated taxonomic validity of the pale ghost shark Hydrolagus pallidus Hardy & Stehmann, 1990, which was described as a species distinct from the smalleyed rabbitfish H. affinis (de Brito Capello 1868). While few morphological characters distinguish the two taxa, a striking difference in sex ratio and fixed differences (1.1-1.6% divergence) in the cytochrome oxidase subunit I barcoding gene support the recognition of both species. PMID- 29492974 TI - ABO and D typing and alloantibody screening in marrow samples: relevance to intraosseous blood transfusion. AB - BACKGROUND: Blood transfusion through the intraosseous route is gaining popularity in emergency medicine. Pretransfusion peripheral blood (PB) samples are usually not available in these patients, leading to discrepancies in blood group typing and a possible delay in transferring to group-specific blood products. The aim of this study was to assess the feasibility of ABO and D typing and red blood cell alloantibody screening in marrow (BM) samples. STUDY DESIGN AND METHODS: Direct and reverse ABO typing, D typing, and a two-cell alloantibody screen were performed in EDTA-anticoagulated BM samples with standard manual column agglutination techniques. EDTA-anticoagulated PB samples were used as controls. RESULTS: The mean age of the study subjects (n = 71) was 47 years (range, 1-82 years). All ABO groups and both D+ and D- types were represented. In all subjects, concordant results were observed for all analyses in BM and PB samples. In 15 (21%) of the samples, a discrepancy of one reaction strength step (1+) was observed in at least one of the analyses (Cohen's weighted kappa = 0.993); this did not affect interpretation of the results. CONCLUSION: Blood group typing and alloantibody screening are feasible in BM samples, providing proof-of-concept that intraosseous samples for blood group serologic analyses can be collected from emergency patients before intraosseous blood transfusion. This will enable a timely transfer to group-specific blood products and enable conservation of the valuable universal-donor blood products. PMID- 29492975 TI - Sexual-perception processes in acquaintance-targeted sexual aggression. AB - This study analyzes data from seven published studies to examine whether three performance-based indices of men's misperception of women's sexual interest (MSI), derived from a self-report questionnaire, are associated with sexual aggression history, rape-supportive attitudes, sociosexuality, problem drinking, and self-reported MSI. Almost 2000 undergraduate men judged the justifiability of a man's increasingly unwanted advances toward a woman on the Heterosocial Perception Survey-Revised. Participants self-reported any sexual-aggression history, and some completed questionnaires assessing rape-supportive attitudes, sociosexuality, problem drinking, and self-reported MSI. A three-parameter logistic function was fitted to participants' justifiability ratings within a non linear mixed-effects framework, which provided precise participant-specific estimates of three sexual-perception processes (baseline justifiability, bias, and sensitivity). Sexual-aggression history and rape-supportive attitudes predicted: (a) reduced sensitivity to women's affect; (b) more liberal biases, such that the woman's affect had to be more negative before justifiability ratings dropped substantially; and (c) greater baseline justifiability of continued advances after a positive response. Sexual-aggression history and attitudes correlated more strongly with sensitivity than baseline justifiability; remaining variables showed the opposite pattern. This work underscores the role of sexual-perception processes in sexual aggression and illustrates the derivation of performance-based estimates of sexual-perception processes from questionnaire responses. PMID- 29492976 TI - Molecular and serological infection marker screening in blood donors indicates high endemicity of hepatitis E virus in Poland. AB - BACKGROUND: Until now, markers of hepatitis E virus (HEV) infection have not been studied in blood donors throughout Poland, and no acute case of HEV infection has been closely documented or confirmed by HEV RNA detection. The prevalence of HEV infection markers, including HEV RNA in Polish blood donors and virus genotypes was investigated. STUDY DESIGN AND METHODS: In total, 12,664 individual donations from 22 Polish blood transfusion centers were tested for HEV RNA by transcription mediated amplification. In addition, 3079 first-time donors sampled throughout Poland also were screened for antibodies to HEV. HEV RNA and immunoglobulin M positive donations were confirmed using real-time reverse transcription polymerase chain reaction and Western blotting, respectively. RESULTS: Ten donors were identified as RNA initial reactive (one of 1266 donors), and six (one of 2109) were identified as repeat reactive and confirmed by real-time reverse transcription-polymerase chain reaction or seroconversion. Sequence analysis identified HEV Genotype 3c in one donor and Genotype 3i in two others. On average, 43.5% of donors were immunoglobulin G-positive. Immunoglobulin G seroprevalence ranged from 22.7% to 60.8% in group ages 18 to 27 years and 48 to 57 years, respectively and differed between administrative regions from 28.9% in Podlasie to 61.3% in Wielkopolska. Thirty-nine of the donors were immunoglobulin M-positive, and seven donors were IgM positive only (0.2%). Of 37 immunoglobulin M-reactive samples tested by Western blot, 24 (64.9%) were confirmed. CONCLUSIONS: The current results indicate a high level of HEV endemicity throughout Poland compared with other countries. There is an urgent need to consider the protection of recipients of blood components against transfusion transmitted HEV infection. PMID- 29492977 TI - Vitamin D levels and risk for periodontal disease: A systematic review. AB - OBJECTIVE: To evaluate the existing evidence supporting or refuting the following questions: (i) Do patients with lower vitamin D levels have higher risk for periodontal disease? (ii) Are periodontal treatment outcomes improved by the adjuvant supplementation of vitamin D or by elevated serum vitamin D levels? MATERIAL AND METHODS: MEDLINE, SCOPUS, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched up to September 2017. Studies were included if they had measured serum vitamin D levels or vitamin D intake and any periodontal parameter. RESULTS: Overall, 27 studies were included (13 cross sectional studies, 6 case-control studies, 5 cohort studies, 2 randomized clinical trials and 1 case series study). Sixty-five percent of the cross sectional studies reported significant associations between low vitamin D levels and poor periodontal parameters. None of the observational longitudinal studies found that periodontal disease progression could be attributed to lower vitamin D levels. No interventional studies that evaluated the use of vitamin D supplementation as a solely adjuvant to periodontal treatment was found. No meta analysis was performed due to high variability across studies. CONCLUSION: The data to support or refute the association between vitamin D levels and periodontal disease are inconclusive at the moment. More rigorously designed longitudinal studies with standardized definitions of periodontal disease and vitamin D are necessary. PMID- 29492978 TI - What distinguishes adolescents with suicidal thoughts from those who have attempted suicide? A population-based birth cohort study. AB - BACKGROUND: Only one-third of young people who experience suicidal ideation attempt suicide. It is important to identify factors which differentiate those who attempt suicide from those who experience suicidal ideation but do not act on these thoughts. METHODS: Participants were 4,772 members of the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK population-based birth cohort. Suicide ideation and attempts were assessed at age 16 years via self-report questionnaire. Multinomial regression was used to examine associations between factors that differentiated adolescents in three groups: no suicidal ideation or attempts, suicidal ideation only and suicide attempts. Analyses were conducted on an imputed data set based on those with complete outcome data (suicidal thoughts and attempts) at age 16 years (N = 4,772). RESULTS: The lifetime prevalence of suicidal ideation and attempts in the sample was 9.6% and 6.8% respectively. Compared to adolescents who had experienced suicidal ideation, those who attempted suicide were more likely to report exposure to self-harm in others (adjusted OR for family member self-harm: 1.95, for friend self-harm: 2.61 and for both family and friend self-harm: 5.26). They were also more likely to have a psychiatric disorder (adjusted OR for depression: 3.63; adjusted OR for anxiety disorder: 2.20; adjusted OR for behavioural disorder: 2.90). Other risk factors included female gender, lower IQ, higher impulsivity, higher intensity seeking, lower conscientiousness, a greater number of life events, body dissatisfaction, hopelessness, smoking and illicit drug use (excluding cannabis). CONCLUSIONS: The extent of exposure to self-harm in others and the presence of psychiatric disorder most clearly differentiate adolescents who attempt suicide from those who only experience suicidal ideation. Further longitudinal research is needed to explore whether these risk factors predict progression from suicidal ideation to attempts over time. PMID- 29492979 TI - The enhanced effect of tetrahydrocurcumin on radiosensitivity of glioma cells. AB - OBJECTIVES: To evaluate the effects of tetrahydrocurcumin (THC) on the radiosensitivity of glioma cells and the possible molecular mechanism. METHODS: MTT assay, colony forming and wound healing assays were performed to detect the proliferation, radiosensitivity and migration of cells with various treatments. Cell apoptosis, cell cycle and GHS level were determined for exploring potent sensitization mechanism of THC. Meanwhile, protein expressions of cyclin D1 and PCNA were also measured. Furthermore, both orthotopic C6 mouse models and C6 subcutaneously grafted mouse models were established to test the tumour inhibitory effects of combined treatment in vivo. KEY FINDINGS: Cells treated with combined THC and radiation demonstrated lower cell viability and higher apoptosis rate as compared to radiation group. Moreover, the intracellular GSH was also decreased in the THC co-treated C6 cells. More importantly, combinatorial treatment group significantly induced G0/G1 cell cycle arrest and a decrease in the S phase cell through the down-regulation of cyclin D1 and PCNA. The in-vivo therapeutic efficacy assay indicated that the growth of tumour was greatly inhibited in combinatorial group. CONCLUSIONS: Tetrahydrocurcumin can synergistically enhance the radiosensitivity of glioma cells by inhibiting the expressions of cyclin D1 and PCNA. PMID- 29492980 TI - Group 2 innate lymphocytes at the interface between innate and adaptive immunity. AB - Group 2 innate lymphoid cells (ILC2) are innate immune cells that respond rapidly to their environment through soluble inflammatory mediators and cell-to-cell interactions. As tissue-resident sentinels, ILC2 help orchestrate localized type 2 immune responses. These ILC2-driven type 2 responses are now recognized in diverse immune processes, different anatomical locations, and homeostatic or pathological settings. ILC2-derived cytokines and cell surface signaling molecules function as key regulators of innate and adaptive immunity. Conversely, ILC2 are governed by their environment. As such, ILC2 form an important nexus of the immune system and may present an attractive target for immune modulation in disease. PMID- 29492981 TI - Evidence for sperm storage in common smoothhound shark Mustelus mustelus and paternity assessment in a single litter from South Africa. AB - The present histological study of adult female common smoothhound shark Mustelus mustelus demonstrates that the species can store sperm in their oviducal glands. In addition, single paternity of a litter of 22 pups is reported, contributing to further knowledge regarding the genetic and behavioural mating strategy of M. mustelus. PMID- 29492982 TI - Palladium-induced granulomas analysed with inductively coupled plasma mass spectrometry. PMID- 29492983 TI - Healing of toothbrush-induced abrasions to keratinized mucosa of the palate in humans: A pilot study. AB - BACKGROUND AND OBJECTIVE: To the best of our knowledge, the healing time for toothbrush-induced gingival abrasions in humans has not yet been explored. The aim of this study was to evaluate the time needed to heal for toothbrush-induced abrasions of the keratinized mucosa of the palate. MATERIAL AND METHODS: In patients without, with mild periodontitis or with periodontitis, gingival abrasion lesions were induced at the keratinized mucosa of the palate by brushing up to 2 minutes. Healing as observed clinically was followed via calibrated digital photographs of the lesion after staining, every 24 hours until the lesion had resolved. In patients without or with only mild periodontitis, the healing time of lesions caused by 30 seconds and 1 minute of brushing was also recorded. RESULTS: Thirty-one participants (11 without or with mild periodontitis, 20 with periodontitis) met the inclusion criteria. In patients without or with mild periodontitis, the lesions induced by brushing for 2 minutes diminished by 48.7% of their original surface area within 24 hours. In patients with periodontitis the respective outcome was 45.4% (P = .87). Abrasions caused by 2 minutes of brushing needed more than 24 hours to heal completely. When decreasing the time exposed to trauma, fewer lesions were visible at baseline and the time needed to heal decreased. The subgroup of smokers was too small to evaluate any effect. CONCLUSION: The longer the exposure time of the keratinized mucosa of the palate to trauma, the more lesions were visible, the larger the abrasions were and the more time they needed to heal completely. More studies are needed to investigate the role of smoking, gingival biotype and to link these findings with gingival recessions. PMID- 29492984 TI - The psychology of social class: How socioeconomic status impacts thought, feelings, and behaviour. AB - Drawing on recent research on the psychology of social class, I argue that the material conditions in which people grow up and live have a lasting impact on their personal and social identities and that this influences both the way they think and feel about their social environment and key aspects of their social behaviour. Relative to middle-class counterparts, lower/working-class individuals are less likely to define themselves in terms of their socioeconomic status and are more likely to have interdependent self-concepts; they are also more inclined to explain social events in situational terms, as a result of having a lower sense of personal control. Working-class people score higher on measures of empathy and are more likely to help others in distress. The widely held view that working-class individuals are more prejudiced towards immigrants and ethnic minorities is shown to be a function of economic threat, in that highly educated people also express prejudice towards these groups when the latter are described as highly educated and therefore pose an economic threat. The fact that middle class norms of independence prevail in universities and prestigious workplaces makes working-class people less likely to apply for positions in such institutions, less likely to be selected and less likely to stay if selected. In other words, social class differences in identity, cognition, feelings, and behaviour make it less likely that working-class individuals can benefit from educational and occupational opportunities to improve their material circumstances. This means that redistributive policies are needed to break the cycle of deprivation that limits opportunities and threatens social cohesion. PMID- 29492985 TI - Radiofrequency exposure assessment of baby surveillance devices in the frequency range 400 MHz-2.45 GHz. PMID- 29492986 TI - Hearing loss among older construction workers: Updated analyses. AB - BACKGROUND: A prior study of this construction worker population found significant noise-associated hearing loss. This follow-up study included a much larger study population and consideration of additional risk factors. METHODS: Data included audiometry, clinical chemistry, personal history, and work history. Qualitative exposure metrics for noise and solvents were developed. Analyses compared construction workers to an internal reference group with lower exposures and an external worker population with low noise exposure. RESULTS: Among participants (n = 19 127) an overall prevalence of hearing loss of 58% was observed, with significantly increased prevalence across all construction trades. Construction workers had significantly increased risk of hearing loss compared to reference populations, with increasing risk by work duration. Noise exposure, solvent exposure, hypertension, and smoking were significant risk factors in multivariate models. CONCLUSIONS: Results support a causal relationship between construction trades work and hearing loss. Prevention should focus on reducing exposure to noise, solvents, and cigarette smoke. PMID- 29492987 TI - Size-dependent superparamagnetic iron oxide nanoparticles dictate interleukin 1beta release from mouse bone marrow-derived macrophages. AB - Superparamagnetic iron oxide nanoparticles (SPIONs) have been widely investigated for their biomedical applications in magnetic resonance imaging, targeting therapy, cell labeling, etc. It has been well documented that macrophages produce interleukin (IL)-1beta via several signaling pathways, such as inflammasome activation in response to particles including silica, asbestos and urea crystals with lipopolysaccharide priming. However, the size and dose effects of SPIONs on macrophages and the mechanisms remain unclear. In this study, we explored the cytotoxicity and mechanisms of the synthesized SPIONs with different size distributions of 30, 80 and 120 nm, and compared their potential capability in inducing IL-1beta release in mouse bone marrow-derived macrophages (BMMs). We found that SPIONs induced IL-1beta release in a size- and dose-dependent manner, in which the smallest SPIONs triggered the highest IL-1beta in BMMs. When cellular uptake of SPIONs was inhibited by the actin polymerization inhibitor, cytochalasin D, SPION-induced IL-1beta release was suppressed in BMMs. Preventing lysosome damage with bafilomycin A1 or CA-074-Me also counteracted SPION-induced IL-1beta release. Moreover, SPION-activated IL-1beta release was also attenuated by reactive oxygen species scavengers, diphenylene iodonium or N-acetylcysteine. Our results elucidated the effects of size and dose on the cytotoxicity and mechanisms of IL-1beta release of SPIONs on macrophages, which facilitate the theoretical and experimental application of SPIONs in biotechnology and biomedicine in the future. PMID- 29492988 TI - Predictors of failure to detect early hepatocellular carcinoma in patients with chronic hepatitis B who received regular surveillance. AB - BACKGROUND: A proportion of chronic hepatitis B (CHB) patients are diagnosed with advanced hepatocellular carcinoma (HCC) despite regular surveillance. AIMS: To determine predictors for HCC detection failure in CHB patients who underwent regular surveillance. METHODS: CHB patients with well-preserved liver function, who underwent ultrasonography and alpha-foetoprotein (AFP) analysis every 6 months, were enrolled. Cox regression analysis was used to identify predictors for detection failure, defined as HCC initially diagnosed at Barcelona Clinic Liver Cancer (BCLC) stage B or C. RESULTS: Of the 4590 CHB patients (mean age, 52.1 years; men, 61.6%), 169 patients were diagnosed with HCC (3.68%) and 35 (20.7%) HCC patients were initially diagnosed with HCC BCLC stage B or C. The cumulative incidence of HCC detection failure was 0.2% at year 1 and 1.3% at year 5. Multivariate analyses indicated that cirrhosis (hazard ratio [HR], 3.078; 95% CI, 1.389-6.821; P = 0.006), AFP levels >=9 ng/mL (HR, 5.235; 95% CI, 2.307 11.957; P = 0.010), and diabetes mellitus (HR, 3.336; 95% CI, 1.341-8.296; P = 0.010) were independent predictors of HCC detection failure. Another model that incorporated liver stiffness (LS) values identified LS values >=11.7 kPa (HR, 11.045; 95% CI, 2.066-59.037; P = 0.005) and AFP levels >=9 ng/mL (HR, 4.802; 95% CI, 1.613-14.297; P = 0.005) as predictors of detection failure. CONCLUSIONS: In CHB patients undergoing regular surveillance with ultrasonography and alpha foetoprotein (AFP) analysis every 6 months, the HCC detection failure rate was not high (0.8% per person; 0.1% per test). However, careful attention should be paid in patients with advanced liver fibrosis (clinical cirrhosis or LS value >11.7 kPa), high AFP levels, or diabetes mellitus, who are prone to surveillance failure. PMID- 29492989 TI - Carvedilol for reducing portal pressure in primary prophylaxis of variceal bleeding: a dose-response study. AB - BACKGROUND: Sequential measurements of hepatic venous pressure gradient (HVPG) are used to assess the haemodynamic response to nonselective betablockers (NSBBs) in patients with portal hypertension. AIMS: To assess the rates of HVPG response to different doses of carvedilol. METHODS: Consecutive patients with cirrhosis undergoing HVPG-guided carvedilol therapy for primary prophylaxis of variceal bleeding between 08/2010 and 05/2015 were retrospectively included. After baseline HVPG measurement, carvedilol 6.25 mg/d was administered and HVPG response (HVPG-decrease >=20% or to <=12 mm Hg) was assessed after 3-4 weeks. In case of nonresponse, carvedilol dose was increased to 12.5 mg/d and a third HVPG measurement was performed after 3-4 weeks. We also assessed HVPG-response rates according to the Baveno VI consensus (HVPG decrease >=10% or to <=12 mm Hg) and changes in systolic arterial pressure (SAP). RESULTS: Seventy-two patients (Child A, 37%; B, 35%; C, 28%) were included. 28 (39%) patients achieved a HVPG-decrease >= 20% with carvedilol 6.25 mg/d and another 10 (14%) with carvedilol 12.5 mg/d. Forty (56%) patients had a HVPG decrease >=10% with carvedilol 6.25 mg/d and 24 (33%) with carvedilol 12.5 mg/d. Thus, in total, a HVPG-response of >=20% and >=10% and was achieved in 38 (53%) and 55 (76%) and of patients respectively. Notably, 6 patients (n = 4 with ascites) did not tolerate an increase to 12.5 mg/d due to hypotension/bradycardia. However, none of the other patients had a SAP < 90 mm Hg at the final HVPG measurement. CONCLUSION: Carvedilol 12.5 mg/d was more effective than 6.25 mg/d in decreasing HVPG in primary prophylaxis. A total of 76% of patients achieved a HVPG-response of >= 10% to carvedilol 12.5 mg/d, however, arterial hypotension might occur, especially in patients with ascites. PMID- 29492990 TI - mQTL-seq and classical mapping implicates the role of an AT-HOOK MOTIF CONTAINING NUCLEAR LOCALIZED (AHL) family gene in Ascochyta blight resistance of chickpea. AB - Ascochyta blight (AB) caused by the fungal pathogen Ascochyta rabiei is a serious foliar disease of chickpea (Cicer arietinum L.). Despite many genetic studies on chickpea-Ascochyta interaction, genome-wide scan of chickpea for the identification of AB-associated quantitative trait loci (QTLs) and their gene(s) has not been accomplished. To elucidate narrow QTLs for AB resistance, here, we report the use of multiple QTL-sequencing approach on 2 sets of extreme AB phenotype bulks derived from Cicer intraspecific and interspecific crosses. Two major QTLs, qABR4.1 and qABR4.2, and a minor QTL, qABR4.3, were identified on assembled chickpea pseudomolecule 4. We narrowed qABR4.1 to a "robust region" at 4.568-4.618 Mb through mapping on a larger intraspecific cross-derived population and comparative analysis. Among 4 genes, the CaAHL18 gene showed higher expression under Ascochyta stress in AB resistant parent suggesting that it is the candidate gene under "robust qABR4.1." Dual-luciferase assay with CaAHL18 polymorphic cis-regulatory sequences showed that allelic variation is associated with higher expression. Thus, our findings on chickpea-Ascochyta interaction have narrowed down AB resistance associated QTLs on chickpea physical map. The narrowed QTLs and gene-associated markers will help in biotechnological and breeding programs for chickpea improvement. PMID- 29492991 TI - Tacrolimus interaction with oral oestrogen in kidney transplant recipients: A case-control study. AB - WHAT IS KNOWN AND OBJECTIVE: Oestrogens could inhibit the metabolism of drugs, such as calcineurin inhibitors, that are substrates for cytochrome P-450 microsomal enzymes. This study assessed the potential tacrolimus interaction with oral conjugated oestrogen in kidney transplant recipients who received conjugated oestrogen as prophylaxis against bleeding, before kidney biopsy. METHODS: In this case-control study, 13 kidney transplant recipients who received oral conjugated oestrogen as prophylaxis against uraemic bleeding before allograft biopsy were considered as cases. Thirteen matched kidney transplant recipients with similar immunosuppressive regimen served as controls. In this study, comparisons were made between the groups regarding daily dose, blood trough concentrations and calculated concentration corrected for dose of tacrolimus at three time points of the study. RESULTS AND DISCUSSION: All patients in the case group received conjugated oestrogen at a dose of 3.75 mg/day for 4.78 +/- 0.83 days. Without any change in tacrolimus dose, the blood concentration of tacrolimus increased during concomitant administration of conjugated oestrogen (from 8.10 +/- 2.85 to 12.35 +/- 4.62 ng/mL; P = .11) and decreased after cessation of conjugated oestrogen (6.07 +/- 2.18 ng/mL; P = .015). The calculated concentration corrected for dose of tacrolimus increased from 127.04 +/- 79.23 to 211.40 +/- 146.38 ngmLmgkg/d after conjugated oestrogen administration (P = .036). Thereafter, it decreased to 108.55 +/- 78.61 ngmLmgkg/d after cessation of oestrogen (P = .003). Only one patient experienced nausea while taking oestrogen without any change in her liver enzymes. WHAT IS NEW AND CONCLUSION: Concomitant administration of oral oestrogen increased tacrolimus blood concentration. Hence, it is necessary to monitor tacrolimus blood levels during concomitant oestrogen therapy and for several days after oestrogen withdrawal. PMID- 29492992 TI - Glaucoma referral refinement in Ireland: managing the sensitivity-specificity paradox in optometric practice. AB - PURPOSE: Glaucoma referral refinement (GRR) has proven a successful demand management strategy for glaucoma suspect cases in the United Kingdom (UK). A GRR clinic was established in Dublin, Ireland to investigate the clinical viability of this pathway outside the UK's National Health Service (NHS) structures, and away from the influence of National Institute for Clinical Excellence (NICE) guidance. METHODS: Glaucoma suspect patients were recruited into the scheme following referral from community optometrists in the greater Dublin area. The GRR exam protocol was designed in consultation with the participating ophthalmology department. The refinement scheme optometrist, trained through apprenticeship style experience at a hospital outpatient clinic, made a tentative management decision after carrying out the GRR exam. The final management decision was made in a 'virtual clinic' by a glaucoma specialist consultant ophthalmologist. RESULTS: Two hundred and twenty-five glaucoma suspect patients were seen in the scheme. After their first GRR visit, 28% were discharged back to their own optometrist, 42% were monitored in the GRR clinic, and 30% were referred to ophthalmology. After this monitoring cohort were further assessed, a total of 38% of the patients seen within the scheme required referral to ophthalmology. Sixteen percent of the total participant group (n = 225) were lost to follow up. Cohen's kappa was used to determine the level of agreement between the scheme optometrist and ophthalmologist. There was substantial agreement, with kappa = 0.63 for the first visit management decisions (n = 225). Agreement increased for subsequent monitoring visits with kappa = 0.85 for second visits (n = 65), and kappa = 0.69 for all management decisions within the scheme (n = 301). We received management outcomes for 44 of the 86 patients referred to ophthalmology. Of these 44, 57% received medical treatment for glaucoma, 34% were monitored without treatment, 2% were discharged, and 7% had comorbidities that were assessed and managed. CONCLUSION: Of the patients seen within the scheme, 62% did not require referral onward to ophthalmology, thus releasing the significant majority of hospital clinic slots that would previously have been required to examine such patients. The high level of inter-professional decision agreement likely reflects the benefits of pre-scheme apprenticeship style training and ongoing hospital clinic participation by the scheme optometrist. The rate of loss to follow up compares favourably with ophthalmology led, hospital based, glaucoma clinics. Nevertheless, the losses indicate that patient education remains a key priority for future planning. PMID- 29492993 TI - Morphology and ultrastructure of the esophagus during the ontogeny of the spider crab Maja brachydactyla (Decapoda, Brachyura, Majidae). AB - The esophagus of the eucrustaceans is known as a short tube that connects the mouth with the stomach but has generally received little attention by the carcinologists, especially during the larval stages. By this reason, the present study is focused on the morphology and ultrastructure of the esophagus in the brachyuran Maja brachydactyla during the larval development and adult stage. The esophagus shows internally four longitudinal folds. The simple columnar epithelium is covered by a thick cuticle. The epithelial cells of the adults are intensively interdigitated and show abundant apical mitochondria and bundles of filamentous structures. The cuticle surface has microspines and mutually exclusive pores. Three muscle layers surrounded by the connective tissue are reported: circular muscles forming a broad continuous band, longitudinal muscle bundles adjacent to the circular muscles, and dilator muscles crossing the connective tissue vertically toward the epithelium. The connective tissue has rosette glands. The esophagus of the larvae have epithelial cells with big vesicles but poorly developed interdigitations and filamentous structures, the cuticle is formed by a procuticle without differentiated exocuticle and endocuticle, the connective layer is thin and the rosette glands are absent. The observed features can be explained by his role in the swallowing of the food. PMID- 29492994 TI - The distribution and heterogeneity of mast cells in tongue from five different avian species. AB - This study was conducted with the aim of determining the morphology, distribution and heterogeneity of mast cells in the tongues of seagull (Larus fuscus), common buzzard (Buteo buteo), goose (Anser anser), white stork (Ciconia ciconia) and Gerze rooster. The study used five samples of tongue material from each of the healthy adult avian species. The samples were fixed in 10% neutral-buffered formalin (NBF) solution, then, after routine tissue follow-up, the samples blocked with paraplast. Cross-sections with 5-6 MUm of thickness were stained with the 0.5% toluidine blue and alcian blue/safranin O (AB/SO). In all five avian species, it was found that the mast cells were in different sizes and round, oval or spindle-shaped based on their place of distribution. Mast cell numbers were determined in stained with toluidine blue, examined *40 objectives in a 1 mm2 area. It was observed that mast cell density in subepithelial lamina propria and microscopic papilla was higher in the tongues of all species. Mast cell distribution and heterogeneity varied through the tongue, and there were more mast cells in the dorsal side of the tongue than the ventral side. The highest amount of mast cells was found in the tongue of the Gerze rooster among all five species. In the tongue cross-sections stained with the combined method of alcian blue/safranin O (AB/SO), the mast cells were stained as AB (+), SO (+) and AB/SO (+) (mixed). PMID- 29492995 TI - Radiological and osteological study of the pelvic limbs in free-ranging capybaras (Hydrochoerus hydrochaeris). AB - This study aimed to describe the radiographic anatomy and osteology and to evaluate angular radiographic measurements-Norberg angle, inclination angle and anteversion angle-of the pelvic limbs in free-ranging capybaras. Twenty cadavers of free-ranging capybaras (Hydrochoerus hydrochaeris), including five adults and 15 subadults, were studied. Ventrodorsal, craniocaudal, dorsoplantar and mediolateral radiographic views of the pelvic limbs were obtained. The radiographic features were described together with bone samples. The hip bone (os coxae), shaped like an isosceles trapezoid, was elongated and narrow with the presence of an oblong obturator foramen, sagittal ilial wing and rectilinear ilial body. The femoral shaft was relatively straight, while the greater trochanter was projected above the femoral head. No sesamoid bones of the gastrocnemius and popliteus muscles were observed radiographically or for those animals used in gross macroscopy. The fibula was located lateral and parallel to the tibia. Eight tarsal bones, four metatarsal bones and three digits were identified. The mean radiographic measurements included Norberg angle of 125.9 degrees ; respective angles of femoral inclination by the Hauptman B and Tomlinson methods of 139.9 and 141 degrees ; anteversion angle of the femoral head and neck of 29.80 degrees . The bones of the pelvic limbs in capybaras have several anatomical characters and radiological features that are shared with members of the caviomorph superfamily Cavioidea. The radiographic angles measured in this study help characterize the functional morphology of this species. PMID- 29492996 TI - Oligodendrocyte morphology in the developing brain of the African giant rat (Cricetomys gambianus, Waterhouse): Histology, immunohistochemistry and electron microscopy. AB - Oligodendrocyte and myelin-related studies have been pivotal in understanding disruption of central nervous system (CNS) myelin through injury, toxicological, pathological degeneration or genetic intervention. The African giant rat (AGR) has been postulated as an indigenous wild-type model within the African context. This work thus describes oligodendrocyte morphologies and myelin components of the developing African giant rat brain using histological, immunohistochemical and ultrastructural techniques. Five types, precursor-progenitor oligodendrocytes, pre-oligodendrocytes, immature oligodendrocytes, mature non myelinating oligodendrocytes and mature myelinating oligodendrocytes, were identified. The first four types were observed in neonates while juvenile and adult AGR had predominantly mature myelinating oligodendrocytes with evidence of myelin sheath deposition. All cell types identified showed positive CNPase positive immunosignalling across all age groups. This suggests CNPase as a suitable, sensitive and reliable biomarker for studying CNS neurodegenerative/demyelinating disorders in the AGR. This baseline study has given detailed insight into the morphology of oligodendrocytes and myelin in the AGR. It may be useful for anatomical studies and detection of alterations in neurocellular profile of oligodendrocytes and myelin in the AGR in real-life or in experimental models. PMID- 29492997 TI - MUFOLD-SS: New deep inception-inside-inception networks for protein secondary structure prediction. AB - Protein secondary structure prediction can provide important information for protein 3D structure prediction and protein functions. Deep learning offers a new opportunity to significantly improve prediction accuracy. In this article, a new deep neural network architecture, named the Deep inception-inside-inception (Deep3I) network, is proposed for protein secondary structure prediction and implemented as a software tool MUFOLD-SS. The input to MUFOLD-SS is a carefully designed feature matrix corresponding to the primary amino acid sequence of a protein, which consists of a rich set of information derived from individual amino acid, as well as the context of the protein sequence. Specifically, the feature matrix is a composition of physio-chemical properties of amino acids, PSI BLAST profile, and HHBlits profile. MUFOLD-SS is composed of a sequence of nested inception modules and maps the input matrix to either eight states or three states of secondary structures. The architecture of MUFOLD-SS enables effective processing of local and global interactions between amino acids in making accurate prediction. In extensive experiments on multiple datasets, MUFOLD-SS outperformed the best existing methods and other deep neural networks significantly. MUFold-SS can be downloaded from http://dslsrv8.cs.missouri.edu/~cf797/MUFoldSS/download.html. PMID- 29492998 TI - Adverse outcome pathway networks II: Network analytics. AB - Toxicological responses to stressors are more complex than the simple one biological-perturbation to one-adverse-outcome model portrayed by individual adverse outcome pathways (AOPs). Consequently, the AOP framework was designed to facilitate de facto development of AOP networks that can aid in the understanding and prediction of pleiotropic and interactive effects more common to environmentally realistic, complex exposure scenarios. The present study introduces nascent concepts related to the qualitative analysis of AOP networks. First, graph theory-based approaches for identifying important topological features are illustrated using 2 example AOP networks derived from existing AOP descriptions. Second, considerations for identifying the most significant path(s) through an AOP network from either a biological or risk assessment perspective are described. Finally, approaches for identifying interactions among AOPs that may result in additive, synergistic, or antagonistic responses (or previously undefined emergent patterns of response) are introduced. Along with a companion article (part I), these concepts set the stage for the development of tools and case studies that will facilitate more rigorous analysis of AOP networks, and the utility of AOP network-based predictions, for use in research and regulatory decision-making. The present study addresses one of the major themes identified through a Society of Environmental Toxicology and Chemistry Horizon Scanning effort focused on advancing the AOP framework. Environ Toxicol Chem 2018;37:1734 1748. (c) 2018 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America. PMID- 29493000 TI - Cartilage cavity-an MRI marker of cartilage lesions in knee OA with Data from CCBR, OAI, and PROOF. AB - PURPOSE: We introduce the quantitative, continuous marker cartilage cavity that quantifies cartilage lesions by the total lesion volume. The aim was to quantify small lesions as well as large, full-depth lesions. METHODS: We included 315 knees from the Center for Clinical and Basic Research (CCBR), 972 knees from the Osteoarthritis Initiative (OAI), and 791 knees from the Prevention of OA in Overweight Females (PROOF) cohorts. In a subset, we digitally inserted artificial lesions. Each knee MRI was segmented using the knee imaging quantification (KIQ) framework. We quantified cartilage mean thickness and cavity from high-resolution cartilage thickness maps. Finally, we quantified lesion volume by the gradient peak method (GPM). RESULTS: Scan-rescan precision for cartilage cavity was 7.1%/3.0%. The cartilage cavity accuracy on the artificial lesions was determined as linear correlation at 0.88 with an average 8% under-estimation of lesion volume. Cavity and degree of radiographic osteoarthritis (ROA) correlated for all compartments (Spearman's rho between 0.14-0.56, P < 0.001). Cavity had modest correlations to whole-organ magnetic resonance imaging score (WORMS) cartilage lesion scores but strong correlations with Boston-Leeds osteoarthritis knee score (BLOKS)/MRI osteoarthritis knee score (MOAKS) scores in most compartments (rho between 0.08-0.65, P < 0.001). Cavity correlated with WOMAC pain for all tibio femoral compartments in OAI (rho between 0.19-0.25, P < 0.001) and most compartments in PROOF. Comparing with the GPM estimate, cavity was more precise, more accurate, and correlated stronger with ROA, lesion scores, and pain levels. CONCLUSION: The strong correlations with ROA, radiologist lesion scores, and pain demonstrated that cavity captured OA and lesion features. Thereby, it may be appropriate for quantification of cartilage surface irregularity. PMID- 29493001 TI - Adapting the bioblitz to meet conservation needs. AB - When conservation strategies require new, field-based information, practitioners must find the best ways to rapidly deliver high-quality survey data. To address this challenge, several rapid-assessment approaches have been developed since the early 1990s. These typically involve large areas, take many months to complete, and are not appropriate when conservation-relevant survey data are urgently needed for a specific locale. In contrast, bioblitzes are designed for quick collection of site-specific survey data. Although bioblitzes are commonly used to achieve educational or public-engagement goals, conservation practitioners are increasingly using a modified bioblitz approach to generate conservation-relevant data while simultaneously enhancing research capacity and building working partnerships focused on conservation concerns. We term these modified events expert bioblitzes. Several expert bioblitzes have taken place on lands of conservation concern in Southern California and have involved collaborative efforts of government agencies, nonprofit organizations, botanic gardens, museums, and universities. The results of expert bioblitzes directly informed on the-ground conservation and decision-making; increased capacity for rapid deployment of expert bioblitzes in the future; and fostered collaboration and communication among taxonomically and institutionally diverse experts. As research and conservation funding becomes increasingly scarce, expert bioblitzes can play an increasingly important role in biodiversity conservation. PMID- 29493002 TI - A general algorithm for compensation of trajectory errors: Application to radial imaging. AB - PURPOSE: To reconstruct artifact-free images from measured k-space data, when the actual k-space trajectory deviates from the nominal trajectory due to gradient imperfections. METHODS: Trajectory errors arising from eddy currents and gradient delays introduce phase inconsistencies in several fast scanning MR pulse sequences, resulting in image artifacts. The proposed algorithm provides a novel framework to compensate for this phase distortion. The algorithm relies on the construction of a multi-block Hankel matrix, where each block is constructed from k-space segments with the same phase distortion. In the presence of spatially smooth phase distortions between the segments, the complete block-Hankel matrix is known to be highly low-rank. Since each k-space segment is only acquiring part of the k-space data, the reconstruction of the phase compensated image from their partially parallel measurements is posed as a structured low-rank matrix optimization problem, assuming the coil sensitivities to be known. RESULTS: The proposed formulation is tested on radial acquisitions in several settings including partial Fourier and golden-angle acquisitions. The experiments demonstrate the ability of the algorithm to successfully remove the artifacts arising from the trajectory errors, without the need for trajectory or phase calibration. The quality of the reconstruction was comparable to corrections achieved using the Trajectory Auto-Corrected Image Reconstruction (TrACR) for radial acquisitions. CONCLUSION: The proposed method provides a general framework for the recovery of artifact-free images from radial trajectories without the need for trajectory calibration. PMID- 29493003 TI - Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) related overgrowth spectrum: A brief report. AB - A patient with extensive multisystem overgrowth caused by a somatic gain of function PIK3CA-mutation is described. This case is an example of the clinical diversity of the PIK3CA-Related Overgrowth Spectrum (PROS) as the patient had overlapping features of Congenital Lipomatous Overgrowth Vascular malformations Epidermal nevi and Skeletal abnormalities (CLOVES) syndrome and Megalencephaly Capillary malformation Polymicrogyria (MCAP) syndrome and underlines the utility of this umbrella term. PMID- 29493004 TI - 3D adiabatic T1rho prepared ultrashort echo time cones sequence for whole knee imaging. AB - PURPOSE: To develop a 3D adiabatic T1rho prepared ultrashort echo time cones (3D AdiabT1rho UTE-Cones) sequence for whole knee imaging on a clinical 3T scanner. METHODS: A train of adiabatic full passage pulses were used for spin locking, followed by time-efficient multispoke UTE acquisition to detect signals from both short and long T2 tissues in the whole knee joint. A modified signal model was proposed for multispoke UTE data fitting. The feasibility of this 3D AdiabT1rho UTE-Cones technique was demonstrated through numerical simulation, phantom, and ex vivo knee sample studies. The 3D AdiabT1rho UTE-Cones technique was then applied to 6 in vivo knee joints of healthy volunteers to measure T1rho values of quadriceps tendon, patellar tendon, anterior cruciate ligament (ACL), posterior cruciate ligament (PCL), meniscus, patellar cartilage, and muscle. RESULTS: Numerical simulation, phantom and ex vivo knee sample studies demonstrated the feasibility of whole knee imaging using the proposed multispoke 3D AdiabT1rho UTE Cones sequence. The healthy volunteer knee study demonstrated an averaged T1rho of 13.9 +/- 0.7 ms for the quadriceps tendon, 9.7 +/- 0.8 ms for the patellar tendon, 34.9 +/- 2.8 ms for the ACL, 21.6 +/- 1.4 ms for the PCL, 22.5 +/- 1.9 ms for the meniscus, 44.5 +/- 2.4 ms for the patellar cartilage, and 43.2 +/- 1.1 ms for the muscle. CONCLUSION: The 3D AdiabT1rho UTE-Cones sequence allows volumetric T1rho assessment of both short and long T2 tissues in the knee joint on a clinical 3T scanner. PMID- 29493006 TI - Low pressure-induced secondary structure transitions of regenerated silk fibroin in its wet film studied by time-resolved infrared spectroscopy. AB - The secondary structure transitions of regenerated silk fibroin (RSF) under different external perturbations have been studied extensively, except for pressure. In this work, time-resolved infrared spectroscopy with the attenuated total reflectance (ATR) accessory was employed to follow the secondary structure transitions of RSF in its wet film under low pressure. It has been found that pressure alone is favorable only to the formation of beta-sheet structure. Under constant pressure there is an optimum amount of D2 O in the wet film (D2 O : film = 2:1) so as to provide the optimal condition for the reorganization of the secondary structure and to have the largest formation of beta-sheet structure. Under constant amount of D2 O and constant pressure, the secondary structure transitions of RSF in its wet film can be divided into three stages along with time. In the first stage, random coil, alpha-helix, and beta-turn were quickly transformed into beta-sheet. In the second stage, random coil and beta-turn were relatively slowly transformed into beta-sheet and alpha-helix, and the content of alpha-helix was recovered to the value prior to the application of pressure. In the third and final stage, no measurable changes can be found for each secondary structure. This study may be helpful to understand the secondary structure changes of silk fibroin in silkworm's glands under hydrostatic pressure. PMID- 29493005 TI - Use of topical therapies for pediatric psoriasis: A systematic review. AB - Psoriasis is one of the most common chronic skin diseases, affecting 1%-3% of the general population. It can have a significant negative impact on a patient's quality of life, and in approximately 30% of patients first symptoms can be traced back to childhood. We have performed a comprehensive literature search using the MEDLINE database in order to ascertain the efficacy and adverse reactions of topical treatments in pediatric psoriasis. A total of 13 relevant articles were identified on the following topical agents: corticosteroids, calcineurin inhibitors, vitamin D analogs, and dithranol. Corticosteroids achieved clearance in 72.7% of patients. Calcitriol lead to a 57.2%-100% mean improvement in severity, and calcipotriol to 52%-64%. Combination of calcipotriol and corticosteroids achieved an improvement in mean severity ranging between 32.1% and 80%. Treatment with tacrolimus lead to an >50% improvement. Finally, short contact dithranol lead to a variable response in clearance between different studies, ranging between 3.7% and 81%. No serious adverse reactions were documented, the most common local reaction being irritation. Pediatric psoriasis is a common and challenging condition with no easy and definitive solution. Topical agents are safe, easy to use, readily available and cheap. However, they need to be applied repeatedly, may cause skin irritation, and can be messy. Based on the results presented above, we recommend utilizing all the available topical options before escalating to systemic treatments. PMID- 29493007 TI - Impact of cyclosporine-A concentration in T-cell replete haploidentical allogeneic stem cell transplantation. AB - This paper aims to study whether cyclosporine-A (CSA) levels have an impact on the clinical outcome of patients with T-cell replete haploidentical allogeneic hematopoietic stem cell transplantation (allo-HSCT). We analyzed 140 consecutive patients who had been given T-cell replete haploidentical allo-HSCT in our institute to assess the effect of CSA concentration in the early stages of allo HSCT on clinical outcomes, such as hematopoietic recovery, acute graft vs host disease (aGVHD), infection, disease-free survival (DFS), and overall survival (OS). The median concentrations of CSA in the blood in the 1st, 2nd, 3rd, and 4th week after allo-HSCT were 218, 235, 263, and 270 ng/mL, respectively. Additionally, 46%, 40%, 27%, and 18% of the patients had CSA blood levels below 200 ng/mL during those weeks. In total, 39 patients developed aGVHD (grade II IV), for a cumulative incidence of 27.8%, at a median of 32 days. Patients having a low CSA concentration (below 200 ng/mL) in the 3rd week had a higher cumulative incidence of grade II-IV aGVHD (P = .02). In addition, multivariate logistic regression analysis showed that low CSA concentration (below 200 ng/mL) in the 3rd week was an independent risk factor of grade II-IV aGVHD (P = .02; odds ratio = 2.66; 95% CI, 1.15-6.17). However, CSA levels during the first 4 weeks did not have a significant impact on the patients' hematopoietic recovery, infection, DFS, and OS. Our data indicated that adequate management of CSA levels during the peri-engraftment period might improve clinical outcomes for those with T-cell replete haploidentical allo-HSCT. PMID- 29493008 TI - Sutureless approach with vein grafts and mesenchymal stem cells in primary nerve repair: Functional and immunohistological results. AB - PURPOSE: The aim of this study was to define a sutureless peripheral nerve repair technique with a vein graft and bone marrow-derived stem cells (BMSC) and compare it to epineural repair. MATERIALS AND METHODS: Thirty Wistar Albino rats were divided into five groups evenly. In the control group (C), epineural repair was performed. In the SV (suture + vein) and MSV (BMSC + suture + vein) groups, epineural repair was wrapped with a vein graft. In the V (vein) and MV (vein + BMSC) groups, sutureless repair using a vein graft was performed by taking sutures away from the regeneration site. Rats were evaluated with pinprick, toe spread tests and sciatic nerve index (SFI) at 4th, 8th, and 12th weeks. They were sacrificed at 12th week, repair sites were harvested and evaluated immunohistochemically. RESULTS: There was no difference in pinprick and toe spread tests between the groups at 12th week. The mean SFI was -76.5 +/- 3.7, 65.2 +/- 11.7, -46.2 +/- 19.4, -68.8 +/- 9.8, -56 +/- 8.8 in the C, SV, MSV, V, MV groups, respectively. The MSV group showed significantly the best SFI results (P < .05). NF-H immunostaining scores were as C; 1 +/- 0.18, SV; 2.5 +/- 0.36, MSV; 4 +/- 0.49, V; 1.56 +/- 0.54, MV; 3 +/- 0.39, whereas GAP-43 scores were as C; 1 +/- 0.31, SV; 2.66 +/- 0.56, MSV; 4.50 +/- 0.23, V; 2 +/- 0.23, MV; 3 +/- 0.6. The best nerve regeneration according to immunostaining results was observed in the MSV group (P < .05). The mean fibrosis area was 221.5 +/- 25.9, 101.6 +/- 7.1, 121.3 +/- 18.8, 150.3 +/- 12.1, 152.4 +/- 11.8 MUm2 in the above groups, respectively. SV and MSV groups showed the significantly less fibrosis area (P < .05). CONCLUSION: Epineural suture repair combined with vein wrapping and BMSCs (MSV) showed the best SFI, GAP-43, and NF-H immunostaining results. PMID- 29493009 TI - Cranial irradiation increases tumor growth in experimental breast cancer brain metastasis. AB - Whole-brain radiotherapy is the standard of care for patients with breast cancer with multiple brain metastases and, although this treatment has been essential in the management of existing brain tumors, there are many known negative consequences associated with the irradiation of normal brain tissue. In our study, we used in vivo magnetic resonance imaging analysis to investigate the influence of radiotherapy-induced damage of healthy brain on the arrest and growth of metastatic breast cancer cells in a mouse model of breast cancer brain metastasis. We observed that irradiated, but otherwise healthy, neural tissue had an increased propensity to support metastatic growth compared with never irradiated controls. The elucidation of the impact of irradiation on normal neural tissue could have implications in clinical patient management, particularly in patients with residual systemic disease or with residual radio resistant brain cancer. PMID- 29493010 TI - Genotypic effect of a mutation of the MYBPC3 gene and two phenotypes with different patterns of inheritance. AB - BACKGROUND: MYBPC3 mutations have been described in dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). A mutation, c.3373G>A, has been reported to cause autosomal recessive form of HCM. Here, we report that this mutation can cause autosomal dominant form of DCM. METHODS: Next-generation sequencing using targeted panel of a total of 23 candidate genes and following Sanger sequencing was applied to detect causal mutations of DCM. Computational analyses were also performed using available software tools. In silico structural and functional analyses including protein modeling and prediction were done for the mutated MYBPC3 protein. RESULTS AND CONCLUSION: Targeted sequencing showed one variant c.3373G>A (p.Val1125Met) in the studied family following autosomal dominant inheritance. Computational programs predicted a high score of pathogenicity. Secondary structure of the region surrounding p.Val1125 was changed to a shortened beta-strand based on prediction of I-TASSER and Phyre2 servers with high confidence value for the mutation. cMyBP-C protein was modeled to 3dmkA. Our findings suggest that one single mutation of MYBPC3 may have different effects on the cellular mechanisms based of its zygosity. Various factors might be considered for explaining this phenomenon. This gene may have an important role in Iranian DCM and HCM patients. PMID- 29493011 TI - Synthesis of 3 H, 13 C2 , 2 H414 C-SCH 430765 and 35 S-SCH 500946, potent and selective inhibitors of the NPY5 receptor. AB - SCH 430765 and SCH 500496 are potent and selective antagonists of the NPY5 receptor. NPY5 receptor antagonists have the potential for the treatment of obesity. [35 S]SCH 500946 was prepared for a competition binding assay which led to the identification of SCH 430765. Three distinct isotopically labelled forms of SCH 430765 were synthesized. [3 H]SCH 430765 was prepared for a preliminary absorption, distribution, metabolism and excretion data evaluation of the compound and [14 C]SCH 430765 for more definitive absorption, distribution, metabolism and excretion data work. In addition, [13 C2 ,2 H4 ]SCH 430765 was prepared as an internal standard for a LC-MS bioanalytical method. The paper discusses the synthesis of 3 isotopically labelled forms of SCH 430765 and [35 S]SCH 500946. PMID- 29493013 TI - Carcass characteristics, chemical and fatty acid composition and oxidative stability of meat from broiler chickens fed black cumin (Nigella sativa) seeds. AB - A study was conducted to investigate the dietary supplementation of black cumin seeds (BCS) on carcass characteristics, chemical and fatty acid (FA) composition and antioxidant properties of thigh and breast meat of broiler chickens at 42 days of age. Three hundred sixty 1-day-old broiler chickens were allocated to five dietary treatment groups (each group containing eight replicate pens with each pen containing nine broiler chickens): basal diet (control; CON), CON + 0.05 g/kg of bacitracin methylene disalicylate (AB), CON + 5 g/kg of BCS (low dose of BCS), CON + 10 g/kg of BCS (medium dose of BCS) and CON + 20 g/kg of BCS (high dose of BCS). Weight (g) of slaughtered birds (p = .03), hot carcass (p = .007), breast (p = .03), thigh (p < .001), wing (p = .06), neck (p = .01), liver (p = .09), abdominal fat (p = .01) and total edible parts (p = .01) increased or tended to increase due to BCS supplementation compared with the CON. The concentrations of dry matter, crude protein and ether extract in chicken thigh and breast meat increased (p = .038 to <.001) with increasing doses of BCS in diets. The ferric reducing antioxidant activity in blood and meat increased linearly with increasing doses of BCS in the diets. However, peroxide values in meat were not affected by BCS and AB on both days 1 and 7 of storage at 4 degrees C. Supplementation of BCS increased the concentrations of C14:1, C18:3n-6, C20:1, C20:2 FA and PUFA linearly (p < .05) and tended to increase (p = .098) the concentration of C18:2cis linearly. However, the concentrations of C16:0 and C16:1 FA decreased linearly with increasing doses of BCS in the diets. In conclusion, dietary supplementation of BCS at 20 g/kg diet may improve slaughter body weight, beneficial FA concentrations and antioxidant properties of broiler chicken meat. PMID- 29493012 TI - Aging-associated changes in hippocampal glycogen metabolism in mice. Evidence for and against astrocyte-to-neuron lactate shuttle. AB - Lactate derived from astrocytic glycogen has been shown to support memory formation in hippocampi of young animals, inhibiting it in old animals. Here we show, using quantitative mass spectrometry-based proteomics, immunofluorescence, and qPCR that aging is associated with an increase of glycogen metabolism enzymes concentration and shift in their localization from astrocytes to neurons. These changes are accompanied with reorganization of hippocampal energy metabolism which is manifested by elevated capacity of aging neurons to oxidize glucose in glycolysis and mitochondria, and decreased ability for fatty acids utilization. Our observations suggest that astrocyte-to-neuron lactate shuttle may operate in young hippocampi, however, during aging neurons become independent on astrocytic lactate and the metabolic crosstalk between the brain's cells is disrupted. PMID- 29493014 TI - Effects of cutbacks on motivating factors among nurses in primary health care. AB - BACKGROUND: When financial cuts are made, staff redundancies and reorganisation in the healthcare system often follow. Little is known how such cutbacks affect work motivation of nurses in primary health care. AIM: Examine the effects of cutbacks on motivating factors among nurses in primary health care. METHODS: A phenomenological approach involving a purposeful sample of ten nurses in primary health care. Average age 44. RESULTS: The participants identified the job itself, autonomy, independence, good communication with co-workers, and the potential for professional training, learning and development as the main internal motivational factors related to their work. However, increased stress and uncertainty, growing fatigue and understaffing were starting to have a negative impact on these internal motivational factors. Moreover, reduced opportunities for professional training and development had negative effects on the participants. Many saw these opportunities as a vital part of recognition for their job performance. Regarding external motivation, the factors identified were job security, salaries and rewards, and interaction with management. The participants expressed their interest in more consultation with managers and most preferred an increased flow of information from managers to staff members during cutbacks. Salaries, professional training opportunities and appreciation were rewards named by participants for a job well done. All agreed that salaries are stronger motivational factors than before cutbacks. CONCLUSIONS: In the case of cutbacks, nursing managers should increase consultations with staff and make sure that nurses maintain their independence, autonomy, opportunities for professional training as well as appreciation for job well done. PMID- 29493015 TI - Multidisciplinary or autonomous discipline? PMID- 29493016 TI - Fluorescein as a Visible-Light-Induced Oxidase Mimic for Signal-Amplified Colorimetric Assay of Carboxylesterase by an Enzymatic Cascade Reaction. AB - We have found that fluorescein possesses high visible-light-induced oxidase mimetic activity and could transform colorless 3,3',5,5'-tetramethylbenzidine (TMB) into blue oxidized TMB (oxTMB) without unstable and destructive H2 O2 under visible-light illumination. Instead, fluorescein uses oxygen as a mild and green electron acceptor, and its activity can be easily controlled by the switching "on/off" of visible light. In addition, the visible-light-induced catalytic mechanism was elucidated in detail and, as the main reactive species h+ and O2.- accounted for TMB oxidation. Based on the fact that fluorescein diacetate (FDA) possessed no activity and generated active fluorescein in situ in the presence of carboxylesterase (CaE), a signal-amplified sensing platform through a cascade reaction for CaE detection was constructed. Our proposed sensing system displayed excellent analytical performance for the detection of CaE in a wide linear range from 0.040 to 20 U L-1 with a low detection limit of 0.013 U L-1 . This work not only changes the conventional concept that fluorescein is generally considered to be photocatalytically inert, but also provides a novel sensing strategy by tailoring the enzyme mimetic activity of fluorescein derivatives with analyte. PMID- 29493018 TI - Surgery without papilla incision: tunneling flap procedures in plastic periodontal and implant surgery. AB - Diverse clinical advancements, together with some relevant technical innovations, have led to an increase in popularity of tunneling flap procedures in plastic periodontal and implant surgery in the recent past. This trend is further promoted by the fact that these techniques have lately been introduced to a considerably expanded range of indications. While originally described for the treatment of gingival recession-type defects, tunneling flap procedures may now be applied successfully in a variety of clinical situations in which augmentation of the soft tissues is indicated in the esthetic zone. Potential clinical scenarios include surgical thickening of thin buccal gingiva or peri-implant mucosa, alveolar ridge/socket preservation and implant second-stage surgery, as well as soft-tissue ridge augmentation or pontic site development. In this way, tunneling flap procedures developed from a technique, originally merely intended for surgical root coverage, into a capacious surgical conception in plastic periodontal and implant surgery. The purpose of this article is to provide a comprehensive overview on tunneling flap procedures, to introduce the successive development of the approach along with underlying ideas on surgical wound healing and to present contemporary clinical scenarios in step-by-step photograph illustrated sequences, which aim to provide clinicians with guidance to help them integrate tunneling flap procedures into their daily clinical routine. PMID- 29493017 TI - Plaque-dependent morphological and electrophysiological heterogeneity of microglia in an Alzheimer's disease mouse model. AB - Microglia, the central nervous system resident innate immune cells, cluster around Abeta plaques in Alzheimer's disease (AD). The activation phenotype of these plaque-associated microglial cells, and their differences to microglia distant to Abeta plaques, are incompletely understood. We used novel three dimensional cell analysis software to comprehensively analyze the morphological properties of microglia in the TgCRND8 mouse model of AD in spatial relation to Abeta plaques. We found strong morphological changes exclusively in plaque associated microglia, whereas plaque-distant microglia showed only minor changes. In addition, patch-clamp recordings of microglia in acute cerebral slices of TgCRND8 mice revealed increased K+ currents in plaque-associated but not plaque distant microglia. Within the subgroup of plaque-associated microglia, two different current profiles were detected. One subset of cells displayed only increased inward currents, while a second subset showed both increased inward and outward currents, implicating that the plaque microenvironment differentially impacts microglial ion channel expression. Using pharmacological channel blockers, multiplex single-cell PCR analysis and RNA fluorescence in situ hybridization, we identified Kir and Kv channel types contributing to the in- and outward K+ conductance in plaque-associated microglia. In summary, we have identified a previously unrecognized level of morphological and electrophysiological heterogeneity of microglia in relation to amyloid plaques, suggesting that microglia may display multiple activation states in AD. PMID- 29493019 TI - Blood donation barriers and facilitators of Sub-Saharan African migrants and minorities in Western high-income countries: a systematic review of the literature. AB - OBJECTIVES: The present study aimed to gain more insight into, and summarise, blood donation determinants among migrants or minorities of Sub-Saharan heritage by systematically reviewing the current literature. BACKGROUND: Sub-Saharan Africans are under-represented in the blood donor population in Western high income countries. This causes a lack of specific blood types for transfusions and prevention of alloimmunisation among Sub-Saharan African patients. METHODS/MATERIALS: Medline, EMBASE, PsycINFO and BIOSIS were searched for relevant empirical studies that focused on barriers and facilitators of blood donation among Sub-Saharan Africans in Western countries until 22 June 2017. Of the 679 articles screened by title and abstract, 152 were subsequently screened by full text. Paired reviewers independently assessed the studies based on predefined eligibility and quality criteria. RESULTS: Of the 31 included studies, 24 used quantitative and 7 used qualitative research methods. Target cohorts varied from Black African Americans and refugees from Sub-Sahara Africa to specific Sub-Saharan migrant groups such as Comorians or Ethiopians. Main recurring barriers for Sub-Saharan Africans were haemoglobin deferral, fear of needles and pain, social exclusion, lack of awareness, negative attitudes and accessibility problems. Important recurring facilitators for Sub-Saharan Africans were altruism, free health checks and specific recruitment and awareness-raising campaigns. CONCLUSION: The findings of this review can be used as a starting point to develop recruitment and retention strategies for Sub-Saharan African persons. Further research is needed to gain more insight in the role of these determinants in specific contexts as socioeconomic features, personal histories and host country regulations may differ per country. PMID- 29493020 TI - Effects of zinc oxide nanoparticles on the egg quality, immune response, zinc retention, and blood parameters of laying hens in the late phase of production. AB - The objective of this study was to evaluate the effects of dietary supplementation with zinc oxide nanoparticles (ZnO-NPs) on the performance, egg quality, Zn retention, immunity responses, superoxide dismutase activity (SOD), egg malondialdehyde (MDA) content, and serum parameters in laying hens in the late phase of production. A total of 288 laying hens at 64 weeks of age were randomly assigned to 4 treatments with 6 replicates, and 12 birds within each group. Experimental diets included a corn-soybean meal-based diet (without Zn supplementation) and a basal diet supplemented with 80 mg/kg of Zn-oxide, ZnO NPs, and Zn-methionine. The results indicated that egg production and egg mass were significantly higher in the Zn-methionine and ZnO-NPs groups (p < .05). Also, eggshell thickness and shell strength increased in the ZnO-NPs group as compared with the other groups (p < .05). Moreover, Zn supplementation decreased egg loss (p < .05). There were significant differences among treatments in Zn deposition in tibiotarsus, liver, pancreas, eggs, and excreta (p < .01). Antibody titre, heterophil (%(, and phytohemagglutinin (PHA) were significantly higher in birds fed with Zn-supplemented diets (p < .05). In treatments supplemented with ZnO-NPs and Zn-methionine, the SOD activity in the liver, pancreas, and plasma was greater as compared with the other treatments (p < .05). The MDA content in eggs was significantly reduced in groups supplemented with Zn (p < .01). Moreover, dietary Zn supplementation significantly affected serum total protein, albumin, glucose, alkaline phosphatase activity, carbonic anhydrase activity, and Zn level (p < .05). In conclusion, this study demonstrated that dietary supplementation with ZnO-NPs can improve the performance of laying hens. Therefore, ZnO-NPs can enhance zinc absorption in the intestine of aged layers and can be a more suitable source of zinc than regular Zn-oxide in diets. PMID- 29493021 TI - Simplified procedures to treat periodontal intraosseous defects in esthetic areas. AB - Successful treatment of deep intraosseous defects in esthetic areas implies clinical improvement of the lesion consistent with long-term tooth survival as well as the preservation (or improvement) of esthetics. It is hoped that such treatment end points may be reached through procedures (which we have termed as 'simplified') that, on the one hand can be easily and successfully applied by the majority of clinicians, and, on the other hand, are well tolerated by patients in terms of postsurgical pain and discomfort, adverse events and cost. In this review, we describe the technical aspects of the simplified procedures currently available (i.e. nonsurgical therapy and the single flap approach and its variants). Also, we analyze the effect of such procedures on clinical parameters and patient-centered outcomes. While nonsurgical therapy seems to be appropriate per se in lesions with a probing depth of < 7 mm and a limited intraosseous component, severe intraosseous defects can be successfully treated using simplified surgical procedures. Overall, data support the effectiveness of simplified surgical procedures and indicate that they result in minimal esthetic impairment (i.e. post-treatment recession) and a more tolerable postoperative course when compared with conventional surgical (double flap) approaches. In particular, the single flap approach was shown to be at least as effective as traditional papilla-preservation techniques when evaluated either as a stand alone protocol or in combination with regenerative devices. Bioactive agents have shown the most appropriate regenerative technology when used in association with simplified surgical procedures. PMID- 29493022 TI - Effects of mannan-oligosaccharides and Lactobacillus acidophilus supplementation on growth performance, nutrient utilization and faecal characteristics in Murrah buffalo calves. AB - A study of 120 days was undertaken to ascertain the effect of mannan oligosaccharides (MOS) and Lactobacillus acidophilus supplementation on growth performance, nutrient utilization and faecal characteristics in Murrah buffalo calves. Twenty Murrah buffalo calves of 5-7 days old and 31 +/- 2.0 kg of body weight (BW) were randomly assigned into four groups. Group I served as the control (CON) in which only basal diet (concentrate mixture and green fodder) was provided, without any supplementation. Mannan-oligosaccharides at 4 g/calf/day were supplemented as prebiotic to Group II (PRE), whereas Group III (PRO) received Lactobacillus acidophilus in the form of fermented milk as probiotic at 200 ml/calf/day having 108 CFU/ml and Group IV (SYN) was supplemented with both MOS and Lactobacillus acidophilus as synbiotic at similar dose. Final BW (kg), dry matter intake, average daily gain, feed conversion efficiency and structural growth measurements were improved (p < .05) in the treatment groups compared to control. Digestibility of neutral detergent fibre was higher (p < .05) in SYN followed by PRE and PRO than control. The faecal lactobacilli and bifidobacterium population was higher (p < .05) in all the supplemented groups with a concomitant reduction in faecal coliform count as compared to control. Faecal ammonia, lactate and pH were also altered favourably (p < .05) in all the supplemented groups as compared to CON. The faecal volatile fatty acids were higher (p < .05) in PRE, PRO and SYN group than CON. The incorporation of MOS and Lactobacillus acidophilus in diet either individually or in combination as synbiotic has the potential to improve the performance and faecal characteristics in Murrah buffalo calves; however, the observed responses among the treatment groups were more evident in the synbiotic fed group compared to individual supplementation of MOS and Lactobacillus acidophilus. PMID- 29493024 TI - Esthetic evaluation and patient-centered outcomes in single-tooth implant rehabilitation in the esthetic area. AB - Criteria for successful implants, in the rehabilitation of a single missing tooth in the esthetic area, should be determined by composite outcomes, including functional and esthetic aspects of soft tissues and the reconstruction, as well as patient-reported outcomes. This paper focuses on current methods in esthetic assessment and patient-centered/reported outcomes in single-tooth implant rehabilitation in the esthetic area. The relationship between subjective, patient based esthetic evaluations and objective, professional-based esthetic evaluations is reviewed. In spite of increasing interest in the assessment of 'success' in implant dentistry, it is not yet possible to provide evidence-based conclusions because of the lack of consensus on a universal implant-supported crown esthetic index. There is also a need to standardize reporting of patient-centered outcomes in partially edentulous patients treated with implants. PMID- 29493023 TI - Conjugation of Indoles to Antibodies through a Novel Self-Immolating Linker. AB - A novel strategy to attach indole-containing payloads to antibodies through a carbamate moiety and a self-immolating, disulfide-based linker is described. This new strategy was employed to connect a selective estrogen receptor down-regulator (SERD) to various antibodies in a site-selective manner. The resulting conjugates displayed potent, antigen-dependent down-regulation of estrogen receptor levels in MCF7-neo/HER2 and MCF7-hB7H4 cells. They also exhibited similar antigen dependent modulation of the estrogen receptor in tumors when administered intravenously to mice bearing MCF7-neo/HER2 tumor xenografts. The indole carbamate moiety present in the new linker was stable in whole blood from various species and also exhibited good in vivo stability properties in mice. PMID- 29493025 TI - Comparative Photothermal Performance among Various Sub-Stoichiometric 2D Oxygen Deficient Molybdenum Oxide Nanoflakes and In Vivo Toxicity. AB - The present study deals with photothermal therapy of solid tumors using different forms of oxygen-deficient sub-stoichiometric two-dimensional (2D) molybdenum oxide nanoflakes (alpha-MoO3-x ). Upon exfoliation of molybdenum oxide power using fine gridding followed by ultrasonication, bluish green molybdenum oxide (BG alpha-MoO3 ) was obtained. Oxygen vacancies in BG were generated upon irradiation with an intense xenon lamp. Irradiating the BG for 3 and 5 h, deep blue (B) and olive green (G) oxygen-deficient nanoflakes were obtained respectively. All exhibited high NIR absorption, making these nanomaterials suitable for photothermal therapy. All three forms were functionalized with polypyrrole (PPy@BG, PPy@B, PPy@G) to boost the photothermal stability and transduction efficiency. After functionalization and irradiation with 808 nm laser, the enhancement of temperature for BG, B, G was 50, 65, 52 degrees C respectively and the corresponding photothermal transduction efficiencies (PTE) were 29.32, 44.42 and 42.00 %. Each of the nanoflakes were found to be highly biocompatible and photostable both in vitro and in vivo. There was substantial decrease in the size of tumors after seven days of treatment on tumor-bearing experimental mice models. PMID- 29493026 TI - Hyperhaemolysis in a pregnant patient with HbH disease. PMID- 29493027 TI - ATP increases [Ca2+ ]i and activates a Ca2+ -dependent Cl- current in rat ventricular fibroblasts. AB - NEW FINDINGS: What is the central question of this study? Although electrophysiological and biophysical characteristics of heart fibroblasts have been studied in detail, their responses to prominent paracrine agents in the myocardium have not been addressed adequately. Our experiments characterize changes in cellular electrophysiology and intracellular calcium in response to ATP. What is the main finding and its importance? In rat ventricular fibroblasts maintained in cell culture, we find that ATP activates a specific subset of Ca2+ activated Cl- channels as a consequence of binding to P2Y purinoceptors and then activating phospholipase C. This response is not dependent on [Ca2+ ]o but requires an increase in [Ca2+ ]i and is modulated by the type of nucleotide that is the purinergic agonist. ABSTRACT: Effects of ATP on enzymatically isolated rat ventricular fibroblasts maintained in short-term (36-72 h) cell culture were examined. Immunocytochemical staining of these cells revealed that a fibroblast, as opposed to a myofibroblast, phenotype was predominant. ATP, ADP or uridine 5' triphosphate (UTP) all produced large increases in [Ca2+ ]i . Voltage-clamp studies (amphotericin-perforated patch) showed that ATP (1-100 MUm) activated an outwardly rectifying current, with a reversal potential very close to the Nernst potential for Cl- . In contrast, ADP was much less effective, and UTP produced no detectable current. The non-selective Cl- channel blockers niflumic acid, DIDS and NPPB (each at 100 MUm), blocked the responses to 100 MUm ATP. An agonist for P2Y purinoceptors, 2-MTATP, activated a very similar outwardly rectifying C1- current. The P2Y receptor antagonists, suramin and PPADS (100 MUm each), significantly inhibited the Cl- current produced by 100 MUm ATP. ATP was able to activate this Cl- current when [Ca2+ ]o was removed, but not when [Ca2+ ]i was buffered with BAPTA-AM. In the presence of the phospholipase C inhibitor U73122, this Cl- current could not be activated. PCR analysis revealed strong signals for a number of P2Y purinoceptors and for the Ca2+ -activated Cl- channel, TMEM16F (also denoted ANO6). In summary, these results demonstrate that activation of P2Y receptors by ATP causes a phospholipase C-dependent increase in [Ca2+ ]i , followed by activation of a Ca2+ -dependent Cl- current in rat ventricular fibroblasts. PMID- 29493029 TI - Abstracts of the British Psychosocial Oncology Society Annual Conference, 8-9 March 2018, Southampton, UK. PMID- 29493028 TI - Strong Depletion in Hybrid Perovskite p-n Junctions Induced by Local Electronic Doping. AB - A semiconductor p-n junction typically has a doping-induced carrier depletion region, where the doping level positively correlates with the built-in potential and negatively correlates with the depletion layer width. In conventional bulk and atomically thin junctions, this correlation challenges the synergy of the internal field and its spatial extent in carrier generation/transport. Organic inorganic hybrid perovskites, a class of crystalline ionic semiconductors, are promising alternatives because of their direct badgap, long diffusion length, and large dielectric constant. Here, strong depletion in a lateral p-n junction induced by local electronic doping at the surface of individual CH3 NH3 PbI3 perovskite nanosheets is reported. Unlike conventional surface doping with a weak van der Waals adsorption, covalent bonding and hydrogen bonding between a MoO3 dopant and the perovskite are theoretically predicted and experimentally verified. The strong hybridization-induced electronic coupling leads to an enhanced built-in electric field. The large electric permittivity arising from the ionic polarizability further contributes to the formation of an unusually broad depletion region up to 10 um in the junction. Under visible optical excitation without electrical bias, the lateral diode demonstrates unprecedented photovoltaic conversion with an external quantum efficiency of 3.93% and a photodetection responsivity of 1.42 A W-1 . PMID- 29493030 TI - Enantioselective Synthesis of Fully Benzenoid Single and Double Carbohelicenes via Gold-Catalyzed Intramolecular Hydroarylation. AB - The enantioselective synthesis of fully benzenoid single and double carbo[6]helicenes has been achieved via the gold-catalyzed intramolecular hydroarylation. The single crystal of the racemic double carbo[6]helicene consists of unique layer structures like timbers with halving joints in the woodworking. Furthermore, the double carbo[6]helicenes exhibited relatively large CPL activities among chiral small organic molecules. PMID- 29493031 TI - Review: An overview and analysis of novel oral anticoagulants and their dental implications. AB - BACKGROUND: Dabigatran, rivaroxaban, apixaban and edoxaban are approved novel oral anticoagulants (NOACs) as alternatives to Vitamin K antagonists (VKA). Physicians are prescribing an ever-increasing amount these drugs to their patients due to various advantages over existing medications. AIMS: The objective of this review is to provide the dental professional with current literature surrounding the emergence of NOACs, as well as various case studies on the subject, in an effort to guide clinical decision making regarding these medications. The pharmacological profiles of these NOACs and idarucizumab, a reversal agent for dabigatran, will be detailed in this review. MATERIALS AND METHODS: A review of the literature on NOACs was undertaken and the Pubmed, Medline, and Embase databases were used to identify articles published in the English language. Additionally, major dental medicine journals were hand searched, followed by a review of the ClinicalTrials.gov database. RESULTS: Due to minimal research regarding dental treatment of patients on NOACs and minimal clinical experience of practitioners treating these patients, there is currently insufficient data to establish an evidence-based NOAC management protocol in a dental setting. DISCUSSION: In this review, the most significant advantages of NOACs over VKAs was found to be limited interactions with other drugs as well as rapid onset and offset of action. CONCLUSION: Despite these benefits, as well as various others, NOACs still lack specific management parameters as well as antidotes or reversal agents. Therefore, dental professionals must use caution when treating patients currently taking these specific anticoagulants. PMID- 29493032 TI - An Overhauser-enhanced-MRI platform for dynamic free radical imaging in vivo. AB - Overhauser-enhanced MRI (OMRI) is an electron-proton double-resonance imaging technique of interest for its ability to non-invasively measure the concentration and distribution of free radicals. In vivo OMRI experiments are typically undertaken at ultra-low magnetic field (ULF), as both RF power absorption and penetration issues-a consequence of the high resonance frequencies of electron spins-are mitigated. However, working at ULF causes a drastic reduction in MRI sensitivity. Here, we report on the design, construction and performance of an OMRI platform optimized for high NMR sensitivity and low RF power absorbance, exploring challenges unique to probe design in the ULF regime. We use this platform to demonstrate dynamic imaging of TEMPOL in a rat model. The work presented here demonstrates improved speed and sensitivity of in vivo OMRI, extending the scope of OMRI to the study of dynamic processes such as metabolism. PMID- 29493033 TI - Dynamic protein folding at the surface of stimuli-responsive peptide fibrils. AB - The repetitive self-assembled structure of amyloid can serve as inspiration to design functional materials. Herein, we describe the design of alpha/beta6, a peptide that contains distinct alpha-helical and beta-structure forming domains. The folding and association state of each domain can be controlled by temperature. At low temperatures, the alpha-domain favors a coiled-coil state while the beta-domain is unstructured. Irreversible fibril formation via self assembly of the beta-domain is triggered at high temperatures where the alpha domain is unfolded. Resultant fibrils serve as templates upon which reversible coiled coil formation of the alpha-domain can be thermally controlled. At concentrations of alpha/beta6 >= 2.5 wt%, the peptide forms a mechanically defined hydrogel highlighting the possibility of designing materials whose function can be actively modulated by controlling the folded state of proteins displayed from the surface of fibrils that constitute the gel. PMID- 29493034 TI - Crystal structure of secretory abundant heat soluble protein 4 from one of the toughest "water bears" micro-animals Ramazzottius Varieornatus. AB - Though anhydrobiotic tardigrades (micro-animals also known as water bears) possess many genes of secretory abundant heat soluble (SAHS) proteins unique to Tardigrada, their functions are unknown. A previous crystallographic study revealed that a SAHS protein (RvSAHS1) from one of the toughest tardigrades, Ramazzottius varieornatus, has a beta-barrel architecture similar to fatty acid binding proteins (FABPs) and two putative ligand binding sites (LBS1 and LBS2) where fatty acids can bind. However, some SAHS proteins such as RvSAHS4 have different sets of amino acid residues at LBS1 and LBS2, implying that they prefer other ligands and have different functions. Here RvSAHS4 was crystallized and analyzed under a condition similar to that for RvSAHS1. There was no electron density corresponding to a fatty acid at LBS1 of RvSAHS4, where a putative fatty acid was observed in RvSAHS1. Instead, LBS2 of RvSAHS4, which was composed of uncharged residues, captured a putative polyethylene glycol molecule. These results suggest that RvSAHS4 mainly uses LBS2 for the binding of uncharged molecules. PMID- 29493035 TI - Promoting CPAP adherence in clinical practice: A survey of Swedish and Norwegian CPAP practitioners' beliefs and practices. AB - The benefits of continuous positive airway pressure (CPAP) treatment for obstructive sleep apnea are well established, but adherence tends to be low. Research exploring CPAP practitioners' beliefs around determinants of CPAP adherence, and the actions they use in clinical practice to promote CPAP adherence is lacking. This study aimed to: (i) develop and validate a questionnaire to assess beliefs and current practices among CPAP practitioners; (ii) explore practitioners' beliefs regarding the main determinants of patient adherence, and the actions practitioners most commonly use to promote CPAP adherence; and (iii) explore the associations between perceived determinants and adherence-promotion actions. One-hundred and forty-two CPAP practitioners in Sweden and Norway, representing 93% of all Swedish and 62% of all Norwegian CPAP centres, were surveyed via a questionnaire exploring potential determinants (18 items) and adherence-promotion actions (20 items). Confirmatory factor analysis and second-order structural equational modelling were used to identify patterns of beliefs, and potential associations with adherence-promotion actions. Patients' knowledge, motivation and attitudes were perceived by practitioners to be the main determinants of CPAP adherence, and educating patients about effects, management and treatment adjustments were the most common practices. Knowledge was shown to predict educational and informational actions (e.g. education about obstructive sleep apnea and CPAP). Educational and informational actions were associated with medical actions (e.g. treatment adjustment), but knowledge, attitude and support had no association with medical actions. These findings indicate that a wide variety of determinants and actions are considered important, though the only relationship observed between beliefs and actions was found for knowledge and educational and informational actions. PMID- 29493037 TI - Growth and protein-rich food intake in infancy is associated with fat-free mass index at 2-3 years of age. AB - AIM: The reduction of infant protein intake and associated growth velocity is a recommended public health strategy for reducing the risk of childhood obesity. This study tests the hypothesis that infants' growth and protein-rich food (dairy, meat, fish and egg) intake influences childhood body size and composition at 2-3 years of age. METHODS: Thirty-six children were studied from the Feeding Queensland Babies Study Cohort, which prospectively collected data on infant growth and diet. Body composition was estimated using the deuterium oxide dilution technique at 2-3 years of age. RESULTS: Fat-free mass index Z score at 2 3 years of age was positively associated with animal protein food (dairy, meat, fish and egg) intake at 12 months of age (r = 0.58, P = 0.002, false discovery rate corrected P value = 0.008) and negatively associated with weight-for-length growth velocity from 6 to 12 months of age (r = -0.75, P = 0.019, false discovery rate corrected P value = 0.038), which in turn was negatively associated with growth velocity from 0 to 6 months of age (r = -0.790, P = 0.007). CONCLUSION: This study suggests that strategies to reduce protein intake and growth velocity in early life may limit fat-free mass growth, potentially predisposing to increased adiposity in later life. PMID- 29493036 TI - Semen-derived amyloidogenic peptides-Key players of HIV infection. AB - Misfolding and amyloid aggregation of intrinsically disordered proteins (IDPs) are implicated in a variety of diseases. Studies have shown that membrane plays important roles on the formation of intermediate structures of IDPs that can initiate (and/or speed-up) amyloid aggregation to form fibers. The process of amyloid aggregation also disrupts membrane to cause cell death in amyloid diseases like Alzheimer's disease and type-2 diabetes. On the other hand, recent studies reported the membrane fusion properties of amyloid fibers. Remarkably, amyloid-fibril formation by short peptide fragments of highly abundant prostatic acidic-phosphatase (PAP) in human semen and are capable of boosting the rate of HIV infection up to 400,000-fold during sexual contact. Unlike the least toxic fully matured fibers of most amyloid proteins, the semen-derived enhancer of virus infection (SEVI) amyloid-fibrils of PAP peptide fragments are highly potent in rendering the maximum rate of HIV infection. This unusual property of amyloid fibers has witnessed increasing number of studies on the biophysical aspects of fiber formation and fiber-membrane interactions. NMR studies have reported a highly disordered partial helical structure in a membrane environment for the intrinsically disordered PAP peptide that promotes the fusion of the viral membrane with that of host cells. The purpose of this review article is to unify and integrate biophysical and immunological research reported in the previous studies on SEVI. Specifically, amyloid aggregation, dramatic HIV infection enhancing properties, membrane fusion properties, high resolution NMR structure, and approaches to eliminate the enhancement of HIV infection of SEVI peptides are discussed. PMID- 29493039 TI - Complement system activation in obstructive sleep apnea. AB - The complement system may play a role in the systemic inflammation characterising obstructive sleep apnea; however, this has not been investigated before. We aimed to study the involvement of effector complement elements in obstructive sleep apnea, namely C3a, C5a and SC5b-9. Venous blood was collected in 50 patients with obstructive sleep apnea and 26 control subjects in the evening and the following morning. Plasma complement proteins were analysed with ELISA. Complement factor levels were compared between the two groups and correlated with clinical variables. Plasma C3a concentration was elevated in obstructive sleep apnea both in the evening (84.1 [0-338.5] ng ml-1 ) and in the morning (85.5 [0-247.8] ng ml 1 ) compared with controls (30.3 [0-176.8] ng ml-1 and 36.3 [0-167.1] ng ml-1 , evening and morning, respectively, both p < 0.05). On the contrary, C5a and SC5b 9 levels were comparable between patients and controls at each time point (p > 0.05). There was no change in complement factors from evening to morning in either group (p > 0.05), except for C5a that decreased from evening to morning in obstructive sleep apnea (from 11.6 [1.6-47.4] ng ml-1 to 9.3 [0-46.4] ng ml-1 , p = 0.01). Elevated C3a levels were directly related to obstructive sleep apnea severity, and were significantly associated with male gender, weight, body mass index, hypertension, high C-reactive protein and low high-density lipoprotein cholesterol (p < 0.05). The complement system is activated in obstructive sleep apnea, which is correlated with disease severity. Our findings highlight the potential role of complement system in the pathophysiology of obstructive sleep apnea, thus facilitating further research. PMID- 29493040 TI - Investigation of sleep spindle activity and morphology as predictors of neurocognitive functioning in medicated patients with schizophrenia. AB - Neurocognitive impairment is a trait marker of schizophrenia, but no effective treatment has yet been identified. Sleep spindle deficits have been associated with diminished sleep-dependent memory learning. We examined whether this link could be extended into various cognitive domains by investigating the association of a neurocognitive test battery (the Brief Assessment of Cognition in Schizophrenia) with sleep spindle activity and morphology. We examined 37 outpatients diagnosed with schizophrenia and medicated with both antipsychotics and benzodiazepines. Participants underwent 1 night polysomnography and test of neurocognitive functioning. We identified and analysed sleep spindles in all non rapid eye movement sleep and in non-rapid eye movement sleep stage 2 in a central electroencephalography channel using an automatic sleep spindle detector previously validated. Slow sleep spindle density was computed from a frontal electroencephalography channel as well. We found no association between cognitive functioning and sleep spindle density or sleep spindle morphology for spindles in non-rapid eye movement sleep when controlling for gender, age, symptom severity, and daily dose of antipsychotics and benzodiazepines. For spindles in non-rapid eye movement sleep stage 2, we found that motor speed was associated with frontal slow sleep spindle density. We conclude that frontal slow spindle density might predict motor speed in medicated patients with schizophrenia, but that no other sleep spindle activity or sleep spindle morphology measures were predictors of neurocognitive functioning. PMID- 29493041 TI - Sleep deprivation compromises resting-state emotional regulatory processes: An EEG study. AB - Resting-state spontaneous neural activities consume far more biological energy than stimulus-induced activities, suggesting their significance. However, existing studies of sleep loss and emotional functioning have focused on how sleep deprivation modulates stimulus-induced emotional neural activities. The current study aimed to investigate the impacts of sleep deprivation on the brain network of emotional functioning using electroencephalogram during a resting state. Two established resting-state electroencephalogram indexes (i.e. frontal alpha asymmetry and frontal theta/beta ratio) were used to reflect the functioning of the emotion regulatory neural network. Participants completed an 8 min resting-state electroencephalogram recording after a well-rested night or 24 hr sleep deprivation. The Sleep Deprivation group had a heightened ratio of the power density in theta band to beta band (theta/beta ratio) in the frontal area than the Sleep Control group, suggesting an affective approach with reduced frontal cortical regulation of subcortical drive after sleep deprivation. There was also marginally more left-lateralized frontal alpha power (left frontal alpha asymmetry) in the Sleep Deprivation group compared with the Sleep Control group. Besides, higher theta/beta ratio and more left alpha lateralization were correlated with higher sleepiness and lower vigilance. The results converged in suggesting compromised emotional regulatory processes during resting state after sleep deprivation. Our work provided the first resting-state neural evidence for compromised emotional functioning after sleep loss, highlighting the significance of examining resting-state neural activities within the affective brain network as a default functional mode in investigating the sleep-emotion relationship. PMID- 29493038 TI - Postnatal development of lymphatic vasculature in the brain meninges. AB - BACKGROUND: Traditionally, the central nervous system (CNS) has been viewed as an immune-privileged environment with no lymphatic vessels. This view was partially overturned by the discovery of lymphatic vessels in the dural membrane that surrounds the brain, in contact with the interior surface of the skull. We here examine the distribution and developmental timing of these lymphatic vessels. RESULTS: Using the Prox1-GFP BAC transgenic reporter and immunostaining with antibodies to lymphatic markers LYVE-1, Prox1, and Podoplanin, we have carried out whole-mount imaging of dural lymphatic vasculature at postnatal stages. We have found that between birth and postnatal day (P) 13, lymphatic vessels extend alongside dural blood vessels from the side of the skull toward the midline. Between P13 and P20, lymphatic vessels along the transverse sinuses reach the superior sagittal sinus (SSS) and extend along the SSS toward the olfactory bulb. CONCLUSIONS: Compared with the embryonic developmental timing of lymphatic vessels in other tissues, e.g. skin, dural lymphatic vessel development is dramatically delayed. This study provides useful anatomical data for continuing investigations of the fundamental mechanisms that underlie dural lymphatic vessel development. Developmental Dynamics 247:741-753, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29493042 TI - Pleiotropic roles of melatonin in endometriosis, recurrent spontaneous abortion, and polycystic ovary syndrome. AB - Melatonin is a neurohormone synthesized from the aromatic amino acid tryptophan mainly by the pineal gland of mammals. Melatonin acts as a broad-spectrum antioxidant, powerful free radical scavenger, anti-inflammatory agent, anticarcinogenic factor, sleep inducer and regulator of the circadian rhythm, and potential immunoregulator. Melatonin and reproductive system are interrelated under both physiological and pathological conditions. Oxidative stress, inflammation, and immune dysregulation are associated with the pathogenesis of the female reproductive system which causes endometriosis (EMS), recurrent spontaneous abortion (RSA), and polycystic ovary syndrome (PCOS). Accumulating studies have indicated that melatonin plays pleiotropic and essential roles in these obstetrical and gynecological disorders and would be a candidate therapeutic drug to regulate inflammation and immune function and protect special cells or organs. Here, we systematically review the pleiotropic roles of melatonin in EMS, RSA, and PCOS to explore its pathological implications and treatment potential. PMID- 29493043 TI - Proton pump inhibitor use and the risk of fractures among an older adult cohort. AB - PURPOSE: The purpose of the study is to determine if the use of a proton pump inhibitor (PPI) is associated with an increased fracture risk, as some prior studies have suggested. METHODS: This retrospective cohort study included data on 4438 participants aged 65 and older who had no fracture in the year prior to baseline and had >=5 years of enrollment history in Kaiser Permanente Washington, an integrated healthcare delivery system in Seattle, WA, during 1994 to 2014. Time-varying cumulative exposure to PPIs was determined from automated pharmacy data by summing standard daily doses (SDDs) across fills, and patients were categorized as no use (reference group, <=30 SDD), light use (31-540 SDD), moderate use (541-1080 SDD), and heavy use (>=1081 SDD). Incident fractures were assessed using International Classification of Diseases, Ninth Revision codes from electronic medical records. Potential confounders, chosen a priori, were assessed at baseline and at each 2-year follow-up visit. Fracture risk was analyzed using a Cox proportional hazards model. RESULTS: Over a mean follow-up of 6.1 years, 802 (18.1%) participants experienced a fracture. No overall association was found between PPI use and fracture risk. Adjusted hazard ratios comparing users to the referent category were 1.08 (95% CI 0.83-1.40) for light users, 1.31 (95% CI 0.86-1.95) for moderate users, and 0.95 (95% CI 0.68-1.34) for heavy users. Among patients with SSD > 30, no appreciable increase in fracture risk was present in persons with recent versus distant use (adjusted hazard ratio of 1.14 [95% CI 0.91-1.42]). CONCLUSIONS: No association was observed between PPI use and fracture risk among older adults. PMID- 29493044 TI - An overview of sleep and circadian dysfunction in Parkinson's disease. AB - Sleep and circadian alterations are amongst the very first symptoms experienced in Parkinson's disease, and sleep alterations are present in the majority of patients with overt clinical manifestation of Parkinson's disease. However, the magnitude of sleep and circadian dysfunction in Parkinson's disease, and its influence on the pathophysiology of Parkinson's disease remains often unclear and a matter of debate. In particular, the confounding influences of dopaminergic therapy on sleep and circadian dysfunction are a major challenge, and need to be more carefully addressed in clinical studies. The scope of this narrative review is to summarise the current knowledge around both sleep and circadian alterations in Parkinson's disease. We provide an overview on the frequency of excessive daytime sleepiness, insomnia, restless legs, obstructive apnea and nocturia in Parkinson's disease, as well as addressing sleep structure, rapid eye movement sleep behaviour disorder and circadian features in Parkinson's disease. Sleep and circadian disorders have been linked to pathological conditions that are often co morbid in Parkinson's disease, including cognitive decline, memory impairment and neurodegeneration. Therefore, targeting sleep and circadian alterations could be one of the earliest and most promising opportunities to slow disease progression. We hope that this review will contribute to advance the discussion and inform new research efforts to progress our knowledge in this field. PMID- 29493045 TI - Lipopolysaccharide and cAMP modify placental calcitriol biosynthesis reducing antimicrobial peptides gene expression. AB - PROBLEM: Calcitriol, the hormonal form of vitamin D3 (VD), stimulates placental antimicrobial peptides expression; nonetheless, the regulation of calcitriol biosynthesis in the presence of bacterial products and its consequence on placental innate immunity have scarcely been addressed. METHOD OF STUDY: We investigated how some bacterial products modify placental VD metabolism and its ability to induce antimicrobial peptides gene expression. RESULTS: Cultured human trophoblasts biosynthesized calcitriol only in the presence of its precursor calcidiol, a process that was inhibited by cyclic-AMP but stimulated by lipopolysaccharide (LPS). Intracrine calcitriol upregulated cathelicidin, S100A9, and beta-defensins (HBDs) gene expression, while LPS further stimulated HBD2 and S100A9. Unexpectedly, LPS significantly repressed cathelicidin basal mRNA levels and drastically diminished calcidiol ability to induce it. Meanwhile, cyclic-AMP, which is used by many microbes to avoid host defenses, suppressed calcitriol biosynthesis, resulting in significant inhibition of most VD-dependent microbicidal peptides gene expression. CONCLUSION: While LPS stimulated calcitriol biosynthesis, cyclic-AMP inhibited it. LPS downregulated cathelicidin mRNA expression, whereas cyclic-AMP antagonized VD-dependent-upregulation of most antimicrobial peptides. These findings reveal LPS and cyclic-AMP involvement in dampening placental innate immunity, highlighting the importance of cyclic-AMP in the context of placental infection and suggesting its participation to facilitate bacterial survival. PMID- 29493046 TI - Ventricular arrhythmias arising from papillary muscle: A primary or secondary disease? PMID- 29493047 TI - Long-term effect of epirubicin on incidence of heart failure in women with breast cancer: insight from a randomized clinical trial. AB - AIMS: Anthracycline-based chemotherapy improves survival in breast cancer patients but is associated with increased risk of heart failure (HF). However, the risk of late-onset HF is debatable and mainly based on observational studies. The aim of this study was to evaluate the effect of anthracycline-based chemotherapy on long-term risk of clinical HF. METHODS AND RESULTS: Between 1990 and 1998 the Danish Breast Cancer Cooperative Group (DBCG) 89D trial randomized 980 Danish women with early breast cancer to adjuvant cyclophosphamide, epirubicin, and fluorouracil or cyclophosphamide, methotrexate, and fluorouracil. Incident HF was the primary endpoint obtained from Danish administrative registries. Follow-up ended at December 2014. The risk of HF was evaluated in a cumulative incidence analysis and a Fine-Gray proportional hazards model. Median follow-up time was 16.9 years [interquartile range (IQR) 3.7-20.9]. In the epirubicin treatment group, 23 new cases of HF were identified vs. 9 in the non epirubicin group corresponding to incidence rates per 1000 patient-years of 3.7 [95% confidence interval (CI) 2.5-5.6] vs. 1.4 (95% CI 0.7-2.7). The cumulative incidence of HF was higher in the epirubicin treatment group compared with the non-epirubicin group (P < 0.01), yielding a hazard ratio of 3.00 (95% CI 1.39 6.49, P < 0.01) for HF associated with epirubicin. The median dose of epirubicin was 451.9 mg/m2 (IQR 400.0-523.5). CONCLUSIONS: Anthracycline-based chemotherapy is associated with a three-fold increased risk of late-onset clinical HF relative to non-anthracycline chemotherapy in this randomized clinical trial, but overall risk is low. PMID- 29493049 TI - Soft-tissue augmentation procedures in edentulous esthetic areas. AB - Loss of dentition leads to functional and esthetic challenges that are determined by the anatomic features of the edentulous area. These features can complicate the prosthetic rehabilitation of such patients, especially in situations where optimal esthetic outcomes are desired. For these reasons, reconstructive plastic surgery procedures, aimed at restoring the alveolar ridge to its former dimensions, have become of great clinical interest. These reconstructive plastic surgery procedures frequently involve soft-tissue augmentation, performed to improve the quality and quantity of mucogingival tissue with the aim to achieve an ideal esthetic result. This review will focus on the description and expected outcomes of different surgical techniques for soft-tissue augmentation in edentulous areas, as described in the literature. Although more information from a larger number of studies and randomized controlled clinical trials is needed, it is possible to draw some conclusions, namely: pouch procedures are the first choice for soft-tissue augmentation, especially in high-demand esthetic areas; roll techniques are possible in shallow buccolingual soft-tissue augmentations; and onlay, inlay and combination grafts are less suitable for soft-tissue augmentation because of their poor esthetic results. PMID- 29493048 TI - Reduced olfactory bulb volume in depression-A structural moderator analysis. AB - BACKGROUND: Removal of the olfactory bulb (OB) leads to depression like behavior in rodents. A link between depression and olfactory function is also established in humans. We hypothesized that the human OB volume relates to depressive state and tested whether such a potential coherence is moderated by structural alterations in other brain regions. METHODS: Eighty-three participants (32 patients with major depression and 51 matched healthy controls) underwent structural MR scanning. Individual OB volumes were compared between patients and controls and the impact of depression and comorbidity was analyzed with multiple regression analysis. Whole-brain voxel-based morphometry revealed structures co varying with both depressive state and OB volume. RESULTS: The OB volume of patients was significantly reduced and this reduction averaged out at 17% compared to the controls. The OB volume was correlated to the volume of the insula, superior temporal cortex, and amygdala. The independent variables of depression (beta = -.37), age (beta = -.25), and gender (beta = -.40) explained the individual OB volume variation (R2 = .37). The correlation between OB volume and depression was moderated by volumetric reductions in a cluster including the insula and superior temporal gyrus (STG). CONCLUSIONS: The OB volume relates to depression in humans and to the volume of structures which are critical for salience detection. We assume that a reduced OB volume causes diminished neural olfactory input which facilitates volume reduction in the insula and STG. The OB volume may hence constitute a factor of vulnerability to depression. Olfactory based deep brain stimulation is discussed as a future therapeutic approach. PMID- 29493050 TI - The impact of permissive and restrictive pharmaceutical policies on quetiapine dispensing: Evaluating a policy pendulum using interrupted time series analysis. AB - PURPOSE: To evaluate the impact of 2 policy changes on quetiapine dispensing in Australia: removal of prior authorisation for prescribing (policy 1: July 2007) and removal of repeat prescriptions for 25-mg quetiapine (policy 2: January 2014). METHODS: We performed an interrupted time series analysis using Pharmaceutical Benefits Scheme claims data (July 2005 to December 2015). We assessed the impact of both policies on monthly quetiapine dispensing (25 mg and >25 mg) and the impact of policy change 2 on monthly rates of 25-mg discontinuation and switching from 25 mg to other quetiapine strengths. We also estimated the impact of both policies on the proportion of people with potentially inappropriate therapy (no evidence of dose escalation) following 25 mg initiation. RESULTS: Following removal of prior authorisation, 25-mg and >25 mg quetiapine dispensing in the Pharmaceutical Benefits Scheme 10% sample increased by 11/month (95% CI: 2-21) and 14/month (95% CI: 8-20), respectively. After removing 25-mg repeats, there was a permanent decrease of 1072 (95% CI 773 1371) dispensings and an increase in discontinuation of this strength; 48% of people dispensed the 25-mg strength that discontinued, discontinued quetiapine completely; the remainder continued to use higher quetiapine strengths. We observed minimal switching to other quetiapine strengths. There was no change in inappropriate 25-mg therapy following policy change 1 and a small decrease (79% to 76%, P = 0.05) following policy change 2. CONCLUSION: More nuanced policies are needed to ensure the appropriate access to 25-mg quetiapine for dose escalation while discouraging use for indications where the evidence of risk and benefit is unclear. PMID- 29493051 TI - Evaluation of a chronic kidney disease risk assessment service in community pharmacies. AB - AIM: Targeted 'opportunistic' screening might be a sustainable approach for the early detection of people with undiagnosed chronic kidney disease (CKD). The aim of this study was to implement and evaluate a CKD risk assessment service in the community pharmacy setting. METHODS: Twenty-four pharmacies in Tasmania, Australia participated in this study. Targeted people were aged between 50-74 years, with at least one CKD risk factor. The QKidney(r) risk calculator was used to estimate the participants' 5-year percentage risk of developing moderate severe CKD. Participants identified with >= 3% risk were referred to their general practitioner (GP) and followed-up after 9 months. Laboratory data was collected from a pathology provider. The main outcome measures were rates of GP referral uptake and of participants who underwent estimated glomerular filtration rate (eGFR) and urine albumin creatinine ratio (ACR) measurement. RESULTS: We analysed data for 389 screened participants, of whom 203 (52.1%) had >= 3% 5-year risk of developing moderate-severe CKD and were referred to their GP. Follow-up was successful for 126 participants and showed low (27%) GP referral uptake. Analysis of the pathology data revealed suboptimal kidney testing in participants with >= 3% risk, with eGFR and ACR tests performed for only 52.7% and 25.1% of these participants, respectively. CONCLUSIONS: There is significant scope for improving early detection of CKD via implementation of a community pharmacy-based CKD risk assessment service. However, a healthcare system that encourages inter professional collaboration between community pharmacists and GPs, and provides a robust referral pathway is needed to optimise the effectiveness of this service. PMID- 29493052 TI - Is hyperkalaemia in heart failure a risk factor or a risk marker? Implications for renin-angiotensin-aldosterone system inhibitor use. PMID- 29493053 TI - Frailty index and its associations with self-neglect, social support and sociodemographic characteristics among older adults in rural China. AB - AIM: The frailty index is used to measure the health status of older individuals. However, its association with self-neglect, social support and sociodemographic characteristics of older adults is underexplored. The purpose of the present study was to explore such associations among the rural older adults in Anhui Province of China, and to provide scientific evidence for policy-makers to improve the health and well-being of older adults in rural China. METHODS: A cross-sectional survey was undertaken among 3048 older adults in rural China. The frailty index was measured by an accumulation of deficits of 40 items. Ordinal logistic regression models were carried out to explore the associations of self neglect, social support and sociodemographic characteristics with the frailty index. RESULTS: The frailty rate was 15.8% among the participants. Older adults who showed self-neglect, were female, had a lower education level, had a lower monthly income and did not drink alcohol were more prone to having frailty in the 60-76 years age group, whereas older adults who showed self-neglect, had poor social support, were female, were not smokers and did not drink alcohol were more likely to have frailty in the >=77 years age group (P < 0.05). The interaction effect on frailty between self-neglect and social support was found in the 60-76 years age group. CONCLUSIONS: Age differences were shown in the associations between self-neglect, social support, sociodemographic characteristics and frailty index, which suggests different measures should be used accordingly for frailty prevention and management. Geriatr Gerontol Int 2018; 18: 987-996. PMID- 29493054 TI - Explaining depression symptoms in patients with social anxiety disorder: Do maladaptive metacognitive beliefs play a role? AB - Social anxiety disorder (SAD) is a major risk factor for developing symptoms of depression. Severity of social anxiety has previously been identified as a risk factor, and cognitive models emphasize dysfunctional schemas and self-processing as the key vulnerability factors underlying general distress in SAD. However, in the metacognitive model, depressive and other symptoms are related to metacognitive beliefs. The aim of this study was therefore to test the relative contribution of metacognitions when controlling for SAD severity and factors postulated in cognitive models. In a cross-sectional design, 102 patients diagnosed with primary SAD were included. We found that negative metacognitive beliefs concerning uncontrollability and danger and low confidence in memory emerged as the only factors explaining depressive symptoms in the regression model, suggesting that metacognitive beliefs are associated with increased depressive symptoms in SAD patients. PMID- 29493055 TI - Autonomic rhythms in health and disease. PMID- 29493056 TI - Anthracycline-induced cardiomyopathy: secrets and lies. PMID- 29493057 TI - An Efficient 1064 nm NIR-II Excitation Fluorescent Molecular Dye for Deep-Tissue High-Resolution Dynamic Bioimaging. AB - A small-molecule fluorophore FD-1080 with both excitation and emission in the NIR II region has been successfully synthesized for in vivo imaging. A heptamethine structure is designed to shift the absorption and emission into NIR-II region. Sulphonic and cyclohexene groups are introduced to enhance its water solubility and stability. The quantum yield of FD-1080 is 0.31 %, and can be increased to 5.94 % after combining with fetal bovine serum (FBS). Significantly, 1064 nm NIR II excitation was demonstrated with the high tissue penetration depth and superior imaging resolution compared to previously reported NIR excitation from 650 nm to 980 nm. FD-1080 is not only capable of realizing non-invasive high resolution deep-tissue hindlimb vasculature and brain vessel bioimaging, but also quantifying the respiratory rate based on the dynamic imaging of respiratory craniocaudal motion of the liver for the awake and anaesthetized mouse. PMID- 29493058 TI - Effect of digoxin in patients with heart failure and mid-range (borderline) left ventricular ejection fraction. AB - AIMS: To evaluate the effects of digoxin in patients with the newly described phenotype of heart failure (HF) and mid-range ejection fraction (HFmrEF), attributed to mild left ventricular systolic dysfunction. METHODS AND RESULTS: We carried out a retrospective analysis of the Digitalis Investigation Group (DIG) trial which had 7788 patients available for analysis with a left ventricular ejection fraction (LVEF) ranging between 3% and 85%. We compared the effect of digoxin to placebo in three mutually exclusive groups of patients defined by LVEF category: <40% (HF with reduced LVEF, HFrEF, n = 5874), 40-49% (HFmrEF, n = 1195) and >=50% (HF with preserved LVEF, HFpEF, n = 719). The primary outcome was the composite of cardiovascular death or HF hospitalisation. Patients with HFmrEF resembled patients with HFrEF, more than those with HFpEF, with respect to age, sex and aetiology but were more like HFpEF patients with respect to blood pressure and the prevalence of hypertension. Event rates in patients with HFmrEF were similar to those in HFpEF and much lower than in HFrEF. Digoxin reduced the primary endpoint in patients with HFrEF, mainly due to reduced HF hospitalisation: the digoxin/placebo hazard ratio (HR) for HF hospitalisation was 0.71 [95% confidence interval (CI) 0.65-0.77]. The digoxin/placebo HR for HF hospitalisation in patients with HFmrEF was 0.80 (95% CI 0.63-1.03) and 0.85 (95% CI 0.62-1.17) in those with HFpEF. The digoxin/placebo HR for the composite of HF death or HF hospitalisation was 0.74 (95% CI 0.68-0.81) in HFrEF, 0.83 (95% CI 0.66-1.05) in HFmrEF and 0.88 (95% CI 0.65-1.19) in HFpEF. CONCLUSIONS: In this study, event rates in patients with HFmrEF were closer to those in HFpEF than HFrEF. Digoxin had most effect on HF hospitalisation in patients with HFrEF, an intermediate effect in HFmrEF, and the smallest effect in HFpEF. PMID- 29493059 TI - Direct comparison of ultrafiltration to pharmacological decongestion in heart failure: a per-protocol analysis of CARRESS-HF. AB - AIMS: Mechanical ultrafiltration (UF) involves the removal of an iso-osmotic filtrate from the blood. Its benefit in acute decompensated heart failure, however, remains inconclusive. We sought to better understand the direct effects of UF in comparison to an aggressive, urine output-guided pharmacological protocol for decongestion on fluid loss, renal function, and neurohormonal activation. METHODS AND RESULTS: A per-protocol analysis of the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial (n = 188) was performed. Participants were included if randomized to UF and had UF output collected, or if randomized to the pharmacological arm and had urine but not UF output collected. Using these definitions, there were 163 participants at 24 h, 156 at 48 h, 129 at 72 h, and 106 at 96 h. UF was associated with higher cumulative fluid loss (P = 0.003), net fluid loss (P = 0.001), and relative reduction in weight (P = 0.02). UF was also associated with higher serum creatinine and blood urea nitrogen by 72 h (P-interaction <0.05 for both), lower serum sodium by 48 h (P-interaction <0.01) and increased plasma renin activity by 96 h (P = 0.04). The pharmacological arm was associated with higher serum bicarbonate after 24 h (P-interaction <0.002). There were no differences in 60 day outcomes between the UF and pharmacological arms. CONCLUSIONS: Ultrafiltration vs. pharmacological therapy was associated with more fluid removal but also rise in serum creatinine and neurohormonal activation. Additionally, loop diuretic use vs. UF was associated with an increase in serum bicarbonate despite less decongestion, data which question the commonly held conception of a 'contraction alkalosis'. PMID- 29493060 TI - Nontuberculous mycobacteria-associated hemophagocytic lymphohistiocytosis in MonoMAC syndrome. PMID- 29493061 TI - Prevalence of sarcopenia and association with oral health-related quality of life and oral health status in older dental clinic outpatients. AB - AIM: The relationship between oral health-related quality of life (OHRQoL) and sarcopenia is unknown. The purpose of the present study was to clarify the prevalence of sarcopenia in older dental clinic outpatients and its relationship with OHRQoL and oral health status. METHODS: This cross-sectional study used data from consecutive dental clinic outpatients aged >=65 years. The Oral Health Impact Profile-14 was used for the evaluation of OHRQoL, and the Oral Health Assessment Tool was used to assess oral health status. Sarcopenia was diagnosed according to the Asian Working Group for Sarcopenia criteria. Uni- and multivariable analyses were carried out to investigate the relationship between sarcopenia and Oral Health Impact Profile-14 and Oral Health Assessment Tool scores. RESULTS: This study involved 279 patients (173 women, 106 men) with a mean age of 76 +/- 7.5 years. The sarcopenia prevalence rate was 30.2%, and patients with sarcopenia had significantly poorer OHRQoL and oral health status than did patients without sarcopenia. Furthermore, sarcopenia was independently associated with Oral Health Impact Profile-14 and Oral Health Assessment Tool scores even after adjusting for confounding factors, such as age, sex, nutritional status, activities of daily living, dysphagia, comorbidities, polypharmacy and clinical dental findings. CONCLUSIONS: Sarcopenia was associated with OHRQoL and oral health status in older dental clinic outpatients. The prevalence of sarcopenia in older outpatients visiting the dental clinic was relatively high. Rehabilitation nutrition together with dental care might be necessary for sarcopenia treatment and prevention. Geriatr Gerontol Int 2018; 18: 915-921. PMID- 29493062 TI - Quantifying effects of biodiversity on ecosystem functioning across times and places. AB - Biodiversity loss decreases ecosystem functioning at the local scales at which species interact, but it remains unclear how biodiversity loss affects ecosystem functioning at the larger scales of space and time that are most relevant to biodiversity conservation and policy. Theory predicts that additional insurance effects of biodiversity on ecosystem functioning could emerge across time and space if species respond asynchronously to environmental variation and if species become increasingly dominant when and where they are most productive. Even if only a few dominant species maintain ecosystem functioning within a particular time and place, ecosystem functioning may be enhanced by many different species across many times and places (beta-diversity). Here, we develop and apply a new approach to estimate these previously unquantified insurance effects of biodiversity on ecosystem functioning that arise due to species turnover across times and places. In a long-term (18-year) grassland plant diversity experiment, we find that total insurance effects are positive in sign and substantial in magnitude, amounting to 19% of the net biodiversity effect, mostly due to temporal insurance effects. Species loss can therefore reduce ecosystem functioning both locally and by eliminating species that would otherwise enhance ecosystem functioning across temporally fluctuating and spatially heterogeneous environments. PMID- 29493063 TI - Cardiovascular autonomic dysfunction in insomnia patients with objective short sleep duration. AB - Two phenotypes have been proposed: insomnia with objective near-normal sleep duration, related to increased psychological symptoms, and insomnia with objective short sleep duration, associated with cardiometabolic morbidity. Reduced heart rate variability has also been implicated in the pathophysiology of cardiometabolic disease; however, there are little data on whether cardiovascular function differs between patients with objective short sleep duration and near normal sleep duration. Participants (Mage = 49.9 +/- 11.3 years; 62.8% female) were 180 adults with chronic insomnia (Mduration = 15.7 +/- 13.6). Objective sleep duration was based on total sleep time averaged across two consecutive nights of polysomnography and subjective sleep duration was based on 2-week sleep diaries. The sample was divided into two groups, with sleep duration shorter (polysomnography-total sleep time: n = 46; sleep diary: n = 95) or equal/longer (polysomnography-total sleep time: n = 134; sleep diary: n = 85) than 6 hr. Electrocardiogram data derived from polysomnography were used to obtain heart rate and heart rate variability during stage 2 (N2) and rapid eye movement sleep. Heart rate variability measures included absolute and normalized high-frequency component, an index of parasympathetic activation, and the ratio of low- to high frequency (LF/HF ratio), an index of sympathovagal balance. After controlling for covariates (e.g., co-morbidity), patients with objective short sleep duration had reduced high-frequency (p < .05) and elevated low-frequency/high-frequency ratio (p = .036) and heart rate (p = .051) compared with patients with near-normal sleep duration. No differences were observed between phenotypes when subjective sleep duration was used. Insomnia patients with objective short sleep duration showed significantly dampened parasympathetic activation and increased sympathovagal imbalance relative to their counterparts with near-normal sleep duration. These findings highlight the importance of treating insomnia, as treatment may reduce the risk of cardiovascular disease. PMID- 29493065 TI - Cardiac iron deficiency-how to refuel the engine out of fuel. PMID- 29493064 TI - Progesterone improves perinatal neuromotor outcomes in a mouse model of intrauterine inflammation via immunomodulation of the placenta. AB - To assess the fetal neuroprotective potential of progesterone using a well validated mouse model of lipopolysaccharide (LPS)-induced intrauterine inflammation (IUI). Embryonic day 17 pregnant mouse dams (n = 69) were randomly allocated to receive 17-hydroxyprogesterone caproate (17-OHPC), micronized progesterone (MP), or vehicle 1 hour prior to intrauterine injection of phosphate buffered saline (PBS) or LPS. After 6 hours, mice were killed for the collection of placentas and fetal brains, or pregnancy continued for the evaluation of preterm birth (PTB) and offspring neuromotor function. Placentas and fetal brains were analyzed by mini-mRNA array for 96 immune markers with individual confirmatory qPCR. Progesterone pre-treatment before LPS-induced IUI improved neuromotor tests in offspring at PND5 compared to no pre-treatment (P < .05). In placentas, 17-OHPC, but not MP, significantly reduced CXCL9 (P < .05) with a trend toward a lower level of CXCL10. In fetal brains, 17-OHPC significantly reduced CXCL9 compared to no pre-treatment (P < .05) and IL-1beta compared to pre treatment with MP (P < .01). Progesterone pre-treatment prior to LPS-induced IUI improved offspring neuromotor outcomes. 17-OHPC, but not MP, resulted in greater immunomodulation of T cell-mediated immunity in placenta and fetal brain, suggesting a possible mechanism for the observed neuroprotective effects. PMID- 29493067 TI - Degradation for better survival? Role of ubiquitination in epithelial morphogenesis. AB - As a prevalent post-translational modification, ubiquitination is essential for many developmental processes. Once covalently attached to the small and conserved polypeptide ubiquitin (Ub), a substrate protein can be directed to perform specific biological functions via its Ub-modified form. Three sequential catalytic reactions contribute to this process, among which E3 ligases serve to identify target substrates and promote the activated Ub to conjugate to substrate proteins. Ubiquitination has great plasticity, with diverse numbers, topologies and modifications of Ub chains conjugated at different substrate residues adding a layer of complexity that facilitates a huge range of cellular functions. Herein, we highlight key advances in the understanding of ubiquitination in epithelial morphogenesis, with an emphasis on the latest insights into its roles in cellular events involved in polarized epithelial tissue, including cell adhesion, asymmetric localization of polarity determinants and cytoskeletal organization. In addition, the physiological roles of ubiquitination are discussed for typical examples of epithelial morphogenesis, such as lung branching, vascular development and synaptic formation and plasticity. Our increased understanding of ubiquitination in epithelial morphogenesis may provide novel insights into the molecular mechanisms underlying epithelial regeneration and maintenance. PMID- 29493068 TI - Derangements in adrenergic-adipokine signalling establish a neurohormonal basis for obesity-related heart failure with a preserved ejection fraction. AB - Among patients with heart failure and a preserved ejection (HFpEF), obesity is associated with a distinct phenotype that is characterized by adiposity-driven plasma volume expansion and cardiac overfilling, which is coupled with an impairment of ventricular distensibility. These pathophysiological abnormalities may be related to the increased actions of specific adipocyte-derived signalling molecules (aldosterone, neprilysin and leptin) that work in concert with increased renal sympathetic nerve traffic and activated beta2 -adrenergic receptors to promote sodium retention, microvascular rarefaction, cardiac fibrosis and systemic inflammation. This interplay leads to striking activation of the mineralocorticoid receptor, possibly explaining why obese patients with heart failure are most likely to benefit from spironolactone and eplerenone in large-scale clinical trials. Additionally, adipocytes express and release neprilysin, which (by degrading endogenous natriuretic peptides) can further promote plasma volume expansion and cardiac fibrosis. Heightened neprilysin activity may explain the low circulating levels of natriuretic peptides in obesity, the accelerated breakdown of natriuretic peptides in HFpEF, and the cardiac decompression following neprilysin inhibition in HFpEF patients who are obese. Furthermore, as adipose tissue accumulates and becomes dysfunctional, its secretion of leptin promotes renal sodium retention, microvascular changes and fibrotic processes in the heart, and systemic inflammation; these effects may be mediated or potentiated by the activation of beta2 -adrenergic receptors. These adrenergic-adipokine interactions provide a mechanistic framework for novel therapeutic strategies to alleviate the pathophysiological abnormalities of obesity-related HFpEF. Ongoing trials are well-positioned to test this hypothesis. PMID- 29493066 TI - Sex-specific regulation of aging in Caenorhabditis elegans. AB - A fascinating aspect of sexual dimorphism in various animal species is that the two sexes differ substantially in lifespan. In humans, for example, women's life expectancy exceeds that of men by 3-7 years. Whether this trait can be attributed to dissimilar lifestyles or genetic (regulatory) factors remains to be elucidated. Herein, we demonstrate that in the nematode Caenorhabditis elegans, the significantly longer lifespan of hermaphrodites-which are essentially females capable of sperm production-over males is established by TRA-1, the terminal effector of the sex-determination pathway. This transcription factor directly controls the expression of daf-16/FOXO, which functions as a major target of insulin/IGF-1 signaling (IIS) and key modulator of aging across diverse animal phyla. TRA-1 extends hermaphrodite lifespan through promoting daf-16 activity. Furthermore, TRA-1 also influences reproductive growth in a DAF-16-dependent manner. Thus, the sex-determination machinery is an important regulator of IIS in this organism. These findings provide a mechanistic insight into how longevity and development are specified unequally in the two genders. As TRA-1 is orthologous to mammalian GLI (glioma-associated) proteins, a similar sex-specific mechanism may also operate in humans to determine lifespan. PMID- 29493069 TI - A case series of DKA occurring in patients receiving treatment with SGLT-2 inhibitors. PMID- 29493071 TI - Long-wave plasma radiofrequency ablation for treatment of xanthelasma palpebrarum. AB - Xanthelasma palpebrarum is the most common type of xanthoma affecting the eyelids. It is characterized by asymptomatic soft yellowish macules, papules, or plaques over the upper and lower eyelids. Many treatments are available for management of xanthelasma palpebrarum, the most commonly used include surgical excision, ablative CO2 or erbium lasers, nonablative Q-switched Nd:YAG laser, trichloroacetic acid peeling, and radiofrequency ablation. This study aims to evaluate the effectiveness of RF ablation in the treatment of xanthelasma palpebrarum, with D.A.S. Medical portable device (Technolux, Italia), a radiofrequency tool working with long-wave plasma energy and without anesthesia. Twenty patients, 15 female and 5 male, affected by xanthelasma palpebrarum, were enrolled for long-wave plasma radiofrequency ablation treatment. The treatment consisted of 3/4 sessions that were carried out at intervals of 30 days. Treatments were well tolerated by all patients with no adverse effects and optimal aesthetic results. The procedure is very fast and can be performed without anesthesia because of the low and tolerable pain stimulation. Long-wave plasma radiofrequency ablation is an effective option for treatment of xanthelasma palpebrarum and adds an additional tool to the increasing list of medical devices for aesthetic treatments. PMID- 29493070 TI - Setup errors in radiation therapy for thoracic tumor patients of different body mass index. AB - PURPOSE: To assess the setup errors in radiation therapy for thoracic tumors patients of different somatotypes, and to seek an individualized mathematical basis for defining the planning target volume (PTV). METHODS: Sixty patients with thoracic tumors were divided into four somatotypes according to their body mass index (BMI), and their body positions were setup by two groups of technicians independently. CT simulations were performed and the reconstructed radiography was digitally generated as reference images for location verification and error measurement. By setting positioning error ranges, the within-range positioning correction rate was compared among groups. RESULTS: Position setups for patients in the emaciated group, moderate group, and overweight group were relatively stable (with minor setup error differences between the two groups of technicians). In emaciated group, moderate group, overweight group, and obese group, setup errors in the right-left direction (R-L) were 2.2 +/- 1.3 mm, 2.2 +/ 1.6 mm, 3.9 +/- 3.1 mm, and 8.8 +/- 3.5 mm, respectively; whereas the setup errors in the four groups in the superior-inferior(S-I) direction were 2.4 +/- 1.8 mm, 2.1 +/- 1.9 mm, 3.2 +/- 2.6 mm, and 5.4 +/- 3.5 mm, and in the anterior posterior (A-P) direction were 2.2 +/- 1.7 mm, 1.9 +/- 1.9 mm, 3.2 +/- 2.9 mm, and 6.2 +/- 4.2 mm, respectively. Moreover, in the moderate group, the positioning correction rate in the three directions (R-L, S-I, and A-P) was 20%, 9%, 8% within the error range of 5-10 mm, and 3%, 0%, 1% with a more than 10 mm error range. However, in overweight group and obese group, the positioning correction rate in these three directions (also with a more than 10 mm error range) was 23%, 27%, 19% and 21%, 16%, 23%, respectively. CONCLUSIONS: In radiation therapy for patients with thoracic tumors, the definition of PTV should be individualized. Meanwhile, with the increase in BMI, positioning correction rate has a tendency to rise too. PMID- 29493072 TI - Re: Should we implement universal screening with late pregnancy ultrasound to prevent stillbirth?: Routine late ultrasound scan, symphysio-fundal height, abdominal palpation, detection of SGA fetuses and perinatal outcome. PMID- 29493073 TI - Type 1 diabetes, sport practiced, and ankle joint mobility in young patients: What is the relationship? AB - BACKGROUND/OBJECTIVE: It is known that patients with diabetes can develop limited joint mobility (LJM) and that this can depend on the metabolic control maintained and the duration of the disease. The aims of this study were to verify the presence of ankle joint mobility (AJM) deficits in both plantar and dorsiflexion in young type 1 diabetic patients (T1D) considering also the possible role of sport practiced as a further factor, able to modify AJM. METHODS: AJM was evaluated by an inclinometer in 82 T1D patients (M/F: 48/34), mean age 12.9 +/- 2.6 years, body mass index (BMI) 19.7 +/- 3.6 kg/m2 , duration of diabetes 5.6 +/ 3.3 years, mean HbA1c 7.5 +/- 1.0% and in 226 healthy controls (M/F: 146/80), age-, gender-, and BMI-matched practicing different sports (soccer, volleyball, basketball, and dance). RESULTS: The patients' ankle range of motion was significantly lower than that in controls (132.7 +/- 22.3 degrees vs 126.1 +/- 17.9 degrees ; P < .017). In particular, ankle plantar flexion was significantly lower in the patients group (31.6 degrees +/- 7.9 degrees vs 28.5 degrees +/- 6.6 degrees ; P < .002). Soccer players showed lower AJM in both groups: patients (120.1 +/- 15.9 degrees vs 127.3 +/- 18.1) and controls (119.4 +/- 21.1 degrees vs 142.0 +/- 18.1; P < .0001) than subjects practicing other sports or who were sedentary. In both groups, patients and controls, age, sex, duration of disease, hemoglobin 1Ac, and BMI have not been shown to be correlated to the mobility assessed. CONCLUSIONS: The results of this study, in addition to confirming the negative effect of diabetes on AJM of young T1D patients, suggest that during these evaluations the sport-related effect should be considered because it can induce significant changes of AJM. PMID- 29493074 TI - Tropical Medicine & International Health. PMID- 29493075 TI - The challenge of the management of adolescents and young adults with soft tissue sarcomas. AB - Soft tissue sarcomas are relatively frequent in adolescents and young adults and their clinical management may be complex, partly due to tumor associated factors, but also because different approaches have been adopted by pediatric and adult medical oncologists dealing with the same disease. However, times are changing and in the last few years, management has tended to converge towards a common strategy. Continued and increased international collaboration between pediatric and adult sarcoma groups is of critical importance to improve the quality of treatment as well as research programs dedicated to young patients with soft tissue sarcomas. PMID- 29493076 TI - Synthesis and photoluminescence properties of co-polyamides with anthrazoline containing units in the main chain. AB - A series of anthrazoline-containing monomers are synthesized, and eight co polyamides of different chemical structures, containing 1,9-anthrazoline fragments in the main chain, are obtained and investigated. Photoluminescent, stress-strain, and thermal properties of these polymers are studied. It is shown that polymers with fragments of 4,4'-(pyrido[3,2-g]-quinoline-2,8-diyl)dianiline and 4,4'-(10-methylpyrido[3,2-g]quinoline-2,8-diyl)dianiline possess an intense luminescence in the range 550-650 nm. The performed investigations made it possible to determine the effect of substituents of various natures in the anthrazoline cycle and the position of amide group (meta- and para configurations) on optical, stress-strain, and thermal properties of copolymers, opening up a prospect for further developments of principles of design of polymers with optimal characteristics. PMID- 29493078 TI - Saudi dental hygienists' opinions regarding establishing a professional association. AB - AIM: To assess the opinions of dental hygienists in Saudi Arabia regarding the establishment of a professional association including the role it should have to meet their professional needs. METHODS: A cross-sectional electronic survey using Qualtrics was utilized. IRB exemption was obtained prior to distribution. Although there are 298 licensed Saudi dental hygienists in Saudi Arabia, email addresses were only available for 101 respondents: those obtained previously by direct contact for the purpose of initiation of a professional association and those referred by the direct contacts. Subjects were emailed a link to the survey. RESULTS: Seventy-seven subjects responded fully to the survey yielding a response rate of 70.3%. Most 91.5% (n = 65) of the respondents favoured the establishment of a Saudi dental hygiene professional association. Eighty-eight per cent (n = 59) responded that such an association would promote development of the profession in the country at least somewhat and 86.6% (n = 58) agreed that their professional needs could be met by its establishment. Interestingly, half of those who did not support the creation of the professional association believed it would promote development of the profession and meet professional needs. CONCLUSIONS: A representative sample of dental hygienists in Saudi Arabia support the establishment of a professional association and feel that it would advocate and promote the dental hygiene profession in the country and meet their professional needs. PMID- 29493077 TI - Quantitative and qualitative evaluation of hybrid iterative reconstruction, with and without noise power spectrum models: A phantom study. AB - The purpose of this phantom study was to investigate the feasibility of dose reduction with hybrid iterative reconstruction, with and without a noise power spectrum (NPS) model, using both quantitative and qualitative evaluations. Standard dose (SD), three-quarter dose (TQD), and half-dose (HD) of radiation were used. Images were reconstructed with filtered back projection (FBP), adaptive iterative dose reduction 3D (AIDR 3D) (MILD, STR), and AIDR 3D enhanced (eAIDR 3D) (eMILD, eSTR). An NPS analysis, task-based modulation transfer function (MTFtask ) analysis, and comparisons of low-contrast detectability and image texture were performed. Although the eAIDR 3D had a higher NPS value in the high-frequency range and improved image texture and resolution as compared with AIDR 3D at the same radiation dose and iteration levels, it yielded higher noise than AIDR 3D. Additionally, although there was no statistically significant difference between SD-FBP and the TQD series in the comparison of the mean area under the curve (AUC), the mean AUC was statistically significantly different between SD-FBP and the HD series. NPS values in the high-frequency range, 10% MTFtask values, low-contrast detectability, and image textures of TQD-eMILD were comparable to those of SD-FBP. Our findings suggested that using eMILD can reduce the radiation dose by 25%, while potentially maintaining diagnostic performance, spatial resolution, and image texture; this could support selecting the appropriate protocol in a clinical setting. PMID- 29493079 TI - Validating kQ =1.0 assumption in TG51 with PTW 30013 farmer chamber for Varian TrueBeam's 2.5 MV imaging beam. AB - AAPM Report 142 recommends and the State of Ohio requires that the imaging dose be quantified in radiotherapy applications. Using the TG51 dose calibration protocol for MV Imaging dose measurement requires knowledge of the kQ parameter for the beam quality and the ionization chamber type under investigation. The %dd(10)x of the Varian TrueBeam 2.5 MV imaging beam falls outside the range of the available data for the calculation of the kQ value. Due to the similarities of the 2.5 MV imaging beam and the 60 Co beam, we and others made the assumption that kQ = 1.0 in TG51 calculations. In this study, we used the TG21 and TG51 calibration protocols in conjunction to validate that kQ = 1.0 for the 2.5 MV imaging beam using a PTW 30013 farmer chamber. Standard measurements for TG51 absolute dosimetry QA were performed at 100 cm SSD, 10 cm depth, 10 * 10 field size, delivering 100 Monitor Units to a waterproof Farmer Chamber (PTW TN30013) for both 2.5 and 6 MV. Both the TG21 and TG51 formalisms were used to calculate the dose to water per MU at dmax (Dw /MU) for the 6 MV beam. The calculated outputs were 1.0005 and 1.0004 cGy/MU respectively. The TG21 formalism was then used to calculate (Dw /MU) for the 2.5 MV imaging beam. This value was then used in the TG51 formalism to find kQ for the 2.5 MV imaging beam. A kQ value of 1.00 +/- 0.01 was calculated for 2.5 MV using this method. PMID- 29493080 TI - Intra-operative high-resolution mapping of slow wave propagation in the human jejunum: Feasibility and initial results. AB - BACKGROUND: Bioelectrical slow waves are a coordinating mechanism of small intestine motility, but extracellular human studies have been restricted to a limited number of sparse electrode recordings. High-resolution (HR) mapping has offered substantial insights into spatiotemporal intestinal slow wave dynamics, but has been limited to animal studies to date. This study aimed to translate intra-operative HR mapping to define pacemaking and conduction profiles in the human small intestine. METHODS: Immediately following laparotomy, flexible printed-circuit arrays were applied around the serosa of the proximal jejunum (128-256 electrodes; 4-5.2 mm spacing; 28-59 cm2 ). Slow wave propagation patterns were mapped, and frequencies, amplitudes, downstroke widths, and velocities were calculated. Pacemaking and propagation patterns were defined. KEY RESULTS: Analysis comprised nine patients with mean recording duration of 7.6 +/- 2.8 minutes. Slow waves occurred at a frequency of 9.8 +/- 0.4 cpm, amplitude 0.3 +/- 0.04 mV, downstroke width 0.5 +/- 0.1 seconds, and with faster circumferential velocity than longitudinal (10.1 +/- 0.8 vs 9.0 +/- 0.7 mm/s; P = .001). Focal pacemakers were identified and mapped (n = 4; mean frequency 9.9 +/- 0.2 cpm). Disordered slow wave propagation was observed, including wavefront collisions, conduction blocks, and breakout and entrainment of pacemakers. CONCLUSIONS & INFERENCES: This study introduces HR mapping of human intestinal slow waves, and provides first descriptions of intestinal pacemaker sites and velocity anisotropy. Future translation to other intestinal regions, disease states, and postsurgical dysmotility holds potential for improving the basic and clinical understanding of small intestine pathophysiology. PMID- 29493081 TI - The optimization and production of stable homogeneous amine enriched surfaces with characterized nanotopographical properties for enhanced osteoinduction of mesenchymal stem cells. AB - Silane modification has been proposed as a powerful biomaterial surface modification tool. This is the first comprehensive investigation into the effect of silane chain length on the resultant properties of -NH2 silane monolayers and the associated osteoinductive properties of the surface. A range of -NH2 presenting silanes, chain length 3-11, were introduced to glass coverslips and characterized using water contact angles, atomic force microscopy, X-ray photoelectron spectroscopy, and Ninhydrin assays. The ability of the variation in chain length to form a homogenous layer across the entirety of the surfaces was also assessed. The osteoinductive potential of the resultant surfaces was evaluated by real-time polymerase chain reaction, immunocytochemistry, and von Kossa staining. Control of surface chemistry and topography was directly associated with changes in chain length. This resulted in the identification of a specific, chain length 11 (CL11) which significantly increased the osteoinductive properties of the modified materials. Only CL11 surfaces had a highly regular nano-topography/roughness which resulted in the formation of an appetite-like layer on the surface that induced a significantly enhanced osteoinductive response (increased expression of osteocalcin, CBFA1, sclerostin, and the production of a calcified matrix) across the entirety of the surface. (c) 2018 The Authors Journal of Biomedical Materials Research Part A Published by Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1862-1877, 2018. PMID- 29493082 TI - Feasibility study of shutter scan acquisition for region of interest (ROI) digital tomosynthesis. AB - Dose reduction techniques have been studied in medical imaging. We propose shutter scan acquisition for region of interest (ROI) imaging to reduce the patient exposure dose received from a digital tomosynthesis system. A prototype chest digital tomosynthesis (CDT) system (LISTEM, Wonju, Korea) and the LUNGMAN phantom (Kyoto Kagaku, Japan) with lung nodules 8, 10, and 12 mm in size were used for this study. A total of 41 projections with shutter scan acquisition consisted of 21 truncated projections and 20 non-truncated projections. For comparison, 41 projections using conventional full view scan acquisition were also acquired. Truncated projections obtained by shutter scan acquisition were corrected by proposed image processing procedure to remove the truncation artifacts. The image quality was evaluated using the contrast to noise ratio (CNR), coefficient of variation (COV), and figure of merit (FOM). We measured the dose area product (DAP) value to verify the dose reduction using shutter scan acquisition. The ROI of the reconstructed image from shutter scan acquisition showed enhanced contrast. The results showed that CNR values of 8 and 12 mm lung nodules increased by 6.38% and 21.21%, respectively, and the CNR value of 10 mm lung nodule decreased by 3.63%. COV values of the lung nodules were lower in a shutter scan image than in a full view scan image. FOM values of 8, 10, and 12 mm lung nodules increased by 3.06, 2.25, and 2.33 times, respectively. This study compared the proposed shutter scan and conventional full view scan acquisition. In conclusion, using a shutter scan acquisition method resulted in enhanced contrast images within the ROI and higher FOM values. The patient exposure dose of the proposed shutter scan acquisition method can be reduced by limiting the field of view (FOV) to focus on the ROI. PMID- 29493083 TI - Beyond left ventricular ejection fraction there is a right heart that pumps. PMID- 29493084 TI - Heart failure management-time to change our script on prognosis? PMID- 29493085 TI - Overcoming resistance to mitochondrial apoptosis by BZML-induced mitotic catastrophe is enhanced by inhibition of autophagy in A549/Taxol cells. AB - OBJECTIVES: Our previous in vitro study showed that 5-(3, 4, 5-trimethoxybenzoyl) 4-methyl-2-(p-tolyl) imidazol (BZML) is a novel colchicine binding site inhibitor with potent anti-cancer activity against apoptosis resistance in A549/Taxol cells through mitotic catastrophe (MC). However, the mechanisms underlying apoptosis resistance in A549/Taxol cells remain unknown. To clarify these mechanisms, in the present study, we investigated the molecular mechanisms of apoptosis and autophagy, which are closely associated with MC in BZML-treated A549 and A549/Taxol cells. METHODS: Xenograft NSCLC models induced by A549 and A549/Taxol cells were used to evaluate the efficacy of BZML in vivo. The activation of the mitochondrial apoptotic pathway was assessed using JC-1 staining, Annexin V FITC/PI double-staining, a caspase-9 fluorescence metric assay kit and western blot. The different functional forms of autophagy were distinguished by determining the impact of autophagy inhibition on drug sensitivity. RESULTS: Our data showed that BZML also exhibited desirable anti-cancer activity against drug resistant NSCLC in vivo. Moreover, BZML caused ROS generation and MMP loss followed by the release of cytochrome c from mitochondria to cytosol in both A549 and A549/Taxol cells. However, the ROS-mediated apoptotic pathway involving the mitochondria that is induced by BZML was only fully activated in A549 cells but not in A549/Taxol cells. Importantly, we found that autophagy acted as a non protective type of autophagy during BZML-induced apoptosis in A549 cells, whereas it acted as a type of cytoprotective autophagy against BZML-induced MC in A549/Taxol cells. CONCLUSIONS: Our data suggest that the anti-apoptosis property of A549/Taxol cells originates from a defect in activation of the mitochondrial apoptotic pathway, and autophagy inhibitors can potentiate BZML-induced MC to overcome resistance to mitochondrial apoptosis. PMID- 29493086 TI - Monitoring the Dynamic Process of Formation of Plasmonic Molecular Junctions during Single Nanoparticle Collisions. AB - The capability to study the dynamic formation of plasmonic molecular junction is of fundamental importance, and it will provide new insights into molecular electronics/plasmonics, single-entity electrochemistry, and nanooptoelectronics. Here, a facile method to form plasmonic molecular junctions is reported by utilizing single gold nanoparticle (NP) collision events at a highly curved gold nanoelectrode modified with a self-assembled monolayer. By using time-resolved electrochemical current measurement and surface-enhanced Raman scattering spectroscopy, the current changes and the evolution of interfacial chemical bonding are successfully observed in the newly formed molecular tunnel junctions during and after the gold NP "hit-n-stay" and "hit-n-run" collision events. The results lead to an in-depth understanding of the single NP motion and the associated molecular level changes during the formation of the plasmonic molecular junctions in a single NP collision event. This method also provides a new platform to study molecular changes at the single molecule level during electron transport in a dynamic molecular tunnel junction. PMID- 29493087 TI - New Insight into Procedure of Interface Electron Transfer through Cascade System with Enhanced Photocatalytic Activity. AB - Recombination of photogenerated electron-hole pairs is extremely limited in the practical application of photocatalysis toward solving the energy crisis and environmental pollution. A rational design of the cascade system (i.e., rGO/Bi2 WO6 /Au, and ternary composites) with highly efficient charge carrier separation is successfully constructed. As expected, the integrated system (rGO/Bi2 WO6 /Au) shows enhanced photocatalytic activity compared to bare Bi2 WO6 and other binary composites, and it is proved in multiple electron transfer (MET) behavior, namely a cooperative electron transfer (ET) cascade effect. Simultaneously, UV vis/scanning electrochemical microscopy is used to directly identify MET kinetic information through an in situ probe scanning technique, where the "fast" and "slow" heterogeneous ET rate constants (Keff ) of corresponding photocatalysts on the different interfaces are found, which further reveals that the MET behavior is the prime source for enhanced photocatalytic activity. This work not only offers a new insight to study catalytic performance during photocatalysis and electrocatalysis systems, but also opens up a new avenue to design highly efficient catalysts in photocatalytic CO2 conversion to useful chemicals and photovoltaic devices. PMID- 29493088 TI - Severe insulin resistance due to insulin antibodies. PMID- 29493089 TI - Intravenous iron: Safe and underutilized in children. PMID- 29493091 TI - The structure identification of a diphenhydramine-related impurity in methamphetamine. AB - Some methamphetamine (MA) crystals contain pharmaceutical impurities resulting from the co-ingredients of medicines used for extracting ephedrine/pseudoephedrine. These pharmaceutical impurities and their related byproducts can reflect the trends in precursor chemicals and manufacturing sources. In this research, 1 pharmaceutical-impurity-related byproduct was detected in several seized MA samples synthesized by I/P (Nagai, Moscow, or Hypo) method. Its structure was postulated through the analysis of fragment ions in electron ionization (EI) mass spectrum. The impurity was further synthesized and analyzed using electrospray ionization-collision-induced dissociation (ESI-CID) mass spectrum and nuclear magnetic resonance (NMR), and finally determined to be N1 ,N1 ,N2 -trimethyl-N2 -(1-phenylpropan-2-yl)ethane-1,2-diamine. The impurity was inferred to be generated by the reaction of MA and the breakdown of diphenhydramine, a co-ingredient of medicines used for extracting ephedrine/pseudoephedrine. Simulation MA synthetic experiments via Nagai, Moscow, and Hypo methods using ephedrine and diphenhydramine as starting materials were performed to prove our presumption. The presence of the impurity indicates that these MA samples were manufactured from pharmaceutical containing ephedrine/pseudoephedrine and diphenhydramine. PMID- 29493090 TI - Clinical heterogeneity of hyperinsulinism due to HNF1A and HNF4A mutations. AB - BACKGROUND: Dominant inactivating mutations in HNF1A and HNF4A have been described to cause hyperinsulinism (HI) before evolving to diabetes. However, information available in the literature regarding the clinical phenotype is limited. OBJECTIVE: To report the prevalence of HNF1A and HNF4A mutations in a large cohort of children with HI, and to describe their genotypes and phenotypes. DESIGN: Retrospective descriptive study. METHODS: Medical records were reviewed to extract clinical information. Mutation analysis was carried out for 8 genes associated with HI (ABCC8, KCNJ11, GLUD1, GCK, HADH, HNF4A, HNF1A, and UCP2). RESULTS: HNF1A and HNF4A mutations were identified in 5.9% (12 out of 204; HNF1A = 7, HNF4A = 5) of diazoxide-responsive HI probands. The clinical phenotypes were extremely variable. Two children showed evidence of ketone production during hypoglycemia, a biochemical profile atypical for hyperinsulinism. At the time of analysis, diazoxide was discontinued in 5 children at a median age of 6.8 years. None had developed diabetes mellitus at a median age of 7.0 years. CONCLUSIONS: Given the heterogeneous clinical phenotypes of HNF1A- and HNF4A-HI, all children with transient, diazoxide-responsive HI without clear history of perinatal stress, should be screened for HNF1A and HNF4A mutations as it predicts the clinical course and affects the subsequent management plan. PMID- 29493094 TI - Engineering Anisotropically Curved Nitrogen-Doped Carbon Nanosheets with Recyclable Binary Flux for Sodium-Ion Storage. AB - As a low-cost substitute of graphene and graphene derivatives, 2D carbon nanosheets are considered to be attractive materials for high-performance electrochemical energy-storage devices. Nevertheless, the lack of cost-effective and green preparation methods still greatly impedes the application of 2D carbon nanosheets in sodium-ion batteries. Herein, an environmental friendly and versatile strategy is proposed to engineer anisotropically curved nitrogen-doped carbon nanosheets (CNCNs) derived from biosources with hydrosoluble and recyclable flux. After undergoing serious corrosion from the LiCl/KCl binary flux, the resulting CNCNs possess high structural stability. Notably, the CNCNs also possess a rational specific surface area, open porous structure, and abundant accessible edges, which can shorten the ion-diffusion path, provide abundant accessible active sites, and result in less charge-transfer impedance and excellent sodium-ion diffusion coefficient (8.9*10-10 cm2 s-1 ). As a consequence, CNCN electrodes can deliver a high specific capacity of 361.6 mAh g 1 at 50 mA g-1 . Such architecture provides a promising structural platform for the fabrication of 2D carbons for highly reversible and high capacity sodium-ion batteries. PMID- 29493092 TI - Simultaneous identification of three pseudoallergic components in Danshen injection by using high-expression Mas-related G protein coupled receptor X2 cell membrane chromatography coupled online to HPLC-ESI-MS/MS. AB - Adverse drug reactions of Danshen injection mainly manifested as pseudoallergic reactions. In the present study, salvianolic acid A and a pair of geometric isomers (isosalvianolic acid C and salvianolic acid C) were identified as pseudoallergic components in Danshen injection by a high-expression Mas-related G protein coupled receptor X2 cell membrane chromatography coupled online with high performance liquid chromatography with electrospray ionization tandem mass spectrometry. Their pseudoallergic activities were evaluated by in vitro assay, which were consistent with the retention times on the cell membrane chromatography column. Salvianolic acid C, the most outstanding compound, was further found to induce pseudoallergic reaction through Mas-related G protein coupled receptor X2. All the results above indicated that the system developed in this study is an effective method for simultaneously analyzing pseudoallergic components, even those with similar structures and the microcomponents in complex samples (salvianolic acid C in Danshen injection). PMID- 29493093 TI - Highlights of the 2017 European AIDS Clinical Society (EACS) Guidelines for the treatment of adult HIV-positive persons version 9.0. AB - BACKGROUND: The European AIDS Clinical Society (EACS) Guidelines have since 2005 provided multidisciplinary recommendations for the care of HIV-positive persons in geographically diverse areas. GUIDELINE HIGHLIGHTS: Major revisions have been made in all sections of the 2017 Guidelines: antiretroviral treatment (ART), comorbidities, coinfections and opportunistic diseases. Newly added are also a summary of the main changes made, and direct video links to the EACS online course on HIV Management. Recommendations on the clinical situations in which tenofovir alafenamide may be considered over tenofovir disoproxil fumarate are provided, and recommendations on which antiretrovirals can be used safely during pregnancy have been revised. Renal and bone toxicity and hepatitis C virus (HCV) treatment have been added as potential reasons for ART switches in fully virologically suppressed individuals, and dolutegravir/rilpivirine has been included as a treatment option. In contrast, dolutegravir monotherapy is not recommended. New recommendations on non-alcoholic fatty liver disease, chronic lung disease, solid organ transplantation, and prescribing in elderly are included, and human papilloma virus (HPV) vaccination recommendations have been expanded. All drug-drug interaction tables have been updated and new tables are included. Treatment options for direct-acting antivirals (DAAs) have been updated and include the latest combinations of sofosbuvir/velpatasvir/voxilaprevir and glecaprevir/pibrentasvir. Recommendations on management of DAA failure and acute HCV infection have been expanded. For treatment of tuberculosis (TB), it is underlined that intermittent treatment is contraindicated, and for resistant TB new data suggest that using a three-drug combination may be as effective as a five-drug regimen, and may reduce treatment duration from 18-24 to 6-10 months. CONCLUSIONS: Version 9.0 of the EACS Guidelines provides a holistic approach to HIV care and is translated into the six most commonly spoken languages. PMID- 29493096 TI - Synthesis, Structure-Activity Relationship Studies, and ADMET Properties of 3 Aminocyclohex-2-en-1-ones as Chemokine Receptor 2 (CXCR2) Antagonists. AB - Herein we describe the synthesis and structure-activity relationships of 3 aminocyclohex-2-en-1-one derivatives as novel chemokine receptor 2 (CXCR2) antagonists. Thirteen out of 44 derivatives were found to inhibit CXCR2 downstream signaling in a Tango assay specific for CXCR2, with IC50 values less than 10 MUm. In silico ADMET prediction suggests that all active compounds possess drug-like properties. None of these compounds show significant cytotoxicity, suggesting their potential application in inflammatory mediated diseases. A structure-activity relationship (SAR) map has been generated to gain better understanding of their binding mechanism to guide further optimization of these new CXCR2 antagonists. PMID- 29493095 TI - Evaluation of the intra- and interfractional tumor motion and variability by fiducial-based real-time tracking in liver stereotactic body radiation therapy. AB - PURPOSE: Tumor motion amplitude varies during treatment. The purpose of the study was to evaluate the intra- and interfraction tumor motion and variability in patients with liver cancer treated with fiducial-based real-time tracking stereotactic body radiotherapy (SBRT). METHODS: Fourteen liver patients were treated with SBRT using a CyberKnife. Two to four fiducial markers implanted near the tumor were used for real-time monitoring using the Synchrony system. The tumor motion information during treatment was extracted from the log files recorded by the Synchrony system. Logfile-based amplitudes in the superior posterior (SI), left-right (LR) and anterior-posterior (AP) directions were compared to the 4DCT-based amplitudes. The intra- and interfraction amplitude variations and the incidence of baseline shifts were analyzed for 66 fractions administered to 14 patients. RESULTS: The median (range) logfile-based liver motion amplitudes for all patients were 11.9 (5.1-17.3) mm, 1.3 (0.4-4) mm and 3.8 (0.9-7.7) mm in the SI, LR and AP directions, respectively. Compared with the logfile-based amplitude, the 4DCT-based amplitude was underestimated (P < 0.05). The median (range) intra- and interfraction liver motion amplitude variations were 4.3 (1.6-6.0) mm (SI), 0.5 (0.2-2.2) mm(LR) and 1.5 (0.3-3.3) mm (AP) and 1.7 (0.5-4.6) mm (SI), 0.3 (0.1-3.0) mm (LR) and 0.7 (0.3-2.7) mm (AP), respectively. Baseline shifts exceeding 2 mm, 3 mm and 5 mm were observed in 27.3%, 7.6% and 3% of the measurements, respectively, within 10 min, and in 66.7%, 38.1% and 19%, respectively, within 30 min for the square root of the sum of the squares of the distances in the SI, LR and AP directions (3D). The tumor motion amplitude was found to be correlated with the baseline shift. CONCLUSIONS: Most patients showed significant intra- and interfraction liver motion amplitude variations over the entire course of radiation. More caution is needed for patients with large tumor motion amplitudes. PMID- 29493098 TI - Fiber-in-tube solid-phase microextraction of caffeine as a molecular tracer in wastewater by electrochemically deposited layered double hydroxide. AB - Modified stainless-steel wires with a layer of polyaniline conductive polymer were coated by electrochemical deposition with Zn/Al layered double hydroxide to make solid-phase microextraction fibers. The coating layer was also electrochemically deposited on the inner surface of a stainless-steel tube. Then, ten prepared fibers were put inside the inner coated tube to make a fiber-in-tube solid phase microextraction device. The device was applied for the extraction of caffeine (1,3,7-trimethylxanthine) from domestic wastewater samples. Extraction conditions including extraction and desorption times, pH and ionic strength of the sample solution, and content of the organic desorption solvent were investigated and optimized. Under the optimized conditions, the fiber-in-tube solid phase microextraction exhibited excellent extraction efficiency toward caffeine. The precision of the method was evaluated. Average relative standard deviation of 5.7% (n = 6) for intraday analysis and 8.3% (n = 5) for interday analysis was obtained. The limits of detection and limits of quantification of the method (at signal to noise ratio of 3 and 10) were obtained as 0.14 and 0.37 ng/mL, respectively. The current study can provide new prospective applications of layered double hydroxide conductive polymer fiber coatings. PMID- 29493097 TI - Increased prevalence of disordered eating in the dual diagnosis of type 1 diabetes mellitus and celiac disease. AB - BACKGROUND: Disordered eating behaviors (DEBs) may lead to full blown eating disorders. Both type 1 diabetes mellitus (T1DM) and celiac disease (CD) have been linked to DEBs. OBJECTIVE: To compare the presence of DEBs between adolescents and young adults with a dual diagnosis of T1DM and CD, and individuals with only one of the diagnoses. METHODS: Individuals with a dual diagnosis of T1DM and CD ("T1DM + CD group" n = 39), with a diagnosis of T1DM only ("T1DM group" n = 97) and with a diagnosis of CD only ("CD group" n = 267) filled the Eating Attitude Test-26 (EAT-26) questionnaire. Those with T1DM completed in addition to the Diabetes Eating Problem Survey-Revised (DEPS-R). RESULTS: The study population comprised of 403 individuals, of whom 65% were females. There were no statistically significant differences among the groups in distribution of sex, age, hemoglobin A1c (HbA1c) levels, age of disease diagnosis and duration. The prevalence of DEBs in the T1DM + CD group was 3-fold higher (26.0%) than in the T1DM (8.2%) and CD (8.2%) groups (P = .003). This trend was observed for both females and males. Multivariate analysis demonstrated that the T1DM + CD group had an increased risk for DEBs (odds ratio, OR: 4.7, 95% confidence interval, CI: 1.9-11.2, P = .001) after adjustment for age, sex, and body mass index. Additionally, being female, older and overweight increased the risk for DEBs. HbA1c values were not associated with an increased DEBs rate. CONCLUSIONS: Individuals with the dual diagnoses of T1DM and CD have an increased likelihood to develop DEBs compared to those with only one of these diagnoses. PMID- 29493100 TI - Glucose excursions and hypoglycemia in patients with type 2 diabetes treated with mitiglinide/voglibose versus glimepiride: A randomized cross-over trial. AB - BACKGROUND: Glucose excursions and hypoglycemia are associated with cardiovascular complications. However, no studies have evaluated glucose excursions and the frequency of hypoglycemia in patients treated with mitiglinide/voglibose versus glimepiride as add-on to dipeptidyl peptidase-4 inhibitor therapy. METHODS: This cross-over trial included 20 patients with type 2 diabetes. After initiating vildagliptin 100 mg, patients were randomly assigned to receive mitiglinide 10 mg/voglibose 0.2 mg three times daily for 3 days followed by glimepiride 1 mg once daily for the subsequent 3 days as add-on therapy, or vice versa. Glucose excursions and hypoglycemia frequency were measured using 24-h continuous glucose monitoring. Metabolic profile changes were evaluated using a meal tolerance test. RESULTS: The mean glucose levels in the mitiglinide/voglibose and glimepiride phases were identical (8.01 vs 8.24 mmol/L, respectively). However, during the mitiglinide/voglibose phase compared with the glimepiride phase, the standard deviation of glucose (1.30 vs 2.10 mmol/L; P < 0.001), mean amplitude of glycemic excursions (3.47 vs 5.28 mmol/L; P < 0.001), M value (24.6 vs 70.0; P < 0.001), continuous overlapping net glycemic action for a 1-h time interval (22.6 vs 31.0; P < 0.001), and area under the curve >10 mmol/L (0.18 vs 0.52 mmol/L per h; P < 0.001) were significantly lower. Hypoglycemia (glucose <3.8 mmol/L) was not observed during the mitiglinide/voglibose phase, but occurred 0.35 times/day in those taking glimepiride. Moreover, the mitiglinide/voglibose phase had higher premeal and lower post-meal glucose levels than the glimepiride phase. CONCLUSIONS: Adding mitiglinide/voglibose to vildagliptin therapy results in more efficient postprandial glucose control and less hypoglycemia than adding glimepiride. PMID- 29493099 TI - T-Cell Immunopeptidomes Reveal Cell Subtype Surface Markers Derived From Intracellular Proteins. AB - Immunopeptidomes promise novel surface markers as ideal immunotherapy targets, but their characterization by mass spectrometry (MS) remains challenging. Until recently, cell numbers exceeding 109 were needed to survey thousands of HLA ligands. Such limited analytical sensitivity has historically constrained the types of clinical specimens that can be evaluated to cell cultures or bulk tissues. Measuring immunopeptidomes from purified cell subpopulations would be preferable for many applications, particularly those evaluating rare, primary hematopoietic cell lineages. Here, we test the feasibility of immunopeptidome profiling from limited numbers of primary purified human regulatory T cells (TReg ), conventional T cells (Tconv ), and activated T cells. The combined T cell immunopeptide dataset reported here contains 13 804 unique HLA ligands derived from 5049 proteins. Of these, more than 700 HLA ligands were derived from 82 proteins that we exclusively identified from TReg -enriched cells. This study 1) demonstrates that primary, lineage-enriched T cell subpopulations recovered from single donors are compatible with immunopeptidome analysis; 2) presents new TReg biased ligand candidates; and 3) supports immunopeptidome surveys' value for revealing T cell biology that may not be apparent from expression data alone. Taken together, these findings open up new avenues for targeting TReg and abrogating their suppressive functions to treat cancer. PMID- 29493101 TI - Dosimetric assessment of an air-filled balloon applicator in HDR vaginal cuff brachytherapy using the Monte Carlo method. AB - PURPOSE: As an alternative to cylindrical applicators, air-inflated balloon applicators have been introduced into high-dose-rate (HDR) vaginal cuff brachytherapy to achieve sufficient dose to the vagina mucosa as well as to spare organs at risk, mainly the rectum and bladder. Commercial treatment planning systems which employ formulae in the AAPM Task Group No. 43 (TG 43) report do not take into account tissue inhomogeneity. Consequently, the low-density air in a balloon applicator induces different doses delivered to the mucosa from planned by these planning systems. In this study, we investigated the dosimetric effects of the air in a balloon applicator using the Monte Carlo (MC) method. METHODS: The thirteen-catheter CapriTM applicator by VarianTM for vaginal cuff brachytherapy was modeled together with the Ir-192 radioactive source for the microSelectronTM Digital (HDR-V3) afterloader by ElektaTM using the MCNP MC code. The validity of charged particle equilibrium (CPE) with an air balloon present was evaluated by comparing the kerma and the absorbed dose at various distances from the applicator surface. By comparing MC results with and without air cavity present, dosimetric effects of the air cavity were studied. Clinical patient cases with optimized multiple Ir-192 source dwell positions were also explored. Four treatment plans by the Oncentra BrachyTM treatment planning system were re calculated with MCNP. RESULTS: CPE fails in the vicinity of the air-water interface. One millimeter beyond the air-water boundary the kerma and the absorbed dose are equal (0.2% difference), regardless of air cavity dimensions or iridium source locations in the balloon. The air cavity results in dose increase, due to less photon absorption in the air than in water or solid materials. The extent of the increase depends on the diameter of the air balloon. The average increment is 3.8%, 4.5% and 5.3% for 3.0, 3.5, and 4.0 cm applicators, respectively. In patient cases, the dose to the mucosa is also increased with the air cavity present. The point dose difference between Oncentra Brachy and MC at 5 mm prescription depth is 8% at most and 5% on average. CONCLUSIONS: Except in the vicinity of the air-mucosa interface, the dosimetric difference is not significant enough to mandate tissue inhomogeneity correction in HDR treatment planning. PMID- 29493102 TI - Tracking patients with advanced kidney disease in the last 12 months of life. AB - BACKGROUND: There is increasing recognition of the clinical need for timely and coordinated supportive and palliative care for those with terminal organ failure. OBJECTIVE: To describe symptoms, quality of life and supportive care needs in the anticipated 12-month period prior to death in adults with chronic kidney disease (CKD) stages 4 or 5. METHOD: An observational, prospective, longitudinal design was used to follow 19 patients. The measures used were the Chronic Kidney Disease Symptom Burden Index (CKD-SBI), the Australian Karnofsky Performance Scale (AKPS), the Functional Assessment of Chronic illness Therapy Palliative-14 (FACIT PAL-14), the Assessment of Quality of Life 6 Dimensions (AQoL-6D) and the Sheffield Profile for Assessment and Referral for Care (SPARC). Data were collected at study entry and three monthly until death or study end. RESULTS: Patients' median age was 78 years (range 42-90), most were male (63%), 10 were receiving dialysis and seven died during the study. The most prevalent symptoms reported differed from those that were most troublesome. The median AKPS score did not change over time (60). Quality of life remained steady over time [FACIT PAL median range: 43.5-46; AQoL-6D means range: 0.66 (SD 0.19) to 0.75 (SD 0.2)]. Supportive care needs were few. CONCLUSION: We found a substantial symptom burden and slow functional decline in this group of patients. Regular assessment of both symptoms and QOL is warranted particularly if clinical experience indicates that the person is likely to be in their last year of life. Integrated supportive care programmes could assist with easing symptom burden during this time. PMID- 29493103 TI - Metastatic hepatocellular carcinoma diagnosed by fine needle aspiration: A clinical and cytologic study. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths worldwide. The clinical and cytological features of metastatic HCC have not been well established. METHODS: To determine the clinical and cytological features of metastatic HCC, we retrospectively searched for all HCC metastasis diagnosed by fine needle aspiration or core biopsy. RESULTS: We found 12 bone metastases, 11 intra-abdominal, 4 lung, 3 soft tissue, and 2 lymph node metastases from 32 patients. 7/12 bone metastases were vertebral body, 4 were pelvic bone, and 1 case was humerus. 10/32 cases showed concurrent metastasis at a different location. The average metastasis size was 40.9 mm. Tumor grades of HCC showed near equal distribution. The following cytological features are most frequently associated with metastatic HCC: single tumor cells (88.9%), cytoplasmic vacuolization (70.4%), trabecular pattern (70.4%), bare nuclei (66.7%), prominent nucleoli (66.7%), tumor giant cells (44.4%), and traversing capillaries (44.4%) and encased by endothelium (18.5%). Immunohistochemical stains of 12 cases showed the majority were positive for E-Cadherin, Carcinoembryonic Antigen, and HepPar1. Negativity for CK7 and CK20 is contributory to making the diagnosis. CONCLUSION: The most frequent metastatic HCC diagnosed by FNA was from bone, especially the vertebral body. The frequent cytomorphology and immunophenotype seen in primary HCC are good diagnostic criteria for diagnosing metastatic HCC. PMID- 29493104 TI - A week in the life of the JACMP. PMID- 29493105 TI - Probiotic supplementation increases obesity with no detectable effects on liver fat or gut microbiota in obese Hispanic adolescents: a 16-week, randomized, placebo-controlled trial. AB - BACKGROUND: Numerous studies have shown that there are links between obesity, liver fat and the gut microbiome. However, there are mixed results on whether probiotics could impact the gut microbiome and/or help to decrease liver fat and obesity outcomes. OBJECTIVE: This study aimed to determine whether a probiotic supplement (VSL#3(r) ) intervention altered gut microbiota and/or gut hormones associated with appetite regulation. The secondary aim of this study was to determine whether VSL#3(r) altered body composition and liver fat and fibrosis. METHODS: We conducted a double-blind, randomized placebo-controlled trial in 19 obese Latino adolescents. The intervention consisted of three packets per day of VSL#3(r) or a matched placebo for 16 weeks. Pre-intervention and post intervention measures included gut microbial abundance, gut appetite regulating hormones, anthropometrics, body composition, liver fat and liver fibrosis. We conducted linear models to determine whether there were any significant differences in the changes in these outcomes following VSL#3(r) intervention. RESULTS: Compared with placebo, adolescents that received VSL#3 had significant increases in total adiposity (%) (+1.7 +/- 0.6 vs. -1.3 +/- 0.5, p < 0.01) and trunk adiposity (%) (+3.3 +/- 0.8 vs. -1.8 +/- 0.8, p < 0.01) with no significant effects on liver fat/fibrosis, insulin/glucose, gut microbial abundances or gut hormones. CONCLUSION: VSL#3 supplementation may lead to increased adiposity in obese Latino adolescents with no significant detectable changes in gut microbiota, gut appetite-regulating hormones, liver fat and fibrosis and dietary intake. However, it is important to note that recruitment efforts were terminated early and the sample size fell short of what was planned for this trial. PMID- 29493106 TI - A Lithium-Ion Battery using a 3 D-Array Nanostructured Graphene-Sulfur Cathode and a Silicon Oxide-Based Anode. AB - An efficient lithium-ion battery was assembled by using an enhanced sulfur-based cathode and a silicon oxide-based anode and proposed as an innovative energy storage system. The sulfur-carbon composite, which exploits graphene carbon with a 3 D array (3DG-S), was synthesized by a reduction step through a microwave assisted solvothermal technique and was fully characterized in terms of structure and morphology, thereby revealing suitable features for lithium-cell application. Electrochemical tests of the 3DG-S electrode in a lithium half-cell indicated a capacity ranging from 1200 to 1000 mAh g-1 at currents of C/10 and 1 C, respectively. Remarkably, the Li-alloyed anode, namely, Liy SiOx -C prepared by the sol-gel method and lithiated by surface treatment, showed suitable performance in a lithium half-cell by using an electrolyte designed for lithium sulfur batteries. The Liy SiOx -C/3DG-S battery was found to exhibit very promising properties with a capacity of approximately 460 mAh gS-1 delivered at an average voltage of approximately 1.5 V over 200 cycles, suggesting that the characterized materials would be suitable candidates for low-cost and high-energy storage applications. PMID- 29493107 TI - The positive association of infant weight gain with adulthood body mass index has strengthened over time in the Fels Longitudinal Study. AB - BACKGROUND: Infant weight gain is positively related to adulthood body mass index (BMI), but it is unknown whether or not this association is stronger for individuals born during (compared with before) the obesity epidemic. OBJECTIVES: The aim of the study was to examine how the infant weight gain-adulthood BMI association might have changed across successive birth year cohorts spanning most of the 20th century. METHODS: The sample comprised 346 participants in the Fels Longitudinal Study. Confounder-adjusted regression models were used to test the associations of conditional weight-for-length Z-score, capturing weight change between ages 0-2 years, with young adulthood BMI and blood pressure, including cohort [1933-1949 {N = 137}, 1950-1969 {N = 108}, 1970-1997 {N = 101}] as an effect modifier. RESULTS: Conditional weight-for-length Z-score was positively related to adulthood BMI, but there was significant effect modification by birth year cohort such that the association was over two times stronger in the 1970 1997 cohort (beta 2.31; 95% confidence interval 1.59, 3.03) compared with the 1933-1949 (0.98; 0.31, 1.65) and 1950-1969 (0.87; 0.21, 1.54) cohorts. A similar pattern was found for systolic blood pressure. CONCLUSIONS: The infant weight gain-adulthood BMI association was over two times stronger among a cohort born during the obesity epidemic era compared with cohorts born earlier in the 20th century. PMID- 29493108 TI - Residual confounding in the study by van Dalem et al. PMID- 29493110 TI - Cytological investigation of a first case of basal cell adenocarcinoma arising in the minor salivary glands. Case report and review of the literature. AB - Basal cell adenocarcinoma (BCAC) of salivary glands is uncommon low-grade malignancy. Only 19 cases of preoperative cytology were reported up to date. We present here a new case of BCAC arising in the minor salivary gland. Tumor was composed of clustered or isolated roundish, dark cells with small and regular nuclei. Chromatin was dusty with small nucleoli. Cytoplasm was gray and scant. Clusters showed typical and characteristic basal architecture with peripheral palisading neighboring eosinophilic basal membranes. A false-negative diagnosis of basal cell adenoma was rendered. In our knowledge it is the first cytological description of BCAC arising in the minor salivary gland. PMID- 29493111 TI - Neonatal outcomes following fresh as compared to frozen/thawed embryo transfer in in vitro fertilization. AB - In vitro fertilization (IVF) and embryo cryopreservation have become increasingly common in recent years. As utilization increases, it is important to understand the clinical effects these technologies have on offspring, as well as the mechanisms behind these effects. Many epidemiologic studies have observed that pregnancies following IVF are more likely to be affected by obstetric complications such as pre-eclampsia, preterm birth, and small for gestational age neonates compared with naturally conceived pregnancies. There has been a great deal of research emerging suggesting that these differences are related to the supraphysiologic hormonal environment that results from ovarian superovulation. While pregnancies resulting from frozen embryo transfer are less likely to experience these complications, babies born after frozen transfer are more likely to be large for gestational age. Epigenetic studies point toward differential methylation of genes critical for growth that may be responsible for the increased incidence of larger neonates following transfer of vitrified embryos. Although it does appear that perinatal outcomes are improved by transferring frozen embryos instead of fresh, it would be premature at this time to recommend universal freeze-all protocols in all patients. This article, as part of the "IVF Reviews" special issue of this journal, aims to expound on the issues outlined above. PMID- 29493109 TI - Molecular mechanism and therapy application of necrosis during myocardial injury. AB - Necrosis is an ancient topic which gains new attraction in the research area these years. There is no doubt that some necrosis can be regulated by genetic manipulation other than an accidental cell death resulting from physical or chemical stimuli. Recent advances in the molecular mechanism underlying the programmed necrosis show a fine regulation network which indicates new therapy targets in human diseases. Heart diseases seriously endanger our health and have high fatality rates in the patients. Cell death of cardiac myocytes is believed to be critical in the pathogenesis of heart diseases. Although necrosis is likely to play a more important role in cardiac cell death than apoptosis, apoptosis has been paid much attention in the past 30 years because it used to be considered as the only form of programmed cell death. However, recent findings of programmed necrosis and the related signalling pathways have broadened our horizon in the field of programmed cell death and promote new pharmacological application in the treatment of heart diseases. In this review, we summarize the advanced progress in these signalling pathways and discuss the pathos-physiological relevance and therapeutic implication of targeting necrosis in heart diseases treatment. PMID- 29493112 TI - Synergetic Exfoliation and Lateral Size Engineering of MoS2 for Enhanced Photocatalytic Hydrogen Generation. AB - Generally, exfoliation is an efficient strategy to create more edge site so as to expose more active sites on molybdenum disulphide (MoS2 ). However, the lateral sizes of the resultant MoS2 monolayers are relatively large (~50-500 nm), which retain great potential to release more active sites. To further enhance the catalytic performance of MoS2 , a facile cascade centrifugation-assisted liquid phase exfoliation method is introduced here to fabricate monolayer enriched MoS2 nanosheets with nanoscale lateral sizes. The as-prepared MoS2 revealed a high monolayer yield of 36% and small average lateral sizes ranging from 42 to 9 nm under gradient centrifugations, all exhibiting superior catalytic performances toward photocatalytic H2 generation. Particularly, the optimized monolayer MoS2 with an average lateral size of 9 nm achieves an apparent quantum efficiency as high as 77.2% on cadmium sulphide at 420 nm. This work demonstrates that the catalytic performances of MoS2 could be dramatically enhanced by synergistic exfoliation and lateral size engineering as a result of increased density of active sites and shortened charge diffusion distance, paving a new way for design and fabrication of transition-metal dichalcogenides-based materials in the application of hydrogen generation. PMID- 29493113 TI - Aberrant intrinsic functional connectivity in thalamo-cortical networks in major depressive disorder. AB - OBJECTIVE: Growing evidence has implicated dysfunction of the thalamus and its projection cortical targets in depression. However, the anatomical specificity of thalamo-cortical connectivity in major depressive disorder (MDD) remains unknown due to the regional heterogeneity of the thalamus and limited methods to examine this. METHODS: Resting-state fMRI was collected on 70 MDD patients and 70 healthy controls. The thalamus was parcellated based on connectivity with six predefined cortical regions of interest (ROIs). The segmented thalamic nuclei were used as seeds to map connectivity with the rest of the whole brain. The cortical-to thalamus connectivity values and thalamus-based connectivity maps were compared between groups. RESULTS: The cortical ROIs demonstrated correlations with spatially distinct zones within the thalamus. We found a trend toward reduced parietal ROI-to-thalamus connectivity in MDD. Importantly, MDD patients demonstrated reduced connectivity between prefrontal and parietal thalamus ROIs and bilateral middle frontal gyrus (MFG) and the right posterior default mode network (DMN) and between the prefrontal and motor thalamus ROIs and lateral temporal regions. Conversely, increased connectivity emerged between the motor thalamus ROI and right MFG and right medial frontal gyrus/anterior cingulate; between motor/somatosensory thalamus ROIs and right posterior DMN; between prefrontal/somatosensory thalamus ROIs and cerebellum; and between the parietal thalamus ROI and left insula. CONCLUSIONS: This study is the first to examine the anatomical specificity of thalamo-cortical connectivity disturbances in MDD. Subjects with MDD demonstrated altered thalamo-cortical connectivity characterized by a complex pattern of region-dependent hypo- or hyperconnectivity. We therefore speculate that selectively modulating the connectivity of thalamo-cortical circuitry may be a potential novel therapeutic mechanism for MDD. PMID- 29493114 TI - Cytomorphologic patterns of Pap and PAS-stained oral exfoliative cytology smears in adult Saudi diabetic patients as compared to healthy controls. AB - INTRODUCTION: Diabetes mellitus (DM) is one of the most common metabolic disorders worldwide and 425 million people were estimated to have diabetes by 2017. Oral manifestations reflect the metabolic control of diabetes. Exfoliative cytology using Papanicolaou (Pap) and periodic acid Schiff (PAS) stains is a practical technique to evaluate oral epithelial cytomorphologic changes in diabetes. AIM: This study analyzes the cytomorphologic changes and the glycogen content in exfoliated oral epithelial cells among diabetic patients as compared to healthy controls using Pap and PAS stains to verify the utility of exfoliative cytology as adjunct to diagnosis, follow up or screening of diabetes. SUBJECTS AND METHODS: Eighty-nine participants; 38 adult diabetic patients (case group) and 51 age-matching nondiabetics (control group) were enrolled in the study after fulfilling appropriate inclusion and exclusion criteria. Sampling and staining procedures were performed using routine protocols. Slides were observed by two pathologists and categorized as inflammatory, dyskaryotic and negative. Glycogen content was expressed as PAS negative or +, ++, and +++ positive. RESULTS: The difference between the diabetics and the controls was statistically significant regarding inflammatory, dyskaryotic/nuclear changes and glycogen content and staining intensity. Other observed finding in diabetic patient smears included binucleation, polychromic, and/or vacuolated cytoplasm. CONCLUSIONS: Cytomorphologic changes of oral epithelial cells reflect the complex pathological mechanisms by which DM affects cellular metabolism and function. Cytomorphologic patterns of Pap and PAS-stained oral exfoliative cytology smears can be helpful for diagnosis, follow up as well as for screening for diabetes in high prevalence communities. PMID- 29493115 TI - Temperature-controlled liquid-liquid microextraction combined with high performance liquid chromatography for the simultaneous determination of diazinon and fenitrothion in water and fruit juice samples. AB - A simple, environmentally benign, and rapid method based on temperature controlled liquid-liquid microextraction using a deep eutectic solvent was developed for the simultaneous extraction/preconcentration of diazinon and fenitrothion. The method involved the addition of deep eutectic solvent to the aqueous sample followed by heating the mixture in a 75 degrees C water bath until the solvent was completely dissolved in the aqueous phase. Then, the resultant solution was cooled in an ice bath and a cloudy solution was formed. Afterward, the mixture was centrifuged and the enriched deep eutectic solvent phase was analyzed by high-performance liquid chromatography with ultraviolet detection for quantification of the analytes. The factors affecting the extraction efficiency were optimized. Under the optimized extraction conditions, the limits of detection for diazinon and fenitrothion were 0.3 and 0.15 MUg/L, respectively. The calibration curves for diazinon and fenitrothion exhibited linearity in the concentration range of 1-100 and 0.5-100 MUg/L, respectively. The relative standard deviations for five replicate measurements at 10.0 MUg/L level of analytes were less than 2.8 and 4.5% for intra- and interday assays, respectively. The developed method was successfully applied to the determination of diazinon and fenitrothion in water and fruit juice samples. PMID- 29493116 TI - Serum IGFBP-2 levels are associated with reduced insulin sensitivity in obese children. AB - Insulin-like growth factor binding protein 2 (IGFBP-2) may represent a critical link between body composition and insulin sensitivity. We investigated the relationship between circulating IGFBP-2 levels, body composition, insulin sensitivity, energy intake and physical activity in children with obesity. Children were recruited via the Weight Management Service at the Royal Children's Hospital, Melbourne, as part of the Childhood Overweight BioRepository of Australia (COBRA). Comprehensive anthropometric, biochemical and environmental data were collected and compared to serum IGFBP-2 levels (measured by enzyme linked immunosorbent assay). Multiple regression modelling was used to assess the influence of circulating IGFBP-2 levels on anthropometric and biochemical measures. One hundred and ninety-four children were included in this study (46% male). Circulating IGFBP-2 negatively correlated with age, anthropometric measures, blood pressure and insulin concentration. Positive associations were observed between insulin sensitivity index-homeostasis model assessment (ISI HOMA) and serum IGFBP-2. In multiple regression modelling, IGFBP-2 significantly contributes to variance in systolic blood pressure (-19%, P < 0.05), circulating triglycerides (-16%, P < 0.05) and ISI-HOMA (18%, P < 0.05). No associations were observed between dietary energy intake or physical activity and IGFBP-2 levels. Circulating IGFBP-2 levels in children with obesity correlate inversely with body mass and markers of metabolic dysfunction, and positively with insulin sensitivity. These findings suggest that reduced levels of IGFBP-2 may play an important role in the pathogenesis of obesity complications in early life. PMID- 29493117 TI - High-Potential Metalless Nanocarbon Foam Supercapacitors Operating in Aqueous Electrolyte. AB - Light-weight graphite foam decorated with carbon nanotubes (dia. 20-50 nm) is utilized as an effective electrode without binders, conductive additives, or metallic current collectors for supercapacitors in aqueous electrolyte. Facile nitric acid treatment renders wide operating potentials, high specific capacitances and energy densities, and long lifespan over 10 000 cycles manifested as 164.5 and 111.8 F g-1 , 22.85 and 12.58 Wh kg-1 , 74.6% and 95.6% capacitance retention for 2 and 1.8 V, respectively. Overcharge protection is demonstrated by repetitive cycling between 2 and 2.5 V for 2000 cycles without catastrophic structural demolition or severe capacity fading. Graphite foam without metallic strut possessing low density (~0.4-0.45 g cm-3 ) further reduces the total weight of the electrode. The thorough investigation of the specific capacitances and coulombic efficiencies versus potential windows and current densities provides insights into the selection of operation conditions for future practical devices. PMID- 29493118 TI - Greater early postprandial suppression of endogenous glucose production and higher initial glucose disappearance is achieved with fast-acting insulin aspart compared with insulin aspart. AB - AIM: To investigate the mechanisms behind the lower postprandial glucose (PPG) concentrations achieved with fast-acting insulin aspart (faster aspart) than with insulin aspart (IAsp). MATERIALS AND METHODS: In a randomized, double-blind, crossover trial, 41 people with type 1 diabetes received identical subcutaneous single faster aspart and IAsp doses (individualized for each participant), together with a standardized mixed meal (including 75 g carbohydrate labelled with [1-13 C] glucose). PPG turnover was determined by the triple-tracer meal method using continuous, variable [6-3 H] glucose and [6,6-2 H2 ] glucose infusion. RESULTS: Insulin exposure within the first hour was 32% greater with faster aspart than with IAsp (treatment ratio faster aspart/IAsp 1.32 [95% confidence interval {CI} 1.18;1.48]; P < .001), leading to a 0.59-mmol/L non significantly smaller PPG increment at 1 hour (DeltaPG1h ; treatment difference faster aspart-IAsp -0.59 mmol/L [95% CI -1.19; 0.01]; P = .055). The trend towards reduced DeltaPG1h with faster aspart was attributable to 12% greater suppression of endogenous glucose production (EGP; treatment ratio 1.12 [95% CI 1.01; 1.25]; P = .040) and 23% higher glucose disappearance (1.23 [95% CI 1.05; 1.45]; P = .012) with faster aspart than with IAsp during the first hour. Suppression of free fatty acid levels during the first hour was 36% greater for faster aspart than for IAsp (1.36 [95% CI 1.01;1.88]; P = .042). CONCLUSIONS: The trend towards improved PPG control with faster aspart vs IAsp in this study was attributable to both greater early suppression of EGP and stimulation of glucose disappearance. PMID- 29493119 TI - Modeling Composite Assessment Data Using Item Response Theory. AB - Composite assessments aim to combine different aspects of a disease in a single score and are utilized in a variety of therapeutic areas. The data arising from these evaluations are inherently discrete with distinct statistical properties. This tutorial presents the framework of the item response theory (IRT) for the analysis of this data type in a pharmacometric context. The article considers both conceptual (terms and assumptions) and practical questions (modeling software, data requirements, and model building). PMID- 29493121 TI - Endolysosomal-Escape Nanovaccines through Adjuvant-Induced Tumor Antigen Assembly for Enhanced Effector CD8+ T Cell Activation. AB - The activation of tumor-specific effector immune cells is key for successful immunotherapy and vaccination is a powerful strategy to induce such adaptive immune responses. However, the generation of effective anticancer vaccines is challenging. To overcome these challenges, a novel straight-forward strategy of adjuvant-induced tumor antigen assembly to generate nanovaccines with superior antigen/adjuvant loading efficiency is developed. To protect nanovaccines in circulation and to introduce additional functionalities, a biocompatible polyphenol coating is installed. The resulting functionalizable nanovaccines are equipped with a pH (low) insertion peptide (pHLIP) to facilitate endolysosomal escape and to promote cytoplasmic localization, with the aim to enhance cross presentation of the antigen by dendritic cells to effectively activate CD8+ T cell. The results demonstrate that pHLIP-functionalized model nanovaccine can induce endolysosomal escape and enhance CD8+ T cell activation both in vitro and in vivo. Furthermore, based on the adjuvant-induced antigen assembly, nanovaccines of the clinically relevant tumor-associated antigen NY-ESO-1 are generated and show excellent capacity to elicit NY-ESO-1-specific CD8+ T cell activation, demonstrating a high potential of this functionalizable nanovaccine formulation strategy for clinical applications. PMID- 29493120 TI - Mitochondrial Acetyl-CoA Synthetase 3 is Biosignature of Gastric Cancer Progression. AB - Cholesterol affects cancer progression, and acetyl-CoA is the primary cholesterogenesis substrate. The previous work has defined cholesterol bioflux via lipoprotein/receptor route is the gastric cancer (GCa) prognosis biosignature. The prognosis importance of acetyl-CoA to cholesterogenesis (mevalonate pathway) in GCa is yet to be defined. Using Kaplan-Meier Plotter web based gene survival analyzer and The Cancer Genome Atlas (TCGA)-database analyzed with DBdriver.v2 platform, we revealed acetyl-CoA production and the mevalonate pathway are associated with GCa prognosis. We found mitochondrial-derived acetyl CoA contributing enzymes (acyl-coA synthetase super-family 3; ACSS3) is the GCa progression confounder. Interestingly, it is not HMGCR (the committee enzyme of mevalonate pathway), but lower mevalonate pathway enzymes (e.g., MVK, LSS, DHCR14A1, SC4MOL, HSD17B7, SC5D) promote GCa patients 5-years overall survival in a differential level. Advanced analyses found ACSS3 is prognosis biosignatures for multiple GCa disease conditions. This report uncovered a higher expression of ACSS3 in tumor comparing to normal parental lesions, which implicates a targeting value for GCa therapy. While knockdown ACSS3 could suppress growth and invasion of GCa cells, of which even more impactful under starvation condition. This is the first report, surprisingly, revealed ACSS3 as important cancer prognosis biomarker. Targeting ACSS3 could be a novel therapeutic strategy for cancer, in this case, GCa. PMID- 29493124 TI - For Debate: Combination Growth Hormone and Insulin-Like Growth Factor-I Therapy for Childhood Growth Disorders: Prime Time or Too Much Dime? AB - Although metabolic outcomes may be aided by dual therapy with GI and IGF-I, the one published study of the combination approach to treat children with non-GH deficient short stature showed only a meager additional height response compared to that achieved with GH alone. PMID- 29493122 TI - The longitudinal relationship between community programmes and policies to prevent childhood obesity and BMI in children: the Healthy Communities Study. AB - BACKGROUND: Although a national epidemic of childhood obesity is apparent, how community-based programmes and policies (CPPs) affect this outcome is not well understood. OBJECTIVES: This study examined the longitudinal relationship between the intensity of CPPs in 130 communities over 10 years and body mass index (BMI) of resident children. We also examined whether these relationships differ by key family or community characteristics. METHODS: Five thousand one hundred thirty eight children in grades K-8 were recruited through 436 schools located within 130 diverse US communities. Measures of height, weight, nutrition, physical activity and behavioural and demographic family characteristics were obtained during in-home visits. A subsample of families consented to medical record review; these weight and height measures were used to calculate BMI over time for 3227 children. A total of 9681 CPPs were reported during structured interviews of 1421 community key informants, and used to calculate a time series of CPP intensity scores within each community over the previous decade. Linear mixed effect models were used to assess longitudinal relationships between childhood BMI and CPP intensity. RESULTS: An average BMI difference of 1.4 kg/m2 (p-value < 0.01) was observed between communities with the highest and lowest observed CPP intensity scores, after adjusting for community and child level covariates. BMI/CPP relationships differed significantly by child grade, race/ethnicity, family income and parental education; as well as community-level race/ethnicity. CONCLUSIONS: These results indicate that, over time, more intense CPP interventions are related to lower childhood BMI, and that there are disparities in this association by sociodemographic characteristics of families and communities. PMID- 29493125 TI - Genetics of Primary Congenital Hypothyroidism. AB - Congenital hypothyroidism (CH) is one of the most common preventable forms of mental retardation and since the implementation of neonatal screening programs in the mid-1970s, early detection and treatment have proven to be very successful in preventing brain damage. CH may be of thyroidal (= primary) or of hypothalamic pituitary (= central) origin. Primary CH may be due to abnormal thyroid gland formation (dysgenesis) or defective thyroid hormone syntheses by a structurally normal gland (dyshormonogenesis). While thyroid dysgenesis is the most common form of CH, accounting for approximately 85% of cases, genetic defects are only found in a very low proportion of patients. On the other hand, thyroid dyshormonogenesis is less common, but is usually a genetic condition with autosomal recessive inheritance. In this review we provide an overview of all known monogenetic causes of primary CH, including promising new candidate genes. In addition, alternative genetic mechanisms are discussed. PMID- 29493126 TI - Prolactin - Not Only a "Milk Hormone" Prolactin - Growth Hormone Relationships with Emphasis on Cancer. AB - Prolactin (PRL) is a hormone secreted by lactotrophic cells in the anterior pituitary gland and its main function is the stimulation of lactogenesis. Research in recent years has revealed that PRL is also related to cancer development and plays a role in autoimmune diseases. PRL and Growth Hormone (GH) belong to the same cytokine family, both are, at least in part, secreted by the same somatomammotrophic cells in the anterior pituitary, and share similar signaling pathways. These common features raise the question whether PRL and GH share also joint actions especially in the pathogenesis of cancer. PMID- 29493127 TI - Options for Fertility Preservation in Children. AB - Fertility preservation therapies can conserve future reproductive potential for persons facing serious medical diagnoses. With cure rates for childhood cancer reaching almost 80%, quality-of-life concerns for long-term survivors, including future parenting, are becoming more pertinent. Late effects of childhood cancer can be divided into physical, social, psychological, and spiritual domains. Potential loss of fertility threatens the well-being of these children in all these domains. Providers often hesitate to discuss fertility preservation with the patients. However, parental attitudes toward discussion of fertility preservation have been found to be open to such conversations for both prepubertal and postpubertal children who have a cancer diagnosis. Multiple national and international organizations recommend discussion with all persons having gonadotoxic therapy, including children, regarding the effect of planned treatment on future fertility and their options for fertility preservation. Renal or rheumatologic disease treated with high-dose cyclophosphamide and chromosomal anomalies such as Turner or Klinefelter syndrome may be amenable to fertility preservation. This essay reviews fertility preservation options available to children, as well as the expanding list of indications for fertility preservation. PMID- 29493128 TI - Fertility Preservation in Pubertal and Pre-Pubertal Boys with Cancer. AB - Children diagnosed with cancer continue to have improved survival due to advances in effective treatment options. Increased attention is therefore now focused on quality of life issues once they are cured. Fertility preservation is of paramount concern since gonadotoxic treatments, especially radiation and chemotherapy, often impair future fertility. The importance of family counseling and having an informed discussion about the potential for treatment to impair fertility and the options available for fertility preservation is crucial. However, fertility preservation in prepubertal boys is challenging, but not impossible. Experimental methods are being investigated including cryopreservation of immature testicular tissue, xenografting, and in vitro germ cell maturation. Despite the success and relative ease of sperm banking, barriers exist and affect the number of patients offered treatment. Education and awareness of the possibilities can overcome these barriers. In this way we will continue to preserve young patients' future fertility and quality of life. PMID- 29493129 TI - Present Knowledge on the Etiology and Treatment of Adrenarche. AB - Premature adrenarche (PA) has been assumed to be a benign variant of normal pubertal development. Yet, current collective information suggests associations between PA and potential risks for development of polycystic ovary syndrome and adult diseases such as the metabolic syndrome. Adrenarche refers to the increased secretion of the adrenal androgen precursors DHEA, DHEAS, and androstenedione, which normally occurs in children at age 6-8 years. PA may be identified clinically by early pubarche, which is defined as the development of pubic or axillary hair before 8 years in girls or 9 years in boys. This paper will consider adrenal steroidogenesis, genetic markers, neurobiological changes, skeletal maturation, and associations with adult disorders. The differential diagnosis will be reviewed because PA remains a diagnosis of exclusion. Finally, synthesis of current knowledge regarding PA, suggestions for evaluation, management, and treatment are offered. PMID- 29493130 TI - Meeting Report: 2017 International Joint Meeting of Pediatric Endocrinology Washington DC (September 14-17, 2017) Selected Highlights. PMID- 29493132 TI - [Bio-adhesive drug delivery system and its application in traditional Chinese medicine]. AB - Bio-adhesive drug delivery system (BDDS) is a novel drug delivery system, which can prolong the retention time of the preparation, improve the stability of the drug, and improve the mucosa absorption and the targeting of the drug. With the development of polymer materials over the past 30 years, BDDS made a great progress. This paper reviews the muco-adhesion theory, adhesive materials, and methods to evaluate muco-adhesive properties and applications in traditional Chinese medicine according to domestic and foreign literatures, in order to provide new ideas for further studies. PMID- 29493131 TI - [Risk control of traditional Chinese medicines containing aristolochis acids (AAs) based on influencing factors of content of AAs]. AB - Aristolochic acids (AAs) widely exist in such plants as Aristolochia and Asarum. The renal toxicity of AAs as well as its carcinogenicity to urinary system have been widely known. In 2003 and 2004, China prohibited the use of Aristolochiae Radix, Aristolochiae Manshuriensis Caulis and Aristolochiae Fangchi Radix, and required administering other AAs-containing medicines in accordance with the regulations for prescription drugs. In this paper, we retrieved literatures on the content determination of AAs in recent 10 years in China. It suggested that the AAs content is lower in Asarum herb, especially in its roots and rhizomes, and most of which do not show detectable amount of AA-I. Some of traditional Chinese medicines show fairly small amount of detectable AA-I. The AAs content in Aristolochia herb (including Fructus Aristolochiae, kaempfer dutchmanspipe root) is relatively high; however, there are fewer literatures for studying the content determination of AAs in Chinese patent medicines. There were many factors affecting AAs content, including the parts used, origins, processing methods, extraction process. It suggested that we should pay attention to the toxicity of Chinese medicines containing AAs and use these decoction pieces and traditional Chinese medicines cautiously. In addition, basic studies for the origins, processing methods and extraction process of Chinese patent medicines containing AAs, as well as supervision and detection of AAs content in traditional Chinese medicinal materials, decoction pieces and Chinese patent medicines shall be strengthened for reducing medication risk and guaranteeing clinical medication safety. PMID- 29493133 TI - [Pharmacological actions and mechanism of saponins from Dioscorea nipponica]. AB - Dioscorea nipponica, a famous traditional Chinese medicine, belongs to the Dioscoreaceae family and has been widely distributed in the north, northeast and Qinghai regions of China. With its root and rhizome as an important herb material, it has been applied in China for several thousand years. Traditional Chinese medicine reported that this plant had been used for relieving cough and asthma, eliminating rheumatic aches, alleviating pain and improving blood circulation. Modern pharmacology studies have confirmed that saponins, the major active compounds in this herb, have shown various pharmacological actions including anti-tumor, anti-inflammatory,lipid-lowering, anti-fungal and anti virus activities. Therefore, the studies on saponins from D. nipponica are valuable and promising. In this present research, the pharmacological actions, therapeutic effects and mechanism of saponins from D. nipponica were summarized in order to provide the theoretical basis for the further research. PMID- 29493134 TI - [Research advances on astragaloside-IV in treatment of diabetes mellitus and its complications pharmacological effects]. AB - Diabetes has become a global public health problem that seriously threatens human health. Traditional Chinese medicine, the characteristics of the role of multiple targets, has a unique advantage in the prevention and treatment of diabetes mellitus and its complications. Astragaloside-IV (AS-IV), one of the main activities of Astragalus membranaceus, has a series of pharmacological effects including improvement in the function of endothelial cells and neovascularization, anti-inflammatory, antioxidant, regulating energy metabolism, protectionnervous, anti-cancer and so on. In this paper, AS-IV to prevent and treat diabetes and its complications has been reviewed, which has effect on lowering blood sugar, lowering blood pressure, improving insulin resistance, inhibiting inflammatory reaction and oxidative stress. Additionally, it also can improve the diabetic animal and cell model of diabetic vascular disease, diabetic nephropathy, diabetic retinopathy, diabetic peripheral neuropathy, diabetic cardiomyopathy and other pathological damages. AS-IV may be a potential active substance for the treatment of diabetes and its complications. PMID- 29493135 TI - [Neoflavonoids and their pharmacological activities in Dalbergia genus]. AB - Neoflavonoids are a kind of characteristic components in the Dalbergia genus. Based on the previous researches, 59 neoflavonoids have been obtained from the Dalbergia genus. According to their molecular skeleton, the neoflavonoids can be divided intodalbergiphenols, dalbergiones, dalbergins, benzophenones and other types. Modern research shows that neoflavonoids displayed a variety of pharmacological activities, such as anti-osteoporosis, anti-inflammatory, antitumor, anti-androgen, anti-allergic, antioxidation etc. This paper reviewed neoflavonoids and their pharmacological functions, which could provide the valuable reference for comprehensive utilization and new drug development in the Dalbergia genus. PMID- 29493136 TI - [Antagonistic effect of ginkgolide homologues on PAF-induced platelet aggregation and neuroprotective effect]. AB - To study the antagonistic effect of ginkgolide homologues on platelet-activating factor (PAF)-induced platelet aggregation and investigate its neuroprotective effect. PAF was used as a coagulant, and ginkgolides were added to the rabbit blood samples respectively. The inhibitory effect of each compound on platelet aggregation was detected by turbidimetry. In L-glutamate induced primary cortical neuron cell injury model, MTT assay was used to detect cell viability. Intracellular free Ca2+ concentration in neurons was measured by using the fluorescent Ca2+ indicator Fura-2 AM. Morphological observation and Hoechst 33258 staining were used to detect the inhibitory effect of ginkgolide on neuronal apoptosis. The results showed that the inhibitory effect on PAF-induced platelet aggregation activity in ginkgolide homologues was ginkgolide K (GK), ginkgolide B (GB), ginkgolide A (GA), ginkgolide C (GC), ginkgolide M (GM), ginkgolide J (GJ) and ginkgolide (GL) from high to low. GB and GK (1-100 MUmol*L -1) could significantly reduce the cell damage caused by L-glutamate, with survival rate increasing, intracellular calcium concentration reducing and cell morphology restoring. This paper has identified the activities and characteristics of various compounds of ginkgolide homologues on PAF-induced platelet aggregation as well as its neuroprotective effect. PMID- 29493138 TI - [Effects of ginkgolide K on platelet aggregation activity and neuroprotection]. AB - To investigate the antagonism effects of different concentrations of ginkgolide K(GK) on platelet activating factor (PAF)-induced platelet aggregation and neuroprotective effect on cells and animal models of ischemia-reperfusion injury. GK-containing serum in rabbit was prepared, and the effects of GK-containing serum on PAF-induced platelet aggregation was observed by platelet aggregation assay. The effect of different concentrations of GK on apoptosis of SH-SY5Y cells injured by oxygen-glucose deprivation/reoxygenation (OGD/R) was investigated by Hoechst 33342/PI double staining in OGD/R cell model. The focal cerebral ischemia reperfusion model (I/R)was established in rats to detect the effects of GK on neurobehavioral scores and cerebral infarction volume. GK could inhibit PAF induced platelet aggregation, reverse the apoptosis induced by OGD/R injury and improve the neurobehavioral score and cerebral infarction volume after cerebral ischemia-reperfusion injury in rats in a dose-dependent manner. GK can inhibit PAF-induced platelet aggregation and improve nerve injury after cerebral ischemia reperfusion. PMID- 29493137 TI - [Effects of ginkgolide A, B and K on platelet aggregation]. AB - To investigate the effects of ginkgolide A (GA), ginkgolide B (GB) and ginkgolide K (GK) on platelet aggregation in rabbits, and compare the similarities and differences among these three components. The effects of different doses of ginkgolide A, B and K on platelet aggregation induced by platelet activating factor (PAF) were observed by using in vitro experiment. The results showed that three compounds could inhibit platelet aggregation induced by PAF in vitro, and the intensity was GK> GB> GA. It was further found that all of them can mobilize [Ca2+]i and enhance intracellular c-AMP level in a dose-dependent manner, which was consistent to the ability to antagonize PAF receptor. These findings indicated that GK was highly selective for PAF receptor, and may inhibit platelet aggregation by activating cAMP signaling pathway and inhibiting intracellular [Ca2+]i mobilization; GB and GA also had strong antagonism to PAF receptor, but the effect was weaker than that of GK. PMID- 29493139 TI - [Protective effects of Ginkgo Terpene Lactones Meglumine Injection on focal cerebral ischemia in rats]. AB - To investigate the protective effects of ginkgo diterpene lactone meglumine injection (GDLMI) on cerebral focal ischemia reperfusion injury induced by middle cerebral artery occlusion (MCAO) in rats, and explore its possible mechanism. One hundred and forty male SD rats were randomly divided into sham operation group, model group, ginkgo biloba extract injection (Ginaton, 1.0 mL*kg-1) group, nimodipine (0.4 mg*kg-1) group, and GDLMI (5.2, 2.6, 1.3 mg*kg-1) groups; All of rats received corresponding drugs by tail vein injection 4 days before operation (normal saline in model group and sham operation group). Except the sham operation group, the cerebral ischemic stroke model was established by MCAO method in right brain of the other rats. After 3 h of ischemia, all the animals received intravenous administration again. The neurobehavioral scores of rats after ischemia-reperfusion were evaluated and the infarct rate of brain tissue was observed by TTC staining. The super oxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA) and lactic acid (LA) contents in brain tissue homogenate and the concentration of Ca2+, glutamate (Glu) and aspartate (Asp), creatine phosphate kinase (CK-BB) and lactate dehydrogenase (LDH) content changes in cerebrospinal fluid were measured. As compared with the sham operation group, the cerebral infarction rate was increased significantly in the model group; the content of MDA and LA in the homogenate of brain tissue was increased, and the content of GSH and SOD was decreased; in cerebrospinal fluid, Ca2+ concentration was decreased, and the content of Glu and Asp, CK-BB and LDH increased significantly. As compared with the model group, the high and medium dose GDLMI groups can significantly reduce the cerebral infarction rate and improve the symptoms of neurological impairment; increase SOD and GSH activity, reduce MDA and LA content in serum; increase Ca2+ concentration in cerebrospinal fluid and decrease the content of neurotransmitter Glu and Asp as well as CK-BB and LDH. GDLMI could obviously improve neurologic impairment in model rats, and the mechanism may be related to recovering the blood brain barrier, scavenging free radicals, decreasing free Ca2+ inflow into the cells and the content of excitatory amino acid in cerebrospinal fluid to improve its protective effect on cerebral ischemia. PMID- 29493140 TI - [Cerebral vascular protective effect of ginkgo diterpene lactone meglumine injection]. AB - The left middle cerebral artery occlusion (MCAO) model was made by inserting the nylon thread plug into the internal carotid artery. The behavioral score, cerebral infarction area, brain water content, ethidium bromide (EB) spillover, coagulation four indices, occludin and MMP-9 expression in brain tissues were detected after 14 days of administration, to investigate whether the protective effect of ginkgo diterpene lactone meglumine injection (GDLMI) which had obvious protective effect on cerebral ischemic injury in the previous experiment was related to reducing the permeability of the blood-brain barrier (BBB) and reducing the risk of bleeding, and to explore its possible mechanism of action. The results showed that GDLMI could effectively alleviate the behavioral changes caused by MCAO at 24 h, reduce the behavioral score, improve the edema of brain tissue, reduce the EB overflow rate, reduce the bleeding tendency caused by long term administration, significantly reduce the occlusion deficiency in ischemic brain tissue of model rats, and down-regulate MMP-9 expression. The above results indicate that GDLMI has obvious effect on cerebral ischemia, and the therapeutic effect of GDLMI may mainly depend on lowering the permeability of blood-brain barrier to improve brain edema. PMID- 29493141 TI - [Post-marketing study on clinical safety of ginkgo diterpene lactone meglumine injection in 6 300 patients with ischemic stroke]. AB - To further evaluate the safety of ginkgo diterpene lactone meglumine injection in the clinical use in ischemic stroke patients. Clinical safety study was conducted in 82 clinical units and 6 300 cases were completed and included from June 2013 to December 2014 by using multicenter, prospective, open and uncontrolled design methods for clinical research. A total of 29 cases of adverse reactions were observed in the experiment. Adverse reaction ratio (ADR) was 0.46%, and about 86.21% (25 cases) of them was mild with transient response which could be alleviated or disappeared without intervention; about 13.79% (4 cases) was moderate, including 2 cases of headache, 1 case of dizziness and 1 case of rash; no serious adverse reactions were found. The adverse reactions occurred in this study were pre-known adverse reactions or common adverse reactions of Chinese medicine injection. The overall incidence of adverse reactions was low, and the risk was controllable. PMID- 29493142 TI - [Stroke, platelet activating factor and receptor antagonists]. AB - Stroke is an acute cerebrovascular disease with high morbidity, disability and mortality. The prevention and treatment conditions for stroke is severe all over the world. Antiplatelet aggregation is an effective treatment. Platelet activation factor (PAF) is another important medium in mediating platelet aggregation, which plays an important role in the pathogenesis of stroke. In recent years, PAF receptor antagonists have attracted international attention in the field of stroke prevention and treatment. In this review, we would summarize the classification, mechanism and drug characteristics of PAF receptor antagonists in order to provide the valuable guidance and direction for clinical medicine and research. PMID- 29493143 TI - [Influence of exogenous ginsenosides on new forest soil microbial communities]. AB - Ginsenosides are the main active ingredient and allelochemicals of Panax ginseng, and they play an important role in ginseng growth and in ecological adaptation. To study the influence of ginsenosides on soil microbial communities, the method of given exogenous total ginsenosides of different concentrations were used to study the influence of ginsenosides on new forest soil microbial community, evaluate the change of metabolic activity of microbial community and investigate the ecological effect of ginsenosides on soil microbial community. Results showed that, exogenous total ginsenosides promoted metabolic activity of microbial community in new forest soil at different concentrations compared with the control after 10 d and 40 d treatment. After 10 d,except for the Evenness index, all of the other indices indicated that the functional diversity of the soil microbial community in the new forest firstly increased then decreased with increase of the total ginsenosides concentration. The Substrate richness for 0.01 g*L-1 soil treatment was significantly different from that of the control. After 20 d, 30 d and 40 d, except for the Evenness index, all of the other indices indicated that the functional diversity of the soil microbial community in the new forest increased with total ginsenosides. These results suggested that ginsenosids can change soil microbial community and microbial metabolic activity, which alter soil microbial ecology and accordingly affect the growth of ginseng with accumulation of ginsenosides in the soil. PMID- 29493144 TI - [Morphological and microscopical identification of Genkwa Ramulus and its adulterants]. AB - The purpose of this article is to identify Daphne genkwa and its adulterants, Wikstroemia chamaedaphne, according to the morphological and microstructure characteristics of their stem and foliage. The root of D.genkwa was studied simultaneously. The results indicated that the crude drug and processed pieces of Genkwa Ramulus were mainly composed of stems and branches where obvious opposite petiole scars and branch marks were able to be seen on their nodes. Otherwise, foliage or peduncles generally couldn't be found. Moreover, the fine silver flocculent fibers could be observed in the bark of fracture surface. The adulterants were the plant segments which were composed of stems, foliage and peduncles with spikelet-pedicel scars. There existed microstructures differences between Genkwa Ramulus and its adulterants. In the former, single thick lignified phloem fibers were interspersed in the stem phloem of the transverse section with very thick wall and unicellular non-glandular hairs could be observed on the lower epidermis of foliage. Nevertheless, in the latter, there was no thick lignified phloem fibers in cross section of stem phloem, the outer wall of epidermal cells of foliage hadthick cuticles and no non-glandular hairs in lower epidermis of foliage. The results can be used for the identification and the quality standard of the crude drug and processed pieces of D.genkwa.The characteristics of the microstructures and the transverse section can be used to identify the radix D.genkwa. PMID- 29493145 TI - [Correlation analysis between quality and habitat phenotype of Hovenia acerba]. AB - The contents of dihydromyricetin and total flavonoids of Hovenia acerba seeds were detected by HPLC-DAD and UV spectrophotometer. And then the correlation between the habitat, phenotype and quality of H. acerba seeds were deeply studied. There were big differences in both appearance and quality among the H. acerba seeds from different places. It showed that the content of dihydromyricetin in H. acerba seeds was 0.41-9.81 mg*g-1, and the content of total flavonoids was 5.52-21.98 mg*g-1. The cluster analysis showed that the quality of H. acerba seeds was related to the habitat. The samples from Jianghan Plain Area showed relatively stable and excellent quality. According to the correlation analysis, there was a significant positive correlation between 1 000 seeds weight, red-black seeds ratio and the content of dihydromyricetin, while the content of total flavonoids was not related to the 1 000-seeds weight and red black seeds ratio. So the 1 000-seeds weight and red-black seeds ratio could be used as an initial judgment of the quality of H. acerba seeds. As dihydromyricetin and total flavonoids content was not related, both dihydromyricetin and total flavonoids should be taken into account when the quality of H. acerba seeds was studied. PMID- 29493146 TI - [Study on early screening of high saponin ginseng lines]. AB - The study aims at screening the specific bands by PCR, quickly and accurately evaluating the quality of ginseng seeding, accelerating the process of ginseng breeding. Based on the correlation of genetic differences and saponin content between individuals, a pair of specific primer GC1 was screened by PCR. According to the experiment by L16 (45) orthogonal test, a PCR system most suitable for GC1 was established, which came out total 25 MUL reaction system containing DNA 2.60 mg*L-1, Mg2+ 1.44 mmol*L-1, dNTP 0.19 mmol*L-1, primer 0.32 MUmol*L-1 and Taq enzyme concentration 0.076 U*MUL-1. By comparing the saponin content and the GC1 PCR electrophoretogram of samples, the ginseng, with 1 200 bp specific band by PCR of GC1, the contents of 9 monosodium saponins and their additions were higher than others, which provided a reliable method for accelerating the process of ginseng breeding. The sequence was sequenced and 99% homologous to glycerol-3 phosphate dehydrogenase. PMID- 29493147 TI - [Quality of realgar and its influencing factors based on toxicity]. AB - The results of a toxicity analysis showed differences from those of the existing experimental data. Therefore, HPLC-ICP-MS was used to analyze the soluble arsenic content at different valences in realgar prepared with water grind processing, which were collected from 3 companies. The results showed that the free arsenic of the 3 companies did not exceed the limit of Chinese Pharmacopoeia. However, if the free arsenic was calculated based on the total value of As(III) + As(V), free arsenic of 1 company exceeded the limit of Chinese Pharmacopoeia. The method of determining free arsenic in Chinese Pharmacopoeia. was ancient Cai's arsenic detection method, which had a certain limitation and failed to effectively avoid the toxicity of remaining arsenics except for trivalent arsenic. Then, we examined the effects of water and temperature on the content and form of soluble arsenic in realgar. The results showed that the content of soluble arsenic increased with the rise of water content, and the form of soluble arsenic did not change, there were only As (III) and As (V); With the simple temperature factor, there was an increasing trend in the content of soluble arsenic in the samples, the maximum increment was As (III) 2.489 mg*g-1 and As (V) 0.546 mg*g-1; When water and temperature played an synergistic effect, the increase of soluble arsenic in the samples significantly changed, the maximum increment was As (III) 23.690 mg*g-1, As (V) 0.468 mg*g-1, respectively. Through comprehensive analysis, we believed that the quality of realgar was susceptible to water content and temperature. Both of the single effect of water content and the synergistic effect of water and temperature can significantly change the content of soluble arsenic in realgar, and the water content was a high-risk factor. In the current Chinese Pharmacopoeia 2015 version, the free arsenic detection method had limitations, hence new techniques shall be introduced; At the same time, realgar does not have a water content inspection item in the current pharmacopoeia, which shall be added. However, due to the limit of water content, more in-depth studies are required. PMID- 29493148 TI - [Studies on chemical constituents of Clerodendrum bungei]. AB - Ten compounds were isolated from the 95% aqueous EtOH extract of Clerodendrum bungei by a combination of various chromatographic techniques including column chromatography over silica gel, Sephadex LH-20, MCI, ODS, and semi-preparative HPLC. Their structures were elucidated as 11,12,16S-trihydroxy-7-oxo-17(15 >16),18(4->3)-diabeo-abieta-3,8,11,13-tetraen-18-oic acid (1), 12S*,13R* dihydroxy-9-oxo-octadeca-10(E)-enoic acid (2), clerodenoside A (3), trichotomoside (4), glycosmisic acid (5), 4'-O-methylscutellarein (6), neroplomacrol (7), butylitaconic acid (8), hexylitaconic acid (9), p hydroxybenzonic acid (10) by their physicochemical properties and spectroscopic data. Compounds 1 and 2 are new natural products, while compounds 7-10 were obtained from the genus Clerodendrum for the first time, and compounds 3, 5, 6 were isolated from this plant for the first time. PMID- 29493149 TI - [Anti-complement alkaloids from whole plants of Viola yedoensis]. AB - Fifteen alkaloids were isolated from the 95% ethanol extract of the whole plants of Viola yedoensis by various column chromatographic techniques such as silica gel and Sephadex LH-20. Their structures were identified as neoechinulin A(1),N benzoyl-L-p-hydroxy-phenylalaninol(2),aurantiamide acetate(3),aurantiamide(4),anabellamide(5),trichosanatine(6),indole-3-carboxylic acid methyl ester(7),3-carboxyindole(8),N-trans-feruloyl tyramine(9),paprazine(10),7'-(3', 4'-dihydroxyphenyl)-N-[(4 methoxyphenyl)ethyl]propenamide(11),cannabisin F(12),N-(4 hydroxyphenethyl)octacosanamide(13),N-(4-hydroxyphenethyl)hexacosanamide(14)and N benzoyl-L-phenylalaninol(15). All the compounds except 3 and 4 were isolated from this plant for the first time. These alkaloids exhibited anti-complement activity against the classical pathway(CP)and the alternative pathway(AP)with the CH50 and AP50 values ranging from 0.12 to 0.33 g*L-1 and 0.22 to 0.50 g*L-1, respectively. Preliminary mechanism study using complement-depleted sera showed that these alkaloids acted on different complement components in the complement activation cascade. PMID- 29493150 TI - [Determination of mycotoxins in pu-erh tea, black tea, and green tea samples]. AB - To establish a robust method for the determination of mycotoxins in tea samples, and to provide means for the quality and safety control of tea products. Samples of 20 tea products acquired from international market were extracted by organic solvents (acetonitrile containing 0.1% formic acid) or hot water, respectively. The extracts were analyzed by UPLC-MS/MS.A good linear regression was achieved in a range of 39.1 to 5 000 ng*L-1 for aflatoxin B1 (AFB1) and aflatoxin G1 (AFG1), 117 to 15 000 ng*L-1 for aflatoxin B2 (AFB2) and aflatoxin G2 (AFG2), 2.44 to 313 ng*L-1 for fumonisin B1 (FB1), fumonisinB2 (FB2) and fumonisin B3 (FB3), and 3 125 to 5 000 ng*L-1 for deoxynivalenol, with recovery rates between 85.7% and 99.6%. The coefficient of the linear equation for all standards was greater than 0.999 0, and the RSD value was less than 10%. Mycotoxins were detected in several tea samples using the two extraction methods but with different outcomes. The levels of mycotoxins detected ranging from 0.15 to 7.31 MUg*kg-1 were well below the State or US FDA regulation limits of mycotoxins in food products. Both methods are simple, accurate, and sensitive, and thus, suitable for the quantitative determination of mycotoxins in different food products. The method with the 80 C hot-water extraction is more appropriate to determine the trace amounts of mycotoxins in tea leaves that are likely to be present in brewed tea liquor, while organic solvent method is more suitable for the detection of mycotoxins in ingestible foods. PMID- 29493151 TI - [Determination of eight components in Lamiophlomis rotate by UPLC method and preliminary study on influencing factors of contents]. AB - To establish a method for simultaneous determination of the contents of sesamoside, menthyl chloride, chlorogenic acid, caffeic acid, 8-O-acetyl phloridzin methyl ester, forsythiaside B, luteolin, and ergosterol, the LIPLC analysis was performed on a Kinetex XB-C18 (4.6 mm*50 mm,2.6 MUm)column with acetonitrile (A)-0.1% phosphoric acid solution (B) as the mobile phase. The flow rate is 1.0 mL min-1. The detection wavelength was 238, 320 and 350 nm and column temperature was 30 C. The results showed that the eight components could be completely separated with good linear relationships (r>=0.999 8) in the linear range. The average recoveries were 96.61%-100.4%. The method was simple with strong specificity and high precision. It can be used for the identification and quality evaluation of the Lamiophlomis rotate.The results also showed that there was a correlation between the various components, and the habitat was the main factor affecting the content of the eight components. However, the degradation gradient had no obvious effect on the contents, while the content of sesamoside was significantly decreased after one year of storage. PMID- 29493152 TI - [Structural characterization of Glehniae Radix polysaccharides using partial acid hydrolysis-hydrophilic interaction liquid chromatography-mass spectrometry]. AB - Water-soluble polysaccharides from traditional Chinese medicine have properties of complex structure and high molecular, resulting in hardly complete their structural characterization.However, a "bottom-up" approach could solve this problem.Glehniae Radix extract was extracted with hot water and then precipitated by 40% ethanol to obtain Glehniae Radix polysaccharides (RGP). Subsequently, a partial acid hydrolysis method was carried out and the effects of acid concentration, time and temperature on hydrolysis were investigated. Under the optimum hydrolysis condition (1.5 mol*L-1 trifluoroacetic acid, 4 h, and 80 C), RGP were hydrolyzed to characteristic oligosaccharide fragments. Futher, a hydrophilic liquid chromatography- mass spectrometry method was used for the separation and structural characterization of the polysaccharide hydrolysates. According to MS and MS/MS analysis of several standard disaccharides, a method for determining the type of polysaccharide glycosidic linkage by mass spectrometry was established. The results showed that the polysaccharide hydrolysates were linear glucan containing 1, 4-glycosidic bonds. And gluco oligosaccharides with the degrees of polymerization (DP) of 4-11 were obtained after partial acid hydrolysis. PMID- 29493153 TI - [Research on improving memory impairment of blue lavender volatile oil]. AB - In order to study the potential application value of lavender volatile oil (LVO), the chemical composition of the volatile oil of lavender was analyzed by GC-MS, and the mouse model of Alzheimer's disease (AD) was established. Additionally, the antioxidant enzymes activity of T-SOD, GSH-PX, CAT and MDA content were studied. Experimental results showed that 55 kinds of chemical constituents including terpene, terpene alcohol and ester compounds from LVO were identified, and the content of linalool and linalyl acetate was the highest, accounting for 49.71% of the total volatile oil. The ability of mouse platform memory was improved significantly. The levels of GSH-PX, CAT and T-SOD of mouse brain tissue in the treatment group were significantly higher than those in the model group (P<0.05). The level of MDA reached the maximum value in the model group, while there was no notable difference between the levels of MDA in the drug group and the normal group. The result indicated the significant oxidative activity of LVO, the possibility of induced oxidative stress reduction in neurons, and the reversal effect of memory acquired disorder. PMID- 29493154 TI - [Transcriptional regulation effect of THSG and anthraquinones in tubers of Polygonum multiflorum based on human progesterone X receptor (PXR) mediated CYP3A4 rapid screening system]. AB - The rapid screening technology was used to investigate the transcriptional regulation effect of main chemical constituents in tubers of Polygonum multiflorum, including 2,3,5,4'-tetrahydroxystilbene-2-O-beta-D glucopyranoside(THSG) and anthraquinones (such as rhein, chrysophanol, aloe emodin, emodin) on CYP3A4 drug inducers induced by human pregnancy X receptor (PXR).The effect of chemical composition on the cell activity was detected by MTS cell viability assay. IC50 was calculated. The expression vector and the reporter vector were co-transfected into HepG2 cells, with 10 MUmol*L-1 rifampicin (RIF) as a positive control, and 10 MUmol*L-1 ketoconazole (TKZ) as a negative control. After treated with different concentrations of anthraquinones (2.5, 5, 10 MUmol*L 1) for 24 h, the cells were tested for dual luciferase activity. The results show that the inhibitory effect of THSG, chrysophanol, emodin, rhein and aloe-emodin on CYP3A4 was inhibited by co-transfection of pcDNA3.1 and pGL4.17-CYP3A4. The expressions of pcDNA3.14-PXR and pGL4.17-CYP3A4 were induced by the four compounds. Besides, emodin had a direct inducing effect. In conclusion, the four anthraquinone compounds have an inducing effect on CYP3A4 by PXR, but emodin can directly induce CYP3A4. THSG can inhibit CYP3A4, but plasmid can induce CYP3A4 after intervened with PXR.These results suggest that we should pay attention to the liver function and avoid liver damage in the combined administration of drugs. PMID- 29493155 TI - [Prevention effect of Ligusticum chuanxiong extraction against oxidative stress injury induced by myocardial ischemia through activation of Nrf2 signaling pathway]. AB - Ligusticum chuanxiong is one of the common traditional Chinese medicinal herbs for treating various cardiovascular and cerebrovascular diseases, and a number of previous studies have demonstrated that the extract of L. chuanxiong has strong antioxidative activity. This paper was mainly aimed to investigate the effects and possible mechanisms of L. chuanxiong extraction on oxidative stress induced by myocardial ischemia injury in rats. The rats were subcutaneously injected with isoprenaline hydrochloride to induce myocardial ischemia injury and treated for 2 weeks. Then the cardiac indexes of the rats were recorded. The concentration of malondialdehyde (MDA) and activities of serum creatine kinase (CK), lactate dehydrogenase (LDH), aspartate transaminase (AST), superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) were measured by colorimetry. Light microscope was used to observe the morphological changes of myocardium, and the protein expressions of nuclear factor E2 related factor 2 (Nrf2), quinone oxidoreductase (NQO1) and hemeoxygenase-1 (HO-1) in cardiac tissue were evaluated by Western blot. The results showed that L. chuanxiong extraction could decrease cardiac indexes and the values of CK, LDH and AST in blood serum, increase activities of serum SOD and T-AOC, reduce serum MDA concentration, improve myocardium structure after ischemia injury, and up-regulate the protein expressions of Nrf2, NQO1 and HO-1 in cardiac tissue. These findings revealed that the cardioprotective effects of L. chuanxiong extraction may be related to inhibiting oxidative stress through the activation of Nrf2 signaling pathway. PMID- 29493156 TI - [Total flavonoids in Scutellaria barbata prevents NLRP3 inflammasome expression in tumor cells by affecting autologous pathway]. AB - This paper was aimed to investigate the relationship between autophagy and NLRP3 inflammasome activation by studying the effect oftotal flavonoids in Scutellaria barbata (TF-SB) on autophagy in tumor cells and NLRP3 inflammasome, and to provide experimental evidence for further study of the anti-tumor mechanism of TF SB. Mielanoma models were established by inoculating B16-F1 cell line to mice, and then were randomly divided into 5 groups (n=10 in each group): model control, positive control control(Rap, 1.5 mg*kg-1), and TF-SB low, middle and high groups (50, 100 and 200 mg*kg-1). Meanwhile, healthy C57BL/6J mice were used as normal control group (n=10). The drugs were given once daily for 2 weeks consecutively. Thirty minutes after last treatment, the determinations at endpoint were performed; pathological changes of tumor tissue were evaluated by using HE staining; protein expressions of LC3-II/LC3-I or NLRP3inflammasome/caspase-1/IL 1beta and IL-18 in tumor tissues were detected by using Western-blot; and serum levels of IL-1beta and IL-18 were detected by using Elisa kit. The results showed that the tumor cells in model group showed obvious atypia and malignant proliferation; the invasion of tumor tissue was significantly reduced, the tumor necrosis area was significantly increased, and the inflammatory reaction was significantly alleviated in positive control group and various TF-SB groups. As compared with model control group, LC3-II/LC3-I was significantly increased, while NLRP3/caspase-1/IL-1betaand IL-18 protein expressions were significantly decreased in positive control group and TF-SB groups. Serum IL-1beta and IL-18 levels in model control group were found higher than those in control group (P<0.001), but they were significantly lowered in positive control group and TF SB groups (P<0.05, P<0.01 or P<0.001). Taken together, total flavonoids in S. barbata could effectively alter the tumor growth micro-environment by inhibiting the expression of NLRP3 inflammasome, and its anti-tumor effect may be associated with the induction of tumor cell autophagy. PMID- 29493157 TI - [Protective effect of beta-asarone on AD rat model induced by intracerebroventricular injection of Abeta1-42 combined 2-VO and its mechanism]. AB - This study was aimed to investigate the protective effect and mechanism of beta asarone on the animal model of Alzheimer's disease(AD) which was induced by intracerebroventricular injection of Abeta1-42 combined cerebral ischemia. One hundred and five rats were randomly divided into seven groups including sham operated group, AD model group, beta-asarone 10 mg*kg-1 group, beta-asarone 20 mg*kg-1 group, beta-asarone 30 mg*kg-1 group, donepezil group(0.75 mg*kg-1) and Ginkgo biloba extract group(24 mg*kg-1). Rats' learning and memory abilities, cerebric regional blood flow, pathological changes in hippocampal CA1 region, the expression level of HIF-1alpha and serum CAT, SOD and MDA level were detected 4 weeks later. The results showed that the application of intracerebroventricular injection of Abeta1-42 joint 2-VO could lead to rats' dysfunction of learning and memory, decrease in regional cerebral blood flow. Neurons in CA1 region were arranged in disorder, and amyloid deposition was increased. The number of cerebral cortical cells expressing HIF-1alpha was increased as well. The level of serum CAT and SOD decreased, while level of serum MDA increased. However these symptoms were improved by 20 mg*kg-1 and 30 mg*kg-1 beta-asarone. The results indicated that beta-asarone could effectively relieve the symptoms of the AD model induced by intracerebroventricular injection of Abeta1-42 combined cerebral ischemia, and the potential mechanism might be that it could attenuate damage of MDA to the body by improving the level of CAT and SOD, meanwhile the level of HIF 1alpha decreased as the decline of hyperoxide which might attenuate its damage to neuron, so it finally achieved alleviating Alzheimer's disease. PMID- 29493159 TI - [Effects of isovitexin on transient outward potassium current of ventricular myocytes in rats]. AB - To investigate the effects of isovitexin IV on transient outward potassium current in rat ventricular myocytes. In this study, MTT assay was used to investigate the safe range of isovitexin. The results showed that the IC50 of the drug was in the range of 10-30 MUmol*L-1, and the drug concentration of 1-3 MUmol*L-1 for the patch clamp test was within the safe range. In addition, the single ventricular myocytes were obtained by single-enzymatic hydrolysis through aortic retrograde perfusion. The transient outward potassium current (Ito) of rat ventricular myocytes was guided and measured by whole-cell patch-clamp technique and the changes of current characteristics were recorded after isovite was applied. When the concentration of IV was less than 0.1 MUmol*L-1, there was no significant effect on Ito. However, with the increase in the concentration of IV (>=0.3 MUmol*L-1), the peak of Ito was decreased gradually, from (32.32+/-2.9) pA/pF to (25.83+/-4.3) pA/pF, 1 MUmol*L-1 IV and (19.51+/-3.5) pA/pF, 3 MUmol*L-1 IV respectively, with an inhibition effect in a concentration-dependent manner. In the range of 1-3 MUmol*L-1, IV down-regulated the I-V curve of Ito significantly. The activation curve showed that IV can enable the maximum half activation potential (V1/2) to move to the positive direction, and the V1/2 was increased from (19.59+/-1.6) mV to (22.81+/-1.7) mV and (28.86+/-1.4) mV at concentration of 1, 3 MUmol*L-1, meanwhile the activation curve moved to the right. However, the maximum half inactivating potential (V1/2) of the steady state inactivation curve of Ito was significantly decreased from (-51.43+/-0.99) mV to (-61.81+/-1.3) mV with concentration of 1 MUmol*L-1 and (-71.50+/-1.4) mV with concentration of 3 MUmol*L-1. The inactivation time constant of recovery from inactivation (tau) was up-regulated significantly from (94.89+/-0.73) ms to (118.5+/-1.5) ms and (162.4+/-1.4) ms at concentration of 1, 3 MUmol*L-1 respectively. Meanwhile IV could enable the inactivation recovery curve to move to the right, which suggested that it can prolong the recovery time from inactivation of the transient outward potassium channel. In conclusion, isovitexin had a high inhibitory effect on Ito in rat ventricular myocytes. PMID- 29493158 TI - [Identification of biomarkers in urine of rats with spleen Qi deficiency and biological significance]. AB - To identify biomarkers for spleen Qi deficiency by analyzing small molecule metabolites in urine, in order to expound the relationship between biomarkers and metabolic pathways. The spleen Qi deficiency model was established through dietary restriction and overstrain. All of the rats received D-xylose absorption experiment and blood routine test. Urine samples were collected in the next day. The urine samples were analyzed using UPLC-Q-TOF-MS to obtain the dataset of urine metabolic group. Principal component analysis (PCA), orthogonal partialleast squares-discriminant analysis (OPLS-DA) and other multivariate statistical methods were employed to evaluate the quality of the dataset and screen out potential biomarkers of spleen Qi deficiency. The results of D-xylose absorption and blood routine demonstrated that the spleen Qi deficiency model was successfully established. In positive ion mode and negative ion mode, PCA and OPLS-DA score plots could clearly distinguish model group and blank group. According to S-plot of OPLS-DA, VIP value, t-test and area under receiver operating characteristic curve (ROC), 24 biomarkers, including phenylalanine, succinic acid, aconitic acid, isocitrate acid, betaine, kynurenine, indole, creatine, creatinine, orotic acid, xanthine, and xanthurenic acid, were identified as associated with the spleen Qi deficiency, mainly involving energy metabolism, amino acid metabolism, tryptophan metabolism, purine metabolism and pyrimidine metabolism. Urine metabolomics method combined with online software package for data processing and analysis metabolic pathway can provide new methods and ideas for studies for spleen Qi deficiency and other traditional Chinese medicine symptoms. PMID- 29493161 TI - [Analysis of clinical characteristics of traditional Chinese and Western medicine in Professor Jiang Liangduo's theory of "sanjiao meridian stasis"]. AB - In the clinical practice, Professor Jiang Liangduo, a national senior Chinese medicine doctor, has created the theory of "sanjiao meridian stasis" from the theory of meridian dialectics and from the overall state. In this paper, the traditional Chinese medicine and Western medicine clinical characteristics of sanjiao meridian stasis theory which is often used by Professor Jiang Liangduo in the treatment of out-patient syndrome differentiation, were first studied and summarized to investigate its inherent regularity. First, the source of data and research methods were introduced, and then the Traditional Chinese Medicine Inheritance Support System was used with the method of data mining to retrospectively analyze the disease characteristics of Chinese and Western medicine in 279 patients with sanjiao meridian stasis diagnosed by Professor Jiang in 2014. Then the following main conclusions were made after research: sanjiao meridian stasis was more common in women as well as young and middle-aged population. Often manifested by prolonged treatment course, red tongue with yellowishfur, with good correlation between modern Western medicine diagnosis and TCM differentiation syndrome. The symptoms of sanjiao meridian stasis syndrome are mostly of heat syndromes, and middle-aged patients are the most common patients with stasis and stasis of sanjiao. Related information of Western medicine diagnosis can help to diagnose the "sanjiao meridian stasis". PMID- 29493160 TI - [Effect investigation of coumarin constituents in Angelica dahurica on pharmacokinetics of docetaxel by LC-MS]. AB - The study was aimed to establish a liquid chromatography-tandem mass spectrometric method for the determination of the docetaxel concentration in rat plasma, and study the effect of coumarin constituents (imperatorin, isoimperatorin and oxypeucedanin) in Angelica dahurica on pharmacokinetics of docetaxel.Plasma was precipitated with acetonitrile and determined by LC-MS method with Paclitaxel as an internal standard. The specificity, linearity, range, accuracy, precision and stability of the method were suitable for the determination of docetaxel in plasma.Six sprague-dawley rats in each group received intragastric administration of docetaxel (50 mg*kg-1), oxypeucedanin (8 mg*kg-1) combined with docetaxel (50 mg*kg-1), imperatorin (15 mg*kg-1) combined with docetaxel (50 mg*kg-1), and isoimperatorin(15 mg*kg-1) combined with docetaxel (50 mg*kg-1).Their drug plasma concentration was determined by LC-MS with Paclitaxel as an internal standard to draw plasma concentration-time curve, and the phamacokinetic parameters were calculated by DAS 2.0. The results showed that the phamacokinetic parameters of docetaxel all had notable changes when combined with imperatorin, isoimperatorin, and oxypeucedanin, respectively. The phamacokinetic parameters AUC and Cmax were significantly increased, indicating that coumarin constituents in Angelica dahurica could promote the oral bioavailability of docetaxel, and their effects were in the following order: oxypeucedanin> isoimperatorin> imperatorin. PMID- 29493162 TI - [Clinical therapy of Zisheng decoction recipe for chronic atrophic gastritis with intestinal metaplasia]. AB - To explore the therapeutic effect and security of Zisheng decoction recipein treatment of the chronic atrophic gastritis (CAG) with intestinal metaplasia(IM). A total of 147 eligible cases were randomly divided into the traditional Chinese medicine group, Western medicine group and the combined group,47 cases in each group. Zisheng decoction recipe, famotidine, as well as Zisheng decoction recipe + famotidine were respectively given in the above three groups, with a treatment course of 30 d. The symptoms of traditional Chinese medicine, pathological score of gastric mucosa and the negative rate of Helicobacter pylori before and after treatment were observed in each group.The changes in pepsinogen I (PGI), pepsinogen II (PGII), gastrin-17 (GAS-17) and endothelin-1 (ET-1)were also detected to compare the efficient and safety indexes in the three groups. The combined group was better than the traditional Chinese medicine groupand the Western medicine group in total effective rate (P<0.05), pathological score of gastric mucosa and the negative rate of Helicobacter pylori, and serum indexes improvement (P<0.05). The improvement in TCM symptom score was more obvious in traditional Chinese medicine group and combined group than the Western medicine group (P<0.05). In the comparison ofincidence of complications,heart, liver and renal dysfunction, the traditional Chinese medicine group (2 case,4.8%)< the combined group (7 case,15.2%) =10 ppm. This discrepancy is attributed to the ratio of charge carriers contributing to gas capture with respect to total carriers. This capacity for the excellent detection of low-concentration NO2 gas can be realized through (i) three-terminal TFT gas sensors using amorphous oxide, (ii) measurement of the drain current variation rate for high selectivity, and (iii) an EM mode driven by tuning the electrical conductivity of channel layers. PMID- 29493207 TI - Dual Superlyophobic Copper Foam with Good Durability and Recyclability for High Flux, High Efficiency, and Continuous Oil-Water Separation. AB - Traditional oil-water separation materials have to own ultrahigh or ultralow surface energy. Thus, they can only be wetted by one of the two, oil or water. Our experiment here demonstrates that the wettability in oil-water mixtures can be tuned by oil and water initially. Hierarchical voids are built on commercial copper foams with the help of hydrothermally synthesized titanium dioxide nanorods. The foams can be easily wetted by both oil and water. The water prewetted foams are superhydrophilic and superoleophobic under oil-water mixtures, meanwhile the oil prewetted foams are superoleophilic and superhydrophobic. In this paper, many kinds of water-oil mixtures were separated by two foams, prewetted by corresponding oil or water, respectively, combining a straight tee in a high flux, high efficiency, and continuous mode. This research indicates that oil-water mixtures can be separated more eco-friendly and at lower cost. PMID- 29493208 TI - An Efficient Electron-Blocking Interlayer Induced by Metal Ion Diffusion for SOFC Based on Y-Doped Ceria Electrolyte. AB - To suppress the internal electronic leakage at ceria-based electrolyte, a novel electron-blocking layer consisting of doped BaCe0.8Y0.2O3-delta was fabricated in situ at the interface of Ba-containing anode and Y-doped ceria electrolyte. The anode-supported full cell based on Y0.2Ce0.8O1.9 (YDC20) electrolyte presents a remarkable peak power density of 814 mW/cm2 as well as an open-circuit voltage of 1.0 V at 650 degrees C, which are much higher than those of the cells with Gd0.1Ce0.9O1.95 (GDC10) electrolyte (453 mW/cm2 at 650 degrees C) and BaCe0.8Y0.2O3-delta|Y0.2Ce0.8O1.9 (BCY|YDC20) bilayered electrolyte (419 mW/cm2 at 650 degrees C). The efficient promotion of the electron-blocking interlayer with high oxygen ionic conductivity is considered as the main reason for the improved performance of YDC20-based solid oxide fuel cell. The composition and the microstructure of the electron-blocking interlayer are further analyzed by scanning electron microscope and transmission electron microscope characterizations. PMID- 29493209 TI - Thermal Stability of Metal-Organic Frameworks and Encapsulation of CuO Nanocrystals for Highly Active Catalysis. AB - We report an aerosol-based approach to study the thermal stability of metal organic frameworks (MOFs) for gas-phase synthesis of MOF-based hybrid nanostructures used for highly active catalysis. Temperature-programmed electrospray-differential mobility analysis (TP-ES-DMA) provides the characterization of temperature-dependent morphological change directly in the gas phase, and the results are shown to be highly correlated with the structural thermal stability of MOFs determined by the traditional measurements of porosity and crystallinity. The results show that MOFs underwent thermal decomposition via simultaneous disassembly and deaggregation. Trimeric Cr-based MIL-88B-NH2 exhibited a higher temperature of decomposition ( Td), 350 degrees C, than trimeric Fe-based MIL-88B-NH2, 250 degrees C. For UiO-66, a significant decrease of Td by ~100 degrees C was observed by using amine-functionalized ligands in the MOF structure. Copper oxide nanocrystals were successfully encapsulated in the UiO-66 crystal (Cu xO@UiO-66) by using a gas-phase evaporation-induced self assembly approach followed by a suitable thermal treatment below Td (i.e., determined by TP-ES-DMA). Cu xO@UiO-66 demonstrated a very high catalytic activity and stability to CO oxidation, showing at least a 3-time increase in CO conversion compared to the bare CuO nanoparticle samples. The study demonstrates a prototype methodology (1) to determine structural thermal stability of MOFs using a gas-phase electrophoretic method (TP-ES-DMA) and (2) to gas-phase synthesize CuO nanocrystals encapsulated in MOFs. PMID- 29493210 TI - 3.0 V High Energy Density Symmetric Sodium-Ion Battery: Na4V2(PO4)3?Na3V2(PO4)3. AB - Symmetric sodium-ion batteries (SIBs) are considered as promising candidates for large-scale energy storage owing to the simplified manufacture and wide abundance of sodium resources. However, most symmetric SIBs suffer from suppressed energy density. Here, a superior congeneric Na4V2(PO4)3 anode is synthesized via electrochemical preintercalation, and a high energy density symmetric SIB (Na3V2(PO4)3 as a cathode and Na4V2(PO4)3 as an anode) based on the deepened redox couple of V4+/V2+ is built for the first time. When measured in half cell, both electrodes show stabilized electrochemical performance (over 3000 cycles). The symmetric SIBs exhibit an output voltage of 3.0 V and a cell-level energy density of 138 W h kg-1. Furthermore, the sodium storage mechanism under the expanded measurement range of 0.01-3.9 V is disclosed through an in situ X-ray diffraction technique. PMID- 29493211 TI - Through-Layer Buckle Wavelength-Gradient Design for the Coupling of High Sensitivity and Stretchability in a Single Strain Sensor. AB - Recent years have witnessed a breathtaking development of wearable strain sensors. Coupling high sensitivity and stretchability in a strain sensor is greatly desired by emerging wearable applications but remains a big challenge. To tackle this issue, a through-layer buckle wavelength-gradient design is proposed and a facile and universal fabrication strategy is demonstrated to introduce such a gradient into the sensing film with multilayered sensing units. Following this strategy, strain sensors are fabricated using graphene woven fabrics (GWFs) as sensing units, which exhibit highly tunable electromechanical performances. Specifically, the sensor with 10-layer GWFs has a gauge factor (GF) of 2996 at a maximum strain of 242.74% and an average GF of 327. It also exhibits an extremely low minimum detection limit of 0.02% strain, a fast signal response of less than 90 ms, and a high cyclic durability through more than 10 000 cycling test. Such excellent performances qualify it in accurately monitoring full-range human activities, ranging from subtle stimuli (e.g., pulse, respiration, and voice recognition) to vigorous motions (finger bending, walking, jogging, and jumping). The combination of experimental observations and modeling study shows that the predesigned through-layer buckle wavelength gradient leads to a layer-by-layer crack propagation process, which accounts for the underlying working mechanism. Modeling study shows a great potential for further improvement of sensing performances by adjusting fabrication parameters such as layers of sensing units ( n) and step pre-strain (epsilonsp). For one thing, when epsilonsp is fixed, the maximum sensing strain could be adjusted from >240% ( n = 10) to >450% ( n = 15) and >1200% ( n = 20). For the other, when n is fixed, the maximum sensing strain could be adjusted from >240% (epsilonsp = 13.2%) to >400% (epsilonsp = 18%) and >800% (epsilonsp = 25%). PMID- 29493212 TI - Exploring Strategies To Bias Sequence in Natural and Synthetic Oligomers and Polymers. AB - Millions of years of biological evolution have driven the development of highly sophisticated molecular machinery found within living systems. These systems produce polymers such as proteins and nucleic acids with incredible fidelity and function. In nature, the precise molecular sequence is the factor that determines the function of these macromolecules. Given that the ability to precisely define sequence emerges naturally, the fact that biology achieves unprecedented control over the unit sequence of the monomers through evolved enzymatic catalysis is incredible. Indeed, the ability to engineer systems that allow polymer synthesis with precise sequence control is a feat that technology is yet to replicate in artificial synthetic systems. This is the case because, without access to evolutionary control for finely tuned biological catalysts, the inability to correct errors or harness multiple competing processes means that the prospects for digital control of polymerization have been firmly bootstrapped to biological systems or limited to stepwise synthetic protocols. In this Account, we give an overview of strategies that have been used over the last 5 years in efforts to program polymer synthesis with sequence control in the laboratory. We also briefly explore how the use of robotics, algorithms, and stochastic chemical processes might lead to new understanding, mechanisms, and strategies to achieve full digital control. The aim is to see whether it is possible to go beyond bootstrapping to biological polymers or stepwise chemical synthesis. We start by describing nonenzymatic techniques used to obtain sequence-controlled natural polymers, a field that lends itself to direct application of insights gleaned from biology. We discuss major advances, such as the use of rotaxane-based molecular machines and templated approaches, including the utilization of biological polymers as templates for purely synthetic chains. We then discuss synthetic polymer chemistry, whose array of techniques allows the production of polymers with enormous structural and functional diversity, but so far with only limited control over the unit sequence itself. Synthetic polymers can be subdivided into multiple classes depending on the nature of processes used to synthesize them, such as by addition or condensation. Consequently, varied approaches for sequence control have been demonstrated in the area, including but not limited to click reactions, iterative solid-phase chemistry, and exploiting the chemical affinity of the monomers themselves. In addition to those, we highlight the importance of environmental bias in possible control of polymerization at the single-unit level, such as using catalyst switching or external stimuli. Even the most successful experimental sequence control approach needs appropriate tools to verify its scope and validity; therefore, we devote part of the present Account to possible analytical approaches to sequence readout, starting with well-established tandem mass spectrometry techniques and touching on those more applicable to specific classes of processes, such as diffusion-ordered NMR spectroscopy. Finally, we discuss progress in modeling and automation of sequence-controlled polymers. We postulate that developments in analytical chemistry, bioinformatics, and computer modeling will lead to new ways of exploring the development of new strategies for the realization of sequence control by means of sequence bias. This is the case because treating the assembly of polymers as a network of chemical reactions will enable the development of control strategies that can bias the outcome of the polymer assembly. The grand aim would be the synthesis of complex polymers in one step with a precisely defined digital sequence. PMID- 29493213 TI - Nanoclay-Based Self-Supporting Responsive Nanocomposite Hydrogels for Printing Applications. AB - Stimuli-responsive hydrogels and/or composite hydrogels have been of great interest for various printing applications including four-dimensional printing. Although various responsive hydrogels and/or composite hydrogels have been found to respond to given stimuli and change shapes as designed, the fabrication of three-dimensional (3D) structures from such responsive hydrogels is still a challenge due to their poor 3D printability, and most of the responsive material based patterns are two-dimensional (2D) in nature. In this study, Laponite nanoclay is studied as an effective additive to improve the self-supporting printability of N-isopropylacrylamide (NIPAAm), a thermoresponsive hydrogel precursor while keeping the responsive functionality of NIPAAm. Graphene oxide (GO) is further added as a nanoscale heater, responding to near-infrared radiation. Due to the different shrinking ratios and mechanical properties of the poly( N-isopropylacrylamide) (pNIPAAm)-Laponite and pNIPAAm-Laponite-GO nanocomposite hydrogels, printed 2D patterns deform in a predictable way. In addition, 3D microfluidic valves are directly printed and cured in air, which can effectively control the flow directions in response to different stimuli as validated in a microfluidic system. Because Laponite nanoclay can be mixed with various responsive hydrogel precursors to improve their 3D printability, the proposed Laponite nanoclay-based nanocomposite hydrogels can be further expanded to prepare various 3D printable responsive nanocomposite hydrogels. PMID- 29493214 TI - Flexible Photonic Crystal Material for Multiple Anticounterfeiting Applications. AB - In this study, a nanoimprinting method was introduced to fabricate polycarbonate films with transparent and flexible photonic crystal (FPC) structures. The fabricated flexible polymer films display a full-color grating because of the nanohemispherical structures on the surface. Through the Bragg diffraction formula, it was confirmed that the FPC polymer films transfer a part of the light energy to the second-order diffraction spectrum. Furthermore, the full-color grating properties can be modulated through geometric deformation because of the film's elasticity. Additionally, anticounterfeiting features were also successfully achieved when the polymer films were either engraved with drawings and bent or patterned with fluorophores, which can be revealed under ultraviolet light. The most important aspect of this research is that the preparation of this FPC-structured polymer film is inexpensive and convenient, enabling the mass production of a new generation of smart materials. PMID- 29493215 TI - Viscoplastic Matrix Materials for Embedded 3D Printing. AB - Embedded three-dimensional (EMB3D) printing is an emerging technique that enables free-form fabrication of complex architectures. In this approach, a nozzle is translated omnidirectionally within a soft matrix that surrounds and supports the patterned material. To optimize print fidelity, we have investigated the effects of matrix viscoplasticity on the EMB3D printing process. Specifically, we determine how matrix composition, print path and speed, and nozzle diameter affect the yielded region within the matrix. By characterizing the velocity and strain fields and analyzing the dimensions of the yielded regions, we determine that scaling relationships based on the Oldroyd number, Od, exist between these dimensions and the rheological properties of the matrix materials and printing parameters. Finally, we use EMB3D printing to create complex architectures within an elastomeric silicone matrix. Our methods and findings will both facilitate future characterization of viscoplastic matrices and motivate the development of new materials for EMB3D printing. PMID- 29493216 TI - Defined Bilayer Interactions of DNA Nanopores Revealed with a Nuclease-Based Nanoprobe Strategy. AB - DNA nanopores are a recent class of bilayer-puncturing nanodevices that can help advance biosensing, synthetic biology, and nanofluidics. Here, we create archetypal lipid-anchored DNA nanopores and characterize them with a nanoprobe based approach to gain essential information about their interactions with bilayers. The strategy determines the molecular accessibility of DNA pores with a nuclease and can thus distinguish between the nanopores' membrane-adhering and membrane-spanning states. The analysis reveals, for example, that pores interact with bilayers in two steps whereby fast initial membrane tethering is followed by slower reorientation to the puncturing state. Tethering occurs for pores with one anchor, while puncturing requires multiple anchors. Both low and high-curvature membranes are good substrates for tethering, but efficient insertion proceeds only for high-curvature bilayers of the examined lipid composition. This is likely due to the localized lipid misalignments and the associated lower energetic barrier for pore permeation. Our study advances the fields of DNA nanotechnology and nanopores by overcoming the considerable experimental hurdle of efficient membrane insertion. It also provides mechanistic insights to aid the design of advanced nanopores, and offers a useful route to probe bilayer orientation of DNA nanostructures. PMID- 29493217 TI - Au Nanocage-Strengthened Dissolving Microneedles for Chemo-Photothermal Combined Therapy of Superficial Skin Tumors. AB - For superficial skin tumors (SST) with high incidence, surgery and systemic therapy are relatively invasive and possible to cause severe side effect, respectively. Yet, topical therapy is confronted with the limited transdermal capacity because of the stratum corneum barrier layer of skin. Therefore, it is crucial to develop a highly effective and minimally invasive alternative transdermal approach for treating SST. Here, we developed gold nanocage (AuNC)- and chemotherapeutic drug doxorubicin (DOX)-loaded hyaluronic acid dissolving microneedle (MN) arrays. The loaded AuNCs are not only reinforcers to enhance the mechanical strength of the MNs, but also effective agents for photothermal therapy to obtain effective transdermal therapy for SST. The resultant MNs can effectively penetrate the skin, dissolve in the skin and release cargoes within the tumor site. Photothermal effect of AuNCs initiated by near-infrared laser irradiation combined with the chemotherapy effect of DOX destroyed tumors synergistically. Moreover, we verified the potent antitumor effects of the DOX/AuNC-loaded MNs after four administrations to SST-bearing mice without obvious side effects. Therefore, the drug/AuNC-loaded dissolving MN system provides a promising platform for effective, safe, minimally invasive combined treatment of SST. PMID- 29493218 TI - Below the Hall-Petch Limit in Nanocrystalline Ceramics. AB - Reducing the grain size of metals and ceramics can significantly increase strength and hardness, a phenomenon described by the Hall-Petch relationship. The many studies on the Hall-Petch relationship in metals reveal that when the grain size is reduced to tens of nanometers, this relationship breaks down. However, experimental data for nanocrystalline ceramics are scarce, and the existence of a breakdown is controversial. Here we show the Hall-Petch breakdown in nanocrystalline ceramics by performing indentation studies on fully dense nanocrystalline ceramics fabricated with grain sizes ranging from 3.6 to 37.5 nm. A maximum hardness occurs at a grain size of 18.4 nm, and a negative (or inverse) Hall-Petch relationship reduces the hardness as the grain size is decreased to around 5 nm. At the smallest grain sizes, the hardness plateaus and becomes insensitive to grain size change. Strain rate studies show that the primary mechanism behind the breakdown, negative, and plateau behavior is not diffusion based. We find that a decrease in density and an increase in dissipative energy below the breakdown correlate with increasing grain boundary volume fraction as the grain size is reduced. The behavior below the breakdown is consistent with structural changes, such as increasing triple-junction volume fraction. Grain- and indent-size-dependent fracture behavior further supports local structural changes that corroborate current theories of nanocrack formation at triple junctions. The synergistic grain size dependencies of hardness, elasticity, energy dissipation, and nanostructure of nanocrystalline ceramics point to an opportunity to use the grain size to tune the strength and dissipative properties. PMID- 29493219 TI - Pac1 Signals of Human Herpesviruses Contain a Highly Conserved G-Quadruplex Motif. AB - Packaging signals ( pac1 and pac2) of human herpesviruses (HHVs) that contain GC rich elements are essential for cleavage and packaging of the virus. Here, we report the presence of putative G-quadruplex sequences (PQSs) in the packaging signal ( pac1) of all HHVs. Importantly, the residues critical for the formation of G-quadruplex structures were highly conserved as compared to those not critical for the formation of this DNA secondary structure, indicating that G quadruplexes are positively selected within pac1 in the evolution of herpesviruses. CD spectroscopy, NMR spectroscopy, native/denaturing gel, and DMS footprinting confirmed the formation of G-quadruplex structures in all pac1 PQS oligonucleotides analyzed; the majority of the PQS had the propensity to form intermolecular structures. The presence of highly conserved G-quadruplex motifs at genomic locations critical for virus packaging has not been previously recognized. Our findings provide a new perspective on the putative functions of G quadruplexes in virus genomes. PMID- 29493220 TI - Atomistic Simulations of Graphene Growth: From Kinetics to Mechanism. AB - Epitaxial growth is a promising strategy to produce high-quality graphene samples. At the same time, this method has great flexibility for industrial scale up. To optimize growth protocols, it is essential to understand the underlying growth mechanisms. This is, however, very challenging, as the growth process is complicated and involves many elementary steps. Experimentally, atomic-scale in situ characterization methods are generally not feasible at the high temperature of graphene growth. Therefore, kinetics is the main experimental information to study growth mechanisms. Theoretically, first-principles calculations routinely provide atomic structures and energetics but have a stringent limit on the accessible spatial and time scales. Such gap between experiment and theory can be bridged by atomistic simulations using first-principles atomic details as input and providing the overall growth kinetics, which can be directly compared with experiment, as output. Typically, system-specific approximations should be applied to make such simulations computationally feasible. By feeding kinetic Monte Carlo (kMC) simulations with first-principles parameters, we can directly simulate the graphene growth process and thus understand the growth mechanisms. Our simulations suggest that the carbon dimer is the dominant feeding species in the epitaxial growth of graphene on both Cu(111) and Cu(100) surfaces, which enables us to understand why the reaction is diffusion limited on Cu(111) but attachment limited on Cu(100). When hydrogen is explicitly considered in the simulation, the central role hydrogen plays in graphene growth is revealed, which solves the long-standing puzzle into why H2 should be fed in the chemical vapor deposition of graphene. The simulation results can be directly compared with the experimental kinetic data, if available. Our kMC simulations reproduce the experimentally observed quintic-like behavior of graphene growth on Ir(111). By checking the simulation results, we find that such nonlinearity is caused by lattice mismatch, and the induced growth front inhomogeneity can be universally used to predict growth behaviors in other heteroepitaxial systems. Notably, although experimental kinetics usually gives useful insight into atomic mechanisms, it can sometimes be misleading. Such pitfalls can be avoided via atomistic simulations, as demonstrated in our study of the graphene etching process. Growth protocols can be designed theoretically with computational kinetic and mechanistic information. By contrasting the different activation energies involved in an atom-exchange-based carbon penetration process for monolayer and bilayer graphene, we propose a three-step strategy to grow high quality bilayer graphene. Based on first-principles parameters, a kinetic pathway toward the high-density, ordered N doping of epitaxial graphene on Cu(111) using a C5NCl5 precursor is also identified. These studies demonstrate that atomistic simulations can unambiguously produce or reproduce the kinetic information on graphene growth, which is pivotal to understanding the growth mechanism and designing better growth protocols. A similar strategy can be used in growth mechanism studies of other two-dimensional atomic crystals. PMID- 29493221 TI - Ionic Correlations in Random Ionomers. AB - Understanding the electrostatic interactions in ion-containing polymers is crucial to better design shape memory polymers and ion-conducting membranes for multiple energy storage and conversion applications. In molten polymers, the dielectric permittivity is low, generating strong ionic correlations that lead to clustering of the charges. Here, we investigate the influence of electrostatic interactions on the nanostructure of randomly charged polymers (ionomers) using coarse-grained molecular dynamics simulations. Densely packed branched structures rich in charged species are found as the strength of the electrostatic interactions increases. Polydispersity in charge fraction and composition combined with ion correlations leads to percolated nanostructures with long-range fluctuations. We identify the percolation point at which the ionic branched nanostructures percolate and offer a rigorous investigation of the statistics of the shape of the aggregates. The extra degree of freedom introduced by the charge polydispersity leads to bicontinuous structures with a broad range of compositions, similar to neutral A-B random copolymers, as well as to desirable percolated ionic structure in randomly charged-neutral diblock copolymers. These findings provide insight into the design of conducting and robust nanostructures in ion-containing polymers. PMID- 29493222 TI - Density and Homogeneous Internal Composition of Primary Brown Carbon Aerosol. AB - The presence of atmospheric brown carbon (BrC) has been the focus of many recent studies. These particles, predominantly emitted from smoldering biomass burning, absorb light in the near-ultraviolet and short visible wavelengths and offset the radiative cooling effects associated with organic aerosols. Particle density dictates their transport properties and is an important parameter in climate models and aerosol instrumentation algorithms, but our knowledge of this particle property is limited, especially as functions of combustion temperature and fuel type. We measured the effective density (rhoeff) and optical properties of primary BrC aerosol emitted from smoldering combustion of Boreal peatlands. Energy transfer into the fuel was controlled by selectively altering the combustion ignition temperature, and we find that the particle rhoeff ranged from 0.85 to 1.19 g cm-3 corresponding to ignition temperatures from 180 to 360 degrees C. BrC particles exhibited spherical morphology and a constant 3.0 mass mobility exponent, indicating no internal microstructure or void spaces. Upon partial thermal volatilization, rhoeff of the remaining particle mass was confined to a narrow range between 0.9 and 1.1 g cm-3. These findings lead us to conclude that primary BrC aerosols from biomass burning have homogeneous internal composition, and their rhoeff is in fact their actual density. PMID- 29493224 TI - Ruthenium Catalysts for the Reduction of N-Nitrosamine Water Contaminants. AB - N-Nitrosamines have raised extensive concern due to their high toxicity and detection in treated wastewater and drinking water. Catalytic reduction is a promising alternative technology to treat N-nitrosamines, but to advance this technology pathway, there is a need to develop more-efficient and cost-effective catalysts. We have previously discovered that commercial catalysts containing ruthenium (Ru) are unexpectedly active in reducing nitrate. This study evaluated supported Ru activity for catalyzing reduction of N-nitrosamines. Experiments with N-nitrosodimethylamine (NDMA) show that contaminant is rapidly reduced on both commercial and in-house prepared Ru/Al2O3 catalysts, with the commercial material yielding an initial metal weight-normalized pseudo-first-order rate constant ( k0) of 1103 +/- 133 L.gRu-1.h-1 and an initial turnover frequency (TOF0) of 58.0 +/- 7.0 h-1. NDMA is reduced to dimethylamine (DMA) and ammonia end-products, and a small amount of 1,1-dimethylhydrazine (UDMH) was detected as a transient intermediate. Experiment with a mixture of five N-nitrosamines spiked into tap water (1 MUg L-1 each) demonstrates that Ru catalysts are very effective in reducing a range of N-nitrosamine structures at environmentally relevant concentrations. Cost competitiveness and high catalytic activities with a range of contaminants provide a strong argument for developing Ru catalysts as part of the water purification and remediation toolbox. PMID- 29493223 TI - Ratiometric Near-Infrared Fluorescent Probes Based On Through-Bond Energy Transfer and pi-Conjugation Modulation between Tetraphenylethene and Hemicyanine Moieties for Sensitive Detection of pH Changes in Live Cells. AB - In this paper, we present three ratiometric near-infrared fluorescent probes (A C) for accurate, ratiometric detection of intracellular pH changes in live cells. Probe A consists of a tetraphenylethene (TPE) donor and near-infrared hemicyanine acceptor in a through-bond energy transfer (TBET) strategy, while probes B and C are composed of TPE and hemicyanine moieties through single and double sp2 carbon carbon bond connections in a pi-conjugation modulation strategy. The specific targeting of the probes to lysosomes in live cells was achieved by introducing morpholine residues to the hemicyanine moieties to form closed spirolactam ring structures. Probe A shows aggregation-induced emission (AIE) property at neutral or basic pH, while probes B and C lack AIE properties. At basic or neutral pH, the probes only show fluorescence of TPE moieties with closed spirolactam forms of hemicyanine moieties, and effectively avoid blind fluorescence imaging spots, an issue which typical intensity-based pH fluorescent probes encounter. Three probes show ratiometric fluorescence responses to pH changes from 7.0 to 3.0 with TPE fluorescence decreases and hemicyanine fluorescence increases, because acidic pH makes the spirolactam rings open to enhance pi-conjugation of hemicyanine moieties. However, probe A shows much more sensitive ratiometric fluorescence responses to pH changes from 7.0 to 3.0 with remarkable ratio increase of TPE fluorescence to hemicyanine fluorescence up to 238-fold than probes B and C because of its high efficiency of energy transfer from TPE donor to the hemicyanine acceptor in the TBET strategy. The probe offers dual Stokes shifts with a large pseudo-Stokes shift of 361 nm and well-defined dual emissions, and allows for colocalization of the imaging readouts of visible and near-infrared fluorescence channels to achieve more precisely double-checked ratiometric fluorescence imaging. These platforms could be employed to develop a variety of novel ratiometric fluorescent probes for accurate detection of different analytes in applications of chemical and biological sensing, imaging, and diagnostics by introducing appropriate sensing ligands to hemicyanine moieties to form on-off spirolactam switches. PMID- 29493225 TI - Automated Microfluidic Instrument for Label-Free and High-Throughput Cell Separation. AB - Microfluidic technologies for cell separation were reported frequently in recent years. However, a compact microfluidic instrument enabling thoroughly automated cell separation is still rarely reported until today due to the difficult hybrid between the macrosized fluidic control system and the microsized microfluidic device. In this work, we propose a novel and automated microfluidic instrument to realize size-based separation of cancer cells in a label-free and high-throughput manner. Briefly, the instrument is equipped with a fully integrated microfluidic device and a set of robust fluid-driven and control units, and the instrument functions of precise fluid infusion and high-throughput cell separation are guaranteed by a flow regulatory chip and two cell separation chips which are the key components of the microfluidic device. With optimized control programs, the instrument is successfully applied to automatically sort human breast adenocarcinoma cell line MCF-7 from 5 mL of diluted human blood with a high recovery ratio of ~85% within a rapid processing time of ~23 min. We envision that our microfluidic instrument will be potentially useful in many biomedical applications, especially cell separation, enrichment, and concentration for the purpose of cell culture and analysis. PMID- 29493226 TI - Ultrasensitive Tyrosinase-Activated Turn-On Near-Infrared Fluorescent Probe with a Rationally Designed Urea Bond for Selective Imaging and Photodamage to Melanoma Cells. AB - Melanoma is a highly aggressive malignancy and early monitoring and diagnosis are challenging at present. Tyrosinase is overexpressed in melanoma and regarded as an important biological marker for diagnosis and treatment. Thus, the selective and sensitive detection of tyrosinase is of great significance. To date, a few fluorescent probes have been reported for the detection of tyrosinase in vitro or in vivo. However, a highly sensitive near-infrared probe for tyrosinase monitoring is still missing. In this study, the Gibbs free energy change of different urea bonds during spontaneous hydrolysis is analyzed with the aid of chemical thermodynamic computation. On the basis of this analysis, we modified the dye methylene blue with a rationally designed urea bond to specifically create a probe, called MB1, for rapid detection of tyrosinase. Our experimental results demonstrated that MB1 can serve as a highly sensitive near-infrared responsive fluorescent probe for the monitoring and bioimaging of tyrosinase. In addition, the activated MB1 probe can effectively kill melanoma cells by photodynamic therapy. Thus, the near-infrared probe has great potential for monitoring and treating melanoma. PMID- 29493227 TI - Assessment of the Allergenic Potential of the Main Egg White Proteins in BALB/c Mice. AB - This work aimed to assess the contribution of the major egg white proteins, ovalbumin, ovomucoid, and lysozyme, to the induction and elicitation of allergenic responses. For this purpose, BALB/c mice were orally administered either the individual egg allergens or a mixture of the three proteins in the same proportion, to evaluate their relative allergenicity avoiding their different abundance in egg white. Cholera toxin was used as a T helper 2 (Th2) polarizing adjuvant. Ovomucoid and lysozyme triggered the most severe anaphylaxis reactions upon oral challenge. In comparison to ovalbumin and ovomucoid, lysozyme was a more active promotor of early immunoglobulin E and immunoglobulin G1 production and stimulated stronger Th2-biased responses from both mesenteric lymph node and spleen cells. These results indicate that lysozyme is highly immunogenic and should be considered as a major allergen, whose clinical usefulness in the diagnosis, prognosis, and therapeutic approaches of egg allergy deserves further consideration. PMID- 29493228 TI - Activatable Near-Infrared Fluorescent Probe for Dipeptidyl Peptidase IV and Its Bioimaging Applications in Living Cells and Animals. AB - Visualization of endogenous disease-associated enzymes is of great clinical significance, as it could allow earlier clinical diagnosis and timely intervention. Herein, we first synthesized and characterized an enzyme activatable near-infrared fluorescent probe, GP-DM, for determining the activity of dipeptidyl peptidase IV (DPP IV), which is associated with various pathological processes, especially in diabetes and malignant tumors. GP-DM emitted significant turn-on NIR fluorescent signals simultaneously in response to DPP IV, making it favorable for accurately and dynamically monitoring DPP IV activity in vitro and in vivo. GP-DM exhibited excellent specificity and sensitivity in DPP IV imaging, as indicated by its higher catalytic activity than other human serine hydrolases and by its strong anti-interference ability to a complex biological matrix, which was fully characterized in a series of phenotyping reactions and inhibition assays. Encouraged by the advantages mentioned above, we successfully used GP-DM to evaluate endogenous DPP IV activity in various biological samples (plasma and tissue preparations) and living tumor cells and performed real-time in vivo bioimaging of DPP IV in zebrafish and tumor-bearing nude mice. All of the results reflected and highlighted the potential application value of GP-DM in the early detection of pathologies, individual tailoring of drug therapy, and image-guided tumor resection. Furthermore, our results revealed that DPP IV, a key target enzyme, is closely associated with the migration and proliferation of cancer cells and regulating the biological activity of DPP IV may be a useful approach for cancer therapy. PMID- 29493229 TI - Synthesis, Structure, and Vibrational Properties of [Ph4P]2NpO2Cl4 and [Ph4P]2PuO2Cl4 Complexes. AB - The synthesis, structure, and vibrational properties are presented for an isostructural series of Np(VI) and Pu(VI) complexes of the form [Ph4P]2AnO2Cl4, where An = Np(VI) or Pu(VI). The reported complexes are readily synthesized in ambient laboratory conditions, and their molecular structures were determined using single crystal X-ray diffraction. Their vibrational spectra were studied using a combination of Raman and FT-IR vibrational spectroscopies. Analysis of the vibrational spectra and force constants highlight the periodic properties associated with the actinide contraction and filling of the 5f electronic shells. Additionally, we have assessed the utility of these complexes as conveniently synthesized starting materials for non-aqueous synthesis of transuranium molecules and materials. PMID- 29493230 TI - Correction to Simbiotics: A Multiscale Integrative Platform for 3D Modeling of Bacterial Populations. PMID- 29493232 TI - Spectroscopic Evidence of Pore Geometry Effect on Axial Coordination of Guest Molecules in Metalloporphyrin-Based Metal Organic Frameworks. AB - A systematic comparison of host-guest interactions in two iron porphyrin-based metal-organic frameworks (MOFs), FeCl-PCN222 and FeCl-PCN224, with drastically different pore sizes and geometries is reported in this fundamental spectroscopy study. Guest molecules (acetone, imidazole, and piperidine) of different sizes, axial binding strengths, and reactivity with the iron porphyrin centers are employed to demonstrate the range of possible interactions that occur at the porphyrin sites inside the pores of the MOF. Binding patterns of these guest species under the constraints of the pore geometries in the two frameworks are established using multiple spectroscopy methods, including UV-vis diffuse reflectance, Raman, X-ray absorption, and X-ray emission spectroscopy. Line shape analysis applied to the latter method provides quantitative information on axial ligation through its spin state sensitivity. The observed coordination behaviors derived from the spectroscopic analyses of the two MOF systems are compared to those predicted using space-filling models and relevant iron porphyrin molecular analogues. While the space-filling models show the ideal axial coordination behavior associated with these systems, the spectroscopic results provide powerful insight into the actual binding interactions that occur in practice. Evidence for potential side reactions occurring within the pores that may be responsible for the observed deviation from model coordination behavior in one of the MOF/guest molecule combinations is presented and discussed in the context of literature precedent. PMID- 29493233 TI - Tandem Hydroaminomethylation Reaction to Synthesize Amines from Alkenes. AB - In the context of atom economy and low environmental impact, synthesis of amines by an efficient catalytic process is of great importance to produce these building blocks for fine chemical industry. The one-pot hydroaminomethylation of alkenes is a tandem reaction which involves three successive steps under CO/H2 pressure to perform the catalyzed hydroformylation of the alkene into the corresponding aldehyde followed by its condensation with a N-H function and the catalyzed hydrogenation of the imine/enamine intermediate into the corresponding saturated amine. Rhodium and more recently ruthenium complexes have been designed to combine high conversions of the reactants and chemoselectivity in the expected amines with high regioselectivity in either the linear or the branched amine. The coordination sphere of the metal according to the presence of ligands, temperature, CO/H2 partial pressures, and nature of the solvent is essential for complying with these selectivity requirements. The rate of the hydroformylation step needs to be fast with regard to the hydrogenation step. The role of amines in the coordination sphere and water, presumably in the second sphere, on the mechanism requires some more studies. Similarly, the enantioselective synthesis of amine is not yet achieved directly and interrupted processes or use of asymmetric organo-catalyzed reductive amination are efficient synthetic ways for producing chiral amines. The separation of the catalyst from the organic products by biphasic or (semi-) heterogeneized systems and its recycling have been demonstrated in many cases. The present review provides a report of the state of the art in this autotandem hydroaminomethylation catalysis and should open prospects in the design of less expensive and abundant metal complexes for reaching at low cost similar and even superior performances. PMID- 29493231 TI - Small Molecular Weight Soybean Protein-Derived Peptides Nutriment Attenuates Rat Burn Injury-Induced Muscle Atrophy by Modulation of Ubiquitin-Proteasome System and Autophagy Signaling Pathway. AB - This article describes results of the effect of dietary supplementation with small molecular weight soybean protein-derived peptides on major rat burn injury induced muscle atrophy. As protein nutrients have been previously implicated to play an important role in improving burn injury outcomes, optimized more readily absorbed small molecular weight soybean protein-derived peptides were evaluated. Thus, the quantity, sodium dodecyl sulfate polyacrylamide-gel electrophoresis patterns, molecular weight distribution, and composition of amino acids of the prepared peptides were analyzed, and a major full-thickness 30% total body surface area burn-injury rat model was utilized to assess the impact of supplementation with soybean protein-derived peptides on initial systemic inflammatory responses as measured by interferon-gamma (IFN-gamma), chemokine (C C motif) ligand 2 (CCL2, also known as MCP-1), chemokine (C-C motif) ligand 7 (CCL7, also known as MCP-3), and generation of muscle atrophy as measured by tibialis anterior muscle (TAM) weight relative to total body weight. Induction of burn injury-induced muscle atrophy ubiquitin-proteasome system (UPS) signaling pathways in effected muscle tissues was determined by Western blot protein expression measurements of E3 ubiquitin-protein ligase TRIM-63 (TRIM63, also known as MuRF1) and F-box only protein 32 (FBXO32, also known as atrogin-1 or MAFbx). In addition, induction of burn injury-induced autophagy signaling pathways associated with muscle atrophy in effected muscle tissues was assessed by immunohistochemical analysis as measured by microtubule-associated proteins 1 light chain 3 (MAP1LC3, or commonly abbreviated as LC3) and beclin-1 (BECN1) expression, as well as relative induction of cytoplasmic-liberated form of MAP1LC3 (LC3-I) and phagophore and autophagosome membrane-bound form of MAP1LC3 (LC3-II), and BECN1 protein expression by Western blot analysis. Nutrient supplementation with small molecular weight soybean protein-derived peptides resulted a significant reduction in burn injury-induced inflammatory markers, muscle atrophy, induction of TRIM63 and FBXO32 muscle atrophy signaling pathways, and induction of autophagy signaling pathways LC3 and BECN1 associated with muscle atrophy. These results implicated that small molecular weight soybean derived peptides dietary supplementation could be used as an adjunct therapy in burn injury management to reduce the development or severity of muscle atrophy for improved burn patient outcomes. PMID- 29493234 TI - Chemi- and Bioluminescence of Cyclic Peroxides. AB - Bioluminescence is a phenomenon that has fascinated mankind for centuries. Today the phenomenon and its sibling, chemiluminescence, have impacted society with a number of useful applications in fields like analytical chemistry and medicine, just to mention two. In this review, a molecular-orbital perspective is adopted to explain the chemistry behind chemiexcitation in both chemi- and bioluminescence. First, the uncatalyzed thermal dissociation of 1,2-dioxetane is presented and analyzed to explain, for example, the preference for triplet excited product states and increased yield with larger nonreactive substituents. The catalyzed fragmentation reaction and related details are then exemplified with substituted 1,2-dioxetanone species. In particular, the preference for singlet excited product states in that case is explained. The review also examines the diversity of specific solutions both in Nature and in artificial systems and the difficulties in identifying the emitting species and unraveling the color modulation process. The related subject of excited-state chemistry without light absorption is finally discussed. The content of this review should be an inspiration to human design of new molecular systems expressing unique light-emitting properties. An appendix describing the state-of-the-art experimental and theoretical methods used to study the phenomena serves as a complement. PMID- 29493235 TI - Carbon Isotope Fractionation of 1,2-Dibromoethane by Biological and Abiotic Processes. AB - 1,2-Dibromethane (EDB) is a toxic fuel additive that likely occurs at many sites where leaded fuels have impacted groundwater. This study quantified carbon (C) isotope fractionation of EDB associated with anaerobic and aerobic biodegradation, abiotic degradation by iron sulfides, and abiotic hydrolysis. These processes likely contribute to EDB degradation in source zones (biodegradation) and in more dilute plumes (hydrolysis). Mixed anaerobic cultures containing dehalogenating organisms (e.g., Dehaloccoides spp.) were examined, as were aerobic cultures that degrade EDB cometabolically. Bulk C isotope enrichment factors (epsilonbulk) associated with biological degradation covered a large range, with mixed anaerobic cultures fractionating more (epsilonbulk from -8 to 200/00) than aerobic cultures (epsilonbulk from -3 to -60/00). epsilonbulk magnitudes associated with the abiotic processes (dihaloelimination by FeS/FeS2 and hydrolysis) were large but fairly well constrained (epsilonbulk from -19 to 290/00). As expected, oxidative mechanisms fractionated EDB less than dihaloelimination and substitution mechanisms, and biological systems exhibited a larger range of fractionation, potentially due to isotope masking effects. In addition to quantifying and discussing epsilonbulk values, which are highly relevant for quantifying in situ EDB degradation, an innovative approach for constraining the age of EDB in the aqueous phase, based on fractionation during hydrolysis, is described. PMID- 29493236 TI - Terbium(III) Modified Fluorescent Carbon Dots for Highly Selective and Sensitive Ratiometry of Stringent. AB - Highly selective and sensitive detection of guanosine 3'-diphosphate-5' diphosphate (ppGpp), namely, the stringent in plants or microorganisms responding to strict or extreme environmental conditions such as stress and starvation, which plays an important role in gene expression, rRNA and antibiotics production, regulations of virulence of bacteria, and growth of plants, faces a great challenge owing to its extreme similarity to normal nucleotides. By modifying the surface groups of a facile two-step hydrothermal route prepared carbon dots (CDs) with terbium ions (Tb3+) in this contribution, a novel fluorescent probe with excellent properties such as highly physical and chemical stability, narrow emission and excitation wavelength-independent emission was prepared. The Tb3+ ions on the surface of CDs cannot only preserve the intrinsic fluorescence (FL) of CDs but also keep its own coordination capacity with rare earth complex, and thus the clamp structure (four phosphate groups) of ppGpp can specific binding with Tb3+ ions on the surface of CDs to produce antenna effect. Therefore, a highly selective and sensitive fluorescent ratiometry of ppGpp was developed by terbium-modified carbon dots (CDs-Tb) with the limit of detection as low as 50 nM based on the synergistic effect of antenna effect of Tb3+ ions and specific recognition capacity of CDs. The applicability of this assay was demonstrated by CDs-Tb-based paper sensor for high distinguishing ppGpp from other nucleotides with similar structure. PMID- 29493237 TI - Structurally Diverse Diterpenoids from Sandwithia guyanensis. AB - Bioassay-guided fractionation of an EtOAc extract of the trunk bark of Sandwithia guyanensis, using a chikungunya virus (CHIKV)-cell-based assay, afforded 17 new diterpenoids 1-17 and the known jatrointelones A and C (18 and 19). The new compounds included two tetranorditerpenoids 1 and 2, a trinorditerpenoid 3, euphoractines P-W (4-11), and euphactine G (13) possessing the rare 5/6/7/3 (4 7), 5/6/6/4 (8-11), and 5/6/8 (13) fused ring skeletons, sikkimenoid E (12), and jatrointelones J-M (14-17) possessing jatropholane and lathyrane carbon skeletons, respectively. Jatrointelones J (14) and M (17) represent the first naturally occurring examples of C-15 nonoxidized lathyrane-type diterpenoids. The structures of the new compounds were elucidated by NMR spectroscopic data analysis. The relative configuration of compound 16 and the absolute configurations of compounds 3-6 and 14 were determined by single-crystal X-ray diffraction analysis. In addition, jatrointelone K (15) was chemically transformed to euphoractine T (8) supporting the biosynthetic relationships between the two types of diterpenoids. Only compound 15 showed a moderate anti CHIKV activity with an EC50 value of 14 MUM. Finally, using a molecular networking-based dereplication strategy, several close analogues of 12- O tetradecanoylphorbol-13-acetate (TPA), one of the most potent inhibitors of CHIKV replication, were dereplicated. PMID- 29493238 TI - Obesity-Related Metabolomic Profiles and Discrimination of Metabolically Unhealthy Obesity. AB - A particular subgroup of obese adults, considered as metabolically healthy obese (MHO), has a reduced risk of metabolic complications. However, the molecular basis contributing to this healthy phenotype remains unclear. The objective of this work was to identify obesity-related metabolite patterns differed between MHO and metabolically unhealthy obese (MUHO) groups and examine whether these patterns are associated with the development of cardiometabolic disorders in a sample of Iranian adult population aged 18-50 years. Valid metabolites were defined as metabolites that passed the quality control analysis of the study. In this case-control study, 104 valid metabolites of 107 MHO and 100 MUHO patients were separately compared to those of 78 normal-weight metabolically healthy (NWMH) adults. Multivariable linear regression was used to investigate all potential relations in the study. A targeted metabolomic approach using liquid chromatography coupled to triple quadrupole mass spectrometry was employed to profile plasma metabolites. The study revealed that, after Bonferroni correction, branched-chain amino-acids, tyrosine, glutamic acid, diacyl-phosphatidylcholines C32:1 and C38:3 were directly and acyl-carnitine C18:2, acyl lysophosphatidylcholines C18:1 and C18:2, and alkyl-lysophosphatidylcholines C18.0 were inversely associated with MHO phenotype. The same patterns were observed in MUHO patients except for the acyl-carnitine and lysophosphatidylcholine profiles where acyl-carnitine C3:0 and acyl lysophosphatidylcholine C16:1 were higher and acyl-lysophosphatidylcholines C18:1, C18:2 were lower in this phenotype. Furthermore, proline, and diacyl phosphatidylcholines C32:2 and C34:2 were directly and serine, asparagines, and acyl-alkyl-phosphatidylcholine C34:3 were negatively linked to MUHO group. Factors composed of amino acids were directly and those containing lysophosphatidylcholines were inversely related to cardiometabolic biomarkers in both phenotypes. Interestingly, the diacyl-phosphatidylcholines-containing factor was directly associated with cardiometabolic disorders in the MUHO group. A particular pattern of amino acids and choline-containing phospholipids may aid in the identification of metabolic health among obese patients. PMID- 29493239 TI - Liquid-Crystalline Tris[60]fullerodendrimers. AB - Liquid-crystalline tris[60]fullerodendrimers based on first- and second generation poly(arylester)dendrons carrying cyanobiphenyl mesogens were synthesized for the first time by the olefin cross-metathesis reaction between type I (terminal) and type II (alpha,beta-unsaturated carbonyl) olefinic precursors, using a second-generation Grubbs or Hoveyda-Grubbs catalyst. The modular synthetic approach developed here also allowed the selective preparation of the [60]fullerene-free, mono[60]fullerodendrimer, and bis[60]fullerodendrimer derivatives from the appropriate precursors. As revealed by polarized optical microscopy, differential scanning calorimetry, and small-angle X-ray scattering, all of the materials displayed liquid-crystalline properties. In agreement with the nature of the dendritic building blocks, the emergence of lamellar mesophases (smectic C and/or smectic A phases), with the segregation of the various constitutive parts, was systematically observed. The small variation of the mesomorphic temperature range and of the mesophase stability suggested that the mesomorphism is essentially dominated by the dendrimer itself and is regulated by a subtle adaptive mechanism, in which the proportion of monolayering and bilayering arrangements of the multisegregated lamellar mesophases is modified in order to compensate the space requirements of each of the elementary building blocks, namely, the [60]fullerene units, the cyanobiphenyl mesogens, and the dendritic matrix. PMID- 29493240 TI - Spin-Coated Crystalline Molecular Monolayers for Performance Enhancement in Organic Field-Effect Transistors. AB - In organic field-effect transistors, the first few molecular layers at the semiconductor/dielectric interface are regarded as the active channel for charge transport; thus, great efforts have been devoted to the modification and optimization of molecular packing at such interfaces. Here, we report organic monolayers with large-area uniformity and high crystallinity deposited by an antisolvent-assisted spin-coating method acting as the templating layers between the dielectric and thermally evaporated semiconducting layers. The predeposited crystalline monolayers significantly enhance the film crystallinity of upper layers and the overall performance of transistors using these hybrid-deposited semiconducting films, showing a high carrier mobility up to 11.3 cm2 V-1 s-1. Additionally, patterned transistor arrays composed of the templating monolayers are fabricated, yielding an average mobility of 7.7 cm2 V-1 s-1. This work demonstrates a promising method for fabricating low-cost, high-performance, and large-area organic electronics. PMID- 29493241 TI - Au279(SR)84: The Smallest Gold Thiolate Nanocrystal That Is Metallic and the Birth of Plasmon. AB - We report a detailed study on the optical properties of Au279(SR)84 using steady state and transient absorption measurements to probe its metallic nature, time dependent density functional theory (TDDFT) studies to correlate the optical spectra, and density of states (DOS) to reveal the factors governing the origin of the collective surface plasmon resonance (SPR) oscillation. Au279 is the smallest identified gold nanocrystal to exhibit SPR. Its optical absorption exhibits SPR at 510 nm. Power-dependent bleach recovery kinetics of Au279 suggests that electron dynamics dominates its relaxation and it can support plasmon oscillations. Interestingly, TDDFT and DOS studies with different tail group residues (-CH3 and -Ph) revealed the important role played by the tail groups of ligands in collective oscillation. Also, steady-state and time-resolved absorption for Au36, Au44, and Au133 were studied to reveal the molecule-to-metal evolution of aromatic AuNMs. The optical gap and transient decay lifetimes decrease as the size increases. PMID- 29493242 TI - Controlled Single and Double Iodofluorination of Alkynes with DIH- and HF-Based Reagents. AB - A novel protocol for the regio- and stereoselective iodofluorination of internal and terminal alkynes using 1,3-diiodo-5,5,-dimethylhydantoin and HF-based reagents is disclosed. This approach is used to prepare a fluorinated tamoxifen derivative in two steps from commercially available starting materials. A facile method enabling controlled regioselective double iodofluorination of terminal alkynes is also presented. PMID- 29493243 TI - Synthesis of Di(hetero)arylamines from Nitrosoarenes and Boronic Acids: A General, Mild, and Transition-Metal-Free Coupling. AB - The synthesis of di(hetero)arylamines by a transition-metal-free cross-coupling between nitrosoarenes and boronic acids is reported. The procedure is experimentally simple, fast, mild, and scalable and has a wide functional group tolerance, including carbonyls, nitro, halogens, free OH and NH groups. It also permits the synthesis of sterically hindered compounds. PMID- 29493244 TI - Surgically Facilitated Orthodontic Therapy: Optimizing Dentoalveolar Bone and Space Appropriation for Facially Prioritized Interdisciplinary Dentofacial Therapy. AB - Comorbidities that negatively impact orthodontic (malocclusion), periodontal (periodontitis, deficient dentoalveolar bone volume, mucogingival), and prosthetic (structural integrity compromise from caries, attrition, and erosion) conditions can affect the general health of the patient. In addition, emerging data highlights the importance of undiagnosed airway volume deficiencies and sleep-disordered breathing conditions in the adult and pediatric population. Deficiencies in dentoalveolar bone and discrepancies in skeletal relationships can impact the volume of hard- and soft-tissue structures of the periodontium and decrease oral cavity volume. Contemporary interdisciplinary dentofacial therapy (IDT) is a key process for addressing the comprehensive problems of patients based on etiology, homeostasis, and sustainability of physiologically sound outcomes. These provide the patient with sustainable esthetics and function. Surgically facilitated orthodontic therapy (SFOT) uses corticotomies and dentoalveolar bone decortication to stimulate the regional acceleratory phenomenon and upregulate bone remodeling and tooth movement as a part of orthodontic decompensation. It also generally includes guided periodontal tissue regeneration and/or dentoalveolar bone augmentation. SFOT as a part of IDT is demanding and requires extensive attentiveness and communication among all team members. This article focuses on the role of SFOT as an integral component of contemporary IDT to facilitate highly predictable and sustainable outcomes. PMID- 29493245 TI - Drug Abuse Among the Elderly: Implications for Dental Practice. AB - Current demographic data demonstrate an aging North American population, and projections suggest that the percentage of the elderly will increase. Substance abuse among seniors is a common problem, though it is often unidentified and frequently undiagnosed. The most predominant drugs abused by the geriatric individual are alcohol; analgesics, including opioids; central nervous system depressants; and illicit drugs. This article will discuss reasons for drug abuse among the elderly, warning signs associated with substance abuse, and the implications of this problem to the oral cavity and the dental practice. PMID- 29493246 TI - Keys to Achieving Predictable Single-Unit Implant Esthetics in the Smile Zone. AB - When planned and implemented appropriately, single-unit implant dentistry in the smile zone can be an excellent alternative to attempting to save a failing natural tooth. Historically, implant success has revolved around assessment of osseointegration and the healing of bone around the implant, without much regard for esthetics upon completion. As implant dentistry has evolved, the expectations of both restoring clinicians and patients have expanded to emphasize the esthetic outcome as well as faster treatment with immediate implant placement. Advancements in dental radiography have increased the accuracy of diagnosing and planning, enabling more timely recognition of potential inadequacies and providing more predictable results. Even with the advances in implant dentistry over the past several decades, however, it is virtually impossible to reproduce nature; therefore, every effort should be made to preserve natural dentition. This article, which presents two case reports, will discuss differentiation between surgical success and restorative success of implants in the smile zone, identify key predictive factors associated with restorative implant success, and identify benefits of immediate implant placement. PMID- 29493247 TI - The Metal-Zirconia Implant Fixed Hybrid Full-Arch Prosthesis: An Alternative Technique for Fabrication. AB - The metal-resin hybrid full-arch prosthesis has been a traditionally used type of restoration for full-arch implant fixed dentures. A newer development has centered around the use of monolithic zirconia or zirconia veneered with porcelain. Being a ceramic, zirconia has the potential for fracture. This article describes a technique that utilizes a metal substructure to support a chemically and mechanically resinbonded shell of zirconia. The workflow is discussed, ranging from in-office master cast fabrication to the CAD/ CAM production of the provisional and the definitive metal-zirconia prosthesis. The article also highlights the advantages and disadvantages of various materials used for hybrid prostheses. PMID- 29493248 TI - Direct and Indirect Pulp Capping: A Brief History, Material Innovations, and Clinical Case Report. AB - Among the goals of pulp capping are to manage bacteria, arrest caries progression, stimulate pulp cells to form new dentin, and produce a durable seal that protects the pulp complex. This article will provide a general discussion of direct and indirect pulp capping procedures, offering practitioners a pragmatic and science-based clinical protocol for treatment of vital pulp exposures. A clinical case will be presented in which a novel light-cured resin-modified mineral trioxide aggregate hybrid material was used to manage a mechanical vital pulp exposure that occurred during deep caries excavation. PMID- 29493249 TI - Dental Impressions: Maturity of Imaging Technologies Driving Shift to Digital. PMID- 29493250 TI - Preservation of Natural Gingival Pigmentation When Treating Multiple Gingival Recession Defects. AB - Proper surgical techniques can permit treatment of multiple gingival recession defects without altering the visible gingival pigmentation. In this case report, a patient presented with multiple adjacent sites displaying gingival recession. Natural pigmentation was present in the interdental papillae and in the zone of keratinized gingiva. This patient wanted his natural pigmentation to be preserved. A modified tunnel technique was used to avoid traumatizing the pigmented tissues and allow placement of a large graft. A double layer of an acellular dermal matrix (ADM) was implanted and the gingival complex was relocated coronally. Root coverage and preservation of the natural gingival pigmentation were achieved. The use of the modified tunnel technique with a double layer of ADM can preserve natural gingival pigmentation when treating adjacent gingival recession defects. PMID- 29493251 TI - Ten Steps to Create Virtual Smile Design Templates With Adobe Photoshop(r) CS6. AB - Computer design software has become a primary tool for communication among the dentist, patient, and ceramist. Virtual smile design can be carried out using various software programs, most of which use assorted forms of teeth templates that are made based on the concept of "golden proportion." Despite current advances in 3-dimensional imaging and smile designing, many clinicians still employ conventional design methods and analog (ie, man-made) mock-ups in assessing and establishing esthetic makeovers. To simplify virtual smile designing, the teeth templates should be readily available. No literature has provided details as to how to create these templates. This article explains a technique for creating different forms of teeth templates using Adobe Photoshop(r) CS6 that eventually can be used for smile design purposes, either in Photoshop or Microsoft Powerpoint. Clinically speaking, various smile design templates created using set proportions in Adobe Photoshop CS6 can be used in virtual smile designing, a valuable resource in diagnosis, treatment planning, and communicating with patients and ceramists, thus providing a platform for a successful esthetic rehabilitation. PMID- 29493252 TI - Temporary Shell Proof-of-Concept Technique: Digital-Assisted Workflow to Enable Customized Immediate Function in Two Visits in Partially Edentulous Patients AB - The growing interest in minimally invasive implant placement and delivery of a prefabricated provisional prosthesis immediately, thus minimizing "time to teeth," has led to the development of numerous 3-dimensional (3D) planning software programs. Given the enhancements associated with fully digital workflows, such as better 3D soft-tissue visualization and virtual tooth rendering, computer-guided implant surgery and immediate function has become an effective and reliable procedure. This article describes how modern implant planning software programs provide a comprehensive digital platform that enables efficient interplay between the surgical and restorative aspects of implant treatment. These new technologies that streamline the overall digital workflow allow transformation of the digital wax-up into a personalized, CAD/CAM-milled provisional restoration. Thus, collaborative digital workflows provide a novel approach for time-efficient delivery of a customized, screw-retained provisional restoration on the day of implant surgery, resulting in improved predictability for immediate function in the partially edentate patient. PMID- 29493253 TI - Protection From Dental Erosion: All Fluorides are Not Equal. AB - All fluoride sources help strengthen teeth against bacterial acids that cause caries. However, excessive exposure to dietary acids, which can result in dental erosion, presents a more aggressive level of challenge compared to caries. Despite the fact that almost all toothpastes contain fluoride, both the incidence and prevalence of dental erosion appear to be on the rise. This article: (1) describes key differences between caries and dental erosion and the ability of different fluoride sources to help prevent erosion; (2) discusses the importance of the evaluation of patients for dental erosion at the earliest stages using the Basic Erosive Wear Examination scoring system to help assess and educate patients; and (3) provides evidence-based information for making specific recommendations to patients with dental erosion. The objective of this article is to assess the comparative ability of fluoride agents to protect against dental erosion. Though all fluorides are able to help strengthen teeth against cariogenic acids, not all available sources of fluoride provide the same level of erosion protection. Daily use of a stabilized stannous fluoride dentifrice has been shown to provide the most effective means of protecting teeth against the increasing risk of dental erosion and erosive tooth wear. PMID- 29493254 TI - Immediate Implant Placement and Provisionalization Using the Patient's Extracted Crown: 12-Month Follow-Up. AB - STATEMENT OF PROBLEM: Immediate placement and provisionalization of implants in fresh sockets has been previously demonstrated to be a predictable treatment in the restoration of non-recoverable teeth in the anterior regions of the maxilla. PURPOSE: This article reports a clinical case in which an immediate implant placement protocol was used in combination with two distinct and sequential grafts (bovine bone and connective tissue, respectively) followed by immediate implant provisionalization using the patient's crown of an extracted tooth. CLINICAL REPORT: Physical, clinical, and image examinations of the patient (female, 23 years old) revealed a maxillary central incisor (tooth No. 8) with slight mobility due the presence of extensive cervical resorption. The treatment proposed was the atraumatic extraction of the tooth followed by immediate implant placement and provisionalization. Two grafts (bovine bone and connective tissue) were used due to the presence of a very thin maxillary bone plate associated with a thin gingival biotype. RESULTS: The use of the extracted crown as a temporary crown after immediate implant placement resulted in immediate attainment of an esthetically pleasing outcome and long-term favorable results. CONCLUSION: The treatment protocol proposed can be efficiently used to immediately restore the patient's esthetics and function while maintaining the health, volume, and contours of gingival tissues over a 12-month follow-up period. CLINICAL IMPLICATIONS: Anterior teeth extractions typically require the execution of single-unit prostheses using dental materials of synthetic origin (such as polymers), which often are incapable of achieving the esthetic and physiological results patients expect. The use of the patient's own crown was demonstrated, which allowed good clinical results to be achieved and the natural shape and function of tissues to be maintained. PMID- 29493255 TI - Consensus in Traditional Chinese Medical Diagnosis in Open Populations. AB - OBJECTIVES: An acceptable level of diagnostic agreement is a prerequisite for consistent administration of treatment. It is critical for investigating effectiveness of different treatment approaches using multiple practitioners. To the best of our knowledge, no previous investigation of diagnostic consensus using open populations in Chinese medicine (CM) has been reported. Investigations restricted to individual medical conditions, such as have been usually studied, do not reveal any information as to what occurs in real world clinical settings. This knowledge gap led to the current study being conducted. Design/Location/Subjects/Interventions: Investigating diagnostic agreement specifically in Traditional Chinese Medicine (TCM) in an open population, two or three practitioners diagnosed 35 subjects at the University of Technology, Sydney (UTS), TCM clinic. The practitioners were restricted to a list of the 56 most frequently used TCM diagnoses at the UTS clinic. Up to three diagnostic patterns per subject could be selected, with nominated patterns scored between 1 and 5. OUTCOME MEASURES: Agreement was determined with two criteria, both expressed as simple percentages: pattern and linearly weighted agreements. RESULTS: The results showed that 23% of practitioners obtained pattern agreement, while 19% demonstrated weighted agreement. CONCLUSION: There appears to be very low diagnostic agreement between practitioners. This is an important finding. If unchallenged by further investigation, the recognition of such poor diagnostic consensus may lead to rejection of TCM theory before it has been adequately assessed. Diagnostic agreement must be improved so that future investigations into treatment effectiveness or mechanisms of action are made on a valid basis. Additionally, the current TCM diagnostic format must be altered to allow the application of chance-removed statistics or the calculation of a standard error with open populations. This article is the first of a series of three that report problems in TCM diagnostic reliability and proposes solutions to the issues outlined. PMID- 29493256 TI - What Is the Point? The Problem with Acupuncture Research That No One Wants to Talk About. AB - Despite having made substantial progress in academic rigor over the past decades, acupuncture research has been the focus of long-standing and persistent attacks by skeptics. One recurring theme of critics is that the concept of acupuncture points has no scientific validity. Meanwhile, the subject of whether-or-not acupuncture points "exist" has been given too little attention within the acupuncture research community. In this article, we argue that failure to use clear terminology and rigorously investigate the subject of acupuncture points has hindered the growing legitimacy of acupuncture as an evidence-based therapy. We propose that a coordinated effort is needed to improve the use of terminology related to acupuncture points, combined with rigorous investigation of their "specificity" and possible biological basis. PMID- 29493258 TI - Development of a Neo-Epitope Specific Assay for Serological Assessment of Type VII Collagen Turnover and Its Relevance in Fibroproliferative Disorders. AB - Type VII collagen is the main component of the anchoring fibrils connecting the basement membrane to the underlying interstitial matrix. Mutations in the type VII collagen gene cause dystrophic epidermolysis bullosa. Increased levels of type VII collagen in the skin have been reported in patients with systemic sclerosis (SSc), whereas reduced levels in the airways have been related to asthma. This indicates that type VII collagen plays an important part in upholding tissue integrity and that its remodeling may lead to pathological states. The aim of this study was to investigate the role of type VII collagen remodeling in fibroproliferative disorders. We produced monoclonal antibody targeting a specific fragment of type VII collagen (C7M) released to the systemic circulation and developed a neo-epitope specific competitive enzyme-linked immunosorbent assay (ELISA). Biological relevance was evaluated in serum from patients with SSc or chronic obstructive pulmonary disease (COPD). The C7M ELISA was technically robust and specific for the C7M neo-epitope. Serum C7M levels were significantly elevated in two cohorts of patients with SSc and in patients with COPD as compared with healthy individuals (P < 0.0001). The C7M ELISA enabled quantification of type VII collagen turnover in serum. Elevated serum C7M levels indicated that the turnover rate of type VII collagen was significantly increased in patients with SSc or COPD, suggesting a pathological role. Thus, the C7M ELISA may become useful in future investigations of type VII collagen turnover in fibroproliferative disorders, and it may prove a valuable tool for evaluating novel anti-fibrotic drugs. PMID- 29493259 TI - Imaging of symptomatic total knee arthroplasty with cone beam computed tomography. AB - BACKGROUND: Computed tomography (CT) can be used to assess the rotational alignment of prosthesis components to identify possible underlying causes of symptomatic total knee arthroplasty (TKA). The use of cone beam computed tomography (CBCT) for the imaging of extremities is relatively new, although it has been widely used in dental imaging. PURPOSE: To assess the intra- and inter observer reproducibility of CBCT, as well as to validate CBCT for TKA component and periprosthetic bone diagnostics. MATERIAL AND METHODS: CBCT scans were performed on 18 patients the day before a scheduled revision TKA, from which the intra- and inter-observer reproducibility were assessed. Component rotation and loosening were evaluated. Perioperative bone defects were classified. RESULTS: The inter-observer intraclass coefficient correlation (ICC) for femoral component rotation was 0.41 (95% confidence interval [CI] = 0.12-0.69). For the tibial component, the ICC was 0.87 (95% CI = 0.74-0.94). Intra-observer reproducibilities were 0.70 (95% CI = 0.35-0.87) and 0.92 (95% CI = 0.80-0.97), respectively. The sensitivity for tibial component loosening was 97% and the specificity was 85%. The reliability of bone defect classification was only weak to moderate. CONCLUSION: Two-dimensional (2D) CBCT scanning provides reliable and reproducible data for determining the rotation of femoral and tibial components, while showing minor overestimation of tibial component loosening. CBCT is a promising new tool for the evaluation of symptomatic knee arthroplasty patients, with a substantially lower radiation dose compared to conventional 2D multi-slice CT. PMID- 29493260 TI - Emergency service experiences of adults with autism spectrum disorder without intellectual disability. AB - This study aimed to describe patterns of emergency department use and police interactions, as well as satisfaction with emergency services of 40 adults with autism spectrum disorder without intellectual disability over 12-18 months. Approximately 42.5% of the sample reported visiting the emergency department and 32.5% reported interactions with police during the study period. Presenting concerns for emergency department use and police interactions varied widely, highlighting the heterogeneous needs of this population. On average, participants reported being dissatisfied with care received in the emergency department while police interactions were rated relatively more favourably. PMID- 29493257 TI - Seeing cilia: imaging modalities for ciliary motion and clinical connections. AB - The respiratory tract is lined with multiciliated epithelial cells that function to move mucus and trapped particles via the mucociliary transport apparatus. Genetic and acquired ciliopathies result in diminished mucociliary clearance, contributing to disease pathogenesis. Recent innovations in imaging technology have advanced our understanding of ciliary motion in health and disease states. Application of imaging modalities including transmission electron microscopy, high-speed video microscopy, and micron-optical coherence tomography could improve diagnostics and be applied for precision medicine. In this review, we provide an overview of ciliary motion, imaging modalities, and ciliopathic diseases of the respiratory system including primary ciliary dyskinesia, cystic fibrosis, chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis. PMID- 29493261 TI - Low tube voltage prospectively ECG-triggered coronary CT angiography: a systematic review of image quality and radiation dose. AB - OBJECTIVE: This study aimed (1) to perform a systematic review on scanning parameters and contrast medium (CM) reduction methods used in prospectively electrocardiography (ECG-triggered low tube voltage coronary CT angiography (CCTA), (2) to compare the achievable dose reduction and image quality and (3) to propose appropriate scanning techniques and CM administration methods. METHODS: A systematic search was performed in PubMed, the Cochrane library, CINAHL, Web of Science, ScienceDirect and Scopus, where 20 studies were selected for analysis of scanning parameters and CM reduction methods. RESULTS: The mean effective dose (HE) ranged from 0.31 to 2.75 mSv at 80 kVp, 0.69 to 6.29 mSv at 100 kVp and 1.53 to 10.7 mSv at 120 kVp. Radiation dose reductions of 38 to 83% at 80 kVp and 3 to 80% at 100 kVp could be achieved with preserved image quality. Similar vessel contrast enhancement to 120 kVp could be obtained by applying iodine delivery rate (IDR) of 1.35 to 1.45 g s-1 with total iodine dose (TID) of between 10.9 and 16.2 g at 80 kVp and IDR of 1.08 to 1.70 g s-1 with TID of between 18.9 and 20.9 g at 100 kVp. CONCLUSION: This systematic review found that radiation doses could be reduced to a rate of 38 to 83% at 80 kVp, and 3 to 80% at 100 kVp without compromising the image quality. Advances in knowledge: The suggested appropriate scanning parameters and CM reduction methods can be used to help users in achieving diagnostic image quality with reduced radiation dose. PMID- 29493262 TI - Clinical and histological features of second breast cancers following radiotherapy for childhood and young adult malignancy. AB - OBJECTIVE: The purpose of this study was to determine the characteristics of early second breast cancer (SBC) among survivors of childhood and young adult malignancy treated with irradiation. METHODS: We conducted a multicenter retrospective study of women who presented with breast cancer aged 50 years or younger in nine French centers. RESULTS: 121 patients and 141 SBC were analyzed (invasive = 130; non-invasive = 11). The mean age at first cancer diagnosis was 15 years and at initial SBC diagnosis was 38 years. Bilateral disease before the age of 51 years was diagnosed in 16% of the females. The majority of SBC were invasive carcinomas (92%). Among the invasive carcinomas, 39% had a histoprognostic score of III, 3.1% overexpressed HER2 and 29% were triple negative. The proportion of triple negative phenotype SBC was higher in patients older at first cancer diagnosis [RR = 1.2, 95% CI (1.1-1.3)]. 94% of triple negative SBCs developed in breast tissue which had received >20 Gy. CONCLUSION: We found a high proportion of aggressive SBC following thoracic radiotherapy in childhood or early adulthood. Advances in knowledge: SBC screening is recommended by scientific societies for these child/young-adulthood cancer survivors in the same way as the one for high risk women because of constitutional mutations. Our results support these recommendations, not only because of a similar cumulative risk, but also because of the aggressive histological characteristics. PMID- 29493263 TI - Safety and effectiveness of the different types of embolic materials for the treatment of testicular varicoceles: a systematic review. AB - OBJECTIVE: The purpose of this study is to assess the current evidence regarding the safety and effectiveness of the various embolic materials used in varicoceles embolization. METHODS: A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Databases were searched for clinical studies that investigated the clinical outcomes of embolization treatment for the management of testicular varicoceles. Study methodological quality was analyzed. RESULTS: 23 retrospective and 7 prospective clinical studies were identified with a total of 3505 patients. Technical success rates appear to be above 90% for all embolic materials without any significant differences. In terms of recurrence rates, glue (N = 251) appeared to have the lowest and sclerosants alone (N = 728) the highest recurrence rates which were 4.2% (11-3.08%, SD: 5.9) and 11.03% (18.8-5.15%, SD: 6.06) within an average follow up (f/u) of 16.13 and 25.48 months respectively. Coils alone (N = 898) had an average recurrence rate of 9.1% (17.8-1.4%; SD: 5.79) and a mean f/u of 39.3 months. After an average of 12 months of f/u, the addition of sclerosants (N = 1628) as an adjunct to coils did not improve recurrence rates (8.44%, 16.5-5.1%; SD: 3.4). No differences were reported regarding the safety profile of the various embolic materials. CONCLUSION: Despite the heterogeneity of the included studies, preliminary evidence supports the safe and effective use of the various embolic materials currently used for the management of varicoceles. At 1 year, glue appears to be the most effective in preventing recurrence with coils being the second most effective. The addition of sclerosants to the coil embolization did not appear to have an impact on recurrence rates. Further research is required to elucidate the cost effectiveness of these approaches. Advances in knowledge: Varicocele embolization appears to be a safe and effective technique regardless of the embolic agent. Addition of a sclerosant agent to coil embolization does not appear to improve outcomes. PMID- 29493264 TI - Salmonella enterica subsp. salamae serovar Sofia, a prevalent serovar in Australian broiler chickens, is also capable of transient colonisation in layers. AB - 1. Salmonella enterica subsp. salamae serovar sofia (S. sofia) is a prevalent strain of Salmonella in Australian broilers and has been isolated from broiler chickens, litter, dust, as well as pre- and post-processing carcasses, and retail chicken portions but has never been reported in commercial Australian layers or eggs. 2. To investigate whether a S. sofia isolate from a broiler could colonise layers, one-month-old Hyline brown layers were orally inoculated with S. sofia and colonisation was monitored for 2-4 weeks. 3. Overall, 30-40% of the chickens shed S. sofia from the cloaca between 6 and 14 d post-inoculation which then declined to 10% by d 21. Necropsy at 2 weeks post-inoculation revealed 80% of birds harboured S. sofia in the caecum, whilst, by 4 weeks post-infection, no chickens were colonised with S. sofia in the gastrointestinal tract, liver or spleen. Additionally, no aerosol 'bird to bird' transfer was evident. 4. This study demonstrated that laying hens can be colonised by broiler-derived S. sofia; however, this colonisation was transient, reaching a peak at 14 d post inoculation, and was completely cleared by 28 d post-inoculation. The transience of colonisation of S. sofia in layers could be a factor explaining why S. sofia has never been detected when screening for Salmonella serotypes found in Australian laying hens or eggs. PMID- 29493265 TI - HPV, hypoxia and radiation response in head and neck cancer. AB - Over the last decades, the incidence of human papilloma virus (HPV) positive head and neck squamous-cell carcinoma (HNSCC) has significantly increased. Infection with high-risk HPV types drives tumourigenesis through expression of the oncoproteins E6 and E7. Currently, the primary treatment of HNSCC consists of radiotherapy, often combined with platinum-based chemotherapeutics. One of the common features of HNSCC is the occurrence of tumour hypoxia, which impairs the efficacy of radiotherapy and is a negative prognostic factor. Therefore, it is important to detect and quantify the severity of hypoxia, as well as develop strategies to specifically target hypoxic tumours. HPV-positive tumours are remarkably radiosensitive compared to HPV-negative tumours and consequently the HPV-positive patients have a better prognosis. This provides an opportunity to elucidate mechanisms of radiation sensitivity, which may reveal targets for improved therapy for HPV-negative head and neck cancers. In this review, we will discuss the differences between HPV-positive and HPV-negative head and neck tumours and methods of hypoxia detection and targeting in these disease types. Particular emphasis will be placed on the mechanisms by which HPV infection impacts radiosensitivity. PMID- 29493266 TI - Effects of brief mindfulness-based cognitive behavioural therapy on health related quality of life and sense of coherence in atrial fibrillation patients. AB - BACKGROUND: The aim of this study was to evaluate the effects of a brief dyadic cognitive behavioural therapy (CBT) programme on the health-related quality of life (HRQoL), as well as the sense of coherence in atrial fibrillation patients, up to 12 months post atrial fibrillation. METHODS: A longitudinal randomised controlled trial with a pre and 12-month post-test recruitment of 163 persons and their spouses, at a county hospital in southern Sweden. In all, 104 persons were randomly assigned to either a CBT ( n=56) or a treatment as usual (TAU) group ( n=55). The primary outcome was changes in the HRQoL (Euroqol questionnaire; EQ 5D), and the secondary outcomes were changes in psychological distress (hospital anxiety and depression scale; HADS) and sense of coherence (sense of coherence scale; SOC-13). RESULTS: At the 12-month follow-up, the CBT group experienced a higher HRQoL than the TAU group (mean changes in the CBT group 0.062 vs. mean changes in the TAU group -0.015; P=0.02). The sense of coherence improved in the CBT group after the 12-month follow-up, compared to the TAU group (mean changes in the CBT group 0.062 vs. mean changes in the TAU group -0.16; P=0.04). The association between the intervention effect and the HRQoL was totally mediated by the sense of coherence ( z=2.07, P=0.04). CONCLUSIONS: A dyadic mindfulness-based CBT programme improved HRQoL and reduced psychological distress up to 12 months post atrial fibrillation. The sense of coherence strongly mediated the HRQoL; consequently, the sense of coherence is an important determinant to consider when designing programmes for atrial fibrillation patients. PMID- 29493267 TI - Dying at home and effective prescribing. PMID- 29493269 TI - Dealing with violence as a community nurse. PMID- 29493268 TI - District nurses now less likely to face prosecution for gross negligence manslaughter. AB - In this article the author discusses the Court of Appeal decision in R v Rose [2017] that redefines the threshold for prosecution for gross negligence manslaughter. The impact on district nurses will be that they are unlikely to face prosecution where a careless error contributed to a patient's death unless there was a serious and obvious risk of death at the time the error was made. PMID- 29493270 TI - Supporting the spread of health technology in community services. AB - Health technology has been proposed as a route to financial savings and improved patient safety for many years within the NHS. Nurses have a key role to play in transforming care through such technology but, despite high-level endorsement, implementation of health technology has been uneven across NHS community services. This article looks at three promising applications of health technology in community nursing: mobile access to digital care records; digital imaging; and remote face-to-face consultations. Current evidence for these technologies gives some indication of what is required before health technologies can benefit patients. Rapidly changing health technologies make it difficult for community services to make fully informed decisions when implementing them. There are challenges in predicting the full financial and efficiency impacts, in making robust estimates of costs and workload implications and in anticipating the effects on patient care and staff experience. Despite these problems, there is mounting evidence of the benefits of technological innovations available to community nurses and their patients. PMID- 29493271 TI - Research into dementia care, treatment and prevention is more active than ever. PMID- 29493272 TI - Community palliative care clinical nurse specialists as independent prescribers: part 2. AB - This study explored the lived experiences of clinical nurse specialists who can prescribe independently in their role of providing support to patients with palliative care needs within the community. Part 1 of this study examined how the study was carried out; this second part explores the findings. The nurses reported that being able to prescribe enabled them to provide seamless, holistic care, which gave patients faster access to medicines, especially at weekends when their GP was unavailable. Prompt availability of medicines led to effective symptom control and consequently a better quality of life for patients. The main barrier to prescribing was difficulty in accessing patient records. Independent prescribing by community nurse specialists is beneficial for patients receiving palliative care and their families while they are being cared for at home, and provides job satisfaction for the nurses. PMID- 29493273 TI - Why nurses volunteering for the QNI Keep in Touch project are part of something special. PMID- 29493274 TI - Implementing a sustainable clinical supervision model for Isles nurses in Orkney. AB - The Isles Network of Care (INOC) community nurses work at the extreme of the remote and rural continuum, working mostly as lone practitioners. Following the development of sustainable clinical supervision model for Isles nurses in Orkney, clinical supervision was found to improve both peer support and governance for this group of isolated staff. A literature overview identified the transition of clinical supervision in general nursing over 24 years from 'carrot' to 'stick'. The study included a questionnaire survey that was sent to the 2017 Queen's Nursing Institute Scotland cohort to elicit information about the nurses' experience of clinical supervision. The survey found that 55% provide supervision and 40% receive it. Health board encouragement of its use was found to be disappointingly low at 40%. The INOC nurses were surveyed about the new peer support (restorative) model, which relies on video-conference contact to allow face to face interaction between isolated isles nurses. Feedback prompted a review of clinical supervision pairings, and the frequency and methods of meeting. The need for supervisor training led to agreement with the Remote and Rural Health Education Alliance to provide relevant support. The perceived benefits of supervision included increased support and reflection, and improved relationships with isolated colleagues. PMID- 29493275 TI - Caring through crisis. PMID- 29493276 TI - Male urinary incontinence management: penile sheaths. AB - Urinary incontinence is a hidden problem that affects 14 million adults in the UK. It affects around 30% of men aged 65 and over and can have a huge effect on quality of life. Often this distressing symptom can be treated effectively. It is important to manage incontinence while the man is undergoing investigations and treatment or when treatment is not possible. This article examines the role of urinary sheaths in the management of incontinence and provides links to further information. PMID- 29493277 TI - Getting palliative care right. PMID- 29493278 TI - Meaning of life for patients in palliative and end-of-life care. PMID- 29493281 TI - 'Stand up' for a healthy lifestyle. PMID- 29493280 TI - Addition of an educational programme for primary caregivers to rehabilitation improves self-care and mobility in children with cerebral palsy: a randomized controlled trial. AB - OBJECTIVE: To assess whether the addition of an education programme for primary caregivers to rehabilitation improves daily functioning in children with cerebral palsy. DESIGN: A randomized, single-blind, controlled study. SETTING: This study was conducted in a rehabilitation centre in Salvador, Brazil. PARTICIPANTS: A total of 63 boys and girls with cerebral palsy, at 1-12 years of age, with Gross Motor Function Classification Systems I-V, were randomly assigned to two groups: educational programme for primary caregivers and conventional rehabilitation ( n = 29) or conventional rehabilitation alone ( n = 31). INTERVENTION: Each group received 12 sessions of 30 minutes of conventional rehabilitation and 12 sessions of 45 minutes to intervention group. MEASUREMENTS: Gross Motor Function Classification System, Gross Motor Function Measure and daily functioning with the Pediatric Evaluation of Disability Inventory were assessed by a blinded assessor. The clinical outcomes were obtained at the completion of treatment (12 weeks). RESULTS: Of the 63 patients included, 60 (mean +/- SD age: 4.6 +/- 2.74 years) completed the protocol. The combined education and rehabilitation, as compared with conventional rehabilitation alone, yielded significantly greater benefit in the self-care domain of the Functional Skills Scale (mean change 1.74 versus 5; P = 0.001), self-care (mean change 5.52 versus 13.99; P = 0.017) and the mobility domain of the Caregiver Assistance Scale of Pediatric Evaluation of Disability Inventory (mean change 0.87 versus 17.88; P = 0.002). CONCLUSION: Self care and mobility improved in children with cerebral palsy with the addition to conventional rehabilitation of an educational programme for primary caregivers. PMID- 29493279 TI - MR imaging features of mammary analogue secretory carcinoma and acinic cell carcinoma of the salivary gland: a preliminary report. AB - OBJECTIVES: To report MR imaging features of mammary analogue secretory carcinoma (MASC) and acinic cell carcinoma (AciCC) of the salivary gland based on the latest version of the World Health Organization (WHO) 2017 classification of head and neck tumours. METHODS: MR images in 4 patients with MASC and 4 with AciCC were reviewed for margin characteristics, the presence of pathological cervical nodes, the presence of a cystic component and interface between cystic and solid component, signal intensity of the cystic components on T1 weighted images, and signal intensity of the solid component on T1 and T2 weighted images. RESULTS: All the MASCs and AciCCs had well-defined boundaries, and 1 AciCC had pathological nodes. All 4 MASCs presented as predominantly cystic tumours with papillary projection of the solid component. All 4 AciCCs presented as solid tumours. The signal intensity of the cystic components on T1 weighted images was entirely hyperintense in 2, and partly hyperintense demonstrating fluid-fluid level in 2. In all the MASCs, the signal intensity of the solid components on T1 weighted images was intermediate. In the AciCCs, the signal intensity of the solid components on T1 weighted images was high in 2 tumours and intermediate in 2. The signal intensity of the solid components on T2 weighted images varied from low to high in both MSACs and AciCCs. CONCLUSIONS: All 4 MASCs had a large cystic component, including areas of high signal intensity on T1 weighted images. The solid component appeared as a papillary projection into the cystic component. All 4 AciCCs presented as solid tumours, 2 of which showed high signal intensity on T1 weighted images. PMID- 29493282 TI - Diagnostic yield of 90-kVp low-tube-voltage carotid and intracerebral CT angiography: effects on radiation dose, image quality and diagnostic performance for the detection of carotid stenosis. AB - OBJECTIVE: To investigate the impact of low-tube-voltage 90-kVp acquisition combined with advanced modeled iterative reconstruction algorithm (Admire) on radiation exposure, image quality, artifacts, and assessment of stenosis in carotid and intracranial CT angiography (CTA). METHODS: Dual-energy CTA studies of 43 patients performed on a third-generation 192-slice dual-source CT were retrospectively evaluated. Intraindividual comparison of 90-kVp and linearly blended 120-kVp equivalent image series (M_0.6, 60% 90-kVp, 40% Sn-150-kVp) was performed. Contrast-to-noise and signal-to-noise ratios of common carotid artery, internal carotid artery, middle cerebral artery, and basilar artery were calculated. Qualitative image analysis included evaluation of artifacts and suitability for angiographical assessment at shoulder level, carotid bifurcation, siphon, and intracranial by three independent radiologists. Detection and quantification of carotid stenosis were performed. Radiation dose was expressed as dose-length product (DLP). RESULTS: Contrast-to-noise values of all arteries were significantly increased in 90-kVp compared to M_0.6 (p < 0.001). Suitability for angiographical evaluation was rated excellent with low artifacts for all levels in both image series. Both 90-kVp and M_0.6 showed excellent accordance for detection and grading of carotid stenosis with almost perfect interobserver agreement (carotid stenoses in 32 of 129 segments; intraclass correlation coefficient, 0.94). dose-length product was reduced by 40.3% in 90-kVp (110.6 +/- 32.1 vs 185.4 +/- 47.5 mGy.cm, p < 0.001). CONCLUSION: 90-kVp carotid and intracranial CTA with Admire provides increased quantitative and similarly good qualitative image quality, while reducing radiation exposure substantially compared to M_0.6. Diagnostic performance for arterial stenosis detection and quantification remained excellent. Advances in knowledge: 90-kVp carotid and intracranial CTA with an advanced iterative reconstruction algorithm results in excellent image quality and reduction of radiation exposure without limiting diagnostic performance. PMID- 29493285 TI - Recent developments of artificial intelligence in drying of fresh food: A review. AB - Intellectualization is an important direction of drying development and artificial intelligence (AI) technologies have been widely used to solve problems of nonlinear function approximation, pattern detection, data interpretation, optimization, simulation, diagnosis, control, data sorting, clustering, and noise reduction in different food drying technologies due to the advantages of self learning ability, adaptive ability, strong fault tolerance and high degree robustness to map the nonlinear structures of arbitrarily complex and dynamic phenomena. This article presents a comprehensive review on intelligent drying technologies and their applications. The paper starts with the introduction of basic theoretical knowledge of ANN, fuzzy logic and expert system. Then, we summarize the AI application of modeling, predicting, and optimization of heat and mass transfer, thermodynamic performance parameters, and quality indicators as well as physiochemical properties of dried products in artificial biomimetic technology (electronic nose, computer vision) and different conventional drying technologies. Furthermore, opportunities and limitations of AI technique in drying are also outlined to provide more ideas for researchers in this area. PMID- 29493284 TI - Multiparametric MR imaging of peripheral zone prostate cancer: effect of postbiopsy hemorrhage on cancer detection according to Gleason score and tumour volume. AB - OBJECTIVE: To evaluate effect of postbiopsy hemorrhage on detection of peripheral zone (PZ) prostate cancer by multiparametric MR imaging according to Gleason score and tumor volume. METHODS: This retrospective study included 54 biopsy proven prostate cancer patients (median age, 67.0 years) who underwent multiparametric MR imaging. Two independent readers evaluated each sextant of the PZ using the PI-RADS v2. One reader recorded the presence or absence of hemorrhage per sextant on T1 weighted MR images. Areas under the receiver operating characteristic curves (AUCs) were used to evaluate cancer detection accuracy. RESULTS: Postbiopsy hemorrhage was noted in 122 (37.7%) of 324 sextants of all patients. There was no significant difference in the AUC for detection of cancer with Gleason score >=3 + 4 or volume >=0.5 ml between sextants with and without hemorrhage (with hemorrhage, reader 1, 0.83 for Gleason score >=3 + 4, 0.84 for tumor volume >=0.5 ml; reader 2, 0.74 for Gleason score >=3 + 4, 0.77 for tumor volume >=0.5 ml; without hemorrhage, reader 1, 0.86 for Gleason score >=3 + 4, 0.88 for tumor volume >=0.5 ml; reader 2, 0.79 for Gleason score >=3 + 4, 0.83 for tumor volume >=0.5 ml; p > 0.2 for all). CONCLUSION: Postbiopsy hemorrhage did not negatively affect the detection of clinically significant PZ prostate cancer on multiparametric MR imaging. Advances in knowledge: Under influence of postbiopsy hemorrhage, multiparametric MR can be useful for the detection of clinically significant PZ prostate cancer. PMID- 29493286 TI - Imaginability of adoption, foster care, and life without a(nother) child and stress in women and men in fertility treatment. AB - We study whether the imaginability of adoption, foster care, and life without a(nother) child protects from stress during fertility treatment. Data from a self administered prospective cohort study of couples who had just started treatment were used (T1 = 441 respondents; T2 = 142 respondents). Most respondents cannot imagine alternatives to treatment. Adoption/foster care is preferred over life without children. Imaginability of alternatives is associated with lower fertility-related (T1) and treatment-related stress (T2). Experience of a pregnancy/birth does not moderate the association. Thus, the availability of alternatives to treatment turns out to be helpful in terms of self-regulation during fertility treatment. PMID- 29493287 TI - Vitamin D serum levels and receptor genetic polymorphisms are associated with hepatitis B virus and HIV infections and IFN-lambda levels. AB - AIM: Vitamin D is involved in antiviral/antitumor activities. Its associations to hepatitis B virus (HBV), HIV and hepatocellular carcinoma (HCC) are unclear. MATERIALS & METHODS: A retrospective study was conducted on 232 chronic hepatitis B (CHB) patients and 72 HIV-infected patients. The correlation between serum 25(OH)D3 and 25 vitamin D receptor single nucleotide polymorphisms to disease progression and interferons were evaluated. RESULTS: The 25(OH)D3 was associated with HBV infection and progression. In HIV, it was linked to treatment responsiveness. In CHB, cirrhotic and HCC patients, it was associated with viral load. Fourteen single nucleotide polymorphisms were related to disease progression in HBV infection. In HCC, IFN-lambda levels were associated with 25(OH)D3 levels negatively. CONCLUSION: Serum vitamin D level and vitamin D receptor genetic polymorphisms are associated with CHB and HIV disease progression and IFN-lambdas. PMID- 29493289 TI - Capecitabine lipid nanoparticles for anti-colon cancer activity in 1,2 dimethylhydrazine-induced colon cancer: preparation, cytotoxic, pharmacokinetic, and pathological evaluation. AB - The cornerstone of this investigation is to determine the pharmacokinetic and histopathological behavior of solid lipid nanoparticles of capecitabine (CB-SLNs) in 1,2-dimethylhydrazine (DMH) induced colon cancer. The nanoparticles were prepared by microemulsion method. CB-SLNs were characterized for an optimal system. The cytotoxicity of CB-SLNs was evaluated by using MTT assay method. Further, pharmacokinetic and histopathological behavior of SLNs were studied in DMH induced colon cancer rats. The optimized nanoparticles have the particle size, zeta potential, and entrapment efficiency of 145.6 +/- 3.6 nm, -26.9 +/- 2.7 mV, and 88.33 +/- 3.74%, respectively. Particles of CB were nearly spherical in shape and converted to amorphous form revealed by SEM and DSC, XRD studies. The nanoparticles showed dose-dependent cytotoxicity activity from 10 to 125 ug/mL compared with suspension. Pharmacokinetic studies revealed that 2.7-folds enhancement in the oral bioavailability and in aberrant crypt foci number, apoptotic index comparison with suspension formulation. PMID- 29493288 TI - Impact of room lighting and image display device in the radiographic appearances of the endodontic treatments. AB - OBJECTIVES: To assess the radiographic appearances of the endodontic treatment in different room lighting conditions and image display devices. METHODS: After approval by Research Ethical Board, 20 images were obtained from blocks with one endodontically treated tooth. Of the 20 endodontic treatments conducted in the laboratory, of those the randomly selected 10 teeth (50% of sample) received some quality defect in three parameters-apical limit, adaptation to root canal and homogeneity of the root canal filling material. Digital radiographs (DIGORA(r) Optime, Soredex, Milwaukee, WI) were obtained, which were evaluated (8 times) by 10 observers in two different conditions of room lighting, with bright (1000 to 1200 lux) and dim light (25 to 50 lux), using two different image display devices, smartphones and laptop computers. The observers assessed the radiographic appearances of the endodontic treatment with respect to quality of each one of three parameters individually. The data of observers' responses in terms of the quality of each parameter were statistically compared using Cronbach's alpha coefficient, diagnostic tests, pi coefficient and ANOVA with Tukey tests, at a significant level setting of 5% (alpha = 0.05). RESULTS: The mean of reliability of observer responses ranged from 0.89 (intra-evaluator) to 0.66 (inter-evaluator). The mean values of the receiver operating characteristic (ROC) area were 0.661 (PD = 0.098), with laptop in bright lighting appraising homogeneity of the root canal filling material on the worst performance (ROC area = 0.57), which was statistically significant (p < 0.05), and 0.81 with laptop in dim lighting appraising apical limit on the best performance. Differences (p < 0.05) occurred mainly among parameters used for assessment. CONCLUSIONS: Room lighting and image display devices have very little influence in the radiographic appearances of the endodontic treatment. Thus, we suggest the use of smartphones as an acceptable image display device in daily clinical practice in routine bright lighting conditions. PMID- 29493290 TI - Suicidal ideation in patients with obstructive sleep apnoea and its relationship with disease severity, sleep-related problems and social support. AB - We aimed to assess the prevalence of suicidal ideation and to examine the relationships between obstructive sleep apnoea severity, sleep-related problems, social support and suicidal ideation in obstructive sleep apnoea patients. We included 149 patients (68% male; mean age, 48.99 +/- 9.57 years) with diagnosed obstructive sleep apnoea (Apnoea-Hypopnoea Index ?5) based on full-night polysomnography. The prevalence of suicidal ideation among obstructive sleep apnoea patients was 20.1 per cent. Structural equation modelling showed that suicidal ideation in obstructive sleep apnoea was strongly related to poor sleep quality and high fatigue levels. No relationship between social support and suicidal ideation in obstructive sleep apnoea patients was found. PMID- 29493291 TI - 2017 Acknowledgment of Reviewers. PMID- 29493292 TI - From the Editor-in-Chief's Desk. PMID- 29493293 TI - Latino Solo Grandparents Raising Grandchildren: Health Risks and Behaviors. AB - INTRODUCTION: The purpose of this descriptive report is to provide the first representative information on the sociodemographic profile and the prevalence of mental and physical health conditions of two "at-risk" groups of Latino caregivers: solo grandparent caregivers and single parents. METHODS: The 2012 Behavior Risk Factor Surveillance System was used to compare five dimensions of health on a sample of Latino solo grandparents and Latino single parents, raising their grandchildren/children alone. Bivariate and logistic regression comparative analyses were conducted on study measures. RESULTS: Latino solo grandparents have a high prevalence of chronic health conditions, including arthritis (51%), depression (40%), diabetes (34%), and asthma (34%). Latino single parents have lower but troubling health risks, including depression (22%), diabetes (14%), and asthma (14%). Differences between the two groups were largely due to the grandparents older age. DISCUSSION: Latino solo grandparents have a high prevalence of several chronic medical conditions. The prevalence of disorders is much lower for Latino single parents, although they too have disturbing health risks. CONCLUSION: Latino solo grandparents perform their parenting role under intense physical and emotional strain. Health professionals can be instrumental in facilitating interventions that affect the well-being of this expanding family group. PMID- 29493294 TI - Water-soluble substituted chitosan derivatives as technology platform for inhalation delivery of siRNA. AB - Despite research efforts full potential of siRNA-based therapeutics has not yet been fully realized due to a need for suitable, effective delivery formulations. Here, we examine a potential of a new class of water-soluble chitosans as siRNA platform for pulmonary delivery. The system is based on piperazine-substituted chitosans, a material designed to integrate established, safe application of chitosan for mucosal administration with novel properties: the piperazine substituted chitosans are freely water-soluble at physiological pH, possess low cytotoxicity (no significant reduction in cell viability up to 0.1 mg/ml), and provide efficient incorporation of siRNA into sub-300 nm colloidal complexes (at relatively low polymer/siRNA ratio of 5:1). In vitro, the complexes achieved silencing of a model gene at a level of 40-80%, when tested in a panel of lung epithelial cells. Considering the formulation 'developability', there were no significant changes in the complexes' size and integrity on aerosolisation by microsprayer (PenCenturyTM) device. Following intratracheal aerolisation, the complexes deposited throughout the lung, although relatively inhomogeneously, as judged from IVIS imaging of the isolated mouse lung (visualizing DY647-siRNA). In vivo data illustrate absence of adverse effects on repeated administration of complexes and significant tumor reduction in atopical lung cancer model in mice. Altogether, the data illustrates potential of substituted chitosan derivatives to be utilized as a safe system for inhalation delivery of siRNA. PMID- 29493295 TI - Surgical challenges in the treatment of perimenopausal and postmenopausal endometriosis. AB - Endometriosis is classically defined as a chronic, recurrent and progressive disease. It is known to be estrogen-dependent, but can still be observed during the peri- and postmenopausal periods. Medical management of endometriosis is palliative symptomatic relief. Surgery when properly and timely performed for the right person may treat endometriosis. However, there is always a risk of possible major or minor surgical complications, as well as loss of some functions due to nerve damage. Management of endometriosis in the woman approaching the end of her reproductive life may require special attention both due to the potential for recurrence and transformation into various endometriosis-associated malignancies. PMID- 29493296 TI - Regression of prostate tumors after intravenous administration of lactoferrin bearing polypropylenimine dendriplexes encoding TNF-alpha, TRAIL, and interleukin 12. AB - The possibility of using gene therapy for the treatment of prostate cancer is limited by the lack of intravenously administered delivery systems able to safely and selectively deliver therapeutic genes to tumors. Given that lactoferrin (Lf) receptors are overexpressed on prostate cancer cells, we hypothesized that the conjugation of Lf to generation 3-diaminobutyric polypropylenimine dendrimer would improve its transfection and therapeutic efficacy in prostate cancer cells. In this study, we demonstrated that the intravenous administration of Lf-bearing DAB dendriplexes encoding TNFalpha resulted in the complete suppression of 70% of PC-3 and 50% of DU145 tumors over one month. Treatment with DAB-Lf dendriplex encoding TRAIL led to tumor suppression of 40% of PC-3 tumors and 20% of DU145 tumors. The treatment was well tolerated by the animals. Lf-bearing generation 3 polypropylenimine dendrimer is therefore a highly promising delivery system for non-viral gene therapy of prostate cancer. PMID- 29493297 TI - Assessment of DNA damages in lymphocytes of agricultural workers exposed to pesticides by comet assay in a cross-sectional study. AB - PURPOSE: To assess the predictive power of the comet assay in the context of occupational exposure to pesticides. MATERIALS AND METHODS: The recruited subjects completed a structured questionnaire and gave a blood sample. Exposure to pesticides was measured by means of an algorithm based on Dosemeci's work (Agricultural Health Study). Approximately 50 images were analyzed for each sample via fluorescence microscopy. The extent of DNA damage was estimated by tail moment (TM) and is the product of tail DNA (%) and tail Length. RESULTS: Crude significant risks (odds ratios, ORs) for values higher than the 75th percentile of TM were observed among the exposed subjects (score > 1). The frequency of some confounding factors (sex, age and smoking) was significantly higher among the exposed workers. A significant dose-effect relationship was observed between TM and exposure score. Significant high-risk estimates (ORs), adjusted by the studied confounding factors, among exposure to pesticides and TM, % tail DNA and tail length were confirmed using unconditional logistic regression models. CONCLUSIONS: The adjusted associations (ORs) between the comet parameters and exposure to pesticides were significant. The sensitivity of the comet test was low (41%), the specificity (89%) and the predictive positive value (0.77) were found acceptable. PMID- 29493298 TI - Phenotypic and genotypic studies of ALS cases in ALS-SMA families. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are the most frequent motor neuron disorders in adulthood and infancy, respectively. There is a growing literature supporting common pathophysiological patterns between those disorders. One important clinical issue for that is the co occurrence of both diseases within a family. OBJECTIVES: To collect families in which ALS and SMA patients co-exist and describe the phenotype and the genotype of ALS patients. PATIENTS AND METHODS: Nine families with co-occurrence of SMA and ALS have been gathered over the last 15 years. Epidemiological, phenotype and genetic status were collected. RESULTS: Out of the nine families, six corresponded to the criteria of familial ALS (FALS). Clinical data were available for 11 patients out of the 15 ALS cases. Mean age of onset was 58.5 years, site of onset was lower limbs in nine cases (81.8%), median duration was 22 months. Four ALS patients carried a mutation: three mutations in SOD1 gene (G147N in two cases and one with E121G) and one repeat expansion in the C9ORF72 gene. Three patients had abnormal SMN1 copy numbers. CONCLUSIONS: While the high proportion of familial history of ALS cases in these ALS-SMA pedigrees could have suggested that these familial clusters of the two most frequent MND rely on a genetic background, we failed to exclude that this occurred by chance. PMID- 29493299 TI - Predicting the cardiac toxicity of drugs using a novel multiscale exposure response simulator. AB - A common but serious side effect of many drugs is torsades de pointes, a rhythm disorder that can have fatal consequences. Torsadogenic risk has traditionally been associated with blockage of a specific potassium channel and an increased recovery period in the electrocardiogram. However, the mechanisms that trigger torsades de pointes remain incompletely understood. Here we establish a computational model to explore how drug-induced effects propagate from the single channel, via the single cell, to the whole heart level. Our mechanistic exposure response simulator translates block-concentration characteristics for arbitrary drugs into three-dimensional excitation profiles and electrocardiogram recordings to rapidly assess torsadogenic risk. For the drug of dofetilide, we show that this risk is highly dose-dependent: at a concentration of 1x, QT prolongation is 55% but the heart maintains its regular sinus rhythm; at 5.7x, QT prolongation is 102% and the heart spontaneously transitions into torsades de points; at 30x, QT prolongation is 132% and the heart adapts a quasi-depolarized state with numerous rapidly flickering local excitations. Our simulations suggest that neither potassium channel blockage nor QT interval prolongation alone trigger torsades de pointes. The underlying mechanism predicted by our model is early afterdepolarization, which translates into pronounced U waves in the electrocardiogram, a signature that is correctly predicted by our model. Beyond the risk assessment of existing drugs, our exposure-response simulator can become a powerful tool to optimize the co-administration of drugs and, ultimately, guide the design of new drugs toward reducing life threatening drug-induced rhythm disorders in the heart. PMID- 29493301 TI - Recent developments with tau-based drug discovery. AB - INTRODUCTION: Alzheimer's disease (AD), which accounts for three fourth of all cases of dementia, is a major public health problem in modern society and, yet, there is no effective treatment available that can prevent or inhibit this chronic progressive neurodegenerative disease. A major current drug target is intraneuronal abnormally hyperphosphorylated microtubule-associated protein tau which is a histopathological hallmark of this disease and of a family of neurodegenerative diseases called tauopathies. Areas covered: In this review, the authors discuss a growing number of studies that describe the nature and mechanism of tau pathology and various drug discovery options and most recent developments in tau-based therapeutics. PubMed was used to obtain relevant literature while clinicaltrials.gov site and Google search were employed to obtain the latest information on tau based AD clinical trials. Expert opinion: In authors' opinion, loss of neuronal connectivity leads to the hyperphosphorylation of tau and is thus a key therapeutic target. Rescue of neuronal connectivity loss and hyperphosphorylation of tau are most promising approaches. Consequently, tau immunotherapy has a high therapeutic potential. PMID- 29493300 TI - Multiseed liposomal drug delivery system using micelle gradient as driving force to improve amphiphilic drug retention and its anti-tumor efficacy. AB - To improve drug retention in carriers for amphiphilic asulacrine (ASL), a novel active loading method using micelle gradient was developed to fabricate the ASL loaded multiseed liposomes (ASL-ML). The empty ML were prepared by hydrating a thin film with empty micelles. Then the micelles in liposomal compartment acting as 'micelle pool' drove the drug to be loaded after the outer micelles were removed. Some reasoning studies including critical micelle concentration (CMC) determination, influencing factors tests on entrapment efficiency (EE), structure visualization, and drug release were carried out to explore the mechanism of active loading, ASL location, and the structure of ASL-ML. Comparisons were made between pre-loading and active loading method. Finally, the extended drug retention capacity of ML was evaluated through pharmacokinetic, drug tissue irritancy, and in vivo anti-tumor activity studies. Comprehensive results from fluorescent and transmission electron microscope (TEM) observation, encapsulation efficiency (EE) comparison, and release studies demonstrated the formation of ML shell structure for ASL-ML without inter-carrier fusion. The location of drug mainly in inner micelles as well as the superiority of post-loading to the pre loading method , in which drug in micelles shifted onto the bilayer membrane was an additional positive of this delivery system. It was observed that the drug amphiphilicity and interaction of micelles with drug were the two prerequisites for this active loading method. The extended retention capacity of ML has been verified through the prolonged half-life, reduced paw-lick responses in rats, and enhanced tumor inhibition in model mice. In conclusion, ASL-ML prepared by active loading method can effectively load drug into micelles with expected structure and improve drug retention. PMID- 29493302 TI - Intensity-time dependence dosing criterion in the EMF exposure guidelines in Russia. AB - Major approaches of the Russian Federation in setting of exposure guidelines to electromagnetic fields (EMF) in occupational and public environments are discussed in this paper. EMF exposure guidelines in Russia are based on the results of hygienic, clinical, physiological, epidemiological and experimental studies and are frequency-dependent. The concept of a threshold principle of occupational and environmental factors due to hazardous exposure effects has been used to set permissible exposure levels of different EMF frequency ranges. The data of experimental studies showed hazardous threshold levels of EMF effects. The main criteria of EMF hazardous exposure evaluated in the experimental study concerned both estimation of threshold levels of chronic (long-term) and acute exposure. Also, this paper contains some recent experimental study data on correlation of long-term radiofrequency and power-frequency EMF exposure effects with regard to time duration, the so-called time-dependence approach. It enables identification of the value of permissible EMF exposure levels depending on exposure duration. This approach is used in occupational exposure guideline setting and requires the introduction of "power exposition" (PE) and "maximal permissible level" (MPL). In general, EMF exposure guidelines are established with regard to possible duration of exposure per day. PMID- 29493303 TI - Genetic Polymorphisms of Glucose-6-Phosphate Dehydrogenase in Lagos, Nigeria. AB - Glucose-6-phosphate dehydrogenase (G6PD) is an essential enzyme in the pentose phosphate pathway that prevents oxidative damage to cells. This study determined the genotypic and allelic frequencies of G6PD G202A and A376G and also investigated correlation between G6PD polymorphisms and hemoglobin (Hb) phenotypes in children in Lagos, Nigeria. Seventy-eight children [55 with Hb AA (betaAlpha/betaA) and 23 with Hb AS (betaAlpha/betaS) trait] and 65 Hb SS (betaS/betaS) (HBB: c.20A>T) subjects in steady state with age range between 5-15 years were recruited for the study. Hemoglobin phenotypes of all study participants were carried out using alkaline electrophoresis and solubility tests. Genomic DNA was extracted from whole blood and restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) was used to determine the G202A and the A376G mutations of the G6PD gene. The genotype and allele distributions of G6PD G202A and A376G according to the Hb phenotypes were not statistically significant (p > 0.05). The minor allele frequency 202A was 0.15 (15.0%) and 0.14 (14.0%) in cases and controls, respectively. The overall frequency of 376G allele in the case group was 0.35 (35.0%) and 0.38 (38.0%) in the control group. No statistical significance was observed in the genotype and allele distributions of A376G in both the case and control groups (p > 0.05). The G6PD A- frequency in Hb SS subjects and the control group were 6.2 and 2.6%, respectively. G6PD G202A and A376G polymorphisms were not associated with Hb phenotypes and the allele distributions of 202A and 376G in this study are typical of West African populations. PMID- 29493304 TI - The social aspect of Leg Clubs and how that aids healing. PMID- 29493305 TI - Interrogate, inform and inspire. PMID- 29493306 TI - Identifying and managing wound infection in the community. AB - A large proportion of community wound care consists of managing chronic wounds. Given the increasingly complex patient comorbidities, early identification and treatment of wound infection can impact greatly not only on wound healing but also on the patient physically, psychologically and socially. Identifying wound infection can be challenging for clinicians, particularly in the chronic wound where infection may not always present itself as it does in acute wounds. The management of infected wounds can be complicated. Managing multiple symptoms and recognising these as being due to infection is not always straightforward and relies on the practitioner's knowledge and skills. An understanding of more commonly used antimicrobial treatments and when to employ these is paramount in enabling the practitioner to provide care that is effective, evidence based and cost efficient. PMID- 29493307 TI - Chronic venous leg ulcer care: Putting the patient at the heart of leg ulcer care. Part 1: exploring the consultation. AB - This article, the first of two, summarises a study that explored the lived experiences of patients with leg ulcers and the impact of this condition on their quality of life. The study had four study phases; phases 1 and 2 employed qualitative methods and are reported here. Initially, unstructured interviews were held; these revealed significant issues for the patients including the dominance of pain, issues relating to exudate and odour, social isolation and psychological effects. A checklist based on these issues was completed by the researcher during observations of routine care for these same patients; this revealed the extent and depth to which these matters were addressed. On many occasions, significant issues were not disclosed or explored during consultations. These findings confirmed that participants with chronic venous leg ulcers have concerns far beyond wound care. PMID- 29493308 TI - Reflection: navigation for continuous improvement. PMID- 29493309 TI - The influence of matrix metalloproteases and biofilm on chronic wound healing: a discussion. AB - Chronicity in wound healing is a challenge for health services financially and scientifically, with negative consequences on patients' lives. This paper seeks to explore why chronic wounds fail to heal in relation to the inflammatory cellular dysfunction associated with biofilm development. Findings demonstrate an association between chronic wounds failing to heal, the presence of devitalised tissue and abnormal immune cell activity with a consequential excessive release of harmful matrix metalloproteases (MMPs). This process perpetuates the cycle of wound chronicity and extracellular matrix destruction, which prolongs the inflammatory response, fuelling biofilm formation. Evidence suggests that 'trapping' MMPs may increase new tissue growth but, while devitalised tissue is present, phagocytic cells continue to secrete MMPs and chronicity persists. Consequently, by removing the trigger and implementing effective, sustained debridement of devitalised tissue, both MMP and biofilm production will be diminished, with positive healing outcomes. PMID- 29493310 TI - The importance of accurate methodology in ABPI calculation when assessing lower limb wounds. AB - Recent health economic publications have highlighted the cost of wound care and demonstrated the important role played by community and practice nurses in delivering care. Leg ulcers form a significant proportion of the wounds managed in the community. Data indicates that many patients are managed with no specific diagnosis or without calculation of the ankle brachial pressure index (ABPI), despite care guidelines emphasising the importance of a full assessment including Doppler ABPI calculation in patient management. This article highlights the important role Doppler ABPI plays in patient assessment and describes the methodology, focusing on the importance of correct application of the technique if reliable reproducible results are to be obtained. The rationale for obtaining blood pressure readings from both arms is discussed, and the possible error resulting from reliance on single upper limb blood pressure measurement for both manual and automated ABPI calculation is highlighted and its impact on ABPI calculation illustrated. PMID- 29493311 TI - Does vitamin D deficiency predict early conversion of clinically isolated syndrome? A preliminary Egyptian study. AB - BACKGROUND: It has been suggested that vitamin D influences the immunoregulation and subsequently affects the risk for conversion of clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (MS). There is little information regarding the relationship between levels of vitamin D and CIS conversion to MS in Egyptian patients. OBJECTIVE: It is to study contribution of vitamin D deficiency to conversion of CIS to clinically definite multiple sclerosis (CDMS) and correlation of vitamin D level to cognitive and magnetic resonance imaging (MRI) results. PATIENTS AND METHODS: A longitudinal prospective case control study was conducted on 43 Egyptian patients diagnosed as CIS according to McDonald criteria (2010). Clinical presentation, brain MRI and 25-hydroxyvitamin D levels were evaluated at baseline and after one-year follow-up. RESULTS: The CIS patients that converted to MS showed significant lower vitamin D level (p < 0.001) than the non-convertors. Multivariate logistic regression analysis revealed that the CIS patients with lower 25-hydroxyvitamin D level (p < 0.001) are at higher risk for early conversion to MS. There was a significant positive correlation between the vitamin D level and PASAT (r = 0.36, p = 0.02). It was found that there was a significant negative correlation between vitamin D level and MRI T2 load (r = -0.38, p = 0.01). CONCLUSION: The low level of 25 hydroxyvitamin D may predict early conversion to clinically definite MS. Early vitamin D supplementation is recommended in patients with CIS. PMID- 29493312 TI - Hepatocellular Carcinoma in a beta-Thalassemia Intermedia Patient: Yet Another Case in the Expanding Epidemic. AB - The incidence of hepatocellular carcinoma (HCC) in patients with thalassemia is increasing, the two well recognized HCC risk factors in thalassemia being iron overload and chronic hepatitis C. The carcinogenicity of iron is related to its induction of oxidative damage, whereas chronic hepatitis leads to necroinflammation that can accelerate progression to HCC. We hereby report the case of a non transfused, hepatitis C-negative, beta-thalassemia intermedia (beta TI) patient from our practice who had evidence of significant iron overload, suggesting the importance of increased iron burden as a HCC risk factor in this patient population. As such, screening thalassemia patients using magnetic resonance imaging (MRI)-based liver iron concentration (LIC) measurement and liver ultrasound is strongly recommended for early detection of iron overload and HCC, respectively. Data appears to be lacking on HCC treatment outcomes in patients who have thalassemia, but an approach tailored to each patient's comorbidities is key to treatment success. The prognosis of these patients can be improved by multicenter studies investigating novel HCC therapeutic targets in the thalassemia realm. PMID- 29493313 TI - Factors associated with early initiation of disease-modifying drug treatment in newly-diagnosed patients with multiple sclerosis. AB - OBJECTIVE: To examine the time to first disease-modifying drug (DMD) treatment and to identify factors associated with early DMD initiation in newly-diagnosed patients with MS. METHODS: This retrospective cohort study included newly diagnosed patients with MS from a US administrative claims database, aged 18-65 years, with a first MS diagnosis (ICD-9-CM code: 340.xx) between January 1, 2007 and June 30, 2013 (index date), continuous eligibility for 12 months pre- and 24 months post-index, and initiated DMD treatment within 2 years. Time to first DMD within 24 months post-index was evaluated. A logistic regression model predicted earlier initiation of DMD treatment (within 60 days of MS diagnosis). RESULTS: In total, 37.4% of patients initiated DMD treatment within 2 years of MS diagnosis and were included in the primary analysis (n = 7,124). Mean (standard deviation [SD]) time from MS diagnosis to first DMD was 112.6 (148.3) days (median = 51); 30.7% received first DMD in <30 days, 55.1% in <60 days, and 18.5% not until >=180 days after diagnosis. Logistic regression found that younger age; not living in the Northeast; diagnoses of balance disorders, numbness, and optical neuritis; the absence of musculoskeletal diagnoses; and a neurologist visit or MRI within 90 days before diagnosis were associated with DMD initiation within 60 days. CONCLUSIONS: In this population of patients initiating DMD treatment within 2 years of MS diagnosis, mean time to first DMD was 112.6 days. Identifying factors associated with delayed treatment may provide better understanding of the reasons for delay, leading to improved disease management. PMID- 29493316 TI - Cigars. PMID- 29493315 TI - Preschool Multiple-Breath Washout Testing. An Official American Thoracic Society Technical Statement. AB - BACKGROUND: Obstructive airway disease is nonuniformly distributed throughout the bronchial tree, although the extent to which this occurs can vary among conditions. The multiple-breath washout (MBW) test offers important insights into pediatric lung disease, not available through spirometry or resistance measurements. The European Respiratory Society/American Thoracic Society inert gas washout consensus statement led to the emergence of validated commercial equipment for the age group 6 years and above; specific recommendations for preschool children were beyond the scope of the document. Subsequently, the focus has shifted to MBW applications within preschool subjects (aged 2-6 yr), where a "window of opportunity" exists for early diagnosis of obstructive lung disease and intervention. METHODS: This preschool-specific technical standards document was developed by an international group of experts, with expertise in both custom built and commercial MBW equipment. A comprehensive review of published evidence was performed. RESULTS: Recommendations were devised across areas that place specific age-related demands on MBW systems. Citing evidence where available in the literature, recommendations are made regarding procedures that should be used to achieve robust MBW results in the preschool age range. The present work also highlights the important unanswered questions that need to be addressed in future work. CONCLUSIONS: Consensus recommendations are outlined to direct interested groups of manufacturers, researchers, and clinicians in preschool device design, test performance, and data analysis for the MBW technique. PMID- 29493317 TI - Retraction: Mitigation of azathioprine-induced testicular atrophy by taurine; an impact on inflammation, oxidative perturbations and apoptosis. PMID- 29493318 TI - Retraction: Role and potential targeting of hepatic apurinic/apyrimidinic endonuclease-1 and cyclin-dependent kinase-4 in hepatocellular carcinoma. PMID- 29493321 TI - E-Cigarettes: Inducing Inflammation that Spans Generations. PMID- 29493322 TI - Role of the Aryl Hydrocarbon Receptor in Su5416/Hypoxia-induced Pulmonary Hypertension: A New Mechanism for an "Old" Model. PMID- 29493323 TI - Fighting Bacterial Pathogens in the Lung: Platelets to the Rescue? PMID- 29493324 TI - Importance of the IL-1 Axis in Haemophilus influenzae-stimulated M1 Macrophages Driving Transepithelial Signaling. PMID- 29493325 TI - Inflammation Gets on the Lung's Nerves: IL-17 and Neuroendocrine Cells Mediate Ozone Responses in Obesity. PMID- 29493326 TI - theta-Defensins-A Magic Bullet for Acute Lung Injury? PMID- 29493327 TI - Good adherence to adjuvant endocrine therapy in early breast cancer - a population-based study based on the Swedish Prescribed Drug Register. AB - INTRODUCTION: Adjuvant endocrine therapy improves recurrence-free and overall survival in primary breast cancer. However, not all patients complete their planned treatment, mostly because of side-effects. The aim of this study was to examine the adherence to adjuvant endocrine therapy in a cohort of primary breast cancer patients in Region Jonkoping County, Sweden, after 3 and 5 years. MATERIAL AND METHODS: The Swedish Breast Cancer Register was used to identify patients diagnosed with hormone receptor positive breast cancer in Region Jonkoping County between 2009 and 2012. Adherence was evaluated based on data from the Swedish Prescribed Drug Register, and Medication Possession Ratio (MPR), defined as the days' supply of medication during the period from the first dispensing till the last dispensing in the time period (3 and 5 years), divided by number of days. Adherence was defined as MPR >=80%. Regression analyses were used to identify subgroups associated with adherence; age, type of endocrine treatment, additional adjuvant therapy, and hospital responsible for the follow-up (Eksjo, Jonkoping, and Varnamo). RESULTS: We identified 634 patients who were recommended adjuvant endocrine therapy and to be able to estimate adherence after 3 and 5 years, 488 patients were included in the analysis. After 3 years of treatment, 91.2% of the patients (95% confidence interval (CI) 88.7-93.6; n = 445), were found to be adherent. The corresponding figure for the 271 patients who had completed 5 years of treatment was 91.5% (95% CI 88.2-94.8; n = 248). No subgroups (age, endocrine therapy, radio/chemotherapy, or hospital) were significantly associated with adherence in the multiple logistic regression analysis. DISCUSSION: This study shows substantially higher adherence to adjuvant endocrine therapy than previously reported. Reasons for this could be differences in routines for therapy information and follow-up, but this needs to be further investigated. PMID- 29493328 TI - No effect of double nerve block of the lateral cutaneous nerve and subcostal nerves in total hip arthroplasty. AB - Background and purpose - The use of local infiltration anesthesia (LIA) has become one of the cornerstones of rapid recovery protocols in total knee arthroplasty patients during the past decade. In total hip arthroplasty (THR), however, the study results are more variable and LIA has therefore not yet been generally accepted. There is no consensus on which structure should be infiltrated and the cutaneous nerves are generally neglected. Hence, we hypothesized a pain-reducing effect of specifically blocking these nerves. Patients and methods - We performed a single-center randomized placebo-controlled trial in 162 subjects to evaluate the infiltration of the lateral cutaneous femoral and subcostal nerve with ropivacaine in patients undergoing total hip arthroplasty via a straight lateral approach. The primary endpoint was pain at rest after 24 hours. Patients were followed up to 6 weeks postoperatively. Results - After correction for multiple testing, no statistically significant differences in pain scores were found between the ropivacaine compared with the placebo group after surgery. In addition, no differences were observed in the use of escape pain medication, complications, and the length of hospital stay. Interpretation - We found no clinically meaningful differences in pain scores between placebo and ropivacaine patients in the postoperative period after THA performed via a straight lateral approach under spinal anesthesia and a multimodal pain regimen. Moreover, our primary endpoint, pain reduction after 24 hours, was not met. Further research should focus on the composition and volume of the LIA suspension, the optimal localization of the infiltration, and should be evaluated for every surgical approach separately. PMID- 29493329 TI - Analysis of Common beta-Thalassemia Mutations in North Vietnam. AB - Available and flexible choice of methods for screening and detecting beta thalassemia (beta-thal) can promote control of thalassemia in developing countries. In this study, two methods, the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and reverse dot-blot hybridization assays were developed to detect common beta-thal mutations in 244 thalassemia patients and 152 healthy people in North Vietnam. The most common mutation was codon 26 (G>A), also known as Hb E (HBB: c.79G>A), accounting for 26.4% of the total studied chromosomes, followed by codons 41/42 (-TCTT) (HBB: c.126_129delCTTT) and codon 17 (A>T) (HBB: c.c.52A>T), accounting for 19.4 and 16.4%, respectively. In addition, codon 95 (+A) (HBB: c.c.287_288insA) that is known as the Vietnamese mutation, accounted for 0.6%. Moreover, the heterozygous state of the four mutations was also found in healthy people, of which Hb E was again the most common mutation with a frequency 3.0%. The results of this study provide available methods and indicative data for preventive and control strategies concerning the genetic diagnosis of thalassemia. PMID- 29493330 TI - Fecal microbiota transplantation for managing irritable bowel syndrome. AB - INTRODUCTION: Irritable bowel syndrome (IBS) is a widespread gastrointestinal disorder affecting 11.2% of the world adult population. The intestinal microbiome is thought to play a pivotal role in the pathophysiology of IBS. The composition of the fecal microbiome in IBS patients differs from that in healthy individuals, but the exact bacteria species involved in the development of IBS remain to be determined. There is also an imbalance between useful and harmful bacteria (dysbiosis) in the intestinal microbiome in patients with IBS. Consuming prebiotics, probiotics, or synbiotics has a limited effect on IBS symptoms. In contrast, fecal microbiome transplantation (FMT) in IBS patients reverses the dysbiosis to normobiosis and reduces the IBS symptoms in about 70% of patients, and is not associated with any serious adverse events. Area covered: The available data on the microbiome and FMT in IBS regarding the efficacy of FMT in managing IBS were found using a PubMed search of these topics. Expert commentary: FMT is a promising tool for managing irritable syndrome. It appears to be effective, easy, and inexpensive procedure. However, more controlled studies involving larger cohorts of IBS are needed before FMT can be used as a routine procedure in the clinic. PMID- 29493332 TI - Isoniazid Monoresistance: A Precursor to Multidrug-Resistant Tuberculosis? PMID- 29493331 TI - Characterization of Hb Bart's Hydrops Fetalis Caused by - -SEA and a Large Novel alpha0-Thalassemia Deletion. AB - Hb Bart's hydrops fetalis is the most severe and generally fatal clinical phenotype of alpha-thalassemia (alpha-thal), which is due to the deletion of all four functional alpha-globin genes of hemoglobin (Hb), resulting in no alpha globin chain production (- -/- -). Homozygosity for the - -SEA (Southeast Asian) alpha-globin gene deletion is the main cause of the Hb Bart's hydrops fetalis in Asia, especially South China. Occasionally, other alpha0-thal deletions can also be found. In this study, we report a case with an atypical form of Hb Bart's hydrops fetalis that was caused by - -SEA and a large novel alpha0-thal deletion (- -GX) (Guangxi). The fetus with Hb Bart's in our study presented fetal hydrops features in early gestation which was different from that of traditional Hb Bart's hydrops fetalis with a homozygous - -SEA deletion. The early onset of fetal hydrops is attributed to the decreased formation of embryonic Hb Portland (zeta2gamma2), which is proposed as a candidate for reactivation in cases of severe alpha-thal. Our findings indicated that it was important to characterize new or rare mutations, and highlighted the significance of using ultrasonography to identify signs of Hb Bart's hydrops fetalis. PMID- 29493333 TI - Proactively Engaging Smokers with Chronic Respiratory Disease in Tobacco Treatment. PMID- 29493334 TI - Bronchiectasis Exacerbations Are Heart-Breaking. PMID- 29493335 TI - A Woman with a 15-Year History of Bronchiectasis and Recurrent Nontuberculous Mycobacterium Pulmonary Disease. PMID- 29493336 TI - Imaging Adipose Tissue: New Insights into Asthma. PMID- 29493337 TI - 2017 Reviewers. PMID- 29493338 TI - Physiologic Approach to Mechanical Ventilation in Right Ventricular Failure. PMID- 29493340 TI - Is My Intensivist Better Than Your Intensivist? PMID- 29493339 TI - Understanding the Role of Staphylococcus aureus in Non-Cystic Fibrosis Bronchiectasis: Where Are We Now? PMID- 29493341 TI - CFTR Modulators: Deciding What Is Best for Individuals in an Era of Precision Medicine. PMID- 29493343 TI - Robert Bidder: body squabbles. PMID- 29493342 TI - Comparison of non-contact infrared skin thermometers. AB - Non-contact infra-red skin thermometers (NCITs) are becoming more prevalent for use in medical diagnostics. Not only are they used as an alternative means of estimating core body temperature but also to assess the diabetic foot for signs of inflammation prior to ulceration. Previous investigations have compared the performance of NCITs in a clinical setting against other gold standard methods. However, there have been no previous investigations comparing the performance of NCITs in assessing temperature measurement capability traceable to the International Temperature Scale of 1990 (ITS-90). A metrological assessment of nine common NCITs was carried out over the temperature range of 15-45 degrees C using the National Physical Laboratory's blackbody reference sources to identify their accuracy, repeatability, size-of-source and distance effects. The results are concerning in that five of the NCITs fell far outside the accuracy range stated by their manufacturers as well as the medical standard to which the NCITs are supposed to adhere. Furthermore, a 6 degrees C step change in measurement error over the temperature range of interest for the diabetic foot was found for one NCIT. These results have implications for all clinicians using NCITs for temperature measurement and demonstrate the need for traceable calibration to ITS 90. PMID- 29493344 TI - ALSUntangled 44: curcumin. PMID- 29493345 TI - Negative effect of zoledronic acid on tendon-to-bone healing. AB - Background and purpose - Outcome after ligament reconstruction or tendon repair depends on secure tendon-to-bone healing. Increased osteoclastic activity resulting in local bone loss may contribute to delayed healing of the tendon-bone interface. The objective of this study was to evaluate the effect of the bisphosphonate zoledronic acid (ZA) on tendon-to-bone healing. Methods - Wistar rats (n = 92) had their right Achilles tendon cut proximally, pulled through a bone tunnel in the distal tibia and sutured anteriorly. After 1 week animals were randomized to receive a single dose of ZA (0.1 mg/kg IV) or control. Healing was evaluated at 3 and 6 weeks by mechanical testing, dual-energy X-ray absorptiometry and histology including immunohistochemical staining of osteoclasts. Results - ZA treatment resulted in 19% (95% CI 5-33%) lower pullout strength and 43% (95% CI 14-72%) lower stiffness of the tendon-bone interface, compared with control (2-way ANOVA; p = 0.009, p = 0.007). Administration of ZA did not affect bone mineral density (BMD) or bone mineral content (BMC). Histological analyses did not reveal differences in callus formation or osteoclasts between the study groups. Interpretation - ZA reduced pullout strength and stiffness of the tendon-bone interface. The study does not provide support for ZA as adjuvant treatment in tendon-to-bone healing. PMID- 29493346 TI - Consumerism: a threat to health? PMID- 29493347 TI - A randomized controlled trial on maximal strength training in 60 patients undergoing total hip arthroplasty. AB - Background and purpose - Total hip arthroplasty (THA) patients have reduced muscle strength after rehabilitation. In a previous efficacy trial, 4 weeks' early supervised maximal strength training (MST) increased muscle strength in unilateral THA patients <65 years. We have now evaluated muscle strength in an MST and in a conventional physiotherapy (CP) group after rehabilitation in regular clinical practice. Patients and methods - 60 primary THA patients were randomized to MST or CP between August 2015 and February 2016. The MST group trained at 85-90% of their maximal capacity in leg press and abduction of the operated leg (4 * 5 repetitions), 3 times a week at a municipal physiotherapy institute up to 3 months postoperatively. The CP group followed a training program designed by their respective physiotherapist, mainly exercises performed with low or no external loads. Patients were tested pre- 3, 6, and 12 months postoperatively. Primary outcomes were abduction and leg press strength at 3 months. Other parameters evaluated were pain, 6-min walk test, Harris Hip Score (HHS) and Hip disability and Osteoarthritis Outcome Score (HOOS) Physical Function Short-form score. Results - 27 patients in each group completed the intervention. MST patients were substantially stronger in leg press and abduction than CP patients 3 (43 kg and 3 kg respectively) and 6 months (30 kg and 3 kg respectively) postoperatively (p <= 0.002). 1 year postoperatively, no intergroup differences were found. No other statistically significant intergroup differences were found. Interpretation - MST increases muscle strength more than CP in THA patients up to 6 months postoperatively, after 3 months' rehabilitation in clinical practice. It was well tolerated by the THA patients and seems feasible to conduct within regular clinical practice. PMID- 29493349 TI - Completion Gastrectomy with Esophagojejunostomy for Management of Complications of Benign Foregut Surgery. AB - BACKGROUND: With the worldwide epidemic of obesity, an increasing number of bariatric operations and antireflux fundoplications are being performed. Despite low morbidity of the primary foregut surgery, completion gastrectomy may be necessary as a definitive procedure for complications of prior foregut surgery; however, the literature evaluating outcomes after completion gastrectomy with esophagojejunostomy (EJ) for benign diseases is limited. We present our experience of completion gastrectomy with Roux-en-Y EJ in the setting of benign disease at a single tertiary center. METHODS AND PROCEDURES: All patients who underwent total, proximal, or completion gastrectomy with EJ for complications of benign foregut surgery from January 2006 to December 2015 were retrospectively identified. All cancer operations were excluded. RESULTS: There were 23 patients who underwent gastrectomy with EJ (13 laparoscopic EJ [LEJ] and 10 open EJ). The index operations included 12 antireflux, 9 bariatric, and 2 peptic ulcer disease surgeries. Seventy-eight percent of patients had surgical or endoscopic interventions before EJ, with a median of one prior intervention and a median interval from the index operation to EJ of 25 months (interquartile range 9-87). The 30-day perioperative complication rate was 30% with 17% classified being major (Clavien-Dindo >= III) and no 30-day perioperative mortality. Comparing laparoscopic and open approaches showed similar operative times, estimated blood loss, and overall complication rate. LEJ was associated with a shorter length of stay (LOS) (P < .001), fewer postoperative ICU days (P = .002), fewer 6-month complication rates (P < .007), and decreased readmission rate (P = .024). CONCLUSION: Our series demonstrates that EJ is a reasonable option for reoperative foregut surgery. The laparoscopic approach appears to be associated with decreased LOS and readmissions. PMID- 29493348 TI - Revision surgery of metal-on-metal hip arthroplasties for adverse reactions to metal debris. AB - Background and purpose - The initial outcomes following metal-on-metal hip arthroplasty (MoMHA) revision surgery performed for adverse reactions to metal debris (ARMD) were poor. Furthermore, robust thresholds for performing ARMD revision are lacking. This article is the second of 2. The first article considered the various investigative modalities used during MoMHA patient surveillance (Matharu et al. 2018a ). The present article aims to provide a clinical update regarding ARMD revision surgery in MoMHA patients (hip resurfacing and large-diameter MoM total hip arthroplasty), with specific focus on the threshold for performing ARMD revision, the surgical strategy, and the outcomes following revision. Results and interpretation - The outcomes following ARMD revision surgery appear to have improved with time for several reasons, among them the introduction of regular patient surveillance and lowering of the threshold for performing revision. Furthermore, registry data suggest that outcomes following ARMD revision are influenced by modifiable factors (type of revision procedure and bearing surface implanted), meaning surgeons could potentially reduce failure rates. However, additional large multi-center studies are needed to develop robust thresholds for performing ARMD revision surgery, which will guide surgeons' treatment of MoMHA patients. The long-term systemic effects of metal ion exposure in patients with these implants must also be investigated, which will help establish whether there are any systemic reasons to recommend revision of MoMHAs. PMID- 29493350 TI - Tyrosine receptor kinase B receptor activation reverses the impairing effects of acute nicotine on contextual fear extinction. AB - Anxiety and stress disorders have been linked to deficits in fear extinction. Our laboratory and others have demonstrated that acute nicotine impairs contextual fear extinction, suggesting that nicotine exposure may have negative effects on anxiety and stress disorder symptomatology. However, the neurobiological mechanisms underlying the acute nicotine-induced impairment of contextual fear extinction are unknown. Therefore, based on the previous studies showing that brain-derived neurotrophic factor is central for fear extinction learning and acute nicotine dysregulates brain-derived neurotrophic factor signaling, we hypothesized that the nicotine-induced impairment of contextual fear extinction may involve changes in tyrosine receptor kinase B signaling. To test this hypothesis, we systemically, intraperitoneally, injected C57BL/6J mice sub threshold doses (2.5 and 4.0 mg/kg) of 7,8-dihydroxyflavone, a small-molecule tyrosine receptor kinase B agonist that fully mimics the effects of brain-derived neurotrophic factor, or vehicle an hour before each contextual fear extinction session. Mice also received injections, intraperitoneally, of acute nicotine (0.18 mg/kg) or saline 2-4 min before extinction sessions. While the animals that received only 7,8-dihydroxyflavone did not show any changes in contextual fear extinction, 4.0 mg/kg of 7,8-dihydroxyflavone ameliorated the extinction deficits in mice administered acute nicotine. Overall, these results suggest that acute nicotine-induced impairment of context extinction may be related to a disrupted brain-derived neurotrophic factor signaling. PMID- 29493351 TI - The NORSe: changing the way we communicate. AB - Introduction Rapid, reliable and efficient communication in healthcare systems with finite resources promises to improve patient care. Telephone engagement has effectively monopolised the referral process in the acute setting. Hence, traditional inter-hospital referral networks are potentially time consuming, not expeditious and frustrating. There is often no comprehensive documented communication record or audit trail. Social media, however, suggest that instantaneous, secure and dependable exchanges of information can occur via alternative conduits, potentially transforming the acute clinical referral system. The National On-Call Referral System (NORSe) was established in 2010 as an alternative referral paradigm. We explore the literature evidence surrounding the clinical impact of the NORSe referral system and analogous models. Early evidence suggests that NORSe may minimise delays in obtaining specialist advice and management, particularly in the acute setting. It enables the specialist to receive and address a large number of fact intense referrals that would otherwise be unpalatable and unmanageable. We summarise recent developments with the NORSe and give an overview of its clinical applications and links with clinical governance. NORSe and similar models promise to change the way we communicate as doctors, making the process more efficient, with a robust audit trail facilitating service appraisal and training. PMID- 29493352 TI - Type II papillary renal cell carcinoma with heterotrophic ossification: a case report. AB - Heterotrophic ossification in tumours is an uncommon phenomenon. The presence of ossification in renal cell carcinomas is extremely rare. In this report, we present a unique case of type II papillary renal cell carcinoma associated with heterotrophic ossification. PMID- 29493354 TI - The surgical personality. PMID- 29493353 TI - A standardised pathway for the surveillance of stable vestibular schwannoma. AB - Introduction Conservative management of patients with a stable vestibular schwannoma (VS) places a significant burden on National Health Service (NHS) resources and yet patients' surveillance management is often inconsistent. Our unit has developed a standardised pathway to guide surveillance imaging of patients with stable VS. In this article, we provide the basis for our imaging protocol by reviewing the measurement, natural history and growth patterns of VS, and we present a cost analysis of implementing the pathway both regionally and nationally. Methods Patients with an extrameatal VS measuring <=20mm in maximal diameter receive magnetic resonance imaging (MRI) six months after their index imaging, followed by three annual MRI scans, two two-year interval MRI scans, a single three-year interval MRI scan and then five-yearly MRI scans to be continued lifelong. Patients with purely intrameatal tumours follow the same protocol but the initial six-month imaging is omitted. A cost analysis of the new pathway was modelled on our unit's retrospective data for 2015 and extrapolated to reflect the cost of VS surveillance nationally. Results Based on an estimation that imaging surveillance would last approximately 25 years (+/- 10 years), the cost of implementing our regional surveillance programme would be L151,011 per year (for 99 new referrals per year) and it would cost the NHS L1,982,968 per year if implemented nationally. Conclusions A standardised surveillance pathway promotes safe practice in the conservative management of VS. The estimated cost of a national surveillance programme compares favourably with other tumour surveillance initiatives, and would enable the NHS to provide a safe and economical service to patients with VS. PMID- 29493355 TI - A cost-effective cell- and matrix-based minimally invasive single-stage chondroregenerative technique developed with validated vertical translation methodology. AB - Introduction The morbidity and significant health economic impact associated with the chondral lesion has led to a large number of strategies for therapeutic neochondrogenesis. The challenge has been to develop techniques that are cost effective single-stage procedures with minimal surgical trauma that have undergone rigorous preclinical scrutiny and robust reproducible assessment of effectiveness. A biological repair requires the generation of a cellular and matrix composite with appropriate signalling for chondrogenic differentiation. Methods and results A technique was developed that allowed chondrogenic primary (uncultured) cells from bone marrow aspirate concentrate, combined with a composite hydrophilic and fibrillar matrix to be applied arthroscopically to a site of a chondral lesion. The construct was tested in vitro and in animal experiments before clinical trials. Clinical trials involved 60 patients in a prospective study. Symptomatic International Cartilage Repair Society grade 3 and 4a lesions were mapped and treated. Pre- and postoperative clinical assessments showed statistically significant improved outcomes; Lysholm Knee Scoring Scale (mean 52.8 to > 76.4; P < 0.05) International Knee Documentation Committee (mean 39 to > 79 P < 0.05) and Knee injury and Osteoarthritis Outcome Score (64.5 to >89.2 P < 0.05). Postoperative magnetic resonance imaging was evaluated morphologically (magnetic resonance observation of cartilage repair tissue, average MOCART score 72) and qualitatively; the regenerate was comparable to native cartilage. Conclusions This technique is effective, affordable, requires no complex tools and delivers a single-stage treatment that is potentially accessible to any centre capable of performing arthroscopic surgery. Good clinical results were found to be sustained at five years of follow-up with a regenerate that appears hyaline like using multiple magnetic resonance measures. PMID- 29493356 TI - A Neural-Network-Based Approach to Personalize Insulin Bolus Calculation Using Continuous Glucose Monitoring. AB - BACKGROUND: In type 1 diabetes (T1D) therapy, the calculation of the meal insulin bolus is performed according to a standard formula (SF) exploiting carbohydrate intake, carbohydrate-to-insulin ratio, correction factor, insulin on board, and target glucose. Recently, some approaches were proposed to account for preprandial glucose rate of change (ROC) in the SF, including those by Scheiner and by Pettus and Edelman. Here, the aim is to develop a new approach, based on neural networks (NN), to optimize and personalize the bolus calculation using continuous glucose monitoring information and some easily accessible patient parameters. METHOD: The UVa/Padova T1D Simulator was used to simulate data of 100 virtual adults in a single-meal noise-free scenario with different conditions in terms of meal amount and preprandial blood glucose and ROC values. An NN was trained to learn the optimal insulin dose using the SF parameters, ROC, body weight, insulin pump basal infusion rate and insulin sensitivity as features. The performance of the NN for meal bolus calculation was assessed by blood glucose risk index (BGRI) and compared to the methods by Scheiner and by Pettus and Edelman. RESULTS: The NN approach brings to a small but statistically significant ( P < .001) reduction of BGRI value, equal to 0.37, 0.23, and 0.20 versus SF, Scheiner, and Pettus and Edelman, respectively. CONCLUSION: This preliminary study showed the potentiality of using NNs for the personalization and optimization of the meal insulin bolus calculation. Future work will deal with more realistic scenarios including technological and physiological/behavioral sources of variability. PMID- 29493357 TI - 2017 Diabetes Technology Meeting Agenda. PMID- 29493358 TI - 2017 Diabetes Technology Meeting Abstracts. PMID- 29493360 TI - Careflow Mining Techniques to Explore Type 2 Diabetes Evolution. AB - In this work we describe the application of a careflow mining algorithm to detect the most frequent patterns of care in a type 2 diabetes patients cohort. The applied method enriches the detected patterns with clinical data to define temporal phenotypes across the studied population. Novel phenotypes are discovered from heterogeneous data of 424 Italian patients, and compared in terms of metabolic control and complications. Results show that careflow mining can help to summarize the complex evolution of the disease into meaningful patterns, which are also significant from a clinical point of view. PMID- 29493359 TI - Automatic Adaptation of Basal Insulin Using Sensor-Augmented Pump Therapy. AB - BACKGROUND: People with insulin-dependent diabetes rely on an intensified insulin regimen. Despite several guidelines, they are usually impractical and fall short in achieving optimal glycemic outcomes. In this work, a novel technique for automatic adaptation of the basal insulin profile of people with diabetes on sensor-augmented pump therapy is presented. METHODS: The presented technique is based on a run-to-run control law that overcomes some of the limitations of previously proposed methods. To prove its validity, an in silico validation was performed. Finally, the artificial intelligence technique of case-based reasoning is proposed as a potential solution to deal with variability in basal insulin requirements. RESULTS: Over a period of 4 months, the proposed run-to-run control law successfully adapts the basal insulin profile of a virtual population (10 adults, 10 adolescents, and 10 children). In particular, average percentage time in target [70, 180] mg/dl was significantly improved over the evaluated period (first week versus last week): 70.9 +/- 11.8 versus 91.1 +/- 4.4 (adults), 46.5 +/- 11.9 versus 80.1 +/- 10.9 (adolescents), 49.4 +/- 12.9 versus 73.7 +/- 4.1 (children). Average percentage time in hypoglycemia (<70 mg/dl) was also significantly reduced: 9.7 +/- 6.6 versus 0.9 +/- 1.2 (adults), 10.5 +/- 8.3 versus 0.83 +/- 1.0 (adolescents), 10.9 +/- 6.1 versus 3.2 +/- 3.5 (children). When compared against an existing technique over the whole evaluated period, the presented approach achieved superior results on percentage of time in hypoglycemia: 3.9 +/- 2.6 versus 2.6 +/- 2.2 (adults), 2.9 +/- 1.9 versus 2.0 +/- 1.5 (adolescents), 4.6 +/- 2.8 versus 3.5 +/- 2.0 (children), without increasing the percentage time in hyperglycemia. CONCLUSION: The present study shows the potential of a novel technique to effectively adjust the basal insulin profile of a type 1 diabetes population on sensor-augmented insulin pump therapy. PMID- 29493361 TI - Decision Support in Diabetes Care: The Challenge of Supporting Patients in Their Daily Living Using a Mobile Glucose Predictor. AB - BACKGROUND: In type 1 diabetes mellitus (T1DM), patients play an active role in their own care and need to have the knowledge to adapt decisions to their daily living conditions. Artificial intelligence applications can help people with type 1 diabetes in decision making and allow them to react at time scales shorter than the scheduled face-to-face visits. This work presents a decision support system (DSS), based on glucose prediction, to assist patients in a mobile environment. METHODS: The system's impact on therapeutic corrective actions has been evaluated in a randomized crossover pilot study focused on interprandial periods. Twelve people with type 1 diabetes treated with insulin pump participated in two phases: In the experimental phase (EP) patients used the DSS to modify initial corrective decisions in presence of hypoglycemia or hyperglycemia events. In the control phase (CP) patients were asked to follow decisions without knowing the glucose prediction. A telemedicine platform allowed participants to register monitoring data and decisions and allowed endocrinologists to supervise data at the hospital. The study period was defined as a postprediction (PP) time window. RESULTS: After knowing the glucose prediction, participants modified the initial decision in 20% of the situations. No statistically significant differences were found in the PP Kovatchev's risk index change (-1.23 +/- 11.85 in EP vs -0.56 +/- 6.06 in CP). Participants had a positive opinion about the DSS with an average score higher than 7 in a usability questionnaire. CONCLUSION: The DSS had a relevant impact in the participants' decision making while dealing with T1DM and showed a high confidence of patients in the use of glucose prediction. PMID- 29493363 TI - The roles of basic psychological needs, self-compassion, and self-efficacy in the development of mastery goals among medical students. AB - AIM: Competency-based medical education aims to foster mastery goals in learners. We examined medical students' mastery approach (beneficial) and mastery avoidance (maladaptive) goals and their associations with students' basic psychological needs, self-compassion, and self-efficacy. METHODS: This was a cross-sectional study employing an online questionnaire. Two hundred medical students in all four years of the medical program completed the questionnaire, containing measures of mastery goals, basic psychological needs (autonomy, competence, relatedness), self-compassion, and self-efficacy. Regression analyses were performed. RESULTS: Of the three basic psychological needs, the need for competence was significant in explaining both types of mastery goals. Self-efficacy and self-compassion were significant in explaining mastery approach and mastery avoidance goals, respectively. CONCLUSIONS: Creating learning environments that are supportive of students' need for competence, raising students' awareness of the value of learning from mistakes in competency acquisition, and providing opportunities for students to experience self-efficacy may foster beneficial mastery approach goals in medical students. PMID- 29493362 TI - The State of the Science on Integrating Palliative Care in Heart Failure. AB - BACKGROUND: Heart failure (HF) is a chronic progressive illness associated with physical and psychological burdens, high morbidity, mortality, and healthcare utilization. Palliative care is interdisciplinary care that aims to relieve suffering and improve quality of life for persons with serious illness and their families. It is offered simultaneously with disease-oriented care, unlike hospice or end-of-life care. Despite the demonstrated benefits of palliative care in other populations, evidence for palliative care in the HF population is limited. OBJECTIVE: The objective of this article is to describe the current evidence and the gaps in the evidence that will need to be improved to demonstrate the benefits of integrating palliative care into the care of patients with advanced HF and their family caregivers. METHODS: We reviewed the literature to examine the state of the science and to identify gaps in palliative care integration for persons with HF and their families. We then convened an interdisciplinary working group at an NIH/NPCRC sponsored workshop to review the evidence base and develop a research agenda to address these gaps. RESULTS: We identified four key research priorities to improve palliative care for patients with HF and their families: (1) to better understand patients' uncontrolled symptoms, (2) to better characterize and address the needs of the caregivers of advanced HF patients, (3) to improve patient and family understanding of HF disease trajectory and the importance of advance care planning, and (4) to determine the best models of palliative care, including models for those who want to continue life-prolonging therapies. CONCLUSIONS: The goal of this research agenda is to motivate patient, provider, policy, and payor stakeholders, including funders, to identify the key research topics that have the potential to improve the quality of care for patients with HF and their families. PMID- 29493365 TI - Prediction of age at menopause in women with polycystic ovary syndrome: methodological issues. PMID- 29493366 TI - Authors' reply. PMID- 29493364 TI - Investigations on clonazepam-loaded polymeric micelle-like nanoparticles for safe drug administration during pregnancy. AB - Medication during pregnancy is often a necessity for women to treat their acute or chronic diseases. The goal of this study is to evaluate the potential of micelle-like nanoparticles (MNP) for providing safe drug usage in pregnancy and protect both foetus and mother from medication side effects. Clonazepam-loaded MNP were prepared from copolymers [polystyrene-poly(acrylic acid) (PS-PAA), poly(ethylene glycol)-b-poly(lactic acid) (PEG-PLA) and distearyl-sn-glycero-3 phosphoethanolamine-N-[methoxy-poly(ethylene glycol) (PEG-DSPE)] with varying monomer ratios and their drug-loading efficiency, drug release ratio, particle size, surface charge and morphology were characterised. The cellular transport and cytotoxicity experiments were conducted on clonazepam and MNP formulations using placenta-choriocarcinoma-BeWo and brain-endothelial-bEnd3 cells. Clonazepam loaded PEG5000-PLA4500 MNP reduced the drug transport through BeWo cells demonstrating that MNP may lower foetal drug exposure, thus reduce the drug side effects. However, lipofectamine modified MNP improved the transport of clonazepam and found to be promising for brain and in-utero-specific drug treatment. PMID- 29493367 TI - Editor's comment. PMID- 29493368 TI - Corrigendum. PMID- 29493370 TI - Update on current research into haploidentical hematopoietic stem cell transplantation. AB - INTRODUCTION: Haploidentical stem cell transplantation (Haplo-SCT) is currently a suitable alternative worldwide for patients with hematological diseases, who lack human leukocyte antigen (HLA)-matched siblings or unrelated donors. Areas covered: This review summarizes the advancements in Haplo-SCT in recent years, primarily focusing on the global trends of haploidentical allograft, the comparison of outcomes between Haplo-SCT and other transplantation modalities, strategies for improving clinical outcomes, including donor selection, hematopoietic reconstitution promotion, and graft-versus-host disease, and relapse prevention/management, as well as the expanded indications of Haplo-SCT, such as severe aplastic anemia, myeloma and lymphoma. Expert commentary: Haploidentical allografts, including granulocyte colony-stimulating factor-based protocol and a post-transplant cyclophosphamide-based protocol, have been the mainstream strategy for Haplo-SCT. However, there are many unanswered questions in this field. PMID- 29493369 TI - To Ligate or Not to Ligate? Managing the Difficult Indirect Sac in Laparoscopic Totally Extraperitoneal Repair of the Inguinal Hernia. AB - BACKGROUND: A laparoscopic approach to repair of inguinal hernia has become popular. The reduction of an indirect sac can be challenging especially if it is long standing or is large. In such situations, the established practice is to divide the sac at the neck and ligate it. Ligation of the sac has been shown to cause increased postoperative pain. Hence we postulated that we could possibly avoid ligation of this divided sac without causing increased intraoperative difficulty or postoperative complications. METHODS: This was a retrospective review of a prospectively maintained database of all patients who underwent laparoscopic totally extraperitoneal repair (TEP) during a 7-year period at our center with a minimum of 1 year of follow-up. We compared the outcomes of the patients who underwent only a division (group I) versus those who underwent division followed by ligation (group II) of the indirect sac. RESULTS: There were 189 and 126 patients in groups I and II, respectively. Group I patients fared better in terms of operative times and postoperative pain scores. The postoperative complication and short-term outcomes were not significantly different between the two groups. CONCLUSION: Non-ligation of a divided indirect sac during TEP is feasible and has the advantages of reduced operative times and postoperative pain and does not lead to increased complications. PMID- 29493371 TI - Therapy for pruritus in the elderly: a review of treatment developments. AB - INTRODUCTION: The prevalence of chronic pruritus (CP) in the general population is high and increases with age. Owing to high rates of comorbidities and polypharmacy in patients aged 65 or older, the clinical management of these patients is challenging. Areas covered: In this review, the authors discuss the available therapy options for patients aged >= 65 with CP, including emollients for dry skin, topical therapies, phototherapy and systemic agents for CP of various origins. Expert opinion: For multimorbid patients, topical substances and phototherapy constitute the best initial options. If systemic drugs are needed, the potential side-effects need to be closely monitored. In elderly patients, multiple possible factors for CP, including dermatological and systemic diseases, may be found, complicating the treatment of the underlying cause. In these cases, or when the origin remains unknown, a step-wise symptomatic therapy is recommended. The therapeutic choices should be made on an individual basis after carefully outweighing possible risks and benefits. Novel agents such as neurokinin-1 receptor antagonists and opioid-targeting drugs show promising antipruritic effects on refractory CP and seem to be well tolerated. They may be useful for elderly patients, who cannot tolerate conventional systemic agents. PMID- 29493373 TI - Can Building Design Impact Physical Activity? A Natural Experiment. AB - BACKGROUND: Workplace design can impact workday physical activity (PA) and sedentary time. The purpose of this study was to evaluate PA behavior among university employees before and after moving into a new building. METHODS: A pre post, experimental versus control group study design was used. PA data were collected using surveys and accelerometers from university faculty and staff. Accelerometry was used to compare those moving into the new building (MOVERS) and those remaining in existing buildings (NONMOVERS) and from a control group (CONTROLS). RESULTS: Survey results showed increased self-reported PA for MOVERS and NONMOVERS. All 3 groups significantly increased in objectively collected daily energy expenditure and steps per day. The greatest steps per day increase was in CONTROLS (29.8%) compared with MOVERS (27.5%) and NONMOVERS (15.9%), but there were no significant differences between groups at pretest or posttest. CONCLUSIONS: Self-reported and objectively measured PA increased from pretest to posttest in all groups; thus, the increase cannot be attributed to the new building. Confounding factors may include contamination bias due to proximity of control site to experimental site and introduction of a university PA tracking contest during postdata collection. Methodology and results can inform future studies on best design practices for increasing PA. PMID- 29493374 TI - In vitro immunomodulatory activity of celastrol against influenza A virus infection. AB - CONTEXT: The influenza A virus (IAV) causes severe respiratory disease that remains a leading reason for morbidity and mortality. Previous studies have indicated that influenza complications in addition to viral replication are due to overproduction of pro-inflammatory cytokines. Therefore, a new compound is needed to be used with current antiviral drugs to modulate overproduction of pro inflammatory cytokines in IAV infection. OBJECTIVE: This study investigated the effect of celastrol on mRNA expression and concentration levels of the pro inflammatory cytokines tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL6) that are induced by influenza A/Puerto Rico/8/34 (H1N1; PR8) in Madin-Darby Canine Kidney (MDCK) cells. The effect of this compound on virus titration and viral mRNA expression was also investigated. METHODS: Confluent MDCK cells were infected with influenza virus (H1N1; PR8) and treated with celastrol at different concentrations. After incubation, mRNA expression and concentrations of TNFalpha and IL6 were investigated using real-time polymerase chain reaction (PCR) and ELISA. The viral mRNA expression and virus titration were investigated using real time PCR and 50% tissue culture infectious dose (TCID50) assay, respectively. RESULTS: mRNA expression and concentrations of TNFalpha and IL6 increased significantly in control virus compared to cell control, and decreased significantly when compared with control virus after celastrol treatment. Viral mRNA expression and virus titration did not decrease after celastrol treatment. CONCLUSION: Due to reducing mRNA expression and concentrations of TNFalpha and IL6, celastrol can serve as a suitable choice to control cytokine-induced inflammation in IAV infection, and therefore it can be used with current antiviral drugs. PMID- 29493372 TI - Cardiac Tamponade as a Life-Threatening Complication of Laparoscopic Antireflux Surgery: The Real Incidence and 3D Anatomy of a Heart Injury by Helical Tacks. AB - BACKGROUND: Cardiac tamponade (CT) is a dreadful complication of laparoscopic antireflux surgery (LARS) with unknown incidence, and preventive measures are yet to be defined. Incidence during LARS with respect to usage/configuration of graft deployment is analyzed. Three-dimensional (3D) analysis of tack distribution provided anatomical insight to prevent cardiac injury. MATERIALS AND METHODS: Data regarding the usage and configuration of graft deployment are retrieved from the prospective database. Grafting was "posterior" or "posterior + anterior." Incidence of CT in all hiatoplasties is calculated. Tomography is reconstructed in 3D, showing the spatial distribution of the tacks. Tacks are numbered in the surgical video. Corresponding numbering is applied to the tacks in any particular tomography slice, utilizing the 3D images as an interface. A numbering-blinded radiologist is asked to identify the offending and the nonoffending tacks as the cause of tamponade. Tack-to-pericardium distances are recorded. Tacks having no measurable distance from the pericardium are regarded as offensive. RESULTS: One CT occurred in 1302 consecutive LARS (0.076%). The incidence is 0% when "no" (379) or "posterior" (880) graft is used as opposed to 2.3% rate in "posterior + anterior" (43) grafting. The distribution of "offensive," "nonoffensive but nearest," and "safe" tacks followed a pattern. All offensive tacks belonged to the anterior graft fixation, which we referred as the critical zone. CONCLUSION: CT during LARS is rare, and associated with graft fixation anterior to the hiatal opening. Avoiding graft fixation to the critical zone may prevent cardiac injury. PMID- 29493376 TI - A penalized quantitative structure-property relationship study on melting point of energetic carbocyclic nitroaromatic compounds using adaptive bridge penalty. AB - A penalized quantitative structure-property relationship (QSPR) model with adaptive bridge penalty for predicting the melting points of 92 energetic carbocyclic nitroaromatic compounds is proposed. To ensure the consistency of the descriptor selection of the proposed penalized adaptive bridge (PBridge), we proposed a ridge estimator ([Formula: see text]) as an initial weight in the adaptive bridge penalty. The Bayesian information criterion was applied to ensure the accurate selection of the tuning parameter ([Formula: see text]). The PBridge based model was internally and externally validated based on [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], the Y-randomization test, [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text] and the applicability domain. The validation results indicate that the model is robust and not due to chance correlation. The descriptor selection and prediction performance of PBridge for the training dataset outperforms the other methods used. PBridge shows the highest [Formula: see text] of 0.959, [Formula: see text] of 0.953, [Formula: see text] of 0.949 and [Formula: see text] of 0.959, and the lowest [Formula: see text] and [Formula: see text]. For the test dataset, PBridge shows a higher [Formula: see text] of 0.945 and [Formula: see text] of 0.948, and a lower [Formula: see text] and [Formula: see text], indicating its better prediction performance. The results clearly reveal that the proposed PBridge is useful for constructing reliable and robust QSPRs for predicting melting points prior to synthesizing new organic compounds. PMID- 29493377 TI - Dose reduction of risperidone and olanzapine can improve cognitive function and negative symptoms in stable schizophrenic patients: A single-blinded, 52-week, randomized controlled study. AB - BACKGROUND: The long-term effects of dose reduction of atypical antipsychotics on cognitive function and symptomatology in stable patients with schizophrenia remain unclear. We sought to determine the change in cognitive function and symptomatology after reducing risperidone or olanzapine dosage in stable schizophrenic patients. METHODS: Seventy-five stabilized schizophrenic patients prescribed risperidone (>=4 mg/day) or olanzapine (>=10 mg/day) were randomly divided into a dose-reduction group ( n=37) and a maintenance group ( n=38). For the dose-reduction group, the dose of antipsychotics was reduced by 50%; for the maintenance group, the dose remained unchanged throughout the whole study. The Positive and Negative Syndrome Scale, Negative Symptom Assessment-16, Rating Scale for Extrapyramidal Side Effects, and Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery were measured at baseline, 12, 28, and 52 weeks. Linear mixed models were performed to compare the Positive and Negative Syndrome Scale, Negative Symptom Assessment-16, Rating Scale for Extrapyramidal Side Effects and MATRICS Consensus Cognitive Battery scores between groups. RESULTS: The linear mixed model showed significant time by group interactions on the Positive and Negative Syndrome Scale negative symptoms, Negative Symptom Assessment-16, Rating Scale for Extrapyramidal Side Effects, speed of processing, attention/vigilance, working memory and total score of MATRICS Consensus Cognitive Battery (all p<0.05). Post hoc analyses showed significant improvement in Positive and Negative Syndrome Scale negative subscale, Negative Symptom Assessment-16, Rating Scale for Extrapyramidal Side Effects, speed of processing, working memory and total score of MATRICS Consensus Cognitive Battery for the dose reduction group compared with those for the maintenance group (all p<0.05). CONCLUSIONS: This study indicated that a risperidone or olanzapine dose reduction of 50% may not lead to more severe symptomatology but can improve speed of processing, working memory and negative symptoms in patients with stabilized schizophrenia. PMID- 29493375 TI - TDM in psychiatry and neurology: A comprehensive summary of the consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology, update 2017; a tool for clinicians. AB - OBJECTIVES: Therapeutic drug monitoring (TDM) combines the quantification of drug concentrations in blood, pharmacological interpretation and treatment guidance. TDM introduces a precision medicine tool in times of increasing awareness of the need for personalized treatment. In neurology and psychiatry, TDM can guide pharmacotherapy for patient subgroups such as children, adolescents, pregnant women, elderly patients, patients with intellectual disabilities, patients with substance use disorders, individuals with pharmacokinetic peculiarities and forensic patients. Clear indications for TDM include lack of clinical response in the therapeutic dose range, assessment of drug adherence, tolerability issues and drug-drug interactions. METHODS: Based upon existing literature, recommended therapeutic reference ranges, laboratory alert levels, and levels of recommendation to use TDM for dosage optimization without specific indications, conversion factors, factors for calculation of dose-related drug concentrations and metabolite-to-parent ratios were calculated. RESULTS: This summary of the updated consensus guidelines by the TDM task force of the Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie offers the practical and theoretical knowledge for the integration of TDM as part of pharmacotherapy with neuropsychiatric agents into clinical routine. CONCLUSIONS: The present guidelines for TDM application for neuropsychiatric agents aim to assist clinicians in enhancing safety and efficacy of treatment. PMID- 29493380 TI - George L. Stewart. PMID- 29493378 TI - Liraglutide prevents metabolic side-effects and improves recognition and working memory during antipsychotic treatment in rats. AB - BACKGROUND: Antipsychotic drugs (APDs), olanzapine and clozapine, do not effectively address the cognitive symptoms of schizophrenia and can cause serious metabolic side-effects. Liraglutide is a synthetic glucagon-like peptide-1 (GLP 1) receptor agonist with anti-obesity and neuroprotective properties. The aim of this study was to examine whether liraglutide prevents weight gain/hyperglycaemia side-effects and cognitive deficits when co-administered from the commencement of olanzapine and clozapine treatment. METHODS: Rats were administered olanzapine (2 mg/kg, three times daily (t.i.d.)), clozapine (12 mg/kg, t.i.d.), liraglutide (0.2 mg/kg, twice daily (b.i.d.)), olanzapine + liraglutide co-treatment, clozapine + liraglutide co-treatment or vehicle (Control) ( n = 12/group, 6 weeks). Recognition and working memory were examined using Novel Object Recognition (NOR) and T-Maze tests. Body weight, food intake, adiposity, locomotor activity and glucose tolerance were examined. RESULTS: Liraglutide co treatment prevented olanzapine- and clozapine-induced reductions in the NOR test discrimination ratio ( p < 0.001). Olanzapine, but not clozapine, reduced correct entries in the T-Maze test ( p < 0.05 versus Control) while liraglutide prevented this deficit. Liraglutide reduced olanzapine-induced weight gain and adiposity. Olanzapine significantly decreased voluntary locomotor activity and liraglutide co-treatment partially reversed this effect. Liraglutide improved clozapine induced glucose intolerance. CONCLUSION: Liraglutide co-treatment improved aspects of cognition, prevented obesity side-effects of olanzapine, and the hyperglycaemia caused by clozapine, when administered from the start of APD treatment. The results demonstrate a potential treatment for individuals at a high risk of experiencing adverse effects of APDs. PMID- 29493379 TI - Sexual Desire in Opiate-Dependent Men Receiving Methadone-Assisted Treatment. AB - Low sexual desire (SD) is not life threatening, but its negative impact on the quality of life and intimacy of a relationship among the patients on methadone maintenance therapy (MMT) is significant. This cross-sectional study involved 183 men on MMT who were interviewed and who completed the Malay version of the SDI-2 (SDI-2-BM), the Malay version of the self-rated Montgomery-Asberg Depression Rating Scale (MADRS-BM) and World Health Organization Quality of Life-BREF Scale (WHOQOL-BREF) questionnaires. Findings showed 32.8% ( n = 60) participants had low SD. Those who were older, had sexual partners, and were smokers achieved lower scores in both dyadic SD (<=24) and solitary SD (<=6), and suffered lower quality of life in their social relationship. MMT is very cost-effective in rehabilitating opioid dependence; however, as clinicians, we need to address and manage the issues of low SD and depression among patients on MMT, especially the older men. PMID- 29493381 TI - Comparing the effectiveness of biological disease-modifying antirheumatic drugs using real-world data. AB - OBJECTIVES: The objective of this study is to compare the effectiveness of biological disease-modifying antirheumatic drugs (bDMARDs) by analyzing claims data of 13 Japanese national university hospitals. METHODS: We evaluated 4970 cases of rheumatoid arthritis treated with bDMARDs from the Clinical Information Statistical Analysis database, which has collected and integrated 13 Japanese national university hospitals' claims data for 10 years. We surveyed the medications and calculated the retention rates of bDMARDs using the Kaplan-Meier method and differentiated the effectiveness between the two bDMARDs by comparing the retention rates after switching from one drug to another. RESULTS: Of the 4970 cases, 1364 switched bDMARDs at least once. Tocilizumab (TCZ) reported the highest retention rate, whereas abatacept (ABT) revealed a similar rate compared with only naive cases. The retention rate curves were higher in cases on TCZ that switched from the other bDMARDs than those in the reversed cases. Following TCZ, ABT and etanercept indicated better results than the other bDMARDs. CONCLUSION: We could compare the effectiveness among bDMARDs by differentiating the retention rates from big claims data. TCZ reported higher retention rates in both naive and switched cases than other bDMARDs. PMID- 29493382 TI - Alu exaptation enriches the human transcriptome by introducing new gene ends. AB - In mammals, transposable elements are largely silenced, but under fortuitous circumstances may be co-opted to play a functional role. Here, we show that when Alu elements are inserted within or nearby genes in sense orientation, they may contribute to the transcriptome diversity by forming new cleavage and polyadenylation sites. We mapped these new gene ends in human onto the Alu sequence and identified three hotspots of cleavage and polyadenylation site formation. Interestingly, the native Alu sequence does not contain any canonical polyadenylation signal. We therefore studied what evolutionary processes might explain the formation of these specific hotspots of novel gene ends. We show that two of the three hotspots might have emerged from mutational processes that turned sequences that resemble polyadenylation signals into full-blown canonical signals, whereas one hotspot is tightly linked to the process of Alu insertion into the genome. Overall, Alu elements may lie behind the formation of 302 new gene end variants, affecting a total of 243 genes. Intergenic Alu elements may elongate genes by creating a downstream cleavage site, intronic Alu elements may lead to gene variants which code for truncated proteins, and 3'UTR Alu elements may result in gene variants with alternative 3'UTR. PMID- 29493383 TI - MiR-130a is aberrantly overexpressed in adult acute myeloid leukemia with t(8;21) and its suppression induces AML cell death. AB - BACKGROUND: Emerging evidence has revealed that miRNAs can function as oncogenes or tumor suppressor genes in leukemia. The ectopic expression of miR-130a has been reported in chronic leukemia, but our understanding of the biological implications of miR-130a expression remains incomplete. METHODS: We quantified a cohort of de novo acute myeloid leukemia (AML) by bead-based miRNA and real-time quantitative PCR (Rq-PCR). The luciferase reporter gene assay was analyzed after the plasmid constructs which contain 5'-UTR of miR-130a and a Renilla luciferase reporter plasmid were transfected simultaneously into 293T cells. MTT and caspase 3/7 apoptosis assays were used to test cell viability and apoptosis. RESULTS: We identified miR-130a as significantly overexpressed in t(8;21) AML. Expression of miR-130a decreased significantly once patients with t(8;21) achieved complete remission, but increased sharply at the time of relapse. In patients with t(8;21) AML, KIT mutational status was associated with miR-130a expression-with higher expression associated with KIT activating mutations. Increased miR-130a expression in t(8;21) AML was associated with slightly worse event-free survival; however, no impact on overall survival was observed. Knockdown of AML1/ETO protein in the SKNO-1 cell line resulted in decrease of expression of miR-130a. Direct binding of AML1/ETO fusion protein with the promoter sequence of miR-130a was detected with luciferase reporter gene assay. Following miR-130a knockdown, SKNO-1 demonstrated increased sensitivity to etoposide. CONCLUSIONS: Our data suggest that miR-130a is directly activated by AML1/ETO, and may act as a factor which is associated with leukemia burden, event-free survival, and chemotherapy sensitivity in t(8;21) AML. PMID- 29493384 TI - Prophylactic function of excellent compliance with LTOT in the development of pulmonary hypertension due to COPD with hypoxemia. AB - The long-term oxygen therapy (LTOT) for patients with chronic obstructive pulmonary disease (COPD) has been shown to increase survival in patients with severe resting hypoxemia. The adherence to LTOT may also simultaneously affect the development of concomitant pulmonary hypertension (PH) due to COPD with hypoxemia. We retrospectively reviewed 276 cases of COPD with or without PH assessed by right heart catheterization (RHC) to investigate whether adherence to continuous LTOT had a prophylactic effect on the development of PH in a time interval of two years. In contrast to the patients in the non-compliance group (PH prevalence 64.2%), patients with excellent compliance of adhering to continuous LTOT > 15 h per day in the compliance group (PH prevalence 37.6%) are more liable to postpone the development of PH due to hypoxic COPD for at least two years. Adherence to LTOT >= 15 h/day is strongly recommended in order to lower the risk and delay the development of consequent PH in COPD with hypoxemia. PMID- 29493386 TI - News Update. PMID- 29493385 TI - Use of next-generation sequencing in the CHAT study (acute HCV in HIV): effect of baseline resistance-associated NS3 variants on treatment failure. AB - Background The epidemic of acute HCV infection among HIV-infected men who have sex with men (MSM) is ongoing. Transmission of drug-resistant variants (DRVs) after HCV treatment failure could pose a major threat to the effectiveness of future therapies. We determined the baseline prevalence of pre-existing DRVs in the HCV NS3 protease gene and their effects on the addition of telaprevir (TVR) to standard pegylated interferon and ribavirin (PEG-IFN/RBV) for acute HCV infection in individuals enrolled in a multicentre randomized controlled trial (2013 and 2014). Methods The HCV NS3 viral protease was analyzed using Sanger and next-generation sequencing (NGS) for DRVs at baseline (n = 31), and at viral breakthrough following TVR-based treatment (n = 3) or PEG-IFN/RBV alone (n = 2). Results Sequence analysis indicated that all individuals were infected with HCV genotype 1a. Complete (100%) concordance was seen between Sanger and NGS for high levels of mutant viral populations. The simeprevir-associated Q80K variant was present at high frequency in the German samples (7/11-64%) and infrequently in the UK samples (1/20-5%). In the three TVR-based treatment failures, V36M/l and R155K/T emerged, but not R155G which was detectable at low levels in two individuals at baseline. Failure rate at week 24 was 26.7% (with baseline DRVs) vs. 6.3% (without baseline DRVs), p = 0.17). Comparison of sequences pre- and post-therapy in 5 who failed therapy revealed the emergence of not previously described variants V193G, E176K, P189S (on TVR), and V181S in one instance each. Conclusion The presence of baseline DRVs for the NS3 protease gene of HCV genotype 1a did not appear to predict treatment failure in our patient cohort. Where detected, Q80K was present at high levels (>98%), but had no effect on outcomes and remained high after failure. PMID- 29493387 TI - Intraoperative cell salvage in obstetrics. PMID- 29493388 TI - Delivering expectations: unto us a child is born! PMID- 29493389 TI - Perioperative care of pregnant women with previous uterine surgery. PMID- 29493390 TI - The management of undiagnosed placenta percreta at caesarean section. PMID- 29493391 TI - The introduction of an enhanced recovery pathway for elective caesarean sections. AB - This article will focus on the establishment of an enhanced recovery pathway (ERP) for women undergoing elective caesarean section in a busy maternity unit. It will consider the background to this project, the impact on services and the improvements in service that have been achieved as well as the challenges that have been experienced in this process. PMID- 29493392 TI - The challenges of perioperative midwifery in Malawi. PMID- 29493394 TI - Communication and Interpersonal Skills in Nursing, Third Edition. PMID- 29493393 TI - Lost in translation - the role of prospective partners within the perioperative setting. PMID- 29493395 TI - Comparison of the Clinical Efficacy of Topical and Systemic Azithromycin Treatment for Posterior Blepharitis. AB - PURPOSE: To compare the clinical efficacy of topical and oral azithromycin treatments for posterior blepharitis. METHODS: Both topical and oral treatment groups comprised 15 patients. In the topical group, azithromycin 15 mg/g ophthalmic solution (Azyter; Thea Pharmaceuticals, Clermont-Ferrand, France) was used twice a day for 3 days and then once a day until the treatment completes a month. In the systemic treatment group, azithromycin 250 mg tablets (Azitro; Deva Pharmaceuticals, Istanbul, Turkey) were used, 1 * 2 tablets (500 mg) at the first day of treatment and then 1 * 1 tablet (250 mg) for 4 days. Three cycles of treatment with 5-day intervals were completed. The ocular symptoms, eyelid margin sings, Ocular Surface Disease Index (OSDI), tear film break-up time, corneal/conjunctival staining score, Schirmer test, and conjunctival brush cytology were evaluated at baseline, 1, and 5 weeks after the end of treatment. RESULTS: Both topical azithromycin and oral azithromycin were found to be effective in improving the clinical signs and symptoms of posterior blepharitis. The mean OSDI scores, lissamine green staining scores, and Schirmer test results showed improvements after both topical and oral treatments. However, topical treatment was shown to be associated with longer cytological improvements that persist at least 5 weeks and with better stabilization of the tear film, which is well documented by showing longer tear film break up time (TFBUT) in the topical treatment group. CONCLUSIONS: Although both treatment methods are found to be effective, the results of topical treatment group showed some superiority over those of systemic treatment group, which may be associated with a higher ocular tissue concentration of azithromycin after topical administration. PMID- 29493396 TI - Highly integrated nanocomposites of RGO/TiO2 nanotubes for enhanced removal of microbes from water. AB - Highly integrated nanocomposite of Graphene oxide (GO) and its derivatives with metal oxides is essential for enhanced performance for various applications. Tuning the morphology is an important aspect during nanomaterials synthesis; this has an amplifying influence upon physicochemical properties of advanced functional materials. In this research work, GO/TiO2 nanotube composites have been successfully synthesized via alkaline hydrothermal treatment method by augmenting GO layers with two different phases of TiO2 (anatase and rutile) nanoparticles, followed by the hydrothermal treatment that also have caused reduction of GO to reduced GO (RGO). The morphology of the as-prepared samples appeared to be nanotubes with a large aspect ratio (length to diameter). The synthesized materials have been characterized using various techniques to determine their morphological and functional properties. Large surface area (158 m2/g) nanotube composites found accountable as effective disinfectant for water containing microorganisms. The antimicrobial activity of the synthesized composites was examined by disk diffusion method and optical density for bacterial growth using two different bacterial species; Escherichia Coli (E.coli, Gram-negative) and Staphylococcus Aureus (Methicillin-resistant Staphylococcus aureus, Gram-positive). The antibacterial study revealed that, the anatase phase RGO/TiO2 nanotube composites manifested appreciable effect on both bacteria as compared to rutile phase RGO/TiO2 nanotubecomposite. PMID- 29493397 TI - Ceftolozane/tazobactam: place in therapy. AB - INTRODUCTION: Ceftolozane/tazobactam (C/T) is a new antibiotic resulting from the combination of a novel cephalosporin, structurally similar to ceftazidime, with tazobactam, a well-known beta-lactamase inhibitor. C/T remains active against extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae and multi drug resistant (MDR) P. aeruginosa, and has been recently approved for the treatment of complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI). A trial on hospital-acquired pneumonia is ongoing. Areas covered: The place in therapy of C/T is delineated by addressing the following main topics: (i) antimicrobial properties; (ii) pharmacological properties; (iii) results of clinical studies. Expert commentary: C/T is approved for cIAI and cUTI. However, the drug has a special value for clinicians in any kind of infectious localization for two main reasons. The first is that C/T is especially valuable in suspected or documented severe infections due to MDR P. aeruginosa, which is not a rare occurrence in many countries. The second is that C/T may provide an alternative to carbapenems for the treatment of infections caused by ESBL-producers, thus allowing a carbapenem-sparing strategy. Reporting of off-label use is mandatory to increase the body of evidence and the clinicians' confidence in using it for indications other than cIAI and cUTI. PMID- 29493398 TI - Three-dimensional assessment of squats and drop jumps using the Microsoft Xbox One Kinect: Reliability and validity. AB - The Microsoft Xbox One KinectTM (Kinect V2) contains a depth camera that can be used to manually identify anatomical landmark positions in three-dimensions independent of the standard skeletal tracking, and therefore has potential for low-cost, time-efficient three-dimensional movement analysis (3DMA). This study examined inter-session reliability and concurrent validity of the Kinect V2 for the assessment of coronal and sagittal plane kinematics for the trunk, hip and knee during single leg squats (SLS) and drop vertical jumps (DVJ). Thirty young, healthy participants (age = 23 +/- 5yrs, male/female = 15/15) performed a SLS and DVJ protocol that was recorded concurrently by the Kinect V2 and 3DMA during two sessions, one week apart. The Kinect V2 demonstrated good to excellent reliability for all SLS and DVJ variables (ICC >= 0.73). Concurrent validity ranged from poor to excellent (ICC = 0.02 to 0.98) during the SLS task, although trunk, hip and knee flexion and two-dimensional measures of knee abduction and frontal plane projection angle all demonstrated good to excellent validity (ICC >= 0.80). Concurrent validity for the DVJ task was typically worse, with only two variables exceeding ICC = 0.75 (trunk and hip flexion). These findings indicate that the Kinect V2 may have potential for large-scale screening for ACL injury risk, however future prospective research is required. PMID- 29493399 TI - Fear of falling in acute stroke: The Fall Study of Gothenburg (FallsGOT). AB - Objective Little is known about which factors are associated with a patient's fear of falling (FoF) after acute stroke. The aim of this study was to investigate baseline variables and their association with FoF during rehabilitation in acute stroke. Patients and methods The study population consisted of the 462 patients with acute stroke who were admitted to a stroke unit, included in the observational study "The Fall Study in Gothenburg (FallsGOT)" and were able to answer a single question: "Are you afraid of falling?" (Yes/No). To analyze any association between FoF and clinical variables, univariable and multivariable stepwise multiple logistic regression analyses were performed. Results In the stepwise multivariable regression analysis, only female sex (OR = 2.25 [95% confidence interval (CI) 1.46-3.46, p = 0.0002]), the use of a walking aid (OR 3.40, [95% CI 2.12-5.43, p < 0.0001]), and postural control as assessed with the SwePASS total score were statistically significant associated with FoF. Among patients with a SwePASS score of 24 or less, the OR was 9.41 [95% CI 5.13-17.25, p < 0.0001] for FoF compared to patients with a SwePASS score of 31 or above; among the patients with a SwePASS score of 25-30, the OR was 2.29 [95% CI = 1.36-3.83, p = 0.0017]. Conclusions Our findings provide valuable insight for those involved in stroke rehabilitation during the acute phase after stroke. FoF is associated with poor postural control, female sex and the use of a walking aid. PMID- 29493400 TI - QTc interval is prolonged in Wilson's disease with neurologic involvement. AB - Background Neurologic and liver involvement in Wilson's disease (WD) is well documented, however, few reports demonstrated cardiac involvement. Tpe and Tpe/QT are new measures of ventricular repolarization which were recently suggested as predictor of arrythmogenesis. We aimed to evaluate ventricular depolarization and repolarization parameters including QT, QTc, Tpe intervals, Tpe/QT, Tpe/QTc ratios, and QT dispersion (QTd) in patients with WD. Materials and methods Thirty five patients with WD and 30 healthy controls were included in the study. Patients were evaluated by a neurologist in addition to MR imaging. Twenty-one of 35 patients were diagnosed as neuroWilson (NW), whereas 14 patients as non-NW. ECG recordings were obtained using a 12-lead commercial device (Cardiac Science, Burdick s500,USA). All patients underwent standard echocardiographic evaluation. These two groups of patients and healthy controls were compared. Results There were no difference between patients with WD and healthy controls in terms of age sex, BMI, liver, and kidney functions where as patients with WD were anemic and thrombocytopenic. Left atrial, ventricular dimensions, left ventricular systolic, and diastolic functions were similar between patients and healthy control. QT interval was prolonged in patient group, however, QTc, Tpe intervals, Tpe/QT, and Tpe/QTc ratios and QTd did not differ between groups. When patients with NW and non-NW were compared, both QT and QTc intervals were significantly longer in patients with NW, however, Tpe interval, Tpe/QT and Tpe/QTc ratios, and QTd did not differ. Conclusion QT and QTc intervals are prolonged in patients with Wilson's disease and neurologic involvement. PMID- 29493401 TI - Bone marrow-derived mesenchymal stem cells promote cell proliferation of multiple myeloma through inhibiting T cell immune responses via PD-1/PD-L1 pathway. AB - OBJECTIVES: This study aims to explore the effect of bone marrow mesenchymal stem cells (BMSCs) on multiple myeloma (MM) development and the underlying mechanism. MATERIALS AND METHODS: BMSCs from C57BL/6 J mice were isolated and the third passage was used for subsequent experiments. Additionally, a series of in vitro transwell coculture assays were performed to explore the effects of BMSCs on the proliferation of MM cells 5TGM1 and CD4+ T cells. Furthermore, a 5TGM1-induced MM mice model was established. Moreover, PD-L1 shRNA was transfected into BMSCs to investigate whether PD-1/PD-L1 pathway involved in BMSCs-mediated regulation of T cells and MM growth. RESULTS: Data revealed that BMSCs significantly promoted 5TGM1 proliferation in a dose-dependent manner. Furthermore, BMSCs administration exerted stimulatory effects on MM development in terms of shortening the mouse survival rate, promoting tumor growth, and enhancing inflammatory infiltration in the MM model mice. Moreover, BMSCs decreased the percentage of Th1 and Th17 cells, whereas increased that of Th2 and Treg cells. Their corresponding cytokines of these T cell subsets showed similar alteration in the presence of BMSCs. Additionally, BMSCs significantly suppressed CD4+ T cell proliferation. We also found that PD-L1 shRNA inhibited 5TGM1 proliferation likely through activation of CD4+ T cells. Further in vivo experiments confirmed that PD-L1 inhibition attenuated BMSCs-induced MM growth, inflammation infiltration and imbalance of Th1/Th2 and Th17/Treg. CONCLUSION: In summary, our findings demonstrated that BMSCs promoted cell proliferation of MM through inhibiting T cell immune responses via PD-1/PD-L1 pathway. PMID- 29493403 TI - Vaspin and Omentin-1 in Obese Children with Metabolic Syndrome: Two New Kids on the Block? PMID- 29493402 TI - Pharmacokinetics of Salmeterol and Fluticasone Propionate Delivered in Combination via Easyhaler and Diskus Dry Powder Inhalers in Healthy Subjects. AB - BACKGROUND: Easyhaler(r) dry powder inhaler (DPI) containing salmeterol and fluticasone propionate was developed for the treatment of asthma and chronic obstructive pulmonary disease. Three different Salmeterol/fluticasone Easyhaler test products (Orion Pharma, Finland) were compared against the reference product Seretide(r) Diskus(r) DPI (GlaxoSmithKline, United Kingdom) to study whether any of the test products are bioequivalent with the reference. METHODS: Open and randomized pharmacokinetic four-period crossover study on 65 healthy volunteers was performed in a single center to compare the lung deposition and total systemic exposure of salmeterol and fluticasone propionate after administration of single doses (two inhalations of 50/500 MUg/inhalation strength) in fasting conditions. Blood samples were drawn before dosing and at frequent time points between 2 minutes and 34 hours after dosing for determination of drug concentrations. The primary variables for total systemic exposure and lung deposition of fluticasone propionate were maximum concentration of the concentration-time curve (Cmax) and area under the concentration-time curve from time zero to the last sample with quantifiable concentration (AUCt). For salmeterol, the primary variables for total systemic exposure were Cmax and AUCt and for lung deposition Cmax and AUC up to 30 minutes after study treatment administration (AUC30min). RESULTS: One of the Easyhaler test products met all the criteria for bioequivalence with the reference. The 96.7% confidence intervals (CIs) for the test/reference ratios of fluticasone propionate Cmax and AUCt were 0.9901-1.1336 and 0.9448-1.0542, respectively. Ninety percent CIs for salmeterol Cmax, AUC30min, and AUCt ratios were 1.0567-1.2012, 1.0989-1.2255, and 1.0769-1.1829, respectively. Median salmeterol time to maximum concentration (tmax) was 4.0 minutes. Median fluticasone propionate tmax was from 1.5 to 2.0 hours. Terminal elimination half-life was 11 hours for salmeterol and 9-10 hours for fluticasone propionate. CONCLUSIONS: Salmeterol/fluticasone Easyhaler was shown to be bioequivalent with the reference product. PMID- 29493404 TI - Mycobacterium marinum infection in fish and man: epidemiology, pathophysiology and management; a review. AB - Mycobacterium marinum is an opportunistic pathogen inducing infection in fresh and marine water fish. This pathogen causes necrotizing granuloma like tuberculosis, morbidity and mortality in fish. The cell wall-associated lipid phthiocerol dimycocerosates, phenolic glycolipids and ESAT-6 secretion system 1 (ESX-1) are the conserved virulence determinant of the organism. Human infections with Mycobacterium marinum hypothetically are classified into four clinical categories (type I-type IV) and have been associated with the exposure of damaged skin to polluted water from fish pools or contacting objects contaminated with infected fish. Fish mycobacteriosis is clinically manifested and characterized in man by purple painless nodules, liable to develop into superficial crusting ulceration with scar formation. Early laboratory diagnosis of M. marinum including histopathology, culture and PCR is essential and critical as the clinical response to antibiotics requires months to be attained. The pathogenicity and virulence determinants of M. marinum need to be thoroughly and comprehensively investigated and understood. In spite of accumulating information on this pathogen, the different relevant data should be compared, connected and globally compiled. This article is reviewing the epidemiology, virulence factors, diagnosis and disease management in fish while casting light on the potential associated public health hazards. PMID- 29493405 TI - Accuracy of Presumptive Gonorrhea Treatment for Gay, Bisexual, and Other Men Who Have Sex with Men: Results from a Large Sexual Health Clinic in Los Angeles, California. AB - PURPOSE: This study analyzed the accuracy of presumptive gonorrhea treatment in a sexual health clinic serving primarily gay, bisexual, and other men who have sex with men (MSM). Treating suspected gonorrhea before laboratory confirmation can reduce symptoms and transmission; however, this strategy can overtreat uninfected individuals, which may promote antimicrobial resistance. We identified differences in accuracy of gonorrhea presumptive treatment by site of infection and presence of signs or symptoms. METHODS: We conducted a cross-sectional study of gay, bisexual, and other MSM who were treated presumptively for gonorrhea at the Los Angeles LGBT Center between February and July 2015. We calculated positivity of treated patients, proportion of infections treated, and positive predictive value (PPV) of treating gonorrhea presumptively based on signs, symptoms, or exposure at the urethral, rectal, or pharyngeal site. RESULTS: Of 9141 testing visits, presumptive treatment was provided at 1677 (18%). Overall, gonococcal infections were identified at 31% (n = 527) of visits where presumptive treatment was provided, compared to 9% (n = 657) of visits without presumptive treatment (P < 0.01). Forty-five percent of gonococcal infections were treated presumptively, and treatment was provided at 14% of gonorrhea negative visits. Seventy-eight percent of urethral, 54% of rectal, and 35% of pharyngeal infections were treated presumptively. PPV was highest for genitourinary signs. CONCLUSION: Approximately one-third of gay, bisexual, or other MSM treated presumptively for gonorrhea at a sexual health clinic tested positive for gonorrhea. These findings highlight the potential contribution of point-of-care tests in reducing overtreatment resulting from presumptive treatment. PMID- 29493408 TI - Patients' Positive and Negative Responses to Reading Mental Health Clinical Notes Online. AB - OBJECTIVE: This study describes responses to OpenNotes, clinical notes available online, among patients receiving mental health care and explores whether responses vary by patient demographic or clinical characteristics. METHODS: Survey data from 178 veterans receiving mental health treatment at a large Veterans Affairs medical center included patient-reported health self-efficacy, health knowledge, alliance with clinicians, and negative emotional responses after reading OpenNotes. Health care data were extracted from the patient care database. RESULTS: Reading OpenNotes helped many participants feel in control of their health care (49%) and have more trust in clinicians (45%), although a few (8%) frequently felt upset after reading their notes. In multivariate models, posttraumatic stress disorder was associated with increased patient-clinician alliance (p=.046) but also with negative emotional responses (p<.01). CONCLUSIONS: Patients receiving mental health care frequently reported benefits from reading OpenNotes, yet some experienced negative responses. PMID- 29493407 TI - Stories Matter-And Shape Our Field Every Day. PMID- 29493409 TI - Differential Effects of Brief CBT Versus Treatment as Usual on Posttreatment Suicide Attempts Among Groups of Suicidal Patients. AB - OBJECTIVE: The purpose of this study was to examine variability in outcomes (suicide attempt rates) across subgroups of patients who were randomly enrolled in brief cognitive-behavioral therapy (CBT) and treatment as usual. METHODS: A secondary analysis was conducted of data collected during a randomized clinical trial of brief CBT for suicide prevention in a sample of 176 U.S. military personnel who reported active suicide ideation in the past week or a suicide attempt in the past month. Latent-class analysis was used to identify empirically distinct and clinically meaningful patient subgroups. Rates of suicide attempts during a two-year follow-up period were compared across classes and treatment groups. RESULTS: Three latent classes corresponding to low (N=55), moderate (N=40), and high (N=57) suicide risk were identified. The classes significantly differed with respect to psychiatric symptom severity but not demographic or historical variables. Rates of suicide attempts during the two-year follow-up significantly varied across classes in treatment as usual but did not vary across classes in brief CBT (21% versus 10%, respectively, in the low-severity class, 8% versus 13% in the moderate-severity class, and 41% versus 10% in the high severity class). Differences between treatment conditions in suicide attempt rates were statistically significant for the high-severity class. CONCLUSIONS: Treatment as usual was associated with variable rates of suicidal behavior, depending on suicide risk severity. Brief CBT contributed to consistently low rates of suicidal behavior regardless of patient severity. PMID- 29493410 TI - Community-Academic Partnership: Establishing the Institute for Mental Health Research Early Psychosis Intervention Center. AB - Growing evidence suggests that specialized, multicomponent intervention provided early in the course of a psychotic disorder may have a positive effect in ameliorating the morbidity and mortality associated with these disorders. This column describes the development of the Institute for Mental Health Research Early Psychosis Intervention Center, which leverages the unique strengths of a community and academic partnership to provide such specialty care in a youth friendly, stigma-free environment. Since it opened in 2016, the program has had numerous successes, including securing increased reimbursements rates and performance-based incentives for the treatment of first-episode psychosis. PMID- 29493411 TI - Implicit Bias and Mental Health Professionals: Priorities and Directions for Research. AB - This Open Forum explores the role of implicit bias along the mental health care continuum, which may contribute to mental health disparities among vulnerable populations. Emerging research shows that implicit bias is prevalent among service providers. These negative or stigmatizing attitudes toward population groups are held at a subconscious level and are automatically activated during practitioner-client encounters. The authors provide examples of how implicit bias may impede access to care, clinical screening and diagnosis, treatment processes, and crisis response. They also discuss how implicit attitudes may manifest at the intersection between mental health and criminal justice institutions. Finally, they discuss the need for more research on the impact of implicit bias on health practices throughout the mental health system, including the development of interventions to address implicit bias among mental health professionals. PMID- 29493412 TI - State Adoption of Incentives to Promote Evidence-Based Practices in Behavioral Health Systems. AB - OBJECTIVE: Despite the critical role behavioral health care payers can play in creating an incentive to use evidence-based practices (EBPs), little research has examined which incentives are used in public mental health systems, the largest providers of mental health care in the United States. METHODS: The authors surveyed state mental health directors from 44 states about whether they used any of seven strategies to increase the use of EBPs. Participants also ranked attributes of each incentive on the basis of key characteristics of diffusion of innovation theory (perceived advantage, simplicity, compatibility, observability, and gradually implementable) and perceived effectiveness. RESULTS: Almost three quarters of state directors endorsed using at least one financial incentive; most paid for training and technical assistance. Few used other incentives. Strategies perceived as simple and compatible were more readily adopted. Enhanced rates and paying for better outcomes were perceived as the most effective but were the least deployed, suggesting that simplicity and organizational compatibility may be the most decisive factors when choosing incentives. CONCLUSIONS: Payers are not using the incentives they perceive as most effective, and they are mostly using only one strategy for reasons of simplicity and compatibility. Future work should focus on barriers to measurement that likely hinder the adoption and implementation of paying for better outcomes and enhanced reimbursement rates, with the ultimate goal of measuring the effectiveness of incentives on EBP implementation efforts. PMID- 29493413 TI - Integrating Safety Plans for Suicidal Patients Into Patient Portals: Challenges and Opportunities. AB - Safety planning is an emerging evidence-based practice that is effective at decreasing suicidal behaviors. As electronic medical records and patient portals become more prevalent, patients and clinicians have recognized the value of using this technology in the safety planning process. This column describes the experience of one federally qualified health center, the Institute for Family Health, in integrating safety plans into the patient portal. The authors argue that incorporating safety plans into patient portals may unlock a new to way to expand safety planning efforts in health settings-a way that may ultimately save lives. PMID- 29493414 TI - Understanding Pathways to Care of Individuals Entering a Specialized Early Intervention Service for First-Episode Psychosis. AB - OBJECTIVE: This study aimed to understand the pathways to care from the onset of a first episode of psychosis to entry into a specialized early intervention service (EIS) for individuals with nonaffective psychosis. METHODS: A sample of 20 individuals who participated in an EIS and ten of their family members were enrolled. Semistructured qualitative interviews were used to characterize participants' lives during the onset of psychosis and explore their help-seeking events from the onset of psychosis to entry into the EIS. Data were analyzed by using grounded theory and a case study methodology. RESULTS: The median duration between the onset of psychosis and EIS entry was 4.5 months. A grounded model emerged from the analysis that captured how help-seeking decisions were influenced by the misattribution of symptoms, stigma, and self-reliance. These factors created a cloud of uncertainty in which individuals experiencing early psychosis and their family members struggled to make sense of what was happening, how and when to seek help, and what to expect from treatment. Contacts with the health care system were critical junctures in the pathway to care that could reduce or increase uncertainty and expedite or delay EIS entry. CONCLUSIONS: Findings indicate that efforts to expedite EIS entry should focus on reducing the uncertainty that affected individuals and their family members face when seeking care by improving their experiences with mental health services. PMID- 29493415 TI - A Medicaid Quality Improvement Collaborative on Psychotropic Medication Prescribing for Children. AB - A Medicaid statewide quality improvement (QI) collaborative was developed to improve antipsychotic prescribing practices for children. With use of a multistrategy approach that incorporated data-driven feedback and evidence-based recommendations, improvements were seen in three measures: antipsychotics prescribed to children under age six, prescription of two or more concomitant antipsychotics for longer than two months, and prescription of four or more psychotropic medications. Challenges and complexities are reviewed, including use of ongoing QI to address factors influencing antipsychotic prescribing behaviors, engagement of providers in QI efforts, and financial sustainability of such efforts. PMID- 29493416 TI - The Michigan Peer-to-Peer Depression Awareness Program: School-Based Prevention to Address Depression Among Teens. AB - OBJECTIVE: The Peer-to-Peer Depression Awareness Program (P2P) is a school-based program that aims to decrease mental illness and promote well-being among students by empowering high school students as both learners and educators. Specific goals include improving the school climate around mental health, directing students to resources, and encouraging help-seeking behavior. METHODS: In the 2015-2016 academic year, 121 students across 10 high schools organized into teams and were trained to develop and implement peer-to-peer depression awareness campaigns. Outcomes were assessed via pre- and posttest questionnaires. RESULTS: A total of 878 students completed questionnaires. Outcomes demonstrated improved knowledge and attitudes toward depression, increased confidence in identifying and referring peers with depression, improved help-seeking intentions, and reduced stigma. CONCLUSIONS: The P2P program increased depression literacy through the use of youth-designed and youth-implemented depression awareness and outreach activities, which may ultimately result in earlier detection of depression and in fewer depression sequelae. PMID- 29493418 TI - Provider-Payer Partnerships as an Engine for Continuous Quality Improvement. AB - The authors describe a quality improvement approach in which a crisis center and a payer collaborate to improve care. Each crisis visit is considered as a potentially missed opportunity for community stabilization. Daily data on crisis visits are sent to the payer for a more up-to-date analysis of trends than is possible with financial claims data, which may lag behind services provided by up to 90 days. Using these trend data, the two organizations collaborate to identify patterns that lead to opportunities for improvement and develop multiple rapid cycle projects for better management of services, resulting in significant decreases in readmissions and in the number of high utilizers. PMID- 29493417 TI - Ending AIDS as a Public Health Threat: Treatment-as-Usual Risk Reduction Services for Persons With Mental Illness in Brazil. AB - OBJECTIVE: Persons with mental illness have higher HIV infection rates than the general population. Little is known about whether care systems for this population are effectively participating in global efforts to end AIDS as a public health threat. This study examined treatment-as-usual HIV risk reduction services within public mental health settings. METHODS: The authors interviewed 641 sexually active adults attending eight public psychiatric clinics in Rio de Janeiro about participation in a sexual risk reduction program, HIV testing, HIV knowledge, and sexual behaviors. RESULTS: Nine percent reported participation in a risk reduction program in the past year, and 75% reported having unprotected sex in the past three months. Program participants had greater HIV knowledge (p=.04) and were more likely to have had HIV testing in the past three months (p=.02), compared with nonparticipants. Participation was not associated with sexual behaviors. CONCLUSIONS: Including persons with mental illness in efforts to end AIDS requires a greater commitment to implementing effective interventions in public mental health systems. PMID- 29493419 TI - Durability and tolerability of first-line regimens including two nucleoside reverse transcriptase inhibitors and raltegravir or ritonavir boosted-atazanavir or -darunavir: data from the ICONA Cohort. AB - Background We aimed to mimic the ACTG 5257 trial, comparing raltegravir (RAL), ritonavir-boosted atazavavir (ATV/r) and ritonavir-boosted darunavir (DRV/r) in the observational setting. Methods All the ICONA patients starting a first cART with 2NRTI + ATV/r, DRV/r or RAL were included. Primary end-point was treatment failure, i.e. virological failure (confirmed HIV-RNA > 200copies/mL > 6 months therapy) or discontinuation for any reason of the third drug. Secondary end points: virological failure50 (50 copies/mL threshold), and discontinuation of the third drug due to intolerance/toxicity. Cox regression analyses were run to compare the risk of outcomes between the three regimens. Results 2249 patients were included, 985 (44%) initiated ATV/r, 1023 (45%) DRV/r and 241 (11%) RAL; median follow-up of 3.6 years (IQR: 2.3-5.2). After controlling for baseline confounding factors, patients given ATV/r showed a 26% higher risk of treatment failure (TF) vs. DRV/r (AHR 1.26, 95%CI 1.11-1.43); patients on RAL had a lower risk of TF vs. ATV/r (AHR 0.81, 95%CI 0.66-0.99). The probability of virological failure50 was significantly lower for people initiating RAL vs. DRV/r (AHR 0.46, 95%CI 0.24-0.87) or ATV/r (AHR 0.52, 95%CI 0.27-0.99). In addition, RAL was associated to a lower risk of discontinuation for toxicity vs. both DRV/r (AHR: 0.37, 95%CI: 0.19-0.72) and ATV/r (AHR: 0.18, 95%CI: 0.09-0.34). ATV/r was associated with a higher risk of discontinuing due to toxicity (AHR 2.09, 95%CI 1.63-2.67) vs. DRV/r. Conclusions In our observational study, we confirmed higher risk of treatment failure and lower tolerability of ATV/r-based regimens as compared to those including DRV/r or RAL. PMID- 29493420 TI - Activity-dependent neuronal Klotho enhances astrocytic aerobic glycolysis. AB - Mutations of the beta-glucuronidase protein alpha-Klotho have been associated with premature aging, and altered cognitive function. Although highly expressed in specific areas of the brain, Klotho functions in the central nervous system remain unknown. Here, we show that cultured hippocampal neurons respond to insulin and glutamate stimulation by elevating Klotho protein levels. Conversely, AMPA and NMDA antagonism suppress neuronal Klotho expression. We also provide evidence that soluble Klotho enhances astrocytic aerobic glycolysis by hindering pyruvate metabolism through the mitochondria, and stimulating its processing by lactate dehydrogenase. Pharmacological inhibition of FGFR1, Erk phosphorylation, and monocarboxylic acid transporters prevents Klotho-induced lactate release from astrocytes. Taken together, these data suggest Klotho is a potential new player in the metabolic coupling between neurons and astrocytes. Neuronal glutamatergic activity and insulin modulation elicit Klotho release, which in turn stimulates astrocytic lactate formation and release. Lactate can then be used by neurons and other cells types as a metabolic substrate. PMID- 29493421 TI - Responding to children and adolescents who have been sexually abused: WHO recommendations. PMID- 29493422 TI - Transient pseudohypo-aldosteronism. PMID- 29493423 TI - Immune cell infiltration in head and neck squamous cell carcinoma and patient outcome: a retrospective study. AB - BACKGROUND: Human papillomavirus (HPV) prevalence in oropharynx squamous cell carcinoma (OPSCC) is on the rise. HPV-linked OPSCCs represent a distinct clinical entity with a better treatment response and patient survival compared to tumors not linked to HPV. An emerging role in treatment response has been attributed to immune cell infiltration in human tumors. In this study, we investigated immune cell infiltration in human SCC of the head and neck region and its relation to overall survival after treatment with surgery (with or without radiotherapy) or concomitant chemo (or cetuximab)-radiotherapy. MATERIALS AND METHODS: Paraffin embedded tumor samples of 136 patients with SCC of the larynx, hypopharynx, oral cavity and oropharynx were processed for immunohistochemical detection of CD3+ T cells, CD8+ cytotoxic T-cells, CD20+ B-cells and CD163+ M2 macrophages within the tumor infiltrated area. Clinico-pathological data were analyzed as a function of tumor location and p16-status. Immune cell infiltration was represented as stained area on the whole tumor infiltrated area, compared for the different tumor locations and correlated to patient survival. RESULTS: Patients with oropharynx tumors expressing significant p16 levels (p16-sg) had a 5-year overall survival of 85% compared to 43% for patients with no significant p16 (p16-ns) expression (HR: 0.3 - 95% CI: 0.1-0.6). Median immune cell infiltration (T- and B lymphocytes) was significantly elevated in p16-sg oropharyngeal tumors, compared to p16-ns oropharyngeal tumors and to all other head and neck tumor locations. No difference in CD163+ macrophage infiltration was observed across the different patient groups. In the whole population, a high infiltration by CD3+ T lymphocytes was associated to a significantly (p = .03; HR: 0.6, 95% CI: 0.4 0.97) better overall survival. CONCLUSION: Oropharynx cancer with significant p16 expression showed an increased overall survival and elevated T- and B-lymphocyte infiltration, which suggests a prognostic relevance of immune cell infiltration. PMID- 29493424 TI - In their own words: disaster and emotion, suffering, and mental health. AB - PURPOSE: In this article, I explore emotions, trauma, and mental health issues residents experienced after tornadoes in Tuscaloosa, Alabama and Joplin, Missouri in 2011. METHODS: The research is based on 162 interviews and fieldwork from 2013 2015. I draw from literature on social suffering and trauma to ask how experiencing mental health and trauma changes how people make sense of their social worlds. RESULTS: I discuss four common themes: 1. Emotions in immediate aftermath, 2. Relationship strain, 3. Mental health problems, and 4. Emotions in long-term recovery. Throughout the article, I pay attention to the bodily experiences of suffering and trauma. CONCLUSION: I argue experiencing mental health and suffering may be a critical perspective-one that can shed light on being in the world in ways that other perspectives may be less suitable to do. PMID- 29493425 TI - Pharmacophore and structure-based drug design, molecular dynamics and admet/tox studies to design novel potential pad4 inhibitors. AB - We have used docking (GLIDE), pharmacophore modeling (Discovery Studio), long trajectory molecular dynamics (Discovery Studio) and ADMET/Tox (QikProp and DEREK) to investigate PAD4 in order to determine potential novel inhibitors and hits. We have carried out virtual screening in the ZINC natural compounds database. Pharmacokinetics and Toxicity of the best hits were assessed using databases implemented in softwares that create models based on chemical structures taking into account consideration about the toxicophoric groups. A wide variety of pharmaceutical relevant properties are determined in order to make decisions about molecular suitability. After screening and analysis, the 6 most promising PAD4 inhibitors are suggested, with strong interactions (pi stacking, hydrogen bonds, hydrophobic contacts) and suitable pharmacotherapeutic profile as well. PMID- 29493426 TI - Assessing biomass diversity and performance of an activated sludge process treating saline table olive processing wastewater. AB - This study aimed to determine the effects of salinity on the biomass behavior and its diversity in activated sludge process (ASP) treating the table olive processing wastewater (TOPW), and to evaluate ASP performances under increased TOPW concentration feeding, the numerical abundance, diversity and activity of the biomass, removal efficiencies of chemical oxygen demand (COD), phenolic compounds, nitrogen and phosphorus were evaluated. Results showed that biomass growth is very high and became faster according to an increase in the percentage of TOPW feeding and reached 5.2 gMLVSS l-1. The specific oxygen uptake rate (SOUR) analysis revealed that salinity up to 10 g l-1 provides an increase in biomass activity. SOUR reached a maximum of 20.3 gO2 gMLVSS-1 h-1. The increasing percentages of TOPW induce actually an evolution of microorganism's biodiversity; the microorganism communities were characterized by the abundance of halotolerant, Pseudomonas and Yeast genus that became the most abundant in the bioreactor as adaptation response against salinity. Furthermore, COD, phenolic compounds, nitrogen and phosphorus removal efficiencies attained 92.3%, 84.5%, 80% and 60%, respectively. A satisfactory release of extracellular polymeric substances is found to occur in the reactor with regard to increased saline TOPW, providing significant removal efficiencies and best settling of sludge. PMID- 29493427 TI - A biomechanical comparison in the lower limb and lumbar spine between a hit and drag flick in field hockey. AB - Research has revealed that field hockey drag flickers have greater odds of hip and lumbar injuries compared to non-drag flickers (DF). This study aimed to compare the biomechanics of a field hockey hit and a specialised field hockey drag flick. Eighteen male and seven female specialised hockey DF performed a hit and a drag flick in a motion analysis laboratory with an 18-camera three dimensional motion analysis system and a calibrated multichannel force platform to examine differences in lower limb and lumbar kinematics and kinetics. Results revealed that drag flicks were performed with more of a forward lunge on the left lower limb resulting in significantly greater left ankle dorsiflexion, knee, hip and lumbar flexion (Ps<0.001) compared to a hit. Drag flicks were also performed with significantly greater lateral flexion (P < 0.002) and rotation of the lumbar spine (P < 0.006) compared to a hit. Differences in kinematics lead to greater shear, compression and tensile forces in multiple left lower limb and lumbar joints in the drag flick compared to the hit (P < 0.05). The biomechanical differences in drag flicks compared to a hit may have ramifications with respect to injury in field hockey drag flickers. PMID- 29493428 TI - Fuzzy risk assessment for mechanized underground coal mines in Turkey. AB - The decision matrix method is preferred as a measure of risk evaluation considering the risk value obtained by two risk factors such as the likelihood and severity of a hazard. However, it has some deficiencies since a crisp risk score is assigned for likelihood and severity. In this article, a fuzzy logic based safety evaluation method to enhance the risk assessment process is introduced to overcome the uncertainties encountered in the classical decision matrix risk assessment method. The proposed method is a more realistic evaluation of the risks which may be available in mechanized coal mines in Turkey. In this way, risky situations and operations in mechanized underground coal mines have been determined by expert knowledge and engineering judgement in linguistic forms. Thus, such an evaluation will be a valuable guide for coal mines in which fully mechanized coal production is expected in the near future. PMID- 29493429 TI - Parenting styles and emerging adult depressive symptoms in Cebu, the Philippines. AB - Incidence of depressive disorders and symptoms increases during the transition to adulthood. The parenting relationship is a potential target for interventions to reduce risk for depression in offspring during this time period, and a four category typology of parenting styles (authoritative, permissive, authoritarian, and neglectful) has been found to correlate with offspring psychological functioning. The majority of studies, however, have examined this four-category parenting style typology in Western populations. We used the Cebu Longitudinal Health and Nutrition Survey (CLHNS) from the Philippines to assess associations between parenting styles reported by offspring at age 18 and depressive symptoms reported by offspring at age 21 ( N = 1,723). Using adjusted linear regression models, we found that authoritarian and neglectful mothering styles were positively associated with daughters' depressive symptoms, whereas authoritarian mothering was negatively associated with sons' depressive symptoms. Findings suggest both cross-cultural similarities and variability in positive parenting. Results may have implications for family-based depression prevention interventions in the Philippines. PMID- 29493430 TI - The outcome of two-step blood pressure screening in dental healthcare. AB - AIM: The purpose of this study was to evaluate a two-step screening method for hypertension in dentistry regarding the number needed to screen (NNS) and positive predictive value (PPV) and to risk-classify those with newly diagnosed hypertension. METHODS: In connection with their regular dental care check-up, 2025 subjects aged 40-75 years were screened for high blood pressure. Via a health questionnaire, data were collected concerning risk factors. Blood pressure was screened comprehensively in two steps, which included screening in a dental clinic and home measurements for one week. Recently discovered hypertensive participants were assessed for 10-year risk of cardiovascular mortality according to the guidelines of the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC). RESULTS: A total of 170 new hypertensive participants were found (NNS = 12; 95% confidence interval (CI): 11-13). The method yielded a PPV of 0.73 (95% CI: 0.68-0.78) and eliminated 84.8% of the false-positive participants. The results also showed that based on ESH/ESC risk estimation, 76.5% of those newly diagnosed hypertensive participants had a moderate or high risk of cardiovascular mortality within 10 years. CONCLUSIONS: The study shows that a two-step method for blood pressure screening in a dental setting including home measurement resulted in a high PPV and eliminated most of those with a false high blood pressure reading. The findings also show that two step screening for hypertension is feasible in a larger population with more screening providers involved. PMID- 29493431 TI - Content and validation of the Electronic Patient Medication module (EPM)-the administrative in-hospital drug use database in the Capital Region of Denmark. AB - AIMS: Registries on in-hospital drug use are sparse, especially those that can be linked to nationwide registries. In this study, we present and validate the Electronic Patient Medication module (EPM)-the electronic administrative database on in-hospital drug use covering the Capital Region of Denmark. METHODS: The research database (EPM-research) is an adaptation of the database underlying the electronic administrative database for in-hospital drug use (EPM-clinic). The validation study was comprised of two sub-studies. Sub-study 1: Accordance of registration between EPM-clinic and EPM-research was investigated by analyzing randomly chosen retrospective patient records. Sub-study 2: Workflows and real life registration practices were investigated through visits to three different (two medical and one emergency) departments. An observer followed a nurse while dispensing and administering drugs. This information was compared with EPM research. The primary endpoint for both sub-studies was accordance of generic name between registrations. Secondary endpoints were exact brand name, dose, and time of each administration. Accordance (proportions) with 95% confidence intervals (CI) using the Clopper-Pearson method were calculated. The study was approved by the Danish Data Protection Agency (BFH-2016-058-04906) and the Danish Patient Safety Authority (3-3013-1884/1/). RESULTS: In sub-study 1 227 retrospective drug administrations were reviewed. Accordance of generic name was 100.0% (CI 98.4%-100.0%). In sub-study 2 176 drug administrations were observed of which 173 were recorded with identical generic name, resulting in 98.3% (CI 95.1%-99.6%) accordance of data. CONCLUSIONS: Our validation of the EPM-research showed very high accordance. With detailed information on in-hospital drug use, the EPM-research may be a useful tool in pharmacoepidemiological research. PMID- 29493432 TI - Mortality trends in external causes of death in people with mental health disorders in Sweden, 1987-2010. AB - AIM: We investigated mortality from external causes in Swedish people who had been hospitalised with a severe mental disorder. METHODS: Hospitalisations in people aged 15 years or older admitted to hospital with a main diagnosis of schizophrenia, bipolar mood disorder or unipolar mood disorder between 1987 and 2010 were linked to their causes of death. RESULTS: The mortality rate from all external causes was 20-fold higher in those with unipolar mood disorder, 15-fold higher in those with bipolar disorder and 12-fold higher in those with schizophrenia than in the general population. Over the study periods, the mortality rate declined more for people with unipolar mood disorder (-35%) and schizophrenia (-29%) than the total population (-25%) and those with bipolar mood disorder (-15%). The suicide rate declined most for those with unipolar mood disorder and schizophrenia (-42% for both) and less for the general population ( 37%) and those with bipolar mood disorder (-21%). For external causes other than suicide, the mortality rate declined in the general population (-17%) but increased in people with schizophrenia (14%), bipolar mood disorder (30%) and unipolar mood disorder (52%). CONCLUSIONS: People with mental disorders have high but declining excess mortality from suicide. Mortality from other external causes has increased, as has the gap in mortality rates between psychiatric patients and the general population. PMID- 29493433 TI - Total sitting time, leisure time physical activity and risk of hospitalization due to low back pain: The Danish Health Examination Survey cohort 2007-2008. AB - AIMS: This study aimed to test the hypotheses that a high total sitting time and vigorous physical activity in leisure time increase the risk of low back pain and herniated lumbar disc disease. METHODS: A total of 76,438 adults answered questions regarding their total sitting time and physical activity during leisure time in the Danish Health Examination Survey 2007-2008. Information on low back pain diagnoses up to 10 September 2015 was obtained from The National Patient Register. The mean follow-up time was 7.4 years. Data were analysed using Cox regression analysis with adjustment for potential confounders. Multiple imputations were performed for missing values. RESULTS: During the follow-up period, 1796 individuals were diagnosed with low back pain, of whom 479 were diagnosed with herniated lumbar disc disease. Total sitting time was not associated with low back pain or herniated lumbar disc disease. However, moderate or vigorous physical activity, as compared to light physical activity, was associated with increased risk of low back pain (HR = 1.16, 95% CI: 1.03-1.30 and HR = 1.45, 95% CI: 1.15-1.83). Moderate, but not vigorous physical activity was associated with increased risk of herniated lumbar disc disease. CONCLUSIONS: The results suggest that total sitting time is not associated with low back pain, but moderate and vigorous physical activity is associated with increased risk of low back pain compared with light physical activity. PMID- 29493434 TI - Novel cognitive insights from the first year after bi-thalamic infarct. AB - Neuropsychological consequences of bi-thalamic damage are scarcely known. This case study documents cognitive (in particular memory and executive) functioning in a man with a medial bi-thalamic infarct in the first year (8 and 12 months) post injury. NG showed persistent memory (including autobiographical) impairment, but improved executive functions at one year post injury. On a response inhibition task his speed of response improved but his ability to inhibit a "prepotent" automatic response declined, corresponding to an increase in behavioral disinhibition. Despite this, he showed intact performances on several social cognition tasks. This case contributes to our understanding of the role of the thalamus in mediating retrograde memory, executive, and social cognition functions. PMID- 29493435 TI - History and challenges of Brazilian social movements for the achievement of the right to adequate food. AB - The historical struggles that Brazil faced to overcome malnutrition coincided with the empowerment of civil society and social movements which played a crucial role in the affirmation of health and food as social rights. After two decades under military dictatorship, Brazil went through a redemocratization process in the 1980s when activism emerged to demand spaces to participate in policy-making regarding the social agenda, including food and nutrition security (FNS). From 1988 onward institutional structures were established: the National Council of FNS (CONSEA) convenes government and civil society sectors to develop and monitor the implementation of policies, systems and actions. Social participation has been at the heart of structural changes achieved since then. Nevertheless, the country faces multiple challenges regarding FNS such as the double burden of disease, increasing use of pesticides and genetically modified seeds, weak regulation of ultra-processed products, and marketing practices that affect the environment, population health, and food sovereignty. This article aims at examining the development of the participatory political system and the role played by Brazilian social movements in the country's policies on FNS, in addition to outlining challenges faced by those policies. PMID- 29493437 TI - Severe acute kidney injury owing to rhabdomyolysis and intravascular haemolysis in an 11-year-old child with G6PD deficiency. AB - Glucose-6-phosphate dehydrogenase (G6PD) deficiency leading to acute intravascular haemolysis and acute kidney injury (AKI) is a known clinical presentation. However, there is a paucity of information regarding the occurrence of rhabdomyolysis and myoglobinuria in G6PD-deficient individuals, especially children. An 11-year-old south Indian Tamil girl presented with severe anaemia and anuric AKI following a short febrile illness. Investigations demonstrated evidence of intravascular haemolysis and rhabdomyolysis, and on histopathology myoglobin deposits (casts) were detected in the renal tubules. She was successfully managed with repeated sessions of haemodialysis and blood transfusions. Follow-up estimation of G6PD levels after 3 months confirmed severe G6PD deficiency (0.003 nkat/g haemoglobin). Although there are anecdotal reports of myoglobinuria in G6PD-deficient individuals, the occurrence of severe anuric AKI in this clinical setting has not been reported. It can be speculated that myoglobinuria (in addition to haemoglobinuria) can contribute towards jeopardising renal function in G6PD deficiency-related acute haemolytic crisis. PMID- 29493436 TI - Trifecta and Pentafecta Rates After Robotic Assisted Partial Nephrectomy: Comparative Study of Patients with Renal Masses <4 and >=4 cm. AB - OBJECTIVES: Robotic-assisted partial nephrectomy (RAPN) is preferred to radical nephrectomy because it guarantees superior functional outcomes in patients with small renal masses (RMs). Only a few studies so far have evaluated the feasibility of RAPN for the treatment of RM >=4 cm. The aim of this study is to evaluate the safety and feasibility of RAPN based on a comparison of trifecta and pentafecta rates for RMs >=4 cm. MATERIAL AND METHODS: We retrospectively analyzed prospectively collected data from an institutional database of patients undergoing RAPN from September 2013 to November 2016. Demographic and perioperative data were collected and statistically analyzed. Pentafecta is defined as achievement of trifecta (negative surgical margins, no postoperative complications, and warm ischemia time <=25 minutes) with the addition of two other variables, namely, over 90% estimated glomerular filtration rate preservation and no chronic kidney disease stage progression 1 year after surgery. RESULTS: Overall, 123 patients underwent RAPN. Of those, 38 (30.9%) had RMs >=4 cm. Trifecta was achieved in 72.9% of patients with RMs <4 cm and in 44.7% of those with >=4 cm, whereas pentafecta was achieved by 23.5% of patients with RMs <4 cm and by 10.5% of those with RMs >=4 cm. No significant predictive factors were found in connection with trifecta, whereas only one was found in connection with pentafecta, namely, age (odds ratio: 0.91; 95% confidence interval 0.85-0.98; P = .01). CONCLUSIONS: RAPN may be considered a feasible and safe surgical approach ensuring good functional outcome even for patients with RMs >=4 cm. Pentafecta rates after RAPN were comparable between RMs <4 and >=4 cm in diameter. PMID- 29493439 TI - Isolated parapharyngeal cold abscess in a 9-year-old boy. AB - Tuberculous adenitis presenting as an isolated cold abscess in the parapharyngeal space is very uncommon and has not been reported in the paediatric age group; presentation as a retropharyngeal abscess, however, is well known. Nine-year-old boy with a progressively increasing swelling on the right side of the neck for 2 months was referred with a clinical diagnosis of neuroblastoma. Surgical exploration of the parapharyngeal space by needle aspiration yielded a cheesy material and Mycobacterium tuberculosis was detected by DNA TB PCR. Tuberculosis should always be considered in the differential diagnosis of a cervical swelling in a child. PMID- 29493438 TI - Is Balint training associated with the reduced burnout among primary health care doctors? AB - The aim of our study was to examine whether the participation in Balint group is associated with the reducing burnout syndrome among primary health care doctors. This investigation was conducted on a population of 210 doctors employed in primary health centers in Belgrade. Out of 210 doctors, 70 have completed Balint training for a period of at least 1 year, whereas 140 doctors have never attended this training (the Non-Balint group). The level of burnout among physicians was assessed with the Serbian translation of the original 22-item version of the Maslach Burnout Inventory - Human Services Survey which defines burnout in relation to emotional exhaustion, depersonalization and personal accomplishment. We found that 45.0% of the Non-Balint participants and 7.1% of the Balint-trained participants responded with symptoms of high level of emotional exhaustion, with a statistically significant difference (p < 0.001). In relation to depersonalization, 20% of the Non-Balint subjects were highly depersonalized compared to 4.4% of the Balint-trained subjects, with a statistically significant difference (p < 0.001). Regarding the personal accomplishment, 21.4% of the Non Balint subjects and 7.1% of the Balint-trained subjects had a perception of low personal accomplishment, with a statistical significance (p < 0.001). In the multiple ordinal logistic model, with emotional exhaustion as a dependent variable, statistically significant predictor was female gender (OR = 2.51; p = 0.021), while Balint training was obtained as a protective factor (OR = 0.12; p < 0.001). Non-specialists were detected as a risk factor for depersonalization (OR = 2.14; p = 0.026) while Balint group was found as a protective factor (OR = 0.10; p < 0.001), according to the multiple ordinal logistic regression analysis. Regarding the reduced personal accomplishment, our results indicated that nonspecialists were at risk for this subdimension (OR = 2.09; p = 0.025), whereas Balint participants were protected (OR = 0.18; p < 0.001). Participation in Balint groups is associated with the reduced burnout syndrome among primary health care doctors. PMID- 29493441 TI - Environmental Training And Synaptic Functions In Young And Old Brain: A Presynaptic Perspective. AB - BACKGROUND: Aging is an unavoidable, physiological process that reduces the complexity and the plasticity of the synaptic contacts in central nervous system (CNS), having profound implications for human wellbeing. The term "cognitive reserve" refers to central cellular adaptations that augment the resilience of human brain to damage and aging. The term "Cognitive training" indicates the cultural, social and physical stimulations proposed as add-on therapy for the cure of central neurological diseases. "Cognitive training" reinforces the "cognitive reserve" permitting to counteract brain impairments and rejuvenating synaptic complexity. The research has begun investigating the clinical impact of the "cognitive training" in aged people, but additional work is needed to definitively assess its effectiveness. In particular, there is a need to understand, by a preclinical point of view, whether "cognitive training" promotes compensatory effects or, alternatively, if it elicits genuine recovery of neuronal defects. Although the translation from rodent studies to the clinical situation could be difficult, the results from pre-clinical models are of high clinical relevance, since they should allow a better understanding of the effects of environmental interventions in aging-associated chronic derangements in mammals. CONCLUSION: Data in literature and the recent results obtained in our laboratory concerning the impact of environmental stimulation on the presynaptic release of noradrenaline, glutamate and gamma amino butyric acid (GABA) suggest that these neurotransmitters undergo different adaptations during aging and that they are differently tuned by "cognitive training". The impact of "cognitive training" on neurotransmitter exocytosis might account for the cellular events involved in reinforcement of "cognitive reserve" in young and old animals. PMID- 29493442 TI - Sensing, transport and other potential biomedical applications of pseudopeptides. AB - Pseudopeptides are privileged synthetic molecules built from the designed combination of peptide-like and abiotic artificial moieties. Consequently, they are benefited from the advantages of both families of chemical structures: modular synthesis, chemical and functional diversity, tailored three-dimensional structure, usually high stability in biological media and low non-specific toxicity. Accordingly, in the last years, these compounds have been used for different biomedical applications, ranging from bio-sensing, ion transport, the molecular recognition of biologically relevant species, drug delivery or gene transfection. This review highlights a selection of the most remarkable and recent advances in this field. PMID- 29493443 TI - Antimicrobial and structural properties of metal ions complexes with thiosemicarbazide motif and related heterocyclic compounds. AB - Antibiotic resistance acquired by various bacterial fungal and viral pathogens poses therapeutic problems of increasing severity. Among the infections that are very difficult to treat, biofilm-associated cases are one of the most hazardous. Complex structure of a biofilm and unique physiology of the biofilm cells contribute to their extremely high resistance to environmental conditions, antimicrobial agents and the mechanisms of host immune response. Therefore, the biofilm formation, especially by multidrug-resistant pathogens, is a serious medical problem, playing a pivotal role in the development of chronic and recurrent infections. These factors create a limitation for using traditional chemiotherapeutics and contribute to a request for development of new approaches for treatment of infectious diseases. Therefore, early reports on antimicrobial activity of several complexes of metal ions, bearing thiosemicarbazide or thiosemicarbazones as the ligands, gave a boost to worldwide search for new, more efficient compounds of this class, to be used as alternatives to commonly known drugs. In general, depending on the presence of other heteroatoms, these ligands may function in a di-, tri- or tetradentate forms (e.g., of N,S,-, N,N,S-, N,N,N,S-, N,N,S,S-, or N,S,O-type), which impose different coordination geometries to the resultant complexes. In the first part of this review, we describe the ways of synthesis and the structures of the ligands based on the thiosemicarbazone motif, while the second part deals with the antimicrobial activity of their complexes with selected metal ions. PMID- 29493445 TI - Editorial: Towards MiRNA Based Therapeutics for Lung Cancer. PMID- 29493440 TI - Potential roles for G-quadruplexes in mitochondria. AB - Some DNA or RNA sequences rich in guanine (G) nucleotides can adopt non-canonical conformations known as G-quadruplexes (G4). In the nuclear genome, G4 motifs have been associated with genome instability and gene expression defects, but they are increasingly recognized to be regulatory structures. Recent studies have revealed that G4 structures can form in the mitochondrial genome (mtDNA) and G4 forming potential sequences are associated with the origin of mtDNA deletions. However, little is known about the regulatory role of G4 structures in mitochondria. In this short review, we will explore the potential for G4 structures to regulate mitochondrial function, based on evidence from the nucleus. PMID- 29493446 TI - Editorial; Natural Product Inhibitors of Enzymatic Targets in Anticancer Drug Discovery - Part II. PMID- 29493447 TI - Editorial: Phosphoproteomics in Plant Growth and Stress Tolerance. PMID- 29493448 TI - Editorial: Smart Drug Delivery Systems (Part 2). PMID- 29493449 TI - Synthesis and Kinetics of Highly Substituted Piperidines in the Presence of Tartaric Acid as a Catalyst. AB - Aim & Scope: The synthesis of highly substituted piperidine from the one-pot reaction between aromatic aldehydes, anilines and beta-ketoesters in the presence of tartaric acid as a catalyst has been investigated in both methanol and ethanol media at ambient temperature. Different conditions of temperature and solvent were employed for calculating the thermodynamic parameters and obtaining an experimental approach to the kinetics and mechanism. Experiments were carried out under different temperature and solvent conditions. MATERIAL AND METHODS: Products were characterized by comparison of physical data with authentic samples and spectroscopic data (IR and NMR). Rate constants are presented as an average of several kinetic runs (at least 6-10) and are reproducible within +/- 3%. The overall rate of reaction is followed by monitoring the absorbance changes of the products versus time on a Varian (Model Cary Bio- 300) UV-vis spectrophotometer with a 10 mm light-path cell. RESULTS: The best result was achieved in the presence of 0.075 g (0.1 M) of catalyst and 5 mL methanol at ambient temperature. When the reaction was carried out under solvent-free conditions, the product was obtained in a moderate yield (25%). Methanol was optimized as a desirable solvent in the synthesis of piperidine, nevertheless, ethanol in a kinetic investigation had none effect on the enhancement of the reaction rate than methanol. Based on the spectral data, the overall order of the reaction followed the second order kinetics. The results showed that the first step of the reaction mechanism is a rate determining step. CONCLUSION: The use of tartaric acid has many advantages such as mild reaction conditions, simple and readily available precursors and inexpensive catalyst. The proposed mechanism was confirmed by experimental results and a steady state approximation. PMID- 29493450 TI - Virtual Combinatorial Library Design, Synthesis and In vitro Anticancer Assessment of -2-Amino-3-Cyanopyridine Derivatives. AB - AIM AND OBJECTIVE: For the development of new class of anticancer agents, a series of novel 2-amino-3-cyanopyridine derivatives were designed from virtual screening with Glide program by setting Topoisomerase II as the target. MATERIALS AND METHODS: The top ranked ten molecules from the virtual screening were synthesized by microwave assisted technique and investigated for their cytotoxic activity against MCF-7 and A- 549 cell lines by using sulforhodamine B assay method. RESULTS: The most active compound 2-amino-4-(3,5-dibromo-4-hydroxyphenyl) 6-(2,4- dichlorophenyl) nicotinonitrile (CG-5) showed significant cytotoxic profile with (LC50 = 97.1, TGI = 29.9 and GI50 = <0.1 uM) in MCF-7 and (LC50= 93.0, TGI= 50.0 and GI50= <7 uM) in A-549 cell lines. A molecular docking study was performed to explore the binding interaction of CG-5with the active site of Topoisomerase II. CONCLUSION: It can be concluded that halogen substituent pyridine ring was benefit for cytotoxicity. PMID- 29493451 TI - Applications and Prospects of Non-viral Vectors in Bone Regeneration. AB - INTRODUCTION: Bone tissue has an intrinsic ability to repair and regenerate itself through a continuous remodelling cycle of resorption of old or damaged bone and deposition of new. However, significant morbidity and mortality arise when bone cannot heal itself. Effective bone regeneration strategy can improve the current clinical therapies of many orthopaedic disorders. Cell activity stimulation, growth factors, and appropriate mechanical conditions are essential components of clinical treatment. However, growth factors tend to degrade over time in the human body. Gene therapy offers an alternative method to cure bone defects, with the advent of exciting new delivery capabilities via gene vectors. Gene vectors accurately deliver regenerative molecules to the lesion site. Additionally, gene therapy provides a highly efficient treatment option with a lower effective concentration. Compared with viral gene vectors, non-viral gene vectors have proven to be more potent due to their safety, non-immunogenicity, and ease of manufacture. CONCLUSION: Thus, in this paper, we review the application and progress of non-viral gene vector therapy in bone regeneration. PMID- 29493452 TI - Insulin Therapy for Diabetes Epidemic: A Patent Review. AB - Diabetes is a serious and chronic problem that can be attributed to the insufficient release of the insulin or when body does not respond to the insulin which is already present. This disease has been targeted for corrective action and implementation among four non-communicable diseases by world leaders according to WHO report. The prevalence of diabetes has been estimated to be double from 4.7% of adult population in 1980 to 8.5% in the present scenario. The estimated deaths due to this epidemic disease were 1.5 million in 2012 alone. Currently, approximately 400 million people are suffering from diabetes worldwide. Although the factors leading to Type I diabetes are unknown, there are many therapies available in market for Type II disease which bags more than 90% of the total diabetes cases. But, the current treatment for this disease seems to be lacking in terms of proper management of disease, while insulin still remains the ultimate therapy to achieve comparatively effective glycemic control. In this review, an attempt has been made to summarize the patent applications filed in the field of pulmonary delivery of insulin as dry powder through an inhaler in various formulations. This review will provide an insight to the development and advancement for various formulations of insulin and the design of inhaler to improve the bioavailability of powder formulation of insulin, which would provide an alternate treatment with better acceptability or tolerability among the patients as compared to the intravenous delivery to offer better management of epidemic diabetes. PMID- 29493453 TI - Therapeutic Nanotechnology for Bone Infection Treatment - State of the Art. AB - Despite extended, aggressive use of conventional antibiotics, drug treatment of bone infections frequently fails as a combined result of the widespread of drug resistant bacteria, poor accessibility of many antimicrobials to the deeper portion of the bones, the ease of biofilm formation on the bone surface, and high risk of drug toxicity. Emerging therapeutic nanotechnology offers potential solutions to these issues. In recent years, a number of nanoantimicrobials, i.e. nanoscale devices with intrinsic antibacterial activities or capacity for delivering antibiotics, have been developed for the treatment and prevention of bone infections. These nanoantimicrobials can be designed to have controlled and sustained drug release kinetics, surface-modifications for bone or bacteria targeting, and increased affinity for biofilms. Given the potential value of nanoantimicrobials, clinical application of nanoantimicrobials for bone infection treatment remains scant when compared with the number of ongoing research. It is, therefore, a good time to carefully examine this promising yet relatively uncharted area. This review will extensively discuss the development and state of the art of different classes of nanoantimicrobials for bone infections with emphasis on the treatment aspect and identify the factors that prevent the clinical translation of nanoantimicrobial therapy from bench to bedside. PMID- 29493454 TI - Design and Characterization of Apocynin Loaded PLGA Nanoparticles and their In vivo Efficacy in Hyperoxaluric Rats. AB - BACKGROUND: Apocynin has become a drug of choice in NADPH oxidase induced pathological conditions. Hyperoxaluria is one such pathological condition where NADPH oxidase is involved in eliciting renal injury. OBJECTIVE: Recently apocynin has shown to reverse the transcriptome profile of the NADPH oxidaseassociated genes and reduced oxidative burden in hyperoxaluric animals. The poor solubility of this drug creates certain apprehensions about its bioavailability. PLGA (Poly Lactic co-Glycolic Acid) encapsulation of drug nanoparticles have showed to induce sustain release and henceforth enhance the efficiency and bioavailability of drugs. Therefore, the present study is aimed to envisage a novel approach of synthesizing apocynin doped PLGA nanoparticles. METHODS: The PLGA nanoparticles (both unloaded and loaded) were prepared using solvent extraction method and analyzed for size and stability by Dynamic Light Scattering (DLS), TEM (transmission electron microscopy) and zeta potential. Furthermore, the drug release and encapsulation efficiency of the drug was calculated in vitro. RESULTS: The nanoencapsulation formed was stable with desired size (217-259 nm) and posses a controlled drug release of 20%. Further this nanoencapsulation was explored for its potential to reduce hyperoxaluric manifestations in rats given ethylene glycol with ammonium chloride for 9 days. CONCLUSION: In comparison to free apocynin, it was found that nanoparticles containing apocynin showed moderately better results in vivo by maintaining serum urea and createnine levels. These nanoparticles can be used in diseases where a sustained release of apocynin is required. PMID- 29493455 TI - Effects of Estrogen in Gender-dependent Fetal Programming of Adult Cardiovascular Dysfunction. AB - BACKGROUND: Epidemiological studies and experimental studies have demonstrated that intrauterine adverse environment increases the risk of cardiovascular disease (CVD) in adulthood. However, whether an individual develops a cardiovascular dysfunctional phenotype may depend on genetic background, age, and sex. METHODS: In this review, we summarize some of the recent experimental animal studies in the developmental programming of adult CVD with an emphasis on sex differences and the potential role of estrogen in mediating sexual dimorphism. RESULTS: Few epidemiological studies report the effect of sex on the developmental programming of CVD. However, numerous experimental animal studies have shown a sex difference in fetal programming of adult cardiovascular dysfunction. Most of the animal studies indicate that male offspring develop cardiovascular dysfunction and CVD in adulthood, whereas adult females appear to be protected. Estrogen is one of the key factors that contributes to the sex difference of adult CVD. Estrogen/its receptor (ER) may interact with the RAS system by changes of DNA methylation patterns at the target gene promoter, serve as an antioxidant to counteract the prenatal insults-induced heightened ROS, and function as an eNOS activator to increase vasodilation, resulting in the protection of female offspring from the development of hypertension and other CVDs. CONCLUSION: These studies suggest that estrogen/ER may contribute to sex differences in cardiovascular response to an adverse intrauterine environment and play a significant role in modulating the cardiovascular response in adulthood. PMID- 29493456 TI - A systematic review on popularity, application and characteristics of protein secondary structure prediction tools. AB - BACKGROUND: Prediction of proteins' secondary structure is one of the major steps in the generation of homology models. These models provide structural information which is used to design suitable ligands for potential medicinal targets. However, selecting a proper tool between multiple secondary structure prediction (SSP) options is challenging. The current study is an insight onto currently favored methods and tools, within various contexts. OBJECTIVE: A systematic review was performed for a comprehensive access to recent (2013-2016) studies which used or recommended protein SSP tools. METHOD: Three databases, Web of Science, PubMed and Scopus were systematically searched and 99 out of 209 studies were finally found eligible to extract data. RESULTS: Four categories of applications for 59 retrieved SSP tools were: (I) prediction of structural features of a given sequence, (II) evaluation of a method, (III) providing input for a new SSP method and (IV) integrating a SSP tool as a component for a program. PSIPRED was found to be the most popular tool in all four categories. JPred and tools utilizing PHD (Profile network from HeiDelberg) method occupied second and third places of popularity in categories I and II. JPred was only found in the two first categories, while PHD was present in three fields. CONCLUSION: This study provides a comprehensive insight about the recent usage of SSP tools which could be helpful for selecting a proper tool's choice. PMID- 29493457 TI - The modulatory effect of lead drug candidates on inflammatory gene expression in sepsis: A mini-review. AB - Sepsis is a debilitating clinical syndrome of systemic inflammation in response to microorganisms especially Gram positive and Gram negative bacteria. A minority of sepsis cases could be due to non-pathogenic insult such as trauma. Much of the tissue and organ injury observed among septic patients is a consequence of the inflammatory response. The search for effective treatments of sepsis has led to several studies by different research groups across the globe. Although many targets and molecules have been identified, there is still no effective treatment for sepsis. The aim of this report is to review literature on drugs and drug candidates against sepsis and how they modulate the expression of inflammatory genes. Many compounds have been identified to regulate inflammatory gene expression by interacting with targets such as topoisomerase 1 and nuclear factor kappa B, which regulate the production of pro- and anti-inflammatory cytokines. Even though these compounds appear promising as potential drugs against sepsis, no effective therapies have been discovered to date and thus the fight against sepsis continues. PMID- 29493458 TI - Critical Insight into Design of PPAR-gamma Agonists by Virtual Screening Techniques. AB - Design of novel PPAR-gamma modulators with better binding efficiency and fewer side effects to treat type 2 diabetes is still a challenge for medicinal chemists. Cost and time efficient computational methods have presently become an integral part of research in nuclear receptors and their ligands, enabling hit to lead identification and lead optimization. This review will focus on cutting-edge technologies used in most recent studies on the design of PPAR- gamma agonists and will discuss the chemistry of a few molecules which emerged successful. Virtual screening of natural product libraries is an effective strategy to harness nature as the source of ligands for PPARs. Databases of natural products, drug molecules, and chemical substances facilitate this approach, where these molecules are virtually screened by similarity search, ADMETox properties, pharmacophore modelling and shape-based modelling. Docking is a valuable in silico approach to probe the PPAR-ligand interaction. Rigid docking of ligands with various crystallized structures of the PPARs is a routinely used model. Induced fit docking and core hopping approach in docking were reported as rapid screening methods to identify novel leads and to predict the PPAR- gamma and PPAR alpha/ gamma dual agonistic activity. One-dimensional drug profile matching is one of the recent virtual screening methods by which an antiprotozoal drug, Nitazoxanide, was identified as a PPAR- gamma agonist. Virtual screening workflow can be customized by choosing appropriate models and applying them either sequentially or simultaneously to achieve convincing and reliable results. PMID- 29493461 TI - More Evidence for the Therapeutic Role of Pramipexole in Upper Limb Restlessness Due to Cervical Disc Pathology? AB - BACKGROUND: The causal link between upper limb restlessness and cervical disc prolapsus is still unclear, and the exact role of the spinal cord in the origination of limb restlessness is not yet completely understood. METHODS: Here we have evaluated the therapeutic effect of pramipexole (0.5 mg/kg) in a 47-year old male with cervical disc prolapsus who described restlessness in his upper limb and neck. RESULTS: The patient felt significantly better, and his symptoms improved near to complete after five days when we initiated 0.5 mg/day pramipexole treatment. CONCLUSION: In our present paper, we provide more evidence for the role of pramipexole (0.5 mg/day) in limb restlessness which is associated with cervical disc herniation. In this context, we also have discussed the underlying pathophysiology which seems to be responsible for the restlessness symptoms of the patients. PMID- 29493460 TI - Molecular Modeling, Docking, Dynamics and Simulation of Gefitinib and its Derivatives with EGFR in Non-small Cell Lung Cancer. AB - BACKGROUND: Gefitinib (lressa) is the most prescribed drug, highly effective to treat nonsmall cell lung cancer; primarily it was considered that targeted therapy is a kinase inhibitor. The nonsmall cell lung cancer is caused by mutation in the Epithelial Growth Factor Receptor (EGFR) gene. Iressa works by blocking the EGFR protein that helps the cancer cell growth. EGFR protein has lead to the development of anticancer therapeutics directed against EGFR inhibitor including Gefitinib for non-small cell lung cancer. METHODS: To explore the interaction between Gefitinib and its derivatives with crystal structure of EGFR to understand the better molecular insights interaction strategies. Molecular modeling of ligands (Gefitinib and its derivatives) was carried out by Avogadro software till atomic angle stable confirmation was obtained. The partial charges for the ligands were assigned as per standard protocol for molecular docking. All docking simulations were performed with AutoDockVina. Virtual screening was carried out based on binding energy and hydrogen bonding affinity. Molecular dynamics (MD) and Simulation EGFR were done using GROMACS 5.1.1 software to explore the interaction stability in a cell. RESULTS: The stable conformation for EGFR protein trajectories were captured at various time intervals 0-20ns. Few compounds screen based on high affinity as the inhibitor for EGFR may inhibit the cell cycle signaling in non-small cell lung cancer. CONCLUSION: These result suggested a computer-aided screening approach of Gefitinib derivatives with regard to their binding to EGFR for identifying novel drugs for the treatment of non-small cell lung cancer. PMID- 29493459 TI - Anti-diabetic Phenolic Compounds of Black Carrot (Daucus carota Subspecies sativus var. atrorubens Alef.) Inhibit Enzymes of Glucose Metabolism: An in silico and in vitro Validation. AB - BACKGROUND: Black carrot is known to be effective against Type 2 diabetes. The phenolic compounds present in black carrot are responsible for this property, but limited information was available about the mechanism of action and target enzymes. OBJECTIVE: The present study aims at understanding molecular interactions of phenolic compounds of black carrot with enzymes involved in glucose metabolism in human to identify the potential inhibitor that can be used as candidate drug molecule to control diabetes. METHOD: In vitro assay for inhibition of alpha-amylase, alpha-glucosidase and DPP-IV was carried out using black carrot purified extract and the standard inhibitor acarbose and vildagliptin, recpectively. The inhibition activity of selected phenolic compounds was also studied by in silico docking with all these three enzymes for the proper understanding of interactions. Encapsulation of purified black carrot extract was also carried out. RESULTS: In vitro IC50 value of purified extract was found to be better than the standard inhibitor acarbose for alpha-amylase and alpha-glucosidase, and vildagliptin for DPP-IV. Similarly, docking scores of few anthocyanin molecules were found to be higher than their respective inhibitors, suggesting more effective inhibition. Among anthocyanin molecules of black carrot, cyanidin 3-xylosyl galactoside was found to be the potential drug to inhibit these enzymes, whereas dipeptidyl peptidase IV was identified as the best target to control diabetes with anthocyanins of black carrot. CONCLUSION: Anthocyanins from black carrot were found to be effective to control diabetes and very first time we propose that cyanidin 3-xylosyl galactoside is the best potential molecule for inhibiting enzymes involved in glucose metabolism. The study also shows the encapsulation of anthocyanin compounds using beta cyclodextrin. PMID- 29493462 TI - Minocycline in Alcohol Withdrawal Induced Anxiety and Alcohol Relapse in Rats. AB - INTRODUCTION: Anxiety and negative sensations due to alcohol withdrawal are factors leading to alcohol relapse and addiction. Minocycline, an antibiotic, can decrease alcohol consumption in rats, however, its effects on alcohol withdrawal anxiety and relapse have not been studied. MATERIAL AND METHODS: Part 1: Forced alcohol drinking in gradually increasing concentration was administered till day 22 in rats. Effect of drugs on anxiety was assessed using elevated plus maze (EPM) and two-chambered box apparatus, after removal of alcohol. Part 2: For relapse, an alcohol deprivation effect model was used, rats were continuously offered alcohol and water for 4 consecutive weeks in a two-bottle choice paradigm, followed by 2 weeks of alcohol deprivation. Effect of drugs on alcohol consumption during the first hour of alcohol reintroduction was assessed. Animals were sacrificed and whole brain Tumor Necrosis Factor (TNF) alpha was estimated. RESULTS: Part 1: Anxiety at 3 hours was significantly lower following minocycline (20 mg/kg i.p.) or diazepam compared to vehicle control. Part 2: Acute administration of minocycline (5,10 and 20 mg/kg, i.p.) suppressed alcohol consumption significantly (p value<0.05) as compared to vehicle control. A significant decrease in whole brain TNF alpha was observed in animals treated with minocycline compared to untreated animals. CONCLUSION: Minocycline attenuates alcohol withdrawal anxiety and disrupts alcohol relapse. PMID- 29493463 TI - Determination of Parameters of Oxidative Stress in vitro Models of Neurodegenerative Diseases-A Review. AB - Oxidative stress is a major mechanism underlying the development of various neurodegenerative diseases (Alzheimer, Parkinson, Huntington and amyotrophic lateral sclerosis). Excessive formation of reactive oxygen species (ROS) and nitrogen (RNSs) can overburden the ability of the enzymatic antioxidant defense mechanisms (superoxide dismutase, catalase and glutathione reductase) and non enzymatic (uric acid, ascorbic acid, alpha-tocopherol and reduced glutathione), causing the development of oxidative stress, and consequently, impairing the neuronal system cells by means of oxidative damage to a variety of important biological molecules such as lipids, DNA and proteins. Considering the importance of oxidative stress in neurodegenerative diseases, the present review aims to address the main parameters evaluated in in vitro studies on oxidative stress in different models of neurodegenerative diseases.The literary review was conducted through Pubmed, Science Direct, LILACS, Scielo and Google using following keywords: oxidative stress, neurodegenerative diseases and parameters of oxidative stress. We selected articles published between 2002 and 2017.The in vitro evaluation of the oxidative stress related parameters has provided a preliminary view about the pathogenesis of many neurodegenerative diseases (Alzheimer's, Parkinson's, Huntington's and Amyotrophic lateral sclerosis). In this way, it has demonstrated the mechanism of action of ROS/RNSs in these diseases by direct or indirect detection through several experimental procedures in vitro. PMID- 29493464 TI - AMPA Receptor Antagonist CFM-2 Decreases Survivin Expression in Cancer Cells. AB - BACKGROUND: Glutamate receptors are widely expressed in different types of cancer cells. alpha-Amino-3- hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors are ionotropic glutamate receptors which are coupled to intracellular signaling pathways that influence cancer cell survival, proliferation, and migration. Blockade of AMPA receptors by pharmacologic compounds may potentially constitute an effective tool in anticancer treatment strategies. METHOD: Here we investigated the impact of the AMPA receptor antagonist CFM-2 on the expression of the protein survivin, which is known to promote cancer cell survival and proliferation. We show that CFM-2 inhibits survivin expression at mRNA and protein levels and decreases the viability of cancer cells. Using a stably transfected cell line which overexpresses survivin, we demonstrate that over expression of survivin enhances cancer cell viability and attenuates CFM-2 mediated inhibition of cancer cell growth. RESULT: These findings point towards suppression of survivin expression as a new mechanism contributing to anticancer effects of AMPA antagonists. PMID- 29493465 TI - Riluzole Inhibits Proliferation, Migration and Cell Cycle Progression and Induces Apoptosis in Tumor Cells of Various Origins. AB - BACKGROUND: Regardless of contemporary improvements in cancer treatment, the results of drug treatment are not always efficacious. Thus, the development of novel approaches that affect cancer cell-specific metabolic pathways is needed. Since much evidence has shown that tumor cell proliferation and motility are stimulated by glutamate via activation of its receptors, use of antagonists to these receptors may be the key to control cancer cell progression. Riluzole noncompetitive metabotropic glutamate receptor 1 (mGluR1) antagonist, commonly used to treat patients with amyotrophic lateral sclerosis (ALS), has shown some antineoplastic properties against melanoma, breast and prostate cancer. Yet little is known about its molecular mode of action. AIMS: The current study aims at evaluating the abilities of Riluzole to inhibit proliferation of several cancer cell lines, as well as resolve the mechanism of its action. METHOD: We demonstrated antiproliferative and antimigrative properties of Riluzole in rhabdomyosarcomamedulloblastoma, neuroblastoma, astrocytoma, glioma, colon cancer, lung cancer, thyroid carcinoma, leukemia, erythroleukemia and multiple myeloma. Our studies revealed apoptosis induction and G2-M cell cycle arrest in Riluzole treated A549, C6 and HT-29 cells. RESULT: At the molecular level, we found that these cells treated with Riluzole had a decrease of Cyclin B and an increase of p21 Waf1/Cip1 and p53 expression. We also observed an enhancement of CDK1 and Chk2 phosphorylation. Reported changes may suggest the involvement of these proteins in G2-M arrest, observed in flow cytometry analysis. These data indicated the potential use of Riluzole in the treatment of different types of cancers. PMID- 29493466 TI - PLK1 inhibition radiosensitizes breast cancer cells, but shows low efficacy as monotherapy or in combination with other cytotoxic drugs. AB - : Over the last decade, the inhibition of PLK1 has proven potent antiproliferative activity in vitro. However, the effectiveness of most synthetic targeted drugs has not translated into clinics. Herein, we investigated the in vitro effects of two second-generation PLK1 inhibitors BI 6727 and GSK461364 in breast cancer cell lines as monotherapy or in combination with other drugs or ionizing radiation. MATERIAL AND METHODS: Cell survival was analyzed through XTT(r), clonogenicity and caspase-3 activation assays were also studied, and drug interactions analyzed through a nonlinear regression of a sigmoid dose response model. Sensibilization to radiation was assessed through enhancement ratio calculation. RESULTS: Mild effects on the viability of both cell lines tested (MCF-7 and Hs578T) were observed irrespective of the PLK1 inhibitor used. Alternatively, abrogation of PLK1 significantly reduced clonogenicity while effectively sensitized cells to ionizing radiation. Drug interactions showed dissimilar results with antagonistic effects with any drug combination in MCF-7 and clear synergic interactions between both PLK1 inhibitors and cisplatin, temozolomide or doxorubicin in Hs578T, which is TP53 mutated. CONCLUSION: Targeting kinases involved in mitotic checkpoints are expected to prevent mitotic exit and enhance chemosensitization. Nonetheless, despite overexpressing PLK1, in our model, expressive results after its inhibition were only seen through clonogenic assays or when BI 6727 and GSK461364 were combined with ionizing radiation. Disparate responses of cell lines to drug combinations, might denote a partial reflection of the substantial differences in the vast spectrum of genetic, biological and epigenetic burden observed in breast cancer. In the near future, individual genomic/proteomic profiling will allow its further classification and will consent the initiation of novel strategies for therapy. Even though the future impact of PLK1-tailored treatment still needs validation, much more pre-clinical and clinical research for this kinase is warranted. PMID- 29493467 TI - Chemical Composition and Antioxidant Potential of Essential Oil and Organic Extracts of Euphorbia tithymaloides L. from Kushtia Region. AB - In traditional system of medicine, leaves and stem bark of Euphorbia tithymaloides L. have been used for the treatment of asthma, persistent coughing, laryngitis, skin diseases and mouth ulcers. Some studies have reported the anti inflammatory and antimicrobial activities of phytochemicals from leaf; however, the analysis of essential oil and its antioxidant property is still unexplored. This study evaluates the in vitro antioxidant potential of the essential oil and organic extracts from aerial parts of Euphorbia tithymaloides L. Thirty one compounds representing 96.37% of total oil were detected by GC-MS, of which eugenol (22.52%), phenyl ethyl alcohol (14.63%), 3-pentanol (9.22%), caryophyllene oxide (7.73%), isoeugenol (7.32%), pentadecanol (5.14%), spathulenol (5.11%) and alpha-pinene (3.32%) were the major compounds. The oil and ethyl acetate extract displayed potent DPPH (IC50 = 13.67 and 17.59 MUg/mL, respectively) and superoxide (IC50 = 21.83 and 42.34 MUg/mL, respectively) radical-scavenging activities among all the tested samples. The oil and methanol extract also exhibited remarkable nitric oxide radical-scavenging activities (IC50 = 90.45 and 112.63 MUg/mL, respectively) among other extracts. Furthermore, the methanol extract contained the highest amount of total phenolics as compared to other samples. The results demonstrate that the oil and extracts of E. tithymaloides could serve as natural antioxidants for using in pharmaceutical or cosmetic industries. PMID- 29493468 TI - Evaluation of the QuantiFERON(r)-TB Gold In-Tube assay and tuberculin skin test for the diagnosis of latent tuberculosis infection in an Iranian referral hospital. AB - Mycobacterium tuberculosis remains as a vital threat to global health and its diagnosis is still complicated. Since there is no gold standard for the diagnosis of latent tuberculosis infection (LTBI), its diagnosis routinely relies on measurement of host immune responses to M. tuberculosis antigens using the tuberculin skin test (TST) and Interferon-Y release assays (IGRAs). The aim of this study was to evaluate LTBI among hospitalized children and their patents/guardians as general populations in Children Medical Center, an Iranian referral hospital. During this cross-sectional study, 81 patients hospitalized in CMC and 102 patents/guardians (as general population) were included. A total of 57 patients (70.4%) had performed a TST and were interpreted during the study. Among them, 32 (56%) had a positive test result when a cutoff of 10 mm induration. There were fewer positive IGRA test results than positive TST results (33% versus 56%) in children. Among patents/guardians, TST and IGRA were positive in 41% and 40% respectively. The agreement between the IGRA test and the TST among them was 0.7, while this was as slightly lower in children (0.63). The results of our study indicate that the IGRA test has a higher specificity than TST, especially in children, while the frequency of positive results with both tests in adults was similar. Considering the false positive results reported with the TST, replacement of the IGRA test with TST in children is recommended. PMID- 29493469 TI - [Spinal cord injury after a fall in patients with cervical spinal canal stenosis]. AB - In patients with pre-existent cervical spinal canal stenosis, minimal trauma, leading to neck hyperextension, can cause a significant increase of spinal cord compression. However, spinal cord injury is generally associated with major trauma and is usually not expected in patients with minor trauma. The resulting symptoms are diverse, making it even more difficult to diagnose. To illustrate the variety in symptoms at presentation, we describe two male patients aged 66 and 69. Rapid diagnosis is important as acute neurosurgical intervention may be indicated. Physical neurological examination, and in particular testing peripheral reflexes, can contribute to the rapid diagnosis of spinal cord injury. Cervical spine CT should not only be assessed for acute traumatic injury, but also for possible stenosis of the cervical spinal canal. PMID- 29493470 TI - [Transplantation of islets of Langerhans: procedure, indications and challenges]. AB - Pancreatic islet isolation and transplantation are complicated procedures, indicated for a carefully selected group of patients. After isolation from the pancreas, the islets are infused into the portal vein. Allogeneic islet transplantation is performed in patients with diabetes mellitus, who suffer from severe hypoglycaemic events and/or progressive complications. One or more donor pancreases are used, which necessitates immunosuppressive treatment. In autologous islet transplantation, which is performed in patients in whom the pancreas has to be removed due to a non-malignant disease, the patients' own islets are isolated and reinfused. No immunosuppressive treatment is required. Reconstitution of endogenous insulin production in allogeneic islet transplantation leads to marked improvements in glycaemic regulation, protection against severe hypoglycaemic episodes and fewer diabetes-related complications. Autologous islet transplantation allows for preservation of endogenous insulin production, which prevents (unstable) diabetes from occurring. This article describes the indications, procedure and pitfalls of islet isolation and transplantation, including three representative cases. PMID- 29493471 TI - [Hodgkin and the classification of malignant lymphomas: how the British physician also became associated with later discovered lymphomas]. AB - Thomas Hodgkin was the first to describe a malignant lymphoma, which would later carry his name. Over the course of time, other lymphoid malignancies were recognised that showed no similarity with Hodgkin's disease. They were subsequently named after the - at that time - applicable morphological nomenclature of the associated cells. Later, nomenclature also took immunological features into consideration. However, we still describe the group of lymphomas recognised after Hodgkin's discovery as 'not being Hodgkin's disease', i.e. non Hodgkin lymphoma. We feel it is unjust that not many people know about the man behind this prominent disease. In this article, an historic overview is given of Thomas Hodgkin, 'his' lymphoma and the other malignant lymphomas. PMID- 29493472 TI - [Who does my leg belong to after amputation?; informed consent on amputation of body parts]. AB - In the Netherlands, when body parts are amputated as part of a medical procedure the patient's consent is required if this body part is used for, or subjected to, medical tests. The patient's consent is, however, rarely obtained, when body parts are discarded as 'pathological waste'. This can raise concerns, as patients have good reasons and distinct rights to demand a different fate, such as a burial or cremation, for their amputated limb. This article analyses the legal status of an amputated body part. We conclude that, legally, the amputated part does not belong to the hospital or doctor and can therefore not be disposed of at whim, in accordance with the hospital's wishes. Doctors have an obligation to actively inform their patients of their property rights over the amputated limbs and of the alternatives to disposal that are available. Doctors might find themselves exposed to tortuous liability procedures if they dispose of amputated body parts without proper consent. PMID- 29493473 TI - [Severe vaginal discharge following rectal surgery]. AB - BACKGROUND: Almost 50% of women who have had rectal surgery subsequently develop vaginal discharge. Due to the recurrent and unexpected nature of this heavy discharge, they often experience it as very distressing. Many of these women undergo extensive diagnostic tests that are mainly focused on identifying fistula formation. If no fistula is found, in most cases no other cause for severe vaginal discharge can be demonstrated. CASE DESCRIPTION: In our practice, we saw three patients (49-, 54- and 74-years-old, respectively) with similar severe vaginal discharge after rectal surgery and in whom no explanation for the vaginal discharge could be found. For this reason we conducted a literature search into this condition. CONCLUSION: Anatomical changes appear to be responsible for heavy vaginal discharge following rectal surgery. Changes in pelvic floor muscles and compression of the distal part of the vagina may lead to pooling of fluid in the proximal part of the vagina, resulting in severe discharge. Symptomatic treatment may reduce the symptoms. PMID- 29493474 TI - Physical activity-equivalent label reduces consumption of discretionary snack foods. AB - OBJECTIVE: The present research aimed to investigate the impact of the physical activity calorie equivalent (PACE) front-of-pack label on consumption, prospective consumption and liking of familiar and unfamiliar discretionary snack foods. DESIGN: In a within-subject randomised design, participants tasted and rated liking (9-point hedonic scale) and prospective consumption (9-point category scale) of four different snack foods with four different labels (i.e. blank, fake, PACE, PACE doubled) and four control snack foods. The twenty snack foods were presented during two 45 min sessions (i.e. ten snack foods per session) which were separated by one week. The amount participants sampled of each snack food was measured. SETTING: The study was conducted in the Centre for Advanced Sensory Sciences laboratory at Deakin University, Australia. SUBJECTS: The participants were 153 university students (126 females, twenty-seven males, mean age 24.3 (sd 4.9) years) currently enrolled in an undergraduate nutrition degree at Deakin University. RESULTS: When the PACE label was present on familiar snack foods, participants sampled 9.9 % (22.8 (sem 1.4) v. 25.3 (sem 1.5) g, P=0.03) less than when such label was not present. This was in line with a decreased prospective snack food consumption of 9.1 % (3.0 (sem 0.2) v. 3.3 (sem 0.2) servings, P=0.03). Such pattern was not seen in unfamiliar snacks. CONCLUSIONS: The PACE label appears to be a promising way to decrease familiar discretionary snack food consumption in young, health-minded participants. PMID- 29493475 TI - Differential Effects of Chlorhexidine Skin Cleansing Methods on Residual Chlorhexidine Skin Concentrations and Bacterial Recovery. AB - BACKGROUND Bathing intensive care unit (ICU) patients with 2% chlorhexidine gluconate (CHG)-impregnated cloths decreases the risk of healthcare-associated bacteremia and multidrug-resistant organism transmission. Hospitals employ different methods of CHG bathing, and few studies have evaluated whether those methods yield comparable results. OBJECTIVE To determine whether 3 different CHG skin cleansing methods yield similar residual CHG concentrations and bacterial densities on skin. DESIGN Prospective, randomized 2-center study with blinded assessment. PARTICIPANTS AND SETTING Healthcare personnel in surgical ICUs at 2 tertiary-care teaching hospitals in Chicago, Illinois, and Boston, Massachusetts, from July 2015 to January 2016. INTERVENTION Cleansing skin of one forearm with no-rinse 2% CHG-impregnated polyester cloth (method A) versus 4% CHG liquid cleansing with rinsing on the contralateral arm, applied with either non antiseptic-impregnated cellulose/polyester cloth (method B) or cotton washcloth dampened with sterile water (method C). RESULTS In total, 63 participants (126 forearms) received method A on 1 forearm (n=63). On the contralateral forearm, 33 participants received method B and 30 participants received method C. Immediately and 6 hours after cleansing, method A yielded the highest residual CHG concentrations (2500 ug/mL and 1250 ug/mL, respectively) and lowest bacterial densities compared to methods B or C (P<.001). CONCLUSION In healthy volunteers, cleansing with 2% CHG-impregnated cloths yielded higher residual CHG concentrations and lower bacterial densities than cleansing with 4% CHG liquid applied with either of 2 different cloth types and followed by rinsing. The relevance of these differences to clinical outcomes remains to be determined. Infect Control Hosp Epidemiol 2018;39:405-411. PMID- 29493476 TI - Traffic-light labels and financial incentives to reduce sugar-sweetened beverage purchases by low-income Latino families: a randomized controlled trial. AB - OBJECTIVE: The objective of the present study was to test the effectiveness of financial incentives and traffic-light labels to reduce purchases of sugar sweetened beverages in a community supermarket. DESIGN: In this randomized controlled trial, after a 2-month baseline period (February-March 2014), in-store traffic-light labels were posted to indicate healthy (green), less healthy (yellow) or unhealthy (red) beverages. During the subsequent five months (April August 2014), participants in the intervention arm were eligible to earn a $US 25 in-store gift card each month they refrained from purchasing red-labelled beverages. SETTING: Urban supermarket in Chelsea, MA, USA, a low-income Latino community. SUBJECTS: Participants were customers of this supermarket who had at least one child living at home. A total of 148 customers (n 77 in the intervention group and n 71 in the control group) were included in the final analyses. RESULTS: Outcomes were monthly in-store purchases tracked using a store loyalty card and self-reported consumption of red-labelled beverages. Compared with control participants, the proportion of intervention participants who purchased any red-labelled beverages decreased by 9 % more per month (P=0.002). More intervention than control participants reduced their consumption of red labelled beverages (-23 % v. -2 % for consuming >=1 red beverage/week, P=0.01). CONCLUSIONS: Overall, financial incentives paired with in-store traffic-light labels modestly reduced purchase and consumption of sugar-sweetened beverages by customers of a community supermarket. PMID- 29493477 TI - Legionnaires' Disease and Use of Water Dispensers With an Ultraviolet Sterilizer. PMID- 29493478 TI - Deep brain stimulation of the supero-lateral branch of the medial forebrain bundle does not lead to changes in personality in patients suffering from severe depression. AB - BACKGROUND: Reports of changes in patients' social behavior during deep brain stimulation (DBS) raised the question whether DBS induces changes in personality. This study explored if (1) DBS is associated with changes in personality in patients suffering from treatment-resistant depression (TRD), (2) how personality dimensions and depression are associated, and (3) if TRD patients' self-ratings of personality are valid. METHODS: TRD patients were assessed before DBS (n = 30), 6 months (t2, n = 21), 2 (t3, n = 17) and 5 years (t4, n = 11) after the initiation of DBS of the supero-lateral branch of the medial forebrain bundle (slMFB-DBS). Personality was measured with the NEO-Five-Factor Inventory (NEO FFI), depression severity with Hamilton (HDRS), and Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: Personality dimensions did not change with slMFB DBS compared with baseline. Extraversion was negatively correlated with HDRS28 (r = -0.48, p < 0.05) and MADRS (r = -0.45, p < 0.05) at t2. Inter-rater reliability was high for the NEO-FFI at baseline (Cronbach's alpha = 0.74) and at t4 (alpha = 0.65). Extraversion [t(29) = -5.20; p < 0.001] and openness to experience [t(29) = -6.96; p < 0.001] differed statistically significant from the normative sample, and did not predict the antidepressant response. CONCLUSIONS: slMFB-DBS was not associated with a change in personality. The severity of depression was associated with extraversion. Personality of TRD patients differed from the healthy population and did not change with response, indicating a possible scar effect. Self-ratings of personality seem valid to assess personality during TRD. PMID- 29493479 TI - Francis Fontan: an appreciation. PMID- 29493480 TI - Adolescent perspectives of the recreational ice hockey food environment and influences on eating behaviour revealed through photovoice. AB - OBJECTIVE: Unhealthy dietary behaviours are prevalent among adolescents. This might relate, in part, to obesogenic environments, including recreation food facilities. The REFRESH Study (Recreation Environment and Food Research: Experiences from Hockey) aimed to explore, from the perspectives of adolescent ice hockey players and parents, broad social and physical environmental influences on adolescent food behaviours associated with hockey participation. DESIGN: Players used photovoice to describe their food experiences in relation to ice hockey. The approach included photos, individual interviews and focus groups. Exemplar photographs were exhibited for stakeholders, including five parents who were interviewed. Interview and focus group transcripts were thematically analysed. SETTING: Recreational ice hockey environment, Ontario, Canada, 2015-16. SUBJECTS: Ice hockey players (n 24) aged 11-15 years recruited from five leagues. RESULTS: Dominant influences among players included: their perceived importance of nutrients (e.g. protein) or foods (e.g. chocolate milk) for performance and recovery; marketing and branding (e.g. the pro-hockey aura of Tim Horton's(r), Canada's largest quick-service restaurant); social aspects of tournaments and team meals; and moral values around 'right' and 'wrong' food choices. Both players and parents perceived recreational facility food options as unhealthy and identified that travel and time constraints contributed to less healthy choices. CONCLUSIONS: Results indicate recreation facilities are only one of a range of environments that influence eating behaviours of adolescent ice hockey players. Players' susceptibility to advertising/brand promotion and the value of healthy food choices for performance are findings that can inform policy and interventions to support healthy environments and behaviours. PMID- 29493481 TI - Empiric Antibiotic Prescribing Decisions Among Medical Residents: The Role of the Antibiogram. AB - OBJECTIVETo assess general medical residents' familiarity with antibiograms using a self-administered surveyDESIGNCross-sectional, single-center surveyPARTICIPANTSResidents in internal medicine, family medicine, and pediatrics at an academic medical centerMETHODSParticipants were administered an anonymous survey at our institution during regularly scheduled educational conferences between January and May 2012. Questions collected data regarding demographics, professional training; further open-ended questions assessed knowledge and use of antibiograms regarding possible pathogens, antibiotic regimens, and prescribing resources for 2 clinical vignettes; a series of directed, closed-ended questions followed. Bivariate analyses to compare responses between residency programs were performed.RESULTSOf 122 surveys distributed, 106 residents (87%) responded; internal medicine residents accounted for 69% of responses. More than 20% of residents could not accurately identify pathogens to target with empiric therapy or select therapy with an appropriate spectrum of activity in response to the clinical vignettes; correct identification of potential pathogens was not associated with selecting appropriate therapy. Only 12% of respondents identified antibiograms as a resource when prescribing empiric antibiotic therapy for scenarios in the vignettes, with most selecting the UpToDate online clinical decision support resource or The Sanford Guide. When directly questioned, 89% reported awareness of institutional antibiograms, but only 70% felt comfortable using them and only 44% knew how to access them.CONCLUSIONSWhen selecting empiric antibiotics, many residents are not comfortable using antibiograms as part of treatment decisions. Efforts to improve antibiotic use may benefit from residents being given additional education on both infectious diseases pharmacotherapy and antibiogram utilization.Infect Control Hosp Epidemiol 2018;39:578-583. PMID- 29493482 TI - Neighbourhood food environments: food choice, foodscapes and planning for health. AB - The burden of obesity contributes to increasing health inequality, and placing healthcare systems under huge strain. The modern society could broadly be described to support unhealthful eating patterns and sedentary behaviour; also described as obesogenic. Obesity prevention and treatment has focused on educational and behavioural interventions, with limited overall success. A sustainable approach is to address the environments that promote less healthy eating and high energy intake as well as sedentary behaviour. Approaches which modify the environment have the potential to assist in the prevention of this complex condition. The present paper focuses on food environments within the context of obesogenic environments. Takeaway and fast food, a fixture of our diet, is usually nutrient poor and energy dense. A 'concentration effect' has been observed, where there is a clustering of fast food and takeaway outlets in more deprived areas. Access to food and intake are associated; however, there are methodological challenges in associating the effect of the food environment on obesity. While there is an imperfect evidence base relating to the role of the food environment in terms of the obesity crisis; policy, practice, civic society and industry must work together and take action now, where current evidence suggests a change. Shaping the environment to better support healthful eating decisions has the potential to be a key aspect of a successful obesity prevention intervention. PMID- 29493484 TI - The effect of concomitant use of systemic antibiotics in patients with Clostridium difficile infection receiving metronidazole therapy. AB - Management of Clostridium difficile infection (CDI) involves discontinuation of the offending antibiotic agent as soon as possible. However, the ongoing infection does not allow discontinuation of the offending antibiotic. We aimed to retrospectively investigate the predictors of treatment failure and impact of the concomitant use of systemic antibiotics in patients receiving metronidazole therapy. This study was conducted among patients hospitalised at a second care academic hospital from January 2013 to December 2014. Eligible patients were identified by reviewing stool toxin enzyme immunoassay results for C. difficile. Diarrhoea was defined as the passage of at least three loose or watery stools within 24 h. Among 314 patients with CDI receiving metronidazole therapy, 62 (19.7%) showed treatment failure and 105 (33.4%) received concomitant antibiotics. Underlying dialysis, fever >38.3 degrees C, low median serum albumin levels and concomitant use of antibiotics were independent predictors of treatment failure in patients with CDI receiving metronidazole therapy. The concomitant use of antibiotics increased the rates of treatment failure and 30 day mortality in patients receiving metronidazole therapy. These results suggest that metronidazole should be used in mild cases of CDI only after discontinuation of the offending antibiotics. PMID- 29493485 TI - Notification that new names of prokaryotes, new combinations, and new taxonomic opinions have appeared in volume 67, part 12, of the IJSEM. PMID- 29493486 TI - List of new names and new combinations previously effectively, but not validly, published. PMID- 29493483 TI - Parsing profiles of temperamental reactivity and differential routes to delay of gratification: A person-based approach. AB - Informed by a developmental psychopathology perspective, the present study applied a person-based approach to examine whether associations between early sociocontextual experiences (e.g., socioeconomic factors and maternal discipline practices) and preschool-age children's delay of gratification vary across profiles of children's temperamental reactivity. In addition, the study examined the direct and mediating role of children's set shifting in associations with delay of gratification within each profile. The sample consisted of 160 socioeconomically and ethnically diverse mothers and their 5-year-old children drawn from a longitudinal study of mother-child relationships. Latent profile analyses identified three profiles of temperamental reactivity distinguished by sensitivity to reward and punishment and negative affectivity. Multigroup analysis revealed maternal sensitive discipline (observed during a parent-child compliance task) at age 3.5 predicted longer delay of gratification at age 5 in the punishment reactivity/negative affectivity group. Maternal inductive reasoning discipline at age 3.5 predicted longer delay in the low temperamental reactivity group. For children with the reward reactivity/negative affectivity profile, higher family income at age 3.5 predicted longer delay of gratification at age 5, which was mediated by children's set shifting. Findings underscore the utility of person-based approaches for delineating differential developmental routes toward children's delay of gratification. PMID- 29493487 TI - Corrigendum: Floricoccus tropicus gen. nov., sp. nov. and Floricoccus penangensis sp. nov. isolated from fresh flowers of durian tree and hibiscus. PMID- 29493488 TI - Corrigendum: Clotrimazole is highly effective in vitro against feline Sporothrix brasiliensis isolates. PMID- 29493489 TI - Three novel proteins co-localise with polyhydroxybutyrate (PHB) granules in Rhodospirillum rubrum S1. AB - Polyhydroxybutyrate (PHB), a biodegradable polymer accumulated by bacteria is deposited intracellularly in the form of inclusion bodies often called granules. The granules are supramolecular complexes harbouring a varied number of proteins on their surface, which have specific but incompletely characterised functions. By comparison with other organisms that produce biodegradable polymers, only two phasins have been described to date for Rhodosprillum rubrum, raising the possibility that more await discovery. Using a comparative proteomics strategy to compare the granules of wild-type R. rubrum with a PHB-negative mutant housing artificial PHB granules, we identified four potential PHB granules' associated proteins. These were: Q2RSI4, an uncharacterised protein; Q2RWU9, annotated as an extracellular solute-binding protein; Q2RQL4, annotated as basic membrane lipoprotein; and Q2RQ51, annotated as glucose-6-phosphate isomerase. In silico analysis revealed that Q2RSI4 harbours a Phasin_2 family domain and shares low identity with a single-strand DNA-binding protein from Sphaerochaeta coccoides. Fluorescence microscopy found that three proteins Q2RSI4, Q2EWU9 and Q2RQL4 co localised with PHB granules. This work adds three potential new granule associated proteins to the repertoire of factors involved in bacterial storage granule formation, and confirms that proteomics screens are an effective strategy for discovery of novel granule associated proteins. PMID- 29493490 TI - Corrigendum: Reclassification of Thiomicrospira hydrogeniphila (Watsuji et al. 2016) to Thiomicrorhabdus hydrogenophila comb. nov., with emended description of Thiomicrorhabdus (Boden et al., 2017). PMID- 29493491 TI - Disruption of the GDP-mannose synthesis pathway in Streptomyces coelicolor results in antibiotic hyper-susceptible phenotypes. AB - Actinomycete bacteria use polyprenol phosphate mannose as a lipid linked sugar donor for extra-cytoplasmic glycosyl transferases that transfer mannose to cell envelope polymers, including glycoproteins and glycolipids. We showed recently that strains of Streptomyces coelicolor with mutations in the gene ppm1 encoding polyprenol phosphate mannose synthase were both resistant to phage phiC31 and have greatly increased susceptibility to antibiotics that mostly act on cell wall biogenesis. Here we show that mutations in the genes encoding enzymes that act upstream of Ppm1 in the polyprenol phosphate mannose synthesis pathway can also confer phage resistance and antibiotic hyper-susceptibility. GDP-mannose is a substrate for Ppm1 and is synthesised by GDP-mannose pyrophosphorylase (GMP; ManC) which uses GTP and mannose-1-phosphate as substrates. Phosphomannomutase (PMM; ManB) converts mannose-6-phosphate to mannose-1-phosphate. S. coelicolor strains with knocked down GMP activity or with a mutation in sco3028 encoding PMM acquire phenotypes that resemble those of the ppm1- mutants i.e. phiC31 resistant and susceptible to antibiotics. Differences in the phenotypes of the strains were observed, however. While the ppm1- strains have a small colony phenotype, the sco3028 :: Tn5062 mutants had an extremely small colony phenotype indicative of an even greater growth defect. Moreover we were unable to generate a strain in which GMP activity encoded by sco3039 and sco4238 is completely knocked out, indicating that GMP is also an important enzyme for growth. Possibly GDP-mannose is at a metabolic branch point that supplies alternative nucleotide sugar donors. PMID- 29493492 TI - Corrigendum: ICTV Virus Taxonomy Profile: Chrysoviridae. PMID- 29493493 TI - An I436N substitution confers resistance of influenza A(H1N1)pdm09 viruses to multiple neuraminidase inhibitors without affecting viral fitness. AB - The resistance of influenza viruses to neuraminidase (NA) inhibitors (NAIs; i.e. oseltamivir, zanamivir, peramivir and laninamivir) can be associated with several NA substitutions, with differing effects on viral fitness. To identify novel molecular markers conferring multi-NAI resistance, the NA gene of oseltamivir resistant (H275Y, N1 numbering) 2009 pandemic influenza [A(H1N1)pdm09] virus was enriched with random mutations. This randomly mutated viral library was propagated in Madin-Darby canine kidney (MDCK) cells under zanamivir pressure and gave rise to additional changes within NA, including an I436N substitution located outside the NA enzyme active site. We generated four recombinant A(H1N1)pdm09 viruses containing either wild-type NA or NA with single (I436N or H275Y) or double (H275Y-I436N) substitutions. The double H275Y-I436N mutation significantly reduced inhibition by oseltamivir and peramivir and reduced inhibition by zanamivir and laninamivir. I436N alone reduced inhibition by all NAIs, suggesting that it is a multi-NAI resistance marker. I436N did not affect viral fitness in vitro or in a murine model; however, H275Y and I436N together had a negative impact on viral fitness. Further, I436N alone did not have an appreciable impact on viral replication in the upper respiratory tract or transmissibility in ferrets. However, the rg-H275Y-I436N double mutant transmitted less efficiently than either single mutant via the direct contact and respiratory droplet routes in ferrets. Overall, these results highlight the usefulness of a random mutagenesis approach for identifying potential molecular markers of resistance and the importance of I436N NA substitution in A(H1N1)pdm09 virus as a marker for multi-NAI resistance. PMID- 29493494 TI - A novel mutation in the neuraminidase gene of the 2009 pandemic H1N1 influenza A virus confers multidrug resistance. PMID- 29493495 TI - Triggering the stringent response: signals responsible for activating (p)ppGpp synthesis in bacteria. AB - The stringent response is a conserved bacterial stress response mechanism that allows bacteria to respond to nutritional challenges. It is mediated by the alarmones pppGpp and ppGpp, nucleotides that are synthesized and hydrolyzed by members of the RSH superfamily. Whilst there are key differences in the binding targets for (p)ppGpp between Gram-negative and Gram-positive bacterial species, the transient accumulation of (p)ppGpp caused by nutritional stresses results in a global change in gene expression in all species. The RSH superfamily of enzymes is ubiquitous throughout the bacterial kingdom, and can be split into three main groups: the long-RSH enzymes; the small alarmone synthetases (SAS); and the small alarmone hydrolases (SAH). Despite the prevalence of these enzymes, there are important differences in the way in which they are regulated on a transcriptional and post-translational level. Here we provide an overview of the diverse regulatory mechanisms that are involved in governing this crucial signalling network. Understanding how the RSH superfamily members are regulated gives insights into the varied important biological roles for this signalling pathway across the bacteria. PMID- 29493496 TI - Release of nitric oxide by the Escherichia coli YtfE (RIC) protein and its reduction by the hybrid cluster protein in an integrated pathway to minimize cytoplasmic nitrosative stress. AB - Synthesis of the Escherichia coli YtfE protein, also known as RIC, for the repair of damaged iron centres, is highly induced during anaerobic growth under conditions of nitrosative stress. How YtfE repairs nitrosative damage remains unclear. Contrary to previous reports, we show that strains defective in YtfE that lack the high-affinity NO reductase activity of the hybrid cluster protein (Hcp) are less sensitive to nitrosative stress than isogenic ytfE+ strains, which are extremely sensitive. Evidence that this sensitivity is due to YtfE-dependent release of NO into the cytoplasm includes: relief of growth inhibition by PTIO (2 phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide), which degrades NO; relief of nitrosative stress by deletion of narG encoding the nitrate reductase that is the major source of NO from nitrite; partial suppression of nitrosative stress due to loss of Hcp function by a further mutation in ytfE; YtfE-dependent loss of aconitase and fumarase activities in the absence of Hcp; and YtfE-dependent relief of NsrR repression of the hcp promoter in response to cytoplasmic NO. We suggest that a major role for YtfE is to reverse nitrosative damage by releasing, directly or indirectly, NO from nitrosylated proteins into the cytoplasm where the high-affinity NO reductase activity of Hcp ensures its reduction to N2O. If so, the concerted action of YtfE and Hcp would not only maintain the cytoplasmic concentration of NO in the low nM range, but also provide a rationalization for the coordinate regulation of Hcp and YtfE synthesis by NsrR. PMID- 29493497 TI - ? PMID- 29493498 TI - ? PMID- 29493499 TI - [Penis arcuatus]. AB - Deviation of the penis may be congenital or acquired. The latter, also known as Peyronie's disease, is seen in 0.4-9% of patients. The aetiology is not fully understood, but the hypothesis is that microtrauma leads to scar tissue formation, plaques, which deform the penis. The disease is divided into a first, painful, progressive, inflammatory phase and a latter, steady, chronic phase. The symptoms are mainly sexual dysfunction and psychological problems. Surgery is recommended in congenital cases and in the chronic phase of Peyronie's disease, where the medical treatment has not been convincing. PMID- 29493500 TI - [The choice of diagnostic modality for acute pulmonary embolism]. AB - The diagnosis of pulmonary embolism (PE) relies on clinical assessment, D-dimer test and diagnostic imaging. Modern CT pulmonary angiography (CTPA), ventilation/perfusion single-photon emission computed tomography (SPECT) and SPECT/CT are rather equal in terms of sensitivity, specificity and inconclusive results for the diagnosis of PE, outper-forming planar lung scintigraphy. Furthermore, SPECT/CT and CTPA can both provide important information regarding differential diagnoses. Thus, the choice of primary diag-nostic modality relies on local expertise, availability and special circumstances like radiation dose, contraindications and the clinical urgency. PMID- 29493501 TI - [Surgical stabilization of multiple rib fractures can shorten inpatient stay]. AB - Flail chest is a common complication in patients with blunt chest wall traumas resulting in high mortality rates. In this case report a 43-year-old woman was stepped on by a horse, thereby receiving multiple rib fractures and pneumohaemothorax. She was not able to wean from epidural analgesia after ten days and maintained a "thoracic floating feeling". In opposition to the non operative management previously preferred, a surgical stabilization was then performed in the patient, who was discharged only five days later. Thus, surgical fixation of multiple rib fractures may reduce inpatient stay. PMID- 29493502 TI - [Hypochondrical paranoia]. AB - This is a case report of hypochondrical paranoia in a young man, who was convinced of a toxic infection by fungi following mold growth exposure. The patient was admitted to a psychiatric facility, severely pained by the delusional perception of his insides being eaten by fungus. He had undergone a thorough medical examination without the discovery of any somatic irregularities and had attempted to treat himself several times. After four months of hospital-ization and the prescription of antipsychotic treatment, he was in recovery. Mild delusions persisted but were no longer pathologically painful. PMID- 29493503 TI - [Complex interventions in medical research]. AB - Complex interventions consist of multiple components, which interact to create intervention effects. Thus, special attention is required concerning the development, the pilot testing, the evaluation and the scientific reporting. Inadequate recognition of the complexity of these interventions by clinicians and researchers may unintentionally prevent implementation of the results of complex interventions. We present a framework, which highlights aspects of the development, the modelling and the analysis of complex interventions, so that clinicians and researchers can untangle "the black box" of these clinical trials. PMID- 29493504 TI - [Talus fracture in a young woman with a dislocated ankle]. AB - Talus fractures are rare but often associated with complications and significant post-traumatic patient morbidity. They frequently occur at high-energy traumas such as traffic accidents. This is a case report of a young woman who after a fall from a roof, presented in an emergency department with a dislocated ankle which was initially misdiagnosed as a bimalleolar fracture and attempted repositioned as such before X-ray. Dislocated talus fractures, however, need urgent anatomic reduction after diagnostic imaging and often subsequent and acute osteosynthesis. PMID- 29493505 TI - Renovascular disease: Is there still a role for revascularization??. AB - There are substantial doubts pertaining to the clinical usefulness of radiological and surgical interventions in the management of renovascular disease, particularly in patients with diffuse atherosclerotic vascular disease. This article reviews the current knowledge on advantages and limitations of interventional techniques in the management of patients with atherosclerotic renovascular disease.?. PMID- 29493506 TI - In sight, in mind. AB - A region of the brain called the perirhinal cortex represents both what things look like and what they mean. PMID- 29493507 TI - A new role for a tumor-suppressing protein. AB - In addition to its role in preventing tumors, the protein p53 appears to participate in a DNA repair process known as the replication-stress response. PMID- 29493508 TI - Exploring the social brain. AB - How does the brain physiology of young children with autism differ from that of typically-developing children? PMID- 29493510 TI - Short-Term Outcome After Left Main Interventions in Patients Presenting With Acute Coronary Syndrome. AB - OBJECTIVE: To assess the efficacy and safety of coronary left main (LM) disease interventions in patients with acute coronary syndromes (ACS) as compared to those without LM coronary artery disease. METHODS: A total of 2899 patients with ACS, enrolled in the prospective Swiss Program University Medicine ACS (SPUM-ACS) cohort, were included. The primary endpoints of independently adjudicated major adverse cardiovascular and cerebrovascular event (MACCE) and net adverse clinical event (NACE) were determined at 30-day follow-up. RESULTS: Seventy-one (2.0%) of the 2899 ACS patients had significant LM disease. At 30-day follow-up, the primary outcomes of MACCE and NACE occurred in 140 patients (4.8%) and 272 patients (9.4%), respectively. Compared to those without LM disease, patients in the LM group were significantly older (P<.001), had a higher incidence of hypertension (P<.001) and diabetes (P=.013), and more often had a history of coronary artery bypass graft (CABG) surgery (P<.001). Analyses on non-matched populations showed a nearly significant trend toward a higher incidence of MACCE (P=.06) and NACE (P=.10) in patients with LM disease compared to those without LM disease. This trend, however, disappeared after matching the populations for all significant confounding variables on a 3:1 basis. This subanalysis showed MACCE rates of 10.0% in the LM group and 7.3% in the non-LM group (P=.61). Notably, the matched patients with LM disease treated with percutaneous coronary intervention had a lower NACE incidence when compared to those undergoing urgent CABG surgery (P<.01). CONCLUSIONS: In ACS patients with LM disease, revascularization with PCI is feasible and safe, with short-term outcomes comparable to ACS patients without significant LM disease. PMID- 29493509 TI - Mechanical Circulatory Support in Chronic Total Occlusion Percutaneous Coronary Intervention: Insights From a Multicenter U.S. Registry. AB - OBJECTIVE: To study outcomes with use of percutaneous mechanical circulatory support (MCS) devices in chronic total occlusion (CTO) percutaneous coronary intervention (PCI). METHODS: We examined characteristics and outcomes of 1598 CTO PCIs performed from 2012-2017 at 12 high-volume centers. RESULTS: Patient age was 66 +/- 10 years; 86% were men. An MCS device was used electively in 69 procedures (4%) and urgently in 22 procedures (1%). The most commonly used elective MCS device was Impella 2.5 or CP (62%). Compared to patients without elective MCS, patients with elective MCS had higher prevalence of prior heart failure (55% vs 29%; P<.001), prior coronary artery bypass graft surgery (49% vs 35%; P=.02), and lower left ventricular ejection fraction (34 +/- 14% vs 50 +/- 14%; P<.001). MCS patients had a higher prevalence of moderate/ severe calcification (88% vs 55%; P<.001) and higher J-CTO scores (3.1 +/- 1.2 vs 2.6 +/- 1.2; P<.01), and a greater proportion underwent retrograde crossing attempts (55% vs 39%; P<.01). Despite more complex characteristics in MCS patients, technical success rates (88% vs 87%; P=.70) and procedural success rates (83% vs 87%; P=.32) were similar in the two groups. Use of elective MCS was associated with longer procedure and fluoroscopy times, and higher incidences of in-hospital major adverse cardiovascular events (8.7% vs 2.5%; P<.01) and bleeding (7.3% vs 1.0%; P<.001). CONCLUSION: Elective MCS was used in 4% of patients undergoing CTO-PCI. Despite more complex clinical and angiographic characteristics, elective use of MCS in high-risk patients is associated with similar technical and procedural success rates, but higher risk of complications, compared to cases without elective MCS. PMID- 29493511 TI - Favorable Short-Term and Long-Term Outcomes Among Patients With Prior History of Malignancy Undergoing Transcatheter Aortic Valve Implantation. AB - BACKGROUND: Transcatheter aortic valve replacement (TAVR) is now the treatment of choice for high-surgical risk patients with symptomatic aortic stenosis. Little is known regarding the outcome of TAVR in patients with previous malignancy. METHODS: We investigated 477 patients who underwent TAVR in a tertiary medical center. Subjects were divided into two groups according to malignancy status: no history of malignancy (n = 386) and positive history of malignancy (n = 91). RESULTS: Mean age of the study population was 81 +/- 7 years, and 52% were men. No major differences in baseline characteristics were found between groups. All cause mortality was 24% for both malignancy and non-malignancy groups at a mean follow-up of 851 +/- 629 days. Kaplan-Meier survival analysis demonstrated no difference in all-cause mortality between groups. Multivariate Cox regression analysis showed that malignancy status did not affect prognosis regarding overall mortality (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.5-1.4; P=.46). However, cancer therapy administered within 12-months of TAVR was significantly associated with increased total mortality among patients undergoing TAVR (HR, 4.38; 95% CI, 1.14-16.77; P=.03). CONCLUSIONS: Malignancy is a common comorbidity among TAVR candidates. Mere history of malignancy among elderly patients does not adversely affect short-term or long-term outcomes after TAVR; however, history of recent (<1 year) cancer-related treatment increases the risk for long-term mortality after TAVR. Decisions regarding TAVR among oncological patients should be individualized according to their malignancy status and anticipated life expectancy. PMID- 29493513 TI - Suggested Bony Landmarks for Safe Axillary Artery Access. AB - OBJECTIVE: To identify a fluoroscopic bony landmark for safe percutaneous axillary artery cannulation. BACKGROUND: No bony landmarks exist to guide safe percutaneous axillary artery cannulation, which is an important alternate access site for catheter-based procedures in selected patients. METHODS: We retrospectively analyzed 51 consecutive percutaneous axillary artery sheath angiograms and attempted to correlate a fixed bony landmark to the proximal end of the third part of the artery. Proximal to this site, no cords of the brachial plexus traverse the anterior aspect of the vessel. Moreover, this site is proximal to the subscapular branch of the axillary artery, the first branch of its third part, and a sentinel component of the scapular anastomosis responsible for collateral blood flow to the arm. RESULTS: With the arm abducted at 135 degrees , the subscapular artery originated at, or distal to, the inferior border of the glenoid cavity, as seen on fluoroscopy in the anterior-posterior projection, in all patients. The origin was within 5 mm distal to the inferior border of the glenoid cavity in 17 patients (46%), 5-10 mm in 13 patients (35%), and between 10 mm and 20 mm in 7 patients (19%). CONCLUSIONS: With the arm abducted, the origin of the subscapular artery correlates well with the inferior most aspect of the glenoid cavity of the scapula under fluoroscopy. Axillary artery cannulation medial to this bony landmark typically lands the sheath in the second part or proximal end of the third part of the artery, thereby theoretically sparing injury to the brachial plexus and the subscapular artery. PMID- 29493512 TI - Forearm Versus Femoral Approach for Cardiac Catheterization in End-Stage Renal Disease Patients. AB - BACKGROUND: End-stage renal disease (ESRD) is considered a relative contraindication for forearm (radial or ulnar) cardiac catheterization. However, in everyday practice, many ESRD patients are catheterized from the forearm. The aim of this study was to compare femoral and forearm approach for cardiac catheterization in ESRD patients. METHODS: All cardiac catheterization procedures performed in ESRD patients in three Greek hospitals in a 2-year period (2014 2015) were retrospectively evaluated. The primary endpoint of the study was major access-site complication, defined as any Blood Academic Research Consortium class >=3 bleeding or limb ischemia requiring intervention or prolonging hospitalization. RESULTS: During the study period, a total of 124 procedures were performed in 109 ESRD patients: 44 procedures (35.5%) were performed transfemorally and 80 procedures (64.5%) were performed from the forearm approach (77 transradial [96.3%] and 3 transulnar [3.7%]). Forearm access was always performed from the contralateral arm of a functional hemodialysis access site. Sixty-one procedures (49.6%) were diagnostic coronary artery angiographies (CAAs) and 63 procedures (50.4%) were percutaneous coronary interventions with or without CAA. Two deaths and 1 procedure-related myocardial infarction were recorded during hospitalization. Five patients suffered major access-site complications, all from the femoral group (5/44 vs 0/80; P<.01). Three transradial patients had asymptomatic radial artery occlusion after a diagnostic procedure. Five patients (4.0%) had problems with their hemodialysis access site during long-term follow-up, and required a new access site. CONCLUSION: Forearm approach for cardiac catheterization is feasible and safe in ESRD patients. All measures to preserve radial patency should be taken in this high-risk patient group, where a possible forearm artery occlusion might have serious consequences. PMID- 29493514 TI - The Apophenia of Interventional Cardiology. PMID- 29493515 TI - Role of Diastology in Transcatheter Aortic Valve Implantation. AB - Transient elevation of LV diastolic pressure above LA pressure can occur in severe aortic regurgitation in the diastasis phase. Mitral E wave reversal in such a situation could serve as non-invasive evidence of elevated left ventricular diastolic pressures, thereby guiding therapeutic decision making. PMID- 29493516 TI - Kinking of Right Coronary Artery as a Complication in Pulmonary and Tricuspid Valve Replacement. AB - A 47-year-old patient with severe tricuspid and pulmonary regurgitation was electively admitted for surgical replacement of both valves. Post-op ECG changes suggested acute myocardial ischemia. Angiography revealed kinking in the distal RCA causing significant stenosis, which was treated by stenting. PMID- 29493517 TI - High-Risk Atherosclerotic Plaque in Aberrant Circumflex Coronary Artery. AB - A 45-year-old man presented after an episode of central chest pain. Catheter angiography revealed an aberrant circumflex artery and high-grade stenosis in the mid RCA and proximal CX arteries. Previous case series have suggested that the retroaortic portion of aberrant circumflex arteries may be particularly prone to the development of atherosclerosis. PMID- 29493518 TI - Quadricuspid Aortic Valve Stenosis: Expanding Our Experience in Transcatheter Aortic Valve Implantation. AB - To our knowledge, this is the first documented case of successful TAVI for severe quadricuspid aortic valve (QAV) stenosis performed in the U.S. and the first documented Sapien 3 valve implantation in a severely stenotic QAV. PMID- 29493519 TI - Comminuted Fractures of the Distal Femur Treated with Ilizarov External Fixator. Case Series Study. AB - BACKGROUND: Distal femoral fractures constitute a type of lower limb injuries that is rare and difficult to treat. Despite advances in surgical technique and development of implants used for internal fixation of fracture fragments, the treatment continues to result in numerous complications. The Ilizarov External Fixator reduces the risk of complications and allows for bone union. MATERIAL AND METHODS: Six men with distal femoral fractures resulting from multisite and multiorgan injuries were treated at the Department of Orthopaedics and Musculoskeletal Traumatology of the Medical Uni-versity of Warsaw between 2008 and 2016. Mean age of the patients was 42.6 years. Four of them were mana-ged with the Ilizarov method as a primary treatment and two wore the apparatus as a second-line treatment following unsuccessful plate osteosynthesis. RESULTS: Mean treatment duration with the Ilizarov apparatus was 29 weeks. Bone union was achieved in all patients. After the treatment, the patients ambulated unassisted, without orthopaedic aids. All patients re-turned to work. CONCLUSIONS: 1. The Ilizarov method allows for efficient fixation of comminuted distal femoral fractures, in-clud-ing C2 and C3 intra-articular fractures (AO/ASIF classification). 2. The use of the Ilizarov apparatus re-duces soft tissue laceration, preserves blood supply to the bone fragments, and allows for easier skin care, which is particularly important in the case of open fractures. 3. Early rehabilitation with the patient fully loading the operated limb reduces muscle atrophy and stimulates bone union. PMID- 29493520 TI - Neuropathy - Damage to Peripheral Nerves in Diseases and Injuries of the Musculoskeletal System. AB - The musculoskeletal diseases and injuries affect not only the musculoskeletal system itself, but also the closely related structures, such as blood vessels and nerves (both within the central and the peripheral nervous system). If these relationships are neglected or the directed neuroprotective and neuro regeneration therapy is delayed, the final effect of the treatment is compromised. The aim if this paper is describing the important medical and social problem of peripheral neuropathies from the point of view of epidemiology, etiopathogenesis, imaging diagnostics and complex medical procedures using modern approaches and techniques, based on the available literature. PMID- 29493521 TI - Use of Functional Scores For Assessing Patients Following Total Knee Replacement. AB - This paper discusses key aspects of the use of functional scores, including their reliability conditions, differences between subjective and objective assessment and types. Functional scores used for assessing patients following total knee replacement, both objective and those including elements of patient-reported subjective evaluation, are discussed in detail, including scales that can be used in pre-operative assessment. PMID- 29493522 TI - Operative Versus Non-operative Treatment of Grade III Acromioclavicular Joint Dislocations and the Use of SurgiLig: a Retrospective Review. AB - BACKGROUND: Acromioclavicular joint dislocations are common shoulder girdle injuries. The treatment of grade III acromioclavicular joint dislocations is controversial. Furthermore, the literature on the use of the Sur-giligTM synthetic ligament for reconstruction of dislocations is sparse. MATERIALS AND METHODS: This retrospective review aimed to establish whether operative treatment was superior to non-operative treatment in grade III acromioclavicular joint dislocations treated at our institute over a 5-year period. We also reviewed the effectiveness of reconstruction with SurgiligTM after acute and chronic dislocations across all grades of acromioclavicular joint dislocations. RESULTS: Twenty-five patients completed full follow-up with grade III dislocations. The mean follow-up in the operated group was 3.56 years and in the non-operated group this was 3.29 years. The mean Oxford Shoul-der Score (OSS) in the operated group was 39.8, whereas the mean OSS in the non-operated group was 45.9 (p=0.01). The mean pain score in the operated group was 2.2, and in the non-operated group this was 1.6. The mean satisfaction score in the operated group was 8.2 and that in the non-operated group was 7.8. There was no statistically significant difference in pain or satisfaction scores. In respect to the cohort treated with Surg-iligTM synthetic ligament, 22 patients across all grades of dislocations had this procedure performed. The mean post-operative Oxford Shoulder Score (OSS) was 40. CONCLUSIONS: 1. Non-operative treatment is not inferior to operative treatment for grade III acromioclavicular joint dislocations. The data from this study demonstrat-ed that the non-operated group had superior Ox-ford Shoul-der Scores that were statistically significant. 2. Additionally, the use of the SurgiligTM ligament appears to be effective in treating both chronic and acute acromioclavicular joint dislocations. PMID- 29493523 TI - Assessment of the Effect of Swedish Massage and Acupressure in Rehabilitation of Patients with Low Back Pain. Preliminary Report. AB - BACKGROUND: Low-back pain is a common problem in developed societies. The quest for methods to reduce this com-plaint may contribute to improving the quality of life for many people. The aim of the study was to compare the effect of Swedish massage combined with acupressure vs. Swedish massage alone in patients with low back pain. MATERIAL AND METHODS: The study involved 20 women and 20 men with lumbosacral pain. The group was clinically ho-mo-geneous. The participants were randomized into two groups: Group 1, which received Swedish massage with acu pressure techniques, and Group 2, treated with Swedish massage only. The research tools comprised the Laitinen Pain Score, the International Physical Activity Questionnaire, the Roland-Morris Ques-tion-naire, the Thomayer test, and the measurement of lumbar spine extension. Differences between the mea-surements were evaluated with the Wilcoxon test, with the minimum significance level set at p<=0.05. RESULTS: Both groups demonstrated a significant (p<0.05) decrease in pain intensity, improvement in quality of life and increase in physical activity. Increased segmental mobility of the spine was also observed in all patients, with significant changes (p<0.05) noted only in Group 1. In Group 2, the differences tended towards significance. CONCLUSION: In selected cases, Swedish massage combined with acupressure techniques may be more effective as a mo-notherapy in patients with non-specific low back pain than massage alone. PMID- 29493524 TI - Operative Management of Distal Tibial Extra-articular Fractures - Intramedullary Nail Versus Minimally Invasive Percutaneous Plate Osteosynthesis. AB - BACKGROUND: The ideal treatment of distal tibial extra articular fractures remains controversial. Minimally invasive percutaneous plate osteosynthesis and intramedullary nailing are the two most commonly used methods. We did a prospective randomized controlled study to assess the functional outcome of distal tibial extra articular tibial fractures by comparing these treatment methods. MATERIALS AND METHODS: Sixty patients with distal tibial extra articular fractures were randomly assigned to an IMN (intramedullary nailing) group and a MIPPO (minimally invasive percutaneous plate osteosynthesis) group. All patients were followed up for a period of one year. At final follow-up, clinical and radiological outcome was assessed by foot function index. Malunion, infection, implant removal, time to union and secondary interventions were compared between the two groups. The comparison of continuous variables was performed by using the Student t-test or Mann-Whitney U test in accordance with normality testing. A value of p less than 0.05 was considered statistically significant. RESULTS: All patients were followed up for a period of one year. Time to callus formation was equal in both groups. There was no non-union in our series. Malunion was more common in the nailing group. The foot function index was similar in both groups. CONCLUSION: MIPPO and intramedullary nailing are effective treatment options in the management of distal tibial extra particular fractures, with comparable functional outcomes. PMID- 29493525 TI - Current Uses of Ultrasound Imaging in Musculoskeletal Rehabilitation. AB - The term Rehabilitative Ultrasound Imaging (RUSI) refers to the use of ultrasound imaging by physiothera-pists. Ultrasound is used by physiotherapists to evaluate the morphology of muscles and other associated soft tissues not only at rest but also for a dynamic assessment of those structures during physical activities and tasks. RUSI is most commonly utilized as part of a biofeedback mechanism, which shows good efficacy in lower back pain treatment. Several possibilities have been also described for clinically adapting this method in the rehabilitation of the shoulder and knee and postoperative improvement of tendons. RUSI is a novel method with a high clinical potential to support physiotherapeutic therapies. PMID- 29493526 TI - Hand Therapist Led Follow-up for Paediatric Hand Trauma - a Retrospective Study of 139 Closed Hand Injuries. AB - BACKGROUND: Most hand injuries in children can be managed non-operatively and are associated with excellent outcomes. Whilst the majority of our patients are discharged to the care of hand therapists, there is no literature to support this protocol. Our aim was to ensure this is safe and effective practice. MATERIAL AND METHODS: We conducted a retrospective analysis of all patients referred to our paediatric hand trauma clinic for closed injuries over a four month period between December 2014 and March 2015. Data related to demographics, injury pattern and clinical outcomes was recorded and analysed. A telephone interview with a patient satisfaction questionnaire was attempted with all patients discharged to the care of hand therapists. RESULTS: 139 patients were seen in the study period, including 90 males and 49 females. Phalangeal fractures (39%), volar plate injuries (19%) and metacarpal fractures (16%) were the commonest causes of hand trauma. The majority of patients (88%) were managed non operatively. 97 patients were discharged to hand therapy follow-up and we managed to contact 51 patients (53%). Fifty-one patients (100%) completed a patient satisfaction questionnaire. 100% of the parents were happy with the care, 96% were not disappointed they did not see a doctor and 96% denied any complications. CONCLUSION: 1. The majority of paediatric hand injuries can be managed non operatively with excellent outcomes. 2. Hand therapy led follow-up is appropriate for a selected group of paediatric hand injuries. This study pro-ves that it is safe and effective for the majority of closed hand trauma, as illustrated by low complication rates. 3. Hand therapist led follow up for paediatric hand injuries is associated with high patient satisfaction. PMID- 29493527 TI - Radionegative Low Grade Chondrosarcoma in Distal Third of Femur. Case Study. AB - We present the case of a 43-year-old patient with a radionegative tumor of the distal third of the femur. Work-up following a knee injury without any abnormalities on x-ray was extended to include an MRI study, which revealed an osteolytic lesion in the distal third of the femur. Extended work-up including an open biopsy identified a low-grade chondrosarcoma. Considering the patient's clinical status and the diagnostic findings, tumour resection and placement of a resection knee endoprosthesis appeared to be the best solution. The clinical outcome was good. PMID- 29493529 TI - [Human rights in Turkey]. PMID- 29493528 TI - [Non-Therapeutic Male Circumcision: Primum Non Nocere]. PMID- 29493530 TI - [Hepatitis A in Iceland]. AB - INTRODUCTION: Hepatitis A virus (HAV) epidemics occurred repeatedly in Iceland in the early 20th century, but since then few cases have been reported and no epidemics since 1952. The latest Icelandic studies on HAV from around 1990 showed low incidence of infection and de-- creasing prevalence of antibodies. The objective of this study was to determine the incidence, clinical presentation and origin of HAV, abroad or in Iceland. MATERIAL AND METHODS: A retrospective search was undertaken on all patients with positive anti-HAV IgM during the 11 years period of 2006-2016 in the virological database of the National University Hospital of Iceland. Clinical data was collected from medical records on symptoms at diagnosis, blood test results and possible route of transmission. RESULTS: A total of 12 individuals were diagnosed with acute hepatitis A during the period and 6691 HAV total andibody tests and 1984 HAV IgM antibody tests were performed. Nine (75%) had been abroad within 7 weeks from initial symptoms. The most common symptoms were jaundice (83%), fever (67%) and nausea and/or vomiting (58%). 50% were admitted to a hospital. 42% had elevated INR/PT. Everyone sur-vived without complications. CONCLUSION: Annually, approximately one case of acute hepatitis A was diagnosed in Iceland during the study period but a very high number of antibody tests were performed. The majority of cases occurred among individuals who had recently been abroad. If patients have jaundice, fever and nausea, testing for HAV infection should be undertaken. HAV is not endemic in Iceland. PMID- 29493531 TI - [Comparison of pelvic floor muscle strength in competition-level athletes and untrained women]. AB - INTRODUCTION: Exercise can stress the pelvic floor muscles. Numerous women experience urinary incontinence while exercising or competing in sports. This study investigated pelvic floor muscle strength, urinary incontinence, and knowledge in contracting pelvic floor muscles among female athletes and untrained women. MATERIALS AND METHODS: This was a prospective case-control study measuring pelvic floor muscle strength using vaginal pressure meas-urement. Participants answered questions regarding general health, urinary incontinence, and knowledge on pelvic floor muscles. Partici-pants were healthy nulliparous women aged 18-30 years, athletes and untrained women. The athletes had competed in their sport for at least three years; including handball, soccer, gymnastics, badminton, BootCamp and CrossFit. RESULTS: The women were comparable in age and height. The athletes (n=18) had a body mass index (BMI) of 22.8 kg/m2 vs. 25 kg/m2 for the untrained (n=16); p<0.05. The athletes trained on average 11.4 hours/week while the untrained women participated in some activity on average for 1.3 hours/week; p< 0.05. Mean pelvic floor strength was 45+/-2 hPa in the athletes vs. 43+/-4 hPa in the untrained; p=0.36 for whether the athletes were stronger. Of the athletes, 61.1% experienced urinary incontinence (n=11) compared with 12.5% of the untrained women (n=2); p<0.05. Incontinence usually occurred during high intensity exercise. The athletes were more knowledgeable about the pelvic floor muscles; p<0.05. CONCLUSION: There was not a significant difference in the strength of pelvic floor muscles of athletes and untrained women. This suggests that pelvic floor muscles are not strengthened during general training but require specific exercises. This holds especially for football, handball and sports with high physical intensity. Coaches need to pay special attention to training and strengthening women's pelvic floor muscles to reduce the occurrence of urinary incontinence. PMID- 29493533 TI - Design and implementation of a 3D-MR/CT geometric image distortion phantom/analysis system for stereotactic radiosurgery. AB - The design, construction and application of a multimodality, 3D magnetic resonance/computed tomography (MR/CT) image distortion phantom and analysis system for stereotactic radiosurgery (SRS) is presented. The phantom is characterized by (1) a 1 * 1 * 1 (cm)3 MRI/CT-visible 3D-Cartesian grid; (2) 2002 grid vertices that are 3D-intersections of MR-/CT-visible 'lines' in all three orthogonal planes; (3) a 3D-grid that is MR-signal positive/CT-signal negative; (4) a vertex distribution sufficiently 'dense' to characterize geometrical parameters properly, and (5) a grid/vertex resolution consistent with SRS localization accuracy. When positioned correctly, successive 3D-vertex planes along any orthogonal axis of the phantom appear as 1 * 1 (cm)2-2D grids, whereas between vertex planes, images are defined by 1 * 1 (cm)2-2D arrays of signal points. Image distortion is evaluated using a centroid algorithm that automatically identifies the center of each 3D-intersection and then calculates the deviations dx, dy, dz and dr for each vertex point; the results are presented as a color-coded 2D or 3D distribution of deviations. The phantom components and 3D-grid are machined to sub-millimeter accuracy, making the device uniquely suited to SRS applications; as such, we present it here in a form adapted for use with a Leksell stereotactic frame. Imaging reproducibility was assessed via repeated phantom imaging across ten back-to-back scans; 80%-90% of the differences in vertex deviations dx, dy, dz and dr between successive 3 T MRI scans were found to be ?0.05 mm for both axial and coronal acquisitions, and over >95% of the differences were observed to be ?0.05 mm for repeated CT scans, clearly demonstrating excellent reproducibility. Applications of the 3D phantom/analysis system are presented, using a 32-month time-course assessment of image distortion/gradient stability and statistical control chart for 1.5 T and 3 T GE TwinSpeed MRI systems. PMID- 29493532 TI - Effective scheme of photolysis of GFP in live cell as revealed with confocal fluorescence microscopy. AB - We proposed an effective kinetics scheme of photolysis of green fluorescent protein (GFP) observed in live cells with a commercial confocal fluorescence microscope. We investigated the photolysis of GFP-tagged heterochromatin protein, HP1beta-GFP, in live nucleus with the pulse position modulation approach, which has several advantages over the classical pump-and-probe method. At the basis of the proposed scheme lies a process of photoswitching from the native fluorescence state to the intermediate fluorescence state, which has a lower fluorescence yield and recovers back to native state in the dark. This kinetics scheme includes four effective parameters (photoswitching, reverse switching, photodegradation rate constants, and relative brightness of the intermediate state) and covers the time scale from dozens of milliseconds to minutes of the experimental fluorescence kinetics. Additionally, the applicability of the scheme was demonstrated in the cases of continuous irradiation and the classical pump and-probe approach using numerical calculations and analytical solutions. An interesting finding of experimental data analysis was that the overall photodegradation of GFP proceeds dominantly from the intermediate state, and demonstrated approximately the second-order reaction versus irradiation power. As a practical example, the proposed scheme elucidates the artifacts of fluorescence recovery after the photobleaching method, and allows us to propose some suggestions on how to diminish them. PMID- 29493534 TI - Correlation between physical structure and magnetic anisotropy of a magnetic nanoparticle colloid. AB - We show the effects of a time-invariant magnetic field on the physical structure and magnetic properties of a colloid comprising 44 nm diameter magnetite magnetic nanoparticles, with a 24 nm dextran shell, in water. Structural ordering in this colloid parallel to the magnetic field occurs simultaneously with the onset of a colloidal uniaxial anisotropy. Further increases in the applied magnetic field cause the nanoparticles to order perpendicular to the field, producing unexpected colloidal unidirectional and trigonal anisotropies. This magnetic behavior is distinct from the cubic magnetocrystalline anisotropy of the magnetite and has its origins in the magnetic interactions among the mobile nanoparticles within the colloid. Specifically, these field-induced anisotropies and colloidal rearrangements result from the delicate balance between the magnetostatic and steric forces between magnetic nanoparticles. These magnetic and structural rearrangements are anticipated to influence applications that rely upon time dependent relaxation of the magnetic colloids and fluid viscosity, such as magnetic hyperthermia and shock absorption. PMID- 29493535 TI - Design and evaluation of a deformable wing configuration for economical hovering flight of an insect-like tailless flying robot. AB - Studies on wing kinematics indicate that flapping insect wings operate at higher angles of attack (AoAs) than conventional rotary wings. Thus, effectively flying an insect-like flapping-wing micro air vehicle (FW-MAV) requires appropriate wing design for achieving low power consumption and high force generation. Even though theoretical studies can be performed to identify appropriate geometric AoAs for a wing for achieving efficient hovering flight, designing an actual wing by implementing these angles into a real flying robot is challenging. In this work, we investigated the wing morphology of an insect-like tailless FW-MAV, which was named KUBeetle, for obtaining high vertical force/power ratio or power loading. Several deformable wing configurations with various vein structures were designed, and their characteristics of vertical force generation and power requirement were theoretically and experimentally investigated. The results of the theoretical study based on the unsteady blade element theory (UBET) were validated with reference data to prove the accuracy of power estimation. A good agreement between estimated and measured results indicated that the proposed UBET model can be used to effectively estimate the power requirement and force generation of an FW-MAV. Among the investigated wing configurations operating at flapping frequencies of 23 Hz to 29 Hz, estimated results showed that the wing with a suitable vein placed outboard exhibited an increase of approximately 23.7% +/- 0.5% in vertical force and approximately 10.2% +/- 1.0% in force/power ratio. The estimation was supported by experimental results, which showed that the suggested wing enhanced vertical force by approximately 21.8% +/- 3.6% and force/power ratio by 6.8% +/- 1.6%. In addition, wing kinematics during flapping motion was analyzed to determine the reason for the observed improvement. PMID- 29493536 TI - Spatial displacement of forward-diffracted X-ray beams by perfect crystals. AB - Time-delayed, narrow-band echoes generated by forward Bragg diffraction of an X ray pulse by a perfect thin crystal are exploited for self-seeding at hard X-ray free-electron lasers. Theoretical predictions indicate that the retardation is strictly correlated to a transverse displacement of the echo pulses. This article reports the first experimental observation of the displaced echoes. The displacements are in good agreement with simulations relying on the dynamical diffraction theory. The echo signals are characteristic for a given Bragg reflection, the structure factor and the probed interplane distance. The reported results pave the way to exploiting the signals as an online diagnostic tool for hard X-ray free-electron laser seeding and for dynamical diffraction investigations of strain at the femtosecond timescale. PMID- 29493537 TI - The development of powder profile refinement at the Reactor Centre Netherlands at Petten. AB - With thousands of references to 'Rietveld refinement' it is forgotten that the method did not suddenly appear in a flash of inspiration of a single person, but was the result of the work of three individuals working in the 1960s at the Reactor Centre Netherlands at Petten, Loopstra, van Laar and Rietveld. This paper outlines the origins of 'profile refinement', as it was called at Petten, and also looks at why it took so long for the scientific community to recognize its importance. With the recent passing of Hugo Rietveld, the death of Bert Loopstra in 1998 and before other pioneers also disappear, it is important to set down a first-hand account. PMID- 29493538 TI - Ab initio structure determination and quantitative disorder analysis on nanoparticles by electron diffraction tomography. AB - Nanoscaled porous materials such as zeolites have attracted substantial attention in industry due to their catalytic activity, and their performance in sorption and separation processes. In order to understand the properties of such materials, current research focuses increasingly on the determination of structural features beyond the averaged crystal structure. Small particle sizes, various types of disorder and intergrown structures render the description of structures at atomic level by standard crystallographic methods difficult. This paper reports the characterization of a strongly disordered zeolite structure, using a combination of electron exit-wave reconstruction, automated diffraction tomography (ADT), crystal disorder modelling and electron diffraction simulations. Zeolite beta was chosen for a proof-of-principle study of the techniques, because it consists of two different intergrown polymorphs that are built from identical layer types but with different stacking sequences. Imaging of the projected inner Coulomb potential of zeolite beta crystals shows the intergrowth of the polymorphs BEA and BEB. The structures of BEA as well as BEB could be extracted from one single ADT data set using direct methods. A ratio for BEA/BEB = 48:52 was determined by comparison of the reconstructed reciprocal space based on ADT data with simulated electron diffraction data for virtual nanocrystals, built with different ratios of BEA/BEB. In this way, it is demonstrated that this smart interplay of the above-mentioned techniques allows the elaboration of the real structures of functional materials in detail - even if they possess a severely disordered structure. PMID- 29493539 TI - Electron-density critical points analysis and catastrophe theory to forecast structure instability in periodic solids. AB - The critical points analysis of electron density, i.e. rho(x), from ab initio calculations is used in combination with the catastrophe theory to show a correlation between rho(x) topology and the appearance of instability that may lead to transformations of crystal structures, as a function of pressure/temperature. In particular, this study focuses on the evolution of coalescing non-degenerate critical points, i.e. such that ?rho(xc) = 0 and lambda1, lambda2, lambda3 ? 0 [lambda being the eigenvalues of the Hessian of rho(x) at xc], towards degenerate critical points, i.e. ?rho(xc) = 0 and at least one lambda equal to zero. The catastrophe theory formalism provides a mathematical tool to model rho(x) in the neighbourhood of xc and allows one to rationalize the occurrence of instability in terms of electron-density topology and Gibbs energy. The phase/state transitions that TiO2 (rutile structure), MgO (periclase structure) and Al2O3 (corundum structure) undergo because of pressure and/or temperature are here discussed. An agreement of 3-5% is observed between the theoretical model and experimental pressure/temperature of transformation. PMID- 29493540 TI - Coordination numbers of the vertex graph of a Penrose tiling. AB - A new approach to study coordination shells and coordination sequences of quasiperiodic graphs is suggested. The structure of the coordination shells in the vertex graph of a Penrose tiling is described. An asymptotic formula for its coordination numbers is obtained. An essentially different behaviour of the coordination numbers for even and odd shells is revealed. PMID- 29493541 TI - Phasing via pure crystallographic least squares: an unexpected feature. AB - Crystallographic least-squares techniques, the main tool for crystal structure refinement of small and medium-size molecules, are for the first time used for ab initio phasing. It is shown that the chief obstacle to such use, the least squares severe convergence limits, may be overcome by a multi-solution procedure able to progressively recognize and discard model atoms in false positions and to include in the current model new atoms sufficiently close to correct positions. The applications show that the least-squares procedure is able to solve many small structures without the use of important ancillary tools: e.g. no electron density map is calculated as a support for the least-squares procedure. PMID- 29493543 TI - Monoclinic sphere packings. II. Trivariant lattice complexes with mirror symmetry. AB - All homogeneous sphere packings were derived that refer to the three trivariant monoclinic lattice complexes with mirror symmetry. In total, 29 types of sphere packings have been found. Only for three types is the maximal inherent symmetry of their sphere packings monoclinic whereas the inherent symmetry is orthorhombic for 13 types, tetragonal for eight types, hexagonal for four types and cubic for one type. PMID- 29493542 TI - Development of a joint refinement model for the spin-resolved one-electron reduced density matrix using different data sets. AB - The paper describes a joint refinement model of the spin-resolved one-electron reduced density matrix using simultaneously magnetic structure factors and magnetic directional Compton profiles. The model is guided by two strategies: (i) variation of basis functions and (ii) variation of the spin population matrix. The implementation for a finite system is based on an expansion of the natural orbitals on basis sets. To show the potential benefits brought by the joint refinement model, the paper also presents the refinement results using magnetic structure factors only. The joint refinement model provides very satisfactory results reproducing the pseudo-data. In particular, magnetic Compton profiles have a strong effect not only on the off-diagonal elements of the spin-resolved one-electron reduced density matrix but also on its diagonal elements. PMID- 29493547 TI - Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling. PMID- 29493548 TI - CXCL11-dependent induction of FOXP3-negative regulatory T cells suppresses autoimmune encephalomyelitis. PMID- 29493549 TI - The performance of the new prognostic grade and stage groups in conservatively treated prostate cancer. AB - We evaluated the prognosis of the new grade groups and American Joint Committee on Cancer (AJCC) stage groups in men with prostate cancer (PCa) who were treated conservatively. A total of 13 798 eligible men were chosen from the Surveillance Epidemiology and End Results database. The new grade and AJCC stage groups were investigated on prostate biopsy specimens. Kaplan-Meier survival analysis and multivariable hazards models were applied to estimate the association of new grade and stage groups with overall survival (OS) and PCa-specific survival (CSS). Mean follow-up was 42.65 months (95% confidence interval: 42.47-42.84) in the entire cohort. The 3-year OS and CSS rates stepped down for grade groups 1-5 and AJCC stage groups I-IVB, respectively. After adjusting for clinical and pathological characteristics, all grade groups and AJCC stage groups were associated with higher all-cause and PCa-specific mortality compared to the reference group (all P <= 0.003). In conclusion, we evaluated the oncological outcome of the new grade and AJCC stage groups on biopsy specimens of conservatively treated PCa. These two novel clinically relevant classifications can assist physicians to determine different therapeutic strategies for PCa patients. PMID- 29493551 TI - Staff and family response to end-of-life care in the ICU. AB - PURPOSE OF REVIEW: End-of-life (EOL) care can be stressful for clinicians as well as patients and their relatives. Decisions to withhold or withdraw life sustaining therapy vary widely depending on culture, beliefs and organizational norms. The following review will describe the current understanding of the problem and give an overview over interventional studies. RECENT FINDINGS: EOL care is a risk factor for clinician burnout; poor work conditions contribute to emotional exhaustion and intent to leave. The impact of EOL care on families is part of the acute Family Intensive Care Unit Syndrome (FICUS) and the Post Intensive Care Syndrome-Family (PICS-F). Family-centered care (FCC) acknowledges the importance of relatives in the ICU. Several interventions have been evaluated, but evidence for their effectiveness is at best moderate. Some interventions even increased family stress. Interventional studies, which address clinician burnout are rare. SUMMARY: EOL care is associated with negative outcomes for ICU clinicians and relatives, but strength of evidence for interventions is weak because we lack understanding of associated factors like work conditions, organizational issues or individual attitudes. In order to develop complex interventions that can successfully mitigate stress related to EOL care, more research is necessary, which takes into account all potential determinants. PMID- 29493550 TI - Decline in semen concentration of healthy Chinese adults: evidence from 9357 participants from 2010 to 2015. AB - The present study aims to analyze sperm concentration trends among young and healthy Chinese adults in Wuhan, Central China, from 2010 to 2015. Semen analysis data from 9357 participants were collected and analyzed using a general linear model and the Cochran-Armitage trend test. A significant decline was observed in sperm concentration (beta [standard deviation]: -1.53 [0.16]; P < 0.001). In addition, a decline in sperm density was observed by stratifying student versus nonstudent sperm donors and by analyzing the year of birth or birth year cohort of the participants. Furthermore, the percentage of participants with sperm densities of over 40 * 106 ml-1 significantly decreased with year. Notably, a dramatic decline in sperm density was recorded over the first 5 years of study. This research reported a decline in sperm concentration among young adults in Wuhan, Central China, in 2010-2015. PMID- 29493552 TI - Pediatric trauma transfusion and cognitive aids. AB - PURPOSE OF REVIEW: Trauma is the most common cause of pediatric mortality. Much of the research that led to life-saving interventions in adults, however, has not been replicated in the pediatric population. Children have important physiologic and anatomic differences from adults, which impact hemostasis and transfusion. Hemorrhage is a leading cause of death in trauma, and children have important differences in their coagulation profiles. Transfusion strategies, including the massive transfusion protocol and use of antifibrinolytics, are still controversial. In addition to the blood that is lost from the injury itself, trauma leads to inflammation and to a dysfunction in hemostasis, causing coagulopathy. RECENT FINDINGS: In one study in which children suffered from mainly blast and penetrating injuries in a combat setting (PEDTRAX trial), the early administration of tranexamic acid was associated with decreased mortality. Some authors suggest that this result may not apply to blunt trauma, which is much more common in children in noncombat settings. Using thromboelastography to guide the administration of recombinant Factor VIIa has been done in selected cases and may represent a future avenue of research. SUMMARY: This article explores new research from the past year in pediatric trauma, starting with the physiologic differences in pediatric red blood cells and coagulation profiles. We also looked at the dramatic change in thinking over the past decade in the tolerable level of anemia in critically ill pediatric patients, as well as scales for determining the need for massive transfusion and exploring if the concepts of damage control resuscitation apply to children. Other strategies, such as avoiding hypothermia, and the selective administration of antifibriniolytics, are important in pediatric trauma as well. Future research that is pediatric focused is needed for the optimal care of our youngest patients. PMID- 29493553 TI - Postprandial remnant lipoproteins as targets for the prevention of atherosclerosis. AB - PURPOSE OF REVIEW: Oxidized low-density lipoprotein (Ox-LDL) and chylomicron remnants were previously proposed as the most atherogenic lipoproteins for the causal lipoproteins of atherosclerosis. However, there are still controversies on these hypothesizes. Therefore, we have proposed a new hypothesis based on our recent findings of remnant lipoproteins (RLPs) in postprandial plasma. RECENT FINDINGS: Plasma RLP-C and RLP-TG increased significantly after fat load. More than 80% of the increased triglycerides after fat load consisted of the triglycerides in RLP, which contained greater amount of apoB100 than apoB48 particles as mostly very low density lipoproteins (VLDL) remnants. The majority of lipoprotein lipase (LPL) in plasma was found in RLP as RLP-LPL complex, which is released into circulation after hydrolysis. LPL activity and concentration in plasma did not increase after food intake associated with the insufficient hydrolysis of chylomicrons and VLDL and resulted in the significant increase of RLP-TG. Plasma LPL was inversely correlated with RLP particle size and number. SUMMARY: VLDL remnants have been shown as the major atherogenic lipoproteins in postprandial plasma associated with LPL activity as the targets for prevention of atherosclerosis. We also proposed a new definition of RLPs, 'LPL bound TG-rich lipoproteins' based on the findings of RLP-LPL complex. PMID- 29493554 TI - Elevated triglycerides and low high-density lipoprotein cholesterol level as marker of very high risk in type 2 diabetes. AB - PURPOSE OF REVIEW: The aim of this review is to describe in diabetic patients the determinants underlying atherogenic dyslipidemia, a complex dyslipidemia defined as the coexistence of fasting hypertriglyceridemia and low high-density lipoprotein cholesterol level. Atherogenic dyslipidemia is often comorbid with hyperglycemia in patients with the common form of type 2 diabetes mellitus (T2DM), namely that associated with obesity, insulin resistance, hyperinsulinemia and the metabolic syndrome phenotype. RECENT FINDINGS: The role of triglyceride rich lipoproteins, both fasting and nonfasting, is increasingly considered as a direct driver of atherosclerosis in diabetic patients, even in those receiving best standards of care, including low-density lipoprotein cholesterol level adequately controlled by statins and/or ezetimibe. The residual cardiovascular risk related to atherogenic dyslipidemia in T2DM patients can be inferred from subgroup analysis of diabetic patients within landmark lipid-lowering trials, or from T2DM-only trials, such as Fenofibrate Intervention and Event Lowering in Diabetes study or Action to Control Cardiovascular Risk in Diabetes-Lipid trial. SUMMARY: The presence of atherogenic dyslipidemia markedly increases cardiovascular risk, and there is evidence that part of the residual cardiovascular risk in T2DM can be safely and effectively reduced by fibrates. Ongoing trials will determine whether new classes of drugs or dietary intervention targeting hypertriglyceridemia (such as n-3 fatty acids or SPPARMalpha) will reduce macro and microvascular residual risk in T2DM patients with atherogenic dyslipidemia at inclusion. PMID- 29493555 TI - Assessing the impact of air pollution on childhood asthma morbidity: how, when, and what to do. AB - PURPOSE OF REVIEW: Exposure to air pollutants is linked with poor asthma control in children and represents a potentially modifiable risk factor for impaired lung function, rescue medication use, and increased asthma-related healthcare utilization. Identification of the most relevant pollutants to asthma as well as susceptibility factors and strategies to reduce exposure are needed to improve child health. RECENT FINDINGS: The current available literature supports the association between pollutants and negative asthma outcomes. Ethnicity, socioeconomic status, and presence of certain gene polymorphisms may impact susceptibility to the negative health effects of air pollution. Improved air quality standards were associated with better asthma outcomes. SUMMARY: The link between air pollution and pediatric asthma morbidity is supported by the recent relevant literature. Continued efforts are needed to identify the most vulnerable populations and develop strategies to reduce exposures and improve air quality. PMID- 29493558 TI - Epilepsy: a special disease. PMID- 29493557 TI - Motor development and delay: advances in assessment of motor skills in autism spectrum disorders. AB - PURPOSE OF REVIEW: Motor impairments in neurodevelopmental disorders, specifically autism spectrum disorder (ASD), are prevalent and pervasive. Moreover, motor impairments may be the first sign of atypical development in ASD and likely contribute to abnormalities in social communication. However, measurement of motor function in ASD has lagged behind other behavioral phenotyping. Quantitative and neurodiagnostic measures of motor function can help identify specific motor impairments in ASD and the underlying neural mechanisms that might be implicated. These findings can serve as markers of early diagnosis, clinical stratification, and treatment targets. RECENT FINDINGS: Here, we briefly review recent studies on the importance of motor function to other developmental domains in ASD. We then highlight studies that have applied quantitative and neurodiagnostic measures to better measure motor impairments in ASD and the neural mechanisms that may contribute to these abnormalities. SUMMARY: Information from advanced quantitative and neurodiagnostic methods of motor function contribute to a better understanding of the specific and subtle motor impairments in ASD, and the relationship of motor function to language and social development. Greater utilization of these methods can assist with early diagnosis and development of targeted interventions. However, there remains a need to utilize these approaches in children with neurodevelopmental disorders across a developmental trajectory and with varying levels of cognitive function. PMID- 29493556 TI - Behavioral and neuroanatomical approaches in models of neurodevelopmental disorders: opportunities for translation. AB - PURPOSE OF REVIEW: This review highlights the invaluable contribution of in-vivo rodent models in dissecting the underlying neurobiology for numerous neurodevelopmental disorders. Currently, models are routinely generated with precision genomics and characterized for research on neurodevelopmental disorders. In order to impact translation, outcome measures that are translationally relevant are essential. This review emphasizes the importance of accurate neurobehavioral and anatomical analyses. RECENT FINDINGS: Numerous well validated assays for testing alterations across behavioral domains with sensitivity and throughput have become important tools for studying the effects of genetic mutations on neurodevelopment. Recent work has highlighted relationships and links between behavioral outcomes and various anatomical metrics from neuroimaging via magnetic resonance. These readouts are biological markers and outcome measures for translational research and will be have important roles for genetic or pharmacologic intervention strategies. SUMMARY: Combinatorial approaches that leverage translationally relevant behavior and neuroanatomy can be used to develop a platform for assessment of cutting edge preclinical models. Reliable, robust behavioral phenotypes in preclinical model systems, with clustering of brain disease will lead to well informed, precise biochemical mechanistic hypotheses. Ultimately, these steadfast workhorse techniques will accelerate the progress of developing and testing targeted treatments for multiple neurodevelopmental disorders. PMID- 29493559 TI - Neurostimulation for drug-resistant epilepsy: a systematic review of clinical evidence for efficacy, safety, contraindications and predictors for response. AB - PURPOSE OF REVIEW: Neurostimulation is becoming an increasingly accepted treatment alternative for patients with drug-resistant epilepsy (DRE) who are unsuitable surgery candidates. Standardized guidelines on when or how to use the various neurostimulation modalities are lacking. We conducted a systematic review on the currently available neurostimulation modalities primarily with regard to effectiveness and safety. RECENT FINDINGS: For vagus nerve stimulation (VNS), there is moderate-quality evidence for its effectiveness in adults with drug resistant partial epilepsies. Moderate-to-low-quality evidence supports the efficacy and safety of deep brain stimulation (DBS) and responsive neurostimulation (RNS) in patients with DRE. There is moderate-to-very low quality evidence that transcranial direct current stimulation (tDCS) is effective or well tolerated. For transcutaneous vagus nerve stimulation (tVNS), transcranial magnetic stimulation (TMS) and trigeminal nerve stimulation (TNS), there are insufficient data to support the efficacy of any of these modalities for DRE. These treatment modalities, nevertheless, appear well tolerated, with no severe adverse events reported. SUMMARY: Head-to-head comparison of treatment modalities such as VNS, DBS and RNS across different epileptic syndromes are required to decide which treatment modality is the most effective for a given patient scenario. Such studies are challenging and it is unlikely that data will be available in the near future. Additional data collection on potentially promising noninvasive neurostimulation modalities like tVNS, TMS, TNS and tDCS is warranted to get a more precise estimate of their therapeutic benefit and long term safety. PMID- 29493560 TI - Continuing Education for Nursing Contact Hours and CRNI(r) Recertification Units. PMID- 29493561 TI - Role of cannabinoid receptor type 1 in rostral ventrolateral medulla in high-fat diet-induced hypertension in rats. AB - BACKGROUND: Stimulation of cannabinoid type 1 (CB1) receptor in the rostral ventrolateral medulla (RVLM) increases renal sympathetic activity (RSNA) and blood pressure (BP) in rats. Thus, we hypothesized that CB1 receptor in the RVLM may play a critical role in the development of obesity-induced hypertension. METHODS: To this end, we evaluated the levels of endocannabinoids and CB1 receptors in the RVLM in high-fat diet (HFD)-induced hypertensive rats. We then used pharmacological and molecular methods to examine the role of RVLM CB1 receptors in regulation of BP, heart rate (HR), and RSNA in obesity-induced hypertensive rats. RESULTS: We found that HFD-fed rats exhibited higher basal BP, HR, and RSNA than standard diet-fed rats, which were associated with increased levels of endocannabinoids and CB1 receptor expression in the RVLM. Furthermore, unilateral intra-RVLM microinjections of AM251 (0, 100, or 500 nM/0.5 MUl/site) dose-dependently decreased BP, HR, and RSNA to a greater extent in HFD-fed rats than in standard diet-fed rats. Finally, siRNA-mediated knockdown of CB1 receptor expression in the RVLM robustly decreased BP, HR, and RSNA in HFD-fed rats. CONCLUSION: Taken together, our results suggested that enhanced CB1 receptor mediated neurotransmissions in the RVLM may play a role in the development of obesity-induced hypertension. PMID- 29493562 TI - Gender, blood pressure, and cardiovascular and renal outcomes in adults with hypertension from the Systolic Blood Pressure Intervention Trial. AB - BACKGROUND: To determine if the effects of intensive lowering of systolic blood pressure (goal of less than 120 mmHg) versus standard lowering (goal of less than 140 mmHg) upon cardiovascular, renal, and safety outcomes differed by gender. METHODS: Nine thousand three hundred and sixty-one men and women aged 50 years or older with systolic blood pressure of 130 mmHg or greater, taking 0-4 antihypertensive medications, and with increased risk of cardiovascular disease, but free of diabetes, were randomly assigned to either a systolic blood pressure target of less than 120 mmHg (intensive treatment) or a target of less than 140 mmHg (standard treatment). The primary composite outcome encompassed incident myocardial infarction, heart failure, other acute coronary syndromes, stroke, or cardiovascular-related death. All-cause mortality, renal outcomes, and serious adverse events were also assessed. RESULTS: Compared with the standard treatment group, the primary composite outcome in the intensive treatment group was reduced by 16% [hazard ratio 0.84 (0.61-1.13)] in women, and by 27% in men [hazard ratio 0.73 (0.59-0.89), P value for interaction between treatment and gender is 0.45]. Similarly, the effect of the intensive treatment on individual components of the primary composite outcome, renal outcomes, and overall serious adverse events was not significantly different according to gender. CONCLUSION: In adults with hypertension but not with diabetes, treatment to a systolic blood pressure goal of less than 120 mmHg, compared with a goal of less than 140 mmHg, resulted in no heterogeneity of effect between men and women on cardiovascular or renal outcomes, or on rates of serious adverse events.ClinicalTrials.gov number, NCT01206062. PMID- 29493563 TI - The Natural History of Idiopathic Scoliosis During Growth: A Meta-Analysis. AB - OBJECTIVE: The aim of the study was to provide a meta-analysis of current literature concerning the natural history of idiopathic scoliosis during growth. DESIGN: A comprehensive search of Medline, Embase, And Scopus databases was conducted up to November 2016. Eligible works were prospective or retrospective studies that enrolled patients with infantile idiopathic scoliosis, juvenile idiopathic scoliosis, or adolescent idiopathic scoliosis, followed up without any treatment from the time of detection. A meta-analysis for proportion was performed. The following studies were grouped per diagnosis: infantile idiopathic scoliosis, juvenile idiopathic scoliosis, and adolescent idiopathic scoliosis. RESULTS: Of the 1797 citations screened, we assessed 61 full-text articles and included 13 of these (2301 participants). Three studies included infantile idiopathic scoliosis patients (347 participants), five studies included a mixed population of juvenile idiopathic scoliosis and adolescent idiopathic scoliosis (1330 participants), and five studies included adolescent idiopathic scoliosis patients only (624 participants). The random pooled estimated progression rate was 49% (95% confidence interval = 1%-97%) for infantile idiopathic scoliosis, 49% in a mixed group of patients affected by juvenile idiopathic scoliosis or adolescent idiopathic scoliosis (95% confidence interval = 19%-79%), and 42% in adolescent idiopathic scoliosis (95% confidence interval = 11%-73%). CONCLUSIONS: During growth, idiopathic scoliosis tends to progress in a high percentage of cases. The progression rate varies according to the age at diagnosis, with infantile scoliosis being the most unpredictable. There are many confounders, such as age, Risser sign and baseline Cobb angles that were not consistent among studies, making the data very heterogeneous. PMID- 29493564 TI - Pretreatment with Erythropoietin Attenuates Lung Ischemia/Reperfusion Injury via Toll-Like Receptor-4/Nuclear Factor-kappaB (TLR4/NF-kappaB) Pathway. AB - BACKGROUND Lung ischemia/reperfusion injury (LIRI) is a medical problem featuring pulmonary dysfunction and damage. The present study aimed to investigate the protective effects of erythropoietin (EPO), which has been reported to be an anti inflammatory agent, on LIRI through inhibiting the TLR-4/NF-kappaB signaling pathway. MATERIAL AND METHODS All rats were randomly divided into 3 groups (n=8): a control group, a vehicle+LIRI group, and an EPO+LIRI group. LIRI included 90 min ischemia and 120-min reperfusion, while RhEpo was administered (3 kU/kg) intraperitoneally 2 h before the operation. Levels of pulmonary inflammatory responses were examined by analyzing pulmonary permeability index (PPI), oxygenation index, histology, and expressions of inflammatory cytokines. RESULTS Pretreatment with EPO significantly decreased lung W/D ratio, BALF leukocytes count and percentage, and PPI but increased oxygenation index compared with the LIRI group (P<0.05). More importantly, with EPO pretreatment there was less pathological damage compared with the vehicle group. Expressions of inflammatory cytokines (TNF-alpha, IL-6, and IL-1beta) in the serum were significantly lower in the EPO group than in the LIRI group (P<0.05). In addition, gene expression and protein expression of TLR-4 and NF-kappaB were significantly inhibited with EPO pretreatment compared with the LIRI group (P<0.05). CONCLUSIONS Our study id the first to report that EPO protects lung injuries after LIRI through inhibiting the TLR4-NF-kappaB signaling pathway, which provides solid evidence for the use of EPO as a therapeutic agent for treating LIRI in the future. PMID- 29493566 TI - Cluster headache. AB - Cluster headache is an excruciating, strictly one-sided pain syndrome with attacks that last between 15 minutes and 180 minutes and that are accompanied by marked ipsilateral cranial autonomic symptoms, such as lacrimation and conjunctival injection. The pain is so severe that female patients describe each attack as worse than childbirth. The past decade has seen remarkable progress in the understanding of the pathophysiological background of cluster headache and has implicated the brain, particularly the hypothalamus, as the generator of both the pain and the autonomic symptoms. Anatomical connections between the hypothalamus and the trigeminovascular system, as well as the parasympathetic nervous system, have also been implicated in cluster headache pathophysiology. The diagnosis of cluster headache involves excluding other primary headaches and secondary headaches and is based primarily on the patient's symptoms. Remarkable progress has been achieved in developing effective treatment options for single cluster attacks and in developing preventive measures, which include pharmacological therapies and neuromodulation. PMID- 29493565 TI - [Health care for adolescents with gender dysphoria]. AB - OBJECTIVE: Dysphoria gender treatment in adolescents is recent. Studies of adolescents treated with analogs are reduced. To ensure the quality of care and safety of the child, follow-up studies are necessary. The aim of the present research was to describe the characteristics of the process of medical and psychological attention in adolescents with the DG in the Gender Identity Treatment Unit of Asturias in the period 2007-2015. METHODS: The sample included 20 minors attended in the Gender Identity Treatment Unit of Asturias in the period 2007-2015. The clinical history was made to collect the variables. It was made descriptive analysis. RESULTS: 10% of adolescents abandoned in the process of psychological counseling, 80% began to be valued by endocrinology and 10% continued exclusively in psychological consultations. Of the medical treated adolescents, 13.3% were treated with analogues and 86.7% received cross-hormonal treatment (THC) directly. The most prevalent secondary effects were dermatological problems (40%), followed by mastodynia without galactorrhea (26.7%) and hot flashes (20%). 20% performed gender confirmation surgeries. CONCLUSIONS: The profile of the adolescent treated in the unit of Asturias is a subject that begins hormonal treatment after psychological accompaniment and endocrinological evaluation. The minor has adverse effects after treatment. Once the hormonal treatment has been established, they do not abandon the process. PMID- 29493567 TI - Corrigendum: Benefit-cost Trade-offs of Early Learning in Foraging Predatory Mites Amblyseius Swirskii. AB - This corrects the article DOI: 10.1038/srep23571. PMID- 29493568 TI - Corrigendum: A multi-functional bubble-based microfluidic system. AB - This corrects the article DOI: 10.1038/srep09942. PMID- 29493569 TI - Atherosclerosis: A new role for lncRNAs in atherosclerosis. PMID- 29493571 TI - Transplantation: Sirolimus after heart transplantation. PMID- 29493570 TI - Arrhythmias: Atrial fibrillation in heart failure - time to revise the guidelines? PMID- 29493572 TI - Heart failure: Macrophages promote cardiac fibrosis and diastolic dysfunction. PMID- 29493573 TI - Heart failure: Histone deacetylases and diastolic dysfunction. PMID- 29493574 TI - Hypertension: Lifestyle offsets genetic risk of hypertension. PMID- 29493575 TI - Cluster headache. PMID- 29493576 TI - Response to Peron et al. PMID- 29493577 TI - Mosaic maternal 10qter deletions are associated with FRA10B expansions and may cause false-positive noninvasive prenatal screening results. AB - PURPOSE: Using genome-wide noninvasive prenatal screening (NIPS), we detected a 20-megabase specific deletion starting at 10q25 in eight pregnancies. The deletion could not be confirmed by invasive testing. Since all 10(q25->qter) deletions started close to the FRA10B fragile site in 10q25, we investigated whether the pregnant women were indeed carriers of FRA10B. METHODS: We performed NIPS analysis for all autosomes using single-read sequencing. Analysis was done with the WISECONDOR algorithm. Culture of blood lymphocytes with bromodeoxyuridine was used to detect FRA10B expansions. Fluorescence in situ hybridization and array analysis were used to find maternal and/or fetal deletions. RESULTS: We confirmed the presence of a FRA10B expansion in all four tested mothers. Fluorescence in situ hybridization and array analysis confirmed the presence of a maternal mosaic deletion of 10(q25->qter). CONCLUSION: The recurring 10(q25->qter) deletion detected with NIPS is a false-positive result caused by a maternal low-level mosaic deletion associated with FRA10B expansions. This has important consequences for clinical follow-up, as invasive procedures are unnecessary. Expanded maternal FRA10B repeats should be added to the growing group of variants in the maternal genome that may cause false-positive NIPS results. PMID- 29493578 TI - Cell-free fetal DNA versus maternal serum screening for trisomy 21 in pregnant women with and without assisted reproduction technology: a prospective interventional study. AB - PURPOSE: Cell-free DNA (cfDNA) as a primary screening test has been available for years but few studies have addressed this option in a prospective manner. The question is of interest after reports that maternal serum screening (MSS) is less accurate for pregnancies resulting from assisted reproduction technologies (ART) than for spontaneous pregnancies (SP). METHODS: A prospective interventional study was designed to address the performances of cfDNA compared with MSS in pregnancies with or without ART. Each patient was offered both MSS and cfDNA testing. The primary analysis cohort ultimately included 794 patients with a spontaneous pregnancy (SP) (n = 472) or pregnancy obtained after ART (n = 322). RESULTS: Overall, the false-positive rate and positive predictive value were 6.6% and 8.8% for MSS but 0% and 100% for cfDNA. MSS false-positive rate and positive predictive values were clearly poorer in the ART group (11.7% and 2.6%) than in the SP group (3.2% and 21.1%). The global rates of invasive procedures were 1.9% (15/794) with cfDNA but 8.4% (65/794) if MSS alone was proposed. CONCLUSION: cfDNA achieved better performance than MSS in both spontaneous and ART pregnancies, thus decreasing the number of invasive procedures. Our findings suggest that cfDNA should be considered for primary screening, especially in pregnancies obtained after ART. PMID- 29493579 TI - A counseling framework for moderate-penetrance colorectal cancer susceptibility genes. PMID- 29493580 TI - Response to Walker. PMID- 29493581 TI - ClinGen's RASopathy Expert Panel consensus methods for variant interpretation. AB - PURPOSE: Standardized and accurate variant assessment is essential for effective medical care. To that end, Clinical Genome (ClinGen) Resource clinical domain working groups (CDWGs) are systematically reviewing disease-associated genes for sufficient evidence to support disease causality and creating disease-specific specifications of American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines for consistent and accurate variant classification. METHODS: The ClinGen RASopathy CDWG established an expert panel to curate gene information and generate gene- and disease-specific specifications to ACMG-AMP variant classification framework. These specifications were tested by classifying 37 exemplar pathogenic variants plus an additional 66 variants in ClinVar distributed across nine RASopathy genes. RESULTS: RASopathy-related specifications were applied to 16 ACMG-AMP criteria, with 5 also having adjustable strength with availability of additional evidence. Another 5 criteria were deemed not applicable. Key adjustments to minor allele frequency thresholds, multiple de novo occurrence events and/or segregation, and strength adjustments impacted 60% of variant classifications. Unpublished case-level data from participating laboratories impacted 45% of classifications supporting the need for data sharing. CONCLUSION: RAS-specific ACMG-AMP specifications optimized the utility of available clinical evidence and Ras/MAPK pathway-specific characteristics to consistently classify RASopathy-associated variants. These specifications highlight how grouping genes by shared features promotes rapid multigenic variant assessment without sacrificing specificity and accuracy. PMID- 29493582 TI - Hereditary cancer gene panel test reports: wide heterogeneity suggests need for standardization. AB - PURPOSE: Laboratory-generated genomic test reports are used to convey complex, and frequently multivariant or uncertain, information about disease risk to medical genetics professionals as well as to nonspecialist clinicians, patients, and family members. However, few guidelines exist to guide the content and format of genomic test reports, and little is known about variation in current reporting practices. METHODS: We conducted a structured content analysis of hereditary cancer gene panel test reports obtained from 16 United States-based CLIA certified laboratories, including reports describing a variant of uncertain significance (VUS) only and reports with both a VUS and pathogenic or likely pathogenic (P/LP) test result. RESULTS: Report content and format varied widely across laboratories and between VUS and VUS + P/LP reports from the same laboratory, with regard to the inclusion and visual prominence of key content as well as in terms of overall length and readability. CONCLUSION: Test report heterogeneity is likely to reflect both the lack of comprehensive reporting guidelines and disagreements between laboratories about the salience of specific types of information to test interpretation and use. Future research should explore the impact of reporting differences on clinician interpretation and shared decision making. PMID- 29493583 TI - Anticipating uncertainty and irrevocable decisions: provider perspectives on implementing whole-genome sequencing in critically ill children with heart disease. AB - PURPOSE: To investigate the potential impacts of whole-genome sequencing (WGS) in the pediatric critical-care context, we examined how clinicians caring for critically ill children with congenital heart disease (CHD) anticipate and perceive the impact of WGS on their decision-making process and treatment recommendations. METHODS: We conducted semistructured in-person and telephone interviews of clinicians involved in the care of critically ill children with CHD at a high-volume pediatric heart center. We qualitatively analyzed the transcribed interviews. RESULTS: In total, 34 clinicians were interviewed. Three themes emerged: (i) uncertainty about the accuracy of WGS testing and adequacy of testing validation; (ii) the use of WGS to facilitate life-limiting decisions such as futility, rationing, and selective prenatal termination; and (iii) moral distress over using WGS with a lack of decision support. CONCLUSION: Despite uncertainty about WGS testing, the interviewed clinicians were using, and anticipated expanding the use of, WGS results to justify declarations of futility, withdrawal of care, and rationing in critically ill children with CHD. This situation is causing moral distress in providers who have to make high stakes decisions involving WGS results, with only partial understanding of them. Decision support for clinicians, and discussion with families of the risks of using WGS for rationing or withdrawal, is needed. PMID- 29493584 TI - Tell me once, tell me soon: parents' preferences for clinical genetics services for congenital heart disease. AB - PURPOSE: As the molecular basis of congenital heart disease (CHD) comes into sharper focus, cardiac genetics services are likely to play an increasingly important role. This study aimed to identify parents' preferences for, and willingness to participate in, clinical genetics services for CHD. METHODS: A discrete choice experiment was developed to assess parents' preferences for pediatric cardiogenetics services based on four attributes: appointment format, health professionals involved, waiting time, and information format. Data were analyzed using a mixed logit model. RESULTS: One hundred parents with a living child diagnosed with CHD requiring surgical intervention between 2000 and 2009 completed the discrete choice experiment. Parents expressed a clear preference for cardiac genetics services featuring (i) a single appointment, (ii) the presence of a clinical geneticist and a genetic counselor, (iii) both verbal (oral) and Web-based information about CHD and genetics, and (iv) availability of an appointment within 2 weeks. If offered such conditions, 93% of respondents indicated that they would attend. The choice of service was most strongly influenced by the presence of both a clinical geneticist and a genetic counselor. CONCLUSION: Parents of children with CHD favor a single, timely genetics appointment with both a geneticist and a genetic counselor present. If appointments offered match these preferences, uptake is likely to be high. PMID- 29493585 TI - Response to Brosens et al. PMID- 29493586 TI - Do RET somatic mutations play a role in Hirschsprung disease? PMID- 29493587 TI - An absorption profile centred at 78 megahertz in the sky-averaged spectrum. AB - After stars formed in the early Universe, their ultraviolet light is expected, eventually, to have penetrated the primordial hydrogen gas and altered the excitation state of its 21-centimetre hyperfine line. This alteration would cause the gas to absorb photons from the cosmic microwave background, producing a spectral distortion that should be observable today at radio frequencies of less than 200 megahertz. Here we report the detection of a flattened absorption profile in the sky-averaged radio spectrum, which is centred at a frequency of 78 megahertz and has a best-fitting full-width at half-maximum of 19 megahertz and an amplitude of 0.5 kelvin. The profile is largely consistent with expectations for the 21-centimetre signal induced by early stars; however, the best-fitting amplitude of the profile is more than a factor of two greater than the largest predictions. This discrepancy suggests that either the primordial gas was much colder than expected or the background radiation temperature was hotter than expected. Astrophysical phenomena (such as radiation from stars and stellar remnants) are unlikely to account for this discrepancy; of the proposed extensions to the standard model of cosmology and particle physics, only cooling of the gas as a result of interactions between dark matter and baryons seems to explain the observed amplitude. The low-frequency edge of the observed profile indicates that stars existed and had produced a background of Lyman-alpha photons by 180 million years after the Big Bang. The high-frequency edge indicates that the gas was heated to above the radiation temperature less than 100 million years later. PMID- 29493589 TI - Corrigendum: Progress in and promise of bacterial quorum sensing research. AB - This corrects the article DOI: 10.1038/nature24624. PMID- 29493590 TI - Possible interaction between baryons and dark-matter particles revealed by the first stars. AB - The cosmic radio-frequency spectrum is expected to show a strong absorption signal corresponding to the 21-centimetre-wavelength transition of atomic hydrogen around redshift 20, which arises from Lyman-alpha radiation from some of the earliest stars. By observing this 21-centimetre signal-either its sky averaged spectrum or maps of its fluctuations, obtained using radio interferometers-we can obtain information about cosmic dawn, the era when the first astrophysical sources of light were formed. The recent detection of the global 21-centimetre spectrum reveals a stronger absorption than the maximum predicted by existing models, at a confidence level of 3.8 standard deviations. Here we report that this absorption can be explained by the combination of radiation from the first stars and excess cooling of the cosmic gas induced by its interaction with dark matter. Our analysis indicates that the spatial fluctuations of the 21-centimetre signal at cosmic dawn could be an order of magnitude larger than previously expected and that the dark-matter particle is no heavier than several proton masses, well below the commonly predicted mass of weakly interacting massive particles. Our analysis also confirms that dark matter is highly non-relativistic and at least moderately cold, and primordial velocities predicted by models of warm dark matter are potentially detectable. These results indicate that 21-centimetre cosmology can be used as a dark-matter probe. PMID- 29493588 TI - Mapping local variation in educational attainment across Africa. AB - Educational attainment for women of reproductive age is linked to reduced child and maternal mortality, lower fertility and improved reproductive health. Comparable analyses of attainment exist only at the national level, potentially obscuring patterns in subnational inequality. Evidence suggests that wide disparities between urban and rural populations exist, raising questions about where the majority of progress towards the education targets of the Sustainable Development Goals is occurring in African countries. Here we explore within country inequalities by predicting years of schooling across five by five kilometre grids, generating estimates of average educational attainment by age and sex at subnational levels. Despite marked progress in attainment from 2000 to 2015 across Africa, substantial differences persist between locations and sexes. These differences have widened in many countries, particularly across the Sahel. These high-resolution, comparable estimates improve the ability of decision makers to plan the precisely targeted interventions that will be necessary to deliver progress during the era of the Sustainable Development Goals. PMID- 29493592 TI - Hadean silicate differentiation preserved by anomalous 142Nd/144Nd ratios in the Reunion hotspot source. AB - Active volcanic hotspots can tap into domains in Earth's deep interior that were formed more than two billion years ago. High-precision data on variability in tungsten isotopes have shown that some of these domains resulted from differentiation events that occurred within the first fifty million years of Earth history. However, it has not proved easy to resolve analogous variability in neodymium isotope compositions that would track regions of Earth's interior whose composition was established by events occurring within roughly the first five hundred million years of Earth history. Here we report 142Nd/144Nd ratios for Reunion Island igneous rocks, some of which are resolvably either higher or lower than the ratios in modern upper-mantle domains. We also find that Reunion 142Nd/144Nd ratios correlate with helium-isotope ratios (3He/4He), suggesting parallel behaviour of these isotopic systems during very early silicate differentiation, perhaps as early as 4.39 billion years ago. The range of 142Nd/144Nd ratios in Reunion basalts is inconsistent with a single-stage differentiation process, and instead requires mixing of a conjugate melt and residue formed in at least one melting event during the Hadean eon, 4.56 billion to 4 billion years ago. Efficient post-Hadean mixing nearly erased the ancient, anomalous 142Nd/144Nd signatures, and produced the relatively homogeneous 143Nd/144Nd composition that is characteristic of Reunion basalts. Our results show that Reunion magmas tap into a particularly ancient, primitive source compared with other volcanic hotspots, offering insight into the formation and preservation of ancient heterogeneities in Earth's interior. PMID- 29493593 TI - Corrigendum: Greater post-Neolithic wealth disparities in Eurasia than in North America and Mesoamerica. AB - This corrects the article DOI: 10.1038/nature24646. PMID- 29493591 TI - Mapping child growth failure in Africa between 2000 and 2015. AB - Insufficient growth during childhood is associated with poor health outcomes and an increased risk of death. Between 2000 and 2015, nearly all African countries demonstrated improvements for children under 5 years old for stunting, wasting, and underweight, the core components of child growth failure. Here we show that striking subnational heterogeneity in levels and trends of child growth remains. If current rates of progress are sustained, many areas of Africa will meet the World Health Organization Global Targets 2025 to improve maternal, infant and young child nutrition, but high levels of growth failure will persist across the Sahel. At these rates, much, if not all of the continent will fail to meet the Sustainable Development Goal target-to end malnutrition by 2030. Geospatial estimates of child growth failure provide a baseline for measuring progress as well as a precision public health platform to target interventions to those populations with the greatest need, in order to reduce health disparities and accelerate progress. PMID- 29493594 TI - Erratum: Pluripotent state transitions coordinate morphogenesis in mouse and human embryos. AB - This corrects the article DOI: 10.1038/nature24675. PMID- 29493596 TI - UK university strike, quark pioneer and the ancient-genome boom. PMID- 29493595 TI - Fast quantum logic gates with trapped-ion qubits. AB - Quantum bits (qubits) based on individual trapped atomic ions are a promising technology for building a quantum computer. The elementary operations necessary to do so have been achieved with the required precision for some error-correction schemes. However, the essential two-qubit logic gate that is used to generate quantum entanglement has hitherto always been performed in an adiabatic regime (in which the gate is slow compared with the characteristic motional frequencies of the ions in the trap), resulting in logic speeds of the order of 10 kilohertz. There have been numerous proposals of methods for performing gates faster than this natural 'speed limit' of the trap. Here we implement one such method, which uses amplitude-shaped laser pulses to drive the motion of the ions along trajectories designed so that the gate operation is insensitive to the optical phase of the pulses. This enables fast (megahertz-rate) quantum logic that is robust to fluctuations in the optical phase, which would otherwise be an important source of experimental error. We demonstrate entanglement generation for gate times as short as 480 nanoseconds-less than a single oscillation period of an ion in the trap and eight orders of magnitude shorter than the memory coherence time measured in similar calcium-43 hyperfine qubits. The power of the method is most evident at intermediate timescales, at which it yields a gate error more than ten times lower than can be attained using conventional techniques; for example, we achieve a 1.6-microsecond-duration gate with a fidelity of 99.8 per cent. Faster and higher-fidelity gates are possible at the cost of greater laser intensity. The method requires only a single amplitude shaped pulse and one pair of beams derived from a continuous-wave laser. It offers the prospect of combining the unrivalled coherence properties, operation fidelities and optical connectivity of trapped-ion qubits with the submicrosecond logic speeds that are usually associated with solid-state devices. PMID- 29493597 TI - Why I won't be silenced on climate resilience. PMID- 29493599 TI - Risk and resilience must be independently managed. PMID- 29493598 TI - How flashing lights and pink noise might banish Alzheimer's, improve memory and more. PMID- 29493600 TI - Tight complexes from disordered proteins. PMID- 29493602 TI - Corrections. PMID- 29493601 TI - A gut feeling for cellular fate. PMID- 29493603 TI - How to write a first-class paper. PMID- 29493604 TI - Quantum upside-down cake. PMID- 29493605 TI - Call for research into a wider range of behavioural addictions. PMID- 29493606 TI - Promising HIV vaccines could stall without coordinated research. PMID- 29493607 TI - Qubits break the sound barrier. PMID- 29493608 TI - Lessons from Italy's policy shift on immunization. PMID- 29493609 TI - Researchers have finally created a tool to spot duplicated images across thousands of papers. PMID- 29493610 TI - UK scientists brace for disruption from huge academic strike. PMID- 29493611 TI - Six research priorities for cities and climate change. PMID- 29493614 TI - A surprising chill before the cosmic dawn. PMID- 29493613 TI - The mazes with minds of their own. PMID- 29493615 TI - Oil and gas emissions could far exceed current estimates. PMID- 29493616 TI - Florida residents could soon get the power to alter science classes. PMID- 29493617 TI - China's lust for jaguar fangs imperils big cats. PMID- 29493618 TI - Precision maps for public health. PMID- 29493619 TI - Indian scientist's sacking spotlights sexual harassment. PMID- 29493621 TI - Nature journals announce two steps to improve transparency. PMID- 29493623 TI - A code of ethics to get scientists talking. PMID- 29493625 TI - Data can help to end malnutrition across Africa. PMID- 29493626 TI - Enter our 'scientist at work' photo contest. PMID- 29493627 TI - Smallholders need access to big-data agronomy too. PMID- 29493631 TI - [Some considerations about adherence to therapy.] AB - Poor adherence to therapy is a proven cause of therapeutic failure, transversal to all areas of medicine with broad health and economic repercussions. There are many factors that can lead to inadequate adherence, currently also economic reasons. The evidence available from the intervention studies implemented to improve adherence in various clinical conditions offers disappointing results, particularly in chronic conditions where the interventions implemented were found to be complex and relatively ineffective. Poor adherence persists widely because it is a complex problem and resistant to generic approaches. In conditions of chronicity, where polypharmacy is frequent and the patient has difficulties to manage it adequately, an overall and long-lasting approach is required, involving a review of the whole therapy and, with the patient's involvement and consent, of deprescription of those therapies no longer essential. PMID- 29493628 TI - [Functional assessment of patients with vertigo and dizziness in occupational medicine]. AB - BACKGROUND: Balance assessment relies on symptoms, clinical examination and functional assessment and their verification in objective tests. Our study was aimed at calculating the assessment compatibility between questionnaires, functional scales and objective vestibular and balance examinations. MATERIAL AND METHODS: A group of 131 patients (including 101 women; mean age: 59+/-14 years) of the audiology outpatient clinic was examined. Benign paroxysmal positional vertigo, phobic vertigo and central dizziness were the most common diseases observed in the study group. Patients' symptoms were tested using the questionnaire on Cawthworne-Cooksey exercises (CC), Dizziness Handicap Inventory (DHI) and Duke Anxiety-Depression Scale. Berg Balance Scale (BBS), Dynamic Gait Index (DGI), the Tinetti test, Timed Up and Go test (TUG), and Dynamic Visual Acuity (DVA) were used for the functional balance assessment. Objective evaluation included: videonystagmography caloric test and static posturography. RESULTS: The study results revealed statistically significant but moderate compatibility between functional tests BBS, DGI, TUG, DVA and caloric results (Kendall's W = 0.29) and higher for posturography (W = 0.33). The agreement between questionnaires and objective tests were very low (W = 0.08-0.11).The positive predictive values of BBS were 42% for caloric and 62% for posturography tests, of DGI - 46% and 57%, respectively. CONCLUSIONS: The results of functional tests (BBS, DGI, TUG, DVA) revealed statistically significant correlations with objective balance tests but low predictive values did not allow to use these tests in vestibular damage screening. Only half of the patients with functional disturbances revealed abnormal caloric or posturography tests. The qualification to work based on objective tests ignore functional state of the worker, which may influence the ability to work. Med Pr 2018;69(2):179-189. PMID- 29493632 TI - [Patients' rights]. AB - Forty years have passed since the publication of the "Patients' Rights Charter" (included in a separate section at the end of the work: "Patients' rights: a critical guide to understanding and usage of civil hospital facilities"), but it still remains remarkably topical. We here provide an analysis of the original Charter (1975) taking into consideration the changes that have occurred in sensitivity to gender, cultural as well as socioeconomic differences, the right to body privacy and to continuity of care, the key role of general practitioners, the reciprocal relations in the information and decision-making processes with shared diagnostic and therapeutic pathways and active patient participation, which mandates that adequate education in communication and care strategies be provided to all caregivers. PMID- 29493633 TI - [Prevention of medication errors during intravenous drug administration in intensive care units: a literature review.] AB - Medication errors during drug administration represent a current issue in intensive care units due to the complexity of patients, the large quantity of drugs administered intravenously, the frequent prescription changes and frenetic activities in an emergency setting. The aim of this review is to increase knowledge about prevention and types of medication errors in intensive care units. The review was conducted using the following biomedical databases: PubMed, Cinahl, and Google Scholar. A total of 40 studies were considered useful for research purposes. Most studies showed a higher prevalence of medication errors in complex and intensive care settings. Although there are several different strategies aimed at preventing and reducing errors, available literature data show that a multimodal and multidimensional approach is required to make their use effective. PMID- 29493634 TI - [Medication adherence in cardiovascular diseases.] AB - Nonadherence to medications is common in cardiovascular diseases because of their long duration, the patient age and the complexity of therapy. Its prevalence depends on the population, the types of drugs and the disease under study. Adherence decreases from the initial prescription and it is usually under 80%, a value defined as satisfactory. Adverse outcomes of nonadherence consist of an increase in ambulatory visits and hospitalization and death rates. The causes of nonadherence are multiple and depend on the patient, the type of medication, the healthcare professional, and the health system. Methods adopted to reduce nonadherence include sanitary education, direct patient-doctor-pharmacist interactions and the use of electronic devices of alert. "Deprescribing", a mechanism proposed to reduce unnecessary or redundant medications, may improve the situation of long-term drug use in patients with cardiovascular disease, thus increasing adherence. Recommendations from the guidelines are sometimes confounding and the role of polypill therapy is still controversial. PMID- 29493635 TI - Non-persistence risk and health care resource utilization of Italian patients with non-valvular atrial fibrillation AB - The aim of this study is to compare discontinuation risk and health care resource utilization between vitamin K antagonists (VKAs) and non-vitamin K antagonist oral anticoagulants (NOACs) in newly treated patients with non-valvular atrial fibrillation (NVAF). Based on administrative databases of five Italian Local Healthcare Units, all patients with a discharge diagnosis of NVAF between 2011 and 2014 were selected. Among them, the incident users of NOACs and VKAs in 2014 were followed-up to from the first prescription date to the occurrence of anyone of the following events: a 90-day gap in therapy, switch to a different molecule or add-on of a different molecule into the regimen, death of patient, end of follow-up (December 2015). All-cause hospitalizations, outpatient visits and examinations within the persistence period were also evaluated. The final cohort was composed of 2909 and 765 incident users of VKA and NOACs, respectively. Cox regressionto model time to non-persistence within 12 months showed a 62% reduction in risk of drug discontinuation in NOAC patients compared to VKA patients (HR,0.38 [0.33-0.44]). In the adjusted analyses with warfarin as reference, apixaban patients (HR, 0.35 [0.24-0.50]) had the lowest risk of non persistence, followed by rivaroxoban (HR, 0.42 [0.33-0.54]) and dabigatran users (HR, 0.51 [0.43-0.61]). The mean total numbers of all-cause hospitalization records in 12-month persistent patients were significantly less in NOACs users compared with VKA users (0.36 vs 0.47, p-value:0.03). Similarly, the differences in the mean numbers of all-cause visits and examinations were statistically significant between VKA and NOAC patients, whoregistered on average 2.33 vs 1.84 visits (p-value: 0.01) and 24.4 vs 9.2 exams referrals (p-value: <0.0001), respectively.NOACs showed a better profile in terms of both resource utilization and persistence compared with VKAs. In particular, apixaban returned the lowest risk of discontinuation than dabigatran and rivaroxaban. PMID- 29493636 TI - [Pharmaceutical preparations in the hospital. Analysis and in-house development of an automated system of management.] AB - INTRODUCTION: In the past couple of years, the demand of galenic compounds has risen sharply. In order to plan the activity, our team designed and set up a database which stores all the necessary information related to drugs and ingredients. This allows our internal Galenic Laboratory to better manage the pharmaceutical prescriptions for the hospital and the outpatients, optimizing the use of raw materials. METHODS: The application is based on the interconnection of prescription-related aspects (patients' and prescriber's details and prescription information). The prescription name is linked to the list of substances, which allows to monitor the stock levels. Inserting the daily dosage into the system, our personnel can calculate the monthly supply of the medicine. Each prescription contains specific warnings on printable labels. A printed sheet, inclusive of label and checks on the final preparation, is produced for each prescription. RESULTS: After a testing phase, the application gradually replaced our traditional process of pharmaceutical activity management, allowing for a more accurate scheduling of the medicine requests. The worksheet and its specific label are automatically generated. Then a prediction scheme is generated for the ordinary programmable galenic activity. CONCLUSIONS: The project successfully achieved the following goals: 1) automate the information flow related to preparations; 2) improve the response time in terms of drug preparation and delivery; 3) minimize the number of emergencies. PMID- 29493638 TI - [Cochrane Rehabilitation: a new field for evidence production and dissemination.] AB - INTRODUCTION: After approval by Cochrane Steering Group, Cochrane Rehabilitation has been launched on 16th December 2016. The aim of Cochrane Rehabilitation is to bridge between Cochrane and Rehabilitation stakeholders, systematically identifying and spreading evidence, but also improving its quality and quantity production per clinical needs. METHODS: Cochrane Rehabilitation is a network of individuals, coming from all continents. Therefore, a clear and well-structured organisation is required to make Cochrane Rehabilitation functioning effectively. RESULTS: Up to now 272 people from 52 countries expressed their willingness to collaborate. The Field Director will be directly responsible for the Knowledge Translation strategy and will be assisted by the Executive Committee, including the Chairs of the Committees (Review Tagging, Methodology, Publication, Communication, Education). The Field Coordinator will ensure the implementation of a networking strategy and coordination of activities between the Committees, Units and individual members. The Advisory Board includes key persons from different international stakeholders, recognised as opinion leaders in rehabilitation. CONCLUSIONS: Cochrane Rehabilitation is working to drive, on one side, evidence and methods developed by Cochrane to the world of Rehabilitation and, on the other, to convey priorities, needs and specificities of Rehabilitation to Cochrane. PMID- 29493637 TI - [Genotyping in patients affected by HLA-related diseases. App development for diagnostic support.] AB - HLA typing requests for association studies of immune-mediated diseases are often redundant and inadequate. We designed a series of meta-analyses to evaluate the accuracy of typing and distribution of HLA alleles predisposing to diseases, aiming at developing an app that can help doctors in choosing the most suitable molecular analysis. The first study was on celiac disease (CD) and HLA-DQ in children. We searched all english articles published in the main bibliographic databases up to May 2016. The search strategy has been developed using controlled terms (e.g. MeSH) and free terms. We identified 1885 articles. 1334 abstracts were examined. 46 manuscripts were evaluated, and 13 studies were included in the meta-analysis (740 CD and 943 controls). The risk of developing CD in children with allelic variants encoding the HLA-DQ2.5 and/or HLA-DQ8 molecules has been confirmed. The greatest CD risk resides in carriers of two DQ2.5 molecules, i.e. subjects homozygous for the DQB1*02:01 and DQA1*05 alleles (OR=5.4, 95 % CI=4.1 6.8) compared to any other DQ genotype. Carriers of two DQB1*02:01 (chain beta2) alleles and one DQA1*05 (chain alpha5) allele have the same risk (p=0.8089) of DQ2.5 homozygotes (OR=5.3%, 95 CI=4,1 to 6.5). We found no differences between DQ8/beta2 and DQ2.5/DQ8, nor between beta2/DQX and DQ2.5/X. We suggest a two-step process: first typing the DQB1*02:01 allele and, in case of a negative result, full typing of HLA-DQ. PMID- 29493639 TI - [Neurofeedback in Parkinson's disease: technologies in speech and language therapy.] AB - : Neurofeedback (NF) is a form of biofeedback based on the self-modulation of brain activity; it aims to enhance mental and behavioral performances. The user modifies his brain functions thanks to EEG-mediated self-regulation and therapist's guidance. Recent advances in Brain-Computer Interfaces (BCI) have provided new evidence on the effectiveness of NF in reinforcing cognitive functions expecially in children with ADHD. The applications on adults with cognitive deficits are still few. The study aims to investigate the possible effect of NF techniques on cognitive performance of patients with Parkinson's disease (PD) in terms of changes in scores at the neurocognitive assessment. Ten PD patients, staged according to Hoehn & Yahr scale and cognitively evaluated, were recruited. INCLUSION CRITERIA: age 55-85, correct audio-visual functions, phase-on of dopaminergic therapy, Mild Cognitive Impairment. The rehabilitation program has been structured in 24 sessions. The NeuroSky MindWave headset and related software were used as BCI. At the end of the therapeutic path, the pre and post-treatment test's results were compared. Statistical analyzes were performed with SAS. Cognitive revaluation showed a significant increase in scores and satisfaction questionnaires reported high values. The application of NF techniques in PD patients was promising. The increase in satisfaction levels seems to be due to the perception of a direct control over one's cognitive performances. PMID- 29493641 TI - [Relation between work-related stress and metabolic syndrome among Italian nurses.] AB - AIM: To investigate the prevalence of metabolic syndrome (MS) among nurses, as well as the organizational impact of work-related stress as a consequence of MS among nurses in Italy. To study the organizational models, turnover rates, and job satisfaction among nurses, in a sample of Italian healthcare facilities. BACKGROUND: MS is considered an important metabolic disorder in the modern world, responsible for diseases with economic effects on hospitals. Shift work (SW) seems to be a risk factor for MS, while the Mediterranean diet appears to be protective. Work-related stress causes loss of working days, and generates high costs for hospitals. DESIGN: Prospective observational study. METHODS: The first step will be to create and validate a questionnaire to investigate the prevalence of MS among Italian nurses. The second step will be to estimate the risk of work related stress. Data regarding absenteeism and turnover will be collected, as indicators of impact on organization. DISCUSSION: This study is the first to investigate the previously describe SW's factors and their impact on organizing nursing work. This study is relevant for the organizations because it helps to define organizational strategies that permit nurses to remain healthy, to be work efficient and therefore to be able to provide high level care. PMID- 29493640 TI - [The interplay of diagnostic and antimicrobial stewardship for the management of septic patients: the Tuscan model.] AB - Antimicrobial resistance is a global threat caused by the rapid spread of multiresistant microorganisms. Antimicrobial stewardship (AS) is a coordinated intervention designed to improve the appropriate use of antimicrobials by promoting the selection of the optimal drug regimen, dose, duration of therapy and route of administration. AS programs have proved effective in reducing antimicrobial resistance, inappropriate antimicrobial use and in improving patient outcomes. Recently developed rapid diagnostic technologies in microbiology (RDTM) allows a faster and etiological diagnosis of infection and a reduction in the use of unnecessary empirical therapies. This may result in important advancement in time-critical care pathways for septic patients. Nevertheless, RDTM are costly and if not rationally positioned may consume resources and hinder the efficacy of AS programs. In this regard, Tuscany Region is engaged in designing, through a systemic approach, an effective high-quality clinical microbiological service grid. In order to develop a sustainable and equitable model for integrating diagnostic and antimicrobial stewardship we conducted a survey in the regional network of 14 microbiological laboratories. The results shows that in order to develop a sustainable service we need to improve the communication at the interface between laboratories and care unit, harmonize the time windows for processing samples and to devise a robust score for stratifying patient with suspected sepsis. PMID- 29493642 TI - [Decision aid and informed decision on breast cancer screening: the "DonnaInformata-Mammografia" project.] AB - : In Italy women aged 50-69 are invited for a population-based breast cancer (BC) screening. Physicians, policy makers and patient associations agree on the need to inform women about the benefits and harms in order to permit an informed decision. Decision aids (DA) are an effective way to support people in their decisions about health. This trial aims to assess women's informed choices, according to their health literacy and values, on participating or not in BC screening for the first time. Benefits, harms and controversies are presented. The contents of the DA were developed on the basis of: a) findings of three focus groups and four interviews, organized in the three Italian screening centers; b) analysis of the literature. A web-based platform (www.donnainformata-mammografia) was developed to implement the DA in a multilevel model. The impact of the DA will be evaluated in a randomized controlled trial with a one week follow-up. The women will be randomized to DA or a standard brochure via web. We will invite 8160 women to obtain the final sample size of 816 women. The primary outcome will be informed choice, measured via knowledge, attitudes and intentions on BC screening. SECONDARY OUTCOMES: participation rate and decisional conflict process. If the informed choice will be reached, the web DA will be open source and could be implemented in BC screenings. This model could be applied to other health care settings and cancer screenings. PMID- 29493643 TI - [The strategic research areas of a University Hospital: proposal of a quali quantitative method.] AB - This work aimed to objectively identify the main research areas at the University Hospital of Parma. To this end, a multidisciplinary working group, comprising clinicians, researchers, and hospital management, was formed to develop a shared quali-quantitative method. Easily retrievable performance indicators were selected from the literature (concerning bibliometric data and grant acquisition), and a scoring system developed to assign weights to each indicator. Subsequently, Research Team Leaders were identified from the hospital's "Research Plan", a document produced every three years which contains information on the main research themes carried out at each Department, involved staff and available resources, provided by health care professionals themselves. The selected performance indicators were measured for each Team Leader, and scores assigned, thus creating a ranking list. Through the analyses of the research themes of top Team Leaders, the Working Group identified the following five strategic research areas: (a) personalized treatment in oncology and hematology; (b) chronicization mechanisms in immunomediate diseases; (c) old and new risk factors for cardiovascular diseases; (d) nutritional disorders, metabolic and chronic degenerative diseases; (e) molecular diagnostic and predictive markers. We have developed an objective method to identify a hospital's main research areas. Its application can guide resource allocation and can offer ways to value the work of professionals involved in research. PMID- 29493644 TI - [Telemonitoring of swallowing function: technologies in speech therapy practice.] AB - The process of medical-healthcare technological revolution represents an advantage for the patient and for the care provider, in terms of costs and distances reduction. The telehomecare approach could be useful for monitoring the swallowing disorder in neurodegenerative diseases, preventing complications. In this study the applicability of telemedicine techniques for the monitoring of swallowing function, in patients affected by Huntington's disease (HD), was evaluated through the acquisition and analysis of the sound of swallowing. Two patients with HD were outpatient screened for dysphagia through the Bedside Swallowing Assessment Scale (BSAS) sensitized with pulse oximetry and cervical auscultation. Subsequently, the swallowing functionality was telemonitored for three months with Skype. The swallowing sounds were acquired with a detection microphone attached to the lateral edge of the trachea during fluid intake. The sounds were instantly processed and graphically represented through the Praat software. The analysis of the acoustic signal acquired remotely has made it possible to identify the situations that required immediate speech therapy intervention, suggesting to the patients further modifications of food consistencies, and saving frequent moving to the hospital even in the absence of critical situations. Remote assistance applied to speech therapy could represent a benefit for patients and their carers and a more efficient use of medical and health resources. PMID- 29493646 TI - ? PMID- 29493647 TI - ? PMID- 29493645 TI - [Cochrane and World Health Organization "Rehabilitation 2030: a call for action".] AB - INTRODUCTION: The World Health Organization (WHO) has launched in February 2017 "Rehabilitation 2030: a call for action". This is likely to have a deep impact in the Health Systems in the next few years. The new Cochrane Rehabilitation Field has been invited by WHO as a relevant stakeholder in this effort. WHO recognizes the dramatic changes in health and demographic profiles of populations that are characterizing the 21st century. Main goals of WHO are to ensure healthy lives and promote well-being for all at all ages, and to promote healthy life expectancy. METHODS: Health systems and health policies are placing increased emphasis on services targeted at improving functioning, and not only at decreasing morbidity and mortality. According to WHO, rehabilitation could be an answer to this need. Cochrane's strategy becomes significant in this context, as it is based on the production of high-quality evidence through systematic reviews to inform health decision making. RESULTS: Cochrane Rehabilitation is the appropriate instrument in this endeavour: its main goal is to convey to all rehabilitation professionals the best available evidence, but also to improve the Cochrane methods for evidence synthesis. This will help rehabilitation professionals to make decisions according to the best and most appropriate evidence. CONCLUSION: An important challenge of Cochrane Rehabilitation in the next future is to respond to the WHO "Rehabilitation 2030" call for action. PMID- 29493648 TI - [Red yeast rice, monacolin K, and pleiotropic effects.] AB - The extracts of red yeast rice represent a nutraceutical with proven cholesterol lowering effect. Its efficacy is proportional to the concentration on monacolin K in the extract that could reach the amount of 10 mg per daily dose. The daily assumption of monacolin K could then reduce LDL-cholesterol plasma levels by 15 25% in 6-8 weeks. The LDL-cholesterol reduction is associated with a proportional reduction in total cholesterolemia, non-HDL cholesterolemia, plasma apolipoprotein B, high-sensitivity C-reactive protein, and matrix metalloproteinases 2 and 9. Then, the red yeast rice lipid-lowering efficacy is associated with a significant improvement of endothelial function and pulse wave velocity, which are well-known and validated instrumental biomarkers of vascular aging. Beyond the cholesterol lowering efficacy and the statin-like mechanism of action, the risk of the use of monacolin K 10 mg per day are minimal, and mild myalgias could be foreseen only in frail patients previously intolerant to minimal statin dosages. In conclusion, red yeast rice titrated in monacolin K represents a good therapeutic tool for the management of moderate hypercholesterolemias in patients with low added cardiovascular disease risk. PMID- 29493649 TI - [The reform of the Penitentiary Order. A cultural revolution that involve the Mental Health Services]. AB - The reform of the penitentiary system (law 103/2017) which is about to enter into force in Italy represents a Copernican revolution for the management of psychiatric patients who are also authors of a crime. The change would have consequences similar to what happened with the law 180 of 1978. The basic principles on which the new Law is based are: 1) the extension of the faculty to suspend the sentence also for inmates and prisoners affected by a serious mental illness; 2) the full integration of the National Health System (SSN) and DSM in the penitentiary institutions; 3) the establishment of "sections for prisoners with disabilities", special sections for exclusive management for individuals with mental disorders, to be implemented inside the prisons and jails; 4) the possibility probation and parole for prisoners with sentences up to 6 years if suffering from mental illness with a procedure similar to the one already enacted for persons with drug dependency. The article deals with the positive aspects of the reform, but also with the critical aspects it presents in its implementation aspects: training of prison police officers and health workers; substantial and decisive employment of psychiatry in penal institutions; control functions by the DSM on patients; lack of staff and funds. The final aim of the reform is to contain recidivism, and the system must be organized on this goal. PMID- 29493650 TI - [Managing insomnia in the elderly patient: from pharmacology to subthreshold depression]. AB - Insomnia is the most common and widespread sleep disorder. Managing insomnia in the elderly patient becomes a difficult challenge for the presence of a multi disease and multi-drug condition. An organic and functional background that becomes even more fragile when the picture is complicated by psychomotor agitation and cognitive impairment. From the contribution of four experts of different fields and disciplines, stems the need to share an integrated vision that starts from the pharmacological basis of hypnotic drugs, delineates the features of depression in the elderly, addressed the delicate issue of chronic use/abuse of benzodiazepines and ultimately arrives to the management of behavioral disturbances. The pathway includes studies of clinical pharmacology and investigates the potential properties of trazodone, a multifunctional drug capable of acting on different biochemical and neurotransmitter pathways. PMID- 29493651 TI - [The origin of depression in Alzheimer disease: a systematic review]. AB - AIM: Depression was associated to Alzheimer's disease (AD), even if its role as predictive symptom, risk factor or reactive factor remains unclear. The aim of this review was to investigate the relation between depression and AD. More specifically, we aimed to examine if depression may be a prodrome of AD or an early reaction to cognitive decline. METHODS: A systematic review based on the electronic bibliographic databases (PsycINFO, PubMed, Scopus, Web of Science, Web of Knowledge) was carried out on the scientific literature from 2010 to 2016. Observational studies and literature reviews were included, searched for predefined inclusion criteria. RESULTS: A total of 29 studies were included. Most of the reviews reported that depression may be a risk factor for dementia. Moreover, frequency and severity of depressive episodes may increase the risk for dementia. However, the results are contradictory to a possible risk difference between early or late depression in determining the occurrence of AD. CONCLUSIONS: Depression may be a prodrome of dementia and a risk factor of AD. However, the hypothesis of depression as risk factor is the most accredited one. Finally, there is one evidence suggesting that depression is a reaction to cognitive decline of AD. PMID- 29493653 TI - Dimensional psychopathology of schizophrenia: SVARAD dimensional profiles in an acute inpatient sample AB - Objective: This study aimed at describing the dimensional profile of schizophrenia in an acute inpatient sample, and at exploring the different components of psychopathological suffering within this single diagnostic category according to a dimensional perspective. Methods: The sample consisted of 81 schizophrenic patients consecutively admitted to a psychiatric inpatient care unit. Each patient was administered the rapid dimensional assessment scale SVARAD (acronym for the Italian name "Scala per la VAlutazione RApida Dimensionale")and the Global Assessment of Functioning scale. Dimensional profiles were obtained from mean scores on each SVARAD item. Analysis of variance was used to test for differences between groups in mean SVARAD item scores. Results: The findings indicated that age, sex, psychosocial functioning, involuntary nature of the admission, and predominance of positive or disorganisation symptomatology are associated with differences in the mean dimensional profile. Also, sizable subgroups of patients with clinically significant levels of psychopathological dimensions (e.g., Sadness/Demoralisation, Anger/Aggressiveness, Impulsivity) that have limited overlap with the traditionally acknowledged domains of positive symptoms, negative symptoms, and disorganisation, were identified. No differences in any psychopathological dimension were found between the classical schizophrenia subtypes. Conclusions: The dimensional assessment with SVARAD helps appreciate the singularity of each patient within the same diagnostic category. The study suggests that recognising different dimensional profiles with the SVARAD may allow more personalised choices of treatment. PMID- 29493652 TI - [From OPG to REMS: the role of a territorial health service in the implementation of security and non-custodial measures towards offenders with psychological problems]. AB - AIMS: Managing health care for people suffering from mental illness is undergoing deep changes in recent years in Italy. The purpose of this study is to describe the progressive process of overcoming the Forensic Hospitals in Italy (OPGs) and to identify the necessary care and rehabilitation pathways in this process, in the experience of the territorial health service in Salerno, Italy. METHODS: An analysis of the recent laws related to the ongoing process and an analysis of epidemiological and structural data referring to the time interval between 2010 and 2017 concerning the OPGs/Residential Services for the Execution of Security Measures (RSESM)/Mental Health System in Campania, Italy and in the territory of Salerno in particular. RESULTS: The acts governing the transition from OPG to RSESM include DPCM 1/4/2008 and subsequent "Conferenza Unificata" agreements, other laws and regional health organizational regulations. A thorough restructuring of the National Health Service is required. A substantial path in Campania has been completed, with the closure of OPGs, the realization of definitive RSESM, the Departments for Mental Health Care in prison, the Regional Technical Group for overcoming the OPGs, the territorial Services for overcoming the OPGs and for Mental Health in Prison. The result of these transformations is a deep change in the health care approach, as evidenced by the current changes in action in indicative parameters of care pathways and their outcomes. CONCLUSIONS: The new approach shows both improvement features and totally or partially unaddressed problematic features. As for the actual management issues, improvements in communication between Mental Health Care and the magistracy. The overall evaluation of the transformations in progress is positive. At this stage, it is crucial to identify and monitor indicators of the pathways of care and their outcomes and to implement synergies among the systems involved. PMID- 29493654 TI - Preliminary findings on the association between attachment patterns and levels of growth hormone in a sample of children with non-organic failure to thrive AB - Introduction: Deficiency of growth hormone (GH) in absence of pituitary injuries is one of the causes of short stature and of the non organic failure to thrive (NOFTT) condition. Advances in developmental psychology have highlighted the role of emotions and caregiving behaviors in the organization of child's personality and psychobiology, with the mother-son attachment bond being considered a fundamental developmental experience. The objective of the present preliminary study was to assess whether there are significant correlations between attachment patterns and GH levels in a sample of subjects with NOFTT. Methods: Overall, 27 children (mean age 9.49+/-2.63 years) with NOFTT were enrolled. Perceived attachment security was assessed through the Security Scale (SS) and its subscales focused on maternal and paternal security. Pearson partial correlation was used to test associations between GH levels and SS measures adjusting for confounding factors (i.e. age, gender and body mass index). Results: Across all subjects, GH was significantly positively correlated with general security (r=0.425; p=0.038) and maternal security (r=0.451; p=0.027) and not significantly correlated with paternal security (r=0.237; p=0.264). Discussion: These findings preliminarily suggest that the association between GH levels and perceived attachment security may play a role in the pathophysiology of NOFTT and add to the accumulating evidence that attachment patterns may be related with specific psychoendocrine underpinnings. PMID- 29493655 TI - [The Rorschach method for obesity assessment: clinical study on a group of obese women]. AB - AIM: The purpose of this study is to explore through the Rorschach method the psychological and personological profile of the woman with obesity. METHODS: The Rorschach test was administered to 10 women with body mass index of 41.86+/-9.9 kg/m2 at the clinic for obesity surgical treatment at the University Hospital "Paolo Giaccone" of Palermo. RESULTS: The quantitative and qualitative analysis of the Rorschach responses detected in the study show: limited practical and creative sense in managing daily life situations, rigid control of emotions, affective turmoil, sense of inadequacy; sufficient examination of reality and adaptation social. CONCLUSION: The Rorschach method can be the privileged instrument for obesity, for its remarkable projective value, because it allows to capture the psychic suffering of the obese person, the representation and the image of the self, to identify the interaction between psycho-physical state and emotional investments. PMID- 29493657 TI - Erratum: Aplasia cutis congenita: Two case reports and discussion of the literature. AB - [This corrects the article on p. 273 in vol. 8, PMID: 29204308.]. PMID- 29493658 TI - Erratum: A longitudinal network analysis of social dynamics in rooks Corvus frugilegus: repeated group modifications do not affect social network in captive rooks. AB - [This corrects the article DOI: 10.1093/cz/zow083.]. PMID- 29493659 TI - Findings of Research Misconduct. PMID- 29493660 TI - Core principles of evolutionary medicine: A Delphi study. AB - Background and objectives: Evolutionary medicine is a rapidly growing field that uses the principles of evolutionary biology to better understand, prevent and treat disease, and that uses studies of disease to advance basic knowledge in evolutionary biology. Over-arching principles of evolutionary medicine have been described in publications, but our study is the first to systematically elicit core principles from a diverse panel of experts in evolutionary medicine. These principles should be useful to advance recent recommendations made by The Association of American Medical Colleges and the Howard Hughes Medical Institute to make evolutionary thinking a core competency for pre-medical education. Methodology: The Delphi method was used to elicit and validate a list of core principles for evolutionary medicine. The study included four surveys administered in sequence to 56 expert panelists. The initial open-ended survey created a list of possible core principles; the three subsequent surveys winnowed the list and assessed the accuracy and importance of each principle. Results: Fourteen core principles elicited at least 80% of the panelists to agree or strongly agree that they were important core principles for evolutionary medicine. These principles over-lapped with concepts discussed in other articles discussing key concepts in evolutionary medicine. Conclusions and implications: This set of core principles will be helpful for researchers and instructors in evolutionary medicine. We recommend that evolutionary medicine instructors use the list of core principles to construct learning goals. Evolutionary medicine is a young field, so this list of core principles will likely change as the field develops further. PMID- 29493661 TI - Right to Try Legislation Should Focus on Patients, Not Politics. PMID- 29493662 TI - Corrigendum: Effects on Subclinical Heart Failure in Type 2 Diabetic Subjects on Liraglutide Treatment vs. Glimepiride Both in Combination with Metformin: A Randomized Open Parallel-Group Study. AB - [This corrects the article on p. 325 in vol. 8, PMID: 29184539.]. PMID- 29493663 TI - Corrigendum: Monitoring T-Cell Responses in Translational Studies: Optimization of Dye-Based Proliferation Assay for Evaluation of Antigen-Specific Responses. AB - [This corrects the article on p. 1870 in vol. 8, PMID: 29312346.]. PMID- 29493664 TI - Erratum: Spinal cord herniation after brachial plexus injury. AB - [This corrects the article on p. 305 in vol. 8, PMID: 29404192.]. PMID- 29493665 TI - Lanthanide-doped upconversion nanoparticles complexed with nano-oxide graphene used for upconversion fluorescence imaging and photothermal therapy. AB - In recent years, multifunctional nanoparticles have attracted much research interest in various biomedical applications such as biosensors, diagnosis, and drug delivery systems. In this study, we report an NIR imaging diagnosis and therapy nanoplatform which is developed by complexing upconversion nanoparticles (UCNP@OA) NaLuF4:Er3+,Yb3+ with nanographene oxide (NGO). The obtained nanocomposites UCNP@NGO showed excellent stability and low cell toxicity, which not only acted as upconversion luminescence (UCL) probes for tumor imaging, but also served as therapy agents by converting laser energy into thermal energy for photothermal therapy (PTT) with high photothermal conversion efficiency. This work highlights the potential of UCNP@NGO nanocomposites as an integrated theranostic nanoplatform for the UCL image combinatorial PTT of cancer, providing a promising candidate for clinical antitumor treatments. PMID- 29493666 TI - Predictive modeling of intrinsic strengths for several groups of chemically related monolayers by a reference model. AB - The linear correlation between the ratios of linear and nonlinear intrinsic mechanical properties allows the prediction of largely unknown nonlinear fracture properties of brittle two-dimensional (2D) solids using a reference model. It is demonstrated that from accurately known Young's moduli unknown theoretical strengths can be derived. The predictive power of the reference model for the systematic evaluation of the fundamental mechanical behavior of whole groups of compounds with chemically-related configurations is shown. This is revealed for graphene-like atomic monolayers, various derivatives of graphene, transition metal dichalcogenide (TMDC), and transition-metal monochalcogenide (TMMC) molecular monolayers of the fast growing family of 2D solids. The estimated unknown intrinsic strengths represent the upper limits for the mechanical performance of 2D compounds and can be used to judge the actual deviations between real monolayers and their ideal counterparts. A detailed comparison of the reference model with existing experiments and density functional theory (DFT) calculations confirmed that the ratios of Young's moduli and intrinsic strengths reach a factor of ~6 for strongly bonded TMMCs, the bulk value of ~9 for graphene like monolayers, ~11 for graphene derivatives, whereas for transition-metal dichalcogenide (TMDC) monolayers the ratio is ~13.5. With its minimal requirement of mechanical input data and its versatility the reference model provides a unique tool to predict unknown nonlinear mechanical properties. PMID- 29493667 TI - Understanding proton capture and cation-induced dimerization of [Ag29(BDT)12]3- clusters by ion mobility mass spectrometry. AB - Proton transfer reactions have been a topic of fundamental interest in several areas of chemistry and biology. However, such reactivity has not been explored in detail for nanoscale materials. In this article, we present a unique reaction of an atomically precise monolayer-protected silver nanocluster, [Ag29(BDT)12]3-, with a proton (H+). Under controlled conditions, the strong proton affinity facilitated a complete conversion of the cluster to its protonated form, [Ag29(BDT)12H]2-. Moreover, binding of alkali metal ions (Li+, Na+, K+, Rb+ and Cs+) induced specific structural changes and also favored dimerization of the cluster. In this case, the cations acted as a bridge between the two clusters and the degree of dimerization was specific to the size of the cations. The conformational changes and separation of the alkali-metal ion bound dimers from their respective monomers have been investigated by ion mobility mass spectrometry (IM MS) and tandem mass spectrometric studies. Density functional theory (DFT) calculations have been used to determine the possible structures of the monomers and the dimers. Similar reactivity of the cluster can also be extended to other metal ions. While the present study helps to expand the ion chemistry of atomically precise clusters, gas-phase basicity of the molecule can be explored in further detail and this can find applications in the areas of sensing and materials in general. PMID- 29493668 TI - Solid-phase extraction as sample preparation of water samples for cell-based and other in vitro bioassays. AB - In vitro bioassays are increasingly used for water quality monitoring. Surface water samples often need to be enriched to observe an effect and solid-phase extraction (SPE) is commonly applied for this purpose. The applied methods are typically optimised for the recovery of target chemicals and not for effect recovery for bioassays. A review of the few studies that have evaluated SPE recovery for bioassays showed a lack of experimentally determined recoveries. Therefore, we systematically measured effect recovery of a mixture of 579 organic chemicals covering a wide range of physicochemical properties that were spiked into a pristine water sample and extracted using large volume solid-phase extraction (LVSPE). Assays indicative of activation of xenobiotic metabolism, hormone receptor-mediated effects and adaptive stress responses were applied, with non-specific effects determined through cytotoxicity measurements. Overall, effect recovery was found to be similar to chemical recovery for the majority of bioassays and LVSPE blanks had no effect. Multi-layer SPE exhibited greater recovery of spiked chemicals compared to LVSPE, but the blanks triggered cytotoxicity at high enrichment. Chemical recovery data together with single chemical effect data were used to retrospectively estimate with reverse recovery modelling that there was typically less than 30% effect loss expected due to reduced SPE recovery in published surface water monitoring studies. The combination of targeted experiments and mixture modelling clearly shows the utility of SPE as a sample preparation method for surface water samples, but also emphasizes the need for adequate controls when extraction methods are adapted from chemical analysis workflows. PMID- 29493669 TI - Identification and characterization of proteolytically resistant gluten-derived peptides. AB - The lack of digestibility of certain gluten proteins is essential in the development of celiac disease (CD). Gluten proteins are remarkably resistant to luminal and brush-border proteolysis owing to their high proline and glutamine content. Consequently, large fragments remain intact after digestion exerting toxic effects. Intestinal brush-border membrane vesicles (BBMV) have been described as having strong proteolytic activity mainly through prolyl endopeptidase enzymes. The purpose of this work was to monitor the gastrointestinal digestion of specific CD epitopes by means of an in vitro gastrointestinal digestion model that included incubation with brush-border membrane enzymes. Gluten hydrolysates were characterized by mass spectrometry and the immunologic peptides were tracked by searching the main T-cell stimulating epitopes which have been widely described. The immunologic potential of gluten hydrolysates was further analysed by enzyme-linked immunosorbent assay (ELISA). The results showed that the composition of gluten hydrolysates depended on the digestion time and protein structural characteristics. On the other hand, the main T-cell stimulating epitopes formed during hydrolysis depend on the precursor protein. Glutenin oligopeptides were degraded faster whereas gliadin, mainly alpha-gliadin oligopeptides, remained intact for a long time. MS-based analysis showed that the formation of the epitopes from gamma-gliadin and omega-gliadin or glutenin was favoured but they were generally degraded during the gastrointestinal treatment. However, the peptides containing the epitope PFPQPQLPY (alpha-gliadin) remained intact even after 180 min of digestion time. Overall, from all the epitopes tracked, PFPQPQLPY was the most resistant to in vitro BBMV digestion. PMID- 29493681 TI - In situ fabrication of two-dimensional g-C3N4/Ba5Ta4O15 nanosheet heterostructures with efficient charge separations and photocatalytic hydrogen evolution under visible light illumination. AB - Separation of photo-generated electron-hole pairs plays a crucial role in determining the practical performance of semiconductor photocatalysts. Here we have successfully fabricated two dimensional g-C3N4/Ba5Ta4O15 nanosheet heterostructures through an in situ urea degradation method. The so-formed nanosheet heterostructures demonstrate superior photocatalytic activities in H2 evolution reactions over individual component. Further analysis using photoelectrochemical measurements suggests efficient charge separations at the interfaces of these heterostructures which contribute to a prolonged lifetime of photo-generated charges as well as the much enhanced photocatalytic activities. The in situ fabrication method adopted in this work ensures a firm anchorage of g C3N4 onto Ba5Ta4O15 nanosheets and a face-to-face contact between these two semiconductors. Such a peculiar microstructure is critical to the high photocatalytic activity and apparently outweighs the conventional ones that involve only physical mixtures of two semiconductors and a point-to-point contact. PMID- 29493671 TI - Locating the binding domains in a highly selective mixed matrix membrane via synchrotron IR microspectroscopy. AB - The binding domains within a mixed matrix membrane (MMM) that is selective for CO2 comprising MFM-300(Al) and the polymer 6FDA-Durene-DABA have been established via in situ synchrotron IR microspectroscopy. The MOF crystals are fully accessible and play a critical role in the binding of CO2, creating a selective pathway to promote permeation of CO2 within and through the MMM. This study reveals directly the molecular mechanism for the overall enhanced performance of this MMM in terms of permeability, solubility and selectivity for CO2. PMID- 29493682 TI - A numerical calculation method of environmental impacts for the deep sea mining industry - a review. AB - Since the gradual decrease of mineral resources on-land, deep sea mining (DSM) is becoming an urgent and important emerging activity in the world. However, until now there has been no commercial scale DSM project in progress. Together with the reasons of technological feasibility and economic profitability, the environmental impact is one of the major parameters hindering its industrialization. Most of the DSM environmental impact research focuses on only one particular aspect ignoring that all the DSM environmental impacts are related to each other. The objective of this work is to propose a framework for the numerical calculation methods of the integrated DSM environmental impacts through a literature review. This paper covers three parts: (i) definition and importance description of different DSM environmental impacts; (ii) description of the existing numerical calculation methods for different environmental impacts; (iii) selection of a numerical calculation method based on the selected criteria. The research conducted in this paper provides a clear numerical calculation framework for DSM environmental impact and could be helpful to speed up the industrialization process of the DSM industry. PMID- 29493670 TI - ZnO nanoparticles affect intestinal function in an in vitro model. AB - Zinc oxide nanoparticles (ZnO NP) may be present in food packaging, which would put consumers at risk of NP ingestion. There is little information on the amount of ZnO NP that are present in food packaging and the effects of ZnO exposure on intestinal function. To estimate physiologically relevant ZnO exposures, foods that are naturally low in zinc (Zn), but are commonly packaged with ZnO NP, such as tuna, corn, and asparagus, were analyzed with inductively coupled plasma mass spectrometry (ICP-MS). It was found that the Zn present in a serving of these foods is approximately one hundred times higher than the recommended dietary allowance. An in vitro model of the small intestine composed of Caco-2 and HT29 MTX cells was used to investigate the effects of ZnO NP exposure. Cells were exposed to physiologically realistic doses of pristine NP in culture medium and to NP subjected to an in vitro digestion to better reflect the transformation that the NP may undergo once they enter the human GI tract. Uptake and/or transport of iron (Fe), Zn, glucose, and fatty acids were assessed and intestinal alkaline phosphatase (IAP) levels were measured before and after NP exposure. The findings show that there is a 75% decrease in Fe transport and a 30% decrease in glucose transport following ZnO NP exposure. These decreases were consistent with gene expression changes for their transporters. There is also evidence that the ZnO NP affect the microvilli of the intestinal cells, therefore reducing the amount of surface area available to absorb nutrients. These results suggest that the ingestion of physiologically relevant doses of ZnO NP can alter intestinal function in an in vitro model of the human small intestine. PMID- 29493683 TI - The kinetics and mechanism of oxidation of reduced phosphovanadomolybdates by molecular oxygen: theory and experiment in concert. AB - The reactivity of the H5PV2Mo10O40 polyoxometalate and its analogues as an electron transfer and electron transfer-oxygen transfer oxidant has been extensively studied in the past and has been shown to be useful in many transformations. One of the hallmarks of this oxidant is the possibility of its re-oxidation with molecular oxygen, thus enabling aerobic catalytic cycles. Although the re-oxidation reaction was known, the kinetics and mechanism of this reaction have not been studied in any detail. Experimentally, we show that both the one- and two-electron reduced polyoxometalate are reactive with O2, the two electron one more so. The reactions are first-order in the polyoxometalate and O2. Solvents also have a considerable effect, protic solvents being preferred over aprotic ones. H5PV2Mo10O40 was reduced either by an electron transfer reaction (H2) or an electron transfer-oxygen transfer reaction (Ph3P). Similar rate constants and activation parameters were observed for both. DFT calculations carried out on the re-oxidation reactions strongly suggest an inner-sphere process. The process involves first the formation of a coordinatively unsaturated site (CUS) and subsequently the binding of O2 to form superoxo and then peroxo eta2-O2 adducts. Most interestingly, although vanadium is the reactive redox centre as well as a necessary component for the oxidative activity of H5PV2Mo10O40, and a CUS can be formed at both Mo and V sites, O2 coordination occurs mostly at the Mo CUSs, preferably those where the vanadium centers are distal to each other. PMID- 29493685 TI - Rapid fabrication of solid-state nanopores with high reproducibility over a large area using a helium ion microscope. AB - The fabrication of solid-state nanopores in an insulating membrane has attracted much attention for biomolecule analysis such as DNA sequencing and detection in recent years. For practical applications and device integration, the challenges include precise size control for sub 10 nm nanopores, excellent repeatability and rapid fabrication over a large area to reduce the cost for mass production. A helium ion beam could provide an effective fabrication approach to produce such solid-state nanopores. It is easy to control the nanopore size and reach sub 10 nm pore size with a simple change in the milling time with an appropriate ion beam current. Here we report new results in a set of experiments demonstrating that with a small range of stage automatized motions and equal mill times one can obtain good fabrication reproducibility in nanopore sizes (<10% variation in size). The automation in the stage motion and milling time opens a door for the rapid mass production of nanopore chips over a wafer size of several inches. PMID- 29493684 TI - Molecular logic gates: the past, present and future. AB - The field of molecular logic gates originated 25 years ago, when A. P. de Silva published a seminal article in Nature. Stimulated by this ground breaking research, scientists were inspired to join the race to simulate the workings of the fundamental components of integrated circuits using molecules. The rules of this game of mimicry were flexible, and have evolved and morphed over the years. This tutorial review takes a look back on and provides an overview of the birth and growth of the field of molecular logics. Spinning-off from chemosensor research, molecular logic gates quickly proved themselves to be more than intellectual exercises and are now poised for many potential practical applications. The ultimate goal of this vein of research became clearer only recently - to "boldly go where no silicon-based logic gate has gone before" and seek out a new deeper understanding of life inside tissues and cells. PMID- 29493686 TI - Organic field-effect transistors integrated with Ti2CTx electrodes. AB - Recently, MXenes, which are two-dimensional early transition metal carbides and carbonitrides, have attracted wide attention because of their unique properties. In this study, the electrode applications of Ti2CTx, a member of the MXene family, in pentacene organic field-effect transistors (OFETs) are assessed. Kelvin probe force microscopy analysis was performed to determine the work function of Ti2CTx, which is estimated to be around 5.1 eV. Devices with Ti2CTx electrodes and pentacene channels were fabricated and their electronic performances were evaluated. The contact resistance between Ti2CTx and pentacene is as low as 3 kOmega cm, superior to those of other reported electrode materials. The temperature-dependent current-voltage transfer characteristics of the devices were used to extract activation energy, estimated to be 0.17 eV. This activation energy value is much lower than those of other electrode materials and demonstrates that Ti2CTx is a promising electrode for high performance OFET applications. PMID- 29493687 TI - Precision compatibilizers for composites: in-between self-aggregation, surfaces recognition and interface stabilization. AB - Peptide-polymer conjugates are applied as interface stabilizers that are precisely tuned to recognize the surfaces of inorganic constituents in composites. A set of peptide sequences is usually selected through phage-display and a strategy is presented for the identification of the most effective sequences through the evaluation of secondary interactions, including not only surface binding but also solubility and self-aggregation tendency. PMID- 29493688 TI - Two dimensional semiconductors for ultrasound-mediated cancer therapy: the case of black phosphorus nanosheets. AB - With black phosphorus (BP) as an example, the first two-dimensional (2D) semiconductor based sonosensitizer (Au@BP nanohybrids) was fabricated. Under ultrasound irradiation, Au@BP nanohybrids can generate 1O2 in deep tissues and eradicate tumors with high efficacy. This platform paves the way for the application of 2D semiconductors in sonodynamic cancer therapy. PMID- 29493689 TI - Assembly-disassembly switching of self-sorted nanotubules forming dynamic 2-D porous heterostructure. AB - We report the pH-driven formation of a dynamic 2-D porous heterostructure through assembly-disassembly switching of the stacked macrocycles of nanotubules and their subsequent spreading on the surfaces of a self-sorted sheet assembly in a hierarchical co-assembly. The 2-D ordered porous heterostructure is able to discriminate spherical C60 from flat coronene through shape selective adsorption. PMID- 29493691 TI - Fluorescence quantum yields of dye aggregates: a showcase example based on self assembled perylene bisimide dimers. AB - Constituting an intermediate state of matter between molecules and solid state materials, dye aggregates can give important insights into functional properties. Despite the importance of fluorescence for many applications, it turns out that the conventional methods for quantum yield determination are not applicable to dye aggregates and so far no method has been introduced for the accurate determination of the fluorescence quantum yields of dye aggregates. Here we suggest two measurement routines for the quantum yield determination of strongly absorbing dye aggregates. Both methods provide the quantum yield of the aggregated species without the necessity of reaching a fully aggregated state, which is particularly important for the most common case imparted by the low association constants of pi-pi-stacking interactions. The routines are experimentally validated with two perylene bisimide dyes whose self-assembly is driven by the concerted interplay of hydrogen bonding and pi-pi-stacking interactions, leading to structurally well defined co-facially stacked dimers at intermediate concentrations and a further growth into larger H-aggregates at a higher concentration. Compared to other H-aggregates relatively high fluorescence quantum yields of up to 28% are found for both the co-facially stacked dimers and the larger H-aggregates. PMID- 29493690 TI - Importance of matrix inelastic deformations in the initial response of magnetic elastomers. AB - Being able to predict and understand the behaviour of soft magnetic materials paves the way to their technological applications. In this study we analyse the magnetic response of soft magnetic elastomers (SMEs) with magnetically hard particles. We present experimental evidence of a difference between the first and next magnetisation loops exhibited by these SMEs, which depends non-monotonically on the interplay between the rigidity of the polymer matrix, its mechanical coupling with the particles, and the magnetic interactions in the system. In order to explain the microstructural mechanism behind this behaviour, we used a minimal computer simulation model whose results evidence the importance of irreversible matrix deformations due to both translations and rotations of the particles. To confirm the simulation findings, computed tomography (CT) was used. We conclude that the initial exposure to the field triggers the inelastic matrix relaxation in the SMEs, as particles attempt to reorient. However, once the necessary degree of freedom is achieved, both the rotations and the magnetisation behaviour become stationary. We expect this scenario not only to be limited to the materials studied here, but also to apply to a broader class of hybrid SMEs. PMID- 29493692 TI - Soft to tough: ordering in and tack of polymeric materials. AB - In the present paper, adhesive properties (in terms of practical work of adhesion, Wa, and maximum stress in probe tack test) of blends of polyvinyl pyrrolidone (PVP) with polyethylene glycol (PEG-400) are studied at different level of stretching stress, applied perpendicular to the probe. The anisotropic behavior in both directions is investigated. Upon stretching, blends of 50/50 wt% PVP-PEG demonstrate little decrease in tack and little increase in maximum debonding stress. Whereas for more cohesive blends like PVP-PEG mixtures with down to 35 wt% of PEG, a significant reduction in Wa at the size of an order of a magnitude is observed. Similar behavior is measured with a commercial product from 3M with the trade name "Command". For the first time, the anisotropy of probe tack properties of two identical strips after stretching is demonstrated via a specially designed quasi-2D setup, where the external force is applied either along or transverse the long side of the quasi-2D substrate, resulting in a significant difference in the measured probe tack curves. This phenomenon has been described by the block model, developed by Yamaguchi et al. We extended the block model by introducing the stretching stress into the model. The differences are explained by the difference in kinetics of the cavity growth between the two directions. PMID- 29493693 TI - Construction of alpha-methoxyimidoyl ketonitrones via phosphite-mediated addition of alpha-keto N-tert-butanesulfinyl imidates to nitrosoarenes. AB - A dimethyl phosphite-mediated addition of alpha-keto N-tert-butanesulfinyl imidates to nitrosoarenes was developed. Nitrosoarenes were successfully used as electrophiles to trap aza-enolate intermediates that were generated from nucleophilic addition of deprotonated phosphite to alpha-keto N-tert butanesulfinyl imidates and following phospha-Brook rearrangement, allowing efficient construction of ketonitrones with excellent (Z)-geometries. PMID- 29493694 TI - An atmosphere and light tuned highly diastereoselective synthesis of cyclobuta/penta[b]indoles from aniline-tethered alkylidenecyclopropanes with alkynes. AB - Metal-free and environmentally friendly synthesis highly controlled by natural sources like visible light and air (or oxygen) is always a pursuit of green chemistry. In this paper, an atmosphere and light tuned highly diastereoselective synthesis of two important polyheterocyclic skeletons: cyclobuta/penta[b]indoles from aniline-tethered alkylidenecyclopropanes with alkynes, has been developed. The chiral cyclobuta/penta[b]indoles have also been obtained by optical resolution. PMID- 29493696 TI - B3@Si12+: strong stabilizing effects of a triatomic cyclic boron unit on tubular silicon clusters. AB - Remarkably strong effects of the aromatic B3 cycle in stabilizing tubular silicon clusters were observed for the first time. The doped cluster B3@Si12+ presents a novel structural motif for silicon clusters in which a B3 cycle is encapsulated into a (6 * 2) Si12 prism giving rise to a high symmetry stable tubular structure (D3h). A large amount of electron density is transferred to the boron cycle, and the B3delta- unit not only retains a delocalized bonding pattern within the Si12 prism but also enables a two-fold aromaticity for the resulting silicon double ring. This double ring can be used as a building block to make longer nanotubes. PMID- 29493697 TI - Using lead chalcogenide nanocrystals as spin mixers: a perspective on near infrared-to-visible upconversion. AB - The process of upconversion leads to emission of photons higher in energy than the incident photons. Near-infrared-to-visible upconversion, in particular, shows promise in sub-bandgap sensitization of silicon and other optoelectronic materials, resulting in potential applications ranging from photovoltaics that exceed the Shockley-Queisser limit to infrared imaging. A feasible mechanism for near-infrared-to-visible upconversion is triplet-triplet annihilation (TTA) sensitized by colloidal nanocrystals (NCs). Here, the long lifetime of spin triplet excitons in the organic materials that undergo TTA makes upconversion possible under incoherent excitation at relatively low photon fluxes. Since this process relies on optically inactive triplet states, semiconductor NCs are utilized as efficient spin mixers, absorbing the incident light and sensitizing the triplet states of the TTA material. The state-of-the-art system uses rubrene with a triplet energy of 1.14 eV as the TTA medium, and thus allows upconversion of light with photon energies above ~1.1 eV. In this perspective, we review the field of lead sulfide (PbS) NC-sensitized near-infrared-to-visible upconversion, discuss solution-based upconversion, and highlight progress made on solid-state upconversion devices. PMID- 29493698 TI - Poly(meta-phenylene oxides) for the design of a tunable, efficient, and reusable catalytic platform. AB - We present poly(meta-phenylene oxides) as versatile and tunable scaffolds for immobilized catalyst design. Their modular synthesis enables the rational incorporation of different side chain groups with positional control along the polymer backbone, providing an easy means to modulate polymer properties, and their corresponding catalytic activity. The coordinative convolution of these polymers with (NH4)2PdCl4 affords efficient, reusable catalysts for various organic transformations. PMID- 29493701 TI - Edge-on and face-on functionalized Pc on enriched semiconducting SWCNT hybrids. AB - Enriched semiconducting single-walled carbon nanotubes (SWCNT (6,5) and SWCNT (7,6)) and HiPco nanotubes were covalently functionalized with either zinc phthalocyanine or silicon phthalocyanine as electron donors. The synthetic strategy resulted in edge-on and face-on geometries with respect to the phthalocyanine geometry, with both phthalocyanines held by an electronically conducting diphenylacetylene linker. The extent of functionalization in the MPc SWCNT (M = Zn or Si) donor-acceptor nanohybrids was determined by systematic studies involving AFM, TGA, XPS, optical and Raman techniques. Intramolecular interactions in MPc-SWCNT nanohybrids were probed by studies involving optical absorbance, Raman, luminescence and electrochemical studies. Different degrees of interactions were observed depending on the type of MPc and mode of attachment. Substantial quenching of MPc fluorescence in these hybrids was observed from steady-state and three-dimensional fluorescence mapping, which suggests the occurrence of excited state events. Evidence for the occurrence of excited state charge transfer type interactions was subsequently secured from femtosecond transient absorption studies covering both the visible and near-infrared regions. Furthermore, electron-pooling experiments performed in the presence of a sacrificial electron donor and a second electron acceptor revealed accumulation of one-electron reduced product upon continuous irradiation of the nanohybrids. In such experiments, the ZnPc-SWCNT (6,5) nanohybrid outperformed other nanohybrids and this suggests that this is a superior donor-acceptor system for photocatalytic applications. PMID- 29493702 TI - Fabrication, characterization, and high temperature surface enhanced Raman spectroscopic performance of SiO2 coated silver particles. AB - We present a systematic study on the fabrication, characterization and high temperature surface enhanced Raman spectroscopy (SERS) performance of SiO2 coated silver nanoparticles (Ag@SiO2) on a flat substrate, aiming to obtain a thermally robust SERS substrate for monitoring high temperature reactions. We confirm that a 10-15 nm SiO2 coating provides a structure stability up to 900 degrees C without significantly sacrificing the enhancement factor, while the uncoated particle cannot retain the SERS effect above 500 degrees C. The finite difference time domain (FDTD) simulation results supported that the SiO2 coating almost has no influence on the distribution of the electric field but only physically trapped the most enhanced spot inside the coating layer. On this thermally robust substrate, we confirmed that the SERS of horizontally aligned single walled carbon nanotubes is stable at elevated temperatures, and demonstrate an in situ Raman monitoring of the atmosphere of the annealing process of nanodiamonds, in which the interconverting process of C-C bonds is unambiguously observed. We claim that this is a first experimental proof that the high temperature SERS effect can be preserved and applied in a chemical reaction at temperature above 500 degrees C. This versatile substrate also enables novel opportunities for observing growth, etching, and structure transformation of many 0D and 2D nano-materials. PMID- 29493703 TI - Mechanism of the formation of microphase separated water clusters in a water mediated physical network of perfluoropolyether tetraol. AB - Perfluoropolyether tetraol (PFPE tetraol) possesses a hydrophobic perfluoropolyether chain in the backbone and two hydroxyl groups at each chain terminal, which facilitates the formation of hydrogen bonds with water molecules resulting in the formation an extended physical network. About 3 wt% water was required for the formation of the microphase separated physical network of PFPE tetraol. The mechanism responsible for the microphase separation of water clusters in the physical network was studied using a combination of techniques such as NMR spectroscopy, molecular dynamics (MD) simulations and DSC. MD simulation studies provided evidence for the formation of clusters in the PFPE tetraol physical network and the size of these clusters increased gradually with an increase in the extent of hydration. Both MD simulations and NMR spectroscopy studies revealed that these clusters position themselves away from the hydrophobic backbone or vice versa. The presence of intra- and inter-chain aggregation possibility among hydrophilic groups was evident. DSC results demonstrated the presence of tightly and loosely bound water molecules to the terminal hydroxyl groups of PFPE tetraol through hydrogen bonding. The data from all the three techniques established the formation of a physical network driven by hydrogen bonding between the hydrophilic end groups of PFPE tetraol and water molecules. The flexible nature of the PFPE tetraol backbone and its low solubility parameter favour clustering of water molecules at the terminal groups and result in the formation of a gel. PMID- 29493705 TI - Braille and the Need to Innovate for the Blind. PMID- 29493707 TI - Projection of Eye Disease Burden in Singapore. AB - INTRODUCTION: Singapore's ageing population is likely to see an increase in chronic eye conditions in the future. This study aimed to estimate the burden of eye diseases among resident Singaporeans stratified for age and ethnicity by 2040. MATERIALS AND METHODS: Prevalence data on myopia, epiretinal membrane (ERM), retinal vein occlusion (RVO), age macular degeneration (AMD), diabetic retinopathy (DR), cataract, glaucoma and refractive error (RE) by age cohorts and educational attainment from the Singapore Epidemiology of Eye Diseases (SEED) study were applied to population estimates from the Singapore population model. RESULTS: All eye conditions are projected to increase by 2040. Myopia and RE will remain the most prevalent condition, at 2.393 million (2.32 to 2.41 million) cases, representing a 58% increase from 2015. It is followed by cataract and ERM, with 1.33 million (1.31 to 1.35 million), representing an 81% increase, and 0.54 million (0.53 to 0.549 million) cases representing a 97% increase, respectively. Eye conditions that will see the greatest increase from 2015 to 2040 in the Chinese are: DR (112%), glaucoma (100%) and ERM (91.4%). For Malays, DR (154%), ERM (136%), and cataract (122%) cases are expected to increase the most while for Indians, ERM (112%), AMD (101%), and cataract (87%) are estimated to increase the most in the same period. CONCLUSION: Results indicate that the burden for all eye diseases is expected to increase significantly into the future, but at different rates. These projections can facilitate the planning efforts of both policymakers and healthcare providers in the development and provision of infrastructure and resources to adequately meet the eye care needs of the population. By stratifying for age and ethnicity, high risk groups may be identified and targeted interventions may be implemented. PMID- 29493706 TI - Predictors of General Functioning and Correlates of Quality of Life: A Cross Sectional Study among Psychiatric Outpatients. AB - INTRODUCTION: Functioning and quality of life (QOL) are negatively impacted as a result of mental illness. This study aimed to determine the: i) socio-demographic and clinical correlates of functioning and; ii) associations between functioning and QOL in a multiethnic sample of psychiatric outpatients. MATERIALS AND METHODS: This was a cross-sectional study of outpatients receiving treatment from a tertiary psychiatric hospital. Functioning was assessed using the Global Assessment of Functioning (GAF) scale, while QOL was measured using the World Health Organization Quality of Life-BREF (WHOQOL-BREF) which comprises 4 domains: physical health, psychological health, social relationships and environment. RESULTS: Various socio-demographic and clinical correlates were associated with functioning including employment and marital status, education and diagnosis. Depression was the only clinical characteristic which negatively correlated with functioning (P = 0.035). Amongst the whole sample, multiple linear regressions revealed that functioning was positively associated with all 4 QOL domains (physical health [P <0.001], psychological health [P <0.001], social relationships [P <0.001] and environment [P <0.001]). Further analysis of each diagnostic group revealed that functioning was positively associated with all 4 QOL domains in the anxiety, depression and obsessive compulsive disorder subsamples, while in the schizophrenia subsample, functioning was only significantly associated with all environment domain. CONCLUSION: Functional impairments were associated with different socio-demographic and clinical characteristics, which should be addressed when planning tailored treatment and interventions. Given that functioning is significantly associated with QOL, it is crucial to regularly assess and monitor them (in addition to symptomatic outcomes and adopting a more holistic and biopsychosocial approach). PMID- 29493708 TI - Can Robots Accelerate the Learning Curve for Surgical Training? An Analysis of Residents and Medical Students. AB - Surgical traineeship has traditionally been based on a master apprentice model where learning takes place in the operating theatre. This approach has changed over the past few years with greater emphasis on surgical training taking place within the surgical skills laboratory. We developed a high fidelity simulator, the Image-guided Robotic Assisted Surgical simulator (IRAS) with an incorporated robotic guidance feature. The robot system is developed to mimic the process of an experienced surgeon physically holding a trainee's hands to demonstrate maneuvering of the laparoscopic instruments. We aimed to assess the efficacy of incorporating robotic guidance into this high fidelity surgical simulator. Forty two participants (13 surgical residents and 29 medical students) were recruited. Participants had one practice run for familiarisation and subsequently performed the virtual laparoscopic cholecystectomy (LC) once. Among the medical students, they were ransomised to either a control or intervention group. They were tasked to perform a second- and third-timed LC assessment. Participants were asked to rate the simulator using a 5-point Likert scale Questionnaire. IRAS rated favourably in hand-eye coordination and training bimanual dexterity (mean score: 4.1 and 4.0 among students, 3.4 and 3.4 among residents) though it faired suboptimally in realism. At baseline, residents were statistically faster compared to students (overall time: 418.9 vs 586.8 seconds, P = 0.001). Participants randomised to the intervention group consistently scored better. However, their overall time were not statistically significant from the control group. The robotic guidance capability of the IRAS is a key advantage of this simulator platform over the conventional platform. PMID- 29493709 TI - Clinical and Reproductive Outcomes Following Hysteroscopic Adhesiolysis for Asherman Syndrome in an Asian Population. PMID- 29493710 TI - Preschool Teachers' and Parents' Understanding of Early Childhood Temperament in an Asian Culture - Implications on Child Health and Development. PMID- 29493711 TI - Birth Outcomes and Successive Pregnancy Rates in Adolescents Attending a Specialised Antenatal Clinic. PMID- 29493712 TI - Recurrent Wheeze in a Young Patient. PMID- 29493713 TI - Workplace interventions to improve work ability: A systematic review and meta analysis of their effectiveness. AB - Objective Extended working lives due to an ageing population will necessitate the maintenance of work ability across the life course. This systematic review aimed to analyze whether workplace interventions positively impact work ability. Methods We searched Medline, PsycINFO, CINAHL and Embase databases using relevant terms. Work-based interventions were those focused on individuals, the workplace, or multilevel (combination). Work ability - measured using the work ability index (WAI) or the single-item work ability score (WAS) - was the outcome measure. Grading of Recommendations Assessment, Development & Evaluation (GRADE) criteria was used to assess evidence quality, and impact statements were developed to synthesize the results. Meta-analysis was undertaken where appropriate. Results We reviewed 17 randomized control trials (comprising 22 articles). Multilevel interventions (N=5) included changes to work arrangements and liaisons with supervisors, whilst individual-focused interventions (N=12) involved behavior change or exercise programs. We identified only evidence of a moderate quality for either individual or multilevel interventions aiming to improve work ability. The meta-analysis of 13 studies found a small positive significant effect for interventions on work ability [overall pooled mean 0.12, 95% confidence interval (CI) 0.03-0.21] with no heterogeneity for the effect size (Chi 2=11.28, P=0.51; I 2=0%). Conclusions The meta-analysis showed a small positive effect, suggesting that workplace interventions might improve work ability. However, the quality of the evidence base was only moderate, precluding any firm conclusion. Further high quality studies are require to establish the role of interventions on work ability. PMID- 29493714 TI - Prevention of hand eczema: effect of an educational program versus treatment as usual - results of the randomized clinical PREVEX trial. AB - Objective Occupational hand eczema has adverse health and socioeconomic impacts for the afflicted individuals and society. Prevention and treatment strategies are needed. This study aimed to assess the effectiveness of an educational intervention on sickness absence, quality of life and severity of hand eczema. Methods PREVEX (PreVention of EXema) is an individually randomized, parallel group superiority trial investigating the pros and cons of one-time, 2-hour, group-based education in skin-protective behavior versus treatment as usual among patients with newly notified occupational hand eczema, with follow-up after one year. Co-primary outcomes were total sickness absence, health-related quality of life (HR-QoL), and self-reported severity of hand eczema. Results Patients (N=1668) with notified occupational skin diseases from July 2012 to November 2014 were invited to participate in the trial. Of these, 756 were randomized to the intervention (N= 376) versus control (N=380) group. The intervention group had 21% fewer sickness absence days compared with the control group [95% confidence interval (CI) -55-40%, P=0.43]. We found no significant difference in the change of HR-QoL for the intervention compared with the control group (4% lower in the intervention group, 95% CI -18-13%, P=0.67). The ordinal odds of scoring worse on self-reported hand eczema severity was 15% lower in the intervention compared with the control group (95% CI -39-18%, P=0.34). Post-hoc sub-group analyses indicated that the effect of the intervention on severity differed between occupations, being detrimental to healthcare workers and beneficial in all other occupations. Conclusion The educational skincare program had no marked effect on the primary outcomes sickness absence, HR-QoL, and severity of hand eczema when compared with treatment as usual. PMID- 29493716 TI - Open access: Is there a predator at the door? PMID- 29493715 TI - Haematopoietic cell transplantation in Switzerland, changes and results over 20 years: a report from the Swiss Blood Stem Cell Transplantation Working Group for Blood and Marrow Transplantation registry 1997-2016. AB - In 1997, the Swiss Blood Stem Cell Transplantation Group (SBST) initiated a mandatory national registry for all haematopoietic stem cell transplants (HCTs) in Switzerland. As of 2016, after 20 years, information was available for 7899 patients who had received an HCT (2781 allogeneic [35%] and 5118 autologous [65%]). As some patients had more than one transplant the total number of transplants was 3067 allogeneic and 6448 autologous. We compared patient characteristics and outcome of the first decade (1997-2006) and second decade (2007-2016) of the registry. There were numerous changes over time. For allogeneic HCT, transplant rates, and therefore use of HCT technology, increased from 14 to 21.8 HCTs per 1 million inhabitants per year from the first to the second decade. Likewise autologous HCTs increased from 24.8 to 37.2 annually corrected for population growth. Allogeneic transplant recipients were older (38.4 vs 48.3 years) and more frequently had unrelated donors in the second decade. Similarly, age increased for recipients of autologous HCT (50.8 vs 56.4 years). Analysis of outcome showed that the probabilities of overall and progression-free survival were stable over time, in spite of the treatment of older and higher risk patients. In multivariate analysis, nonrelapse mortality decreased in recipients of allogeneic HCT (relative risk 0.68, 95% confidence interval 0.52-0.87) over the two decades. Improvement in adjusted nonrelapse mortality compensated for the fact that higher risk patients were treated in more recent years, resulting in similar overall survival. Five-year survival probabilities were 56% (53-59%) in the first and 54% (51-57%) in the second decade for allogeneic HCT, and 59% (57-61%) in the first and 61% (59-63%) in the second decade for autologous HCT. Detailed analyses of changes over time are presented. This study included all HCTs performed in Switzerland during the period of observation and the data are useful for quality assurance programmes, healthcare cost estimation and healthcare planning. Between 50 and 60% of patients were long-term survivors after both types of HCT, indicating growing populations of surviving patients requiring long-term care and observation. PMID- 29493717 TI - Endoscopic view of a mucocele obstructing a middle meatal antrostomy. PMID- 29493718 TI - Langerhans cell histiocytosis presenting as a scalp mass in a child. PMID- 29493719 TI - The head impulse test as a predictor of videonystagmography caloric test lateralization according to the level of examiner experience: A prospective open label study. AB - We conducted a study to compare how well the head impulse test (HIT), without and with eye-movement recordings, would predict videonystagmographic (VNG) caloric test lateralization when performed by a resident and an experienced otoneurologist. This prospective, open-label, blinded study was conducted in an ambulatory tertiary care referral center. Our study population was made up of 60 patients-29 men and 31 women, aged 20 to 82 years (mean: 56.4 +/- 11.4)-with peripheral vestibulopathy who underwent HIT and VNG caloric testing. The HIT was conducted in two protocols: HIT0 and HIT1. The HIT0 was performed with passive brisk movements of the patient's head from the 0 degrees null position to 20 degrees sideways, and the HIT1 was performed toward the center while the null position was a 20 degrees head rotation to the right and to the left. Each protocol was carried out without video eye-movement recordings (HIT0 and HIT1) and with such recordings (rHIT0 and rHIT1). The primary outcome measures were (1) a comparison of the HIT's sensitivity and specificity when performed by the resident and by the experienced otoneurologist and (2) the ability of video recorded HIT to predict VNG caloric test lateralization. The sensitivity and specificity obtained by the resident were 41 and 81%, respectively, for HIT0 and 41 and 90% for HIT1. The sensitivity and specificity obtained by the experienced otoneurologist were 18 and 89% for HIT0 and 32 and 85% for HIT1. Analysis of the recorded eye-movement clips of the HIT0 and HIT1 obtained by a second experienced otoneurologist found a sensitivity and specificity of 32 and 63% for rHIT0 and 33 and 82% for rHIT1. We conclude that the HIT yields high false-negative rates in predicting significant caloric lateralization. Analysis of the eye-movement recordings was no better than normal testing alone for detecting saccades. The experience of the examining physician had no impact on test performance characteristics. PMID- 29493720 TI - Risk of posterior semicircular canal trauma when using a retrosigmoid approach for acoustic neuroma surgery and role of endoscopy: An imaging study. AB - The rate of hearing preservation after vestibular schwannoma surgery is variable and is not as high as expected, possibly due to injuries to the posterior semicircular canal while exposing the tumor. The aim of this study was to estimate the risk of posterior semicircular canal injuries using temporal bone computed tomography (CT) scan findings. Temporal bone CT scans of 30 patients selected between 2013 and 2015 were studied. The median age of the patients was 40 years. Two planes were studied: (1) the axial plane that shows the common crus of the posterior semicircular canal and (2) the coronal plane that shows the two crura of the posterior semicircular canal. Five lines were drawn and four angles and three distances were measured. In this study, we divided the patients into three groups consisting of 10 patients each: (1) patients with no evidence of inflammatory or neoplastic disease, (2) those with chronic ear disease, and (3) those with vestibular schwannomas. The portion of the internal auditory canal that was exposed by drilling while preserving the posterior semicircular canal was 53 to 64% and 61 +/- 9% in whole temporal bones in the three groups. The mean angle of vision with an endoscope was less than 105 degrees in 56% of cases, which means even with a 30 degrees endoscope, the fundus could not be visualized. Therefore, according to our data, it seemed impossible to expose the whole length of the internal auditory canal from the porus to the fundus without causing injury to the posterior semicircular canal. However, the use of endoscopes may help to prevent injury. PMID- 29493721 TI - Elastography as a potential modality for screening cervical lymph nodes in patients with papillary thyroid cancer: A review of literature. AB - Papillary thyroid cancer often presents with cervical lymph node involvement and has a high incidence of recurrence, which requires routine follow-up with ultrasound imaging. Elastography is a novel ultrasound technique that has been demonstrated to be effective clinically in detecting tissue pathology in areas such as the liver and breast. Preliminary data suggest that it may be effective in screening tissues in the neck for malignancy, specifically cervical lymph nodes. However, diagnostic criteria and elastographic techniques vary significantly among the studies we have reviewed, which all tend to focus on populations of patients with many different types of primary malignancies. Further research is required on the feasibility of creating standardized and reproducible clinical criteria in a specific patient population. To study the clinical utility of elastography in cervical lymph nodes, patients with diagnosed papillary thyroid carcinoma may serve as an ideal population because of their need for ultrasound surveillance and the propensity of papillary thyroid cancer to metastasize to and recur in cervical lymph nodes. We will review the limitations, techniques, and reported clinical utility of elastography on cervical lymph nodes and its potential as a screening modality for papillary thyroid cancer. PMID- 29493722 TI - The effects of mometasone furoate and strontium chloride in a rat model of allergic rhinitis. AB - Neurogenic inflammation plays a role in the pathophysiology of allergic rhinitis. Highly effective in reducing the sensory irritation caused by some substances, strontium salts directly affect C-type nerve fibers. The aim of this study was to compare the efficacy of mometasone furoate and strontium chloride on early-phase symptoms in a rat model of allergic rhinitis. Wistar albino rats (n = 24) were randomly divided into three groups: the mometasone group, receiving 1 MUg mometasone furoate (2 ul/site); the strontium 3% group, receiving 3% strontium chloride (2 MUl/site); and the strontium 5% group, receiving 5% strontium chloride (2 MUl/site). To induce significant nasal symptoms of allergic rhinitis, 5 umol of histamine dihydrochloride (HDC) (2 ul/site) was administered. Symptoms of allergic rhinitis were recorded as frequencies of sneezing and nasal rubbing during a 15-minute interval. On days 1 and 2, respectively, 0.9% sodium chloride (NaCl) (2 MUl/site to each nasal cavity) and HDC were administered in all of the study groups. On days 3 and 4, the study drugs were administered 10 and 30 minutes before the administration of HDC. On day 5, the study drugs were administered 10 minutes after the administration of HDC. The results of the present study revealed that when strontium chloride or mometasone furoate was administered 30 minutes before the onset of symptoms, a significant decrease was observed in sneezing and nasal rubbing. The number of sneezing occurrences was significantly lower and the number of nasal rubbing occurrences was higher in the strontium 3% group compared to the groups in which mometasone furoate and 5% strontium chloride were administered after onset of symptoms. Recent studies have investigated the efficacy and safety of strontium chloride nasal drops compared with common pharmacologic treatments of allergic rhinitis. These studies have revealed that allergic rhinitis can be successfully and safely treated with strontium-chloride-containing products, thus offering a potential new treatment strategy. PMID- 29493723 TI - A South African first: Congenital absence of the cartilaginous nasal septum. AB - Congenital absence of the cartilaginous nasal septum has been reported just once in the literature. We present a case of a young child, diagnosed by exclusion, with complete agenesis of the cartilaginous septum. We believe it is only the second case worldwide, and the first in South Africa, to be reported. PMID- 29493724 TI - Buccal space malignancy in the setting of chronic sialadenitis: A report of 2 cases. AB - We report the cases of an 89-year-old woman and a 77-year-old woman with long standing chronic sialadenitis (60 and 10 years, respectively) who were referred to our large academic medical center for sialendoscopy. Both patients presented with symptoms of acute parotid duct obstruction in the background of long standing parotid duct disease. Imaging demonstrated ductal dilation and periductal inflammation and, along with the clinical findings, was supportive of a diagnosis of acute parotitis in the setting of chronic obstructive parotid disease. Both patients underwent sialendoscopy. Intraoperative findings suggested the presence of a mass lesion in both cases, and biopsy confirmed a buccal space malignancy in each. Although benign processes such as ductal strictures and sialolithiasis are frequent causes of parotid duct system complaints, the possibility of a malignancy should be entertained and ruled out. Even in patients who have long-standing obstructive parotid symptoms, malignancy can be encountered as a new diagnosis. We discuss the unique presentation, workup, and management of our 2 patients, and we briefly review the current literature. PMID- 29493725 TI - Inferior turbinate reduction: Diode laser or conventional partial turbinectomy? AB - Hypertrophy of the inferior nasal turbinate is one of the most common causes of nasal obstruction. The diode laser has proven to be as effective as other lasers for this indication. Our objective was to study various outcomes associated with the use of the diode laser, such as improvements in nasal obstruction and postoperative pain, reduction in intraoperative bleeding, and rapidity of healing. A nonrandomized, controlled trial was conducted in which outcomes were compared between diode laser turbinate reduction (LTR) and conventional partial inferior turbinectomy (PIT) in 60 patients, 30 who underwent LTR and 30 who underwent PIT. The improvement in nasal obstruction was measured postoperatively up to 6 months. Intraoperative bleeding was measured and postoperative pain scores were assessed each day up to the fifth postoperative day. Rapidity of healing was evaluated until 6 months postoperatively. Subjective relief of nasal obstruction occurred in 90.8% of the LTR group and 65% of the PIT group at 6 months (p < 0.05). Pain scores were significantly higher until 5 days postoperatively in the PIT group compared with the LTR group (p = 0.0001). Intraoperative bleeding mean scores (ml) were 8.03 in the LTR group and 23.29 in the PIT group (p = 0.00001). Healing was faster in the LTR group at a mean of 3.03 weeks compared with 6.33 weeks in the PIT group (p = 0.00001). Outcomes with the diode laser were better and diode LTR caused less morbidity compared with the conventional technique. PMID- 29493726 TI - Contact allergy to benzalkonium chloride in patients using a steroid nasal spray: A report of 3 cases. AB - Benzalkonium chloride (BAC) is a bactericidal preservative excipient commonly found in steroid nasal sprays used to treat allergic rhinitis and nasal polyposis. In rare cases, BAC can be responsible for type I and type IV hypersensitivity reactions that can manifest as rhinorrhea, which a clinician might misinterpret as a lack of response to nasal spray therapy rather than a complication of it. We report 3 cases of type IV hypersensitivity reactions in patients who were being treated with mometasone nasal spray. We describe the epidemiology, clinical features, diagnosis, and treatment of these reactions. PMID- 29493727 TI - Syncope caused by a pleomorphic adenoma: Case report and literature review. AB - Pleomorphic adenomas are considered the most common salivary gland tumors, although they rarely occur in the parapharyngeal space. To the best of our knowledge, this is the first case report of a parapharyngeal parotid pleomorphic adenoma causing syncope. A 57-year-old man was admitted for left-sided blurred vision, left-sided weakness, dysarthria, lightheadedness, and syncope. Upon his admission, an electrocardiogram showed sinus bradycardia, and computed tomography of the neck with contrast showed a large parapharyngeal mass involving the prestyloid compartment, leading to compression of blood flow through the internal carotid artery. The mass was biopsied via intraoral fine-needle aspiration, which revealed cytology consistent with pleomorphic adenoma. The mass was resected via a transcervical approach, and a total parotidectomy was performed. The patient's hypotensive and bradycardic episodes disappeared after surgery. Surgical pathology showed a benign pleomorphic adenoma with a hemorrhagic and necrotic center and without capsular invasion or malignant transformation. PMID- 29493728 TI - Microbial flora and antibiotic resistance in odontogenic abscesses in Upstate New York. AB - Abscesses in the head and neck frequently have odontogenic sources. As bacterial pathogens and antibiotic resistance patterns may change over time and based on location, we describe the current common bacteria found in odontogenic abscesses, the prevalence of antibiotic resistance, and differences in each between pediatric and adult patients in Upstate New York. This is a retrospective review of patients who underwent drainage of odontogenic abscesses (n = 131) from 2002 to 2012 at an academic institution. The medical records were reviewed for results of abscess cultures, comorbidities, and drainage procedures. Polymicrobial sources were identified in 60.3% and monomicrobial in 33.6%. Overall, the most common bacteria were alpha hemolytic Streptococci (33.6%), Streptococcus milleri (32.1%), Prevotella (16.8%), and coagulase-negative Staphylococcus (14.5%). Candida and Morganella spp were more common in children than in adults. Overall, antibiotic resistance was observed in seven different pathogens. The most common antibiotic resistances were to clindamycin and erythromycin, which should be considered when deciding initial antibiotic therapy, especially in adult patients, who trended in this study toward having pathogens with higher rates of resistance. PMID- 29493729 TI - The sensitivity and specificity of touch preparation for rapid diagnosis of invasive fungal sinusitis: A pilot study. AB - Invasive fungal sinusitis is a morbid pathology that typically affects immunocompromised patients and may quickly progress to fulminant disease. The purpose of this study was to measure the sensitivity and specificity of touch preparation of nasal debridement specimens as a rapid diagnostic tool for invasive fungal sinusitis. A retrospective chart review was performed of 22 patients undergoing nasal debridement due to suspicion for invasive fungal sinusitis over a 10-year period. Thirteen patients had touch preparation of nasal specimens followed by routine histologic processing; 2 of these patients underwent two and 1 patient had three separate debridements, for a total of 17 touch preparations performed. The sensitivity and specificity of touch preparation were calculated by correlating the initial results with the presence of fungal invasion on final pathologic analysis. The sensitivity of touch preparation was 56% (95% confidence interval [CI]: 0.23 to 0.85), specificity was 100% (95% CI: 0.60 to 1.00), positive predictive value was 100% (95% CI: 0.46 to 1.00), and negative predictive value was 67% (95% CI: 0.35 to 0.89). This procedure may be a useful adjunct in situations requiring rapid diagnosis of invasive fungal sinusitis but should not be used as the sole criterion for determining the need for surgical intervention. PMID- 29493730 TI - A case of squamous cell carcinoma of the nasal cavity in a patient with granulomatosis with polyangiitis (Wegener granulomatosis). AB - We report a rare case of squamous cell carcinoma (SCC) of the nasal cavity arising in a patient with granulomatosis with polyangiitis (GPA). The patient was a 35-year-old man who had been diagnosed 15 years earlier with GPA and treated medically for sinonasal, pulmonary, and renal involvement. He presented to us with left-sided orbital and cheek pain and nasal obstruction. Endoscopy detected a friable, exophytic mass that involved the left lateral nasal wall and septum. Biopsy analysis identified the mass as an SCC. A definitive endoscopic resection was performed, followed by chemoradiation, but the patient exhibited progression of disease 2 months after the cessation of therapy. He then underwent an open craniofacial resection and a second round of chemoradiation. At 7 months of follow-up, he remained disease-free. Sinonasal symptoms in GPA are consistent with those in chronic rhinosinusitis, but the presence of unilateral symptoms may suggest a neoplastic process. Immunosuppressants are implicated in the pathophysiology of this malignancy, but equally plausible is the oncogenic role of chronic inflammation. PMID- 29493731 TI - Use of the microdebrider in the surgical management of rhinophyma. AB - Rhinophyma is a disfiguring end-stage manifestation of acne rosacea. It is characterized by a painless hyperplasia of the sebaceous glands and connective tissues of the nose. Numerous surgical modalities-including scalpel surgery, dermabrasion, CO2 laser ablation, and electrocautery-have been reported with varying results. We describe our experience with using a microdebrider to treat 2 patients-a 65-year-old man and a 74-year-old man-who presented with rhinophyma. The instrument we used was the Medtronic Straightshot M4 Microdebrider. Using a low revolution speed, we easily excised the bulky superficial tissue. At higher revolution speeds with the use of a small shaver tip, we were able to achieve delicate contouring of the nasal tip and ala without causing scarring. Postoperatively, both patients exhibited an excellent cosmetic outcome and expressed a high degree of patient satisfaction. We conclude that the microdebrider is an excellent surgical tool for treating rhinophyma lesions. Its ease of use and its availability at most surgical centers makes it a favorable surgical option. PMID- 29493732 TI - Granuloma formation secondary to silicone injection for soft-tissue augmentation in facial cosmetics: Mechanisms and literature review. AB - The use of injectable fillers is increasingly popular as an alternative to surgery for facial cosmetic applications. In this regard, silicone is a versatile biomaterial filler that has been used for these purposes, but its use warrants further investigation, especially since it is not clinically approved for such uses. We describe the use of silicone as a facial injectable filler through a scholarly review of the literature for cases of silicone granuloma formation published from September 2007 through September 2017, and we present various contexts in which this complication has been observed. We further review the immunologic etiology of granuloma formation and other complications of silicone injections. We write this report to caution physicians on the use of silicone fillers which, for all their advantages, are associated with significant long term risks that are frequently overlooked. PMID- 29493733 TI - Silicone granuloma formation associated with dermal injection. PMID- 29493734 TI - Temporal bone anomalies associated with unbalanced 9;13 chromosome translocation depicted on CT and MRI. PMID- 29493735 TI - Transnasal vocal fold augmentation. PMID- 29493736 TI - Distant metastasis to the external auditory canal. PMID- 29493737 TI - Endoscopic finding of two osteomas in the frontal sinus. PMID- 29493775 TI - Study of the beneficial effects of green light on lettuce grown under short-term continuous red and blue light-emitting diodes. AB - Red and blue light are the most important light spectra for driving photosynthesis to produce adequate crop yield. It is also believed that green light may contribute to adaptations to growth. However, the effects of green light, which can trigger specific and necessary responses of plant growth, have been underestimated in the past. In this study, lettuce (Lactuca sativa L.) was exposed to different continuous light (CL) conditions for 48 h by a combination of red and blue light-emitting diodes (LEDs) supplemented with or without green LEDs, in an environmental-controlled growth chamber. Green light supplementation enhanced photosynthetic capacity by increasing net photosynthetic rates, maximal photochemical efficiency, electron transport for carbon fixation (JPSII ) and chlorophyll content in plants under the CL treatment. Green light decreased malondialdehyde and H2 O2 accumulation by increasing the activities of superoxide dismutase (EC 1.15.1.1) and ascorbate peroxidase (EC 1.11.1.11) after 24 h of CL. Supplemental green light significantly increased the expression of photosynthetic genes LHCb and PsbA from 6 to 12 h, and these gene expressions were maintained at higher levels than those under other light conditions between 12 and 24 h. However, a notable downregulation of both LHCb and PsbA was observed during 24 to 48 h. These results indicate that the effects of green light on lettuce plant growth, via enhancing activity of particular components of antioxidative enzyme system and promoting of LHCb and PsbA expression to maintain higher photosynthetic capacity, alleviated a number of the negative effects caused by CL. PMID- 29493777 TI - Closing the gap in Indigenous health inequity - Is it making a difference? AB - AIM: This paper will review progress towards the identified targets within the Australian government policy document commonly known as 'Closing the Gap' and examine the role of nurses in supporting its implementation. BACKGROUND: Australia is not alone in seeking to address the health inequity between Indigenous and non-Indigenous people. Globally such health inequities are similar and require interventions supported by governments in conjunction with health and education systems to affect desired change. For this reason, it is timely to undertake a review of progress on the impact of the Closing the Gap initiative. SOURCES OF EVIDENCE: The Australian national partnership agreement and subsequent annual performance reports issued between 2010 and 2017. DISCUSSION: Targets set within the Australian government national partnership agreement have had a range of success. Those targets not on track require significant long-term investment to ensure their success. Nurses as a large professional group are powerful advocates to speak up and support policy change that affects disempowered social groups. CONCLUSION: Long-term social change takes time, yet without the commitment of Australian Governments through effective policy and economic support, the inequity in the health of Indigenous people will continue both now and in the future. IMPLICATIONS FOR HEALTH AND SOCIAL POLICY: Nurses, as the largest health professional group, are uniquely placed to support and implement social change at all levels of health care (primary, secondary and tertiary) and to lobby government to amend policy alongside those who are disempowered. IMPLICATIONS FOR NURSING PRACTICE: Health promotion and education programmes that are led by nurses can make an impact to health disparities within groups who are most at risk. PMID- 29493776 TI - Ericoid plant species and Pinus sylvestris shape fungal communities in their roots and surrounding soil. AB - Root-colonizing fungi can form mycorrhizal or endophytic associations with plant roots, the type of association depending on the host. We investigated the differences and similarities of the fungal communities of three boreal ericoid plants and one coniferous tree, and identified the community structure of fungi utilizing photosynthates from the plants studied. The fungal communities of roots and soils of Vaccinium myrtillus, Vaccinium vitis-idaea, Calluna vulgaris and Pinus sylvestris were studied in an 18-month-long experiment where the plants were grown individually in natural substrate. Photosynthates utilizing fungi were detected with DNA stable-isotope probing using 13 CO2 (13 C-DNA-SIP). The results indicated that the plants studied provide different ecological niches preferred by different fungal species. Those fungi which dominated the community in washed roots had also the highest 13 C-uptake. In addition, a common root endophyte without confirmed mycorrhizal status also obtained 13 C from all the plants, indicating close plant-association of this fungal species. We detect several fungal species inhabiting the roots of both ericoid mycorrhizal and ectomycorrhizal plants. Our results highlight that the ecological role of co occurrence of fungi with different life styles (e.g. mycorrhizal or endophytic) in plant root systems should be further investigated. PMID- 29493778 TI - Effects of betamethasone on fetoplacental and maternal hemodynamics in preterm pregnancies. AB - OBJECTIVE: To evaluate the possible effects of prenatal steroid administration on Doppler parameters of the umbilical artery, uterine artery, middle cerebral artery, and ductus venosus, the cerebroplacental ratio, and the amniotic fluid index in preterm fetuses. METHODS: The present prospective observational study was performed at the Perinatology Department of Trakya University, Edirne, Turkey, between June 1, 2015, and September 1, 2016. It included patients with healthy singleton pregnancies who had received betamethasone at 24-34 weeks of pregnancy. Doppler parameters were measured before (0 hours) and 24, 48, and 72 hours after the administration of betamethasone (two intramuscular doses of 12 mg each, administered 24 hours apart). RESULTS: There were 68 patients included. Pairwise comparisons demonstrated that, at 72 hours after betamethasone administration, the umbilical artery resistance index (P=0.038), the middle cerebral artery systolic/diastolic velocity ratio (P=0.007), and the amniotic fluid index (P=0.017) were reduced, whereas the end-diastolic velocity of the middle cerebral artery was increased (P=0.012), compared with baseline values. CONCLUSION: Betamethasone had favorable effects on fetal cerebral circulation, with increased end-diastolic velocity in the middle cerebral artery; this could represent a positive effect on cerebral blood circulation and decreased flow resistance in the umbilical artery. PMID- 29493779 TI - Multicentre study evaluating the surgical learning curve for posterior retroperitoneoscopic adrenalectomy. AB - BACKGROUND: Posterior retroperitoneoscopic adrenalectomy has gained international popularity in the past decade. Despite major advantages, including shorter duration of operation, minimal blood loss and decreased postoperative pain, many surgeons still prefer laparoscopic transperitoneal adrenalectomy. It is likely that the unfamiliar anatomical environment, smaller working space and long learning curve impede implementation. The present study assessed the number of procedures required to fulfil the surgical learning curve for posterior retroperitoneoscopic adrenalectomy. METHODS: The first consecutive posterior retroperitoneoscopic adrenalectomies performed by four surgical teams from university centres in three different countries were analysed. The primary outcome measure was duration of operation. Secondary outcomes were conversion to an open or laparoscopic transperitoneal approach, complications and recovery time. The learning curve cumulative sum (LC-CUSUM) was used to assess the learning curves for each surgical team. RESULTS: A total of 181 surgical procedures performed by four surgical teams were analysed. The median age of the patients was 57 (range 15-84) years and 61.3 per cent were female. Median tumour size was 25 (range 4-85) mm. There were no significant differences in patient characteristics and tumour size between the teams. The median duration of operation was 89 (range 29-265) min. There were 35 perioperative and postoperative complications among the 181 patients (18.8 per cent); 17 of 27 postoperative complications were grade 1. A total of nine conversions to open procedures (5.0 per cent) were observed. The LC-CUSUM analysis showed that competency was achieved after a range of 24-42 procedures. CONCLUSION: In specialized endocrine surgical centres between 24 and 42 procedures are required to fulfil the entire surgical learning curve for the posterior retroperitoneoscopic adrenalectomy. PMID- 29493780 TI - Care delivery and self-management strategies for children with epilepsy. AB - BACKGROUND: In response to criticism that epilepsy care for children has little impact, healthcare professionals and administrators have developed various service models and strategies to address perceived inadequacies. OBJECTIVES: To assess the effects of any specialised or dedicated intervention for epilepsy versus usual care in children with epilepsy and in their families. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialized Register (27 September 2016), the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 9) in the Cochrane Library, MEDLINE (1946 to 27 September 2016), Embase (1974 to 27 September 2016), PsycINFO (1887 to 27 September 2016) and CINAHL Plus (1937 to 27 September 2016). In addition, we also searched clinical trials registries for ongoing or recently completed trials, contacted experts in the field to seek information on unpublished and ongoing studies, checked the websites of epilepsy organisations and checked the reference lists of included studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs), cohort studies or other prospective studies with a (matched or unmatched) control group (controlled before-and-after studies), or time series studies. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: Our review included six interventions reported through seven studies (of which five studies were designed as RCTs). They reported on different education and counselling programmes for children and parents; teenagers and parents; or children, adolescents and their parents. Each programme showed some benefits for the well-being of children with epilepsy, but all had methodological flaws (e.g. in one of the studies designed as an RCT, randomisation failed), no single programme was independently evaluated with different study samples and no interventions were sufficiently homogeneous enough to be included in a meta-analysis,. AUTHORS' CONCLUSIONS: While each of the programmes in this review showed some benefit to children with epilepsy, their impacts were extremely variable. No programme showed benefits across the full range of outcomes, and all studies had major methodological problems. At present there is insufficient evidence in favour of any single programme. PMID- 29493781 TI - ZNF687 mutations are frequently found in pagetic patients from South Italy: implication in the pathogenesis of Paget's disease of bone. AB - Paget's disease of bone (PDB) is a skeletal disorder whose molecular basis is not fully elucidated. However, 10% of patients show a familial PDB and 35% of them carry mutations in the SQSTM1 gene. We recently reported a founder mutation (p.Pro937Arg) in the ZNF687 gene, underlying PDB complicated by giant cell tumor (GCT/PDB) and rarely occurring in PDB patients without neoplastic degeneration. Since 80% of Italian GCT/PDB patients derive from Avellino, we hypothesized that ZNF687 mutation rate was higher in this region than elsewhere. Interestingly, our molecular analysis on 30 PDB patients showed that 33% hosted ZNF687 mutations, with the p.Pro937Arg identified in 8 familial cases. Two novel ZNF687 mutations (p.Pro665Leu and p.Gln784Glu) were detected in 2 sporadic patients. Only 2 subjects were positive for the p.Pro392Leu mutation in SQSTM1. ZNF687-mutated patients showed a severe PDB, with a remarkable number of affected sites. in vitro studies revealed that the ZNF687-mutant osteoclasts appeared as giant sized with up to 150 nuclei, never described in PDB. Finally, we also confirmed the causality of the p.Pro937Arg mutation in 4 additional GCT/PDB cases deriving from the same geographic area, indicating that PDB and GCT/PDB represent 2 sides of the same coin. PMID- 29493782 TI - Treatment of disseminated Strongyloides spp. infection in an infant Sumatran orangutan (Pongo abelii). AB - Strongyloides nematodes have been reported in all species of great apes with orangutans <=5 years old most susceptible to severe clinical disease. This brief communication describes the first published case of antemortem diagnosis and treatment of disseminated strongyloidiasis in a clinically affected 5-month-old Sumatran orangutan (Pongo abelii). PMID- 29493784 TI - Propensity score-matched comparison of oncological outcomes between laparoscopic and open distal pancreatic resection. AB - BACKGROUND: Selected studies have reported improved outcomes in laparoscopic compared with open distal pancreatic resection. Concerns regarding failure to achieve proper oncological resection and compromised long-term outcomes remain. This study investigated whether postoperative outcomes and long-term survival after laparoscopic distal pancreatectomy are comparable to those after an open procedure. METHODS: This retrospective case-control study included patients who underwent distal pancreatectomy for resectable pancreatic adenocarcinoma between 2010 and 2013, identified from the National Cancer Database. Propensity score nearest-neighbour 1 : 1 matching was performed between patients undergoing laparoscopic or open distal pancreatectomy based on all relevant co-variables. The primary outcome was overall survival. RESULTS: Of 1947 eligible patients, 605 (31.1 per cent) underwent laparoscopic distal pancreatectomy. After propensity score matching, two well balanced groups of 563 patients each were analysed. There was no difference in overall survival at 3 years after laparoscopic versus open distal pancreatectomy (41.6 versus 36.0 per cent; hazard ratio 0.93, 95 per cent c.i. 0.77 to 1.12; P = 0.457). The overall conversion rate was 27.3 per cent (165 of 605). Patients who underwent laparoscopic distal pancreatectomy had outcomes comparable to those of patients who had an open procedure with regard to median time to chemotherapy (50 versus 50 days; P = 0.342), median number of nodes examined (12 versus 12; P = 0.759); 30-day mortality (1.2 versus 0.9 per cent; P = 0.562); 90-day mortality (2.8 versus 3.7 per cent; P = 0.403), 30-day readmission rate (9.6 versus 9.2 per cent; P = 0.838) and positive margin rate (14.9 versus 18.5 per cent; P = 0.110). However, median duration of hospital stay was shorter in the laparoscopic group (6 versus 7 days; P < 0.001). CONCLUSION: Laparoscopic distal pancreatectomy is an acceptable alternative to open distal pancreatectomy with no detriment to survival. PMID- 29493783 TI - Precious GEMMs: emergence of faithful models for ovarian cancer research. AB - The development of Genetically Engineered Mouse Models (GEMMs) has catalyzed tremendous progress in cancer research. However, it has been difficult to design adequate mouse models for high-grade serous carcinoma (HGSC), the most common and lethal form of ovarian cancer. The genetic complexity of the disease, as well as the recent appreciation that most HGSCs arise from the fallopian tube (FT) secretory epithelium rather than the ovarian surface epithelium, has stifled the development of robust GEMMs. In a recent issue of this journal, Zhai et al presented an elegant mouse model for ovarian cancer that uses Ovgp1 as an FT specific promoter to inactivate Brca1, Trp53, Rb1, Nf1, and Pten. The authors showed that loss of these genes in the mouse FT epithelium can mimic the different stages of human HGSC tumorigenesis. Their robust model emphasizes the importance of considering both the cell of origin and tumor genetics in developing accurate model systems. They provide a useful tool for studying mechanisms of disease in vivo and for research into novel methods of prevention, early detection, and treatment of HGSC. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29493786 TI - Anatomical and hormonal description of rootlet primordium development along white lupin cluster root. AB - Cluster root (CR) is one of the most spectacular plant developmental adaptations to hostile environment. It can be found in a few species from a dozen botanical families, including white lupin (Lupinus albus) in the Fabaceae family. These amazing structures are produced in phosphate-deprived conditions and are made of hundreds of short roots also known as rootlets. White lupin is the only crop bearing CRs and is considered as the model species for CR studies. However, little information is available on CRs atypical development, including the molecular events that trigger their formation. To provide insights on CR formation, we performed an anatomical and cellular description of rootlet development in white lupin. Starting with a classic histological approach, we described rootlet primordium development and defined eight developmental stages from rootlet initiation to their emergence. Due to the major role of hormones in the developmental program of root system, we next focussed on auxin-related mechanisms. We observed the establishment of an auxin maximum through rootlet development in transgenic roots expressing the DR5:GUS auxin reporter. Expression analysis of the main auxin-related genes [TIR, Auxin Response Factor (ARF) and AUX/IAA] during a detailed time course revealed specific expression associated with the formation of the rootlet primordium. We showed that L. albus TRANSPORT INHIBITOR RESPONSE 1b is expressed during rootlet primordium formation and that L. albus AUXIN RESPONSE FACTOR 5 is expressed in the vasculature but absent in the primordium itself. Altogether, our results describe the very early cellular events leading to CR formation and reveal some of the auxin-related mechanisms. PMID- 29493785 TI - Randomized clinical trial of intracutaneously versus transcutaneously sutured ileostomy to prevent stoma-related complications (ISI trial). AB - BACKGROUND: Ileostomy construction is a common procedure but can be associated with morbidity. The stoma is commonly secured to the skin using transcutaneous sutures. It is hypothesized that intracutaneous sutures result in a tighter adherence of the peristomal skin to the stoma plate to prevent faecal leakage. The study aimed to compare the effect of intracutaneous versus transcutaneous suturing of ileostomies on faecal leakage and quality of life. METHODS: This randomized trial was undertaken in 11 hospitals in the Netherlands. Patients scheduled to receive an ileostomy for any reason were randomized to intracutaneous or transcutaneous suturing (IC and TC groups respectively). The primary outcome was faecal leakage. Secondary outcomes were stoma-related quality of life and costs of stoma-related materials and reinterventions. RESULTS: Between April 2011 and February 2016, 339 patients were randomized to the IC (170) or TC (169) group. Leakage rates were higher in the IC than in the TC group (52.4 versus 41.4 per cent respectively; risk difference 11.0 (95 per cent c.i. 0.3 to 21.2) per cent). Skin irritation rates were high (78.2 versus 72.2 per cent), but did not differ significantly between the groups (risk difference 6.1 (95 per cent c.i. -3.2 to 15.10) per cent). There were no significant differences in quality of life or costs between the groups. CONCLUSION: Intracutaneous suturing of an ileostomy is associated with more peristomal leakage than transcutaneous suturing. Overall stoma-related complications did not differ between the two techniques. Registration number: NTR2369 ( http://www.trialregister.nl). PMID- 29493787 TI - Plant soil feedback strength in relation to large-scale plant rarity and phylogenetic relatedness. AB - Understanding why some species are rare while others are common remains a central and fascinating question in ecology. Recently, interactions with soil organisms have been shown to affect local abundances of plant species within communities, however, it is not known whether they might also drive patterns of rarity at large scales. Further, little is known about the specificity of soil-feedback effects, and whether closely related plants share more soil pathogens than more distantly related plants. In a multi-species soil-feedback experiment (using 19 species) we tested whether regionally and locally rare species differed in their response to soil biota. Regional rarity was measured using range size or IUCN status and local rarity by typical abundance within an area. All species were grown on soils trained by a variety of regionally and locally rare and common species, which also varied in their degree of relatedness to the target. We found that, in general, regionally rare species suffered more than twice as much from soil biota than regionally common species. Soil cultured by regionally rare species also had a more negative effect on subsequent plant growth, suggesting they may have also accumulated more pathogens. Local rarity did not predict feedback strength. Further, soil trained by closely related plants had a more negative effect on growth than soil trained by distant relatives, which indicates a phylogenetic signal in the host range of soil biota. We conclude that soil biota may well contribute to plant rarity at large spatial scales, which offers a novel explanation for plant rarity and commonness. Moreover, our results show that phylogenetic relatedness between plants was a good predictor of the likelihood that two plant species interacted negatively via soil biota, which might mean that soil pathogens could prevent the coexistence of closely related plants and could drive patterns of phylogenetic overdispersion. Our results suggest that soil pathogens could restrict the ability of rare species to shift their ranges and might need to be considered by conservation biologists seeking to protect populations of rare plants. PMID- 29493788 TI - Recent Publications of Interest. PMID- 29493789 TI - Reminiscence therapy for dementia. AB - BACKGROUND: This updated Cochrane Review of reminiscence therapy (RT) for dementia was first published in 1998, and last updated in 2005. RT involves the discussion of memories and past experiences with other people using tangible prompts such as photographs or music to evoke memories and stimulate conversation. RT is implemented widely in a range of settings using a variety of formats. OBJECTIVES: To assess the effects of RT on people living with dementia and their carers, taking into account differences in its implementation, including setting (care home, community) and modality (group, individual). SEARCH METHODS: We searched ALOIS (the Cochrane Dementia and Cognitive Improvement Group's Specialized Register) on 6 April 2017 using the search term 'reminiscence.' SELECTION CRITERIA: We included all randomised controlled trials of RT for dementia in which the duration of the intervention was at least four weeks (or six sessions) and that had a 'no treatment' or passive control group. Outcomes of interest were quality of life (QoL), cognition, communication, behaviour, mood and carer outcomes. DATA COLLECTION AND ANALYSIS: Two authors (LOP and EF) independently extracted data and assessed risk of bias. Where necessary, we contacted study authors for additional information. We pooled data from all sufficiently similar studies reporting on each outcome. We undertook subgroup analysis by setting (community versus care home) and by modality (individual versus group). We used GRADE methods to assess the overall quality of evidence for each outcome. MAIN RESULTS: We included 22 studies involving 1972 people with dementia. Meta-analyses included data from 16 studies (1749 participants). Apart from six studies with risk of selection bias, the overall risk of bias in the studies was low.Overall, moderate quality evidence indicated RT did not have an important effect on QoL immediately after the intervention period compared with no treatment (standardised mean difference (SMD) 0.11, 95% confidence interval (CI) -0.12 to 0.33; I2 = 59%; 8 studies; 1060 participants). Inconsistency between studies mainly related to the study setting. There was probably a slight benefit in favour of RT in care homes post-treatment (SMD 0.46, 95% CI 0.18 to 0.75; 3 studies; 193 participants), but little or no difference in QoL in community settings (867 participants from five studies).For cognitive measures, there was high quality evidence for a very small benefit, of doubtful clinical importance, associated with reminiscence at the end of treatment (SMD 0.11, 95% CI 0.00 to 0.23; 14 studies; 1219 participants), but little or no difference at longer-term follow-up. There was a probable slight improvement for individual reminiscence and for care homes when analysed separately, but little or no difference for community settings or for group studies. Nine studies included the widely used Mini-Mental State Examination (MMSE) as a cognitive measure, and, on this scale, there was high quality evidence for an improvement at the end of treatment (mean difference (MD) 1.87 points, 95% CI 0.54 to 3.20; 437 participants). There was a similar effect at longer-term follow-up, but the quality of evidence for this analysis was low (1.8 points, 95% CI -0.06 to 3.65).For communication measures, there may have been a benefit of RT at the end of treatment (SMD -0.51 points, 95% CI -0.97 to -0.05; I2 = 62%; negative scores indicated improvement; 6 studies; 249 participants), but there was inconsistency between studies, related to the RT modality. At follow-up, there was probably a slight benefit of RT (SMD -0.49 points, 95% CI -0.77 to -0.21; 4 studies; 204 participants). Effects were uncertain for individual RT, with very low quality evidence available. For reminiscence groups, evidence of moderate quality indicated a probable slight benefit immediately (SMD -0.39, 95% CI -0.71 to 0.06; 4 studies; 153 participants), and at later follow-up. Community participants probably benefited at end of treatment and follow-up. For care home participants, the results were inconsistent between studies and, while there may be an improvement at follow-up, at the end of treatment the evidence quality was very low and effects were uncertain.Other outcome domains examined for people with dementia included mood, functioning in daily activities, agitation/irritability and relationship quality. There were no clear effects in these domains. Individual reminiscence was probably associated with a slight benefit on depression scales, although its clinical importance was uncertain (SMD -0.41, 95% CI -0.76 to -0.06; 4 studies; 131 participants). We found no evidence of any harmful effects on people with dementia.We also looked at outcomes for carers, including stress, mood and quality of relationship with the person with dementia (from the carer's perspective). We found no evidence of effects on carers other than a potential adverse outcome related to carer anxiety at longer term follow-up, based on two studies that had involved the carer jointly in reminiscence groups with people with dementia. The control group carers were probably slightly less anxious (MD 0.56 points, 95% CI -0.17 to 1.30; 464 participants), but this result is of uncertain clinical importance, and is also consistent with little or no effect. AUTHORS' CONCLUSIONS: The effects of reminiscence interventions are inconsistent, often small in size and can differ considerably across settings and modalities. RT has some positive effects on people with dementia in the domains of QoL, cognition, communication and mood. Care home studies show the widest range of benefits, including QoL, cognition and communication (at follow-up). Individual RT is associated with probable benefits for cognition and mood. Group RT and a community setting are associated with probable improvements in communication. The wide range of RT interventions across studies makes comparisons and evaluation of relative benefits difficult. Treatment protocols are not described in sufficient detail in many publications. There have been welcome improvements in the quality of research on RT since the previous version of this review, although there still remains a need for more randomised controlled trials following clear, detailed treatment protocols, especially allowing the effects of simple and integrative RT to be compared. PMID- 29493790 TI - Child neglect and abuse: a global glimpse within the framework of evidence perspective. AB - AIM: This systematic review was conducted in order to integrate evidence-based knowledge and experience related to child neglect and abuse into the nursing literature. BACKGROUND: The negative and intense effects of neglect and abuse on an individual can last into adulthood. Nurses who are in close contact with such cases have an important role to play in detecting child neglect and abuse and supporting the families involved. When nurses fulfil this role, it is important that evidence-based information and interventions are known to ensure that the process is a healthy one. DATA SOURCES: Medline/Pubmed and Cochrane Library databases, from 2012 to 2016. REVIEW METHODS: The PRISMA guide, a basic search algorithm, was used as a basis for the review. RESULTS: This systematic research involved 32 articles that met the criteria. When the characteristics of the studies were examined, it was found that one study dealt with physical abuse, seven studies dealt with sexual abuse, 21 studies with neglect and abuse and three studies with all abuse types. It was also found that 16% addressed intervention, 22% addressed the relationship between abuse and other factors, 31% addressed prevention and 31% addressed the defining dimension. CONCLUSIONS: It has been found that, in general, all types of negligence and abuse are studied together and that nurses lack the knowledge and skills needed to assess childhood neglect and abuse. IMPLICATIONS FOR NURSING AND HEALTH POLICIES: Nurses have a critical role to play in identifying the dark spots and associated factors in the story of individuals because they are health professionals who are in close contact with patients. It is recommended that guidelines be developed and used in the diagnosis and treatment of abuse and neglect. Thus, in these cases, the standardization of care will be achieved. PMID- 29493791 TI - Antimicrobial Agents and Catheter Complications in Outpatient Parenteral Antimicrobial Therapy. AB - OBJECTIVES: Debate about whether certain antimicrobial agents traditionally considered vesicants increase the risk of catheter complications has led to uncertainty in venous catheter placement protocols. To understand whether patients requiring home-based outpatient parenteral antimicrobial therapy (OPAT) should receive peripheral catheters (e.g., midline catheters) versus central venous catheters, and to understand whether certain antimicrobial agents place home-based OPAT patients at higher risk for catheter complications, we investigated associations between antimicrobial agent(s) and catheter complications. METHODS: We performed a prospective cohort study of patients requiring home-based OPAT discharged from two urban tertiary care academic medical centers, including telephone surveys and chart abstractions. Multivariable Poisson regressions were used to evaluate: (i) associations between antimicrobial agents traditionally considered vesicants, based on pH or osmolarity, and catheter complication rates, and (ii) associations between antimicrobial agent and rates of catheter complications. RESULTS: Vesicant antimicrobials defined using pH or osmolarity criteria were not associated with an increased rate of catheter complications (adjusted incidence rate ratio [aIRR]: 1.63, 95% confidence interval [CI]: 0.89-2.96). Vancomycin was associated with an increased rate of catheter complications, as was daptomycin (aIRR: 2.32 [95% CI: 1.20-4.46] and 4.45 [95% CI: 1.02-19.41], respectively). Staphylococcus aureus infections were also associated with an increased rate of catheter complications (aIRR: 2.13, 95% CI: 1.09-4.19), as were midline catheters (aIRR: 9.44, 95% CI: 2.12-41.97). CONCLUSIONS: Our study supports recent guidance identifying vancomycin as a vesicant, among a subset of antimicrobial agents, and removal of pH criteria for identification of vesicants. PMID- 29493792 TI - Foetal, neonatal and child vitamin D status and enamel hypomineralization. AB - OBJECTIVES: Recent literature suggested that higher vitamin D concentrations in childhood are associated with a lower prevalence of molar incisor hypomineralization (MIH). As tooth development already starts in utero, we aimed to study whether vitamin D status during foetal, postnatal and childhood periods is associated with the presence of hypomineralized second primary molars (HSPMs) and/or MIH at the age of six. METHODS: Our study was embedded in the Generation R Study, a population-based, prospective cohort from foetal life onwards in Rotterdam, the Netherlands. HSPMs and MIH were scored from intraoral photographs of the children at their age of six. Serum 25(OH)D concentrations were measured at three points in time, which resulted in three different samples; mid gestational in mothers' blood (n = 4750), in umbilical cord blood (n = 3406) and in children's blood at the age of 6 years (n = 3983). RESULTS: The children had a mean (+/-SD) age of 6.2 (+/-0.5) years at the moment of taking the intraoral photographs. After adjustment for confounders, no association was found between foetal 25(OH)D concentrations and the presence of HSPMs (OR 1.02 per 10 nmol/L higher 25(OH)D, 95% CI: 0.98-1.07) or MIH (OR 1.05 per 10 nmol/L increase, 95% CI: 0.98-1.12) in 6-year-olds. A higher 25(OH)D concentration in umbilical cord blood resulted in neither lower odds of having HSPM (OR 1.05, 95% CI: 0.98-1.13) nor lower odds of having MIH (OR 0.95, 95% CI: 0.84-1.07) by the age of six. Finally, we did not find higher 25(OH)D concentrations at the age of six to be associated with a significant change in the odds of having HSPM (OR 0.97, 95% CI: 0.92-1.02) or MIH (OR 1.07, 95% CI: 0.98-1.16). CONCLUSIONS: 25(OH)D concentrations in prenatal, early postnatal and later postnatal life are not associated with the presence of HPSMs or with MIH at the age of six. Future observational research is required to replicate our findings. Furthermore, it is encouraged to focus on identifying other modifiable risk factors, because prevention of hypomineralization is possible only if the causes are known. PMID- 29493793 TI - Comparing men and women with binge-eating disorder and co-morbid obesity. AB - OBJECTIVE: This study examined differences in clinical presentation of men and women with binge-eating disorder (BED) who participated in treatment research at a medical-school based program. METHOD: Participants were 682 adults (n = 182 men, n = 500 women) with DSM-IV-defined BED. Doctoral-level research clinicians assessed eating-disorder psychopathology, including BED diagnosis, using the Structured Clinical Interview for DSM-IV Disorders (SCID) and Eating Disorder Examination (EDE) interview. Research clinicians measured height and weight and participants completed a battery of established self-report measures. RESULTS: Men had significantly higher body mass index (BMI) than women; women had significantly higher eating-disorder psychopathology (EDE scales and global score) and depression than men. Differences in eating-disorder psychopathology and depression remained higher for women than men after adjusting for race/ethnicity and BMI. Frequency of binge-eating episodes, subjective binge eating episodes, and overeating episodes did not differ significantly by sex. Women had younger ages of onset for dieting and binge-eating behaviors than men but ages of onset for obesity and BED did not significantly differ between men and women. DISCUSSION: There are some sex differences in clinical presentation and age-of-onset timeline of adults with BED. Men and women develop obesity and BED (at diagnostic threshold) around the same age but women begin dieting and binge-eating behaviors earlier than men. At presentation for treatment for BED, men and women did not differ in binge-eating frequency and although men and women differed significantly on BMI and eating-disorder psychopathology, the magnitude of these differences was quite modest. PMID- 29493794 TI - Health Providers' Narratives on Intimate Partner Violence Against Roma Women in Spain. AB - This qualitative study identifies health professionals' dominant, adaptive, and liberating narratives regarding inter-ethnic relations when talking about intimate partner violence (IPV) and the health system responses to the way it affects Roma women. Dominant narratives are oppressive internalized stories that shape social perceptions of members of both dominant and minority groups, adaptive narratives refer to those that acknowledge asymmetry and inequality, and liberating narratives directly challenge oppression with resistant views of stereotypes and negative interpretations. A total of 25 in-depth interviews were carried out with healthcare professionals in Spain in 2015. A discourse analysis of the interview transcriptions was conducted, showing the way in which different narratives about Roma people and IPV are combined among health providers. Dominant narratives were more salient: they were used by health providers to reflect prejudicial social perceptions in Spain that depict the Roma as a marginalized and traditional group, to construct Roma women in negative and prejudicial terms as patients, and to explain the existence of the cultural normalization of IPV among Roma women. Adaptive and liberating narratives showed a prevailing ideology in terms of the tendency to socially discriminate against Roma people. Using liberating narratives to train and raise awareness among health professionals about IPV among Roma women could facilitate a positive change in their treatment of Roma women who could be affected by IPV, helping to ameliorate the maintenance of existing prejudices. PMID- 29493795 TI - Psychometric evaluation of the nursing child assessment teaching (NCAT) scale in a community-based sample. AB - The effect of the mother-child relationship on long-term child development has received research attention for decades. Because the quality and quantity of mother-infant interactions have been established as important predictors of the child's development, early identification of areas in the relationship requiring support and intervention is essential for promoting positive child outcomes. The Nursing Child Assessment Teaching Scale (NCAT) is an instrument long used to quantify the quality of interaction in the mother-child relationship during the first 36 months of a child's life. While the NCAT has been shown to be a reliable and valid instrument, limited evidence exists of the theoretical congruence between the Barnard Model it is based on and the NCAT scale. The psychometric properties of the NCAT scale and subscales were examined using item response theory in relation to characteristics of interactions in the Barnard Model using data collected during a clinic visit at 12 months of infant age in a sample of mothers and children (N = 1,121 dyads) from a community-based sample in Shelby County, TN. In this secondary analysis, descriptive statistics, reliabilities, and factor loadings for the NCAT were obtained using confirmatory factor analysis and augmented to form multiple indicators, multiple causes models, linking demographic predictors of the mothers and children to the NCAT subscales. Results supported scale abbreviation and theoretical congruence with the Barnard Model, which may provide researchers and practitioners with a more concise, reliable way of measuring maternal-child interaction in community settings. PMID- 29493796 TI - From waste product to blood, brains and narratives: developing a pluralist sociology of contributions to health research. AB - The aim of this paper is to examine the meaning of the concept of donation in health research. Drawing on a set of narrative interviews with people invited to donate biosamples for research and a range of other studies, we identify several conceptual themes that speak to the complexity of the current landscape of critical thinking about donation. These conceptual themes are: the language of 'donation'; a hierarchy of biosamples; alternative informational value; narratives as donation; coincidental donation, convenience and degree of invasiveness; and rights, consent and benefits of research participation. We call for a reconceptualisation of research donation to encompass not only the numerous types of sample readily classed as donations, but also other types of data and contributions, including narrative interviews, psychometric data, patient reported outcome measures, record-linkage, and time and effort. We argue for the development of a pluralist sociology of research donations, and suggest that a 'sociology of research contributions' might better capture this complexity. PMID- 29493797 TI - Development of a sheathless CE-ESI-MS interface. AB - A sheath-flow interface is the most common ionization technique in CE-ESI-MS. However, this interface dilutes the analytes with the sheath liquid and decreases the sensitivity. In this study, we developed a sheathless CE-MS interface to improve sensitivity. The interface was fabricated by making a small crack approximately 2 cm from the end of a capillary column fixed on a plastic plate, and then covering the crack with a dialysis membrane to prevent metabolite loss during separation. A voltage for CE separation was applied between the capillary inlet and the buffer reservoir. Under optimum conditions, 52 cationic metabolite standards were separated and selectively detected using MS. With a pressure injection of 5 kPa for 15 s (ca. 1.4 nL), the detection limits for the tested compounds were between 0.06 and 1.7 MUmol/L (S/N = 3). The method was applied to analysis of cationic metabolites extracted from a small number (12 000) of cancer cells, and the number of peaks detected was about 2.5 times higher than when using conventional sheath-flow CE-MS. Because the interface is easy to construct, it is cost-effective and can be adapted to any commercially available capillaries. This method is a powerful new tool for highly sensitive CE-MS-based metabolomic analysis. PMID- 29493798 TI - What the Women's Health Initiative has taught us about menopausal hormone therapy. AB - Our understanding of the complex relationship between menopausal hormone therapy (MHT) and cardiovascular disease (CVD) risk has been informed by detailed analyses in the Women's Health Initiative (WHI), the largest randomized, placebo controlled trial evaluating MHT in postmenopausal women. Although the WHI demonstrated increased risk of CVD events with MHT in the overall cohort, subsequent secondary analyses demonstrated that these risks were influenced by the woman's age and time since menopause, with lower absolute risks and hazard ratios for younger than older women. As MHT is the most effective treatment for the vasomotor symptoms of menopause, it is important to understand its risks and how to conduct risk stratification for symptomatic women. In addition to reviewing the WHI findings, studies pre- and post-WHI are reviewed to describe the relationship between MHT and CVD risk in menopausal women. The absolute risks of adverse cardiovascular events for MHT initiated in women close to menopause are low, and all-cause mortality effects are neutral or even favorable for younger menopausal women. The WHI has advanced and refined our understanding of the relationship between MHT and CVD risk. Although MHT should not be used for CVD prevention, absolute risks of CVD are low when MHT is started close to menopause in healthy women and hazard ratios tend to be lower for younger than older women. For women in early menopause and without contraindications to treatment, the benefits of MHT are likely to outweigh the risks when used for menopausal symptom management. PMID- 29493799 TI - Naturally Occurring Mentorship in a National Sample of First-Generation College Goers: A Promising Portal for Academic and Developmental Success. AB - Attending college is increasingly important to compete in this global world; however, young people whose parents did not attend college are significantly less likely to enroll in and finish college. Formal programs to support first generation college goers are common, but not scalable to provide support to all young people who need it. Instead, mentoring that naturally occurs on these students' journeys into and out of college may be a more practical avenue for supporting their success. This study investigated the role community members, relatives, and educators play in first-generation college goers' educational outcomes. Data from 4,181 participants of the National Longitudinal Study of Adolescent and Adult Health were used to test differences in supports received between first-generation, continuing-generation, and non-college goers. Results demonstrated that mentorship in adolescence moderated the relationship between parental college attendance and educational attainment in adulthood. Next, findings suggested that first-generation students received less support for identity development from their mentors than continuing-generation students. This study has program implications for facilitating college attendance and fostering the development and success of first-generation students. Moreover, this project continues to concretize an emerging taxonomy of mentoring functions for youth and emerging adults. PMID- 29493800 TI - Noninvasive eye localization in ocular proton therapy through optical eye tracking: A proof of concept. AB - PURPOSE: Over the last four decades, Ocular Proton Therapy has been successfully used to treat patients affected by intraocular lesions. For this, treatment geometry verification is routinely performed using radiographic images to align a configuration of fiducial radiopaque markers implanted on the sclera outer surface. This paper describes the clinical application of an alternative approach based on optical eye tracking for three-dimensional noninvasive and automatic eye localization. An experimental protocol was designed to validate the optical-based eye referencing against both radiographic imaging system and the clinically used EYEPLAN treatment planning system. METHODS: The eye tracking system (ETS) was installed in the OPTIS 2 treatment room at PSI to acquire eye motions during the treatment of nine patients. The pupil position and the cornea curvature center were localized by segmenting the pupil contour and corneal light reflections on the images acquired by a pair of calibrated optical cameras. After calibration of the ETS, a direct comparison of radiopaque markers position, and consequentially eye position and orientation, provided by the ETS, radiographs and EYEPLAN was performed. RESULTS: Nineteen out of thirty total monitored fractions were excluded from the study due to poor visibility of corneal reflection, resulting in a success rate of acquisition of 37%. For these data, overall median agreement between ETS-based and x-ray-based markers position assessment were 0.29 mm and 0.94 degrees for translations and rotations, respectively. Small discrepancies were also measured in the eye center estimates of the ETS and EYEPLAN. Conversely, variations in measured eye orientation were higher, with interquartile range (IQR) between 4.39 degrees and 7.58 degrees . Nonetheless, dosimetric evaluation of the consequence of ETS uncertainties showed that the target volume would still be covered by more than 95% of the dose in all cases. CONCLUSION: An ETS was successfully installed in a clinical ocular proton therapy treatment room and used to monitor eye position and orientation in a clinical scenario. First results show the potential of such a system as an eye localization device. However, the low success rate prevents straightforward clinical application and needs further improvements aimed at increasing corneal reflection visibility. PMID- 29493801 TI - Validation of a smartphone-based event recorder for arrhythmia detection. AB - INTRODUCTION: Ambulatory cardiac monitoring devices such as external loop recorders (ELRs) are often used in the outpatient clinic to evaluate palpitations. However, ELRs can be bulky and uncomfortable to use, especially in public, at work, or in social situations. An alternative approach is a smartphone based electrocardiographic (ECG) recorder/event recorder (Kardia Mobile [KM]), but the comparative diagnostic yield of each approach has not been studied. METHODS: Thirty-three patients with palpitations wore an ELR and carried a KM for a period of 14-30 days. They were instructed to transmit ECGs via KM and also to activate the ELR whenever they had symptoms. The tracings obtained from both devices were independently analyzed by two cardiologists, and the overall arrhythmia yield, as well as patient preference and compliance, were evaluated. The paired binomial data obtained from both devices were compared using an unconditional test of noninferiority. RESULTS: Of the 38 patients enrolled in the study, more patients had a potential diagnosis for their symptoms (i.e., at least one symptomatic recording during the entire monitoring period) with KM than with the ELR (KM = 34 [89.5%] vs ELR = 26 [68.4%]; chi2 = 5.1, P = 0.024). In the per protocol analysis, all 33 patients (100%) had a potential diagnosis using the KM device, which was significantly higher compared to 24 patients (72.2%) using the ELR (chi2 = 10.4, P = 0.001). CONCLUSIONS: KM is noninferior to an ELR for detecting arrhythmias in the outpatient setting. The ease of use and portability of this device make it an attractive option for the detection of symptomatic arrhythmias. PMID- 29493802 TI - Ultrasound-guided serratus anterior plane block combined with the two-incision technique for subcutaneous ICD implantation. AB - BACKGROUND: The standard technique for implanting a subcutaneous implantable cardioverter defibrillator (S-ICD) requires three incisions and the pocket of the device is created in the subcutaneous tissue of the left lateral thoracic wall. However, a two-incision technique may be adopted, in which the cranial parasternal region is avoided and the device is positioned more deeply, completely under the latissimus dorsi muscle. This can also be combined with ultrasound-guided serratus anterior plane block (US-SAPB) for intraoperative anesthesia and perioperative analgesia. We describe our preliminary experience of US-SAPB combined with the two-incision intermuscular technique. METHODS: We performed US-SAPB 40 minutes before starting the procedure, while the patient was in the supine position. The devices were implanted under the latissimus dorsi muscle. All patients were followed-up after hospital discharge. RESULTS: Twelve patients (male 50%, 53 +/- 16 years, body mass index 23 +/- 4) underwent the S ICD implantation with the combined technique. The mean procedure duration was 47 +/- 11 minutes. The procedure was successful and a shock energy of 65 J was successful in converting the induced ventricular fibrillation in all patients. The US-SAPB was successful in 92% of cases and only one patient required convertion into general anesthesia due to pain during the procedure. In the postoperative period, patients did not report major discomfort and analgesics were not required. During a median follow-up of 12 months, no complications were reported. CONCLUSIONS: Serratus anterior plane block combined with the intermuscular and two-incision technique proved to be safe and effective during the S-ICD implantation procedure. PMID- 29493803 TI - Material matters: Analysis of density uncertainty in 3D printing and its consequences for radiation oncology. AB - PURPOSE: Using 3D printing to fabricate patient-specific devices such as tissue compensators, boluses, and phantoms is inexpensive and relatively simple. However, most 3D printing materials have not been well characterized, including their radiologic tissue equivalence. The purposes of this study were to (a) determine the variance in Hounsfield Units (HU) for printed objects, (b) determine if HU varies over time, and (c) calculate the clinical dose uncertainty caused by these material variations. METHODS: For a sample of 10 printed blocks each of PLA, NinjaFlex, ABS, and Cheetah, the average HU and physical density were tracked at initial printing and over the course of 5 weeks, a typical timeframe for a standard course of radiotherapy. After initial printing, half the blocks were stored in open boxes, the other half in sealed bags with desiccant. Variances in HU and density over time were evaluated for the four materials. Various clinical photon and electron beams were used to evaluate potential errors in clinical depth dose as a function of assumptions made during treatment planning. The clinical depth error was defined as the distance between the correctly calculated 90% isodose line and the 90% isodose line calculated using clinically reasonable, but simplified, assumptions. RESULTS: The average HU measurements of individual blocks of PLA, ABS, NinjaFlex, and Cheetah varied by as much as 121, 30, 178, and 30 HU, respectively. The HU variation over 5 weeks was much smaller for all materials. The magnitude of clinical depth errors depended strongly on the material, energy, and assumptions, but some were as large as 9.0 mm. CONCLUSIONS: If proper quality assurance steps are taken, 3D printed objects can be used accurately and effectively in radiation therapy. It is critically important, however, that the properties of any material being used in patient care be well understood and accounted for. PMID- 29493804 TI - Outcomes of low-weight patients with avoidant/restrictive food intake disorder and anorexia nervosa at long-term follow-up after treatment in a partial hospitalization program for eating disorders. AB - OBJECTIVE: To assess long-term outcomes of patients with avoidant/restrictive food intake disorder (ARFID) treated in a partial hospitalization program (PHP) for eating disorders (ED). METHOD: A cross-sectional study comparing patients with ARFID to those with anorexia nervosa (AN) who had been discharged from a PHP for at least 12 months was performed. Percent median body mass index (%MBMI), scores on the Children's Eating Attitudes Test (ChEAT), and treatment utilization were assessed, with intake and discharge data collected via retrospective chart review. RESULTS: Of the 137 eligible patients, 62 (45.3%) consented to follow-up data collection. Patients with ARFID and AN exhibited similar increases in %MBMI from intake to discharge and reported low scores on the ChEAT by discharge. Patients with ARFID and AN maintained good weight outcomes and low ChEAT scores at follow-up. Most participants were still receiving outpatient treatment from a variety of providers, although fewer with ARFID than AN continued to receive services from our multidisciplinary ED clinic. DISCUSSION: Patients with ARFID and AN exhibit similar improvements in %MBMI when treated in the same PHP and appear to maintain treatment gains at long-term follow-up. Additionally, most patients continue to utilize outpatient services after being discharged from a PHP. PMID- 29493805 TI - Dropout from cognitive-behavioral therapy for eating disorders: A meta-analysis of randomized, controlled trials. AB - OBJECTIVE: Cognitive-behavioral therapy (CBT) is efficacious for a range of eating disorder presentations, yet premature dropout is one factor that might limit CBTs effectiveness. Improved understanding of dropout from CBT for eating disorders is important. This meta-analysis aimed to study dropout from CBT for eating disorders in randomized controlled trials (RCTs), by (a) identifying the types of dropout definitions applied, (b) providing estimates of dropout, (c) comparing dropout rates from CBT to non-CBT interventions for eating disorders, and (d) testing moderators of dropout. METHOD: RCTs of CBT for eating disorders that reported rates of dropout were searched. Ninety-nine RCTs (131 CBT conditions) were included. RESULTS: Dropout definitions varied widely across studies. The overall dropout estimate was 24% (95% CI = 22-27%). Diagnostic type, type of dropout definition, baseline symptom severity, study quality, and sample age did not moderate this estimate. Dropout was highest among studies that delivered internet-based CBT and was lowest in studies that delivered transdiagnostic enhanced CBT. There was some evidence that longer treatment protocols were associated with lower dropout. No significant differences in dropout rates were observed between CBT and non-CBT interventions for all eating disorder subtypes. CONCLUSION: Present study dropout estimates are hampered by the use of disparate dropout definitions applied. This meta-analysis highlights the urgency for RCTs to utilize a standardized dropout definition and to report as much information on patient dropout as possible, so that strategies designed to minimize dropout can be developed, and factors predictive of CBT dropout can be more easily identified. PMID- 29493806 TI - Replicating and Cycling Stores of Information Perpetuate Life. AB - Life is perpetuated through a single-cell bottleneck between generations in many organisms. Here, I highlight that this cell holds information in two distinct stores: in the linear DNA sequence that is replicated during cell divisions, and in the three-dimensional arrangement of molecules that can change during development but is recreated at the start of each generation. These two interdependent stores of information - one replicating with each cell division and the other cycling with a period of one generation - coevolve while perpetuating an organism. Unlike the genome sequence, the arrangement of molecules, including DNA, RNAs, proteins, sugars, lipids, etc., is not well understood. Because this arrangement and the genome sequence are transmitted together from one generation to the next, analysis of both is necessary to understand evolution and origins of inherited diseases. Recent developments suggest that tools are in place to examine how all the information to build an organism is encoded within a single cell, and how this cell code is reproduced in every generation. See also the video abstract here: https://youtu.be/IdWEL-T6TPU. PMID- 29493807 TI - Nurses' attitudes and behaviour towards patients' use of complementary therapies: A mixed methods study. AB - AIM: To explore Registered Nurses' attitudes and behaviour towards patients' use of complementary therapies. BACKGROUND: Despite high rates of use of complementary therapies by the general population, little is known of how nurses respond to patients' use of these therapies. DESIGN: A two-phase sequential exploratory mixed methods design. METHODS: Nineteen Registered Nurses working in Australia participated in a semi-structured interview in 2015-2016 and emerging themes informed the development of a quantitative survey instrument administered online nationwide in 2016. FINDINGS: Emerging key themes "Promoting safe care"; "Seeking complementary therapies knowledge";" Supporting holistic health care"; and "Integrating complementary therapies in practice" were reflected in survey results. Survey responses (N = 614) revealed >90% agreement that complementary therapies align with a holistic view of health and that patients have the right to use them. Most nurses (77.5%) discussed complementary therapies with patients and 91.8% believed nurses should have some understanding of the area. One-third did not recommend complementary therapies and there was a lack of overall consensus as to whether these therapies should be integrated into nursing practice. Nurses with training in complementary therapies held more positive views than those without. CONCLUSION: Nurses were generally supportive of patients' interest in complementary therapies, although their primary concern was safety of the patient. Despite broad acceptance that nurses should have a basic understanding of complementary therapies, there was a lack of consensus about recommendation, integration into nursing practice and referral. Further research should explore how nurses can maintain safe, patient-centred care in the evolving pluralistic healthcare system. PMID- 29493808 TI - Spontaneous coronary artery dissection in women: What is known and what is yet to be understood. AB - Spontaneous coronary artery dissection is a nonatherosclerotic etiology of acute coronary syndrome, including sudden cardiac death, which frequently affects younger women. This review highlights contemporary knowledge regarding spontaneous coronary artery dissection demographics, prevalence, diagnosis, presentation, and associated conditions and risks, inpatient treatment, major adverse clinical events, and outpatient management decisions. PMID- 29493810 TI - Effect of T1-mapping technique and diminished image resolution on quantification of infarct mass and its ability in predicting appropriate ICD therapy. AB - PURPOSE: Myocardial infarct (MI) may consist of an infarct core (IC) and a heterogeneous, semi-viable border zone (BZ). Patients with chronic MI in the left ventricular (LV) myocardium are at increased risk of developing ventricular arrhythmias, and may therefore qualify for implantable cardioverter defibrillator (ICD) therapy. Indices based on MI mass, as determined by cardiac magnetic resonance (CMR) imaging, are shown to be sensitive in predicting adverse ventricular arrhythmic events. However, several factors, such as imaging technique and spatial resolution affect the accuracy of MI mass quantification. The aim of this study was to compare the MI masses determined by T1-mapping CMR techniques to those of conventional late Gadolinium-enhanced cardiac magnetic resonance (LGE-CMR) using inversion recovery fast gradient echo (IR-FGRE). We additionally aimed to investigate the effect of diminishing image resolution on quantification of the MI mass and its ability to predict appropriate ICD therapy. METHODS: Thirty-eight patients with known MI underwent acquisitions of three CMR imaging techniques: the multicontrast late enhancement (MCLE) and modified look locker inversion recovery (MOLLI) T1-mapping techniques, and conventional inversion recovery fast gradient echo (IR-FGRE) about 20 min after double-dose injection of Gadolinium. We postprocessed images to quantify IC and BZ masses determined by each CMR technique using a full-width half-maximum (FWHM) approach in IR-FGRE images and a fuzzy c-means clustering algorithm for T1-mapping images. To determine the impact of spatial resolution in sensitivity of predicting ICD events, we artificially diminished resolution of MCLE images acquired from a separate group of 27 patients who had been followed up for ICD therapy and compared the MI masses estimated from the original and downsampled MCLE images. RESULTS: Twelve patients out of 27 (44%) received ICD therapy (i.e., one or more delivered shock) during the follow-up stage. Between each of the three imaging methods, IC masses were not significantly different. Conversely, BZ masses determined by MOLLI were larger compared to those determined by MCLE and IR-FGRE (P value = 0.0022 and 0.0003, respectively). The BZ masses determined by MCLE were not significantly different from those determined by IR-FGRE; however, BZ masses determined by the downsampled MCLE were significantly larger than those determined by IR-FGRE and original MCLE (P value = 0.0033 and 0.0003, respectively). The BZ mass estimated by original MCLE was larger in patients who had received ICD therapy compared to those who did not (P value = 0.044). However, when the spatial resolution of the MCLE images was diminished to that of MOLLI, BZ masses were not significantly different between patients with and without ICD therapy. CONCLUSIONS: While estimated IC masses were consistent among all three techniques, the estimated BZ masses were not consistent, especially when spatial resolution of images differed between the techniques. In particular, our study showed that diminished image resolution caused an increase in estimation of the BZ mass, likely due to partial volume effects, which led to a reduced sensitivity in the prediction of appropriate ICD therapy. PMID- 29493811 TI - How do Housing Subsidies Improve Quality of Life Among Homeless Adults? A Mediation Analysis. AB - Supported housing, combining rent subsidies with intensive case management, is associated with improvements in quality of life of homeless adults, but factors mediating their impact on quality of life have not been studied. Twelve-month outcome data from a randomized trial of the Housing and Urban Development- Veterans Affairs Supported Housing program (HUD-VASH) showed that access to a housing rent subsidy plus intensive case management (ICM) was associated with greater improvement in subjective quality of life than ICM alone. Multiple mediation analyses were applied to identify variables that significantly mediated the relationship between receipt of housing voucher and improvements in quality of life. Significant mediating covariates were those whose 95% bias-corrected confidence intervals, when added to the model predicting improvement in quality of life, did not overlap zero. Increases in the number of days housed, size of social network, and availability of emotional support appear to mediate improvement in quality of life and account for 71% of the benefit attributable to having a rent subsidy. Improvement in subjective quality of life though housing subsidies is mediated by gains in both material and psychosocial factors. Mediating factors deserve special attention in supported housing services. PMID- 29493809 TI - Use of attention-deficit/hyperactivity disorder medication among older adults in Denmark. AB - AIMS: Knowledge on the use of attention-deficit/hyperactivity disorder (ADHD) medication among older adults is limited. We hypothesized that ADHD medication is used off-label in adults aged >=50 years as part of palliative care in e.g. cancer patients. The aim of this study was to describe the use of ADHD medication among adults aged >=50 years in Denmark. METHODS: Using the Danish health registries, we identified new users >=50 years of ADHD medication during 2000 2012. We estimated the annual incidence of ADHD medication use and ADHD diagnoses. We described new users of ADHD medication according to co-medication, comorbidities and assessed the 1-year cumulative mortality rate. A posthoc analysis allowed us to include new users until 2015. RESULTS: We identified 6690 new users of ADHD medication from 2000 to 2012. From 2000 to 2015 we observed an increase in the incidence of ADHD medication use from 12.5 to 30.3 per 100 000 person-years. However, the incidence rate decreased from 2010 to 2015. Throughout the study period, the incidence rate of ADHD diagnoses was low (overall prevalence among new users <=2%). Opioids were the most frequent comedication used (used by 54%), while cancer was the most frequent diagnosis preceding treatment (prevalence of 52%). The 1-year cumulative mortality was 50%, primarily driven by patients with a preceding cancer diagnosis. CONCLUSION: There was an increase in the incidence of ADHD medication use in adults aged >=50 years from 2000-2010 and a decreasing incidence from 2010-2015. Our results suggest that ADHD medication is used off-label in older adults as part of palliative care. PMID- 29493814 TI - Crown lengthening and restorative procedures in the esthetic zone. AB - Crown lengthening is one of the most common surgical procedures in periodontal practice. Its indications include subgingival caries, crown or root fractures, altered passive eruption, cervical root resorption and short clinical abutment, and its aim is to re-establish the biologic width in a more apical position. While the procedure in posterior areas of the dentition has been thoroughly investigated, crown lengthening performed for esthetic reasons in the anterior areas is still a matter of debate and an evidence-based technique is not available. This paper provides accurate descriptions of the surgical and restorative phases of the esthetic crown-lengthening procedure by answering the following questions: what is the ideal surgical flap design? how much supporting bone should be removed? how should the position of the flap margin relate to the alveolar bone at surgical closure? and how should the healing phase be managed in relation to the timing and the position of the provisional restoration with respect to the gingival margin? PMID- 29493813 TI - Frontline Science: Rapid adipose tissue expansion triggers unique proliferation and lipid accumulation profiles in adipose tissue macrophages. AB - Obesity-related changes in adipose tissue leukocytes, in particular adipose tissue macrophages (ATMs) and dendritic cells (ATDCs), are implicated in metabolic inflammation, insulin resistance, and altered regulation of adipocyte function. We evaluated stromal cell and white adipose tissue (WAT) expansion dynamics with high fat diet (HFD) feeding for 3-56 days, quantifying ATMs, ATDCs, endothelial cells (ECs), and preadipocytes (PAs) in visceral epididymal WAT and subcutaneous inguinal WAT. To better understand mechanisms of the early response to obesity, we evaluated ATM proliferation and lipid accumulation. ATMs, ATDCs, and ECs increased with rapid WAT expansion, with ATMs derived primarily from a CCR2-independent resident population. WAT expansion stimulated proliferation in resident ATMs and ECs, but not CD11c+ ATMs or ATDCs. ATM proliferation was unperturbed in Csf2- and Rag1-deficient mice with WAT expansion. Additionally, ATM apoptosis decreased with WAT expansion, and proliferation and apoptosis reverted to baseline with weight loss. Adipocytes reached maximal hypertrophy at 28 days of HFD, coinciding with a plateau in resident ATM accumulation and the appearance of lipid-laden CD11c+ ATMs in visceral epididymal WAT. ATM increases were proportional to tissue expansion and adipocyte hypertrophy, supporting adipocyte-mediated regulation of resident ATMs. The appearance of lipid-laden CD11c+ ATMs at peak adipocyte size supports a role in responding to ectopic lipid accumulation within adipose tissue. In contrast, ATDCs increase independently of proliferation and may be derived from circulating precursors. These changes precede and establish the setting in which large-scale adipose tissue infiltration of CD11c+ ATMs, inflammation, and adipose tissue dysfunction contributes to insulin resistance. PMID- 29493815 TI - Real-time histological imaging of a superficial non-ampullary duodenal epithelial tumor using endocytoscopy. PMID- 29493812 TI - BET proteins in abnormal metabolism, inflammation, and the breast cancer microenvironment. AB - Obesity and its associated pathology Type 2 diabetes are two chronic metabolic and inflammatory diseases that promote breast cancer progression, metastasis, and poor outcomes. Emerging critical opinion considers unresolved inflammation and abnormal metabolism separately from obesity; settings where they do not co-occur can inform disease mechanism. In breast cancer, the tumor microenvironment is often infiltrated with T effector and T regulatory cells programmed by metabolic signaling. The pathways by which tumor cells evade immune surveillance, immune therapies, and take advantage of antitumor immunity are poorly understood, but likely depend on metabolic inflammation in the microenvironment. Immune functions are abnormal in metabolic disease, and lessons learned from preclinical studies in lean and metabolically normal environments may not translate to patients with obesity and metabolic disease. This problem is made more urgent by the rising incidence of breast cancer among women who are not obese but who have metabolic disease and associated inflammation, a phenotype common in Asia. The somatic BET proteins, comprising BRD2, BRD3, and BRD4, are new critical regulators of metabolism, coactivate transcription of genes that encode proinflammatory cytokines in immune cell subsets infiltrating the microenvironment, and could be important targets in breast cancer immunotherapy. These transcriptional coregulators are well known to regulate tumor cell progression, but only recently identified as critical for metabolism, metastasis, and expression of immune checkpoint molecules. We consider interrelationships among metabolism, inflammation, and breast cancer aggressiveness relevant to the emerging threat of breast cancer among women with metabolic disease, but without obesity. PMID- 29493817 TI - Cobalt-Iron-Manganese Catalysts for the Conversion of End-of-Life-Tire-Derived Syngas into Light Terminal Olefins. AB - Co-Fe-Mn/gamma-Al2 O3 Fischer-Tropsch synthesis (FTS) catalysts were synthesized, characterized and tested for CO hydrogenation, mimicking end-of-life-tire (ELT) derived syngas. It was found that an increase of C2 -C4 olefin selectivities to 49 % could be reached for 5 wt % Co, 5 wt % Fe, 2.5 wt % Mn/gamma-Al2 O3 with Na at ambient pressure. Furthermore, by using a 5 wt % Co, 5 wt % Fe, 2.5 wt % Mn, 1.2 wt % Na, 0.03 wt % S/gamma-Al2 O3 catalyst the selectivity towards the fractions of C5+ and CH4 could be reduced, whereas the selectivity towards the fraction of C4 olefins could be improved to 12.6 % at 10 bar. Moreover, the Na/S ratio influences the ratio of terminal to internal olefins observed as products, that is, a high Na loading prevents the isomerization of primary olefins, which is unwanted if 1,3-butadiene is the target product. Thus, by fine-tuning the addition of promoter elements the volume of waste streams that need to be recycled, treated or upgraded during ELT syngas processing could be reduced. The most promising catalyst (5 wt % Co, 5 wt % Fe, 2.5 wt % Mn, 1.2 wt % Na, 0.03 wt % S/gamma-Al2 O3 ) has been investigated using operando transmission X-ray microscopy (TXM) and X-ray diffraction (XRD). It was found that a cobalt-iron alloy was formed, whereas manganese remained in its oxidic phase. PMID- 29493816 TI - On modeling. AB - Mapping tissue microstructure with MRI holds great promise as a noninvasive window into tissue organization at the cellular level. Having originated within the realm of diffusion NMR in the late 1970s, this field is experiencing an exponential growth in the number of publications. At the same time, model-based approaches are also increasingly incorporated into advanced MRI acquisition and reconstruction techniques. However, after about two decades of intellectual and financial investment, microstructural mapping has yet to find a single commonly accepted clinical application. Here, we suggest that slow progress in clinical translation may signify unresolved fundamental problems. We outline such problems and related practical pitfalls, as well as review strategies for developing and validating tissue microstructure models, to provoke a discussion on how to bridge the gap between our scientific aspirations and the clinical reality. We argue for recalibrating the efforts of our community toward a more systematic focus on fundamental research aimed at identifying relevant degrees of freedom affecting the measured MR signal. Such a focus is essential for realizing the truly revolutionary potential of noninvasive three-dimensional in vivo microstructural mapping. PMID- 29493818 TI - Cytomegalovirus reactivation in liver transplant recipients due to hepatitis C cirrhosis is associated with higher cardiovascular risk - an observational, retrospective study. AB - The association between cytomegalovirus (CMV) reactivation and cardiovascular risk has been reported in solid organ transplant populations; however, it has yet to be assessed in liver transplantation (LT). We aim to evaluate whether CMV reactivation is associated with cardiovascular events (CVE) in HCV-LT patients. LT patients (2010 and 2014) due to HCV cirrhosis were included. Clinically significant CMV (CS-CMV) was defined as viral load (VL) >5000 copies/ml, need of therapy or CMV disease. Baseline variables and endpoint measures (CVE, survival, severe recurrent hepatitis C, de novo tumors, and diabetes) were collected. One hundred and forty patients were included. At LT, a history of AHT was present in 23%, diabetes 22%, tobacco use 45%, obesity 20%, and renal impairment (eGFR < 60 ml/min) in 26.5%. CS-CMV reactivation occurred in 25% of patients. Twenty-six patients (18.5%) developed a CVE. Cox regression analysis revealed two factors significantly associated with CVE: Pre-LT DM [HR = 4.6 95% CI (1.6, 13), P = 0.004] and CS-CMV [HR = 4.7 95% CI (1.8, 12.5), P = 0.002]. CS-CMV was not independently associated with the remaining endpoints except for survival (P = 0.03). In our series, CS-CMV reactivation was associated with a greater risk of developing CVE, thus confirming data from other solid organ transplant populations and emphasizing the need for adequate CMV control. PMID- 29493819 TI - Identifying On-Surface Site-Selective Chemical Conversions by Theory-Aided NEXAFS Spectroscopy: The Case of Free-Base Corroles on Ag(111). AB - We demonstrate here that theory-assisted near-edge X-ray absorption fine structure (NEXAFS) spectroscopy enables the site-sensitive monitoring of on surface chemical reactions, thus, providing information not accessible by other techniques. As a prototype example, we have used free-base 5,10,15 tris(pentafluorophenyl)corroles (3H-TpFPC) adsorbed on Ag(111) and present a detailed investigation of the angle-dependent NEXAFS of this molecular species as well as of their thermally induced derivatives. For this, we have recorded experimental C and N K-edge NEXAFS spectra and interpret them based on XAS cross section calculations by using a continuous fraction approach and core-hole including multiprojector PAW pseudopotentials within DFT. We have characterized the as-deposited low temperature (200 K) phase and unraveled the subsequent changes induced by dehydrogenation (at 330 K) and ring-closure reactions (at 430 K). By exemplarily obtaining profound insight into the on-surface chemistry of free-base corrolic species adsorbed on a noble metal this work highlights how angle-dependent XAS combined with accurate theoretical modeling can serve for the investigation of on-surface reactions, whereby even highly similar molecular structures, such as tautomers and isomers, can be distinguished. PMID- 29493820 TI - Reversible Nanogate System for Mesoporous Silica Nanoparticles Based on Diels Alder Adducts. AB - The implementation of nanoparticles as nanomedicines requires sophisticated surface modifications to reduce the immune response and enhance recognition abilities. Mesoporous silica nanoparticles present extraordinary host-guest abilities and facile surface functionalization. These two factors make them ideal candidates for the development of novel drug-delivery systems, at the expense of increasing structural complexity. With this idea in mind, a system composed of triggerable and tunable silica nanoparticles was developed for application as drug-delivery nanocarriers. Diels-Alder cycloaddition adducts were chosen as thermal-responsive units that permitted the binding of gold nanocaps able to block the pores and allow the incorporation of targeting fragments. The capping efficiency was tested under different thermal conditions to give outstanding efficiencies within the physiological range and mild temperatures, as well as enhanced release under pulsing heating cycles, which showed the best release profiles. PMID- 29493822 TI - Detailed analysis of inflammatory cell infiltration and the prognostic impact on nasopharyngeal carcinoma. AB - BACKGROUND: One of the most striking characteristics of nasopharyngeal carcinoma (NPC) is the presence of a very abundant immune cells infiltrate containing mainly T-lymphocytes. The purpose of this study was to present our analysis providing a comprehensive characterization of antitumor inflammatory response in NPC. METHODS: The densities of 9 types of inflammatory cells were assessed in 197 patients with NPC, including CD3 + T-lymphocytes, CD8 + cytotoxic T-lymphocytes, CD20 + B-lymphocytes, CD56 + natural killer (NK) cells, FOXP3 + regulatory T lymphocytes, CD1a + immature dendritic cells, CD83 + mature dendritic cells, neutrophil elastase + neutrophils, and tryptase + mast cells. We characterized the inflammatory infiltrate in relation to clinical stage and patient survival. The expression of programmed death-1 (PD-1) on tumor-infiltrating lymphocytes (TILs) was also detected. The correlations between PD-1 expression and clinical characteristics and posttreatment outcome were analyzed. RESULTS: The patients with NPC with a low density of tumor-infiltrating FOXP3+, CD8 + T-lymphocytes, neutrophils, and mast cells showed a significantly longer overall survival (OS) and progression-free survival (PFS). However, patients with a high density of NK cells showed a better OS and PFS. The densities of NK cells and mast cells could be served as biomarkers for predicting recurrence or distant metastasis in patients with NPC. Moreover, PD-1 positivity predicted poor prognosis in patients with NPC. CONCLUSION: The densities of inflammatory cells are correlated with the prognosis of patients with NPC. PMID- 29493821 TI - Reach and messages of the world's largest ivory burn. AB - Recent increases in ivory poaching have depressed African elephant populations. Successful enforcement has led to ivory stockpiling. Stockpile destruction is becoming increasingly popular, and most destruction has occurred in the last 5 years. Ivory destruction is intended to send a strong message against ivory consumption, both in promoting a taboo on ivory use and catalyzing policy change. However, there has been no effort to establish the distribution and extent of media reporting on ivory destruction events globally. We analyzed media coverage of the largest ivory destruction event in history (Kenya, 30 April 2016) across 11 nation states connected to ivory trade. We used an online-media crawling tool to search online media outlets and subjected 5 of the largest print newspapers (by circulation) in 5 nations of interest to content analysis. Most online news on the ivory burn came from the United States (81% of 1944 articles), whereas most of the print news articles came from Kenya (61% of 157 articles). Eighty-six to 97% of all online articles reported the burn as a positive conservation action, whereas 4-50% discussed ivory burning as having a negative impact on elephant conservation. Most articles discussed law enforcement and trade bans as effective for elephant conservation. There was more relative search interest globally in the 2016 Kenyan ivory burn than any other burn in 5 years. Ours is the first attempt to track the reach of media coverage relative to an ivory burn and provides a case study in tracking the effects of a conservation-marketing event. PMID- 29493823 TI - Quantification of hand synovitis in rheumatoid arthritis: Arterial mask subtraction reinforced with mutual information can improve accuracy of pixel-by pixel time-intensity curve shape analysis in dynamic MRI. AB - BACKGROUND: Synovitis, which is a hallmark of rheumatoid arthritis (RA), needs to be precisely quantified to determine the treatment plan. Time-intensity curve (TIC) shape analysis is an objective assessment method for characterizing the pixels as artery, inflamed synovium, or other tissues using dynamic contrast enhanced MRI (DCE-MRI). PURPOSE/HYPOTHESIS: To assess the feasibility of our original arterial mask subtraction method (AMSM) with mutual information (MI) for quantification of synovitis in RA. STUDY TYPE: Prospective study. SUBJECTS: Ten RA patients (nine women and one man; mean age, 56.8 years; range, 38-67 years). FIELD STRENGTH/SEQUENCE: 3T/DCE-MRI. ASSESSMENT: After optimization of TIC shape analysis to the hand region, a combination of TIC shape analysis and AMSM was applied to synovial quantification. The MI between pre- and postcontrast images was utilized to determine the arterial mask phase objectively, which was compared with human subjective selection. The volume of objectively measured synovitis by software was compared with that of manual outlining by an experienced radiologist. Simple TIC shape analysis and TIC shape analysis combined with AMSM were compared in slices without synovitis according to subjective evaluation. STATISTICAL TESTS: Pearson's correlation coefficient, paired t-test and intraclass correlation coefficient (ICC). RESULTS: TIC shape analysis was successfully optimized in the hand region with a correlation coefficient of 0.725 (P < 0.01) with the results of manual assessment regarded as ground truth. Objective selection utilizing MI had substantial agreement (ICC = 0.734) with subjective selection. Correlation of synovial volumetry in combination with TIC shape analysis and AMSM with manual assessment was excellent (r = 0.922, P < 0.01). In addition, negative predictive ability in slices without synovitis pixels was significantly increased (P < 0.01). DATA CONCLUSIONS: The combination of TIC shape analysis and image subtraction reinforced with MI can accurately quantify synovitis of RA in the hand by eliminating arterial pixels. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. PMID- 29493824 TI - Metal- and Reagent-Free Anodic C-C Cross-Coupling of Phenols with Benzofurans leading to a Furan Metathesis. AB - Heterobiaryls consisting of a phenol and a benzofuran motif are of significant importance for pharmaceutical applications. An attractive sustainable, metal- and reagent-free, electrosynthetic, and highly efficient method, that allows access to (2-hydroxyphenyl)benzofurans is presented. Upon the electrochemical dehydrogenative C-C cross-coupling reaction, a metathesis of the benzo moiety at the benzofuran occurs. This gives rise to a substitution pattern at the hydroxyphenyl moiety which would not be compatible by a direct coupling process. The single-step protocol is easy to conduct in an undivided electrolysis cell, therefore scalable, and inherently safe. PMID- 29493825 TI - Thirty-day readmission in patients undergoing head and neck microvascular reconstruction. AB - BACKGROUND: Characteristics of 30-day unplanned readmissions after head and neck microvascular reconstruction remain poorly understood. METHODS: We conducted a retrospective cohort of patients who underwent head and neck microvascular reconstruction between 2010 and 2015. RESULTS: The 30-day unplanned readmission rate was 13.0% (64/493). The most common readmission diagnoses were dehiscence, surgical site infection, or fistula (45.3%; n = 29). Of the readmissions, 46.9% (30/64) occurred within 7 days of discharge from the hospital. Risk factors for readmission on multivariable analysis included body mass index (BMI) < 21 kg/m (odds ratio [OR] 2.47; 95% confidence interval [CI] 1.36-4.47), primary site of oropharynx (OR 1.66; 95% CI 1.17-6.06), hypopharynx/larynx (OR 3.66; 95% CI 1.70 7.88), or sinonasal/skull base (OR 4.07; 95% CI 1.43-11.55), and fistula during the index hospitalization (OR 2.98; 95% CI 1.22-7.24). CONCLUSION: More than 1 in 10 patients undergoing head and neck microvascular reconstruction has a 30-day unplanned readmission, most commonly related to wound complications. Further efforts are needed to determine optimal 30-day unplanned readmission reduction strategies. PMID- 29493826 TI - Cooperative Iodide Pd(0)-Catalysed Coupling of Alkoxyallenes and N Tosylhydrazones: A Selective Synthesis of Conjugated and Skipped Dienes. AB - Palladium(0)-catalysed hydro-alkylation or -alkenylation of alkoxyallenes with N tosylhydrazones gives direct access to conjugated and skipped 1-alkoxydienes with high efficiency and excellent functional-group compatibility. The reaction is proposed to involve the in situ-formed t-butanol as proton source in the key step of the allylpalladium(II) species generation. Moreover, lithium iodide or iodobenzene are employed as an unprecedented iodide (I- ) reservoir to sustain the catalytic cycle. PMID- 29493828 TI - Fundamentals of Electrophoresis 2018. PMID- 29493829 TI - Response to Darbyshire 2018: Nursing a media grievance. PMID- 29493830 TI - Anthracene Bisureas as Powerful and Accessible Anion Carriers. AB - Synthetic anion carriers (anionophores) have potential as biomedical research tools and as treatments for conditions arising from defective natural transport systems (notably cystic fibrosis). Highly active anionophores that are readily accessible and easily deliverable are especially valuable. Previous work has resulted in steroid and trans-decalin based anionophores with exceptional activity for chloride/nitrate exchange in vesicles, but poor accessibility and deliverability. This work shows that anthracene 1,8-bisureas can fulfil all three criteria. In particular, a bis-nitrophenyl derivative is prepared in two steps from commercial starting materials, yet shows comparable transport activity to the best currently known. Moreover, unlike earlier highly active systems, it does not need to be preincorporated in test vesicles but can be introduced subsequent to vesicle formation. This transporter also shows the ability to transfer between vesicles, and is therefore uniquely effective for anion transport at low transporter loadings. The results suggest that anthracene bisureas are promising candidates for application in biological research and medicine. PMID- 29493831 TI - Mothers' experiences of managing their child's pain before and during attendance at the emergency department. AB - AIMS AND OBJECTIVES: To explore mothers' experiences of managing their child's pain before and during attendance at the emergency department. BACKGROUND: Pain accounts for 50%-80% of all visits to the emergency department. Historically paediatric pain has been poorly managed in the emergency department and there remains variability in practice. It is mothers who usually bring their child to the emergency department and as such it is important to explore their perspectives of how pain is managed. DESIGN: Exploratory qualitative study. METHODOLOGY: Semi-structured interviews were carried out with mothers (n = 10) of children who have attended the emergency department in one hospital in the East of England during April 2015. RESULTS: Most mothers felt able to assess their child's pain and reported attending the emergency department when their normal pain-relieving strategies failed following an injury. Several mothers sought advice from elsewhere before bringing their child to the emergency department. The advice received was usually to take their child to the emergency department. Mothers welcomed the professional approach to pain management in the emergency department and valued being kept informed about their child's care. Mothers rated the care provided in the emergency department as good or very good. CONCLUSIONS: Mothers attended the emergency department when their normal pain-relieving strategies failed. This suggests there is a need to provide additional resources to support parents in this context. Mothers often brought their child to the emergency department rather than their General Practitioner or other primary healthcare providers. The reasons for this need exploring further. RELEVANCE TO CLINICAL PRACTICE: The results suggest that mothers need additional resources to enable them to manage their child's pain at home following an injury. The reasons mothers attend the emergency department rather than other healthcare providers need exploring in more depth. PMID- 29493832 TI - Experiences of cancer rehabilitation: A cross-sectional study. AB - AIMS AND OBJECTIVES: To investigate the cancer rehabilitation experiences of working-age cancer survivors. BACKGROUND: Cancer survivors have extremely complex needs, spanning physical, vocational and sexual domains. Although cancer rehabilitation services have been found to eliminate or reduce these strains, these services are often underutilised. DESIGN: A cross-sectional study design was employed. METHODS: A survey of persons over the age of 18 with a cancer diagnosis, enrolled in the Social Insurance Agency in a municipality in southern Sweden (n = 168, 68% women), was conducted. RESULTS: Patients who used the cancer rehabilitation service (57%) were generally satisfied with it. Of participants, 26% reported not having received an offer of rehabilitation. Of those who reported that they received information about cancer rehabilitation services, most also reported that they received this information from a healthcare service professional (69%); for example, from the oncology nurse or the oncologist, whereas 20% claimed they received the information from the administrator of the Swedish Social Insurance Agency. A minority of children and family members of patients received support from the healthcare system. CONCLUSIONS: More efforts should be taken to reach patients in need of cancer rehabilitation. Additionally, more attention should be directed towards family members and young children. RELEVANCE TO CLINICAL PRACTICE: More than one in four patients claimed to not have received an offer of cancer rehabilitation, and an even greater number of patients claimed that their spouses and children had never received an offer for this service either. Hence, there is a communication barrier that needs to be overcome. Health providers should be aware that information needs to be repeated several times, and presented both orally and in writing. PMID- 29493833 TI - Exploring staff perceptions and experiences of volunteers and visitors on the hospital ward at mealtimes using an ethnographic approach. AB - AIMS AND OBJECTIVES: To explore multiple perspectives and experiences of volunteer and visitor involvement and interactions at hospital mealtimes. In addition, to understand how the volunteer and visitor role at mealtimes is perceived within the hospital system. BACKGROUND: Mealtime assistance can improve patients' food intake and mealtime experience. Barriers to providing mealtime assistance include time pressures, staff availability and inadequate communication. Volunteers and visitors can encourage and assist patients at mealtimes. There is a lack of evidence on the relationship between hospital staff, volunteers and visitors. DESIGN: A qualitative, ethnographic approach. METHODS: Sixty-seven hours of fieldwork were conducted on two subacute wards within an Australian healthcare network in 2015. Mealtime practices and interactions of hospital staff, volunteers and visitors were observed. Sixty-one staff, volunteers and visitors were interviewed in 75 ethnographic and semi structured interviews. Data were inductively and thematically analysed. RESULTS: Three key themes emerged as follows: "help"-volunteers and visitors were considered helpful when they assisted patients at mealtimes, supported well-being and aided staff-patient communication; "hindrance"-staff perceived visitors as negative presences when they inhibited patient progress and impacted staff work practices; and "reality of practice"-visiting hours, visitor engagement in patient therapy and communication between staff, volunteers and visitors were important practical considerations of mealtime involvement. CONCLUSIONS: The findings show how and why volunteers and visitors can be helpful and unhelpful at hospital mealtimes on subacute wards. More research on the role and contribution of volunteers and visitors on hospital wards will inform future practice in healthcare settings. RELEVANCE TO CLINICAL PRACTICE: This healthcare organisation should continue to encourage volunteer and visitor involvement at hospital mealtimes. More effort is needed to educate visitors about patients' therapeutic goals and the importance of nutrition. The working relationship between hospital staff, volunteers and visitors should be strengthened to improve nutritional care. PMID- 29493834 TI - Voices used by nurses when communicating with patients and relatives in a department of medicine for older people-An ethnographic study. AB - AIMS AND OBJECTIVES: To describe how nurses communicate with older patients and their relatives in a department of medicine for older people in western Sweden. BACKGROUND: Communication is an essential tool for nurses when working with older patients and their relatives, but often patients and relatives experience shortcomings in the communication exchanges. They may not receive information or are not treated in a professional way. Good communication can facilitate the development of a positive meeting and improve the patient's health outcome. DESIGN: An ethnographic design informed by the sociocultural perspective was applied. METHODS: Forty participatory observations were conducted and analysed during the period October 2015-September 2016. The observations covered 135 hours of nurse-patient-relative interaction. Field notes were taken, and 40 informal field conversations with nurses and 40 with patients and relatives were carried out. Semistructured follow-up interviews were conducted with five nurses. RESULTS: In the result, it was found that nurses communicate with four different voices: a medical voice described as being incomplete, task-oriented and with a disease perspective; a nursing voice described as being confirmatory, process oriented and with a holistic perspective; a pedagogical voice described as being contextualised, comprehension-oriented and with a learning perspective; and a power voice described as being distancing and excluding. The voices can be seen as context-dependent communication approaches. When nurses switch between the voices, this indicates a shift in the orientation or situation. CONCLUSION: The results indicate that if nurses successfully combine the voices, while limiting the use of the power voice, the communication exchanges can become a more positive experience for all parties involved and a good nurse-patient-relative communication exchange can be achieved. RELEVANCE TO CLINICAL PRACTICE: Working for improved communication between nurses, patients and relatives is crucial for establishing a positive nurse-patient-relative relationship, which is a basis for improving patient care and healthcare outcomes. PMID- 29493835 TI - Hypertension among adults living in Haiti: An integrative review. AB - AIMS AND OBJECTIVES: To determine what is known about hypertension among adults living in Haiti. BACKGROUND: Hypertension is the leading cause of morbidity, the identified cause of heart failure in 45% of patients and is associated with more than 70% of cardiovascular disease-related hospital admissions in Haiti. DESIGN: An integrative review of the literature. METHODS: Searching four databases from 2007 to 2018, Whittemore and Knafl's method was used to review the literature. Three nurse researchers independently reviewed and appraised each publication applying the Johns Hopkins Evidence-based Practice Appraisal tool. RESULTS: Eight publications were identified and appraised for level and quality of evidence. The synthesis of the literature yielded common themes of (i) high prevalence of hypertension among adults living in rural areas, (ii) public health challenges, (iii) lack of knowledge and awareness of hypertension and (iv) barriers to effective treatment. CONCLUSION: Hypertension is a highly prevalent disease in Haiti that is understudied and warrants attention. To better serve this vulnerable population, culturally tailored prevention strategies and disease management programmes are recommended. RELEVANCE TO CLINICAL PRACTICE: There is a lack of quality evidence to guide nurses in the management of hypertension for this vulnerable population. Identification of barriers to effective treatment among this underserved population will assist nurses and other healthcare professionals in identifying best possible practices for patient care in clinical settings across Haiti. PMID- 29493836 TI - Extended-release naltrexone (XR-NTX) for opioid use disorder in clinical practice: Vivitrol's Cost and Treatment Outcomes Registry. AB - BACKGROUND AND AIMS: Extended-release naltrexone (XR-NTX), a MU-opioid receptor antagonist for prevention of relapse to opioid dependence, has demonstrated efficacy compared with placebo and comparative effectiveness with buprenorphine naloxone. We report outcomes for XR-NTX in Vivitrol's Cost and Treatment Outcomes Registry. DESIGN: Observational, open-label, single-arm, multi-center registry assessing baseline characteristics and clinical and health-related quality-of life outcomes associated with XR-NTX treatment in clinical practice. SETTING: 32 US treatment centers from 2011 to 2013. PARTICIPANTS: Patients with opioid dependence who were prescribed XR-NTX treatment and then enrolled into the registry. MEASUREMENTS: Monthly visits were evaluated for the full population and for patient ubgroups retrospectively, defined by injection number, focusing on the period between baseline and month 6 (1-, 2/3- or 6-XR-NTX). FINDINGS: Of 403 enrolled patients, 395 were analyzed. Most patients (n = 349) received out patient care. On average, patients received five injections (median = 3; range = 1-25). The median number of injections administered within 6 months was higher in patients who at baseline were employed (three versus two unemployed, P = 0.02) or had private insurance (five versus two self-payment, P = 0.005; versus two state funded, P < 0.001). The 1-, 2/3- and 6-XR-NTX groups had 132, 152 and 111 patients, respectively. At baseline, the 6-XR-NTX patients were more likely to meet normal/minimal mental illness criteria and attend school and less likely to report recent drug use. Within 6 months, the 6-XR-NTX group demonstrated improvements in employment, mental health and psychosocial functioning, and decreases in opioid craving, drug use and drug-related behavior. CONCLUSIONS: Among opioid-dependent people receiving XR-NTX treatment, better mental health, higher education and lower recent drug use at baseline are associated with greater treatment duration; in turn, longer treatment duration is associated with lower relapse rates and improved outcomes generally. PMID- 29493837 TI - Delirium in ICU patients following cardiac surgery: An observational study. AB - AIMS AND OBJECTIVES: To observe the clinical and structural factors that can be associated with the post-operative onset of delirium in patients who have undergone heart surgery. BACKGROUND: Several risk factors could contribute to the development of delirium, such as the use of some sedative drugs and a patient's history with certain types of acute chronic disease. However, in the literature, there is little knowledge about the association between delirium in patients who have undergone cardiac surgical intervention and their clinical and environmental predictors. DESIGN: We used an observational design. METHODS: We enrolled 89 hospitalised patients in the ICU. Patients were first evaluated using the Richmond Agitation Sedation Scale and subsequently using the Confusion Assessment Method for the ICU. A linear model of regression was used to identify the predictors of delirium in patients. RESULTS: The patients had an average age of 89 years (SD = 6.9), were predominantly male (84.3%) and were mostly married (79.8%). The majority of patients had been subjected to bypass (80.9%), while 19.1% had undergone the intervention of endoprosthesis. The logistic regression model showed that patient age, the duration of mechanically assisted ventilation, continuous exposure to artificial light and the presence of sleep disorders were predictors of the onset of delirium. CONCLUSION: This study further confirms that clinical aspects such as insomnia and one's circadian rhythm as well as structural elements such as exposure to artificial light are variables that should be monitored in order to prevent and treat the onset of severe post operative delirium. RELEVANCE TO CLINICAL PRACTICE: Identifying the possible factors that predispose a patient to the onset of delirium during intensive therapy following cardiac surgery, it is fundamental to implement interventions to prevent this syndrome. PMID- 29493838 TI - Regional cerebral blood flow in natives at high altitude: An arterial spin labeled MRI study. AB - BACKGROUND: It is known that a neurologic sequence occurs at high altitudes (HA); hence, cerebral blood flow (CBF) might vary by altitude. PURPOSE: To use arterial spin labeled (ASL) MRI to evaluate absolute CBF differences between subjects who live at HA and lowlands. STUDY TYPE: Cohort prospective trial. POPULATION: In all, 64 HA Tibetans, 19 lowland Tibetans, and 25 lowland Han subjects. FIELD STRENGTH/SEQUENCE: CBF was measured with the pulsed ASL sequence at 3T. ASSESSMENT: CBF was correlated with abode altitude in HA Tibetans; CBF differences among HA Tibetans, lowland Tibetans, and lowland Han subjects was assessed. STATISTICAL TESTS: Pearson correlation assessed the correlation. Independent t-tests analyzed group differences. RESULTS: In HA Tibetans, CBF decreased with altitude in the bilateral anterior and posterior cingulate gyri, fusiform gyrus, cerebellar tonsil and cortices, and thalamus as well as left middle and inferior temporal gyri and right insula (P < 0.05); HA Tibetans (vs. lowland Tibetans) had lower CBF in the left hemisphere (precuneus, anterior cingulate gyrus, fusiform gyrus, and lingual gyrus) and right hemisphere (superior parietal lobule, precuneus, posterior cingulate gyrus, and cerebellar tonsil), while they had higher CBF in the left inferior parietal lobule, lentiform nucleus, and inferior frontal gyrus (P < 0.05). The overlapping regions, in which CBF in HA Tibetans correlated with altitude and decreased (vs. lowland Tibetans), were selected for region of interest analysis, and the results showed lower CBF in HA Tibetans than lowland Han subjects (P < 0.05). DATA CONCLUSION: HA adaptation in Tibetans is associated with a decrease of regional CBF. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2018. PMID- 29493839 TI - The influence of social determinants of health among young adults after they have left foster care in the US. AB - AIMS AND OBJECTIVES: To describe the influence of the social determinants of health on health care seeking among young adults after they left foster care. BACKGROUND: Extensive research suggests that stakeholders in foster care systems throughout the world struggle to consistently and effectively manage the health and well-being of youth. These struggles extend beyond time in foster care as indicated by poor health and social outcomes throughout the life course. Evidence that describes how young adults address health and related social needs after leaving foster care is missing. DESIGN: A phenomenological design, Phenomenology of Practice, was used to collect data. Content analysis was used to analyse the data, using constructs from the Healthy People 2020 SDOH Model to organise the data. METHODS: Thirteen young adults who left foster care in the southwestern US were recruited using convenience sampling. Data were collected via individual interviews. RESULTS: Young adults formerly in foster care reported using and lacking social support networks to navigate SDOH. The interrelatedness of SDOH on health outcomes after foster care is evident. CONCLUSIONS: Social support networks can help explain how young adults are both able and unable to navigate systems to address health issues. Evaluating social networks used to access care is an important aspect of assessment and intervention for these vulnerable young adults. RELEVANCE TO CLINICAL PRACTICE: Healthcare providers facilitate healthcare access for young adults who have been in foster care through evaluation of social determinants. Assessment and care planning based on social determinants for those who have been in foster care are critical to ensure the efficacy of interventions designed to address health outcomes. Social support systems are key factors for young adults formerly in foster care to access resources, substantiating the need for ongoing assessment and development of these support systems. PMID- 29493840 TI - What are they talking about? Content of the communication exchanges between nurses, patients and relatives in a department of medicine for older people-An ethnographic study. AB - AIMS AND OBJECTIVES: To explore and describe the content of the communication exchanges between nurses, patients and their relatives in a department of medicine for older people in western Sweden. BACKGROUND: Information, messages and knowledge are constantly being communicated between nurses, older patients and relatives in the healthcare sector. The quality of communication between them has a major influence on patient outcomes. A prerequisite for good care to be given and received is that there is mutual understanding between the parties involved. DESIGN: An ethnographic study was informed by a sociocultural perspective. METHOD: Data were collected through 40 participatory observations of meetings between nurses and older patients and/or relatives which covered 135 hr of nurse-patient-relative interaction, field notes, 40 field conversations with 24 nurses and 40 field conversations with patients (n = 40) and relatives (n = 26). Five semi-structured interviews were conducted with nurses. An ethnographic analysis was performed. RESULTS: The analysis identified three categories of content of the communication exchanges: medical content focusing on the patient's medical condition, personal content focusing on the patient's life story and explanatory content focusing on the patient's health and nursing needs. The content is influenced by the situation and context. CONCLUSIONS: Nurses would benefit from more awareness and understanding of the importance of the communication content and of the value of asking the didactic questions (how, when, what and why) to improve the patients' and relatives' understanding of the information exchanges and to increase patient safety. RELEVANCE TO CLINICAL PRACTICE: Nurses can use the communication content to create conditions enabling them to obtain a holistic view of the patient's life history and to develop an appropriate person-centred care plan. PMID- 29493841 TI - Picolinamide-Based Iridium Catalysts for Dehydrogenation of Formic Acid in Water: Effect of Amide N Substituent on Activity and Stability. AB - To develop highly efficient catalysts for dehydrogenation of formic acid in water, we investigated several Cp*Ir catalysts with various amide ligands. The catalyst with an N-phenylpicolinamide ligand exhibited a TOF of 118 000 h-1 at 60 degrees C. A constant rate (TOF>35 000 h-1 ) was maintained for six hours, and a TON of 1 000 000 was achieved at 50 degrees C. PMID- 29493842 TI - Prognostic significance of grade 3/4 neutropenia in Japanese prostate cancer patients treated with cabazitaxel. AB - The present study aimed to evaluate the efficacy of cabazitaxel in Japanese patients affected by metastatic castration-resistant prostate cancer (mCRPC) previously treated with a docetaxel-containing regimen. In this retrospective study, 41 patients with mCRPC treated with cabazitaxel at Keio University Hospital were retrospectively reviewed. Cabazitaxel at a dose of 20-25 mg/m2 was administered every 3 or 4 weeks. Clinicopathological factors and laboratory data were collected to assess the prognostic factors for overall survival (OS) and progression-free survival (PFS). An upfront dose-reduction was required in 52.5% of patients due to their reduced general condition or advanced age. Prophylactic G-CSF was prescribed to all the patients. Grade >=3 neutropenia and febrile neutropenia occurred in 21 patients (53.6%) and 3 patients (6.8%), respectively. Treatment was generally well tolerated, with a median of 5 cycles (range 1-17). Median PFS and OS from the start of cabazitaxel treatment were 4.4 and 15.0 months (95% CI 8.9-21.2), respectively. Waterfall plot analysis revealed that a prostate-specific antigen (PSA) decline >50% was noticed in n = 11 patients receiving cabazitaxel (26.8%). Univariate analysis revealed that poor performance status, PSA >=100 ng/mL prior to cabazitaxel treatment, visceral metastasis, absence of grade 3/4 neutropenia during cabazitaxel therapy and neutrophil lymphocyte ratio were significantly associated with shorter overall survival. Multivariate analysis revealed that poor performance status, visceral metastasis, and the absence of grade 3/4 neutropenia during cabazitaxel therapy were the independent prognostic indicators for OS. The practical implication of our results might be to tailor cabazitaxel dosing on the basis of its hematological effects. PMID- 29493843 TI - Renal resistance thresholds during hypothermic machine perfusion and transplantation outcomes - a retrospective cohort study. AB - Renal resistance (RR), of allografts undergoing hypothermic machine perfusion (HMP), is considered a measure of organ quality. We conducted a retrospective cohort study of adult deceased donor kidney transplant (KT) recipients whose grafts underwent HMP. Our aim was to evaluate whether RR is predictive of death censored graft failure (DCGF). Of 274 KT eligible for analysis, 59% were from expanded criteria donor. RR was modeled as a categorical variable, using a previously identified terminal threshold of 0.4, and 0.2 mmHg/ml/min (median in our cohort). Hazard ratios (HR) of DCGF were 3.23 [95% confidence interval (CI): 1.12-9.34, P = 0.03] and 2.67 [95% CI: 1.14-6.31, P = 0.02] in univariable models, and 2.67 [95% CI: 0.91-7.86, P = 0.07] and 2.42 [95% CI: 1.02-5.72, P = 0.04] in multivariable models, when RR threshold was 0.4 and 0.2, respectively. Increasing risk of DCGF was observed when RR over the course of HMP was modeled using mixed linear regression models: HR of 1.31 [95% CI: 1.07-1.59, P < 0.01] and 1.25 [95% CI: 1.00-1.55, P = 0.05], in univariable and multivariable models, respectively. This suggests that RR during HMP is a predictor of long-term KT outcomes. Prospective studies are needed to assess the survival benefit of patients receiving KT with higher RR in comparison with staying wait-listed. PMID- 29493844 TI - Use of ultrasound for evaluation of painful joint episodes perceived as haemarthrosis in adult patients with severe haemophilia. PMID- 29493845 TI - The role of skin biopsy in differentiating small-fiber neuropathy from ganglionopathy. AB - BACKGROUND AND PURPOSE: We aimed to test the clinical utility of the leg:thigh intraepidermal nerve-fiber (IENF) density ratio as a parameter to discriminate between length-dependent small-fiber neuropathy (SFN) and small-fiber sensory ganglionopathy (SFSG) in subjects with signs and symptoms of small-fiber pathology. METHODS: We retrospectively evaluated thigh and leg IENF density in 314 subjects with small-fiber pathology (173 with distal symmetrical length dependent SFN and 141 with non-length-dependent SFSG). A group of 288 healthy subjects was included as a control group. The leg:thigh IENF density ratio was calculated for all subjects. We used receiver operating characteristic curve analyses to assess the ability of this parameter to discriminate between length dependent SFN and SFSG, and the decision curve analysis to estimate its net clinical benefit. RESULTS: In patients with neuropathy, the mean IENF density was 14.8 +/- 6.8/mm at the thigh (14.0 +/- 6.9/mm in length-dependent SFN and 15.9 +/ 6.7/mm in patients with SFSG) and 7.5 +/- 4.5/mm at the distal leg (5.4 +/- 3.2/mm in patients with length-dependent SFN and 10.1 +/- 4.6/mm in patients with SFSG). The leg:thigh IENF density ratio was significantly (P < 0.01) lower in patients with length-dependent SFN (0.44 +/- 0.23) compared with patients with SFSG (0.68 +/- 0.28). The area under the curve of the receiver operating characteristic analysis to discriminate between patients with length-dependent SFN and SFSG was 0.79. The decision curve analysis demonstrated the clinical utility of this parameter. CONCLUSIONS: The leg:thigh IENF ratio represents a valuable tool in the differential diagnosis between SFSG and length-dependent SFN. PMID- 29493846 TI - Clinically important difference on the Erectile Dysfunction Inventory of Treatment Satisfaction questionnaire in patients with erectile dysfunction. AB - AIM: To determine what constitutes a clinically important difference (CID) on the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS), an 11-item validated questionnaire assessing treatment satisfaction used in clinical trials for patients with erectile dysfunction (ED). METHODS: Erectile Dysfunction Inventory of Treatment Satisfaction data were evaluated from a double-blind, fixed-dose trial of 279 men aged 18-65 years with ED who were treated with sildenafil 50 or 100 mg or placebo. The primary anchor measure was the erectile function (EF) domain of the International Index of Erectile Function (IIEF), which has a 4-point minimal CID. The CID on the EDITS index score was determined using a regression analysis comparing EDITS and IIEF EF scores at the end of the 8-week treatment. A similar analysis was performed for EDITS and the Erection Hardness Score (EHS) instrument, a single-item questionnaire measuring hardness, which was used as a secondary anchor measure. RESULTS: Erectile Dysfunction Inventory of Treatment Satisfaction and IIEF EF domain scores were highly correlated (Pearson correlation coefficient = 0.75). EDITS total scores across treatments at week 8 averaged (mean +/- standard deviation [SD]) 67.5 +/- 21.6 (range, 0-100; higher scores indicate greater treatment satisfaction); IIEF EF domain scores averaged 22.2 +/- 6.9 (range, 1-30; higher scores indicate higher erectile functioning). The calculated CID for EDITS scores was 9.5 (95% CI, 8.5 10.4; 0.44 SD units), corresponding to a medium effect size. EDITS and EHS instrument scores also correlated highly (Pearson correlation coefficient = 0.64). Placebo-adjusted EDITS mean scores were more than twice the CID, at 23 (95% CI, 17-28) and 28 (95% CI, 23-33) for the 50- and 100-mg doses, respectively. CONCLUSION: Approximately 10 points on the EDITS index score is considered a CID. Serving as a benchmark, this finding aids interpretation of the clinical relevance of a difference in mean EDITS index scores between treatments for patients with ED. PMID- 29493847 TI - Comparison of cause of death between anzdata and the australian national death index. AB - AIM: To understand the differences in how cause of death for patients receiving renal replacement therapy in Australia is recorded in The Australian and New Zealand Dialysis and Transplant Registry (ANZDATA) compared to the National Death Index (NDI). METHODS: Data linkage was performed between ANZDATA and NDI for all deaths in the period 1980-2013. Cause of death was classified according to ICD-10 chapter. Overall and chapter specific agreement were assessed using the Kappa statistic. Descriptive analysis was used to explore differences where there was disagreement on primary cause of death. RESULTS: The analysis cohort included 28,675 patients. Ninety five percent of ANZDATA reported deaths fell within +/- 3 days of the date recorded by NDI. Circulatory death was the most common cause of death in both databases (ANZDATA 48%, NDI 32%). Overall agreement at ICD chapter level of primary cause was poor (36%, kappa 0.22). Agreement was best for malignancy (kappa 0.71). When there was disagreement on primary cause of death these were most commonly coded as genitourinary (35%) and endocrine (25.0%) in NDI, and circulatory (39%) and withdrawal (24%) in ANZDATA. Sixty-nine percent of patients had a renal related cause documented as either primary or a contributing cause of death in the NDI. CONCLUSION: There is poor agreement in primary cause of death between ANZDATA and NDI which is in part explained by the absence of diabetes and renal failure as causes of death in ANZDATA and the absence of 'withdrawal' in NDI. These differences should be appreciated when interpreting epidemiological data on cause of death in the Australian end stage kidney disease population. PMID- 29493849 TI - Reduction of Parenteral Opioid Use in Community Emergency Departments Following Implementation of Treatment Guidelines. AB - OBJECTIVE: Opioid prescribing guidelines are commonly seen as part of the solution to America's opioid epidemic. However, the effectiveness of specific treatment guidelines on altering opioid prescribing in the emergency department (ED) is unclear. We examined provider ordering patterns before and after implementation of opioid use guidelines for ED patients overall and the specific subsets of ED patients with either chronic opioid use or fracture. METHODS: We conducted a pre-post interrupted time series analysis of adult (>=18 years old) ED encounters in 14 integrated community EDs before (2013) and after (2014) the implementation of opioid prescribing guidelines. We compared opioid use pre- and postintervention using segmented logistic regression for primary and secondary analyses. The primary outcome was parenteral opioid use in the ED, with additional subgroup analysis of chronic pain and fracture cohorts. We also examined ED oral opioid use and discharge prescribing. RESULTS: There were 508,337 pre- and 531,620 postintervention encounters. The intervention was associated with an initial reduction in the odds of parenteral opioids ordered (odds ratio [OR] = 0.89, 95% CI = 0.87-0.91) and a decrease in the monthly trend compared to the preintervention period (OR = 0.99, 95% CI = 0.99-0.99). The immediate reduction in parenteral opioid use was significantly larger in the cohort of patients with chronic pain (OR = 0.81, 95% CI = 0.72-0.91), whereas the fracture cohort showed no change (OR = 1.10, 95% CI = 0.97-1.25). CONCLUSION: The use of an opioid ordering guideline was associated with significant reduction in parenteral opioid use in the ED and as intended subgroup comparisons suggest that acute fractures were not affected and chronic pain visits were associated with larger decreases in opioid use. PMID- 29493848 TI - Long-term clinical and economic outcomes in previously untreated paediatric patients with severe haemophilia A: A nationwide real-world study with 700 person years. AB - AIM: For previously untreated patients (PUPs) with severe haemophilia A in Finland for the past 2 decades, the standard practice has been to start early primary prophylaxis. We evaluated the long-term clinical outcomes and costs of treatment with high-dose prophylaxis in PUPs from birth to adolescence, including immune tolerance induction (ITI). METHODS: From the medical records of all PUPs born between June 1994 and May 2013 in Finland, we retrospectively extracted data on clinical outcomes and healthcare use. Using linear mixed models, we analysed longitudinal clinical outcome data. To analyse skewed cost data, including zero costs, we applied hurdle regression. RESULTS: All 62 patients received early regular prophylaxis; totally, they have had treatment for nearly 700 patient years. The median age of starting home treatment was 1.1 years. The mean (SD) annual treatment costs (? per kg) were 4391? (3852). For ages 1-3, ITI comprised over half of the costs; in other groups, prophylactic FVIII treatment dominated. With these high costs, however, clinical outcomes were desirable; median (IQR) ABR was low at 0.19 (0.07-0.46) and so was AJBR at 0.06 (0-0.24). Thirteen (21%) patients developed a clinically significant inhibitor, 10 (16%) with a high titre. All ITIs were successful. The mean costs for ITI were 383 448? (259 085). The expected ITI payback period was 1.81 (95% CI 0.62-12.12) years. CONCLUSIONS: Early high-dose prophylaxis leads to excellent long-term clinical outcomes, and early childhood ITI therapy seems to turn cost-neutral generally already in 2 years. PMID- 29493850 TI - Droplet digital polymerase chain reaction assay and peptide nucleic acid-locked nucleic acid clamp method for RHOA mutation detection in angioimmunoblastic T cell lymphoma. AB - Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of nodal peripheral T-cell lymphoma (PTCL). Somatic RHOA mutations, most frequently found at the hotspot site c.50G > T, p.Gly17Val (G17V RHOA mutation) are a genetic hallmark of AITL. Detection of the G17V RHOA mutations assists prompt and appropriate diagnosis of AITL. However, an optimal detection method for the G17V RHOA mutation remains to be elucidated. We compared the sensitivity and concordance of next-generation sequencing (NGS), droplet digital PCR (ddPCR) and peptide nucleic acid-locked nucleic acid (PNA-LNA) clamp method for detecting the G17V RHOA mutation. G17V RHOA mutations were identified in 27 of 67 (40.3%) PTCL samples using NGS. ddPCR and PNA-LNA clamp method both detected G17V mutations in 4 samples in addition to those detected with NGS (31 of 67, 46.3%). Additionally, variant allele frequencies with ddPCR and those with NGS showed high concordance (P < .001). Three other RHOA mutations involving the p.Gly17 position (c.[49G > T;50G > T], p.Gly17Leu in PTCL198; c.[50G > T;51A > C], p.Gly17Val in PTCL216; and c.50G > A, p.Gly17Glu in PTCL223) were detected using NGS. These sequence changes could not appropriately be detected using the ddPCR assay and the PNA-LNA clamp method although both indicated that the samples might have mutations. In total, 34 out of 67 PTCL samples (50.7%) had RHOA mutations at the p.Gly17 position. In conclusion, our results suggested that a combination of ddPCR/PNA-LNA clamp methods and NGS are best method to assist the diagnosis of AITL by detecting RHOA mutations at the p.Gly17 position. PMID- 29493852 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 11/2018. PMID- 29493851 TI - A retrospective multicenter study of carbon-ion radiotherapy for major salivary gland carcinomas: Subanalysis of J-CROS 1402 HN. AB - A retrospective multicenter study was carried out to assess the clinical outcomes of carbon-ion radiotherapy for head and neck malignancies (Japan Carbon-Ion Radiation Oncology Study Group [J-CROS] study: 1402 HN). We evaluated the safety and efficacy of carbon-ion radiotherapy in patients with major salivary gland carcinoma. Sixty-nine patients treated with carbon-ion radiotherapy at four Japanese institutions were analyzed. Thirty-three patients (48%) had adenoid cystic carcinomas, 10 (14%) had mucoepidermoid carcinomas, and 26 (38%) had other disease types. Three patients (4%) had T1 disease, 8 (12%) had T2, 25 (36%) had T3, and 33 (48%) had T4. The median radiation dose was 64 Gy (relative biological effectiveness) in 16 fractions. The median gross tumor volume was 27 mL. The median follow-up period was 32.7 months. The 3-year local control rate and overall survival rate were 81% and 94%, respectively. Regarding acute toxicities, seven patients had grade 3 mucositis and seven had grade 3 dermatitis. Regarding late toxicities, one patient had grade 3 dysphagia and one had a grade 3 brain abscess. No grade 4 or worse late reactions were observed. In conclusion, definitive carbon-ion radiotherapy was effective with acceptable toxicity for major salivary gland carcinomas. PMID- 29493853 TI - Physiotherapist inter-rater reliability of the Haemophilia Early Arthropathy Detection with Ultrasound protocol. AB - INTRODUCTION: Prevention of arthropathy is the major goal of haemophilia treatment, and early detection of the first signs of joint damage is important so that prevention strategies can be initiated to limit physical disability and improve quality of life. AIM: The aim of this study was to determine the inter rater repeatability of the HEAD-US protocol when performed by haemophilia physiotherapists. METHODS: Sixty-three joints (21 elbows, 21 knees and 21 ankles) were examined in 21 patients (mean age; 29.14 +/- 10.09 years) according to the HEAD-US protocol by four of six physiotherapists blinded to clinical information. Inter-rater repeatability was evaluated by comparing the concordance of scores between the different clinicians using weighted Kappa (kappaw ) statistics and 95% confidence intervals. RESULTS: Substantial agreement was found when evaluating synovial hypertrophy (kappaw = 0.69), articular cartilage (kappaw = 0.60) and bone (kappaw = 0.74). Near perfect repeatability (kappaw > 0.80) was found when scoring synovitis profiles of the elbow joint and bone profiles of the knee joint. Repeatability was moderate for scoring synovitis and articular cartilage profiles of the ankle joint. A moderate correlation between HEAD-US and HJHS was found for the elbow and ankle joint and a strong correlation for the knee joint. Discordance between clinical and ultrasound examination was 19.30%. CONCLUSION: Overall, we found repeatability of the HEAD-US protocol was good when performed by physiotherapists, and our results support the emerging view that US imaging complements the physical examination when screening and monitoring joint health of people with haemophilia at the point of care. PMID- 29493854 TI - Epidemiology of atrial fibrillation. AB - BACKGROUND: The most common type of arrhythmia in the USA and in European countries is atrial fibrillation (AF). The prevalence of AF is increasing worldwide with advances in technology, better prediction methods and increased awareness among healthcare professionals and patients. METHODS: This article summarises the literature on the epidemiology of AF worldwide according to continents, age and ethnicity/race, and also includes the prevalence of AF in stroke patients. RESULTS: In Australia, Europe and the USA, the current estimated prevalence of AF is about between 1% and 4%, with lower prevalence evident in Asia (0.49%-1.9%). AF prevalence is highest among Whites. In Western Europe, Australia and North America 70% of people with AF are aged >65 years, whereas the average age of AF patients in other geographical regions is often lower. CONCLUSIONS: Although the prevalence of AF worldwide is increasing steadily, large variation can be seen between studies and countries. Further epidemiological studies should be undertaken globally, especially in Asian and African countries so that a better and more accurate picture of the incidence and prevalence of AF can be captured, to enable stroke prevention strategies to be appropriately implemented to prevent or reduce the risk of stroke, the most severe consequence of AF. PMID- 29493855 TI - Impact of Jahnigen/GEMSSTAR Scholarships on Careers of Recipients in Emergency Medicine and on Development of Geriatric Emergency Medicine. AB - BACKGROUND: The Jahnigen Career Development Awards program was launched in 2002 with private funding and transformed into the Grants for Early Medical/Surgical Specialists' Transition to Aging Research (GEMSSTAR) program in 2011 through support from the National Institute on Aging and medical specialty professional societies. The Jahnigen/GEMSSTAR program has provided grants to early career physician-scientists from 10 surgical and related medical specialties to initiate and sustain research careers in the geriatric aspect of their discipline. From 2002 to 2016, there were 20 Jahnigen/GEMSSTAR recipients in emergency medicine (EM). The goal of this investigation was to examine the impact of Jahnigen/GEMSSTAR awards on careers of EM recipients and on development of academic geriatric EM. METHODS: We conducted an online survey of the 20 EM recipients from 2002 to 2016 and analyzed their academic productivity, research impact, career trajectory, and contributions to geriatric EM since receiving the award. RESULTS: All 20 Jahnigen/GEMSSTAR scholars completed the survey. Scholars have published a median of 33 peer-reviewed articles (interquartile range [IQR] = 10-97) since the award, with median annual publication rates of 4.5 (IQR = 1.6 7.0). All scholars had h-indices of 6 or more, with a median of 18 (IQR = 9-28). Jahnigen/GEMSSTAR scholars have served as principal investigator (PI) or co-PI on 126 grants since their award, with 90% having served as PI on at least one additional grant and 30% having received National Institutes of Health Career Development Awards. All scholars reported believing that the Jahnigen/GEMSSTAR was very helpful or helpful for career progress. Most (85%) reported ongoing contributions to geriatric EM in research, education, or administration. CONCLUSIONS: After the Jahnigen/GEMSSTAR award, EM scholars have been highly academically productive and successful, and the award has been instrumental in their career development. Awardees have been critical to the development of geriatric EM. PMID- 29493856 TI - Analysis of genotyping for predicting liver injury marker, procollagen III in persons at risk of non-alcoholic fatty liver disease. AB - BACKGROUND & AIMS: Chronic liver disease presents a major global public health challenge. Stratification of asymptomatic, at-risk patients in primary care using non-invasive methods has the potential to address this by identifying those likely to progress. We, therefore, evaluated variant alleles at loci associated with non-alcoholic fatty liver disease as genetic determinants of substantial liver injury in patients with disease risk factors. METHODS: Levels of serum procollagen III (PIIINP), an established fibrosis and steatohepatitis marker, were determined in 467 people who had type 2 diabetes and/or BMI > 27.3 (identified from registration with general practitioners) in this observational cross-sectional study. Patients were genotyped for characterised risk alleles in PNPLA3 (rs738409), GCKR (rs1260326) and TM6SF2 (rs58542926) and associations with PIIINP assessed. RESULTS: The risk alleles in PNPLA3, GCKR or TM6SF2 were not found to be individually associated with the presence of a disease risk factor and were not significantly more common in patients with raised serum PIIINP. The prevalence of possession of both PNPLA3 and GCKR variant alleles combined was significantly higher in at-risk patients with clinically significant liver disease indicated by serum PIIINP above 11 ng/mL (P = .014). CONCLUSIONS: Genotyping, therefore, has limited value for predicting severe liver disease in at-risk individuals identified in a community setting. PMID- 29493857 TI - Association between dehydration on admission and postoperative complications in older persons undergoing orthopaedic surgery. AB - AIM AND OBJECTIVES: To examine the prevalence of dehydration upon hospital admission and its association with postoperative complications in older persons undergoing orthopaedic surgery. BACKGROUND: Ageing-related physiological and pathological changes, as well as suboptimal care quality, can render older persons vulnerable to dehydration. However, few empirical studies have been conducted to examine the association between dehydration and care outcomes in this population. DESIGN: Retrospective documentary review. METHODS: The medical records of patients who were aged 65 years or above and admitted for orthopaedic surgery at an acute hospital in Hong Kong over the period of January 2013 to June 2013 were reviewed. The sociodemographic characteristics, health conditions, laboratory results during index hospitalisation, postoperative care and 1-month survival were analysed. Dehydration status was defined on the basis of the ratio of blood urea nitrogen to creatinine upon admission. RESULTS: Of 310 reviewed records, 216 records were included in the analysis. A total of 21.8% of the patients in the included cases were defined as dehydrated and 35.2% were defined as at risk of dehydration. There were significantly more patients in the dehydrated group were female, having diuretic medication, swallowing difficulty, oedema, tube feeding, diaper or urinary catheter use, with postoperative complications in respiratory, gastrointestinal and haematological systems, and died within 30 days than those in the euhydrated group. CONCLUSIONS: The findings of this study reveal that dehydration is highly prevalent among older persons on admission. Female gender and swallowing difficulty were found to be significantly associated with dehydration, although causal inference could not be delineated through this retrospective study. RELEVANCE TO CLINICAL PRACTICE: Given its significant influence on care outcomes and postoperative recovery, hydration care that promotes early recognition and timely management of dehydration is an integral part of fundamental care for older persons. PMID- 29493858 TI - Radical Anions from Urea-type Carbonyls: Radical Cyclizations and Cyclization Cascades. AB - Radical anions generated from urea carbonyls by reductive electron transfer are exploited in carbon-carbon bond formation. New radical cyclizations of urea radical anions deliver complex nitrogen heterocycles and, depending upon the proton source used in the reactions, a chemoselective switch between reaction pathways can deliver two heterobicyclic scaffolds. A computational study has been used to investigate the selectivity of the urea radical processes. Furthermore, radical cyclization cascades involving urea radical anions deliver unusual spirocyclic aminal architectures. PMID- 29493859 TI - Effect of alirocumab on lipids and lipoproteins in individuals with metabolic syndrome without diabetes: Pooled data from 10 phase 3 trials. AB - AIMS: This analysis assessed the efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, in patients with or without metabolic syndrome (MetS) using pooled data from 10 phase 3 ODYSSEY trials. MATERIALS AND METHODS: Data from 4983 randomized patients (1940 with MetS; 1642 with diabetes excluded) were assessed in subgroups by MetS status. Efficacy data were analysed in 4 pools per study design: 2 placebo-controlled pools (1 using alirocumab 150 mg every 2 weeks [Q2W], 1 using 75/150 mg Q2W) with background statin, and 2 ezetimibe-controlled pools (both alirocumab 75/150 mg Q2W), 1 with and 1 without background statin. Alirocumab 75/150 mg indicates possible dose increase from 75 to 150 mg at Week 12 based on Week 8 LDL-C. RESULTS: LDL-C percentage reduction from baseline at Week 24 with alirocumab was 63.9% (MetS) and 56.8% (non-MetS) in the pool of alirocumab 150 mg Q2W, and 42.2% to 52.2% (MetS) and 45.0% to 52.6% (non-MetS) in 3 pools using 75/150 mg Q2W. Levels of other lipid and lipoprotein parameters were also improved with alirocumab treatment, including apolipoprotein B, non-high-density lipoprotein cholesterol (non-HDL-C), lipoprotein(a) and HDL-C. Overall, the percentage change at Week 24 in LDL-C and other lipids and lipoproteins did not vary by MetS status. Adverse event rates were generally similar between treatment groups, regardless of MetS status; injection-site reactions occurred more frequently in alirocumab vs control groups. CONCLUSIONS: Across study pools, alirocumab-associated reductions in LDL-C, apolipoprotein B, and non-HDL-C were significant vs control, and did not vary by MetS status. PMID- 29493860 TI - 2-Hydroxybenzophenone as a Chemical Auxiliary for the Activation of Ketiminoesters for Highly Enantioselective Addition to Nitroalkenes under Bifunctional Catalysis. AB - An organocatalytic system is presented for the Michael addition of monoactivated glycine ketimine ylides with a bifunctional catalyst. The ketimine bears an ortho hydroxy group, which increases the acidity of the methylene hydrogen atoms and enhances the reactivity, thus allowing the synthesis of a large variety of alpha,gamma-diamino acid derivatives with excellent stereoselectivity. PMID- 29493861 TI - Nuclear parameters and chromatin remodeling in epithelial cells and lymphocytes from the palpebral conjunctiva of dogs with keratoconjunctivitis sicca. AB - OBJECTIVE: To study parameters related to nuclear morphology and chromatin remodeling in epithelial cells and lymphocytes from the inferior palpebral conjunctiva of dogs with and without keratoconjunctivitis sicca (KCS). ANIMALS STUDIED: Thirty-two dogs (64 eyes) were included in the study. Based on the tear production measured by Schirmer tear test 1, the dogs were distributed into control and KCS groups. PROCEDURES: Epithelial cells and lymphocytes were collected by conjunctival brush cytology, fixed on glass slides, and subjected to the Feulgen reaction, a topochemical method specific for DNA/chromatin. Feulgen stained cells were studied by microscopy and video image analysis to establish nuclear size (area and perimeter) and shape (relative nuclear roundness factor = RNRF), DNA content (ploidy), and compaction and texture of chromatin. RESULTS: Conjunctival samples in the KCS group showed infiltration of inflammatory and immune cells. Micronuclei, snake-like chromatin, aberrant chromosomes, and goblet cells were not detected. Compared with the controls, cells on the conjunctival surface of dogs with KCS showed altered nuclei. Conjunctival epithelial cells were more affected by KCS (changes in nuclear size, shape, DNA content, and chromatin compaction) than lymphocytes (changes in chromatin compaction, only). Significant chromatin decompaction was observed in both conjunctival epithelial cells and lymphocytes. CONCLUSIONS: Our results show that KCS promotes chromatin remodeling in epithelial cells and lymphocytes on the conjunctival surface of dogs. The changes described in this study are different from those reported for conjunctival cell nuclei of human KCS patients. PMID- 29493863 TI - A Cooperative Pillar-Template Strategy as a Generalized Synthetic Method for Flexible Homochiral Porous Frameworks. AB - A new strategy for creating homochiral metal-organic frameworks through a fusion of pillaring and templating concepts is demonstrated. This strategy makes use of the synergy among various chemical interactions during self-assembly processes, and leads to the synthesis of a series of homochiral frameworks. In the presence of only pillar-to-pillar pi-pi interactions, inter-pillar forces compete against metal-pillar interactions, resulting in mismatch between pillar-to-pillar and metal-to-metal separations and consequently 2D materials without pillaring. To create 3D materials, a method was developed to use various aromatic molecules, polycyclic aromatic hydrocarbons in particular, as templates to modulate the inter-pillar interaction and separation, leading to the formation of 3D homochiral frameworks. The use of aromatic molecules, especially hydrocarbons, as structure-directing agents, represents a new approach in the development of crystalline porous materials. Aromatic templates can be post-synthetically extracted to yield flexible porous homochiral materials with gate-opening gas sorption behaviors for both N2 and CO2 at partial pressures tunable by temperature. PMID- 29493862 TI - Multiple ocular developmental defects in four closely related alpacas. AB - OBJECTIVE: To describe the clinical, gross pathologic, and histopathologic findings for a visually impaired 5.8-year-old female alpaca with multiple ocular abnormalities, as well as the clinical findings for three closely related alpacas. ANIMALS STUDIED: Four alpacas. PROCEDURES: Ophthalmic examination was performed on a 16-month-old female alpaca following observation of visual impairment while hospitalized for an unrelated illness. Following acute systemic decline and death 4.5 years later, the alpaca's brain, optic nerves, and eyes were examined grossly and histologically. Ophthalmic examination of three closely related alpacas was subsequently performed. RESULTS: The 16-month-old female alpaca (Alpaca 1) had ophthalmoscopic findings suggestive of a coloboma or hypoplasia of the retinal pigment epithelium (RPE) and choroid, and suspected optic nerve hypoplasia OU. Histopathology performed 4.5 years later revealed moderate to severe choroidal, RPE, and retinal hypoplasia with multifocal retinal detachments OU. However, the optic nerves were normal in size and histologic appearance when compared to an age-matched control. Clinical evaluation of the 2 year-old son of Alpaca 1 revealed iris colobomata OU and choroidal dysplasia/hypoplasia OD in addition to nonpathologic variations in melanin density including heterochromia iridis and a subalbinotic fundus OU. Clinical evaluation of the 13-year-old mother of Alpaca 1 revealed heterochromia iridis, cataracts, and a subalbinotic fundus OU. A 2-year-old half-brother of Alpaca 1 had an RPE and choroidal coloboma OS. CONCLUSION: The developmental ocular abnormalities diagnosed in these closely related alpacas are likely hereditary. PMID- 29493864 TI - Effectiveness of the Medtep Hemophilia online platform for adherence to prophylactic treatment in haemophilia patients: Results from a 1-year observational study. AB - INTRODUCTION: Medtep Hemophilia platform is an online tool that allows patients with congenital coagulopathies to keep track of their daily condition-related events with the objective of ensuring successful adherence to therapy. AIM: To assess the effectiveness of Medtep Hemophilia in improving adherence to prophylactic treatment in haemophilia A and B patients in a 1-year prospective observational study, as well as its impact on the patient's disease status. METHODS: Patients (>13 years old) received support material to familiarize themselves with Medtep Hemophilia. Adherence to treatment, quality of life (QoL) and illness perception were assessed. Values at baseline, 1, 6 and 12 months, and changes from baseline value were analysed. The Hemophilia Joint Health Score (HJHS) test was applied at baseline and study completion. RESULTS: Forty-six patients were enrolled (43 evaluable). After 1 year, 56.4% patients showed continued use of the platform (100% compliance) whereas 25.6% were inactive. Treatment adherence increased both significantly (P < .001) and progressively during the study. Similarly, improved QoL and illness perception were observed with respect to baseline in most of the questionnaire components (P < .05 after 12 months). A patient's age had no influence on the results, whereas compliant patients (>80% of platform use) tended to score better than noncompliant. The HJHS test values remained similar during the study. CONCLUSION: The Medtep Hemophilia online platform helped the studied patients with haemophilia to improve their adherence to prophylactic treatment, while increasing their QoL and illness perception, as well as joint arthropathies stabilization. PMID- 29493865 TI - Intramolecular (4+3) Cycloadditions of Pyrroles and Application to the Synthesis of the Core of Class II Galbulimima Alkaloids. AB - The first intramolecular (4+3) cycloaddition of pyrroles with epoxy enolsilanes as the electrophiles was developed and used to generate optically-enriched cycloadducts containing the nortropane substructure in good yields. Using this pyrrole cycloaddition as the key step, we achieved the asymmetric synthesis of a nortropane compound bearing the BCDEF ring structure common to the Class II galbulimima alkaloids. PMID- 29493866 TI - Evaluation of transconjunctival thermal electrocautery for treatment of canine distichiasis: 88 eyelids (2013-2016). AB - OBJECTIVE: To describe a successful, simple treatment for canine distichiasis. ANIMALS STUDIED: Client-owned dogs presenting to Veterinary Specialty and Emergency Center, Levittown, Pennsylvania. PROCEDURE: Retrospective analysis of medical records for canine patients that underwent transconjunctival thermal electrocautery treatment (TCEC) for distichiasis alone or with concurrent eyelid surgery between 2013 and 2016. Fifty eyes of 26 dogs (n = 88 eyelids) were included in the study. Sixty-five eyelids (74%) were treated for distichia only, while 23 eyelids (26%) underwent concurrent eyelid surgery. Successful treatment was defined as resolution of clinical signs attributable to distichiasis. Forty eight of 50 eyes (96%) were successfully treated with a single TCEC treatment (mean follow-up 187 +/- 222 days). Sixty-one of 88 eyelids (69%) had no distichia at any follow-up time. Twenty-two eyelids (25%) had recurrence at or near a previously treated site (mean 150 +/- 152 days). Of the eyes with recurrent distichia, all but 2 (91%) remained asymptomatic, requiring no further treatment. One dog with extensive TCEC treatment had significant recurrence on all eyelids requiring retreatment that resulted in focal entropion of 1 eyelid. Transient eyelid margin pigment loss and mild-to-moderate eyelid swelling were noted in all treated eyelids postoperatively. Suspected treatment site infection occurred 2 days postoperatively in 2/50 eyes (4%) of 1 patient. Two of 10 eyes (20%) with extensive eyelid treatment developed qualitative tear film deficiency OU (554 days postoperatively) and responded to topical tear stimulant therapy. CONCLUSION: TCEC is a successful, simple treatment for canine distichiasis. PMID- 29493867 TI - Heterobimetallic Catalysis: Platinum-Gold-Catalyzed Tandem Cyclization/C-X Coupling Reaction of (Hetero)Arylallenes with Nucleophiles. AB - Heterobimetallic catalysis offers new opportunities for reactivity and selectivity but still presents challenges, and only a few metal combinations have been explored so far. Reported here is a Pt-Au heterobimetallic catalyst system for the synthesis of a family of multi-heteroaromatic structures through tandem cyclization/C-X coupling reaction. Au-catalyzed 6-endo-cyclization takes place as the first fast step. Pt-Au clusters are proposed to be responsible for the increased reactivity in the second step, that is, the intermolecular nucleophilic addition which occurs through an outer-sphere mechanism by hybrid homogeneous heterogeneous catalysis. PMID- 29493868 TI - Glucose-lowering effects and mechanisms of the bile acid-sequestering resin sevelamer. AB - AIMS: Sevelamer, a non-absorbable amine-based resin used for treatment of hyperphosphataemia, has been demonstrated to have a marked bile acid-binding potential alongside beneficial effects on lipid and glucose metabolism. The aim of this study was to investigate the glucose-lowering effect and mechanism(s) of sevelamer in patients with type 2 diabetes. MATERIALS AND METHODS: In this double blinded randomized controlled trial, we randomized 30 patients with type 2 diabetes to sevelamer (n = 20) or placebo (n = 10). Participants were subjected to standardized 4-hour liquid meal tests at baseline and after 7 days of treatment. The main outcome measure was plasma glucagon-like peptide-1 excursions as measured by area under the curve. In addition, blood was sampled for measurements of glucose, lipids, glucose-dependent insulinotropic polypeptide, C peptide, glucagon, fibroblast growth factor-19, cholecystokinin and bile acids. Assessments of gastric emptying, resting energy expenditure and gut microbiota composition were performed. RESULTS: Sevelamer elicited a significant placebo corrected reduction in plasma glucose with concomitant reduced fibroblast growth factor-19 concentrations, increased de novo synthesis of bile acids, a shift towards a more hydrophilic bile acid pool and increased lipogenesis. No glucagon like peptide-1-mediated effects on insulin, glucagon or gastric emptying were evident, which points to a limited contribution of this incretin hormone to the glucose-lowering effect of sevelamer. Furthermore, no sevelamer-mediated effects on gut microbiota composition or resting energy expenditure were observed. CONCLUSIONS: Sevelamer reduced plasma glucose concentrations in patients with type 2 diabetes by mechanisms that seemed to involve decreased intestinal and hepatic bile acid-mediated farnesoid X receptor activation. PMID- 29493869 TI - Host-mediated RNA interference targeting a cuticular protein gene impaired fecundity in the green peach aphid Myzus persicae. AB - BACKGROUND: The green peach aphid (Myzus persicae) is a devastating sap-sucking insect pest that damages many host plants worldwide and causes billions of dollars of crop losses. Induction of RNA interference (RNAi) through oral feeding of small interfering RNA (siRNA) has been demonstrated in aphids. Therefore, host mediated delivery of double-stranded RNA (dsRNA) specific to vital structural genes of aphids has been envisaged as a tool for the development of resistance against this aphid species. RESULTS: Cuticular protein (CP) senses seasonal photoperiodism and drives a shift from clonal to sexual generation in aphids. Thus, attenuation of CP gene expression is likely to result in a different reproductive orientation in aphids and thereby affect their fecundity. A gene encoding CP in M. persicae has been targeted for RNAi-mediated knockdown. Transgenic Arabidopsis expressing dsRNA homologous to the MyCP gene was developed. The dsRNA-transgenics produced gene-specific siRNAs fed by aphids infesting the transgenics. A reverse transcription-quantitative polymerase chain reaction (RT-qPCR) study revealed an attenuated level of transcripts of the CP gene in aphid nymphs reared on the transgenic plants. Decreased expression of the CP gene resulted in a noticeable decline in aphid fecundity on the transgenic Arabidopsis plants. CONCLUSION: Increasing genetic resistance is the only sustainable way of minimizing the use of toxic agrochemicals to protect plants. Host-mediated RNAi of important insect genes has been proposed as a potential avenue for developing crop resistance against insect pests. This study demonstrated the potential of MyCP dsRNA in developing RNAi-based resistance to M. persicae. RNAi-mediated resistance is expected to be more durable compared with other transgenic strategies. (c) 2018 Society of Chemical Industry. PMID- 29493870 TI - Pesticide durability and the evolution of resistance: A novel application of survival analysis. AB - BACKGROUND: Arthropod pests are widely perceived to evolve resistance to insecticides at different rates. Although widespread "successful" species are assumed to evolve quickly and minor pests slowly, few studies have utilized published data on resistance events to test for differences among species. Using 532 records from the Arthropod Pesticide Resistance Database covering 20 species, we applied a survival analysis to model the number of generations from insecticide introduction to the first report of arthropod resistance, providing one of the most comprehensive analyses of this question to date. Our approach tested: 1) whether successful pests evolve resistance faster than close relatives, 2) whether species differ significantly in the time to demonstrate resistance, and 3) whether different insecticide classes differ in durability (length of time an insecticide is used before resistance arises). RESULTS: We found that species differed significantly in the amount of time it took for resistance to be reported. Overall, the median duration between the introduction of an insecticide and the first report of resistance was 66 generations (95% c.i. 60-78 generations), and highly-resistant arthropods did not evolve resistance faster than their relatives. Insecticide durability did not differ by the mode of action or year of introduction. CONCLUSION: Arthropod species significantly varied in how rapidly they evolve resistance to new insecticides, regardless of their chemistry. Visualization of the history of insecticide resistance provides information to be used for understanding how pesticide resistance evolved and how it can best be managed. (c) 2018 Society of Chemical Industry. PMID- 29493871 TI - Montelukast reverses airway remodeling in actively sensitized young mice. AB - : Asthma is characterized by airway hyperresponsiveness (AHR) and inflammation leading to airway remodeling (AR). In children, AR may occur very early prior to the age of 6 years. Treatments to prevent or reverse AR are unknown. AIM: We sought to determine (i) whether short allergenic sensitization at a young age in a mouse model may induce enhanced AR and inflammation compared to adults; (ii) the effect of Montelukast on such AR. METHODS: Immature and adult Balb/c mice were sensitized and challenged with ovalbumin. AHR and AR were measured using cultured precision-cut lung slices and inflammation by bronchoalveolar lavage. Experiments were repeated after administration of Montelukast. RESULTS: OVA challenged mice developed AHR to methacholine regardless of age of first exposure to OVA. Young mice developed greater thickened basement membrane, increased smooth muscle mass, and increased area of bronchovascular fibrosis compared with adult mice. Cellular infiltrates in BAL differed depending upon animal age at first exposure with higher eosinophilia measured in younger animals. Montelukast decreased ASM mass, BAL cellularity. CONCLUSION: We provide thus evidence for a greater degree of AR after allergenic sensitization and challenge in younger mice versus adults. This study provides proof of concept that airway remodeling can be prevented and reversed in this case by anti-asthmatic drug Montelukast in this model. PMID- 29493872 TI - Designing Nanoparticles and Nanoalloys with Controlled Surface and Reactivity. AB - Designing well-defined nanoparticles and nanoalloys is a tremendous way to achieve in-depth understanding of their intrinsic properties. In particular, structure and composition of the core and the surface of nanoalloys can be investigated by a combination of state-of-the-art in situ microscopy and spectroscopy. These nanoalloys represent a playground to establish structure properties relationships within the nano-matter. They provide a much needed understanding of the distribution of each element within the nanoparticles, depending on the environment (gaseous atmosphere, temperature, etc.). This distribution may evolve over time. Lighter elements, such as phosphorus, are critical to the reactivity of the nanoparticle's surface in reactions such as CO or CO2 hydrogenation. Here, the rational design of nanoalloys will be discussed (reactants choice, composition control), in relation with their surface state. Consequences on heterogeneous and homogeneous catalytic reactions, as well as for energy storage and conversion, will be illustrated through examples. PMID- 29493873 TI - Rapid Detection of Copper in Biological Systems Using Click Chemistry. AB - A fast (1 min), straightforward but efficient, click chemistry-based system that enables the rapid detection of free copper (Cu) ions in either biological fluids or living cells without tedious pretreatment is provided. Cu can quickly induce the conjugation between graphene oxide (GO) and a fluorescent dye via click reaction. On the basis of the high specificity of bioorthogonal reaction and the effective quenching ability of GO, the assay studied in this paper can respond to Cu ions in less than 1 min with excellent selectivity and sensitivity, which is the fastest sensor for Cu as far as it is known. In addition, the application of this system is verified by performing assays in living cells and untreated urine samples from patients suffering from Wilson's Disease. Such a Cu detection system shows great promises in both fundamental research and routine clinical diagnostics. PMID- 29493874 TI - Dynamic changes in plasma Epstein-Barr virus DNA load during treatment have prognostic value in nasopharyngeal carcinoma: a retrospective study. AB - Circulating plasma Epstein-Barr virus DNA (EBV DNA) is related to tumor recurrence and metastasis and has potential as a dynamic, sensitive, and specific marker in nasopharyngeal carcinoma (NPC). We investigated the clinical significance of assessing plasma EBV DNA load at various time points during treatment. Patients with NPC (n = 949) for whom plasma EBV DNA load was measured by real-time quantitative polymerase chain reaction (RT-qPCR) before treatment (pre-EBV) and at midtreatment (mid-EBV), end of treatment (end-EBV), and 3 months after completing treatment (3 m-EBV) were retrospectively assessed. Receiver operating characteristic (ROC) curve analysis was used to identify the optimal EBV DNA cutoff point for each time point. Overall survival (OS), distant metastasis-free survival (DMFS), and progression-free survival (PFS) were compared using Kaplan-Meier estimates. High pre-EBV, high mid-EBV, high end-EBV, and high 3 m-EBV were all associated with significantly poorer OS, DMFS, and PFS in the entire cohort. Detectable end-EBV and 3 m-EBV was associated with significantly poorer OS, DMFS, and PFS. Among patients with detectable end-EBV, adjuvant therapy significantly improved OS (HR 2.419; 95% CI 1.297-4.51, P = 0.03) and DMFS (HR 2.45; 95% CI 1.243-4.828, P = 0.04), but not PFS (P = 0.17). EBV DNA represents a dynamic biomarker for monitoring treatment and predicting survival in NPC. Assessing plasma EBV DNA before, during, and after chemoradiotherapy could be clinically valuable and enable selection of patients most likely to benefit from additional therapy and improve assessment of treatment response and disease surveillance. Further multicenter prospective investigations are warranted. PMID- 29493875 TI - Efficiency of physiotherapy with Caycedian Sophrology on children with asthma: A randomized controlled trial. AB - BACKGROUND: Asthma is the most common chronic disease in pediatrics. Along with the usual drug therapy using corticosteroids and bronchodilators, some interest has been shown for adjuvant therapies, such as sophrology. However, the level of evidence for non-pharmaceutical therapies in asthma remains low, especially in children. This study aimed to assess whether in children with asthma, peak expiratory flow (PEF) improved more after a sophrology session alongside standard treatment than after standard treatment alone. METHODS: We carried out a prospective randomized controlled clinical trial among 74 children aged 6-17 years old, hospitalized for an asthma attack. Group 1: conventional treatment (oxygen, corticosteroids, bronchodilators, physiotherapy) added to one session of sophrology. Group 2: conventional treatment alone. The primary outcome was the PEF variation between the initial and final evaluations (PEF2 -PEF1 ). RESULTS: Demographic and clinical characteristics were similar in both groups at baseline. Measures before and after the sophrology session showed that the PEF increased by mean 30 L/min in the sophrology group versus 20 L/min in the control group (P = 0.02). Oxygen saturation increased by 1% versus 0% (P = 0.02) and the dyspnea score with visual analogue scale improved by two points point (P = 0.01). No differences were observed between the two groups in terms of duration of hospitalization, use and doses of conventional medical treatment (oxygen, corticosteroids, and bronchodilators), and quality of life scores. CONCLUSIONS: Sophrology appears as a promising adjuvant therapy to current guideline-based treatment for asthma in children. PMID- 29493877 TI - Combined Dual-Kidney Liver Transplantation in the United States: A Review of United Network for Organ Sharing/Organ Procurement and Transplantation Network Data Between 2002 and 2012. AB - In kidney-alone recipients, dual-kidney transplantation using "higher-risk" donor organs has shown outcomes comparable to those of single-kidney transplantation using extended criteria donor (ECD) organs. To investigate the feasibility of a similar approach with combined kidney-liver transplantation, we identified 22 dual-kidney liver transplantations (DKLTs) and 3044 single-kidney liver transplantations (SKLTs) performed in the United States between 2002 and 2012 using United Network for Organ Sharing/Organ Procurement and Transplantation Network registry data. We compared donor/recipient characteristics as well as graft/recipient survival between DKLT recipients and SKLT recipients of "higher risk" kidneys (ECD and high kidney donor profile index [KDPI; >85%] donors). Despite having overall similar donor and recipient characteristics compared with both "higher-risk" donor groups, recipient survival in the DKLT group at 36 months was markedly inferior at 40.9% (compared with 67.5% for ECD SKLT recipients and 64.5% for high-KDPI SKLT recipients); nondeath-censored graft survival did not differ. Death was the most common cause of graft loss in all groups. Contrary to dual-kidney transplantation data in kidney-alone recipients, DKLT recipients in our study had inferior survival when compared with SKLT recipients of "higher-risk" donor kidneys. These findings would suggest that dual kidney-liver transplantation has an uncertain role as a strategy to expand the existing kidney donor pool in combined transplantation. PMID- 29493876 TI - Movement behaviour in adults with haemophilia compared to healthy adults. AB - BACKGROUND: Limited research has been published regarding movement behaviour of adult persons with haemophilia (PWH). It is hypothesized that avoidance of activities and more sedentary behaviour cause poorer physical functioning. AIM: To determine differences in movement behaviour between PWH and healthy adults. METHODS: Movement behaviour was measured with an accelerometer distinguishing between; lying/non-wear, sitting, standing, walking, running and cycling. Time spent on activities was compared between PWH and healthy adults, using absolute time spent on activities and activities as percentage of wear time. RESULTS: One hundred and five PWH (32 mild/moderate with a mean age of 42.8 +/- 15.1, severe 42.1 +/- 13.6) and 98 healthy adults (mean age 41.9 +/- 15.5) showed that adults with severe haemophilia sit and stand more than healthy adults (4.5 [CI 0.6-8.4] and 4.2 [CI 1.8-6.6] h/wk, respectively) and walk and run less (3.4 [CI 1.4-5.3] hours and 33.6 [CI 19.0-41.7] min/wk, respectively). Patients with mild/moderate haemophilia stand more than healthy adults (3.3 [CI 0.1-6.4] h/wk). Differences in sitting between severe haemophilia and healthy adults and differences in standing between mild/moderate haemophilia and healthy adults disappeared when using activities as percentage of wear time. CONCLUSION: Movement behaviour of adults with severe haemophilia differs from healthy adults, mainly due to less walking and less running. No differences were found in other activities and postures or the distribution of movement behaviour over the day. No significant differences were found between adults with mild/moderate haemophilia and healthy adults. PMID- 29493878 TI - Developing a piggyBac Transposon System and Compatible Selection Markers for Insertional Mutagenesis and Genome Engineering in Yarrowia lipolytica. AB - Yarrowia lipolytica is a non-conventional yeast of interest to the biotechnology industry. However, the physiology, metabolism, and genetic regulation of Y. lipolytica diverge significantly from more well-studied and characterized yeasts such as Saccharomyces cerevisiae. To develop additional genetic tools for this industrially relevant host, the piggyBac transposon system to enable efficient generation of genome-wide insertional mutagenesis libraries and introduction of scarless, footprint-free genomic modifications in Y. lipolytica. Specifically, we demonstrate piggyBac transposition in Y. lipolytica, and then use the approach to screen transposon insertion libraries for rapid isolation of mutations that confer altered canavanine resistance, pigment formation, and neutral lipid accumulation. We also develop a variety of piggyBac compatible selection markers for footprint-free genome engineering, including a novel dominant marker cassette (Escherichia coli guaB) for effective Y. lipolytica selection using mycophenolic acid. We utilize these marker cassettes to construct a piggyBac vector set that allows for auxotrophic selection (uracil or tryptophan biosynthesis) or dominant selection (hygromycin, nourseothricin, chlorimuron ethyl, or mycophenolic acid resistance) and subsequent marker excision. These new genetic tools and techniques will help to facilitate and accelerate the engineering of Y. lipolytica strains for efficient and sustainable production of a wide variety of small molecules and proteins. PMID- 29493879 TI - Immobilization of Nanoparticles on Fibrous Clay Surfaces: Towards Promising Nanoplatforms for Advanced Functional Applications. AB - This account discusses on diverse general approaches employed for the preparation of heterostructured materials based on the immobilization of metal oxides and other nanoparticles on sepiolite and palygorskite fibrous clay minerals, showing the many opportunities of application offered by the resulting materials. Various examples from our own experience have been selected to show how sepiolite acts as a convenient nanoplatform for immobilization of diverse type of nanoparticles, such as TiO2 , Fe3 O4 , Prussian blue, zeolites, layered double hydroxides, carbon nanotubes and graphenes, etc., to produce functional materials for applications in catalysis, environmental remediation, sensing devices, energy production, and others. PMID- 29493880 TI - Efficacy and safety of a second-generation biodegradable polymer sirolimus eluting stent: One-year results of the CREDIT 2 trial. AB - AIMS: We performed a multicenter, randomized controlled trial to determine the noninferiority of a novel biodegradable polymer drug-eluting stent (BP-DES), the EXCEL 2 stent, to the first-generation BP-DES, the EXCEL stent. METHODS AND RESULTS: Patients (n = 419) scheduled to undergo percutaneous coronary intervention (PCI) were randomized to receive either the EXCEL 2 stent (n = 208) or the EXCEL stent (n = 211) from 15 Chinese centers. At 9 months, primary endpoint in-stent late loss (LL) difference was -0.03 mm (95% confidence interval: -0.09 mm to 0.04 mm) between the EXCEL 2 group (0.14 +/- 0.26 mm) and the EXCEL group (0.16 +/- 0.36 mm), demonstrating the noninferiority of EXCEL 2 to EXCEL in terms of in-stent LL (P for noninferiority < .0001). Besides, target lesion failure (TLF) was statistically lower in EXCEL 2 group compared with EXCEL through 1 year (HR [95%CI] = 0.45 [0.20,0.98], Plog-rank = .04). Definite/probable ST was observed in 0.0% vs 1.9% (P = .12) of EXCEL 2 vs EXCEL treated subjects. CONCLUSIONS: The second-generation BP-DES (EXCEL 2) was noninferior to the first-generation BP-DES (EXCEL) for the primary endpoint of in stent LL at 9 months. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02057978. PMID- 29493882 TI - The use of pharmacogenomics, epigenomics, and transcriptomics to improve childhood asthma management: Where do we stand? AB - Asthma is a complex multifactorial disease and it is the most common chronic disease in children. There is a high variability in response to asthma treatment, even in patients with good adherence to maintenance treatment, and a correct inhalation technique. Distinct underlying disease mechanisms in childhood asthma might be the reason of this heterogeneity. A deeper knowledge of the underlying molecular mechanisms of asthma has led to the recent development of advanced and mechanism-based treatments such as biologicals. However, biologicals are recommended only for patients with specific asthma phenotypes who remain uncontrolled despite high dosages of conventional asthma treatment. One of the main unmet needs in their application is lack of clinically available biomarkers to individualize pediatric asthma management and guide treatment. Pharmacogenomics, epigenomics, and transcriptomics are three omics fields that are rapidly advancing and can provide tools to identify novel asthma mechanisms and biomarkers to guide treatment. Pharmacogenomics focuses on variants in the DNA, epigenomics studies heritable changes that do not involve changes in the DNA sequence but lead to alteration of gene expression, and transcriptomics investigates gene expression by studying the complete set of mRNA transcripts in a cell or a population of cells. Advances in high-throughput technologies and statistical tools together with well-phenotyped patient inclusion and collaborations between different centers will expand our knowledge of underlying molecular mechanisms involved in disease onset and progress. Furthermore, it could help to select and stratify appropriate therapeutic strategies for subgroups of patients and hopefully bring precision medicine to daily practice. PMID- 29493883 TI - Prostate cancer surveillance by occupation and industry: the Canadian Census Health and Environment Cohort (CanCHEC). AB - As there are no well-established modifiable risk factors for prostate cancer, further evidence is needed on possible factors such as occupation. Our study uses one of the largest Canadian worker cohorts to examine occupation, industry, and prostate cancer and to assess patterns of prostate cancer rates. The Canadian Census Health and Environment Cohort (CanCHEC) was established by linking the 1991 Canadian Census Cohort to the Canadian Cancer Database (1969-2010), Canadian Mortality Database (1991-2011), and Tax Summary Files (1981-2011). A total of 37,695 prostate cancer cases were identified in men aged 25-74 based on age at diagnosis. Cox proportional hazards models were used to estimate hazards ratios and 95% confidence intervals. In men aged 25-74 years, elevated risks were observed in the following occupations: senior management (HR = 1.12, 95% CI: 1.04 1.20); office and administration (HR = 1.19, 95% CI: 1.11-1.27); finance services (HR = 1.09, 95% CI: 1.04-1.14); education (HR = 1.05, 95% CI: 1.00-1.11); agriculture and farm management (HR = 1.12, 95% CI: 1.06-1.17); farm work (HR = 1.11, 95% CI: 1.01-1.21); construction managers (HR = 1.07, 95% CI: 1.01-1.14); firefighting (HR = 1.17, 95% CI: 1.01-1.36); and police work (HR = 1.22, 95% CI: 1.09-1.36). Decreased risks were observed across other construction and transportation occupations. Results by industry were consistent with occupation results. Associations were identified for white-collar, agriculture, protective services, construction, and transportation occupations. These findings emphasize the need for further study of job-related exposures and the potential influence of nonoccupational factors such as screening practices. PMID- 29493884 TI - Changes in maxillofacial morphology due to improvement of nasal obstruction in rats. AB - OBJECTIVES: To investigate the effect of release of experimentally introduced nasal obstruction on maxillofacial morphology and percutaneous arterial oxygen saturation (SpO2 ) in rats. MATERIALS AND METHODS: Six-week-old male Wistar rats (n = 36) were divided into a control group (n = 6) and a nasal obstruction group (n = 30). In the nasal obstruction group, the right nostril was occluded with silicon, which was subsequently removed after a given experimental period (days 7, 21, 35, 49 and 63). These animals were then divided into groups D7, D21, D35, D49 and D63 (each n = 6), according to the day at which the obstruction was released. The SpO2 was measured in rats with nasal obstruction at five experimental points. The maxillofacial morphology in rats on the first day and 63 days after the start of the experiment was evaluated by microcomputed tomography. RESULTS: The SpO2 was still lower at 2 weeks after the improvement of the nasal obstruction in the D49 group than in the control group. In addition, the height of the nasal maxillary complex of the D35, D49 and D63 groups was significantly decreased compared with the control group. CONCLUSIONS: The results of this study suggest that long-term unilateral nasal obstruction in growing rats may affect the growth of the nasomaxillary complex and reduce the SpO2 permanently. Therefore, early improvement of nasal obstruction in rats during the growth period may improve the SpO2 and cranial development and promote normal growth and development. PMID- 29493885 TI - CO2 Binding and Splitting by Boron-Boron Multiple Bonds. AB - The room-temperature, ambient-pressure reactions of CO2 with two species containing boron-boron multiple bonds led to the incorporation of either one or two CO2 molecules. The structural characterization of a thermally unstable intermediate in one case indicates that an initial [2+2] cycloaddition is the key step in the reaction mechanism. PMID- 29493881 TI - Mental distress and health-related quality of life among type 1 and type 2 diabetes patients using self-monitoring of blood glucose: A cross-sectional questionnaire study in Japan. AB - AIMS/INTRODUCTION: The present multicenter, cross-sectional survey was initiated to evaluate self-monitoring of blood glucose (SMBG)-associated mental distress among patients with diabetes. MATERIALS AND METHODS: The survey was carried out in patients with type 1 diabetes and type 2 diabetes using SMBG recruited from 42 medical institutions. Profiles of Mood States 2 and diabetes therapy-related quality of life questionnaires were used to evaluate mood status and health related quality of life. Two original questionnaires were also developed to evaluate SMBG 'importance,' 'painfulness' and 'confidence' among patients, and to evaluate physician attitudes to SMBG use. RESULTS: Questionnaires from 517 type 1 diabetes and 1,648 type 2 diabetes patients showed that 46.0% of type 1 diabetes and 37.5% of type 2 diabetes patients reported 'painfulness,' and that these patients reporting 'painfulness' showed significantly higher Profiles of Mood States 2 scores, lower diabetes therapy-related quality of life scores and higher glycated hemoglobin compared with those not reporting 'painfulness,' whereas the number of their daily SMBG tests were comparable. Patients reporting 'painfulness' also reported that SMBG use was significantly less important. Whether or not patients recognized the importance of SMBG use was well correlated with the frequency of physicians checking patient diaries. CONCLUSIONS: Type 1 diabetes and type 2 diabetes patients reporting 'painfulness' in SMBG use had more mental distress, lower health-related quality of life and higher glycated hemoglobin regardless of their number of daily SMBG tests. The importance of SMBG use was recognized less by patients experiencing pain, and the importance of SMBG use was recognized more in medical institutions in which physicians regularly checked SMBG diaries to provide meaningful feedback to patients in clinical settings. PMID- 29493886 TI - Increased expression of miR-641 contributes to erlotinib resistance in non-small cell lung cancer cells by targeting NF1. AB - Epidermal growth receptor (EGFR)-targeted tyrosine kinase inhibitors (TKIs) have emerged as first-line drugs for advanced non-small-cell lung cancer (NSCLC) patients with EFGR mutations. However, most patients with NSCLC show acquired resistance to EGFR-TKIs, and low expression of NF1 is a mechanism of EGFR-TKI resistance in lung cancer. However, the mechanism by which NF1 is downregulated in EGFR-TKI-resistant NSCLC is unclear. Here, we found the increased expression of miR-641 in NSCLC cells and human NSCLC samples with resistance to TKI compared to those with sensitive to TKI. In addition, our in vitro experiments show that overexpression of miR-641 induces TKI resistance in NSCLC cells. Furthermore, we identified that miR-641 activates ERK signaling by direct targeting of neurofibromatosis 1 (NF1) in NSCLC cells. Our data show that overexpression of NF1 or silencing of ERK can block miR-641-induced resistance of NSCLC cells to erlotinib treatment. Importantly, our animal experiments show that combination of miR-641 inhibition and erlotinib treatment can significantly inhibit erlotinib resistant NSCLC growth, inhibit proliferation and induce apoptosis compared to single-drug treatment. Our findings suggest that increased expression of miR-641 significantly contributes to erlotinib resistance development in NSCLC cells through activating ERK signaling by targeting NF1 and that inhibition of miR-641 may reverse acquired resistance of NSCLC cells to erlotinib treatment. PMID- 29493887 TI - A novel HLA-A*31 allele, A*31:126N, was identified by sequence-based typing. AB - A novel allele A*31:126N was identified in a Chinese individual by sequence-based typing method. PMID- 29493888 TI - Dual specificity phosphatase DUSP6 promotes endothelial inflammation through inducible expression of ICAM-1. AB - Tumor necrosis factor (TNF)-alpha activates a diverse array of signaling pathways in vascular endothelial cells (ECs), leading to the inflammatory phenotype that contributes to the vascular dysfunction and neutrophil emigration in patients with sepsis. To date, it is not well understood what key regulator might coordinate signaling pathways to achieve inflammatory response in TNF-alpha stimulated ECs. This study investigated the role of dual specificity phosphatase 6 (DUSP6) in the regulation of endothelial inflammation. Using knockout mice, we found that DUSP6 is important for TNF-alpha-induced endothelial intercellular adhesion molecule-1 (ICAM-1) expression in aorta and in vein. Moreover, genetic deletion of Dusp6 in pulmonary circulation significantly alleviated the susceptibility of mice to lung injury caused by neutrophil recruitment during experimental sepsis induced by TNF-alpha or lipopolysaccharide (LPS). The role of DUSP6 was further investigated in primary human umbilical vein endothelial cells (HUVECs). Employing RNAi approach in which endogenous DUSP6 was ablated, we showed a critical function of DUSP6 to facilitate TNF-alpha-induced ICAM-1 expression and endothelial leukocyte interaction. Interestingly, DUSP6-promoted endothelial inflammation is independent of extracellular signaling-regulated kinase (ERK) signaling. On the other hand, inducible DUSP6 leads to activation of canonical nuclear factor (NF)-kappaB-mediated transcription of ICAM-1 gene in TNF alpha-stimulated human ECs. These results are the first to demonstrate a positive role of DUSP6 in endothelial inflammation-mediated pathological process and the underlying mechanism through which DUSP6 promotes NF-kappaB signaling in the inflamed ECs. Our findings suggest that manipulation of DUSP6 holds great potential for the treatment of acute inflammatory diseases. PMID- 29493889 TI - The impact of comorbidity on overall survival in elderly nasopharyngeal carcinoma patients: a National Cancer Data Base analysis. AB - The number of elderly patients with cancer is increasing. Medical comorbidities are more common in this population. Little is known regarding the prognostic relevance of comorbidities in elderly patients with nasopharyngeal carcinoma (NPC). Using the National Cancer Data Base (NCDB), we queried patients age >65 years diagnosed with NPC and treated with definitive radiation between 2004 and 2012 to examine the association between comorbidity and survival outcomes. Comorbidity was assessed with the Charlson Comorbidity Index (CCI). The influence of comorbidity on overall survival (OS) was evaluated. Cox proportional hazards model was used to study the impact of comorbidity on OS. A total of 1137 patients met the specified criteria. Median follow-up was 61.2 months. Five-year OS was 50.4%. Comorbidities were present in 22.4% of patients, with 17.6% of patients having a CCI score of 1% and 4.8% having a CCI score of >=2. Patients with a CCI score of 0 had significantly higher 5-year OS than patients with a CCI score of 1 or >=2 (53.1% vs. 42.2% vs. 32.9%, P < 0.001). In multivariate analysis, CCI was a statistically significant independent prognostic factor for the risk of death of all causes for patients with a CCI score of 1 (hazard ratio [HR]: 1.242; 95% confidence interval [CI]: 1.002-1.539) or CCI score of >=2 (HR: 1.625; 95% CI: 1.157-2.283) when compared to patients with a CCI score of 0. Comorbidity as measured by CCI is a strong independent prognostic factor for OS in elderly patients with NPC and lends support to the inclusion of comorbidity assessment due to its prognostic value when treating elderly patients with NPC. PMID- 29493890 TI - Dynamic behavior of different quantities of osteoblasts during formation of micromass cultures. AB - Implantation of micromass cultures of osteoblastic cells offers the possibility of scaffold free tissue engineering for example, regeneration of bone defects. However, the details of cell dynamics during the formation of these micromasses are still not well understood. This study aims to investigate and clarify the extent to which cell quantity influences the dynamics of micromass formation of osteoblastic cell cultures. For this purpose, the migration and aggregation during this process are investigated by optical inspection employing image processing software that allows for automated tracking of cell groups using digital image correlation. An exponential time behavior is observed with respect to the velocity of the cells and the distance of the cells to their common center of gravity. Characteristic time constants are derived as quantitative measures of the cell dynamics. The results indicate that the time constants strongly depend on the quantity of cells, that is, will decrease with increasing cell quantity. (c) 2018 International Society for Advancement of Cytometry. PMID- 29493891 TI - Aromatic Aminocatalysis. AB - Aromatic aminocatalysis refers to transformations that employ aromatic amines, such as anilines or aminopyridines, as catalysts. Owing to the conjugation of the amine moiety with the aromatic ring, aromatic amines demonstrate distinctive features in aminocatalysis compared with their aliphatic counterparts. For example, aromatic aminocatalysis typically proceeds with slower turnover, but is more active and conformationally rigid as a result of the stabilized aromatic imine or iminium species. In fact, the advent of aromatic aminocatalysis can be traced back to before the renaissance of organocatalysis in the early 2000s. So far, aromatic aminocatalysis has been widely applied in bioconjugation reactions through transamination; in asymmetric organocatalysis through imine/enamine tautomerization; and in cooperative catalysis with transition metals through C H/C-C activation and functionalization. This Focus Review summarizes the advent of and major advances in the use of aromatic aminocatalysis in bioconjugation reactions and organic synthesis. PMID- 29493892 TI - Motor competency and social communication skills in preschool children with autism spectrum disorder. AB - : This study aimed to investigate the association between motor competency and social communication in children with Autism Spectrum Disorder (ASD) compared with children with Intellectual Disabilities (ID) and typically developing (TD) children. Motor competency, ASD symptoms, and nonverbal Intelligent Quotient (IQ) were investigated through the following tests: Movement Assessment Battery for Children, second edition (MABC-2), Social Communication Questionnaire (SCQ), Autism Classification System of Functioning: Social Communication (ACSF:SC) and Leiter International Performances Scale Revised (Leiter-R). The ASD + ID and ID groups had lower MABC-2-manual dexterity mean scores, MABC-2-aiming and catching mean scores, MABC-2-static and dynamic balance mean scores and MABC-2-TTS compared with the TD group (P < 0.05). In addition, the ASD + ID group had lower MABC-2-aiming and catching mean scores compared with the ID group. In the ASD + ID group, we found a significant negative correlation (P < 0.001) between MABC-2 aiming and catching scores with SCQ scores, nonverbal IQ and ACSF:SC levels. Our findings provide new insight into the common neuropsychological mechanisms underlying social communication and motor deficits in ASD. Multiple deficits in motor functioning may be present in ASD and ID, however deficits involving the ability to integrate motor and social cues are somewhat specific to ASD. Autism Res 2018, 11: 893-902. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: This study highlighted the specificity of motor impairment in ASD comparing performances on a frequently used measure of motor impairment between clinical groups (ASD + ID and ID) and a non-clinical group. While previous research has suggested that multiple deficits in motor functioning may be present in ASD, our findings suggest that deficits in tasks involving the ability to integrate visual and motor cues (aiming and catching task) are somewhat specific to ASD. PMID- 29493893 TI - Improved Photodynamic Cancer Treatment by Folate-Conjugated Polymeric Micelles in a KB Xenografted Animal Model. PMID- 29493894 TI - Assessment of sella turcica area and skeletal maturation patterns of children with unilateral cleft lip and palate. AB - OBJECTIVES: The aim of this case-control study was to assess sella turcica area and skeletal maturity in children with unilateral cleft lip and palate (UCLP) and compare with those of non-cleft children. SETTING AND SAMPLE POPULATION: A total of 85 UCLP patients aged 7.5-17.08 years (Group 1: age 7-11 years, Group 2: age 11-14 years and Group 3: age 14-18 years) were compared with 85 control subjects without clefts who were divided into similar age groups. MATERIALS AND METHODS: Hand-wrist radiographs and cervical vertebra maturation stages (CVMS) were used to evaluate growth. Lateral cephalograms were traced, and reference points of sella were determined. Sella turcica area was measured using a digital planimeter. RESULTS: Comparison of overall growth on hand-wrist radiographs revealed no significant difference between cleft and non-cleft subjects. However, according to the chronological age groups, Group 1-UCLP showed statistically significant delay in skeletal maturation when compared with the age-matched control subjects (P = .05). This difference was due to the delay among male subjects (P = .05). As for CVMS, more significant maturation delay was observed in Group 1-UCLP (P = .001) and was attributable to both male and female subjects (P = .05). Comparison of sella turcica area showed no significant difference between UCLP patients and controls. CONCLUSION: Although children with CLP showed significant delay in growth when they are younger compared with the non-cleft children, sella turcica area measurements were similar for individuals in both groups. PMID- 29493895 TI - Hepatic artery occlusion in liver transplantation: What counts more, the type of reconstruction or the severity of the recipient's disease? AB - Although the type of hepatic artery revascularization technique is known to have an impact on patency rates, independent perioperative risk factors on patient outcomes are poorly defined. All consecutive adult patients undergoing cadaveric liver transplantation (n = 361) from July 2007 to June 2016 in a single institution were analyzed. Primary outcomes were early (<30 days) hepatic artery occlusion and primary hepatic artery patency rate. A multivariate model was used to identify independent risk factors for occlusion and the need of arterial conduit, as well as their impact on graft and patient survival. Arterial revascularization without additional reconstruction (end-to-end arterial anastomosis [AA]) was performed in 77% (n = 279), arterial reconstruction (AR) in 15% (n = 53), and aortohepatic conduit (AHC) in 8% (n = 29) of patients. AHC had the highest mean intraoperative flow (275 mL/minute; P = 0.02) compared with AA (250 mL/minute) and AR (200 mL/minute; P = 0.02). There were 43 recipients (12%) who had an occlusive event with successful revascularization in 20 (47%) recipients. One-year primary patency rates of AA, AR, and AHC were 97%, 88%, and 74%, respectively. Aortic calcification had an impact on early occlusion. AR (odds ratio [OR], 3.68; 95% confidence interval [CI], 1.26-10.75; P = 0.02) and AHC (OR, 6.21; 95% CI, 2.02-18.87; P = 0.001) were independent risk factors for early occlusion. Dyslipidemia additionally independently contributed to early occlusion (OR, 2.74; 95% CI, 0.96-7.87; P = 0.06). The 1- and 5-year graft survival rates were 83% and 70% for AA, 75% and 69% for AR, and 59% and 50% for AHC (P = 0.004), respectively. In conclusion, arterial patency is primarily determined by the type of vascular reconstruction rather than patient or disease characteristics. The preoperative lipid status is an independent risk factor for early occlusion, whereas overall occlusion is only based on the performed vascular reconstruction, which is also associated with reduced graft and patient survival. Liver Transplantation 24 790-802 2018 AASLD. PMID- 29493896 TI - Prevalence of and factors associated with antenatal care seeking and adherence to recommended iron-folic acid supplementation among pregnant women in Zinder, Niger. AB - The World Health Organization recommends iron and folic acid (IFA) supplementation for pregnant women. The high prevalence of anaemia among pregnant women in Niger warrants better understanding of the utilization of antenatal care (ANC) and IFA. We aimed to assess the prevalence of and factors associated with ANC coverage and adherence to IFA recommendation among pregnant women. Pregnant women (n = 923) from 64 randomly selected villages within the catchment area of 12 health centres were interviewed during a baseline household survey in Zinder, Niger. ANC and IFA coverage were 60.1% and 43.6%, respectively. Only 71.7% of women who attended ANC received IFA. Of the 401 women who reportedly received any IFA supplements, 99.3% had attended any ANC during their current pregnancy and 68.6% reported adherence to recommended IFA supplementation (i.e., consumed IFA every day in the previous week). Women with gestational age >=27 weeks were more likely to have attended ANC than women with gestational age <27 weeks (85.9% vs. 27.5%, odds ratio [OR]: 21.81, 95% confidence interval [CI]: 13.81, 34.45). Women who reportedly received husbands' advice about attending ANC were more likely to attend ANC (OR: 1.48, 95% CI [1.03, 2.11]) and adhere to IFA recommendations (OR: 1.80, 95% CI [1.04, 3.13]) compared to those who did not receive any advice. ANC attendance is crucial to ensure distribution of IFA supplementation among pregnant women in Zinder. Interventions to improve ANC and IFA adherence will require promotion of early ANC, ensure availability of IFA at ANC, and involve husbands in ANC. PMID- 29493897 TI - Feasibility of integrating calcium and iron-folate supplementation to prevent preeclampsia and anemia in pregnancy in primary healthcare facilities in Kenya. AB - Calcium (Ca) supplementation to prevent preeclampsia can save maternal and newborn lives, but there are no program models for integration into existing antenatal care platforms. We used a program impact pathway model to guide the design of integrated Ca and iron-folate (IFA) supplementation in Kenya. We provided healthcare providers with job aids (posters and counseling cards), trained them on counseling techniques and supplementation guidelines, and developed behavior change materials for pregnant women (pill-taking calendars). We allocated health facilities to prescribe either 1.0 or 1.5 g/day Ca, with standard IFA. We collected implementation data from 16 facilities and 990 women. We also explored effects of supplementation on percentage of the population meeting recommended daily allowance. Supplements and job aids were available during 90% of facility spot-check episodes; calendar availability was lower (78%). Over 98% of clients received Ca and IFA supplements, but only 76% received enough Ca supplements to last between antenatal care visits. Among clients that still had pills by return date, adherence was 77% and 83% for the IFA and Ca regimen, respectively. When 1.5 g/day of Ca supplements were prescribed, over 75% of participants met recommended daily allowance. Only 54% met the recommended daily allowance when 1.0 g was prescribed. This study illustrates a systematic approach for integrating Ca supplementation into primary healthcare and demonstrates that such integration is feasible when contextual bottlenecks are addressed. Policy makers and program planners should pay attention to supply chain, healthcare worker dispensing behavior, and appropriateness of regimen for their settings. PMID- 29493898 TI - Measuring movement towards improved emergency obstetric care in rural Kenya with implementation of the PRONTO simulation and team training program. AB - As the proportion of facility-based births increases, so does the need to ensure that mothers and their newborns receive quality care. Developing facility oriented obstetric and neonatal training programs grounded in principles of teamwork utilizing simulation-based training for emergency response is an important strategy for improving the quality care. This study uses 3 dimensions of the Kirkpatrick Model to measure the impact of PRONTO International (PRONTO) simulation-based training as part of the Linda Afya ya Mama na Mtoto (LAMMP, Protect the Health of mother and child) in Kenya. Changes in knowledge of obstetric and neonatal emergency response, self-efficacy, and teamwork were analyzed using longitudinal, fixed-effects, linear regression models. Participants from 26 facilities participated in the training between 2013 and 2014. The results demonstrate improvements in knowledge, self-efficacy, and teamwork self-assessment. When comparing pre-Module I scores with post-training scores, improvements range from 9 to 24 percentage points (p values < .0001 to .026). Compared to baseline, post-Module I and post-Module II (3 months later) scores in these domains were similar. The intervention not only improved participant teamwork skills, obstetric and neonatal knowledge, and self-efficacy but also fostered sustained changes at 3 months. The proportion of facilities achieving self-defined strategic goals was high: 95.8% of the 192 strategic goals. Participants rated the PRONTO intervention as extremely useful, with an overall score of 1.4 out of 5 (1, extremely useful; 5, not at all useful). Evaluation of how these improvements affect maternal and perinatal clinical outcomes is forthcoming. PMID- 29493899 TI - Ethiopian women's perspectives on antenatal care and iron-folic acid supplementation: Insights for translating global antenatal calcium guidelines into practice. AB - After decades of global response to iron-deficiency anemia, lessons learned from antenatal iron-folic acid (IFA) supplementation can inform new micronutrient supplementation efforts. The World Health Organization recommends calcium supplementation for the prevention of preeclampsia; however, little is documented on how to design programs to integrate calcium into the standard of care. Twenty interviews with pregnant women and 22 interviews with health providers and volunteers in two districts in Ethiopia were conducted to examine how barriers and facilitators to antenatal care, IFA supplementation, and initial reactions to calcium supplements and regimen might influence adherence and inform future programs. Women viewed supplementation positively but cited lack of information on benefits and risks, forgetfulness, and inconsistent IFA supply as challenges. Though knowledge and awareness of anemia and IFA supplements were widespread, preeclampsia was mostly unknown. Some symptoms of preeclampsia were viewed as normal in pregnancy, making it difficult to convey risk to motivate supplement use. Some women viewed co-consumption of IFA and calcium as potentially harmful and were confused regarding the simultaneous risks of anemia and hypertension, understood as "low" and "high" blood levels in pregnancy. However, most said they would take both IFA and calcium supplements if provided with supplements and counseling on purpose and benefits. Strategies such as social support from families, stronger community-based counseling, and increased health care provider and community awareness of preeclampsia are critical for women to understand the benefits of supplementation and resolve confusion caused by current descriptors used for anemia and hypertension. PMID- 29493900 TI - Community perceptions towards the new role of traditional birth attendants as birth companions and nutrition advocates in Kakamega County, Kenya. AB - Delivery with skilled birth attendants is important for reducing maternal mortality in developing countries. However, traditional birth attendants (TBAs) are abundant in such settings, managing deliveries without the skills and resources necessary to prevent mortality in this situations. Interventions that have been proposed to mitigate the situation include redefining the role of TBAs to nutrition advocates and birth companions for pregnant women to health facilities. We thus explored community perceptions on these new roles of TBAs, as birth companions and nutrition advocates, and their influence on health facility deliveries in Kakamega County, Kenya. Qualitative data was collected through key informant interviews with health workers and focus group discussions with lactating mothers, pregnant women, husbands, community leaders, community health volunteers, and TBA. Content analysis was conducted; data was organized into subthemes and conclusions made from each subtheme using Atlas.ti software. TBAs adopted their birth companion role as the majority offered companionship to mothers delivering at health facilities. Mothers were happy with this role as TBAs continued providing companionship even after delivery. The community members were happy with the new role of TBAs and reported increased deliveries at the health facilities. In contrast, TBAs did not adopt the nutrition advocacy role sufficiently. We found that redefining the role of the TBAs into birth companions to support facility-based delivery is thus feasible and acceptable. Nutrition advocacy by the TBAs should be strengthened to maximize on the opportunity provided by the close association between TBAs and mothers and the community. PMID- 29493901 TI - Design and implementation of a health systems strengthening approach to improve health and nutrition of pregnant women and newborns in Ethiopia, Kenya, Niger, and Senegal. AB - Maternal and neonatal mortality are unacceptably high in developing countries. Essential nutrition interventions contribute to reducing this mortality burden, although nutrition is poorly integrated into health systems. Universal health coverage is an essential prerequisite to decreasing mortality indices. However, provision and utilization of nutrition and health services for pregnant women and their newborns are poor and the potential for improvement is limited where health systems are weak. The Community-Based Maternal and Neonatal Health and Nutrition project was established as a set of demonstration projects in 4 countries in Africa with varied health system contexts where there were barriers to safe maternal health care at individual, community and facility levels. We selected project designs based on the need, context, and policies under consideration. A theory driven approach to programme implementation and evaluation was used involving developing of contextual project logic models that linked inputs to address gaps in quality and uptake of antenatal care; essential nutrition actions in antenatal care, delivery, and postnatal care; delivery with skilled and trained birth attendant; and postnatal care to outcomes related to improvements in maternal health service utilization and reduction in maternal and neonatal morbidity and mortality. Routine monitoring and impact evaluations were included in the design. The objective of this paper is to describe the rationale and methods used in setting up a multi-country study that aimed at designing the key maternal and neonatal health interventions and identifying indicators related to inputs, outcomes, and impact that were measured to track change associated with our interventions. PMID- 29493902 TI - Integrating nutrition into health systems at community level: Impact evaluation of the community-based maternal and neonatal health and nutrition projects in Ethiopia, Kenya, and Senegal. AB - Maternal undernutrition and mortality remain high in several African countries. Key nutrition and health interventions improve maternal and birth outcomes. Evidence is scarce on how to strengthen health systems to ensure pregnant women and newborns are reached with these interventions. We conducted three quasi experimental nonrandomized Community Based Maternal and Neonatal Health and Nutrition projects in regions of Ethiopia, Senegal, and Kenya to demonstrate how proven nutrition interventions could be integrated into health programs to improve knowledge and practices during pregnancy, birth, and postpartum. We evaluated impact on knowledge and practices related to maternal and neonatal care using logistic regression and repeated-measures models with districts as a fixed variable and adjusted for covariates. Combined country analyses show significant positive effects of the intervention on women receiving first antenatal care visit (ANC) during first trimester (OR = 1.44; p < .001), those consuming any iron and folic acid supplement during their latest pregnancy (OR = 1.60; p = .005), those whose <6 months infants were exclusively breastfed (OR = 2.01; p=.003), those whose delivery was facility based (OR = 1.48; p=.031), and those whose postnatal care was facility based (OR = 2.15; p<.001). There was no significant differences between intervention and control groups regarding one or more and four or more ANC visits, women consuming iron and folic acid for >=90 days, and early initiation of breastfeeding. We conclude that integrating proven nutrition interventions into health programs at community level improved components of access to and use of ANC, delivery services, and postnatal care by women in three African countries. PMID- 29493903 TI - Factors associated with socio-demographic characteristics and antenatal care and iron supplement use in Ethiopia, Kenya, and Senegal. AB - Antenatal care (ANC) offers remarkable opportunities to reach a large number of women with effective nutrition and health interventions, including iron (Fe) supplementation. However, all women do not equally seek nor benefit from ANC. We aimed to identify characteristics associated with ANC and Fe use among women in hard-to-reach areas in Afar, Ethiopia; Sedhiou and Kolda, Senegal; and Kakamega, Kenya. Women who gave birth within 1 year preceding the survey (n = 4,575) from 15 different sub-regions were randomly selected and surveyed. Multivariable logistic regression was used to identify associations of socio-demographic characteristics with ANC and Fe use. Factors that showed positive associations with ANC uptake included education, income, possession of a mobile phone, and the occupation of the mother or another household member. Beginning ANC in the first trimester associated positively with achievement of 4 or more ANC visits, and having any ANC visits related positively with Fe intake. Distance to the nearest health facility was negatively associated, and type of nearest facility and counselling and health education were positively associated with some outcomes. The results from these surveys demonstrate the need to ensure access of services across all population groups and can help identify ANC programming needs. PMID- 29493904 TI - Treatment efficiency and stability of skeletal Class III malocclusion with a surgery-first approach. AB - OBJECTIVES: To compare treatment duration in skeletal Class III malocclusion patients managed with a 2-step treatment (surgery-first approach, SFA) and conventional 3-step treatment, and to compare stability of surgical outcomes between segmentation and non-segmentation in the 2-step treatment group. SETTING AND SAMPLE POPULATION: The sample population consisted of 37 patients who completed orthognathic surgery (OGS) and orthodontic correction at the Charm Aesthetic Surgery Clinic (Taipei, Taiwan) between 2012 and 2015. Of these, 26 received 2-step treatment and 11 received 3-step treatment. MATERIALS AND METHODS: To compare treatment efficiency and stability, three time points were analysed: T0 , before treatment (before OGS in the 2-step group and before orthodontic treatment in the 3-step group); T1 , after OGS but before orthodontic correction (cone beam computed tomography (CBCT) was obtained within 2 weeks of OGS); and T2 , after orthodontic correction (CBCT was obtained on the day of bracket removal). The post-OGS (T1 ) CBCT items were individually superimposed on the pre-treatment (T0 ) CBCT items to determine the distance of B point migration. RESULTS: A significant difference was found in treatment times between 2-step treatment and conventional 3-step treatment. In addition, no significant difference was found when comparing B-X (mm) and B-Y (mm) at T2 -T1 for the segmentation and non-segmentation groups. CONCLUSIONS: Using SFA for skeletal Class III malocclusions saves approximately 6 months of treatment time over 3 step treatment; the stability of the segmentation group was comparable to that of the non-segmentation group, a result that is possibly associated with the fixation of 2 miniplates. PMID- 29493905 TI - An Artificial Lithium Protective Layer that Enables the Use of Acetonitrile-Based Electrolytes in Lithium Metal Batteries. AB - The resurgence of the lithium metal battery requires innovations in technology, including the use of non-conventional liquid electrolytes. The inherent electrochemical potential of lithium metal (-3.04 V vs. SHE) inevitably limits its use in many solvents, such as acetonitrile, which could provide electrolytes with increased conductivity. The aim of this work is to produce an artificial passivation layer at the lithium metal/electrolyte interface that is electrochemically stable in acetonitrile-based electrolytes. To produce such a stable interface, the lithium metal was immersed in fluoroethylene carbonate (FEC) to generate a passivation layer via the spontaneous decomposition of the solvent. With this passivation layer, the chemical stability of lithium metal is shown for the first time in 1 m LiPF6 in acetonitrile. PMID- 29493906 TI - The N-Terminal Domain of the Pullulanase from Anoxybacillus sp. WB42 Modulates Enzyme Specificity and Thermostability. AB - Anoxybacillus sp. WB42 pullulanase (PulWB42) is a novel thermophilic amylopullulanase that was assigned to the glycoside hydrolase family 13 subfamily 14 (GH13_14) type I pullulanases in the carbohydrate-active enzymes database. Its N-terminal domain (Met1-Phe101) was identified as the carbohydrate-binding module 68 (CBM68) by homology modeling. The N-domain-deleted PulWB42 exhibited an equivalent Michaelis constant (Km ) for pullulan and significant decreases in pullulytic activity, amylose selectivity, and thermostability relative to PulWB42 having a high alpha-amylase-to-pullulanase activity ratio. Furthermore, the replacement of Ala90 or Arg93 significantly changed the substrate specificity and catalytic efficiency of PulWB42, whereas Q87A, L173D, and H5A/R6A/T7A showed improvements in thermostability and changes in catalytic kinetics. Therefore, the N domain of PulWB42 is not essential for catalysis, but it does modulate enzyme catalysis, especially with respect to substrate specificity. The modulation was achieved mainly by the Leu86-Arg93 segment adjacent to the CBM48 domain and the catalytic A domain in the modeled structure of PulWB42. PMID- 29493907 TI - 2-Methyltetrahydrofuran: A Green Solvent for Iron-Catalyzed Cross-Coupling Reactions. AB - Iron-catalyzed cross-coupling reactions allow sustainable formation of C-C bonds using cost-effective, earth-abundant base-metal catalysis for complex syntheses of pharmaceuticals, natural products, and fine chemicals. The major challenge to maintain full sustainability of the process is the identification of green and renewable solvents that can be harnessed to replace the conventional solvents for this highly attractive reaction. Herein, iron-catalyzed cross-coupling of aryl chlorides and tosylates with challenging organometallic reagents possessing beta hydrogens is found to proceed in good to excellent yields with the green, sustainable, and eco-friendly 2-methyltetrahydrofuran (2-MeTHF) as solvent. The reaction operates with excellent functional group tolerance under very mild conditions. Furthermore, large-scale cross-coupling, cross-coupling of heteroaromatic substrates, and cross-coupling of challenging aryl tosylates and carbamates mediated by Fe-N-heterocyclic carbene catalytic systems in eco friendly 2-MeTHF were also carried out. The developed method was applied to the key cross-coupling in the synthesis of a fibrinolysis inhibitor, further highlighting the potential of 2-MeTHF as a general solvent for sustainable iron catalyzed cross-coupling reactions. PMID- 29493908 TI - A Methodological Study on Tuning the Thermally Activated Delayed Fluorescent Performance by Molecular Constitution in Acridine-Benzophenone Derivatives. AB - Thermally activated delayed fluorescent (TADF) emitters are usually designed as donor-acceptor structures with large dihedral angles, which tend to incur low fluorescent efficiency, and therefore, through molecular design various strategies have been proposed to increase the efficiency of emitters; however, few studies have compared these strategies in one TADF system. In this study, a novel TADF molecule, [4-(9,9-diphenylacridin-10-yl)phenyl](phenyl)methanone (BP DPAC), was designed as a prototype, and two derivatives, BP-Ph-DPAC and DPAC-BP DPAC, were also prepared to represent two common approaches to enhance TADF performance. Compared with the maximum external quantum efficiency (EQE) of 6.82 % for BP-DPAC, organic light-emitting diodes (OLED) devices based on DPAC-BP-DPAC exhibited enhanced TADF properties with the highest maximum EQE of 18.67 %, owing to an additional diphenylacridine donor, whereas BP-Ph-DPAC showed non-TADF properties and exhibited the lowest EQE of 4.25 %, owing to the insertion of a phenyl ring between donor and acceptor. PMID- 29493909 TI - Improving Online Interactions: Lessons from an Online Anatomy Course with a Laboratory for Undergraduate Students. AB - An online section of a face-to-face (F2F) undergraduate (bachelor's level) anatomy course with a prosection laboratory was offered in 2013-2014. Lectures for F2F students (353) were broadcast to online students (138) using Blackboard Collaborate (BBC) virtual classroom. Online laboratories were offered using BBC and three-dimensional (3D) anatomical computer models. This iteration of the course was modified from the previous year to improve online student-teacher and student-student interactions. Students were divided into laboratory groups that rotated through virtual breakout rooms, giving them the opportunity to interact with three instructors. The objectives were to assess student performance outcomes, perceptions of student-teacher and student-student interactions, methods of peer interaction, and helpfulness of the 3D computer models. Final grades were statistically identical between the online and F2F groups. There were strong, positive correlations between incoming grade average and final anatomy grade in both groups, suggesting prior academic performance, and not delivery format, predicts anatomy grades. Quantitative student perception surveys (273 F2F; 101 online) revealed that both groups agreed they were engaged by teachers, could interact socially with teachers and peers, and ask them questions in both the lecture and laboratory sessions, though agreement was significantly greater for the F2F students in most comparisons. The most common methods of peer communication were texting, Facebook, and meeting F2F. The perceived helpfulness of the 3D computer models improved from the previous year. While virtual breakout rooms can be used to adequately replace traditional prosection laboratories and improve interactions, they are not equivalent to F2F laboratories. PMID- 29494122 TI - Nucleotide-Based Assemblies for Green Synthesis of Silver Nanoparticles with Controlled Localized Surface Plasmon Resonances and Their Applications. AB - The sizes, shapes, and surface characteristics of nanomaterials determine their unique physical, chemical, and biological properties. Localized surface plasmon resonance (LSPR) is one of the unique optical properties of noble-metal nanoparticles. The synthesis of nanomaterials using biomolecules as templates offers an excellent strategy to control and regulate their features. Herein, for the first time, we demonstrate a green synthesis approach of silver nanoparticles (AgNPs) using nucleotide-based assemblies as templates. Moreover, we investigate the influence of different nucleotide-based assemblies and metal ions on the preparation of AgNPs, implying that AgNPs with different LSPR absorptions originating from their surrounding and size could be synthesized. The synthetic route is green, energy-effective, and feasible. On the basis of the unique LSPR controlled property, the AgNP composites were applied for cryptography, biothiol detection, and designing logic gates. This work offers a promising method for the synthesis of nanomaterials with multiapplications. PMID- 29494123 TI - Manipulating Refractive Index in Organic Light-Emitting Diodes. AB - In a conventional organic light-emitting diode (OLED), only a fraction of light can escape to the glass substrate and air. Most radiation is lost to two major channels: waveguide modes and surface plasmon polaritons. It is known that reducing the refractive indices of the constituent layers in an OLED can enhance light extraction. Among all of the layers, the refractive index of the electron transport layer (ETL) has the largest impact on light extraction because it is the layer adjacent to the metallic cathode. Oblique angle deposition (OAD) provides a way to manipulate the refractive index of a thin film by creating an ordered columnar void structure. In this work, using OAD, the refractive index of tris(8-hydroxyquinoline)aluminum (Alq3) can be tuned from 1.75 to 1.45. With this low-index ETL deposited by OAD, the resulting phosphorescent OLED shows nearly 30% increase in light extraction efficiency. PMID- 29494124 TI - Role of Surface Tension in Gas Nanobubble Stability Under Ultrasound. AB - Shell-stabilized gas nanobubbles have recently captured the interest of the research community for their potential application as ultrasound contrast agents for molecular imaging and therapy of cancer. However, the very existence of submicron gas bubbles (especially uncoated bubbles) has been a subject of controversy in part due to their predicted Laplace overpressure reaching several atmospheres, making them supposedly thermodynamically unstable. In addition, the backscatter resulting from ultrasound interactions with nanoparticles is not predicted to be readily detectable at clinically relevant frequencies. Despite this, a number of recent reports have successfully investigated the presence and applications of nanobubbles for ultrasound imaging. The mechanism behind these observations remains unclear but is thought to be, in part, influenced heavily by the biophysical properties of the bubble-stabilizing shell. In this study, we investigated the effects of incorporating the triblock copolymer surfactant, Pluronic, into the lipid monolayer of nanobubbles. The impact of shell composition on membrane equilibrium surface tension was investigated using optical tensiometry, using both pendant drop and rising drop principles. However, these techniques proved to be insufficient in explaining the observed behavior and stability of nanobubbles under ultrasound. Additionally, we sought to investigate changes in membrane surface tension (surface pressure) at different degrees of compression (analogous to the bubble oscillations in the ultrasound field) via Langmuir-Blodgett experiments. Results from this study show a significant decrease ( p < 0.0001) in the nanobubble equilibrium surface tension through the incorporation of Pluronic L10, especially at a ratio of 0.2, where this value decreased by 28%. However, this reduction in surface pressure was seen only for specific compositions and varied with monolayer structure (crystalline phase or liquid-crystalline packing). These results indicate a potential for optimization wherein surface pressure can be maximized for both contraction and expansion phases with the proper lipid to Pluronic balance and microstructure. PMID- 29494125 TI - Bioluminescent Low-Affinity Ca2+ Indicator for ER with Multicolor Calcium Imaging in Single Living Cells. AB - The sarco/endoplasmic reticulum (SR/ER) is the foremost intercellular Ca2+ store (at submillimolar concentrations), playing a crucial role in controlling intracellular Ca2+ levels. For the investigation of SR/ER Ca2+ dynamics in cells, fluorescent protein-based genetically encoded calcium indicators (GECIs) with low Ca2+ affinity have been used. Recently, bioluminescent protein-based GECIs with high brightness have been reported to counter the constraints of fluorescence imaging, such as phototoxicity. However, their Ca2+ affinity is high and limited for imaging in the cytosol, nucleus, or mitochondria. In this study, we developed a novel cyan color, low-affinity ( Kd = 110 MUM) intensiometric bioluminescent GECI, which enables monitoring of the Ca2+ dynamics in the ER of HeLa cells and the SR of C2C12-derived myotubes. To facilitate the broad concentration range of Ca2+ in cellular organelles, we additionally developed an intermediate affinity ( Kd = 18 MUM), orange color, and bioluminescent GECI, which enables monitoring of Ca2+ dynamics in the mitochondria of HeLa cells. With these indicators, in conjunction with an existing high-affinity, green, bioluminescent GECI, we succeeded in multicolor bioluminescent Ca2+ imaging in three distinct organelles (nuclei, mitochondria, and ER) simultaneously. The multicolor, live, bioluminescent Ca2+ imaging demonstrated here can be used to stably reveal the ER Ca2+ homeostasis and cooperative Ca2+ regulation among organelles. This will lead to the further understanding of Ca2+-related physiological functions and pathophysiological mechanisms. PMID- 29494126 TI - Metal-Free Carbocatalysis in Advanced Oxidation Reactions. AB - Catalytic processes have remarkably boosted the rapid industrializations in chemical production, energy conversion, and environmental remediation. As one of the emerging applications of carbocatalysis, metal-free nanocarbons have demonstrated promise as catalysts for green remediation technologies to overcome the poor stability and undesirable metal leaching in metal-based advanced oxidation processes (AOPs). Since our reports of heterogeneous activation of persulfates with low-dimensional nanocarbons, the novel oxidative system has raised tremendous interest for degradation of organic contaminants in wastewater without secondary contamination. In this Account, we showcase our recent contributions to metal-free catalysis in advanced oxidation, including design of nanocarbon catalysts, exploration of intrinsic active sites, and identification of reactive species and reaction pathways, and we offer perspectives on carbocatalysis for future environmental applications. The journey starts with the discovery of peroxymonosulfate (PMS) and peroxydisulfate (PDS) activation by graphene-based materials. With the systematic investigations on most carbon allotropes, for the first time the carbocatalysis for PMS or PDS activation was correlated with the pristine carbon configuration, oxygen functionality (ketonic groups), defect degree (exposed edge sites and vacancies), and dimensional structure. Moreover, an intrinsic difference in catalytic oxidation does exist between PMS and PDS activation. For example, the PMS/carbon reaction is dominated by free radicals, while PDS/carbon catalysis was unveiled as a singlet oxygen- or nonradical-based process in which the surface-activated PDS complex directly degrades the organic pollutants without relying on the generation of free radicals. Nitrogen doping significantly enhances the carbocatalysis because of the positively charged carbon domains, which strongly bind with persulfates to form reactive intermediates toward organic reactions. More importantly, N doping substantially alters the catalytic oxidation from a radical process to a nonradical pathway in PMS activation. Codoping of sulfur or boron with nitrogen at a rational level will synergistically promote the catalysis as a result of the formation of more catalytic centers by improved charge/spin redistribution of the carbon framework. Furthermore, a structure-performance relationship was established for annealed nanodiamonds with a characteristic sp3/sp2 (core/shell) hybridization, where the catalytic pathways were intimately dependent on the thickness of the graphitic shells. Interestingly, the introduction of structural defects and N dopants into the well-defined graphitic carbon framework and alteration of graphene/diamond hybrids can transform the persulfate/carbon system from a radical oxidation pathway to a nonradical pathway. Encapsulation of metal nanoparticles within carbon layers further modulates the electronic states of the interacting carbon via charge transport to increase the electron density. Overall, this Account contributes to unveiling the mist of carbocatalysis in AOPs and to summarizing the achievements of metal-free remediation. We also present future research directions on underpinning the knowledge base to facilitate the applications of nanocarbons in sustainable catalysis and environmental chemistry. PMID- 29494127 TI - Triboelectric-Nanogenerator-Based Soft Energy-Harvesting Skin Enabled by Toughly Bonded Elastomer/Hydrogel Hybrids. AB - A major challenge accompanying the booming next-generation soft electronics is providing correspondingly soft and sustainable power sources for driving such devices. Here, we report stretchable triboelectric nanogenerators (TENG) with dual working modes based on the soft hydrogel-elastomer hybrid as energy skins for harvesting biomechanical energies. The tough interfacial bonding between the hydrophilic hydrogel and hydrophobic elastomer, achieved by the interface modification, ensures the stable mechanical and electrical performances of the TENGs. Furthermore, the dehydration of this toughly bonded hydrogel-elastomer hybrid is significantly inhibited (the average dehydration decreases by over 73%). With PDMS as the electrification layer and hydrogel as the electrode, a stretchable, transparent (90% transmittance), and ultrathin (380 MUm) single electrode TENG was fabricated to conformally attach on human skin and deform as the body moves. The two-electrode mode TENG is capable of harvesting energy from arbitrary human motions (press, stretch, bend, and twist) to drive the self powered electronics. This work provides a feasible technology to design soft power sources, which could potentially solve the energy issues of soft electronics. PMID- 29494128 TI - High-Efficiency Polycrystalline Perovskite Light-Emitting Diodes Based on Mixed Cations. AB - We have achieved high-efficiency polycrystalline perovskite light-emitting diodes (PeLEDs) based on formamidinium (FA) and cesium (Cs) mixed cations without quantum dot synthesis. Uniform single-phase FA1- xCs xPbBr3 polycrystalline films were fabricated by one-step formation with various FA:Cs molar proportions; then the influences of chemical composition on film morphology, crystal structure, photoluminescence (PL), and electroluminescence (EL) were systematically investigated. Incorporation of Cs+ cations in FAPbBr3 significantly reduced the average grain size (to 199 nm for FA:Cs = 90:10) and trap density; these changes consequently increased PL quantum efficiency (PLQE) and PL lifetime of FA1- xCs xPbBr3 films and current efficiency (CE) of PeLEDs. Further increase in Cs molar proportion from 10 mol % decreased crystallinity and purity, increased trap density, and correspondingly decreased PLQE, PL lifetime, and CE. Incorporation of Cs also increased photostability of FA1- xCs xPbBr3 films, possibly due to suppressed formation of light-induced metastable states. FA1- xCs xPbBr3 PeLEDs show the maximum CE = 14.5 cd A-1 at FA:Cs = 90:10 with very narrow EL spectral width (21-24 nm); this is the highest CE among FA-Cs-based PeLEDs reported to date. This work provides an understanding of the influences of Cs incorporation on the chemical, structural, and luminescent properties of FAPbBr3 polycrystalline films and a breakthrough to increase the efficiency of FA1- xCs xPbBr3 PeLEDs. PMID- 29494129 TI - Copper Ion Assisted Photochemical Vapor Generation of Chlorine for Its Sensitive Determination by Sector Field Inductively Coupled Plasma Mass Spectrometry. AB - A novel, reliable, and sensitive approach for the determination of chlorine by sector field inductively coupled plasma mass spectrometry (SF-ICPMS) using photochemical vapor generation for sample introduction is presented. Methyl chloride is generated from different chlorine species in a flow-through photochemical reactor using a 1% solution of acetic acid containing 7.5 MUg g-1 of Cu2+. The volatile product is directed by an argon carrier gas to a gas-liquid separator and introduced into the instrument. A sample flow rate at 1.7 mL min-1 and a 45 s irradiation time provided a 74-fold enhancement in sensitivity compared to conventional nebulization. A blank-limited detection limit of 0.5 ng g-1 for chloride, suitable for quantitation at trace levels, was achieved. The proposed method was validated by analysis of two certified reference materials, NIST SRM 1568b rice flour and SRM 1571 orchard leaves, with satisfactory results, as well as three varieties of bottled water, achieving spike recoveries between 101% and 105%. PMID- 29494130 TI - Improved Charge Transfer in a Mn2O3@Co1.2Ni1.8O4 Hybrid for Highly Stable Alkaline Direct Methanol Fuel Cells with Good Methanol Tolerance. AB - A three-dimensional Mn2O3@Co1.2Ni1.8O4 hybrid was synthesized via facile two-step processes and employed as a cathode catalyst in direct methanol fuel cells (DMFCs) for the first time. Because of the unique architecture with ultrathin and porous nanosheets of the Co1.2Ni1.8O4 shell, this composite exhibits better electrochemical performance than the pristine Mn2O3. Remarkably, it shows excellent methanol tolerance, even in a high concentration solution. The DMFC was assembled with Mn2O3@Co1.2Ni1.8O4, polymer fiber membranes, and PtRu/C as the cathode, membrane, and anode, respectively. The power densities of 57.5 and 70.5 mW cm-2 were recorded at 18 and 28 degrees C, respectively, especially the former is the best result reported in the literature at such a low temperature. The stability of the Mn2O3@Co1.2Ni1.8O4 catalyzed cathode was evaluated, and the results show that this compound possesses excellent stability in a high methanol concentration. The improved electrochemical activity could be attributed to the narrow band gap of the hybrid, which accelerates the electrons jumping from the valence band to the conduction band. Therefore, MnIII could be oxidized into MnIV more easily, simultaneously providing an electron to the absorbed oxygen. PMID- 29494131 TI - Nano-Sized Structurally Disordered Metal Oxide Composite Aerogels as High-Power Anodes in Hybrid Supercapacitors. AB - A general method for preparing nano-sized metal oxide nanoparticles with highly disordered crystal structure and their processing into stable aqueous dispersions is presented. With these nanoparticles as building blocks, a series of nanoparticles@reduced graphene oxide (rGO) composite aerogels are fabricated and directly used as high-power anodes for lithium-ion hybrid supercapacitors (Li HSCs). To clarify the effect of the degree of disorder, control samples of crystalline nanoparticles with similar particle size are prepared. The results indicate that the structurally disordered samples show a significantly enhanced electrochemical performance compared to the crystalline counterparts. In particular, structurally disordered Ni xFe yO z@rGO delivers a capacity of 388 mAh g-1 at 5 A g-1, which is 6 times that of the crystalline sample. Disordered Ni xFe yO z@rGO is taken as an example to study the reasons for the enhanced performance. Compared with the crystalline sample, density functional theory calculations reveal a smaller volume expansion during Li+ insertion for the structurally disordered Ni xFe yO z nanoparticles, and they are found to exhibit larger pseudocapacitive effects. Combined with an activated carbon (AC) cathode, full-cell tests of the lithium-ion hybrid supercapacitors are performed, demonstrating that the structurally disordered metal oxide nanoparticles@rGO||AC hybrid systems deliver high energy and power densities within the voltage range of 1.0-4.0 V. These results indicate that structurally disordered nanomaterials might be interesting candidates for exploring high-power anodes for Li-HSCs. PMID- 29494132 TI - Printed Thin-Film Transistors: Research from China. AB - Thin-film transistors (TFTs) have experienced tremendous development during the past decades and show great promising applications in flat displays, sensors, radio frequency identification tags, logic circuit, and so on. The printed TFTs are the key components for rapid development and commercialization of printed electronics. The researchers in China play important roles to accelerate the development and commercialization of printed TFTs. In this review, we comprehensively summarize the research progress of printed TFTs on rigid and flexible substrates from China. The review will focus on printing techniques of TFTs, printed TFT components including semiconductors, dielectrics and electrodes, as well as fully printed TFTs and printed flexible TFTs. Furthermore, perspectives on the remaining challenges and future developments are proposed. PMID- 29494133 TI - Charge Variant Analysis of Monoclonal Antibodies Using Direct Coupled pH Gradient Cation Exchange Chromatography to High-Resolution Native Mass Spectrometry. AB - Charge variant analysis (CVA) of monoclonal antibodies (mAbs) using cation exchange chromatography is routinely used as a fingerprint of the distribution of posttranslational modifications present on the molecule. Traditional salt or pH based eluents are not suited for direct coupling to mass spectrometry due to nonvolatility or high ionic strength. This makes further analysis complicated when an alteration in the charge variant profile or the emergence of an additional peak is encountered. Here, the use of pH gradient elution using volatile, low ionic strength buffers is reported with direct coupling to high resolution Orbitrap mass spectrometry. The development of a universal method based on pH elution was explored using a number of mAb drug products. Optimized methods facilitated the separation and identification of charge variants including individual glycoforms of the mAbs investigated using the same buffer system but with tailored gradient slopes. The developed method represents an exciting advance for the characterization of biopharmaceuticals as intact entities through the combination of native charge variant separations with high resolution native mass spectrometry. PMID- 29494134 TI - Redox-Mediated Stabilization in Zinc Molybdenum Nitrides. AB - We report on the theoretical prediction and experimental realization of new ternary zinc molybdenum nitride compounds. We used theory to identify previously unknown ternary compounds in the Zn-Mo-N systems, Zn3MoN4 and ZnMoN2, and to analyze their bonding environment. Experiments show that Zn-Mo-N alloys can form in broad composition range from Zn3MoN4 to ZnMoN2 in the wurtzite-derived structure, accommodating very large off-stoichiometry. Interestingly, the measured wurtzite-derived structure of the alloys is metastable for the ZnMoN2 stoichiometry, in contrast to the Zn3MoN4 stoichiometry, where ordered wurtzite is predicted to be the ground state. The formation of Zn3MoN4-ZnMoN2 alloy with wurtzite-derived crystal structure is enabled by the concomitant ability of Mo to change oxidation state from +VI in Zn3MoN4 to +IV in ZnMoN2, and the capability of Zn to contribute to the bonding states of both compounds, an effect that we define as "redox-mediated stabilization". The stabilization of Mo in both the +VI and +IV oxidation states is due to the intermediate electronegativity of Zn, which enables significant polar covalent bonding in both Zn3MoN4 and ZnMoN2 compounds. The smooth change in the Mo oxidation state between Zn3MoN4 and ZnMoN2 stoichiometries leads to a continuous change in optoelectronic properties-from resistive and semitransparent Zn3MoN4 to conductive and absorptive ZnMoN2. The reported redox-mediated stabilization in zinc molybdenum nitrides suggests there might be many undiscovered ternary compounds with one metal having an intermediate electronegativity, enabling significant covalent bonding, and another metal capable of accommodating multiple oxidation states, enabling stoichiometric flexibility. PMID- 29494135 TI - Elucidation of a Self-Sustaining Cycle in Escherichia coli l-Serine Biosynthesis That Results in the Conservation of the Coenzyme, NAD. AB - The equilibrium of the reaction catalyzed by d-3-phosphoglycerate dehydrogenase (PGDH), the first enzyme in the l-serine biosynthetic pathway, is far in the direction away from serine synthesis. As such, the enzyme is usually assayed in this direction. To easily assay it in the direction of l-serine synthesis, it can be coupled to the next enzyme in the pathway, phosphoserine aminotransferase (PSAT), with the activity monitored by the conversion of NAD+ to NADH by PGDH. However, when PGDHs from several different species were coupled to PSAT, it was found that one of them, ecPGDH, conserves the coenzyme in the production of l serine by utilizing an intrinsic cycle of NAD+/NADH interconversion coupled with the conversion of alpha-ketoglutarate (alphaKG) to alpha-hydroxyglutarate. Furthermore, the cycle can be maintained by production of alphaKG by the second enzyme in the pathway, PSAT, and does not require any additional enzymes. This is not the case for PGDH from another bacterial source, Mycobacterium tuberculosis, and a mammalian source, human liver, where net consumption of NAD+ occurs. Both NAD+ and NADH appear to remain tightly bound to ecPGDH during the cycle, effectively removing a requirement for the presence of an exogenous coenzyme pool to maintain the pathway and significantly reducing the energy requirement needed to maintain this major metabolic pathway. PMID- 29494136 TI - Unique [Mn6Bi5]- Nanowires in KMn6Bi5: A Quasi-One-Dimensional Antiferromagnetic Metal. AB - We report a new quasi-one-dimensional compound KMn6Bi5 composed of parallel nanowires crystallizing in a monoclinic space group C2/ m with a = 22.994(2) A, b = 4.6128(3) A, c = 13.3830(13) A and beta = 124.578(6) degrees . The nanowires are infinite [Mn6Bi5]- columns each of which is composed of a nanotube of Bi atoms acting as the cladding with a nanorod of Mn atoms located in the central axis of the nanotubes. The nanorods of Mn atoms inside the Bi cladding are stabilized by Mn-Mn bonding and are defined by distorted Mn-centered cluster icosahedra of Mn13 sharing their vertices along the b axis. The [Mn6Bi5]- nanowires are linked with weak internanowire Bi-Bi bonds and charge balanced with K+ ions. The [Mn6Bi5]- nanowires were directly imaged by high-resolution transmission electron microscopy and scanning transmission electron microscopy. Magnetic susceptibility studies show one-dimensional characteristics with an antiferromagnetic transition at ~75 K and a small average effective magnetic moment (1.56 MUB/Mn for H ? b and 1.37 MUB/Mn for H ? b) of Mn from Curie-Weiss fits above 150 K. Specific heat measurements reveal an electronic specific heat coefficient gamma of 6.5(2) mJ K-2(mol-Mn)-1 and a small magnetic entropy change Delta Smag ~ 1.6 J K-1 (mol-Mn)-1 across the antiferromagnetic transition. In contrast to a metallic resistivity along the column, the resistivity perpendicular to the column shows a change from a semiconducting behavior at high temperatures to a metallic one at low temperatures, indicating an incoherent-to coherent crossover of the intercolumn tunneling of electrons. PMID- 29494138 TI - Competing Hydrogen-Bond Polarities in a Dynamic Oligourea Foldamer: A Molecular Spring Torsion Balance. AB - Symmetrical oligourea foldamers were made from meso cyclohexane-1,2-diamine and desymmetrised by incorporating terminal functional groups (carbamates, ureas or thioureas) with differing hydrogen-bonding capacities. Irrespective of solvent, the foldamers populate a dynamic equilibrium of two alternative screw-sense conformers whose relative population is determined by the competing hydrogen bonding properties of the terminal groups, dictating the foldamer's global hydrogen-bond directionality. Intermolecular association of these dynamic foldamers with achiral anionic guests (acetate or phosphate, but not neutral hydrogen-bonding solvents) leads to inversion of the conformational preference, as strong intermolecular hydrogen bonding induces reorganization of the intramolecular hydrogen-bond network. The foldamers behave as a molecular torsion balance whose conformational preference is governed by competing hydrogen-bond pairing. PMID- 29494137 TI - Interaction of Calmodulin with the cSH2 Domain of the p85 Regulatory Subunit. AB - Calmodulin (CaM) is a calcium sensor protein that directly interacts with the dual-specificity (lipid and protein) kinase PI3Kalpha through the SH2 domains of the p85 regulatory subunit. In adenocarcinomas, the CaM interaction removes the autoinhibition of the p110 catalytic subunit of PI3Kalpha, leading to activation of PI3Kalpha and promoting cell proliferation, survival, and migration. Here we demonstrate that the cSH2 domain of p85alpha engages its two CaM-binding motifs in the interaction with the N- and C-lobes of CaM as well as the flexible central linker, and our nuclear magnetic resonance experiments provide structural details. We show that in response to binding CaM, cSH2 exposes its tryptophan residue at the N-terminal region to the solvent. Because of the flexible nature of both CaM and cSH2, multiple binding modes of the interactions are possible. Binding of CaM to the cSH2 domain can help release the inhibition imposed on the p110 subunit, similar to the binding of the phosphorylated motif of RTK, or phosphorylated CaM (pCaM), to the SH2 domains. Amino acid sequence analysis shows that CaM-binding motifs are common in SH2 domains of non-RTKs. We speculate that CaM can also activate these kinases through similar mechanisms. PMID- 29494140 TI - Effects of Pressure on the Microstructure and Simultaneous Optimization of the Electrical and Thermal Transport Properties of Yb0.5Ba7.5Ga16Ge30. AB - The thermoelectric (TE) properties of n-type polycrystalline Yb0.5Ba7.5Ga16Ge30 bulks can be optimized by high-pressure and high-temperature (HPHT) sintering. After HPHT sintering, abundant nanograins are randomly distributed in the sample. Grains are refined by HPHT, with the grains being smaller with higher pressure. In comparison with the arc-melted sample, the samples obtained by quenching under high pressure possess a great number of nanograins and lattice structural disorders. Lower thermal conductivity is benefited by our deliberately engineered microstructures via HPHT, and the minimum thermal conductivity is 0.86 W m-1 K-1 at 773 K. The thermal conductivity and electrical properties are optimized simultaneously by raising the reactive sintering pressure. In comparison with the arc-melted sample (0.56), a maximum zT value of 1.13 at 773 K is obtained for the Yb0.5Ba7.5Ga16Ge30 sample fabricated at 5 GPa. This demonstrates that HPHT provides an effective strategy to improve TE performance through simultaneously enhancing electrical and thermal transport properties and should be applicable to other thermoelectric materials. PMID- 29494139 TI - Air-Stable In-Plane Anisotropic GeSe2 for Highly Polarization-Sensitive Photodetection in Short Wave Region. AB - In-plane anisotropic layered materials such as black phosphorus (BP) have emerged as an important class of two-dimensional (2D) materials that bring a new dimension to the properties of 2D materials, hence providing a wide range of opportunities for developing conceptually new device applications. However, all of recently reported anisotropic 2D materials are relatively narrow-bandgap semiconductors (<2 eV), and there has been no report about this type of materials with wide bandgap, restricting the relevant applications such as polarization sensitive photodetection in short wave region. Here we present a new member of the family, germanium diselenide (GeSe2) with a wide bandgap of 2.74 eV, and systematically investigate the in-plane anisotropic structural, vibrational, electrical, and optical properties from theory to experiment. Photodetectors based on GeSe2 exhibit a highly polarization-sensitive photoresponse in short wave region due to the optical absorption anisotropy induced by in-plane anisotropy in crystal structure. Furthermore, exfoliated GeSe2 flakes show an outstanding stability in ambient air which originates from the high activation energy of oxygen chemisorption on GeSe2 (2.12 eV) through our theoretical calculations, about three times higher than that of BP (0.71 eV). Such unique in plane anisotropy and wide bandgap, together with high air stability, make GeSe2 a promising candidate for future 2D optoelectronic applications in short wave region. PMID- 29494141 TI - A Hydride-Shuttle Mechanism for the Catalytic Hydroboration of CO2. AB - Herein we report our investigation into the mechanism of CO2 reduction by HBpin catalyzed by [Ru(CO)H(L)(PPh3)2] (2; L is the 4,5-diazafluorenyl ligand with a Bpin functional group at the 9-position) through computational studies using the model complex [Ru(CO)H(L)(PMe3)2] (A1). The reaction consists of four stages: (1) CO2 insertion into the C-B bond of A1 to form A4, (2) the reduction of A4 by HBpin to afford HCOOBpin (P2) and regenerate A1, (3) the reduction of P2 by HBpin to HCHO (P5), and (4) the reduction of P5 to CH3OBpin (P6). We found that Lewis adduct formation plays a key role in all stages of the mechanism, in that it forms more relaxed rings in the key transition states and makes the hydride more hydridic. Oftentimes, the hydride and Bpin moieties can transfer within the Lewis adducts in a concerted manner in our proposed hydride-shuttle mechanism. The energy spans for all stages of our proposed mechanism are within the range of 15.7-22.6 kcal/mol in terms of Gibbs free energy. In contrast, the direct hydroboration and sigma-bond metathesis mechanisms proposed in the literature have extremely high energy barriers because of the highly strained four-membered rings in the transition states and the unactivated hydride in HBpin. PMID- 29494142 TI - Total Synthesis of Hybridaphniphylline B. AB - Hybridaphniphylline B (1) is a Daphniphyllum alkaloid possessing 11 rings and 19 stereocenters. Here we report the first total synthesis of 1 featuring a late stage intermolecular Diels-Alder reaction of a fully elaborated cyclopentadiene and asperuloside tetraacetate. The diene was prepared on the basis of a scalable route to daphnilongeranin B (4). Claisen rearrangement of an allyl dienol ether was exploited as a key step; the subtle variation of the substrate and use of protic solvents suppressed the undesired Cope rearrangement. Daphniyunnine E (6) and dehydrodaphnilongeranin B (7), two congeners of 4, were also synthesized. The dienophile arose from (+)-genipin through glycosylation and lactonization. A one pot protocol was developed for the diene formation and Diels-Alder reaction; one of the cycloadducts was converted into 1 through reductive desulfurization and global deacetylation. PMID- 29494143 TI - GeI-GeI Coupling Reaction Induced by a Mixture of CoBr2 and a Seven-Membered N Heterocyclic Carbene. AB - A new digermylene has been synthesized through the reaction of a six-membered cyclic radical germylene precursor with a mixture of CoBr2 and a seven-membered N heterocyclic carbene. The density functional theory simulation on the geometry of the digermylene agrees well with the experimental X-ray diffraction result. The digermylene possesses the shortest GeI-GeI bond [2.4853(6) A] compared to the known singly bonded analogues, which can be attributed to sigma -> pi* conjugation. In addition, it is revealed that a stable dative bond cannot form for the reductive radical germylene with the oxidative metal centers. PMID- 29494144 TI - Superficial or Substantial: Why Care about Microplastics in the Anthropocene? PMID- 29494145 TI - Isoselective Polymerization of rac-Lactide Catalyzed by Ion-Paired Potassium Amidinate Complexes. AB - Three potassium crown ether complexes supported with bulky amidinate ligands were synthesized for the ring-opening polymerization (ROP) of rac-lactide. The side polymerization reaction initiated directly by ligand anion was suppressed well in the presence of alcohol as our design, and the synthesis of linear polylactide with a molecular weight as high as 117.7 kg/mol was successful together with an isoselectivity value of Pm = 0.88 at -70 degrees C. In this system, lactide can be deprotonated by amidinate anion to give lactide enolate, which can initiate the ROP of lactide as a side reaction in the absence of alcohol; however, this side reaction can also be suppressed well in the presence of alcohol by a decrease in temperature. An interesting anti-Arrhenius-like behavior in the polymerization was discovered, which can be attributed to the fact that the active catalyst can be converted to a less active lactide enolate potassium complex at a high temperature. PMID- 29494146 TI - Effects of Condensed and Hydrolyzable Tannins on Rumen Metabolism with Emphasis on the Biohydrogenation of Unsaturated Fatty Acids. AB - The hypothesis that condensed tannins have higher inhibitory effect on ruminal biohydrogenation than hydrolyzable tannins was tested. Condensed tannin extract from mimosa (CT) and hydrolyzable tannin extract from chestnut (HT) or their mixture (MIX) were incorporated (10%) into oil supplemented diets and fed to rumen fistulated sheep. Fatty acid and dimethyl acetal composition of rumen contents and bacterial biomass were determined. Selected rumen bacteria were analyzed by quantitative real time PCR. Lower ( P < 0.05) rumen volatile fatty acids concentrations were observed with CT compared to HT. Moreover, lower concentration ( P < 0.05) of Fibrobacter succinogenes, Ruminococcus flavefaciens, Ruminococcus albus, and Butyrivibrio proteoclasticus were observed with CT compared to HT. The extension of biohydrogenation of 18:2n-6 and 18:3n-3 did not differ among treatments but was much more variable with CT and MIX than with HT. The trans-/ cis-18:1 ratio in bacterial biomass was higher ( P < 0.05) with HT than CT. Thus, mimosa condensed tannins had a higher inhibitory effect on ruminal metabolism and biohydrogenation than chestnut hydrolyzable tannins. PMID- 29494147 TI - Robotic Surface Analysis Mass Spectrometry (RoSA-MS) of Three-Dimensional Objects. AB - Many technologies currently exist that are capable of analyzing the surface of solid samples under ambient or vacuum conditions, but they are typically limited to smooth, planar surfaces. Those few that can be applied to nonplanar surfaces, however, require manual sampling and a high degree of human intervention. Herein, we describe a new platform, Robotic Surface Analysis Mass Spectrometry (RoSA-MS), for direct surface sampling of three-dimensional (3D) objects. In RoSA-MS, a sampling probe is attached to a robotic arm that has 360 degrees rotation through 6 individual joints. A 3D laser scanner, also attached to the robotic arm, generates a digital map of the sample surface that is used to direct a probe to specific ( x, y, z) locations. The sampling probe consists of a spring-loaded needle that briefly contacts the object surface, collecting trace amounts of material. The probe is then directed at an open port liquid sampling interface coupled to the electrospray ion source of a mass spectrometer. Material on the probe tip is dissolved by the solvent flow in the liquid interface and mass analyzed with high mass resolution and accuracy. The surface of bulky, nonplanar objects can thus be probed to produce chemical maps at the molecular level. Applications demonstrated herein include the examination of food sample surfaces, lifestyle chemistry, and chemical reactions on curved substrates. The modular design of this system also allows for modifications to the sampling probe and the ionization source, thereby expanding the potential of RoSA-MS for a great diversity of applications. PMID- 29494148 TI - Structure-Activity Relationship in Monosaccharide-Based Toll-Like Receptor 4 (TLR4) Antagonists. AB - The structure-activity relationship was investigated in a series of synthetic TLR4 antagonists formed by a glucosamine core linked to two phosphate esters and two linear carbon chains. Molecular modeling showed that the compounds with 10, 12, and 14 carbons chains are associated with higher stabilization of the MD 2/TLR4 antagonist conformation than in the case of the C16 variant. Binding experiments with human MD-2 showed that the C12 and C14 variants have higher affinity than C10, while the C16 variant did not interact with the protein. The molecules, with the exception of the C16 variant, inhibited the LPS-stimulated TLR4 signal in human and murine cells, and the antagonist potency mirrored the MD 2 affinity calculated from in vitro binding experiments. Fourier-transform infrared, nuclear magnetic resonance, and small angle X-ray scattering measurements suggested that the aggregation state in aqueous solution depends on fatty acid chain lengths and that this property can influence TLR4 activity in this series of compounds. PMID- 29494149 TI - Critical Role of Water and Oxygen Defects in C-O Scission during CO2 Reduction on Zn2GeO4(010). AB - Exploration of catalyst structure and environmental sensitivity for C-O bond scission is essential for improving the conversion efficiency because of the inertness of CO2. We performed density functional theory calculations to understand the influence of the properties of adsorbed water and the reciprocal action with oxygen vacancy on the CO2 dissociation mechanism on Zn2GeO4(010). When a perfect surface was hydrated, the introduction of H2O was predicted to promote the scission step by two modes based on its appearance, with the greatest enhancement from dissociative adsorbed H2O. The dissociative H2O lowers the barrier and reaction energy of CO2 dissociation through hydrogen bonding to preactivate the C-O bond and assisted scission via a COOH intermediate. The perfect surface with bidentate-binding H2O was energetically more favorable for CO2 dissociation than the surface with monodentate-binding H2O. Direct dissociation was energetically favored by the former, whereas monodentate H2O facilitated the H-assisted pathway. The defective surface exhibited a higher reactivity for CO2 decomposition than the perfect surface because the generation of oxygen vacancies could disperse the product location. When the defective surface was hydrated, the reciprocal action for vacancy and surface H2O on CO2 dissociation was related to the vacancy type. The presence of H2O substantially decreased the reaction energy for the direct dissociation of CO2 on O2c1- and O3c2-defect surfaces, which converts the endoergic reaction to an exoergic reaction. However, the increased decomposition barrier made the step kinetically unfavorable and reduced the reaction rate. When H2O was present on the O2c2 defect surface, both the barrier and reaction energy for direct dissociation were invariable. This result indicated that the introduction of H2O had little effect on the kinetics and thermodynamics. Moreover, the H-assisted pathway was suppressed on all hydrated defect surfaces. These results provide a theoretical perspective for the design of highly efficient catalysts. PMID- 29494151 TI - Screening in Orbital-Density-Dependent Functionals. AB - Electronic-structure functionals that include screening effects, such as Hubbard or Koopmans' functionals, are required to describe the response of a system to the fractional addition or removal of an electron from an orbital or a manifold. Here, we present a general method to incorporate screening based on linear response theory, and we apply it to the case of orbital-by-orbital screening of Koopmans' functionals. We illustrate the importance of such generalization when dealing with challenging systems containing orbitals with very different chemical character, also highlighting the simple dependence of the screening on the localization of the orbitals. We choose a set of 46 transition-metal complexes for which experimental data and accurate many-body perturbation theory calculations are available. When compared to experiment, results for ionization potentials show a very good performance, with a mean absolute error of 0.2 eV, comparable to the most accurate many-body perturbation theory approaches. These results reiterate the role of Koopmans-compliant functionals as simple and accurate quasiparticle approximations to the exact spectral functional, bypassing diagrammatic expansions and relying only on the physics of the local density or generalized-gradient approximation. PMID- 29494150 TI - Circulating Microvesicles from Pancreatic Cancer Accelerate the Migration and Proliferation of PANC-1 Cells. AB - Circulating microvesicles are able to mediate long-distance cell-cell communications. It is essential to understand how microvesicles from pancreatic cancer act on other cells in the body. In this work, serum-derived microvesicles were isolated from 10 patients with locally advanced pancreatic cancer and healthy controls. Using Cell Transwell and WST-1 reagents, we found that microvesicles from pancreatic cancer accelerated migration and proliferation of PANC-1 cells. Meanwhile, the proliferation of these cancer-microvesicle-treated cells (CMTCs) was affected less by 10 MUM of gemcitabine relative to healthy microvesicle-treated cells (HMTCs). Next, we optimized the filter-aided sample preparation method to increase the recovery of protein samples and then applied it to the quantification of the proteome of CMTCs and HMTCs. The peptides were labeled and analyzed by liquid chromatography-tandem mass spectrometry. In total, 4102 proteins were identified, where 35 proteins were up-regulated with 27 down regulated in CMTCs. We verified the quantitative results of three key proteins CD44, PPP2R1A, and TP53 by Western blot. The Ingenuity Pathway Analysis revealed pathways that cancer microvesicles might participate in to promote cell migration and proliferation. These findings may provide novel clues of treatment for tumorigenesis and metastasis. PMID- 29494152 TI - Catalyst-Free Ring Opening of Spiroaziridine Oxindoles by Heteronucleophiles: An Approach to the Synthesis of Enantiopure 3-Substituted Oxindoles. AB - A simple catalyst-free method was developed for the ring opening of spiroaziridine oxindoles by three different nucleophiles, namely, amines, thiols, and methanol, to produce enantiopure (up to 99%) vicinal diaminooxindoles, beta aminosulfides, and beta-amino-3-methoxyoxindole, respectively, in good to excellent yields. In contrast to the spiroepoxides, spiroaziridines are opened regio- and stereospecifically through the pseudobenzylic spirocenter under catalyst-free conditions. Moreover, unlike simple 2-substituted aziridines, these spiroaziridines are opened up with retention in configuration at the C3 spirocenter. PMID- 29494154 TI - First-Principle Molecular Dynamics Investigation of Waterborne As-V Species. AB - The toxicity, mobility, and geochemical behaviors of arsenic are known to vary enormously with its speciation and oxidation states. The present work details results on the basis of ab initio molecular dynamics analysis of various waterborne As-V species, namely, H3AsO4, H2AsO4-, HAsO42-, and AsO43-. The nature of hydrogen bonding of these species with water and its influence on the solvent structure and relaxation behavior are discussed. Useful microscopic insights on the structural and spectroscopic signatures of the species in aqueous media are reported. Comparison of normal-mode frequencies of the species in gas phases to the vibrational density of states in solution provides insights on the influences of solvation and H bonding. The results are compared with the previous experimental and simulation studies, where available. PMID- 29494153 TI - Correction to "Contact Angle of Sessile Drops in Lennard-Jones Systems". PMID- 29494155 TI - Projection-Based Correlated Wave Function in Density Functional Theory Embedding for Periodic Systems. AB - We present a level shift projection operator-based embedding method for systems with periodic boundary conditions-where the "active" subsystem can be described using either density functional theory (DFT) or correlated wave function (WF) methods and the "environment" is described using DFT. Our method allows for k point sampling, is shown to be exactly equal to the canonical DFT solution of the full system under the limit that we use the full system basis to describe each subsystem, and can treat the active subsystem either with periodic boundary conditions-in what we term "periodic-in-periodic" embedding-or as a molecular cluster-in "cluster-in-periodic" embedding. We explore each of these methods and show that cluster WF-in-periodic DFT embedding can accurately calculate the absorption energy of CO on to a Si(100)-2*1 surface. PMID- 29494156 TI - Hemisynthesis of 2,3,4-13C3-1,4-Androstadien-3,17-dione: A Key Precursor for the Synthesis of 13C3-Androstanes and 13C3-Estranes. AB - In this contribution, we describe two simple and efficient routes for the preparation of keto-aldehyde 1, a key intermediate for the synthesis of 13C3 androstanes and 13C3-estranes. In the first route, the targeted aldehyde 1 was obtained in 40% overall yield from 1,4-androstadien-3,17-dione (3 mmol scale) via a two-step sequence involving a one-pot, abnormal ozonolysis/sulfur oxidation/retro-Michael/ozonolysis process. Alternatively, a second route from 4 androsten-3,17-dione, using a six-step sequence, was optimized to produce 40 mmol batches of the key intermediate 1 in 42% overall yield. At the final stage, the A ring was reconstructed through a Wittig reaction with the 1 triphenylphosphoranylidene-13C3-2-propanone 2, followed by an intramolecular condensation assisted by thioacetic acid via a Michael addition/retro-Michael reaction sequence to provide 2,3,4-13C3-1,4-androstadien-3,17-dione. PMID- 29494157 TI - Synthesis and Structure of Functionalized Homo Heteracalix[2]arene[2]triazines: Effect of All Heteroatom Bridges on Macrocyclic Conformation. AB - A number of unprecedented homo heteracalix[2]arene[2]triazines were synthesized by means of a fragment coupling approach. Two directional nucleophilic substitution reactions of N-Boc-protected 1,3-dihydrazobenzene with cyanuric acid chloride and 2-butoxy-4,6-dichloro-1,3,5-triazine led to hydrazo-linked trimers, which underwent an efficient macrocyclic condensation reaction with functionalized resorcinol derivatives to afford (NHNBoc)2,O2 calix[2]arene[2]triazine macrocycles, which contain a functional group either on the upper rim or the lower rim. The use of 1,3-phenylenediamines instead of resorcinol in the reaction produced (NR)2,(NHNBoc)2-calix[2]arene[2]triazines. Postmacrocyclization modifications such as a nucleophilic substitution reaction of chloro on triazine by amines and the removal of Boc from hydrazo moieties produced homo calix[2]arene[2]triazine derivatives. In the solid state, (NHNR)2,O2-bridged calix[2]arene[2]triazines with and without a substituent on the upper rim position and (NMe)2,(NHNBoc)2-calix[2]arene[2]triazine adopted a typical partial cone conformation while the heavily twisted 1,3-alternate conformational structures were observed for both (NHNBoc)2,O2 calix[2]arene[2]triazines bearing a functional group on the lower rim position and (NH)2,(NHNBoc)2-calix[2]arene[2]triazine. In solution, all synthesized homo heteracalix[2]arene[2]triazines existed as the mixture of different macrocyclic conformers, which underwent slow interconversions at room temperature relative to the NMR time scale. PMID- 29494158 TI - Selenolactams as Synthetic Intermediates for the Synthesis of Polycyclic Amines via Seleno-Claisen Rearrangements. AB - A highly diastereoselective alpha-allylation of selenolactams with allyl halides is reported. DFT analyses and experimental observations suggested that this reaction proceeds via a Se-allylation of the eneselenolates of the lactams followed by a seleno-Claisen rearrangement. The thus-obtained products could be efficiently transformed into polycyclic amines using a previously developed sequential addition of organometallic reagents and ring-closing metathesis. PMID- 29494159 TI - Extraction Optimization and Structural and Thermal Characterization of the Antimicrobial Abietane 7alpha-Acetoxy-6beta-hydroxyroyleanone. AB - The abietane 7alpha-acetoxy-6beta-hydroxyroyleanone (AHR), obtained from plant extracts, is an attractive lead for drug development, given its known antimicrobial properties. Two basic requirements to establish any compound as a new drug are the development of a convenient extraction process and the characterization of its structural and thermal properties. In this work seven different methods were tested to optimize the extraction of AHR from Plectranthus grandidentatus. Supercritical fluid extraction (SFE) proved to be the method of choice, delivering an amount of AHR (57.351 MUg.mg-1) approximately six times higher than the second best method (maceration in acetone; 9.77 MUg.mg-1). Single crystal X-ray diffraction analysis of the ARH molecular and crystal structure carried out at 167 +/- 2 K and 296 +/- 2 K showed only a single phase, here dubbed form III (orthorhombic space group P21212), at those temperatures. The presence of two other polymorphs above room temperature was, however, evidenced by differential scanning calorimetry (DSC). The three forms are enantiotropically related, with the form III -> form II and form II -> form I transitions occurring at 333.5 +/- 1.6 K and 352.0 +/- 1.6 K, respectively. The fact that the transitions are reversible suggests that polymorphism is not likely to be an issue in the development pharmaceutical formulations based on ARH. DSC experiments also showed that the compound decomposes on melting at 500.8 +/- 0.8 K. Melting should therefore be avoided if, for example, strategies to improve solubility based on the production of glassy materials or solid dispersions are considered. PMID- 29494160 TI - Quantum Optics with Near-Lifetime-Limited Quantum-Dot Transitions in a Nanophotonic Waveguide. AB - Establishing a highly efficient photon-emitter interface where the intrinsic linewidth broadening is limited solely by spontaneous emission is a key step in quantum optics. It opens a pathway to coherent light-matter interaction for, e.g., the generation of highly indistinguishable photons, few-photon optical nonlinearities, and photon-emitter quantum gates. However, residual broadening mechanisms are ubiquitous and need to be combated. For solid-state emitters charge and nuclear spin noise are of importance, and the influence of photonic nanostructures on the broadening has not been clarified. We present near-lifetime limited linewidths for quantum dots embedded in nanophotonic waveguides through a resonant transmission experiment. It is found that the scattering of single photons from the quantum dot can be obtained with an extinction of 66 +/- 4%, which is limited by the coupling of the quantum dot to the nanostructure rather than the linewidth broadening. This is obtained by embedding the quantum dot in an electrically contacted nanophotonic membrane. A clear pathway to obtaining even larger single-photon extinction is laid out; i.e., the approach enables a fully deterministic and coherent photon-emitter interface in the solid state that is operated at optical frequencies. PMID- 29494162 TI - Deactivation of Zeolite Catalyst H-ZSM-5 during Conversion of Methanol to Gasoline: Operando Time- and Space-Resolved X-ray Diffraction. AB - The deactivation of zeolite catalyst H-ZSM-5 by coking during the conversion of methanol to hydrocarbons was monitored by high-energy space- and time-resolved operando X-ray diffraction (XRD) . Space resolution was achieved by continuous scanning along the axial length of a capillary fixed bed reactor with a time resolution of 10 s per scan. Using real structural parameters obtained from XRD, we can track the development of coke at different points in the reactor and link this to a kinetic model to correlate catalyst deactivation with structural changes occurring in the material. The "burning cigar" model of catalyst bed deactivation is directly observed in real time. PMID- 29494161 TI - Potent and Selective Inhibitors of Human Sirtuin 5. AB - Sirtuins are protein deacylases that regulate metabolism and stress responses and are implicated in aging-related diseases. Modulators of the human sirtuins Sirt1 7 are sought as chemical tools and potential therapeutics, e.g., for cancer. Selective and potent inhibitors are available for Sirt2, but selective inhibitors for Sirt5 with Ki values in the low nanomolar range are lacking. We synthesized and screened 3-arylthiosuccinylated and 3-benzylthiosuccinylated peptide derivatives yielding Sirt5 inhibitors with low-nanomolar Ki values. A biotinylated derivative with this scaffold represents an affinity probe for human Sirt5 that is able to selectively extract this enzyme out of complex biological samples like cell lysates. Crystal structures of Sirt5/inhibitor complexes reveal that the compounds bind in an unexpected manner to the active site of Sirt5. PMID- 29494163 TI - Radical C-H Arylation of Oxazoles with Aryl Iodides: dppf as an Electron-Transfer Mediator for Cs2CO3. AB - A radical C-H arylation reaction of oxazoles with (hetero)aryl iodides using Cs2CO3 as base/electron donor and 1,1'-bis(diphenylphosphino) ferrocene (dppf) as a catalytic SET mediator is reported. The overall reaction likely follows the general base-promoted homolytic aromatic substitution mechanism through a radical chain pathway. DFT calculations suggest that dppf forms a complex with CsCO3-, enhancing its SET reducing ability to generate an aryl radical from ArI. PMID- 29494165 TI - Cascade and Effective Syntheses of Functionalized Tellurophenes. AB - A one-pot and transition-metal-catalyst-free synthetic strategy to construct functionalized tellurophenes has been developed. Substituted 1,1-dibromo-1-en-3 ynes are smoothly converted to tellurophenes with telluride salts in high yield via a series of cascade reactions through reductive debromination, hydrotelluration, nucleophilic cyclization, and aromatization. Close inspection of the results clearly showed that the reactivity of in situ prepared telluride salts are significantly influenced by the polarity of the solvent system and the electronic nature of the substituent on the enyne substrate. This method reports the first direct synthesis of 3-aryltellurophenes in high yields at room temperature. This novel reaction strategy is also found to be a promising synthetic method for multisubstituted tellurophenes and selenophenes. PMID- 29494164 TI - Theoretical Study of Infrared Spectra of OCS-( pH2)2, OCS-( oD2)2, OCS-(HD)2, and Mixed OCS- pH2-He Trimers. AB - The calculated rovibrational energy levels and infrared spectra for OCS-( pH2)2, OCS-( oD2)2, OCS-(HD)2 and mixed OCS- pH2-He trimers are obtained by performing the exact basis-set calculations for the first time based on the newly developed potential energy surfaces ( J. Chem. Phys. 2017, 147, 044313). The "adiabatic hindered-rotor" (AHR) method is used for reduced-dimension treatment of the hydrogen rotation. The predicted band origin shifts and the infrared spectra are in good agreement with the available experimental values: for the band origin shifts and infrared transitions, the root-mean-square(rms) deviations are smaller than 0.044 and 0.002 cm-1, respectively. We extend the assignments to the unrecorded infrared transitions for OCS-( pH2)2 and OCS-(HD)2 complexes and identify the infrared spectra for OCS-( oD2)2 and OCS- pH2-He for the first time. Three-dimensional density distributions for the ground states of OCS-( pH2)2, OCS pH2-He, and OCS-(He)2 show that the pH2 molecules are localized in their corresponding global minimum regions, while the pronounced locations of the He atoms are missing in OCS- pH2-He and OCS-(He)2 with forming incomplete circles around the OCS axis. A clear tunneling splitting is observed for the torsional motion of the two hydrogen molecules ( pH2, HD, or oD2) on a ring about the OCS molecular axis, whereas no tunneling splitting is found in OCS- pH2-He or OCS (He)2 due to a much lower torsional barrier. PMID- 29494166 TI - A Maze of Dyotropic Rearrangements and Triple Shifts: Carbocation Rearrangements Connecting Stemarene, Stemodene, Betaerdene, Aphidicolene, and Scopadulanol. AB - Results of quantum chemical investigations shed new light on the mechanisms of formation of the stemarene, stemodene, betaerdene, aphidicolene, and scopadulanol diterpenes from syn-copalyl diphosphate ( syn-CPP). These terpenes are shown to be connected by a complex network of reaction pathways involving concerted but asynchronous dyotropic rearrangements and triple shift rearrangements. The interconnection of these pathways leads to multiple routes for formation of each diterpene, which could lead to different origins for some carbon atoms in a given diterpenes under different conditions. PMID- 29494167 TI - Suppressing Dendritic Lithium Formation Using Porous Media in Lithium Metal-Based Batteries. AB - Because of its ultrahigh specific capacity, lithium metal holds great promise for revolutionizing current rechargeable battery technologies. Nevertheless, the unavoidable formation of dendritic Li, as well as the resulting safety hazards and poor cycling stability, have significantly hindered its practical applications. A mainstream strategy to solve this problem is introducing porous media, such as solid electrolytes, modified separators, or artificial protection layers, to block Li dendrite penetration. However, the scientific foundation of this strategy has not yet been elucidated. Herein, using experiments and simulation we analyze the role of the porous media in suppressing dendritic Li growth and probe the underlying fundamental mechanisms. It is found that the tortuous pores of the porous media, which drastically reduce the local flux of Li+ moving toward the anode and effectively extend the physical path of dendrite growth, are the key to achieving the nondendritic Li growth. On the basis of the theoretical exploration, we synthesize a novel porous silicon nitride submicron wire membrane and incorporate it in both half-cell and full-cell configurations. The operation time of the battery cells is significantly extended without a short circuit. The findings lay the foundation to use a porous medium for achieving nondendritic Li growth in Li metal-based batteries. PMID- 29494168 TI - Inter- and intra-mouse variability in odor preferences revealed in an olfactory multiple-choice test. AB - Animals choose between sensory stimuli, a highly complex behavior which includes detection, discrimination, preference, and memory processes. Rodents are reported to display robust preferences for some odors, for instance, in the context of choosing among possible mates or food items. In contrast to the apparent robustness of responses toward these and other "ethologically relevant" odors, little is known about the robustness of behaviors toward odors which have no overt role in the rodent ecological niche, so-called "nonethologically relevant" odors. We developed an apparatus for monitoring the nose-poking behavior of mice and used this apparatus to explore the prevalence and stability of choices among different odors both across mice, and within mice over successive days. Mice were tested with a panel of either ethologically relevant or nonethologically relevant odors in an olfactory multiple-choice test. Significant preferences to nonethologically relevant odors were observed across the population of mice, with longer investigation durations to some odors more than to others. However, we found substantial inter-mouse variability in these responses, and that responses to these odors even varied within mice across days of testing. Tests with ethologically relevant odors revealed that responses toward these odors were also variable across mice, but within individual mice, responses were somewhat stable. This work establishes an olfactory multiple-choice test for monitoring odor investigation, choice, and preference behaviors and the application of this apparatus to assess across- and within-mouse odor-preference choice stability. These results highlight that odor preferences, as assayed by measuring choice behaviors, are variable. (PsycINFO Database Record PMID- 29494169 TI - Attachment-security prime effect on skin-conductance synchronization in psychotherapists: An empirical study. AB - Physiological synchronization (PS) is a phenomenon of simultaneous activity between two persons' physiological signals. It has been associated with empathy, shared affectivity, and efficacious therapeutic relationships. The aim of the present study was to explore the possible connections between PS and the attachment system, seeking preliminary evidence of this link by means of an experimental manipulation of the sense of attachment security in psychotherapists according to a protocol by Mikulincer and Shaver (2001), which has been proven to elicit empathetic behavior. We compared the synchronization of skin-conductance signals in brief psychological interviews between 18 psychodynamic therapists and 18 healthy volunteers. A sense of attachment-security priming was administered to half of the therapists, whereas the other half received a positive-affect control prime. Lag analysis was performed to investigate the "leading" or "following" attitudes of the participants in the two conditions. Mixed-model regressions and evidence-ratio model comparisons were used to investigate the effects of the manipulation on PS. Therapist attachment anxiety and avoidance traits were considered covariates. The attachment-security prime showed a significant effect on PS lag dynamics, but not on overall PS amount. Lag analysis showed that the therapists in the attachment-security condition were significantly more prone to assume a leading attitude in the physiological coupling than the therapists in the control condition. Therapist attachment anxiety and avoidance had no apparent effect. Our result paves the way for further exploration of the clinical relationship from a physiological standpoint. (PsycINFO Database Record PMID- 29494170 TI - Bi-national cross-validation of an evidence-based conduct problem prevention model. AB - OBJECTIVES: To (a) explore the preferences of Mexican parents and Spanish speaking professionals working with migrant Latino families in Minnesota regarding the Mexican-adapted brief model versus the original conduct problems intervention and (b) identifying the potential challenges, and preferred solutions, to implementation of a conduct problems preventive intervention. METHOD: The core practice elements of a conduct problems prevention program originating in the United States were adapted for prevention efforts in Mexico. Three focus groups were conducted in the United States, with Latino parents (n = 24; 2 focus groups) and professionals serving Latino families (n = 9; 1 focus group), to compare and discuss the Mexican-adapted model and the original conduct problems prevention program. Thematic analysis was conducted on the verbatim focus group transcripts in the original language spoken. RESULTS: Participants preferred the Mexican-adapted model. The following key areas were identified for cultural adaptation when delivering a conduct problems prevention program with Latino families: recruitment/enrollment strategies, program delivery format, and program content (i.e., child skills training, parent skills training, child parent activities, and child-parent support). For both models, strengths, concerns, barriers, and strategies for overcoming concerns and barriers were identified. CONCLUSIONS: We summarize recommendations offered by participants to strengthen the effective implementation of a conduct problems prevention model with Latino families in the United States. This project demonstrates the strength in binational collaboration to critically examine cultural adaptations of evidence-based prevention programs that could be useful to diverse communities, families, and youth in other settings. (PsycINFO Database Record PMID- 29494171 TI - Implications of research staff demographics for psychological science. AB - Long-standing research traditions in psychology have established the fundamental impact of social categories, such as race and gender, on people's perceptions of themselves and others, as well as on general human cognition and behavior. However, there is a general tendency to ignore research staff demographics (e.g., researchers' race and gender) in research development and research reports. Variation in research staff demographics can exert systematic and scientifically informative influences on results from psychological research. Consequently, research staff demographics need to be considered, studied, and/or reported, along with how these demographics were allowed to vary across participants or conditions (e.g., random assignment, matched with participant demographics, or included as a factor in the experimental design). In addition to providing an overview of multidisciplinary evidence of research staff demographics effects, it is discussed how research staff demographics might influence research findings through (a) ingroup versus outgroup effects, (b) stereotype and (implicit) bias effects, and (c) priming and social tuning effects. Finally, an overview of recommended considerations is included (see Appendix) to help illustrate how to systematically incorporate relevant research staff demographics in psychological science. (PsycINFO Database Record PMID- 29494173 TI - Age-related differences in associative memory: Empirical evidence and theoretical perspectives. AB - Systematic research and anecdotal evidence both indicate declines in episodic memory in older adults in good health without dementia-related disorders. Several hypotheses have been proposed to explain these age-related changes in episodic memory, some of which attribute such declines to a deterioration in associative memory. The current special issue of Psychology and Aging on Age-Related Differences in Associative Memory includes 16 articles by top researchers in the area of memory and aging. Their contributions provide a wealth of empirical work that addresses different aspects of aging and associative memory, including different mediators and predictors of age-related declines in binding and associative memory, cognitive, noncognitive, genetic, and neuro-related ones. The contributions also address the processing phases where these declines manifest themselves and look at ways to ameliorate these age-related declines. Furthermore, the contributions in this issue draw on different theoretical perspectives to explain age-related changes in associative memory and provide a wealth of varying methodologies to assess older and younger adults' performance. Finally, although most of the studies focus on normative/healthy aging, some of them contain insights that are potentially applicable to disorders and pathologies. (PsycINFO Database Record PMID- 29494174 TI - Effects of time of day on age-related associative deficits. AB - Time of day is known to influence cognition differently across age groups, with young adults performing better later than earlier in the day and older adults showing the opposite pattern. Thus age-related deficits can be smaller when testing occurs in the morning compared with the afternoon/evening, particularly for tasks requiring executive/controlled/inhibitory processes. Stronger influences of time of day were therefore predicted on associative than on item recognition memory based on their differential requirements for demanding recollective (rather than familiarity) processes. In 2 experiments, participants were presented with unrelated word pairs and then tested on both item recognition (old/new item?) and associative recognition (intact/recombined pair?). In Experiment 1, young adults were tested either in the morning or in the evening; recognition memory was better when time of testing matched participants' morningness-eveningness preferences, and more so for associative than for item memory. In Experiment 2, young and older adults (evening and morning types, respectively) were tested both in the morning and in the evening; again, recognition memory was better at participants' preferred times of day, especially for associative memory. Consequently, age-related associative deficits varied considerably-indeed more than fourfold-from a nonsignificant 8% for testing in the morning to a substantial 35% for testing in the evening, suggesting that it is important to consider time of day effects in future studies of the associative deficit hypothesis. (PsycINFO Database Record PMID- 29494172 TI - Memory creation and modification: Enhancing the treatment of psychological disorders. AB - Modification of the ongoing influence of maladaptive cognitive, emotional, and behavioral patterns is a fundamental feature of many psychological treatments. Accordingly, a clear understanding of the nature of memory adaptation and accommodation to therapeutic learning becomes an important issue for (1) understanding the impact of clinical interventions, and (2) considering innovations in treatment strategies. In this article, we consider advances in the conceptualization of memory processes and memory modification research relative to clinical treatment. We review basic research on the formation of memories, the way in which new learning is integrated within memory structures, and strategies to influence the nature and degree to which new learning is integrated. We then discuss cognitive/behavioral and pharmacological strategies for influencing memory formation in relation to disorder prevention or treatment. Our goal is to foster awareness of current strategies for enhancing therapeutic learning and to encourage research on potential new avenues for memory enhancement in service of the treatment of mental health disorders. (PsycINFO Database Record PMID- 29494175 TI - The effects of stereotype threat on the associative memory deficit of older adults. AB - The purpose of the current study was to assess whether the age-related associative memory deficit is affected by stereotype threat, which has been shown to negatively affect performance on a wide variety of cognitive tasks, including memory performance of older adults. To date, the effects of stereotype threat on older adults' memory performance have only been shown using tests of item memory, and using only between-subjects manipulations. The first experiment manipulated stereotype threat by providing younger and older adults with either stereotype consistent (threat condition) or stereotype inconsistent (nonthreat condition) information before studying lists of item pairs and being tested for both item and associative memory. The results revealed a triple interaction of Age * Test * Condition (a strong associative memory deficit in the threat condition that disappeared in the nonthreat condition), and this pattern of results was found both between- and within-subjects. A follow-up control experiment also yielded an age-related associative deficit, suggesting that stereotype threat may be activated even under normal testing conditions. These results imply that stereotype threat could affect older adults' associative memory, and that one effective strategy to reduce the associative deficit of older adults is to reverse negative stereotypes that exist. (PsycINFO Database Record PMID- 29494176 TI - Memory for important item-location associations in younger and older adults. AB - Older adults typically experience memory impairments for verbal and visuospatial episodic information, which are most pronounced for associative information. Although some age-related verbal memory deficits may be reduced by selectively focusing on high-value item information, the binding of items to locations in visuospatial memory involves different processes that are impaired in older adults. In the current study, we examined whether age-related impairment in visuospatial binding could be alleviated by strategic focus on important information and whether varying study time and presentation formats would affect such selectivity. We also used novel spatial resolutions analysis to examine participants' gist-based visuospatial memory with respect to information importance. Younger and older adults were presented with items worth different point values in a visuospatial display, either sequentially (Experiment 1) or simultaneously (Experiment 2). When items were presented sequentially, participants became more selective with task experience, but when items were presented simultaneously, selectivity was maintained throughout the task. These patterns were also observed when encoding time was reduced for younger adults. Although older adults successfully engaged in value-based memory strategies, age related visuospatial memory deficits were still present, even for high-value information, consistent with the associative deficit hypothesis. However, under some conditions, older adults showed reduced spatial relocation errors for high value item-location associations. The results suggest that strategic control can be used when binding information in visuospatial memory, and that both younger and older adults can benefit by focusing on high-value items and their locations, despite associative memory deficits present in old age. (PsycINFO Database Record PMID- 29494177 TI - The effects of value on context-item associative memory in younger and older adults. AB - Valuable items are often remembered better than items that are less valuable by both older and younger adults, but older adults typically show deficits in binding. Here, we examine whether value affects the quality of recognition memory and the binding of incidental details to valuable items. In Experiment 1, participants learned English words each associated with a point-value they earned for correct recognition with the goal of maximizing their score. In Experiment 2, value was manipulated by presenting items that were either congruent or incongruent with an imagined state of physiological need (e.g., hunger). In Experiment 1, point-value was associated with enhanced recollection in both age groups. Memory for the color associated with the word was in fact reduced for high-value recollected items compared with low-value recollected items, suggesting value selectively enhances binding of task-relevant details. In Experiment 2, memory for learned images was enhanced by value in both age groups. However, value differentially enhanced binding of an imagined context to the item in younger and older adults, with a strong trend for increased binding in younger adults only. These findings suggest that value enhances episodic encoding in both older and younger adults but that binding of associated details may be reduced for valuable items compared to less valuable items, particularly in older adults. (PsycINFO Database Record PMID- 29494178 TI - Effects of changes in schematic support and of item repetition on age-related associative memory deficits: Theoretically-driven empirical attempts to reduce older adults' high false alarm rate. AB - Older adults seem to have a special difficulty binding components of their episodic memories to each other and retrieving these bound units. This phenomenon, known as the age-related associative memory deficit, is partially driven by high false alarm rates in the associative test. The current research examines whether 2 factors: (a) manipulations of changes of schematic support between study and test (potentially affecting recollection) and (b) item repetition (potentially affecting item familiarity) might decrease older adults' false alarm rate, thereby resulting in a smaller associative memory deficit. Younger and older adults were tested for their item and associative recognition memory after viewing product-price pairs (Experiment 1) and face-name pairs (Experiment 2). In Experiment 1, products were paired with either an underestimated price, a market-value price, or an overestimated price, with the match or mismatch in the product-price relationships between study and test serving as the manipulation of schematic information. In Experiment 2, schematic information was manipulated by the match of the age of the face (young or old) appearing with a given name between study and test. Item familiarity was manipulated by having a preexposure phase of the item components in both experiments. Results indicated that low item familiarity (Experiment 2), which potentially reduces the familiarity of a given pair, and mismatch in schematic knowledge between study and test (Experiments 1 and 2), increase older adults' ability to reject recombined item-price and face-name pairs at retrieval, resulting in a reduced associative memory deficit. (PsycINFO Database Record PMID- 29494179 TI - Age differences in memory for meaningful and arbitrary associations: A memory retrieval account. AB - Older adults typically show poor associative memory performance relative to younger adults. This age-related effect, however, is mediated by the meaningfulness of the materials used, such that age differences are minimized with the use of information that is consistent with prior knowledge. While this effect has been interpreted as facilitative learning through schematic support, the role of memory retrieval on this effect has yet to be explored. Using an associative memory paradigm that varied the extent of controlled retrieval for previously studied meaningful or arbitrary associations, older and younger adults in the present study retrieved realistic and unrealistic grocery item prices in a speeded, or in a slow, more control-based retrieval condition. There were no age differences in memory for realistic (meaningful) prices in either condition; however, younger adults showed better memory than older adults for unrealistic prices in the controlled retrieval condition only. These results suggest that age differences in memory for arbitrary associations can, at least partly, be accounted for by age reductions in strategic, controlled retrieval. (PsycINFO Database Record PMID- 29494180 TI - Older adults' associative memory is modified by manner of presentation at encoding and retrieval. AB - Relative to young adults, older adults typically exhibit a reduced ability to accurately remember associations between stimuli. Prior research has assumed that this age-related memory impairment affects different types of associations similarly. However, research in young adults has suggested that item-item and item-context associations are supported by different underlying neural mechanisms that could be unequally affected by aging. This experiment compared memory across association types in younger and older adults by presenting the same types of stimuli as either item-item or item-context pairs. Manner of presentation during retrieval was also manipulated so that pairs were presented in a manner that was either congruent or incongruent with their presentation during encoding. Older adults showed a particular benefit of encoding-retrieval congruency for item context associations, supporting the idea that the associative deficit may be reduced by unitization at encoding and reinstatement of this prior stimulus configuration at retrieval. (PsycINFO Database Record PMID- 29494181 TI - Repetition lag training eliminates age-related recollection deficits (and gains are maintained after three months) but does not transfer: Implications for the fractionation of recollection. AB - The objectives of this study were to replicate age-related decrements in recollection and source memory, and to determine if repetition lag training improves recollection and whether these effects maintain and transfer to other tasks. Sixteen young adults and 46 healthy older adults participated, the latter of whom comprised hi-old (n = 16) and lo-old (n = 30) based on neuropsychological memory tests. All participants completed memory tests and questionnaires at baseline, and then half of the lo-old underwent nine days of repetition lag training while the other half engaged in a 9-day active control program. The memory tests and questionnaires were repeated immediately after the training or control program, and again three months later. The baseline data replicated well established age-related decrements in recollection. Repetition lag training improved objective measures of recollection, eliminated the age-related recollection decrement, and these improvements maintained over three months. However, training did not transfer to any other objective test of memory thought to rely on recollection, or to any subjective memory measure. The results demonstrate for the first time that repetition lag training improves objective measures of recollection, eliminates recollection differences between younger and older adults, and that these gains maintain over a 3-month period posttraining. The lack of transfer to other tasks, however, indicates that training one type of recollection (for the studied modality in this case) does not affect other types of recollection (e.g., of an item's recency). We suggest that recollection can be fractionated into many distinct types. (PsycINFO Database Record PMID- 29494183 TI - Age differences in false memory: The importance of retrieval monitoring processes and their modulation by memory quality. AB - Older adults are more likely than younger adults to falsely recall past episodes that occurred differently or not at all. We examined whether older adults' propensity for false associative memory is related to declines in postretrieval monitoring processes and their modulation with varying memory representations. Younger (N = 20) and older adults (N = 32) studied and relearned unrelated scene word pairs, followed by a final cued recall that was used to distribute the pairs for an associative recognition test 24 hours later. This procedure allowed individualized formation of rearranged pairs that were made up of elements of pairs that were correctly recalled in the final cued recall ("high-quality" pairs), and of pairs that were not correctly recalled ("low-quality" pairs). Both age groups falsely recognized more low-quality than high-quality rearranged pairs, with a less pronounced reduction in false alarms to high-quality pairs in older adults. In younger adults, cingulo-opercular activity was enhanced for false alarms and for low-quality correct rejections, consistent with its role in postretrieval monitoring. Older adults did not show such modulated recruitment, suggesting deficits in their selective engagement of monitoring processes given variability in the fidelity of memory representations. There were no age differences in hippocampal activity, which was higher for high-quality than low quality correct rejections in both age groups. These results demonstrate that the engagement of cingulo-opercular monitoring mechanisms varies with memory representation quality and contributes to age-related deficits in false associative memory. (PsycINFO Database Record PMID- 29494182 TI - Association between subjective memory assessment and associative memory performance: Role of ad risk factors. AB - Decline in associative memory abilities is a common cognitive complaint among older adults and is detectable in both normal aging and in prodromal Alzheimer's disease (AD). Subjective memory (SM) complaints may serve as an earlier marker of these mnemonic changes; however, previous research examining the predictive utility of SM to observed memory performance yielded inconsistent results. This inconsistency is likely due to other sources of variance that occur with memory decline such as mood/depression issues, presence of apolipoprotein E (APOE epsilon4) genotype, or beta-amyloid deposition. Here we examine the relationship between SM and associative memory ability in the context of factors that increase susceptibility to AD in 195 healthy adults (79 men) aged 20-94 years. Participants completed an SM questionnaire, a mood/depression scale, two associative memory tests (a word-pair and a name-face test), and were genotyped for APOE epsilon4. PET-amyloid imaging data were collected for a subset of those over 50 years of age (N = 74). We found that SM predicted performance on both associative memory tests even after covarying for age, sex, mood, and APOE epsilon4 status. Interestingly, for the name-face associative task, increased SM concerns predicted memory performance selectively in participants over the age of 60, with the APOEepsilon4 risk group showing the strongest effect. Finally, men with higher beta-amyloid deposition reported more memory complaints. Our findings suggest that SM reliably tracks memory performance, even in cognitively healthy adults, and may reflect an increased risk for AD. (PsycINFO Database Record PMID- 29494184 TI - Flexible retrieval mechanisms supporting successful inference produce false memories in younger but not older adults. AB - Episodic memory involves flexible retrieval processes that allow a person to link elements of distinct episodes in order to make novel inferences across events. In younger adults, we recently found that the same retrieval-related recombination mechanism that supports successful associative inference produces source misattributions as a consequence of erroneous binding of contextual elements from distinct episodes. In the current experiment, we found that older adults, in contrast to younger adults, did not show an increase in source misattributions following successful associative inference. We observed this pattern both when (a) younger and older adults were tested under identical experimental conditions and (b) younger and older adults were matched on associative inference accuracy and overall source memory errors. We suggest that the differing patterns of results are a consequence of age-related deficits in associative binding during successful inferential retrieval. (PsycINFO Database Record PMID- 29494185 TI - Age differences in episodic associative learning. AB - Compared with young adults, older adults demonstrate difficulty forming and retrieving episodic memories. One proposed mechanism is that older adults are impaired at binding information into nonoverlapping representations, which is a key function of the hippocampus. The current experiments evaluate age differences in acquiring new memories using a novel episodic associative learning (EAL) task designed to tap hippocampal-dependent binding. The task involved repeated exposure of stimuli pairs and required the formation of new representations of each stimulus pair, as each pair was mapped to a unique keypress response. Notably, individual stimuli appeared in multiple pairs, so pair retrieval was necessary for correct response production. Experiment 1 demonstrated that older adults learned more slowly, and less overall, than young adults on this task. We also found that older adults benefited less than young adults from correct responses and as the number of intervening pairs between repetitions of a pair increased, older adults showed larger decrements in accuracy than young adults. Experiment 2 replicated these findings while minimizing motor demands and providing more practice. We also measured processing speed and spatial reconstruction to determine the involvement of specific cognitive mechanisms in observed age effects. We found that young adults with better spatial reconstruction abilities performed better on the EAL task than young adults with lower abilities and older adults overall. These findings suggest that older adults' lower performance on the task may be partly explained by a decline in hippocampal-supported binding processes and a greater reliance on extrahippocampal learning systems. (PsycINFO Database Record PMID- 29494186 TI - Leveraging older adults' susceptibility to distraction to improve memory for face name associations. AB - Forgetting people's names is a common memory complaint among older adults and one that is consistent with experimental evidence of age-related decline in memory for face-name associations. Despite this difficulty intentionally forming face name associations, a recent study demonstrated that older adults hyperbind distracting names and attended faces, which produces better learning of these face-name pairs when they reappear on a memory test (Weeks, Biss, Murphy, & Hasher, 2016). The current study explored whether this effect could be leveraged as an intervention to reduce older adults' forgetting of face-name associations, using a method previously shown to improve older adults' retention of a word list (Biss, Ngo, Hasher, Campbell, & Rowe, 2013). Twenty-five younger and 32 older adults studied 24 face-name pairs and were tested via immediate and delayed memory tests. During the 30-min retention interval, 10 of the face-name pairs reoccurred as distraction in an ostensibly unrelated face-judgment task, providing an opportunity to implicitly rehearse these pairs. Older adults showed reduced forgetting of repeated face-name pairs as well as improved recollection. Younger adults showed no reliable benefit. These findings indicate that useful distraction benefits older adults' memory for face-name associations, suggesting its potential utility as a memory intervention technique. (PsycINFO Database Record PMID- 29494187 TI - Using attribute amnesia to test the limits of hyper-binding and associative deficits in working memory. AB - Previous work has shown mixed evidence regarding age-related deficits for binding in working memory. The current study used the newly developed attribute amnesia effect (H. Chen & Wyble, 2015a) to test the associative-deficit hypothesis during working memory and to probe whether hyper-binding extends to include binding of de-selected information. In studies of attribute amnesia, participants use target attributes (e.g., identity, color) to demonstrate near ceiling levels of reporting of a second target attribute (e.g., location) across a series of trials (H. Chen & Wyble, 2015a, 2016). Yet, despite having just processed the target defining attribute, they have difficulty reporting it on a surprise trial. This effect provides several predictions for associative binding in aging. The associative-deficit hypothesis predicts age-related decline on the surprise trial, whereas an extension of hyper-binding predicts age-related increase in performance in older adults. In Experiment 1, when working memory load was low, older adults demonstrated attribute amnesia equal to that found in younger adults. When load increased in Experiment 2, older adults again demonstrated attribute amnesia as well as an age deficit for reporting target attributes. In lieu of spontaneous binding, results suggest that expectancy plays a critical role in older adults' propensity to encode and bind target attributes in working memory. Results further suggest that expectancy alone is not enough for older adults to form bound representations when task demands are high. Taken together results revealed a boundary condition of hyper-binding and further provided conditional support for the associative-deficit hypothesis in working memory. (PsycINFO Database Record PMID- 29494188 TI - Hyper-binding only apparent under fully implicit test conditions. AB - We have previously shown that older adults hyper-bind, or form more extraneous associations than younger adults. For instance, when asked to perform a 1-back task on pictures superimposed with distracting words, older adults inadvertently form associations between target-distractor pairs and implicitly transfer these associations to a later paired associate learning task (showing a boost in relearning of preserved over disrupted pairs). We have argued that younger adults are better at suppressing the distracting words and thus, do not form these extraneous associations in the first place. However, an alternative explanation is that younger adults simply fail to access these associations during relearning, possibly because of their superior ability to form boundaries between episodes or shift mental contexts between tasks. In this study, we aimed to both replicate this original implicit transfer effect in older adults and to test whether younger adults show evidence of hyper-binding when informed about the relevance of past information. Our results suggest that regardless of the test conditions, younger adults do not hyper-bind. In contrast, older adults showed hyper-binding under (standard) implicit instructions, but not when made aware of a connection between tasks. These results replicate the original hyper-binding effect and reiterate its implicit nature. (PsycINFO Database Record PMID- 29494189 TI - Modeling age differences in effects of pair repetition and proactive interference using a single parameter. AB - In this article, we apply the REM model (Shiffrin & Steyvers, 1997) to age differences in associative memory. Using Criss and Shiffrin's (2005) associative version of REM, we show that in a task with pairs repeated across 2 study lists, older adults' reduced benefit of pair repetition can be produced by a general reduction in the diagnosticity of information stored in memory. This reduction can be modeled similarly well by reducing the overall distinctiveness of memory features, or by reducing the accuracy of memory encoding. We report a new experiment in which pairs are repeated across 3 study lists and extend the model accordingly. Finally, we extend the model to previously reported data using the same task paradigm, in which the use of a high-association strategy introduced proactive interference effects in young adults but not older adults. Reducing the diagnosticity of information in memory also reduces the proactive interference effect. Taken together, the modeling and empirical results reported here are consistent with the claim that some age differences that appear to be specific to associative information can be produced via general degradation of information stored in memory. The REM model provides a useful framework for examining age differences in memory as well as harmonizing seemingly conflicting prior modeling approaches for the associative deficit. (PsycINFO Database Record PMID- 29494190 TI - Four- and five-factor models of the WAIS-IV in a clinical sample: Variations in indicator configuration and factor correlational structure. AB - A growing body of research supports the validity of 5-factor models for interpreting the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV). The majority of these studies have utilized the WAIS-IV normative or clinical sample, the latter of which differs in its diagnostic composition from the referrals seen at outpatient neuropsychology clinics. To address this concern, 2 related studies were conducted on a sample of 322 American military Veterans who were referred for outpatient neuropsychological assessment. In Study 1, 4 hierarchical models with varying indicator configurations were evaluated: 3 extant 5-factor models from the literature and the traditional 4-factor model. In Study 2, we evaluated 3 variations in correlation structure in the models from Study 1: indirect hierarchical (i.e., higher-order g), bifactor (direct hierarchical), and oblique models. The results from Study 1 suggested that both 4- and 5-factor models showed acceptable fit. The results from Study 2 showed that bifactor and oblique models offer improved fit over the typically specified indirect hierarchical model, and the oblique models outperformed the orthogonal bifactor models. An exploratory analysis found improved fit when bifactor models were specified with oblique rather than orthogonal latent factors. (PsycINFO Database Record PMID- 29494192 TI - The guidance of visual search by shape features and shape configurations. AB - Representations of target features (attentional templates) guide attentional object selection during visual search. In many search tasks, targets objects are defined not by a single feature but by the spatial configuration of their component shapes. We used electrophysiological markers of attentional selection processes to determine whether the guidance of shape configuration search is entirely part-based or sensitive to the spatial relationship between shape features. Participants searched for targets defined by the spatial arrangement of two shape components (e.g., hourglass above circle). N2pc components were triggered not only by targets but also by partially matching distractors with one target shape (e.g., hourglass above hexagon) and by distractors that contained both target shapes in the reverse arrangement (e.g., circle above hourglass), in line with part-based attentional control. Target N2pc components were delayed when a reverse distractor was present on the opposite side of the same display, suggesting that early shape-specific attentional guidance processes could not distinguish between targets and reverse distractors. The control of attention then became sensitive to spatial configuration, which resulted in a stronger attentional bias for target objects relative to reverse and partially matching distractors. Results demonstrate that search for target objects defined by the spatial arrangement of their component shapes is initially controlled in a feature-based fashion but can later be guided by templates for spatial configurations. (PsycINFO Database Record PMID- 29494191 TI - Evidence of gradual loss of precision for simple features and complex objects in visual working memory. AB - Previous studies have suggested that people can maintain prioritized items in visual working memory for many seconds, with negligible loss of information over time. Such findings imply that working memory representations are robust to the potential contaminating effects of internal noise. However, once visual information is encoded into working memory, one might expect it to inevitably begin degrading over time, as this actively maintained information is no longer tethered to the original perceptual input. Here, we examined this issue by evaluating working memory for single central presentations of an oriented grating, color patch, or face stimulus, across a range of delay periods (1, 3, 6, or 12 s). We applied a mixture-model analysis to distinguish changes in memory precision over time from changes in the frequency of outlier responses that resemble random guesses. For all 3 types of stimuli, participants exhibited a clear and consistent decline in the precision of working memory as a function of temporal delay, as well as a modest increase in guessing-related responses for colored patches and face stimuli. We observed a similar loss of precision over time while controlling for temporal distinctiveness. Our results demonstrate that visual working memory is far from lossless: while basic visual features and complex objects can be maintained in a quite stable manner over time, these representations are still subject to noise accumulation and complete termination. (PsycINFO Database Record PMID- 29494193 TI - Normative changes in interests from adolescence to adulthood: A meta-analysis of longitudinal studies. AB - Vocational interests predict a variety of important outcomes and are among the most widely applied individual difference constructs in psychology and education. Despite over 90 years of research, little is known about the longitudinal development of interests. In this meta-analysis, the authors investigate normative changes in interests through adolescence and young adulthood. Effect sizes were aggregated from 49 longitudinal studies reporting mean-level changes in vocational interests, containing 98 total samples and 20,639 participants. Random effects meta-analytic regression models were used to assess age-related changes and gender differences across Holland's (1959, 1997) RIASEC categories and composite dimensions (people, things, data, and ideas). Results showed that mean-level interest scores generally increase with age, but effect sizes varied across interest categories and developmental periods. Adolescence was defined by two broad patterns of change: interest scores generally decreased during early adolescence, but then increased during late adolescence. During young adulthood, the most striking changes were found across the people and things orientations. Interests involving people tended to increase (artistic, social, and enterprising), whereas interests involving things either decreased (conventional) or remained constant (realistic and investigative). Gender differences associated with occupational stereotypes reached a lifetime peak during early adolescence, then tended to decrease in all subsequent age periods. Overall findings suggest there are normative changes in vocational interests from adolescence to adulthood, with important implications for developmental theories and the applied use of interests. (PsycINFO Database Record PMID- 29494195 TI - Is bilingualism associated with enhanced executive functioning in adults? A meta analytic review. AB - Because of enduring experience of managing two languages, bilinguals have been argued to develop superior executive functioning compared with monolinguals. Despite extensive investigation, there is, however, no consensus regarding the existence of such a bilingual advantage. Here we synthesized comparisons of bilinguals' and monolinguals' performance in six executive domains using 891 effect sizes from 152 studies on adults. We also included unpublished data, and considered the potential influence of a number of study-, task-, and participant related variables. Before correcting estimates for observed publication bias, our analyses revealed a very small bilingual advantage for inhibition, shifting, and working memory, but not for monitoring or attention. No evidence for a bilingual advantage remained after correcting for bias. For verbal fluency, our analyses indicated a small bilingual disadvantage, possibly reflecting less exposure for each individual language when using two languages in a balanced manner. Moreover, moderator analyses did not support theoretical presuppositions concerning the bilingual advantage. We conclude that the available evidence does not provide systematic support for the widely held notion that bilingualism is associated with benefits in cognitive control functions in adults. (PsycINFO Database Record PMID- 29494196 TI - Brain volume change and cognitive trajectories in aging. AB - OBJECTIVE: Examine how longitudinal cognitive trajectories relate to brain baseline measures and change in lobar volumes in a racially/ethnically and cognitively diverse sample of older adults. METHOD: Participants were 460 older adults enrolled in a longitudinal aging study. Cognitive outcomes were measures of episodic memory, semantic memory, executive function, and spatial ability derived from the Spanish and English Neuropsychological Assessment Scales (SENAS). Latent variable multilevel modeling of the four cognitive outcomes as parallel longitudinal processes identified intercepts for each outcome and a second order global change factor explaining covariance among the highly correlated slopes. We examined how baseline brain volumes (lobar gray matter, hippocampus, and white matter hyperintensity) and change in brain volumes (lobar gray matter) were associated with cognitive intercepts and global cognitive change. Lobar volumes were dissociated into global and specific components using latent variable methods. RESULTS: Cognitive change was most strongly associated with brain gray matter volume change, with strong independent effects of global gray matter change and specific temporal lobe gray matter change. Baseline white matter hyperintensity and hippocampal volumes had significant incremental effects on cognitive decline beyond gray matter change. Baseline lobar gray matter was related to cognitive decline, but did not contribute beyond gray matter change. CONCLUSION: Cognitive decline was strongly influenced by gray matter volume change and, especially, temporal lobe change. The strong influence of temporal lobe gray matter change on cognitive decline may reflect involvement of temporal lobe structures that are critical for late life cognitive health but also are vulnerable to diseases of aging. (PsycINFO Database Record PMID- 29494194 TI - A meta-analysis of longitudinal associations between substance use and interpersonal attachment security. AB - Substance use has long been associated with close relationship distress. Although the direction of influence for this association has not been established, it has often been assumed that substance use is the causal agent and that close relationship distress is the effect. But research seeking to establish temporal precedence in this link has produced mixed findings. Further, theoretical models of substance use and close relationship processes present the plausibility of the inverse pathway-that insecure close relationships may serve as a vulnerability factor for the development of later substance problems. The current review applies an attachment-theoretical framework to the association between close social bonds and substance use and substance-related problems. Targeting longitudinal studies of attachment and substance use, we examined 665 effect sizes drawn from 34 samples (total N = 56,721) spanning time frames ranging from 1 month to 20 years (M = 3.8 years). Results revealed a significant prospective correlation between earlier attachment and later substance use (r = -.11, 95% CI [-.14, -0.08]). Further, cross-lagged coefficients were calculated which parsed auto-regressive effects, indicating that lower attachment security temporally preceded increases in substance use (r = -.05, 95% CI [-.06, -.04]). Analyses further indicated that the pathway from earlier attachment to later substance use was significantly stronger than that from earlier substance use to later attachment. Results also revealed several moderators of the attachment-substance use link. These findings suggest that insecure attachment may be a vulnerability factor for substance use, and indicate close relationship quality as a promising line of inquiry in research on substance use disorder risk. (PsycINFO Database Record PMID- 29494198 TI - The global need for lived experience leadership. AB - TOPIC: Common challenges and experiences of the lived experience/peer workforce globally are considered, with an emphasis on ensuring that future developments both protect and promote the unique lived experience perspective. PURPOSE: In the Western world, rapid growth in lived experience roles has led to an urgent need for training and workforce development. However, research indicates the roles risk being coopted without clear lived experience leadership, which is often not occurring. In developing countries and in many Western contexts, the lived experience role has not yet been accepted within the mental health workforce. The need for lived experience leadership to guide these issues is highlighted. SOURCES: Peer-reviewed research, relevant gray literature, and professional experience in countries where little published material currently exists. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: A window of opportunity currently exists to maximize lived experience leadership, and that window may be closing fast if broad-based actions are not initiated now. (PsycINFO Database Record PMID- 29494197 TI - Three agendas for changing the public stigma of mental illness. AB - OBJECTIVE: Antistigma programs may be guided by 3 differing agendas: services (promote treatment engagement), rights (help people achieve rightful goals), and self-worth (facilitate self-worth and efficacy). This study examined the construct validity of this perspective by examining the factor structure of importance ratings of the 3 agendas. The study examined how importance might be viewed differently by the population as a whole versus a subsample of people who reported previous experience with mental health services and hence could be directly harmed by stigma. METHODS: 373 individuals recruited using Mechanical Turk completed importance ratings for each of the 3 agendas. Measures of public stigma were completed to examine concurrent validity of importance ratings. Those who reported taking medications for a psychiatric disorder were divided into a separate group and completed a measure of self-stigma. RESULTS: Outcomes seemed to confirm the factor structure of the 3 agendas model thereby offering partial support for the framework. Group analyses showed the services agenda was viewed as more important than rights or self-worth. People with mental health experience viewed the services agenda as more important than the other 2. However, dividing the mental health group into low and high self-stigma revealed that those with low self-stigma rated the rights agenda as more important. Conclusions and Implication for Practice: Participants with lower self-stigma identify the harm brought by stigma and thus endorse rights and self-worth more than those with higher self-stigma. Implications of these findings are discussed to assist to prioritize agendas for public health campaigns. (PsycINFO Database Record PMID- 29494199 TI - Training evaluation. AB - TOPIC: Training evaluations may encompass different dimensions, from engagement of learners to the achievement of specific and meaningful learning objectives to the ultimate goal of changing what the learners do after completing the training. Yet, most behavioral health agencies fail to evaluate training at all, or limit their evaluations to simple satisfaction measures. PURPOSE: Well-designed evaluations can inform decisions on how to use an agency's limited training budget or whether to renew a contract for an external trainer. These decisions, and related training investment choices, are not trivial, as service delivery resources are limited and the costs of education and training can be substantial. SOURCES USED: Sources include the personal experience of the author and the available literature on training effectiveness and evaluation. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Evaluation of education and training programs should go beyond simple satisfaction ratings. A multilevel training evaluation strategy will yield rich information that can be used to refine content, improve instruction, ensure greater relevance to learners' work roles, and lead to improvements in day-to-day practice. (PsycINFO Database Record PMID- 29494200 TI - Changes in subjective well-being following the U.S. Presidential election of 2016. AB - This investigation examined predictors of changes over time in subjective well being (SWB) after the 2016 United States presidential election. Two indicators of SWB-general happiness and life satisfaction-were assessed three weeks before the election, the week of the election, three weeks later, and six months later. Partisanship predicted both indicators of SWB, with Trump supporters experiencing improved SWB after the election, Clinton supporters experiencing worsened SWB after the election, and those who viewed both candidates as bad also experiencing worsened SWB after the election. The impact of the election on SWB decreased over time, with all participants returning to baseline life satisfaction six months after the election. Trump supporters and those who viewed both candidates as bad for the country also returned to baseline general happiness six months after the election. Clinton supporters, in contrast, remained below baseline levels of general happiness six months after the election. Moral and political values, and exposure to media inconsistent with those values, predicted lasting change in subjective well-being. National events can affect how people perceive the overall quality of their lives and these effects are exacerbated when moral and political values are involved. (PsycINFO Database Record PMID- 29494201 TI - Disgust and the sacred: Do people react to violations of the sacred with the same emotion they react to something putrid? AB - Disgust has been hypothesized to be uniquely linked to violations of a distinct moral domain (called divinity, purity, or sacred) aimed at preserving one's body from contamination with pathogens and preserving one's soul from violations of what is sacred. Here we examined whether the same emotion-core disgust-occurs when witnessing both types of violation, and we proposed a specific method for doing so. In two studies (N = 160; 240), American and Indian participants indicated their emotional reaction to (stories depicting) sacred or nonsacred violations, each either with or without pathogens. Both Americans and Indians felt "grossed out" (a term for core disgust) by events with pathogens (whether violations of the sacred or not). They felt disgusted and angered, but not grossed out, by violations of the sacred. For both Americans and Indians, grossed out was never the modal emotion when a sacred violation did not involve pathogens. Results were inconsistent with a focus on any single emotion: sacred violations were associated with several different negative emotions. (PsycINFO Database Record PMID- 29494202 TI - Beyond belief: The probability-based notion of surprise in children. AB - Improbable events are surprising. However, it is unknown whether children consider probability when attributing surprise to other people. We conducted four experiments that investigate this issue. In the first three experiments, children saw stories in which two characters received a red gumball from two gumball machines with different distributions, and children then judged which character was more surprised. Experiment 1 (N = 120) shows development in children's use of probability to infer surprise. Children aged 7 correctly inferred that the character with a lower chance of getting a red gumball would be more surprised, but 4- to 6-year-olds did not. Experiment 2 (N = 120) shows that children's performance does not improve when the probability of getting a red gumball is zero and should be maximally surprising. Experiment 3 (N = 120) demonstrates that 6-year-olds' performance improves when they are prompted to consider probabilities, but not when they are prompted to consider the characters' beliefs. Experiment 4 (N = 60) replicates this finding, but using a new design in which children attributed emotions to just a single character. Together these findings suggest that by age 6, a conceptual shift occurs, in which children begin to integrate their understanding of probability with their understanding of surprise. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29494203 TI - Investigating the relationships between subjective well-being and psychological well-being over two decades. AB - Although much research has been conducted on the predictors and outcomes of both subjective well-being (SWB) and psychological well-being (PWB), the magnitude and direction of the causal relationship between these constructs remain unclear. The studies reported in this article were designed to assess the temporal relationship between SWB and PWB during a period of 20 years. The studies used 3 waves of survey data, with intervals of 10 years, from the Midlife in the United States project, a representative longitudinal panel study of American adults (N = 2,731). Cross-lagged panel analyses were conducted to examine directionality of the relationships. Results showed that the autoregressive effects were large, suggesting a high degree of stability in SWB and PWB over time. Yet the levels of stability were generally higher for PWB than SWB. Whereas PWB unequivocally predicted increases in SWB over time, the prospective effects of SWB on PWB were inconsistent (i.e., positive, negative, or nonsignificant) across various points in time. The study findings suggest that PWB represents a more robust and consistent antecedent of future well-being than SWB. (PsycINFO Database Record PMID- 29494204 TI - Attentional capture by simultaneous pleasant and unpleasant emotional distractors. AB - Both high-arousal pleasant and unpleasant task-irrelevant stimuli capture attention and divert processing away from the main task leading to impaired behavioral performance in concurrent tasks. Most studies have separately investigated interference effects of unpleasant and pleasant stimuli on behavior. Thus, little is known about how pleasant and unpleasant task-irrelevant stimuli influence behavior simultaneously. In the present study, we investigated this question during a visual-letter search task. We tested two alternative hypotheses about the influence of simultaneous pleasant and unpleasant task-irrelevant stimuli on task performance. If behavior is purely determined by the intensity of the distractor stimuli (independent of valence), then we would expect the interference effect of simultaneous pleasant and unpleasant distractors to be similar to the influence of two pleasant or two unpleasant distractor stimuli. In contrast, because of opponent interactions between appetitive and aversive motivational systems, the interference effect of simultaneous pleasant and unpleasant stimuli might be weakened. We found that the interference effect of a compound pleasant-plus-unpleasant stimulus was greater than that of a neutral plus-emotional stimulus and similar to that of two pleasant or two unpleasant stimuli. These results suggest that at the level of behavior, the influence of joint pleasant and unpleasant task-irrelevant stimuli during perception is mainly determined by the intensity of the stimuli, and independent of their valence. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29494205 TI - How does high DHA fish oil affect health? A systematic review of evidence. AB - The health benefits of fish oil, and its omega-3 long chain polyunsaturated fatty acid content, have attracted much scientific attention in the last four decades. Fish oils that contain higher amounts of eicosapentaenoic acid (EPA; 20:5n-3) than docosahexaenoic acid (DHA; 22:6n-3), in a distinctive ratio of 18/12, are typically the most abundantly available and are commonly studied. Although the two fatty acids have traditionally been considered together, as though they were one entity, different physiological effects of EPA and DHA have recently been reported. New oils containing a higher quantity of DHA compared with EPA, such as fractionated and concentrated fish oil, tuna oil, calamari oil and microalgae oil, are increasingly becoming available on the market, and other oils, including those extracted from genetically modified oilseed crops, soon to come. This systematic review focuses on the effects of high DHA fish oils on various human health conditions, such as the heart and cardiovascular system, the brain and visual function, inflammation and immune function and growth/Body Mass Index. Although inconclusive results were reported in several instances, and inconsistent outcomes observed in others, current data provides substantiated evidence in support of DHA being a beneficial bioactive compound for heart, cardiovascular and brain function, with different, and at times complementary, effects compared with EPA. DHA has also been reported to be effective in slowing the rate of cognitive decline, while its possible effects on depression disorders are still unclear. Interestingly, gender- and age- specific divergent roles for DHA have also been reported. This review provides a comprehensive collection of evidence and a critical summary of the documented physiological effects of high DHA fish oils for human health. PMID- 29494206 TI - Viruses, Aging, and Chronic Lung Disease. PMID- 29494207 TI - Assessing Risk and Treatment Responsiveness in ARDS. Beyond Physiology. PMID- 29494208 TI - The impact of short-chain fatty acids on GLP-1 and PYY secretion from the isolated perfused rat colon. AB - The colonic epithelium harbors a large number of endocrine cells, but little is known about the endocrine functions of the colon. However, the high density of glucagon like peptide-1 (GLP-1)- and peptide-YY (PYY)-secreting L cells is of great interest because of the potential antidiabetic and antiobesity effects of GLP-1 and PYY. Short-chain fatty acids (SCFAs) produced by local bacterial fermentation are suggested to activate the colonic free fatty acid receptors FFAR2 (GPR43) and FFAR3 (GPR41), stimulating the colonic L cells. We used the isolated perfused rat colon as a model of colonic endocrine secretion and studied the effects of the predominant SCFAs formed: acetate, propionate, and butyrate. We show that luminal and especially vascular infusion of acetate and butyrate significantly increases colonic GLP-1 secretion, and to a minor extent also PYY secretion, but only after enhancement of intracellular cAMP. Propionate neither affected GLP-1 nor PYY secretion whether administered luminally or vascularly. A FFAR2- and FFAR3-specific agonist [( S)-2-(4-chlorophenyl)-3,3-dimethyl- N-(5 phenylthiazol-2-yl)butamide (CFMB)/ AR420626 ] had no effect on colonic GLP-1 output, and a FFAR3 antagonist ( AR399519 ) did not decrease the SCFA-induced GLP 1 response. However, the voltage-gated Ca2+-channel blocker nifedipine, the KATP channel opener diazoxide, and the ATP synthesis inhibitor 2,4-dinitrophenol completely abolished the responses. FFAR2 receptor studies confirmed low-potent partial agonism of acetate, propionate, and butyrate, compared with CFMB, which is a full agonist with ~750-fold higher potency than the SCFAs. In conclusion, SCFAs may increase colonic GLP-1/PYY secretion, but FFAR2/FFAR3 do not seem to be involved. Rather, SCFAs are metabolized and appear to function as a colonocyte energy source. NEW & NOTEWORTHY By the use of in situ isolated perfused rat colon we show that short-chain fatty acids (SCFAs) primarily are used as a colonocyte energy source in the rat, subsequently triggering glucagon like peptide-1 (GLP-1) secretion independent of the free fatty acid receptors FFAR2 and FFAR3. Opposite many previous studies on SCFAs and FFAR2/FFAR3 and GLP-1 secretion, this experimental model allows investigation of the physiological interactions between luminal nutrients and secretion from cells whose function depend critically on their blood supply as well as nerve and paracrine interactions. PMID- 29494210 TI - Asthma: From Diagnosis to Endotype to Treatment. PMID- 29494209 TI - Biliverdin reductase and bilirubin in hepatic disease. AB - The buildup of fat in the liver (hepatic steatosis) is the first step in a series of incidents that may drive hepatic disease. Obesity is the leading cause of nonalcoholic fatty liver disease (NAFLD), in which hepatic steatosis progresses to liver disease. Chronic alcohol exposure also induces fat accumulation in the liver and shares numerous similarities to obesity-induced NAFLD. Regardless of whether hepatic steatosis is due to obesity or long-term alcohol use, it still may lead to hepatic fibrosis, cirrhosis, or possibly hepatocellular carcinoma. The antioxidant bilirubin and the enzyme that generates it, biliverdin reductase A (BVRA), are components of the heme catabolic pathway that have been shown to reduce hepatic steatosis. This review discusses the roles for bilirubin and BVRA in the prevention of steatosis, their functions in the later stages of liver disease, and their potential therapeutic application. PMID- 29494213 TI - Electrophysiological Source Imaging: A Noninvasive Window to Brain Dynamics. AB - Brain activity and connectivity are distributed in the three-dimensional space and evolve in time. It is important to image brain dynamics with high spatial and temporal resolution. Electroencephalography (EEG) and magnetoencephalography (MEG) are noninvasive measurements associated with complex neural activations and interactions that encode brain functions. Electrophysiological source imaging estimates the underlying brain electrical sources from EEG and MEG measurements. It offers increasingly improved spatial resolution and intrinsically high temporal resolution for imaging large-scale brain activity and connectivity on a wide range of timescales. Integration of electrophysiological source imaging and functional magnetic resonance imaging could further enhance spatiotemporal resolution and specificity to an extent that is not attainable with either technique alone. We review methodological developments in electrophysiological source imaging over the past three decades and envision its future advancement into a powerful functional neuroimaging technology for basic and clinical neuroscience applications. PMID- 29494211 TI - Disease Management Plus Recommended Care versus Recommended Care Alone for Ambulatory COPD Patients. AB - RATIONALE: The efficacy of disease management programs in the treatment of patients with chronic obstructive pulmonary disease (COPD) remains uncertain. OBJECTIVE: To study the effect of disease management (DM) added to recommended care (RC) in ambulatory COPD patients. MEASUREMENTS AND MAIN RESULTS: In this trial, 1,202 COPD patients (age >40 years), with moderate to very severe airflow limitation were randomly assigned either to DM plus RC (study intervention) or to RC alone (control intervention). RC included follow-up by pulmonologists; inhaled long-acting bronchodilators and corticosteroids; smoking cessation intervention; nutritional advice and psychosocial support when indicated, and supervised physical activity sessions. DM, delivered by trained nurses during patients' visits to the designated COPD centers and remote contacts with the patients between these visits, included patient self-care education; monitoring patients' symptoms and adherence to treatment; provision of advice in case of acute disease exacerbation, and coordination of care vis-a-vis other healthcare providers. The primary composite endpoint was first hospital admission for respiratory symptoms or death from any cause. During 3,537 patient-years, 284 (47.2%) patients in the control group and 264 (44.0%) in the study intervention group had a primary endpoint event. The median (range) time elapsed until a primary endpoint event was 1.0 (0-4.0) years among patients assigned to the study intervention and 1.1 (0-4.1) years among patients assigned to the control intervention; adjusted hazard ratio, 0.92 (95%CI: 0.77 to 1.08). CONCLUSIONS: DM added to RC was not superior to RC alone in delaying first hospital admission or death among ambulatory COPD patients. Clinical trial registration available at www.clinicaltrials.gov, ID NCT00982384. PMID- 29494212 TI - Evaluating lipid mediator structural complexity using ion mobility spectrometry combined with mass spectrometry. AB - AIM: Lipid mediators (LMs) are broadly defined as a class of bioactive lipophilic molecules that regulate cell-to-cell communication events with many having a strong correlation with various human diseases and conditions. LMs are usually analyzed with LC-MS, but their numerous isomers greatly complicate the measurements with essentially identical fragmentation spectra and LC separations are not always sufficient for distinguishing the features. Results/methodology: In this work, we characterized LMs using ion mobility spectrometry (IMS) coupled with MS (IMS-MS). The collision cross-sections and m/z values from the IMS and MS analyses displayed distinct trend lines. Specifically, the structural trend lines for sodiated LMs originating from docosahexaenoic acid had the smallest collision cross-section values in relation to m/z, while those from linoleic acid had the largest. LC-IMS-MS analyses were also performed on LMs in flu infected mouse tissue samples. These multidimensional studies were able to assess known LMs while also detecting new species. CONCLUSION: Adding IMS separations to conventional LC-MS analyses show great utility for enabling better identification and characterization of LMs in complex biological samples. PMID- 29494214 TI - Facet Joints of the Spine: Structure-Function Relationships, Problems and Treatments, and the Potential for Regeneration. AB - The zygapophysial joint, a diarthrodial joint commonly referred to as the facet joint, plays a pivotal role in back pain, a condition that has been a leading cause of global disability since 1990. Along with the intervertebral disc, the facet joint supports spinal motion and aids in spinal stability. Highly susceptible to early development of osteoarthritis, the facet is responsible for a significant amount of pain in the low-back, mid-back, and neck regions. Current noninvasive treatments cannot offer long-term pain relief, while invasive treatments can relieve pain but fail to preserve joint functionality. This review presents an overview of the facet in terms of its anatomy, functional properties, problems, and current management strategies. Furthermore, this review introduces the potential for regeneration of the facet and particular engineering strategies that could be employed as a long-term treatment. PMID- 29494215 TI - Expanding lipidome coverage using MS/MS-aided untargeted data-independent RP-UPLC TOF-MSE acquisition. AB - Lipid function and importance in disease are being rediscovered due to modern advancements in chemical analysis. RP-UPLC-TOF-MSE is now the lipidomics tool of choice and can provide the demanded specificity for detecting the great diversity of the lipidome. It can offer simplicity, rapidity, robustness and high throughputness, without the need for further optimization in current sample preparation protocols. This method can cover the major lipid categories with the ability to detect several corresponding subclasses. It can deliver adequate information for deciphering fatty chain length, unsaturation and regioisomerism. It has enabled the detection of a vast number of lipids, of which more than 250 are reported here. These lipids were detected from applications in a variety of biological matrices and species. PMID- 29494216 TI - Want to Elevate Your Game? You May Want to Bring Along the Team. PMID- 29494219 TI - Molecular Diagnostics in Pathology: Time for a Next-Generation Pathologist? AB - CONTEXT: - Comprehensive molecular investigations of mainstream carcinogenic processes have led to the use of effective molecular targeted agents in most cases of solid tumors in clinical settings. OBJECTIVE: - To update readers regarding the evolving role of the pathologist in the therapeutic decision-making process and the introduction of next-generation technologies into pathology practice. DATA SOURCES: - Current literature on the topic, primarily sourced from the PubMed (National Center for Biotechnology Information, Bethesda, Maryland) database, were reviewed. CONCLUSIONS: - Adequate evaluation of cytologic-based and tissue-based predictive diagnostic biomarkers largely depends on both proper pathologic characterization and customized processing of biospecimens. Moreover, increased requests for molecular testing have paralleled the recent, sharp decrease in tumor material to be analyzed-material that currently comprises cytology specimens or, at minimum, small biopsies in most cases of metastatic/advanced disease. Traditional diagnostic pathology has been completely revolutionized by the introduction of next-generation technologies, which provide multigene, targeted mutational profiling, even in the most complex of clinical cases. Combining traditional and molecular knowledge, pathologists integrate the morphological, clinical, and molecular dimensions of a disease, leading to a proper diagnosis and, therefore, the most-appropriate tailored therapy. PMID- 29494221 TI - In Reply. PMID- 29494220 TI - Cytology Smears in the Era of Molecular Biomarkers in Non-Small Cell Lung Cancer: Doing More With Less. AB - CONTEXT: - The rapid advances in targeted therapies in non-small cell lung cancer (NSCLC) make the optimization and implementation of cytology specimens for molecular testing a priority. Up to 70% of patients with NSCLC are diagnosed at advanced stages and tissue biopsies often cannot be taken. Although cytology samples provide high-quality material for molecular testing, molecular cytopathology is not yet well known or widely used. OBJECTIVE: - To report the many advances in molecular cytopathology and the suitability and utility of cytology samples in molecular and genetic testing of NSCLC. DATA SOURCES: - Data sources comprised published peer-reviewed literature and personal experience of the authors. CONCLUSIONS: - Molecular testing can be performed on cytologic specimens, especially on direct smears. Rapid on-site evaluation by cytopathologists has improved the adequacy and the management of cytology samples for molecular testing. Mutational profiling of NSCLC using next-generation sequencing can be performed on cytology samples from very small amounts of DNA. Fluorescence in situ hybridization assays on cytology specimens, including stained direct smear, offer some distinct advantages over their histologic counterpart, and are used to detect ALK and ROS1 rearrangements in NSCLC. Cytology specimens allow assessment of the entire tumor cell nucleus, avoiding signal loss from truncation artifacts. The use of cytology samples for assessing programmed death ligand-1 protein expression is currently being developed. Protocols for bisulfite conversion and DNA droplet digital polymerase chain reaction assays have been optimized for cytology smear to investigate aberrant DNA methylation of several NSCLC-related genes. PMID- 29494218 TI - "It is not possible to go inside and have a discussion": how fear of stigma affects delivery of community-based support for children's HIV care. AB - Caregivers mediate children's access to HIV care and their adherence to treatment. Support for caregivers may improve health outcomes in children, but fear of HIV stigma and discrimination can affect both uptake and delivery of support services. Within a trial evaluating community-based support for caregivers of newly HIV diagnosed children in Harare, Zimbabwe, we conducted a longitudinal qualitative study to explore how stigma affected delivery and acceptance of the intervention. We conducted semi-structured interviews with 36 caregivers, 15 children, and 20 community health workers (CHWs). Children and caregivers described experiencing or witnessing stigma and discrimination, causing some to resist home visits by CHWs. Anxiety around stigma made it difficult for CHWs to promote key messages. In response, CHWs adapted the intervention by meeting caregivers outside the home, pretending to be friends or relatives, and proactively counteracting stigmatising beliefs. As members of local communities, some CHWs shared concerns about discrimination. HIV stigma can hinder "getting a foot over the threshold" in community-based programmes, particularly for households most affected by discrimination and thus least likely to engage with services. For community support programmes to be effective, stigma related resistance should be addressed from the outset, including CHWs' own concerns regarding HIV stigma. PMID- 29494222 TI - Key Issues in Molecular Cytopathology. PMID- 29494223 TI - Microscopic Screening of Reduction Mammoplasties Risks Overdiagnosis. PMID- 29494224 TI - Intraductal Tubulopapillary Neoplasm of the Pancreas: An Overview. AB - Intraductal tubulopapillary neoplasm is a rare tumor that the World Health Organization recognized in 2010 as a subtype of premalignant pancreatic neoplasms. It is important to distinguish it from other intraductal neoplasms, including intraductal papillary mucinous neoplasm, pancreatic ductal adenocarcinoma, and intraductal variant of acinar cell carcinoma, because intraductal tubulopapillary neoplasm has a favorable prognosis. Histopathologically, intraductal tubulopapillary neoplasms are characterized by tubulopapillary growth, uniform high-grade cytologic atypia, frequent necrotic foci, evident ductal differentiation, and absence of mucin. Intraductal tubulopapillary neoplasms show distinct immunohistochemical and molecular findings, with positive cytokeratin 7, cytokeratin 19, MUC1, and MUC6, and somatic PIK3CA mutations (2 of 11; 18%), and low rates of KRAS (2 of 20; 10%), TP53 (5 of 22; 23%), and BRAF (2 of 13; 15%) mutations. These differences also highlight the fact that intraductal tubulopapillary pancreatic neoplasm is distinct from other similar neoplasms. PMID- 29494225 TI - To Obtain More With Less: Cytologic Samples With Ancillary Molecular Techniques The Useful Role of Liquid-Based Cytology. AB - CONTEXT: - Fine-needle aspiration cytology has been increasingly used as the first tool in the evaluation of several diseases. Although cytology has a relevant role in the discrimination between benign and malignant lesions, conventional slides cannot lead to 100% conclusive results. It was hoped that the introduction of liquid-based cytology (LBC) would improve the efficacy of cytology through standardization, quality improvement, and the possibility of carrying out ancillary techniques on the residual stored material. In recent decades, the application of genomic alterations has been studied on cytologic samples with feasible and reliable results. The molecular analysis offers a powerful aid to define the best clinical or surgical approaches and follow-up for patients. In recent years, the application of different ancillary techniques has been carried out on conventional slides even though LBC represents a useful additional and alternative method for molecular testing. OBJECTIVE: - To demonstrate the relevance of LBC as a valid aid to overcoming the difficulties encountered in the application of ancillary techniques on conventional slides. DATA SOURCES: - We examined and reviewed our experience with the application of ancillary techniques on LBC performed on different body sites. CONCLUSIONS: - We emphasize that LBC achieves significant and accurate results. It represents a valid method for cytologic evaluation and it provides highly reproducible and informative molecular yields. PMID- 29494226 TI - FTA Cards for Preservation of Nucleic Acids for Molecular Assays: A Review on the Use of Cytologic/Tissue Samples. AB - CONTEXT: - Traditional methods for storing histologic and cytologic specimens for future use in molecular assays have consisted of either snap-freezing with cryopreservation or formalin-fixing, paraffin-embedding the samples. Although snap-freezing with cryopreservation is recommended for better preservation of nucleic acids, the infrastructure and space required for archiving impose challenges for high-volume pathology laboratories. Cost-effective, long-term storage at room temperature; relatively easy shipment; and standardized handling can be achieved with formalin-fixed, paraffin-embedded samples, but formalin fixation induces fragmentation and chemical modification of nucleic acids. Advances in next-generation sequencing platforms, coupled with an increase in diagnostic, prognostic, and predictive molecular biomarkers have created a demand for high-quality nucleic acids. To address issues of the quality of nucleic acid and logistics in sample acquisition, alternatives for specimen preservation and long-term storage have been described and include novel universal tissue fixatives, stabilizers, and technologies. OBJECTIVE: - To collect, retrieve, and review information from studies describing the use of nucleic acids recovered from cytologic/tissue specimens stored on Flinders Technology Associates (FTA, GE Whatman, Maidstone, Kent, United Kingdom) cards for downstream molecular applications. DATA SOURCES: - An electronic literature search in the PubMed (National Center for Biotechnology Information, Bethesda, Maryland) database allowed the selection of manuscripts addressing the use of FTA cards for storage of cytologic samples for molecular analysis. Only articles published in English were retrieved. CONCLUSIONS: - The use of FTA cards is a versatile method for fostering multicenter, international collaborations and clinical trials that require centralized testing, long-distance shipment, and high-quality nucleic acids for molecular techniques. Studies with controlled temperature are required to test the quality of recovered RNA after long-term storage. PMID- 29494229 TI - HIV-related stigma and optimism as predictors of anxiety and depression among HIV positive men who have sex with men in the United Kingdom and Ireland. AB - This study investigated the associations between forms of HIV-related optimism, HIV-related stigma, and anxiety and depression among HIV-positive men who have sex with men (MSM) in the United Kingdom and Ireland. HIV health optimism (HHO) and HIV transmission optimism (HTO) were hypothesised to be protective factors for anxiety and depression, while the components of HIV-related stigma (enacted stigma, disclosure concerns, concern with public attitudes, and internalised stigma) were hypothesised to be risk factors. Data were collected from 278 HIV positive MSM using an online questionnaire. The prevalence of psychological distress was high, with close to half (48.9%) of all participants reporting symptoms of anxiety, and more than half (57.9%) reporting symptoms of depression. Multiple linear regressions revealed that both anxiety and depression were positively predicted by internalised stigma and enacted stigma, and negatively predicted by HHO. For both anxiety and depression, internalised stigma was the strongest and most significant predictor. The results highlight the continued psychological burden associated with HIV infection among MSM, even as community support services are being defunded across the United Kingdom and Ireland. The results point to the need for clinicians and policy makers to implement stigma reduction interventions among this population. PMID- 29494232 TI - Cationic lipid bioanalysis: understanding distribution of lipid nanoparticles for delivery of RNA therapeutics. PMID- 29494236 TI - An Autobiography of Ronald W. Rousseau. AB - This article provides a synopsis of my professional career, from the decision to study chemical engineering to leadership of one of the top academic programs in that field. I describe how I chose to devote my research to phenomena associated with crystallization as practiced for separation and purification and then made the transition to leader of an academic program. Embedded in the coverage are descriptions of research advances coming from exploration of secondary nucleation, especially how collisions of crystals in supersaturated environments dominate the behavior of industrially relevant crystallization processes. I recount some of the challenges associated with becoming a school chair and how the program I led grew. The story illuminates the contributions of my many mentors, colleagues, and students. PMID- 29494237 TI - Lipid Cell Biology: A Focus on Lipids in Cell Division. AB - Cells depend on hugely diverse lipidomes for many functions. The actions and structural integrity of the plasma membrane and most organelles also critically depend on membranes and their lipid components. Despite the biological importance of lipids, our understanding of lipid engagement, especially the roles of lipid hydrophobic alkyl side chains, in key cellular processes is still developing. Emerging research has begun to dissect the importance of lipids in intricate events such as cell division. This review discusses how these structurally diverse biomolecules are spatially and temporally regulated during cell division, with a focus on cytokinesis. We analyze how lipids facilitate changes in cellular morphology during division and how they participate in key signaling events. We identify which cytokinesis proteins are associated with membranes, suggesting lipid interactions. More broadly, we highlight key unaddressed questions in lipid cell biology and techniques, including mass spectrometry, advanced imaging, and chemical biology, which will help us gain insights into the functional roles of lipids. PMID- 29494239 TI - 2-Oxoglutarate-Dependent Oxygenases. AB - 2-Oxoglutarate (2OG)-dependent oxygenases (2OGXs) catalyze a remarkably diverse range of oxidative reactions. In animals, these comprise hydroxylations and N demethylations proceeding via hydroxylation; in plants and microbes, they catalyze a wider range including ring formations, rearrangements, desaturations, and halogenations. The catalytic flexibility of 2OGXs is reflected in their biological functions. After pioneering work identified the roles of 2OGXs in collagen biosynthesis, research revealed they also function in plant and animal development, transcriptional regulation, nucleic acid modification/repair, fatty acid metabolism, and secondary metabolite biosynthesis, including of medicinally important antibiotics. In plants, 2OGXs are important agrochemical targets and catalyze herbicide degradation. Human 2OGXs, particularly those regulating transcription, are current therapeutic targets for anemia and cancer. Here, we give an overview of the biochemistry of 2OGXs, providing examples linking to biological function, and outline how knowledge of their enzymology is being exploited in medicine, agrochemistry, and biocatalysis. PMID- 29494240 TI - Defining Adult Stem Cells by Function, not by Phenotype. AB - Central to the classical hematopoietic stem cell (HSC) paradigm is the concept that the maintenance of blood cell numbers is exclusively executed by a discrete physical entity: the transplantable HSC. The HSC paradigm has served as a stereotypic template in stem cell biology, yet the search for rare, hardwired professional stem cells has remained futile in most other tissues. In a more open approach, the focus on the search for stem cells as a physical entity may need to be replaced by the search for stem cell function, operationally defined as the ability of an organ to replace lost cells. The nature of such a cell may be different under steady state conditions and during tissue repair. We discuss emerging examples including the renewal strategies of the skin, gut epithelium, liver, lung, and mammary gland in comparison with those of the hematopoietic system. While certain key housekeeping and developmental signaling pathways are shared between different stem cell systems, there may be no general, deeper principles underlying the renewal mechanisms of the various individual tissues. PMID- 29494241 TI - Directed Evolution of Protein Catalysts. AB - Directed evolution is a powerful technique for generating tailor-made enzymes for a wide range of biocatalytic applications. Following the principles of natural evolution, iterative cycles of mutagenesis and screening or selection are applied to modify protein properties, enhance catalytic activities, or develop completely new protein catalysts for non-natural chemical transformations. This review briefly surveys the experimental methods used to generate genetic diversity and screen or select for improved enzyme variants. Emphasis is placed on a key challenge, namely how to generate novel catalytic activities that expand the scope of natural reactions. Two particularly effective strategies, exploiting catalytic promiscuity and rational design, are illustrated by representative examples of successfully evolved enzymes. Opportunities for extending these approaches to more complex biocatalytic systems are also considered. PMID- 29494252 TI - Hemagglutinin-Mediated Membrane Fusion: A Biophysical Perspective. AB - Influenza hemagglutinin (HA) is a viral membrane protein responsible for the initial steps of the entry of influenza virus into the host cell. It mediates binding of the virus particle to the host-cell membrane and catalyzes fusion of the viral membrane with that of the host. HA is therefore a major target in the development of antiviral strategies. The fusion of two membranes involves high activation barriers and proceeds through several intermediate states. Here, we provide a biophysical description of the membrane fusion process, relating its kinetic and thermodynamic properties to the large conformational changes taking place in HA and placing these in the context of multiple HA proteins working together to mediate fusion. Furthermore, we highlight the role of novel single particle experiments and computational approaches in understanding the fusion process and their complementarity with other biophysical approaches. PMID- 29494253 TI - Cryo-EM Studies of Pre-mRNA Splicing: From Sample Preparation to Model Visualization. AB - The removal of noncoding introns from pre-messenger RNA (pre-mRNA) is an essential step in eukaryotic gene expression and is catalyzed by a dynamic multi megadalton ribonucleoprotein complex called the spliceosome. The spliceosome assembles on pre-mRNA substrates by the stepwise addition of small nuclear ribonucleoprotein particles and numerous protein factors. Extensive remodeling is required to form the RNA-based active site and to mediate the pre-mRNA branching and ligation reactions. In the past two years, cryo-electron microscopy (cryo-EM) structures of spliceosomes captured in different assembly and catalytic states have greatly advanced our understanding of its mechanism. This was made possible by long-standing efforts in the purification of spliceosome intermediates as well as recent developments in cryo-EM imaging and computational methodology. The resulting high-resolution densities allow for de novo model building in core regions of the complexes. In peripheral and less ordered regions, the combination of cross-linking, bioinformatics, biochemical, and genetic data is essential for accurate modeling. Here, we summarize these achievements and highlight the critical steps in obtaining near-atomic resolution structures of the spliceosome. PMID- 29494254 TI - Nanodiscs: A Controlled Bilayer Surface for the Study of Membrane Proteins. AB - The study of membrane proteins and receptors presents many challenges to researchers wishing to perform biophysical measurements to determine the structure, function, and mechanism of action of such components. In most cases, to be fully functional, proteins and receptors require the presence of a native phospholipid bilayer. In addition, many complex multiprotein assemblies involved in cellular communication require an integral membrane protein as well as a membrane surface for assembly and information transfer to soluble partners in a signaling cascade. Incorporation of membrane proteins into Nanodiscs renders the target soluble and provides a native bilayer environment with precisely controlled composition of lipids, cholesterol, and other components. Likewise, Nanodiscs provide a surface of defined area useful in revealing lipid specificity and affinities for the assembly of signaling complexes. In this review, we highlight several biophysical techniques made possible through the use of Nanodiscs. Expected final online publication date for the Annual Review of Biophysics Volume 47 is May 20, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 29494238 TI - Translesion and Repair DNA Polymerases: Diverse Structure and Mechanism. AB - The number of DNA polymerases identified in each organism has mushroomed in the past two decades. Most newly found DNA polymerases specialize in translesion synthesis and DNA repair instead of replication. Although intrinsic error rates are higher for translesion and repair polymerases than for replicative polymerases, the specialized polymerases increase genome stability and reduce tumorigenesis. Reflecting the numerous types of DNA lesions and variations of broken DNA ends, translesion and repair polymerases differ in structure, mechanism, and function. Here, we review the unique and general features of polymerases specialized in lesion bypass, as well as in gap-filling and end joining synthesis. PMID- 29494255 TI - The Jigsaw Puzzle of mRNA Translation Initiation in Eukaryotes: A Decade of Structures Unraveling the Mechanics of the Process. AB - Translation initiation in eukaryotes is a highly regulated and rate-limiting process. It results in the assembly and disassembly of numerous transient and intermediate complexes involving over a dozen eukaryotic initiation factors (eIFs). This process culminates in the accommodation of a start codon marking the beginning of an open reading frame at the appropriate ribosomal site. Although this process has been extensively studied by hundreds of groups for nearly half a century, it has been only recently, especially during the last decade, that we have gained deeper insight into the mechanics of the eukaryotic translation initiation process. This advance in knowledge is due in part to the contributions of structural biology, which have shed light on the molecular mechanics underlying the different functions of various eukaryotic initiation factors. In this review, we focus exclusively on the contribution of structural biology to the understanding of the eukaryotic initiation process, a long-standing jigsaw puzzle that is just starting to yield the bigger picture. Expected final online publication date for the Annual Review of Biophysics Volume 47 is May 20, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 29494256 TI - From a Single Child to Uniform Newborn Screening: My Lucky Life in Pediatric Medical Genetics. AB - Mike, a memorable young patient with untreated phenylketonuria, as well as others affected by genetic disorders that could be treated if diagnosed in infancy, launched my six-decade career. This autobiographical article reflects on my childhood, early research, and professional experiences in pediatric genetics. My laboratory research focused on inborn errors of metabolism, including the glycogen storage diseases. My effort to organize newborn screening through the recommended uniform screening panel shaped and standardized newborn screening nationwide. Looking ahead, the expansion of whole-genome and whole-exome sequencing into newborn screening raises ethical and policy issues regarding informed consent procedures and the storage and use of residual blood spots. PMID- 29494257 TI - Stress, Telomeres, and Psychopathology: Toward a Deeper Understanding of a Triad of Early Aging. AB - Telomeres play an important part in aging and show relationships to lifetime adversity, particularly childhood adversity. Meta-analyses demonstrate reliable associations between psychopathology (primarily depression) and shorter telomere length, but the nature of this relationship has not been fully understood. Here, we review and evaluate the evidence for impaired telomere biology as a consequence of psychopathology or as a contributing factor, and the important mediating roles of chronic psychological stress and impaired allostasis. There is evidence for a triadic relationship among stress, telomere shortening, and psychiatric disorders that is positively reinforcing and unfolds across the life course and, possibly, across generations. We review the role of genetics and biobehavioral responses that may contribute to shorter telomere length, as well as the neurobiological impact of impaired levels of telomerase. These complex interrelationships are important to elucidate because they have implications for mental and physical comorbidity and, potentially, for the prevention and treatment of depression. PMID- 29494258 TI - Treatment Selection in Depression. AB - Mental health researchers and clinicians have long sought answers to the question "What works for whom?" The goal of precision medicine is to provide evidence based answers to this question. Treatment selection in depression aims to help each individual receive the treatment, among the available options, that is most likely to lead to a positive outcome for them. Although patient variables that are predictive of response to treatment have been identified, this knowledge has not yet translated into real-world treatment recommendations. The Personalized Advantage Index (PAI) and related approaches combine information obtained prior to the initiation of treatment into multivariable prediction models that can generate individualized predictions to help clinicians and patients select the right treatment. With increasing availability of advanced statistical modeling approaches, as well as novel predictive variables and big data, treatment selection models promise to contribute to improved outcomes in depression. PMID- 29494260 TI - EML4-ALK Variant Affects ALK Resistance Mutations. PMID- 29494259 TI - Symptom Burden in the First Year After Cancer Diagnosis: An Analysis of Patient Reported Outcomes. AB - Purpose Improvement in the quality of life of patients with cancer requires attention to symptom burden across the continuum of care, with the use of patient reported outcomes key to achieving optimal care. Yet there have been few studies that have examined symptoms in the early postdiagnosis period during which suboptimal symptom control may be common. A comprehensive analysis of temporal trends and risk factors for symptom burden in newly diagnosed patients with cancer is essential to guide supportive care strategies. Methods A retrospective observational study was performed of patients who were diagnosed with cancer between January 2007 and December 2014 and who survived at least 1 year. Patient reported Edmonton Symptom Assessment System scores, which are prospectively collected at outpatient visits, were linked to provincial administrative health care data. We described the proportion of patients who reported moderate-to severe symptom scores by month during the first year after diagnosis according to disease site. Multivariable logistic regression models were constructed to identify risk factors for moderate-to-severe symptom scores. Results Of 120,745 patients, 729,861 symptom assessments were recorded within 12 months of diagnosis. For most symptoms, odds of elevated scores were highest in the first month, whereas nausea had increased odds of elevated scores up to 6 months after diagnosis. On multivariable analysis, cancer site, younger age, higher comorbidity, female sex, lower income, and urban residence were associated with significantly higher odds of elevated symptom burden. Conclusion A high prevalence of moderate-to-severe symptom scores was observed in cancers of all sites. Patients are at risk of experiencing multiple symptoms in the immediate postdiagnosis period, which underscores the need to address supportive care requirements early in the cancer journey. Patient subgroups who are at higher risk of experiencing moderate-to-severe symptoms should be targeted for tailored supportive care interventions. PMID- 29494261 TI - Sentence production in Parkinson's disease. AB - While growing evidence reports changes in language use in non-demented individuals with Parkinson's disease (PD), the presence and nature of the deficits remain largely unclear. Researchers have proposed that dysfunctioning fronto-basal ganglia circuit results in impaired grammatical processes, predicting qualitatively similar language impairments between individuals with PD and agrammatic Broca's aphasia, whereas others suggest that PD is not associated with language-specific grammatical impairment. In addition, there is a paucity of research examining syntactic production in PD at the sentence-level. This study examined sentence production of individuals with PD, healthy older adults, and individuals with agrammatic Broca's aphasia. In Experiment 1, using a Cinderella story-telling task, proportion of grammatical sentences, number of embedded clauses and production of verb arguments in sentences were examined. In Experiment 2, a structured sentence elicitation task was used in which syntactic complexity of sentences (canonical vs. non-canonical word order) was systematically manipulated while minimizing demands for non-syntactic processing. Only the participants with agrammatic Broca's aphasia showed significantly impaired syntactic production in both experiments. Participants with PD did not show impaired syntactic production in either task, despite impairments in lexical retrieval, repetition of words and sentences, and speech production. These findings suggest that impaired syntactic processing may not be a core deficit underlying the changes in language use in non-demented PD. Changes in language use in PD are qualitatively different from language deficits in aphasia. PMID- 29494262 TI - The ER-localized autophagy protein EPG-3/VMP1 regulates ER contacts with other organelles by modulating ATP2A/SERCA activity. AB - The ER forms contacts with other endomembrane systems to exchange materials (e.g., calcium and lipids) and also to modulate dynamic organelle processes, including fission, cargo sorting and movement. During autophagosome formation, dynamic contacts between the ER and the phagophore membrane are crucial for phagophore expansion and closure. Little is known about the mechanisms underlying the formation and disassembly of the ER contacts. We found that the ER-localized autophagy protein EPG-3/VMP1 plays an essential role in controlling ER-phagophore dissociation and also the disassembly of ER contacts with LDs, mitochondria and endolysosomes. VMP1 regulates the ER contact by activating the ER calcium channel ATP2A/SERCA (ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting). CALM (calmodulin) acts as one of the downstream calcium effectors that controls the PIK3C3/VPS34 phosphatidylinositol (PtdIns) 3-kinase (PtdIns3K) activity to maintain these contacts. Our study provides insights into the molecular mechanisms which regulate ER contacts and generate autophagosomes. PMID- 29494263 TI - Clinical and Histopathologic Features of Consecutive Exotropia. AB - PURPOSE: The purpose of this study is to investigate clinical and histopathologic features of consecutive exotropia. METHODS: Thirty patients with consecutive exotropia and negative forced duction testing underwent unilateral medial rectus resection and advancement. Abnormal scleral attachment (appearance of stretched scar or slipped muscle) was documented and compared with histopathology results. The term "stretched scar" is used when tendon-like scar appears between muscle fibers and scleral attachment. The term "slipped muscle" is used when a thin capsule is attached to the sclera and the muscle fibers retracted posteriorly in the capsule. Histopathologic results of resected medial rectus muscles of 11 control patients were compared with cases of consecutive exotropia. Surgical success was defined as <10 PD deviation at both distance and near, 6 months after the surgery. Dose-response and risk factors for abnormal scleral attachment were also evaluated. RESULTS: Forty percent of the cases had abnormal scleral attachment. Nineteen patients (63%) showed successful results. The mean dose responses were for near 4.7 and for distance 4.2 prism diopters per millimeters of resection plus advancement. Preoperative medial rectus underaction was a risk factor for abnormal scleral attachment. The mean muscle percentage in pathology was 10 +/- 18.7 in patients with abnormal scleral attachment, 28.3 +/- 27.9 in other consecutive exotropia patients, and 26.5 +/- 30.6 in 11 control eyes. CONCLUSION: This study showed surgical success of 63% with one-muscle surgery in consecutive exotropia. Calculated dose-responses could be helpful in surgical planning. In the cases with preoperative medial rectus underaction, risk of abnormal scleral attachment is increased. PMID- 29494265 TI - Pharmacological interventions for psychosis in Parkinson's disease patients. AB - INTRODUCTION: Psychosis is a common problem for people treated for Parkinson's disease. The syndrome is quite stereotypic, with hallucinations being the most common, followed by delusions. While the hallucinations are usually not very bothersome, the delusions are typically paranoid in nature. Treatment is often, but not always, required. Areas covered: This article reviews the therapeutic approaches of this syndrome focusing on drug treatments used once contributory factors have been removed. This includes a review of the evidence supporting the use of clozapine and, most recently, pimavanserin, the first drug with antipsychotic efficacy that has no effect on dopamine. Treatment with second generation antipsychotic drugs and cholinesterase inhibitors are also reviewed. Expert opinion: Clozapine and pimavanserin have proven efficacy for Parkinson's disease psychosis (PDP), without impairing motor function. In clozapine's favor are its antipsychotic benefits seen within 1 week and its effectiveness in improving tremor in PD. However, this is counterbalanced by the need for blood monitoring, despite the extremely low doses used, and sedation. Pimanvanserin is well tolerated, without sedation or other significant side effects. Its onset of benefit, however takes 4-6 weeks. While quetiapine is also frequently used, its efficacy is not supported by double blinded, randomized trials. PMID- 29494264 TI - Cystathionine beta-synthase regulates mitochondrial morphogenesis in ovarian cancer. AB - Deregulation of mitochondrial morphogenesis, a dynamic equilibrium between mitochondrial fusion and fission processes, is now evolving as a key metabolic event that fuels tumor growth and therapy resistance. However, fundamental knowledge underpinning how cancer cells reprogram mitochondrial morphogenesis remains incomplete. Here, we report that cystathionine beta-synthase (CBS) reprograms mitochondrial morphogenesis in ovarian cancer (OvCa) cells by selectively regulating the stability of mitofusin 2 (MFN2). Clinically, high expression of both CBS and MFN2 implicates poor overall survival of OvCa patients, and a significant association between CBS and MFN2 expression exists in individual patients in the same data set. The silencing of CBS by small interfering RNA or inhibition of its catalytic activity by a small molecule inhibitor creates oxidative stress that activates JNK. Activated JNK phosphorylates MFN2 to recruit homologous to the E6-AP carboxyl terminus' domain containing ubiquitin E3 ligase for its degradation via the ubiquitin-proteasome system. Supplementation with hydrogen sulfide or glutathione (the catalytic products of CBS enzymatic activity), anti-oxidants, or a JNK inhibitor restores MFN2 expression. In CBS-silenced orthotopic xenograft tumor tissues, MFN2 but not MFN1 is selectively downregulated. In summary, this report reveals a role for deregulated mitochondrial morphogenesis in OvCa, suggests one of the mechanisms for this deregulation, and provides a way to correct it through modulation of the metabolic enzyme CBS.-Chakraborty, P. K., Murphy, B., Mustafi, S. B., Dey, A., Xiong, X., Rao, G., Naz, S., Zhang, M., Yang, D., Dhanasekaran, D. N., Bhattacharya, R., Mukherjee, P. Cystathionine beta-synthase regulates mitochondrial morphogenesis in ovarian cancer. PMID- 29494267 TI - The Effects of Local and Systemic Administration of Proline on Wound Healing in Rats. AB - PURPOSE: Wound healing consists of a sequence of complex molecular and cellular events. Collagen is composed mainly of proline and hydroxyproline. Proline and hydroxyproline constitute 1/3 of the amino acids in collagen, which makes up approximately 30% of the proteins within the body. The hydroxylation of proline found in collagen determines the stability of the triple helical structure of collagen. In this study, we examined the effects of local and systemic administration of proline on wound healing. MATERIALS AND METHODS: 24 female Sprague-Dawley rats were used in the study and divided into three groups. Group 1: The defect created in the backs of the subjects was left to secondary healing. Group 2: 200 ul proline per day was administered topically for 30 days on the defect in the backs of the subjects. Group 3: 200 ul per day was administered intraperitoneally for 30 days on the defect in the backs of the subjects. RESULTS: On day 21, there was a statistically significant difference between the groups in terms of the mean re-epithelialization score. On days 7 and 14, there was a statistically significant difference between the groups in terms of the mean granulation score. On days 7, 14, and 21, there was a statistically significant difference between the groups in terms of the mean collagen accumulation score. On day 30, there was a statistically significant difference between Groups 1 and 3 in terms of the mean E-mode score on mechanical tensile test. CONCLUSION: Our study confirmed that proline has positive effects on wound healing. However, it revealed that systemic administration of proline is more effective than local administration of proline. PMID- 29494266 TI - Abiraterone is effective and should be considered for the treatment of metastatic castrate-naive prostate cancer. AB - INTRODUCTION: Androgen deprivation therapy (ADT) has been the standard of care for the treatment of newly diagnosed metastatic prostate cancer for the past 70 years. Furthermore, adding docetaxel chemotherapy to ADT significantly improved patient survival, and thus became the new standard for patients with high volume disease. However, recent evidence has called this treatment strategy into question since a published study has shown that the drug abiraterone has a similar benefit to docetaxel in a similar patient population group but with less toxicity. The following article considers this key paper and its implications. Areas covered: In this key paper evaluation, the authors discuss the rational, trial design and results of the LATITUDE trial. Furthermore, the past and current standard of care of metastatic castrate-naive prostate cancer (mCNPC) is discussed, while the authors also compare abiraterone and docetaxel in terms of benefit, safety profile, and affordability. Expert opinion: Abiraterone is highly effective and has an excellent safety profile for the treatment of metastatic castrate-naive prostate cancer. It is the authors' opinion that it should now be considered the new standard of care. PMID- 29494268 TI - The relationship between caregivers' subjective social status and asthma symptoms and management for urban children. AB - OBJECTIVE: Subjective social status (SSS) is a person's perception of his/her social standing among others. We explored the relationship between caregivers' SSS and asthma symptoms, visits, and medication use among children with persistent asthma. METHODS: We analyzed baseline data of children (3-10 years) from the SB-TEAM trial in Rochester, NY. Using a modified MacArthur Scale of SSS, caregivers rated themselves "a lot worse off" to "a lot better off" compared to 4 groups (e.g., neighbors). "Low SSS" was defined by a response of "a lot worse off" or "somewhat worse off" for any of the referent groups. Caregivers reported their child's asthma symptoms, healthcare visits for asthma, and medication use. Bivariate and multivariate statistics were used. RESULTS: We found that, of the 230 children enrolled (participation rate:78%, 62% Black, 72% Medicaid), 29% of caregivers had low SSS. Caregivers with low SSS had more depressive symptoms (46% vs. 28%) and lower social support (69.1 vs. 77.7). In multivariable analyses, children of caregivers with low SSS had fewer symptom-free days/2 weeks (5.8 vs. 7.9, p = .01). While they were more likely to have a routine asthma visit in the past year (35% vs. 23%, adjusted p = .03), there was no difference in their use of preventive medication. CONCLUSIONS: Many caregivers of children with persistent asthma report low SSS. While children of these caregivers had fewer symptom-free days, they were not more likely to use preventive medications. Efforts are needed to support these caregivers to ensure optimal preventive care and reduce morbidity. PMID- 29494269 TI - Decomposition of leg movements during overground walking in individuals with traumatic brain injury. AB - OBJECTIVE: Walking requires precise coordination of bilateral lower extremity motions at all joints. This ability can be affected by traumatic brain injury (TBI). The study investigated inter-joint coordination of lower extremities during overground walking after TBI. METHODS: Ten individuals with post-injury ataxia, postural stability and gait abnormalities, as well as 10 sex- and age matched control subjects were involved in the study. Participants walked at self selected speed in three experimental conditions: normal walking without any additional task; walking with a narrow base of support, and walking while holding a cup full of water. Inter-joint coordination was analysed as the percentage of gait cycle during which the leg movement was decomposed with 0% indicating simultaneous motion of the two joints (i.e. hip-knee, knee-ankle, and hip-ankle) through the entire gait cycle or 100% indicating motion of only one joint. Decomposition was calculated for each pair of joints and for the left and right leg separately. RESULTS: Participants with TBI showed greater decomposition indices and poorer inter-joint coordination respectively than control individuals for all joint pairs (p < 0.01). Walking with the narrower base of support or with a cup, increased movement decomposition in the TBI group, but not in the control group. CONCLUSION: The results revealed post-injury gait impairment that manifests as decomposition of multi-joint motions of the lower extremities during overground walking. PMID- 29494271 TI - Molecular identification and in vitro antifungal susceptibility of Scedosporium complex isolates from high-human-activity sites in Mexico. AB - The genus Scedosporium is a complex of ubiquitous moulds associated with a wide spectrum of clinical entities, with high mortality principally in immunocompromised hosts. Ecology of these microorganisms has been studied performing isolations from environmental sources, showing a preference for human impacted environments. This study aimed to evaluate the presence and antifungal susceptibility of Scedosporium complex species in soil samples collected in high human-activity sites of Mexico. A total of 97 soil samples from 25 Mexican states were collected. Identifications were performed by microscopic morphology and confirmed by sequencing of the rDNA (internal transcribed spacer [ITS], D1/D2) and beta-tubulin partial loci. Antifungal susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI) protocols. Soil samples of urban gardens and industrial parks constituted the best sources for isolation of Scedosporium complex species. S. apiospermum sensu stricto was the most prevalent species (69%), followed by S. boydii (16%). Voriconazole (minimal inhibitory concentration [MIC] geometric mean <=2.08 ug/mL), followed by posaconazole (MIC geometric mean <=2.64 ug/mL), exhibited excellent in vitro activity for most species. Amphotericin B and fluconazole demonstrated limited antifungal activity, and all of the strains were resistant to echinocandins. This is the first report in Mexico of environmental distribution and antifungal in vitro susceptibility of these emergent pathogens. PMID- 29494272 TI - The general ventilation multipliers calculated by using a standard Near-Field/Far Field model. AB - In conceptual exposure models, the transmission of pollutants in an imperfectly mixed room is usually described with general ventilation multipliers. This is the approach used in the Advanced REACH Tool (ART) and Stoffenmanager(r) exposure assessment tools. The multipliers used in these tools were reported by Cherrie (1999; http://dx.doi.org/10.1080/104732299302530 ) and Cherrie et al. (2011; http://dx.doi.org/10.1093/annhyg/mer092 ) who developed them by positing input values for a standard Near-Field/Far-Field (NF/FF) model and then calculating concentration ratios between NF and FF concentrations. This study revisited the calculations that produce the multipliers used in ART and Stoffenmanager and found that the recalculated general ventilation multipliers were up to 2.8 times (280%) higher than the values reported by Cherrie (1999) and the recalculated NF and FF multipliers for 1-hr exposure were up to 1.2 times (17%) smaller and for 8 hr exposure up to 1.7 times (41%) smaller than the values reported by Cherrie et al. (2011). Considering that Stoffenmanager and the ART are classified as higher tier regulatory exposure assessment tools, the errors is general ventilation multipliers should not be ignored. We recommend revising the general ventilation multipliers. A better solution is to integrate the NF/FF model to Stoffenmanager and the ART. PMID- 29494270 TI - When is Helicobacter pylori acquired in populations in developing countries? A birth-cohort study in Bangladeshi children. AB - Helicobacter pylori colonization is prevalent throughout the world, and is predominantly acquired during childhood. In developing countries, >70% of adult populations are colonized with H. pylori and >50% of children become colonized before the age of 10 years. However, the exact timing of acquisition is unknown. We assessed detection of H. pylori acquisition among a birth cohort of 105 children in Mirzapur, Bangladesh. Blood samples collected at time 0 (cord blood), and at 6, 12, 18, and 24 months of life were examined for the presence of IgG and IgA antibodies to whole cell H. pylori antigen and for IgG antibodies to the CagA antigen using specific ELISAs and immunoblotting. Breast milk samples were analyzed for H. pylori-specific IgA antibodies. Cord blood was used to establish maternal colonization status. H. pylori seroprevalence in the mothers was 92.8%. At the end of the two-year follow-up period, 50 (47.6%) of the 105 children were positive for H. pylori in more than one assay. Among the colonized children, CagA prevalence was 78.0%. A total of 58 children seroconverted: 50 children showed persistent colonization and 8 (7.6%) children showed transient seroconversion, but immunoblot analysis suggested that the transient seroconversion observed by ELISA may represent falsely positive results. Acquisition of H. pylori was not influenced by the mother H. pylori status in serum or breastmilk. In this population with high H. pylori prevalence, we confirmed that H. pylori in developing countries is detectable mainly after the first year of life. PMID- 29494273 TI - Automated high throughput microscale antibody purification workflows for accelerating antibody discovery. AB - To rapidly find "best-in-class" antibody therapeutics, it has become essential to develop high throughput (HTP) processes that allow rapid assessment of antibodies for functional and molecular properties. Consequently, it is critical to have access to sufficient amounts of high quality antibody, to carry out accurate and quantitative characterization. We have developed automated workflows using liquid handling systems to conduct affinity-based purification either in batch or tip column mode. Here, we demonstrate the capability to purify >2000 antibodies per day from microscale (1 mL) cultures. Our optimized, automated process for human IgG1 purification using MabSelect SuRe resin achieves ~70% recovery over a wide range of antibody loads, up to 500 ug. This HTP process works well for hybridoma derived antibodies that can be purified by MabSelect SuRe resin. For rat IgG2a, which is often encountered in hybridoma cultures and is challenging to purify via an HTP process, we established automated purification with GammaBind Plus resin. Using these HTP purification processes, we can efficiently recover sufficient amounts of antibodies from mammalian transient or hybridoma cultures with quality comparable to conventional column purification. PMID- 29494274 TI - Understanding the barriers to uptake of antenatal vaccination by women from culturally and linguistically diverse backgrounds: A cross-sectional study. AB - The role of maternal vaccination in reducing neonatal morbidity and mortality is expanding but uptake remains suboptimal. While the barriers to uptake have been well described, women from minority groups have not been well represented in previous studies. In this study we examine the facilitators and barriers to uptake of antenatal vaccination by women from culturally and linguistically diverse backgrounds in Melbourne, Australia. 537 women attending antenatal care completed a survey; 69% were born overseas. 63% had or intended to receive pertussis vaccine and 57% had or intended to receive influenza vaccine during their pregnancy. On multivariable analysis, predictors of uptake of pertussis vaccine were healthcare provider recommendation (OR 10, 95% CI 5-21, p < 0.001) and belief maternal pertussis vaccination is safe (OR 36, 95% CI 18-70, p < 0.001). For influenza vaccine, predictors of uptake were previous receipt of influenza vaccine (OR 8, 95% CI 5-15, p < 0.001) and healthcare provider recommendation (OR 30, 95% CI 16-56, p < 0.001). Lack of healthcare provider recommendation was the main reason for non-vaccination (17/46, 37%). While most women were aware of and intended to receive recommended vaccinations, recently arrived migrant women (resident in Australia for less than two years) were less likely to be aware of pertussis vaccine (15/22, 68% vs 452/513, 88%, p = 0.01) and less likely to believe it to be safe during pregnancy (4/22, 18% vs 299/514, 58%, p < 0.001). This highlights the important role of healthcare providers in recommending and educating women, particularly newly arrived migrant women, in their decisions about vaccination during pregnancy. PMID- 29494276 TI - Deja Vu: An Illusion of Prediction. AB - Deja vu is beginning to be scientifically understood as a memory phenomenon. Despite recent scientific advances, a remaining puzzle is the purported association between deja vu and feelings of premonition. Building on research showing that deja vu can be driven by an unrecalled memory of a past experience that relates to the current situation, we sought evidence of memory-based predictive ability during deja vu states. Deja vu did not lead to above-chance ability to predict the next turn in a navigational path resembling a previously experienced but unrecalled path (although such resemblance increased reports of deja vu). However, deja vu states were accompanied by increased feelings of knowing the direction of the next turn. The results suggest that feelings of premonition during deja vu occur and can be illusory. Metacognitive bias brought on by the state itself may explain the peculiar association between deja vu and the feeling of premonition. PMID- 29494275 TI - The gut microbiota and immune checkpoint inhibitors. AB - Although immunotherapy has been remarkably effective across multiple cancer types, there continues to be a significant number of non-responding patients. A possible factor proposed to influence the efficacy of immunotherapies is the gut microbiome. We discuss the results and implications of recent research on the relationship between the gut microbiome, our immune systems, and immune checkpoint inhibitor therapies including anti-CTLA-4 Ab and anti-PD-1 Ab. While the investigations all exhibit interesting results and conclusions, we find little congruence in the specific bacteria that were found favorable for antitumor responses. It is unclear whether the inconsistencies are due to differential approaches in study design (pre-clinical or clinical subjects, anti CTLA-4 Ab or anti-PD-1 Ab), experimental methods and measurements (metagenomics sequencing and clustering variations) or subject population dynamics (differential cancer types and baseline characteristics). Moreover, we note studies regarding particular bacterial commensals and autoimmune diseases, which challenge findings from these investigations. We conclude that with the current research, clinical investigators can appreciate the critical role of gut microbiota in mediating immunostimulant response. However, prospective research exploring the biochemical mechanisms which commensal bacteria communicate with each other and the immune system is imperative to understand how they can be adjusted properly for higher immunotherapy response. PMID- 29494277 TI - Do Evaluations Rise With Experience? AB - Sequential evaluation is the hallmark of fair review: The same raters assess the merits of applicants, athletes, art, and more using standard criteria. We investigated one important potential contaminant in such ubiquitous decisions: Evaluations become more positive when conducted later in a sequence. In four studies, (a) judges' ratings of professional dance competitors rose across 20 seasons of a popular television series, (b) university professors gave higher grades when the same course was offered multiple times, and (c) in an experimental test of our hypotheses, evaluations of randomly ordered short stories became more positive over a 2-week sequence. As judges completed repeated evaluations, they experienced more fluent decision making, producing more positive judgments (Study 4 mediation). This seemingly simple bias has widespread and impactful consequences for evaluations of all kinds. We also report four supplementary studies to bolster our findings and address alternative explanations. PMID- 29494278 TI - Adaptation of adherent-invasive E. coli to gut environment: Impact on flagellum expression and bacterial colonization ability. AB - The pathogenesis of Crohn's disease (CD) is multifactorial and involves genetic susceptibility, environmental triggers and intestinal microbiota. Adherent invasive Escherichia coli (AIEC) are flagellated bacteria more prevalent in CD patients than in healthy subjects and promote chronic intestinal inflammation. We aim at deciphering the role of flagella and flagellin modulation by intestinal conditions. AIEC flagellum expression is required for optimal adhesion to and invasion of intestinal epithelial cells. Interestingly, differential flagellin regulation was observed between commensal E. coli (HS) and AIEC (LF82) strains: flagellum expression by AIEC bacteria, in contrast to that of commensal E. coli, is enhanced under intestinal conditions (the presence of bile acids and mucins). Flagella are involved in the ability of the AIEC LF82 strain to cross a mucus layer in vitro and in vivo, conferring a selective advantage in penetrating the mucus layer and reaching the epithelial surface. In a CEABAC10 mouse model, a non motile mutant (LF82-DeltafliC) exhibits reduced colonization that is restored by a dextran sodium sulfate treatment that alters mucus layer integrity. Moreover, a mutant that continuously secretes flagellin (LF82-DeltaflgM) triggers a stronger inflammatory response than the wild-type strain, and the mutant's ability to colonize the CEABAC10 mouse model is decreased. Overexpression of flagellin in bacteria in contact with epithelial cells can be detrimental to their virulence by inducing acute inflammation that enhances AIEC clearance. AIEC pathobionts must finely modulate flagellum expression during the infection process, taking advantage of their specific virulence gene regulation to improve their adaptability and flexibility within the gut environment. PMID- 29494279 TI - A multiplatform strategy for the discovery of conventional monoclonal antibodies that inhibit the voltage-gated potassium channel Kv1.3. AB - Identifying monoclonal antibodies that block human voltage-gated ion channels (VGICs) is a challenging endeavor exacerbated by difficulties in producing recombinant ion channel proteins in amounts that support drug discovery programs. We have developed a general strategy to address this challenge by combining high level expression of recombinant VGICs in Tetrahymena thermophila with immunization of phylogenetically diverse species and unique screening tools that allow deep-mining for antibodies that could potentially bind functionally important regions of the protein. Using this approach, we targeted human Kv1.3, a voltage-gated potassium channel widely recognized as a therapeutic target for the treatment of a variety of T-cell mediated autoimmune diseases. Recombinant Kv1.3 was used to generate and recover 69 full-length anti-Kv1.3 mAbs from immunized chickens and llamas, of which 10 were able to inhibit Kv1.3 current. Select antibodies were shown to be potent (IC50<10 nM) and specific for Kv1.3 over related Kv1 family members, hERG and hNav1.5. PMID- 29494280 TI - Experimental Increases in Foraging Costs Affect Pectoralis Muscle Mass and Myostatin Expression in Female, but Not Male, Zebra Finches (Taeniopygia guttata). AB - Skeletal muscle remodeling is an important component of phenotypic flexibility in birds and impacts organismal metabolism and performance, which could potentially influence fitness. One regulator of skeletal muscle remodeling is myostatin, an autocrine/paracrine muscle growth inhibitor that may be down-regulated under conditions promoting heavier muscle masses. In this study, we employed protocols requiring hovering while foraging to increase foraging costs and modify phenotypes of zebra finches (Taeniopygia guttata). We examined the effects of high-cost foraging (HF) on skeletal muscle masses and used real-time reverse transcription polymerase chain reaction and Western blots to measure gene and protein expression of myostatin and its metalloproteinase activators tolloid-like proteases TLL-1 and TLL-2 in pectoralis muscle. Female finches average shorter wings and higher wing loading than males, so increased flight costs might be expected to disproportionately affect females. Indeed, HF female finches exhibited reduced total fat masses, increased pectoralis muscle masses, and lower myostatin protein levels than controls. Male finches showed no significant differences in pectoralis muscle masses or myostatin protein levels between HF and control birds. Myostatin, TLL-1, and TLL-2 messenger RNA (mRNA) expression remained stable between treatments for both female and male finches. Myostatin mRNA and protein levels showed variable directions of correlations with pectoralis mass residuals among treatments. Thus, these data offer only mixed support for a regulatory role for myostatin in mediating the flexibility of pectoralis muscle phenotypes of small birds. PMID- 29494281 TI - Antioxidant Enzyme Activities Vary with Predation Risk and Environmental Conditions in Free-Living Passerine Birds. AB - Prolonged physiological stress response may lead to an excessive production of reactive oxygen species (ROS) and ultimately to oxidative stress and severe fitness costs. We investigated whether natural variation in predation risk, induced by pygmy owls (Glaucidium passerinum), modifies the oxidative status of two free-living food-supplemented passerine bird species-the great tit (Parus major) and the willow tit (Poecile montanus)-in March 2012 and 2013. Predation risk significantly affected antioxidant enzyme activities of willow tits. Antioxidant enzyme activities (principal component factor 2 [PC2] representing glutathione-S-transferase and superoxide dismutase activities) were higher in high predation risk areas in 2013 than in low predation risk areas in the same year. Higher enzyme activities may suggest higher ROS production in birds living under high predation risk. In addition, antioxidant enzyme activities (PC2) were also higher in high predation risk areas in 2013 than in high predation risk areas in the previous year, 2012. This may represent variation in the risk represented by pygmy owls, which is probably inversely related to the natural fluctuations in the densities of their main prey, voles. In willow tits, PC1 (representing catalase, total glutathione, the ratio of reduced to oxidized glutathione, and protein carbonylation) was not affected by perceived predation risk, nor were antioxidant levels or enzyme activities in great tits. Higher enzyme activities observed in willow tits suggest that predator presence can modify the antioxidant status of avian prey, but the response also seem to be influenced by other environmental characteristics, like harsh winter conditions. PMID- 29494282 TI - Polyozellus multiplex (Thelephorales) is a species complex containing four new species. AB - Geographic, morphological, and internal transcribed spacer (ITS)-based molecular review of collections identified as Polyozellus multiplex revealed that it is a complex of five phylogenetic species. Average spore size-either less or more than 7 * 6 um-splits the complex into a small-spored group of two (P. multiplex and P. atrolazulinus) and a large-spored group of three (P. mariae, P. marymargaretae, and P. purpureoniger). Basidiocarps of the small-spored species are somewhat smaller than the large-spored ones, are various shades of blue, dark all the way to black, with brownish tomentum only in early growth, have dark context, and have pilei that tend to flare out at the edge. The large-spored species produce somewhat larger sporocarps, have light or lighter context than the pileipelis, and usually retain some brown on the mature pileipellis, the edge of which tends to curl like a cabbage leaf. All will darken or blacken with age. The species of the P. multiplex complex are distributed in the northern coniferous region, with the exception of Europe. One species (P. atrolazulinus) is known from three regions, eastern Asia, western North America, and northeastern North America. Two species are known from two regions: P. purpureoniger in eastern Asia and northwestern North America and P. multiplex in eastern Asia and eastern North America. Two species have been documented in one region only: P. mariae in northeastern North America and P. marymargaretae in western North America. A combination of location, macromorphology, and spore size will usually differentiate the species of the complex. PMID- 29494283 TI - Exploring nighttime road traffic noise: A comprehensive predictive surface for Toronto, Canada. AB - Road traffic noise can adversely impact the health of city residents, particularly when it occurs at night. The objective of this study was to evaluate nighttime traffic ambient noise in Toronto, Canada using measured and model estimated noise levels. Road traffic noise was measured at 767 locations over 3 seasonal sampling campaigns between June 2012 and October 2013 to fully capture noise variability in Toronto. Temporal and campaign-specific spatial models, developed using the noise measurements, were used to build a final predictive surface. The surface was capable of estimating noise across the city over a 24-hr time frame. Measured and surface-estimated noise levels were compared with guidelines from the World Health Organization and the Province of Ontario to identify areas where noise may pose a health risk. Measured mean nighttime noise in Toronto exceeded World Health Organization (40 dBA) guidelines and mean daytime noise exceeded provincial (55 dBA) guidelines. The final predictive surface, incorporating spatial variables and daily cycles in noise levels, provides noise estimates geocoded for the entire study area. This tool could be used for epidemiological studies and to inform noise mitigation efforts. Based on surface-estimated noise levels during the quietest time of night (2 a.m.-2:30 a.m.), 100% of Toronto has nighttime noise exceeding 40 dBA (mean = 57 dBA, range = 49-110 dBA). A predictive surface was developed to estimate geocoded noise levels and facilitate further study of noise in Toronto. This tool can be used to assess road traffic noise, particularly at night, as an environmental health hazard. PMID- 29494284 TI - Taurine alleviates endoplasmic reticulum stress in the chondrocytes from patients with osteoarthritis. AB - Osteoarthritis (OA), characterized by pain and stiffness, swelling, deformity and dysfunction of joints, affects large numbers of population. The purpose of this study was to discover the effects of taurine in human OA chondrocytes and explore the underlying mechanisms. 46 patients with different grades of OA were recruited. Of these patients, 24 underwent total knee replacement and cartilages were harvested. The mRNA expressions of type II collagen (Collagen II) and endoplasmic reticulum (ER) stress markers (GRP78, GADD153 and Caspase-12) in cartilages were quantified by qRT-PCR. Cell viability and apoptosis of patient derived chondrocytes were assessed by the CCK-8 assay and flow cytometry assay, respectively. Meanwhile, protein levels of Collagen II and ER stress markers both in cartilages and chondrocytes were evaluated by Western blot. The mRNA and protein levels of Collagen II decreased as OA progressed, while the expressions of ER stress markers increased dramatically. H2O2 induced ER stress in chondrocytes, as shown by the significant increase in the expression of ER stress markers, inhibited chondrocyte viability and Collagen II synthesis, promoted apoptosis. However, taurine treatment inhibited these above phenomena. These results indicated that taurine exhibited anti-OA effect by alleviating H2O2 induced ER stress and subsequently inhibiting chondrocyte apoptosis. PMID- 29494285 TI - Assessing indoor air quality in New York City nail salons. AB - Nail salons are an important business and employment sector for recent immigrants offering popular services to a diverse range of customers across the United States. However, due to the nature of nail products and services, salon air can be burdened with a mix of low levels of hazardous airborne contaminants. Surveys of nail technicians have commonly found increased work-related symptoms, such as headaches and respiratory irritation, that are consistent with indoor air quality problems. In an effort to improve indoor air quality in nail salons, the state of New York recently promulgated regulations to require increased outdoor air and "source capture" of contaminants. Existing indoor air quality in New York State salons is unknown. In advance of the full implementation of the rules by 2021, we sought to establish reliable and usable baseline indoor air quality metrics to determine the feasibility and effectiveness of the requirement. In this pilot study, we measured total volatile organic compounds (TVOC) and carbon dioxide (CO2) concentrations in 10 nail salons located in New York City to assess temporal and spatial trends. Within salon contaminant variation was generally minimal, indicating a well-mixed room and similar general exposure despite the task being performed. TVOC and CO2 concentrations were strongly positively correlated (rho = 0.81; p < 0.01) suggesting that CO2 measurements could potentially be used to provide an initial determination of acceptable indoor air quality for the purposes of compliance with the standard. An almost tenfold increase in TVOC concentration was observed when the American National Standards Institute/American Society of Heating, Refrigerating and Air-Conditioning Engineers (ANSI/ASHRAE) target CO2 concentration of 850 ppm was exceeded compared to when this target was met. PMID- 29494286 TI - Oxygen dependence of respiration in rat spinotrapezius muscle contracting at 0.5 8 twitches per second. AB - The oxygen dependence of respiration was obtained in situ in microscopic regions of rat spinotrapezius muscle for different levels of metabolic activity produced by electrical stimulation at rates from 0.5 to 8 Hz. The rate of O2 consumption (Vo2) was measured with phosphorescence quenching microscopy (PQM) as the rate of O2 disappearance in a muscle with rapid flow arrest. The phosphorescent oxygen probe was loaded into the interstitial space of the muscle to give O2 tension (Po2) in the interstitium. A set of sigmoid curves relating the Po2 dependence of Vo2 was obtained with a Po2-dependent region below a characteristic Po2 (~30 mmHg) and a Po2-independent region above this Po2. The Vo2(Po2) plots were fit by the Hill equation containing O2 demand (rest to 8 Hz: 216 +/- 26 to 636 +/- 77 nl O2/cm3 s) and the Po2 value corresponding to O2 demand/2 (rest to 8 Hz: 22 +/- 4 to 11 +/- 1 mmHg). The initial Po2 and Vo2 pairs of values measured at the moment of flow arrest formed a straight line, determining the rate of oxygen supply. This line had a negative slope, equal to the oxygen conductance for the O2 supply chain. For each level of tissue blood flow the set of possible values of Po2 and Vo2 consists of the intersection points between this O2 supply line and the set of Vo2 curves. An electrical analogy for the intraorgan O2 supply and consumption is an inverting transistor amplifier, which allows the use of graphic analysis methods for prediction of the behavior of the oxygen processing system in organs. NEW & NOTEWORTHY The sigmoidal shape of curves describing oxygen dependence of muscle respiration varies from basal to maximal workload and characterizes the oxidative metabolism of muscle. The rate of O2 supply depends on extracellular O2 tension and is determined by the overall oxygen conductance in the muscle. The dynamics of oxygen consumption is determined by the supply line that intersects the oxygen demand curves. An electrical analogy for the oxygen supply/consumption system is an inverting transistor amplifier. PMID- 29494287 TI - Resveratrol regulates blood pressure by enhancing AMPK signaling to downregulate a Rac1-derived NADPH oxidase in the central nervous system. AB - Resveratrol is a polyphenol with pleiotropic effects against oxidative damage that has been widely implicated in lowering hypertension risk. The purpose of this study was to determine whether improve nitric oxide (NO) release in the brain, either through the activation of AMP-activated protein kinase (AMPK) or reduced Ras-related C3 botulinum toxin substrate 1 (Rac1)-induced reactive oxygen species (ROS) generation, thereby reducing blood pressure (BP) in rats with fructose-induced hypertension. The rats were fed with 10% fructose or Crestor (rosuvastatin; 1.5 mg.kg-1.day-1) and resveratrol (10 mg.kg-1.day-1) treatment for 1 wk, then the systolic blood pressure of the rats was measured by tail-cuff method. Endogenous in vivo superoxide radical production in the nucleus tractus solitarii (NTS) was determined with dihydroethidium. Immunoblotting analyses were used to quantify protein expression levels. Oral resveratrol treatment for 1 wk decreased BP and increased NO production in the NTS of fructose-fed rats but not in the control Wistar-Kyoto rats. The effect of Crestor is opposite that of resveratrol. Fructose induced hypertension by inactivating AMPK, which in turn enhanced the generation of ROS and reduced manganese superoxide dismutase by increasing the activity of Rac1-induced NADPH oxidase, abolishing the activity of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) and ribosomal protein S6 kinase (RSK) and neuronal nitric oxide synthase (nNOS) phosphorylation signaling pathway in the brain. However, resveratrol had the opposite effect in the fructose-fed rats. Overall, we show that the resveratrol decreased BP better than Crestor, abolished ROS generation, and enhanced the ERK1/2-RSK-nNOS pathway by activating AMPK to downregulate Rac1-induced NADPH oxidase levels in the NTS during oxidative stress-associated hypertension. NEW & NOTEWORTHY 1) Evidence showed that the Ras-related C3 botulinum toxin substrate 1 (Rac1) augmented by Crestor (rosuvastatin) did not result in a significant change in blood pressure (BP) in fructose-induced hypertension. 2) Fructose induced hypertension by inactivating AMP-activated protein kinase (AMPK), which in turn enhanced the generation of reactive oxygen species (ROS) and reduced manganese superoxide dismutase in the brain. 3) Resveratrol decreased BP better than Crestor, abolished ROS generation, and enhanced the ERK1/2-ribosomal protein S6 kinase neuronal nitric oxide synthase pathway by activating AMPK to negatively regulate Rac1-induced NADPH oxidase levels in the nucleus tractus solitarii during oxidative stress-associated hypertension. PMID- 29494288 TI - Respiratory pump maintains cardiac stroke volume during hypovolemia in young, healthy volunteers. AB - Spontaneous breathing has beneficial effects on the circulation, since negative intrathoracic pressure enhances venous return and increases cardiac stroke volume. We quantified the contribution of the respiratory pump to preserve stroke volume during hypovolemia in awake, young, healthy subjects. Noninvasive stroke volume, cardiac output, heart rate, and mean arterial pressure (Finometer) were recorded in 31 volunteers (19 women), 19-30 yr old, during normovolemia and hypovolemia (approximating 450- to 500-ml reduction in central blood volume) induced by lower-body negative pressure. Control-mode noninvasive positive pressure ventilation was employed to reduce the effect of the respiratory pump. The ventilator settings were matched to each subject's spontaneous respiratory pattern. Stroke volume estimates during positive-pressure ventilation and spontaneous breathing were compared with Wilcoxon matched-pairs signed-rank test. Values are overall medians. During normovolemia, positive-pressure ventilation did not affect stroke volume or cardiac output. Hypovolemia resulted in an 18% decrease in stroke volume and a 9% decrease in cardiac output ( P < 0.001). Employing positive-pressure ventilation during hypovolemia decreased stroke volume further by 8% ( P < 0.001). Overall, hypovolemia and positive-pressure ventilation resulted in a reduction of 26% in stroke volume ( P < 0.001) and 13% in cardiac output ( P < 0.001) compared with baseline. Compared with the situation with control-mode positive-pressure ventilation, spontaneous breathing attenuated the reduction in stroke volume induced by moderate hypovolemia by 30% (i.e., -26 vs. -18%). In the patient who is critically ill with hypovolemia or uncontrolled hemorrhage, spontaneous breathing may contribute to hemodynamic stability, whereas controlled positive-pressure ventilation may result in circulatory decompensation. NEW & NOTEWORTHY Maintaining spontaneous respiration has beneficial effects on hemodynamic compensation, which is clinically relevant for patients in intensive care. We have quantified the contribution of the respiratory pump to cardiac stroke volume and cardiac output in healthy volunteers during normovolemia and central hypovolemia. The positive hemodynamic effect of the respiratory pump was abolished by noninvasive, low-level positive pressure ventilation. Compared with control-mode positive-pressure ventilation, spontaneous negative-pressure ventilation attenuated the fall in stroke volume by 30%. PMID- 29494289 TI - Effects of triceps surae muscle strength and tendon stiffness on the reactive dynamic stability and adaptability of older female adults during perturbed walking. AB - This study aimed to examine whether the triceps surae (TS) muscle-tendon unit (MTU) mechanical properties affect gait stability and its reactive adaptation potential to repeated perturbation exposure in older adults. Thirty-four older adults each experienced eight separate unexpected perturbations during treadmill walking, while a motion capture system was used to determine the margin of stability (MoS) and base of support (BoS). Ankle plantar flexor muscle strength and Achilles tendon (AT) stiffness were analyzed using ultrasonography and dynamometry. A median split and separation boundaries classified the subjects into two groups with GroupStrong ( n = 10) showing higher ankle plantar flexor muscle strength (2.26 +/- 0.17 vs. 1.47 +/- 0.20 N.m/kg, means +/- SD; P < 0.001) and AT stiffness (544 +/- 75 vs. 429 +/- 86 N/mm; P = 0.004) than GroupWeak ( n = 12). The first perturbation caused a negative DeltaMoS (MoS in relation to unperturbed baseline walking) at touchdown of perturbed step (PertR), indicating an unstable position. GroupStrong required four recovery steps to return to DeltaMoS zero level, whereas GroupWeak was unable to return to baseline within the analyzed steps. However, after repeated perturbations, both groups increased DeltaMoS at touchdown of PertR with a similar magnitude. Significant correlations between DeltaBoS and DeltaMoS at touchdown of the first recovery step and TS MTU capacities (0.41 < r < 0.57; 0.006 < P < 0.048) were found. We conclude that older adults with TS muscle weakness have a diminished ability to control gait stability during unexpected perturbations, increasing their fall risk, but that degeneration in muscle strength and tendon stiffness may not inhibit the ability of the locomotor system to adapt the reactive motor response to repeated perturbations. NEW & NOTEWORTHY Triceps surae muscle weakness and a more compliant Achilles tendon partly limit older adults' ability to effectively enlarge the base of support and recover dynamic stability after an unexpected perturbation during walking, increasing their fall risk. However, the degeneration in muscle strength and tendon stiffness may not inhibit the ability of the locomotor system to adapt the reactive motor response to repeated perturbations. PMID- 29494290 TI - Augmenting exercise capacity with noninvasive ventilation in high-level spinal cord injury. AB - High-level spinal cord injury (SCI) results in a very limited innervated skeletal muscle mass that strongly reduces exercise capacity. Our recent work showed that when adding functional electrical stimulation (FES) of the paralyzed legs (hybrid FES-exercise) to produce higher exercise capacity, peak ventilation became a limiting factor to training-induced improvement in aerobic capacity. Our assumption was that the systemic adaptations to exercise training are delimited by the maximal ventilation that can be achieved. However, herein, we present a case showing an acute increase in aerobic capacity when using noninvasive ventilatory support (NIV) during FES-rowing test in an individual who had previously experimented a plateau in his aerobic capacity for 18 mo. An 18-yr-old man with C5 SCI trained with arms-only rowing for 6 mo and subsequently trained with hybrid FES-rowing for 18 mo. Peak minute ventilation (Vepeak) and peak oxygen consumption (Vo2peak) were increased after arms-only training and increased further with 6 mo of hybrid FES-row training. Despite continued intense and frequent, hybrid FES-row training, neither Vepeak nor Vo2peak increased further over the next year (1.94 and 66.0 l/min). However, when this individual performed a FES-rowing Vo2peak test with the addition of NIV, Vepeak increased by 5 l/min, resulting in an improved Vo2peak (2.23 l/min, +12%). This case demonstrates that noninvasive ventilation can overcome limitations to ventilation in high-level SCI and improve aerobic capacity during hybrid FES-exercise to a level not otherwise achievable. In addition, it broadly illustrates the intimate role of pulmonary function in determining the capacity to perform exercise. PMID- 29494291 TI - An advanced magnetic resonance imaging perspective on the etiology of deep tissue injury. AB - Early diagnosis of deep tissue injury remains problematic due to the complicated and multifactorial nature of damage induction and the many processes involved in damage development and recovery. In this paper, we present a comprehensive assessment of deep tissue injury development and remodeling in a rat model by multiparametric magnetic resonance imaging (MRI) and histopathology. The tibialis anterior muscle of rats was subjected to mechanical deformation for 2 h. Multiparametric in vivo MRI, consisting of T2, T2*, mean diffusivity (MD), and angiography measurements, was applied before, during, and directly after indentation as well as at several time points during a 14-day follow-up. MRI readouts were linked to histological analyses of the damaged tissue. The results showed dynamic change in various MRI parameters, reflecting the histopathological status of the tissue during damage induction and repair. Increased T2 corresponded with edema, muscle cell damage, and inflammation. T2* was related to tissue perfusion, hemorrhage, and inflammation. MD increase and decrease was reported on the tissue's microstructural integrity and reflected muscle degeneration and edema as well as fibrosis. Angiography provided information on blockage of blood flow during deformation. Our results indicate that the effects of a single damage-causing event of only 2 h of deformation were present up to 14 days. The initial tissue response to deformation, as observed by MRI, starts at the edge of the indentation. The quantitative MRI readouts provided distinct and complementary information on the extent, temporal evolution, and microstructural basis of deep tissue injury-related muscle damage. NEW & NOTEWORTHY We have applied a multiparametric MRI approach linked to histopathology to characterize damage development and remodeling in a rat model of deep tissue injury. Our approach provided several relevant insights in deep tissue injury. Response to damage, as observed by MRI, started at some distance from the deformation. Damage after a single indentation period persisted up to 14 days. The MRI parameters provided distinct and complementary information on the microstructural basis of the damage. PMID- 29494294 TI - Discrete physiological effects of beetroot juice and potassium nitrate supplementation following 4-wk sprint interval training. AB - The physiological and exercise performance adaptations to sprint interval training (SIT) may be modified by dietary nitrate ([Formula: see text]) supplementation. However, it is possible that different types of [Formula: see text] supplementation evoke divergent physiological and performance adaptations to SIT. The purpose of this study was to compare the effects of 4-wk SIT with and without concurrent dietary [Formula: see text] supplementation administered as either [Formula: see text]-rich beetroot juice (BR) or potassium [Formula: see text] (KNO3). Thirty recreationally active subjects completed a battery of exercise tests before and after a 4-wk intervention in which they were allocated to one of three groups: 1) SIT undertaken without dietary [Formula: see text] supplementation (SIT); 2) SIT accompanied by concurrent BR supplementation (SIT + BR); or 3) SIT accompanied by concurrent KNO3 supplementation (SIT + KNO3). During severe-intensity exercise, Vo2peak and time to task failure were improved to a greater extent with SIT + BR than SIT and SIT + KNO3 ( P < 0.05). There was also a greater reduction in the accumulation of muscle lactate at 3 min of severe intensity exercise in SIT + BR compared with SIT + KNO3 ( P < 0.05). Plasma [Formula: see text] concentration fell to a greater extent during severe intensity exercise in SIT + BR compared with SIT and SIT + KNO3 ( P < 0.05). There were no differences between groups in the reduction in the muscle phosphocreatine recovery time constant from pre- to postintervention ( P > 0.05). These findings indicate that 4-wk SIT with concurrent BR supplementation results in greater exercise capacity adaptations compared with SIT alone and SIT with concurrent KNO3 supplementation. This may be the result of greater NO-mediated signaling in SIT + BR compared with SIT + KNO3. NEW & NOTEWORTHY We compared the influence of different forms of dietary nitrate supplementation on the physiological and performance adaptations to sprint interval training (SIT). Compared with SIT alone, supplementation with nitrate-rich beetroot juice, but not potassium [Formula: see text], enhanced some physiological adaptations to training. PMID- 29494293 TI - Mechanisms for the age-related increase in fatigability of the knee extensors in old and very old adults. AB - The mechanisms for the age-related increase in fatigability during high-velocity contractions in old and very old adults (>=80 yr) are unresolved. Moreover, whether the increased fatigability with advancing age and the underlying mechanisms differ between men and women is not known. The purpose of this study was to quantify the fatigability of knee extensor muscles and identify the mechanisms of fatigue in 30 young (22.6 +/- 0.4 yr; 15 men), 62 old (70.5 +/- 0.7 yr; 33 men), and 12 very old (86.0 +/- 1.3 yr; 6 men) men and women elicited by high-velocity concentric contractions. Participants performed 80 maximal velocity contractions (1 contraction per 3 s) with a load equivalent to 20% of the maximum voluntary isometric contraction. Voluntary activation and contractile properties were quantified before and immediately following exercise (<10 s) using transcranial magnetic stimulation and electrical stimulation. Absolute mechanical power output was 97 and 217% higher in the young compared with old and very old adults, respectively. Fatigability (reductions in power) progressively increased across age groups, with a power loss of 17% in young, 31% in old, and 44% in very old adults. There were no sex differences in fatigability among any of the age groups. The age-related increase in power loss was strongly associated with changes in the involuntary twitch amplitude ( r = 0.75, P < 0.001). These data suggest that the age-related increased power loss during high-velocity fatiguing exercise is unaffected by biological sex and determined primarily by mechanisms that disrupt excitation contraction coupling and/or cross-bridge function. NEW & NOTEWORTHY We show that aging of the neuromuscular system results in an increase in fatigability of the knee extensors during high-velocity exercise that is more pronounced in very old adults (>=80 yr) and occurs similarly in men and women. Importantly, the age-related increase in power loss was strongly associated with the changes in the electrically evoked contractile properties suggesting that the increased fatigability with aging is determined primarily by mechanisms within the muscle for both sexes. PMID- 29494292 TI - Paralytic and nonparalytic muscle adaptations to exercise training versus high protein diet in individuals with long-standing spinal cord injury. AB - This study compares the effects of an 8-wk isocaloric high-protein (HP) diet versus a combination exercise (Comb-Ex) regimen on paralytic vastus lateralis (VL) and nonparalytic deltoid muscle in individuals with long-standing spinal cord injury (SCI). Fiber-type distribution, cross-sectional area (CSA), levels of translation initiation signaling proteins (Erk-1/2, Akt, p70S6K1, 4EBP1, RPS6, and FAK), and lean thigh mass were analyzed at baseline and after the 8-wk interventions. A total of 11 participants (C5-T12 levels, 21.8 +/- 6.3 yr postinjury; 6 Comb-Ex and 5 HP diet) completed the study. Comb-Ex training occurred 3 days/wk and consisted of upper body resistance training (RT) in addition to neuromuscular electrical stimulation (NMES)-induced-RT for paralytic VL muscle. Strength training was combined with high-intensity arm-cranking exercises (1-min intervals at 85-90%, Vo2peak) for improving cardiovascular endurance. For the HP diet intervention, protein and fat each comprised 30%, and carbohydrate comprised 40% of total energy. Clinical tests and muscle biopsies were performed 24 h before and after the last exercise or diet session. The Comb Ex intervention increased Type IIa myofiber distribution and CSA in VL muscle and Type I and IIa myofiber CSA in deltoid muscle. In addition, Comb-Ex increased lean thigh mass, Vo2peak, and upper body strength ( P < 0.05). These results suggest that exercise training is required to promote favorable changes in paralytic and nonparalytic muscles in individuals with long-standing SCI, and adequate dietary protein consumption alone may not be sufficient to ameliorate debilitating effects of paralysis. NEW & NOTEWORTHY This study is the first to directly compare the effects of an isocaloric high-protein diet and combination exercise training on clinical and molecular changes in paralytic and nonparalytic muscles of individuals with long-standing spinal cord injury. Our results demonstrated that muscle growth and fiber-type alterations can best be achieved when the paralyzed muscle is sufficiently loaded via neuromuscular electrical stimulation-induced resistance training. PMID- 29494295 TI - Treating cardiovascular complications of radiotherapy: a role for new pharmacotherapies. AB - INTRODUCTION: Available data indicate that survivors of breast cancer and Hodgkin lymphoma who received mediastinal radiotherapy are at increased risk of developing radiation-induced cardiovascular diseases (RICVD) one or two decades after treatment. Although the risk with modern radiation treatment is likely to be lower in these patient groups, cardiotoxicity is still observed in a subset of patients. In addition, radiation-associated cardiovascular complications can, in the future, extend to other groups of cancer patients who are treated for tumors that are localized near the heart. Areas covered: The authors briefly describe the most commonly observed types of RICVD. They then present an overview of preclinical animal and cellular models that have been used to investigate the mechanisms underlying RICVD pathophysiology. The beneficial effects of available drugs, and potential targets for new molecules are also reported. Expert opinion: There is a need to develop cardio-oncological programs and pharmacotherapies specifically targeting RICVD. Beyond statins, ACE inhibitors, anti-inflammatory and antioxidant agents, preclinical studies indicate that TGFbeta receptor I inhibitors, Sestrin2 inducers, recombinant neuregulin-1 and miR-21 inhibitors might represent novel promising strategies. In order to properly determine the optimal therapeutic index for these molecules, in vivo models combining cancer and RICVD should be envisioned. PMID- 29494296 TI - Grouping schemes of welding fume exposure in shipyard welders. AB - Welding fume exposure can increase the risk of chronic obstructive pulmonary disease (COPD). The aim of this study was to evaluate the optimal grouping schemes of welding fume exposure in shipyard welders for future accurate examination of the association between welding fume exposure and COPD. Industrial hygiene records, including welding fume measurements between 2002 and 2009 were collected from a shipyard. A total of 2,360 personal welding fume measurements was compiled with a geometric mean of 1.66 mg/m3 and a geometric standard deviation of 4.02. Welding jobs were categorized into 8 groups. There were 9 working areas. To obtain the optimal grouping scheme, various grouping schemes were created using job, area, and job*area combination. To compare various grouping schemes, contrast and precision were calculated for each grouping scheme. For all measurement data, group mean ranking method created by ranking geometric means of the job*area combination into 3 groups (group mean ranking method) showed the best contrast and precision values among various grouping schemes, followed by grouping based on the job. For a subset of the data excluding job*area combinations with less than 10 measurements, grouping based on the job showed greater contrast than group mean ranking method, while for other subsets, including only repeated measurement data or further excluding job*area combinations with less than 10 measurements from the repeated measurement subset, group mean ranking method showed greater contrast than grouping based on the job. Our results showed that group mean ranking or grouping based on the job could be a candidate for the optimal grouping schemes in this shipyard. Our efforts for optimal grouping scheme may aid future cohort study to elucidate the association between welding fume exposure and COPD. PMID- 29494297 TI - Airborne contaminants during controlled residential fires. AB - In this study, we characterize the area and personal air concentrations of combustion byproducts produced during controlled residential fires with furnishings common in 21st century single family structures. Area air measurements were collected from the structure during active fire and overhaul (post suppression) and on the fireground where personnel were operating without any respiratory protection. Personal air measurements were collected from firefighters assigned to fire attack, victim search, overhaul, outside ventilation, and command/pump operator positions. Two different fire attack tactics were conducted for the fires (6 interior and 6 transitional) and exposures were compared between the tactics. For each of the 12 fires, firefighters were paired up to conduct each job assignment, except for overhaul that was conducted by 4 firefighters. Sampled compounds included polycyclic aromatic hydrocarbons (PAHs), volatile organic compounds (VOCs, e.g., benzene), hydrogen cyanide (HCN), and particulate (area air sampling only). Median personal air concentrations for the attack and search firefighters were generally well above applicable short-term occupational exposure limits, with the exception of HCN measured from search firefighters. Area air concentrations of all measured compounds decreased after suppression. Personal air concentrations of total PAHs and benzene measured from some overhaul firefighters exceeded exposure limits. Median personal air concentrations of HCN (16,300 ppb) exceeded the exposure limit for outside vent firefighters, with maximum levels (72,900 ppb) higher than the immediately dangerous to life and health (IDLH) level. Median air concentrations on the fireground (including particle count) were above background levels and highest when collected downwind of the structure and when ground-level smoke was the heaviest. No statistically significant differences in personal air concentrations were found between the 2 attack tactics. The results underscore the importance of wearing self-contained breathing apparatus when conducting overhaul or outside ventilation activities. Firefighters should also try to establish command upwind of the structure fire, and if this cannot be done, respiratory protection should be considered. PMID- 29494307 TI - Recurrent Spindle Cell Carcinoma Shows Features of Mesenchymal Stem Cells. AB - This study investigated a case of spindle cell carcinoma (SpCC) in tongue pathological lesions. The patient experienced a local recurrence and distant metastasis after surgical intervention. Although standard chemotherapy was administered, a granulomatous mass continued to develop. This aggressive growth led to survival of the tumor. Secondary debulking surgery was performed to improve the patient's quality of life at the request of the patient. Using a tissue sample derived from the secondary debulking surgery, we performed an analysis of the tumor's cell surface antigens, differentiation potential, metastatic ability, and inhibition potential by anticancer reagents. In vitro analysis revealed that the cell population grown under adherent culture conditions expressed the mesenchymal stem cell (MSC) markers CD73, CD90, and CD105. The cell line established from this SpCC contained colony-forming unit fibroblasts (CFU-Fs) and exhibited multipotent differentiation into several mesenchymal lineages, including bone, cartilage, and fat. The SpCC cells also displayed vigorous mobilization. These characteristics suggested that they had the differentiation potential of mesenchymal cells, especially MSCs, rather than that of epithelial cells. The surgical specimen analyzed in this study resisted the molecular target reagent cetuximab, which is an epidermal growth factor receptor inhibitor. This clinical insight revealed that chemotherapy-resistant SpCC cells have different characteristics compared to most other cancer cells, which are sensitive to cetuximab. Our cell death assay revealed that SpCC cell death was induced by the anticancer drug imatinib, which is known to inhibit protein tyrosine kinase activity of ABL, platelet-derived growth factor receptor alpha (PDGFRalpha), and KIT. Here, we report recurrent SpCC with characteristics of MSCs and potential for treatment with imatinib. PMID- 29494308 TI - Rapid Bactericidal Action of Propolis against Porphyromonas gingivalis. AB - Propolis, a resinous substance produced by bees, is used as a folk medicine for treatment of periodontal diseases. However, its mode of the action and the compounds responsible for its activities remain obscure. In the present study, we comprehensively investigated the antibacterial activities of ethanol-extracted propolis (EEP) and EEP-derived compounds toward Porphyromonas gingivalis, a keystone pathogen for periodontal diseases. Broth microdilution and agar dilution assays were used to determine the minimum inhibitory concentrations of EEP against a range of oral bacterial species, of which P. gingivalis showed a higher level of sensitivity than oral commensals such as streptococci. Its antibacterial activity toward P. gingivalis was maintained even after extensive heat treatment, demonstrating a high level of thermostability. EEP also induced death of P. gingivalis cells by increasing membrane permeability within 30 min. Spatiotemporal analysis based on high-speed atomic force microscopy revealed that EEP immediately triggered development of aberrant membrane blebs, followed by bleb fusion events on the bacterial surface. Furthermore, we isolated artepillin C, baccharin, and ursolic acid from EEP as antibacterial compounds against P. gingivalis. Of those, artepillin C and baccharin showed bacteriostatic activities with membrane blebbing, while ursolic acid showed bactericidal activity with membrane rupture. In particular, ursolic acid demonstrated a greater ability to affect bacterial membrane potential with increased membrane permeability, probably because of its highly lipophilic nature as compared with other compounds. Taken together, these findings provide mechanistic insight into the antibacterial activities of EEP and its exquisite membrane-targeting antibacterial compounds and imply the applicability of narrow-spectrum therapeutics with EEP for treatment of periodontitis. In addition, the advanced technology utilized in the present study to visualize the nanometer-scale dynamics of microorganisms will contribute to expanding our understanding of the activities of antimicrobials and the mechanism of drug resistance in bacteria. PMID- 29494309 TI - Thoracic and lumbar spine responses in high-speed rear sled tests. AB - OBJECTIVE: This study analyzed thoracic and lumbar spine responses with in position and out-of-position (OOP) seated dummies in 40.2 km/h (25 mph) rear sled tests with conventional and all-belts-to-seat (ABTS) seats. Occupant kinematics and spinal responses were determined with modern (>=2000 MY), older (<2000 MY), and ABTS seats. METHODS: The seats were fixed in a sled buck subjected to a 40.2 km/h (25 mph) rear sled test. The pulse was a 15 g double-peak acceleration with 150 ms duration. The 50th percentile Hybrid III was lap-shoulder belted in the FMVSS 208 design position or OOP, including leaning forward and leaning inboard and forward. There were 26 in-position tests with 11 <2000 MY, 8 >=2000 MY, and 7 ABTS and 14 OOP tests with 6 conventional and 8 ABTS seats. The dummy was fully instrumented. This study addressed the thoracic and lumbar spine responses. Injury assessment reference values are not approved for the thoracic and lumbar spine. Conservative thresholds exist. The peak responses were normalized by a threshold to compare responses. High-speed video documented occupant kinematics. RESULTS: The extension moments were higher in the thoracic than lumbar spine in the in-position tests. For <2000 MY seats, the thoracic extension moment was 76.8 +/- 14.6% of threshold and the lumbar extension moment was 50.5 +/- 17.9%. For the >=2000 MY seats, the thoracic extension moment was 54.2 +/- 26.6% of threshold and the lumbar extension moment was 49.8 +/- 27.7%. ABTS seats provided similar thoracic and lumbar responses. Modern seat designs lowered thoracic and lumbar responses. For example, the 1996 Taurus had -1,696 N anterior lumbar shear force and -205.2 Nm extension moment. There was -1,184 N lumbar compression force and 1,512 N tension. In contrast, the 2015 F-150 had -500 N shear force and -49.7 Nm extension moment. There was -839 N lumbar compression force and 535 N tension. On average, the 2015 F-150 had 40% lower lumbar spine responses than the 1996 Taurus. The OOP tests had similar peak lumbar responses; however, they occurred later due to the forward lean of the dummy. CONCLUSIONS: The design and performance of seats have significantly changed over the past 20 years. Modern seats use a perimeter frame allowing the occupant to pocket into the seatback. Higher and more forward head restraints allow a stronger frame because the head, neck, and torso are more uniformly supported with the seat more upright in severe rear impacts. The overall effect has been a reduction in thoracic and lumbar loads and risks for injury. PMID- 29494310 TI - Climate change and the health impact of aflatoxins exposure in Portugal - an overview. AB - Climate change has been indicated as a driver for food safety issues worldwide, mainly due to the impact on the occurrence of food safety hazards at various stages of food chain. Mycotoxins, natural contaminants produced by fungi, are among the most important of such hazards. Aflatoxins, which have the highest acute and chronic toxicity of all mycotoxins, assume particular importance. A recent study predicted aflatoxin contamination in maize and wheat crops in Europe within the next 100 years and aflatoxin B1 is predicted to become a food safety issue in Europe, especially in the most probable scenario of climate change (+2 degrees C). This review discusses the potential influence of climate change on the health risk associated to aflatoxins dietary exposure of Portuguese population. We estimated the burden of disease associated to the current aflatoxin exposure for Portuguese population in terms of Disability Adjusted Life Years (DALYs). It is expected that in the future the number of DALYs and the associated cases of hepatocellular carcinoma due to aflatoxins exposure will increase due to climate change. The topics highlighted through this review, including the potential impact on health of the Portuguese population through the dietary exposure to aflatoxins, should represent an alert for the potential consequences of an incompletely explored perspective of climate change. Politics and decision-makers should be involved and committed to implement effective measures to deal with climate change issues and to reduce its possible consequences. This review constitutes a contribution for the prioritisation of strategies to face the unequal burden of effects of weather-related hazards in Portugal and across Europe. PMID- 29494311 TI - The impact of phenotypic and molecular data on the inference of Colletotrichum diversity associated with Musa. AB - Developing a comprehensive and reliable taxonomy for the Colletotrichum gloeosporioides species complex will require adopting data standards on the basis of an understanding of how methodological choices impact morphological evaluations and phylogenetic inference. We explored the impact of methodological choices in a morphological and molecular evaluation of Colletotrichum species associated with banana in Brazil. The choice of alignment filtering algorithm has a significant impact on topological inference and the retention of phylogenetically informative sites. Similarly, the choice of phylogenetic marker affects the delimitation of species boundaries, particularly if low phylogenetic signal is confounded with strong discordance, and inference of the species tree from multiple-gene trees. According to both phylogenetic informativeness profiling and Bayesian concordance analyses, the most informative loci are DNA lyase (APN2), intergenic spacer (IGS) between DNA lyase and the mating-type locus MAT1-2-1 (APN2/MAT-IGS), calmodulin (CAL), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), glutamine synthetase (GS), beta-tubulin (TUB2), and a new marker, the intergenic spacer between GAPDH and an hypothetical protein (GAP2 IGS). Cornmeal agar minimizes the variance in conidial dimensions compared with potato dextrose agar and synthetic nutrient-poor agar, such that species are more readily distinguishable based on phenotypic differences. We apply these insights to investigate the diversity of Colletotrichum species associated with banana anthracnose in Brazil and report C. musae, C. tropicale, C. theobromicola, and C. siamense in association with banana anthracnose. One lineage did not cluster with any previously described species and is described here as C. chrysophilum. PMID- 29494312 TI - Combined effect of boundary layer recirculation factor and stable energy on local air quality in the Pearl River Delta over southern China. AB - : Atmospheric boundary layer (ABL) has a significant impact on the spatial and temporal distribution of air pollutants. In order to gain a better understanding of how ABL affects the variation of air pollutants, atmospheric boundary layer observations were performed at Sanshui in the Pearl River Delta (PRD) region over southern China during the winter of 2013. Two types of typical ABL status that could lead to air pollution were analyzed comparatively: weak vertical diffusion ability type (WVDAT) and weak horizontal transportation ability type (WHTAT). Results show that (1) WVDAT was featured by moderate wind speed, consistent wind direction, and thick inversion layer at 600~1000 m above ground level (AGL), and air pollutants were restricted in the low altitudes due to the stable atmospheric structure; (2) WHTAT was characterized by calm wind, varied wind direction, and shallow intense ground inversion layer, and air pollutants accumulated in locally because of strong recirculation in the low ABL; (3) recirculation factor (RF) and stable energy (SE) were proved to be good indicators for horizontal transportation ability and vertical diffusion ability of the atmosphere, respectively. Combined utilization of RF and SE can be very helpful in the evaluation of air pollution potential of the ABL. IMPLICATIONS: Air quality data from ground and meteorological data collected from radio sounding in Sanshui in the Pearl River Delta showed that local air quality was poor when wind reversal was pronounced or temperature stratification state was stable. The combination of horizontal and vertical transportation ability of the local atmosphere should be taken into consideration when evaluating local environmental bearing capacity for air pollution. PMID- 29494313 TI - Anaerobic treatment of blended sugar industry and ethanol distillery wastewater through biphasic high rate reactor. AB - This study aimed to investigate the physicochemical properties of sugar industry and ethanol distillery wastewater and the treatment of the blended wastewater through a two-stage anaerobic reactor. For this treatment, different initial chemical oxygen demand (COD) concentrations (5-20 g/L) and hydraulic retention times (HRTs) (2-10 days) were applied. The sugar industry effluent characteristics obtained in terms of organic matter (mg/L) were as follows: 5 days biochemical oxygen demand (BOD5): 654.5-1,968; COD: 1,100-2,148.9; total solids (TS): 2,467-4,012 mg/L; and pH: 6.93-8.43. The ethanol distillery spent wash strengths obtained were: BOD5: 27,600-42,921 mg/L; COD: 126,000-167,534 mg/L; TS: 140,160-170,000 mg/L; and pH: 3.9-4.2. Maximum COD removal of 65% was obtained at optimum condition (initial COD concentration of 10 g/L and HRT of 10 days), and maximum color removal of 79% was recorded under similar treatment conditions. Hence, the performance of the two-stage anaerobic reactor for simultaneous removal of COD and color from high-strength blended wastewater is promising for scaling up in order to mitigate environmental problems of untreated effluent discharge. PMID- 29494314 TI - Molecular Epidemiological Survey of Leptospira Infection of Wild Rodents in the Urban Settlement of Cambodia. AB - INTRODUCTION: Leptospirosis remains a major public health threat in Cambodia. In this study, we aimed at facilitating the development of preventive strategies against leptospirosis in Cambodia by conducting molecular epidemiological surveys of Leptospira infection among wild rodents. MATERIALS AND METHODS: One hundred sixty-three wild rodents were captured in the capital Phnom Penh and surrounding areas, and their kidneys and bladders were collected for analysis. Identification of wild rodent species was determined by using the cytochrome c oxidase I gene. TaqMan PCR of the flagellin B gene (flaB) was performed to detect Leptospira, and species of the isolates were identified by flaB sequencing analysis. RESULTS: The species and respective number of rodents collected were as follows: Rattus norvegicus, 80 (49.1%); Rattus argentiventer, 53 (32.5%); Rattus exulans, 6 (3.7%); Rattus indica, 15 (9.2%); Maxomys surifer, 3 (1.8%); and Rattus sp., 6 (3.7%). Leptospira was detected in 20 out of the 163 rodents (12.3%) and was categorized as either Leptospira interrogans or Leptospira noguchii. R. norvegicus had the highest prevalence of Leptospira (17.5%), and R. argentiventer and Rattus sp. showed infection rates of 9.4% and 16.7%, respectively. CONCLUSIONS: Based on these results, wild rodents living in urban areas of Cambodia were found to be important reservoirs of highly virulent Leptospira. The flaB sequence results of our study provided information regarding the prevalence of Leptospira species, which was dependent on the rodent species. This study is the first study on leptospirosis in wild rodents in the urban areas of Cambodia, where there is limited information on leptospirosis. PMID- 29494315 TI - Plain Language Summary: Hoarseness (Dysphonia). AB - This plain language summary for patients serves as an overview in explaining hoarseness (dysphonia). The summary applies to patients in all age groups and is based on the 2018 "Clinical Practice Guideline: Hoarseness (Dysphonia) (Update)." The evidence-based guideline includes research to support more effective identification and management of patients with hoarseness (dysphonia). The primary purpose of the guideline is to improve the quality of care for patients with hoarseness (dysphonia) based on current best evidence. PMID- 29494317 TI - Highlights from the Current Issue: March 2018. PMID- 29494318 TI - Commentary on "The Role of Tonsillectomy in Adults with Tonsillar Hypertrophy and Obstructive Sleep Apnea". PMID- 29494319 TI - Response to Comments on "The Role of Tonsillectomy in Adults with Tonsillar Hypertrophy and Obstructive Sleep Apnea". PMID- 29494316 TI - Clinical Practice Guideline: Hoarseness (Dysphonia) (Update) Executive Summary. AB - Objective This guideline provides evidence-based recommendations on treating patients presenting with dysphonia, which is characterized by altered vocal quality, pitch, loudness, or vocal effort that impairs communication and/or quality of life. Dysphonia affects nearly one-third of the population at some point in its life. This guideline applies to all age groups evaluated in a setting where dysphonia would be identified or managed. It is intended for all clinicians who are likely to diagnose and treat patients with dysphonia. Purpose The primary purpose of this guideline is to improve the quality of care for patients with dysphonia, based on current best evidence. Expert consensus to fill evidence gaps, when used, is explicitly stated and supported with a detailed evidence profile for transparency. Specific objectives of the guideline are to reduce inappropriate variations in care, produce optimal health outcomes, and minimize harm. For this guideline update, the American Academy of Otolaryngology Head and Neck Surgery Foundation selected a panel representing the fields of advanced practice nursing, bronchoesophagology, consumer advocacy, family medicine, geriatric medicine, internal medicine, laryngology, neurology, otolaryngology-head and neck surgery, pediatrics, professional voice, pulmonology, and speech-language pathology. Action Statements The guideline update group made strong recommendations for the following key action statements (KASs): (1) Clinicians should assess the patient with dysphonia by history and physical examination to identify factors where expedited laryngeal evaluation is indicated. These include but are not limited to recent surgical procedures involving the head, neck, or chest; recent endotracheal intubation; presence of concomitant neck mass; respiratory distress or stridor; history of tobacco abuse; and whether the patient is a professional voice user. (2) Clinicians should advocate voice therapy for patients with dysphonia from a cause amenable to voice therapy. The guideline update group made recommendations for the following KASs: (1) Clinicians should identify dysphonia in a patient with altered voice quality, pitch, loudness, or vocal effort that impairs communication or reduces quality of life (QOL). (2) Clinicians should assess the patient with dysphonia by history and physical examination for underlying causes of dysphonia and factors that modify management. (3) Clinicians should perform laryngoscopy, or refer to a clinician who can perform laryngoscopy, when dysphonia fails to resolve or improve within 4 weeks or irrespective of duration if a serious underlying cause is suspected. (4) Clinicians should perform diagnostic laryngoscopy, or refer to a clinician who can perform diagnostic laryngoscopy, before prescribing voice therapy and document/communicate the results to the speech-language pathologist (SLP). (5) Clinicians should advocate for surgery as a therapeutic option for patients with dysphonia with conditions amenable to surgical intervention, such as suspected malignancy, symptomatic benign vocal fold lesions that do not respond to conservative management, or glottic insufficiency. (6) Clinicians should offer, or refer to a clinician who can offer, botulinum toxin injections for the treatment of dysphonia caused by spasmodic dysphonia and other types of laryngeal dystonia. (7) Clinicians should inform patients with dysphonia about control/preventive measures. (8) Clinicians should document resolution, improvement or worsened symptoms of dysphonia, or change in QOL of patients with dysphonia after treatment or observation. The guideline update group made a strong recommendation against 1 action: (1) Clinicians should not routinely prescribe antibiotics to treat dysphonia. The guideline update group made recommendations against other actions: (1) Clinicians should not obtain computed tomography (CT) or magnetic resonance imaging (MRI) for patients with a primary voice complaint prior to visualization of the larynx. (2) Clinicians should not prescribe antireflux medications to treat isolated dysphonia, based on symptoms alone attributed to suspected gastroesophageal reflux disease (GERD) or laryngopharyngeal reflux (LPR), without visualization of the larynx. (3) Clinicians should not routinely prescribe corticosteroids in patients with dysphonia prior to visualization of the larynx. The policy level for the following recommendation about laryngoscopy at any time was an option: (1) Clinicians may perform diagnostic laryngoscopy at any time in a patient with dysphonia. Differences from Prior Guideline (1) Incorporating new evidence profiles to include the role of patient preferences, confidence in the evidence, differences of opinion, quality improvement opportunities, and any exclusion to which the action statement does not apply (2) Inclusion of 3 new guidelines, 16 new systematic reviews, and 4 new randomized controlled trials (3) Inclusion of a consumer advocate on the guideline update group (4) Changes to 9 KASs from the original guideline (5) New KAS 3 (escalation of care) and KAS 13 (outcomes) (6) Addition of an algorithm outlining KASs for patients with dysphonia. PMID- 29494320 TI - Reg-ent within the Learning Health System. AB - Clinical data registries are perhaps one of the most powerful outcomes of electronic medical records, and their benefits are projected to redound to patients and clinicians across the nation. The American Academy of Otolaryngology Head and Neck Surgery Foundation's Reg-ent fits within the conceptual framework of a learning health system. Because the data within this system are deidentified, research informed consent is not legally required. But ethical concerns remain regarding whether and how to best notify, and whether to obtain consent from, patients whose data are included. Particularly because data corroborate that a substantial minority of survey respondents believe that consent should be obtained for each research protocol (even for deidentified research) and because data breaches are, unfortunately, a serious risk, we recommend that the American Academy of Otolaryngology-Head and Neck Surgery Foundation ensure best practices for patient engagement as it continues to build Reg-ent. PMID- 29494321 TI - Clinical Practice Guideline: Hoarseness (Dysphonia) (Update). AB - Objective This guideline provides evidence-based recommendations on treating patients who present with dysphonia, which is characterized by altered vocal quality, pitch, loudness, or vocal effort that impairs communication and/or quality of life. Dysphonia affects nearly one-third of the population at some point in its life. This guideline applies to all age groups evaluated in a setting where dysphonia would be identified or managed. It is intended for all clinicians who are likely to diagnose and treat patients with dysphonia. Purpose The primary purpose of this guideline is to improve the quality of care for patients with dysphonia, based on current best evidence. Expert consensus to fill evidence gaps, when used, is explicitly stated and supported with a detailed evidence profile for transparency. Specific objectives of the guideline are to reduce inappropriate variations in care, produce optimal health outcomes, and minimize harm. For this guideline update, the American Academy of Otolaryngology Head and Neck Surgery Foundation selected a panel representing the fields of advanced practice nursing, bronchoesophagology, consumer advocacy, family medicine, geriatric medicine, internal medicine, laryngology, neurology, otolaryngology-head and neck surgery, pediatrics, professional voice, pulmonology, and speech-language pathology. Action Statements The guideline update group made strong recommendations for the following key action statements (KASs): (1) Clinicians should assess the patient with dysphonia by history and physical examination to identify factors where expedited laryngeal evaluation is indicated. These include, but are not limited to, recent surgical procedures involving the head, neck, or chest; recent endotracheal intubation; presence of concomitant neck mass; respiratory distress or stridor; history of tobacco abuse; and whether the patient is a professional voice user. (2) Clinicians should advocate voice therapy for patients with dysphonia from a cause amenable to voice therapy. The guideline update group made recommendations for the following KASs: (1) Clinicians should identify dysphonia in a patient with altered voice quality, pitch, loudness, or vocal effort that impairs communication or reduces quality of life (QOL). (2) Clinicians should assess the patient with dysphonia by history and physical examination for underlying causes of dysphonia and factors that modify management. (3) Clinicians should perform laryngoscopy, or refer to a clinician who can perform laryngoscopy, when dysphonia fails to resolve or improve within 4 weeks or irrespective of duration if a serious underlying cause is suspected. (4) Clinicians should perform diagnostic laryngoscopy, or refer to a clinician who can perform diagnostic laryngoscopy, before prescribing voice therapy and document/communicate the results to the speech-language pathologist (SLP). (5) Clinicians should advocate for surgery as a therapeutic option for patients with dysphonia with conditions amenable to surgical intervention, such as suspected malignancy, symptomatic benign vocal fold lesions that do not respond to conservative management, or glottic insufficiency. (6) Clinicians should offer, or refer to a clinician who can offer, botulinum toxin injections for the treatment of dysphonia caused by spasmodic dysphonia and other types of laryngeal dystonia. (7) Clinicians should inform patients with dysphonia about control/preventive measures. (8) Clinicians should document resolution, improvement or worsened symptoms of dysphonia, or change in QOL of patients with dysphonia after treatment or observation. The guideline update group made a strong recommendation against 1 action: (1) Clinicians should not routinely prescribe antibiotics to treat dysphonia. The guideline update group made recommendations against other actions: (1) Clinicians should not obtain computed tomography (CT) or magnetic resonance imaging (MRI) for patients with a primary voice complaint prior to visualization of the larynx. (2) Clinicians should not prescribe antireflux medications to treat isolated dysphonia, based on symptoms alone attributed to suspected gastroesophageal reflux disease (GERD) or laryngopharyngeal reflux (LPR), without visualization of the larynx. (3) Clinicians should not routinely prescribe corticosteroids for patients with dysphonia prior to visualization of the larynx. The policy level for the following recommendation about laryngoscopy at any time was an option: (1) Clinicians may perform diagnostic laryngoscopy at any time in a patient with dysphonia. Disclaimer This clinical practice guideline is not intended as an exhaustive source of guidance for managing dysphonia (hoarseness). Rather, it is designed to assist clinicians by providing an evidence-based framework for decision-making strategies. The guideline is not intended to replace clinical judgment or establish a protocol for all individuals with this condition, and it may not provide the only appropriate approach to diagnosing and managing this problem. Differences from Prior Guideline (1) Incorporation of new evidence profiles to include the role of patient preferences, confidence in the evidence, differences of opinion, quality improvement opportunities, and any exclusion to which the action statement does not apply (2) Inclusion of 3 new guidelines, 16 new systematic reviews, and 4 new randomized controlled trials (3) Inclusion of a consumer advocate on the guideline update group (4) Changes to 9 KASs from the original guideline (5) New KAS 3 (escalation of care) and KAS 13 (outcomes) (6) Addition of an algorithm outlining KASs for patients with dysphonia. PMID- 29494322 TI - Digital Breast Tomosynthesis and Synthetic 2D Mammography versus Digital Mammography: Evaluation in a Population-based Screening Program. AB - Purpose To compare the performance of digital breast tomosynthesis (DBT) and two dimensional synthetic mammography (SM) with that of digital mammography (DM) in a population-based mammographic screening program. Materials and Methods In this prospective cohort study, data from 37 185 women screened with DBT and SM and from 61 742 women screened with DM as part of a population-based screening program in 2014 and 2015 were included. Early performance measures, including recall rate due to abnormal mammographic findings, rate of screen-detected breast cancer, positive predictive value of recall, positive predictive value of needle biopsy, histopathologic type, tumor size, tumor grade, lymph node involvement, hormonal status, Ki-67 level, and human epidermal growth factor receptor 2 status were compared in women who underwent DBT and SM screening and in those who underwent DM screening by using chi2 tests, two-sample unpaired t tests, and tests of proportions. Results Recall rates were 3.4% for DBT and SM screening and 3.3% for DM screening (P = .563). DBT and SM screening showed a significantly higher rate of screen-detected cancer compared with DM screening (9.4 vs 6.1 cancers per 1000 patients screened, respectively; P < .001). The rate of detection of tumors 10 mm or smaller was 3.2 per 1000 patients screened with DBT and SM and 1.8 per 1000 patients screened with DM (P < .001), and the rate of grade 1 tumors was 3.3 per 1000 patients screened with DBT and SM versus 1.4 per 1000 patients screened with DM (P < .001). On the basis of immunohistochemical analyses, rates of lymph node involvement and tumor subtypes did not differ between women who underwent DBT and SM screening and those who underwent DM screening. Conclusion DBT and SM screening increased the detection rate of histologically favorable tumors compared with that attained with DM screening. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 29494323 TI - An Assessment of Radiation-Associated Risks of Mortality from Circulatory Disease in the Cohorts of Mayak and Sellafield Nuclear Workers. AB - Mortality from circulatory disease (CD), ischemic heart disease (IHD) and cerebrovascular disease (CeVD) was investigated in relationship to cumulative doses of external gamma radiation and internal alpha radiation to the liver from deposited plutonium over long follow-up periods in two large cohorts of nuclear workers: the Russian Mayak Worker Cohort (MWC) and the UK Sellafield Worker Cohort (SWC). The MWC comprised 22,374 workers (74.6% males) with 5,123 CD deaths registered during 842,538 person-years of follow-up, while the SWC comprised 23,443 workers (87.8% males) with 2,322 CD deaths registered during 602,311 person-years of follow-up. Dose estimates for external gamma radiation and internal alpha radiation to the liver were calculated via a common methodology, in accordance with an agreed protocol. The mean cumulative external Hp(10) dose was 0.52 Sv for the MWC and 0.07 Sv for the SWC, while the mean cumulative internal dose was 0.19 Gy for the MWC and 0.01 Gy for the SWC. Categorical relative risks (RR) and excess relative risks (ERR) per unit dose were estimated for each cohort and for the pooled cohort when appropriate. The dose responses for CD, IHD and CeVD in relationship to internal alpha-particle dose did not differ significantly from the null for either the MWC, the SWC or the pooled plutonium worker cohort. The ERR/Sv estimates in relationship to external exposure were significantly raised for both cohorts (marginally so for the MWC) for CD and IHD (but not for CeVD), but differed significantly between the two cohorts, the estimate for the SWC being approximately ten times greater than that for the MWC. Examination of the ERR/Sv estimates for two periods of first employment at the two facilities revealed that the significant heterogeneity was confined to the earlier sub-cohorts, and that the estimates for the later sub cohorts were compatible. The two sub-cohorts for the later first-employment periods were pooled, producing risk estimates that were raised, but not significantly so: ERR/Sv for CD, IHD and CeVD of 0.22 (95% CI: -0.01, 0.49), 0.22 (95% CI: -0.06, 0.57) and 0.24 (95% CI: -0.17, 0.80), respectively. The reasons for the complex pattern of results found in this study are unclear. Among potential explanations are the influence of differences in background CD mortality rates, an effect of other occupational factors, substantial uncertainties in doses, particularly during earlier periods of operations, as well as confounding and/or modifying factors that were not taken into account in the current analysis. PMID- 29494324 TI - Correlation of Radiation Dose Estimates by DIC with the METREPOL Hematological Classes of Disease Severity. AB - The degree of severity of hematologic acute radiation syndrome (HARS) may vary across the range of radiation doses, such that dose alone may be a less reliable predictor of clinical course. We sought to elucidate the relationship between absorbed dose and risk of clinically relevant HARS in humans. We used the database SEARCH (System for Evaluation and Archiving of Radiation Accidents based on Case Histories), which contains the histories of radiation accident victims. From 153 cases we extracted data on dose estimates using the dicentric assay to measure individual biological dosimetry. The data were analyzed according to the corresponding hematological response categories of clinical significance (H1-4). These categories are derived from the medical treatment protocols for radiation accident victims (METREPOL) and represent the clinical outcome of HARS based on severity categories ranging from 1-4. In addition, the category H0 represents a post-exposure hematological response that is within the normal range for nonexposed individuals. Age at exposure, gender and ethnicity were considered as potential confounders in unconditional cumulative logistic regression analysis. In most cases, victims were Caucasian (82.4%) and male (92.8%), who originated from either the Chernobyl (69.3%) or Goiania (10.5%) accident, and nearly 60% were aged 20-40 years at time of exposure. All individuals were whole-body exposed (mean 3.8 Gy, stdev +/-3.1), and single exposures were predominantly reported (79%). Seventy percent of victims in category H0 were exposed to <=1 Gy, with rapidly decreasing proportions of H0 seen at doses up to 5 Gy. There were few HARS H4 cases reported at exposed dose of 1-2 Gy, while 82% of H4 cases received doses of >5 Gy. HARS H1-3 cases varied among dose ranges from 1-5 Gy. In summary, single whole-body radiation doses <1 Gy and >5 Gy corresponded in general with H0 and H3-4, respectively, and this was consistent with medical expectations. This underlines the usefulness of dose estimates for HARS prediction. However, whole-body doses between 1-5 Gy poorly corresponded to HARS H1-3. The dose range of 1-5 Gy was of limited value for medical decision-making regarding, e.g., hospitalization for H2-3, but not H1 and treatment decisions that differ between H1-3. Also, there were some H0 cases at high doses and H2-4 cases at low doses, thereby challenging an individual recommendation based solely on dose. PMID- 29494325 TI - Editorial: Throwing Light on Recent Advances on Metallodrugs: From Deemed Poisons to a Striking Hope for the Future. PMID- 29494326 TI - Introduction. PMID- 29494327 TI - Dyspnea and Hyperinflation in Chronic Obstructive Pulmonary Disease: Impact on Physical Activity. PMID- 29494328 TI - Anxiety and Depression in Chronic Obstructive Pulmonary Disease: Recognition and Management. PMID- 29494329 TI - Considerations for Optimal Inhaler Device Selection in Chronic Obstructive Pulmonary Disease. PMID- 29494330 TI - Treatment Options for Stable Chronic Obstructive Pulmonary Disease: Current Recommendations and Unmet Needs. PMID- 29494331 TI - Identifying Windows of Opportunity for Active Living and Healthy Eating Policies in Connecticut, 2016. AB - We examined the relative importance of 23 community issues among elected officials and health directors in Connecticut in 2016. For this cross-sectional study, 74 elected officials (40.7% response rate) and 47 health directors (62.7% response rate), who were purposively sampled, completed a questionnaire to rate their perceived importance of 23 community issues. Eight of these issues were related to active living, healthy eating, or obesity. We used chi2 tests to evaluate differences in responses. Compared with elected officials, health directors significantly more often perceived obesity, access to healthy groceries, poor nutrition, lack of pedestrian walkways, and pedestrian safety as important. Elected officials significantly more often than health directors perceived lack of good jobs, quality of public education, and cost of living as important. Health advocates should work with both groups to develop and frame policies to address both upstream (eg, jobs, education) and downstream (eg, healthy eating policies) determinants of obesity. PMID- 29494333 TI - Abstracts of the 29th Annual Scientific Conference of the International Society for Environmental Epidemiology (ISEE), 24-28 September 2017, Sydney, Australia. AB - SUMMARY: The 29th Annual Scientific Conference of the International Society for Environmental Epidemiology was held 24-28 September 2017 in Sydney, Australia. The conference theme was "Healthy Places, Healthy People-Where Are the Connections?" The focus of this year's conference was the recognition that there are many different places (the natural environment, the built environment, and the social environment) and many different people (the young, the old, the disadvantaged, and the marginalized), and that the connections between them may be physical, psychological, social, or political. PMID- 29494332 TI - Hypertension in Florida: Data From the OneFlorida Clinical Data Research Network. AB - INTRODUCTION: Hypertension is highly prevalent in Florida, but surveillance through the Behavioral Risk Factor Surveillance System (BRFSS) is limited to self reported hypertension and does not capture data on undiagnosed hypertension or measure blood pressure. We aimed to characterize the hypertensive population in the OneFlorida Clinical Research Consortium by using electronic health records and provide proof-of-concept for using routinely collected clinical data to augment surveillance efforts. METHODS: We identified patients with hypertension, defined as having at least 1 outpatient visit from January 2012 through June 2016 with an ICD-9-CM or ICD-10-CM diagnosis code for hypertension, or in the absence of a diagnosis, an elevated blood pressure (systolic >=140 mm Hg or diastolic >=90 mm Hg) recorded in the electronic health record at the most recent visit. The hypertensive population was characterized and mapped by zip code of patient residence to county prevalence. RESULTS: Of 838,469 patients (27.9% prevalence) who met the criteria for hypertension, 68% had received a diagnosis and 61% had elevated blood pressure. The geographic distribution of hypertension differed between diagnosed hypertension (highest prevalence in northern Florida) and undiagnosed hypertension (highest prevalence along eastern coast, in southern Florida, and in some rural western Panhandle counties). Uncontrolled hypertension was concentrated in southern Florida and the western Panhandle. CONCLUSION: Our use of clinical data, representing usual care for Floridians, allows for identifying cases of uncontrolled hypertension and potentially undiagnosed cases, which are not captured by existing surveillance methods. Large-scale pragmatic research networks, like OneFlorida, may be increasingly important for tailoring future health care services, trials, and public health programs. PMID- 29494334 TI - Kallikrein-related peptidase 14 is the second KLK protease targeted by the serpin vaspin. AB - Kallikrein-related peptidases KLK5, KLK7 and KLK14 are important proteases in skin desquamation and aberrant KLK activity is associated with inflammatory skin diseases such as Netherton syndrome but also with various serious forms of cancer. Previously, we have identified KLK7 as the first protease target of vaspin (Serpin A12). Here, we report KLK14 as a second KLK protease to be inhibited by vaspin. In conclusion, vaspin represents a multi-specific serpin targeting the kallikrein proteases KLK7 and KLK14, with distinct exosites regulating recognition of these target proteases and opposing effects of heparin binding on the inhibition reaction. PMID- 29494335 TI - Diffuse near-infrared imaging of tissue with picosecond time resolution. AB - Optical imaging of biological tissue in vivo at multiple wavelengths in the near infrared (NIR) spectral range can be achieved with picosecond time resolution at high sensitivity by time-correlated single photon counting. Measuring and analyzing the distribution of times of flight of photons randomly propagated through the tissue has been applied for diffuse optical imaging and spectroscopy, e.g. of human breast tissue and of the brain. In this article, we review the main features and the potential of NIR multispectral imaging with picosecond time resolution and illustrate them by exemplar applications in these fields. In particular, we discuss the experimental methods developed at the Physikalisch Technische Bundesanstalt (PTB) to record optical mammograms and to quantify the absorption and scattering properties from which hemoglobin concentration and oxygen saturation of healthy and diseased breast tissue have been derived by combining picosecond time-domain and spectral information. Furthermore, optical images of functional brain activation were obtained by a non-contact scanning device exploiting the null source-detector separation approach which takes advantage of the picosecond time resolution as well. The recorded time traces of changes in the oxy- and deoxyhemoglobin concentrations during a motor stimulation investigation show a localized response from the brain. PMID- 29494336 TI - Telomere biology and age-related diseases. AB - Telomeres are the protective end caps of chromosomes and shorten with every cell division. Telomere length has been proposed as a biomarker of biological age and a risk factor for age-related diseases. Epidemiologic studies show an association between leukocyte telomere length (LTL) and mortality. There is solid evidence that links LTL with cardiovascular disease. Short telomeres promote atherosclerosis and impair the repair of vascular lesions. Alzheimer's disease patients have also a reduced LTL. Telomeres measured in tumor tissue from breast, colon and prostate are shorter than in healthy tissue from the same organ and the same patient. In healthy tissue directly adjacent to these tumors, telomeres are also shorter than in cells that are more distant from the cancerous lesion. A reduced telomere length in cancer tissue from breast, colon and prostate is associated with an advanced disease state at diagnosis, faster disease progression and poorer survival. By contrast, results regarding LTL and cancer are inconsistent. Furthermore, the majority of studies did not find significant associations between LTL, bone mineral density (BMD) and osteoporosis. The present manuscript gives an overview about our current understanding of telomere biology and reviews existing knowledge regarding the relationship between telomere length and age-related diseases. PMID- 29494337 TI - Paraprotein interference in the diagnosis of hepatitis C infection. PMID- 29494338 TI - Free light chains in the cerebrospinal fluid. Do we still need oligoclonal IgG? PMID- 29494339 TI - The relationship between diet quality and insulin resistance in obese children: adaptation of the Healthy Lifestyle-Diet Index in Turkey. AB - BACKGROUND: Childhood obesity and its complications are serious health problems and diet/lifestyle changes can be beneficial for the prevention of diseases. Adaptation of the Healthy Lifestyle-Diet (HLD) Index in accordance with the dietary guidelines for Turkey (TR) and determination of the relationship between metabolic syndrome risk factors in obese children were the aims of this study. METHODS: This study was conducted on 164 overweight or obese children (87 male, 77 female) aged 9-13 years. For all participants, the HLD-TR Index and a 24-h dietary recall were performed and the mean adequacy ratio (MAR) was calculated. Anthropometric measurements and the body composition of the children were taken. Metabolic syndrome risk factors and insulin resistance were assessed. RESULTS: The mean age of the male and female children was 11.2+/-1.49 and 11.0+/-1.40 years, respectively. The majority of the children were obese in both genders. There were no statistically significant differences in the HLD-TR scores between the genders. As the index scores increased, a decrease in the energy intake and an increase in the MAR were observed. Negative correlations between the index scores and body mass, waist circumference and body fat mass were observed. Furthermore, a one-unit increase in the index score decreases the insulin resistance risk by 0.91 times after adjustments for age and gender (odds ratio: 0.91 [0.85-0.97]). CONCLUSIONS: The HLD-TR Index is a valid tool that can give an idea about the quality of the diet in obese children. Furthermore, with the increase in the compliance with recommendations for diet/lifestyle changes, indicators of obesity and metabolic syndrome were decreased. PMID- 29494340 TI - Sanjad-Sakati syndrome with macrocytic anemia and failure to thrive: a case from South Jordan. AB - : Backgorund: Sanjad-Sakati syndrome (SSS) is a rare autosomal recessive disease caused by a deletion mutation (155-166del) in exon 3 of the TBCE gene on chromosome 1q42-43. The syndrome is characterized by primary hypoparathyroidism, typical dysmorphic features and severe growth retardation. CASE PRESENTATION: We encountered a 2-year-old boy with hypocalcemia, failure to thrive and macrocytic anemia. The patient had the characteristic features of SSS and genetic testing confirmed that he was homozygous for the TBCE mutation. Although malabsorption was initially considered the cause of his symptoms, the results did not confirm that diagnosis. Our patient had cow milk protein allergy and folic acid deficiency, which has not been described in previous SSS cases. It was difficult to treat the patient's hyperphosphatemia and we ultimately selected sevelamer treatment, which was tolerated well and improved his hypocalcemia. CONCLUSIONS: SSS should be considered in the differential diagnosis of any infant with hypocalcemia, dysmorphism and failure to thrive. PMID- 29494341 TI - HbA1c levels in children with type 1 diabetes and correlation to diabetic retinopathy. AB - BACKGROUND: Type 1 diabetes mellitus (T1D) is a metabolic disease causing hyperglycemia due to beta-cell destruction. Despite adequate treatment, complications such as diabetic retinopathy (DR) are common. The first aim was to investigate if acute onset of type 1 diabetes differed between those who had developed retinopathy and who had not after 15 years from diagnosis. The second aim was to investigate if mean glycosylated hemoglobin (HbA1c) levels affect the time to development of DR. METHODS: The medical records of all children and adolescents diagnosed with type 1 diabetes during 1993-2001 in our area in Sweden were studied retrospectively and the mean HbA1c each year until the development of retinopathy was investigated. In total 72 patients were included and the follow-up time was between 15 and 23 years. Gender, p-glucose, age and HbA1c at diagnosis were analyzed for possible correlations to years to retinopathy. RESULTS: HbA1c was significantly higher among those who had developed DR after 15 years from diagnosis, 98+/-9.2 (n=25) vs. 86+/-9.2 (n=46; p=0.025). A negative correlation was found between age at diagnosis and years to DR (rs=-0.376; p=0.026). Mean HbA1c levels at years 6-10 after diabetes diagnosis correlated significantly (rs=-0.354, p=0.037) to years until retinopathy. Mean HbA1c levels at years 1-15 after diabetes diagnosis were significantly higher at years 2-3 and years 5-8 for those who had developed retinopathy after 15 years from diagnosis. CONCLUSIONS: Higher HbA1c levels shortened the time to development of retinopathy. It is therefore important to keep HbA1c as close to normal as possible. PMID- 29494342 TI - Hyperthyroidism in an infant of a mother with autoimmune hypothyroidism with positive TSH receptor antibodies. AB - BACKGROUND: Neonatal hyperthyroidism is rare, seen in infants of mothers with Graves' disease (GD), with transplacental transfer of thyroid-stimulating hormone receptor (TSHR) antibodies (TRAbs). We describe a neonate with severe hyperthyroidism due to TRAbs, born to a mother with autoimmune hypothyroidism. CASE PRESENTATION: A baby boy born preterm at 35 weeks had irritability, tachycardia and proptosis after birth. The mother had autoimmune hypothyroidism, from age 10, with thyroxine replacement and normal thyroid function throughout her pregnancy. She had never been thyrotoxic. There was a family history of Hashimoto's thyroiditis (HT) and GD. The baby's thyroid function on day 3 demonstrated gross thyrotoxicosis, TSH<0.01 mIU/L (normal range [NR]<10 mIU/L), free thyroxine (FT4)>77 pmol/L (20-35), free triiodothyronine (FT3) 15.4 pmol/L (4.2-8.3) and TRAb 18.4 IU/L (<1.8). The mother's TRAb was 24.7 IU/L. Thyrotoxicosis required propranolol and carbimazole (CBZ). Thyroid function normalized within 10 days. The baby was weaned off medication by 7 weeks. He remains euthyroid. CONCLUSIONS: We postulate that this mother had co-existing destructive thyroiditis and thyroid-stimulating antibodies (TSAbs) and TSHR blocking antibodies (TBAb), rendering her unable to raise a thyrotoxic response to the TSAbs but with predominant TSAb transmission to her infant. Maternal history of any thyroid disorder may increase the risk of transmission to an infant, requiring a careful clinical assessment of the neonate, with important implications for future pregnancies. PMID- 29494343 TI - Transition-metal-doped group-IV monochalcogenides: a combination of two dimensional triferroics and diluted magnetic semiconductors. AB - We report the first-principles evidence of a series of two-dimensional triferroics (ferromagnetic + ferroelectric + ferroelastic), which can be obtained by doping transition-metal ions in group-IV monochalcogenide (SnS, SnSe, GeS, GeSe) monolayers, noting that a ferromagnetic Fe-doped SnS2 monolayer has recently been realized (Li B et al 2017 Nat. Commun. 8 1958). The ferroelectricity, ferroelasticity and ferromagnetism can be coupled and the magnetization direction may be switched upon ferroelectric/ferroelastic switching, rendering electrical writing + magnetic reading possible. They can be also two-dimensional half-metals or diluted magnetic semiconductors, where p/n channels or even multiferroic tunneling junctions can be designed by variation in doping and incorporated into a monolayer wafer. PMID- 29494344 TI - Stable and efficient retrospective 4D-MRI using non-uniformly distributed quasi random numbers. AB - The purpose of this work is the development of a robust and reliable three dimensional (3D) Cartesian imaging technique for fast and flexible retrospective 4D abdominal MRI during free breathing. To this end, a non-uniform quasi random (NU-QR) reordering of the phase encoding (k y -k z ) lines was incorporated into 3D Cartesian acquisition. The proposed sampling scheme allocates more phase encoding points near the k-space origin while reducing the sampling density in the outer part of the k-space. Respiratory self-gating in combination with SPIRiT reconstruction is used for the reconstruction of abdominal data sets in different respiratory phases (4D-MRI). Six volunteers and three patients were examined at 1.5 T during free breathing. Additionally, data sets with conventional two dimensional (2D) linear and 2D quasi random phase encoding order were acquired for the volunteers for comparison. A quantitative evaluation of image quality versus scan times (from 70 s to 626 s) for the given sampling schemes was obtained by calculating the normalized mutual information (NMI) for all volunteers. Motion estimation was accomplished by calculating the maximum derivative of a signal intensity profile of a transition (e.g. tumor or diaphragm). The 2D non-uniform quasi-random distribution of phase encoding lines in Cartesian 3D MRI yields more efficient undersampling patterns for parallel imaging compared to conventional uniform quasi-random and linear sampling. Median NMI values of NU-QR sampling are the highest for all scan times. Therefore, within the same scan time 4D imaging could be performed with improved image quality. The proposed method allows for the reconstruction of motion artifact reduced 4D data sets with isotropic spatial resolution of 2.1 * 2.1 * 2.1 mm3 in a short scan time, e.g. 10 respiratory phases in only 3 min. Cranio-caudal tumor displacements between 23 and 46 mm could be observed. NU-QR sampling enables for stable 4D-MRI with high temporal and spatial resolution within short scan time for visualization of organ or tumor motion during free breathing. Further studies, e.g. the application of the method for radiotherapy planning are needed to investigate the clinical applicability and diagnostic value of the approach. PMID- 29494345 TI - Time-resolved C-arm cone beam CT angiography (TR-CBCTA) imaging from a single short-scan C-arm cone beam CT acquisition with intra-arterial contrast injection. AB - Time-resolved C-arm cone-beam CT (CBCT) angiography (TR-CBCTA) images can be generated from a series of CBCT acquisitions that satisfy data sufficiency condition in analytical image reconstruction theory. In this work, a new technique was developed to generate TR-CBCTA images from a single short-scan CBCT data acquisition with contrast media injection. The reconstruction technique enabling this application is a previously developed image reconstruction technique, synchronized multi-artifact reduction with tomographic reconstruction (SMART-RECON). In this new application, the acquired short-scan CBCT projection data were sorted into a union of several sub-sectors of view angles and each sub sector of view angles corresponds to an individual image volume to be reconstructed. The SMART-RECON method was then used to jointly reconstruct all of these individual image volumes under two constraints: (1) each individual image volume is maximally consistent with the measured cone-beam projection data within the corresponding view angle sector and (2) the nuclear norm of the image matrix is minimized. The difference between these reconstructed individual image volumes is used to generated the desired subtracted angiograms. To validate the technique, numerical simulation data generated from a fractal tree angiogram phantom were used to quantitatively study the accuracy of the proposed method and retrospective in vivo human subject studies were used to demonstrate the feasibility of generating TR-CBCTA in clinical practice. PMID- 29494347 TI - Apocrine Axillary Adenocarcinoma: An Aggressive Adnexal Tumor in Middle-Age Individuals. PMID- 29494346 TI - Protein kinase N1 critically regulates cerebellar development and long-term function. AB - Increasing evidence suggests that synapse dysfunctions are a major determinant of several neurodevelopmental and neurodegenerative diseases. Here we identify protein kinase N1 (PKN1) as a novel key player in fine-tuning the balance between axonal outgrowth and presynaptic differentiation in the parallel fiber-forming (PF-forming) cerebellar granule cells (Cgcs). Postnatal Pkn1-/- animals showed a defective PF-Purkinje cell (PF-PC) synapse formation. In vitro, Pkn1-/- Cgcs exhibited deregulated axonal outgrowth, elevated AKT phosphorylation, and higher levels of neuronal differentiation-2 (NeuroD2), a transcription factor preventing presynaptic maturation. Concomitantly, Pkn1-/- Cgcs had a reduced density of presynaptic sites. By inhibiting AKT with MK-2206 and siRNA-mediated knockdown, we found that AKT hyperactivation is responsible for the elongated axons, higher NeuroD2 levels, and reduced density of presynaptic specifications in Pkn1-/- Cgcs. In line with our in vitro data, Pkn1-/- mice showed AKT hyperactivation, elevated NeuroD2 levels, and reduced expression of PF-PC synaptic markers during stages of PF maturation in vivo. The long-term effect of Pkn1 knockout was further seen in cerebellar atrophy and mild ataxia. In summary, our results demonstrate that PKN1 functions as a developmentally active gatekeeper of AKT activity, thereby fine-tuning axonal outgrowth and presynaptic differentiation of Cgcs and subsequently the correct PF-PC synapse formation. PMID- 29494348 TI - Methodological challenges in indirect treatment comparisons: spotlight on a recent comparison of long-acting injectable aripiprazole versus paliperidone palmitate in the treatment of schizophrenia. AB - In a recent study, an indirect treatment comparison was performed to examine the relative efficacy and tolerability of aripiprazole once monthly and paliperidone palmitate once monthly. The authors concluded that the results may suggest relative advantages for aripiprazole once monthly over paliperidone palmitate once monthly in the short-term treatment of schizophrenia. However, the validity of the study is compromised as an indirect treatment comparison using extant data may violate important assumptions. Other methodological issues identified further highlight the challenges of performing indirect treatment comparisons. PMID- 29494349 TI - Phenotypic Multiorgan Involvement of Subclinical Disease as Quantified by Magnetic Resonance Imaging in Subjects With Prediabetes, Diabetes, and Normal Glucose Tolerance. AB - INTRODUCTION: Detailed mechanisms in the pathophysiology of diabetes disease are poorly understood, but structural alterations in various organ systems incur an elevated risk for cardiovascular events and adverse outcome. The aim of this study was to compare multiorgan subclinical disease phenotypes by magnetic resonance (MR) imaging to study differences between subjects with prediabetes, diabetes, and normal controls. MATERIALS AND METHODS: Subjects without prior cardiovascular disease were enrolled in a prospective case-control study and underwent multiorgan MR for the assessment of metabolic and arteriosclerotic alterations, including age-related white matter changes, hepatic proton density fat fraction, visceral adipose tissue volume, left ventricular remodeling index, carotid plaque, and late gadolinium enhancement. Magnetic resonance features were summarized in a phenotypic-based score (range, 0-6). Univariate, multivariate correlation, and unsupervised clustering were performed. RESULTS: Among 243 subjects with complete multiorgan MR data sets included in the analysis (55.6 +/- 8.9 years, 62% males), 48 were classified as subjects with prediabetes and 38 as subjects with diabetes. The MR phenotypic score was significantly higher in subjects with prediabetes and diabetes as compared with controls (mean score, 3.00 +/- 1.04 and 2.69 +/- 0.98 vs 1.22 +/- 0.98, P < 0.001 respectively), also after adjustment for potential confounders. We identified 2 clusters of MR phenotype patterns associated with glycemic status (P < 0.001), independent of the MR score (cluster II-metabolic specific: odds ratio, 2.49; 95% CI, 1.00-6.17; P = 0.049). DISCUSSION: Subjects with prediabetes and diabetes have a significantly higher phenotypic-based score with a distinctive multiorgan phenotypic pattern, which may enable improved disease characterization. PMID- 29494350 TI - Continuous Hepatic Arterial Multiphase Magnetic Resonance Imaging During Free Breathing. AB - PURPOSE: The aim of this study was to evaluate the feasibility of a prototype volume-interpolated breath-hold examination (VIBE) sequence using compressed sensing (VIBECS) for rapid multiphase arterial magnetic resonance imaging (MRI) at different temporal resolution during free-breathing in comparison with a conventional breath-hold approach (VIBESTD). MATERIAL AND METHODS: A total of 40 patients with liver malignancies were prospectively included in this study and underwent contrast-enhanced liver MRI at 1.5 T to evaluate the performance of VIBECS for rapid arterial multiphase imaging. An additional 40 patients examined with a VIBESTD were included serving as standard of reference. The VIBECS study cohort was subdivided into 2 groups (each n = 20). In both groups, VIBECS was continuously acquired for 60 seconds starting with the contrast agent administration (group A, temporal resolution 4 seconds; group B, temporal resolution 8 seconds). Subsequently, the time point with the subjectively best image quality was selected and defined as hepatic arterial dominant (HAD) phase. Overall image quality, lesion conspicuity, vessel contrast, and artifacts of HAD phase were assessed by 2 radiologists independently on a 5-point Likert scale (5 = excellent) and compared with arterial phase images of VIBESTD. In addition, signal attenuation/time curves of VIBECS were plotted for each patient to quantify the hepatic arterial enhancement. RESULTS: No patients were excluded and all HAD phases were reliably recorded in the investigated VIBECS cohort. Most commonly, HAD was observed at the ninth time point (36 seconds after intravenous contrast injection) in group A and at the fifth time point (40 seconds after intravenous contrast injection) in group B. Timing with VIBESTD was only adequate in 65% (26/40). Image quality, lesion conspicuity, and vessel contrast were good to excellent without significant differences between both VIBECS groups (P >= 0.2) and with significantly higher reading scores as compared with VIBESTD with respect to lesion conspicuity (P <= 0.006) and image quality (group B; P < 0.001). VIBECS showed reconstruction artifacts, which were significantly higher in group A (P = 0.001). Mean peak arterial enhancement was observed at the ninth time point (36 seconds) in group A and at the sixth (48 seconds) in group B. CONCLUSION: VIBECS allows for robust multiphase arterial imaging during free breathing at high spatial and temporal resolution (preferably 8 seconds) with improved image quality and lesion conspicuity as compared with VIBESTD. PMID- 29494351 TI - Sexual Satisfaction Changes Reported by Men After Their Partners' Robotic Assisted Laparoscopic Sacrocolpopexies. AB - OBJECTIVES: This study aimed to compare the preoperative and postoperative sexual satisfaction reported by male sexual partners of women undergoing surgical correction of pelvic organ prolapse. METHODS: This was a single-center prospective cohort study. Heterosexual, sexually active English-speaking couples in which the women were planning to undergo robotic-assisted laparoscopic sacrocolpopexy for correction of pelvic organ prolapse were eligible for enrollment in the study. Validated sexual function questionnaires-the Sexual Experience Questionnaire (SEX-Q; Mulhall et al. J Sex Med. 2008) and Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire-12 (Rogers, et al. Int Urogynecol J Pelvic Floor Dysfunct. 2003)-were used to evaluate preoperative and postoperative male and female sexual experience, respectively. These preoperative scores were compared using paired t tests. The Student t and the Mann-Whitney tests were used to compare study-eligible couples with noneligible couples and to compare study participants with nonparticipants. RESULTS: During the study enrollment period, 92 couples met the inclusion criteria and 45 of those were enrolled. Complete data sets of preoperative and postoperative questionnaires were obtained for 36 couples. After their partners' successful reconstructive surgery, male study subjects reported improved total SEX-Q scores (mean +/- SD, 71 +/- 16.7 vs 76.5 +/- 17.8; P = 0.025). Within the subscales of the SEX-Q, there was significant improvement between preoperative and postoperative "individual satisfaction" scores (mean +/- SD, 65.7 +/- 16.8 vs 78.9 +/- 17.5; P < 0.0001), but not within the "erectile dysfunction" or "couple satisfaction" subscales. Female partners reported improved Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire-12 scores after surgery (mean +/- SD, 36.6 +/- 5.5 vs 40.0 +/- 4.6; P = 0.003). CONCLUSIONS: Sexually active heterosexual men and women reported improved sexual experience after successful prolapse repair. PMID- 29494352 TI - Tenosynovial Giant Cell Tumors in Children: A Similar Entity Compared With Adults. AB - BACKGROUND: Tenosynovial giant cell tumor (TGCT) is a rare, benign, monoarticular entity. Many case-series in adults are described, whereas TGCT is only incidentally reported in children. Therefore, its incidence rate and natural history in children are unknown. QUESTIONS/PURPOSES: (1) How many cases have been reported of this condition, and what were their characteristics? (2) What is the standardized pediatric incidence rate for TGCT? (3) Is there a clinical difference in TGCT between children and adults? (4) What is the risk of recurrence after open resection in children compared with adults? METHODS: Data were derived from three sources: (1) a systematic review on TGCT in children, seeking sources published between 1990 and 2016, included 17 heterogeneous, small case-series; (2) the nationwide TGCT incidence study: the Dutch pediatric incidence rate was extracted from this nationwide study by including patients younger than 18 years of age. This registry-based study, in which eligible patients with TGCT were clinically verified, calculated Dutch incidence rates for localized and diffuse-type TGCT in a 5-year timeframe. Standardized pediatric incidence rates were obtained by using the direct method; (3) from our nationwide bone and soft tissue tumor data registry, a clinical data set was derived. Fifty seven children with histologically proven TGCT of large joints, diagnosed and treated between 1995 and 2015, in all four tertiary sarcoma centers in The Netherlands, were included. These clinically collected data were compared with a retrospective database of 423 adults with TGCT. Chi-square test and independent t test were used to compare children and adults for TGCT type, sex, localization, symptoms before diagnosis, first treatment, recurrent disease, followup status, duration of symptoms, and time to followup. The Kaplan-Meier method was used to evaluate recurrence-free survival at 2.5 years. RESULTS: TGCT is seldom reported because only 76 pediatric patients (39 female), 29 localized, 38 diffuse, and nine unknown type, were identified from our systematic review. The standardized pediatric TGCT incidence rate of large joints was 2.42 and 1.09 per million person-years in localized and diffuse types, respectively. From our clinical data set, symptoms both in children and adults were swelling, pain, and limited ROM with a median time before diagnosis of 12 months (range, 1-72 months). With the numbers available, we did not observe differences in presentation between children and adults in terms of sex, symptoms before diagnosis, first treatment, recurrent disease, followup status, or median time to followup. The 2.5-year recurrence-free TGCT survival rate after open resection was not different with the numbers available between children and adults: 85% (95% confidence interval [CI], 67%-100%) versus 89% (95% CI, 83%-96%) in localized, respectively (p = 0.527) and 53% (95% CI, 35%-79%) versus 56% (95% CI, 49%-64%) in diffuse type, respectively (p = 0.691). CONCLUSIONS: Although the incidence of pediatric TGCT is low, it should be considered in the differential diagnosis in children with chronic monoarticular joint effusions. Recurrent disease after surgical treatment of this orphan disease seems comparable between children and adults. With targeted therapies being developed, future research should define the most effective treatment strategies for this heterogeneous disease. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29494354 TI - Facial Plaque in a Woman With Sjogren Syndrome: Challenge. PMID- 29494353 TI - Changes in liver stiffness and steatosis among patients with hepatitis C virus infection who received direct-acting antiviral therapy and achieved sustained virological response. AB - AIM: Whether direct-acting antiviral (DAA) therapy can reduce liver fibrosis and steatosis in patients with chronic hepatitis C virus (HCV) infection remains unclear. We evaluated sequential changes in liver stiffness and steatosis using transient elastography (TE) and the TE-based controlled attenuation parameter (CAP) in patients with HCV who received DAA therapy. PATIENTS AND METHODS: A total of 57 patients with HCV who received DAA therapy and achieved sustained virological response (SVR) were analyzed. Liver stiffness as evaluated with TE, steatosis as evaluated with CAP, and laboratory data were assessed before treatment (baseline), at end of treatment (EOT), 24 weeks after EOT (SVR24), and 48 weeks after EOT (SVR48). RESULTS: Alanine aminotransferase levels, corresponding to the presence of necroinflammatory activity, significantly decreased overall, with significant differences between baseline and EOT, EOT, and SVR24, and baseline and SVR48. However, alanine aminotransferase levels showed no significant changes between SVR24 and SVR48. Median (interquartile range) liver stiffness values at baseline, EOT, SVR24, and SVR48 were 8.3 (5.0 14.8), 7.4 (4.6-14.7), 5.3 (4.1-11.8), and 5.4 (4.0-13.4) kPa, respectively (baseline vs. EOT, P=0.044; EOT vs. SVR24, P=0.011; and SVR24 vs. SVR48, P=0.054). In patients with fatty liver (CAP>=236 dB/m, n=14), CAP values at baseline and SVR48 were 253 (245-278) and 229 (209-249) dB/m, respectively (P=0.020). CONCLUSION: Liver stiffness at SVR24 might reflect liver fibrosis in the patients who received DAA therapy and achieved SVR. In addition, liver steatosis reduces in the same cohort with fatty liver. PMID- 29494355 TI - Photosensitive Eruption in a Patient with Metastatic Non-small Cell Lung Cancer: Challenge. PMID- 29494356 TI - A novel penicillin derivative induces antitumor effect in melanoma cells. AB - In this study, we explored the in-vitro and in-vivo mechanism of antitumor action of a novel synthetic nonantibiotic triazolylpeptidyl penicillin derivative, named TAP7f, on B16-F0 murine melanoma cells. In-vitro assays showed that TAP7f caused an inhibition of S phase progression and a concomitant decrease of the percentage of cells in G0/G1 phase. We also found that TAP7f treatment induced an apoptotic response characterized by an increase of the sub-G1 fraction of B16-F0 hypodiploid cells, the occurrence of cells with picnotic nuclei, and the detection of phosphatidylserine exposure on the outer side of the plasma membrane. Apoptotic cell death was further characterized by the activation of caspase-8, caspase-9, and caspase-3; the increase in the proapoptotic/antiapoptotic ratio of Bcl-2 family proteins; the higher expression levels of Fas receptor and TRAIL ligand; and the cleavage of poly(ADP-ribose) polymerase, a caspase-3 substrate. The in-vivo effect of TAP7f was studied in a syngeneic C57BL/6J mouse melanoma model. Results showed that TAP7f inhibited melanoma cell proliferation in vivo, as determined by a decreased expression of proliferating cell nuclear antigen, inducing a significant reduction of tumor growth. Apoptosis in vivo was assessed by detecting active caspase-3 in tumor slices from treated mice and the expression levels of Fas, TRAIL, and Bcl-2 proteins in tumor lysates. The administration of 80 mg/kg of TAP7f to non-tumor bearing mice showed no histopathological effects on different organ tissues. Our results suggest that TAP7f might be considered as a potential therapeutic agent for cancer treatment. PMID- 29494357 TI - miR-340 alleviates chemoresistance of osteosarcoma cells by targeting ZEB1. AB - Chemoresistance during treatment of osteosarcoma (OS) is attracting more and more attention as the main clinical obstacle. The purpose of this study was to elucidate the role of miR-340 in chemoresistance of OS. Plasmid construction and transfection, miRNA arrays, PCR analyses, and western blot analysis, as well as MTT, apoptosis, and luciferase assays were carried out in MG-63 cells and MG 63/cisplatin (DDP)-resistant cells. The results showed that miR-340 was downregulated in OS tissues and drug-resistant OS cells. Moreover, a negative correlation was observed between miR-340 and ZEB1 expression in OS tissues. Forced expression of miR-340 in drug-resistant OS cells significantly reduced multidrug resistance-1 and P-gp expression. Overexpression of miR-340 enhanced sensitivity to DDP by inhibiting viability and promoting apoptosis. The luciferase assay and western blot analysis identified ZEB1 as a direct target of miR-340, and miR-340 negatively regulated ZEB1 expression. Ectopic expression of ZEB1 reversed the effects of miR-340 on P-gp expression, cell viability, and apoptosis. miR-340 alleviated chemoresistance of OS cells by targeting ZEB1. Our results indicate that targeting miR-340 may be a potential therapeutic approach to treat drug-resistant OS. PMID- 29494359 TI - Using Technologies in Nursing Research Education: A Mixed Methods Case Study. AB - To better prepare nurses for the new and expanding roles required in healthcare, faculty are expected to integrate emerging technology into educational processes. Using a mixed methods research design, this study aimed to examine nursing student reactions and learning based on their participation in an online research course through two technology-enhanced assignments: (1) annotation of the structure of a research article and (2) reflection on the content of a research article. Quantitative analysis examined students' questionnaire responses, and qualitative analysis explored students' reflective learning journals and the instructor's notes. These two separate strands of data were then integrated using a joint display. The discussion was guided by two components of the New World Kirkpatrick model, reaction and learning. Our findings suggest that the use of technology in the design of assignments is a way to engage students in learning and can be used to enhance nursing students' research learning online. PMID- 29494360 TI - A Hospital Bed Allocation Hybrid Model Based on Situation Awareness. AB - Bed management is an important area of planning and control for hospitals, as it has the important role of maintaining the balance between patients from the emergency department, patients who have elective surgery or scheduled treatment, and patients who are discharged from the hospital, while maintaining high bed occupancy rates. Effective management of these resources has always been a challenge for managers. In the 1980s and 1990s, thousands of patients had operations canceled due to nonmedical reasons. Due to the constant uncertainty experienced by hospitals today, use of the cognitive model known as situation awareness has been increasing in healthcare. Situation awareness seeks to understand environmental context to design the future, using artificial intelligence techniques. In this context, this article contributes the use of situation awareness in bed management using a hybrid system that combines known techniques of artificial neural networks and multiattribute value theory for decision-making by automating the process of bed allocation. The system was evaluated in a hospital in Porto Alegre, Brazil, yielding a result of 93.5% similarity between the beds determined by the proposed model and those chosen by the hospital manager. PMID- 29494358 TI - Complex cranio-vertebral malformation: disruption sequence or iniencephaly? PMID- 29494361 TI - Using Unsupervised Machine Learning to Identify Subgroups Among Home Health Patients With Heart Failure Using Telehealth. AB - This study explored the use of unsupervised machine learning to identify subgroups of patients with heart failure who used telehealth services in the home health setting, and examined intercluster differences for patient characteristics related to medical history, symptoms, medications, psychosocial assessments, and healthcare utilization. Using a feature selection algorithm, we selected seven variables from 557 patients for clustering. We tested three clustering techniques: hierarchical, k-means, and partitioning around medoids. Hierarchical clustering was identified as the best technique using internal validation methods. Intercluster differences among patient characteristics and outcomes were assessed with either chi test or one-way analysis of variance. Ranging in size from 153 to 233 patients, three clusters displayed patterns that differed significantly (P < .05) in patient characteristics of age, sex, medical history of comorbid conditions, use of beta blockers, and quality of life assessment. Significant (P < .001) intercluster differences in number of medications, comorbidities, and healthcare utilization were also revealed. The study identified patterns of association between (1) mental health status, pulmonary disorders, and obesity, and (2) healthcare utilization for patients with heart failure who used telehealth in the home health setting. Study results also revealed a lack of prescription guideline-recommended heart failure medications for the subgroup with the highest proportion of older female adults. PMID- 29494362 TI - Exploring the Knowledge Structure of Nursing Care for Older Patients With Delirium: Keyword Network Analysis. AB - Prevention of delirium is considered a critical part of the agenda for patient safety and an indicator of healthcare quality for older patients. As the incidence rate of delirium for older patients has increased in recent years, there has been a significant expansion in knowledge relevant to nursing care. The purposes of this study were to analyze the knowledge structure and trends in nursing care for older adults with delirium based on a keyword network analysis, and to provide a foundation for future research. Data analysis showed that knowledge structure in this area consists of three themes of research: postoperative acute care for older patients with delirium, prevention of delirium for older patients in intensive care units, and safety management for the improvement of outcomes for patients with delirium. Through research trend analysis, we found that research on care for patients with delirium has achieved both quantitative and qualitative improvements over the last decades. Concerning future research, we propose the expansion of patient- and family-centered care, community care, specific nursing interventions, and the integration of new technology into care for patients with delirium. These results provide a reference framework for understanding and developing nursing care for older adults with delirium. PMID- 29494363 TI - Thrombus resolution with tirofiban in the conservative management of patients presenting with plaque erosion. AB - OBJECTIVE: Recent studies suggest that conservative management with antithrombotic therapy without stenting may be an option in selected patients with acute coronary syndrome (ACS). We evaluated whether a glycoprotein IIb/IIIa inhibitor, tirofiban, would offer additional benefit in patients with plaque erosion presenting with ACS who were treated with antiplatelet therapy without stenting. PATIENTS AND METHODS: Forty-nine patients who completed 1-year follow up optical coherence tomography imaging in the EROSION study were divided into two groups: tirofiban (n=32) versus no tirofiban (n=17). Thrombus volume, thrombus burden, and the incidence of major adverse cardiovascular events were evaluated. RESULTS: At baseline, the tirofiban group had similar thrombus volume [3.73 (1.27-12.49) vs. 3.51 (1.70-8.65) mm, P=0.983] and marginally greater thrombus burden [17.9 (10.1-26.1) vs. 10.6 (6.8-19.0)%, P=0.097]. At 1 month, the tirofiban group had smaller residual thrombus volume [0.00 (0.00-1.78) vs. 0.94 (0.07-4.20) mm, P=0.054], thrombus burden [0.0 (0.0-6.4) vs. 7.0 (1.8-14.8)%, P=0.024], and greater reduction of thrombus volume (85.4+/-24.6 vs. 67.1+/-27.1%, P=0.021). These differences were maintained up to 1 year. Complete resolution of thrombus at 1 month was more frequent in the tirofiban group (53.1 vs. 17.6%, P=0.031). None of the patients experienced major bleeding during the initial hospitalization. The 1-year major adverse cardiovascular events rate was not different (5.6 vs. 15.0%, P=0.336). CONCLUSION: In patients with ACS caused by plaque erosion who were managed conservatively without stenting, tirofiban provided additional benefit in reducing residual thrombus without an increased risk for bleeding. PMID- 29494364 TI - Foreword. PMID- 29494365 TI - Point-of-Care Ultrasonography in Emergency and Critical Care Medicine. AB - To stabilize critically ill patients, emergency and critical care medicine providers often require rapid diagnosis and intervention. The demand for a safe, timely diagnostic device, alongside technological innovation, led to the advent of point-of-care ultrasonography (POCUS). POCUS allows the provider to gain invaluable clinical information with a high level of accuracy, leading to better clinical decision-making and improvements in patient safety. We have outlined the history of POCUS adaptation in emergency and critical care medicine and various clinical applications of POCUS described in literature. PMID- 29494366 TI - Targeted Temperature Management for Improved Outcomes: Are We There Yet? AB - Therapeutic hypothermia, also referred to as targeted temperature management, has been a component of the postcardiac arrest treatment guidelines since 2010. Although almost a decade has passed since its inclusion in the postarrest guidelines, many unanswered questions remain regarding selection of the appropriate patient population, optimal target temperature, ideal window of time in which to initiate therapy after arrest, most efficient, safe, and accurate equipment choice for inducing and maintaining hypothermia, most effective duration of treatment, and rate of cooling or rewarming. On a national and international level, critical care nurses are in a unique position to participate in research that will define targeted temperature management protocols and practices. Nurses are also ideal for standardizing the targeted temperature management policy and protocol locally and nationally based on current available evidence. This review aims to serve 2 purposes: first, to provide a broad update on the current clarifications and limitations per research findings on target temperature management therapy; second, to explain how critical care nurses can use this updated information to improve outcomes for their patients with cardiac arrest. PMID- 29494367 TI - An Assessment of an Outpatient Antimicrobial Therapy Program in a Rural Medical Center : A Retrospective Chart Review. AB - Current literature supports outpatient parenteral antimicrobial therapy (OPAT). This article presents results from a research study that evaluated an OPAT program that treated community-acquired pneumonia. If patients had the opportunity to receive outpatient intravenous antibiotics for community-acquired pneumonia, would this prevent future hospitalization? Was there a decrease in hospital admissions? An informal cost-benefit analysis comparing OPAT with inpatient hospital admissions for the same disease was also reviewed to provide evidence whether there was a change. What was the overall health care cost savings? The medical charts of 50 patients with confirmed pneumonia who had received OPAT in a 3-month period were reviewed. A retrospective medical record review was performed. All patients were evaluated by the in-house OPAT team. The resulting analysis provided evidence that an estimated savings of approximately $2100 per day would be achieved by decreasing hospital readmissions for patient who had been treated with OPAT. The conclusion of this study provides evidence that the implement of an OPAT program was, and is, essential for patient care and evidence-based best practice adherence. PMID- 29494368 TI - Pharmacologic Reversal of Direct Oral Anticoagulants. AB - Direct oral anticoagulants are becoming increasingly popular in outpatient use. These medications have lacked specific reversal agents. However, this is changing. The Federal Food and Drug Administration approved idarucizumab for reversal of dabigatran in 2016, and another agent, andexanet alfa, is currently in clinical trials for reversal of rivaroxaban and apixaban. This article examines the efficacy and safety of these emerging reversal agents, as well as other historical agents for reversal of direct oral anticoagulants. PMID- 29494369 TI - Effects of Multimethod Intervention on Bedside Report Compliance and Patient Satisfaction. AB - Miscommunication is a large contributing factor to hospital sentinel events. Communication with nurses is a component of the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey. The HCAHPS survey not only assesses patient satisfaction but also impacts how hospitals are reimbursed. A literature review reveals that nursing bedside shift positively impacts patient satisfaction and nurse communication. There is limited research on how to implement bedside report as well as what to include during report. A pilot study evaluated an educational intervention and its impact on nurses' compliance with bedside report. The study also evaluated whether bedside report compliance affected HCAHPS scores. A test of independent proportions showed that overall compliance scores increased significantly from period 1 (46%) to period 3 (81%), z = 2.23, P = -.017, one-tailed. HCAHPS scores for nursing communication went from 69.9% in quarter 1 of 2015 to 73.8% in quarter 4 of 2016, but there was no statistically significant change. PMID- 29494370 TI - Evaluation of an Educational Video: What to Expect on the First Day of Chemotherapy. AB - According to the American Cancer Society, more than 1.6 million new cases of cancer were diagnosed in 2015. Anxiety levels in individuals diagnosed with cancer are high, with the highest levels occurring at the time of diagnosis. A cancer diagnosis and the associated chemotherapy are life-altering events for patients and their families. In addition to managing the devastating news about the disease, patients are tasked with learning to manage the impact of chemotherapy and its impact on their bodies and sense of well-being. These authors report the development of an education video aimed at addressing typical questions and concerns about treatment regimens. Results of their studies to determine the effectiveness of their video indicate significant value for the patient, especially anxiety reduction and enhanced ability to absorb new information and instructions from their caregiving team. PMID- 29494371 TI - Effects of Nurse-Led Intervention on Patients' Anxiety and Sleep Before Coronary Artery Bypass Grafting. AB - The aim of this study to examine the effects of supportive-educational nurse-led intervention on the patients' anxiety and sleep before the coronary artery bypass grafting.The current clinical trial recruited 160 patients (N = 160) waiting for the coronary artery bypass grafting by random block sampling and divided them into two 80-people experimental and control groups. Spielberger's State Anxiety Inventory was completed on the first day. The Groningen's Sleep Quality Index was also completed by the patients on the day of surgery. Data were analyzed in SPSS software version 16, using descriptive and inferential statistics tests.The mean anxiety score in the experimental group decreased to 48.39, whereas in the control group, the mean anxiety score saw a rise after the intervention (61.09). The comparison of the mean quality of sleep the night before the surgery for both groups showed that sleep in the control group compared with sleep in the experimental group had a lower quality, and statistically, it was significant (P < .001).Results showed that nonpharmacological and supportive interventions can reduce patients' anxiety and sleep disturbance before the coronary artery bypass grafting. According to the results, nonpharmacological therapies should be placed at the top of nurses' tasks. PMID- 29494372 TI - Quality of Sleep Among Intensive Care Unit Patients: A Literature Review. AB - Investigating sleep disturbances among intensive care unit (ICU) patients and its serious consequences is considered a crucial issue for nurses. The need of sleep increases during hospitalization time to preserve energy for the healing process. Previous studies have demonstrated that sleep disturbance is one of the most common complaints of patients in the ICUs, with a prevalence of more than 50%. Although the total sleep time might be normal, the patients' sleep is fragmented and light in the intensive care settings. The main purpose of this review is to generate a clear view of what is known about sleep disturbances among ICU patients as well as to identify the gap in knowledge regarding this issue. This was done by describing, summarizing, clarifying, and evaluating well-selected previous studies about this topic. In addition, this concise review has focused on the prevalence of sleep disturbances in the ICU, factors contributing to poor quality of sleep among ICU patients, and the physiological effects of poor sleep on the patients' prognosis. PMID- 29494373 TI - Incorporation of Daily Goals in Daily Care Planning Does Not Shorten Length of Stay in the Intensive Care Unit. AB - A strategy of defining and checking explicitly formulated patient-specific treatments targets or "daily goals" in the intensive care unit has been associated with improved communication. We investigated the effect of incorporation of daily goals into daily care planning on length of stay in the intensive care unit. Furthermore, the type of daily goals and deviations from daily goals in daily care with or without documented reason were evaluated. Four university hospitals in the Netherlands, of which 2 study "daily goal" hospitals and 2 control hospitals, participated in a prospective before-after study. During the before phase of the study, daily goals were formulated by the attending physician but kept blinded from doctors and nurses caring for the patient. During the after phase of the study, daily goals were integrated in the care plan for patients admitted to the 2 study hospitals but not for patients admitted to the control hospitals. The implementation of daily goals was, after case-mix correction, not associated with a change in intensive care unit length of stay. However, this study showed that an improved administrative discipline, that is, the recording of the reason why a daily goal or standard protocol was not accomplished, is in favor of the daily goal implementation. PMID- 29494374 TI - Stress Reduction in Postcardiac Surgery Family Members: Implementation of a Postcardiac Surgery Tool Kit. AB - The intensive care unit (ICU) can be a place of stress, anxiety, and emotional instability for both patients and families. Medical and nursing care during this acute time is patient focused, and family members are often left in the dark. Unintentional exclusion from information results in high levels of stress, anxiety, and uncertainty for families. Due to the acuity of illness, family members of cardiac surgery patients experience the highest levels of stress. Spouses may experience intense psychosomatic symptoms such as depression, anxiety, and fear for several months after the surgery. The purpose of this study was aimed at decreasing those feelings of anxiety in family members with postcardiac surgery through the use of a cardiac surgery tool kit. The study was a quality improvement project utilizing a convenience sample of 83 participants 18 years and older. Participants were asked to use the State Trait Anxiety Inventory (STAI) Form Y-1 (state anxiety) to rate their anxiety level preintervention and then again postintervention. Data were collected over a 6 month period. Descriptive data including age, education level, ethnicity, relationship, experience in the ICU, and active diagnoses of mental disorders did not affect the changes in the pre- and posttest data. A paired t test was conducted on the sample to assess changes in state anxiety, using the STAI Form Y 1. The results were statistically significant (t = 11.97, df = 81, P < .001). Respondents' scores decreased significantly from pre intervention (mean = 53.01, standard deviation = 12.19) to postintervention (mean = 37.38, standard deviation = 10.94). The data suggest that the use of a postcardiac surgery tool kit is a low-risk measure that can decrease the anxiety in family members of postcardiac surgery patients. PMID- 29494375 TI - Perceptual Effects of Physical and Visual Accessibilities in Intensive Care Units: A Quasi-experimental Study. AB - This article reports the findings of a 2-phase quasi-experimental study looking at the perceptual effects of physical and visual accessibilities on clinical staff in intensive care units (ICUs). In a previous CCNQ article by Rashid et al, the first phase of the study was reported comparing, among other things, physical and visual accessibilities and their associations with staff perception in 2 ICUs with the open-plan and racetrack-type layouts. The data for that phase of the study were collected in December 2014, which included the data on physical and visual accessibilities collected using the spatial analysis techniques of Space Syntax, and the data on staff perception collected using a questionnaire survey. Since then, the open-plan ICU has been completely redesigned using a layout composed of 4-bed pods (each dubbed as a HYPERPOD by the designer). However, the racetrack ICU has remained unchanged. In August 2016, more than years after the data for the first phase of this study were collected, the authors went back to the study sites to collect similar data using the methods of the previous study by Rashid et al. The purpose of the 2-phase study was 2-fold: (1) to see whether staff perception and their associations with physical and visual accessibilities observed in the racetrack ICU during the first phase would remain unchanged during the second phase of the study; and (2) to see whether staff perception and their associations with physical and visual accessibilities observed in the open plan ICU during the first phase would change in the new ICU during the second phase of the study. The findings of the study comparing the racetrack ICU of the first and second phases show that while staff perception in this unit changed, its associations with the physical and visual accessibilities of the unit did not change during the period between the first and second phases of the study. In contrast, the findings of the study comparing the open-plan ICU of the first phase and the new ICU with 4-bed pods of the second phase show that staff perception as well as its associations with the physical and visual accessibilities of the unit changed in a positive direction from the open-plan ICU to the new ICU. It is concluded that staff perception is likely to change over time even in the absence of environmental changes, but any change in staff perception can be made more effective when it is associated with thoughtful environmental design changes. PMID- 29494376 TI - The Stay S.A.F.E. Strategy for Managing Interruptions Reduces Distraction Time in the Simulated Clinical Setting. AB - Interruptions occurring during the delivery of health care are frequent and create a serious threat to patient safety. It is important to test strategies directed at decreasing the negative effects of interruptions. The purpose of this pilot study was to test the Stay S.A.F.E. strategy for managing interruptions. A pretest, posttest quasi-experimental design was used to test the primary hypothesis that the Stay S.A.F.E. interruption management strategy would significantly (P < .05) reduce distraction time away from a primary task following an interruption. Twenty nurses with a median of 12 years of experience (range: 1-45 years) participated in the study. There was a significant decrease in the amount of time that participants were distracted away from the primary task between the pretest (134.47 seconds, SD = 6.87) and posttest (6.08 seconds, SD = 1.27) periods; P = .0004. The results of this study suggest that the Stay S.A.F.E. interruption management strategy was effective in reducing the length of time participants were distracted from the primary task in a simulated clinical setting. In addition, nurses confirmed the reports of others that interruptions are frequent, dangerous, and result in errors. PMID- 29494377 TI - Age-Group Differences in the Performance of Selected Tests of Physical Function and Association With Lower Extremity Strength. AB - BACKGROUND AND PURPOSE: It is not known whether short functional performance tests used in aging research are appropriate for use in healthy older adults. The purpose of this study was to investigate age-group differences (sixth decade vs seventh decade) in selected functional performance tests and the association between lower extremity strength and functional performance. METHODS: One hundred fifty-nine (18.2% [n = 29] male) healthy older, mean (standard deviation) age: 60.4 (5.3) years, adults were recruited from the University of Limerick Campus Community. Knee extensor (KE) peak torque (PT) was assessed from a maximal voluntary isometric contraction. Subsequently, participants completed 10-m maximal and habitual gait speed tests, 5 repetition and 30-second chair rise tests, and a 900-m gait speed test. RESULTS AND DISCUSSION: There was no difference in 10-m gait speed between those in the sixth and seventh decades (P > .05). Compared with the sixth decade, those in the seventh decade required an extra 39 seconds to complete 900 m, an extra 0.6 seconds to complete 5 chair rises and performed 2 less chair rises in a 30-second time period (P < .05). All tests had a weak association with KE strength (r = 0.226-0.360; P < .05), except for 900-m gait speed that had a moderate association (r = -0.537; P < .001). Our findings suggest that gait speed tests of 10 m or less cannot detect age-related difference in functional capacity when used in healthy older adults. CONCLUSION: Extended physical performance tests should be used in aging research on healthy older adults. PMID- 29494378 TI - Fibrous Histiocytoma of the Lacrimal Sac in an 11-Year-Old Male. AB - Fibrous histiocytoma is a soft tissue tumor with cells resembling both fibroblasts and histiocytes. Occasionally in the orbit, they rarely arise in the lacrimal sac. Similar to prior cases described, the patient presented with symptoms of epiphora and a slowly enlarging mass inferior to the right medial canthus. Imaging demonstrated a circumscribed 1.2 cm * 1.1 cm * 1.1 cm mass within the lacrimal sac without surrounding bony destruction. Grossly, the tumor appeared homogenous and rubbery. Pathologic study results from the case demonstrated zones of hypercellularity and hypocellularity with a fibrous appearance, admixed with spindle cells and collections of foamy histiocytes. A diagnosis of benign fibrous histiocytoma was rendered, with the patient experiencing a complete resolution of symptoms at subsequent follow up. To the authors' knowledge, this is the first reported solitary case report of a fibrous histiocytoma of the lacrimal sac in a pediatric patient. PMID- 29494379 TI - Orbital Hobnail Hemangioma. AB - A 64-year-old woman presented with a 1 year history of progressive left proptosis and "blurry vision." Imaging studies revealed a left superior orbital mass distorting the optic nerve and superior rectus muscle. Excisional biopsy established the diagnosis of hobnail hemangioma. This report describes the first case of an orbital hobnail hemangioma, a lesion that more commonly presents in the dermis. PMID- 29494380 TI - Left Ventricular Structural and Functional Changes in Children With beta Thalassemia and Sickle Cell Disease: Relationship to Sleep-disordered Breathing. AB - Cardiovascular complications are well recognized in beta-thalassemia and sickle cell disease (SCD). The objective of this study was to evaluate left ventricular (LV) structural and functional changes and their relationship to sleep-disordered breathing (SDB) in children with beta-thalassemia and SCD. One hundred patients recruited from the hematology clinic were subjected to Pittsburgh Sleep Quality Index score; 26 patients had positive score (Pittsburgh Sleep Quality Index >=5) (15 beta-thalassemia major and 11 SCD) and were compared with 25 age-matched and sex-matched controls. All underwent polysomnography and tissue Doppler echocardiography. SDB was detected in 73% of thalassemia patients (all had increased LV mass index [LVMI], diastolic dysfunction [increased E/Em], and 53% had pulmonary hypertension [tricuspid valve resurgence (TR) velocity >=2.5 m/s]) and in 46% of SCD patients ( all had increased LVMI, 81.8% had pulmonary hypertension, and 76% had diastolic dysfunction). Sleep O2 saturation of beta thalassemia patients negatively correlated with TR velocity and LVMI (P=0.027, 0.015), and lower asleep O2 saturation was associated with increased E/Em. In SCD patients, sleep and awake O2 saturation negatively correlated with TR velocity and E/Em (P=0.024 and 0.041), and lower sleep O2 saturation was associated with increased LV diameter (P=0.021). SDB is common and associated with LV structural and functional changes in beta-thalassemia and SCD. PMID- 29494381 TI - Moral Injury and Religiosity in US Veterans With Posttraumatic Stress Disorder Symptoms. AB - Moral injury (MI) involves feelings of shame, grief, meaninglessness, and remorse from having violated core moral beliefs related to traumatic experiences. This multisite cross-sectional study examined the association between religious involvement (RI) and MI symptoms, mediators of the relationship, and the modifying effects of posttraumatic stress disorder (PTSD) severity in 373 US veterans with PTSD symptoms who served in a combat theater. Assessed were demographic, military, religious, physical, social, behavioral, and psychological characteristics using standard measures of RI, MI symptoms, PTSD, depression, and anxiety. MI was widespread, with over 90% reporting high levels of at least one MI symptom and the majority reporting at least five symptoms or more. In the overall sample, religiosity was inversely related to MI in bivariate analyses (r = -0.25, p < 0.0001) and multivariate analyses (B = -0.40, p = 0.001); however, this relationship was present only among veterans with severe PTSD (B = -0.65, p = 0.0003). These findings have relevance for the care of veterans with PTSD. PMID- 29494382 TI - Facial Behavior During an Attachment Interview in Patients With Complicated Grief. AB - The present study investigated differences in various aspects of facial behavior among female patients with complicated grief (CG; n = 18) and healthy controls (n = 18) during the assessment of their attachment representation using the Adult Attachment Projective Picture System. All patients were classified with an unresolved attachment status. On a behavioral level, they demonstrated longer gazing behavior away from the interviewer and the picture stimuli, more speech pauses, less smiling toward the interviewer, and more crying, especially in response to stimuli portraying the theme of loss. Focusing on the in-depth analysis of death-related stimuli using the Facial Action Coding System, patients demonstrated less facial affective behavior, less disgust, and less smiling in response to these stimuli compared with the healthy controls. The impaired capacity of patients with CG responding in an affective appropriate manner regarding bereavement might be interpreted as a specific emotion dysregulation when their attachment and mourning system is activated. PMID- 29494383 TI - Trends in Eyelid Dermatitis. PMID- 29494385 TI - Rubber Accelerators in Medical Examination and Surgical Gloves. AB - BACKGROUND: Rubber accelerators play a significant role in glove-related occupational contact dermatitis, especially among health care workers. Currently, there is limited information readily available outlining the accelerators used in specific medical examination and surgical gloves. OBJECTIVE: The aim of this study was to ascertain the accelerators used in medical examination and surgical gloves for major glove manufacturers within the United States. METHODS: An initial Internet-based search was performed to establish relevant manufacturers and product lines, with subsequent inquiry with each corresponding company regarding accelerators used in each medical and surgical glove line. RESULTS: Eleven glove manufacturers were identified and contacted. Responses were obtained from all manufacturers, but because of legal limitations, changes in product lines, or inability to supply necessary data, only 8 companies were able to be included in the final analysis, totaling data for 190 gloves. Carbamates were the most common accelerator, used in 90.5% (172/190) of gloves, whereas thiurams were used in only 11 gloves (5.8%). Eight companies surveyed are now advertising and offering touted accelerator-free gloves. CONCLUSIONS: Accelerators are used in most examination and surgical gloves; however, manufacturers are now expanding their product offerings to include accelerator-free options. PMID- 29494384 TI - Allergic Contact Dermatitis to Electronic Cigarette. PMID- 29494386 TI - Patch Testing for the Evaluation of Metal Hypersensitivity in the Nuss Procedure. AB - The Nuss procedure has become the predominant reason for the use of metal implants by pediatric general and thoracic surgeons. Current guidelines recommend preimplant testing for all patients undergoing the Nuss procedure, which differs from the guidelines for all other orthopedic procedures. This review was done to further evaluate this discrepancy. PMID- 29494387 TI - Immune Dysregulation in the Pathogenesis of Atopic Dermatitis. AB - Atopic dermatitis is a multifactorial disease. Epidermal barrier impairment often plays the initial role in the initiation of the disease. Immune dysregulation of the innate and adaptive immunity plays a central role in the pathogenesis of atopic dermatitis. Alteration of the epidermal microbiome-host interaction serves a catalytic role in propagating this immune response. The understanding of this disease pathogenesis is important in generating treatment options, especially those such as biologic agents that can target a specific immune pathway. PMID- 29494388 TI - Contact Urticaria to Ultrasound Gel: A Case Report. PMID- 29494389 TI - Positive Patch Test Reaction in a Patient Taking Dupilumab. PMID- 29494391 TI - Contact Allergy to Cocamide Diethanolamine and Cross-reactions. PMID- 29494390 TI - Patch Testing in Vulvar Allergic Contact Dermatitis. PMID- 29494393 TI - The Role of Cleaning Products in Epidemic Allergic Contact Dermatitis to Methylchloroisothiazolinone/Methylisothiazolinone. AB - BACKGROUND: Sensitivity to methylchloroisothiazolinone (MCI)/methylisothiazolinone (MI) has increased rapidly over recent years. This increase is mainly related to the extensive use of high concentrations of MI in cosmetic products, although a growing number of cases of occupational allergic contact dermatitis are caused by MCI/MI. OBJECTIVE: The aim of this study was to examine the association between the increase in MCI/MI sensitization and the work performed by the patients in our area. METHODS: A retrospective study was undertaken of the records of a total of 1179 patients who had undergone contact skin patch tests for MCI/MI from January 2005 to December 2015. A multivariate logistic regression analysis was performed to identify the factors independently associated with sensitivity to MCI/MI. RESULTS: A constant increase in MCI/MI sensitization was observed over the observation period. The only work associated with a significant increase in the prevalence of MCI/MI sensitization was cleaning, with 38.5% of the cleaning professionals with MCI/MI sensitization consulting for cosmetics-related dermatitis. CONCLUSIONS: Occupational sensitization to MCI/MI in cleaning professionals is worryingly increasing. This, in turn, could possibly account for many cases of cosmetics-associated contact dermatitis. Our findings suggest that a review of the regulations with regard to isothiazolinone concentrations in industrial and household detergents is necessary. PMID- 29494394 TI - Carmine Red: A Potentially Overlooked Allergen in Children. PMID- 29494392 TI - Prevalence of Contact Allergens in Personal Care Products for Babies and Children. AB - BACKGROUND: Personal care products marketed for babies and children are often regarded as "safe" or "gentle." However, little is known about the prevalence of contact allergens in these types of products. OBJECTIVE: This study assessed the prevalence of important sensitizers in personal care products marketed for babies and children. A secondary objective of this study was to determine whether a product's cost correlates with content of sensitizing ingredients. METHODS: The ingredient lists of 533 unique personal care products were analyzed for presence of fragrance, betaines, propylene glycol, methylchloroisothiazolinone, methylisothiazolinone, formaldehyde, lanolin, and neomycin. Price per ounce was determined for each product as well. CONCLUSIONS: Most personal care products for babies and children contain 1 or more sensitizers. Products containing more sensitizers tend to cost less than those without any sensitizing ingredients. PMID- 29494395 TI - Survey of Patch Test Business Models in the United States by the American Contact Dermatitis Society. AB - BACKGROUND: Allergic contact dermatitis (ACD) remains a significant burden of disease in the United States. Patch testing is the criterion standard for diagnosing ACD, but its use may be limited by reimbursement challenges. OBJECTIVE: This study aimed to assess the current rate of patch test utilization among dermatologists in academic, group, or private practice settings to understand different patch testing business models that address these reimbursement challenges. METHODS: All members of the American Contact Dermatitis Society received an online survey regarding their experiences with patch testing and reimbursement. RESULTS: A "yes" response was received from 28% of survey participants to the question, "Are you or have you been less inclined to administer patch tests or see patients needing patch tests due to challenges with receiving compensation for patch testing?" The most commonly reported barriers include inadequate insurance reimbursement and lack of departmental support. CONCLUSIONS: Compensation challenges to patch testing limit patient access to appropriate diagnosis and management of ACD. This can be addressed through a variety of innovative business models, including raising patch testing caps, negotiating relative value unit compensation, using a fixed salary model with directorship support from the hospital, and raising the percentages of collection reimbursement for physicians. PMID- 29494396 TI - Allergic Contact Stomatitis Associated With Sweet Vermouth. PMID- 29494397 TI - "A Seat at the Table"-Reflections From Two Presidents of the American Contact Dermatitis Society. PMID- 29494398 TI - RANK and RANK Ligand Expression in Parotid Gland Carcinomas. AB - Recently, it has been reported that deregulation of the receptor activator of NFkB ligand (RANKL)/RANK signaling axis results in salivary gland tumor development in a mouse transgenic model. The aim of this study was to ascertain RANKL and RANK protein expression in a series of primary parotid gland carcinomas and to correlate it with clinicopathologic parameters. Formalin-fixed paraffin embedded tumor samples from 46 consecutive cases of parotid gland carcinoma were selected for this study. For comparison, we examined a group of 40 randomly chosen parotid gland adenomas, including 20 pleomorphic adenomas, 10 myoepitheliomas, and 10 Warthin tumors. Immunohistochemical analysis for RANK and RANKL was conducted on tissue microarrays. Overall, 33 carcinomas (71.7%) were scored as positive for RANK and 25 (54.3%) for RANKL. The expression of both RANK and RANKL was significantly higher in carcinomas than in adenomas as only 6 (15%) adenomas were positive for RANK, and RANKL was negative in all benign tumors (P<0.001 for both, Fisher exact test). Some histologic types, including salivary duct carcinoma, mucoepidermoid carcinoma, and carcinoma ex-pleomorphic adenoma presented a high frequency of RANK and RANKL expression. No significant correlation was observed between RANK/RANKL expression and clinical parameters. Our study indicates that the expression of RANK and RANKL in parotid gland neoplasms is associated with the acquisition of a malignant phenotype and this pathway may represent an attractive therapeutic target in patients with parotid gland carcinomas. PMID- 29494399 TI - Clinicopathologic Characteristics of Thyroid-like Low-grade Nasopharyngeal Papillary Adenocarcinoma: A Case Report. AB - Thyroid-like low-grade nasopharyngeal papillary adenocarcinoma (TL-LGNPPA) is an extremely rare neoplasm. It morphologically resembles papillary thyroid carcinoma and is immunochemically positive for thyroid transcription factor 1. Herein, we reported a case of TL-LGNPPA in a female patient of 35 years old. She felt pharyngeal foreign body sensation of unknown cause and subsequently developed dyspnea after activities. Nasopharyngeal plain computerized tomography showed no abnormalities, but laryngoscopy showed a peanut-sized smooth neoplasm with a pedicel at the posterior edge of the nasal septum. The mass was completely resected by nasopharyngoscopy. Histologic examination showed the tumor was composed of papillary configuration and tubular glands; each papilla was covered with cuboidal or columnar epithelial cells; tubular architecture and spindle cell component were also observed; some tumor cells had psammoma bodies. Immunohistochemically, tumor cells were positive for CKpan, CK7, CK19, VIM, and thyroid transcription factor 1, but negative for thyroglobulin, CK20, S-100, P63, P40, smooth muscle actin, CDX-2, and glial fibrillary acidic protein. This patient was diagnosed with TL-LGNPPA and followed up for 16 months, and metastasis and recurrence were not observed. PMID- 29494400 TI - About PD-L1 Immunohistochemistry and RNA In Situ Hybridization in Lung Adenocarcinoma. PMID- 29494402 TI - Influence of Cardiac Output on the Pharmacokinetics of Sufentanil in Anesthetized Pigs. AB - BACKGROUND: Sufentanil is used for general anesthesia and analgesia. The study aim was to determine the effect of pharmacologically induced changes in cardiac output on the pharmacokinetics of sufentanil in anesthetized pigs. METHODS: Twenty-four pigs were randomly assigned to low, high, and control cardiac output groups. Cardiac output was decreased or increased from baseline by at least 40%, or maintained within +/- 10% of baseline, respectively. Sufentanil was administered as a bolus followed by a continuous infusion for 120 min. Timed arterial samples were drawn for sufentanil concentration measurements. RESULTS: Data from 20 animals were analyzed. The cardiac outputs (means +/- SD) were 2.9 +/- 0.7, 5.4 +/- 0.7, and 9.6 +/- 1.6 l/min in the low, control, and high cardiac output groups, respectively. The parameters of the two-compartment pharmacokinetic model for these cardiac outputs were: CL1: 0.9, 1.2, and 1.7 l/min; CL2: 0.9, 3.1, and 6.9 l/min; V1: 1.6, 2.9, and 5.2 l; and V2: 27.5, 47.0, and 79.8 l, respectively. Simulated sufentanil doses to maintain a target plasma concentration of 0.5 ng/ml for 3 h were 99.5, 128.6, and 157.6 MUg for cardiac outputs of 3, 5, and 7 l/min, respectively. The context-sensitive half-times for these cardiac outputs increased from 3.1 to 19.9 and 25.9 min, respectively. CONCLUSIONS: Cardiac output influences the pharmacokinetics of sufentanil. Simulations suggest that in the case of increased cardiac output, the dose should be increased to avoid inadequate drug effect at the expense of prolonged recovery, whereas for low cardiac output the dose should be reduced, and a faster recovery may be expected. PMID- 29494401 TI - Neuroimaging of Pain: Human Evidence and Clinical Relevance of Central Nervous System Processes and Modulation. AB - Neuroimaging research has demonstrated definitive involvement of the central nervous system in the development, maintenance, and experience of chronic pain. Structural and functional neuroimaging has helped elucidate central nervous system contributors to chronic pain in humans. Neuroimaging of pain has provided a tool for increasing our understanding of how pharmacologic and psychologic therapies improve chronic pain. To date, findings from neuroimaging pain research have benefitted clinical practice by providing clinicians with an educational framework to discuss the biopsychosocial nature of pain with patients. Future advances in neuroimaging-based therapeutics (e.g., transcranial magnetic stimulation, real-time functional magnetic resonance imaging neurofeedback) may provide additional benefits for clinical practice. In the future, with standardization and validation, brain imaging could provide objective biomarkers of chronic pain, and guide treatment for personalized pain management. Similarly, brain-based biomarkers may provide an additional predictor of perioperative prognoses. PMID- 29494403 TI - Pharmacokinetic/Pharmacodynamic Model of CW002, an Investigational Intermediate Neuromuscular Blocking Agent, in Healthy Volunteers. AB - BACKGROUND: CW002 is an investigational nondepolarizing, neuromuscular blocking agent with a rapid onset and intermediate duration of action in animals. This is a single ascending dose, healthy subject study exploring tolerability, pharmacokinetics, and potency. METHODS: Population pharmacokinetic and pharmacokinetic/pharmacodynamic models were developed using plasma drug concentration data from a previously published dose-response study in 28 healthy subjects receiving single doses of CW002 during sevoflurane anesthesia. Subjects included in the models were from five different dose cohorts (cohorts 3, 4, 5, 6, and 8 receiving 0.04, 0.06, 0.08, 0.10, and 0.14 mg/kg, respectively). Serial arterial plasma concentrations and muscle twitch heights were monitored. RESULTS: A four-compartment model was fit to the concentration-time data, whereas a transit compartment with a sigmoid Emax model was fit to the pharmacokinetic/pharmacodynamic data. The population pharmacokinetics of CW002 was linear with very low interindividual variability in clearance (10.8%). Simulations were conducted to predict the onset and offset of effect at 2*, 3*, and 4* ED95. The time to 80% block was predicted to be 1.5, 0.8, and 0.7 min for 2*, 3*, and 4* ED95 doses, respectively. The simulated 25 to 75% recovery index was independent of dose. CONCLUSIONS: CW002 has predictable pharmacokinetics and is likely to have a rapid onset with an intermediate duration of action at 3* ED95. This model provides information to inform critical decisions (e.g., dose, study design) for continued development of CW002. PMID- 29494404 TI - Images in Anesthesiology: Point-of-care Ultrasound to Diagnose Esophageal Intubation: "The Double Trachea". PMID- 29494407 TI - Lip Enhancement: Physical Assessment, Injection Techniques, and Potential Adverse Events. AB - Lip enhancement is a common injection treatment that may involve several different injection techniques based on the patient's goals, expectations, and facial anatomy. It is the aesthetic provider's professional judgment to determine which technique will provide the desired results. Taking the time to provide a thorough assessment, review the potential complications, and discuss expectations is an important step in building a patient-nurse therapeutic relationship. Understanding the anatomy and the supporting structures around the perioral area will improve the overall results of a lip enhancement treatment. PMID- 29494408 TI - Attention to Infection Prevention in Medical Aesthetic Clinics. AB - The risk of infection is a concern for all medical aesthetic industry and all providers. Steps to reduce the risk and improve patient outcomes begin with vigilance to proper aseptic technique and being less concerned about the "beauty image" to attract new patients. This article is based on the guidelines outlined in Infection Prevention and Control for Clinical Office Practice by Public Health Ontario. PMID- 29494409 TI - The Art of the Consultation Experience. AB - Looks matter! "Almost from the moment of birth, each of us is judged-silently, unconsciously, and nearly instantly on the basis of everything that goes into the mix of qualities known as "physical attractiveness" (). Aging may be one of the most foreseeable facts of life. As aesthetic providers, we routinely hear concerns about the effects of aging on our looks; it is important that we address these concerns. How do we set our client/provider relationship up for success by providing superb aesthetic solutions to the age-old challenges that we are faced with every day? Having an advanced clinical knowledge, a thorough aesthetic analysis, and an aesthetic plan specific to the client's needs ensure success. The aesthetic plan requires a shift from a two-dimensional to a three-dimensional approach as well as a shift from one product and/or procedure to combination therapy. Providing safe treatments, establishing trust, managing expectations, producing positive outcomes, and creating an engaging experience will ensure loyalty, future treatments, referrals, and a long-term client/provider relationship. PMID- 29494410 TI - Accurately Assessing Lines on the Aging Face. AB - The ongoing positive aging trend has resulted in many research studies being conducted to determine the characteristics of aging and what steps we can take to prevent the extrinsic signs of aging. Much of this attention has been focused on the prevention and treatment of facial wrinkles. To treat or prevent facial wrinkles correctly, their causative action first needs to be determined. published very compelling evidence that the development of wrinkles is complex and is caused by more factors than just the combination of poor lifestyle choices. PMID- 29494411 TI - Common Conditions of the Hand for the Nurse Practitioner: How to Diagnose, How to Manage, and When to Refer to a Hand Surgeon. AB - In many parts of the United States, a plastics-trained hand surgeon can be in limited supply. Depending on individual state law, nurse practitioners can manage common and moderately complex hand conditions, the undertaking of which requires extensive training, high command of the anatomy, and knowing when referral is necessary. PMID- 29494413 TI - The Evolution of Trauma in Los Angeles County Over More Than a Decade. AB - OBJECTIVE: Explore trends in trauma incidence and mortality rates in Los Angeles County. DESIGN: Data for patients treated at Los Angeles County trauma centers from 2000 to 2011 were analyzed for this study. Age-adjusted incidence and mortality rates were calculated by gender, race, injury type, injury severity, and mechanism of injury. Trends were assessed using linear regression to determine the annual percentage change (APC). RESULTS: There were 223 773 patients included. The trauma incidence rate increased by 14.6% driven by an increase in blunt injury of 5.4% annually (P < .05). Penetrating injury decreased at -6.9% APC (P < .01). Mortality rate decreased at -11.5% APC (P < .01), with reduction in both blunt (-6.8% APC [P < .01]) and penetrating injuries (-16.7% APC [P < .01]). The trends in mortality persisted with stratification by age, gender, race, and injury severity score. CONCLUSION: In this mature trauma system, the trauma incidence increased slightly from 2000 to 2011, while the mortality steadily declined. Public health officials in other areas could perform a similar self-evaluation to describe and monitor injury events and trends in their jurisdictions, a reassessment of priority and trauma system resource allocation, which will directly benefit the regional population. PMID- 29494414 TI - Inflammatory Markers in Serum and Cerebrospinal Fluid for Early Detection of External Ventricular Drain-associated Ventriculitis in Patients With Subarachnoid Hemorrhage. AB - BACKGROUND: External ventricular drain (EVD)-associated ventriculitis is a serious complication. Early diagnosis can be difficult particularly in critically ill patients with aneurysmal subarachnoid hemorrhage (aSAH). We examined the diagnostic potential of standard serum and cerebrospinal fluid (CSF) biomarkers to differentiate between EVD-associated infections and aseptic courses in patients with aSAH. MATERIALS AND METHODS: We retrospectively evaluated the levels of inflammatory markers in serum (white blood cell count, percentage of neutrophils [sN%], and procalcitonin) and CSF (total leukocyte count [CSFTLC], CSFglucose, CSF/serumglucose ratio, CSF total protein [CSFTP]) of 63 consecutive patients with aSAH. Receiver operating characteristic curves and the area-under the-curve (AUC) were calculated to detect the diagnostic potential, optimized threshold, sensitivity (SE), specificity (SP), + likelihood ratio (LR), and -LR of each biomarker. RESULTS: Of all patients, 17 (27%) developed an EVD-associated ventriculitis within a mean of 7.8+/-2.3 days after implantation. sN% had a very good diagnostic potential (AUC=0.900, SE=70.0%, SP=100%), followed by the CSFTLC with good diagnostic potential (AUC=0.841, SE=75.0%, SP=88.5%), and the CSFTP with moderate diagnostic potential (AUC=0.772, SE=73.3%, SP=76.0%). sN% higher than 70% and a CSFTLC higher than 635/uL were highly associated with the diagnosis of ventriculitis (+LR=infinity and 6.5), sN%<70% or a CSFTLC<635 made a diagnosis of ventriculitis unlikely (-LR=0.3 and 0.28). CONCLUSIONS: Routine determination of N% and CSFTLC are useful to distinguish ventriculitis from aseptic courses in the acute phase after aSAH and regardless of the bacteriological test result. PMID- 29494415 TI - A Comparison of Regional Versus General Anesthesia for Lumbar Spine Surgery: An Untouched Aspect of the Meta-Analysis. PMID- 29494416 TI - Pathophysiological mechanisms of neuropathic pain: comparison of sensory phenotypes in patients and human surrogate pain models. AB - As an indirect approach to relate previously identified sensory phenotypes of patients suffering from peripheral neuropathic pain to underlying mechanisms, we used a published sorting algorithm to estimate the prevalence of denervation, peripheral and central sensitization in 657 healthy subjects undergoing experimental models of nerve block (NB) (compression block and topical lidocaine), primary hyperalgesia (PH) (sunburn and topical capsaicin), or secondary hyperalgesia (intradermal capsaicin and electrical high-frequency stimulation), and in 902 patients suffering from neuropathic pain. Some of the data have been previously published. Randomized split-half analysis verified a good concordance with a priori mechanistic sensory profile assignment in the training (79%, Cohen kappa = 0.54, n = 265) and the test set (81%, Cohen kappa = 0.56, n = 279). Nerve blocks were characterized by pronounced thermal and mechanical sensory loss, but also mild pinprick hyperalgesia and paradoxical heat sensations. Primary hyperalgesia was characterized by pronounced gain for heat, pressure and pinprick pain, and mild thermal sensory loss. Secondary hyperalgesia was characterized by pronounced pinprick hyperalgesia and mild thermal sensory loss. Topical lidocaine plus topical capsaicin induced a combined phenotype of NB plus PH. Topical menthol was the only model with significant cold hyperalgesia. Sorting of the 902 patients into these mechanistic phenotypes led to a similar distribution as the original heuristic clustering (65% identity, Cohen kappa = 0.44), but the denervation phenotype was more frequent than in heuristic clustering. These data suggest that sorting according to human surrogate models may be useful for mechanism-based stratification of neuropathic pain patients for future clinical trials, as encouraged by the European Medicines Agency. PMID- 29494417 TI - Monthly vitamin D supplementation, pain, and pattern of analgesic prescription: secondary analysis from the randomized, double-blind, placebo-controlled Vitamin D Assessment study. AB - Observational studies suggest that vitamin D deficiency is associated with higher risk of pain. However, evidence on the effect of vitamin D supplementation on pain is limited and contradictory. The aim of this study was to compare the effect of monthly high-dose vitamin D supplementation on a pain impact questionnaire (PIQ-6) score and prescription of analgesics in the general population. We performed a randomized, double-blind, placebo-controlled trial of 5108 community-dwelling participants, aged 50 to 84 years, who were randomly assigned to receive monthly 100,000-IU capsules of vitamin D3 (n = 2558) or placebo (n = 2550) for a median of 3.3 years. The PIQ-6 was administered at baseline, year 1, and final follow-up. Analgesic prescription data were collected from Ministry of Health. There was no difference in mean PIQ-6 score at the end of follow-up (adjusted mean difference: 0.06; P = 0.82) between the vitamin D (n = 2041) and placebo (n = 2014) participants. The proportion of participants dispensed one or more opioids was similar in the vitamin D group (n = 559, 21.9%) compared with placebo (n = 593, 23.3%); the relative risk (RR) adjusted for age, sex, and ethnicity was 0.94 (P = 0.24). Similar results were observed for dispensing of nonsteroidal anti-inflammatory drugs (RR = 0.94; P = 0.24) and other nonopioids (RR = 0.98; P = 0.34). Focusing on vitamin D deficient participants (<50 nmol/L, 24.9%), there was a lower risk of dispensing nonsteroidal anti-inflammatory drugs in the vitamin D group compared with placebo (RR = 0.87; P = 0.009); all other subgroup analyses were not significant. Long term monthly high-dose vitamin D supplementation did not improve mean PIQ-6 score or reduce analgesic dispensing in the general population. PMID- 29494419 TI - ABO-incompatible Living Donor Liver Transplantation With Rituximab and Total Plasma Exchange Does Not Increase Hepatocellular Carcinoma Recurrence. AB - BACKGROUND: ABO-incompatible (ABO-I) living donor liver transplantation (LDLT) has a high success rate. This study compares hepatocellular carcinoma (HCC) recurrence in ABO-I LDLT with that in ABO-compatible (ABO-C) LDLT and explores the effects of rituximab prophylaxis and total plasma exchange on HCC recurrence after LDLT. METHODS: Two hundred forty patients with a diagnosis of HCC underwent LDLT between 2010 and 2015. Fifty-nine patients underwent ABO-I LDLT. RESULTS: Baseline, perioperative, and tumor characteristics did not vary between the 2 groups. The 1-, 2-, and 3-year disease-free survival rates in the ABO-I LDLT and ABO-C LDLT groups were 90.3%, 79.7%, and 73.3% and 86.7%, 79.0%, and 75.3%, respectively (P = 0.96). The overall patient survival rates for the same period in the ABO-I LDLT and ABO-C LDLT groups were 90.6%, 85.0%, and 81.9% and 88.0%, 83.5%, and 82.5%, respectively (P = 0.77). Hepatocellular carcinoma recurrence after LDLT was associated with preoperative alpha-fetoprotein greater than 35 ng/mL, increased tumor size, encapsulation, and microvascular invasion. ABO incompatibility was not related to HCC recurrence after LDLT. CONCLUSIONS: Hepatocellular carcinoma recurrence and patient survival in the ABO-I LDLT group are comparable to those in the ABO-C LDLT group. Rituximab prophylaxis and total plasma exchange do not increase HCC recurrence after LT. PMID- 29494418 TI - Evolution of Glycemic Control and Variability After Kidney Transplant. AB - BACKGROUND: The evolution of glycemic changes after kidney transplantation has not been described. We prospectively examined glycemic control and variability over time from transplantation using continuous glucose monitoring (CGM). METHOD: Continuous glucose monitoring devices were fitted for 3 to 5 days at time of transplant, month 3, and month 6 posttransplant. Indices of glucose control (mean glucose, percent time in hyperglycemic range, and Glycemic Risk Assessment Diabetes Equation score) and variability were calculated. An oral glucose tolerance test was performed at month 3. RESULTS: Twenty-eight patients (mean age, 45 +/- 15 years) were enrolled, 64% male, 75% white, receiving tacrolimus, mycophenolate, and prednisolone (93%). Of 24 patients with complete CGM data at month 0, 3 had prior diabetes and 6 (25%) developed new-onset diabetes after transplant (NODAT). Hyperglycemia (>11.1 mM) was evident in 79% during days 0 to 3 posttransplant, particularly between 1 and 9 PM. Compared with recipients without diabetes, recipients with prior diabetes had higher mean glucose (7.8 mM; 95% confidence interval [CI], 7.4-8.2 vs 9.9 mM; 95% CI, 8.9-10.8; P < 0.001), Glycemic Risk Assessment Diabetes Equation (GRADE) score (4.5; 95% CI, 3.7-5.4 vs 7.8; 95% CI, 5.6-10.4; P = 0.003) and percent time with hyperglycemia. Glycemic control was also inferior in those that subsequently developed NODAT (mean glucose, 8.8 mM; 95% CI, 8.2-9.4; P = 0.004, GRADE: 6.2, 95% CI, 5.2-7.7; P = 0.04 vs no diabetes). Glucose variability was increased in patients with prior diabetes (glucose standard deviation, 1.99; 95% CI, 1.72-2.27 vs 2.97; 95% CI, 2.27-3.67; P = 0.006) but not in NODAT. All measures of glucose control and variability significantly improved over time after transplantation (P < 0.001). CONCLUSIONS: Dysglycemia is very common after renal transplantation, exhibiting a distinct diurnal pattern of afternoon and evening hyperglycemia. The magnitude of hyperglycemia and variability are maximal in recipients with preexisting diabetes and significant in those who go on to develop NODAT. Dysglycemia improves with time. PMID- 29494420 TI - Vancomycin Area Under the Curve Simplified. AB - BACKGROUND: Serum trough concentrations as the sole means of monitoring safety and efficacy of vancomycin are insufficient. The daily area under the curve (AUC24) of serum concentration versus time to minimum inhibitory concentration (MIC) ratio of greater than 400 mg * h/L has emerged as a more robust dosing target. A simple and practical method to extrapolate AUC24 from troughs is needed. METHODS: This mathematical model computes the median and range AUC24 using the dose in mg/kg and the observed serum trough concentration. AUC24 is calculated using dose in mg/kg divided by the volume of distribution (Vd) and elimination constant (Ke). Vd is provided using the population median (range) of 0.7 (0.4-1) L/kg. Ke is calculated using the trough and population Vd. RESULTS: For doses of 15-20 mg/kg, troughs of at least 11 mg/L will achieve AUC24 of greater than 400 mg * h/L, even with a Vd of 1 L/kg. Using the median Vd and lower, AUC24 greater than 400 mg * h/L can be achieved with troughs as little as 9 mg/L using doses of 15 mg/kg and greater. The AUC24:MIC goal of greater than 400 can still be attained with an MIC of 1.5 mg/L by using doses of at least 15 mg/kg and targeting troughs of at least 16 mg/L for a patient with a Vd of 0.7 L/kg or less. CONCLUSIONS: Troughs of 15-20 mg/L are rarely needed for organisms with an MIC of 1 mg/L or less. AUC24:MIC goals of greater than 400 can best be achieved with higher doses in mg/kg while targeting lower troughs. PMID- 29494421 TI - Phase II Clinical Trial of Lenalidomide and Dexamethasone Therapy in Japanese Elderly Patients With Newly Diagnosed Multiple Myeloma to Determine Optimal Plasma Concentration of Lenalidomide. AB - BACKGROUND: The authors conducted a phase II clinical trial of lenalidomide and dexamethasone combination therapy in Japanese elderly patients with newly diagnosed multiple myeloma to evaluate its safety and efficacy and to determine whether safety and efficacy correlate with the plasma concentration of lenalidomide. METHODS: Forty patients received oral lenalidomide on days 1-21 of a 28-day cycle in addition to weekly doses of dexamethasone. Plasma concentrations of lenalidomide were measured, and the area under the concentration-time curve from 0 to 24 hours (AUC0-24) of lenalidomide was predicted using a formula the authors previously reported in this journal. RESULTS: The median age was 75.5 years. Twenty-one patients had renal impairment severe enough to require dose adjustment of lenalidomide. The median initial doses of lenalidomide and dexamethasone were 12.5 and 20 mg, respectively. The overall response rate was 68.6%, and the 2-year overall survival rate was 88.5%. There was no correlation between the response rate and plasma concentration of lenalidomide. Grade 3-4 adverse events (AEs) were observed in 57.5% of patients. The AUC0-24 of lenalidomide was significantly higher in patients with grade 3-4 AEs than in those who did not suffer from AEs (median = 4852.0 versus 2464.9 ng.h.mL, P = 0.027). Receiver-operating characteristic curve analysis showed that the AUC0-24 of lenalidomide was a good predictor of grade 3-4 AEs, with an area under the receiver-operating characteristic curve of 0.758 (95% confidence interval, 0.572-0.943, P = 0.027). The cutoff value for best prediction of grade 3-4 AEs was 2613.5 ng.h.mL (sensitivity 86.7%, specificity 54.5%). Multivariate logistic analysis confirmed the significance of this cutoff value. CONCLUSIONS: These data suggest that overexposure to lenalidomide could contribute to toxicity. Furthermore, the predicted cutoff value of AUC0-24 can be clinically used to prevent severe AEs. PMID- 29494422 TI - Measurement of Teicoplanin Concentration with Lc-Ms/Ms Method Demonstrates the Usefulness of Therapeutic Drug Monitoring in Hematologic Patient Populations. AB - BACKGROUND: Teicoplanin is a glycopeptide antibiotic that has become increasingly popular with the spread of methicillin-resistant Staphylococcus aureus. The aim of the study was to develop and validate a UHPLC-MS/MS (ultra-high performance liquid chromatography tandem mass spectrometry) method for teicoplanin, and analyze trough teicoplanin concentrations achieved in patients with hematological diseases. METHODS: The UHPLC-MS/MS method for teicoplanin was developed, validated, and applied in a retrospective analysis of trough plasma teicoplanin concentrations from 305 patients receiving standard dose, and 17 patients receiving TDM-guided individualized dose. RESULTS: The linear range was 3.9-52.9 mg/L. The imprecision was less than 12%, the limits of detection and quantification were less than 0.13 and 0.72 mg/L, respectively. The sample carry over and ion suppression were insignificant. In the standard dose group, the median teicoplanin concentrations were 7.5 mg/L (days 3-5) and 8.9 mg/L (on days 6-8) and the proportion of trough levels achieving >=10 mg/L, was 20% (days 3-5) and 38% (days 6-8), respectively. In the TDM-guided individualized dose group, median teicoplanin concentration was higher (16.9 mg/L), and the proportion of trough levels >=10 mg/L was also higher (77%) when compared with the standard dose group CONCLUSIONS:: Based on these results, the present UHPLC-MS/MS method can be considered suitable for routine TDM of teicoplanin. Also based on the insufficient trough teicoplanin concentrations achieved with standard dose regimen, and the higher trough teicoplanin concentrations achieved with TDM guided individualized dose regimen, this study highlights the importance of TDM of teicoplanin, especially in high-risk patient groups. PMID- 29494423 TI - Warfarin Dosing According to the Genotype-guided Algorithm is Most Beneficial in Patients With Atrial Fibrillation: A Randomized Parallel Group Trial. AB - BACKGROUND: Observational studies have indicated potential benefits of CYP2C9- and VKORC1-guided dosing of warfarin but randomized clinical trials have resulted in contradictory findings. One of the reasons for contradiction may be the negligence of possible differences between warfarin indications. This study aims to determine efficacy and safety of genotype-guided and clinically guided dosing of warfarin in atrial fibrillation (AF), deep-vein thrombosis (DVT), and pulmonary embolism (PE) within the first 5 days after the introduction of therapy. METHODS: In this single-center, single-blinded, randomized, controlled trial including patients of both sexes, >=18 years of age, and diagnosed with AF, DVT, or PE, a total of 205 consecutive patients were allocated into the group where warfarin therapy was genotype-guided pharmacogenetics guided (PHG), and where it was adjusted according to the clinical parameters non pharmacogenetics guided (NPHG). Genotyping of CYP2C9*2, *3, and VKORC1 was performed using the real-time polymerase chain reaction method. The primary outcomes were the percentage of time in the therapeutic international normalized ratio (INR) (2.0 3.0) range and the percentage of patients who achieved a stable anticoagulation defined as the INR (2.0-3.0) range in at least 2 consecutive measurements. RESULTS: In patients with AF, the percentage of time spent in the therapeutic range of INR was higher in the PHG group [mean = 26% (SD 25.0)] than in the NPHG group [mean = 14% (SD 18.6)], [Delta = 12; 95% confidence interval, 0-23; P = 0.040]. There was no significant difference in other 2 indications for warfarin treatment. A stable dose of warfarin was achieved in a statistically higher number of patients in the PHG group 14/30 (47%) than in the NPHG group 7/32 (22%) (odds ratio = 3.13, 95% confidence interval, 0.92-10.98; P = 0.039). CONCLUSIONS: CYP2C9 and VKORC1 genotype-guided dosing of warfarin may be beneficial in patients diagnosed with AF. There is no evidence for such conclusion in patients with DVT and PE. PMID- 29494425 TI - Cancer risk in HIV-infected patients: elite controllers are also concerned. PMID- 29494424 TI - Effect of HIV self-testing on the number of sexual partners among female sex workers in Zambia. AB - OBJECTIVES: To assess the effect of two health system approaches to distribute HIV self-tests on the number of female sex workers' client and nonclient sexual partners. DESIGN: Cluster randomized controlled trial. METHODS: Peer educators recruited 965 participants. Peer educator-participant groups were randomized 1 : 1 : 1 to one of three arms: delivery of HIV self-tests directly from a peer educator, free facility-based delivery of HIV self-tests in exchange for coupons, or referral to standard-of-care HIV testing. Participants in all three arms completed four peer educator intervention sessions, which included counseling and condom distribution. Participants were asked the average number of client partners they had per night at baseline, 1 and 4 months, and the number of nonclient partners they had in the past 12 months (at baseline) and in the past month (at 1 month and 4 months). RESULTS: At 4 months, participants reported significantly fewer clients per night in the direct delivery arm (mean difference -0.78 clients, 95% CI -1.28 to -0.28, P = 0.002) and the coupon arm (-0.71, 95% CI -1.21 to -0.21, P = 0.005) compared with standard of care. Similarly, they reported fewer nonclient partners in the direct delivery arm (-3.19, 95% CI -5.18 to -1.21, P = 0.002) and in the coupon arm (-1.84, 95% CI -3.81 to 0.14, P = 0.07) arm compared with standard of care. CONCLUSION: Expansion of HIV self testing may have positive behavioral effects enhancing other HIV prevention efforts among female sex workers in Zambia. TRIAL REGISTRATION: ClinicalTrials.gov NCT02827240. PMID- 29494426 TI - The role for hepatitis A vaccination in HIV pre-exposure prophylaxis. PMID- 29494427 TI - Fewer pills do not mean fewer drug-drug interactions: severe rhabdomyolysis on Elvitegravir/Cobicistat and statin treatment. PMID- 29494428 TI - Soluble CD163 predicts incident chronic lung, kidney and liver disease in HIV infection: Erratum. PMID- 29494429 TI - Immunodeficiency, AIDS-related pneumonia, and risk of lung cancer among HIV infected individuals: Erratum. PMID- 29494430 TI - Relationship between untimed plasma lopinavir concentrations and virological outcome on second-line antiretroviral therapy: Erratum. PMID- 29494431 TI - Reducing HIV infection in people who inject drugs is impossible without targeting recently-infected subjects: Erratum. PMID- 29494432 TI - Preventive Antibiotics for Poststroke Infection in Patients With Acute Stroke: A Systematic Review and Meta-analysis. AB - AIMS: To determine if preventive antibiotics is effective in poststroke infection in patients with acute stroke in comparison with no prophylaxis. MATERIALS AND METHODS: MEDLINE (1950 to January 2017), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2017) and EMBASE (1974 to January 2017) databases were used to search for randomized controlled trials with intervening measures related to the preventive antibiotics in patients with acute stroke. Besides, the reference lists of the retrieved publications were manually searched to explore other relevant studies. RESULTS: We included 6 randomized controlled trials involving 4110 stroke patients. The study population, study design, intervening measures, and definition of infection were different. Preventive antibiotics significantly reduced the incidence of algorithm-defined infection in patients with acute stroke from 11.14% (220/1975) to 7.43% (149/2006); odds ratio (OR)=0.41; 95% confidence interval (CI), 0.20 0.87; P=0.02. There was no difference in mortality between 2 groups, the mortality in preventive antibiotics group was 17.03% (347/2037) and control group was 16.10% (328/2037); OR=1.07; 95% CI, 0.90-1.27; P=0.44. And preventive antibiotics did not improve the proportion of good outcome, the proportion of good outcome in preventive antibiotics group was 45.47% (909/1999) and control group was 45.76% (913/1995); OR=0.89; 95% CI, 0.62-1.28; P=0.53. None of the studies reported severe adverse relevant to the study antibiotics. CONCLUSIONS: Preventive antibiotics significantly reduced the incidence of algorithm-defined infection in patients with acute stroke, but did not decrease the mortality or improve the proportion of good outcome. Future research should aim to identify the group of stroke patients who will benefit most from antibiotic prophylaxis. PMID- 29494433 TI - Continuous Intravenous Valproate as Abortive Therapy for Pediatric Status Migrainosus. AB - OBJECTIVE: This study describes the use of continuous intravenous valproate as an abortive therapy for pediatric status migrainosus. BACKGROUND: Intravenous valproate as a bolus dose has been shown to be an effective abortive therapy for status migrainosus in children; however, Valproate's pharmacokinetic profile suggests that it would be safer and more therapeutic as a continuous infusion. This dosing strategy results in less serum concentration fluctuations, more consistent therapeutic effects, and less adverse effects. METHODS: A retrospective chart review between August 2009 and August 2012 identified 83 patients who had presented with status migrainosus and had received continuous intravenous valproate after failing to respond to initial abortive treatment. These patients had received a 20 mg/kg loading dose, followed by continuous infusion at 1 mg/kg/h. Serum valproate levels had been drawn 4 hours and 24 hours after the loading dose. Infusion rate had been adjusted to maintain serum levels of 80 to 100 mcg/mL. Age-appropriate pain assessments had been recorded at regular intervals. Excellent response was defined as a 100% reduction in pain scores, moderate response as 50% to 99% reduction, and poor response as <50% reduction. RESULTS: Of the 83 patients, 55 (66.2%) had reported an excellent response, 4 (4.8%) a moderate response, and 24 (28.9%) a poor response. Of those reporting an excellent response, 76% had responded within 24 hours. Nausea (8.4%) and vomiting (2.4%) had been the only reported side effects. Twenty-four hour serum levels had been within the goal range 91.9% of the time. CONCLUSIONS: Continuous intravenous valproate is safe, easy to monitor, and therapeutic in the abortive treatment of status migrainosus in pediatric patients. PMID- 29494435 TI - Valproate-induced Hyperammonemic Encephalopathy Presenting as Catatonia. AB - Hyperammonemic encephalopathy secondary to the use of valproate is rare without evidence of hepatotoxicity, and it usually presents with confusion, agitation, irritability, cognitive disturbances, lethargy, coma, and death. We present the case of a 21-year-old woman presenting with catatonia as a manifestation of hyperammonemic encephalopathy that resolved with the normalization of ammonia and suspension of valproate. PMID- 29494434 TI - Association Between the Apolipoprotein E Gene Polymorphism and Atherosclerotic Middle Cerebral Artery Stenosis. AB - OBJECTIVES: Stenosis of the intracranial large arteries, especially the middle cerebral artery (MCA), is common in the Chinese population. We conducted a case control study to investigate clinical and apolipoprotein E (ApoE) gene polymorphism of MCA atherosclerosis in the Chinese population. MATERIALS AND METHODS: Polymerase chain reaction-based protocols were used to identify the genotypes of polymorphisms in ApoE genes. Clinical parameters and the genotypes of polymorphisms in the ApoE genes were compared in patients with and without MCA stenosis. The ApoE exon epsilon4 genotypes with risk factors were compared in the patients with and without MCA stenosis. RESULTS: In total, 337 ischemic stroke patients were recruited, 156 cases with and 181 without MCA stenosis. Univariate analysis showed that the levels of systolic blood pressure and pulse pressure were higher in the MCA-stenosis group. There were no significant differences in the genotype and allele frequencies of the ApoE polymorphism observed between patients with and without MCA stenosis. However, there was a trend that the MCA stenosis group tended to have more of genotype epsilon4/epsilon4 (3.8% vs. 0.6%, P=0.052) than the non-MCA-stenosis group. There was no effect of ApoE genotype and genotype-by-environment interactions on ischemic stroke susceptibility. CONCLUSIONS: This present study indicated that the hypertension (ie, systolic blood pressure and pulse pressure) and the ApoEepsilon4/epsilon4 genotype may be associated with the occurrence of MCA stenosis in the ischemic stroke Chinese patients. PMID- 29494436 TI - Diagnostic Evaluation in Primary CNS Lymphoma. AB - The diagnosis of primary central nervous system lymphoma (PCNSL) may be fraught with difficulty. After initial imaging reveals enhancing intracranial mass lesions steroids are often initiated. This leads to a decreased diagnostic yield of tumor biopsies which may be associated with delay in treatment initiation. We review a case of PCNSL treated with a very brief steroid course. Initial nondiagnostic biopsy histopathology is juxtaposed against subsequent diagnostic pathology. Imaging before and after steroids is presented, as is imaging after tumor regrowth in a noncontiguous location. Elements in the clinical history and radiographic presentation which should raise suspicion for PCNSL are reviewed. Increased understanding of the potential pitfalls surrounding PCNSL diagnosis may limit their future occurrence. PMID- 29494438 TI - Admission Systolic Blood Pressure Predicts the Number of Blood Pressure Medications at Discharge in Patients With Primary Intracerebral Hemorrhage. AB - BACKGROUND: Control of systolic blood pressure (SBP) after primary intracerebral hemorrhage improves outcomes. Factors determining the number of blood pressure medications (BPM) required for goal SBP<160 mm Hg at discharge are unknown. We hypothesized that higher admission-SBPs require a greater number of BPM for goal discharge-SBP<160 mm Hg, and investigated factors influencing this goal. MATERIALS AND METHODS: We conducted a retrospective review of 288 patients who presented with primary intracerebral hemorrhage. Admission-SBP was obtained. Primary outcome was the number of BPM at discharge. Comparison was made between patients presenting with and without a history of hypertension, and patients discharged on <3 and >=3 BPM. RESULTS: Patients with hypertension history had a higher median admission-SBP compared with those without (180 vs. 157 mm Hg, P=0.0001). In total, 133 of 288 (46.2%) patients were discharged on <3 BPM; 155/288 (53.8%) were discharged on >=3 BPM. Hypertension history (P<0.0001) and admission-SBP (P<0.0001) predicted the number of BPM at discharge. In patients without hypertension history, every 10 mm Hg increase in SBP resulted in an absolute increase of 0.5 BPM at discharge (P=0.0011), whereas in those with hypertension, the absolute increase was 1.3 BPM (P=0.0012). In comparison with patients discharged on <3 BPM, patients discharged on >=3 BPM were more likely to have a higher median admission-SBP, be younger in age, belong to the African American race, have a history of diabetes, have higher median admission-National Institutes of Health Stroke Scale and modified Rankin Scale of 4 to 5 at discharge. CONCLUSIONS: An understanding of the factors influencing BPM at discharge may help clinicians better optimize blood pressure control both before and after discharge. PMID- 29494437 TI - Autoimmune Encephalitis With Multiple Autoantibodies: A Diagnostic and Therapeutic Challenge. AB - INTRODUCTION: Indications for autoantibody testing in patients with rapid-onset cognitive impairment have expanded in step with the growing number of disease associated autoantibodies and clinical syndromes. Although increased access to autoantibody testing has broadened our understanding of the spectrum of autoimmune encephalitis (AE), it has also produced new challenges associated with deciphering the contributions of disease-associated autoantibodies in patients with atypical clinical features and/or multiple autoantibodies. These challenges are illustrated through presentation of a patient with AE associated with autoantibodies against intracellular and cell-surface neuronal antigens. The implications of detection of multiple autoantibodies are considered in the context of relevant literature, and used to frame a diagnostic and therapeutic approach. CASE REPORT: A previously well 67-year-old man presented with encephalopathy and psychosis, impaired visual fixation, and ataxia, emerging over 3 months. Hu, CRMP-5, and NMDAR autoantibodies were identified in the cerebrospinal fluid. No malignancy was discovered despite extensive investigations. An aggressive course of immunotherapy temporarily stabilized his course; however, the patient succumbed to his illness 10 months after symptom onset. Lack of sustained response to immunotherapy and neuropathologic findings suggested that AE associated with Hu antibodies was primarily responsible for this patient's progressive decline. CONCLUSIONS: Multiple autoantibodies may be detected in patients with AE. When antibodies targeting intracellular and cell surface antigens are detected together, investigation and treatment of syndromes associated with intracellular antibodies should be prioritized, acknowledging the link between these antibodies and irreversible neuronal injury. In paraneoplastic cases, prognosis may be tied to early detection and treatment of the underlying malignancy. PMID- 29494439 TI - Magnesium Sulfate Treatment Correlates With Improved Neurological Function in Posterior Reversible Encephalopathy Syndrome (PRES): Report of a Case. AB - Posterior reversible encephalopathy syndrome (PRES) is a potentially reversible failure of cerebral autoregulation managed by correction of hypertension or underlying medical condition. Nonresponding cases progress to irreversible brain damage. There is some evidence of association of hypomagnesemia with PRES. We describe a case of nonresolving PRES where use of magnesium sulfate led to improvement in neurological function and eventual recovery. Our case highlights the need for a randomized controlled trial to test the efficacy of magnesium in PRES. PMID- 29494440 TI - Frequency of and Factors Associated With Obstructive Sleep Apnea and Periodic Limb Movements in Stroke and TIA Patients. AB - INTRODUCTION: Obstructive sleep apnea (OSA) and periodic limb movements (PLMs) have been associated with an increased risk of cardiovascular disease. There is limited data on the relationship between OSA and PLMs with atrial fibrillation and resistant hypertension in stroke and transient ischemic attack (TIA) patients. METHODS: Consecutive stroke and TIA patients referred by a vascular neurologist for diagnostic polysomnography (PSG) from September 1, 2012 to August 31, 2015 were included in a retrospective analysis. Baseline clinical characteristics, PSG results and outcomes were collected to identify the frequency of and factors associated with PLMs (mild 5 to 10/h; severe >=15/h), PLM arousals (>=5/h) and moderate-severe OSA (apna-hypopnea Index >=15) including atrial fibrillation and resistant hypertension. RESULTS: Among 103 patients (mean age, 60+/-15 y; 50% female; 61% nonwhites; 77% ischemic stroke; 23% resistant hypertension) who underwent PSG, 20% had mild PLMs, 28% had severe PLMs, 14% had PLM arousals, and 22% had moderate-severe OSA. Factors associated with moderate severe OSA included older age (odds ratio, 1.06; 95% confidence interval, 1.02 1.11) and presence of atrial fibrillation (odds ratio, 4.26; 95% confidence interval, 1.17-15.44). Nonwhite race was associated with lower likelihood of mild and severe PLMs, whereas female sex was associated with lower likelihood of PLM arousals. OSA and PLMs were not associated with resistant hypertension. CONCLUSIONS: A significant number of stroke and TIA patients who underwent PSG have PLMs and moderate-severe OSA. Stroke and TIA patients with atrial fibrillation are more likely to have moderate-severe OSA and may benefit from PSG evaluation. PMID- 29494441 TI - Acute Basilar Artery Occlusion: Does Recanalization Improve Clinical Outcome? A Critically Appraised Topic. AB - BACKGROUND: Acute basilar artery occlusion (BAO) is a devastating, life threatening condition that accounts for approximately 1% of all strokes. Currently, there is no consensus on the best treatment strategy for patients with BAO. Whereas endovascular reperfusion therapy is proven to improve outcomes in anterior circulation stroke, its benefit in acute BAO has not been confirmed in randomized controlled trials. OBJECTIVE: To critically assess the current evidence regarding recanalization in acute BAO, and to discuss the outcomes of different treatment strategies in the management of acute BAO. MATERIALS AND METHODS: The objective was addressed through the development of a critically appraised topic that included a clinical scenario, structured question, literature search strategy, critical appraisal, assessment of results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, and content experts in the field of vascular and hospital neurology. RESULTS: A recent meta-analysis was selected for critical appraisal to assess the recanalization hypothesis in acute BAO. The authors performed a systematic literature search through August 2013 and pooled in the analysis of 45 studies and 2056 patients. The overall recanalization rate was 75% in this meta-analysis. The authors concluded that recanalization was associated with a 1.5-fold reduction in the risk of death or dependency, and a 2 fold reduction in the risk of mortality. Subgroup analysis comparing different modes of intervention revealed data that favor endovascular intervention over intravenous thrombolysis (IVT). However, the authors were not able to obtain a statistically valid direct comparison of the 2 therapies as their meta-analysis included observational studies. Subgroup analysis on the treatment window revealed that onset-to-treatment time of <12 hours was associated with a higher recanalization rate (81%) and a lower intracranial hemorrhage rate (10%) compared with onset-to-treatment time >12 hours. CONCLUSIONS: IVT is the standard of care for BAO patients presenting within 4.5 hours of symptom onset, whereas recanalization is associated with better outcomes regardless of how recanalization is achieved. Randomized controlled trials comparing IVT plus endovascular treatment versus IVT in the treatment of acute BAO are needed to provide evidence-based management guidance. PMID- 29494442 TI - From the Editor. PMID- 29494444 TI - Advocacy for All-But Especially for the Most Vulnerable. PMID- 29494443 TI - Guest Editorial. PMID- 29494445 TI - Leadership Advocacy: Bringing Nursing to the Homeless and Underserved. AB - Nurses have historically played a key role in advocacy and service for all members of the community, including those who are traditionally underserved by other providers or the health system. Nurses from a local Atlanta community health system, both clinical and administrative, have continued this tradition by developing an advocacy and service program for the downtown homeless of Atlanta. From its beginnings as a highly informal volunteer program to its current structure as a strongly integrated community health center for the underserved and homeless of Atlanta, local nurses have demonstrated their strong value of service advocacy. Their leadership, insight, discipline, and strategic development have facilitated the growth of a focused, viable health service network for marginalized people of the city of Atlanta. PMID- 29494446 TI - Addressing Social Determinants of Health Through Advocacy. AB - The social determinants of health (SDOH) are receiving increased attention due to their influence on health disparities, health outcomes, and overall quality of life. Nurse leaders must take an active role in advocating for strategies that address these important issues. The purpose of this descriptive study was to explore nurses' knowledge, attitudes, and behaviors related to SDOH. A sample of 107 registered nurses completed the SDOH survey. Findings revealed that nurses experience personal discomfort and anticipate patient discomfort related to addressing the SDOH in their practice. They also voice a lack of skill, lack of time, and a dependency on other professionals to address these issues. The findings highlight the need for nurse leaders to advocate for nurses and those they care for through policy development, collaboration, and education. Based on the findings of this study, multiple strategies for nurse leaders serving as advocates are presented. PMID- 29494447 TI - LGBT Older Adults and Nurse Administrators: An Opportunity for Advocacy. AB - One of the greatest health care challenges of the 21st century is the rapidly growing number of older adults in the United States. This aging population is also becoming increasingly diverse, and with this diversity comes an increased number of older adults who identify as lesbian, gay, bisexual, and transgender (LGBT). The needs and health outcomes of this specific subgroup of the older adult population cannot be extrapolated from the more general population of older adults. Nurses have the opportunity to lead health care providers in improving care for this vulnerable and sometimes invisible population. Leading this charge will require nurse executives who advocate, create care environments that are inclusive, and staff with nurses who can care for the specific needs of LGBT older adults. The purpose of this article is to raise awareness of the health needs of LGBT older adults and identify how nurse executives can advocate to improve care for this overlooked population. PMID- 29494448 TI - Advocacy: Perspectives of Future Nurse Administrators. AB - Advocacy is a core competency of the nurse, and especially the nurse leader. It is a multidimensional concept that requires knowledge, experience, self confidence, and above all, courage. This article describes and illustrates the perspectives of nursing administration graduate students, as they depict advocacy in many relationships. These include advocacy for the patient, family, self, community, organization, profession, and society. The themes that emerged from narratives written by these nurse leaders were the development of courage and the finding of their voices. Stories demonstrate participants' courage to speak up despite feeling conflicted due to issues of autonomy, moral distress, or fear of retribution. Implications for nurse administrators to support advocacy at all levels are presented. PMID- 29494449 TI - Advocating for Nursing Research: The Friends of the National Institute for Nursing Research (FNINR) Ambassador Program. AB - The National Institute of Nursing Research (NINR) has a Friends group. This organization, the Friends of the National Institute of Nursing Research (FNINR), has been in place for over 20 years. It serves as a bold voice to communicate the impact of NINR's work to elevate nursing science, improve lives, while advancing the nation's health. FNINR's mission is to provide resources to support nursing research and advance the mission of the NINR. In 2013, the FNINR led the creation, development, and growth of an Ambassadors Program. The Ambassador Program is a group of committed individuals who are willing to serve as advocates of the NINR. Chosen through an application process reviewed by the FNINR Advocacy Committee of the FNINR Board, these selected Ambassadors work to influence Congress and advocate for the goals and visions of the NINR. This designation was initially limited to an elite group, and peer networking and communication was built into the program. The goal of the FNINR Ambassadors Program is to extend the reach of advocacy efforts for improving the funding and knowledge about the NINR. Thirty ambassadors across the country are working to expand knowledge and educate stakeholders about the impact of nursing science on the health of the country. This article describes the process the FNINR conducted to develop the Ambassadors Program, and the outcomes associated with this program. PMID- 29494450 TI - Leadership Influence: A Core Foundation for Advocacy. AB - As the largest segment of the health care workforce, nurses have the greatest potential for advancing systems and services to improve health care delivery in the United States. This article presents a framework for nurse administrators to use in developing direct care nurses in their leadership influence competency as a means of increasing their advocacy potential. A systematic review resulted in establishing a nurse leadership influence framework based on the Kouzes and Posner leadership model. The framework includes leadership competencies by nursing professional organizations and was validated by 2 national nurse leader focus groups. Nurse administrators have the opportunity to adopt an evidence based leadership influence framework to ensure development of advocacy competency in direct care nurses. The impact of nurse administrators systematically adopting a standardized leadership influence framework will result in setting a strong foundation for nurse advocacy. Successful long-term impacts will result in nurses skillfully integrating leadership influence and advocacy into all aspects of daily practice. PMID- 29494451 TI - A Narrative Analysis of Nurses' Experiences With Meaning and Joy in Nursing Practice. AB - Health care transformation is guided by the triple aim of improving health, enhancing the patient experience, and reducing costs. Experts have recommended the addition of a fourth aim, improving the experience of providing care. They advise that achievement of the triple aim will only be possible if we create the conditions where health care workers can find meaning and joy in their work. Nurses' experiences with meaning and joy in their practice have not been well described. In an effort to fill this knowledge gap, nurses across the nation recently participated in a qualitative study to share their experiences with meaning and joy in their nursing practice. The study utilized a narrative inquiry approach with a lens of appreciation to elicit and interpret nurses' stories. The stories, recorded and archived in StoryCorps, provided rich insight into meaning and joy in nursing practice. The study captured contemporary themes that crossed practice settings and generations across the United States. Four themes emerged from the analysis, including: fulfilling purpose-"I am a nurse"; meaningful connection; impact-the wow factor; and the practice environment. The practice environment theme included 3 subthemes: teams work, leaders model the way, and opportunities to learn and grow. The themes are described and illustrated with participant quotes. The study findings build on published evidence related to meaning in nursing practice and our conceptual understanding of joy. Results align with recommendations for defining and focusing on the fourth aim: To improve the practice experiences of nurses so they can more fully contribute to achieving both the triple aim in health care and their own well-being. Specific implications for leaders and supportive practice environments are discussed. PMID- 29494452 TI - International Nursing: Nurse Managers' Leadership and Management Competencies Assessed by Nursing Personnel in a Finnish Hospital. AB - The aim of this research was to describe nurse managers' leadership and management competencies (NMLMC) from the perspective of nursing personnel. Nurse managers are responsible for the management of the largest professional group in social and health care. The assessment of NMLMC is needed because of their powerful influence on organizational effectiveness. An electronic survey was conducted among the nursing personnel (n = 166) of 1 Finnish hospital in spring 2016. Nursing personnel assessed their manager using a NMLMC scale consisting of general and special competences. The data were statistically analyzed. Leadership and management competencies were assessed as being quite good by the nursing personnel. The best-assessed area of general competence was professional competence and credibility and the weakest was service initiation and innovation. The best-assessed area of special competence was substance knowledge and the weakest was research and development. The nursing personnel's assessment of their nurse manger's competencies was associated with the personnel's education level, working experience, and with their knowledge of the manager's education. Conclusion was made that nursing personnel highly value professional competence as part of nursing leadership and management. To achieve more appreciation, nurse managers have to demonstrate their education and competence. They must also work in more open and versatile ways with their nursing personnel. PMID- 29494453 TI - Outsourcing an Effective Postdischarge Call Program: A Collaborative Approach. AB - To improve patient satisfaction ratings and decrease readmissions, many organizations utilize internal staff to complete postdischarge calls to recently released patients. Developing, implementing, monitoring, and sustaining an effective call program can be challenging and have eluded some of the renowned medical centers in the country. Using collaboration with an outsourced vendor to bring state-of-the-art call technology and staffed with specially trained callers, health systems can achieve elevated levels of engagement and satisfaction for their patients postdischarge. PMID- 29494454 TI - Nursing Informatics Year in Review 2017. PMID- 29494456 TI - TO THE EDITOR. PMID- 29494457 TI - TO THE EDITOR. PMID- 29494458 TI - Influence of Derotation Connectors on 3D Surgical Correction of Adolescent Idiopathic Scoliosis. AB - STUDY DESIGN: Monocentric study comparing results of simultaneous translation on 2 rods (ST2R) with derotation connectors (prospective series) or without derotation connectors (retrospective series) in Adolescent Idiopathic Scoliosis (AIS) surgery. OBJECTIVE: The objective of this study was to assess if derotation connectors influence axial, coronal, and sagittal results in AIS surgery. SUMMARY OF BACKGROUND DATA: Conventional reduction techniques remain limited in their ability to reduce axial torsion. Direct vertebral derotation technique accomplishes partial axial derotation but decreases thoracic kyphosis. METHODS: Monocentric study including AIS surgeries performed using ST2R technique with derotation connectors (group D+, n=44) or without derotation connectors (group D , n=24). The axial intervertebral rotation was measured between apical and neutral vertebra on pre and postoperative computed tomography scan. T test was used to compare mean values. ANCOVA analyzed the influence of connectors and covariates on the primary outcome, which was the difference between preoperative and postoperative intervertebral rotation. RESULTS: The mean axial torsion gain in the D+ group was 23% (+3.84 degrees, 95% confidence interval, +1.95/+5.73). In the D- group, mean axial torsion increase of 4% (-0.42 degrees, 95% confidence interval, -1.19/+2.03). The result was significantly different between the 2 groups (P=0.005). The coronal correction of the main curve angle was 80% in the D+ group and 64% in the D- group (P=0.004). Kyphosis correction was similar between the 2 groups (P=0.3) with significant increase of thoracic kyphosis in the whole series (P=0.02) and no patients with postoperative hypokyphosis <10 degrees. Multivariate analysis confirmed the influence of derotation connectors on both axial and coronal correction (P<0.05). CONCLUSIONS: The use of derotation connectors in the surgical treatment of AIS significantly improved axial and coronal correction compared to nonuse of connectors without compromising the sagittal plane. PMID- 29494459 TI - A Survey of Restraint Methods for the Safe Transport of Children in Ground Ambulances. AB - OBJECTIVES: The National Highway Traffic Safety Administration (NHTSA) released draft recommendations in 2010 on the safe transport of children in ground ambulances. The purpose of this study was to assess awareness of these guidelines among emergency medical service (EMS) agencies and to identify implementation barriers. METHODS: We conducted a cross-sectional, anonymous online survey of 911 responding, ground transport EMS agencies in Texas. Demographics, modes of transport based on case scenarios, and barriers to implementation were assessed. RESULTS: Of 62 eligible EMS agencies that took the survey, 35.7% were aware of the NHTSA guidelines, 62.5% agreed they would improve safety, and 41.1% planned to implement them. Seventy-five percent of EMS agencies used the ideal or acceptable alternative to transport children requiring continuous monitoring, and 69.5% chose ideal or acceptable alternatives for children requiring spinal immobilization. The ideal or acceptable alternative was not chosen for children who were not injured or ill (93.2%), ill or injured but not requiring continuous monitoring (53.3%), and situations when multiple patients required transport (57.6%). The main requirements for implementation were provider education, ambulance interior modifications, new guidelines in the EMS agency, and purchase of new equipment. CONCLUSIONS: Few EMS agencies are aware of the NHTSA guidelines on safe transport of children in ground ambulances. Although most agencies appropriately transport children who require monitoring, interventions, or spinal immobilization, they use inappropriate means to transport children in situations with multiple patients, lack of injury or illness, or lack of need for monitoring. PMID- 29494460 TI - Reexpansion Pulmonary Edema in Pediatrics. AB - Reexpansion pulmonary edema is a rare complication that may occur after drainage of pneumothorax or pleural effusion. A number of factors have been identified that increase the risk of developing reexpansion pulmonary edema, and pathophysiologic mechanisms have been postulated. Patients may present with radiographic findings alone or may have signs or symptoms that prompt evaluation and diagnosis. Clinical presentations range from mild cough to respiratory failure and hemodynamic compromise. Treatment strategies are supportive, and should be tailored to match the severity of the condition. PMID- 29494461 TI - Reexpansion Pulmonary Edema in Pediatrics. PMID- 29494462 TI - Point-of-Care Ultrasound to Identify Congenital Heart Disease in the Pediatric Emergency Department. AB - The first presentation of congenital heart disease can be a diagnostic challenge in the emergency department. We report on 2 cases where point-of-care ultrasound identified gross cardiac abnormalities in 2 children and expedited disposition and downstream care. PMID- 29494463 TI - A 2-Year-old Girl With Bradycardia and Lethargy: Is Perseus to the Rescue? PMID- 29494464 TI - Simultaneous Acute Femoral Deformity Correction and Gradual Limb Lengthening Using a Retrograde Femoral Nail: Technique and Clinical Results. AB - INTRODUCTION: Patients with limb-length discrepancies often have concomitant deformity. We describe the outcomes of acute, fixator-assisted deformity correction with gradual lengthening using the retrograde femoral Precice nail (NuVasive). METHODS: We analyzed a retrospective series of 27 patients in whom an external fixator was combined with a Precice nail to correct angular or rotational deformity and limb-length discrepancy. The fixator was applied temporarily to restore normal alignment. The Precice nail was inserted and locked in place to hold the correction, with gradual restoration of limb length. RESULTS: The 27 patients (mean age, 28 years) had a mean follow-up of 13 months. Secondary deformities were mainly valgus (15 patients) and varus (10 patients). Postoperatively, 93% of patients had correction of limb length to within 3 mm of the discrepancy (mean lengthening, 30 mm). Mechanical axis deviation was corrected to within 8 mm of neutral (ie, zero) in 81% of patients. The mechanical lateral distal femoral angle was corrected to a mean of 88 degrees postoperatively. Final Association for the Study and Application of Methods of Ilizarov (ASAMI)-Paley scores were excellent for 96% of patients. DISCUSSION: The use of intramedullary lengthening nails has revolutionized the field of limb lengthening. The results of our study show that a retrograde femoral Precice nail can be used safely and accurately to correct both limb-length discrepancy and deformity with minimal complications. The benefits of using this implant include the ability to maintain knee range of motion during the lengthening process. Rapid bone healing allows a relatively fast return to weight-bearing ambulation. CONCLUSIONS: The Precice nail was effectively used to correct both limb-length discrepancy and deformity, with excellent overall outcomes. This surgical technique may help avoid the complications that can occur with prolonged postoperative use of an external fixator. LEVEL OF EVIDENCE: Level IV retrospective study. PMID- 29494465 TI - Elimination of Preoperative Flexion Contracture as a Contraindication for Unicompartmental Knee Arthroplasty. AB - INTRODUCTION: Unicompartmental knee arthroplasty (UKA) is an effective alternative to total knee arthroplasty (TKA) for the management of unicondylar osteoarthritis. Historical contraindications limit patients' eligibility for UKA. However, recent reports have suggested that some contraindications may not be absolute. This study evaluates preoperative flexion contracture with regard to UKA. METHODS: This study was a retrospective review of 53 patients with preoperative flexion contracture between 11 degrees and 20 degrees who underwent fixed-bearing UKA and a matched cohort of 53 patients who underwent cruciate-retaining TKA. RESULTS: Preoperatively, the average flexion contracture was 13.8 degrees in the UKA group and 14.1 degrees in the TKA group (P = 0.42). Mean preoperative motion was greater in the patients treated with UKA (106 degrees ) than in those treated with TKA (97 degrees ; P < 0.001). Postoperatively, patients who underwent UKA had greater motion than patients who underwent TKA had (121 degrees versus 113 degrees ; P < 0.01). Residual flexion contracture was greater in the UKA group (4.1 degrees ) than in the TKA group (2.1 degrees ; P = 0.02). The two groups demonstrated similar improvements in Knee Society clinical scores (P = 0.32). However, patients treated with UKA demonstrated higher Knee Society functional scores, compared with patients treated with TKA (86 versus 75; P = 0.03). DISCUSSION: Although residual flexion contracture was worse after UKA, this group had similar clinical improvement, greater postoperative motion, and greater function scores, compared with the matched TKA group. Preoperative flexion contracture >5 degrees may not be an absolute contraindication to UKA. CONCLUSION: The contraindications to UKA regarding flexion contracture may not be as absolute as previously thought. Larger, prospective studies are needed to generalize these findings to a wider population. PMID- 29494466 TI - Discharge Destination After Shoulder Arthroplasty: An Independent Risk Factor for Readmission and Complications. AB - INTRODUCTION: Postdischarge disposition after shoulder replacement lacks uniform guidelines. The goal of this study was to identify complication and readmission rates by discharge disposition and determine whether disposition was an independent risk factor for adverse events, using a statewide database. METHODS: Data from the California Office of Statewide Health Planning and Development discharge database were used. Patient information was assessed, and 30- and 90 day complication rates were identified. Univariate and multivariate analyses were used to determine the complication risk. RESULTS: From 2011 to 2013, 10,660 procedures were identified, with 7,709 patients discharged home, 1,858 discharged home with home health support, and 1,093 discharged to postacute care (PAC) facilities. Patients discharged to PAC facilities or to home with health support tended to be older, female, and using Medicare. After controlling for confounders, at 30 and 90 days, patients discharged to PAC facilities were found to be more likely to experience a complication. DISCUSSION: Discharge to a PAC facility was an independent risk factor for complications and readmission. LEVEL OF EVIDENCE: Level III, retrospective cohort design, observational study. PMID- 29494467 TI - A Mid-scala Cochlear Implant Electrode Design Achieves a Stable Post-surgical Position in the Cochlea of Patients Over Time-A Prospective Observational Study. AB - INTRODUCTION: Cochlear implant (CI) electrode design impacts the clinical performance of patients. Stability and the occurrence of electrode array migration, which is the postoperative movement of the electrode array, were investigated using a mid-scalar electrode array and postoperative image analysis. METHODS: A prospective observational study was conducted. A mid-scalar electrode was surgically placed using a mastoidectomy, followed by a posterior tympanotomy and an extended round-window or cochleostomy insertion. A few days after surgery and 3 months later Cone Beam Computed Tomography (CBCT) was performed. The two different CBCT's were fused, and the differences between the electrode positions in three dimensions were calculated (the migration). A migration greater than 0.5 mm was deemed clinically relevant. RESULTS: Fourteen subjects participated. The mid-scalar electrode migrated in one patient (7%). This did not lead to the extrusion of an electrode contact. The mean migration of every individual electrode contact in all patients was 0.36 mm (95% confidence interval 0.22-0.50 mm), which approximates to the estimated measurement error of the CBCT technique. CONCLUSION: A mid-scalar electrode array achieves a stable position in the cochlea in a small but representative group of patients. The methods applied in this work can be used for providing postoperative feedback for surgeons and for benchmarking electrode designs. PMID- 29494468 TI - RESPONSE TO "MICHAEL YONG, ERICA ZAIA, BRIAN WESTERBERG, AND JANE LEA. DIAGNOSIS OF SUPERIOR SEMICIRCULAR CANAL DEHISCENCE IN THE PRESENCE OF CONCOMITANT OTOSCLEROSIS". OTOL NEUROTOL 2017;38: 1071-1075. PMID- 29494469 TI - Comparison of Video Head Impulse Test in the Posterior Semicircular Canal Plane and Cervical Vestibular Evoked Myogenic Potential in Patients With Vestibular Neuritis. AB - OBJECTIVE: The purpose of this study was to evaluate and compare the results of cervical vestibular evoked myogenic potential (cVEMP) and video head impulse test (p-vHIT) of posterior semicircular canal considered tools of inferior vestibular nerve function in vestibular neuritis. STUDY DESIGN: Prospective cohort study. SETTING: Tertiary otology clinic. PATIENTS AND INTERVENTIONS: Seventy-nine patients with vestibular neuritis participated in this study. We analyzed the interaural amplitude difference in cVEMP with a positive rate of p-vHIT according to gain and corrective saccade in the study population. MAIN OUTCOME MEASURE: To evaluate the concordance rate of both tests, we analyzed Fleiss' Kappa value inter-test agreement of cVEMP with p-vHIT. Finally, we performed detailed analysis of the bilaterally absent response on cVEMP according to the p-vHIT results. RESULTS: The inter-test agreement between cVEMP and p-vHIT was 69.8% as we also considered the lesion side. This result indicated a statistically fair to good agreement in both tests. In mostly elderly patients with a bilaterally absent response (11 patients) on cVEMP, as a result of vHIT, nine patients with a bilaterally negative response on p-vHIT showed only canal paresis. Two patients showed canal paresis and a unilaterally positive response on p-vHIT. CONCLUSIONS: Inter-test agreement between cVEMP and p-vHIT assessed in vestibular neuritis was relatively lower than we had predicted. Probably, p-vHIT can provide additional information on the differential diagnosis of dysfunction of the inferior vestibular nerve which is composed of the saccular nerve and the posterior ampullary nerve. PMID- 29494470 TI - Case of a Rare "White Epidermoid Tumor" Involving the Cerebellopontine Angle. PMID- 29494471 TI - Comparison Study of Percutaneous Osseointegrated Bone Conduction Device Complications When Using the 9 mm Abutment Versus 6 mm Abutment at Initial Implantation. AB - OBJECTIVES: To assess differences in the incidence, type, and management of complications encountered with implantation of percutaneous osseointegrated bone conduction devices when using a 9 mm abutment versus 6 mm abutment at initial implantation. STUDY DESIGN: Retrospective cohort study. METHODS: One hundred thirty consecutive patients between January 2010 and December 2011 underwent single-stage percutaneous osseointegrated bone conduction device implantation using a 9 or 6 mm abutment. Clinical outcomes assessed for the two groups included the incidence, type, and management of postoperative complications. Abutment size, age, sex, indication for surgery, implant device type, duration of follow-up, and patient comorbidities were evaluated as potential factors affecting outcomes. RESULTS: Average duration of follow-up was 16 months (range 6 29 mo). Postoperative complications occurred in 38 (29.2%) patients. Twenty-four (18.4%) patients experienced minor complications requiring simple, local care; eight (6.1%) patients required in-office procedural intervention; and six (4.6%) patients required revision surgery in the operating room. Implant extrusion occurred in three (2.3%) patients. Eleven (8.5%) patients required placement of a longer abutment. Patients receiving the 6 mm abutment at initial surgery were significantly more likely to encounter a complication requiring in-office procedural intervention or revision surgery (p = 0.001). CONCLUSION: Minor complications after implantation of percutaneous osseointegrated bone conduction devices are common. The vast majority of these complications are due to localized skin reactions, most of which are readily addressed through local care. Patients receiving the 9 mm abutment during initial implantation are significantly less likely to require in-office procedural intervention or revision surgery postoperatively as compared with those receiving the shorter, 6 mm abutment. PMID- 29494472 TI - Positioning a Novel Transcutaneous Bone Conduction Hearing Implant: a Systematic Anatomical and Radiological Study to Standardize the Retrosigmoid Approach, Correlating Navigation-guided, and Landmark-based Surgery. AB - HYPOTHESIS: Anatomical and radiological evaluation improves safety and accuracy of the retrosigmoid approach for positioning a transcutaneous bone conduction implant and provides anatomical reference data for standardized, landmark-based implantation at this alternative site. BACKGROUND: The primary implantation site for the floating mass transducer of a novel bone conduction hearing implant is the mastoid. However, anatomical limitations or previous mastoid surgery may prevent mastoid implantation. Therefore, the retrosigmoid approach has been introduced as an alternative. METHODS: Mastoid and retrosigmoid implantation sites were radiologically identified and evaluated in preoperative computed tomography scans of anatomical head specimens. Navigation-guided implantation was then performed in the retrosigmoid site (n = 20). The optimal retrosigmoid position was determined in relation to both the asterion and the mastoid notch as surgical landmarks in an anatomical coordinate system. RESULTS: Preoperative radiological analysis revealed spatial limitations in the mastoid in 45% of the specimens. Navigation-guided retrosigmoid implantation was possible without affecting the sigmoid sinus in all the specimens. The optimal implantation site was located 1.9 +/- 0.1 cm posterior/1.7 +/- 0.1 cm inferior to the asterion and 3.3 +/- 0.2 cm posterior/2.1 +/- 0.1 cm superior to the mastoid notch.Retrosigmoid skull thickness was 6.6 +/- 0.4 mm, measured anatomically, 7.0 +/- 0.4 mm, measured radiologically and 6.7 +/- 0.5 mm, measured with the navigation software. CONCLUSION: The navigation-guided retrosigmoid approach seemed to be a reliable procedure in all the specimens. Measurements of bone thickness revealed the need for spacers in 95% of the specimens. Reference coordinates of the optimal implantation site are provided and can confirm image guided surgery or facilitate orientation if a navigation system is not available. PMID- 29494473 TI - Tablet-based Screening for Hearing Loss: Feasibility of Testing in Nonspecialty Locations. AB - OBJECTIVE: To determine the feasibility of audiometric screening with tablet based applications in typical clinic locations: examination room and clinic waiting area. STUDY DESIGN: A randomized prospective study. SETTING: Tertiary referral center. PATIENTS: Participants included 107 adult patients referred for audiometric testing to assess hearing loss. INTERVENTION: Each patient completed standard audiometry testing and one of three tablet-based audiometric applications that included pure-tone air conduction testing. The tablet-based audiometric testing was completed in a quiet examination room and a clinic waiting area using noise-cancellation headphones. A 5-question patient satisfaction survey was completed at the end of the testing. MAIN OUTCOME MEASURE: Thresholds at each frequency were compared with those obtained from tablet-based audiometric applications in a quiet examination room and clinic waiting area. Sensitivity and specificity of each tablet-based audiogram in detecting a hearing loss at each frequency was determined. RESULTS: All three tablet-based audiometric applications were user-friendly for hearing screening. However, one application was shown to be feasible and the most accurate of the three tested with 92% of thresholds within 10 dB of conventional audiometry across all test conditions. This application had a sensitivity of 96 to 100% and specificity of 72 to 85% for identifying a hearing loss in each frequency tested. Variability was noted among applications between testing in a quiet clinic room and testing in the clinic waiting area. Patients showed no preference for either conventional audiometry or the tablet-based device. CONCLUSION: Tablet-based audiometric applications can be used to screen for hearing loss in typical clinic locations. This tool does not replace standard audiometry testing but allows for screening for hearing disorders when appropriate and in settings without access to audiometric equipment. PMID- 29494474 TI - Hearing Restoration in Cochlear Nerve Deficiency: the Choice Between Cochlear Implant or Auditory Brainstem Implant, a Meta-analysis. AB - OBJECTIVE: To answer the dilemma clinician's face when deciding between cochlear implant (CI) and auditory brainstem implant (ABI) treatment options in patients with cochlear nerve deficiency (CND). STUDY DESIGN: Case study supplemented with literature review and meta-analysis. SETTING: Tertiary referral center. PATIENT(S): Child with CHARGE syndrome and congenital deafness. INTERVENTION(S): ABI as there was no benefit after bilateral cochlear implantation. MAIN OUTCOME MEASURES: Speech and language development, quality of life. RESULTS: In one ear the cochleovestibular nerve was present on magnetic resonance imaging (MRI) without preoperative ABR responses. In the contra lateral ear the nerve could not be identified, despite present ABR responses. Nevertheless, there was no positive outcome with CI. The patient had improved speech and language and quality of life with ABI. Of the 108 patients with CND and CI identified in the literature review, 25% attained open-set speech perception, 34% attained closed-set speech perception, and 41% detected sounds or less. The appearance of the cochlear nerve on MRI was a useful predictor of success, with cochlear nerve aplasia on MRI associated with a smaller chance of a positive outcome post cochlear implantation compared with patients with cochlear nerve hypoplasia. CONCLUSION: Although patients with (apparent) cochlear nerve aplasia are less likely to benefit from CI, CI before ABI is supported as some patients attain closed or open-set levels of speech perception after cochlear implantation. PMID- 29494475 TI - Survival and Safety Outcomes of ICU Patients Discharged Directly Home-A Direct From ICU Sent Home Study. AB - OBJECTIVES: Evaluate outcomes (mortality, morbidity, unplanned return visits) of patients who are discharged directly to home from the ICU. DESIGN: Prospective cohort study. SETTING: Two tertiary care medical-surgical-trauma ICUs at Canadian hospitals over 1 year (February 2016-2017). SUBJECTS: All adult patients who were either discharged directly to home (Recruited and Nonrecruited cohorts) from ICU or discharged home within 24 hours after ward transfer (Ward Transfer cohort). INTERVENTIONS: Direct discharge home from ICU or discharge home within 24 hours of ward transfer from ICU. MEASUREMENTS AND MAIN RESULTS: One-hundred ninety eight patients were in the study, 100 patients in the discharged directly to home Recruited arm, 37 patients in the discharged directly to home Nonrecruited arm, and 61 patients in the Ward cohort. All three patient cohorts had 0% mortality at 8 weeks post discharge. The unplanned return visit rate for the Recruited cohort was 24% (emergency department 18%, Ward 4%, ICU 1%), whereas the rate for the Nonrecruited cohort was 52% (emergency department 34%, Ward 14%, ICU 3%) and the Ward Transfer cohort was 46% (emergency department 17%, Ward 26%, ICU 3%) (p = 0.005). No home support was available for 7% of the discharged directly to home Recruited cohort. Twenty-four percent of patients had funded home care nursing, but the majority of patients (81%) relied on help from friends/family. CONCLUSIONS: Recruited discharged directly to home patients experienced very good 8-week postdischarge outcomes with 0% mortality and a low rate of ICU readmission (1%) or ward readmission (4%), but not an insignificant rate of emergency department visits (18%). Recruited discharged directly to home patients had better outcomes compared with nonrecruited discharged directly to home patients and patients transferred briefly to the ward prior to discharge home. Future work should include derivation of a clinical prediction tool to identify patient characteristics that make discharged directly to home safe and a randomized control trial to compare discharged directly to home with short stay ward transfers. PMID- 29494476 TI - The Effectiveness of Standing on a Balance Board for Increasing Energy Expenditure. AB - PURPOSE: This study aimed to investigate differences in energy expenditure (EE), heart rate (HR), productivity, fatigue, and pain while performing desk work while sitting (SIT), standing (STAND), and standing on a balance board (BOARD). METHODS: Thirty healthy adults (60% female, age = 39.7 +/- 11.8 yr, body mass index = 26.7 +/- 5.0 kg.m) employed in sedentary-based jobs volunteered for this randomized crossover trial. Participants performed typing work in three different positions: SIT, STAND, and BOARD, each condition lasting 30 min. Oxygen consumption (VO2) was measured via indirect calorimetry, and EE was calculated using respiratory quotient and corresponding caloric equivalent values. Productivity was quantified by measuring words typed per minute, accuracy, and typing mistakes. Overall feelings of fatigue and pain were self-reported three times during each position using validated 10-cm visual analog scales. Repeated measures ANOVA was used to assess differences in outcome variables across conditions. RESULTS: VO2 was significantly different among all conditions regardless of current standing desk use (SIT = 3.35 +/- 0.53, STAND = 3.77 +/- 0.48, BOARD = 3.92 +/- 0.54 mL.kg.min, P < 0.001). EE (kcal.min) also differed (P < 0.001) among SIT (1.27 +/- 0.22), STAND (1.42 +/- 0.26), and BOARD (1.48 +/- 0.29). Compared with sitting (67 +/- 9 bpm), HR was higher in STAND (76 +/- 11 bpm) and BOARD (76 +/- 11 bpm, P < 0.001). Measures of productivity were not different across conditions (P > 0.05). Fatigue progressively increased over each 30-min condition, whereas pain in SIT and BOARD increased from minute 10 to minute 20 and then leveled off between minutes 20 and 30. For STAND, pain continued to increase over time. CONCLUSION: Compared with sitting, a balance board may be effective for increasing EE without interfering with productivity in an occupational setting. PMID- 29494477 TI - Design and Fabrication of a Miniaturized GMI Magnetic Sensor Based on Amorphous Wire by MEMS Technology. AB - A miniaturized Co-based amorphous wire GMI (Giant magneto-impedance) magnetic sensor was designed and fabricated in this paper. The Co-based amorphous wire was used as the sense element due to its high sensitivity to the magnetic field. A three-dimensional micro coil surrounding the Co-based amorphous wire was fabricated by MEMS (Micro-Electro-Mechanical System) technology, which was used to extract the electrical signal. The three-dimensional micro pick-up coil was designed and simulated with HFSS (High Frequency Structure Simulator) software to determine the key parameters. Surface micro machining MEMS (Micro-Electro Mechanical System) technology was employed to fabricate the three-dimensional coil. The size of the developed amorphous wire magnetic sensor is 5.6 * 1.5 * 1.1 mm3. Helmholtz coil was used to characterize the performance of the device. The test results of the sensor sample show that the voltage change is 130 mV/Oe and the linearity error is 4.83% in the range of 0~45,000 nT. The results indicate that the developed miniaturized magnetic sensor has high sensitivity. By testing the electrical resistance of the samples, the results also showed high uniformity of each device. PMID- 29494478 TI - Antimicrobial Activity and Chemical Composition of Essential Oils from Verbenaceae Species Growing in South America. AB - The Verbenaceae family includes 2600 species grouped into 100 genera with a pantropical distribution. Many of them are important elements of the floras of warm-temperature and tropical regions of America. This family is known in folk medicine, and its species are used as digestive, carminative, antipyretic, antitussive, antiseptic, and healing agents. This review aims to collect information about the essential oils from the most reported species of the Verbenaceae family growing in South America, focusing on their chemical composition, antimicrobial activity, and synergism with commercial antimicrobials. The information gathered comprises the last twenty years of research within the South American region and is summarized taking into consideration the most representative species in terms of their essential oils. These species belong to Aloysia, Lantana, Lippia, Phyla, and Stachytarpheta genera, and the main essential oils they contain are monoterpenes and sesquiterpenes, such as beta-caryophyllene, thymol, citral, 1,8-cineole, carvone, and limonene. These compounds have been found to possess antimicrobial activities. The synergism of these essential oils with antibiotics is being studied by several research groups. It constitutes a resource of interest for the potential use of combinations of essential oils and antibiotics in infection treatments. PMID- 29494479 TI - Concurrent and Simultaneous Use of Cannabis and Tobacco and Its Relationship with Academic Achievement amongst University Students. AB - The combined use of cannabis and tobacco is frequent in Europe. Few studies have nonetheless explored this pattern of consumption and its relationship with academic achievement in Spanish population. The aim of the present study was to analyze (1) the frequency of four patterns of polydrug use the last year (non dual users of cannabis and tobacco; concurrent users: cannabis and tobacco separately; simultaneous users: tobacco in cannabis "joints"; simultaneous users: tobacco in cannabis joints alongside alcohol) by gender and age; (2) grade point average (GPA) by gender and age; (3) the association between the frequency of the four patterns of use and the GPA amongst a sample of 477 Spanish university students. The use of cannabis and tobacco (concurrent and simultaneous) and GPA were assessed by means of self-reported questionnaires. Statistically significant differences were found for the GPA with respect to gender. The GPA by the non dual users of cannabis and tobacco was significantly higher than the GPA corresponding to the concurrent and simultaneous users. The combined use of cannabis and tobacco, regardless of the type of use (concurrent or simultaneous), is moderately related to poor academic achievement amongst university students. PMID- 29494480 TI - Biosynthesis and Characterization of Zearalenone-14-Sulfate, Zearalenone-14 Glucoside and Zearalenone-16-Glucoside Using Common Fungal Strains. AB - Zearalenone (ZEN) and its phase II sulfate and glucoside metabolites have been detected in food and feed commodities. After consumption, the conjugates can be hydrolyzed by the human intestinal microbiota leading to liberation of ZEN that implies an underestimation of the true ZEN exposure. To include ZEN conjugates in routine analysis, reliable standards are needed, which are currently not available. Thus, the aim of the present study was to develop a facilitated biosynthesis of ZEN-14-sulfate, ZEN-14-glucoside and ZEN-16-glucoside. A metabolite screening was conducted by adding ZEN to liquid fungi cultures of known ZEN conjugating Aspergillus and Rhizopus strains. Cultivation conditions and ZEN incubation time were varied. All media samples were analyzed for metabolite formation by HPLC-MS/MS. In addition, a consecutive biosynthesis was developed by using Fusarium graminearum for ZEN biosynthesis with subsequent conjugation of the toxin by utilizing Aspergillus and Rhizopus species. ZEN-14 sulfate (yield: 49%) is exclusively formed by Aspergillus oryzae. ZEN-14 glucoside (yield: 67%) and ZEN-16-glucoside (yield: 39%) are formed by Rhizopus oryzae and Rhizopusoligosporus, respectively. Purities of >=73% ZEN-14-sulfate, >=82% ZEN-14-glucoside and >=50% ZEN-16-glucoside were obtained by 1H-NMR. In total, under optimized cultivation conditions, fungi can be easily utilized for a targeted and regioselective synthesis of ZEN conjugates. PMID- 29494481 TI - A Three Monoclonal Antibody Combination Potently Neutralizes Multiple Botulinum Neurotoxin Serotype E Subtypes. AB - Human botulism is most commonly caused by botulinum neurotoxin (BoNT) serotypes A, B, and E. For this work, we sought to develop a human monoclonal antibody (mAb)-based antitoxin capable of binding and neutralizing multiple subtypes of BoNT/E. Libraries of yeast-displayed single chain Fv (scFv) antibodies were created from the heavy and light chain variable region genes of humans immunized with pentavalent-toxoid- and BoNT/E-binding scFv isolated by Fluorescence Activated Cell Sorting (FACS). A total of 10 scFv were isolated that bound one or more BoNT/E subtypes with nanomolar-level equilibrium dissociation constants (KD). By diversifying the V-regions of the lead mAbs and selecting for cross reactivity, we generated three scFv that bound all four BoNT/E subtypes tested at three non-overlapping epitopes. The scFvs were converted to IgG that had KD values for the different BoNT/E subtypes ranging from 9.7 nM to 2.28 pM. An equimolar combination of the three mAbs was able to potently neutralize BoNT/E1, BoNT/E3, and BoNT/E4 in a mouse neutralization assay. The mAbs have potential utility as therapeutics and as diagnostics capable of recognizing multiple BoNT/E subtypes. A derivative of the three-antibody combination (NTM-1633) is in pre clinical development with an investigational new drug (IND) application filing expected in 2018. PMID- 29494482 TI - Earable TEMPO: A Novel, Hands-Free Input Device that Uses the Movement of the Tongue Measured with a Wearable Ear Sensor. AB - In this study, an earphone-type interface named "earable TEMPO" was developed for hands-free operation, wherein the user can control the device by simply pushing the tongue against the roof of the mouth for about one second. This interface can be used to start and stop the music from a portable audio player. The earable TEMPO uses an earphone-type sensor equipped with a light emitting diode (LED) and a phototransistor to optically measure shape variations that occur in the external auditory meatus when the tongue is pressed against the roof of the mouth. To evaluate the operation of the earable TEMPO, experiments were performed on five subjects (men and women aged 22-58) while resting, chewing gum (representing mastication), and walking. The average accuracy was 100% while resting and chewing and 99% while walking. The precision was 100% under all conditions. The average recall value of the five subjects was 92%, 90%, and 48% while resting, masticating, and walking, respectively. All subjects were reliably able to perform the action of pressing the tongue against the roof of the mouth. The measured shape variations in the ear canal were highly reproducible, indicating that this method is suitable for various applications such as controlling a portable audio player. PMID- 29494483 TI - Genotoxic and Cytotoxic Effects on the Immune Cells of the Freshwater Bivalve Dreissena polymorpha Exposed to the Environmental Neurotoxin BMAA. AB - The environmental neurotoxin beta-N-Methylamino-l-alanine (BMAA) has been pointed out to be involved in human neurodegenerative diseases. This molecule is known to be bioaccumulated by bivalves. However, little data about its toxic effects on freshwater mussels is available, particularly on the hemolymphatic compartment and its hemocyte cells involved in various physiological processes such as immune defenses, digestion and excretion, tissue repair, and shell production. Here we exposed Dreissena polymorpha to dissolved BMAA, at the environmental concentration of 7.5 ug of /mussel/3 days, during 21 days followed by 14 days of depuration in clear water, with the objective of assessing the BMAA presence in the hemolymphatic compartment, as well as the impact of the hemocyte cells in terms of potential cytotoxicity, immunotoxicity, and genotoxiciy. Data showed that hemocytes were in contact with BMAA. The presence of BMAA in hemolymph did not induce significant effect on hemocytes phagocytosis activity. However, significant DNA damage on hemocytes occurred during the first week (days 3 and 8) of BMAA exposure, followed by an increase of hemocyte mortality after 2 weeks of exposure. Those effects might be an indirect consequence of the BMAA-induced oxidative stress in cells. However, DNA strand breaks and mortality did not persist during the entire exposure, despite the BMAA persistence in the hemolymph, suggesting potential induction of some DNA-repair mechanisms. PMID- 29494484 TI - The Burden of Fungal Diseases in Romania. AB - OBJECTIVE: To estimate for the first time the burden of fungal infections in Romania. METHODS: Data derived from the World Health Organization (WHO), National Institute of Statistics, Romanian public health agencies and non-profit health organizations, and published annual reports on local epidemiology were used in the present study. When no data were available, specific at-risk populations were used to calculate frequencies of serious fungal diseases, using previously published epidemiological parameters. All data refer to the year 2016. RESULTS: The estimated number of serious fungal infections in Romanian population was 436,230 in 2016. Recurrent vulvovaginal candidiasis accounted for up to 80% of total cases (more than 350,000 women annually). Concerning HIV-related infections, among 14,349 infected persons, Pneumocystis pneumonia occurred in about 10% of late presenters (30 cases in 2016), while cryptococcal meningitis was rarely diagnosed (less than 20 cases). Annually, the total number of oesophageal candidiasis and oral thrush cases in HIV-positive patients may have been as high as 1229 and 3066, respectively. In immunocompromised and cancer patient populations, the annual incidence of candidaemia was 295, and at least 458 invasive aspergillosis cases and 4 mucormycosis cases occurred yearly. With 4966 critical care beds and approximately 200,000 abdominal surgeries performed, the estimated annual incidence of candidaemia and Candida peritonitis was 689 and 344, respectively. The annual incidence of pulmonary tuberculosis is still high in Romania (12,747 cases). Thus, the prevalence of post-TB chronic pulmonary aspergillosis is estimated to be 8.98/100,000 (1768 cases). The prevalence of chronic obstructive pulmonary disease (COPD) and asthma in adults is 6% and 6.5%, respectively. Therefore, allergic bronchopulmonary aspergillosis prevalence is estimated at 29,387 and severe asthma with fungal sensitisation at 38,731 cases annually. CONCLUSIONS: Not being on the list of reportable diseases, the number of patients presenting with severe mycoses in Romania can only be roughly estimated. Based on local reports and prevalence estimation, we consider that at least 2.23% of Romanians suffer from a serious form of fungal disease. PMID- 29494485 TI - Expression of Vitis amurensis VaERF20 in Arabidopsis thaliana Improves Resistance to Botrytis cinerea and Pseudomonas syringae pv. Tomato DC3000. AB - Ethylene response factor (ERF) transcription factors play important roles in regulating immune responses in plants. In our study, we characterized a member of the ERF transcription factor family, VaERF20, from the Chinese wild Vitis genotype, V. amurensis Rupr "Shuangyou". Phylogenetic analysis indicated that VaERF20 belongs to group IXc of the ERF family, in which many members are known to contribute to fighting pathogen infection. Consistent with this, expression of VaERF20 was induced by treatment with the necrotrophic fungal pathogen Botrytis cinerea (B. cinerea) in "Shuangyou" and V. vinifera "Red Globe". Arabidopsis thaliana plants over-expressing VaERF20 displayed enhanced resistance to B. cinerea and the bacterium Pseudomonas syringae pv. tomato (Pst) DC3000. Patterns of pathogen-induced reactive oxygen species (ROS) accumulation were entirely distinct in B. cinerea and PstDC3000 inoculated plants. Examples of both salicylic acid (SA) and jasmonic acid/ethylene (JA/ET) responsive defense genes were up-regulated after B. cinerea and PstDC3000 inoculation of the VaERF20 overexpressing transgenic A. thaliana plants. Evidence of pattern-triggered immunity (PTI), callose accumulation and stomatal defense, together with increased expression of PTI genes, was also greater in the transgenic lines. These data indicate that VaERF20 participates in various signal transduction pathways and acts as an inducer of immune responses. PMID- 29494486 TI - Comparative Study of Ferroelectric and Piezoelectric Properties of BNT-BKT-BT Ceramics near the Phase Transition Zone. AB - We report a comprehensive comparative study of ferroelectric and piezoelectric properties of BNT-BKT-BT ceramics through the MPB (morphotropic phase boundary) zone, from the rhombohedral to the tetragonal phases in the system (97.5 x)(Bi0.5Na0.5)TiO3 + x(Bi0.5K0.5)TiO3 + 2.5(BaTiO3), where x = 0 to 24.5 mol %. The structural transitions were studied by XRD patterns and Raman spectra. The MPB was confirmed between x = 10 and 12.5 mol % BKT. The dielectric/ferroelectric/piezoelectric properties of the BNT-BKT-BT system are maximized in the MPB region exhibiting a dielectric constant of 1506, a remanent polarization of 34.4 MUC/cm2, a coercive field = 36.9 kV/cm, and piezoelectric values of d33 = 109 pC/N, kt = 0.52, and kp = 0.24. Changes in microstructure as a function of BKT content are also presented and discussed. PMID- 29494488 TI - Overexpression of HvIcy6 in Barley Enhances Resistance against Tetranychus urticae and Entails Partial Transcriptomic Reprogramming. AB - Cystatins have been largely used for pest control against phytophagous species. However, cystatins have not been commonly overexpressed in its cognate plant species to test their pesticide capacity. Since the inhibitory role of barley HvCPI-6 cystatin against the phytophagous mite Tetranychus urticae has been previously demonstrated, the purpose of our study was to determine if barley transgenic lines overexpressing its own HvIcy6 gene were more resistant against this phytophagous infestation. Besides, a transcriptomic analysis was done to find differential expressed genes among wild-type and transformed barley plants. Barley plants overexpressing HvIcy6 cystatin gene remained less susceptible to T. urticae attack when compared to wild-type plants, with a significant lesser foliar damaged area and a lower presence of the mite. Transcriptomic analysis revealed a certain reprogramming of cellular metabolism and a lower expression of several genes related to photosynthetic activity. Therefore, although caution should be taken to discard potential deleterious pleiotropic effects, cystatins may be used as transgenes with impact on agricultural crops by conferring enhanced levels of resistance to phytophagous pests. PMID- 29494490 TI - Brain Response to Non-Painful Mechanical Stimulus to Lumbar Spine. AB - Pressure application to the lumbar spine is an important assessment and treatment method of low back pain. However, few studies have characterized brain activation patterns in response to mechanical pressure. The objective of this study was to map brain activation associated with various levels of mechanical pressure to the lumbar spine in healthy subjects. Fifteen healthy subjects underwent functional magnetic resonance imaging (fMRI) scanning while mechanical pressure was applied to their lumbar spine with a custom-made magnetic resonance imaging (MRI) compatible pressure device. Each subject received three levels of pressure (low/medium/high) based on subjective ratings determined prior to the scan using a block design (pressure/rest). Pressure rating was assessed with an 11-point scale (0 = no touch; 10 = max pain-free pressure). Brain activation differences between pressure levels and rest were analyzed. Subjective pressure ratings were significantly different across pressure levels (p < 0.05). The overall brain activation pattern was not different across pressure levels (all p > 0.05). However, the overall effect of pressure versus rest showed significant decreases in brain activation in response to the mechanical stimulus in regions associated with somatosensory processing including the precentral gyri, left hippocampus, left precuneus, left medial frontal gyrus, and left posterior cingulate. There was increase in brain activation in the right inferior parietal lobule and left cerebellum. This study offers insight into the neural mechanisms that may relate to manual mobilization intervention used for managing low back pain. PMID- 29494491 TI - Antimicrobial Membranes of Bio-Based PA 11 and HNTs Filled with Lysozyme Obtained by an Electrospinning Process. AB - Bio-based membranes were obtained using Polyamide 11 (PA11) from renewable sources and a nano-hybrid composed of halloysite nanotubes (HNTs) filled with lysozyme (50 wt % of lysozyme), as a natural antimicrobial molecule. Composites were prepared using an electrospinning process, varying the nano-hybrid loading (i.e., 1.0, 2.5, 5.0 wt %). The morphology of the membranes was investigated through SEM analysis and there was found to be a narrow average fiber diameter (0.3-0.5 MUm). The mechanical properties were analyzed and correlated to the nano hybrid content. Controlled release of lysozyme was followed using UV spectrophotometry and the release kinetics were found to be dependent on HNTs lysozyme loading. The experimental results were analyzed by a modified Gallagher Corrigan model. The application of the produced membranes, as bio-based pads, for extending the shelf life of chicken slices has been tested and evaluated. PMID- 29494489 TI - Galacto-Oligosaccharide/Polidextrose Enriched Formula Protects against Respiratory Infections in Infants at High Risk of Atopy: A Randomized Clinical Trial. AB - BACKGROUND: Early nutrition affects the risk of atopy and infections through modifications of intestinal microbiota. The Prebiotics in the Prevention of Atopy (PIPA) study was a 24-month randomised, double-blind, placebo-controlled trial. It aimed to evaluate the effects of a galacto-oligosaccharide/polydextrose (GOS/PDX)-formula (PF) on atopic dermatitis (AD) and common infections in infants who were born to atopic parents and to investigate the relationship among early nutrition, gut microbiota and clinical outcomes. METHODS: A total of 201 and 199 infants were randomized to receive a PF and standard formula (SF), respectively; 140 infants remained on exclusive breastfeeding (BF). RESULTS: The cumulative incidence of AD and its intensity and duration were not statistically different among the three groups. The number of infants with at least one episode of respiratory infection (RI) and the mean number of episodes until 48 weeks of age were significantly lower in the PF group than in the SF group. The number of patients with recurrent RIs and incidence of wheezing lower RIs until 96 weeks were lower in the PF group than the SF group, but similar to the BF group. Bifidobacteria and Clostridium cluster I colonization increased over time in the PF group but decreased in the SF and BF groups. Bifidobacteria had a protective role in RIs, whereas Clostridium cluster I was associated with atopy protection. CONCLUSION: The early administration of PF protects against RIs and mediates a species-specific modulation of the intestinal microbiota. TRIAL REGISTRATION: clinicaltrial.gov Identifier: NCT02116452. PMID- 29494487 TI - Dairy Fats and Cardiovascular Disease: Do We Really Need to be Concerned? AB - Cardiovascular diseases (CVD) remain a major cause of death and morbidity globally and diet plays a crucial role in the disease prevention and pathology. The negative perception of dairy fats stems from the effort to reduce dietary saturated fatty acid (SFA) intake due to their association with increased cholesterol levels upon consumption and the increased risk of CVD development. Institutions that set dietary guidelines have approached dairy products with negative bias and used poor scientific data in the past. As a result, the consumption of dairy products was considered detrimental to our cardiovascular health. In western societies, dietary trends indicate that generally there is a reduction of full-fat dairy product consumption and increased low-fat dairy consumption. However, recent research and meta-analyses have demonstrated the benefits of full-fat dairy consumption, based on higher bioavailability of high value nutrients and anti-inflammatory properties. In this review, the relationship between dairy consumption, cardiometabolic risk factors and the incidence of cardiovascular diseases are discussed. Functional dairy foods and the health implications of dairy alternatives are also considered. In general, evidence suggests that milk has a neutral effect on cardiovascular outcomes but fermented dairy products, such as yoghurt, kefir and cheese may have a positive or neutral effect. Particular focus is placed on the effects of the lipid content on cardiovascular health. PMID- 29494493 TI - The Effect of Processing and Seasonality on the Iodine and Selenium Concentration of Cow's Milk Produced in Northern Ireland (NI): Implications for Population Dietary Intake. AB - Cow's milk is the most important dietary source of iodine in the UK and Ireland, and also contributes to dietary selenium intakes. The aim of this study was to investigate the effect of season, milk fat class (whole; semi-skimmed; skimmed) and pasteurisation on iodine and selenium concentrations in Northern Ireland (NI) milk, and to estimate the contribution of this milk to consumer iodine and selenium intakes. Milk samples (unpasteurised, whole, semi-skimmed and skimmed) were collected weekly from two large NI creameries between May 2013 and April 2014 and were analysed by inductively coupled plasma-mass spectrometry (ICP-MS). Using milk consumption data from the National Diet and Nutrition Survey (NDNS) Rolling Programme, the contribution of milk (at iodine and selenium concentrations measured in the present study) to UK dietary intakes was estimated. The mean +/- standard deviation (SD) iodine concentration of milk was 475.9 +/- 63.5 ug/kg and the mean selenium concentration of milk was 17.8 +/- 2.7 ug/kg. Season had an important determining effect on the iodine, but not the selenium, content of cow's milk, where iodine concentrations were highest in milk produced in spring compared to autumn months (534.3 +/- 53.7 vs. 433.6 +/- 57.8 ug/kg, respectively; p = 0.001). The measured iodine and selenium concentrations of NI milk were higher than those listed in current UK Food Composition Databases (Food Standards Agency (FSA) (2002); FSA (2015)). The dietary modelling analysis confirmed that milk makes an important contribution to iodine and selenium intakes. This contribution may be higher than previously estimated if iodine and selenium (+25.0 and +1.1 ug/day respectively) concentrations measured in the present study were replicable across the UK at the current level of milk consumption. Iodine intakes were theoretically shown to vary by season concurrent with the seasonal variation in NI milk iodine concentrations. Routine monitoring of milk iodine concentrations is required and efforts should be made to understand reasons for fluctuations in milk iodine concentrations, in order to realise the nutritional impact to consumers. PMID- 29494492 TI - Importance of ERK1/2 in Regulation of Protein Translation during Oocyte Meiosis. AB - Although the involvement of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathway in the regulation of cytostatic factor (CSF) activity; as well as in microtubules organization during meiotic maturation of oocytes; has already been described in detail; rather less attention has been paid to the role of ERK1/2 in the regulation of mRNA translation. However; important data on the role of ERK1/2 in translation during oocyte meiosis have been documented. This review focuses on recent findings regarding the regulation of translation and the role of ERK1/2 in this process in the meiotic cycle of mammalian oocytes. The specific role of ERK1/2 in the regulation of mammalian target of rapamycin (mTOR); eukaryotic translation initiation factor 4E (eIF4E) and cytoplasmic polyadenylation element binding protein 1 (CPEB1) activity is addressed along with additional focus on the other key players involved in protein translation. PMID- 29494495 TI - Erratum: Differences in Ribosome Binding and Sarcin/Ricin Loop Depurination by Shiga and Ricin Holotoxins. Toxins 2017, 9, 133. AB - We wish to make the following correction to the published paper [1].[...]. PMID- 29494494 TI - l-Glutamine Attenuates DSS-Induced Colitis via Induction of MAPK Phosphatase-1. AB - Inflammatory bowel disease (IBD), encompassing ulcerative colitis and Crohn's disease, is a multifactorial inflammatory disease of the small intestine and colon. Many investigators have reported that l-glutamine (Gln) therapy improves outcomes of experimental colitis models, although the mechanism is not fully understood. Regarding the anti-inflammatory properties of Gln, we have shown that Gln can effectively deactivate cytosolic phospholipase A2 (cPLA2) by rapid induction of MAPK phosphatase (MKP)-1. In this study, we explore the possibility that Gln ameliorates dextran sulfate sodium (DSS)-induced colitis via MKP-1 induction, resulting in inhibition of cPLA2, which has been reported to play a key role in the pathogenesis of IBD. Oral Gln intake attenuated DSS-induced colitis. Gln inhibited cPLA2 phosphorylation, as well as colonic levels of TNF alpha and leukotriene (LT)B4. Gln administration resulted in early and enhanced MKP-1 induction. Importantly, MKP-1 small interfering RNA (siRNA), but not control siRNA, significantly abrogated the Gln-mediated (1) induction of MKP-1; (2) attenuation of colitis (colon length, histological abnormality, and inflammation; and (3) inhibition of cPLA2 phosphorylation and colonic levels of TNF-alpha and LTB4. These data indicated that Gln ameliorated DSS-induced colitis via MKP-1 induction. PMID- 29494496 TI - Identifying Time Periods of Minimal Thermal Gradient for Temperature-Driven Structural Health Monitoring. AB - Temperature changes play a large role in the day to day structural behavior of structures, but a smaller direct role in most contemporary Structural Health Monitoring (SHM) analyses. Temperature-Driven SHM will consider temperature as the principal driving force in SHM, relating a measurable input temperature to measurable output generalized strain (strain, curvature, etc.) and generalized displacement (deflection, rotation, etc.) to create three-dimensional signatures descriptive of the structural behavior. Identifying time periods of minimal thermal gradient provides the foundation for the formulation of the temperature deformation-displacement model. Thermal gradients in a structure can cause curvature in multiple directions, as well as non-linear strain and stress distributions within the cross-sections, which significantly complicates data analysis and interpretation, distorts the signatures, and may lead to unreliable conclusions regarding structural behavior and condition. These adverse effects can be minimized if the signatures are evaluated at times when thermal gradients in the structure are minimal. This paper proposes two classes of methods based on the following two metrics: (i) the range of raw temperatures on the structure, and (ii) the distribution of the local thermal gradients, for identifying time periods of minimal thermal gradient on a structure with the ability to vary the tolerance of acceptable thermal gradients. The methods are tested and validated with data collected from the Streicker Bridge on campus at Princeton University. PMID- 29494497 TI - An Interoperable System toward Cardiac Risk Stratification from ECG Monitoring. AB - Many indices have been proposed for cardiovascular risk stratification from electrocardiogram signal processing, still with limited use in clinical practice. We created a system integrating the clinical definition of cardiac risk subdomains from ECGs and the use of diverse signal processing techniques. Three subdomains were defined from the joint analysis of the technical and clinical viewpoints. One subdomain was devoted to demographic and clinical data. The other two subdomains were intended to obtain widely defined risk indices from ECG monitoring: a simple-domain (heart rate turbulence (HRT)), and a complex-domain (heart rate variability (HRV)). Data provided by the three subdomains allowed for the generation of alerts with different intensity and nature, as well as for the grouping and scrutinization of patients according to the established processing and risk-thresholding criteria. The implemented system was tested by connecting data from real-world in-hospital electronic health records and ECG monitoring by considering standards for syntactic (HL7 messages) and semantic interoperability (archetypes based on CEN/ISO EN13606 and SNOMED-CT). The system was able to provide risk indices and to generate alerts in the health records to support decision-making. Overall, the system allows for the agile interaction of research and clinical practice in the Holter-ECG-based cardiac risk domain. PMID- 29494498 TI - Comparison of Growth of Healthy Term Infants Fed Extensively Hydrolyzed Protein- and Amino Acid-Based Infant Formulas. AB - The aim of this narrative review was to assess published growth data for healthy, term, infants consuming extensively hydrolyzed protein-based (EHF), or amino acid based formulas (AAF). These data may be of use to clinicians managing infants with medical conditions consuming these products. A search was conducted using key terms: amino acid-based, hydrolysate, hydrolyzed, hydrolysed, infant formula, infant formulae or formulas, baby formula, or formulae or formulas, infant, infants, infantile, and growth. Seven controlled, randomized, prospective growth trials of healthy term infants fed EHFs or AAFs at similar time points during the first four months of age met these and other criteria, including that the trial was published in a peer-reviewed journal, subjects were enrolled by <=14 days of age and were exclusively formula-fed at entry and throughout the duration of the trial, and infants were assessed at regular intervals with weight measures available ideally at 14 days, one, two, three, and four months of age. Results suggested that healthy infants receiving commonly available EHFs and AAFs do not appear to experience accelerated growth as reported for infants fed many standard formulas. Differences in growth patterns were observed with some formulas supporting normative growth patterns during the first four months but others appearing to support markedly lower growth patterns. These observations should be confirmed in well-designed prospective randomized trials. Until that time, it is recommended that EHFs and AAFs be chosen carefully with individual patient needs considered. PMID- 29494499 TI - Humans' Relationship to Flowers as an Example of the Multiple Components of Embodied Aesthetics. AB - This paper phenomenologically and qualitatively explores the relationship between humans and flowers as a relationship that throws light on the synergetic dynamics of embodied aesthetics. Its methods include qualitative description and thematic analyses of preferred flower types, as well as concept maps of the general term 'flower' by 120 students in Israel. The results revealed the interactive perceptual-compositional elements, as well as embodied, relational, and socially embedded elements of the aesthetic pleasure associated with flowers. Implications of this case study are generalized to understand the multiple and interactive components of embodied aesthetic experiences as a deep source of pleasure through interactive stimulation by and connection to the natural world. PMID- 29494501 TI - A Narrative Review on the Human Health Effects of Ambient Air Pollution in Sub Saharan Africa: An Urgent Need for Health Effects Studies. AB - An important aspect of the new sustainable development goals (SDGs) is a greater emphasis on reducing the health impacts from ambient air pollution in developing countries. Meanwhile, the burden of human disease attributable to ambient air pollution in sub-Saharan Africa is growing, yet estimates of its impact on the region are possibly underestimated due to a lack of air quality monitoring, a paucity of air pollution epidemiological studies, and important population vulnerabilities in the region. The lack of ambient air pollution epidemiologic data in sub-Saharan Africa is also an important global health disparity. Thousands of air pollution health effects studies have been conducted in Europe and North America, rather than in urban areas that have some of the highest measured air pollution levels in world, including urban areas in sub-Saharan Africa. In this paper, we provide a systematic and narrative review of the literature on ambient air pollution epidemiological studies that have been conducted in the region to date. Our review of the literature focuses on epidemiologic studies that measure air pollutants and relate air pollution measurements with various health outcomes. We highlight the gaps in ambient air pollution epidemiological studies conducted in different sub-regions of sub Saharan Africa and provide methodological recommendations for future environmental epidemiology studies addressing ambient air pollution in the region. PMID- 29494500 TI - Effects of Fullerenol Nanoparticles on Rat Oocyte Meiosis Resumption. AB - The excellent biocompatibility and biological effects of fullerenol and its derivatives make their biomedical application promising. The potential effects of fullerenol in mammals have been extensively studied, but little is known about its effects on female reproduction. Using canonical oocyte-granulosa cell complexes (OGCs) in vitro maturation culture model, we investigated the effect of fullerenol on the first oocyte meiotic resumption. In the surrounding granulosa cells, fullerenol nanoparticles occluded the extracellular domain of the epidermal growth factor receptor (EGFR) to reduce EGFR-ligand binding and subsequent extracellular signal-regulated kinase 1 and 2 (ERK1/2) activation, which involved the regulation of connexin 43 (CX43) expression and internalization. Downregulation of CX43 expression and the retraction of transzonal projections (TZPs) interrupted the gap junction channel and TZPs based mass transportation. This effect decreased cyclic adenosine monophosphate (cAMP) levels in the oocyte and thereby accelerated rat oocyte meiosis resumption. Moreover, perinuclear distribution of CX43 and EGFR was observed in granulosa cells, which could further exacerbate the effects. Fullerenol nanoparticles interfered with the strict process of oocyte meiosis resumption, which likely reduced the oocyte quality. PMID- 29494502 TI - Cryptococcosis in Colombia: Compilation and Analysis of Data from Laboratory Based Surveillance. AB - The passive and voluntary surveillance of cryptococcosis in Colombia since 1997 has seen an increasing participating rate, revealing its importance to both in immunosuppressed and immunocompetent people. The present work details the national data gathered in 1997-2016, through a retrospective analysis of the information collected in the survey. From a total of 1974 cases reported, an overall incidence of 0.23 cases per 100,000 people was found. This incidence rose to 1.1 cases per 1000 people in the Acquired Immunodeficiency Syndrome (AIDS) population. Cryptococcosis was most common in male young adults (26-40 years), with a male:female ratio of 3.9:1 in the general population and 5.4:1 in Human Immunodeficiency Virus (HIV) patients. Culture was the most common form of diagnosis in 96.3% of cases, recovering C. neoformans species in 87.5% and C. gattii in 3.1% of samples. VNI was the most prevalent (96.1%) molecular type, while VGII predominated in C. gattii isolates (54.3%). Early mortality was reported as the outcome in 47.5% of patients. Cryptococcosis remains an important opportunistic disease in Colombia and is gaining status as a primary pathogen in apparently immunocompetent patients. Our findings show the importance of including cryptococcosis as a notifiable disease, which will allow for improving opportune diagnosis and treatment, resulting in better patient outcomes. PMID- 29494504 TI - The Effect of Film Thickness on the Gas Sensing Properties of Ultra-Thin TiO2 Films Deposited by Atomic Layer Deposition. AB - Analyte sensitivity for gas sensors based on semiconducting metal oxides should be highly dependent on the film thickness, particularly when that thickness is on the order of the Debye length. This thickness dependence has previously been demonstrated for SnO2 and inferred for TiO2. In this paper, TiO2 thin films have been prepared by Atomic Layer Deposition (ALD) using titanium isopropoxide and water as precursors. The deposition process was performed on standard alumina gas sensor platforms and microscope slides (for analysis purposes), at a temperature of 200 degrees C. The TiO2 films were exposed to different concentrations of CO, CH4, NO2, NH3 and SO2 to evaluate their gas sensitivities. These experiments showed that the TiO2 film thickness played a dominant role within the conduction mechanism and the pattern of response for the electrical resistance towards CH4 and NH3 exposure indicated typical n-type semiconducting behavior. The effect of relative humidity on the gas sensitivity has also been demonstrated. PMID- 29494503 TI - Recent Advances in Biomaterials for 3D Printing and Tissue Engineering. AB - Three-dimensional printing has significant potential as a fabrication method in creating scaffolds for tissue engineering. The applications of 3D printing in the field of regenerative medicine and tissue engineering are limited by the variety of biomaterials that can be used in this technology. Many researchers have developed novel biomaterials and compositions to enable their use in 3D printing methods. The advantages of fabricating scaffolds using 3D printing are numerous, including the ability to create complex geometries, porosities, co-culture of multiple cells, and incorporate growth factors. In this review, recently developed biomaterials for different tissues are discussed. Biomaterials used in 3D printing are categorized into ceramics, polymers, and composites. Due to the nature of 3D printing methods, most of the ceramics are combined with polymers to enhance their printability. Polymer-based biomaterials are 3D printed mostly using extrusion-based printing and have a broader range of applications in regenerative medicine. The goal of tissue engineering is to fabricate functional and viable organs and, to achieve this, multiple biomaterials and fabrication methods need to be researched. PMID- 29494505 TI - Novel Precursor-Derived Meso-/Macroporous TiO2/SiOC Nanocomposites with Highly Stable Anatase Nanophase Providing Visible Light Photocatalytic Activity and Superior Adsorption of Organic Dyes. AB - Titania (TiO2) is considered to have immense potential as a photocatalyst, the anatase phase in particular. There have been numerous attempts to push the limits of its catalytic activity to higher wavelengths to harness the visible electromagnetic radiation. Most of the investigations till date have been restricted to fine-tuning the bandgap by doping, control of defect chemistry at the surface and several to first principle simulations either with limited success or success at the cost of complexities in processing. Here, we report a simple and elegant way of preparing ceramics through precursor chemistry which involves synthesis of macroporous and mesoporous nanocomposites with in situ formation of TiO2 nanocrystals into a robust and protecting SiOC matrix. The in situ nanoscaled TiO2 is anatase of size 9-10 nm, which is uniformly distributed in an amorphous SiOC matrix forming a new generation of nanocomposites that combine the robustness, structural stability and durability of the SiOC matrix while achieving nanoscaled TiO2 functionalities. The stabilization of the anatase phase even at temperature as high as 1200 degrees C was evident. With an average pore size of 6.8 nm, surface area of 129 m2/g (BET) and pore volume of 0.22 cm3/g (BET), mesoporosity was achieved in the nanocomposites. The composites exhibited visible light photocatalytic activity, which is attributed to the Ti-O-C/TiC bonds resulting in the reduction of band gap by 0.2 to 0.9 eV. Furthermore, the heterojunction formed between the amorphous SiOC and crystalline TiO2 is also expected to minimize the recombination rate of electron-hole pair, making these novel nanocomposites based on TiO2 extremely active in visible wavelength regime. PMID- 29494506 TI - Anti-Hypertensive Effects of Acacia Polyphenol in Spontaneously Hypertensive Rats. AB - We have previously demonstrated that acacia polyphenol (AP) exerts strong anti obesity, anti-diabetic, and anti-atopic dermatitis effects. In the present study, we investigated the anti-hypertensive effects of AP. Spontaneously hypertensive rats (SHR) with hypertension and control Wistar Kyoto rats (WKY) were used. WKY and SHR were fed AP-containing food or AP-free food (control group) ad libitum for 4 weeks, and their blood pressures were measured. After AP administration, both systolic and diastolic blood pressures were significantly lower in the SHR group than in the control group. There were no differences in the systolic or diastolic blood pressure of WKY between the AP group and the control group. Angiotensin-converting enzyme (ACE) activity, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expression, and superoxide dismutase (SOD) activity in SHR kidneys were not altered by AP administration. Blood SOD activity in SHR was significantly higher in the AP group than in the control group. AP exerts anti hypertensive effects on hypertension but has almost no effect on normal blood pressure. The anti-hypertensive effects of AP may be related to the anti oxidative effects of increased blood SOD activity. PMID- 29494507 TI - Inhibition of E. coli Growth by Nanodiamond and Graphene Oxide Enhanced by Luria Bertani Medium. AB - Nanodiamonds (NDs) and graphene oxide (GO) are modern carbon-based nanomaterials with promising features for the inhibition of microorganism growth ability. Here we compare the effects of nanodiamond and graphene oxide in both annealed (oxidized) and reduced (hydrogenated) forms in two types of cultivation media Luria-Bertani (LB) and Mueller-Hinton (MH) broths. The comparison shows that the number of colony forming unit (CFU) of Escherichia coli is significantly lowered (45%) by all the nanomaterials in LB medium for at least 24 h against control. On the contrary, a significant long-term inhibition of E. coli growth (by 45%) in the MH medium is provided only by hydrogenated NDs terminated with C-HX groups. The use of salty agars did not enhance the inhibition effects of nanomaterials used, i.e. disruption of bacterial membrane or differences in ionic concentrations do not play any role in bactericidal effects of nanomaterials used. The specific role of the ND and GO on the enhancement of the oxidative stress of bacteria or possible wrapping bacteria by GO nanosheets, therefore isolating them from both the environment and nutrition was suggested. Analyses by infrared spectroscopy, photoelectron spectroscopy, scanning electron microscopy and dynamic light scattering corroborate these conclusions. PMID- 29494508 TI - Iodine as Essential Nutrient during the First 1000 Days of Life. AB - Iodine is an essential micronutrient incorporated into thyroid hormones. Although iodine deficiency can lead to a broad spectrum of disorders throughout life, it is most critical in the early stages of development, as the foetal brain is extremely dependent on iodine supply. During the last two decades, our understanding of thyroid physiology during gestation has substantially improved. Furthermore, thyroid hormone receptors have been identified and characterised in placental and embryonic tissues, allowing us to elucidate the maternal-foetal transfer of thyroid hormones. Experimental studies have demonstrated that the cyto-architecture of the cerebral cortex can be irreversibly disturbed in iodine deficiency causing abnormal neuron migratory patterns which are associated with cognitive impairment in children. In this context, the role of iodine as key factor in the programming of foetal and infant neurodevelopment, needs to be revisited with a special focus on areas of mild to moderate iodine deficiency. The objective of this review is to summarize the available evidence from both animals and human studies, for the effect of iodine deficiency (particularly, of maternal hypothyroxinemia) on brain development and neurological or behavioural disorders, such as lower intelligence quotient (IQ) or attention deficit hyperactivity disorder (ADHD). PMID- 29494509 TI - Complete Chloroplast Genome Sequences of Four Meliaceae Species and Comparative Analyses. AB - The Meliaceae family mainly consists of trees and shrubs with a pantropical distribution. In this study, the complete chloroplast genomes of four Meliaceae species were sequenced and compared with each other and with the previously published Azadirachta indica plastome. The five plastomes are circular and exhibit a quadripartite structure with high conservation of gene content and order. They include 130 genes encoding 85 proteins, 37 tRNAs and 8 rRNAs. Inverted repeat expansion resulted in a duplication of rps19 in the five Meliaceae species, which is consistent with that in many other Sapindales, but different from many other rosids. Compared to Azadirachta indica, the four newly sequenced Meliaceae individuals share several large deletions, which mainly contribute to the decreased genome sizes. A whole-plastome phylogeny supports previous findings that the four species form a monophyletic sister clade to Azadirachta indica within the Meliaceae. SNPs and indels identified in all complete Meliaceae plastomes might be suitable targets for the future development of genetic markers at different taxonomic levels. The extended analysis of SNPs in the matK gene led to the identification of four potential Meliaceae-specific SNPs as a basis for future validation and marker development. PMID- 29494510 TI - Functional Anthocyanin-Rich Sausages Diminish Colorectal Cancer in an Animal Model and Reduce Pro-Inflammatory Bacteria in the Intestinal Microbiota. AB - Colorectal cancer is the fourth most common neoplasia in Europe, where it accounts for 28.2 new cases per 100,000 inhabitants. In an effort to decrease the incidence of this disease, various prevention measures are being studied, one of which are anthocyanin-rich foods. Anthocyanins are potent antioxidant flavonoids mainly found in flowers and colorful fruits and vegetables. These nutraceuticals have diverse biological functions once ingested, including immunomodulatory, anti inflammatory and antitumor functions. In order to test the preventive effect of these flavonoids against colorectal cancer, an animal model (Rattus norvegicus F344) was developed. In this model two doses of azoxymethane (10 mg/kg) and two treatments with dextran sodium sulfate (DSS) were administered to the animals. For 20 weeks they were fed either control rat feed, control sausages, or functional sausages containing 0.1% (w/w) of anthocyanins from a mixture of dehydrated blackberries and strawberries. At the end of that period, the animals were sacrificed and their antioxidant plasma levels and digestive tract tissues were analyzed. The results revealed a statistically significant reduction in the number of colon tumors in the functional sausages cohort with respect to the control animals and an increase in the FRAP (ferric reducing ability of plasma) total antioxidant activity in that same cohort. Colon microbiota differences were also examined via metagenomics 16S ribosomal RNA (rRNA) sequencing, revealing a significant reduction in populations of the pro-inflammatory Bilophila wadsworthia. Therefore, the design of functional processed meat products, such as ones enriched with anthocyanins, may be an effective strategy for preventing inflammatory digestive diseases and colorectal cancer in human populations. PMID- 29494511 TI - Synthesis and Effect of Hierarchically Structured Ag-ZnO Hybrid on the Surface Antibacterial Activity of a Propylene-Based Elastomer Blends. AB - In this study, a hybrid Ag-ZnO nanostructured micro-filler was synthesized by the drop technique for used in plastic and medical industry. Furthermore, new antibacterial polymer nanocomposites comprising particles of Ag-ZnO up to 5 wt % and a blend of a thermoplastic polyolefin elastomer (TPO) with polypropylene were prepared using twin screw micro-compounder. The morphology and crystalline-phase structure of the hybrid Ag-ZnO nanostructured microparticles obtained was characterized by scanning electron microscopy and powder X-ray diffractometry. The specific surface area of this filler was investigated by means of nitrogen sorption via the Brunauer-Emmet-Teller method. A scanning electron microscope was used to conduct a morphological study of the polymer nanocomposites. Mechanical and electrical testing showed no adverse effects on the function of the polymer nanocomposites either due to the filler utilized or the given processing conditions, in comparison with the neat polymer matrix. The surface antibacterial activity of the compounded polymer nanocomposites was assessed against Escherichia coli ATCC 8739 and Staphylococcus aureus ATCC 6538P, according to ISO 22196:2007 (E). All the materials at virtually every filler-loading level were seen to be efficient against both species of bacteria. PMID- 29494512 TI - Selenium and Selenoproteins in Gut Inflammation-A Review. AB - Inflammatory bowel disease (IBD), characterized by severe flares and remissions, is a debilitating condition. While the etiology is unknown, many immune cells, such as macrophages, T cells and innate lymphoid cells, are implicated in the pathogenesis of the disease. Previous studies have shown the ability of micronutrient selenium (Se) and selenoproteins to impact inflammatory signaling pathways implicated in the pathogenesis of the disease. In particular, two transcription factors, nuclear factor-kappaB (NF-kappaB), and peroxisome proliferator activated receptor (PPAR)gamma, which are involved in the activation of immune cells, and are also implicated in various stages of inflammation and resolution, respectively, are impacted by Se status. Available therapies for IBD produce detrimental side effects, resulting in the need for alternative therapies. Here, we review the current understanding of the role of NF-kappaB and PPARgamma in the activation of immune cells during IBD, and how Se and selenoproteins modulate effective resolution of inflammation to be considered as a promising alternative to treat IBD. PMID- 29494513 TI - Health Disparities in the Relationship of Neighborhood Greenness to Mental Health Outcomes in 249,405 U.S. Medicare Beneficiaries. AB - Prior studies suggest that exposure to the natural environment may be important for optimal mental health. The present study examines the association between block-level greenness (vegetative presence) and mental health outcomes, in a population-based sample of 249,405 U.S. Medicare beneficiaries aged >=65 years living in Miami-Dade County, Florida, USA, whose location did not change from 2010 to 2011. Multilevel analyses examined relationships between greenness, as measured by mean Normalized Difference Vegetation Index from satellite imagery at the Census block level, and each of two mental health outcomes; Alzheimer's disease and depression, respectively, after statistically adjusting for age, gender, race/ethnicity, and neighborhood income level of the individuals. Higher block-level greenness was linked to better mental health outcomes: There was a reduced risk of Alzheimer's disease (by 18%) and depression (by 28%) for beneficiaries living in blocks that were 1 SD above the mean for greenness, as compared to blocks that were 1 SD below the mean. Planned post-hoc analyses revealed that higher levels of greenness were associated with even greater mental health benefits in low-income neighborhoods: An increase in greenness from 1 SD below to 1 SD above the mean was associated with 37% lower odds of depression in low-income neighborhoods, compared to 27% and 21% lower odds of depression in medium- and high-income neighborhoods, respectively. Greenness may be effective in promoting mental health in older adults, particularly in low-income neighborhoods, possibly as a result of the increased opportunities for physical activity, social interaction, or stress mitigation. PMID- 29494514 TI - Hydrogen Peroxide-Induced Root Ca2+ and K+ Fluxes Correlate with Salt Tolerance in Cereals: Towards the Cell-Based Phenotyping. AB - Salinity stress-induced production of reactive oxygen species (ROS) and associated oxidative damage is one of the major factors limiting crop production in saline soils. However, the causal link between ROS production and stress tolerance is not as straightforward as one may expect, as ROS may also play an important signaling role in plant adaptive responses. In this study, the causal relationship between salinity and oxidative stress tolerance in two cereal crops barley (Hordeum vulgare) and wheat (Triticum aestivum)-was investigated by measuring the magnitude of ROS-induced net K+ and Ca2+ fluxes from various root tissues and correlating them with overall whole-plant responses to salinity. We have found that the association between flux responses to oxidative stress and salinity stress tolerance was highly tissue specific, and was also dependent on the type of ROS applied. No correlation was found between root responses to hydroxyl radicals and the salinity tolerance. However, when oxidative stress was administered via H2O2 treatment, a significant positive correlation was found for the magnitude of ROS-induced K+ efflux and Ca2+ uptake in barley and the overall salinity stress tolerance, but only for mature zone and not the root apex. The same trends were found for wheat. These results indicate high tissue specificity of root ion fluxes response to ROS and suggest that measuring the magnitude of H2O2-induced net K+ and Ca2+ fluxes from mature root zone may be used as a tool for cell-based phenotyping in breeding programs aimed to improve salinity stress tolerance in cereals. PMID- 29494515 TI - Comparison of Airway Responses Induced in a Mouse Model by the Gas and Particulate Fractions of Gasoline Direct Injection Engine Exhaust. AB - Diesel exhaust has been associated with asthma, but its response to other engine emissions is not clear. The increasing prevalence of vehicles with gasoline direct injection (GDI) engines motivated this study, and the objective was to evaluate pulmonary responses induced by acute exposure to GDI engine exhaust in an allergic asthma murine model. Mice were sensitized with an allergen to induce airway hyperresponsiveness or treated with saline (non-allergic group). Animals were challenged for 2-h to exhaust from a laboratory GDI engine operated at conditions equivalent to a highway cruise. Exhaust was filtered to assess responses induced by the particulate and gas fractions. Short-term exposure to particulate matter from GDI engine exhaust induced upregulation of genes related to polycyclic aromatic hydrocarbon (PAH) metabolism (Cyp1b1) and inflammation (TNFalpha) in the lungs of non-allergic mice. High molecular weight PAHs dominated the particulate fraction of the exhaust, and this response was therefore likely attributable to the presence of these PAHs. The particle fraction of GDI engine exhaust further contributed to enhanced methacholine responsiveness in the central and peripheral tissues in animals with airway hyperresponsiveness. As GDI engines gain prevalence in the vehicle fleet, understanding the health impacts of their emissions becomes increasingly important. PMID- 29494517 TI - Immune Monitoring of Cancer Patients Prior to and During CTLA-4 or PD-1/PD-L1 Inhibitor Treatment. AB - Targeting the immune checkpoint receptors cytotoxic T lymphocyte antigen 4 (CTLA 4), programmed cell death protein 1 (PD-1), or programmed cell death 1 ligand 1 (PD-L1) represents a very attractive treatment modality for tumor patients. The administration of antibodies against these receptors can promote efficient antitumor effects and can induce objective clinical responses in about 20-40% patients with various tumor types, accompanied by improved survival. Based on their therapeutic efficiency, several antibodies have been approved for the treatment of tumor patients. However, many patients do not respond to checkpoint inhibitor therapy. Therefore, the identification of biomarkers is required to guide patient selection for this treatment modality. Here, we summarize recent studies investigating the PD-L1 expression or mutational load of tumor tissues as well as the frequency and phenotype of immune cells in tumor patients prior to and during CTLA-4 or PD-1/PD-L1 inhibitor treatment. PMID- 29494519 TI - A Manganin Thin Film Ultra-High Pressure Sensor for Microscale Detonation Pressure Measurement. AB - With the development of energetic materials (EMs) and microelectromechanical systems (MEMS) initiating explosive devices, the measurement of detonation pressure generated by EMs in the microscale has become a pressing need. This paper develops a manganin thin film ultra-high pressure sensor based on MEMS technology for measuring the output pressure from micro-detonator. A reliable coefficient is proposed for designing the sensor's sensitive element better. The sensor employs sandwich structure: the substrate uses a 0.5 mm thick alumina ceramic, the manganin sensitive element with a size of 0.2 mm * 0.1 mm * 2 MUm and copper electrodes of 2 MUm thick are sputtered sequentially on the substrate, and a 25 MUm thick insulating layer of polyimide is wrapped on the sensitive element. The static test shows that the piezoresistive coefficient of manganin thin film is 0.0125 GPa-1. The dynamic experiment indicates that the detonation pressure of micro-detonator is 12.66 GPa, and the response time of the sensor is 37 ns. In a word, the sensor developed in this study is suitable for measuring ultra-high pressure in microscale and has a shorter response time than that of foil-like manganin gauges. Simultaneously, this study could be beneficial to research on ultra-high-pressure sensors with smaller size. PMID- 29494518 TI - Structural Basis for the Specific Neutralization of Stx2a with a Camelid Single Domain Antibody Fragment. AB - BACKGROUND: Shiga toxin-producing Escherichia coli (STEC) are a subset of pathogens leading to illnesses such as diarrhea, hemolytic uremic syndrome and even death. The Shiga toxins are the main virulence factors and divided in two groups: Stx1 and Stx2, of which the latter is more frequently associated with severe pathologies in humans. RESULTS: An immune library of nanobodies (Nbs) was constructed after immunizing an alpaca with recombinant Shiga toxin-2a B subunit (rStx2aB), to retrieve multiple rStx2aB-specific Nbs. The specificity of five Nbs towards rStx2aB was confirmed in ELISA and Western blot. Nb113 had the highest affinity (9.6 nM) and its bivalent construct exhibited a 100-fold higher functional affinity. The structure of the Nb113 in complex with rStx2aB was determined via X-ray crystallography. The crystal structure of the Nb113-rStx2aB complex revealed that five copies of Nb113 bind to the rStx2aB pentamer and that the Nb113 epitope overlaps with the Gb3 binding site, thereby providing a structural basis for the neutralization of Stx2a by Nb113 that was observed on Vero cells. Finally, the tandem-repeated, bivalent Nb1132 exhibits a higher toxin neutralization capacity compared to monovalent Nb113. CONCLUSIONS: The Nb of highest affinity for rStx2aB is also the best Stx2a and Stx2c toxin neutralizing Nb, especially in a bivalent format. This lead Nb neutralizes Stx2a by competing for the Gb3 receptor. The fusion of the bivalent Nb1132 with a serum albumin specific Nb is expected to combine high toxin neutralization potential with prolonged blood circulation. PMID- 29494516 TI - The Unforeseen Non-Coding RNAs in Head and Neck Cancer. AB - Previously ignored non-coding RNAs (ncRNAs) have become the subject of many studies. However, there is an imbalance in the amount of consideration that ncRNAs are receiving. Some transcripts such as microRNAs (miRNAs) or small interfering RNAs (siRNAs) have gained much attention, but it is necessary to investigate other "pieces of the RNA puzzle". These can offer a more complete view over normal and pathological cell behavior. The other ncRNA species are less studied, either due to their recent discovery, such as stable intronic sequence RNA (sisRNA), YRNA, miRNA-offset RNAs (moRNA), telomerase RNA component (TERC), natural antisense transcript (NAT), transcribed ultraconserved regions (T-UCR), and pseudogene transcript, or because they are still largely seen as non-coding transcripts with no relevance to pathogenesis. Moreover, some are still considered housekeeping RNAs, for instance small nucleolar RNAs (snoRNAs) and TERC. Our review summarizes the biogenesis, mechanism of action and potential role of less known ncRNAs in head and neck cancer, with a particular focus on the installment and progress for this particular cancer type. PMID- 29494520 TI - Iodine Status during Pregnancy in a Region of Mild-to-Moderate Iodine Deficiency is not Associated with Adverse Obstetric Outcomes; Results from the Avon Longitudinal Study of Parents and Children (ALSPAC). AB - Severe iodine deficiency during pregnancy has been associated with pregnancy/neonatal loss, and adverse pregnancy outcomes; however, the impact of mild-to-moderate iodine insufficiency, though prevalent in pregnancy, is not well documented. We assessed whether mild iodine deficiency during pregnancy was associated with pregnancy/infant loss, or with other adverse pregnancy outcomes. We used samples and data from the Avon Longitudinal Study of Parents and Children (ALSPAC), from 3140 singleton pregnancies and from a further 42 women with pregnancy/infant loss. The group was classified as mildly-to-moderately iodine deficient with a median urinary iodine concentration of 95.3 ug/L (IQR 57.0 153.0; median urinary iodine-to-creatinine ratio (UI/Creat) 124 ug/g, IQR 82 198). The likelihood of pregnancy/infant loss was not different across four UI/Creat groups (<50, 50-149, 150-250, >250 ug/g). The incidence of pre eclampsia, non-proteinuric gestational hypertension, gestational diabetes, glycosuria, anaemia, post-partum haemorrhage, preterm delivery, mode of delivery, being small for gestational age, and large for gestational age did not differ significantly among UI/Creat groups, nor were there any significant differences in the median UI/Creat. We conclude that maternal iodine status was not associated with adverse pregnancy outcomes in a mildly-to-moderately iodine deficient pregnant population. However, in view of the low number of women with pregnancy/infant loss in our study, further research is required. PMID- 29494521 TI - Influence of Single-Nucleotide Polymorphisms in PPAR-delta, PPAR-gamma, and PRKAA2 on the Changes in Anthropometric Indices and Blood Measurements through Exercise-Centered Lifestyle Intervention in Japanese Middle-Aged Men. AB - The purpose of the current study was to examine the influence of single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptor delta (PPAR-delta), PPAR-gamma, and alpha2 isoforms of the catalytic subunit of AMP-activated protein kinase (PRKAA2) on the extent of changes in anthropometric indices and blood measurements through exercise-centered lifestyle intervention in middle-aged men. A total of 109 Japanese middle-aged male subjects (47.0 +/- 0.4 years) participated in the baseline health checkup, 6-month exercise-centered lifestyle intervention, and second checkup conducted several months after the subject completed the intervention. The body mass index (BMI), waist circumference, and clinical measurements, including hemoglobin Alc (HbA1c), triglyceride (TG), alanine aminotransferase (ALT), and gamma-glutamyl transpeptidase (gamma-GTP), were measured at the baseline and second checkup. The three SNPs of PPAR-delta A/G (rs2267668), PPAR-gamma C/G (rs1801282), and PRKAA2 A/G (rs1418442) were determined. Blunted responses in the reduction in the BMI and waist circumference were observed in A/A carriers of PPAR-delta SNP compared with G allele carriers (all p < 0.05). The A/A carriers also displayed less marked improvements in HbA1c, TG, ALT, and gamma-GTP (all p < 0.05). The current results suggest that A/A carriers of PPAR-delta SNP (rs2267668) may enjoy fewer beneficial effects of exercise-centered lifestyle intervention on anthropometric indices and blood measurements. PMID- 29494522 TI - Chemical and Nutritional Characterization of Seed Oil from Cucurbita maxima L. (var. Berrettina) Pumpkin. AB - Pumpkin (Cucurbita spp.) has received considerable attention in recent years because of the nutritional and health-protective value of seed oil. The nutritional composition of pumpkin native to central Italy, locally known as "Berrettina" (Cucurbita maxima L.), was evaluated. In particular, the lipid fraction of seed oil was characterized, and the triacylglycerol (TAG) was thoroughly studied by using a stereospecific procedure to obtain the intrapositional fatty acid composition of the three sn-positions of the glycerol backbone of TAG. Moreover, alkaline hydrolysis was carried out to study the main components of the unsaponifiable fraction, i.e., sterols and alcohols. It was observed that monounsaturated fatty acids and polyunsaturated fatty acids were the most abundant (41.7% and 37.2%, respectively) in Berrettina pumpkin seed oil, with high content of oleic and linoleic acid (41.4% and 37.0%, respectively). The main sterols of Berrettina pumpkin seed oil were Delta7,22,25-stigmastatrienol, Delta7,25-stigmastadienol, and spinasterol; with regard to the alcoholic fraction, triterpenic compounds were more abundant than aliphatic compounds (63.2% vs. 36.8%). The obtained data are useful to evaluate pumpkin seed oil from a nutritional point of view. The oil obtained from the seed could be used as a preservative and as a functional ingredient in different areas, e.g., cosmetics, foods, and nutraceuticals. PMID- 29494524 TI - Region Based CNN for Foreign Object Debris Detection on Airfield Pavement. AB - In this paper, a novel algorithm based on convolutional neural network (CNN) is proposed to detect foreign object debris (FOD) based on optical imaging sensors. It contains two modules, the improved region proposal network (RPN) and spatial transformer network (STN) based CNN classifier. In the improved RPN, some extra select rules are designed and deployed to generate high quality candidates with fewer numbers. Moreover, the efficiency of CNN detector is significantly improved by introducing STN layer. Compared to faster R-CNN and single shot multiBox detector (SSD), the proposed algorithm achieves better result for FOD detection on airfield pavement in the experiment. PMID- 29494523 TI - The Multivariate Regression Statistics Strategy to Investigate Content-Effect Correlation of Multiple Components in Traditional Chinese Medicine Based on a Partial Least Squares Method. AB - Amultivariate regression statisticstrategy was developed to clarify multi components content-effect correlation ofpanaxginseng saponins extract and predict the pharmacological effect by components content. In example 1, firstly, we compared pharmacological effects between panax ginseng saponins extract and individual saponin combinations. Secondly, we examined the anti-platelet aggregation effect in seven different saponin combinations of ginsenoside Rb1, Rg1, Rh, Rd, Ra3 and notoginsenoside R1. Finally, the correlation between anti platelet aggregation and the content of multiple components was analyzed by a partial least squares algorithm. In example 2, firstly, 18 common peaks were identified in ten different batches of panax ginseng saponins extracts from different origins. Then, we investigated the anti-myocardial ischemia reperfusion injury effects of the ten different panax ginseng saponins extracts. Finally, the correlation between the fingerprints and the cardioprotective effects was analyzed by a partial least squares algorithm. Both in example 1 and 2, the relationship between the components content and pharmacological effect was modeled well by the partial least squares regression equations. Importantly, the predicted effect curve was close to the observed data of dot marked on the partial least squares regression model. This study has given evidences that themulti-component content is a promising information for predicting the pharmacological effects of traditional Chinese medicine. PMID- 29494525 TI - Impact of Different Binders on the Roughness, Adhesion Strength, and Other Properties of Mortars with Expanded Cork. AB - The aim of the research that is presented in this paper was to evaluate the physical and mechanical properties of heat-insulating mortars with expanded cork aggregates and different binders. In this work, the measurements of surface roughness and adhesion strength, supported by determination of basic mechanical and physical parameters, such as density, bulk density, open porosity, total porosity, absorbability, thermal conductivity coefficient, compressive strength, flexural strength, and frost resistance of mortars containing expanded oak cork, were performed. The scanning electron microscope (SEM) investigations demonstrated the microstructure, contact zone, and distribution of pores in the heat-insulating mortars containing expanded cork. The results indicated that the addition of expanded cork and different binders in heat-insulating mortars triggers changes in their roughness and adhesion strength. The SEM research confirmed the very good adhesion of the paste to the cork aggregate. PMID- 29494526 TI - An Injectable, Dual Responsive, and Self-Healing Hydrogel Based on Oxidized Sodium Alginate and Hydrazide-Modified Poly(ethyleneglycol). AB - Oxidized sodium alginate is a handily modifiable polysaccharide owing to the pendant aldehyde groups which can form dynamic covalent bonds with amines, acylhydrazines, etc., providing oxidized sodium alginate-based hydrogels with stimuli-responsive properties. However, due to the stiffness and, in particular, the hydrophobicity of sodium alginate dialdehyde at low pH, the mechanical performance and pH stimuli responsiveness of oxidized sodium alginate-based hydrogels are still strictly limited. Herein, we report a new strategy to build an injectable, dual responsive, and self-healing hydrogel based on oxidized sodium alginate and hydrazide-modified poly(ethyleneglycol) (PEG). The hydrazide modified PEG, referred to as PEG-DTP, acts as a macromolecule crosslinker. We found that the presence of PEG-DTP reduces the hydrophobicity of oxidized sodium alginate at low pH so effectively that even a pH-induced reversible sol-gel transitions can be realized. Meanwhile, the disulfide bonds in PEG-DTP endows the hydrogel with the other reversible sol-gel transitions by redox stimuli. In particular, due to the softness of PEG-DTP chains, mechanical performance was also enhanced significantly. Our results indicate we can easily integrate multi stimuli responsiveness, injectability, and self-healing behavior together into an oxidized sodium alginate-based hydrogel merely by mixing an oxidized sodium alginate solution with PEG-DTP solution in certain proportions. PMID- 29494527 TI - Effects of Styrene-Acrylic Sizing on the Mechanical Properties of Carbon Fiber Thermoplastic Towpregs and Their Composites. AB - Thermoplastic towpregs are convenient and scalable raw materials for the fabrication of continuous fiber-reinforced thermoplastic matrix composites. In this paper, the potential to employ epoxy and styrene-acrylic sizing agents was evaluated for the making of carbon fiber thermoplastic towpregs via a powder coating method. The protective effects and thermal stability of these sizing agents were investigated by single fiber tensile test and differential scanning calorimetry (DSC) measurement. The results indicate that the epoxy sizing agent provides better protection to carbon fibers, but it cannot be used for thermoplastic towpreg processing due to its poor chemical stability at high temperature. The bending rigidity of the tows and towpregs with two styrene acrylic sizing agents was measured by cantilever and Kawabata methods. The styrene-acrylic sized towpregs show low torque values, and are suitable for further processing, such as weaving, preforming, and winding. Finally, composite panels were fabricated directly from the towpregs by hot compression molding. Both of the composite panels show superior flexural strength (>400 MPa), flexural modulus (>63 GPa), and interlaminar shear strength (>27 MPa), indicating the applicability of these two styrene-acrylic sizing agents for carbon fiber thermoplastic towpregs. PMID- 29494528 TI - A New Black Carbon Sensor for Dense Air Quality Monitoring Networks. AB - Low-cost air pollution sensors are emerging and increasingly being deployed in densely distributed wireless networks that provide more spatial resolution than is typical in traditional monitoring of ambient air quality. However, a low-cost option to measure black carbon (BC)-a major component of particulate matter pollution associated with adverse human health risks-is missing. This paper presents a new BC sensor designed to fill this gap, the Aerosol Black Carbon Detector (ABCD), which incorporates a compact weatherproof enclosure, solar powered rechargeable battery, and cellular communication to enable long-term, remote operation. This paper also demonstrates a data processing methodology that reduces the ABCD's sensitivity to ambient temperature fluctuations, and therefore improves measurement performance in unconditioned operating environments (e.g., outdoors). A fleet of over 100 ABCDs was operated outdoors in collocation with a commercial BC instrument (Magee Scientific, Model AE33) housed inside a regulatory air quality monitoring station. The measurement performance of the 105 ABCDs is comparable to the AE33. The fleet-average precision and accuracy, expressed in terms of mean absolute percentage error, are 9.2 +/- 0.8% (relative to the fleet average data) and 24.6 +/- 0.9% (relative to the AE33 data), respectively (fleet-average +/- 90% confidence interval). PMID- 29494529 TI - MycoKey Round Table Discussions of Future Directions in Research on Chemical Detection Methods, Genetics and Biodiversity of Mycotoxins. AB - MycoKey, an EU-funded Horizon 2020 project, includes a series of "Roundtable Discussions" to gather information on trending research areas in the field of mycotoxicology. This paper includes summaries of the Roundtable Discussions on Chemical Detection and Monitoring of mycotoxins and on the role of genetics and biodiversity in mycotoxin production. Discussions were managed by using the nominal group discussion technique, which generates numerous ideas and provides a ranking for those identified as the most important. Four questions were posed for each research area, as well as two questions that were common to both discussions. Test kits, usually antibody based, were one major focus of the discussions at the Chemical Detection and Monitoring roundtable because of their many favorable features, e.g., cost, speed and ease of use. The second area of focus for this roundtable was multi-mycotoxin detection protocols and the challenges still to be met to enable these protocols to become methods of choice for regulated mycotoxins. For the genetic and biodiversity group, both the depth and the breadth of trending research areas were notable. For some areas, e.g., microbiome studies, the suggested research questions were primarily of a descriptive nature. In other areas, multiple experimental approaches, e.g., transcriptomics, proteomics, RNAi and gene deletions, are needed to understand the regulation of toxin production and mechanisms underlying successful biological controls. Answers to the research questions will provide starting points for developing acceptable prevention and remediation processes. Forging a partnership between scientists and appropriately-placed communications experts was recognized by both groups as an essential step to communicating risks, while retaining overall confidence in the safety of the food supply and the integrity of the food production chain. PMID- 29494530 TI - Oral Immunization against PEDV with Recombinant Lactobacillus casei Expressing Dendritic Cell-Targeting Peptide Fusing COE Protein of PEDV in Piglets. AB - Porcine epidemic diarrhea (PED) is a highly contagious disease in newborn piglets. In our previous study, a genetically engineered Lactobacillus casei oral vaccine (pPG-COE-DCpep/L393) expressing a dendritic cell (DC)-targeting peptide fused with porcine epidemic diarrhea virus (PEDV) COE antigen was developed. This vaccine induced significant levels of anti-PEDV specific IgG and IgA antibody responses in mice, indicating a potential strategy against PEDV infection. In this study, pPG-COE-DCpep/L393 was used for oral vaccination of newborn piglets against PEDV. We then assessed the immune responses and protection efficacy of pPG-COE-DCpep/L393. An indirect enzyme-linked immunosorbent assay (ELISA) showed that the recombinant Lactobacillus vaccine elicits a specific systemic and mucosal immune response. The T-helper cells mediated by pPG-COE-DCpep/L393 and PEDV infection display a Th1 phenotype. The histopathological results showed that pPG-COE-DCpep/L393 promotes lymphocyte proliferation and effectively protects piglets against PEDV infection. The transforming growth factor-beta level indicated that the recombinant Lactobacillus vaccine plays a role in anti inflammatory responses in mesenteric lymph nodes during PEDV infection. These results show that pPG-COE-DCpep/L393 is a potential vaccine against PEDV infection. PMID- 29494531 TI - Biological Sexing of a 4000-Year-Old Egyptian Mummy Head to Assess the Potential of Nuclear DNA Recovery from the Most Damaged and Limited Forensic Specimens. AB - High throughput sequencing (HTS) has been used for a number of years in the field of paleogenomics to facilitate the recovery of small DNA fragments from ancient specimens. Recently, these techniques have also been applied in forensics, where they have been used for the recovery of mitochondrial DNA sequences from samples where traditional PCR-based assays fail because of the very short length of endogenous DNA molecules. Here, we describe the biological sexing of a ~4000-year old Egyptian mummy using shotgun sequencing and two established methods of biological sex determination (RX and RY), by way of mitochondrial genome analysis as a means of sequence data authentication. This particular case of historical interest increases the potential utility of HTS techniques for forensic purposes by demonstrating that data from the more discriminatory nuclear genome can be recovered from the most damaged specimens, even in cases where mitochondrial DNA cannot be recovered with current PCR-based forensic technologies. Although additional work remains to be done before nuclear DNA recovered via these methods can be used routinely in operational casework for individual identification purposes, these results indicate substantial promise for the retrieval of probative individually identifying DNA data from the most limited and degraded forensic specimens. PMID- 29494532 TI - iTRAQ-Based Identification of Proteins Related to Lignin Synthesis in the Pear Pollinated with Pollen from Different Varieties. AB - Most pears in Anhui Province are a kind of self-incompatible fruit whose quality is strongly influenced by the male pollen. The proteomic variation of Dangshan Su pollinated by different varieties was analysed using the isobaric tag for relative and absolute quantitation (iTRAQ) to investigate the effect of pollination by different varieties on the pear lignin pathway. Among the 3980 proteins identified from the two samples, 139 proteins were identified as differentially expressed proteins (DEPs). Of these proteins, laccase-4 (LAC4), was found to be related with lignin synthesis, and beta-glucosidase 15 (BGLU15) and peroxidase 47 (PER47) were involved in the phenylpropanoid pathway. Moreover, the lignin and stone cell contents were lower in DW (Dangshan Su pollinated by Wonhwang) than those in DJ (Dangshan Su pollinated by Jingbaili). The effect of pollination on the synthesis of lignin through the regulation of the expression of PER47, BGLU15 and LAC4 ultimately affects the formation of stone cells and the fruit quality. We report for the first time that different pollinations influence the protein expression profile in the Dangshan Su pear, and this result provides some new epididymal targets for regulating the synthesis of lignin, regulating the content of stone cells and improving the quality of the pears. PMID- 29494534 TI - RGB-Stack Light Emitting Diode Modules with Transparent Glass Circuit Board and Oil Encapsulation. AB - The light emitting diode (LED) is widely used in modern solid-state lighting applications, and its output efficiency is closely related to the submounts' material properties. Most submounts used today, such as low-power printed circuit boards (PCBs) or high-power metal core printed circuit boards (MCPCBs), are not transparent and seriously decrease the output light extraction. To meet the requirements of high light output and better color mixing, a three-dimensional (3 D) stacked flip-chip (FC) LED module is proposed and demonstrated. To realize light penetration and mixing, the mentioned 3-D vertically stacking RGB LEDs use transparent glass as FC package submounts called glass circuit boards (GCB). Light emitted from each GCB stacked LEDs passes through each other and thus exhibits good output efficiency and homogeneous light-mixing characteristics. In this work, the parasitic problem of heat accumulation, which caused by the poor thermal conductivity of GCB and leads to a serious decrease in output efficiency, is solved by a proposed transparent cooling oil encapsulation (OCP) method. PMID- 29494533 TI - ATG5 Promotes Death Signaling in Response to the Cyclic Depsipeptides Coibamide A and Apratoxin A. AB - Our understanding of autophagy and lysosomal function has been greatly enhanced by the discovery of natural product structures that can serve as chemical probes to reveal new patterns of signal transduction in cells. Coibamide A is a cytotoxic marine natural product that induces mTOR-independent autophagy as an adaptive stress response that precedes cell death. Autophagy-related (ATG) protein 5 (ATG5) is required for coibamide-induced autophagy but not required for coibamide-induced apoptosis. Using wild-type and autophagy-deficient mouse embryonic fibroblasts (MEFs) we demonstrate that coibamide-induced toxicity is delayed in ATG5-/- cells relative to ATG5+/+ cells. Time-dependent changes in annexin V staining, membrane integrity, metabolic capacity and caspase activation indicated that MEFs with a functional autophagy pathway are more sensitive to coibamide A. This pattern could be distinguished from autophagy modulators that induce acute ER stress (thapsigargin, tunicamycin), ATP depletion (oligomycin A) or mTORC1 inhibition (rapamycin), but was shared with the Sec61 inhibitor apratoxin A. Coibamide- or apratoxin-induced cell stress was further distinguished from the action of thapsigargin by a pattern of early LC3-II accumulation in the absence of CHOP or BiP expression. Time-dependent changes in ATG5-ATG12, PARP1 and caspase-3 expression patterns were consistent with the conversion of ATG5 to a pro-death signal in response to both compounds. PMID- 29494535 TI - Trimethylamine-N-Oxide (TMAO)-Induced Impairment of Cardiomyocyte Function and the Protective Role of Urolithin B-Glucuronide. AB - One of the most recently proposed candidates as a potential trigger for cardiovascular diseases is trimethylamine-N-oxide (TMAO). Possible direct effects of TMAO on myocardial tissue, independent of vascular damage, have been only partially explored so far. In the present study, we assessed the detrimental direct effects of TMAO on cardiomyocyte contractility and intracellular calcium dynamics, and the ability of urolithin B-glucuronide (Uro B-gluc) in counteracting TMAO-induced cell damage. Cell mechanics and calcium transients were measured, and ultrastructural analysis was performed in ventricular cardiomyocytes isolated from the heart of normal adult rats. Cells were either untreated, exposed to TMAO, or to TMAO and Uro B-gluc. TMAO exposure worsened cardiomyocyte mechanics and intracellular calcium handling, as documented by the decrease in the fraction of shortening (FS) and the maximal rate of shortening and re-lengthening, associated with reduced efficiency in the intracellular calcium removal. Ultrastructurally, TMAO-treated cardiomyocytes also exhibited glycogen accumulation, a higher number of mitochondria and lipofuscin-like pigment deposition, suggesting an altered cellular energetic metabolism and a higher rate of protein oxidative damage, respectively. Uro B-gluc led to a complete recovery of cellular contractility and calcium dynamics, and morphologically to a reduced glycogen accumulation. We demonstrated for the first time a direct negative role of TMAO on cardiomyocyte functional properties and the ability of Uro B-gluc in counteracting these detrimental effects. PMID- 29494536 TI - Periconceptional Folic Acid Supplementation Benefit to Development of Early Sensory-Motor Function through Increase DNA Methylation in Rat Offspring. AB - Periconceptional maternal folate levels may alter DNA methylation patterns and health outcomes in offspring. We hypothesized that maternal folic acid supplementation alters fetal neural development through DNA methylation in the fetal brain. Twenty-eight rats were randomly assigned to four groups: three groups of the female rats were fed folate-normal, folate-deficient or folate supplemented diets from seven days before mating to delivery. In another group, folic acid supplementation diet short-period group was fed a folate-normal diet, except for 10 days (begin mating) when this group was fed a folate-supplemented diet. After delivery, the diets were changed to folate-normal diet for all four groups. The cliff avoidance and forelimb grip tests were used to assess sensory motor function of rat offspring. The results indicate that maternal folic acid supplementation improved the early development of sensory-motor function in offspring. Maternal folic acid supplementation increased the methylation potential, global DNA methylation (5-mC) and DNA methyltransferase expression and activity in the brains of the offspring. In conclusion, maternal folic acid supplementation increases DNA methylation pattern in offspring brain and improves the early development of sensory-motor function. PMID- 29494537 TI - Characteristics of Effective Interventions Promoting Healthy Eating for Pre Schoolers in Childcare Settings: An Umbrella Review. AB - Early Childhood Education and Care (ECEC) settings have a pivotal role in shaping children's dietary food habits by providing the contextual environment within which they develop these behaviours. This study examines systematic reviews for (1) the effectiveness of interventions to promote healthy eating in children aged 2-5 years attending centre-based childcare; (2) intervention characteristics which are associated with promoting healthy eating and; (3) recommendations for child-health policies and practices. An Umbrella review of systematic reviews was undertaken using a standardized search strategy in ten databases. Twelve systematic reviews were examined using validated critical appraisal and data extraction tools. Children's dietary food intake and food choices were significantly influenced. Interventions to prevent obesity did not significantly change children's anthropometric measures or had mixed results. Evidence was more convincing if interventions were multi-component, addressed physical activity and diet, targeted individual-level and environmental-level determinants and engaged parents. Positive outcomes were mostly facilitated by researchers/external experts and these results were not replicated when implemented in centres by ECEC providers without this support. The translation of expert-led interventions into practice warrants further exploration of implementation drivers and barriers. Based on the evidence reviewed, recommendations are made to inform child-health directed practices and policies. PMID- 29494538 TI - Systematic Review of Vitamin D and Hypertensive Disorders of Pregnancy. AB - This narrative systematic review evaluates growing evidence of an association between low maternal vitamin D status and increased risk of hypertensive disorders. The inclusion of interventional, observational, and dietary studies on vitamin D and all hypertensive disorders of pregnancy is a novel aspect of this review, providing a unique contribution to an intensively-researched area that still lacks a definitive conclusion. To date, trial evidence supports a protective effect of combined vitamin D and calcium supplementation against preeclampsia. Conflicting data for an association of vitamin D with gestational hypertensive disorders in observational studies arises from a number of sources, including large heterogeneity between study designs, lack of adherence to standardized perinatal outcome definitions, variable quality of analytical data for 25-hydroxyvitamin D (25(OH)D), and inconsistent data reporting of vitamin D status. While evidence does appear to lean towards an increased risk of gestational hypertensive disorders at 25(OH)D concentrations <50 nmol/L, caution should be exercised with dosing in trials, given the lack of data on long-term safety. The possibility that a fairly narrow target range for circulating 25(OH)D for achievement of clinically-relevant improvements requires further exploration. As hypertension alone, and not preeclampsia specifically, limits intrauterine growth, evaluation of the relationship between vitamin D status and all terms of hypertension in pregnancy is a clinically relevant area for research and should be prioritised in future randomised trials. PMID- 29494539 TI - Use of Table Sugar and Artificial Sweeteners in Brazil: National Dietary Survey 2008-2009. AB - The study aimed to describe the use of table sugar and artificial sweeteners (AS) in Brazil. A representative sample (n = 32,749) of individuals aged > 10 years was examined from the Brazilian National Dietary Survey (2008-2009). Participants reported whether they use table sugar, AS, both, or none as sweeteners for their foods and beverages. Energy intake and the contribution of selected food groups to energy intake were evaluated according to the type of sweetener reported. Sample weights and design effects were considered in the analysis. The majority of the population (85.7%) used sugar to sweeten foods and beverages, 7.6% used AS, and 5.1% utilized both products. The use of AS was more frequent among the elderly (20%), women (10% versus 5.5%), overweight individuals (10% versus 6%), those who live in urban areas (8.5% versus 3%), and those who belong to the highest income quartile (14% versus 1.6%), compared with men, normal weight individuals, those who live in rural areas, and those who belong to the first income quartile, respectively. Overall, the mean daily energy intake of individuals using only sugar was approximately 16% higher than those who used AS exclusively. The contribution of staple foods to daily energy intake was higher in individuals who used sugar than those who used AS. PMID- 29494540 TI - Wide Swath Stereo Mapping from Gaofen-1 Wide-Field-View (WFV) Images Using Calibration. AB - The development of Earth observation systems has changed the nature of survey and mapping products, as well as the methods for updating maps. Among optical satellite mapping methods, the multiline array stereo and agile stereo modes are the most common methods for acquiring stereo images. However, differences in temporal resolution and spatial coverage limit their application. In terms of this issue, our study takes advantage of the wide spatial coverage and high revisit frequencies of wide swath images and aims at verifying the feasibility of stereo mapping with the wide swath stereo mode and reaching a reliable stereo accuracy level using calibration. In contrast with classic stereo modes, the wide swath stereo mode is characterized by both a wide spatial coverage and high temporal resolution and is capable of obtaining a wide range of stereo images over a short period. In this study, Gaofen-1 (GF-1) wide-field-view (WFV) images, with total imaging widths of 800 km, multispectral resolutions of 16 m and revisit periods of four days, are used for wide swath stereo mapping. To acquire a high-accuracy digital surface model (DSM), the nonlinear system distortion in the GF-1 WFV images is detected and compensated for in advance. The elevation accuracy of the wide swath stereo mode of the GF-1 WFV images can be improved from 103 m to 30 m for a DSM with proper calibration, meeting the demands for 1:250,000 scale mapping and rapid topographic map updates and showing improved efficacy for satellite imaging. PMID- 29494541 TI - Optical Fibre NO2 Sensor Based on Lutetium Bisphthalocyanine in a Mesoporous Silica Matrix. AB - In this article, we describe a NO2 sensor consisting of a coating based on lutetium bisphthalocyanine (LuPc2) in mesoporous silica. The sensor exploits the absorption spectrum change of this material which strongly and reversibly decreases in contact with NO2. NO2 is measured by following the amplitude change in the reflected spectrum of the coating deposited on the tip of a silica fibre. As diffusion of NO2 in LuPc2 is slow, the response time could be slow. To reduce it, the active molecules are dispersed in a mesoporous silica matrix deposited by a sol-gel process (Evaporation Induced Self Assembly) avoiding the formation of large crystals. Doing so, the response is fairly fast. As the recovery is slow at room temperature, the recovery time is reduced by exposure to UV light at 365 nm. This UV light is directly introduced in the fibre yielding a practical sensor sensitive to NO2 in the ppm range suitable for pollution monitoring. PMID- 29494542 TI - A Foot-Mounted Inertial Measurement Unit (IMU) Positioning Algorithm Based on Magnetic Constraint. AB - With the development of related applications, indoor positioning techniques have been more and more widely developed. Based on Wi-Fi, Bluetooth low energy (BLE) and geomagnetism, indoor positioning techniques often rely on the physical location of fingerprint information. The focus and difficulty of establishing the fingerprint database are in obtaining a relatively accurate physical location with as little given information as possible. This paper presents a foot-mounted inertial measurement unit (IMU) positioning algorithm under the loop closure constraint based on magnetic information. It can provide relatively reliable position information without maps and geomagnetic information and provides a relatively accurate coordinate for the collection of a fingerprint database. In the experiment, the features extracted by the multi-level Fourier transform method proposed in this paper are validated and the validity of loop closure matching is tested with a RANSAC-based method. Moreover, the loop closure detection results show that the cumulative error of the trajectory processed by the graph optimization algorithm is significantly suppressed, presenting a good accuracy. The average error of the trajectory under loop closure constraint is controlled below 2.15 m. PMID- 29494543 TI - Online Sensor Drift Compensation for E-Nose Systems Using Domain Adaptation and Extreme Learning Machine. AB - Sensor drift is a common issue in E-Nose systems and various drift compensation methods have received fruitful results in recent years. Although the accuracy for recognizing diverse gases under drift conditions has been largely enhanced, few of these methods considered online processing scenarios. In this paper, we focus on building online drift compensation model by transforming two domain adaptation based methods into their online learning versions, which allow the recognition models to adapt to the changes of sensor responses in a time-efficient manner without losing the high accuracy. Experimental results using three different settings confirm that the proposed methods save large processing time when compared with their offline versions, and outperform other drift compensation methods in recognition accuracy. PMID- 29494544 TI - Modeling and Analysis of a Combined Stress-Vibration Fiber Bragg Grating Sensor. AB - A combined stress-vibration sensor was developed to measure stress and vibration simultaneously based on fiber Bragg grating (FBG) technology. The sensor is composed of two FBGs and a stainless steel plate with a special design. The two FBGs sense vibration and stress and the sensor can realize temperature compensation by itself. The stainless steel plate can significantly increase sensitivity of vibration measurement. Theoretical analysis and Finite Element Method (FEM) were used to analyze the sensor's working mechanism. As demonstrated with analysis, the obtained sensor has working range of 0-6000 Hz for vibration sensing and 0-100 MPa for stress sensing, respectively. The corresponding sensitivity for vibration is 0.46 pm/g and the resulted stress sensitivity is 5.94 pm/MPa, while the nonlinearity error for vibration and stress measurement is 0.77% and 1.02%, respectively. Compared to general FBGs, the vibration sensitivity of this sensor is 26.2 times higher. Therefore, the developed sensor can be used to concurrently detect vibration and stress. As this sensor has height of 1 mm and weight of 1.15 g, it is beneficial for minimization and integration. PMID- 29494545 TI - Facile Quantification and Identification Techniques for Reducing Gases over a Wide Concentration Range Using a MOS Sensor in Temperature-Cycled Operation. AB - Dedicated methods for quantification and identification of reducing gases based on model-based temperature-cycled operation (TCO) using a single commercial MOS gas sensor are presented. During high temperature phases the sensor surface is highly oxidized, yielding a significant sensitivity increase after switching to lower temperatures (differential surface reduction, DSR). For low concentrations, the slope of the logarithmic conductance during this low-temperature phase is evaluated and can directly be used for quantification. For higher concentrations, the time constant for reaching a stable conductance during the same low temperature phase is evaluated. Both signals represent the reaction rate of the reducing gas on the strongly oxidized surface at this low temperature and provide a linear calibration curve, which is exceptional for MOS sensors. By determining these reaction rates on different low-temperature plateaus and applying pattern recognition, the resulting footprint can be used for identification of different gases. All methods are tested over a wide concentration range from 10 ppb to 100 ppm (4 orders of magnitude) for four different reducing gases (CO, H2, ammonia and benzene) using randomized gas exposures. PMID- 29494546 TI - Effects of ReadiSorb L-GSH in Altering Granulomatous Responses against Mycobacterium tuberculosis Infection. AB - Mycobacterium tuberculosis (M. tb), a rod-shaped acid-fast bacterium, is the causative agent of tuberculosis (TB). TB remains one of the leading causes of morbidity and mortality worldwide. Additionally, approximately one-third of the world's population has latent tuberculosis infection (LTBI) as a result of the body's primary mechanism of defense against M. tb infection, the formation of a granuloma. A granuloma is the aggregation of immune cells that encapsulate the bacteria to keep them localized to prevent further infection and thus the bacteria become quiescent. However, if an individual becomes immunocompromised, they become more susceptible to M. tb, which may lead to bacterial reactivation and an active infection, because the host is no longer able to generate adequate immune responses. In this study, we examined liposomal glutathione's (L-GSH) effectiveness in promoting the formation of solid, stable granulomas. We assessed this ability by generating in vitro human granulomas constructed from peripheral blood mononuclear cells (PBMCs) that were derived from healthy subjects and testing their granulomatous effector responses against both M. bovis bacille Calmette-Guerin (BCG) and the highly virulent Erdman strain of M. tb. Additionally, we measured the survival and immune characteristics of the Erdman strain of M. tb in THP-1 originated macrophages as well as in vitro granulomas generated from individuals from type 2 diabetes (T2DM). Our results demonstrate that L-GSH treatment can decrease the intracellular survival of both BCG and virulent M. tb, as well as downregulate the levels of overexpressed proinflammatory cytokines delegated from the granulomas derived from not only healthy subjects but also individuals with T2DM. PMID- 29494547 TI - Biochemical and Physiological Characteristics of Photosynthesis in Plants of Two Calathea Species. AB - Plants of the genus Calathea possess many leaf colors, and they are economically important because they are widely used as ornamentals for interior landscaping. Physiological performances and photosynthetic capacities of C. insignis and C. makoyana were investigated. The photosynthetic efficiencies of C. insignis and C. makoyana were significantly increased when the photosynthetic photon flux density (PPFD) increased from 0 to 600 MUmol photons.m-2.s-1 and became saturated with a further increase in the PPFD. The two Calathea species had lower values of both the light saturation point and maximal photosynthetic rate, which indicated that they are shade plants. No significant differences in predawn Fv/Fm values (close to 0.8) were observed between dark-green (DG) and light-green (LG) leaf sectors in all tested leaves. However, the effective quantum yield of photosystem II largely decreased as the PPFD increased. An increase in the apparent photosynthetic electron transport rate was observed in both species to a maximum at 600 MUmol.m-2.s-1 PPFD, following by a decrease to 1500 MUmol.m-2.s-1 PPFD. Compared to LG leaf extracts, DG leaf extracts contained higher levels of chlorophyll (Chl) a, Chl b, Chls a + b, carotenoids (Cars), anthocyanins (Ants), flavonoids (Flas), and polyphenols (PPs) in all plants, except for the Ant, Fla and PP contents of C. insignis plants. Calathea insignis also contained significantly higher levels of total protein than did C. makoyana. The adjusted normalized difference vegetation index (NDVI), photochemical reflectance index (PRI), red-green, and flavonol index (FlavI) were significantly correlated to leaf Chls a + b, Cars, Ants, and Flas in C. makoyana, respectively, and can be used as indicators to characterize the physiology of these plants. PMID- 29494548 TI - Nanosystems in Edible Coatings: A Novel Strategy for Food Preservation. AB - Currently, nanotechnology represents an important tool and an efficient option for extending the shelf life of foods. Reducing particle size to nanometric scale gives materials distinct and improved properties compared to larger systems. For food applications, this technology allows the incorporation of hydrophilic and lipophilic substances with antimicrobial and antioxidant properties that can be released during storage periods to increase the shelf life of diverse products, including whole and fresh-cut fruits and vegetables, nuts, seeds, and cheese, among others. Edible coatings are usually prepared with natural polymers that are non-toxic, economical, and readily available. Nanosystems, in contrast, may also be prepared with biodegradable synthetic polymers, and liquid and solid lipids at room temperature. In this review, recent developments in the use of such nanosystems as nanoparticles, nanotubes, nanocomposites, and nanoemulsions, are discussed critically. The use of polymers as the support matrix for nanodispersions to form edible coatings for food preservation is also analyzed, but the central purpose of the article is to describe available information on nanosystems and their use in different food substrates to help formulators in their work. PMID- 29494549 TI - Kinases and Cancer. AB - Protein kinases are a large family of enzymes catalyzing protein phosphorylation. The human genome contains 518 protein kinase genes, 478 of which belong to the classical protein kinase family and 40 are atypical protein kinases [...]. PMID- 29494550 TI - Aged Mouse Cortical Microglia Display an Activation Profile Suggesting Immunotolerogenic Functions. AB - Microglia are the resident immune cells of the central nervous system (CNS) and participate in physiological and pathological processes. Their unique developmental nature suggests age-dependent structural and functional impairments that might contribute to neurodegenerative diseases. In the present study, we addressed the age-dependent changes in cortical microglia gene expression patterns and the expression of M1- and M2-like activation markers. Iba1 immunohistochemistry, isolation of cortical microglia followed by fluorescence activated cell sorting and RNA isolation to analyze transcriptional changes in aged cortical microglia was performed. We provide evidence that aging is associated with decreased numbers of cortical microglia and the establishment of a distinct microglia activation profile including upregulation of Ifi204, Lilrb4, Arhgap, Oas1a, Cd244 and Ildr2. Moreover, flow cytometry revealed that aged cortical microglia express increased levels of Cd206 and Cd36. The data presented in the current study indicate that aged mouse cortical microglia adopt a distinct activation profile, which suggests immunosuppressive and immuno-tolerogenic functions. PMID- 29494551 TI - Low Cost Efficient Deliverying Video Surveillance Service to Moving Guard for Smart Home. AB - Low-cost video surveillance systems are attractive for Smart Home applications (especially in emerging economies). Those systems use the flexibility of the Internet of Things to operate the video camera only when an intrusion is detected. We are the only ones that focus on the design of protocols based on intelligent agents to communicate the video of an intrusion in real time to the guards by wireless or mobile networks. The goal is to communicate, in real time, the video to the guards who can be moving towards the smart home. However, this communication suffers from sporadic disruptions that difficults the control and drastically reduces user satisfaction and operativity of the system. In a novel way, we have designed a generic software architecture based on design patterns that can be adapted to any hardware in a simple way. The implanted hardware is of very low economic cost; the software frameworks are free. In the experimental tests we have shown that it is possible to communicate to the moving guard, intrusion notifications (by e-mail and by instant messaging), and the first video frames in less than 20 s. In addition, we automatically recovered the frames of video lost in the disruptions in a transparent way to the user, we supported vertical handover processes and we could save energy of the smartphone's battery. However, the most important thing was that the high satisfaction of the people who have used the system. PMID- 29494552 TI - The Complete Plastome Sequence of an Antarctic Bryophyte Sanionia uncinata (Hedw.) Loeske. AB - Organellar genomes of bryophytes are poorly represented with chloroplast genomes of only four mosses, four liverworts and two hornworts having been sequenced and annotated. Moreover, while Antarctic vegetation is dominated by the bryophytes, there are few reports on the plastid genomes for the Antarctic bryophytes. Sanionia uncinata (Hedw.) Loeske is one of the most dominant moss species in the maritime Antarctic. It has been researched as an important marker for ecological studies and as an extremophile plant for studies on stress tolerance. Here, we report the complete plastome sequence of S. uncinata, which can be exploited in comparative studies to identify the lineage-specific divergence across different species. The complete plastome of S. uncinata is 124,374 bp in length with a typical quadripartite structure of 114 unique genes including 82 unique protein coding genes, 37 tRNA genes and four rRNA genes. However, two genes encoding the alpha subunit of RNA polymerase (rpoA) and encoding the cytochrome b6/f complex subunit VIII (petN) were absent. We could identify nuclear genes homologous to those genes, which suggests that rpoA and petN might have been relocated from the chloroplast genome to the nuclear genome. PMID- 29494555 TI - An Empirical Study of Chronic Diseases in the United States: A Visual Analytics Approach. AB - In this research we explore the current state of chronic diseases in the United States, using data from the Centers for Disease Control and Prevention and applying visualization and descriptive analytics techniques. Five main categories of variables are studied, namely chronic disease conditions, behavioral health, mental health, demographics, and overarching conditions. These are analyzed in the context of regions and states within the U.S. to discover possible correlations between variables in several categories. There are widespread variations in the prevalence of diverse chronic diseases, the number of hospitalizations for specific diseases, and the diagnosis and mortality rates for different states. Identifying such correlations is fundamental to developing insights that will help in the creation of targeted management, mitigation, and preventive policies, ultimately minimizing the risks and costs of chronic diseases. As the population ages and individuals suffer from multiple conditions, or comorbidity, it is imperative that the various stakeholders, including the government, non-governmental organizations (NGOs), policy makers, health providers, and society as a whole, address these adverse effects in a timely and efficient manner. PMID- 29494553 TI - Comparison of Tumor- and Bone Marrow-Derived Mesenchymal Stromal/Stem Cells from Patients with High-Grade Osteosarcoma. AB - Osteosarcoma (OS) is suspected to originate from dysfunctional mesenchymal stromal/stem cells (MSC). We sought to identify OS-derived cells (OSDC) with potential cancer stem cell (CSC) properties by comparing OSDC to MSC derived from bone marrow of patients. This study included in vitro characterization with sphere forming assays, differentiation assays, cytogenetic analysis, and in vivo investigations of their tumorigenicity and tumor supportive capacities. Primary cell lines were isolated from nine high-grade OS samples. All primary cell lines demonstrated stromal cell characteristics. Compared to MSC, OSDC presented a higher ability to form sphere clones, indicating a potential CSC phenotype, and were more efficient at differentiation towards osteoblasts. None of the OSDC displayed the complex chromosome rearrangements typical of high grade OS and none of them induced tumors in immunodeficient mice. However, two OSDC demonstrated focused genomic abnormalities. Three out of seven, and six out of seven OSDC showed a supportive role on local tumor development, and on metastatic progression to the lungs, respectively, when co-injected with OS cells in nude mice. The observation of OS-associated stromal cells with rare genetic abnormalities and with the capacity to sustain tumor progression may have implications for future tumor treatments. PMID- 29494554 TI - Molecular Epidemiology of Helicobacter pylori Infection in a Minor Ethnic Group of Vietnam: A Multiethnic, Population-Based Study. AB - The Helicobacter pylori-induced burden of gastric cancer varies based on geographical regions and ethnic grouping. Vietnam is a multiethnic country with the highest incidence of gastric cancer in Southeast Asia, but previous studies focused only on the Kinh ethnic group. A population-based cross-sectional study was conducted using 494 volunteers (18-78 years old), from 13 ethnic groups in Daklak and Lao Cai provinces, Vietnam. H. pylori status was determined by multiple tests (rapid urease test, culture, histology, and serology). cagA and vacA genotypes were determined by PCR-based sequencing. The overall H. pylori infection rate was 38.1%. Multivariate analysis showed that variations in geographical region, age, and ethnicity were independent factors associated with the risk of H. pylori acquisition. Therefore, multicenter, multiethnic, population based study is essential to assess the H. pylori prevalence and its burden in the general population. Only the E De ethnicity carried strains with Western-type CagA (82%) and exhibited significantly lower gastric mucosal inflammation compared to other ethnic groups. However, the histological scores of Western-type CagA and East-Asian-type CagA within the E De group showed no significant differences. Thus, in addition to bacterial virulence factors, host factors are likely to be important determinants for gastric mucosal inflammation and contribute to the Asian enigma. PMID- 29494557 TI - LESS: Link Estimation with Sparse Sampling in Intertidal WSNs. AB - Deploying wireless sensor networks (WSN) in the intertidal area is an effective approach for environmental monitoring. To sustain reliable data delivery in such a dynamic environment, a link quality estimation mechanism is crucial. However, our observations in two real WSN systems deployed in the intertidal areas reveal that link update in routing protocols often suffers from energy and bandwidth waste due to the frequent link quality measurement and updates. In this paper, we carefully investigate the network dynamics using real-world sensor network data and find it feasible to achieve accurate estimation of link quality using sparse sampling. We design and implement a compressive-sensing-based link quality estimation protocol, L E S S , which incorporates both spatial and temporal characteristics of the system to aid the link update in routing protocols. We evaluate L E S S in both real WSN systems and a large-scale simulation, and the results show that L E S S can reduce energy and bandwidth consumption by up to 50 % while still achieving more than 90 % link quality estimation accuracy. PMID- 29494556 TI - Partial Discharge Spectral Characterization in HF, VHF and UHF Bands Using Particle Swarm Optimization. AB - The measurement of partial discharge (PD) signals in the radio frequency (RF) range has gained popularity among utilities and specialized monitoring companies in recent years. Unfortunately, in most of the occasions the data are hidden by noise and coupled interferences that hinder their interpretation and renders them useless especially in acquisition systems in the ultra high frequency (UHF) band where the signals of interest are weak. This paper is focused on a method that uses a selective spectral signal characterization to feature each signal, type of partial discharge or interferences/noise, with the power contained in the most representative frequency bands. The technique can be considered as a dimensionality reduction problem where all the energy information contained in the frequency components is condensed in a reduced number of UHF or high frequency (HF) and very high frequency (VHF) bands. In general, dimensionality reduction methods make the interpretation of results a difficult task because the inherent physical nature of the signal is lost in the process. The proposed selective spectral characterization is a preprocessing tool that facilitates further main processing. The starting point is a clustering of signals that could form the core of a PD monitoring system. Therefore, the dimensionality reduction technique should discover the best frequency bands to enhance the affinity between signals in the same cluster and the differences between signals in different clusters. This is done maximizing the minimum Mahalanobis distance between clusters using particle swarm optimization (PSO). The tool is tested with three sets of experimental signals to demonstrate its capabilities in separating noise and PDs with low signal-to-noise ratio and separating different types of partial discharges measured in the UHF and HF/VHF bands. PMID- 29494558 TI - Magnetometer and Gyroscope Calibration Method with Level Rotation. AB - Micro electro mechanical system (MEMS) gyroscopes and magnetometers are usually integrated into a sensor module or chip and widely used in a variety of applications. In existing integrated gyroscope and magnetometer calibration methods, rotation in all possible orientations is a necessary condition for a good calibration result. However, rotation around two or more axes is difficult to attain, as it is limited by the range of movement of vehicles such as cars, ships, or planes. To solve this problem, this paper proposes an integrated magnetometer and gyroscope calibration method with level rotation. The proposed method presents a redefined magnetometer output model using level attitude. New gyroscope and magnetometer calibration models are then deduced. In addition, a simplified cubature Kalman filter (CKF) is established to estimate calibration parameters. This method possesses important value for application in actual systems, as it only needs level rotation for real-time calibration of gyroscopes and magnetometers. Theoretical analysis and test results verify the validity and feasibility of this method. PMID- 29494559 TI - Filament Breakage Monitoring in Fused Deposition Modeling Using Acoustic Emission Technique. AB - Polymers are being used in a wide range of Additive Manufacturing (AM) applications and have been shown to have tremendous potential for producing complex, individually customized parts. In order to improve part quality, it is essential to identify and monitor the process malfunctions of polymer-based AM. The present work endeavored to develop an alternative method for filament breakage identification in the Fused Deposition Modeling (FDM) AM process. The Acoustic Emission (AE) technique was applied due to the fact that it had the capability of detecting bursting and weak signals, especially from complex background noises. The mechanism of filament breakage was depicted thoroughly. The relationship between the process parameters and critical feed rate was obtained. In addition, the framework of filament breakage detection based on the instantaneous skewness and relative similarity of the AE raw waveform was illustrated. Afterwards, we conducted several filament breakage tests to validate their feasibility and effectiveness. Results revealed that the breakage could be successfully identified. Achievements of the present work could be further used to develop a comprehensive in situ FDM monitoring system with moderate cost. PMID- 29494560 TI - Design and Deployment of Low-Cost Sensors for Monitoring the Water Quality and Fish Behavior in Aquaculture Tanks during the Feeding Process. AB - The monitoring of farming processes can optimize the use of resources and improve its sustainability and profitability. In fish farms, the water quality, tank environment, and fish behavior must be monitored. Wireless sensor networks (WSNs) are a promising option to perform this monitoring. Nevertheless, its high cost is slowing the expansion of its use. In this paper, we propose a set of sensors for monitoring the water quality and fish behavior in aquaculture tanks during the feeding process. The WSN is based on physical sensors, composed of simple electronic components. The system proposed can monitor water quality parameters, tank status, the feed falling and fish swimming depth and velocity. In addition, the system includes a smart algorithm to reduce the energy waste when sending the information from the node to the database. The system is composed of three nodes in each tank that send the information though the local area network to a database on the Internet and a smart algorithm that detects abnormal values and sends alarms when they happen. All the sensors are designed, calibrated, and deployed to ensure its suitability. The greatest efforts have been accomplished with the fish presence sensor. The total cost of the sensors and nodes for the proposed system is less than 90 ?. PMID- 29494561 TI - A Trust-Based Secure Routing Scheme Using the Traceback Approach for Energy Harvesting Wireless Sensor Networks. AB - The Internet of things (IoT) is composed of billions of sensing devices that are subject to threats stemming from increasing reliance on communications technologies. A Trust-Based Secure Routing (TBSR) scheme using the traceback approach is proposed to improve the security of data routing and maximize the use of available energy in Energy-Harvesting Wireless Sensor Networks (EHWSNs). The main contributions of a TBSR are (a) the source nodes send data and notification to sinks through disjoint paths, separately; in such a mechanism, the data and notification can be verified independently to ensure their security. (b) Furthermore, the data and notification adopt a dynamic probability of marking and logging approach during the routing. Therefore, when attacked, the network will adopt the traceback approach to locate and clear malicious nodes to ensure security. The probability of marking is determined based on the level of battery remaining; when nodes harvest more energy, the probability of marking is higher, which can improve network security. Because if the probability of marking is higher, the number of marked nodes on the data packet routing path will be more, and the sink will be more likely to trace back the data packet routing path and find malicious nodes according to this notification. When data packets are routed again, they tend to bypass these malicious nodes, which make the success rate of routing higher and lead to improved network security. When the battery level is low, the probability of marking will be decreased, which is able to save energy. For logging, when the battery level is high, the network adopts a larger probability of marking and smaller probability of logging to transmit notification to the sink, which can reserve enough storage space to meet the storage demand for the period of the battery on low level; when the battery level is low, increasing the probability of logging can reduce energy consumption. After the level of battery remaining is high enough, nodes then send the notification which was logged before to the sink. Compared with past solutions, our results indicate that the performance of the TBSR scheme has been improved comprehensively; it can effectively increase the quantity of notification received by the sink by 20%, increase energy efficiency by 11%, reduce the maximum storage capacity needed by nodes by 33.3% and improve the success rate of routing by approximately 16.30%. PMID- 29494562 TI - Production of Barbari Bread (Traditional Iranian Bread) Using Different Levels of Distillers Dried Grains with Solubles (DDGS) and Sodium Stearoyl Lactate (SSL). AB - Bread is one of the oldest foods known throughout history and even though it is one of the principal types of staple around the world, it usually lacks enough nutrients, including protein and fiber. As such, fortification is one of the best solutions to overcome this problem. Thus, the objective this study was to examine the effect of three levels of distillers dried grains with solubles (DDGS) (0%, 10% and 20%) in conjunction with three levels of SSL (sodium stearoyl lactate) (0%, 2% and 5%) on physical and chemical properties of Barbari bread (traditional Iranian bread). To the best of our knowledge, this is the first study to evaluate DDGS and Sodium Stearoyl-2-Lactilate (SSL), as sources of fortification in Barbari bread. The results showed that incorporation of 20% of DDGS and 0% SSL caused a significant increase in the amount of fiber and protein. As for the physical attributes, using higher amount of DDGS caused a darker color, and as for the texture parameters, the highest firmness was measured when 10% DDGS and 5% of SSL were used. Different Mixolab and Rapid Visco Analyzer (RVA) parameters also were measured with varying results. The findings of this study show that DDGS can be a valuable source of fiber and protein, which can be used as a cost effective source to fortify cereal-based products. PMID- 29494563 TI - Graphene Oxide-Silver Nanocomposite Enhances Cytotoxic and Apoptotic Potential of Salinomycin in Human Ovarian Cancer Stem Cells (OvCSCs): A Novel Approach for Cancer Therapy. AB - The use of graphene to target and eliminate cancer stem cells (CSCs) is an alternative approach to conventional chemotherapy. We show the biomolecule mediated synthesis of reduced graphene oxide-silver nanoparticle nanocomposites (rGO-Ag) using R-phycoerythrin (RPE); the resulting RPE-rGO-Ag was evaluated in human ovarian cancer cells and ovarian cancer stem cells (OvCSCs). The synthesized RPE-rGO-Ag nanocomposite (referred to as rGO-Ag) was characterized using various analytical techniques. rGO-Ag showed significant toxicity towards both ovarian cancer cells and OvCSCs. After 3 weeks of incubating OvCSCs with rGO Ag, the number of A2780 and ALDH+CD133+ colonies was significantly reduced. rGO Ag was toxic to OvCSCs and reduced cell viability by mediating the generation of reactive oxygen species, leakage of lactate dehydrogenase, reduced mitochondrial membrane potential, and enhanced expression of apoptotic genes, leading to mitochondrial dysfunction and possibly triggering apoptosis. rGO-Ag showed significant cytotoxic potential towards highly tumorigenic ALDH+CD133+ cells. The combination of rGO-Ag and salinomycin induced 5-fold higher levels of apoptosis than each treatment alone. A combination of rGO-Ag and salinomycin at very low concentrations may be suitable for selectively killing OvCSCs and sensitizing tumor cells. rGO-Ag may be a novel nano-therapeutic molecule for specific targeting of highly tumorigenic ALDH+CD133+ cells and eliminating CSCs. This study highlights the potential for targeted therapy of tumor-initiating cells. PMID- 29494565 TI - Albumin Overload and PINK1/Parkin Signaling-Related Mitophagy in Renal Tubular Epithelial Cells. AB - BACKGROUND Albumin, as a major urinary protein component, is a risk factor for chronic kidney disease progression. Mitochondrial dysfunction is one of the main causes of albumin-induced proximal tubule cells injury. Mitophagy is considered as a pivotal protective mechanism for the elimination of dysfunctional mitochondria. The objective of this research was to determine whether albumin overload-induced mitochondrial dysfunction can activate PINK1/Parkin-mediated mitophagy in renal tubular epithelial cells (TECs). MATERIAL AND METHODS Immunofluorescence assay and Western blot assay were used to detect the effects of albumin overload on autophagy marker protein LC3. Transmission electron microscopy and Western blot assay were used to investigate the role of albumin in mitochondrial injury. Western blot assay and co-localization of acidic lysosomes and mitochondria assay were employed to detect the activation of mitophagy induced by albumin. Finally, we explored the role of PINK1/Parkin signaling in albumin-induced mitophagy by inhibiting mitophagy by knockdown of PARK2 (Parkin) level. RESULTS Immunofluorescence and Western blot results showed that the expression level of LC3-II increased, and the maximum increase point was observed after 8 h of albumin treatment. Transmission electron microscopy results demonstrated that albumin overload-induced mitochondrial injury and quantity of autophagosomes increased. Additionally, expression of PINK1 and cytosolic cytochrome C increased and mitochondria cytochrome C decreased in the albumin group. The co-localization of acidic lysosomes and mitochondria demonstrated that the number of albumin overload-induced mitophagy-positive dots increased. The transient transfection of PARK2 siRNA result showed knockdown of the expression level of PARK2 can inhibit mitophagy induced by albumin. CONCLUSIONS In conclusion, our study suggests that mitochondrial dysfunction activates the PINK1/Parkin signaling and mitophagy in renal tubular epithelial cells under albumin overload condition. PMID- 29494566 TI - Rabies Vaccine Hesitancy and Deaths Among Pregnant and Breastfeeding Women - Vietnam, 2015-2016. AB - Human rabies deaths are preventable through prompt administration of postexposure prophylaxis (PEP) with rabies immune globulin and rabies vaccine after exposure to a rabid animal (1); there are no known contraindications to receiving PEP (1,2). Despite widespread availability of PEP in Vietnam, in 2015 the Ministry of Health (MoH) received reports of pregnant and breastfeeding women with clinically diagnosed rabies. MoH investigated factors associated with these rabies cases. MoH found that, during 2015-2016, among 169 cases reported in Vietnam, two probable cases of rabies were reported in breastfeeding mothers and four in pregnant women, all of whom had been bitten by dogs. All six patients died. Three of the four pregnant women had cesarean deliveries. One of the three newborns died from complications believed to be unrelated to rabies; the fourth pregnant woman contracted rabies too early in pregnancy for the fetus to be viable. Two of the patients sought care from a medical provider or traditional healer; however, none sought PEP after being bitten. In each case, families reported the patient's fear of risk to the fetus or breastfed child as the primary barrier to receiving PEP. These findings highlight the need for public health messaging about the safety and effectiveness of PEP in preventing rabies among all persons with exposures, including pregnant and breastfeeding women. PMID- 29494564 TI - Translational Advances of Hydrofection by Hydrodynamic Injection. AB - Hydrodynamic gene delivery has proven to be a safe and efficient procedure for gene transfer, able to mediate, in murine model, therapeutic levels of proteins encoded by the transfected gene. In different disease models and targeting distinct organs, it has been demonstrated to revert the pathologic symptoms and signs. The therapeutic potential of hydrofection led different groups to work on the clinical translation of the procedure. In order to prevent the hemodynamic side effects derived from the rapid injection of a large volume, the conditions had to be moderated to make them compatible with its use in mid-size animal models such as rat, hamster and rabbit and large animals as dog, pig and primates. Despite the different approaches performed to adapt the conditions of gene delivery, the results obtained in any of these mid-size and large animals have been poorer than those obtained in murine model. Among these different strategies to reduce the volume employed, the most effective one has been to exclude the vasculature of the target organ and inject the solution directly. This procedure has permitted, by catheterization and surgical procedures in large animals, achieving protein expression levels in tissue close to those achieved in gold standard models. These promising results and the possibility of employing these strategies to transfer gene constructs able to edit genes, such as CRISPR, have renewed the clinical interest of this procedure of gene transfer. In order to translate the hydrodynamic gene delivery to human use, it is demanding the standardization of the procedure conditions and the molecular parameters of evaluation in order to be able to compare the results and establish a homogeneous manner of expressing the data obtained, as 'classic' drugs. PMID- 29494567 TI - CDC Grand Rounds: Promoting Hearing Health Across the Lifespan. AB - Globally, one in three adults has some level of measurable hearing loss, and 1.1 billion young persons are at risk for hearing loss attributable to noise exposure. Although noisy occupations such as construction, mining, and manufacturing are primary causes of hearing loss in adults, nonoccupational noise also can damage hearing. Loud noises can cause permanent hearing loss through metabolic exhaustion or mechanical destruction of the sensory cells within the cochlea. Some of the sounds of daily life, including those made by lawn mowers, recreational vehicles, power tools, and music, might play a role in the decline in hearing health. Hearing loss as a disability largely depends on a person's communication needs and how hearing loss affects the ability to function in a job. The loss of critical middle and high frequencies can significantly impair communication in hearing-critical jobs (e.g., law enforcement and air traffic control). PMID- 29494569 TI - Notes from the Field: HIV Infection Investigation in a Rural Area - West Virginia, 2017. PMID- 29494568 TI - Progress Toward Poliomyelitis Eradication - Nigeria, January-December 2017. AB - Nearly three decades after the World Health Assembly launched the Global Polio Eradication Initiative in 1988, four of the six World Health Organization (WHO) regions have been certified polio-free (1). Nigeria is one of three countries, including Pakistan and Afghanistan, where wild poliovirus (WPV) transmission has never been interrupted. In September 2015, after >1 year without any reported WPV cases, Nigeria was removed from WHO's list of countries with endemic WPV transmission (2); however, during August and September 2016, four type 1 WPV (WPV1) cases were reported from Borno State, a state in northeastern Nigeria experiencing a violent insurgency (3). The Nigerian government, in collaboration with partners, launched a large-scale coordinated response to the outbreak (3). This report describes progress in polio eradication activities in Nigeria during January-December 2017 and updates previous reports (3-5). No WPV cases have been reported in Nigeria since September 2016; the latest case had onset of paralysis on August 21, 2016 (3). However, polio surveillance has not been feasible in insurgent-controlled areas of Borno State. Implementation of new strategies has helped mitigate the challenges of reaching and vaccinating children living in security-compromised areas, and other strategies are planned. Despite these initiatives, however, approximately 130,000-210,000 (28%-45%) of the estimated 469,000 eligible children living in inaccessible areas in 2016 have not been vaccinated. Sustained efforts to optimize surveillance and improve immunization coverage, especially among children in inaccessible areas, are needed. PMID- 29494570 TI - Trichinellosis Outbreak Linked to Consumption of Privately Raised Raw Boar Meat - California, 2017. AB - On January 15, 2017, a hospital physician notified the Alameda County Public Health Department (ACPHD) in California of a patient with a suspected diagnosis of trichinellosis, a roundworm disease transmitted by the consumption of raw or undercooked meat containing Trichinella spp. larvae (1). A family member of the initial patient reported that at least three other friends and family members had been evaluated at area hospitals for fever, myalgia, abdominal pain, diarrhea, and vomiting. The patients had attended a celebration on December 28, 2016, at which several pork dishes were served, including larb, a traditional Laotian raw pork dish, leading the hospital physician to suspect a diagnosis of trichinellosis. Although the event hosts did not know the exact number of attendees, ACPHD identified 29 persons who attended the event and seven persons who did not attend the event, but consumed pork taken home from the event by attendees. The event hosts reported that the meat had come from a domesticated wild boar raised and slaughtered on their private family farm in northern California. ACPHD conducted a case investigation that included identification of additional cases, testing of leftover raw meat, and a retrospective cohort study to identify risk factors for infection. PMID- 29494571 TI - QuickStats: Percentage of Children Aged 1-5 Years Who Had Never Been to a Dentist,* by Age and Year - National Health Interview Survey,? United States, 2006-2016. AB - During 2006-2016, the percentage of children aged 1-5 years who had never seen a dentist decreased as age increased. In 2016, 80.2% of children aged 1 year, 49.7% of children aged 2 years, 28.6% of children aged 3 years, 18.3% of children aged 4 years, and 6.8% of children aged 5 years had never seen a dentist. For all ages, the percentage of children who had never seen a dentist declined from 2006 to 2016. PMID- 29494572 TI - Suicides Among American Indian/Alaska Natives - National Violent Death Reporting System, 18 States, 2003-2014. AB - Suicide disproportionately affects American Indians/Alaska Natives (AI/AN). The suicide rate among AI/AN has been increasing since 2003 (1), and in 2015, AI/AN suicide rates in the 18 states participating in the National Violent Death Reporting System (NVDRS) were 21.5 per 100,000, more than 3.5 times higher than those among racial/ethnic groups with the lowest rates.* To study completed suicides across all ages of AI/AN, NVDRS data collected from 2003 to 2014 were analyzed by comparing differences in suicide characteristics and circumstances between AI/AN and white decedents. Group differences were assessed using chi squared tests and logistic regression. Across multiple demographics, incident characteristics, and circumstances, AI/AN decedents were significantly different from white decedents. More than one third (35.7%) of AI/AN decedents were aged 10 24 years (versus 11.1% of whites). Compared with whites, AI/AN decedents had 6.6 times the odds of living in a nonmetropolitan area, 2.1 times the odds of a positive alcohol toxicology result, and 2.4 times the odds of a suicide of a friend or family member affecting their death. Suicide prevention efforts should incorporate evidence-based, culturally relevant strategies at individual, interpersonal, and community levels (2) and need to account for the heterogeneity among AI/AN communities (3,4). PMID- 29494573 TI - Notes from the Field: Occupational Hazards Associated with Harvesting and Processing Cannabis - Washington, 2015-2016. PMID- 29494574 TI - Data processing, multi-omic pathway mapping, and metabolite activity analysis using XCMS Online. AB - Systems biology is the study of complex living organisms, and as such, analysis on a systems-wide scale involves the collection of information-dense data sets that are representative of an entire phenotype. To uncover dynamic biological mechanisms, bioinformatics tools have become essential to facilitating data interpretation in large-scale analyses. Global metabolomics is one such method for performing systems biology, as metabolites represent the downstream functional products of ongoing biological processes. We have developed XCMS Online, a platform that enables online metabolomics data processing and interpretation. A systems biology workflow recently implemented within XCMS Online enables rapid metabolic pathway mapping using raw metabolomics data for investigating dysregulated metabolic processes. In addition, this platform supports integration of multi-omic (such as genomic and proteomic) data to garner further systems-wide mechanistic insight. Here, we provide an in-depth procedure showing how to effectively navigate and use the systems biology workflow within XCMS Online without a priori knowledge of the platform, including uploading liquid chromatography (LC)-mass spectrometry (MS) data from metabolite-extracted biological samples, defining the job parameters to identify features, correcting for retention time deviations, conducting statistical analysis of features between sample classes and performing predictive metabolic pathway analysis. Additional multi-omics data can be uploaded and overlaid with previously identified pathways to enhance systems-wide analysis of the observed dysregulations. We also describe unique visualization tools to assist in elucidation of statistically significant dysregulated metabolic pathways. Parameter input takes 5-10 min, depending on user experience; data processing typically takes 1-3 h, and data analysis takes ~30 min. PMID- 29494575 TI - Exponential scaling of single-cell RNA-seq in the past decade. AB - Measurement of the transcriptomes of single cells has been feasible for only a few years, but it has become an extremely popular assay. While many types of analysis can be carried out and various questions can be answered by single-cell RNA-seq, a central focus is the ability to survey the diversity of cell types in a sample. Unbiased and reproducible cataloging of gene expression patterns in distinct cell types requires large numbers of cells. Technological developments and protocol improvements have fueled consistent and exponential increases in the number of cells that can be studied in single-cell RNA-seq analyses. In this Perspective, we highlight the key technological developments that have enabled this growth in the data obtained from single-cell RNA-seq experiments. PMID- 29494577 TI - Correction: The BRCT Domain of PARP-1 Is Required for Immunoglobulin Gene Conversion. AB - [This corrects the article DOI: 10.1371/journal.pbio.1000428.]. PMID- 29494576 TI - Preparation of chiral-at-metal catalysts and their use in asymmetric photoredox chemistry. AB - Asymmetric catalysis is a powerful approach for the synthesis of optically active compounds, and visible light constitutes an abundant source of energy to enable chemical transformations, which are often triggered by photoinduced electron transfer (photoredox chemistry). Recently, bis-cyclometalated iridium(III) and rhodium(III) complexes were introduced as a novel class of catalysts for combining asymmetric catalysis with visible-light-induced photoredox chemistry. These catalysts are attractive because of their unusual feature of chirality originating exclusively from a stereogenic metal center, which offers the prospect of an especially effective asymmetric induction upon direct coordination of the substrate to the metal center. As these chiral catalysts contain only achiral ligands, special strategies are required for their synthesis. In this protocol, we describe strategies for preparing two types of chiral-at-metal catalysts, namely the Lambda- and Delta-enantiomers (left- and right-handed propellers, respectively) of the iridium complex IrS and the rhodium complex RhS. Both contain two cyclometalating 5-tert-butyl-2-phenylbenzothiazoles in addition to two acetonitrile ligands and a hexafluorophosphate counterion. The two cyclometalated ligands set the propeller-shaped chiral geometry, but the acetonitriles are labile and can be replaced by substrate molecules. The synthesis protocol consists of three stages: first, preparation of the ligand 5 tert-butyl-2-phenylbenzothiazole; second, preparation of salicylthiazoline (used for iridium) and salicyloxazoline (used for rhodium) chiral auxiliaries; and third, the auxiliary-mediated synthesis of the individual enantiopure Lambda- and Delta-configured catalysts. This class of stereogenic-only-at-metal complexes is of substantial value in the field of asymmetric catalysis, offering stereocontrolled radical reactions based on visible-light-activated photoredox chemistry. Representative examples of visible-light-induced asymmetric catalysis are provided. PMID- 29494578 TI - Inverse tissue mechanics of cell monolayer expansion. AB - Living tissues undergo deformation during morphogenesis. In this process, cells generate mechanical forces that drive the coordinated cell motion and shape changes. Recent advances in experimental and theoretical techniques have enabled in situ measurement of the mechanical forces, but the characterization of mechanical properties that determine how these forces quantitatively affect tissue deformation remains challenging, and this represents a major obstacle for the complete understanding of morphogenesis. Here, we proposed a non-invasive reverse-engineering approach for the estimation of the mechanical properties, by combining tissue mechanics modeling and statistical machine learning. Our strategy is to model the tissue as a continuum mechanical system and to use passive observations of spontaneous tissue deformation and force fields to statistically estimate the model parameters. This method was applied to the analysis of the collective migration of Madin-Darby canine kidney cells, and the tissue flow and force were simultaneously observed by the phase contrast imaging and traction force microscopy. We found that our monolayer elastic model, whose elastic moduli were reverse-engineered, enabled a long-term forecast of the traction force fields when given the tissue flow fields, indicating that the elasticity contributes to the evolution of the tissue stress. Furthermore, we investigated the tissues in which myosin was inhibited by blebbistatin treatment, and observed a several-fold reduction in the elastic moduli. The obtained results validate our framework, which paves the way to the estimation of mechanical properties of living tissues during morphogenesis. PMID- 29494579 TI - Results of the first mapping of soil-transmitted helminths in Benin: Evidence of countrywide hookworm predominance. AB - BACKGROUND: National mapping of soil-transmitted helminth infections (STH) was conducted for the first time in all of the 77 districts of Benin (West Africa) from 2013 to 2015. This mapping aimed to provide basic epidemiological data essential for the implementation of the national strategy against the neglected tropical diseases (NTDs) in the context of achieving the WHO target of controlling these infections by 2020. METHODS: In each district, 5 schools were purposively selected in 5 villages and 50 school-children (25 girls and 25 boys) from ages 8 to 14 years were randomly enrolled in each school. In total, 19,250 stool samples of school children (9,625 girls and 9,625 boys) from 385 schools were examined by Kato-Katz technique. RESULTS: The three major species of STH (hookworm, Ascaris lumbricoides and Trichuris trichiura) were observed with intra and inter-specific variations in the prevalence and the intensity of these parasites. Hookworm infection was present in all of the surveyed districts with an average prevalence of 17.14% (95% CI 16.6%-17.6%). Among the infected schoolchildren, at national level, 90.82%, 6.73% and 2.45% of infections were of light, moderate and heavy parasite intensities respectively. A. lumbricoides infection, with a national average prevalence of 5.35% (95% CI 5.00%-5.60%),was the second most prevalent STH, and 84.37%, 14.27% and 1.36% of the infections were of light, moderate and heavy parasite intensities, respectively. T. trichiura had a national average prevalence of 1.15% (95% CI 0.90%-1.20%) and 80.45%, 13.18% and 6.36% infections were of light, moderate and heavy parasite intensities, respectively. The national cumulative prevalence of the three STH infections was 22.74% (95% CI 22.15%-23.33%), with58.44% (45/77) of the districts requiring mass treatment according to WHO recommendations. In all of the surveyed districts, multiple infections by STH species were common, and boys seemed more at risk of hookworm and Ascaris infections. CONCLUSIONS: This first national mapping provided an overview of the epidemiological pattern of STH infections and was essential for the implementation of a control strategy with an effective preventive chemotherapy treatment (PCT). Results show that while preventive chemotherapy is not indicated for children in 32/77 districts, 43 require annual deworming and two require twice yearly deworming. If no environmental change occurs, and no mass treatment is delivered, prevalence is likely to remain stable for many years owing to poor hygiene and sanitation. PMID- 29494580 TI - Hyperendemic dengue transmission and identification of a locally evolved DENV-3 lineage, Papua New Guinea 2007-2010. AB - BACKGROUND: Dengue is endemic in the Western Pacific and Oceania and the region reports more than 200,000 cases annually. Outbreaks of dengue and severe dengue occur regularly and movement of virus throughout the region has been reported. Disease surveillance systems, however, in many areas are not fully established and dengue incidence is underreported. Dengue epidemiology is likely least understood in Papua New Guinea (PNG), where the prototype DENV-2 strain New Guinea C was first isolated by Sabin in 1944 but where routine surveillance is not undertaken and little incidence and prevalence data is available. METHODOLOGY/PRINCIPAL FINDINGS: Serum samples from individuals with recent acute febrile illness or with non-febrile conditions collected between 2007-2010 were tested for anti-DENV neutralizing antibody. Responses were predominantly multitypic and seroprevalence increased with age, a pattern indicative of endemic dengue. DENV-1, DENV-2 and DENV-3 genomes were detected by RT-PCR within a nine month period and in several instances, two serotypes were identified in individuals sampled within a period of 10 days. Phylogenetic analysis of whole genome sequences identified a DENV-3 Genotype 1 lineage which had evolved on the northern coast of PNG which was likely exported to the western Pacific five years later, in addition to a DENV-2 Cosmopolitan Genotype lineage which had previously circulated in the region. CONCLUSIONS/SIGNIFICANCE: We show that dengue is hyperendemic in PNG and identify an endemic, locally evolved lineage of DENV-3 that was associated with an outbreak of severe dengue in Pacific countries in subsequent years, although severe disease was not identified in PNG. Additional studies need to be undertaken to understand dengue epidemiology and burden of disease in PNG. PMID- 29494581 TI - Diagnostic tools for soil-transmitted helminths control and elimination programs: A pathway for diagnostic product development. PMID- 29494582 TI - Surveillance of antimicrobial consumption in animal production sectors of low- and middle-income countries: Optimizing use and addressing antimicrobial resistance. AB - In a policy forum, Daniel Schar and colleagues discuss the need for surveillance of antimicrobial consumption in animals in low- and middle-income countries and propose the establishment of antimicrobial consumption monitoring systems. PMID- 29494585 TI - Ten simple rules for collaborative lesson development. PMID- 29494584 TI - Tegumentary leishmaniasis and coinfections other than HIV. AB - BACKGROUND: Tegumentary leishmaniasis (TL) is a disease of skin and/or mucosal tissues caused by Leishmania parasites. TL patients may concurrently carry other pathogens, which may influence the clinical outcome of TL. METHODOLOGY AND PRINCIPAL FINDINGS: This review focuses on the frequency of TL coinfections in human populations, interactions between Leishmania and other pathogens in animal models and human subjects, and implications of TL coinfections for clinical practice. For the purpose of this review, TL is defined as all forms of cutaneous (localised, disseminated, or diffuse) and mucocutaneous leishmaniasis. Human immunodeficiency virus (HIV) coinfection, superinfection with skin bacteria, and skin manifestations of visceral leishmaniasis are not included. We searched MEDLINE and other databases and included 73 records: 21 experimental studies in animals and 52 studies about human subjects (mainly cross-sectional and case studies). Several reports describe the frequency of Trypanosoma cruzi coinfection in TL patients in Argentina (about 41%) and the frequency of helminthiasis in TL patients in Brazil (15% to 88%). Different hypotheses have been explored about mechanisms of interaction between different microorganisms, but no clear answers emerge. Such interactions may involve innate immunity coupled with regulatory networks that affect quality and quantity of acquired immune responses. Diagnostic problems may occur when concurrent infections cause similar lesions (e.g., TL and leprosy), when different pathogens are present in the same lesions (e.g., Leishmania and Sporothrix schenckii), or when similarities between phylogenetically close pathogens affect accuracy of diagnostic tests (e.g., serology for leishmaniasis and Chagas disease). Some coinfections (e.g., helminthiasis) appear to reduce the effectiveness of antileishmanial treatment, and drug combinations may cause cumulative adverse effects. CONCLUSIONS AND SIGNIFICANCE: In patients with TL, coinfection is frequent, it can lead to diagnostic errors and delays, and it can influence the effectiveness and safety of treatment. More research is needed to unravel how coinfections interfere with the pathogenesis of TL. PMID- 29494583 TI - Atf3 links loss of epithelial polarity to defects in cell differentiation and cytoarchitecture. AB - Interplay between apicobasal cell polarity modules and the cytoskeleton is critical for differentiation and integrity of epithelia. However, this coordination is poorly understood at the level of gene regulation by transcription factors. Here, we establish the Drosophila activating transcription factor 3 (atf3) as a cell polarity response gene acting downstream of the membrane-associated Scribble polarity complex. Loss of the tumor suppressors Scribble or Dlg1 induces atf3 expression via aPKC but independent of Jun-N terminal kinase (JNK) signaling. Strikingly, removal of Atf3 from Dlg1 deficient cells restores polarized cytoarchitecture, levels and distribution of endosomal trafficking machinery, and differentiation. Conversely, excess Atf3 alters microtubule network, vesicular trafficking and the partition of polarity proteins along the apicobasal axis. Genomic and genetic approaches implicate Atf3 as a regulator of cytoskeleton organization and function, and identify Lamin C as one of its bona fide target genes. By affecting structural features and cell morphology, Atf3 functions in a manner distinct from other transcription factors operating downstream of disrupted cell polarity. PMID- 29494587 TI - Mortality, ethnicity, and country of birth on a national scale, 2001-2013: A retrospective cohort (Scottish Health and Ethnicity Linkage Study). AB - BACKGROUND: Migrant and ethnic minority groups are often assumed to have poor health relative to the majority population. Few countries have the capacity to study a key indicator, mortality, by ethnicity and country of birth. We hypothesized at least 10% differences in mortality by ethnic group in Scotland that would not be wholly attenuated by adjustment for socio-economic factors or country of birth. METHODS AND FINDINGS: We linked the Scottish 2001 Census to mortality data (2001-2013) in 4.62 million people (91% of estimated population), calculating age-adjusted mortality rate ratios (RRs; multiplied by 100 as percentages) with 95% confidence intervals (CIs) for 13 ethnic groups, with the White Scottish group as reference (ethnic group classification follows the Scottish 2001 Census). The Scottish Index of Multiple Deprivation, education status, and household tenure were socio-economic status (SES) confounding variables and born in the UK or Republic of Ireland (UK/RoI) an interacting and confounding variable. Smoking and diabetes data were from a primary care sub sample (about 53,000 people). Males and females in most minority groups had lower age-adjusted mortality RRs than the White Scottish group. The 95% CIs provided good evidence that the RR was more than 10% lower in the following ethnic groups: Other White British (72.3 [95% CI 64.2, 81.3] in males and 75.2 [68.0, 83.2] in females); Other White (80.8 [72.8, 89.8] in males and 76.2 [68.6, 84.7] in females); Indian (62.6 [51.6, 76.0] in males and 60.7 [50.4, 73.1] in females); Pakistani (66.1 [57.4, 76.2] in males and 73.8 [63.7, 85.5] in females); Bangladeshi males (50.7 [32.5, 79.1]); Caribbean females (57.5 [38.5, 85.9]); and Chinese (52.2 [43.7, 62.5] in males and 65.8 [55.3, 78.2] in females). The differences were diminished but not eliminated after adjusting for UK/RoI birth and SES variables. A mortality advantage was evident in all 12 minority groups for those born abroad, but in only 6/12 male groups and 5/12 female groups of those born in the UK/RoI. In the primary care sub-sample, after adjustment for age, UK/RoI born, SES, smoking, and diabetes, the RR was not lower in Indian males (114.7 [95% CI 78.3, 167.9]) and Pakistani females (103.9 [73.9, 145.9]) than in White Scottish males and females, respectively. The main limitations were the inability to include deaths abroad and the small number of deaths in some ethnic minority groups, especially for people born in the UK/RoI. CONCLUSIONS: There was relatively low mortality for many ethnic minority groups compared to the White Scottish majority. The mortality advantage was less clear in UK/RoI born minority group offspring than in immigrants. These differences need explaining, and health-related behaviours seem important. Similar analyses are required internationally to fulfil agreed goals for monitoring, understanding, and improving health in ethnically diverse societies and to apply to health policy, especially on health inequalities and inequities. PMID- 29494586 TI - An evolutionary learning and network approach to identifying key metabolites for osteoarthritis. AB - Metabolomics studies use quantitative analyses of metabolites from body fluids or tissues in order to investigate a sequence of cellular processes and biological systems in response to genetic and environmental influences. This promises an immense potential for a better understanding of the pathogenesis of complex diseases. Most conventional metabolomics analysis methods exam one metabolite at a time and may overlook the synergistic effect of combining multiple metabolites. In this article, we proposed a new bioinformatics framework that infers the non linear synergy among multiple metabolites using a symbolic model and subsequently, identify key metabolites using network analysis. Such a symbolic model is able to represent a complex non-linear relationship among a set of metabolites associated with osteoarthritis (OA) and is automatically learned using an evolutionary algorithm. Applied to the Newfoundland Osteoarthritis Study (NFOAS) dataset, our methodology was able to identify nine key metabolites including some known osteoarthritis-associated metabolites and some novel metabolic markers that have never been reported before. The results demonstrate the effectiveness of our methodology and more importantly, with further investigations, propose new hypotheses that can help better understand the OA disease. PMID- 29494588 TI - speaq 2.0: A complete workflow for high-throughput 1D NMR spectra processing and quantification. AB - Nuclear Magnetic Resonance (NMR) spectroscopy is, together with liquid chromatography-mass spectrometry (LC-MS), the most established platform to perform metabolomics. In contrast to LC-MS however, NMR data is predominantly being processed with commercial software. Meanwhile its data processing remains tedious and dependent on user interventions. As a follow-up to speaq, a previously released workflow for NMR spectral alignment and quantitation, we present speaq 2.0. This completely revised framework to automatically analyze 1D NMR spectra uses wavelets to efficiently summarize the raw spectra with minimal information loss or user interaction. The tool offers a fast and easy workflow that starts with the common approach of peak-picking, followed by grouping, thus avoiding the binning step. This yields a matrix consisting of features, samples and peak values that can be conveniently processed either by using included multivariate statistical functions or by using many other recently developed methods for NMR data analysis. speaq 2.0 facilitates robust and high-throughput metabolomics based on 1D NMR but is also compatible with other NMR frameworks or complementary LC-MS workflows. The methods are benchmarked using a simulated dataset and two publicly available datasets. speaq 2.0 is distributed through the existing speaq R package to provide a complete solution for NMR data processing. The package and the code for the presented case studies are freely available on CRAN (https://cran.r-project.org/package=speaq) and GitHub (https://github.com/beirnaert/speaq). PMID- 29494589 TI - Correction: Defining the genetic susceptibility to cervical neoplasia-A genome wide association study. AB - [This corrects the article DOI: 10.1371/journal.pgen.1006866.]. PMID- 29494590 TI - Receptor recharge time drastically reduces the number of captured particles. AB - Many diverse biological systems are described by randomly moving particles that can be captured by traps in their environment. Examples include neurotransmitters diffusing in the synaptic cleft before binding to receptors and prey roaming an environment before capture by predators. In most cases, the traps cannot capture particles continuously. Rather, each trap must wait a transitory "recharge" time after capturing a particle before additional captures. This recharge time is often overlooked. In the case of instant recharge, the average number of particles captured before they escape grows linearly in the total number of particles. In stark contrast, we prove that for any nonzero recharge time, the average number of captured particles grows at most logarithmically in the total particle number. This is a fundamental effect of recharge, as it holds under very general assumptions on particle motion and spatial domain. Furthermore, we characterize the parameter regime in which a given recharge time will dramatically affect a system, allowing researchers to easily verify if they need to account for recharge in their specific system. Finally, we consider a few examples, including a neural system in which recharge reduces neurotransmitter bindings by several orders of magnitude. PMID- 29494591 TI - Maternal or zygotic: Unveiling the secrets of the Pancrustacea transcription factor zelda. PMID- 29494592 TI - Delays in completion and results reporting of clinical trials under the Paediatric Regulation in the European Union: A cohort study. AB - BACKGROUND: Few medicines have been approved for children, leading to rates of off-label prescribing reported to be as high as 90%. In 2007, the European Union adopted the Paediatric Regulation, which mandates that pharmaceutical companies conduct paediatric studies for all new medicines, unless granted a waiver. We aimed to evaluate the availability of paediatric trial results from studies required under the Paediatric Regulation for new medicines authorised in the EU. METHODS AND FINDINGS: The European Medicines Agency (EMA) public database of paediatric investigation plans was searched for new medicines centrally authorised in the EU between 1 January 2010 and 31 December 2014 with at least 1 required paediatric study. For our study cohort of paediatric clinical trials required for these medicines, we used internal EMA databases and publicly available trial registries to determine changes to the planned completion date or study design, rates of trial completion, time to trial completion, and results reporting (peer-reviewed publication or posting on trial registry). Cox proportional hazards regression models were constructed to examine factors associated with study completion. A total of 326 paediatric clinical trials were required for 122 novel medicines authorised by the EMA between 2010 and 2014. In all, 76% (247/326) of paediatric studies were not planned to be completed until after the initial marketing authorisation. The planned completion dates for 50% (162/326) were further postponed by a median of 2.2 years. Overall, 38% (124/326) of paediatric studies were completed as of 30 November 2017. The rate of trial completion for paediatric studies planned to be completed after initial marketing authorisation was 23% (56/247), versus 86% (68/79) for trials planned to be completed before authorisation (adjusted hazard ratio 0.11; 95% CI 0.06-0.19). Among completed studies, the results were reported in a public registry or in the peer-reviewed literature for 85% (105/124) at a median of 1.1 years after study completion, and 60% (74/124) were published in a peer-reviewed journal. Limitations of this study include the potential lack of generalisability to medicines not authorised by the EMA and the possibility for more of these trials to be completed or published in the future. CONCLUSIONS: The completion of many paediatric studies required under the Paediatric Regulation has been delayed. Paediatric studies planned to be completed after marketing authorisation were associated with a lower likelihood of eventual completion, highlighting the need to examine the implementation of current policies in ensuring timely availability of important paediatric information. PMID- 29494594 TI - Male grower pigs fed cereal soluble dietary fibres display biphasic glucose response and delayed glycaemic response after an oral glucose tolerance test. AB - Acute and sustained soluble dietary fibre (SDF) consumption are both associated with improved glucose tolerance in humans and animal models (e.g. porcine). However, the effects on glucose tolerance in grower pigs, adapted to diets with a combination of SDF have not been studied previously. In this experiment, cereal SDF wheat arabinoxylan (AX) and oat beta-glucan (BG) were fed individually and in combination to determine the effect on glucose tolerance in jugular vein catheterized grower pigs. Five groups of Large White male grower pigs were fed highly digestible diets containing either 10% AX, 10% BG, 5% AX with 5% BG, a model cereal whole wheat flour (WWF), or a control wheat starch diet (WS) with no SDF. Blood was collected via jugular vein catheters over 240 minutes following a feed challenge and an oral glucose tolerance test (OGTT) on two separate days. Postprandial blood samples were used to determine plasma glucose, insulin, non esterified fatty acids (NEFA), glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), peptide tyrosine tyrosine (PYY), ghrelin, glucagon and cortisol concentrations. No dietary effects on glycaemic response were observed following the feed challenge or the OGTT as determined by the area under the curve (AUC). A biphasic glucose and insulin response was detected for all pigs following the OGTT. The current study showed male grower pigs have tight glycaemic control and glucose tolerance regardless of diet. In addition, pigs fed the combined SDF had a reduced GIP response and delayed insulin peak following the feed challenge. Incretin (GLP-1 and GIP) secretion appeared asynchronous reflecting their different enteroendocrine cell locations and response to nutrient absorption. PMID- 29494593 TI - The epidemiology of adolescents living with perinatally acquired HIV: A cross region global cohort analysis. AB - BACKGROUND: Globally, the population of adolescents living with perinatally acquired HIV (APHs) continues to expand. In this study, we pooled data from observational pediatric HIV cohorts and cohort networks, allowing comparisons of adolescents with perinatally acquired HIV in "real-life" settings across multiple regions. We describe the geographic and temporal characteristics and mortality outcomes of APHs across multiple regions, including South America and the Caribbean, North America, Europe, sub-Saharan Africa, and South and Southeast Asia. METHODS AND FINDINGS: Through the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER), individual retrospective longitudinal data from 12 cohort networks were pooled. All children infected with HIV who entered care before age 10 years, were not known to have horizontally acquired HIV, and were followed up beyond age 10 years were included in this analysis conducted from May 2016 to January 2017. Our primary analysis describes patient and treatment characteristics of APHs at key time points, including first HIV associated clinic visit, antiretroviral therapy (ART) start, age 10 years, and last visit, and compares these characteristics by geographic region, country income group (CIG), and birth period. Our secondary analysis describes mortality, transfer out, and lost to follow-up (LTFU) as outcomes at age 15 years, using competing risk analysis. Among the 38,187 APHs included, 51% were female, 79% were from sub-Saharan Africa and 65% lived in low-income countries. APHs from 51 countries were included (Europe: 14 countries and 3,054 APHs; North America: 1 country and 1,032 APHs; South America and the Caribbean: 4 countries and 903 APHs; South and Southeast Asia: 7 countries and 2,902 APHs; sub-Saharan Africa, 25 countries and 30,296 APHs). Observation started as early as 1982 in Europe and 1996 in sub-Saharan Africa, and continued until at least 2014 in all regions. The median (interquartile range [IQR]) duration of adolescent follow-up was 3.1 (1.5 5.2) years for the total cohort and 6.4 (3.6-8.0) years in Europe, 3.7 (2.0-5.4) years in North America, 2.5 (1.2-4.4) years in South and Southeast Asia, 5.0 (2.7 7.5) years in South America and the Caribbean, and 2.1 (0.9-3.8) years in sub Saharan Africa. Median (IQR) age at first visit differed substantially by region, ranging from 0.7 (0.3-2.1) years in North America to 7.1 (5.3-8.6) years in sub Saharan Africa. The median age at ART start varied from 0.9 (0.4-2.6) years in North America to 7.9 (6.0-9.3) years in sub-Saharan Africa. The cumulative incidence estimates (95% confidence interval [CI]) at age 15 years for mortality, transfers out, and LTFU for all APHs were 2.6% (2.4%-2.8%), 15.6% (15.1%-16.0%), and 11.3% (10.9%-11.8%), respectively. Mortality was lowest in Europe (0.8% [0.5% 1.1%]) and highest in South America and the Caribbean (4.4% [3.1%-6.1%]). However, LTFU was lowest in South America and the Caribbean (4.8% [3.4%-6.7%]) and highest in sub-Saharan Africa (13.2% [12.6%-13.7%]). Study limitations include the high LTFU rate in sub-Saharan Africa, which could have affected the comparison of mortality across regions; inclusion of data only for APHs receiving ART from some countries; and unavailability of data from high-burden countries such as Nigeria. CONCLUSION: To our knowledge, our study represents the largest multiregional epidemiological analysis of APHs. Despite probable under ascertained mortality, mortality in APHs remains substantially higher in sub Saharan Africa, South and Southeast Asia, and South America and the Caribbean than in Europe. Collaborations such as CIPHER enable us to monitor current global temporal trends in outcomes over time to inform appropriate policy responses. PMID- 29494595 TI - Ratio of low molecular weight serum adiponectin to the total adiponectin value is associated with type 2 diabetes through its relation to increasing insulin resistance. AB - AIM: Among the three adiponectin isoforms, a lower ratio of high molecular weight (HMW) adiponectin to total adiponectin (TA) is well known to cause insulin resistance and type 2 diabetes (T2D). However, how the levels of other adiponectin isoforms, such as the middle molecular weight (MMW) and low molecular weight (LMW) isoforms, and their relative ratio to TA change in T2D subjects has not been determined. Therefore, we investigated the association of these adiponectin-related parameters with T2D. METHODS: We examined the associations between adiponectin-related parameters and diabetes in a group of 394 T2D subjects and 374 controls (1st group) randomly selected from among the participants in our previous study. The associations between these parameters and the HOMA-IR in a 2nd group, consisting of the subjects remaining in the 1st group after the exclusion of subjects receiving diabetic medication, were also examined. RESULT: In the 1st group, after adjusting for confounding factor, the levels of all the adiponectin isoforms and the HMW/TA ratio were significantly lower among the diabetic subjects than among the controls (all P values < 0.01). On the contrary, the LMW/TA ratio was significantly higher among the diabetic subjects (P < 0.01) and was positively associated with T2D (odds ratio = 8.64, P < 0.01). In the 2nd group, the HMW/TA ratio was inversely associated with the HOMA-IR; however, the LMW/TA ratio was positively associated with the HOMA-IR (beta for LMW/TA ratio = 0.89, SE = 0.24, P < 0.001), similar to the association with T2D. The MMW/TA ratio was not associated with T2D or the HOMA-IR. CONCLUSION: The current investigation demonstrated that, unlike the reduction in the levels of all the adiponectin isoforms and the HMW/TA ratio, an increased LMW/TA ratio was associated with T2D through its relation to insulin resistance. PMID- 29494596 TI - Validation of rK39 immunochromatographic test and direct agglutination test for the diagnosis of Mediterranean visceral leishmaniasis in Spain. AB - BACKGROUND: Visceral leishmaniasis (VL), the most severe form of leishmaniasis, is endemic in Europe with Mediterranean countries reporting endemic status alongside a worrying northward spread. Serological diagnosis, including immunochromatographic test based on the recombinant antigen rK39 (rK39-ICT) and a direct agglutination test (DAT) based on the whole parasite antigen, have been validated in regions with high VL burden, such as eastern Africa and the Indian subcontinent. To date, no studies using a large set of patients have performed an assessment of both methods within Europe. METHODOLOGY/PRINCIPAL FINDINGS: We selected a range of clinical serum samples from patients with confirmed VL (including HIV co-infection), Chagas disease, malaria, other parasitic infections and negative samples (n = 743; years 2009-2015) to test the performance of rK39 ICT rapid test (Kalazar Detect Rapid Test; InBios International, Inc., USA) and DAT (ITM-DAT/VLG; Institute of Tropical Medicine Antwerp, Belgium). An in-house immunofluorescence antibody test (IFAT), was included for comparison. Estimated sensitivities for rK39-ICT and DAT in HIV-negative VL patients were 83.1% [75.1 91.2] and 84.2% [76.3-92.1], respectively. Sensitivity was reduced to 67.3% [52.7 82.0] for rK39 and increased to 91.3% [82.1-100.0] for DAT in HIV/VL co-infected patients. The in-house IFAT was more sensitive in HIV-negative VL patients, 84.2% [76.3-92.1] than in HIV/VL patients, 79.4% [73.3-96.2]. DAT gave 32 false positives in sera from HIV-negative VL suspects, compared to 0 and 2 for rK39 and IFAT, respectively, but correctly detected more HIV/VL patients (42/46) than rK39 (31/46) and IFAT (39/46). CONCLUSIONS/SIGNIFICANCE: Though rK39-ICT and DAT exhibited acceptable sensitivity and specificity a combination with other tests is required for highly sensitive diagnosis of VL cases in Spain. Important variation in the performance of the tests were seen in patients co-infected with HIV or with other parasitic infections. This study can help inform the choice of serological test to be used when screening or diagnosing VL in a European Mediterranean setting. PMID- 29494597 TI - Can scrotal circumference-based selection discard bulls with good productive and reproductive potential? AB - Nonlinear mixed models were used to describe longitudinal scrotal circumference (SC) measurements of Nellore bulls. Models comparisons were based on Akaike's information criterion, Bayesian information criterion, error sum of squares, adjusted R2 and percentage of convergence. Sequentially, the best model was used to compare the SC growth curve in bulls divergently classified according to SC at 18-21 months of age. For this, bulls were classified into five groups: SC < 28cm; 28cm <= SC < 30cm, 30cm <= SC < 32cm, 32cm <= SC < 34cm and SC >= 34cm. Michaelis Menten model showed the best fit according to the mentioned criteria. In this model, beta1 is the asymptotic SC value and beta2 represents the time to half final growth and may be related to sexual precocity. Parameters of the individual estimated growth curves were used to create a new dataset to evaluate the effect of the classification, farms, and year of birth on beta1 and beta2 parameters. Bulls of the largest SC group presented a larger predicted SC along all analyzed periods; nevertheless, smaller SC group showed predicted SC similar to intermediate SC groups (28cm <= SC < 32cm), around 1200 days of age. In this context, bulls classified as improper for reproduction at 18-21 months old can reach a similar condition to those considered as good condition. In terms of classification at 18-21 months, asymptotic SC was similar among groups, farms and years; however, beta2 differed among groups indicating that differences in growth curves are related to sexual precocity. In summary, it seems that selection based on SC at too early ages may lead to discard bulls with suitable reproductive potential. PMID- 29494598 TI - 18F-fluorodeoxyglucose positron-emission tomography (FDG-PET)-Radiomics of metastatic lymph nodes and primary tumor in non-small cell lung cancer (NSCLC) - A prospective externally validated study. AB - BACKGROUND: Lymph node stage prior to treatment is strongly related to disease progression and poor prognosis in non-small cell lung cancer (NSCLC). However, few studies have investigated metabolic imaging features derived from pre radiotherapy 18F-fluorodeoxyglucose (FDG) positron-emission tomography (PET) of metastatic hilar/mediastinal lymph nodes (LNs). We hypothesized that these would provide complementary prognostic information to FDG-PET descriptors to only the primary tumor (tumor). METHODS: Two independent cohorts of 262 and 50 node positive NSCLC patients were used for model development and validation. Image features (i.e. Radiomics) including shape and size, first order statistics, texture, and intensity-volume histograms (IVH) (http://www.radiomics.io/) were evaluated by univariable Cox regression on the development cohort. Prognostic modeling was conducted with a 10-fold cross-validated least absolute shrinkage and selection operator (LASSO), automatically selecting amongst FDG-PET-Radiomics descriptors from (1) tumor, (2) LNs or (3) both structures. Performance was assessed with the concordance-index. Development data are publicly available at www.cancerdata.org and Dryad (doi:10.5061/dryad.752153b). RESULTS: Common SUV descriptors (maximum, peak, and mean) were significantly related to overall survival when extracted from LNs, as were LN volume and tumor load (summed tumor and LNs' volumes), though this was not true for either SUV metrics or tumor's volume. Feature selection exclusively from imaging information based on FDG-PET Radiomics, exhibited performances of (1) 0.53 -external 0.54, when derived from the tumor, (2) 0.62 -external 0.56 from LNs, and (3) 0.62 -external 0.59 from both structures, including at least one feature from each sub-category, except IVH. CONCLUSION: Combining imaging information based on FDG-PET-Radiomics features from tumors and LNs is desirable to achieve a higher prognostic discriminative power for NSCLC. PMID- 29494599 TI - Autofluorescence microscopy for paired-matched morphological and molecular identification of individual chigger mites (Acari: Trombiculidae), the vectors of scrub typhus. AB - BACKGROUND: Conventional gold standard characterization of chigger mites involves chemical preparation procedures (i.e. specimen clearing) for visualization of morphological features, which however contributes to destruction of the arthropod host DNA and any endosymbiont or pathogen DNA harbored within the specimen. METHODOLOGY/PRINCIPAL FINDINGS: In this study, a novel work flow based on autofluorescence microscopy was developed to enable identification of trombiculid mites to the species level on the basis of morphological traits without any special preparation, while preserving the mite DNA for subsequent genotyping. A panel of 16 specifically selected fluorescence microscopy images of mite features from available identification keys served for complete chigger morphological identification to the species level, and was paired with corresponding genotype data. We evaluated and validated this method for paired chigger morphological and genotypic ID using the mitochondrial cytochrome c oxidase subunit I gene (coi) in 113 chigger specimens representing 12 species and 7 genera (Leptotrombidium, Ascoschoengastia, Gahrliepia, Walchia, Blankaartia, Schoengastia and Schoutedenichia) from the Lao People's Democratic Republic (Lao PDR) to the species level (complete characterization), and 153 chiggers from 5 genera (Leptotrombidium, Ascoschoengastia, Helenicula, Schoengastiella and Walchia) from Thailand, Cambodia and Lao PDR to the genus level. A phylogenetic tree constructed from 77 coi gene sequences (approximately 640 bp length, n = 52 new coi sequences and n = 25 downloaded from GenBank), demonstrated clear grouping of assigned morphotypes at the genus levels, although evidence of both genetic polymorphism and morphological plasticity was found. CONCLUSIONS/SIGNIFICANCE: With this new methodology, we provided the largest collection of characterized coi gene sequences for trombiculid mites to date, and almost doubled the number of available characterized coi gene sequences with a single study. The ability to provide paired phenotypic-genotypic data is of central importance for future characterization of mites and dissecting the molecular epidemiology of mites transmitting diseases like scrub typhus. PMID- 29494600 TI - Computational de novo discovery of distinguishing genes for biological processes and cell types in complex tissues. AB - Bulk tissue samples examined by gene expression studies are usually heterogeneous. The data gained from these samples display the confounding patterns of mixtures consisting of multiple cell types or similar cell types in various functional states, which hinders the elucidation of the molecular mechanisms underlying complex biological phenomena. A realistic approach to compensate for the limitations of experimentally separating homogenous cell populations from mixed tissues is to computationally identify cell-type specific patterns from bulk, heterogeneous measurements. We designed the CellDistinguisher algorithm to analyze the gene expression data of mixed samples, identifying genes that best distinguish biological processes and cell types. Coupled with a deconvolution algorithm that takes cell type specific gene lists as input, we show that CellDistinguisher performs as well as partial deconvolution algorithms in predicting cell type composition without the need for prior knowledge of cell type signatures. This approach is also better in predicting cell type signatures than the one-step traditional complete deconvolution methods. To illustrate its wide applicability, the algorithm was tested on multiple publicly available data sets. In each case, CellDistinguisher identified genes reflecting biological processes typical for the tissues and development stages of interest and estimated the sample compositions accurately. PMID- 29494602 TI - Runoff response to climate change and human activities in a typical karst watershed, SW China. AB - This study aims to reveal the runoff variation characteristics of long time series in a karst region, analyse comprehensively its different driving factors, and estimate quantitatively the contribution rates of climate change and human activities to net runoff variation. Liudong river basin, a typical karst watershed in southwest China, is the study site. Statistical methods, such as linear fitting, the Morlet wavelet analysis, normalized curve and double mass curve, are applied to analyse the runoff of the watershed. Results show that the runoff in the karst watershed during the research period exhibits a three-stage change and the abrupt change points are the years 1981 and 2007: (1) 1968-1980, the runoff initially exhibited a trend of sustained decreasing and then an abrupt fluctuation. The runoff was obviously destroyed through precipitation-producing processes. Improper land utilisation and serious forest and grass destruction intensified the fluctuation variation amplitude of the runoff. (2) 1981-2006, the changing processes of runoff and precipitation exhibited good synchronism. Precipitation significantly affected runoff variation and human activities had a slight interference degree. (3) 2007-2013, the fluctuation range of runoff was considerably smaller than that of precipitation. The significant growth of forest and grassland areas and the increase in water consumption mitigated runoff fluctuation and greatly diminished runoff variation amplitude. According to calculation, the relative contribution rates of precipitation and human activities to net runoff variation with 1981-2007 as the reference period were 81% and 181% in average, respectively, during 1968-1980, and -117% and 217% in average, respectively, during 2007-2013. In general, the analysis of runoff variation trend and of the contribution rate of its main influencing factors in the typical karst watershed for nearly half a century may be significant to solve the drought problem in the karst region and for the sustainable development of the drainage basin. PMID- 29494601 TI - Mining telemonitored physiological data and patient-reported outcomes of congestive heart failure patients. AB - This paper addresses patient-reported outcomes (PROs) and telemonitoring in congestive heart failure (CHF), both increasingly important topics. The interest in CHF trials is shifting from hard end-points such as hospitalization and mortality, to softer end-points such health-related quality of life. However, the relation of these softer end-points to objective parameters is not well studied. Telemonitoring is suitable for collecting both patient-reported outcomes and objective parameters. Most telemonitoring studies, however, do not take full advantage of the available sensor technology and intelligent data analysis. The Chiron clinical observational study was performed among 24 CHF patients (17 men and 7 women, age 62.9 +/- 9.4 years, 15 NYHA class II and 9 class III, 10 of ishaemic, aetiology, 6 dilated, 2 valvular, and 6 of multiple aetiologies or cardiomyopathy) in Italy and UK. A large number of physiological and ambient parameters were collected by wearable and other devices, together with PROs describing how well the patients felt, over 1,086 days of observation. The resulting data were mined for relations between the objective parameters and the PROs. The objective parameters (humidity, ambient temperature, blood pressure, SpO2, and sweeting intensity) could predict the PROs with accuracies up to 86% and AUC up to 0.83, making this the first report providing evidence for ambient and physiological parameters to be objectively related to PROs in CHF patients. We also analyzed the relations in the predictive models, gaining some insights into what affects the feeling of health, which was also generally not attempted in previous investigations. The paper strongly points to the possibility of using PROs as primary end-points in future trials. PMID- 29494604 TI - Demand driven salt clean-up in a molten salt fast reactor - Defining a priority list. AB - The PUREX technology based on aqueous processes is currently the leading reprocessing technology in nuclear energy systems. It seems to be the most developed and established process for light water reactor fuel and the use of solid fuel. However, demand driven development of the nuclear system opens the way to liquid fuelled reactors, and disruptive technology development through the application of an integrated fuel cycle with a direct link to reactor operation. The possibilities of this new concept for innovative reprocessing technology development are analysed, the boundary conditions are discussed, and the economic as well as the neutron physical optimization parameters of the process are elucidated. Reactor physical knowledge of the influence of different elements on the neutron economy of the reactor is required. Using an innovative study approach, an element priority list for the salt clean-up is developed, which indicates that separation of Neodymium and Caesium is desirable, as they contribute almost 50% to the loss of criticality. Separating Zirconium and Samarium in addition from the fuel salt would remove nearly 80% of the loss of criticality due to fission products. The theoretical study is followed by a qualitative discussion of the different, demand driven optimization strategies which could satisfy the conflicting interests of sustainable reactor operation, efficient chemical processing for the salt clean-up, and the related economic as well as chemical engineering consequences. A new, innovative approach of balancing the throughput through salt processing based on a low number of separation process steps is developed. Next steps for the development of an economically viable salt clean-up process are identified. PMID- 29494603 TI - Lipopolysaccharide-binding protein (LBP) can reverse the amyloid state of fibrin seen or induced in Parkinson's disease. AB - The thrombin-induced polymerisation of fibrinogen to form fibrin is well established as a late stage of blood clotting. It is known that Parkinson's Disease (PD) is accompanied by dysregulation in blood clotting, but it is less widely known as a coagulopathy. In recent work, we showed that the presence of tiny amounts of bacterial lipopolysaccharide (LPS) in healthy individuals could cause clots to adopt an amyloid form, and this could be observed via scanning electron microscopy (SEM) or via the fluorescence of thioflavin-T. This could be prevented by the prior addition of lipopolysaccharide-binding protein (LBP). We had also observed by SEM this unusual clotting in the blood of patients with Parkinson's Disease. We hypothesised, and here show, that this too can be prevented by LBP in the context of PD. This adds further evidence implicating inflammatory microbial cell wall products as an accompaniment to the disease, and may be part of its aetiology. This may lead to novel treatment strategies in PD designed to target microbes and their products. PMID- 29494605 TI - Copolymer-1 enhances cognitive performance in young adult rats. AB - Cognitive impairment is a dysfunction observed as a sequel of various neurodegenerative diseases, as well as a concomitant element in the elderly stages of life. In clinical settings, this malfunction is identified as mild cognitive impairment. Previous studies have suggested that cognitive impairment could be the result of a reduction in the expression of brain-derived neurotrophic factor (BDNF) and/or immune dysfunction. Copolymer-1 (Cop-1) is an FDA-approved synthetic peptide capable of inducing the activation of Th2/3 cells, which are able to release BDNF, as well as to migrate and accumulate in the brain. In this study, we evaluated the effect of Cop-1 immunization on improvement of cognition in adult rats. For this purpose, we performed four experiments. We evaluated the effect of Cop-1 immunization on learning/memory using the Morris water maze for spatial memory and autoshaping for associative memory in 3- or 6-month-old rats. BDNF concentrations at the hippocampus were determined by ELISA. Cop-1 immunization induced a significant improvement of spatial memory and associative memory in 6-month-old rats. Likewise, Cop-1 improved spatial memory and associative memory when animals were immunized at 3 months and evaluated at 6 months old. Additionally, Cop-1 induced a significant increase in BDNF levels at the hippocampus. To our knowledge, the present investigation reports the first instance of Cop-1 treatment enhancing cognitive function in normal young adult rats, suggesting that Cop-1 may be a practical therapeutic strategy potentially useful for age- or disease-related cognitive impairment. PMID- 29494606 TI - Onchocerca volvulus infection and serological prevalence, ocular onchocerciasis and parasite transmission in northern and central Togo after decades of Simulium damnosum s.l. vector control and mass drug administration of ivermectin. AB - BACKGROUND: Mass drug administration (MDA) of ivermectin has become the main intervention to control onchocerciasis or "river blindness". In Togo, after many years of MDA, Onchocerca volvulus infection has declined dramatically, and elimination appears achievable, but in certain river basins the current situation remains unknown. We have conducted parasitological, serological, ophthalmological, and entomological assessments in northern and central Togo within the river basins of Oti, Keran and Mo. METHODOLOGY/PRINCIPAL FINDINGS: Examinations were completed in 1,455 participants from 11 onchocerciasis sentinel villages, and O. volvulus transmission by Simulium damnosum sensu lato (s.l.) was evaluated. In children (aged 1-10 years), the prevalence of microfilariae (Mf) was 2.3% and in adults it ranged from 5.1 to 13.3%. Positive IgG4 responses to O. volvulus adult (crude) worm antigen (OvAg) and the recombinant Ov16 antigen were in all-ages 48.7% and 34.4%, and 29.1% and 14.9% in children, respectively. In the river basin villages of Keran, Mo and Oti, the IgG4 seroprevalences to OvAg in children were 51.7%, 23.5% and 12.7%, respectively, and to the Ov16 antigen 33.3% (Keran) and 5.2% (Oti). Onchocerciasis ocular lesions (punctate keratitis, evolving iridocyclitis and chorioretinitis) were observed in children and young adults. O. volvulus-specific DNA (Ov150) was detected by poolscreen in vector samples collected from Tchitchira/Keran(22.8%), Bouzalo/Mo(11.3%), Baghan/Mo(2.9%) and Pancerys/Oti(4.9%); prevalences of O. volvulus infection in S. damnosum s.l. were, respectively, 1%, 0.5%, 0.1% and 0.2%. CONCLUSIONS/SIGNIFICANCE: In the northern and central river basins in Togo, interruption of O. volvulus transmission has not yet been attained. Patent O. volvulus infections, positive antibody responses, progressive ocular onchocerciasis were diagnosed, and parasite transmission by S. damnosum s.l. occurred close to the survey locations. Future interventions may require approaches selectively targeted to non-complying endemic populations, to the seasonality of parasite transmission and national onchocerciasis control programs should harmonize cross-border MDA as a coordinated intervention. PMID- 29494607 TI - Predicting the accumulation of storage compounds by Rhodococcus jostii RHA1 in the feast-famine growth cycles using genome-scale flux balance analysis. AB - Feast-famine cycles in biological wastewater resource recovery systems select for bacterial species that accumulate intracellular storage compounds such as poly beta-hydroxybutyrate (PHB), glycogen, and triacylglycerols (TAG). These species survive better the famine phase and resume rapid substrate uptake at the beginning of the feast phase faster than microorganisms unable to accumulate storage. However, ecophysiological conditions favouring the accumulation of either storage compounds remain to be clarified, and predictive capabilities need to be developed to eventually rationally design reactors producing these compounds. Using a genome-scale metabolic modelling approach, the storage metabolism of Rhodococcus jostii RHA1 was investigated for steady-state feast famine cycles on glucose and acetate as the sole carbon sources. R. jostii RHA1 is capable of accumulating the three storage compounds (PHB, TAG, and glycogen) simultaneously. According to the experimental observations, when glucose was the substrate, feast phase chemical oxygen demand (COD) accumulation was similar for the three storage compounds; when acetate was the substrate, however, PHB accumulation was 3 times higher than TAG accumulation and essentially no glycogen was accumulated. These results were simulated using the genome-scale metabolic model of R. jostii RHA1 (iMT1174) by means of flux balance analysis (FBA) to determine the objective functions capable of predicting these behaviours. Maximization of the growth rate was set as the main objective function, while minimization of total reaction fluxes and minimization of metabolic adjustment (environmental MOMA) were considered as the sub-objective functions. The environmental MOMA sub-objective performed better than the minimization of total reaction fluxes sub-objective function at predicting the mixture of storage compounds accumulated. Additional experiments with 13C-labelled bicarbonate (HCO3 ) found that the fluxes through the central metabolism reactions during the feast phases were similar to the ones during the famine phases on acetate due to similarity in the carbon sources in the feast and famine phases (i.e., acetate and poly-beta-hydroxybutyrate, respectively); this suggests that the environmental MOMA sub-objective function could be used to analyze successive environmental conditions such as the feast and famine cycles while the metabolically similar carbon sources are taken up by microorganisms. PMID- 29494608 TI - Chlorella diet alters mitochondrial cardiolipin contents differentially in organs of Danio rerio analyzed by a lipidomics approach. AB - The zebrafish (Danio rerio) is an important and widely used vertebrate model organism for the study of human diseases which include disorders caused by dysfunctional mitochondria. Mitochondria play an essential role in both energy metabolism and apoptosis, which are mediated through a mitochondrial phospholipid cardiolipin (CL). In order to examine the cardiolipin profile in the zebrafish model, we developed a CL analysis platform by using liquid chromatography-mass spectrometry (LC-MS). Meanwhile, we tested whether chlorella diet would alter the CL profile in the larval fish, and in various organs of the adult fish. The results showed that chlorella diet increased the chain length of CL in larval fish. In the adult zebrafish, the distribution patterns of CL species were similar between the adult brain and eye tissues, and between the heart and muscles. Interestingly, monolyso-cardiolipin (MLCL) was not detected in brain and eyes but found in other examined tissues, indicating a different remodeling mechanism to maintain the CL integrity. While the adult zebrafish were fed with chlorella for four weeks, the CL distribution showed an increase of the species of saturated acyl chains in the brain and eyes, but a decrease in the other organs. Moreover, chlorella diet led to a decrease of MLCL percentage in organs except the non-MLCL-containing brain and eyes. The CL analysis in the zebrafish provides an important tool for studying the mechanism of mitochondria diseases, and may also be useful for testing medical regimens targeting against the Barth Syndrome. PMID- 29494609 TI - A modified artificial neural network based prediction technique for tropospheric radio refractivity. AB - Radio refractivity plays a significant role in the development and design of radio systems for attaining the best level of performance. Refractivity in the troposphere is one of the features affecting electromagnetic waves, and hence the communication system interrupts. In this work, a modified artificial neural network (ANN) based model is applied to predict the refractivity. The suggested ANN model comprises three modules: the data preparation module, the feature selection module, and the forecast module. The first module applies pre processing to make the data compatible for the feature selection module. The second module discards irrelevant and redundant data from the input set. The third module uses ANN for prediction. The ANN model applies a sigmoid activation function and a multi-variate auto regressive model to update the weights during the training process. In this work, the refractivity is predicted and estimated based on ten years (2002-2011) of meteorological data, such as the temperature, pressure, and humidity, obtained from the Pakistan Meteorological Department (PMD), Islamabad. The refractivity is estimated using the method suggested by the International Telecommunication Union (ITU). The refractivity is predicted for the year 2012 using the database of the previous ten years, with the help of ANN. The ANN model is implemented in MATLAB. Next, the estimated and predicted refractivity levels are validated against each other. The predicted and actual values (PMD data) of the atmospheric parameters agree with each other well, and demonstrate the accuracy of the proposed ANN method. It was further found that all parameters have a strong relationship with refractivity, in particular the temperature and humidity. The refractivity values are higher during the rainy season owing to a strong association with the relative humidity. Therefore, it is important to properly cater the signal communication system during hot and humid weather. Based on the results, the proposed ANN method can be used to develop a refractivity database, which is highly important in a radio communication system. PMID- 29494610 TI - Transcriptome-based signature predicts the effect of taxol in serous ovarian cancer. AB - Taxol is a widely used chemotherapy drug used clinically for ovarian cancer, although the response to Taxol among individuals varies due to the heterogeneity among ovarian cancer patients. In this work, we analyzed differences in the prognostic effect of gene expression and Taxol usage in the Cancer Genome Atlas (TCGA) dataset and identified specific genes associated with the Taxol effect. Using the Cox regression model, a risk model (Taxol score) was developed to assess the outcome of ovarian cancer patients who underwent chemotherapy with Taxol. According to the results, survival was significantly associated with the Taxol score. Moreover, the patients in the high and low Taxol score group had different responses to Taxol. This result was further validated in another two independent datasets. The correlation between clinicopathological indicators was also analyzed, and we determined that the Taxol score is not associated with age, pathological stage, or Taxol treatment, while there was significant correlation with tumor size and grade. Gene Set Enrichment Analysis (GSEA) showed that various signaling pathways including ECM receptor, drug metabolism and ascorbate metabolism pathways were significantly enriched in the high Taxol score group. Collectively, these results indicate that the model is robust for predicting the effectiveness of Taxol by reflecting the various cell statuses of serous ovarian carcinoma. PMID- 29494611 TI - Association between health service use and diarrhoea management approach among caregivers of under-five children in Nepal. AB - INTRODUCTION: Diarrhoea among children under-five is a serious public health problem in many developing countries, including Nepal. This study aimed to examine the association between health service utilization and diarrhoea management approaches among children under-five years in Nepal. METHODS: The combined 2001, 2006 and 2011 Nepal Demographic and Health Survey (NDHS) data sets were examined and the sample included 2,655 children aged 0-59 months who had diarrhoea 2-weeks prior to the each survey. Multilevel logistic regression analyses that adjust for clustering and sampling weight were used to examine the association between health service utilization and diarrhoea management approaches (Oral Rehydration Solution, increased fluids and/or continued feeding). RESULTS: The prevalence of extra fluids decreased significantly from 27% in 2001 to 15% in 2011 while that of ORS increased significantly from 32% in 2001 to 40% in 2011. The prevalence of continued feeding fluctuated between 83 89%. Multivariate analysis revealed that caregivers whose children received treatment or advice from health care providers during diarrhoea were 5.78 times more likely to treat diarrhoea with Oral Rehydration Solution (ORS) [adjusted Odds Ratio (aOR) 5.78, 95% confidence interval (CI) 4.50, 7.44], 1.56 (aOR 1.56, 95% CI 1.19, 2.05) times more likely to offer extra fluids, and 2.25 (aOR 2.25, 95% CI 1.50, 3.39) times more likely to use continued feeding than those who did not seek advice. CONCLUSIONS: Our findings indicate that health service utilization significantly improves diarrhoea management among under-five children. However, a broader national diarrhoeal disease control program to further reduce diarrhoea related morbidity and mortality in Nepal should focus on educating caregivers about the importance of the use of ORS as well as increase fluid intake to children under-five years with diarrhoea. PMID- 29494612 TI - An outbreak of Leishmania major from an endemic to a non-endemic region posed a public health threat in Iraq from 2014-2017: Epidemiological, molecular and phylogenetic studies. AB - BACKGROUND: Cutaneous leishmaniasis (CL) is a neglected worldwide, zoonotic, vector-borne, tropical disease that is a threat to public health. This threat may spread from endemic to non-endemic areas. Current research has exploited epidemiological, molecular and phylogenetical studies to determine the danger of an outbreak of CL in the borderline area between northern and central Iraq from 2014-2017. METHODOLOGY/PRINCIPAL FINDINGS: For the first time, using sequence analysis of the cytochrome b gene, the occurrence of CL in the borderline area between northern and central Iraq was confirmed to be due to Leishmania major. The phylogenetic analysis indicated that it was closely related to the L. major MRHO/IR/75/ER strain in Iran. CONCLUSIONS AND SIGNIFICANCE: In conclusion, the genotype confirmation of the L. major strain will improve our understanding of the epidemiology of the disease. This is important for facilitating control programs to prevent the further spread of CL. Furthermore, this area could be considered as a model for further research on the risk of global CL epidemics in other non-endemic countries where both reservoir hosts and sandfly vectors are present. PMID- 29494613 TI - Advancing the integration of spatial data to map human and natural drivers on coral reefs. AB - A major challenge for coral reef conservation and management is understanding how a wide range of interacting human and natural drivers cumulatively impact and shape these ecosystems. Despite the importance of understanding these interactions, a methodological framework to synthesize spatially explicit data of such drivers is lacking. To fill this gap, we established a transferable data synthesis methodology to integrate spatial data on environmental and anthropogenic drivers of coral reefs, and applied this methodology to a case study location-the Main Hawaiian Islands (MHI). Environmental drivers were derived from time series (2002-2013) of climatological ranges and anomalies of remotely sensed sea surface temperature, chlorophyll-a, irradiance, and wave power. Anthropogenic drivers were characterized using empirically derived and modeled datasets of spatial fisheries catch, sedimentation, nutrient input, new development, habitat modification, and invasive species. Within our case study system, resulting driver maps showed high spatial heterogeneity across the MHI, with anthropogenic drivers generally greatest and most widespread on O'ahu, where 70% of the state's population resides, while sedimentation and nutrients were dominant in less populated islands. Together, the spatial integration of environmental and anthropogenic driver data described here provides a first-ever synthetic approach to visualize how the drivers of coral reef state vary in space and demonstrates a methodological framework for implementation of this approach in other regions of the world. By quantifying and synthesizing spatial drivers of change on coral reefs, we provide an avenue for further research to understand how drivers determine reef diversity and resilience, which can ultimately inform policies to protect coral reefs. PMID- 29494615 TI - Correction: Correlated receptor transport processes buffer single-cell heterogeneity. AB - [This corrects the article DOI: 10.1371/journal.pcbi.1005779.]. PMID- 29494614 TI - A novel potential role of pituitary gonadotropins in the pathogenesis of human colorectal cancer. AB - BACKGROUND: Colorectal cancer (CRC) is a leading cause of death in the western world, and its incidence increases with patient age. It is also known that with age there occur changes in the levels of certain hormones, including an increase in the secretion of pituitary gonadotropins (PtGs) as a result of the loss of gonadal hormone feedback. We recently reported that functional PtG receptors are expressed in human lung cancer cells, rhabdomyosarcoma cells, and malignant hematopoietic stem cells. FINDINGS: Here we report for the first time that the receptors for follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are expressed in primary tumor samples isolated from CRC patients as well as in the established human CRC cell lines HTC116 and HTB37. Moreover, we also report that PtGs stimulate chemotaxis, adhesion, and proliferation of these cell lines. CONCLUSIONS: Our results suggest that PtGs play an important and underappreciated role in CRC pathogenesis, and we call for further studies to better define their role in gastrointestinal malignancies and their direct effect on putative CRC cancer stem cells. PMID- 29494616 TI - Genetic polymorphism and expression of HSF1 gene is significantly associated with breast cancer in Saudi females. AB - The transcription factor, heat shock factor 1 (HSF1), influences the expression of heat shock proteins as well as other activities like the induction of tumor suppressor genes, signal transduction pathway, and glucose metabolism. We hypothesized that single nucleotide polymorphisms (SNPs) in HSF1 gene might affect its expression or function which might have an influence on the development of breast cancer. The study group included 242 individuals (146 breast cancer patients and 96 healthy controls). From the cancer patients, genomic DNA was extracted from 96 blood samples and 50 Formalin-Fixed Paraffin Embedded (FFPE) tissues, while from the controls DNA were extracted from blood only. Genotype was carried out for four SNPs in the HSF1 gene (rs78202224, rs35253356, rs4977219 and rs34404564) using Taqman genotyping assay method. The HSF1 expression was investigated using immunohistochemistry on FFPE tissues (cancer tissue and adjacent normal tissue). The SNP rs78202224 (G>T) was significantly associated with increased risk of breast cancer. The combined TT + GT genotype (OR: 6.91; p: 0.035) and the T allele showed high risk (OR: 5.81; p:0.0085) for breast cancer development. The SNP rs34404564 (A>G) had a protective effect against the development of breast cancer. The genotype AG (OR: 0.41; p = 0.0059) and GG+AG (OR: 0.52; p: 0.026) occurred at a significantly lower frequency in the breast cancer patients compared to the frequency in healthy controls. No significant relationship was identified between either rs35253356 (A>G) or rs4977219 (A>C) and breast cancer in Saudi. The HSF1 protein expression was higher in all invasive and in situ breast carcinoma compared to the normal tissue. A stronger positive staining for HSF1 was found in the nucleus compared to the cytoplasm. Our results show that HSF1 gene expression is elevated in breast cancer tissue and two of the studied SNPs correlate significantly with cancer development. PMID- 29494618 TI - Recombination and peak jumping. AB - We show that genetic recombination can be a powerful mechanism for escaping suboptimal peaks. Recent studies of empirical fitness landscapes reveal complex gene interactions and multiple peaks. However, classical work on recombination largely ignores the effect of complex gene interactions. Briefly, we restrict to fitness landscapes where the global peak is difficult to access. If the optimal genotype can be generated by shuffling genes present in the population, then recombination will produce the genotype. If, in addition, recombination is sufficiently rare, then the proportion of the genotype is expected to increase. Specifically, we consider landscapes where shuffling of suboptimal peak genotypes can produce the global peak genotype. The advantage of recombination we identify has no correspondence for 2-locus systems or for smooth landscapes. The effect of recombination indicated is sometimes extreme, also for rare recombination, in the sense that shutting off recombination could result in the organism failing to adapt. A standard question about recombination is whether the mechanism tends to accelerate or decelerate adaptation. However, we argue that extreme effects may be more important than how the majority falls. In a limited sense, our result can be considered a support for Sewall Wright's view that adaptation sometimes works better in subdivided populations. PMID- 29494617 TI - Effects of lead stress on the growth, physiology, and cellular structure of privet seedlings. AB - In this study, we investigated the effects of different lead (Pb) concentrations (0, 200, 600, 1000, 1400 mg kg-1 soil) on the growth, ion enrichment in the tissues, photosynthetic and physiological characteristics, and cellular structures of privet seedlings. We observed that with the increase in the concentrations of Pb, the growth of privet seedlings was restricted, and the level of Pb ion increased in the roots, stem, and leaves of the seedlings; however, most of the ions were concentrated in the roots. Moreover, a decreasing trend was observed for chlorophyll a, chlorophyll b, total chlorophyll, net photosynthesis (Pn), transpiration rate (Tr), stomatal conductance (Gs), sub stomatal CO2 concentration (Ci), maximal photochemical efficiency (Fv/Fm), photochemical quenching (qP), and quantum efficiency of photosystem II (PhiPSII). In contrast, the carotene levels, minimum fluorescence (F0), and non photochemical quenching (qN) showed an increasing trend. Under Pb stress, the chloroplasts were swollen and deformed, and the thylakoid lamellae were gradually expanded, resulting in separation from the cell wall and eventual shrinkage of the nucleus. Using multiple linear regression analysis, we found that the content of Pb in the leaves exerted the maximum effect on the seedling growth. We observed that the decrease in photosynthetic activation energy, increase in pressure because of the excess activation energy, and decrease in the transpiration rate could result in maximum effect on the photosynthetic abilities of the seedlings under Pb stress. Our results should help in better understanding of the effects of heavy metals on plants and in assessing their potential for use in bioremediation. PMID- 29494620 TI - Using machine-learning to optimize phase contrast in a low-cost cellphone microscope. AB - Cellphones equipped with high-quality cameras and powerful CPUs as well as GPUs are widespread. This opens new prospects to use such existing computational and imaging resources to perform medical diagnosis in developing countries at a very low cost. Many relevant samples, like biological cells or waterborn parasites, are almost fully transparent. As they do not exhibit absorption, but alter the light's phase only, they are almost invisible in brightfield microscopy. Expensive equipment and procedures for microscopic contrasting or sample staining often are not available. Dedicated illumination approaches, tailored to the sample under investigation help to boost the contrast. This is achieved by a programmable illumination source, which also allows to measure the phase gradient using the differential phase contrast (DPC) [1, 2] or even the quantitative phase using the derived qDPC approach [3]. By applying machine-learning techniques, such as a convolutional neural network (CNN), it is possible to learn a relationship between samples to be examined and its optimal light source shapes, in order to increase e.g. phase contrast, from a given dataset to enable real time applications. For the experimental setup, we developed a 3D-printed smartphone microscope for less than 100 $ using off-the-shelf components only such as a low-cost video projector. The fully automated system assures true Koehler illumination with an LCD as the condenser aperture and a reversed smartphone lens as the microscope objective. We show that the effect of a varied light source shape, using the pre-trained CNN, does not only improve the phase contrast, but also the impression of an improvement in optical resolution without adding any special optics, as demonstrated by measurements. PMID- 29494619 TI - Shared activity patterns arising at genetic susceptibility loci reveal underlying genomic and cellular architecture of human disease. AB - Genetic variants underlying complex traits, including disease susceptibility, are enriched within the transcriptional regulatory elements, promoters and enhancers. There is emerging evidence that regulatory elements associated with particular traits or diseases share similar patterns of transcriptional activity. Accordingly, shared transcriptional activity (coexpression) may help prioritise loci associated with a given trait, and help to identify underlying biological processes. Using cap analysis of gene expression (CAGE) profiles of promoter- and enhancer-derived RNAs across 1824 human samples, we have analysed coexpression of RNAs originating from trait-associated regulatory regions using a novel quantitative method (network density analysis; NDA). For most traits studied, phenotype-associated variants in regulatory regions were linked to tightly coexpressed networks that are likely to share important functional characteristics. Coexpression provides a new signal, independent of phenotype association, to enable fine mapping of causative variants. The NDA coexpression approach identifies new genetic variants associated with specific traits, including an association between the regulation of the OCT1 cation transporter and genetic variants underlying circulating cholesterol levels. NDA strongly implicates particular cell types and tissues in disease pathogenesis. For example, distinct groupings of disease-associated regulatory regions implicate two distinct biological processes in the pathogenesis of ulcerative colitis; a further two separate processes are implicated in Crohn's disease. Thus, our functional analysis of genetic predisposition to disease defines new distinct disease endotypes. We predict that patients with a preponderance of susceptibility variants in each group are likely to respond differently to pharmacological therapy. Together, these findings enable a deeper biological understanding of the causal basis of complex traits. PMID- 29494621 TI - The rocky road to prosocial behavior at work: The role of positivity and organizational socialization in preventing interpersonal strain. AB - Among relevant consequences of organizational socialization, a key factor is the promotion of organizational citizenship behaviors toward individuals (i.e. OCBI). However, the relation between organizational socialization and OCBI has received little attention. This study tests the validity of a moderated mediation model in which we examine the mediating effect of a decreased interpersonal strain on the relationship between organizational socialization and OCBI, and the moderation role of a positive personal resource in reducing interpersonal strain when an unsuccessful socialization subsists. A cross-sectional study was conducted on 765 new recruits of the Guardia di Finanza-a military Police Force reporting to the Italian Minister of Economy. Findings confirm our hypothesis that interpersonal strain mediates the relationship between organizational socialization and OCBI. The index of moderated mediation results significant, showing that this effect exists at different levels of positivity. Theoretical and practical implications for promoting pro-organizational behaviors are discussed. PMID- 29494622 TI - AHR2 required for normal behavioral responses and proper development of the skeletal and reproductive systems in zebrafish. AB - The aryl hydrocarbon receptor (AHR) is a conserved ligand-activated transcription factor required for proper vertebrate development and homeostasis. The inappropriate activation of AHR by ubiquitous pollutants can lead to adverse effects on wildlife and human health. The zebrafish is a powerful model system that provides a vertebrate data stream that anchors hypothesis at the genetic and cellular levels to observations at the morphological and behavioral level, in a high-throughput format. In order to investigate the endogenous functions of AHR, we generated an AHR2 (homolog of human AHR)-null zebrafish line (ahr2osu1) using the clustered, regulatory interspaced, short palindromic repeats (CRISPR)-Cas9 precision genome editing method. In zebrafish, 2,3,7,8-tetrachlorodibenzo-p dioxin (TCDD) mediated toxicity requires AHR2. The AHR2-null line was resistant to TCDD-induced toxicity, indicating the line can be used to investigate the biological and toxicological functions of AHR2. The AHR2-null zebrafish exhibited decreased survival and fecundity compared to the wild type line. At 36 weeks, histological evaluations of the AHR2-null ovaries revealed a reduction of mature follicles when compared to wild type ovaries, suggesting AHR2 regulates follicle growth in zebrafish. AHR2-null adults had malformed cranial skeletal bones and severely damaged fins. Our data suggests AHR2 regulates some aspect(s) of neuromuscular and/or sensory system development, with impaired behavioral responses observed in larval and adult AHR2-null zebrafish. This study increases our understanding of the endogenous functions of AHR, which may help foster a better understanding of the target organs and molecular mechanisms involved in AHR-mediated toxicities. PMID- 29494623 TI - The effects of socioecological factors on variation of communicable diseases: A multiple-disease study at the national scale of Vietnam. AB - OBJECTIVE: To examine the effects of socioecological factors on multiple communicable diseases across Vietnam. METHODS: We used the Moran's I tests to evaluate spatial clusters of diseases and applied multilevel negative binomial regression models using the Bayesian framework to analyse the association between socioecological factors and the diseases queried by oral, airborne, vector-borne, and animal transmission diseases. RESULTS AND SIGNIFICANCE: The study found that oral-transmission diseases were spatially distributed across the country; whereas, the airborne-transmission diseases were more clustered in the Northwest and vector-borne transmission diseases were more clustered in the South. Most of diseases were sensitive with climatic factors. For instance, a 1 degrees C increase in average temperature is significantly associated with 0.4% (95CI, 0.3 0.5), 2.5% (95%CI, 1.4-3.6), 0.9% (95%CI, 0.6-1.4), 1.1% (95%CI), 5% (95%CI, 3 .7.4), 0.4% (95%CI, 0.2-0.7), and 2% (95%CI, 1.5-2.8) increase in risk of diarrhoea, shigellosis, mumps, influenza, dengue, malaria, and rabies respectively. The influences of socio-economic factors on risk of communicable diseases are varied by factors with the biggest influence of population density. The research findings reflect an important implication for the climate change adaptation strategies of health sectors. A development of weather-based early warning systems should be considered to strengthen communicable disease prevention in Vietnam. PMID- 29494624 TI - Selection and testing of reference genes for accurate RT-qPCR in rice seedlings under iron toxicity. AB - Reverse Transcription quantitative PCR (RT-qPCR) is a technique for gene expression profiling with high sensibility and reproducibility. However, to obtain accurate results, it depends on data normalization by using endogenous reference genes whose expression is constitutive or invariable. Although the technique is widely used in plant stress analyzes, the stability of reference genes for iron toxicity in rice (Oryza sativa L.) has not been thoroughly investigated. Here, we tested a set of candidate reference genes for use in rice under this stressful condition. The test was performed using four distinct methods: NormFinder, BestKeeper, geNorm and the comparative DeltaCt. To achieve reproducible and reliable results, Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines were followed. Valid reference genes were found for shoot (P2, OsGAPDH and OsNABP), root (OsEF-1a, P8 and OsGAPDH) and root+shoot (OsNABP, OsGAPDH and P8) enabling us to perform further reliable studies for iron toxicity in both indica and japonica subspecies. The importance of the study of other than the traditional endogenous genes for use as normalizers is also shown here. PMID- 29494625 TI - On the effects of signal processing on sample entropy for postural control. AB - Sample entropy, a measure of time series regularity, has become increasingly popular in postural control research. We are developing a virtual reality assessment of sensory integration for postural control in people with vestibular dysfunction and wished to apply sample entropy as an outcome measure. However, despite the common use of sample entropy to quantify postural sway, we found lack of consistency in the literature regarding center-of-pressure signal manipulations prior to the computation of sample entropy. We therefore wished to investigate the effect of parameters choice and signal processing on participants' sample entropy outcome. For that purpose, we compared center-of pressure sample entropy data between patients with vestibular dysfunction and age matched controls. Within our assessment, participants observed virtual reality scenes, while standing on floor or a compliant surface. We then analyzed the effect of: modification of the radius of similarity (r) and the embedding dimension (m); down-sampling or filtering and differencing or detrending. When analyzing the raw center-of-pressure data, we found a significant main effect of surface in medio-lateral and anterior-posterior directions across r's and m's. We also found a significant interaction group * surface in the medio-lateral direction when r was 0.05 or 0.1 with a monotonic increase in p value with increasing r in both m's. These effects were maintained with down-sampling by 2, 3, and 4 and with detrending but not with filtering and differencing. Based on these findings, we suggest that for sample entropy to be compared across postural control studies, there needs to be increased consistency, particularly of signal handling prior to the calculation of sample entropy. Procedures such as filtering, differencing or detrending affect sample entropy values and could artificially alter the time series pattern. Therefore, if such procedures are performed they should be well justified. PMID- 29494626 TI - Characterization of the volatile components in green tea by IRAE-HS-SPME/GC-MS combined with multivariate analysis. AB - In the present work, a novel infrared-assisted extraction coupled to headspace solid-phase microextraction (IRAE-HS-SPME) followed by gas chromatography-mass spectrometry (GC-MS) was developed for rapid determination of the volatile components in green tea. The extraction parameters such as fiber type, sample amount, infrared power, extraction time, and infrared lamp distance were optimized by orthogonal experimental design. Under optimum conditions, a total of 82 volatile compounds in 21 green tea samples from different geographical origins were identified. Compared with classical water-bath heating, the proposed technique has remarkable advantages of considerably reducing the analytical time and high efficiency. In addition, an effective classification of green teas based on their volatile profiles was achieved by partial least square-discriminant analysis (PLS-DA) and hierarchical clustering analysis (HCA). Furthermore, the application of a dual criterion based on the variable importance in the projection (VIP) values of the PLS-DA models and on the category from one-way univariate analysis (ANOVA) allowed the identification of 12 potential volatile markers, which were considered to make the most important contribution to the discrimination of the samples. The results suggest that IRAE-HS-SPME/GC-MS technique combined with multivariate analysis offers a valuable tool to assess geographical traceability of different tea varieties. PMID- 29494627 TI - Clout, activists and budget: The road to presidency. AB - Political campaigns involve, in the simplest case, two competing campaign groups which try to obtain a majority of votes. We propose a novel mathematical framework to study political campaign dynamics on social networks whose constituents are either political activists or persuadable individuals. Activists are convinced and do not change their opinion and they are able to move around in the social network to motivate persuadable individuals to vote according to their opinion. We describe the influence of the complex interplay between the number of activists, political clout, budgets, and campaign costs on the campaign result. We also identify situations where the choice of one campaign group to send a certain number of activists already pre-determines their victory. Moreover, we show that a candidate's advantage in terms of political clout can overcome a substantial budget disadvantage or a lower number of activists, as illustrated by the US presidential election 2016. PMID- 29494628 TI - Short-term action potential memory and electrical restitution: A cellular computational study on the stability of cardiac repolarization under dynamic pacing. AB - Electrical restitution (ER) is a major determinant of repolarization stability and, under fast pacing rate, it reveals memory properties of the cardiac action potential (AP), whose dynamics have never been fully elucidated, nor their ionic mechanisms. Previous studies have looked at ER mainly in terms of changes in AP duration (APD) when the preceding diastolic interval (DI) changes and described dynamic conditions where this relationship shows hysteresis which, in turn, has been proposed as a marker of short-term AP memory and repolarization stability. By means of numerical simulations of a non-propagated human ventricular AP, we show here that measuring ER as APD versus the preceding cycle length (CL) provides additional information on repolarization dynamics which is not contained in the companion formulation. We focus particularly on fast pacing rate conditions with a beat-to-beat variable CL, where memory properties emerge from APD vs CL and not from APD vs DI and should thus be stored in APD and not in DI. We provide an ion-currents characterization of such conditions under periodic and random CL variability, and show that the memory stored in APD plays a stabilizing role on AP repolarization under pacing rate perturbations. The gating kinetics of L-type calcium current seems to be the main determinant of this safety mechanism. We also show that, at fast pacing rate and under otherwise identical pacing conditions, a periodically beat-to-beat changing CL is more effective than a random one in stabilizing repolarization. In summary, we propose a novel view of short-term AP memory, differentially stored between systole and diastole, which opens a number of methodological and theoretical implications for the understanding of arrhythmia development. PMID- 29494629 TI - Revealing the ecological content of long-duration audio-recordings of the environment through clustering and visualisation. AB - Audio recordings of the environment are an increasingly important technique to monitor biodiversity and ecosystem function. While the acquisition of long duration recordings is becoming easier and cheaper, the analysis and interpretation of that audio remains a significant research area. The issue addressed in this paper is the automated reduction of environmental audio data to facilitate ecological investigations. We describe a method that first reduces environmental audio to vectors of acoustic indices, which are then clustered. This can reduce the audio data by six to eight orders of magnitude yet retain useful ecological information. We describe techniques to visualise sequences of cluster occurrence (using for example, diel plots, rose plots) that assist interpretation of environmental audio. Colour coding acoustic clusters allows months and years of audio data to be visualised in a single image. These techniques are useful in identifying and indexing the contents of long-duration audio recordings. They could also play an important role in monitoring long-term changes in species abundance brought about by habitat degradation and/or restoration. PMID- 29494630 TI - Juvenile honest food solicitation and parental investment as a life history strategy: A kin demographic selection model. AB - Parent-offspring communication remains an unresolved challenge for biologist. The difficulty of the challenge comes from the fact that it is a multifaceted problem with connections to life-history evolution, parent-offspring conflict, kin selection and signalling. Previous efforts mainly focused on modelling resource allocation at the expense of the dynamic interaction during a reproductive season. Here we present a two-stage model of begging where the first stage models the interaction between nestlings and parents within a nest and the second stage models the life-history trade-offs. We show in an asexual population that honest begging results in decreased variance of collected food between siblings, which leads to mean number of surviving offspring. Thus, honest begging can be seen as a special bet-hedging against informational uncertainty, which not just decreases the variance of fitness but also increases the arithmetic mean. PMID- 29494631 TI - Polymorphism of floral type gene Cly1 and its association with thermal stress in barley. AB - Cleistogamy refers to a type of sexual breeding system with closed flowers. Cleistogamous flowers shed their pollen before flower opening, which leads to autogamy. Two SNPs in the open reading frame region of the Cly1 gene are associated with floral type. In the present study, we investigated the floral type of 436 barley accessions. Molecular markers were developed to genotype these barley accessions based on the two SNPs in the Cly1 gene region. The molecular markers explained floral type in 90% of the accessions. The Cly1 gene was sequenced in accessions with inconsistent genotype and phenotype. Thirteen SNPs were detected with ten new SNPs in the gene region. We further investigated whether floral type was associated with temperature stress tolerance in four field trials. One site experienced frost stress with a minimum temperature of 3.4 degrees C during flowering. Grain fertility rates as low as 85% were observed at this site but ranged from 92-96% at the other three sites. The relationship between grain fertility rate and floral type under temperature stress was inconclusive. Some lines with higher grain fertility rates were identified under frost stress, and would be useful for frost stress studies in barley. PMID- 29494632 TI - The effect of increasing the sulfation level of chondroitin sulfate on anticoagulant specific activity and activation of the kinin system. AB - Oversulfated chondroitin sulfate (OSCS) was identified as a contaminant in certain heparin preparations as the cause of adverse reactions in patients. OSCS was found to possess both plasma anticoagulant activity and the ability to activate prekallikrein to kallikrein. Differentially sulfated chondroitin sulfates were prepared by synthetic modification of chondroitin sulfate and were compared to the activity of OSCS purified from contaminated heparin. Whilst chondroitin sulfate was found to have minimal anticoagulant activity, increasing sulfation levels produced an anticoagulant response which we directly show for the first time is mediated through heparin cofactor II. However, the tetra sulfated preparations did not possess any higher anticoagulant activity than several tri-sulfated variants, and also had lower heparin cofactor II mediated activity. Activation of prekallikrein was concentration dependent for all samples, and broadly increased with the degree of sulfation, though the di sulfated preparation was able to form more kallikrein than some of the tri sulfated preparations. The ability of the samples to activate the kinin system, as measured by bradykinin, was observed to be through kallikrein generation. These results show that whilst an increase in sulfation of chondroitin sulfate did cause an increase in anticoagulant activity and activation of the kinin system, there may be subtler structural interactions other than sulfation at play given the different responses observed. PMID- 29494633 TI - A spontaneous model of spondyloarthropathies that develops bone loss and pathological bone formation: A process regulated by IL27RA-/- and mutant-p53. AB - Spondyloarthropathies, the second most frequently occurring form of chronic inflammatory arthritis, affects young adults in particular. However, a proper model with which to study the biology of this disease and to develop therapeutics is lacking. One of the most accepted animal models for this disease uses HLA B27/Hu-beta2m transgenic rats; however, only 30%-50% of male HLA-B27/Hu-beta2m rats develop spontaneous, clinically apparent spondylitis and have a variable time until disease onset. Here, we report a high-incidence, low-variation spontaneous mouse model that delineates how the combination of inflammatory cytokine interleukin-27 (IL-27) signaling deficiency and mitogenic signaling (mutant p53R172H) in vivo, leads to bone loss in the vertebral bodies and ossification of the cartilage in the intervertebral discs. In this human disease like mouse model, bone loss and pathogenic bone development are seen as early as 4 months of age in the absence of inflammatory aggregates in the enthesis or intervertebral disc. PMID- 29494635 TI - Effects of microplastic exposure on the body condition and behaviour of planktivorous reef fish (Acanthochromis polyacanthus). AB - The effect of a pollutant on the base of the food web can have knock-on effects for trophic structure and ecosystem functioning. In this study we assess the effect of microplastic exposure on juveniles of a planktivorous fish (Acanthochromis polyacanthus), a species that is widespread and abundant on Indo Pacific coral reefs. Under five different plastic concentration treatments, with plastics the same size as the natural food particles (mean 2mm diameter), there was no significant effect of plastic exposure on fish growth, body condition or behaviour. The amount of plastics found in the gastro-intestinal (GI) tract was low, with a range of one to eight particles remaining in the gut of individual fish at the end of a 6-week plastic-exposure period, suggesting that these fish are able to detect and avoid ingesting microplastics in this size range. However, in a second experiment the number of plastics in the GI tract vastly increased when plastic particle size was reduced to approximately one quarter the size of the food particles, with a maximum of 2102 small (< 300MUm diameter) particles present in the gut of individual fish after a 1-week plastic exposure period. Under conditions where food was replaced by plastic, there was a negative effect on the growth and body condition of the fish. These results suggest plastics could become more of a problem as they break up into smaller size classes, and that environmental changes that lead to a decrease in plankton concentrations combined with microplastic presence is likely have a greater influence on fish populations than microplastic presence alone. PMID- 29494634 TI - Vitamin C alters the amount of specific endoplasmic reticulum associated proteins involved in lipid metabolism in the liver of mice synthesizing a nonfunctional Werner syndrome (Wrn) mutant protein. AB - Werner syndrome (WS) is a premature aging disorder caused by mutations in a protein containing both a DNA exonuclease and DNA helicase domain. Mice lacking the helicase domain of the Wrn protein orthologue exhibit transcriptomic and metabolic alterations, some of which are reversed by vitamin C. Recent studies on these animals indicated that the mutant protein is associated with enriched endoplasmic reticulum (ER) fractions of tissues resulting in an ER stress response. In this study, we identified proteins that exhibit actual level differences in the ER enriched fraction between the liver of wild type and Wrn mutant mice using quantitative proteomic profiling with label-free Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). Multiple Reaction Monitoring (MRM) and immunoblotting were performed to validate findings in a secondary independent cohort of wild type and Wrn mutant mice. DAVID 6.7 (NIH) was used for functional annotation analysis and indicated that the identified proteins exhibiting level changes between untreated wild type, Wrn mutant, and vitamin C treated Wrn mutant mice (ANOVA P-value < 0.05) were involved in fatty acid and steroid metabolism pathways (Bonferroni P-value = 0.0137). Finally, when we compared the transcriptomic and the proteomic data of our mouse cohorts only ~7% of the altered mRNA profiles encoding for ER gene products were consistent with their corresponding protein profiles measured by the label-free quantification methods. These results suggest that a great number of ER gene products are regulated at the post-transcriptional level in the liver of Wrn mutant mice exhibiting an ER stress response. PMID- 29494636 TI - Causes of death and early life determinants of survival in homozygous sickle cell disease: The Jamaican cohort study from birth. AB - Globally, the majority of persons born with sickle cell disease do not have access to hydroxyurea or more expensive interventions. The objectives were to estimate the survival in homozygous sickle cell disease, unbiased by symptomatic selection and to ascertain the causes of death in a pre-hydroxyurea population. The utility of early life biomarkers and genetically determined phenotypes to predict survival was assessed. A cohort study based on neonatal diagnosis was undertaken at the Sickle Cell Unit, a specialist clinic delivering care to persons with sickle cell disease in Jamaica. Screening of 100,000 deliveries detected 315 babies with homozygous sickle cell disease of whom 311 have been followed from birth for periods up to 43 years. Pneumococcal prophylaxis and teaching mothers splenic palpation were important, inexpensive interventions. Anticipatory guidance, routine care and out-patient acute care were provided. Each participant was classified as alive, dead, or defaulted (usually emigration). Causes of death were ascertained from clinical records and/or post mortem reports. Survival was assessed using the Kaplan-Meier function. Sex adjusted Cox semi-parametric proportional hazards and Weibull modelling were used to assess the effects on survival of biomarkers. Survival to 40 years was 55.5% (95% CI 48.7% to 61.7%). Acute Chest Syndrome (n = 31) and septicemia (n = 14) were significant causes of death at all ages. Acute splenic sequestration (n = 12) was the most common cause of early deaths. Survival was significantly shorter in those with lower hemoglobin at 1 year, high total nucleated count at 1 year, and a history of dactylitis ever. In these hydroxyurea naive patients, survival into midlife was common. Causes of death were often age specific and some may be preventable. Early life biomarkers predictive of decreased survival in SS disease identify a patient group likely to benefit from close clinical supervision and potentially high risk therapies. PMID- 29494637 TI - Individualized prediction of mortality using multiple inflammatory markers in patients on dialysis. AB - This study aimed to evaluate whether the combination of inflammatory markers could provide predictive powers for mortality in individual patients on dialysis and develop a predictive model for mortality according to dialysis modality. Data for inflammatory markers were obtained at the time of enrollment from 3,309 patients on dialysis from a prospective multicenter cohort. Net reclassification index (NRI) and integrated discrimination improvement (IDI) were calculated. Cox proportional hazards regression analysis was used to derive a prediction model of mortality and the integrated area under the curve (iAUC) was calculated to compare the predictive accuracy of the models. The incremental additions of albumin, high-sensitive C-reactive protein (hsCRP), white blood count (WBC), and ferritin to the conventional risk factors showed the highest predictive powers for all-cause mortality in the entire population (NRI, 21.0; IDI, 0.045) and patients on peritoneal dialysis (NRI, 25.7; IDI, 0.061). The addition of albumin and hsCRP to the conventional risk factors markedly increased predictive powers for all-cause mortality in HD patients (NRI, 19.0; IDI, 0.035). The prediction model for all-cause mortality using conventional risk factors and combination of inflammatory markers with highest NRI value (iAUC, 0.741; 95% CI, 0.722-0.761) was the most accurate in the entire population compared with a model including conventional risk factors alone (iAUC, 0.719; 95% CI, 0.700-0.738) or model including only significant conventional risk factors and inflammatory markers (iAUC, 0.734; 95% CI, 0.714-0.754). Using multiple inflammatory markers practically available in a clinic can provide higher predictive power for all cause mortality in patients on dialysis. The predictive model for mortality based on combinations of inflammatory markers enables a stratified risk assessment. However, the optimal combination for the predictive model was different in each dialysis modality. PMID- 29494638 TI - Glycogen synthase kinase 3beta functions as a positive effector in the WNK signaling pathway. AB - The with no lysine (WNK) protein kinase family is conserved among many species. Some mutations in human WNK gene are associated with pseudohypoaldosteronism type II, a form of hypertension, and hereditary sensory and autonomic neuropathy type 2A. In kidney, WNK regulates the activity of STE20/SPS1-related, proline alanine rich kinase and/or oxidative-stress responsive 1, which in turn regulate ion co transporters. The misregulation of this pathway is involved in the pathogenesis of pseudohypoaldosteronism type II. In the neural system, WNK is involved in the specification of the cholinergic neuron, but the pathogenesis of hereditary sensory and autonomic neuropathy type 2A is still unknown. To better understand the WNK pathway, we isolated WNK-associated genes using Drosophila. We identified Glycogen synthase kinase 3beta (GSK3beta)/Shaggy (Sgg) as a candidate gene that was shown to interact with the WNK signaling pathway in both Drosophila and mammalian cells. Furthermore, GSK3beta was involved in neural specification downstream of WNK. These results suggest that GSK3beta/Sgg functions as a positive effector in the WNK signaling pathway. PMID- 29494639 TI - Variability of non-Gaussian diffusion MRI and intravoxel incoherent motion (IVIM) measurements in the breast. AB - We prospectively examined the variability of non-Gaussian diffusion magnetic resonance imaging (MRI) and intravoxel incoherent motion (IVIM) measurements with different numbers of b-values and excitations in normal breast tissue and breast lesions. Thirteen volunteers and fourteen patients with breast lesions (seven malignant, eight benign; one patient had bilateral lesions) were recruited in this prospective study (approved by the Internal Review Board). Diffusion weighted MRI was performed with 16 b-values (0-2500 s/mm2 with one number of excitations [NEX]) and five b-values (0-2500 s/mm2, 3 NEX), using a 3T breast MRI. Intravoxel incoherent motion (flowing blood volume fraction [fIVIM] and pseudodiffusion coefficient [D*]) and non-Gaussian diffusion (theoretical apparent diffusion coefficient [ADC] at b value of 0 sec/mm2 [ADC0] and kurtosis [K]) parameters were estimated from IVIM and Kurtosis models using 16 b-values, and synthetic apparent diffusion coefficient (sADC) values were obtained from two key b-values. The variabilities between and within subjects and between different diffusion acquisition methods were estimated. There were no statistical differences in ADC0, K, or sADC values between the different b-values or NEX. A good agreement of diffusion parameters was observed between 16 b-values (one NEX), five b-values (one NEX), and five b-values (three NEX) in normal breast tissue or breast lesions. Insufficient agreement was observed for IVIM parameters. There were no statistical differences in the non-Gaussian diffusion MRI estimated values obtained from a different number of b-values or excitations in normal breast tissue or breast lesions. These data suggest that a limited MRI protocol using a few b-values might be relevant in a clinical setting for the estimation of non-Gaussian diffusion MRI parameters in normal breast tissue and breast lesions. PMID- 29494640 TI - Consistent individual differences and population plasticity in network-derived sociality: An experimental manipulation of density in a gregarious ungulate. AB - In many taxa, individual social traits appear to be consistent across time and context, thus meeting the criteria for animal personality. How these differences are maintained in response to changes in population density is unknown, particularly in large mammals, such as ungulates. Using a behavioral reaction norm (BRN) framework, we examined how among- and within-individual variation in social connectedness, measured using social network analyses, change as a function of population density. We studied a captive herd of elk (Cervus canadensis) separated into a group of male elk and a group of female elk. Males and females were exposed to three different density treatments and we recorded social associations between individuals with proximity-detecting radio-collars fitted to elk. We constructed social networks using dyadic association data and calculated three social network metrics reflective of social connectedness: eigenvector centrality, graph strength, and degree. Elk exhibited consistent individual differences in social connectedness across densities; however, they showed little individual variation in their response to changes in density, i.e., individuals oftentimes responded plastically, but in the same manner to changes in density. Female elk had highest connectedness at an intermediate density. In contrast, male elk increased connectedness with increasing density. Whereas this may suggest that the benefits of social connectedness outweigh the costs of increased competition at higher density for males, females appear to exhibit a threshold in social benefits (e.g. predator detection and forage information). Our study illustrates the importance of viewing social connectedness as a density dependent trait, particularly in the context of plasticity. Moreover, we highlight the need to revisit our understanding of density dependence as a population-level phenomenon by accounting for consistent individual differences not only in social connectedness, but likely in other ecological processes (e.g., predator-prey dynamics, mate choice, disease transfer). PMID- 29494641 TI - Statistical power and utility of meta-analysis methods for cross-phenotype genome wide association studies. AB - Advances in recent genome wide association studies (GWAS) suggest that pleiotropic effects on human complex traits are widespread. A number of classic and recent meta-analysis methods have been used to identify genetic loci with pleiotropic effects, but the overall performance of these methods is not well understood. In this work, we use extensive simulations and case studies of GWAS datasets to investigate the power and type-I error rates of ten meta-analysis methods. We specifically focus on three conditions commonly encountered in the studies of multiple traits: (1) extensive heterogeneity of genetic effects; (2) characterization of trait-specific association; and (3) inflated correlation of GWAS due to overlapping samples. Although the statistical power is highly variable under distinct study conditions, we found the superior power of several methods under diverse heterogeneity. In particular, classic fixed-effects model showed surprisingly good performance when a variant is associated with more than a half of study traits. As the number of traits with null effects increases, ASSET performed the best along with competitive specificity and sensitivity. With opposite directional effects, CPASSOC featured the first-rate power. However, caution is advised when using CPASSOC for studying genetically correlated traits with overlapping samples. We conclude with a discussion of unresolved issues and directions for future research. PMID- 29494642 TI - Global epidemiology of podoconiosis: A systematic review. AB - BACKGROUND: Podoconiosis is one of the few diseases that could potentially be eliminated within one generation. Nonetheless, the global distribution of the disease remains largely unknown. The global atlas of podoconiosis was conceived to define the epidemiology and distribution of podoconiosis through dedicated surveys and assembling the available epidemiological data. METHODS: We have synthesized the published literature on the epidemiology of podoconiosis. Through systematic searches in SCOPUS and MEDLINE from inception to February 14, 2018, we identified observational and population-based studies reporting podoconiosis. To establish existence of podoconiosis, we used case reports and presence data. For a study to be included in the prevalence synthesis, it needed to be a population based survey that involved all residents within a specific area. Studies that did not report original data were excluded. We undertook descriptive analyses of the extracted data. This study is registered with PROSPERO, number CRD42018084959. RESULTS: We identified 3,260 records, of which 27 studies met the inclusion criteria. Podoconiosis was described to exist or be endemic in 32 countries, 18 from the African Region, 3 from Asia and 11 from Latin America. Overall, podoconiosis prevalence ranged from 0.10% to 8.08%, was highest in the African region, and was substantially higher in adults than in children and adolescents. The highest reported prevalence values were in Africa (8.08% in Cameroon, 7.45% in Ethiopia, 4.52% in Uganda, 3.87% in Kenya and 2.51% in Tanzania). In India, a single prevalence of 0.21% was recorded from Manipur, Mizoram and Rajasthan states. None of the Latin American countries reported prevalence data. CONCLUSION: Our data suggest that podoconiosis is more widespread in the African Region than in the rest of the regions, although this could be related to the fact that most podoconiosis epidemiological research has been focused in the African continent. The assembled dataset confirms that comprehensive podoconiosis control strategies such as promotion of footwear and personal hygiene are urgently needed in endemic parts of Africa. Mapping, active surveillance and a systematic approach to the monitoring of disease burden must accompany the implementation of podoconiosis control activities. PMID- 29494643 TI - The importance of negative determinants as modulators of CK2 targeting. The lesson of Akt2 S131. AB - CK2 is a pleiotropic S/T protein kinase (formerly known as casein kinase 2) which is attracting increasing interest as therapeutic target, and the identification of its substrates is a crucial step in determining its involvement in different pathological conditions. We recently found that S131 of Akt2 (homologous to the well established CK2 target S129 of Akt1) is not phosphorylated by CK2 either in vitro or in vivo, although the consensus sequence recognized by CK2 (S/T-x-x E/D/pS/pT) is conserved in it. Here, by exploiting synthetic peptides, in cell transfection experiments, and computational analysis, we show that a single sequence element, a T at position n+1, hampers phosphorylation, causing an alpha helix structure organization which prevents the recognition of its own consensus by CK2. Our results highlight the role of negative determinants as crucial modulators of CK2 targeting and corroborate the concept that Akt1 and Akt2 display isoform specific features. Experiments with synthetic peptides suggest that Akt2 S131 could be phosphorylated by kinases of the Plk (Polo-like kinase) family, which are insensitive to the presence of the n+1 T. The low phylogenetic conservation of the Akt2 sequence around S131, as opposed to the extremely well conserved Akt1 homologous sequence, would indicate a dominant positive role in the selective pressure only for the Akt1 phosphoacceptor site committed to undergo phosphorylation by CK2. By contrast, Akt2 S131 may mediate the response to specific physio/pathological conditions, being consequently shielded against basal CK2 targeting. PMID- 29494644 TI - Knowledge diffusion within a large conservation organization and beyond. AB - The spread and uptake of new ideas (diffusion of innovations) is critical for organizations to adapt over time, but there is little evidence of how this happens within organizations and to their broader community. To address this, we analyzed how individuals accessed information about a recent science innovation at a large, international, biodiversity conservation non-profit-The Nature Conservancy-and then traced the flow of how this information was shared within the organization and externally, drawing on an exceptionally data-rich environment. We used surveys and tracking of individual internet activity to understand mechanisms for early-stage diffusion (knowledge seeking and sharing) following the integration of social science and evidence principles into the institutional planning framework: Conservation by Design (CbD 2.0). Communications sent to all employees effectively catalyzed 56.4% to exhibit knowledge seeking behavior, measured by individual downloads from and visits to a restricted-access site. Individuals who self-reported through a survey that they shared information about CbD 2.0 internally were more likely to have both received and sought out information about the framework. Such individuals tended to hold positions within a higher job grade, were more likely to train others on CbD as part of their job, and to enroll in other online professional development offerings. Communication strategies targeting external audiences did not appear to influence information seeking behavior. Staff who engaged in internal knowledge sharing and adopting "evidence" practices from CbD 2.0 were more likely to have shared the document externally. We found a negative correlation with external sharing behavior and in-person trainings. Our findings suggest repeated, direct email communications aimed at wide audiences can effectively promote diffusion of new ideas. We also found a wide range of employee characteristics and circumstances to be associated with knowledge diffusion behavior (at both an organizational and individual level). PMID- 29494645 TI - Association of whole blood n-6 fatty acids with stunting in 2-to-6-year-old Northern Ghanaian children: A cross-sectional study. AB - In Northern Ghana, 33% of children are stunted due to economic disparities. Dietary fatty acids (FA) are critical for growth, but whether blood FA levels are adequate in Ghanaian children is unknown. The objective of this study was to determine the association between whole blood FAs and growth parameters in Northern Ghanaian children 2-6 years of age. A drop of blood was collected on an antioxidant treated card and analyzed for FA composition. Weight and height were measured and z-scores were calculated. Relationships between FAs and growth parameters were analyzed by Spearman correlations, linear regressions, and factor analysis. Of the 307 children who participated, 29.7% were stunted and 8% were essential FA deficient (triene/tetraene ratio>0.02). Essential FA did not differ between stunted and non-stunted children and was not associated with height-for age z-score (HAZ) or weight-for-age z-score (WAZ). In hemoglobin adjusted regression models, both HAZ and WAZ were positively associated with arachidonic acid (p<=0.01), dihomo-gamma-linolenic acid (DGLA, p<=0.05), docosatetraenoic acid (p<=0.01) and the ratio of DGLA/linoleic acid (p<=0.01). These data add to the growing body of evidence indicating n-6 FAs are critical in childhood linear growth. Our findings provide new insights into the health status of an understudied Northern Ghanaian population. PMID- 29494647 TI - Remote magnetic actuation using a clinical scale system. AB - Remote magnetic manipulation is a powerful technique for controlling devices inside the human body. It enables actuation and locomotion of tethered and untethered objects without the need for a local power supply. In clinical applications, it is used for active steering of catheters in medical interventions such as cardiac ablation for arrhythmia treatment and for steering of camera pills in the gastro-intestinal tract for diagnostic video acquisition. For these applications, specialized clinical-scale field applicators have been developed, which are rather limited in terms of field strength and flexibility of field application. For a general-purpose field applicator, flexible field generation is required at high field strengths as well as high field gradients to enable the generation of both torques and forces on magnetic devices. To date, this requirement has only been met by small-scale experimental systems. We have built a highly versatile clinical-scale field applicator that enables the generation of strong magnetic fields as well as strong field gradients over a large workspace. We demonstrate the capabilities of this coil-based system by remote steering of magnetic drills through gel and tissue samples with high torques on well-defined curved trajectories. We also give initial proof that, when equipped with high frequency transmit-receive coils, the machine is capable of real-time magnetic particle imaging while retaining a clinical-scale bore size. Our findings open the door for image-guided radiation-free remote magnetic control of devices at the clinical scale, which may be useful in minimally invasive diagnostic and therapeutic medical interventions. PMID- 29494646 TI - Optimization of culture conditions for the derivation and propagation of baboon (Papio anubis) induced pluripotent stem cells. AB - Induced pluripotent stem cells (iPSCs) offer the possibility of cell replacement therapies using patient-matched cells to treat otherwise intractable diseases and debilitations. To successfully realize this potential, several factors must be optimized including i) selection of the appropriate cell type and numbers to transplant, ii) determination of the means of transplantation and the location into which the transplanted cells should be delivered, and iii) demonstration of the safety and efficacy of the cell replacement protocol to mitigate each targeted disease state. A majority of diseases or debilitations likely to be targeted by cell-based therapeutic approaches represent complex conditions or physiologies manifest predominantly in primates including humans. Nonhuman primates afford the most clinically relevant model system for biomedical studies and testing of cell-based therapies. Baboons have 92% genomic similarity with humans overall and especially significant similarities in their immunogenetic system, rendering this species a particularly valuable model for testing procedures involving cell transplants into living individuals. To maximize the utility of the baboon model, standardized protocols must be developed for the derivation of induced pluripotent stem cells from living adults and the long-term maintenance of these cells in culture. Here we tested four commercially available culture systems (ReproFF, mTeSR1, E8 and Pluristem) for competence to maintain baboon iPSCs in a pluripotent state over multiple passages, and to support the derivation of new lines of baboon iPSCs. Of these four media only Pluristem was able to maintain baboon pluripotency as assessed by morphological characteristics, immunocytochemistry and RT-qPCR. Pluristem also facilitated the derivation of new lines of iPSCs from adult baboon somatic cells, which had previously not been accomplished. We derived multiple iPS cell lines from adult baboon peripheral blood mononuclear cells cultured in Pluristem. These were validated by expression of the pluripotency markers OCT4, NANOG, SOX2, SSEA4 and TRA181, as well as the ability to differentiate into tissues from all three germ layers when injected into immunocompromised mice. These findings further advance the utility of the baboon as an ideal preclinical model system for optimizing iPS cell-based, patient-specific replacement therapies in humans. PMID- 29494648 TI - A comparative analysis of microbial profile of Guinea fowl and chicken using metagenomic approach. AB - Probiotics are live microbial feed supplements that promote growth and health to the host by minimizing non-essential and pathogenic microorganisms in the host's gastrointestinal tract (GIT). The campaign to minimize excessive use of antibiotics in poultry production has necessitated development of probiotics with broad application in multiple poultry species. Design of such probiotics requires understanding of the diversity or similarity in microbial profiles among avian species of economic importance. Therefore, the objective of this research was to establish and compare the microbial profiles of the GIT of Guinea fowl and chicken and to establish the microbial diversity or similarity between the two avian species. A metagenomic approach consisting of the amplification and sequence analysis of the hypervariable regions V1-V9 of the 16S rRNA gene was used to identify the GIT microbes. Collectively, we detected more than 150 microbial families. The total number of microbial species detected in the chicken GIT was higher than that found in the Guinea Fowl GIT. Our studies also revealed phylogenetic diversity among the microbial species found in chicken and guinea fowl. The phylum Firmicutes was most abundant in both avian species whereas Phylum Actinobacteria was most abundant in chickens than Guinea fowls. The diversity of the microbial profiles found in broiler chickens and Guinea fowls suggest that the design of effective avian probiotics would require species specificity. PMID- 29494649 TI - The role of multislice computed tomography (MSCT) angiography in the diagnosis and therapy of non-occlusive mesenteric ischemia (NOMI): Could MSCT replace DSA in diagnosis? AB - OBJECTIVES: Evaluation of multislice-CT (MSCT) during diagnosis and therapeutic decision-making in patients with suspected non-occlusive mesenteric ischemia (NOMI). METHODS: Retrospective, institutional review board-approved study of 30 patients (20 men, 10 women, mean age 64.6+/-14.2 years, range 24-87 years) undergoing biphasic abdominal MSCT followed by digital subtraction angiography (DSA) due to suspected NOMI. MSCT and DSA were qualitatively and quantitatively evaluated independently by two radiologists with respect to the possible diagnosis of NOMI. MSCT analysis included quantitative measurements, qualitative evaluation of contrast enhancement and assessment of secondary findings (bowel wall thickening, hypo-enhancement, intestinal pneumatosis). MSCT diagnosis and secondary findings were compared against DSA diagnosis. RESULTS: NOMI was diagnosed in a total of n = 28 patients. No differences were found when comparing the R1-rated MSCT diagnosis (p = 0.09) to the "gold standard", while MSCT diagnosis was slightly inferior with R2 (p = 0.02). With R1, vessel-associated parameters revealed the best correlation, i.e. qualitative vessel width (r = 0.39;p = 0.03) and vessel contrast (r = 0.45;p = 0.01). Moderate correlations were found for quantitative vessel diameters in the middle segments (r = -0.48,p = 0.01), increasing to almost high correlations in the distal (r = 0.66;p<0.00001) superior mesenteric artery (SMA) segments. No significant correlation was apparent from secondary findings. CONCLUSIONS: MSCT is an appropriate non-invasive method for diagnosing NOMI and leads to adequate and immediate therapeutic stratification. PMID- 29494650 TI - Crystal structure and insights into the oligomeric state of UDP-glucose pyrophosphorylase from sugarcane. AB - UDP-glucose pyrophosphorylase (UGPase) is found in all organisms and catalyses the formation of UDP-glucose. In sugarcane, UDP-glucose is a branch-point in the carbon channelling into other carbohydrates, such as sucrose and cellulose, which are the major factors for sugarcane productivity. In most plants, UGPase has been described to be enzymatically active in the monomeric form, while in human and yeast, homo-octamers represent the active form of the protein. Here, we present the crystal structure of UGPase from sugarcane (ScUGPase-1) at resolution of 2.0 A. The crystals of ScUGPase-1 reveal the presence of two molecules in the asymmetric unit and the multi-angle light scattering analysis shows that ScUGPase 1 forms a mixture of species ranging from monomers to larger oligomers in solution, suggesting similarities with the orthologs from yeast and human. PMID- 29494652 TI - Electrothermal bipolar vessel sealing device (LigaSureTM) versus conventional diathermy in laparoscopic myomectomy: A propensity-matched analysis. AB - The purpose of this study was to compare the safety and efficacy of an electrothermal bipolar vessel sealing device (LigaSureTM) and traditional electrical cauterization in laparoscopic myomectomy (LM). A total of 756 patients with symptomatic uterine myomas who underwent LM were reviewed retrospectively. A total of 225 cases of LM using LigaSureTM (LML group) were compared with a control group treated with traditional electrical cauterization (LME group) under propensity-matched analysis. Outcome measures for both groups were compared, such as operative time, blood loss (BL), complications, need for blood transfusion, hospital expenses, and hospital stay. Six subgroups were divided according to main myoma size and energy source. No cases required switching to abdominal myomectomy. The number of myomas removed, BL, need for blood transfusion, and complications were not significantly different, whereas hospital stay was longer in the LME group than in the LML group and total hospital expenses were higher in the LML group (p < 0.001). The overall operation duration was significantly longer in the LML group but was not significantly different for main myoma >10 cm (LML vs LME, 121.58 +/- 41.77 vs 121.69 +/- 44.95, p = 0.99); this likely reflects the operative efficiency on using LigaSureTM to manage large tumors. Significant linear correlations between myoma weight and operative time and BL were seen in both groups. Conventional diathermy is more effective for small-to medium myomas. Use of the LigaSureTM was efficient for myomas >10 cm. PMID- 29494651 TI - A streamlined workflow for single-cells genome-wide copy-number profiling by low pass sequencing of LM-PCR whole-genome amplification products. AB - Chromosomal instability and associated chromosomal aberrations are hallmarks of cancer and play a critical role in disease progression and development of resistance to drugs. Single-cell genome analysis has gained interest in latest years as a source of biomarkers for targeted-therapy selection and drug resistance, and several methods have been developed to amplify the genomic DNA and to produce libraries suitable for Whole Genome Sequencing (WGS). However, most protocols require several enzymatic and cleanup steps, thus increasing the complexity and length of protocols, while robustness and speed are key factors for clinical applications. To tackle this issue, we developed a single-tube, single-step, streamlined protocol, exploiting ligation mediated PCR (LM-PCR) Whole Genome Amplification (WGA) method, for low-pass genome sequencing with the Ion TorrentTM platform and copy number alterations (CNAs) calling from single cells. The method was evaluated on single cells isolated from 6 aberrant cell lines of the NCI-H series. In addition, to demonstrate the feasibility of the workflow on clinical samples, we analyzed single circulating tumor cells (CTCs) and white blood cells (WBCs) isolated from the blood of patients affected by prostate cancer or lung adenocarcinoma. The results obtained show that the developed workflow generates data accurately representing whole genome absolute copy number profiles of single cell and allows alterations calling at resolutions down to 100 Kbp with as few as 200,000 reads. The presented data demonstrate the feasibility of the Ampli1TM WGA-based low-pass workflow for detection of CNAs in single tumor cells which would be of particular interest for genome-driven targeted therapy selection and for monitoring of disease progression. PMID- 29494653 TI - Prevalence and risk of skeletal complications and use of radiation therapy in elderly women diagnosed with metastatic breast cancer. AB - OBJECTIVE: Real-world data regarding patient factors associated with the occurrence of spinal cord compression (SCC) or pathological fracture (PF), or need for bone surgery (BS), or use of radiation therapy (RAD) (i.e. skeletal complications and radiation therapy; SCRT) are limited for women with metastatic breast cancer (BCa). Given the substantial clinical and economic burden of these events in advanced BCa, we conducted the present study to understand the prevalence and identify the risk factors associated with these events among elderly women presenting with de novo metastatic BCa. METHODS: Using linked Surveillance, Epidemiology, and End Results and Medicare data, we identified women with incident metastatic BCa diagnosed during 2005-2009. Associations between patient demographics and select clinically relevant factors, and SCRT were examined using the Cox proportional hazards model, accounting for death as a competing risk. RESULTS: Of 3,731 Medicare beneficiaries with incident metastatic BCa, 1,808 (48.5%) experienced at least one SCRT event during a median follow-up of 13.2 months; a majority (69%) experienced a subsequent SCRT event. The proportions of women who had RAD, PF, BS, and SCC were: 32%, 28%, 8%, and 4%. Older women (80+ years), or those with more comorbid conditions (CCI>=2) had a statistically significant lower risk of SCRT (HR 0.78 [CI: 0.67-0.92, p<0.01]; HR 0.77 [CI: 0.67-0.89, p<0.01], respectively), primarily due to lower frequency of radiotherapy (p<0.01). Compared to Caucasians, African Americans had lower risk of SCRT (HR 0.70 [CI: 0.60-0.82, p<0.01]), as well as all SCRT subtypes defining this group except for SCC, which was the same for both race groups. CONCLUSION: This study highlights that certain patient characteristics and clinical factors are associated with the risk of spinal cord compression or pathologic fractures, or need for bone surgery or radiation among women with metastatic BCa. In future studies, it will also be important to consider the clinical and economic burden based on these components of skeletal complications and radiation therapy use in order to guide and improve the management of women with advanced BCa. PMID- 29494654 TI - Preparation of plasticized poly (lactic acid) and its influence on the properties of composite materials. AB - Plasticized poly (lactic acid) (PPLA) was prepared by melt blending poly (lactic acid) (PLA) with 10 wt% of poly (ethylene glycol) (PEG), with varied molecular weights range from 400 to 4000. The structure, thermal property, morphology, and surface free energy of the PPLA were investigated by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimeter (DSC), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), and contact angles (CA). The resulting PPLA results indicated that the introduction of PEG to the blend systems resulted in a ductile fracture, a decrease in the melt temperature (Tm) and glass transfer temperature (Tg), and an increase in the degree of crystallization (chic), which indicated an improved flexibility. In addition, the polarity of the PPLA increased and the surface free energy decreased. The resulting PPLA was subsequently used as matrix to blend with wood flour to prepare composites. The mechanical strength, melting behavior, thermal stability, and microscopy of the PPLA/wood flour composites were also evaluated. These results illustrated that the plasticized PPLA matrix was beneficial to the interfacial compatibility between the polar filler and the substrate. PMID- 29494656 TI - Bile acid patterns in commercially available oxgall powders used for the evaluation of the bile tolerance ability of potential probiotics. AB - This study aimed to analyze the bile acid patterns in commercially available oxgall powders used for evaluation of the bile tolerance ability of probiotic bacteria. Qxgall powders purchased from Sigma-Aldrich, Oxoid and BD Difco were dissolved in distilled water, and analyzed. Conjugated bile acids were profiled by ion-pair high-performance liquid chromatography (HPLC), free bile acids were detected as their p-bromophenacyl ester derivatives using reversed-phase HPLC after extraction with acetic ether, and total bile acids were analyzed by enzymatic-colorimetric assay. The results showed that 9 individual bile acids (i.e., taurocholic acid, glycocholic acid, taurodeoxycholic acid, glycodeoxycholic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, cholic acid, chenodeoxycholic acid, deoxycholic acid) were present in each of the oxgall powders tested. The content of total bile acid among the three oxgall powders was similar; however, the relative contents of the individual bile acids among these oxgall powders were significantly different (P < 0.001). The oxgall powder from Sigma-Aldrich was closer to human bile in the ratios of glycine conjugated bile acids to taurine-conjugated bile acids, dihydroxy bile acids to trihydroxy bile acids, and free bile acids to conjugated bile acids than the other powders were. It was concluded that the oxgall powder from Sigma-Aldrich should be used instead of those from Oxoid and BD Difco to evaluate the bile tolerance ability of probiotic bacteria as human bile model. PMID- 29494655 TI - Minimizing activation of overlying axons with epiretinal stimulation: The role of fiber orientation and electrode configuration. AB - : Currently, a challenge in electrical stimulation of the retina with a visual prosthesis (bionic eye) is to excite only the cells lying directly under the electrode in the ganglion cell layer, while avoiding excitation of axon bundles that pass over the surface of the retina in the nerve fiber layer. Stimulation of overlying axons results in irregular visual percepts, limiting perceptual efficacy. This research explores how differences in fiber orientation between the nerve fiber layer and ganglion cell layer leads to differences in the electrical activation of the axon initial segment and axons of passage. APPROACH: Axons of passage of retinal ganglion cells in the nerve fiber layer are characterized by a narrow distribution of fiber orientations, causing highly anisotropic spread of applied current. In contrast, proximal axons in the ganglion cell layer have a wider distribution of orientations. A four-layer computational model of epiretinal extracellular stimulation that captures the effect of neurite orientation in anisotropic tissue has been developed using a volume conductor model known as the cellular composite model. Simulations are conducted to investigate the interaction of neural tissue orientation, stimulating electrode configuration, and stimulation pulse duration and amplitude. MAIN RESULTS: Our model shows that simultaneous stimulation with multiple electrodes aligned with the nerve fiber layer can be used to achieve selective activation of axon initial segments rather than passing fibers. This result can be achieved while reducing required stimulus charge density and with only modest increases in the spread of activation in the ganglion cell layer, and is shown to extend to the general case of arbitrary electrode array positioning and arbitrary target volume. SIGNIFICANCE: These results elucidate a strategy for more targeted stimulation of retinal ganglion cells with experimentally-relevant multi-electrode geometries and achievable stimulation requirements. PMID- 29494657 TI - Nutrient enrichment shifts mangrove height distribution: Implications for coastal woody encroachment. AB - Global changes, such as increased temperatures and elevated CO2, are driving shifts in plant species distribution and dominance, like woody plant encroachment into grasslands. Local factors within these ecotones can influence the rate of regime shifts. Woody encroachment is occurring worldwide, though there has been limited research within coastal systems, where mangrove (woody shrub/tree) stands are expanding into salt marsh areas. Because coastal systems are exposed to various degrees of nutrient input, we investigated how nutrient enrichment may locally impact mangrove stand expansion and salt marsh displacement over time. We fertilized naturally co-occurring Avicennia germinans (black mangrove) and Spartina alterniflora (smooth cordgrass) stands in Port Aransas, TX, an area experiencing mangrove encroachment within the Northern Gulf of Mexico mangrove marsh ecotone. After four growing seasons (2010-2013) of continuous fertilization, Avicennia was more positively influenced by nutrient enrichment than Spartina. Most notably, fertilized plots had a higher density of taller (> 0.5 m) mangroves and mangrove maximum height was 46% taller than in control plots. Fertilization may promote an increase in mangrove stand expansion within the mangrove-marsh ecotone by shifting Avicennia height distribution. Avicennia individuals, which reach certain species-specific height thresholds, have reduced negative neighbor effects and have higher resilience to freezing temperatures, which may increase mangrove competitive advantage over marsh grass. Therefore, we propose that nutrient enrichment, which augments mangrove height, could act locally as a positive feedback to mangrove encroachment, by reducing mangrove growth suppression factors, thereby accelerating the rates of increased mangrove coverage and subsequent marsh displacement. Areas within the mangrove-marsh ecotone with high anthropogenic nutrient input may be at increased risk of a regime shift from grass to woody dominated ecosystems. PMID- 29494658 TI - Anti-Epstein-Barr virus antibodies in Beijing during 2013-2017: What we have found in the different patients. AB - BACKGROUND: Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC) which is prevalent in South China, and its association with systemic lupus erythematosus (SLE) or other autoimmune diseases has not been studied in the mainland of China. The EBV serological tests have been performed on patients with various diseases or manifestations for years at our institution and their values need to be evaluated. METHODS: For routine medical purposes, anti-EB viral capsid antigen (VCA) IgG, IgA and IgM antibodies, anti-EBV diffuse early antigen (EA-D) IgA antibodies, and anti-EBV nuclear antigen-1(EBNA-1) IgG antibodies were tested with commercial enzyme-linked immunosorbent assay (ELISA) in patients visiting Peking Union Medical College Hospital between 2013 and 2017. The test results were analyzed in this retrospective study. RESULTS: There were a total of 11122 serum samples available to be tested in the study. As indicators of past EBV infection, the prevalence of VCA-IgG/EBNA1-IgG were 66.6%/58.5%, 84.3%/78.8%, 92.9%/87.0% and 98.5%/95.4% in patients aged under 5 years, 6-10 years, 11-20 years and 21-30 years old, respectively, and these values maintained at this highest rate as age increased further. The prevalence of VCA-IgM, as a parameter of acute EBV infection, was 14.6%, 10.2%, 10.4%, 6.3% and 3.1% in patients aged under 5 years, 6-10 years,11-20 years, 21-30 years, 31-40 years old, respectively, and decreased to 2%~3% in older patients. Patients with elevated serum liver enzymes were more likely to have a higher prevalence of EA/D IgA antibody (P < 0.01) and young patients (<=30 years) with lymphadenopathy were more likely to have higher prevalence of VCA-IgM antibody (P < 0.01). The prevalence of VCA-IgA and EAD-IgA were 87.0% and 59.2% in NPC patients, respectively, and both were significantly higher (P < 0.001) than that in non-NPC patients. The prevalence of VCA-IgA was 45.4% and 25.6% in SLE patients and patients with other autoimmune diseases, respectively, which were significantly (P < 0.001) and mildly (P = 0.039) higher than their controls. In pediatric SLE patients between 6 and10 years old, the prevalence of VCA-IgG, VCA-IgA and EBNA1 IgG was 100%, 59.5% and 100%, respectively, all being significantly higher than the age (6-10y) related controls (P< 0.01). In the 705 cerebral spinal fluid (CSF) specimens, VCA-IgG, VCA-IgM, VCA-IgA and EAD-IgA were found to be positive in 12.1%, 0.15%, 0.25% and 0.25%, respectively. There were 157 paired specimens (CSF and serum were collected simultaneously) and VCA-IgG was identified as positive in 12.7% of the CSF and 100% of the serum specimens. CONCLUSIONS: Around 98% of Chinese patients were infected with EBV before 30 years of age and the highest rate of acute EBV infection were observed in patients under 5 years old. EBV infection was found to be associated with elevated serum liver enzymes, NPC and SLE. Acute anti-EBV antibody was valued for young patients with lymphadenopathy but limited value for CNS neuropathy. PMID- 29494659 TI - Recommended next care following hospital-treated self-harm: Patterns and trends over time. AB - OBJECTIVE: The specific objectives of this study were to examine variation in the care of self-harm patients in hospital settings and to identify the factors that predict recommended next care following self-harm. METHODS: Data on consecutive presentations to Irish emergency departments (EDs) involving self-harm from the National Self-Harm Registry Ireland from 2004 to 2012 were utilised. Univariate and multivariate regression analyses were performed to assess the associations between patients' clinical and demographic characteristics, and recommended next care received. RESULTS: Across the study period a total 101,904 self-harm presentations were made to hospital EDs, involving 63,457 individuals. Over the course of the study there was a declining number of presentations resulting in patient admission following attendance with self-harm. Recommended next care varied according to hospital location, with general admission rates ranging from 11% to 61% across administrative health regions. Multinomial logistic regression identified that the factor which most strongly affected next care was the presenting hospital. Being male, older age, method, repeat self-harm, time of attendance and residence of the patient were all identified as influencing care received. Psychiatric admission was most common when highly lethal methods of self-harm were used (OR = 4.00, 95% CI, 3.63-4.41). A relatively large proportion of patients left the ED without being seen (15%) and the risk of doing so was highest for self-harm repeaters (1.64, 1.55-1.74 for those with 5+ presentations). CONCLUSIONS: The extensive hospital variation in recommended next care indicates that management of self-harm patients may be determined more by where they present than by the needs of the patient. The study outcomes underline the need to standardise the clinical management of self-harm patients in general hospital settings. PMID- 29494660 TI - Relationship between the degree of antioxidant protection and the level of malondialdehyde in high-performance Polish Holstein-Friesian cows in peak of lactation. AB - Lipid peroxidation can be described as a process under which free radicals attack carbon double bonds of omega-3 and omega-6 fatty acids. Whereas the end products of this process are reactive aldehydes, such as malondialdehyde (MDA). Lipid peroxidation leads to adverse changes in the nutritional value of milk; therefore, higher degree of antioxidant protection (DAP) ensures higher stability of dairy products by effecting their high antioxidative potential. Therefore, the purpose of this study was to demonstrate the relationship between the DAP and the level of MDA in high-performance Polish Holstein-Friesian cows in peak of lactation. Sixty-three Polish Holstein-Friesian cows were selected to the experiment according to: parity (all in the 2nd lactation), phase of lactation (peak of lactation), cytological quality of milk (somatic cell count < 150 thousand/ml) and without diagnosed metabolic diseases. The data obtained were analyzed statistically by two-way ANOVA, and Tukey's post-hoc test. After analysis of performance the cows were divided into 3 groups (twenty one cows in each group) based on milk yield and MDA concentration. The study revealed a significant effect of the lactation performance of cows on MDA levels in milk (P <= 0.01). The highest concentration of MDA (61.137 nM/mL) was shown in milk of cows yielding between 50.00 and 55.80 kg/day. The highest concentration of fat was found in milk in which the MDA level ranged from 48 to 86 nM/mL. Whereas, the inverse relationship was demonstrated in case of protein concentration. The highest level of protein was found in cows with MDA levels in the range of 18-28 nM/mL (P <= 0.01). The lowest MDA level (in the range of 18-28 nM/mL) was associated with the highest concentration of vitamin E, beta-carotene, total antioxidant status (TAS) and DAP, measured in both milk and plasma. The obtained results show that lipid peroxidation leads to adverse changes in the nutritional value of milk; the highest DAP (7.89 x 10-3) was found in the cows with the lowest MDA concentration in milk. PMID- 29494661 TI - Effects of truck-mounted, ultra low volume mosquito adulticides on honey bees (Apis mellifera) in a suburban field setting. AB - Few studies have examined the impact of mosquito adulticides on honey bees under conditions that reflect actual field exposure. Whereas several studies have evaluated the toxicity of mosquito control products on honey bees, most have been laboratory based and have focused solely on acute mortality as a measure of impact. The goal of this study was to determine effects of routine applications of truck-based ultra-low volume (ULV) mosquito adulticides (i.e., Scourge, Duet, and Deltagard) on honey bees in a suburban setting. The mosquito adulticides used in this study were pyrethroids with active ingredients resmethrin (Scourge), prallethrin and sumithrin (Duet), and deltamethrin (Deltagard), in which resmethrin, prallethrin, and sumithrin were synergized with piperonyl butoxide. We measured and compared mortality and detoxification enzyme activities (esterase and glutathione S-transferase) from sentinel beehives within and outside of mosquito control areas. Concurrently, colony health (i.e., number of adult bees, brood quantity and brood quality) was compared throughout the study period. No significant differences were observed in honey bee mortality, colony health or detoxification enzyme activities between treated (five sprayed areas each received one to three insecticide treatment) and control sites (four unsprayed areas that did not receive insecticide treatment) over the seven week study period. However, our laboratory study showed that exposure to resmethrin, the active ingredient in Scourge, caused significant inhibition of esterase activity compared with the control group. Our findings suggest that proper application of truck based insecticides for mosquito control results in little or no exposure and therefore minimal effects on domestic honey bees. PMID- 29494662 TI - Combined effect of glutamine at position 70 of HLA-DRB1 and alanine at position 57 of HLA-DQB1 in type 1 diabetes: An epitope analysis. AB - The contribution of specific HLA Class II alleles in type 1 diabetes is determined by polymorphic amino acid epitopes that direct antigen binding therefore, along with conventional allele frequency analysis, epitope analysis can provide important insights into disease susceptibility. We analyzed the highly heterogeneous Cypriot population for the HLA class II loci of T1DM patients and controls and we report for the first time their allele frequencies. Within our patient cohort we identified a subgroup that did not carry the DRB1*03:01-DQA1*05:01-DQB1*02:01 and DRB1*04:xx-DQA1*03:01-DQB1*03:02 risk haplotypes but a novel recombinant one, DRB1*04:XX-DQA1*03:01-DQB1*02:01 designated DR4-DQ2.3. Through epitope analysis we identified established susceptibility (DQB1 A57, DRB1 H13) and resistance (DQB1 D57) residues as well as other novel susceptibility residues DRB1 Q70, DQB1 L26 and resistance residues DRB1 D70, R70 and DQB1 Y47. Prevalence of susceptibility epitopes was higher in patients and was not exclusively a result of linkage disequilibrium. Residues DRB1 Q70, DQB1 L26 and A57 and a 10 amino acid epitope of DQA1 were the most significant in discriminating risk alleles. An extended haplotype containing these epitopes was carried by 92% of our patient cohort. Sharing of susceptibility epitopes could also explain the absence of risk haplotypes in patients. Finally, many significantly associated epitopes were non-pocket residues suggesting that critical immune functions may exist spanning further from the binding pockets. PMID- 29494663 TI - Separation and identification of bioactive peptides from stem of Tinospora cordifolia (Willd.) Miers. AB - Enzyme hydrolysates (trypsin, papain, pepsin, alpha-chymotrypsin, and pepsin pancreatin) of Tinospora cordifolia stem proteins were analyzed for antioxidant efficacy by measuring (1) 1,1-diphenyl-2-picrylhydrazyl (DPPH*) radical scavenging activity, (2) 2,20-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+) radical scavenging capacity, and (3) Fe2+ chelation. Trypsin hydrolysate showed the strongest DPPH* scavenging, while alpha-chymotrypsin hydrolysate exhibited the highest ABTS+ scavenging and Fe2+ chelation. Undigested protein strongly inhibited the gastrointestinal enzymes, trypsin (50% inhibition at enzyme/substrate ratio = 1:6.9) and alpha-chymotrypsin (50% inhibition at enzyme/substrate ratio = 1:1.82), indicating the prolonged antioxidant effect after ingestion. Furthermore, gel filtration purified peptide fractions of papain hydrolysates exhibited a significantly higher ABTS+ and superoxide radical scavenging as compared to non-purified digests. Active fraction 9 showing the highest radical scavenging ability was further purified and confirmed by MALDI TOF MS followed by MS/MS with probable dominant peptide sequences identified are VLYSTPVKMWEPGR, VITVVATAGSETMR, and HIGININSR. The obtained results revealed that free radical scavenging capacity of papain hydrolysates might be related to its consistently low molecular weight hydrophobic peptides. PMID- 29494664 TI - Cardiorespiratory, enzymatic and hormonal responses during and after walking while fasting. AB - The aim of the present study was to observe whether performing a low intensity endurance exercise following an overnight fasted (FAST) or fed (FED) condition promotes different cardiorespiratory, enzymatic and hormonal responses. Nine male physical active subjects, (age 21.89 +/- 2.52 years old, height 175.89 +/- 5.16 cm, weight 72.10 +/- 4.31 kg, estimated body fat 7.25 +/- 2.11%), randomly performed two sessions of 45 minutes' low intensity exercise (individual ventilator threshold) interspersed by seven days, differentiated only in whether they were provided with a standardized meal or not. The oxygen consumption (VO2) and heart rate (HR) were measured continuously at the 30-min rest, the 45-min during and the 30-min post-exercise. The testosterone (T) and cortisol (C) hormones were measured at rest, immediately post-exercise and 15-min post exercise. The Glucose (GLU), Free fatty acids (FFA) and enzyme lipase activity (ELP) were measured at rest, 15-min and 30-min exercise, immediately, 15-min and 30-min post-exercise. Significantly lower values were observed in FED compared to FAST with: C (nmol/L) from pre (428.87 +/- 120.41; 454.62 +/- 148.33, respectively) to immediately post-exercise (285.10 +/- 85.86; 465.66 +/- 137.70, respectively) and 15-min post-exercise (248.00 +/- 87.88; 454.31 +/- 112.72, respectively) (p<0.05); and GLU at all times, with an exception at 15-min post exercise. The testosterone/cortisol ratio (T/C) was significantly higher in the FED compared with FAST from pre (0.05 +/- 0.02, 0.05 +/- 0.01, respectively) to 15-min post-exercise (0.08 +/- 0.03, 0.05 +/- 0.02, respectively). No other significant differences were observed between conditions. We conclude that fasting prior to low intensity endurance exercise does not seem be advantageous, when it comes to fat loss, compared with the same exercise performed after a meal. PMID- 29494665 TI - MicroRNA-124-loaded nanoparticles increase survival and neuronal differentiation of neural stem cells in vitro but do not contribute to stroke outcome in vivo. AB - There is a high quest for novel therapeutic strategies to enhance recovery after stroke. MicroRNA-124 (miR-124) has been described as neuroprotective and anti inflammatory molecule. Moreover, miR-124 is a well described enhancer of adult neurogenesis that could offer potentially beneficial effects. Herein, we used miR 124-loaded nanoparticles (miR-124 NPs) to evaluate their therapeutic potential in an in vitro and in vivo model of stroke. For that, neuroprotective and neurogenic responses were assessed in an in vitro model of stroke. Here, we found that miR 124 NPs decreased cell death and improved neuronal differentiation of subventricular zone (SVZ) neural stem cell cultures after oxygen and glucose deprivation. In contrast, intravenous injection of miR-124 NPs immediately after permanent focal ischemia induced by photothrombosis (PT) did not provide a better neurological outcome. In addition, treatment did not affect the number of 5-bromo 2'-deoxyuridine (BrdU)- and doublecortin/BrdU- positive cells in the SVZ at the study endpoint of 14 days after PT. Likewise, the ischemic insult did not affect the numbers of neuronal progenitors in the SVZ. However, in PT mice miR-124 NPs were able to specifically augment interleukin-6 levels at day 2 post-stroke. Furthermore, we also showed that NPs reached the brain parenchyma and were internalized by brain resident cells. Although, promising in vitro data could not be verified in vivo as miR-124 NPs treatment did not improve functional outcome nor presented beneficial actions on neurogenesis or post-stroke inflammation, we showed that our NP formulation can be a safe alternative for drug delivery into the brain. PMID- 29494666 TI - Variables associated with subclinical atherosclerosis in a cohort of rheumatoid arthritis patients: Sex-specific associations and differential effects of disease activity and age. AB - OBJECTIVE: To advance the study of variables associated with subclinical atherosclerosis in rheumatoid arthritis (RA) with special consideration for the degree of disease activity, age and gender. METHODS: The carotid intima-media thickness (cIMT) and the presence of carotid atherosclerotic plaques along with clinical and biochemical characteristics were determined in 214 RA patients. RESULTS: Adjusted analysis reveals that men had a 0.059 mm significantly increased cIMT compared with women (p = 0.001; R2 = 3.8%) and that age was associated with cIMT (beta = 0.0048 mm; p = 0.0001; R2 = 16%). Interestingly, we observed a significant interaction between gender and age. Thus, the effect of age on cIMT was significantly increased (12%) in men compared with women (p-value for interaction term = 0.041). Moreover, adjusted multivariable linear regression analysis revealed that disease activity score (DAS28) was significantly associated with cIMT in women (beta = 0.021; p = 0.018: R2 = 0.03) but not men. In particular, women with high disease activity had a 0.079 mm increased cIMT compared with women in remission (p = 0.026). In addition, men in remission had a 0.134 mm increased cIMT compared with women in remission (p = 0.003; R2 = 8.7%). Active patients did not exhibit differences in cIMT values. Furthermore, 43% of patients presented carotid plaques. The variables independently associated with carotid plaques were age, smoking, health assessment questionnaire, erythrocyte sedimentation rate and rheumatoid factor (p<0.0001; R2 = 46%). CONCLUSION: In our cohort of patients with RA, DAS28 and age are differentially associated with cIMT in men and women. Our findings could explain the contradictory results that have previously been published in the literature. PMID- 29494667 TI - Spatiotemporal distribution and fluctuation of radiocesium in Tokyo Bay in the five years following the Fukushima Daiichi Nuclear Power Plant (FDNPP) accident. AB - A monitoring survey was conducted from August 2011 to July 2016 of the spatiotemporal distribution in the 400 km2 area of the northern part of Tokyo Bay and in rivers flowing into it of radiocesium released from the Fukushima Daiichi Nuclear Power Plant (FDNPP) accident. The average inventory in the river mouth (10 km2) was 131 kBq?m-2 and 0.73 kBq?m-2 in the central bay (330 km2) as the decay corrected value on March 16, 2011. Most of the radiocesium that flowed into Tokyo Bay originated in the northeastern section of the Tokyo metropolitan area, where the highest precipitation zone of 137Cs in soil was almost the same level as that in Fukushima City, then flowed into and was deposited in the Old-Edogawa River estuary, deep in Tokyo Bay. The highest precipitation of radiocesium measured in the high contaminated zone was 460 kBq?m-2. The inventory in sediment off the estuary of Old-Edogawa was 20.1 kBq?m-2 in August 2011 immediately after the accident, but it increased to 104 kBq?m-2 in July 2016. However, the radiocesium diffused minimally in sediments in the central area of Tokyo Bay in the five years following the FDNPP accident. The flux of radiocesium off the estuary decreased slightly immediately after the accident and conformed almost exactly to the values predicted based on its radioactive decay. Contrarily, the inventory of radiocesium in the sediment has increased. It was estimated that of the 8.33 TBq precipitated from the atmosphere in the catchment regions of the rivers Edogawa and Old-Edogawa, 1.31 TBq migrated through rivers and was deposited in the sediments of the Old-Edogawa estuary by July 2016. Currently, 0.25 TBq?yr-1 of radiocesium continues to flow into the deep parts of Tokyo Bay. PMID- 29494668 TI - Pathological hypertrophy and cardiac dysfunction are linked to aberrant endogenous unsaturated fatty acid metabolism. AB - Pathological cardiac hypertrophy leads to derangements in lipid metabolism that may contribute to the development of cardiac dysfunction. Since previous studies, using high saturated fat diets, have yielded inconclusive results, we investigated whether provision of a high-unsaturated fatty acid (HUFA) diet was sufficient to restore impaired lipid metabolism and normalize diastolic dysfunction in the pathologically hypertrophied heart. Male, Wistar rats were subjected to supra-valvar aortic stenosis (SVAS) or sham surgery. After 6 weeks, diastolic dysfunction and pathological hypertrophy was confirmed and both sham and SVAS rats were treated with either normolipidic or HUFA diet. At 18 weeks post-surgery, the HUFA diet failed to normalize decreased E/A ratios or attenuate measures of cardiac hypertrophy in SVAS animals. Enzymatic activity assays and gene expression analysis showed that both normolipidic and HUFA-fed hypertrophied hearts had similar increases in glycolytic enzyme activity and down-regulation of fatty acid oxidation genes. Mass spectrometry analysis revealed depletion of unsaturated fatty acids, primarily linoleate and oleate, within the endogenous lipid pools of normolipidic SVAS hearts. The HUFA diet did not restore linoleate or oleate in the cardiac lipid pools, but did maintain body weight and adipose mass in SVAS animals. Overall, these results suggest that, in addition to decreased fatty acid oxidation, aberrant unsaturated fatty acid metabolism may be a maladaptive signature of the pathologically hypertrophied heart. The HUFA diet is insufficient to reverse metabolic remodeling, diastolic dysfunction, or pathologically hypertrophy, possibly do to preferentially partitioning of unsaturated fatty acids to adipose tissue. PMID- 29494669 TI - K-ras mutation analysis of residual liquid-based cytology specimens from endoscopic ultrasound-guided fine needle aspiration improves cell block diagnosis of pancreatic ductal adenocarcinoma. AB - BACKGROUND: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) technology is widely used for the diagnosis of pancreatic masses. However, in some cases, inadequate tissue volume or difficulty of morphological diagnosis are constraining factors for adequate cytopathological evaluation. K-ras mutation is the most frequently acquired genetic abnormality, occurring in approximately 90% of all patients with pancreatic ductal adenocarcinoma (PDAC). In the present study, the clinical utility of residual liquid-based cytology (LBC) specimens obtained using EUS-FNA for K-ras mutation analysis was evaluated. METHODS: In this study, 81 patients with pancreatic lesions were examined. The cell block (CB) specimens separated from EUS-FNA samples were morphologically evaluated by hematoxylin-eosin (HE) staining. Final diagnoses were confirmed by CB specimens, surgical resection specimens, diagnostic imaging, and clinical follow-up. Genomic DNA of residual LBC specimens stored at 4 degrees C for several months were extracted and assessed for K-ras mutations using a fluorescence resonance energy transfer-based preferential homoduplex formation assay. RESULTS: K-ras mutation analysis using residual LBC samples was successful in all cases. The sensitivity, specificity, and accuracy of CB examination alone were 77.4%, 100%, and 81.3%, respectively, and those of the combination of CB examination and K-ras mutation analysis were 90.3%, 92.3%, and 90.7%, respectively. Furthermore, K-ras mutations were detected in 8 (57.1%) of 14 PDAC samples for which the CB results were inconclusive. CONCLUSION: These findings suggest that K-ras mutation analysis using residual LBC specimens improves the diagnostic accuracy of EUS-FNA. PMID- 29494670 TI - Dissociable effects of practice variability on learning motor and timing skills. AB - Motor skill acquisition inherently depends on the way one practices the motor task. The amount of motor task variability during practice has been shown to foster transfer of the learned skill to other similar motor tasks. In addition, variability in a learning schedule, in which a task and its variations are interweaved during practice, has been shown to help the transfer of learning in motor skill acquisition. However, there is little evidence on how motor task variations and variability schedules during practice act on the acquisition of complex motor skills such as music performance, in which a performer learns both the right movements (motor skill) and the right time to perform them (timing skill). This study investigated the impact of rate (tempo) variability and the schedule of tempo change during practice on timing and motor skill acquisition. Complete novices, with no musical training, practiced a simple musical sequence on a piano keyboard at different rates. Each novice was assigned to one of four learning conditions designed to manipulate the amount of tempo variability across trials (large or small tempo set) and the schedule of tempo change (randomized or non-randomized order) during practice. At test, the novices performed the same musical sequence at a familiar tempo and at novel tempi (testing tempo transfer), as well as two novel (but related) sequences at a familiar tempo (testing spatial transfer). We found that practice conditions had little effect on learning and transfer performance of timing skill. Interestingly, practice conditions influenced motor skill learning (reduction of movement variability): lower temporal variability during practice facilitated transfer to new tempi and new sequences; non-randomized learning schedule improved transfer to new tempi and new sequences. Tempo (rate) and the sequence difficulty (spatial manipulation) affected performance variability in both timing and movement. These findings suggest that there is a dissociable effect of practice variability on learning complex skills that involve both motor and timing constraints. PMID- 29494671 TI - Full-length genome sequences of porcine epidemic diarrhoea virus strain CV777; Use of NGS to analyse genomic and sub-genomic RNAs. AB - Porcine epidemic diarrhoea virus, strain CV777, was initially characterized in 1978 as the causative agent of a disease first identified in the UK in 1971. This coronavirus has been widely distributed among laboratories and has been passaged both within pigs and in cell culture. To determine the variability between different stocks of the PEDV strain CV777, sequencing of the full-length genome (ca. 28kb) has been performed in 6 different laboratories, using different protocols. Not surprisingly, each of the different full genome sequences were distinct from each other and from the reference sequence (Accession number AF353511) but they are >99% identical. Unique and shared differences between sequences were identified. The coding region for the surface-exposed spike protein showed the highest proportion of variability including both point mutations and small deletions. The predicted expression of the ORF3 gene product was more dramatically affected in three different variants of this virus through either loss of the initiation codon or gain of a premature termination codon. The genome of one isolate had a substantially rearranged 5'-terminal sequence. This rearrangement was validated through the analysis of sub-genomic mRNAs from infected cells. It is clearly important to know the features of the specific sample of CV777 being used for experimental studies. PMID- 29494672 TI - Genetic approaches to identify pathological limitations in aortic smooth muscle contraction. AB - Aortic smooth muscle contains limiting amounts of myosin light chain kinase (MLCK) for myosin regulatory light chain (RLC) phosphorylation and contraction that predisposes to thoracic aortic disease in humans containing heterozygous loss-of-function mutations in MYLK. We tested the hypothesis that thoracic aortic smooth muscle contraction may also be susceptible to variations in the smooth muscle-specific isoform of the motor protein myosin where inactivation of one Myh11 allele or the presence of one Myh11 missense variant associated with an increased risk of human aortic disease may result in a reduced force development response. Additionally, other kinds of smooth muscles may be less sensitive to the effects of mutations in one smooth muscle myosin allele, similar to results obtained with Mylk. Force development responses were reduced in aortic tissue from a conditional knockout of smooth muscle myosin heavy chain in adult mice (Myh11+/- or Myh11-/-) with a greater reduction with homozygous vs heterozygous tissues. Similar reductions in force responses were obtained with tissues containing either a heterozygous or homozygous knockin mutation in smooth muscle myosin heavy chain (Myh11+/R247C or Myh11R247C/R247C mutations that cause human aortic disease) with no significant changes in RLC phosphorylation. Agonist dependent force responses were not reduced significantly in urinary bladder, ileal, or tracheal tissues from Myh11+/- mice while only ileal tissue showed a reduced force response in Myh11R247C/R247C mice. Thus, heterozygous mutations in Myh11 associated with reduced myosin function result in compromised contractile function primarily in aortic smooth muscle. PMID- 29494673 TI - The bovine TRPV3 as a pathway for the uptake of Na+, Ca2+, and NH4+ AB - Absorption of ammonia from the gastrointestinal tract results in problems that range from hepatic encephalopathy in humans to poor nitrogen efficiency of cattle with consequences for the global climate. Previous studies on epithelia and cells from the native ruminal epithelium suggest functional involvement of the bovine homologue of TRPV3 (bTRPV3) in ruminal NH4+ transport. Since the conductance of TRP channels to NH4+ has never been studied, bTRPV3 was overexpressed in HEK-293 cells and investigated using the patch-clamp technique and intracellular calcium imaging. Control cells contained the empty construct. Divalent cations blocked the conductance for monovalent cations in both cell types, with effects higher in cells expressing bTRPV3. In bTRPV3 cells, but not in controls, menthol, thymol, carvacrol, or 2-APB stimulated whole cell currents mediated by Na+, Cs+, NH4+, and K+, with a rise in intracellular Ca2+ observed in response to menthol. While only 25% of control patches showed single-channel events (with a conductance of 40.8 +/- 11.9 pS for NH4+ and 25.0 +/- 5.8 pS for Na+), 90% of bTRPV3 patches showed much larger conductances of 127.8 +/- 4.2 pS for Na+, 240.1 +/- 3.6 pS for NH4+, 34.0 +/- 1.7 pS for Ca2+, and ~ 36 pS for NMDG+. Open probability, but not conductance, rose with time after patch excision. In conjunction with previous research, we suggest that bTRPV3 channels may play a role in the transport of Na+, K+, Ca2+ and NH4+ across the rumen with possible repercussions for understanding the function of TRPV3 in other epithelia. PMID- 29494674 TI - Post mortem findings and their relation to AA amyloidosis in free-ranging Herring gulls (Larus argentatus). AB - Since the late 1990s, high mortality and declining populations have been reported among sea birds including Herring gulls (Larus argentatus) from the Baltic Sea area in Northern Europe. Repeated BoNT type C/D botulism outbreaks have occurred, but it remains unclear whether this is the sole and primary cause of mortality. Thiamine deficiency has also been suggested as a causal or contributing factor. With this study, we aimed to investigate gross and microscopic pathology in Herring gulls from affected breeding sites in Sweden in search of contributing diseases. Herring gulls from Iceland served as controls. Necropsies and histopathology were performed on 75 birds, of which 12 showed signs of disease at the time of necropsy. Parasites of various classes and tissues were commonly observed independent of host age, e.g. oesophageal capillariosis and nematode infection in the proventriculus and gizzard with severe inflammation, air sac larid pentastomes and bursal trematodiasis in pre-fledglings. Gross and microscopic findings are described. Notably, amyloidosis was diagnosed in 93 and 33% of the adult birds from Sweden and Iceland, respectively (p<0.001), with more pronounced deposits in Swedish birds (p<0.001). Gastrointestinal deposits were observed in the walls of arteries or arterioles, and occasionally in villi near the mucosal surface. Amyloid was identified within the intestinal lumen in one severely affected gull suggesting the possibility of oral seeding and the existence of a primed state as previously described in some mammals and chickens. This could speculatively explain the high occurrence and previously reported rapid onset of amyloidosis upon inflammation or captivity in Herring gulls. Amyloid-induced malabsorbtion is also a possibility. The Herring gull SAA/AA protein sequence was shown to be highly conserved but differed at the N-terminus from other avian species. PMID- 29494675 TI - Indoleamine 2 3-dioxygenase knockout limits angiotensin II-induced aneurysm in low density lipoprotein receptor-deficient mice fed with high fat diet. AB - AIMS: Abdominal aortic aneurysm (AAA) is an age-associated disease characterized by chronic inflammation, vascular cell apoptosis and metalloproteinase-mediated extracellular matrix degradation. Despite considerable progress in identifying targets involved in these processes, therapeutic approaches aiming to reduce aneurysm growth and rupture are still scarce. Indoleamine 2-3 dioxygenase 1 (IDO) is the first and rate-limiting enzyme involved in the conversion of tryptophan (Trp) into kynurenine (Kyn) pathway. In this study, we investigated the role of IDO in two different models of AAA in mice. METHODS AND RESULTS: Mice with deficiencies in both low density receptor-deficient (Ldlr-/-) and IDO (Ldlr-/ Ido1-/-) were generated by cross-breeding Ido1-/- mice with Ldlr-/-mice. To induce aneurysm, these mice were infused with angiotensin II (Ang II) (1000 ng/min/kg) and fed with high fat diet (HFD) during 28 days. AAAs were present in almost all Ldlr-/- infused with AngII, but only in 50% of Ldlr-/-Ido1-/- mice. Immunohistochemistry at an early time point (day 7) revealed no changes in macrophage and T lymphocyte infiltration within the vessel wall, but showed reduced apoptosis, as assessed by TUNEL assay, and increased alpha-actin staining within the media of Ldlr-/-Ido1-/- mice, suggesting enhanced survival of vascular smooth muscle cells (VSMCs) in the absence of IDO. In another model of elastase induced AAA in C57Bl/6 mice, IDO deficiency had no effect on aneurysm formation. CONCLUSION: Our study showed that the knockout of IDO prevented VSMC apoptosis in AngII -treated Ldlr-/- mice fed with HFD, suggesting a detrimental role of IDO in AAA formation and thus would be an important target for the treatment of aneurysm. PMID- 29494676 TI - Correction: A systematic review of the relationship between internet use, self harm and suicidal behaviour in young people: The good, the bad and the unknown. AB - [This corrects the article DOI: 10.1371/journal.pone.0181722.]. PMID- 29494677 TI - How education systems shape cross-national ethnic inequality in math competence scores: Moving beyond mean differences. AB - Here we examine a conceptualization of immigrant assimilation that is based on the more general notion that distributional differences erode across generations. We explore this idea by reinvestigating the efficiency-equality trade-off hypothesis, which posits that stratified education systems educate students more efficiently at the cost of increasing inequality in overall levels of competence. In the context of ethnic inequality in math achievement, this study explores the extent to which an education system's characteristics are associated with ethnic inequality in terms of both the group means and group variances in achievement. Based on data from the 2012 PISA and mixed-effect location scale models, our analyses revealed two effects: on average, minority students had lower math scores than majority students, and minority students' scores were more concentrated at the lower end of the distribution. However, the ethnic inequality in the distribution of scores declined across generations. We did not find compelling evidence that stratified education systems increase mean differences in competency between minority and majority students. However, our analyses revealed that in countries with early educational tracking, minority students' math scores tended to cluster at the lower end of the distribution, regardless of compositional and school differences between majority and minority students. PMID- 29494678 TI - Correction: A mathematical model of multisite phosphorylation of tau protein. AB - [This corrects the article DOI: 10.1371/journal.pone.0192519.]. PMID- 29494680 TI - Edge effects and beta diversity in ground and canopy beetle communities of fragmented subtropical forest. AB - Clearing of dry forests globally creates edges between remnant forest and open anthropogenic habitats. We used flight intercept traps to evaluate how forest beetle communities are influenced by distance from such edges, together with vertical height, spatial location, and local vegetation structure, in an urbanising region (Brisbane, Australia). Species composition (but not total abundance or richness) differed greatly between ground and canopy. Species composition also varied strongly among sites at both ground and canopy levels, but almost all other significant effects occurred only at ground level, where: species richness declined from edge to interior; composition differed between positions near edges (<10 m) and interiors (> 50 m); high local canopy cover was associated with greater total abundance and richness and differing composition; and greater distances to the city centre were associated with increased total abundances and altered composition. Analyses of individual indicator species associated with this variation enabled further biological interpretations. A global literature synthesis showed that most spatially well-replicated studies of edge effects on ground-level beetles within forest fragments have likewise found that positions within tens of metres from edges with open anthropogenic habitats had increased species richness and different compositions from forest interior sites, with fewer effects on abundance. Accordingly, negative edge effects will not prevent relatively small compact fragments (if >10-20 ha) from supporting forest-like beetle communities, although indirect consequences of habitat degradation remain a threat. Retention of multiple spatially scattered forest areas will also be important in conserving forest-dependent beetles, given high levels of between-site diversity. PMID- 29494679 TI - Wolbachia-mediated virus blocking in mosquito cells is dependent on XRN1-mediated viral RNA degradation and influenced by viral replication rate. AB - Wolbachia is currently being developed as a novel tool to block the transmission of dengue viruses (DENV) by Aedes aegypti. A number of mechanisms have been proposed to explain the DENV-blocking phenotype in mosquitoes, including competition for fatty acids like cholesterol, manipulation of host miRNAs and upregulation of innate immune pathways in the mosquito. We examined the various stages in the DENV infection process to better understand the mechanism of Wolbachia-mediated virus blocking (WMVB). Our results suggest that infection with Wolbachia does not inhibit DENV binding or cell entry, but reduces virus replication. In contrast to a previous report, we also observed a similar reduction in replication of West Nile virus (WNV). This reduced replication is associated with rapid viral RNA degradation in the cytoplasm. We didn't find a role for host miRNAs in WMVB. Further analysis showed that the 3' end of the virus subgenomic RNA was protected and accumulated over time suggesting that the degradation is XRN1-mediated. We also found that sub genomic flavivirus RNA accumulation inactivated XRN1 in mosquito cells in the absence of Wolbachia and led to enhancement of RNA degradation in its presence. Depletion of XRN1 decreased WMVB which was associated with a significant increase in DENV RNA. We also observed that WMVB is influenced by virus MOI and rate of virus replication. A comparatively elevated blocking was observed for slowly replicating DENV, compared to WNV. Similar results were obtained while analysing different DENV serotypes. PMID- 29494681 TI - A new cell culture model to genetically dissect the complete human papillomavirus life cycle. AB - Herein, we describe a novel infection model that achieves highly efficient infection of primary keratinocytes with human papillomavirus type 16 (HPV16). This cell culture model does not depend on immortalization and is amenable to extensive genetic analyses. In monolayer cell culture, the early but not late promoter was active and yielded a spliced viral transcript pattern similar to HPV16-immortalized keratinocytes. However, relative levels of the E8^E2 transcript increased over time post infection suggesting the expression of this viral repressor is regulated independently of other early proteins and that it may be important for the shift from the establishment to the maintenance phase of the viral life cycle. Both the early and the late promoter were strongly activated when infected cells were subjected to differentiation by growth in methylcellulose. When grown as organotypic raft cultures, HPV16-infected cells expressed late E1^E4 and L1 proteins and replication foci were detected, suggesting that they supported the completion of the viral life cycle. As a proof of principle that the infection system may be used for genetic dissection of viral factors, we analyzed E1, E6 and E7 translation termination linker mutant virus for establishment of infection and genome maintenance. E1 but not E6 and E7 was essential to establish infection. Furthermore, E6 but not E7 was required for episomal genome maintenance. Primary keratinocytes infected with wild type HPV16 immortalized, whereas keratinocytes infected with E6 and E7 knockout virus began to senesce 25 to 35 days post infection. The novel infection model provides a powerful genetic tool to study the role of viral proteins throughout the viral life cycle but especially for immediate early events and enables us to compare low- and high-risk HPV types in the context of infection. PMID- 29494683 TI - Design and feasibility testing of a novel group intervention for young women who binge drink in groups. AB - BACKGROUND: Young women frequently drink alcohol in groups and binge drinking within these natural drinking groups is common. This study describes the design of a theoretically and empirically based group intervention to reduce binge drinking among young women. It also evaluates their engagement with the intervention and the acceptability of the study methods. METHODS: Friendship groups of women aged 18-35 years, who had two or more episodes of binge drinking (>6 UK units on one occasion; 48g of alcohol) in the previous 30 days, were recruited from the community. A face-to-face group intervention, based on the Health Action Process Approach, was delivered over three sessions. Components of the intervention were woven around fun activities, such as making alcohol free cocktails. Women were followed up four months after the intervention was delivered. RESULTS: The target of 24 groups (comprising 97 women) was recruited. The common pattern of drinking was infrequent, heavy drinking (mean consumption on the heaviest drinking day was UK 18.1 units). Process evaluation revealed that the intervention was delivered with high fidelity and acceptability of the study methods was high. The women engaged positively with intervention components and made group decisions about cutting down. Twenty two groups set goals to reduce their drinking, and these were translated into action plans. Retention of individuals at follow up was 87%. CONCLUSIONS: This study successfully recruited groups of young women whose patterns of drinking place them at high risk of acute harm. This novel approach to delivering an alcohol intervention has potential to reduce binge drinking among young women. The high levels of engagement with key steps in the behavior change process suggests that the group intervention should be tested in a full randomised controlled trial. PMID- 29494684 TI - Neurogenic bladder findings in patients with Congenital Zika Syndrome: A novel condition. AB - INTRODUCTION: Congenital Zika Syndrome (CZS) has been associated with microcephaly and other central nervous system abnormalities including areas that have been implicated in the control of the lower urinary tract. As such, this descriptive case series has aimed to investigate whether CZS is linked with neurogenic bladder. Identifying such an association is paramount in the effort to recognize CZS complications that have putative treatment options that could mitigate the impact of CZS in infected children. METHODS: Following IRB approval, urological assessment was performed in all patients referred to our clinic between June 2016 and May 2017 who presented with confirmed CZS-associated microcephaly. The research protocol consisted of obtaining clinical history, laboratory tests, lower and upper urinary tract ultrasounds, as well as a diagnostic urodynamic evaluation. ZIKA virus infection was previously confirmed by maternal history and positive PCR in babies and mothers. Microcephaly and other central nervous system abnormalities were established based on neurological assessment and associated imaging of the central nervous system (CT head and/or Brain MRI). RESULTS: Twenty-two consecutive CZS patients were tested and confirmed to have neurogenic bladder. Of the 22 patients assessed, 21 presented with an overactive bladder combined with reduced bladder capacity and elevated detrusor filling pressures. Clinically significant increases in postvoid residual (PVR) were confirmed in 40% of cases while a urinary tract infection (UTI) was identified in 23% of cases. CONCLUSION: Neurogenic bladder, a known treatable health condition, was confirmed in 100% of patients tested in this study, most presenting with high-risk urodynamic patterns known to lead to renal damage when left untreated. Follow up studies are necessary to provide further insight onto long-term disease progression and to investigate the response to standard therapies for neurogenic bladder. Nonetheless, we emphasize the importance of proactive management of neurogenic bladder and prompt referral so as to help mitigate CZS disease burden for patients and their families. PMID- 29494682 TI - Overproduction of Sch9 leads to its aggregation and cell elongation in Saccharomyces cerevisiae. AB - The Sch9 kinase of Saccharomyces cerevisiae is one of the major TOR pathway effectors and regulates diverse processes in the cell. Sch9 belongs to the AGC kinase family. In human, amplification of AGC kinase genes is connected with cancer. However, not much is known about the effects of Sch9 overproduction in yeast cells. To fill this gap, we developed a model system to monitor subcellular location and aggregation state of overproduced Sch9 or its regions fused to a fluorescent protein. With this system, we showed that Sch9-YFP forms detergent resistant aggregates, and multiple protein regions are responsible for this. This finding corroborated the fact that Sch9-YFP is visualized as various fluorescent foci. In addition, we found that Sch9 overproduction caused cell elongation, and this effect was determined by its C-terminal region containing kinase domains. The constructs we present can be exploited to create superior yeast-based model systems to study processes behind kinase overproduction in cancers. PMID- 29494685 TI - Does dexmedetomidine have an antiarrhythmic effect on cardiac patients? A meta analysis of randomized controlled trials. AB - BACKGROUND: Cardiac surgery patients often experience several types of tachyarrhythmias after admission to the intensive care unit (ICU), which increases mortality and morbidity. Dexmedetomidine (DEX) is a popular medicine used for sedation in the ICU, and its other pharmacological characteristics are gradually being uncovered. PURPOSE: To determine whether DEX has an antiarrhythmic effect after cardiac surgery. METHODS: The three primary databases MEDLINE, Embase (OVID SP) and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched, and all English-language and randomized control-designed clinical publications comparing DEX to control medicines for sedation after elective cardiac surgery were included. Two colleagues independently extracted the data and performed other quality assessments. A subgroup analysis was performed according to the different medicines used and whether cardiopulmonary bypass (CPB) was applied. All tachyarrhythmias that occurred in the atria and ventricles were analyzed. RESULTS: A total of 1295 patients in 9 studies met the selection criteria among 2587 studies that were screened. After quantitative synthesis, our results revealed that the DEX group was associated with a lower incidence of ventricular arrhythmia (VA, OR 0.24, 95% CI 0.09-0.64, I2 = 0%, P = 0.005) than the control group. Subgroup analysis did not reveal a significant difference between the DEX and propofol subgroups (OR 0.13, 95% CI 0.03-0.56, I2 = 0%, P = 0.007). Additionally, no difference in the incidence of atrial fibrillation (AF) was observed regardless of the different control medicines (OR 0.82, 95% CI 0.60-1.10, I2 = 25%, P = 0.19) or whether CPB was applied. CONCLUSIONS: This meta-analysis revealed that DEX has an antiarrhythmic effect that decreases the incidence of VA compared to other drugs used for sedation following cardiac surgery. DEX may not have an effect on AF, but cautious interpretation should be exercised due to high heterogeneity. PMID- 29494687 TI - A novel badnavirus discovered from Betula sp. affected by birch leaf-roll disease. AB - In declining birches (Betula sp.) from different European stands affected by the "birch leaf-roll disease" (BLRD) a novel virus is identified by means of RNA-Seq virome analysis. The virus represents a new member in the genus Badnavirus, family Caulimoviridae, tentatively named Birch leaf roll-associated virus (BLRaV) and it is the first badnavirus found to infect birch. Complete genome sequences (7,862-7,864 nucleotides) of three viral isolates of Finnish and German origin have been determined. The virus sequences show a typical badnavirus organization with three major open reading frames (ORFs) and a fourth potential ORF overlapping with the end of ORF3. ORFs 1-2-3 show low level of amino acid identity to the corresponding proteins encoded by other badnaviruses, reaching a maximum of 44% identity (ORF3). Grapevine vein-clearing virus appears as the closest badnavirus when considering the polymerase region. So far, we can exclude evidence for presence of endogenous BLRaV elements in the birch genome, while evidence for the episomal activity of BLRaV is provided. The viral population holds significant haplotype diversity, while co-infection by different BLRaV variants are observed in single hosts. BLRaV presence is associated with the BLRD in both silver (B. pendula) and downy birch (B. pubescens). These results challenge the earlier hypothesis of a causal role of Cherry leaf roll virus in BLRD. Further work is now needed to finally prove that BLRaV is the causal agent for the BLRD. PMID- 29494686 TI - Single-sex schistosome infections of definitive hosts: Implications for epidemiology and disease control in a changing world. PMID- 29494689 TI - If there's a penis, it's most likely a man: Investigating the social construction of gender using eye tracking. AB - In their foundational work on the social construction of gender, Kessler and McKenna (1978) investigated the relationship between gender attribution and genital attribution. We used digital reproductions of the original stimuli to replicate their findings in the current social context. To further investigate the underlying decision processes we applied eye tracking. The stimuli shown varied in the composition of gender cues: from those more commonly associated with maleness to associated with femaleness. Applying the ethnomethodological approach originally used, participants were asked to decide for each stimulus whether they saw a man or a woman and to indicate subjective confidence with the decision. In line with the original results we found that the genital attribution contributed immensely to the gender attribution. Also, male gender was ascribed more often when the penis was present than was female gender when the vulva was shown. Eye tracking revealed that overall most dwell time as a proxy for important information was dedicated to the head, chest and genital areas of all the stimuli. Total dwell time depended on whether the gender attribution was made in line with the depicted genital, if the genital was a penis. Attributing female gender when a penis was present was associated with longer total dwell time, unlike attributing male gender with a vulva shown. This is indicative of higher cognitive effort and more difficulty ignoring the penis as opposed to the vulva. We interpret this finding in context of the persistent male dominance as well as to the socio-cultural understanding of the vulva as a concealed and therefore seemingly absent organ. In summary, we were able to show that the gender attribution is still closely linked to genital attribution when having a binary forced choice task and that the penis is a special cue in this attribution process. PMID- 29494688 TI - Establishment and evaluation of the goose embryo epithelial (GEE) cell line as a new model for propagation of avian viruses. AB - In this study, we report the establishment and characterization of a new epithelial cell line, goose embryonated epithelial cell line (GEE), derived from embryonic goose tissue. The purified GEE cell line can efficiently grow over 65 passages in the M199 medium supplemented with 10% fetal bovine serum at 37 degrees C. Immunofluorescence assay was used to identify purified GEE cells as epithelial cell line by detecting expression of the Keratin-18 and -19. Further characterizations demonstrated that the GEE cell line can be continuously subcultured with (i) a high capacity to replicate for over 65 passages, (ii) a spontaneous epithelial-like morphology, (iii) constant chromosomal features and (iv) without an evidence of converting to tumorigenic cells either in vitro or in vivo study. Moreover, the GEE cell line can be effectively transfected with plasmids expressing reporter genes of different avian viruses, such as VP3, VP1 and F of goose parvo virus (GPV), duck hepatitis virus (DHV), and Newcastle disease virus (NDV), respectively. Finally, the established GEE cell line was evaluated for avian viruses infection susceptibility. Our results showed that the tested GPV, DHAV and NDV were capable to replicate in the new cell line with titers a comparatively higher to the ones detected in the traditional culture system. Accordingly, our established GEE cell line is apparently a suitable in vitro model for transgenic, and infection manipulation studies. PMID- 29494690 TI - When the mother-in-law is just as good-Differential mortality of reproductive females by family network composition. AB - Motivated by the cooperative breeding hypothesis, we investigate the effect of having kin on the mortality of reproductive women based on family reconstitutions for the Krummhorn region (East Frisia, Germany, 1720-1874). We rely on a combination of Cox clustered hazard models and hazard models stratified at the family level. In order to study behavior-related effects, we run a series of models in which only kin who lived in the same parish are considered. To investigate structural, non-behavior-related effects, we run a different model series that include all living kin, regardless their spatial proximity. We find that women of reproductive age who had a living mother had a reduced mortality risk. It appears that having living sisters had an ambivalent impact on women's mortality: i.e., depending on the socioeconomic status of the family, the effect of having living sisters ranged between representing a source of competition and representing a source of support. Models which are clustered at the family level suggest that the presence of a living mother-in-law was associated with reduced mortality among her daughters-in-law especially among larger-scale farm families. We interpret this finding as a consequence of augmented consanguineous marriages among individuals of higher social strata. For instance, in first cousin marriages, the mother-in-law could also be a biological aunt. Thus, it appears that among the wealthy elite, the genetic in-law conflict was neutralized to some extent by family solidarity. This result further suggests that the tipping point of the female trade-off between staying with the natal family and leaving the natal family to join an economically well-established in-law family might have been reached very quickly among women living under the socioeconomic conditions of the Krummhorn region. PMID- 29494691 TI - In vivo biomechanical measurement and haptic simulation of portal placement procedure in shoulder arthroscopic surgery. AB - A survey of 67 experienced orthopedic surgeons indicated that precise portal placement was the most important skill in arthroscopic surgery. However, none of the currently available virtual reality simulators include simulation / training in portal placement, including haptic feedback of the necessary puncture force. This study aimed to: (1) measure the in vivo force and stiffness during a portal placement procedure in an actual operating room and (2) implement active haptic simulation of a portal placement procedure using the measured in vivo data. We measured the force required for port placement and the stiffness of the joint capsule during portal placement procedures performed by an experienced arthroscopic surgeon. Based on the acquired mechanical property values, we developed a cable-driven active haptic simulator designed to train the portal placement skill and evaluated the validity of the simulated haptics. Ten patients diagnosed with rotator cuff tears were enrolled in this experiment. The maximum peak force and joint capsule stiffness during posterior portal placement procedures were 66.46 (+/-10.76N) and 2560.82(+/-252.92) N/m, respectively. We then designed an active haptic simulator using the acquired data. Our cable driven mechanism structure had a friction force of 3.763 +/- 0.341 N, less than 6% of the mean puncture force. Simulator performance was evaluated by comparing the target stiffness and force with the stiffness and force reproduced by the device. R-squared values were 0.998 for puncture force replication and 0.902 for stiffness replication, indicating that the in vivo data can be used to implement a realistic haptic simulator. PMID- 29494693 TI - An assessment of direct and indirect costs of dementia in Brazil. AB - BACKGROUND: To analyze costs associated with dementia based on a cross-sectional study in the Brazilian health system. METHODS: Direct and indirect costs were estimated by conducting comprehensive interviews on the use of resources in a sample of 156 patients with dementia treated at an outpatient memory clinic of a tertiary hospital. A regression model was used to determine the main determinants of costs associated with dementia. RESULTS: Global costs of dementia were US$1,012.35; US$1,683.18 and US$1,372.30 per patient/month for mild, moderate and severe stages, respectively. Indirect costs ranged from US$536.62 to US$545.17 according to severity. Dementia costs were influenced by medication, FAST score, and educational level of caregiver. DISCUSSION: The study represents an original contribution toward establishing direct and indirect costs of dementia in Brazil. Results indicate significant economic impacts, including projection of annual costs of US$16,548.24 per patient. PMID- 29494692 TI - IL-12/23p40 overproduction by dendritic cells leads to an increased Th1 and Th17 polarization in a model of Yersinia enterocolitica-induced reactive arthritis in TNFRp55-/- mice. AB - Dendritic cells (DCs) play critical functions in the initiation of immune responses. Understanding their role in reactive arthritis (ReA) will help delineate the pathogenesis of this arthropathy. In early studies, we detected IL 12/23p40 deregulation in Yersinia entercolitica (Ye)-induced ReA in TNFRp55 deficient (TNFRp55-/-) mice. In this study, we assessed the contribution of DCs in this overproduction. First, greater levels of IL-12/23p40, IFN-gammaand IL-17A were confirmed in supernatants of lipopolysaccharide (LPS)-stimulated TNFRp55-/ splenocytes obtained on arthritis onset (day 14 after Ye infection). Later, DCs were identified as a precise source of IL-12/23p40 since increased frequency of splenic IL-12/23p40+DCs was detected in TNFRp55-/- mice. After robust in vivo amplification of DCs by injection of Fms-like tyrosine kinase 3-Ligand (Flt3L) transfected BL16 melanoma, DCs were purified. These cells recapitulated the higher production of IL-12/23p40 under TNFRp55deficiency. In agreement with these results, TNFRp55-/- DCs promoted Th1 and Th17 programs by co-culture with WT CD4+lymphocytes. A mechanistic study demonstrated that JNK and p38 MAPK pathways are involved in IL-12/23p40 overproduction in purified TNFRp55-/- DCs as well as in the JAWS II cell line. This deregulation was once again attributed to TNFRp55 deficiency since CAY10500, a specific inhibitor of this pathway, compromised TNF mediated IL-12/23p40 control in LPS-stimulated WT DCs. Simultaneously, this inhibition reduced IL-10 production, suggesting its role mediating IL-12/23p40 regulation by TNFRp55 pathway. These results provide experimental data on the existence of a TNFRp55-mediated anti-inflammatory circuit in DCs. Moreover, these cells may be considered as a novel target in the treatment of ReA. PMID- 29494694 TI - Development of image analysis software for quantification of viable cells in microchips. AB - Over the past few years, image analysis has emerged as a powerful tool for analyzing various cell biology parameters in an unprecedented and highly specific manner. The amount of data that is generated requires automated methods for the processing and analysis of all the resulting information. The software available so far are suitable for the processing of fluorescence and phase contrast images, but often do not provide good results from transmission light microscopy images, due to the intrinsic variation of the acquisition of images technique itself (adjustment of brightness / contrast, for instance) and the variability between image acquisition introduced by operators / equipment. In this contribution, it has been presented an image processing software, Python based image analysis for cell growth (PIACG), that is able to calculate the total area of the well occupied by cells with fusiform and rounded morphology in response to different concentrations of fetal bovine serum in microfluidic chips, from microscopy images in transmission light, in a highly efficient way. PMID- 29494695 TI - Drug loss while crushing tablets: Comparison of 24 tablet crushing devices. AB - This study investigated 24 tablet crushing devices for drug loss using different methods to recover the crushed tablet. 24 devices were compared: 3 with disposable cups, 6 with disposable bags, 12 without separate vessels and 3 types of mortar and pestle. One paracetamol tablet was crushed and recovered by tapping the powder out. Where appropriate, depending on crusher size and manufacturer instructions, the powder was also recovered by mixing with water or food. Paracetamol recovery (quantity that can be delivered to a patient) and leftover (quantity remaining in the device) were measured using a validated UV method and the entire experiment was replicated 3 times. Drug recovery ranged from 86.7 98.1% when the crushed tablet was tapped out of the crushers (average loss 5.8%). Significant losses were measured for 18 crushers, particularly manually operated hand-twist crushers with a serrated crushing surface, and some devices with disposable bags or cups. Rinsing the crushed powder with water once resulted in an average of 24.2% drug loss, and this was reduced to 4.2% after a second rinse. If crushing is unavoidable, maximizing medication delivery to the patient is essential. Rinsing twice resulted in similar paracetamol recovery to tapping the powder out; however only water rinses have the potential for direct consumption by the patient, minimizing drug loss across the entire crushing and transfer process. PMID- 29494696 TI - Assessing the probability of introduction and spread of avian influenza (AI) virus in commercial Australian poultry operations using an expert opinion elicitation. AB - The objective of this study was to elicit experts' opinions and gather estimates on the perceived probability of introduction and spread of avian influenza (AI) virus in the Australian broiler and layer industry. Using a modified Delphi method and a 4-step elicitation process, 11 experts were asked to give initial individual estimates for the various pathways and practices in the presented scenarios using a questionnaire. Following this, a workshop was conducted to present group averages of estimates and discussion was facilitated to obtain final individual estimates. For each question, estimates for all experts were combined using a discrete distribution, with weights allocated representing the level of expertise. Indirect contact with wild birds either via a contaminated water source or fomites was considered the most likely pathway of introduction of low pathogenic avian influenza (LPAI) on poultry farms. Presence of a water body near the poultry farm was considered a potential pathway for introduction only when the operation type was free range and the water body was within 500m distance from the shed. The probability that LPAI will mutate to highly pathogenic avian influenza (HPAI) was considered to be higher in layer farms. Shared personnel, equipment and aerosol dispersion were the most likely pathways of shed to shed spread of the virus. For LPAI and HPAI spread from farm to farm, shared pick-up trucks for broiler and shared egg trays and egg pallets for layer farms were considered the most likely pathways. Findings from this study provide an insight on most influential practices on the introduction and spread of AI virus among commercial poultry farms in Australia, as elicited from opinions of experts. These findings will be used to support parameterization of a modelling study assessing the risk of AI introduction and spread among commercial poultry farms in Australia. PMID- 29494697 TI - Sickle cell maculopathy: Identification of systemic risk factors, and microstructural analysis of individual retinal layers of the macula. AB - PURPOSE: To identify systemic risk factors for sickle cell maculopathy, and to analyze the microstructure of the macula of Sickle Cell Disease (SCD) patients by using automated segmentation of individual retinal layers. METHODS: Thirty consecutive patients with SCD and 30 matched controls underwent spectral-domain optical coherence tomography (SD-OCT) and automated thickness measurement for each retinal layer; thicknesses for SCD patients were then compared to normal controls. Demographic data, systemic data, and lab results were collected for each SCD patient; multivariate logistic regression analysis was used to identify potential risk factors for sickle cell maculopathy. RESULTS: Ongoing chelation treatment (p = 0.0187) was the most predictive factor for the presence of sickle cell maculopathy; the odds were 94.2% lower when chelation was present. HbF level tended to influence sickle cell maculopathy (p = 0.0775); the odds decreased by 12.9% when HbF increased by 1%. Sickle cell maculopathy was detected in 43% of SCD patients as patchy areas of retinal thinning on SD-OCT thickness map, mostly located temporally to the macula, especially in eyes with more advanced forms of sickle cell retinopathy (p = 0.003). In comparison to controls, SCD patients had a subtle thinning of the overall macula and temporal retina compared to controls (most p<0.0001), involving inner and outer retinal layers. Thickening of the retinal pigment epithelium was also detected in SCD eyes (p<0.0001). CONCLUSIONS: Chronic chelation therapy and, potentially, high levels of HbF are possible protective factors for the presence of sickle cell maculopathy, especially for patients with more advanced forms of sickle cell retinopathy. A subtle thinning of the overall macula occurs in SCD patients and involves multiple retinal layers, suggesting that ischemic vasculopathy may happen in both superficial and deep capillary plexi. Thinning of the outer retinal layers suggests that an ischemic insult of the choriocapillaris may also occur in SCD patients. PMID- 29494698 TI - Microspore culture reveals high fitness of B. napus-like gametes in an interspecific hybrid between Brassica napus and B. oleracea. AB - The strategies of crossing B. napus with parental species play important role in broadening and improving the genetic basis of B. napus by the introgression of genetic resources from parental species. With these strategies, it is easy to select new types of B. napus, but difficult to select new types of B. rapa or B. oleracea by self-pollination. This characteristic may be a consequence of high competition with B. napus gametes. To verify the role of gamete viability in producing new B. napus individuals, the meiotic chromosome behavior of the interspecific hybrid between B. napus (Zhongshuang 9) and B. oleracea (6m08) was studied, and microspore-derived (MD) individuals were analyzed. The highest fitness of the 9:19 (1.10%) pattern was observed with a 5.49-fold higher than theoretical expectation among the six chromosome segregation patterns in the hybrid. A total of 43 MD lines with more than 14 chromosomes were developed from the hybrid, and 8 (18.6%) of them were B. napus-like (n = 19) type gametes, having the potential to broaden the genetic basis of natural B. napus (GD = 0.43 +/- 0.04). It is easy to produce B. napus-like gametes with 19 chromosomes, and these gametes showed high fitness and competition in the microspore-derived lines, suggesting it might be easy to select new types of B. napus from the interspecific hybrid between B. napus and B. oleracea. PMID- 29494699 TI - Effects of Didymosphenia geminata massive growth on stream communities: Smaller organisms and simplified food web structure. AB - This study aims to contribute to the understanding of the impact of Didymosphenia geminata massive growths upon river ecosystem communities' composition and functioning. This is the first study to jointly consider the taxonomic composition and functional structure of diatom and macroinvertebrate assemblages in order to determine changes in community structure, and the food web alterations associated with this invasive alga. This study was carried out in the Lumbreras River (Ebro Basin, La Rioja, Northern Spain), which has been affected by a considerable massive growth of D. geminata since 2011. The study shows a profound alteration in both the river community composition and in the food web structure at the sites affected by the massive growth, which is primarily due to the alteration of the environmental conditions, thus demonstrating that D. geminata has an important role as an ecosystem engineer in the river. Thick filamentous mats impede the movement of large invertebrates-especially those that move and feed up on it-and favor small, opportunistic, herbivorous organisms, mainly chironomids, that are capable of moving between filaments and are aided by the absence of large trophic competitors and predators -prey release effect-. Only small predators, such as hydra, are capable of surviving in the new environment, as they are favored by the increase in chironomids, a source of food, and by the reduction in both their own predators and other midge predators mesopredator release-. This change in the top-down control affects the diatom community, since chironomids may feed on large diatoms, increasing the proportion of small diatoms in the substrate. The survival of small and fast-growing pioneer diatoms is also favored by the mesh of filaments, which offers them a new habitat for colonization. Simultaneously, D. geminata causes a significant reduction in the number of diatoms with similar ecological requirements (those attached to the substrate). Overall, D. geminata creates a community dominated by small organisms that is clearly different from the existing communities in the same stream where there is an absence of massive growths. PMID- 29494700 TI - Chronic rhinosinusitis increases the risk of hemorrhagic and ischemic stroke: A longitudinal follow-up study using a national sample cohort. AB - BACKGROUND: Several studies have reported that chronic rhinosinusitis (CRS) increases the risk of stroke. The aim of this study is to elucidate the putative association between CRS and stroke (ischemic or hemorrhagic) using large population-based national health insurance data. METHODS: Using the national cohort study from the Korean Health Insurance Review and Assessment Service, CRS patients (n = 22,959) and control participants (n = 91,836) were selected and matched at a rate of 1:4 (age, sex, income, region, hypertension, diabetes, and dyslipidemia). A Cox-proportional hazard model was used to analyze the hazard ratio (HR) of CRS for hemorrhagic stroke and ischemic stroke. We divided the participants according to age and gender for the subgroup analysis. RESULTS: The HR for hemorrhagic and ischemic stroke was significantly increased in the CRS patients compared to that in the controls (adjusted HR = 2.43, 95% confidence interval [CI] = 2.10-2.80 for hemorrhagic stroke; adjusted HR = 1.76, 95% CI = 1.61-1.92 for ischemic stroke) after adjusting for age, sex, income, region of residence, hypertension, diabetes, dyslipidemia, ischemic heart disease, migraine, chronic kidney disease, depression, sleep disorder, and chronic obstructive pulmonary disorder. In the subgroup analysis, the HR of hemorrhagic stroke was significantly increased in the CRS group regardless of age and gender. The HR of ischemic stroke was also significantly increased in all subgroups of the CRS group. CONCLUSION: CRS consistently increased the risk of ischemic and hemorrhagic stroke regardless of age and gender. PMID- 29494701 TI - Wicked: The untold story of ciprofloxacin. PMID- 29494702 TI - Comprehensive transcriptome analysis and flavonoid profiling of Ginkgo leaves reveals flavonoid content alterations in day-night cycles. AB - Ginkgo leaves are raw materials for flavonoid extraction. Thus, the timing of their harvest is important to optimize the extraction efficiency, which benefits the pharmaceutical industry. In this research, we compared the transcriptomes of Ginkgo leaves harvested at midday and midnight. The differentially expressed genes with the highest probabilities in each step of flavonoid biosynthesis were down-regulated at midnight. Furthermore, real-time PCR corroborated the transcriptome results, indicating the decrease in flavonoid biosynthesis at midnight. The flavonoid profiles of Ginkgo leaves harvested at midday and midnight were compared, and the total flavonoid content decreased at midnight. A detailed analysis of individual flavonoids showed that most of their contents were decreased by various degrees. Our results indicated that circadian rhythms affected the flavonoid contents in Ginkgo leaves, which provides valuable information for optimizing their harvesting times to benefit the pharmaceutical industry. PMID- 29494703 TI - Premanifest Huntington's disease: Examination of oculomotor abnormalities in clinical practice. AB - INTRODUCTION: Different oculomotor abnormalities have been reported to occur in premanifest Huntington's disease. The aim of this study is to investigate which oculomotor items of the Unified Huntington's Disease Rating Scale (UHDRS) are affected in premanifest individuals compared to healthy controls, and if CAG repeat length and age are correlated with oculomotor abnormalities in premanifest Huntington's disease gene carriers. METHODS: We compared baseline data of 70 premanifest individuals and 27 controls who participated in the Enroll-HD study at the Leiden University Medical Center, the Netherlands. Premanifest gene carriers were divided in individuals near to disease onset and individuals far from disease onset. RESULTS: Using a logistic regression model, only horizontal ocular pursuit of the six oculomotor items of the UHDRS was significantly more frequently affected in premanifest individuals close to disease onset compared to controls (p = 0.044, OR 13.100). Age was significantly higher in premanifest individuals with affected horizontal ocular pursuit (p = 0.016, OR 1.115) and with affected vertical ocular pursuit (p = 0.030, OR 1.065) compared to premanifest individuals without ocular pursuit deficits. CONCLUSIONS: Our results suggest that horizontal ocular pursuit is the only affected oculomotor item of the UHDRS in premanifest individuals and could be used to assess early clinical signs of Huntington's disease. Saccade initiation and saccade velocity do not seem useful for detecting differences between premanifest individuals and controls. PMID- 29494704 TI - Highly sensitive detection and quantification of the secreted bacterial benevolence factor RoxP using a capacitive biosensor: A possible early detection system for oxidative skin diseases. AB - The impact of the microbiota on our health is rapidly gaining interest. While several bacteria have been associated with disease, and others being indicated as having a probiotic effect, the individual biomolecules behind these alterations are often not known. A major problem in the study of these factors in vivo is their low abundance in complex environments. We recently identified the first secreted bacterial antioxidant protein, RoxP, from the skin commensal Propionibacterium acnes, suggesting its relevance for maintaining the redox homeostasis on the skin. In order to study the effect, and prevalence, of RoxP in vivo, a capacitive biosensor with a recognition surface based on molecular imprinting was used to detect RoxP on skin in vivo. In vitro analyses demonstrated the ability to detect and quantify RoxP in a concentration range of 1 x 10-13 M to 1 x 10-8 M from human skin swabs; with a limit of detection of 2.5 x 10-19 M in buffer systems. Further, the biosensor was highly selective, not responding to any other secreted protein from P. acnes. Thus, it was possible to demonstrate the presence, and quantity, of RoxP on human skin. Therefore, the developed biosensor is a very promising tool for the detection of RoxP from clinical samples, offering a rapid, cost-effective and sensitive means of detecting low-abundant bacterial proteins in vivo in complex milieus. PMID- 29494705 TI - When does risk perception predict protection motivation for health threats? A person-by-situation analysis. AB - Although risk perception is a key concept in many health behavior theories, little research has explicitly tested when risk perception predicts motivation to take protective action against a health threat (protection motivation). The present study tackled this question by (a) adopting a multidimensional model of risk perception that comprises deliberative, affective, and experiential components (the TRIRISK model), and (b) taking a person-by-situation approach. We leveraged a highly intensive within-subjects paradigm to test features of the health threat (i.e., perceived severity) and individual differences (e.g., emotion reappraisal) as moderators of the relationship between the three types of risk perception and protection motivation in a within-subjects design. Multi level modeling of 2968 observations (32 health threats across 94 participants) showed interactions among the TRIRISK components and moderation both by person level and situational factors. For instance, affective risk perception better predicted protection motivation when deliberative risk perception was high, when the threat was less severe, and among participants who engage less in emotional reappraisal. These findings support the TRIRISK model and offer new insights into when risk perceptions predict protection motivation. PMID- 29494706 TI - Acquisition of extended spectrum beta-lactamase-producing enterobacteriaceae in neonates: A community based cohort in Madagascar. AB - In low and middle income countries (LMICs), where the burden of neonatal sepsis is the highest, the spread of extended spectrum beta-lactamase-producing enterobacteriaceae (ESBL-PE) in the community, potentially contributing to the neonatal mortality, is a public health concern. Data regarding the acquisition of ESBL-PE during the neonatal period are scarce. The routes of transmission are not well defined and particularly the possible key role played by pregnant women. This study aimed to understand the neonatal acquisition of ESBL-PE in the community in Madagascar. The study was conducted in urban and semi-rural areas. Newborns were included at birth and followed-up during their first month of life. Maternal stool samples at delivery and six stool samples in each infant were collected to screen for ESBL-PE. A Cox proportional hazards model was performed to identify factors associated with the first ESBL-PE acquisition. The incidence rate of ESBL-PE acquisition was 10.4 cases/1000 newborn-days [95% CI: 8.0-13.4 cases per 1000 newborn-days]. Of the 83 ESBL-PE isolates identified, Escherichia coli was the most frequent species (n = 28, 34.1%), followed by Klebsiella pneumoniae (n = 20, 24.4%). Cox multivariate analysis showed that independent risk factors for ESBL-PE acquisition were low birth weight (adjusted Hazard-ratio (aHR) = 2.7, 95% CI [1.2; 5.9]), cesarean-section, (aHR = 3.4, 95% CI [1.7; 7.1]) and maternal use of antibiotics at delivery (aHR = 2.2, 95% CI [1.1; 4.5]). Our results confirm that mothers play a significant role in the neonatal acquisition of ESBL-PE. In LMICs, public health interventions during pregnancy should be reinforced to avoid unnecessary caesarean section, unnecessary antibiotic use at delivery and low birth weight newborns. PMID- 29494707 TI - Opposite effect of polyamines on In vitro gene expression: Enhancement at low concentrations but inhibition at high concentrations. AB - BACKGROUND: Polyamines have various biological functions including marked effects on the structure and function of genomic DNA molecules. Changes in the higher order structure of DNA caused by polyamines are expected to be closely related to genetic activity. To clarify this issue, we examined the relationship between gene expression and the higher-order structure of DNA under different polyamine concentrations. PRINCIPAL FINDINGS: We studied the effects of polyamines, spermidine SPD(3+) and spermine SP(4+), on gene expression by a luciferase assay. The results showed that gene expression is increased by ca. 5-fold by the addition of SPD(3+) at 0.3 mM, whereas it is completely inhibited above 2 mM. Similarly, with SP(4+), gene expression is maximized at 0.08 mM and completely inhibited above 0.6 mM. We also performed atomic force microscopy (AFM) observations on DNA under different polyamine concentrations. AFM revealed that a flower-like conformation is generated at polyamine concentrations associated with maximum expression as measured by the luciferase assay. On the other hand, DNA molecules exhibit a folded compact conformation at polyamine concentrations associated with the complete inhibition of expression. Based on these results, we discuss the plausible mechanism of the opposite effect, i.e., enhancement and inhibition, of polyamines on gene expression. CONCLUSION AND SIGNIFICANCE: It was found that polyamines exert opposite effect, enhancement and inhibition, on gene expression depending on their concentrations. Such an opposite effect is argued in relation to the conformational change of DNA: enhancement is due to the parallel ordering of DNA segments that is accompanied by a decrease in the negative charge of double-stranded DNA, and inhibition is caused by the compaction of DNA into a tightly packed state with almost perfect charge neutralization. PMID- 29494708 TI - A hierarchical anatomical classification schema for prediction of phenotypic side effects. AB - Prediction of adverse drug reactions is an important problem in drug discovery endeavors which can be addressed with data-driven strategies. SIDER is one of the most reliable and frequently used datasets for identification of key features as well as building machine learning models for side effects prediction. The inherently unbalanced nature of this data presents with a difficult multi-label multi-class problem towards prediction of drug side effects. We highlight the intrinsic issue with SIDER data and methodological flaws in relying on performance measures such as AUC while attempting to predict side effects.We argue for the use of metrics that are robust to class imbalance for evaluation of classifiers. Importantly, we present a 'hierarchical anatomical classification schema' which aggregates side effects into organs, sub-systems, and systems. With the help of a weighted performance measure, using 5-fold cross-validation we show that this strategy facilitates biologically meaningful side effects prediction at different levels of anatomical hierarchy. By implementing various machine learning classifiers we show that Random Forest model yields best classification accuracy at each level of coarse-graining. The manually curated, hierarchical schema for side effects can also serve as the basis of future studies towards prediction of adverse reactions and identification of key features linked to specific organ systems. Our study provides a strategy for hierarchical classification of side effects rooted in the anatomy and can pave the way for calibrated expert systems for multi-level prediction of side effects. PMID- 29494709 TI - Japanese quince (Chaenomeles japonica L.) fruit polyphenolic extract modulates carbohydrate metabolism in HepG2 cells via AMP-activated protein kinase. AB - Type 2 diabetes mellitus (T2D) is a chronic diet-related disease which due to many dangerous complications has become a prominent health problem of the world. The aim of the study was to explore the in vitro activity of Japanese quince (Chaenomeles japonica L., family Rosaceae, JQ) fruit polyphenolic extract as modulator of carbohydrates metabolism. The research was designed to investigate the effect of JQ polyphenolic extract on glucose metabolism in human hepatoma HepG2 cell line cultured under normal non-metabolically changed and hyperglycemic conditions. Pretreatment of the cells with JQ preparation caused decrease of intracellular ROS generation and influenced mitochondrial membrane polarization which seemed to lead to AMPK activation. Further effects observed in HepG2 cells were associated with activation of the enzyme: elevation of glucose uptake and glycogen content, and alleviation of gluconeogenesis through modulation of PEPCK, PTP1B, FOXO1 and GLUT2/4 expression. These findings suggest that JQ polyphenols exhibit hypoglycemic effects via modulation of AMPK signaling in hepatocytes. PMID- 29494712 TI - Humeral Bone Loss in Revision Shoulder Arthroplasty. AB - Revision shoulder arthroplasty is becoming more prevalent as the rate of primary shoulder arthroplasty in the US continues to increase. The management of proximal humeral bone loss in the revision setting presents a difficult problem without a clear solution. Different preoperative diagnoses often lead to distinctly different patterns of bone loss. Successful management of these cases requires a clear understanding of the normal anatomy of the proximal humerus, as well as structural limitations imposed by significant bone loss and the effect this loss has on component fixation. Our preferred technique differs depending on the pattern of bone loss encountered. The use of allograft-prosthetic composites, the cement-within-cement technique, and combinations of these strategies comprise the mainstay of our treatment algorithm. This article focuses on indications, surgical techniques, and some of the published outcomes using these strategies in the management of proximal humeral bone loss. PMID- 29494710 TI - Peripheral regulatory T cells and anti-inflammatory cytokines in children with juvenile idiopathic arthritis. AB - BACKGROUND: Juvenile idiopathic arthritis (JIA) is a chronic, heterogenous inflammatory disease of unclear pathogenesis. JIA is hypothesized to be linked to a defective immune regulation. Anti-inflammatory cytokines belong to the best known regulatory factors. T-regulatory cells are a crucial cellular component of immune tolerance. One of their functions is synthesis of interleukin 10 (IL-10) and transforming growth factor beta1 (TGF-beta1). The aim of this study was to determine the proportion of T-regulatory cells (CD4+CD25highFOXP3+) in peripheral blood, and serum levels of TGF-beta1 and IL-10 in patients with JIA. METHODS: The study included 25 patients with newly diagnosed JIA: oligoarthritis (n=17) and polyarthritis (n=8). The control group was comprised of 17 healthy children. CD4+CD25highFOXP3+ T cells in peripheral blood were quantified by means of three color flow cytometry. Serum concentrations of TGF-beta1 and IL-10 were estimated with ELISA. RESULTS: The proportion of peripheral CD4+CD25highFOXP3+ cells in patients with JIA was significantly higher than in the controls (p=0.04). The two groups did not differ significantly in terms of their TGF-beta1 and IL-10 concentrations. CONCLUSIONS: At the time of diagnosis, children with JIA presented with an elevated proportion of T-regulatory cells (CD4+CD25highFOXP3+) in peripheral blood. Anti-inflammatory cytokines, IL-10 and TGF-beta1, are not upregulated in the serum of patients with JIA, and therefore should not be considered as biomarkers of this condition. PMID- 29494711 TI - Use of a Small-Bore Needle Arthroscope to Diagnose Intra-Articular Knee Pathology: Comparison With Magnetic Resonance Imaging. AB - The use of arthroscopy for purely diagnostic purposes has been largely supplanted by noninvasive technologies, such as magnetic resonance imaging (MRI). The mi eye+TM (Trice Medical) technology is a small-bore needle unit for in-office arthroscopy. We conducted a pilot study comparing the mi-eye+TM unit with MRI, using surgical arthroscopy as a gold-standard reference. We hypothesized that the mi-eye+TM needle arthroscope, which can be used in an office setting, would be equivalent to MRI for the diagnosis of intra-articular pathology of the knee. This prospective, multicenter, observational study was approved by the Institutional Review Board. There were 106 patients (53 males, 53 females) in the study. MRIs were interpreted by musculoskeletally trained radiologists. The study was conducted in the operating room using the mi-eye+TM device. The mi-eye+TM device findings were compared with the MRI findings within individual pathologies, and a "per-patient" analysis was performed to compare the arthroscopic findings with those of the mi-eye+TM and the MRI. Additionally, we identified all mi-eye+TM findings and MRI findings that exactly matched the surgical arthroscopy findings. The mi-eye+TM demonstrated complete accuracy of all pathologies for 97 (91.5%) of the 106 patients included in the study, whereas MRI demonstrated complete accuracy for 65 patients (61.3%) (P < .0001). All discrepancies between mi-eye+TM and arthroscopy were false-negative mi-eye+TM results, as the mi-eye+TM did not reveal some aspect of the knee's pathology for 9 patients. The mi-eye+TM was more sensitive than MRI in identifying meniscal tears (92.6% vs 77.8%; P = .0035) and more specific in diagnosing these tears (100% vs 41.7%; P < .0001). The mi-eye+TM device proved to be more sensitive and specific than MRI for intra-articular findings at time of knee arthroscopy. Certainly there are contraindications to using the mi-eye+TM, and our results do not obviate the need for MRI, but our study did demonstrate that the mi-eye+TM needle arthroscope can safely provide excellent visualization of intra-articular knee pathology. PMID- 29494713 TI - Total Shoulder Arthroplasty Using a Bone-Sparing, Precision Multiplanar Humeral Prosthesis. AB - Proper reconstruction of proximal humeral anatomy is of primary importance to maximize patient outcomes after total shoulder arthroplasty. This article describes a new arthroplasty technique, where a fixed multiplanar bone resection is made and a novel implant, which is designed to precisely match the bone resection, is inserted. PMID- 29494714 TI - Patient-Specific Implants in Severe Glenoid Bone Loss. AB - Complex glenoid bone deformities present the treating surgeon with a complex reconstructive challenge. Although glenoid bone loss can be encountered in the primary setting (degenerative, congenital, post-traumatic), severe glenoid bone loss is encountered in most revision total shoulder arthroplasties. Severe glenoid bone loss is treated with various techniques including hemiarthroplasty, eccentric reaming, and glenoid reconstruction with bone autografts and allografts. Despite encouraging short- to mid-term results reported with these reconstruction techniques, the clinical and radiographic outcomes remain inconsistent and the high number of complications is a concern. To overcome this problem, more recently augmented components and patient specific implants were introduced. Using the computer-aided design and computer-aided manufacturing technology patient-specific implants have been created to reconstruct the glenoid vault in cases of severe glenoid bone loss. In this article we describe a patient specific glenoid implant, its indication, technical aspects and surgical technique, based on the author's experience as well as a review of the current literature on custom glenoid implants. PMID- 29494715 TI - Use of a Novel Magnesium-Based Resorbable Bone Cement for Augmenting Anchor and Tendon Fixation. AB - The aim of this study was to assess the efficacy and safety of a novel magnesium based resorbable bone cement (OsteoCrete, Bone Solutions Incorporated) for anchor and tendon fixation. Cadaveric humeral testing involved straight pull-to-failure of rotator cuff suture anchors; OsteoCrete was injected through one anchor, and a second anchor served as the uninjected control. Testing was conducted 15 minutes post-injection. A canine preclinical model was used to evaluate the safety of the following parameters: Rotator cuff repair: A double-row technique was used to repair transected infraspinatus tendons; OsteoCrete was injected through both anchors in one limb, and the contralateral limb served as the uninjected control. Biceps tenodesis: The transected biceps tendon was implanted into a proximal humeral socket with a transcortical button; OsteoCrete was injected into the socket of one limb, and a screw was used for final fixation in the contralateral control limb. Nondestructive biomechanical testing and histologic assessment were performed after 12 weeks. OsteoCrete-augmented anchors showed significantly higher load-to-failure compared to that with uninjected controls. In cadaveric humeri with reduced bone quality, OsteoCrete increased the mean load-to-failure by 99%. Within the preclinical model, there were no complications or statistically significant biomechanical/histologic differences between the techniques. OsteoCrete has the potential for safely providing improved suture anchor and tissue fixation in patients with poor bone or tissue quality. PMID- 29494716 TI - Treating Humeral Bone Loss in Shoulder Arthroplasty: Modular Humeral Components or Allografts. AB - Reconstructing proximal humeral bone loss in the setting of shoulder arthroplasty can be a daunting task. Proposed techniques include long-stemmed humeral components, allograft-prosthesis composites (APCs), and modular endoprosthetic reconstruction. While unsupported long-stemmed components are at high risk for component loosening, APC reconstruction techniques have been reported with success. However, graft resorption and eventual failure are significant concerns. Modular endoprosthetic systems allow bone deficiencies to be reconstructed with metal, which may allow for a more durable reconstruction. PMID- 29494717 TI - Convertible Glenoid Components Facilitate Revisions to Reverse Shoulder Arthroplasty Easier: Retrospective Review of 13 Cases. AB - Removal of a cemented glenoid component often leads to massive glenoid bone loss, which makes it difficult to implant a new glenoid baseplate. The purpose of this study was to demonstrate the feasibility of revisions with a completely convertible system and to report clinical and radiographic results of a retrospective review of 13 cases. Between 2003 and 2011, 104 primary total shoulder arthroplasties (TSAs) were performed with an uncemented glenoid component in our group. Of these patients, 13 (average age, 64 years) were revised to reverse shoulder arthroplasty (RSA) using a modular convertible platform system and were included in this study. Average follow-up after revision was 22 months. Outcome measures included pain, range of motion, Constant-Murley scores, Simple Shoulder Tests, and subjective shoulder values. Active flexion increased significantly from a mean of 93 degrees (range, 30 degrees -120 degrees ) to 138 degrees (range, 95 degrees -170 degrees ) (P = 0.021), and active external rotation increased significantly from 8 degrees (range, -20 degrees -15 degrees ) to 25 degrees (range, -10 degrees -60 degrees ). Mean pain scores significantly improved from 4.2 to 13.3 points. The mean Constant Scores improved from 21 (range, 18-32) to 63 (range, 43-90). Subjectively, 12 patients rated their shoulder as better or much better than preoperatively. This retrospective study shows that a complete convertible system facilitates conversion of TSAs to RSAs with excellent pain relief and a significant improvement in shoulder function. PMID- 29494718 TI - Patient-Specific Guides/Instrumentation in Shoulder Arthroplasty. AB - Optimal outcomes following total shoulder arthroplasty TSA and reverse shoulder arthroplasty RSA are dependent on proper implant position. Multiple cadaver studies have demonstrated improved accuracy of implant positioning with use of patient-specific guides/instrumentation compared to traditional methods. At this time, there are 3 commercially available single use patient-specific instrumentation systems and 1 commercially available reusable patient-specific instrumentation system. Currently though, there are no studies comparing the clinical outcomes of patient-specific guides to those of traditional methods of glenoid placement, and limited research has been done comparing the accuracy of each system's 3-dimensional planning software. Future work is necessary to elucidate the ideal indications for the use of patient-specific guides and instrumentation, but it is likely, particularly in the setting of advanced glenoid deformity, that these systems will improve a surgeon's ability to put the implant in the best position possible. PMID- 29494719 TI - Fall With e-Cigarette in Mouth Resulting in Pharyngeal and Esophageal Burns. PMID- 29494720 TI - Lymph Node Yield as Quality Metric for Clinically N0 Oral Cancer-Reply. PMID- 29494721 TI - Conjunctival Hyperemia or Vasodilation and Central Corneal Ulcer in a Neonate. PMID- 29494722 TI - Bilateral Corneal Deposits 1 Week After Starting Oral Prednisone Therapy. PMID- 29494724 TI - Association of Retinal Macrovessels With Venous Malformations of the Brain. PMID- 29494723 TI - Lymph Node Yield as Quality Metric for Clinically N0 Oral Cancer. PMID- 29494726 TI - Questions About Emergency Department Treatment of Patients With Solid Tumors and Hematological Malignant Neoplasms-Reply. PMID- 29494725 TI - Congenital Retinal Macrovessel and the Association of Retinal Venous Malformations With Venous Malformations of the Brain. AB - Importance: Congenital retinal macrovessel (CRM) is a rarely reported venous malformation of the retina that is associated with venous anomalies of the brain. Objective: To study the multimodal imaging findings of a series of eyes with congenital retinal macrovessel and describe the systemic associations. Design, Setting, and Participants: In this cross-sectional multicenter study, medical records were retrospectively reviewed from 7 different retina clinics worldwide over a 10-year period (2007-2017). Patients with CRM, defined as an abnormal, large, macular vessel with a vascular distribution above and below the horizontal raphe, were identified. Data were analyzed from December 2016 to August 2017. Main Outcomes and Measures: Clinical information and multimodal retinal imaging findings were collected and studied. Pertinent systemic information, including brain magnetic resonance imaging findings, was also noted if available. Results: Of the 49 included patients, 32 (65%) were female, and the mean (SD) age at onset was 44.0 (20.9) years. A total of 49 eyes from 49 patients were studied. Macrovessel was unilateral in all patients. Color fundus photography illustrated a large aberrant dilated and tortuous retinal vein in all patients. Early-phase frames of fluorescein angiography further confirmed the venous nature of the macrovessel in 40 of 40 eyes. Optical coherence tomography angiography, available in 17 eyes (35%), displayed microvascular capillary abnormalities around the CRM, which were more evident in the deep capillary plexus. Of the 49 patients with CRM, 39 (80%) did not illustrate any evidence of ophthalmic complications. Ten patients (20%) presented with retinal complications, typically an incidental association with CRM. Twelve patients (24%) were noted to have venous malformations of the brain with associated magnetic resonance imaging. Of these, location of the venous anomaly in the brain was ipsilateral to the CRM in 10 patients (83%) and contralateral in 2 patients (17%), mainly located in the frontal lobe in 9 patients (75%). Conclusions and Relevance: Our study has identified an association between macrovessels in the retina and venous anomalies of the brain (24% compared with 0.2% to 6.0% in the normal population). Thus, we recommend new guidelines for the systemic workup of patients with CRM to include brain magnetic resonance imaging with contrast. These lesions may be more accurately referred to as retinal venous malformations, which may raise awareness regarding potential cerebral associations. PMID- 29494728 TI - Treatment of Advanced Non-Small Cell Lung Cancer in 2018. PMID- 29494727 TI - Association of Changes in Macular Perfusion With Ranibizumab Treatment for Diabetic Macular Edema: A Subanalysis of the RESTORE (Extension) Study. AB - Importance: Anti-vascular endothelial growth factor treatment is the first-line therapy in the treatment of center-involving diabetic macular edema. Data on capillary perfusion changes under repeated treatment in a possibly compromised vascular network are limited. Objective: To evaluate the association of repeated ranibizumab injections on macular perfusion in patients with diabetic macular edema. Design, Setting, and Participants: This study analyzed prospectively collected data from the 12-month RESTORE core study and the 24-month open label RESTORE extension study, which assessed the efficacy and safety of ranibizumab in patients with visual impairment due to diabetic macular edema. Of 345 patients with center-involving diabetic macular edema who had enrolled in the 12-month RESTORE core study, 240 entered the 24-month RESTORE extension study. Of these, 83 (34.6%) received ranibizumab, 83 (34.6%) received ranibizumab and laser combination therapy, and 74 (30.8%) received laser monotherapy in the first year of the study; 208 completed the 24-month extension study. Fluorescence angiography images were taken from each participant twice each year graded by Vienna Reading Center on severity of capillary loss in the parafoveal area, regularity of the foveal avascular zone outline, and measurement of the size of the foveal avascular zone, following a standardized protocol. Data analysis took place from July 2014 through December 2017. Main Outcomes and Measures: Change in 3 fluorescence angiography perfusion parameters over the course of treatment. Results: Mean (SD) patient age was 62.6 (8.8) years; 124 of 208 (59.2%) were male and 197 of 208 (94.6%) were white. The number of patients with definite altered foveal avascular zone regularity at baseline was 103 of 240 patients (42.9%); another 118 patients (49.2%) had questionably altered regularity at baseline. Definitive capillary loss was found in 65 of 240 patients (27.1%) at baseline. Mean (SD) foveal avascular zone size at baseline was 0.261 (0.232) mm2 in ranibizumab monotherapy, 0.231 (0.219) mm2 in ranibizumab and macular laser combination therapy, and 0.201 (0.13) mm2 in laser monotherapy. No treatment arm experienced significant increase in foveal avascular zone size at any time in the study period. At month 36, ranibizumab monotherapy resulted in a mean increase of 0.073 mm2 (95% CI, 0.005-0.142 mm2) and combination therapy resulted in a mean increase of 0.117 mm2 (95% CI, 0.045-0.188 mm2), but no changes were statistically significant. No changes occurred in foveal avascular zone regularity in any treatment group, and no differences were found in capillary loss around the fovea in the 3 treatment groups; neither element could be correlated with visual acuity or central retinal thickness. Conclusions and Relevance: Repeated ranibizumab treatment was not associated with impaired macular perfusion in our study cohort. Because our data do not suggest a harmful effect of anti-vascular endothelial growth factor therapy on capillary integrity, patients with severe microangiopathy and advanced capillary dropout should not be denied these treatments. PMID- 29494729 TI - Association of Reduced Delay in Care With a Dedicated Operating Room in Pediatric Otolaryngology. AB - Importance: Obtaining sufficient operating room time for inpatient consults requiring an operative intervention is a persistent challenge for otolaryngologists. Objective: To examine the institution of an otolaryngology specific operating room (OR) for unscheduled (add-on) cases for its association with time from initial consultation to surgery and, secondarily, to determine utilization of a dedicated block of time. Design, Setting, and Participants: Retrospective review of medical records of a tertiary care pediatric hospital for patients treated between January 1, 2015, and March 31, 2016; analysis was concluded by June 2016. Included were all patients undergoing inpatient otolaryngology consultations who required nonemergency operative procedures. Interventions: In August 2015, a once-weekly 5-hour block of OR time dedicated to inpatient otolaryngology consults was instituted. Prior to this, cases were placed on an add-on list shared between all surgical services. Main Outcomes and Measures: It was hypothesized that institution of a dedicated block of OR time would decrease the time from initial consultation to operative intervention and would be utilized at a high rate. Operating room utilization was calculated by dividing scheduled OR time by actual OR time utilized. Time from initial consultation to OR intervention was compared before and after the institution of the dedicated OR block. Results: A total of 316 inpatient add-on pediatric cases (including 108 patients from the intensive care unit [ICU]) were scheduled during the study period. The most common cases were microlaryngoscopy/bronchoscopy (79%) and tracheostomy (8%). Mean (SD) time between consultation and OR intervention was 7.8 (1.6) days prior to establishing the add-on OR and 4.4 (1.3) days after it was established (absolute difference of 3.4 days; 95% CI, 3.1-3.7 days). Mean (SD) time between consultation and OR intervention was 7.4 (5.0) days for ICU patients prior to intervention and 5.6 (3.0) days after intervention (absolute difference of 1.8 days; 95% CI, 1.6-2.0 days). Total utilization of the OR block time was 74%, and adjusted utilization was 86%. There was a 15% drop in the number of unscheduled add-on cases after the intervention (from 10 cases/mo to 8.5 cases/mo; absolute difference of 1.5 cases; 95% CI, 1.1-1.9 cases). Conclusions and Relevance: Instituting a dedicated otolaryngology add-on OR was associated with significantly reduced time between initial consultation and operative care, by approximately 3 days, decreased the number of unscheduled add on cases, and was utilized at a high level. PMID- 29494730 TI - Can Infection Prevention Programs in Hospitals and Nursing Facilities Be Integrated?: From Silos to Partners. PMID- 29494731 TI - Detecting Chemotherapeutic Skin Adverse Reactions in Social Health Networks Using Deep Learning. PMID- 29494732 TI - Prevalence of Cognitive Impairment and Association With Survival Among Older Patients With Hematologic Cancers. AB - Importance: As the population ages, cognitive impairment has promised to become increasingly common among patients with cancer. Little is known about how specific domains of cognitive impairment may be associated with survival among older patients with hematologic cancers. Objective: To determine the prevalence of domain-specific cognitive impairment and its association with overall survival among older patients with blood cancer. Design, Setting, and Participants: This prospective observational cohort study included all patients 75 years and older who presented for initial consultation in the leukemia, myeloma, or lymphoma clinics of a large tertiary hospital in Boston, Massachusetts, from February 1, 2015, to March 31, 2017. Patients underwent screening for frailty and cognitive dysfunction and were followed up for survival. Exposures: The Clock-in-the-Box (CIB) test was used to screen for executive dysfunction. A 5-word delayed recall test was used to screen for impairment in working memory. The Fried frailty phenotype and Rockwood cumulative deficit model of frailty were also assessed to characterize participants as robust, prefrail, or frail. Results: Among 420 consecutive patients approached, 360 (85.7%) agreed to undergo frailty assessment (232 men [64.4%] and 128 women [35.6%]; mean [SD] age, 79.8 [3.9] years), and 341 of those (94.7%) completed both cognitive screening tests. One hundred twenty seven patients (35.3%) had probable executive dysfunction on the CIB, and 62 (17.2%) had probable impairment in working memory on the 5-word delayed recall. Impairment in either domain was modestly correlated with the Fried frailty phenotype (CIB, rho = 0.177; delayed recall, rho = 0.170; P = .01 for both), and many phenotypically robust patients also had probable cognitive impairment (24 of 104 [23.1%] on CIB and 9 of 104 [8.7%] on delayed recall). Patients with impaired working memory had worse median survival (10.9 [SD, 12.9] vs 12.2 [SD, 14.7] months; log-rank P < .001), including when stratified by indolent cancer (log rank P = .01) and aggressive cancer (P < .001) and in multivariate analysis when adjusting for age, comorbidities, and disease aggressiveness (odds ratio, 0.26; 95% CI, 0.13-0.50). Impaired working memory was also associated with worse survival for those undergoing intensive treatment (log-rank P < .001). Executive dysfunction was associated with worse survival only among patients who underwent intensive treatment (log-rank P = .03). Conclusions and Relevance: These data suggest that domains of cognitive dysfunction may be prevalent in older patients with blood cancer and may have differential predictive value for survival. Targeted interventions are needed for this vulnerable patient population. PMID- 29494733 TI - A 25-Year Experience of US Food and Drug Administration Accelerated Approval of Malignant Hematology and Oncology Drugs and Biologics: A Review. AB - Importance: Accelerated approval (AA) is a US Food and Drug Administration (FDA) expedited program intended to speed the approval of drugs and biologics that may demonstrate a meaningful advantage over available therapies for diseases that are serious or life-threatening. Observations: This review describes all malignant hematology and oncology AAs from inception of the program on December 11, 1992, to May 31, 2017. During this period, the FDA granted AA to 64 malignant hematology and oncology products for 93 new indications. Of these AAs, 53 were for new molecular entities. Overall, the end point of response rate, including hematologic response rates, accounted for most AAs (81 [87%]), followed by time to-event end points of progression-free survival or time to progression (8 [9%]) and disease-free survival or recurrence-free survival (4 [4%]). Single-arm trial designs provided the data for 67 (72%) of the initial AA indications. Of the 93 AAs, 51 (55%) have fulfilled their postmarketing requirement and verified benefit in a median of 3.4 years after their initial AA. Thirty-seven (40%) indications have not yet completed confirmatory trial(s) or verified benefit, and 5 indications receiving AA (5%) have been withdrawn from the market. Conclusions and Relevance: The use of the AA program during the past 25 years has increased over time, and only a small portion of indications under the AA program fail to verify clinical benefit. For patients with serious or life-threatening oncologic diseases, AA brings products to the market years before confirmatory trials are typically completed. PMID- 29494734 TI - Insights Into the Management of Lymph Node-Positive Penile Cancer. PMID- 29494735 TI - Nasal Distortion in Short-Distance Photographs: The Selfie Effect. PMID- 29494736 TI - Association of Continued Preoperative Aspirin Use and Bleeding Complications in Patients Undergoing Thyroid Surgery. AB - Importance: No evidence exists to direct the management of preoperative aspirin (acetylsalicylic acid) use in patients undergoing thyroid surgery. Nevertheless, a considerable number of patients interrupt receiving aspirin therapy during the preoperative period to minimize bleeding complications despite the increased risk of experiencing major adverse cardiac events. Objective: To determine whether aspirin therapy continued preoperatively increases bleeding complications in patients undergoing thyroid surgery. Design, Setting, and Participants: Retrospective analysis of a consecutive sample of 570 patients, aged 18 to 100 years, who underwent thyroid surgery for benign and malignant disease from January 1, 2010, to December 31, 2015, by a single surgeon at a tertiary referral hospital center in New Orleans, Louisiana. Exposures: Patients receiving aspirin therapy and patients not receiving aspirin therapy (aspirin naive) preoperatively. Main Outcomes and Measures: Comparison of estimated blood loss, substantial blood loss, operative hematoma, nonoperative hematoma, and recurrent laryngeal nerve injury. Results: Of 570 patients who underwent thyroid surgery, 106 (18.6%) were performed in patients receiving aspirin; of these, 23 (21.7%) were men and 105 (99.1%) were older than 45 years. Those receiving aspirin therapy displayed a 14.4-year difference in age (95% CI, 11.6-17.1). The aspirin group displayed a 20.3% absolute increase (95% CI, 9.3-30.7) in African American patients. Aspirin therapy was not associated with a statistically significant or clinically meaningful increase in intraoperative blood loss (2.5 mL; 95% CI, -0.4 to 5.3). Aspirin therapy was associated with a statistically significant increase in total hematoma formation (3.3%; 95% CI, 0.4-9.0), but the results were inconclusive. Aspirin therapy was not associated with a statistically significant increase in recurrent laryngeal nerve injury (2.6%; 95% CI, -1.1 to 8.6), but the results were inconclusive. Conclusions and Relevance: These results suggest that aspirin therapy can be maintained prior to thyroid surgery without increased intraoperative bleeding. Further research with a larger sample size and more outcome events are required to make definitive conclusions regarding the association between aspirin use and complications, including hematoma and recurrent laryngeal nerve injury. PMID- 29494737 TI - Lymphedema. PMID- 29494738 TI - Mantle Cell Lymphoma-Time to Dismantle the Treatment Paradox. PMID- 29494739 TI - Treatment Trends and Outcomes for Patients With Lymph Node-Positive Cancer of the Penis. AB - Importance: Penile cancer is an uncommon disease with minimal level I evidence to guide therapy. The National Comprehensive Cancer Network (NCCN) guidelines advocate a lymph node dissection (LND) or radiotherapy with consideration of perioperative chemotherapy for all patients with lymph node-positive (LN+) penile cancer without metastasis. Objectives: To determine temporal trends in use of chemotherapy for patients with LN+ penile cancer without metastasis and to evaluate outcomes between those who did or did not receive LND, chemotherapy, and radiotherapy. Design, Setting, and Participants: The US National Cancer Database (NCDB) was queried for all 1123 patients with LN+, squamous cell carcinoma of the penis without metastasis from January 1, 2004, through December 31, 2014. Temporal trends were assessed using Cochran-Armitage tests. Multivariable logistic models were used to examine the association between treatments, clinicopathologic variables, and receipt of chemotherapy. Kaplan-Meier analyses with log-rank tests and multivariable Cox regressions were used to analyze overall survival. Data were analyzed between January 2017 and September 2017. Main Outcomes and Measures: Use of chemotherapy over time. Survival outcomes by receipt or nonreceipt of LND, radiotherapy, and chemotherapy. Results: Of 1123 patients identified, most were white (924 [82.3%]) vs African American (141 [12.6%]) or of other or unknown race (58 [5.2%]). The age of most patients (727 [64.7%]) was between 50 and 75 years, and 750 patients (66.8%) underwent an LND. From 2004 to 2014, the use of systemic therapy significantly increased (26 of 68 patients, 38.2% vs 65 of 136, 47.8%; P < .001). However, only 177 of 335 patients with N3 disease (52.8%) received chemotherapy (N1: 106 of 338, 31.4%; N2: 178 of 450, 39.6%). Following adjustment, older patients (>76 years: OR, 0.28; 95% CI, 0.15-0.50; P < .001) were less likely to receive chemotherapy. Patients who received radiotherapy (OR, 4.38; 95% CI, 3.10-6.18; P < .001) and those patients with N2 (OR, 1.62; 95% CI, 1.16-2.27; P = .005) or N3 (OR, 2.32; 95% CI, 1.67 3.22; P < .001) cancer were more likely to receive chemotherapy. On multivariable analysis, LND (HR, 0.64; 95% CI, 0.52-0.78; P < .001) was associated with better overall survival, while neither chemotherapy (HR, 1.01; 95% CI, 0.80-1.26; P = .95) nor radiotherapy (HR, 0.85; 95% CI, 0.70-1.04; P = .11) was associated with overall survival. Conclusions and Relevance: In hospitals reporting to the NCDB, only 66.8% of patients with LN+ penile cancer received an LND. While chemotherapy use has increased since 2004, rates remain low (52.8% for patients with N3 cancer). Receipt of LND, but not chemotherapy or radiotherapy, is associated with overall survival. This may reflect the aggressive natural history of penile cancer as well as the inherent analysis limitation of a relatively small sample size. These data highlight opportunities to improve adherence to guideline recommended care. PMID- 29494740 TI - Questions About Emergency Department Treatment of Patients With Solid Tumors and Hematological Malignant Neoplasms. PMID- 29494742 TI - Clinical Results of Fixed-Bearing and Rotating-Platform Total Knee Prostheses. AB - Inconsistent results have been reported for posterior-stabilized fixed-bearing and rotating-platform total knee prostheses. The authors sought to determine whether the design changes of these prostheses had led to their achieving their intended objectives at minimum 10-year follow-up. Furthermore, the authors sought to delineate the specific features of these knee prostheses to which good outcomes are attributed. One hundred patients (mean age, 66.2 years) were included in this study. Mean follow-up was 10.4 years (range, 10-11 years). The patients were assessed clinically and radiographically with the Knee Society clinical rating system. In addition, the Western Ontario and McMaster Universities Osteoarthritis Index questionnaire was used and the University of California at Los Angeles activity scores were determined preoperatively and at each follow-up visit. The mean Knee Society knee score was 90 points (range, 70 100 points) in the fixed-bearing group and 92 points (range, 75-100 points) in the rotating-platform group at final follow-up. Mean Western Ontario and McMaster Universities Osteoarthritis Index score was 16 points (range, 5-46 points) in the fixed-bearing group and 16 points (range, 6-49 points) in the rotating-platform group. Mean University of California at Los Angeles activity score was 6.5 points (range, 4-10 points) at final follow-up in both groups. No knee had aseptic loosening of the components, and neither group had osteolysis. The predicted implant survival at 10.4 years was 99% as the endpoint of any reoperation in both groups. The findings of this study suggest that cemented posterior-stabilized fixed-bearing and rotating-platform prostheses have favorable clinical and radiographic results. [Orthopedics. 2018; 41(2):88-94.]. PMID- 29494741 TI - SIRT1 and NRF2 Gene Transfer Mediate Distinct Neuroprotective Effects Upon Retinal Ganglion Cell Survival and Function in Experimental Optic Neuritis. AB - Purpose: Optic neuritis is a condition defined by autoimmune-mediated demyelination of the optic nerve and death of retinal ganglion cells. SIRT1 and NRF2 stimulate anti-inflammatory mechanisms and have previously demonstrated therapeutic value in preclinical models of neurodegenerative disease. Here we investigated the neuroprotective potential of SIRT1 or NRF2 gene transfer using adeno-associated virus (AAV) vectors in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. Methods: C57Bl/6J mice were administered intravitreal doses of AAV2 vectors and immunized to induce EAE symptoms. Visual function was examined by recording the optokinetic response (OKR) just prior to EAE induction and once every 7 days postinduction for 7 weeks. Retina and optic nerves were harvested to investigate retinal ganglion cell survival (immunolabeling with Brn3a antibodies); inflammation (hematoxylin and eosin staining); and demyelination (luxol fast blue staining). Results: Animals modeling EAE demonstrate reduced visual acuity compared to sham-induced controls. Intravitreal delivery of AAV2-NRF2 did not preserve visual function. However, AAV2-SIRT1 mediated significant preservation of the OKR compared to AAV2 eGFP controls. Treatment with AAV2-NRF2 promoted RGC survival while AAV2-SIRT1 mediated an upward trend in protection compared to vehicle and AAV2-eGFP controls. Neither NRF2 nor SIRT1 gene augmentation was able to suppress optic nerve inflammation or demyelination. Conclusions: AAV-mediated overexpression of NRF2 or SIRT1 within RGCs mediates distinct neuroprotective effects upon visual function and RGC survival. This study expands our understanding of SIRT1 and NRF2 mediated neuroprotection in the context of MS pathogenesis and optic neuropathies. PMID- 29494743 TI - Degradation of Cylindrical Poly-Lactic Co-Glycolide/Beta-Tricalcium Phosphate Biocomposite Anchors After Arthroscopic Bankart Repair: A Prospective Study. AB - The purpose of this study was to examine widening and ossification of anchor holes after arthroscopic Bankart repair with the use of cylindrical biocomposite anchors made of 70% poly-L-lactide-co-glycolide acid (PLGA) and 30% beta tricalcium phosphate (beta-TCP). Twenty-two patients were enrolled in a clinical trial to acquire marketing approval of a PLGA/beta-TCP biocomposite suture anchor in Japan and underwent arthroscopic Bankart repairs with the anchors. Eleven of 22 patients had computed tomography scans after 2-year follow-up. Three surgeons independently evaluated width and ossification of anchor holes in 4 grades using computed tomography scans. When the evaluations disagreed, the final grade was determined based on the 3 surgeons' consensus. Seven men and 4 women were evaluated at a mean of 30 months (range, 28-32 months) after surgery, and a total of 47 anchors were implanted. Anchor holes were narrowed in 39 (83%) of 47 anchor sites and were almost or completely filled in (type 3 or 4) in 21 (45%) of 47 anchor sites. Ossification was seen in 46 (98%) of 47 anchor sites and was nearly complete or complete (type 3 or 4) in 16 (34%) of 47 anchor sites. There were no significant differences in both anchor hole width and ossification score on comparison of the anteroinferior (4- to 6-o'clock positions in the right shoulder) with other anchor sites. Cylindrical biocomposite anchors made of 70% PLGA/30% beta-TCP showed a low incidence of anchor hole widening and excellent ossification regardless of anchor site. [Orthopedics. 2018; 41(3):e348-e353.]. PMID- 29494744 TI - Day of Surgery Affects Length of Hospitalization for Patients Undergoing Total Joint Arthroplasty Discharged to Extended Care Facilities. AB - Although the average hospital length of stay (LOS) after total joint arthroplasty (TJA) has decreased during the past 10 years, it continues to play a significant role in postoperative costs. The purpose of this study was to determine the effect of surgical day of the week on hospital LOS among TJA patients discharged to an extended care facility (ECF). A TJA database from a single hospital was used to identify all patients who underwent primary total knee arthroplasty (TKA) and total hip arthroplasty (THA) between January 2013 and December 2016. Inclusion criteria were age older than 50 years, surgery Monday through Friday, and discharge to an ECF. A total of 2184 patients met inclusion criteria. Patients were divided into groups based on surgical day of the week. There was no statistically significant difference in age (P=.120), sex (P=.959), or procedure (TKA vs THA, P=.395) between groups based on surgery day. The LOS varied significantly by the day of the week (P<.001). Thursday varied significantly from every other day of the week (P<.001), with the greatest LOS (mean, 3.56+/-0.84 days) and the highest percentage of patients discharged (27.8%) compared with all other days. Tuesday had the shortest LOS (mean, 3.25+/-0.70 days) and differed significantly from Thursday and Friday (P<.05). Patients discharged to an ECF after primary TKA and THA have an increased mean hospital LOS when their surgery falls on a Thursday. The authors recommend preferentially scheduling patients with planned postoperative discharge to an ECF for surgery on Tuesday and avoiding surgery on Thursday. [Orthopedics. 2018; 41(2):82-86.]. PMID- 29494745 TI - Functional Outcomes and Predictors of Failure After Rotator Cuff Repair During Total Shoulder Arthroplasty. AB - A well-functioning rotator cuff is necessary for successful anatomic total shoulder arthroplasty (TSA). This study evaluated patients who underwent concomitant TSA and rotator cuff repair (RCR) for functional outcomes, revision rates, and predictors of poor results. Retrospective chart review was conducted to identify patients who underwent TSA and RCR. Demographic data, rotator cuff tear and RCR characteristics, range of motion, and radiographs were recorded. Minimum 2-year functional outcomes were obtained. Predictors of reoperation and/or poor clinical results were determined. Forty-five patients met inclusion criteria (22 high-grade partial-thickness and 23 full-thickness tears). Fourteen (31%) patients were labeled as having a poor result; 8 (18%) patients required reoperation. There was a significant difference between the acromiohumeral interval preoperatively and immediately postoperatively (P=.013). However, at maximum radiographic follow-up, the acromiohumeral interval was not significantly different from preoperative values (P=.86). Patients with a preoperative acromiohumeral interval of less than 8 mm had an increased rate of cuff-related reoperation (P=.003). Although concomitant TSA and RCR is a reasonable consideration, 31% of patients had a poor clinical result. An acromiohumeral interval of less than 8 mm was a predictor of cuff-related reoperation and may be an indication to consider reverse arthroplasty in the setting of joint arthrosis with a rotator cuff tear. [Orthopedics. 2018; 41(3):e334-e339.]. PMID- 29494746 TI - Preoperative Bariatric Surgery and the Risk of Readmission Following Total Joint Replacement. AB - The purpose of this study was to compare nonelective and all-cause readmission rates and to identify risk factors for readmission of total joint arthroplasty (TJA) patients who had preoperative bariatric surgery (BS) compared with TJA patients without preoperative BS. The New York Statewide Planning and Research Cooperative System database was queried to identify 343,710 TJA patients between 2005 and 2014. Three patient groups were evaluated: group 1 (patients with preoperative BS within 2 years of TJA [N=1478]); group 2 (obese patients without preoperative BS [N=60,259]); and group 3 (nonobese patients without preoperative BS [N=281,973]). Nonelective and all-cause readmission rates (30 days, 90 days, and 1 year) were compared, and multivariate analyses of readmission risk factors were performed. Group 1 had no significant difference in nonelective readmission rates compared with groups 2 and 3. However, when elective TJA readmissions were included, group 1 had significantly higher all-cause readmission rates at 30 days, 90 days, and 1 year compared with groups 2 and 3. Bariatric surgery was not a risk factor for nonelective readmissions at any time point. When elective TJA admissions were included, BS was an independent risk factor for all-cause readmission at all time points. Patients who have BS prior to TJA do not have higher nonelective readmission rates than obese TJA patients without BS. Bariatric surgery is not a risk factor for nonelective readmissions. However, BS is a significant predictor of elective TJA admissions up to 1 year following the index TJA. [Orthopedics. 2018; 41(2):107-114.]. PMID- 29494747 TI - Insurance Status Affects In-Hospital Complication Rates After Total Knee Arthroplasty. AB - Insurance status has been shown to be a predictor of patient morbidity and mortality. The purpose of this study was to evaluate the effect of patient insurance status on the in-hospital complication rates following total knee arthroplasty. Data were obtained from the Nationwide Inpatient Sample (2004 through 2011). Patient demographics and comorbidities were analyzed and stratified by insurance type. Analysis was performed with a matched cohort comparing complication rates between patients with Medicare vs private insurance using the coarsened exact matching algorithm and multivariable logistic regression. A total of 1,352,505 patients (Medicare, 57.8%; private insurance, 35.6%; Medicaid/uninsured, 3.1%; other, 3.3%; unknown, 0.2%) fulfilled the inclusion criteria. The matched cohort analysis comparing Medicare with privately insured patients showed significantly higher risk of mortality (relative risk [RR], 1.34; P<.001), wound dehiscence (RR, 1.32; P<.001), central nervous system complications (RR, 1.16; P=.030), and gastrointestinal complications (RR, 1.13; P<.001) in Medicare patients, whereas privately insured patients had a higher risk of cardiac complications (RR, 0.93; P=.003). Independent of insurance status, older patients and patients with an increased comorbidity index were also associated with a higher complication rate and mortality following total knee arthroplasty. These data suggest that insurance status may be considered as an independent risk factor for increased complications when stratifying patients preoperatively for total knee replacement. Further research is needed to investigate the disparities in these findings to optimize patient outcomes following total knee arthroplasty. [Orthopedics. 2018; 41(3):e340-e347.]. PMID- 29494748 TI - Trends in Medicare Reimbursement for Orthopedic Procedures: 2000 to 2016. AB - Understanding trends in reimbursement is critical to the financial sustainability of orthopedic practices. Little research has examined physician fee trends over time for orthopedic procedures. This study evaluated trends in Medicare reimbursements for orthopedic surgical procedures. The Medicare Physician Fee Schedule was examined for Current Procedural Terminology code values for the most common orthopedic and nonorthopedic procedures between 2000 and 2016. Prices were adjusted for inflation to 2016-dollar values. To assess mean growth rate for each procedure and subspecialty, compound annual growth rates were calculated. Year-to year dollar amount changes were calculated for each procedure and subspecialty. Reimbursement trends for individual procedures and across subspecialties were compared. Between 2000 and 2016, annual reimbursements decreased for all orthopedic procedures examined except removal of orthopedic implant. The orthopedic procedures with the greatest mean annual decreases in reimbursement were shoulder arthroscopy/decompression, total knee replacement, and total hip replacement. The orthopedic procedures with the least annual reimbursement decreases were carpal tunnel release and repair of ankle fracture. Rate of Medicare procedure reimbursement change varied between subspecialties. Trauma had the smallest decrease in annual change compared with spine, sports, and hand. Annual reimbursement decreased at a significantly greater rate for adult reconstruction procedures than for any of the other subspecialties. These findings indicate that reimbursement for procedures has steadily decreased, with the most rapid decrease seen in adult reconstruction. [Orthopedics. 2018; 41(2):95-102.]. PMID- 29494749 TI - Tips Under the Skin: A Simple Modification of Extension Block Pinning for Mallet Fractures. AB - Pins exposed out of the skin after surgery for mallet fractures keep patients from washing their hands. The authors buried the tips of all pins under the skin while performing extension block pinning for 14 patients with mallet fractures. The patients were allowed to wash their hands 4 to 5 days postoperatively, without any dressing or splinting. The pins were removed at a mean of 8 weeks postoperatively. Solid union was achieved in all 14 fractures. No pull-out or subsidence of the pin was observed. No patient developed infection or other pin related complications. Mean extension lag at final follow-up was 4 degrees . [Orthopedics. 2018; 41(2):e299-e302.]. PMID- 29494750 TI - Pulse oximetry screening for critical congenital heart defects. AB - BACKGROUND: Health outcomes are improved when newborn babies with critical congenital heart defects (CCHDs) are detected before acute cardiovascular collapse. The main screening tests used to identify these babies include prenatal ultrasonography and postnatal clinical examination; however, even though both of these methods are available, a significant proportion of babies are still missed. Routine pulse oximetry has been reported as an additional screening test that can potentially improve detection of CCHD. OBJECTIVES: * To determine the diagnostic accuracy of pulse oximetry as a screening method for detection of CCHD in asymptomatic newborn infants* To assess potential sources of heterogeneity, including:? characteristics of the population: inclusion or exclusion of antenatally detected congenital heart defects;? timing of testing: < 24 hours versus >= 24 hours after birth;? site of testing: right hand and foot (pre-ductal and post-ductal) versus foot only (post-ductal);? oxygen saturation: functional versus fractional;? study design: retrospective versus prospective design, consecutive versus non-consecutive series; and? risk of bias for the "flow and timing" domain of QUADAS-2. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2) in the Cochrane Library and the following databases: MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Health Services Research Projects in Progress (HSRProj), up to March 2017. We searched the reference lists of all included articles and relevant systematic reviews to identify additional studies not found through the electronic search. We applied no language restrictions. SELECTION CRITERIA: We selected studies that met predefined criteria for design, population, tests, and outcomes. We included cross-sectional and cohort studies assessing the diagnostic accuracy of pulse oximetry screening for diagnosis of CCHD in term and late preterm asymptomatic newborn infants. We considered all protocols of pulse oximetry screening (eg, different saturation thresholds to define abnormality, post-ductal only or pre-ductal and post-ductal measurements, test timing less than or greater than 24 hours). Reference standards were diagnostic echocardiography (echocardiogram) and clinical follow-up, including postmortem findings, mortality, and congenital anomaly databases. DATA COLLECTION AND ANALYSIS: We extracted accuracy data for the threshold used in primary studies. We explored between-study variability and correlation between indices visually through use of forest and receiver operating characteristic (ROC) plots. We assessed risk of bias in included studies using the QUADAS-2 tool. We used the bivariate model to calculate random-effects pooled sensitivity and specificity values. We investigated sources of heterogeneity using subgroup analyses and meta regression. MAIN RESULTS: Twenty-one studies met our inclusion criteria (N = 457,202 participants). Nineteen studies provided data for the primary analysis (oxygen saturation threshold < 95% or <= 95%; N = 436,758 participants). The overall sensitivity of pulse oximetry for detection of CCHD was 76.3% (95% confidence interval [CI] 69.5 to 82.0) (low certainty of the evidence). Specificity was 99.9% (95% CI 99.7 to 99.9), with a false-positive rate of 0.14% (95% CI 0.07 to 0.22) (high certainty of the evidence). Summary positive and negative likelihood ratios were 535.6 (95% CI 280.3 to 1023.4) and 0.24 (95% CI 0.18 to 0.31), respectively. These results showed that out of 10,000 apparently healthy late preterm or full-term newborn infants, six will have CCHD (median prevalence in our review). Screening by pulse oximetry will detect five of these infants as having CCHD and will miss one case. In addition, screening by pulse oximetry will falsely identify another 14 infants out of the 10,000 as having suspected CCHD when they do not have it.The false-positive rate for detection of CCHD was lower when newborn pulse oximetry was performed longer than 24 hours after birth than when it was performed within 24 hours (0.06%, 95% CI 0.03 to 0.13, vs 0.42%, 95% CI 0.20 to 0.89; P = 0.027).Forest and ROC plots showed greater variability in estimated sensitivity than specificity across studies. We explored heterogeneity by conducting subgroup analyses and meta-regression of inclusion or exclusion of antenatally detected congenital heart defects, timing of testing, and risk of bias for the "flow and timing" domain of QUADAS-2, and we did not find an explanation for the heterogeneity in sensitivity. AUTHORS' CONCLUSIONS: Pulse oximetry is a highly specific and moderately sensitive test for detection of CCHD with very low false-positive rates. Current evidence supports the introduction of routine screening for CCHD in asymptomatic newborns before discharge from the well-baby nursery. PMID- 29494752 TI - Structural characterization of the intrinsically disordered domain of Mycobacterium tuberculosis protein tyrosine kinase A. AB - Although intrinsically disordered proteins or protein domains (IDPs or IDD) are less abundant in bacteria than in eukaryotes, their presence in pathogenic bacterial proteins is important for protein-protein interactions. The protein tyrosine kinase A (PtkA) from Mycobacterium tuberculosis possesses an 80-residue disordered region (IDDPtkA ) of unknown function, located N-terminally to the well-folded kinase core domain. Here, we characterize the conformation of IDDPtkA under varying biophysical conditions and phosphorylation using NMR-spectroscopy. Our results confirm that the N-terminal domain of PtkA exists as an IDD at physiological pH. Furthermore, phosphorylation of IDDPtkA increases the activity of PtkA. Our findings will complement future approaches in understanding molecular mechanisms of key proteins in pathogenic virulence. PMID- 29494751 TI - Structural and histone binding studies of the chromo barrel domain of TIP60. AB - Tat-interactive protein 60 consists of an N-terminal chromo barrel domain (TIP60 CB) and a C-terminal acetyltransferase domain and acetylates histone and nonhistone proteins in diverse cellular processes. While TIP60-CB is thought to recognize histone tails, molecular details of this interaction remain unclear. Here, we attempted a quantitative analysis of the interaction between the human TIP60-CB and histone peptides, but did not observe any detectable binding by either fluorescence polarization or isothermal titration calorimetry assays. We also determined the crystal structure of the TIP60-CB alone. Analysis of the apo structure reveals a putative peptide-binding site that might be occluded by the basic side chain of a residue in a unique beta hairpin between the two N-terminal strands of the beta barrel, leading to the inability of TIP60-CB to bind histones. PMID- 29494753 TI - Seed banks of native forbs, but not exotic grasses, increase during extreme drought. AB - Extreme droughts such as the one that affected California in 2012-2015 have been linked to severe ecological consequences in perennial-dominated communities such as forests. In annual communities, drought impacts are difficult to assess because many species persist through facultative multiyear seed dormancy, which leads to the development of seed banks. Impacts of extreme drought on the abundance and composition of the seed banks of whole communities are little known. In 80 heterogeneous grassland plots where cover is dominated by ~15 species of exotic annual grasses and diversity is dominated by ~70 species of native annual forbs, we grew out seeds from soil cores collected early in the California drought (2012) and later in the multiyear drought (2014), and analyzed drought-associated changes in the seed bank. Over the course of the study we identified more than 22,000 seedlings to species. We found that seeds of exotic annual grasses declined sharply in abundance during the drought while seeds of native annual forbs increased, a pattern that resembled but was even stronger than the changes in aboveground cover of these groups. Consistent with the expectation that low specific leaf area (SLA) is an indicator of drought tolerance, we found that the community-weighted mean SLA of annual forbs declined both in the seed bank and in the aboveground community, as low-SLA forbs increased disproportionately. In this system, seed dormancy reinforces the indirect benefits of extreme drought to the native forb community. PMID- 29494754 TI - Development of Latent Fingermarks on Nonporous and Semiporous Substrates Using Photoluminescent Eu(Phen)2 Complex Intercalated Clay Hybrids with Enhanced Adhesion. AB - In forensic science, developing latent fingermarks using powders is a critical, general method to identify individuals. Photoluminescent Eu(Phen)2 complex intercalated clay hybrids have been used to improve the visualization of fingermarks on nonporous (glass and polymer film) and semiporous (euro and dollar banknotes) substrates. An ion exchange reaction has been successfully used to intercalate Eu(Phen)2 complex ions into the interlayer spacing of two different Na+ -clays, Na+ -montmorillonite and Na+ -hectorite, with different primary particle sizes. To change the surface properties of the obtained hybrid to be more lipophilic, the hydroxyl groups at the edge of the hectorite hybrid were modified with hexadecyltrimethoxysilane via silylation. We investigated the correlation of the size and surface properties of the hybrids with their adhesion to fingermark residues. Fingermarks were successfully visualized using hybrids under UV illumination. In particular, ridge details on semiporous substrates can be more clearly seen using hybrids with smaller primary particles and greater lipophilicity. PMID- 29494755 TI - Punctate palmoplantar keratoderma: an unusual mutation causing an unusual phenotype. PMID- 29494756 TI - A rare BRAF T599dup mutation conferring sensitivity to BRAF inhibitor in a patient with metastatic melanoma. PMID- 29494757 TI - Evaluation of treatment results in multifocal primary cutaneous anaplastic large cell lymphoma: report of the Dutch Cutaneous Lymphoma Group. AB - BACKGROUND: There is no consensus on the treatment of multifocal primary cutaneous anaplastic large cell lymphoma (C-ALCL). Radiotherapy (RT) and methotrexate (MTX) are the current treatment options, but their efficacy is unknown. Recently, targeted therapies showed promising results in C-ALCL, and may therefore be an attractive first choice of treatment. OBJECTIVES: To assess the efficacy of conventional treatment strategies for patients with multifocal C ALCL, and to define which patients may require novel targeted therapies. METHODS: In this multicentre study, treatment was evaluated in patients initially presenting (n = 24) or relapsing with multifocal C-ALCL (n = 17; 23 relapses). Distinction was made between patients with five or less lesions (n = 36) and more than five lesions (n = 11). RESULTS: Treatments most commonly used were RT (n = 21), systemic chemotherapy (n = 9) and low-dose MTX (n = 7) with complete response rates of 100%, 78% and 43%, respectively, and an overall response rate of 100%, 100% and 57%, respectively. Four patients showed complete spontaneous regression. In total, 16 of 24 patients (67%) first presenting with multifocal C ALCL relapsed, including all five patients initially treated with CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone). Compared with patients presenting with two to five skin lesions, patients presenting with more than five lesions had a higher chance of developing extracutaneous relapse (56% vs. 20%) and more often died of lymphoma (44% vs. 7%). CONCLUSIONS: Patients with five or less lesions should be treated with low-dose RT (2 * 4 Gy). Maintenance low-dose MTX (20 mg weekly) is a suitable option in patients with more than five lesions. Targeted therapies may be considered in rare patients who are refractory to MTX or patients developing extracutaneous disease. PMID- 29494759 TI - Transcriptional co-repressor SIN3A silencing rescues decline in memory consolidation during scopolamine-induced amnesia. AB - Epigenetic modifications through methylation of DNA and acetylation of histones modulate neuronal gene expression and regulate long-term memory. Earlier we demonstrated that scopolamine-induced decrease in memory consolidation is correlated with enhanced expression of hippocampal DNA methyltransferase 1 (DNMT1) and histone deacetylase 2 (HDAC2) in mice. DNMT1 and HDAC2 act together by recruiting a co-repressor complex and deacetylating the chromatin. The catalytic activity of HDACs is mainly dependent on its incorporation into multiprotein co-repressor complexes, among which SIN3A-HDAC2 co-repressor is widely studied to regulate synaptic plasticity. However, the involvement of co repressor complex in regulating memory loss or amnesia is unexplored. This study examines the role of co-repressor SIN3A in scopolamine-induced amnesia through epigenetic changes in the hippocampus. Scopolamine treatment remarkably enhanced hippocampal SIN3A expression in mice. To prevent such increase in SIN3A expression, we used hippocampal infusion of SIN3A-siRNA and assessed the effect of SIN3A silencing on scopolamine-induced amnesia. Silencing of SIN3A in amnesic mice reduced the binding of HDAC2 at neuronal immediate early genes (IEGs) promoter, but did not change the expression of HDAC2. Furthermore, it increased acetylation of H3K9 and H3K14 at neuronal IEGs (Arc, Egr1, Homer1 and Narp) promoter, prevented scopolamine-induced down-regulation of IEGs and improved consolidation of memory during novel object recognition task. These findings together suggest that SIN3A has a critical role in regulation of synaptic plasticity and might act as a potential therapeutic target to rescue memory decline during amnesia and other neuropsychiatric pathologies. PMID- 29494758 TI - Genome-wide association study identifies three novel susceptibility loci for systemic lupus erythematosus in Han Chinese. PMID- 29494760 TI - Massively Parallel Sequencing of Forensic STRs Using the Ion ChefTM and the Ion S5TM XL Systems. AB - Next-generation sequencing (NGS) has been used to genotype forensic short tandem repeat (STR) markers for individual identification and kinship analysis. STR data from several NGS platforms have been published, but forensic application trials using the Ion S5TM XL system have not been reported. In this work, we report sensitivity, reproducibility, mixture, simulated degradation, and casework sample data on the Ion ChefTM and S5TM XL systems using an early access 25-plex panel. Sensitivity experiments showed that over 97% of the alleles were detectable with down to 62 pg input of genomic DNA. In mixture studies, alleles from minor contributors were correctly assigned at 1:9 and 9:1 ratios. NGS successfully gave 12 full genotype results from 13 challenging casework samples, compared with five full results using the CE platform. In conclusion, the Ion ChefTM and the Ion S5TM XL systems provided an alternative and promising approach for forensic STR genotyping. PMID- 29494761 TI - A Rare Fatal Complication of Llizarov Procedure. AB - Ilizarov process is used for the management of multiple fractures, polytrauma conditions, cosmetic limb lengthening, and fracture malunion. Complications associated with the process are nerve palsy, joint contracture, premature or delayed osseous consolidation, a nonunion and permanent stiffness of the joint, pin tract infection, edema, and transient paresthesia, etc. In our case, there was a fatal complication. A 25-year-old African lady underwent the Ilizarov procedure for femur lengthening in a hospital in New Delhi, India. During her first distraction process, she suddenly collapsed at the hospital and could not be revived. At postmortem, a small hematoma was seen around the surgically fractured area. On histopathology of internal organs, fat globules were present in the vasculature of brain and lungs. Cause of death was opined as due to fat embolism. This is the first case reported of a fatal fat embolism following Ilizarov procedure for limb lengthening in a healthy adult. PMID- 29494764 TI - QM/MM Study of Static and Dynamic Energetic Disorder in the Emission Layer of an Organic Light-Emitting Diode. AB - Static and dynamic energetic disorder in emission layers of organic light emitting diodes (OLEDs) is investigated through combined molecular dynamics and hybrid quantum mechanics/molecular mechanics (QM/MM) calculations. The analysis is based on a comparison of ensemble and time distributions of site energies of guest and host components in an emission layer. The law of total variance is applied to decompose the total disorder into its static and dynamic contributions. It is found that both contributions are of the same order of magnitude. While the dynamic disorder is not affected by intermolecular interactions, the static disorder for both guests and hosts is determined by the polarity of host molecules. The amount of static disorder affects charge transport properties and exciton formation pathways, which consequently influence the overall efficiency of an OLED device. The simulations indicate that the amount of static disorder induced by the host should be considered for the optimization of the emission layer. PMID- 29494763 TI - Itch in dermatomyositis: the role of increased skin interleukin-31. AB - BACKGROUND: Interleukin (IL)-31 is implicated in pruritus associated with pruritic skin diseases like atopic dermatitis. Although pruritus is a prominent feature in dermatomyositis (DM), few studies have evaluated the pathogenesis of DM-associated itch. OBJECTIVES: To establish the prevalence of itch in DM, and to investigate the role of IL-31 in DM-related itch. METHODS: Pruritus and disease activity of DM were evaluated by a visual analogue scale (VAS) and the Cutaneous Disease and Activity Severity Index (CDASI), respectively. Expression of IL-31 and IL-31 receptor alpha (IL-31RA) in lesional DM, nonlesional DM and healthy control skin was evaluated by quantitative reverse-transcriptase polymerase chain reaction and immunofluorescence. Flow cytometry was performed on skin cells isolated from lesional DM skin to identify cellular sources of IL-31 in DM. RESULTS: Among 191 patients with DM, 50.8% had moderate-to-severe itch, and itch was correlated with increased cutaneous severity (r = 0.34). In patients with itchy DM, gene expression of IL31 and IL31RA in lesional skin was upregulated compared with nonlesional skin and healthy control skin. IL31 mRNA expression positively correlated with VAS itch score (r = 0.67). On immunofluorescence, immunoreactivity for IL-31 and IL-31RA was stronger in lesional skin. Flow cytometry showed that lesional DM skin contained significantly more IL-31 producing cells, and CD4+ cells were the most common cell type. Lenabasum, an emerging treatment for DM, significantly downregulated IL-31 from CpG-stimulated peripheral blood mononuclear cells. CONCLUSIONS: Increased skin IL-31 may play a role in DM-associated itch, and ongoing trials will evaluate the effects of systemic treatment on IL-31 and itch in DM. PMID- 29494765 TI - Correlation between Electronic Shell Structure and Inertness of Cu n+ toward O2 Adsorption at n = 15, 21, 41, and 49. AB - The inertness of metal clusters in air is important for their application to novel materials and catalysts. The adsorption reactivity of copper clusters with O2 has been discussed in connection with the electronic structure of clusters because of its importance in electron transfer from the cluster to O2. Mass spectrometry was used to observe the reaction of Cu n+ + O2 ( n = 13-60) in the gas phase. For O2 adsorption on Cu n+, the relative rate constants of the n = 15, 21, 41, and 49 clusters were clearly lower than those with other n. Theoretical calculations indicated that the inertness of Cu15+ with 14 valence electrons was related to the large HOMO-LUMO gap predicted for the oblate Cu15+ structure. The Clemenger-Nilsson model was used to predict that the electronic subshell of oblate Cu49+ with 48 electrons was closed. This electronic shell closing of Cu49+ corresponds to the inertness for O2 adsorption. PMID- 29494762 TI - Immune responses in stroke: how the immune system contributes to damage and healing after stroke and how this knowledge could be translated to better cures? AB - Stroke is one of the leading causes of death and disability worldwide. The long standing dogma that stroke is exclusively a vascular disease has been questioned by extensive clinical findings of immune factors that are associated mostly with inflammation after stroke. These have been confirmed in preclinical studies using experimental animal models. It is now accepted that inflammation and immune mediators are critical in acute and long-term neuronal tissue damage and healing following thrombotic and ischaemic stroke. Despite mounting information delineating the role of the immune system in stroke, the mechanisms of how inflammatory cells and their mediators are involved in stroke-induced neuroinflammation are still not fully understood. Currently, there is no available treatment for targeting the acute immune response that develops in the brain during cerebral ischaemia. No new treatment has been introduced to stroke therapy since the discovery of tissue plasminogen activator therapy in 1996. Here, we review current knowledge of the immunity of stroke and identify critical gaps that hinder current therapies. We will discuss advances in the understanding of the complex innate and adaptive immune responses in stroke; mechanisms of immune cell-mediated and factor-mediated vascular and tissue injury; immunity induced tissue repair; and the importance of modulating immunity in stroke. PMID- 29494767 TI - Flipped Phenyl Ring Orientations of Dopamine Binding with Human and Drosophila Dopamine Transporters: Remarkable Role of Three Nonconserved Residues. AB - Molecular modeling and molecular dynamics simulations were performed in the present study to examine the modes of dopamine binding with human and Drosophila dopamine transporters (hDAT and dDAT). The computational data revealed flipped binding orientations of dopamine in hDAT and dDAT due to the major differences in three key residues (S149, G153, and A423 of hDAT vs A117, D121, and S422 of dDAT) in the binding pocket. These three residues dictate the binding orientation of dopamine in the binding pocket, as the aromatic ring of dopamine tends to take an orientation with both the para- and meta-hydroxyl groups being close to polar residues and away from nonpolar residues of the protein. The flipped binding orientations of dopamine in hDAT and dDAT clearly demonstrate a generally valuable insight concerning how the species difference could drastically affect the protein-ligand binding modes, demonstrating that the species difference, which is a factor rarely considered in early drug design stage, must be accounted for throughout the ligand/drug design and discovery processes in general. PMID- 29494768 TI - Covalent Allosteric Probe for the Metabotropic Glutamate Receptor 2: Design, Synthesis, and Pharmacological Characterization. AB - Covalent labeling of G protein-coupled receptors (GPCRs) by small molecules is a powerful approach to understand binding modes, mechanism of action, pharmacology, and even facilitate structure elucidation. We report the first covalent positive allosteric modulator (PAM) for a class C GPCR, the mGlu2 receptor. Three putatively covalent mGlu2 PAMs were designed and synthesized. Pharmacological characterization identified 2 to bind the receptor covalently. Computational modeling combined with receptor mutagenesis revealed T7917.29*30 as the likely position of covalent interaction. We show how this covalent ligand can be used to characterize the PAM binding mode and that it is a valuable tool compound in studying receptor function and binding kinetics. Our findings advance the understanding of the mGlu2 PAM interaction and suggest that 2 is a valuable probe for further structural and chemical biology approaches. PMID- 29494766 TI - Red Walnut: Characterization of the Phenolic Profiles, Activities and Gene Expression of Selected Enzymes Related to the Phenylpropanoid Pathway in Pellicle during Walnut Development. AB - A rare walnut variant with a red seed coat (pellicle) was examined for alterations in its phenolic profile during development. The red-walnut (RW) pellicle was compared with two commonly colored walnut varieties: 'Lara' (brown) and 'Fernor' (light brown). Furthermore, the activities of selected enzymes of the phenylpropanoid- and flavonoid-related pathways and the relative expressions of the structural genes phenylalanine ammonia lyase ( PAL) and anthocyanidin synthase ( ANS) were examined in the pellicles of the three varieties. In the pellicles of the RWs, phenylalanine ammonia lyase (PAL) activity and related PAL expression was most pronounced in August, about one month before commercial maturity, suggesting a high synthesis rate of phenolic compounds at this development stage. The most pronounced differences between the red and light- and dark-brown varieties were the increased PAL activity, PAL expression, and ANS expression in RWs in August. The vibrant color of the RW pellicle is based on the presence of four derivatives of cyanidin- and delphinidin-hexosides. PMID- 29494769 TI - Increases in the Charge Separation Barrier in Organic Solar Cells Due to Delocalization. AB - Because of the low dielectric constant, charges in organic solar cells must overcome a strong Coulomb attraction in order to separate. It has been widely argued that intermolecular delocalization would assist charge separation by increasing the effective initial electron-hole separation in a charge-transfer state, thus decreasing their barrier to separation. Here we show that this is not the case: including more than a small amount of delocalization in models of organic solar cells leads to an increase in the free-energy barrier to charge separation. Therefore, if delocalization were to improve the charge separation efficiency, it would have to do so through nonequilibrium kinetic effects that are not captured by a thermodynamic treatment of the barrier height. PMID- 29494770 TI - Virus-Induced Gene Silencing of the Eggplant Chalcone Synthase Gene during Fruit Ripening Modifies Epidermal Cells and Gravitropism. AB - Eggplant ( Solanum melongena L.) fruits accumulate flavonoids in their cuticle and epidermal cells during ripening. Although many mutants available in model plant species, such as Arabidopsis thaliana and Medicago truncatula, are enabling the intricacies of flavonoid-related physiology to be deduced, the mechanisms whereby flavonoids influence eggplant fruit physiology are unknown. Virus-induced gene silencing (VIGS) is a reliable tool for the study of flavonoid function in fruit, and in this study, we successfully applied this technique to downregulate S. melongena chalcone synthase gene ( SmCHS) expression during eggplant fruit ripening. In addition to the expected change in fruit color attributable to a lack of anthocyanins, several other modifications, including differences in epidermal cell size and shape, were observed in the different sectors. We also found that silencing of CHS gene expression was associated with a negative gravitropic response in eggplant fruits. These observations indicate that epidermal cell expansion during ripening is dependent upon CHS expression and that there may be a relationship between CHS expression and gravitropism during eggplant fruit ripening. PMID- 29494771 TI - Nitrate: An Environmental Endocrine Disruptor? A Review of Evidence and Research Needs. AB - Nitrate is heavily used as an agricultural fertilizer and is today a ubiquitous environmental pollutant. Environmental endocrine effects caused by nitrate have received increasing attention over the last 15 years. Nitrate is hypothesized to interfere with thyroid and steroid hormone homeostasis and developmental and reproductive end points. The current review focuses on aquatic ecotoxicology with emphasis on field and laboratory controlled in vitro and in vivo studies. Furthermore, nitrate is just one of several forms of nitrogen that is present in the environment and many of these are quickly interconvertible. Therefore, the focus is additionally confined to the oxidized nitrogen species (nitrate, nitrite and nitric oxide). We reviewed 26 environmental toxicology studies and our main findings are (1) nitrate has endocrine disrupting properties and hypotheses for mechanisms exist, which warrants for further investigations; (2) there are issues determining actual nitrate-speciation and abundance is not quantified in a number of studies, making links to speciation-specific effects difficult; and (3) more advanced analytical chemistry methodologies are needed both for exposure assessment and in the determination of endocrine biomarkers. PMID- 29494772 TI - Ultrafast Charge Migration in XUV Photoexcited Phenylalanine: A First-Principles Study Based on Real-Time Nonequilibrium Green's Functions. AB - The early-stage density oscillations of the electronic charge in molecules irradiated by an attosecond XUV pulse takes place on femto- or subfemtosecond time scales. This ultrafast charge migration process is a central topic in attoscience because it dictates the relaxation pathways of the molecular structure. A predictive quantum theory of ultrafast charge migration should incorporate the atomistic details of the molecule, electronic correlations, and the multitude of ionization channels activated by the broad-bandwidth XUV pulse. We propose a first-principles nonequilibrium Green's function method fulfilling all three requirements and apply it to a recent experiment on the photoexcited phenylalanine amino acid. Our results show that dynamical correlations are necessary for a quantitative overall agreement with the experimental data. In particular, we are able to capture the transient oscillations at frequencies 0.15 and 0.30 PHz in the hole density of the amine group as well as their suppression and the concomitant development of a new oscillation at frequency 0.25 PHz after ~14 fs. PMID- 29494773 TI - Assembly of Complex Macrocycles by Incrementally Amalgamating Unprotected Peptides with a Designed Four-Armed Insert. AB - We describe the asymmetric synthesis of a highly substituted omega-octynoic acid derivative and demonstrate its utility for generating complex macrocycles from unprotected peptides. The molecule harbors an isolated quaternary center that displays four uniquely functionalized arms, each of which can be reacted orthogonally in sequence as the molecule is integrated into peptide structure. These processing sequences entail (1) scaffold ligation, (2) macrocyclization via internal aromatic alkylations or catalyzed etherifications, (3) acyliminium ion mediated embedding of condensed heterocycles, and (4) terminal alkyne derivatization or dimerization reactions. Numerous polycycles are prepared and fully characterized in this study. Factors that influence reaction efficiencies and selectivity are also probed. We construct a novel mimic of the second mitochondria derived activator of caspase using these techniques, wherein subtle variations in macrocycle connectivity have a marked impact on performance. In general, the chemistry is an important step toward facile, systematic access to complex peptidomimetics synthesized by directly altering the structure and properties of machine-made oligomers. PMID- 29494774 TI - Out-of-Hospital Research in the Era of Electronic Health Records. AB - Conducting out-of-hospital research is unique and challenging and requires tracking patients across multiple phases of care, using multiple sources of patient records and multiple hospitals. The logistics and strategies used for out of-hospital research are distinct from other forms of clinical research. The increasing use of electronic health records (EHRs) by hospitals and emergency medical services (EMS) agencies presents a large opportunity for accelerating out of-hospital research, as well as particular challenges. In this study, we describe seven key aspects of designing and implementing out-of-hospital research in the era of EHRs: (1) selection of research sites, (2) defining the patient population, (3) patient sampling and sample size calculations, (4) EMS data, (5) hospital selection, (6) handling missing data, and (7) statistical analysis. We use examples from a recent prospective out-of-hospital cohort study to illustrate these topics, including lessons learned. PMID- 29494775 TI - International Olympic Committee Expert Group Statement on Dietary Supplements in Athletes. PMID- 29494776 TI - Simulation of the Effects of Co-Locating Naloxone with Automated External Defibrillators. AB - INTRODUCTION: Opioid-related overdoses have been steadily increasing over the past decade in the United States. Naloxone is used by first responders to revive overdose victims, but results may be improved by increasing access to and usage of naloxone by bystanders. Automated External Defibrillators (AEDs) are pervasive, recognizable, and publicly accessible. Co-locating naloxone kits with AEDs could increase public naloxone access and usage. However, the impact of co locating naloxone kits with AEDs is not known. OBJECTIVES: We sought to evaluate the impact of co-locating naloxone kits with AEDs in a simulation study centered on Allegheny County, Pennsylvania. METHODS: Naloxone administration frequency (N = 3,650) at the zip-code level from March 2016 to March 2017 was provided by the Allegheny County Health Department. AED point locations (N = 1,653) were obtained from the University of Pittsburgh's Resuscitation Logistics and Informatics Venture. Zip-code level geospatial analyses were conducted using QGIS and STATA to determine the correlation between AED count and naloxone administrations. AED naloxone kit (N-AED) coverage, based on a maximum "walking-distance" radius of 200 m, was estimated at a zip-code level using the QGIS buffer tool and a custom MATLAB script. Potential impact of N-AEDs was estimated assuming uniform spatial distribution of naloxone administrations. RESULTS: The median (IQR) AED coverage based on a 200 m access radius per zip code was 4% (0-7). The median (IQR) number of naloxone administrations per zip code was 27(7-55). A total of 82 zip codes had data for both AED locations and naloxone administrations. The correlation between number of AEDs and naloxone administrations per zip code was 0.20. Overall, 16% of naloxone administrations were estimated to be covered by an N AED. CONCLUSION: Using these limited methods, co-locating naloxone with AEDs is not likely to have a standalone impact on preventing overdose fatalities. PMID- 29494777 TI - Prehospital Interventions Performed on Pediatric Trauma Patients in Iraq and Afghanistan. AB - BACKGROUND: United States (US) and coalition military medical units deployed to combat zones frequently encounter pediatric trauma patients. Pediatric patients may present unique challenges due to their anatomical and physiological characteristics and most military prehospital providers lack pediatric-specific training. A minimal amount of data exists to illuminate the prehospital care of pediatric patients in this environment. We describe the prehospital care of pediatric trauma patients in Iraq and Afghanistan. METHODS: We queried the Department of Defense Trauma Registry (DODTR) for all pediatric subjects admitted to US and Coalition fixed-facility hospitals in Iraq and Afghanistan from January 2007 to January 2016. Subjects were grouped by age: <1, 1-4, 5-9, 10-14, and 15 17 years. We focused our analysis on interventions related to trauma resuscitation. RESULTS: Of 42,790 encounters in the DODTR during the study period, 3,439 (8.0%) were aged <18 years. Most subjects were in the 5-9 age group (33.1%), male (77.1%), located in Afghanistan (67.8%), injured by explosives (43.1%). Most subjects survived to hospital discharge (90.2%). The most frequently performed interventions were tourniquet placement (6.6%), intubation (6.1%), supplemental oxygen (11.7%), IV access (24.8%), IV fluids (13.3%), IO access (5.1%), and hypothermia prevention (44.5%). The most frequently administered medications were antibiotics (6.2%) and opioids (15.0%). Most procedural and medication interventions occurred in subjects injured by explosives (43.1%) and gunshot wounds (22.1%). CONCLUSIONS: Pediatric subjects comprised over 1 in 13 casualties treated in the joint theaters with the majority injured by explosives. Vascular access and hypothermia prevention interventions were the most frequently performed procedures. PMID- 29494778 TI - A Psychometric Examination of the Pathological Obsessive Compulsive Personality Scale (POPS): Initial Study in an Undergraduate Sample. AB - Obsessive-compulsive personality disorder (OCPD) has been subject to numerous definition and classification changes, which has contributed to difficulties in reliable measurement of the disorder. Consequently, OCPD measures have yielded poor validity and inconsistent prevalence estimates. Reliable and valid measures of OCPD are needed. The aim of the current study was to examine the factor structure and psychometric properties of the Pathological Obsessive Compulsive Personality Scale (POPS). Participants (N = 571 undergraduates) completed a series of self-report measures online, including the POPS. Confirmatory factor analysis was used to compare the fit of unidimensional, five factor, and bifactor models of the POPS. Convergent and divergent validity were assessed in relation to other personality dimensions. A bifactor model provided the best fit to the data, indicating that the total POPS scale and four subscales can be scored to obtain reliable indicators of OCPD. The POPS was most strongly associated with a disorder-specific measure of OCPD, however there were also positive associations with theoretically disparate constructs, thus further research is needed to clarify validity of the scale. PMID- 29494779 TI - Gallbladder Polyps in Metachromatic Leukodystrophy. AB - BACKGROUND: Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease, caused by a deficiency of arylsulfatase A, and leads to demyelination of the nervous system. A putative association between MLD and gallbladder pathology including malignancy is documented in the medical literature. CASE REPORT: A 10-year-old boy with MLD was found to have a papillary growth within a cystically dilated gallbladder. The lesion was confirmed to be papillomatosis/polyp with focal intestinal metaplasia. Dysplasia was not identified. CONCLUSION: MLD may be associated with a spectrum of gallbladder pathology including neoplastic conditions. Pathologists and clinicians should be aware of this association/risk. The patient may be offered regular ultrasound screening of the gallbladder. PMID- 29494780 TI - Unstable Inflation Is Harmful and More Common Supine Than Prone. PMID- 29494781 TI - Lead (Pb) neurotoxicology and cognition. AB - Lead (Pb) is a neurotoxic substance. While it is widely understood that Pb exposure in early childhood adversely impacts neurodevelopment and intelligence, other aspects of cognition that are negatively affected, and the neuroanatomy and neurophysiology underlying Pb-related cognitive impairment are not widely appreciated by clinicians. This critical review gives a broad synopsis of the current literature in the field. The means by which Pb enters the body, crosses the blood-brain barrier, alters brain structure and function, and consequently impacts measurable aspects of cognition are reviewed. We detail research relating exposure to Pb at various levels in early childhood to deficits in IQ, academic achievement, executive functioning, and cognition in general. Clinical disorders associated with early Pb exposure, common and uncommon routes of environmental exposure, and potential confounding variables are discussed. We discuss methods of statistically accounting for these issues in the context of potential means of relying upon existing research and specific individuals' known blood Pb levels to make reasonable calculations regarding Pb-related compromise of intellectual functioning for individuals in clinical settings. PMID- 29494782 TI - Level of Personality Functioning Scale-Brief Form 2.0: Utility in Capturing Personality Problems in Psychiatric Outpatients and Incarcerated Addicts. AB - This study examined the utility of the Level of Personality Functioning Scale Brief Form 2.0 (LPFS-BF 2.0) in measuring features corresponding to self-other impairment of personality functioning as defined in the new general diagnostic guidelines for Personality Disorder in DSM-5 Section III and ICD-11. A mixed clinical sample (N = 228) composed of 121 psychiatric outpatients and 107 incarcerated addicts was administered the LPFS-BF 2.0, World Health Organization Wellbeing Index (WHO-5), Symptom Checklist-90-Revised (SCL-90-R), Personality Inventory for DSM-5 (PID-5), and the Schema Mode Inventory (SMI). The LPFS-BF 2.0 yielded two latent components that correspond to an interpretation of self- and interpersonal functioning, and showed relevant associations with severity indexes, well-being, dysfunctional schema modes, and lack of healthy functioning modes. The LPFS-BF 2.0 also demonstrated incremental prediction of reduced healthy adult functioning, fulfillment, and well-being over and above the total PID-5 trait score, although this did not apply to dysregulated anger and overcompensatory coping. Taken together, the LPFS-BF 2.0 is a psychometrically satisfactory instrument that generally captures theoretically expected self-other features of personality dysfunctioning, in particular lack of healthy functioning and fulfillment but to a lesser degree overcompensatory and antagonistic features. Findings warrant replication in different clinical and forensic populations. PMID- 29494783 TI - Tianeptine Abuse and Dependence in Psychiatric Patients: A Review of 18 Case Reports in the Literature. AB - Tianeptine is an atypical antidepressant approved in 25 countries for the treatment of depressive syndromes. Tianeptine abuse among psychiatric patients in the community and at inpatient wards has been increasingly reported in recent years. The purpose of this article is to alert clinicians to tianeptine abuse potential and identify any patterns in the literature. We searched the Academic Search Complete, Google Scholar, MEDLINE, Science Citation Index, Scopus, and the Social Sciences Citation Index for articles published between 1960-2017 in any language containing the keywords: "tianeptine abuse," "tianeptine misuse," "tianeptine dependence." The search retrieved 18 cases. Higher frequency of tianeptine abuse/dependence was observed in women and 30- to 45-year-olds. Most cases (n = 13) reported a previous history of substance abuse. The therapeutic dose of tianeptine was exceeded 110-fold (i.e., up to 4125 mg/day) with a mean of about 1469 mg/day. The most prominent phenomena associated with tianeptine abuse and dependence were marked euphoria and withdrawal symptoms perpetuating further drug misuse. Tianeptine is a drug with potential for abuse and addiction. Caution should be taken when considering the prescription of tianeptine to patients with prior history of substance abuse, and close monitoring for drug misuse is needed during the treatment period. PMID- 29494785 TI - Gender differences in health expenditure determinants: A follow-up study. AB - Researchers' aim was to investigate if patients/physicians characteristics could differently affect males/females health care expenditure. In 2009/2010, a health related-quality-of-life (HRQL) measure was distributed to 887 general practitioners' (GP) patients in Siena's province-Italy. Severity of diseases was calculated through Cumulative Illness Rating Scale Severity Index (CIRS-SI). Information about GPs' gender and age and patients' gender, age, and socio economic variables were recorded. 2012 data about pharmaceutical, outpatient and hospital expenditure were obtained. Multivariate regression was carried out. In males, hospital expenditure increased with higher CIRS-SI and female GP whilst in females it was not influenced by any of the variables. Outpatient and pharmaceutical expenditure increased with aging, higher CIRS-SI, and lower HRQL and education, both in males and females. Gender differences in health expenditure determinants emerged for hospital expenditure. PMID- 29494784 TI - Cognitive-Functional (Cog-Fun) Dyadic Intervention for Children with ADHD and Their Parents: Impact on Parenting Self-Efficacy. AB - AIM: The family context of children with ADHD plays a role in intervention outcomes, especially when parents are involved in treatment. Parental participation in evidence-based treatment for ADHD may play a role in improving their own parenting self-efficacy (PSE) as well as child outcomes. This study examined the impact of Cognitive-Functional (Cog-Fun) intervention in occupational therapy (OT) for school-aged children with ADHD, on PSE. METHODS: In this randomized controlled trial with crossover design, 107 children were allocated to intervention and waitlist control groups. Intervention participants (n = 50) received Cog-Fun after baseline assessment and waitlist controls (n = 49) received treatment 3 months later. Intervention participants received 3-month follow-up assessment. Treatment included 10 parent-child Cog-Fun weekly sessions. PSE was assessed with the Tool to measure Parenting Self-Efficacy (TOPSE). RESULTS: All children who began treatment completed it. Mixed ANOVA revealed significant Time x Group interaction effects on TOPSE scales of Play and Enjoyment, Control, Self-Acceptance, Knowledge and Learning and Total score, which showed significant improvement with moderate treatment effects for the intervention group. Results were replicated in the control group after crossover. CONCLUSION: The findings of this study suggest that Cog-Fun OT intervention may be effective for improving aspects of PSE among parents of children with ADHD. PMID- 29494786 TI - Disaster Victim Identification: Psychological Distress and Posttraumatic Stress in Dentists After the 2011 Fukushima Disaster. AB - OBJECTIVE: To evaluate the correlates of psychological responses in dentists who conducted disaster victim identification (DVI) in Fukushima following the 2011 earthquake/tsunami/nuclear disaster. METHOD: Self-report questionnaires were administered to 49 male dentists six to nine months after the disaster. Psychological distress and posttraumatic stress were measured using the General Health Questionnaire-30 (GHQ-30) and Impact of Event Scale-Revised (IES-R), respectively. Independent variables included sociodemographic characteristics, participant disaster exposures, DVI-related exposures, and fear of radiation exposure during DVI. Hierarchical multiple regression analysis was performed to examine independent-dependent variable relations. RESULTS: Thirty-eight participants (77.6%) had examined >= 40 corpses, 20 (40.8%) reported >= 4 corpse related exposures, and six (12.2%) reported >= 5 gruesome corpse exposures. Mean (SD) GHQ-30 and IES-R scores were 5.08 (5.31) and 9.90 (10.1), respectively. Higher levels of psychological distress were associated with younger age (adjusted beta = -0.29), extensive property loss (beta = 0.34), and anxiety for the future (beta = 0.33). Higher levels of posttraumatic stress were associated with extensive property loss (adjusted R2 = 17.7%, beta = 0.30). Neither outcome was associated with DVI-related exposures or fear of radiation exposure during DVI (p < 0.05). CONCLUSIONS: Dentists' psychological burden was associated with disaster, but not DVI, exposures. PMID- 29494787 TI - The effect of transcendental meditation on self-efficacy, perceived stress, and quality of life in mothers in Uganda. AB - Vulnerable women living in poverty in Uganda, who are primarily single, illiterate mothers, face high levels of physical and psychological stress. Our study assessed the impact of the Transcendental Meditation(r) (TM(r)) technique on self-efficacy, perceived stress, and mental and physical quality of life of these women. This single-blind controlled study involved 81 women who were assigned to either practice of the Transcendental Meditation program (n = 42) or wait-list (delayed start) control group (n = 39). Participants learned the Transcendental Meditation program over five sessions, then practiced at home for 20 minutes twice a day, and attended twice monthly group meetings over a 3-month period. The primary outcome measure was self-efficacy using the General Self Efficacy Scale (GSES). Perceived stress using Cohen's Perceived Stress Scale, and physical and mental quality of life using subscales of the Medical Outcomes Survey (MOS, HIV version) were secondary outcome measures. Significant improvements were shown in self-efficacy (p < .001), perceived stress (p < .010), and mental and physical well-being (p < .010). Compliance with TM home practice was >88%. This is the first controlled study to demonstrate the effect of TM in the daily lives of mothers living in impoverished conditions. Further questionnaires were administered to participants at 8 months and at 36 months with questions about changes they may have experienced in their daily life since starting TM. "Yes," "No" self-reported answers suggested that the women experienced improved health, improved relationships with others, and increased employment rates. These findings taken as a whole have important implications for developing self-efficacy, improving mental and physical quality of life, and reducing stress in the lives of these vulnerable women. PMID- 29494788 TI - Posttraumatic Stress Among Syrian Refugees: Trauma Exposure Characteristics, Trauma Centrality, and Emotional Suppression. AB - OBJECTIVES: This study revisited the prevalence of posttraumatic stress disorder (PTSD) and examined a hypothesized model describing the interrelationship between trauma exposure characteristics, trauma centrality, emotional suppression, PTSD, and psychiatric comorbidity among Syrian refugees. METHODS: A total of 564 Syrian refugees participated in the study and completed the Harvard Trauma Questionnaire, General Health Questionnaire (GHQ-28), Centrality of Event Scale, and Courtauld Emotional Control Scale. RESULTS: Of the participants, 30% met the cutoff for PTSD. Trauma exposure characteristics (experiencing or witnessing horror and murder, kidnapping or disappearance of family members or friends) were associated with trauma centrality, which was associated with emotional suppression. Emotional suppression was associated with PTSD and psychiatric comorbid symptom severities. Suppression mediated the path between trauma centrality and distress outcomes. CONCLUSIONS: Almost one-third of refugees can develop PTSD and other psychiatric problems following exposure to traumatic events during war. A traumatized identity can develop, of which life-threatening experiences is a dominant feature, leading to suppression of depression with associated psychological distress. PMID- 29494789 TI - A pilot test of a self-guided, home-based intervention to improve condom-related sexual experiences, attitudes, and behaviors among young women. AB - OBJECTIVE: To conduct a pilot test of a brief, self-guided, home-based program designed to improve male condom use attitudes and behaviors among young women. PARTICIPANTS: Women aged 18-24 years from a large Midwestern University reporting having had penile-vaginal sex with two or more partners in the past 3 months. Sixty-seven enrolled; 91.0% completed the study. METHODS: A repeated measures design was used, with assessments occurring at baseline, immediately post intervention (T2), and 30 days subsequent (T3). RESULTS: Condom use errors and problems decreased, condom-related attitudes and self-efficacy improved, and experiences of condom-protected sex were rated more positively when comparing baseline with T2 and T3 scores. Further, the proportion of condom-protected episodes more than doubled between T1 and T3 for those in the lowest quartile for condom use at baseline. CONCLUSION: This low-resource, home-based program improved condom-related attitudes and promoted the correct and consistent use of condoms. PMID- 29494790 TI - Flexible Eating Behavior Predicts Greater Weight Loss Following a Diet and Exercise Intervention in Older Women. AB - Eating behaviors (cognitive restraint, flexible and rigid restraint, disinhibition, hunger) have been associated with obesity and weight loss success in middle-aged individuals, but little is known about these relationships in older adults. This study examined relationships between eating behaviors and weight loss in overweight/obese older women (n = 61; 69 +/- 3.6 years; body mass index = 31.1 +/- 5.0 kg/m2) completed a 6-month behavioral weight loss intervention. Baseline, postintervention, and change measures of eating behaviors (51-items Three-Factor Eating Questionnaire) were assessed for relationships with weight loss. In the final regression model, an increase in flexible restraint accompanied by a decrease in rigid restraint predicted greater weight loss (adjusted R2 = 0.21, Model F (4, 56) = 4.97, P < 0.01). No associations were found with disinhibition or hunger and degree of weight loss (all P > 0.05). Results suggest encouraging a flexible approach to eating behavior and discouraging rigid adherence to a diet may lead to better intentional weight loss for overweight and obese older women. PMID- 29494791 TI - Physician-Assisted Suicide and Midwest Social Workers: Where Do They Stand? AB - Physician-assisted suicide (PAS) is explicitly legal in five states and by court decision in one. Legislative bills have been introduced in other states including Minnesota, Iowa, and Wisconsin. This quantitative study was designed to understand Midwest, hospice and palliative care at end-of-life social workers' attitudes toward PAS, preferred terminology, perception of preparedness for the implementation, and awareness of PAS legislation in their state. Sixty-two social workers from Minnesota, Iowa, and Wisconsin completed an anonymous online survey. The results indicated that over one-half of the participants supported PAS legislation and is consistent with previous research on social workers across the country. While there was a range of perceived preparedness for implementation, a majority felt moderately to very prepared. Professional and personal values as well as professional experience influenced their perceived preparedness. Few social workers had accurate awareness of PAS legislation in their state or had attended workshops/events for further education or as a policy advocate. To practice competently and advocate at all levels of practice, hospice and palliative care at end-of-life social workers' need to understand their own attitudes and values toward PAS and pursue additional education around this ethical issue. PMID- 29494792 TI - Internalized Sexual Stigma in Italian Lesbians and Gay Men: The Roles of Outness, Connectedness to the LGBT Community, and Relationship Satisfaction. AB - The authors examined the extent to which outness, connectedness to the LGBT community, and relationship satisfaction could be used to predict internalized sexual stigma scores. A total of 279 Italian lesbians (47%) and gay men (53%) in a same-sex relationship for at least six months completed the web-based survey. Significant correlations were found between outness, connectedness, relationship satisfaction, and internalized stigma. Analyses of variance were conducted on demographic variables to explore group differences. Multivariate regression analysis suggests that demographic variables, outness, connectedness, and relationship satisfaction combined accounted for 32.8% of the variance in overall internalized sexual stigma. Clinical implications are discussed. PMID- 29494793 TI - Supported Decision Making in Serious Mental Illness. AB - OBJECTIVE: Making decisions is central to the exercise of control over one's well being. Many individuals with serious mental illness (SMI) experience limitations in their decision-making capacity. These individuals have often been placed under legal guardianship and substitute decision makers have been appointed to make decisions on their behalf. More recently, supported decision making (SDM) has emerged as a possible alternative in some cases. SDM involves recruitment of trusted supports to enhance an individual's capacity in the decision-making process, enabling him or her to retain autonomy in life decisions. This overview examines issues associated with decision-making capacity in SMI, frameworks of substitute decision making and SDM, and emerging empirical research on SDM. METHOD: This is an overview of the medical and legal literature on decision making capacity and supported decision making for persons with SMI. RESULTS: Many but not all individuals with SMI exhibit decrements in decision-making capacity and skill, in part due to cognitive impairment. There are no published data on rates of substitute decision making/guardianship or SDM for SMI. Only three empirical studies have explored SDM in this population. These studies suggest that SDM is viewed as an acceptable and potentially superior alternative to substitute decision making for patients and their caretakers. CONCLUSIONS: SDM is a promising alternative to substitute decision making for persons with SMI. Further empirical research is needed to clarify candidates for SDM, decisions in need of support, selection of supporters, guidelines for the SDM process, integration of SDM with emerging technological platforms, and outcomes of SDM. Recommendations for implementation of and research on SDM for SMI are provided. PMID- 29494794 TI - Parental Discussion of Child Sexual Abuse: Is It Associated with the Parenting Practices of Involvement, Monitoring, and General Communication? AB - We investigated whether parents who reported more positive parenting practices (i.e., monitoring, involvement, and communication) reported more discussion of child sexual abuse (CSA) with their children. Parents from Australia and the UK (N = 248), with children aged 6 to 11 years, completed an online survey. About half of parents reported directly discussing CSA, whereas 35% reported telling their children that CSA perpetrators may be family members. Rates of discussion were higher for other CSA-related topics such as body integrity and abduction. Correlational analyses showed that parents who reported speaking to their children about CSA also reported more positive parenting practices, more discussion of other sensitive topics, and assessed CSA risk for children (in general) to be higher. Discussion of CSA risk was not associated with parents' CSA knowledge, confidence or appraisal of own-child risk. Parents higher in positive parenting believed their children to be at less CSA risk. Parents who appraised higher own-child risk reported less positive parenting practices and were less confident about their parenting and their ability to protect their children from CSA. The findings are the first to report on the associations of parenting practices with parents' CSA discussion with their children. PMID- 29494795 TI - Concurrent Disorders and Health Care Utilization Among Homeless and Vulnerably Housed Persons in Canada. AB - OBJECTIVE: Individuals who are homeless or vulnerably housed have a higher prevalence of concurrent disorders, defined as having a mental health diagnosis and problematic substance use, compared to the general housed population. The study objective was to investigate the effect of having concurrent disorders on health care utilization among homeless or vulnerably housed individuals, using longitudinal data from the Health and Housing in Transition Study. METHODS: In 2009, 1190 homeless or vulnerably housed adults were recruited in Ottawa, Toronto, and Vancouver, Canada. Participants completed baseline interviews and four annual follow-up interviews, providing data on sociodemographics, housing history, mental health diagnoses, problematic drug use with the Drug Abuse Screening Test (DAST-10), problematic alcohol use with the Alcohol Use Disorders Identification Test (AUDIT), chronic health conditions, and utilization of the following health care services: emergency department (ED), hospitalization, and primary care. Concurrent disorders were defined as the participant having ever received a mental health diagnosis at baseline and having problematic substance use (i.e., DAST-10 >= 6 and/or AUDIT >= 20) at any time during the study period. Three generalized mixed effects logistic regression models were used to examine the independent association of having concurrent disorders and reporting ED use, hospitalization, or primary care visits in the past 12 months. RESULTS: Among our sample of adults who were homeless or vulnerably housed, 22.6% (n = 261) reported having concurrent disorders at baseline. Individuals with concurrent disorders had significantly higher odds of ED use (adjusted odds ratio [AOR] = 1.71; 95% confidence interval [CI], 1.4-2.11), hospitalization (AOR = 1.45; 95% CI, 1.16 1.81), and primary care visits (AOR = 1.34; 95% CI, 1.05-1.71) in the past 12 months over the four-year follow-up period, after adjusting for potential confounders. CONCLUSIONS: Concurrent disorders were associated with higher rates of health care utilization when compared to those without concurrent disorders among homeless and vulnerably housed individuals. Comprehensive programs that integrate mental health and addiction services with primary care as well as community-based outreach may better address the unmet health care needs of individuals living with concurrent disorders who are vulnerable to poor health outcomes. PMID- 29494797 TI - Energy landscaping in supramolecular materials. AB - This review details recent developments in the design of supramolecular materials with customizable properties that can be coordinated in space and time. We highlight examples where both kinetic and thermodynamic considerations are incorporated in design, to address three challenges: control of order/disorder in supramolecular assembly; formation of structures with distinct functional domains; formation of out-of-equilibrium structures with controlled lifetimes. The examples that are discussed are based on self-assembling peptide and saccharide-based amphiphiles. These biomolecular amphiphiles are of low complexity and ideally suited to fundamental, systematic studies while they are also considered for applications in environmental remediation, food science, cosmetics and nanomedicine. PMID- 29494796 TI - Seroprevalence of hepatitis E virus in chronic hepatitis C in Brazil. AB - BACKGROUND AND AIMS: Hepatitis E virus infection in patients with underlying chronic liver disease is associated with liver decompensation and increased lethality. The seroprevalence of hepatitis E virus in patients with chronic hepatitis C in Brazil is unknown. This study aims to estimate the seroprevalence of hepatitis E virus in patients with chronic hepatitis C and to describe associated risk factors. METHODS: A total of 618 patients chronically infected with hepatitis C virus from three reference centers of Sao Paulo, Brazil were included. Presence of anti-HEV IgG was assessed by enzyme-linked immunosorbent assay (WANTAI HEV-IgG ELISA). RESULTS: Out of the 618 patients tested, 10.2% turned out positive for anti-HEV IgG (95% CI 8.0-12.8%). Higher seroprevalence was found independently associated with age over 60 years (OR=2.04; p=0.02) and previous contact with pigs (OR=1.99; p=0.03). CONCLUSIONS: Patients with chronic hepatitis C are under risk of hepatitis E virus superinfection in Sao Paulo. Contact with pigs is a risk factor for the infection, suggesting a possible zoonosis with oral transmission. PMID- 29494798 TI - Temporal binding effect in the action observation domain: Evidence from an action based somatosensory paradigm. AB - Temporal binding is understood as an effect in which a temporal interval between a voluntary action and its consequent effect is perceived as compressed. It denotes an implicit measure of a sense of agency. When people observe someone else performing an action that generates an effect, temporal binding also takes place. We aimed to test whether the interaction between observed actions and tactile sensation influences temporal binding. Participants observed finger tapping movements (of a human or wooden hand), in parallel to receiving tactile stimulations on their fingertip. These stimulations were either congruent or incongruent with the tactile consequences of the observed movement. The finger tapping movement was followed by a tone. Participants estimated the intervals between the observed action and the tone. We found that temporal binding for observed actions depends on the congruency between the perceived touch and tactile consequences of observed actions restricted to intentional actors. PMID- 29494799 TI - Principles of Systems Biology, No. 26. AB - This month: metabolic networks (Picotti, Shoichet/Sali, Maranas), evolution (Sole, Sunyaev), chaperones shape protein production costs (Pal), the size control strategy of archaea (Schmid/Garner/Amir), and monitoring mRNA degradation (Singer). PMID- 29494800 TI - How Can Systems Biology Test Principles and Tools Using Immune Cells as a Model? AB - The field of systems immunology has grown extensively over the last few years, spurred by the generation of large datasets, new analytical tools, and modeling approaches. In this piece and its counterpart in Trends in Immunology [http://www.cell.com/trends/immunology/fulltext/S1471-4906(18)30013-9], eight authors discuss what immunologists can learn from systems biology and, conversely, how systems biologists can use immune cells as a model and outline the many directions this interdisciplinary field can expand in. PMID- 29494801 TI - Assessing Inequality in Transcriptomic Data. AB - Two studies in this issue of Cell Systems use the Gini index from economics to benchmark and quantify gene expression heterogeneity in single-cell or bulk RNA seq datasets. PMID- 29494802 TI - Merged Map of the Yeast Proteome. AB - A comprehensive reference map of protein abundances in budding yeast is generated by combining the 21 largest quantitative proteome datasets currently available for this model organism. PMID- 29494803 TI - Capturing a Long Look at Our Genetic Library. AB - Long-read sequencing, coupled to cDNA capture, provides an unrivaled view of the transcriptome of chromosome 21, revealing surprises about the splicing of long noncoding RNAs. PMID- 29494805 TI - Erratum. PMID- 29494804 TI - Patient-Specific Topographic Anatomy of the Deep Circumflex Iliac Artery Flap: Comparing Standard and Modified Computed Tomographic Angiography. AB - PURPOSE: Computed tomographic angiography (CTA) is reported to give insight into patient-specific anatomy of the flap pedicle preoperatively. We compared information available from standard CTA (s-CTA) with that gained by modifying the conventional CTA technique (modified CTA [m-CTA]). Dissected cadavers served as the control group. MATERIALS AND METHODS: We evaluated 16 s-CTA scans (32 deep circumflex iliac arteries [DCIAs]) and 12 m-CTA scans (17 DCIAs) using 3 dimensional software (Vesalius; ps-medtech, Amsterdam, The Netherlands). We dissected 17 cadavers (n = 34 DCIAs) to serve as the control group. The positions of 4 landmarks (anterior superior iliac spine, origin of DCIA, origin of ascending branch, and crossing of horizontal branch and iliac crest) were defined in a 3-dimensional coordinate system. RESULTS: We found significant differences concerning the distances from the origin of the DCIA to the femoral bifurcation (P < .05) and the anterior superior iliac spine to the crossing point of the horizontal branch with the iliac crest (P < .05) between CTA scans and cadaveric studies. The imaging quality of the m-CTA scans was shown to be more consistent than and superior to that of the s-CTA scans. The visible length of the DCIA was longer on m-CTA scans (mean, 134.32 mm) than on s-CTA scans (mean, 73.62 mm). We could evaluate the branching off of perforators and the relation of the pedicle to the surrounding bone and soft tissue in more detail on m-CTA scans. Standard CTA allowed the bilateral evaluation of the pedicle, whereas m-CTA allowed the evaluation of the injected side only. CONCLUSIONS: The quality and quantity of information available from CTA could be improved by modifying the s-CTA examination by injection as close as possible to the target vessel. Standard CTA delivered information about both sides, whereas m-CTA may need an additional injection for contralateral-side imaging. PMID- 29494806 TI - Synaptic vesicle cycle and amyloid beta: Biting the hand that feeds. AB - The synaptic vesicle cycle (SVC) holds center stage in the biology of presynaptic terminals. Through recurrent exocytosis and endocytosis, it facilitates a sequence of events enabling chemical neurotransmission between functionally related neurons. As a fundamental process that links the interior of nerve cells with their environment, the SVC is also critical for signaling and provides an entry route for a range of pathogens and toxins, enabling detrimental effects. In Alzheimer's disease, the SVC is both the prime site of amyloid beta production and toxicity. In this study, we discuss the emerging evidence for physiological and pathological effects of Abeta on various stages of the SVC, from postfusion membrane recovery to trafficking, docking, and priming of vesicles for fusion and transmitter release. Understanding of the mechanisms of Abeta interaction with the SVC within the unifying calcium hypothesis of aging and Alzheimer's disease should further elucidate the fundamental biology of the presynaptic terminal and reveal novel therapeutic targets for Alzheimer's disease and other age-related dementias. PMID- 29494807 TI - Principles for central nervous system inflammation research: A call for a consortium approach. AB - INTRODUCTION: Neuroinflammation is now considered to be of pathophysiologic significance in Alzheimer's disease and other neurodegenerative conditions. Nonetheless, there is no consensus as to what inflammatory mechanisms need to be combated (or facilitated), how therapies for them should be applied, or when they might be efficacious. METHODS: This article seeks to put forward cornerstone facts about neuroinflammation, with suggestions for future directions. RESULTS: Multiple scientific points about neuroinflammation still remain unaddressed. The main issue, however, is political. An expert body is needed that can sort through the myriad findings and provide consensus advice to agencies that fund basic and clinical research. DISCUSSION: Consortium approaches have shown immense value in other Alzheimer's disease research areas and are badly needed in neuroinflammation research. Lacking a consensus, neuroinflammation is just a very large number of isolated articles clamoring for attention. PMID- 29494808 TI - Coronary heart disease, heart failure, and the risk of dementia: A systematic review and meta-analysis. AB - INTRODUCTION: Cardiovascular risk factors are closely linked with dementia risk, but whether heart disease predisposes to dementia is uncertain. METHODS: We systematically reviewed the literature and meta-analyzed risk estimates from longitudinal studies reporting the association of coronary heart disease (CHD) or heart failure (HF) with risk of dementia. RESULTS: We identified 16 studies (1,309,483 individuals) regarding CHD, and seven studies (1,958,702 individuals) about HF. A history of CHD was associated with a 27% increased risk of dementia (pooled relative risk [RR] [95% confidence interval, CI]: 1.27 [1.07-1.50]), albeit with considerable heterogeneity across studies (I2 = 80%). HF was associated with 60% increased dementia risk (pooled RR 1.60 [1.19-2.13]) with moderate heterogeneity (I2 = 59%). Among prospective population-based cohorts, pooled estimates were similar (for CHD, RR 1.26 [1.06-1.49], nine studies; and HF, RR 1.80 [1.41-2.31], four studies) and highly consistent (I2 = 0%). CONCLUSION: CHD and HF are associated with an increased risk of dementia. PMID- 29494809 TI - Disentangling the biological pathways involved in early features of Alzheimer's disease in the Rotterdam Study. AB - INTRODUCTION: Exploring the role of Alzheimer's disease (AD) implicated pathways in the predementia phase may provide new insight for preventive and clinical trials targeting disease specific pathways. METHODS: We constructed weighted Genetic risk scores, first based on 20 genome-wide significant AD risk variants and second clustering these variants within pathways. Risk scores were investigated for their association with AD, mild cognitive impairment, and brain magnetic resonance imaging phenotypes including white matter lesions, hippocampal volume, and brain volume. RESULTS: The risk score capturing endocytosis pathway was significantly associated with mild cognitive impairment (P = 1.44 * 10-4). Immune response (P = .016) and clathrin/AP2 adaptor complex pathway (P = 3.55 * 10-3) excluding apolipoprotein E also showed modest association with white matter lesions but did not sustain Bonferroni correction (P = 9.09 * 10-4). DISCUSSION: Our study suggests that the clinical spectrum of early AD pathology is explained by different biological pathways, in particular, the endocytosis, clathrin/AP2 adaptor complex, and immune response pathways, that are independent of apolipoprotein E (APOE). PMID- 29494811 TI - Corrigendum to "Tooth damage in captive orcas (Orcinus orca)" [Arch. Oral Biol. 84 (2017) 151-160]. PMID- 29494810 TI - Developmental characteristics of secondary cartilage in the mandibular condyle and sphenoid bone in mice. AB - OBJECTIVE: Secondary cartilage develops from osteochondral progenitor cells. Hypertrophic chondrocytes in secondary cartilage increase within a very short time and then ossify rapidly. In the present study, we investigated the sequential development process of osteochondral progenitor cells, and the morphology and size of hypertrophic chondrocytes in secondary cartilage. DESIGN: ICR mice at embryonic days (E) 14.5-17.5 were used. The mandibular condyle and the medial pterygoid process of the sphenoid bone were observed as secondary cartilage, and the cranial base and the lateral pterygoid process of the sphenoid bone, which is primary cartilage, were observed as a control. Thin sections were subjected to immunostaining and alkaline phosphatase (ALP) staining. Using a confocal laser microscope, 3D stereoscopic reconstruction of hypertrophic cells was performed. To evaluate the size of hypertrophic chondrocytes objectively, the cell size was measured in each cartilage. RESULTS: Hypertrophic chondrocytes of secondary cartilage first expressed type X collagen (Col X) at E15.5. SRY-box 9 (Sox 9) and ALP were co-expressed in the fibroblastic/polymorphic tissue layer of secondary cartilage. This layer was very thick at E15.5, and then rapidly became thin. Hypertrophic cells in secondary cartilage were markedly smaller than those in primary cartilage. CONCLUSIONS: The small hypertrophic cells present in secondary cartilage may have been a characteristic acquired in order for the cartilage to smoothly promote a marked increase in hypertrophic cells and rapid calcification. PMID- 29494812 TI - PhotoVoice is a feasible method of program evaluation at a center serving adults with autism. AB - The purpose of this small-scale pilot study, was to assess the feasibility of PhotoVoice as a participatory method of program evaluation for the Hussman Center for Adults with Autism (HCAA), a community-based center in greater Baltimore, MD. PhotoVoice is a data collection method that uses photography to give informants, in this case three adults with autism spectrum disorder (ASD), the opportunity to voice their opinions, concerns, and ideas for programs they participate in. This participatory approach serves to empower individuals and communities, and increases the likelihood that the generated information will be used and recommendations will be implemented. Although some challenges to implementation have been described in the literature, PhotoVoice has also been shown to improve the quality and validity of findings. This benefit is especially relevant when targeting feedback from individuals such as those with ASD, whose voices have to date been underrepresented in the literature. In conducting a PhotoVoice pilot study, the researchers sought to determine its effectiveness as a data collection method and to identify potential roadblocks that may affect applicability to a larger study. Collected photographs and feedback allowed for rich analysis and interpretation. Researchers determined that PhotoVoice was a feasible participatory method of program evaluation that highlighted the strengths and capabilities of the community, and could enable informants to have a collaborative role in shaping a program designed to address their needs. Based on the outcomes of this pilot study, it is recommended that PhotoVoice be used in a larger population of adults with ASD. PMID- 29494813 TI - Biochemical characterization of microbial type terpene synthases in two closely related species of hornworts, Anthoceros punctatus and Anthoceros agrestis. AB - Microbial terpene synthase-like (MTPSL) genes are a type of terpene synthase genes only recently identified in plants. In contrast to typical plant terpene synthase genes, which are ubiquitous in land plants, MTPSL genes appear to occur only in nonseed plants. Our knowledge of catalytic functions of MTPSLs is very limited. Here we report biochemical characterization of the enzymes encoded by MTPSL genes from two closely related species of hornworts, Anthoceros punctatus and Anthoceros agrestis. Seven full-length MTPSL genes were identified in A. punctatus (ApMTPSL1-7) based on the analysis of its genome sequence. Using homology-based cloning, the apparent orthologs for six of the ApMTPSL genes, except ApMTPSL2, were cloned from A. agrestis. They were designated AaMTPSL1, 3 7. The coding sequences for each of the 13 Anthoceros MTPSL genes were cloned into a protein expression vector. Escherichia coli-expressed recombinant MTPSLs from hornworts were assayed for terpene synthase activities. Six ApMTPSLs and five AaMTPSLs, except for ApMTPSL5 and AaMTPSL5, showed catalytic activities with one or more isoprenyl diphosphate substrates. All functional MTPSLs exhibited sesquiterpene synthase activities. In contrast, only ApMTPSL7 and AaMTPSL7 showed monoterpene synthase activity and only ApMTPSL2, ApMTPSL6 and AaMTPSL6 showed diterpene synthase activity. Most MTPSLs from Anthoceros contain uncanonical aspartate-rich motif in the form of either 'DDxxxD' or 'DDxxx'. Homology-based structural modeling analysis of ApMTPSL1 and ApMTPSL7, which contain 'DDxxxD' and 'DDxxx' motif, respectively, showed that 'DDxxxD' and 'DDxxx' motifs are localized in the similar positions as the canonical 'DDxxD' motif in known terpene synthases. To further understand the role of individual aspartate residues in the motifs, ApMTPSL1 and ApMTPSL7 were selected as two representatives for site-directed mutagenesis studies. No activities were detected when any of the conserved aspartic acid was mutated into alanine. This study provides new information about the catalytic functions of MTPSLs and the functionality of their uncanonical aspartate-rich motifs, and builds a knowledge base for studying the biological importance of MTPSL genes and their terpene products in nonseed plants. PMID- 29494814 TI - An OMIC approach to elaborate the antibacterial mechanisms of different alkaloids. AB - Plant-derived substances have regained interest in the fight against antibiotic resistance owing to their distinct antimicrobial mechanisms and multi-target properties. With the recent advances in instrumentation and analysis techniques, OMIC approaches are extensively used for target identification and elucidation of the mechanism of phytochemicals in drug discovery. In the current study, RNA sequencing based transcriptional profiling together with global differential protein expression analysis was used to comparatively elaborate the activities and the effects of the plant alkaloids boldine, bulbocapnine, and roemerine along with the well-known antimicrobial alkaloid berberine in Bacillus subtilis cells. The transcriptomic findings were validated by qPCR. Images from scanning electron microscope were obtained to visualize the effects on the whole-cells. The results showed that among the three selected alkaloids, only roemerine possessed antibacterial activity. Unlike berberine, which is susceptible to efflux through multidrug resistance pumps, roemerine accumulated in the cells. This in turn resulted in oxidative stress and building up of reactive oxygen species, which eventually deregulated various pathways such as iron uptake. Treatment with boldine or bulbocapnine slightly affected various metabolic pathways but has not changed the growth patterns at all. PMID- 29494815 TI - Comparison of acromiohumeral distance in symptomatic and asymptomatic patient shoulders and those of healthy controls. AB - BACKGROUND: The reduction of the subacromial space has traditionally been linked to rotator cuff pathology. The contribution of this narrowing, both in the development and maintenance of rotator cuff tendinopathy, is still under debate. The objective of the present study was compare the acromiohumeral distance at 0 and 60 degrees of active shoulder abduction in scapular plane, static position, in both symptomatic and contralateral shoulders, between participants with unilateral rotator cuff related shoulder pain, and in asymptomatic participants. METHOD: This was a cross-sectional observational study. Seventy-six participants with chronic shoulder pain were assessed. Forty participants without shoulder pain were also recruited to compare the acromiohumeral distance with symptomatic participants. The acromiohumeral distance was measured at 0 and 60 degrees of active shoulder abduction in all the groups by ultrasound imaging. Mean differences between symptomatic versus contralateral shoulders, and versus healthy controls, were calculated. FINDINGS: There were no statistical significant differences (p > .05) in the acromiohumeral distance at 0 degrees of shoulder elevation between the groups. However, significant differences were found at 60 degrees between symptomatic and contralateral shoulder groups (0,51 mm; 95% CI: -0.90 to -0.12). INTERPRETATIONS: Differences in shoulder pain perception at 0 degrees are not attributable to acromiohumeral distance differences. However, treatments focused on increasing AHD at 60 degrees could be prescribed, as a significantly reduced AHD was found in symptomatic shoulders when compared with contralateral shoulders. Further research is needed to determine, not only static differences in AHD, but also dynamic differences. PMID- 29494816 TI - 4-Bromophenylhydrazinyl benzenesulfonylphenylureas as indoleamine 2,3-dioxygenase inhibitors with in vivo target inhibition and anti-tumor efficacy. AB - Indoleamine 2,3-dioxygenase is a heme-containing enzyme implicated in the down regulation of the anti-tumor immune response, and considered a promising anti cancer drug target. Several pharmaceutical companies, including Pfizer, Merck, and Bristol-Myers Squibb, are known to be in pursuit of IDO inhibitors, and Incyte recently reported good results in the phase II clinical trial of the IDO inhibitor Epacadostat. In previous work, we developed a series of IDO inhibitors based on a sulfonylhydrazide core structure, and explored how they could serve as potent IDO inhibitors with good drug profiles. Herein, we disclose the development of the 4-bromophenylhydrazinyl benzenesulfonylphenylurea 5k, a potent IDO inhibitor which demonstrated 25% tumor growth inhibition in a murine CT26 syngeneic model on day 18 with 100 mg/kg oral administration twice daily, and a 30% reduction in tumor weight. Pharmacodynamic testing of 5k found it to cause a 25% and 21% reduction in kyn/trp ratio at the plasma and tumor, respectively. In the CT26 tumor model, 5k was found to slightly increase the percentage of CD3+ T cells and lymphocyte responsiveness, indicating that 5k may have potential in modulating anti-tumor immunity. These data suggest 5k to be worthy of further investigation in the development of anti-tumor drugs. PMID- 29494817 TI - Metabotropic glutamate receptors as targets for novel anxiolytics. AB - Anxiety disorders are highly prevalent psychiatric illnesses posing an important social and economic burden. Their current pharmacotherapy shows short term efficacy, though nearly one third of patients do not achieve sustained remission. There is, therefore, a strong medical need for new therapeutic agents acting through novel mechanisms of action. Considerable work has focused on metabotropic glutamate (mGlu) receptors as potential targets for novel anxiolytics. Ligands acting at mGlu receptors showed promising results in preclinical studies, whereas their efficacy was dubious in clinical trials. Recent preclinical and clinical studies have opened new prospects for targeting mGlu receptors to treat anxiety disorders. This review provides an outlook on these progresses. PMID- 29494818 TI - Randomised phase III trial of concurrent chemoradiotherapy with extended nodal irradiation and erlotinib in patients with inoperable oesophageal squamous cell cancer. AB - BACKGROUND: This randomised phase III study was conducted to investigate the efficacy of extended nodal irradiation (ENI) and/or erlotinib in inoperable oesophageal squamous cell cancer (ESCC). PATIENTS AND METHODS: Patients with histologically confirmed locally advanced ESCC or medically inoperable disease were randomly assigned (ratio 1:1:1:1) to one of four treatment groups: group A, radiotherapy adoption of ENI with two cycles of concurrent TP chemotherapy (paclitaxel 135 mg/m2 day 1 and cisplatin 20 mg/m2 days 1-3, every 4 weeks) plus erlotinib (150 mg per day during chemoradiotherapy); group B, radiotherapy adoption of ENI with two cycles of concurrent TP; group C, radiotherapy adoption of conventional field irradiation (CFI) with two cycles of concurrent TP plus erlotinib; group D, radiotherapy adoption of CFI with two cycles of concurrent TP. RESULTS: A total of 352 patients (88 assigned to each treatment group) were enrolled. The 2-year overall survival rates of group A, B, C and D were 57.8%, 49.9%, 44.9% and 38.7%, respectively (P = 0.015). Group A significantly improved 2-year overall survival compared with group D. The ENI significantly improved overall survival in patients with inoperable ESCC (P = 0.014). The addition of erlotinib significantly decreased loco-regional recurrence (P = 0.042). Aside from rash and radiation oesophagitis, the incidence of grade 3 or greater toxicities did not differ among 4 groups. CONCLUSION: Chemoradiotherapy with ENI and erlotinib might represent a substantial improvement on the standard of care for inoperable ESCC. ENI alone should be adopted in concurrent chemoradiotherapy for ESCC patients. PMID- 29494819 TI - Healthy individuals are more maneuverable when walking slower while navigating a virtual obstacle course. AB - INTRODUCTION: Maintaining stability, especially in the mediolateral direction, is important for successful walking. Navigating in the community, however, may require people to reduce stability to make quick lateral transitions, creating a tradeoff between stability and maneuverability. Walking slower can improve stability during steady state walking, but there remains a need to better understand how walking speed influences maneuverability. This study investigated how walking at different speeds influenced how individuals modulate both stability and maneuverability in a virtual obstacle course. METHODS: Fifteen healthy adults walked on a treadmill in a virtual environment for 6 trials each at typical and slower speed. Participants made repeated transitions between virtual sets of arches displayed in any of 4 lanes. Participants were instructed to walk under the arches and hit as few arches as possible. To quantify stability, mean step width and mean lateral margin of stability (Mean MOS) were calculated and averaged for ipsilateral and contralateral steps. To quantify maneuverability, the number of arches hit when entering or exiting each arch set was calculated and averaged for each condition. RESULTS: Participants exhibited high levels of variability in their stepping patterns. Mean MOS and mean step width were significantly greater for the typical speed than slower speed for the ipsilateral steps (p < 0.001). Participants hit more arches during the typical speed than during the slow speed (p = 0.039). CONCLUSION: When walking at the slower speed, healthy individuals exhibited decreased stability of ipsilateral steps, but increased maneuverability and better transition performance. PMID- 29494820 TI - Influence of stride frequency manipulation on muscle activity during running with body weight support. AB - BACKGROUND: Running with body weight support (BWS) has been used for physical fitness enhancement. Nevertheless, gait mechanics of running with BWS is not fully understood. RESEARCH QUESTION: We investigated influence of stride frequency manipulation on muscle activity during running at various BWS conditions. METHODS: Nineteen participants (23.8 +/- 4.1 years) ran on a lower body positive pressure treadmill at their preferred speed and preferred stride frequency (PSF) for 0%BWS, 50%BWS, and 80%BWS conditions. Preferred speed and PSF were selected for each of the BWS conditions. The stride frequency conditions consisted of running at PSF, PSF+10%, and PSF-10%. Muscle activity from the rectus femoris (RF), biceps femoris (BF), tibialis anterior (TA), and gastrocnemius (GA) were measured. RESULTS: RF and BF during running at the PSF+10% were higher than when running at the PSF, regardless of BWS (P < 0.01). Additionally, RF and TA during running at the PSF-10% were higher than when running at the PSF, regardless of BWS (P < 0.05). Furthermore, RF, TA, GA, and PSF during running decreased with increasing BWS (P < 0.05), although preferred speed increased with increasing BWS (P < 0.001). SIGNIFICANCE: These observations suggest that manipulating stride frequency by 10% from the PSF during running produces greater RF, BF, and TA than when running at the PSF, regardless of BWS. Furthermore, it was suggested that a change in BWS influences RF, TA, GA, PSF, and preferred speed during running. Such information may be useful to enable the practitioner to refine the use of running with BWS in exercise programs. PMID- 29494821 TI - The walk ratio: Investigation of invariance across walking conditions and gender in community-dwelling older people. AB - BACKGROUND: The step length-cadence ratio, also called the walk ratio (WR; cm/steps/min) is a measure of cautious gait, poor balance control or impaired gait, but has not been investigated for both genders in a general population of older adults across different speeds and conditions. METHOD: The participants were community-dwelling volunteers between 70 and 81 years. They walked 6.5 m under four different conditions: At preferred speed, fast speed, during a dual task condition and on an uneven surface. Step length (cm) and cadence (steps/minute) was captured using a body-worn sensor. Both cadence and step lengths were adjusted for body height. RESULTS: 70 older adults participated (mean age 75.5 (SD 3.4), 60 percent women). The WR was 0.60 cm/steps/min (SD 0.07) during preferred speed walking, 0.58 cm/steps/min (SD 0.07) during fast walking, 0.68 cm/steps/min (SD 0.18) during dual task-walking and 0.59 cm/steps/min (0.07) during uneven surface-walking. In planned pairwise comparisons, the WR during dual task was significantly different from preferred speed walking (mean difference -0.087 cm/steps/min, 95% CI -0.140, -0.033), from fast speed walking (mean difference -0.098 cm/steps/min, 95% CI -0.154, -0.041) and uneven surface walking (mean difference 0.092 cm/steps/min, 95% CI 0.040, 0.145). There were no gender differences except during the fast walking condition, where women had a significantly lower WR than the men (0.56 cm/steps/min vs 0.61 cm/steps/min, p = 0.002). DISCUSSION: We found that the WR is invariant during different speeds, and during an uneven surface condition, but is affected during a dual task-condition, when attention must be divided between a cognitive and a motor task. PMID- 29494822 TI - Reduction of frontal plane knee load caused by lateral trunk lean depends on step width. AB - The internal knee abduction moment (KAM) in osteoarthritis is reduced by increased lateral trunk lean (TL). Mechanistically, this occurs as the Centre of Mass (COM) moves further over the stance leg. Since the size of the base of support constrains the COM, an associated increase in step width (SW) would be expected to maintain stability. This study tested the effects of TL on SW and KAM in healthy participants (n = 21) who performed normal and 6 degrees TL walks. The latter was controlled via audio-visual biofeedback. We found two distinct gait strategies in TL walk: widening the step width substantially (>50%) to permit an increase in the COM displacement (WSW, n = 13), or maintaining a baseline SW and minimally displacing the COM by moving the hip/pelvic complex in the opposite direction (NSW, n = 8). WSW doubled SW (11.3 +/- 2.4 v. 24.7 +/- 5.5 cm, p < .0001), NSW did not change SW (12.2 +/- 2.8 v. 13.7 +/- 4.7 cm, p > .05). These two distinct gait strategies resulted in unique patterns of KAM reduction across the stance phase. NSW reduced KAM impulse significantly in the initial half (0.08 +/- 0.02 v. 0.06 +/- 0.02, p = .04) but not in the later stance phase (0.07 +/- 0.02 v. 0.07 +/- 0.04, p > .05). WSW reduced KAM significantly in both initial (0.11 +/- 0.03 v. 0.08 +/- 0.04, p < .001) and later stance phase (0.09 +/- 0.02 v. 0.06 +/- 0.03, p < .001). KAM peak results followed the pattern of impulse. This study has revealed two distinct mechanisms for increasing lateral trunk lean which can be used to explain discrepancies in past research and in the future could be used to individualise gait re-training strategies. PMID- 29494823 TI - Evaluation of factors that affect hip moment impulse during gait: A systematic review. AB - BACKGROUND: Decreasing the daily cumulative hip moments in the frontal and sagittal planes may lower the risk of hip osteoarthritis. Therefore, it may be important to evaluate factors that affect hip moment impulse during gait. RESEARCH QUESTION: It is unclear what factors affect hip moment impulse during gait. This systematic review aimed to evaluate different factors that affect hip moment impulse during gait in healthy adults and patients with hip osteoarthritis. METHODS: Four databases (Scopus, ScienceDirect, PubMed, and PEDro) were searched up to August 2017 to identify studies that examined hip moment impulse during gait. Data extracted for analysis included the sample size, age, height, body mass, type of intervention, and main findings. RESULTS: After screening, 10 of the 975 studies identified were included in our analysis. Several factors, including a rocker bottom shoe, FitFlopTM sandals, ankle push off, posture, stride length, body-weight unloading, a rollator, walking poles, and a knee brace, were reviewed. The main findings were as follows: increasing ankle push-off decreased both the hip flexion and extension moment impulses; body weight unloading decreased both the hip extension and adduction moment impulses; the FitFlopTM sandal increased the sum of the hip flexion and extension moment impulses; long strides increased the hip extension moment impulse; and the use of a knee brace increased hip flexion moment impulse. Of note, none of the eligible studies included patients with hip osteoarthritis. SIGNIFICANCE: The hip moment impulses can be modified by person-specific factors (ankle push-off and long strides) and external factors (body-weight unloading and use of the FitFlopTM sandals and a knee brace). Effects on the progression of hip osteoarthritis remain to be evaluated. PMID- 29494824 TI - The association between punishment and cooperation in children with high functioning autism. AB - This study examined judgment about punishment and whether punishment promoted cooperation in the prisoner's dilemma game (PDG) in children with high functioning autism (HFA) and typically developing (TD) children. In total, 66 6- to 12-year-olds participated in this study. Children were first asked about judgments regarding rewards and punishment in stories, and then they were asked to play the PDG with a partner in conditions with and without punishment. Results showed that children with HFA believed that hitting others should deserve punishment to a greater extent than TD children did. It indicated that children with HFA understood that bad acts should be punished, suggesting that these children have already acquired the general concept of "punishment." Children displayed higher levels of cooperation in the condition with punishment than in the condition without punishment in the PDG, suggesting that punishment promoted cooperation in the PDG in both children with HFA and TD children. PMID- 29494825 TI - Gemfibrozil and carbamazepine decrease steroid production in zebrafish testes (Danio rerio). AB - Gemfibrozil (GEM) and carbamazepine (CBZ) are two environmentally relevant pharmaceuticals and chronic exposure of fish to these compounds has decreased androgen levels and fish reproduction in laboratory studies. The main focus of this study was to examine the effects of GEM and CBZ on testicular steroid production, using zebrafish as a model species. Chronic water borne exposures of adult zebrafish to 10 MUg/L of GEM and CBZ were conducted and the dosing was confirmed by chemical analysis of water as 17.5 +/- 1.78 and 11.2 +/- 1.08 MUg/L respectively. A 67 day exposure led to reduced reproductive output and lowered whole body, plasma, and testicular 11-ketotestosterone (11-KT). Testicular production of 11-KT was examined post exposure (42 days) using ex vivo cultures to determine basal and stimulated steroid production. The goal was to ascertain the step impaired in the steroidogenic pathway by each compound. Ex vivo 11-KT production in testes from males chronically exposed to GEM and CBZ was lower than that from unexposed males. Although hCG, 25-OH cholesterol, and pregnenolone stimulation increased 11-KT production in all treatment groups over basal levels, hCG stimulated 11-KT production remained significantly less in testes from exposed males compared to controls. 25-OH cholesterol and pregnenolone stimulated 11-KT production was similar between GEM and control groups but the CBZ group had lower 11-KT production than controls with both stimulants. We therefore propose that chronic GEM and CBZ exposure can reduce production of 11-KT in testes through direct effects independent of mediation through HPG axis. The biochemical processes for steroid production appear un-impacted by GEM exposure; while CBZ exposure may influence steroidogenic enzyme expression or function. PMID- 29494826 TI - Effects of single and combined exposure of pharmaceutical drugs (carbamazepine and cetirizine) and a metal (cadmium) on the biochemical responses of R. philippinarum. AB - In the aquatic environment, organisms are exposed to complex mixtures of contaminants which may alter the toxicity profile of each compound, compared to its toxicity alone. Pharmaceutical drugs (e.g. carbamazepine (CBZ) and cetirizine (CTZ)) and metals (e.g. cadmium (Cd)) are among those contaminants that co-occur in the environment. However, most studies concerning their toxicity towards aquatic species are based on single exposure experiments. Thus, the present study aimed to evaluate single and combined effects of Cd and CBZ or CTZ (single conditions: Cd, CTZ, CBZ; combined conditions: CTZ + Cd, CBZ + Cd) on biomarkers related to oxidative stress and energy metabolism in the edible clam Ruditapes philippinarum, by exposing the organisms for 28 days to environmentally relevant concentrations of these contaminants. The biomarkers studied were: i) the electron transport system activity, protein and glycogen contents (indicators of organisms' metabolic status and energy reserves); ii) lipid peroxidation and the ratio between reduced and oxidized glutathione (indicators of oxidative stress); iii) superoxide dismutase and catalase activities (enzymes indicators of antioxidant defence) and iv) activity of glutathione S-transferases (family of enzymes indicators of biotransformation capacity). Results obtained showed that the uptake of Cd and CBZ was not affected by the combined presence of the contaminants. However, for CTZ, the uptake was higher in the presence than in the absence of Cd. Concerning toxicity data, in general, the combined exposures (CTZ + Cd, CBZ + Cd) had lower biological effects than the contaminants alone. Nevertheless, our data showed that despite the low concentrations tested, they were enough to exert biological effects that differed between single and combined treatments, evidencing the need to conduct more co-exposure studies to increase the environmental relevance of the gathered data. PMID- 29494827 TI - Anal squamous cell carcinoma - State of the art management and future perspectives. AB - Anal squamous cell carcinoma (ASCC) is associated with infection with high-risk strains of human papilloma virus (HPV) in 70-90% of cases and a rise in incidence has been observed in the last decades. Definitive chemoradiotherapy (CRT) using 5 fluorouracil and mitomycin C constitutes the standard treatment for localized disease, but about 30% of patients do not respond or relapse locally. Phase I/II trials testing targeted agents, such as epidermal-growth-factor receptor (EGFR) inhibitors, have failed to improve clinical outcome and resulted in increased toxicities. Modern imaging methods and biomarkers, also in the context of HPV status, should be further explored to improve patient stratification. In the present review, we will discuss the current clinical evidence and future perspectives in the management of ASCC. HPV-positive ASCC is more immunogenic with a higher density of tumor infiltrating lymphocytes that correlate with better response to CRT and more favorable prognosis compared to HPV-negative tumors. Immunotherapies including immune checkpoint inhibitors have brought new hope and promising results were recently demonstrated in metastatic ASCC. The addition of immunotherapies to CRT for localized disease is tested in early phase trials, and these results could have a profound impact on the way we treat ASCC in near future. Further research and novel approaches are expected to enhance our understanding of tumor biology and immunology, and improve patient stratification and treatment adaptation in the context of personalized medicine. PMID- 29494829 TI - Psychometric evaluation and sex invariance of the Spanish version of the Body and Appearance Self-Conscious Emotions Scale. AB - This study examined the psychometric properties of a Spanish translation of the Body and Appearance Self-Conscious Emotions Scale (BASES; Castonguay et al., 2014) in a sample of university Spanish students. A total of 815 participants enrolled in two public universities located in Almeria and Elche, Spain, completed the BASES along with measures of social physique anxiety and positive/negative affect. Exploratory and confirmatory factor analyses showed that one item failed to load clearly on the hypothesized factor (guilt). Once it was removed, results supported the hypothesized four-factor structure. Evidence of invariance of the four-factor structure across sex was obtained. Scores on the BASES showed adequate internal consistency and acceptable convergent validity. Compared to men, women reported significantly higher body and appearance-related guilt and shame, and significant lower authentic and hubristic pride. Preliminary evidence supporting the validity and reliability of the Spanish translation of the BASES is provided. PMID- 29494828 TI - Studies of biochemical crosstalk in chromatin with semisynthetic histones. AB - Reversible post-translational modifications of histone proteins in eukaryotic chromatin are closely tied to gene function and cellular development. Specific combinations of histone modifications, or marks, are implicated in distinct DNA templated processes mediated by a range of chromatin-associated enzymes that install, erase and interpret the histone code. Mechanistic studies of the precise biochemical relationship between sets of marks and their effects on chromatin function are significantly complicated by the dynamic nature and heterogeneity of marks in cellular chromatin. Protein semisynthesis is a chemical technique that enables the piecewise assembly of uniformly and site-specifically modified histones in quantities sufficient for biophysical and biochemical analyses. Recent pioneering efforts in semisynthesis have yielded access to histones site specifically modified by entire proteins, such as ubiquitin (Ub) and the small ubiquitin-like modifier (SUMO). Herein, we highlight key studies of biochemical crosstalk involving Ub and SUMO in chromatin that were enabled by histone semisynthesis. PMID- 29494830 TI - Reinforcing effect of graphene oxide reinforcement on the properties of poly (vinyl alcohol) and carboxymethyl tamarind gum based phase-separated film. AB - The current study deals with the preparation and the characterization of the PVA CMT-GO films. The PVA-CMT film was translucent in nature and smooth to touch. The addition of GO resulted in the formation of agglomerated structures. XRD studies suggested that the incorporation of GO increased the average crystallite size. The mechanical properties of the films as determined by stress relaxation studies suggested that all the films were viscoelastic in nature. The drug release study showed a decrease in the amount of the drug release with the increase in the GO content. The PVA-CMT-GO films (without drug) showed certain degree of antimicrobial activity owing to the inherent antimicrobial property of GO. The drug loaded films also showed good antimicrobial property. It was found that the prepared films altered the cell proliferation of the human skin keratinocytes in a composition-dependent manner. PMID- 29494831 TI - Increased TERRA levels and RNase H sensitivity are conserved hallmarks of post senescent survivors in budding yeast. AB - Cancer cells activate telomere maintenance mechanisms (TMMs) to bypass replicative senescence and achieve immortality by either upregulating telomerase or promoting homology-directed repair (HDR) at chromosome ends to maintain telomere length, the latter being referred to as ALT (Alternative Lengthening of Telomeres). In yeast telomerase mutants, the HDR-based repair of telomeres leads to the generation of 'survivors' that escape senescence and divide indefinitely. So far, yeast has proven to provide an accurate model to study the generation and maintenance of telomeres via HDR. Recently, it has been established that up regulation of the lncRNA, TERRA (telomeric repeat-containing RNA), is a novel hallmark of ALT cells. Moreover, RNA-DNA hybrids are thought to trigger HDR at telomeres in ALT cells to maintain telomere length and function. Here we show that, also in established yeast type II survivors, TERRA levels are increased in an analogous manner to human ALT cells. The elevated TERRA levels are independent of yeast-specific subtelomeric structures, i.e. the presence or absence of Y' repetitive elements. Furthermore, we show that RNase H1 overexpression, which degrades the RNA moiety in RNA-DNA hybrids, impairs the growth of yeast survivors. We suggest that even in terms of TERRA regulation, yeast survivors serve as an accurate model that recapitulates many key features of human ALT cells. PMID- 29494832 TI - Complexity-aware simple modeling. AB - Mathematical models continue to be essential for deepening our understanding of biology. On one extreme, simple or small-scale models help delineate general biological principles. However, the parsimony of detail in these models as well as their assumption of modularity and insulation make them inaccurate for describing quantitative features. On the other extreme, large-scale and detailed models can quantitatively recapitulate a phenotype of interest, but have to rely on many unknown parameters, making them often difficult to parse mechanistically and to use for extracting general principles. We discuss some examples of a new approach-complexity-aware simple modeling-that can bridge the gap between the small-scale and large-scale approaches. PMID- 29494833 TI - Normal width of the inter-recti distance in pregnant and postpartum primiparous women. AB - STUDY DESIGN: Longitudinal descriptive exploratory study. OBJECTIVES: Evaluate the normal width of the linea alba in first-time pregnant women during pregnancy and postpartum. BACKGROUND: There are normative values on the width of the linea alba for nulliparous women, but limited knowledge about the normal width of the inter-rectus distance (IRD) in pregnant and postpartum women. METHODS: Ultrasound images were recorded in 84 primiparous women, at 3 locations on the linea alba (2 cm below the umbilicus, and 2 and 5 cm above the umbilicus) and at 4 time points (gestational weeks 35-41 and 6th to 8th, 12th to 14th, and 24th to 26th weeks postpartum). The 20th and 80th percentiles were used to define the normal width of the linea alba. RESULTS: During pregnancy, the 20th and the 80th percentile corresponded to 49-79 mm below the umbilicus, 54-86 mm at 2 cm above the umbilicus and 44-79 mm at 5 cm above the umbilicus. At 6 months postpartum, the 20th and the 80th percentile corresponded to 9-21 mm at 2 cm below the umbilicus, from 17 to 28 mm at 2 cm above the umbilicus and from 12 to 24 mm at 5 cm above the umbilicus. CONCLUSION: Different normative values for the width of the linea alba were found at different locations of the anterior abdominal wall. In primiparous women, the IRD may be considered "normal" up to values wider than in nulliparous. PMID- 29494834 TI - Proximity effects in chromosome aberration induction: Dependence on radiation quality, cell type and dose. AB - It is widely accepted that, in chromosome-aberration induction, the (mis )rejoining probability of two chromosome fragments depends on their initial distance, r. However, several aspects of these "proximity effects" need to be clarified, also considering that they can vary with radiation quality, cell type and dose. A previous work performed by the BIANCA (BIophysical ANalysis of Cell death and chromosome Aberrations) biophysical model has suggested that, in human lymphocytes and fibroblasts exposed to low-LET radiation, an exponential function of the form exp(-r/r0), which is consistent with free-end (confined) diffusion, describes proximity effects better than a Gaussian function. Herein, the investigation was extended to intermediate- and high-LET. Since the r0 values (0.8 MUm for lymphocytes and 0.7 MUm for fibroblasts) were taken from the low-LET study, the results were obtained by adjusting only one model parameter, i.e. the yield of "Cluster Lesions" (CLs), where a CL was defined as a critical DNA damage producing two independent chromosome fragments. In lymphocytes, the exponential model allowed reproducing both dose-response curves for different aberrations (dicentrics, centric rings and excess acentrics), and values of F-ratio (dicentrics to centric rings) and G-ratio (interstitial deletions to centric rings). In fibroblasts, a good correspondence was found with the dose-response curves, whereas the G-ratio (and, to a lesser extent, the F-ratio) was underestimated. With increasing LET, F decreased and G increased in both cell types, supporting their role as "fingerprints" of high-LET exposure. A dose dependence was also found at high LET, where F increased with dose and G decreased, possibly due to inter-track effects. We therefore conclude that, independent of radiation quality, in lymphocytes an exponential function can describe proximity effects at both inter- and intra-chromosomal level; on the contrary, in fibroblasts further studies (experimental and theoretical) are needed to explain the strong bias for intra-arm relative to inter-arm exchanges. PMID- 29494835 TI - Residue determination of triclopyr and aminopyralid in pastures and soil by gas chromatography-electron capture detector: Dissipation pattern under open field conditions. AB - In this study, a new method for the simultaneous quantitative determination of triclopyr and aminopyralid in forage grass, hay, and soil was developed and validated using gas chromatography coupled with electron capture detector (GC ECD). In this method, a simple and maneuverable esterification reaction was applied to convert the two acidic herbicides into their ester form with methanol. The target compounds were extracted with 1% hydrochloric acid-acetonitrile, esterified, purified by florisil solid-phase extraction cartridge, and detected in a single run by the GC-ECD. The average recoveries using this method, at different fortified levels, ranged from 80% to 104% with intra-day and inter-day RSDs in the range of 1.2-10.8% and 3.3-10.3% for both the herbicides, respectively. The LODs were below 0.02 mg/kg while the LOQs were below 0.05 mg/kg, both of which were much lower than the maximum residue limits (MRLs) of 25 700 mg/kg in pastures, as established by the USA (the code of federal regulations). The open field dissipation and residual analysis in pastures and soil were conducted with the commercial formulation at two locations. With time, both triclopyr and aminopyralid dissipated via first-order kinetics. In forage grass, both compounds degraded rapidly over the first 14- or 21-d period and at a slow rate over the remainder of experimental days. In soil, they degraded at a relatively slow rate, and dissipated steadily to below or close to the LOQ by 60 d post application. The half-lives of triclopyr were 1.4-1.8 d and 6.2-9.0 d and aminopyralid were 1.7-2.1 d and 8.2-10.6 d in terms of forage grass and soil, respectively. The terminal residue results indicated that on 7 d after the treatment, the residues of aminopyralid and triclopyr in forage grass and hay were lower than the MRLs set by the USA. This work can provide guidance on the reasonable use of these herbicides and also provide an analytical method for the determination of triclopyr and aminopyralid in pasture and soil. PMID- 29494836 TI - The combined use of chemical and biochemical markers in Rutilus rutilus to assess the effect of dredging in the lower course of the Ebro River. AB - The lower course of the Ebro River is polluted with high concentrations of organochlorine compounds dumped by a chloro-alkali plant during the last century. A remediation plan, including building of a protective wall, removal and disposal of polluted sediments started in 2012. With the aim of assessing the effects of dredging of contaminated sediments and potential alterations of water quality, areas located upstream (RR) and downstream (BE, A) the chemical plant (FL) were monitored prior (October 2012) and during dredging (June 2013) using roach (Rutilus rutilus) as sentinel organisms. Concentrations of organochlorine compounds (OCs) in fish muscle and biliary levels of polycyclic aromatic hydrocarbons (PAHs), galaxolide (HHCB) and alkyphenols (APEs) were determined together with selected enzymatic activities (7-ethoxyresorufin-O-deethylase (EROD), 7-benzyloxy-4-trifluoromethyl-coumarin O-debenzyloxylase (BFCOD) and UDP glucuronyltransferase (UGT)) in the liver. The obtained results proved the effectiveness of the wall retaining suspended particles and avoiding further contamination of downstream sites as fish sampled at downstream sites showed up to 9-fold higher concentrations of OCs in muscle during wall construction than during dredging. EROD and UGT activities were induced in fish from downstream sites; however, no clear response to the observed pollution gradient was detected. PMID- 29494837 TI - Effect of consecutive re-synchronization protocols on pregnancy rate in buffalo (Bubalus bubalis) heifers out of the breeding season. AB - The combined effect of six consecutive timed artificial inseminations (TAIs) on pregnancy rates, following two different synchronization protocols on buffalo heifers, over a period of seven months typically characterized by low breeding performances, were investigated in this study. A total of 2189 TAIs were performed on 1463 buffalo heifers within a large buffalo farm in the south of Italy. Individual animals were allowed to undergo synchronization protocol (either a slightly modified Ovsynch or Progesterone treatment) and TAI until establishment of pregnancy or else for not more than six consecutive times. Semen of seven proven bulls was used throughout the study, which was carried out from March to September of the same year. Therefore, other than the effect given by consecutive TAIs over time, a monthly and a seasonal effect could also be tested, once the entire period was split into a Low Breeding Season (LBS) from March to June, and a Transition to Breeding Season (TBS) from July to September. From the data recorded in this study and the statistical analysis performed, it can be stated that the two protocols for the synchronization of ovulation were similar in efficiency in determining pregnancies with an overall fertility rate of 89.4% when the comparison was run both on a monthly basis or when months were grouped into two different seasons. In addition, an average of 1.83 AI/pregnancy was reported, slightly higher for the Ovsynch when compared to the Progesterone protocol: 1.91 vs 1.70, respectively. Finally, when considering the number of progressive synchronization treatments implemented over time as covariate, neither Ovsynch nor Progesterone treatment significantly affected pregnancy rates following the first of the six synchronization sessions. However, repeating the synchronization procedure, the progesterone based protocol resulted in significantly higher probability of success in terms of established pregnancies during the second and third re-synchronization sessions. PMID- 29494838 TI - Influence of size reduction treatments on sugar recovery from Norway spruce for butanol production. AB - This study investigated whether the effectiveness of pretreatment is limited by a size reduction of Norway spruce wood in biobutanol production. The spruce was milled, chipped, and mashed for hydrogen peroxide-acetic acid (HPAC) and dilute acid (DA) pretreatment. Sugar recoveries from chipped and mashed spruce after enzymatic hydrolysis were higher than from milled spruce, and the recoveries were not correlated with the spruce fiber length. HPAC pretreatment resulted in almost 100% glucose and 88% total reducing sugars recoveries from chipped spruce, which were apparently higher than DA pretreatment, demonstrating greater effectiveness of HPAC pretreatment on sugar production. The butanol and ABE yield from chipped spruce were 126.5 and 201.2 g/kg pretreated spruce, respectively. The yields decreased with decreasing particle size due to biomass loss in the pretreatment. The results suggested that Norway spruce chipped to a 20 mm length is applicable to the production of platform sugars for butanol fermentation. PMID- 29494839 TI - Quantification and characterisation of fatty acid methyl esters in microalgae: Comparison of pretreatment and purification methods. AB - A systematic qualitative and quantitative analysis of fatty acid methyl esters (FAMEs) is crucial for microalgae species selection for biodiesel production. The aim of this study is to identify the best method to assess microalgae FAMEs composition and content. A single-step method, was tested with and without purification steps-that is, separation of lipid classes by thin-layer chromatography (TLC) or solid-phase extraction (SPE). The efficiency of a direct transesterification method was also evaluated. Additionally, the yield of the FAMEs and the profiles of the microalgae samples with different pretreatments (boiled in isopropanol, freezing, oven-dried and freeze-dried) were compared. The application of a purification step after lipid extraction proved to be essential for an accurate FAMEs characterisation. The purification methods, which included TLC and SPE, provided superior results compared to not purifying the samples. Freeze-dried microalgae produced the lowest FAMEs yield. However, FAMEs profiles were generally equivalent among the pretreatments. PMID- 29494840 TI - Understanding the mechanisms of lipid extraction from microalga Chlamydomonas reinhardtii after electrical field solicitations and mechanical stress within a microfluidic device. AB - One way envisioned to overcome part of the issues biodiesel production encounters today is to develop a simple, economically viable and eco-friendly process for the extraction of lipids from microalgae. This study investigates the lipid extraction efficiency from the microalga Chlamydomonas reinhardtii as well as the underlying mechanisms. We propose a new methodology combining a pulsed electric field (PEF) application and mechanical stresses as a pretreatment to improve lipid extraction with solvents. Cells enriched in lipids are therefore submitted to electric field pulses creating pores on the cell membrane and then subjected to a mechanical stress by applying cyclic pressures on the cell wall (using a microfluidic device). Results showed an increase in lipid extraction when cells were pretreated by the combination of both methods. Microscopic observations showed that both pretreatments affect the cell structure. Finally, the dependency of solvent lipid extraction efficiency with the cell wall structure is discussed. PMID- 29494841 TI - Design, synthesis and ability of non-gold complexed substituted purine derivatives to inhibit LPS-induced inflammatory response. AB - In order to study the anti-inflammatory activity of novel 6-substituted and 6,9 disubstituted purine derivatives, 20 compounds, L1-10 and W1-10, derived from purine and lacking a gold complex were designed, synthesized and their anti inflammatory activity was screened. LPS-induced TNF-alpha, IL-1beta, IL-6, PGE2, NO, COX-2 and iNOS mRNA were evaluated, and western blot and NF-kappaB p65 translocation assay were performed in RAW 264.7 macrophages. Furthermore, carrageenan-induced hind paw edema experiments were performed in mice. Compound L1, L4, W2, and W4 markedly exerted a dose-dependent inhibition of TNF-alpha, IL 1beta, IL-6 and PGE2 release induced by LPS in RAW 264.7 macrophages. Moreover, these compounds strongly inhibited LPS-induced NO, COX-2 and iNOS mRNA in the same cells. Anti-inflammatory activity tests in vivo showed that L1 and L4 were more effective than Au(L3)(PPh3), a known anti-inflammatory agent, at 2-5 h, and W4 was the most effective at 3-5 h after dosing. Thus, W2, W4, and L1, L4, could effectively inhibit LPS-induced inflammatory response in vitro and in vivo suggesting a promising role as anti-inflammatory agents. PMID- 29494842 TI - Identification of cisapride as new inhibitor of putrescine uptake in Trypanosoma cruzi by combined ligand- and structure-based virtual screening. AB - Nowadays, the pharmacological therapy for the treatment of Chagas disease is based on two old drugs, benznidazole and nifurtimox, which have restricted efficacy against the chronic phase of the illness. To overcome the lack of efficacy of the traditional drugs (and their considerable toxicity), new molecular targets have been studied as starting points to the discovery of new antichagasic compounds. Among them, polyamine transporter TcPAT12 (also known as TcPOT1.1) represents an interesting macromolecule, since polyamines are essential for Trypanosoma cruzi, the parasite that causes the illness, but it cannot synthesize them de novo. In this investigation we report the results of a combined ligand- and structure-based virtual screening for the discovery of new inhibitors of TcPAT12. Initially we filtered out ZINC and Drugbank databases with similarity and QSAR models and then we submitted the candidates to a validated docking based screening. Four structures were selected and tested in T. cruzi epimastigotes proliferation and two of them, Cisapride and [2 (cyclopentyloxy)phenyl]methanamine showed inhibitory effects. Additionally, we performed transport assays which demonstrated that Cisapride interferes with putrescine uptake in a specific mode. PMID- 29494843 TI - Design, synthesis, and structure-activity-relationship of a novel series of CXCR4 antagonists. AB - The important roles of the CXCL12/CXCR4 axis in numerous pathogenic pathways involving HIV infection and cancer metastasis make the CXCR4 receptor an attractive target for the development of therapeutic agents. Through scaffold hybridization of a few known CXCR4 antagonists, a series of novel aminopyrimidine derivatives was developed. Compound 3 from this new scaffold demonstrates excellent binding affinity with CXCR4 receptor (IC50 = 54 nM) and inhibits CXCL12 induced cytosolic calcium increase (IC50 = 2.3 nM). Furthermore, compound 3 possesses good physicochemical properties (MW 353, clogP 2.0, PSA 48, pKa 6.7) and exhibits minimal hERG and CYP isozyme (e.g. 3A4, 2D6) inhibition. Collectively, these results strongly support further optimization of this novel scaffold to develop better CXCR4 antagonists. PMID- 29494844 TI - Discovery and evolution of aloperine derivatives as novel anti-filovirus agents through targeting entry stage. AB - Preventing filoviruses in the entry stage is an attractive antiviral strategy. Taking aloperine, a Chinese natural herb with an endocyclic skeleton, as the lead, 23 new aloperine derivatives were synthesized and evaluated for their anti filovirus activities including ebola virus (EBOV) and marburg virus (MARV) using pseudotyped virus model. Structure-activity relationship (SAR) analysis indicated that the introduction of a 12N-dichlorobenzyl group was beneficial for the potency. Compound 2e exhibited the most potent anti-EBOV and anti-MARV effects both in vitro and in vivo. It also displayed a good pharmacokinetic and safety profile in vivo, indicating an ideal druglike feature. The primary mechanism study showed that 2e could block a late stage of viral entry, mainly through inhibiting cysteine cathepsin B activity of host components. We consider compound 2e to be a promising broad-spectrum anti-filovirus agent with the advantages of a unique chemical scaffold and a specific biological mechanism. PMID- 29494845 TI - Microfluidics and single-cell microscopy to study stochastic processes in bacteria. AB - Bacteria have molecules present in low and fluctuating numbers that randomize cell behaviors. Understanding these stochastic processes and their impact on cells has, until recently, been limited by the lack of single-cell measurement methods. Here, we review recent developments in microfluidics that enable following individual cells over long periods of time under precisely controlled conditions, and counting individual fluorescent molecules in many cells. We showcase discoveries that were made possible using these devices in various aspects of microbiology, such as antibiotic tolerance/persistence, cell-size control, cell-fate determination, DNA damage response, and synthetic biology. PMID- 29494846 TI - Health care experiences of pregnant, birthing and postnatal women of color at risk for preterm birth. AB - BACKGROUND: Chronic stress is a known risk factor for preterm birth, yet little is known about how healthcare experiences add to or mitigate perceived stress. In this study, we described the pregnancy-related healthcare experiences of 54 women of color from Fresno, Oakland, and San Francisco, California, with social and/or medical risk factors for preterm birth. METHODS: This study was a secondary analysis of focus group data generated as part of a larger project focused on patient and community involvement in preterm birth research. English and Spanish speaking women, age 18 or greater with social and/or medical risk factors for preterm birth participated in two focus groups, six weeks apart. Data from the first focus groups are included in this analysis. RESULTS: Five themes emerged from thematic analysis of the transcripts. Participants described disrespect during healthcare encounters, including experiences of racism and discrimination; stressful interactions with all levels of staff; unmet information needs; and inconsistent social support. Despite these adverse experiences, women felt confidence in parenting and newborn care. Participant recommendations for healthcare systems improvement included: greater attention to birth plans, better communication among multiple healthcare providers, more careful listening to patients during clinical encounters, increased support for social programs such as California's Black Infant Health, and less reliance on past carceral history and/or child protective services involvement. DISCUSSION: The women in this study perceived their prenatal healthcare as a largely disrespectful and stressful experience. Our findings add to the growing literature that women of color experience discrimination, racism and disrespect in healthcare encounters and that they believe this affects their health and that of their infants. PMID- 29494847 TI - Production and characterization of CSSI003 (2961) human induced pluripotent stem cells (iPSCs) carrying a novel puntiform mutation in RAI1 gene, Causative of Smith-Magenis syndrome. AB - Smith-Magenis syndrome (SMS) is a complex genetic disorder characterized by developmental delay, behavioural problems and circadian rhythm dysregulation. About 90% of SMS cases are due to a 17p11.2 deletion containing retinoic acid induced1 (RAI1) gene, 10% are due to heterozygous mutations affecting RAI1 coding region. Little is known about RAI1 role. PMID- 29494848 TI - Bacterially activated B-cells drive T cell differentiation towards Tr1 through PD 1/PD-L1 expression. AB - Regulatory B cells (Bregs) play a crucial role in immunological tolerance primarily through the production of IL-10 in many diseases including autoimmune disorders, allergy, infectious diseases, and cancer. To date, various Breg subsets with overlapping phenotypes have been identified. However, the roles of Bregs in Helicobacter infection are largely unknown. In the present study, we investigate the phenotype and function of Helicobacter -stimulated B cells. Our results demonstrate that Helicobacter felis -stimulated IL-10- producing B cells (Hfstim- IL-10+ B) are composed of B10 and Transitional 2 Marginal Zone Precursor (T2-MZP) cells with expression of CD9, Tim-1, and programmed death 1 (PD-1). On the other hand, Helicobacter felis -stimulated IL-10- nonproducing B (Hfstim- IL 10- B) cells are mainly marginal zone (MZ) B cells that express PD-L1 and secrete TGF-beta, IL-6, and TNF-alpha, and IgM and IgG2b. Furthermore, we show that both Hfstim- IL-10+ B cells and Hfstim- IL-10- B cells induce CD49b+LAG-3+ Tr1 cells. Here, we describe a novel mechanism for PD-1/PD-L1- driven B cell-dependent Tr1 cell differentiation. Finally, we explore the capability of Hfstim- IL-10- B cells to induce Th17 cell differentiation, which we find to be dependent on TGF beta. Taken together, the current study demonstrates that Hfstim- B cells induce Tr1 cells through the PD-1/PD-L1 axis and Th17 cells by secreting TGF-beta. PMID- 29494849 TI - A web-based application for automated quantification of chemical gradients induced in microfluidic devices. AB - Advances in microfabrication have allowed the development and popularization of microfluidic devices, which are powerful tools to recreate three-dimensional (3 D) biologically relevant in vitro models. These microenvironments are usually generated by using hydrogels and induced chemical gradients. Going further, computational models enable, after validation, the simulation of such conditions without the necessity of real experiments, thus saving costs and time. In this work we present a web-based application that allows, based on a previous numerical model, the assessment of different chemical gradients induced within a 3-D extracellular matrix. This application enables the estimation of the spatio temporal chemical distribution inside microfluidic devices, by defining a first set of parameters characterizing the chip geometry, and a second set characterizing the diffusion properties of the hydrogel-based matrix. The simulated chemical concentration profiles generated within a synthetic hydrogel are calculated remotely on a server and returned to the website in less than 3 min, thus offering a quick automatic quantification to any user. To ensure the day-to-day applicability, user requirements were investigated prior to tool development, pre-selecting some of the most common geometries. The tool is freely available online, after user registration, on http://m2be.unizar.es/insilico_cell under the software tab. Four different microfluidic device geometries were defined to study the dependence of the geometrical parameters onto the gradient formation processes. The numerical predictions demonstrate that growth factor diffusion within 3-D matrices strongly depends not only on the physics of diffusion, but also on the geometrical parameters that characterizes these complex devices. Additionally, the effect of the combination of different hydrogels inside a microfluidic device was studied. The automatization of microfluidic device geometries generation provide a powerful tool which facilitates to any user the possibility to automatically create its own microfluidic device, greatly reducing the experimental validation processes and advancing in the understanding of in vitro 3-D cell responses without the necessity of using commercial software or performing real testing experiments. PMID- 29494851 TI - Enhanced perforin expression associated with dasatinib therapy in natural killer cells. AB - We investigated the effects of dasatinib on natural killer (NK) cell-induced signaling protein and perforin expression as well as plasma cytokine levels by analyzing blood samples from patients with well-controlled chronic myeloid leukemia receiving tyrosine kinase inhibitor (TKI) therapy. Perforin expression and phosphorylation of signal transducer and activator of transcription (STAT) 1, STAT3, Janus kinase (JAK) 1, and JAK2 in NK cells were evaluated by flow cytometry, and the levels of plasma cytokines, including interferon (IFN)-gamma and interleukin (IL)-2, were determined by enzyme-linked immunosorbent assays in 40 patients (dasatinib, n = 23; imatinib, n = 11; and nilotinib, n = 6). Perforin levels in NK cells were higher in dasatinib-treated patients before TKI treatment; phospho (p)-STAT1 levels were closely correlated with pJAK1 and perforin levels, and pSTAT3 levels were correlated with pJAK2 and perforin levels. The correlation between pJAK1 and pSTAT1 was apparent in dasatinib treated patients but not in other TKI-treated patients, and the correlation between pJAK2 and pSTAT3 was apparent in patients treated with other TKIs. Constitutive expression of IFN-gamma was higher in patients treated with dasatinib or with other TKIs than in those who were in treatment-free remission (TFR). In contrast, constitutive expression of IL-2 was lower in patients treated with other TKIs than in those treated with dasatinib or in those who were in TFR. These results provided insights into the effects of dasatinib on JAK/STAT signaling in NK cells in vivo and the mechanisms underlying NK cell activation induced by dasatinib therapy. PMID- 29494850 TI - Inferential language use by school-aged boys with fragile X syndrome: Effects of a parent-implemented spoken language intervention. AB - This study examined the impact of a distance-delivered parent-implemented narrative language intervention on the use of inferential language during shared storytelling by school-aged boys with fragile X syndrome, an inherited neurodevelopmental disorder. Nineteen school-aged boys with FXS and their biological mothers participated. Dyads were randomly assigned to an intervention or a treatment-as-usual comparison group. Transcripts from all pre- and post intervention sessions were coded for child use of prompted and spontaneous inferential language coded into various categories. Children in the intervention group used more utterances that contained inferential language than the comparison group at post-intervention. Furthermore, children in the intervention group used more prompted inferential language than the comparison group at post intervention, but there were no differences between the groups in their spontaneous use of inferential language. Additionally, children in the intervention group demonstrated increases from pre- to post-intervention in their use of most categories of inferential language. This study provides initial support for the utility of a parent-implemented language intervention for increasing the use of inferential language by school aged boys with FXS, but also suggests the need for additional treatment to encourage spontaneous use. PMID- 29494852 TI - Practices during the active second stage of labor: A survey of French midwives. AB - OBJECTIVE: the principal objective of our study was to describe the practices reported by French midwives during the active second stage of labor (expulsion phase). DESIGN: this cross-sectional Internet survey questioned French midwives who attended at least one childbirth in 2013. SETTING: this open survey was posted on a website from June 15 through December 1, 2014. PARTICIPANTS: 1496 midwives from 377 maternity units participated in the study. MEASUREMENTS AND FINDINGS: the midwives most often reported suggesting horizontal positions during the active second stage (supine with footholds, lithotomy, lithotomy with knees turned in, or lateral positions). Non-horizontal positions were more often proposed by midwives in level I units (p<0.0001). Almost half the midwives responding (46.4%), especially those working in level III units (51.1%, p = 0.006), advised Valsalva pushing. The mean maximum pushing time was 35.3 minutes+/-12.8 minutes. Nearly all the midwives favored the 'hands on' technique at childbirth (91.4%), and 24% reported using warm compresses on the perineum at childbirth. KEY CONCLUSION: most midwives advised horizontal positions for childbirth. The practices of French midwives differed as a function of where they worked. The midwives, especially those in level III facilities, reported that they cannot always ensure 'physiological childbirth'. IMPLICATIONS FOR PRACTICE: the practices of French midwives must become more evidence-based. The development of professional guidelines for midwives in France appears essential. This study also helps to prioritise national training for midwives. PMID- 29494853 TI - Attachment orientations and emotion regulation. AB - According to attachment theory, individual differences in the availability and responsiveness of close relationship partners, beginning in infancy, and the resulting formation of fairly stable attachment orientations are crucial for understanding the ways people experience and regulate emotions. In this article, we review what has been learned during the last decade about attachment-related individual differences in emotion regulation. We begin with a brief account of the hypothesized links between different forms of attachment insecurity (anxiety, avoidance) and strategies people use in regulating distress and coping with threatening events. We then review findings from correlational and experimental studies showing that individual differences in attachment orientation are reflected in cognitive, behavioral, and neural patterns of emotion regulation. PMID- 29494855 TI - Effect of fluoxetine on three-year recurrence in acute ischemic stroke: A randomized controlled clinical study. AB - OBJECTIVE: To evaluate the effect of fluoxetine on three-year recurrence rate of acute ischemic stroke. PATIENTS AND METHODS: 404 enrolled patients with acute ischemic stroke were randomly divided into control and treatment groups, and underwent conventional secondary preventive therapy for ischemic stroke. In addition, the treatment group was administered fluoxetine (20 mg daily for 90 days). A three-year follow-up was performed, and indicators related to risk factors of stroke were assessed at day 90 of follow-up. The effect of fluoxetine on the three-year recurrence rate of acute ischemic stroke was evaluated by survival analysis, as well as multifactor Cox regression analysis. RESULTS: The values of systolic blood pressure, blood total cholesterol, blood low density lipoprotein and glycosylated hemoglobin at day 90 of follow-up were significantly lower in treatment group than control group (P = 0.002, P = 0.002, P = 0.018, P = 0.011, respectively). The occurrence rates of epilepsy, gastrointestinal bleeding, syncope, allergic reactions, hemorrhagic infarction, and death were not significantly different between the two groups during the follow-up (P > 0.05). The recurrence-free survival rate of ischemic stroke was significantly lower in the treatment group than control group as assessed by the Kaplan-Meier test (85.1% Vs 75.7%, P = 0.016), as well as the recurrence-free survival rate after day 90 in the three-year follow-up (87.0% Vs 79.3%, P = 0.043). Multifactor Cox regression analysis demonstrated treatment with fluoxetine was an independent factor reducing three-year recurrence in acute ischemic stroke (HR = 0.594, 95% CI: 0.376-0.938). CONCLUSION: Treatment with fluoxetine for 90 days after acute ischemic stroke significantly reduces the three-year recurrence rate of ischemic stroke. PMID- 29494854 TI - Text messaging to support a perinatal collaborative care model for depression: A multi-methods inquiry. AB - OBJECTIVE: Mental health care integrated into obstetric settings improves access to perinatal depression treatments. Digital interactions such as text messaging between patient and provider can further improve access. We describe the use of text messaging within a perinatal Collaborative Care (CC) program, and explore the association of text messaging content with perinatal depression outcomes. METHODS: We analyzed data from an open treatment trial of perinatal CC in a rural obstetric clinic. Twenty five women with Patient Health Questionnaire-9 score of >=10 enrolled in CC, and used text messaging to communicate with their Care Manager(CM). We used surveys and focus groups to assessacceptability of text messaging with surveys and focus groups. We calculated the number of text messages exchanged, and analyzed content to understand usage patterns. We explored association between text messaging content and depression outcomes. RESULTS: CMs initiated 85.4% messages, and patients responded to 86.9% messages. CMs used text messaging for appointment reminders, and patients used it to obtain obstetric and parenting information. CMs had concerns about the likelihood of boundary violations. Patients appreciated the asynchronous nature of text messaging. CONCLUSION: Text messaging is feasible and acceptable within a perinatal CC program. We need further research into the effectiveness of text messaging content, and response protocols. PMID- 29494856 TI - Role of plasminogen activator inhibitor-1 in coronary pathophysiology. AB - The standard of care for obstructive atherosclerotic coronary disease is revascularization, predominantly achieved via percutaneous placement of a stent with concurrent medical therapy. Advancements in percutaneous coronary intervention (PCI) have dramatically improved outcomes. However, major complications from PCI due to target lesion failure continue to occur at rates between 5 and 10% in the first twelve months following intervention limiting its therapeutic efficacy. Plasminogen activator inhibitor-1 (PAI-1) is a protein of interest for both arterial remodeling and thrombotic risk as it regulates cell migration and vascular thrombosis. Elevated PAI-1 antigen levels have been identified as a potential biomarker for coronary artery disease and metabolic syndrome while being modulated by a number of atherosclerotic risk factors. Although linked by some studies as a marker of disease severity and prognosis, it remains to be understood whether it is also a mediator and/or therapeutic target of vascular disease. In this review, we discuss the current understanding of PAI 1 in vascular disease and its potential role in in-stent restenosis and stent thrombosis. PMID- 29494857 TI - Alternative pathway activation due to low level of complement factor H in primary antiphospholipid syndrome. AB - INTRODUCTION: Although complement activation has been proposed as a possible thrombophilic mechanism in antiphospholipid syndrome (APS), the origin of complement activation in APS remains unclear. Here, we focused on complement regulatory factors (CRF), which control the complement system to prevent damage to host tissue. We evaluated the function of two major CRF, membrane cofactor protein (MCP) and factor H (FH), in APS patients. MATERIALS AND METHODS: In this study, we analyzed preserved serum samples from 27 patients with primary APS (PAPS), 20 with APS complicated with SLE (APS + SLE), 24 with SLE (SLE), and 25 with other connective tissue diseases (Other CTD). Serum MCP and FH levels were tested by ELISA. Autoantibodies against FH were determined by both ELISA and western-blotting. RESULTS: Serum complement levels of PAPS were lower than those of other CTD (median C3: 82 vs 112 mg/dL, p < 0.01, C4: 15 vs 22 mg/dL, p < 0.05). Serum MCP levels did not significantly differ among the groups. Serum FH levels were significantly lower in PAPS patients compared with SLE or other CTD (median 204, 1275, and 1220 MUg/mL, respectively, p < 0.01). In PAPS patients, serum FH levels were positively correlated with serum C3 levels (p < 0.01, R = 0.55), but no correlation was found with serum C4 levels (p = 0.22, R = 0.33). Autoantibodies against FH were not detected in any of our patients. CONCLUSIONS: Activation of the alternative complement pathway due to low level of FH is one of the possible thrombophilic mechanisms in PAPS. PMID- 29494858 TI - Mindfulness-based interventions modulate structural network strength in patients with opioid dependence. AB - Mindfulness-based interventions (MBI) are increasingly used in the treatment of patients with mental disorders, in particular in individuals presenting with affective disorders or in patients exhibiting abnormal levels of impulsive behavior. MBI have been also offered to patients with substance use disorders, where such treatment options may yield considerable clinical effects. Neural effects associated with MBI have been increasingly acknowledged, but is unknown whether MBI exert specific effects on brain structure in patients with substance use disorders. In this study, we investigated 19 inpatients with opioid dependence receiving treatment-as-usual (TAU, n = 9) or additional MBI (n = 10). Structural magnetic resonance imaging data were acquired before and after four weeks of treatment. Source-based morphometry was used to investigate modulation of structural networks after treatment. Both treatment modalities led to significant clinical improvement. Patients receiving MBI showed a significant change in distress tolerance levels. An increase in bilateral striatal/insular and prefrontal/cingulate network strength was found in patients receiving MBI compared to individuals receiving TAU. Prefrontal/cingulate cortical network strength was associated with impulsivity levels. These findings suggest that MBI can have a recognizable role in treatment of substance use disorders and that neural effects of MBI may be captured in terms of frontostriatal structural network change. PMID- 29494859 TI - Predicting pornography use over time: Does self-reported "addiction" matter? AB - In recent years, several works have reported on perceived addiction to internet pornography, or the potential for some individuals to label their own use of pornography as compulsive or out of control. Such works have consistently found that perceived addiction is related to concerning outcomes such as psychological distress, relational distress, and other addictive behaviors. However, very little work has specifically examined whether or not perceived addiction is actually related to increased use of pornography, cross-sectionally or over time. The present work sought to address this deficit in the literature. Using two longitudinal samples (Sample 1, Baseline N = 3988; Sample 2, Baseline N = 1047), a variety of factors (e.g., male gender, lower religiousness, and lower self control) were found to predict any use of pornography. Among those that acknowledged use (Sample 1, Baseline N = 1352; Sample 2, Baseline N = 793), perceived addiction to pornography consistently predicted greater average daily use of pornography. At subsequent longitudinal follow-ups (Sample 1, Baseline N = 265; Sample 2, One Month Later, N = 410, One Year Later, N = 360), only male gender and baseline average pornography use consistently predicted future use. These findings suggest that perceived addiction to pornography is associated with concurrent use of pornography, but does not appear to predict use over time, suggesting that perceived addiction may not always be an accurate indicator of behavior or addiction. PMID- 29494860 TI - Sleep and behavioral control in earlier life predicted resilience in young adulthood: A prospective study of children of alcoholics and controls. AB - AIMS: Children of alcoholics (COAs) are at higher risk for developing an alcohol use disorder and substance-related problems than non-COAs. This study examined (i) the relationships between sleep rhythmicity in childhood (aged 3-5) and behavioral control in adolescence (aged 9-14) and (ii) whether sleep rhythmicity and behavioral control predicted resilience in COAs in emerging adulthood (aged 21-26). Resilience was defined as successful adaptation in spite of adversity. Resilience among COAs was operationalized in three different ways (i) absence of alcohol disorder diagnoses, (ii) absence of alcohol and drug related problems, (iii) a continuous latent variable measured by depressive symptoms, work satisfaction and relationship satisfaction. DESIGN: A prospective, longitudinal study of children assessed from early childhood (ages 3-5) to emerging adulthood (ages 21-26). SETTING: A community study of families at high risk for alcoholism and matched controls conducted in a 4-county area in the Midwest. PARTICIPANTS: 715 children (75% children of alcoholics, 29% female). MEASUREMENT: Data on sleep were gathered by the Dimensions of Temperament Survey (DOTS) and Child Behavior Checklist. Behavioral Control was measured by Child and Adult Q-sort. Substance use data were collected by Drinking and Drug History - Youth form. FINDINGS: Structural equation modeling analyses indicated that higher rhythmicity of sleep, lower level of tiredness and infrequent sleep difficulties predicted higher behavioral control in adolescence, which in turn predicted two resilience outcomes in young adulthood. Behavioral control significantly mediated the effect of childhood sleep rhythmicity and resilience. No group differences between COAs and controls were found. CONCLUSIONS: Good sleep and higher self-regulation act as resource factors for young adults, regardless of parent alcoholism status. PMID- 29494861 TI - Impairment of memory generalization in preclinical autosomal dominant Alzheimer's disease mutation carriers. AB - Fast, inexpensive, and noninvasive identification of Alzheimer's disease (AD) before clinical symptoms emerge would augment our ability to intervene early in the disease. Individuals with fully penetrant genetic mutations causing autosomal dominant Alzheimer's disease (ADAD) are essentially certain to develop the disease, providing a unique opportunity to examine biomarkers during the preclinical stage. Using a generalization task that has previously shown to be sensitive to medial temporal lobe pathology, we compared preclinical individuals carrying ADAD mutations to noncarrying kin to determine whether generalization (the ability to transfer previous learning to novel but familiar recombinations) is vulnerable early, before overt cognitive decline. As predicted, results revealed that preclinical ADAD mutation carriers made significantly more errors during generalization than noncarrying kin, despite no differences between groups during learning or retention. This impairment correlated with the left hippocampal volume, particularly in mutation carriers. Such identification of generalization deficits in early ADAD may provide an easily implementable and potentially linguistically and culturally neutral way to identify and track cognition in ADAD. PMID- 29494862 TI - High-resolution magnetic resonance elastography reveals differences in subcortical gray matter viscoelasticity between young and healthy older adults. AB - Volumetric structural magnetic resonance imaging (MRI) is commonly used to determine the extent of neuronal loss in aging, indicated by cerebral atrophy. The brain, however, exhibits other biophysical characteristics such as mechanical properties, which can be quantified with magnetic resonance elastography (MRE). MRE is an emerging noninvasive imaging technique for measuring viscoelastic tissue properties, proven to be sensitive metrics of neural tissue integrity, as described by shear stiffness, MU and damping ratio, xi parameters. The study objective was to evaluate global and regional MRE parameter differences between young (19-30 years, n = 12) and healthy older adults (66-73 years, n = 12) and to assess whether MRE measures provide additive value over volumetric magnetic resonance imaging measurements. We investigated the viscoelasticity of the global cerebrum and 6 regions of interest (ROIs) including the amygdala, hippocampus, caudate, pallidum, putamen, and thalamus. In older adults, we found a decrease in MU in all ROIs, except for the hippocampus, indicating widespread brain softening; an effect that remained significant after controlling for ROI volume. In contrast, the relative viscous-to-elastic behavior of the brain xi did not differ between age groups, suggesting a preservation of the organization of the tissue microstructure. These data support the use of MRE as a novel imaging biomarker for characterizing age-related differences to neural tissue not captured by volumetric imaging alone. PMID- 29494863 TI - GABA levels and measures of intracortical and interhemispheric excitability in healthy young and older adults: an MRS-TMS study. AB - Edited magnetic resonance spectroscopy (MRS) and transcranial magnetic stimulation (TMS) have often been used to study the integrity of the GABAergic neurotransmission system in healthy aging. To investigate whether the measurement outcomes obtained with these 2 techniques are associated with each other in older human adults, gamma-aminobutyric acid (GABA) levels in the left sensorimotor cortex were assessed with edited MRS in 28 older (63-74 years) and 28 young adults (19-34 years). TMS at rest was then used to measure intracortical inhibition (short-interval intracortical inhibition/long-interval intracortical inhibition), intracortical facilitation, interhemispheric inhibition from left to right primary motor cortex (M1) and recruitment curves of left and right M1. Our observations showed that short-interval intracortical inhibition and long interval intracortical inhibition in the left M1 were reduced in older adults, while GABA levels did not significantly differ between age groups. Furthermore, MRS-assessed GABA within left sensorimotor cortex was not correlated with TMS assessed cortical excitability or inhibition. These observations suggest that healthy aging gives rise to altered inhibition at the postsynaptic receptor level, which does not seem to be associated with MRS-assessed GABA+ levels. PMID- 29494865 TI - Autologous neural progenitor cell transplantation into newborn mice modeling for E200K genetic prion disease delays disease progression. AB - TgMHu2ME199K mice, a transgenic line mimicking genetic prion disease, are born healthy and gradually deteriorate to a terminal neurological condition concomitant with the accumulation of disease-related PrP. To investigate whether transplantation of neural progenitor cells (NPCs) to these mice can delay disease aggravation, we first tested the properties of mutant PrP in homogenates and enriched NPCs from TgMHu2ME199K embryos, as compared to PrP in sick TgMHu2ME199K brains. Next, we tested the clinical effect of NPCs transplantation into newborn TgMHu2ME199K mice. We show that mutant PrP does not convert into a disease related isoform while in progenitor cells. Most important, transplantation of both wild type and transgenic NPCs significantly delayed the progression of spontaneous prion disease in TgMHu2ME199K mice. While the strong clinical effect was not accompanied by a reduced accumulation of disease-related PrP, treated mouse brains presented a significant reduction in amyloid glycosaminoglycans and preservation of neurogenesis levels, indicating a strong neuroprotective effect. These results may encourage the investigation of new pathways for treatment in these terrible diseases. PMID- 29494866 TI - A brief cognitive therapy intervention for internalised stigma in acute inpatients who experience psychosis: A feasibility randomised controlled trial. AB - Internalised stigma is problematic for people who experience psychosis therefore psychological interventions are required. This study examine the feasibility and acceptability of a brief Cognitive Behavioural Therapy (CBT) intervention for internalised stigma with psychiatric inpatients experiencing psychosis. A feasibility randomised controlled trial was conducted, comparing CBT with a psychoeducational (PE) control arm. Thirty participants (aged 18-65, with psychosis, and currently admitted to a psychiatric hospital) were randomised to one of two conditions. Participants were assessed at baseline, post-intervention (two weeks) and at follow-up (one month). Both interventions incorporated two hours of sessions over a two week period. The outcomes examined were internalised stigma (primary outcome), stigma, attitudes toward mental health problems, personal recovery, depression and self-esteem. Recruitment was conducted over a seven month period from five psychiatric wards. Forty five potential participants were approached and 30 (66%) consented to take part. Fifteen participants were randomised to CBT and 15 to PE. Feasibility data demonstrated that both the research process and interventions were feasible and acceptable. Examination of outcomes demonstrated that there was no identified benefit of one intervention type over another. There were no adverse events related to study participation. A future definitive trial is required with improved methodological rigor. PMID- 29494867 TI - Exposure to interpersonal violence and risk of post-traumatic stress disorder among women with borderline personality disorder. AB - BACKGROUND: This study aims to determine the validity of the Karolinska Interpersonal Violence Scale (KIVS), as a screening tool for PTSD, among women with borderline personality disorder (BPD) and severe suicidal behavior. METHOD: 106 women with BPD and at least two suicide attempts were assessed with the KIVS for exposure to interpersonal violence as a child and as an adult. The screening ability of the KIVS for the diagnosis of PTSD was analyzed using receiver operating characteristic curve analysis. RESULTS: PTSD diagnosis was valid for 61 (58%) women with BPD. The KIVS - exposure of lifetime interpersonal violence, displayed fair accuracy of predicting diagnosis of PTSD (area under the curve 0.79, confidence interval [0.71, 0.88]) and performed well (sensitivity 0.90 and specificity 0.62), with a cut-off score of 4 (range 0-10). Poly-traumatization was not significantly related to PTSD diagnosis as compared to single traumatization, whereas sexual victimization was significantly more prevalent in women with PTSD diagnosis, as compared to other types of traumatic events. CONCLUSION: A score of 4 or more on the KIVS - exposure to interpersonal lifetime violence presents well as a screening instrument for risk of PTSD, among women with BPD. PMID- 29494868 TI - Endogenous salivary alpha-amylase does not interact with skin conductance response during fear extinction in posttraumatic stress disorder. AB - Posttraumatic Stress Disorder (PTSD) is associated with elevated noradrenergic signaling, which has an impact on emotional learning and memory. Fear extinction is thought to underlie the processes of exposure therapy, however the relationship between noradrenaline and extinction in PTSD is unclear. Participants with PTSD (n = 21), trauma-exposure without PTSD (TC; n = 36), and non-trauma-exposed controls (NTC; n = 27) completed a fear conditioning and extinction paradigm, and conditioned fear was indexed by skin conductance response (SCR). Salivary alpha-amylase (sAA) collected at baseline and immediately post-fear acquisition was used as an index of noradrenaline, and we examined whether sAA in response to fear acquisition was a moderator between fear extinction and PTSD symptoms. While there was a significant increase in sAA from baseline to post-fear acquisition, this was not modulated by group. Compared to TC and NTC, the PTSD group displayed a slower decline in SCRs during early extinction, which generalized across stimulus type, and was not moderated by sAA. These findings suggest that the relationship between fear extinction and PTSD symptoms does not change as a function of sAA levels; however previous research suggests other processes of fear learning may be associated with noradrenergic activity in PTSD. PMID- 29494869 TI - Identification of a putative man-made object from an underwater crash site using CAD model superimposition. AB - In order to identify an object in video, a comparison with an exemplar object is typically needed. In this paper, we discuss the methodology used to identify an object detected in underwater video that was recorded during an investigation into Amelia Earhart's purported crash site. A computer aided design (CAD) model of the suspected aircraft component was created based on measurements made from orthogonally rectified images of a reference aircraft, and validated against historical photographs of the subject aircraft prior to the crash. The CAD model was then superimposed on the underwater video, and specific features on the object were geometrically compared between the CAD model and the video. This geometrical comparison was used to assess the goodness of fit between the purported object and the object identified in the underwater video. PMID- 29494864 TI - The effects of aging on biosynthetic processes in the rat hypothalamic osmoregulatory neuroendocrine system. AB - Elderly people exhibit a diminished capacity to cope with osmotic challenges such as dehydration. We have undertaken a detailed molecular analysis of arginine vasopressin (AVP) biosynthetic processes in the supraoptic nucleus (SON) of the hypothalamus and secretory activity in the posterior pituitary of adult (3 months) and aged (18 months) rats, to provide a comprehensive analysis of age associated changes to the AVP system. By matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis, we identified differences in pituitary peptides, including AVP, in adult and aged rats under both basal and dehydrated states. In the SON, increased Avp gene transcription, coincided with reduced Avp promoter methylation in aged rats. Based on transcriptome data, we have previously characterized a number of novel dehydration-induced regulatory factors involved in the response of the SON to osmotic cues. We found that some of these increase in expression with age, while dehydration-induced expression of these genes in the SON was attenuated in aged rats. In summary, we show that aging alters the rat AVP system at the genome, transcriptome, and peptidome levels. These alterations however did not affect circulating levels of AVP in basal or dehydrated states. PMID- 29494870 TI - Enhancing teamwork using a creativity-focussed learning intervention for undergraduate nursing students - A pilot study. AB - A cohort of year two students (n = 181) was exposed to a transformational and experiential learning intervention in the form of team-led poster development workshops to enhance competence and interpersonal skills for working in teams. The aims of this study were to test the suitability of an amended TeamSTEPPS teamwork perceptions questionnaire (T-TPQ) for measuring the impact of the intervention on students' perceptions of team working, and to ascertain students' views about the experience. This was a two phase pilot study. Phase 1 was a repeated measures design to test the T-TPQ for evaluating the impact of the experiential intervention, and Phase 2 was a survey of students' views and opinions. Descriptive and statistical analysis of the data were performed. Our findings suggest that age and part-time employment mediate towards more positive teamwork perceptions. Teamwork perceptions increased from week 3 to week 9 of the experiential intervention, and students viewed the experience positively. This was the first time that the T-TPQ was tested for suitability for measuring the impact of an experiential learning intervention among nursing students. Despite limitations, our study indicates that the amended T-TPQ is sensitive to changes in teamwork perceptions in repeated measures design studies among nursing students. PMID- 29494871 TI - Predictive validity of the Brazilian version of the Tilburg Frailty Indicator for adverse health outcomes in older adults. AB - PURPOSE: This study aimed to determine the predictive value of the Brazilian Tilburg Frailty Indicator (TFI) for adverse health outcomes (falls, hospitalization, disability and death), in a follow-up period of twelve months. METHODS: This longitudinal study was carried out with a sample of people using primary health care services in Rio de Janeiro, Brazil. At baseline the sample consisted of 963 people aged 60 years and older. A subset of all respondents participated again one year later (n = 640, 66.6% response rate). We used the TFI, the Katz's scale for assessing ADL disability and the Lawton Scale for assessing IADL disability. Falls, hospitalization and death were also assessed using a questionnaire. RESULTS: The prevalence of frailty was 44.2% and the mean score of the TFI was 4.4 (SD = 3.0). There was a higher risk of loss in functional capacity in ADL (OR = 3.03, CI95% 1.45-6.29) and in IADL (OR = 1.51, CI95% 1.05-2.17), falls (OR = 2.08, CI95% 1.21-3.58), hospitalization (OR = 1.83, CI95% 1.10-3.06), and death (HR = 2.73, CI95% 1.04-7.19) for frail when compared to non-frail elderly, in the bivariate analyses. Controlling for the sociodemographic variables, the frailty domains together improved the prediction of hospitalization, falls and loss in functional capacity in ADL, but not loss in functional capacity in IADL. CONCLUSION: The TFI is a good predictor of adverse health outcomes among elderly users of primary care services in Brazil and appears an adequate and easy to administer tool for monitoring their health conditions. PMID- 29494872 TI - Sarcopenia is associated to an impaired autonomic heart rate modulation in community-dwelling old adults. AB - PURPOSE: The aims of this study were to compare the autonomic heart control parameters from sarcopenic and non-sarcopenic community-dwelling elders. METHODS: This is a cross-sectional study including 76 community-dwelling old adults, which was clinically stratified as sarcopenic or non-sarcopenic, according to the current recommendations. They were submitted to 5-min recordings of successive RR intervals. The analysis of the RR intervals variability was carried out in time (mean RR, RMSSD, pNN50, SDNN and triangular index) and frequency domains (LFnu, HFnu and LF/HF ratio), and with nonlinear methods (SD1, SD2, and D2). The parameters of autonomic heart rate modulation (AHRM) were adjusted for potential confounders: sex, diabetes, beta-blockers use, cardiovascular disease, body mass index and physical activity level, smoking habit. Normality of the data was tested by Kolmogorov-Smirnov test and, since most variables did not exhibit a normal distribution the Mann-Whitney test was used to compare the parameters of AHRM. The significance level was set as p <= 0.05 and all statistical procedures were performed with SPSS(r). RESULTS: Adjusted parameters of AHRM obtained from time domain and nonlinear methods were significantly different between sarcopenic and non-sarcopenic elders (p < 0.05), while parameters obtained from frequency domain analysis did not were different between groups (p > 0.05). CONCLUSION: Sarcopenic old adults exhibited lower parasympathetic-associated modulation, suggesting a poor cardioprotection associated to this condition. PMID- 29494873 TI - Effective neural network training with adaptive learning rate based on training loss. AB - A method that uses an adaptive learning rate is presented for training neural networks. Unlike most conventional updating methods in which the learning rate gradually decreases during training, the proposed method increases or decreases the learning rate adaptively so that the training loss (the sum of cross-entropy losses for all training samples) decreases as much as possible. It thus provides a wider search range for solutions and thus a lower test error rate. The experiments with some well-known datasets to train a multilayer perceptron show that the proposed method is effective for obtaining a better test accuracy under certain conditions. PMID- 29494874 TI - Robust Latent Regression with discriminative regularization by leveraging auxiliary knowledge. AB - For a domain adaptation learning problem, how to minimize the distribution mismatch between different domains is one of key challenges. In real applications, it is reasonable to obtain an optimal latent space for both domains so as to reduce the domain distribution discrepancy as much as possible. We therefore propose in this paper a Robust Latent Regression (RLR) framework with discriminative regularization by uncovering a compact and more informative latent space as well as leveraging the source domain knowledge, which learns a discriminative representation of domain data by considering the recognition task in the procedure of domain adaptation learning. On the one hand, to leverage the prior information in the source domain, RLR incorporates both the source and target classification loss functions as parts of its objective function, and simultaneously trains these two classifiers by encoding the common components of the classifier models as a low-rank regularization term, thus exploiting the discriminative information shared by different domains. On the other hand, to guarantee that the latent space is more compact and discriminative, the intrinsic geometric structure of data, and the local and global structural consistencies over labels are exploited simultaneously and incorporated into RLR. Lastly, to make our algorithm robust to the outliers and noise, we additionally introduce the l2,1-norm into the loss function. To solve the proposed problem, an effective iterative algorithm is proposed. Extensive experiments are conducted on several visual datasets and the results show that the proposed approach achieves outstanding performance for almost all learning tasks compared with several representative algorithms. PMID- 29494875 TI - Distributed support vector machine in master-slave mode. AB - It is well known that the support vector machine (SVM) is an effective learning algorithm. The alternating direction method of multipliers (ADMM) algorithm has emerged as a powerful technique for solving distributed optimisation models. This paper proposes a distributed SVM algorithm in a master-slave mode (MS-DSVM), which integrates a distributed SVM and ADMM acting in a master-slave configuration where the master node and slave nodes are connected, meaning the results can be broadcasted. The distributed SVM is regarded as a regularised optimisation problem and modelled as a series of convex optimisation sub-problems that are solved by ADMM. Additionally, the over-relaxation technique is utilised to accelerate the convergence rate of the proposed MS-DSVM. Our theoretical analysis demonstrates that the proposed MS-DSVM has linear convergence, meaning it possesses the fastest convergence rate among existing standard distributed ADMM algorithms. Numerical examples demonstrate that the convergence and accuracy of the proposed MS-DSVM are superior to those of existing methods under the ADMM framework. PMID- 29494876 TI - Facile fabrication of organic dyed polymer nanoparticles with aggregation-induced emission using an ultrasound-assisted multicomponent reaction and their biological imaging. AB - Ultrasound as a powerful technique has increasingly been used in both industry and academia in recent years. Herein, an efficient approach to the ultrafast preparation of cross-linked fluorescent copolymers (PEGMA-AEMA-TPE) with aggregation-induced emission (AIE) via an ultrasound-assisted multicomponent reaction (MCR) is described. A number of characterization techniques were carried out to certify the successful preparation of these AIE-active copolymers. Due to the introduction of a hydrophilic PEG fragment and a hydrophobic AIE-active dye, the obtained fluorescent copolymers showed amphiphilic properties and could assemble into organic dyed polymer nanoparticles (ODPNs) with great water dispersibility. The final PEGMA-AEMA-TPE ODPNs demonstrated intense fluorescence, strong photostability, a low critical micelle concentration (CMC) of 0.007 mg mL 1 and high biocompatibility. More importantly, the PEGMA-AEMA-TPE ODPNs show obvious AIE characteristics, which could elegantly overcome the quenching effect caused by the aggregation of ODPNs based on conventional organic dyes. Considered the above results, we believe that these AIE-active ODPNs should be promising candidates for biological imaging and other biomedical applications. PMID- 29494877 TI - Remarkably enhanced activity and substrate affinity of lipase covalently bonded on zwitterionic polymer-grafted silica nanoparticles. AB - Enzymes are promising biocatalysts for the production or degradation of chemical compounds, but low stabilities of free enzymes restrict their industrial applications. Therefore, development of effective immobilization methods to maintain or increase enzyme activity and stability remains a challenge. In this work, a novel support made of zwitterionic polymer-grafted silica nanoparticles (p-SNPs) was fabricated and Candida rugosa lipase (CRL) was covalently attached onto the p-SNPs. The zwitterionic polymer was a product of the reaction between poly(maleic anhydride-alt-1-octadecene) and N,N-dimethylenediamine and contained a cetane side chain. The hydrolytic activity, reaction kinetics, thermal stability, pH tolerance, storage stability and reusability of the immobilized CRL (SNPs-CRL) were investigated. It revealed that the specific activity of SNPs-CRL was two to four times higher than the free CRL in the temperature range of 25-60 degrees C. It is considered mainly due to the interfacial activation effect regulated by the cetane side chains of the zwitterionic polymer. Kinetic studies revealed remarkable improvement of the enzymatic reaction efficiency by the immobilized enzyme as demonstrated by the significant increases of the reaction rate constant and the decreases of Michaelis constant (i.e., increase of enzyme substrate affinity) determined with two different substrates (p-nitrophenyl acetate and p-nitrophenyl palmitate). Moreover, the immobilization improved the enzyme stabilities and SNPs-CRL displayed good reusability. Finally, the SNPs-CRL was proven to catalyze the hydrolysis of methyl mandelate to produce mandelic acid at an activity three times higher than the free enzyme. The results indicate that zwitterionic polymers deserved further development for enzyme immobilization. PMID- 29494878 TI - Modelling of dye adsorption from aqueous solution on polyaniline/carboxymethyl cellulose/TiO2 nanocomposites. AB - In the present study, a polyaniline/carboxymethyl cellulose/TiO2 nanocomposite (PAn/CMC/TiO2) was synthesized by a polymerization method, and was used for adsorption of Congo Red from aqueous solution. The effects of operational parameters of the adsorption process including pH, initial dye concentration, temperature, adsorbent dosage, and adsorption time on adsorption efficiency were investigated, and response surface methodology was used for their optimization. Optimal adsorption conditions were determined at pH of 2.6, initial concentration of 82mgL, temperature of 56 degrees C, adsorption time of 24 min, and adsorbent dose of 0.14 g. In addition, the system was also simulated using artificial neural network (ANN) and genetic programming (GP). It was found that the behavior of the system could be well predicted by ANN using 5, 1 and 8 neurons for input, middle and output layers, respectively. Kinetic and isothermal analyses showed that the maximum adsorption capacities were obtained at 94.28, 97.53 and 119.9 mgg by Langmuir model at temperatures of 25, 40 and 50 degrees C, respectively and that adsorption kinetics followed the pseudo-second-order model. The nano adsorbent was also found to be reusable without a significant change in adsorption capacity for at least five adsorption-desorption cycles. Finally, the mechanism of dye adsorption on the nano-adsorbent was investigated and proposed. PMID- 29494879 TI - Semi-interpenetrating network hyaluronic acid microgel delivery systems in micro flow. AB - Macroscopic hydrogels are commonly used as injectable scaffolds or fillers, however they may easily obstruct blood vessels, which poses risks and limits their clinical use. In the present study, three types of hyaluronic acid (HA) based hydrogel micro-particles with non-covalent, covalent semi-interpenetrating and conventional 3D molecular networks, have been designed, fabricated and characterized. The micro-particles are spherical, biconcave or irregular in shape and their diameter ranged between 2.5 and 3.5 um; their suspensions exhibit a tuneable viscosity, shear-thinning behaviour, dynamic stability and dispersity in microfluidic flow as a result of their specific particulate nature, providing thus a well-controlled injectable platform. Hydrogel particle suspensions also demonstrate an enhanced safety profile, in terms of the dispersity, cell safety, and hemocompatibility. In addition, Rhodamine 6G has successfully been loaded and released from the particles as a model for drug delivery. Functionalisation of hydrogel microparticles using synthetic polymers has been proven to be a cost effective way to achieve desirable rheological properties and flow dynamic stability with improved physicochemical properties and biocompatibility in vitro, showing promise as a multifunctional biomedical material for various advanced surgical devices and therapies. PMID- 29494880 TI - Improving the efficacy of the standard DNA differential extraction method for sexual assault evidence. AB - The efficacy of a DNA differential extraction procedure relies on reducing the amount of non-sperm female DNA carryover into the sperm fraction, while providing a sufficient recovery of male DNA from the sperm cell component. A standard approach to this extraction is to use a mild initial lysis step to digest the female (epithelial cell) component in the mixture, followed by a series of centrifugation and wash steps to further purify the resulting sperm-pellet fraction. This sperm fraction is then digested in the presence of a chemical reducing agent in preparation for DNA extraction. This method has been employed with relatively few changes since its introduction in the mid-1980s, despite numerous attempts to develop new or improved procedures. In this report, we demonstrate that it is possible to improve the efficacy of the standard differential extraction by applying simple modifications that can reduce the amount of female DNA carryover into the sperm fraction, with no adverse effects on the recovery of male DNA. In one modification, the addition of a second mild lysis step at the beginning of the differential extraction procedure improved the average male-to-female DNA ratio in the sperm fraction by 3- to 6-fold. In another modification, a "tube transfer" step was added to move the re-suspended sperm pellet to a new tube for the second mild lysis and subsequent wash steps. With this modification, the average male-to-female DNA ratio in the sperm fraction was improved by 4- to 90-fold, relative to results obtained for the non modified differential extraction method. These modifications may be accomplished using tools and reagents that are already present in most forensic DNA laboratories, so that implementation should be relatively low-cost and practical. PMID- 29494882 TI - Neuropeptide Y, stressful life events and personality trait conscientiousness: Preliminary associations from a Swedish longitudinal study. AB - The heritability of the Five-Factor Model (FFM) of human personality is high, but few genes have been identified to underlie FFM traits. Neuropeptide Y (NPY) is a pleiotropic gene implicated in stress resilience that contains two well-studied functional SNPs: (1) rs16147, which lies in the NPY promoter and affects expression levels, and (2) rs16139, which lies in the coding sequence of NPY's precursor peptide, pre-pro NPY, and affects precursor processing. In the present study we examined whether these two polymorphisms are associated with FFM traits, using a Swedish cohort (rs16147, N = 2113; and rs16139, N = 1971), and found a significant association with rs16139. Specifically, the minor G-allele of the SNP, which encodes proline instead of leucine and leads to higher processing of pre-pro NPY into mature NPY, was associated with higher levels of conscientiousness. Next, we looked at exposure to life adversities, both in childhood and adulthood, and found that stressful life events were significantly associated with reduced levels of conscientiousness. These data provide insights into the neurobiology of human personality. However, given the difficulty in replicating genetic and environmental associations with behaviorally complex traits, these findings should be considered preliminary and warrant replication in additional cohorts. PMID- 29494881 TI - Framingham coronary score in individuals with symptoms or diagnoses of mental disorders: A review and meta-analysis. AB - Patients with mental disorders have a higher coronary morbidity and mortality as compared to the general population. However, it remains unclear whether their coronary risk scores are higher than those of the general population. We reviewed studies and meta-analyze case-control studies about coronary risk scores in individuals with symptoms or diagnoses of mental disorders. Search was performed in Pubmed and clinical trial registration databases. Four case-control studies were identified, comprising 963 individuals with symptoms or diagnoses of mental disorders and 1681 controls. They focused on the most validated coronary risk score, the Framingham Risk Score 1998 (FRS 1998). The mean FRS 1998 was significantly higher in individuals with symptoms or diagnoses of mental disorders than in the general population 7.9( +/- 6.9) vs. 5.0( +/- 4.8). FRS 1998 differs between individuals with symptoms or diagnoses of mental disorders and controls (Mean difference:1.84 [95% CI:0.57-3.11], p = 0.005]; high heterogeneity was observed (I2= 78%; p < 0.003). The difference was driven by three FRS 1998 criteria: smoking, diabetes and HDL cholesterolemia. The mean FRS 1998 was significantly higher in men, and to a trend in women. In conclusion, individuals with symptoms or diagnoses of mental disorders have a higher coronary risk score than controls. The FRS 1998 should be used as a simple and objective way of monitoring coronary risk in order to improve prevention of coronary events in psychiatric settings. PMID- 29494883 TI - A novel flurophore-cyano-carboxylic-Ag microhybrid: Enhanced two photon absorption for two-photon photothermal therapy of HeLa cancer cells by targeting mitochondria. AB - In this study, a novel two-photon photothermal therapy (TP-PTT) agent based on an organic-metal microhybrid with surface Plasmon resonance (SPR) enhanced two photon absorption (TPA) characteristic was designed and synthesized using a fluorescent cyano-carboxylic derivative 2-cyano-3-(9-ethyl-9H-carbazol-3-yl) acrylic acid (abbreviated as CECZA) and silver nanoparticles through self assembly process induced by the interfacial coordination interactions between the O/N atom of CECZA and Ag+ion at the surface of Ag nanoparticles. The coordination interactions caused electron transfer from the Ag nanoparticles to CECZA molecules at the excited state, resulting in a decreased fluorescence quantum yield. The interfacial coordination interactions also enhanced the nonlinear optical properties, including 13 times increase in the TPA cross-section (delta). The decreased fluorescence quantum yield and increased two photon absorption caused by the SPR effect led excellent two-photon photothermal conversion, which was beneficial for the TP-PTT effect on HeLa cancer cells. PMID- 29494884 TI - Facilitated extracellular electron transfer of Geobacter sulfurreducens biofilm with in situ formed gold nanoparticles. AB - The conductivity of a biofilm is the key factor for the high current density of a bioelectrochemical system (BES). Most previous works have focused on electrode modification, but, this only benefits the microorganisms that directly contact the electrode. The low conductivity of biofilm limits the current density of the BES. In this work, gold nanoparticles (Au-NPs) were successfully fabricated in situ into a Geobacter sulfurreducens biofilm to increase the conductivity. 20 ppm NaAuCl4 (the precursor) was slowly dropped into the anode chamber at a rate of 1.3 mL/h in a continuous-flow three-electrode BES. The Au(III) was transformed to Au-NPs, which then precipitated in the biofilm via biological mineralization. The current density of the anode increased by 40%. Meanwhile, the removal percentage of the organic substrate (acetate) was enhanced 2.2 times, from 24.7% to 53.3%, after the in situ fabrication of Au-NPs. This method greatly lowered the charge transfer resistance of the anode and enhanced the anodic limiting current. Our results proved that the current density and organic removal rate of the G. sulfurreducens biofilm in the anode were effectively enhanced by in situ Au-NP fabrication. This work not only provides a simple and effective strategy for enhancing the electricity generation of BES with conductive NP fabrication, but also improves the understanding of the extracellular electron transfer (EET) of exoelectrogens. PMID- 29494885 TI - Electrochemical sensors and biosensors for the analysis of antineoplastic drugs. AB - Cancer is a leading cause of death worldwide, often being treated with antineoplastic drugs that have high potential for toxicity to humans and the environment, even at very low concentrations. Therefore, monitoring these drugs is of utmost importance. Among the techniques used to detect substances at low concentrations, electrochemical sensors and biosensors have been noted for their practicality and low cost. This review brings, for the first time, a simplified outline of the main electrochemical sensors and biosensors developed for the analysis of antineoplastic drugs. The drugs analyzed and the methodology used for electrochemical sensing are described, as are the techniques used for drug quantification and the analytical performance of each sensor, highlighting the limit of detection (LOD), as well as the linear range of quantification (LR) for each system. Finally, we present a technological prospection on the development and use of electrochemical sensors and biosensors in the quantification of antineoplastic drugs. A search of international patent databases revealed no patents currently submitted under this topic, suggesting this is an area to be further explored. We also show that the use of these systems has been gaining prominence in recent years, and that the quantification of antineoplastic drugs using electrochemical techniques could bring great financial and health benefits. PMID- 29494886 TI - Rapid molecular diagnosis of infectious viruses in microfluidics using DNA hydrogel formation. AB - There has been an urgent need to quickly screen and isolate patients with viral infections from patients with similar symptoms at point-of-care. In this study, we introduce a new microfluidic method for detection of various viruses using rolling circle amplification (RCA) of pathogens on the surface of thousands of microbeads packed in microchannels. When a targeted pathogen meets the corresponding particular template, the DNAs are rapidly amplified into a specific dumbbell shape through the RCA process, forming a DNA hydrogel and blocking the flow path formed between the beads. Due to the significant increase in reaction surface area, the detection time was shortened to less than 15 min and the detection limit of various pathogens has been reached to 0.1 pM. By injecting the stained liquid, the existence of the target pathogens in a sample fluid can be determined with the naked eye. Furthermore, by integrating multi-channel design, simultaneous phenotyping of various infective pathogens (i.e., Ebola, Middle East respiratory syndrome (MERS), and others) in biological specimens can be performed at a point-of-care. PMID- 29494887 TI - Construction of an optimized method for quality evaluation and species discrimination of Coptidis Rhizoma by ion-pair high performance liquid chromatography combined with response surface methodology. AB - Coptidis Rhizoma (CR), the dried rhizome of three perennial Coptis specices, was widely used as a famous herbal medicine in China. Although the quantification of main alkaloids in CR has been extensively conducted, the existing analytical methods suffer from some flaws that restrict the general applicability in the routine quality assessment. In this work, we constructed an optimized method for quality evaluation and species discrimination of CR by ion-pairing high performance liquid chromatography (IP-HPLC) combined with response surface methodology (RSM). By employing Box-Behnken designs (BBD), 30 sets of experimental runs were performed to build the response surface models, and Derringer's desirability was used to optimize the IP-HPLC separation conditions by simultaneously taking resolutions between two pairs of hardly - separated alkaloids and the retention time of the last eluted analyte as optimization criteria. Meanwhile, a single standard to determine multi-components (SSDMC) method based on the optimized IP-HPLC was set up and fully validated, to simultaneously determine six alkaloids including jatrorrhizine (JAT), columbamine (COL), epiberberine (EPI), coptisine (COP), palmatine (PAL) and berberine (BER), using BER as internal standard. Finally, the quantitative data from 33 batches of CR samples were comparatively analyzed, and the ratios of JAT/COL and EPI/JAT were discovered for species classification. Collectively, the established IP-HPLC method can be adopted for comprehensive quality evaluation and species discrimination of CR due to its general applicability. PMID- 29494888 TI - In vitro Phase I and Phase II metabolism of the new designer benzodiazepine cloniprazepam using liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. AB - Designer benzodiazepines have recently emerged as a class of new psychoactive substances. These substances are used in recreational settings and as alternatives to prescription benzodiazepines as self-medication for patients suffering from anxiety or other mental disorders. Due to the limited information available on the metabolic fate of these new substances, it is challenging to reliably detect their usage in bioanalytical (e.g. clinical and forensic) settings. The objective of this study was to investigate the in vitro Phase I and Phase II metabolism of the new designer benzodiazepine cloniprazepam and identify potential biomarkers for its detection in human biological fluids. Cloniprazepam was incubated with human liver microsomes and cytosolic fractions to generate both Phase I and II metabolites. The extracts were analysed using liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. Identification of the metabolites was performed using two complementary workflows, including a suspect screening based on in silico predictions and a non targeted screening. A total of nine metabolites were identified, eight Phase I metabolites and one Phase II metabolite, of which five were specific for cloniprazepam. Clonazepam was the major metabolite of cloniprazepam. Hydroxy cloniprazepam, dihydroxy-cloniprazepam, 3-keto-cloniprazepam, 7-amino cloniprazepam, hydroxy-clonazepam, 7-amino-clonazepam and 3-hydroxy-7-amino clonazepam were formed through oxidation, hydroxylation, and/or reduction of the nitro-group. Glucuronidated hydroxy-cloniprazepam was the only Phase II metabolite detected. Five metabolites were specific for cloniprazepam. This study provided a set of human in vitro biotransformation products which can assist specific detection of cloniprazepam consumption in future studies. PMID- 29494889 TI - Improving reliability of chemometric models for authentication of species origin of heparin by switching from 1D to 2D NMR experiments. AB - Nuclear magnetic resonance (NMR) spectroscopy is regarded as one of the most powerful and versatile analytical approaches to assure the quality of heparin preparations. In particular, it was recently demonstrated that by using 1H NMR coupled with chemometrics heparin and low molecular weight heparin (LMWH) samples derived from three major animal species (porcine, ovine and bovine) can be differentiated [Y.B. Monakhova et al. J. Pharm. Anal. 149 (2018) 114-119]. In this study, significant improvement of existing chemometric models was achieved by switching to 2D NMR experiments (heteronuclear multiple-quantum correlation (HMQC) and diffusion-ordered spectroscopy (DOSY)). Two representative data sets (sixty-nine heparin and twenty-two LMWH) belonged to different batches and distributed by different commercial companies were investigated. A trend for animal species differentiation was observed in the principal component analysis (PCA) score plot built based on the DOSY data. A superior model was constructed using HMQC experiments, where individual heparin (LMWH) clusters as well as their blends were clearly differentiated. The predictive power of different classification methods as well as unsupervised techniques (independent components analysis, ICA) clearly proved applicability of the model for routine heparin and LMWH analysis. The switch from 1D to 2D NMR techniques provides a wealth of additional information, which is beneficial for multivariate modeling of NMR spectroscopic data for heparin preparations. PMID- 29494890 TI - Outcome of diabetes insipidus in patients with Rathke's cleft cysts. AB - OBJECTIVES: It is well-known that Rathke's cleft cysts (RCCs) infrequently cause headache, endocrinological dysfunction, and visual disturbance, and in rare cases, cause diabetes insipidus (DI). Although surgical evacuation of the cyst content can result in high rates of symptomatic improvement, not only the treatment efficacy but also the pathophysiology of DI with RCC are undetermined. The aim of this study is to elucidate the underlying mechanisms and outcomes of DI associated with RCCs. PATIENTS AND METHODS: We retrospectively studied 109 patients with RCCs treated at Kanazawa University Hospital between 2000 and 2016. Their age, sex, symptoms, endocrinological status, DI, visual disturbance, neuroradiological findings, pathological appearances, and pre-/post-operative hormone levels and status of anti-diuretic hormone replacements were assessed. RESULTS: Among 109 cases of RCCs, five cases (4.6%, 2 males and 3 females) manifested with DI as initial presentation were included. These five cases could be divided into two types: the acute type and the chronic type, based on the onset and duration of symptoms. Three acute onset cases presented with not only strong thirst but also sudden headaches without pituitary dysfunction, whereas the two chronic onset cases presented with chronic headaches and hypopituitarism. Pathological examination in the acute type revealed inflammatory cell infiltration into only the posterior lobe of the pituitary and disruption of the cyst wall adjacent to the posterior lobe, which might suggest RCC rupture. In contrast, the chronic type showed inflammatory cell infiltration into both the anterior and posterior lobes of the pituitary and thickened fibrosis beneath the cyst wall. Postoperatively, two cases of the acute type could be controlled with a smaller amount of 1-deamino-8-D-arginine vasopressin (DDAVP) than that required preoperatively, whereas no change was observed in the cases of the chronic type. CONCLUSION: The cases of DI onset caused by RCCs could be divided into the acute type and the chronic type. In the chronic type, surgical treatment could not affect the status of DI. However, in acute type, urgent surgical intervention partially relieved DI. PMID- 29494891 TI - Maternal immune activation induced by lipopolysaccharide triggers immune response in pregnant mother and fetus, and induces behavioral impairment in adult rats. AB - Evidence suggest that prenatal immune system disturbance contributes largely to the pathophysiology of neuropsychiatric disorders. We investigated if maternal immune activation (MIA) could induce inflammatory alterations in fetal brain and pregnant rats. Adult rats subjected to MIA also were investigated to evaluate if ketamine potentiates the effects of infection. On gestational day 15, Wistar pregnant rats received lipopolysaccharide (LPS) to induce MIA. After 6, 12 and 24 h, fetus brain, placenta, and amniotic fluid were collected to evaluate early effects of LPS. MIA increased oxidative stress and expression of metalloproteinase in the amniotic fluid and fetal brain. The blood brain barrier (BBB) integrity in the hippocampus and cortex as well integrity of placental barrier (PB) in the placenta and fetus brain were dysregulated after LPS induction. We observed elevated pro- and anti-inflammatory cytokines after LPS in fetal brain. Other group of rats from postnatal day (PND) 54 after LPS received injection of ketamine at the doses of 5, 15, and 25 mg/kg. On PND 60 rats were subjected to the memories tests, spontaneous locomotor activity, and pre-pulse inhibition test (PPI). Rats that receive MIA plus ketamine had memory impairment and a deficit in the PPI. Neurotrophins were increased in the hippocampus and reduced in the prefrontal cortex in the LPS plus ketamine group. MIA induced oxidative stress and inflammatory changes that could be, at least in part, related to the dysfunction in the BBB and PB permeability of pregnant rats and offspring. Besides, this also generates behavioral deficits in the rat adulthood's that are potentiated by ketamine. PMID- 29494892 TI - Evaluating the probiotic potential and technological characteristics of yeasts implicated in cv. Kalamata natural black olive fermentation. AB - In the present study, 49 yeast strains previously isolated from cv. Kalamata table olive fermentation were assessed for their probiotic potential and technological characteristics. The probiotic assays included the in vitro survival in simulated gastric and pancreatic digestions, surface adhesion to the intestinal cell line Caco-2, hydrophobicity, autoaggregation and haemolytic activity. The technological features of the strains were also elucidated in terms of enzymatic activity and susceptibility to diverse salt levels (0-250 g/L) and pH values (3.5, 5.0, and 6.5). The obtained results indicated that during the simulated gastric and pancreatic digestions, 42 out of the 49 yeast strains presented overall survival rate higher than 50%, while 24 strains showed survival percentage higher than 70% at the end of the digestions. Furthermore, the majority of the assayed strains presented hydrophobicity percentage higher than 75%, while the autoaggregation ability ranged between 72 and 91%. None of the strains showed haemolytic activity. The majority of the strains presented high tolerance to salt with some strains exhibiting tolerance even at salt concentrations higher than 200 g/L. Concerning the enzymatic activity, 45 strains presented valine and cystine arylamidase activity, while positive reactions for the enzymes beta- and alpha-glucosidase were observed for 27 and 14 strains, respectively. Moreover, 11 strains presented alpha-galactosidase and alkaline phosphatase activity. From the total number of studied yeasts, the strain Y34 belonging to Saccharomyces cerevisiae presented positive results in the majority of both probiotic and technological assays and thus it could be considered a potential starter either as single or as combined culture with lactic acid bacteria in the fermentation of Greek-style natural black olives. PMID- 29494893 TI - A new method to bio-preserve sea bass fillets. AB - In this work a bio-preservation technique was applied to sea bass fillets in order to preserve their quality. The preservation consisted in the application of two kinds of active coatings on the product surface differing in the fermentation time of alginate solution by L. reuteri plus glycerol (24 and 48 h). This technological strategy was chosen because it has been demonstrated that L. reuteri produces the reuterin as an intermediate metabolite during the anaerobic fermentation of glycerol. To assess the antimicrobial effects of sodium alginate with L. reuteri and glycerol, both in vitro and in vivo tests were carried out. The active films, in particular at 48 h fermentation, showed a good antibacterial activity, confirmed also by the major reuterin concentration. To prove the effectiveness of the treatments, microbial and sensory attributes were monitored by in vivo test on fish fillets. Results highlighted that the two active sodium alginate coatings showed a good antibacterial activity. In sea bass fillets stored at 4 degrees C, proliferation of main spoilage microorganisms was delayed with a consequent preservation of sensory attributes. In particular, it was found that improving the fermentation time (48 h) a better microbiological and sensory quality was achieved. PMID- 29494894 TI - Application of a new dynamic transport model to predict the evolution of performances throughout the nanofiltration of single salt solutions in concentration and diafiltration modes. AB - Although many knowledge models describing the rejection of ionic compounds by nanofiltration membranes are available in literature, they are all used in full recycling mode. Indeed, both permeate and retentate streams are recycled in order to maintain constant concentrations in the feed solution. However, nanofiltration of real effluents is implemented either in concentration or diafiltration modes, for which the permeate stream is collected. In these conditions, concentrations progressively evolve during filtration and classical models fail to predict performances. In this paper, an improvement of the so called "Donnan Steric Pore Model", which includes both volume and concentration variations over time is proposed. This dynamic model is used here to predict the evolution of volumes and concentrations in both permeate and retentate streams during the filtration of salt solutions. This model was found to predict accurately the filtration performances with various salts whether the filtration is performed in concentration or diafiltration modes. The parameters of the usual model can be easily assessed from full batch experiments before being used in the dynamic version. Nevertheless, it is also highlighted that the variation of the membrane charge due to the evolution of feed concentration over time has to be taken into account in the model through the use of adsorption isotherms. PMID- 29494895 TI - An improved method for PCR-based detection and routine monitoring of geosmin producing cyanobacterial blooms. AB - Production of taste and odour (T/O) compounds, principally geosmin, by complex cyanobacterial blooms is a major water quality issue globally. Control of these cyanobacteria imposes a significant cost on water producing and dependent industries, and requires routine monitoring and management. Classic monitoring methods, including microscopy and direct chemical analysis, lack sensitivity, are laborious, expensive or cannot reliably identify the source of geosmin production. Polymerase Chain Reaction (PCR) based tools targeting the geosmin synthase gene (geoA) provide a novel tool for routine monitoring. However, geoA is variable at the nucleotide level and potential geosmin producers represent a broad taxonomic distribution, such that multiple PCR primers with distinct amplification protocols are needed to target all potential sources of this important T/O compound. Development of novel primers is hindered by a lack of sequence data and limited field and laboratory data on geosmin producers prevents prioritizing taxa for PCR testing. Here we performed a genetic screen of 253 bloom samples from Victoria, Australia using each existing PCR protocol targeting geoA. We detected Dolichospermum ucrainicum as the major geosmin producer (87% of sequenced samples) along with 3 unknown geoA sequence types. Using these data, we designed a novel, short amplicon, PCR protocol utilising a single standardised primer pair, capable of amplifying all geoA positive samples in our study, as well as a Nostoc punctiforme positive control. This single protocol geoA PCR can further be tested on other geosmin producers and will simplify routine monitoring of T/O producing cyanobacteria. PMID- 29494896 TI - Enhancing anaerobic digestion and methane production of tetracycline wastewater in EGSB reactor with GAC/NZVI mediator. AB - Packing nano mediators into anaerobic system is an attractive technology to strengthen refractory pollutant removal and methane production from wastewater, but is limited by the drawbacks such as easy loss and poor mass transfer. In this study, GAC/NZVI mediator was added into EGSB reactor to investigate the enhancement effects and mechanism for anaerobic digestion of tetracycline wastewater and its impacts on microbial community structure. The results indicated that GAC/NZVI could enhance COD and TOC removal by 12.1% and 10.3%, while have no evident influence on tetracycline removal and sulfide production. The biogas production and methane content were increased by 21.2% and 26.9%, respectively. GAC/NZVI addition resulted in formation of densely packed aggregates, and evidently increased the electrical conductivity and EPS content in sludge. Fe content in sludge was 20.43% with the loss of only 5.4% during 34 d operation. Microbial community analysis revealed that GAC/NZVI addition could both increase the Chao 1 richness index and Shannon diversity index of bacteria and archaea. It was notable that total methanogens contents increased from 74.7% to 81.74% at genera level, resulting in higher methane production, while Treponema increase might promote the degradation of tetracycline and its metabolite, leading to higher COD removal. PMID- 29494897 TI - Ciprofloxacin degradation in anaerobic sulfate-reducing bacteria (SRB) sludge system: Mechanism and pathways. AB - Ciprofloxacin (CIP), a fluoroquinolone antibiotic, removal was examined for the first time, in an anaerobic sulfate-reducing bacteria (SRB) sludge system. About 28.0% of CIP was biodegraded by SRB sludge when the influent CIP concentration was 5000 MUg/L. Some SRB genera with high tolerance to CIP (i.e. Desulfobacter), were enriched at CIP concentration of 5000 MUg/L. The changes in antibiotic resistance genes (ARGs) of SRB sludge coupled with CIP biodegradation intermediates were used to understand the mechanism of CIP biodegradation for the first time. The percentage of efflux pump genes associated with ARGs increased, while the percentage of fluoroquinolone resistance genes that inhibit the DNA copy of bacteria decreased during prolonged exposure to CIP. It implies that some intracellular CIP was extruded into extracellular environment of microbial cells via efflux pump genes to reduce fluoroquinolone resistance genes accumulation caused by exposure to CIP. Additionally, the degradation products and the possible pathways of CIP biodegradation were also examined using the new method developed in this study. The results suggest that CIP was biodegraded intracellularly via desethylation reaction in piperazinyl ring and hydroxylation reaction catalyzed by cytochrome P450 enzymes. This study provides an insight into the mechanism and pathways of CIP biodegradation by SRB sludge, and opens-up a new opportunity for the treatment of CIP-containing wastewater using sulfur mediated biological process. PMID- 29494899 TI - Ancestry and different rates of suicide and homicide in European countries: A study with population-level data. AB - INTRODUCTION: There are large differences in suicide rates across Europe. The current study investigated the relationship of suicide and homicide rates in different countries of Europe with ancestry as it is defined with the haplotype frequencies of Y-DNA and mtDNA. MATERIAL AND METHODS: The mortality data were retrieved from the WHO online database. The genetic data were retrieved from http://www.eupedia.com. The statistical analysis included Forward Stepwise Multiple Linear Regression analysis and Pearson Correlation Coefficient (R). RESULTS: In males, N and R1a Y-DNA haplotypes were positively related to both homicidal and suicidal behaviors while I1 was negatively related. The Q was positively related to the homicidal rate. Overall, 60-75% of the observed variance was explained. L, J and X mtDNA haplogroups were negatively related with suicide in females alone, with 82-85% of the observed variance described. DISCUSSION: The current study should not be considered as a study of genetic markers but rather a study of human ancestry. Its results could mean that research on suicidality has a strong biological but locally restricted component and could be limited by the study population; generalizability of the results at an international level might not be possible. Further research with patient-level data are needed to verify whether these haplotypes could serve as biological markers to identify persons at risk to commit suicide or homicide and whether biologically-determined ancestry could serve as an intermediate grouping method or even as an endophenotype in suicide research. PMID- 29494898 TI - Changes in brain connectivity during a sham-controlled, transcranial magnetic stimulation trial for depression. AB - BACKGROUND: The subgenual anterior cingulate cortex (sgACC) has been implicated in major depressive disorder (MDD), and this study evaluated sgACC connectivity before and after repetitive transcranial magnetic stimulation (rTMS) treatment. METHODS: Thirty-two MDD patients entered a sham-controlled, double-blinded, randomized trial of rTMS to the left dorsolateral prefrontal cortex (dlFPC). Subjects underwent resting state functional magnetic resonance imaging before and after 20 sessions of high frequency rTMS. Seed voxels identified the affective network (AN; sgACC, amygdala), default mode network (DMN; posterior cingulate cortex [PCC]), and fronto-parietal network (FPN; dlPFC stimulation site). RESULTS: There was no significant effect of active rTMS over sham on the primary outcome measure (Montgomery-Asberg Depression Scale rating), with both groups improving over time, and no specific effect of rTMS (sham vs active) on connectivity. However, among patients who showed significant improvement, sgACC connectivity decreased for sham (to AN, trend to DMN) and active rTMS responders (to AN, DMN, FPN), but not in non-responders, who tended to maintain connectivity. Including subjects who started with sham but then received open label active treatment, baseline connectivity from the PCC to the anterior insula was greater in non-responders compared to responders (n = 27, excluding 5 sham responders). LIMITATIONS: The sample size was small; the stimulation target was non-standard, and the lack of a significant clinical effect of rTMS limits conclusions about negative findings. CONCLUSIONS: sgACC connectivity reduces along with depressive symptoms, not specific to rTMS therapy. Altered connectivity of DMN with anterior insula may reflect a type of patient less likely to respond to an intervention. PMID- 29494900 TI - A systematic review of the association of anxiety with health care utilization and costs in people aged 65 years and older. AB - THEORETICAL BACKGROUND: In older people, anxiety disorders are among the most prevalent mental disorders and a high proportion suffers from clinically relevant anxiety symptoms. Despite studies suggesting an association of anxiety with health care utilization (HCU) and a resulting economic burden to the health care system, we found no review systematically analyzing evidence on this association in older people. OBJECTIVE: To analyze and synthesize evidence on the association of anxiety disorders and symptoms with HCU and costs in people aged 65 years and over in a systematic review. METHODS: A systematic search of peer-reviewed literature was conducted in three electronic databases. Additional references were identified through reference lists of included studies. Inclusion criteria were: studies reporting the association of anxiety disorders or symptoms with HCU or costs, specifically in people aged 65 years and over, with observational study design, in German or English language. Findings were synthesized qualitatively and study quality was assessed. RESULTS: N = 15 studies (HCU n = 10, costs n = 5) were included in the final synthesis. Overall, studies either reported significantly increased HCU in anxiety disorders compared to a healthy comparison group/according to degree of symptoms, or found no significant association between these variables. Total excess costs for anxiety disorders ranged from 116 to 19,003 $PPP per year. LIMITATIONS: Differences in methodology limited the comparability of included studies. CONCLUSION: Most studies suggest an increased economic burden due to anxiety in older people. Studies using standardized instruments are needed. PMID- 29494902 TI - A systematic review of the associations between maternal nutritional biomarkers and depression and/or anxiety during pregnancy and postpartum. AB - BACKGROUND: Nutritional requirements need to be met in order to adapt to pre- and postnatal changes. Our aim was to systematically review the evidence of associations between nutritional biomarkers and psychological distress during pregnancy and in the first postnatal year. METHODS: MEDLINE, EMBASE, PsycINFO, Scielo, LILACS, clinicaltrials.gov, International Clinical Trials Registry, Cochrane Library, Scopus and Web of Science databases were searched for articles from inception to 4/15/2016. Studies of maternal nutritional biomarkers in blood (fatty acids/micronutrients/amino acids) and associations with psychological distress (depression/anxiety/stress) were included. Two independent reviewers extracted data based on study designs, participants, outcomes, exposures, and association measures. RESULTS: Thirty-eight studies were included. A total of 13 studies showed divergent or no associations between serum/plasma/erythrocyte fatty acid concentrations and depression/anxiety during pregnancy and postpartum. Changes in serum cholesterol levels from pregnancy to postpartum showed a significant inverse correlation with depression in one out of three studies. Five out of seven studies found an inverse association between serum vitamin D levels and pre- and postnatal depression. Plasma tryptophan levels were inversely correlated with postnatal depression scores in three out of four studies. We identified that one out of two studies presented no significant association between vitamin B12/folate/ferritin concentrations and depression in postpartum. LIMITATIONS: There was higher variability between association measures, time and scales of depression and anxiety assessments. CONCLUSIONS: The majority of high quality studies suggest that lower vitamin D levels may be associated with postpartum depression. However, further evidence is needed for guiding clinical practice on nutritional biomarkers. PMID- 29494903 TI - Performance of passive sampling with low-density polyethylene membranes for the estimation of freely dissolved DDx concentrations in lake environments. AB - Laboratory and field studies were used to evaluate the performance of low-density polyethylene (PE) passive samplers for assessing the freely dissolved concentrations of DDT and its degradates (DDD and DDE, together referred to as DDx) in an Italian lake environment. We tested commercially available 25 MUm thick PE sheets as well as specially synthesized, 10 MUm thick PE films which equilibrated with their surroundings more quickly. We measured PE-water partitioning coefficients (Kpew) of the 10 MUm thick PE films, finding good correspondence with previously reported values for thicker PE. Use of the 10 MUm PE for ex situ sampling of a lake sediment containing DDx in laboratory tumbling experiments showed repeatability of +/-15% (= standard deviation/mean). Next, we deployed replicate 10 MUm and 25 MUm PE samplers (N = 4 for 10 d and for 30 d) in the water and sediment of a lake located in northern Italy; the results showed dissolved DDx concentrations in the picogram/L range in porewater and the bottom water. Values deduced from 10 MUm thick PE films compared well (95% of all comparison pairs matched within a factor of 5) with those obtained using PE films of 25 MUm thickness when dissolved DDx concentrations were estimated using performance reference compound (PRC) corrections, whether left at the bed-water interface for 10 or 30 days. These results demonstrated the potential of this sampling method to provide estimation of the truly dissolved DDx concentrations, and thereby the mobile and bio-available fractions in both surface waters and sediment beds. PMID- 29494901 TI - Attempted suicide in Sri Lanka - An epidemiological study of household and community factors. AB - BACKGROUND: An individual's suicide risk is determined by personal characteristics, but is also influenced by their environment. Previous studies indicate a role of contextual effects on suicidal behaviour, but there is a dearth of quantitative evidence from Asia. METHODS: Individual and community level data were collected on 165,233 people from 47,919 households in 171 communities in rural Sri Lanka. Data were collected on individual (age, sex, past suicide attempts and individual socioeconomic position (SEP)) and household (household SEP, pesticide access, alcohol use and multigenerational households) level factors. We used 3-level logit models to investigate compositional (individual) and contextual (household/community) effects. RESULTS: We found significant variation between households 21% (95% CI 18%, 24%) and communities 4% (95% CI 3%, 5%) in the risk of a suicide attempt. Contextual factors as measured by low household SEP (OR 2.37 95% CI 2.10, 2.67), low community SEP (OR 1.45 95% CI 1.21, 1.74), and community 'problem' alcohol use (OR 1.44 95% CI 1.19, 1.75) were associated with an increased risk of suicide attempt. Women living in households with alcohol misuse were at higher risk of attempted suicide. We observed a protective effect of living in multigenerational households (OR 0.53 95% CI 0.42, 0.65). LIMITATIONS: The outcome was respondent-reported and refers to lifetime reports of attempted suicide, therefore this study might be affected by socially desirable responding. CONCLUSIONS: Our study finds that contextual factors are associated with an individual's risk of attempted suicide in Sri Lanka, independent of an individual's personal characteristics. PMID- 29494904 TI - Free-standing hierarchical alpha-MnO2@CuO membrane for catalytic filtration degradation of organic pollutants. AB - Catalytic membrane, due to its compact reactor assembling, high catalytic performance as well as low energy consumption, has proved to be more attractive for wastewater treatment. In this work, a free-standing alpha-MnO2@CuO membrane with hierarchical nanostructures was prepared and evaluated as the catalytic membrane to generate radicals from peroxymonosulfate (PMS) for the oxidative degradation of organic dyes in aqueous solution. Benefiting from the high mass transport efficiency and the hierarchical nanostructures, a superior catalytic activity of the membrane was observed for organic dyes degradation. As a typical organic dye, more than 99% of methylene blue (MB) was degraded within 0.23 s using dead-end filtration cell. The effects of flow rate, PMS concentration and buffer solution on MB degradation were further investigated. Besides MB, the catalytic membrane also showed excellent performance for the removal of other dyes, such as congo red, methyl orange, rhodamine B, acid chrome blue K and malachite green. Moreover, the mechanism study indicated that OH and SO4- generated from the interaction between PMS and Mn/Cu species with different oxidation states mainly accounted for the dyes degradation. The catalytic filtration process using alpha-MnO2@CuO catalytic membrane could provide a novel method for wastewater purification with high efficiency and low energy consumption. PMID- 29494905 TI - Investigation of biotransformation, sorption, and desorption of multiple chemical contaminants in pilot-scale drinking water biofilters. AB - The evolving demands of drinking water treatment necessitate processes capable of removing a diverse suite of contaminants. Biofiltration can employ biotransformation and sorption to remove various classes of chemicals from water. Here, pilot-scale virgin anthracite-sand and previously used biological activated carbon (BAC)-sand dual media filters were operated for ~250 days to assess removals of 0.4 mg/L ammonia as nitrogen, 50-140 MUg/L manganese, and ~100 ng/L each of trace organic compounds (TOrCs) spiked into pre-ozonated Colorado River water. Anthracite achieved complete nitrification within 200 days and started removing ibuprofen at 85 days. Limited manganese (10%) removal occurred. In contrast, BAC completely nitrified ammonia within 113 days, removed all manganese at 43 days, and exhibited steady state removal of most TOrCs by 140 days. However, during the first 140 days, removal of caffeine, DEET, gemfibrozil, naproxen, and trimethoprim decreased, suggesting a shift from sorption to biotransformation. Acetaminophen and sulfamethoxazole were removed at consistent levels, with complete removal of acetaminophen achieved throughout the study; ibuprofen removal increased with time. When subjected to elevated (1 MUg/L) concentrations of TOrCs, BAC removed larger masses of chemicals; with a subsequent decrease and ultimate cease in the TOrCs spike, caffeine, DEET, gemfibrozil, and trimethoprim notably desorbed. By the end of operation, anthracite and BAC exhibited equivalent quantities of biomass measured as adenosine triphosphate, but BAC harbored greater microbial diversity (examined with 16S rRNA sequencing). Improved insight was gained regarding concurrent biotransformation, sorption, and desorption of multiple organic and inorganic contaminants in pilot-scale drinking water biofilters. PMID- 29494906 TI - Pb-induced phytotoxicity in para grass (Brachiaria mutica) and Castorbean (Ricinus communis L.): Antioxidant and ultrastructural studies. AB - Hydroponics experiment was conducted to investigate the effects of different levels of Pb on Para Grass (Brachiaria mutica) and Castorbean (Ricinus communis L). Generally, Para Grass exhibited higher tolerance to excessive concentrations of Pb in nutrient solution, whereas a consistent decline was observed in growth of Castorbean plants exposed to similar Pb levels. Malondialdehyde (MDA) and H2O2 contents exhibited contrasting results with a general decrease in Para Grass and a linear increase in case of Castorbean. In both species a decrease was noticed in the activities of superoxide dismutase (SOD) and guaiacol peroxidase (G-POD) while catalase (CAT) activity was significantly increased. Ultrastructural studies revealed increased starch grains and adversely affected thylakoid membranes in chloroplasts of leaf cells of plants treated with 500 MUM Pb. Photosynthetic parameters such as CO2 assimilation rate, stomatal conductance (gs) and transpiration rate (E) decreased in both plant species under different levels of Pb. Maximum concentrations of Pb in shoots of Para Grass and Castorbean were 1.29 and 0.352 g kg-1, respectively while in roots maximum values were 8.88 and 49.86 g kg-1, respectively. The high concentrations of Pb (about 5%) in the roots of Castorbean plants suggest its possible role in the phytoremediation/rhizofiltration of Pb contaminated water. PMID- 29494907 TI - Development of a two-stage biotransformation system for mercury-contaminated soil remediation. AB - Utilization of bacterial volatilization can be problematic to remediate mercury (Hg)-contaminated soils because most of the Hg in soils is bound to soil particles. The objective of this study was to develop a two-stage system (chemical extraction followed by microbial reduction) for Hg-contaminated soil remediation. The tasks were to (1) select the extraction reagents for Hg extraction, (2) assess the effects of extraction reagents on the growth of Hg reducing bacterial strains, and (3) evaluate the effectiveness of Ca2+ and Mg2+ addition on merA gene (Hg reductase) induction. Bacterial inhibition was observed with the addition of 0.1 M ethylenediaminetetraacetic acid or citric acid. Up to 65% of Hg was biotransformed (Hg concentration = 69 mg/kg) from the soils after a 24 h extraction using 0.5 M ammonium thiosulfate. Ca2+ and Mg2+ were selected because they have the same electric charge as Hg and the studied groundwater contained high concentrations of Ca2+ and Mg2+. Results showed that the addition of 200 mg/L Ca2+ or 650 mg/L Mg2+ could reach effective merA induction. In the two-stage experiment, 120 mg/kg Hg-contaminated soils were extracted with 2 rounds of extraction processes for 10 h using 0.5 M ammonium thiosulfate. Approximately 77% of Hg was extracted from the soils after the first-step extraction process. Up to 81% of Hg2+ was transformed from the washing solution via the biotransformation processes with Enterobacter cloacae addition and Ca2+ and Mg2+ supplementation. The two-stage remedial system has the potential to be developed into a practical technology to remediate Hg-contaminated sites. PMID- 29494908 TI - Impact of sugarcane bagasse-derived biochar on heavy metal availability and microbial activity: A field study. AB - In the current study, we conducted a field experiment using the test plant, Brassica chinesis L. (pak choi), to investigate the effect of sugarcane bagasse derived biochar on the bioavailability of cadmium (Cd), copper (Cu) and lead (Pb), and the health of soil microbiota in a contaminated soil. Biochar application significantly (P < 0.05) increased pak choi yield. Bioavailability of heavy metals to plant shoots and roots decreased with increasing biochar application rates (at 0, 1.5, 2.25 and 3.0 t ha-1). Sequential extraction of the biochar-treated and -untreated soil revealed that exchangeable Cd reduced whereas organically-bound fraction increased with increasing biochar rate. The labile fractions of Cu and Pb decreased, but the residual fraction increased in biochar treated soils compared to the control. Urease, catalase and invertase activities, and the populations of bacteria and actinomycetes were significantly enhanced, whereas fungi population declined in biochar-treated soils. This study highlights that sugarcane bagasse biochar has the potential to support the remediation of soils contaminated with heavy metals, and as such can improve the yield and quality of agricultural crops. PMID- 29494909 TI - Effect of perfluorooctane sulphonate-induced Kupffer cell activation on hepatocyte proliferation through the NF-kappaB/TNF-alpha/IL-6-dependent pathway. AB - Perfluorooctane sulfonate (PFOS), one member of polyfluoroalkyl chemicals (PFASs), persist in the environment and are found in relatively high concentrations in animal livers. PFOS has been shown to induce tumour of the liver in rats following chronic dietary administration. However, the molecular mechanisms involved in PFOS-induced hepatocellular hypertrophy are still not well characterized. In this study, male Sprague-Dawley rats were daily gavaged with PFOS (1 or 10 mg/kg body weight) for 28 days. Rat primary cultured Kupffer cells or hepatocytes were exposed to 100 MUM PFOS for 0-48 h. Our results showed that PFOS exposure caused serious hepatocellular damage and obvious inflammatory cell infiltration and increased serum tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) levels. Particularly, PFOS exposure triggered Kupffer cell activation and significantly upregulated the expression of proliferating cell nuclear antigen (PCNA), c-Jun, c-MYC and Cyclin D1 (CyD1) in liver. In vitro, PFOS significantly induced production of TNF-alpha and IL-6 in Kupffer cells and increased PCNA, c-Jun, c-MYC and CyD1 expression in the primary hepatocytes co cultured with Kupffer cells. However, Kupffer cell activation was mostly abolished by anti-TNF-alpha or anti-IL6 treatment. Furthermore, blockage of TNF alpha and IL-6 significantly inhibited hepatocyte proliferation by gadolinium chloride (GdCl3) pre-treatment in PFOS-treated mice and primary cultured Kupffer cells. On the other hand, NF-kappaB inhibitor (PDTC) and c-Jun amino-terminal kinase (JNK) inhibitor (SP600125) significantly inhibited production of PFOS induced TNF-alpha and IL-6. Taken together, these data suggest that PFOS induces Kupffer cell activation, leading to hepatocyte proliferation by through the NF kappaB/TNF-alpha/IL-6-dependent pathway. PMID- 29494911 TI - Toxic effects and foundation of proton radiation on the early-life stage of zebrafish development. AB - Proton is a major particle of space radiation environment and a prospective radiotherapy beam. However, its risk needs to be fully evaluated for the understanding and to establish the better protective strategy for astronaut and patient. Zebrafish is an ideal model for the toxicity studies on medicines and environmental genetic toxicants. In the current study, embryos of zebrafish at 24 h post-fertilization (hpf) were exposed to proton beam. Some toxic parameters of embryo-larval development were investigated. Microarray combining with qRT-PCR were used to detect the gene expression situation. Generally, fractions of a variety of abnormal phenotypes of embryos and larvae increased in a dose dependent manner after irradiation. The copy number of mitochondria, the basal respiration rate and the maximum respiration rate of embryos significantly decreased after irradiation. Microarray data demonstrated that MAPK signaling pathway, cell communication, glycolysis and TGF-beta signaling pathway were significantly affected in the irradiated group. The expressions of matrix metallopeptidase 9 (mmp9) and TIMP metallopeptidase inhibitor 2b (timp2b) genes, and enzymatic activity of MMP9 were significantly upregulated in irradiated group. Overall, these results suggest that acute radiation of proton severely affects the development of organism and results in aberration occurrence in the early stage of zebrafish development, which may relates to mitochondrial and glycolytic dysfunction. PMID- 29494910 TI - Identification of circular RNAs and their alterations involved in developing male Xenopus laevis chronically exposed to atrazine. AB - Atrazine (AZ) is an environmental endocrine disrupting chemical which can affect the development of amphibians. In our past studies, we demonstrated that chronical exposure to 100 MUg/L AZ can cause abnormalities in development and related genes expression of gonads in developing male Xenopus laevis (X. laevis) tadpoles. Recent studies by others have demonstrated that circular RNAs (circRNAs) are implicated in multiple developmental anomalies. However, whether circRNAs involve in the effects in AZ-exposed X. laevis remains unknown. In this study, over 68575 circRNAs were detected by circRNA sequencing of testis tissues from control groups (n = 3) and AZ-treated X. laevis (n = 3). Treatment of AZ led to 405 circRNAs differentially expressed including 44 upregulated and 361 downregulated compared with froglets in the control groups. Two upregulated and 6 downregulated circRNAs were further validated by real-time PCR assay which displayed consistent regulation patterns as shown by the transcriptome sequencing results. Two hundreds and eighty two differentially expressed circRNAs played miRNA sponges roles. Kyoto Encyclopedia of Genes and Genomes pathway analysis of miRNA targets showed that AZ-affected circRNAs are mainly involved in 19 pathways. The Wnt signaling pathway and progesterone-mediated oocyte maturation pathway may be two involved signal pathways. This study for the first time provides evidence that AZ can alter circRNAs which play a role in AZ-induced testicular degeneration of developing male X. laevis through regulation of expressions of functional genes in the testes of X. laevis. PMID- 29494912 TI - Effects of organic wastes on structural characterizations of humic acid in semiarid soil under plastic mulched drip irrigation. AB - The objective of this work was to evaluate the variation in the amount and structure of humic acid (HA) after the application of organic wastes (OWs) in semiarid soil under plastic mulched drip irrigation, measured by elemental composition, excitation-emission matrix (EEM) fluorescence, and carbon 13 nuclear magnetic resonance (13C CPMAS NMR). The experiment involved chemical fertilizer combined with chicken manure (CM), sheep manure (SM), maize straw (MS), fodder grass (FG), and tree leaves (TL), while chemical fertilizer only was used as control (CK). The highest cation exchange capacity (CEC), soil organic carbon (SOC), and HA contents (P < 0.05) were achieved for TL compared to other OWs. The E4/E6 ratio, DeltalogK value, and the aliphatic C/aromatic C ratio of HA were the lowest for TL treatment than for other OW treatments, whereas the highest C/H ratio was obtained. The specific fluorescence intensities (SFI) of peak A (330 370/460-490 nm), peak B (450-465/515-525 nm), and peak C (255-270/465-490 nm) mainly referred to humic acid component from EEM fluorescence spectrum of HA were lower for TL compared to other OWs. In conclusion, the application of TL was the most effective for improving the accumulation of SOC and HA, and making the structure of HA complex and stability. Thus, TL is the recommended OW for use in semiarid soil under plastic mulched drip irrigation conditions. PMID- 29494913 TI - Application of a bacterial whole cell biosensor for the rapid detection of cytotoxicity in heavy metal contaminated seawater. AB - A toxicity biosensor Acinetobacter baylyi Tox2 was constructed with the host strain A. baylyi ADP1 harboring a new and medium-copy-number plasmid pWH1274_lux, and was applied to detect the cytotoxicity of heavy metal contaminated seawater. The gene cassette luxCDABE was controlled by constitutively expressed promoter Ptet on pWH1274_lux and the bioluminescence intensity of the biosensor reduces in proportional to the concentrations of toxic compounds. A. baylyi Tox2 exhibits tolerance to salinity, hence it is applicable to seawater samples. A. baylyi Tox2 and Mugilogobius chulae were exposed to different concentrations of heavy metals (Hg2+, Zn2+, Cu2+, and Cd2+) in artificial seawater for performance comparison and Pearson correlation analysis showed a significant correlation (p < 0.01) between A. baylyi Tox2 toxicity detection and the fish (M. chulae) exposure test. This suggests that the performance of A. baylyi Tox2 is comparable to the conventional fish toxicity test in terms of cytotoxicity detection of heavy metal contaminated seawater. Furthermore, A. baylyi Tox2 was used to evaluate cytotoxicity of field-collected seawater samples. The results indicate that there was a significant correlation between the luminescence inhibition ratio (IR) of A. baylyi Tox2 and heavy metal concentrations detected by ICP-MS in the samples. Two seawater samples, which contained a high concentration of total heavy metals, exhibited stronger cytotoxicity than the samples containing low concentrations of heavy metals. In conclusion, A. baylyi Tox2 can be used as an alternative tool to aquatic animals for the evaluation of the cytotoxicity of heavy metal contamination in the marine environment. PMID- 29494915 TI - Chemical speciation and risk assessment of Cu and Zn in biochars derived from co pyrolysis of pig manure with rice straw. AB - Pig manure has been utilized as a good feedstock to produce biochar. However, the pig manure-derived biochar from intensive pig cultivation contains high levels of total and bioavailable heavy metals. In this study, the co-pyrolysis of pig manure with other biomass (e.g. rice straw) at 300-700 degrees C was investigated to solve the above-mentioned topic. The ammonium acetate (CH3COONH4), Tessier sequential extraction procedure and hydrogen peroxide were adopted to evaluate the bioavailability, chemical speciation, and potential risk of Cu and Zn in the biochars. Results showed that the addition of rice straw significantly reduced the concentrations of total, exchangeable and carbonate associated Cu and Zn in the biochars compared to the single pig manure biochars. Co-pyrolysis of pig manure with rice straw at a mass ratio of 1:3 and at 600 degrees C could be most effective to reduce the concentrations of CH3COONH4 extractable and potential released Cu and Zn in the biochars. In conclusion, the co-pyrolysis process is a feasible management for the safe disposal of metal polluted pig manure in an attempt to reduce the bioavailability and potential risk of heavy metals at relatively high pyrolysis temperatures. PMID- 29494914 TI - A review on experimental design for pollutants removal in water treatment with the aid of artificial intelligence. AB - Water pollution occurs mainly due to inorganic and organic pollutants, such as nutrients, heavy metals and persistent organic pollutants. For the modeling and optimization of pollutants removal, artificial intelligence (AI) has been used as a major tool in the experimental design that can generate the optimal operational variables, since AI has recently gained a tremendous advance. The present review describes the fundamentals, advantages and limitations of AI tools. Artificial neural networks (ANNs) are the AI tools frequently adopted to predict the pollutants removal processes because of their capabilities of self-learning and self-adapting, while genetic algorithm (GA) and particle swarm optimization (PSO) are also useful AI methodologies in efficient search for the global optima. This article summarizes the modeling and optimization of pollutants removal processes in water treatment by using multilayer perception, fuzzy neural, radial basis function and self-organizing map networks. Furthermore, the results conclude that the hybrid models of ANNs with GA and PSO can be successfully applied in water treatment with satisfactory accuracies. Finally, the limitations of current AI tools and their new developments are also highlighted for prospective applications in the environmental protection. PMID- 29494916 TI - Investigation and application of diffusive gradients in thin-films technique for measuring endocrine disrupting chemicals in seawaters. AB - Endocrine disrupting chemicals (EDCs) can be released to coastal waters and affect the endocrine system of marine organisms. To monitor their levels in seawaters, a simple, robust passive sampling method, the diffusive gradients in thin-films (DGT) technique, was developed with XDA-1 resin as a binding agent. Six EDCs (including three estrogens, two pesticides and bisphenol A) were used to assess the performance of the DGT. The XDA-1 binding gel showed adequate ability for adsorbing EDCs in seawaters. The DGT sampler exhibited linear accumulation for the EDCs during a 15-day deployment and diffusion coefficients and sampling rates were calculated. The DGT measurement was independent of pH in the range 7.0 9.0 and ionic strength in the range 0.4-0.8 M. Field applications of this DGT in a coast of Dalian (China) showed comparable results to those from grab sampling. Five EDCs were detected with concentrations ranging from 0.7 to 19.4 ng L-1. This study is a first attempt to apply DGT sampler for determining EDCs in seawaters. PMID- 29494917 TI - Histone methylation-associated transgenerational inheritance of reproductive defects in Caenorhabditis elegans exposed to crude oil under various exposure scenarios. AB - As part of a study to explore the long-term effects of the Hebei Spirit oil spill accident, transgenerational toxicity and associated epigenetic changes were investigated in the nematode Caenorhabditis elegans. Under experimental conditions, worms were exposed to Iranian heavy crude oil (IHC) under three different scenarios: partial early-life exposure (PE), partial late-life exposure (PL), and whole-life exposure (WE). Growth, reproduction, and histone methylation were monitored in the exposed parental worms (P0) and in three consecutive unexposed offspring generations (F1-3). Reproductive potential in the exposed P0 generation in the WE treatment group was reduced; additionally, it was inhibited in the unexposed offspring generations of the P0 worms. This suggests that there was transgenerational inheritance of defective reproduction. Comparison of developmental periods of exposure showed that IHC-treated worms in the PL group had a greater reduction in reproductive capacity than those in the PE group. Decreased methylation of histone H3 (H3K9) was found in the IHC-exposed parental generation. A heritable reduction in reproductive capacity occurred in wildtype N2 but was not found in a H3K9 histone methyltransferase (HMT) mutant, met 2(n4256), suggesting a potential role for HMT in transgenerational toxicity. Our results suggest that the reproductive toxicity after IHC exposure could be heritable and that histone methylation is associated with the transmission of the inherited phenotype. PMID- 29494918 TI - Treatment of Helicobacter pylori with dielectric barrier discharge plasma causes UV induced damage to genomic DNA leading to cell death. AB - Gastrointestinal endoscopy is an important tool for the indentification and treatment of disorders of the gastrointestinal tract. However, nosocomial infections of Helicobacter pylori have been linked to the use of contaminated endoscopes. Disinfectants such as glutaraldehyde, ortho-phthalaldehyde and peracetic acid are generally used in the reprocesssing of endoscopes, but these chemicals are hazardous to human health. Thus, safer reprocessing and disinfecion methods are needed. In this study, we applied a dielectric barrier discharge (DBD) plasma torch for inactivation of H. pylori to investigate a potential new methodology to disinfect endoscopes. Suspensions of H. pylori in 10% glycerol were subjected to the DBD plasma torch, which reduced the viable cell count to undetectable levels after 2 min of treatment. Furthermore, urease activity of H. pylori was eliminated after 2 min-plasma treatment, while plasma-treatment reduced the intact DNA of H. pylori in a time-dependent manner. Next, we examined several potential bactericidal factors produced by the DBD plasma torch. Two min plasma treatment resulted in a small temperature rise (4 degrees C), ultraviolet radiation (UV) generation, and the production of hydrogen peroxide. H. pylori samples were then exposed to equivalent levels of each of these factors in turn. Our results showed that treatment with heat and hydrogen peroxide at the levels produced after 2-min of plasma treatment did not efficiently inactivate H. pylori, whereas exposure to UV had a significant bactericidal effect. Taken together, UV generated by the plasma torch may be crucial for efficient inactivation of H. pylori by damaging the bacterial DNA. PMID- 29494919 TI - Microplastic pollution increases gene exchange in aquatic ecosystems. AB - Pollution by microplastics in aquatic ecosystems is accumulating at an unprecedented scale, emerging as a new surface for biofilm formation and gene exchange. In this study, we determined the permissiveness of aquatic bacteria towards a model antibiotic resistance plasmid, comparing communities that form biofilms on microplastics vs. those that are free-living. We used an exogenous and red-fluorescent E. coli donor strain to introduce the green-fluorescent broad host-range plasmid pKJK5 which encodes for trimethoprim resistance. We demonstrate an increased frequency of plasmid transfer in bacteria associated with microplastics compared to bacteria that are free-living or in natural aggregates. Moreover, comparison of communities grown on polycarbonate filters showed that increased gene exchange occurs in a broad range of phylogenetically diverse bacteria. Our results indicate horizontal gene transfer in this habitat could distinctly affect the ecology of aquatic microbial communities on a global scale. The spread of antibiotic resistance through microplastics could also have profound consequences for the evolution of aquatic bacteria and poses a neglected hazard for human health. PMID- 29494920 TI - Ground ozone concentrations over Beijing from 2004 to 2015: Variation patterns, indicative precursors and effects of emission-reduction. AB - Based on ozone observation data from urban stations and the Dingling (DL) background station, we investigated the trend of ozone concentrations in Beijing during 2004-2015. For urban stations, both O3_1 h and O3_8 h increased stably with a clear and significant linear pattern and the increase rate was notably higher during the period of May to Sep. Meanwhile, the variation of O3_1 h and O3_8 h for the DL station did not demonstrate a regular pattern. During this period, the differences between the diurnal peak of ozone concentrations at the DL background station and urban stations decreased significantly due to the rapid urbanization of Beijing. Furthermore, we examined simultaneous variations of ozone and its precursors during 2015 Grand Military Parade and 2014 APEC meeting and evaluated the performances of different emission-reduction measures during the two specific events. For 2015 Grand Military Parade, emission-reduction measures were implemented 14 days in advance, which led to a notable decrease of ozone concentrations during the Parade period. For 2014 APEC meeting, emission reduction measures were not implemented in advance, which led to incomplete VOCs reduction and high VOCs/NOx values, and thus a significant increase of ozone concentrations during the APEC period. The emission-reduction measures during APEC and PARADE periods both slowed down the accumulation and cut down the concentration peaks of ozone. We also analyzed simultaneous concentration variations of ozone and its precursors in long time-series. The results proved that compared with other precursors, NO2/NO was an effective indicator for ozone concentration in Beijing, especially in urban areas. The findings from this research provide useful reference for better monitoring and managing ozone concentrations in Beijing and other cities through properly designed and implemented emission-reduction measures. PMID- 29494921 TI - Marine environment microfiber contamination: Global patterns and the diversity of microparticle origins. AB - Microplastic and microfiber pollution has been documented in all major ocean basins. Microfibers are one of the most common microparticle pollutants along shorelines. Over 9 million tons of fibers are produced annually; 60% are synthetic and ~25% are non-synthetic. Non-synthetic and semi-synthetic microfibers are infrequently documented and not typically included in marine environment impact analyses, resulting in underestimation of a potentially pervasive and harmful pollutant. We present the most extensive worldwide microparticle distribution dataset using 1-liter grab samples (n = 1393). Our citizen scientist driven study shows a global microparticle average of 11.8 +/- 24.0 particles L-1 (mean +/- SD), approximately three orders of magnitude higher than global model predictions. Open ocean samples showed consistently higher densities than coastal samples, with the highest concentrations found in the polar oceans (n = 51), confirming previous empirical and theoretical studies. Particles were predominantly microfibers (91%) and 0.1-1.5 mm in length (77%), a smaller size than those captured in the majority of surface studies. Using MUFT IR we determined the material types of 113 pieces; 57% were classified as synthetic, 12% as semi-synthetic, and 31% as non-synthetic. Samples were taken globally, including from coastal environments and understudied ocean regions. Some of these sites are emerging as areas of concentrated floating plastic and anthropogenic debris, influenced by distant waste mismanagement and/or deposition of airborne particles. Incorporation of smaller-sized microfibers in oceanographic models, which has been lacking, will help us to better understand the movement and transformation of synthetic, semi-synthetic and non-synthetic microparticles in regional seas and ocean basins. PMID- 29494922 TI - Impacts of springtime biomass burning in the northern Southeast Asia on marine organic aerosols over the Gulf of Tonkin, China. AB - Fine particles (PM2.5) samples, collected at Weizhou Island over the Gulf of Tonkin on a daytime and nighttime basis in the spring of 2015, were analyzed for primary and secondary organic tracers, together with organic carbon (OC), elemental carbon (EC), and stable carbon isotopic composition (delta13C) of total carbon (TC). Five organic compound classes, including saccharides, lignin/resin products, fatty acids, biogenic SOA tracers and phthalic acids, were quantified by gas chromatography/mass spectrometry (GC/MS). Levoglucosan was the most abundant organic species, indicating that the sampling site was under strong influence of biomass burning. Based on the tracer-based methods, the biomass burning-derived fraction was estimated to be the dominant contributor to aerosol OC, accounting for 15.7% +/- 11.1% and 22.2% +/- 17.4% of OC in daytime and nighttime samples, respectively. In two episodes E1 and E2, organic aerosols characterized by elevated concentrations of levoglucosan as well as its isomers, sugar compounds, lignin products, high molecular weight (HMW) fatty acids and beta-caryophyllinic acid, were attributed to the influence of intensive biomass burning in the northern Southeast Asia (SEA). However, the discrepancies in the ratios of levoglucosan to mannosan (L/M) and OC (L/OC) as well as the delta13C values suggest the type of biomass burning and the sources of organic aerosols in E1 and E2 were different. Hardwood and/or C4 plants were the major burning materials in E1, while burning of softwood and/or C3 plants played important role in E2. Furthermore, more complex sources and enhanced secondary contribution were found to play a part in organic aerosols in E2. This study highlights the significant influence of springtime biomass burning in the northern SEA to the organic molecular compositions of marine aerosols over the Gulf of Tonkin. PMID- 29494923 TI - The influence of hydrogeological and anthropogenic variables on phthalate contamination in eogenetic karst groundwater systems. AB - This study investigates the occurrence of six phthalates and distribution of the three most-detected phthalates in the karst region of northern Puerto Rico (KRNPR) using data from historical records and current field measurements. Statistical data analyses, including ANOVA, Chi-Square, and logistic regression models are used to examine the major factors affecting the presence and concentrations of phthalates in the KRNPR. The most detected phthalates include DEHP, DBP, and DEP. At least one phthalate specie is detected above DL in 7% of the samples and 24% of the sampling sites. Concentrations of total phthalates average 5.08 +/- 1.37 MUg L-1, and range from 0.093 to 58.4 MUg L-1. The analysis shows extensive spatial and temporal presence of phthalates resulting from dispersed phthalate sources throughout the karst aquifers. Hydrogeological factors are significantly more important in predicting the presence and concentrations of phthalates in eogenetic karst aquifers than anthropogenic factors. Among the hydrogeological factors, time of detection and hydraulic conductivities larger than 300 m d-1 are the most influential factors. Persistent presence through time reflects continuous sources of phthalates entering the aquifers and a high capacity of the karst aquifers to store and slowly release contaminants for long periods of time. The influence of hydraulic conductivity reveals the importance of contaminant fate and transport mechanisms from contamination sources. This study improves the understanding of factors affecting the spatial variability and fate of phthalates in karst aquifers, and allows us to better predict their occurrence based on these factors. PMID- 29494924 TI - Imidazolium ionic liquids as effective antiseptics and disinfectants against drug resistant S. aureus: In silico and in vitro studies. AB - This paper describes Quantitative Structure-Activity Relationships (QSAR) studies, molecular docking and in vitro antibacterial activity of several potent imidazolium-based ionic liquids (ILs) against S. aureus ATCC 25923 and its clinical isolate. Small set of 131 ILs was collected from the literature and uploaded in the OCHEM database. QSAR methodologies used Associative Neural Networks and Random Forests (WEKA-RF) methods. The predictive ability of the models was tested through cross-validation, giving cross-validated coefficients q2 = 0.82-0.87 for regression models and overall prediction accuracies of 80 82.1% for classification models. The proposed QSAR models are freely available online on OCHEM server at https://ochem.eu/article/107364 and can be used for estimation of antibacterial activity of new imidazolium-based ILs. A series of synthesized 1,3-dialkylimidazolium ILs with predicted activity were evaluated in vitro. The high activity of 7 ILs against S. aureus strain and its clinical isolate was measured and thereafter analyzed by the molecular docking to prokaryotic homologue of a eukaryotic tubulin FtsZ. PMID- 29494925 TI - CCFS: A cooperating coevolution technique for large scale feature selection on microarray datasets. AB - Recently, advances in bioinformatics lead to microarray high dimensional datasets. These kinds of datasets are still challenging for researchers in the area of machine learning since they suffer from small sample size and extremely large number of features. Therefore, feature selection is the problem of interest in the learning process in this area. In this paper, a novel feature selection method based on a global search (by using the main concepts of divide and conquer technique) which is called CCFS, is proposed. The proposed CCFS algorithm divides vertically (on features) the dataset by random manner and utilizes the fundamental concepts of cooperation coevolution by using a filter criterion in the fitness function in order to search the solution space via binary gravitational search algorithm. For determining the effectiveness of the proposed method some experiments are carried out on seven binary microarray high dimensional datasets. The obtained results are compared with nine state-of-the art feature selection algorithms including Interact (INT), and Maximum Relevancy Minimum Redundancy (MRMR). The average outcomes of the results are analyzed by a statistical non-parametric test and it reveals that the proposed method has a meaningful difference to the others in terms of accuracy, sensitivity, specificity and number of selected features. PMID- 29494926 TI - Scaffold-based novel SHP2 allosteric inhibitors design using Receptor-Ligand pharmacophore model, virtual screening and molecular dynamics. AB - SHP2 is a potential target for the development of novel therapies for SHP2 dependent cancers. In our research, with the aid of the 'Receptor-Ligand Pharmacophore' technique, a 3D-QSAR method was carried out to explore structure activity relationship of SHP2 allosteric inhibitors. Structure-based drug design was employed to optimize SHP099, an efficacious, potent, and selective SHP2 allosteric inhibitor. A novel class of selective SHP2 allosteric inhibitors was discovered by using the powerful 'SBP', 'ADMET' and 'CDOCKER' techniques. By means of molecular dynamics simulations, it was observed that these novel inhibitors not only had the same function as SHP099 did in inhibiting SHP2, but also had more favorable conformation for binding to the receptor. Thus, this report may provide a new method in discovering novel and selective SHP2 allosteric inhibitors. PMID- 29494927 TI - Comparative homology model building and docking evaluation for RNA III inhibiting peptide of Multi drug resistant Staphylococcus aureus strain MRSA252. AB - Since last several years, infection caused by Staphylococcus aureus is challenging to cure using conventional antibiotics. The organism is a Gram positive bacterial pathogen that can cause serious diseases not only in humans but also in animals, such as various skin infections, pneumonia, endocarditis and toxin shock syndrome. This bacterium causes such diseases by producing macromolecules such as hemolysins, enterotoxins, proteases and toxic shock syndrome toxin (TSST-1). This organism had developed the multidrug resistance by acquiring MEC-A gene. This account for made organism to come into the category of Superbug. Several studies showed that, the toxin production is induced by AIP and RAP via the phosphorylation of TRAP. TRAP is a 21 kDa protein and was believed to be associated with the membrane via SvrA Phosphoamino acid analysis revealed that TRAP is histidine phosphorylated in a signal transduction pathway that is activated by RAP. The inhibition of TRAP could be done by RIP (RNAIII-inhibiting peptide). The structure for RIP is still undiscovered to be used as inhibitor. Present work has been carried out to get the structural insight with various online and offline homology modeling techniques such as SWISS-MODEL, MODBASE, GENO3D, CPHmodels and I-TASSER for getting unknown structural information target of RNAIII-activating protein from Staphylococcus aureus strain MRSA252 origin for their future exploration as a target in drug discovery process against MRSA. PMID- 29494928 TI - Efficacy and safety of nilotinib 300 mg twice daily in patients with chronic myeloid leukemia in chronic phase who are intolerant to prior tyrosine kinase inhibitors: Results from the Phase IIIb ENESTswift study. AB - BACKGROUND: Some patients receiving a tyrosine kinase inhibitor (TKI) for the first-line treatment of chronic phase chronic myeloid leukemia (CML-CP) experience intolerable adverse events. Management strategies include dose adjustments, interrupting or discontinuing therapy, or switching to an alternative TKI. METHODS: This multicenter, single-arm, Phase IIIb study included CML-CP patients intolerant of, but responsive to, first-line treatment with imatinib or dasatinib. All patients were switched to nilotinib 300 mg bid for up to 24 months. The primary endpoint was achievement of MR4.5 (BCR-ABL transcript level of <=0.0032% on the International Scale) by 24 months. RESULTS: Twenty patients were enrolled in the study (16 imatinib-intolerant, 4 dasatinib intolerant); which was halted early because of low recruitment. After the switch to nilotinib 300 mg bid, MR4.5 at any time point up to month 24 was achieved in 10 of 20 patients (50%) in the full analysis set. Of the non-hematological adverse events associated with intolerance to prior imatinib or dasatinib, 74% resolved within 12 weeks of switching to nilotinib 300 mg bid. CONCLUSION: Nilotinib 300 mg bid shows minimal cross intolerance in patients with CML-CP who have prior toxicities to other TKIs and can lead to deep molecular responses. PMID- 29494929 TI - Agricultural reuse of municipal wastewater through an integral water reclamation management. AB - The DESERT-prototype, a state-of-the-art compact combination of water treatment technologies based on filtration and solar-based renewable energy, was employed to reclaim water for agricultural irrigation. Water reclaimed through the DESERT prototype (PW) from a secondary effluent of a wastewater treatment plant, as well as conventional irrigation water (CW) and the secondary effluent (SW) itself, were employed to cultivate baby romaine lettuces in a greenhouse in Murcia (Spain), by means of drip and sprinkler irrigation methods, thus establishing six treatments. Assessments of physicochemical and microbiological quality of irrigation water, as well as agronomic and microbiological quality of crops from all treatments, showed that results associated to PW complied in all cases with relevant standards and guidelines. In contrast, results linked to SW and CW presented certain non-compliance cases of water and crop microbiological quality. These assessments lead to conclude that the DESERT-prototype is an appropriate technology for safe water reclamation oriented to agricultural production, that can be complemented by a proper irrigation method in reaching safety targets. PMID- 29494930 TI - Rice-duck co-culture for reducing negative impacts of biogas slurry application in rice production systems. AB - Nitrogen (N) and phosphorus (P) losses are a potential limitation for the direct application of biogas slurry as a substitute for chemical fertilizer in irrigated rice production systems. The hypothesis was tested that a rice-duck co-culture promotes the rice N and P use efficiencies, reducing the losses of these nutrient elements through run-offs and enabling the use of biogas slurry as a substitute for chemical fertilizers. A field split-plot experiment was carried out to test the hypothesis. Our results showed that the direct application of biogas slurry was harmful for rice production. Compared with rice monoculture under chemical fertilization, biogas slurry application reduced N and P accumulation in grains, P use efficiency, and grain yield by 3.6%, 7.8%, 12.7%, and 14.8%, respectively, but increased the total N and P concentrations in the surface water 1.4- and 2.7 fold, respectively, on average on the eleventh day after fertilization. However, rice-duck co-culture compensated for the negative effects of biogas slurry on rice production. Under the biogas slurry application and in line with our hypothesis, the rice-duck co-culture significantly increased N and P accumulation and use efficiencies, as well as grain yield to levels similar to those acquired with chemical fertilization treatments. Meanwhile, total N and P concentrations were significantly lower for rice-duck co-culture than those of rice monoculture under biogas slurry application. Our results suggest that rice-duck co-culture can maintain rice yield and reduce the risks of N and P loss to local environments when utilizing biogas slurry as a substitute for chemical fertilizers. PMID- 29494931 TI - Enhanced nitrate-nitrogen removal by modified attapulgite-supported nanoscale zero-valent iron treating simulated groundwater. AB - Attapulgite (or palygorskite) is a magnesium aluminium phyllosilicate. Modified attapulgite-supported nanoscale zero-valent iron (NZVI) was created by a liquid phase reduction method and then applied for nitrate-nitrogen (NO3-N) removal (transformation) in simulated groundwater. Nanoscale zero-valent iron was sufficiently dispersed on the surface of thermally modified attapulgite. The NO3 N removal efficiency reached up to approximately 83.8% with an initial pH values of 7.0. The corresponding thermally modified attapulgite-supported nanoscale zero valent iron (TATP-NZVI) and NO3-N concentrations were 2.0 g/L and 20 mg/L respectively. Moreover, 72.1% of the water column NO3-N was converted to ammonium nitrogen (NH4-N) within 6 h. The influence of environmental boundary conditions including dissolved oxygen (DO) concentration, light illumination and water temperature on NO3-N removal was also investigated with batch experiments. The results indicated that the DO concentration greatly impacted on NO3-N removal in the TATP-NZVI-contained solution, and the NO3-N removal efficiencies were 58.5% and 83.3% with the corresponding DO concentrations of 9.0 and 0.3 mg/L after 6 h of treatment, respectively. Compared to DO concentrations, no significant (p > 0.05) effect of light illumination on NO3-N removal and NH4-N generation was detected. The water temperature also has great importance concerning NO3-N reduction, and the removal efficiency of NO3-N at 25 degrees C was 1.25 times than that at 15 degrees C. For groundwater, therefore, environmental factors such as water temperature, anaerobic conditions and darkness could influence the NO3-N removal efficiency when TATP-NZVI is present. This study also demonstrated that TATP-NZVI has the potential to be developed as a suitable material for direct remediation of NO3-N-contaminated groundwater. PMID- 29494932 TI - Anaerobic degradation of glycol ether-ethanol mixtures using EGSB and hybrid reactors: Performance comparison and ether cleavage pathway. AB - The anaerobic biodegradation of ethanol-glycol ether mixtures as 1-ethoxy-2 propanol (E2P) and 1-methoxy-2-propanol (M2P), widely used in printing facilities, was investigated by means of two laboratory-scale anaerobic bioreactors at 25oC: an expanded granular sludge bed (EGSB) reactor and an anaerobic hybrid reactor (AHR), which incorporated a packed bed to improve biomass retention. Despite AHR showed almost half of solid leakages compared to EGSB, both reactors obtained practically the same performance for the operating conditions studied with global removal efficiencies (REs) higher than 92% for organic loading rates (OLRs) as high as 54 kg of chemical oxygen demand (COD) m-3 d-1 (REs of 70% and 100% for OLRs of 10.6 and 8.3 kg COD m-3 d-1 for E2P and M2P, respectively). Identified byproducts allowed clarifying the anaerobic degradation pathways of these glycol ethers. Thus, this study shows that anaerobic scrubber can be a feasible treatment for printing emissions. PMID- 29494933 TI - Preparation, characterisation and critical flux determination of graphene oxide blended polysulfone (PSf) membranes in an MBR system. AB - Microfiltration membranes having different blends of graphene-oxide (GO) (0-1 wt%) and Polysulfone (PSf) (15-20 wt%) were prepared using the classical non solvent induced phase inversion process. The prepared membranes were characterised for their structural morphology, surface properties, mechanical strength, porosity and pure water flux. Based on the initial characterisation results, four membranes (15 wt% PSf, 15 wt% PSf + 0.25 wt% GO, 15 wt% PSf + 1 wt% GO and 20 wt% PSf + 1 wt% GO) were chosen for critical flux study, that was conducted using flux-step method in a lab scale MBR system. In order to study the application potential of GO blended membranes, the critical flux of each membrane was evaluated in two operational modes i.e., continuous and intermittent modes with backwash. The membranes with maximal GO concentration (15 wt% PSf + 1 wt% GO and 20 wt% PSf + 1 wt% GO) showed higher critical flux (16.5, 12.8 L/m2h and 19, 15 L/m2h for continuous and intermittent mode, respectively). It was observed that the operational modes did not have a significant effect on the critical flux of the membranes with low GO concentration (15 wt% PSf and 15 wt% PSf + 0.25 wt% GO), indicating a minimal of 1 wt% GO was required for an observable effect that favoured intermittent mode of operation. Through these results, ideal operating condition was arrived (i.e., flux maintained at 6.4 L/m2h operated under intermittent mode) and the membranes 15 wt% PSf and 15 wt% PSf + 1 wt% GO were studied for their long-term operation. The positive effect of GO on filtration time, cleaning frequency and against fouling was demonstrated through long term TMP profile of the membranes, indicating the suitability of GO blended membrane for real time wastewater treatment. PMID- 29494934 TI - Evaluating the influence of pH adjustment on chemical purification efficiency and the suitability of industrial by-products as alkaline agents. AB - Metal salts of iron are currently used in several treatment facilities purifying peat extraction runoff water. Although chemical purification is considered best available technology for the treatment of this natural humic water, fluctuations in purification efficiency occur with low pH (3-4) and high metal concentration found in treated waters. The need for pH neutralisation increases the costs and overall environmental impacts related to chemical purification. The use of industrial by-products can decrease costs while supporting the sustainable use of natural resources and the principle of a circular economy. This study investigated the suitability of a range of calcium-based alkaline products (including by-products of the paper, cement and mineral industries) for neutralisation of chemically treated runoff water. The influence of the time of pH adjustment relative to time of coagulant addition (before coagulant, after but within coagulation, during flocculation and after sedimentation) on purification efficiency was evaluated. The hypotheses that the physical form of the coagulant was a relevant factor affecting purification was also assessed. The best performing pH-adjusting products were cement kiln dust (CaO and SiO2) and Mahtikalkki (Ca(OH)2, CaCO3 and CaO), by-products of the cement and paper industry, respectively. Time of pH adjustment in relation to time of coagulation addition had a significant influence on purification efficiency, especially when solid coagulant was used. Adjustment of pH at 30 s before coagulant dosing resulted in a negative effect on treatment results. Based on results obtained, suitable points of pH adjustment are during the flocculation stage or at the outlet of sedimentation, particularly if solid coagulants are used. PMID- 29494936 TI - Airborne gamma-ray spectra processing: Extracting photopeaks. AB - The acquisition of information from the airborne gamma-ray spectra is based on the ability to evaluate photopeak areas in regular spectra from natural and other sources. In airborne gamma-ray spectrometry, extraction of photopeaks of radionuclides from regular one-second spectra is a complex problem. In the region of higher energies, difficulties are associated with low signal level, i.e. low count rates, whereas at lower energies difficulties are associated with high noises due to a high signal level. In this article, a new procedure is proposed for processing the measured spectra up to and including the extraction of evident photopeaks. The procedure consists of reducing the noise in the energy channels along the flight lines, transforming the spectra into the spectra of equal resolution, removing the background from each spectrum, sharpening the details, and transforming the spectra back to the original energy scale. The resulting spectra are better suited for examining and using the photopeaks. No assumptions are required regarding the number, locations, and magnitudes of photopeaks. The procedure does not generate negative photopeaks. The resolution of the spectrometer is used for the purpose. The proposed methodology, apparently, will contribute also to study environmental problems, soil characterization, and other near-surface geophysical methods. PMID- 29494935 TI - A review of mobile apps for epilepsy self-management. AB - Mobile health app developers increasingly are interested in supporting the daily self-care of people with chronic conditions. The purpose of this study was to review mobile applications (apps) to promote epilepsy self-management. It investigates the following: 1) the available mobile apps for epilepsy, 2) how these apps support patient education and self-management (SM), and 3) their usefulness in supporting management of epilepsy. We conducted the review in Fall 2017 and assessed apps on the Apple App Store that related to the terms "epilepsy" and "seizure". Inclusion criteria included apps (adult and pediatric) that, as follows, were: 1) developed for patients or the community; 2) made available in English, and 3) less than $5.00. Exclusion criteria included apps that were designed for dissemination of publications, focused on healthcare providers, or were available in other languages. The search resulted in 149 apps, of which 20 met the selection criteria. A team reviewed each app in terms of three sets of criteria: 1) epilepsy-specific descriptions and SM categories employed by the apps and 2) Mobile App Rating Scale (MARS) subdomain scores for reviewing engagement, functionality, esthetics, and information; and 3) behavioral change techniques. Most apps were for adults and free. Common SM domains for the apps were treatment, seizure tracking, response, and safety. A number of epilepsy apps existed, but many offered similar functionalities and incorporated few SM domains. The findings underline the need for mobile apps to cover broader domains of SM and behavioral change techniques and to be evaluated for outcomes. PMID- 29494937 TI - Review of reduction factors by buildings for gamma radiation from radiocaesium deposited on the ground due to fallout. AB - In order to estimate residents' external dose due to radionuclide exposure resulting from fallout deposit on the ground, the shielding and dose reduction effects provided by structures such as houses and workplaces are taken into account as most individuals spend a large portion of their time indoors. Many works on both calculation and measurement for European and American settlements have been reported and factors such as, shielding factors, protection factors, reduction factors, and location factors have been determined. However, measurement data for Japanese settlements are lacking. Thus, the Japanese government used reduction factors given in the International Atomic Energy Agency documents from American and European settlements when Fukushima Dai-ichi Nuclear Power Plant (FDNPP) accident occurred. The United Nations Scientific Committee on the Effects of Atomic Radiation used location factors from European settlements for the same reason. Soon after the FDNPP accident, several measurements and calculations were performed to obtain specific reduction factors for Japanese settlements due to this lack of data. This research reviews previous studies that determined factors such as, shielding factors, protection factors, reduction factors, and location factors and summarizes specific results for Japan. We discuss the issues in determining these factors and in applying them to estimate indoor dose. The contribution of surface contamination to the indoor ambient dose equivalent rate is also discussed. PMID- 29494938 TI - The good wife - A television series suitable for life review psychotherapy, guided by nurses: Big ideas. PMID- 29494939 TI - Reliability and validity of the student stress inventory-stress manifestations questionnaire and its association with personal and academic factors in university students. AB - BACKGROUND: Stress affects us in every environment and it is also present in the educational sphere. Previous studies have reported a high prevalence of stress in university students. The Student Stress Inventory-Stress Manifestations (SSI-SM), identify stressors and evaluate stress manifestations in adolescents but its validity in university students remains uncertain. OBJECTIVES: We aimed to determine the internal consistency and validity of an adapted version of the Student Stress Inventory-Stress Manifestations (SSI-SM) for university students and to investigate if high stress levels are associated with personal and academic factors. DESIGN AND METHODS: In this quantitative, descriptive, cross sectional study, we included 115 university students of the Nursing Degree during the second semester of the 2014/2015 academic year. Information about personal issues, lifestyle and academic performance was recorded and the stress was evaluated with the SSI-SM questionnaire. The internal consistency and homogeneity of the SSI-SM questionnaire was tested and a factorial analysis was performed. RESULTS: After the homogeneity analysis, the final version of the SSI-SM questionnaire included 19 items, with a Cronbach's alpha of 0.924. In the factorial analysis, 4 factors were found ('Self-concept', 'Sociability', 'Uncertainty' and 'Somatization'; all Cronbach's alpha >0.700). Students with higher values on the SSI-SM were, in overall, women (41.0 +/- 12.7 vs. 33.2 +/- 9.5; p = 0.001) and had significantly more family conflicts (47.6 +/- 13.8 vs. 35.2 +/- 9.6; p < 0.001), consumed less alcohol (R = -0.184, p = 0.048), slept less hours (R = -0.193, p = 0.038) and had worse academic performance in Clinical Nursing (36.3 +/- 10.4 vs. 41.2 +/- 13.3, p = 0.039). CONCLUSIONS: After exclude three items of the original SSI-SM, higher scores in the SSI-SM are correlated with stress level in a cohort of university students of the Nursing Degree. Family conflicts, female gender, absence of alcohol consumption, few sleep hours and poor academic performance are associated with higher stress levels. PMID- 29494940 TI - Mental health nurses' views and experiences of working with undergraduate nursing students: A descriptive exploratory study. AB - BACKGROUND: The core of pre-registration nursing education is the learning that takes place during the clinical placement. However, despite the fact that registered nurse preceptors are key players in supporting students during their placements there is a lack of literature examining the views of preceptors working with nursing students in mental health settings. OBJECTIVES: To explore mental health nurses' views and experiences of working with undergraduate nursing students and determine what factors influence this experience. DESIGN: A descriptive exploratory study approach using an on-line questionnaire was adopted for this study. SETTINGS: A specialist mental health service (SMHS) within one District Health Board in New Zealand. PARTICIPANTS: 89 registered nurses who had been involved in working with nursing students participated in this study. METHODS: Data was collected using an online questionnaire. RESULTS: The majority of the respondents in this study reported that they felt confident and well supported in the work they did with nursing students and had a positive perception of this role. However, one significant negative factor identified was the extra stress and workload pressure they reported when working with students, when no allowance was made for this. Another key finding was that engaging in some form of education related to the preceptorship role was positively correlated with nurses knowing what was required of them, feeling confident, the extent to which they planned clinical education, and feeling that they were sufficiently appreciated. CONCLUSIONS: Ensuring nurses have access to education related to clinical teaching and learning increases their confidence in the work they do with nursing students and has also been shown to have a positive impact on how they view this role. PMID- 29494942 TI - A Monte Carlo investigation of the dose distribution for 60Co high dose rate brachytherapy source in water and in different media. AB - In this study, the dosimetric characterization for The BEBIG 60Co High Dose Rate (HDR) brachytherapy source model Co0.A86 was investigated and the validity of the EGS5 Monte Carlo code to reproduce the dosimetric parameters in water phantom was checked. In addition, the dose distribution for different tissue phantoms was calculated. The BEBIG 60Co HDR brachytherapy source was modeled using EGS5 Monte Carlo simulation code. A description of the source design, geometry and materials used in this work were provided. According to the update TG43-U1 formalism of AAPM, the air kerma strength, the dose rate constant, 2D rectangular dose distribution in water were calculated, moreover, the results of the radial dose function were obtained in water and different tissue phantoms; bone, lung, adipose tissue, breast and muscle. The obtained results were tabulated and presented in graphical formats for the comparison with available data. The calculated value of the air kerma strength of this study, 3.0419 U Bq-1, agree well with that of the other Monte Carlo calculation. The 2D look-up along-away rectangular dose were obtained in water, the results were similar to the published data for all distances larger than 1 cm, for the distances near to the source region on the transversal source axis small differences are apparent. The radial dose function were presented in graphical format for the comparison between the dose distribution in water and different tissue phantoms. The EGS5 results obtained in this study shows good consistency with the published data for the dosimetric parameters of the of the BEBIG 60Co HDR brachytherapy source. It seems that the radial dose function calculated in water differed in tissue phantoms due to the atomic composition and densities for media that are not taken account by the TG43-U1 formalism. PMID- 29494941 TI - Physical function impairment in survivors of critical illness in an ICU Recovery Clinic. AB - PURPOSE: The aims were to 1) determine feasibility of measuring physical function in our ICU Recovery Clinic (RC), 2) determine if physical function was associated with 6-month re-hospitalization and 1-year mortality and 3) compare ICU survivors' physical function to other comorbid populations. MATERIALS AND METHODS: We established the Wake Forest ICU RC. Patients were seen in clinic 1month following hospital discharge. Testing included the Short Form-36 questionnaire and Short Physical Performance Battery (SPPB). We related these measures to 6month re-hospitalizations and 1year mortality, and compared patients' functional performance with other comorbid populations. RESULTS: Thirty six patients were seen in clinic from July 2014 to June 2015; the median SPPB score was 5 (IQR 5). The median SF-36 physical component summary score was 21.8 (IQR 28.8). Mortality was 14% at 1year. Of those who did not die by 1year, 35% were readmitted to our hospital within 6months of hospital discharge. SPPB scores demonstrated a non-significant trend with both mortality (p=0.06) and readmissions (p=0.09). ICU survivors' SPPB scores were significantly lower than those of other chronically ill populations (p<0.001). CONCLUSIONS: Physical function measurement in a recovery clinic is feasible and may inform subsequent morbidity and mortality. PMID- 29494943 TI - Synthesis and dosimetry features of novel sensitive thermoluminescent phosphor of LiF doped with Mg and Dy impurities. AB - Lithium fluoride doped with Mg and Dy was fabricated for the first time using melting method. The optimum concentrations of impurities and thermal treatment were studied to achieve high thermoluminescence (TL) sensitivity. TL sensitivity of the fabricated phosphor is close to that of TLD-100 powder. Tm-Tstop technique was used to identify the number of overlapped TL glow peaks. Initial rise, isothermal decay and computerized glow curve deconvolution (CGCD) methods were applied to obtain kinetic parameters of the prepared TL material. Three component glow peaks were distinguished at temperatures 395, 448 and 510 K. Other TL properties such as fading, linearity of dose response and reusability are also presented and discussed. PMID- 29494944 TI - Optical and thermal pre-readout treatments to reduce the influence of fading on LiMgPO4 OSL measurements. AB - TL (Thermoluminescent) and OSL (Optically Stimulated Luminescence) techniques are both luminescent techniques widely applied in several areas into radiation dosimetry. The main difference between them are related to the employed stimulus (thermal or optical) for luminescent emission, as well as the advantages of each technique. Due to simplicity and not to be required heating, the OSL technique has been continuously improved and new researches in materials to be used with this technique have grown in the last decades. Nowadays the main problems in the application of the developed new materials are the poor stability and loss of OSL signal over time (fading). In this study, we performed a sequence of thermal (preheat) and optical (OSL with infra-red light stimulus) pre-readout treatments immediately before OSL readouts of LiMgPO4 based detectors (LMP), aiming the applicability of novel materials, contributing to find solutions to minimize the influence of fading. Moreover, it was demonstrated that the influence of fading is minimized and the stability of OSL signal from LMP is achieved using just optical process, without heating the material. PMID- 29494945 TI - Changes in community structure of active protistan assemblages from the lower Pearl River to coastal Waters of the South China Sea. AB - Protists make up an important component of aquatic ecosystems, playing crucial roles in biogeochemical processes on local and global scales. To reveal the changes of diversity and community structure of protists along the salinity gradients, community compositions of active protistan assemblages were characterized along a transect from the lower Pearl River estuary to the open waters of the South China Sea (SCS), using high-throughput sequencing of the hyper-variable V9 regions of 18S rRNA. This study showed that the alpha diversity of protists, both in the freshwater and in the coastal SCS stations was higher than that in the estuary. The protist community structure also changed along the salinity gradient. The relative sequence abundance of Stramenopiles was highest at stations with lower salinity and decreased with the increasing of salinity. By contrast, the contributions of Alveolata, Hacrobia and Rhizaria to the protistan communities generally increased with the increasing of salinity. The composition of the active protistan community was strongly correlated with salinity, indicating that salinity was the dominant factor among measured environmental parameters affecting protistan community composition and structure. PMID- 29494946 TI - Influence of microplastics on the toxicity of the pharmaceuticals procainamide and doxycycline on the marine microalgae Tetraselmis chuii. AB - Microplastics and pharmaceuticals are considered ubiquitous and emergent pollutants of high concern but the knowledge on their effects on primary producers is still limited, especially those caused by mixtures. Thus, the goal of the present study was to investigate if the presence of microplastics (1-5 MUm diameter) influences the toxicity of the pharmaceuticals procainamide and doxycycline to the marine microalga Tetraselmis chuii. Bioassays (96 h) to investigate the toxicity of those substances individually and in mixtures (i.e. microplastics-procainamide mixtures and microplastics-doxycycline mixtures) were carried out. Effect criteria were the average specific growth rate (growth rate) and chlorophyll a concentration (chlorophyll). EC10, EC20 and EC50 were determined. Microplastics alone had no significant effects on growth rate up to 41.5 mg/l, whereas chlorophyll was significantly reduced at 0.9 and 2.1 mg/l of microplastics, but not at higher concentrations. The 96 h EC50 (growth rate and chlorophyll, respectively) determined for the other bioassays were: 104 and 143 mg/l for procainamide alone; 125 and 31 mg/l for procainamide in the presence of microplastics; 22 and 14 mg/l for doxycycline alone; 11 and 7 mg/l for doxycycline in the presence of microplastics. Significant differences (p < 0.001) between the toxicity curves of each pharmaceutical alone and in mixture with microplastics were found for procainamide (chlorophyll), and doxycycline (both parameters). Thus, both pharmaceuticals were toxic to T. chuii in the low ppm range, and microplastics-pharmaceutical mixtures were more toxic than the pharmaceuticals alone. Very high decreases of doxycycline concentrations in test media were found, indicating degradation of the antibiotic. Thus, although the biological results are expressed in relation to doxycycline concentration, the effects were likely caused by a mixture of the parental compound and its degradation products. The concentrations of microplastics and pharmaceuticals tested (low ppm range) are higher than those expected to be found in waters of the most part of marine ecosystems (ppt or ppb ranges). However, considering the widespread contamination by microplastics and pharmaceuticals, the concentrations already found in waters, sediments and/or organism of heavily polluted areas, the long-term exposure (over generations) of wild populations to such substances in polluted ecosystems and the possibilities of bioaccumulation and toxicological interactions, these findings are of concern and further research on microplastics pharmaceuticals toxicological interactions is needed. PMID- 29494947 TI - Influence of age at onset on the course and outcome of bipolar I disorder: Findings from a retrospective study. PMID- 29494948 TI - The Chemokine Receptor CXCR4 and c-MET Cooperatively Promote Epithelial Mesenchymal Transition in Gastric Cancer Cells. AB - The C-X-C motif chemokine receptor 4 (CXCR4) pathway can promote tumor metastasis but is dependent on cross talk with other signaling pathways. The MET proto oncogene (c-MET) participates in metastasis and is highly expressed in gastric cancer. However, the relationship between CXCR4 and c-MET signaling and their mechanisms of action in gastric cancer metastasis remain unclear. In this study, in vitro experiments demonstrated that C-X-C motif chemokine ligand 12 (CXCL12)/CXCR4 induces epithelial-mesenchymal transition (EMT) and promotes migration in gastric cancer cells, which is accompanied by c-MET activation. These phenomena were reversed by c-MET inhibition. Further investigation revealed that c-MET activation correlated with its interaction with caveolin 1 in lipid rafts, induced by CXCL12. In clinical samples, we observed a significant positive association between CXCR4 expression and c-MET phosphorylation (r = 0.259, P = .005). Moreover, samples expressing both receptors were found to indicate significantly poorer patient prognosis (P < .001). These results suggest that CXCL12 induces EMT at least partially through cross talk between CXCR4 and c-MET signaling. In addition, changes in these pathways could have clinical importance for the treatment of gastric cancer. PMID- 29494949 TI - Usefulness of unenhanced post mortem computed tomography - Findings in postmortem non-contrast computed tomography of the head, neck and spine compared to traditional medicolegal autopsy. AB - INTRODUCTION/BACKGROUND: Post-mortem CT (PMCT) is becoming an essential tool available to forensic pathologists worldwide, but its validity with respect to evidence for legal purposes still requires more comprehensive large-scale studies, comparing PMCT to autopsy. This article compares PMCT and autopsy findings of the head, neck, and spine during a period of five years. MATERIALS AND METHODS: The study included 203 cases for which both autopsy and PMCT were performed. All relevant findings were extracted from the reports and divided into 30 categories based on anatomical location and tissue characteristics. Data were evaluated quantitatively in a binary fashion. RESULTS/FINDINGS: A high level of agreement was noted for skull fractures, intraventricular- and subarachnoid hemorrhages, bullet trajectories, and intracranial shrapnel. A fair correlation was demonstrated for brain atrophy or herniation, and findings in the facial soft tissues. PMCT had higher sensitivity to brain edema, presence of gas in tissues or cavities, and findings in the spinal column and spinal canal, whereas autopsy better demonstrated pathologies in the brain tissue, hemorrhages in the neck and fractures of the larynx and hyoid bone. A relatively low correlation was noted for subdural and epidural hematomata. CONCLUSIONS/INTERPRETATION: For several locations, structures, and specific findings in the head, neck and spine, autopsy remains indispensable. However, PMCT better demonstrated some findings in locations that are difficult to access by autopsy, or structures that might be damaged due to autopsy procedure. For the examinations of these, PMCT may in specific cases serve as an alternative to autopsy. Generally, however, due to the vast and fundamental differences that distinguish each case from the next, and the different purposes that autopsy may serve, we propose that the decision as to which method (or a combination of both) should be used, be made according to the circumstances and expected findings of each case. PMID- 29494950 TI - Clinical decision making in the emergency department setting using rapid PCR: Results of the CLADE study group. AB - BACKGROUND: Emergency Departments (ED) are challenged during influenza season by patients who present acutely during sporadic ED visits. ED management is largely empiric, often occurring without reliable diagnostics needed for targeted therapies, safe outpatient discharge, or hospital admissions. OBJECTIVE: To evaluate the impact of the influenza diagnosis on physician decision making during ED visits using the Cobas Liat(r) influenza A + B assay. STUDY DESIGN: Prospective study assessing the impact of rapid (<30 min), reverse-transcriptase polymerase chain reaction (RT-PCR) influenza testing on physician decision making in the ED. Physician responses established pre-and post-diagnosis management courses which required confirmation via secondary documentation in the medical record. Changes in physician decision making were analyzed across four clinical touchpoints: (i) admission/discharge status, (ii) medical procedures, (iii) antiviral and antibiotic prescribing, and (iv) laboratory studies. RESULTS: An influenza diagnosis changed patient management courses, relative to empiric, pre diagnosis plans, in in 61% of the cases resulting in cost savings of $49,420-to $42,270 over 143 patients and 104 days during influenza season resulting in a cost savings of $200.40/ED visit. Evaluation over 2000 ED patient visits projects cost savings > $578,000 due to deferred admissions, and reduction in antiviral prescribing. Sensitivity of ED-based influenza testing using the Cobas Liat(r) assay was equivalent to centralized lab testing at 98.8% sensitivity and 98.5% specificity respectively. CONCLUSION: Providing rapid, RT-PCR influenza testing to ED settings is actionable and used to guide patient care decisions. Understanding the cascade of events linked to the influenza diagnosis in the ED provides overall cost savings which offset the cost of providing ED-based testing. PMID- 29494951 TI - Human CD134 (OX40) expressed on T cells plays a key role for human herpesvirus 6B replication after allogeneic hematopoietic stem cell transplantation. AB - BACKGROUND: CD134 (OX40), which is a cellular receptor for human herpesvirus-6B (HHV-6B) and expresses on activated T cells, may play a key role for HHV-6B replication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). OBJECTIVES: Therefore, we examined the CD134 expression on T cells and HHV-6B replication after allo-HSCT, and analyzed the correlation between them. STUDY DESIGN: Twenty-three patients after allo-HSCT were enrolled. The percentages of CD134-positive cells within the CD4+ and CD8+ cell populations were measured by flow cytometry, and the viral copy number of HHV-6B was simultaneously quantified by real-time PCR. The correlation between CD134 and HHV-6B viral load was then statistically analyzed. RESULTS: HHV-6B reactivation occurred in 11 of 23 patients (47.8%). CD134 expression was seen on T cells and was coincident with the time of peak viral load. The percentage of CD134-positive cells decreased significantly when HHV-6B DNA disappeared (p = .005 in CD4+ T cells, p = .02 in CD8+ T cells). In the 4 patients who underwent umbilical cord blood transplantation (UCBT), the viral load varied with the percentage of CD134 positive cells. In the comparison between the HHV-6B reactivation group and non reactivation group, maximum percentages of CD134-positive cells among CD4+ T cells in reactivation group were significantly higher than those in non reactivation group (p = .04). CONCLUSIONS: This is the first study to show that a correlation of CD134 expression on T cells with HHV-6B replication after allo HSCT, especially in UCBT. The results possibly indicate that CD134 on T cells plays a key role for HHV-6B replication after allo-HSCT. PMID- 29494953 TI - To mirror or not to mirror upon mutual gaze, oxytocin can pave the way: A cross over randomized placebo-controlled trial. AB - The eyes constitute a highly salient cue to communicate social intent. Previous research showed that direct eye contact between two individuals can readily evoke an increased propensity to 'mirror' other peoples' actions. Considering the implicated role of the prosocial neuropeptide oxytocin (OXT) in enhancing the saliency of social cues and modulating approach/avoidance motivational tendencies, the current study adopted the non-invasive brain stimulation technique transcranial magnetic stimulation (TMS) to explore whether a single dose of intranasal OXT (24 IU) modulated (enhanced) a person's propensity to show heightened mirroring or motor resonance upon salient social cues, such as eye contact. The study involved a double-blind, placebo-controlled, cross-over trial with twenty-seven healthy adult men (19-32 y). By applying single-pulse TMS over the primary motor cortex during movement observation, it was shown that motor resonance was significantly higher when movement observation was accompanied by direct, compared to averted gaze, but that a single dose of OXT did not uniformly enhance this effect. Significant moderations of the treatment effect were noted however, indicating that participants with high self-reports of attachment avoidance displayed a stronger OXT-treatment effect (enhancement of motor resonance upon direct eye contact), compared to participants with low attachment avoidance. Particularly, while participants with high attachment avoidance initially displayed a reduced propensity to increase their motor resonance upon direct eye contact, a single dose of OXT was able to promote an otherwise avoidant individual's propensity to engage in motor resonance upon a salient social cue such as eye contact. PMID- 29494952 TI - Association of psychosocial stressors with metabolic syndrome severity among African Americans in the Jackson Heart Study. AB - INTRODUCTION: Using Jackson Heart Study (JHS) data, we assessed the association between perceived psychosocial stressors and metabolic syndrome (MetS) severity in African American adults. METHODS: Participants included 3870 African American JHS participants aged 21-95 years (63.1% women; mean age 53.8 +/- 13.0). Psychosocial stressors assessed included: major life events (MLEs); global stress; and weekly stress inventory. Each stress measure was classified into tertiles (low, medium, and high). Associations of psychosocial stressors with a sex- and race/ethnic-specific MetS severity Z-score were examined after adjustment for demographics and MetS risk factors (i.e., nutrition, physical activity, smoking status, and alcohol consumption). RESULTS: Independent of lifestyle factors, participants who reported high (versus low) perceived global stress and MLEs had significantly greater MetS severity (p = .0207 and p = .0105, respectively). Weekly stress was not associated with MetS severity. Compared to men, women reported significantly higher global stress and MLEs (p < 0.0001). A significant interaction between sex and MLEs (p = .0456) demonstrated men significantly increased their MetS severity at medium levels of stress, whereas women's MetS severity was significantly increased at high levels of MLEs. CONCLUSIONS: In the total sample, higher reported global stress and MLEs were associated with increased risk of MetS severity, while weekly stress was not. Men's and women's stress responses to MLEs were differentially associated with MetS severity, with male MetS severity increasing significantly at lower levels of MLEs relative to women's MetS severity. These data may have implications for targeting stress-related factors in interventions to improve cardiometabolic health in African American adults. PMID- 29494954 TI - Poly(acrylic acid)-grafted magnetite nanoparticle conjugated with pyrrolidinyl peptide nucleic acid for specific adsorption with real DNA. AB - Magnetite nanoparticle conjugated with pyrrolidinyl peptide nucleic acid (MNP@PNA) was synthesized for use as both a magnetic nano-support and a probe for specific adsorption with complementary deoxyribonucleic acid (DNA). MNP@PNA with the size ranging between 120 and 170 nm in diameter was prepared via a free radical polymerization of acrylic acid in the presence of acrylamide-grafted MNP to obtain negatively charged magnetic nanoclusters, followed by ionic adsorption with PNA. According to fluorescence spectrophotometry and gel electrophoresis, this MNP@PNA can differentiate between fully matched, single-base mismatched and fully mismatched synthetic DNAs tagged with different fluorophores. UV-vis spectrophotometry and gel electrophoresis indicated that MNP@PNA can be used for specific adsorption with real DNA (zein gene of maize) having complementary sequence with the PNA probe. This novel anionic MNP conjugated with the PNA probe might be potentially applicable for use as a magnetic support for DNA base discrimination and might be a promising tool for testing genetic modification. PMID- 29494955 TI - Viral vector mimicking and nucleus targeted nanoparticles based on dexamethasone polyethylenimine nanoliposomes: Preparation and evaluation of transfection efficiency. AB - Non-viral vectors such as polymers and liposomes have been used as gene delivery systems to overcome intrinsic problems of viral vectors, but transfection efficiency of these vectors is lower than viral vectors. In the present study, we tried to design non-viral gene delivery vectors that mimic the viral vectors using the benefits of both cationic liposomes and cationic polymer vectors along with targeting glucocorticoid receptors to enhance cellular trafficking of vectors. Cationic liposomes containing DOTAP and cholesterol were prepared by thin-film hydration following extrusion method. Dexamethasone mesylate was synthesized and then conjugated to polyethylenimine through a one-step reaction. A novel gene delivery system, Lipopolyplex was developed by premixing liposome and different molecular weight of bPEI-Dexa as carriers followed by addition of plasmid at three different carrier/pDNA (C/P) weight ratios. The resulted complexes were characterized for their size, zeta potential and ability of DNA condensation. Transfection efficiency of vectors in neuro2A was determined by Luciferase reporter gene assay. Also, the toxicity of gene carriers was investigated in this cell line. Mean particle size of prepared complexes was less than 200 nm and there was no significant difference in their size by increasing the molecular weight of PEIs. All complexes had positive surface charge. Complete condensation of DNA was occurred at C/P ratio of one for all complexes. Lipopolyplexes were more efficient than polyplexes and lipoplexes alone and transfection efficiency was improved by adding dexamethasone. The complexes containing liposome, PEI 10 kDa and dexamethasone (PEI10:Lipo:Dexa(0.05)) had the highest transfection activity about 40-fold and 3.6-fold in comparison with PEI10 and PEI10:Lipo, respectively. Furthermore, the non-viral vectors described in this study showed low cytotoxicity. The results of this study confirmed that PEI in combination with liposome forms lipopolyplex with low toxicity and enhanced transfection efficiency. Moreover, using dexamethasone, in combination with lipopolyplex might be useful to increase the gene delivery potential of these lipopolyplexes. PMID- 29494956 TI - MiR-133a/133b inhibits Treg differentiation in IgA nephropathy through targeting FOXP3. AB - OBJECTIVE: The aim of this study was to investigate the effect of miR-133a and miR-133b on regulatory T cell (Treg) differentiation in IgA nephropathy (IgAN) through targeting forkhead box P3 (FOXP3). METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from IgAN patients (n = 20) and healthy controls (n = 20). Percentage of Tregs defined as CD4 + CD25 + FOXP3 + T cells were determined by flow cytometry. The mRNA expression levels of miR-133a, miR-133b and FOXP3 were measured by real-time PCR. FOXP3 protein level was analyzed by western blotting. RESULTS: Tregs percentage in PBMCs of IgAN patients was significantly lower than that of healthy controls, whereas the expression levels of miR-133a and miR-133b in IgAN patients were dramatically higher than that in the control group. Treg percentage was negatively correlated with miR-133a and miR-133b expressions. Meanwhile, miR-133a and miR-133b modulated FOXP3 expression by detecting of its gene 3'-untranslated region. MiR-133a or miR-133b overexpression significantly decreased the % Tregs (CD4 + CD25 + FOXP3+) of the total CD4 + T cells while miR-133a or miR-133b knockdown led to an opposite effect. Moreover, FOXP3 levels in IgAN patients was significantly lower than that in the control group and was negatively correlated with miR-133a and miR-133b expression. CONCLUSION: MiR-133a and miR-133b inhibited Treg differentiation in IgA nephropathy through targeting FOXP3. PMID- 29494957 TI - Polysaccharide isolated from Aloe vera gel suppresses ovalbumin-induced food allergy through inhibition of Th2 immunity in mice. AB - An allergic reaction occurs when the immune system overreacts to harmless substance called allergen that gains access to the body. Food allergy is a hypersensitive immune reaction to food proteins and the number of patients with food allergy has recently increased. Aloe Vera is used for wellness and medicinal purposes. In particular, Aloe vera has been reported to enhance immunity. However, the effect of Aloe vera on food allergy is not yet known. In this study, we investigated the effects of processed Aloe vera gel (PAG) containing low molecular weight Aloe polysaccharide (AP) on ovalbumin (OVA)-induced food allergy in mice. Allergic symptoms, rectal temperature, and diarrhea were measured in OVA induced food allergy mice. Other allergic parameters were also analyzed by RT PCR, ELISA, flow cytometry, and other biochemical methods. As the results, PAG suppressed the decrease of body temperature, diarrhea, and allergic symptoms in OVA-induced food allergy mice. PAG also reduced serum concentrations of type 2 helper T cell (Th2) cytokines (Interleukin-(IL)-4, IL-5, and IL-13) as well as histamine, mast cell protease-1 (MCP-1), and immunoglobulin (Ig)E. PAG blocked the degranulation of mast cells and infiltration of eosinophils in intestine. Furthermore, PAG suppressed the population of Th2 cells in spleen and mesenteric lymph nodes. PAG also increased the production of IL-10 and population of type 1 regulatory T (Tr1) cells in mice with food allergy. Taken together, our findings suggest that PAG suppressed Th2 immune responses through, at least partially, stimulating the secretion of IL-10 in food allergy mice. PMID- 29494958 TI - Abiraterone acetate in the treatment of prostate cancer. AB - Among all cancer-related death, prostate cancer accounts for the second prominent reason for cancer-associated death in men. Despite the castration mediated reduction in testosterone synthesis, adrenal glands, as well as tissues of prostate cancer, continue to produce androgens, which ultimately lead to the growth of prostate cancer. This phase is referred as metastatic castration resistant prostate cancer, which throws an obstacle to treatment. Androgen antagonists, in addition to deprivation of hormone, is being used for reducing the level of prostate-specific antigen but has not successfully come in front as a choice for prolonging the life of patients suffering from prostate cancer. In this prevailing scenario, abiraterone acetate (AA) has proved to be a boon for patients suffering from prostate cancer. AA selectively inhibits the actions of enzymes C17, 20-lyase and 17alpha-hydroxylase on cytochrome P450 (CYP) 17 when administered orally. The signaling of androgen receptor, being important for primary to metastatic phases of prostate cancer, CYP17 is essential for the synthesis of androgen. Herein, the in-detail pharmacological profile of AA, including androgen signaling, mechanism of action of AA, mechanism of AA resistance, pharmacokinetics, latest clinical findings, predictive markers, optimal treatment sequence, toxicity, and food interaction profiles have been reviewed. PMID- 29494959 TI - Up-regulated MiR-27-3p promotes the G1-S phase transition by targeting inhibitor of growth family member 5 in osteosarcoma. AB - OBJECTIVE: MicroRNAs (miRNAs) play an essential role in regulating malignant progression of tumour cells by inhibiting translation or stability of messenger RNA. However, the expression pattern and regulatory mechanism of miR-27-3p in osteosarcoma remains unclear. METHODS: We examined the expression of miR-27-3p in 5 osteosarcoma cell lines compared with that in 2 normal osteocyte cell lines. Osteosarcoma cells U-2OS and MG-63 were transduced to up-regulate or down regulate the expression of miR-27-3p. The 3-(4, 5-Dimethyl-2-thiazolyl)-2, 5 diphenyl-2H-tetrazolium bromide, or MTT, assay, colony formation assays, BrdUrd labelling, immunofluorescence, anchorage-independent growth ability assay and flow cytometry analysis were used to test the effect of miR-27-3p. Luciferase assays were added to verify the direct relationship between miR-27-3p and the predicted target gene inhibitor of growth family member 5 (ING5). RESULTS: The expression of miR-27-3p was significantly increased in examined osteosarcoma cell lines compared with that in normal osteocyte cell lines. Up-regulation of miR-27 3p significantly accelerated osteosarcoma cell growth via promoting G1-S transition. In addition, the opposite result was observed in miR-27-3p-down regulated cells. Up-regulation of ING5 significantly attenuated the miR-27-3p induced proliferation in osteosarcoma cells. CONCLUSIONS: These data suggested that miR-27-3p could promote the G1-S phase transition that leads to proliferation by down-regulating the expression of ING5 in osteosarcoma. PMID- 29494960 TI - Prevention of doxorubicin (DOX)-induced genotoxicity and cardiotoxicity: Effect of plant derived small molecule indole-3-carbinol (I3C) on oxidative stress and inflammation. AB - Doxorubicin (DOX) is an anthracycline group of antibiotic available for the treatment of broad spectrum of human cancers. However, patient receiving DOX therapy, myelosuppression and genotoxicity which may lead to secondary malignancy and dose dependent cardiotoxicity is an imperative adverse effect. Mechanisms behind the DOX-induced toxicities are increased level of oxidative damage, inflammation and apoptosis. Therefore, in search of a potential chemoprotectant, naturally occurring glucosinolate breakdown product Indole-3-Carbinol (I3C) was evaluated against DOX-induced toxicities in Swiss albino mice. DOX was administered (5 mg/kg b.w., i.p.) and I3C was administered (20 mg/kg b.w., p.o.) in concomitant and 15 days pretreatment schedule. Results of the present study showed that I3C appreciably mitigated DOX-induced chromosomal aberrations, micronuclei formation, DNA damage and apoptosis in bone marrow niche. Histopathological observations revealed that DOX-intoxication resulted in massive structural and functional impairment of heart and bone marrow niche. However, oral administration of I3C significantly attenuated DOX-induced oxidative stress in the cardiac tissues as evident from decreased levels of ROS/RNS and lipid peroxidation, and by increased level of glutathione (reduced) and the activity of phase-II antioxidant enzymes. Additionally, administration of I3C significantly (P < 0.05) stimulated Nrf2-mediated activation of antioxidant response element (ARE) pathway and promoted expression of cytoprotective proteins heme oxygenase 1 (HO-1), NAD(P)H:quinine oxidoreductase 1 (NQO1) and GSTpi in bone marrow and cardiac tissues. In connection with that, I3C significantly attenuated DOX induced inflammation by downregulation of pro-inflammatory mediators, viz., NF kbeta(p50), iNOS, COX-2 and IL-6 expression. Moreover, I3C attenuate DOX-induced apoptosis by up-regulation of Bcl2 and down-regulation of Bax and caspase-3 expression in bone marrow cells. Thus, this study suggests that I3C has promising chemoprotective efficacy against DOX-induced toxicities and indicates its future use as an adjuvant in chemotherapy. PMID- 29494961 TI - Silymarin ameliorates expression of urotensin II (U-II) and its receptor (UTR) and attenuates toxic oxidative stress in the heart of rats with type 2 diabetes. AB - Type 2 diabetes mellitus (T2DM) is associated with an increased risk of cardiovascular disease (CVD). Urotensin II ((U-II)) and its receptor (UTR) are involved in the progression of CVD through enhancement in the production of reactive oxygen species (ROS). Since silymarin (SMN) is a natural agent with anti diabetic effects, this study aimed to investigate the antioxidant potency of SMN on the expression of (U-II)/UTR system and oxidative stress status in the heart of type 2 diabetic rats. Thirty-six male Wistar rats were randomly divided into six groups (n = 6). Control and diabetic groups treated with or without SMN (60 and 120 mg/kg/day) for 2 months. Fasting blood sugar (FBS), insulin, lipid profile, creatine kinase-MB ((CK-MB)), lactate dehydrogenase (LDH) and markers of oxidative stress were measured by spectrophotometric methods while (U-II) and UTR gene expression was determined by qPCR method. SMN significantly reduced the FBS level, increased the concentration of insulin and improved HOMA-IR. SMN prevented diabetes-induced weight loss, and attenuated the increased levels of total oxidative status (TOS), malondialdehyde (MDA), and nitric oxide (NO). Diabetes induced reduction of total thiol molecules content (TTM) was normalized to the normal level in SMN treated rats. SMN significantly modulated serum lipid profile, reduced the expression of (U-II) and UTR in the heart, and improved histopathological changes in the heart tissues. Therefore, the current study indicated that SMN ameliorated unpleasant diabetic characteristics via down regulation of (U-II) and UTR gene expression and modulation of oxidative stress in the heart tissue of type 2 diabetic rats. PMID- 29494962 TI - Association between apolipoprotein E genotype and warfarin response during initial anticoagulation. AB - Apolipoprotein E (APOE) genotypes are associated with warfarin dose requirements in various populations. Whether APOE genotypes mediate the warfarin response is unknown. The aim of this study was to evaluate the genetic contributions of different APOE genotypes to the early phase of anticoagulation in Han Chinese patients. We conducted a retrospective cohort study and assessed APOE genotypes, clinical characteristics, international normalized ratio (INR) responses, warfarin dose requirements and bleeding events in 429 Han Chinese patients. The study outcomes were the time to the first INR within the therapeutic range, the time to the first INR of more than 4, the INR response over time, and the warfarin dose requirement. Compared with patients with the epsilon3/epsilon3 genotype, patients with at least one epsilon4 allele had significantly longer times to the first INR of more than 4 during both the initial 20 days (P = 0.001, HR 2.9; 95%CI, 1.54-5.45) and the entire follow-up period (P < 0.001, HR 3.26; 95%CI,1.94-5.47), but this allele was not a significant predictor of the time to the first INR within the therapeutic range. No association was observed between the epsilon2 allele and INR response, and both the epsilon4 allele and the epsilon2 allele did not significantly affect the required warfarin dose during the follow-up. These observations suggest that genetic variants of APOE are associated with an increased risk of overanticoagulation among the Han Chinese population. However, these variants may not be useful in predicting warfarin maintenance dose requirements. PMID- 29494963 TI - miR-24 inhibited the killing effect of natural killer cells to colorectal cancer cells by downregulating Paxillin. AB - OBJECTIVE: To identify the molecular mechanism that modulates the killing effect of natural killer (NK) cells to colorectal cancer cells. MATERIALS AND METHODS: Expressions of miR-24 and Paxillin were detected by qRT-PCR and Western blot. Secretions of IFN-gamma and TNF-alpha were measured by ELISA. The killing effect of NK cells was detected by CytoTox 96 non-radioactive cytotoxicity assay. Luciferase reporter assay was conducted to confirm the regulation of miR-24 on Paxillin. RESULTS: miR-24 was overexpressed in NK cells from patients with colorectal cancer than healthy volunteers. Secretions of IFN-gamma and TNF-alpha in activated NK cells were significantly increased, indicating the enhancement of the killing effect of NK cells. Paxillin expression was overexpressed in activated NK cells. Interference of Paxillin significantly decreased Paxillin expression, secretions of IFN-gamma and TNF-alpha, and the killing effect of NK cells to colorectal cancer cells. In addition, we confirmed that Paxillin was a direct target of miR-24, and miR-24 was negatively correlated with Paxillin. Moreover, overexpression of miR-24 inhibited secretions of IFN-gamma and TNF alpha, and decreased cytotoxicity by downregulating Paxillin expression. Finally, we observed that overexpression of Paxillin significantly decreased tumor volume of colorectal cancer. CONCLUSION: Overexpression of miR-24 supressed the killing effect of NK cells to colorectal cancer cells by downregulating Paxillin expression. PMID- 29494964 TI - Ganoderma applanatum secondary metabolites induced apoptosis through different pathways: In vivo and in vitro anticancer studies. AB - Ganoderma applanatum is a widely distributed saprobic or parasitic mushroom, it was found at the bases of decaying logs in Hakozaki Higashi-ku Fukuoka-shi. Japan. The mushroom was extracted with 80% methanol, and LC-HRMS analysis was conducted to illustrate the bioactive ingredients. The cytotoxicity of the total metabolite extract was evaluated against human colon cancer cell line (Caco-2) which showed IC50 value of 160 +/- 4.08 MUg/ml. G. applanatum methanolic extract caused different morphological alterations and increased glutathione level in the treated cells. Interestingly, G. applanatum increased Bax/Bcl-2 ratio significantly (P ? 0.05) at concentrations of 80 and 160 MUg/ml on Caco-2 undergoing apoptotic p53-independent pathway with lake expression of p53 protein and up-regulated Cas-3 mRNA. The in vivo study on solid Ehrlich tumor (SEC) revealed a decrease in the volume of the developed tumor mass after five days of G. applanatum (200 MUg/ml) treatment. The apoptotic p53-dependant pathway was confirmed by mRNA Bax/Bcl-2 increased ratio in addition to p53 and Cas-3 up regulation. In conclusion, G. applanatum could exert apoptotic antitumor properties in Caco-2 by p53-independent pathway and p53-dependant in SEC. The findings proved that G. applanatum can be a promising candidate as alternative or co-anticancer medications. PMID- 29494965 TI - Exogenously triggered response inhibition in developmental stuttering. AB - PURPOSE: The purpose of the present study was to examine relations between children's exogenously triggered response inhibition and stuttering. METHOD: Participants were 18 children who stutter (CWS; mean age = 9;01 years) and 18 children who not stutter (CWNS; mean age = 9;01 years). Participants were matched on age (+/-3 months) and gender. Response inhibition was assessed by a stop signal task (Verbruggen, Logan, & Stevens, 2008). RESULTS: Results suggest that CWS, compared to CWNS, perform comparable to CWNS in a task where response control is externally triggered. CONCLUSIONS: Our findings seem to indicate that previous questionnaire-based findings (Eggers, De Nil, & Van den Bergh, 2010) of a decreased efficiency of response inhibition cannot be generalized to all types of response inhibition. PMID- 29494966 TI - Engine cold start analysis using naturalistic driving data: City level impacts on local pollutants emissions and energy consumption. AB - The analysis of vehicle cold start emissions has become an issue of utmost importance since the cold phase occurs mainly in urban context, where most of the population lives. In this sense, this research work analyzes and quantifies the impacts of cold start in urban context using naturalistic driving data. Furthermore, an assessment of the influence of ambient temperature on the percentage of time spent on cold start was also performed. Regarding the impacts of ambient temperature on cold start duration, a higher percentage of time spent on cold start was found for lower ambient temperatures (80% of the time for 0 degrees C and ~50% for 29 degrees C). Results showed that, during cold start, energy consumption is >110% higher than during hot conditions while emissions are up to 910% higher. Moreover, a higher increase on both energy consumption and emissions was found for gasoline vehicles than for diesel vehicles. When assessing the impacts on a city perspective, results revealed that the impacts of cold start increase for more local streets. The main finding of this study is to provide evidence that a higher increase on emissions occurs on more local streets, where most of the population lives. This kind of knowledge is of particular relevance to urban planners in order to perform an informed definition of public policies and regulations to be implemented in the future, to achieve a cleaner and healthier urban environment. PMID- 29494967 TI - Phytoextraction of rhenium by lucerne (Medicago sativa) and erect milkvetch (Astragalus adsurgens) from alkaline soils amended with coal fly ash. AB - Coal fly ash (CFA) is an industrial waste generated in huge amounts worldwide, and the management of CFA has become an environmental concern. Recovery of valuable metals from CFA is one of the beneficial reuse options of CFA. Rhenium (Re) is one of the rarest metals in the Earth's crust and one of the most expensive metals of strategic significance in the world market. A CFA at the Jungar Thermal Power Plant, Inner Mongolia, China, contains more Re than two alkaline soils in the surrounding region. Pot experiments were undertaken to grow lucerne (Medicago sativa) and erect milkvetch (Astragalus adsurgens) in a loessial soil and an aeolian sandy soil amended with different rates (5%, 10%, 20%, and 40%) of CFA. The results show that plant growth was considerably enhanced and Re concentration in plants was significantly increased when CFA was applied to the alkaline soils at rates of <=20%; while in some cases plant growth was also markedly enhanced by the 40% CFA treatment, which increased plant Re concentration the most of all treatments. Both lucerne and erect milkvetch showed potential for phytoextracting Re from CFA-amended alkaline soils. Using CFA for soil amendment not only offers a potential solution for the waste disposal problem of CFA, but the phytoextraction of Re by both lucerne and erect milkvetch may also bring an economic profit in the future. PMID- 29494968 TI - Constructed wetlands for greywater recycle and reuse: A review. AB - Concern over dwindling water supplies for urban areas as well as environmental degradation from existing urban water systems has motivated research into more resilient and sustainable water supply strategies. Greywater reuse has been suggested as a way to diversify local water supply portfolios while at the same time lessening the burden on existing environments and infrastructure. Constructed wetlands have been proposed as an economically and energetically efficient unit process to treat greywater for reuse purposes, though their ability to consistently meet applicable water quality standards, microbiological in particular, is questionable. We therefore review the existing case study literature to summarize the treatment performance of greywater wetlands in the context of chemical, physical and microbiological water quality standards. Based on a cross-section of different types of wetlands, including surface flow, subsurface flow, vertical and recirculating vertical flow, across a range of operating conditions, we show that although microbiological standards cannot reliably be met, given either sufficient retention time or active recirculation, chemical and physical standards can. We then review existing case study literature for typical water supply disinfection unit processes including chlorination, ozonation and ultraviolet radiation treating either raw or treated greywater specifically. An evaluation of effluent water quality from published wetland case studies and the expected performance from disinfection processes shows that under appropriate conditions these two unit processes together can likely produce effluent of sufficient quality to meet all nonpotable reuse standards. Specifically, we suggest that recycling vertical flow wetlands combined with ultraviolet radiation disinfection and chlorine residual is the best combination to reliably meet the standards. PMID- 29494969 TI - Tourism in protected areas: Disentangling road and traffic effects on intra-guild scavenging processes. AB - The expansion of road networks and the increase in traffic have emerged in recent years as key threats to the conservation of biodiversity. This is particularly concerning in many protected areas because the increase of recreational activities requiring the use of vehicles. Effects of roads and traffic within guild scenarios and ecological processes remain however poorly known. Here we examined how road proximity and traffic intensity influence patterns of resource use in an Old-World avian scavenger guild living in a protected natural park in northern Spain. We experimentally placed 130 carcasses at different distances from a scenic road in the centre of the park. Vehicles were recorded by means of traffic counters which revealed that maximum numbers were reached during weekends and holidays and during the middle hours of the day. Avian scavenger attendance at carcasses was recorded by means of camera-traps. Obligated scavengers, Eurasian griffon (Gyps fulvus) and Egyptian vultures (Neophron percnopterus) were frequently observed (59.4% and 37.7% of the consumed carcasses) together with five other facultative scavenger species. We found that the richness (number of species) and the probability of consumption of the resource were reduced the smaller the distance to the road and in days with higher traffic intensity. The same factors affected the probability of presence of all the scavenger species. Moreover, some of them, notably griffon vultures, showed hourly patterns of carcass attendance suggesting avoidance of maximum traffic levels. Our results highlight that roads and traffic would trigger consequences on the structure and functioning of scavenger food webs, which may be particularly concerning in protected areas with remarkable levels of biodiversity. Future regulations at protected areas should couple both traffic and tourist affluence with wildlife conservation. In this way important ecological processes would be preserved while maintaining a good dissemination of natural values. PMID- 29494970 TI - Influence of soil type on TiO2 nanoparticle fate in an agro-ecosystem. AB - Nanoparticles (NPs) and in particular TiO2-NPs are increasingly included in commercial goods leading to their accumulation in sewage sludge which is spread on agricultural soils as fertilizers in many countries. Crop plants are thus a very likely point of entry for NPs in the food chain up to humans. So far, soil influence on NP fate has been under-investigated. In this article, we studied the partitioning of TiO2-NPs between soil and soil leachate, their uptake and biotransformation in wheat seedlings and their impact on plant development after exposure on 4 different types of soil with different characteristics: soil texture (from sandy to clayey), soil pH, cationic exchange capacity, organic matter content. Results suggest that a NP contamination occurring on agricultural soils will mainly lead to NP accumulation in soil (increase of Ti concentration up to 302% in sand) but to low to negligible transfer to soil leachate and plant shoot. In our experimental conditions, no sign of acute phytotoxicity has been detected (growth, biomass, chlorophyll content). Clay content above 6% together with organic matter content above 1.5% lead to translocation factor from soil to plant leaves below 2.5% (i.e. below 13mgTi.kg-1 dry leaves). Taken together, our results suggest low risk of crop contamination in an agro-ecosystem. PMID- 29494971 TI - Occurrence and risk assessment of potentially toxic elements and typical organic pollutants in contaminated rural soils. AB - The residual levels and risk assessment of several potentially toxic elements (PTEs), phthalate esters (PAEs) and polycyclic aromatic hydrocarbons (PAHs) in rural soils near different types of pollution sources in Tianjin, China, were studied. The soils were found to be polluted to different extents with PTEs, PAEs and PAHs from different pollution sources. The soil concentrations of chromium (Cr), nickel (Ni), di-n-butyl phthalate (DnBP), acenaphthylene (Any) and acenaphthene (Ane) were higher than their corresponding regulatory reference limits. The health risk assessment model used to calculate human exposure indicates that both non-carcinogenic and carcinogenic risks from selected pollutants were generally acceptable or close to acceptable. Different types of pollution sources and soil physicochemical properties substantially affected the soil residual concentrations of and risks from these pollutants. PTEs in soils collected from agricultural lands around industrial and residential areas and organic pollutants (PAEs and PAHs) in soils collected from agricultural areas around livestock breeding were higher than those from other types of pollution sources and merit long-term monitoring. PMID- 29494972 TI - Terrestrial dissolved organic matter distribution in the North Sea. AB - The flow of terrestrial carbon to rivers and inland waters is a major term in the global carbon cycle. The organic fraction of this flux may be buried, remineralized or ultimately stored in the deep ocean. The latter can only occur if terrestrial organic carbon can pass through the coastal and estuarine filter, a process of unknown efficiency. Here, data are presented on the spatial distribution of terrestrial fluorescent and chromophoric dissolved organic matter (FDOM and CDOM, respectively) throughout the North Sea, which receives organic matter from multiple distinct sources. We use FDOM and CDOM as proxies for terrestrial dissolved organic matter (tDOM) to test the hypothesis that tDOM is quantitatively transferred through the North Sea to the open North Atlantic Ocean. Excitation emission matrix fluorescence and parallel factor analysis (EEM PARAFAC) revealed a single terrestrial humic-like class of compounds whose distribution was restricted to the coastal margins and, via an inverse salinity relationship, to major riverine inputs. Two distinct sources of fluorescent humic like material were observed associated with the combined outflows of the Rhine, Weser and Elbe rivers in the south-eastern North Sea and the Baltic Sea outflow to the eastern central North Sea. The flux of tDOM from the North Sea to the Atlantic Ocean appears insignificant, although tDOM export may occur through Norwegian coastal waters unsampled in our study. Our analysis suggests that the bulk of tDOM exported from the Northwest European and Scandinavian landmasses is buried or remineralized internally, with potential losses to the atmosphere. This interpretation implies that the residence time in estuarine and coastal systems exerts an important control over the fate of tDOM and needs to be considered when evaluating the role of terrestrial carbon losses in the global carbon cycle. PMID- 29494973 TI - Biotic phase micropollutant distribution in horizontal sub-surface flow constructed wetlands. AB - The distribution of micropollutants in biotic phases of horizontal sub-surface flow (HSSF) constructed wetlands was investigated. 88 diverse micropollutants (personal care products, pharmaceuticals and illicit drugs) were monitored for in full-scale HSSF steel slag and gravel beds to assess their fate and behaviour during tertiary wastewater treatment. Of the studied micropollutants 54 were found in receiving and treated wastewaters. Treatment reduced concentrations of several micropollutants by >50% (removal range -112% to 98%) and resulted in changes to the stereo-isomeric composition of chiral species. For example, stereo selective changes were observed for 3,4-methylenedioxymethamphetamine (MDMA) and atenolol during HSSF constructed wetland treatment for the first time. Analysis of sludge present within the HSSF beds found 37 micropollutants to be present. However, concentrations for the majority of these micropollutants were not considered high enough to suggest partitioning into sludge was a contributing mechanism of removal. Nevertheless the preservative methylparaben was found at 2772mgbed-1. Its daily removal from wastewater of 3.4mgd-1 indicates partitioning and accumulation in sludge contributes to its removal. Other micropollutants found at high levels in sludge (relative to their overall removals) were the antidepressants sertraline and fluoxetine, and the metabolite desmethylcitalopram. Furthermore, process balances indicated uptake and metabolism by Phragmites australis (Cav.) Trin. ex Steud did not contribute significantly to micropollutant removal. However analysis of plant tissues evidenced uptake, metabolism and accumulation of recalcitrant micropollutants such as ketamine and carbamazepine. It is considered that the rate of uptake was too slow to have a notable impact on removal at the 14h hydraulic retention time. Despite evidence of other removal mechanisms at play (e.g., partitioning into sludge and plant uptake), findings indicate biodegradation is the dominant mechanism of micropollutant removal in HSSF constructed wetlands. PMID- 29494974 TI - Community assembly processes underlying phytoplankton and bacterioplankton across a hydrologic change in a human-impacted river. AB - Although the influence of microbial community assembly processes on aquatic ecosystem function and biodiversity is well known, the processes that govern planktonic communities in human-impacted rivers remain largely unstudied. Here, we used multivariate statistics and a null model approach to test the hypothesis that environmental conditions and obstructed dispersal opportunities, dictate a deterministic community assembly for phytoplankton and bacterioplankton across contrasting hydrographic conditions in a subtropical mid-sized river (Jiulong River, southeast China). Variation partitioning analysis showed that the explanatory power of local environmental variables was larger than that of the spatial variables for both plankton communities during the dry season. During the wet season, phytoplankton community variation was mainly explained by local environmental variables, whereas the variance in bacterioplankton was explained by both environmental and spatial predictors. The null model based on Raup-Crick coefficients for both planktonic groups suggested little evidences of the stochastic processes involving dispersal and random distribution. Our results showed that hydrological change and landscape structure act together to cause divergence in communities along the river channel, thereby dictating a deterministic assembly and that selection exceeds dispersal limitation during the dry season. Therefore, to protect the ecological integrity of human-impacted rivers, watershed managers should not only consider local environmental conditions but also dispersal routes to account for the effect of regional species pool on local communities. PMID- 29494976 TI - Heatwave and health events: A systematic evaluation of different temperature indicators, heatwave intensities and durations. AB - OBJECTIVES: Temperature observation time and type influenced the assessment of heat impact on mortality, and different health events may have different temperature thresholds beyond which these health events increase substantially. This study aimed to investigate whether temperature observation time and type influenced the assessment of heatwave impact on morbidity, to assess how heatwave duration modified heatwave impact on morbidity, and to examine whether there was a consistent temperature threshold beyond which five different types of health events increased sharply. METHODS: Minutely air temperature data in Brisbane, Australia, were collected and converted into five daily temperature indicators observed at different time points or calculated using different approaches. Twenty-nine heatwave definitions for each temperature indicator were used to examine the effects of heatwaves on five health events (i.e., ambulance service uses, emergency department attendances (EDAs), hospitalizations, possible EDAs of heat and/or dehydration, and possible hospitalizations of heat and/or dehydration) by quasi-Poisson models. RESULTS: Mean temperature was slightly better than maximum temperature in predicting heatwave impact on morbidity (P<0.05), and no appreciable difference in model performance was observed amongst different mean temperature indicators. Two-day-duration heatwaves were more detrimental than longer-lasting heatwaves when heatwave intensity was not high, and 97th percentile appeared to be a consistent temperature threshold for most heatwave-related health events (P<0.05). CONCLUSIONS: It seems desirable in the development of heatwave definition and early warning systems to use mean temperature as an exposure indicator, and to adopt the 97th percentile of temperature as the trigger in Brisbane. Health sectors need to better prepare for short-lasting heatwaves. PMID- 29494975 TI - Variation in personality traits across a metal pollution gradient in a free living songbird. AB - Anthropogenic contaminants could alter traits central to animal behavioral types, or personalities, including aggressiveness, boldness and activity level. Lead and other toxic metals are persistent inorganic pollutants that affect organisms worldwide. Metal exposure can alter behavior by affecting neurology, endocrinology, and health. However, the direction and magnitude of the behavioral effects of metal exposure remain equivocal. Moreover, the degree to which metal exposure simultaneously affects suites of correlated behavioral traits (behavioral syndromes) that are controlled by common mechanisms remains unclear, with most studies focusing on single behaviors. Using a model species for personality variation, the great tit (Parus major), we explored differences in multiple behavioral traits across a pollution gradient where levels of metals, especially lead and cadmium, are elevated close to a smelter. We employed the novel environment exploration test, a proxy for variation in personality type, and also measured territorial aggressiveness and nest defense behavior. At polluted sites birds of both sexes displayed slower exploration behavior, which could reflect impaired neurological or physiological function. Territorial aggression and nest defense behavior were individually consistent, but did not vary with proximity to the smelter, suggesting that metal exposure does not concurrently affect exploration and aggression. Rather, exploration behavior appears more sensitive to metal pollution. Effects of metal pollution on exploration behavior, a key animal personality trait, could have critical effects on fitness. PMID- 29494977 TI - A new wearable monitoring system for investigating pedestrians' environmental conditions: Development of the experimental tool and start-up findings. AB - Urban population is predicted to increase rapidly and massively in the next decades, by producing also the exacerbation of urban scale climate change imputable to anthropogenic actions, such as urban heat island. In this view, urban pedestrians assume a key role in determining city livability in dense built environments, typically much more polluted than suburban or rural areas. Despite that, urban heat island experimental studies are pretty focused on data collected by means of permanent microclimate stations for environmental monitoring, also coupled with satellite measurements or mobile stations equipped over transportation media. This work deals with the development, experimental startup with field test and critical data analysis of a brand new wearable system for microclimate and air quality investigation, just developed with the purpose to characterize livability environmental conditions which affect urban population wellbeing. To this aim, the experimental tool definition and the first field test are carried out in a historical city centre in Italy, where cluster analysis is performed in order to also identify the role of urban design in affecting key microclimate parameters such as air temperature, solar radiation, daylight, air pollution and pedestrian thermal comfort in general. The analysis showed that very site-specific environmental conditions may be detected while several environmental spheres are investigated by the novel wearable system in summer conditions. PMID- 29494978 TI - Worsened physical condition due to climate change contributes to the increasing hypoxia in Chesapeake Bay. AB - There are increasing concerns about the impact of worsened physical condition on hypoxia in a variety of coastal systems, especially considering the influence of changing climate. In this study, an EOF analysis of the DO data for 1985-2012, a long-term numerical simulation of vertical exchange, and statistical analysis were applied to understand the underlying mechanisms for the variation of DO condition in Chesapeake Bay. Three types of analysis consistently demonstrated that both biological and physical conditions contribute equally to seasonal and interannual variations of the hypoxic condition in Chesapeake Bay. We found the physical condition (vertical exchange+temperature) determines the spatial and seasonal pattern of the hypoxia in Chesapeake Bay. The EOF analysis showed that the first mode, which was highly related to the physical forcings and correlated with the summer hypoxia volume, can be well explained by seasonal and interannual variations of physical variables and biological activities, while the second mode is significantly correlated with the estuarine circulation and river discharge. The weakened vertical exchange and increased water temperature since the 1980s demonstrated a worsened physical condition over the past few decades. Under changing climate (e.g., warming, accelerated sea-level rise, altered precipitation and wind patterns), Chesapeake Bay is likely to experience a worsened physical condition, which will amplify the negative impact of anthropogenic inputs on eutrophication and consequently require more efforts for nutrient reduction to improve the water quality condition in Chesapeake Bay. PMID- 29494979 TI - Combined top-down and bottom-up climate change impact assessment for the hydrological system in the Vu Gia- Thu Bon River Basin. AB - Vu Gia- Thu Bon (VGTB) River Basin, located in the Central Coastal zone of Viet Nam currently faces water shortage. Climate change is expected to exacerbate the challenge. Therefore, there is a need to study the impacts of climate change on water shortage in the river basin. The study adopts a combined top-down and bottom-up climate change impact assessment to address the impacts of climate change on water shortage in the VGTB River Basin. A MIKE BASIN water balance model for the river basin was established to simulate the response of the hydrological system. Simulations were performed through parametrically varying temperature and precipitation to determine the vulnerability space of water shortage. General Circulation Models (GCMs) were then utilized to provide climate projections for the river basin. The output from GCMs was then mapped onto the vulnerability space determined earlier. In total, 9 out of 55 water demand nodes in the simulation are expected to face problematic conditions as future climate changes. PMID- 29494980 TI - Below the surface: Twenty-five years of seafloor litter monitoring in coastal seas of North West Europe (1992-2017). AB - Marine litter presents a global problem, with increasing quantities documented in recent decades. The distribution and abundance of marine litter on the seafloor off the United Kingdom's (UK) coasts were quantified during 39 independent scientific surveys conducted between 1992 and 2017. Widespread distribution of litter items, especially plastics, were found on the seabed of the North Sea, English Channel, Celtic Sea and Irish Sea. High variation in abundance of litter items, ranging from 0 to 1835 pieces km-2 of seafloor, was observed. Plastic tems such as bags, bottles and fishing related debris were commonly observed across all areas. Over the entire 25-year period (1992-2017), 63% of the 2461 trawls contained at least one plastic litter item. There was no significant temporal trend in the percentage of trawls containing any or total plastic litter items across the long-term datasets. Statistically significant trends, however, were observed in specific plastic litter categories only. These trends were all positive except for a negative trend in plastic bags in the Greater North Sea - suggesting that behavioural and legislative changes could reduce the problem of marine litter within decades. PMID- 29494981 TI - Effect of reclamation of abandoned salinized farmland on soil bacterial communities in arid northwest China. AB - Understanding the impact of reclamation of abandoned salinized farmland on soil bacterial community is of great importance for maintaining soil health and sustainability in arid regions. In this study, we used field sampling and 454 pyrosequencing methods to investigate the effects of 5-year reclamation treatments on soil properties, bacterial community composition and diversity. The four reclamation treatments are: abandoned salinized farmland (CK), cropland (CL), grassland (GL) and woodland (WL). We have found soil properties are significantly altered by abandoned salinized farmland reclamation. In particular, the lowest soil pH and electrical conductivity (EC) values are observed in CL (P<0.05). The dominant phyla are Firmicutes, Proteobacteria, Chloroflexi, Actinobacteria and Acidobacteria in all treatments. At the genus levels, the relative abundance of Bacillus, Lactococcus, Streptococcus and Enterococcus in CK, GL and WL is significantly higher than in CL. Bacterial diversity indices (i.e. ACE, Chao and Shannon) dramatically increase after the reclamation, with the highest in CL. Similar patterns of bacterial communities have been observed in CK, GL and WL soils, but significantly different from CL. Regression analyses indicate that the relative abundance of these phyla are significantly correlated with soil Fe, pH and EC. Results from non-metric multidimensional scaling (NMDS) and redundancy analysis (RDA) indicate that soil Fe content, EC and pH are the most important factors in shaping soil bacterial communities. Overall, results indicate that abandoned salinized farmland reclaimed for CL significantly decrease soil pH and EC, and increase soil bacterial community diversity. Soil Fe concentration, EC and pH are the dominant environmental factors affecting soil bacterial community composition. The important role of Fe concentration in shaping bacterial community composition is a new discovery among the similar studies. PMID- 29494982 TI - Toxicity assessment of pharmaceutical compounds on mixed culture from activated sludge using respirometric technique: The role of microbial community structure. AB - Micropollutants of emerging concern such as pharmaceuticals can significantly affect the performance of secondary biological processes in wastewater treatment plants. The present study is aimed to evaluate the toxicity and inhibition of three pharmaceutical compounds (caffeine, sulfamethoxazole and carbamazepine) on two cultures of microbial consortia enriched from wastewater aerobic activated sludge. One of them was acclimated to pharmaceuticals and the other was non acclimated as control bioassay. The toxic and inhibitory effects on these cultures were assessed by respirometric tests through the oxygen uptake rate as an indicator of their capacity to degrade a readily available carbon source. Higher values of toxicity and inhibition of pharmaceutical compounds were observed for the control culture as compared to the acclimated one. Sulfamethoxazole and carbamazepine exhibited higher toxicity and inhibition effects than caffeine in both acclimated and control cultures. The microbial diversity of the two cultures was also studied. The composition of microbial community of acclimated and control cultures, was determined by targeting the 16S ribosomal RNA gene. It was observed that Proteobacteria was the most abundant phylum, with Gammaproteobacteria dominating both cultures. Control culture was dominated by Gammaproteobacteria and mostly by the genera Pseudomonas and Sodalis, which belong to common families present in wastewater. Results suggested that the acclimated culture to the three pharmaceuticals was mostly comprised of the extremely multiresistant genera Escherichia-Shigella (38%) of Gammaproteobacteria, resulting to higher resistance as compared to the control culture (Escherichia-Shigella, 7%). Finally, the microbial structure of the microorganisms present in a real bioreactor, which was initially seeded with the acclimated culture and fed in a continuous mode with the selected pharmaceuticals, was also analyzed. The continuous loading of pharmaceuticals in the bioreactor affected its microbial diversity, leading to the dominance of Betaproteobacteria and to the resistant genus Rhizobium of Alphaproteobacteria. PMID- 29494983 TI - Synthesis and characterization of Ag+-decorated poly(glycidyl methacrylate) microparticle design for the adsorption of nucleic acids. AB - In this study, we report on the adsorption of RNA and DNA molecules by exploiting the high binding affinity of these nucleic acids to Ag+ ions anchored on magnetic poly(glycidyl methacrylate) (PGMA) microparticles. PGMA microparticles were synthesized and modified with nicotinamide which enabled to anchor Ag+ ions on the surface. The successful preparation of PGMA was confirmed by the presence of characteristic FTIR peaks. The ESR results showed that the incorporation of FeNi salt to the polymeric structure provided a magnetic property to the microparticles. The amount of nicotinamide and Ag+ ions used to modify the surface of the particles were found to be 1.79 wt% and 52.6 mg Ag/g microparticle, respectively. The high affinity of nucleic acids to Ag+ ions were exploited for the adsorption studies. At the optimum working conditions, the adsorption capacity of microparticles was found to be 40.1 and 11.48 mg nucleic acid/g microparticle for RNA and DNA, respectively. Our study indicated that the use of novel Ag+-decorated magnetic PGMA particles can be successfully employed as adsorbents for fast, easy, and cost-friendly adsorption of nucleic acids with high purity as well as high in quantity. PMID- 29494984 TI - In-vivo metabolite profiling of chicoric acid in rat plasma, urine and feces after oral administration using liquid chromatography quadrupole time of flight mass spectrometry. AB - Chicoric acid (CA) is an active derivative of caffeic acid, which is naturally present in many medicinal plants and vegetables. In the present study, the metabolic profile of CA was determined in rat plasma, urine and feces and was subsequently used to propose the metabolic pathways of CA. CA (100 mg/kg) was orally administered to rats by gastric intubation. Then, the plasma, urine and feces samples were collected and treated with methanol and acetonitrile (1:1, V/V) to precipitate the proteins. The pretreated samples were separated by ultra performance liquid chromatography (UPLC) equipped with an HSS T3 column (2.1 mm * 100 mm I.D., 1.7 MUm) and with quadrupole time-of-flight mass spectrometry (Q-TOF MS) as the detection method. A total of nineteen metabolites were detected and identified based on the characteristics of their deprotonated ions in the plasma, urine and feces samples. The results revealed that the metabolism of CA followed a number of known in-vivo mammalian biotransformation pathways including hydrolysis, reduction, methylation, sulfation, glucuronidation, acetylation, isomerization and deoxygenation. PMID- 29494985 TI - Functional analysis of overexpressed PtDRS1 involved in abiotic stresses enhances growth in transgenic poplar. AB - Drought and salinity are two main abiotic stressors that can disrupt plant growth and survival. Various biotechnological approaches have been used to alleviate the problem of drought stress by improving water stress resistance in forestry and agriculture. The drought sensitive 1 (DRS1) gene acts as a regulator of drought stress, identified in human, yeast and some model plants, such as Arabidopsis thaliana, but there have been no reports of DRS1 transformation in poplar plants to date. In this study, we transformed the DRS1 gene from Populus trichocarpa into Populus deltoides * Populus euramericana 'Nanlin895' using Agrobacterium tumefaciens-mediated transformation. We confirmed that the DRS1 gene was transformed into 'Nanlin895' poplar genomes using reverse transcription polymerase chain reaction (PCR), multiplex PCR, real-time PCR, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. All transformed and wild-type (WT) plants were then transferred into a greenhouse for complementary experiments. We analyzed the physiological and biochemical responses of transgenic plants under drought and salt stresses in the greenhouse, and the results were compared with control WT plants. Responses to abiotic stress were greater in transgenic plants compared with WT. Based on our results, introduction of the DRS1 gene into poplar 'Nanlin895' plants significantly enhanced the resistance of those plants to water deficit and high salinity, allowing higher growth rates of roots and shoots in those plants. Additionally, the clawed root rate increased in transformed poplars grown in culture media or in soil, and improved survival under drought and salt stress conditions. PMID- 29494986 TI - Low expression of GFI-1 Gene is associated with Panobinostat-resistance in acute myeloid leukemia through influencing the level of HO-1. AB - To improve the treatment outcomes of acute myeloid leukemia (AML), epigenetic modification has been widely tested and used in recent years. However, drug resistance is still a choke point to cure the malignancy. The growth factor independent 1 transcriptional repressor (GFI-1), as a zinc-finger transcriptional repressor, can bind histone deacetylases to allow the transcriptional repression. According to the finding of our study, AML patients with low level of GFI-1 not only implicated poor prognosis but also caused Panobinostat-resistance. In our prevent study revealed that heme oxygenase-1(HO-1) was one of the main factors leading to chemotherapy sensitivity to AML. Thus, this study tried to test the correlation between GFI-1 and HO-1. Our study discovered that AML patients with lower expression of GFI-1 had higher level of HO-1, HDAC1, HDAC2 and HDAC3, which resulted in poor prognosis in AML. The results of the in vitro study were the same. Panobinostat is a promising new class of anti-cancer drugs in AML. However, knocking down GFI-1 by siRNA could eliminate the Panobinostat-induced cell apoptosis. Subsequently, we utilized ZnPP to down regulate the level of HO-1, finding that the Panobinostat-resistance between the low level of GFI-1 and empty vector had eased. After further exploring the mechanism, it could be found that with knock down GFI-1, the phosphorylation of Akt and PI3K could be activated. Subsequently, Akt pathway and HO-1 inhibitor were utilized respectively and the resistance was reversed. It suggested that the resistance of Panobinostat to AML cells at low level of GFI-1 was mainly due to up-regulated level of HO-1 through the PI3K-Akt pathway. PMID- 29494987 TI - Therapeutic effects of Saussurea involucrata injection against severe acute pancreatitis- induced brain injury in rats. AB - OBJECTIVES: To observe the therapeutic effects of Saussurea involucrata (Sau) injection against severe acute pancreatitis (SAP)-induced brain injury. METHODS: Sodium taurocholate-induced SAP-modeled rats were equally randomized into an SAP model group (SAP group) and a Sau treated group (Sau + S group). Healthy rats were equally randomized into a Sau treated group (Sau + H group) and a sham operation group (SO group). Serum amylase levels, endothelin-1 (ET-1) and nitric oxide (NO) contents were determined by optical turbidimetry, ELISA and nitrate reductase method respectively. Western blot was used to detect protein expression levels of phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), ET-1, inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) while mRNA levels of these biomarkers in brain tissue were measured by quantitative real time PCR. Furthermore, pathological changes, as well as all above indexes of pancreas and brain, were observed at 6, 24 and 48 h after administration. RESULTS: There was a significant difference in mortality between SAP and Sau + S groups (P < 0.05). Serum amylase levels, ET-1 and NO contents, ET-1/NO ratio, relative expression levels of ET-1 and iNOS protein/mRNA of brain tissue in Sau + S group were lower than those in SAP group at 24 and 48 h post-operation (P < 0.05 or 0.01), meanwhile, pancreas and brain pathological scores showed similar tendency (P < 0.01). However, both protein and mRNA levels of PI3K, Akt and eNOS of brain tissue in Sau + S group were higher than those in SAP group (P < 0.05 or P < 0.01). There were no significant differences in all indexes between Sau + H and SO groups at all designated time points (P > 0.05). CONCLUSIONS: Sau injection has therapeutic effects on SAP-induced brain injury in rats. PMID- 29494988 TI - The protective effect of astaxanthin against cisplatin-induced nephrotoxicity in rats. AB - PURPOSE: The aim of this experimental study was to investigate the antioxidant effects of astaxanthin against cisplatin-induced nephrotoxicity in rats. METHODS: Forty-eight male Sprague-Dawley rats weighing 264.83 +/- 7.39 g were randomly divided into six groups of eight animals each. These were constituted as control, olive oil control, astaxanthin control, cisplatin control, 16 mg/kg cisplatin & 25 mg/kg astaxanthin and 16 mg/kg cisplatin & 75 mg/kg astaxanthin groups. Biochemical evaluation was performed by measuring blood urea nitrogen, serum creatinine, total oxidant status and total antioxidant status. Renal corpuscle, proximal and distal tubules areas (MUm2) were calculated for histopathological evaluation, and Caspase-3 staining was performed for immunohistochemical evaluation. RESULTS: Cisplatin reduced total antioxidant status levels and increased blood urea nitrogen, serum creatinine, total oxidant status, and Caspase-3 levels. It also caused dilatation, vacuolization, and loss of tubular epithelial cells in the proximal and distal tubules, and glomerular degeneration and edema were determined in kidney tissue (p < 0.05). Administration of 25 mg and 75 mg astaxanthin increased total antioxidant status levels, reduced blood urea nitrogen, serum creatinine, total oxidant status, and Caspase-3, and ameliorated degenerative distal and proximal tubules, glomerular degeneration and edema in kidney tissue (p < 0.05). CONCLUSIONS: The nephrotoxic effect of cisplatin was diminished by the antioxidant effect of astaxanthin. PMID- 29494989 TI - Design of butterfly type organic dye sensitizers with double electron donors: The first principle study. AB - In this work, we designed a series of butterfly type organic dyes, named ME07 ME13 by introducing such as triphenylamine, phenothiazine, coumarin groups etc. as electron donors and further investigated their absorption spectra using density functional theory (DFT) and time-dependent DFT (TDDFT). All designed dyes cover the entire visible absorption spectrum from 300 to 800nm. It's fascinating that ME13 molecule has two absorption peak and the molar coefficient of two absorption peaks are above 4.645*104M-1.cm-1. The light absorption area of ME13 exhibits an increment of 16.5-19.1% compared to ME07-ME12. Furthermore, we performed a detailed analysis on their geometrical and electronic properties, including molecular structures, energy levels, light harvesting efficiency (LHE), driving force (DeltaGinject), regeneration (DeltaGregen),electron dipole moments (MUnormal), intermolecular electron transfer and dye/(TiO2)38 system electron transitions. The results of calculation reveal that double coumarin donors in ME13 are promising functional groups for butterfly type organic dye sensitizers. It is expected that the design of double donors can provide a new strategy and guidance for the investigation in high efficiency dye-sensitized devices. PMID- 29494990 TI - Developing on-site paper colorimetric monitoring technique for quick evaluating copper ion concentration in mineral wastewater. AB - With the reinforce of the copper mining, the on-site monitoring of the accompanied effluent discharge is highly demanded for the emergency response to minimize the negative effect of the effluent on the surrounding ecosystem. On the basis of the specific interaction between Cu2+ and l-Cysteine (l-Cys), which was modified on gold nanoparticles (Au NPs), and the aggregation dependent surface plasmon resonance (SPR) of Au NPs, we developed an easy-on-going paper colorimetric method for the quick evaluating the copper ion concentration in the waste water excreted from the copper mine. The color change of l-Cys modified Au NPs (l-Cys-Au NPs)immobilized on a filter paper was very sensitive to the Cu2+ concentration and free of interference from other metal ions typically in waste water. The proposed paper colorimetry has the LOD of 0.09mg/L and the linear range of 0.1-10mg/L, respectively, with the RSD (n=5) was 6.6% for 1mg/L Cu2+ and 3.5% for 5mg/L Cu2+. The quantitative analysis results for the mineral wastewater is in good agreement the China National Environmental Protection Standards HJ485 2009, which indicates the current method could be developed to the on-site detection technique for the emergency response in monitoring Cu2+ in industrial wastewater or polluted water. PMID- 29494991 TI - Structural and spectrophotometric characterization of 2-[4-(dimethylamino)styryl] 1-ethylquinolinium iodide as a reagent for sequential injection determination of tungsten. AB - Structure, spectrophotometric and protolytic properties of the styryl dye 2-[4 (dimethylamino)styryl]-1-ethylquinolinium iodide (R) as well as its complex with tungsten were studied. The selective protonation of dimethylamino group was confirmed by density functional theory investigation through the computation of Fukui function, NPA partial atomic charges, and NICS(0) aromaticity indexes. The TD-DFT study explains the experimental change of color by excluding the dimethylamino group from HOMO orbital upon protonation. The acid dissociation constant, the optimum wavelength and the molar absorptivity of R were found to be: 3.02, 501nm and 4.0*104Lmol-1cm-1, respectively. The protolytic properties of the reagent were found to change significantly in the presence of tungsten(VI). Analysis of bond critical points between the anions and Quinaldine Red cation gives the selectivity raw HWO4->MoO4->H2VO4->ReO4->ClO4-, that perfectly match with the experimental data. Based on this observation, a non-extractive sequential-injection spectrophotometric method for the determination of tungsten was developed. The absorbance of the colored extracts obeys Beer's law up to 55.2mgL-1 of W at 520nm wavelength. The limit of detection calculated from a blank test (n=10) based on 3s was 0.96mgL-1. The developed method was applied for the determination of tungsten in model samples. PMID- 29494992 TI - Reducing artifacts of gadoxetate disodium-enhanced MRI with oxygen inhalation in patients with prior episode of arterial phase motion: intra-individual comparison. AB - PURPOSE: To determine whether oxygen inhalation reducing artifacts in patients with previous transient severe motion (TSM) on gadoxetate-disodium-enhanced MRI. MATERIALS AND METHODS: Fifty-one patients with TSM on previous gadoxetate disodium-enhanced MRI (Baseline examination) were evaluated. Image quality in the examination with oxygen inhalation (Oxygen examination) and that in Baseline examination and the examination before Baseline examination without oxygen inhalation (Past examination) were qualitatively compared in dynamic study. RESULTS: Image quality was significantly higher in Oxygen examination than Baseline examination in arterial phase, but there was no statistical difference between Baseline and Past examinations. CONCLUSION: Oxygen inhalation improved image quality in patients with a prior episode of arterial phase TSM. PMID- 29494993 TI - Syncope in a middle aged female: Splenic artery aneurysm revisited. AB - Splenic artery aneurysm (SAA) is a rare potentially fatal condition with an estimated prevalence in the general population ranging between 0.2 and 10.4%. Ruptured splenic artery aneurysm poses a great diagnostic challenge to emergency physicians due to non-specific and potentially fatal presentations. Dual (arterial and venous) phase imaging is very important for identifying the source of an active intraabdominal bleed when patients are stable enough to tolerate the exam. Here, we present a case of a 54-year-old female who presented with syncope to the emergency department, diagnosed with ruptured splenic artery aneurysm. PMID- 29494994 TI - Analysis of stationary and dynamic factors affecting highway accident occurrence: A dynamic correlated grouped random parameters binary logit approach. AB - Traditional accident analysis typically explores non-time-varying (stationary) factors that affect accident occurrence on roadway segments. However, the impact of time-varying (dynamic) factors is not thoroughly investigated. This paper seeks to simultaneously identify pre-crash stationary and dynamic factors of accident occurrence, while accounting for unobserved heterogeneity. Using highly disaggregate information for the potential dynamic factors, and aggregate data for the traditional stationary elements, a dynamic binary random parameters (mixed) logit framework is employed. With this approach, the dynamic nature of weather-related, and driving- and pavement-condition information is jointly investigated with traditional roadway geometric and traffic characteristics. To additionally account for the combined effect of the dynamic and stationary factors on the accident occurrence, the developed random parameters logit framework allows for possible correlations among the random parameters. The analysis is based on crash and non-crash observations between 2011 and 2013, drawn from urban and rural highway segments in the state of Washington. The findings show that the proposed methodological framework can account for both stationary and dynamic factors affecting accident occurrence probabilities, for panel effects, for unobserved heterogeneity through the use of random parameters, and for possible correlation among the latter. The comparative evaluation among the correlated grouped random parameters, the uncorrelated random parameters logit models, and their fixed parameters logit counterpart, demonstrate the potential of the random parameters modeling, in general, and the benefits of the correlated grouped random parameters approach, specifically, in terms of statistical fit and explanatory power. PMID- 29494995 TI - Size of uterine leiomyoma is a predictor for massive haemorrhage during caesarean delivery. AB - BACKGROUND: Uterine leiomyoma is a common benign tumour, and a risk factor for various complications during pregnancy and peripartum period. Peripartum haemorrhage is the most critical complication that can cause maternal death. Although the relationship of leiomyoma and peripartum haemorrhage has been indicated, little is known about the characteristics of leiomyoma as predictors for massive haemorrhage in caesarean delivery. OBJECTIVE: We examined whether characteristics of leiomyoma and pregnant patients could predict massive haemorrhage in women undergoing caesarean delivery. STUDY DESIGN: This is a single-institution, retrospective cohort study. We reviewed singleton caesarean deliveries between January 2005 and December 2011. We excluded women with the following risk factors for massive haemorrhage: abnormality of placental position, abruptio placentae, haemorrhagic diseases, hydramnios, and labour arrest after induction. Myomectomy was not performed during delivery. Multivariate logistic regression analysis was performed to identify predictors of massive intraoperative haemorrhage (>=1000 ml). The following predictors were evaluated: maternal age, body mass index, parity, gestational week, birth weight, number of leiomyomas, and volume of the largest leiomyoma. Detailed characteristics of leiomyomas were evaluated using sonography or magnetic resonance imaging. RESULTS: Seven hundred and fifty-nine women were included; 55 women (7.25%) had leiomyoma. Thirty-eight women with leiomyoma underwent magnetic resonance imaging scan. The median intraoperative haemorrhage was 939 ml (395 5296 ml) in women with leiomyoma and 689 ml (129-3060 ml) in women without. Multivariate analysis revealed that a largest leiomyoma >=175 cm3 (odds ratio 6.4 [95% confidence interval: 1.5-27], P = 0.007), birth weight of >=2500 g (2.3 [1.53.6], P < 0.001), and primipara (1.5 [1.1-2.1], P = 0.025) were significant predictors of massive intraoperative haemorrhage. CONCLUSIONS: The presence of a leiomyoma of >=175 cm3, birth weight of >=2500 g, and primipara were found to be predictors for massive intraoperative haemorrhage during caesarean delivery. A leiomyoma >=175 cm3 which is equivalent volume to a 7 cm diameter sphere can be diagnosed in the first trimester using sonography. In cases of cesarean delivery with these predictors, preparation for massive haemorrhage, including storage of autologous blood, may be considered. PMID- 29494996 TI - In vivo systems biology approaches to chronic immune/inflammatory pathophysiology. AB - Systems biology offers an emphasis on integrative computational analysis of complex multi-component processes to enhance capability for predictive insights concerning operation of those processes. The immune system represents a prominent arena in which such processes are manifested for vital roles in physiology and pathology, encompassing dozens of cell types and hundreds of reciprocal interactions. Chronic, debilitating pathologies involving immune system dysregulation have become recognized as increasing in incidence over recent decades. While clinical consequences of immune dysregulation in such pathologies are well characterized, treatment options remain limited and focus on ameliorating symptoms. Because it is difficult to recapitulate more than a severely limited facet of the immune system in vitro, application of systems biology approaches to autoimmune and inflammatory pathophysiology in vivo has opened a new door toward discerning disease sub-groups and developing associated stratification strategies for patient treatment. In particular, early instances of these approaches have demonstrated advances in uncovering previously under appreciated dysregulation of signaling networks between immune system and tissue cells, raising promise for improving upon current therapeutic approaches. PMID- 29494997 TI - Causes of preweaning mortality in organic outdoor sow herds. AB - The aims of the current study were to identify the causes of preweaning piglet mortality and investigate the effect of season and parity on the proportions of mortality causes. The study was conducted in nine herds over a one-year period, and dead piglets were collected for necropsy once during each of the four seasons. In total, 2672 piglets were necropsied of which 60% were live-born but died post-partum (pp), 32% were stillborn and 8% were euthanised. Intra-partum deaths accounted for 88% of stillborn piglets. Eighty-one percent of necropsied live-born piglets died within four days pp. Half of these had a body weight of <1 kg at the time of death. Crushed and starved piglets accounted for 83% and 9% of mortalities until day four pp, respectively. Thirty-three percent of the crushed piglets (age zero to four days) had not suckled prior to death and the proportion of these piglets was lower in summer compared to the remaining part of the year (OR = 0.6, 95% CI [0.5;0.9]) and was higher for multiparous sows compared to first parity sows (OR = 1.7, 95% CI [1.1;2.6]). In conclusion, sow parity and season affected the proportion of crushed piglets before four days of age. Furthermore, the group of crushed piglets was heterogeneous and consisted of both heavy well-fed piglets and small piglets with empty stomachs. Thus, management implementations to lower mortality may differ depending on sow parity, season and individual piglet characteristics. PMID- 29494998 TI - The learning process of gait retraining using real-time feedback in patients with medial knee osteoarthritis. AB - The objective of this study was to investigate the learning process of knee osteoarthritis (KOA) patients learning to change their foot progression angle (FPA) over a six-week toe-in gait training program. Sixteen patients with medial KOA completed a six-week toe-in gait training program with real-time biofeedback. Patients walked on an instrumented treadmill while receiving real-time feedback on their foot progression angle (FPA) with reference to a target angle. The FPA difference (difference between target and actual FPA) was analyzed during i) natural walking, ii) walking with feedback, iii) walking without feedback and iv) walking with a dual-task at the start and end of the training program. Self reported difficulty and abnormality and time spent walking and training were also analyzed. The FPA difference during natural walking was significantly decreased from median 6.9 to median 3.6 degrees i.e. by 3.3 degrees in week six (p < 0.001); adding feedback reduced FPA difference to almost zero. However the dual task condition increased the FPA difference at week one compared to the feedback condition (median difference: 1.8 degrees , p = 0.022), but after training this effect was minimized (median difference: 0.6 degrees , p = 0.167). Self-reported abnormality and difficulty decreased from median 5 to 3 and from median 6 to 3 on the NRS respectively (p < 0.05). Patients with medial KOA could reduce the FPA difference during natural walking after the gait retraining program, with some evidence of a reduction in the cognitive demand needed to achieve this. Automation of adaptions might need support from more permanent feedback using wearable technologies. PMID- 29494999 TI - Flaxseed (linum usitatissimum) flour contributes to bone health in adult male rats. AB - OBJECTIVE: This study evaluated effects of flaxseed flour diet on bone health in adult Wistar male rats at 180 d. METHODS: After birth, pups were randomly assigned: Control (C, n = 12) and flaxseed flour (FF, n = 12) diet during lactation period. At 21 d, pups were weaned and they continued to receive the control and experimental diet, respectively. At 180 d, body length, total bone structure, and femur and lumbar vertebrae were evaluated by dual-energy X-ray absorptiometry. Femoral and lumbar vertebra dimensions, biomechanical properties of femur, and serum osteocalcin were measured. RESULTS: FF produced greater (P <0.05) total (+3.4%) and spine (+5.9%) bone mineral density, total (+10%) and spine (+12%) bone mineral content, total bone area (+8.7%), and osteocalcin (+82%). As to femur, FF produced greater (P <0.05) width of diaphysis (+8.1%), bone mineral density (+5.2%), maximum force (+10.6%), breaking strength (+12.9%), and stiffness (+23%). CONCLUSION: This experimental study found that a diet containing flaxseed flour contributed to bone mineral density and femur resistance at 180 d. PMID- 29495000 TI - Thickened infant formula: What to know. AB - OBJECTIVES: This study aimed to provide an overview of the characteristics of thickened formulas to aid health care providers manage infants with regurgitations. METHODS: The indications, properties, and efficacy of different thickening agents and thickened formulas on regurgitation and gastroesophageal reflux in infants were reviewed. PubMed and the Cochrane database were searched up to December 2016. RESULTS: Based on the literature review, thickened formulas reduce regurgitation, may improve reflux-associated symptoms, and increase weight gain. However, clinical efficacy is related to the characteristics of the formula and of the infant. Commercial thickened formulas are preferred over the supplementation of standard formulas with thickener because of the better viscosity, digestibility, and nutritional balance. Rice and corn starch, carob bean gum, and soy bean polysaccharides are available as thickening agents. Hydrolyzed formulas have recently shown promising additional benefit. CONCLUSIONS: Thickened formulas reduce the frequency and severity of regurgitation and are indicated in formula-fed infants with persisting symptoms despite reassurance and appropriate feeding volume intake. PMID- 29495001 TI - AKT-independent activation of p38 MAP kinase promotes vascular calcification. AB - Vascular calcification is prevalent in patients with atherosclerosis, and oxidative stress promotes pathogenesis of atherosclerosis. We have previously reported that activation of AKT by oxidative stress induces vascular calcification. Using sodium dichloroacetate (DCA), a previously reported small molecule inhibitor of AKT, the present studies uncovered an AKT-independent mechanism in regulating vascular calcification. We found that DCA dose dependently induced calcification of vascular smooth muscle cells (VSMC) in vitro and aortic rings ex vivo. Furthermore, DCA markedly enhanced vascular calcification in atherosclerotic ApoE knockout mice in vivo. DCA-induced VSMC calcification was associated with increased Runx2, but not via activation of AKT, a key upstream signal that upregulates Runx2 during VSMC calcification. In contrast, DCA inhibited AKT activation and induced activation of p38 MAPK in calcified atherosclerotic lesions in vivo and calcified VSMC in vitro. Using a pharmacological inhibitor and shRNA for p38 MAPK, we demonstrated that inhibition of p38 MAPK blocked DCA-induced Runx2 upregulation and VSMC calcification. Furthermore, Runx2 deletion attenuated DCA-induced VSMC calcification. Immunoprecipitation analysis revealed association of p38 MAPK with Runx2, which was enhanced by DCA treatment. Knockdown p38 MAPK inhibited DCA-induced Runx2 transactivity, supporting the function of p38 MAPK in regulating Runx2 transactivity. Our studies have uncovered a new function of DCA in regulating vascular calcification, via AKT-independent activation of p38 MAPK. Furthermore, we have identified novel interaction between p38 MAPK and Runx2 enhances Runx2 transactivity, thus promoting VSMC calcification. These results revealed a novel signaling mechanism underlying DCA-induced vascular calcification, and offer opportunities to identify new therapeutic targets. PMID- 29495002 TI - Synergistic Antitumor Effect of BKM120 with Prima-1Met Via Inhibiting PI3K/AKT/mTOR and CPSF4/hTERT Signaling and Reactivating Mutant P53. AB - BACKGROUND/AIMS: PI3KCA and mutant p53 are associated with tumorigenesis and the development of cancers. NVP-BKM120, a selective pan-PI3K inhibitor, exerts the antitumor activity by suppressing the PI3K signaling pathway. Prima-1Met, a low molecular weight compound, can rescue the gain-of-function of mutant p53 by restoring its transcriptional function. In this study, we investigated whether PI3K inhibition combined with mutant p53 reactivation could enhance the antitumor effect in thyroid cancer cells. METHODS: The effects of BKM120 and Prima-1Met on the proliferation, apoptosis, migration and invasion of thyroid cancer cells were measured by MTT, colony formation, flow cytometry, wound-healing and transwell assays, respectively. Thyroid differentiation was assessed by detecting the expression levels of specific markers using RT-PCR and Western blot. The in vivo antitumor efficacy was analyzed in a mouse xenograft model. RESULTS: The combinational treatment of BKM120 and Prima-1Met significantly enhanced the inhibitions of cell viability, colony formation, migration and invasion, and the induction of apoptosis in thyroid cell lines, and synergistically suppressed tumor xenograft growth by inhibiting the PI3K/Akt/mTOR and EMT signaling pathways, up-regulating p53 targeted genes, and triggering the release of cytochrome c. Moreover, the combination of BKM120 and Prima-1Met suppressed the stemlike traits of thyroid cancer cells and promoted their differentiation by upregulating the expression of thyroid-specific differentiation markers and repressing the expression of cancer stem cell markers. Furthermore, the mechanism study demonstrated that the combinational treatment synergistically abrogated the binding of CPSF4 at the promoter of hTERT and thus suppressed hTERT expression. Consistently, overexpression of hTERT rescued the inhibitions of cell viability, invasion and stem-like traits mediated by the combination of BKM120 and Prima 1Met. CONCLUSION: Our results showed that the combination of BKM120 with Prima 1Met synergistically suppressed the growth of thyroid cancer cells and tumor xenografts via inhibiting PI3K/Akt/mTOR and CPSF4/hTERT signaling and reactivating mutant p53. PMID- 29495003 TI - Knockdown of Bone Morphogenetic Proteins Type 1a Receptor (BMPR1a) in Breast Cancer Cells Protects Bone from Breast Cancer-Induced Osteolysis by Suppressing RANKL Expression. AB - BACKGROUND/AIMS: Bone morphogenetic proteins (BMPs) and BMP receptors widely participate in osteolytic metastasis of breast cancer, while their role in tumor stromal interaction is largely unknown. In this study, we investigated whether BMP receptor type 1a (BMPR1a) can alter the interaction between metastatic cancer cells and osteoclast precursors. METHODS: Adenovirus-mediated RNA interference was used to interrupt target genes of human breast cancer cell lines and nude mice were injected intratibially with the cancer cells. Tumor-bearing mice were examined by bioluminescence imaging and microCT. Sections of metastatic legs were measured by a series of staining methods. Murine bone marrow mononuclear cells or RAW264.7 cells were cultured with conditioned media of breast cancer cells. RT PCR, Western blotting and ELISA were used to test mRNA and protein expressions of target molecules. RESULTS: Expression of BMPR1a of MDA-MB-231-luc cells at tumor bone interface was apparently stronger than that of cancer cells distant from the interface. Mice injected with BMPR1a-knockdown MDA-MB-231-luc cells showed reduced tumor growth and bone destruction compared with control groups. Knockdown (KD) of BMPR1a of MDA-MB-231-luc cells or MCF-7 cells decreased the level of receptor activator for NF-kappaB ligand (RANKL). Level of RANKL in MDA-MB-231-luc cells or MCF-7 cells was reduced by p38 inhibitor. Compared with control group, knockdown of p38 of breast cancer cells decreased cancer-induced osteoclastogenesis. CONCLUSION: Knockdown of BMPR1a of breast cancer cells suppresses their production of RANKL via p38 pathway and inhibits cancer-induced osteoclastogenesis, which indicates that BMPR1a might be a possible target in breast cancer-induced osteolytic metastasis. PMID- 29495004 TI - A Comparative Study of Albumin-Bilirubin Score with Child-Pugh Score, Model for End-Stage Liver Disease Score and Indocyanine Green R15 in Predicting Posthepatectomy Liver Failure for Hepatocellular Carcinoma Patients. AB - BACKGROUND: The albumin-bilirubin (ALBI) grade is a newly proposed model for assessing the hepatic function. This study aimed to compare the value of the ALBI score with Child-Pugh score, model for end-stage liver disease (MELD) score and indocyanine green (ICG) R15 in predicting posthepatectomy liver failure (PHLF). METHODS: Patients undergoing curative resection for hepatocellular carcinoma (HCC) between January 2014 and June 2017 were enrolled. The values of the Child Pugh score, MELD score, ICG R15 and ALBI score in predicting PHLF were evaluated. RESULTS: A total of 473 HCC patients were enrolled. The ALBI score was identified as an independent predictor of PHLF. The AUCs for the Child-Pugh score, MELD score, ICG R15 and ALBI score in predicting PHLF were 0.665, 0.649, 0.668, and 0.745 respectively. Multivariable analyses revealed that the ALBI score was an independent predictor of PHLF regardless of the hepatectomy subgroups, but the Child-Pugh score and MELD score were not significant predictors of PHLF both in major and minor hepatectomy subgroups, and ICG R15 was only a significant predictor of PHLF in minor hepatectomy subgroup. CONCLUSION: The ALBI score showed superior predictive value of PHLF over Child-Pugh score, MELD score and ICG R15. We propose to use the ALBI score to evaluate surgical risk for HCC patients undergoing hepatic resection. PMID- 29495005 TI - Elevated HPV16 E1 Expression Is Associated with Cervical Cancer Progression. AB - OBJECTIVES: The primary replication protein, HPV E1, has been shown to play a role in mitigating host defence and disrupting normal cell cycle processes, leading to the development of cancer. This study investigated the expression profile of HPV16 E1 in various stages of cervical cancer development and the factors that control E1 expression. METHODS: One hundred and twenty-four HPV16 positive cervical samples ranging from normal to CIN 1, CIN 2/3, and SCC lesions were studied. E1 mRNA expression was determined by ddPCR. Methylation of promoters p97 and p670 was quantified by pyrosequencing, while PCR, qPCR, and sequencing were used to determine the physical state and variations of the HPV16 E1 genome. RESULTS: Increased E1 mRNA expression related to disease progression (normal 0.18, CIN 1 0.41, CIN 2/3 0.65, and SCC 0.79) was demonstrated with a significant positive correlation (r = 0.661, p = 0.019). No association between physical state and E1 expression was found. Methylation of p97 and p670 promoters showed significant elevation in SCC compared to normal samples. Only 4.2% showed genomic variations of HPV16 E1 63-bp duplication. CONCLUSION: E1 may play a role in cancer development. The detection of E1 mRNA and promoter methylation may be useful as cancer prognostic markers. PMID- 29495006 TI - Heterozygosity and Chain Multivalents during Meiosis Illustrate Ongoing Evolution as a Result of Multiple Holokinetic Chromosome Fusions in the Genus Melinaea (Lepidoptera, Nymphalidae). AB - Mitotic and meiotic chromosomes from 2 taxa of the genus Melinaea, M. satevis cydon and M. "satevis" tarapotensis (Lepidoptera: Nymphalidae), and from hybrids produced in captivity were obtained using an improved spreading technique and were subsequently analyzed. In one of the taxa, the presence of trivalents and tetravalents at diakinesis/metaphase I is indicative of heterozygosity for multiple chromosome fusions or fissions, which might explain the highly variable number of chromosomes previously reported in this genus. Two large and complex multivalents were observed in the meiotic cells of the hybrid males (32 chromosomes) obtained from a cross between M. "s." tarapotensis (28 chromosomes) and M. s. cydon (40-43 chromosomes). The contribution of the 2 different haploid karyotypes to these complex figures during meiosis is discussed, and a taxonomic revision is proposed. We conclude that chromosome evolution is active and ongoing, that the karyotype of the common ancestor consisted of at least 48 chromosomes, and that evolution by chromosome fusion rather than fission is responsible for this pattern. Complex chromosome evolution in this genus may drive reproductive isolation and speciation, and highlights the difficulties inherent to the systematics of this group. We also show that Melinaea chromosomes, classically considered as holocentric, are attached to unique, rather than multiple, spindle fibers. PMID- 29495007 TI - Functional Morphology of Thecal Glands in the Ovary of Japanese Quails (Coturnix japonica). AB - The role of thecal glands in the ovary of birds remains controversial. Using transmission electron microscopy and immunohistochemistry, immunohistochemical localisation of cyclooxygenase I and II (COX-1 and COX-2), oestrogen receptor alpha and beta (ER-alpha and ER-beta), androgen receptor (AR) and progesterone receptor (PR), a detailed analysis of the thecal glands was performed. Our ultrastructural studies revealed that the thecal glands of the quail ovary consist of 2 cell types, steroid-producing cells (SPCs) and enclosing cells (ENCs). The SPCs are large, light cells containing a varying number of lipid droplets. Their cytoplasm is characterised by a large amount of smooth endoplasmic reticulum. The ENCs are always located at the periphery of the gland. Some ENCs contain an abundant number of microfilaments, but lipid droplets and dense bodies were rare. Within 1 gland, SPCs with distinct COX-2 immunostaining were interspersed between usually larger numbers of moderately COX-2-positive cells. A completely different staining pattern was observed for COX-1, where the cytoplasm of the ENCs was distinctly immunopositive. The SPCs stained only weakly with antibodies to COX-1. The thecal glands showed distinct reactions for ER-beta but only a weak to negative one for ER-alpha, PR, and AR. Our immunohistochemical and ultrastructural data support our hypothesis that the thecal glands of the quail are involved in steroid hormone and prostaglandin synthesis. The prostaglandins secreted by the thecal glands probably contribute to the ovulation of the follicle first in the hierarchy. PMID- 29495008 TI - Identification of Potential Therapeutic Targets Among CXC Chemokines in Breast Tumor Microenvironment Using Integrative Bioinformatics Analysis. AB - BACKGROUND/AIMS: Breast cancer is a common cause of cancer mortality throughout the world. The cross-talk between cancer cells and interstitial cells exerts significant effects on neoplasia and tumor development and is modulated in part by chemokines. CXC is one of four chemokine families involved in mediating survival, angiogenesis, and immunosensitization by chemoattracting leukocytes, and it incentivizes tumor cell growth, invasion and metastasis in the tumor microenvironment. However, the differential expression profiles and prognostic values of these chemokines remains to be elucidated. METHODS: In this study, we compared transcriptional CXC chemokines and survival data of patients with breast carcinoma (BC) using the ONCOMINE dataset, Kaplan-Meier Plotter, TCGA and cBioPortal. RESULTS: We discovered increased mRNA levels for CXCL8/10/11/16/17, whereas mRNA expression of CXCL1/2/3/4/5/6/7/12/14 was lower in BC patients compared to non-tumor tissues. Kaplan-Meier plots revealed that high mRNA levels of CXCL1/2/3/4/5/6/7/12/14 correlate with relapse-free survival (RFS) in all types of BC patients. Conversely, high CXCL8/10/11 predicted worse RFS in BC patients. Significantly, high transcription levels of CXCL9/12/13/14 conferred an overall survival (OS) advantage in BC patients, while high levels of CXCL8 demonstrated shorter OS in all BC sufferers. CONCLUSIONS: Integrative bioinformatics analysis suggests that CXCL8/12/14 are potential suitable targets for precision therapy in BC patients compared to other CXC chemokines. PMID- 29495009 TI - Hidradenitis Suppurativa: Disease Burden and Etiology in Skin of Color. AB - Hidradenitis suppurativa (HS) is a chronic, debilitating skin disease. Although most studies on HS are conducted in largely Caucasian populations, evidence demonstrates a higher prevalence in patients with skin of color, including African and Hispanic populations. These racial subgroups are likely at risk for greater disease burden due to a higher prevalence of components of the metabolic syndrome, comorbid depression, and low socioeconomic status; however, there is a paucity of research in these populations. Additionally, studies examining the genetic and anatomical basis for HS, as well as the response to HS therapies, are lacking for patients with skin of color. Complicating this issue is the limited access to effective medical care, including dermatologists, for African and Hispanic populations as well as other minority groups. In this review, we identify gaps in the knowledge base, highlight the association between HS and patients with skin of color, and provide direction for much needed research into this condition. PMID- 29495010 TI - Impaired Recognition of Positive Emotions in Individuals with Posttraumatic Stress Disorder, Cumulative Traumatic Exposure, and Dissociation. PMID- 29495012 TI - Caprio and Merola: Latin American Contribution to the Development of Liver Surgery. AB - Regarding the history of liver surgery, Latin American pioneers have only occasionally been mentioned in the Anglo-Saxon literature. One of such rare cases was Uruguayan surgeon Gerardo Caprio, who in 1931 published a report about a resection of the left lobe of the liver. This was done during an uneventful period in the development of ideas on this surgical technique, following the remarkable advances made in the last quarter of the 19th Century. The anatomic and liver manipulation concepts used by Caprio had been developed by Merola in reports dating back to 1916 and 1920, which revealed well-grounded disagreements with the most renowned anatomists of the time. This paper discusses Merola and Caprio's academic profile by analyzing their publications, the knowledge base and experience that led the latter to perform such liver resection, and the surgical principles applied to it, which would only be formally adopted worldwide 20 years later. PMID- 29495013 TI - High Tumor Volume to Fetal Weight Ratio Is Associated with Worse Fetal Outcomes and Increased Maternal Risk in Fetuses with Sacrococcygeal Teratoma. AB - OBJECTIVE: Tumor volume to fetal weight ratio (TFR) > 0.12 before 24 weeks has been associated with poor outcome in fetuses with sacrococcygeal teratoma (SCT). We evaluated TFR in predicting poor fetal outcome and increased maternal operative risk in our cohort of SCT pregnancies. METHODS: This is a retrospective, single-center review of fetuses seen with SCT from 1997 to 2015. Patients who chose termination of pregnancy (TOP), delivered elsewhere, or had initial evaluation at > 24 weeks were excluded. Receiver operating characteristic (ROC) analysis determined the optimal TFR to predict poor fetal outcome and increased maternal operative risk. Poor fetal outcome included fetal demise, neonatal demise, or fetal deterioration warranting open fetal surgery or delivery < 32 weeks. Increased maternal operative risk included cases necessitating open fetal surgery, classical cesarean delivery, or ex utero intrapartum treatment (EXIT). RESULTS: Of 139 pregnancies with SCT, 27 chose TOP, 14 delivered elsewhere, and 40 had initial evaluation at > 24 weeks. Thus, 58 fetuses were reviewed. ROC analysis revealed that at <=24 weeks, TFR > 0.095 was predictive of poor fetal outcome and TFR > 0.12 was predictive of increased maternal operative risk. CONCLUSION: This study supports the use of TFR at <=24 weeks for risk stratification of pregnancies with SCT. PMID- 29495011 TI - Potentially Inappropriate Prescribing in Older Adults with Hypertension or Diabetes Mellitus and Hypertension in a Primary Care Setting in Bahrain. AB - OBJECTIVES: The aims of this study were to evaluate: (1) the prevalence and types of potentially inappropriate prescribing in older adults with hypertension or diabetes mellitus and hypertension, and (2) whether or not differences in the training of primary care physicians were associated with potentially inappropriate prescribing. MATERIALS AND METHODS: Primary care prescriptions issued by family physicians and general practitioners were audited using Screening Tool of Older Persons' Prescriptions criteria (version 1), with 18 out of 65 applicable criteria. Descriptive statistics were used to test the difference between proportions, and two-tailed t test was used for continuous variables. RESULTS: A total of 2,090 outpatient prescriptions were written during the study period; of these, 712 (34.1%) were potentially inappropriate. The mean number of drugs per patient was 6.03 (+/-2.5). Of the 712 prescriptions, 543 (76.3%) were used for the treatment of acute medical illnesses. The most common examples of potentially inappropriate prescribing were: orphenadrine (n = 174; 8.33%), long-term nonsteroidal anti-inflammatory drugs for > 3 months (n = 150; 7.18%), proton pump inhibitors for > 8 weeks (n = 135; 6.46%), antihypertensive therapy duplication (n = 59; 2.82%), long-acting glyburide (n = 48; 2.29%), and chlordiazepoxide for > 1 month (n = 44; 2.11%). Family physicians showed a greater tendency toward potentially inappropriate prescribing compared to general practitioners, but the difference was nonsignificant (n = 514 [34.75%] vs. n = 162 [31.3%]; p = 0.16). CONCLUSIONS: The prevalence of potentially inappropriate prescribing (i.e., 34.1%) was within the spectrum reported worldwide and unrelated to the training backgrounds of physicians. Most of the identified potentially inappropriate prescribing (76.3%) in older adults was associated with medications for acute medical illnesses and hence inappropriate polypharmacy should be discouraged. PMID- 29495014 TI - Venous Thromboembolism during Interventional MRI-Guided Stereotactic Surgery. AB - BACKGROUND/AIMS: Interventional MRI (iMRI) allows real-time confirmation of electrode and microcatheter location in anesthetized patients; however, MRI compatible pneumatic compression devices (PCD) to reduce the periprocedural venous thromboembolism (VTE) risk are not commercially available. Given the paucity of literature on VTE following iMRI surgery, better characterizing patients suffering this complication and the incidence of this event following iMRI procedures is pivotal for defining best surgical practices. We aim to investigate the incidence of postoperative VTE in iMRI procedures without the use of PCD. METHODS: Medical records and operative times of patients were retrospectively reviewed. Patient demographics and mean surgical durations were reported with statistical comparisons via ANOVA and the 2-tailed Student t test, an alpha of 0.05, and the Bonferroni correction. Patients experiencing postoperative VTE underwent an in-depth chart review. RESULTS: Two out of two hundred ten (0.95%) iMRI procedures resulted in postoperative VTE events. There were statistically significant differences in procedure times between unilateral electrode (157.5 +/- 5.7 min), bilateral electrode (193.6 +/- 2.9 min), and bilateral gene therapy procedures (467.3 +/- 26.5 min). Both patients had longer than-average operative times for their respective procedures. CONCLUSIONS: The incidence of postoperative VTE is low following iMRI procedures, even without the use of PCD during surgery. PMID- 29495016 TI - Age Invariance of the Cannabis Abuse Screening Test in a Probabilistic Sample of Cannabis Users. AB - The Cannabis abuse screening test (CAST) is a short test used for screening those with problematic cannabis use. Recently, its invariance toward age was tested in an Israeli sample of cannabis users, but this study had some sample and methodological limitations: it was conducted in a volunteer sample aged 18-40 and considered the CAST items as continuous variables, although they are based on 5 point Likert scales. We thus tested the CAST invariance toward age (15-24, 25-34, and 35-64 years old) using a French probabilistic sample of 1,351 past-year cannabis users aged 15-64 and using appropriate methods for categorical items and survey weights. Factors retained (non-recreational use and problems) were the same as those mentioned in previous studies. Scalar invariance held for the "problems" factor but only partial scalar invariance was supported for the "non recreational use" factor. Caution is thus needed when the CAST score is compared across age groups. PMID- 29495015 TI - Symptom-Specific Effects of Psychotherapy versus Combined Therapy in the Treatment of Mild to Moderate Depression: A Network Approach. PMID- 29495017 TI - Detection of Genotype 1a and 1f of Hepatitis E Virus in Patients Treated at Tertiary Care Hospitals in Central India. AB - BACKGROUND AND AIMS: An acute hepatitis, caused by hepatitis E virus (HEV), is a significant global health concern, especially in developing countries. HEV has 1 serotype and 8 genotypes, which are further divided into subtypes. Despite the availability of sporadic cases and outbreak data from India, specific information regarding HEV epidemiological data is lacking from central India. This study was conducted to understand epidemiological and molecular features of HEV in central India. METHODS: In this 3-year study conducted from July 2012 to June 2015, IgM ELISA was used for the diagnosis of suspected HEV cases. For identifying the genotype, nRT PCR was conducted and the PCR products were sequenced and analysed. Clinical and demographic data were analysed using statistical tools to highlight the trends. RESULT: Out of 1,369 suspected cases, 341 (24.9%) were positive for HEV. The positivity was significantly higher in males (69.2%) and in the age group of > 15-45 years (72.5%). The HEV cases peaked during the summer. Subtypes 1a and 1f of genotype 1 were detected in the area during the study period. CONCLUSION: HEV is a major aetiological agent of viral hepatitis in central India with adults and males at higher risk of infection. Two subtypes of the virus were detected in the region. Continuous serological surveillance and molecular monitoring will help to understand the epidemiology of HEV infection, outbreak mitigation and aid in providing treatment. PMID- 29495018 TI - Localization and Spatial Discrimination in Children and Adolescents with Moderate Sensorineural Hearing Loss Tested without Their Hearing Aids. AB - The present study investigated two measures of spatial acoustic perception in children and adolescents with sensorineural hearing loss (SNHL) tested without their hearing aids and compared it to age-matched controls. Auditory localization was quantified by means of a sound source identification task and auditory spatial discrimination acuity by measuring minimum audible angles (MAA). Both low and high-frequency noise bursts were employed in the tests to separately address spatial auditory processing based on interaural time and intensity differences. In SNHL children, localization (hit accuracy) was significantly reduced compared to normal-hearing children and intraindividual variability (dispersion) considerably increased. Given the respective impairments, the performance based on interaural time differences (low frequencies) was still better than that based on intensity differences (high frequencies). For MAA, age-matched comparisons yielded not only increased MAA values in SNHL children, but also no decrease with increasing age compared to normal-hearing children. Deficits in MAA were most apparent in the frontal azimuth. Thus, children with SNHL do not seem to benefit from frontal positions of the sound sources as do normal-hearing children. The results give an indication that the processing of spatial cues in SNHL children is restricted, which could also imply problems regarding speech understanding in challenging hearing situations. PMID- 29495019 TI - Effects of Psychological Intervention in Glycemic Control of Patients with Type 2 Diabetes in Integrated Primary Care Setting. PMID- 29495020 TI - Effectiveness of Resin-Based Sealants with and without Fluoride Placed in a High Caries Risk Population: Multicentric 2-Year Randomized Clinical Trial. AB - A split-mouth randomized clinical trial was carried out to assess the effectiveness of sealants in preventing carious ICDAS (International Caries Detection and Assessment System) 3-6 lesions within a 2-year follow-up. We evaluated the effectiveness of 2 types of resin-based sealants, with and without fluoride, their retention rates, and the caries risk factors related to their outcomes. The study included 663 tooth pairs in 400 children (aged 5-15 years) considered to be at high individual caries risk (ICR) and presenting permanent molars free of caries or affected by ICDAS 1-2 lesions. In the first randomization, molars were either randomized to the treatment group receiving a dental sealant or the control group (nontreatment), and in the second randomization the sealant material to be used in the intervention group was selected. Uni- and multivariate Cox proportional hazard models were employed. At the 2-year follow-up, 483 tooth pairs were assessed: sealed molars had 83% (adjusted HR = 0.17; 95% CI: 0.15-0.20) less risk of developing ICDAS 3-6 lesions than molars without sealant. The magnitude of the protective effect was lower among teeth with ICDAS 1-2 lesions or with occlusal deep fissures than without. If the total retention rate of sealants was 70% at 2 years, sealant loss was not associated with the risk of caries (HR = 1.29, 95% CI: 0.92-1.79, p = 0.14). Sealants allow the prevention of new ICDAS 3-6 lesions or progression of noncavitated carious lesions in children at high ICR, and the effect of the sealant was similar regardless of whether it contained fluoride or not. PMID- 29495021 TI - Dapagliflozin Aggravates Renal Injury via Promoting Gluconeogenesis in db/db Mice. AB - BACKGROUND/AIMS: A sodium-glucose co-transporter-2 inhibitor dapagliflozin is widely used for lowering blood glucose and its usage is limited in type 2 diabetes mellitus patients with moderate renal impairment. As its effect on kidney function is discrepant and complicated, the aim of this study is to determine the effect of dapagliflozin on the progression of diabetic nephropathy and related mechanisms. METHODS: Twelve-week-old male C57BL/6 wild-type and db/db mice were treated with vehicle or 1 mg/kg dapagliflozin for 12 weeks. Body weight, blood glucose, insulin tolerance, glucose tolerance, pyruvate tolerance and 24-hour urine were measured every 4 weeks. At 24 weeks of age, renal function was evaluated by blood urea nitrogen level, creatinine clearance, urine output, urinary albumin excretion, Periodic Acid-Schiff staining, Masson's trichrome staining and electron microscopy. Changes in insulin signaling and gluconeogenic key regulatory enzymes were detected using Western blot analysis. RESULTS: Dapagliflozin did not alleviate but instead aggravated diabetic nephropathy manifesting as increased levels of microalbuminuria, blood urea nitrogen, and glomerular and tubular damage in db/db mice. Despite adequate glycemic control by dapagliflozin, urinary glucose excretion increased after administration before 24 weeks of age and was likely associated with renal impairment. Increased urinary glucose excretion was mainly derived from the disturbance of glucose homeostasis with elevated hepatic and renal gluconeogenesis induced by dapagliflozin. Although it had no effect on insulin sensitivity and glucose tolerance, dapagliflozin further induced the expression of gluconeogenic key rate-limiting enzymes through increasing the expression levels of FoxO1 in the kidney and liver. CONCLUSION: These experimental results indicate that dapagliflozin aggravates diabetes mellitus-induced kidney injury, mostly through increasing gluconeogenesis. PMID- 29495022 TI - Medical conditions and erosive tooth wear. AB - There are many reasons why it is vital that dental professionals identify signs and symptoms that suggest that an individual's erosive tooth wear (ETW) may be linked to a broader medical problem than just poor diet. Primarily, spotting an underlying medical cause for ETW increases the likelihood that further deterioration in the individual's oral health will be prevented. However, perhaps more importantly, many of the medical conditions which are commonly related to ETW can have serious and even possibly fatal consequences if left untreated or not diagnosed. This paper reviews the nature of the most common and serious medical conditions related to ETW, such as gastro-oesophageal reflux disease (GORD), laryngo-pharyngeal reflux (LPR) and eating disorders. This article also covers the role of the dental team in the diagnoses, prevention and management of these conditions. PMID- 29495023 TI - A guide to managing tooth wear: the Radboud philosophy. AB - This paper explains a conservative, pragmatic and minimally invasive intervention concept for the treatment of severe tooth wear patients based on the Radboud Tooth Wear Project in the Netherlands. Guidelines and flowcharts for management of severe tooth wear patients and rehabilitation in increased vertical dimension of occlusion are presented. We concluded that: (a) Restorative treatment is not always indicated, even for patients with severe tooth wear. (b) If the patient has no complaints, counselling and monitoring is probably the best option. (c) Minimally invasive and adhesive restorative strategies are preferred when severe tooth wear patients are to be treated in increased vertical dimension, especially when young patients are involved. (d) Clinical evidence for a suitable restorative treatment protocol is limited to five-year follow up for direct composites. This material seems to be suitable for rehabilitation in increased vertical dimension on the middle long term. Clinical results for indirect techniques are not available yet. (e) Restorations, including those that are considered 'definitive' may prove to have a limited lifetime in patients with severe tooth wear due to bruxism and erosion. Explanation of the possible treatment options and expected complications should be included in the informed consent. PMID- 29495024 TI - The restorative management of tooth wear involving the aesthetic zone. AB - The aim of this article is to describe a systematic approach that facilitates the establishment of a clear and appropriate diagnosis when a dentate patient presents with tooth wear involving their aesthetic zone. It will also detail the protocols that are required to allow for the development of an acceptable aesthetic prescription within the limits of the functional constraints presented by the patient (where active restorative intervention may be indicated), as well as to communicate the manner by which this information can be transferred to ultimately enable the successful and predictable rehabilitation of the affected areas. An overview will also be provided of the tooth-coloured dental materials and restorative techniques that have been commonly applied to deliver the predictable and effective dental care of worn teeth in the aesthetic zone. PMID- 29495025 TI - Early diagnosis and daily practice management of erosive tooth wear lesions. AB - This paper explores some of the most relevant questions faced by dental practitioners when diagnosing early erosive tooth wear (ETW) and implementing non operative management of this condition over time. It focuses on the identification of clinical signs and common locations of ETW lesions, the assessment of individual risk and the implementation of non-operative management strategies, aiming to arrest and/or reduce the rate of ETW progression and avoid its advance to pathological stages. To this end, we present a novel and comprehensive approach that considers the whole dentition of patients rather than individual groups of teeth or dental surfaces only, illustrating it with a series of clinical photographs. Dental practitioners may find this approach particularly helpful as it closely simulates the clinical examinations of patients of all age groups carried out in daily practice. The clinical signs of early ETW lesions are subtle and often not perceived as relevant by unaware clinicians. However, the early diagnosis and implementation of non-operative management strategies, especially at younger ages, is fundamental for the proper control of ETW over time. PMID- 29495026 TI - Clinical guidance and an evidence-based approach for restoration of worn dentition by direct composite resin. AB - This paper aims to provide the dentist with practical guidance on the technique for direct composite restoration of worn teeth. It is based on current evidence and includes practical advice regarding type of composite, enamel and dentine preparation, dentine bonding and stent design. The application of direct composite has the advantage of being additive, conserving as much of the remaining worn tooth as possible, ease of placement and adjustment, low maintenance and reversibility. A pragmatic approach to management is advocated, particularly as many of the cases are older patients with advanced wear. Several cases restored by direct composite build-ups illustrate what can be achieved. The restoration of the worn dentition may be challenging for many dentists. Careful planning and simple treatment strategies, however, can prove to be highly effective and rewarding. By keeping any intervention as simple as possible, problems with high maintenance are avoided and management of future failure is made easier. An additive rather than a subtractive treatment approach is more intuitive for worn down teeth. Traditional approaches of full-mouth rehabilitation with indirect cast or milled restorations may still have their place but complex treatment modalities will inevitably be more time consuming, more costly, possibly require specialist care and still have an unpredictable outcome. Composite resin restorations are a universal restorative material familiar to dentists from early-on in the undergraduate curriculum. This review paper discusses the application of composite to restore the worn dentition. PMID- 29495028 TI - A guide to the clinical management of attrition. AB - Attrition is an enigmatic condition often found in older individuals and often as a result of bruxism which can take place as a result of either day bruxism, night bruxism or both. Various studies and systemic reviews clearly shown that tooth wear is an age-related phenomena and the last Adult Dental Health Survey showed that 15% of participants showed moderate wear and 3% severe wear with 80% of patients over 50 years of age showing signs of wear. This review examines current theories around the aetiological factors contributing to attrition together with the clinical management of attrition focusing on minimal intervention where possible. PMID- 29495029 TI - Tooth wear risk assessment and care-planning in general dental practice. AB - Objective To assess charting, risk assessment and treatment-planning of tooth wear between recently qualified and experienced dentists in general dental practice.Design Service evaluation.Setting Multi-setting evaluation of three mixed NHS/Private general dental practices in North-East London.Methods The clinical notes of new patient examinations on dentate adults presenting from the 1 October 2016 to 31 December 2016 were audited collecting data on tooth wear charting, risk assessment and treatment planning. Data were analysed using descriptives, chi square and logistic regressions in SPSS. Significance was inferred at p <0.05.Results Foundation dentists and experienced dentists performed 85 and 200 new patient examinations, respectively, during the evaluation period. Tooth wear was charted for 48% of those attending foundation dentists and 5% of those attending experienced dentists. Diet was assessed in 50.6% of patients examined by foundation dentists and 1.0% of patients examined by experienced dentists. Foundation dentists were more likely to chart tooth wear, risk assess and preventively manage tooth wear compared to experienced dentists (p <0.001).Conclusion This service evaluation highlights that improvements are required in recording, risk assessing and preventive treatment planning of erosive tooth wear. Experienced dentists were less likely to risk assess tooth wear and less likely to provide preventive treatment. Experienced GDPs may benefit from re-training in this area. PMID- 29495027 TI - Erosive tooth wear - a review on global prevalence and on its prevalence in risk groups. AB - Erosion is a common phenomenon in the general population of developed countries. However, due to variations in indices, sample sizes and general study designs, it is difficult to compare the various studies and to estimate actual global prevalence. Therefore, the aim of this present paper is to give a narrative overview on the data available on the global prevalence of erosion. Information on prevalence is not available from each country; in particular, data from Asia, Africa, South America, North America and large parts of South-Eastern Europe are unavailable. There is a large variation in global prevalence ranging between 0 and 100%. Calculating a rough mean from the data available, a mean prevalence in deciduous teeth between 30% and 50% and in permanent teeth between 20% and 45% can be estimated. There seems to be a gender difference and an increase in prevalence with age. Prevalence studies on erosion risk groups show comparable variation. Only in patients with gastro-oesophageal reflux disease (GORD) and eating disorders associated with vomiting can a clear impact on erosion prevalence be found. In people who consume acidic foods and drinks, a higher risk can be found for some specific comestibles. However, there is a lack of controlled epidemiological studies, making it difficult to generalise. There is a clear need for well-designed studies on this issue. PMID- 29495030 TI - The management of tooth wear with crowns and indirect restorations. AB - This manuscript summarises the reasons behind choosing indirect restorations in the treatment of tooth wear. The purpose of this article is to discuss the use of crowns as a restorative treatment option for tooth wear. There are also challenges with the use of composites as they can repeatedly fail and in these situations the indications for crowns for treatment of tooth wear is worthy of consideration. This article is part of a themed issue discussing the management of tooth wear. PMID- 29495032 TI - [Editor's Comment]. PMID- 29495034 TI - ? PMID- 29495035 TI - ? PMID- 29495036 TI - ? PMID- 29495031 TI - Prevention of erosive tooth wear: targeting nutritional and patient-related risks factors. AB - This article provides an overview of the nutritional and patient-related risk factors involved in the aetiology of erosive tooth wear (ETW) and the preventive strategies to counteract them. The first step is to diagnose clinical signs of ETW and to recognise causal factors. Low pH and high buffer capacity of foods/drinks are the major risk factors, while the calcium concentration is the main protective factor. Reduction of frequency of consumption and contact time of erosive foods/drinks with the teeth, use of straws appropriately positioned and consumption of dairy products are advisable. Oral hygiene has a role in the development of ETW, however, postponing toothbrushing is not clinically advisable. In cases of drug abuse, chronic alcoholism, GERD or bulimia, the patient must be referred to a doctor. Immediately after vomiting, patients might be advised to rinse the mouth. Saliva has an important protective role and patients with reduced salivary flow can benefit from the use of chewing gum. Recent studies have focused on improving the protective capacity of the acquired pellicle as well as on the role of protease inhibitors on dentine erosion. However, the degree of evidence for these preventive measures is low. Clinical trials are necessary before these measures can be recommended. PMID- 29495039 TI - ? PMID- 29495040 TI - [A new atraumatic device for liposuction and injection represents a technical advance for primary fat injection after cordectomy]. AB - Lipoinjections into the vocal folds are well established in otorhinolaryngology. Currently, lipofilling in patients with surgical defects after laser cordectomy is discussed. We describe a new device for liposuction and lipofilling for primary vocal fold reconstruction after laser cordectomy. A patient with a surgical defect after pT1a glottic cancer is presented. Primary lipoinjection after laser cordectomy was documented as a safe and easy method to reconstruct the surgical defect. No relevant complications have been observed. PMID- 29495041 TI - [Gastro-Oesophageal Reflux Disease - How to Manage if PPI are not Sufficiently Effective, not Tolerated, or not Wished?] PMID- 29495042 TI - [Through Cochlear Implant to CODA? - Cochlear Implantation in Children with Deaf or Severely Hearing-impaired Parents: Conditions, Problems, Results]. AB - Cochlear implantation in children with deaf or severely hearing-impaired parents is possible. It is necessary to organize intensive auditory-verbal training before the children undergo implantation. Success of the children depends on mediators supporting the parents. These children grow up bilingually: sign language and spoken language. They can attend schools for the hard-of-hearing or regular schools for the hearing. PMID- 29495043 TI - [From the Expert's Office: What is a biopsy with incision? Examination of encoding in German Diagnosis Related Groups in Otorhinolaryngology]. PMID- 29495044 TI - [Head & Neck MRI: What ENT specialists should know]. AB - Magnetic resonance imaging (MRI) has become an important imaging technique for otorhinolaryngology. The aim of the present CME contribution for ENT physicians is to provide an overview of the advantages and disadvantages as well as the possibilities of head and neck MRI and to summarize the main clinical applications of the various MRI sequences. Basic sequences (T1w, T2w, T1wC+) and fat suppression sequences (TIRM/STIR, Dixon, Spectral Fat sat) are the basis for evaluating inflammation, congenital lesions and tumors. High-resolution 3D sequences - SSFP (CISS, FIESTA), SPACE, VISTA, 3D-FLAIR - are used to assess the cranial nerves, labyrinth, and endolymphatic hydrops in Morbus Meniere. Vascular sequences (3D-TOF, TWIST/TRICKS) are used in vascular contact syndromes and vascular malformations. Diffusion sequences (EPI-DWI, non-EPI-DWI, RESOLVE) are used for the evaluation of cholesteatoma, assessment of malignancy and evaluation of response to radio (chemo) therapy. PMID- 29495045 TI - ? PMID- 29495046 TI - ? PMID- 29495047 TI - [Oral health-related quality of life in cancer patients]. AB - OBJECTIVE: To date, only a few studies have investigated oral health-related quality of life (OH-QoL) in cancer patients. The European Organisation for Research and Treatment of Cancer (EORTC) has therefore developed a questionnaire, the Quality of Life Questionnaire - Oral Health Module 15 (EORTC QLQ-OH15), to enable investigation of OH-QoL. The aim of this study was to examine OH-QoL in a real-world setting. PATIENTS AND METHODS: OH-QoL was measured using the EORTC QLQ OH15 in cancer patients at a non-specified time during treatment (t1) as well as two weeks (t2) and three months (t3) after baseline. Potential predictors of OH QoL such as age, sex, education, cancer entity and therapy were explored. RESULTS: At baseline 40 patients participated in the study. At t2, patients suffered more often from sticky saliva and experienced a higher sensitivity during eating or drinking compared to t1. Additionally, dentures were worn less often. At t3, patients were less often satisfied with information concerning oral side effects. Furthermore, patients older than 50 years, women, patients with poorer education, patients with head and neck cancer, and patients undergoing palliative therapy, surgery or targeted therapy indicated worse OH-QoL at t2 than other patients. CONCLUSIONS: OH-QoL is of clinical importance in cancer patients. It seems to be decreased after the end of treatment, and not only in patients with head and neck cancer. Despite its brevity, the EORTC QLQ-OH15 is able to capture these differences, and is well accepted by patients. It can be recommended for future studies in this area. PMID- 29495048 TI - [A german-wide inquiry about the significance of ultrasound in the head and neck area]. AB - A german-wide inquiry was performed for the evaluation of diagnostic ultrasound, current applications and the significance in the head and neck area throughout 2013 and 2014. We focused on the integration of the ultrasound diagnostic in the ENT routine and compared the implementation of ultrasound in the practice and in the clinical setting. Furthermore the current concepts of standardization in sonographic documentation, training guidelines and assessment of clinical impact of the ultrasound were evaluated. PMID- 29495049 TI - [Restricted sleep as a secondary psychosocial consequence of facial palsy]. AB - BACKGROUND: Facial palsy (FP) is a paralysis of facial muscles and one of the most common motor failures. It is associated with intense impairment of health related quality of life and depressive symptoms. Sleep disorders as a result of FP are often attributed to illness-related impairments, although psychosocial problems might also be the cause. This study examined the direct and indirect effects of FP on sleep quality. METHODS: The sample of this cross-sectional study included N = 81 patients with FP. Symptoms of FP (FACE), sleep quality (PSQI), quality of life (SF36), depression (PHQ9) and social anxiety (LSAS) were measured. Mediation models were used to investigate the relationship between symptoms of FP, social anxiety, depression and sleep quality. RESULTS: Sleep quality was decreased in 33.3 % of patients. The subjective severity of the FP correlated significantly with sleep quality. Mediation analyses suggest a causal link between the severity of FP, symptoms of social anxiety, depressive symptoms and restricted sleep quality. However, including social anxiety and depression as mediators resulted in no direct effects of FP on sleep quality. CONCLUSION: Sleep problems related to FP seem to be caused less by physical than by an indirect consequence of psychosocial impairment. The change in the face associated with FP causes psychological problems which in turn lead to reduced sleep quality. The medical care of FP patients should therefore also consider the psychosocial consequences in order to prevent the onset of mental disorders (such as depression) and sleep disorders. PMID- 29495051 TI - [Ecological Momentary Interventions in Psychiatry: The Momentum for Change in Daily Social Context]. PMID- 29495050 TI - Comparison of the Revenue Situation in Interventional Radiology Based on the Example of Peripheral Artery Disease in the Case of a DRG Payment System and Various Internal Treatment Charges. AB - PURPOSE: Calculation of process-orientated costs for inpatient endovascular treatment of peripheral artery disease (PAD) from an interventional radiology (IR) perspective. Comparison of revenue situations in consideration of different ways to calculate internal treatment charges (ITCs) and diagnosis-related groups (DRG) for an independent IR department. MATERIALS AND METHODS: Costs (personnel, operating, material, and indirect costs) for endovascular treatment of PAD patients in an inpatient setting were calculated on a full cost basis. These costs were compared to the revenue situation for IR for five different scenarios: 1) IR receives the total DRG amount. IR receives the following DRG shares using ITCs based on InEK shares for 2) "Radiology" cost center type, 3) "OP" cost center type, 4) "Radiology" and "OP" cost center type, and 5) based on DKG-NT (scale of charges of the German Hospital Society). RESULTS: 78 patients (mean age: 68.6 +/- 11.4y) with the following DRGs were evaluated: F59A (n = 6), F59B (n = 14), F59C (n = 20) and F59 D (n = 38). The length of stay for these DRG groups was 15.8 +/- 12.1, 9.4 +/- 7.8, 2.8 +/- 3.7 and 3.4 +/- 6.5 days Material costs represented the bulk of all costs, especially if new and complex endovascular procedures were performed. Revenues for neither InEK shares nor ITCs based on DKG-NT were high enough to cover material costs. Contribution margins for the five scenarios were 1 = ? 1,539.29, 2 = ? -1,775.31, 3 = ? -2,579.41, 4 = ? -963.43, 5 = ? -2,687.22 in F59A, 1 = ? -792.67, 2 = ? -2,685.00, 3 = ? 2,600.81, 4 = ? -1,618.94, 5 = ? -3,060.03 in F59B, 1 = ? -879.87, 2 = ? 2,633.14, 3 = ? -3,001.07, 4 = ? -1,952.33, 5 = ? -3,136.24 in F59C and 1 = ? 703.65, 2 = ? -106.35, 3 = ? -773.86, 4 = ? 205.14, 5 = ? -647.22 in F59 D. InEK shares return on average ? 150 - 500 more than ITCs based on the DKG-NT catalog. CONCLUSION: In this study positive contribution margins were seen only if IR receives the complete DRG amount. InEK shares do not cover incurred costs, with material costs representing the main part of treatment costs. Internal treatment charges based on the DKG-NT catalog provide the worst cost coverage. KEY POINTS: . Internal treatment charges based on the DKG-NT catalog provide the worst cost coverage for interventional radiology at our university hospital.. . Shares from the InEK matrix such as the cost center "radiology" or "OP" as revenue for IR are not sufficient to cover incurred costs. A positive contribution margin is achieved only in the case of a compensation method in which IR receives the total DRG amount.. CITATION FORMAT: . Vogt FM, Hunold P, Haegele J et al. Comparison of the Revenue Situation in Interventional Radiology Based on the Example of Peripheral Artery Disease in the Case of a DRG Payment System and Various Internal Treatment Charges. Fortschr Rontgenstr 2017; 190: 348 - 357. PMID- 29495052 TI - [Image Findings in Spontaneous Intracranial Hypotension (SIH)]. PMID- 29495053 TI - ? PMID- 29495054 TI - ? PMID- 29495055 TI - ? PMID- 29495056 TI - ? PMID- 29495058 TI - ? PMID- 29495057 TI - ? PMID- 29495059 TI - ? PMID- 29495060 TI - ? PMID- 29495061 TI - ? PMID- 29495062 TI - Who's doing your scan? A reply to Dr Seitz. PMID- 29495063 TI - Slow-release fluoride devices for the control of dental decay. AB - BACKGROUND: Slow-release fluoride devices have been investigated as a potentially cost-effective method of reducing dental caries in people with high risk of disease. This is the second update of the Cochrane Review first published in 2006 and previously updated in 2014. OBJECTIVES: To evaluate the effectiveness and safety of different types of slow-release fluoride devices on preventing, arresting, or reversing the progression of carious lesions on all surface types of primary (deciduous) and permanent teeth. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following electronic databases: Cochrane Oral Health's Trials Register (to 23 January 2018); the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 12) in the Cochrane Library (searched 23 January 2018); MEDLINE Ovid (1946 to 23 January 2018); and Embase Ovid (1980 to 23 January 2018). The US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials (23 January 2018). We placed no restrictions on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: Parallel randomised controlled trials (RCTs) comparing slow-release fluoride devices with an alternative fluoride treatment, placebo, or no intervention in all age groups. The main outcome measures sought were changes in numbers of decayed, missing, and filled teeth or surfaces (DMFT/DMFS in permanent teeth or dmft/dmfs in primary teeth), and progression of carious lesions through enamel and into dentine. DATA COLLECTION AND ANALYSIS: We conducted data collection and analysis using standard Cochrane review methods. At least two review authors independently performed all the key steps in the review such as screening of abstracts, application of inclusion criteria, data extraction, and risk of bias assessment. We resolved discrepancies through discussions or arbitration by a third or fourth review author. MAIN RESULTS: We found no evidence comparing slow-release fluoride devices against other types of fluoride therapy.We found only one double-blind RCT involving 174 children comparing a slow-release fluoride device (glass beads with fluoride were attached to buccal surfaces of right maxillary first permanent molar teeth) against control (glass beads without fluoride were attached to buccal surfaces of right maxillary first permanent molar teeth). This study was assessed to be at high risk of bias. The study recruited children from seven schools in an area of deprivation that had low levels of fluoride in the water. The mean age at the beginning of the study was 8.8 years and at the termination was 10.9 years. DMFT in permanent teeth or dmft in primary teeth was greater than one at the start of the study and greater than one million colony-forming units of Streptococcus mutans per millilitre of saliva.Although 132 children were still included in the trial at the two-year completion point, examination and statistical analysis was performed on only the 63 children (31 in intervention group, 32 in control group) who had retained the beads (retention rate was 47.7% at 2 years). Among these 63 children, caries increment was reported to be statistically significantly lower in the intervention group than in the control group (DMFT: mean difference -0.72, 95% confidence interval (CI) -1.23 to -0.21; DMFS: mean difference -1.52, 95% CI -2.68 to -0.36 (very low-quality evidence)). Although this difference was clinically significant, it only holds true for those children who maintain the fluoride beads; over 50% of children did not retain the beads.Harms were not reported within the trial report. Evidence for other outcomes sought in this review (progression to of caries lesion, dental pain, healthcare utilisation data) were also not reported. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine the caries-inhibiting effect of slow release fluoride glass beads. The body of evidence available is of very low quality and there is a potential overestimation of benefit to the average child. The applicability of the findings to the wider population is unclear; the study had included children from a deprived area that had low levels of fluoride in drinking water, and were considered at high risk of caries. In addition, the evidence was only obtained from children who still had the bead attached at 2 years (48% of all available children); children who had lost their slow-release fluoride devices earlier might not have benefited as much from the devices. PMID- 29495064 TI - Impact of maternal HIV on umbilical cord lactate measurement at delivery in a South African labor ward. AB - OBJECTIVE: To assess umbilical artery lactate levels and perinatal outcomes among women with and without HIV infection. METHODS: The present prospective cohort study recruited women planning to undergo vaginal delivery at Kalafong Hospital, South Africa, between March 3 and November 12, 2014. Umbilical artery lactate levels were measured and perinatal outcome data were recorded. Outcome analyses were stratified by maternal HIV status, and a subgroup analysis was performed where women with a CD4 count below 350 * 106 cells/L were compared with women without HIV. RESULTS: In total, 936 women with singleton fetuses were enrolled. Maternal HIV status was available for 897 (95.8%) participants, of whom 202 (21.6%) had HIV infections. Overall, 186 (92.1%) women with HIV infections received prophylaxis or treatment. There was no difference between participants with and without HIV infections in the preterm delivery rate (P=0.770), mode of delivery (P=0.354), neonatal resuscitation rate (P=0.717), 1- or 5-minute Apgar scores below 7 (P=0.353), or the rate of having an umbilical artery lactate level above 5.45 mmol/L (P=0.301). Similarly, there were no differences in outcomes in the subgroup analysis of women with a CD4 count below 350 * 106 cells/L. CONCLUSION: Umbilical artery lactate levels and perinatal outcomes were found to be comparable between patients with and without HIV infections in a South African setting. PMID- 29495065 TI - Growth Patterns and Individual Variation in Mid-sagittal Facial Soft Tissue Depth from Childhood to Adulthood. AB - Previous studies have used longitudinal samples to investigate growth of the skeletal aspects of the face, although far less has been done on facial soft tissue. This study uses a larger sample than previous studies on the same data (Denver and Fels growth series) to explore covariation of bony and soft facial dimensions comprehensively from childhood to adulthood. A total of 1036 lateral cephalometric radiographs were digitized from 60 individuals, and distances between facial landmarks were measured using ImageJ. Multivariate analysis of variance (MANOVA) showed all bony facial landmark distances were significantly different (p > 0.05) between age groups; however, only half were significantly different between sexes. Further analysis showed the effect of age (calculated as eta-squared) explained a greater percentage of total variation (20%) than sex (15%). Overall, soft tissue changes between 0 and 19 years of age were small (<3 mm) and only some were correlated to underlying facial skeleton dimensions. PMID- 29495066 TI - The Effects of Storage and Additives on Postmortem HbA1c Measurements. AB - HbA1c is used in forensic toxicology to identify undiagnosed diabetes mellitus (DM) and those with poor glycemic control prior to death. HbA1c is typically measured in whole blood collected in tubes containing ethylenediaminetetraacetic acid (EDTA). The effect of other additives, including sodium fluoride (NaF), is unclear. Furthermore, the assessment of short- and long-term stability of HbA1c has produced conflicting results. In this study, we collected paired postmortem blood samples in EDTA and NaF tubes (n = 142) to assess their comparability for HbA1c measurement. Stability was assessed by measuring HbA1c at baseline, 2, 3, and 4 weeks postcollection (stored at 4 degrees C) and at 2, 4, 6, and 12 months postcollection (stored at -20 degrees C). We found no significant difference in HbA1c between the two preservatives at any of the time points indicating NaF is a suitable preservative for HbA1c measurement. We also determined that DM status, postmortem interval, and decomposition had no effect on stability. PMID- 29495067 TI - Drug Contamination of U.S. Paper Currency and Forensic Relevance of Canine Alert to Paper Currency: A Critical Review of the Scientific Literature. AB - Several studies have reported on wide-spread contamination of U.S. paper currency with cocaine and to a lesser extent other illicit drugs. Canines are trained and employed to search for and alert to drugs. Canine alert to currency has been used as evidence that currency has been directly involved in illicit drug trafficking to justify currency seizure and forfeiture. This assertion, particularly when the only evidence is based upon canine alert, has been challenged in the courts considering that most currency in circulation is contaminated with cocaine. Comprehensive review of the scientific literature establishes that (i) 67-100% of circulated U.S. currency is contaminated with cocaine ranging from a few nanograms to over one milligram/bill (ii) various biological and environmental parameters impact canine alert to drugs. It is concluded that canine alert to U.S. currency is not sufficiently reliable to determine that currency was directly used in an illicit drug transaction. PMID- 29495068 TI - Fatal Chest Injury Caused by Windblown Beach Umbrella. AB - We present the case of a windblown beach umbrella inflicting fatal penetrating blunt force to the chest of a 55-year-old female beachgoer. A postmortem examination and detailed case history review were performed which revealed left ventricular trauma, determined to be the cause of death. Using recorded wind speeds from the date of the incident and the weight of the umbrella, we were able to calculate the pressure with which the umbrella struck the victim to be 16,000 PSI. Witness reports, medical records, scene details, and examination of a rental beach umbrella allowed the forensic pathologist to conclude that the object causing this woman's death was a windblown beach umbrella. PMID- 29495069 TI - Reply to Authors' Response. PMID- 29495070 TI - Commentary on: Lockhart JJ, Satya-Murti S. Diagnosing crime and diagnosing disease: bias reduction strategies in the forensic and clinical sciences. J Forensic Sci 2017;62(6):1534-41. PMID- 29495071 TI - Authors' Response. PMID- 29495072 TI - Commentary on: Langlois NEI, Byard RW. Arterial perfusion-a useful technique for evaluating incised wounds. J Forensic Sci https://doi.org/10.1111/1556 4029.13682. Epub 2017 Oct 30. PMID- 29495073 TI - Evaluation of Rhodosporidium fluviale as biocontrol agent against Botrytis cinerea on apple fruit. AB - : The aim of the present work was to evaluate the ability of the native yeast Rhodosporidium fluviale to control Botrytis cinerea on apple fruit and to study the possible mechanisms of action with the goal of improving the control of gray mold. For this, the influence of application time of the yeast was studied simulating preventive and curative effects. Also, the effect of nonviable cells of the yeast in the biocontrol was assessed. According to the results obtained, the following mechanisms of action of R. fluviale could be proposed: 1- competition for space, 2- direct interaction between antagonist and pathogen, 3- induction of beta-1,3-glucanase in apple tissue, 4- Probable production of glucanase in the apple wounds and 5- antifungal action of cellular components, probably chitin, present in the wall of yeast cells that could be the explanation for the activity of nonviable cells. SIGNIFICANCE AND IMPACT OF THE STUDY: Significance and Impact of the Study: Botrytis cinerea Pers: Fr, which causes gray mold of fruits and vegetables around the world, is difficult to control successfully because it is genetically variable and rapidly develops resistance to the chemicals commonly used for its control. This study is a contribution to the biocontrol of this phytopathogen fungus. The evaluation of the native yeast Rhodosporidium fluviale as biocontrol agent and the elucidation of possible mechanisms of action, including the participation of nonviable cells of this yeast, have not been reported up to date. PMID- 29495074 TI - Solid-phase extraction based on amino-functionalized graphene oxide nanocomposites for analysis of short-chain perfluorinated alkyl acids in human serum by ion chromatography mass spectrometry. AB - A highly sensitive method was developed for the analysis of short-chain perfluorinated alkyl acids (PFAAs) in serum samples using solid-phase extraction (SPE) coupled with ion chromatography-electrospray ionization-mass spectrometry. The synthesized amino-functionalized graphene oxide nanocomposites were used as an SPE sorbent for the enrichment of trace analytes and purification of samples. They exhibited high selectivity to polar compounds. The suppressor was employed to remove counterions and reduce background signals of mobile phase. These two crucial steps could effectively eliminate matrix effects and enhance analytical sensitivity. The lowest limits of quantification were 2.0 MUg L-1 for perfluorobutanoic acid and perfluorovaleric acid, 1.0 MUg L-1 for perfluorocaproic acid and 0.50 MUg L-1 for perfluorobutane sulfonic acid, respectively. The procedure was successfully applied for determination of trace PFAAs in 25 serum samples. Mean recoveries ranged from 86.3 to 101.4% with relative standard deviations of 1.6-6.8%. The method allowed an excellent separation and quantification of short-chain PFAAs that were difficult to analyze by conventional chromatography. PMID- 29495075 TI - Vacuolar Protein Sorting 26C encodes an evolutionarily conserved large retromer subunit in eukaryotes that is important for root hair growth in Arabidopsis thaliana. AB - The large retromer complex participates in diverse endosomal trafficking pathways and is essential for plant developmental programs, including cell polarity, programmed cell death and shoot gravitropism in Arabidopsis. Here we demonstrate that an evolutionarily conserved VPS26 protein (VPS26C; At1G48550) functions in a complex with VPS35A and VPS29 necessary for root hair growth in Arabidopsis. Bimolecular fluorescence complementation showed that VPS26C forms a complex with VPS35A in the presence of VPS29, and this is supported by genetic studies showing that vps29 and vps35a mutants exhibit altered root hair growth. Genetic analysis also demonstrated an interaction between a VPS26C trafficking pathway and one involving the SNARE VTI13. Phylogenetic analysis indicates that VPS26C, with the notable exception of grasses, has been maintained in the genomes of most major plant clades since its evolution at the base of eukaryotes. To test the model that VPS26C orthologs in animal and plant species share a conserved function, we generated transgenic lines expressing GFP fused with the VPS26C human ortholog (HsDSCR3) in a vps26c background. These studies illustrate that GFP-HsDSCR3 is able to complement the vps26c root hair phenotype in Arabidopsis, indicating a deep conservation of cellular function for this large retromer subunit across plant and animal kingdoms. PMID- 29495076 TI - Empowering members of a rural southern community in Nigeria to plan to take action to prevent maternal mortality: A participatory action research project. AB - AIMS AND OBJECTIVES: To facilitate the empowerment of members of a rural community to plan to take action to prevent maternal mortality. BACKGROUND: Globally, about 300,000 maternal deaths occur yearly. Sub-Saharan Africa and Southern Asia regions account for almost all the deaths. Within those regions, India and Nigeria account for over a third of the global maternal deaths. Problem of maternal mortality in Nigeria is multifaceted. About 80% of maternal deaths are avoidable, given strategies which include skilled attendants, emergency obstetric care and community mobilisation. In this article, a strategy of community empowerment to plan to take action to prevent maternal mortality is discussed. DESIGN: Participatory action research was used. METHODS: Twelve volunteers were recruited as coresearchers into the study through purposive and snowball sampling who, following an orientation workshop, undertook participatory qualitative data collection with an additional 29 community members. Participatory thematic analysis of the data was undertaken which formed the basis of the plan of action. RESULTS: Community members attributed maternal morbidities and deaths to superstitious causes, delayed referrals by traditional birth attendants, poor transportation and poor resourcing of health facilities. Following critical reflection, actions were planned to empower the people to prevent maternal deaths through community education and advocacy meetings with stakeholders to improve health and transportation infrastructures; training of existing traditional birth attendants in the interim and initiating their collaboration with skilled birth attendants. CONCLUSION: The community is a resource which if mobilised through the process of participatory action research can be empowered to plan to take action in collaboration with skilled birth attendants to prevent maternal mortality. RELEVANCE TO CLINICAL PRACTICE: Interventions to prevent maternal deaths should include community empowerment to have better understanding of their circumstances as well as their collaboration with health professionals. PMID- 29495077 TI - STOPDVTs: Development and testing of a clinical assessment tool to guide nursing assessment of postoperative patients for Deep Vein Thrombosis. AB - AIMS AND OBJECTIVES: To develop and test a clinical tool to guide nurses' assessment of postoperative patients for Deep Vein Thrombosis. BACKGROUND: Preventing venous thromboembolism in hospitalised patients is an international patient safety priority. Despite high-level evidence for optimal venous thromboembolism prophylaxis, implementation is inconsistent and the incidence of Deep Vein Thrombosis remains high. METHODS: A two-stage sequential multi-method design was used. In stage 1, the STOPDVTs tool was developed using a review of the literature and focus groups with local clinical experts. Stage 2 involved pilot testing the tool with 38 surgical nurses who conducted repeated assessments on a prospective sample of 50 postoperative orthopaedic patients. RESULTS: Stage 1: The focus group members who were members of the nursing leadership team agreed on eight local and systemic signs and symptoms that should be included in a nursing patient assessment tool for early Deep Vein Thrombosis. Local symptoms were pain in the limbs, calf swelling and tightness, changes in the affected limb's skin temperature. Systemic signs included in the tool were as follows: increased shortness of breath, increased respiratory and heart rates, and decreased oxygen saturation. Stage 2: The STOPDVTs tool had acceptable face and content validity, the agreement between the expert nurse and surgical nurses on assessments of individual signs and symptoms varied between 44%-94%. Surgical nurses were less likely than the expert nurse to identify signs indicative of Deep Vein Thrombosis. CONCLUSION: Despite finding the STOPDVTs clinical assessment tool was a useful guide for nursing assessment, surgical nurses often underestimated the potential importance of clinical signs. The findings reveal a gap in nursing knowledge and skill in assessing for Deep Vein Thrombosis in postoperative orthopaedic patients. RELEVANCE TO CLINICAL PRACTICE: This study identified a possible risk to patient safety related to under-recognition of the signs and symptoms of possible Deep Vein Thrombosis (DVT) in postoperative orthopaedic patients. The findings demonstrate the feasibility of developing and implementing a protocol for consistent screening by nurses for possible DVT in the postoperative period. PMID- 29495078 TI - Corticocortical projections to area 1 in squirrel monkeys (Saimiri sciureus). AB - Cortical area 1 is a non-primary somatosensory area in the primate anterior parietal cortex that is critical to tactile discrimination. The corticocortical projections to area 1 in squirrel monkeys were determined by placing multiple injections of anatomical tracers into separate body part representations defined by multiunit microelectrode mapping in area 1. The pattern of labeled cells in the cortex indicated that area 1 has strong intrinsic connections within each body part representation and has inputs from somatotopically matched regions of areas 3b, 3a, 2 and 5. Somatosensory areas in the lateral sulcus, including the second somatosensory area (S2), the parietal ventral area (PV), and the presumptive parietal rostral (PR) and ventral somatosensory (VS) areas, also project to area 1. Topographically organized projections to area 1 also came from the primary motor cortex (M1), the dorsal and ventral premotor areas (PMd and PMv), and the supplementary motor area (SMA). Labeled cells were also found in cingulate motor and sensory areas on the medial wall of the hemisphere. Previous studies revealed a similar pattern of projections to area 1 in Old World macaque monkeys, suggesting a pattern of cortical inputs to area 1 that is common across anthropoid primates. PMID- 29495079 TI - Natural variation in the promoter of rice calcineurin B-like protein10 (OsCBL10) affects flooding tolerance during seed germination among rice subspecies. AB - Rice (Oryza sativa L.) has two ecotypes, upland and lowland rice, that have been observed to show different tolerance levels under flooding stress. In this study, two rice cultivars, upland (Up221, flooding-intolerant) and lowland (Low88, flooding-tolerant), were initially used to study their molecular mechanisms in response to flooding germination. We observed that variations in the OsCBL10 promoter sequences in these two cultivars might contribute to this divergence in flooding tolerance. Further analysis using another eight rice cultivars revealed that the OsCBL10 promoter could be classified as either a flooding-tolerant type (T-type) or a flooding-intolerant type (I-type). The OsCBL10 T-type promoter only existed in japonica lowland cultivars, whereas the OsCBL10 I-type promoter existed in japonica upland, indica upland and indica lowland cultivars. Flooding tolerant rice cultivars containing the OsCBL10 T-type promoter have shown lower Ca2+ flow and higher alpha-amylase activities in comparison to those in flooding intolerant cultivars. Furthermore, the OsCBL10 overexpression lines were sensitive to both flooding and hypoxic treatments during rice germination with enhanced Ca2+ flow in comparison to wild-type. Subsequent findings also indicate that OsCBL10 may affect OsCIPK15 protein abundance and its downstream pathways. In summary, our results suggest that the adaptation to flooding stress during rice germination is associated with two different OsCBL10 promoters, which in turn affect OsCBL10 expression in different cultivars and negatively affect OsCIPK15 protein accumulation and its downstream cascade. PMID- 29495080 TI - Cultural aspects of death notification following cardiopulmonary resuscitation. AB - AIMS: To explore the lived experience of resuscitation team members involved in notifying family members when a patient dies following a resuscitation event in an Iranian cultural context. BACKGROUND: Death notification to the family is indeed a difficult and an important issue for resuscitation team members. The way health professionals deliver news to family members should incorporate elements of sensitivity, timing and adequate clinical explanations with emphasis on the efforts made by the professionals during the resuscitation. DESIGN: A phenomenological study. METHOD: Over a period of 5 months (June 2016-November 2016) eleven nurses and six physicians were interviewed using an in-depth interview process applying Van Manen's hermeneutic phenomenological approach for data collection and analysis. The participants were recruited from six tertiary hospitals in Tabriz, Iran. FINDINGS: There were two main themes that emerged from the data analysis including: "contributing factors on the impact of notification" and "notification strategies". A further 13 subthemes emerged under the main themes. Several culturally related issues emerged with the participants feeling more comfortable informing male rather than female relatives about the death of the patient following a resuscitation. CONCLUSIONS: Notifying family members of a patient's death is a stressful and culturally sensitive task for the resuscitation team members. The nature of the patient's presenting condition, together with the various resuscitation interventions can result in relatives responding unpredictably. Providing health professionals with the appropriate training and skills to effectively communicate with family members will ensure that the families' level of preparedness, understanding and cultural beliefs are taken into consideration. PMID- 29495081 TI - Community case management and unplanned hospital admissions in patients with heart failure: A systematic review and qualitative evidence synthesis. AB - AIMS: The aim of this study was to describe case management as experienced by patients with heart failure and their health professionals with the aim of understanding why case management might contribute in reducing hospital admissions. BACKGROUND: Heart failure is a common cause of unplanned hospital admission. The evidence for case management in patients with heart failure for reducing admissions is promising. DESIGN: Systematic review and qualitative evidence synthesis. DATA SOURCE: Searches were conducted in Medline, Psychinfo, Kings Fund database and Cinahl from inception of each database to 16 February 2017. REVIEW METHODS: Robust systematic review methodology was used to identify qualitative studies describing the experiences of patients with heart failure and healthcare providers of case management. Data were synthesized thematically, and analytic themes were developed. FINDINGS: Five studies (six papers) from which nine descriptive themes were used to determine three analytic themes. This synthesis showed that case management provides positive quality of care for patients, increases perceived access to services and creates more time to ask questions and develop trusted relationships. For health professionals, case management enhanced care by improved relationships with both patients and colleagues although concerns remained around resources, training and inter professional conflict. CONCLUSIONS: This synthesis emphasizes the importance of the quality of being cared for as a patient and caring as a health professional. Case management enhances communication between patients and health professionals, supports patient self-care and self-management and can be an important contributing factor in reducing unplanned admissions for patients with heart failure. PMID- 29495082 TI - Protective effect of melatonin in the diabetic rat retina. AB - Diabetic retinopathy (DR) is one of the most common and serious microvascular complications of diabetes. The aim of this study was to evaluate the effects of melatonin (MEL) on retinal injury in diabetic rats. In this study, 21 rats were randomly divided into three groups: control, diabetic, and diabetic + MEL. Streptozotocin was used to induce diabetes at a dose of 50 mg/kg, i.p., and blood glucose was measured to choose the diabetic rats for the study. MEL (20 mg/kg) was given orally for 7 weeks in diabetic rats starting 1 week after induction of diabetes. After 8 weeks, the groups were compared in terms of mean scores of fluorescein leakage, using fluorescein angiography. Reactive oxygen species (ROS) and malondialdehyde (MDA) levels were estimated in retina using commercially available assays. Structural changes in retinas were evaluated by light microscopy. Results showed that diabetes significantly increased the mean scores of fluorescein leakage, and MDA and ROS levels compared to control group. Treatment of the diabetic rats with MEL for 7 weeks prevented the alterations induced by diabetes in comparison with the diabetic control group.Based on these findings, it can be concluded that MEL might have beneficial effects in prevention of DR. PMID- 29495083 TI - Influence of physical restraint on delirium of adult patients in ICU: A nested case-control study. AB - AIMS AND OBJECTIVES: To investigate the impact of physical restraint on delirium of adult patients in intensive care unit. BACKGROUND: Delirium is a common clinical syndrome in intensive care unit, correlated with various adverse clinical outcomes. Physical restraint is a precipitating factor for delirium; however, the effect of physical restraint on delirium, such as duration, number and appliance is still unclear. DESIGN: A nested case-control study. METHODS: A cohort of 593 intensive care unit patients were observed for 12 months, and 447 of them who received physical restraint were included for analysis. Delirium was assessed using the Confusion Assessment Method for the intensive care unit. During hospitalisation in intensive care unit, newly-onset delirium patients (the delirium group), and nondelirium patients of similar age, same gender, and conditions of mechanical ventilation and sedative drug usage (the nondelirium group) were included as the matching criteria. Patient data were acquired by reviewing medical and nursing electronic records. RESULTS: Among the 447 patients that had been physically restrained, 178 (39.8%) developed delirium. Delirium risk in patients with restraint >=6 days was 26.30 times higher than in those <6 days. Patients who had two and three times of restraint had a 2.38-fold and 3.62 fold higher risk of delirium than those with one time of restraint. However, the appliance, site, time to apply and remove restraint had no effect on the incidence of delirium. CONCLUSIONS: The incidence of delirium is high when patients use physical restraint. Duration and number of restraint are positively related to delirium. Restrictions on the use of restraint in intensive care unit are required to reduce the occurrence of delirium. RELEVANCE TO CLINICAL PRACTICE: To reduce delirium risk of patients in intensive care unit, nurses need to assess the risk of physical restraint and consider alternative measures, thereby to achieve the minimisation of the use of restraint. PMID- 29495084 TI - What is "moral distress" in nursing? How, can and should we respond to it? PMID- 29495085 TI - Pharmacokinetics and pharmacodynamics of dexmedetomidine-induced vasoconstriction in healthy volunteers. AB - AIMS: Alpha-2 agonists are direct peripheral vasoconstrictors, which achieve these effects by activating vascular smooth muscle alpha-2 adrenoceptors. The impact of this response during dexmedetomidine infusion remains poorly quantified. Our goal was to investigate the pharmacokinetic (PK) and pharmacodynamic (PD, vasoconstriction) effects of a computer-controlled dexmedetomidine infusion in healthy volunteers. METHODS: After local ethics committee approval, we studied 10 healthy volunteers. To study the peripheral vasoconstrictive effect of dexmedetomidine without concurrent sympatholytic effects, sympathetic fibres were blocked with a brachial plexus block. Volunteers received a dexmedetomidine target-controlled infusion for 15 min, to a target concentration of 0.3 ng ml-1 . Arterial blood samples were collected during and for 60 min after dexmedetomidine infusion for PK analysis. Peripheral vasoconstriction (PD) was assessed using finger photoelectric plethysmography. PK/PD analysis was carried out using nonlinear mixed-effect models. RESULTS: We found that the computer-controlled infusion pump delivered mean concentrations greater than 0.3 ng ml-1 over the 15-min infusion duration. The peripheral vasoconstrictive effect correlated with dexmedetomidine plasma concentrations during and after the infusion. A three-compartment model provided a better fit to the data than a two-compartment model. CONCLUSIONS: We found that dexmedetomidine induced vasoconstriction is concentration dependent over time. Dexmedetomidine PK were best estimated by a three-compartment model with allometric scaling. Our results may contribute to future modelling of dexmedetomidine-induced haemodynamic effects. PMID- 29495086 TI - Effect of multicomponent interventions on competence of family caregivers of people with dementia: A systematic review. AB - AIMS AND OBJECTIVES: This review aims to summarise and evaluate multicomponent interventions focused on improving the competence of family members of people with dementia (PwD) who undertake the caregiving tasks. BACKGROUND: Caregiver competence is essential for family members of PwD acting as caregivers. Competence affects the physical and mental health of both PwD and caregivers. Many kinds of multicomponent interventions are used to improve caregiver competence. DESIGN: A systematic review. METHODS: A literature search from six databases was conducted. Articles published until January 2017 were screened. Intervention studies that measured caregiver competence of family members of PwD as an outcome were included. The Oxford Center Evidence-based Medicine criteria and the Cochrane Handbook for Systematic Reviews of Interventions were used for quality assessment. RESULTS: Fifteen studies were included, and number of participants was 1096. The characteristics of the included studies and key findings were analysed. Multicomponent interventions may improve the family caregivers' competence. Caregivers in the intervention group were confident and skilful in managing their role. CONCLUSION: The intervention design, treatment content and length and intensity of the intervention varied in the included studies. Given that heterogeneity was high, combining these results via narrative synthesis is more appropriate than a meta-analysis. The current study provides recommendations regarding the formulation and implementation of interventions based on relevant literature. In view of existing research, researchers should conduct an in-depth study in this area and provide evidence-based interventions to support family members caring for PwD. RELEVANCE TO CLINICAL PRACTICE: The competence of family caregivers is essential for the life quality of PwD. To promote the health of the family caregiver and PwD, multicomponent interventions may be appropriate for nurses to practice. PMID- 29495087 TI - Non-meningothelial meningeal tumours with meningioangiomatosis-like pattern of spread. PMID- 29495088 TI - Ambiguous loss and post-traumatic growth: Experiences of mothers whose school aged children were born extremely prematurely. AB - AIMS AND OBJECTIVES: To develop insight into the experiences of mothers whose school-aged children were born extremely prematurely. BACKGROUND: Extreme prematurity, where infants are born at 28 weeks or earlier, has significant initial maternal impact in terms of distress, uncertainty and disruption to maternal identity. However, little is known about the experiences of these mothers beyond their child's infancy. DESIGN: A qualitative study was undertaken using thematic analysis, drawing on a cluster of social constructionist theories that have been applied to studies investigating mothers' early preterm or childhood disability experiences. METHODS: The study involved face-to-face interviews with nine mothers whose children were born prior to 28 weeks and were now aged between 4-to-7 years old. RESULTS: Participants described a prolonged period of anxiety, and relative isolation due to infection fears and complex care regimes. Although they grieved their different mothering trajectory, they celebrated their children's successes and noted their own resilience. The following themes were identified: traumatic beginnings; dialectics and the horror miracle contradiction; labour-intensive parenting and managing the multidisciplinary team; stigma and storying the meaning of premature birth; and impact on relationships. CONCLUSIONS: Women's vulnerability and resilience are evident long after the birth of an extremely prematurely born infant. Women value connection with similar mothers, and yet finding community is often daunting due to their children's early complex needs. Generalist healthcare providers may be unaware of the experiences these mothers have endured, and need to enquire about their well-being. RELEVANCE TO CLINICAL PRACTICE: The lives of mothers of extremely preterm infants may take years to merge with the world of those mothers who parent healthy, term infants. Neonatal nurses and those in primary health care are well placed to notice signs of isolation, depression and anxiety, and to support and refer women appropriately. PMID- 29495089 TI - Systematic review and narrative summary: Treatments for and risk factors associated with respiratory tract secretions (death rattle) in the dying adult. AB - AIM: To identify effective treatments and risk factors associated with death rattle in adults at the end of life. BACKGROUND: The presence of noisy, pooled respiratory tract secretions is among the most common symptoms in dying patients around the world. It is unknown if "death rattle" distresses patients, but it can distress relatives and clinicians. Treatments appear unsatisfactory, so prophylaxis would be ideal if possible. DESIGN: Quantitative systematic review and narrative summary following Cochrane Collaboration guidelines. DATA SOURCES: CINAHL, MEDLINE, Health Source Nursing and Web of Science were searched for international literature in any language published from 1993 - 2016 using MeSH headings and iterative interchangeable terms for "death rattle". REVIEW METHODS: Randomized controlled trials were appraised using the Cochrane Collaboration's tool for assessing risk of bias. Non-randomized studies were assessed using ROBINS-I tool for assessing risk of bias in non-randomized studies of interventions. Instances of treatment and risk were extracted and relevant key findings extracted in line with Cochrane methods. RESULTS: Five randomized trials and 23 non-randomized studies were analysed. No pharmacological or non pharmacological treatment was found superior to placebo. There was a weak association between lung or brain metastases and presence of death rattle, but otherwise inconsistent empirical support for a range of potential risk factors. CONCLUSIONS: Clinicians have no clear evidence to follow in either treating death rattle or preventing it occurring. However, several risk factors look promising candidates for prospective analysis, so this review concludes with clear recommendations for further research. PMID- 29495090 TI - Scoping review: Hospital nursing factors associated with 30-day readmission rates of patients with heart failure. AB - AIMS AND OBJECTIVES: To review the current literature on hospital nursing factors associated with 30-day readmission rates of patients with heart failure. BACKGROUND: Heart failure is a common, yet debilitating chronic illness with high mortality and morbidity. One in five patients with heart failure will experience unplanned readmission to a hospital within 30 days. Given the significance of heart failure to individuals, families and healthcare system, the Center for Medicare and Medicaid Services has made reducing 30-day readmission rates a priority. DESIGN: Scoping review, which maps the key concepts of a research area, is used. METHODS: Published primary studies in English assessing factors related to nurses in hospitals and readmission of patients with heart failure were included. Other inclusion criteria were written in English and published in peer reviewed journals. RESULTS: The search resulted in 2,782 articles. After removing duplicates and reviewing the inclusion and exclusion criteria, five articles were selected. Three nursing workforce factors emerged as follows: (i) nursing staffing, (ii) nursing care and work environment, and (iii) nurses' knowledge of heart failure. CONCLUSIONS: This is the first scoping review examining the association between hospital nursing factors and 30-day readmission rates of patients with heart failure. Further studies examining the extent of nursing structural and process factors influencing the outcomes of patients with heart failure are needed. RELEVANCE TO CLINICAL PRACTICE: Nurses are an integral part of the healthcare system. Identifying the factors related to nurses in hospitals is important to ensure comprehensive delivery of care to the chronically ill population. Hospital administrators, managers and policymakers can use the findings from this review to implement strategies to reduce 30-day readmission rates of patients with heart failure. PMID- 29495091 TI - Recognition of preclinical signs of dementia: A qualitative study exploring the experiences of family carers and professional care assistants. AB - AIMS AND OBJECTIVES: To identify preclinical signs of dementia by exploring the experiences of family caregivers and professional care assistants. BACKGROUND: Dementia results in disability, emotional strain and financial loss for people with dementia, family members and nations. Informal identification of social and behavioural risk signifiers could facilitate timely interventions with potential to delay onset of serious disability. DESIGN: A retrospective qualitative approach using a naturalistic interpretive design was used. Focus groups enabled in-depth understanding of the participants' experiences of life or work with people who subsequently developed dementia. METHODS: Purposive sampling was used to recruit family carers and professional carers who had cared for people who later developed dementia. The data from focus groups were fully transcribed and anonymised, and transcripts were analysed by two researchers. These researchers coded and analysed the transcripts independently; subsequently, overlapping and similar themes were identified and consensus reached on final themes. A third researcher was invited to review the analysis and ensure trustworthiness of the study findings. RESULTS: Findings revealed that preclinical signs of dementia were identifiable in retrospect Participants' accounts resulted in four themes, "Lowered Threshold of Frustration", "Insight and Coping Strategies," "Early signs of poor memory" and "Alarming Events." CONCLUSIONS: Earlier recognition of preclinical signs of dementia would allow affected individuals to follow health promotion advice and plan for the future. Identification of social exclusion prior to diagnosis has implications for antistigma campaigns and development of "dementia-friendly communities." RELEVANCE TO CLINICAL PRACTICE: Healthcare professionals could work with those at risk, facilitating lifestyle changes to postpone symptoms and advance planning for improved autonomy. Predementia should be viewed as a disability for which reasonable adjustments can be made at a community level, to enhance and extend emotional well-being and social inclusion. PMID- 29495092 TI - Tumour budding in pancreatic cancer revisited: validation of the ITBCC scoring system. AB - AIMS: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with rising incidence. Biomarkers that would help the prognostic stratification of patients are needed urgently. Although tumour budding (BD) is a strong and independent prognostic factor in PDAC it is not included in histopathology reports, due partly to the lack of a standardised scoring system. The aim of the present work is to assess the reliability and reproducibility of the BD scoring system proposed recently by the International Tumour Budding Consensus Conference (ITBCC) 2016 in a well-characterised PDAC cohort (n = 120) with complete clinicopathological and follow-up information. METHODS AND RESULTS: BD was scored independently by two pathologists on haematoxylin and eosin-stained PDAC sections by assessing the densest budding area at *20 magnification (one hot-spot, 0.785 mm2 ), regardless of intra- or peritumoural localisation, and assigned to four categories: BD0: no buds; BD1: one to four buds; BD2: five to nine buds; and BD3: >= 10 buds. Findings were correlated to patient and tumour characteristics and interobserver agreement was assessed. The weighted kappa value for BD category was 0.62 (0.5-0.73), indicating strong agreement. Increasing BD category (BD3 versus BD0-2) correlated with higher grade (P = 0.002) and shorter overall [OS, P < 0.0001, hazard ratio (HR) = 3.234, 95% confidence interval (CI) = 1.95-5.37] and disease-free survival (DFS, P = 0.0135, HR = 1.974, 95% CI = 1.15-3.39). BD (BD3 versus BD0-2) was an independent prognostic factor for OS and DFS, after adjusting for tumour-node-metastasis (TNM) stage by using both the 8th American Joint Committee on Cancer (AJCC) edition (OS: P = 0.0031, HR = 2.298, 95% CI = 1.32-0.99; DFS: P = 0.0458, HR = 1.713, 95% CI = 1.01-2.91) and the 7th AJCC edition (OS: P < 0.0001, HR = 2.795,95% CI = 1.71-4.57 and DFS: P = 0.00786, HR = 1.643, 95% CI = 0.95-2.86). CONCLUSIONS: ITBCC scoring is a simple, reliable and reproducible method to evaluate BD in PDAC and facilitates its documentation in histopathology reports, allowing the prognostic stratification of PDAC patients. PMID- 29495093 TI - Nurses' role in recognising and responding to clinical deterioration in surgical patients. AB - AIM AND OBJECTIVES: To explore nurse' role in recognising and responding to deteriorating post-operative patients. BACKGROUND: Clinical deterioration is a significant problem in acute care settings. Nurses play a vital role in post operative patient monitoring; however, there is limited understanding of the nurses' role in recognising and responding to clinical deterioration in surgical patients. METHODS: This qualitative exploratory study was conducted at a metropolitan teaching hospital in Melbourne, Australia. Data were collected through focus groups from 1 September to 31 October 2014. Four focus groups of 2 5 surgical nurses (n = 14) were conducted to explore the nurses' perception of their role in managing deterioration over the first 72 hr postoperatively. Qualitative data were recorded, transcribed and key themes identified. RESULTS: Nurses demonstrated a high level of awareness of their role in recognising and responding to early signs of deterioration. The themes that arose from the focus group interviews were "struggling with blood pressure," and "we know our patient is sick." The nurses were confident about the clinical indicators of deterioration and the appropriate channels to use to escalate care. Using track and trigger observation charts enabled nurses to identify deteriorating patients prior to the patient fulfilling rapid response system escalation criteria. CONCLUSIONS: These findings highlight the importance of a collective team approach to preventing, recognising and responding to clinical deterioration across the whole patient journey. Initiatives to ensure accurate written and verbal communication between medical and nursing staff warrants further assessment. RELEVANCE TO CLINICAL PRACTICE: Nurses working in acute surgical wards are highly engaged in the process of recognising and responding to clinical deterioration in post-operative patients. Many nurses reported being able to anticipate deterioration occurring but are required by current organisational frameworks to escalate care to rapid response systems. How nurses anticipate and manage deterioration prior to the patient fulfilling rapid response system criteria warrants further investigation. PMID- 29495094 TI - Challenges in everyday life among recently diagnosed and more experienced adults with type 2 diabetes: A multistage focus group study. AB - AIMS AND OBJECTIVES: To identify perceived challenges related to self-management among recently diagnosed adults and those with longer experience of type 2 diabetes as a foundation for the future development of a person-centred information and communication technology service. BACKGROUND: Learning self management of type 2 diabetes includes mastering the skills required to complete complex emotional and physical tasks. A service developed with the participation of stakeholders may be an alternative way to meet rising needs for self management. DESIGN: Qualitative descriptive design influenced by a participatory approach. METHODS: Multistage focus group interviews among one group of recently diagnosed (<=3 years, n = 4) adults and one group with longer experience (>=5 years, n = 7) of type 2 diabetes. RESULTS: Challenges in self-management in everyday life with type 2 diabetes were identified: understanding; developing skills and abilities; and mobilising personal strengths. Both groups described challenges in understanding the causes of fluctuating blood glucose and in developing and mobilising skills for choosing healthful food and eating regularly. The recently diagnosed group was more challenged by learning to accept the diagnosis and becoming motivated to change habits while the experienced group was mainly challenged by issues about complications and medications. CONCLUSION: Adults with diabetes have different needs for support during different phases of the disease. From a person-centred perspective, it would be desirable to meet individual needs for self-management on peoples' own terms through a technological service that could reach and connect to a large number of people. RELEVANCE TO CLINICAL PRACTICE: Diabetes nurses need to address the knowledge needs of patients with diabetes and support them in developing self-management skills. Consistent with person-centred care, practitioners should also encourage patients' abilities to mobilise their own personal strengths to maintain self management. PMID- 29495095 TI - The role of empathy and emotional intelligence in nurses' communication attitudes using regression models and fuzzy-set qualitative comparative analysis models. AB - AIMS AND OBJECTIVES: To analyse link between empathy and emotional intelligence as a predictor of nurses' attitudes towards communication while comparing the contribution of emotional aspects and attitudinal elements on potential behaviour. BACKGROUND: Nurses' attitudes towards communication, empathy and emotional intelligence are key skills for nurses involved in patient care. There are currently no studies analysing this link, and its investigation is needed because attitudes may influence communication behaviours. DESIGN: Correlational study. METHOD: To attain this goal, self-reported instruments (attitudes towards communication of nurses, trait emotional intelligence (Trait Emotional Meta-Mood Scale) and Jefferson Scale of Nursing Empathy (Jefferson Scale Nursing Empathy) were collected from 460 nurses between September 2015-February 2016. Two different analytical methodologies were used: traditional regression models and fuzzy-set qualitative comparative analysis models. RESULTS: The results of the regression model suggest that cognitive dimensions of attitude are a significant and positive predictor of the behavioural dimension. The perspective-taking dimension of empathy and the emotional-clarity dimension of emotional intelligence were significant positive predictors of the dimensions of attitudes towards communication, except for the affective dimension (for which the association was negative). The results of the fuzzy-set qualitative comparative analysis models confirm that the combination of high levels of cognitive dimension of attitudes, perspective-taking and emotional clarity explained high levels of the behavioural dimension of attitude. CONCLUSIONS: Empathy and emotional intelligence are predictors of nurses' attitudes towards communication, and the cognitive dimension of attitude is a good predictor of the behavioural dimension of attitudes towards communication of nurses in both regression models and fuzzy-set qualitative comparative analysis. In general, the fuzzy-set qualitative comparative analysis models appear to be better predictors than the regression models are. RELEVANCE TO CLINICAL PRACTICE: To evaluate current practices, establish intervention strategies and evaluate their effectiveness. The evaluation of these variables and their relationships are important in creating a satisfied and sustainable workforce and improving quality of care and patient health. PMID- 29495096 TI - The older patient's experience of the healthcare chain and information when undergoing colorectal cancer surgery according to the enhanced recovery after surgery concept. AB - AIMS AND OBJECTIVES: To describe how older patients experience the healthcare chain and information given before, during and after colorectal cancer surgery. BACKGROUND: Most persons with colorectal cancer are older than 70 years and undergo surgery with subsequent enhanced recovery programmes aiming to quickly restore preoperative function. However, adaptation of such programmes to suit the older patient has not been made. DESIGN: Qualitative descriptive study. METHOD: Semi-structured interviews were conducted on 16 patients undergoing colorectal cancer surgery at a Swedish University Hospital. The inductive content analysis was employed. RESULTS: During the period of primary investigation and diagnosis, a paucity of information regarding the disease and management, and lack of help in coping with the diagnosis of cancer and its impact on future life, leads to a feeling of vulnerability. During their stay in hospital, the patient's negative perception of the hospital environment, their need for support, and uncertainty and anxiety about the future are evident. After discharge, rehabilitation is perceived as lacking in structure and individual adaptation, leading to disappointment. Persistent difficulty with nutrition delays recovery, and confusion regarding division of responsibility between primary and specialist care leads to increased anxiety and feelings of vulnerability. Information on self-care is perceived as inadequate. Furthermore, provided information is not always understood and therefore not useful. CONCLUSION: Information before and after surgery must be tailored to meet the needs of older persons, considering the patient's knowledge and ability to understand. Furthermore, individual nutritional requirements and preoperative physical activity and status must be taken into account when planning rehabilitation. RELEVANCE TO CLINICAL PRACTICE: Patient information must be personalised and made understandable. This can improve self-preparation and participation in the own recovery. Special needs must be addressed early and followed up. PMID- 29495097 TI - Knowing how to get things done: Nurse consultants as clinical leaders. AB - BACKGROUND: Clinical leaders drive healthcare performance in the provision of safe, high-quality patient care by influencing others and augmenting change. Clinical leadership features strongly in nurse consultant roles and holds potential to strengthen the nurse consultant's place in healthcare teams, making their contribution as clinical leaders more recognisable. This study explores how clinical leadership is enacted through the nurse consultant role, providing understanding of the elements that influence their effectiveness as clinical leaders. DESIGN: This study presents qualitative findings from a larger sequential mixed-method study conducted in a large Local Health District in New South Wales, Australia. METHODS: Focus groups were held with nurse consultants, managers and other stakeholders from a variety of context including acute, primary and community care settings across metropolitan and rural locations. An online discussion forum was provided for nurse consultants unable to attend focus groups. Transcript data were analysed using iterative theming techniques. RESULTS: A total of 26 nurse consultants, 20 managers and 16 other stakeholders participated in focus groups and 22 nurse consultants contributed to the discussion forum. The role of the nurse consultant as clinical leader was a dominant feature, manifested through the following four themes: knowing and being known, being a collaborator, being a utility player and working across and within. CONCLUSIONS: Nurse consultants are cogent clinical leaders, recognised and valued for their contribution to interprofessional teams and service delivery. The nurse consultant role is seen as having a broad sphere of influence and is able to action change through clinical leadership. RELEVANCE TO CLINICAL PRACTICE: Findings give organisational leaders and other healthcare professional's greater understanding of nurse consultants as clinical leaders. This informs how nurse consultants are appointed and positioned and how they can be supported in fulfilling their clinical leadership potential. PMID- 29495099 TI - Stormwater wetlands can function as ecological traps for urban frogs. AB - Around cities, natural wetlands are rapidly being destroyed and replaced with wetlands constructed to treat stormwater. Although the intended purpose of these wetlands is to manage urban stormwater, they are inhabited by wildlife that might be exposed to contaminants. These effects will be exacerbated if animals are unable to differentiate between stormwater treatment wetlands of varying quality and some function as "ecological traps" (i.e., habitats that animals prefer despite fitness being lower than in other habitats). To examine if urban stormwater wetlands can be ecological traps for frogs, we tested if survival, metamorphosis-related measures, and predator avoidance behaviors of frogs differed within mesocosms that simulated stormwater wetlands with different contaminant levels, and paired this with a natural oviposition experiment to assess breeding-site preferences. We provide the first empirical evidence that these wetlands can function as ecological traps for frogs. Tadpoles had lower survival and were less responsive to predator olfactory cues when raised in more polluted stormwater wetlands, but also reached metamorphosis earlier and at a larger size. A greater size at metamorphosis was likely a result of increased per capita food availability due to higher mortality combined with eutrophication, although other compensatory effects such as selective-mortality removing smaller individuals from low-quality mesocosms may also explain these results. Breeding adults laid comparable numbers of eggs across wetlands with high and low contaminant levels, indicating no avoidance of the former. Since stormwater treatment wetlands are often the only available aquatic habitat in urban landscapes we need to better understand how they perform as habitats to guide management decisions that mitigate their potential ecological costs. This may include improving wetland quality so that fitness is no longer compromised, preventing colonization by animals, altering the cues animals use when selecting habitats, pretreating contaminated water prior to release, providing off-line wetlands nearby, or simply not constructing stormwater treatment wetlands in sensitive areas. Our study confirms the potential for urban stormwater treatment wetlands to function as ecological traps and highlights the need for greater awareness of their prevalence and impact at landscape scales. PMID- 29495098 TI - Presepsin as a predictor of early onset neonatal sepsis in the umbilical cord blood of premature infants with premature rupture of membranes. AB - BACKGROUND: The aim of this study was to investigate whether presepsin level in umbilical cord blood can be used as a predictor of early onset neonatal sepsis (EONS) in preterm labor with premature rupture of membranes (PROM), allowing rational use of antibiotics. METHODS: All preterm infants between 24 + 0 and 36 + 6 weeks of gestation born to pregnant women with PROM were enrolled in the study. Blood samples were obtained from clamped umbilical cords after delivery of the neonate and prior to the delivery of the placenta for C-reactive protein and presepsin measurement. A diagnosis or suspicion of EONS was based on clinical symptoms or laboratory results in the absence of positive blood culture. RESULTS: A total of 288 women were included in the study and delivered at 31 + 4 weeks (range, 25-36 + 5 weeks). Microbial invasion of the amniotic cavity was identified in 62 women (81.6%) with EONS and in 31 (14.6%) without (P = 0.004). The prevalence of EONS was 26.4% (76/288). Median umbilical cord presepsin was significantly higher in neonates with EONS than in those without: 2,231 pg/mL (range, 1,442-3,988 pg/mL) versus 275 pg/mL (range, 116-326 pg/mL; P < 0.000). On logistic regression analysis the only independent predictor of EONS was umbilical cord blood presepsin (OR, 12.6; 95% CI: 2.5-28.1, P = 0.000). CONCLUSIONS: Umbilical cord blood presepsin is a predictor for EONS in preterm infants with PROM and may help to reduce the unnecessary use of antibiotics. PMID- 29495100 TI - Antinociceptive potency of enkephalins and enkephalinase inhibitors in the mouse model of colorectal distension-proof-of-concept. AB - Irritable bowel syndrome (IBS) is a chronic disease characterized by abdominal pain and changes in bowel habits. Patients with IBS comprise a significant portion of attendants at the outpatient clinics. Targeting intestinal opioid receptors was found successful in alleviating pain and diarrhea-two major symptoms of IBS. In this study, we aimed to evaluate a novel potential pharmacological option: the use of enkephalinase inhibitors in therapy of visceral pain occurring in the course of IBS. We thus assessed the antinociceptive efficacy of enkephalins: Leu-enkephalin and Met-enkephalin, and enkephalinase inhibitors: opiorphin and sialorphin in the mouse model of visceral pain induced by colorectal distension. Leu-enkephalin, Met-enkephalin, and sialorphin, but not opiorphin, at the dose of 1 mg/kg injected subcutaneously potently decreased the visceromotor response to colon distension as compared to control. To conclude, enkephalinase inhibitors are worth being considered as potential therapeutics in patients with chronic abdominal pain and/or changed bowel habits, that is, suffering from IBS. PMID- 29495101 TI - Decreasing cytokeratin 17 expression in head and neck cancer predicts nodal metastasis and poor prognosis: The first evidence. AB - OBJECTIVES: Cytokeratins (CKs) are mainly expressed in epithelial carcinomas and are valuable for making diagnoses and identifying metastatic status. Changes in the expression of individual CKs in certain carcinoma may be relevant to establishing a prognosis. However, the prognostic significance of CKs in head and neck squamous cell carcinoma (HNSCC) remains elusive. Herein, we investigated the diverse and unique expression patterns of Cytokeratin 13 (CK13) and Cytokeratin 17 (CK17) and assessed the role of CK17 as a predictor for HNSCC metastasis and prognosis. METHODS: CK13 and CK17 expressions were evaluated using immunohistochemical tissue microarray (TMA) analysis with 106 patients of HNSCC. To clarify the characterisation of CK17 expression with respect to its ability in predicting metastatic disease, an in vitro study of cells migration/invasion assays was conducted. Furthermore, the correlation of CK17 expression to clinicopathologic variables and prognosis was analyzed using a serial statistical method. RESULTS: CK13 was predominately expressed in non-cancerous tissues and was lost in HNSCC. Decreasing expression of CK17 correlated with cancerous cell migration and invasion (P < .0001) in an in vitro study. CK17 expression was lower in the N1 and N2 nodal metastases category compared to the N0 stage. Moreover, Kaplan-Meier survival analyses showed that a lower CK17 expression was associated with a poorer survival connotation in HNSCC patients (P < .05) with 10 year follow-up. CONCLUSION: Our findings provide the first evidence that CK17 under-expression might be a potential predictor of nodal metastasis and adverse prognosis. PMID- 29495102 TI - New Lignans from the Flower of Forsythia koreana and Their Suppression Effect on VCAM-1 Expression in MOVAS Cells. AB - Six lignans including two new lignans were obtained as the principal components of the Forsythia koreana flowers via silica gel (SiO2 ), octadecyl SiO2 (ODS) as well as Sephadex LH-20 column chromatography. In addition to two new lignans, named koreanaside A ((7R,8S,7'R,8'S)-7,7'-diepoxy-5'-hydroxy-3,3'-dimethoxylignan 4-O-beta-d-glucopyranoside) and koreanaside B ((7R,8S,7'S,8'R)-7,9'-epoxy-9,5',7' trihydroxy-3,3'-dimethoxylignan 4-O-beta-d-glucopyranoside), four known lignans were identified to be (+)-phylligenin, (-)-epipinoresinol, pinoresinol, and tinosposide A. The structures and absolute configurations of koreanasides A and B were established by means of analysis of spectroscopic data (NMR, IR, FAB-MS, and CD), whereas the structures of known lignans were identified by comparison their NMR and MS values with those in the reported literature. Their chemical structures including configuration were established by means of analysis of spectroscopic data (NMR, IR, FAB-MS, and CD) but also comparison of their NMR and MS values with those in the reported literature. This is the first article for isolation of six lignans of F. koreana flowers. Koreanasides A and B showed high radical scavenging activity with oxygen radical absorbance capacity (ORAC) values of 0.97 +/- 0.01 and 1.02 +/- 0.01, respectively. Koreanaside A also prohibited expressing VCAM-1 in MOVAS cells with 80.5% at 25 mg/mL. PMID- 29495103 TI - Effects of sumatriptan nasal spray (Imigran) on human nasal mucosa. AB - OBJECTIVES: Sumatriptan (Imigran) is a potent and highly selective 5-HT1 receptor agonist often used in treating acute migraine. Intranasal sumatriptan is well absorbed and is generally effective in relieving headache. However, the effects of Imigran on human nasal mucosa have rarely been well explored, to verify the effect of Imigran, which act on human nasal mucosa directly in vitro. DESIGN AND PARTICIPANTS: We examined the effectiveness of Imigran on human nasal mucosa by testing: (i) effect on human nasal mucosa resting tension; (ii) effect on contraction caused by 10-6 mol/L methoxamine as a sympathetic mimetic; and (iii) effect of the drugs on electrically induced on human nasal mucosa contractions. RESULTS: The results indicated that addition of methoxamine to the incubation medium caused the nasal mucosa to contract in a dose-dependent manner. Addition of Imigran at doses of 10-4 mol/L elicited a significant relaxation response to 10-6 mol/L methoxamine-induced contraction. Imigran could not inhibit electrical field stimulation-induced spike contraction. It also had a minimal effect on the basal tension of nasal mucosa as the concentration increased. CONCLUSIONS: The study indicated that high concentrations of Imigran had a significant spasmolytic effect by antagonising alpha-adreoceptors and nasal obstruction could not be released in the patient combined with acute migraine and stuffy nose by concomitant alpha-adrenergic agonist nasal spray plus Imigran nasal spray. PMID- 29495104 TI - ent-Sauchinone as Potential Anticancer Agent Inhibiting Migration and Invasion of Human Liver Cancer Cells via Suppressing the STAT3 Signaling Pathway. AB - ent-Sauchinone, a lignan isolated from Saururus chinensis (Lour.) Baill., was reported that it could modulate the expression of signal transducer and activator of transcription 3 (STAT3). Since STAT3 plays a key role in invasion, migration, and metastasis of cancer, we investigated whether ent-sauchinone could exert promising inhibitory effects on the invasion and migration of the metastatic human liver cancer cell line SMMC-7721 in the present study. ent-Sauchinone was extracted from dried herbs of Saururus chinensis (Lour.) Baill. Human liver cancer cell lines SMMC-7721 and HCCLM3 were used to test the effect of ent sauchinone on cell viability. The IC50 values and time-dependent effect of ent sauchinone were determined by MTT assay. Cell migration and invasion of SMMC-7721 were evaluated by the wound healing test and transwell assay respectively, the known anti-metastasis agent curcumin was used as a positive control. Western blotting assay was used to investigate relevant molecular mechanisms of cell invasion and migration. Though ent-sauchinone didn't show high cytotoxicity, the wound healing assay and transwell migration assay revealed a profound impairment in the metastatic potential of SMMC-7721 cells due to down-regulation of N cadherin, MMP-2, and MMP-9 proteins induced by inhibiting the phosphorylation of STAT3. These findings suggest that ent-sauchinone could be used as a promising agent to treat cancer metastasis. PMID- 29495106 TI - Long-term effects of traumatic dental injuries of primary dentition on permanent successors: A retrospective study of 596 teeth. AB - BACKGROUND/AIMS: Traumatic dental injuries of the primary dentition (TDI-p) have a global prevalence of approximately 11%-47%. They have immediate and long-term effects. Original research analysing the long-term sequelae of TDI-p on permanent dentition (LSP) are few in number. The aim of this study was to explore the correlation between age of TDI-p, type of TDI-p and LSP. MATERIAL AND METHODS: Retrospective analysis of patient data from 2008-2017, reporting with LSP due to TDI-p, was performed. Uniform protocols and complete radiographic-photographic records were analysed. There were 638 LSP reported with 596 teeth having complete records. RESULTS: There were 286 children with 153 males (53.5%) and 133 females (46.5%). Mean age of TDI-p causing LSP was 36.57 +/- 11.51 months, with severity increasing in the younger age group. The highest number of LSP was associated with avulsion injuries (218, 36.58%), and the odds ratio of the type of TDI-p affect the severity of LSP was 2.0163. Mean age of reporting was 8.54 +/- 2.19 years and was lowest for enamel discolorations. Most LSP were not associated with any associated feature (AF), although impaction was highest among all AF (63, 10.57%). CONCLUSION: Age and type of TDI-p affect LSP, with the former being the stronger determinant of its severity. Mean age of reporting of LSP is dependent upon both type of LSP and AF. LSP due to TDI-p can further be graded in terms of severity. PMID- 29495105 TI - The plasminogen receptor, Plg-RKT, is essential for mammary lobuloalveolar development and lactation. AB - : Essentials Plg-RKT-/- female mice give birth, but no offspring of Plg-RKT-/- female mice survive to weaning. Causal mechanisms of potential lactational failure in Plg-RKT-/- mice are unknown. Plg-RKT regulates extracellular matrix remodeling, cell proliferation, apoptosis, fibrin surveillance. Plg-RKT is essential for lactogenesis and mammary lobuloalveolar development. SUMMARY: Background Lactational competence requires plasminogen, the zymogen of the serine protease, plasmin. Plg-RKT is a unique transmembrane plasminogen receptor that promotes plasminogen activation to plasmin on cell surfaces. Plg-RKT-/- mice are viable, but no offspring of Plg-RKT-/- female mice survive to weaning. Objectives We investigated potential lactational failure in Plg-RKT-/- mice and addressed causal mechanisms. Methods Fibrin accumulation, macrophage infiltration, processing of extracellular matrix components, effects of genetic deletion of fibrinogen, expression of fibrosis genes, and proliferation and apoptosis of epithelial cells were examined in lactating mammary glands of Plg-RKT-/- and Plg RKT+/+ mice. Results Milk was not present in the stomachs of offspring of Plg-RKT /- female mice and the pups were rescued by foster mothers. Although the mammary ductal tree developed normally in Plg-RKT-/- glands, lobuloalveolar development was blocked by a hypertrophic fibrotic stroma and infiltrating macrophages were present. A massive accumulation of fibrin was also present in Plg-RKT-/- alveoli and ducts. Although this accumulation was decreased when Plg-RKT-/- mice were made genetically heterozygous for fibrinogen, defects in lobuloalveolar development were not rescued by fibrinogen heterozygosity. Transcriptional profiling revealed that EGF was downregulated 12-fold in Plg-RKT-/- glands. Furthermore, proliferation of epithelial cells was not detectable. In addition, the pro-survival protein, Mcl-1, was markedly downregulated and apoptosis was observed in Plg-RKT-/- but not Plg-RKT+/+ glands. Conclusions Plg-RKT is essential for lactogenesis and functions to maintain the appropriate stromal extracellular matrix environment, regulate epithelial cell proliferation and apoptosis, and, by regulating fibrinolysis, preserve alveolar and ductal patency. PMID- 29495107 TI - Enhancing total lipid and stearidonic acid yields in Buglossoides arvensis through PGPR inoculation. AB - AIM: This study was performed to identify bacterial isolates capable of enhancing total lipid and stearidonic acid (SDA) yields in Buglossoides arvensis. METHODS AND RESULTS: Pot experiments were conducted to screen the effects of 40 bacterial isolates on different B. arvensis growth parameters. Five isolates increased total lipid and SDA yields by at least 20%. These isolates were tested in a second pot experiment and in field trials. The second pot experiment confirmed that all isolates significantly increased total lipid and SDA yields over controls. Plants inoculated with four bacterial strains experienced significantly higher shoot weights, however, the increase in shoot weight decreased over time. Three isolates led to higher total seed numbers. In field trials, the inoculations had no significant effect on seed or lipid yields. However, isolate Pseudomonas fluorescens LBUM677 significantly increased SDA yield by 33% as compared to control plants. This strain was also the most efficient biofilm producer. CONCLUSIONS: Pseudomonas fluorescens LBUM677 can significantly increase SDA yield in B. arvensis under controlled and field conditions. SIGNIFICANCE AND IMPACT OF THE STUDY: Using bacterial strains to increase plant yield is of great interest under commercial settings. Pseudomonas fluorescens LBUM677 shows promise to promote SDA accumulation in B. arvensis under production conditions. PMID- 29495108 TI - The C-MAC(r) video-assisted nasoendoscopy vs traditional direct flexible nasoendoscopy: A pilot randomised controlled study. PMID- 29495109 TI - Farm and abattoir sources of Carnobacterium species and implications for lamb meat spoilage. AB - AIMS: To investigate the transmission route of Carnobacterium from the farm environment to the meat-manufacturing plant and potential risk for meat spoilage. METHODS AND RESULTS: A sheep farm-level survey of Carnobacterium, consisting of 150 environmental and animal (no 100) associated samples, was carried out on two farms. A further 20 lamb carcass samples were taken from an abattoir servicing one of the farms. The majority of Carnobacterium maltaromaticum isolates were associated with fleece followed by hard sheep contact surfaces, rectal-anal mucosal swabs and carcasses. Enterobacterial repetitive intergenic consenus PCR (ERIC-PCR) profiling revealed four distinct ERIC types. Each ERIC type was found on both farms, three of which were also found on lamb carcasses. CONCLUSIONS: Enterobacterial repetitive intergenic consenus PCR was effective at demonstrating within-species variability in C. maltaromaticum. This study provides initial information showing that farm sources maybe an important transmission route of Carnobacterium for contamination of lamb carcasses and subsequently the meat processing environment. SIGNIFICANCE AND IMPACT OF THE STUDY: Data on distribution, diversity, sources and transmission routes for meat product contamination is limited for spoilage bacteria. This study highlights the importance of good hygienic slaughter practices and cleaning routines to remove accumulated detritus from the handling of animals that may lead to cross contamination. PMID- 29495110 TI - Complementary crops and landscape features sustain wild bee communities. AB - Wild bees, which are important for commercial pollination, depend on floral and nesting resources both at farms and in the surrounding landscape. Mass-flowering crops are only in bloom for a few weeks and unable to support bee populations that persist throughout the year. Farm fields and orchards that flower in succession potentially can extend the availability of floral resources for pollinators. However, it is unclear whether the same bee species or genera will forage from one crop to the next, which bees specialize on particular crops, and to what degree inter-crop visitation patterns will be mediated by landscape context. We therefore studied local- and landscape-level drivers of bee diversity and species turnover in apple orchards, blueberry fields, and raspberry fields that bloom sequentially in southern Quebec, Canada. Despite the presence of high bee species turnover, orchards and small fruit fields complemented each other phenologically by supporting two bee genera essential to their pollination: mining bees (Andrena spp.) and bumble bees (Bombus spp.). A number of bee species specialized on apple, blueberry, or raspberry blossoms, suggesting that all three crops could be used to promote regional bee diversity. Bee diversity (rarefied richness, wild bee abundance) was highest across crops in landscapes containing hedgerows, meadows, and suburban areas that provide ancillary nesting and floral resources throughout the spring and summer. Promoting phenological complementarity in floral resources at the farmstead and landscape scales is essential to sustaining diverse wild bee populations. PMID- 29495111 TI - Does otitis media in early childhood affect later behavioural development? Results from the Western Australian Pregnancy Cohort (Raine) Study. AB - OBJECTIVES: To examine the relationship between early life episodes of otitis media and later behavioural development with adjustment for confounders. DESIGN: Longitudinal cohort study. SETTING: The Western Australian Pregnancy Cohort (Raine) Study recruited 2900 pregnant women from King Edward Memorial Hospital (KEMH) in Perth, Western Australia, between 1989 and 1991. PARTICIPANTS: Data from the children born were collected at both the Year 3 and Year 5 follow-up. At Year 3, n = 611 were diagnosed with recurrent otitis media through parent-report and clinical examination. At Year 5, n = 299 were considered exposed to otitis media based upon tympanometry results. MAIN OUTCOME MEASURES: Performance in the Child Behaviour Checklist (CBCL), a questionnaire completed by the primary caregiver at Year 10. RESULTS: Significant associations were found between recurrent otitis media at Year 3 and internalising behaviours (P = .011), and the somatic (P = .011), withdrawn (P = .014), attention (P = .003) and thought problems domains (P = .021), and the total CBCL score (P = .010). A significant association was also found between exposure to otitis media at Year 5 and externalising behaviours (P = .026). CONCLUSIONS: A modest association was seen between recurrent otitis media at Year 3 and exposure to otitis media at Year 5 and a number of behaviour domains at Year 10. PMID- 29495113 TI - Validation of the Baveno VI and the expanded Baveno VI criteria to identify patients who could avoid screening endoscopy. AB - BACKGROUND & AIMS: The Baveno VI and the expanded Baveno VI criteria were proposed to help identify patients who could safely avoid screening endoscopies for clinically significant varices among patients with compensated advanced chronic liver disease. However, these criteria require cross-validation, especially in Asian populations where the aetiologies of liver disease are different. METHODS: A total of 1035 patients, including 282 patients with compensated advanced chronic liver disease of different aetiology, were analysed. The compensated advanced chronic liver disease was defined by liver stiffness measurement >=10 kPa, Child-Pugh class A and absence of prior liver decompensation. High-risk varix was defined as a grade >=2 oesophageal varix, any varix with a red colour sign or gastric varices. RESULTS: High-risk varixs were present in 19.5% (55/282 patients) with compensated advanced chronic liver disease. Among compensated advanced chronic liver disease patients, the expanded criteria could spare more endoscopies (51.7%) than the original criteria (27.6%). However, the expanded criteria missed a greater number of high-risk varixs (6.8%) than the original criteria (3.8%). When stratified according to liver disease aetiology, the negative predictive values for the original Baveno VI criteria were 0.92, 1.00, 1.00 and 1.00, and the negative predictive values for the expanded criteria were 0.92, 0.96, 0.92 and 0.93 for hepatitis B, hepatitis C, alcohol and non-alcoholic fatty liver disease, respectively. High-risk varixs were rarely detected in patients without compensated advanced chronic liver disease (1.1%, 8/753 patients). CONCLUSIONS: In this Asian cohort study, the Baveno VI criteria were able to identify who could safely avoid screening endoscopy. The expanded Baveno VI criteria could spare more endoscopies but also could increase the odds of missing a high-risk varix. PMID- 29495112 TI - Assessment of HER2 status in breast cancer biopsies is not affected by accelerated tissue processing. AB - AIMS: To establish whether core needle biopsy (CNB) specimens processed with an accelerated processing method with short fixation time can be used to determine accurately the human epidermal growth factor receptor 2 (HER2) status of breast cancer. METHODS AND RESULTS: A consecutive case-series from two high-volume breast clinics was created. We compared routine HER2 immunohistochemistry (IHC) assessment between accelerated processing CNB specimens and routinely processed postoperative excision specimens. Additional amplification-based testing was performed in cases with equivocal results. The formalin fixation time was less than 2 h and between 6 and 72 h, respectively. Fluorescence in-situ hybridisation and multiplex ligation-dependent probe amplification were used for amplification testing. One hundred and forty-four cases were included, 15 of which were HER2 positive on the routinely processed excision specimens. On the CNB specimens, 44 were equivocal on IHC and required an amplification-based test. Correlation between the CNB specimens and the corresponding excision specimens was high for final HER2 status, with an accuracy of 97% and a kappa of 0.85. CONCLUSIONS: HER2 status can be determined reliably on CNB specimens with accelerated processing time using standard clinical testing methods. Using this accelerated technology the minimum 6 h of formalin fixation, which current guidelines consider necessary, can be decreased safely. This allows for a complete and expedited histology-based diagnosis of breast lesions in the setting of a one-stop-shop, same-day breast clinic. PMID- 29495114 TI - MicroRNA-622 is a novel mediator of tumorigenicity in melanoma by targeting Kirsten rat sarcoma. AB - The network of molecular players is similar when comparing neural crest-derived, actively migrating melanoblasts to melanoma cells. However, melanoblasts are sensitive to differentiation-initiating signals at their target site (epidermis), while melanoma cells maintain migratory and undifferentiated features. We aimed at identifying downregulated genes in melanoma that are particularly upregulated in melanoblasts. Loss of such genes could contribute to stabilization of a dedifferentiated, malignant phenotype in melanoma. We determined that microRNA 622 (miR-622) expression was strongly downregulated in melanoma cells and tissues compared to melanocytes and melanoblast-related cells. miR-622 expression correlated with survival of patients with melanoma. miR-622 re-expression inhibited clonogenicity, proliferation, and migration in melanoma. Inhibition of miR-622 in melanocytes induced enhanced migration. Kirsten rat sarcoma (KRAS) was identified as a major functional target of miR-622 in melanoma. We conclude that miR-622 is a novel tumor suppressor in melanoma and identify the miR-622-KRAS axis as potential therapeutic target. PMID- 29495115 TI - Influence Factors Regarding the Effectiveness of Automated Ballistic Comparison on 0.38 Special Caliber Bullets and Cartridge Cases. AB - Factors influencing effectiveness of automated comparisons, test-fired bullets, and cartridge cases from 0.38 Special revolvers were logged into the Evofinder(r) Ballistic ID System. Tests were performed as follows: First test correlated test fires of the same type, second test compared different types of ammunition components, third test replicated the second test in a larger database, and fourth test replicated the third test with students having no previous firearm identification experience. System effectiveness with projectiles in the first test was 0.89. With cartridge cases, effectiveness was 0.79 with combined results, but analysis of separate results by breech face and firing pin revealed low effectiveness by breech face (0.40). In the second, third, and fourth tests, effectiveness with projectiles were 0.61, 0.51, and 0.44. In addition, these tests had effectiveness with cartridge cases equivalent to 0.55, 0.43, and 0.44. Results are useful to establish routine protocols, system improvements, or comparative assessment of other electronic systems. PMID- 29495117 TI - Stillbirth: moving from advocacy to action. PMID- 29495116 TI - Reproducibility of European Association for the Study of the Liver criteria and modified Response Evaluation Criteria in Solid Tumors in patients treated with sorafenib. AB - BACKGROUND & AIMS: The European Association for the Study of the Liver criteria and the modified Response Evaluation Criteria in Solid Tumors are used for assessing the treatment outcomes of hepatocellular carcinoma. We investigated the inter- and intra-observer reproducibility of the European Association for the Study of the Liver criteria and modified Response Evaluation Criteria in Solid Tumors in patients with advanced hepatocellular carcinoma treated with sorafenib. METHODS: A total of 99 patients with treatment-naive advanced hepatocellular carcinoma receiving sorafenib were included. The kappa-values for the inter- and intra-observer agreement of the treatment response were calculated. RESULTS: Inter-observer agreement for baseline tumour number was excellent, as reflected by the high kappa-value. The kappa-statistics showed "excellent" concordance between the 2 sets of measurements by observer A regarding the overall responses using the European Association for the Study of the Liver criteria (kappa = .948, agreement rate = 84.8%) and modified Response Evaluation Criteria in Solid Tumors (kappa = .944, agreement rate = 83.8%; all P < .001). In addition, high kappa values indicated concordance between the first sets of measurements by observers A and B (kappa = .991 by the European Association for the Study of the Liver criteria and .988 by modified Response Evaluation Criteria in Solid Tumors, all P < .001). When agreements in radiological overall responses between the 2 sets of measurements by observer B and between the second sets of measurements by observers A and B were calculated, similar results regarding high kappa-values (>.8) were obtained. CONCLUSIONS: The reproducibility of the European Association for the Study of the Liver criteria and modified Response Evaluation Criteria in Solid Tumors in assessing treatment outcomes was high in patients with advanced hepatocellular carcinoma treated with sorafenib. PMID- 29495118 TI - What are the predictive factors of caecal perforation in patients with obstructing distal colon cancer? AB - AIM: In the presence of large bowel obstruction, the choice of treatment is determined by the patient's general status, the tumour characteristics and the perceived risk of caecal perforation. This study was designed to evaluate the predictive factors of impending caecal perforation, and also investigated the use of caecal volumetry. METHOD: From January 2011 to June 2016, patients with obstructive distal colon cancer undergoing emergency laparotomy, for whom a pretreatment CT scan was available, were included in this retrospective, case control, two-centre study. Two patient groups were defined: patients with and without impending caecal perforation. The primary end-point of the study was a determination of predictive factors for caecal perforation. RESULTS: A total of 72 patients (45 men, 62.5%) were included. Univariate analysis revealed that the presence of pericaecal fluid (P < 0.0001), caecal pneumatosis (P < 0.0001), mean maximum caecal diameter (P = 0.001), mean caecal diameter at the ileocaecal junction (P = 0.0001) and mean caecal volume (P = 0.001) were associated with caecal perforation. Receiver operating characteristic curve analysis revealed that a caecal volume greater than 400 cm3 (P < 0.0001), a maximum caecal diameter > 9 cm (P = 0.002) and a caecal diameter at the ileocaecal junction > 7.5 cm (P = 0.001) were associated with impending caecal perforation. In multivariate analysis, only caecal volume > 400 cm3 (P = 0.001) was correlated with the risk of impending caecal perforation. CONCLUSION: Caecal volumetry is an easy and useful tool to predict impending caecal perforation in patients with large bowel obstruction. PMID- 29495119 TI - Barriers to medication error reporting among hospital nurses. AB - AIMS AND OBJECTIVES: The study purpose was to report medication error reporting barriers among hospital nurses, and to determine validity and reliability of an existing medication error reporting barriers questionnaire. BACKGROUND: Hospital medication errors typically occur between ordering of a medication to its receipt by the patient with subsequent staff monitoring. To decrease medication errors, factors surrounding medication errors must be understood; this requires reporting by employees. Under-reporting can compromise patient safety by disabling improvement efforts. DESIGN: This 2017 descriptive study was part of a larger workforce engagement study at a faith-based Magnet(r) -accredited community hospital in California (United States). METHODS: Registered nurses (~1,000) were invited to participate in the online survey via email. Reported here are sample demographics (n = 357) and responses to the 20-item medication error reporting barriers questionnaire. Using factor analysis, four factors that accounted for 67.5% of the variance were extracted. These factors (subscales) were labelled Fear, Cultural Barriers, Lack of Knowledge/Feedback and Practical/Utility Barriers; each demonstrated excellent internal consistency. RESULTS: The medication error reporting barriers questionnaire, originally developed in long term care, demonstrated good validity and excellent reliability among hospital nurses. Substantial proportions of American hospital nurses (11%-48%) considered specific factors as likely reporting barriers. Average scores on most barrier items were categorised "somewhat unlikely." The highest six included two barriers concerning the time-consuming nature of medication error reporting and four related to nurses' fear of repercussions. CONCLUSIONS: Hospitals need to determine the presence of perceived barriers among nurses using questionnaires such as the medication error reporting barriers and work to encourage better reporting. RELEVANCE TO CLINICAL PRACTICE: Barriers to medication error reporting make it less likely that nurses will report medication errors, especially errors where patient harm is not apparent or where an error might be hidden. Such under reporting impedes collection of accurate medication error data and prevents hospitals from changing harmful practices. PMID- 29495120 TI - Right atrial myxoma induced right ventricular inflow obstruction. PMID- 29495121 TI - Functional outcome after laparoscopic nerve-sparing sacrocolpopexy: a prospective cohort study. AB - INTRODUCTION: To date sacrocolpopexy is regarded as the reference standard treatment for primarily apical compartment prolapse and multicompartment prolapse. Most bladder and bowel dysfunction improves postoperatively after sacrocolpopexy; however, de novo bowel or de novo bladder dysfunction can occur. The inferior hypogastric nerve is commonly known among pelvic surgeons. However, the inferior hypogastric nerve and its fine fibers are difficult to identify; iatrogenic lesion is commonly tolerated although this can lead to bladder, bowel and sexual dysfunction. This study was performed to assess the functional outcome after nerve-sparing sacrocolpopexy. MATERIAL AND METHODS: From 2014 to 2016 all women undergoing a laparoscopic sacrocolpopexy for apical or multicompartment prolapse stage >2 were included in this prospective study. Laparoscopic sacrocolpopexy was performed using the nerve-sparing approach. Objective outcome was assessed by preoperative and postoperative POP-Q changes. De novo bladder and de novo bowel dysfunction were subjectively and objectively evaluated. RESULTS: In all, 137 women were included. Significant objective improvement for point Aa and C (p < 0.0001) preoperatively to postoperatively was seen. The posterior compartment remained unchanged with point Ba -2. De novo overactive bladder and de novo bladder outlet obstruction with elevated postresidual volume were seen for both in 0.7% (1/137). De novo stress urinary incontinence was seen in 0.7% (5/137). De novo constipation was seen in 5%, bowel incontinence in 0% and resolution of pre-existing obstipation in 14.5%. De novo laxative use (9%) in the first 12 weeks was the most common postoperative problem. CONCLUSION: We could demonstrate that when a nerve-sparing technique is applied for sacrocolpopexy low de novo bladder (18%) and de novo bowel dysfunction can be seen. PMID- 29495122 TI - Ostial left main occlusion following surgical aortic valve replacement (SAVR). PMID- 29495124 TI - 119th Meeting of the British Neuropathological Society Institute of Child health, Epilepsy Neuropathology Symposium, 28th February, 2018. PMID- 29495123 TI - An updated systematic review and meta-analysis of early outcomes after left atrial appendage occlusion. AB - BACKGROUND: Left atrial appendage occlusion (LAAO) is a promising intervention for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). Early outcomes following LAAO have been published in many studies with variable results. OBJECTIVE: This updated meta-analysis aims to provide a summary of the early outcomes of LAAO. METHODS: Medline/Pubmed, Ovid Journals, Clinical trials, Abstract meetings, Cochrane databases were searched from January 1st, 1999 to November 30th, 2016. RESULTS: This meta-analysis included 49 studies involving 12 415 patients. The median age was 73.5 years (IQR 72-75 years) and 43% were males. Hypertension and diabetes were present in 36% and 15% of the population, respectively. There was a prior history of stroke and congestive heart failure in 14% and 18% of the population, respectively. The median CHADS2 score was 2.9 (IQR 2.6-3.3) and the median HASBLED score was 3.3 (IQR 3-4). LAAO implantation was successful in 96.3% of patients (95.40-97.08, I2 = 76.1%). The pooled proportion of all-cause mortality was 0.28% (0.19-0.38, I2 = 0%). The pooled proportion of all-cause stroke was 0.31% (0.22-0.42, I2 = 9.4%), major bleeding requiring transfusion was 1.71% (1.13-2.41, I2 = 73.2%), and pericardial effusion was 3.25% (2.46-4.14, I2 = 79%). Sub analysis of randomized clinical trials comparing LAAO devices to warfarin showed lower mortality (P = 0.03) with similar bleeding risk (P = 0.20) with LAAO. CONCLUSIONS: This meta-analysis concludes that LAAO occlusion is a safe and effective stroke prevention strategy in patients with NVAF. PMID- 29495125 TI - The impact of successful revascularization of coronary chronic total occlusions on long-term clinical outcomes in patients with non-ST-segment elevation myocardial infarction. AB - OBJECTIVES: The purpose of this study was to assess the long-term clinical impact of revascularization of coronary concomitant coronary chronic total occlusion (CTO) in patients with Non-ST-segment elevation myocardial infarction (NSTEMI). BACKGROUND: CTO is associated with poorer prognosis in patients with NSTEMI. The evidence of revascularization of CTO in patients with NSTEMI is still conflicting. METHODS: Consecutive patients with NSTEMI and CTO who underwent percutaneous coronary intervention (PCI) within 72 h of admission from 2006 to 2015 were retrospectively recruited and analyzed. A total of 967 patients underwent PCI for NSTEMI. Among them, 106 (11%) patients had concomitant CTO and were recruited for analysis. CTO lesions were revascularized successfully in 67 (63.2%) patients (successful CTO PCI group), while the CTO in the remaining 39 patients were either not attempted or failed (No/failed CTO PCI group). RESULTS: The 30-day cardiac death and major adverse cardiac events (MACE) were significantly lower in the successful CTO PCI group (both cardiac death and MACE were 3% vs 30%, P < 0.001, respectively). A landmark analysis set at 30th day for 30-day survivals was performed. After a mean of 2.5-year follow-up, the long-term cardiac death was still significantly lower (16.9% vs 42.3%, P < 0.001), whereas the MACE showed a trend toward lower incidence (26.2% vs 40.7%, P = 0.051) in the successful CTO PCI group. In multivariate Cox regression analysis, successful revascularization of CTO is an independent protective predictor for long-term cardiac death (HR 0.310, 95% CI, 0.109-0.881, P = 0.028) in all population and in propensity-score matched cohort (P = 0.007). CONCLUSIONS: Successful revascularization of CTO was associated with reduced risk of long-term cardiac death in patients with NSTEMI and concomitant CTO. PMID- 29495126 TI - Repair of a pseudoaneurysm following a Yacoub procedure. PMID- 29495127 TI - The breakdown of the Simon effect in cross-modal contexts: EEG evidence. AB - In everyday life, we often must coordinate information across spatial locations and different senses for action. It is well known, for example, that reactions are faster when an imperative stimulus and its required response are congruent than when they are not, even if stimulus location itself is completely irrelevant for the task (the so-called Simon effect). However, because these effects have been frequently investigated in single-modality scenarios, the consequences of spatial congruence when more than one sensory modality is at play are less well known. Interestingly, at a behavioral level, the visual Simon effect vanishes in mixed (visual and tactile) modality scenarios, suggesting that irrelevant spatial information ceases to exert influence on vision. To shed some light on this surprising result, here we address the expression of irrelevant spatial information in EEG markers typical of the visual Simon effect (P300, theta power modulation, LRP) in mixed-modality contexts. Our results show no evidence for the visual-spatial information to affect performance at behavioral and neurophysiological levels. The absence of evidence of the neural markers of visual S-R conflict in the mixed-modality scenario implies that some aspects of spatial representations that are strongly expressed in single-modality scenarios might be bypassed. PMID- 29495128 TI - High-resolution multiple reaction monitoring method for quantification of steroidal hormones in plasma. AB - Multiple reaction monitoring (MRM) is one of the most powerful modes of analysis in liquid chromatographic tandem mass spectrometry for quantification of low concentration metabolites in biological samples. The advances in mass spectrometry enabled the development of high-resolution multiple reaction monitoring (MRMHR ) and became suitable for the more specific analysis of target analytes. This is important for lipidomic studies and contributes in the medical and pharmaceutical fields, primarily in investigating alterations in cells or fluids relevant to various diseases. Therefore, this work proposes the development of the MRMHR method for quantification of circulating steroids. We focused on the determination of corticosterone, 11-dehydrocorticosterone (11 DHC), cortisol, cortisone, aldosterone, and progesterone concentration in serum, by using 129sv male mice exposed to chronic unpredictable stress to validate the quantification. The method was conducted according to the ANVISA normative, adopting a coefficient of variation, as well as relative standard deviation and relative error lower than 15% in linearity, intraday and interday precision, and accuracy. For cortisol, corticosterone, and their inert metabolites (cortisone and 11-DHC), the lower limit of quantification was 3.9 ng. mL-1 , while that for progesterone and aldosterone was 7.8 and 15.6 ng. mL-1 , respectively. MRMHR analysis showed that animals submitted to stressors have 4.5 times more corticosterone in their serum than nonstressed mice. However, 11-DHC concentration does not vary significantly in response to stress for these animals. The results indicate that the method can be applied for quantification of steroids in several biological samples, such as human plasma. PMID- 29495129 TI - Ecological determinants of avian malaria infections: An integrative analysis at landscape, mosquito and vertebrate community levels. AB - Vector and host communities, as well as habitat characteristics, may have important but different impacts on the prevalence, richness and evenness of vector-borne parasites. We investigated the relative importance of (1) the mosquito community composition, (2) the vertebrate community composition and (3) landscape characteristics on the prevalence, richness and evenness of avian Plasmodium. We hypothesized that parasite prevalence will be more affected by vector-related parameters, while host parameters should be also important to explain Plasmodium richness and evenness. We sampled 2,588 wild house sparrows (Passer domesticus) and 340,829 mosquitoes, and we performed vertebrate censuses at 45 localities in the Southwest of Spain. These localities included urban, rural and natural landscapes that were characterized by several habitat variables. Twelve Plasmodium lineages were identified in house sparrows corresponding to three major clades. Variation partitioning showed that landscape characteristics explained the highest fraction of variation in all response variables (21.0%-44.8%). Plasmodium prevalence was in addition explained by vector-related variables (5.4%) and its interaction with landscape (10.2%). Parasite richness and evenness were mostly explained by vertebrate community related variables. The structuring role of landscape characteristics in vector and host communities was a key factor in determining parasite prevalence, richness and evenness, although the role of each factor differed according to the parasite parameters studied. These results show that the biotic and abiotic contexts are important to explain the transmission dynamics of mosquito-borne pathogens in the wild. PMID- 29495131 TI - Repair of a Kommerell's diverticulum with an absent left subclavian artery and a right aortic arch. PMID- 29495132 TI - Acid-base assessment of patients receiving hemodialysis. What are our management goals? AB - Acid-base assessment of patients receiving conventional hemodialysis (HD) has been based solely on predialysis serum [total CO2 ], and treatment is currently driven by the KDOQI guideline from 2000. This guideline was directed solely at minimizing metabolic acidosis and thereby improving bone and muscle metabolism. In 2000, no data were available to assess the effects of acid-base status on morbidity and mortality. Since then, new data have emerged from several large cohort studies about the association between variations in predialysis serum [total CO2 ], as well as blood pH, and morbidity and mortality risk. These studies have shown increased risk not only with very low predialysis [total CO2 ] values, but also with predialysis alkaline pH and very high predialysis serum [total CO2 ] values. At present, our major concern is not for patients with metabolic acidosis, but rather for the growing numbers of patients with metabolic alkalosis. This review discusses the controversies around assessing and treating acid-base status in HD patients, and recommends a practical approach based on the results of these recent studies. The new approach provides recommendations for patients both with very low and very high predialysis serum [total CO2 ] values. PMID- 29495133 TI - The Emerging Method of Suicide by Electronic Cigarette Liquid: a Case Report. AB - Electronic cigarettes (ECs) are a device that aerosolize liquid nicotine by heating a solution of nicotine, glycerol and flavoring agents. The awareness and the usage of ECs has increased in many countries. Due to the online sales and the absence of EC regulations, the prevalence of EC usage is especially high in adolescents and young adults. Due to the large amount and the high nicotine concentration of EC liquid, the ingestion for suicide can lead to cardiac death. We had two patients, a 27-year-old male who ingested about 23 mg/kg of nicotine and a 17-year-old female who ingested about 30 mg/kg of nicotine. Both patients presented seizure-like movement and cardiac arrest. They had metabolic acidosis and transient cardiomyopathy. They were ultimately discharged with a cerebral performance category of 2 and 4, respectively. Increasing EC use may produce more cases of medical problems or suicide by nicotine intoxication. PMID- 29495134 TI - Associations of Generalized Trust and Social Participation at the Individual Level with Unmet Healthcare Needs in Communities with High Mortality. AB - BACKGROUND: The aim of this study was to investigate whether generalized trust and/or social participation at an individual level have negative associations with unmet healthcare needs. METHODS: Door-to-door interviews were conducted by trained interviewers to collect information. The 8,800 study participants included 220 adults sampled systematically using the resident registration database from 40 sub-municipal-level administrative units in Korea. Unmet healthcare needs were measured subjectively by the following question: "During the past 12 months, was there ever a time when you felt that you needed healthcare (excluding dental care) but did not receive it?" The responses were classified as either "yes" or "no." RESULTS: The adjusted odds ratios (ORs) for unmet healthcare needs based on one positive response, two positive responses, and three positive responses to the three items of generalized trust compared to no positive responses were 0.92 (95% confidence interval [CI], 0.77-1.09), 0.90 (95% CI, 0.74-1.09), and 0.73 (95% CI, 0.61-0.87), respectively. The adjusted ORs for unmet healthcare needs based on social participation only in informal organizations, only in formal organizations, and in both informal and formal organizations compared to no social participation were 0.83 (95% CI, 0.71-0.98), 0.97 (95% CI, 0.77-1.21), and 0.97 (95% CI, 0.82-1.15), respectively. The covariates included in the multiple logistic regression were sociodemographic variables (gender, age, marital status, educational level, occupation, food security, and administrative unit), self-rated health, and perceived stress. CONCLUSION: Therefore, generalized trust and social participation in informal organizations can decrease the incidence of unmet healthcare needs. PMID- 29495135 TI - The Effect of Inter-Departmental Stroke Meetings on Rehabilitation in a Comprehensive Cerebrovascular Center. AB - BACKGROUND: Stroke is the number one cause of adulthood disability in Korea. Rehabilitation after stroke can minimize functional disability, enhance recovery toward independence, and optimize community reintegration. The inter-departmental stroke meeting (IDSM) is a potential method to improve rehabilitation outcomes in patients with stroke. We aimed to analyze the effect of IDSM on rehabilitation after acute ischemic stroke management. METHODS: Medical records of 753 patients with acute ischemic stroke admitted to the neurology department of our medical center between January and December 2014 were reviewed retrospectively. In May 2014, weekly IDSMs were initiated. All physicians responsible for the patient's care reviewed patient treatment, methods of secondary prevention, and future rehabilitation plans. RESULTS: The transfer rate significantly increased after initiation of IDSM (phase 2, 3) and the length of stay (LOS) before transfer to the rehabilitation department decreased significantly from 9.68 +/- 8.50 days to 5.75 +/- 2.12 days. There was a reduction in the total LOS from 52 +/- 28.57 days to 35 +/- 27.21 days after IDSMs were introduced. In non-transferred patients also, the total LOS reduced significantly. The transfer rate increased significantly and the LOS before transfer to the rehabilitation department decreased significantly after implementation of IDSM in a subgroup of patients with moderate to severe stroke. CONCLUSION: The introduction of IDSM was significantly correlated with improvements in transfer rates and reduction of LOS in hospital. This finding shows that IDSMs are an important intervention to improve therapeutic progress and outcomes for patients with stroke. PMID- 29495136 TI - Characteristics of Drugs Ingested for Suicide Attempts in the Elderly. AB - BACKGROUND: Suicide is a significant public health problem worldwide. Suicide rates among elderly persons (>= 65 years of age) are three times higher than those of younger people in Korea. The emergency department is an important entry of drug-related suicide attempt patients. In this study, we compared the frequency of drug types by age subgroup. Furthermore, we provide suggestions for preventing suicide attempts in the elderly. METHODS: We investigated 433 patients who were admitted to the emergency department for drug-related suicide attempts between 1 May 2015 and 30 April 2017. RESULTS: The proportion of patients who overdosed on antidepressants was 32.5% in the non-elderly age group and 8.0% in the elderly group (>= 65 years of age) (P < 0.001). Among the elderly, the most commonly ingested agent was hypnotics (59.1%) (P < 0.001). Compared with the non elderly, the results showed that the elderly used fewer antidepressants (P < 0.001) and analgesics (P < 0.001). Meanwhile, the elderly used more hypnotics (P < 0.001). Over-the-counter drugs and other medications showed similar usage trends in both age groups (P = 0.664, P = 0.193). CONCLUSION: The categories of drugs ingested for suicide attempts vary widely between different age groups. Younger people used antidepressants more frequently in suicide attempts, while the elderly used hypnotics more frequently. And the elderly required longer hospital stays. Suicide ideation and depressive mood in older patients who are prescribed hypnotics for various reasons should not be neglected. Further prevention efforts are needed to prevent suicide among the elderly. PMID- 29495137 TI - Factors Associated with Post-traumatic Stress Symptoms in Students Who Survived 20 Months after the Sewol Ferry Disaster in Korea. AB - BACKGROUND: The Sewol ferry disaster caused national shock and grief in Korea. The present study examined the prevalence and associated factors of post traumatic stress disorder (PTSD) symptoms among the surviving students 20 months after that disaster. METHODS: This study was conducted using a cross-sectional design and a sample of 57 students (29 boys and 28 girls) who survived the Sewol ferry disaster. Data were collected using a questionnaire, including instruments that assessed psychological status. A generalized linear model using a log link and Poisson distribution was performed to identify factors associated with PTSD symptoms. RESULTS: The results showed that 26.3% of participants were classified in the clinical group by the Child Report of Post-traumatic Symptoms score. Based on a generalized linear model, Poisson distribution, and log link analyses, PTSD symptoms were positively correlated with the number of exposed traumatic events, peers and social support, peri-traumatic dissociation and post-traumatic negative beliefs, and emotional difficulties. On the other hand, PTSD symptoms were negatively correlated with psychological well-being, family cohesion, post traumatic social support, receiving care at a psychiatry clinic, and female gender. CONCLUSION: This study uncovered risk and protective factors of PTSD in disaster-exposed adolescents. The implications of these findings are considered in relation to determining assessment and interventional strategies aimed at helping survivors following similar traumatic experiences. PMID- 29495138 TI - Diagnostic Performance of %[-2]proPSA and Prostate Health Index for Prostate Cancer: Prospective, Multi-institutional Study. AB - BACKGROUND: We evaluated the clinical performance of [-2]proPSA (p2PSA) and its derivatives in predicting the presence and aggressiveness of prostate cancer (PCa) in Korean men. METHODS: A total of 246 men with total prostate-specific antigen (tPSA) >= 3.5 ng/mL who underwent their first prostate biopsy were included in this prospective, multicenter, observational study. Diagnostic accuracy of tPSA, free-to-total PSA ratio (%fPSA), p2PSA, %p2PSA, and the Beckman Coulter prostate health index (PHI) was assessed by receiver operating characteristic curve analyses and logistic regression analyses. RESULTS: Overall, PCa was detected in 125 (50.8%) subjects. In men with tPSA 3.5-10 ng/mL, the detection rate of PCa was 39.4% (61/155). In this group, PHI and %p2PSA were the most accurate predictors of PCa and significantly outperformed tPSA and %fPSA; area under the curve for tPSA, %fPSA, %p2PSA, and PHI was 0.56, 0.69, 0.74, and 0.76, respectively. PHI was also the strongest predictor of PCa with Gleason score >= 7. CONCLUSION: This study demonstrates the superior clinical performance of %p2PSA and PHI in predicting the presence and aggressiveness of PCa in Korean men. The %p2PSA and PHI appear to improve detection of PCa and provide prognostic information. PMID- 29495139 TI - Cost-Benefit Analysis of Malaria Chemoprophylaxis and Early Diagnosis for Korean Soldiers in Malaria Risk Regions. AB - BACKGROUND: Chemoprophylaxis has been used to prevent malaria among soldiers and secondary transmission, as it effectively facilitates a decline in disease occurrence and secondary prevention. However, poor compliance and decreased risk of exposure to malaria necessitate that control strategies be reestablished. METHODS: To predict the incidence of malaria according to a control strategy, we proposed a mathematical model for its transmission using epidemiological data from 2010 to 2012. The benefit component included in the analyses was the averted cost with each control strategy, and the cost components were the cost of implementing chemoprophylaxis and early diagnosis. RESULTS: The chemoprophylaxis regimen with hydroxychloroquine sulfate and primaquine was Intervention 1, the regimen with primaquine only was Intervention 2, and diagnosis with a rapid diagnostic test (RDT) kit within 5 days of fever was Intervention 3. The simulation indicated that the combined control program with chemoprophylaxis and early diagnosis would be the most effective strategy, whereas sole early diagnosis would be the least effective strategy. However, the cost-benefit ratio of chemoprophylaxis was less than Intervention 1, irrespective of the varying range of chemoprophylaxis compliance, and that of early diagnosis was more than Intervention 1, regardless of the varying early diagnosis rate and demand for the RDT kit. Although chemoprophylaxis would be more effective at reducing the incidence of malaria than early diagnosis, it is less economical due to the higher cost. CONCLUSION: Our results support the introduction of early diagnosis with a RDT kit to control malaria in the Republic of Korea Army. PMID- 29495140 TI - Epidemiologic Characteristics of Injured School-age Patients Transported via Emergency Medical Services in Korea. AB - BACKGROUND: The purpose of this study was to identify the characteristics of injuries of school-aged children transported via emergency medical services (EMS) that occurred in schools by comparing with injuries that occurred outside of school. METHODS: Data from the 119 EMS from 2012 to 2014 were analyzed. School and non-school injuries were analyzed in children 6 to 17 years of age. The epidemiologic characteristics were assessed according to school-age groups; low grade primary (6-8 years), high-grade primary (9-13 years), middle (13-15 years) and high (15-17 years) school. Gender-stratified multivariable logistic regression analysis was conducted to estimate the risks of school injury in each age group. RESULTS: During the study period, a total of 167,104 children with injury were transported via 119 ambulances. Of these injuries, 13.3% occurred at schools. Boys accounted for 76.9% of school injuries and middle school children accounted for a significantly greater proportion (39.6%) of school injuries (P < 0.001). The most frequent mechanisms of injury at school were falls (43.8%). The peak times for school injury occurrence were lunch time (13:00-13:59) in all age groups. Multivariate regression identified the risky age groups as high-grade primary (odds ratio [OR], 1.14; 95% confidence interval [CI], 1.09-1.20) and middle school-aged boys (OR, 1.82; 95% CI, 1.74-1.90) and middle school-aged girls (OR, 1.30; 95% CI, 1.21-1.40). CONCLUSION: Notable epidemiologic differences exist between in- and out-of-school injuries. The age groups at risk for school injuries differ by gender. PMID- 29495141 TI - Revascularization of Concurrent Renal and Cerebral Artery Stenosis in a 14-Year Old Girl with Takayasu Arteritis and Moyamoya Syndrome. AB - Concurrent involvement of bilateral renal and cerebral arteries, usually incurred as stenosis, is rare in childhood-onset Takayasu arteritis (c-TA). We report the case of a 14-year-old girl, with c-TA, presenting with transient ischemic attack after endovascular revascularization for renal artery stenosis and cerebrovascular stroke after surgical revascularization for cerebral artery stenosis associated with childhood-onset moyamoya syndrome. We deem that decrease of blood pressure by endovascular revascularization and improvement of cerebral perfusion by surgical revascularization may have jeopardized the cerebral deep watershed zone to cerebral ischemia followed by cerebral hyperperfusion syndrome and caused transient ischemic attack and cerebrovascular stroke in our patient. Revascularization could be a double-edge sword for c-TA patients presenting with concomitant renal artery stenosis and cerebral artery stenosis, and should be performed with caution. Quantitative analysis of cerebral blood flow by brain magnetic resonance imaging and angiography should be performed within 48 hours after surgical revascularization in c-TA. PMID- 29495142 TI - Adenoidectomy May Not Be Effective to Reduce the Number of Hospital Visits for Sinusitis. AB - BACKGROUND: The objective of this study was to compare post-operative (post-op) visits for sinusitis between adenoidectomy and non-adenoidectomy participants (control). METHODS: Using the national cohort study from the Korean Health Insurance Review and Assessment Service, we used 1:4 matching to select 2,593 adenoidectomy participants and 10,372 control participants. Post-op visits for sinusitis were measured from post-op 1 year through post-op 9 years. Equivalence testing was used. Margin of equivalence of difference was set as -0.5 to 0.5 in this study. RESULTS: There were trivial differences between the two groups from post-op 1 to 2 years. However, there was no difference between the two groups from post-op 3 through 9 years. Visits for sinusitis gradually decreased in both groups. In the rare and frequent pre-operative sinusitis group, there were minor differences in both groups from post-op 1 to 2 years. In contrast, there were no differences between the two groups in rare and frequent pre-operative sinusitis groups from post-op 3 through 9 years. In the 0-4 years old group, there were minor differences between both groups from post-op 1 to 2 years. However, no differences in the number of visits for sinusitis were found between the two groups during follow up periods from post-op 3 through 9 years. Additionally, there were no differences between the two groups during the entire follow up period. CONCLUSION: Adenoidectomy does not reduce post-op visits for sinusitis. Sinusitis decreased over time whether adenoidectomy was performed or not. PMID- 29495143 TI - Optimal Timing of Delivery Based on the Risk of Stillbirth and Infant Death Associated with Each Additional Week of Expectant Management in Multiple Pregnancies: a National Cohort Study of Koreans. AB - BACKGROUND: The purpose of this study was to compare the fetal/infant mortality risk associated with each additional week of expectant management to that associated with immediate delivery in women with multiple gestations. METHODS: This was a retrospective national cohort study of 94,170 multiple deliveries, 92,619 (98.4%) twin and 1,352 (1.44%) triplet pregnancies, between 32 0/7 and 42 6/7 weeks of gestation recorded in the Korean vital statistics database. We investigated the risks of stillbirth and infant death after birth in Korea according to the week of gestation in twin and triplet pregnancies. RESULTS: The risk of stillbirth significantly increased between 34 and 35 weeks of gestation and between 37 and 38 weeks of gestation in twin pregnancies and between 34 and 37 weeks of gestation in triplet pregnancies. The risk of infant death following delivery gradually decreased as pregnancies approached full term. Week-by-week differences were statistically significant between 33 and 34 weeks, with decreasing risks of infant death at advancing gestational ages in twin pregnancies. At 37 weeks of gestation, the relative risk of mortality was significantly higher with expectant management compared with immediate delivery (relative risk, 3.00; 95% confidence interval, 1.41-6.38). CONCLUSION: In twin pregnancies, delivery at 37 weeks of gestation can minimize the risks of stillbirth and infant death in uncomplicated cases, although individual maternal and fetal characteristics must be considered when determining the optimal timing of delivery. In multiple pregnancies, close fetal surveillance is needed after 34 weeks of gestation. PMID- 29495145 TI - Cutaneous Cytomegalovirus Infection in a Healthy Infant. PMID- 29495144 TI - Effect of the Standardization of Diagnostic Tests on the Prevalence of Diabetes Mellitus and Impaired Fasting Glucose. AB - BACKGROUND: Without standardization of medical laboratory's testing practices, there is an increase in false diagnoses when relying on test results. However, the effect of test standardization is difficult to assess numerically. This study's purpose is to quantify the effect of the standardization level of a laboratory on the prevalence of diabetes mellitus (DM) and impaired fasting glucose (IFG). METHODS: Laboratories were classified into three levels: 'highly standardized laboratory,' 'basically-standardized laboratory,' and 'non standardized laboratory.' Based on the results of Korean External Quality Assessment Scheme (KEQAS), the cutoff values for diagnosis of DM and IFG were recalculated, given false positive and false negative rates. RESULTS: The prevalence of DM and IFG in the population as a whole was estimated using the 2013 Korea National Health and Nutrition Examination Survey (KNHANES) database. When the prevalence of DM from KNHANES was 11.88% (95% confidence interval [CI], 10.59%-13.17%), the proportion with a systematic false error ranged from 10.91% (95% CI, 9.65%-12.17%) to 13.09% (95% CI, 11.74%-14.45%). The prevalence of IFG varied from 13.59% (95% CI, 12.25%-14.91%) to 40.49% (95% CI, 38.54%-42.43%), in contrast to 24.58% (95% CI, 22.85%-26.31%) of the reference value. The prevalence of DM and IFG tended to be over- and under-estimated more as the laboratory standardization level became lower, respectively. CONCLUSION: Our study proved that standardization of clinical laboratory tests is an important factor affecting the prevalence estimation of national disease statistics based on the simulation using KNHANES data. PMID- 29495147 TI - [The roles of TSP-1 and its receptor CD47 in pathogenesis of paraquat-induced pulmonary fibrosis in rats]. AB - Objective: To establish a rat model of paraquat (PQ) -induced pulmonary fibrosis and observe the changes in thrombospondin-1 (TSP-1) and its receptor CD47 in lung tissue, and to investigate their roles in the pathogenesis of PQ-induced pulmonary fibrosis. Methods: Fifty-four clean adult male Sprague-Dawley rats were randomly divided into normal control group (n=6) and 2 h, 12 h, 1 d, 3 d, 7 d, and 14 d PQ poisoning groups (n=8 per group). A rat model of PQ poisoning was established by a single gavage of 20 wt.% PQ solution (50 mg/kg). Flow cytometry was used to determine the concentration of reactive oxygen species (ROS) in blood and lung tissue. Enzyme-linked immunosorbent assay was used to determine the concentrations of hydroxyl radicals, malondialdehyde, and hydroxyproline in lung tissue. HE staining and Masson staining were used to observe the pathological damage of lung tissue after PQ poisoning. The expression of TSP-1 and CD47 in lung tissue was measured by Immunohistochemistry. Results: Compared with the normal control group, the 2 h to 7 d PQ poisoning groups showed significant increases in ROS fluorescence intensity in red blood cells and lung tissues and the concentrations of malondialdehyde and hydroxyl radicals in lung tissue (P<0.05) , and the 14 d PQ poisoning group had a significant increase in the concentration of hydroxyproline in lung tissue (P<0.05). HE staining showed that the 2 h to 7 d PQ poisoning groups had significantly higher semiquantitative pathological scores of pulmonary alveolitis than the normal control group (P<0.05). The Masson staining showed that the 7 d and 14 d PQ poisoning groups had significantly higher semiquantitative pathological scores of pulmonary fibrosis than the normal control group (P<0.05). Compared with the normal control group, all PQ poisoning groups (except the 12 h group) had significantly increased expression of TSP-1 in lung tissue (P<0.05) , and all PQ poisoning groups (except the 1 d group) had significantly increased expression of CD47 in lung tissue (P<0.05). Within 2 h after PQ poisoning, the expression of TSP-1 and CD47 was positively correlated with the concentrations of ROS, hydroxyl radicals, and malondialdehyde and the degree of pulmonary alveolitis (P<0.01) ; at 1 d after PQ poisoning, the expression of TSP-1 and CD47 was positively correlated with the concentration of hydroxyproline in lung tissue (P<0.01) . Conclusion: The expression of TSP-1 and CD47 is closely related to oxidative stress and subsequent pulmonary fibrosis, and they may be involved in the development and progression of pulmonary alveolitis and subsequent pulmonary fibrosis in rats with PQ poisoning. PMID- 29495146 TI - Sudden Deaths of Neonates Receiving Intravenous Infusion of Lipid Emulsion Contaminated with Citrobacter freundii. AB - At an intensive care unit, four neonates died consecutively within 80 minutes. Citrobacter freundii was isolated from blood samples of the 4 patients. It was also cultured from the leftover SMOFlipid that had been infused intravenously into the patients. In this in vitro study, we evaluated the bacterial growth kinetics and change in size of fat globules in SMOFlipid contaminated with C. freundii. Following the growth of bacteria, pH of SMOFlipid decreased to < 6, and the number of fat globules larger than 5 MUm increased. Pulmonary fat embolism is proposed as a possible cause of the sudden deaths as well as fulminant sepsis. PMID- 29495148 TI - [Effects of fluoride exposure on thyroid hormone level and intelligence in rats]. AB - Objective: To investigate the effects of fluoride exposure on the thyroid hormone level and intelligence in rats and to investigate the biomarkers of intellectual impairment induced by high fluoride exposure. Methods: A total of 24 clean healthy Sprague-Dawley rats were randomly divided into control group (tap water containing 0.344 mg/L fluoride) and low-, medium-, and high-fluoride exposure groups (tap waters containing 10, 50, and 100 mg/L sodium fluoride, respectively). One male rat was cohabited with two female rats in the same group. After the offspring rats were weaned, 12 offspring rats (male/female ratio=1?1) with a similar body weight in each group were subjected to the same treatment for the parental offspring. The offspring rats were sacrificed on the 60th day after birth. The weight of offspring rats was measured. Serum thyrotropin (TSH) , free triiodothyronine (FT(3)) , and free thyroxine (FT(4)) levels were measured by enzyme-linked immunosorbent assay. The learning and memory abilities of the rats were evaluated by Morris water maze test. The expression of mitochondrial fission 1 (Fis1) and mitofusin 1 (Mfn1) in blood was measured by Western blot. Results: The offspring rats in the medium-and high-fluoride exposure groups had significantly lower serum TSH and FT(4) levels than those in the control group (P<0.05). The place navigation test showed that the offspring rats in the medium and high-fluoride exposure groups had significantly longer escape latency than those in the control group (P<0.05) , and the high-fluoride exposure group had a significantly longer escape distance than those in the control group (P<0.05). The spatial probe test showed that the offspring rats in the low-, medium-, and high-fluoride exposure groups had significantly shorter swimming time and distance in the target quadrant and total swimming time and distance than those in the control group (P<0.05). Compared with the offspring rats in the control group, those in the low-, medium-, and high-fluoride exposure groups had significantly higher expression of Fis1 (P<0.05) , and those in the low- and medium-fluoride exposure groups had significantly higher expression of Mfn1 (P<0.05) . Conclusion: High fluoride exposure can reduce the secretion of thyroid hormone and the abnormality of mitochondrial dynamics in peripheral lymphocytes may provide a clue to identifying the biomarkers of intellectual impairment induced by fluoride exposure. PMID- 29495149 TI - [Current status of job burnout in in-service sailors from 13 provinces and cities in China]. AB - Objective: To investigate the current status of job burnout in in-service sailors, and to provide a basis for the development of intervention measures for job burnout in sailors. Methods: From September 2015 to May 2016, stratified cluster random sampling was used to select 6 172 in-service sailors from 13 provinces and cities as research subjects. General demographic data including age, education background, and household registration and occupational characteristics such as job position, navigating zone, and nature of employment were collected. The Maslach Burnout Inventory-General Survey (MBI-GS) was used to measure the levels of emotional exhaustion, depersonalization, low occupational efficiency, and job burnout, and the influencing factors for job burnout were also analyzed. Results: Of all 6 172 in-service sailors, 112 (1.8%) had a positive result in emotional exhaustion, 870 (14.1%) had a positive result in depersonalization, and 3 517 (57.0%) had a positive result in low occupational efficiency. Of all sailors, 63.3% had job burnout, among whom 54.1% had mild burnout, 8.7% had moderate burnout, and 0.5% had severe burnout. There was a significant difference in the score of job burnout between the sailors with different ages, education backgrounds, types of household registration, job positions, navigating zones, ornature of employment (P<0.05). Age, education background, household registration, job position, navigating zone, and nature of employment were major influencing factors for job burnout in in-service sailors (P<0.05) , and there was a higher level of job burnout in the sailors with an age of 30-39 years, education background of junior college or above, urban registration, a job position of second mate/third engineer, a navigating zone of coastal lines, orthe nature of employment of freelance sailor. Conclusion: There is a high incidence rate of job burnout among in-service sailors, and the sailors with a young age, urban registration, a navigating zone of coastal lines, or thenature of employment of freelance sailor tend to have low occupational efficiency. Related measures should be adopted for active intervention. PMID- 29495150 TI - [Effect of leader-member exchange on nurses'sense of calling in workplace]. AB - Objective: To investigate the effect of leader-member exchange on nurses'sense of calling in workplace based on self-determination theory. Methods: A total of 381 nurses were randomly selected from five tertiary general hospitals in Zhejiang province, China from October to December, 2016. They were subjected to a survey using the Leader-Member Exchange Scale, Job Autonomy Scale, Core Self-Evaluation Scale, and Calling Scale. The mediating effect was used to test the procedures and the data were subjected to hierarchical regression analysis. Results: The leader-member exchange was positively correlated with job autonomy, core self evaluation, and sense of calling (r=0.471, P<0.001; r=0.373, P<0.001; r=0.475, P<0.001) ; the leader-member exchange had a positive predictive effect on job autonomy and sense of calling (beta= 0.47, P<0.001; beta=0.48, P<0.001) ; the job autonomy had a partial mediating effect on the relationship between leader-member exchange and sense of calling (F=66.50, P<0.001) ; the core self-evaluation negatively adjusted the positive relationship between leader-member exchange and job autonomy (F=27.81, P<0.001) . Conclusion: High-quality leader-member exchange enhances the sense of calling by improving staffs' job autonomy and the core self evaluation reduces the positive relationship between leader-member exchange and job autonomy. PMID- 29495151 TI - [Analysis on occupational health surveillance to workers exposed to toxic environment in a city]. AB - Objective: To understand the status of occupational health surveillance to workers exposed to toxic environment in a city, so as to provide scientific basis for strategy of occupational diseases prevention. Methods: In January 2017, collecting the data of on-the-job poisonous and harmful workers occupational health surveillance in the city from January 1, 2010 to December 31, 2016 in China Information System for Disease Control and Prevention, the trend of occupational health monitoring in the city was analyzed, and the differences between diverseeconomic types, enterprise scale, industry nature and hazard factors were analyzed and compared. Results: The occupational health examination rate showed an overall upward trend in workers exposed to dust in the city from 2010-2016 (t=3.607, P<0.05) , and the detection rate of occupational contraindications was on the rise in workers exposed to chemical factors (t=3.071, P<0.05). The detection rate of occupational contraindications and suspected occupational diseaseswere significant in different economic types, enterprise scale, industry nature and hazard factors (P<0.05). The detection rate of occupational contraindications was the highest among the large enterprises (1.24%) , the manufacturing industry (0.84%) and the state-owned economy (1.49%). The detection rate of suspected occupational diseases (0.04%) and occupational contraindications (1.15%) were the highest in the physical factors. Conclusion: Occupational health monitoring in the city is not optimistic. It is necessary to focuson the occupational health care of manufacturing practitioners, raise the detection rate of suspected occupational diseases, and standard the occupational health check work to protect the occupational health. PMID- 29495152 TI - [Relationship between occupational stress and working ability of workers in a petroleum processing enterprise in high altitude area]. AB - Objective: To investigate the relationship between occupational stress and working ability of workers in a petroleum processing enterprise in a high altitude area. Methods: A total of 728 workers in a petroleum processing enterprise at an altitude of 2850 m were subjected to a survey using Occupational Stress Inventory (OSI) , Work Ability Index (WAI) Scale, Occupational Role Questionnaire (ORQ) , Personal Strain Questionnaire (PSQ) , and Personal Resource Questionnaire (PRQ) from May 2014 to August 2016. Results: Of the 728 workers, 55 (7.6%) had a poor working ability, moderate in 262 (35.9%) , and good in 411 (56.5%). There were significant differences in WAI between the workers with different types of work, sexes, ages, and working years (P<0.05). There was a significant difference in WAI between different occupational stress groups (P<0.05). WAI was negatively correlated with ORQ score and PSQ score (r(s)= 0.387, P<0.05; r(s)=-0.467, P<0.05) and positively correlated with PRQ score (r(s)=0.343, P<0.05). The multiple linear regression analysis showed that high ORQ score and PSQ score were the inhibitory factors for high WAI (B=-0.058; B= 0.082) and high PRQ score was a contributing factor for high WAI (B=0.029) . Conclusion: Occupational stress is an influencing factor for the working ability of workers in the petroleum processing enterprise in the high altitude area. Hypoxia in high altitude area may further reduce the working ability. In order to reduce occupational stress and improve work ability, it should be considered to strengthen skills training, improve the working environment, and pay attention to mental health. PMID- 29495153 TI - [Intervention study of compassion fatigue of oncology nurses in Balint group activities]. AB - Objective: To explore the effectiveness of Balint group on compassion fatigue among oncology nurses. Methods: From January to December 2016, 35 oncology nurses from one general hospital were enrolled. 18 cases were allocated in the observation group and 17 cases in the control group by computer randomization. Nurses in the observation group were received a total of 8 times Balint Group activities, with 2 times a month and 1.5 hours each time, which is aiming to discuss difficult cases encountered in the clinic to help nurses have a deeper experience and a better understanding of the emotions and behaviors, fantasies and needs between nurse-patient interaction. Nurses in the control group without intervention. All the Participants were requested to complete the survey of the Professional Quality of Life (ProQOL) , the Jefferson Scale of Empathy-Health Professionals (JSE-HP) , and the General Health Questionnaire (GHQ) at pre and post intervention. Results: Before intervention, two group of nurses in age, working years, marriage, and education were not statistically significant (P>0.05). There was no difference in the scores of empathy, compassion satisfaction, secondary traumatic stress, and General health (P>0.05). After intervention, the scores of JSE-HP and its three dimensions of perspective taking, emotional care, and trans-positional consideration in the observation group had significantly higher than the control group (P<0.05). The level of compassion satisfaction in the observation group was higher, and the general health status was lower (P<0.05). There was no statistically difference in the level of burnout and secondary traumatic stress between two groups (P>0.05) . Conclusion: Balint group has a positive role in promoting nurses'empathetic skills, compassion satisfaction and mental health. PMID- 29495154 TI - [Investigation on physical activity and serum lipid level among male taxi drivers of a city in China]. AB - Objective: To investigate the relationship between physical activity (PA) and serum lipid level among male taxi drivers of a city in china. Methods: A total of 360 male taxi drivers were collected by two-stage random sampling method from september to november in 2016, the questionnaires were used to survey the status of PA and serum total cholesterol (TC) , triglyceride (TG) , low-density lipoprotein cholesterol (LDL-C) , high-density lipoprotein cholesterol (HDL-C) , according to the recommended standards of the intenational consensus group on physical activity measurement (ICGPAM) , the participants were divided into 3 groups: high PA level group, moderate PA level group and low PA level group. Results: The percentages of individuals with high, moderate and low PA levels were 60.7%, 22.1%and 17.2% respectively, the levels of TG, LDL-C had a declining trend along with the PA level increase, and the level of HDL-C had a increasing trend, the difference was statistically significant (P<0.05). Compared with low PA group, the incidence of dyslipidemia in high PA group showed a declining trend in the indexes of TG, LDL-C, any kind of dyslipidemia and any two kinds of dyslipidemia, the difference was statistically significant (P<0.05). After controlling the potentially confounding effects, compared with low PA group, the risk of dyslipidemia were reduced in the indexes of TG (OR=0.68, 95%CI: 0.55 0.84) , LDL-C (OR=0.67, 95%CI: 0.54-0.83) , HDL-C (OR=0.70, 95%CI: 0.56-0.88) , any kind of dyslipidemia (OR=0.65, 95%CI: 0.54-0.85) , any two kinds of dyslipidemia (OR=0.68, 95%CI: 0.55-0.86) in high PA group, there were significant differences between of them (all P<0.05) . Conclusion: The PA level of male taxi drivers in this city is relatively low, and high PA can reduce the risk of dyslipidemia. PMID- 29495155 TI - [An analysis of coping styles and subjective well-being among nurses in the emergency treatment room of grade A tertiary hospitals in a province of China]. AB - Objective: To investigate the coping styles and subjective well-being of nurses in the emergency treatment room of grade A tertiary hospitals in a province of China, and to explore the relationship between coping styles and subjective well being. Methods: In January 2016, 189 nurses in the emergency treatment room were selected from 9 grade A tertiary hospitals in a province of China by random sampling. The general data, coping styles, and subjective well-being of these nurses were analyzed using the general questionnaire, coping style questionnaire, and Campbell index of well-being scale, respectively. Results: The total score of subjective well-being of nurses in the emergency treatment room was 7.54, and the subjective well-being was significantly different between the nurses with different professional titles and between those with different education levels (F=3.46 and 3.47, both P<0.05). The score of illusion coping style differed significantly across the nurses of different ages (F=5.17, P<0.05) , the scores of self-reproach, illusion, and withdrawal coping styles differed significantly across the nurses with different nursing years (F=3.99, 5.30, and 4.97, all P<0.05) , and the score of illusion coping style differed significantly across the nurses with different education levels (F=5.09, P<0.05). Most (71.9%) of the nurses in the emergency treatment room adopted the mature coping style. Subjective well-being was positively correlated with problem-solving, help seeking, and rationalization (r=0.232, 0.018, and 0.167, all P<0.05) and negatively correlated with withdrawal (r=-0.146, P<0.05) . Conclusion: Most nurses in the emergency treatment room adopt the mature coping style. Their subjective well-being and coping style vary with different ages, nursing years, professional titles, and education levels, and the subjective well-being is relatively low. PMID- 29495156 TI - [Analysis of the impact of job characteristics and organizational support for workplace violence]. AB - Objective: To analyze the effect of job characteristics and organizational support for workplace violence, explore the influence path and the theoretical model, and provide a theoretical basis for reducing workplace violence. Methods: Stratified random sampling was used to select 813 medical staff, conductors and bus drivers in Chongqing with a self-made questionnaire to investigate job characteristics, organization attitude toward workplace violence, workplace violence, fear of violence, workplace violence, etc from February to October, 2014. Amos 21.0 was used to analyze the path and to establish a theoretical model of workplace violence. Results: The odds ratio of work characteristics and organizational attitude to workplace violence were 6.033 and 0.669, respectively, and the path coefficients were 0.41 and-0.14, respectively (P<0.05). The Fitting indexes of the model: Chi-square (chi(2)) =67.835, The ratio of the chi-square to the degree of freedom (chi(2)/df) =5.112, Good-of-fit index (GFI) =0.970, Adjusted good-of-fit index (AGFI) =0.945, Normed fit index (NFI) =0.923, Root mean square error of approximation (RMSEA) =0.071, Fit criterion (Fmin) =0.092, so the model fit well with the data. Conclusion: The job characteristic is a risk factor for workplace violence while organizational attitude is a protective factor for workplace violence, so changing the job characteristics and improving the enthusiasm of the organization to deal with workplace violence are conducive to reduce workplace violence and increase loyalty to the unit. PMID- 29495157 TI - [Incidence of occupational diseases in a province of China during the period of "Twelfth Five-Year Plan" and its trend]. AB - Objective: To investigate the incidence of occupational diseases in a province of China during the period of "Twelfth Five-Year Plan" , and to analyze the features of disease spectrum, the characteristics of regional and industrial distribution, and incidence trend. Methods: Data (2011-2015) were collected from the Information System of Occupational Diseases and Occupational Health to analyze the reported cases of occupational diseases during the period of "Twelfth Five Year Plan". A statistical analysis was performed to identify the characteristics of the disease distribution in terms of sex, age, working years, enterprise type, enterprise scale, and region, as well as the incidence trend. Results: The overall incidence of occupational diseases in this province fluctuated and decreased gradually. There were a total of 5036 new cases of occupational diseases during the period of "Twelfth Five-Year Plan" ; 89.45% of them were male, and 69.78% of them were aged 40-69 years; the most frequently seen occupational diseases were pneumoconiosis (72.48%) and ear, nose, throat, and oral diseases (7.23%). Most cases of pneumoconiosis occurred after 5-10 years of exposure, and other occupational diseases usually developed within 10 years of exposure. New cases of occupational diseases were often seen in small and micro enterprises, as well as Wuxi, Suzhou, and Yancheng. Conclusion: During the period of "Twelfth Five-Year Plan" , the incidence of occupational diseases in this province decreased gradually, indicating improved control of occupational diseases, but we still need to pay attention to the high-risk population (male, aged over 40 years) , as well as the prevention of occupational noise-induced hearing loss, and to strengthen the supervision of small and micro enterprises. PMID- 29495158 TI - [Current prevalence and prevention of work-related musculoskeletal disorders among physicians for internal medical examination in tertiary hospitals in a city of China]. AB - Objective: To investigate the current prevalence and prevention of work-related musculoskeletal disorders (WMSDs) among physicians for internal medical examination, and to provide a theoretical basis for the prevention and treatment of WMSDs in physicians for internal medical examination. Methods: In February 2017, 326 physicians for internal medical examination were randomly selected from 5 general tertiary hospitals and 2 specialized tertiary hospitals in a city of China. A questionnaire was designed according to the Nordic Musculoskeletal Questionnaire and the occupational features of doctors in China to investigate the prevalence of musculoskeletal pain over the past year, the cognitive attitude to WMSDs, the knowledge of WMSDs prevention, and ways to get the knowledge of WMSDs prevention. Results: In the tertiary hospitals of this city, the symptoms of WMSDs were mainly seen in the wrist (75.78%) , neck (67.19%) , and lower back (58.59%) among male physicians, and in the wrist (73.74%) , lower back (70.95%) , and upper back (60.89%) among female physicians. Compared with the female physicians, the male physicians had a significantly increased detection rate of symptoms of WMSDs in the neck (P<0.05) and significantly reduced detection rates of symptoms of WMSDs in the upper and lower back (P<0.05). There were significant differences between the detection rates of symptoms of WMSDs in the neck, wrist, and lower back within the past 12 months, 7 days, and >1 month (P<0.01). The rates of knowledge of the severity and prevention of WMSDs were significantly different between the physicians with different working years and professional titles (P<0.01) . Conclusion: Among the physicians for internal medical examination in the tertiary hospitals of this city, WMSDs are mostly seen in the wrist, neck, and waist, and the knowledge of WMSDs prevention varies with different working years and professional titles. PMID- 29495159 TI - [A bibliometric analysis of literature on hand-transmitted vibration in China, 1990-2016]. AB - Objective: To investigate the features of literature on hand-transmitted vibration in China, 1990-2016. Methods: In September 2017, the studies on hand transmitted vibration in China, which were published in Chinese or English during 1990-2016, with "China" and "Taiwan" as the places where author affiliations were located, were retrieved. A bibliometric analysis was performed to investigate the type of articles, publication time, the journals in which articles were published, author affiliations, author regions, and funding. Results: A total of 205 articles on hand-transmitted vibration were retrieved. There were 7.59 articles on average published annually from 1990 to 2016. In the 205 articles, 114 (55.61%) were published in the journals indexed in one or two core journal databases. In the 64 journals, 22 (34.38%) were indexed in one or two core journal databases. The first authors were from 22 provincial regions (provinces, autonomous regions, or centrally administered municipalities) in China, with 152 articles (74.15%) by the authors in the top five regions. There were a total of 876 authors, and the co-authorship degree was 4.27 (876/205). Most of the first authors (136 articles, 66.34%) were affiliated with universities or institutes for prevention and control of occupational diseases. Among the 205 articles, 103 (50.24%) were original articles or investigations, and 72 (35.12%) were funded. Conclusion: The studies on hand-transmitted vibration fluctuated and increased from 1990 to 2016, with a relatively concentrated distribution in terms of sources, regions, and institutions. Interregional and international academic exchange should be strengthened. PMID- 29495160 TI - [Relationship between personality characteristics and turnover intention of medical staff in an infectious disease hospital]. AB - Objective: To investigate the relationship between personality characteristics and turnover intention of the medical staff in an infectious diseases hospital. Methods: Using the cluster sampling method, a total of 366 members of medical staff were selected from different departments in an infectious disease hospital from May to August, 2013. The general information, such as sex, age, education level, and professional title, were collected and they were subjected to a survey using Cattell's 16 Personality Factor Questionnaire and Turnover Intention Scale. The data were subjected to logistic regression analysis. Results: Compared with the Chinese norm, the medical staff in the infectious disease hospital had significantly higher scores of intelligence, stability, bullying, excitability, perseverance, social boldness, fantasy, privateness, independence, and self discipline and significantly lower scores of gregariousness, sensitivity, suspicion, anxiety, and tension (P<0.05). Of the 366 members of medical staff, 22 (6.01%) had a very low turnover intention, low in 152 (41.53%) , high in 61 (16.67%) , and very high in 131 (35.79%). The logistic regression analysis showed that sensitivity, suspicion, fantasy, privateness, anxiety, openness to change, and independence were the risk factors for turnover intention (P<0.05) . Conclusion: Compared with the Chinese norm, the medical staff in the infectious disease hospital have a better mental quality and a higher turnover intention. The individuals with sensitivity, suspicion, fantasy, and anxiety are prone to having turnover intention. PMID- 29495161 TI - [Study on antimicrobial susceptibility of Brucella in a city]. AB - Objective: To investigate the antimicrobial susceptibility of Brucella and to provide a scientific basis for rational drug use and effective treatment of patients with brucellosis. Methods: A total of 41 Brucella strains were isolated from the blood of patients with brucellosis in 5 counties and 2 districts in Yuxi City, China from 2014 to 2016. The susceptibility to 23 antimicrobial drugs was tested using Kirby-Bauer (K-B) disk diffusion method and the sizes of antimicrobial rings were recorded. The susceptibility testing results were interpreted according to the Drug Susceptibility Testing Guideline (2009 version) . Results: The susceptibility rate of Brucella was 100.00% to ofloxacin, ciprofloxacin, levofloxacin, and amikacin and >90% to cefotaxime, cefepime, imipenem, doxycycline, cefoperazone, minocycline, tobramycin, rifampicin, cefoperazone/sulbactam, and chloramphenicol. The high resistance to aztreonam and ampicillin was observed (87.80% and 41.46%). Doxycycline-intermediate strains, rifampicin-intermediate strains, and rifampicin-resistant strains were identified. Conclusion: Doxycycline and rifampicin are commonly used in the treatment of brucellosis, but doxycycline/rifampicin-intermediate and-resistant strains have been identified. The susceptibility of Brucella to fluoroquinolones and cephalosporins was high, so the two drugs can be considered in the treatment of brucellosis. PMID- 29495163 TI - [Development of diagnostic criteria for occupational bromopropane poisoning]. PMID- 29495162 TI - [An analysis of intraocular metallic foreign body injury during hammer percussion]. AB - Objective: To investigate the cause of intraocular metallic foreign body injury during hammer percussion and to observe the structure of the metallic foreign bodies. Methods: A retrospective analysis was performed in 21 inpatients with metallic foreign body injury in the posterior segment from January 2013 to April 2016. The foreign bodies were removed by magnetic drawing through external route of the sclera or vitrectomy. The shape of the foreign bodies was analyzed and the structural characteristics were observed under a metallurgical microscope. The visual acuity of the patients was compared before and after treatment. Results: All patients were discharged at one week after surgery. There was no significant difference in mean best corrected visual acuity of the patients between before treatment and after treatment (1.20+/-0.87 vs. 1.08+/-0.89, t=1.516, P>0.05). The metallic foreign bodies in all the 21 cases were magnetic and the injuries in 15 cases (71.43%) were caused by hammering on hard objects. The foreign bodies were mainly lamellar and shaped like a leaf or a lance. And the lamellar martensite structure was observed under a metallurgical microscope. Conclusion: The intraocular metallic foreign body injury often occurs during hammer percussion and the microstructure of the foreign bodies is lamellar martensite structure. PMID- 29495164 TI - [Research progress on the role of Wnt/beta-catenin signaling pathway in disease and its regulatory mechanism]. PMID- 29495165 TI - [Emerging role of long noncoding RNAs in several common respiratory diseases: a systematic review]. PMID- 29495166 TI - [Research progress on the injurious effects of ionizing radiation on human eyes]. PMID- 29495167 TI - [Effects of microwave radiation on female reproductive system]. PMID- 29495168 TI - [The protective effect of Xuebijing on paraquat-induced HK-2 cells apoptosis and the underlying mechanisms]. AB - Objective: To investigate the protective effect and mechanism of Xuebijing (XBJ) on paraquat (PQ) -induced apoptosis in Human kidney cell line-2 (HK-2) cells. Methods: Routinely cultured HK-2 cells, (1) Cell growth inhibition experiment after PQ and XBJ intervention: PQ was divided into 0,200,400,800,1600 and 3200 MUmol/L PQ groups, and the cell survival rate was detected after intervening 24,48 and 72 h. XBJ was divided into 0,5,10,20,40 mg/ml XBJ groups, and the cell survival rate was detected after intervening 24,48 and 72 h.To determine the rational drug concentration and the duration of action of XBJ and PQ. (2) PQ induced HK-2 cell growth inhibition experiment antagonized by XBJ: The cells were divided into normal control group, PQ group (800 MUmol/L) and PQ+XBJ group (The cells were pretreated with 5,10 and 20 mg/ml XBJ for 1 h, then cultured with PQ of 800 MUmol/L) , After cultured 24 h,48 h and 72 h separately, the cell survival rate was detected. (3) HK-2 cells were divided into normal control group,PQ group (800 MUmol/L PQ cultured for 24 h) ,PQ+XBJ group (pretreated with 10 mg/ml XBJ for 1 h, and then 800 MUmol/L PQ cultured for 24 h) and XBJ group (10 mg/ml XBJ cultured 24 h). The apoptosis of cells was detected by flow cytometry. The protein expression of Bcl-2 and BAX in each group was detected by Western blotting. The expressions of caspase-3 and caspase-9 were detected by caspase-3 and caspase-9 activity kit active. Results: (1) PQ could significantly reduced the survival rate of HK-2 cells and showed time and concentration dependence. The survival rate of HK-2 cells was about 55% after 800 MUmol/L PQ contacted 24 h, XBJ under 20 mg/ml was no significant effect on the survival rate of HK-2 cells after cultured 72 h. (2) Compared with the PQ group, the survival rate of HK-2 cells of PQ+XBJ group was significantly increased (P<0.05). (3) Compared with the normal control group, the cell apoptosis rate of PQ group was significantly increased (P<0.05). Compared with the PQ group, the cell apoptosis rate of PQ+XBJ group was significantly decreased (P<0.05). (4) Compared with the normal control group, Bcl-2 protein expression in PQ group was significantly decreased and BAX protein expression in PQ group was significantly increased (P<0.05) ; compared with PQ group, Bcl-2 protein expression in PQ+XBJ group was significantly increased, BAX protein expression in PQ+XBJ group was significantly decreased (P<0.05). (5) Compared with the normal control group, the activities of caspase-3 and caspase-9 in PQ group were significantly increased (P<0.05). Compared with PQ group, the activities of caspase-3 and caspase-9 in PQ+XBJ group were decreased significantly (P<0.05) . Conclusion: XBJ (10 mg/ml) has obvious protective effect on HK-2 cell injuried by PQ (800 MUmol/L) , It can improve the survival rate of cells through reducing the apoptosis of HK-2 cells which induced by PQ. PMID- 29495170 TI - [A case report of oral paraquatgranulates poisoning]. PMID- 29495169 TI - [The comparison of heparan sulfate and its fragments on the protection against extracellular histones during the pathogenesis of acute respiratory distress syndrome]. AB - Objective: In order to explore the role of heparan sulfate (HS) during the pathogenesis of acute respiratory distress syndrome (ARDS) , the protective effect of HS and its fragments against extracellular histones was compared. Methods: Calf thymus histones (CTH) were injected via femoral vein to induce ARDS in rats. HS, HS fragments or saline was intraperitoneally injected (10mg/kg, Q6h, 24h) to test the protective effect against CTH. The ratio of wet/dry lung weight, protein content in bronchoalveolar lavage fluid (BALF) , total leukocyte and neutrophil count in BALF were measured. Results: After CTH injection, the ratio of wet/dry lung weight (5.7+/-0.95) was much higher than the saline control group (3.1+/-0.15). The protein content (0.47+/-0.086mg/ml) , total leukocyte[ (97.4+/ 15.6l) *10(4)/ml] and neutrophil (18+/-3.4/LPF) in BALF were obviously increased compared with the saline control group. The intervention of HS evidently decreased ratio of wet/dry lung weight (4.2+/-0.41) , protein content[ (0.26+/ 0.019) mg/ml], leukocyte[ (61.3+/-5.74) *10(4)/ml] and neutrophil (12+/-1.8/LPF) in BALF. HS fragments also decreased ratio of wet/dry lung weight, protein content, leukocyte and neutrophil count in BALF though the strength was much less than HS. Conclusion: HS and its fragments could provide protection against extracellular histones during the pathogenesis of ARDS. For the protective effect full length HS was much better than HS fragments. PMID- 29495171 TI - [Effect of paraquat on the expression of a disintegrin and metalloproteinase-17 in A549 cells]. AB - Objective: Construct a paraquat (PQ) cell fibrosis model in vitro, observe the effect of PQ on the expression of a disintegrin and metalloproteinase-17 (ADAM17) in A549 cells, and explore the role of ADAM17 in the pulmonary fibrosis induced by PQ poisoning. Methods: A549 cells are divided into normal control group, different concentration of PQ groups, CCK-8 is used to detect cell viability, screening concentration and time of PQ, cell morphology is observed under microscope; Enzyme-linked immunosorbent assay (ELISA) detectes fibrosis markers of collagen type I (Col I) and fibronectin (FN) expression. Establishment of cell model of fibrosis; distribution by immunocytochemical detection of ADAM17 in A549 cells, Reverse transcription-polymerase chain reaction and Western blot are used to detect the expression of ADAM17 mRNA and protein. Results: 1. With the increase of PQ concentration and the prolongation of the action time, the activity of A549 cells decreased (P< 0.05) , which is dose-dependent and time dependent. 2.The normal A549 cells fusion is paving stone growth and arranged more closely. After PQ induction, the cell arrangement was loose, the intercellular connection became loose, and some cells dissolved and died. 3.ELISA showed that with the increase of PQ concentration, the expression of Col I and FN increased (P<0.05) , and Col I and FN expression gradually increased with the prolongation of PQ time (P<0.05) , and the fibroblast model is successfully established. 4. Immunocytochemistry showes that ADAM17 is expressed in the cytoplasm of A549 cells. 5. RT-PCR and Western blot showed that the expression of ADAM17 mRNA and protein increased significantly with the increase of PQ concentration (P<0.05) , which is most obvious at PQ 200 MUmol/L. With the prolonged action of PQ, the expression level of ADAM17 mRNA and protein also increased significantly (P<0.05) , and reached the peak in 24 h. Conclusion: PQ can induce morphological changes of alveolar epithelial cells, cause cell damage, and successfully establish a cell fibrosis model, which has a dose and time dependence on the toxicity of A549 cells. ADAM17 is overexpressed in the A549 cells induced by PQ and may be involved in the process of pulmonary fibrosis induced by paraquat. PMID- 29495172 TI - [Application of occupational hazard risk index model in occupational health risk assessment in a decorative coating manufacturing enterprises]. AB - Objective: To evaluate the occupational health risk of decorative coating manufacturing enterprises and to explore the applicability of occupational hazard risk index model in the health risk assessment, so as to provide basis for the health management of enterprises. Methods: A decorative coating manufacturing enterprise in Hebei Province was chosen as research object, following the types of occupational hazards and contact patterns, the occupational hazard risk index model was used to evaluate occupational health risk factors of occupational hazards in the key positions of the decorative coating manufacturing enterprise, and measured with workplace test results and occupational health examination. Results: The positions of oily painters, water-borne painters, filling workers and packers who contacted noise were moderate harm. And positions of color workers who contacted chromic acid salts, oily painters who contacted butyl acetate were mild harm. Other positions were harmless. The abnormal rate of contacting noise in physical examination results was 6.25%, and the abnormality was not checked by other risk factors. Conclusion: The occupational hazard risk index model can be used in the occupational health risk assessment of decorative coating manufacturing enterprises, and noise was the key harzard among occupational harzards in this enterprise. PMID- 29495173 TI - [Effect of workplace bullying on posttraumatic stress disorder in nursing staff]. AB - Objective: To investigate the relationship between workplace bullying and posttraumatic stress disorder (PTSD) in nursing staff, and to analyze the role of psychological capital between workplace bullying and PTSD. Methods: From December 2014 to June 2015, convenience sampling was used to collect 496 nurses from 5 grade A tertiary hospitals in a province of China. Their workplace bullying, psychological capital, and PTSD status were assessed using the Negative Acts Questionnaire, Psychological Capital Questionnaire, and Posttraumatic Stress Disorder Self-Rating Scale, respectively. The correlation between variables was analyzed using a structural equation model. Results: Among these nurses, the scores of negative acts, psychological capital, and PTSD were 37.15+/-12.83, 78.81+/-16.54, and 34.56+/-12.52, respectively. The score on each dimension of negative acts was positively correlated with that on each dimension of PTSD (P<0.01) ; the score on each dimension of psychological capital was negatively correlated with that on each dimension of PTSD and negative acts (P<0.01). Negative acts had a positive predictive effect on PTSD (beta=0.539, P<0.01) , which was reduced after inclusion of psychological capital (beta=0.513, P<0.01). The path coefficient was 0.62 for the effect of negative acts on PTSD, -0.18 for the effect of negative acts on psychological capital, and -0.11 for the effect of psychological capital on PTSD (P<0.05) . Conclusion: Workplace bullying is a predictive factor for PTSD, and psychological capital plays a mediating role between workplace bullying and PTSD. The manager should reduce workplace bullying to improve the psychological capital in nursing staff and to prevent and reduce PTSD. PMID- 29495175 TI - [Investigation and analysis on occupational disease in one province from 2006 2015]. PMID- 29495174 TI - [Analysis of acute pesticide poisoning in Ningbo city from 2011 to 2016]. AB - Objective: To analyze the characteristics of acute pesticide poisoning in Ningbo, and to provide scientific basis for the prevention and control strategy. Methods: In February 2017, the pesticide poisoning report card of Ningbo from 2011 to 2016 was drawn from the China Disease Control and prevention information system. The data of the report card was organized by Excel and analyzed by SPSS19.0 software. Results: 2593 cases of acute pesticide poisoning were reported in Ningbo from 2011 to 2016, 125 deaths, and the case fatality rate was 4.82%. The productive pesticide poisoning and unproductive pesticide poisoning were 299 and 2294, respectively, the ratio was 1: 7.67. The case fatality rate were 0.33% and 5.41%, respectively. The difference was statistically significant (chi(2)=14.83, P<0.01). The productive Pesticide poisoning mainly occurred from July to September (55.85%) , the unproductive pesticides mainly occurred from April to June (30.64%) and July to September (30.34%). The seasonal distribution of the pesticide poisoning in the two groups was statistically significant (chi2=82.21, P<0.01). The productive pesticide poisoning in male (80.27%) was significantly higher than the proportion of unproductive pesticide poisoning (52.09%) , the differences in gender composition between the two types of pesticide poisoning was significant (chi2=84.97, P<0.01). The productive pesticide poisoning from 55 to 65 years old group was in the largest number (35.45%) , and the distribution of unproductive pesticide poisoning was uniform in each age group including 25 years old and above, the difference in age composition between two types of pesticide poisoning was statistically significant (chi2=177.84, P<0.01). All of the 10 counties of Ningbo had reports of pesticide poisoning. The counties with more reports were Ninghai county (18.28%) , Fenghua district (14.69%) and Yuyao (12.42%). The acute pesticide poisoning was mainly caused by pesticides and herbicides, mainly in organophosphorus (45.74%) and paraquat (16.81%) . Conclusions: At present, the pesticide poisoning in Ningbo is given priority to unproductive pesticide poisoning currently, seasonal distribution characteristics was obvious, and occurred both in different sex and age groups, suggesting that the relevant departments should carry out targeted health education, and strengthen the management of high toxic and highly toxic pesticides. PMID- 29495176 TI - [An analysis of status of personnel in occupational disease prevention and treatment institutions in Hunan Province, China, from 1996 to 2015]. AB - Objective: To analyze the status of personnel in occupational disease prevention and treatment institutions in Hunan Province, China, from 1996 to 2015, to predict staff composition using grey model (GM) (1, 1) , and to provide a scientific basis and reference for optimizing human resource planning of occupational disease prevention and treatment in other provinces and regions and promoting the service capacity of the institutions. Methods: The data of the staff in occupational disease prevention and treatment institutions in Hunan Province, China, from 1996 to 2015 were obtained from the established basic information management system. The descriptive analysis method was used to analyze the dynamic changes in number and composition of the staff and the GM (1, 1) was used to predict the staff composition. Results: The numbers of the staff members in 1996 and 2015 in occupational disease prevention and treatment institutions in Hunan Province, China were 1591 and 1429, respectively. In the twenty years, the main education level of the staff transformed from "technical secondary school education and non-academic qualifications" to "bachelor degree or above and college degree"; the main major of the staff transformed from "other majors" to "public health and clinical medicine"; the proportion of the staff members without professional titles changed from >1/3 to 5%; and the proportions of the staff members with senior, intermediate, and junior professional titles were steadily rising. GM prediction showed that the proportions of highly educated staff members in 2018 and 2020 would be up to 41.00% and 45.61%, respectively; and the proportions of the staff members with a major in public health in 2018 and 2020 would be up to 44.15% and 46.60%, respectively. Conclusion: The staff in occupational disease prevention and treatment institutions in Hunan Province, China, in the twenty years have slight changes in staff size and great improvement in staff quality, which is beneficial to sustainable development of the occupational disease prevention and treatment undertakings. The education level and major will be further optimized in the next five years. PMID- 29495177 TI - [Occupational characteristics of 318 cases diagnosed as occupational asthma]. AB - Objective: To summarize the clinical characteristics of occupational asthma and provide a basis for revising the diagnosis of occupational asthma in China. Methods: Taking "occupational asthma" , "occupational bronchial asthma" and "bronchial provocation test at work site" as key words, the case reports of occupational asthma in China were retrieved. The general data, latent period, allergen, clinical manifestation, and diagnostic methods were analyzed. Results: A total 318 cases from 14 published literatures were reported.The incidence of male and female is basically similar. The average age of onset is 38 years, and the latent period is from 2 months to 19 years. The top 3 allergens were isocyanates, penicillin and cephalosporins, formaldehyde. During the diagnosis process, 48.8% of the patients were diagnosed by bronchial provocation test, and 19 cases were diagnosed according to the specific IgE antibody. Only 1 case was diagnosed according to the specific skin test. Conclusion: The etiological diagnosis of occupational asthma is not easy. Nearly half of the patients in our country have been diagnosed as occupational asthma by bronchial provocation test at work site. How to identify the relationship between occupational exposure and the occurrence of asthma is one of the main problems we need to solve. PMID- 29495178 TI - [PAHs exposure and occupational health risk assessment of workers in coal tar pitch factory]. AB - Objective: To Investigation of industrial sites involving coal tar pitch to detect PAHs in the occupational environment and to assess their occupational health risks to workers. Methods: Taking coal tar pitch enterprises as the research object, and making the occupational health field investigation and inspection. Detecting the 16 PAHs in the samples by high performance liquid chromatography (HPLC) , analyze the PAHs exposed dose of the workers in the place, and using cumulative toxic equivalent quantity method, loss of life expectancy method and carcinogenic risk factor method to assessment worker's occupational health risk. Results: In the 15 posts involved, Some workers' exposed to the total concentration of PAHs is higher than others, the maximum exposure concentration is 1931.45ng/m3. There are different hazard risk levels in different working post due to different processes.The lifetime risk of workers is significantly higher than the acceptable range. Some workers has higher carcinogenic risk and workers' life expectancy loss is up to 1033.95 hours. Conclusion: Part of the coal tar pitch workers exposed to higher concentrations of PAHs, and beyond the occupational exposure limits.And there is a high occupational health risk due to high exposure to PAHs. PMID- 29495179 TI - [Analysis of epidemiological characteristics of intoxication cases in Shandong Province in 2015]. PMID- 29495180 TI - [The role of acoustic impedance test in the diagnosis for occupational noise induced deafness]. AB - Objective: To investigate the characteristics of acoustic impedance test and its diagnostic role for occupational noise induced deafness, in order to provide an objective basis for the differential diagnosis of occupational noise induced deafness. Methods: A retrospective study was conducted to investigate the cases on the diagnosis of occupational noise-induced deafness in Guangdong province hospital for occupational disease prevention and treatment from January 2016 to January 2017. A total of 198 cases (396 ears) were divided into occupation disease group and non occupation disease group based on the diagnostic criteria of occupational noise deafness in 2014 edition, acoustic conductivity test results of two groups were compared including tympanograms types, external auditory canal volume, tympanic pressure, static compliance and slope. Results: In the occupational disease group, 204 ears were found to have 187 ears (91.67%) of type A, which were significantly higher than those in the non occupational disease group 143/192 (74.48%) , the difference was statistically significant (chi(2)=21.038, P<0.01). Detection of Ad or As type, occupation disease group in other type were 16/204 (7.84%) , 3/204 (1.47%) , were lower than Ad or As type of occupation disease group (15.63%) , other type (9.38%) , the differences were statistically significant[ (chi(2)=5.834, P<0.05) , (chi(2)=12.306, P<0.01) ]. Occupation disease group canal volume average (1.68+/-0.39) ml higher than that of non occupation disease group (1.57+/-0.47) ml, the difference was statistically significant (t=2.756, P<0.01) ; occupation disease group mean static compliance (1.06+/-0.82) ml higher than that of non occupation disease group (0.89+/-0.64) ml. The difference was statistically singificant (t=2.59, P<0.01) . Conclusion: We observed that acoustic impedance test had obvious auxiliary function in the differential diagnosis of occupational noise induced deafness, More than 90% of the confirmed cases showed an A-form tympanograms, it is one of the objective examination methods which can be used in the differential diagnosis of pseudo deafness. PMID- 29495181 TI - [Experimental study of miRNA200a regulating Wnt/beta-catenin signaling pathway in silica-induced mouse lung epithelial cells]. AB - Objective: To observe the effect of overexpression of miRNA200a (miR-200a) recombinant lentivirus on the expression of Wnt/beta-catenin signaling pathway in mouse lung epithelial cell line MLE-12 induced by silica (SiO(2)) . Methods: The mice were divided into SiO(2) control group (SiO(2)) , virus control group (SiO(2)+Lv-NC) group and overexpressing miR-200a virus group (SiO(2)+Lv-miR 200a). The expression of beta-catenin, MMP2, MMP9, TCF-4 and Cyclin D1 mRNA and protein were detected by realtime-PCR and western blot after incubating cells for 18 h stimulating at the final concentration of 200 MUg/ml of SiO(2). Results: The expression of miR-200a in MLE-12 cells of SiO(2)+Lv-miR-200 a group was significantly higher than that in SiO(2) group and SiO(2)+Lv-NC group. The mRNA and protein expression of beta-catenin, MMP2, MMP9, TCF-4 and Cyclin D1 in MLE-12 cells of SiO(2)+Lv-miR-200a group were significantly lower than those in SiO(2) group and SiO(2)+Lv-NC group (P<0.05) . Conclusion: Overexpression of miR-200a can inhibit the expression of related genes of Wnt/beta-catenin signaling pathway in silica-induced mouse lung epithelial cells. PMID- 29495182 TI - [Reproductive and developmental toxicity of 2- (2H-1, 2, 3-benzotriazol-2-yl) -4 methyl-6- (2-methylpropen-2-yl) phenol in mice: an experimental study]. AB - Objective: To investigate the reproductive and developmental toxicity of 2- (2H 1, 2, 3-benzotriazol-2-yl) -4-methyl-6- (2-methylpropen-2-yl) phenol in mice and to provide a basis for its risk assessment. Methods: The reproductive and developmental toxicity of 2- (2H-1, 2, 3-benzotriazol-2-yl) -4-methyl-6- (2 methylpropen-2-yl) phenol was tested using the screening method of chemicals with reproductive and developmental toxicity in "Chemical Testing Method" (SEPA). After five days of adaptive feeding, 120 specific pathogen-free healthy Kunming mice (male/female ratio=1:1) were orally administered 0 (control) , 146, 292, and 584 mg/kg 2- (2H-1, 2, 3-benzotriazol-2-yl) -4-methyl-6- (2-methylpropen-2-yl) phenol for two weeks. One male mouse was mated with one female mouse in a single cage. The day on which a vaginal plug was observed was defined as gestation day 0 (GD0). The exposure for female mice was sustained to four days postpartum and the exposure for male mice was sustained for two weeks after mating. The body weight, food intake, body length, tail length, and sex ratio were recorded and the reproductive index was calculated. The reproductive organs were weighed and subjected to histopathological examination. Results: The 584 mg/kg group had significantly lower body weight at weeks 5 and 6 and food intake at week 6 in male mice, uterus weight and uterus/body weight ratio in female mice, and body weight, body length, and tail length on day 0 in offspring compared with the control group (all P<0.05). The 292 mg/kg group had significantly lower testis weight of male mice and food intake of female mice at gestational week 2 than the control group (both P<0.05). The 146 mg/kg group had significantly lower food intake of female mice at gestational week 2 than the control group (P<0.05) . Conclusion: For male and female Kunming mice, the no observed adverse effect levels of 2- (2H-1, 2, 3, -benzotriazol-2-yl) -4-methyl-6- (2-methylpropen-2-yl) phenol are both 146 mg/kg. PMID- 29495183 TI - [A case of interstitial lung disease induced by acute inhalation of aluminiumoxide]. PMID- 29495184 TI - [A case report of acute severe hydrogen cyanide poisoning]. PMID- 29495185 TI - [Clinical analysis of lower limb thrombosis caused by paraquat poisoning]. AB - Objective: To investigate the causes of peripheral vascular thrombosis in patients with paraquat poisoning. Methods: The patients with paraquat poisoning who were admitted to our department in recent two years were observed to screen out the patients with large vessel thrombosis. The data on toxic exposure history, clinical features, and treatment were collected to analyze the causes of thrombosis in the patients with paraquat poisoning. Results: Three patients had typical lower limb thrombosis. There was one case of right common femoral vein thrombosis, one case of bilateral calf muscle vein thrombosis, and one case of right calf superficial vein thrombosis and right calf muscle vein thrombosis. Conclusions: After paraquat poisoning, the blood is in a hypercoagulable state and prolonged bed rest may increase the risk of thrombosis. PMID- 29495186 TI - [Diagnosis of occupational pneumoconiosis in the absence of one side lung tissue]. PMID- 29495188 TI - [Therapeutic effect of Prussian blue with hemoperfusion in treatment on five patients of acute thalliumpoisoning]. PMID- 29495187 TI - [A case of occupational sulfur dioxide gas inhalation poisoning]. PMID- 29495189 TI - [A case report of aspiration pneumonia cased by diesel aspiration]. PMID- 29495190 TI - [A case report of acute occupational inhaled nitric acid poisoning]. PMID- 29495191 TI - [Review on nervous systeminjury caused by carbon disulfide]. PMID- 29495192 TI - [Advances in researches on the role of ribosomal DNA in DNA damage response]. PMID- 29495193 TI - [The role of miRNA in DNA damage response]. PMID- 29495194 TI - [Expert consensus on immunization for prevention of pneumococcal disease in China (2017)]. AB - Pneumococcal disease is one of the serious global public health problems, and an important leading cause of the morbidity and mortality of children and adults in China. Currently, antibiotics are the most choices for its clinical treatment. However, antibiotic resistance of Streptococcus pneumoniae has become a severe problem around the world due to the wide use of antibiotics. Hence, the prevention of pneumococcal disease by using pneumococcal vaccines is of great importance. In this article, we reviewed the etiology, clinic, epidemiology, disease burden of pneumococcal disease, and the vaccinology of pneumococcal vaccines, based on the Pneumococcal Vaccines WHO Position Paper (2012) and other latest evidence globally, to introduce comprehensive knowledge of pneumococcal disease, and for the purpose to improve the capacity of the professionals working on pneumococcal disease control and prevention and to provide appropriate evidences of pneumococcal vaccine applications for people who are engaged in public health and immunization vaccination. PMID- 29495195 TI - [Sustainability of cancer screening program in urban China: a multicenter assessment from service supplier's and demander's perspectives]. AB - In a real-world running of cancer screening programs or intervention strategies, multiple influencing factors need to be considered other than the effectiveness and cost-effectiveness. The articles in this special issue summarize the main findings related to sustainability of cancer screening program in urban China from four perspectives of cancer screening service, including actual supplier, potential supplier, actual demander and potential demander. These evidences are expected to provide references for decision-making on suitable strategies and running mechanism for large-scale cancer screening program in local populations. PMID- 29495196 TI - [Willingness and preferences of actual service suppliers regarding cancer screening programs: a multi-center survey in urban China]. AB - Objective: From the perspective of actual service suppliers regarding cancer screening, this study aimed to assess the long-term sustainability of cancer screening programs in China. Methods: Based on a Cancer Screening Program in Urban China (CanSPUC), our survey focused on all the hospitals, centers for disease control and prevention (CDC) and community service centers across 16 provinces in China which participated in the programs between 2013 and 2015. All the managers (institutional/department level) and professional staff involved in the program were interviewed using either paper-based questionnaire or online approach. Results: A total of 4 626 participants completed the interview. It showed that the main gains from providing screening service emphasized promotion in social value (63.6%), local reputation (35.9%), and professional skills (30.6%), whereas difficulties encountered included inadequate compensation (30.9%) and discordance among information systems (28.3%). When the service remuneration amounts to about 50 Chinese Yuan per screening item, those professional staff self-reported that they would like to work overtime. More than half (63.7%) of the staff expressed willingness to provide routine screening service, the main expectations were to promote their reputation to the local residents (48.7%) and to promote professional skills (43.1%). Those who were not willing to provide screening services were worried about the potential heavy workload (59.8%) or being interfered with their routine work (49.8%). Further detailed results regarding the different organization types and program roles were presented in the following detailed report. Conclusions: Findings of gains and difficulties showed that if cancer screening is expected to become a long term running, incentive mechanism from the program, external promotion and advocacy as well as capacity building should be strengthened; furthermore, rewards to staff's screening services should be raised according to the local situations. Results regarding the "willingness to provide service" showed that management of the program should also be strengthened, including information system building and inter-agency and inter-department coordination at the government levels. PMID- 29495197 TI - [Willingness of potential service suppliers to provide cancer screening in urban China]. AB - Objective: Based on the investment for potential suppliers of cancer screening services, we assessed the reasons that affecting their participation motivation related to the long-term sustainability of cancer screening in China. Methods: Hospitals that had never been involved in any national level cancer screening project were selected by using the convenient sampling method within the 16 project cities of Cancer Screening Program in Urban China (CanSPUC) with 1 or 2 hospitals for each city. All the managers from the institutional/department level and professional staff working and providing screening services in these hospitals, were interviewed by paper-based questionnaire. SAS 9.4 was used for logical verification and data analysis. Results: A total of 31 hospitals (18 hospitals at the third level and, 13 hospitals at the second level) and 2 201 staff (508 hospital and clinic unit managers, 1 693 professional staff) completed the interview. All the hospitals guaranteed their potential capacity in service providing. 92.5% hospital managers showed strong willingness in providing cancer screening services, while 68.3% of them declared that the project fund-raising function was the responsibility of the government. For professional staff, their prospect gains from providing screening service would include development on professional skills (72.4%) and material rewards (46.8%). Their main worries would include extra work for CanSPUC might interfere their routine work (42.1%) plus inadequate compensation (41.8%). Medians of the prospect compensation for extra work ran between 20 to 90 Chinese Yuan per screening item respectively. For all the screening items, workers from the third-level hospitals expected their compensation to be twice as much of those working at the second level hospitals. Conclusion: Professional capacity building and feasible material incentive seemed to be the two key factors that influenced the sustainability and development of the programs. PMID- 29495198 TI - [Preference on screening frequency and willingness-to-pay for multiple-cancer packaging screening programs in urban populations in China]. AB - Objective: From an actual cancer screening service demanders' perspective, we tried to understand the preference on screening frequency and willingness-to-pay for the packaging screening program on common cancers and to evaluate its long term sustainability in urban populations in China. Methods: From 2012 to 2014, a multi-center cross-sectional survey was conducted among the actual screening participants from 13 provinces covered by the Cancer Screening Program in Urban China (CanSPUC). By face-to-face interview, information regarding to preference to screening frequency, willingness-to-pay for packaging screening program, maximum amount on payment and related reasons for unwillingness were investigated. Results: A total of 31 029 participants were included in this survey, with an average age as (55.2+/-7.5) years and median annual income per family as 25 000 Chinese Yuan. People's preference to screening frequency varied under different assumptions ( " totally free" and "self-paid" ). When the packaging screening was assumed totally free, 93.9% of residents would prefer to take the screening program every 1 to 3 years. However, the corresponding proportion dropped to 67.3% when assuming a self-paid pattern. 76.7% of the participants had the willingness-to-pay for the packaging screening, but only 11.2% of them would like to pay more than 500 Chinese Yuan (the expenditure of the particular packaging screening were about 1 500 Chinese Yuan). The remaining 23.3% of residents showed no willingness-to-pay, and the main reasons were unaffordable expenditure (71.7%) and feeling'no need'(40.4%). Conclusions: People who participated in the CanSPUC program generally tended to choose high-frequency packaging screening program, indicating the high potential acceptance for scale up packaging screening, while it needs cautious assessments and rational guidance to the public. Although about seven in ten of the residents were willing to pay, the payment amount was limited, revealing the necessity of strengthening individual's awareness of his or her key role in health self-management, and a reasonable payment proportion should be considered when establishing co compensation mechanism. PMID- 29495200 TI - [Family history and risk of coronary heart disease]. AB - Objective: To evaluate the association of family history with risk of major coronary events (MCE) and ischemic heart disease (IHD). Methods: After excluding participants with heart disease, stroke or cancer at baseline survey, a total of 485 784 participants from the China Kadoorie Biobank, who had no missing data on critical variables, were included in the analysis. Cox regression analysis was used to estimate the hazard ratios (HR) and 95% CI. Subgroup analyses were performed according to the baseline characteristics. Results: During a median of 7.2 years of follow-up, we documented 3 934 incident cases of MCE and 24 537 cases of IHD. In multivariable-adjusted models, family history was significantly associated with risk of MCE and IHD. The adjusted HRs (95%CI) were 1.41 (1.19 1.65) and 1.25 (1.18-1.33), respectively. History of disease among siblings was more strongly associated with early-onset MCE than parental history (HR=2.97, 95%CI: 1.80-4.88). Moreover, the association of family history with MCE and IHD was stronger in persons who were overweight or obesive, and the association between family history and MEC was stronger in smokers. Conclusion: This large scale, prospective study indicated that family history was an independent risk factor for MCE and IHD in China. The intervention targeting major known lifestyle risk factors and the management of chronic diseases should be strengthened for Chinese population, especially for the individuals with family history were at high risk. PMID- 29495199 TI - [Cancer screening service utilization and willingness-to-pay of urban populations in China: a cross-sectional survey from potential service demander's perspective]. AB - Objective: To explore the sustainability of cancer screening strategy from potential demander's perspective in Chinese country, we conducted a study on the use of cancer screening services and willingness-to-pay among the urban community residents. All the participants of this study had not been on the Cancer Screening Program in Urban China (CanSPUC) or any other national level cancer screening projects. Methods: Target communities and populations were selected from the 16 project provinces in China which were on the program between 2014 and 2015, by using the multi-center cross-sectional convenience sampling method. Chi square was used to compare the rates on the utilization of service and willingness-to-pay across the different subgroups. Logistic progression was conducted to examine factors that associated with the service utilization and willingness-to-pay. Results: A total of 16 394 participants were included in this study. Among them, 12.1% (1 984/16 394) had ever been on a cancer screening program. Populations with following characteristics as: being elderly (60-69 years, OR=1.27, 95% CI: 1.13-1.43), female (male, OR= 0.56, 95%CI: 0.50-0.62), having had higher education (high school/specialized secondary school, OR= 1.51, 95%CI: 1.35-1.70; college or over, OR=2.10, 95%CI: 1.36-3.25), working for public (OR=2.85, 95% CI: 2.26-3.59), enterprises or self-employed agencies (OR=1.32, 95% CI: 1.06-1.64), having higher income (60 000-150 000 Chinese Yuan, OR=1.55, 95%CI: 1.39-1.73; >=150 000 Chinese Yuan, OR=2.57, 95% CI: 2.09-3.15), under basic medical insurance programs for urban employees/for government servants'(OR=1.15, 95% CI: 1.01-1.32), on basic medical insurance set for urban residents'/on commercial medical insurance programs etc. (OR=1.01, 95%CI: 0.84 1.22), were in favor of the services. When neglecting the fee for charge, 65.8% (10 795/16 394) of the participants said that they could accept the cancer screening program, particularly in those who had already been on the screening program (P<0.05). 61.2% (10 038/16 392) of all the participants showed the willingness-topay for a long-term packaging screening services, particularly in those who were relatively younger (60-69 years, OR=0.80, 95%CI: 0.74-0.87), working for public (OR=1.76, 95%CI: 1.56-1.98) or enterprise sectors or self employed households (OR=1.32, 95%CI: 1.18-1.47), having higher income (60 000-150 000 Chinese Yuan, OR=1.51, 95%CI: 1.40-1.63; >=150 000 Chinese Yuan,OR= 1.95, 95% CI: 1.60-2.38), utilized screening services (OR=2.18, 95% CI: 1.94-2.46). Conclusions: The rate of using the cancer screening services should be improved. Factors including age, gender, education, occupation, income and insurance appeared as major factors related to the use of cancer screening services. Willingness-to-pay seemed relatively high, but the amount of payment they could afford was limited. Factors including age, occupation, income and insurance appeared as major factors to the willingness-to-pay. PMID- 29495201 TI - [Prevalence, awareness, treatment and control of hypertension in population older than 15 years of age in Beijing, 2013-2014]. AB - Objective: To investigate the rates on prevalence, awareness, treatment and control of hypertension in population older than 15 years of age in Beijing, 2013 2014. Methods: A cross-sectional survey was conducted in Beijing between 2013 2014. Stratified multistage random sampling method was used to select representative sample of 13 057 Chinese individuals aged over 15 years, from the general population. Blood pressure was measured for three readings at sitting position after resting for at least five minutes with an average reading recorded. A standardized structured questionnaire was developed to collect history of hypertension and antihypertensive treatment. Results: A total of 4 663 community residents aged over 15 years were hypertensive among the 13 057 individuals, with the standardized prevalence rate as 32.7%, in Beijing area. The age-standardized prevalence rates of hypertension appeared 34.6% in men and 30.8% in women. The age-and sexstandardized prevalence of hypertension rates were 33.3% in urban and 24.6% in rural areas. The prevalence of hypertension increased with age and appeared higher in men than in women, in urban than in rural residents. Among the hypertensive patients, rates of awareness, treatment and control were 66.8%, 64.6% and 31.6%, respectively. Conclusion: High prevalence of hypertension with low rates on awareness and treatment and control, appeared in the general population of Beijing. Related strategies should be developed regarding prevention, control and management of hypertension, to reduce the burden of this disease. PMID- 29495202 TI - [A cross-sectional study on the status of tobacco use among junior middle school students in Shaanxi province]. AB - Objective: To understand the rate on tobacco use and associated factors in junior middle school students in Shaanxi province. Methods: We used a multi-stage stratified random sampling method to select students from 30 junior middle schools in 10 areas of Shaanxi province in 2013. All the participants completed a self-administered questionnaire. Results: A total of 4 633 questionnaires were dispatched and 4 298 were qualified for further analysis. The current smoking rate of junior middle school students in Shaanxi was 6.5%, with rate in male (11.1%) higher than that of female students (1.7%). The current smoking rate of students in grade three (9.3%) was higher than those of students in grade one (3.5%) or in grade two (7.0%). The smoking rate of students with pocket money more than 31 Yuan per week was (10.0%) higher than those of students with pocket money less than 10 Yuan (4.6%) or 10-30 Yuan (6.3%) per week. Results from the logistic regression analysis showed that factors as: male, school located in the city, older age, with more pocket money, having smokers in the family and exposure to second hand smoking were high risk factors for current smoking. Conclusion: Rate on current smoking was high in junior middle schools students in Shaanxi, suggesting that comprehensive intervention programs be developed to reduce the rate of tobacco use in junior middle school students. PMID- 29495203 TI - [Exposure to bisphenol A during maternal pregnancy and the emotional and behavioral impact on their preschool children]. AB - Objective: To explore the long-term effects of maternal pregnancy bisphenol A (BPA) exposure on emotional and behavioral problems appeared in their preschool children. Methods: The study sample was a subset of the China-Anhui Birth Cohort Study (C-ABCS). A unified questionnaire was used to collect basic information on both pregnant women and their children. Free BPA concentration in maternal serum was determined by high-performance liquid chromatographytandem mass spectrometry (HPLC-MS/MS). The parent-report version of the Strengths and Difficulties Questionnaire (SDQ) was used to estimate the emotional and behavioral problems in preschool children. A total of 1 713 pairs of mothers and children were included in this study. Association between BPA exposure during pregnancy and the emotional and behavioral problems in preschool children was evaluated with multinomial logistic regression model. Results: Prevalence rates in 1 713 preschool children appeared as: 6.48% of emotional problems, 8.11% for conduct problems, 8.35% for hyperactivity/inattention, 2.86% for peer problems, 11.38% for prosocial behaviors and 7.94% for total difficulties. Subjects were divided according to the degrees of exposure and the results showed as: low exposure group (<=0.120 ng/ml), medium exposure group (0.120=0.400 ng/ml) according to the serum BPA concentration in tertile. Results from the multivariate logistic regression analysis showed that high level of maternal BPA exposure appeared a risk factor on children's abnormal conducts (OR=1.876, 95% CI: 1.161-3.029), more obvious in boys (OR=2.291, 95%CI: 1.126-4.661). Conclusion: Maternal exposure to high level of BPA during pregnancy might increase the detrimental effects of abnormal conducts in their preschool children, more obviously seen in boys. PMID- 29495204 TI - [Association between DRD2 gene polymorphisms and the dosage used on methadone maintenance treatment program]. AB - Objective: To investigate the association between three single nucleotide polymorphism (SNP) genes DRD2 (rs1800497, rs6275, and rs1799978) and the dosage used on methadone maintenance treatment (MMT). Methods: From the methadone maintenance treatment centers, 257 MMT patients were recruited to participate in a case-control study and divided into two groups-control groups under low dosage (n=89) and case (n=168) group with high dosage. Quanto software was used to estimate the sample size as 180. Information related to social-demographic status, history on drug use and medication were collected. And DRD2 SNPs were genotyped to explore the relationship between polymorphism of DRD2 gene and the dosage of methadone maintenance treatment. Results: Distributions of DRD2 rs6275 between different groups were significantly different. Patients carrying TC genotype needed lower dose of methadone when compared to the patients that carrying CC genotype counterparts (OR=0.338, 95% CI: 0.115-0.986). Patients that carrying C allele at rs6275 needed lower methadone dose than those that carrying genotype TT (OR=0.352, 95% CI: 0.127-0.975). Distributions of genotypes, alles in the other two SNPs (rs1800497, rs1799978) were not significantly different between groups under different dosages. Conclusion: DRD2 rs6275 was associated with dosage of methadone used for the MMT patients. However, no significant associations were found between rs1800497, rs1799978 and the dosage of methadone. PMID- 29495205 TI - [Herpes simplex virus-2 infection and related factors among female drug abusers in the women's compulsory drug rehabilitation center of Shandong province]. AB - Objective: This study aimed to understand the herpes simplex virus-2 (HSV-2) infection and related factors among female drug abusers in the women's compulsory drug rehabilitation center of Shandong province and to provide reference for the prevention and control of HSV-2 in these settings. Methods: We screened all of 451 female drug abusers in the women's compulsory drug rehabilitation centers in of Shandong province and conducted a study using both questionnaire investigation and serological tests for HSV-2, HIV and syphilis. We also used EpiData 3.1 software to establish a database and SPSS 20.0 software to conduct the chi(2) test and multivariate logistic regression analysis. Results: A total of 451 female drug abusers were under study. We noticed that the rates for HSV-2 infection, HIV infection and syphilis infection appeared as 72.1% (325/451), 2.2% (10/451) and 33.5% (151/451) respectively. Results from univariate analysis showed that factors as: awareness on AIDS, having temporary sex partner after using the drug, having multiple sex partners after using the drug, providing commercial services or having temporary sex practice before being detained, with syphilis infection etc., were associated with HSV-2 infection. Data from the multivariate analysis showed that the OR (95%CI) value of HSV-2 infection was 2.90 (1.19-7.06) for those who providing commercial service, when comparing to those who did not. Compared to those who did not suffer from syphilis infection, the OR (95%CI) value of HSV-2 infection for those with syphilis infection was 2.75 (1.63-4.63). Conclusions: The rate of HSV-2 infection was high in the women's compulsory drug rehabilitation center of Shandong province. We should enhance measures and promote condom use to prevent from HSV-2 and other sexually transmitted diseases among them. PMID- 29495206 TI - [Willingness and influencing factors related to "centralized slaughtering, fresh poultry listing and marketing" strategy among the household chefs in Guangzhou]. AB - Objective: To study the willingness and influence factors related to "centralized slaughtering, fresh poultry listing and marketing" strategy, among the household chefs, and provide reference for government to adjust and optimize the strategy on avian influenza prevention. Methods: According to the geographical characteristics and regional functions, 6 'monitoring stations' were selected from 12 residential districts of Guangzhou, respectively. Another 21 meat markets which selling live poultry, were selected in each station and 5 household chefs of each market were invited to attend a face to face interview. Basic information, personal cognitive, willingness and influencing factors to the policy were under study. Univariate and multivariate logistic regression methods were used. Results: A total of 664 household chefs underwent the survey and results showed that the rate of support to the "centralized slaughtering, fresh poultry listing and marketing" strategy was 44.6% (296/664). Results from the multi-factor logistic regression showed that those household chefs who were males (OR=1.618, 95% CI: 1.156-2.264, P=0.005), having received higher education (OR=1.814, 95% CI: 1.296-2.539, P=0.001), or believing that the existence of live poultry stalls was related to the transmission of avian influenza (OR=1.918, 95% CI: 1.341-2.743, P<0.001) were factors at higher risk. These household chefs also intended to avoid the use of live poultry stalls (OR=1.666, 95%CI: 1.203-2.309, P=0.002) and accept the "centralized slaughtering, fresh poultry listing and marketing" strategy. Conclusion: Detailed study on this subject and, setting up pilot project in some areas as well as prioritizing the education programs for household chefs seemed helpful to the implementation of the 'freezing-fresh poultry' policy. PMID- 29495207 TI - [Study on the coverage of cervical and breast cancer screening among women aged 35-69 years and related impact of socioeconomic factors in China, 2013]. AB - Objective: To estimate the cervical and breast cancer screening coverage and related factors among women aged 35-69 years who were in the National Cervical and Breast Screening Program, to provide evidence for improving cervical and breast cancer control and prevention strategy. Methods: Data used in this study were abstracted from the 2013 Chinese Chronic Diseases and Risk Factors Surveillance Program. A total of 66 130 women aged 35-64 years and 72 511 women aged 35-69 years were included for this study. Weighted prevalence, (with 95% confidence interval, CI) was calculated for complex sampling design. Rao-Scott chi(2) method was used to compare the screening coverage among subgroups. A random intercept equation which involved the logit-link function, was fitted under the following five levels: provincial, county, township, village and individual. Fix effects of all explanatory variables were converted into OR with 95%CI. Results: In 2013, 26.7% (95%CI: 24.6%-28.9%) of the 35-64 year-old women reported that they ever had been screened for cervical cancer and 22.5% (95% CI: 20.4%-24.6%) of the 35-69 year-olds had ever undergone breast cancer screening. Lower coverage was observed among women residing in rural and central or western China than those in urban or eastern China (P<0.000 1). The coverage among women aged 50 years or older was substantially lower than those aged 35-49 years. Those who were with low education level, unemployed, low household income and not covered by insurance, appeared fewer number on this cervical or breast cancer screening program (P<0.000 1). Women living in rural and western China were having less chance of receiving the breast cancer screening (P<0.05), but the difference was not statistically significant. Conclusion: It is essential to strengthen the community-based cervical and breast cancer screening programs, in order to increase the coverage. More attention should be paid to women aged 50 years or older, especially those socioeconomically disadvantaged ones. PMID- 29495208 TI - [Prevalence, awareness, status of treatment and control on type 2 diabetes mellitus among Chinese premenopausal women aged 18-49 in 2013]. AB - Objective: To analyze the rates on prevalence, awareness, status on treatment and control of type 2 diabetes mellitus among Chinese premenopausal women aged 18-49, in 2013. Methods: Data on China Chronic and Non-Communicable Disease Surveillance in year 2013 was used for analysis. Source of data covered 302 surveillance points which were selected by Multi-stage cluster random sampling method that including 176 534 adults over 18 years of age, with 46 674 premenopausal women aged 18-49. Plasma glucose and hemoglobin A1c levels were determined after a 10 hour overnight fast for all the participants, before a 2-hour oral glucose tolerance test was conducted among participants without a self-reported history of diagnosed diabetes. Diabetes was defined according to the 1999 WHO diagnostic criteria-fasting blood glucose level as >=7.0 mmol/L and/or 2 hours oral glucose tolerance test (OGTT-2 h) level as >=11.1 mmol/L. After being weighed, according to complex sampling scheme and post-stratification, the sample was used to estimate the rates of prevalence, awareness, treatment and control of type 2 diabetes mellitus by age, education, urban and rural areas, and geographic locations. Results: The overall prevalence of type 2 diabetes mellitus was 5.6% among the Chinese premenopausal women aged 18-49. No statistical difference on the prevalence rates (5.7% and 5.4%, respectively) was seen, between participants from the rural or the urban areas. Prevalence rates in the eastern, central or western geographic areas were 5.8%, 6.2% and 4.4% respectively. The rates of awareness, treatment and control of diabetes appeared as 29.3%, 27.9% and 29.4% in childbearing women aged 18-49. The rate of treatment was 95.4% among those who knew their diabetic situation in childbearing women aged 18-49 years. The control rate of diabetes was 38.9% among those who had taken measures to control glucose, in 18-49-year-old childbearing women. The rate of awareness on diabetes in childbearing women aged 18-49 years in urban areas was higher than that in the rural areas. There were significantly statistical differences on the treatment rates among groups of different education levels but not in the trend test. Conclusion: The prevalence of type 2 diabetes mellitus in childbearing women aged 18-49 appeared high, but with low rates on awareness, treatment and control. However, statistical difference was seen on awareness, between urban and rural areas. PMID- 29495209 TI - [Cases diagnosis of imported malaria in Jiangsu province, 2014-2016]. AB - Objective: To understand the situation related to health seeking and diagnosis of imported malaria and to provide practical measures for malaria elimination in Jiangsu province. Methods: Data on imported malaria cases in Jiangsu province was retrieved in CISDCP from 2014 to 2016. Relevant information on health seeking behavior, diagnosis and treatment of the disease was gathered. Results: A total of 1 068 imported cases were reported in Jiangsu province from 2014 to 2016. Except for one malaria case that was caused by blood transfusion, the rest patients were all recognized as 'imported'. Majority of the cases were migrant laborers working in African countries. The accurate rates on the diagnosis of ovale, vivax and quartan malaria and mixed infection were relatively low, as 79.3% (107/135), 29.5% (18/61), 52.9% (18/34) and 0.0% (0/2) at the primary health care settings, respectively. Rate of seeking health care on the same day of onset was more in 2015 than in 2014 and 2016 (chi(2)=18.6, P=0.001). While only 65.4% (699/1 068) of the patients were diagnosed correctly at the primary health care settings. There appeared no statistical difference in the 3-year study period (chi(2)=5.4, P=0.246). Capacity on 'correct diagnosis' seemed stronger at the CDC than at the hospital levels (chi(2)=13.2, P=0.000; chi(2)=5.4, P=0.020). Totally, 72.7% (32/44) of the severe falciparum malaria cases did not immediately seek for health care when the symptoms started. Conclusions: Migrant workers returning from the high endemic malaria areas seemed to have poor awareness in seeking health care services. Capability on correct diagnosis for malaria at the primary health care settings remained unsatisfactory and staff from these settings needs to receive adequate training. PMID- 29495210 TI - [The PRECIS-2 tool: designing trials that are fit for purpose]. AB - To evaluate the intervention effects of randomized controlled trials (RCT) involved in theoretical efficacy and actual clinical outcome (effectiveness). Pragmatic-Explanatory Continuum Indicator Summary (PRECIS) is a tool to help researchers make decisions in study design which is consistent with the intended purpose of their trial which can be used in the design of RCT to balance the internal validity and external validity. The role of PRECIS has been gradually recognized in the practice of designing clinical trials. To ensure that the design choices are concordant with the intention and the facilitation of use set by patients, clinicians and policy makers, a new PRECIS-2 tool has been developed by mangy international team experts under modification and upgrading the existing PRECIS. The PRECIS-2 tool mainly focuses on trial design choices which determining the applicability of a trial. PRECIS-2 has nine domains, with each of them intends to help the researchers consider the consequences of that design decision in terms of the applicability of the results under particular setting. The purpose of this paper is to introduce the development, basic principle, characteristics and application of PRECIS-2 for the designers and decision makers when working on clinical trials. PMID- 29495211 TI - [Bibliometrics and visualization analysis of land use regression models in ambient air pollution research]. AB - Objective: To quantitatively analyze the current status and development trends regarding the land use regression (LUR) models on ambient air pollution studies. Methods: Relevant literature from the PubMed database before June 30, 2017 was analyzed, using the Bibliographic Items Co-occurrence Matrix Builder (BICOMB 2.0). Keywords co-occurrence networks, cluster mapping and timeline mapping were generated, using the CiteSpace 5.1.R5 software. Relevant literature identified in three Chinese databases was also reviewed. Results: Four hundred sixty four relevant papers were retrieved from the PubMed database. The number of papers published showed an annual increase, in line with the growing trend of the index. Most papers were published in the journal of Environmental Health Perspectives. Results from the Co-word cluster analysis identified five clusters: cluster#0 consisted of birth cohort studies related to the health effects of prenatal exposure to air pollution; cluster#1 referred to land use regression modeling and exposure assessment; cluster#2 was related to the epidemiology on traffic exposure; cluster#3 dealt with the exposure to ultrafine particles and related health effects; cluster#4 described the exposure to black carbon and related health effects. Data from Timeline mapping indicated that cluster#0 and#1 were the main research areas while cluster#3 and#4 were the up-coming hot areas of research. Ninety four relevant papers were retrieved from the Chinese databases with most of them related to studies on modeling. Conclusion: In order to better assess the health-related risks of ambient air pollution, and to best inform preventative public health intervention policies, application of LUR models to environmental epidemiology studies in China should be encouraged. PMID- 29495212 TI - [Data harmonization and sharing in study cohorts of respiratory diseases]. AB - Objective: Chronic obstructive pulmonary disease, asthma, interstitial lung disease and pulmonary thromboembolism are the most common and severe respiratory diseases, which seriously jeopardizing the health of the Chinese citizens. Large scale prospective cohort studies are needed to explore the relationships between potential risk factors and respiratory disease outcomes and to observe disease prognoses through long-term follow-ups. We aimed to develop a common data model (CDM) for cohort studies on respiratory diseases, in order to harmonize and facilitate the exchange, pooling, sharing, and storing of data from multiple sources to serve the purpose of reusing or uniforming those follow-up data appeared in the cohorts. Methods: The process of developing this CDM of respiratory diseases would follow the steps as: 1Reviewing the international standards, including the Clinical Data Interchange Standards Consortium (CDISC), Clinical Data Acquisition Standards Harmonization (CDASH) and the Observational Medical Outcomes Partnership (OMOP) CDM; 2Summarizing four cohort studies of respiratory diseases recruited in this research and assessing the data availability; 3Developing a CDM related to respiratory diseases. Results: Data on recruited cohorts shared a few similar domains but with various schema. The cohorts also shared homogeneous data collection purposes for future follow-up studies, making the harmonization of current and future data feasible. The derived CDM would include two parts: 1thirteen common domains for all the four cohorts and derived variables from disparate questions with a common schema, 2additional domains designed upon disease-specific research needs, as well as additional variables that were disease-specific but not initially included in the common domains. Conclusion: Data harmonization appeared essential for sharing, comparing and pooled analyses, both retrospectively and prospectively. CDM was needed to convert heterogeneous data from multiple studies into one harmonized dataset. The use of a CDM in multicenter respiratory cohort studies would make the constant collection of uniformed data possible, so to guarantee the data exchange and sharing in the future. PMID- 29495213 TI - [Risk related to bias assessment: (4) Revised Cochrane Risk of Bias Tool for cluster-randomized control trials (RoB2.0)]. AB - This paper introduced the Revised Cochrane Risk of Bias Tool RoB2.0 for cluster randomized control trials (CRCT) and compared RoB2.0 of CRCT with individually randomized, parallel group trials, and illustrated the application of RoB2.0 for CRCT in a published CRCT. Special signal questions were designed for CRCT according to its specialty that different from individually randomized, parallel group trials in RoB2.0 and also providing information on risk of bias about CRCT in systematic reviews for the synthesis of evidence. PMID- 29495214 TI - [A review on the research progress related to ambient air pollution and depression]. AB - It is reported that depression has caused heavy disease burden across the world, with an possible association between ambient air pollution and depressive symptoms. In this paper, we reviewed relative literature in this field and summarized the research events on association between ambient air pollution and depression, both in China and abroad and found that the results of the existed studies were inconsistent, with most studies showing that there existed a positive correlation between the exposure of air pollution and depression, but few studies showing the negative correlation or no correlation between the two. PMID- 29495216 TI - [Controlling perioperative bleeding, improving treatment quality of neurosurgery]. PMID- 29495215 TI - [Progress on influencing factors regarding the neonatal group B streptococcal infectious diseases]. AB - Group B streptococcus (GBS) is one of the severe pathogenic bacteria during the perinatal period, both on pregnant women and newborns. GBS infection may lead to pneumonia, septicemia, meningitis or other severe disease, even death in neonates. Although only 1%-2% infections will develop into GBS disease among the neonates, the etiological mechanism of which is worth researching. This review summarizes the possible factors related to GBS infection or occurrence of the disease, including the risk in gestation period (for example, colonization of GBS on vagina of pregnant women, preterm birth or premature rupture of fetal membranes and so on), related pathogens (bacteria strains, loads or virulence), immune level (inflammatory factor or neutralizing anticytokine auto-Abs), gene defect or primary immunodeficiencies of the hosts. PMID- 29495217 TI - [Predictive value of GRACE discharge score for long-term out-of-hospital death in acute coronary syndrome after percutaneous coronary intervention]. AB - Objective: To evaluate the prognostic value of Global Registry of Acute Coronary Events(GRACE) discharge score for long-term out-of-hospital death in acute coronary syndrome (ACS) after drug-eluting stents (DES) and with Dual antiplatelet Therapy (DAPT). Methods: Our study was a prospective, observational, single center (Fuwai Hospital of China) study.A total of 6 431consecutive ACS patients underwent percutaneous coronary intervention(PCI)between January 2013 and December 2013 were involved.The primary endpoint was all-cause death and second endpoint was major adverse cardiovascular and cerebrovascular events (MACCE) as a composite of all-cause death, myocardial infarction, revascularization, stent thrombosis or stroke. Results: Finally, 5 867 ACS patients who were received DES with DAPT and had no in-hospital event included in this study, and 59 (1.01%) death and 608 (10.36%) MACCE were reported during 2 year follow-up after discharge.GRACE score was significantly higher among death patients than those survivalpatients (94+/- 28 vs 78+/- 24, P<0.001). According to risk stratification of GRACE discharge score, as compared to the low-risk group, death risk in high-risk group was 6.73 times (HR=6.73, 95%CI 3.53-12.84; P<0.001) higher, but could not distinguish between the moderate and low risk group (HR=1.61, 95%CI 0.88-2.95; P=0.124). The GRACE score showed predictive value in ACS patients after DESand with DAPT (area under the receiver operating characteristic curve (AUROC)=0.661; 95%CI 0.586-0.736, P<0.001). In subgroup analysis, GRACE score also showed predictive value both in unstable angina pectoris (UAP)(AUROC=0.660, 95%CI 0.576-0.744; P<0.001) and acute myocardial infarction(AMI)subgroup (AUROC=0.748, 95%CI 0.631-0.864; P=0.001). Conclusion: GRACE discharge score shows prognostic value for long-term out-of-hospital death in ACS patients undergoing PCI with DES and DAPT, and demonstrates good risk stratification of high and low-risk of death. PMID- 29495218 TI - [Difference of one year death and stroke recurrence in ischemic stroke patients with anterior and posterior circulation intracranial atherosclerosis]. AB - Objective: To explore the differences of one year death and stroke recurrence between ischemic stroke patients with intracranial atherosclerotic stenosis or occlusion of anterior circulation and those of posterior circulation. Methods: All the patients were from the Chinese Intracranial Atherosclerosis Study (CICAS), between October 2007 and June 2009; patients with extracranial stenosis or occlusion, patients without acute infarction by diffusion weighted image, and patients with intracranial atherosclerosis of both anterior and posterior circulation were excluded.All the enrolled patients were divided into three groups: no significant intracranial atherosclerosis group (n=964), anterior circulation intracranial atherosclerosis group (n=440), posterior circulation intracranial atherosclerosis group (n=233). One year outcome was evaluated by any cause of death and stroke recurrence. Results: Of the 1 637 patients, 30 cases were died and 58 cases had stroke recurrence within one year.Compared with : no significant intracranial atherosclerosis group, adjusted hazard ratio (95% confidence interval) of one-year death for anterior and posterior circulation intracranial atherosclerosis group were 1.349 (0.311-5.851), 4.542 (1.227 16.813), respectively.Adjusted hazard ratio (95% confidence interval) of one year stroke recurrence were 1.663 (0.620-4.460) and 2.464 (0.935-6.493), respectively. Conclusions: Ischemic stroke patients with intracranial atherosclerosis of posterior circulation has higher risk of one year death. One year stroke recurrence risk for patients with intracranial atherosclerosis of anterior and posterior circulation needs to be further evaluated. PMID- 29495219 TI - [Central venous-arterial carbon dioxide tension to arterial-central venous oxygen content ratio combined with lactate clearance rate as early resuscitation goals of septic shock]. AB - Objective: To investigate the prognostic significance of central venous-arterial carbon dioxide tension to arterial-venous oxygen content ratio (Pcv-aCO(2)/Ca cvO(2)) combined with lactate clearance rate (LCR) as early resuscitation goals of septic shock. Methods: One hundred and forty-five septic shock patients admitted to Second Department of Critical Care Medicine of Lanzhou University Second Hospital from March 2013 to May 2017 were enrolled in this study.All septic shock patients received an initial resuscitation therapy according to early goal-directed therapy.The arterial and central venous blood gases were measured simultaneously at baseline (T0) and 6 hours after resuscitation (T6). Pcv-aCO(2)/Ca-cvO(2) and LCR were calculated.Patients were classified into four groups according to Pcv-aCO(2)/Ca-cvO(2) and LCR at T6: group A, Pcv-aCO(2)/Ca cvO(2)>1.8 and LCR<30%; group B, Pcv-aCO(2)/Ca-cvO(2)>1.8 and LCR>=30%; group C, Pcv-aCO(2)/Ca-cvO(2)<=1.8 and LCR<30%; group D, Pcv-aCO(2)/Ca-cvO(2)<=1.8 and LCR>=30%.General demographics, hemodynamic parameters, oxygen metabolism parameters, acute physiology and chronic health evaluation (APACHE II) scores, sequential organ failure assessment (SOFA) scores, length of intensive care unit (ICU) stay, and 28-day mortality rate were compared among the 4 groups.A Kaplan Meier curve showed the survival probabilities at day 28 using a log-rank test for multiple comparisons.Parameters were introduced into a Cox's proportional hazards regression model to analyze the prediction of 28-day mortality.Receiver operating characteristics (ROC) curves were constructed to evaluate the ability of Pcv aCO(2)/Ca-cvO(2), LCR, Pcv-aCO(2)/Ca-cvO(2) combined with LCR at T6 to predict 28 day mortality. Results: Compared with patients in group A, patients from group D had the lower APACHE II and SOFA score at day 3 (t=-2.909, -3.630, both P<0.05), shorter ICU stay (t=-2.575, P=0.011), and lower mortality rate at day 28 (chi(2)=3.124, P=0.011). Survival curves up to day 28, illustrated by Kaplan Meier method, showed that group A had the shortest median survival time (chi(2)=10.332, P=0.016), difference between group A and group D was statistically significant (chi(2)=8.304, P=0.004). The Cox regression analysis revealed that Pcv-aCO(2)/Ca-cvO(2) (RR=3.888, 95%CI: 2.443-6.189, P<0.001) and LCR (RR=0.073, 95%CI: 0.008-0.640, P=0.018) at T6 were independent predictors of 28-day mortality.The area under ROC curve for Pcv-aCO(2)/Ca-cvO(2) combined with LCR (0.919, 95%CI: 0.862-0.958) was significantly greater than whether Pcv aCO(2)/Ca-cvO(2) (0.862, 95%CI: 0.795-0.914) or LCR (0.820, 95%CI: 0.748-0.879) alone (Z=2.032, 2.364, both P<0.05). Conclusion: Combination of Pcv-aCO(2)/Ca cvO(2) and LCR is better than single parameter to predict the risk of adverse outcomes of septic shock patients, and may provide useful information for assessing the adequacy of resuscitation at early stage of septic shock. PMID- 29495220 TI - [Study on apoptosis, cytochrome C and mitochondrial membrane potential in CD71(+) nucleated erythrocytes in patients with chronic mountain sickness]. AB - Objective: To investigate the changes of CD71(+) nucleated erythrocyte apoptosis, cytochrome C (Cyt-C) and mitochondrial membrane potential (MMP) in bone marrow of chronic mountain sickness (CMS). Methods: 14 patients with CMS and 15 patients with simple old fracture were divided into CMS group and control group, respectively.Bone marrow mononuclear cells (BMMNC) were separated, marked with CD71 monoclonal antibody and stained with Annexin V-FITC/PI.Then the apoptotic index of CD71(+) nucleated erythrocytes was determined by flow cytometry.CD71(+) nucleated erythrocytes were sorted out by magnetic column separation, and Cyt-C mRNA was detected by RT-qPCR, MMP was detected by JC-1 staining flow cytometry. Results: The apoptotic index of CD71(+) nucleated erythrocytes was (1.9+/-1.4)% in the CMS group, and was (3.2+/-1.5)% in the control group, with significant difference between the two groups (P<0.05). The expression of Cyt-C mRNA was (0.72+/-0.14) in the CMS group, and was (1.00+/-0.15) in the control group, with significant difference between the two groups (P<0.01). The MMP was (5.0+/-2.2) in the CMS group, and was (3.3+/-0.9) in the control group, with significant difference between the two groups (P<0.05). The apoptotic index of CD71(+) nucleated erythrocytes was negatively correlated with hemoglobin in CMS group (r= 0.569, P=0.034). But there was no significant correlation among apoptosis index, MMP and Cyt-C mRNA. Conclusions: The apoptosis index of CD71(+) nucleated erythrocytes decreased in CMS patients, which was negatively correlated with the level of hemoglobin, indicating that the decline of apoptosis index of CD71(+) nucleated erythrocytes may be related to the accumulation of red blood cells in CMS.The MMP increased and Cyt-C mRNA expression decreased in CD71(+) nucleated erythrocytes of CMS patients, which suggests that the change of mitochondrial pathway of apoptosis might be involved in the down-regulation of CD71(+) nucleated erythrocytes apoptosis in CMS patients.But there was no significant correlation among CD71(+) nucleated erythrocyte apoptosis index, MMP and Cyt-C mRNA levels, which indicates that the mechanism of CD71(+) nucleated erythrocytes apoptosis is complex in CMS. PMID- 29495221 TI - [Effectiveness evaluation between enhanced recovery after surgery and traditional treatment in unilateral total knee arthroplasty]. AB - Objective: To investigate the clinical effect of enhanced recovery after surgery (ERAS) in unilateral total knee arthroplasty (TKA). Methods: Retrospective analysis of 98 patients received unilateral TKA from September 2015 to September 2016 in the Orthopaedic Departmentof Affiliated Hospital of Logistics University of Chinese People's Armed Police Forces.Of the patients, 52 cases were treated by traditional operation (routine group) and the other 46 cases were treated with ERAS concept (ERAS group). The following data were gathered and statistically analyzed between the groups: gender, age, body mass index, preoperative hemoglobin, preoperative visual analogue scale (VAS) score, postoperative visible blood loss, postoperative hemoglobin at 24 hour after operation, blood transfusion rate, postoperative VAS score, length of hospital stay, the satisfaction rate, preoperative and 1 and 6 months postoperative evaluation with hospital for special surgery knee score (HSS), postoperative range of motion (ROM) of knees after 2 weeks, 1 month and 6 months of surgery, incidence rate of complications after surgery.Data between groups were analyzed with one-factor analysis of variance or chi-square test. Results: There was no significant difference in preoperative data between two groups.Postoperative visible blood loss of ERAS group was significantly lower than that in routine group[(224+/-59) vs (361+/-70) ml, t=4.723, P<0.01]; postoperative hemoglobin after 24 hours in ERAS group was significantly higher than that in routine group[(109+/-8) vs (96+/ 10) g/L, t=-3.297, P=0.004]; blood transfusion rate of ERAS group was significantly lower than that in routine group[6.5 %(3/46) vs 46.2%(24/52), chi(2)=19.207, P<0.01]; the 12-hour and 48-hour postoperative VAS scores in ERAS groups were both significantly lower than those in routine group (t=3.708, 3.894, both P<0.05); length of hospital stay in ERAS group was significantly shorter than that in routine group[(6.8+/-1.2) vs (13.1+/-2.6) d, t=6.924, P<0.01]; HSS scores of ERAS groups at 1 month and 6 months after surgery were both significantly higher than those in routine group (t=-3.677, -3.594, both P<0.05); knees ROM in ERAS group at 2 weeks and 1 month after surgery were both significantly higher than those in routine group (t=-4.628, -4.442, both P<0.05); the rate of postoperative nausea vomiting in ERAS group was significantly lower than that in routine group[13.0%(6/46) vs 48.1%(25/52), chi(2)=13.852, P=0.002]. VAS score at 1 month after surgery, knees ROM at 6 months after surgery and the satisfaction rate were all comparable between the two groups (t=0.412, -1.026, chi(2)=3.695, all P>0.05). Conclusions: Condition of patients treated by unilateral TKA under ERAS model improves effectively during perioperative period when compared with routine treatment, patients have earlier rehabilitation and better experience in hospital and operation. PMID- 29495222 TI - [The curative effect analysis of unilateral subfrontal combined with interhemispheric approach on the microsurgery of large anterior skull base meningioma]. AB - Objective: To explore the surgical technique and curative effect of microsurgical resection of large anterior skull base meningioma via unilateral subfrontal and interhemispheric approach. Method: The clinical data of 14 patients with large anterior skull base meningioma who received surgical treatment in the Department of neurosurgery in First Affiliated Hospital of Bengbu Medical College from April 2015 to September 2017 were analysed retrospectively.Of 9 cases were olfactory groove meningioma and 5 cases were tuberculum sellae meningioma.The microsurgical resection approach of all the patients was the unilateral subfrontal combined with interhemispheric approach. Results: According to the Simpson classification of meningioma resection, 13 cases(92.8%) were Simpson grade Iand II, 1 case was grade III.The clinical symptoms were improved in 12 cases (85.7%), and no improvement in 2 cases.Fourteen patients had postoperative complications in 2 cases (14.2%), and all of them were no cerebrospinal fluid leakage and death. Conclusion: Microsurgical removal of large anterior skull base meningioma through unilateral frontal and interhemispheric approach is safe and effective, providing a new way for surgical treatment of large anterior skull base meningioma. It had a positive significance for the prognosis of patients. PMID- 29495223 TI - [Effect of Kruppel-like factor 2 on the migration of human liver sinusoidal endothelial cells]. AB - Objective: To investigate the effect and mechanism of Kruppel-like factor 2 (KLF2) on the migration of human liver sinusoidal endothelial cells (LSEC). Methods: Cultured human LSEC were infected with different lenti-viruses to overexpress or suppress KLF2 expression (LV5-KLF2 and LV3-shKLF2, respectively), the infection efficacies were examined by real-time PCR and Western blot analysis.Transwell migration assay was used to investigate the role of KLF2 on the migration of LSEC.The mRNA and protein expression of vascular endothelial growth factor receptor-2 (VEGFR-2) were detected by real-time PCR and Western blot analysis, respectively.The expression and phosphorylation of Src, P38 MAPK, and P44/42 MAPK were detected by Western blot. Results: The up-regulation of KLF2 expression dramatically inhibited migration of treated LSEC, compared with LV5-NC and WT control cells, fewer LV5-KLF2 cells migrated to the lower side of the filter after 12 h [ (35.6+/-1.4), (71.3+/-2.4) and (69.3+/-1.6), P<0.001 for all comparisons]. In contrast, the down-regulation of KLF2 expression promoted the migration of LSEC, more LV3-KLF2 cells migrated to the lower side of the filter compared with the LV3-NC and WT control cells [(189.5+/-5.4), (83.4+/-2.5) and (82.2+/-3.4), P<0.001 for all comparisons]. Furthermore, up-regulation of KLF2 reduced the mRNA and protein expression level of VEGFR2, while down-regulation of KLF2 significantly increased its expression in LSEC.Additionally, up-regulation of KLF2 inhibited the phosphorylation of Src, P38 MAPK, and P44/42 MAPK pathway in LSEC, whereas down-regulation of KLF2 promoted the phosphorylation of those signaling pathway proteins. Conclusions: KLF2 may inhibit the migration of human LSEC through the Src/ MAPK signaling pathway. PMID- 29495224 TI - [Therapeutic effects of rutaecarpine on dextran sodium sulfate-induced experimental colitis in mice]. AB - Objective: To determine the therapic effects of rutaecarpine in dextran sodium sulfate (DSS)induced experimental colitis and explore whether the protective role of rutaecarpine is related to the synthesis and release of CGRP. Methods: Fifty female BABL/c strain mice were randomly divided into untreated model control group and DSS-exposed groups.DSS-exposed groups were given administration of 5% DSS for 7 days and respectively treated with vehicle, rutacarpine(30 mg/kg, 100 mg/kg) , prednisone by intragastric administration from day 8 to day 14.The disease activity index (DAI) scores, the histological scores, the mRNA and protein concentrations of CGRP in colonic tissues were measured. Results: On day 7, the DAI scores of the DSS-exposed groups[vehicle group (8.9+/-0.9), low-dose Rut group(8.9+/-0.6), high-dose Rut group(8.2+/-0.8), prednisone group(8.7+/ 1.6)] were much higher, compared with the untreated model control group(0+/ 0)(P<0.01). The DAI scores on day 14 of the vehicle, rutaecarpine or prednisone treated groups were respectively markedly lower than on day 7(3.2+/-0.6, 0.9+/ 0.6, 3.1+/-0.7 vs 8.9+/-0.6, 8.2+/-0.8, 8.7+/-1.6, P<0.05). The DAI score of mice treated with high-dose rutaecarpine was significantly lower, compared with those treated with low-dose rutaecarpine and prednisone.Compared to the untreated model control group, the histological scores in other four groups significantly increased.Comparisons of values among the post-treatment groups had statistical significance (0.2+/-0.4 vs 6.9+/-0.9, 4.5+/-0.9, 2.8+/-0.8, 5.7+/-0.7, P<0.01), while the high-dose rutaecarpine group presented the lowest score.The colonic mucosal CGRP mRNA and CGRP protein expressions in groups receiving vehicle, low dose rutaecarpine and prednisone were significantly reduced than those in the untreated model control group(0.32+/-0.03 vs 0.15+/-0.02, 0.18+/-0.01, 0.22+/ 0.01, P<0.01). The CGRP mRNA and CGRP protein expressions in the untreated model control group was similar to those in the DSS+ high-dose rutaecarpine group with no statistic significance between them(0.32+/-0.03 vs 0.31+/-0.02, P>0.05). Pearson correlation analysis between CGRP mRNA levels, CGRP immunohistochemisty levels and DAI, histological scores showed a statistically negative relationship respectively(r=-0.797, -0.819, -0.863, -0.845, all P<0.01). Conclusions: Rutaecarpine can ameliorate the DAI scores and histological scores of ulcerative colitis in mice.Rutaecarpine can upregulate the expressions of CGRP mRNA and CGRP protein.Correlation between CGRP mRNA, CGRP protein levels and DAI scores, histological scores respectively showed a statistically negative relationship. PMID- 29495225 TI - [Effects of prenatal tetrandrine treatment on the expression of Kruppel-like factor 5 and Survivin in the lung of congenital diaphragmatic hernia rat model induced by nitrofen]. AB - Objective: To investigate the effect of prenatal administration of tetrandrine on the expression of Kruppel-like factors 5 (KLF5) and Survivin in the lung of congenital diaphragmatic hernia (CDH) rat model. Methods: This experiment took simple random group method, 11 pregnant SD rats were randomly divided into three groups: normal control group (group NC, 3), model control group (group MC, 4), model+ tetrandrine group (group MT, 4). The rats in group MC and MT were given gavage administration with 125 mg nitrofen to induce CDH and the rats in group MT were administered with 30 mg/kg tetrandrine for three days (gestational age of 18.5, 19.5 and 20.5 d). All fetuses were delivered by caesarian section at the gestational age of 21.5 d to observe the formation of diaphragmatic hernia in 3 groups and to record the ratio of lung weight and body weight (Lw/Bw). The maturity situation of fetal lung tissue was evaluated by hematoxylin-eosin staining (HE staining). The expression of KLF5 and Survivin were detected by immune-histochemical staining and quantitatively analyzed by Western blotting methods.Single factor analysis of variance was taken among 3 groups to compare means of variables and the chi-square test was used to compare the difference of birth defect rates. Results: There was significant difference in CDH incidence between group MC [56.1%(37/66)] and MT[50.0%(28/56)](chi(2)=122.00, P<0.05). There was no significant difference in Lw/Bw among the three groups (F=0.985, P=0.376). The HE staining showed that pulmonary vascular-related and pulmonary alveolar-related developmental indexes in group MC were lower than those in the group NC, and those in the group MT were between the two groups.In addition, immunohistochemical staining showed that the average optical density (AOD) of KLF5 in group NC, MC, MT was 0.194 8+/-0.007 4, 0.212 1+/-0.004 9 and 0.192 7+/ 0.001 9, respectively (F=14.53, P=0.002); and AOD of Survivin was 0.185 2+/-0.008 7, 0.209 2+/-0.003 6 and 0.192 8+/-0.007 5, respectively (F=12.31, P=0.003). The expression level of Survivin was positively correlated with that of KLF5 (r=0.993, P=0.039). Western blotting revealed that there were remarkable difference in the protein expression of KLF5 and Survivin among the three groups (F=4.29, 10.13, both P<0.05). Conclousions: Prenatal gavage of tetrandrine to CDH rats induced by nitrofen promotes the development of fetal lung parenchyma and vascellum, and reduces the expression level of KLF5 and Survivin protein in fetal lung, which may be the mechanism of tetrandrine in improving lung hypoplasia of CDH. PMID- 29495226 TI - [Trends study of diet consulting for discharged patients with acute myocardial infarction in China from 2001 to 2011]. AB - Objective: To describe trends in diet consulting at discharge for patients with acute myocardial infarction (AMI) in China from 2001-2011. Methods: A representative sample of patients in China admitted to hospital for AMI was created from a two-stage sampling approach; profiles for patients with AMI were retrospectively abstracted through their medical records.The study described the overall trends in diet consulting for patients with AMI in China, the rates of diet consulting among patients with hypertension, diabetes, and hyperlipidemia, and the variation in diet consulting across different regions. Results: We sampled 162 hospitals and included 16 100 patients with AMI in total.The weighted rates of diet consulting at AMI discharge in China was 16.5%, 28.8%, and 40.8% in 2001, 2006 and 2011, respectively (P for trend <0.001). The rates and trends among patients with hypertension, diabetes, and hyperlipidemia were similar to those among all patients with AMI (hypertension: 16.4%, 31.4%, and 41.1% in 2001, 2006 and 2011, respectively; diabetes: 18.2%, 32.2%, and 42.8%; hyperlipidemia: 18.6%, 31.4%, and 41.5%; all P for trend <0.001). The rates has not changed much for those in central rural region over the decade (19.2%, 19.4%, and 22.8% in 2001, 2006 and 2011, respectively; P for trend=0.09); meanwhile, the rates of diet consulting in other four regions increased over years (all P for trend<0.001). Conclusions: From 2001 to 2011, the rates of diet consulting at discharge for patients with AMI has increased in China; however, there are still substantial rooms for improvement, especially for central rural region.Dietitian could work with clinician and be involved in diet consulting for AMI at discharge in order to improve prognosis for patients with AMI. PMID- 29495227 TI - [Intensive lipid-lowering strategy for Chinese population at high risk of cardiovascular disease]. PMID- 29495228 TI - [New risk assessment tool of atherosclerotic cardiovascular disease for Chinese adults]. PMID- 29495229 TI - [Residual risk of cardiovascular disease: high blood lipoprotein (a)]. PMID- 29495231 TI - [Chinese expert consensus on screening,diagnosis and treatment of familial hypercholesterolemia]. PMID- 29495230 TI - [Review on animal models of thoracic aortic aneurysm and dissection]. PMID- 29495232 TI - [Prevalence and clinical characteristics of familial hypercholesterolemia among Chinese patients undergoing coronary angiography due to angina-like chest pain]. AB - Objectives: To investigate the prevalence rate and clinical characteristics of familial hypercholesterolemia (FH) in Chinese patients undergoing coronary angiography due to angina-like chest pain. Methods: From March 2011 to December 2016, a total of 9 908 consecutive patients undergoing coronary angiography in Fuwai Hospital due to angina-like chest pain were enrolled. The age of enrolled patients was (56.6+/-11.1) years old, and 6 782 cases (68.4%) were male. The patients were divided into two groups: FH group (n=271) and non-FH group (n=9 637) according to the Dutch Lipid Clinic Network diagnostic criteria. A retrospective analyze was performed on the baseline features between the two groups including lipids levels, coronary artery disease (CAD) characteristics, and lipids-lowering treatments. Results: In the total cohort, the prevalence of definite/probable FH was 2.7% (271/9 908). The incidence of premature coronary artery disease (PCAD) (women < 60 years old, or men < 55 years old) was higher in patients with FH than that in patients without FH (70.2%(201/271) vs. 44.5% (4 287/9 637); chi(2)=93.738, P<0.001). Patients with FH had higher level of TC and LDL-C when compared with patients without FH ((6.74+/-2.48) mmol/L vs. (4.15+/ 1.10) mmol/L; (4.53+/-2.39) mmol/L vs. (2.52+/-0.97) mmol/L; t=19.403, 22.233, P<0.001, respectively). Additionally, 84.9% (230/271) of FH patients were treated with statin at different intensities, but none of them achieved the LDL-C<2.6 mmol/L. Conclusions: Chinese patients with familial hypercholesterolemia not only showed a high presence of PCAD and higher lipids levels, but also exhibited a low rate of achievement of low-density lipoprotein cholesterol targets despite statin therapy. Our results thus highlight the importance of early diagnosis and intensive treatment of FH patients. PMID- 29495233 TI - [Prevalence and clinical features of familial hypercholesterolemia in Chinese patients with myocardial infarction]. AB - Objective: To analyze the prevalence and clinical features of familial hypercholesterolemia (FH) in Chinese patients with myocardial infarction (MI). Method: This retrospective study recruited a total of 2 119 consecutive patients (age (56.7+/-10.9) years old) undergoing coronary angiography with first MI from April 2011 to December 2016. Patients were divided into 2 groups: premature MI (male<55 years old, female<60 years old) and non-premature MI. The diagnosis of FH was established according to Dutch Lipid Clinic Network (DLCN) diagnostic criteria and referred as definite/probable FH in our study. The prevalence and clinical features of FH, including lipid level, MI characteristics and stain therapy, were explored. Multivariable logistic regression analysis was used to assess the predictive value of FH for the presence of premature MI. Results: The prevalence of definite/probable FH was 3.68% (78/2 119) in MI patients and 7.28% (68/934) in premature MI patients. Onset of MI occurred 10 years earlier in patients with definite/probable FH than those without FH ((47.9+/-9.4) years vs. (58.8+/-10.7) years, P<0.01). Additionally, we found that the risk of premature MI was significantly and independently increased in definite/probable FH patients (OR=5.32, 95%CI 2.77-10.22, P<0.01). None of FH patients reached the target of LDL-C<1.8 mmol/L under statin therapy. Conclusions: The prevalence of FH in Chinese patients with MI is not rare. Clinically, FH is linked with the early onset of MI. PMID- 29495234 TI - [A study on the epidemic characteristics of dyslipidemia in adults of nine provinces of China]. AB - Objective: To explore the current prevalence of dyslipidemia in adult population of 9 provinces of China and the epidemic characteristics of this disease. The potential influence of social economic development on dyslipidemia was also observed. Methods: Present research data are derived from the result of the investigation about survey on health and nutrition in China in 2011, in which multistage stratified cluster random sampling method was adopted to investigate the 24 345 individuals in 216 communities from 9 provinces in China and 10 242 blood samples were collected. In this research, 8 669 blood samples of people over 18 years old were selected for final analysis. After adjustment of age, the percentage of dyslipidemia patients in Chinese adults was calculated. Results: The percentage of dyslipidemia in Chinese adults is 39.91% (3 460/8 669). The percentage of dyslipidemia at the age of 18-24, 35-44, 45-59 and over 60 years old were 30.25% (373/1 233),37.19% (774/2 081), 44.22% (1 304/2 949) and 41.94%(1 009/2 406),respectively (chi(2)=333.02, P<0.01); the percentage of dyslipidemia in male and female population was 51.11% (1 956/3 827) and 31.06%(1 504/4 842), respectively (chi(2)=60.35, P<0.01); the percentage of dyslipidemia in urban residents and rural residents was 42.56% (1 144/2 687) and 38.72%(2 316/5 982), respectively (chi(2)=11.72, P<0.01);the percentage of dyslipidemia in high-GDP regions and low-GDP regions was 43.04% (1 567/3 641) and 37.65% (1 893/5 028), respectively (chi(2)=25.57, P<0.01) .The prevalence of adult hypercholesterolemia in Chinese adult is 9.01% (781/8 669), the prevalence of borderline increased cholesterol is 22.54% (1 954/8 669), the prevalence of hypertriglyceridemia is 27.02% (2 342/8 669), the prevalence of lower high-density lipoproteinemia is 14.36% (1 245/8 669) and the prevalence of increased low-density lipoproteinemia was 10.23% (887/8 669). All prevalence rates are significantly higher compared to the 2005 survey results. Conclusion: The prevalence of dyslipidemia in Chinese adults is high and the prevalence increases in a fast pace. The current situation of dyslipidemia in Chinese adults is critical and targeted strategies should be applied to control the dyslipidemia in adult Chinese population. PMID- 29495235 TI - [Effects of apolipoprotein A5 on adipogenic differentiation of human adipose mesenchymal stem cells]. AB - Objective: To verify whether Apo A5 could inhibit the adipogenic differentiation of adipose mesenchymal stem cells (AMSCs). Methods: We isolated AMSCs by collagenase digestion method from the adipocyte tissue of patients underwent abdominal surgery in our hospital from February to July 2015. AMSCs were differentiated into mature adipocytes and incubated with Apo A5 (600 and 1 200 ng/ml) for 7, 14 and 21 days. Morphological changes, TG content, and gene expression levels of adipogenic differentiation markers were determined. Results: (1) The results of detecting the oil red O absorbance by spectrophotometer are as follows: At the 7th, 14th and 21st days after intervention, the absorbance of oil red O with 600 and 1 200 ng/ml Apo A5 intervention was lower than that of the control group (Day 7: 145.6+/-21.1, 110.5+/-31.5 vs. 195.4+/-35.7; Day 14: 289.2+/-24.2, 250.4+/-45.2 vs. 341.6+/-34.5; Day 21: 431.9+/-33.2, 374.7+/-26.4 vs. 488.2+/-22.5, all P<0.05). (2) The intracellular TG content after Apo A5 intervention were detected by TG quantitative detection kit detection. At the 7th, 14th and 21st days, intracellular TG contents in 600 and 1 200 ng/ml Apo A5 groups were lower than that in the control group (Day 7:(203.1+/-22.6), (174.2+/ 25.8)nmol/mg protein in Apo A5 intervention group vs. (266.25+/-23.7)nmol/mg protein in control group; Day 14: (332.5+/-23.2), (231.1+/-22.2)nmol/mg protein in Apo A5 intervention group vs. (452.2+/-16.4)nmol/mg protein in control group; Day 21: (482.8+/-21.2), (294.2+/-29.9)nmol/mg protein vs. (597.2+/-22.1)nmol/mg protein in control group, P<0.05). (3) aP2 gene expression detected by real-time PCR and intracellular fatty acid synthase and lipid droplets coated protein gene expression levels determined by Western blot on day 7, 14 and 21 were significantly lower in Apo A5 groups than in control group (all P<0.05). Conclusions: Apo A5 significantly reduced intracellular TG content and modulated the gene expression levels of adipogenic differentiation marker, thus, Apo A5 treatment can inhibit the adipogenic differentiation of adipose mesenchymal stem cells. PMID- 29495236 TI - [Impact of different intervention models on adherence to secondary prevention therapies in patients with acute coronary syndrome]. AB - Objective: To evaluate the impact of different intervention models on adherence to secondary prevention therapies in patients with acute coronary syndrome (ACS). Methods: This multi-center cross-sectional study collected data from 34 hospitals covering 22 provinces in China. Hospitals were randomly divided into four groups: control group(routine treatment and care), promotional calendar group (routine treatment and care plus giving propaganda desk calendar to patients), education group (routine treatment and care add patients education by nurses) and combined intervention group (promotional calendar and education).At least 90 patients with ACS were consecutively enrolled from each involved hospital from April 15, 2012 to June 30, 2013. To reduce the impact of uneven distribution of inter-group variables on the results, 1?1?1?1 propensity score matching method was used. The drug usage for secondary prevention and prognosis wasobtainedat 6 months after hospital discharge. Results: (1) A total of 3 391 patients were selected and 2 244 patients were included for the final analysisafter propensity score analysis. (2) At 6 months after discharge, the adherence rates of antiplatelet, statins, angiotensin converting enzyme inhibitor(ACEI)/angiotensin II receptor blocker(ARB), beta-blocker and the combination of 4 medications were similar between control group and promotional calendar group (all P>0.016).The adherence rates of antiplatelet and statins were 97.0% (526/542) and 91.0% (493/542) in the education group, 3.7% and 5.5% higher than in the control group (both P<0.016). The adherence rates of statins,ACEI/ARB and combined medication were 91.0% (496/545), 68.3% (372/545) and 53.2% (290/545) in the combined intervention group,significantly higher than in the control group (5.5%,8.3% and 9.6%, all P<0.016). (3) Poisson regression analysis showed that the adherence of antiplatelet drugs in the education group was 3.4%(OR=1.034, 95%CI 1.007 1.060,P<0.05) and 3.5%(OR=1.035, 95%CI 1.007-1.063, P<0.05) higher than in the control group and the promotional calendar group, and the statins adherence rate was 5.5%(OR=1.055, 95%CI 1.012-1.101,P<0.05) higher than in the control group. The antiplatelet drug adherence rates in the combined intervention group were 3.0% (OR=1.030, 95%CI 1.002-1.058,P<0.05) and 3.1% (OR=1.031, 95%CI 1.003 1.060,P<0.05) higher than in the control group and the promotional calendar group, respectively, and statin adherence was 6.1% (OR=1.061, 95%CI 1.017 1.107,P<0.01) higher than in the control group. The adherence rates of ACEI/ARB in combined intervention group were respectively 15.4%(OR=1.154, 95%CI 1.057 1.259, P<0.01),20.0%(OR=1.200, 95%CI 1.096-1.314, P<0.01) and 25.5%(OR=1.255, 95%CI 1.142-1.380, P<0.01) higher than in the control group, promotional calendar group and education group. The adherence rates of combined medication in combined intervention group were respectively 21.6%(OR=1.216, 95%CI 1.079-1.371, P<0.01),21.5%(OR=1.215, 95%CI 1.077-1.371, P<0.01) and 27.8%(OR=1.278, 95%CI 1.126-1.450, P<0.01) higher than in the control group, promotional calendar group and education group. (4) At 6 months after discharge, the control rates of blood pressure (<140/90 mmHg,1 mmHg=0.133 kPa) in the education group were significantly higher than in the control group and promotional calendar group (78.7% (398/506) vs. 70.2%(373/531) and 71.1% (354/498) , all P<0.016),and the control rates of blood pressure in combined intervention group were higher than in the control group and promotional calendar group (78.2% (376/481) vs. 70.2%(373/531) and 71.1% (354/498) , all P<0.016).The rehospitalization rates were 7.0% (39/561) in the promotional calendar group, and 7.6% (42/561) in the education group, both significantly higher than in the control group (3.8% (21/561), all P<0.016).The rate of the low density lipoprotein cholesterol<2.07 mmol/L and the rate for all-cause mortality were similar among groups (all P>0.016) . Conclusion: Post-discharge medication adherence in ACS patients can be enhanced by either promotional calendaror nurses education strategy, and the efficacy is better by nurse education as compared with promotional calendar, the combination of both methods can further increase the post-discharge medication adherence rates in ACS patients. PMID- 29495237 TI - [Development and prospective validation of an ischemic risk score for acute chest pain patients with normal high-sensitivity troponin I levels and without obvious ST-segment deviation]. AB - Objective: To develop and prospectively validate a risk score for acute chest pain patients with normal high-sensitivity troponin I (hs-TnI) levels and without obvious ST-segment deviation in China. Methods: Chest pain patients admitted to the emergency department of Beijing Anzhen Hospital from September 2014 to July 2015 were enrolled. Baseline characteristics of patients met inclusion criteria including normal hs-TnI levels and without obvious ST-segment deviation were included. The endpoint (major adverse cardiovascular events) was a composite of acute myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft, and all-cause death within 3 months after initial presentation. Predictors were screened and used to develop the risk score model by logistic regression analysis in a retrospective cohort. Then, the risk score model was evaluated in a prospective validation cohort. Results: The study population of derivation cohort included 1 735 consecutive chest pain patients. Finally, 1 030 eligible patients were enrolled. Multivariate regression analysis defined five independent predictors: male gender (beta=0.88); history of chest pain (beta value of moderate and high suspicion of coronary heart artery was 2.70 and 3.51 respectively); electrocardiogram (beta=0.84); >=60 years old (beta=0.51) and >=3 risk factors (beta=0.85).The range of weighted score was set as 0-13. The area under a receiver operating characteristic (ROC) curve was 0.75 (95%CI 0.72-0.78) in the final model. Major adverse cardiovascular events rates increased in proportion to score increase (P<0.01). The internal validity used bootstrap technique showed the same predictor factors as the final model, and its area under a ROC curve was 0.75(95%CI 0.72-0.78).MACE rates in the low risk group (score 0-3), intermediate risk group (score 4-7), and high risk group (score 8 13) were 1.3% (1/77) ,19.0% (22/116) ,and 42.2% (122/289) in the prospective validation cohort, respectively (P<0.01). Conclusion: The developed ischemic risk score is feasible for risk stratification of acute chest pain patients with normal hs-TnI and without obvious ST-segment deviation, this score might be helpful to the decision making of treatment and management strategies for these patients. PMID- 29495238 TI - [Establishment of beta-aminopropionitrile-induced aortic dissection model in C57Bl/6J mice]. AB - Objective: To establish the mouse aorta dissection (AD) model through drinking water containing beta-aminopropionitrile (BAPN). Methods: Forty 3-week-old C57B1/6J male mice were divided into four groups according to randomized block design: control, 0.2, 0.4 and 0.8 g.kg(-1).d(-1) BAPN groups (dissolving respective dose of BAPN in the drinking water, n=10 each group). Arterial systolic blood pressure and heart rate were measured weekly in conscious, restrained mice using a noninvasive computerized tail-cuff system. Mice those died of rupture of aortic dissecting aneurysm during the study were autopsied and the aorta was examined. After 4 weeks, survived mice were sacrificed by an overdose of sodium pentobarbital and the whole aorta was harvested and analyzed. Results: The incidence of AD and the mortality of ruptured AD was 0 and 0 in control group, 30% (3/10) and 20% (2/10) in 0.2 g.kg(-1).d(-1) BAPN group, 50% (5/10) and 40% (4/10) in 0.4 g.kg(-1).d(-1) BAPN group, 90% (9/10) and 70% (7/10) in 0.8 g.kg(-1).d(-1) BAPN group (both P<0.05 vs. control group). The incidence of AD and the mortality of ruptured AD increased in proportion to BAPN concentration increase. In 0.8 g.kg(-1).d(-1) BAPN group, 7 mice died of dissecting aneurysm rupture during the experiment, among which 5 dissecting aneurysms were mainly located in the thoracic aorta and 2 dissecting aneurysms in abdominal aorta. The diameters of thoracic aorta and abdominal aorta were (1.38+/ 0.19) and (1.23+/-0.13) mm in control group, (2.43+/-1.56) and (1.30+/-0.26) mm in 0.2 g.kg(-1).d(-1) BAPN group, (2.45+/-1.28) and (1.30+/-0.31) mm in 0.4 g.kg( 1).d(-1) BAPN group, (2.87+/-0.57) and (1.95+/-0.81) mm in 0.8 g.kg(-1).d(-1) BAPN group (both P<0.05 vs. control group). The diameters of thoracic aorta and abdominal aorta in mice also increased in proportion with BAPN concentration increase. Furthermore, blood-filled false lumen formation and elastic fibers fragmentation were evidenced in hematoxylin-eosin stained and Vitoria blue-Sirius red stained aortic cross-sections of mice in the 0.8 g.kg(-1).d(-1) BAPN group. Conclusion: BAPN treatment induced aortic dissection model in C57Bl/6J mice can serve as a useful wild-type mouse model for the mechanism and pharmaceutical studies of AD. PMID- 29495239 TI - [Homocysteine induces calcium overload in neonatal rat atrial cells through activation of sodium current and CaMKIIdelta]. AB - Objective: To investigate the effect and related mechanism of homocysteine (Hcy) on calcium overload in neonatal rat atrial cells (NRICs). Methods: NRICs were assigned to 9 groups after culture for 3 days: (1) control group; (2) Hcy group (0, 50, 100, 200, 500 MUmol/L for 48 hours); (3) antioxidant group (NAC, 10 MUmol/L for 24 hours); (4) Hcy+NAC group (500 MUmol/L Hcy for 48 hours, then treated with 10 MUmol/L NAC for 24 hours); (5) calcium/calmodulin dependent protein kinase IIdelta (CaMKIIdelta) inhibitor group (KN-93, 3 MUmol/L KN-93 for 5 hours); (6) specific sodium current inhibitor group (ELE, 1 MUmol/L ELE for 5 hours); (7) Hcy+KN-93 group (500 MUmol/L Hcy for 48 hours, then treated with 3 MUmol/L KN-93 for 5 hours); (8) Hcy+ELE group (500 MUmol/L Hcy for 48 hours, then treated with 1 MUmol/L ELE for 5 hours; (9) Hcy+KN-93+ELE group (500 MUmol/L Hcy for 48 hours, then treated with 3 MUmol/L KN-93 and 1 MUmol/L ELE for 5 hours). Moreover, NRICs were also treated with CaMKIIdelta-siRNA lentivirus, and Nav1.5 siRNA lentivirus, negative lentivirus carrier containing green fluorescent protein (GFP) for 24 hours. The MOI values of the three groups were 10. Infection efficiency of lentivirus was determined by observing the percentage of GFP fluorescence under inverted fluorescence microscope after transfection for 24 hours, and cultured regularly with simultaneous Puro screening, then cells were grouped as Hcy+CaMKIIdelta-siRNA group, Hcy+Nav1.5-siRNA group and Hcy+negative group. The concentration of Ca(2+) in NRICs ([Ca(2+)]i) of various groups was detected through Fluo-4/AM fluorescence probe, then 2', 7'- two chlorofluorescein diacetate (DCFH-DA) was used as a probe to detect reactive oxygen species (ROS) in NRICs by flow cytometry. The malondialdehyde (MDA) was detected by the activity of superoxide dismutase (SOD) and xanthine oxidase was detected by thiobarbituric acid colorimetry. The protein and mRNA expression level of CaMKIIdelta and Nav1.5 in NRICs were detected by Western blot and quantitative real-time PCR. Results: (1) ROS, MDA and SOD were similar between NAC group and control group, ROS and MDA were significantly increased, while SOD was significantly reduced in Hcy group in a concentration-dependent manner. (2) [Ca(2+)]i: The level of [Ca(2+)]i was (155.57+7.25), (187.43+13.07), (248.98+27.22) and (307.36+15.09) nmol/L in 50, 100, 200 and 500 MUmol/L Hcy groups, which was significantly higher than that in the control group ((123.18+7.24) nmol/L, P<0.01). In addition, the level of [Ca(2+)]i in Hcy+NAC group ((222.87+23.71)nmol/L) was significantly lower than that in Hcy 500 MUmol/L group ((305.15+39.45) nmol/L, P<0.05), while [Ca(2+)]i level was similar between NAC group and the control group. (3) The protein expression of CaMKIIdelta and Nav1.5 was significantly upregulated in Hcy groups than in the control group. The protein expression level of CaMKIIdelta-Thr287 was significantly lower in NAC group than in Hcy 500 MUmol/L group (P<0.01), however, there was no significant difference on the protein expression levels of CaMKIIdelta-Thr287 and Nav1.5 between NAC group and control group (all P>0.05). (4) The protein expression levels of CaMKIIdelta-Thr287 and the concentration of [Ca(2+)]i were significantly lower in Hcy+KN-93 group and Hcy+KN-93+ELE group than in Hcy 500 MUmol/L group (P<0.05). [Ca(2+)]i concentration was significantly lower in Hcy+KN 93 group, Hcy+ELE group and KN-93+ELE+Hcy group than in Hcy 500 MUmol/L group (P<0.05). (5) The mRNA and protein expression levels of CaMKIIdelta and Nav1.5 in each group infected with lentivirus: the GFP expression was ideal post lentivirus transfection for 24 hours (up to 90%), which was significantly lower in the CaMKIIdelta-siRNA group and Nav1.5-siRNA group than in the negative infection group (all P<0.05), which was similar between negative infection group and control group (P>0.05). Moreover, the mRNA and protein expression levels of CaMKIIdelta and CaMKIIdelta-Thr287 was significantly lower in Hcy+Nav1.5-siRNA group than in Hcy+negative infection group (P<0.05). The protein and mRNA levels of Nav1.5 were similar between Hcy+CaMKIIdelta-siRNA group and Hcy+negative infection group (P>0.05). Conclusions: Hcy can induce calcium overload in NRICs by increasing oxidative stress, upregulating the sodium channel protein, and activating the late sodium current and phosphorylating CaMKIIdelta. PMID- 29495240 TI - [Analysis on trend of cerebral infarction mortality from 1999 to 2015 in Tianjin of China]. AB - Objective: To explore the trends and distribution of cerebral infarction between sexes, ages and urban-rural areas from 1999 to 2015 in Tianjin, China, and provide data for targeted prevention and control strategies of cerebral infarction in Tianjin. Methods: Cerebral infarction mortality data from January 1, 1999 to December 31, 2015 were obtained from Tianjin population based mortality surveillance system established by the Tianjin Centers for Disease Control and Prevention, and population data of permanent residents were obtained from Tianjin Municipal Public Security Bureau. The trends change and affecting factors including gender, age, and geographic distribution on mortality following cerebral infarction were analyzed. Results: (1) Cerebral infarction mortality rate in Tianjin increased from 1999 to 2015 with the crude mortality rate of 57.06/100 000 to 105.22/100 000 (Z=59.65, P<0.01, annual percent change(APC)=3.39%) and decreased with the standardized mortality rate from 55.59/100 000 to 56.12/100 000 (Z=-5.47, P<0.01, APC=-0.35%). (2) The crude mortality rate (64.23/100 000 to 118.72/100 000) and standardized mortality rate (65.44/100 000 to 67.23/100 000) of male cerebral infarction was higher than that of female (crude: 49.73/100 000 to 91.64/1/100 000, standardized: 45.73/100 000 to 45.01/100 000) from 1999 to 2015. (3) With the increase of age, the mortality of cerebral infarction increased gradually from 1999 to 2015 (all Z>0.00,all P<0.01). (4) The mortality rate of cerebral infarction in urban areas increased with the crude mortality rate from 71.43/100 000 to 103.20/100 000 (Z=17.34, P<0.01, APC=1.30%) and decreased with the standardized mortality rate from 61.04/100 000 to 43.77/100 000 (Z=-32.49, P<0.01, APC=-3.06%) from 1999 to 2015. The mortality rate of cerebral infarction in rural areas increased with the crude mortality rate from 42.63/100 000 to 107.32/100 000 (Z=69.14, P<0.01, APC=5.95%) and with the standardized mortality rate from 48.34/100 000 to 77.09/100 000 (Z=36.88, P<0.01, APC=5.95%) from 1999 to 2015. Conclusions: Cerebral infarction crude mortality increased and standardized mortality decreased from 1999 to 2015 in Tianjin. Further efforts to reduce cerebral infarction mortality in Tianjin are needed, special attention should be focused on the elderly, male and rural residents. PMID- 29495241 TI - [Infective endocarditis post percutaneous pulmonary valve implantation: one case report]. PMID- 29495242 TI - [Impact of platelet mRNA/miRNA transfer on vascular cell function]. PMID- 29495243 TI - [Advances in research on the relationship between intestinal microecology and cardiovascular diseases]. PMID- 29495244 TI - [Research progress on the relationship between sarcopenia and cardiovascular diseases]. PMID- 29495245 TI - YH18968, a Novel 1,2,4-Triazolone G-Protein Coupled Receptor 119 Agonist for the Treatment of Type 2 Diabetes Mellitus. AB - G protein-coupled receptor 119 (GPR119) is expressed in the pancreas and gastrointestinal tract, and its activation promotes insulin secretion in the beta cells of the pancreatic islets as well as the secretion of glucagon-like peptide 1 (GLP-1) in intestinal L cells, consequently improving glucose-stimulated insulin secretion. Due to this dual mechanism of action, the development of small molecule GPR119 agonists has received significant interest for the treatment of type 2 diabetes. We newly synthesized 1,2,4-triazolone derivatives of GPR119 agonists, which demonstrated excellent outcomes in a cyclic adenosine monophosphate (cAMP) assay. Among the synthesized derivatives, YH18968 showed cAMP=2.8 nM; in GLUTag cell, GLP-1secretion=2.3 fold; in the HIT-T15 cell, and insulin secretion=1.9 fold. Single oral administration of YH18968 improved glucose tolerance and combined treatment with a dipeptidyl peptidase 4 (DPP-4) inhibitor augmented the glucose lowering effect as well as the plasma level of active GLP-1 in normal mice. Single oral administration of YH18968 improved glucose tolerance in a diet induced obese mice model. This effect was maintained after repeated dosing for 4 weeks. The results indicate that YH18968 combined with a DPP-4 inhibitor may be an effective therapeutic candidate for the treatment of type 2 diabetes. PMID- 29495246 TI - In Nano, Volume 12, Issue 2. PMID- 29495247 TI - International Chemistry, Nanoscience, and Engagement. PMID- 29495248 TI - Estimation of Handgrip Force from SEMG Based on Wavelet Scale Selection. AB - This paper proposes a nonlinear correlation-based wavelet scale selection technology to select the effective wavelet scales for the estimation of handgrip force from surface electromyograms (SEMG). The SEMG signal corresponding to gripping force was collected from extensor and flexor forearm muscles during the force-varying analysis task. We performed a computational sensitivity analysis on the initial nonlinear SEMG-handgrip force model. To explore the nonlinear correlation between ten wavelet scales and handgrip force, a large-scale iteration based on the Monte Carlo simulation was conducted. To choose a suitable combination of scales, we proposed a rule to combine wavelet scales based on the sensitivity of each scale and selected the appropriate combination of wavelet scales based on sequence combination analysis (SCA). The results of SCA indicated that the scale combination VI is suitable for estimating force from the extensors and the combination V is suitable for the flexors. The proposed method was compared to two former methods through prolonged static and force-varying contraction tasks. The experiment results showed that the root mean square errors derived by the proposed method for both static and force-varying contraction tasks were less than 20%. The accuracy and robustness of the handgrip force derived by the proposed method is better than that obtained by the former methods. PMID- 29495249 TI - Phytochemical Analysis by HPLC-HRESI-MS and Anti-Inflammatory Activity of Tabernaemontana catharinensis. AB - Tabernaemontana catharinensis (Apocynaceae) has been popularly used by folk medicine because of its anti-inflammatory, analgesic, and antiophidic properties. This study aims to analyze the flavonoids composition of the hydroethanolic extract and of the ethyl acetate (EtOAc) and butanol (BuOH) fractions of T. catharinensis leaves, as well as to evaluate their anti-inflammatory activity using in vivo models. The phytochemical profile, determined by High-Performance Liquid Chromatography-High-Resolution Electrospray Ionization-Mass Spectrometry (HPLC-HRESI-MS), showed the presence of flavonoids mainly having an isorhamnetin nucleus. The anti-inflammatory activity was evaluated in carrageenan-induced paw edema (pre- and post-treatment) with oral administration of a T. catharinensis hydroethanolic extract (50, 100, and 150 mg/kg) and of organic fractions (50 mg/kg). The extract and fractions showed antiedematogenic activity by decreasing myeloperoxidase (MPO) production. In the zymosan-air-pouch model, the extract and fractions inhibited leukocyte migration and significantly decreased the levels of various proteins, such as MPO, interleukin (IL)-1beta, and tumor necrosis factor (TNF)-alpha. The cytotoxicity was evaluated by the 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay, which revealed no cytotoxicity of the extract and the fractions. These results suggest that the hydroethanolic extract and organic fractions of T. catharinensis leaves have sufficient anti inflammatory activity to support the popular use of this plant in the treatment of inflammatory disorders. PMID- 29495252 TI - User Access Management Based on Network Pricing for Social Network Applications. AB - Social applications play a very important role in people's lives, as users communicate with each other through social networks on a daily basis. This presents a challenge: How does one receive high-quality service from social networks at a low cost? Users can access different kinds of wireless networks from various locations. This paper proposes a user access management strategy based on network pricing such that networks can increase its income and improve service quality. Firstly, network price is treated as an optimizing access parameter, and an unascertained membership algorithm is used to make pricing decisions. Secondly, network price is adjusted dynamically in real time according to network load. Finally, selecting a network is managed and controlled in terms of the market economy. Simulation results show that the proposed scheme can effectively balance network load, reduce network congestion, improve the user's quality of service (QoS) requirements, and increase the network's income. PMID- 29495251 TI - Graphene Oxide as a Nanocarrier for a Theranostics Delivery System of Protocatechuic Acid and Gadolinium/Gold Nanoparticles. AB - We have synthesized a graphene oxide (GO)-based theranostic nanodelivery system (GOTS) for magnetic resonance imaging (MRI) using naturally occurring protocatechuic acid (PA) as an anticancer agent and gadolinium (III) nitrate hexahydrate (Gd) as the starting material for a contrast agent,. Gold nanoparticles (AuNPs) were subsequently used as second diagnostic agent. The GO nanosheets were first prepared from graphite via the improved Hummer's protocol. The conjugation of the GO and the PA was done via hydrogen bonding and pi-pi stacking interactions, followed by surface adsorption of the AuNPs through electrostatic interactions. GAGPA is the name given to the nanocomposite obtained from Gd and PA conjugation. However, after coating with AuNPs, the name was modified to GAGPAu. The physicochemical properties of the GAGPA and GAGPAu nanohybrids were studied using various characterization techniques. The results from the analyses confirmed the formation of the GOTS. The powder X-ray diffraction (PXRD) results showed the diffractive patterns for pure GO nanolayers, which changed after subsequent conjugation of the Gd and PA. The AuNPs patterns were also recorded after surface adsorption. Cytotoxicity and magnetic resonance imaging (MRI) contrast tests were also carried out on the developed GOTS. The GAGPAu was significantly cytotoxic to the human liver hepatocellular carcinoma cell line (HepG2) but nontoxic to the standard fibroblast cell line (3T3). The GAGPAu also appeared to possess higher T1 contrast compared to the pure Gd and water reference. The GOTS has good prospects of serving as future theranostic platform for cancer chemotherapy and diagnosis. PMID- 29495250 TI - MERS-CoV: Understanding the Latest Human Coronavirus Threat. AB - Human coronaviruses cause both upper and lower respiratory tract infections in humans. In 2012, a sixth human coronavirus (hCoV) was isolated from a patient presenting with severe respiratory illness. The 60-year-old man died as a result of renal and respiratory failure after admission to a hospital in Jeddah, Saudi Arabia. The aetiological agent was eventually identified as a coronavirus and designated Middle East respiratory syndrome coronavirus (MERS-CoV). MERS-CoV has now been reported in more than 27 countries across the Middle East, Europe, North Africa and Asia. As of July 2017, 2040 MERS-CoV laboratory confirmed cases, resulting in 712 deaths, were reported globally, with a majority of these cases from the Arabian Peninsula. This review summarises the current understanding of MERS-CoV, with special reference to the (i) genome structure; (ii) clinical features; (iii) diagnosis of infection; and (iv) treatment and vaccine development. PMID- 29495253 TI - Expert Views on HPV Infection. PMID- 29495254 TI - Kinetics and Optimization of Lipophilic Kojic Acid Derivative Synthesis in Polar Aprotic Solvent Using Lipozyme RMIM and Its Rheological Study. AB - The synthesis of kojic acid derivative (KAD) from kojic and palmitic acid (C16:0) in the presence of immobilized lipase from Rhizomucor miehei (commercially known as Lipozyme RMIM), was studied using a shake flask system. Kojic acid is a polyfunctional heterocycles that acts as a source of nucleophile in this reaction allowing the formation of a lipophilic KAD. In this study, the source of biocatalyst, Lipozyme RMIM, was derived from the lipase of Rhizomucor miehei immobilized on weak anion exchange macro-porous Duolite ES 562 by the adsorption technique. The effects of solvents, enzyme loading, reaction temperature, and substrate molar ratio on the reaction rate were investigated. In one-factor-at-a time (OFAT) experiments, a high reaction rate (30.6 * 10-3 M.min-1) of KAD synthesis was recorded using acetone, enzyme loading of 1.25% (w/v), reaction time of 12 h, temperature of 50 degrees C and substrate molar ratio of 5:1. Thereafter, a yield of KAD synthesis was optimized via the response surface methodology (RSM) whereby the optimized molar ratio (fatty acid: kojic acid), enzyme loading, reaction temperature and reaction time were 6.74, 1.97% (w/v), 45.9 degrees C, and 20 h respectively, giving a high yield of KAD (64.47%). This condition was reevaluated in a 0.5 L stirred tank reactor (STR) where the agitation effects of two impellers; Rushton turbine (RT) and pitch-blade turbine (PBT), were investigated. In the STR, a very high yield of KAD synthesis (84.12%) was achieved using RT at 250 rpm, which was higher than the shake flask, thus indicating better mixing quality in STR. In a rheological study, a pseudoplastic behavior of KAD mixture was proposed for potential application in lotion formulation. PMID- 29495255 TI - Effects of Graphene Oxide Nanoparticles on the Immune System Biomarkers Produced by RAW 264.7 and Human Whole Blood Cell Cultures. AB - Graphene oxide nanoparticles (GONPs) have attracted a lot of attention due to their many applications. These applications include batteries, super capacitors, drug delivery and biosensing. However, few studies have investigated the effects of these nanoparticles on the immune system. In this study, the in vitro effects of GONPs on the immune system was evaluated by exposing murine macrophages, RAW 264.7 cells and human whole blood cell cultures (to GONPs. The effects of GONPs on RAW cells were monitored under basal conditions. The whole blood cell cultures were exposed to GONPs in the presence or absence of the mitogens lipopolysaccharide (LPS) and phytohaemmagglutinin (PHA). A number of parameters were monitored for both RAW and whole blood cell cultures, these included cytotoxicity, inflammatory biomarkers, cytokines of the acquired immune system and a proteome profile analysis. The GONPs were cytotoxic to both RAW and whole blood cell cultures at 500 MUg/mL. In the absence of LPS, GONPs elicited an inflammatory response from the murine macrophage, RAW and whole blood cell cultures at 15.6 and 5 MUg/mL respectively. This activation was further corroborated by proteome profile analysis of both experimental cultures. GONPs inhibited LPS induced interleukin 6 (IL-6) synthesis and PHA induced interferon gamma (IFNgamma) synthesis by whole blood cell cultures in a dose dependent manner. In the absence of mitogens, GONPs stimulated IL-10 synthesis by whole blood cell cultures. The current study shows that GONPs modulate immune system biomarkers and that these may pose a health risk to individuals exposed to this type of nanoparticle. PMID- 29495256 TI - Identification of Uncultured Bacterial Species from Firmicutes, Bacteroidetes and CANDIDATUS Saccharibacteria as Candidate Cellulose Utilizers from the Rumen of Beef Cows. AB - The ability of ruminants to utilize cellulosic biomass is a result of the metabolic activities of symbiotic microbial communities that reside in the rumen. To gain further insight into this complex microbial ecosystem, a selection-based batch culturing approach was used to identify candidate cellulose-utilizing bacterial consortia. Prior to culturing with cellulose, rumen contents sampled from three beef cows maintained on a forage diet shared 252 Operational Taxonomic Units (OTUs), accounting for 41.6-50.0% of bacterial 16S rRNA gene sequences in their respective samples. Despite this high level of overlap, only one OTU was enriched in cellulose-supplemented cultures from all rumen samples. Otherwise, each set of replicate cellulose supplemented cultures originating from a sampled rumen environment was found to have a distinct bacterial composition. Two of the seven most enriched OTUs were closely matched to well-established rumen cellulose utilizers (Ruminococcusflavefaciens and Fibrobactersuccinogenes), while the others did not show high nucleotide sequence identity to currently defined bacterial species. The latter were affiliated to Prevotella (1 OTU), Ruminococcaceae (3 OTUs), and the candidate phylum Saccharibacteria (1 OTU), respectively. While further investigations will be necessary to elucidate the metabolic function(s) of each enriched OTU, these results together further support cellulose utilization as a ruminal metabolic trait shared across vast phylogenetic distances, and that the rumen is an environment conducive to the selection of a broad range of microbial adaptations for the digestion of plant structural polysaccharides. PMID- 29495257 TI - A Fluorescent Cell-Based System for Imaging Zika Virus Infection in Real-Time. AB - Zika virus (ZIKV) is a re-emerging flavivirus that is transmitted to humans through the bite of an infected mosquito or through sexual contact with an infected partner. ZIKV infection during pregnancy has been associated with numerous fetal abnormalities, including prenatal lethality and microcephaly. However, until recent outbreaks in the Americas, ZIKV has been relatively understudied, and therefore the biology and pathogenesis of ZIKV infection remain incompletely understood. Better methods to study ZIKV infection in live cells could enhance our understanding of the biology of ZIKV and the mechanisms by which ZIKV contributes to fetal abnormalities. To this end, we developed a fluorescent cell-based reporter system allowing for live imaging of ZIKV-infected cells. This system utilizes the protease activity of the ZIKV non-structural proteins 2B and 3 (NS2B-NS3) to specifically mark virus-infected cells. Here, we demonstrate the utility of this fluorescent reporter for identifying cells infected by ZIKV strains of two lineages. Further, we use this system to determine that apoptosis is induced in cells directly infected with ZIKV in a cell-autonomous manner. Ultimately, approaches that can directly track ZIKV infected cells at the single cell-level have the potential to yield new insights into the host-pathogen interactions that regulate ZIKV infection and pathogenesis. PMID- 29495258 TI - Study of the Serum Metabolomic Profile in Nonalcoholic Fatty Liver Disease: Research and Clinical Perspectives. AB - In recent years, metabolomics has attracted great scientific attention. The metabolomics methodology might permit a view into transitional phases between healthy liver and nonalcoholic steatohepatitis. Metabolomics can help to analyze the metabolic alterations that play a main role in the progression of nonalcoholic steatohepatitis. Lipid, glucose, amino acid, and bile acid metabolism should be widely studied to understand the complex pathogenesis of nonalcoholic steatohepatitis. The discovery of new biomarkers would be important for diagnosis and staging of liver disease as well as for the assessment of efficacy of new drugs. Here, we review the metabolomics data regarding nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. We analyzed the main studies regarding the application of metabolomics methodology in the complex context of nonalcoholic steatohepatitis, trying to create a bridge from the basic to the clinical aspects. PMID- 29495259 TI - Non-Nutritive Sweeteners in the Packaged Food Supply-An Assessment across 4 Countries. AB - Increased interest among consumers in the reduction of dietary sugar intake has led to the wider availability of food products containing non-nutritive sweeteners (NNS). However, the extent to which NNS are currently being used by manufacturers to sweeten processed food and beverage products, and how NNS may be displacing added sugars as a sweetener is unknown. The current study utilized branded food composition databases from Australia, Mexico, New Zealand and the US to determine the percentage of processed food and beverage products for which there are nutrition data containing NNS and to compare total sugar density (g per 100 mL for beverages and g per 100 g for foods) between products with and without NNS. Ordinary least squares regression at the country-product level was performed to examine associations between presence of NNS and total sugar. Across all countries, 5% of products contained at least one NNS, with the highest prevalence among beverages (22%). Mexico had the highest percentage of products with NNS (11%), as compared to the United States (US) (4%), New Zealand (1%), and Australia (<1%). The presence of NNS was associated with lower mean total sugar density among beverages (range across countries: 7.5 to 8.7 g per 100 mL) and among foods (23.2 to 25.5 g per 100 g). Products with both added sugar ingredients and NNS had a lower overall mean total sugar density when compared to products containing only added sugar ingredients. Due to paucity of data on sales and market shares across these countries, our results do not reflect the extent to which consumers purchase NNS containing products. Continued monitoring of NNS in the food supply, extension of work from these data, and inclusion of market shares of products will be important as more countries introduce policies to reduce sugar. PMID- 29495260 TI - Pilot Study of 64CuCl2 for PET Imaging of Inflammation. AB - Copper(II) ion (Cu2+) is the essential element for numerous pathophysiological processes in vivo. Copper transporter 1 (CTR1) is mainly responsible for maintaining Cu2+ accumulation in cells, which has been found to be over-expressed in inflammatory tissues. Therefore, we explored the potential application of 64CuCl2 for PET imaging of inflammation through targeting CTR1. The animal models of H2O2 induced muscle inflammation and lipopolysaccaharide induced lung inflammation were successfully established, then imaged by small animal PET (PET/CT) post-injection of 64CuCl2, and PET images were quantitatively analyzed. H&E and immunohistochemical (IHC) staining and western blot experiments were performed for evaluating CTR1 levels in the inflammatory and control tissues. Both inflammatory muscle and lungs can be clearly imaged by PET. PET image quantitative analysis revealed that the inflammatory muscle and lungs showed significantly higher 64Cu accumulation than the controls, respectively (p < 0.05). Furthermore, IHC staining and western blot analysis demonstrated that compared with the controls, CTR1 expression was increased in both the inflammatory muscle and lungs, which was consistent with the levels of 64Cu2+ accumulation in these tissues. 64CuCl2 can be used as a novel, simple, and highly promising PET tracer for CTR1 targeted imaging of inflammation. PMID- 29495261 TI - Less Is More in Biosignal Analysis: Compressed Data Could Open the Door to Faster and Better Diagnosis. AB - In the digital medicine field, biosignals, such as those of an electrocardiogram (ECG), are collected regularly for screening and diagnosis, and there continues to be an increasingly substantial shift towards collecting long-term ECG signals for remote monitoring, e.g., in smart homes. ECG signal collection is quite simple and only requires the use of inexpensive sensors, an active Internet connection, and a mobile device that acts as the medium between the sensors and the Internet (e.g., a mobile phone or laptop). Despite the ease and convenience of remote ECG data collection and transmission, the amount of time and energy required for the related remote computational processes remains a major limitation. This short note discusses a biosignal approach that uses fewer biomedical data for screening and diagnosis that is, compared to current data collection methods, equally, if not more, efficient. PMID- 29495263 TI - High-Speed Interrogation for Large-Scale Fiber Bragg Grating Sensing. AB - A high-speed interrogation scheme for large-scale fiber Bragg grating (FBG) sensing arrays is presented. This technique employs parallel computing and pipeline control to modulate incident light and demodulate the reflected sensing signal. One Electro-optic modulator (EOM) and one semiconductor optical amplifier (SOA) were used to generate a phase delay to filter reflected spectrum form multiple candidate FBGs with the same optical path difference (OPD). Experimental results showed that the fastest interrogation delay time for the proposed method was only about 27.2 us for a single FBG interrogation, and the system scanning period was only limited by the optical transmission delay in the sensing fiber owing to the multiple simultaneous central wavelength calculations. Furthermore, the proposed FPGA-based technique had a verified FBG wavelength demodulation stability of +/-1 pm without average processing. PMID- 29495262 TI - Preparative Separation and Purification of Trichothecene Mycotoxins from the Marine Fungus Fusarium sp. LS68 by High-Speed Countercurrent Chromatography in Stepwise Elution Mode. AB - The contamination of foods and animal feeds with trichothecene mycotoxins is a growing concern for human and animal health. As such, large quantities of pure trichothecene mycotoxins are necessary for food safety monitoring and toxicological research. A new and effective method for the purification of trichothecene mycotoxins from a marine fungus, Fusarium sp. LS68, is described herein. Preparative high-speed countercurrent chromatography (HSCCC) was utilized for the scalable isolation and purification of four trichothecene mycotoxins for the first time in stepwise elution mode, with a biphasic solvent system composed of hexanes-EtOAc-CH3OH-H2O (6:4:5:5, v/v/v/v) and (8.5:1.5:5:5,v/v/v/v). This preparative HSCCC separation was performed on 200 mg of crude sample to yield four trichothecene mycotoxins, roridin E (1), roridin E acetate (2), verrucarin L acetate (3), and verrucarin J (4) in a single run, with each of >98% purity. These compounds were identified by MS, 1H NMR, 13C NMR, and polarimetry. The results demonstrate an efficient HSCCC method for the separation of trichothecene mycotoxins, which can be utilized to produce pure commercial and research standards. PMID- 29495264 TI - Engineering of Corneal Tissue through an Aligned PVA/Collagen Composite Nanofibrous Electrospun Scaffold. AB - Corneal diseases are the main reason of vision loss globally. Constructing a corneal equivalent which has a similar strength and transparency with the native cornea, seems to be a feasible way to solve the shortage of donated cornea. Electrospun collagen scaffolds are often fabricated and used as a tissue engineered cornea, but the main drawback of poor mechanical properties make it unable to meet the requirement for surgery suture, which limits its clinical applications to a large extent. Aligned polyvinyl acetate (PVA)/collagen (PVA COL) scaffolds were electrospun by mixing collagen and PVA to reinforce the mechanical strength of the collagen electrospun scaffold. Human keratocytes (HKs) and human corneal epithelial cells (HCECs) inoculated on aligned and random PVA COL electrospun scaffolds adhered and proliferated well, and the aligned nanofibers induced orderly HK growth, indicating that the designed PVA-COL composite nanofibrous electrospun scaffold is suitable for application in tissue engineered cornea. PMID- 29495266 TI - TopUp SERS Substrates with Integrated Internal Standard. AB - Surface-enhanced Raman spectroscopy (SERS) is known as a molecular-specific and highly sensitive method. In order to enable the routine application of SERS, powerful SERS substrates are of great importance. Within this manuscript, a TopUp SERS substrate is introduced which is fabricated by a top-down process based on microstructuring as well as a bottom-up generation of silver nanostructures. The Raman signal of the support material acts as an internal standard in order to improve the quantification capabilities. The analyte molecule coverage of sulfamethoxazole on the surface of the nanostructures is characterized by the SERS signal evolution fitted by a Langmuir-Freundlich isotherm. PMID- 29495265 TI - Bacillus Cellulase Molecular Cloning, Expression, and Surface Display on the Outer Membrane of Escherichia coli. AB - One of the main challenges of using recombinant enzymes is that they are derived from genetically-modified microorganisms commonly located in the intracellular region. The use of these recombinant enzymes for commercial purposes requires the additional processes of cell disruption and purification, which may result in enzyme loss, denaturation, and increased total production cost. In this study, the cellulase gene of Bacillus licheniformis ATCC 14580 was cloned, over expressed, and surface displayed in recombinant Escherichia coli using an ice nucleation protein (INP). INP, an outer membrane-bound protein from Pseudomonas syringae, was utilized as an anchor linker, which was cloned with a foreign cellulase gene into the pET21a vector to develop a surface display system on the outer membrane of E. coli. The resulting strain successfully revealed cellulase on the host cell surface. The over-expressed INP-cellulase fusion protein was confirmed via staining assay for determining the extracellular cellulase and Western blotting method for the molecular weight (MW) of cellulase, which was estimated to be around 61.7 kDa. Cell fractionation and localization tests demonstrated that the INP-cellulase fusion protein was mostly present in the supernatant (47.5%) and outer membrane (19.4%), while the wild-type strain intracellularly retained enzymes within cytosol (>61%), indicating that the INP gene directed the cellulase expression on the bacteria cell surface. Further studies of the optimal enzyme activity were observed at 60 degrees C and pH 7.0, and at least 75% of maximal enzyme activity was preserved at 70 degrees C. PMID- 29495268 TI - Phosphate-Catalyzed Succinimide Formation from Asp Residues: A Computational Study of the Mechanism. AB - Aspartic acid (Asp) residues in proteins and peptides are prone to the non enzymatic reactions that give biologically uncommon l-beta-Asp, d-Asp, and d-beta Asp residues via the cyclic succinimide intermediate (aminosuccinyl residue, Suc). These abnormal Asp residues are known to have relevance to aging and pathologies. Despite being non-enzymatic, the Suc formation is thought to require a catalyst under physiological conditions. In this study, we computationally investigated the mechanism of the Suc formation from Asp residues that were catalyzed by the dihydrogen phosphate ion, H2PO4-. We used Ac-l-Asp-NHMe (Ac = acetyl, NHMe = methylamino) as a model compound. The H2PO4- ion (as a catalyst) and two explicit water molecules (as solvent molecules stabilizing the negative charge) were included in the calculations. All of the calculations were performed by density functional theory with the B3LYP functional. We revealed a phosphate catalyzed two-step mechanism (cyclization-dehydration) of the Suc formation, where the first step is predicted to be rate-determining. In both steps, the reaction involved a proton relay mediated by the H2PO4- ion. The calculated activation barrier for this mechanism (100.3 kJ mol-1) is in reasonable agreement with an experimental activation energy (107 kJ mol-1) for the Suc formation from an Asp-containing peptide in a phosphate buffer, supporting the catalytic mechanism of the H2PO4- ion that is revealed in this study. PMID- 29495267 TI - Arabidopsis RETICULON-LIKE3 (RTNLB3) and RTNLB8 Participate in Agrobacterium Mediated Plant Transformation. AB - Agrobacterium tumefaciens can genetically transform various eukaryotic cells because of the presence of a resident tumor-inducing (Ti) plasmid. During infection, a defined region of the Ti plasmid, transfer DNA (T-DNA), is transferred from bacteria into plant cells and causes plant cells to abnormally synthesize auxin and cytokinin, which results in crown gall disease. T-DNA and several virulence (Vir) proteins are secreted through a type IV secretion system (T4SS) composed of T-pilus and a transmembrane protein complex. Three members of Arabidopsis reticulon-like B (RTNLB) proteins, RTNLB1, 2, and 4, interact with VirB2, the major component of T-pilus. Here, we have identified that other RTNLB proteins, RTNLB3 and 8, interact with VirB2 in vitro. Root-based A. tumefaciens transformation assays with Arabidopsis rtnlb3, or rtnlb5-10 single mutants showed that the rtnlb8 mutant was resistant to A. tumefaciens infection. In addition, rtnlb3 and rtnlb8 mutants showed reduced transient transformation efficiency in seedlings. RTNLB3- or 8 overexpression transgenic plants showed increased susceptibility to A. tumefaciens and Pseudomonas syringae infection. RTNLB1-4 and 8 transcript levels differed in roots, rosette leaves, cauline leaves, inflorescence, flowers, and siliques of wild-type plants. Taken together, RTNLB3 and 8 may participate in A. tumefaciens infection but may have different roles in plants. PMID- 29495269 TI - SmartVeh: Secure and Efficient Message Access Control and Authentication for Vehicular Cloud Computing. AB - With the growing number of vehicles and popularity of various services in vehicular cloud computing (VCC), message exchanging among vehicles under traffic conditions and in emergency situations is one of the most pressing demands, and has attracted significant attention. However, it is an important challenge to authenticate the legitimate sources of broadcast messages and achieve fine grained message access control. In this work, we propose SmartVeh, a secure and efficient message access control and authentication scheme in VCC. A hierarchical, attribute-based encryption technique is utilized to achieve fine grained and flexible message sharing, which ensures that vehicles whose persistent or dynamic attributes satisfy the access policies can access the broadcast message with equipped on-board units (OBUs). Message authentication is enforced by integrating an attribute-based signature, which achieves message authentication and maintains the anonymity of the vehicles. In order to reduce the computations of the OBUs in the vehicles, we outsource the heavy computations of encryption, decryption and signing to a cloud server and road-side units. The theoretical analysis and simulation results reveal that our secure and efficient scheme is suitable for VCC. PMID- 29495271 TI - Mn4+-Doped Magnesium Titanate-A Promising Phosphor for Self-Referenced Optical Temperature Sensing. AB - Phosphors based on magnesium titanate activated with Mn 4 + ions are of great interest because, when excited with blue light, they display a strong red emitting luminescence. They are characterized by a luminescence decay which is strongly temperature dependent in the range from -50 ? C to 150 ? C, making these materials very promising for temperature sensing in the biochemical field. In this work, the optical and thermal properties of the luminescence of Mg 2 TiO 4 are investigated for different Mn 4 + doping concentrations. The potential of this material for temperature sensing is demonstrated by fabricating a fiber optic temperature microsensor and by comparing its performance against a standard resistance thermometer. The response of the fiber optic sensor is exceptionally fast, with a response time below 1 s in the liquid phase and below 1.1 s in the gas phase. PMID- 29495273 TI - The Design of a Single-Bit CMOS Image Sensor for Iris Recognition Applications. AB - This paper presents a single-bit CMOS image sensor (CIS) that uses a data processing technique with an edge detection block for simple iris segmentation. In order to recognize the iris image, the image sensor conventionally captures high-resolution image data in digital code, extracts the iris data, and then compares it with a reference image through a recognition algorithm. However, in this case, the frame rate decreases by the time required for digital signal conversion of multi-bit digital data through the analog-to-digital converter (ADC) in the CIS. In order to reduce the overall processing time as well as the power consumption, we propose a data processing technique with an exclusive OR (XOR) logic gate to obtain single-bit and edge detection image data instead of multi-bit image data through the ADC. In addition, we propose a logarithmic counter to efficiently measure single-bit image data that can be applied to the iris recognition algorithm. The effective area of the proposed single-bit image sensor (174 * 144 pixel) is 2.84 mm2 with a 0.18 MUm 1-poly 4-metal CMOS image sensor process. The power consumption of the proposed single-bit CIS is 2.8 mW with a 3.3 V of supply voltage and 520 frame/s of the maximum frame rates. The error rate of the ADC is 0.24 least significant bit (LSB) on an 8-bit ADC basis at a 50 MHz sampling frequency. PMID- 29495272 TI - Second Generation Small Pixel Technology Using Hybrid Bond Stacking. AB - In this work, OmniVision's second generation (Gen2) of small-pixel BSI stacking technologies is reviewed. The key features of this technology are hybrid-bond stacking, deeper back-side, deep-trench isolation, new back-side composite metal oxide grid, and improved gate oxide quality. This Gen2 technology achieves state of-the-art low-light image-sensor performance for 1.1, 1.0, and 0.9 um pixel products. Additional improvements on this technology include less than 100 ppm white-pixel process and a high near-infrared (NIR) QE technology. PMID- 29495270 TI - Bacteriophage Interactions with Marine Pathogenic Vibrios: Implications for Phage Therapy. AB - A global distribution in marine, brackish, and freshwater ecosystems, in combination with high abundances and biomass, make vibrios key players in aquatic environments, as well as important pathogens for humans and marine animals. Incidents of Vibrio-associated diseases (vibriosis) in marine aquaculture are being increasingly reported on a global scale, due to the fast growth of the industry over the past few decades years. The administration of antibiotics has been the most commonly applied therapy used to control vibriosis outbreaks, giving rise to concerns about development and spreading of antibiotic-resistant bacteria in the environment. Hence, the idea of using lytic bacteriophages as therapeutic agents against bacterial diseases has been revived during the last years. Bacteriophage therapy constitutes a promising alternative not only for treatment, but also for prevention of vibriosis in aquaculture. However, several scientific and technological challenges still need further investigation before reliable, reproducible treatments with commercial potential are available for the aquaculture industry. The potential and the challenges of phage-based alternatives to antibiotic treatment of vibriosis are addressed in this review. PMID- 29495274 TI - Error Analysis of the K-Rb-21Ne Comagnetometer Space-Stable Inertial Navigation System. AB - According to the application characteristics of the K-Rb-21Ne comagnetometer, a space-stable navigation mechanization is designed and the requirements of the comagnetometer prototype are presented. By analysing the error propagation rule of the space-stable Inertial Navigation System (INS), the three biases, the scale factor of the z-axis, and the misalignment of the x- and y-axis non-orthogonal with the z-axis, are confirmed to be the main error source. A numerical simulation of the mathematical model for each single error verified the theoretical analysis result of the system's error propagation rule. Thus, numerical simulation based on the semi-physical data result proves the feasibility of the navigation scheme proposed in this paper. PMID- 29495275 TI - The Interactions between Host Glycobiology, Bacterial Microbiota, and Viruses in the Gut. AB - Rotavirus (RV) and norovirus (NoV) are the major etiological agents of viral acute gastroenteritis worldwide. Host genetic factors, the histo-blood group antigens (HBGA), are associated with RV and NoV susceptibility and recent findings additionally point to HBGA as a factor modulating the intestinal microbial composition. In vitro and in vivo experiments in animal models established that the microbiota enhances RV and NoV infection, uncovering a triangular interplay between RV and NoV, host glycobiology, and the intestinal microbiota that ultimately influences viral infectivity. Studies on the microbiota composition in individuals displaying different RV and NoV susceptibilities allowed the identification of potential bacterial biomarkers, although mechanistic data on the virus-host-microbiota relation are still needed. The identification of the bacterial and HBGA interactions that are exploited by RV and NoV would place the intestinal microbiota as a new target for alternative therapies aimed at preventing and treating viral gastroenteritis. PMID- 29495276 TI - Avian Respiratory Coinfection and Impact on Avian Influenza Pathogenicity in Domestic Poultry: Field and Experimental Findings. AB - The avian respiratory system hosts a wide range of commensal and potential pathogenic bacteria and/or viruses that interact with each other. Such interactions could be either synergistic or antagonistic, which subsequently determines the severity of the disease complex. The intensive rearing methods of poultry are responsible for the marked increase in avian respiratory diseases worldwide. The interaction between avian influenza with other pathogens can guarantee the continuous existence of other avian pathogens, which represents a global concern. A better understanding of the impact of the interaction between avian influenza virus and other avian respiratory pathogens provides a better insight into the respiratory disease complex in poultry and can lead to improved intervention strategies aimed at controlling virus spread. PMID- 29495277 TI - Study of Impact Damage in PVA-ECC Beam under Low-Velocity Impact Loading Using Piezoceramic Transducers and PVDF Thin-Film Transducers. AB - Compared to conventional concrete, polyvinyl alcohol fiber reinforced engineering cementitious composite (PVA-ECC) offers high-strength, ductility, formability, and excellent fatigue resistance. However, impact-induced structural damage is a major concern and has not been previously characterized in PVA-ECC structures. We investigate the damage of PVA-ECC beams under low-velocity impact loading. A series of ball-drop impact tests were performed at different drop weights and heights to simulate various impact energies. The impact results of PVA-ECC beams were compared with mortar beams. A combination of polyvinylidene fluoride (PVDF) thin-film sensors and piezoceramic-based smart aggregate were used for impact monitoring, which included impact initiation and crack evolution. Short-time Fourier transform (STFT) of the signal received by PVDF thin-film sensors was performed to identify impact events, while active-sensing approach was utilized to detect impact-induced crack evolution by the attenuation of a propagated guided wave. Wavelet packet-based energy analysis was performed to quantify failure development under repeated impact tests. PMID- 29495278 TI - Tolerance and Excretion of the Mycotoxins Aflatoxin B1, Zearalenone, Deoxynivalenol, and Ochratoxin A by Alphitobius diaperinus and Hermetia illucens from Contaminated Substrates. AB - This study aimed to investigate the potential accumulation of mycotoxins in the lesser mealworm (Alphitobius diaperinus, LMW) and black soldier fly (Hermetia illucens, BSF) larvae. Feed was spiked with aflatoxin B1, deoxynivalenol (DON), ochratoxin A or zearalenone, and as a mixture of mycotoxins, to concentrations of 1, 10, and 25 times the maximum limits set by the European Commission for complete feed. This maximum limit is 0.02 mg/kg for aflatoxin B1, 5 mg/kg for DON, 0.5 mg/kg for zearalenone and 0.1 mg/kg for ochratoxin A. The mycotoxins and some of their metabolites were analysed in the larvae and residual material using a validated and accredited LC-MS/MS-based method. Metabolites considered were aflatoxicol, aflatoxin P1, aflatoxin Q1, and aflatoxin M1, 3-acetyl-DON, 15 acetyl-DON and DON-3-glycoside, and alpha- and beta-zearalenol. No differences were observed between larvae reared on mycotoxins individually or as a mixture with regards to both larvae development and mycotoxin accumulation/excretion. None of the mycotoxins accumulated in the larvae and were only detected in BSF larvae several orders of magnitude lower than the concentration in feed. Mass balance calculations showed that BSF and LMW larvae metabolized the four mycotoxins to different extents. Metabolites accounted for minimal amounts of the mass balance, except for zearalenone metabolites in the BSF treatments, which accounted for an average maximum of 86% of the overall mass balance. Both insect species showed to excrete or metabolize the four mycotoxins present in their feed. Hence, safe limits for these mycotoxins in substrates to be used for these two insect species possibly could be higher than for production animals. However, additional analytical and toxicological research to fully understand the safe limits of mycotoxins in insect feed, and thus the safety of the insects, is required. PMID- 29495279 TI - Ten Prominent Host Proteases in Plant-Pathogen Interactions. AB - Proteases are enzymes integral to the plant immune system. Multiple aspects of defence are regulated by proteases, including the hypersensitive response, pathogen recognition, priming and peptide hormone release. These processes are regulated by unrelated proteases residing at different subcellular locations. In this review, we discuss 10 prominent plant proteases contributing to the plant immune system, highlighting the diversity of roles they perform in plant defence. PMID- 29495280 TI - Non-Native Conformational Isomers of the Catalytic Domain of PCSK9 Induce an Immune Response, Reduce Lipids and Increase LDL Receptor Levels. AB - PCSK9 (Proprotein convertase subtilisin/kexin type 9) increases plasma cholesterol levels by promoting LDL receptor degradation. Current antibody inhibitors block the interaction between PCSK9 and LDL receptors, significantly decrease plasma cholesterol levels, and provide beneficial clinical outcomes. To reduce the action of PCSK9 in plasma, a novel strategy that will produce a panel of non-native, conformationally-altered isomers of PCSK9 (X-PCSK9) to develop active immunotherapy targeting of native PCSK9 and inhibiting/blocking the interaction of PCSK9 with LDL receptor, thus decreasing plasma cholesterol levels is proposed. The authors used the scrambled disulfide bond technique to generate conformationally-altered isomers of the catalytic domain of mouse PCSK9. The focus was on the immune response of four X-isomers and their effects on plasma cholesterol and triglyceride levels in both C57BL/6J and Apoe-/- mice. The authors showed that the four immunogens produced significant immunogenicity against native PCSK9 to day 120 after immunization of C57BL/6J and Apoe-/- mice. This resulted in significantly decreased plasma cholesterol levels in C57BL/6J mice, and to a lesser degree in Apoe-/- mice. The X-PCSK9-B1 treated mice had increased LDL receptor mRNA and protein levels at day 120 after treatment. Thus, this study provides a new, potentially promising approach that uses long-term immunotherapy for a treatment of hypercholesterolemia. PMID- 29495282 TI - Refining the Results of a Classical SELEX Experiment by Expanding the Sequence Data Set of an Aptamer Pool Selected for Protein A. AB - New, as yet undiscovered aptamers for Protein A were identified by applying next generation sequencing (NGS) to a previously selected aptamer pool. This pool was obtained in a classical SELEX (Systematic Evolution of Ligands by EXponential enrichment) experiment using the FluMag-SELEX procedure followed by cloning and Sanger sequencing. PA#2/8 was identified as the only Protein A-binding aptamer from the Sanger sequence pool, and was shown to be able to bind intact cells of Staphylococcus aureus. In this study, we show the extension of the SELEX results by re-sequencing of the same aptamer pool using a medium throughput NGS approach and data analysis. Both data pools were compared. They confirm the selection of a highly complex and heterogeneous oligonucleotide pool and show consistently a high content of orphans as well as a similar relative frequency of certain sequence groups. But in contrast to the Sanger data pool, the NGS pool was clearly dominated by one sequence group containing the known Protein A-binding aptamer PA#2/8 as the most frequent sequence in this group. In addition, we found two new sequence groups in the NGS pool represented by PA-C10 and PA-C8, respectively, which also have high specificity for Protein A. Comparative affinity studies reveal differences between the aptamers and confirm that PA#2/8 remains the most potent sequence within the selected aptamer pool reaching affinities in the low nanomolar range of KD = 20 +/- 1 nM. PMID- 29495281 TI - Plant Mitochondrial Inner Membrane Protein Insertion. AB - During the biogenesis of the mitochondrial inner membrane, most nuclear-encoded inner membrane proteins are laterally released into the membrane by the TIM23 and the TIM22 machinery during their import into mitochondria. A subset of nuclear encoded mitochondrial inner membrane proteins and all the mitochondrial-encoded inner membrane proteins use the Oxa machinery-which is evolutionarily conserved from the endosymbiotic bacterial ancestor of mitochondria-for membrane insertion. Compared to the mitochondria from other eukaryotes, plant mitochondria have several unique features, such as a larger genome and a branched electron transport pathway, and are also involved in additional cellular functions such as photorespiration and stress perception. This review focuses on the unique aspects of plant mitochondrial inner membrane protein insertion machinery, which differs from that in yeast and humans, and includes a case study on the biogenesis of Cox2 in yeast, humans, two plant species, and an algal species to highlight lineage-specific similarities and differences. Interestingly, unlike mitochondria of other eukaryotes but similar to bacteria and chloroplasts, plant mitochondria appear to use the Tat machinery for membrane insertion of the Rieske Fe/S protein. PMID- 29495283 TI - Fowl Adenovirus 4 (FAdV-4)-Based Infectious Clone for Vaccine Vector Development and Viral Gene Function Studies. AB - Fowl adenovirus 4 (FAdV-4) is associated with economically important poultry diseases. Recent studies of fully sequenced genomes of FAdV-4 isolates suggest potential genomic regions associated with virulence and amenable for manipulation and vector development. Direct manipulation of viral genomes is cumbersome, as opposed to that of infectious clones-viral genomes cloned into plasmid or cosmid vectors. In this work, we generated an infectious clone, pFAdV-4 ON1, containing the entire viral genome of a nonpathogenic FAdV-4 (ON1 isolate). pFAdV-4 ON1 was used for targeted deletion of open reading frames (ORFs) 16 and 17 and replacement with the enhanced green fluorescence protein (EGFP) expression cassette to generate recombinant viruses. These viruses were viable, and EGFP was expressed in infected cells. Their replication, however, was significantly reduced with respect to that of the wild-type virus. These observations suggest the potential utility of FAdV-4 as a vaccine vector and the importance of ORFs 16 and 17 for virus replication at wild-type levels. To our knowledge, this is the first report of an infectious clone based on the FAdV-4 genome, and our results demonstrate its utility for studies of virulence determinants and as a platform for either vaccine or gene delivery vectors. PMID- 29495284 TI - Discovery of Flavonoids from Scutellaria baicalensis with Inhibitory Activity Against PCSK 9 Expression: Isolation, Synthesis and Their Biological Evaluation. AB - Nine flavonoids were isolated and identified from a chloroform-soluble fraction of the roots of Scutellaria baicalensis through a bioactivity-guided fractionation using a proprotein convertase subtilisin/kexin type 9 (PCSK9) monitoring assay in HepG2 cells. All structures were established by interpreting the corresponding spectroscopic data and comparing measured values from those in the literature. All compounds were assessed for their ability to inhibit PCSK9 mRNA expression; compounds 1 (3,7,2'-trihydroxy-5-methoxy-flavanone) and 4 (skullcapflavone II) were found to suppress PCSK9 mRNA via SREBP-1. Furthermore, compound 1 was found to increase low-density lipoprotein receptor protein expression. Also, synthesis of compound 1 as a racemic mixture form (1a) was completed for the first time. Natural compound 1 and synthetic racemic 1a were evaluated for their inhibitory activities against PCSK9 mRNA expression and the results confirmed the stereochemistry of 1 was important. PMID- 29495285 TI - Separation of Seven Polyphenols from the Rhizome of Smilax glabra by Offline Two Dimension Recycling HSCCC with Extrusion Mode. AB - An offline two-dimensional recycling high-speed countercurrent chromatography (2D R-HSCCC) strategy with extrusion mode was developed for isolating polyphenols from the rhizome of Smilax glabra. Firstly, the ethyl acetate extract was divided into two fractions, Fr.1 and Fr.2, by silica gel column chromatography. Then, HSCCC was applied to separate polyphenols from the two fractions using a solvent system consisting of petroleum ether-ethyl acetate-methanol-water (1:3:0.5:5, v/v). Fifty milligrams of Fr.1 was separated by conventional HSCCC, yielding 5-O caffeoylshikimic acid (1, 15.8 mg) and taxifolin (2, 4.8 mg). Offline 2D R-HSCCC with extrusion mode was used to separate Fr.2, and astilbin (4, 37.3 mg), neoisoastilbin (5, 8.8 mg), engeletin (7, 7.9 mg), and a mixture of two polyphenols were obtained from 100 mg of Fr.2. The mixture of two polyphenols was further separated by pre-HPLC, yielding neoastilbin (3, 15.2 mg) and isoastilbin (6, 9.9 mg). The purities of these seven compounds were all over 96.0%. Their structures were identified by MS and NMR. The results demonstrated that the strategy based on offline 2D R-HSCCC with extrusion mode was a powerful tool to separate the main compounds from the rhizome of Smilax glabra and valued for the preparative separation compounds with broad K-values and similar structures. PMID- 29495286 TI - Triterpene Acids from Frankincense and Semi-Synthetic Derivatives That Inhibit 5 Lipoxygenase and Cathepsin G. AB - Age-related diseases, such as osteoarthritis, Alzheimer's disease, diabetes, and cardiovascular disease, are often associated with chronic unresolved inflammation. Neutrophils play central roles in this process by releasing tissue degenerative proteases, such as cathepsin G, as well as pro-inflammatory leukotrienes produced by the 5-lipoxygenase (5-LO) pathway. Boswellic acids (BAs) are pentacyclic triterpene acids contained in the gum resin of the anti inflammatory remedy frankincense that target cathepsin G and 5-LO in neutrophils, and might thus represent suitable leads for intervention with age-associated diseases that have a chronic inflammatory component. Here, we investigated whether, in addition to BAs, other triterpene acids from frankincense interfere with 5-LO and cathepsin G. We provide a comprehensive analysis of 17 natural tetra- or pentacyclic triterpene acids for suppression of 5-LO product synthesis in human neutrophils. These triterpene acids were also investigated for their direct interference with 5-LO and cathepsin G in cell-free assays. Furthermore, our studies were expanded to 10 semi-synthetic BA derivatives. Our data reveal that besides BAs, several tetra- and pentacyclic triterpene acids are effective or even superior inhibitors of 5-LO product formation in human neutrophils, and in parallel, inhibit cathepsin G. Their beneficial target profile may qualify triterpene acids as anti-inflammatory natural products and pharmacological leads for intervention with diseases related to aging. PMID- 29495287 TI - Resveratrol-Inspired Benzo[b]selenophenes Act as Anti-Oxidants in Yeast. AB - Resveratrol is a natural (poly)phenol primarily found in plants protecting them against pathogens, as well as harmful effects of physical and chemical agents. In higher eukaryotic cells and organisms, this compound displays a remarkable range of biological activities, such as anti-oxidant, anti-inflammatory, anti-cancer, anti-aging, cardio- and neuro-protective properties. Here, biological activities of synthetic selenium-containing derivatives of resveratrol-benzo[b]selenophenes have been studied in lower eukaryotes Saccharomyces cerevisiae. Their toxicity, as well as DNA damaging and reactive oxygen species (ROS) inducing potencies, manifested through their ability to act as redox active anti-microbial agents, have been examined. We show that some benzo[b]selenophenes can kill yeast cells and that the killing effects are not mediated by DNA damage types that can be detected as DNA double-strand breaks. These benzo[b]selenophenes could potentially be used as anti-fungal agents, although their concentrations relevant to application in humans need to be further evaluated. In addition, most of the studied benzo[b]selenophenes display redox-modulating/anti-oxidant activity (comparable or even higher than that of resveratrol or Trolox) causing a decrease in the intracellular ROS levels in yeast cells. Therefore, after careful re evaluation in other biological systems these observations might be transferred to humans, where resveratrol-inspired benzo[b]selenophenes could be used as supra anti-oxidant supplements. PMID- 29495288 TI - Intake of 3 Eggs per Day When Compared to a Choline Bitartrate Supplement, Downregulates Cholesterol Synthesis without Changing the LDL/HDL Ratio. AB - Cardiovascular disease (CVD) risk is associated with high concentrations of low density lipoprotein cholesterol (LDL-C). The impact of dietary cholesterol on plasma lipid concentrations still remains a concern. The effects of egg intake in comparison to choline bitartrate supplement was studied in a young, healthy population. Thirty participants were enrolled for a 13-week intervention. After a 2-week run-in period, subjects were randomized to consume either 3 eggs/day or a choline bitartrate supplement (~400 mg choline for both treatments) for 4-weeks each. After a 3-week washout period, they were allocated to the alternate treatment. Dietary records, plasma lipids, apolipoproteins (apo) concentrations, and peripheral blood mononuclear cell expression of regulatory genes for cholesterol homeostasis were assessed at the end of each intervention. Dietary intakes of saturated and monounsaturated fat were higher with the consumption of eggs compared to the choline period. In addition, higher plasma concentrations of total cholesterol (7.5%), high density lipoprotein cholesterol (HDL-C) (5%) and LDL-C (8.1%) were observed with egg consumption (p < 0.01), while no change was seen in LDL-C/HDL-C ratio, a key marker of heart disease risk. Compared to choline supplementation, intake of eggs resulted in higher concentrations of plasma apoA-I (8%) and apoE (17%) with no changes in apoB. Sterol regulatory element-binding protein 2 and 3-hydroxy-3-methylglutaryl-CoA reductase expression were lower with egg consumption by 18% and 31%, respectively (p < 0.05), suggesting a compensation to the increased dietary cholesterol load. Therefore, dietary cholesterol from eggs appears to regulate endogenous synthesis of cholesterol in such a way that the LDL-C/HDL-C ratio is maintained. PMID- 29495289 TI - Algal Blooms and Cyanotoxins in Jordan Lake, North Carolina. AB - The eutrophication of waterways has led to a rise in cyanobacterial, harmful algal blooms (CyanoHABs) worldwide. The deterioration of water quality due to excess algal biomass in lakes has been well documented (e.g., water clarity, hypoxic conditions), but health risks associated with cyanotoxins remain largely unexplored in the absence of toxin information. This study is the first to document the presence of dissolved microcystin, anatoxin-a, cylindrospermopsin, and beta-N-methylamino-l-alanine in Jordan Lake, a major drinking water reservoir in North Carolina. Saxitoxin presence was not confirmed. Multiple toxins were detected at 86% of the tested sites and during 44% of the sampling events between 2014 and 2016. Although concentrations were low, continued exposure of organisms to multiple toxins raises some concerns. A combination of discrete sampling and in-situ tracking (Solid Phase Adsorption Toxin Tracking [SPATT]) revealed that microcystin and anatoxin were the most pervasive year-round. Between 2011 and 2016, summer and fall blooms were dominated by the same cyanobacterial genera, all of which are suggested producers of single or multiple cyanotoxins. The study's findings provide further evidence of the ubiquitous nature of cyanotoxins, and the challenges involved in linking CyanoHAB dynamics to specific environmental forcing factors are discussed. PMID- 29495290 TI - A Feasibility Study on the Use of a Structured Light Depth-Camera for Three Dimensional Body Measurements of Dairy Cows in Free-Stall Barns. AB - Frequent checks on livestock's body growth can help reducing problems related to cow infertility or other welfare implications, and recognizing health's anomalies. In the last ten years, optical methods have been proposed to extract information on various parameters while avoiding direct contact with animals' body, generally causes stress. This research aims to evaluate a new monitoring system, which is suitable to frequently check calves and cow's growth through a three-dimensional analysis of their bodies' portions. The innovative system is based on multiple acquisitions from a low cost Structured Light Depth-Camera (Microsoft KinectTM v1). The metrological performance of the instrument is proved through an uncertainty analysis and a proper calibration procedure. The paper reports application of the depth camera for extraction of different body parameters. Expanded uncertainty ranging between 3 and 15 mm is reported in the case of ten repeated measurements. Coefficients of determination R2 > 0.84 and deviations lower than 6% from manual measurements where in general detected in the case of head size, hips distance, withers to tail length, chest girth, hips, and withers height. Conversely, lower performances where recognized in the case of animal depth (R2 = 0.74) and back slope (R2 = 0.12). PMID- 29495291 TI - Towards an Iterated Game Model with Multiple Adversaries in Smart-World Systems. AB - Diverse and varied cyber-attacks challenge the operation of the smart-world system that is supported by Internet-of-Things (IoT) (smart cities, smart grid, smart transportation, etc.) and must be carefully and thoughtfully addressed before widespread adoption of the smart-world system can be fully realized. Although a number of research efforts have been devoted to defending against these threats, a majority of existing schemes focus on the development of a specific defensive strategy to deal with specific, often singular threats. In this paper, we address the issue of coalitional attacks, which can be launched by multiple adversaries cooperatively against the smart-world system such as smart cities. Particularly, we propose a game-theory based model to capture the interaction among multiple adversaries, and quantify the capacity of the defender based on the extended Iterated Public Goods Game (IPGG) model. In the formalized game model, in each round of the attack, a participant can either cooperate by participating in the coalitional attack, or defect by standing aside. In our work, we consider the generic defensive strategy that has a probability to detect the coalitional attack. When the coalitional attack is detected, all participating adversaries are penalized. The expected payoff of each participant is derived through the equalizer strategy that provides participants with competitive benefits. The multiple adversaries with the collusive strategy are also considered. Via a combination of theoretical analysis and experimentation, our results show that no matter which strategies the adversaries choose (random strategy, win-stay-lose-shift strategy, or even the adaptive equalizer strategy), our formalized game model is capable of enabling the defender to greatly reduce the maximum value of the expected average payoff to the adversaries via provisioning sufficient defensive resources, which is reflected by setting a proper penalty factor against the adversaries. In addition, we extend our game model and analyze the extortion strategy, which can enable one participant to obtain more payoff by extorting his/her opponents. The evaluation results show that the defender can combat this strategy by encouraging competition among the adversaries, and significantly suppress the total payoff of the adversaries via setting the proper penalty factor. PMID- 29495292 TI - Recent Evidence on Bioactive Glass Antimicrobial and Antibiofilm Activity: A Mini Review. AB - Bone defects caused by trauma or pathological events are major clinical and socioeconomic burdens. Thus, the efforts of regenerative medicine have been focused on the development of non-biodegradable materials resembling bone features. Consequently, the use of bioactive glass as a promising alternative to inert graft materials has been proposed. Bioactive glass is a synthetic silica based material with excellent mechanical properties able to bond to the host bone tissue. Indeed, when immersed in physiological fluids, bioactive glass reacts, developing an apatite layer on the granule's surface, playing a key role in the osteogenesis process. Moreover, the contact of bioactive glass with biological fluids results in the increase of osmotic pressure and pH due to the leaching of ions from granules' surface, thus making the surrounding environment hostile to microbial growth. The bioactive glass antimicrobial activity is effective against a wide selection of aerobic and anaerobic bacteria, either in planktonic or sessile forms. Furthermore, bioglass is able to reduce pathogens' biofilm production. For the aforementioned reasons, the use of bioactive glass might be a promising solution for the reconstruction of bone defects, as well as for the treatment and eradication of bone infections, characterized by bone necrosis and destruction of the bone structure. PMID- 29495293 TI - Tetrocarcin Q, a New Spirotetronate with a Unique Glycosyl Group from a Marine Derived Actinomycete Micromonospora carbonacea LS276. AB - A new spirotetronate glycoside tetrocarcin Q (1) and six known analogues tetrocarcin A (2), AC6H (3), tetrocarcin N (4), tetrocarcin H (5), arisostatin A (6), and tetrocarcin F1 (7) were isolated from the fermentation broth of the marine-derived actinomycete Micromonospora carbonacea LS276. Their chemical structures were established on the basis of 1D- and 2D-NMR spectroscopy, as well as HR-ESI-MS analysis. The absolute configurations of their stereogenic carbons were determined by circular dichroism (CD) analysis. Compound 1 possesses 2-deoxy allose, which is a unique sugar type at the C-9 position. This type has not been found in the previously reported spirotetronate glycosides. Compound 1 displayed moderate antibacterial activity against Bacillus subitlis ATCC 63501 with minimum inhibitory concentration (MIC) value of 12.5 MUM. PMID- 29495294 TI - Integrated Affinity Biosensing Platforms on Screen-Printed Electrodes Electrografted with Diazonium Salts. AB - Adequate selection of the electrode surface and the strategies for its modification to enable subsequent immobilization of biomolecules and/or nanomaterials integration play a major role in the performance of electrochemical affinity biosensors. Because of the simplicity, rapidity and versatility, electrografting using diazonium salt reduction is among the most currently used functionalization methods to provide the attachment of an organic layer to a conductive substrate. This particular chemistry has demonstrated to be a powerful tool to covalently immobilize in a stable and reproducible way a wide range of biomolecules or nanomaterials onto different electrode surfaces. Considering the great progress and interesting features arisen in the last years, this paper outlines the potential of diazonium chemistry to prepare single or multianalyte electrochemical affinity biosensors on screen-printed electrodes (SPEs) and points out the existing challenges and future directions in this field. PMID- 29495295 TI - An Automatic and Novel SAR Image Registration Algorithm: A Case Study of the Chinese GF-3 Satellite. AB - The Chinese GF-3 satellite launched in August 2016 is a Synthetic Aperture Radar (SAR) satellite that has the largest number of imaging modes in the world. It achieves a free switch in the spotlight, stripmap, scanSAR, wave, global observation and other imaging modes. In order to further utilize GF-3 SAR images, an automatic and fast image registration procedure needs to be done. In this paper, we propose a novel image registration technique for GF-3 images of different imaging modes. The proposed algorithm consists of two stages: coarse registration and fine registration. In the first stage, we combine an adaptive sampling method with the SAR-SIFT algorithm to efficiently eliminate obvious translation, rotation and scale differences between the reference and sensed images. In the second stage, uniformly-distributed control points are extracted, then the fast normalized cross-correlation of an improved phase congruency model is utilized as a new similarity metric to match the reference image and the coarse-registered image in a local search region. Moreover, a selection strategy is used to remove outliers. Experimental results on several GF-3 SAR images of different imaging modes show that the proposed algorithm gives a robust, efficient and precise registration performance, compared with other state-of-the art algorithms for SAR image registration. PMID- 29495296 TI - Production of Curcumin-Loaded Silk Fibroin Nanoparticles for Cancer Therapy. AB - Curcumin, extracted from the rhizome of Curcuma longa, has been widely used in medicine for centuries due to its anti-inflammatory, anti-cancer, anti-oxidant and anti-microbial effects. However, its bioavailability during treatments is poor because of its low solubility in water, slow dissolution rate and rapid intestinal metabolism. For these reasons, improving the therapeutic efficiency of curcumin using nanocarriers (e.g., biopolymer nanoparticles) has been a research focus, to foster delivery of the curcumin inside cells due to their small size and large surface area. Silk fibroin from the Bombyx mori silkworm is a biopolymer characterized by its biocompatibility, biodegradability, amphiphilic chemistry, and excellent mechanical properties in various material formats. These features make silk fibroin nanoparticles useful vehicles for delivering therapeutic drugs, such as curcumin. Curcumin-loaded silk fibroin nanoparticles were synthesized using two procedures (physical adsorption and coprecipitation) more scalable than methods previously described using ionic liquids. The results showed that nanoparticle formulations were 155 to 170 nm in diameter with a zeta potential of approximately -45 mV. The curcumin-loaded silk fibroin nanoparticles obtained by both processing methods were cytotoxic to carcinogenic cells, while not decreasing viability of healthy cells. In the case of tumor cells, curcumin loaded silk fibroin nanoparticles presented higher efficacy in cytotoxicity against neuroblastoma cells than hepatocarcinoma cells. In conclusion, curcumin loaded silk fibroin nanoparticles constitute a biodegradable and biocompatible delivery system with the potential to treat tumors by local, long-term sustained drug delivery. PMID- 29495297 TI - Fine Physical Bin Mapping of the Powdery Mildew Resistance Gene Pm21 Based on Chromosomal Structural Variations in Wheat. AB - Pm21, derived from wheat wild relative Dasypyrum villosum, is one of the most effective powdery mildew resistance genes and has been widely applied in wheat breeding in China. Mapping and cloning Pm21 are of importance for understanding its resistance mechanism. In the present study, physical mapping was performed using different genetic stocks involving in structural variations of chromosome 6VS carrying Pm21. The data showed that 6VS could be divided into eight distinguishable chromosomal bins, and Pm21 was mapped to the bin FLb4-b5/b6 closely flanked by the markers 6VS-08.6 and 6VS-10.2. Comparative genomic mapping indicated that the orthologous regions of FLb4-b5/b6 carrying Pm21 were narrowed to a 117.7 kb genomic region harboring 19 genes in Brachypodium and a 37.7 kb region harboring 5 genes in rice, respectively. The result was consistent with that given by recent genetic mapping in diploid D. villosum. In conclusion, this study demonstrated that physical mapping based on chromosomal structural variations is an efficient method for locating alien genes in wheat background. PMID- 29495298 TI - Transcranial Direct Current Stimulation for Obsessive-Compulsive Disorder: A Systematic Review. AB - Despite the advances in psychopharmacology and established psychotherapeutic interventions, more than 40% of patients with obsessive-compulsive disorder (OCD) do not respond to conventional treatment approaches. Transcranial direct current stimulation (tDCS) has been recently proposed as a therapeutic tool to alleviate treatment-resistant symptoms in patients with OCD. The aim of this review was to provide a comprehensive overview of the current state of the art and future clinical applications of tDCS in patients with OCD. A literature search conducted on the PubMed database following PRISMA guidelines and completed by a manual search yielded 12 results: eight case reports, three open-label studies (with 5, 8, and 42 participants), and one randomized trial with two active conditions (12 patients). There was no sham-controlled study. A total of 77 patients received active tDCS with a large diversity of electrode montages mainly targeting the dorsolateral prefrontal cortex, the orbitofrontal cortex or the (pre-) supplementary motor area. Despite methodological limitations and the heterogeneity of stimulation parameters, tDCS appears to be a promising tool to decrease obsessive-compulsive symptoms as well as comorbid depression and anxiety in patients with treatment-resistant OCD. Further sham-controlled studies are needed to confirm these preliminary results. PMID- 29495300 TI - Quadrature Errors and DC Offsets Calibration of Analog Complex Cross-Correlator for Interferometric Passive Millimeter-Wave Imaging Applications. AB - The design and calibration of the cross-correlator are crucial issues for interferometric imaging systems. In this paper, an analog complex cross correlator with output DC offsets and amplitudes calibration capability is proposed for interferometric passive millimeter-wave security sensing applications. By employing digital potentiometers in the low frequency amplification circuits of the correlator, the outputs characteristics of the correlator could be digitally controlled. A measurement system and a corresponding calibration scheme were developed in order to eliminate the output DC offsets and the quadrature amplitude error between the in-phase and the quadrature correlating subunits of the complex correlator. By using vector modulators to provide phase controllable correlated noise signals, the measurement system was capable of obtaining the output correlation circle of the correlator. When injected with -18 dBm correlated noise signals, the calibrated quadrature amplitude error was 0.041 dB and the calibrated DC offsets were under 26 mV, which was only 7.1% of the uncalibrated value. Furthermore, we also described a quadrature errors calibration algorithm in order to estimate the quadrature phase error and in order to improve the output phase accuracy of the correlator. After applying this calibration, we were able to reduce the output phase error of the correlator to 0.3 degrees . PMID- 29495299 TI - An Automatic Gait Feature Extraction Method for Identifying Gait Asymmetry Using Wearable Sensors. AB - This paper aims to assess the use of Inertial Measurement Unit (IMU) sensors to identify gait asymmetry by extracting automatic gait features. We design and develop an android app to collect real time synchronous IMU data from legs. The results from our method are validated using a Qualisys Motion Capture System. The data are collected from 10 young and 10 older subjects. Each performed a trial in a straight corridor comprising 15 strides of normal walking, a turn around and another 15 strides. We analyse the data for total distance, total time, total velocity, stride, step, cadence, step ratio, stance, and swing. The accuracy of detecting the stride number using the proposed method is 100% for young and 92.67% for older subjects. The accuracy of estimating travelled distance using the proposed method for young subjects is 97.73% and 98.82% for right and left legs; and for the older, is 88.71% and 89.88% for right and left legs. The average travelled distance is 37.77 (95% CI +/- 3.57) meters for young subjects and is 22.50 (95% CI +/- 2.34) meters for older subjects. The average travelled time for young subjects is 51.85 (95% CI +/- 3.08) seconds and for older subjects is 84.02 (95% CI +/- 9.98) seconds. The results show that wearable sensors can be used for identifying gait asymmetry without the requirement and expense of an elaborate laboratory setup. This can serve as a tool in diagnosing gait abnormalities in individuals and opens the possibilities for home based self-gait asymmetry assessment. PMID- 29495301 TI - Low Computational Signal Acquisition for GNSS Receivers Using a Resampling Strategy and Variable Circular Correlation Time. AB - For the objective of essentially decreasing computational complexity and time consumption of signal acquisition, this paper explores a resampling strategy and variable circular correlation time strategy specific to broadband multi-frequency GNSS receivers. In broadband GNSS receivers, the resampling strategy is established to work on conventional acquisition algorithms by resampling the main lobe of received broadband signals with a much lower frequency. Variable circular correlation time is designed to adapt to different signal strength conditions and thereby increase the operation flexibility of GNSS signal acquisition. The acquisition threshold is defined as the ratio of the highest and second highest correlation results in the search space of carrier frequency and code phase. Moreover, computational complexity of signal acquisition is formulated by amounts of multiplication and summation operations in the acquisition process. Comparative experiments and performance analysis are conducted on four sets of real GPS L2C signals with different sampling frequencies. The results indicate that the resampling strategy can effectively decrease computation and time cost by nearly 90-94% with just slight loss of acquisition sensitivity. With circular correlation time varying from 10 ms to 20 ms, the time cost of signal acquisition has increased by about 2.7-5.6% per millisecond, with most satellites acquired successfully. PMID- 29495302 TI - Physicochemical Characterization and Functional Analysis of the Polysaccharide from the Edible Microalga Nostoc sphaeroides. AB - Nostoc colonies have been used as food and medicine for centuries, and their main supporting matrix is polysaccharides, which help Nostoc cells resist various environmental stresses including oxidative stress. Here we isolated a polysaccharide, nostoglycan, from cultured Nostocsphaeroides colonies and determined its physicochemical properties, which revealed a characteristic infrared absorption spectrum typical of polysaccharides and an amorphous morphology with rough surfaces. We also show that nostoglycan has strong moisture absorption and retention capacities and a high relative viscosity. Using Caenorhabditis elegans models, we then demonstrate that nostoglycan is capable of improving overall survival rate of the animals under increased oxidative stress caused by paraquat. Nostoglycan also reduces reactive oxygen species level, inhibits protein carbonyl formation and lipid peroxidation, and increases activities of superoxide dismutase and catalase in paraquat-exposed nematodes. As oxidative stress may drive tumor progression, we further demonstrate that nostoglycan can suppress the proliferation of several types of tumor cells and induce apoptosis of human lung adenocarcinoma A549 cells via caspase-3 activation. Together, our results yield important information on the physicochemical characteristics and demonstrate the antioxidant and anti proliferative functions of nostoglycan, and thus provide an insight into its potential in food and health industries. PMID- 29495304 TI - Mesoscopic Constitutive Model for Predicting Failure of Bulk Metallic Glass Composites Based on the Free-Volume Model. AB - A meso-mechanical damage model is developed to predict the tensile damage behaviors of bulk metallic glass composites (BMGCs) toughened by ductile particles. In this model, the deformation behaviors of the BMG matrix and particles are described by the free volume model and Ludwik flow equation, respectively. Weng's dual-phase method is used to establish the relationship between the constituents and the composite system. The strain-based Weibull probability distribution function and percolation theory are adopted in characterizing the evolution of shear bands leading to the progressive failure of BMGCs. Moreover, the present model is performed under strain-controlled loading. Comparing to experiments on various BMGCs, the predictions are in good agreement with the measured results, which confirms that the present model successfully depicts the composite properties, such as yield strength, uniform deformation and strain softening elongation. PMID- 29495303 TI - Mitochondria: Central Organelles for Melatonin's Antioxidant and Anti-Aging Actions. AB - Melatonin, along with its metabolites, have long been known to significantly reduce the oxidative stress burden of aging cells or cells exposed to toxins. Oxidative damage is a result of free radicals produced in cells, especially in mitochondria. When measured, melatonin, a potent antioxidant, was found to be in higher concentrations in mitochondria than in other organelles or subcellular locations. Recent evidence indicates that mitochondrial membranes possess transporters that aid in the rapid uptake of melatonin by these organelles against a gradient. Moreover, we predicted several years ago that, because of their origin from melatonin-producing bacteria, mitochondria likely also synthesize melatonin. Data accumulated within the last year supports this prediction. A high content of melatonin in mitochondria would be fortuitous, since these organelles produce an abundance of free radicals. Thus, melatonin is optimally positioned to scavenge the radicals and reduce the degree of oxidative damage. In light of the "free radical theory of aging", including all of its iterations, high melatonin levels in mitochondria would be expected to protect against age-related organismal decline. Also, there are many age-associated diseases that have, as a contributing factor, free radical damage. These multiple diseases may likely be deferred in their onset or progression if mitochondrial levels of melatonin can be maintained into advanced age. PMID- 29495305 TI - Characterization of the Lytic Capability of a LysK-Like Endolysin, Lys-phiSA012, Derived from a Polyvalent Staphylococcus aureus Bacteriophage. AB - Antibiotic-resistant bacteria (ARB) have spread widely and rapidly, with their increased occurrence corresponding with the increased use of antibiotics. Infections caused by Staphylococcus aureus have a considerable negative impact on human and livestock health. Bacteriophages and their peptidoglycan hydrolytic enzymes (endolysins) have received significant attention as novel approaches against ARB, including S. aureus. In the present study, we purified an endolysin, Lys-phiSA012, which harbors a cysteine/histidine-dependent amidohydrolase/peptidase (CHAP) domain, an amidase domain, and a SH3b cell wall binding domain, derived from a polyvalent S. aureus bacteriophage which we reported previously. We demonstrate that Lys-phiSA012 exhibits high lytic activity towards staphylococcal strains, including methicillin-resistant S. aureus (MRSA). Analysis of deletion mutants showed that only mutants possessing the CHAP and SH3b domains could lyse S. aureus, indicating that lytic activity of the CHAP domain depended on the SH3b domain. The presence of at least 1 mM Ca2+ and 100 uM Zn2+ enhanced the lytic activity of Lys-phiSA012 in a turbidity reduction assay. Furthermore, a minimum inhibitory concentration (MIC) assay showed that the addition of Lys-phiSA012 decreased the MIC of oxacillin. Our results suggest that endolysins are a promising approach for replacing current antimicrobial agents and may contribute to the proper use of antibiotics, leading to the reduction of ARB. PMID- 29495306 TI - Sharply Reduced but Still Heavy Self-Harm Burdens in Hubei Province, China, 1990 2015. AB - The aims of this study were to describe fatal and non-fatal self-harm burdens, as well as burdens from the main preventable risk factors, and to investigate the different suicide methods in Hubei province in central China utilizing data from both Global Burden of Disease Study 2015 and Hubei Disease Surveillance Points system. All self-harm burdens including mortality, years of life lost (YLLs), prevalence, years lived with disability (YLDs), and disability adjusted life years (DALYs) consistently demonstrated downward trends in Hubei from 1990 to 2015, with a bigger decline gap observed among females and narrower decreasing amplitudes among the elderly. Hubei experienced much higher age-standardized rates for self-harm mortality (22.0 per 100,000), YLLs (560.1 per 100,000) and DALYs (563.9 per 100,000) than the national (9.0, 292.3 and 295.0 per 100,000 respectively) and global levels (11.5, 453.3 and 457.9 per 100,000 respectively) in 2015. Self-harm burdens have begun shifting from females to males and the elderly suffered more self-harm burdens than other age groups. Alcohol use accounted for 20.9% of all self-harm DALYs for males, whereas intimate partner violence accounted for 24.4% of all self-harm DALYs for females. Poisoning, mainly pesticide self-poisoning, was still the most common method of suicide. Effective interventions by multi-sectoral collaboration are urgently needed to reduce the alarmingly heavy self-harm burdens in Hubei. PMID- 29495307 TI - Preparing Physical and Occupational Therapists to Be Health Promotion Practitioners: A Call for Action. AB - Experts around the world support the integration of health promotion and wellness (HPW) services into traditional health care services. If successfully executed, the addition of HPW services would reduce rates of death and disability and significantly reduce health care costs. While all health care providers should be engaged in providing HPW services, many believe that physical therapists (PTs) and occupational therapists (OTs) are uniquely positioned to provide these services. However, research suggests that clinicians in both fields may fall short in doing so. Likewise, research indicates that entry-level educational programs inadequately prepare PT and OT students to be HPW practitioners. The overall purpose of this paper is to provide recommendations to educators for preparing PT and OT students and clinicians to better meet the HPW needs of the clients and patients they serve. PMID- 29495310 TI - Comparison of Feature Learning Methods for Human Activity Recognition Using Wearable Sensors. AB - Getting a good feature representation of data is paramount for Human Activity Recognition (HAR) using wearable sensors. An increasing number of feature learning approaches-in particular deep-learning based-have been proposed to extract an effective feature representation by analyzing large amounts of data. However, getting an objective interpretation of their performances faces two problems: the lack of a baseline evaluation setup, which makes a strict comparison between them impossible, and the insufficiency of implementation details, which can hinder their use. In this paper, we attempt to address both issues: we firstly propose an evaluation framework allowing a rigorous comparison of features extracted by different methods, and use it to carry out extensive experiments with state-of-the-art feature learning approaches. We then provide all the codes and implementation details to make both the reproduction of the results reported in this paper and the re-use of our framework easier for other researchers. Our studies carried out on the OPPORTUNITY and UniMiB-SHAR datasets highlight the effectiveness of hybrid deep-learning architectures involving convolutional and Long-Short-Term-Memory (LSTM) to obtain features characterising both short- and long-term time dependencies in the data. PMID- 29495309 TI - Identifying Biomarkers of Wharton's Jelly Mesenchymal Stromal Cells Using a Dynamic Metabolic Model: The Cell Passage Effect. AB - Because of their unique ability to modulate the immune system, mesenchymal stromal cells (MSCs) are widely studied to develop cell therapies for detrimental immune and inflammatory disorders. However, controlling the final cell phenotype and determining immunosuppressive function following cell amplification in vitro often requires prolonged cell culture assays, all of which contribute to major bottlenecks, limiting the clinical emergence of cell therapies. For instance, the multipotent Wharton's Jelly mesenchymal stem/stromal cells (WJMSC), extracted from human umbilical cord, exhibit immunosuppressive traits under pro inflammatory conditions, in the presence of interferon-gamma (IFNgamma), and tumor necrosis factor-alpha (TNFalpha). However, WJMSCs require co-culture bioassays with immune cells, which can take days, to confirm their immunomodulatory function. Therefore, the establishment of robust cell therapies would benefit from fast and reliable characterization assays. To this end, we have explored the metabolic behaviour of WJMSCs in in vitro culture, to identify biomarkers that are specific to the cell passage effect and the loss of their immunosuppressive phenotype. We clearly show distinct metabolic behaviours comparing WJMSCs at the fourth (P4) and the late ninth (P9) passages, although both P4 and P9 cells do not exhibit significant differences in their low immunosuppressive capacity. Metabolomics data were analysed using an in silico modelling platform specifically adapted to WJMSCs. Of interest, P4 cells exhibit a glycolytic metabolism compared to late passage (P9) cells, which show a phosphorylation oxidative metabolism, while P4 cells show a doubling time of 29 h representing almost half of that for P9 cells (46 h). We also clearly show that fourth passage WJMSCs still express known immunosuppressive biomarkers, although, this behaviour shows overlapping with a senescence phenotype. PMID- 29495308 TI - The Peripheral and Intratumoral Immune Cell Landscape in Cancer Patients: A Proxy for Tumor Biology and a Tool for Outcome Prediction. AB - Functional systemic and local immunity is required for effective anti-tumor responses. In addition to an active engagement with cancer cells and tumor stroma, immune cells can be affected and are often found to be dysregulated in cancer patients. The impact of tumors on local and systemic immunity can be assessed using a variety of approaches ranging from low-dimensional analyses that are performed on large patient cohorts to multi-dimensional assays that are technically and logistically challenging and are therefore confined to a limited sample size. Many of these strategies have been established in recent years leading to exciting findings. Not only were analyses of immune cells in tumor patients able to predict the clinical course of the disease and patients' survival, numerous studies also detected changes in the immune landscape that correlated with responses to novel immunotherapies. This review will provide an overview of established and novel tools for assessing immune cells in tumor patients and will discuss exemplary studies that utilized these techniques to predict patient outcomes. PMID- 29495312 TI - Effects of Temperature and Pressure of Hot Isostatic Pressing on the Grain Structure of Powder Metallurgy Superalloy. AB - The microstructure with homogeneously distributed grains and less prior particle boundary (PPB) precipitates is always desired for powder metallurgy superalloys after hot isostatic pressing (HIPping). In this work, we studied the effects of HIPping parameters, temperature and pressure on the grain structure in PM superalloy FGH96, by means of scanning electron microscope (SEM), electron backscatter diffraction (EBSD), transmission electron microscope (TEM) and Time of-flight secondary ion spectrometry (ToF-SIMS). It was found that temperature and pressure played different roles in controlling PPB precipitation and grain structure during HIPping, the tendency of grain coarsening under high temperature could be inhibited by increasing HIPping pressure which facilitates the recrystallization. In general, relatively high temperature and pressure of HIPping were preferred to obtain an as-HIPped superalloy FGH96 with diminished PPB precipitation and homogeneously refined grains. PMID- 29495311 TI - Development and Validation of a Novel Dual Luciferase Reporter Gene Assay to Quantify Ebola Virus VP24 Inhibition of IFN Signaling. AB - The interferon (IFN) system is the first line of defense against viral infections. Evasion of IFN signaling by Ebola viral protein 24 (VP24) is a critical event in the pathogenesis of the infection and, hence, VP24 is a potential target for drug development. Since no drugs target VP24, the identification of molecules able to inhibit VP24, restoring and possibly enhancing the IFN response, is a goal of concern. Accordingly, we developed a dual signal firefly and Renilla luciferase cell-based drug screening assay able to quantify IFN-mediated induction of Interferon Stimulated Genes (ISGs) and its inhibition by VP24. Human Embryonic Kidney 293T (HEK293T) cells were transiently transfected with a luciferase reporter gene construct driven by the promoter of ISGs, Interferon-Stimulated Response Element (ISRE). Stimulation of cells with IFN-alpha activated the IFN cascade leading to the expression of ISRE. Cotransfection of cells with a plasmid expressing VP24 cloned from a virus isolated during the last 2014 outbreak led to the inhibition of ISRE transcription, quantified by a luminescent signal. To adapt this system to test a large number of compounds, we performed it in 96-well plates; optimized the assay analyzing different parameters; and validated the system by calculating the Z'- and Z-factor, which showed values of 0.62 and 0.53 for IFN-alpha stimulation assay and VP24 inhibition assay, respectively, indicative of robust assay performance. PMID- 29495313 TI - Improved Formability of Mg-AZ80 Alloy under a High Strain Rate in Expanding-Ring Experiments. AB - Magnesium alloys offer a favored alternative to steels and aluminum alloys due to their low density and relatively high specific strength. Their application potentials are, however, impeded by poor formability at room temperature. In the current work, improved formability for the commercial magnesium AZ80 alloy was attained through the application of the high-rate electro-magnetic forming (EMF) technique. With the EMF system, elongation of 0.2 was achieved while only 0.11 is obtained through quasistatic loading. Systematic microstructural and textural investigations prior, during and post deformation under high strain-rate experiments were carried out using electron back-scattered diffraction (EBSD) and other microscopic techniques. The analysis indicates that enhanced elongation is achieved as a result of the combination of deformation, comprising basal and non basal slip systems, twinning and dynamic recrystallization. An adopted EMF forming technique is tested which results in enhanced elongation without failure and a higher degree of dynamically annealed microstructure. PMID- 29495314 TI - Investigation of a Brownfield Conflict Considering the Strength of Preferences. AB - By employing the Graph Model for Conflict Resolution methodology, this paper models and analyzes a brownfield conflict that occurred at the Changzhou Foreign Language School in Jiangsu, China, in 2016. This conflict made national headlines when news reports revealed that a large number of students and staff suffered from health issues after the school moved to a new site that is built on recently restored land adjacent to the original "Chang Long Chemical" block. Since stakeholders in the conflict hold different strengths of preference, a new option prioritization technique is employed to elicit both crisp preferences and the strength of preferences for the decision-makers (DMs) in the conflict. The conflict analysis result is consistent with the actual trajectory of the conflict and provides strategic insights into the conflict. More specifically, equilibrium results suggest that the firm should have been required to thoroughly clean the site, the local government should not have relocated the school, and the environmental agency and other stakeholders should have closely monitored the firm's activities. In short, strategic insights garnered from this case study indicate that positive interactions should be fostered among the local government, the enterprise, and the public to ensure sustainable brownfield land redevelopment in the future. PMID- 29495315 TI - Facile Fabrication of 100% Bio-based and Degradable Ternary Cellulose/PHBV/PLA Composites. AB - Modifying bio-based degradable polymers such as polylactide (PLA) and poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV) with non-degradable agents will compromise the 100% degradability of their resultant composites. This work developed a facile and solvent-free route in order to fabricate 100% bio-based and degradable ternary cellulose/PHBV/PLA composite materials. The effects of ball milling on the physicochemical properties of pulp cellulose fibers, and the ball-milled cellulose particles on the morphology and mechanical properties of PHBV/PLA blends, were investigated experimentally and statistically. The results showed that more ball-milling time resulted in a smaller particle size and lower crystallinity by way of mechanical disintegration. Filling PHBV/PLA blends with the ball-milled celluloses dramatically increased the stiffness at all of the levels of particle size and filling content, and improved their elongation at the break and fracture work at certain levels of particle size and filling content. It was also found that the high filling content of the ball-milled cellulose particles was detrimental to the mechanical properties for the resultant composite materials. The ternary cellulose/PHBV/PLA composite materials have some potential applications, such as in packaging materials and automobile inner decoration parts. Furthermore, filling content contributes more to the variations of their mechanical properties than particle size does. Statistical analysis combined with experimental tests provide a new pathway to quantitatively evaluate the effects of multiple variables on a specific property, and figure out the dominant one for the resultant composite materials. PMID- 29495316 TI - Bioinspired Design of Alcohol Dehydrogenase@nano TiO2 Microreactors for Sustainable Cycling of NAD+/NADH Coenzyme. AB - The bioinspired design and construction of enzyme@capsule microreactors with specific cell-like functionality has generated tremendous interest in recent years. Inspired by their fascinating complexity, scientists have endeavored to understand the essential aspects of a natural cell and create biomimicking microreactors so as to immobilize enzymes within the hierarchical structure of a microcapsule. In this study, simultaneous encapsulation of alcohol dehydrogenase (ADH) was achieved during the preparation of microcapsules by the Pickering emulsion method using amphiphilic modified TiO2 nanoparticles (NPs) as building blocks for assembling the photocatalytic microcapsule membrane. The ADH@TiO2 NP microreactors exhibited dual catalytic functions, i.e., spatially confined enzymatic catalysis and the membrane-associated photocatalytic oxidation under visible light. The sustainable cycling of nicotinamide adenine dinucleotide (NAD) coenzyme between NADH and NAD+ was realized by enzymatic regeneration of NADH from NAD+ reduction, and was provided in a form that enabled further photocatalytic oxidation to NAD+ under visible light. This bioinspired ADH@TiO2 NP microreactor allowed the linking of a semiconductor mineral-based inorganic photosystem to enzymatic reactions. This is a first step toward the realization of sustainable biological cycling of NAD+/NADH coenzyme in synthetic functional microsystems operating under visible light irradiation. PMID- 29495317 TI - Spray-Dried Potato Juice as a Potential Functional Food Component with Gastrointestinal Protective Effects. AB - BACKGROUND: Peptic ulcer disease, including its complications and functional dyspepsia, are prevalent gastrointestinal diseases, etiopathogenesis of which is associated with mucosal inflammation. Research into new therapeutics capable of preventing or curing gastrointestinal mucosal damage has been steadily developing over past decades. This study was undertaken to evaluate whether a spray-dried preparation of potato juice is applicable for treating and preventing gastrointestinal mucosal damage. METHODS: We assessed potential protective effects of spray-dried potato juice (SDPJ) against gut inflammation in the co culture Caco-2/RAW264.7 system, as well as a gastroprotective activity in a rat model of gastric ulceration. RESULTS: The obtained results indicated that SDPJ down-regulates lipopolysaccharide (LPS)-induced mRNA expression and protein production of proinflammatory cytokines IL-6 and TNF-alpha in the co-culture model. Moreover, SDPJ provided dose-dependent protection against LPS-induced disruption of intestinal barrier integrity. In rats, five-day pretreatment with SDPJ in doses of 200 mg/kg and 500 mg/kg suppressed HCl/ethanol-induced TNF-alpha expression in gastric mucosa by 52% and 35%, respectively. In addition, the pretreatment with the lower dose of SDPJ reduced the incidence of ulcers (by 34%) expressed as ulcer index. CONCLUSION: The spray-dried potato juice appears to be an attractive candidate for ameliorating inflammation-related diseases of the gastrointestinal tract. PMID- 29495318 TI - Novel Antimicrobial Titanium Dioxide Nanotubes Obtained through a Combination of Atomic Layer Deposition and Electrospinning Technologies. AB - The search for new antimicrobial substances has increased in recent years. Antimicrobial nanostructures are one of the most promising alternatives. In this work, titanium dioxide nanotubes were obtained by an atomic layer deposition (ALD) process over electrospun polyvinyl alcohol nanofibers (PVN) at different temperatures with the purpose of obtaining antimicrobial nanostructures with a high specific area. Electrospinning and ALD parameters were studied in order to obtain PVN with smallest diameter and highest deposition rate, respectively. Chamber temperature was a key factor during ALD process and an appropriate titanium dioxide deposition performance was achieved at 200 degrees C. Subsequently, thermal and morphological analysis by SEM and TEM microscopies revealed hollow nanotubes were obtained after calcination process at 600 degrees C. This temperature allowed complete polymer removal and influenced the resulting anatase crystallographic structure of titanium dioxide that positively affected their antimicrobial activities. X-ray analysis confirmed the change of titanium dioxide crystallographic structure from amorphous phase of deposited PVN to anatase crystalline structure of nanotubes. These new nanostructures with very large surface areas resulted in interesting antimicrobial properties against Gram positive and Gram-negative bacteria. Titanium dioxide nanotubes presented the highest activity against Escherichia coli with 5 log cycles reduction at 200 MUg/mL concentration. PMID- 29495319 TI - Content of Heavy Metal in the Dust of Leisure Squares and Its Health Risk Assessment-A Case Study of Yanta District in Xi'an. AB - Taking Yanta District in Xi'an as the research object, the present study measures the contents of Cadmium (Cd), Lead (Pb), Copper (Cu), Nickel (Ni), and Chromium (Cr) in dust samples and further assesses the health risk of heavy metals intake through dust based on the assessment method of human exposure risk proposed by U.S. EPA, with an aim to investigate the content of heavy metal in the dust of leisure squares and its exposure risk. As the results indicate, the average contents of five heavy metals are obviously higher than the soil background value in Shaanxi Province. Therefore, Cd, Ni, Cu, Pb, and Cr are obviously enriched in urban surface dust in Shaanxi Province, due to the influence of human activities. In addition, it can also be found that the non-carcinogen exposure risk in children is significantly higher than that in adults with the risk values of these five heavy metals all one order of magnitude higher than those of adults. Irrespective of whether addressing the results for children or adults, the non carcinogen exposure doses of five heavy metals are sorted as Cr > Pb > Cu > Ni > Cd. According to the present situation, for a child, the total non-carcinogenic risk values of five heavy metals have exceeded the safety limit in 11 of the 20 leisure squares in Yanta District of Xi'an. That means the leisure squares are no longer suitable for physical and recreational activities. For the five heavy metals, the average non-carcinogenic risk value of Cr is largest, and causes the largest threat to health in Yanta District, Xi'an. The carcinogenic exposure doses of the heavy metals Cr, Cd, and Ni are very low in respiratory pathways and there is no carcinogenic health risk. In general, the Cr content in dust in domestic cities is higher than that of foreign cities; however, the Pb content is much lower. PMID- 29495320 TI - Understanding the Pathological Basis of Neurological Diseases Through Diagnostic Platforms Based on Innovations in Biomedical Engineering: New Concepts and Theranostics Perspectives. AB - The pace of advancement of genomics and proteomics together with the recent understanding of the molecular basis behind rare diseases could lead in the near future to significant advances in the diagnosing and treating of many pathological conditions. Innovative diagnostic platforms based on biomedical engineering (microdialysis and proteomics, biochip analysis, non-invasive impedance spectroscopy, etc.) are introduced at a rapid speed in clinical practice: this article primarily aims to highlight how such platforms will advance our understanding of the pathological basis of neurological diseases. An overview of the clinical challenges and regulatory hurdles facing the introduction of such platforms in clinical practice, as well as their potential impact on patient management, will complement the discussion on foreseeable theranostic perspectives. Indeed, the techniques outlined in this article are revolutionizing how we (1) identify biomarkers that better define the diagnostic criteria of any given disease, (2) develop research models, and (3) exploit the externalities coming from innovative pharmacological protocols (i.e., those based on monoclonal antibodies, nanodrugs, etc.) meant to tackle the molecular cascade so far identified. PMID- 29495321 TI - Insights into Natural Products in Inflammation. PMID- 29495322 TI - Nanosphere Lithography on Fiber: Towards Engineered Lab-On-Fiber SERS Optrodes. AB - In this paper we report on the engineering of repeatable surface enhanced Raman scattering (SERS) optical fiber sensor devices (optrodes), as realized through nanosphere lithography. The Lab-on-Fiber SERS optrode consists of polystyrene nanospheres in a close-packed arrays configuration covered by a thin film of gold on the optical fiber tip. The SERS surfaces were fabricated by using a nanosphere lithography approach that is already demonstrated as able to produce highly repeatable patterns on the fiber tip. In order to engineer and optimize the SERS probes, we first evaluated and compared the SERS performances in terms of Enhancement Factor (EF) pertaining to different patterns with different nanosphere diameters and gold thicknesses. To this aim, the EF of SERS surfaces with a pitch of 500, 750 and 1000 nm, and gold films of 20, 30 and 40 nm have been retrieved, adopting the SERS signal of a monolayer of biphenyl-4-thiol (BPT) as a reliable benchmark. The analysis allowed us to identify of the most promising SERS platform: for the samples with nanospheres diameter of 500 nm and gold thickness of 30 nm, we measured values of EF of 4 * 105, which is comparable with state-of-the-art SERS EF achievable with highly performing colloidal gold nanoparticles. The reproducibility of the SERS enhancement was thoroughly evaluated. In particular, the SERS intensity revealed intra-sample (i.e., between different spatial regions of a selected substrate) and inter-sample (i.e., between regions of different substrates) repeatability, with a relative standard deviation lower than 9 and 15%, respectively. Finally, in order to determine the most suitable optical fiber probe, in terms of excitation/collection efficiency and Raman background, we selected several commercially available optical fibers and tested them with a BPT solution used as benchmark. A fiber probe with a pure silica core of 200 um diameter and high numerical aperture (i.e., 0.5) was found to be the most promising fiber platform, providing the best trade-off between high excitation/collection efficiency and low background. This work, thus, poses the basis for realizing reproducible and engineered Lab-on-Fiber SERS optrodes for in-situ trace detection directed toward highly advanced in vivo sensing. PMID- 29495323 TI - Comparative Genomics and Identification of an Enterotoxin-Bearing Pathogenicity Island, SEPI-1/SECI-1, in Staphylococcus epidermidis Pathogenic Strains. AB - Staphylococcus epidermidis is a leading cause of nosocomial infections, majorly resistant to beta-lactam antibiotics, and may transfer several mobile genetic elements among the members of its own species, as well as to Staphylococcus aureus; however, a genetic exchange from S. aureus to S. epidermidis remains controversial. We recently identified two pathogenic clinical strains of S. epidermidis that produce a staphylococcal enterotoxin C3-like (SEC) similar to that by S. aureus pathogenicity islands. This study aimed to determine the genetic environment of the SEC-coding sequence and to identify the mobile genetic elements. Whole-genome sequencing and annotation of the S. epidermidis strains were performed using Illumina technology and a bioinformatics pipeline for assembly, which provided evidence that the SEC-coding sequences were located in a composite pathogenicity island that was previously described in the S. epidermidis strain FRI909, called SePI-1/SeCI-1, with 83.8-89.7% nucleotide similarity. Various other plasmids were identified, particularly p_3_95 and p_4_95, which carry antibiotic resistance genes (hsrA and dfrG, respectively), and share homologies with SAP085A and pUSA04-2-SUR11, two plasmids described in S. aureus. Eventually, one complete prophage was identified, PhiSE90, sharing 30 out of 52 coding sequences with the Acinetobacter phage vB_AbaM_IME200. Thus, the SePI-1/SeCI-1 pathogenicity island was identified in two pathogenic strains of S. epidermidis that produced a SEC enterotoxin causing septic shock. These findings suggest the existence of in vivo genetic exchange from S. aureus to S. epidermidis. PMID- 29495324 TI - Protein Bread Fortification with Cumin and Caraway Seeds and By-Product Flour. AB - Malnutrition continues to be a key health problem in developing regions. The valorization of food waste appears as an ideal way to prevent malnutrition and improve people's access to food. Cumin (Cuminum cyminum L.) and caraway (Carum carvi L.) oilseeds are commonly used for cuisine and medicinal purposes. However, remaining cakes after oil extraction are usually underutilized. In order to assess the usefulness of these by-products in food applications, this study investigated the effect of their addition to protein bread formulations. Different levels (2, 4 and 6%) of whole seeds and cakes flour were used in the study. Fortified protein bread samples were compared to control protein bread and evaluated for their sensory, color, moisture, hardness properties, nutritional values as well as their biological activity. Results indicated that bread fortification shows a significant effect on bread properties depending on fortification level. A higher acceptability was observed specially for bread fortified with by-products flour. Increased tendencies of color darkness, moisture content, bread hardness, nutritional values as well as total phenolic content and radical scavenging activity compared to control bread were observed as the percentage of fortification increased in both cases. The overall results showed that the addition of cumin and caraway seeds and by-product flour can improve the antioxidant potential and overall quality of protein bread. PMID- 29495326 TI - Disruption of Central Antioxidant Property of Nuclear Factor Erythroid 2-Related Factor 2 Worsens Circulatory Homeostasis with Baroreflex Dysfunction in Heart Failure. AB - Heart failure is defined as a disruption of circulatory homeostasis. We have demonstrated that baroreflex dysfunction strikingly disrupts circulatory homeostasis. Moreover, previous many reports have suggested that central excess oxidative stress causes sympathoexcitation in heart failure. However, the central mechanisms of baroreflex dysfunction with oxidative stress has not been fully clarified. Our hypothesis was that the impairment of central antioxidant property would worsen circulatory homeostasis with baroreflex dysfunction in heart failure. As the major antioxidant property in the brain, we focused on nuclear factor erythroid 2-related factor 2 (Nrf2; cytoprotective transcription factor). Hemodynamic and baroreflex function in conscious state were assessed by the radio telemetry system. In the heart failure treated with intracerebroventricular (ICV) infusion of angiotensin II type 1 receptor blocker (ARB), sympathetic activation and brain oxidative stress were significantly lower, and baroreflex sensitivity and volume tolerance were significantly higher than in heart failure treated with vehicle. ICV infusion of Nrf2 activator decreased sympathetic activation and brain oxidative stress, and increased baroreflex sensitivity and volume tolerance to a greater extent than ARB. In conclusion, the disruption of central antioxidant property of Nrf2 worsened circulatory homeostasis with baroreflex dysfunction in heart failure. PMID- 29495325 TI - Tau Spreading Mechanisms; Implications for Dysfunctional Tauopathies. AB - Tauopathies comprise a group of progressive age-associated neurodegenerative diseases where tau protein deposits are found as the predominant pathological signature (primary tauopathies) or in combination with the presence of other toxic aggregates (secondary tauopathies). In recent years, emerging evidence suggests that abnormal tau accumulation is mediated through spreading of seeds of the protein from cell to cell, favouring the hypothesis of a prion-like transmission of tau to explain the propagation of the pathology. This would also support the concept that the pathology initiates in a very small part of the brain before becoming symptomatic and spreads across the brain over time. To date, many key questions still remain unclear, such as the nature of the tau species involved in the spreading, the precise seeding/template and uptaking mechanisms or the selectivity explaining why certain neurons are affected and some others are not. A better understanding of the tau spreading machinery will contribute to the development of new therapeutic approaches focused on halting the abnormal propagation, offering also new perspectives for early diagnosis and preventive therapies. In this review, we will cover the most recent advances in tau spreading mechanisms as well as the implications of these findings for dysfunctional tauopathies. PMID- 29495327 TI - N-Methylcytisine Ameliorates Dextran-Sulfate-Sodium-Induced Colitis in Mice by Inhibiting the Inflammatory Response. AB - This study aimed to investigate the anti-inflammatory effects of N-methylcytisine (NMC) in a dextran sulfate sodium (DSS)-induced colitis model and explore its possible mechanisms. Experimental colitis was induced by administering the mice with 5% DSS for 7 days. Different doses of NMC (1, 4 and 16 mg/kg) and 5 aminosalicylic acid (100 mg/kg) were given orally once every day for 7 days. The protective effect of NMC was evaluated using the disease activity index, colon length and results of histopathological examination. The possible mechanisms of NMC were explored by evaluating the expression levels of tumour necrosis factor alpha, interleukin-1beta and interleukin-6 (IL-6) using ELISA and analysing the protein expression levels of nuclear factor (NF)-kappaB p65, p-NF-kappaB p65, p IkappaB, IkappaB, IkappaB kinase (IKK) and p-IKK using western blots. Results demonstrated that the oral administration of NMC attenuated the DSS-induced clinical symptoms and pathological damage. In addition, NMC treatment significantly reduced myeloperoxidase activity and level of pro-inflammatory cytokines. Further studies revealed that NMC blocked the activation of NF-kappaB by inhibiting IkappaB and IKK phosphorylation. These findings suggested that NMC exerts anti-inflammatory effects on DSS-induced colitis, and its mechanism may be related to the suppression of NF-kappaB activation. Thus, NMC may have potential therapeutic value in the treatment of colitis. PMID- 29495328 TI - Application of Silver Nanostructures Synthesized by Cold Atmospheric Pressure Plasma for Inactivation of Bacterial Phytopathogens from the Genera Dickeya and Pectobacterium. AB - Pectinolytic bacteria are responsible for significant economic losses by causing diseases on numerous plants. New methods are required to control and limit their spread. One possibility is the application of silver nanoparticles (AgNPs) that exhibit well-established antibacterial properties. Here, we synthesized AgNPs, stabilized by pectins (PEC) or sodium dodecyl sulphate (SDS), using a direct current atmospheric pressure glow discharge (dc-APGD) generated in an open-to-air and continuous-flow reaction-discharge system. Characterization of the PEC-AgNPs and SDS-AgNPs with UV/Vis absorption spectroscopy, transmission electron microscopy, energy dispersive X-ray spectroscopy, and selected area electron diffraction revealed the production of spherical, well dispersed, and face cubic centered crystalline AgNPs, with average sizes of 9.33 +/- 3.37 nm and 28.3 +/- 11.7 nm, respectively. Attenuated total reflection-Fourier transformation infrared spectroscopy supported the functionalization of the nanostructures by PEC and SDS. Antibacterial activity of the AgNPs was tested against Dickeya spp. and Pectobacterium spp. strains. Both PEC-AgNPs and SDS-AgNPs displayed bactericidal activity against all of the tested isolates, with minimum inhibitory concentrations of 5.5 mg?L-1 and 0.75-3 mg?L-1, respectively. The collected results suggest that the dc-APGD reaction-discharge system can be applied for the production of defined AgNPs with strong antibacterial properties, which may be further applied in plant disease management. PMID- 29495329 TI - The Association between Maternal Stress and Childhood Eczema: A Systematic Review. AB - Eczema is a chronic atopic disease that is highly prevalent among children worldwide. Identification of factors that may contribute to childhood eczema is needed in order to develop strategies in its prevention. Over the past decade, accumulating evidence has suggested a potential correlation between the experience of stress by mothers and the risk of eczema development in their child. The present review attempts to provide an overview of the studies that contribute data on this correlation. The literature search was conducted using five databases, resulting in the inclusion of eleven studies in the review. The findings of these studies were summarized narratively. Further, an appraisal of the reporting quality of the included studies was conducted using a twelve-item checklist adapted from the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist. Overall, the included studies showed that a positive correlation exists between the experience of stress among mothers and eczema risk of their child. The findings highlight the importance of the implementation of stress reduction programs for pregnant women and those in their postpartum period within communities in order to enable these individuals to relieve stress effectively. PMID- 29495330 TI - Serum Carotenoids Are Inversely Associated with RBP4 and Other Inflammatory Markers in Middle-Aged and Elderly Adults. AB - (1) Background: Carotenoids may be inversely associated with inflammatory markers (i.e., TNF-alpha, IL-6, IL-1beta). However, data are scarce on retinol binding protein 4 (RBP4) in humans. We examined the associations among serum carotenoids, RBP4 and several inflammatory markers in a Chinese population. (2) Methods: This community-based cross-sectional study included 3031 participants (68% males) aged 40-75 years in Guangzhou, China. Serum concentrations of carotenoids, RBP4, and inflammatory markers were measured. (3) Results: Generally, serum individual and total carotenoids were significantly and inversely associated with retinol adjusted RBP4, RBP4, hsCRP, MCP1, and TNF-alpha levels. Age- and gender-adjusted partial correlation coefficients between total carotenoids and the above inflammatory markers were -0.129, -0.097, -0.159, -0.079, and -0.014 (all p < 0.01, except for TNF-alpha with p >0.05), respectively. The multivariate-adjusted values of partial correlation coefficients for these inflammation-related markers were -0.098, -0.079, -0.114, -0.090, and -0.079 (all p < 0.01), respectively. Among the individual carotenoids, those with the most predominant association were lutein-zeaxanthin and total carotenoids for retinol-adjusted RBP4 and RBP4, alpha- and beta-carotene for hsCRP, and alpha-carotene for MCP1 and TNF-alpha. No significant associations were observed for IL-6 and IL-1beta. (4) Conclusions: Serum carotenoids were inversely associated with RBP4, hsCRP, MCP1 and TNF-alpha among middle-aged and elderly Chinese adults. PMID- 29495331 TI - The Trace Detection of Nitrite Ions Using Neutral Red Functionalized SH-beta Cyclodextrin @Au Nanoparticles. AB - A novel fluorescence sensor of NR-beta-CD@AuNPs was prepared for the trace detection of nitrite in quantities as low as 4.25 * 10-3 MUg?mL-1 in an aqueous medium. The fluorescence was due to the host-guest inclusion complexes between neutral red (NR) molecules and gold nanoparticles (AuNPs), which were modified by per-6-mercapto-beta-cyclodextrins (SH-beta-CDs) as both a reducing agent and a stabilizer under microwave radiation. The color of the NR-beta-CD@AuNPs changed in the presence of nitrite ions. A sensor was applied to the determination of trace nitrites in environmental water samples with satisfactory results. PMID- 29495333 TI - Object-Oriented Hierarchy Radiation Consistency for Different Temporal and Different Sensor Images. AB - In the paper, we propose a novel object-oriented hierarchy radiation consistency method for dense matching of different temporal and different sensor data in the 3D reconstruction. For different temporal images, our illumination consistency method is proposed to solve both the illumination uniformity for a single image and the relative illumination normalization for image pairs. Especially in the relative illumination normalization step, singular value equalization and linear relationship of the invariant pixels is combined used for the initial global illumination normalization and the object-oriented refined illumination normalization in detail, respectively. For different sensor images, we propose the union group sparse method, which is based on improving the original group sparse model. The different sensor images are set to a similar smoothness level by the same threshold of singular value from the union group matrix. Our method comprehensively considered the influence factors on the dense matching of the different temporal and different sensor stereoscopic image pairs to simultaneously improve the illumination consistency and the smoothness consistency. The radiation consistency experimental results verify the effectiveness and superiority of the proposed method by comparing two other methods. Moreover, in the dense matching experiment of the mixed stereoscopic image pairs, our method has more advantages for objects in the urban area. PMID- 29495334 TI - Combined Effect of Ultrasound Stimulations and Autoclaving on the Enhancement of Antibacterial Activity of ZnO and SiO2/ZnO Nanoparticles. AB - This study investigates the antibacterial activity (ABA) of suspensions of pure ZnO nanoparticles (ZnO-NPs) and mesoporous silica doped with ZnO (ZnO-UVM7), as well as electrospun nanofibers containing those nanoparticles. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of these two materials were also determined under the same conditions. The results showed a concentration-dependent effect of antibacterial nanoparticles on the viability of Escherichia coli (E. coli). Moreover, the combination of the stimulations and sterilization considerably enhanced the antimicrobial activity (AMA) of the ZnO suspensions. Poly (lactic acid) (PLA) solutions in 2,2,2 trifluoroethanol (TFE) were mixed with different contents of nanoparticles and spun into nonwoven mats by the electrospinning process. The morphology of the mats was analyzed by scanning electron microscopy (SEM). The amount of nanoparticles contained in the mats was determined by thermogravimetric analysis (TGA). The obtained PLA-based mats showed a fibrous morphology, with an average diameter ranging from 350 to 450 nm, a porosity above 85%, but with the nanoparticles agglomeration on their surface. TGA analysis showed that the loss of ZnO-NPs increased with the increase of ZnO-NPs content in the PLA solutions and reached 79% for 1 wt % of ZnO-NPs, which was mainly due to the aggregation of nanoparticles in solution. The ABA of the obtained PLA mats was evaluated by the dynamic method according to the ASTM standard E2149. The results showed that, above an optimal concentration, the nanoparticle agglomeration reduced the antimicrobial efficiency of PLA mats. These mats have potential features for use as antimicrobial food packaging material. PMID- 29495332 TI - Mechanisms of Sodium Transport in Plants-Progresses and Challenges. AB - Understanding the mechanisms of sodium (Na+) influx, effective compartmentalization, and efflux in higher plants is crucial to manipulate Na+ accumulation and assure the maintenance of low Na+ concentration in the cytosol and, hence, plant tolerance to salt stress. Na+ influx across the plasma membrane in the roots occur mainly via nonselective cation channels (NSCCs). Na+ is compartmentalized into vacuoles by Na+/H+ exchangers (NHXs). Na+ efflux from the plant roots is mediated by the activity of Na+/H+ antiporters catalyzed by the salt overly sensitive 1 (SOS1) protein. In animals, ouabain (OU)-sensitive Na+, K+-ATPase (a P-type ATPase) mediates sodium efflux. The evolution of P-type ATPases in higher plants does not exclude the possibility of sodium efflux mechanisms similar to the Na+, K+-ATPase-dependent mechanisms characteristic of animal cells. Using novel fluorescence imaging and spectrofluorometric methodologies, an OU-sensitive sodium efflux system has recently been reported to be physiologically active in roots. This review summarizes and analyzes the current knowledge on Na+ influx, compartmentalization, and efflux in higher plants in response to salt stress. PMID- 29495335 TI - Health Care Utilisation by Bullying Victims: A Cross-Sectional Study of A 9-Year Old Cohort in Ireland. AB - Children frequently refrain from disclosing being bullied. Early identification of bullying by healthcare professionals in children may prevent adverse health consequences. The aim of our study was to determine whether Health Care Utilisation (HCU) is higher in 9-year-olds who report being bullied and factors influencing type of HCU. The study consists of cross-sectional surveys of Child Cohort of Irish National Longitudinal Study of Children (Wave 1), 8,568 9-year olds, and their carers. Being bullied was assessed by a self-reported questionnaire completed by children at home. HCU outcomes consisted of the following: visits to GP, Mental Health Practitioner (MHP), Emergency Department (ED), and nights in hospital by parent interview. Bivariate logistic regression and gender-stratified Poisson models were used to determine association. Victimisation by bullying independently increased visits to GP (OR 1.13, 95% confidence interval (CI): 1.03 to 1.25; p = 0.02), MHP (OR 1.31, 95% CI: 1.05 to 1.63; p = 0.02), though not ED visits (OR 0.99, 95% CI: 0.87 to 1.13; p = 0.8) or nights in hospital (OR 1.07 95% CI: 0.97 to 1.18; p = 0.2), adjusting for underlying chronic condition(s) and socio-demographic confounders. Victimised girls made higher GP visits (RR 1.14, 95% CI: 1.06 to 1.23; p < 0.001) and spent more nights in hospital (RR 1.10, 95% CI: 1.04 to 1.15; p < 0.001). Victimised boys were more likely to contact MHPs (RR 1.21, 95% CI: 1.02 to 1.44; p = 0.03). 9-year-old bullied subjects were more likely to utilise primary care services than non-bullied 9-year-olds. Different HCU patterns were observed according to gender and gender differences in the presentation of victimisation. Our findings may lead to the development of clinical practice guidelines for early detection and appropriate management of bullied children. PMID- 29495336 TI - Cys Site-Directed Mutagenesis of the Human SLC1A5 (ASCT2) Transporter: Structure/Function Relationships and Crucial Role of Cys467 for Redox Sensing and Glutamine Transport. AB - The human plasma membrane transporter ASCT2 is responsible for mediating Na- dependent antiport of neutral amino acids. New insights into structure/function relationships were unveiled by a combined approach of recombinant over expression, site-directed mutagenesis, transport assays in proteoliposomes and bioinformatics. WT and Cys mutants of hASCT2 were produced in P. pastoris and purified for functional assay. The reactivity towards SH reducing and oxidizing agents of WT protein was investigated and opposite effects were revealed; transport activity increased upon treatment with the Cys reducing agent DTE, i.e., when Cys residues were in thiol (reduced) state. Methyl-Hg, which binds to SH groups, was able to inhibit WT and seven out of eight Cys to Ala mutants. On the contrary, C467A loses the sensitivity to both DTE activation and Methyl-Hg inhibition. The C467A mutant showed a Km for Gln one order of magnitude higher than that of WT. Moreover, the C467 residue is localized in the substrate binding region of the protein, as suggested by bioinformatics on the basis of the EAAT1 structure comparison. Taken together, the experimental data allowed identifying C467 residue as crucial for substrate binding and for transport activity modulation of hASCT2. PMID- 29495337 TI - Protective Effects of Bacteriophages against Aeromonas hydrophila Species Causing Motile Aeromonas Septicemia (MAS) in Striped Catfish. AB - To determine the effectivity of bacteriophages in controlling the mass mortality of striped catfish (Pangasianodonhypophthalmus) due to infections caused by Aeromonas spp. in Vietnamese fish farms, bacteriophages against pathogenic Aeromonashydrophila were isolated. A.hydrophila-phage 2 and A.hydrophila-phage 5 were successfully isolated from water samples from the Saigon River of Ho Chi Minh City, Vietnam. These phages, belonging to the Myoviridae family, were found to have broad activity spectra, even against the tested multiple-antibiotic resistant Aeromonas isolates. The latent periods and burst size of phage 2 were 10 min and 213 PFU per infected host cell, respectively. The bacteriophages proved to be effective in inhibiting the growth of the Aeromonas spp. under laboratory conditions. Phage treatments applied to the pathogenic strains during infestation of catfish resulted in a significant improvement in the survival rates of the tested fishes, with up to 100% survival with MOI 100, compared to 18.3% survival observed in control experiments. These findings illustrate the potential for using phages as an effective bio-treatment method to control Motile Aeromonas Septicemia (MAS) in fish farms. This study provides further evidence towards the use of bacteriophages to effectively control disease in aquaculture operations. PMID- 29495338 TI - A Neural Network Approach for Building An Obstacle Detection Model by Fusion of Proximity Sensors Data. AB - Proximity sensors are broadly used in mobile robots for obstacle detection. The traditional calibration process of this kind of sensor could be a time-consuming task because it is usually done by identification in a manual and repetitive way. The resulting obstacles detection models are usually nonlinear functions that can be different for each proximity sensor attached to the robot. In addition, the model is highly dependent on the type of sensor (e.g., ultrasonic or infrared), on changes in light intensity, and on the properties of the obstacle such as shape, colour, and surface texture, among others. That is why in some situations it could be useful to gather all the measurements provided by different kinds of sensor in order to build a unique model that estimates the distances to the obstacles around the robot. This paper presents a novel approach to get an obstacles detection model based on the fusion of sensors data and automatic calibration by using artificial neural networks. PMID- 29495339 TI - Electrochemical Study of Polymer and Ceramic-Based Nanocomposite Coatings for Corrosion Protection of Cast Iron Pipeline. AB - Coating is one of the most effective measures to protect metallic materials from corrosion. Various types of coatings such as metallic, ceramic and polymer coatings have been investigated in a quest to find durable coatings to resist electrochemical decay of metals in industrial applications. Many polymeric composite coatings have proved to be resistant against aggressive environments. Two major applications of ferrous materials are in marine environments and in the oil and gas industry. Knowing the corroding behavior of ferrous-based materials during exposure to these aggressive applications, an effort has been made to protect the material by using polymeric and ceramic-based coatings reinforced with nano materials. Uncoated and coated cast iron pipeline material was investigated during corrosion resistance by employing EIS (electrochemical impedance spectroscopy) and electrochemical DC corrosion testing using the "three electrode system". Cast iron pipeline samples were coated with Polyvinyl Alcohol/Polyaniline/FLG (Few Layers Graphene) and TiO2/GO (graphene oxide) nanocomposite by dip-coating. The EIS data indicated better capacitance and higher impedance values for coated samples compared with the bare metal, depicting enhanced corrosion resistance against seawater and "produce water" of a crude oil sample from a local oil rig; Tafel scans confirmed a significant decrease in corrosion rate of coated samples. PMID- 29495340 TI - Dietary Approach to Recurrent or Chronic Hyperkalaemia in Patients with Decreased Kidney Function. AB - Whereas the adequate intake of potassium is relatively high in healthy adults, i.e., 4.7 g per day, a dietary potassium restriction of usually less than 3 g per day is recommended in the management of patients with reduced kidney function, especially those who tend to develop hyperkalaemia including patients who are treated with angiotensin pathway modulators. Most potassium-rich foods are considered heart-healthy nutrients with high fibre, high anti-oxidant vitamins and high alkali content such as fresh fruits and vegetables; hence, the main challenge of dietary potassium management is to maintain high fibre intake and a low net fixed-acid load, because constipation and metabolic acidosis are per se major risk factors for hyperkalaemia. To achieve a careful reduction of dietary potassium load without a decrease in alkali or fibre intake, we recommend the implementation of certain pragmatic dietary interventions as follows: Improving knowledge and education about the type of foods with excess potassium (per serving or per unit of weight); identifying foods that are needed for healthy nutrition in renal patients; classification of foods based on their potassium content normalized per unit of dietary fibre; education about the use of cooking procedures (such as boiling) in order to achieve effective potassium reduction before eating; and attention to hidden sources of potassium, in particular additives in preserved foods and low-sodium salt substitutes. The present paper aims to review dietary potassium handling and gives information about practical approaches to limit potassium load in chronic kidney disease patients at risk of hyperkalaemia. PMID- 29495342 TI - Hazard Screening Methods for Nanomaterials: A Comparative Study. AB - Hazard identification is the key step in risk assessment and management of manufactured nanomaterials (NM). However, the rapid commercialisation of nano enabled products continues to out-pace the development of a prudent risk management mechanism that is widely accepted by the scientific community and enforced by regulators. However, a growing body of academic literature is developing promising quantitative methods. Two approaches have gained significant currency. Bayesian networks (BN) are a probabilistic, machine learning approach while the weight of evidence (WoE) statistical framework is based on expert elicitation. This comparative study investigates the efficacy of quantitative WoE and Bayesian methodologies in ranking the potential hazard of metal and metal oxide NMs-TiO2, Ag, and ZnO. This research finds that hazard ranking is consistent for both risk assessment approaches. The BN and WoE models both utilize physico-chemical, toxicological, and study type data to infer the hazard potential. The BN exhibits more stability when the models are perturbed with new data. The BN has the significant advantage of self-learning with new data; however, this assumes all input data is equally valid. This research finds that a combination of WoE that would rank input data along with the BN is the optimal hazard assessment framework. PMID- 29495343 TI - Archetype-Based Modeling of Persona for Comprehensive Personality Computing from Personal Big Data. AB - A model describing the wide variety of human behaviours called personality, is becoming increasingly popular among researchers due to the widespread availability of personal big data generated from the use of prevalent digital devices, e.g., smartphones and wearables. Such an approach can be used to model an individual and even digitally clone a person, e.g., a Cyber-I (cyber individual). This work is aimed at establishing a unique and comprehensive description for an individual to mesh with various personalized services and applications. An extensive research literature on or related to psychological modelling exists, i.e., into automatic personality computing. However, the integrity and accuracy of the results from current automatic personality computing is insufficient for the elaborate modeling in Cyber-I due to an insufficient number of data sources. To reach a comprehensive psychological description of a person, it is critical to bring in heterogeneous data sources that could provide plenty of personal data, i.e., the physiological data, and the Internet data. In addition, instead of calculating personality traits from personal data directly, an approach to a personality model derived from the theories of Carl Gustav Jung is used to measure a human subject's persona. Therefore, this research is focused on designing an archetype-based modeling of persona covering an individual's facets in different situations to approach a comprehensive personality model. Using personal big data to measure a specific persona in a certain scenario, our research is designed to ensure the accuracy and integrity of the generated personality model. PMID- 29495341 TI - Messenger RNA Life-Cycle in Cancer Cells: Emerging Role of Conventional and Non Conventional RNA-Binding Proteins? AB - Functional specialization of cells and tissues in metazoans require specific gene expression patterns. Biological processes, thus, need precise temporal and spatial coordination of gene activity. Regulation of the fate of messenger RNA plays a crucial role in this context. In the present review, the current knowledge related to the role of RNA-binding proteins in the whole mRNA life cycle is summarized. This field opens up a new angle for understanding the importance of the post-transcriptional control of gene expression in cancer cells. The emerging role of non-classic RNA-binding proteins is highlighted. The goal of this review is to encourage readers to view, through the mRNA life-cycle, novel aspects of the molecular basis of cancer and the potential to develop RNA based therapies. PMID- 29495346 TI - Load Balancing Integrated Least Slack Time-Based Appliance Scheduling for Smart Home Energy Management. AB - The emergence of smart devices and smart appliances has highly favored the realization of the smart home concept. Modern smart home systems handle a wide range of user requirements. Energy management and energy conservation are in the spotlight when deploying sophisticated smart homes. However, the performance of energy management systems is highly influenced by user behaviors and adopted energy management approaches. Appliance scheduling is widely accepted as an effective mechanism to manage domestic energy consumption. Hence, we propose a smart home energy management system that reduces unnecessary energy consumption by integrating an automated switching off system with load balancing and appliance scheduling algorithm. The load balancing scheme acts according to defined constraints such that the cumulative energy consumption of the household is managed below the defined maximum threshold. The scheduling of appliances adheres to the least slack time (LST) algorithm while considering user comfort during scheduling. The performance of the proposed scheme has been evaluated against an existing energy management scheme through computer simulation. The simulation results have revealed a significant improvement gained through the proposed LST-based energy management scheme in terms of cost of energy, along with reduced domestic energy consumption facilitated by an automated switching off mechanism. PMID- 29495344 TI - Recent Advances in Solvents for the Dissolution, Shaping and Derivatization of Cellulose: Quaternary Ammonium Electrolytes and their Solutions in Water and Molecular Solvents. AB - There is a sustained interest in developing solvents for physically dissolving cellulose, i.e., without covalent bond formation. The use of ionic liquids, ILs, has generated much interest because of their structural versatility that results in efficiency as cellulose solvents. Despite some limitations, imidazole-based ILs have received most of the scientific community's attention. The objective of the present review is to show the advantages of using quaternary ammonium electrolytes, QAEs, including salts of super bases, as solvents for cellulose dissolution, shaping, and derivatization, and as a result, increase the interest in further investigation of these important solvents. QAEs share with ILs structural versatility; many are liquids at room temperature or are soluble in water and molecular solvents (MSs), in particular dimethyl sulfoxide. In this review we first give a historical background on the use of QAEs in cellulose chemistry, and then discuss the common, relatively simple strategies for their synthesis. We discuss the mechanism of cellulose dissolution by QAEs, neat or as solutions in MSs and water, with emphasis on the relevance to cellulose dissolution efficiency of the charge and structure of the cation and. We then discuss the use of cellulose solutions in these solvents for its derivatization under homogeneous and heterogeneous conditions. The products of interest are cellulose esters and ethers; our emphasis is on the role of solvent and possible side reactions. The final part is concerned with the use of cellulose dopes in these solvents for its shaping as fibers, a field with potential commercial application. PMID- 29495345 TI - Mesenchymal Stem Cell Protection of Neurons against Glutamate Excitotoxicity Involves Reduction of NMDA-Triggered Calcium Responses and Surface GluR1, and Is Partly Mediated by TNF. AB - Mesenchymal stem cells (MSC) provide therapeutic effects in experimental CNS disease models and show promise as cell-based therapies for humans, but their modes of action are not well understood. We previously show that MSC protect rodent neurons against glutamate excitotoxicity in vitro, and in vivo in an epilepsy model. Neuroprotection is associated with reduced NMDA glutamate receptor (NMDAR) subunit expression and neuronal glutamate-induced calcium (Ca2+) responses, and increased expression of stem cell-associated genes. Here, to investigate whether MSC-secreted factors modulate neuronal AMPA glutamate receptors (AMPAR) and gene expression, we performed longitudinal studies of enriched mouse cortical neurons treated with MSC conditioned medium (CM). MSC CM did not alter total levels of GluR1 AMPAR subunit in neurons, but its distribution, reducing cell surface levels compared to non-treated neurons. Proportions of NeuN-positive neurons, and of GFAP- and NG2-positive glia, were equal in untreated and MSC CM-treated cultures over time suggesting that neurons, rather than differentially-expanded glia, account for the immature gene profile previously reported in MSC CM-treated cultures. Lastly, MSC CM contained measurable amounts of tumor necrosis factor (TNF) bioactivity and pre-treatment of MSC CM with the TNF inhibitor etanercept reduced its ability to protect neurons. Together these results indicate that MSC-mediated neuroprotection against glutamate excitotoxicity involves reduced NMDAR and GluR1-containing AMPAR function, and TNF-mediated neuroprotection. PMID- 29495347 TI - Meningococcal Vaccines: Current Status and Emerging Strategies. AB - Neisseria meningitidis causes most cases of bacterial meningitis. Meningococcal meningitis is a public health burden to both developed and developing countries throughout the world. There are a number of vaccines (polysaccharide-based, glycoconjugate, protein-based and combined conjugate vaccines) that are approved to target five of the six disease-causing serogroups of the pathogen. Immunization strategies have been effective at helping to decrease the global incidence of meningococcal meningitis. Researchers continue to enhance these efforts through discovery of new antigen targets that may lead to a broadly protective vaccine and development of new methods of homogenous vaccine production. This review describes current meningococcal vaccines and discusses some recent research discoveries that may transform vaccine development against N. meningitidis in the future. PMID- 29495348 TI - Synthesis, Characterization and In Vitro Study of Synthetic and Bovine-Derived Hydroxyapatite Ceramics: A Comparison. AB - The physicochemical properties and biological behavior of sintered-bovine-derived hydroxyapatite (BHAp) are here reported and compared to commercial synthetic-HAp (CHAp). Dense ceramics were sintered for 2 h and 4 h at 1200 degrees C to investigate their microstructure-structure-in-vitro behavior relationship for both HAp ceramics. Densification was directly proportional to sintering time, showing a grain coarsening behavior with a greater effect on BHAp. Lattice parameters, crystallite size, cell volume and Ca/P ratio were determined by Rietveld refinement of X-ray diffraction (XRD) patterns using GSAS(r). Ionic substitutions (Na+, Mg2+, CO32-) related to BHAp structure were associated with their position changes in the vibrational modes and correlated with the structural parameters obtained from the XRD analysis. Variations in the structural parameters and surface morphology were also evaluated after different soaking periods in simulated body fluid, which is associated with the formation of bone-like apatite layer and thus bioactivity. Mitochondrial activity (MTS) and lactate dehydrogenase (LDH) assays showed that the material released by the ceramics does not induce toxicity after exposure in human fetal osteoblastic (hFOB) cells. Furthermore, no statistically significant differences were found between the HAp obtained from different sources. These results show that BHAp can be used with no restrictions for the same biomedical applications as CHAp. PMID- 29495350 TI - The Role of Insulin Resistance/Hyperinsulinism on the Rising Trend of Thyroid and Adrenal Nodular Disease in the Current Environment. AB - Thyroid follicular cells, as well as adrenocortical cells, are endowed by an intrinsic heterogeneity regarding their growth potential, in response to various stimuli. This heterogeneity appears to constitute the underlying cause for the focal cell hyperplasia and eventually the formation of thyroid and adrenal nodules, under the influence of growth stimulatory factors. Among the main stimulatory factors are the pituitary tropic hormones, thyroid-stimulating hormone (TSH) or thyrotropin and adrenocorticotropic hormone (ACTH), which regulate the growth and function of their respective target cells, and the insulin/insulin-like growth factor system, that, through its mitogenic effects, can stimulate the proliferation of these cells. The predominance of one or the other of these growth stimulatory factors appears to determine the natural history of thyroid and adrenal nodular disease. Thus, iodine deficiency was, in the past, the main pathogenic factor responsible, through a transient rise in TSH secretion, for the endemic nodular goiter with the characteristic colloid thyroid nodules among the inhabitants in iodine deficient areas. The correction of iodine deficiency was followed by the elimination of endemic colloid goiter and the emergence of thyroid autoimmunity. The recent epidemic of obesity and metabolic syndrome (MS), or insulin resistance syndrome, has been associated with the re emergence of nodular thyroid disease. A parallel rise in the incidence of benign, nonfunctional adrenocortical tumors, known as adrenal incidentalomas, has also been reported in association with the manifestations of the MS. It is likely that the compensatory to insulin resistance hyperinsulinemia may be responsible for the rising trend of thyroid and adrenal nodular disease in the current environment. PMID- 29495351 TI - Epidemiological Characteristics and Space-Time Analysis of the 2015 Dengue Outbreak in the Metropolitan Region of Tainan City, Taiwan. AB - The metropolitan region of Tainan City in southern Taiwan experienced a dengue outbreak in 2015. This manuscript describes basic epidemiological features of this outbreak and uses spatial and temporal analysis tools to understand the spread of dengue during the outbreak. The analysis found that, independently of gender, dengue incidence rate increased with age, and proportionally affected more males below the age of 40 years but females above the age of 40 years. A spatial scan statistic was applied to detect clusters of disease transmission. The scan statistic found that dengue spread in a north-south diffusion direction, which is across the North, West-Central and South districts of Tainan City. Spatial regression models were used to quantify factors associated with transmission. This analysis indicated that neighborhoods with high proportions of residential area (or low wetland cover) were associated with dengue transmission. However, these association patterns were non-linear. The findings presented here can help Taiwanese public health agencies to understand the fundamental epidemiological characteristics and diffusion patterns of the 2015 dengue outbreak in Tainan City. This type of information is fundamental for policy making to prevent future uncontrolled dengue outbreaks, given that results from this study suggest that control interventions should be emphasized in the North and West-Central districts of Tainan city, in areas with a moderate percentage of residential land cover. PMID- 29495349 TI - Neuroprotective Effects and Mechanisms of Tea Bioactive Components in Neurodegenerative Diseases. AB - As the population ages, neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD) impose a heavy burden on society and families. The pathogeneses of PD and AD are complex. There are no radical cures for the diseases, and existing therapeutic agents for PD and AD have diverse side effects. Tea contains many bioactive components such as polyphenols, theanine, caffeine, and theaflavins. Some investigations of epidemiology have demonstrated that drinking tea can decrease the risk of PD and AD. Tea polyphenols can lower the morbidity of PD and AD by reducing oxidative stress and regulating signaling pathways and metal chelation. Theanine can inhibit the glutamate receptors and regulate the extracellular concentration of glutamine, presenting neuroprotective effects. Additionally, the neuroprotective mechanisms of caffeine and theaflavins may contribute to the ability to antagonize the adenosine receptor A2AR and the antioxidant properties, respectively. Thus, tea bioactive components might be useful for neuronal degeneration treatment in the future. In the present paper, the neuro protection and the mechanisms of tea and its bioactive components are reviewed. Moreover, the potential challenges and future work are also discussed. PMID- 29495352 TI - An Amperometric Biosensor for the Determination of Bacterial Sepsis Biomarker, Secretory Phospholipase Group 2-IIA Using a Tri-Enzyme System. AB - A tri-enzyme system consisting of choline kinase/choline oxidase/horseradish peroxidase was used in the rapid and specific determination of the biomarker for bacterial sepsis infection, secretory phospholipase Group 2-IIA (sPLA2-IIA). These enzymes were individually immobilized onto the acrylic microspheres via succinimide groups for the preparation of an electrochemical biosensor. The reaction of sPLA2-IIA with its substrate initiated a cascading enzymatic reaction in the tri-enzyme system that led to the final production of hydrogen peroxide, which presence was indicated by the redox characteristics of potassium ferricyanide, K3Fe(CN)6. An amperometric biosensor based on enzyme conjugated acrylic microspheres and gold nanoparticles composite coated onto a carbon-paste screen printed electrode (SPE) was fabricated and the current measurement was performed at a low potential of 0.20 V. This enzymatic biosensor gave a linear range 0.01-100 ng/mL (R2 = 0.98304) with a detection limit recorded at 5 * 10-3 ng/mL towards sPLA2-IIA. Moreover, the biosensor showed good reproducibility (relative standard deviation (RSD) of 3.04% (n = 5). The biosensor response was reliable up to 25 days of storage at 4 degrees C. Analysis of human serum samples for sPLA2-IIA indicated that the biosensor has potential for rapid bacterial sepsis diagnosis in hospital emergency department. PMID- 29495353 TI - Genome-Wide Identification of circRNAs in Pathogenic Basidiomycetous Yeast Cryptococcus neoformans Suggests Conserved circRNA Host Genes over Kingdoms. AB - Circular RNAs (circRNAs), a novel class of ubiquitous and intriguing noncoding RNA, have been found in a number of eukaryotes but not yet basidiomycetes. In this study, we identified 73 circRNAs from 39.28 million filtered RNA reads from the basidiomycete Cryptococcus neoformans JEC21 using next-generation sequencing (NGS) and the bioinformatics tool circular RNA identification (CIRI). Furthermore, mapping of newly found circRNAs to the genome showed that 73.97% of the circRNAs originated from exonic regions, whereas 20.55% were from intergenic regions and 5.48% were from intronic regions. Enrichment analysis of circRNA host genes was conducted based on the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway databases. The results reveal that host genes are mainly responsible for primary metabolism and, interestingly, ribosomal protein production. Furthermore, we uncovered a high-level circRNA that was a transcript from the guanosine triphosphate (GTP)ase gene CNM01190 (gene ID: 3255052) in our yeast. Coincidentally, YPT5, CNM01190's ortholog of the GTPase in Schizosaccharomyces pombe, protists, and humans, has already been proven to generate circRNAs. Additionally, overexpression of RNA debranching enzyme DBR1 had varied influence on the expression of circRNAs, indicating that multiple circRNA biosynthesis pathways exist in C. neoformans. Our study provides evidence for the existence of stable circRNAs in the opportunistic human pathogen C. neoformans and raises a question regarding their role related to pathogenesis in this yeast. PMID- 29495354 TI - The Effect of Music on Exercise Intensity among Children with Autism Spectrum Disorder: A Pilot Study. AB - Children with autism spectrum disorder (ASD) are at risk for obesity, commonly have sleep disorders, and exhibit stereotypic behaviors that disrupt their learning. Vigorous levels of exercise have been shown to ameliorate these issues in children with ASD, but little research exists to provide techniques for motivating children with ASD to engage in exercise. The present study examined the effect of music on exercise intensity in a group of 13 elementary school students with ASD. Data were collected across six days during structured (e.g., verbal and physical prompts) and unstructured (e.g., minimal prompting) exercise periods. During these exercise periods, three music conditions were randomized: no music, slow-tempo music, and fast-tempo music. Exercise intensity, measured in Metabolic Equivalent of Tasks by triaxial accelerometers, was greatest during the structured exercise periods and during the slow music condition. Student characteristics moderated the impact of music condition on exercise intensity, such that students with high levels of adaptive behavior or lower levels of maladaptive behavior displayed greater exercise intensity during the fast music condition. PMID- 29495355 TI - Semi-Solid and Solid Dosage Forms for the Delivery of Phage Therapy to Epithelia. AB - The delivery of phages to epithelial surfaces for therapeutic outcomes is a realistic proposal, and indeed one which is being currently tested in clinical trials. This paper reviews some of the known research on formulation of phages into semi-solid dosage forms such as creams, ointments and pastes, as well as solid dosage forms such as troches (or lozenges and pastilles) and suppositories/pessaries, for delivery to the epithelia. The efficacy and stability of these phage formulations is discussed, with a focus on selection of optimal semi-solid bases for phage delivery. Issues such as the need for standardisation of techniques for formulation as well as for assessment of efficacy are highlighted. These are important when trying to compare results from a range of experiments and across different delivery bases. PMID- 29495356 TI - Relating Stool Microbial Metabolite Levels, Inflammatory Markers and Dietary Behaviors to Screening Colonoscopy Findings in a Racially/Ethnically Diverse Patient Population. AB - Colorectal cancer (CRC) is the third leading cause of cancer death for both men and women in the United States, yet it is treatable and preventable. African Americans have higher incidence of CRC than other racial/ethnic groups, however, it is unclear whether this disparity is primarily due to environmental or biological factors. Short chain fatty acids (SCFAs) are metabolites produced by bacteria in the colon and are known to be inversely related to CRC progression. The aim of this study is to investigate how stool SCFA levels, markers of inflammation in stool and dietary intake relate to colonoscopy findings in a diverse patient population. Stool samples from forty-eight participants were analyzed for SCFA levels and inflammatory markers (lysozyme, secretory IgA, lactoferrin). Additionally, participants completed the National Cancer Institute's Diet History Questionnaire II (DHQ II) to report dietary intake over the past year. Subsequently, the majority of participants underwent screening colonoscopy. Our results showed that African Americans had higher total levels of SCFAs in stool than other racial/ethnic groups, significantly lower intake of non starchy vegetables and similar inflammatory marker expression and colonoscopy outcomes, compared to others. This work is an initial exploration into the biological and clinical factors that may ultimately inform personalized screening approaches and clinical decision-making to improve colorectal cancer disparities for African Americans. PMID- 29495357 TI - Regulation of Cell Signaling Pathways and miRNAs by Resveratrol in Different Cancers. AB - Genomic and proteomic studies have helped improve our understanding of the underlying mechanism(s) of cancer development and progression. Mutations, overexpressed oncogenes, inactivated/downregulated tumor suppressors, loss of apoptosis, and dysregulated signal transduction cascades are some of the well studied areas of research. Resveratrol has gained considerable attention in the last two decades because of its pleiotropic anticancer activities. In this review, we have summarized the regulation of WNT, SHH (sonic hedgehog)/GLI (glioma-associated oncogene homolog), TGFbeta1 (transforming growth factor beta 1)/SMAD, NOTCH, TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), STAT (signal transducer and activator of transcription), and microRNAs by resveratrol in different cancers. The importance of these signaling pathways in cancer progression, along with their modulation by resveratrol, is discussed. Further, we also evaluate the mechanisms and implications of the downregulation of oncogenic miRNAs and the upregulation of tumor suppressor miRNAs by resveratrol, both of which also define its ability to inhibit tumor growth and metastasis. It is envisioned that designing effective clinical trials will be helpful for the identification of resveratrol responders and non-responders and the elucidation of how this phytochemical can be combined with current therapeutic options to improve their clinical efficacy and reduce off-target effects. PMID- 29495358 TI - Modulation of Osteoclast Interactions with Orthopaedic Biomaterials. AB - Biomaterial integration in bone depends on bone remodelling at the bone-implant interface. Optimal balance of bone resorption by osteoclasts and bone deposition by osteoblasts is crucial for successful implantation, especially in orthopaedic surgery. Most studies examined osteoblast differentiation on biomaterials, yet few research has been conducted to explore the effect of different orthopaedic implants on osteoclast development. This review covers, in detail, the biology of osteoclasts, in vitro models of osteoclasts, and modulation of osteoclast activity by different implant surfaces, bio-ceramics, and polymers. Studies show that surface topography influence osteoclastogenesis. For instance, metal implants with rough surfaces enhanced osteoclast activity, while smooth surfaces resulted in poor osteoclast differentiation. In addition, surface modification of implants with anti-osteoporotic drug further decreased osteoclast activity. In bioceramics, osteoclast development depended on different chemical compositions. Strontium-incorporated bioceramics decreased osteoclast development, whereas higher concentrations of silica enhanced osteoclast activity. Differences between natural and synthetic polymers also modulated osteoclastogenesis. Physiochemical properties of implants affect osteoclast activity. Hence, understanding osteoclast biology and its response to the natural microarchitecture of bone are indispensable to design suitable implant interfaces and scaffolds, which will stimulate osteoclasts in ways similar to that of native bone. PMID- 29495360 TI - Stress-Preventive Management Competencies, Psychosocial Work Environments, and Affective Well-Being: A Multilevel, Multisource Investigation. AB - The Management Competencies for Preventing and Reducing Stress at Work framework represents one of the few tailored models of leadership for work stress prevention purposes, but it has never been empirically evaluated. The aim of this study was to investigate whether supervisors' stress-preventive management competencies, as measured by the Stress Management Competencies Indicator Tool (SMCIT), are related to employees' affective well-being through psychosocial work environmental factors. To this end, multilevel structural equation modelling (MSEM) was developed and tested, including data provided by both supervisors and employees. Supervisors (n = 84) self-assessed their stress-preventive management competencies (i.e., being respectful and responsible, managing and communicating existing and future work, reasoning and managing difficult situations, and managing the individual within the team) with a previously validated reduced version of the SMCIT. The supervised employees (n = 584) rated job content (e.g., job demands) and work context (e.g., role clarity) psychosocial factors and their job-related affective well-being. Supervisors' job-related affective well-being was also included in the tested model. The results revealed that the stress preventive competencies factor was related to employees' affective well-being through the psychosocial work environment only when the latter was operationalized by means of contextual work factors. Supervisors' affective well being was related to their stress-preventive competencies, but it was not related to employees' affective well-being. We discuss the implications of the results obtained. PMID- 29495359 TI - Mechanistic Pathways Underlying the Antihypertensive Effect of Fermented Milk with Lactococcus lactis NRRL B-50571 in Spontaneously Hypertensive Rats. AB - It has been reported that fermented milk (FM) with Lactococcus lactis NRRL B 50571 had an antihypertensive effect in spontaneously hypertensive rats (SHR) and prehypertensive subjects. Therefore, the objective of the present study was to evaluate the possible mechanisms involved (angiotensin converting enzyme inhibition (ACEI), enhancement of nitric oxide production, antioxidant activity and opioid effect), in the antihypertensive effect of FM with SHR. First, twenty one SHR were randomized into three groups to either receive in a single-oral dose of purified water (negative control), FM, or naloxone (opioid receptor antagonist) + FM. In a parallel study, twenty seven SHR were randomized into three groups to either receive ad libitum purified water (negative control), Captopril or FM. After six weeks of treatment ACEI activity, enhancement of nitric oxide production, and antioxidant activity were evaluated in plasma. Results indicated that opioid receptors were not involved in the hypotensive effect of FM. However, ACEI activity (94 U/L), the oxidative stress index (malondialdehyde/catalase + glutathione peroxidase) 0.9, and nitric oxide in plasma (4.4 +/- 1.3 U/L), were significantly different from the negative control, and not significantly different from the Captopril group. Thus, these results suggested that these mechanisms are involved in the hypotensive effect of FM. PMID- 29495361 TI - Lab-on-a-Disc Platform for Automated Chemical Cell Lysis. AB - Chemical cell lysis is an interesting topic in the research to Lab-on-a-Disc (LOD) platforms on account of its perfect compatibility with the centrifugal spin column format. However, standard procedures followed in chemical cell lysis require sophisticated non-contact temperature control as well as the use of pressure resistant valves. These requirements pose a significant challenge thereby making the automation of chemical cell lysis on an LOD extremely difficult to achieve. In this study, an LOD capable of performing fully automated chemical cell lysis is proposed, where a combination of chemical and thermal methods has been used. It comprises a sample inlet, phase change material sheet (PCMS)-based temperature sensor, heating chamber, and pressure resistant valves. The PCMS melts and solidifies at a certain temperature and thus is capable of indicating whether the heating chamber has reached a specific temperature. Compared to conventional cell lysis systems, the proposed system offers advantages of reduced manual labor and a compact structure that can be readily integrated onto an LOD. Experiments using Salmonella typhimurium strains were conducted to confirm the performance of the proposed cell lysis system. The experimental results demonstrate that the proposed system has great potential in realizing chemical cell lysis on an LOD whilst achieving higher throughput in terms of purity and yield of DNA thereby providing a good alternative to conventional cell lysis systems. PMID- 29495363 TI - Efficiency Evaluation of Food Waste Materials for the Removal of Metals and Metalloids from Complex Multi-Element Solutions. AB - Recent studies have shown the potential of food waste materials as low cost adsorbents for the removal of heavy metals and toxic elements from wastewater. However, the adsorption experiments have been performed in heterogeneous conditions, consequently it is difficult to compare the efficiency of the individual adsorbents. In this study, the adsorption capacities of 12 food waste materials were evaluated by comparing the adsorbents' efficiency for the removal of 23 elements from complex multi-element solutions, maintaining homogeneous experimental conditions. The examined materials resulted to be extremely efficient for the adsorption of many elements from synthetic multi-element solutions as well as from a heavy metal wastewater. The 12 adsorbent surfaces were analyzed by Fourier transform infrared spectroscopy and showed different types and amounts of functional groups, which demonstrated to act as adsorption active sites for various elements. By multivariate statistical computations of the obtained data, the 12 food waste materials were grouped in five clusters characterized by different elements' removal efficiency which resulted to be in correlation with the specific adsorbents' chemical structures. Banana peel, watermelon peel and grape waste resulted the least selective and the most efficient food waste materials for the removal of most of the elements. PMID- 29495364 TI - Controlling Within-Field Sheep Movement Using Virtual Fencing. AB - Virtual fencing has the potential to greatly improve livestock movement, grazing efficiency, and land management by farmers; however, relatively little work has been done to test the potential of virtual fencing with sheep. Commercial dog training equipment, comprising of a collar and GPS hand-held unit were used to implement a virtual fence in a commercial setting. Six, 5-6 year-old Merino wethers, which were naive to virtual fencing were GPS tracked for their use of a paddock (80 * 20 m) throughout the experiment. The virtual fence was effective at preventing a small group of sheep from entering the exclusion zone. The probability of a sheep receiving an electrical stimulus following an audio cue was low (19%), and declined over the testing period. It took an average of eight interactions with the fence for an association to be made between the audio and stimulus cue, with all of the animals responding to the audio alone by the third day. Following the removal of the virtual fence, sheep were willing to cross the previous location of the virtual fence after 30 min of being in the paddock. This is an important aspect in the implementation of virtual fencing as a grazing management tool and further enforces that the sheep in this study were able to associate the audio with the virtual fence and not the physical location itself. PMID- 29495362 TI - In Vivo Protective Effects of Nootkatone against Particles-Induced Lung Injury Caused by Diesel Exhaust Is Mediated via the NF-kappaB Pathway. AB - Numerous studies have shown that acute particulate air pollution exposure is linked with pulmonary adverse effects, including alterations of pulmonary function, inflammation, and oxidative stress. Nootkatone, a constituent of grapefruit, has antioxidant and anti-inflammatory effects. However, the effect of nootkatone on lung toxicity has not been reported so far. In this study we evaluated the possible protective effects of nootkatone on diesel exhaust particles (DEP)-induced lung toxicity, and the possible mechanisms underlying these effects. Mice were intratracheally (i.t.) instilled with either DEP (30 ug/mouse) or saline (control). Nootkatone was given to mice by gavage, 1 h before i.t. instillation, with either DEP or saline. Twenty-four hours following DEP exposure, several physiological and biochemical endpoints were assessed. Nootkatone pretreatment significantly prevented the DEP-induced increase in airway resistance in vivo, decreased neutrophil infiltration in bronchoalveolar lavage fluid, and abated macrophage and neutrophil infiltration in the lung interstitium, assessed by histolopathology. Moreover, DEP caused a significant increase in lung concentrations of 8-isoprostane and tumor necrosis factor alpha, and decreased the reduced glutathione concentration and total nitric oxide activity. These actions were all significantly alleviated by nootkatone pretreatment. Similarly, nootkatone prevented DEP-induced DNA damage and prevented the proteolytic cleavage of caspase-3. Moreover, nootkatone inhibited nuclear factor-kappaB (NF-kappaB) induced by DEP. We conclude that nootkatone prevented the DEP-induced increase in airway resistance, lung inflammation, oxidative stress, and the subsequent DNA damage and apoptosis through a mechanism involving inhibition of NF-kappaB activation. Nootkatone could possibly be considered a beneficial protective agent against air pollution-induced respiratory adverse effects. PMID- 29495365 TI - Black Tea Samples Origin Discrimination Using Analytical Investigations of Secondary Metabolites, Antiradical Scavenging Activity and Chemometric Approach. AB - A comprehensive study on the composition and antioxidant properties of black tea samples with a chemometric approach was performed via LC-ESI-Q-TOF-MS, DPPH radical scavenging assay, and Folin-Ciocalteu assay (TPC). Marked differences between the teas from seven different countries (China, India, Iran, Japan, Kenya, Nepal, Sri Lanka) were shown. The Indian samples demonstrated the highest total catechin content (184.8 mg/100 mL), the largest TPC and DPPH scavenging potential (58.2 mg/100 mL and 84.5%, respectively). The applied principal component analysis (PCA) and ANOVA revealed several correlations between the level of catechins in tea infusions. EC (epicatechin), ECG (epicatechin gallate), EGC (epigallocatechin), and EGCG (epigallocatechin-3-gallate) content was not correlated with DPPH, gallic acid, and TPC; however, a strong correlation of EC and ECG between themselves and a negative correlation of these two catechins with EGCG and EGC was noted. Interestingly, simple catechins were not found to be responsible for antioxidant properties of the black teas. The samples collected in the higher altitudes were similar. PMID- 29495366 TI - Floating Gate, Organic Field-Effect Transistor-Based Sensors towards Biomedical Applications Fabricated with Large-Area Processes over Flexible Substrates. AB - Organic Field-Effect Transistors (OFETs) are attracting a rising interest for the development of novel kinds of sensing platforms. In this paper, we report about a peculiar sensor device structure, namely Organic Charge-Modulated Field-Effect Transistor (OCMFET), capable of operating at low voltages and entirely fabricated with large-area techniques, i.e., inkjet printing and chemical vapor deposition, that can be easily upscaled to an industrial size. Device fabrication is described, and statistical characterization of the basic electronic parameters is reported. As an effective benchmark for the application of large-area fabricated OCMFET to the biomedical field, its combination with pyroelectric materials and compressible capacitors is discussed, in order to employ the proposed device as a temperature pressure sensor. The obtained sensors are capable to operate in conditions which are relevant in the biomedical field (temperature in the range of 18.5-50 degrees C, pressure in the range of 102-103 Pa) with reproducible and valuable performances, opening the way for the fabrication of low-cost, flexible sensing platforms. PMID- 29495369 TI - The Effect of Weak Confinement on the Orientation of Nanorods under Shear Flows. AB - We performed a numerical analysis to study the orientation distribution of a dilute suspension of thin, rigid, rod-like nanoparticles under shearing flow near a solid boundary of weak confinement. Brownian dynamics simulation of a rod was performed under various ratios of shear rate and rod diffusivity (Peclet number), as well as the center-of-mass position (wall confinement). We discuss the effects of Peclet number and wall confinement on the angle distributions, Jeffery orbit distribution and average orientation moments. The average orientation moments, obtained as a function of Peclet number and wall confinement, can be used to improve a previous shear-induced migration model. We demonstrate that the improved model can give excellent prediction of the orientation moment distributions in a microchannel flow. PMID- 29495368 TI - How Nanotechnology and Biomedical Engineering Are Supporting the Identification of Predictive Biomarkers in Neuro-Oncology. AB - The field of neuro-oncology is rapidly progressing and internalizing many of the recent discoveries coming from research conducted in basic science laboratories worldwide. This systematic review aims to summarize the impact of nanotechnology and biomedical engineering in defining clinically meaningful predictive biomarkers with a potential application in the management of patients with brain tumors. Data were collected through a review of the existing English literature performed on Scopus, MEDLINE, MEDLINE in Process, EMBASE, and/or Cochrane Central Register of Controlled Trials: all available basic science and clinical papers relevant to address the above-stated research question were included and analyzed in this study. Based on the results of this systematic review we can conclude that: (1) the advances in nanotechnology and bioengineering are supporting tremendous efforts in optimizing the methods for genomic, epigenomic and proteomic profiling; (2) a successful translational approach is attempting to identify a growing number of biomarkers, some of which appear to be promising candidates in many areas of neuro-oncology; (3) the designing of Randomized Controlled Trials will be warranted to better define the prognostic value of those biomarkers and biosignatures. PMID- 29495367 TI - The Aquaporin 1 Inhibitor Bacopaside II Reduces Endothelial Cell Migration and Tubulogenesis and Induces Apoptosis. AB - Expression of aquaporin-1 (AQP1) in endothelial cells is critical for their migration and angiogenesis in cancer. We tested the AQP1 inhibitor, bacopaside II, derived from medicinal plant Bacopa monnieri, on endothelial cell migration and tube-formation in vitro using mouse endothelial cell lines (2H11 and 3B11) and human umbilical vein endothelial cells (HUVEC). The effect of bacopaside II on viability, apoptosis, migration and tubulogenesis was assessed by a proliferation assay, annexin-V/propidium iodide flow cytometry, the scratch wound assay and endothelial tube-formation, respectively. Cell viability was reduced significantly for 2H11 at 15 MUM (p = 0.037), 3B11 at 12.5 MUM (p = 0.017) and HUVEC at 10 MUM (p < 0.0001). At 15 MUM, the reduced viability was accompanied by an increase in apoptosis of 38%, 50% and 32% for 2H11, 3B11 and HUVEC, respectively. Bacopaside II at >=10 MUM significantly reduced migration of 2H11 (p = 0.0002) and 3B11 (p = 0.034). HUVECs were most sensitive with a significant reduction at >=7.5 MUM (p = 0.037). Tube-formation was reduced with a 15 MUM dose for all cell lines and 10 MUM for 3B11 (p < 0.0001). These results suggest that bacopaside II is a potential anti-angiogenic agent. PMID- 29495370 TI - Clozapine Patients at the Interface between Primary and Secondary Care. AB - Patients receiving clozapine must undergo routine blood monitoring to screen for neutropenia, and to monitor for potential agranulocytosis. In Cork University Hospital, Cork, Ireland, clozapine is dispensed in the hospital pharmacy and the pharmacists are not aware of co-prescribed medicines, potentially impacting upon patient safety. The aim of this study was to examine the continuity of care of patients prescribed clozapine. A retrospective audit was conducted on patients attending the clozapine clinic at Cork University Hospital and assessed patients' (i) independent living, (ii) co-prescribed medicines and (iii) knowledge of their community pharmacists regarding co-prescribed clozapine. A list of prescribed medicines for each patient was obtained, and potential drug-drug interactions between these medicines and clozapine were examined using Lexicomp(r) and Stockley's Interaction checker. Secondary outcomes included patients' physical health characteristics, and a review of co-morbidities. Data were collected between the 29 May 2017 and 20 June 2017. Local ethics committee approval was granted. Patients were eligible for inclusion if they were receiving clozapine treatment as part of a registered programme, were aged 18 years or more, and had the capacity to provide written informed consent. Microsoft Excel was used for data analysis. Of 112 patients, (33% female; mean age (SD) 43.9 (11.3) years; 87.5% living independently/in the family home) 86.6% patients reported that they were taking other prescribed medicines from community pharmacies. The mean (SD) number of co-prescribed medicines in addition to clozapine was 4.8 (4) per patient. Two thirds of community pharmacists were unaware of co-prescribed clozapine. Interactions with clozapine were present in all but 3 patients on co prescribed medicines (n = 97). Lexicomp(r) reported 2.9 drug-drug interactions/patient and Stockley's Interaction Checker reported 2.5 drug-drug interactions/patient. Secondary outcomes for patients included BMI, total cholesterol, and HbA1c levels, which were elevated in 75%, 54% and 17% respectively. Patients prescribed clozapine did not receive a seamless service, between primary and secondary care settings. Community pharmacists were not informed of clozapine, prescribed for their patients, in two thirds of cases. Patients in this study were exposed to clozapine-related drug-drug interactions and hence potential adverse effects. This study supports reports in the literature of substandard management of the physical health of this patient group. This study shows that there is an opportunity for pharmacists to develop active roles in the management of all clozapine-related effects, in addition to their traditional obligatory role in haematological monitoring. This study supports the need for a clinical pharmacist to review inpatients commencing on clozapine, monitor for drug-drug interactions and provide counselling. PMID- 29495371 TI - The Cost of Inadequate Sleep among On-Call Workers in Australia: A Workplace Perspective. AB - On-call or stand-by is becoming an increasingly prevalent form of work scheduling. However, on-call arrangements are typically utilised when workloads are low, for example at night, which can result in inadequate sleep. It is a matter of concern that on-call work is associated with an increased risk of workplace injury. This study sought to determine the economic cost of injury due to inadequate sleep in Australian on-call workers. The prevalence of inadequate sleep among on-call workers was determined using an online survey, and economic costs were estimated using a previously validated costing methodology. Two-thirds of the sample (66%) reported obtaining inadequate sleep on weekdays (work days) and over 80% reported inadequate sleep while on-call. The resulting cost of injury is estimated at $2.25 billion per year ($1.71-2.73 billion). This equates to $1222 per person per incident involving a short-term absence from work; $2.53 million per incident classified as full incapacity, and $1.78 million for each fatality. To the best of our knowledge this is the first study to quantify the economic cost of workplace injury due to inadequate sleep in on-call workers. Well-rested employees are critical to safe and productive workplace operations. Therefore, it is in the interest of both employers and governments to prioritise and invest far more into the management of inadequate sleep in industries which utilise on-call work arrangements. PMID- 29495372 TI - Ultrahigh-Density Linkage Map Construction Using Low-Coverage Whole-Genome Sequencing of a Doubled Haploid Population: Case Study of Torafugu (Takifugu rubripes). AB - Next-generation sequencing enables genome-wide genotyping of a large population and further facilitates the construction of a genetic linkage map. Low-coverage whole-genome sequencing has been employed for genetic linkage map construction in several species. However, this strategy generally requires available high-quality reference genomes and/or designed inbred pedigree lines, which restrict the scope of application for non-model and unsequenced species. Here, using torafugu (Takifugu rubripes) as a test model, we propose a new strategy for ultrahigh density genetic linkage map construction using low-coverage whole-genome sequencing of a haploid/doubled haploid (H/DH) population without above requirements. Low-coverage (~1*) whole-genome sequencing data of 165 DH individuals were used for de novo assembly and further performed single nucleotide polymorphisms (SNPs) calling, resulting in the identification of 1,070,601 SNPs. Based on SNP genotypes and de novo assembly, genotypes were associated with short DNA segments and an ultrahigh-density linkage map was constructed containing information of 802,277 SNPs in 3090 unique positions. Comparative analyses showed near-perfect concordance between the present linkage map and the latest published torafugu genome (FUGU5). This strategy would facilitate ultrahigh-density linkage map construction in various sexually reproducing organisms for which H/DH populations can be generated. PMID- 29495373 TI - Correlation between Changes in Local Earth's Magnetic Field and Cases of Acute Myocardial Infarction. AB - The impact of changes in the geomagnetic field on the human body remains the subject of studies across the world, yet there is no consensus. Current studies are observing effects that require further work by researchers in order to find out the mechanisms that would allow a proper assessment of the correlations between the Earth's magnetic field variations and changes in human organisms. The main purpose of this study was to investigate possible correlations between the strength of time-varying aspects of the local Earth's magnetic field and incidence of myocardial infarctions. Study participants included 435 males and 268 females who had diagnosis of myocardial infarction during the period of 1 January 2016 to 31 December 2016 and attended the Department of Cardiology at the Hospital of Lithuanian University of Health Sciences (LUHS), Kauno klinikos. Time varying magnetic field data was collected at the magnetometer site located in Lithuania. After mathematical analysis, the results support the hypothesis that the Earth's magnetic field has a relationship between the number of acute myocardial infarction with ST segment elevation (STEMI) cases per week and the average weekly geomagnetic field strength in different frequency ranges. Correlations varied in different age groups as well as in males and females, which may indicate diverse organism sensitivity to the Earth's magnetic field. PMID- 29495374 TI - New Insights into Mn1-xZnxFe2O4 via Fabricating Magnetic Photocatalyst Material BiVO4/Mn1-xZnxFe2O4. AB - BiVO4/Mn1-xZnxFe2O4 was prepared by the impregnation roasting method. XRD (X-ray Diffractometer) tests showed that the prepared BiVO4 is monoclinic crystal, and the introduction of Mn1-xZnxFe2O4 does not change the crystal structure of BiVO4. The introduction of a soft-magnetic material, Mn1-xZnxFe2O4, was beneficial to the composite photocatalyst's separation from the liquid solution using an extra magnet after use. UV-vis spectra analysis indicated that Mn1-xZnxFe2O4 enhanced the absorption intensity of visible light for BiVO4. EIS (electrochemical impedance spectroscopy) investigation revealed that the introduction of Mn1 xZnxFe2O4 enhanced the conductivity of BiVO4, further decreasing its electron transfer impedance. The photocatalytic efficiency of BiVO4/Mn1-xZnxFe2O4 was higher than that of pure BiVO4. In other words, Mn1-xZnxFe2O4 could enhance the photocatalytic reaction rate. PMID- 29495375 TI - Simultaneous Separation of Eight Lignans in Forsythia suspensa by beta Cyclodextrin-Modified Capillary Zone Electrophoresis. AB - The aim of the study was to develop an alternative capillary zone electrophoresis (CZE) for simultaneous determination of phillyrin (1), phillygenin (2), epipinoresinol-4-O-beta-glucoside (3), pinoresinol-4-O-beta-glucoside (4), lariciresinol (5), pinoresinol (6), isolariciresinol (7) and vladinol D (8) in Forsythia suspensa. The structural types of lignans 1-8 could be attributed to bisepoxylignans (1-4 and 6), monoepoxylignans (5 and 8) and cyclolignan (7). The major difficulties in the CZE separation of 1-8 could be summarization as the simultaneous presence of free lignans (1, 2 and 5-8) and lignan glucosides (3 and 4) and simultaneous occurrence of two pairs of isomers (3 and 4 as well as 5 and 7). Without the addition of beta-CD and methanol, the resolution of these analytes was quite poor. However, in this study, compounds 1-8 were excellently separated from each other within 15 min under optimized conditions with a borax running buffer (40 mM borax, pH 10.30) containing 2 mM beta-CD and 5% methanol (v/v) at the voltage of 20 kV, temperature of 35 degrees C and detection wavelength of 234 nm. Validation of the method included tests of linearity, precision, repeatability, stability and accuracy. In addition, the method offered inherent advantages such as lower analytical cost, no need of specific columns and use of small amounts of organic solvents and reagents. Finally, this green and economic CZE was successfully applied for the determination of these bioactive components 1-8 in F. suspensa fruits and its commercial extracts. PMID- 29495376 TI - Lead Affects Vitamin D Metabolism in Rats. AB - A negative association between blood lead and vitamin D concentrations has been reported, however, experimental data on the effect of lead (Pb) on vitamin D metabolism is scarce. We investigated the effects of Pb on serum vitamin D metabolites, vitamin D activating enzymes and vitamin D receptor (VDR) in rats. Newborn Wistar rat pups were exposed to 0.2% Pb-acetate via their dams' drinking water from post-natal day (PND) 1 to 21 and directly in drinking water until PND30. Serum 25-hydroxyvitamin D was analyzed with LC-MS/MS and 1,25 dihydroxyvitamin D with an immunoassay. Tissue expression of vitamin D activating enzymes and VDR were measured by Western blot and immunohistochemistry. Serum 25 hydroxyvitamin D was significantly decreased at both PND21 and PND30, whereas 1,25-dihydroxyvitamin D was decreased (p < 0.05) only at PND21 in the Pb-exposed rats. Expression of renal 1-alpha-hydroxylase was decreased by Pb only at PND21 (p < 0.05) but the brain 1-alpha-hydroxylase was not affected. Hepatic 25 hydroxylase expression was significantly decreased at PND21 but significantly increased at PND30 by Pb exposure. VDR expression in the brain was increased at both PND21 and PND30 (p < 0.05). These results suggest that Pb interferes with vitamin D metabolism by affecting the expression of its metabolizing enzymes. PMID- 29495377 TI - Embodied Cognition and the Direct Induction of Affect as a Compliment to Cognitive Behavioural Therapy. AB - We make the case for the possible integration of affect experience induced via embodiment techniques with CBT for the treatment of emotional disorders in clinical settings. Theoretically we propose a possible integration of cognitive behavioural theory, neuroscience, embodied cognition and important processes of client change outcomes such as the therapeutic alliance to enhance client outcomes. We draw from evidence of bidirectional effects between embodiment modes of bottom-up (sensory-motor simulations giving rise to important basis of knowledge) and top-down (abstract mental representations of knowledge) processes such as CBT in psychotherapy. The paper first describes the dominance and success of CBT for the treatment of a wide range of clinical disorders. Some limitations of CBT, particularly for depression are also outlined. There is a growing body of evidence for the added value of experiential affect-focused interventions combined with CBT. Evidence for the embodied model of cognition and emotion is reviewed. Advantages of embodiment is highlighted as a complimentary process model to deepen the intensity and valence of affective experience. It is suggested that an integrated embodiment approach with CBT enhances outcomes across a wide range of emotional disorders. A description of our embodiment method integrated with CBT for inducing affective experience, emotional regulation, acceptance of unwanted emotions and emotional mastery is given. Finally, the paper highlights the importance of the therapeutic alliance as a critical component of the change process. The paper ends with a case study highlighting some clinical strategies that may aid the therapist to integrate embodiment techniques in CBT that can further explore in future research on affective experience in CBT for a wider range of clinical disorders. PMID- 29495379 TI - Preparation and Characterization of Quaternized Chitosan Derivatives and Assessment of Their Antioxidant Activity. AB - Chitosan (CS) is an abundant and renewable polysaccharide that is reported to exhibit a great variety of beneficial properties. However, the poor solubility of chitosan in water limits its applications. In this paper, we successfully synthesized single N-quaternized (QCS) and double N-diquaternized (DQCS) chitosan derivatives, and the resulting quaternized materials were water-soluble. The degree of quaternization (DQ) of QCS and DQCS was 0.8 and 1.3, respectively. These derivatives were characterized by FTIR, 1H NMR, 13C NMR, TGA, and SEM. Moreover, the antioxidant activity of the chitosan was evaluated by free radical scavenging ability (against DPPH-radical, hydroxyl-radical, and superoxide radical) and ferric reducing power. Our results suggested that the antioxidant abilities were in the order of DQCS > QCS > CS, which was consistent with the number of quaternized groups. These data demonstrate that the number of quaternized groups of chitosan derivatives contributes to their antioxidant activity. Therefore, DQCS, with a higher number of quaternized groups and higher positive charge density, is endowed with high antioxidant activity, and can be used as a candidate material in food and pharmaceutical industries. PMID- 29495378 TI - Tinkering and the Origins of Heritable Anatomical Variation in Vertebrates. AB - Evolutionary change comes from natural and other forms of selection acting on existing anatomical and physiological variants. While much is known about selection, little is known about the details of how genetic mutation leads to the range of heritable anatomical variants that are present within any population. This paper takes a systems-based view to explore how genomic mutation in vertebrate genomes works its way upwards, though changes to proteins, protein networks, and cell phenotypes to produce variants in anatomical detail. The evidence used in this approach mainly derives from analysing anatomical change in adult vertebrates and the protein networks that drive tissue formation in embryos. The former indicate which processes drive variation-these are mainly patterning, timing, and growth-and the latter their molecular basis. The paper then examines the effects of mutation and genetic drift on these processes, the nature of the resulting heritable phenotypic variation within a population, and the experimental evidence on the speed with which new variants can appear under selection. The discussion considers whether this speed is adequate to explain the observed rate of evolutionary change or whether other non-canonical, adaptive mechanisms of heritable mutation are needed. The evidence to hand suggests that they are not, for vertebrate evolution at least. PMID- 29495380 TI - Synthesis and Evaluation of Bakuchiol Derivatives as Potential Anticancer Agents. AB - A series of bakuchiol derivatives were synthesized and evaluated for their anti proliferative and the inhibitory activities on SMMC7721 cell line migration using PX-478 as a positive control. The results showed (S,E)-4-(7-methoxy-3,7-dimethyl 3-vinyloct-1-en-1-yl)phenol (10) to have the best activity among the tested compounds, which included PX-478. In addition, compound 10 showed greater inhibitory activity than that of bakuchiol in the transwell migration and invasion assays at every dose. In western blotting tests, compound 10 showed a promising ability to downregulate the expression of HIF-1alpha and its associated downstream proteins MMP-2 and MMP-9. Moreover, this effect was dose-dependent and could represent a possible mechanism of action for the anticancer activity of compound 10. PMID- 29495381 TI - Strain-Compensated InGaAsP Superlattices for Defect Reduction of InP Grown on Exact-Oriented (001) Patterned Si Substrates by Metal Organic Chemical Vapor Deposition. AB - We report on the use of InGaAsP strain-compensated superlattices (SC-SLs) as a technique to reduce the defect density of Indium Phosphide (InP) grown on silicon (InP-on-Si) by Metal Organic Chemical Vapor Deposition (MOCVD). Initially, a 2 MUm thick gallium arsenide (GaAs) layer was grown with very high uniformity on exact oriented (001) 300 mm Si wafers; which had been patterned in 90 nm V grooved trenches separated by silicon dioxide (SiO2) stripes and oriented along the [110] direction. Undercut at the Si/SiO2 interface was used to reduce the propagation of defects into the III-V layers. Following wafer dicing; 2.6 MUm of indium phosphide (InP) was grown on such GaAs-on-Si templates. InGaAsP SC-SLs and thermal annealing were used to achieve a high-quality and smooth InP pseudo substrate with a reduced defect density. Both the GaAs-on-Si and the subsequently grown InP layers were characterized using a variety of techniques including X-ray diffraction (XRD); atomic force microscopy (AFM); transmission electron microscopy (TEM); and electron channeling contrast imaging (ECCI); which indicate high-quality of the epitaxial films. The threading dislocation density and RMS surface roughness of the final InP layer were 5 * 108/cm2 and 1.2 nm; respectively and 7.8 * 107/cm2 and 10.8 nm for the GaAs-on-Si layer. PMID- 29495382 TI - Carboxylic Terminated Thermo-Responsive Copolymer Hydrogel and Improvement in Peptide Release Profile. AB - To improve the release profile of peptide drugs, thermos-responsive triblock copolymer poly (epsilon-caprolactone-co-p-dioxanone)-b-poly (ethylene glycol)-b poly (epsilon-caprolactone-co-p-dioxanone) (PECP) was prepared and end capped by succinic anhydride to give its carboxylic terminated derivative. Both PCEP block copolymer and its end group modified derivative showed temperature-dependent reversible sol-gel transition in water. The carboxylic end group could significantly decrease the sol-gel transition temperature by nearly 10 degrees C and strengthen the gel due to enhanced intermolecular force among triblock copolymer chains. Furthermore, compared with the original PECP triblock copolymer, HOOC-PECP-COOH copolymer displayed a retarded and sustained release profile for leuprorelin acetate over one month while effectively avoiding the initial burst. The controlled release was believed to be related to the formation of conjugated copolymer-peptide pair by ionic interaction and enhanced solubility of drug molecules into the hydrophobic domains of the hydrogel. Therefore, carboxyl terminated HOOC-PECP-COOH hydrogel was a promising and well-exhibited sustained release carrier for peptide drugs with the advantage of being able to develop injectable formulation by simple mixing. PMID- 29495383 TI - Bond-Slip Relationship for CFRP Sheets Externally Bonded to Concrete under Cyclic Loading. AB - The objective of this paper was to explore the bond-slip relationship between carbon fiber-reinforced polymer (CFRP) sheets and concrete under cyclic loading through experimental and analytical approaches. Modified beam tests were performed in order to gain insight into the bond-slip relationship under static and cyclic loading. The test variables are the CFRP-to-concrete width ratio, and the bond length of the CFRP sheets. An analysis of the test results in this paper and existing test results indicated that the slope of the ascending segment of the bond-slip curve decreased with an increase in the number of load cycles, but the slip corresponding to the maximum shear stress was almost invariable as the number of load cycles increased. In addition, the rate of reduction in the slope of the ascending range of the bond-slip curve during cyclic loading decreased as the concrete strength increased, and increased as the load level or CFRP-to concrete width ratio enhanced. However, these were not affected by variations in bond length if the residual bond length was longer than the effective bond length. A bilinear bond-slip model for CFRP sheets that are externally bonded to concrete under cyclic loading, which considered the effects of the cyclic load level, concrete strength, and CFRP-to-concrete ratio, was developed based on the existing static bond-slip model. The accuracy of this proposed model was verified by a comparison between this proposed model and test results. PMID- 29495384 TI - Emerging Methodologies in Pediatric Palliative Care Research: Six Case Studies. AB - Given the broad focus of pediatric palliative care (PPC) on the physical, emotional, and spiritual needs of children with potentially life-limiting illnesses and their families, PPC research requires creative methodological approaches. This manuscript, written by experienced PPC researchers, describes issues encountered in our own areas of research and the novel methods we have identified to target them. Specifically, we discuss potential approaches to: assessing symptoms among nonverbal children, evaluating medical interventions, identifying and treating problems related to polypharmacy, addressing missing data in longitudinal studies, evaluating longer-term efficacy of PPC interventions, and monitoring for inequities in PPC service delivery. PMID- 29495385 TI - Fatal Canine Intoxications Linked to the Presence of Saxitoxins in Stranded Marine Organisms Following Winter Storm Activity. AB - At the start of 2018, multiple incidents of dog illnesses were reported following consumption of marine species washed up onto the beaches of eastern England after winter storms. Over a two-week period, nine confirmed illnesses including two canine deaths were recorded. Symptoms in the affected dogs included sickness, loss of motor control, and muscle paralysis. Samples of flatfish, starfish, and crab from the beaches in the affected areas were analysed for a suite of naturally occurring marine neurotoxins of dinoflagellate origin. Toxins causing paralytic shellfish poisoning (PSP) were detected and quantified using two independent chemical testing methods in samples of all three marine types, with concentrations over 14,000 ug saxitoxin (STX) eq/kg found in one starfish sample. Further evidence for PSP intoxication of the dogs was obtained with the positive identification of PSP toxins in a vomited crab sample from one deceased dog and in gastrointestinal samples collected post mortem from a second affected dog. Together, this is the first report providing evidence of starfish being implicated in a PSP intoxication case and the first report of PSP in canines. PMID- 29495386 TI - Critical Current Simulation and Measurement of Second Generation, High Temperature Superconducting Coil under External Magnetic Field. AB - This paper studies the critical current of second generation, high temperature superconducting coils under an external magnetic field experimentally and numerically. Two identical coils with different coated conductors are fabricated and tested under a direct current (DC) magnetic field along the axis of the coil. Then, a numerical model in cylindrical coordinates based on a sheet current model is built by taking the measured magnetic field dependency to analyze the current distribution and magnetic field distribution. The simulated critical currents of the coils under the DC magnetic field have good agreement with the measured results. We find that under the in-phase field, the critical current decreases as the magnetic field in the innermost turn is enhanced by the external field. Meanwhile, the anti-phase external field increases the critical current a bit at first, then decreases the critical current. We further discuss the critical current criteria of the coils, showing that the parallel field plays a more important role in critical current determination. PMID- 29495388 TI - Does Electronic Cigarette Use Predict Abstinence from Conventional Cigarettes among Smokers in Hong Kong? AB - OBJECTIVES: To investigate the effects of ever use of electronic cigarettes (ECs), many of which lack nicotine, on abstinence from convention cigarettes among Hong Kong adult smokers. METHODS: We collected data from 956 daily smokers in 2014-2015 regarding ever EC use and smoking behaviors at baseline, any and past 30-day EC use at the 3-month follow-up. Outcomes measured at 6 months included past 7-day point prevalence abstinence (PPA), biochemically validated quitting, smoking reduction (>=50% from baseline) and cessation attempt. Logistic regression yielded adjusted odds ratios (AOR) for quitting in relation to EC use, adjusting for socio-demographic characteristics and smoking profile. Complete case, missing observation as smoking and propensity score analyses were conducted. RESULTS: By complete case, ever EC use at baseline did not predict self-reported PPA (AOR 0.99, 95% CI 0.57-1.73), biochemically validated quitting (AOR 1.22, 95% CI 0.64-2.34), cessation attempt (AOR 0.74, 95% CI 0.48-1.14), or smoking reduction (AOR 0.89, 95% CI 0.54-1.47). EC use during the first 3 months did not predict quitting (AOR 1.02, 95% CI 0.22-4.71). Similar results were observed for missing observations as smoking and propensity score analyses. CONCLUSIONS: Any use of ECs, many of which lack nicotine, did not predict smoking abstinence among Hong Kong adult smokers. PMID- 29495387 TI - Formation and Change of Chloroplast-Located Plant Metabolites in Response to Light Conditions. AB - Photosynthesis is the central energy conversion process for plant metabolism and occurs within mature chloroplasts. Chloroplasts are also the site of various metabolic reactions involving amino acids, lipids, starch, and sulfur, as well as where the production of some hormones takes place. Light is one of the most important environmental factors, acting as an essential energy source for plants, but also as an external signal influencing their growth and development. Plants experience large fluctuations in the intensity and spectral quality of light, and many attempts have been made to improve or modify plant metabolites by treating them with different light qualities (artificial lighting) or intensities. In this review, we discuss how changes in light intensity and wavelength affect the formation of chloroplast-located metabolites in plants. PMID- 29495389 TI - The rs2910164 Genetic Variant of miR-146a-3p Is Associated with Increased Overall Mortality in Patients with Follicular Variant Papillary Thyroid Carcinoma. AB - Aberrant expression of the sodium-iodide symporter (NIS) and the resistance to post-operative radioactive iodide treatment is a crucial cause of higher mortality of some thyroid cancer patients. In this study, we analyzed the impact of miR-146a on the expression and function of NIS and on the overall survival of thyroid cancer patients. The study included 2441 patients (2163 women; 278 men); including 359 cases with follicular variant of papillary thyroid carcinoma (fvPTC). miR:NIS interactions were analyzed in cell lines using in vivo binding and inhibition assays and radioactive iodine uptake assays. Tumor/blood DNA was used for rs2910164 genotyping. Overall survival was assessed retrospectively. In the results, we showed that miR-146a-3p directly binds to and inhibits NIS. Inhibition of miR-146a-3p restores the expression and function of NIS, increasing radioactive iodine uptake. Rs2910164 functional variant within miR-146a-3p is associated with increased overall mortality among fvPTC female patients. The deaths per 1000 person-years were 29.7 in CC carriers vs. 5.08 in GG/GC-carriers (HR = 6.21, p = 0.006). Higher mortality of CC vs. GG/GC carriers was also observed in patients with lower clinical stage (HR = 22.72, p < 0.001), smaller tumor size (pT1/pT2) (HR = 25.05, p < 0.001), lack of extrathyroidal invasion (HR = 9.03, p = 0.02), lack of nodular invasion (HR = 7.84, p = 0.002), lack of metastases (HR = 6.5, p = 0.005) and older (age at diagnosis >50 years) (HR = 7.8, p = 0.002). MiR-146a-3p underwent somatic mutations in 16.1% of analyzed specimens, mainly towards the deleterious C allele. In this report we propose a novel molecular marker of the clinical outcome of fvPTC patients. Rs2910164 increases the overall mortality with inhibition of NIS and disruption of radioiodine uptake as a possible mechanism. PMID- 29495390 TI - Aloin Suppresses Lipopolysaccharide-Induced Inflammatory Response and Apoptosis by Inhibiting the Activation of NF-kappaB. AB - Numerous herbal-derived natural products are excellent anti-inflammatory agents. Several studies have reported that aloin, the major anthraquinone glycoside obtained from the Aloe species, exhibits anti-inflammatory activity. However, the molecular mechanism of this activity is not well understood. In this report, we found that aloin suppresses lipopolysaccharide-induced pro-inflammatory cytokine secretion and nitric oxide production, and downregulates the expression of tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Aloin inhibits the phosphorylation and acetylation of the NF-kappaB p65 subunit by suppressing the upstream kinases p38 and Msk1, preventing LPS-induced p65 translocation to the nucleus. We have also shown that aloin inhibits LPS-induced caspase-3 activation and apoptotic cell death. Collectively, these findings suggest that aloin effectively suppresses the inflammatory response, primarily through the inhibition of NF kappaB signaling. PMID- 29495391 TI - Expression Profiling of Regulatory and Biosynthetic Genes in Contrastingly Anthocyanin Rich Strawberry (Fragaria * ananassa) Cultivars Reveals Key Genetic Determinants of Fruit Color. AB - Anthocyanins are the resultant end-point metabolites of phenylapropanoid/flavonoid (F/P) pathway which is regulated at transcriptional level via a series of structural genes. Identifying the key genes and their potential interactions can provide us with the clue for novel points of intervention for improvement of the trait in strawberry. We profiled the expressions of putative regulatory and biosynthetic genes of cultivated strawberry in three developmental and characteristically colored stages of fruits of contrastingly anthocyanin rich cultivars: Tokun, Maehyang and Soelhyang. Besides FaMYB10, a well-characterized positive regulator, FaMYB5, FabHLH3 and FabHLH3-delta might also act as potential positive regulators, while FaMYB11, FaMYB9, FabHLH33 and FaWD44-1 as potential negative regulators of anthocyanin biosynthesis in these high-anthocyanin cultivars. Among the early BGs, Fa4CL7, FaF3H, FaCHI1, FaCHI3, and FaCHS, and among the late BGs, FaDFR4-3, FaLDOX, and FaUFGT2 showed significantly higher expression in ripe fruits of high anthocyanin cultivars Maehyang and Soelhyang. Multivariate analysis revealed the association of these genes with total anthocyanins. Increasingly higher expressions of the key genes along the pathway indicates the progressive intensification of pathway flux leading to final higher accumulation of anthocyanins. Identification of these key genetic determinants of anthocyanin regulation and biosynthesis in Korean cultivars will be helpful in designing crop improvement programs. PMID- 29495392 TI - Impact of Genetic Variants on the Individual Potential for Body Fat Loss. AB - The past decade has witnessed the discovery of obesity-related genetic variants and their functions through genome-wide association studies. Combinations of risk alleles can influence obesity phenotypes with different degrees of effectiveness across various individuals by interacting with environmental factors. We examined the interaction between genetic variation and changes in dietary habits or exercise that influences body fat loss from a large Korean cohort (n = 8840). Out of 673 obesity-related SNPs, a total of 100 SNPs (37 for carbohydrate intake; 19 for fat intake; 44 for total calories intake; 25 for exercise onset) identified to have gene-environment interaction effect in generalized linear model were used to calculate genetic risk scores (GRS). Based on the GRS distribution, we divided the population into four levels, namely, "very insensitive", "insensitive", "sensitive", and "very sensitive" for each of the four categories, "carbohydrate intake", "fat intake", "total calories intake", and "exercise". Overall, the mean body fat loss became larger when the sensitivity level was increased. In conclusion, genetic variants influence the effectiveness of dietary regimes for body fat loss. Based on our findings, we suggest a platform for personalized body fat management by providing the most suitable and effective nutrition or activity plan specific to an individual. PMID- 29495393 TI - Immunomodulatory and Inhibitory Effect of Immulina(r), and Immunloges(r) in the Ig-E Mediated Activation of RBL-2H3 Cells. A New Role in Allergic Inflammatory Responses. AB - Immulina(r), a high-molecular-weight polysaccharide extract from the cyanobacterium Arthrospira platensis (Spirulina) is a potent activator of innate immune cells. On the other hand, it is well documented that Spirulina exerts anti inflammatory effects and showed promising effects with respect to the relief of allergic rhinitis symptoms. Taking into account these findings, we decided to elucidate whether Immulina(r), and immunLoges(r) (a commercial available multicomponent nutraceutical with Immulina(r) as a main ingredient) beyond immune enhancing effects, might also exert inhibitory effects in the induced allergic inflammatory response and on histamine release from RBL-2H3 mast cells. Our findings show that Immulina(r) and immunLoges(r) inhibited the IgE-antigen complex-induced production of TNF-alpha, IL-4, leukotrienes and histamine. The compound 48/80 stimulated histamine release in RBL-2H3 cells was also inhibited. Taken together, our results showed that Immulina(r) and immunLoges(r) exhibit anti-inflammatory properties and inhibited the release of histamine from mast cells. PMID- 29495394 TI - Electrophoretic Deposition of Hydroxyapatite Film Containing Re-Doped MoS2 Nanoparticles. AB - Films combining hydroxyapatite (HA) with minute amounts (ca. 1 weight %) of (rhenium doped) fullerene-like MoS2 (IF) nanoparticles were deposited onto porous titanium substrate through electrophoretic process (EPD). The films were analyzed by scanning electron microscopy (SEM), X-ray diffraction and Raman spectroscopy. The SEM analysis showed relatively uniform coatings of the HA + IF on the titanium substrate. Chemical composition analysis using energy dispersive X-ray spectroscopy (EDS) of the coatings revealed the presence of calcium phosphate minerals like hydroxyapatite, as a majority phase. Tribological tests were undertaken showing that the IF nanoparticles endow the HA film very low friction and wear characteristics. Such films could be of interest for various medical technologies. Means for improving the adhesion of the film to the underlying substrate and its fracture toughness, without compromising its biocompatibility are discussed at the end. PMID- 29495395 TI - Eight-Legged Encounters-Arachnids, Volunteers, and Art help to Bridge the Gap between Informal and Formal Science Learning. AB - Increased integration and synergy between formal and informal learning environments is proposed to provide multiple benefits to science learners. In an effort to better bridge these two learning contexts, we developed an educational model that employs the charismatic nature of arachnids to engage the public of all ages in science learning; learning that aligns with the Next Generation Science Standards (NGSS Disciplinary Core Ideas associated with Biodiversity and Evolution). We created, implemented, and evaluated a family-focused, interactive science event-Eight-Legged Encounters (ELE)-which encompasses more than twenty modular activities. Volunteers facilitated participant involvement at each activity station and original artwork scattered throughout the event was intended to attract visitors. Initial ELE goals were to increase interest in arachnids and science more generally, among ELE participants. In this study, we tested the efficacy of ELE in terms of (i) activity-specific visitation rates and self reported interest levels, (ii) the self-reported efficacy of our use of volunteers and original artwork on visitor engagement, and (iii) self-reported increases in interest in both spiders and science more generally. We collected survey data across five ELE events at four museum and zoo sites throughout the Midwest. We found that all activities were successful at attracting visitors and capturing their interest. Both volunteers and artwork were reported to be effective at engaging visitors, though likely in different ways. Additionally, most participants reported increased interest in learning about arachnids and science. In summary, ELE appears effective at engaging the public and piquing their interest. Future work is now required to assess learning outcomes directly, as well as the ability for participants to transfer knowledge gain across learning environments. PMID- 29495396 TI - Exploring Heat Stress Relief Measures among the Australian Labour Force. AB - Australia experiences frequent heat waves and generally high average temperatures throughout the continent with substantial impacts on human health and the economy. People adapt to heat by adopting various relief measures in their daily lives including changing their behaviour. Many labour intensive outdoor industries implement standards for heat stress management for their workforce. However, little is known about how people cope with heat at their workplaces apart from studies targeting some specific industries where labourers are exposed to extreme heat. Here, we analysed responses from 1719 people in the Australian labour force to self-reported heat stress and associated coping mechanisms. Three quarters of respondents experienced heat stress at their workplace with fatigue and headache being the two most frequently stated symptoms. Almost all of those who were affected by heat would hydrate (88%), 67% would cool, and 44% would rest as a strategy for coping with heat. About 10% intended to change their jobs because of heat stress in the workplace. We found differences in heat relief measures across gender, education, health, level of physical intensity of job, and time spent working outside. People working in jobs that were not very demanding physically were more likely to choose cooling down as a relief measure, while those in labour intensive jobs and jobs that required considerable time outside were more likely to rest. This has potential consequences for their productivity and work schedules. Heat affects work in Australia in many types of industry with impact dependent on workforce acclimatisation, yet public awareness and work relief plans are often limited to outdoor and labour intensive industries. Industries and various levels of government in all sectors need to implement standards for heat management specific to climate zones to help people cope better with high temperatures as well as plan strategies in anticipation of projected temperature increases. PMID- 29495397 TI - Eucommia ulmoides Ameliorates Glucotoxicity by Suppressing Advanced Glycation End Products in Diabetic Mice Kidney. AB - Eucommia ulmoides Oliv. (EU), also known as Du-Zhong, is a medicinal herb commonly used in Asia to treat hypertension and diabetes. Despite evidence of the protective effects of EU against diabetes, its precise effects and mechanisms of action against advanced glycation end-products (AGEs) are unclear. In this study, we evaluated the effects of EU on AGEs-induced renal disease and explored the possible underlying mechanisms using streptozotocin (STZ)-induced diabetic mice. STZ-induced diabetic mice received EU extract (200 mg/kg) orally for 6 weeks. EU treatment did not change blood glucose and glycated hemoglobin (HbA1c) levels in diabetic mice. However, the EU-treated group showed a significant increase in the protein expression and activity of glyoxalase 1 (Glo1), which detoxifies the AGE precursor, methylglyoxal (MGO). EU significantly upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) expression but downregulated that of receptor for AGE (RAGE). Furthermore, histological and immunohistochemical analyses of kidney tissue showed that EU reduced periodic acid-Schiff (PAS)-positive staining, AGEs, and MGO accumulation in diabetic mice. Based on these findings, we concluded that EU ameliorated the renal damage in diabetic mice by inhibiting AGEs formation and RAGE expression and reducing oxidative stress, through the Glo1 and Nrf2 pathways. PMID- 29495398 TI - Melatonin and Cancer Hallmarks. AB - Melatonin is a natural indoleamine produced by the pineal gland that has many functions, including regulation of the circadian rhythm. Many studies have reported the anticancer effect of melatonin against a myriad of cancer types. Cancer hallmarks include sustained proliferation, evading growth suppressors, metastasis, replicative immortality, angiogenesis, resisting cell death, altered cellular energetics, and immune evasion. Melatonin anticancer activity is mediated by interfering with various cancer hallmarks. This review summarizes the anticancer role of melatonin in each cancer hallmark. The studies discussed in this review should serve as a solid foundation for researchers and physicians to support basic and clinical studies on melatonin as a promising anticancer agent. PMID- 29495399 TI - Protein Phosphatase 2A in the Regulation of Wnt Signaling, Stem Cells, and Cancer. AB - Protein phosphorylation is a ubiquitous cellular process that allows for the nuanced and reversible regulation of protein activity. Protein phosphatase 2A (PP2A) is a heterotrimeric serine-threonine phosphatase-composed of a structural, regulatory, and catalytic subunit-that controls a variety of cellular events via protein dephosphorylation. While much is known about PP2A and its basic biochemistry, the diversity of its components-especially the multitude of regulatory subunits-has impeded the determination of PP2A function. As a consequence of this complexity, PP2A has been shown to both positively and negatively regulate signaling networks such as the Wnt pathway. Wnt signaling modulates major developmental processes, and is a dominant mediator of stem cell self-renewal, cell fate, and cancer stem cells. Because PP2A affects Wnt signaling both positively and negatively and at multiple levels, further understanding of this complex dynamic may ultimately provide insight into stem cell biology and how to better treat cancers that result from alterations in Wnt signaling. This review will summarize literature that implicates PP2A as a tumor suppressor, explore PP2A mutations identified in human malignancy, and focus on PP2A in the regulation of Wnt signaling and stem cells so as to better understand how aberrancy in this pathway can contribute to tumorigenesis. PMID- 29495400 TI - Delimiting Coalescence Genes (C-Genes) in Phylogenomic Data Sets. AB - coalescence methods have emerged as a popular alternative for inferring species trees with large genomic datasets, because these methods explicitly account for incomplete lineage sorting. However, statistical consistency of summary coalescence methods is not guaranteed unless several model assumptions are true, including the critical assumption that recombination occurs freely among but not within coalescence genes (c-genes), which are the fundamental units of analysis for these methods. Each c-gene has a single branching history, and large sets of these independent gene histories should be the input for genome-scale coalescence estimates of phylogeny. By contrast, numerous studies have reported the results of coalescence analyses in which complete protein-coding sequences are treated as c-genes even though exons for these loci can span more than a megabase of DNA. Empirical estimates of recombination breakpoints suggest that c-genes may be much shorter, especially when large clades with many species are the focus of analysis. Although this idea has been challenged recently in the literature, the inverse relationship between c-gene size and increased taxon sampling in a dataset-the 'recombination ratchet'-is a fundamental property of c-genes. For taxonomic groups characterized by genes with long intron sequences, complete protein-coding sequences are likely not valid c-genes and are inappropriate units of analysis for summary coalescence methods unless they occur in recombination deserts that are devoid of incomplete lineage sorting (ILS). Finally, it has been argued that coalescence methods are robust when the no-recombination within loci assumption is violated, but recombination must matter at some scale because ILS, a by-product of recombination, is the raison d'etre for coalescence methods. That is, extensive recombination is required to yield the large number of independently segregating c-genes used to infer a species tree. If coalescent methods are powerful enough to infer the correct species tree for difficult phylogenetic problems in the anomaly zone, where concatenation is expected to fail because of ILS, then there should be a decreasing probability of inferring the correct species tree using longer loci with many intralocus recombination breakpoints (i.e., increased levels of concatenation). PMID- 29495401 TI - Proper Authentication of Ancient DNA Is Still Essential. AB - Santiago-Rodriguez et al. [1] report on the putative gut microbiome and resistome of Inca and Italian mummies, and find that Italian mummies exhibit higher bacterial diversity compared to the Inca mummies.[...]. PMID- 29495402 TI - Convergent Synthesis of N,S-bis Glycosylquinolin-2-ones via a Pd-G3-XantPhos Precatalyst Catalysis. AB - Buchwald-Hartwig-Migita cross-coupling of 1-thiosugars with alpha- or beta-3-iodo N-glycosylquinolin-2-ones has been accomplished under mild and operationally simple reaction conditions through the use of a Pd-G3 XantPhos palladacycle precatalyst. This new methodology has been successfully applied to a variety of alpha- or beta-mono-, di-, and poly-thiosugar derivatives to efficiently synthesize a series of alpha- or beta-N,S-bis-glycosyl quinolin-2-ones, which are difficult to synthesize by classical methods. PMID- 29495404 TI - Targeting Glioblastoma Cells Expressing CD44 with Liposomes Encapsulating Doxorubicin and Displaying Chlorotoxin-IgG Fc Fusion Protein. AB - We recently have established a successful xenograft model of human glioblastoma cells by enriching hyaluronic acid-dependent spheroid-forming populations termed U251MG-P1 cells from U251MG cells. Since U251MG-P1 cells have been confirmed to express CD44 along with principal stemness marker genes, OCT3/4, SOX2, KLF4 and Nanog, this CD44 expressing population appeared to majorly consist of undifferentiated cells. Evaluating the sensitivity to anti-cancer agents, we found U251MG-P1 cells were sensitive to doxorubicin with IC50 at 200 nM. Although doxorubicin has serious side-effects, establishment of an efficient therapy targeting undifferentiated glioblastoma cell population is necessary. We previously designed a chlorotoxin peptide fused to human IgG Fc region without hinge sequence (M-CTX-Fc), which exhibited a stronger growth inhibitory effect on the glioblastoma cell line A172 than an original chlorotoxin peptide. Combining these results together, we designed M-CTX-Fc conjugated liposomes encapsulating doxorubicin and used U251MG-P1 cells as the target model in this study. The liposome modified with M-CTX-Fc was designed with a diameter of approximately 100 150 nm and showed high encapsulation efficiency, adequate loading capacity of anticancer drug, enhanced antitumor effects demonstrating increasing uptake into the cells in vitro; M-CTX-Fc-L-Dox shows great promise in its ability to suppress tumor growth in vivo and it could serve as a template for targeted delivery of other therapeutics. PMID- 29495403 TI - Seihai-to (TJ-90)-Induced Activation of Airway Ciliary Beatings of Mice: Ca2+ Modulation of cAMP-Stimulated Ciliary Beatings via PDE1. AB - Sei-hai-to (TJ-90, Qing Fei Tang), a Chinese traditional medicine, increases ciliary beat frequency (CBF) and ciliary bend angle (CBA) mediated via cAMP (3',5'-cyclic adenosine monophosphate) accumulation modulated by Ca2+-activated phosphodiesterase 1 (PDE1A). A high concentration of TJ-90 (>=40 MUg/mL) induced two types of CBF increases, a transient increase (an initial increase, followed by a decrease) and a sustained increase without any decline, while it only sustained the CBA increase. Upon inhibiting increases in intracellular Ca2+ concentration ([Ca2+]i) by 10 MUM BAPTA-AM (Ca2+-chelator, 1,2-Bis(2 aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester) or Ca2+/calmodulin-dependent PDE1 by 8MmIBMX (a selective PDE1 inhibitor), TJ-90 (400 MUg/mL) induced only the sustained CBF increase without any transient CBF increase. The two types of the CBF increase (the transient increase and the sustained increase) induced by TJ-90 (>=40 MUg/mL) were mimicked by the stimulation with both procaterol (100 pM) and ionomycin (500 nM). Thus, TJ-90 stimulates small increases in the intracellular cAMP concentration ([cAMP]i) and [Ca2+]i in airway ciliary cells of mice. These small increases in [cAMP]i and [Ca2+]i cause inducing a transient CBF increase or a sustained CBF increase in an airway ciliary cells, depending on the dominant signal, Ca2+-signal, or cAMP signal. PMID- 29495405 TI - Cross-Resistance: A Consequence of Bi-partite Host-Parasite Coevolution. AB - Host-parasite coevolution can influence interactions of the host and parasite with the wider ecological community. One way that this may manifest is in cross resistance towards other parasites, which has been observed to occur in some host parasite evolution experiments. In this paper, we test for cross-resistance towards Bacillus thuringiensis and Pseudomonasentomophila in the red flour beetle Triboliumcastaneum, which was previously allowed to coevolve with the generalist entomopathogenic fungus Beauveriabassiana. We combine survival and gene expression assays upon infection to test for cross-resistance and underlying mechanisms. We show that larvae of T.castaneum that evolved with B.bassiana under coevolutionary conditions were positively cross-resistant to the bacterium B. thuringiensis, but not P.entomophila. Positive cross-resistance was mirrored at the gene expression level with markers that were representative of the oral route of infection being upregulated upon B.bassiana exposure. We find that positive cross-resistance towards B. thuringiensis evolved in T.castaneum as a consequence of its coevolutionary interactions with B.bassiana. This cross-resistance appears to be a consequence of resistance to oral toxicity. The fact that coevolution with B.bassiana results in resistance to B. thuringiensis, but not P.entomophila implies that B. thuringiensis and B.bassiana may share mechanisms of infection or toxicity not shared by P.entomophila. This supports previous suggestions that B.bassiana may possess Cry-like toxins, similar to those found in B. thuringiensis, which allow it to infect orally. PMID- 29495406 TI - An Energy-Efficient Approach to Enhance Virtual Sensors Provisioning in Sensor Clouds Environments. AB - Virtual sensors provisioning is a central issue for sensors cloud middleware since it is responsible for selecting physical nodes, usually from Wireless Sensor Networks (WSN) of different owners, to handle user's queries or applications. Recent works perform provisioning by clustering sensor nodes based on the correlation measurements and then selecting as few nodes as possible to preserve WSN energy. However, such works consider only homogeneous nodes (same set of sensors). Therefore, those works are not entirely appropriate for sensor clouds, which in most cases comprises heterogeneous sensor nodes. In this paper, we propose ACxSIMv2, an approach to enhance the provisioning task by considering heterogeneous environments. Two main algorithms form ACxSIMv2. The first one, ACASIMv1, creates multi-dimensional clusters of sensor nodes, taking into account the measurements correlations instead of the physical distance between nodes like most works on literature. Then, the second algorithm, ACOSIMv2, based on an Ant Colony Optimization system, selects an optimal set of sensors nodes from to respond user's queries while attending all parameters and preserving the overall energy consumption. Results from initial experiments show that the approach reduces significantly the sensor cloud energy consumption compared to traditional works, providing a solution to be considered in sensor cloud scenarios. PMID- 29495407 TI - Spatio-Temporal Analysis of Urban Acoustic Environments with Binaural Psycho Acoustical Considerations for IoT-Based Applications. AB - Sound pleasantness or annoyance perceived in urban soundscapes is a major concern in environmental acoustics. Binaural psychoacoustic parameters are helpful to describe generic acoustic environments, as it is stated within the ISO 12913 framework. In this paper, the application of a Wireless Acoustic Sensor Network (WASN) to evaluate the spatial distribution and the evolution of urban acoustic environments is described. Two experiments are presented using an indoor and an outdoor deployment of a WASN with several nodes using an Internet of Things (IoT) environment to collect audio data and calculate meaningful parameters such as the sound pressure level, binaural loudness and binaural sharpness. A chunk of audio is recorded in each node periodically with a microphone array and the binaural rendering is conducted by exploiting the estimated directional characteristics of the incoming sound by means of DOA estimation. Each node computes the parameters in a different location and sends the values to a cloud-based broker structure that allows spatial statistical analysis through Kriging techniques. A cross validation analysis is also performed to confirm the usefulness of the proposed system. PMID- 29495409 TI - Enhancing Perception with Tactile Object Recognition in Adaptive Grippers for Human-Robot Interaction. AB - The use of tactile perception can help first response robotic teams in disaster scenarios, where visibility conditions are often reduced due to the presence of dust, mud, or smoke, distinguishing human limbs from other objects with similar shapes. Here, the integration of the tactile sensor in adaptive grippers is evaluated, measuring the performance of an object recognition task based on deep convolutional neural networks (DCNNs) using a flexible sensor mounted in adaptive grippers. A total of 15 classes with 50 tactile images each were trained, including human body parts and common environment objects, in semi-rigid and flexible adaptive grippers based on the fin ray effect. The classifier was compared against the rigid configuration and a support vector machine classifier (SVM). Finally, a two-level output network has been proposed to provide both object-type recognition and human/non-human classification. Sensors in adaptive grippers have a higher number of non-null tactels (up to 37% more), with a lower mean of pressure values (up to 72% less) than when using a rigid sensor, with a softer grip, which is needed in physical human-robot interaction (pHRI). A semi rigid implementation with 95.13% object recognition rate was chosen, even though the human/non-human classification had better results (98.78%) with a rigid sensor. PMID- 29495408 TI - Label-Free Quantification of Anti-TNF-alpha in Patients Treated with Adalimumab Using an Optical Biosensor. AB - This study describes the development of an immunosensory label-free quantification methodology based on surface plasmon resonance (SPR) and its applicability in measuring/evaluating therapeutic drug monitoring (TDM) of anti TNF-alpha monoclonal antibody (adalimumab) in rheumatoid arthritis (RA) patients. The experimental parameters evaluated in this study were immobilising ligands by pre-concentration assays, sensor surface regeneration, ascertaining the method's sensitivity and correlating the results from quantifying plasma samples by ELISA immunoassay. The results showed that TNF-alpha quantification values (in RU) were significantly different when comparing patients (~50-250 RU) to controls (~10-20 RU). Likewise, there was 0.97 correlation for patients and 0.91 for healthy volunteers using SPR and ELISA comparison methodologies. SPR immunosensory detection provided a precise, sensitive strategy, along with real-time determination, for quantifying adalimumab, having great potential for clinical routine regarding TDM. PMID- 29495410 TI - An Unsupervised Deep Hyperspectral Anomaly Detector. AB - Hyperspectral image (HSI) based detection has attracted considerable attention recently in agriculture, environmental protection and military applications as different wavelengths of light can be advantageously used to discriminate different types of objects. Unfortunately, estimating the background distribution and the detection of interesting local objects is not straightforward, and anomaly detectors may give false alarms. In this paper, a Deep Belief Network (DBN) based anomaly detector is proposed. The high-level features and reconstruction errors are learned through the network in a manner which is not affected by previous background distribution assumption. To reduce contamination by local anomalies, adaptive weights are constructed from reconstruction errors and statistical information. By using the code image which is generated during the inference of DBN and modified by adaptively updated weights, a local Euclidean distance between under test pixels and their neighboring pixels is used to determine the anomaly targets. Experimental results on synthetic and recorded HSI datasets show the performance of proposed method outperforms the classic global Reed-Xiaoli detector (RXD), local RX detector (LRXD) and the-state-of-the art Collaborative Representation detector (CRD). PMID- 29495411 TI - Probabilities of False Alarm for Vital Sign Detection on the Basis of a Doppler Radar System. AB - Vital detection on the basis of Doppler radars has drawn a great deal of attention from researchers because of its high potential for applications in biomedicine, surveillance, and finding people alive under debris during natural hazards. In this research, the signal-to-noise ratio (SNR) of the remote vital sign detection system is investigated. On the basis of different types of noise, such as phase noise, Gaussian noise, leakage noise between the transmitting and receiving antennae, and so on, the SNR of the system has first been examined. Then the research has focused on the investigation of the detection and false alarm probabilities of the system when the transmission link between the human and the radar sensor system took the Nakagami-m channel model. The analytical model for the false alarm and the detection probabilities of the system have been derived. The proposed theoretical models for the SNR and detection probability match with the simulation and measurement results. These theoretical models have the potential to be used as good references for the hardware development of the vital-sign detection radar sensor system. PMID- 29495413 TI - A Novel Adaptively-Robust Strategy Based on the Mahalanobis Distance for GPS/INS Integrated Navigation Systems. AB - As an optimal estimation method, the Kalman filter is the most frequently-used data fusion strategy in the field of dynamic navigation and positioning. Nevertheless, the abnormal model errors seriously degrade performance of the conventional Kalman filter. The adaptive Kalman filter was put forward to control the influences of model errors. However, the adaptive Kalman filter based on the predicted residuals (innovation vector) requires reliable observation information, and its performance is significantly affected by outliers in the measurements. In this paper, a novel adaptively-robust strategy based on the Mahalanobis distance is proposed to weaken the effects of abnormal model deviations and outliers in the measurements. In the proposed scheme, the judging index is defined based on the Mahalanobis distance, and the adaptively-robust filtering is performed when the observations are reliable, otherwise, the robust filtering is performed based on the robust estimation method. Various experiments with the actual data of GPS/INS integrated navigation systems are implemented to examine validity of the proposed scheme. Results show that both the influences of model deviations and outliers are weakened effectively by using the proposed adaptive robust filtering scheme. Moreover, the proposed scheme is easy to implement with a reasonable calculation burden. PMID- 29495412 TI - Design of Two Alternative Routes for the Synthesis of Naftifine and Analogues as Potential Antifungal Agents. AB - Two practical and efficient approaches have been implemented as alternative procedures for the synthesis of naftifine and novel diversely substituted analogues 16 and 20 in good to excellent yields, mediated by Mannich-type reactions as the key step of the processes. In these approaches, the gamma aminoalcohols 15 and 19 were obtained as the key intermediates and their subsequent dehydration catalyzed either by Bronsted acids like H2SO4 and HCl or Lewis acid like AlCl3, respectively, led to naftifine, along with the target allylamines 16 and 20. The antifungal assay results showed that intermediates 18 (bearing both a beta-aminoketo- and N-methyl functionalities in their structures) and products 20 were the most active. Particularly, structures 18b, 18c, and the allylamine 20c showed the lowest MIC values, in the 0.5-7.8 ug/mL range, against the dermatophytes Trichophyton rubrum and Trichophyton mentagrophytes. Interesting enough, compound 18b bearing a 4-Br as the substituent of the phenyl ring, also displayed high activity against Candida albicans and Cryptococcus neoformans with MIC80 = 7.8 ug/mL, being fungicide rather than fungistatic with a relevant MFC value = 15.6 ug/mL against C. neoformans. PMID- 29495414 TI - Analysis of Resonance Asymmetry Phenomenon in Resonant Fiber Optic Gyro. AB - This experiment demonstrated the resonance asymmetry phenomenon in the resonant fiber optic gyro. The asymmetry of resonant curve affects the system open-loop bias and its stability, which directly affects the accuracy of angular velocity measurement. In this paper, a new mathematic model is established. The influence of the coupler normal mode loss difference (the phase difference between the coupler cross port output optical field and direct port is less than the ideal pi/2) on the symmetry of resonant curve, the resonant signal modulated by the triangular wave, and the demodulation curve are analyzed. Moreover, the asymmetry of the resonant curve leads to the asymmetry of the resonant signal, as modulated by the triangular wave and the demodulation curve from the theoretical simulation and the experiment. PMID- 29495415 TI - Embedding Dimension Selection for Adaptive Singular Spectrum Analysis of EEG Signal. AB - The recorded electroencephalography (EEG) signal is often contaminated with different kinds of artifacts and noise. Singular spectrum analysis (SSA) is a powerful tool for extracting the brain rhythm from a noisy EEG signal. By analyzing the frequency characteristics of the reconstructed component (RC) and the change rate in the trace of the Toeplitz matrix, it is demonstrated that the embedding dimension is related to the frequency bandwidth of each reconstructed component, in consistence with the component mixing in the singular value decomposition step. A method for selecting the embedding dimension is thereby proposed and verified by simulated EEG signal based on the Markov Process Amplitude (MPA) EEG Model. Real EEG signal is also collected from the experimental subjects under both eyes-open and eyes-closed conditions. The experimental results show that based on the embedding dimension selection method, the alpha rhythm can be extracted from the real EEG signal by the adaptive SSA, which can be effectively utilized to distinguish between the eyes-open and eyes closed states. PMID- 29495416 TI - New Keypoint Matching Method Using Local Convolutional Features for Power Transmission Line Icing Monitoring. AB - Power transmission line icing (PTLI) problems, which cause tremendous damage to the power grids, has drawn much attention. Existing three-dimensional measurement methods based on binocular stereo vision was recently introduced to measure the ice thickness in PTLI, but failed to meet requirements of practical applications due to inefficient keypoint matching in the complex PTLI scene. In this paper, a new keypoint matching method is proposed based on the local multi-layer convolutional neural network (CNN) features, termed Local Convolutional Features (LCFs). LCFs are deployed to extract more discriminative features than the conventional CNNs. Particularly in LCFs, a multi-layer features fusion scheme is exploited to boost the matching performance. Together with a location constraint method, the correspondence of neighboring keypoints is further refined. Our approach achieves 1.5%, 5.3%, 13.1%, 27.3% improvement in the average matching precision compared with SIFT, SURF, ORB and MatchNet on the public Middlebury dataset, and the measurement accuracy of ice thickness can reach 90.9% compared with manual measurement on the collected PTLI dataset. PMID- 29495417 TI - Combining Deep and Handcrafted Image Features for Presentation Attack Detection in Face Recognition Systems Using Visible-Light Camera Sensors. AB - Although face recognition systems have wide application, they are vulnerable to presentation attack samples (fake samples). Therefore, a presentation attack detection (PAD) method is required to enhance the security level of face recognition systems. Most of the previously proposed PAD methods for face recognition systems have focused on using handcrafted image features, which are designed by expert knowledge of designers, such as Gabor filter, local binary pattern (LBP), local ternary pattern (LTP), and histogram of oriented gradients (HOG). As a result, the extracted features reflect limited aspects of the problem, yielding a detection accuracy that is low and varies with the characteristics of presentation attack face images. The deep learning method has been developed in the computer vision research community, which is proven to be suitable for automatically training a feature extractor that can be used to enhance the ability of handcrafted features. To overcome the limitations of previously proposed PAD methods, we propose a new PAD method that uses a combination of deep and handcrafted features extracted from the images by visible light camera sensor. Our proposed method uses the convolutional neural network (CNN) method to extract deep image features and the multi-level local binary pattern (MLBP) method to extract skin detail features from face images to discriminate the real and presentation attack face images. By combining the two types of image features, we form a new type of image features, called hybrid features, which has stronger discrimination ability than single image features. Finally, we use the support vector machine (SVM) method to classify the image features into real or presentation attack class. Our experimental results indicate that our proposed method outperforms previous PAD methods by yielding the smallest error rates on the same image databases. PMID- 29495418 TI - Deep-Coverage MPS Analysis of Heteroplasmic Variants within the mtGenome Allows for Frequent Differentiation of Maternal Relatives. AB - Abstract: Distinguishing between maternal relatives through mitochondrial (mt) DNA sequence analysis has been a longstanding desire of the forensic community. Using a deep-coverage, massively parallel sequencing (DCMPS) approach, we studied the pattern of mtDNA heteroplasmy across the mtgenomes of 39 mother-child pairs of European decent; haplogroups H, J, K, R, T, U, and X. Both shared and differentiating heteroplasmy were observed on a frequent basis in these closely related maternal relatives, with the minor variant often presented as 2-10% of the sequencing reads. A total of 17 pairs exhibited differentiating heteroplasmy (44%), with the majority of sites (76%, 16 of 21) occurring in the coding region, further illustrating the value of conducting sequence analysis on the entire mtgenome. A number of the sites of differentiating heteroplasmy resulted in non synonymous changes in protein sequence (5 of 21), and to changes in transfer or ribosomal RNA sequences (5 of 21), highlighting the potentially deleterious nature of these heteroplasmic states. Shared heteroplasmy was observed in 12 of the 39 mother-child pairs (31%), with no duplicate sites of either differentiating or shared heteroplasmy observed; a single nucleotide position (16093) was duplicated between the data sets. Finally, rates of heteroplasmy in blood and buccal cells were compared, as it is known that rates can vary across tissue types, with similar observations in the current study. Our data support the view that differentiating heteroplasmy across the mtgenome can be used to frequently distinguish maternal relatives, and could be of interest to both the medical genetics and forensic communities. PMID- 29495420 TI - Evaluation of Peripheral Blood and Cord Blood Platelet Lysates in Isolation and Expansion of Multipotent Mesenchymal Stromal Cells. AB - Abstract: Background: Multipotent Mesenchymal Stromal Cells (MSCs) are used in tissue engineering and regenerative medicine. The in vitro isolation and expansion of MSCs involve the use of foetal bovine serum (FBS). However, many concerns have been raised regarding the safety of this product. In this study, alternative additives derived either from peripheral or cord blood were tested as an FBS replacement. Methods: Platelet lysates (PL) from peripheral and cord blood were used for the expansion of MSCs. The levels of growth factors in peripheral blood (PB) and cord blood (CB) PLs were determined using the Multiple Reaction Monitoring (MRM). Finally, the cell doubling time (CDT), tri-lineage differentiation and phenotypic characterization of the MSCs expanded with FBS and PLs were determined. Results: MSCs treated with culture media containing FBS and PB-PL, were successfully isolated and expanded, whereas MSCs treated with CB-PL could not be maintained in culture. Furthermore, the MRM analysis yielded differences in growth factor levels between PB-PL and CB-PL. In addition, the MSCs were successfully expanded with FBS and PB-PL and exhibited tri-lineage differentiation and stable phenotypic characteristics. Conclusion: PB-PL could be used as an alternative additive for the production of MSCs culture medium applied to xenogeneic-free expansion and maintenance of MSCs in large scale clinical studies. PMID- 29495421 TI - A Micro-Damage Detection Method of Litchi Fruit Using Hyperspectral Imaging Technology. AB - The non-destructive testing of litchi fruit is of great significance to the fresh keeping, storage and transportation of harvested litchis. To achieve quick and accurate micro-damage detection, a non-destructive grading test method for litchi fruits was studied using 400-1000 nm hyperspectral imaging technology. The Huaizhi litchi was chosen in this study, and the hyperspectral data average for the region of interest (ROI) of litchi fruit was extracted for spectral data analysis. Then the hyperspectral data samples of fresh and micro-damaged litchi fruits were selected, and a partial least squares discriminant analysis (PLS-DA) was used to establish a prediction model for the realization of qualitative analysis for litchis with different qualities. For the external validation set, the mean per-type recall and precision were 94.10% and 93.95%, respectively. Principal component analysis (PCA) was used to determine the sensitive wavelength for recognition of litchi quality characteristics, with the results of wavelengths corresponding to the local extremum for the weight coefficient of PC3, i.e., 694, 725 and 798 nm. Then the single-band images corresponding to each sensitive wavelength were analyzed. Finally, the 7-dimension features of the PC3 image were extracted using the Gray Level Co-occurrence Matrix (GLCM). Through image processing, least squares support vector machine (LS-SVM) modeling was conducted to classify the different qualities of litchis. The model was validated using the experiment data, and the average accuracy of the validation set was 93.75%, while the external validation set was 95%. The results indicate the feasibility of using hyperspectral imaging technology in litchi postpartum non destructive detection and classification. PMID- 29495419 TI - Effects of Dietary Vitamin E Supplementation in Bladder Function and Spasticity during Spinal Cord Injury. AB - Traumatic spinal cord injury (SCI) results in debilitating autonomic dysfunctions, paralysis and significant sensorimotor impairments. A key component of SCI is the generation of free radicals that contributes to the high levels of oxidative stress observed. This study investigates whether dietary supplementation with the antioxidant vitamin E (alpha-tocopherol) improves functional recovery after SCI. Female adult Sprague-Dawley rats were fed either with a normal diet or a dietary regiment supplemented with vitamin E (51 IU/g) for eight weeks. The rats were subsequently exposed either to a contusive SCI or sham operation, and evaluated using standard functional behavior analysis. We report that the rats that consumed the vitamin E-enriched diet showed an accelerated bladder recovery and significant improvements in locomotor function relative to controls, as determined by residual volumes and Basso, Beatie, and Bresnaham BBB scores, respectively. Interestingly, the prophylactic dietary intervention did not preserve neurons in the ventral horn of injured rats, but it significantly increased the numbers of oligodendrocytes. Vitamin E supplementation attenuated the depression of the H-reflex (a typical functional consequence of SCI) while increasing the levels of supraspinal serotonin immunoreactivity. Our findings support the potential complementary use of vitamin E to ameliorate sensory and autonomic dysfunctions associated with spinal cord injury, and identified promising new cellular and functional targets of its neuroprotective effects. PMID- 29495422 TI - A Genome-Wide Association Study of Idiopathic Dilated Cardiomyopathy in African Americans. AB - Idiopathic dilated cardiomyopathy (IDC) is the most common form of non-ischemic chronic heart failure. Despite the higher prevalence of IDC in African Americans, the genetics of IDC have been relatively understudied in this ethnic group. We performed a genome-wide association study to identify susceptibility genes for IDC in African Americans recruited from five sites in the U.S. (662 unrelated cases and 1167 controls). The heritability of IDC was calculated to be 33% (95% confidence interval: 19-47%; p = 6.4 * 10-7). We detected association of a variant in a novel intronic locus in the CACNB4 gene meeting genome-wide levels of significance (p = 4.1 * 10-8). The CACNB4 gene encodes a calcium channel subunit expressed in the heart that is important for cardiac muscle contraction. This variant has not previously been associated with IDC in any racial group. Pathway analysis, based on the 1000 genes most strongly associated with IDC, showed an enrichment for genes related to calcium signaling, growth factor signaling, neuronal/neuromuscular signaling, and various types of cellular level signaling, including gap junction and cAMP signaling. Our results suggest a novel locus for IDC in African Americans and provide additional insights into the genetic architecture and etiology. PMID- 29495423 TI - C-Reactive Protein to Albumin Ratio Predicts 30-Day and 1-Year Mortality in Postoperative Patients after Admission to the Intensive Care Unit. AB - C-reactive protein and albumin are associated with poor outcomes in critically ill patients. This study aimed to investigate the significance of the C-reactive protein/albumin (CRP/ALB) ratio as a novel prognostic factor for 30-day or 1-year mortality after admission to the postoperative intensive care unit (ICU). This retrospective study was conducted by examining the medical records of postoperative patients aged 19 years or older admitted to the ICU at a tertiary care hospital from January 2007 to July 2016. This study included data on 11,832 postoperative patients in the analysis. The cut-off value of the CRP/ALB ratio was set at 1.75 and 1.58 for 30-day and 1-year mortality after ICU admission, respectively. In postoperative patients with a high CRP/ALB ratio (>1.75 or >1.58), the probability of death within 30 days or 1 year after ICU admission were 30% or 43% higher than that in the group with the least CRP/ALB ratio, respectively (<=1.75 or <=1.58)(p < 0.05). This study found the CRP/ALB ratio measured immediately after ICU admission to be an independent risk factor for 30 day and 1-year mortality in postoperative patients admitted to the ICU. PMID- 29495424 TI - Simple Approaches to Minimally-Instrumented, Microfluidic-Based Point-of-Care Nucleic Acid Amplification Tests. AB - Designs and applications of microfluidics-based devices for molecular diagnostics (Nucleic Acid Amplification Tests, NAATs) in infectious disease testing are reviewed, with emphasis on minimally instrumented, point-of-care (POC) tests for resource-limited settings. Microfluidic cartridges ('chips') that combine solid phase nucleic acid extraction; isothermal enzymatic nucleic acid amplification; pre-stored, paraffin-encapsulated lyophilized reagents; and real-time or endpoint optical detection are described. These chips can be used with a companion module for separating plasma from blood through a combined sedimentation-filtration effect. Three reporter types: Fluorescence, colorimetric dyes, and bioluminescence; and a new paradigm for end-point detection based on a diffusion reaction column are compared. Multiplexing (parallel amplification and detection of multiple targets) is demonstrated. Low-cost detection and added functionality (data analysis, control, communication) can be realized using a cellphone platform with the chip. Some related and similar-purposed approaches by others are surveyed. PMID- 29495425 TI - Resilience in Elders of the Sardinian Blue Zone: An Explorative Study. AB - Background: older adults from the Sardinian Blue Zone self-report low depressive symptoms and high psychological well-being. However, the role of dispositional resilience as a determinant of these characteristics is unknown. Objectives: the current study had three aims. First, to investigate associations among several putative predictors, including dispositional resilience and three established markers of positive and negative mental health. Second, to determine if gender differences in dispositional resilience, independent of age and cognitive impairment, are present in this population. Third, to examine the relative importance of the predictors of self-reported mental health and well-being. Methods: 160 elders were recruited in the Sardinian Blue Zone. The participants completed self-report measures of dispositional resilience, satisfaction with social ties, physical health, depressive symptoms, and psychological well-being. Results: trait resilience was significantly associated with predictors and markers of mental health. Males had significantly greater trait resilience. In regression analyses, dispositional resilience and satisfaction with social ties were significant predictors of all markers of mental health. Other factors were significantly associated only with certain markers. Conclusions: trait resilience and strong social ties appear to be key determinants of the high mental health of Sardinian Blue Zone older adults. PMID- 29495427 TI - Synthesis of ZnMn2O4 Nanoparticles by a Microwave-Assisted Colloidal Method and their Evaluation as a Gas Sensor of Propane and Carbon Monoxide. AB - Spinel-type ZnMn2O4 nanoparticles were synthesized via a simple and inexpensive microwave-assisted colloidal route. Structural studies by X-ray diffraction showed that a spinel crystal phase of ZnMn2O4 was obtained at a calcination temperature of 500 degrees C, which was confirmed by Raman and UV-vis characterizations. Spinel-type ZnMn2O4 nanoparticles with a size of 41 nm were identified by transmission electron microscopy. Pellet-type sensors were fabricated using ZnMn2O4 nanoparticles as sensing material. Sensing measurements were performed by exposing the sensor to different concentrations of propane or carbon monoxide at temperatures in the range from 100 to 300 degrees C. Measurements performed at an operating temperature of 300 degrees C revealed a good response to 500 ppm of propane and 300 ppm of carbon monoxide. Hence, ZnMn2O4 nanoparticles possess a promising potential in the gas sensors field. PMID- 29495428 TI - A Text Structuring Method for Chinese Medical Text Based on Temporal Information. AB - Chinese Electronic Medical Records (EMRs) contains a large number of complex medical free text which includes a variety of information, such as temporal information, patients' symptoms and laboratory data. However, as an important knowledge base, these unstructured text data in EMR are hard to process directly by computer to support further medical research. This paper proposes a novel text structuring method to extract knowledge from EMR texts and reorganize them in chronological order according to the temporal information in the text. By implementing some entropy-based algorithms as contrast, experiments evaluate the performance of the proposed method, which indicates the new method can significantly reduce the complexity of EMR text. This work is significant in structuring the EMR free text into temporal-structured data for further medical analysis. PMID- 29495426 TI - Chronic Blockade of Brain Endothelin Receptor Type-A (ETA) Reduces Blood Pressure and Prevents Catecholaminergic Overactivity in the Right Olfactory Bulb of DOCA Salt Hypertensive Rats. AB - Overactivity of the sympathetic nervous system and central endothelins (ETs) are involved in the development of hypertension. Besides the well-known brain structures involved in the regulation of blood pressure like the hypothalamus or locus coeruleus, evidence suggests that the olfactory bulb (OB) also modulates cardiovascular function. In the present study, we evaluated the interaction between the endothelinergic and catecholaminergic systems in the OB of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Following brain ET receptor type A (ETA) blockade by BQ610 (selective antagonist), transcriptional, traductional, and post-traductional changes in tyrosine hydroxylase (TH) were assessed in the OB of normotensive and DOCA-salt hypertensive rats. Time course variations in systolic blood pressure and heart rate were also registered. Results showed that ETA blockade dose dependently reduced blood pressure in hypertensive rats, but it did not change heart rate. It also prevented the increase in TH activity and expression (mRNA and protein) in the right OB of hypertensive animals. However, ETA blockade did not affect hemodynamics or TH in normotensive animals. Present results support that brain ETA are not involved in blood pressure regulation in normal rats, but they significantly contribute to chronic blood pressure elevation in hypertensive animals. Changes in TH activity and expression were observed in the right but not in the left OB, supporting functional asymmetry, in line with previous studies regarding cardiovascular regulation. Present findings provide further evidence on the role of ETs in the regulation of catecholaminergic activity and the contribution of the right OB to DOCA-salt hypertension. PMID- 29495429 TI - Enhanced Delivery of Therapeutic siRNA into Glioblastoma Cells Using Dendrimer Entrapped Gold Nanoparticles Conjugated with beta-Cyclodextrin. AB - We describe a safe and highly effective non-viral vector system based on beta cyclodextrin (beta-CD)-modified dendrimer-entrapped gold nanoparticles (Au DENPs) for improved delivery small interfering RNA (siRNA) to glioblastoma cells. In our approach, we utilized amine-terminated generation 5 poly(amidoamine) dendrimers partially grafted with beta-CD as a nanoreactor to entrap Au NPs. The acquired beta-CD-modified Au DENPs (Au DENPs-beta-CD) were complexed with two different types of therapeutic siRNA (B-cell lymphoma/leukemia-2 (Bcl-2) siRNA and vascular endothelial growth factor (VEGF) siRNA). The siRNA compression ability of the Au DENPs-beta-CD was evaluated by various methods. The cytocompatibility of the vector/siRNA polyplexes was assessed by viability assay of cells. The siRNA transfection capability of the formed Au DENPs-beta-CD vector was evaluated by flow cytometric assay of the cellular uptake of the polyplexes and Western blot assays of the Bcl-2 and VEGF protein expression. Our data reveals that the formed Au DENPs-beta-CD carrier enables efficiently delivery of siRNA to glioma cells, has good cytocompatibility once complexed with the siRNA, and enables enhanced gene silencing to inhibit the expression of Bcl-2 and VEGF proteins. The developed Au DENPs-beta-CD vector may be used for efficient siRNA delivery to different biosystems for therapeutic purposes. PMID- 29495430 TI - Low Transfer of Tacrolimus and Its Metabolites into Colostrum of Graft Recipient Mothers. AB - Currently, the majority of neonates born to organ recipient mothers on chronic immunosuppressive therapy are formula fed. However, over the past few years, evidence has grown, suggesting that breastfeeding might be possible and beneficial. We designed a study assessing the transfer of tacrolimus into the colostrum of posttransplant mothers. We assessed the amount of tacrolimus and its metabolites, M-1 and M-3, that would be ingested by the breastfed neonates. Concentrations of tacrolimus and its metabolites were measured in colostrum from 14 posttransplant mothers as well as in venous cord blood and venous blood of the neonates. Test material analysis was performed by liquid chromatography coupled with mass spectrometry (LC/MS). The amount of ingested formula was registered, which allowed for estimation of the amount of tacrolimus and its metabolites that would be ingested by breastfed infants. The mean amount of tacrolimus that would be ingested by the neonates in maternal milk was 151.4 ng/kg/24 h (standard deviation SD +/- 74.39); metabolite M-1: 23.80 ng/kg/24 h (SD +/- 14.53); and metabolite M-3: 13.25 ng/kg/24 h (SD +/- 9.05). The peak level of tacrolimus and metabolite M-1 in colostrum was noted 8 h after an oral dose (3.219 ng/mL SD +/- 2.22 and 0.56 ng/mL SD +/- 0.60, respectively) and metabolite M-3 after 6 h (0.29 ng/mL SD +/- 0.22). Low concentrations of tacrolimus and its metabolites, M-1 and M-3, in colostrum show that neonates will ingest trace amounts of the drug. Further studies are required to fully assess the safety of breastfeeding by posttransplant mothers. PMID- 29495431 TI - Evaluation of Anti-Metastatic Potential of the Combination of Fisetin with Paclitaxel on A549 Non-Small Cell Lung Cancer Cells. AB - The identification and development of new agents with a therapeutic potential as well as novel drug combinations are gaining the attention of scientists and clinicians as a plausible approach to improve therapeutic regimens for chemoresistant tumors. We have recently reported that the flavonoid fisetin (FIS), at physiologically attainable concentrations, acts synergistically with clinically achievable doses of paclitaxel (PTX) to produce growth inhibitory and pro-death effects on A549 human non-small cell lung cancer (NSCLC) cells. To further investigate a potential therapeutic efficacy of the combination of fisetin with paclitaxel, we decided to assess its impact on metastatic capability of A549 cells as well as its toxicity toward normal human lung fibroblast. Cell viability, cell migration, and invasion were measured by thiazolyl blue tetrazolium bromide (MTT) assay, wound healing assay, and Transwell chamber assay, respectively. The expression of metastasis-related genes was assessed with quantitative reverse transcriptase real-time polymerase chain reaction (qRT-PCR). Actin and vimentin filaments were examined under the fluorescence microscope. The combination of FIS and PTX significantly reduced cancer cell migration and invasion, at least partially, through a marked rearrangement of actin and vimentin cytoskeleton and the modulation of metastasis-related genes. Most of these effects of the combination treatment were significantly greater than those of individual agents. Paclitaxel alone was even more toxic to normal cells than the combination of this drug with the flavonoid, suggesting that FIS may provide some protection against PTX-mediated cytotoxicity. The combination of FIS and PTX is expected to have a synergistic anticancer efficacy and a significant potential for the treatment of NSCLC, however, further in vitro and in vivo studies are required to confirm this preliminary evidence. PMID- 29495432 TI - Compatibility between Legumes and Rhizobia for the Establishment of a Successful Nitrogen-Fixing Symbiosis. AB - The root nodule symbiosis established between legumes and rhizobia is an exquisite biological interaction responsible for fixing a significant amount of nitrogen in terrestrial ecosystems. The success of this interaction depends on the recognition of the right partner by the plant within the richest microbial ecosystems on Earth, the soil. Recent metagenomic studies of the soil biome have revealed its complexity, which includes microorganisms that affect plant fitness and growth in a beneficial, harmful, or neutral manner. In this complex scenario, understanding the molecular mechanisms by which legumes recognize and discriminate rhizobia from pathogens, but also between distinct rhizobia species and strains that differ in their symbiotic performance, is a considerable challenge. In this work, we will review how plants are able to recognize and select symbiotic partners from a vast diversity of surrounding bacteria. We will also analyze recent advances that contribute to understand changes in plant gene expression associated with the outcome of the symbiotic interaction. These aspects of nitrogen-fixing symbiosis should contribute to translate the knowledge generated in basic laboratory research into biotechnological advances to improve the efficiency of the nitrogen-fixing symbiosis in agronomic systems. PMID- 29495434 TI - Auto-Calibration and Fault Detection and Isolation of Skewed Redundant Accelerometers in Measurement While Drilling Systems. AB - The present study designed skewed redundant accelerometers for a Measurement While Drilling (MWD) tool and executed auto-calibration, fault diagnosis and isolation of accelerometers in this tool. The optimal structure includes four accelerometers was selected and designed precisely in accordance with the physical shape of the existing MWD tool. A new four-accelerometer structure was designed, implemented and installed on the current system, replacing the conventional orthogonal structure. Auto-calibration operation of skewed redundant accelerometers and all combinations of three accelerometers have been done. Consequently, biases, scale factors, and misalignment factors of accelerometers have been successfully estimated. By defecting the sensors in the new optimal skewed redundant structure, the fault was detected using the proposed FDI method and the faulty sensor was diagnosed and isolated. The results indicate that the system can continue to operate with at least three correct sensors. PMID- 29495433 TI - Inhibiting the NLRP3 Inflammasome Activation with MCC950 Ameliorates Diabetic Encephalopathy in db/db Mice. AB - Diabetes is associated with a high risk of developing cognitive dysfunction and neuropsychiatric disabilities, and these disease symptomsare termed diabetic encephalopathy (DEP). Inflammation is involved in the development of DEP. The cleavage and maturation of the proinflammatory cytokine interleukin (IL)-1beta is regulated by the NLRP3 inflammasome. Obese and type 2 diabetic db/db mice show anxiety- and depression-like behaviors and cognitive disorders associated with hippocampal inflammation. The purpose of this study was to explore the role of NLRP3 inflammasome in DEP. Results showed that expression levels of inflammasome components including NLRP3, apoptosis-associated speck-like protein (ASC), and caspase-1, as well as IL-1beta in the hippocampus of diabetic db/db mice were higher than those of non-diabetic db/m mice. Treatment of db/db mice with NLRP3 inflammasome inhibitor MCC950 ameliorated anxiety- and depression-like behaviors as well as cognitive dysfunction, and reversed increased NLRP3, ASC, and IL 1betaexpression levels and caspase-1 activity in hippocampus. Moreover, MCC950 treatment significantly improved insulin sensitivity in db/db mice. These results demonstrate that inhibition of NLRP3 inflammasome activation may prove to be a potential therapeutic approach for DEP treatment. PMID- 29495435 TI - Melatonin in Apples and Juice: Inhibition of Browning and Microorganism Growth in Apple Juice. AB - Synthetic melatonin (N-acetyl-5-methoxytryptamine, MT) is popular in the US and Asian markets as a health supplement. Here, we identified a naturally occurring melatonin source in apple juice. Melatonin was present in all 18 apple cultivars tested. The highest melatonin level of the edible part of apple was detected in the apple peel. The melatonin content in 'Fuji' apple juice is comparable to the level of its flesh. Melatonin was consumed during the process of juicing due to its interaction with the oxidants. Melatonin addition significantly reduced the juice color change to brown (browning). The mechanism is that melatonin scavenges the free radicals, which was indicated by the ASBT analysis; therefore, inhibiting the conversion of o-diphenolic compounds into quinones. Most importantly, melatonin exhibited powerful anti-microorganism activity in juice. The exact mechanisms of this action are currently unknown. These effects of melatonin can preserve the quality and prolong the shelf life of apple juice. The results provide valuable information regarding commerciall apple juice processing and storage. PMID- 29495436 TI - Aberrant Glycosylation Augments the Immuno-Stimulatory Activities of Soluble Calreticulin. AB - Calreticulin (CRT), a luminal resident calcium-binding glycoprotein of the cell, is a tumor-associated antigen involved in tumorigenesis and also an autoantigen targeted by autoantibodies found in patients with various autoimmune diseases. We have previously shown that prokaryotically expressed recombinant murine CRT (rCRT) exhibits strong stimulatory activities against monocytes/macrophages in vitro and potent immunogenicity in vivo, which is partially attributable to self oligomerization of soluble rCRT. However, even in oligomerized form native CRT (nCRT) isolated from mouse liver is much less active than rCRT, arguing against the possibility that self-oligomerization alone would license potent pro inflammatory properties to nCRT. Since rCRT differs from nCRT in its lack of glycosylation, we wondered if aberrant glycosylation of eukaryotically expressed CRT (eCRT) would significantly enhance its immunological activity. In the present study, tunicamycin, an N-glycosyltransferase inhibitor, was employed to treat CHO cells (CHO-CRT) stably expressing full-length recombinant mouse CRT in secreted form for preparation of aberrantly glycosylated eCRT (tun-eCRT). Our biochemical and immunological analysis results indicate that eCRT produced by CHO-CRT cells is similar to nCRT in terms of glycosylation level, lack of self-oligomerization, relatively poor immunogenicity and weak macrophage-stimulatory activity, while tun-eCRT shows reduced glycosylation yet much enhanced ability to elicit specific humoral responses in mice and TNF-alpha and nitric oxide production by macrophages in vitro. Given that abberant glycosylation of proteins is a hallmark of cancer cells and also related to the development of autoimmune disorders in humans, our data may provide useful clues for better understanding of potentiating roles of dysregulated glycosylation of molecules such as CRT in tumorigenesis and autoimmunity. PMID- 29495438 TI - Numerical Study and Optimisation of a Novel Single-Element Dual-Frequency Ultrasound Transducer. AB - A dual-frequency ultrasound transducer (DFUT) is usually preferred for its numerous advantageous applications, especially in biomedical imaging and sensing. However, most of DFUTs are based on the combination of fundamental and harmonic operations, or integration of multiple different single-frequency ultrasound transducers, hindering perfect beam alignment and acoustic impedance matching. A novel single-element DFUT has been proposed in this paper. A small piezoelectric membrane is used as the high-frequency ultrasound transducer, which is stacked on a large non-piezoelectric elastic membrane with a groove used as the low frequency capacitive ultrasound transducer. Such a capacitive-piezoelectric hybrid structure is theoretically analysed in details, based on the electrostatic attraction force and converse piezoelectric effect. Both the low and high resonance frequencies are independently derived, with a maximum deviation of less than 4% from the finite element simulations. Besides, a lumped-parameter equivalent circuit model of combining both the capacitive and piezoelectric ultrasound transducers was also described. Based on our dual-frequency structure design, a high-to-low frequency ratio of about 2 to more than 20 could be achieved, with easy and independent controllability of two frequencies, and the high-frequency operation shows at least an order-of-magnitude displacement sensitivity improvement compared with the conventional harmonic operations. PMID- 29495439 TI - Prolonged Screen Viewing Times and Sociodemographic Factors among Pregnant Women: A Cross-Sectional Survey in China. AB - Objectives: This study aimed to assess the prevalence of prolonged television, computer, and mobile phone viewing times and examined related sociodemographic factors among Chinese pregnant women. Methods: In this study, a cross-sectional survey was implemented among 2400 Chinese pregnant women in 16 hospitals of 5 provinces from June to August in 2015, and the response rate of 97.76%. We excluded women with serious complications and cognitive disorders. The women were asked about their television, computer, and mobile phone viewing during pregnancy. Prolonged television watching or computer viewing was defined as spending more than two hours on television or computer viewing per day. Prolonged mobile phone viewing was watching more than one hour on mobile phone per day. Results: Among 2345 pregnant women, about 25.1% reported prolonged television viewing, 20.6% reported prolonged computer viewing, and 62.6% reported prolonged mobile phone viewing. Pregnant women with long mobile phone viewing times were likely have long TV (Estimate = 0.080, Standard Error (SE) = 0.016, p < 0.001) and computer viewing times (Estimate = 0.053, SE = 0.022, p = 0.015). Pregnant women with long TV (Estimate = 0.134, SE = 0.027, p < 0.001) and long computer viewing times (Estimate = 0.049, SE = 0.020, p = 0.015) were likely have long mobile phone viewing times. Pregnant women with long TV viewing times were less likely to have long computer viewing times (Estimate = -0.032, SE = 0.015, p = 0.035), and pregnant women with long computer viewing times were less likely have long TV viewing times (Estimate = -0.059, SE = 0.028, p = 0.035). Pregnant women in their second pregnancy had lower prolonged computer viewing times than those in their first pregnancy (Odds Ratio (OR) 0.56, 95% Confidence Interval (CI) 0.42 0.74). Pregnant women in their second pregnancy were more likely have longer prolonged mobile phone viewing times than those in their first pregnancy (OR 1.25, 95% CI 1.01-1.55). Conclusions: The high prevalence rate of prolonged TV, computer, and mobile phone viewing times was common for pregnant women in their first and second pregnancy. This study preliminarily explored the relationship between sociodemographic factors and prolonged screen time to provide some indication for future interventions related to decreasing screen-viewing times during pregnancy in China. PMID- 29495437 TI - The Complexity of Mitochondrial Complex IV: An Update of Cytochrome c Oxidase Biogenesis in Plants. AB - Mitochondrial respiration is an energy producing process that involves the coordinated action of several protein complexes embedded in the inner membrane to finally produce ATP. Complex IV or Cytochrome c Oxidase (COX) is the last electron acceptor of the respiratory chain, involved in the reduction of O2 to H2O. COX is a multimeric complex formed by multiple structural subunits encoded in two different genomes, prosthetic groups (heme a and heme a3), and metallic centers (CuA and CuB). Tens of accessory proteins are required for mitochondrial RNA processing, synthesis and delivery of prosthetic groups and metallic centers, and for the final assembly of subunits to build a functional complex. In this review, we perform a comparative analysis of COX composition and biogenesis factors in yeast, mammals and plants. We also describe possible external and internal factors controlling the expression of structural proteins and assembly factors at the transcriptional and post-translational levels, and the effect of deficiencies in different steps of COX biogenesis to infer the role of COX in different aspects of plant development. We conclude that COX assembly in plants has conserved and specific features, probably due to the incorporation of a different set of subunits during evolution. PMID- 29495440 TI - A Geographical Information System Based Approach for Integrated Strategies of Tick Surveillance and Control in the Peri-Urban Natural Reserve of Monte Pellegrino (Palermo, Southern Italy). AB - Ticks (Acari: Ixodidae) are bloodsucking arthropods involved in pathogen transmission in animals and humans. Tick activity depends on various ecological factors such as vegetation, hosts, and temperature. The aim of this study was to analyse the spatial/temporal distribution of ticks in six sites within a peri urban area of Palermo (Natural Reserve of Monte Pellegrino) and correlate it with field data using Geographical Information System (GIS) data. A total of 3092 ticks were gathered via dragging method from June 2012 to May 2014. The species collected were: Ixodes ventalloi (46.09%), Hyalomma lusitanicum (19.99%), Rhipicephalus sanguineus (17.34%), Rhipicephalus pusillus (16.11%), Haemaphisalis sulcata (0.36%), Dermacentor marginatus (0.10%), and Rhipicephalus turanicus (0.03%). GIS analysis revealed environmental characteristics of each site, and abundance of each tick species was analysed in relation to time (monthly trend) and space (site-specific abundance). A relevant presence of I. ventalloi in site 2 and H. lusitanicum in site 5 was observed, suggesting the possible exposure of animals and humans to tick-borne pathogens. Our study shows the importance of surveillance of ticks in peri-urban areas and the useful implementation of GIS analysis in vector ecology; studies on temporal and spatial distribution of ticks correlated to GIS-based ecological analysis represent an integrated strategy for decision support in public health. PMID- 29495441 TI - Detection of Aggregation-Competent Tau in Neuron-Derived Extracellular Vesicles. AB - Progressive cerebral accumulation of tau aggregates is a defining feature of Alzheimer's disease (AD). A popular theory that seeks to explain the apparent spread of neurofibrillary tangle pathology proposes that aggregated tau is passed from neuron to neuron. Such a templated seeding process requires that the transferred tau contains the microtubule binding repeat domains that are necessary for aggregation. While it is not clear how a protein such as tau can move from cell to cell, previous reports have suggested that this may involve extracellular vesicles (EVs). Thus, measurement of tau in EVs may both provide insights on the molecular pathology of AD and facilitate biomarker development. Here, we report the use of sensitive immunoassays specific for full-length (FL) tau and mid-region tau, which we applied to analyze EVs from human induced pluripotent stem cell (iPSC)-derived neuron (iN) conditioned media, cerebrospinal fluid (CSF), and plasma. In each case, most tau was free-floating with a small component inside EVs. The majority of free-floating tau detected by the mid region assay was not detected by our FL assays, indicating that most free floating tau is truncated. Inside EVs, the mid-region assay also detected more tau than the FL assay, but the ratio of FL-positive to mid-region-positive tau was higher inside exosomes than in free solution. These studies demonstrate the presence of minute amounts of free-floating and exosome-contained FL tau in human biofluids. Given the potential for FL tau to aggregate, we conclude that further investigation of these pools of extracellular tau and how they change during disease is merited. PMID- 29495442 TI - Soluble CD14 as a Diagnostic Biomarker for Smear-Negative HIV-Associated Tuberculosis. AB - Sputum smear-negative HIV-associated active tuberculosis (TB) is challenging to diagnose. CD14 is a pattern recognition receptor that is known to mediate monocyte activation. Prior studies have shown increased levels of soluble CD14 (sCD14) as a potential biomarker for TB, but little is known about its value in detecting smear-negative HIV-associated TB. We optimized a sandwich ELISA for the detection of sCD14, and tested sera from 56 smear-negative South African (39 culture-positive and 17 culture-negative) HIV-infected pulmonary TB patients and 24 South African and 43 US (21 positive and 22 negative for tuberculin skin test, respectively) HIV-infected controls. SCD14 concentrations were significantly elevated in smear-negative HIV-associated TB compared with the HIV-infected controls (p < 0.0001), who had similar concentrations, irrespective of the country of origin or the presence or absence of latent M. tuberculosis infection (p = 0.19). The culture-confirmed TB group had a median sCD14 level of 2199 ng/mL (interquartile range 1927-2719 ng/mL), versus 1148 ng/mL (interquartile range 1053-1412 ng/mL) for the South African controls. At a specificity of 96%, sCD14 had a sensitivity of 95% for culture-confirmed smear-negative TB. These data indicate that sCD14 could be a highly accurate biomarker for the detection of HIV associated TB. PMID- 29495443 TI - Time Intervals in Sequence Sampling, Not Data Modifications, Have a Major Impact on Estimates of HIV Escape Rates. AB - The ability of human immunodeficiency virus (HIV) to avoid recognition by humoral and cellular immunity (viral escape) is well-documented, but the strength of the immune response needed to cause such a viral escape remains poorly quantified. Several previous studies observed a more rapid escape of HIV from CD8 T cell responses in the acute phase of infection compared to chronic infection. The rate of HIV escape was estimated with the help of simple mathematical models, and results were interpreted to suggest that CD8 T cell responses causing escape in acute HIV infection may be more efficient at killing virus-infected cells than responses that cause escape in chronic infection, or alternatively, that early escapes occur in epitopes mutations in which there is minimal fitness cost to the virus. However, these conclusions were challenged on several grounds, including linkage and interference of multiple escape mutations due to a low population size and because of potential issues associated with modifying the data to estimate escape rates. Here we use a sampling method which does not require data modification to show that previous results on the decline of the viral escape rate with time since infection remain unchanged. However, using this method we also show that estimates of the escape rate are highly sensitive to the time interval between measurements, with longer intervals biasing estimates of the escape rate downwards. Our results thus suggest that data modifications for early and late escapes were not the primary reason for the observed decline in the escape rate with time since infection. However, longer sampling periods for escapes in chronic infection strongly influence estimates of the escape rate. More frequent sampling of viral sequences in chronic infection may improve our understanding of factors influencing the rate of HIV escape from CD8 T cell responses. PMID- 29495445 TI - Fast Detection of Copper Content in Rice by Laser-Induced Breakdown Spectroscopy with Uni- and Multivariate Analysis. AB - Fast detection of heavy metals is very important for ensuring the quality and safety of crops. Laser-induced breakdown spectroscopy (LIBS), coupled with uni- and multivariate analysis, was applied for quantitative analysis of copper in three kinds of rice (Jiangsu rice, regular rice, and Simiao rice). For univariate analysis, three pre-processing methods were applied to reduce fluctuations, including background normalization, the internal standard method, and the standard normal variate (SNV). Linear regression models showed a strong correlation between spectral intensity and Cu content, with an R 2 more than 0.97. The limit of detection (LOD) was around 5 ppm, lower than the tolerance limit of copper in foods. For multivariate analysis, partial least squares regression (PLSR) showed its advantage in extracting effective information for prediction, and its sensitivity reached 1.95 ppm, while support vector machine regression (SVMR) performed better in both calibration and prediction sets, where R c 2 and R p 2 reached 0.9979 and 0.9879, respectively. This study showed that LIBS could be considered as a constructive tool for the quantification of copper contamination in rice. PMID- 29495446 TI - EEMD-Based Steady-State Indexes and Their Applications to Condition Monitoring and Fault Diagnosis of Railway Axle Bearings. AB - Railway axle bearings are one of the most important components used in vehicles and their failures probably result in unexpected accidents and economic losses. To realize a condition monitoring and fault diagnosis scheme of railway axle bearings, three dimensionless steadiness indexes in a time domain, a frequency domain, and a shape domain are respectively proposed to measure the steady states of bearing vibration signals. Firstly, vibration data collected from some designed experiments are pre-processed by using ensemble empirical mode decomposition (EEMD). Then, the coefficient of variation is introduced to construct two steady-state indexes from pre-processed vibration data in a time domain and a frequency domain, respectively. A shape function is used to construct a steady-state index in a shape domain. At last, to distinguish normal and abnormal bearing health states, some guideline thresholds are proposed. Further, to identify axle bearings with outer race defects, a pin roller defect, a cage defect, and coupling defects, the boundaries of all steadiness indexes are experimentally established. Experimental results showed that the proposed condition monitoring and fault diagnosis scheme is effective in identifying different bearing health conditions. PMID- 29495444 TI - Magnesium Replacement to Protect Cardiovascular and Kidney Damage? Lack of Prospective Clinical Trials. AB - Patients with advanced chronic kidney disease exhibit an increase in cardiovascular mortality. Recent works have shown that low levels of magnesium are associated with increased cardiovascular and all-cause mortality in hemodialysis patients. Epidemiological studies suggest an influence of low levels of magnesium on the occurrence of cardiovascular disease, which is also observed in the normal population. Magnesium is involved in critical cellular events such as apoptosis and oxidative stress. It also participates in a number of enzymatic reactions. In animal models of uremia, dietary supplementation of magnesium reduces vascular calcifications and mortality; in vitro, an increase of magnesium concentration decreases osteogenic transdifferentiation of vascular smooth muscle cells. Therefore, it may be appropriate to evaluate whether magnesium replacement should be administered in an attempt to reduce vascular damage and mortality in the uremic population In the present manuscript, we will review the magnesium homeostasis, the involvement of magnesium in enzymatic reactions, apoptosis and oxidative stress and the clinical association between magnesium and cardiovascular disease in the general population and in the context of chronic kidney disease. We will also analyze the role of magnesium on kidney function. Finally, the experimental evidence of the beneficial effects of magnesium replacement in chronic kidney disease will be thoroughly described. PMID- 29495447 TI - Virtual Screening of Small Molecular Inhibitors against DprE1. AB - Decaprenylphosphoryl-beta-d-ribose oxidase (DprE1) is the flavoprotein subunit of decaprenylphosphoryl-d-ribose epimerase involved in cell wall synthesis in Mycobacterium tuberculosis and catalyzes the conversion of decaprenylphosphoryl ribose to decaprenylphosphoryl arabinose. DprE1 is a potential target against tuberculosis, including multidrug-resistant tuberculosis. We identified potential DprE1 inhibitors from the ChemDiv dataset through virtual screening based on pharmacophore and molecular docking. Thirty selected compounds were subjected to absorption, distribution, metabolism, excretion, and toxicity prediction with the Discovery Studio software package. Two compounds were obtained as hits for inhibiting DprE1 activity in M. tuberculosis and are suitable for further in vitro and in vivo evaluation. PMID- 29495449 TI - Using Individual GPS Trajectories to Explore Foodscape Exposure: A Case Study in Beijing Metropolitan Area. AB - With the growing interest in studying the characteristics of people's access to the food environment and its influence upon individual health, there has been a focus on assessing individual food exposure based on GPS trajectories. However, existing studies have largely focused on the overall activity space using short period trajectories, which ignores the complexity of human movements and the heterogeneity of the spaces that are experienced by the individual over daily life schedules. In this study, we propose a novel framework to extract the exposure areas consisting of the localized activity spaces around daily life centers and non-motorized commuting routes from long-term GPS trajectories. The newly proposed framework is individual-specific and can incorporate the internal heterogeneity of individual activities (spatial extent, stay duration, and timing) in different places as well as the dynamics of the context. A pilot study of the GeoLife dataset suggests that there are significant variations in the magnitude as well as the composition of the food environment in different parts of the individual exposure area, and residential environment is not representative of the overall foodscape exposure. PMID- 29495450 TI - High Efficient Reduction of Graphene Oxide via Nascent Hydrogen at Room Temperature. AB - To develop a green and efficient method to synthesize graphene in relative milder conditions is prerequisite for graphene applications. A chemical reducing method has been developed to high efficiently reduce graphene oxide (GO) using Fe2O3 and NH3BH3 as catalyst and reductants, respectively. During the process, environmental and strong reductive nascent hydrogen were generated surrounding the surface of GO sheets by catalyst hydrolysis reaction of NH3BH3 and were used for reduction of GO. The reduction process was studied by ultraviolet absorption spectroscopy, Raman spectroscopy, and Fourier transform infrared spectrum. The structure and morphology of the reduced GO were characterized with scanning electron microscopy and transmission electron microscopy. Compared to metal (Mg/Fe/Zn/Al) particles and acid system which also use nascent hydrogen to reduce GO, this method exhibited higher reduction efficiency (43.6%). Also the reduction was carried out at room temperature condition, which is environmentally friendly. As a supercapacitor electrode, the reversible capacity of reduced graphene oxide was 113.8 F g-1 at 1 A g-1 and the capacitance retention still remained at 90% after 200 cycles. This approach provides a new method to reduce GO with high reduction efficiency by green reductant. PMID- 29495448 TI - Calcium Signalling in Plant Biotic Interactions. AB - Calcium (Ca2+) is a universal second messenger involved in various cellular processes, leading to plant development and to biotic and abiotic stress responses. Intracellular variation in free Ca2+ concentration is among the earliest events following the plant perception of environmental change. These Ca2+ variations differ in their spatio-temporal properties according to the nature, strength and duration of the stimulus. However, their conversion into biological responses requires Ca2+ sensors for decoding and relaying. The occurrence in plants of calmodulin (CaM) but also of other sets of plant-specific Ca2+ sensors such as calmodulin-like proteins (CMLs), Ca2+-dependent protein kinases (CDPKs) and calcineurin B-like proteins (CBLs) indicate that plants possess specific tools and machineries to convert Ca2+ signals into appropriate responses. Here, we focus on recent progress made in monitoring the generation of Ca2+ signals at the whole plant or cell level and their long distance propagation during biotic interactions. The contribution of CaM/CMLs and CDPKs in plant immune responses mounted against bacteria, fungi, viruses and insects are also presented. PMID- 29495451 TI - Phenotyping of Chronic Obstructive Pulmonary Disease Based on the Integration of Metabolomes and Clinical Characteristics. AB - Apart from the refined management-oriented clinical stratification of chronic obstructive pulmonary disease (COPD), the molecular pathologies behind this highly prevalent disease have remained obscure. The aim of this study was the characterization of patients with COPD, based on the metabolomic profiling of peripheral blood and exhaled breath condensate (EBC) within the context of defined clinical and demographic variables. Mass-spectrometry-based targeted analysis of serum metabolites (mainly amino acids and lipid species), untargeted profiles of serum and EBC of patients with COPD of different clinical characteristics (n = 25) and control individuals (n = 21) were performed. From the combined clinical/demographic and metabolomics data, associations between clinical/demographic and metabolic parameters were searched and a de novo phenotyping for COPD was attempted. Adjoining the clinical parameters, sphingomyelins were the best to differentiate COPD patients from controls. Unsaturated fatty acid-containing lipids, ornithine metabolism and plasma protein composition-associated signals from the untargeted analysis differentiated the Global Initiative for COPD (GOLD) categories. Hierarchical clustering did not reveal a clinical-metabolomic stratification superior to the strata set by the GOLD consensus. We conclude that while metabolomics approaches are good for finding biomarkers and clarifying the mechanism of the disease, there are no distinct co-variate independent clinical-metabolic phenotypes. PMID- 29495452 TI - In Vitro Evaluation of Sunscreen Safety: Effects of the Vehicle and Repeated Applications on Skin Permeation from Topical Formulations. AB - The evaluation of UV-filter in vitro percutaneous absorption allows the estimation of the systemic exposure dose (SED) and the margin of safety (MoS) of sunscreen products. As both the vehicle and pattern of application may affect sunscreen safety and efficacy, we evaluated in vitro release and skin permeation of two widely used UV-filters, octylmethoxycinnamate (OMC) and butylmethoxydibenzoylmethane (BMBM) from topical formulations with different features (oil in water (O/W) emulsions with different viscosity, water in oil (W/O) emulsion, oils with different lipophilicity). To mimic in-use conditions, we carried out experiments repeating sunscreen application on the skin surface for three consecutive days. BMBM release from all these vehicles was very low, thus leading to poor skin permeation. The vehicle composition significantly affected OMC release and skin permeation, and slight increases of OMC permeation were observed after repeated applications. From skin permeation data, SED and MoS values of BMBM and OMC were calculated for all the investigated formulations after a single application and repeated applications. While MoS values of BMBM were always well beyond the accepted safety limit, the safety of sunscreen formulations containing OMC may depend on the vehicle composition and the application pattern. PMID- 29495453 TI - Wnt Signaling in Stem Cell Maintenance and Differentiation in the Drosophila Germarium. AB - Wnt signaling is a conserved regulator of stem cell behaviors, and the Drosophila germarium has been an important model tissue for the study of stem cell maintenance, differentiation, and proliferation. Here we review Wnt signaling in the germarium, which houses two distinct types of ovarian stem cells: the anteriorly located germline stem cells (GSCs), which give rise to oocytes; and the mid-posteriorly located follicle stem cells (FSCs), which give rise to the somatic follicle cells that cover a developing oocyte. The maintenance and proliferation of GSCs and FSCs is regulated by the stem cell niches, whereas differentiation of the germline is regulated by the differentiation niche. Four distinct Wnt ligands are localized in the germarium, and we focus review on how these Wnt ligands and Wnt signaling affects maintenance and differentiation of both germline and follicle stem cells in their respective niches. PMID- 29495454 TI - Regional Assessment of Temperature-Related Mortality in Finland. AB - The aim of this study was to assess regional differences in temperature-mortality relationships across 21 hospital districts in Finland. The temperature dependence of the daily number of all-cause, all-aged deaths during 2000-2014 was studied in each hospital district by using daily mean temperatures, spatially averaged across each hospital district, to describe exposure to heat stress and cold stress. The relationships were modelled using distributed lag non-linear models (DLNM). In a simple model version, no delayed impacts of heat and cold on mortality were taken into account, whereas a more complex version included delayed impacts up to 25 days. A meta-analysis with selected climatic and sociodemographic covariates was conducted to study differences in the relationships between hospital districts. A pooled mortality-temperature relationship was produced to describe the average relationship in Finland. The simple DLNM model version without lag gave U-shaped dependencies of mortality on temperature almost without exception. The outputs of the model version with a 25 day lag were also U-shaped in most hospital districts. According to the meta analysis, the differences in the temperature-mortality relationships between hospital districts were not statistically significant on the absolute temperature scale, meaning that the pooled mortality-temperature relationship can be applied to the whole country. However, on a relative temperature scale, heterogeneity was found, and the meta-regression suggested that morbidity index and population in the hospital districts might explain some of this heterogeneity. The pooled estimate for the relative risk (RR) of mortality at a daily mean temperature of 24 degrees C was 1.16 (95% CI 1.12-1.20) with reference at 14 degrees C, which is the minimum mortality temperature (MMT) of the pooled relationship. On the cold side, the RR at a daily mean temperature of -20 degrees C was 1.14 (95% CI 1.12-1.16). On a relative scale of daily mean temperature, the MMT was found at the 79th percentile. PMID- 29495455 TI - Subcellular Proteomics: Application to Elucidation of Flooding-Response Mechanisms in Soybean. AB - Soybean, which is rich in protein and oil, is cultivated in several climatic zones; however, its growth is markedly decreased by flooding. Proteomics is a useful tool for understanding the flooding-response mechanism in soybean. Subcellular proteomics has the potential to elucidate localized cellular responses and investigate communications among subcellular components during plant growth and during stress. Under flooding, proteins related to signaling, stress and the antioxidative system are increased in the plasma membrane; scavenging enzymes for reactive-oxygen species are suppressed in the cell wall; protein translation is suppressed through inhibition of proteins related to preribosome biogenesis and mRNA processing in the nucleus; levels of proteins involved in the electron transport chain are reduced in the mitochondrion; and levels of proteins related to protein folding are decreased in the endoplasmic reticulum. This review discusses the advantages of a gel-free/label-free proteomic technique and methods of plant subcellular purification. It also summarizes cellular events in soybean under flooding and discusses future prospects for generation of flooding-tolerant soybean. PMID- 29495456 TI - Mycobacterium tuberculosis H37Rv LpqG Protein Peptides Can Inhibit Mycobacterial Entry through Specific Interactions. AB - Mycobacterium tuberculosis is the causative agent of tuberculosis, a disease causing major mortality worldwide. As part of a systematic methodology for studying M. tuberculosis surface proteins which might be involved in host pathogen interactions, our group found that LpqG surface protein (Rv3623) found in M. tuberculosis complex strains was located on the mycobacterial envelope and that peptide 16661 (21SGCDSHNSGSLGADPRQVTVY40) had high specific binding to U937 monocyte-derived macrophages and inhibited mycobacterial entry to such cells in a concentration-dependent way. A region having high specific binding to A549 alveolar epithelial cells was found which had low mycobacterial entry inhibition. As suggested in previous studies, relevant sequences in the host-pathogen interaction do not induce an immune response and peptides characterised as HABPs are poorly recognised by sera from individuals regardless of whether they have been in contact with M. tuberculosis. Our approach to designing a synthetic, multi-epitope anti-tuberculosis vaccine has been based on identifying sequences involved in different proteins' mycobacteria-target cell interaction and modifying their sequence to improve their immunogenic characteristics, meaning that peptide 16661 sequence should be considered in such design. PMID- 29495457 TI - MicroRNA and Transcriptomic Profiling Showed miRNA-Dependent Impairment of Systemic Regulation and Synthesis of Biomolecules in Rag2 KO Mice. AB - The Rag2 knockout (KO) mouse is a well-established immune-compromised animal model for biomedical research. A comparative study identified the deregulated expression of microRNAs (miRNAs) and messenger RNAs (mRNAs) in Rag2 KO mice. However, the interaction between deregulated genes and miRNAs in the alteration of systemic (cardiac, renal, hepatic, nervous, and hematopoietic) regulations and the synthesis of biomolecules (such as l-tryptophan, serotonin, melatonin, dopamine, alcohol, noradrenaline, putrescine, and acetate) are unclear. In this study, we analyzed both miRNA and mRNA expression microarray data from Rag2 KO and wild type mice to investigate the possible role of miRNAs in systemic regulation and biomolecule synthesis. A notable finding obtained from this analysis is that the upregulation of several genes which are target molecules of the downregulated miRNAs in Rag2 KO mice, can potentially trigger the degradation of l-tryptophan, thereby leading to the systemic impairment and alteration of biomolecules synthesis as well as changes in behavioral patterns (such as stress and fear responses, and social recognition memory) in Rag2 gene-depleted mice. These findings were either not observed or not explicitly described in other published Rag2 KO transcriptome analyses. In conclusion, we have provided an indication of miRNA-dependent regulations of clinical and pathological conditions in cardiac, renal, hepatic, nervous, and hematopoietic systems in Rag2 KO mice. These results may significantly contribute to the prediction of clinical disease caused by Rag2 deficiency. PMID- 29495458 TI - Substrate Binding Switches the Conformation at the Lynchpin Site in the Substrate Binding Domain of Human Hsp70 to Enable Allosteric Interdomain Communication. AB - The stress-induced 70 kDa heat shock protein (Hsp70) functions as a molecular chaperone to maintain protein homeostasis. Hsp70 contains an N-terminal ATPase domain (NBD) and a C-terminal substrate-binding domain (SBD). The SBD is divided into the beta subdomain containing the substrate-binding site (betaSBD) and the alpha-helical subdomain (alphaLid) that covers the betaSBD. In this report, the solution structures of two different forms of the SBD from human Hsp70 were solved. One structure shows the alphaLid bound to the substrate-binding site intramolecularly, whereas this intramolecular binding mode is absent in the other structure solved. Structural comparison of the two SBDs from Hsp70 revealed that client-peptide binding rearranges residues at the interdomain contact site, which impairs interdomain contact between the SBD and the NBD. Peptide binding also disrupted the inter-subdomain interaction connecting the alphaLid to the betaSBD, which allows the binding of the alphaLid to the NBD. The results provide a mechanism for interdomain communication upon substrate binding from the SBD to the NBD via the lynchpin site in the betaSBD of human Hsp70. In comparison to the bacterial ortholog, DnaK, some remarkable differences in the allosteric signal propagation among residues within the Hsp70 SBD exist. PMID- 29495459 TI - Enhanced Hydrolysis of Cellulose in Ionic Liquid Using Mesoporous ZSM-5. AB - Mesoporous ZSM-5 prepared by alkaline treatment was demonstrated as an efficient catalyst for the cellulose hydrolysis in ionic liquid (IL), affording a high yield of reducing sugar. It was demonstrated that mesoporous ZSM-5 (SiO2/Al2O3 = 38) had 76.2% cellulose conversion and 49.6% yield of total reducing sugar (TRS). In comparison, the conventional ZSM-5 had a mere 41.3% cellulose conversion with 33.2% yield of TRS. The results indicated that the important role of mesopores in zeolites in elevating the TRS yield may be due to the diffusional alleviation of cellulose macromolecules. The effects of reaction time, temperature, and the ratio of catalyst to cellulose were investigated for optimal reaction conditions. It was found that IL could enter the inner channel of mesoporous ZSM-5 to promote the generation of H+ from Bronsted acid sites, which facilitated hydrolysis. Moreover, the mesoporous ZSM-5 showed excellent reusability for catalytic cycles by means of calcination of the used one, promising for its practical applications in the hydrolysis of cellulose. PMID- 29495463 TI - Microstructure Evolution during Dissimilar Friction Stir Welding of AA7003-T4 and AA6060-T4. AB - In this work, the dissimilar joint of AA7003-T4 and 6060-T4 alloy has been produced by friction stir welding (FSW). The microstructure was examined by optical microscope (OM), electron back scattered diffraction (EBSD), transmission electron microscopy (TEM), and the mechanical properties of the joint were investigated. It is demonstrated that sound dissimilar joint can be produced through FSW. In the nugget; precipitations dissolve into the matrix and eta' reprecipitate subsequently; and the elongated aluminum grains are replaced by fine and equiaxed grains due to dynamic recrystallization (DRX). In the heat affected zone (HAZ), coarse beta' and eta precipitates are formed and the aluminum grains are coarser as compared to the base materials. In the thermo mechanical affected zone (TMAZ), equiaxed and elongated grains coexist due to incomplete DRX. The ultimate tensile strength of the dissimilar joint is 159.2 MPa and its elongation is 10.4%. The weak area exists in the HAZ of 6060 alloy, which is placed in the retreating side during FSW. The correlations between the microstucture and mechanical properties of the dissimilar joint are discussed. PMID- 29495462 TI - Comparison of Six Different Silicones In Vitro for Application as Glaucoma Drainage Device. AB - Silicones are widely used in medical applications. In ophthalmology, glaucoma drainage devices are utilized if conservative therapies are not applicable or have failed. Long-term success of these devices is limited by failure to control intraocular pressure due to fibrous encapsulation. Therefore, different medical approved silicones were tested in vitro for cell adhesion, cell proliferation and viability of human Sclera (hSF) and human Tenon fibroblasts (hTF). The silicones were analysed also depending on the sample preparation according to the manufacturer's instructions. The surface quality was characterized with environmental scanning electron microscope (ESEM) and water contact angle measurements. All silicones showed homogeneous smooth and hydrophobic surfaces. Cell adhesion was significantly reduced on all silicones compared to the negative control. Proliferation index and cell viability were not influenced much. For development of a new glaucoma drainage device, the silicones Silbione LSR 4330 and Silbione LSR 4350, in this study, with low cell counts for hTF and low proliferation indices for hSF, and silicone Silastic MDX4-4210, with low cell counts for hSF and low proliferation indices for hTF, have shown the best results in vitro. Due to the high cell adhesion shown on Silicone LSR 40, 40,026, this material is unsuitable. PMID- 29495461 TI - Artemisinin and Its Synthetic Derivatives as a Possible Therapy for Cancer. AB - To assess the possibility of using the antimalarial drug artemisinin and its synthetic derivatives as antineoplastic drugs. A Pubmed and Google Scholar (1983 2018) search was performed using the terms artemisinin, cancer, artesunate and Artemisia annua. Case reports and original research articles, review articles, and clinical trials in both humans and animals were evaluated. Both in vitro and in vivo clinical trials and case reports have shown promising activity of the artemisinin drug derivatives in treating certain types of cancer. However, the reported articles are few, and therefore not statistically significant. The minimal toxicity shown in clinical trials and case reports, along with the selective cytotoxic activity of the compounds, make them possible cancer therapies due to the emerging evidence of the drug's effectiveness. PMID- 29495464 TI - Fabrication of Completely Polymer-Based Solar Cells with p- and n-Type Semiconducting Block Copolymers with Electrically Inert Polystyrene. AB - It is widely recognized that fullerene derivatives show several advantages as n type materials in photovoltaic applications. However, conventional [6,6]-phenyl C61-butyric acid methyl ester (PCBM) exhibits weak absorption in the visible region, and poor morphological stability, due to the facile aggregation. For further improvement of the device performance and durability, utilization of n type polymeric materials instead of PCBM is considered to be a good way to solve the problems. In this study, we fabricated completely polymer-based solar cells utilizing p- and n-type block copolymers consisting of poly(3-hexylthiophene) (P3HT) and poly{[N,N'-bis(2-octyldodecyl)naphthalene-1,4,5,8-bis(dicarboximide) 2,6-diyl]-alt-5,5'-(2,2'-bithiophene)} [P(NDI2OD-T2)], respectively, containing common polystyrene (PSt) inert blocks, which decreased the size of phase separated structures. Electron mobility in synthesized P(NDI2OD-T2)-b-PSt film enhanced by a factor of 8 compared with homopolymer. The root mean square roughness of the blend film of two block copolymers (12.2 nm) was decreased, compared with that of the simple homopolymers blend (18.8 nm). From the current density-voltage characteristics, it was confirmed that the introduction of PSt into both P3HT and P(NDI2OD-T2) improves short-circuit current density (1.16 to 1.73 mA cm-2) and power-conversion efficiency (0.24% to 0.32%). Better performance is probably due to the uniformity of the phase separation, and the enhancement of charge mobility. PMID- 29495466 TI - Domain III of Cry1Ac Is Critical to Binding and Toxicity against Soybean Looper (Chrysodeixis includens) but Not to Velvetbean Caterpillar (Anticarsia gemmatalis). AB - Insecticidal proteins Cry1Ac and Cry2Ac7 from the bacterium Bacillus thuringiensis (Bt) belong to the three-domain family of Bt toxins. Commercial transgenic soybean hybrids produce Cry1Ac to control the larvae of the soybean looper (Chrysodeixis includens) and the velvet bean caterpillar (Anticarsia gemmatalis). The specificity of Cry1Ac is determined by loops extending from domain II and regions of domain III in the three-dimensional structure of the toxin. In this study, we constructed a hybrid toxin (H1.2Ac) containing domains I and II of Cry1Ac and domain III of Cry2Ac7, in an attempt to obtain a protein with enhanced toxicity compared to parental toxins. Bioassays with H1.2Ac revealed toxicity against the larvae of A. gemmatalis but not against C. includens. Saturation binding assays with radiolabeled toxins and midgut brush border membrane vesicles demonstrated no specific H1.2Ac binding to C. includens, while binding in A. gemmatalis was specific and saturable. Results from competition binding assays supported the finding that Cry1Ac specificity against A. gemmatalis is mainly dictated by domain II. Taken together, these distinct interactions with binding sites may help explain the differential susceptibility to Cry1Ac in C. includens and A. gemmatalis, and guide the design of improved toxins against soybean pests. PMID- 29495460 TI - Melatonin: A Versatile Protector against Oxidative DNA Damage. AB - Oxidative damage to DNA has important implications for human health and has been identified as a key factor in the onset and development of numerous diseases. Thus, it is evident that preventing DNA from oxidative damage is crucial for humans and for any living organism. Melatonin is an astonishingly versatile molecule in this context. It can offer both direct and indirect protection against a wide variety of damaging agents and through multiple pathways, which may (or may not) take place simultaneously. They include direct antioxidative protection, which is mediated by melatonin's free radical scavenging activity, and also indirect ways of action. The latter include, at least: (i) inhibition of metal-induced DNA damage; (ii) protection against non-radical triggers of oxidative DNA damage; (iii) continuous protection after being metabolized; (iv) activation of antioxidative enzymes; (v) inhibition of pro-oxidative enzymes; and (vi) boosting of the DNA repair machinery. The rather unique capability of melatonin to exhibit multiple neutralizing actions against diverse threatening factors, together with its low toxicity and its ability to cross biological barriers, are all significant to its efficiency for preventing oxidative damage to DNA. PMID- 29495465 TI - Post-Translational Modifications of H2A Histone Variants and Their Role in Cancer. AB - Histone variants are chromatin components that replace replication-coupled histones in a fraction of nucleosomes and confer particular characteristics to chromatin. H2A variants represent the most numerous and diverse group among histone protein families. In the nucleosomal structure, H2A-H2B dimers can be removed and exchanged more easily than the stable H3-H4 core. The unstructured N terminal histone tails of all histones, but also the C-terminal tails of H2A histones protrude out of the compact structure of the nucleosome core. These accessible tails are the preferential target sites for a large number of post translational modifications (PTMs). While some PTMs are shared between replication-coupled H2A and H2A variants, many modifications are limited to a specific histone variant. The present review focuses on the H2A variants H2A.Z, H2A.X, and macroH2A, and summarizes their functions in chromatin and how these are linked to cancer development and progression. H2A.Z primarily acts as an oncogene and macroH2A and H2A.X as tumour suppressors. We further focus on the regulation by PTMs, which helps to understand a degree of context dependency. PMID- 29495467 TI - MS Sunshine Study: Sun Exposure But Not Vitamin D Is Associated with Multiple Sclerosis Risk in Blacks and Hispanics. AB - Multiple sclerosis (MS) incidence and serum 25-hydroxyvitamin D (25OHD) levels vary by race/ethnicity. We examined the consistency of beneficial effects of 25OHD and/or sun exposure for MS risk across multiple racial/ethnic groups. We recruited incident MS cases and controls (blacks 116 cases/131 controls; Hispanics 183/197; whites 247/267) from the membership of Kaiser Permanente Southern California into the MS Sunshine Study to simultaneously examine sun exposure and 25OHD, accounting for genetic ancestry and other factors. Higher lifetime ultraviolet radiation exposure (a rigorous measure of sun exposure) was associated with a lower risk of MS independent of serum 25OHD levels in blacks (adjusted OR = 0.53, 95% CI = 0.31-0.83; p = 0.007) and whites (OR = 0.68, 95% CI = 0.48-0.94; p = 0.020) with a similar magnitude of effect that did not reach statistical significance in Hispanics (OR = 0.66, 95% CI = 0.42-1.04; p = 0.071). Higher serum 25OHD levels were associated with a lower risk of MS only in whites. No association was found in Hispanics or blacks regardless of how 25OHD was modeled. Lifetime sun exposure appears to reduce the risk of MS regardless of race/ethnicity. In contrast, serum 25OHD levels are not associated with MS risk in blacks or Hispanics. Our findings challenge the biological plausibility of vitamin D deficiency as causal for MS and call into question the targeting of specific serum 25OHD levels to achieve health benefits, particularly in blacks and Hispanics. PMID- 29495469 TI - Carbon Nitride Decorated Ball-Flower like Co3O4 Hybrid Composite: Hydrothermal Synthesis and Ethanol Gas Sensing Application. AB - Recently, semiconducting metal oxide (SMO) gas sensors have attracted the attention of researchers for high conductivity, labile features by environment, low cost, easy preparation, etc. However, traditional SMOs have some defects such as higher operating temperature and lower response value, which greatly limit their application in the field of gas sensor. In this work, the carbon nitride decorated ball-flower like Co3O4 composite was successfully synthesized via a facile hydrothermal method, the composition and morphology of the as-synthesized samples were studied by the techniques of X-ray powder diffraction (XRD), Field emission scanning electron microscopy (FESEM), Transmission electron microscopy (TEM), Fourier transform infrared spectrometer (FT-IR) and N2-sorption. As a consequence, the pure Co3O4 and the carbon nitride decorated Co3O4 both possess ball-flower like structure, and the as-synthesized carbon nitride decorated Co3O4 composite exhibits significant sensing properties to ethanol which is 1.6 times higher than that of pure Co3O4, furthermore, the composite possesses high selectivity and stability towards ethanol detection. PMID- 29495470 TI - Determination of Propionylbrassinolide and Its Impurities by High-Performance Liquid Chromatography with Evaporative Light Scattering Detection. AB - The discovery of brassinolide in 1979, a milestone in brassinosteroids research, has sparked great interest of brassinolide analogs (BLs) in agricultural applications. Among these BLs, propionylbrassinolide has captured considerable attention because it shows plant growth regulating activity with an excellent durability. Two impurities of propionylbrassinolide were isolated and purified by semi-preparative high-performance liquid chromatography (HPLC), and the chemical structures were confirmed. For simultaneous separation and determination of propionylbrassinolide and impurities, an efficient analytical method based on HPLC with evaporative light scattering detector (HPLC-ELSD) was developed. The optimized analysis was performed on a C18 reversed phase column (250 mm * 4.60 mm, 5 MUm) with isocratic elution of acetonitrile and water (90:10, v/v) as the mobile phase. The drift tube temperature of the ELSD system was set to 50 degrees C and the auxiliary gas pressure was 150 kPa. The regression equations demonstrated a good linear relationship (R2 = 0.9989-0.9999) within the test ranges. The limits of detection (LODs) and quantification (LOQs) for propionylbrassinolide, impurity 1 and 2 were 1.3, 1.2, 1,3 and 4.3, 4.0, 4.2 mg/L, respectively. The fully validated HPLC-ELSD method was readily applied to quantify the active ingredient and impurities in propionylbrassinolide technical concentrate. Moreover, the optimized separation conditions with ELSD have been successfully transferred to mass spectrometry (MS) detector for LC-MS determination. PMID- 29495471 TI - Radical Chemistry in a Femtosecond Laser Plasma: Photochemical Reduction of Ag+ in Liquid Ammonia Solution. AB - Plasmas with dense concentrations of reactive species such as hydrated electrons and hydroxyl radicals are generated from focusing intense femtosecond laser pulses into aqueous media. These radical species can reduce metal ions such as Au3+ to form metal nanoparticles (NPs). However, the formation of H2O2 by the recombination of hydroxyl radicals inhibits the reduction of Ag+ through back oxidation. This work has explored the control of hydroxyl radical chemistry in a femtosecond laser-generated plasma through the addition of liquid ammonia. The irradiation of liquid ammonia solutions resulted in a reaction between NH3 and OH., forming peroxynitrite and ONOO-, and significantly reducing the amount of H2O2 generated. Varying the liquid ammonia concentration controlled the Ag+ reduction rate, forming 12.7 +/- 4.9 nm silver nanoparticles at the optimal ammonia concentration. The photochemical mechanisms underlying peroxynitrite formation and Ag+ reduction are discussed. PMID- 29495473 TI - Resilience of an Earthquake-Stricken Rural Community in Southwest China: Correlation with Disaster Risk Reduction Efforts. AB - Disaster risk reduction (DRR) activities have given growing attention to building community resilience, but the effects of such efforts on community resilience are still under-investigated, especially in China where the concept of community resilience has only just emerged. Using the Communities Advancing Resilience Toolkit Assessment Survey, data on self-perceived community resilience were collected in 2017 from a post-disaster Chinese rural community in Yingxiu Town, which was the epicenter of the Wenchuan earthquake (Magnitude = 8.0) in the year 2008. Linear regression analyses were conducted to explore the correlations between residents' DRR behaviors and perceived community resilience with the control of their socio-demographic characteristics including age, ethnicity, gender, education, income level, employment status and marital status. Results indicate that residents who volunteered for DRR activities received geological disaster education, participated in evacuation drills, and reported higher income levels had a perception of higher community resilience. Practice research is suggested to help clarify the cause and effect of DRR work on the enhancement of community resilience to disasters in China and abroad. Attention is also called to the development of a Chinese indigenous community resilience concept and assessment instrument. PMID- 29495468 TI - Nutrition in the Very Old. AB - The population of older adults aged 85 years and over (the very old) is growing rapidly in many societies because of increases in life expectancy and reduced mortality at older ages. In 2016, 27.3 million very old adults were living in the European Union, and in the UK, 2.4% of the population (1.6 million) were aged 85 and over. Very old age is associated with increased risks of malnutrition, multimorbidity, and disability. Diet (nutrition) is a modifiable risk factor for multiple age-related conditions, including sarcopenia and functional decline. Dietary characteristics and nutrient intakes of the very old have been investigated in several European studies of ageing to better understand their nutritional requirements, which may differ from those in the young-old. However, there is a major gap in regard to evidence for the role of dietary patterns, protein, vitamin D and other nutrients for the maintenance of physical and cognitive functioning in later life. The Newcastle 85+ Study, UK and the Life and Living in Advanced Age, New Zealand are unique studies involving single birth cohorts which aim to assess health trajectories in very old adults and their biological, social and environmental influences, including nutrition. In this review, we have updated the latest findings in nutritional epidemiology with results from these studies, concentrating on the diet-physical functioning relationship. PMID- 29495474 TI - Exposure to Toxoplasma gondii in the Roma and Non-Roma Inhabitants of Slovakia: A Cross-Sectional Seroprevalence Study. AB - The lifestyle, health and social status of the Roma are generally below the standards characteristic for the non-Roma population. This study aimed to find out the seropositivity to Toxoplasma gondii (T. gondii) in the population of Roma living in segregated settlements and to compare it with the prevalence of antibodies in the non-Roma population from the catchment area of eastern Slovakia. The seroprevalence of antibodies to T. gondii was significantly higher in the Roma group (45.0%) than in non-Roma inhabitants (24.1%). A statistically significant difference was also recorded between the two non-Roma groups in the study, 30.4% of those from the catchment area and 19.7% from the non-catchment area were seropositive. Univariate logistic regression confirmed poverty and higher age to be significant risk factors influencing the seropositivity to T. gondii. Of the clinical symptoms analyzed in the study, only muscle and back pain were associated with seropositivity to T. gondii. The close contact of Roma with an environment contaminated by different infectious agents and the insufficient hygiene, lower level of education, poverty, lack of water and household equipment and high number of domestic animals increase the risk of infectious diseases in the Roma settlements and subsequently the spread of communicable diseases at the national or even international level. PMID- 29495472 TI - World-Wide Variation in Incidence of Staphylococcus aureus Associated Ventilator Associated Pneumonia: A Meta-Regression. AB - Staphylococcus aureus (S. aureus) is a common Ventilator-Associated Pneumonia (VAP) isolate. The objective here is to define the extent and possible reasons for geographic variation in the incidences of S. aureus-associated VAP, MRSA-VAP and overall VAP. A meta-regression model of S. aureus-associated VAP incidence per 1000 Mechanical Ventilation Days (MVD) was undertaken using random effects methods among publications obtained from a search of the English language literature. This model incorporated group level factors such as admission to a trauma ICU, year of publication and use of bronchoscopic sampling towards VAP diagnosis. The search identified 133 publications from seven worldwide regions published over three decades. The summary S. aureus-associated VAP incidence was 4.5 (3.9-5.3) per 1000 MVD. The highest S. aureus-associated VAP incidence is amongst reports from the Mediterranean (mean; 95% confidence interval; 6.1; 4.1 8.5) versus that from Asian ICUs (2.1; 1.5-3.0). The incidence of S. aureus associated VAP varies by up to three-fold (for the lowest versus highest incidence) among seven geographic regions worldwide, whereas the incidence of VAP varies by less than two-fold. Admission to a trauma unit is the most important group level correlate for S. aureus-associated VAP. PMID- 29495475 TI - Burden of Injuries in Bangladesh: A Population-Based Assessment. AB - Injuries claim over 5 million lives, with more than 90% of those occurring in low and middle-income countries (LMICS) [...]. PMID- 29495477 TI - "Pets Negotiable": How Do the Perspectives of Landlords and Property Managers Compare with Those of Younger Tenants with Dogs? AB - Previous research has shown that housing insecurity contributes to animal relinquishment and that tenants with dogs face disadvantages in the rental market. Still, little is known about how dog owners navigate rental markets, nor how landlords and property managers perceive dogs and other pets. This case study reports on in-depth interviews with younger tenants with dogs and on open-ended survey responses from landlords and property managers. In their housing searches, tenants with dogs reported feeling powerless in negotiations and feeling discriminated against. They described settling for substandard properties, often located in less desirable neighborhoods. Also, some said they felt obliged to stay put in these rentals, given how difficult it had been to find a place that would accommodate their dogs. Meanwhile, landlords and property managers indicated that listings advertised as "pet-friendly" tend to receive more applicants than listings in which pets are prohibited. Suggestions for improvement included meeting pets prior to signing the lease; getting everything in writing; steering clear from furnished units; charging utilities to tenants; and speeding up the pet approval process when dealing with condominium boards. These suggestions offer implications for future research, partnerships, and policy options to improve the prospects of pets and their people in rental housing. PMID- 29495478 TI - Developing an Ethically Acceptable Virtual Fencing System for Sheep. AB - To ensure animal welfare isn't compromised when using virtual fencing, animals must be able to associate a benign conditioned stimulus with an aversive stimulus. This study used an associative learning test to train 30, four-year old, Merino x Suffolk ewes, to associate an audio cue with an electric stimulus. Collars manually controlled by a GPS hand-held unit were used to deliver the audio and electric stimuli cues. For the associative learning, when sheep approached an attractant at a distance of three m from the trough, an audio cue was applied for one s. If the sheep stopped or changed direction, the audio cue ceased immediately and no electrical stimulus was applied. If the sheep did not respond to the audio cue it was followed by a low-level electrical stimulus. Approaches to the attractant significantly decreased from day one to day two. It took a mean of three pairings of the audio cue and electrical stimulus for a change in behaviour to occur, after which sheep that approached the attractant had a 52% probability of avoiding the electrical stimulus and responding to the audio cue alone. Further research is required to determine whether sheep can be trained to associate an audio cue with a negative stimulus for use in group grazing situations. PMID- 29495479 TI - Investigation of Zinc and Phosphorus Elements Incorporated into Micro-Arc Oxidation Coatings Developed on Ti-6Al-4V Alloys. AB - In order to clarify the mechanism that zinc and phosphorus elements entering the micro-arc oxidation (MAO) coatings developed on Ti-6Al-4V alloys, anodic coatings containing different zinc and phosphorus were fabricated using an orthogonal experiment of four factors with three levels in an electrolyte containing EDTA ZnNa2, KOH, and phytic acid. Surface morphology, element composition, chemical state and phase structure of MAO coatings were characterized by scanning electron microscope (SEM), energy dispersive X-ray spectrometer (EDS), X-ray photoelectron spectroscopy (XPS) and X-ray diffraction (XRD). The concentrations of zinc and phosphorus in the electrolyte were analyzed by an inductively coupled plasma optical emission spectrometry (ICP-OES). The results show that zinc and phosphorus elements in MAO coatings exist in the form of Zn3(PO4)2. Phytic acid is the most important factor on both zinc and phosphorus contents of MAO coatings. With the increase of phytic acid concentration or the decrease of KOH concentration, the contents of zinc and phosphorus in MAO coatings present a similarly increasing tendency. Our results indicate that phosphorus takes part in coating formation mainly by diffusion, while zinc enters into MAO coatings with phosphorus from phytic acid. PMID- 29495476 TI - Potential for Bacteriophage Endolysins to Supplement or Replace Antibiotics in Food Production and Clinical Care. AB - There is growing concern about the emergence of bacterial strains showing resistance to all classes of antibiotics commonly used in human medicine. Despite the broad range of available antibiotics, bacterial resistance has been identified for every antimicrobial drug developed to date. Alarmingly, there is also an increasing prevalence of multidrug-resistant bacterial strains, rendering some patients effectively untreatable. Therefore, there is an urgent need to develop alternatives to conventional antibiotics for use in the treatment of both humans and food-producing animals. Bacteriophage-encoded lytic enzymes (endolysins), which degrade the cell wall of the bacterial host to release progeny virions, are potential alternatives to antibiotics. Preliminary studies show that endolysins can disrupt the cell wall when applied exogenously, though this has so far proven more effective in Gram-positive bacteria compared with Gram-negative bacteria. Their potential for development is furthered by the prospect of bioengineering, and aided by the modular domain structure of many endolysins, which separates the binding and catalytic activities into distinct subunits. These subunits can be rearranged to create novel, chimeric enzymes with optimized functionality. Furthermore, there is evidence that the development of resistance to these enzymes may be more difficult compared with conventional antibiotics due to their targeting of highly conserved bonds. PMID- 29495480 TI - Current Modulation of a Heterojunction Structure by an Ultra-Thin Graphene Base Electrode. AB - Graphene has been proposed as the current controlling element of vertical transport in heterojunction transistors, as it could potentially achieve high operation frequencies due to its metallic character and 2D nature. Simulations of graphene acting as a thermionic barrier between the transport of two semiconductor layers have shown cut-off frequencies larger than 1 THz. Furthermore, the use of n-doped amorphous silicon, (n)-a-Si:H, as the semiconductor for this approach could enable flexible electronics with high cutoff frequencies. In this work, we fabricated a vertical structure on a rigid substrate where graphene is embedded between two differently doped (n)-a-Si:H layers deposited by very high frequency (140 MHz) plasma-enhanced chemical vapor deposition. The operation of this heterojunction structure is investigated by the two diode-like interfaces by means of temperature dependent current-voltage characterization, followed by the electrical characterization in a three-terminal configuration. We demonstrate that the vertical current between the (n)-a-Si:H layers is successfully controlled by the ultra-thin graphene base voltage. While current saturation is yet to be achieved, a transconductance of ~230 MU S was obtained, demonstrating a moderate modulation of the collector-emitter current by the ultra-thin graphene base voltage. These results show promising progress towards the application of graphene base heterojunction transistors. PMID- 29495481 TI - Briaviolides K-N, New Briarane-Type Diterpenoids from Cultured Octocoral Briareum violaceum. AB - Four new briarane diterpenoids, briaviolides K-N (1-4), have been obtained from the cultured-type octocoral Briareum violaceum. Using a spectroscopic approach, the structures of briaranes 1-4 were identified. This study employed an in vitro model of lipopolysaccharide (LPS)-induced inflammation in the murine macrophage RAW 264.7 cell line, and found that among the four briaranes, briarane 2 possessed anti-inflammatory activity against inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expressions in cells. In addition, principal component analysis using the chemical global positioning system (ChemGPS) for natural products (ChemGPS-NP) was employed in order to analyze the structure-activity relationship (SAR), and the results indicated that the ring conformation of the compound has a leading role in suppressing the expressions of pro-inflammatory iNOS and COX-2 proteins in macrophages. PMID- 29495483 TI - Dramatic Reduction in Diarrhoeal Diseases through Implementation of Cost Effective Household Drinking Water Treatment Systems in Makwane Village, Limpopo Province, South Africa. AB - The main purpose of this study was to implement cost-effective household water treatment systems in every household of Makwane Village for the reduction of diarrhoeal diseases. These household water treatment systems were constructed with locally available materials and consisted of the biosand zeolite-silver impregnated granular clay filters and the silver-impregnated porous pot filters. During the study period (April 2015 to September 2015), the entire village had 88 households with a population size of 480. Prior to the implementation, a survey was conducted and results revealed that 75% (360/480) of the Makwane residents suffered from diarrhoeal disease and the majority of the cases were reported in children that were less than five years of age. Out of the 480 participants, 372 (77.5%) from 70 households accepted the installation of the systems (intervention group) and 108 (25.5%) from 18 households were reluctant to use the systems (the control group). To date, in the intervention group, only 3.8% (14/372) of participants reported cases of diarrhoea. In the control group, 57.4% (62/108) participants reported cases of diarrhoea and most of the episodes of diarrhoea were reported in children of less than five years old (85%), followed by the group aged >=56 years (75%). The findings of the current study unequivocally demonstrated that the BSZ-SICG and SIPP filters were able to reduce the incidence of diarrhoea by 96.2%. These findings further demonstrate the importance of household water treatment systems (HWTS) interventions in rural areas to bring about meaningful reductions in diarrhoeal diseases by providing safe potable water. PMID- 29495482 TI - iTRAQ-Based Proteomic Analysis Reveals Potential Regulation Networks of IBA Induced Adventitious Root Formation in Apple. AB - Adventitious root (AR) formation, which is controlled by endogenous and environmental factors, is indispensable for vegetative asexual propagation. However, comprehensive proteomic data on AR formation are still lacking. The aim of this work was to study indole-3-butyric acid (IBA)-induced AR formation in the dwarf apple rootstock 'T337'. In this study, the effect of IBA on AR formation was analysed. Subsequent to treatment with IBA, both the rooting rate and root length of 'T337' increased significantly. An assessment of hormone levels in basal stem cuttings suggested that auxin, abscisic acid, and brassinolide were higher in basal stem cuttings that received the exogenous IBA application; while zeatin riboside, gibberellins, and jasmonic acid were lower than non-treated basal stem cuttings. To explore the underlying molecular mechanism, an isobaric tags for relative and absolute quantification (iTRAQ)-based proteomic technique was employed to identify the expression profiles of proteins at a key period of adventitious root induction (three days after IBA treatment). In total, 3355 differentially expressed proteins (DEPs) were identified. Many DEPs were closely related to carbohydrate metabolism and energy production, protein homeostasis, reactive oxygen and nitric oxide signaling, and cell wall remodeling biological processes; as well as the phytohormone signaling, which was the most critical process in response to IBA treatment. Further, RT-qPCR analysis was used to evaluate the expression level of nine genes that are involved in phytohormone signaling and their transcriptional levels were mostly in accordance with the protein patterns. Finally, a putative work model was proposed. Our study establishes a foundation for further research and sheds light on IBA-mediated AR formation in apple as well as other fruit rootstock cuttings. PMID- 29495484 TI - Resolving the Enigma of the Clonal Expansion of mtDNA Deletions. AB - Mitochondria are cell organelles that are special since they contain their own genetic material in the form of mitochondrial DNA (mtDNA). Damage and mutations of mtDNA are not only involved in several inherited human diseases but are also widely thought to play an important role during aging. In both cases, point mutations or large deletions accumulate inside cells, leading to functional impairment once a certain threshold has been surpassed. In most cases, it is a single type of mutant that clonally expands and out-competes the wild type mtDNA, with different mutant molecules being amplified in different cells. The challenge is to explain where the selection advantage for the accumulation comes from, why such a large range of different deletions seem to possess this advantage, and how this process can scale to species with different lifespans such as those of rats and man. From this perspective, we provide an overview of current ideas, present an update of our own proposal, and discuss the wider relevance of the phenomenon for aging. PMID- 29495485 TI - Archaeal Viruses from High-Temperature Environments. AB - Archaeal viruses are some of the most enigmatic viruses known, due to the small number that have been characterized to date. The number of known archaeal viruses lags behind known bacteriophages by over an order of magnitude. Despite this, the high levels of genetic and morphological diversity that archaeal viruses display has attracted researchers for over 45 years. Extreme natural environments, such as acidic hot springs, are almost exclusively populated by Archaea and their viruses, making these attractive environments for the discovery and characterization of new viruses. The archaeal viruses from these environments have provided insights into archaeal biology, gene function, and viral evolution. This review focuses on advances from over four decades of archaeal virology, with a particular focus on archaeal viruses from high temperature environments, the existing challenges in understanding archaeal virus gene function, and approaches being taken to overcome these limitations. PMID- 29495489 TI - Residual Tensile Strength and Bond Properties of GFRP Bars after Exposure to Elevated Temperatures. AB - The use of fiber reinforced polymer (FRP) bars in reinforced concrete members enhances corrosion resistance when compared to traditional steel reinforcing bars. Although there is ample research available on the behavior of FRP bars and concrete members reinforced with FRP bars under elevated temperatures (due to fire), there is little published information available on their post-fire residual load capacity. This paper reports residual tensile strength, modulus of elasticity, and bond strength (to concrete) of glass fiber reinforced polymer (GFRP) bars after exposure to elevated temperatures of up to 400 degrees C and subsequent cooling to an ambient temperature. The results showed that the residual strength generally decreases with increasing temperature exposure. However, as much as 83% of the original tensile strength and 27% of the original bond strength was retained after the specimens were heated to 400 degrees C and then cooled to ambient temperature. The residual bond strength is a critical parameter in post-fire strength assessments of GFRP-reinforced concrete members. PMID- 29495487 TI - DOT1L and H3K79 Methylation in Transcription and Genomic Stability. AB - The organization of eukaryotic genomes into chromatin provides challenges for the cell to accomplish basic cellular functions, such as transcription, DNA replication and repair of DNA damage. Accordingly, a range of proteins modify and/or read chromatin states to regulate access to chromosomal DNA. Yeast Dot1 and the mammalian homologue DOT1L are methyltransferases that can add up to three methyl groups to histone H3 lysine 79 (H3K79). H3K79 methylation is implicated in several processes, including transcription elongation by RNA polymerase II, the DNA damage response and cell cycle checkpoint activation. DOT1L is also an important drug target for treatment of mixed lineage leukemia (MLL)-rearranged leukemia where aberrant transcriptional activation is promoted by DOT1L mislocalisation. This review summarizes what is currently known about the role of Dot1/DOT1L and H3K79 methylation in transcription and genomic stability. PMID- 29495488 TI - Analysis of Health Behaviors and Personal Values of Childless Women, Pregnant Women and Women Who Recently Delivered. AB - Preconception lifestyle modifications and reduction of several known risk factors may have an influence on future pregnancy outcomes. The aim of the study was to analyze health behaviors and personal values as well as to assess the relationship between these factors in women without children, in pregnant women and in women who had already delivered babies. The questionnaire survey included the Health Behavior Inventory (HBI), the Personal Value List (PVL) and sociodemographic data and was conducted in 538 women. These women were divided into three groups: women who had recently delivered (n = 235), pregnant women (n = 121) and childless women (n = 182). Pregnant women demonstrated a significantly higher level of declared health behaviors, and also, they rated higher on the subscales values "positive mental attitude" and "health practices", in comparison to women who had recently delivered and to childless women. In all tested groups, the highest rated personal value was "a successful family life", while the most appreciated symbol of happiness was "love and friendship". Our results suggest that the system of values and the perception of happiness symbols may influence women's health behaviors. Positioning "health" in the hierarchy of personal values as the most important one may facilitate the introduction of healthy behaviors. This, in turn, could reduce several adverse pregnancy outcomes that are potentially modifiable with changing preconception health attitudes. Our results also identify several unanswered questions and highlight areas where new research is needed. PMID- 29495486 TI - Aptamers Selected for Recognizing Amyloid beta-Protein-A Case for Cautious Optimism. AB - Aptamers are versatile oligonucleotide ligands used for molecular recognition of diverse targets. However, application of aptamers to the field of amyloid beta protein (Abeta) has been limited so far. Abeta is an intrinsically disordered protein that exists in a dynamic conformational equilibrium, presenting time dependent ensembles of short-lived, metastable structures and assemblies that have been generally difficult to isolate and characterize. Moreover, despite understanding of potential physiological roles of Abeta, this peptide has been linked to the pathogenesis of Alzheimer disease, and its pathogenic roles remain controversial. Accumulated scientific evidence thus far highlights undesirable or nonspecific interactions between selected aptamers and different Abeta assemblies likely due to the metastable nature of Abeta or inherent affinity of RNA oligonucleotides to beta-sheet-rich fibrillar structures of amyloidogenic proteins. Accordingly, lessons drawn from Abeta-aptamer studies emphasize that purity and uniformity of the protein target and rigorous characterization of aptamers' specificity are important for realizing and garnering the full potential of aptamers selected for recognizing Abeta or other intrinsically disordered proteins. This review summarizes studies of aptamers selected for recognizing different Abeta assemblies and highlights controversies, difficulties, and limitations of such studies. PMID- 29495490 TI - Clinically Usable Interleukin 12 Plasmid without an Antibiotic Resistance Gene: Functionality and Toxicity Study in Murine Melanoma Model. AB - Plasmids, which are currently used in interleukin 12 (IL-12) gene electrotransfer (GET) clinical trials in the USA, contain antibiotic resistance genes and are thus, according to the safety recommendation of the European Medicines Agency (EMA), not suitable for clinical trials in the EU. In the current study, our aim was to prepare an IL-12 plasmid without an antibiotic resistance gene and test its functionality and toxicity after GET in a preclinical B16F10 mouse melanoma model. The antibiotic resistance-free plasmid encoding the human IL-12 fusion gene linked to the p21 promoter, i.e., p21-hIL-12-ORT, was constructed using operator-repressor titration (ORT) technology. Next, the expression profile of the plasmid after GET was determined in B16F10 cells and tumors. Additionally, blood chemistry, hematological and histological changes, and antitumor response were evaluated after GET of the plasmid in melanoma tumors. The results demonstrated a good expression and safety profile of the p21-hIL-12-ORT GET and indications of efficacy. We hope that the obtained results will help to accelerate the transfer of this promising treatment from preclinical studies to clinical application in the EU. PMID- 29495491 TI - A Facile Strategy to Enhance the Dielectric and Mechanical Properties of MWCNTs/PVDF Composites with the Aid of MMA-co-GMA Copolymer. AB - A facile strategy is adopted to prepare carboxylic functionalized multiwalled carbon nanotube (c-MWCNT) modified high dielectric constant (high-k) poly(vinylidene fluoride) (PVDF) composites with the aid of methyl methacrylate co-glycidyl methacrylate copolymer (MG). The MG is miscible with PVDF and the epoxy groups of the copolymer can react with the carboxylic groups of c-MWCNT, which induce the uniform dispersion of c-MWCNT and a form insulator layer on the surface of c-MWCNT. The c-MWCNTs/MG/PVDF composites with 8 vol % c-MWCNT present excellent dielectric properties with high dielectric constant (~448) and low dielectric loss (~2.36) at the frequency of 1 KHz, the dielectric loss is much lower than the c-MWCNT/PVDF composites without MG. The obvious improvement in dielectric properties ascribes to the existence of MG, which impede the direct contact of c-MWCNTs and PVDF and avoid the formation of conductive network. Therefore, we propose a practical and simple strategy for preparing composites with excellent dielectric properties, which are promising for applications in electronics devices. PMID- 29495493 TI - Comparison of Commercial Calcium Hydroxide Pastes for Prolonged Antibacterial Effect using a Colourimetric Assessment. AB - The anti-microbial activity of calcium hydroxide pastes used in endodontics is dependent on establishing high levels of hydroxyl ions in dentine. This study investigated hydroxyl ion diffusion from different commercial calcium hydroxide pastes using a novel colourimetric method. In this method, human tooth roots were stained with anthocyanin dye, which changed their colour according to the local pH conditions. Prepared root canals were filled with pastes formulated with the vehicle of water (PulpdentTM, Calasept PlusTM), polyethylene glycol (PEG) (CalmixTM) or a mixture of water, PEG and ibuprofen (OdontocideTM). The changes in dye colour at fixed distances from the canal wall were monitored using standardised digital photography over a period of 3 weeks. A repeated measures analysis tracked changes in each root from baseline. Release of hydroxyl ions varied between the different commercial compositions containing water or PEG as solvents. The colour changes in the dentine, due to released hydroxyl ions, were greatest and more prolonged for completely non-aqueous compositions, when using PEG 400 as the vehicle. When water was present in the product, the duration of the pH changes was shorter. This was attributed to the presence of hydroxyl ions in the water (the common-ion effect) and a more vigorous buffering of hydroxyl ions by dentine proteins. PMID- 29495492 TI - The Impact of a Single Dose of a Polyphenol-Rich Seaweed Extract on Postprandial Glycaemic Control in Healthy Adults: A Randomised Cross-Over Trial. AB - This study investigated the impact of a polyphenol-rich seaweed extract on postprandial glycaemia in healthy adults, and, as a secondary outcome, the influence of ethnicity on these outcomes. Thirty-eight volunteers (26 non-Asian, 12 Asian) aged 19 to 56 years participated in this double-blind, placebo controlled, randomised cross-over trial. Participants each consumed a low (500 mg), and high (2000 mg) dose of the polyphenol-rich brown seaweed (Fucus vesiculosus) extract, as well as a cellulose placebo (2000 mg), 30 min prior to 50 g of available carbohydrate from white bread. Postprandial blood glucose and plasma insulin concentrations were measured over two hours (fasting, 15, 30, 45, 60, 90, and 120 min) from a finger prick blood sample. Data were analysed using a repeated measures analysis of variance. Compared with the placebo, neither dose had a lowering effect on postprandial glucose or insulin responses. However, individuals of an Asian background experienced consistently elevated plasma insulin responses, assessed using an incremental area under the curve, compared with non-Asian participants, irrespective of supplement (p = 0.016). These results suggest an increased risk of insulin resistance among Asian populations, compared with non-Asian, and that measurement of blood glucose levels alone may be insufficient to diagnose diabetes risk in this population. PMID- 29495494 TI - The Pharmaceutical Industry in 2017. An Analysis of FDA Drug Approvals from the Perspective of Molecules. AB - This is an analysis from a chemical point of view of the 46 drugs (34 New Chemical Entities and 12 Biologics) approved by the FDA during 2017. The drugs included in the 2017 "harvest" have been classified on the basis of their chemical structure: biologics (antibodies and proteins); peptides; amino acids and natural products; drug combinations; and small molecules. PMID- 29495496 TI - Temporal Noise Analysis of Charge-Domain Sampling Readout Circuits for CMOS Image Sensors. AB - This paper presents a temporal noise analysis of charge-domain sampling readout circuits for Complementary Metal-Oxide Semiconductor (CMOS) image sensors. In order to address the trade-off between the low input-referred noise and high dynamic range, a Gm-cell-based pixel together with a charge-domain correlated double sampling (CDS) technique has been proposed to provide a way to efficiently embed a tunable conversion gain along the read-out path. Such readout topology, however, operates in a non-stationery large-signal behavior, and the statistical properties of its temporal noise are a function of time. Conventional noise analysis methods for CMOS image sensors are based on steady-state signal models, and therefore cannot be readily applied for Gm-cell-based pixels. In this paper, we develop analysis models for both thermal noise and flicker noise in Gm-cell based pixels by employing the time-domain linear analysis approach and the non stationary noise analysis theory, which help to quantitatively evaluate the temporal noise characteristic of Gm-cell-based pixels. Both models were numerically computed in MATLAB using design parameters of a prototype chip, and compared with both simulation and experimental results. The good agreement between the theoretical and measurement results verifies the effectiveness of the proposed noise analysis models. PMID- 29495495 TI - An Affordable Insole-Sensor-Based Trans-Femoral Prosthesis for Normal Gait. AB - This paper proposes a novel and an affordable lower limb prosthesis to enable normal gait kinematics for trans-femoral amputees. The paper details the design of a passive prosthesis with magneto-rheological (MR) damping system and electronic control. A new control approach based on plantar insole feedback was employed here. Strategically placed sensors on the plantar insole provide required information about gait cycle to a finite state controller for suitable action. A proportional integral (PI) based current controller controls the required current for necessary damping during gait. The prosthesis was designed and developed locally in India keeping in view the cost, functionality, socio economic, and aesthetic requirements. The prototype was experimentally tested on a trans-femoral amputee and the results are presented in this work. The implementation of the proposed design and control scheme in the prototype successfully realizes the notion that normal gait kinematics can be achieved at a low cost comparable to passive prostheses. The incurring cost and power expenditure of the proposed prosthesis are evaluated against passive and active prostheses, respectively. The commercial implications for the prosthesis were explored on the basis of recommendations of ISPO Consensus Conference on Appropriate Prosthetic Technology in Developing Countries. The key objective of this work is to enable lucid design for development of an affordable prosthesis in a low-resource setting. PMID- 29495497 TI - Using a Mobile Device "App" and Proximal Remote Sensing Technologies to Assess Soil Cover Fractions on Agricultural Fields. AB - Quantifying the amount of crop residue left in the field after harvest is a key issue for sustainability. Conventional assessment approaches (e.g., line transect) are labor intensive, time-consuming and costly. Many proximal remote sensing devices and systems have been developed for agricultural applications such as cover crop and residue mapping. For instance, current mobile devices (smartphones & tablets) are usually equipped with digital cameras and global positioning systems and use applications (apps) for in-field data collection and analysis. In this study, we assess the feasibility and strength of a mobile device app developed to estimate crop residue cover. The performance of this novel technique (from here on referred to as "app" method) was compared against two point counting approaches: an established digital photograph-grid method and a new automated residue counting script developed in MATLAB at the University of Guelph. Both photograph-grid and script methods were used to count residue under 100 grid points. Residue percent cover was estimated using the app, script and photograph-grid methods on 54 vertical digital photographs (images of the ground taken from above at a height of 1.5 m) collected from eighteen fields (9 corn and 9 soybean, 3 samples each) located in southern Ontario. Results showed that residue estimates from the app method were in good agreement with those obtained from both photograph-grid and script methods (R2 = 0.86 and 0.84, respectively). This study has found that the app underestimates the residue coverage by -6.3% and -10.8% when compared to the photograph-grid and script methods, respectively. With regards to residue type, soybean has a slightly lower bias than corn (i.e., 5.3% vs. -7.4%). For photos with residue <30%, the app derived residue measurements are within +/-5% difference (bias) of both photograph-grid- and script-derived residue measurements. These methods could therefore be used to track the recommended minimum soil residue cover of 30%, implemented to reduce farmland topsoil and nutrient losses that impact water quality. Overall, the app method was found to be a good alternative to the point counting methods, which are more time-consuming. PMID- 29495498 TI - Bioactive Glass-Ceramic Foam Scaffolds from 'Inorganic Gel Casting' and Sinter Crystallization. AB - Highly porous bioactive glass-ceramic scaffolds were effectively fabricated by an inorganic gel casting technique, based on alkali activation and gelification, followed by viscous flow sintering. Glass powders, already known to yield a bioactive sintered glass-ceramic (CEL2) were dispersed in an alkaline solution, with partial dissolution of glass powders. The obtained glass suspensions underwent progressive hardening, by curing at low temperature (40 degrees C), owing to the formation of a C-S-H (calcium silicate hydrate) gel. As successful direct foaming was achieved by vigorous mechanical stirring of gelified suspensions, comprising also a surfactant. The developed cellular structures were later heat-treated at 900-1000 degrees C, to form CEL2 glass-ceramic foams, featuring an abundant total porosity (from 60% to 80%) and well-interconnected macro- and micro-sized cells. The developed foams possessed a compressive strength from 2.5 to 5 MPa, which is in the range of human trabecular bone strength. Therefore, CEL2 glass-ceramics can be proposed for bone substitutions. PMID- 29495499 TI - Fabrication and Anti-Oxidation Ability of SiC-SiO2 Coated Carbon Fibers Using Sol Gel Method. AB - The paper proposed a method to improve the anti-oxidation performance of carbon fibers (CF) at high temperature environment by coating silicon dioxide (SiO2) and silicon carbide (SiC). The modified sol-gel method had been used to ensure the proper interface between fibers and coating. We used polydimethylsiloxane and ethyl orthosilicate to make stable emulsion to uniformly disperse SiC nanoparticles. The modified SiO2/SiC coating had been coated on CF successfully. Compared with the untreated CF, the coated fibers started to be oxidized around 900 degrees C and the residual weight was 57% at 1400 degrees C. The oxidation mechanism had been discussed. The structure of SiC/SiO2 coated CF had been characterized by scanning electron microscope and X-ray diffraction analysis. Thermal gravimetric analysis was used to test the anti-oxidation ability of CF with different coatings. PMID- 29495501 TI - Cavity-Enhanced Raman Spectroscopy for Food Chain Management. AB - Comprehensive food chain management requires the monitoring of many parameters including temperature, humidity, and multiple gases. The latter is highly challenging because no low-cost technology for the simultaneous chemical analysis of multiple gaseous components currently exists. This contribution proposes the use of cavity enhanced Raman spectroscopy to enable online monitoring of all relevant components using a single laser source. A laboratory scale setup is presented and characterized in detail. Power enhancement of the pump light is achieved in an optical resonator with a Finesse exceeding 2500. A simulation for the light scattering behavior shows the influence of polarization on the spatial distribution of the Raman scattered light. The setup is also used to measure three relevant showcase gases to demonstrate the feasibility of the approach, including carbon dioxide, oxygen and ethene. PMID- 29495502 TI - Single Particle Differentiation through 2D Optical Fiber Trapping and Back Scattered Signal Statistical Analysis: An Exploratory Approach. AB - Recent trends on microbiology point out the urge to develop optical micro-tools with multifunctionalities such as simultaneous manipulation and sensing. Considering that miniaturization has been recognized as one of the most important paradigms of emerging sensing biotechnologies, optical fiber tools, including Optical Fiber Tweezers (OFTs), are suitable candidates for developing multifunctional small sensors for Medicine and Biology. OFTs are flexible and versatile optotools based on fibers with one extremity patterned to form a micro lens. These are able to focus laser beams and exert forces onto microparticles strong enough (piconewtons) to trap and manipulate them. In this paper, through an exploratory analysis of a 45 features set, including time and frequency-domain parameters of the back-scattered signal of particles trapped by a polymeric lens, we created a novel single feature able to differentiate synthetic particles (PMMA and Polystyrene) from living yeasts cells. This single statistical feature can be useful for the development of label-free hybrid optical fiber sensors with applications in infectious diseases detection or cells sorting. It can also contribute, by revealing the most significant information that can be extracted from the scattered signal, to the development of a simpler method for particles characterization (in terms of composition, heterogeneity degree) than existent technologies. PMID- 29495503 TI - An Adaptive Method for Switching between Pedestrian/Car Indoor Positioning Algorithms based on Multilayer Time Sequences. AB - Pedestrian dead reckoning (PDR) positioning algorithms can be used to obtain a target's location only for movement with step features and not for driving, for which the trilateral Bluetooth indoor positioning method can be used. In this study, to obtain the precise locations of different states (pedestrian/car) using the corresponding positioning algorithms, we propose an adaptive method for switching between the PDR and car indoor positioning algorithms based on multilayer time sequences (MTSs). MTSs, which consider the behavior context, comprise two main aspects: filtering of noisy data in small-scale time sequences and using a state chain to reduce the time delay of algorithm switching in large scale time sequences. The proposed method can be expected to realize the recognition of stationary, walking, driving, or other states; switch to the correct indoor positioning algorithm; and improve the accuracy of localization compared to using a single positioning algorithm. Our experiments show that the recognition of static, walking, driving, and other states improves by 5.5%, 45.47%, 26.23%, and 21% on average, respectively, compared with convolutional neural network (CNN) method. The time delay decreases by approximately 0.5-8.5 s for the transition between states and by approximately 24 s for the entire process. PMID- 29495500 TI - Teaming Up for Trouble: Cancer Cells, Transforming Growth Factor-beta1 Signaling and the Epigenetic Corruption of Stromal Naive Fibroblasts. AB - It is well recognized that cancer cells subvert the phenotype of stromal naive fibroblasts and instruct the neighboring cells to sustain their growth agenda. The mechanisms underpinning the switch of fibroblasts to cancer-associated fibroblasts (CAFs) are the focus of intense investigation. One of the most significant hallmarks of the biological identity of CAFs is that their tumor promoting phenotype is stably maintained during in vitro and ex vivo propagation without the continual interaction with the adjacent cancer cells. In this review, we discuss robust evidence showing that the master cytokine Transforming Growth Factor-beta1 (TGFbeta-1) is a prime mover in reshaping, via epigenetic switches, the phenotype of stromal fibroblasts to a durable state. We also examine, in detail, the pervasive involvement of TGFbeta-1 signaling from both cancer cells and CAFs in fostering cancer development, taking colorectal cancer (CRC) as a paradigm of human neoplasia. Finally, we review the stroma-centric anticancer therapeutic approach focused on CAFs-the most abundant cell population of the tumor microenvironment (TME)-as target cells. PMID- 29495505 TI - A Reply to "Comments on "A New Elliptical Model for Device-Free Localization"". AB - Recently, a comment paper on "A New Elliptical Model for Device-Free Localization" (Sensors 2016, 16, 577) has been presented, and the authors have provided a modified model. However, there are still some misunderstandings. In this reply, we further explain the proposed elliptical model in (Sensors 2016, 16, 577) to make it more understandable. PMID- 29495504 TI - Saliency Detection and Deep Learning-Based Wildfire Identification in UAV Imagery. AB - An unmanned aerial vehicle (UAV) equipped with global positioning systems (GPS) can provide direct georeferenced imagery, mapping an area with high resolution. So far, the major difficulty in wildfire image classification is the lack of unified identification marks, the fire features of color, shape, texture (smoke, flame, or both) and background can vary significantly from one scene to another. Deep learning (e.g., DCNN for Deep Convolutional Neural Network) is very effective in high-level feature learning, however, a substantial amount of training images dataset is obligatory in optimizing its weights value and coefficients. In this work, we proposed a new saliency detection algorithm for fast location and segmentation of core fire area in aerial images. As the proposed method can effectively avoid feature loss caused by direct resizing; it is used in data augmentation and formation of a standard fire image dataset 'UAV_Fire'. A 15-layered self-learning DCNN architecture named 'Fire_Net' is then presented as a self-learning fire feature exactor and classifier. We evaluated different architectures and several key parameters (drop out ratio, batch size, etc.) of the DCNN model regarding its validation accuracy. The proposed architecture outperformed previous methods by achieving an overall accuracy of 98%. Furthermore, 'Fire_Net' guarantied an average processing speed of 41.5 ms per image for real-time wildfire inspection. To demonstrate its practical utility, Fire_Net is tested on 40 sampled images in wildfire news reports and all of them have been accurately identified. PMID- 29495506 TI - High-Precision Ionosphere Monitoring Using Continuous Measurements from BDS GEO Satellites. AB - The current constellation of the BeiDou Navigation Satellite System (BDS) consists of five geostationary earth orbit (GEO) satellites, five inclined geosynchronous satellite orbit (IGSO) satellites, and four medium earth orbit (MEO) satellites. The advantage of using GEO satellites to monitor the ionosphereis the almost motionless ionospheric pierce point (IPP), which is analyzed in comparison with the MEO and IGSO satellites. The results from the analysis of the observations using eight tracking sites indicate that the ionospheric total electron content (TEC) sequence derived from each GEO satellite at their respective fixed IPPs is always continuous. The precision of calculated vertical TEC (VTEC) using BDS B1/B2, B1/B3, and B2/B3 dual-frequency combinationsis compared and analyzed. The VTEC12 precision based on the B1/B2 dual-frequency measurements using the smoothed code and the raw code combination is 0.69 and 5.54 TECU, respectively, which is slightly higher than VTEC13 and much higher than VTEC23. Furthermore, the ionospheric monitoring results of site JFNG in the northern hemisphere, and CUT0 in the southern hemisphere during the period from 1 January to 31 December 2015 are presented and discussed briefly. PMID- 29495507 TI - Optical Properties of Complex Plasmonic Materials Studied with Extended Effective Medium Theories Combined with Rigorous Coupled Wave Analysis. AB - In this study we fabricate gold nanocomposites and model their optical properties. The nanocomposites are either homogeneous films or gratings containing gold nanoparticles embedded in a polymer matrix. The samples are fabricated using a recently developed technique making use of laser interferometry. The gratings present original plasmon-enhanced diffraction properties. In this work, we develop a new approach to model the optical properties of our composites. We combine the extended Maxwell-Garnett model of effective media with the Rigorous Coupled Wave Analysis (RCWA) method and compute both the absorption spectra and the diffraction efficiency spectra of the gratings. We show that such a semi-analytical approach allows us to reproduce the original plasmonic features of the composites and can provide us with details about their inner structure. Such an approach, considering reasonably high particle concentrations, could be a simple and efficient tool to study complex micro-structured system based on plasmonic components, such as metamaterials. PMID- 29495508 TI - Electrospun CuO-Nanoparticles-Modified Polycaprolactone @Polypyrrole Fibers: An Application to Sensing Glucose in Saliva. AB - A non-invasive method for detecting glucose is pursued by millions of diabetic patients to improve their personal management of blood glucose. In this work, a novel CuO nanoparticles (NPs) decorated polycaprolactone@polypyrrole fibers modified indium-tin oxide (denoted as CuO/PCL@PPy/ITO) electrode has been fabricated by electrospinning combined with the electrodeposition method for non enzymatic detection of glucose in saliva fluid. The electrospun composite fibers exhibit high sensitivity for the glucose detection. The synergistic effect between CuO and PPy together with the unique three-dimensional net structure contributes the reliable selectivity, good test repeatability, large-scale production reproducibility in massive way, the reasonable stability and a high catalytic surface area to the sensor. Quantitative detection of glucose is determined in the linear range from 2 MUM to 6 mM and the lowest detection limit is 0.8 MUM. The CuO/PCL@PPy/ITO electrode shows potential for the non-invasive detection of salivary glucose. PMID- 29495509 TI - Individual and School Correlates of Adolescent Leisure Time Physical Activity in Quebec, Canada. AB - Background: Leisure time physical activity (LTPA) correlates have been mostly studied in relation to adolescents' home neighbourhoods, but not so much in relation to the environment of their schools' neighbourhoods. We sought to investigate how objective environmental measures of the schools' vicinity are related to adolescents' self-reported LTPA. Methods: Individual data from the Quebec High School Students Health Survey (QHSSHS) were matched with schools' socioeconomic indicators, as well as geographic information system-based indicators of their built environments. Self-reported levels of LTPA during the school year were assessed according to intensity, frequency and index of energy expenditure. Associations per gender between covariates and LTPA were estimated using ordinal multilevel regression with multiple imputations. Results: Boys (21% of which were highly active) were more active than girls (16% of which were highly active) (p <= 0.01). The incremental variance between schools explained by the contextual variables in the final models was higher among girls (7.8%) than boys (2.8%). The number of parks or green spaces within 750 m around their schools was positively associated with student LTPA in both genders. Conclusions: The promotion of parks around schools seems to be an avenue to be strengthened. PMID- 29495510 TI - Polyurethanes Crosslinked with Poly(vinyl alcohol) as a Slowly-Degradable and Hydrophilic Materials of Potential Use in Regenerative Medicine. AB - Novel, slowly-degradable and hydrophilic materials with proper mechanical properties and surface characteristics are in great demand within the biomedical field. In this paper, the design, synthesis, and characterization of polyurethanes (PUR) crosslinked with poly(vinyl alcohol) (PVA) as a new proposition for regenerative medicine is described. PVA-crosslinked PURs were synthesized by a two-step polymerization performed in a solvent (dimethylsulfoxide, DMSO). The raw materials used for the synthesis of PVA crosslinked PURs were poly(epsilon-caprolactone) (PCL), 1,6-hexamethylene diisocyanate (HDI), and PVA as a crosslinking agent. The obtained materials were studied towards their physicochemical, mechanical, and biological performance. The tests revealed contact angle of the materials surface between 38-47 degrees and tensile strength in the range of 41-52 MPa. Mechanical characteristics of the obtained PURs was close to the characteristics of native human bone such as the cortical bone (TSb = 51-151 MPa) or the cancellous bone (TSb = 10-20 MPa). The obtained PVA-crosslinked PURs did not show significant progress of degradation after 3 months of incubation in a phosphate-buffered saline (PBS). Accordingly, the obtained materials may behave similar to slowly-degradable materials, which can provide long-term physical support in, for example, tissue regeneration, as well as providing a uniform calcium deposition on the material surface, which may influence, for example, bone restoration. A performed short-term hemocompatibility study showed that obtained PVA-crosslinked PURs do not significantly influence blood components, and a cytotoxicity test performed with the use of MG 63 cell line revealed the great cytocompatibility of the obtained materials. According to the performed studies, such PVA-crosslinked PURs may be a suitable proposition for the field of tissue engineering in regenerative medicine. PMID- 29495511 TI - Nanotransition Materials (NTMs): Photocatalysis, Validated High Effective Sorbent Models Study for Organic Dye Degradation and Precise Mathematical Data's at Standardized Level. AB - The present work describes the synthesis of copper oxide nanoparticles (CuONPs) via a solution process with the aim of applying the nano-adsorbent for the reduction of methylene blue (MB) dye in alkaline media. These NPs were characterized via Field emission scanning electron microscopy (FE-SEM), X-ray diffraction, high-resolution Transmission electron microscopy (TEM), and ultra violet UV-visible spectroscopy to confirm their morphology and crystalline and optical properties in order to design an adsorption-degradation process. The photocatalytic CuONPs exhibited dynamic properties, great adsorption affinity during the chemisorption process, and operated at various modes with a strong interaction between the adsorbent and the adsorptive species, and equilibrium isotherm, kinetic isotherm, and thermodynamic activities in the presence of UV light. All basic quantities, such as concentration, pH, adsorbent dose, time, and temperature, were determined by an optimization process. The best-fitted adsorption Langmuir model (R2 = 0.9988) and performance, including adsorption capacity (350.87 mg/g), photocatalytic efficiency (90.74%), and degradation rate constant (Ks = 2.23 *10-2 min-1), illustrate good feasibility with respect to sorption-reduction reactions but followed a pseudo-second-order kinetic on the adsorbent surface, reaching an equilibrium point in 80 min. The thermodynamic analysis suggests that the adsorption reaction is spontaneous and endothermic in nature. The thermodynamic parameters such as enthalpy (?H degrees ), entropy (?S degrees ), and Gibbs free energy (?G degrees ) give effective results to support a chemical reduction reaction at 303 K temperature. The equilibrium isotherm and kinetic and thermodynamic models with error function analysis explore the potential, acceptability, accuracy, access to adsorbents, and novelty of an unrivaled-sorption system. PMID- 29495513 TI - Towards the Development of a More Accurate Monitoring Procedure for Invertebrate Populations, in the Presence of an Unknown Spatial Pattern of Population Distribution in the Field. AB - Studies addressing many ecological problems require accurate evaluation of the total population size. In this paper, we revisit a sampling procedure used for the evaluation of the abundance of an invertebrate population from assessment data collected on a spatial grid of sampling locations. We first discuss how insufficient information about the spatial population density obtained on a coarse sampling grid may affect the accuracy of an evaluation of total population size. Such information deficit in field data can arise because of inadequate spatial resolution of the population distribution (spatially variable population density) when coarse grids are used, which is especially true when a strongly heterogeneous spatial population density is sampled. We then argue that the average trap count (the quantity routinely used to quantify abundance), if obtained from a sampling grid that is too coarse, is a random variable because of the uncertainty in sampling spatial data. Finally, we show that a probabilistic approach similar to bootstrapping techniques can be an efficient tool to quantify the uncertainty in the evaluation procedure in the presence of a spatial pattern reflecting a patchy distribution of invertebrates within the sampling grid. PMID- 29495512 TI - Characterizing the DNA Methyltransferases of Haloferax volcanii via Bioinformatics, Gene Deletion, and SMRT Sequencing. AB - DNA methyltransferases (MTases), which catalyze the methylation of adenine and cytosine bases in DNA, can occur in bacteria and archaea alongside cognate restriction endonucleases (REases) in restriction-modification (RM) systems or independently as orphan MTases. Although DNA methylation and MTases have been well-characterized in bacteria, research into archaeal MTases has been limited. A previous study examined the genomic DNA methylation patterns (methylome) of the halophilic archaeon Haloferax volcanii, a model archaeal system which can be easily manipulated in laboratory settings, via single-molecule real-time (SMRT) sequencing and deletion of a putative MTase gene (HVO_A0006). In this follow-up study, we deleted other putative MTase genes in H. volcanii and sequenced the methylomes of the resulting deletion mutants via SMRT sequencing to characterize the genes responsible for DNA methylation. The results indicate that deletion of putative RM genes HVO_0794, HVO_A0006, and HVO_A0237 in a single strain abolished methylation of the sole cytosine motif in the genome (Cm4TAG). Amino acid alignments demonstrated that HVO_0794 shares homology with characterized cytosine CTAG MTases in other organisms, indicating that this MTase is responsible for Cm4TAG methylation in H. volcanii. The CTAG motif has high density at only one of the origins of replication, and there is no relative increase in CTAG motif frequency in the genome of H. volcanii, indicating that CTAG methylation might not have effectively taken over the role of regulating DNA replication and mismatch repair in the organism as previously predicted. Deletion of the putative Type I RM operon rmeRMS (HVO_2269-2271) resulted in abolished methylation of the adenine motif in the genome (GCAm6BN6VTGC). Alignments of the MTase (HVO_2270) and site specificity subunit (HVO_2271) demonstrate homology with other characterized Type I MTases and site specificity subunits, indicating that the rmeRMS operon is responsible for adenine methylation in H. volcanii. Together with HVO_0794, these genes appear to be responsible for all detected methylation in H. volcanii, even though other putative MTases (HVO_C0040, HVO_A0079) share homology with characterized MTases in other organisms. We also report the construction of a multi-RM deletion mutant (DeltaRM), with multiple RM genes deleted and with no methylation detected via SMRT sequencing, which we anticipate will be useful for future studies on DNA methylation in H. volcanii. PMID- 29495514 TI - Quantification of Phenolic Compounds and In Vitro Radical Scavenging Abilities with Leaf Extracts from Two Varieties of Psidium guajava L. AB - Guava leaf (Psidium guajava L.) extracts are used in both traditional medicine and the pharmaceutical industry. The antioxidant compounds in P. guajava leaves can have positive effects including anti-inflammatory, anti-hyperglycemic, hepatoprotective, analgesic, anti-cancer effects, as well as protecting against cardiovascular diseases. In the present study, phenolic compounds and in vitro antioxidant capacity were measured in extracts obtained with polar and non-polar solvents from leaves of two varieties of guava, Calvillo Siglo XXI and Hidrozac. The quantity of total phenolics and total flavonoids were expressed as equivalents of gallic acid and quercetin, respectively. Hydroxyl radical, 2,2' azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS), 2,2-diphenyl-1 picrylhydrazyl (DPPH), and Oxygen Radical Absorbance Capacity using fluorescein (ORAC-FL) in vitro tests were used to assess the radical scavenging abilities of the extracts. The total phenolics were higher in the aqueous fraction of the variety Calvillo Siglo XXI, while in the Hidrozac variety total phenolics were higher in the acetone and chloroform fractions. Total flavonoids were higher in all fractions in the variety Calvillo Siglo XXI. Total phenolics showed a highly positive correlation for ORAC-FL, and a moderately positive correlation with hydroxyl radicals. Finally, total flavonoids showed a slightly positive correlation for ORAC-FL and hydroxyl radicals. Both varieties of guava leaf extract showed excellent antioxidant properties. PMID- 29495515 TI - A Possible Role for Singlet Oxygen in the Degradation of Various Antioxidants. A Meta-Analysis and Review of Literature Data. AB - The thermodynamic parameters Eact, DeltaH?, DeltaS?, and DeltaG? for various processes involving antioxidants were calculated using literature kinetic data (k, T). The DeltaG? values of the antioxidants' processes vary in the range 91.27 116.46 kJmol-1 at 310 K. The similarity of the DeltaG? values (for all of the antioxidants studied) is supported to be an indication that a common mechanism in the above antioxidant processes may be taking place. A value of about 10-30 kJmol 1 is the activation energy for the diffusion of reactants depending on the reaction and the medium. The energy 92 kJmol-1 is needed for the excitation of O2 from the ground to the first excited state (1Deltag, singlet oxygen). We suggest the same role of the oxidative stress and specifically of singlet oxygen to the processes of antioxidants as in the processes of proteinaceous diseases. We therefore suggest a competition between the various antioxidants and the proteins of proteinaceous diseases in capturing singlet oxygen's empty pi* orbital. The concentration of the antioxidants could be a crucial factor for the competition. Also, the structures of the antioxidant molecules play a significant role since the various structures have a different number of regions of high electron density. PMID- 29495516 TI - Effects of a Carob-Pod-Derived Sweetener on Glucose Metabolism. AB - BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) have a higher incidence of cardiovascular (CV) events. The ingestion of high-glycemic index (GI) diets, specially sweetened beverage consumption, has been associated with the development of T2DM and CV disease. OBJECTIVE: We investigated the effects of the intake of a sweetened beverage, obtained from natural carbohydrates containing pinitol (PEB) compared to a sucrose-enriched beverage (SEB) in the context of impaired glucose tolerance (IGT) and diabetes. METHODS: The study was divided in three different phases: (1) a discovery phase where the plasma proteomic profile was investigated by 2-DE (two-dimensional electrophoresis) followed by mass spectrometry (matrix-assisted laser desorption/ionization time-of-flight-MALDI TOF/TOF) in healthy and IGT volunteers; (2) a verification phase where the potential mechanisms behind the observed protein changes were investigated in the discovery cohort and in an additional group of T2DM volunteers; and (3) the results were validated in a proof-of-concept interventional study in an animal model of diabetic rats with complementary methodologies. RESULTS: Six weeks of pinitol-enriched beverage (PEB) intake induced a significant increase in two proteins involved in the insulin secretion pathway, insulin-like growth factor acid labile subunit (IGF1BP-ALS; 1.3-fold increase; P = 0.200) and complement C4A (1.83-fold increase; P = 0.007) in IGT subjects but not in healthy volunteers. Changes in C4A were also found in the serum samples of Zucker diabetic fatty (ZDF) rats after four weeks of PEB intake compared to basal levels (P = 0.042). In addition, an increased expression of the glucose transporter-2 (GLUT2) gene was observed in the jejunum (P = 0.003) of inositol-supplemented rats when compared to sucrose supplementation. This change was correlated with the observed change in C4A (P = 0.002). CONCLUSIONS: Our results suggest that the substitution of a common sugar source, such as sucrose, by a naturally-based, pinitol-enriched beverage induces changes in the insulin secretion pathway that could help to reduce blood glucose levels by protecting beta-cells and by stimulating the insulin secretion pathway. This mechanism of action could have a relevant role in the prevention of insulin resistance and diabetes progression. PMID- 29495518 TI - Vitamin D and Calcium Addition during Denosumab Therapy over a Period of Four Years Significantly Improves Lumbar Bone Mineral Density in Japanese Osteoporosis Patients. AB - This study investigated whether or not vitamin D and calcium supplementation affected bone metabolism and bone mineral density (BMD) over a period of four years of denosumab therapy in patients with primary osteoporosis. Patients were divided into a denosumab monotherapy group (22 cases) or a denosumab plus vitamin D and calcium supplementation group (combination group, 21 cases). We measured serum bone alkaline phosphatase (BAP), tartrate-resistant acid phosphatase (TRACP)-5b, urinary N-terminal telopeptide of type-I collagen (NTX), and BMD of the lumbar 1-4 vertebrae (L-BMD) and bilateral hips (H-BMD) at baseline and at 12, 24, 36, and 48 months of treatment. There were no significant differences in patient background. Serum BAP, TRACP-5b, and urinary NTX were significantly and comparably inhibited in both groups from 12 to 48 months versus baseline values. L-BMD was significantly increased at every time point in both groups, while H-BMD was significantly increased at every time point in the combination group only. There were significant differences between the groups for L-BMD at 24, 36, and 48 months (P < 0.05) and for H-BMD at 12 months (P < 0.05). Compared with denosumab monotherapy, combination therapy of denosumab plus vitamin D and calcium significantly increased H-BMD at 12 months and L-BMD from 24 to 48 months. These findings indicate that continuous vitamin D and calcium supplementation is important, especially for 12 months to improve H-BMD and from 24 to 48 months to improve L-BMD. PMID- 29495517 TI - Calycophyllum spruceanum (Benth.), the Amazonian "Tree of Youth" Prolongs Longevity and Enhances Stress Resistance in Caenorhabditis elegans. AB - The tree popularly known in Brazil as mulateiro or pau-mulato (Calycophyllum spruceanum (Benth.) K. Schum.) is deeply embedded in the herbal medicine of the Amazon region. Different preparations of the bark are claimed to have anti-aging, antioxidant, antimicrobial, emollient, wound healing, hemostatic, contraceptive, stimulant, and anti-diabetic properties. The current study aims to provide the first step towards a science-based evidence of the beneficial effects of C. spruceanum in the promotion of longevity and in the modulation of age-related markers. For this investigation, we used the model system Caenorhabditis elegans to evaluate in vivo antioxidant and anti-aging activity of a water extract from C. spruceanum. To chemically characterize the extract, HPLC MS (High Performance Liquid Chromatography Mass Spectrometry)/MS analyses were performed. Five secondary metabolites were identified in the extract, namely gardenoside, 5 hydroxymorin, cyanidin, taxifolin, and 5-hydroxy-6-methoxycoumarin-7-glucoside. C. spruceanum extract was able to enhance stress resistance and to extend lifespan along with attenuation of aging-associated markers in C. elegans. The demonstrated bioactivities apparently depend on the DAF-16/FOXO pathway. The data might support the popular claims of mulateiro as the "tree of youth", however more studies are needed to clarify its putative benefits to human health. PMID- 29495519 TI - Three-Dimensional Graphene-RGD Peptide Nanoisland Composites That Enhance the Osteogenesis of Human Adipose-Derived Mesenchymal Stem Cells. AB - Graphene derivatives have immense potential in stem cell research. Here, we report a three-dimensional graphene/arginine-glycine-aspartic acid (RGD) peptide nanoisland composite effective in guiding the osteogenesis of human adipose derived mesenchymal stem cells (ADSCs). Amine-modified silica nanoparticles (SiNPs) were uniformly coated onto an indium tin oxide electrode (ITO), followed by graphene oxide (GO) encapsulation and electrochemical deposition of gold nanoparticles. A RGD-MAP-C peptide, with a triple-branched repeating RGD sequence and a terminal cysteine, was self-assembled onto the gold nanoparticles, generating the final three-dimensional graphene-RGD peptide nanoisland composite. We generated substrates with various gold nanoparticle-RGD peptide cluster densities, and found that the platform with the maximal number of clusters was most suitable for ADSC adhesion and spreading. Remarkably, the same platform was also highly efficient at guiding ADSC osteogenesis compared with other substrates, based on gene expression (alkaline phosphatase (ALP), runt-related transcription factor 2), enzyme activity (ALP), and calcium deposition. ADSCs induced to differentiate into osteoblasts showed higher calcium accumulations after 14-21 days than when grown on typical GO-SiNP complexes, suggesting that the platform can accelerate ADSC osteoblastic differentiation. The results demonstrate that a three-dimensional graphene-RGD peptide nanoisland composite can efficiently derive osteoblasts from mesenchymal stem cells. PMID- 29495520 TI - Current Insights into Oral Cancer Epigenetics. AB - Epigenetic modifications have emerged into one of the cancer hallmarks, replacing the concept of malignant pathologies as being solely genetic-based conditions. The epigenetic landscape is responsible for normal development but also for the heterogeneity among tissues in terms of gene expression patterns. Dysregulation in these mechanisms has been associated with disease stage, and increased attention is now granted to cancer in order to take advantage of these modifications in terms of novel therapeutic strategies or diagnosis/prognosis tools. Oral cancer has also been subjected to epigenetic analysis with numerous studies revealing that the development and progression of this malignancy are partially induced by an altered epigenetic substrate together with genetic alterations and prolonged exposure to environmental risk factors. The present review summarizes the most important epigenetic modifications associated with oral cancer and also their potential to be used as new therapeutic targets. PMID- 29495523 TI - Electron Beam Immobilization of Novel Antimicrobial, Short Peptide Motifs Leads to Membrane Surfaces with Promising Antibacterial Properties. AB - In this study, the efficacy of electron beam irradiation versus chemical coupling for yielding polyethersulfone (PES) membranes with antibacterial properties was investigated. For the surface coating, a recently discovered lead compound, IL KKA, comprising a short peptide sequence functionalized with imidazolium groups, was used. For better integration within the membrane, several novel variants of IL-KKA were generated. Membrane immobilization was achieved using different doses of electron beam irradiation and NHS/EDC chemical coupling. Physicochemical characterization of the coated membranes was performed by water contact angle measurements, X-ray photoelectron spectroscopy, and scanning electron microscopy. Our results show that electron beam irradiation is as effective and gentle as chemical coupling using the NHS/EDC method. Moreover, it was demonstrated that the obtained membranes exhibit promising antibacterial activity against B. subtilis. In summary, the technique presented herein might be promising as a template for developing future anti-biofilm devices. PMID- 29495521 TI - A Critical Review on Metallic Glasses as Structural Materials for Cardiovascular Stent Applications. AB - Functional and mechanical properties of novel biomaterials must be carefully evaluated to guarantee long-term biocompatibility and structural integrity of implantable medical devices. Owing to the combination of metallic bonding and amorphous structure, metallic glasses (MGs) exhibit extraordinary properties superior to conventional crystalline metallic alloys, placing them at the frontier of biomaterials research. MGs have potential to improve corrosion resistance, biocompatibility, strength, and longevity of biomedical implants, and hence are promising materials for cardiovascular stent applications. Nevertheless, while functional properties and biocompatibility of MGs have been widely investigated and validated, a solid understanding of their mechanical performance during different stages in stent applications is still scarce. In this review, we provide a brief, yet comprehensive account on the general aspects of MGs regarding their formation, processing, structure, mechanical, and chemical properties. More specifically, we focus on the additive manufacturing (AM) of MGs, their outstanding high strength and resilience, and their fatigue properties. The interconnection between processing, structure and mechanical behaviour of MGs is highlighted. We further review the main categories of cardiovascular stents, the required mechanical properties of each category, and the conventional materials have been using to address these requirements. Then, we bridge between the mechanical requirements of stents, structural properties of MGs, and the corresponding stent design caveats. In particular, we discuss our recent findings on the feasibility of using MGs in self-expandable stents where our results show that a metallic glass based aortic stent can be crimped without mechanical failure. We further justify the safe deployment of this stent in human descending aorta. It is our intent with this review to inspire biodevice developers toward the realization of MG-based stents. PMID- 29495524 TI - Antifungal Potential of Host Defense Peptide Mimetics in a Mouse Model of Disseminated Candidiasis. AB - Invasive candidiasis caused by Candida albicans and non-albicansCandida (NAC) present a serious disease threat. Although the echinocandins are recommended as the first line of antifungal drug class, resistance to these agents is beginning to emerge, demonstrating the need for new antifungal agents. Host defense peptides (HDP) exhibit potent antifungal activity, but as drugs they are difficult to manufacture efficiently, and they are often inactivated by serum proteins. HDP mimetics are low molecular weight non-peptide compounds that can alleviate these problems and were shown to be membrane-active against C. albicans and NAC. Here, we expand upon our previous works to describe the in vitro and in vivo activity of 11 new HDP mimetics that are active against C. albicans and NAC that are both sensitive and resistant to standard antifungal drugs. These compounds exhibit minimum inhibitory/fungicidal concentration (MIC/MFC) in the ug/mL range in the presence of serum and are inhibited by divalent cations. Rapid propidium iodide influx into the yeast cells following in vitro exposure suggested that these HDP mimetics were also membrane active. The lead compounds were able to kill C. albicans in an invasive candidiasis CD-1 mouse model with some mimetic candidates decreasing kidney burden by 3-4 logs after 24 h in a dose dependent manner. The data encouraged further development of this new anti-fungal drug class for invasive candidiasis. PMID- 29495522 TI - Antimicrobial Monomers for Polymeric Dental Restoratives: Cytotoxicity and Physicochemical Properties. AB - A trend for the next generation of polymeric dental restoratives is to incorporate multifunctional capabilities to regulate microbial growth and remineralize tooth surfaces. Polymerizable 2-(methacryloyloxy)-N-(2 (methacryloyloxy)ethyl)-N,N-dimethylethan-1-aminium bromide (IDMA1) and N,N' ([1,1'-biphenyl]-2,2'-diylbis(methylene))bis(2-(methacryloyloxy)-N,N dimethylethan-1-aminium) bromide (IDMA2), intended for utilization in bi functional antimicrobial and remineralizing composites, were synthesized, purified with an ethanol-diethyl ether-hexane solvent system, and validated by nuclear magnetic resonance (1H and 13C NMR) spectroscopy, mass spectrometry, and Fourier-transform infrared spectroscopy. When incorporated into light-curable urethane dimethacrylate (UDMA)/polyethylene glycol-extended UDMA (PEG-U)/ethyl 2 (hydroxymethyl)acrylate (EHMA) (assigned UPE) resins, IDMAs did not affect the overall resins' hydrophilicity/hydrophobicity balance (water contact angle: 60.8 65.5 degrees ). The attained degrees of vinyl conversion (DVC) were consistently higher in both IDMA-containing copolymers and their amorphous calcium phosphate (ACP) composites (up to 5% and 20%, respectively) reaching 92.5% in IDMA2 formulations. Notably, these high DVCs values were attained without an excessive increase in polymerization stress. The observed reduction in biaxial flexure strength of UPE-IDMA ACP composites should not prevent further evaluation of these materials as multifunctional Class V restoratives. In direct contact with human gingival fibroblasts, at biologically relevant concentrations, IDMAs did not adversely affect cell viability or their metabolic activity. Ion release from the composites was indicative of their strong remineralization potential. The above, early-phase biocompatibility and physicochemical tests justify further evaluation of these experimental materials to identify formulation(s) suitable for clinical testing. Successful completion is expected to yield a new class of restoratives with well-controlled bio-function, which will physicochemically, mechanically, and biologically outperform the conventional Class V restoratives. PMID- 29495526 TI - Comments on "A New Elliptical Model for Device-Free Localization". AB - A recent paper "A New Elliptical Model for Device-Free Localization" (Sensors 2016, 16, 577) presents a new geometry-based elliptical model for Device-free localization (DFL). In this comment, we point out some problems of the original paper and exploit the same data used in the original paper to demonstrate the existence of these problems. Then, we give a modified formula to correct their model. Meanwhile, a real experiment is performed to verify our conclusion. PMID- 29495525 TI - De Novo Transcriptome Assembly and Characterization of the Synthesis Genes of Bioactive Constituents in Abelmoschus esculentus (L.) Moench. AB - Abelmoschus esculentus (okra or lady's fingers) is a vegetable with high nutritional value, as well as having certain medicinal effects. It is widely used as food, in the food industry, and in herbal medicinal products, but also as an ornamental, in animal feed, and in other commercial sectors. Okra is rich in bioactive compounds, such as flavonoids, polysaccharides, polyphenols, caffeine, and pectin. In the present study, the concentrations of total flavonoids and polysaccharides in five organs of okra were determined and compared. Transcriptome sequencing was used to explore the biosynthesis pathways associated with the active constituents in okra. Transcriptome sequencing of five organs (roots, stem, leaves, flowers, and fruits) of okra enabled us to obtain 293,971 unigenes, of which 232,490 were annotated. Unigenes related to the enzymes involved in the flavonoid biosynthetic pathway or in fructose and mannose metabolism were identified, based on Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. All of the transcriptional datasets were uploaded to Sequence Read Archive (SRA). In summary, our comprehensive analysis provides important information at the molecular level about the flavonoid and polysaccharide biosynthesis pathways in okra. PMID- 29495527 TI - Glycosaminoglycans and Proteoglycans. AB - In this editorial to MDPI Pharmaceuticals special issue "Glycosaminoglycans and Proteoglycans" we describe in outline the common structural features of glycosaminoglycans and the characteristics of proteoglycans, including the intracellular proteoglycan, serglycin, cell-surface proteoglycans, like syndecans and glypicans, and the extracellular matrix proteoglycans, like aggrecan, perlecan, and small leucine-rich proteoglycans. The context in which the pharmaceutical uses of glycosaminoglycans and proteoglycans are presented in this special issue is given at the very end. PMID- 29495529 TI - Valuing a Lifestyle Intervention for Middle Eastern Immigrants at Risk of Diabetes. AB - Willingness-to-pay (WTP) techniques are increasingly being used in the healthcare sector for assessing the value of interventions. The objective of this study was to estimate WTP and its predictors in a randomized controlled trial of a lifestyle intervention exclusively targeting Middle Eastern immigrants living in Malmo, Sweden, who are at high risk of type 2 diabetes. We used the contingent valuation method to evaluate WTP. The questionnaire was designed following the payment-scale approach, and administered at the end of the trial, giving an ex post perspective. We performed logistic regression and linear regression techniques to identify the factors associated with zero WTP value and positive WTP values. The intervention group had significantly higher average WTP than the control group (216 SEK vs. 127 SEK; p = 0.035; 1 U.S.$ = 8.52 SEK, 2015 price year) per month. The regression models demonstrated that being in the intervention group, acculturation, and self-employment were significant factors associated with positive WTP values. Male participants and lower-educated participants had a significantly higher likelihood of zero WTP. In this era of increased migration, our findings can help policy makers to take informed decisions to implement lifestyle interventions for immigrant populations. PMID- 29495530 TI - Sodium Dodecyl Sulphate-Supported Nanocomposite as Drug Carrier System for Controlled Delivery of Ondansetron. AB - Sodium dodecyl sulphate-supported iron silicophosphate (SDS/FeSP) nanocomposite was successfully fabricated by the co-precipitation method. The SDS/FeSP nanocomposite was investigated as a drug carrier for ondansetron. The cumulative drug release of ondansetron was observed at various pH values for different time intervals, i.e., from 20 min to 48 h. A ranking of the drug release was observed at different pHs; pH 2.2 > saline (pH 5.5) > pH 7.4 > pH 9.4 > distilled water. Maximum release of encapsulated drug was found to be about 45.38% at pH 2.2. The cell viability tests of SDS/FeSP nanocomposite concluded that SDS/FeSP nanocomposite was non-cytotoxic in nature. PMID- 29495528 TI - Ocular Drug Delivery Barriers-Role of Nanocarriers in the Treatment of Anterior Segment Ocular Diseases. AB - Ocular drug delivery is challenging due to the presence of anatomical and physiological barriers. These barriers can affect drug entry into the eye following multiple routes of administration (e.g., topical, systemic, and injectable). Topical administration in the form of eye drops is preferred for treating anterior segment diseases, as it is convenient and provides local delivery of drugs. Major concerns with topical delivery include poor drug absorption and low bioavailability. To improve the bioavailability of topically administered drugs, novel drug delivery systems are being investigated. Nanocarrier delivery systems demonstrate enhanced drug permeation and prolonged drug release. This review provides an overview of ocular barriers to anterior segment delivery, along with ways to overcome these barriers using nanocarrier systems. The disposition of nanocarriers following topical administration, their safety, toxicity and clinical trials involving nanocarrier systems are also discussed. PMID- 29495531 TI - Core Microbiome of Medicinal Plant Salvia miltiorrhiza Seed: A Rich Reservoir of Beneficial Microbes for Secondary Metabolism? AB - Seed microbiome includes special endophytic or epiphytic microbial taxa associated with seeds, which affects seed germination, plant growth, and health. Here, we analyzed the core microbiome of 21 Salvia miltiorrhiza seeds from seven different geographic origins using 16S rDNA and ITS amplicon sequencing, followed by bioinformatics analysis. The whole bacterial microbiome was classified into 17 microbial phyla and 39 classes. Gammaproteobacteria (67.6%), Alphaproteobacteria (15.6%), Betaproteobacteria (2.6%), Sphingobacteria (5.0%), Bacilli (4.6%), and Actinobacteria (2.9%) belonged to the core bacterial microbiome. Dothideomycetes comprised 94% of core fungal microbiome in S. miltiorrhiza seeds, and another two dominant classes were Leotiomycetes (3.0%) and Tremellomycetes (2.0%). We found that terpenoid backbone biosynthesis, degradation of limonene, pinene, and geraniol, and prenyltransferases, were overrepresented in the core bacterial microbiome using phylogenetic examination of communities by reconstruction of unobserved states (PICRUSt) software. We also found that the bacterial genera Pantoea, Pseudomonas, and Sphingomonas were enriched core taxa and overlapped among S. miltiorrhiza, maize, bean, and rice, while a fungal genus, Alternaria, was shared within S. miltiorrhiza, bean, and Brassicaceae families. These findings highlight that seed-associated microbiomeis an important component of plant microbiomes, which may be a gene reservoir for secondary metabolism in medicinal plants. PMID- 29495533 TI - Predicting Circulatory Diseases from Psychosocial Safety Climate: A Prospective Cohort Study from Australia. AB - Circulatory diseases (CDs) (including myocardial infarction, angina, stroke or hypertension) are among the leading causes of death in the world. In this paper, we explore for the first time the impact of a specific aspect of organizational climate, Psychosocial Safety Climate (PSC), on CDs. We used two waves of interview data from Australia, with an average lag of 5 years (excluding baseline CDs, final n = 1223). Logistic regression was conducted to estimate the prospective associations between PSC at baseline on incident CDs at follow-up. It was found that participants in low PSC environments were 59% more likely to develop new CD than those in high PSC environments. Logistic regression showed that PSC at baseline predicts lower CD risk at follow-up (OR = 0.98, 95% CI 0.96 1.00) and this risk remained unchanged even after additional adjustment for known job design risk factors (effort reward imbalance and job strain). These results suggest that PSC is an independent risk factor for CDs in Australia. Beyond job design this study implicates organizational climate and prevailing management values regarding worker psychological health as the genesis of CDs. PMID- 29495532 TI - Hippocampal MicroRNAs Respond to Administration of Antidepressant Fluoxetine in Adult Mice. AB - Current antidepressant treatments to anxiety and depression remain inadequate, burdened by a significant percentage of misuse and drug side-effects, due to unclear mechanisms of actions of antidepressants. To better understand the regulatory roles of antidepressant fluoxetine-related drug reactions, we here investigate changes of expression levels of hippocampal microRNAs (miRNAs) after administration of fluoxetine in normal adult mice. We find that 64 miRNAs showed significant changes between fluoxetine treatment and control groups by analyzing 626 mouse miRNAs. Many miRNAs in response to fluoxetine are involved in neural related signaling pathways by analyzing miRNA-target gene pairs using the Kyoto encyclopedia of genes and genomes (KEGG) and Gene Ontology (GO). Moreover, miRNAs with altered expression are mainly associated with the repression of the dopaminergic synapse signals, which may affect hippocampal function after fluoxetine treatment. Our results demonstrate that a number of miRNAs respond to antidepressants even in normal mice and may affect target gene expression, which supports the safety consideration of inappropriate treatment and off-label use of antidepressant drugs. PMID- 29495534 TI - Biotoxicity of TiO2 Nanoparticles on Raphidocelis subcapitata Microalgae Exemplified by Membrane Deformation. AB - TiO2 nanoparticles (NPs), which are mainly used in consumer products (mostly cosmetics), have been found to cause ecotoxic effects in the aquatic environment. The green algae Raphidocelis subcapitata, as a representative of primary producers of the freshwater ecosystem, has been frequently used to study the effects of metal oxide NPs. An ecotoxicity study was conducted herein to investigate the effects of TiO2 NPs on survival and membrane deformation of algal cells. Five different concentrations of nano-TiO2 particles (1, 10, 50, 100 and 500 mg/L) were prepared in synthetic surface water samples with five different water quality characteristics (pH 6.4-8.4, hardness 10-320 mg CaCO3/L, ionic strength 0.2-8 mM, and alkalinity 10-245 mg CaCO3/L). Results showed a significant increase in the hydrodynamic diameter of NPs with respect to both NP concentrations and ionic content of the test system. A soft synthetic freshwater system at pH 7.3 +/- 0.2 appeared to provide the most effective water type, with more than 95% algal mortality observed at 50, 100 and 500 mg/L NP concentrations. At high exposure concentrations, increased malondialdehyde formations were observed. Moreover, due to membrane deformation, TEM images correlated the uptake of the NPs. PMID- 29495536 TI - Dimensional Changes of Tracheids during Drying of Radiata Pine (Pinus radiata D. Don) Compression Woods: A Study Using Variable-Pressure Scanning Electron Microscopy (VP-SEM). AB - Variable-pressure scanning electron microscopy was used to investigate the dimensional changes in longitudinal, tangential and radial directions, on wetting and drying, of tracheids of opposite wood (OW) and three grades of compression woods (CWs), including severe CW (SCW) and two grades of mild compression wood (MCW) (MCW1 and MCW2) in corewood of radiata pine (Pinus radiata) saplings. The CW was formed on the underside and OW on the upper side of slightly tilted stems. In the longitudinal direction, the shrinkage of SCW tracheids was ~300% greater than that of OW tracheids, with the shrinkage of the MCW1 and MCW2 tracheids being intermediate. Longitudinal swelling was also investigated and hysteresis was demonstrated for the tracheids of all corewood types, with the extent of hysteresis increasing with CW severity. A statistical association was found between longitudinal shrinkage and the content of lignin and galactosyl residues in the cell-wall matrix. The galactosyl residues are present mostly as (1->4) beta-galactans, which are known to have a high capacity for binding water and swell on hydration. The small proportions of (1->3)-beta-glucans in the CWs have similar properties. These polysaccharides may play a functional role in the longitudinal shrinking and swelling of CW tracheids. Tangential shrinkage of tracheids was greater than radial shrinkage but both were greatest for OW and least for SCW, with the MCW1 and MCW2 being intermediate. PMID- 29495535 TI - Xyloglucan, a Plant Polymer with Barrier Protective Properties over the Mucous Membranes: An Overview. AB - Disruption of the epithelial barrier function has been recently associated with a variety of diseases, mainly at intestinal level, but also affecting the respiratory epithelium and other mucosal barriers. Non-pharmacological approaches such as xyloglucan, with demonstrated protective barrier properties, are proposed as new alternatives for the management of a wide range of diseases, for which mucosal disruption and, particularly, tight junction alterations, is a common characteristic. Xyloglucan, a natural polysaccharide derived from tamarind seeds, possesses a "mucin-like" molecular structure that confers mucoadhesive properties, allowing xyloglucan formulations to act as a barrier capable of reducing bacterial adherence and invasion and to preserve tight junctions and paracellular flux, as observed in different in vitro and in vivo studies. In clinical trials, xyloglucan has been seen to reduce symptoms of gastroenteritis in adults and children, nasal disorders and dry eye syndrome. Similar mucosal protectors containing reticulated proteins have also been useful for the treatment of irritable bowel syndrome and urinary tract infections. The role of xyloglucan in other disorders with mucosal disruption, such as dermatological or other infectious diseases, deserves further research. In conclusion, xyloglucan, endowed with film-forming protective barrier properties, is a safe non pharmacological alternative for the management of different diseases, such as gastrointestinal and nasal disorders. PMID- 29495539 TI - Abstraction and Idealization in Biomedicine: The Nonautonomous Theory of Acute Cell Injury. AB - Neuroprotection seeks to halt cell death after brain ischemia and has been shown to be possible in laboratory studies. However, neuroprotection has not been successfully translated into clinical practice, despite voluminous research and controlled clinical trials. We suggested these failures may be due, at least in part, to the lack of a general theory of cell injury to guide research into specific injuries. The nonlinear dynamical theory of acute cell injury was introduced to ameliorate this situation. Here we present a revised nonautonomous nonlinear theory of acute cell injury and show how to interpret its solutions in terms of acute biomedical injuries. The theory solutions demonstrate the complexity of possible outcomes following an idealized acute injury and indicate that a "one size fits all" therapy is unlikely to be successful. This conclusion is offset by the fact that the theory can (1) determine if a cell has the possibility to survive given a specific acute injury, and (2) calculate the degree of therapy needed to cause survival. To appreciate these conclusions, it is necessary to idealize and abstract complex physical systems to identify the fundamental mechanism governing the injury dynamics. The path of abstraction and idealization in biomedical research opens the possibility for medical treatments that may achieve engineering levels of precision. PMID- 29495538 TI - Therapeutics in Osteoarthritis Based on an Understanding of Its Molecular Pathogenesis. AB - Osteoarthritis (OA) is the most prevalent joint disease in older people and is characterized by the progressive destruction of articular cartilage, synovial inflammation, changes in subchondral bone and peri-articular muscle, and pain. Because our understanding of the aetiopathogenesis of OA remains incomplete, we haven't discovered a cure for OA yet. This review appraises novel therapeutics based on recent progress in our understanding of the molecular pathogenesis of OA, including pro-inflammatory and pro-catabolic mediators and the relevant signalling mechanisms. The changes in subchondral bone and peri-articular muscle accompanying cartilage damage are also reviewed. PMID- 29495541 TI - Dosimetry-Based Consideration on Remission and Relapse after Therapy with 223Ra Dichloride in Castration-Resistant Prostate Cancer (CRPC) with Bone Metastases. A Case Report. AB - Here, we present the case of a 64-year-old male patient diagnosed with castration resistant prostate cancer (CRPC) with bone metastasis, treated with abiraterone prednisone/prednisolone in combination with 223Ra-dichloride therapy, who had remission and a subsequent relapse of bone metastasis on repeated bone scans after therapy. We also discuss the possibility of continuing the 223Ra-dichloride therapy over the six planned administrations by administering other cycles at the same dose or at higher doses, if shown to be devoid of a significant increase in side effects, based on dosimetry considerations. PMID- 29495540 TI - The Effects of Cannabinoids on Executive Functions: Evidence from Cannabis and Synthetic Cannabinoids-A Systematic Review. AB - Background-Cannabis is the most popular illicit drug in the Western world. Repeated cannabis use has been associated with short and long-term range of adverse effects. Recently, new types of designer-drugs containing synthetic cannabinoids have been widespread. These synthetic cannabinoid drugs are associated with undesired adverse effects similar to those seen with cannabis use, yet, in more severe and long-lasting forms. Method-A literature search was conducted using electronic bibliographic databases up to 31 December 2017. Specific search strategies were employed using multiple keywords (e.g., "synthetic cannabinoids AND cognition," "cannabis AND cognition" and "cannabinoids AND cognition"). Results-The search has yielded 160 eligible studies including 37 preclinical studies (5 attention, 25 short-term memory, 7 cognitive flexibility) and 44 human studies (16 attention, 15 working memory, 13 cognitive flexibility). Both pre-clinical and clinical studies demonstrated an association between synthetic cannabinoids and executive-function impairment either after acute or repeated consumptions. These deficits differ in severity depending on several factors including the type of drug, dose of use, quantity, age of onset and duration of use. Conclusions-Understanding the nature of the impaired executive function following consumption of synthetic cannabinoids is crucial in view of the increasing use of these drugs. PMID- 29495537 TI - DNA Vaccine-Encoded Flagellin Can Be Used as an Adjuvant Scaffold to Augment HIV 1 gp41 Membrane Proximal External Region Immunogenicity. AB - Flagellin's potential as a vaccine adjuvant has been increasingly explored over the last three decades. Monomeric flagellin proteins are the only known agonists of Toll-like receptor 5 (TLR5). This interaction evokes a pro-inflammatory state that impacts upon both innate and adaptive immunity. While pathogen associated molecular patterns (PAMPs) like flagellin have been used as stand-alone adjuvants that are co-delivered with antigen, some investigators have demonstrated a distinct advantage to incorporating antigen epitopes within the structure of flagellin itself. This approach has been particularly effective in enhancing humoral immune responses. We sought to use flagellin as both scaffold and adjuvant for HIV gp41 with the aim of eliciting antibodies to the membrane proximal external region (MPER). Accordingly, we devised a straightforward step wise approach to select flagellin-antigen fusion proteins for gene-based vaccine development. Using plasmid DNA vector-based expression in mammalian cells, we demonstrate robust expression of codon-optimized full length and hypervariable region-deleted constructs of Salmonella enterica subsp. enterica serovar Typhi flagellin (FliC). An HIV gp41 derived sequence including the MPER (gp41607-683) was incorporated into various positions of these constructs and the expressed fusion proteins were screened for effective secretion, TLR5 agonist activity and adequate MPER antigenicity. We show that incorporation of gp41607-683 into a FliC based scaffold significantly augments gp41607-683 immunogenicity in a TLR5 dependent manner and elicits modest MPER-specific humoral responses in a mouse model. PMID- 29495542 TI - The Impact of Active Workstations on Workplace Productivity and Performance: A Systematic Review. AB - Active workstations have been recommended for reducing sedentary behavior in the workplace. It is important to understand if the use of these workstations has an impact on worker productivity. The aim of this systematic review was to examine the effect of active workstations on workplace productivity and performance. A total of 3303 articles were initially identified by a systematic search and seven articles met eligibility criteria for inclusion. A quality appraisal was conducted to assess risk of bias, confounding, internal and external validity, and reporting. Most of the studies reported cognitive performance as opposed to productivity. Five studies assessed cognitive performance during use of an active workstation, usually in a single session. Sit-stand desks had no detrimental effect on performance, however, some studies with treadmill and cycling workstations identified potential decreases in performance. Many of the studies lacked the power required to achieve statistical significance. Three studies assessed workplace productivity after prolonged use of an active workstation for between 12 and 52 weeks. These studies reported no significant effect on productivity. Active workstations do not appear to decrease workplace performance. PMID- 29495544 TI - Impact of Sexual Dimorphism on Trauma Patterns and Clinical Outcomes of Patients with a High-Risk Score of the Osteoporosis Self-Assessment Tool for Asians: A Propensity Score-Matched Analysis. AB - The Osteoporosis Self-assessment Tool for Asians (OSTA) is a validated index based on age and weight to predict the risk of osteoporosis in women. This cross sectional study was designed to evaluate the impact of sexual dimorphism on the trauma patterns and the clinical outcomes of patients with high-risk OSTA scores. Trauma data of patients with high-risk OSTA scores between 1 January 2009 and 31 December 2015 were retrieved from the trauma registry system of a level I trauma center. A total of 2248 patients including 1585 women and 663 men were included in this study. In-hospital mortality was assessed as the primary outcome in the propensity score-matched analyses of the female and male patients, which were created in a 1:1 ratio under the adjustment of potential confounders, including age, co-morbidity, mechanism and injury-severity score (ISS). Female patients with a high-risk OSTA score had significantly lower mortality rates than their male counterparts. Among the propensity score-matched population, female patients had lower odds of having cerebral contusion and pneumothorax, but higher odds of presenting with radial, ulnar and femoral fractures than male patients. In addition, the female patients still had significantly lower odds of mortality (odds ratio (OR), 0.5; 95% confidence interval (CI), 0.29-0.90; p = 0.019) than the male patients. However, no significant differences were noted in the length of stay (LOS) in hospital, intensive-care unit (ICU) admission, and LOS in the ICU between the sexes. Female patients with high-risk OSTA scores showed different injury patterns and significantly lower mortality rates than their male counterparts, even after controlling for potential confounding factors. PMID- 29495543 TI - Methyl-Donor and Cofactor Nutrient Intakes in the First 2-3 Years and Global DNA Methylation at Age 4: A Prospective Cohort Study. AB - BACKGROUND: During the early postnatal period, the impact of nutrition on DNA methylation has not been well studied in humans. The aim was to quantify the relationship between one-carbon metabolism nutrient intake during the first three years of life and global DNA methylation levels at four years. DESIGN: Childhood dietary intake was assessed using infant feeding questionnaires, food frequency questionnaires, 4-day weighed food records and 24-h food records. The dietary records were used to estimate the intake of methionine, folate, vitamins B2, B6 and B12 and choline. The accumulative nutrient intake specific rank from three months to three years of age was used for analysis. Global DNA methylation (%5 methyl cytosines (%5-mC)) was measured in buccal cells at four years of age, using an enzyme-linked immunosorbent assay (ELISA) commercial kit. Linear regression models were used to quantify the statistical relationships. RESULTS: Data were collected from 73 children recruited from the Women and their Children's Health (WATCH) study. No association was found between one-carbon metabolism nutrient intake and global DNA methylation levels (P > 0.05). Global DNA methylation levels in males were significantly higher than in females (median %5-mC: 1.82 vs. 1.03, males and females respectively, (P < 0.05)). CONCLUSION: No association was found between the intake of one-carbon metabolism nutrients during the early postnatal period and global DNA methylation levels at age four years. Higher global DNA methylation levels in males warrants further investigation. PMID- 29495545 TI - Key Anti-Fibrosis Associated Long Noncoding RNAs Identified in Human Hepatic Stellate Cell via Transcriptome Sequencing Analysis. AB - Hepatic fibrosis is the main pathological basis for chronic cirrhosis, and activated hepatic stellate cells (HSCs) are the primary cells involved in liver fibrosis. Our study analyzed anti-fibrosis long noncoding RNAs (lncRNAs) in activated human HSCs (hHSCs). We performed RNA sequencing (RNA-seq) and bioinformatics analysis to determine whether lncRNA expression profile changes between hHSCs activation and quiescence. Eight differentially expressed (DE) lncRNAs and three pairs of co-expression lncRNAs-mRNAs were verified by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). A total of 34146 DE lncRNAs were identified in this study. Via gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, we found several DE lncRNAs regulated hHSC activation by participating in DNA bending/packaging complex, growth factor binding and the Hippo signaling pathway (p < 0.05). With lncRNA mRNA co-expression analysis, three lncRNAs were identified to be associated with connective tissue growth factor (CTGF), fibroblast growth factor 2 (FGF2) and netrin-4 (NTN4). The quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) results of the eight DE lncRNAs and three pairs of co-expression lncRNAs-mRNAs were consistent with the RNA-seq data and previous reports. Several lncRNAs may serve as potential targets to reverse the progression of liver fibrosis. This study provides a first insight into lncRNA expression profile changes associated with activated human HSCs. PMID- 29495546 TI - The National and Regional Prevalence Rates of Disability, Type, of Disability and Severity in Saudi Arabia-Analysis of 2016 Demographic Survey Data. AB - The prevalence of disability varies between countries ranging from less than 1% to up to 30% in some countries, thus, the estimated global disability prevalence is about 15%. However, it is unknown what the current estimate of disability and its types and severity are in Saudi Arabia. Thus, the objective of this study is to estimate national and regional prevalence rates of any disability, types of disability, and their severity among Saudi populations. Data on disability status were extracted from the national demographic survey conducted in 2016 as reported by the General Authority for Statistics, Saudi Arabia (N = 20,064,970). Prevalence rates per a population of 100,000 of any disability, type of disability, and its severity were calculated at the national level and in all 13 regions. Out of 20,064,970 Saudi citizens surveyed, 667,280 citizens reported disabilities, accounting for a prevalence rate of 3326 per a population of 100,000 (3.3%). Individuals aged 60 years and above (11,014) and males (3818) had a higher prevalence rate of disability compared with females (2813). The Tabuk region has the highest rate of reported disability, at 4.3%. The prevalence rates of extreme disabilities in mobility and sight were higher in Madinah (57,343) and Northern border (41,236) regions, respectively. In Saudi Arabia, more than half a million Saudi citizens (1 out of every 30 individuals) reported the presence of disability during the year 2016. A higher prevalence rate of disability was seen among those aged 60 years and above, and males. Targeted efforts are required at the national and regional levels to expand and improve rehabilitation and social services for all people with disabilities. PMID- 29495548 TI - Tolerance to Stress Combination in Tomato Plants: New Insights in the Protective Role of Melatonin. AB - Abiotic stresses such as drought, heat or salinity are major causes of yield loss worldwide. Recent studies have revealed that the acclimation of plants to a combination of different environmental stresses is unique and therefore cannot be directly deduced from studying the response of plants to each of the different stresses applied individually. The efficient detoxification of reactive oxygen species (ROS) is thought to play a key role in enhancing the tolerance of plants to abiotic stresses. Here, we report on the role of melatonin in the protection of the photosynthetic apparatus through the increase in ROS detoxification in tomato plants grown under the combination of salinity and heat, two of the most common abiotic stresses known to act jointly. Plants treated with exogenous melatonin showed a different modulation in the expression on some antioxidant related genes and their related enzymes. More specifically, ascorbate peroxidase, glutathione reductase, glutathione peroxidase and phospholipid hydroperoxide glutathione peroxidase (APX, GR, GPX and Ph-GPX, resepctively) showed an antagonistic regulation as compared to plants that did not receive melatonin. This translated into a better antioxidant capacity and to a lesser ROS accumulation under stress combination. The performance of the photosynthesis parameters and the photosystems was also increased in plants treated with exogenous melatonin under the combination of salinity and heat. In accordance with these findings, tomato plants treated with melatonin were found to grow better under stress combination that the non-treated ones. Our study highlights the important role that exogenous melatonin plays in the acclimation of plants to a combination of two different abiotic stresses, and how this compound can specifically regulate oxidative stress-related genes and enzymes to increase plant tolerance. PMID- 29495549 TI - Prorocentrolide-A from Cultured Prorocentrum lima Dinoflagellates Collected in Japan Blocks Sub-Types of Nicotinic Acetylcholine Receptors. AB - Prorocentrolides are members of the cyclic imine phycotoxins family. Their chemical structure includes a 26-membered carbo-macrocycle and a 28-membered macrocyclic lactone arranged around a hexahydroisoquinoline that incorporates the characteristic cyclic imine group. Six prorocentrolides are already known. However, their mode of action remains undetermined. The aim of the present work was to explore whether prorocentrolide A acts on nicotinic acetylcholine receptors (nAChRs), using competition-binding assays and electrophysiological techniques. Prorocentrolide-A displaced [125I]alpha-bungarotoxin binding to Torpedo membranes, expressing the muscle-type (alpha12beta1gammadelta) nAChR, and in HEK-293 cells, expressing the chimeric chick neuronal alpha7-5HT3 nAChR. Functional studies revealed that prorocentrolide-A had no agonist action on nAChRs, but inhibited ACh-induced currents in Xenopus oocytes that had incorporated the muscle-type alpha12beta1gammadelta nAChR to their membranes, or that expressed the human alpha7 nAChR, as revealed by voltage-clamp recordings. Molecular docking calculations showed the absence of the characteristic hydrogen bond between the iminium group of prorocentrolide-A and the backbone carbonyl group of Trp147 in the receptor, explaining its weaker affinity as compared to all other cyclic imine toxins. In conclusion, this is the first study to show that prorocentrolide-A acts on both muscle and neuronal nAChRs, but with higher affinity on the muscle-type nAChR. PMID- 29495550 TI - Exploring N-acyl-4-azatetracyclo[5.3.2.02,6.08,10]dodec-11-enes as 11beta-HSD1 Inhibitors. AB - We recently found that a cyclohexanecarboxamide derived from 4 azatetracyclo[5.3.2.02,6.08,10]dodec-11-ene displayed low nanomolar inhibition of 11beta-HSD1. In continuation of our efforts to discover potent and selective 11beta-HSD1 inhibitors, herein we explored several replacements for the cyclohexane ring. Some derivatives exhibited potent inhibitory activity against human 11beta-HSD1, although with low selectivity over the isoenzyme 11beta-HSD2, and poor microsomal stability. PMID- 29495547 TI - Modulating Vaccinia Virus Immunomodulators to Improve Immunological Memory. AB - The increasing frequency of monkeypox virus infections, new outbreaks of other zoonotic orthopoxviruses and concern about the re-emergence of smallpox have prompted research into developing antiviral drugs and better vaccines against these viruses. This article considers the genetic engineering of vaccinia virus (VACV) to enhance vaccine immunogenicity and safety. The virulence, immunogenicity and protective efficacy of VACV strains engineered to lack specific immunomodulatory or host range proteins are described. The ultimate goal is to develop safer and more immunogenic VACV vaccines that induce long-lasting immunological memory. PMID- 29495551 TI - Detection and Characterization of Homologues of Human Hepatitis Viruses and Pegiviruses in Rodents and Bats in Vietnam. AB - Rodents and bats are now widely recognised as important sources of zoonotic virus infections in other mammals, including humans. Numerous surveys have expanded our knowledge of diverse viruses in a range of rodent and bat species, including their origins, evolution, and range of hosts. In this study of pegivirus and human hepatitis-related viruses, liver and serum samples from Vietnamese rodents and bats were examined by PCR and sequencing. Nucleic acids homologous to human hepatitis B, C, E viruses were detected in liver samples of 2 (1.3%) of 157 bats, 38 (8.1%), and 14 (3%) of 470 rodents, respectively. Hepacivirus-like viruses were frequently detected (42.7%) in the bamboo rat, Rhizomys pruinosus, while pegivirus RNA was only evident in 2 (0.3%) of 638 rodent serum samples. Complete or near-complete genome sequences of HBV, HEV and pegivirus homologues closely resembled those previously reported from rodents and bats. However, complete coding region sequences of the rodent hepacivirus-like viruses substantially diverged from all of the currently classified variants and potentially represent a new species in the Hepacivirus genus. Of the viruses identified, their routes of transmission and potential to establish zoonoses remain to be determined. PMID- 29495553 TI - Adherence to Bisphosphonates among People Admitted to an Orthopaedic and Geriatric Ward at a University Hospital in Sweden. AB - Oral bisphosphonates are the first choice of therapy to reduce the risk of osteoporotic fractures. These medications have generally poor oral bioavailability, which may further be reduced by concomitant intake of certain foods and drugs; therefore, it is vital to follow specific instructions. The aim with this study was to assess general adherence to oral bisphosphonates and adherence to specific administration instructions among people admitted to two wards at Umea University hospital in Sweden. This interview study focuses on elderly patients living at home and prescribed oral bisphosphonates. Invited were 27 patients admitted to an orthopaedic ward and a geriatric ward during the period 28 March 2017 and 5 December 2017. In total, 21 patients were interviewed regarding their adherence to oral bisphosphonates. Out of 21 patients, 13 (62%) were considered non-adherent. The most common reason was calcium intake less than 2 h after oral administration of bisphosphonate (54%). The number of regularly prescribed drugs was significantly higher among patients rated non-adherent to bisphosphonates compared to those rated adherent (p = 0.004). Adherence to bisphosphonates administration instruction among elderly people living at home was limited. More research is needed to confirm these results and to investigate the reasons for non-adherence and how adherence to bisphosphonates can be improved. PMID- 29495552 TI - Factors Affecting Gastrointestinal Microbiome Development in Neonates. AB - The gut microbiome is established in the newborn period and is recognised to interact with the host to influence metabolism. Different environmental factors that are encountered during this critical period may influence the gut microbial composition, potentially impacting upon later disease risk, such as asthma, metabolic disorder, and inflammatory bowel disease. The sterility dogma of the foetus in utero is challenged by studies that identified bacteria, bacterial DNA, or bacterial products in meconium, amniotic fluid, and the placenta; indicating the initiation of maternal-to-offspring microbial colonisation in utero. This narrative review aims to provide a better understanding of factors that affect the development of the gastrointestinal (GI) microbiome during prenatal, perinatal to postnatal life, and their reciprocal relationship with GI tract development in neonates. PMID- 29495554 TI - True Lies: Using Proteomics to Assess the Accuracy of Transcriptome-Based Venomics in Centipedes Uncovers False Positives and Reveals Startling Intraspecific Variation in Scolopendra Subspinipes. AB - Centipede venoms have emerged as a rich source of novel bioactive compounds. However, most centipede species are commonly considered too small for venom extraction and transcriptomics is likely to be an attractive way of probing the molecular diversity of these venoms. Examining the venom composition of Scolopendra subspinipes, we test the accuracy of this approach. We compared the proteomically determined venom profile with four common toxin transcriptomic toxin annotation approaches: BLAST search against toxins in UniProt, lineage specific toxins, or species-specific toxins and comparative expression analyses of venom and non-venom producing tissues. This demonstrated that even toxin annotation based on lineage-specific homology searches is prone to substantial errors compared to a proteomic approach. However, combined comparative transcriptomics and phylogenetic analysis of putative toxin families substantially improves annotation accuracy. Furthermore, comparison of the venom composition of S. subspinipes with the closely related S. subspinipes mutilans revealed a surprising lack of overlap. This first insight into the intraspecific venom variability of centipedes contrasts the sequence conservation expected from previous findings that centipede toxins evolve under strong negative selection. Our results highlight the importance of proteomic data in studies of even comparably well-characterized venoms and warrants caution when sourcing venom from centipedes of unknown origin. PMID- 29495555 TI - The Emerging Role of Pattern Recognition Receptors in the Pathogenesis of Malaria. AB - Despite a global effort to develop an effective vaccine, malaria is still a significant health problem. Much of the pathology of malaria is immune mediated. This suggests that host immune responses have to be finely regulated. The innate immune system initiates and sets the threshold of the acquired immune response and determines the outcome of the disease. Yet, our knowledge of the regulation of innate immune responses during malaria is limited. Theoretically, inadequate activation of the innate immune system could result in unrestrained parasite growth. Conversely, hyperactivation of the innate immune system, is likely to cause excessive production of proinflammatory cytokines and severe pathology. Toll-like receptors (TLRs) have emerged as essential receptors which detect signature molecules and shape the complex host response during malaria infection. This review will highlight the mechanisms by which Plasmodium components are recognized by innate immune receptors with particular emphasis on TLRs. A thorough understanding of the complex roles of TLRs in malaria may allow the delineation of pathological versus protective host responses and enhance the efficacy of anti-malarial treatments and vaccines. PMID- 29495556 TI - The New Structure of Core Oligosaccharide Presented by Proteus penneri 40A and 41 Lipopolysaccharides. AB - The new type of core oligosaccharide in Proteus penneri 40A and 41 lipopolysaccharides has been investigated by 1H and 13C NMR spectroscopy, electrospray ionization mass spectrometry and chemical methods. Core oligosaccharides of both strains were chosen for structural analysis based on the reactivity of LPSs with serum against P. penneri 40A core oligosaccharide diphtheria toxoid conjugate. Structural analyses revealed that P. penneri 40A and 41 LPSs possess an identical core oligosaccharide. PMID- 29495557 TI - Estrogen Receptor alpha Is Crucial in Zearalenone-Induced Invasion and Migration of Prostate Cancer Cells. AB - Zearalenone (ZEA), a mycotoxin produced in the genus Fusarium, binds to estrogen receptors (ER) and is therefore regarded as an endocrine disruptor. ZEA has also been found to modulate the proliferation and apoptosis of prostate cancer cells in a dose-dependent manner. This study evaluates whether the effect of a low dose of ZEA (0.1 and 0.001 nM) on the invasion and migration of prostate cancer cell line PC3 is associated with ERs expression. The invasion and migration was evaluated by modified Boyden chamber assay, scratch assay, gelatin zymography, Real Time qPCR (RTqPCR) and Western blot. The involvement of ERs was evaluated with the selective ER antagonists: estrogen receptor alpha (ERalpha) antagonist 1,3-bis (4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy) phenol]-1H-pyrazole dihydrochloride (MPP) and estrogen receptor beta (ERbeta) antagonist 4-[2-phenyl 5,7-bis (trifluoromethyl) pyrazolo [1,5-a]-pyrimidin-3-yl] phenol (PHTPP). ZEA was found to modulate cell motility dependent on estrogen receptors, particularly ERalpha. Increased cell migration and invasion were associated with increased MMP 2 and MMP-9 activity as well as the up-regulation of the EMT-associated genes vimentin (VIM), zinc finger E-box-binding homeobox 1/2 (ZEB1/2) and transforming growth factor beta 1 (TGFbeta1). In conclusion, ZEA might modulate the invasiveness of prostate cancer cells dependently on ERalpha expression. PMID- 29495558 TI - Relationships between Nutrient Heterogeneity, Root Growth, and Hormones: Evidence for Interspecific Variation. AB - (1) Background: Plant roots respond to nutrients through root architecture that is regulated by hormones. Strong inter-specific variation in root architecture has been well documented, but physiological mechanisms that may control the variation have not. (2) Methods: We examined correlations between root architecture and hormones to seek clues on mechanisms behind root foraging behavior. In the green house at Beijing Normal University, hydroponic culture experiments were used to examine the root responses of four species-Callistephus chinensis, Solidago canadensis, Ailanthus altissima, Oryza sativa-to two nitrogen types (NO3- or NH4+), three nitrogen concentrations (low, medium, and high concentrations of 0.2, 1, and 18 mM, respectively) and two ways of nitrogen application (stable vs. variable). The plants were harvested after 36 days to measure root mass, 1st order root length, seminal root length for O. sativa, density of the 1st order laterals, seminal root number for O. sativa, the inter node length of the 1st order laterals, and root hormone contents of indole-3 acetic acid, abscisic acid, and cytokinins (zeatin + zeatinriboside). (3) Results: Species differed significantly in their root architecture responses to nitrogen treatments. They also differed significantly in hormone responses to the nitrogen treatments. Additionally, the correlations between root architecture and hormone responses were quite variable across the species. Each hormone had highly species-specific relationships with root responses. (4) Conclusions: Our finding implies that a particular root foraging behavior is probably not controlled by the same biochemical pathway in all species. PMID- 29495559 TI - Lignin from Hardwood and Softwood Biomass as a Lubricating Additive to Ethylene Glycol. AB - Ethylene glycol (EG)-based lubricant was prepared with dissolved organosolv lignin from birch wood (BL) and softwood (SL) biomass. The effects of different lignin types on the rheological, thermal, and tribological properties of the lignin/EG lubricants were comprehensively investigated by various characterization techniques. Dissolving organosolv lignin in EG results in outstanding lubricating properties. Specifically, the wear volume of the disc by EG-44BL is only 8.9% of that lubricated by pure EG. The enhanced anti-wear property of the EG/lignin system could be attributed to the formation of a robust lubrication film and the strong adhesion of the lubricant on the contacting metal surface due to the presence of a dense hydrogen bonding (H-bonding) network. The lubricating performance of EG-BL outperforms EG-SL, which could be attributed to the denser H-bonding sites in BL and its broader molecular weight distribution. The disc wear loss of EG-44BL is only 45.7% of that lubricated by EG-44SL. Overall, H-bonding is the major contributor to the different tribological properties of BL and SL in EG-based lubricants. PMID- 29495561 TI - Electrochemical Hydrogen Peroxide Sensor Based on Macroporous Silicon. AB - Macroporous silicon was prepared through an anodization process; the prepared samples showed an average pore size ranging from 4 to 6 microns, and the depth of the pores in the silicon wafer was approximately 80 microns. The prepared samples were tested for hydrogen peroxide (H2O2) concentrations, which can be used for industrial and environmental sensing applications. The selected H2O2 concentration covered a wide range from 10 to 5000 MUM. The tested samples showed a linear response through the tested H2O2 concentrations with a sensitivity of 0.55 MUA MUM-1?cm-2 and lower detection limits of 4.35 MUM at an operating voltage of 5 V. Furthermore, the electrode exhibited a rapid response with a response time of ca. two seconds. Furthermore, the prepared sensor showed a reasonable stability over a one-month time period. PMID- 29495562 TI - Necessary, but Not Sufficient. The Benefit Concept in the Project Evaluation of Animal Research in the Context of Directive 2010/63/EU. AB - Directive 2010/63/EU (henceforth "Directive") on the protection of animals used for scientific purposes mandates that every project proposal in EU member states involving procedures on living non-human vertebrates and cephalopods has to be approved in an review process, including a harm-benefit-analysis (HBA), to assess "whether the harm to the animals in terms of suffering, pain and distress is justified by the expected outcome taking into account ethical consideration and may ultimately benefit human beings, animals or the environment". Despite the justifying relevance of "outcome" and "benefit", it remains unclear how to understand these concepts. However, national authorities and applicants require a clear understanding of this to carry out a HBA. To analyze the underlying premises of the HBA and its consequences for the evaluation process, we introduce a heuristic to analyze the relation between "outcome", "benefit" and "prospective benefit assessment". We then apply the heuristic to all seven legitimate purposes for animal research stated in the Directive, namely basic research, translational or applied research, product safety, education and training, protection of the environment, preservation of species and forensic inquiries. As we show, regardless of which purpose is aimed for, applicants are hard-pressed to demonstrate tangible benefits in a prospective assessment. In the HBA, this becomes a problem since-as we argue-the only reasonable, expected and tangible outcome of research can ever be knowledge. The potential long-term benefits on the basis of gained knowledge are unforeseeable and impossible to predict. Research is bound to fall short of these proclaimed societal benefits and its credibility will suffer as long as research has to validate itself through short term societal benefit. We propose to revise the ethical evaluation based on the HBA and we think it necessary to develop an alternative model for project evaluation that focuses on the value of knowledge as a scientific outcome as a necessary but not sufficient condition for societal benefit. PMID- 29495563 TI - Food Insecurity in Homeless Families in the Paris Region (France): Results from the ENFAMS Survey. AB - The number of families living in shelters in the Paris region (France) has increased by a factor of three in 10 years. In 2013, a survey was performed on homeless families in order to characterize their living conditions, their health needs, and the developmental problems in children. This probability survey was conducted in 17 languages among 801 homeless families sheltered in emergency centers for asylum-seekers, emergency housing centers, social rehabilitation centers, and social hotels in the Paris region. Among the 772 families that provided data on food security only 14.0% were with food security, whereas 43.3% were with low food security and 9.8% with very low food security (a situation where children are also affected). Stratified multivariate robust Poisson models showed that some characteristics are associated with a higher risk of food insecurity and/or of falling into very low food security, such as residential instability, single parenthood, having more than three children, depressive symptoms, housing in social hostels, and difficult access to cheap or free food locally. Given the wealth of the Paris region, resources and programs should be concentrated on improving the living situation of this vulnerable population. It needs better detection of these families, a closer social follow-up, and an increase in food aid. PMID- 29495560 TI - Proteomic Methods of Detection and Quantification of Protein Toxins. AB - Biological toxins are a heterogeneous group of compounds that share commonalities with biological and chemical agents. Among them, protein toxins represent a considerable, diverse set. They cover a broad range of molecular weights from less than 1000 Da to more than 150 kDa. This review aims to compare conventional detection methods of protein toxins such as in vitro bioassays with proteomic methods, including immunoassays and mass spectrometry-based techniques and their combination. Special emphasis is given to toxins falling into a group of selected agents, according to the Centers for Disease Control and Prevention, such as Staphylococcal enterotoxins, Bacillus anthracis toxins, Clostridium botulinum toxins, Clostridium perfringens epsilon toxin, ricin from Ricinus communis, Abrin from Abrus precatorius or control of trade in dual-use items in the European Union, including lesser known protein toxins such as Viscumin from Viscum album. The analysis of protein toxins and monitoring for biological threats, i.e., the deliberate spread of infectious microorganisms or toxins through water, food, or the air, requires rapid and reliable methods for the early identification of these agents. PMID- 29495564 TI - Bivariate Correlation Analysis of the Chemometric Profiles of Chinese Wild Salvia miltiorrhiza Based on UPLC-Qqq-MS and Antioxidant Activities. AB - To better understand the mechanisms underlying the pharmacological actions of Salvia miltiorrhiza, correlation between the chemical profiles and in vitro antioxidant activities in 50 batches of wild S. miltiorrhiza samples was analyzed. Our ultra-performance liquid chromatography-tandem mass spectrometry analysis detected twelve phenolic acids and five tanshinones and obtained various chemical profiles from different origins. In a principal component analysis (PCA) and cluster analysis, the tanshinones cryptotanshinone, tanshinone IIA and dihydrotanshinone I exhibited higher weights in PC1, whereas the phenolic acids danshensu, salvianolic acids A and B and lithospermic acid were highly loaded in PC2. All components could be optimized as markers of different locations and might be suitable for S. miltiorrhiza quality analyses. Additionally, the DPPH and ABTS assays used to comprehensively evaluate antioxidant activities indicated large variations, with mean DPPH and ABTS scavenging potencies of 32.24 and 23.39 MUg/mL, respectively, among S. miltiorrhiza extract solutions. Notably, samples that exceeded the mean IC50 values had higher phenolic acid contents. A correlation analysis indicated a strong correlation between the antioxidant activities and phenolic acid contents. Caffeic acid, danshensu, rosmarinic acid, lithospermic acid and salvianolic acid B were major contributors to antioxidant activity. In conclusion, phenolic compounds were the predominant antioxidant components in the investigated plant species. These plants may be sources of potent natural antioxidants and beneficial chemopreventive agents. PMID- 29495565 TI - Mechanistic Insight into the Degradation of Nitrosamines via Aqueous-Phase UV Photolysis or a UV-Based Advanced Oxidation Process: Quantum Mechanical Calculations. AB - Nitrosamines are a group of carcinogenic chemicals that are present in aquatic environments that result from byproducts of industrial processes and disinfection products. As indirect and direct potable reuse increase, the presence of trace nitrosamines presents challenges to water infrastructures that incorporate effluent from wastewater treatment. Ultraviolet (UV) photolysis or UV-based advanced oxidation processes that produce highly reactive hydroxyl radicals are promising technologies to remove nitrosamines from water. However, complex reaction mechanisms involving radicals limit our understandings of the elementary reaction pathways embedded in the overall reactions identified experimentally. In this study, we perform quantum mechanical calculations to identify the hydroxyl radical-induced initial elementary reactions with N-nitrosodimethylamine (NDMA), N-nitrosomethylethylamine, and N-nitrosomethylbutylamine. We also investigate the UV-induced NDMA degradation mechanisms. Our calculations reveal that the alkyl side chains of nitrosamine affect the reaction mechanism of hydroxyl radicals with each nitrosamine investigated in this study. Nitrosamines with one- or two carbon alkyl chains caused the delocalization of the electron density, leading to slower subsequent degradation. Additionally, three major initial elementary reactions and the subsequent radical-involved reaction pathways are identified in the UV-induced NDMA degradation process. This study provides mechanistic insight into the elementary reaction pathways, and a future study will combine these results with the kinetic information to predict the time-dependent concentration profiles of nitrosamines and their transformation products. PMID- 29495567 TI - The Introduction of a Full Medication Review Process in a Local Hospital: Successes and Barriers of a Pilot Project in the Geriatric Ward. AB - For the majority of Belgian hospitals, a pharmacist-led full medication review process is not standard care and, therefore, challenging to introduce. With this study, we aimed to evaluate the successes and barriers of the implementation of a pharmacist-led full medication review process in the geriatric ward at a local Belgian hospital. To this end, we carried out an interventional study, performing a full medication review on older patients (>=70 years) with polypharmacy (>=5 drugs) who had an unplanned admission to the geriatric ward. The process consisted of 3 steps: (1) medication reconciliation upon admission; (2) medication review using an explicit reviewing tool (STOPP/START criteria or GheOP3S tool), followed by a discussion between the pharmacist and the geriatrician; and (3) medication reconciliation upon discharge. Ethical approval was obtained from the Ethical Commission of the Ghent University Hospital. Outcomes included objective data on the interventions (e.g., number of drug discrepancies; number of potentially inappropriate prescriptions (PIP)); as well as subjective experiences (e.g., satisfaction with service; opinion on inter professional communication). There was a special focus on communication aspects within the introduction of this process. In total, 52 patients were included in the study, taking a median of 10 drugs (IQR 8-12). Upon admission, 122 drug discrepancies were detected. During medication review, 254 PIPs were detected and discussed, leading to an improvement in the appropriateness of medication use. The satisfaction of community pharmacists concerning additional communication and the satisfaction of the patients after counselling at discharge were positive. However, several barriers were encountered, such as the time-consuming process to gather necessary information from different sources, the non-continuity of the service due to the lack of trained personnel or the lack of safe, electronic platforms to share information. The communicative and non-communicative successes and hurdles encountered during this project need to be addressed in order to improve the full medication review process and to strengthen the role of the clinical pharmacist. PMID- 29495566 TI - Anti-Inflammatory and Immune Regulatory Actions of Naja naja atra Venom. AB - Naja naja atra venom (NNAV) is composed of various proteins, peptides, and enzymes with different biological and pharmacological functions. A number of previous studies have reported that NNAV exerts potent analgesic effects on various animal models of pain. The clinical studies using whole venom or active components have confirmed that NNAV is an effective and safe medicine for treatment of chronic pain. Furthermore, recent studies have demonstrated that NNAV has anti-inflammatory and immune regulatory actions in vitro and in vivo. In this review article, we summarize recent studies of NNAV and its components on inflammation and immunity. The main new findings in NNAV research show that it may enhance innate and humoral immune responses while suppressing T lymphocytes mediated cellular immunity, thus suggesting that NNAV and its active components may have therapeutic values in the treatment of inflammatory and autoimmune diseases. PMID- 29495568 TI - Study of the Interactions Between Bacteriophage phiIPLA-RODI and Four Chemical Disinfectants for the Elimination of Staphylococcus aureus Contamination. AB - Bacteriophages are currently considered as a promising alternative to antibiotics and disinfectants. However, the use of phages in different clinical and industrial settings will involve their exposure to other disinfectants. As a result, the outcome of the phage treatment will depend on two aspects derived from such interactions. On the one hand, the susceptibility of the phage to disinfectants at the concentrations used for disinfection and at lower residual concentrations needs to be determined. Additionally, the existence of synergistic or antagonistic interactions between phages and disinfectants would also affect the potential success of phage biocontrol applications. Here, we tested these effects for the antistaphylococcal phage phiIPLA-RODI by using four different disinfectants: benzalkonium chloride, triclosan, chlorhexidine and hydrogen peroxide. Our results highlight the differences between disinfectants regarding their effect on phage survival and antimicrobial properties. For instance, our data suggests that, out of the four disinfectants used, benzalkonium chloride would be the most adequate to use in settings where phages are to be applied. Nonetheless, this preliminary analysis grants the need for further studies with a larger number of disinfectants for the development of a phiIPLA-RODI-based product. PMID- 29495571 TI - Innovative Chemical Process for Recycling Thermosets Cured with Recyclamines(r) by Converting Bio-Epoxy Composites in Reusable Thermoplastic-An LCA Study. AB - An innovative recycling process for thermoset polymer composites developed by Connora Technologies (Hayward, CA, USA) was studied. The process efficacy has already been tested, and it is currently working at the plant level. The main aspect investigated in the present paper was the environmental impact by means of the Life Cycle Assessment (LCA) method. Because of the need to recycle and recover materials at their end of life, the Connora process creates a great innovation in the market of epoxy composites, as they are notoriously not recyclable. Connora Technologies developed a relatively gentle chemical recycling process that induces the conversion of thermosets into thermoplastics. The LCA demonstrated that low environmental burdens are associated with the process itself and, furthermore, impacts are avoided due to the recovery of the epoxy composite constituents (fibres and matrix). A carbon fibre (CF) epoxy-composite panel was produced through Vacuum Resin Transfer Moulding (VRTM) and afterwards treated using the Connora recycling process. The LCA results of both the production and the recycling phases are reported. PMID- 29495569 TI - Gastrointestinal Transit Time, Glucose Homeostasis and Metabolic Health: Modulation by Dietary Fibers. AB - Gastrointestinal transit time may be an important determinant of glucose homeostasis and metabolic health through effects on nutrient absorption and microbial composition, among other mechanisms. Modulation of gastrointestinal transit may be one of the mechanisms underlying the beneficial health effects of dietary fibers. These effects include improved glucose homeostasis and a reduced risk of developing metabolic diseases such as obesity and type 2 diabetes mellitus. In this review, we first discuss the regulation of gastric emptying rate, small intestinal transit and colonic transit as well as their relation to glucose homeostasis and metabolic health. Subsequently, we briefly address the reported health effects of different dietary fibers and discuss to what extent the fiber-induced health benefits may be mediated through modulation of gastrointestinal transit. PMID- 29495572 TI - Experimental Investigation of the Influence of the Laser Beam Waist on Cold Atom Guiding Efficiency. AB - The primary purpose of this study is to investigate the influence of the vertical guiding laser beam waist on cold atom guiding efficiency. In this study, a double magneto-optical trap (MOT) apparatus is used. With an unbalanced force in the horizontal direction, a cold atomic beam is generated by the first MOT. The cold atoms enter the second chamber and are then re-trapped and cooled by the second MOT. By releasing a second atom cloud, the process of transferring the cold atoms from MOT to the dipole trap, which is formed by a red-detuned converged 1064-nm laser, is experimentally demonstrated. And after releasing for 20 ms, the atom cloud is guided to a distance of approximately 3 mm. As indicated by the results, the guiding efficiency depends strongly on the laser beam waist; the efficiency reaches a maximum when the waist radius (w0) of the laser is in the range of 15 to 25 MUm, while the initial atom cloud has a radius of 133 MUm. Additionally, the properties of the atoms inside the dipole potential trap, such as the distribution profile and lifetime, are deduced from the fluorescence images. PMID- 29495570 TI - Targeting IgG in Arthritis: Disease Pathways and Therapeutic Avenues. AB - Rheumatoid arthritis (RA) is a polygenic and multifactorial syndrome. Many complex immunological and genetic interactions are involved in the final outcome of the clinical disease. Autoantibodies (rheumatoid factors, anti-citrullinated peptide/protein antibodies) are present in RA patients' sera for a long time before the onset of clinical disease. Prior to arthritis onset, in the autoantibody response, epitope spreading, avidity maturation, and changes towards a pro-inflammatory Fc glycosylation phenotype occurs. Genetic association of epitope specific autoantibody responses and the induction of inflammation dependent and independent changes in the cartilage by pathogenic autoantibodies emphasize the crucial contribution of antibody-initiated inflammation in RA development. Targeting IgG by glyco-engineering, bacterial enzymes to specifically cleave IgG/alter N-linked Fc-glycans at Asn 297 or blocking the downstream effector pathways offers new avenues to develop novel therapeutics for arthritis treatment. PMID- 29495573 TI - Three-Dimensional SnS Decorated Carbon Nano-Networks as Anode Materials for Lithium and Sodium Ion Batteries. AB - The three-dimensional (3D) SnS decorated carbon nano-networks (SnS@C) were synthesized via a facile two-step method of freeze-drying combined with post-heat treatment. The lithium and sodium storage performances of above composites acting as anode materials were investigated. As anode materials for lithium ion batteries, a high reversible capacity of 780 mAh.g-1 for SnS@C composites can be obtained at 100 mA.g-1 after 100 cycles. Even cycled at a high current density of 2 A.g-1, the reversible capacity of this composite can be maintained at 610 mAh.g 1 after 1000 cycles. The initial charge capacity for sodium ion batteries can reach 333 mAh.g-1, and it retains a reversible capacity of 186 mAh.g-1 at 100 mA.g-1 after 100 cycles. The good lithium or sodium storage performances are likely attributed to the synergistic effects of the conductive carbon nano networks and small SnS nanoparticles. PMID- 29495574 TI - A Real-Time Thermal Self-Elimination Method for Static Mode Operated Freestanding Piezoresistive Microcantilever-Based Biosensors. AB - Here, we provide a method and apparatus for real-time compensation of the thermal effect of single free-standing piezoresistive microcantilever-based biosensors. The sensor chip contained an on-chip fixed piezoresistor that served as a temperature sensor, and a multilayer microcantilever with an embedded piezoresistor served as a biomolecular sensor. This method employed the calibrated relationship between the resistance and the temperature of piezoresistors to eliminate the thermal effect on the sensor, including the temperature coefficient of resistance (TCR) and bimorph effect. From experimental results, the method was verified to reduce the signal of thermal effect from 25.6 MUV/ degrees C to 0.3 MUV/ degrees C, which was approximately two orders of magnitude less than that before the processing of the thermal elimination method. Furthermore, the proposed approach and system successfully demonstrated its effective real-time thermal self-elimination on biomolecular detection without any thermostat device to control the environmental temperature. This method realizes the miniaturization of an overall measurement system of the sensor, which can be used to develop portable medical devices and microarray analysis platforms. PMID- 29495575 TI - RPiRLS: Quantitative Predictions of RNA Interacting with Any Protein of Known Sequence. AB - RNA-protein interactions (RPIs) have critical roles in numerous fundamental biological processes, such as post-transcriptional gene regulation, viral assembly, cellular defence and protein synthesis. As the number of available RNA protein binding experimental data has increased rapidly due to high-throughput sequencing methods, it is now possible to measure and understand RNA-protein interactions by computational methods. In this study, we integrate a sequence based derived kernel with regularized least squares to perform prediction. The derived kernel exploits the contextual information around an amino acid or a nucleic acid as well as the repetitive conserved motif information. We propose a novel machine learning method, called RPiRLS to predict the interaction between any RNA and protein of known sequences. For the RPiRLS classifier, each protein sequence comprises up to 20 diverse amino acids but for the RPiRLS-7G classifier, each protein sequence is represented by using 7-letter reduced alphabets based on their physiochemical properties. We evaluated both methods on a number of benchmark data sets and compared their performances with two newly developed and state-of-the-art methods, RPI-Pred and IPMiner. On the non-redundant benchmark test sets extracted from the PRIDB, the RPiRLS method outperformed RPI-Pred and IPMiner in terms of accuracy, specificity and sensitivity. Further, RPiRLS achieved an accuracy of 92% on the prediction of lncRNA-protein interactions. The proposed method can also be extended to construct RNA-protein interaction networks. The RPiRLS web server is freely available at http://bmc.med.stu.edu.cn/RPiRLS. PMID- 29495576 TI - Biochemical and MALDI-TOF Mass Spectrometric Characterization of a Novel Native and Recombinant Cystine Knot Miniprotein from Solanum tuberosum subsp. andigenum cv. Churquena. AB - Cystine-knot miniproteins (CKMPs) are an intriguing group of cysteine-rich molecules that combine the characteristics of proteins and peptides. Typically, CKMPs are fewer than 50 residues in length and share a characteristic knotted scaffold characterized by the presence of three intramolecular disulfide bonds that form the singular knotted structure. The knot scaffold confers on these proteins remarkable chemical, thermal, and proteolytic stability. Recently, CKMPs have emerged as a novel class of natural molecules with interesting pharmacological properties. In the present work, a novel cystine-knot metallocarboxypeptidase inhibitor (chuPCI) was isolated from tubers of Solanum tuberosum, subsp. andigenum cv. Churquena. Our results demonstrated that chuPCI is a member of the A/B-type family of metallocarboxypeptidases inhibitors. chuPCI was expressed and characterized by a combination of biochemical and mass spectrometric techniques. Direct comparison of the MALDI-TOF mass spectra for the native and recombinant molecules allowed us to confirm the presence of four different forms of chuPCI in the tubers. The majority of such forms have a molecular weight of 4309 Da and contain a cyclized Gln in the N-terminus. The other three forms are derived from N-terminal and/or C-terminal proteolytic cleavages. Taken together, our results contribute to increase the current repertoire of natural CKMPs. PMID- 29495577 TI - A Rapid Label-Free Fluorescent Aptasensor PicoGreen-Based Strategy for Aflatoxin B1 Detection in Traditional Chinese Medicines. AB - Aflatoxin B1 (AFB1) is a very hazardous carcinogen, readily contaminating foodstuffs and traditional Chinese medicines (TCMs) that has inspired increasing health concerns due to dietary exposure. Colloidal nanocrystals have been proposed as optical labels for aptasensor assembly, but these typically require tedious multistep conjugation and suffer from unsatisfactory robustness when used for complex matrices. In the present study, we report a rapid and sensitive method for screening for trace AFB1 levels in TCMs using a label-free fluorescent aptasensor PicoGreen dye-based strategy. Using PicoGreen to selectively measure complementary double-stranded DNA, fluorescence enhancement due to dsDNA is 'turned off' in the presence of AFB1 due binding of aptamer target over complementary sequence. Self-assembly of a label-free fluorescent aptasensor based on AFB1 aptamer and PicoGreen dye was performed. Due to competition between the complementary sequence and AFB1 target, this rapid method was capable of highly sensitive and selective screening for AFB1 in five types of TCMs. This proposed approach had a limit of detection as low as 0.1 MUg.L-1 and good linearity with a range of 0.1-10 MUg.L-1 (0.1-10 ppb). Among the 20 samples tested, 6 batches were found to be contaminated with AFB1 using this method, which was confirmed using sophisticated liquid chromatography-electrospray ionization-tandem mass spectrometry/mass spectrometry analysis. The results of this study indicate the developed method has the potential to be a simple, quick, and sensitive tool for detecting AFB1 in TCMs. PMID- 29495578 TI - Cucumis sativus Aqueous Fraction Inhibits Angiotensin II-Induced Inflammation and Oxidative Stress In Vitro. AB - Inflammation and oxidative stress play major roles in endothelial dysfunction, and are key factors in the progression of cardiovascular diseases. The aim of this study was to evaluate in vitro the effect of three subfractions (SFs) from the Cucumis sativus aqueous fraction to reduce inflammatory factors and oxidative stress induced by angiotensin II (Ang II) in human microvascular endothelial cells-1 (HMEC-1) cells. The cells were cultured with different concentrations of Ang II and 0.08 or 10 MUg/mL of SF1, SF2, or SF3, or 10 MUmol of losartan as a control. IL-6 (Interleukin 6) concentration was quantified. To identify the most effective SF combinations, HMEC-1 cells were cultured as described above in the presence of four combinations of SF1 and SF3. Then, the effects of the most effective combination on the expression of adhesion molecules, the production of reactive oxygen species (ROS), and the bioavailability of nitric oxide (NO) were evaluated. Finally, a mass spectrometry analysis was performed. Both SF1 and SF3 subfractions decreased the induction of IL-6 by Ang II, and C4 (SF1 and SF3, 10 MUg/mL each) was the most effective combination to inhibit the production of IL 6. Additionally, C4 prevented the expression of adhesion molecules, reduced the production of ROS, and increased the bioavailability of NO. Glycine, arginine, asparagine, lysine, and aspartic acid were the main components of both subfractions. These results demonstrate that C4 has anti-inflammatory and antioxidant effects. PMID- 29495579 TI - Tectus niloticus (Tegulidae, Gastropod) as a Novel Vector of Ciguatera Poisoning: Clinical Characterization and Follow-Up of a Mass Poisoning Event in Nuku Hiva Island (French Polynesia). AB - Ciguatera fish poisoning (CFP) is the most prevalent non-bacterial food-borne form of poisoning in French Polynesia, which results from the consumption of coral reef fish naturally contaminated with ciguatoxins produced by dinoflagellates in the genus Gambierdiscus. Since the early 2000s, this French territory has also witnessed the emergence of atypical forms of ciguatera, known as ciguatera shellfish poisoning (CSP), associated with the consumption of marine invertebrates. In June 2014, nine tourists simultaneously developed a major and persistent poisoning syndrome following the consumption of the gastropod Tectus niloticus collected in Anaho, a secluded bay of Nuku Hiva Island (Marquesas Archipelago, French Polynesia). The unusual nature and severity of this event prompted a multidisciplinary investigation in order to characterize the etiology and document the short/long-term health consequences of this mass-poisoning event. This paper presents the results of clinical investigations based on hospital medical records, medical follow-up conducted six and 20 months post poisoning, including a case description. This study is the first to describe the medical signature of T. niloticus poisoning in French Polynesia and contributed to alerting local authorities about the potential health hazards associated with the consumption of this gastropod, which is highly prized by local communities in Pacific island countries and territories. PMID- 29495581 TI - Global Evidence on the Association between Cigarette Graphic Warning Labels and Cigarette Smoking Prevalence and Consumption. AB - Background: In 2011, the courts ruled in favor of tobacco companies in preventing the implementation of graphic warning labels (GWLs) in the US, stating that FDA had not established the effectiveness of GWLs in reducing smoking. Methods: Data came from various sources: the WHO MPOWER package (GWLs, MPOWER policy measures, cigarette prices), Euromonitor International (smoking prevalence, cigarette consumption), and the World Bank database (countries' demographic characteristics). The datasets were aggregated and linked using country and year identifiers. Fractional logit regressions and OLS regressions were applied to examine the associations between GWLs and smoking prevalence and cigarette consumption, controlling for MPOWER policy scores, cigarette prices, GDP per capita, unemployment, population aged 15-64 (%), aged 65 and over (%), year indicators, and country fixed effects. Results: GWLs were associated with a 0.9-3 percentage point decrease in adult smoking prevalence and were significantly associated with a reduction of 230-287 sticks in per capita cigarette consumption, compared to countries without GWLs. However, the association between GWLs and cigarette consumption became statistically insignificant once country indicators were included in the models. Conclusions: The implementation of GWLs may be associated with reduced cigarette smoking. PMID- 29495580 TI - Comparative Analysis of Culture Conditions for the Optimization of Carotenoid Production in Several Strains of the Picoeukaryote Ostreococcus. AB - Microalgae are promising sources for the sustainable production of compounds of interest for biotechnologies. Compared to higher plants, microalgae have a faster growth rate and can be grown in industrial photobioreactors. The microalgae biomass contains specific metabolites of high added value for biotechnology such as lipids, polysaccharides or carotenoid pigments. Studying carotenogenesis is important for deciphering the mechanisms of adaptation to stress tolerance as well as for biotechnological production. In recent years, the picoeukaryote Ostreococcustauri has emerged as a model organism thanks to the development of powerful genetic tools. Several strains of Ostreococcus isolated from different environments have been characterized with respect to light response or iron requirement. We have compared the carotenoid contents and growth rates of strains of Ostreococcus (OTTH595, RCC802 and RCC809) under a wide range of light, salinity and temperature conditions. Carotenoid profiles and productivities varied in a strain-specific and stress-dependent manner. Our results also illustrate that phylogenetically related microalgal strains originating from different ecological niches present specific interests for the production of specific molecules under controlled culture conditions. PMID- 29495582 TI - Simultaneous Analysis of Saccharides between Fresh and Processed Radix Rehmanniae by HPLC and UHPLC-LTQ-Orbitrap-MS with Multivariate Statistical Analysis. AB - Radix Rehmanniae (RR) is a kind of herb which is widely used in the clinical and food processing industry. There are four forms of RR used in traditional Chinese medicine practice, which include fresh RR (FRR), raw RR (RRR), processed RR (PRR), and another processed RR (APRR), in which the APRR was processed by nine cycles of repeated steaming and drying. There are a large number of saccharides in RR. However, the differences in content were shown by different processing methods. In this study, an effective method using high-performance liquid chromatography (HPLC) and high-performance liquid chromatography-mass spectrometry (LC-MS) coupled with multivariate statistical analysis to rapidly distinguish different RR samples and validate the proposed chemical conversion mechanism. The datasets of the content of saccharides were subjected to principal component analysis (PCA) and one-way analysis of variance. The results showed that there different changes occurred in the contents of saccharides corresponding to the different processing methods, in which the contents of monosaccharides-namely arabinose, glucose, mannose, and galactose-had an increasing trend or remained relatively stable. However, the contents of fructose and oligosaccharides, including manninotriose, melibiose, sucrose, and raffinose, first increased and then reduced, or gradually decreased, yet the content of stachyose gradually decreased. The MSn data indicated that manninotriose, melibiose, and some monosaccharides were produced by the hydrolysis of oligosaccharides. In addition, the fragmentation pathways of 1-phenyl-3-methyl-5 pyrazolone (PMP) derivatization of monosaccharides were also found that its glycosidic bond was first broken and subsequently its inside ring broke, and the characteristic fragment ions were produced at m/z 511.22, 493.20, 373.16, and 175.08 in the PMP derivatization of monosaccharides. In conclusion, this study illustrates the change and chemical conversion mechanism of saccharides by processing in RR samples which might play a key role in further application of RR. PMID- 29495583 TI - Repeated Dietary Exposure to Low Levels of Domoic Acid and Problems with Everyday Memory: Research to Public Health Outreach. AB - Domoic Acid (DA) is a marine-based neurotoxin. Dietary exposure to high levels of DA via shellfish consumption has been associated with Amnesic Shellfish Poisoning, with milder memory decrements found in Native Americans (NAs) with repetitive, lower level exposures. Despite its importance for protective action, the clinical relevance of these milder memory problems remains unknown. The purpose of this study was to determine whether repeated, lower-level exposures to DA impact everyday memory (EM), i.e., the frequency of memory failures in everyday life. A cross-sectional sample of 60 NA men and women from the Pacific NW was studied with measures of dietary exposure to DA via razor clam (RC) consumption and EM. Findings indicated an association between problems with EM and elevated consumption of RCs with low levels of DA throughout the previous week and past year after controlling for age, sex, and education. NAs who eat a lot of RCs with presumably safe levels of DA are at risk for clinically significant memory problems. Public health outreach to minimize repetitive exposures are now in place and were facilitated by the use of community-based participatory research methods, with active involvement of state regulatory agencies, tribe leaders, and local physicians. PMID- 29495585 TI - Xyleborus bispinatus Reared on Artificial Media in the Presence or Absence of the Laurel Wilt Pathogen (Raffaelea lauricola). AB - Like other members of the tribe Xyleborini, Xyleborus bispinatus Eichhoff can cause economic damage in the Neotropics. X. bispinatus has been found to acquire the laurel wilt pathogen Raffaelea lauricola (T. C. Harr., Fraedrich & Aghayeva) when breeding in a host affected by the pathogen. Its role as a potential vector of R. lauricola is under investigation. The main objective of this study was to evaluate three artificial media, containing sawdust of avocado (Persea americana Mill.) and silkbay (Persea humilis Nash.), for rearing X. bispinatus under laboratory conditions. In addition, the media were inoculated with R. lauricola to evaluate its effect on the biology of X. bispinatus. There was a significant interaction between sawdust species and R. lauricola for all media. Two of the media supported the prolific reproduction of X. bispinatus, but the avocado-based medium was generally more effective than the silkbay-based medium, regardless whether or not it was inoculated with R. lauricola. R. lauricola had a neutral or positive effect on beetle reproduction. The pathogen was frequently recovered from beetle galleries, but only from a few individuals which were reared on inoculated media, and showed limited colonization of the beetle's mycangia. Two media with lower water content were most effective for rearing X. bispinatus. PMID- 29495584 TI - DNA Methylation Levels of the ELMO Gene Promoter CpG Islands in Human Glioblastomas. AB - Complete surgical resection of glioblastoma is difficult due to the invasive nature of this primary brain tumor, for which the molecular mechanisms behind remain poorly understood. The three human ELMO genes play key roles in cellular motility, and have been linked to metastasis and poor prognosis in other cancer types. The aim of this study was to investigate methylation levels of the ELMO genes and their correlation to clinical characteristics and outcome in patients diagnosed with glioblastoma. To measure DNA methylation levels we designed pyrosequencing assays targeting the promoter CpG island of each the ELMO genes. These were applied to diagnostic tumor specimens from a well-characterized cohort of 121 patients who received standard treatment consisting of surgery, radiation therapy, plus concomitant and adjuvant chemotherapy. The promoter methylation levels of ELMO1 and ELMO2 were generally low, whereas ELMO3 methylation levels were high, in the tumor biopsies. Thirteen, six, and 18 biopsies were defined as aberrantly methylated for ELMO1, ELMO2, and ELMO3, respectively. There were no significant associations between the methylation status of any of the ELMO gene promoter CpG islands and overall survival, progression-free survival, and clinical characteristics of the patients including intracranial tumor location. Therefore, the methylation status of the ELMO gene promoter CpG islands is unlikely to have prognostic value in glioblastoma. PMID- 29495586 TI - Lower Vitamin D Status Is Associated with an Increased Risk of Ischemic Stroke: A Systematic Review and Meta-Analysis. AB - In recent years, accumulating evidence has supported the hypothesis that lower vitamin D status is associated with several known risk factors of stroke. However, the relationship between vitamin D and stroke is still uncertain. To explore if there was an association between vitamin D status and the risk of stroke, a systematic review and a meta-analysis were conducted by searching three databases: Pubmed, Embase, and the Cochrane Library. Following the application of inclusion and exclusion criteria, the relative risk estimates of all the included studies were pooled together to compare the risk of stroke between the lowest and the highest category of vitamin D. The Newcastle-Ottawa Scale (NOS) and the Cochrane Risk of Bias Tool were used to assess the risk of bias, and the publication bias was detected by using a funnel plot and Egger's test. Nineteen studies were included and the pooled relative risk was 1.62 (95% CI: 1.34-1.96). Further analysis found that vitamin D status was associated with ischemic stroke (relative risk = 2.45, 95% CI: 1.56-3.86), but not with hemorrhagic stroke (relative risk = 2.50, 95% CI: 0.87-7.15). In conclusion, our meta-analysis supported the hypothesis that lower vitamin D status was associated with an increased risk of ischemic stroke. Further studies are required to confirm this association and to explore the association among different subtypes. PMID- 29495587 TI - Increased Levels of Txa2 Induced by Dengue Virus Infection in IgM Positive Individuals Is Related to the Mild Symptoms of Dengue. AB - The inflammatory process plays a major role in the prognosis of dengue. In this context, the eicosanoids may have considerable influence on the regulation of the Dengue virus-induced inflammatory process. To quantify the molecules involved in the cyclooxygenase and lipoxygenase pathways during Dengue virus infection, plasma levels of thromboxane A2, prostaglandin E2 and leukotriene B4; mRNA levels of thromboxane A2 synthase, prostaglandin E2 synthase, leukotriene A4 hydrolase, cyclooxygenase-2 and 5-lipoxygenase; and the levels of lipid bodies in peripheral blood leukocytes collected from IgM-positive and IgM-negative volunteers with mild dengue, and non-infected volunteers, were evaluated. Dengue virus infection increases the levels of thromboxane A2 in IgM-positive individuals as well as the amount of lipid bodies in monocytes in IgM-negative individuals. We suggest that increased levels of thromboxane A2 in IgM-positive individuals plays a protective role against the development of severe symptoms of dengue, such as vascular leakage. PMID- 29495589 TI - A Frequency-Domain Multipath Parameter Estimation and Mitigation Method for BOC Modulated GNSS Signals. AB - As multipath is one of the dominating error sources for high accuracy Global Navigation Satellite System (GNSS) applications, multipath mitigation approaches are employed to minimize this hazardous error in receivers. Binary offset carrier modulation (BOC), as a modernized signal structure, is adopted to achieve significant enhancement. However, because of its multi-peak autocorrelation function, conventional multipath mitigation techniques for binary phase shift keying (BPSK) signal would not be optimal. Currently, non-parametric and parametric approaches have been studied specifically aiming at multipath mitigation for BOC signals. Non-parametric techniques, such as Code Correlation Reference Waveforms (CCRW), usually have good feasibility with simple structures, but suffer from low universal applicability for different BOC signals. Parametric approaches can thoroughly eliminate multipath error by estimating multipath parameters. The problems with this category are at the high computation complexity and vulnerability to the noise. To tackle the problem, we present a practical parametric multipath estimation method in the frequency domain for BOC signals. The received signal is transferred to the frequency domain to separate out the multipath channel transfer function for multipath parameter estimation. During this process, we take the operations of segmentation and averaging to reduce both noise effect and computational load. The performance of the proposed method is evaluated and compared with the previous work in three scenarios. Results indicate that the proposed averaging-Fast Fourier Transform (averaging FFT) method achieves good robustness in severe multipath environments with lower computational load for both low-order and high-order BOC signals. PMID- 29495588 TI - Complete Mitochondrial Genome of Suwallia teleckojensis (Plecoptera: Chloroperlidae) and Implications for the Higher Phylogeny of Stoneflies. AB - Stoneflies comprise an ancient group of insects, but the phylogenetic position of Plecoptera and phylogenetic relations within Plecoptera have long been controversial, and more molecular data is required to reconstruct precise phylogeny. Herein, we present the complete mitogenome of a stonefly, Suwallia teleckojensis, which is 16146 bp in length and consists of 13 protein-coding genes (PCGs), 2 ribosomal RNAs (rRNAs), 22 transfer RNAs (tRNAs) and a control region (CR). Most PCGs initiate with the standard start codon ATN. However, ND5 and ND1 started with GTG and TTG. Typical termination codons TAA and TAG were found in eleven PCGs, and the remaining two PCGs (COII and ND5) have incomplete termination codons. All transfer RNA genes (tRNAs) have the classic cloverleaf secondary structures, with the exception of tRNASer(AGN), which lacks the dihydrouridine (DHU) arm. Secondary structures of the two ribosomal RNAs were shown referring to previous models. A large tandem repeat region, two potential stem-loop (SL) structures, Poly N structure (2 poly-A, 1 poly-T and 1 poly-C), and four conserved sequence blocks (CSBs) were detected in the control region. Finally, both maximum likelihood (ML) and Bayesian inference (BI) analyses suggested that the Capniidae was monophyletic, and the other five stonefly families form a monophyletic group. In this study, S. teleckojensis was closely related to Sweltsa longistyla, and Chloroperlidae and Perlidae were herein supported to be a sister group. PMID- 29495590 TI - Gonad Transcriptome Analysis of High-Temperature-Treated Females and High Temperature-Induced Sex-Reversed Neomales in Nile Tilapia. AB - BACKGROUND: Nowadays, the molecular mechanisms governing TSD (temperature dependent sex determination) or GSD + TE (genotypic sex determination + temperature effects) remain a mystery in fish. METHODS: We developed three all female families of Nile tilapia (Oreochromis niloticus), and the family with the highest male ratio after high-temperature treatment was used for transcriptome analysis. RESULTS: First, gonadal histology analysis indicated that the histological morphology of control females (CF) was not significantly different from that of high-temperature-treated females (TF) at various development stages. However, the high-temperature treatment caused a lag of spermatogenesis in high temperature-induced neomales (IM). Next, we sequenced the transcriptome of CF, TF, and IM Nile tilapia. 79, 11,117, and 11,000 differentially expressed genes (DEGs) were detected in the CF-TF, CF-IM, and TF-IM comparisons, respectively, and 44 DEGs showed identical expression changes in the CF-TF and CF-IM comparisons. Principal component analysis (PCA) indicated that three individuals in CF and three individuals in TF formed a cluster, and three individuals in IM formed a distinct cluster, which confirmed that the gonad transcriptome profile of TF was similar to that of CF and different from that of IM. Finally, six sex related genes were validated by qRT-PCR. CONCLUSIONS: This study identifies a number of genes that may be involved in GSD + TE, which will be useful for investigating the molecular mechanisms of TSD or GSD + TE in fish. PMID- 29495591 TI - Chronic Administration of Hydroxyurea (HU) Benefits Caucasian Patients with Sickle-Beta Thalassemia. AB - In sickle cell disease (SCD), hydroxyurea (HU) treatment decreases the number of vaso-occlusive crisis (VOC) and acute chest syndrome (ACS) by increasing fetal hemoglobin (HbF). Data are lacking regarding the frequency of HU dose modification or whether sub-therapeutic doses (<15 mg/kg/day) are beneficial. We reviewed the medical records of 140 patients from 2010 to 2014. The laboratory parameters and SCD complications were compared between the first and last visits based on HU use. Fifty patients (36%) never took HU or suspended HU ("no HU" group). Among patients taking <15 mg/kg/day HU on their first visit, half remained at the same dose, and the other half increased to >=15 mg/kg/day. Among patients taking >=15 mg/kg/day, 17% decreased to <15 mg/kg/day, and 83% stayed at >=15 mg/kg/day. The "no HU" group had fewer episodes of VOC and ACS. Both HU treatment groups had a reduction in both complications (p < 0.0001). This improvement was observed in all SCD phenotypes. The white blood cell (WBC) counts were found to be lower, and HbF increased in both HU groups (p = 0.004, 0.001). The maximal HbF response to HU in HbS/beta+-thalassemia was 20%, similar to those observed for HbSS (19%) and HbS/beta0-thalassemia (22%). HbS/beta+-thalassemia could have a similar disease severity as HbSS or HbS/beta0-thalassemia. Patients with HbS/beta0-thalassemia or HbS/beta+-thalassemia phenotypes responded to HU. PMID- 29495593 TI - Advances in the Genetics of Hypertension: The Effect of Rare Variants. AB - Worldwide, hypertension still represents a serious health burden with nine million people dying as a consequence of hypertension-related complications. Essential hypertension is a complex trait supported by multifactorial genetic inheritance together with environmental factors. The heritability of blood pressure (BP) is estimated to be 30-50%. A great effort was made to find genetic variants affecting BP levels through Genome-Wide Association Studies (GWAS). This approach relies on the "common disease-common variant" hypothesis and led to the identification of multiple genetic variants which explain, in aggregate, only 2 3% of the genetic variance of hypertension. Part of the missing genetic information could be caused by variants too rare to be detected by GWAS. The use of exome chips and Next-Generation Sequencing facilitated the discovery of causative variants. Here, we report the advances in the detection of novel rare variants, genes, and/or pathways through the most promising approaches, and the recent statistical tests that have emerged to handle rare variants. We also discuss the need to further support rare novel variants with replication studies within larger consortia and with deeper functional studies to better understand how new genes might improve patient care and the stratification of the response to antihypertensive treatments. PMID- 29495594 TI - D181A Site-Mutagenesis Enhances Both the Hydrolyzing and Transfructosylating Activities of BmSUC1, a Novel beta-Fructofuranosidase in the Silkworm Bombyx mori. AB - beta-fructofuranosidase (beta-FFase) belongs to the glycosyl-hydrolase family 32 (GH32), which can catalyze both the release of beta-fructose from beta-d fructofuranoside substrates to hydrolyze sucrose and the synthesis of short-chain fructooligosaccharide (FOS). BmSuc1 has been cloned and identified from the silkworm Bombyx mori as a first animal type of beta-FFase encoding gene. It was hypothesized that BmSUC1 plays an important role in the silkworm-mulberry adaptation system. However, there is little information about the enzymatic core sites of BmSUC1. In this study, we mutated three amino acid residues (D63, D181, and E234) that represent important conserved motifs for beta-FFase activity in GH32 to alanine respectively by using site-directed mutagenesis. Recombinant proteins of three mutants and wild type BmSUC1 were obtained by using a Bac-to Bac/BmNPV expression system and BmN cells. Enzymatic activity, kinetic properties, and substrate specificity of the four proteins were analyzed. High Performance Liquid Chromatography (HPLC) was used to compare the hydrolyzing and transfructosylating activities between D181A and wtBmSUC1. Our results revealed that the D63A and E234A mutations lost activity, suggesting that D63 and E234 are key amino acid residues for BmSUC1 to function as an enzyme. The D181A mutation significantly enhanced both hydrolyzing and transfructosylating activities of BmSUC1, indicating that D181 may not be directly involved in catalyzation. The results provide insight into the chemical catalyzation mechanism of BmSUC1 in B. mori. Up-regulated transfructosylating activity of BmSUC1 could provide new ideas for using B. mori beta-FFase to produce functional FOS. PMID- 29495592 TI - The Role of Long Non-Coding RNAs in Hepatocarcinogenesis. AB - Whole-transcriptome analyses have revealed that a large proportion of the human genome is transcribed in non-protein-coding transcripts, designated as long non coding RNAs (lncRNAs). Rather than being "transcriptional noise", increasing evidence indicates that lncRNAs are key players in the regulation of many biological processes, including transcription, post-translational modification and inhibition and chromatin remodeling. Indeed, lncRNAs are widely dysregulated in human cancers, including hepatocellular carcinoma (HCC). Functional studies are beginning to provide insights into the role of oncogenic and tumor suppressive lncRNAs in the regulation of cell proliferation and motility, as well as oncogenic and metastatic potential in HCC. A better understanding of the molecular mechanisms and the complex network of interactions in which lncRNAs are involved could reveal novel diagnostic and prognostic biomarkers. Crucially, it may provide novel therapeutic opportunities to add to the currently limited number of therapeutic options for HCC patients. In this review, we summarize the current status of the field, with a focus on the best characterized dysregulated lncRNAs in HCC. PMID- 29495595 TI - Loss of BID Delays FASL-Induced Cell Death of Mouse Neutrophils and Aggravates DSS-Induced Weight Loss. AB - Neutrophils are key players in the early defense against invading pathogens. Due to their potent effector functions, programmed cell death of activated neutrophils has to be tightly controlled; however, its underlying mechanisms remain unclear. Fas ligand (FASL/CD95L) has been shown to induce neutrophil apoptosis, which is accelerated by the processing of the BH3-only protein BH3 interacting domain death agonist (BID) to trigger mitochondrial apoptotic events, and been attributed a regulatory role during viral and bacterial infections. Here, we show that, in accordance with previous works, mouse neutrophils underwent caspase-dependent apoptosis in response to FASL, and that this cell death was significantly delayed upon loss of BID. However, pan-caspase inhibition failed to protect mouse neutrophils from FASL-induced apoptosis and caused a switch to RIPK3-dependent necroptotic cell death. Intriguingly, such a switch was less evident in the absence of BID, particularly under inflammatory conditions. Delayed neutrophil apoptosis has been implicated in several auto-inflammatory diseases, including inflammatory bowel disease. We show that neutrophil and macrophage driven acute dextran sulfate sodium (DSS) induced colitis was slightly more aggravated in BID-deficient mice, based on significantly increased weight loss compared to wild-type controls. Taken together, our data support a central role for FASL > FAS and BID in mouse neutrophil cell death and further underline the anti-inflammatory role of BID. PMID- 29495596 TI - Immunohistochemical Expression of Aquaporin-1 in Fluoro-Edenite-Induced Malignant Mesothelioma: A Preliminary Report. AB - BACKGROUND: The immunohistochemical expression of aquaporin-1 (AQP1) in asbestos related malignant pleural mesothelioma (MPM) is emerging as a useful prognostic indicator of improved survival. A significantly increased incidence of MPM in a small town in southern Italy was ascribed to exposure to fluoro-edenite (FE), a naturally occurring asbestos fiber. We investigated the immunohistochemical expression of AQP1 in patients affected by FE-related MPM; taking into consideration its suggested independent prognostic role, its possible correlation with clinicopathological parameters and patient outcome was also evaluated. METHODS: Ten patients were selected for this study, as neoplastic tissue blocks, clinical and follow-up data were available. The immunohistochemical overexpression of AQP1 was defined as >=50% of tumor cells showing membranous staining. RESULTS: Six cases showed AQP1 expression in >=50% of tumor cells; in this group, a significant association of AQP1 overexpression with an increased median overall survival (OS) of 26.3 months was observed. By contrast, four patients exhibited an AQP1 score of <50% of stained cells, with a shorter median OS of 8.9 months. CONCLUSIONS: The present study represents further confirmation of the hypothesized prognostic role of AQP1, which seems a reliable prognostic indicator. PMID- 29495597 TI - The Relationship Between Sleep and Cognition in Children Referred for Neuropsychological Evaluation: A Latent Modeling Approach. AB - Children with conditions affecting cognitive processes experience high levels of sleep disturbance, which may further compound the cognitive ramifications of their disorders. Despite this, existing studies in this area have been primarily confined to only particular diagnostic groups and/or a limited scope of sleep and cognitive parameters. The current study characterized the nature of sleep problems and examined the relationship between a wide range of sleep-related problems and cognitive functioning in a large (N = 103) diagnostically heterogeneous sample of youth (aged 6-16) referred for neuropsychological assessment. Structural equation modeling was used to examine the relationship between sleep-related problems (i.e., daytime sleepiness, sleep onset latency, sleep fragmentation, sleep time variability, sleep debt) and cognitive performance (i.e., executive functioning, sustained attention, memory, processing speed). Sleep fragmentation emerged as the most prominent sleep-related problem in the present sample. Structural equation modeling demonstrated a negative association between sleep-related problems and cognition that did not reach statistical significance (beta = -0.084, p = 0.629). The current statistical approach may be used as a conceptual framework for future work examining these multi-dimensional constructs in a parsimonious fashion. PMID- 29495599 TI - A Custom Approach for a Flexible, Real-Time and Reliable Software Defined Utility. AB - Information and communication technologies (ICTs) have enabled the evolution of traditional electric power distribution networks towards a new paradigm referred to as the smart grid. However, the different elements that compose the ICT plane of a smart grid are usually conceived as isolated systems that typically result in rigid hardware architectures, which are hard to interoperate, manage and adapt to new situations. In the recent years, software-defined systems that take advantage of software and high-speed data network infrastructures have emerged as a promising alternative to classic ad hoc approaches in terms of integration, automation, real-time reconfiguration and resource reusability. The purpose of this paper is to propose the usage of software-defined utilities (SDUs) to address the latent deployment and management limitations of smart grids. More specifically, the implementation of a smart grid's data storage and management system prototype by means of SDUs is introduced, which exhibits the feasibility of this alternative approach. This system features a hybrid cloud architecture able to meet the data storage requirements of electric utilities and adapt itself to their ever-evolving needs. Conducted experimentations endorse the feasibility of this solution and encourage practitioners to point their efforts in this direction. PMID- 29495598 TI - Potential Health Benefits of Olive Oil and Plant Polyphenols. AB - Beneficial effects of natural plant polyphenols on the human body have been evaluated in a number of scientific research projects. Bioactive polyphenols are natural compounds of various chemical structures. Their sources are mostly fruits, vegetables, nuts and seeds, roots, bark, leaves of different plants, herbs, whole grain products, processed foods (dark chocolate), as well as tea, coffee, and red wine. Polyphenols are believed to reduce morbidity and/or slow down the development of cardiovascular and neurodegenerative diseases as well as cancer. Biological activity of polyphenols is strongly related to their antioxidant properties. They tend to reduce the pool of reactive oxygen species as well as to neutralize potentially carcinogenic metabolites. A broad spectrum of health-promoting properties of plant polyphenols comprises antioxidant, anti inflammatory, anti-allergic, anti-atherogenic, anti-thrombotic, and anti mutagenic effects. Scientific studies present the ability of polyphenols to modulate the human immune system by affecting the proliferation of white blood cells, and also the production of cytokines or other factors that participate in the immunological defense. The aim of the review is to focus on polyphenols of olive oil in context of their biological activities. PMID- 29495600 TI - Inertial Measurement Units for Clinical Movement Analysis: Reliability and Concurrent Validity. AB - The aim of this study was to investigate the reliability and concurrent validity of a commercially available Xsens MVN BIOMECH inertial-sensor-based motion capture system during clinically relevant functional activities. A clinician with no prior experience of motion capture technologies and an experienced clinical movement scientist each assessed 26 healthy participants within each of two sessions using a camera-based motion capture system and the MVN BIOMECH system. Participants performed overground walking, squatting, and jumping. Sessions were separated by 4 +/- 3 days. Reliability was evaluated using intraclass correlation coefficient and standard error of measurement, and validity was evaluated using the coefficient of multiple correlation and the linear fit method. Day-to-day reliability was generally fair-to-excellent in all three planes for hip, knee, and ankle joint angles in all three tasks. Within-day (between-rater) reliability was fair-to-excellent in all three planes during walking and squatting, and poor to-high during jumping. Validity was excellent in the sagittal plane for hip, knee, and ankle joint angles in all three tasks and acceptable in frontal and transverse planes in squat and jump activity across joints. Our results suggest that the MVN BIOMECH system can be used by a clinician to quantify lower-limb joint angles in clinically relevant movements. PMID- 29495601 TI - Diagnosis of Insulation Condition of MV Switchgears by Application of Different Partial Discharge Measuring Methods and Sensors. AB - Partial discharges (PD) measurement provides valuable information for the condition assessment of the insulation status of high-voltage (HV) electrical installations. During the last three decades, several PD sensors and measuring techniques have been developed to perform accurate diagnostics when PD measurements are carried out on-site and on-line. For utilities, the most attractive characteristics of on-line measurements are that once the sensors are installed in the grid, the electrical service is uninterrupted and that electrical systems are tested in real operating conditions. In medium-voltage (MV) and HV installations, one of the critical points where an insulation defect can occur is inside metal-clad switchgears (including the cable terminals connected to them). Thus, this kind of equipment is increasingly being monitored to carry out proper maintenance based on their condition. This paper presents a study concerning the application of different electromagnetic measuring techniques (compliant with IEC 62478 and IEC 60270 standards), together with the use of suitable sensors, which enable the evaluation of the insulation condition mainly in MV switchgears. The main scope is to give a general overview about appropriate types of electromagnetic measuring methods and sensors to be applied, while considering the level of detail and accuracy in the diagnosis and the particular fail-save requirements of the electrical installations where the switchgears are located. PMID- 29495602 TI - 2A-DUB/Mysm1 Regulates Epidermal Development in Part by Suppressing p53-Mediated Programs. AB - Development and homeostasis of the epidermis are governed by a complex network of sequence-specific transcription factors and epigenetic modifiers cooperatively regulating the subtle balance of progenitor cell self-renewal and terminal differentiation. To investigate the role of histone H2A deubiquitinase 2A DUB/Mysm1 in the skin, we systematically analyzed expression, developmental functions, and potential interactions of this epigenetic regulator using Mysm1 deficient mice and skin-derived epidermal cells. Morphologically, skin of newborn and young adult Mysm1-deficient mice was atrophic with reduced thickness and cellularity of epidermis, dermis, and subcutis, in context with altered barrier function. Skin atrophy correlated with reduced proliferation rates in Mysm1-/- epidermis and hair follicles, and increased apoptosis compared with wild-type controls, along with increases in DNA-damage marker gammaH2AX. In accordance with diminished alpha6-Integrinhigh+CD34+ epidermal stem cells, reduced colony formation of Mysm1-/- epidermal progenitors was detectable in vitro. On the molecular level, we identified p53 as potential mediator of the defective Mysm1 deficient epidermal compartment, resulting in increased pro-apoptotic and anti proliferative gene expression. In Mysm1-/-p53-/- double-deficient mice, significant recovery of skin atrophy was observed. Functional properties of Mysm1 /- developing epidermis were assessed by quantifying the transepidermal water loss. In summary, this investigation uncovers a role for 2A-DUB/Mysm1 in suppression of p53-mediated inhibitory programs during epidermal development. PMID- 29495604 TI - Selenium and Mercury Interactions in Apex Predators from the Gulf of Trieste (Northern Adriatic Sea). AB - Since the environmental levels of selenium (Se) can moderate the bioaccumulation and toxicity of mercury (Hg) in marine organisms, their interactions were studied in seawater, sediments, plankton and the benthic (Bull ray Pteromylaeus bovinus, Eagle ray Myliobatis aquila) and the pelagic (Pelagic stingray Dasyiatis violacea) rays, as apex predators in the Gulf of Trieste (Northern Adriatic Sea). Male and female rays showed no difference in the Se contents in muscle tissue. Pelagic species contained higher Se levels in muscle but slightly lower levels in the livers of both genders. The Hg/Se ratios in seawater dissolved and colloidal fractions, plankton and sediment were <0.5, while those in particulate matter were <1.3. In benthic ray species, a parallel increase in Se and Hg in muscle was observed, so that an increased in Hg (MeHg) bioaccumulation results in Se coaccumulation. The Hg/Se ratios (molar) in muscle and liver of pelagic and benthic rays were <1.4 and <0.7, respectively. The low levels of Hg in muscle and liver in all the ray species corresponded to low Hg/Se ratios and increases in muscle and liver to 1 at 7 ug/g, dry weight (dw) and 5 ug/g dw, respectively, i.e., about 1.6 ug/g wet weight (ww). PMID- 29495603 TI - Tumor Resistance against ALK Targeted Therapy-Where It Comes From and Where It Goes. AB - Anaplastic lymphoma kinase (ALK) is a validated molecular target in several ALK rearranged malignancies, particularly in non-small-cell lung cancer (NSCLC), which has generated considerable interest and effort in developing ALK tyrosine kinase inhibitors (TKI). Crizotinib was the first ALK inhibitor to receive FDA approval for ALK-positive NSCLC patients treatment. However, the clinical benefit observed in targeting ALK in NSCLC is almost universally limited by the emergence of drug resistance with a median of occurrence of approximately 10 months after the initiation of therapy. Thus, to overcome crizotinib resistance, second/third generation ALK inhibitors have been developed and received, or are close to receiving, FDA approval. However, even when treated with these new inhibitors tumors became resistant, both in vitro and in clinical settings. The elucidation of the diverse mechanisms through which resistance to ALK TKI emerges, has informed the design of novel therapeutic strategies to improve patients disease outcome. This review summarizes the currently available knowledge regarding ALK physiologic function/structure and neoplastic transforming role, as well as an update on ALK inhibitors and resistance mechanisms along with possible therapeutic strategies that may overcome the development of resistance. PMID- 29495606 TI - Suboptimal Iodine Status among Pregnant Women in the Oslo Area, Norway. AB - Norway has been considered iodine replete for decades; however, recent studies indicate reemergence of inadequate iodine status in different population groups. We assessed iodine status in pregnant women based on urinary iodine concentration (UIC), urinary iodine excretion (UIE), and iodine intake from food and supplements. In 804 pregnant women, 24-h iodine intakes from iodine-rich foods and iodine-containing supplements were calculated. In 777 women, iodine concentration was measured in spot urine samples by inductively coupled plasma/mass spectrometry (ICP-MS). In addition, 49 of the women collected a 24-h urine sample for assessment of UIE and iodine intake from food frequency questionnaire (FFQ). Median UIC was 92 ug/L. Fifty-five percent had a calculated iodine intake below estimated average requirement (EAR) (160 ug/day). Iodine intake from food alone did not provide the amount of iodine required to meet maternal and fetal needs during pregnancy. In multiple regression models, hypothyroidism, supplemental iodine and maternal age were positively associated with UIC, while gestational age and smoking were negatively associated, explaining 11% of the variance. This study clearly shows that pregnant women in the Oslo area are mild to moderate iodine deficient and public health strategies are needed to improve and secure adequate iodine status. PMID- 29495605 TI - Preventive Potential of Resveratrol in Carcinogen-Induced Rat Thyroid Tumorigenesis. AB - Thyroid cancer (TC) is the most common endocrine malignancy without reliable preventive agent. Resveratrol possesses in vitro anti-TC activities; while its effect(s) on thyroid tumorigenesis remains unknown. This study aims to address this issue using DEN/MNU/DHPN-induced rat carcinogenesis model. 50 male Sprague Dawley rats were separated into four groups as Group-1 (5 rats); normally fed; Group-2 (15 rats); DEN/MNU/DHPN treatment only; Group-3 (15 rats) and -4 (15 rats); DEN/MNU/DHPN treatment; followed by resveratrol intragastric (IG) injection and intraperitoneal (IP) injection; respectively; in two-day intervals for 30 weeks. The results revealed that the average resveratrol concentration in thyroid tissues was 1.278 +/- 0.419 nmol/g in IG group and 1.752 +/- 0.398 nmol/g in IP group. The final body weights of Group-3 and Group-4 were lighter than that (p > 0.05) of Group-1; but heavier than Group-2 (p < 0.05). TC-related lesions (hyperplasia and adenomas) were found in 53.3% of Group-2; 33.3% Group-3 and 26.7% Group-4. Lower serum carcino-embryonic antigen (CEA) and thyroglobulin (Tg) levels; down-regulated expression of IL-6 and cyclooxygenase-2 (COX-2); reduction of NF-kappaB/p65 nuclear translocation; and elevated IkBalpha expression were found in the thyroid tissues of Group-3 and Group-4 in comparison with that of Group-2. These results demonstrate that IG and IP administered resveratrol efficiently reduces the frequency and severity of DEN/MNU/DHPN-caused TC-related lesions and would be of values in thyroid tumor prevention. PMID- 29495607 TI - Effects of Dietary Supplementation of Astaxanthin and Sesamin on Daily Fatigue: A Randomized, Double-Blind, Placebo-Controlled, Two-Way Crossover Study. AB - Severe fatigue can negatively affect quality of life, and oxidative stress may play a role in its mechanism. The aim of this study was to evaluate the effect of dietary supplementation of astaxanthin and sesamin (AS), strong food-derived antioxidants, on fatigue. Twenty-four healthy volunteers were supplemented with AS and placebo, each for four weeks. After each supplementation period, participants underwent tasks inducing mental and physical fatigue (visual display terminal task and ergometer task, respectively). Subjective fatigue was evaluated using a visual analogue scale during and after the mental and physical tasks, and daily subjective fatigue was evaluated by the Chalder fatigue questionnaire. Secondary outcomes included other subjective feelings, work efficiency, autonomic nerve activity, levels of an oxidative stress marker (plasma phosphatidylcholine hydroperoxide (PCOOH)) and safety. AS supplementation was associated with significantly improved recovery from mental fatigue compared with placebo. Increased PCOOH levels during mental and physical tasks were attenuated by AS supplementation. No differences between AS and placebo were detected in secondary outcomes, and no adverse effects of AS supplementation were observed. In conclusion, AS supplementation may be a candidate to promote recovery from mental fatigue which is experienced by many healthy people. PMID- 29495609 TI - Three Dimensional Distribution of Sensitive Field and Stress Field Inversion of Force Sensitive Materials under Constant Current Excitation. AB - Force sensitive conductive composite materials are functional materials which can be used as the sensitive material of force sensors. However, the existing sensors only use one-dimensional electrical properties of force sensitive conductive materials. Even in tactile sensors, the measurement of contact pressure is achieved by large-scale arrays and the units of a large-scale array are also based on the one-dimensional electrical properties of force sensitive materials. The main contribution of this work is to study the three-dimensional electrical properties and the inversion method of three-dimensional stress field of a force sensitive material (conductive rubber), which pushes the application of force sensitive material from one dimensional to three-dimensional. First, the mathematical model of the conductive rubber current field distribution under a constant force is established by the effective medium theory, and the current field distribution model of conductive rubber with different geometry, conductive rubber content and conductive rubber relaxation parameters is deduced. Secondly, the inversion method of the three-dimensional stress field of conductive rubber is established, which provides a theoretical basis for the design of a new tactile sensor, three-dimensional stress field and space force based on force sensitive materials. PMID- 29495608 TI - Anti-Inflammatory and Anti-Apoptotic Effects of Acer Palmatum Thumb. Extract, KIOM-2015EW, in a Hyperosmolar-Stress-Induced In Vitro Dry Eye Model. AB - The aim of this study was to assess the anti-inflammatory and anti-apoptotic effects of KIOM-2015EW, the hot-water extract of maple leaves in hyperosmolar stress (HOS)-induced human corneal epithelial cells (HCECs). HCECs were exposed to hyperosmolar medium and exposed to KIOM-2015EW with or without the hyperosmolar media. Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 production and apoptosis were observed, and the activation of mitogen activated protein kinases (MAPKs) including extracellular signal regulated kinase (ERK), p38 and c-JUN N-terminal kinase (JNK) signaling and nuclear factor (NF) kappaB was confirmed. Compared to isomolar medium, the induction of cell cytotoxicity significantly increased in HCECs exposed to hyperosmolar medium in a time-dependent manner. KIOM-2015EW-treatment significantly reduced the mRNA and protein expression of pro-inflammatory mediators and apoptosis. KIOM-2015EW treatment inhibited HOS-induced MAPK signaling activation. Additionally, the HOS induced increase in NF-kappaB phosphorylation was attenuated by KIOM-2015EW. The results demonstrated that KIOM-2015EW protects the ocular surface by suppressing inflammation in dry eye disease, and suggest that KIOM-2015EW may be used to treat several ocular surface diseases where inflammation plays a key role. PMID- 29495610 TI - Ppbv-Level Ethane Detection Using Quartz-Enhanced Photoacoustic Spectroscopy with a Continuous-Wave, Room Temperature Interband Cascade Laser. AB - A ppbv-level quartz-enhanced photoacoustic spectroscopy (QEPAS)-based ethane (C2H6) sensor was demonstrated by using a 3.3 MUm continuous-wave (CW), distributed feedback (DFB) interband cascade laser (ICL). The ICL was employed for targeting a strong C2H6 absorption line located at 2996.88 cm-1 in its fundamental absorption band. Wavelength modulation spectroscopy (WMS) combined with the second harmonic (2f) detection technique was utilized to increase the signal-to-noise ratio (SNR) and simplify data acquisition and processing. Gas pressure and laser frequency modulation depth were optimized to be 100 Torr and 0.106 cm-1, respectively, for maximizing the 2f signal amplitude. Performance of the QEPAS sensor was evaluated using specially prepared C2H6 samples. A detection limit of 11 parts per billion in volume (ppbv) was obtained with a 1-s integration time based on an Allan-Werle variance analysis, and the detection precision can be further improved to ~1.5 ppbv by increasing the integration time up to 230 s. PMID- 29495611 TI - Carbon Nanotubes Reinforced Maleic Anhydride-Modified Xylan-g-Poly(N isopropylacrylamide) Hydrogel with Multifunctional Properties. AB - Introducing multifunctional groups and inorganic material imparts xylan-based hydrogels with excellent properties, such as responsiveness to pH, temperature, light, and external magnetic field. In this work, a composite hydrogel was synthesized by introducing acid treated carbon nanotubes (AT-CNTs) into the maleic anhydride modified xylan grafted with poly(N-isopropylacrylamide) (MAX-g PNIPAM) hydrogels network. It was found that the addition of AT-CNTs affected the MAX-g-PNIPAM hydrogel structure, the swelling ratio and mechanical properties, and imparted the hydrogel with new properties of electrical conductivity and near infrared region (NIR) photothermal conversion. AT-CNTs could reinforce the mechanical properties of MAX-g-PNIPAM hydrogels, being up to 83 kPa for the compressive strength when the amount was 11 wt %, which was eight times than that of PNIPAM hydrogel and four times than that of MAX-g-PNIPAM hydrogel. The electroconductibility was enhanced by the increase of AT-CNTs amounts. Meanwhile, the composite hydrogel also exhibited multiple shape memory and NIR photothermal conversion properties, and water temperature was increased from 26 degrees C to 56 degrees C within 8 min under the NIR irradiation. Thus, the AT-CNTs reinforced MAX-g-PNIPAM hydrogel possessed promising multifunctional properties, which offered many potential applications in the fields of biosensors, thermal arrest technology, and drug-controlled release. PMID- 29495612 TI - Enhanced Charge Extraction of Li-Doped TiO2 for Efficient Thermal-Evaporated Sb2S3 Thin Film Solar Cells. AB - We provided a new method to improve the efficiency of Sb2S3 thin film solar cells. The TiO2 electron transport layers were doped by lithium to improve their charge extraction properties for the thermal-evaporated Sb2S3 solar cells. The Mott-Schottky curves suggested a change of energy band and faster charge transport in the Li-doped TiO2 films. Compared with the undoped TiO2, Li-doped mesoporous TiO2 dramatically improved the photo-voltaic performance of the thermal-evaporated Sb2S3 thin film solar cells, with the average power conversion efficiency (PCE) increasing from 1.79% to 4.03%, as well as the improved open voltage (Voc), short-circuit current (Jsc) and fill factors. The best device based on Li-doped TiO2 achieved a power conversion efficiency up to 4.42% as well as a Voc of 0.645 V, which are the highest values among the reported thermal evaporated Sb2S3 solar cells. This study showed that Li-doping on TiO2 can effectively enhance the charge extraction properties of electron transport layers, offering a new strategy to improve the efficiency of Sb2S3-based solar cells. PMID- 29495613 TI - Inteins: Localized Distribution, Gene Regulation, and Protein Engineering for Biological Applications. AB - Inteins are self-splicing polypeptides with an ability to excise themselves from flanking host protein regions with remarkable precision; in the process, they ligate flanked host protein fragments. Inteins are distributed sporadically across all three domains of life (bacteria, archaea, and unicellular eukaryotes). However, their apparent localized distribution in DNA replication, repair, and recombination proteins (the 3Rs), particularly in bacteria and archaea, is enigmatic. Our understanding of the localized distribution of inteins in the 3Rs, and their possible regulatory role in such distribution, is still only partial. Nevertheless, understanding the chemistry of post-translational self-splicing of inteins has opened up opportunities for protein chemists to modify, manipulate, and bioengineer proteins. Protein-splicing technology is adapted to a wide range of applications, starting with untagged protein purification, site-specific protein labeling, protein biotinylation, isotope incorporation, peptide cyclization, as an antimicrobial target, and so on. This review is focused on the chemistry of splicing; the localized distribution of inteins, particularly in the 3Rs and their possible role in regulating host protein function; and finally, the use of protein-splicing technology in various protein engineering applications. PMID- 29495614 TI - Morphology-Variable Aggregates Prepared from Cholesterol-Containing Amphiphilic Glycopolymers: Their Protein Recognition/Adsorption and Drug Delivery Applications. AB - In this study, a series of diblock glycopolymers, poly(6-O-methacryloyl-d galactopyranose)-b-poly(6-cholesteryloxyhexyl methacrylate) (PMAgala-b-PMAChols), with cholesterol/galactose grafts were prepared through a sequential reversible addition-fragmentation chain transfer (RAFT) polymerization and deprotection process. The glycopolymers could self-assemble into aggregates with various morphologies depending on cholesterol/galactose-containing block weight ratios, as determined by transmission electronic microscopy (TEM) and dynamic laser light scattering (DLS). In addition, the lectin (Ricinus communis agglutinin II, RCA120) recognition and bovine serum albumin (BSA) adsorption of the PMAgala-b PMAChol aggregates were evaluated. The SK-Hep-1 tumor cell inhibition properties of the PMAgala-b-PMAChol/doxorubicin (DOX) complex aggregates were further examined in vitro. Results indicate that the PMAgala-b-PMAChol aggregates with various morphologies showed different interaction/recognition features with RCA120 and BSA. Spherical aggregates (d ~ 92 nm) possessed the highest RCA120 recognition ability and lowest BSA protein adsorption. In addition, the DOX loaded spherical complex aggregates exhibited a better tumor cell inhibition property than those of nanofibrous complex aggregates. The morphology-variable aggregates derived from the amphiphilic glycopolymers may serve as multifunctional biomaterials with biomolecular recognition and drug delivery features. PMID- 29495615 TI - Suicidal Ideation among the Chinese Elderly and Its Correlates: A Comparison between the Rural and Urban Populations. AB - BACKGROUND: As China is going through a profound aging process, the mental health of the elderly is becoming an issue. As in many other societies, the elderly in China is a population at high risk of suicide; Methods: Data for the study were taken from the Sample Survey of the Aged Population in Urban/Rural China (SSAPUR) accomplished in 2010 by the China Ministry of Civil Affairs. The valid sample for this study was composed of 18,683 individuals, including 9416 urban residents and 9267 rural residents both aged 60 or more years; Results: Logistic regression analyses showed that household income and expenditure, the number of children, chronic diseases, disability of daily living, depression, the frequency of visiting neighbors and having friends or relatives who can help or not had remarkable effects on the suicidal ideation among urban and rural old people. Gender, education, political affiliation, marital status and self-rated health status did not work on the dependent variable. However, some risk factors for suicidal ideation among the Chinese elderly were different between rural and urban regions; Conclusions: We should take different measures when facing the different groups of the elderly. PMID- 29495616 TI - Influence of Titanium Dioxide Nanoparticles on the Sulfate Attack upon Ordinary Portland Cement and Slag-Blended Mortars. AB - In this study, the effects of titanium dioxide (TiO2) nanoparticles on the sulfate attack resistance of ordinary Portland cement (OPC) and slag-blended mortars were investigated. OPC and slag-blended mortars (OPC:Slag = 50:50) were made with water to binder ratio of 0.4 and a binder to sand ratio of 1:3. TiO2 was added as an admixture as 0%, 3%, 6%, 9% and 12% of the binder weight. Mortar specimens were exposed to an accelerated sulfate attack environment. Expansion, changes in mass and surface microhardness were measured. Scanning Electron Microscopy (SEM), Energy Dispersive Spectroscopy (EDS), X-ray Diffraction (XRD), Thermogravimetry Analysis (TGA) and Differential Scanning Calorimetry (DSC) tests were conducted. The formation of ettringite and gypsum crystals after the sulfate attack were detected. Both these products had caused crystallization pressure in the microstructure of mortars and deteriorated the mortars. Our results show that the addition of nano-TiO2 accelerated expansion, variation in mass, loss of surface microhardness and widened cracks in OPC and slag-blended mortars. Nano TiO2 containing slag-blended mortars were more resistant to sulfate attack than nano-TiO2 containing OPC mortars. Because nano-TiO2 reduced the size of coarse pores, so it increased crystallization pressure due to the formation of ettringite and gypsum thus led to more damage under sulfate attack. PMID- 29495617 TI - Mapping the Galvanic Corrosion of Three Metals Coupled with a Wire Beam Electrode: The Influence of Temperature and Relative Geometrical Position. AB - The local electrochemical properties of galvanic corrosion for three coupled metals in a desalination plant were investigated with three wire-beam electrodes as wire sensors: aluminum brass (HAl77-2), titanium (TA2), and 316L stainless steel (316L SS). These electrodes were used with artificial seawater at different temperatures. The potential and current-density distributions of the three-metal coupled system are inhomogeneous. The HAl77-2 wire anodes were corroded in the three-metal coupled system. The TA2 wires acted as cathodes and were protected; the 316L SS wires acted as secondary cathodes. The temperature and electrode arrangement have important effects on the galvanic corrosion of the three-metal coupled system. The corrosion current of the HAl77-2 increased with temperature indicating enhanced anode corrosion at higher temperature. In addition, the corrosion of HAl77-2 was more significant when the HAl77-2 wires were located in the middle of the coupled system than with the other two metal arrangement styles. PMID- 29495618 TI - Structure-Activity Relationships of Thiazolyl Resorcinols, Potent and Selective Inhibitors of Human Tyrosinase. AB - Tyrosinase inhibitors are of great clinical interest as agents for the treatment of hyperpigmentary disorders; however, most compounds described in the literature lack clinical efficiency due to insufficient inhibitory activity against human tyrosinase (hTyr). Recently, we reported that thiazolyl resorcinols (4 resorcinylthiazol-2-amines and -amides) are both selective and efficacious inhibitors of hTyr in vitro and in vivo. Here, we measured dose-activity profiles of a large number of thiazolyl resorcinols and analogous compounds to better understand the molecular basis of their interaction with hTyr. We show that both the resorcinyl moiety and the thiazole ring must be intact to allow efficient inhibition of hTyr, while the substituents at the thiazole 2-amino group confer additional inhibitory activity, depending on their size and polarity. The results of molecular docking simulations were in excellent agreement with the experimental data, affording a rationale for the structural importance of either ring. We further propose that a special type of interaction between the thiazole sulfur and a conserved asparagine residue is partially responsible for the superior inhibitory activity of thiazolyl resorcinols against hTyr. PMID- 29495619 TI - Experimental and Numerical Modeling of Aerosol Delivery for Preterm Infants. AB - Respiratory distress syndrome (RDS) represents one of the major causes of mortality among preterm infants, and the best approach to treat it is an open research issue. The use of perfluorocarbons (PFC) along with non-invasive respiratory support techniques has proven the usefulness of PFC as a complementary substance to achieve a more homogeneous surfactant distribution. The aim of this work was to study the inhaled particles generated by means of an intracorporeal inhalation catheter, evaluating the size and mass distribution of different PFC aerosols. In this article, we discuss different experiments with the PFC perfluorodecalin (PFD) and FC75 with a driving pressure of 4-5 bar, evaluating properties such as the aerodynamic diameter (Da), since its value is directly linked to particle deposition in the lung. Furthermore, we develop a numerical model with computational fluid dynamics (CFD) techniques. The computational results showed an accurate prediction of the airflow axial velocity at different downstream positions when compared with the data gathered from the real experiments. The numerical validation of the cumulative mass distribution for PFD particles also confirmed a closer match with the experimental data measured at the optimal distance of 60 mm from the catheter tip. In the case of FC75, the cumulative mass fraction for particles above 10 um was considerable higher with a driving pressure of 5 bar. These numerical models could be a helpful tool to assist parametric studies of new non-invasive devices for the treatment of RDS in preterm infants. PMID- 29495620 TI - Tribological and Wear Performance of Nanocomposite PVD Hard Coatings Deposited on Aluminum Die Casting Tool. AB - In the aluminum die casting process, erosion, corrosion, soldering, and die sticking have a significant influence on tool life and product quality. A number of coatings such as TiN, CrN, and (Cr,Al)N deposited by physical vapor deposition (PVD) have been employed to act as protective coatings due to their high hardness and chemical stability. In this study, the wear performance of two nanocomposite AlTiN and AlCrN coatings with different structures were evaluated. These coatings were deposited on aluminum die casting mold tool substrates (AISI H13 hot work steel) by PVD using pulsed cathodic arc evaporation, equipped with three lateral arc-rotating cathodes (LARC) and one central rotating cathode (CERC). The research was performed in two stages: in the first stage, the outlined coatings were characterized regarding their chemical composition, morphology, and structure using glow discharge optical emission spectroscopy (GDOES), scanning electron microscopy (SEM), and X-ray diffraction (XRD), respectively. Surface morphology and mechanical properties were evaluated by atomic force microscopy (AFM) and nanoindentation. The coating adhesion was studied using Mersedes test and scratch testing. During the second stage, industrial tests were carried out for coated die casting molds. In parallel, tribological tests were also performed in order to determine if a correlation between laboratory and industrial tests can be drawn. All of the results were compared with a benchmark monolayer AlCrN coating. The data obtained show that the best performance was achieved for the AlCrN/Si3N4 nanocomposite coating that displays an optimum combination of hardness, adhesion, soldering behavior, oxidation resistance, and stress state. These characteristics are essential for improving the die mold service life. Therefore, this coating emerges as a novelty to be used to protect aluminum die casting molds. PMID- 29495621 TI - Synthesis and Performance of Iron Oxide-Coated Ceramsite in a Biotrickling Filter for Nitric Oxide Removal under Thermophilic Conditions. AB - A novel medium consisting of iron oxide-coated porous ceramsite (modified ceramsite) was investigated for NO removal under thermophilic conditions in this study. We used a surface coating method with FeCl3.6H2O as the modifier. When ceramsite was calcined for 4 h at 500 degrees C, the surface pH value decreased to 3.46, which is much lower than the isoelectric point of ceramsite, ensuring its surface was electropositive. The surface of modified ceramsite changed from two- to three-dimensional and exhibited excellent adsorption behavior to assist microbial growth; the maximum dry weight of the biofilm was 1.28 mg/g. It only took 8 days for the biofilter constructed from the modified ceramsite to start up, whereas that packed with commercial ceramsite took 22 days. The NO removal efficiency of the biofilter did not decrease apparently at high NO inlet concentration of above 1600 mg/m3 and maintained an average value of above 90% during the whole operation period. Additionally, the morphological observation showed that the loss of the surface coating was not obvious, and the coating properties remained stable during long-term operation. The maximum NO inlet loading of the biotrickling filter was 80 g/(m3.h) with an average removal efficiency of 91.1% along with a quick start-up when using the modified ceramsite filler. Thus, modified ceramsite can be considered a very effective medium in biotrickling filters for NO removal. PMID- 29495623 TI - Epoxidation of Carbon Nanocapsules: Decoration of Single-Walled Carbon Nanotubes Filled with Metal Halides. AB - Methyl(trifluoromethyl)dioxirane (TFDO) can be used for the oxyfunctionalization of SWCNTs filled with NaI and LuCl3 under mild conditions. The chosen metal halides are of interest for theranostics, both for imaging and therapy when in their radioactive form. The applied functionalization methodology does not require metal catalyst, preserves the integrity of the nanotubes during treatment, avoiding the release of the filling material. In this way, epoxidation can be considered as an efficient methodology for the functionalization of carbon nanocapsules, where the traditional harsh oxidation conditions by acids are not applicable. PMID- 29495622 TI - Minoxidil Promotes Hair Growth through Stimulation of Growth Factor Release from Adipose-Derived Stem Cells. AB - Minoxidil directly promotes hair growth via the stimulation of dermal papilla (DP) and epithelial cells. Alternatively, there is little evidence for indirect promotion of hair growth via stimulation of adipose-derived stem cells (ASCs). We investigated whether minoxidil stimulates ASCs and if increased growth factor secretion by ASCs facilitates minoxidil-induced hair growth. Telogen-to-anagen induction was examined in mice. Cultured DP cells and vibrissae hair follicle organ cultures were used to further examine the underlying mechanisms. Subcutaneous injection of minoxidil-treated ASCs accelerated telogen-to-anagen transition in mice, and increased hair weight at day 14 post-injection. Minoxidil did not alter ASC proliferation, but increased migration and tube formation. Minoxidil also increased the secretion of growth factors from ASCs, including chemokine (C-X-C motif) ligand 1 (CXCL1), platelet-derived endothelial cell growth factor (PD-ECGF), and platelet-derived growth factor-C (PDGF-C). Minoxidil increased extracellular signal-regulated kinases 1/2 (ERK1/2) phosphorylation, and concomitant upregulation of PD-ECGF and PDGF-C mRNA levels were attenuated by an ERK inhibitor. Subcutaneous injection of CXCL1, PD-ECGF, or PDGF-C enhanced anagen induction in mice, and both CXCL1 and PDGF-C increased hair length in ex vivo organ culture. Treatment with CXCL1, PD-ECGF, or PDGF-C also increased the proliferation index in DP cells. Finally, topical application of CXCL1, PD-ECGF, or PDGF-C with 2% minoxidil enhanced anagen induction when compared to minoxidil alone. Minoxidil stimulates ASC motility and increases paracrine growth factor signaling. Minoxidil-stimulated secretion of growth factors by ASCs may enhance hair growth by promoting DP proliferation. Therefore, minoxidil can be used as an ASC preconditioning agent for hair regeneration. PMID- 29495625 TI - The Complex Subtype-Dependent Role of Connexin 43 (GJA1) in Breast Cancer. AB - Gap junction transmembrane channels allow the transfer of small molecules between the cytoplasm of adjacent cells. They are formed by proteins named connexins (Cxs) that have long been considered as a tumor suppressor. This widespread view has been challenged by recent studies suggesting that the role of Connexin 43 (Cx43) in cancer is tissue- and stage-specific and can even promote tumor progression. High throughput profiling of invasive breast cancer has allowed for the construction of subtyping schemes that partition patients into at least four distinct intrinsic subtypes. This study characterizes Cx43 expression during cancer progression with each of the tumor subtypes using a compendium of publicly available gene expression data. In particular, we show that Cx43 expression depends greatly on intrinsic subtype. Tumor grade also co-varies with patient subtype, resulting in Cx43 co-expression with grade in a subtype-dependent manner. Better survival was associated with a high expression of Cx43 in unstratified and luminal tumors but with a low expression in Her2e subtype. A better understanding of Cx43 regulation in a subtype-dependent manner is needed to clarify the context in which Cx43 is associated with tumor suppression or cancer progression. PMID- 29495624 TI - Ion Channel Disorders and Sudden Cardiac Death. AB - Long QT syndrome, short QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia are inherited primary electrical disorders that predispose to sudden cardiac death in the absence of structural heart disease. Also known as cardiac channelopathies, primary electrical disorders respond to mutations in genes encoding cardiac ion channels and/or their regulatory proteins, which result in modifications in the cardiac action potential or in the intracellular calcium handling that lead to electrical instability and life-threatening ventricular arrhythmias. These disorders may have low penetrance and expressivity, making clinical diagnosis often challenging. However, because sudden cardiac death might be the first presenting symptom of the disease, early diagnosis becomes essential. Genetic testing might be helpful in this regard, providing a definite diagnosis in some patients. Yet important limitations still exist, with a significant proportion of patients remaining with no causative mutation identifiable after genetic testing. This review aims to provide the latest knowledge on the genetic basis of cardiac channelopathies and discuss the role of the affected proteins in the pathophysiology of each one of these diseases. PMID- 29495626 TI - Chinese Medicines in the Treatment of Prostate Cancer: From Formulas to Extracts and Compounds. AB - In order to fully understand the progresses and achievements in Chinese medicines for the treatment of prostate cancer, we summarize all the available reports on formulas, extracts, and compounds of Chinese medicines against prostate cancer. A number of clinical trials verified that traditional Chinese formulas had some unique advantages in the treatment of prostate cancer. Many Chinese medicine extracts could protect against prostate cancer, and many compounds isolated from Chinese traditional medicines showed a clear anti-prostate cancer effect. However, Chinese medicines are facing many problems regarding their multicomponent nature, complicated mechanisms of action, and high doses required for therapy. Herein, we review the functions of Chinese medicines in prostate cancer and focus on their mechanisms. The review will deepen the understanding of Chinese medicines potential in the anti-prostate cancer field. In addition, we put forward a question concerning the current research on Chinese medicines: in order to better illustrate that Chinese medicines can be used in the clinical treatment of prostate cancer, should our research focus on formulas, extracts, or compounds? PMID- 29495627 TI - Rough Titanium Oxide Coating Prepared by Micro-Arc Oxidation Causes Down Regulation of hTERT Expression, Molecular Presentation, and Cytokine Secretion in Tumor Jurkat T Cells. AB - The response of the human Jurkat T cell leukemia-derived cell line (Jurkat T cells) after 24 h of in vitro exposure to a titanium substrate (12 * 12 * 1 mm3) with a bilateral rough (Ra = 2.2-3.7 MUm) titanium oxide coating (rTOC) applied using the micro-arc method in a 20% orthophosphoric acid solution was studied. A 1.5-fold down-regulation of hTERT mRNA expression and decreases in CD3, CD4, CD8, and CD95 presentation and IL-4 and TNFalpha secretion were observed. Jurkat T cell inactivation was not correlated with the generation of intracellular reactive oxygen species (ROS) and was not mediated by TiO2 nanoparticles with a diameter of 14 +/- 8 nm at doses of 1 mg/L or 10 mg/L. The inhibitory effect of the rTOC (Ra = 2.2-3.7 MUm) on the survival of Jurkat T cells (Spearman's coefficient rs = -0.95; n = 9; p < 0.0001) was demonstrated by an increase in the necrotic cell count among the cell population. In turn, an elevation of the Ra index of the rTOC was accompanied by a linear increase (r = 0.6; p < 0.000001, n = 60) in the magnitude of the negative electrostatic potential of the titanium oxide surface. Thus, the roughness of the rTOC induces an electrostatic potential and decreases the viability of the immortalized Jurkat T cells through mechanisms unrelated to ROS generation. This may be useful for replacement surgery applications of rough TiO2 implants in cancer patients. PMID- 29495628 TI - Sodium Content of Lunches and Snacks Provided in Australian Long Day Care Centres: A Cross-Sectional Study. AB - We determined the average amount of sodium provided in lunches and snacks and the average amount of sodium consumed at lunch in a convenience sample of Australian preschool children attending Long Day Care (LDC). Sodium content of lunches and snacks was determined from standardised recipes. Individual children's sodium intake was estimated by a validated visual plate waste scale method. Five recipes (lunch n = 35, snacks n = 70) collected from 7 LDC centres; 95 children (50 boys) mean age 3.5 (SD) (0.2) years lunch intakes were assessed. Average total amount of sodium provided from two snacks and one lunch: 590 (146) mg, representing ~59% of the Australian Upper Level (UL) of intake (1000 mg/day sodium). Average total amount of sodium consumed: 541 (98) mg representing ~54% of the UL. Across all centres, the average sodium and energy consumed from lunch: 186 (108) mg (~19% of UL); 948 (437) kJ (38% of energy allowance); morning snacks: 63 (45) mg (6% of UL), 535 (183) kJ (21% of energy allowance); afternoon snacks: 291 (97) mg (29% of UL), 464 (171) kJ energy (46% of energy allowance). Australian LDC centres providing lunches cooked on site resulted in relatively low-sodium lunches. PMID- 29495629 TI - The Unexplored Diversity of Pleolipoviruses: The Surprising Case of Two Viruses with Identical Major Structural Modules. AB - Extremely halophilic Archaea are the only known hosts for pleolipoviruses which are pleomorphic non-lytic viruses resembling cellular membrane vesicles. Recently, pleolipoviruses have been acknowledged by the International Committee on Taxonomy of Viruses (ICTV) as the first virus family that contains related viruses with different DNA genomes. Genomic diversity of pleolipoviruses includes single-stranded and double-stranded DNA molecules and their combinations as linear or circular molecules. To date, only eight viruses belong to the family Pleolipoviridae. In order to obtain more information about the diversity of pleolipoviruses, further isolates are needed. Here we describe the characterization of a new halophilic virus isolate, Haloarcula hispanica pleomorphic virus 4 (HHPV4). All pleolipoviruses and related proviruses contain a conserved core of approximately five genes designating this virus family, but the sequence similarity among different isolates is low. We demonstrate that over half of HHPV4 genome is identical to the genome of pleomorphic virus HHPV3. The genomic regions encoding known virion components are identical between the two viruses, but HHPV4 includes unique genetic elements, e.g., a putative integrase gene. The co-evolution of these two viruses demonstrates the presence of high recombination frequency in halophilic microbiota and can provide new insights considering links between viruses, membrane vesicles, and plasmids. PMID- 29495630 TI - A Data-Gathering Scheme with Joint Routing and Compressive Sensing Based on Modified Diffusion Wavelets in Wireless Sensor Networks. AB - Compressive sensing (CS)-based data gathering is a promising method to reduce energy consumption in wireless sensor networks (WSNs). Traditional CS-based data gathering approaches require a large number of sensor nodes to participate in each CS measurement task, resulting in high energy consumption, and do not guarantee load balance. In this paper, we propose a sparser analysis that depends on modified diffusion wavelets, which exploit sensor readings' spatial correlation in WSNs. In particular, a novel data-gathering scheme with joint routing and CS is presented. A modified ant colony algorithm is adopted, where next hop node selection takes a node's residual energy and path length into consideration simultaneously. Moreover, in order to speed up the coverage rate and avoid the local optimal of the algorithm, an improved pheromone impact factor is put forward. More importantly, theoretical proof is given that the equivalent sensing matrix generated can satisfy the restricted isometric property (RIP). The simulation results demonstrate that the modified diffusion wavelets' sparsity affects the sensor signal and has better reconstruction performance than DFT. Furthermore, our data gathering with joint routing and CS can dramatically reduce the energy consumption of WSNs, balance the load, and prolong the network lifetime in comparison to state-of-the-art CS-based methods. PMID- 29495631 TI - Epidemiological Study on Metal Pollution of Ningbo in China. AB - Background: In order to search for effective control and prevention measures, the status of metal pollution in Ningbo, China was investigated. Methods: Nine of the most common contaminating metals including lead (Pb), cadmium (Cd), copper (Cu), iron (Fe), manganese (Mn), chromium (Cr), nickel (Ni), zinc (Zn), and mercury (Hg) in samples of vegetables, rice, soil, irrigation water, and human hair were detected using inductively coupled plasma-mass spectrometry (ICP-MS). Three different districts including industrial, suburban and rural areas in Ningbo were studied through a stratified random sample method. Results: (1) Among all of the detected vegetable samples, Cd exceeded the standard limit rates in industrial, suburban and rural areas as high as 43.9%, 27.5% and 5.0%, respectively; indicating the severity of Cd pollution in Ningbo. (2) The pollution index (PI) of Cd and Zn in soil (1.069, 1.584, respectively) suggests that soil is slightly polluted by Cd and Zn. Among all samples, metal contamination levels in soil were all relatively high. (3) A positive correlation was found between the concentrations of Pb, Cd and Cu in vegetables and soil; Pb, Cu, Cr and Ni in vegetables and irrigation water, as well as, Cu and Ni in rice and irrigation water; and, (4) Higher Pb and Cd concentrations were found in student scalp hair in both industrial and suburban areas compared to rural areas. (5) Hg and Pb that are found in human scalp hair may be more easily absorbed from food than any of the other metals. Conclusions: In general, certain harmful metal pollutions were detected in both industrial and suburban areas of Ningbo in China. PMID- 29495632 TI - Evaluation of the Quebec Healthy Enterprise Standard: Effect on Adverse Psychosocial Work Factors and Psychological Distress. AB - Adverse psychosocial work factors are recognized as a significant source of psychological distress, resulting in a considerable socioeconomic burden. The impact of occupational health standards that aim to reduce these adverse work factors, such as the Quebec Healthy Enterprise Standard (QHES), is of great interest for public health. The aim of this study was to evaluate, for the first time, the effect of QHES interventions targeting adverse psychosocial work factors on the prevalence of these factors and of psychological distress among ten Quebec organizations. These outcomes were assessed by questionnaire using validated instruments before (T1, n = 2849) and 2-3 years following (T2, n = 2560) QHES implementation. Beneficial effects of interventions were observed for two adverse psychosocial work factors: low rewards (ratio of prevalence ratios (PRs) = 0.77, 95% CI = 0.66-0.91) and low social support at work (ratio of PRs = 0.89, 95% CI = 0.77-1.03). Moreover, beneficial effects of interventions were also observed on the prevalence of high psychological distress (ratio of PRs = 0.86, 95% CI = 0.75-0.998). Psychosocial interventions implemented in the context of this standard improved the psychosocial work environment and had beneficial effects on workers' mental health. PMID- 29495633 TI - The Impact of Ambient Air Pollution on Daily Hospital Visits for Various Respiratory Diseases and the Relevant Medical Expenditures in Shanghai, China. AB - The evidence concerning the acute effects of ambient air pollution on various respiratory diseases was limited in China, and the attributable medical expenditures were largely unknown. From 2013 to 2015, we collected data on the daily visits to the emergency- and outpatient-department for five main respiratory diseases and their medical expenditures in Shanghai, China. We used the overdispersed generalized additive model together with distributed lag models to fit the associations of criteria air pollutants with hospital visits, and used the linear models to fit the associations with medical expenditures. Generally, we observed significant increments in emergency visits (8.81-17.26%) and corresponding expenditures (0.33-25.81%) for pediatric respiratory diseases, upper respiratory infection (URI), and chronic obstructive pulmonary disease (COPD) for an interquartile range increase of air pollutant concentrations over four lag days. As a comparison, there were significant but smaller increments in outpatient visits (1.36-4.52%) and expenditures (1.38-3.18%) for pediatric respiratory diseases and upper respiratory infection (URI). No meaningful changes were observed for asthma and lower respiratory infection. Our study suggested that short-term exposure to outdoor air pollution may induce the occurrences or exacerbation of pediatric respiratory diseases, URI, and COPD, leading to considerable medical expenditures upon the patients. PMID- 29495634 TI - MOF-Derived Cu@Cu2O Nanocatalyst for Oxygen Reduction Reaction and Cycloaddition Reaction. AB - Research on the synthesis of nanomaterials using metal-organic frameworks (MOFs), which are characterized by multi-functionality and porosity, as precursors have been accomplished through various synthetic approaches. In this study, copper and copper oxide nanoparticles were fabricated within 30 min by a simple and rapid method involving the reduction of a copper(II)-containing MOF with sodium borohydride solution at room temperature. The obtained nanoparticles consist of a copper core and a copper oxide shell exhibited catalytic activity in the oxygen reduction reaction. The as-synthesized Cu@Cu2O core-shell nanocatalyst exhibited an enhanced limit current density as well as onset potential in the electrocatalytic oxygen reduction reaction (ORR). Moreover, the nanoparticles exhibited good catalytic activity in the Huisgen cycloaddition of various substituted azides and alkynes under mild reaction conditions. PMID- 29495635 TI - The Postprandial Anti-Hyperglycemic Effect of Pyridoxine and Its Derivatives Using In Vitro and In Vivo Animal Models. AB - In the current study, we investigated the inhibitory activity of pyridoxine, pyridoxal, and pyridoxamine, against various digestive enzymes such as alpha glucosidases, sucrase, maltase, and glucoamylase. Inhibition of these enzymes involved in the absorption of disaccharide can improve post-prandial hyperglycemia due to a carbohydrate-based diet. Pyridoxal (4.14 mg/mL of IC50) had the highest rat intestinal alpha-glucosidase inhibitory activity, followed by pyridoxamine and pyridoxine (4.85 and 5.02 mg/mL of IC50, respectively). Pyridoxal demonstrated superior inhibition against maltase (0.38 mg/mL IC50) and glucoamylase (0.27 mg/mLIC50). In addition, pyridoxal showed significant higher alpha-amylase inhibitory activity (10.87 mg/mL of IC50) than that of pyridoxine (23.18 mg/mL of IC50). This indicates that pyridoxal can also inhibit starch hydrolyzing by pancreatic alpha-amylase in small intestine. Based on these in vitro results, the deeper evaluation of the anti-hyperglycemic potential of pyridoxine and its derivatives using Sprague-Dawley (SD) rat models, was initiated. The post-prandial blood glucose levels were tested two hours after sucrose/starch administration, with and without pyridoxine and its derivatives. In the animal trial, pyridoxal (p < 0.05) had a significantly reduction to the postprandial glucose levels, when compared to the control. The maximum blood glucose levels (Cmax) of pyridoxal administration group were decreased by about 18% (from 199.52 +/- 22.93 to 164.10 +/- 10.27, p < 0.05) and 19% (from 216.92 +/ 12.46 to 175.36 +/- 10.84, p < 0.05) in sucrose and starch loading tests, respectively, when compared to the control in pharmacodynamics study. The pyridoxal administration significantly decreased the minimum, maximum, and mean level of post-prandial blood glucose at 0.5 h after meals. These results indicate that water-soluble vitamin pyridoxine and its derivatives can decrease blood glucose level via the inhibition of carbohydrate-hydrolyzing and absorption linked enzymes. Therefore, pyridoxal may have the potential to be used as a food ingredient for the prevention of prediabetes progression to type 2 diabetes. PMID- 29495636 TI - Testing for Polytomies in Phylogenetic Species Trees Using Quartet Frequencies. AB - Phylogenetic species trees typically represent the speciation history as a bifurcating tree. Speciation events that simultaneously create more than two descendants, thereby creating polytomies in the phylogeny, are possible. Moreover, the inability to resolve relationships is often shown as a (soft) polytomy. Both types of polytomies have been traditionally studied in the context of gene tree reconstruction from sequence data. However, polytomies in the species tree cannot be detected or ruled out without considering gene tree discordance. In this paper, we describe a statistical test based on properties of the multi-species coalescent model to test the null hypothesis that a branch in an estimated species tree should be replaced by a polytomy. On both simulated and biological datasets, we show that the null hypothesis is rejected for all but the shortest branches, and in most cases, it is retained for true polytomies. The test, available as part of the Accurate Species TRee ALgorithm (ASTRAL) package, can help systematists decide whether their datasets are sufficient to resolve specific relationships of interest. PMID- 29495637 TI - Real-Time Spaceborne Synthetic Aperture Radar Float-Point Imaging System Using Optimized Mapping Methodology and a Multi-Node Parallel Accelerating Technique. AB - With the development of satellite load technology and very large-scale integrated (VLSI) circuit technology, on-board real-time synthetic aperture radar (SAR) imaging systems have facilitated rapid response to disasters. A key goal of the on-board SAR imaging system design is to achieve high real-time processing performance under severe size, weight, and power consumption constraints. This paper presents a multi-node prototype system for real-time SAR imaging processing. We decompose the commonly used chirp scaling (CS) SAR imaging algorithm into two parts according to the computing features. The linearization and logic-memory optimum allocation methods are adopted to realize the nonlinear part in a reconfigurable structure, and the two-part bandwidth balance method is used to realize the linear part. Thus, float-point SAR imaging processing can be integrated into a single Field Programmable Gate Array (FPGA) chip instead of relying on distributed technologies. A single-processing node requires 10.6 s and consumes 17 W to focus on 25-km swath width, 5-m resolution stripmap SAR raw data with a granularity of 16,384 * 16,384. The design methodology of the multi-FPGA parallel accelerating system under the real-time principle is introduced. As a proof of concept, a prototype with four processing nodes and one master node is implemented using a Xilinx xc6vlx315t FPGA. The weight and volume of one single machine are 10 kg and 32 cm * 24 cm * 20 cm, respectively, and the power consumption is under 100 W. The real-time performance of the proposed design is demonstrated on Chinese Gaofen-3 stripmap continuous imaging. PMID- 29495638 TI - An Optimized Method to Detect BDS Satellites' Orbit Maneuvering and Anomalies in Real-Time. AB - The orbital maneuvers of Global Navigation Satellite System (GNSS) Constellations will decrease the performance and accuracy of positioning, navigation, and timing (PNT). Because satellites in the Chinese BeiDou Navigation Satellite System (BDS) are in Geostationary Orbit (GEO) and Inclined Geosynchronous Orbit (IGSO), maneuvers occur more frequently. Also, the precise start moment of the BDS satellites' orbit maneuvering cannot be obtained by common users. This paper presented an improved real-time detecting method for BDS satellites' orbit maneuvering and anomalies with higher timeliness and higher accuracy. The main contributions to this improvement are as follows: (1) instead of the previous two steps method, a new one-step method with higher accuracy is proposed to determine the start moment and the pseudo random noise code (PRN) of the satellite orbit maneuvering in that time; (2) BDS Medium Earth Orbit (MEO) orbital maneuvers are firstly detected according to the proposed selection strategy for the stations; and (3) the classified non-maneuvering anomalies are detected by a new median robust method using the weak anomaly detection factor and the strong anomaly detection factor. The data from the Multi-GNSS Experiment (MGEX) in 2017 was used for experimental analysis. The experimental results and analysis showed that the start moment of orbital maneuvers and the period of non-maneuver anomalies can be determined more accurately in real-time. When orbital maneuvers and anomalies occur, the proposed method improved the data utilization for 91 and 95 min in 2017. PMID- 29495639 TI - Sulfide Species Optical Monitoring by a Miniaturized Silicon Photomultiplier. AB - The monitoring of water-soluble pollutants is receiving a growing interest from the scientific community. In this context, sulfide anion species S2- and HS- are particularly relevant since they can cause acute and chronic toxicity including neurological effects and at high concentrations, even death. In this study, a new strategy for fast and sensitive optical detection of sulfide species in water samples is described. The method uses an integrated silicon photomultiplier (SiPM) device coupled with the appropriate analytical strategy applied in a plastic microchip with dried reagents on board. More specifically, all sulfide species (H2S, HS- and S2-) in water samples are detected by the fluorescence signal emitted upon the reaction with N,N-dimethyl-phenylenediamine sulfate in the presence of Fe3+, leading to the formation of the fluorescent methylene blue (MB) species. It has been proven that the system herein proposed is able to measure sulfide concentration in a linear range from 0-10 mg L-1 with a sensitivity value of about 6.7 uA mg-1 L and a detection limit of 0.5 mg L-1. A comparison with conventional UV-Vis detection method has been also carried out. Data show a very good linear correlation (R2 = 0.98093), proving the effectiveness of the method. Results pave the way toward the development of portable and low-cost device systems for water-soluble sulfide pollutants. PMID- 29495640 TI - Six Heterocyclic Metabolites from the Myxobacterium Labilithrix luteola. AB - Two new secondary metabolites, labindole A [2-methyl-3-(2-nitroethyl)-3H-indole] (1) and labindole B [2-methyl-3-(2-nitrovinyl)-3H-indole] (2), were isolated from the myxobacterium Labilithrixluteola (DSM 27648T). Additionally, four metabolites 3, 4, 5 and 6 already known from other sources were obtained. Their structures were elucidated from high resolution electrospray ionisation mass spectrometry (HRESIMS) and 1D and 2D nuclear magnetic resonance (NMR) spectroscopy data and their relative configuration was assigned based on nuclear Overhauser effect (NOE) and vicinal 1H-NMR coupling data. The compounds where tested for biological activities; labindoles A (1) and B (2) exhibited significant activity against Hepatitis C Virus, 9H-carbazole (3), 3-chloro-9H-carbazole (4) and 4 hydroxymethyl-quinoline (5) showed antifungal activities. Moreover, compound 3 had weak to moderate antibacterial activities, while labindoles A (1) and B (2) were devoid of significant antifungal and antibacterial effects. PMID- 29495641 TI - A Sample and Sensitive HPLC-MS/MS Method for Simultaneous Determination of Ziyuglycoside I and Its Metabolite Ziyuglycoside II in Rat Pharmacokinetics. AB - Ziyuglycoside I (ZGS1) is a promising drug candidate for the treatment of leucopenia. Currently, information on ZGS1 and its in vivo metabolite ziyuglycoside II (ZGS2) is limited. The objective of this study was to investigate the pharmacokinetics, tissue distribution, and excretion of ziyuglycoside I (ZGS1) and its metabolite ziyuglycoside II (ZGS2) in rats. In our study, a simple and sensitive high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS) method was established for simultaneous determination of ZGS1 and its metabolite for Sprague-Dawley rat pharmacokinetics studies. The method was validated following internationally-approved guidelines. The results presented in this study indicated that subcutaneous administration of ZGS1 prolonged its extension time and increased the area under the curve (AUC0-t) of ZGS2 during 0 to t minutes. In summary, in this study, the pharmacokinetic characteristics of ZGS1 and its metabolite ZGS2 were defined and its tissue distribution, and excretion in rats were described. Our finding may be beneficial for leucopenia drug that focus on ZGS1. PMID- 29495643 TI - When Transcriptomics and Metabolomics Work Hand in Hand: A Case Study Characterizing Plant CDF Transcription Factors. AB - Over the last three decades, novel "omics" platform technologies for the sequencing of DNA and complementary DNA (cDNA) (RNA-Seq), as well as for the analysis of proteins and metabolites by mass spectrometry, have become more and more available and increasingly found their way into general laboratory life. With this, the ability to generate highly multivariate datasets on the biological systems of choice has increased tremendously. However, the processing and, perhaps even more importantly, the integration of "omics" datasets still remains a bottleneck, although considerable computational and algorithmic advances have been made in recent years. In this mini-review, we use a number of recent "multi omics" approaches realized in our laboratories as a common theme to discuss possible pitfalls of applying "omics" approaches and to highlight some useful tools for data integration and visualization in the form of an exemplified case study. In the selected example, we used a combination of transcriptomics and metabolomics alongside phenotypic analyses to functionally characterize a small number of Cycling Dof Transcription Factors (CDFs). It has to be remarked that, even though this approach is broadly used, the given workflow is only one of plenty possible ways to characterize target proteins. PMID- 29495644 TI - A Finite Element Solution of Lateral Periodic Poisson-Boltzmann Model for Membrane Channel Proteins. AB - Membrane channel proteins control the diffusion of ions across biological membranes. They are closely related to the processes of various organizational mechanisms, such as: cardiac impulse, muscle contraction and hormone secretion. Introducing a membrane region into implicit solvation models extends the ability of the Poisson-Boltzmann (PB) equation to handle membrane proteins. The use of lateral periodic boundary conditions can properly simulate the discrete distribution of membrane proteins on the membrane plane and avoid boundary effects, which are caused by the finite box size in the traditional PB calculations. In this work, we: (1) develop a first finite element solver (FEPB) to solve the PB equation with a two-dimensional periodicity for membrane channel proteins, with different numerical treatments of the singular charges distributions in the channel protein; (2) add the membrane as a dielectric slab in the PB model, and use an improved mesh construction method to automatically identify the membrane channel/pore region even with a tilt angle relative to the z-axis; and (3) add a non-polar solvation energy term to complete the estimation of the total solvation energy of a membrane protein. A mesh resolution of about 0.25 A (cubic grid space)/0.36 A (tetrahedron edge length) is found to be most accurate in linear finite element calculation of the PB solvation energy. Computational studies are performed on a few exemplary molecules. The results indicate that all factors, the membrane thickness, the length of periodic box, membrane dielectric constant, pore region dielectric constant, and ionic strength, have individually considerable influence on the solvation energy of a channel protein. This demonstrates the necessity to treat all of those effects in the PB model for membrane protein simulations. PMID- 29495646 TI - Ontology-Based Method for Fault Diagnosis of Loaders. AB - This paper proposes an ontology-based fault diagnosis method which overcomes the difficulty of understanding complex fault diagnosis knowledge of loaders and offers a universal approach for fault diagnosis of all loaders. This method contains the following components: (1) An ontology-based fault diagnosis model is proposed to achieve the integrating, sharing and reusing of fault diagnosis knowledge for loaders; (2) combined with ontology, CBR (case-based reasoning) is introduced to realize effective and accurate fault diagnoses following four steps (feature selection, case-retrieval, case-matching and case-updating); and (3) in order to cover the shortages of the CBR method due to the lack of concerned cases, ontology based RBR (rule-based reasoning) is put forward through building SWRL (Semantic Web Rule Language) rules. An application program is also developed to implement the above methods to assist in finding the fault causes, fault locations and maintenance measures of loaders. In addition, the program is validated through analyzing a case study. PMID- 29495642 TI - Meta-Analysis of the Effects of Foods and Derived Products Containing Ellagitannins and Anthocyanins on Cardiometabolic Biomarkers: Analysis of Factors Influencing Variability of the Individual Responses. AB - Understanding interindividual variability in response to dietary polyphenols remains essential to elucidate their effects on cardiometabolic disease development. A meta-analysis of 128 randomized clinical trials was conducted to investigate the effects of berries and red grapes/wine as sources of anthocyanins and of nuts and pomegranate as sources of ellagitannins on a range of cardiometabolic risk biomarkers. The potential influence of various demographic and lifestyle factors on the variability in the response to these products were explored. Both anthocyanin- and ellagitannin-containing products reduced total cholesterol with nuts and berries yielding more significant effects than pomegranate and grapes. Blood pressure was significantly reduced by the two main sources of anthocyanins, berries and red grapes/wine, whereas waist circumference, LDL-cholesterol, triglycerides, and glucose were most significantly lowered by the ellagitannin-products, particularly nuts. Additionally, we found an indication of a small increase in HDL-cholesterol most significant with nuts and, in flow-mediated dilation by nuts and berries. Most of these effects were detected in obese/overweight people but we found limited or non-evidence in normoweight individuals or of the influence of sex or smoking status. The effects of other factors, i.e., habitual diet, health status or country where the study was conducted, were inconsistent and require further investigation. PMID- 29495647 TI - Redox Cycling Realized in Paper-Based Biochemical Sensor for Selective Detection of Reversible Redox Molecules Without Micro/Nano Fabrication Process. AB - This paper describes a paper-based biochemical sensor that realizes redox cycling with close interelectrode distance. Two electrodes, the generator and collector electrodes, can detect steady-state oxidation and reduction currents when suitable potential is held at each electrode. The sensor has two gold plates on both sides of a piece of chromatography paper and defines the interelectrode distance by the thickness of the paper (180 MUm) without any micro-fabrication processes. Our proposed sensor geometry has successfully exhibited signatures of redox cycling. As a result, the concentration of ferrocyanide as reversible redox molecules was successfully quantified under the interference by ascorbic acid as a strong irreversible reducing agent. This was possible because the ascorbic acids are completely consumed by the irreversible reaction, while maintaining redox cycling of reversible ferrocyanide. This suggests that a sensor based on the redox cycling method will be suitable for detecting target molecules at low concentration. PMID- 29495645 TI - Sensing Magnetic Fields with Magnetosensitive Ion Channels. AB - [-15]Magnetic nanoparticles are met across many biological species ranging from magnetosensitive bacteria, fishes, bees, bats, rats, birds, to humans. They can be both of biogenetic origin and due to environmental contamination, being either in paramagnetic or ferromagnetic state. The energy of such naturally occurring single-domain magnetic nanoparticles can reach up to 10-20 room k B T in the magnetic field of the Earth, which naturally led to supposition that they can serve as sensory elements in various animals. This work explores within a stochastic modeling framework a fascinating hypothesis of magnetosensitive ion channels with magnetic nanoparticles serving as sensory elements, especially, how realistic it is given a highly dissipative viscoelastic interior of living cells and typical sizes of nanoparticles possibly involved. PMID- 29495648 TI - Event-Triggered Fault Estimation for Stochastic Systems over Multi-Hop Relay Networks with Randomly Occurring Sensor Nonlinearities and Packet Dropouts. AB - Wireless sensors have many new applications where remote estimation is essential. Considering that a remote estimator is located far away from the process and the wireless transmission distance of sensor nodes is limited, sensor nodes always forward data packets to the remote estimator through a series of relays over a multi-hop link. In this paper, we consider a network with sensor nodes and relay nodes where the relay nodes can forward the estimated values to the remote estimator. An event-triggered remote estimator of state and fault with the corresponding data-forwarding scheme is investigated for stochastic systems subject to both randomly occurring nonlinearity and randomly occurring packet dropouts governed by Bernoulli-distributed sequences to achieve a trade-off between estimation accuracy and energy consumption. Recursive Riccati-like matrix equations are established to calculate the estimator gain to minimize an upper bound of the estimator error covariance. Subsequently, a sufficient condition and data-forwarding scheme are presented under which the error covariance is mean square bounded in the multi-hop links with random packet dropouts. Furthermore, implementation issues of the theoretical results are discussed where a new data forwarding communication protocol is designed. Finally, the effectiveness of the proposed algorithms and communication protocol are extensively evaluated using an experimental platform that was established for performance evaluation with a sensor and two relay nodes. PMID- 29495650 TI - In Vitro Antimicrobial Activity of Gel Containing the Herbal Ball Extract against Propionibacterium acnes. AB - The herbal ball has been used as a Thai traditional medicine for relieving many diseases including acne. However, the application process of the herbal ball in practice is complicated and time consuming. The objective of this work was to utilize an herbal ball extract to formulate a gel to reach a more favorable use of the herbal ball for acne treatment. An herbal ball consisting of Andrographis paniculata, Centella asiatica, the Benchalokawichian remedy and the stem bark powder of Hesperethusa crenulata was prepared. The obtained herbal ball was steamed and squeezed to obtain the extract. Gel formulations containing the herbal ball extract at concentrations of 0.1, 1 and 5% w/w were prepared based on a carbomer gel. The herbal ball extract had antioxidant (EC50 = 219.27 +/- 36.98 MUg/mL) and anti Propionibacterium acnes activities (minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) = 31.25 MUg/mL). The 5% w/w gel formulation had antimicrobial activity against P. acnes, showing an inhibition zone value of 10.00 +/- 1.00 mm. This indicates that the developed gel formulation has potential for acne treatment. In comparison to the traditional method of herbal ball usage, the application of herbal ball extract in the form of gel should be more convenient to use. PMID- 29495649 TI - Application and Comparative Evaluation of Fluorescent Antibody, Immunohistochemistry and Reverse Transcription Polymerase Chain Reaction Tests for the Detection of Rabies Virus Antigen or Nucleic Acid in Brain Samples of Animals Suspected of Rabies in India. AB - Accurate and early diagnosis of animal rabies is critical for undertaking public health measures. Whereas the direct fluorescent antibody (DFA) technique is the recommended test, the more convenient, direct rapid immunochemistry test (dRIT), as well as the more sensitive, reverse transcription polymerase chain reaction (RT-PCR), have recently been employed for the laboratory diagnosis of rabies. We compared the three methods on brain samples from domestic (dog, cat, cattle, buffalo, horse, pig and goat) and wild (leopard, wolf and jackal) animals from various parts of India. Of the 257 samples tested, 167 were positive by all the three tests; in addition, 35 of the 36 decomposed samples were positive by RT PCR. This is the first study in which such large number of animal samples have been subjected to the three tests simultaneously. The results confirm 100% corroboration between DFA and dRIT, buttress the applicability of dRIT in the simple and rapid diagnosis of rabies in animals, and reaffirm the suitability of RT-PCR for samples unfit for testing either by DFA or dRIT. PMID- 29495651 TI - Intrauterine Transmission of Anaplasma phagocytophilum in Persistently Infected Lambs. AB - Anaplasma phagocytophilum, which causes the disease tick-borne fever (TBF), is the most important tick-borne pathogen in European animals. TBF may contribute to severe welfare challenges and economic losses in the Norwegian sheep industry. The bacterium causes a persistent infection in sheep and several other animal species. The objective of this study was to investigate whether intrauterine transmission occurs in persistently infected sheep. The study included thirteen 5 6-month-old unmated ewes, of which twelve were experimentally infected with A. phagocytophilum (GenBank acc. no. M73220). Four to six weeks later, all ewes were mated, and nine became pregnant. Blood samples were collected from these ewes and their offspring. If the lamb died, tissue samples were collected. The samples were analyzed with real-time PCR (qPCR) targeting the msp2 gene. PCR-positive samples were further analyzed by semi-nested PCR and 16S rDNA sequencing. A total of 20 lambs were born, of which six died within two days. Six newborn lambs (30%) were PCR-positive (qPCR), of which one was verified by 16S rDNA sequencing. The present study indicates that intrauterine transmission of A. phagocytophilum in persistently infected sheep may occur. The importance of these findings for the epidemiology of A. phagocytophilum needs to be further investigated. PMID- 29495653 TI - Effects of Topical Anaesthetic and Buccal Meloxicam Treatments on Concurrent Castration and Dehorning of Beef Calves. AB - The use of pain relief during castration and dehorning of calves on commercial beef operations can be limited by constraints associated with the delivery of analgesic agents. As topical anaesthetic (TA) and buccal meloxicam (MEL) are now available in Australia, offering practical analgesic treatments for concurrent castration and dehorning of beef calves, a study was conducted to determine their efficacy in providing pain relief when applied separately or in combination. Weaner calves were randomly allocated to; (1) no castration and dehorning/positive control (CONP); (2) castration and dehorning/negative control (CONN); (3) castration and dehorning with buccal meloxicam (BM); (4) castration and dehorning with topical anaesthetic (TA); and (5) castration and dehorning with buccal meloxicam and topical anaesthetic (BMTA). Weight gain, paddock utilisation, lying activity and individual behaviours following treatment were measured. CONP and BMTA calves had significantly greater weight gain than CONN calves (p < 0.001). CONN calves spent less time lying compared to BMTA calves on all days (p < 0.001). All dehorned and castrated calves spent more time walking (p = 0.024) and less time eating (p < 0.001) compared to CONP calves. There was a trend for CONP calves to spend the most time standing and CONN calves to spend the least time standing (p = 0.059). There were also trends for the frequency of head turns to be lowest in CONP and BMTA calves (p = 0.098) and tail flicks to be highest in CONN and BM calves (p = 0.061). The findings of this study suggest that TA and MEL can potentially improve welfare and production of calves following surgical castration and amputation dehorning. PMID- 29495655 TI - Single-blind randomized clinical trial on the efficacy of an interdental cleaning device in orthodontic patients. AB - BACKGROUND: It is well-known that poor oral hygiene during orthodontic treatment may lead to development of gingivitis, probing pocket depth, hyperplastic tissue, decalcification, dental caries and white spot lesions on the coronal surfaces of teeth. METHODS: Twenty-two patients with the following inclusion criteria were enrolled in the present study: fixed orthodontic treatment, age 12-18 years, systemically healthy, no history of periodontal treatment, periodontal health or gingivitis. The following clinical parameters were collected: periodontal screening and recording, plaque control record, and bleeding on probing. Oral hygiene instructions were given and a specifically designed technique for orthodontic patients was suggested. Complete information about the mechanical interdental device were also provided. Means and standard deviations or medians and interquartile ranges for each parameter were collected. RESULTS: There was a statistically significant reduction in plaque control record on both sides. The reduction in the experimental group was significantly greater compared to controls after adjusting for baseline values. There was also a statistically significant reduction in bleeding on probing in the experiment group, but not in controls. CONCLUSIONS: The combination of manual toothbrush and mechanical interdental device demonstrated a better plaque control and gingival inflammation levels in orthodontic patients compared to manual brushing alone. PMID- 29495656 TI - Isotope Dilution Mass Spectrometry for Highly Precise Determination of Dissolved Inorganic Carbon in Seawater Aiming at Climate Change Studies. AB - Dissolved inorganic carbon (DIC) is one of the most important parameters to be measured in seawaters for climate change studies. Its quantitative assessment requires analytical methodologies with overall uncertainties around 0.05% RSD for clear evaluation of temporal trends. Herein, two alternative isotope dilution mass spectrometry (IDMS) methodologies (online and species-specific) using an isotope ratio mass spectrometer (IRMS) and two calculation procedures for each methodology have been compared. As a result, a new method for the determination of DIC in seawaters, based on species-specific IDMS with isotope pattern deconvolution calculation, was developed and validated. A 13C-enriched bicarbonate tracer was added to the sample and, after equilibration and acidification, the isotope abundances at CO2 masses 44, 45, and 46 were measured on an IRMS instrument. Notably, early spiking allows correcting for evaporations and/or adsorptions during sample preparation and storage and could be carried out immediately after sampling. Full uncertainty budgets were calculated taking into account all the factors involved in the determination (initial weights, concentration and isotope abundances of standards, and final IRMS measurements). The average DIC value obtained for CRM seawater agreed very well with the certified value. Propagated precision obtained ranged from 0.035 to 0.050% RSD for individual sample triplicates. Reproducibility, assessed by three independent experiments carried out in different working days, was excellent as well (-0.01% and 0.057%, error and full combined uncertainty, respectively). Additionally, the approach proposed improves on established methods by simplicity, higher throughput (15 min per sample), and lower volume requirements (10 mL). PMID- 29495657 TI - Analytical Interfacial Layer Model for the Capacitance and Electrokinetics of Charged Aqueous Interfaces. AB - We construct an analytical model to account for the influence of the subnanometer wide interfacial layer on the differential capacitance and the electro-osmotic mobility of solid-electrolyte interfaces. The interfacial layer is incorporated into the Poisson-Boltzmann and Stokes equations using a box model for the dielectric properties, the viscosity, and the ionic potential of mean force. We calculate the differential capacitance and the electro-osmotic mobility as a function of the surface charge density and the salt concentration, both with and without steric interactions between the ions. We compare the results from our theoretical model with experimental data on a variety of systems (graphite and metallic silver for capacitance and titanium oxide and silver iodide for electro osmotic data). The differential capacitance of silver as a function of salinity and surface charge density is well reproduced by our theory, using either the width of the interfacial layer or the ionic potential of mean force as the only fitting parameter. The differential capacitance of graphite, however, needs an additional carbon capacitance to explain the experimental data. Our theory yields a power-law dependence of the electro-osmotic mobility on the surface charge density for high surface charges, reproducing the experimental data using both the interfacial parameters extracted from molecular dynamics simulations and fitted interfacial parameters. Finally, we examine different types of hydrodynamic boundary conditions for the power-law behavior of the electro osmotic mobility, showing that a finite-viscosity layer explains the experimental data better than the usual hydrodynamic slip boundary condition. Our analytical model thus allows us to extract the properties of the subnanometer-wide interfacial layer by fitting to macroscopic experimental data. PMID- 29495658 TI - Isotope Fractionation Pinpoints Membrane Permeability as a Barrier to Atrazine Biodegradation in Gram-negative Polaromonas sp. Nea-C. AB - Biodegradation of persistent pesticides like atrazine often stalls at low concentrations in the environment. While mass transfer does not limit atrazine degradation by the Gram-positive Arthrobacter aurescens TC1 at high concentrations (>1 mg/L), evidence of bioavailability limitations is emerging at trace concentrations (<0.1 mg/L). To assess the bioavailability constraints on biodegradation, the roles of cell wall physiology and transporters remain imperfectly understood. Here, compound-specific isotope analysis (CSIA) demonstrates that cell wall physiology (i.e., the difference between Gram negative and Gram-positive bacteria) imposes mass transfer limitations in atrazine biodegradation even at high concentrations. Atrazine biodegradation by Gram-negative Polaromonas sp. Nea-C caused significantly less isotope fractionation (epsilon(C) = -3.5 0/00) than expected for hydrolysis by the enzyme TrzN (epsilon(C) = -5.0 0/00) and observed in Gram-positive Arthrobacter aurescens TC1 (epsilon(C) = -5.4 0/00). Isotope fractionation was recovered in cell-free extracts (epsilon(C) = -5.3 0/00) where no cell envelope restricted pollutant uptake. When active transport was inhibited with cyanide, atrazine degradation rates remained constant demonstrating that atrazine mass transfer across the cell envelope does not depend on active transport but is a consequence of passive cell wall permeation. Taken together, our results identify the cell envelope of the Gram-negative bacterium Polaromonas sp. Nea-C as a relevant barrier for atrazine biodegradation. PMID- 29495659 TI - Polymer Inclusion Membrane as an Effective Sorbent To Facilitate Mercury Storage and Detection by X-ray Fluorescence in Natural Waters. AB - A novel and simple method is presented for the preconcentration and determination of mercury (Hg) from natural waters through its extraction into a polymer inclusion membrane (PIM) containing the task-specific ionic liquid trioctylmethylammonium thiosalicylate (TOMATS) followed by Energy Dispersive X ray fluorescence (EDXRF) analysis. The determination was made directly on the membrane without any treatment or elution step, and due to the characteristics of the PIM no matrix or thickness corrections were required in EDXRF analysis. Under the best extracting and EDXRF operating conditions, a Hg limit of detection of 0.2 MUg Hg L-1 was obtained. Moreover, no water matrix effect was observed when Hg was extracted from different types of water such as river, seawater, groundwater, and tap water, showing this extraction system as a global solution when dealing with natural waters. Interestingly, this Hg collected in the PIM has shown to be stable for at least 6 months without the use of any preservative. This fact is of prime importance taking into account the usual stability problems of Hg during sample storage. PMID- 29495660 TI - An Image Auxiliary Method for Quantitative Analysis of Laser-Induced Breakdown Spectroscopy. AB - Improving both the stability and accuracy of laser-induced breakdown spectroscopy (LIBS) is an issue in quantitative analysis. For certain environments outside of the laboratory, consistently and exactly maintaining the distance from the optical system to the sample surface is difficult, and fluctuations of this distance severely affect the stability of the spectrum. In this work, the principal components of the plasma images are extracted and used to correct the spectral line intensities as an auxiliary method to reduce spectral fluctuation. The presented image auxiliary method is combined with univariate analysis and multivariate analysis, and the element concentrations of Cu, Mn, V, and Cr in steel samples are analyzed. For univariate analysis, all the determination coefficients ( R2) of the four elements exceed 0.99, whereas the average relative standard deviations (RSDs) of the intensities decrease from 30.45, 23.14, 27.03, and 22.04%, to 2.13, 3.38, 2.49, and 3.58%, respectively. For the multivariate analysis, the R2 values for Cu, Mn, V, and Cr also all exceed 0.99, and the average RSDs of the predicted concentrations of the validation samples decrease to 2.87, 3.82, 2.86, and 6.51%, respectively. PMID- 29495652 TI - Carbonic Anhydrases: Role in pH Control and Cancer. AB - The pH of the tumor microenvironment drives the metastatic phenotype and chemotherapeutic resistance of tumors. Understanding the mechanisms underlying this pH-dependent phenomenon will lead to improved drug delivery and allow the identification of new therapeutic targets. This includes an understanding of the role pH plays in primary tumor cells, and the regulatory factors that permit cancer cells to thrive. Over the last decade, carbonic anhydrases (CAs) have been shown to be important mediators of tumor cell pH by modulating the bicarbonate and proton concentrations for cell survival and proliferation. This has prompted an effort to inhibit specific CA isoforms, as an anti-cancer therapeutic strategy. Of the 12 active CA isoforms, two, CA IX and XII, have been considered anti-cancer targets. However, other CA isoforms also show similar activity and tissue distribution in cancers and have not been considered as therapeutic targets for cancer treatment. In this review, we consider all the CA isoforms and their possible role in tumors and their potential as targets for cancer therapy. PMID- 29495661 TI - Molecular depth profiling on rat brain tissue sections prepared using different sampling methods. AB - Brain imaging using time-of-flight secondary ion mass spectrometry (ToF-SIMS) has been reported to produce the distorted biomolecular distributions due to the cholesterol-induced matrix effect when cholesterol migrates to the surface, particularly in white matter, which contains a high level of cholesterol. Frozen hydrated analysis has been used to inhibit the movement of cholesterol in the brain. In this paper, the authors propose new sample preparation and drying methods that can be used to obtain accurate biomolecular images at room temperature, instead of frozen-hydrated analysis using liquid-nitrogen, which must be continuously supplied to maintain the sample at -160 degrees C during the experiment. The rat brain prepared by the tape-supporting method on a precooled (-20 degrees C) stainless steel plate was freeze-dried in a load-lock chamber of ToF-SIMS for about an hour and moved directly to the main chamber. Using this preparation method, the authors found that cholesterol did not migrate to the surface in the corpus callosum (white matter) of the rat brain and sulfatide-related signals obtained from the cerebellum were not reduced in white matter. Our tape-supporting and freeze-drying sampling method for brain tissues could be a useful tool to study important metabolites of neurodegenerative diseases. PMID- 29495654 TI - The Enigmatic Alphavirus Non-Structural Protein 3 (nsP3) Revealing Its Secrets at Last. AB - Alphaviruses encode 4 non-structural proteins (nsPs), most of which have well understood functions in capping and membrane association (nsP1), polyprotein processing and RNA helicase activity (nsP2) and as RNA-dependent RNA polymerase (nsP4). The function of nsP3 has been more difficult to pin down and it has long been referred to as the more enigmatic of the nsPs. The protein comprises three domains, an N-terminal macro domain, a central zinc-binding domain and a C terminal hypervariable domain (HVD). In this article, we review old and new literature about the functions of the three domains. Much progress in recent years has contributed to a picture of nsP3, particularly through its HVD as a hub for interactions with host cell molecules, with multiple effects on the biology of the host cell at early points in infection. These and many future discoveries will provide targets for anti-viral therapies as well as strategies for modification of vectors for vaccine and oncolytic interventions. PMID- 29495662 TI - Controlling chaotic spin-motion entanglement of ultracold atoms via spin-orbit coupling. AB - We study the spatially chaoticity-dependent spin-motion entanglement of a spin orbit (SO) coupled Bose-Einstein condensate with a source of ultracold atoms held in an optical superlattice. In the case of phase synchronization, we analytically demonstrate that (a) the SO coupling (SOC) leads to the generation of spin-motion entanglement; (b) the area of the high-chaoticity parameter region inversely relates to the SOC strength which renormalizes the chemical potential; and (c) the high-chaoticity is associated with the lower chemical potential and the larger ratio of the short-lattice depth to the longer-lattice depth. Then, we numerically generate the Poincare sections to pinpoint that the chaos probability is enhanced with the decrease in the SOC strength and/or the spin-dependent current components. The existence of chaos is confirmed by computing the corresponding largest Lyapunov exponents. For an appropriate lattice depth ratio, the complete stop of one of (or both) the current components is related to the full chaoticity. The results mean that the weak SOC and/or the small current components can enhance the chaoticity. Based on the insensitivity of chaos probability to initial conditions, we propose a feasible scheme to manipulate the ensemble of chaotic spin-motion entangled states, which may be useful in coherent atom optics with chaotic atom transport. PMID- 29495663 TI - Clustering promotes switching dynamics in networks of noisy neurons. AB - Macroscopic variability is an emergent property of neural networks, typically manifested in spontaneous switching between the episodes of elevated neuronal activity and the quiescent episodes. We investigate the conditions that facilitate switching dynamics, focusing on the interplay between the different sources of noise and heterogeneity of the network topology. We consider clustered networks of rate-based neurons subjected to external and intrinsic noise and derive an effective model where the network dynamics is described by a set of coupled second-order stochastic mean-field systems representing each of the clusters. The model provides an insight into the different contributions to effective macroscopic noise and qualitatively indicates the parameter domains where switching dynamics may occur. By analyzing the mean-field model in the thermodynamic limit, we demonstrate that clustering promotes multistability, which gives rise to switching dynamics in a considerably wider parameter region compared to the case of a non-clustered network with sparse random connection topology. PMID- 29495664 TI - Phenomenology of coupled nonlinear oscillators. AB - A recently introduced model of coupled nonlinear oscillators in a ring is revisited in terms of its information processing capabilities. The use of Lempel Ziv based entropic measures allows to study thoroughly the complex patterns appearing in the system for different values of the control parameters. Such behaviors, resembling cellular automata, have been characterized both spatially and temporally. Information distance is used to study the stability of the system to perturbations in the initial conditions and in the control parameters. The latter is not an issue in cellular automata theory, where the rules form a numerable set, contrary to the continuous nature of the parameter space in the system studied in this contribution. The variation in the density of the digits, as a function of time is also studied. Local transitions in the control parameter space are also discussed. PMID- 29495665 TI - Comment on "A unifying view of synchronization for data assimilation in complex nonlinear networks" [Chaos 27(12), 126802 (2017)]. PMID- 29495666 TI - Wavefront cellular learning automata. AB - This paper proposes a new cellular learning automaton, called a wavefront cellular learning automaton (WCLA). The proposed WCLA has a set of learning automata mapped to a connected structure and uses this structure to propagate the state changes of the learning automata over the structure using waves. In the WCLA, after one learning automaton chooses its action, if this chosen action is different from the previous action, it can send a wave to its neighbors and activate them. Each neighbor receiving the wave is activated and must choose a new action. This structure for the WCLA is necessary in many dynamic areas such as social networks, computer networks, grid computing, and web mining. In this paper, we introduce the WCLA framework as an optimization tool with diffusion capability, study its behavior over time using ordinary differential equation solutions, and present its accuracy using expediency analysis. To show the superiority of the proposed WCLA, we compare the proposed method with some other types of cellular learning automata using two benchmark problems. PMID- 29495667 TI - Ionic wave propagation and collision in an excitable circuit model of microtubules. AB - In this paper, we report the propensity to excitability of the internal structure of cellular microtubules, modelled as a relatively large one-dimensional spatial array of electrical units with nonlinear resistive features. We propose a model mimicking the dynamics of a large set of such intracellular dynamical entities as an excitable medium. We show that the behavior of such lattices can be described by a complex Ginzburg-Landau equation, which admits several wave solutions, including the plane waves paradigm. A stability analysis of the plane waves solutions of our dynamical system is conducted both analytically and numerically. It is observed that perturbed plane waves will always evolve toward promoting the generation of localized periodic waves trains. These modes include both stationary and travelling spatial excitations. They encompass, on one hand, localized structures such as solitary waves embracing bright solitons, dark solitons, and bisolitonic impulses with head-on collisions phenomena, and on the other hand, the appearance of both spatially homogeneous and spatially inhomogeneous stationary patterns. This ability exhibited by our array of proteinic elements to display several states of excitability exposes their stunning biological and physical complexity and is of high relevance in the description of the developmental and informative processes occurring on the subcellular scale. PMID- 29495668 TI - Diversity of hysteresis in a fully cooperative coinfection model. AB - We propose a fully cooperative coinfection model in which singly infected individuals are more likely to acquire a second disease than susceptible ones and doubly infected individuals are also assumed to be more contagious than singly infected ones. The dynamics of such a fully cooperative coinfection model is investigated through the well-mixed approach. In particular, discontinuous outbreak transitions from the disease free state or the low prevalence state to the high prevalence state can be separately observed as a disease transmission rate crosses a threshold alphao from the below when the epidemic is still in the early stages. Moreover, discontinuous eradications from the high prevalence state to the low prevalence or disease free state are also separately seen as the transmission rate reaches a threshold alphae(1, transitions dynamical characteristics of the reacting wake from a linearly globally stable (or convectively unstable) to a globally unstable mode. In this paper, we propose a framework to analyze the effect of harmonic forcing on the deterministic and synchronization characteristics of reacting wakes. Using the recurrence quantification analysis of the forced wake response, we show that the deterministic behaviour of the reacting wake increases as the amplitude of forcing is increased. Furthermore, for different density ratios, we found that the synchronization of the top and bottom branches of the wake with the forcing signal is dependent on whether the mean frequency of the natural oscillations of the wake (fn) is lesser or greater than the frequency of external forcing (ff). We notice that the response of both branches (top and bottom) of the reacting wake to the external forcing is asymmetric and symmetric for the low and high density ratios, respectively. Furthermore, we characterize the phase-locking behaviour between the top and bottom branches of the wake for different values of density ratios. We observe that an increase in the density ratio results in a gradual decrease in the relative phase angle between the top and bottom branches of the wake, which leads to a change in the vortex shedding pattern from a sinuous (anti-phase) to a varicose (in-phase) mode of the oscillations. PMID- 29495680 TI - Propagation of transition fronts in nonlinear chains with non-degenerate on-site potentials. AB - We address the problem of transition front propagation in chains with a bi-stable nondegenerate on-site potential and a nonlinear gradient coupling. For generic nonlinear coupling, one encounters a special regime of transitions, characterized by extremely narrow fronts, far supersonic velocities of the front propagation, and long waves in the oscillatory tail. This regime can be qualitatively associated with a shock wave. The front propagation can be described with the help of a simple reduced-order model; the latter delivers a kinetic law, which is almost not sensitive to the fine details of the on-site potential. Besides, it is possible to predict all main characteristics of the transition front, including its velocity, as well as the frequency and the amplitude of the oscillatory tail. Numerical results are in good agreement with the analytical predictions. The suggested approach allows one to consider the effects of an external pre-load, the next-nearest-neighbor coupling and the on-site damping. When the damping is moderate, it is possible to consider the shock propagation in the damped chain as a perturbation of the undamped dynamics. This approach yields reasonable predictions. When the damping is high, the transition front enters a completely different asymptotic regime of a subsonic kink. The gradient nonlinearity generically turns negligible, and the propagating front converges to the regime described by a simple exact solution for a continuous model with linear coupling. PMID- 29495681 TI - The role of unfamiliar accents in competing speech. AB - A listeners' ability to comprehend one speaker against a background of other speech-a phenomenon dubbed the cocktail party problem-varies according to the properties of the speech streams and the listener. Although a number of factors that contribute to a listener's ability to successfully segregate two simultaneous speech signals have been identified, comparably little work has focused on the role accents may play in this process. To this end, familiar Canadian-accented voices and unfamiliar British-accented voices were used in a competing talker task. Native speakers of Canadian English heard two different talkers simultaneously read sentences in the form of "[command] [colour] [preposition] [letter] [number] [adverb]" (e.g., "Lay blue at C4 now") and reported the coordinate from a target talker. Results indicate that on all but the most challenging trials, listeners did best when attending to an unfamiliar accented target against a familiarly-accented masker and performed worse when forced to ignore the unfamiliar accent. These results suggest listeners can easily tune out a familiar accent, but are unable to do the same with an unfamiliar accent, indicating that unfamiliar accents are more effective maskers. PMID- 29495682 TI - Rate modulation detection thresholds for cochlear implant users. AB - The perception of temporal amplitude modulations is critical for speech understanding by cochlear implant (CI) users. The present study compared the ability of CI users to detect sinusoidal modulations of the electrical stimulation rate and current level, at different presentation levels (80% and 40% of the dynamic range) and modulation frequencies (10 and 100 Hz). Rate modulation detection thresholds (RMDTs) and amplitude modulation detection thresholds (AMDTs) were measured and compared to assess whether there was a perceptual advantage to either modulation method. Both RMDTs and AMDTs improved with increasing presentation level and decreasing modulation frequency. RMDTs and AMDTs were correlated, indicating that a common processing mechanism may underlie the perception of rate modulation and amplitude modulation, or that some subject dependent factors affect both types of modulation detection. PMID- 29495683 TI - Inducing a nonreflective airborne discontinuity in a circular duct by using a nonresonant side branch to create mode complexity. AB - A nonreflective airborne discontinuity is created in a one-dimensional rigid walled duct when the mode complexity introduced by a nonresonant side branch reaches a maximum, so that a sound wave can be spatially separated into physical regions of traveling and standing waves. The nonresonance of the side branch is demonstrated, the mode complexity is quantified, and a computational method to optimize side-branch parameters to maximize mode complexity in the duct in the presence of three-dimensional effects is presented. The optimal side-branch parameters that maximize the mode complexity and thus minimize reflection are found using finite element analysis and a derivative-free optimization routine. Sensitivity of mode complexity near the optimum with respect to side-branch parameters is then examined. The results show reflection from the impedance discontinuity in the duct can be reduced nearly to zero, providing a practical means of achieving a nonreflective discontinuity for a plane wave propagating in a duct of finite length. PMID- 29495684 TI - Talkers produce more pronounced amplitude modulations when speaking in noise. AB - Speakers adjust their voice when talking in noise (known as Lombard speech), facilitating speech comprehension. Recent neurobiological models of speech perception emphasize the role of amplitude modulations in speech-in-noise comprehension, helping neural oscillators to "track" the attended speech. This study tested whether talkers produce more pronounced amplitude modulations in noise. Across four different corpora, modulation spectra showed greater power in amplitude modulations below 4 Hz in Lombard speech compared to matching plain speech. This suggests that noise-induced speech contains more pronounced amplitude modulations, potentially helping the listening brain to entrain to the attended talker, aiding comprehension. PMID- 29495685 TI - Stereotypic and complex phrase types provide structural evidence for a multi message display in humpback whales (Megaptera novaeangliae). AB - Male humpback whales produce a mating display called "song." Behavioral studies indicate song has inter- and/or intra-sexual functionality, suggesting song may be a multi-message display. Multi-message displays often include stereotypic components that convey group membership for mate attraction and/or male-male interactions, and complex components that convey individual quality for courtship. Humpback whale song contains sounds ("units") arranged into sequences ("phrases"). Repetitions of a specific phrase create a "theme." Within a theme, imperfect phrase repetitions ("phrase variants") create variability among phrases of the same type ("phrase type"). The hypothesis that song contains stereotypic and complex phrase types, structural characteristics consistent with a multi message display, is investigated using recordings of 17 east Australian males (8:2004, 9:2011). Phrase types are categorized as stereotypic or complex using number of unit types, number of phrase variants, and the proportion of phrases that is unique to an individual versus shared amongst males. Unit types are determined using self-organizing maps. Phrase variants are determined by Levenshtein distances between phrases. Stereotypic phrase types have smaller numbers of unit types and shared phrase variants. Complex phrase types have larger numbers of unit types and unique phrase variants. This study supports the hypothesis that song could be a multi-message display. PMID- 29495686 TI - Hydrostatic measurement and finite element simulation of the compliance of the organ of Corti complex. AB - In the mammalian cochlea, the geometrical and mechanical properties of the organ of Corti complex (OCC, consisting of the tectorial membrane, the organ of Corti, and the basilar membrane) have fundamental consequences for understanding the physics of hearing. Despite efforts to correlate the mechanical properties of the OCC with cochlear function, experimental data of OCC stiffness are limited due to difficulties in measurement. Modern measurements of the OCC stiffness use microprobes exclusively, but suffer ambiguity when defining the physiologically relevant stiffness due to the high nonlinearity in the force-displacement relationship. The nonlinearity stems from two sources. First, microprobes apply local force instead of fluid pressure across the OCC. Second, to obtain the functionally relevant stiffness, the OCC is deformed well beyond in vivo levels (>10 MUm). The objective of this study was to develop an alternative technique to overcome challenges intrinsic to the microprobe method. Using a custom-designed microfluidic chamber system, hydrostatic pressures were applied to the excised gerbil cochlea. Deformations of the OCC due to hydrostatic pressures were analyzed through optical-axis image correlation. The pressure-displacement relationship was linear within nanoscale displacement ranges (<1 MUm). To compare the results in this paper with existing measurements, a three-dimensional finite element model was used. PMID- 29495687 TI - A systematic method for isolating, tracking and discriminating time-frequency components of bat echolocation calls. AB - Echolocating bats can rapidly modify frequency modulation (FM) curvatures of their calls when facing challenging echolocation tasks. Frequency parameters, such as start/end/peak frequency, have often been extracted from the time frequency domain to study the call variation. Even though this kind of signal investigation method reveals important findings, these approaches to analyze bat echolocation calls use bulk parameters, which hide subtleties in the call structure that may be important to the bat. In some cases, calls can have the same start and end frequencies but have different FM curvatures, and subsequently may influence the sensory task performance. In the present study, the authors demonstrate an algorithm using a combination of digital filters, power limited time-frequency information, derivative dynamic time warping, and agglomerative hierarchical clustering to extract and categorize the time-frequency components (TFCs) of 21 calls from Brazilian free-tailed bat (Tadarida brasiliensis) to quantitatively compare FM curvatures. The detailed curvature analysis shows an alternative perspective to look into the TFCs and hence serves as the preliminary step to understand the adaptive call design of bats. PMID- 29495688 TI - Reverberation enhances onset dominance in sound localization. AB - Temporal variation in sensitivity to sound-localization cues was measured in anechoic conditions and in simulated reverberation using the temporal weighting function (TWF) paradigm [Stecker and Hafter (2002). J. Acoust. Soc. Am. 112, 1046 1057]. Listeners judged the locations of Gabor click trains (4 kHz center frequency, 5-ms interclick interval) presented from an array of loudspeakers spanning 360 degrees azimuth. Targets ranged +/-56.25 degrees across trials. Individual clicks within each train varied by an additional +/-11.25 degrees to allow TWF calculation by multiple regression. In separate conditions, sounds were presented directly or in the presence of simulated reverberation: 13 orders of lateral reflection were computed for a 10 m * 10 m room ( RT60?300 ms) and mapped to the appropriate locations in the loudspeaker array. Results reveal a marked increase in perceptual weight applied to the initial click in reverberation, along with a reduction in the impact of late-arriving sound. In a second experiment, target stimuli were preceded by trains of "conditioner" sounds with or without reverberation. Effects were modest and limited to the first few clicks in a train, suggesting that impacts of reverberant pre-exposure on localization may be limited to the processing of information from early reflections. PMID- 29495689 TI - Temporal weighting functions for interaural time and level differences. V. Modulated noise carriers. AB - Sound onsets dominate spatial judgments of many types of periodic sound. Conversely, ongoing cues often dominate in spatial judgments of aperiodic noise. This study quantified onset dominance as a function of both the bandwidth and the temporal regularity of stimuli by measuring temporal weighting functions (TWF) from Stecker, Ostreicher, and Brown [(2013) J. Acoust. Soc. Am. 134, 1242-1252] for lateralization of periodic and aperiodic noise-burst trains. Stimuli consisted of 16 noise bursts (1 ms each) repeating at an interval of 2 or 5 ms. TWFs were calculated by multiple regression of lateralization judgments onto interaural time and level differences, which varied independently ( +/-100 MUs, +/-2 dB) across bursts. Noise tokens were either refreshed on each burst (aperiodic) or repeated across sets of 2, 4, 8, or 16 bursts. TWFs revealed strong onset dominance for periodic noise-burst trains (16 repeats per token), which was markedly reduced in aperiodic trains. A second experiment measured TWFs for periodic but sinusoidally amplitude-modulated noise burst trains, revealing greater weight on the earliest and least intense bursts of the rising envelope slope. The results support the view that envelope fluctuations drive access to binaural information in both periodic and aperiodic sounds. PMID- 29495690 TI - An approach for automatic classification of grouper vocalizations with passive acoustic monitoring. AB - Grouper, a family of marine fishes, produce distinct vocalizations associated with their reproductive behavior during spawning aggregation. These low frequencies sounds (50-350 Hz) consist of a series of pulses repeated at a variable rate. In this paper, an approach is presented for automatic classification of grouper vocalizations from ambient sounds recorded in situ with fixed hydrophones based on weighted features and sparse classifier. Group sounds were labeled initially by humans for training and testing various feature extraction and classification methods. In the feature extraction phase, four types of features were used to extract features of sounds produced by groupers. Once the sound features were extracted, three types of representative classifiers were applied to categorize the species that produced these sounds. Experimental results showed that the overall percentage of identification using the best combination of the selected feature extractor weighted mel frequency cepstral coefficients and sparse classifier achieved 82.7% accuracy. The proposed algorithm has been implemented in an autonomous platform (wave glider) for real time detection and classification of group vocalizations. PMID- 29495691 TI - Acoustic characteristics of highly distinguishable Cantonese entering and non entering tones. AB - Cantonese has one of the most complex tone systems. Few studies have thoroughly examined or compared the acoustic properties of the full set of Cantonese tones, particularly the entering tones, compromising deeper understanding of Cantonese tone difficulties in various clinical populations. This study (1) describes a theory-driven method for acoustic analysis of tones that successfully normalized the intrinsic pitch of male and female speakers, (2) provides detailed acoustic data on distinctly enunciated Cantonese tones, (3) examines the acoustic similarities and differences between the entering and non-entering tones, and (4) compares the acoustic properties of three easily confused tone pairs. Seventeen male and female native speakers produced 1802 Cantonese tones that were correctly identified by five judges in filtered stimuli. Counter to the established notion that the entering tones are shorter versions of the three level tones, the results revealed that the entering tones have falling contours, suggesting that the entering and non-entering tones should be examined separately in research and clinical settings. The detailed description of the acoustic properties of the nine tones and the acoustic contrasts of the entering and non-entering tones and the three easily confused tone pairs provides references for future Cantonese tone studies with different populations. PMID- 29495692 TI - Can monaural temporal masking explain the ongoing precedence effect? AB - The precedence effect for transient sounds has been proposed to be based primarily on monaural processes, manifested by asymmetric temporal masking. This study explored the potential for monaural explanations with longer ("ongoing") sounds exhibiting the precedence effect. Transient stimuli were single lead-lag noise burst pairs; ongoing stimuli were trains of 63 burst pairs. Unlike with transients, monaural masking data for ongoing sounds showed no advantage for the lead, and are inconsistent with asymmetric audibility as an explanation for ongoing precedence. This result, along with supplementary measurements of interaural time discrimination, suggests different explanations for transient and ongoing precedence. PMID- 29495694 TI - Source levels of foraging humpback whale calls. AB - Humpback whales produce a wide range of low- to mid-frequency vocalizations throughout their migratory range. Non-song "calls" dominate this species' vocal repertoire while on high-latitude foraging grounds. The source levels of 426 humpback whale calls in four vocal classes were estimated using a four-element planar array deployed in Glacier Bay National Park and Preserve, Southeast Alaska. There was no significant difference in source levels between humpback whale vocal classes. The mean call source level was 137 dBRMS re 1 MUPa @ 1 m in the bandwidth of the call (range 113-157 dBRMS re 1 MUPa @ 1 m), where bandwidth is defined as the frequency range from the lowest to the highest frequency component of the call. These values represent a robust estimate of humpback whale source levels on foraging grounds and should append earlier estimates. PMID- 29495693 TI - Talker identification: Effects of masking, hearing loss, and age. AB - The ability to identify who is talking is an important aspect of communication in social situations and, while empirical data are limited, it is possible that a disruption to this ability contributes to the difficulties experienced by listeners with hearing loss. In this study, talker identification was examined under both quiet and masked conditions. Subjects were grouped by hearing status (normal hearing/sensorineural hearing loss) and age (younger/older adults). Listeners first learned to identify the voices of four same-sex talkers in quiet, and then talker identification was assessed (1) in quiet, (2) in speech-shaped, steady-state noise, and (3) in the presence of a single, unfamiliar same-sex talker. Both younger and older adults with hearing loss, as well as older adults with normal hearing, generally performed more poorly than younger adults with normal hearing, although large individual differences were observed in all conditions. Regression analyses indicated that both age and hearing loss were predictors of performance in quiet, and there was some evidence for an additional contribution of hearing loss in the presence of masking. These findings suggest that both hearing loss and age may affect the ability to identify talkers in "cocktail party" situations. PMID- 29495695 TI - Design of an underwater acoustic bend by pentamode metafluid. AB - In this paper, an impedance matching underwater acoustic bend with pentamode microstructure is designed. The proposed bend is assembled by pentamode lattice. The effective density and compressive modulus of each unit cell can be tuned simultaneously, which are modulated to guarantee both the bending effect and high transmission. The standard deviations (SDs) of transmitted phase are calculated to quantitatively evaluate the degree of the distortion of the transmitted wavefront, while the transmission is calculated to appraise the degree of acoustic impedance matching. The low SDs and high transmission indicate that the designed bend has a nice broadband bending effect and is impedance-matched to water. This design has potential applications in underwater communication and underwater detection. PMID- 29495697 TI - Head waves in ocean acoustic ambient noise: Measurements and modeling. AB - Seismic interferometry recovers the Green's function between two receivers by cross-correlating the field measured from sources that surround the receivers. In the seismic literature, it has been widely reported that this processing can produce artifacts in the Green's function estimate called "spurious multiples" or the "virtual refracted wave." The spurious multiples are attributed to the head wave and its multiples and travels in the seabed. The head wave phenomenon is shown to be observable from both controlled active sources and from ocean ambient noise and for both vertical and horizontal arrays. The processing used is a generalization of the passive fathometer to produce cross-beam correlations. This passive fathometer is equivalent to the seismic interferometry techniques for delay and sum beamforming but not for adaptive beamforming. Modeling and experimental data show the head wave is observed in ocean noise and can be used to estimate the seabed sound speed. PMID- 29495696 TI - Auditory enhancement under simultaneous masking in normal-hearing and hearing impaired listeners. AB - Auditory enhancement, where a target sound within a masker is rendered more audible by the prior presentation of the masker alone, may play an important role in auditory perception under variable everyday acoustic conditions. Cochlear hearing loss may reduce enhancement effects, potentially contributing to the difficulties experienced by hearing-impaired (HI) individuals in noisy and reverberant environments. However, it remains unknown whether, and by how much, enhancement under simultaneous masking is reduced in HI listeners. Enhancement of a pure tone under simultaneous masking with a multi-tone masker was measured in HI listeners and age-matched normal-hearing (NH) listeners as function of the spectral notch width of the masker, using stimuli at equal sensation levels as well as at equal sound pressure levels, but with the stimuli presented in noise to the NH listeners to maintain the equal sensation level between listener groups. The results showed that HI listeners exhibited some enhancement in all conditions. However, even when conditions were made as comparable as possible, in terms of effective spectral notch width and presentation level, the enhancement effect in HI listeners under simultaneous masking was reduced relative to that observed in NH listeners. PMID- 29495698 TI - A steered response power approach with trade-off prewhitening for acoustic source localization. AB - This paper proposes a steered response power (SRP) approach with trade-off prewhitening to acoustic source localization. To obtain effective compromise prefiltering of microphone signals, the sparsity of speech amplitude spectrum is used to establish a convex-constraint linear prediction model, which is solved by a split Bregman method. The presented approach unifies the traditional SRP and steered response power via phase transform prefiltering methods and achieves a good compromise between them from the perspective of localization performance. The superiority of the proposed method is demonstrated in noisy and reverberant environments. PMID- 29495699 TI - Towards acoustic particle velocity sensors in air using entrained balloons: Measurements and modeling. AB - In this article, the feasibility of using balloons for the measurement of acoustic particle velocity in air is investigated by exploring the behavior of an elastic balloon in air as it vibrates in response to an incident acoustic wave. This is motivated by the frequent use of neutrally buoyant spheres as underwater inertial particle velocity sensors. The results of experiments performed in an anechoic chamber are presented, in which a pair of laser Doppler vibrometers simultaneously captured the velocities of the front and back surfaces of a Mylar balloon in an acoustic field. From phase measurements, the motion is described in terms of contributions from odd-order vibration modes (including bulk translation) and even-order vibration modes. The measured entrainment factors for the balloon are seen to be in good agreement with a physical model based on the scattering from an entrained rigid sphere. This demonstrates the feasibility of using entrained balloons for direct measurement of acoustic particle velocity in air. PMID- 29495700 TI - Analysis on the three-dimensional coupled vibration of composite cylindrical piezoelectric transducers. AB - Three-dimensional coupled vibration of the composite cylindrical piezoelectric transducer is analyzed. The composite cylindrical piezoelectric transducer consists of an inner axially polarized piezoelectric ceramic cylinder and an outer metal cylinder with the same height. Coupled vibration of the composite cylindrical piezoelectric transducer is analyzed by equivalent elasticity method, which is an approximate analytical approach. According to this method, coupled vibration of the cylindrical transducer is regarded as an interaction between a plane radial vibration and a longitudinal vibration. The radial and longitudinal electromechanical equivalent circuits of the piezoelectric transducer are acquired. Input impedances as functions of the resonance frequency and the mechanical coupling coefficient are derived to obtain resonance frequency equations. The analytical results are supported by experimental and numerical simulated results of two prototypes of the piezoelectric transducer. The composite cylindrical piezoelectric transducer presented in this paper is superior to single cylindrical piezoelectric transducers, composite ring-type, and tube-type transducers in the field of high output power and efficiency. PMID- 29495701 TI - On the realization of acoustic attenuation using a microperforated panel alone. AB - An attempt is made to achieve acoustic attenuation using a microperforated panel (MPP) without the commonly used backing air cavity. The underlying mechanism is the generation of the air motion inside the micropores as a result of the acoustic pressure difference on the two sides of the MPP. The acoustic environment in which such a mechanism is viable is found in a curved duct where the axial wavenumber below the cut-off frequency of the first dispersive mode is radius dependent. A MPP inserted into this duct results in an acoustic pressure difference on its two sides associated with the two sub-curved duct domains and enables the vibration of the air inside the micropores. Results show that energy is absorbed by the MPP and the effect extends over a broad frequency band and down to very low frequency. PMID- 29495702 TI - Erratum: Eigenfunction approach to the Green's function parabolic equation in outdoor sound: A tutorial [J. Acoust. Soc. Am. 139, 1071-1080 (2016)]. PMID- 29495704 TI - Review on the conversion of thermoacoustic power into electricity. AB - Thermoacoustic engines convert heat energy into high amplitude acoustic waves and subsequently into electric power. This article provides a review of the four main methods to convert the (thermo)acoustic power into electricity. First, loudspeakers and linear alternators are discussed in a section on electromagnetic devices. This is followed by sections on piezoelectric transducers, magnetohydrodynamic generators, and bidirectional turbines. Each segment provides a literature review of the given technology for the field of thermoacoustics, focusing on possible configurations, operating characteristics, output performance, and analytical and numerical methods to study the devices. This information is used as an input to discuss the performance and feasibility of each method, and to identify challenges that should be overcome for a more successful implementation in thermoacoustic engines. The work is concluded by a comparison of the four technologies, concentrating on the possible areas of application, the conversion efficiency, maximum electrical power output and more generally the suggested focus for future work in the field. PMID- 29495703 TI - Correspondence between sound propagation in discrete and continuous random media with application to forest acoustics. AB - Although sound propagation in a forest is important in several applications, there are currently no rigorous yet computationally tractable prediction methods. Due to the complexity of sound scattering in a forest, it is natural to formulate the problem stochastically. In this paper, it is demonstrated that the equations for the statistical moments of the sound field propagating in a forest have the same form as those for sound propagation in a turbulent atmosphere if the scattering properties of the two media are expressed in terms of the differential scattering and total cross sections. Using the existing theories for sound propagation in a turbulent atmosphere, this analogy enables the derivation of several results for predicting forest acoustics. In particular, the second-moment parabolic equation is formulated for the spatial correlation function of the sound field propagating above an impedance ground in a forest with micrometeorology. Effective numerical techniques for solving this equation have been developed in atmospheric acoustics. In another example, formulas are obtained that describe the effect of a forest on the interference between the direct and ground-reflected waves. The formulated correspondence between wave propagation in discrete and continuous random media can also be used in other fields of physics. PMID- 29495705 TI - Modulation detection interference in cochlear implant listeners under forward masking conditions. AB - Little is known about cochlear implant (CI) users' ability to process amplitude modulation (AM) under conditions of forward masking (forward-modulation detection/discrimination interference, or F-MDI). In this study, F-MDI was investigated in adult CI listeners using direct electrical stimulation via research interface. The target was sinusoidally amplitude modulated at 50 Hz, and presented to a fixed electrode in the middle of the array. The forward masker was either amplitude modulated at the same rate (AM) or unmodulated and presented at the peak amplitude of its AM counterpart (steady-state peak, SSP). Results showed that the AM masker produced higher modulation thresholds in the target than the SSP masker. The difference (F-MDI) was estimated to be 4.6 dB on average, and did not change with masker-target delays up to 100 ms or with masker-target spatial electrode distances up to eight electrodes. Results with a coherent remote cue presented with the masker showed that confusion effects did not play a role in the observed F-MDI. Traditional recovery from forward masking using the same maskers and a 20-ms probe, measured in four of the subjects, confirmed the expected result: higher thresholds with the SSP masker than the AM masker. Collectively, the results indicate that significant F-MDI occurs in CI users. PMID- 29495706 TI - Dispersion curves for Lamb wave propagation in prestressed plates using a semi analytical finite element analysis. AB - Acoustoelastic techniques have been recently used to characterize the state of prestress in structures such as plates. The velocity of guided wave modes propagating through plates is sensitive to the magnitude and orientation of the initial state of stress. Dispersion curves for phase velocities of plate guided waves can be computed using the superposition of partial bulk waves (SPBW) method. Here, a semi-analytical finite element (SAFE) method is formulated for the acoustoelastic problem of guided waves in weakly nonlinear elastic plates. The SAFE formulation is shown to provide phase velocity dispersion curve results identical with those provided by the SPBW method for the problem of a plate under a uniaxial and uniform tensile stress. Analytical phase and group velocity dispersion curves are also obtained for a plate with an initial prestress gradient through its thickness using the SAFE method. The magnitude of the prestress gradient is shown to have a significant effect on phase and group velocities of the fundamental and first order Lamb modes, only in certain frequency-thickness regimes. PMID- 29495708 TI - Design optimization of a viscoelastic dynamic vibration absorber using a modified fixed-points theory. AB - A viscoelastic dynamic vibration absorber (VDVA) is proposed for suppressing infrasonic vibrations of heavy structures because the traditional dynamic vibration absorber equipped with a viscous damper is not effective in suppressing low frequency vibrations. The proposed VDVA has an elastic spring and a viscoelastic damper with frequency dependent modulus and damping properties. The standard fixed-points theory cannot be applied to derive the optimum design parameters of the VDVA because both its stiffness and damping are frequency dependent. A modified fixed-points theory is therefore proposed to solve this problem. Hinfinity design optimization of the proposed VDVA have been derived for the minimization of resonant vibration amplitude of a single degree-of-freedom system excited by harmonic forces or due to ground motions. The stiffness and damping of the proposed VDVA can be decoupled such that both of these two properties of the absorber can be tuned independently to their optimal values by following a specified procedure. The proposed VDVA with optimized design is tested numerically using two real commercial viscoelastic damping materials. It is found that the proposed viscoelastic absorber can provide much stronger vibration reduction effect than the conventional VDVA without the elastic spring. PMID- 29495707 TI - Characterization of a polymer, open-cell rigid foam that simulates the ultrasonic properties of cancellous bone. AB - Materials that simulate the ultrasonic properties of tissues are used widely for clinical and research purposes. However, relatively few materials are known to simulate the ultrasonic properties of cancellous bone. The goal of the present study was to investigate the suitability of using a polymer, open-cell rigid foam (OCRF) produced by Sawbones(r). Measurements were performed on OCRF specimens with four different densities. Ultrasonic speed of sound and normalized broadband ultrasonic attenuation were measured with a 0.5 MHz transducer. Three backscatter parameters were measured with a 5 MHz transducer: apparent integrated backscatter, frequency slope of apparent backscatter, and normalized mean of the backscatter difference. X-ray micro-computed tomography was used to measure the microstructural characteristics of the OCRF specimens. The trabecular thickness and relative bone volume of the OCRF specimens were similar to those of human cancellous bone, but the trabecular separation was greater. In most cases, the ultrasonic properties of the OCRF specimens were similar to values reported in the literature for cancellous bone, including dependence on density. In addition, the OCRF specimens exhibited an ultrasonic anisotropy similar to that reported for cancellous bone. PMID- 29495709 TI - Acoustic Tamm states of three-dimensional solid-fluid phononic crystals. AB - In this work, the existence and propagation of acoustic Tamm states at the interface of air and a face-centered cubic solid-fluid phononic crystal composed of spherical air voids interconnected by cylindrical air channels are demonstrated. Supercell band structure computations via the finite element method reveal surface bands for Tamm states on (100), (110), and (111) surfaces of the phononic crystal. The states decay sharply into the phononic crystal so that only a two-row slab is sufficient to guide them over the respective surfaces without leakage, as confirmed by finite element simulations. In addition, surface wave propagation along the [10] direction of the (100) surface is experimentally demonstrated. Ability to confine the Tamm states in all three dimensions is a key aspect in designing few-layer-thick acoustic circuits. Low material filling fraction of the phononic crystal could be leveraged to realize lightweight all acoustic systems where either bulk or surface states can be incorporated. PMID- 29495710 TI - Acoustic noise interferometry in a time-dependent coastal ocean. AB - Interferometry of underwater noise provides a way to estimate physical parameters of the water column and the seafloor without employing any controlled sound sources. In applications of acoustic noise interferometry to coastal oceans, the propagation environment changes appreciably during the averaging times that are necessary for the Green's functions to emerge from noise cross-correlations. Here, a theory is developed to quantify the effects of nonstationarity of the propagation environment on two-point correlation functions of diffuse noise. It is shown that temporal variability of the ocean limits from above the frequency range, where noise cross-correlations approximate the Green's functions. The theoretical predictions are in quantitative agreement with results of the 2012 noise interferometry experiment in the Florida Straits. The loss of coherence at high frequencies constrains the passive acoustic remote sensing to exploiting a low-frequency part of measured noise cross-correlations, thus limiting the resolution of deterministic inversions. On the other hand, the passively measured coherence loss contains information about statistical characteristics of the ocean dynamics at unresolved spatial and temporal scales. PMID- 29495711 TI - Effect of auditory efferent time-constant duration on speech recognition in noise. AB - The human auditory efferent system may play a role in improving speech-in-noise recognition with an associated range of time constants. Computational auditory models with efferent-inspired feedback demonstrate improved speech-in-noise recognition with long efferent time constants (2000 ms). This study used a similar model plus an Automatic Speech Recognition (ASR) system to investigate the role of shorter time constants. ASR speech recognition in noise improved with efferent feedback (compared to no-efferent feedback) for both short and long efferent time constants. For some signal-to-noise ratios, speech recognition in noise improved as efferent time constants were increased from 118 to 2000 ms. PMID- 29495712 TI - The effect of F0 contour on the intelligibility of speech in the presence of interfering sounds for Mandarin Chinese. AB - In Mandarin Chinese, the fundamental frequency (F0) contour defines lexical "Tones" that differ in meaning despite being phonetically identical. Flattening the F0 contour impairs the intelligibility of Mandarin Chinese in background sounds. This might occur because the flattening introduces misleading lexical information. To avoid this effect, two types of speech were used: single-Tone speech contained Tones 1 and 0 only, which have a flat F0 contour; multi-Tone speech contained all Tones and had a varying F0 contour. The intelligibility of speech in steady noise was slightly better for single-Tone speech than for multi Tone speech. The intelligibility of speech in a two-talker masker, with the difference in mean F0 between the target and masker matched across conditions, was worse for the multi-Tone target in the multi-Tone masker than for any other combination of target and masker, probably because informational masking was maximal for this combination. The introduction of a perceived spatial separation between the target and masker, via the precedence effect, led to better performance for all target-masker combinations, especially the multi-Tone target in the multi-Tone masker. In summary, a flat F0 contour does not reduce the intelligibility of Mandarin Chinese when the introduction of misleading lexical cues is avoided. PMID- 29495713 TI - Beamforming using chip-scale atomic clocks in a controlled environment. AB - Recently developed low-power Chip-Scale Atomic Clocks (CSACs) hold promise for underwater acoustics applications because they enable time-coherent processing, critical for estimating the directionality of the sound field, when acoustic array elements cannot share a timing reference. Controlled, tank-based experiments with a small acoustic array (N = 4) featuring CSAC-equipped elements show that optimal disciplining is important for continued array coherence. Clock drift equivalent to a 10% wavelength error at 0.3, 1, and 10 kHz was reached at approximately 25, 10, and 3 days, respectively. Within application-specific limits, this technology brings enhanced capabilities to acoustic thermometry, geoacoustic, biological, and under-ice acoustic oceanography. PMID- 29495714 TI - Deep convolutional neural networks for estimating porous material parameters with ultrasound tomography. AB - The feasibility of data based machine learning applied to ultrasound tomography is studied to estimate water-saturated porous material parameters. In this work, the data to train the neural networks is simulated by solving wave propagation in coupled poroviscoelastic-viscoelastic-acoustic media. As the forward model, a high-order discontinuous Galerkin method is considered, while deep convolutional neural networks are used to solve the parameter estimation problem. In the numerical experiment, the material porosity and tortuosity is estimated, while the remaining parameters which are of less interest are successfully marginalized in the neural networks-based inversion. Computational examples confirm the feasibility and accuracy of this approach. PMID- 29495715 TI - Remote acoustic detection of mechanical changes in a vibrating plate in an unknown reverberant environment. AB - Acoustic radiation from a vibrating mechanical structure subject to broadband forcing is inherently dependent on the structure's material, geometry, and boundary conditions. Remote measurements of radiated sound can be used to detect mechanical changes (i.e., defects) when compared to known baseline measurements from the same structure. However, proper determination of a structure's acoustic signature may not be possible in highly reverberant environments due to reverberation contamination. Herein, experimental results are presented for the remote acoustic detection of clamped-boundary defects in a nominally 30 * 30 * 0.3 cm aluminum plate in a reverberant environment. Synthetic Time Reversal (STR) is used to estimate the free-field acoustic signature of the plate from recordings made in a reverberant environment with a 15-element microphone array at signal-to-reverberation ratio levels of -7 to -13 dB in a 100 Hz to 2.0 kHz bandwidth. These reconstructed time domain signals are then cross-correlated with baseline measurements of a known fully-clamped plate and classified as either changed or unchanged. Using common classifier statistics, this approach to remote acoustic damage detection using STR is found to be superior to equivalent waveform correlation approaches based on unprocessed signals and conventional time-domain beamforming outputs. PMID- 29495716 TI - Role of short-time acoustic temporal fine structure cues in sentence recognition for normal-hearing listeners. AB - Short-time processing was employed to manipulate the amplitude, bandwidth, and temporal fine structure (TFS) in sentences. Fifty-two native-English-speaking, normal-hearing listeners participated in four sentence-recognition experiments. Results showed that recovered envelope (E) played an important role in speech recognition when the bandwidth was > 1 equivalent rectangular bandwidth. Removing TFS drastically reduced sentence recognition. Preserving TFS greatly improved sentence recognition when amplitude information was available at a rate >= 10 Hz (i.e., time segment <= 100 ms). Therefore, the short-time TFS facilitates speech perception together with the recovered E and works with the coarse amplitude cues to provide useful information for speech recognition. PMID- 29495717 TI - Modeling analysis of ultrasonic attenuation and angular scattering measurements of suspended particles. AB - A combination of two models previously developed by Faran, and Atkinson and Kytomaa (Faran-AK model) was used to calculate the ultrasonic attenuation and the backscattering signal of a suspension of particles. The model of Atkinson and Kytomaa yielded the viscoelastic contributions while the model of Faran yielded the scattering contribution. A comparison with the more fundamental model by Epstein, Carhart, Allegra, and Hawley validated the combination, where the combination used here proved to be computationally less intensive and more stable. The Faran-AK model outputs were also compared with ultrasound measurements of glass beads with two different particle size distributions and varying concentrations. The comparison showed a very reasonable agreement of model and experiment. PMID- 29495718 TI - Temporal weights in the perception of sound intensity: Effects of sound duration and number of temporal segments. AB - Loudness is a fundamental aspect of auditory perception that is closely related to the physical level of the sound. However, it has been demonstrated that, in contrast to a sound level meter, human listeners do not weight all temporal segments of a sound equally. Instead, the beginning of a sound is more important for loudness estimation than later temporal portions. The present study investigates the mechanism underlying this primacy effect by varying the number of equal-duration temporal segments (5 and 20) and the total duration of the sound (1.0 to 10.0 s) in a factorial design. Pronounced primacy effects were observed for all 20-segment sounds. The temporal weights for the five-segment sounds are similar to those for the 20-segment sounds when the weights of the segments covering the same temporal range as a segment of the five-segment sounds are averaged. The primacy effect can be described by an exponential decay function with a time constant of about 200 ms. Thus, the temporal weight assigned to a specific temporal portion of a sound is determined by the time delay between sound onset and segment onset rather than by the number of segments or the total duration of the sound. PMID- 29495719 TI - Vector sensor cross-spectral density for surface noise in a stratified ocean Formulas for arbitrary sensor geometries. AB - The cross-spectral density between pressure and particle velocity channels of two vector sensors with arbitrary orientation and separation is developed for a noise field consisting of directional sources distributed on a plane. Equations for arbitrary sensor orientations are necessary because cross-spectral density is an averaged product of two sensors' outputs that cannot be projected onto another direction after it is calculated. This prevents the use of existing methods, which calculate cross-spectral density for orthogonal particle velocity sensors, for sensors with different orientations. Analytic solutions to special cases for azimuthally symmetric environments and orthogonal velocity sensor orientations are developed and compared to previous results. The general equations are stated in a form suitable for use with any propagation model that produces Green's functions for pressure and orthogonal particle velocity components. Simulation examples demonstrate how sensor geometry and propagation conditions affect vector sensor array performance for wind-driven surface noise in deep and shallow water environments. Vector sensor beamforming is shown to provide additional gain in these directional noise fields as compared to isotropic noise. PMID- 29495720 TI - Three-microphone probe bias errors for acoustic intensity and specific acoustic impedance. AB - In acoustic intensity estimation, adding a microphone at the probe center removes errors associated with pressure averaging. Analytical bias errors are presented for a one-dimensional, three-microphone probe for active intensity, reactive intensity, and specific acoustic impedance in a monopole field. Traditional estimation is compared with the Phase and Amplitude Gradient Estimator (PAGE) method; the PAGE method shows an increased bandwidth for all three quantities. The two- and three-microphone methods are compared experimentally, showing reduced bias errors with three-microphone PAGE for active and reactive intensity, whereas using two microphones is preferred for specific acoustic impedance. PMID- 29495721 TI - Timbral Shepard-illusion reveals ambiguity and context sensitivity of brightness perception. AB - Recent research has described strong effects of prior context on the perception of ambiguous pitch shifts of Shepard tones [Chambers, Akram, Adam, Pelofi, Sahani, Shamma, and Pressnitzer (2017). Nat. Commun. 8, 15027]. Here, similar effects are demonstrated for brightness shift judgments of harmonic complexes with cyclic spectral envelope components and fixed fundamental frequency. It is shown that frequency shifts of the envelopes are perceived as systematic shifts of brightness. Analogous to the work of Chambers et al., the perceptual ambiguity of half-octave shifts resolves with the presentation of prior context tones. These results constitute a context effect for the perceptual processing of spectral envelope shifts and indicate so-far unknown commonalities between pitch and timbre perception. PMID- 29495722 TI - Multiple scattering and scattering cross sections. AB - The scattering cross section for a cluster of scatterers can be calculated using various methods, either exactly or by invoking various approximations. Of special interest are methods in which the scattering properties of individual members of the cluster are used. The underlying question is: Can the contribution to the cluster's cross section from any one member of the cluster be identified? Except for situations in which all effects of multiple scattering are ignored, no such method of identification has been found. PMID- 29495723 TI - An online secondary path modeling method with regularized step size and self tuning power scheduling. AB - This paper investigates the active noise control algorithms and improves them by using online secondary path modeling. The proposed method uses three adaptive filters to track the convergence of the system as well as reduce the target noise. By theoretical analysis, the optimized step size and injected random noise gain are derived. The step size is varied according to the convergence of three adaptive filters and the gain of injected random noise is proportional to the power of modeling error, which makes the method more stable even in the presence of strong perturbation. Compared with previous methods, the proposed method improves the convergence rate and estimation accuracy for both the active control system and the secondary path modeling process with less increase of computational complexity. The simulation results verify the above analysis by controlling three different kinds of noise. PMID- 29495724 TI - Numerical study of the influence of the convective heat transport on acoustic streaming in a standing wave. AB - Within this work, acoustic streaming in an air-filled cylindrical resonator with walls supporting a temperature gradient is studied by means of numerical simulations. A set of equations based on successive approximations is derived from the Navier-Stokes equations. The equations take into account the acoustic streaming-driven convective heat transport; as time-averaged secondary-field quantities are directly calculated, the equations are much easier to integrate than the original fluid-dynamics equations. The model equations are implemented and integrated employing commercial software COMSOL Multiphysics. Numerical calculations are conducted for the case of a resonator with a wall-temperature gradient corresponding to the action of a thermoacoustic effect. It is shown that due to the convective heat transport, the streaming profile is considerably distorted even in the case of weak wall-temperature gradients. The numerical results are consistent with available experimental data. PMID- 29495725 TI - Passive acoustic tracking using a library of nearby sources of opportunity. AB - A method of localizing unknown acoustic sources using data derived replicas from ships of opportunity has been reported previously by Verlinden, Sarkar, Hodgkiss, Kuperman, and Sabra [J. Acoust. Soc. Am, 138(1), EL54-EL59 (2015)]. The method is similar to traditional matched field processing, but differs in that data-derived measured replicas are used in place of modeled replicas and, in order to account for differing source spectra between library and target vessels, cross correlation functions are compared instead of comparing acoustic signals directly. The method is capable of localizing sources in positions where data derived replicas are available, such as locations previously transited by ships tracked using the Automatic Identification System, but is limited by the sparsity of ships of opportunity. This paper presents an extension of this localization method to regions where data derived replicas are not available by extrapolating the measured cross-correlation function replicas onto a larger search grid using waveguide invariant theory. This new augmentation provides a method for continuous tracking. PMID- 29495726 TI - Multichannel Multiple Signal Classification for dispersion curves extraction of ultrasonic guided waves. AB - Multichannel acquisition of ultrasonic guided waves can be used to extract dispersion curves, from the time-position domain (t-x) to the frequency wavenumber (f-k), or frequency-velocity domain (f-c). Accurate measurements are needed in order to be able to precisely characterize the specimen, by improving the extraction of low amplitude modes and enhance resolution. The proposed method is based on the MUltiple SIgnal Classification algorithm combined with a multi emitter and multi-receiver acquisition. In this work, this method is applied on experimental data to extract dispersive information from multilayered bonded specimens. PMID- 29495728 TI - Modal smoothing for analysis of room reflections measured with spherical microphone and loudspeaker arrays. AB - Spatial analysis of room acoustics is an ongoing research topic. Microphone arrays have been employed for spatial analyses with an important objective being the estimation of the direction-of-arrival (DOA) of direct sound and early room reflections using room impulse responses (RIRs). An optimal method for DOA estimation is the multiple signal classification algorithm. When RIRs are considered, this method typically fails due to the correlation of room reflections, which leads to rank deficiency of the cross-spectrum matrix. Preprocessing methods for rank restoration, which may involve averaging over frequency, for example, have been proposed exclusively for spherical arrays. However, these methods fail in the case of reflections with equal time delays, which may arise in practice and could be of interest. In this paper, a method is proposed for systems that combine a spherical microphone array and a spherical loudspeaker array, referred to as multiple-input multiple-output systems. This method, referred to as modal smoothing, exploits the additional spatial diversity for rank restoration and succeeds where previous methods fail, as demonstrated in a simulation study. Finally, combining modal smoothing with a preprocessing method is proposed in order to increase the number of DOAs that can be estimated using low-order spherical loudspeaker arrays. PMID- 29495729 TI - Effects of flow gradients on directional radiation of human voice. AB - In voice communication in windy outdoor conditions, complex velocity gradients appear in the flow field around the source, the receiver, and also in the atmosphere. It is commonly known that voice emanates stronger towards the downstream direction when compared with the upstream direction. In literature, the atmospheric effects are used to explain the stronger emanation in the downstream direction. This work shows that the wind also has an effect to the directivity of voice also favouring the downstream direction. The effect is addressed by measurements and simulations. Laboratory measurements are conducted by using a large pendulum with a loudspeaker mimicking the human head, whereas practical measurements utilizing the human voice are realized by placing a subject through the roof window of a moving car. The measurements and a simulation indicate congruent results in the speech frequency range: When the source faces the downstream direction, stronger radiation coinciding with the wind direction is observed, and when it faces the upstream direction, radiation is not affected notably. The simulated flow gradients show a wake region in the downstream direction, and the simulated acoustic field in the flow show that the region causes a wave-guide effect focusing the sound in the direction. PMID- 29495730 TI - Apparent-talker height is influenced by Mandarin lexical tone. AB - Apparent-talker height is determined by a talker's fundamental frequency (f0) and spectral information, typically indexed using formant frequencies (FFs). Barreda [(2017b). J. Acoust. Soc. Am. 141, 4781-4792] reports that the apparent height of a talker can be influenced by vowel-specific variation in the f0 or FFs of a sound. In this experiment, native speakers of Mandarin were presented with a series of syllables produced by talkers of different apparent heights. Results indicate that there is substantial variability in the estimated height of a single talker based on lexical tone, as well as the inherent f0 and FFs of vowel phonemes. PMID- 29495731 TI - Comparison of time-frequency methods for analyzing stimulus frequency otoacoustic emissions. AB - Stimulus frequency otoacoustic emissions (SFOAEs) can have multiple time varying components, including multiple internal reflections. It is, therefore, necessary to study SFOAEs using techniques that can represent their time-frequency behavior. Although various time-frequency schemes can be applied to identify and filter SFOAE components, their accuracy for SFOAE analysis has not been investigated. The relative performance of these methods is important for accurate characterization of SFOAEs that may, in turn, enhance the understanding of SFOAE generation. This study using in silico experiments examined the performance of three linear (short-time Fourier transform, continuous wavelet transform, Stockwell transform) and two nonlinear (empirical mode decomposition and synchrosqueezed wavelet transform) time-frequency approaches for SFOAE analysis. Their performances in terms of phase-gradient delay estimation, frequency specificity, and spectral component extraction are compared, and the relative merits and limitations of each method are discussed. Overall, this paper provides a comparative analysis of various time-frequency methods useful for otoacoustic emission applications. PMID- 29495732 TI - Plane nonlinear shear waves in relaxing media. AB - Model equations with cubic nonlinearity are developed for a plane shear wave of finite amplitude in a relaxing medium. The evolution equation for progressive waves is solved analytically for a jump in stress that propagates into an undisturbed medium. Weak-shock theory is used to determine the amplitude and location of the shock when the solution predicts a multivalued waveform. The solution is similar to that obtained by Polyakova, Soluyan, and Khokhlov [Sov. Phys. Acoust. 8, 78-82 (1962)] for a compressional wave with quadratic nonlinearity in a relaxing fluid. Numerical simulations illustrate the effect of relaxation on shock formation in an initially sinusoidal shear wave. The minimum source amplitude required for an initially sinusoidal waveform to develop shocks in a relaxing medium is determined as a function of the dispersion and relaxation time. Limiting forms of the evolution equation are considered, and analytical solutions incorporating weak-shock theory are presented in the high-frequency limit. A Duffing-type model for a nonlinear shear-wave resonator is developed and investigated. PMID- 29495733 TI - Conditioned attenuation of auditory brainstem responses in dolphins warned of an intense noise exposure: Temporal and spectral patterns. AB - Conditioned reductions in hearing sensitivity were elicited in two bottlenose dolphins by pairing a 10-kHz tone (the conditioned stimulus) with a more intense tone (the unconditioned stimulus) at 20, 40, or 80 kHz. Hearing was assessed via noninvasive measurement of auditory brainstem responses (ABRs) to 20 - to 133-kHz tone bursts presented at randomized intervals from 1 to 3 ms. ABRs within each trial were obtained by averaging the instantaneous electroencephalogram, time locked to tone burst onsets, over 2- to 3-s time intervals. In initial testing, ABR amplitudes were reduced (relative to baseline values) in one dolphin after the conditioned stimulus, but before the unconditioned stimulus, demonstrating conditioned hearing attenuation. In subsequent testing with both dolphins, ABRs were attenuated throughout the entire 31-s trial. Maximum ABR threshold shifts occurred at and above the unconditioned stimulus frequency and were above 40 dB for some conditions. The results (1) confirm that dolphins can be conditioned to reduce hearing sensitivity when warned of an impending noise exposure, (2) show that hearing attenuation occurs within the cochlea or auditory nerve, and (3) support the hypothesis that toothed whales can "self-mitigate" some effects of noise if warned of an impending exposure. PMID- 29495734 TI - A method for testing the wide-sense stationary uncorrelated scattering assumption fulfillment for an underwater acoustic channel. AB - Wide-sense stationary and uncorrelated scattering (WSSUS) assumptions are often applied for the statistical description of wireless communication channels. However, in the case of underwater acoustic channels the WSSUS model is of limited value. The degree of similarity of in-phase and quadrature components of the channel impulse response, measured with the use of bandpass modulated signals, can be used as an indicator of WSSUS assumption fulfillment. The paper describes an experimental method that uses quadrature Pseudo-Random Binary Sequence to evaluate the validity of the WSSUS assumption. The technique was developed by analyzing the shallow water experiment in the Bornholm Basin of the Baltic Sea. PMID- 29495735 TI - Estimating the parameter sensitivity of acoustic mode quantities for an idealized shelf-slope front. AB - The acoustic modes of an idealized three-dimensional model for a curved shelf slope ocean front [Lin and Lynch, J. Acoust. Soc. Am. 131, EL1-EL7 (2012)] is examined analytically and numerically. The goal is to quantify the influence of environmental and acoustic parameters on acoustic field metrics. This goal is achieved by using conserved quantities of the model, including the dispersion relation and a conservation of mode number. Analytic expressions for the horizontal wave numbers can be extracted by asymptotic approximations and perturbations, leading to accurate and convenient approximations for their parameter dependence. These equations provide the dependence on model parameter changes of both the real horizontal wavenumbers, leading to modal phase speeds and other metrics, and the imaginary parts, leading to modal attenuation coefficients. Further approximations for small parameter changes of these equations characterize the parameter sensitivities and produce assessments of environmental and acoustic influences. PMID- 29495736 TI - Modelling the broadband propagation of marine mammal echolocation clicks for click-based population density estimates. AB - Passive acoustic monitoring with widely-dispersed hydrophones has been suggested as a cost-effective method to monitor population densities of echolocating marine mammals. This requires an estimate of the area around each receiver over which vocalizations are detected-the "effective detection area" (EDA). In the absence of auxiliary measurements enabling estimation of the EDA, it can be modelled instead. Common simplifying model assumptions include approximating the spectrum of clicks by flat energy spectra, and neglecting the frequency-dependence of sound absorption within the click bandwidth (narrowband assumption), rendering the problem amenable to solution using the sonar equation. Here, it is investigated how these approximations affect the estimated EDA and their potential for biasing the estimated density. EDA was estimated using the passive sonar equation, and by applying detectors to simulated clicks injected into measurements of background noise. By comparing model predictions made using these two approaches for different spectral energy distributions of echolocation clicks, but identical click source energy level and detector settings, EDA differed by up to a factor of 2 for Blainville's beaked whales. Both methods predicted relative density bias due to narrowband assumptions ranged from 5% to more than 100%, depending on the species, detector settings, and noise conditions. PMID- 29495737 TI - The area discontinuity between probe and ear canal as a source of power reflectance measurement-location variability. AB - This study examined the effect of the area discontinuity between the measurement probe sound source and ear canal on the plane-wave approximation of power reflectance. The area discontinuity was hypothesized to introduce measurement location sensitivity to the power reflectance, especially above 5 kHz. Measurements were made in human and artificial ear canals (tubes coupled to an IEC711 ear simulator). In both cases, the power reflectance exhibited a high frequency notch that decreased in frequency as the residual canal length increased. The area discontinuity between probe and canal was modeled as an inductance in series with the canal's acoustic impedance. To compensate for the effects of the discontinuity, the discontinuity's impedance was subtracted from the measured load impedance of the canal. In the artificial ears, compensation for the estimated area discontinuity removed the high-frequency notch and reduced the position dependence of the power reflectance. Subtracting the estimated discontinuity impedance from the load impedance in the human ears had a minimal effect on the power-reflectance measurement-location variability and magnitude of the high-frequency notch. The area-discontinuity between probe and ear canal is not supported as the primary source of measurement-variability in the plane-wave approximation of the power reflectance in human ears. PMID- 29495738 TI - The impact of brief restriction to articulation on children's subsequent speech production. AB - This project explored whether disruption of articulation during listening impacts subsequent speech production in 4-yr-olds with and without speech sound disorder (SSD). During novel word learning, typically-developing children showed effects of articulatory disruption as revealed by larger differences between two acoustic cues to a sound contrast, but children with SSD were unaffected by articulatory disruption. Findings suggest that, when typically developing 4-yr-olds experience an articulatory disruption during a listening task, the children's subsequent production is affected. Children with SSD show less influence of articulatory experience during perception, which could be the result of impaired or attenuated ties between perception and articulation. PMID- 29495739 TI - Towards real-time assessment of anisotropic plate properties using elastic guided waves. AB - A method to recover the elastic properties, thickness, or orientation of the principal symmetry axes of anisotropic plates is presented. This method relies on the measurements of multimode guided waves, which are launched and detected in arbitrary directions along the plate using a multi-element linear transducer array driven by a programmable electronic device. A model-based inverse problem solution is proposed to optimally recover the properties of interest. The main contribution consists in defining an objective function built from the dispersion equation, which allows accounting for higher-order modes without the need to pair each experimental data point to a specific guided mode. This avoids the numerical calculation of the dispersion curves and errors in the mode identification. Compared to standard root-finding algorithms, the computational gain of the procedure is estimated to be on the order of 200. The objective function is optimized using genetic algorithms, which allow identifying from a single out-of symmetry axis measurement the full set of anisotropic elastic coefficients and either the plate thickness or the propagation direction. The efficiency of the method is demonstrated using data measured on materials with different symmetry classes. Excellent agreement is found between the reported estimates and reference values from the literature. PMID- 29495740 TI - Acoustic pulse propagation in forests. AB - The propagation of acoustic pulses through a forest is considered. Multiple scattering effects are accounted for by using the energy-based radiative transfer theory under a modified Born approximation, resulting in an expression for the diffuse intensity as a function of time and dominant frequency. While this expression is a complicated set of three integrals, certain practical approximations enable analytic evaluation of one, two, or even all three integrals. Any remaining integrals may be numerically calculated. The simple case of an impulse in an infinite homogeneous forest of diffuse scatterers is first considered, and then the effects of successively including non-diffuse scatterers, ground reflections in a forest of finite height, and finally a realistic forest model are analyzed with an emphasis on long-time decay and reverberation times. These theoretical findings are then compared with experimental results. PMID- 29495741 TI - Informational masking of speech by time-varying competitors: Effects of frequency region and number of interfering formants. AB - This study explored the extent to which informational masking of speech depends on the frequency region and number of extraneous formants in an interferer. Target formants-monotonized three-formant (F1+F2+F3) analogues of natural sentences-were presented monaurally, with target ear assigned randomly on each trial. Interferers were presented contralaterally. In experiment 1, single formant interferers were created using the time-reversed F2 frequency contour and constant amplitude, root-mean-square (RMS)-matched to F2. Interferer center frequency was matched to that of F1, F2, or F3, while maintaining the extent of formant-frequency variation (depth) on a log scale. Adding an interferer lowered intelligibility; the effect of frequency region was small and broadly tuned around F2. In experiment 2, interferers comprised either one formant (F1, the most intense) or all three, created using the time-reversed frequency contours of the corresponding targets and RMS-matched constant amplitudes. Interferer formant frequency variation was scaled to 0%, 50%, or 100% of the original depth. Increasing the depth of formant-frequency variation and number of formants in the interferer had independent and additive effects. These findings suggest that the impact on intelligibility depends primarily on the overall extent of frequency variation in each interfering formant (up to ~100% depth) and the number of extraneous formants. PMID- 29495742 TI - Efferent-induced alterations in distortion and reflection otoacoustic emissions in children. AB - The medial olivocochlear efferent fibers control outer hair cell responses and inhibit the cochlear-amplifier gain. Measuring efferent function is both theoretically and clinically relevant. In humans, medial efferent inhibition can be assayed via otoacoustic emissions (OAEs). OAEs arise by two fundamentally different mechanisms-nonlinear distortion and coherent reflection. Distortion and reflection emissions are typically applied in isolation for studying the efferent inhibition. Such an approach inadvertently assumes that efferent-induced shifts in distortion and reflection emissions provide redundant information. In this study, efferent-induced shifts in distortion and reflection emissions (click evoked and stimulus frequency OAEs) were measured in the same subjects-5- to 10 yr-old children. Consistent with the OAE generation theory, efferent-induced shifts in distortion and reflection emissions did not correlate, whereas the two reflection emission shifts correlated. This suggests that using either OAE types provides fragmented information on efferent inhibition and highlights the need to use both distortion and reflection emissions for describing efferent effects. PMID- 29495744 TI - Time reversal focusing of high amplitude sound in a reverberation chamber. AB - Time reversal (TR) is a signal processing technique that can be used for intentional sound focusing. While it has been studied in room acoustics, the application of TR to produce a high amplitude focus of sound in a room has not yet been explored. The purpose of this study is to create a virtual source of spherical waves with TR that are of sufficient intensity to study nonlinear acoustic propagation. A parameterization study of deconvolution, one-bit, clipping, and decay compensation TR methods is performed to optimize high amplitude focusing and temporal signal focus quality. Of all TR methods studied, clipping is shown to produce the highest amplitude focal signal. An experiment utilizing eight horn loudspeakers in a reverberation chamber is done with the clipping TR method. A peak focal amplitude of 9.05 kPa (173.1 dB peak re 20 MUPa) is achieved. Results from this experiment indicate that this high amplitude focusing is a nonlinear process. PMID- 29495743 TI - Across-channel interaural-level-difference processing demonstrates frequency dependence. AB - Accurate localization of complex sounds involves combining interaural information across frequencies to produce a single location percept. Interaural level differences (ILDs) are highly frequency dependent and it is unclear how the auditory system combines differing ILDs across frequency. Therefore, ILD just noticeable differences (JNDs) and intracranial lateralization were measured in young normal-hearing listeners using single- and multi-band stimuli. The bands were 300-ms, 10-Hz narrowband noises; the multi-band condition had three bands; they started and ended synchronously; they were located around three different frequency regions (750, 2000, or 4000 Hz); they had five different frequency separations that ranged from unresolved to resolved; the bands were dichotic with the same non-zero ILD (targets) or were diotic with zero ILD (interferers). Results showed single-band ILD JNDs were marginally frequency dependent. If unresolved diotic interferers were added, ILD JNDs increased greatly because of interaural decorrelation. If well-resolved diotic interferers were added, ILD JNDs were frequency dependent and the worst performance occurred when targets were near 1000 or 4000 Hz. This frequency dependence might be partially explained by ILD vs azimuth non-monotonicities for free-field sound sources in this frequency region. These results suggest that binaural processing models need revision for the processing of complex sounds. PMID- 29495745 TI - Individually tailored spectral-change enhancement for the hearing impaired. AB - An algorithm for enhancing spectral changes over time was previously shown to improve the intelligibility of speech in steady speech-spectrum noise (SSN) for hearing-impaired subjects but tended to impair intelligibility for speech in a background of two-talker speech. Large individual differences were found and the application of a genetic algorithm for selecting the "best" parameter values for each listener was found to be beneficial. In the present study, the spectral change enhancement (SCE) processing was modified by individually tailoring the degree of SCE based on the frequency-dependent hearing loss of the subjects, and by using finer frequency resolution. The effect of the modified SCE processing on the intelligibility and quality of speech in SSN and babble noise (BBN) was evaluated. Ten subjects with mild to moderate hearing loss were tested twice for all tests. The SCE processing led to small but significant improvements in the intelligibility of speech in both SSN and BBN, while the effect of the SCE processing on speech quality was small. PMID- 29495746 TI - Recoverability-driven coarticulation: Acoustic evidence from Japanese high vowel devoicing. AB - High vowel devoicing in Japanese, where /i, u/ in a C1VC2 sequence devoice when both C1 and C2 are voiceless, has been studied extensively, but factors that contribute to the devoiced vowels' likelihood of complete deletion is still debated. This study examines the effects of phonotactic predictability on the deletion of devoiced vowels. Native Tokyo Japanese speakers (N = 22) were recorded in a sound-attenuated booth reading sentences containing lexical stimuli. C1 of the stimuli were /k, ?/, after which either high vowel can occur, and /?, phi, s, c/, after which only one of the two occurs. C2 was always a stop. C1 duration and center of gravity (COG), the amplitude weighted mean of frequencies present in a signal, were measured. Duration results show that devoicing lengthens only non-fricatives, while it has either no effect or a shortening effect on fricatives. COG results show that coarticulatory effects of devoiced vowels are evident in /k, ?/ but not in /?, phi, s, c/. Devoiced high vowels, therefore, seem to be more likely to delete when the vowel is phonotactically predictable than when it is unpredictable. PMID- 29495747 TI - Time-domain sound field reproduction using the group Lasso. AB - A time-domain sound field reproduction (SFR) method based on the group Lasso (GL) is presented. The proposed method optimizes the positions and the number of active loudspeakers in the time domain by iteratively solving a mixed-norm constrained optimization problem. Simulation results demonstrate that the proposed method achieves accurate broadband SFR using a small number of active loudspeakers and significantly outperforms the least-squares method when the desired sound field is under-sampled. Moreover, the GL algorithm can also be used to optimize the loudspeaker placement for sound field control systems. PMID- 29495748 TI - Passive, broadband suppression of radiation of low-frequency sound. AB - Anthropogenic noise pollution of the ocean is an acute and growing problem. This letter explores one possible mechanism of noise abatement. The far-field acoustic pressure due to a compact underwater source can be suppressed by placing a small compliant body in the vicinity of the source. Here, the feasibility and efficiency of the suppression are evaluated by quantifying the reduction in radiated acoustic energy for several simple geometries, which include sound sources in an unbounded fluid, near a reflecting boundary, or in a shallow-water waveguide. The analysis is streamlined using analytic solutions for sound diffraction by simple shapes. PMID- 29495749 TI - Cancellation of room reflections over an extended area using Ambisonics. AB - This paper investigates the compensation of room reflections based on Ambisonics. A multichannel room equalization method for Ambisonic playback systems is proposed. The compensation filters are designed to operate in the spherical harmonics domain, prior to the decoding step. Their design requires the inversion of a matrix which can be ill-conditioned at low frequencies and for higher Ambisonic orders. A crossover and cross-order method is proposed to circumvent this problem and to reduce the amount of necessary regularization. Simulation results are presented in frequency, space, and temporal domains over a wide-range of frequencies. It is shown that the proposed method is efficient and can reduce the reproduction error to -14 dB in the reconstruction area defined in free field. Practical considerations such as Ambisonic room response estimation and robustness of the method are investigated. Experimental results are provided and show good agreement with the theory. Finally, a glimpse into the extension of the proposed method to create three-dimensional measurement-based Ambisonic reverberation is discussed. PMID- 29495750 TI - A deep ocean acoustic noise floor, 1-800 Hz. AB - The ocean acoustic noise floor (observed when the overhead wind is low, ships are distant, and marine life silent) has been measured on an array extending up 987 m from 5048 m depth in the eastern North Pacific, in what is one of only a few recent measurements of the vertical noise distribution near the seafloor in the deep ocean. The floor is roughly independent of depth for 1-6 Hz, and the slope (~ f-7) is consistent with Longuet-Higgins radiation from oppositely-directed surface waves. Above 6 Hz, the acoustic floor increases with frequency due to distant shipping before falling as ~ f-2 from 40 to 800 Hz. The noise floor just above the seafloor is only about 5 dB greater than during the 1975 CHURCH OPAL experiment (50-200 Hz), even though these measurements are not subject to the same bathymetric blockage. The floor increases up the array by roughly 15 dB for 40-500 Hz. Immediately above the seafloor, the acoustic energy is concentrated in a narrow, horizontal beam that narrows as f-1 and has a beam width at 75 Hz that is less than the array resolution. The power in the beam falls more steeply with frequency than the omnidirectional spectrum. PMID- 29495751 TI - High frequency compressional wave speed and attenuation measurements in water saturated granular media with unimodal and bimodal grain size distributions. AB - Compressional wave speed and attenuation were measured for water-saturated granular media employing five kinds of glass beads having unimodal and bimodal grain size distributions. Glass beads with grain sizes ranging from 250 to 850 MUm were used for the acoustic measurements at a frequency range from 350 kHz to 1.1 MHz, which includes the transition range where scattering and non-scattering losses co-exist. The compressional wave speed and attenuation data are presented as a function of frequency and grain size distribution. The compressional wave speed and attenuation data show a variety of frequency dependencies for varying grain size distribution. The observed acoustic properties are investigated for the volume ratio of larger and smaller sized grains in the mixed bimodal media. Also, the measured results are compared with the empirical multiple scattering formula as a function of Rayleigh parameter kd (product of wavenumber in the water k and mean grain diameter of the glass beads d) using weighted mean grain size. The measured results are also discussed, focusing on the geophysical difference between unimodal and bimodal mixed grains. PMID- 29495752 TI - Robust passive reconstruction of dynamic transfer function in dual-output systems. AB - The focus of this paper is the estimation of the dynamic transfer function between two outputs of a linear system subjected to an uncontrolled and generally unknown excitation, and accounting for possible uncorrelated noise present at both outputs. Several applications of this case exist in the passive identification of dynamic systems including the health monitoring and/or non destructive evaluation of structures subjected to natural "ambient" excitations. It is well known that noise-robust transfer function estimation of a single-input single-output system can be achieved by a normalized cross-power spectrum operation. This paper shows that, for the subject case of a dual-output system, particular caution must be placed in the choice of the normalization factor to apply to the cross-power spectrum of the two outputs. In particular, an "inter segment" averaging method is proposed for the normalization factor in combination with the classical "intra-segment" averaging of the cross-power spectrum in order to estimate the transfer function between the two outputs without the influence of the excitation spectrum and of the uncorrelated noise at the two receivers. Validating results are presented for synthetic signals and for experimental signals from an application to high-speed ultrasonic rail inspection exploiting the train wheels as the "ambient" excitation. PMID- 29495753 TI - Progressive phase trends in plates with embedded acoustic black holes. AB - Acoustic black holes (ABHs) have been explored and demonstrated to be effective passive treatments for broadband noise and vibration control. Performance metrics for assessing damping concepts are often focused on maximizing structural damping loss factors. Optimally performing damping treatments can reduce the resonant response of a driven system well below the direct field response. This results in a finite structure whose vibration input-output response follows that of an infinite structure. The vibration mobility transfer functions between locations on a structure can be used to assess the structure's vibration response phase, and compare its phase response characteristics to those of idealized systems. This work experimentally explores the phase accumulation in finite plates, with and without embedded grids of ABHs. The measured results are compared and contrasted with theoretical results for finite and infinite uniform plates. Accumulated phase characteristics, their spatial dependence and limits, are examined for the plates and compared to theoretical estimates. The phase accumulation results show that the embedded acoustic black hole treatments can significantly enhance the damping of the plates to the point that their phase accumulation follows that of an infinite plate. PMID- 29495754 TI - Histogram equalization with Bayesian estimation for noise robust speech recognition. AB - The histogram equalization approach is an efficient feature normalization technique for noise robust automatic speech recognition. However, it suffers from performance degradation when some fundamental conditions are not satisfied in the test environment. To remedy these limitations of the original histogram equalization methods, class-based histogram equalization approach has been proposed. Although this approach showed substantial performance improvement under noise environments, it still suffers from performance degradation due to the overfitting problem when test data are insufficient. To address this issue, the proposed histogram equalization technique employs the Bayesian estimation method in the test cumulative distribution function estimation. It was reported in a previous study conducted on the Aurora-4 task that the proposed approach provided substantial performance gains in speech recognition systems based on the acoustic modeling of the Gaussian mixture model-hidden Markov model. In this work, the proposed approach was examined in speech recognition systems with deep neural network-hidden Markov model (DNN-HMM), the current mainstream speech recognition approach where it also showed meaningful performance improvement over the conventional maximum likelihood estimation-based method. The fusion of the proposed features with the mel-frequency cepstral coefficients provided additional performance gains in DNN-HMM systems, which otherwise suffer from performance degradation in the clean test condition. PMID- 29495755 TI - Perceiving foreign-accented speech with decreased spectral resolution in single- and multiple-talker conditions. AB - To determine the effect of reduced spectral resolution on the intelligibility of foreign-accented speech, vocoder-processed sentences from native and Mandarin accented English talkers were presented to listeners in single- and multiple talker conditions. Reduced spectral resolution had little effect on native speech but lowered performance for foreign-accented speech, with a further decrease in multiple-talker conditions. Following the initial exposure, foreign-accented speech with reduced spectral resolution was less intelligible than unprocessed speech in both single- and multiple-talker conditions. Intelligibility improved with extended exposure, but only for single-talker conditions. Results indicate a perceptual impairment when perceiving foreign-accented speech with reduced spectral resolution. PMID- 29495756 TI - A molecular theory for predicting the thermodynamic efficiency of electrokinetic energy conversion in slit nanochannels. AB - The classical density functional theory is incorporated with the Stokes equation to examine the thermodynamic efficiency of pressure-driven electrokinetic energy conversion in slit nanochannels. Different from previous mean-field predictions, but in good agreement with recent experiments, the molecular theory indicates that the thermodynamic efficiency may not be linearly correlated with the channel size or the electrolyte concentration. For a given electrolyte, an optimal slit nanochannel size and ion concentration can be identified to maximize both the electrical current and the thermodynamic efficiency. The optimal conditions are sensitive to a large number of parameters including ion diameters, valences, electrolyte concentration, channel size, and the valence- and size-asymmetry of oppositely charged ionic species. The theoretical results offer fresh insights into pressure-driven current generation processes and are helpful guidelines for the design of apparatus for the electrokinetic energy conversion. PMID- 29495757 TI - Vibrational energy transfer and dissociation in O2-N2 collisions at hyperthermal temperatures. AB - Simulation of vibrational energy transfer and dissociation in O2-N2 collisions is conducted using the quasi-classical trajectory method on an ab initio potential energy surface. Vibrationally resolved rate coefficients are obtained in a high temperature region between 8000 and 20 000 K by means of the cost-efficient classical trajectory propagation method. A system of master equations is constructed using the new dataset in order to simulate thermal and chemical nonequilibrium observed in shock flows. The O2 relaxation time derived from a solution of the master equations is in good agreement with the Millikan and White correlation at lower temperatures with an increasing discrepancy toward the translational temperature of 20 000 K. At the same time, the N2 master equation relaxation time is similar to that derived under the assumption of a two-state system. The effect of vibrational-vibrational energy transfer appears to be crucial for N2 relaxation and dissociation. Thermal equilibrium and quasi-steady state dissociation rate coefficients in O2-N2 heat bath are reported. PMID- 29495758 TI - Ab initio studies on the photodissociation dynamics of the 1,1-difluoroethyl radical. AB - Born-Oppenheimer molecular dynamics trajectory calculations at the HCTH147/6 31G** level of theory simulate the dissociation dynamics of photolytically excited 1,1-difluoroethyl radicals. EOMCCSD/AUG-cc-pVDZ calculations show that an excitation energy of 94.82 kcal/mol is necessary to initiate photodissociation reactions. In contrast to photodissociation dynamics of ethyl radicals where a large discrepancy between actual dissociation rates and rates that are predicted by statistical rate theories, we find reaction rates of 5.1 * 1011 s-1 for the dissociation of an H atom, which is in perfect accord with what is predicted by Rice-Ramsperger-Kassel-Marcus (RRKM) calculations and there is no indication of any nonstatistical effects. However, our trajectory calculations show a much larger fraction of C-C bond breakage reaction of 56% occurring than that expected by RRKM (only 16%). PMID- 29495759 TI - Dependence of electron impact differential cross sections on the ionic charge to radius ratio for the Al3+(2p) and Be2+(1s) ions. AB - The triple differential cross sections (TDCSs) have been obtained for the electron impact ionization of ionic targets, Al3+(2p) and Be2+(1s), having nearly the same ratio of ionic charge to radius. In the first of this kind of study, the trends of cross sections have been found to match to a greater extent despite ionization taking place from the ionic targets having considerable difference in nuclear charges as well as the ionization taking place from different types of orbitals, p-orbital and s-orbital. The trends of TDCSs have not been found to agree considerably for the neutral Al (3p) and Be (2s) targets. PMID- 29495760 TI - Ab initio study of energy transfer rates and impact sensitivities of crystalline explosives. AB - Impact sensitivities of various crystalline explosives were predicted by means of plane wave-density functional theory calculations. Crystal structures and complete vibrational spectra of TATB, PETN, FOX7, TEX, 14DNI, and beta-HMX molecular crystals were calculated. A correlation between the phonon-vibron coupling (which is proportionally related to the energy transfer rate between the phonon manifold and the intramolecular vibrational modes) and impact sensitivities of secondary explosives was found. We propose a method, based on ab initio calculations, for the evaluation of impact sensitivities, which consequently can assist in screening candidates for chemical synthesis of high energetic materials. PMID- 29495761 TI - Understanding the free energy barrier and multiple timescale dynamics of charge separation in organic photovoltaic cells. AB - By employing several lattice model systems, we investigate the free energy barrier and real-time dynamics of charge separation in organic photovoltaic (OPV) cells. It is found that the combined effects of the external electric field, entropy, and charge delocalization reduce the free energy barrier significantly. The dynamic disorder reduces charge carrier delocalization and results in the increased charge separation barrier, while the effect of static disorder is more complicated. Simulation of the real-time dynamics indicates that the free charge generation process involves multiple time scales, including an ultrafast component within hundreds of femtoseconds, an intermediate component related to the relaxation of the hot charge transfer (CT) state, and a slow component on the time scale of tens of picoseconds from the thermally equilibrated CT state. Effects of hot exciton dissociation as well as its dependence on the energy offset between the Frenkel exciton and the CT state are also analyzed. The current results indicate that only a small energy offset between the band gap and the lowest energy CT state is needed to achieve efficient free charge generation in OPV devices, which agrees with recent experimental findings. PMID- 29495762 TI - Cyanographone and isocyanographone - Two asymmetrically functionalized graphene pseudohalides and their potential use in chemical sensing. AB - Graphene pseudohalides are natural candidates for use in molecular sensing due to their greater chemical activity as compared to both graphene halides and pristine graphene. Though their study is still in its infancy, being hindered until recently by the unavailability of both selective and efficient procedures for their synthesis, they promise to considerably widen the application potential of chemically modified graphenes. Herein, we employ van der Waals density functional theory to study the structural and electronic properties of two selected graphene pseudohalides, namely, cyanographone and isocyanographone and investigate the potential use of the latter as a chemical sensor via electron transport calculations. PMID- 29495763 TI - Liquid-drop model for fragmentation of multiply charged mercury clusters. AB - The fragmentation of doubly and triply charged mercury clusters is theoretically studied to analyze an experiment performed by Katakuse's group at Osaka University [T. Satoh et al., J. Mass Spectrom. Soc. Jpn. 51, 391 (2003)]. The fission barrier is calculated using a liquid-drop model proposed by Echt et al. In the decay of doubly charged clusters, the barrier height is found to take the minimum value for nearly symmetric fission. On the other hand, in the decay of triply charged clusters, the barrier is the lowest for strongly asymmetric fission. These results well explain the product size distribution observed in the experiment. The appearance size for multiply charged clusters measured in the experiment is found to be the size where the fission barrier is equal to the monomer evaporation energy. These findings provide evidence that small mercury clusters behave like van der Waals clusters in the process of fragmentation. PMID- 29495764 TI - Communication: Simple liquids' high-density viscosity. AB - This paper argues that the viscosity of simple fluids at densities above that of the triple point is a specific function of temperature relative to the freezing temperature at the density in question. The proposed viscosity expression, which is arrived at in part by reference to the isomorph theory of systems with hidden scale invariance, describes computer simulations of the Lennard-Jones system as well as argon and methane experimental data and simulation results for an effective-pair-potential model of liquid sodium. PMID- 29495765 TI - Multivalued classical mechanics arising from singularity loops in complex time. AB - Complex-valued classical trajectories in complex time encounter singular times at which the momentum diverges. A closed time contour around such a singular time may result in final values for q and p that differ from their initial values. In this work, we develop a calculus for determining the exponent and prefactor of the asymptotic time dependence of p from the singularities of the potential as the singularity time is approached. We identify this exponent with the number of singularity loops giving distinct solutions to Hamilton's equations of motion. The theory is illustrated for the Eckart, Coulomb, Morse, and quartic potentials. Collectively, these potentials illustrate a wide variety of situations: poles and essential singularities at finite and infinite coordinate values. We demonstrate quantitative agreement between analytical and numerical exponents and prefactors, as well as the connection between the exponent and the time circuit count. This work provides the theoretical underpinnings for the choice of time contours described in the studies of Doll et al. [J. Chem. Phys. 58(4), 1343-1351 (1973)] and Petersen and Kay [J. Chem. Phys. 141(5), 054114 (2014)]. It also has implications for wavepacket reconstruction from complex classical trajectories when multiple branches of trajectories are involved. PMID- 29495766 TI - Capillary waves as eigenmodes of the density correlation at liquid surfaces. AB - We analyze the density correlations in a liquid-vapor surface to establish a quantitative connection between the Density Functional (DF) formalism, Molecular Dynamic (MD) simulations, and the Capillary Wave (CW) theory. Instead of the integrated structure factor, we identify the CW fluctuations as eigenmodes of the correlation function. The square-gradient DF approximation appears as fully consistent with the use of the thermodynamic surface tension to describe the surface fluctuations for any wavevector because it misses the upper cutoff in the surface Hamiltonian from the merging of the CW mode with the non-CW band. This mesoscopic cutoff may be accurately predicted from the main peak in the structure factor of the bulk liquid. We explore the difference between the full density density correlation mode and the bare CW that represents the correlation between the corrugation of the intrinsic surface and the density at the interfacial region. The non-local decay of the CW effects, predicted from DF analysis and observed in MD simulations with the intrinsic sampling method, is found to characterize the bare CW fluctuations, which also require a wavevector-dependent surface tension. PMID- 29495767 TI - A new ab initio potential energy surface for the NH-He complex. AB - We present a new three-dimensional potential energy surface (PES) for the NH(X3Sigma-)-He van der Waals system, which explicitly takes into account the NH vibrational motion. The NH-He PES was obtained using the open-shell single- and double-excitation coupled cluster approach with non-iterative perturbational treatment of triple excitations. The augmented correlation-consistent aug-cc-pVXZ (X = Q, 5, 6) basis sets were employed, and the energies obtained were then extrapolated to the complete basis set limit. Using this new PES, we have studied the spectroscopy of the NH-He complex and we have determined a new rotational constant that agrees well with the available experimental data. Collisional excitation of NH(X3Sigma-) by He was also studied at the close-coupling level. Calculations of the collisional excitation cross sections of the fine-structure levels of NH by He were performed for energies up to 3500 cm-1, which yield, after thermal average, rate coefficients up to 350 K. The calculated rate coefficients are compared with available experimental measurements at room temperature, and a reasonably good agreement is found between experimental and theoretical data. PMID- 29495768 TI - Photoexcitation of iodide ion-pyrimidine clusters above the electron detachment threshold: Intracluster electron transfer versus nucleobase-centred excitations. AB - Laser photodissociation spectroscopy of the I-.thymine (I-.T) and I-.cytosine (I .C) nucleobase clusters has been conducted for the first time across the regions above the electron detachment thresholds to explore the excited states and photodissociation channels. Although photodepletion is strong, only weak ionic photofragment signals are observed, indicating that the clusters decay predominantly by electron detachment. The photodepletion spectra of the I-.T and I-.C clusters display a prominent dipole-bound excited state (I) in the vicinity of the vertical detachment energy (~4.0 eV). Like the previously studied I .uracil (I-.U) cluster [W. L. Li et al., J. Chem. Phys. 145, 044319 (2016)], the I-.T cluster also displays a second excited state (II) centred at 4.8 eV, which we similarly assign to a pi-pi* nucleobase-localized transition. However, no distinct higher-energy absorption bands are evident in the spectra of the I-.C. Time-dependent density functional theory (TDDFT) calculations are presented, showing that while each of the I-.T and I-.U clusters displays a single dominant pi-pi* nucleobase-localized transition, the corresponding pi-pi* nucleobase transitions for I-.C are split across three separate weaker electronic excitations. I- and deprotonated nucleobase anion photofragments are observed upon photoexcitation of both I-.U and I-.T, with the action spectra showing bands (at 4.0 and 4.8 eV) for both the I- and deprotonated nucleobase anion production. The photofragmentation behaviour of the I-.C cluster is distinctive as its I- photofragment displays a relatively flat profile above the expected vertical detachment energy. We discuss the observed photofragmentation profiles of the I .pyrimidine clusters, in the context of the previous time-resolved measurements, and conclude that the observed photoexcitations are primarily consistent with intracluster electron transfer dominating in the near-threshold region, while nucleobase-centred excitations dominate close to 4.8 eV. TDDFT calculations suggest that charge-transfer transitions [Iodide n (5p6) -> Uracil sigma*] may contribute to the cluster absorption profile across the scanned spectral region, and the possible role of these states is also discussed. PMID- 29495770 TI - Steady state sedimentation of ultrasoft colloids. AB - The structural and dynamical properties of ultra-soft colloids-star polymers exposed to a uniform external force field are analyzed by applying the multiparticle collision dynamics technique, a hybrid coarse-grain mesoscale simulation approach, which captures thermal fluctuations and long-range hydrodynamic interactions. In the weak-field limit, the structure of the star polymer is nearly unchanged; however, in an intermediate regime, the radius of gyration decreases, in particular transverse to the sedimentation direction. In the limit of a strong field, the radius of gyration increases with field strength. Correspondingly, the sedimentation coefficient increases with increasing field strength, passes through a maximum, and decreases again at high field strengths. The maximum value depends on the functionality of the star polymer. High field strengths lead to symmetry breaking with trailing, strongly stretched polymer arms and a compact star-polymer body. In the weak-field-linear response regime, the sedimentation coefficient follows the scaling relation of a star polymer in terms of functionality and arm length. PMID- 29495771 TI - Comparing the accuracy of perturbative and variational calculations for predicting fundamental vibrational frequencies of dihalomethanes. AB - Three dihalogenated methane derivatives (CH2F2, CH2FCl, and CH2Cl2) were used as model systems to compare and assess the accuracy of two different approaches for predicting observed fundamental frequencies: canonical operator Van Vleck vibrational perturbation theory (CVPT) and vibrational configuration interaction (VCI). For convenience and consistency, both methods employ the Watson Hamiltonian in rectilinear normal coordinates, expanding the potential energy surface (PES) as a Taylor series about equilibrium and constructing the wavefunction from a harmonic oscillator product basis. At the highest levels of theory considered here, fourth-order CVPT and VCI in a harmonic oscillator basis with up to 10 quanta of vibrational excitation in conjunction with a 4-mode representation sextic force field (SFF-4MR) computed at MP2/cc-pVTZ with replacement CCSD(T)/aug-cc-pVQZ harmonic force constants, the agreement between computed fundamentals is closer to 0.3 cm-1 on average, with a maximum difference of 1.7 cm-1. The major remaining accuracy-limiting factors are the accuracy of the underlying electronic structure model, followed by the incompleteness of the PES expansion. Nonetheless, computed and experimental fundamentals agree to within 5 cm-1, with an average difference of 2 cm-1, confirming the utility and accuracy of both theoretical models. One exception to this rule is the formally IR-inactive but weakly allowed through Coriolis-coupling H-C-H out-of-plane twisting mode of dichloromethane, whose spectrum we therefore revisit and reassign. We also investigate convergence with respect to order of CVPT, VCI excitation level, and order of PES expansion, concluding that premature truncation substantially decreases accuracy, although VCI(6)/SFF-4MR results are still of acceptable accuracy, and some error cancellation is observed with CVPT2 using a quartic force field. PMID- 29495769 TI - Isotopic equilibria in aqueous clusters at low temperatures: Insights from the MB pol many-body potential. AB - By combining path-integrals molecular dynamics simulations with the accurate MB pol potential energy surface, we investigate the role of alternative potential models on isotopic fractionation ratios between H and D atoms at dangling positions in water clusters at low temperatures. Our results show clear stabilizations of the lighter isotope at dangling sites, characterized by free energy differences DeltaG that become comparable to or larger than kBT for temperatures below ~75 K. The comparison between these results to those previously reported using the empirical q-TIP4P/F water model [P. E. Videla et al., J. Phys. Chem. Lett. 5, 2375 (2014)] reveals that the latter Hamiltonian overestimates the H stabilization by ~25%. Moreover, predictions from the MB-pol model are in much better agreement with measured results reported for similar isotope equilibria at ice surfaces. The dissection of the quantum kinetic energies into orthogonal directions shows that the dominant differences between the two models are to be found in the anharmonic characteristics of the potential energy surfaces along OH bond directions involved in hydrogen bonds. PMID- 29495772 TI - Stresses in non-equilibrium fluids: Exact formulation and coarse-grained theory. AB - Starting from the stochastic equation for the density operator, we formulate the exact (instantaneous) stress tensor for interacting Brownian particles and show that its average value agrees with expressions derived previously. We analyze the relation between the stress tensor and forces due to external potentials and observe that, out of equilibrium, particle currents give rise to extra forces. Next, we derive the stress tensor for a Landau-Ginzburg theory in generic, non equilibrium situations, finding an expression analogous to that of the exact microscopic stress tensor, and discuss the computation of out-of-equilibrium (classical) Casimir forces. Subsequently, we give a general form for the stress tensor which is valid for a large variety of energy functionals and which reproduces the two mentioned cases. We then use these relations to study the spatio-temporal correlations of the stress tensor in a Brownian fluid, which we compute to leading order in the interaction potential strength. We observe that, after integration over time, the spatial correlations generally decay as power laws in space. These are expected to be of importance for driven confined systems. We also show that divergence-free parts of the stress tensor do not contribute to the Green-Kubo relation for the viscosity. PMID- 29495773 TI - Universal behavior of soft-core fluids near the threshold of thermodynamic stability. AB - We study, by using liquid-state theories and Monte Carlo simulation, the behavior of systems of classical particles interacting through a finite pair repulsion supplemented with a longer range attraction. Any such potential can be driven Ruelle-unstable by increasing the attraction at the expense of repulsion, until the thermodynamic limit is lost. By examining several potential forms, we find that all systems exhibit a qualitatively similar behavior in the fluid phase as the threshold of thermodynamic stability is approached (and possibly surpassed). The general feature underlying the approach to Ruelle instability is a pronounced widening of the liquid-vapor binodal (and spinodal) line at low temperatures, to such an extent that at the stability threshold a vanishing-density vapor would coexist with a diverging-density liquid. We attempt to rationalize the universal pathway to Ruelle instability in soft-core fluids by appealing to a heuristic argument. PMID- 29495774 TI - Equipartition terms in transition path ensemble: Insights from molecular dynamics simulations of alanine dipeptide. AB - Transition path ensemble consists of reactive trajectories and possesses all the information necessary for the understanding of the mechanism and dynamics of important condensed phase processes. However, quantitative description of the properties of the transition path ensemble is far from being established. Here, with numerical calculations on a model system, the equipartition terms defined in thermal equilibrium were for the first time estimated in the transition path ensemble. It was not surprising to observe that the energy was not equally distributed among all the coordinates. However, the energies distributed on a pair of conjugated coordinates remained equal. Higher energies were observed to be distributed on several coordinates, which are highly coupled to the reaction coordinate, while the rest were almost equally distributed. In addition, the ensemble-averaged energy on each coordinate as a function of time was also quantified. These quantitative analyses on energy distributions provided new insights into the transition path ensemble. PMID- 29495775 TI - Free energy and entropy of a dipolar liquid by computer simulations. AB - Thermodynamic properties for a system composed of dipolar molecules are computed. Free energy is evaluated by means of the thermodynamic integration technique, and it is also estimated by using a perturbation theory approach, in which every molecule is modeled as a hard sphere within a square well, with an electric dipole at its center. The hard sphere diameter, the range and depth of the well, and the dipole moment have been calculated from properties easily obtained in molecular dynamics simulations. Connection between entropy and dynamical properties is explored in the liquid and supercooled states by using instantaneous normal mode calculations. A model is proposed in order to analyze translation and rotation contributions to entropy separately. Both contributions decrease upon cooling, and a logarithmic correlation between excess entropy associated with translation and the corresponding proportion of imaginary frequency modes is encountered. Rosenfeld scaling law between reduced diffusion and excess entropy is tested, and the origin of its failure at low temperatures is investigated. PMID- 29495776 TI - Generalized elimination of the global translation from explicitly correlated Gaussian functions. AB - This paper presents the multi-channel generalization of the center-of-mass kinetic energy elimination approach [B. Simmen et al., Mol. Phys. 111, 2086 (2013)] when the Schrodinger equation is solved variationally with explicitly correlated Gaussian functions. The approach has immediate relevance in many particle systems which are handled without the Born-Oppenheimer approximation and can be employed also for Dirac-type Hamiltonians. The practical realization and numerical properties of solving the Schrodinger equation in laboratory-frame Cartesian coordinates are demonstrated for the ground rovibronic state of the H2+={p+,p+,e-} ion and the H2 = {p+, p+, e-, e-} molecule. PMID- 29495777 TI - Absolute cross section measurements for the scattering of low- and intermediate energy electrons from PF3. II. Inelastic scattering of vibrational and electronic excitations. AB - As a sequel paper to our study of the elastic scattering for electron collisions with phosphorus trifluoride, PF3 molecules, we report absolute inelastic differential and integral cross sections (DCS and ICS) of vibrational excitations for the compound fundamental vibrational modes v13 (v1 + v3), v24 (v2 + v4), and their sum in the impact energy range of 2.0-10 eV and over a scattering angle range of 20 degrees -130 degrees . The measured angular distributions of scattered electron intensities for the present inelastic scattering are normalized to the elastic peak intensity corresponding to the DCSs of He. These vibrational excitation measurements demonstrate the presence of resonances around 2 eV and also around 6-10 eV. In addition, a generalized oscillator strength analysis is applied to derive oscillator strength f0-values and (unscaled Born) ICSs from the corresponding DCSs measured for the low-lying optically allowed 8a1 1 -> 7e (sigma*) excitation band, which is assigned as the Jahn-Teller splitting and 8a1-1 -> 4s Rydberg transition at impact energies of 100, 200, and 300 eV, over a scattering angle range of 1.0 degrees -15 degrees . The f0-values obtained in the present study are compared with the results of previous photoabsorption and pseudo-optical measurements. The unscaled Born ICSs are compared with the binary-encounter f-scaled Born ICSs estimated over a wide impact energy region from the excitation thresholds. PMID- 29495778 TI - Dissociation kinetics of excited ions: PEPICO measurements of Os3(CO)12 - The 7 35 eV single ionization binding energy region. AB - In this article, we study the photoinduced dissociation pathways of a metallocarbonyl, Os3(CO)12, in particular the consecutive loss of CO groups. To do so, we performed photoelectron-photoion coincidence (PEPICO) measurements in the single ionization binding energy region from 7 to 35 eV using 45-eV photons. Zero-energy ion appearance energies for the dissociation steps were extracted by modeling the PEPICO data using the statistical adiabatic channel model. Upon ionization to the excited ionic states above 13 eV binding energy, non statistical behavior was observed and assigned to prompt CO loss. Double ionization was found to be dominated by the knockout process with an onset of 20.9 +/- 0.4 eV. The oscillator strength is significantly larger for energies above 26.6 +/- 0.4 eV, corresponding to one electron being ejected from the Os3 center and one from the CO ligands. The cross section for double ionization was found to increase linearly up to 35 eV ionization energy, at which 40% of the generated ions are doubly charged. PMID- 29495779 TI - Trapping of diffusing particles by spiky absorbers. AB - We study trapping of particles diffusing on a flat surface by complex-shaped absorbers formed by periodic absorbing spikes protruding from absorbing circular cores. It is shown that a spiky absorber can be replaced by an equivalent, from the trapping point of view, circular absorber of properly chosen radius. A simple expression for the effective absorber radius in terms of the geometric parameters of the spiky absorber (the number and length of the spikes and the core radius) is derived. To check its accuracy and to establish the range of its applicability, we run Brownian dynamics simulations and obtain the mean lifetimes of particles diffusing inside a reflecting circle with different spiky absorbers placed in its center. These mean lifetimes are then compared with their counterparts given by the theory for equivalent circular absorbers. There is an excellent agreement between the lifetimes obtained by the two methods when the radius of the reflecting circle is sufficiently large. PMID- 29495780 TI - Bounds on stochastic chemical kinetic systems at steady state. AB - The method of moments has been proposed as a potential means to reduce the dimensionality of the chemical master equation (CME) appearing in stochastic chemical kinetics. However, attempts to apply the method of moments to the CME usually result in the so-called closure problem. Several authors have proposed moment closure schemes, which allow them to obtain approximations of quantities of interest, such as the mean molecular count for each species. However, these approximations have the dissatisfying feature that they come with no error bounds. This paper presents a fundamentally different approach to the closure problem in stochastic chemical kinetics. Instead of making an approximation to compute a single number for the quantity of interest, we calculate mathematically rigorous bounds on this quantity by solving semidefinite programs. These bounds provide a check on the validity of the moment closure approximations and are in some cases so tight that they effectively provide the desired quantity. In this paper, the bounded quantities of interest are the mean molecular count for each species, the variance in this count, and the probability that the count lies in an arbitrary interval. At present, we consider only steady-state probability distributions, intending to discuss the dynamic problem in a future publication. PMID- 29495781 TI - Kosmotropic effect leads to LCST decrease in thermoresponsive polymer solutions. AB - We study the phenomena of decrease in lower critical solution temperature (LCST) with addition of kosmotropic (order-making) cosolvents in thermoresponsive polymer solutions. A combination of explicit solvent coarse-grained simulations and mean-field theory has been employed. The polymer-solvent LCST behavior in the theoretical models has been incorporated through the Kolomeisky-Widom solvophobic potential. Our results illustrate how the decrease in the LCST can be achieved by the reduction in the bulk solvent energy with the addition of cosolvent. It is shown that this effect of cosolvent is weaker with an increase in polymer hydrophilicity which can explain the absence of a LCST decrease in poly(N,N diethylacrylamide), water, and methanol systems. The coarse-grained nature of the models indicates that a mean energetic representation of the system is sufficient to understand the phenomena of LCST decrease. PMID- 29495782 TI - Classification of conductance traces with recurrent neural networks. AB - We present a new automated method for structural classification of the traces obtained in break junction experiments. Using recurrent neural networks trained on the traces of minimal cross-sectional area in molecular dynamics simulations, we successfully separate the traces into two classes: point contact or nanowire. This is done without any assumptions about the expected features of each class. The trained neural network is applied to experimental break junction conductance traces, and it separates the classes as well as the previously used experimental methods. The effect of using partial conductance traces is explored, and we show that the method performs equally well using full or partial traces (as long as the trace just prior to breaking is included). When only the initial part of the trace is included, the results are still better than random chance. Finally, we show that the neural network classification method can be used to classify experimental conductance traces without using simulated results for training, but instead training the network on a few representative experimental traces. This offers a tool to recognize some characteristic motifs of the traces, which can be hard to find by simple data selection algorithms. PMID- 29495784 TI - Ice nucleation rates near ~225 K. AB - We have measured the ice nucleation rates, Jice, in supercooled nano-droplets with radii ranging from 6.6 nm to 10 nm and droplet temperatures, Td, ranging from 225 K to 204 K. The initial temperature of the 10 nm water droplets is ~250 K, i.e., well above the homogeneous nucleation temperature for micron sized water droplets, TH ~235 K. The nucleation rates increase systematically from ~1021 cm-3 s-1 to ~1022 cm-3 s-1 in this temperature range, overlap with the nucleation rates of Manka et al. [Phys. Chem. Chem. Phys. 14, 4505 (2012)], and suggest that experiments with larger droplets would extrapolate smoothly the rates of Hagen et al. [J. Atmos. Sci. 38, 1236 (1981)]. The sharp corner in the rate data as temperature drops is, however, difficult to match with available theory even if we correct classical nucleation theory and the physical properties of water for the high internal pressure of the nanodroplets. PMID- 29495783 TI - Force-extension behavior of DNA in the presence of DNA-bending nucleoid associated proteins. AB - Interactions between nucleoid associated proteins (NAPs) and DNA affect DNA polymer conformation, leading to phenomena such as concentration dependent force extension behavior. These effects, in turn, also impact the local binding behavior of the protein, such as high forces causing proteins to unbind, or proteins binding favorably to locally bent DNA. We develop a coarse-grained NAP DNA simulation model that incorporates both force- and concentration-dependent behaviors, in order to study the interplay between NAP binding and DNA conformation. This model system includes multi-state protein binding and unbinding, motivated by prior work, but is now dependent on the local structure of the DNA, which is related to external forces acting on the DNA strand. We observe the expected qualitative binding behavior, where more proteins are bound at lower forces than at higher forces. Our model also includes NAP-induced DNA bending, which affects DNA elasticity. We see semi-quantitative matching of our simulated force-extension behavior to the reported experimental data. By using a coarse-grained simulation, we are also able to look at non-equilibrium behaviors, such as dynamic extension of a DNA strand. We stretch a DNA strand at different rates and at different NAP concentrations to observe how the time scales of the system (such as pulling time and unbinding time) work in concert. When these time scales are similar, we observe measurable rate-dependent changes in the system, which include the number of proteins bound and the force required to extend the DNA molecule. This suggests that the relative time scales of different dynamic processes play an important role in the behavior of NAP-DNA systems. PMID- 29495785 TI - Kinetics of CO+ and CO2+ with N and O atoms. AB - We have measured reaction rate constants for CO+ and CO2+ reacting with N and O atoms using a selected ion flow tube apparatus equipped with a microwave discharge atom source. Experimental work was supplemented by molecular structure calculations. Calculated pathways show the sensitivity of kinetic barriers to theoretical methods and imply that high-level ab initio methods are required for accurate energetics. We report room-temperature rate constants of 1.0 +/- 0.4 * 10-11 cm3 s-1 and 4.0 +/- 1.6 * 10-11 cm3 s-1 for the reactions of CO+ with N and O atoms, respectively, and 8.0 +/- 3.0 * 10-12 cm3 s-1 and 2.0 +/- 0.8 * 10-11 cm3 s-1 for the reactions of CO2+ with N and O atoms, respectively. The reaction of CO2+ + O is observed to yield O2+ exclusively. These values help resolve discrepancies in the literature and are important for modeling of the Martian atmosphere. PMID- 29495786 TI - An improved coupled-states approximation including the nearest neighbor Coriolis couplings for diatom-diatom inelastic collision. AB - Solving the time-independent close coupling equations of a diatom-diatom inelastic collision system by using the rigorous close-coupling approach is numerically difficult because of its expensive matrix manipulation. The coupled states approximation decouples the centrifugal matrix by neglecting the important Coriolis couplings completely. In this work, a new approximation method based on the coupled-states approximation is presented and applied to time-independent quantum dynamic calculations. This approach only considers the most important Coriolis coupling with the nearest neighbors and ignores weaker Coriolis couplings with farther K channels. As a result, it reduces the computational costs without a significant loss of accuracy. Numerical tests for para-H2+ortho H2 and para-H2+HD inelastic collision were carried out and the results showed that the improved method dramatically reduces the errors due to the neglect of the Coriolis couplings in the coupled-states approximation. This strategy should be useful in quantum dynamics of other systems. PMID- 29495787 TI - Thermodynamics of single polyethylene and polybutylene glycols with hydrogen bonding ends: A transition from looped to open conformations. AB - A variety of linear polymer precursors with hydrogen bonding motifs at both ends enable us to design supramolecular polymer systems with tailored macroscopic properties including self-healing. In this study, we investigate thermodynamic properties of single polyethylene and polybutylene glycols with hydrogen bonding motifs. In this context, we first build a coarse-grained model of building blocks of the supramolecular polymer system based on all-atom molecular structures. The density of states of the single precursor is obtained using the stochastic approximation Monte Carlo method. Constructing canonical partition functions from the density of states, we find the transition from looped to open conformations at transition temperatures which are non-monotonously changing with an increasing degree of polymerization due to the competition between chain stiffness and loop forming entropy penalty. In the complete range of chain length under investigation, a coexistence of the looped and open morphologies at the transition temperature is shown regardless of whether the transition is first order-like or continuous. Polyethylene and polybutylene glycols show similar behavior in all the thermodynamic properties but the transition temperature of the more flexible polybutylene glycol is shown to change more gradually. PMID- 29495788 TI - Density functional theory of electron transfer beyond the Born-Oppenheimer approximation: Case study of LiF. AB - We perform model calculations for a stretched LiF molecule, demonstrating that nonadiabatic charge transfer effects can be accurately and seamlessly described within a density functional framework. In alkali halides like LiF, there is an abrupt change in the ground state electronic distribution due to an electron transfer at a critical bond length R = Rc, where an avoided crossing of the lowest adiabatic potential energy surfaces calls the validity of the Born Oppenheimer approximation into doubt. Modeling the R-dependent electronic structure of LiF within a two-site Hubbard model, we find that nonadiabatic electron-nuclear coupling produces a sizable elongation of the critical Rc by 0.5 bohr. This effect is very accurately captured by a simple and rigorously derived correction, with an M-1 prefactor, to the exchange-correlation potential in density functional theory, M = reduced nuclear mass. Since this nonadiabatic term depends on gradients of the nuclear wave function and conditional electronic density, ?Rchi(R) and ?Rn(r, R), it couples the Kohn-Sham equations at neighboring R points. Motivated by an observed localization of nonadiabatic effects in nuclear configuration space, we propose a local conditional density approximation-an approximation that reduces the search for nonadiabatic density functionals to the search for a single function y(n). PMID- 29495789 TI - Electronic energy transfer through non-adiabatic vibrational-electronic resonance. II. 1D spectra for a dimer. AB - Vibrational-electronic resonance in photosynthetic pigment-protein complexes invalidates Forster's adiabatic framework for interpreting spectra and energy transfer, thus complicating determination of how the surrounding protein affects pigment properties. This paper considers the combined effects of vibrational electronic resonance and inhomogeneous variations in the electronic excitation energies of pigments at different sites on absorption, emission, circular dichroism, and hole-burning spectra for a non-degenerate homodimer. The non degenerate homodimer has identical pigments in different sites that generate differences in electronic energies, with parameters loosely based on bacteriochlorophyll a pigments in the Fenna-Matthews-Olson antenna protein. To explain the intensity borrowing, the excited state vibrational-electronic eigenvectors are discussed in terms of the vibrational basis localized on the individual pigments, as well as the correlated/anti-correlated vibrational basis delocalized over both pigments. Compared to those in the isolated pigment, vibrational satellites for the correlated vibration have the same frequency and precisely a factor of 2 intensity reduction through vibrational delocalization in both absorption and emission. Vibrational satellites for anti-correlated vibrations have their relaxed emission intensity reduced by over a factor 2 through vibrational and excitonic delocalization. In absorption, anti-correlated vibrational satellites borrow excitonic intensity but can be broadened away by the combination of vibronic resonance and site inhomogeneity; in parallel, their vibronically resonant excitonic partners are also broadened away. These considerations are consistent with photosynthetic antenna hole-burning spectra, where sharp vibrational and excitonic satellites are absent. Vibrational excitonic resonance barely alters the inhomogeneously broadened linear absorption, emission, and circular dichroism spectra from those for a purely electronic excitonic coupling model. Energy transfer can leave excess energy behind as vibration on the electronic ground state of the donor, allowing vibrational relaxation on the donor's ground electronic state to make energy transfer permanent by removing excess energy from the excited electronic state of the dimer. PMID- 29495790 TI - Coupled-channel study of the Rydberg-valence interaction in HBr. AB - We report an ab initio study of the low-lying valence and Rydberg states of HBr. The calculations are carried out employing the multireference single- and double excitation configuration interaction method including the spin-orbit interaction. The first excited adiabatic potential of 1Sigma+ symmetry presents two minima which correspond to the Rydberg E1Sigma+ and valence V1Sigma+ observed states. We calculate the vibrational levels of these two states using a coupled-channel treatment based on the two diabatic potentials deduced from the ab initio adiabatic potentials and the Rydberg-valence interaction. The chaotic energy separations between the observed levels are well reproduced in the calculations. We have also obtained for the first time theoretical data for numerous Rydberg states of HBr lying in the (66-79) * 103 cm-1 excitation energy interval. The calculated spectroscopic parameters are found to be in good agreement with experiment and provide a basis for future studies of radiative and non-radiative processes in the HBr molecule. PMID- 29495792 TI - Method for making 2-electron response reduced density matrices approximately N representable. AB - In methods like geminal-based approaches or coupled cluster that are solved using the projected Schrodinger equation, direct computation of the 2-electron reduced density matrix (2-RDM) is impractical and one falls back to a 2-RDM based on response theory. However, the 2-RDMs from response theory are not N representable. That is, the response 2-RDM does not correspond to an actual physical N-electron wave function. We present a new algorithm for making these non-N-representable 2-RDMs approximately N-representable, i.e., it has the right symmetry and normalization and it fulfills the P-, Q-, and G-conditions. Next to an algorithm which can be applied to any 2-RDM, we have also developed a 2-RDM optimization procedure specifically for seniority-zero 2-RDMs. We aim to find the 2-RDM with the right properties which is the closest (in the sense of the Frobenius norm) to the non-N-representable 2-RDM by minimizing the square norm of the difference between this initial response 2-RDM and the targeted 2-RDM under the constraint that the trace is normalized and the 2-RDM, Q-matrix, and G-matrix are positive semidefinite, i.e., their eigenvalues are non-negative. Our method is suitable for fixing non-N-representable 2-RDMs which are close to being N representable. Through the N-representability optimization algorithm we add a small correction to the initial 2-RDM such that it fulfills the most important N representability conditions. PMID- 29495791 TI - Temperature-dependent conformations of exciton-coupled Cy3 dimers in double stranded DNA. AB - Understanding the properties of electronically interacting molecular chromophores, which involve internally coupled electronic-vibrational motions, is important to the spectroscopy of many biologically relevant systems. Here we apply linear absorption, circular dichroism, and two-dimensional fluorescence spectroscopy to study the polarized collective excitations of excitonically coupled cyanine dimers (Cy3)2 that are rigidly positioned within the opposing sugar-phosphate backbones of the double-stranded region of a double-stranded (ds) single-stranded (ss) DNA fork construct. We show that the exciton-coupling strength of the (Cy3)2-DNA construct can be systematically varied with temperature below the ds-ss DNA denaturation transition. We interpret spectroscopic measurements in terms of the Holstein vibronic dimer model, from which we obtain information about the local conformation of the (Cy3)2 dimer, as well as the degree of static disorder experienced by the Cy3 monomer and the (Cy3)2 dimer probe locally within their respective DNA duplex environments. The properties of the (Cy3)2-DNA construct we determine suggest that it may be employed as a useful model system to test fundamental concepts of protein-DNA interactions and the role of electronic-vibrational coherence in electronic energy migration within exciton-coupled bio-molecular arrays. PMID- 29495793 TI - Langevin synchronization in a time-dependent, harmonic basin: An exact solution in 1D. AB - The trajectories of two particles undergoing Langevin dynamics while sharing a common noise sequence can merge into a single (master) trajectory. Here, we present an exact solution for a particle undergoing Langevin dynamics in a harmonic, time-dependent potential, thus extending the idea of synchronization to nonequilibrium systems. We calculate the synchronization level, i.e., the mismatch between two trajectories sharing a common noise sequence, in the underdamped, critically damped, and overdamped regimes. Finally, we provide asymptotic expansions in various limiting cases and compare to the time independent case. PMID- 29495794 TI - Erratum: "Microscopic observation of the segmental orientation autocorrelation function for entangled and constrained polymer chains" [J. Chem. Phys. 146, 094902 (2017)]. PMID- 29495795 TI - The any particle molecular orbital grid-based Hartree-Fock (APMO-GBHF) approach. AB - The any particle molecular orbital grid-based Hartree-Fock approach (APMO-GBHF) is proposed as an initial step to perform multi-component post-Hartree-Fock, explicitly correlated, and density functional theory methods without basis set errors. The method has been applied to a number of electronic and multi-species molecular systems. Results of these calculations show that the APMO-GBHF total energies are comparable with those obtained at the APMO-HF complete basis set limit. In addition, results reveal a considerable improvement in the description of the nuclear cusps of electronic and non-electronic densities. PMID- 29495796 TI - Importance of rotational adiabaticity in collisions of CO2 super rotors with Ar and He. AB - The collision dynamics of optically centrifuged CO2 with Ar and He are reported here. The optical centrifuge produces an ensemble of CO2 molecules in high rotational states (with J ~ 220) with oriented angular momentum. Polarization dependent high-resolution transient IR absorption spectroscopy was used to measure the relaxation dynamics in the presence of Ar or He by probing the CO2 J = 76 and 100 states with Erot=2306 and 3979 cm-1, respectively. The data show that He relaxes the CO2 super rotors more quickly than Ar. Doppler-broadened line profiles show that He collisions induce substantially larger rotation-to translation energy transfer. CO2 super rotors have greater orientational anisotropy with He collisions and the anisotropy from the He collisions persists longer than with Ar. Super rotor relaxation dynamics are discussed in terms of mass effects related to classical gyroscope physics and collisional rotational adiabaticity. PMID- 29495797 TI - A novel multiplex absorption spectrometer for time-resolved studies. AB - A Time-Resolved Ultraviolet/Visible (UV/Vis) Absorption Spectrometer (TRUVAS) has been developed that can simultaneously monitor absorption at all wavelengths between 200 and 800 nm with millisecond time resolution. A pulsed photolysis laser (KrF 248 nm) is used to initiate chemical reactions that create the target species. The absorption signals from these species evolve as the composition of the gas in the photolysis region changes over time. The instrument can operate at pressures over the range ~10-800 Torr and can measure time-resolved absorbances <10-4 in the UV (300 nm) and even lower in the visible (580 nm) 2.3 * 10-5, with the peak of sensitivity at ~500 nm. The novelty of this setup lies in the arrangement of the multipass optics. Although appearing similar to other multipass optical systems (in particular the Herriott cell), there are fundamental differences, most notably the ability to adjust each mirror to maximise the overlap between the probe beam and the photolysis laser. Another feature which aids the sensitivity and versatility of the system is the use of 2 high-throughput spectrographs coupled with sensitive line-array CCDs, which can measure absorbance from ~200 to 800 nm simultaneously. The capability of the instrument is demonstrated via measurements of the absorption spectrum of the peroxy radical, HOCH2CH2O2, and its self-reaction kinetics. PMID- 29495798 TI - Novel instrument for characterizing comprehensive physical properties under multi mechanical loads and multi-physical field coupling conditions. AB - Functional materials represented by ferromagnetics and ferroelectrics are widely used in advanced sensor and precision actuation due to their special characterization under coupling interactions of complex loads and external physical fields. However, the conventional devices for material characterization can only provide a limited type of loads and physical fields and cannot simulate the actual service conditions of materials. A multi-field coupling instrument for characterization has been designed and implemented to overcome this barrier and measure the comprehensive physical properties under complex service conditions. The testing forms include tension, compression, bending, torsion, and fatigue in mechanical loads, as well as different external physical fields, including electric, magnetic, and thermal fields. In order to offer a variety of information to reveal mechanical damage or deformation forms, a series of measurement methods at the microscale are integrated with the instrument including an indentation unit and in situ microimaging module. Finally, several coupling experiments which cover all the loading and measurement functions of the instrument have been implemented. The results illustrate the functions and characteristics of the instrument and then reveal the variety in mechanical and electromagnetic properties of the piezoelectric transducer ceramic, TbDyFe alloy, and carbon fiber reinforced polymer under coupling conditions. PMID- 29495799 TI - Detailed precision and accuracy analysis of swarm parameters from a pulsed Townsend experiment. AB - A newly built pulsed Townsend experimental setup which allows one to measure both electron and ion currents is presented. The principle of pulsed Townsend measurements itself is well established to obtain swarm parameters such as the effective ionization rate coefficient, the density-reduced mobility, and the density-normalized longitudinal diffusion coefficient. The main novelty of the present contribution is a detailed and comprehensive analysis of the entire measurement and evaluation chain with respect to accuracy, precision, and reproducibility. The influence of the input parameters (gap distance, applied voltage, measured pressure, and temperature) is analyzed in detail. An overall accuracy of +/-0.5% in the density reduced electric field (E/N) is achieved, which is close to the theoretically possible limit using the chosen components. The precision of the experimental results is higher than the accuracy. Through an extensive measurement campaign, the repeatability of our measurements proved to be high and similar to the precision. The reproducibility of results at identical (E/N) is similar to the precision for different distances but decreases for varying pressures. For benchmark purposes, measurements for Ar, CO2, and N2 are presented and compared with our previous experimental setup, simulations, and other experimental references. PMID- 29495800 TI - Demonstration of laser-produced neutron diagnostic by radiative capture gamma rays. AB - We report a new scenario of the time-of-flight technique in which fast neutrons and delayed gamma-ray signals were both recorded in a millisecond time window in harsh environments induced by high-intensity lasers. The delayed gamma signals, arriving far later than the original fast neutron and often being ignored previously, were identified to be the results of radiative captures of thermalized neutrons. The linear correlation between the gamma photon number and the fast neutron yield shows that these delayed gamma events can be employed for neutron diagnosis. This method can reduce the detecting efficiency dropping problem caused by prompt high-flux gamma radiation and provides a new way for neutron diagnosing in high-intensity laser-target interaction experiments. PMID- 29495801 TI - Increased interference fringe visibility from the post-fabrication heat treatment of a perfect crystal silicon neutron interferometer. AB - We find that annealing a previously chemically etched interferometer at 800 degrees C dramatically increased the interference fringe visibility from 23% to 90%. The Bragg plane misalignments were also measured before and after annealing using neutron rocking curves, showing that Bragg plane alignment was improved across the interferometer after annealing. This suggests that current interferometers with low fringe visibility may be salvageable and that annealing may become an important step in the fabrication process of future neutron interferometers, leading to less need for chemical etching and larger more exotic neutron interferometers. PMID- 29495802 TI - Noninvasive estimation of assist pressure for direct mechanical ventricular actuation. AB - Direct mechanical ventricular actuation is effective to reestablish the ventricular function with non-blood contact. Due to the energy loss within the driveline of the direct cardiac compression device, it is necessary to acquire the accurate value of assist pressure acting on the heart surface. To avoid myocardial trauma induced by invasive sensors, the noninvasive estimation method is developed and the experimental device is designed to measure the sample data for fitting the estimation models. By examining the goodness of fit numerically and graphically, the polynomial model presents the best behavior among the four alternative models. Meanwhile, to verify the effect of the noninvasive estimation, the simplified lumped parameter model is utilized to calculate the pre-support and the post-support left ventricular pressure. Furthermore, by adjusting the driving pressure beyond the range of the sample data, the assist pressure is estimated with the similar waveform and the post-support left ventricular pressure approaches the value of the adult healthy heart, indicating the good generalization ability of the noninvasive estimation method. PMID- 29495804 TI - Reactor for tracking catalyst nanoparticles in liquid at high temperature under a high-pressure gas phase with X-ray absorption spectroscopy. AB - Structure of catalyst nanoparticles dispersed in liquid phase at high temperature under gas phase of reactant(s) at higher pressure (>=5 bars) is important for fundamental understanding of catalytic reactions performed on these catalyst nanoparticles. Most structural characterizations of a catalyst performing catalysis in liquid at high temperature under gas phase at high pressure were performed in an ex situ condition in terms of characterizations before or after catalysis since, from technical point of view, access to the catalyst nanoparticles during catalysis in liquid phase at high temperature under high pressure reactant gas is challenging. Here we designed a reactor which allows us to perform structural characterization using X-ray absorption spectroscopy including X-ray absorption near edge structure spectroscopy and extended X-ray absorption fine structure spectroscopy to study catalyst nanoparticles under harsh catalysis conditions in terms of liquid up to 350 degrees C under gas phase with a pressure up to 50 bars. This reactor remains nanoparticles of a catalyst homogeneously dispersed in liquid during catalysis and X-ray absorption spectroscopy characterization. PMID- 29495805 TI - A remotely triggered fast neutron detection instrument based on a plastic organic scintillator. AB - A detector system for the characterization of radiation fields of both fast neutrons and gamma rays is described comprising of a gated photomultiplier tube (PMT), an EJ299-33 solid organic scintillator detector, and an external trigger circuit. The objective of this development was to conceive a means by which the PMT in such a system can be actuated remotely during the high-intensity bursts of pulsed gamma-ray contamination that can arise during active interrogation procedures. The system is used to detect neutrons and gamma rays using established pulse-shape discrimination (PSD) techniques. The gating circuit enables the PMT to be switched off remotely. This is compatible with use during intense radiation transients to avoid saturation and the disruption of the operation of the PMT during the burst. Data are presented in the form of pulse height spectra and PSD scatter plots for the system triggered with a strobed light source. These confirm that the gain of the system and the throughput for both triggered and un-triggered scenarios are as expected, given the duty cycle of the stimulating radiation. This demonstrates that the triggering function does not perturb the system response of the detector. PMID- 29495803 TI - Experimental study on secondary electron emission characteristics of Cu. AB - Secondary electron emission (SEE) of a surface is the origin of the multipacting effect which could seriously deteriorate beam quality and even perturb the normal operation of particle accelerators. Experimental measurements on secondary electron yield (SEY) for different materials and coatings have been developed in many accelerator laboratories. In fact, the SEY is just one parameter of secondary electron emission characteristics which include spatial and energy distribution of emitted electrons. A novel experimental apparatus was set up in China Spallation Neutron Source, and an innovative method was applied to obtain the whole characteristics of SEE. Taking Cu as the sample, secondary electron yield, its dependence on beam injection angle, and the spatial and energy distribution of secondary electrons were achieved with this measurement device. The method for spatial distribution measurement was first proposed and verified experimentally. This contribution also tries to give all the experimental results a reasonable theoretical analysis and explanation. PMID- 29495806 TI - A variable partially polarizing beam splitter. AB - We present designs for variably polarizing beam splitters. These are beam splitters allowing the complete and independent control of the horizontal and vertical polarization splitting ratios. They have quantum optics and quantum information applications, such as quantum logic gates for quantum computing and non-local measurements for quantum state estimation. At the heart of each design is an interferometer. We experimentally demonstrate one particular implementation, a displaced Sagnac interferometer configuration, that provides an inherent instability to air currents and vibrations. Furthermore, this design does not require any custom-made optics but only common components which can be easily found in an optics laboratory. PMID- 29495807 TI - Characterization of a new Hencken burner with a transition from a reducing-to oxidizing environment for fundamental coal studies. AB - In pulverized coal burners, coal particles usually transition from a locally reducing environment to an oxidizing environment. The locally reducing environment in the near-burner region is due to a dense region of coal particles undergoing devolatilization. Following this region, the particles move into an oxidizing environment. This "reducing-to-oxidizing" transition can influence combustion processes such as ignition, particulate formation, and char burnout. To understand these processes at a fundamental level, a system is required that mimics such a transition. Hence, we have developed and characterized a two-stage Hencken burner to evaluate the effect of the reducing-to-oxidizing transition and particle-to-particle interaction (which characterizes dense region of coal particles) on ignition and ultrafine aerosol formation. The two-stage Hencken burner allows coal particles to experience a reducing environment followed by a transition to an oxidizing environment. This work presents the results of the design and characterization of the new two-stage Hencken burner and its new coal feeder. In a unique approach to the operation of the flat-flame of the Hencken burner, the flame configurations are operated as either a normal flame or inverse flame. Gas temperatures and oxygen concentrations for the Hencken burner are measured in reducing-to-oxidizing and oxidizing environments. The results show that stable flames with well-controlled conditions, relatively uniform temperatures, and species concentrations can be achieved in both flame configurations. This new Hencken burner provides an effective system for evaluating the effect of the reducing-to-oxidizing transition and particle-to particle interaction on early-stage processes of coal combustion such as ignition and ultrafine particle formation. PMID- 29495808 TI - A radio-frequency ion trap with string electrodes. AB - A radio-frequency (rf) ion trap with string electrodes is introduced. In this trap configuration, the rf electrodes are made of narrow metal strings, by which a negligibly small portion of light-induced fluorescence (LIF) is blocked. Then the LIF collection solid angle can be maximized. In the demonstration, barium ions are trapped and laser-cooled in the rf trap with string electrodes successfully, and the crystallization is confirmed by the LIF spectrum. PMID- 29495809 TI - Continuous stacking computational approach based automated microscope slide scanner. AB - Cost-effective and automated acquisition of whole slide images is a bottleneck for wide-scale deployment of digital pathology. In this article, a computation augmented approach for the development of an automated microscope slide scanner is presented. The realization of a prototype device built using inexpensive off the-shelf optical components and motors is detailed. The applicability of the developed prototype to clinical diagnostic testing is demonstrated by generating good quality digital images of malaria-infected blood smears. Further, the acquired slide images have been processed to identify and count the number of malaria-infected red blood cells and thereby perform quantitative parasitemia level estimation. The presented prototype would enable cost-effective deployment of slide-based cyto-diagnostic testing in endemic areas. PMID- 29495810 TI - Application of SQUIDs to low temperature and high magnetic field measurements Ultra low noise torque magnetometry. AB - Torque magnetometry is a key method to measure the magnetic anisotropy and quantum oscillations in metals. In order to resolve quantum oscillations in sub millimeter sized samples, piezo-electric micro-cantilevers were introduced. In the case of strongly correlated metals with large Fermi surfaces and high cyclotron masses, magnetic torque resolving powers in excess of 104 are required at temperatures well below 1 K and magnetic fields beyond 10 T. Here, we present a new broadband read-out scheme for piezo-electric micro-cantilevers via Wheatstone-type resistance measurements in magnetic fields up to 15 T and temperatures down to 200 mK. By using a two-stage superconducting-quantum interference device as a null detector of a cold Wheatstone bridge, we were able to achieve a magnetic moment resolution of Deltam = 4 * 10-15 J/T at maximal field and 700 mK, outperforming conventional magnetometers by at least one order of magnitude in this temperature and magnetic field range. Exemplary de Haas-van Alphen measurement of a newly grown delafossite, PdRhO2, was used to show the superior performance of our setup. PMID- 29495811 TI - Robust method for long-term energy and pointing stabilization of high energy, high average power solid state lasers. AB - A robust and simple method is presented for ensuring constant energy and pointing of a high average power solid state laser on a target. In addition to providing long-term stability, this scheme also eliminates any drifts in energy or pointing resulting from the initial warm-up after a cold start. This is achieved using two separate feedback loops: one loop stabilizes the pointing of the beam external to the amplifier cavity and the other locks the cavity mode to have optimum overlap with the pump spot on the active medium. The key idea of the cavity mode stabilization is to monitor the overlap of the cavity mode and the gain medium with a camera and control it with an actively controlled, intra-cavity mirror. While this method is demonstrated on a thin-disk regenerative amplifier, it can also be applied to a wide variety of solid state laser amplifiers. PMID- 29495812 TI - A MEMS SOI-based piezoresistive fluid flow sensor. AB - In this paper, a SOI (silicon-on-insulator)-based piezoresistive fluid flow sensor is presented; the presented flow sensor mainly consists of a nylon sensing head, stainless steel cantilever beam, SOI sensor chip, printed circuit board, half-cylinder gasket, and stainless steel shell. The working principle of the sensor and some detailed contrastive analysis about the sensor structure were introduced since the nylon sensing head and stainless steel cantilever beam have distinct influence on the sensor performance; the structure of nylon sensing head and stainless steel cantilever beam is also discussed. The SOI sensor chip was fabricated using micro-electromechanical systems technologies, such as reactive ion etching and low pressure chemical vapor deposition. The designed fluid sensor was packaged and tested; a calibration installation system was purposely designed for the sensor experiment. The testing results indicated that the output voltage of the sensor is proportional to the square of the fluid flow velocity, which is coincident with the theoretical derivation. The tested sensitivity of the sensor is 3.91 * 10-4 V ms2/kg. PMID- 29495813 TI - Evaluation of fiber Bragg grating sensor interrogation using InGaAs linear detector arrays and Gaussian approximation on embedded hardware. AB - Fiber Bragg Grating (FBG) sensors have become popular for applications related to structural health monitoring, biomedical engineering, and robotics. However, for successful large scale adoption, FBG interrogation systems are as important as sensor characteristics. Apart from accuracy, the required number of FBG sensors per fiber and the distance between the device in which the sensors are used and the interrogation system also influence the selection of the interrogation technique. For several measurement devices developed for applications in biomedical engineering and robotics, only a few sensors per fiber are required and the device is close to the interrogation system. For these applications, interrogation systems based on InGaAs linear detector arrays provide a good choice. However, their resolution is dependent on the algorithms used for curve fitting. In this work, a detailed analysis of the choice of algorithm using the Gaussian approximation for the FBG spectrum and the number of pixels used for curve fitting on the errors is provided. The points where the maximum errors occur have been identified. All comparisons for wavelength shift detection have been made against another interrogation system based on the tunable swept laser. It has been shown that maximum errors occur when the wavelength shift is such that one new pixel is included for curve fitting. It has also been shown that an algorithm with lower computation cost compared to the more popular methods using iterative non-linear least squares estimation can be used without leading to the loss of accuracy. The algorithm has been implemented on embedded hardware, and a speed-up of approximately six times has been observed. PMID- 29495814 TI - Soret forced Rayleigh scattering instrument for simultaneous detection of two wavelength signals to measure Soret coefficient and thermodiffusion coefficient in ternary mixtures. AB - We describe an instrument for the measurement of the Soret and thermodiffusion coefficients in ternary systems based on the transient holographic grating technique, which is called Soret forced Rayleigh scattering (SFRS) or thermal diffusion forced Rayleigh scattering (TDFRS). We integrated the SFRS technique and the two-wavelength detection technique, which enabled us to obtain two different signals to determine the two independent Soret coefficients and thermodiffusion coefficients in ternary systems. The instrument has been designed to read the mass transport simultaneously by two-wavelength lasers with wavelengths of lambda = 403 nm and lambda = 639 nm. The irradiation time of the probing lasers is controlled to reduce the effect of laser absorption to the sample with dye (quinizarin), which is added to convert the interference pattern of the heating laser of lambda = 532 nm to the temperature grating. The result of the measurement of binary benchmark mixtures composed of 1,2,3,4 tetrahydronaphthalene (THN), isobutylbenzene (IBB), and n-dodecane (nC12) shows that the simultaneous two-wavelength observation of the Soret effect and the mass diffusion are adequately performed. To evaluate performance in the measurement of ternary systems, we carried out experiments on the ternary benchmark mixtures of THN/IBB/nC12 with the mass fractions of 0.800/0.100/0.100 at a temperature of 298.2 K. The Soret coefficient and thermodiffusion coefficient agreed with the ternary benchmark values within the range of the standard uncertainties (23% for the Soret coefficient of THN and 30% for the thermodiffusion coefficient of THN). PMID- 29495815 TI - Space environment simulation and sensor calibration facility. AB - The Mumbo space environment simulation chamber discussed here comprises a set of tools to calibrate a variety of low flux, low energy electron and ion detectors used in satellite-mounted particle sensors. The chamber features electron and ion beam sources, a Lyman-alpha ultraviolet lamp, a gimbal table sensor mounting system, cryogenic sample mount and chamber shroud, and beam characterization hardware and software. The design of the electron and ion sources presented here offers a number of unique capabilities for space weather sensor calibration. Both sources create particle beams with narrow, well-characterized energetic and angular distributions with beam diameters that are larger than most space sensor apertures. The electron and ion sources can produce consistently low fluxes that are representative of quiescent space conditions. The particle beams are characterized by 2D beam mapping with several co-located pinhole aperture electron multipliers to capture relative variation in beam intensity and a large aperture Faraday cup to measure absolute current density. PMID- 29495816 TI - A practical double-sided frequency selective surface for millimeter-wave applications. AB - Analysis, design, and implementation of a practical, high-rejection frequency selective surface (FSS) are presented in this paper. An equivalent circuit model is introduced for predicting the frequency response of the FSS. The FSS consists of periodic square loop structures fabricated on both sides of the thin dielectric substrate by using the low-cost chemical etching technique. The proposed FSS possesses band-stop characteristics and is implemented to suppress the 170 GHz signal with attenuation of more than 45 dB with insensitivity to an angle of incident plane wave over 20 degrees . Good agreement is observed among calculated, simulated, and measured results. The proposed FSS filter can be used in various millimeter-wave applications such as the protection of imaging diagnostic systems from high spurious input power. PMID- 29495817 TI - Determination of coal ash content by the combined x-ray fluorescence and scattering spectrum. AB - An alternative method is proposed for the determination of the inorganic constituent mass fraction (ash) in solid fuel by the ratio of Compton and Rayleigh X-ray scattering peaks IC/IR subject to the iron fluorescence intensity. An original X-ray optical scheme with a Ti/Mo (or Sc/Cu) double-layer secondary radiator allows registration of the combined fluorescence-and-scattering spectrum at the specified scattering angle. An algorithm for linear calibration of the Compton-to-Rayleigh IC/IR ratio is proposed which uses standard samples with two certified characteristics: mass fractions of ash (Ad) and iron oxide (WFe2O3 ). Ash mass fractions have been determined for coals of different deposits in the wide range of Ad from 9.4% to 52.7% mass and WFe2O3 from 0.3% to 4.95% mass. Due to the high penetrability of the probing radiation with energy E > 17 keV, the sample preparation procedure is rather simplified in comparison with the traditional method of Ad determination by the sum of fluorescence intensities of all constituent elements. PMID- 29495818 TI - Scanning microwave microscopy applied to semiconducting GaAs structures. AB - A calibration algorithm based on one-port vector network analyzer (VNA) calibration for scanning microwave microscopes (SMMs) is presented and used to extract quantitative carrier densities from a semiconducting n-doped GaAs multilayer sample. This robust and versatile algorithm is instrument and frequency independent, as we demonstrate by analyzing experimental data from two different, cantilever- and tuning fork-based, microscope setups operating in a wide frequency range up to 27.5 GHz. To benchmark the SMM results, comparison with secondary ion mass spectrometry is undertaken. Furthermore, we show SMM data on a GaAs p-n junction distinguishing p- and n-doped layers. PMID- 29495819 TI - Stress testing of electrically active FlexMEAs with simultaneous electrical recording in fluidic environment: Introduction of a new measurement setup. AB - We present a measurement setup consisting of two fluid-filled pressure chambers to mimic the mechanical stress likely to that of small body movements on biomedical flexible micro-electrode arrays for the analysis of various degradation mechanisms. Our main goal was the simulation of micro-motions in fluid conditions, while maintaining an electric access to the device. These micro motions would be likely to those occurring in the human body caused by the intracranial pressure in magnitudes of 7-25 mmHg, which translates to a fluid pressure of 9-33 mbar. Furthermore, severe mechanical stress can be administered to the samples under the previously mentioned environment. Therefore, a flexible, polyimide-based sample with various metal test structures was fabricated and analyzed in the presented measurement setup. A comparison of the elongation of the sample's surface as a function of the applied hydrostatic pressure is given with computer simulations. PMID- 29495820 TI - An arbitrary-function light power controller. AB - We describe the design, applications, and performance of a simple light power controller. The device is built on a fiber-coupled electro-optic modulator with an active electronic feedback. It can be used to actively stabilize laser power or to impress an arbitrary waveform onto the power. The bandwidth of the device is ~70 kHz. PMID- 29495821 TI - Instrumentation and signal processing for the detection of heavy water using off axis-integrated cavity output spectroscopy technique. AB - An experimental setup is developed for the trace level detection of heavy water (HDO) using the off axis-integrated cavity output spectroscopy technique. The absorption spectrum of water samples is recorded in the spectral range of 7190.7 cm-1-7191.5 cm-1 with the diode laser as the light source. From the recorded water vapor absorption spectrum, the heavy water concentration is determined from the HDO and water line. The effect of cavity gain nonlinearity with per pass absorption is studied. The signal processing and data fitting procedure is devised to obtain linear calibration curves by including nonlinear cavity gain effects into the calculation. Initial calibration of mirror reflectivity is performed by measurements on the natural water sample. The signal processing and data fitting method has been validated by the measurement of the HDO concentration in water samples over a wide range from 20 ppm to 2280 ppm showing a linear calibration curve. The average measurement time is about 30 s. The experimental technique presented in this paper could be applied for the development of a portable instrument for the fast measurement of water isotopic composition in heavy water plants and for the detection of heavy water leak in pressurized heavy water reactors. PMID- 29495822 TI - Configuration optimization of photothermal deflection for measurement sensitivity enhancement. AB - An accurate theoretical model based on thermoelasticity theory and Fresnel diffraction integral is developed to describe the photothermal deflection (PTD) signal with a continuous-wave modulated Gaussian beam excitation. A PTD experiment is performed to investigate the dependence of PTD amplitude on the experimental parameters, such as the radius, waist position, and wavelength of the probe beam, and the detection distance. Good agreement between the experimental and theoretical results is obtained. The results reveal that the optimal detection distance highly depends on the probe beam waist position and wavelength, and the PTD amplitude can be enhanced by optimizing the probe beam radius and waist position as well as the detection distance. Moreover, it is demonstrated experimentally that the PTD amplitude is inversely proportional to the probe beam wavelength by using three probe lasers with a wavelength of 375 nm, 543 nm, and 632.8 nm. Therefore, the measurement sensitivity of PTD technique could be enhanced by using a short-wavelength probe beam. PMID- 29495823 TI - A broadband variable-temperature test system for complex permittivity measurements of solid and powder materials. AB - A microwave test system to measure the complex permittivity of solid and powder materials as a function of temperature has been developed. The system is based on a TM0n0 multi-mode cylindrical cavity with a slotting structure, which provides purer test modes compared to a traditional cavity. To ensure the safety, effectiveness, and longevity, heating and testing are carried out separately and the sample can move between two functional areas through an Alundum tube. Induction heating and a pneumatic platform are employed to, respectively, shorten the heating and cooling time of the sample. The single trigger function of the vector network analyzer is added to test software to suppress the drift of the resonance peak during testing. Complex permittivity is calculated by the rigorous field theoretical solution considering multilayer media loading. The variation of the cavity equivalent radius caused by the sample insertion holes is discussed in detail, and its influence to the test result is analyzed. The calibration method for the complex permittivity of the Alundum tube and quartz vial (for loading powder sample), which vary with the temperature, is given. The feasibility of the system has been verified by measuring different samples in a wide range of relative permittivity and loss tangent, and variable-temperature test results of fused quartz and SiO2 powder up to 1500 degrees C are compared with published data. The results indicate that the presented system is reliable and accurate. The stability of the system is verified by repeated and long-term tests, and error analysis is presented to estimate the error incurred due to the uncertainties in different error sources. PMID- 29495824 TI - Simultaneous AFM and fluorescence imaging: A method for aligning an AFM-tip with an excitation beam using a 2D galvanometer. AB - Correlative fluorescence and atomic force microscopy (AFM) imaging is a highly attractive technique for use in biological imaging, enabling force and mechanical measurements of particular structures whose locations are known due to the specificity of fluorescence imaging. The ability to perform these two measurements simultaneously (rather than consecutively with post-processing correlation) is highly valuable because it would allow the mechanical properties of a structure to be tracked over time as changes in the sample occur. We present an instrument which allows simultaneous AFM and fluorescence imaging by aligning an incident fluorescence excitation beam with an AFM-tip. Alignment was performed by calibrating a 2D galvanometer present in the excitation beam path and using it to reposition the incident beam. Two programs were developed (one manual and one automated) which correlate sample features between the AFM and fluorescence images, calculating the distance required to translate the incident beam towards the AFM-tip. Using this method, we were able to obtain beam-tip alignment (and therefore field-of-view alignment) from an offset of >15 MUm to within one micron in two iterations of the program. With the program running alongside data acquisition for real-time feedback between AFM and optical images, this offset was maintained over a time period of several hours. Not only does this eliminate the need to image large areas with both techniques to ensure that fields-of-view overlap, but it also raises the possibility of using this instrument for tip enhanced fluorescence applications, a technique in which super-resolution images have previously been achieved. PMID- 29495825 TI - Error analysis of mechanical system and wavelength calibration of monochromator. AB - This study focuses on improving the accuracy of a grating monochromator on the basis of the grating diffraction equation in combination with an analysis of the mechanical transmission relationship between the grating, the sine bar, and the screw of the scanning mechanism. First, the relationship between the mechanical error in the monochromator with the sine drive and the wavelength error is analyzed. Second, a mathematical model of the wavelength error and mechanical error is developed, and an accurate wavelength calibration method based on the sine bar's length adjustment and error compensation is proposed. Based on the mathematical model and calibration method, experiments using a standard light source with known spectral lines and a pre-adjusted sine bar length are conducted. The model parameter equations are solved, and subsequent parameter optimization simulations are performed to determine the optimal length ratio. Lastly, the length of the sine bar is adjusted. The experimental results indicate that the wavelength accuracy is +/-0.3 nm, which is better than the original accuracy of +/-2.6 nm. The results confirm the validity of the error analysis of the mechanical system of the monochromator as well as the validity of the calibration method. PMID- 29495826 TI - Detection of small-size solder ball defects through heat conduction analysis. AB - Aiming to solve the defect detection problem of a small-size solder ball in the high density chip, heat conduction analysis based on eddy current pulsed thermography is put forward to differentiate various defects. With establishing the 3D finite element model about induction heating, defects such as cracks and void can be distinguished by temperature difference resulting from heat conduction. Furthermore, the experiment of 0.4 mm-diameter solder balls with different defects is carried out to prove that crack and void solder can be distinguished. Three kinds of crack length on a gull-wing pin are selected, including 0.24 mm, 1.2 mm, and 2.16 mm, to verify that the small defect can be discriminated. Both the simulation study and experiment result show that the heat conduction analysis method is reliable and convenient. PMID- 29495827 TI - Optimized lighting method of applying shaped-function signal for increasing the dynamic range of LED-multispectral imaging system. AB - This paper proposes an optimized lighting method of applying a shaped-function signal for increasing the dynamic range of light emitting diode (LED) multispectral imaging system. The optimized lighting method is based on the linear response zone of the analog-to-digital conversion (ADC) and the spectral response of the camera. The auxiliary light at a higher sensitivity-camera area is introduced to increase the A/D quantization levels that are within the linear response zone of ADC and improve the signal-to-noise ratio. The active light is modulated by the shaped-function signal to improve the gray-scale resolution of the image. And the auxiliary light is modulated by the constant intensity signal, which is easy to acquire the images under the active light irradiation. The least square method is employed to precisely extract the desired images. One wavelength in multispectral imaging based on LED illumination was taken as an example. It has been proven by experiments that the gray-scale resolution and the accuracy of information of the images acquired by the proposed method were both significantly improved. The optimum method opens up avenues for the hyperspectral imaging of biological tissue. PMID- 29495828 TI - Novel gas target for laser wakefield accelerators. AB - A novel gas target for interactions between high power lasers and gaseous medium, especially for laser wakefield accelerators, has been designed, manufactured, and characterized. The gas target has been designed to provide a uniform density profile along the central gas cell axis by combining a gas cell and slit nozzle. The gas density has been tuned from ~1017 atoms/cm3 to ~1019 atoms/cm3 and the gas target length can be varied from 0 to 10 cm; both changes can be made simultaneously while keeping the uniform gas profile. The gas density profile inside the gas cell has been measured using interferometry and validated using computational fluid dynamics. PMID- 29495829 TI - Compressed gas combined single- and two-stage light-gas gun. AB - With more than 1 trillion artificial objects smaller than 1 MUm in low and geostationary Earth orbit, space assets are subject to the constant threat of space debris impact. These collisions occur at hypervelocity or speeds greater than 3 km/s. In order to characterize material behavior under this extreme event as well as study next-generation materials for space exploration, this paper presents a unique two-stage light-gas gun capable of replicating hypervelocity impacts. While a limited number of these types of facilities exist, they typically are extremely large and can be costly and dangerous to operate. The design presented in this paper is novel in two distinct ways. First, it does not use a form of combustion in the first stage. The projectile is accelerated from a pressure differential using air and inert gases (or purely inert gases), firing a projectile in a nominal range of 1-4 km/s. Second, the design is modular in that the first stage sits on a track sled and can be pulled back and used in itself to study lower speed impacts without any further modifications, with the first stage piston as the impactor. The modularity of the instrument allows the ability to investigate three orders of magnitude of impact velocities or between 101 and 103 m/s in a single, relatively small, cost effective instrument. PMID- 29495830 TI - Note: Possibilities of detecting the trace-level erosion products from an electric propulsion hollow cathode plasma source by the method of time-of-flight mass spectrometry. AB - A hollow cathode produces electrons which neutralize ions from electric propulsion thrusters. After hundreds to thousands of hours of operation in space, the cathode materials can be significantly eroded due to ion bombardment. As a result, the electric propulsion system performance will be obviously changed or even fail. In this work, the erosion products from a LaB6 hollow cathode (widely used presently in electric propulsion systems) are studied by using a specific detection system, which consists of a molecular beam sampler and a time-of-flight mass spectrometer. This system measures trace-level-concentration (10-6-10-3) products. Boron (B), tantalum (Ta), and tungsten (W)-originating from the emitter, keeper, and orifice of the hollow cathode-are measured. It is found that the erosion rate is significantly influenced by the gas flow rate to the cathode. PMID- 29495832 TI - Quantitative characterization of semiconductor structures with a scanning microwave microscope. AB - In this work, our earlier method for measuring resistance Rsh of semiconductor films with a near-field scanning microwave microscope [A. N. Reznik and S. A. Korolyov, J. Appl. Phys. 119, 094504 (2016)] is studied in a 0.1 kOmega/sq < Rsh < 15 kOmega/sq range. The method is based on a microscope model in the form of a monopole or dipole antenna interacting with an arbitrary layered structure. The model fitting parameters are determined from the data yielded by calibration measurements on a system of etalon samples. The performance of the method was analyzed experimentally, using strip-probe and coaxial-probe microscopes in the frequency range of 1-3 GHz. For test structures, we used doped GaN films on the Al2O3 substrate and also transistor structures based on the AlGaN/GaN heterojunction and AlGaAs/GaAs/InGaAs/GaAs/AlGaAs quantum well with a conducting channel. The obtained microwave microscope data were compared with the results of measurements by the van der Pauw method. At the first stage of the experiment, the calibration etalons were bulk homogeneous samples with different permittivity/conductivity values. In this case, satisfactory agreement between the microscope and the van der Pauw data was obtained with a strip probe on all tested samples in the entire range of Rsh. With a coaxial probe, such accordance was observed only in high-ohmic samples with Rsh > 1 kOmega/sq. The use of GaN film structures as a calibration system helped to increase the accuracy of the coaxial-probe-aided measurement of Rsh to a level of ~10%. PMID- 29495831 TI - Spectral characterization of laser-accelerated protons with CR-39 nuclear track detector. AB - CR-39 nuclear track material is frequently used for the detection of protons accelerated in laser-plasma interactions. The measurement of track densities allows for determination of particle angular distributions, and information on the kinetic energy can be obtained by the use of passive absorbers. We present a precise method of measuring spectral distributions of laser-accelerated protons in a single etching and analysis process. We make use of a one-to-one relation between proton energy and track size and present a precise calibration based on monoenergetic particle beams. While this relation is limited to proton energies below 1 MeV, we show that the range of spectral measurements can be significantly extended by simultaneous use of absorbers of suitable thicknesses. Examples from laser-plasma interactions are presented, and quantitative results on proton energies and particle numbers are compared to those obtained from a time-of flight detector. The spectrum end points of continuous energy distributions have been determined with both detector types and coincide within 50-100 keV. PMID- 29495833 TI - A compact fluorescence polarization analyzer with high-transmittance liquid crystal layer. AB - Fluorescence polarization (FP) offers easy operation and rapid processing, making it implementable in molecular interaction analysis. Previously we have developed a unique FP measurement system using a liquid crystal (LC) layer and an image sensor. The system is based on a principle of synchronized detection between the switching rate of the LC layer and the sampling rate of the CCD. The FP system realized simultaneous multiple sample detection; however, the measurement precision was lower than that of the conventional FP apparatus. The main drawbacks were low light transmittance of the LC layer and insufficient synchronization between the LC layer and CCD. In this paper, we developed a new FP analyzer based on LC-CCD synchronization detection. By using a newly designed LC with high transmittance and improving synchronization, the performance of the system has been dramatically improved. Additionally, we reduced the cost by using an inexpensive CCD and an LED as the excitation source. Simultaneous FP immunoassay of multiple samples of prostaglandin E2 was performed. The error rate of the FP system is reduced from 16.9% to 3.9%, as comparable to the commercial conventional FP system. PMID- 29495834 TI - Novel circuit design for high-impedance and non-local electrical measurements of two-dimensional materials. AB - Two-dimensional materials offer a novel platform for the development of future quantum technologies. However, the electrical characterisation of topological insulating states, non-local resistance, and bandgap tuning in atomically thin materials can be strongly affected by spurious signals arising from the measuring electronics. Common-mode voltages, dielectric leakage in the coaxial cables, and the limited input impedance of alternate-current amplifiers can mask the true nature of such high-impedance states. Here, we present an optical isolator circuit which grants access to such states by electrically decoupling the current injection from the voltage-sensing circuitry. We benchmark our apparatus against two state-of-the-art measurements: the non-local resistance of a graphene Hall bar and the transfer characteristic of a WS2 field-effect transistor. Our system allows the quick characterisation of novel insulating states in two-dimensional materials with potential applications in future quantum technologies. PMID- 29495835 TI - Two-dimensional water acoustic waveguide based on pressure compensation method. AB - A two-dimensional (2D) waveguide is a basic facility for experiment measurement due to a much more simplified wave field pattern than that in free space. A waveguide for airborne sound is easily achieved with almost any solid plates. However, the design of a 2D water acoustic waveguide is still challenging because of unavailable solids with a sufficient large impedance difference from water. In this work, a new method of constructing a 2D water acoustic waveguide is proposed based on pressure compensation and has been verified by numerical simulation. A prototype of the water acoustic waveguide is fabricated and complemented by an acoustic pressure scanning system; the measured scattered pressure fields by air and aluminum cylinders both agree quite well with numerical simulations. Most acoustic pressure fields within a frequency range 7 kHz-15 kHz can be measured in this waveguide when the required scanning region is smaller than the aluminum plate area (1800 mm * 800 mm). PMID- 29495836 TI - Note: A 102 dB dynamic-range charge-sampling readout for ionizing particle/radiation detectors based on an application-specific integrated circuit (ASIC). AB - An original technique for the measurement of charge signals from ionizing particle/radiation detectors has been implemented in an application-specific integrated circuit form. The device performs linear measurements of the charge both within and beyond its output voltage swing. The device features an unprecedented spectroscopic dynamic range of 102 dB and is suitable for high resolution ion and X-gamma ray spectroscopy. We believe that this approach may change a widespread paradigm according to which no high-resolution spectroscopy is possible when working close to or beyond the limit of the preamplifier's output voltage swing. PMID- 29495838 TI - Calibration of the low-energy channel Thomson parabola of the LMJ-PETAL diagnostic SEPAGE with protons and carbon ions. AB - The SEPAGE diagnostic will detect charged particles (electrons, protons, and ions) accelerated in the interaction of the PETAL (PETawatt Aquitaine Laser) laser with its targets on the LMJ (Laser MegaJoule)-PETAL laser facility. SEPAGE will be equipped with a proton-radiography front detector and two Thomson parabolas (TP), corresponding to different ranges of the particle energy spectra: Above 0.1 MeV for electrons and protons in the low-energy channel, with a separation capability between protons and 12C6+ up to 20 MeV proton energy and above 8 MeV for the high-energy channel, with a separation capability between protons and 12C6+ up to 200 MeV proton kinetic energy. This paper presents the calibration of the SEPAGE's low-energy channel TP at the Tandem facility of Orsay (France) with proton beams between 3 and 22 MeV and carbon-ion beams from 5.8 to 84 MeV. The magnetic and electric fields' integrals were determined with an accuracy of 10-3 by combining the deflections measured at different energies with different target thicknesses and materials, providing different in-target energy losses of the beam particles and hence different detected energies for given beam energies. PMID- 29495839 TI - A portable extruder for in situ wide angle x-ray scattering study on multi dimensional flow field induced crystallization of polymer. AB - We have designed and constructed a portable extruder with a rotatable mandrel, which can be employed to study the multi-dimensional flow field (MDFF) induced crystallization of polymer combined with in situ wide angle x-ray scattering (WAXS). With the piston driving the melt sample to flow along the channel, a direct axial shear field is achieved. At the same time, the central mandrel keeps rotating under a stable speed, providing the sample with an additional circumferential shear field. By presetting different proportions of the two shear fields, namely, axial and circumferential, various flow states of the sample can be obtained, which makes it capable of investigating the effects of MDFF on polymer crystallization. We have performed an in situ WAXS experiment of MDFF induced crystallization of isotactic polypropylene based on the portable extruder at the beam line BL16B in Shanghai Synchrotron Radiation Facility. The rheological and structural information is collected simultaneously, which manifests the viability of the portable extruder on regulating MDFF and can provide guidance for polymer processing. PMID- 29495837 TI - Adaptive aperture for Geiger mode avalanche photodiode flash ladar systems. AB - Although the Geiger-mode avalanche photodiode (GM-APD) flash ladar system offers the advantages of high sensitivity and simple construction, its detection performance is influenced not only by the incoming signal-to-noise ratio but also by the absolute number of noise photons. In this paper, we deduce a hyperbolic approximation to estimate the noise-photon number from the false-firing percentage in a GM-APD flash ladar system under dark conditions. By using this hyperbolic approximation function, we introduce a method to adapt the aperture to reduce the number of incoming background-noise photons. Finally, the simulation results show that the adaptive-aperture method decreases the false probability in all cases, increases the detection probability provided that the signal exceeds the noise, and decreases the average ranging error per frame. PMID- 29495840 TI - Note: Stability and lifetime of scandium deuteride film cathode in a vacuum arc ion source. AB - This paper reports the properties of the plasma and gas produced in a vacuum arc discharge with scandium deuteride (ScD1.8) film cathodes. The thickness of the ScD1.8 film influences the quantity of the gases released from the cathode material. The deuterium gas releasing in the discharge process was in a depth range from the cathode surface to the cathode interior, that is, between 3 and 6 MUm. Surprisingly, after discharge, the deuterium ion ratio remains the same in the film with different thicknesses. That indicates that the release of deuterium gas in a 3 MUm-thick ScD1.8 film is enough for ionization. In addition, as the number of discharge increases, the stability of atomic fraction ratio gets worse and the ratio of deuterium ions decreases. PMID- 29495841 TI - Stabilization of burst laser pulse storage in an optical enhancement cavity using a counter propagating mode. AB - We describe the stabilization technique of an optical enhancement cavity using a counter propagating mode. The burst amplification of the injection laser in the main path induces a drastic change in the laser intensity and disturbs the stabilization of the enhancement cavity. We have used a counter propagating mode to achieve a 4% intensity jitter and 0.6 mJ pulse storage inside the cavity at the maximum of the burst region. Our results indicate that the counter propagating mode has the same resonant condition as the main mode and thus becomes useful for stabilizing the enhancement cavity. We also determined that the burst amplification brought about no decrease in the enhancement factor in the cavity due to the degradation of laser quality. PMID- 29495842 TI - A new time of flight mass spectrometer for absolute dissociative electron attachment cross-section measurements in gas phase. AB - A new time of flight mass spectrometer (TOFMS) has been developed to study the absolute dissociative electron attachment (DEA) cross section using a relative flow technique of a wide variety of molecules in gas phase, ranging from simple diatomic to complex biomolecules. Unlike the Wiley-McLaren type TOFMS, here the total ion collection condition has been achieved without compromising the mass resolution by introducing a field free drift region after the lensing arrangement. The field free interaction region is provided for low energy electron molecule collision studies. The spectrometer can be used to study a wide range of masses (H- ion to few hundreds atomic mass unit). The mass resolution capability of the spectrometer has been checked experimentally by measuring the mass spectra of fragment anions arising from DEA to methanol. Overall performance of the spectrometer has been tested by measuring the absolute DEA cross section of the ground state SO2 molecule, and the results are satisfactory. PMID- 29495843 TI - The performance and limitations of FPGA-based digital servos for atomic, molecular, and optical physics experiments. AB - In this work, we address the advantages, limitations, and technical subtleties of employing field programmable gate array (FPGA)-based digital servos for high bandwidth feedback control of lasers in atomic, molecular, and optical physics experiments. Specifically, we provide the results of benchmark performance tests in experimental setups including noise, bandwidth, and dynamic range for two digital servos built with low and mid-range priced FPGA development platforms. The digital servo results are compared to results obtained from a commercially available state-of-the-art analog servo using the same plant for control (intensity stabilization). The digital servos have feedback bandwidths of 2.5 MHz, limited by the total signal latency, and we demonstrate improvements beyond the transfer function offered by the analog servo including a three-pole filter and a two-pole filter with phase compensation to suppress resonances. We also discuss limitations of our FPGA-servo implementation and general considerations when designing and using digital servos. PMID- 29495845 TI - Double wedge prism based beam deflector for precise laser beam steering. AB - Aiming to increase laser beam pointing stability required in interferometric measurements, we designed a laser beam deflector intended for active laser beam stabilization systems. The design is based on two wedge-prisms: the deflecting wedge driven by a tilting piezo-platform and the fixed wedge to compensate initial beam deflection. Our design allows linear beam steering, independently in the horizontal or vertical direction, with resolution of less than 1 MUrad in a range of more than 100 MUrad, and no initial deflection of the beam. Moreover, the ratio of the output beam deflection angle and the wedge tilt angle is less than 0.1; therefore, the noise influence is significantly reduced in comparison to standard mirror-based deflectors. The theoretical analyses support the designing process and can serve as a guide to wedge-prism selection. The experimental results are in agreement with theory and confirm the advantages of the presented double wedge system. PMID- 29495844 TI - A sensitive EUV Schwarzschild microscope for plasma studies with sub-micrometer resolution. AB - We present an extreme ultraviolet (EUV) microscope using a Schwarzschild objective which is optimized for single-shot sub-micrometer imaging of laser plasma targets. The microscope has been designed and constructed for imaging the scattering from an EUV-heated solid-density hydrogen jet. Imaging of a cryogenic hydrogen target was demonstrated using single pulses of the free-electron laser in Hamburg (FLASH) free-electron laser at a wavelength of 13.5 nm. In a single exposure, we observe a hydrogen jet with ice fragments with a spatial resolution in the sub-micrometer range. In situ EUV imaging is expected to enable novel experimental capabilities for warm dense matter studies of micrometer-sized samples in laser-plasma experiments. PMID- 29495846 TI - An efficient laser vaporization source for chemically modified metal clusters characterized by thermodynamics and kinetics. AB - A laser vaporization cluster source that has a room for cluster aggregation and a reactor volume, each equipped with a pulsed valve, is presented for the efficient gas-phase production of chemically modified metal clusters. The performance of the cluster source is evaluated through the production of Ta and Ta oxide cluster cations, TaxOy+ (y >= 0). It is demonstrated that the cluster source produces TaxOy+ over a wide mass range, the metal-to-oxygen ratio of which can easily be controlled by changing the pulse duration that influences the amount of reactant O2 introduced into the cluster source. Reaction kinetic modeling shows that the generation of the oxides takes place under thermalized conditions at less than 300 K, whereas metal cluster cores are presumably created with excess heat. These characteristics are also advantageous to yield "reaction intermediates" of interest via reactions between clusters and reactive molecules in the cluster source, which may subsequently be mass selected for their reactivity measurements. PMID- 29495847 TI - Publisher's Note: "GHz modulation detection using a streak camera: Suitability of streak cameras in the AWAKE experiment" [Rev. Sci. Instrum. 88, 025110 (2017)]. PMID- 29495848 TI - Differentiation of nonferrous metal particles in lubrication oil using an electrical conductivity measurement-based inductive sensor. AB - A method that measures the electrical conductivity of metal based on monitoring the inductance changes of coils via an inductive sensor is introduced in this work to differentiate metal particles in lubrication oil. Theoretical analysis coupled with experimentation is employed to differentiate varieties of nonferrous metal particles, including copper and aluminum particles, ranging from 860 MUm to 880 MUm in diameter. The results show that the inductive sensor is capable of the identification and differentiation of nonferrous metal particles in lubrication oil based on the electrical conductivity measurement. The concept demonstrated in this paper can be extended to inductive sensors in metal particle detection and other scientific and industrial applications. PMID- 29495849 TI - Note: Development of a multichannel magnetic probe array for magnetohydrodynamic activity studies in Sino-United Spherical Tokamak. AB - A 30-channel movable magnetic probe radial array measuring the poloidal magnetic field's time derivative Btheta has been developed and installed on the Sino United Spherical Tokamak to investigate the magnetohydrodynamic (MHD) activities in ohmic discharges. The probe array consists of thirty identical commercial chip inductors mounted on a slim printed circuit board and shielded by a customized quartz tube of 14 mm in outer diameter. With the application of instrumentation amplifiers, the system exhibits a good signal to noise ratio and the measured vertical field spatial distribution agrees well with the simulation result. The measured spatial and temporal distribution of Btheta during the MHD activities exhibits a clear phase reversal layer, which is a direct proof of tearing mode and provides a reliable indication of the magnetic island chain position. PMID- 29495850 TI - High-pressure cell for simultaneous dielectric and neutron spectroscopy. AB - In this article, we report on the design, manufacture, and testing of a high pressure cell for simultaneous dielectric and neutron spectroscopy. This cell is a unique tool for studying dynamics on different time scales, from kilo- to picoseconds, covering universal features such as the alpha relaxation and fast vibrations at the same time. The cell, constructed in cylindrical geometry, is made of a high-strength aluminum alloy and operates up to 500 MPa in a temperature range between roughly 2 and 320 K. In order to measure the scattered neutron intensity and the sample capacitance simultaneously, a cylindrical capacitor is positioned within the bore of the high-pressure container. The capacitor consists of two concentric electrodes separated by insulating spacers. The performance of this setup has been successfully verified by collecting simultaneous dielectric and neutron spectroscopy data on dipropylene glycol, using both backscattering and time-of-flight instruments. We have carried out the experiments at different combinations of temperature and pressure in both the supercooled liquid and glassy state. PMID- 29495851 TI - Measuring the Allan variance by sinusoidal fitting. AB - The Allan variance of signal and reference frequencies is measured by a least square fit of the output of two analog-to-digital converters to ideal sine waves. The difference in the fit phase of the two channels generates the timing data needed for the Allan variance. The fits are performed at the signal frequency (~10 MHz) without the use of heterodyning. Experimental data from a modified digital oscilloscope yield a residual Allan deviation of 3 * 10-13/tau, where tau is the observation time in s. This corresponds to a standard deviation in time of <300 fs or 20 MUrad in phase. The experimental results are supported by statistical theory and Monte Carlo simulations which suggest that optimized devices may have one or two orders of magnitude better performance. PMID- 29495852 TI - A table top experiment to investigate production and properties of a plasma confined by a dipole magnet. AB - We report a table top experiment to investigate production and properties of a plasma confined by a dipole magnet. A water cooled, strong, cylindrical permanent magnet (NdFeB) magnetized along the axial direction and having a surface magnetic field of ~0.5 T is employed to create a dipole magnetic field. The plasma is created by electron cyclotron resonance heating. Visual observations of the plasma indicate that radiation belts appear due to trapped particles, similar to the earth's magnetosphere. The electron temperature lies in the range 2-13 eV and is hotter near the magnets and in a downstream region. It is found that the plasma (ion) density reaches a value close to 2 * 1011 cm-3 and peaks at a radial distance about 3 cm from the magnet. The plasma beta beta (beta = plasma pressure/magnetic pressure) increases radially outward, and the maximum beta for the present experimental system is ~2%. It is also found that the singly charged ions are dominant in the discharge. PMID- 29495853 TI - Quantitative magneto-optical investigation of superconductor/ferromagnet hybrid structures. AB - We present a detailed quantitative magneto-optical imaging study of several superconductor/ferromagnet hybrid structures, including Nb deposited on top of thermomagnetically patterned NdFeB and permalloy/niobium with erasable and tailored magnetic landscapes imprinted in the permalloy layer. The magneto optical imaging data are complemented with and compared to scanning Hall probe microscopy measurements. Comprehensive protocols have been developed for calibrating, testing, and converting Faraday rotation data to magnetic field maps. Applied to the acquired data, they reveal the comparatively weaker magnetic response of the superconductor from the background of larger fields and field gradients generated by the magnetic layer. PMID- 29495854 TI - Single crystal to polycrystal neutron transmission simulation. AB - A collection of routines for calculation of the total cross section that determines the attenuation of neutrons by crystalline solids is presented. The total cross section is calculated semi-empirically as a function of crystal structure, neutron energy, temperature, and crystal orientation. The semi empirical formula includes the contribution of parasitic Bragg scattering to the total cross section using both the crystal's mosaic spread value and its orientation with respect to the neutron beam direction as parameters. These routines allow users to enter a distribution of crystal orientations for calculation of total cross sections of user defined powder or pseudo powder distributions, which enables simulation of non-uniformities such as texture and strain. The spectra for neutron transmission simulations in the neutron thermal energy range (2 meV-100 meV) are presented for single crystal and polycrystal samples and compared to measurements. PMID- 29495855 TI - A calibration rig for multi-component internal strain gauge balance using the new design-of-experiment (DOE) approach. AB - In a closed water-tunnel circuit, the multi-component strain gauge force and moment sensor (also known as balance) are generally used to measure hydrodynamic forces and moments acting on scaled models. These balances are periodically calibrated by static loading. Their performance and accuracy depend significantly on the rig and the method of calibration. In this research, a new calibration rig was designed and constructed to calibrate multi-component internal strain gauge balances. The calibration rig has six degrees of freedom and six different component-loading structures that can be applied separately and synchronously. The system was designed based on the applicability of formal experimental design techniques, using gravity for balance loading and balance positioning and alignment relative to gravity. To evaluate the calibration rig, a six-component internal balance developed by Iran University of Science and Technology was calibrated using response surface methodology. According to the results, calibration rig met all design criteria. This rig provides the means by which various methods of formal experimental design techniques can be implemented. The simplicity of the rig saves time and money in the design of experiments and in balance calibration while simultaneously increasing the accuracy of these activities. PMID- 29495856 TI - Design of a multiband near-infrared sky brightness monitor using an InSb detector. AB - Infrared sky background level is an important parameter of infrared astronomy observations from the ground, particularly for a candidate site of an infrared capable observatory since low background level is required for such a site. The Chinese astronomical community is looking for a suitable site for a future 12 m telescope, which is designed for working in both optical and infrared wavelengths. However, none of the proposed sites has been tested for infrared observations. Nevertheless, infrared sky background measurements are also important during the design of infrared observing instruments. Based on the requirement, in order to supplement the current site survey data and guide the design of future infrared instruments, a multiband near-infrared sky brightness monitor (MNISBM) based on an InSb sensor is designed in this paper. The MNISBM consists of an optical system, mechanical structure and control system, detector and cooler, high gain readout electronics, and operational software. It is completed and tested in the laboratory. The results show that the sensitivity of the MNISBM meets the requirements of the measurement of near-infrared sky background level of several well-known astronomical infrared observing sites. PMID- 29495857 TI - Nanocrystalline SiC film thermistors for cryogenic applications. AB - We developed a heat-sensitive material based on nanocrystalline SiC films obtained by direct deposition of carbon and silicon ions onto sapphire substrates. These SiC films can be used for resistance thermometers operating in the 2 K-300 K temperature range. Having high heat sensitivity, they are relatively low sensitive to the magnetic field. The designs of the sensors are presented together with a discussion of their thermometric characteristics and sensitivity to magnetic fields. PMID- 29495859 TI - An analytical model for the detection of levitated nanoparticles in optomechanics. AB - Interferometric position detection of levitated particles is crucial for the centre-of-mass (CM) motion cooling and manipulation of levitated particles. In combination with balanced detection and feedback cooling, this system has provided picometer scale position sensitivity, zeptonewton force detection, and sub-millikelvin CM temperatures. In this article, we develop an analytical model of this detection system and compare its performance with experimental results allowing us to explain the presence of spurious frequencies in the spectra. PMID- 29495860 TI - A robust cloud registration method based on redundant data reduction using backpropagation neural network and shift window. AB - A robust coarse-to-fine registration method based on the backpropagation (BP) neural network and shift window technology is proposed in this study. Specifically, there are three steps: coarse alignment between the model data and measured data, data simplification based on the BP neural network and point reservation in the contour region of point clouds, and fine registration with the reweighted iterative closest point algorithm. In the process of rough alignment, the initial rotation matrix and the translation vector between the two datasets are obtained. After performing subsequent simplification operations, the number of points can be reduced greatly. Therefore, the time and space complexity of the accurate registration can be significantly reduced. The experimental results show that the proposed method improves the computational efficiency without loss of accuracy. PMID- 29495861 TI - Ion temperature measurements of indirect-drive implosions with the neutron time of-flight detector on SG-III laser facility. AB - The accuracy of the determination of the burn-averaged ion temperature of inertial confinement fusion implosions depends on the unfold process, including deconvolution and convolution methods, and the function, i.e., the detector response, used to fit the signals measured by neutron time-of-flight (nToF) detectors. The function given by Murphy et al. [Rev. Sci. Instrum. 68(1), 610-613 (1997)] has been widely used in Nova, Omega, and NIF. There are two components, i.e., fast and slow, and the contribution of scattered neutrons has not been dedicatedly considered. In this work, a new function, based on Murphy's function has been employed to unfold nToF signals. The contribution of scattered neutrons is easily included by the convolution of a Gaussian response function and an exponential decay. The ion temperature is measured by nToF with the new function. Good agreement with the ion temperature determined by the deconvolution method has been achieved. PMID- 29495862 TI - Time-resolved optical absorption microspectroscopy of magnetic field sensitive flavin photochemistry. AB - The photochemical reactions of blue-light receptor proteins have received much attention due to their very important biological functions. In addition, there is also growing evidence that the one particular class of such proteins, the cryptochromes, may be associated with not only a biological photo-response but also a magneto-response, which may be responsible for the mechanism by which many animals can respond to the weak geomagnetic field. Therefore, there is an important scientific question over whether it is possible to directly observe such photochemical processes, and indeed the effects of weak magnetic fields thereon, taking place both in purified protein samples in vitro and in actual biochemical cells and tissues. For the former samples, the key lies in being able to make sensitive spectroscopic measurements on very small volumes of samples at potentially low protein concentrations, while the latter requires, in addition, spatially resolved measurements on length scales smaller than typical cellular components, i.e., sub-micron resolution. In this work, we discuss a two- and three-color confocal pump-probe microscopic approach to this question which satisfies these requirements and is thus useful for experimental measurements in both cases. PMID- 29495863 TI - Note: Reflection zone plates as highly resolving broadband optics for soft X-ray laboratory spectrometers. AB - The resolving power and relative efficiency of two off-axis reflection zone plates (RZPs) in the soft X-ray range between 1 nm and 5 nm were investigated. RZPs focus only a very narrow bandwidth around the design wavelength. By misaligning the RZP, the focused wavelength can be tuned through a much wider spectral range. Using a laser-produced plasma source, we demonstrate that a single RZP can be efficiently used for spectroscopy at arbitrary wavelengths in the investigated soft X-ray range. PMID- 29495864 TI - Note: Narrow x-ray reflections are easier to locate with sandpaper. AB - Synchrotrons can provide almost perfectly unidirectional and monochromatic x rays. Such x-rays reflect from ideal crystals only over a minute part of the angular range that must be searched for the reflection. Spoiling the incoming x rays' directionality with sandpaper makes it easier to find the reflection. PMID- 29495865 TI - A 532 nm fiber-optic displacement interferometer for low-velocity impact experiments. AB - Conventional fiber-optic displacement interferometers operated at 1550 nm suffer from low temporal or velocity resolution for lower velocity measurements. To overcome this drawback, a fiber-optic Doppler pin system operated at 532 nm is developed, and its capability is demonstrated with low-velocity plate impact experiments. The new instrument would be an important supplemental to the existed systems. PMID- 29495866 TI - Evaluation of hydrogen absorption cells for observations of the planetary coronas. AB - Newly designed Lyman-alpha absorption cells for imaging hydrogen planetary corona were characterized using an ultra high resolution Fourier transform spectrometer installed on the DESIRS (Dichroisme Et Spectroscopie par Interaction avec le Rayonnement Synchrotron) beamline of Synchrotron SOLEIL in France. The early absorption cell installed in the Japanese Mars orbiter NOZOMI launched in 1998 had not been sufficiently optimized due to its short development time. The new absorption cells are equipped with the ability to change various parameters, such as filament shape, applied power, H2 gas pressure, and geometrical configuration. We found that the optical thickness of the new absorption cell was ~4 times higher than the earlier one at the center wavelength of Lyman-alpha absorption, by optimizing the condition to promote thermal dissociation of H2 molecules into two H atoms on a hot tungsten filament. The Doppler temperature of planetary coronas could be determined with an accuracy better than 100 K with the performance of the newly developed absorption cell. PMID- 29495867 TI - A 3D-printed device for polymer nanoimprint lithography. AB - Nanoimprint lithography (NIL) is an imprinting technique which has experienced an increasing popularity due to its versatility in fabrication processes. Commercial NIL machines are readily available achieving high quality results; however, these machines involve a relatively high investment. Hence, small laboratories often choose to perform NIL copies in a more rudimentary and cheaper way. A new simple system is presented in this document. It is based on two devices which can be made in-house in plastic by using a 3D printer or in aluminum. Thus, the overall manufacturing complexity is vastly reduced. The presented system includes pressure control and potentially temperature control. Replicas have been made using a sawtooth grating master with a pitch around half micrometre. High quality patterns with low density of imperfections have been achieved in 2.25 cm2 surfaces. The material chosen for the negative intermediary mould is PDMS. Tests of the imprint have been performed using the commercial hybrid polymer Ormostamp(r). PMID- 29495868 TI - Note: An atomic self-sustaining magnetic gradiometer with a 1/tau uncertainty property based on Larmor precession. AB - We demonstrate an atomic magnetic gradiometer based on self-sustaining Larmor precession. By coherent optical pumping, we measure the phase of the Larmor precession directly and observe that the gradiometer shows a 1/tau improvement in magnetic field gradient uncertainty over time tau. Since the measurement gives frequency signals, the gradiometer can be easily implemented by mixing and filtering the different frequency signals from two adjacent magnetometers. A gradient sensitivity of 186 fT/Hz/cm-1) is realized, which is close to the shot noise limit. In a noisy environment, the gradiometer can still maintain its 1/tau behavior by suppressing 90% of the common-mode noise. This method should be widely applicable to the measurement of magnetic field gradients owing to its simplicity and outstanding performance. PMID- 29495869 TI - Note: Erosion of W-Ni-Fe and W-Cu alloy electrodes in repetitive spark gaps. AB - A pair of W-Ni-Fe and W-Cu electrodes were tested under 100 kA level pulsed currents for 10 000 shots, respectively. Surface roughness and morphology characteristics of the two pairs of electrodes were obtained and compared. Experimental results indicated cracks divided the W-Cu electrode surface to polygons while the W-Ni-Fe electrode surface remained as a whole with pits and protrusions. Accordingly, the surface roughness of W-Ni-Fe electrodes increased to ~3 MUm while that of W-Cu electrodes reached ~7 MUm at the end of the test. The results reveal that the W-Ni-Fe alloy has a better erosion resistance and potential to be further applied in spark gaps. PMID- 29495870 TI - Performance evaluation and bias correction of DBS measurements for a 1290-MHz boundary layer profiler. AB - Recently, the government installed a boundary layer profiler (BLP), which is operated under the Doppler beam swinging mode, in a coastal area of China, to acquire useful wind field information in the atmospheric boundary layer for several purposes. And under strong wind conditions, the performance of the BLP is evaluated. It is found that, even though the quality controlled BLP data show good agreement with the balloon observations, a systematic bias can always be found for the BLP data. For the low wind velocities, the BLP data tend to overestimate the atmospheric wind. However, with the increment of wind velocity, the BLP data show a tendency of underestimation. In order to remove the effect of poor quality data on bias correction, the probability distribution function of the differences between the two instruments is discussed, and it is found that the t location scale distribution is the most suitable probability model when compared to other probability models. After the outliers with a large discrepancy, which are outside of 95% confidence interval of the t location scale distribution, are discarded, the systematic bias can be successfully corrected using a first-order polynomial correction function. The methodology of bias correction used in the study not only can be referred for the correction of other wind profiling radars, but also can lay a solid basis for further analysis of the wind profiles. PMID- 29495871 TI - Thermal diffusivity measurement in thin metallic filaments using the mirage method with multiple probe beams and a digital camera. AB - Photothermal beam deflection is a well-established technique for measuring thermal diffusivity. In this technique, a pump laser beam generates temperature variations on the surface of the sample to be studied. These variations transfer heat to the surrounding medium, which may be air or any other fluid. The medium in turn experiences a change in the refractive index, which will be proportional to the temperature field on the sample surface when the distance to this surface is small. A probe laser beam will suffer a deflection due to the refractive index periodical changes, which is usually monitored by means of a quadrant photodetector or a similar device aided by lock-in amplification. A linear relationship that arises in this technique is that given by the phase lag of the thermal wave as a function of the distance to a punctual heat source when unidimensional heat diffusion can be guaranteed. This relationship is useful in the calculation of the sample's thermal diffusivity, which can be obtained straightforwardly by the so-called slope method, if the pump beam modulation frequency is well-known. The measurement procedure requires the experimenter to displace the probe beam at a given distance from the heat source, measure the phase lag at that offset, and repeat this for as many points as desired. This process can be quite lengthy in dependence of the number points. In this paper, we propose a detection scheme, which overcomes this limitation and simplifies the experimental setup using a digital camera that substitutes all detection hardware utilizing motion detection techniques and software digital signal lock-in post processing. In this work, the method is demonstrated using thin metallic filaments as samples. PMID- 29495873 TI - The method of UCN "small heating" measurement in the big gravitational spectrometer (BGS) and studies of this effect on Fomblin oil Y-HVAC 18/8. AB - The Big Gravitational Spectrometer (BGS) takes advantage of the strong influence of the Earth's gravity on the motion of ultracold neutrons (UCNs) that makes it possible to shape and measure UCN spectra. We optimized the BGS to investigate the "small heating" of UCNs, that is, the inelastic reflection of UCNs from a surface accompanied by an energy change comparable with the initial UCN energy. UCNs whose energy increases are referred to as "Vaporized UCNs" (VUCNs). The BGS provides the narrowest UCN spectra of a few cm and the broadest "visible" VUCN energy range of up to ~150 cm (UCN energy is given in units of its maximum height in the Earth's gravitational field, where 1.00 cm ~ 1.02 neV). The dead-zone between the UCN and VUCN spectra is the narrowest ever achieved (a few cm). We performed measurements with and without samples without breaking vacuum. BGS provides the broadest range of temperatures (77-600 K) and the highest sensitivity to the small heating effect, up to ~10-8 per bounce, i.e., two orders of magnitude higher than the sensitivity of alternative methods. We describe the method to measure the probability of UCN "small heating" using the BGS and illustrate it with a study of samples of the hydrogen-free oil Fomblin Y-HVAC 18/8. The data obtained are well reproducible, do not depend on sample thickness, and do not evolve over time. The measured model-independent probability P+ of UCN small heating from an energy "mono-line" 30.2 +/- 2.5 cm to the energy range 35 140 cm is in the range 1.05+/-0.02stat*10-5-1.31+/-0.24stat*10-5 at a temperature of 24 degrees C. The associated systematic uncertainty would disappear if a VUCN spectrum shape were known, for instance, from a particular model of small heating. This experiment provides the most precise and reliable value of small heating probability on Fomblin measured so far. These results are of importance for studies of UCN small heating as well as for analyzing and designing neutron lifetime experiments. PMID- 29495874 TI - A Peltier-based freeze-thaw device for meteorite disaggregation. AB - A Peltier-based freeze-thaw device for the disaggregation of meteorite or other rock samples is described. Meteorite samples are kept in six water-filled cavities inside a thin-walled Al block. This block is held between two Peltier coolers that are automatically cycled between cooling and warming. One cycle takes approximately 20 min. The device can run unattended for months, allowing for ~10 000 freeze-thaw cycles that will disaggregate meteorites even with relatively low porosity. This device was used to disaggregate ordinary and carbonaceous chondrite regoltih breccia meteorites to search for micrometeoroid impact craters. PMID- 29495872 TI - Simple, low-noise piezo driver with feed-forward for broad tuning of external cavity diode lasers. AB - We present an inexpensive, low-noise (<260 MUVrms, 0.1 Hz-100 kHz) design for a piezo driver suitable for frequency tuning of external-cavity diode lasers. This simple driver improves upon many commercially available drivers by incorporating circuitry to produce a "feed-forward" signal appropriate for making simultaneous adjustments to the piezo voltage and laser current, enabling dramatic improvements in a mode-hop-free laser frequency tuning range. We present the theory behind our driver's operation, characterize its output noise, and demonstrate its use in absorption spectroscopy on the rubidium D1 line. PMID- 29495875 TI - An efficient fluorescent single-particle position tracking system for long-term pulsed measurements of nitrogen-vacancy centers in diamond. AB - A simple and convenient design enables real-time three-dimensional position tracking of nitrogen-vacancy (NV) centers in diamond. The system consists entirely of commercially available components (a single-photon counter, a high speed digital-to-analog converter, a phase-sensitive detector-based feedback device, and a piezo stage), eliminating the need for custom programming or rigorous optimization processes. With a large input range of counters and trackers combined with high sensitivity of single-photon counting, high-speed position tracking (upper bound recovery time of 0.9 s upon 250 nm of step-like positional shift) not only of bright ensembles, but also of low-photon-collection efficiency single to few NV centers (down to 103 s-1) is possible. The tracking requires position modulation of only 10 nm, which allows simultaneous position tracking and pulsed measurements in the long term. Therefore, this tracking system enables measuring a single-spin magnetic resonance and Rabi oscillations at a very high resolution even without photon collection optimization. The system is widely applicable to various fields related to NV center quantum manipulation research such as NV optical trapping, NV tracking in fluid dynamics, and biological sensing using NV centers inside a biological cell. PMID- 29495876 TI - Polarisation in spin-echo experiments: Multi-point and lock-in measurements. AB - Spin-echo instruments are typically used to measure diffusive processes and the dynamics and motion in samples on ps and ns time scales. A key aspect of the spin echo technique is to determine the polarisation of a particle beam. We present two methods for measuring the spin polarisation in spin-echo experiments. The current method in use is based on taking a number of discrete readings. The implementation of a new method involves continuously rotating the spin and measuring its polarisation after being scattered from the sample. A control system running on a microcontroller is used to perform the spin rotation and to calculate the polarisation of the scattered beam based on a lock-in amplifier. First experimental tests of the method on a helium spin-echo spectrometer show that it is clearly working and that it has advantages over the discrete approach, i.e., it can track changes of the beam properties throughout the experiment. Moreover, we show that real-time numerical simulations can perfectly describe a complex experiment and can be easily used to develop improved experimental methods prior to a first hardware implementation. PMID- 29495877 TI - Macular sensitivities measured by microperimetry in patients on hydroxychloroquine treatment. AB - PURPOSE: To examine retinal sensitivity in patients on hydroxychloroquine (HCQ) with no evidence of retinopathy. MATERIALS AND METHODS: Seventy patients on HCQ and 30 healthy control subjects were included prospectively. All subjects underwent complete ophthalmic examination including best corrected visual acuity, tonometry, colour vision testing, biomicroscopy of anterior segment, dilated fundoscopy, 10-2 visual field testing, and spectral domain optical coherence tomography. The patients and control subjects who met the inclusion criteria and had normal tests underwent microperimetry (MP) testing. First, all patients were compared with the control group. Secondly, patients were divided into three sets of groups based on (1) duration of use <=5 years (DOU<=5) and >5 years (DOU>5), (2) daily dose <=5 mg/kg/day (DD<= 5) and >5 mg/kg/day (DD>5), and (3) a cumulative dose <=1000 gr (CD<= 1000) and >1000 gr (CD>1000), and these groups were compared to each other and to the control group. A correlation analysis was also performed between MP sensitivity and DOU, DD, and CD. RESULTS: Seven patients on HCQ showing visual field abnormality were excluded which yielded 63 patients and 30 control subjects for the final analysis. We observed significant differences only in the central region but not in the paracentral or peripheral regions on MP in HCQ users. The median MP sensitivities in the central region were significantly lower in all the patients [84 (63-100) dB], and in subgroups of DOU >5 [84 (63-99) dB], DD >5 [82 (63-97) dB] and CD >1000 [82 (63-92) dB] when compared to controls [89.7 (83-98) dB]. A statistically significant correlation was found only between DD and MP sensitivity in the central region (r = -0.263; p = 0.02). CONCLUSIONS: MP sensitivities in the central macula were significantly lower in patients taking HCQ for more than 5 years, at a daily dose more than 5 mg per day, and with a cumulative dose over 1000 gr. Further research investigating long-term follow-up changes in MP sensitivities is needed to determine cutoff values for early retinal toxicity. PMID- 29495878 TI - Perinatal and infant mental health: Further fruitful twists of Rubik's cube. PMID- 29495879 TI - Editorial Comment on: Ureteroscopic High-Frequency Dusting Utilizing a 120-W Holmium Laser by Tracey et al. PMID- 29495880 TI - Prospective study of a Bothrops jararacussu venom batch (Bj2015) - phospholipase A2 activity, immunogenicity, neurotoxicity, and myotoxicity parameters. AB - Bothrops jararacussu venom's (Bj2015) batch was biomonitored quarterly for one year to assess phospholipase A2 (PLA2) activity, immunogenicity, neurotoxicity, and myotoxicity. In silico models were applied to evaluate losses using decay model and recoveries by predictive trend analysis. Mice were immunized with Bj2015. Antibodies were detected by double-immunodiffusion and total protein and albumin were measured. Neuromuscular blockade-induced by 40 MUg mL-1 venom solution was carried out using mouse nerve phrenic-diaphragm preparation. Resulting muscles were submitted to light microscopy to evaluate the myotoxicity. PLA2 activity of 0.1 mg mL-1 Bj2015 was measured using 4-nitro-3 (octanoyloxy)benzoic acid as substrate. Over time, greater losses occurred in neurotoxicity than PLA2, but not in myotoxicity and immunogenicity. Concluding, the neurotoxicity decrease can be related to enzymatic losses, including PLA2. Depending on the purpose of use, the collected venom responds on a long time, avoiding unnecessary new collections, improving life quality of animals in captivity and increasing their longevity. PMID- 29495881 TI - A new actinomycin Z analogue with an additional oxygen bridge between chromophore and beta-depsipentapeptide from Streptomyces sp. KIB-H714. AB - Actinomycin Z6 (1), a new member of the actinomycin family, along with three congeners of the Z-type (Z1, Z3, Z5) actinomycins, are produced from Streptomyces sp. KIB-H714. Their structures were authenticated by comprehensive spectroscopic data interpretation. Different from all the reported Z-type actinomycins, the beta-ring of the new compound actinomycin Z6 includes an additional ring linked between the actinoyl chromophore and beta-peptidolactone. In Z3 and Z5, the L threonine in beta-depsipeptide is replaced by the unusual 4-chlorothreonine, an amino acid rarely found in actinomycin family. All isolates were evaluated for cytotoxicity against five human tumor cell lines and for inhibitory activity against Candida albicans and Staphylococcus aureus. PMID- 29495882 TI - Clinical significance of centripetal propagation of vasoconstriction in patients with reversible cerebral vasoconstriction syndrome: A retrospective case-control study. AB - Introduction We previously reported centripetal propagation of vasoconstriction at the time of thunderclap headache remission in patients with reversible cerebral vasoconstriction syndrome. Here we examine the clinical significance of centripetal propagation of vasoconstriction. Methods Participants comprised 48 patients who underwent magnetic resonance angiography within 72 h of reversible cerebral vasoconstriction syndrome onset and within 48 h of thunderclap headache remission. Results In 24 of the 48 patients (50%), centripetal propagation of vasoconstriction occurred on magnetic resonance angiography at the time of thunderclap headache remission. The interval from first to last thunderclap headache in patients with centripetal propagation of vasoconstriction (14 +/- 10 days) was significantly longer than that of patients without centripetal propagation of vasoconstriction (4 +/- 2 days). In the patients with centripetal propagation of vasoconstriction at the time of thunderclap headache remission, the incidence of another cerebral lesion (38%, 9 of 24 cases) was significantly higher than in patients without centripetal propagation of vasoconstriction (0%). From findings of sequential magnetic resonance angiography before and after thunderclap headache remission, we observed tendencies in which centripetal propagation of vasoconstriction gradually progressed after the onset of reversible cerebral vasoconstriction syndrome and peaked at the time of thunderclap headache remission. The progress of centripetal propagation of vasoconstriction concluded with thunderclap headache remission. Conclusions Centripetal propagation of vasoconstriction has clinical significance as an indicator of the severity of reversible cerebral vasoconstriction syndrome. The presence of centripetal propagation of vasoconstriction is associated with an increased risk of brain lesions and a longer interval from first to last thunderclap headache. Moreover, repeat magnetic resonance angiography to assess centripetal propagation of vasoconstriction during the time from onset to thunderclap headache remission can help diagnose reversible cerebral vasoconstriction syndrome. PMID- 29495884 TI - Myo- and cardiotoxic effects of the wild winter mushroom ( Flammulina velutipes) on mice. AB - Rhabdomyolysis (destruction of striated muscle) is a novel form of mushroom poisoning in Europe and Asia indicated by increased circulating creatine kinase levels. Particular wild fungi have also been reported to induce elevated creatine kinase activities in mice. Flammulina velutipes (enokitake or winter mushroom) is one of the most actively cultivated mushroom species globally. As it is marketed as a medicinal mushroom and functional food, it is important to examine whether it could induce potentially harmful health effects similar to some previously studied edible fungi. The present study examined the effects of F. velutipes consumption on the plasma clinical chemistry, hematology, and organ histology of laboratory mice. Wild F. velutipes were dried, pulverized, mixed with a regular laboratory rodent diet, and fed to the animals at 0, 3, 6, or 9 g/kg body mass/day for five days ( n = 6/group). F. velutipes consumption caused increased activities of plasma creatine kinase and the MB-fraction of creatine kinase at 6 9 g/kg/d, indicating potentially deleterious effects on both skeletal and cardiac muscle. The plasma total and high-density lipoprotein cholesterol concentrations (at 9 g/kg/d) and white blood cell and lymphocyte counts (at 6-9 g/kg/d) decreased. Although the cholesterol-lowering properties of F. velutipes can be beneficial, the previously unexamined, potentially hazardous side effects of mushroom consumption (myo- and cardiotoxicity) should be thoroughly investigated before recommending this mushroom species as a health-promoting food item. Impact statement This work is important to the field of functional foods, as it provides novel information about the potential myo- and cardiotoxic properties of an edible mushroom, Flammulina velutipes. The results are useful and of importance because F. velutipes is an actively cultivated mushroom and marketed as a health promoting food item. The findings contribute to the understanding of the complexity of the balance between the beneficial and potentially harmful effects of mushroom consumption. PMID- 29495883 TI - Integrated Care for Depression in Older Primary Care Patients. AB - For decades, depression in older adults was overlooked and not treated. Most treatment was by primary care providers and typically poorly managed. Recent interventions that integrate mental health services into primary care have increased the number of patients who are treated for depression and the quality of that treatment. The most effective models involve systematic depression screening and monitoring, multidisciplinary teams that include primary care providers and mental health specialists, a depression care manager to work directly with patients over time and the use of guideline-based depression treatment. The article reviews the challenges and opportunities for providing high-quality depression treatment in primary care; describes the 3 major integrated care interventions, PRISM-E, IMPACT, and PROSPECT; reviews the evidence of their effectiveness, and adaptations of the model for other conditions and settings; and explores strategies to increase their scalability into real world practice. PMID- 29495885 TI - Multifunctional nanoemulsions for intraductal delivery as a new platform for local treatment of breast cancer. AB - Considering that breast cancer usually begins in the lining of the ducts, local drug administration into the ducts could target cancers and pre-tumor lesions locally while reducing systemic adverse effects. In this study, a cationic bioadhesive nanoemulsion was developed for intraductal administration of C6 ceramide, a sphingolipid that mediates apoptotic and non-apoptotic cell death. Bioadhesive properties were obtained by surface modification with chitosan. The optimized nanoemulsion displayed size of 46.3 nm and positive charge, properties that were not affected by ceramide encapsulation (0.4%, w/w). C6 ceramide concentration necessary to reduce MCF-7 cells viability to 50% (EC50) decreased by 4.5-fold with its nanoencapsulation compared to its solution; a further decrease (2.6-fold) was observed when tributyrin (a pro-drug of butyric acid) was part of the oil phase of the nanocarrier, a phenomenon attributed to synergism. The unloaded nanocarrier was considered safe, as indicated by a score <0.1 in HET CAM models, by the high survival rates of Galleria mellonella larvae exposed to concentrations <=500 mg/mL, and absence of histological changes when intraductally administered in rats. Intraductal administration of the nanoemulsion prolonged drug localization for more than 120 h in the mammary tissue compared to its solution. These results support the advantage of the optimized nanoemulsion to enable mammary tissue localization of C6 ceramide. PMID- 29495886 TI - What prevents cardioprotective drugs from reaching the market? PMID- 29495887 TI - Essential oil composition of aerial parts from Algerian Anacyclus monanthos subsp. cyrtolepidioides (Pomel) Humphries. AB - The chemical composition of the essential oil from the aerial parts of Anacyclus monanthos subsp. cyrtolepidioides (Pomel) Humphries (Asteraceae) growing in a semi-arid region of Algeria was investigated for the first time. The essential oil was obtained by hydrodistillation and fully characterized by gas chromatography-mass spectrometry (GC-MS). A total of 97 compounds were identified. The essential oil was found to be rich in trans-chrysanthenyl acetate (9.8 +/- 2.0%), (E)-beta-farnesene (7.4 +/- 1.5%), germacrene D (6.9 +/- 1.3%) and myristicin (4.8 +/- 0.8%). PMID- 29495888 TI - Conservative Management of Staghorn Calculi: When Is It Safe? AB - BACKGROUND: To describe the clinical characteristics, infectious and kidney function patterns, and overall outcomes in a cohort of patients with staghorn calculi treated conservatively. METHODS: Staghorn calculi treated nonoperatively between January 2009 and January 2017 were identified. A retrospective analysis was completed. RESULTS: Twenty-nine patients were identified with a median age of 74 years (interquartile range [IQR] 61-81). Mean follow-up was 24 months. Fifty nine percent (17/29) had complete staghorn calculi with 6/29 (21%) bilateral. Mean body mass index was 29.4 (IQR 24.8-31.7). Of the 29 patients, 14 were treated conservatively due to comorbidities, 12 refused treatments, and 3 were due to aberrant anatomy. The age-adjusted Charlson Comorbidity Index (CCI) score demonstrated 8 patients in our cohort with a CCI of <3, 11 patients with a CCI of 4 or 5, 7 patients with a CCI of 6 or 7, and 3 patients with a CCI of >8. Overall, kidney function remained stable for 19/29 patients (66%) and the glomerular filtration rate decreased by <10% for 4/29 (14%), by 10%-29% for 2/29 (7%), and >30% for 4/29 patients (14%) over the study period. None of the study patients required hemodialysis. No patients in the cohort developed an abscess, nor were any patients on daily prophylactic antibiotics. There was only one related admission for a complication during the study; this was for pyelonephritis. There were two deaths during the study period. One death was an unrelated cardiac death and the other was from urosepsis; this patient had been noncompliant with follow-up. CONCLUSIONS: Outcomes for patients treated conservatively were reasonable in this select group. There is a need for future prospective studies to show whether conservative treatment of these patients is safe. PMID- 29495889 TI - Elucidating the link between collagen and pancreatic cancer: what's next? PMID- 29495890 TI - Behavioral indicators of slow growth in nursery pigs. AB - The objective of this study was to determine how feeder-space allowance affects behaviors of slow- and fast-growing pigs during the nursery period. Nursery pigs (n = 192; initial weight = 7.4 +/- 1.6 kg) were housed in 24 pens of 8 pigs, with 12 pens provided with either a two-space feeder or a five-space feeder. Pigs were categorized as slow growers (SG) and fast growers (FG) based on adjusted market weight (SG < 105 kg; FG >= 105 kg). Behaviors of pigs were video-recorded during the first four days after entering the nursery and on Day 21. Eating speed was measured on 96 focal pigs when they were nine weeks old. SG spent more time at the drinker than did FG (p < .05). SG spent less time in the standing/walking posture (p < .05) in pens with five-space feeders compared with SG in pens with two-space feeders. These results suggest that providing more feeder space may benefit SG in terms of improving the welfare of these pigs. PMID- 29495891 TI - Tocilizumab in the treatment of adult rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is the most prevalent immune-mediated chronic rheumatic disease and is associated with joint destruction and disability. Therapeutic strategies, including biological disease-modifying antirheumatic drugs (bDMARDs) have improved the prognosis and quality of life of RA patients. Tocilizumab (TCZ) is a humanized monoclonal antibody against IL-6 receptor licensed in 2009 that has demonstrated clinical efficacy in various adult RA populations. RA management guidelines and recommendations consider TCZ as one of the bDMARDS indicated after methotrexate or other conventional synthetic DMARDs and/or TNF inhibitors failure in adult RA. Of particular interest is the demonstration of its effectiveness in monotherapy in comparison with other bDMARDs. Recent observational studies have shown good results for the safety profile of TCZ with no new alert signals. PMID- 29495892 TI - Intensification of the convective drying process of Salvia officinalis: Modeling and optimization. AB - The current study deals with an innovation in the hot air convective drying process consisting of the application of two consecutive drying steps. Temperatures ranging between 60 and 80 C for times between 200 and 600 s were applied for the first stage, and from 40 to 80 C for the second stage. Salvia officinalis, an aromatic, medicinal Mediterranean plant with remarkable antioxidant properties, was selected for this study. A management of the process regarding the antioxidant capacity of S. officinalis extracts and energy consumption was carried out: (i) artificial neural networks were applied to model the evolution of the antioxidant capacity and moisture content of the product in the drying process; (ii) a genetic algorithm and a multiobjective genetic algorithm were selected to optimize the drying process, considering the antioxidant capacity and/or the energy consumption in the objective function. The results showed that the optimum values depended, logically, on the controllable variables values (hot air temperatures and drying times), but also on the uncontrollable variable values (room air temperature and relative humidity and the product's initial mass and moisture content). PMID- 29495893 TI - Discrimination and sexual risk among Caribbean Latinx young adults. AB - OBJECTIVES: Discrimination, such as being treated unfairly due to race, contributes to stress. Individuals may cope with this by engaging in risky behaviors. Consistent with this premise, prior studies found that discrimination is associated with substance use. Research has also shown that sex while 'high' on alcohol and drugs is associated with increased risk for HIV and other STIs. The present study examines the relationship between discrimination and sexual risk. We investigate whether discrimination is associated with sex while high on alcohol and drugs. DESIGN: Analyses focus on a sample of 356 Caribbean Diasporic young adults, primarily Caribbean Latinx, aged 18 to 25 who participated in the Drug Use and HIV Risk among Youth Survey carried out from 1997 to 2000 in Brooklyn, New York. Logistic regression examined the association between self reported discrimination and sex while high. RESULTS: More than half (52.3%) of respondents reported moderate discrimination. Sex while high was also reported: 35.7% for alcohol, 43.3% for marijuana, and 32.6% for heroin/cocaine. Discrimination was associated with increased risk of sex while high on (1) marijuana and (2) heroin/cocaine, but was not with alcohol. CONCLUSIONS: Discrimination may be a risk factor for engaging in sex while high on drugs, which may put individuals at risk for HIV as well as other STIs. Future research should explore relationships between discrimination and sex while high on alcohol and drugs among various racial/ethnic groups and Diasporas, while also assessing how this relationship may contribute to HIV incidence. PMID- 29495894 TI - Long-Term Outcomes of Laparoendoscopic Single-Site Nephrolithotomy for Caliceal Diverticular Calculi: A Case Series. AB - OBJECTIVE: To evaluate the outcomes of laparoendoscopic single-site nephrolithotomy (LESS-NL) for symptomatic caliceal diverticular calculi. PATIENTS AND METHODS: From November 2009 to March 2014, 11 cases of LESS-NL with a homemade single-port device for caliceal diverticular calculi were performed by a single experienced laparoscopic surgeon. All patients were assessed at postoperative 1 month, 1 year, and 3 years for symptom-free status and by CT for stone-free and caliceal diverticular obliteration status. All complications were categorized by the Clavien-Dindo classification. Demographic parameters and postoperative outcomes were retrospectively analyzed. RESULTS: All procedures were effectively performed without conversion to open or conventional laparoscopic surgery. Median patient age was 53 years (range 22-73), and median diverticular size was 26 mm (range 15-58). Six patients (54.5%) had multiple stones, and five patients (45.5%) had a single stone; median stone size was 20.6 mm (range 12.1-66.4). The transperitoneal approach was used in seven patients (63.6%) and retroperitoneal approach in four patients (36.4%). Median operative time was 161 minutes (range 110-250), median estimated blood loss was 50 mL (range 20-400), and median hospital stay was 4 days (range 3-6). An additional needlescopic instrument was used in five cases (45.5%). There were three cases (27.3%) of grade I complications (two postoperative fever, one ileus), and no intraoperative or major complications. Median visual analog scale score significantly improved by discharge day (from 4.9 preoperatively to 1.4; p = 0.003). After a median follow-up of 38 months (range 36-41), all patients were symptom free with no evidence of stone or caliceal diverticulum on imaging. CONCLUSIONS: LESS-NL is a safe, feasible, and definitive treatment option for symptomatic caliceal diverticular calculi. PMID- 29495896 TI - Polygenic Risk Score for Alzheimer's Disease: Implications for Memory Performance and Hippocampal Volumes in Early Life. AB - OBJECTIVE: Alzheimer's disease is a heritable neurodegenerative disorder in which early-life precursors may manifest in cognition and brain structure. The authors evaluate this possibility by examining, in youths, associations among polygenic risk score for Alzheimer's disease, cognitive abilities, and hippocampal volume. METHOD: Participants were children 6-14 years of age in two Brazilian cities, constituting the discovery (N=364) and replication samples (N=352). As an additional replication, data from a Canadian sample (N=1,029), with distinct tasks, MRI protocol, and genetic risk, were included. Cognitive tests quantified memory and executive function. Reading and writing abilities were assessed by standardized tests. Hippocampal volumes were derived from the Multiple Automatically Generated Templates (MAGeT) multi-atlas segmentation brain algorithm. Genetic risk for Alzheimer's disease was quantified using summary statistics from the International Genomics of Alzheimer's Project. RESULTS: Analyses showed that for the Brazilian discovery sample, each one-unit increase in z-score for Alzheimer's polygenic risk score significantly predicted a 0.185 decrement in z-score for immediate recall and a 0.282 decrement for delayed recall. Findings were similar for the Brazilian replication sample (immediate and delayed recall, beta=-0.259 and beta=-0.232, both significant). Quantile regressions showed lower hippocampal volumes bilaterally for individuals with high polygenic risk scores. Associations fell short of significance for the Canadian sample. CONCLUSIONS: Genetic risk for Alzheimer's disease may affect early-life cognition and hippocampal volumes, as shown in two independent samples. These data support previous evidence that some forms of late-life dementia may represent developmental conditions with roots in childhood. This result may vary depending on a sample's genetic risk and may be specific to some types of memory tasks. PMID- 29495895 TI - Revisiting Antipsychotic Drug Actions Through Gene Networks Associated With Schizophrenia. AB - OBJECTIVE: Antipsychotic drugs were incidentally discovered in the 1950s, but their mechanisms of action are still not understood. Better understanding of schizophrenia pathogenesis could shed light on actions of current drugs and reveal novel "druggable" pathways for unmet therapeutic needs. Recent genome-wide association studies offer unprecedented opportunities to characterize disease gene networks and uncover drug-disease relationships. Polygenic overlap between schizophrenia risk genes and antipsychotic drug targets has been demonstrated, but specific genes and pathways constituting this overlap are undetermined. Risk genes of polygenic disorders do not operate in isolation but in combination with other genes through protein-protein interactions among gene product. METHOD: The protein interactome was used to map antipsychotic drug targets (N=88) to networks of schizophrenia risk genes (N=328). RESULTS: Schizophrenia risk genes were significantly localized in the interactome, forming a distinct disease module. Core genes of the module were enriched for genes involved in developmental biology and cognition, which may have a central role in schizophrenia etiology. Antipsychotic drug targets overlapped with the core disease module and comprised multiple pathways beyond dopamine. Some important risk genes like CHRN, PCDH, and HCN families were not connected to existing antipsychotics but may be suitable targets for novel drugs or drug repurposing opportunities to treat other aspects of schizophrenia, such as cognitive or negative symptoms. CONCLUSIONS: The network medicine approach provides a platform to collate information of disease genetics and drug-gene interactions to shift focus from development of antipsychotics to multitarget antischizophrenia drugs. This approach is transferable to other diseases. PMID- 29495897 TI - Effectiveness of Early Psychosis Intervention: Comparison of Service Users and Nonusers in Population-Based Health Administrative Data. AB - OBJECTIVE: Early psychosis intervention (EPI) programs improve clinical and functional outcomes for people with first-episode psychosis. Less is known about the impact of these programs on the larger health care system. The authors sought to compare indicators of health service use, self-harm, suicide, and mortality between people with first-episode psychosis who were using EPI services and a propensity-matched group of concurrent control subjects who were not accessing EPI services. METHOD: A retrospective cohort of incident cases of nonaffective psychosis in the catchment area of the Prevention and Early Intervention Program for Psychoses in London, Ontario, between 1997 and 2013 was constructed using health administrative data. This cohort was linked to primary data from the same program to identify people who used EPI services. Outcomes for people who used EPI services and those who did not were compared using Cox proportional hazards models. RESULTS: People who used EPI services had substantially lower rates of all-cause mortality in the 2-year period after EPI program admission (hazard ratio=0.24, 95% CI=0.11-0.53), although a significant difference in self-harm (hazard ratio=0.86, 95% CI=0.18-4.24) and suicide (hazard ratio=0.73, 95% CI=0.29 1.80) between the two groups was not observed. Those who used EPI services also had lower rates of emergency department presentation (hazard ratio=0.71, 95% CI=0.60-0.83) but higher rates of hospitalization (hazard ratio=1.42, 95% CI=1.18 1.71). These benefits were not observed after 2 years, when EPI care is typically stepped down to medical management. CONCLUSIONS: People with first-episode psychosis who used EPI services had mortality rates that were four times lower than those with first-episode psychosis who did not use these services, as well as better outcomes across several health care system indicators. These findings support the effectiveness of EPI services for the treatment of first-episode psychosis in the larger context of the overall health care system. PMID- 29495900 TI - MSc Medical Art Masters Show 2017, University of Dundee. PMID- 29495898 TI - Molecular Genetic Analysis Subdivided by Adversity Exposure Suggests Etiologic Heterogeneity in Major Depression. AB - OBJECTIVE: The extent to which major depression is the outcome of a single biological mechanism or represents a final common pathway of multiple disease processes remains uncertain. Genetic approaches can potentially identify etiologic heterogeneity in major depression by classifying patients on the basis of their experience of major adverse events. METHOD: Data are from the China, Oxford, and VCU Experimental Research on Genetic Epidemiology (CONVERGE) project, a study of Han Chinese women with recurrent major depression aimed at identifying genetic risk factors for major depression in a rigorously ascertained cohort carefully assessed for key environmental risk factors (N=9,599). To detect etiologic heterogeneity, genome-wide association studies, heritability analyses, and gene-by-environment interaction analyses were performed. RESULTS: Genome-wide association studies stratified by exposure to adversity revealed three novel loci associated with major depression only in study participants with no history of adversity. Significant gene-by-environment interactions were seen between adversity and genotype at all three loci, and 13.2% of major depression liability can be attributed to genome-wide interaction with adversity exposure. The genetic risk in major depression for participants who reported major adverse life events (27%) was partially shared with that in participants who did not (73%; genetic correlation=+0.64). Together with results from simulation studies, these findings suggest etiologic heterogeneity within major depression as a function of environmental exposures. CONCLUSIONS: The genetic contributions to major depression may differ between women with and those without major adverse life events. These results have implications for the molecular dissection of major depression and other complex psychiatric and biomedical diseases. PMID- 29495901 TI - Retrospective cohort study to investigate the impact of timing for term cesarean delivery on maternal and neonatal outcomes. AB - BACKGROUND: Early-term cesarean delivery (CD) increases neonatal respiratory morbidity; however, planned late-term cesarean delivery (CD) may generate urgent CD related to spontaneous onset of labor. AIMS: We investigated maternal and neonatal morbidity for planned early (37/38 week) versus late-term (39/40 weeks) CD. Our primary study aim was to investigate severe maternal morbidity and general anesthesia rates according to early versus late-term CD. Our secondary study aims were to investigate the rate of urgent surgery and other measures of maternal morbidity, and neonatal morbidity, according to early versus late-term CD and according to urgent versus elective planned CD. METHODS: In our retrospective, ethically approved study of planned CD we compared maternal morbidity and neonatal respiratory morbidity, for early versus late-term CD. RESULTS: Among 370 early versus 300 late-term CD, women who delivered at late term CD had significantly higher rates of urgent surgery 101 (33.7%) versus 85 (23.0%) at early-term, p = .002; spontaneous onset of labor 85 (28.3%) versus 67 (18.1%), p = .0002 and out-of-hours surgery 101 (33.7%) versus 64 (17.3%), p < .0001. The frequency of neonatal respiratory morbidity composite was 10 (2.7%) for early versus 1 (0.3%) for late-term CD, p = .03. CONCLUSIONS: Late-term CD was not associated with increased maternal morbidity or use of general anesthesia in our tertiary institution. Prior reports of increased neonatal respiratory morbidity at early term CD were confirmed. Of concern, late-term CD was associated with urgent and out-of-hours CD. PMID- 29495902 TI - Pharmacological prophylaxis of postpartum exacerbation in depressive and anxiety symptoms: a retrospective study. AB - The aim of this study was to investigate the efficacy of prophylactic treatment with antidepressants for the prevention of postpartum exacerbation in depressive or anxiety symptoms. The study included data on 33 patients who were followed from pregnancy to the postpartum period at the Department of Psychiatry of a university Hospital. Psychiatric diagnoses were determined by means of a structured clinical interview. The severity of depressive and anxiety symptoms were assessed by means of Hamilton Rating Scale for Depression (HAM-D) and Hamilton Rating Scale for Anxiety (HAM-A), respectively. Prophylactic treatment was initiated within the first 3 days after the delivery. The patients were assessed again with HAM-D and HAM-A at 4-week postpartum. Postpartum prophylaxis was carried out with administration of sertraline at 50 mg/day (n = 7, 21.2%), paroxetine at 20 mg/day (n = 24, 72.7%), and escitalopram at 10 mg/day (n = 2, 6.1%). Statistical analyses indicated that the mean HAM-D and HAM-A scores before (9.45 +/- 7.01 and 10.09 +/- 6.42, respectively) and after (9.09 +/- 6.65 and 9.54 +/- 5.97, respectively) the delivery were not significant. Results of the present study suggest that prophylactic use of antidepressants following parturition may be useful in the prevention of postpartum exacerbation of symptoms in women with depression or anxiety disorders. PMID- 29495899 TI - Cortical Thinning and Neuropsychiatric Outcomes in Children Exposed to Prenatal Adversity: A Role for Placental CRH? AB - OBJECTIVE: The authors sought to assess associations among early-life exposure to adversity, the development and maturation of neurons and brain circuits, and neurodevelopmental outcomes. Specifically, they examined whether fetal exposure to placental corticotropin-releasing hormone (CRH), a molecule conveying maternal signals to the fetus, predicts brain growth and neuropsychiatric outcomes in school-age children. METHOD: In a large, well-characterized prospective cohort, concentrations of placental CRH (pCRH) in maternal plasma were determined during five intervals during gestation. When the children reached school age, their brain structures were examined using MRI, and emotional and cognitive tests assessing internalizing and externalizing behaviors and attention were administered (N=97, 49 of them girls). RESULTS: Levels of pCRH during gestation predicted structural and functional brain outcomes in children. Specifically, fetal exposure to elevated pCRH levels was associated with thinning of selective cortical regions and with commensurate cognitive and emotional deficits. The relations among fetal exposure to pCRH, cortical thinning, and childhood function were sex specific. CONCLUSIONS: In view of the established effects of CRH on maturation and arborization of cortical neurons, and the major contribution of dendrites to cortical volume, these findings position pCRH as an important mediator of the consequences of early-life adversity on neuropsychiatric outcomes. PMID- 29495903 TI - A novel scoring system to predict the outcomes of adult patients with hypoxic ischemic encephalopathy. AB - BACKGROUND: Adult patients with hypoxic-ischemic encephalopathy (HIE) often incur large costs, but their outcomes are poor. Currently, there is lack of a comprehensive quantitative approach to predict patient prognoses. METHODS: A total of 73 adult patients with HIE participated in this prospective, observational study. Clinical assessments, laboratory tests, and electrophysiological examinations were conducted within 3 days after HIE occurred. Logistic regression model was used to identify independent factors associated with patient outcomes. RESULTS: After a 6-month follow-up, 44 (61.1%) patients survived, 28 (38.9%) patients died, and one patient was lost to follow up. The level of blood calcium and lactate, the presence of electroencephalography reactivity, and Glasgow Coma Scale (GCS) score were significantly associated with the patient's outcome. Based on the regression coefficients from logistic regression analysis, we constructed a scoring system (CEGL; C: calcium, E: EEG reactivity, G: GCS, L: lactate) to predict the possibility of a patient's death. The area under the receiver operating characteristic curve was 0.91 (P < 0.001, 95% CI [0.87-0.95]) with a specificity of 97.7% and a positive predictive value of 97.4%. CONCLUSION: CEGL score can provide clinicians useful information for assessment of patient prognosis within 6 months after HIE. PMID- 29495904 TI - Minimal residual disease as a biomarker for outcome prediction and therapy optimization in acute myeloid leukemia. AB - INTRODUCTION: Response to therapy is affected by the genetic heterogeneity of acute myeloid leukemia (AML) and persistence of leukemic cells below the threshold of morphological complete remission (mCR). Such persistence is called minimal (or measurable) residual disease (MRD). Areas covered: MRD assessment allows early identification of patients who are at high risk of relapse and who should timely receive aggressive therapy (e.g. allogeneic stem cell transplantation) and of those with a good quality mCR in whom an aggressive front line therapy can be spared, avoiding the harm of excessive treatment toxicity. The most exploited methods to assess MRD are multiparameter flow cytometry (via identification of immunophenotypic aberrancies) or PCR-based assays (via identification of cytogenetic/molecular abnormalities). Expert commentary: A growing body of evidences demonstrates that positive MRD-testing at various time points throughout the treatment course identifies patients at high risk of relapse. We will focus on the role of MRD as a biomarker to refine risk assessment and to prospectively direct treatment choices in adult with AML. PMID- 29495905 TI - Possible targets to treat myeloma-related osteoclastogenesis. AB - INTRODUCTION: Bone destruction is the hallmark of multiple myeloma (MM). About 80% of MM patients at diagnosis presents myeloma bone disease (MBD) leading to bone pain and pathological fractures, significantly affecting patients' quality of life. Bisphosphonates are the treatment of choice for MBD, but osteolytic lesions remain a critical issue in the current management of MM patients. Several studies clarified the mechanisms involved in MM-induced osteoclast formation and activation, leading to the identification of new possible targets and the development of better bone-directed therapies, that are discussed in this review. Areas covered: This review summarizes the latest advances in the knowledge of the pathophysiology of the osteoclast formation and activation induced by MM cells, and the new therapeutic targets identified. Recently, neutralizing antibodies (i.e. denosumab, siltuximab, daratumumab), as well as recombinant fusion proteins, and receptor molecular inhibitors, have been developed to block these targets. Clinical trials testing their anti-MBD potential are ongoing. The emerging role of exosomes and microRNAs in the regulation of osteoclast differentiation has been also discussed. Expert commentary: Although further studies are needed to arrive at a clinical approving, the basis for the development of better bone-directed therapies has been established. PMID- 29495907 TI - Comparison of the in vitro toxicity of ancient Triticum monococcum varieties ID331 and Monlis. AB - Triticum monococcum L. is one of the oldest ancestors of wheat. There is some evidence that einkorn encloses forms of gliadin-deriving peptides which may potentially exert a reduced toxicity to consumers with gluten-related disorders. Accordingly, ID331 and Monlis lines were comparatively investigated in this study. The biological effects of gastro-resistant peptides deriving from an in vitro simulated digestion were evaluated on 21 d differentiated Caco-2 cells. Triticum aestivum digested gliadin was included as the positive control. ID331 neither enhanced cell permeability nor induced zonulin release in Caco-2 monolayers. Monlis exerted a detectable toxicity as confirmed by the reorganisation of enterocyte cytoskeleton, in addition to changes both in monolayers permeability and apical release of zonulin. Differences in patterns of gastro-resistant prolamins may account for the differences. Outcomes support the use of ID331 as a prospective candidate for the development of innovative approaches to reduce wheat flour toxicity. PMID- 29495908 TI - Genome-Wide Profiling of Long Noncoding RNA Expression Patterns in Women With Repeated Implantation Failure by RNA Sequencing. AB - OBJECTIVES: To compare long noncoding RNA (lncRNA) and messenger RNA (mRNA) expression levels in endometrium between patients with repeated implantation failure (RIF) following in vitro fertilization (IVF)-embryo transfer and control women. MATERIALS AND METHODS: RNA sequencing (RNA-seq) and alignments were performed to identify lncRNAs and mRNAs using endometrial samples collected from 3 patients and 3 control women. A subset of 10 differentially expressed lncRNAs and 6 mRNAs were validated in all participants using quantitative reverse transcription polymerase chain reaction. The potential biological roles of identified lncRNAs were predicted via coexpressed mRNA annotations. Twenty patients with RIF and 30 control women were recruited for validation. RESULTS: We identified 1202 differentially expressed genes, including 742 lncRNAs and 460 mRNAs, in mid-secretory phase endometrial tissue from patients with RIF following IVF compared to control women. We analyzed the target genes of the lncRNAs and uncovered 148 lncRNAs corresponding to 147 cis-regulated target genes. The cis regulated target genes of these significantly differentially expressed lncRNAs were clustered into several pathways, such as the tumor necrosis factor signaling pathway, the Toll-like receptor signaling pathway, and the NF-kappa B (NF-kappaB) signaling pathway. CONCLUSION: Our study constitutes the first report on the investigation of the regulatory mechanisms of lncRNAs in endometrial receptivity in women experiencing RIF using RNA-seq. Our results provide a valuable candidate reservoir for future functional studies of lncRNAs. PMID- 29495906 TI - Safety of a physical therapy protocol for women with preeclampsia: a randomized controlled feasibility trial. AB - OBJECTIVE: To assess the feasibility and safety of a physiotherapy protocol applied to pregnant women with preeclampsia. METHODS: Randomized, controlled, single-blind feasibility study, with 24 hospitalized pregnant women with preeclampsia. The intervention group received one session of the physiotherapy. The control group remained under the routine care of the hospital. The primary outcomes were Doppler velocimetry, cardiotocography, and maternal-fetal hemodynamics. Secondary outcomes were pain and anxiety assessed before and after the interventions. A mixed effects linear regression model was used, and the data were compared with the level of significance at 5%. RESULTS: The baseline characteristics of the participants were homogeneous between groups. Resistance index of the Middle Cerebral Artery (MAC) and Umbilical Artery (UA) and cardiotocography did not change significantly. The systolic blood pressure (SBP) increased 4.90 mmHg in the control group and 0.22 mmHg in the intervention group. The diastolic blood pressure (DBP) increased 1.34 mmHg in the control group and decreased 0.40 mmHg in the intervention group. The middle bood pressure (MBP) increased 4.66 mmHg in the control group while there was a decrease of 0.09 mmHg in the intervention group, without statistical difference. Heart rate (HR) decreased 0.94 bpm in the control group; whereas, in the intervention group, there was an increase of 6.30 bpm. The pain reduced clinically 2 points after the intervention. The anxiety reduced clinically in both the groups (-1.26 in the intervention group and -2.17 in the control group). CONCLUSION: The protocol applied in the intervention group is feasible and safe for both mother and fetus. Both groups showed clinical reduction in the levels of anxiety; whereas, pain was clinically reduced in the intervention group. PMID- 29495909 TI - Occupational Therapy Practitioners' Perspectives of Mental Health Practices With Clients in Stroke Rehabilitation. AB - Following a stroke, depression and anxiety may negatively affect recovery and decrease quality of life. Occupational therapy (OT) practitioners are distinctly qualified to address both the physical and psychosocial sequelae of a stroke, including clients' mental and emotional health. This study explored the ways in which OT practitioners address the mental health needs of clients post stroke. A sequential explanatory mixed-methods design was used to collect both survey and focus group data. In all, 754 OT practitioners across the United States completed an online survey, and 10 practitioners participated in focus groups. Practitioners considered their clients' mental health needs to be a priority (68.17%); however, only 56.64% were satisfied with the care they provided related to mental and emotional health. They identified barriers that included limited time, increased productivity standards, expectations related to physical recovery, and poor educational preparation. Practitioners are motivated to improve their provision of mental health services to clients post stroke. To address the conflict between practice realities and professional values, education programs should better integrate curricular components that focus on physical and mental health. PMID- 29495910 TI - Dietary Behaviors and Glucose Metabolism in Young Adults at Risk for Type 2 Diabetes. AB - Purpose The purpose of the study was to examine the associations between dietary behaviors and glucose metabolism in high-risk young adults to increase the precision of nutrition education to prevent early onset type 2 diabetes (T2D). Method Using a descriptive, cross-sectional study design, 106 overweight or obese sedentary young adults ages 18-29 years from the Atlanta metropolitan area were recruited to screen diabetes risk. Survey questionnaires, anthropometric assessment, blood pressure (BP), and laboratory data were collected in a clinical research unit. The Web-based HOMA2 calculator was used to calculate beta cell function and insulin sensitivity. Results The final sample included 103 participants. There were similar patterns of diet (caloric intake and dietary quality) between African Americans and non-African Americans, whereas African Americans showed hyperinsulinemia compared with non-African Americans. When young adults consumed a good quality diet (appropriate carbohydrate intakes; high fiber, low saturated fat but protein rich diet), their insulin resistance was decreased. There was a marginal interaction effect between insulin sensitivity and beta cell function by race. Systolic BP was higher in African Americans, and total cholesterol, triglycerides, and low-density lipoprotein cholesterol were higher in non-African Americans. Conclusion Findings are useful to develop age specific nutrition guidelines to prevent early onset T2D in high-risk young adults. PMID- 29495911 TI - The effects of gonadotropin-releasing hormone agonist (buserelin) and orchidectomy on bone turnover markers and histomorphometry in rats. AB - This study aimed to compare the skeletal effect between GnRH agonist therapy and orchidectomy in male rats assessed using serum turnover markers and bone histomorphometry. Three-month-old male Sprague-Dawley rats (n = 46) were divided into three experimental arms, baseline, buserelin, and orchidectomy. In the buserelin arm, the rats received a daily subcutaneous injection of either normal saline or buserelin acetate at 25 ug/kg or 75 ug/kg. In the orchidectomy arm, the rats were either sham-operated or orchidectomized. The rats were euthanized after the three-month treatment. Blood was collected for the evaluation of bone turnover markers. Femurs were harvested for bone histomorphometry examination. A significant increase in serum C-telopeptide of type 1 collagen was observed in the orchidectomized group compared with the sham group (p < .05). Structural histomorphometry analysis showed that both buserelin (25 ug/kg and 75 ug/kg) and orchidectomy significantly decreased the trabecular bone volume, number and significantly increased trabecular separation in rats compared with their respective controls (p < .05). Osteoclast number and eroded surface were significantly increased in both buserelin (25 ug/kg and 75 ug/kg) and orchidectomized group compared with their respective controls (p < .05). As a conclusion, buserelin causes deterioration of bone microarchitecture and increased bone resorption similar to orchidectomy after three months. PMID- 29495912 TI - More secure attachment to the father and the mother is associated with fewer depressive symptoms in adolescents. AB - AIM: To investigate whether more secure attachment to the father and the mother is associated with less depressive symptoms among adolescents, and to explore possible sex differences. METHOD: A population-based sample of adolescents completed a school-based survey assessing demographic data, attachment to father and mother, as well as depressive symptoms. Participation rate was 80% of the eligible population, and 3,988 adolescents (1,937 boys and 2,051 girls) had complete data for the analyses. RESULTS: Paired samples t tests showed that participants rated their attachment to mothers as slightly more secure than their attachment to fathers (t = 15.94, P < 0.001; boys: t = 5.23, P < 0.001; girls: t = 16.16, P < 0.001). In linear regression analyses there was an association between the outcome, number of depressive symptoms, and more secure attachment to the mother for boys (B = -0.532; 95% confidence interval [CI] -0.656, -0.407, P < 0.001) and for girls (B = -0.623; 95% CI -0.730, -0.516, P < 0.001). Analogous results were found for more secure attachment to the father for boys (B = -0.499; 95% CI -0.608, -0.391, P < 0.001) and for girls (B = -0.494; 95% CI -0.586, 0.401, P < 0.001). CONCLUSIONS: Understanding the relationship between attachment to both father and mother and depressive symptoms in adolescent boys and girls is essential for further development of strategies for prevention and treatment of depression. PMID- 29495913 TI - Screening of broad spectrum natural pesticides against conserved target arginine kinase in cotton pests by molecular modeling. AB - Cotton is an economically important crop and its production is challenged by the diversity of pests and related insecticide resistance. Identification of the conserved target across the cotton pest will help to design broad spectrum insecticide. In this study, we have identified conserved sequences by Expressed Sequence Tag profiling from three cotton pests namely Aphis gossypii, Helicoverpa armigera, and Spodoptera exigua. One target protein arginine kinase having a key role in insect physiology and energy metabolism was studied further using homology modeling, virtual screening, molecular docking, and molecular dynamics simulation to identify potential biopesticide compounds from the Zinc natural database. We have identified four compounds having excellent inhibitor potential against the identified broad spectrum target which are highly specific to invertebrates. PMID- 29495914 TI - Developmental mirror-writing is paralleled by orientation recognition errors. AB - The writing attempts of children often feature mirror-reversals of individual letters. These reversals are thought to arise from an adaptive tendency to mirror generalize. However, it is unclear whether mirror-writing is driven by mirror generalisation of the visual letter forms, or of the actions for writing them. We report two studies of the relationship between mirror-writing and the ability to recognize whether a visually presented letter is in the correct orientation, amongst primary and preschool children learning to read and write in English. Children who produced more mirror-writing also made more orientation recognition errors, for uppercase (Study 1, n = 44) and lowercase letters (Study 2, n = 98), and these relationships remained significant when controlling for age. In both studies, the letters more often reversed in writing were also more prone to orientation recognition errors. Moreover, the rates of mirror-writing of different uppercase letters were closely similar between the dominant and non dominant hands (Study 1). We also note that, in the recognition tasks, children were more likely to accept reversed letters as correct, than to reject correctly oriented letters, consistent with a tendency to mirror-generalize the visual letter forms. In every aspect, these results support a major role for visual representations in developmental mirror-writing. PMID- 29495915 TI - Enhanced Vancomycin Elimination in an Infant Following an Unsuccessful Gastroschisis Repair Surgery. AB - OBJECTIVE: To report the case of an infant who required high-dose vancomycin therapy after an unsuccessful gastroschisis repair surgery. CASE SUMMARY: An infant born at 35 weeks and 5 days of gestation underwent a gastroschisis repair on day of life 47. The repair was unsuccessful causing fluid backup and accumulation into the stomach. A replogle was placed to allow for suctioning of this fluid. During this admission, the patient received 3 courses of vancomycin. During the first course, the patient had minimal output via the replogle tube. On the infant's second and third courses of vancomycin, the infant necessitated vancomycin dosing above that of the neonatal protocol, and subsequent levels were still found to be below goal. Vancomycin was increased to a maximum of 15 mg/kg every 4 hours (90 mg/kg/d) in order to achieve serum trough levels greater than 10 mg/L. Residuals were drawn from the replogle ranging from 0.76 to 4.33 mL/kg/h during the second and third course of vancomycin. DISCUSSION: A premature male infant required up to 90 mg/kg/d of vancomycin to achieve trough levels above 10 mg/L after an unsuccessful gastroschisis repair surgery and gastric suctioning. CONCLUSION: Clinicians should be aware of the possibility for decreased vancomycin levels and the potential need for increased monitoring in postsurgical infants receiving gastric suctioning. PMID- 29495916 TI - Voriconazole Autoinduction and Saturable Metabolism After Cessation of Rifampin in a Patient With Invasive Central Nervous System Aspergillus: Importance of Therapeutic Drug Monitoring. AB - PURPOSE: Optimization of antifungal therapy with voriconazole can be challenging due to inter- and intrapatient variability in voriconazole pharmacokinetics (PK). In this case, we introduce challenges in voriconazole therapy due to drug-drug interactions, autoinduction, and saturable metabolism. SUMMARY: A 32-year-old male on chronic prednisone developed central nervous system (CNS) aspergillosis. He was started on high-dose intravenous (IV) voriconazole 8.5 mg/kg every 12 hours due to concerns for lasting induction effects of recent rifampin therapy. The initial voriconazole trough was 2 MUg/mL. Frequent dose adjustments were made to maintain the therapeutic trough goal. On day 24 of voriconazole therapy, his trough was undetectable on IV voriconazole 5.5 mg/kg every 12 hours. His dose was escalated to 8.5 mg/kg every 12 hours to avoid subtherapeutic levels and therapeutic failure. On day 48, his trough level was 1.1 MUg/mL on the same dose. His regimen was changed to 6.5 mg/kg every 8 hours at this point. Sixteen days after this regimen on day 74 of voriconazole therapy, his trough was 27.2 MUg/mL indicating saturable PK of voriconazole in the absence of interacting drugs. CONCLUSION: Our findings highlight the unpredictable PK of voriconazole and reinforce the importance of continuous therapeutic drug monitoring in critically ill patients. PMID- 29495917 TI - Re-situating abortion: Bio-politics, global health and rights in neo-liberal times. AB - New modes of neoliberal and rights-based reproductive governance are emerging across the world which either paradoxically foreclose access to universal health services or promote legislative reform without providing a continuum of services on the ground. These shifts present new opportunities for the expansion but also the limitation of abortion provision conceptually and 'on-the-ground', both in the Global North and South. The collection of papers in this special issue examine current abortion governance discourse and practice in historical, socio political contexts to analyse the threat posed to women's sexual and reproductive health and rights globally. Focusing on abortion politics in the context of key intersectional themes of morality, law, religion and technology, the papers conceptually 're-situate' the analysis of abortion with reference to a changing global landscape where new modes of consumption, rapid flows of knowledge and information, increasingly routinised recourse to reproductive technologies and related forms of bio-sociality and solidarity amongst recipients and practitioners coalesce. PMID- 29495918 TI - MicroRNA-29a Functions as a Tumor Suppressor and Increases Cisplatin Sensitivity by Targeting NRAS in Lung Cancer. AB - MicroRNAs have been reported to play an important role in diverse biological processes and progression of various cancers. MicroRNA-29a has been observed to be downregulated in human lung cancer tissues, but the function of microRNA-29a in lung cancer has not been well investigated. In this study, we demonstrated that the expression levels of microRNA-29a were significantly downregulated in 38 pairs of lung cancer tissues when compared to adjacent normal tissues. Overexpression of microRNA-29a inhibited the activity of cell proliferation and colony formation of lung cancer cells, H1299 and A549. Furthermore, microRNA-29a targeted NRAS proto-oncogene in lung cancer cells. In human clinical specimens, NRAS proto-oncogene was highly expressed in human lung cancer tissues compared to normal tissues. More interestingly, microRNA-29a also sensitizes lung cancer cells to cisplatin (CDDP[Please replace "CDDP" with its expansion in the abstract and also provide expansion for the same in its first occurrence in text, if appropriate.]) via its target, NRAS proto-oncogene. Thus, our results in this study demonstrated that microRNA-29a acted as a tumor suppressor microRNA, which indicated potential application of microRNAs for the treatment of human lung cancer in the future. PMID- 29495919 TI - Blood Glutamate Scavenger as a Novel Neuroprotective Treatment in Spinal Cord Injury. AB - Neurotrauma causes immediate elevation of extracellular glutamate (Glu) levels, which creates excitotoxicity and facilitates inflammation, glial scar formation, and consequently neuronal death. Finding factors that reduce the inflammatory response and glial scar formation, and increase neuronal survival and neurite outgrowth, are of major importance for improving the outcome after spinal cord injury (SCI). In the present study, we evaluated a new treatment aiming to remove central nervous system (CNS) Glu into the systemic blood circulation by intravenous (IV) administration of blood Glu scavengers (BGS) such as the enzyme recombinant glutamate-oxaloacetate transaminase 1 (rGOT1) and its co-substrate. In this study we induced in mice an SCI (hemisection), and 1 h post-injury started administering BGS treatment for 5 consecutive days. The treatment reduced the expression levels of p-p38, which regulates apoptosis and increased the expression of p-Akt, which mediates cell survival. Moreover, this treatment decreased pro-inflammatory cytokine expression and microglia activation, reduced astrocytes' reactivity, and facilitated expression of radial glia markers such as Pax6 and nestin. BGS treatment increased the survival of neurons at lesion site and enabled axonal regeneration into the injury site. These effects were correlated with improved functional recovery of the left paretic hindlimb. Thus, early pharmacological intervention with BGS following SCI may be neuroprotective and create a pro-regenerative environment by modulating glia cell response. In light of our results, the availability of the method to remove excess Glu from CNS without the need to deliver drugs across the blood-brain barrier (BBB) and with minimal or no adverse effects may provide a major therapeutic asset. PMID- 29495920 TI - Multifocal vertebral sclerosing bone changes and soft tissue masses caused by Hodgkin's lymphoma in a patient with systemic lupus erythematosus: a case report. PMID- 29495921 TI - Relative sensitivity analysis of the predictive properties of sloppy models. AB - Commonly among the model parameters characterizing complex biological systems are those that do not significantly influence the quality of the fit to experimental data, so-called "sloppy" parameters. The sloppiness can be mathematically expressed through saturating response functions (Hill's, sigmoid) thereby embodying biological mechanisms responsible for the system robustness to external perturbations. However, if a sloppy model is used for the prediction of the system behavior at the altered input (e.g. knock out mutations, natural expression variability), it may demonstrate the poor predictive power due to the ambiguity in the parameter estimates. We introduce a method of the predictive power evaluation under the parameter estimation uncertainty, Relative Sensitivity Analysis. The prediction problem is addressed in the context of gene circuit models describing the dynamics of segmentation gene expression in Drosophila embryo. Gene regulation in these models is introduced by a saturating sigmoid function of the concentrations of the regulatory gene products. We show how our approach can be applied to characterize the essential difference between the sensitivity properties of robust and non-robust solutions and select among the existing solutions those providing the correct system behavior at any reasonable input. In general, the method allows to uncover the sources of incorrect predictions and proposes the way to overcome the estimation uncertainties. PMID- 29495922 TI - Boosted neural networks scoring functions for accurate ligand docking and ranking. AB - Predicting the native poses of ligands correctly is one of the most important steps towards successful structure-based drug design. Binding affinities (BAs) estimated by traditional scoring functions (SFs) are typically used to score and rank-order poses to select the most promising conformation. This BA-based approach is widely applied and some success has been reported, but it is inconsistent and still far from perfect. The main reason for this is that SFs are trained on experimental BA values of only native poses found in co-crystallized structures of protein-ligand complexes (PLCs). However, during docking, they are needed to discriminate between native and decoy poses, a task for which they have not been specifically designed. To overcome this limitation, we propose to build task-specific SFs that model binding affinities (scoring task) as well as conformations (docking task) using the root mean square deviation (RMSD) of a ligand pose from the native pose. Our models are based on boosted ensembles of neural networks and other state-of-the-art machine learning (ML) algorithms in conjunction with multi-perspective interaction modeling techniques for accurate characterization of PLCs. We assess the docking and scoring/ranking accuracies of the proposed ML SFs as well as three conventional SFs in the context of the 2014 CSAR benchmark exercise that encompasses three high-quality protein systems and a diverse set of drug-like molecules. Our proposed docking-specific SFs provide a substantial improvement in the docking task. We find that RMSD-based SFs for BsN, an ensemble neural networks (NN) model based on boosting, and six other ML models provide more than 120% improvement, on average, over their BA-based counterparts. In terms of scoring/ranking accuracy, we find that the approach of using RMSD based BsN to select the top ligand pose followed by applying BA-based BsN to rank ligands using predicted BA scores leads to consistent and correctly ranked ligands for the two protein targets Spleen Tyrosine Kinase (SYK) and tRNA (m1G37) methyltransferase (TrmD). In addition, the ensemble NN SF BsN is at least 250% more accurate than a single neural network (SNN) model. We further find that ensemble models based on NNs surpass SFs based on other state-of-the-art ML algorithms such as BRT, RF, SVM, and [Formula: see text]NN. Finally, our RF model fitted to PLCs characterized by multiple sets of descriptors from four different sources (X-Score, AffiScore, RF-Score, and GOLD) substantially outperforms the SF RF-Score that uses only one set of features, underlining the value of multi perspective modeling. PMID- 29495923 TI - Treatment of hepatitis C virus infection for adults and children: updated Swedish consensus guidelines 2017. AB - AIM: Following the approval of two new therapeutic combinations within the European Union in 2017, the former Swedish recommendations for the treatment of hepatitis C virus (HCV) infection from 2016 were deemed in need of updating. MATERIALS AND METHODS: An expert meeting to this end was held in Stockholm, Sweden in October 2017. RESULTS AND CONCLUSIONS: An interferon-free combination of direct-acting antiviral agents is now recommended for all patients with chronic HCV infection, regardless of liver fibrosis stage, in order to limit morbidity and spread of the disease. An extended discussion of treatment for people who inject drugs in order to diminish transmission is included. PMID- 29495924 TI - Can an off-the-rack orthotic stiletto alter pressure and comfort scores in the forefoot, arch and heel? AB - The study sought to investigate whether an orthotic stiletto could modulate the pressure and comfort under the forefoot, arch and heel that stiletto wearers experience. Twenty-two women participated. We measured the peak pressure and pressure-time integral for orthotic stilettos with built-in metatarsal pad, heel cup and arch support; standard stilettos without inlays; and trainers. Comfort was recorded during 3 * 3 working days. The orthotic stiletto exhibited lower metatarsal head1 (MTH) and MTH2+3 and heel pressures than the standard stiletto (p < .01), and a long second metatarsal increased MTH2+3 pressure (p < .01). The comfort in the forefoot and heel was higher in the orthotic stiletto than in the standard one (p < .01), and comfort in the forefoot was correlated to the pressure-time integral of MTH2+3 (p = .03) and not peak pressure. Off-the-rack orthotic stilettos can notably reduce plantar pressures and improve forefoot and heel comfort during everyday use. Practitioner Summary: Off-the-rack orthotic stilettos with built-in metatarsal pad, arch support and heel caps can lower the pressure under the heel and forefoot in comparison with a standard stiletto and can improve comfort during everyday use. Having a long second metatarsal is a risk factor for increased forefoot pressure. PMID- 29495925 TI - In Vivo Periodontium Formation Around Titanium Implants Using Periodontal Ligament Cell Sheet. AB - Osseointegrated implants have been recognized as being very reliable and having long-term predictability. However, host defense mechanisms against infection have been known to be impaired around a dental implant because of the lack of a periodontal ligament (PDL). The purpose of our experimental design was to produce cementum and PDL on the implant surface adopting cell sheet technology. To this aim we used PDL-derived cells, which contain multipotential stem cells, as the cell source and we cultured them on an implant material constituted of commercially pure titanium treated with acid etching, blasting, and a calcium phosphate (CaP) coating to improve cell attachment. Implants with adhered human PDL cell sheets were transplanted into bone defects in athymic rat femurs as a xenogeneic model. Implants with adhered canine PDL-derived cell sheets were transplanted into canine mandibular bone as an autologous model. We confirmed that PDL-derived cells cultured with osteoinductive medium had the ability to induce cementum formation. The attachment of PDL cells onto the titanium surface with three surface treatments was accelerated, compared with that onto the smooth titanium surface, at 40 min after starting incubation. Results in the rat model showed that cementum-like and PDL-like tissue was partly observed on the titanium surface with three surface treatments in combination with adherent PDL-derived cell sheets. On the other hand, osseointegration was observed on almost all areas of the smooth titanium surface that had PDL-derived cell sheets, but did not have the three surface treatments. In the canine model, histological observation indicated that formation of cementum-like and PDL-like tissue was induced on the titanium surface with surface treatments and that the PDL-like tissue was perpendicularly oriented between the titanium surface with cementum-like tissue and the bone. Results demonstrate that a periodontal-like structure was formed around a titanium implant, which is similar to the environment existing around a natural tooth. The clinical application of dental implants combined with a cell sheet technique may be feasible as an alternative implant therapy. Furthermore, application of this methodology may play an innovative role in the periodontal, prosthetic, and orthodontic fields in dentistry. PMID- 29495926 TI - Can nanotechnology hit the spot in aerosol-based drug delivery for lung disorders? PMID- 29495927 TI - How efficient are the efficiency terms of encapsulation? PMID- 29495928 TI - Nanomedicine: is it lost in translation? AB - By the end of 2017 more than 200,000 scientific research articles had been published about nanomedicine. Out of this vast number only a few of the reported nanoconstructs reached clinical trials for various applications, including the diagnosis and treatment of several cancers, and the treatment of infections and other non-cancerous diseases. 30 years after the pioneering work in this field of research, the low product yield at the end of research pipeline leads to a question that is asked by many: 'had nanomedicine been lost in translation?' In this review, we will discuss the landscape of nanomedicine regarding cancer treatment and miscellaneous applications as well as some obstacles toward full utilization of this powerful therapeutic tool and suggest a few solutions to improve the current translational value of nanomedicine research. PMID- 29495929 TI - Lipoproteins for therapeutic delivery: recent advances and future opportunities. AB - The physiological role(s) of mammalian plasma lipoproteins is to transport hydrophobic molecules (primarily cholesterol and triacylglycerols) to their respective destinations. Lipoproteins have also been studied as drug-delivery agents due to their advantageous payload capacity, long residence time in the circulation and biocompatibility. The purpose of this review is to briefly discuss current findings with the focus on each type of formulation's potential for clinical applications. Regarding utilizing lipoprotein type formulation for cancer therapeutics, their potential for tumor-selective delivery is also discussed. PMID- 29495930 TI - Mesoporous inorganic nanoscale particles for drug adsorption and controlled release. AB - The review provides an overview of the mesoporous inorganic particles employed as drug delivery systems for controlled and sustained release of drugs. We have classified promising nanomaterials for drug delivery on the basis of their natural or synthetic origin. Nanoclays are available in different morphologies (nanotubes, nanoplates and nanofibers) and they are typically available at low cost from natural resources. The surface chemistry of nanoclays is versatile for targeted modifications to control loading and release properties. Synthetic nanomaterials (imogolite, laponite and mesoporous silica) present the advantages of well-established purity and availability with size features that are finely controlled. Both nanoclays and inorganic synthetic nanoparticles can be functionalized forming organic/inorganic architectures with stimuli-responsive features. PMID- 29495931 TI - Impact of moral sensitivity on moral distress among psychiatric nurses. AB - BACKGROUND: Moral distress occurs when one knows the right thing to do, but institutional constraints make it nearly impossible to pursue the right course of action. Moral distress was found to cause negative feelings, burnout, and/or resignation. Not only external factors such as lack of staff but also internal ones affect moral distress. Moral sensitivity, which is thought of as an advantage of nurses, could effect moral distress, as nurses being unaware of existing ethical problems must feel little distress. OBJECTIVES: To examine the impact of moral sensitivity on moral distress among psychiatric nurses, and affirm the hypothesis that nurses with higher moral sensitivity will suffer moral distress more than nurses with less moral sensitivity in two different samples. Ethical consideration: The study obtained ethical approval from the Research Ethics Committee of the Faculty of Medicine at Mie University (# 1111, 20.4.2010), and by the Turku University Ethics Board (29.5.2012). Permissions to undertake the study was obtained from the in two hospital districts and in one city (S 48/4.10.2012, S 63/4.9.2012, 51/2012 27.8.2012). Informed consent was not formally obtained, because the questionnaire was anonymously reported by the participants who volunteered to answer. The participants responded voluntarily and anonymously. METHODS: An anonymous questionnaire containing the Revised Moral Sensitivity Questionnaire and the Moral Distress Scale for Psychiatric nurses was conducted to 997 nurses in 12 hospitals in Japan, and 974 nurses in 10 hospitals in Finland after obtaining of approval by research ethics committees. Data were analyzed using a multi-group structural equation model analysis. FINDINGS: A set of analyses imply that the association of moral sensitivity with moral distress is significant and similar between Japan and Finland, whereas the factor structures of moral sensitivity and moral distress may be partially different. DISCUSSION: The result of this study may indicate that nurses with high moral sensitivity can sense and identify moral problems, but not resolve them. Therefore, supporting nurses to solve ethical problems, not benumbing them, can be important for better nursing care and prevention of nurses' resignation. CONCLUSION: Moral sensitivity and moral distress were positively correlated among psychiatric nurses in both Japan and Finland, although the participating nurses from the two countries were different in qualification, age, and cultural background. Nurses with high moral sensitivity suffer from moral distress. PMID- 29495932 TI - Nurses attitudes towards death, dying patients and euthanasia: A descriptive study. AB - BACKGROUND: Attitudes of nurses towards death and related concepts influence end of-life care. Determining nurses' views and attitudes towards these concepts and the factors that affect them are necessary to ensure quality end-of-life care. OBJECTIVES: The purpose of this study was to determine nurses' views and attitudes about death, dying patient, euthanasia and the relationships between nurses' characteristics. METHODS: Participants consist of the nurses who volunteered to take part in this descriptive study from 25 hospitals (n = 340) which has a paediatric or adult intensive care unit and located within the boundaries of Ankara, Turkey. 'Nurse Information Form' and 'Attitude Scale about Euthanasia, Death and Dying Patients (DAS)' were used as data collection tool. Ethical consideration: Written permissions were received from the 'Noninterventional Clinical Researches Ethics Board' of authors' university and education councils of each hospital. Informed consent was obtained from participants. FINDINGS: It is found that there are statistically significant difference among the factors of marital status, having a child, years of experience, bereavement experience, affected by working with dying patient, definition of euthanasia, views about patients who are appropriate for euthanasia, views about patients who desire to die and feeling need for counselling on these concepts according to the mean total score of nurses' attitudes about euthanasia, death and dying patient (p < 0.05). CONCLUSION: The results indicate that nurses are negatively affected to face the concepts of death, euthanasia and work with dying patient. This is reflected in their attitude. In order to gain positive attitude towards death, dying patient and euthanasia, the implementation of training and consulting services to nurses at appropriate intervals during both education and professional life are required. PMID- 29495933 TI - Eliciting critical care nurses' beliefs regarding physical restraint use. AB - BACKGROUND: Despite the reported harms and ethical concerns about physical restraint use in the critical care settings, nurses' intention to apply them is unequal across countries. According to the theory of planned behaviour, eliciting nurses' beliefs regarding the use of physical restraints would provide additional social information about nurses' intention to perform this practice. AIM: To explore the salient behavioural, normative and control beliefs underlying the intention of critical care nurses to use physical restraints from the theory of planned behaviour. RESEARCH DESIGN: A belief elicitation study was conducted. Participants and research context: Twenty-six critical care nurses were purposively sampled across gender, work-shift patterns and professional experience in five intensive care units of three hospitals in Spain. Data were obtained from a nine-item open-ended questionnaire and a focus group. Deductive content analysis was performed. Ethical considerations: Ethical approval was obtained from the hospital ethics committee. Participants were assured their participation was voluntary. FINDINGS: Nurses framed the use of restraints as a way of prioritising patients' physical safety. They referred to contextual factors as the main reasons to justify their application. Nurses perceived that their decision is approved by other colleagues and the patients' relatives. Some nurses started advocating against their use, but felt powerless to change this unsafe practice within an unfavourable climate. Control beliefs were linked to patients' medical condition, availability of alternative solutions, analgo sedation policies and work organisation. DISCUSSION: Safety arguments based on the surrounding work environment were discussed. CONCLUSION: Nurses' behavioural and control beliefs were related. Nurses should be trained in alternatives to physical restraint use. The impact of analgo-sedation protocols, relatives' involvement, leadership support and intensive care unit restraint policies on physical restraint practices need to be revised. Further research is required to explore why nurses do not act with moral courage to change this harmful practice. PMID- 29495934 TI - The moral experiences of pediatric nurses in Brazil: Engagement and relationships. AB - BACKGROUND: Pediatric nursing care involves many significant ethical challenges. Although nurses are broadly recognized as professionals with relevant knowledge about children and families, little is known about how nurses experience ethical concerns in their everyday practice. OBJECTIVE: The objective of this study was to better understand the moral experiences and related moral distress experiences of nurses working in pediatric settings in Brazil. DESIGN: Interpretative phenomenological study conducted through narrative interviews. Participants and research context: Nine nurses working in three pediatric settings of a teaching hospital in a city of Southern Brazil. Ethical considerations: The study was approved by the Research Ethics Committee of the research site, and research ethics principles were respected throughout the study. FINDINGS: This investigation illuminated a broader dimension of nurses' moral distress, which was recognized as moral experience. In advancing our understanding of nurses' moral experiences, engagement was identified as a central phenomenon that is present in the understandings and actions of nurses within their relationships in their daily practice and lived experiences. Three themes were described with regard to nurses' relationships and their moral experiences: (a) relationship with the healthcare team; (b) relationship with the family; and (c) relationship with the child. DISCUSSION: The findings of this study are congruent with emerging health literature that demonstrated the focus on moral distress as limiting for bioethical inquiry. Moreover, it is important to better understand and recognize nurses' relational environment and engagements to advance understandings of the ethical dimensions of pediatric nursing practice. CONCLUSION: This study provides a better understanding on how engagement affects moral experiences, demonstrating how nurses can experience distress but also satisfaction, gratification, rewarding feelings, and a sense of responsibility for the care they provide. PMID- 29495935 TI - Responsibility among bachelor degree nursing students: A concept analysis. AB - BACKGROUND: Responsibility is an important component of the professional values and core competencies for bachelor degree nursing students and has relationships with nursing education and professionalization. It is important for providing safe and high-quality care to the clients for the present and future performance of student. But there is no clear and operational definition of this concept for bachelor degree nursing students; however, there are extensive contents and debates about the definitions, attributes, domains and boundaries of responsibility in nursing and non-nursing literature. OBJECTIVE: To examine the concept of responsibility among bachelor degree nursing students using the evolutionary approach to concept analysis. METHODS: A total of 75 articles published between 1990 and 2016 and related to the concept of responsibility were selected from seven databases and considered for concept analysis based on Rogers' evolutionary approach. Ethical considerations: Throughout all stages of data collection, analysis and reporting, accuracy and bailment were respected. FINDINGS: Responsibility is a procedural, spectral, dynamic and complex concept. The attributes of the concept are smart thinking, appropriate managerial behaviours, appropriate communicational behaviours, situational self-mandatory and task-orientation behaviours. Personal, educational and professional factors lead to the emergence of the responsible behaviours among bachelor degree nursing students. The emergence of such behaviours facilitates the learning and education process, ensures nursing profession life and promotes clients and community health level. Responsibility has some effects on nursing students. DISCUSSION: This concept had been changed over time since 1990-2016. There are similarities and differences in the elements of this concept in disciplines of nursing and other educational disciplines. Conclusion The analysis of this concept can help to develop educational or managerial theories, design instruments for better identification and evaluation of responsible behaviours among bachelor degree nursing students, develop strategies for enhancing the responsibility and improve the safety and quality of nursing care in the community and healthcare system. PMID- 29495936 TI - Mnb/Dyrk1A orchestrates a transcriptional network at the transition from self renewing neurogenic progenitors to postmitotic neuronal precursors. AB - The Down syndrome and microcephaly related gene Mnb/Dyrk1A encodes an evolutionary conserved protein kinase subfamily that plays important roles in neurodevelopment. minibrain (mnb) mutants of Drosophila melanogaster (Dm) exhibit reduced adult brains due to neuronal deficits generated during larval development. These deficits are the consequence of the apoptotic cell death of numerous neuronal precursors that fail to properly exit the cell cycle and differentiate. We have recently found that in both the Dm larval brain and the embryonic vertebrate central nervous system (CNS), a transient expression of Mnb/Dyrk1A promotes the cell cycle exit of newborn neuronal precursors by upregulating the expression of the cyclin-dependent kinase inhibitor p27kip1 (called Dacapo in Dm). In the larval brain, Mnb performs this action by regulating the expression of three transcription factors, Asense (Ase), Deadpan (Dpn) and Prospero (Pros), which are key regulators of the self-renewal, proliferation, and terminal differentiation of neural progenitor cells. We have here studied in detail the cellular/temporal expression pattern of Ase, Dpn, Pros and Mnb, and have analyzed possible regulatory effects among them at the transitions from neurogenic progenitors to postmitotic neuronal precursors in the Dm larval brain. The emerging picture of this analysis reveals an intricate regulatory network in which Mnb appears to play a pivotal role helping to delineate the dynamics of the expression patterns of Ase, Dpn and Pros, as well as their specific functions in the aforementioned transitions. Our results also show that Ase, Dpn and Pros perform several cross-regulatory actions and contribute to shape the precise cellular/temporal expression pattern of Mnb. We propose that Mnb/Dyrk1A plays a central role in CNS neurogenesis by integrating molecular mechanisms that regulate progenitor self-renewal, cell cycle progression and neuronal differentiation. PMID- 29495939 TI - Disruption of transient receptor potential melastatin 2 decreases elastase release and bacterial clearance in neutrophils. AB - Elastase released by neutrophils is critical for eliminating Gram-negative bacteria. Ca2+ influx plays a key role in elastase release and bacterial clearance in neutrophils. Transient receptor potential melastatin 2 (TRPM2) is a Ca2+-permeable cation channel highly expressed in neutrophils. Here, we explore the role and possible mechanism of TRPM2 in bacterial clearance in TRPM2 knockout (TRPM2-KO) mice neutrophils. After exposure to Escherichia coli, TRPM2-KO bone marrow neutrophils (BMNs) had increased bacterial burden and decreased elastase release. The same was observed for septic TRPM2-KO mice which also had decreased survival rate. After stimulation with chemotactic peptide N-formyl-methionyl leucyl-phenylalanine (fMLP), elastase release was lower in TRPM2-KO BMNs than in wild type (WT) BMNs. Pre-treatment of WT BMNs with p38 MAPK inhibitor reduced fMLP-induced elastase release. Compared with WT BMNs, TRPM2-KO BMNs had decreased p38 MAPK phosphorylation after fMLP stimulation. Removal of extracellular Ca2+ reduced fMLP-induced p38 MAPK phosphorylation and elastase release. The concentration of intracellular Ca2+ decreased in TRPM2-KO BMNs compared with WT BMNs after fMLP treatment. Hence, TRPM2 plays an important role in bacterial clearance in neutrophils, possibly by regulating elastase release. TRPM2-mediated Ca2+ influx regulates elastase release partially via p38 MAPK phosphorylation in neutrophils. PMID- 29495940 TI - Fragmented hyaluronan has no alarmin function assessed in arthritis synovial fibroblast and chondrocyte cultures. AB - Hyaluronan (HA) is a large polymer and an important component of the extracellular matrix. During homeostasis, high molecular mass HA is the predominant form, but upon inflammation, degradation products of HA accumulate. These HA fragments (HA-fs) have been reported to possess pro-inflammatory activities and thus act as alarmins, notifying immune cells of danger via TLR4 and CD44. HA is found in large quantities in synovial joint fluid. In order to reveal a potential role of HA-fs in arthritis pathogenesis, the in vitro effects of HA of various molecular masses (from 1680 kDa to oligosaccharide HA) on synovial fibroblasts and chondrocytes from rheumatoid arthritis patients, and on peripheral blood mononuclear cells from healthy donors, were investigated. TLR4 and CD44 surface expression was confirmed by immunocytochemistry, and cell activation was determined based on cytokine and chemokine production. While the cell types investigated expressed TLR4 and CD44, no increased release of IL 1beta, IL-6, IL-8, IL-10, IL-12 or TNF-alpha was detected after HA stimulation. Similarly, HA did not enhance activation after priming cells with low doses of LPS or by forming complexes with LPS. Hence, this study does not support the common view of HA-fs being pro-inflammatory mediators and it is not likely that HA-fs generated during arthritis contribute to disease pathogenesis. PMID- 29495941 TI - Practical Considerations of the Both Hands Assessment (BoHA): A commentary on "Development and Validation of the Both Hands Assessment for Children with Bilateral Cerebral Palsy". PMID- 29495942 TI - Gold extraction from biosolid sludge obtained by sewage treatment. AB - Treatment of municipal wastewater, which involves multiple steps, produces large amounts of biosolid sludge, which is either incinerated or disposed in landfills. This sludge contains carbon, nitrogen, and phosphorous in appreciable amounts, and hence, it is being recently suggested that it should be used as a fertilizer. However, the biosolid sludge also contains large amounts of heavy metals, which exert harmful effects on the plantation and therefore, they must be removed before it can be used as a fertilizer. In addition, some of these heavy metals are precious such as gold. In this work, heavy metals present in the biosolid sludge produced from municipal wastewater plants were extracted using acidic solutions of different strengths. The method of selected gold extraction using tributyl phosphate (TBP) in kerosene solution from the metal rich acidic solution was also tested. The rate and yield of gold extraction increase with the increase in the acidic strength. The highest extracted gold yield was 0.012 mg/g of biomass. The amount of gold recovery into the TBP solution was 26%, which was much higher than that of other metals extracted into the acid solution. The importance of removing the metals from the biosolid is obvious, as it allows the latter to be used as a fertilizer. In addition, using only one additional step, a valuable product, gold, can be selectively separated, despite being present in lower amounts that other metals found in the sludge. PMID- 29495943 TI - Effectiveness of treatment regimens for Typhoid fever in the nalidixic acid resistant S. typhi (NARST) era in South India. AB - The epidemiology of typhoid fever in South Asia has changed. Multi-drug resistant (MDR) Salmonella typhi ( S. typhi) is now frequently resistant to nalidixic acid and thus labelled NARST. Treatment failure with the use of fluoroquinolones has been widely noted, forcing clinicians to adopt alternative treatment strategies. In this observational study, we looked at various treatment regimens and correlated clinical and microbiological outcomes. In 146 hospitalised adults, the median minimum inhibitory concentration (MIC) for ciprofloxacin was 0.38 ug/mL with a median fever clearance time (FCT) of eight days (range = 2-35 days). Of the regimens used, gatifloxacin and azithromycin had a shorter FCT of six days compared to ceftriaxone (ten days; P < 0.001). Though mortality and relapse in our cohort was low, NARST seemed to correlate with mortality ( P = 0.006). Gatifloxacin or azithromycin clearly emerge as the drugs of choice for treatment of typhoid in South India. PMID- 29495944 TI - A case of giant lupus vulgaris. AB - Lupus vulgaris, the commonest form of tuberculosis of the skin, presents with a plaque that enlarges slowly with advancing edges while showing atrophy at other areas. It may be acquired by the blood stream, via lymph, by contiguous spread or from external inoculation. We describe a case of lupus vulgaris with a large erythematous-scaly plaque of 44 * 26 cm over the back and a similar 7 * 5 cm plaque over the right thigh. The plaque over the back was gradually progressive for the previous ten years and showed scarring and atrophy at places. Histopathology of the area showed caseating granulomas with Langhans giant cells, epitheloid cells and lymphocytes. A diagnosis of lupus vulgaris was made. This case is being presented owing to the large size of the lesion. PMID- 29495945 TI - Mesoporous silica nanoparticles as diagnostic and therapeutic tools: how can they combat bacterial infection? PMID- 29495946 TI - CFD Investigation of the effects of bubble aerator layouts on hydrodynamics of an activated sludge channel reactor. AB - In this paper, computational fluid dynamics (CFD) simulations are employed to characterize the effects of bubble aerator layouts (i.e. spatial arrangement) on the hydrodynamics in activated sludge (AS) reactors. The first configuration considered is a channel reactor with aerators placed alongside one lateral wall, for which velocity measurements are available in literature. CFD results were in good agreement with experimental data, which proves that the model is sufficiently accurate and predictive. Accordingly, simulations and numerical residence time distribution tests were conducted for different aerator layouts to determine their effects on the reactor hydrodynamics. The results revealed that the flow characteristics are extremely sensitive to the aerators arrangement given the high gas flow rates used in AS processes. Among the layouts investigated, the one where diffusers are placed all over the reactor floor has led to the least dispersive flow, i.e. which characteristics best tend toward that of an ideal plug flow reactor. Indeed, this flow field presented the lowest average turbulent diffusion and the most uniform axial velocity and turbulence fields. Such a flow behaviour is expected to be highly beneficial for biological treatment since it reduces pollutant dilution by axial diffusion and limits raw wastewater channelling to the outlet. PMID- 29495947 TI - Lifestyle counseling in primary care in the United States and Sweden: a comparison of patients' expectations and experiences. AB - BACKGROUND: Despite various guidelines, shortcomings in lifestyle counseling in primary care have been demonstrated. Comparisons between countries may provide insight on how to improve such counseling. To the best of our knowledge, studies comparing patients' views of lifestyle counseling beween the United States (US) and European countries have not been reported. OBJECTIVES: To quantify and compare patients' perspectives in the US and Sweden on primary care providers' counseling on weight, eating habits, physical activity, smoking, and alcohol consumption. METHODS: In a cross-sectional study, 629 patients from Sweden and the US completed a telephone interview about their experiences after a visit to a physician in primary care. The survey focused on patients' perception of the importance of healthy lifestyle habits, their need to change, their desire to receive support from primary care, and the support they had actually received. Data were analyzed using chi-square or Fisher's exact test. RESULTS: For three of the four lifestyle habits, the proportion saying they needed to change was higher in the US. The exception was for alcohol, where Swedish subjects indicated a greater need to change. Among those stating a need to change, the proportion saying that they would like to have support from primary care was generally above 80% in both countries. The proportion of US patients reporting that their primary care provider had initiated a discussion of lifestyle modification was, with the exception of alcohol, roughly double the level reported by the Swedish patients. CONCLUSIONS: This study demonstrates high and quite similar patient expectations concerning lifestyle counseling in both countries, but more frequent initiation of discussions of most lifestyle issues in US primary care. Further studies, e.g. qualitative interviews with physicians, and medical record reviews, are required to better understand what can explain the differences between countries indicated by the study. PMID- 29495948 TI - Harmful alcohol drinking among HIV-positive people in Nepal: an overlooked threat to anti-retroviral therapy adherence and health-related quality of life. AB - BACKGROUND: People living with Human Immunodeficiency Virus (HIV) often suffer from alcohol-use disorders resulting in their poor health and treatment outcomes. Little is known about the association of harmful alcohol drinking with their adherence to anti-retroviral therapy (ART) and health-related quality of life (QOL) in low-resource settings. OBJECTIVE: This study aimed to investigate associations between harmful alcohol drinking, adherence to ART and health related QOL in HIV-positive people, stratified by gender, in Nepal. METHODS: We conducted a cross-sectional study of 682 HIV-positive people on ART to measure their self-reported harmful alcohol drinking and non-adherence to ART in the previous month of data collection. We also measured health-related QOL using a WHOQOL-HIV BREF scale. The association between harmful alcohol drinking and non adherence to ART was examined using multiple logistic regressions. Additionally, multiple linear regressions examined association between harmful alcohol drinking and QOL. RESULTS: Harmful alcohol drinking was associated with non-adherence to ART among men (AOR: 2.48, 95% CI: 1.50, 4.11, p < 0.001) and women (AOR: 2.52, 95% CI: 1.32, 4.80, p = 0.005). Men were more likely to have lower score for the psychological (beta = -0.55, p = 0.021) and level of independence (beta = -0.68, p = 0.018) domains when they had harmful alcohol drinking. Moreover, women were more likely to have lower scores for the physical (beta = -1.01, p = 0.015), social relations (beta = -0.82, p = 0.033), environmental (beta = -0.88, p = 0.011), and spiritual (beta = -1.30, p = 0.005) domains of QOL when they had harmful alcohol drinking. CONCLUSIONS: Harmful alcohol drinking had a negative association with ART adherence and QOL in both HIV-positive men and women in Nepal. Screening for alcohol-use disorders and community-based counseling services should be provided while delivering ART services to improve treatment adherence and QOL. PMID- 29495949 TI - Regional contextual influences on short sleep duration: a 50 universities population-based multilevel study in China. AB - BACKGROUND: Ecological models have emphasized that short sleep duration (SSD) is influenced by both individual and environmental variables. However, few studies have considered the latter. OBJECTIVES: The present study explores the influence of urban and regional contextual factors, net of individual characteristics, on the prevalence of SSD among university students in China. METHODS: Participants were 11,954 students, who were identified through a multistage survey sampling process conducted in 50 universities. Individual data were obtained through a self-administered questionnaire, and contextual variables were retrieved from a national database. Multilevel logistic regression models were used to examine urban and regional variations in high and moderate levels of SSD. RESULTS: Overall the prevalence of high SSD (<6 hours sleep duration) was 2.8% (95% CI: 1.7%,3.9%) and moderate SSD (<7 hours) 24.7% (95% CI: 19.5%, 29.8%). Multilevel logistic regressions confirmed that home region gross domestic product (GDP) and the university regional unemployment rate were associated with SSD, net of other individual- and city-level covariates. Students attending high-level universities also recorded the highest levels of SSD. Of the individual characteristcs, only mother's occupation and student mental health status were related to SSD. CONCLUSIONS: The results of this study add important insights about the role of contextual factors affecting SSD among young adults and indicate the need to take into account both past, as well as present, environmental influences to control SSD. PMID- 29495951 TI - Mitochondrial dysfunction: maternal protein restriction as a trigger of reactive species overproduction and brainstem energy failure in male offspring brainstem. AB - Mitochondria are important organelles in eukaryotic organisms, wherein their capacity to produce energy vary among the tissues depending upon the amounts of oxygen consumed. Part of the oxygen consumed during ATP generation produces reactive oxygen species, which if not efficiently removed can trigger a systemic damage to molecular compounds characterized as oxidative stress. Several studies have demonstrated that mitochondrial dysfunction and oxidative stress in the central nervous system (CNS) are related to a plethora of neural disorders. Herein, we hypothesize that a late autonomic imbalance-induced hypertension might be related to long-lasting effects of protein restriction during the critical period of the CNS development on the mitochondrial function and oxidative stress in the brainstem of adult (i.e. 150 days of age) male Wistar rats. Maternal protein restriction was induced by offering a diet based on 8% of casein from first day of pregnancy until weaning, when the male pups started to receive laboratory chow up to 150 days of life. The protein restriction induced an extended detrimental modulation in mitochondria function, decreasing the phosphorylation capacity with concomitant decrease in the mitochondrial membrane potential, wherein the reactive species overproduction triggered a disruption in proton conductance, which may gradually compromise mitochondria energy conservation. Interestingly, the elevated activity of glutathione-S-transferase and the augmented expression of uncoupling protein 2 are likely protective mechanisms induced by lipid peroxidation products, being feasible molecular changes attempting to deal with oxidative stress-induced ageing. PMID- 29495950 TI - Improving access to medicines via the Health Impact Fund in India: a stakeholder analysis. AB - BACKGROUND: In India, 50-65% of the population face difficulties in accessing medicines. The Health Impact Fund (HIF) is a novel proposal whereby pharmaceutical companies would be paid based on the measured global health impact of their drugs. We conducted a key stakeholder analysis to explore access to medicines in India, acceptability of the HIF and potential barriers and facilitators at policy level. OBJECTIVES: To conduct a stakeholder analysis of the HIF in India: to determine key stakeholder views regarding access to medicines in India; to evaluate acceptability of the HIF; and to assess potential barriers and facilitators to the HIF as a policy. METHODS: In New Delhi, we conducted semi-structured interviews. There was purposive recruitment of participants with snowball sampling. Transcribed data were analysed using stakeholder analysis frameworks and directed content analysis. RESULTS: Participation rate was 29% (14/49). 14 semi-structured interviews were conducted among stakeholders in New Delhi. All participants highlighted access to medicines as a problem in India. There were mixed views about the HIF in terms of relevance and scaleability. Stakeholders felt it should focus on diseases with limited or no market and potentially incorporate direct investment in research. CONCLUSIONS: First, access to medicines is perceived to be a major problem in India by all stakeholders, but affordability is just one factor. Second, stakeholders despite considerable support for the idea of the HIF, there are major concerns about scaleability, generalisability and impact on access to medicines. Third, the HIF and other novel drug-related health policies can afford to be more radical, e.g. working outside the existing intellectual property rights regime, targeting generic as well as branded drugs, or extending to research and development. Further innovations in access to medicines must involve country-specific key stakeholders in order to increase the likelihood of their success. PMID- 29495952 TI - Cell proliferation and inhibition of apoptosis are related to c-Kit activation in leukaemic lymphoblasts. AB - : Receptor tyrosine kinase (RTK) activity may contribute to carcinogenesis. The c Kit receptor, a member of the RTK family, is expressed in immature haematopoietic system cells. Acute lymphoblastic leukaemia (ALL) presents incompletely differentiated lymphoblasts, and consequently, c-Kit expression can be detected in these cells. The BCR-ABL kinase, which is usually present in both ALL and chronic myeloid leukaemia, can trigger signalling pathways with neoplastic effects. However, a certain number of ALL patients and chronic myeloid leukaemia patients do not express this kinase, raising the question of which other proteins that intervene in signalling pathways may be involved in the development of these diseases. OBJECTIVES: To test whether c-Kit has proliferative effects and affects the inhibition of apoptosis of leukaemic lymphoblasts that do not express BCR ABL. METHODS: We cultured RS4:11 lymphoblasts and analysed the expression and activation of c-Kit by immunofluorescence, and flow cytometry, evaluation of cell proliferation, apoptosis, cyclin D1 and Bak expression were carried out by flow cytometry; activation of AKT and survivin expression were tested by immunoblot. RESULTS: The c-Kit receptor was found to induce proliferation and to increase the expression of cyclin D1 via the PI3K/AKT/NF-kB signalling pathway. Additionally, the c-Kit/PI3K/AKT pathway increased the inhibition of apoptosis and survivin expression. Similarly, c-Kit was observed to reduce the expression of the pro apoptotic Bak protein. CONCLUSION: These results suggest that, in leukaemic lymphoblasts, c-Kit triggers a signalling pathway with proliferative and anti apoptotic effects; information to this effect has not yet been reported in the literature. PMID- 29495953 TI - Voglibose-mediated alterations in neurometabolomic profiles in the hypothalamus of high-fat diet-fed mice. AB - The alpha-glucosidase inhibitor voglibose (VO) was recently reported to have a protective effect against weight gain as well as affect various metabolic changes related to food intake and gut-brain signaling. We hypothesized that VO prevents weight gain by altering neurometabolome profiles in the hypothalamus to reduce food intake. To test this hypothesis, we assessed metabolite profiles in the hypothalamus of standard diet- or high-fat (HF) diet-fed mice in the absence or presence of VO. In total, 29 male C57BL/6 mice were divided into 3 groups: (1) lean control, (2) HF, and (3) HF + VO. Vehicle or VO was administered for 12 weeks. The results showed that there were alterations in levels of metabolites across several metabolic pathways in the hypothalamus. VO treatment increased levels of many amino acids including arginine, glutamine, histidine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine in the hypothalamus. In addition, levels of 2-hydroxy-2 methyl-butyric acid in the hypothalamus were significantly increased after VO administration in HF diet-fed mice. Among lipid metabolites, levels of fatty acids were higher in the hypothalamus of VO-treated mice than in that of HF diet fed mice. In terms of the energy status, the ATP/ADP ratio was higher in the hypothalamus of VO-treated mice (P < 0.001), thereby indicating an energy surplus. In conclusion, VO supplementation altered metabolite profiles in the hypothalamus to enhance catabolism, which is possibly responsible for the hypophagic effect of VO in HF diet-fed mice. PMID- 29495954 TI - Multidrug resistance 1 (MDR1/ABCB1) gene polymorphism (rs1045642 C > T) and susceptibility to multiple myeloma: a systematic review and meta-analysis. AB - INTRODUCTION: Several studies have evaluated the association between the multidrug resistance 1 (MDR1) polymorphism (rs1045642 C > T) and multiple myeloma (MM). However, the results were not consistent. Therefore, to reach a comprehensive and reliable answer we determined the association of the MDR1 (rs1045642 C > T) polymorphism and MM in the context of meta-analysis. METHODS: All eligible studies published in EMBASE, PubMed, and Web of Science databases before July 2017 were reviewed. Subsequently, to assess the strength of association in the dominant model, recessive model, allelic model, homozygotes contrast, and heterozygotes contrast, pooled odds ratios and 95% confidence intervals (CIs) were calculated by the fixed effects model. RESULTS: A total of four case-control studies with 395 MM cases and 418 healthy controls were included in the meta-analysis. The overall results showed no significant association between the MDR1 (rs1045642 C > T) polymorphism and the risk of MM in genetic models (dominant model: OR = 1.04, 95% CI = 0.78-1.38; recessive model: OR = 0.74, 95% CI = 0.52-1.06; allelic model: OR = 0.90, 95% CI = 0.73-1.11; TT vs. CC: OR = 0.80, 95% CI = 0.51-1.25; and CT vs. CC: OR = 1.12, 95% CI = 0.77 1.62). No evidence of publication bias was detected except for the analysis of the recessive model. CONCLUSION: This meta-analysis suggests that the MDR1 C > T polymorphism was not associated with the risk of MM. To confirm these findings, further comprehensive and well-designed studies are needed. PMID- 29495955 TI - Spontaneous Regression of Parapharyngeal Arteriovenous Malformation. AB - Arteriovenous malformations (AVMs) are fast-flow vascular malformations that mostly occur in the head and neck region. They are typically progressive and their spontaneous regression is almost never seen. We present a case with pulsatile tinnitus and a parapharyngeal AVM. It resolved completely after diagnostic catheter-based angiography alone. PMID- 29495956 TI - Non-Small Cell Lung Cancer Invading the Descending Thoracic Aorta: Surgical Resection Without Using Cardiopulmonary Bypass and Without Cross-Clamping the Aorta: Long-Term Follow-Up of 2 Cases. AB - Lung cancer can sometimes invade vital adjacent mediastinal structures, such as the descending thoracic aorta. We describe 2 cases where pulmonary resection was performed en bloc including a patch of the descending thoracic aorta. These procedures were easily performed using an aortic endoprosthesis in the same anesthetic procedure. We also comment some aspects about an intraoperative endoleak, postoperative evolution, and long-term follow-up. PMID- 29495957 TI - Patient Experience of Recovery After Major Leg Amputation for Arterial Disease. AB - OBJECTIVES: To date, studies of vascular amputees primarily examine quantitative outcomes following limb loss. Less is known about the patient's perspective after major lower limb amputation. Here, we define and describe the postamputation recovery period. METHODS: Qualitative study using purposive, maximum variation sampling on the variables of amputation level and times since surgery. We first conducted structured interviews with 20 participants (median age: 65 years, range: 45-88 years; 85% male; below knee amputation n = 14; above knee amputation n = 6; median time from amputation to interview = 16 months, range: 4-51 months). Findings were validated via a focus group with 5 amputees. Data were coded, analyzed, and interpreted by 2 reviewers. RESULTS: All participants expressed the desire to have an active role in the decision to undergo amputation, even while acknowledging that limb salvage options were exhausted. Following amputation, participants described a 6-month recovery period when they learned to modify daily activities to accommodate their new functional and psychological needs. Participants defined recovery as when they had regained functional independence, which was described as a level of mobility that allowed them to perform daily activities with minimal assistance. Concerns that participants felt were poorly addressed included uncontrolled pain, feeling unprepared to live with an amputation, and questions about prosthetics. Two of the 5 focus group participants stated a preference for amputation earlier in the treatment course. CONCLUSIONS: Postamputation recovery has an early (up to 6 months) and late phase (after 6 months) and concludes when amputees regain what they perceive as independence. Patients desire to participate in amputation decision-making; in this study, some would have preferred amputation earlier in their clinical course. Attention to the domains that impact quality of life, and fostering a shared decision-making process, are opportunities to enhance postamputation recovery. PMID- 29495958 TI - Renal Artery Dissection in a Patient With Degenerative Scoliosis: A Rare Complication Caused by Lumbar Vertebra Osteophyte. AB - Isolated spontaneous renal artery dissection (RAD) without known trauma is rare, and its etiology has not been determined. However, notable risk factors including hypertension, strenuous exercise, connective tissue disorders, atherosclerosis, extracorporeal shock wave lithotripsy, and cocaine abuse have been reported. To the best of our knowledge, isolated RAD caused by lumbar vertebra osteophytes in patients with degenerative lumbar scoliosis has not been reported in the literature. In this article, we present a case of RAD caused by lumbar vertebra osteophyte in a patient with degenerative scoliosis and discuss the management of the disease. PMID- 29495959 TI - Successful Resection of a Large Carotid Body Tumor Masquerading Complete Encasement of the Internal Carotid Artery on Preoperative Imaging. AB - A 41-year-old woman presented with a large painful and tender mass of the left side of her neck located just below the angle of the mandible. She was also complaining of frequent attacks of symptoms ranging from dizziness upon resuming the erect position to frank syncope. Color-coded duplex showed a large well vascularized vascular mass at the level of the carotid bifurcation, suggesting the diagnosis of a carotid body tumor (CBT). A computerized tomographic angiography confirmed the diagnosis of a CBT, which measured 5.7 cm in its craniocaudal axis. The tumor appeared to encase the internal carotid artery (ICA) at the level of its origin, indicating the presence of a Shamblin group 3 tumor. During surgery, the CBT seemingly encased the ICA; however, it was successfully taken off the ICA, by establishing an adventitial dissection place, obviating the need for arterial resection and replacement. A brief intraoperative episode of cardiac arrest was successfully managed. Postoperative course was uneventful, and all symptoms were cured. Pathology confirmed the clinical diagnosis and did not show malignancy. In conclusion, meticulous surgical techniques can spare the ICA from removal or inadvertent injury during CBT surgery and reduce the morbidity often associated with the resection of large or advanced tumors but also cure atypical patient symptoms. PMID- 29495960 TI - Correction to: Oncology practitioners' perspectives and practice patterns of post treatment cancer survivorship care in the Asia-Pacific region: results from the STEP study. AB - It has been highlighted that the original manuscript [1] contains a typesetting error in the surname of Jesson Butcon. This was incorrectly captured as Jessica Butcon in the original manuscript which has since been updated. PMID- 29495961 TI - Hospital Mortality - a neglected but rich source of information supporting the transition to higher quality health systems in low and middle income countries. AB - BACKGROUND: There is increasing focus on the strength of primary health care systems in low and middle-income countries (LMIC). There are important roles for higher quality district hospital care within these systems. These hospitals are also sources of information of considerable importance to health systems, but this role, as with the wider roles of district hospitals, has been neglected. KEY MESSAGES: As we make efforts to develop higher quality health systems in LMIC we highlight the critical importance of district hospitals focusing here on how data on hospital mortality offers value: i) in understanding disease burden; ii) as part of surveillance and impact monitoring; iii) as an entry point to exploring system failures; and iv) as a lens to examine variability in health system performance and possibly as a measure of health system quality in its own right. However, attention needs paying to improving data quality by addressing reporting gaps and cause of death reporting. Ideally enabling the collection of basic, standardised patient level data might support at least simple case-mix and case severity adjustment helping us understand variation. Better mortality data could support impact evaluation, benchmarking, exploration of links between health system inputs and outcomes and critical scrutiny of geographic variation in quality and outcomes of care. Improved hospital information is a neglected but broadly valuable public good. CONCLUSION: Accurate, complete and timely hospital mortality reporting is a key attribute of a functioning health system. It can support countries' efforts to transition to higher quality health systems in LMIC enabling national and local advocacy, accountability and action. PMID- 29495962 TI - RNS60 exerts therapeutic effects in the SOD1 ALS mouse model through protective glia and peripheral nerve rescue. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects the motor neuromuscular system leading to complete paralysis and premature death. The multifactorial nature of ALS that involves both cell-autonomous and non-cell-autonomous processes contributes to the lack of effective therapies, usually targeted to a single pathogenic mechanism. RNS60, an experimental drug containing oxygenated nanobubbles generated by modified Taylor-Couette-Poiseuille flow with elevated oxygen pressure, has shown anti-inflammatory and neuroprotective properties in different experimental paradigms. Since RNS60 interferes with multiple cellular mechanisms known to be involved in ALS pathology, we evaluated its effect in in vitro and in vivo models of ALS. METHODS: Co-cultures of primary microglia/spinal neurons exposed to LPS and astrocytes/spinal neurons from SOD1G93A mice were used to examine the effect of RNS60 or normal saline (NS) on the selective motor neuron degeneration. Transgenic SOD1G93A mice were treated with RNS60 or NS (300 MUl/mouse intraperitoneally every other day) starting at the disease onset and examined for disease progression as well as pathological and biochemical alterations. RESULTS: RNS60 protected motor neurons in in vitro paradigms and slowed the disease progression of C57BL/6-SOD1G93A mice through a significant protection of spinal motor neurons and neuromuscular junctions. This was mediated by the (i) activation of an antioxidant response and generation of an anti inflammatory environment in the spinal cord; (ii) activation of the PI3K-Akt pro survival pathway in the spinal cord and sciatic nerves; (iii) reduced demyelination of the sciatic nerves; and (iv) elevation of peripheral CD4+/Foxp3+ T regulatory cell numbers. RNS60 did not show the same effects in 129Sv-SOD1G93A mice, which are unable to activate a protective immune response. CONCLUSION: RNS60 demonstrated significant therapeutic efficacy in C57BL/6-SOD1G93A mice by virtue of its effects on multiple disease mechanisms in motor neurons, glial cells, and peripheral immune cells. These findings, together with the excellent clinical safety profile, make RNS60 a promising candidate for ALS therapy and support further studies to unravel its molecular mechanism of action. In addition, the differences in efficacy of RNS60 in SOD1G93A mice of different strains may be relevant for identifying potential markers to predict efficacy in clinical trials. PMID- 29495963 TI - Interlaboratory comparison of femur surface reconstruction from CT data compared to reference optical 3D scan. AB - BACKGROUND: The present study contrasts the accuracy of different reconstructed models with distinctive segmentation methods performed by various experts. Seven research groups reconstructed nine 3D models of one human femur based on an acquired CT image using their own computational methods. As a reference model for accuracy assessment, a 3D surface scan of the human femur was created using an optical measuring system. Prior to comparison, the femur was divided into four areas; "neck and greater trochanter", "proximal metaphysis", "diaphysis", and "distal metaphysis". The deviation analysis was carried out in GEOMAGIC studio v.2013 software. RESULTS: The results revealed that the highest deviation errors occurred in "neck and greater trochanter" area and "proximal metaphysis" area with RMSE of 0.84 and 0.83 mm respectively. CONCLUSION: In conclusion, this study shows that the average deviation of reconstructed models prepared by experts with various methods, skills and software from the surface 3D scan is lower than 0.79 mm, which is not a significant discrepancy. PMID- 29495965 TI - Standardizing haematopoietic cell transplants in China. PMID- 29495964 TI - Improving eukaryotic genome annotation using single molecule mRNA sequencing. AB - BACKGROUND: The advantages of Pacific Biosciences (PacBio) single-molecule real time (SMRT) technology include long reads, low systematic bias, and high consensus read accuracy. Here we use these attributes to improve on the genome annotation of the parasitic hookworm Ancylostoma ceylanicum using PacBio RNA-Seq. RESULTS: We sequenced 192,888 circular consensus sequences (CCS) derived from cDNAs generated using the CloneTech SMARTer system. These SMARTer-SMRT libraries were normalized and size-selected providing a robust population of expressed structural genes for subsequent genome annotation. We demonstrate PacBio mRNA sequences based genome annotation improvement, compared to genome annotation using conventional sequencing-by-synthesis alone, by identifying 1609 (9.2%) new genes, extended the length of 3965 (26.7%) genes and increased the total genomic exon length by 1.9 Mb (12.4%). Non-coding sequence representation (primarily from UTRs based on dT reverse transcription priming) was particularly improved, increasing in total length by fifteen-fold, by increasing both the length and number of UTR exons. In addition, the UTR data provided by these CCS allowed for the identification of a novel SL2 splice leader sequence for A. ceylanicum and an increase in the number and proportion of functionally annotated genes. RNA-seq data also confirmed some of the newly annotated genes and gene features. CONCLUSION: Overall, PacBio data has supported a significant improvement in gene annotation in this genome, and is an appealing alternative or complementary technique for genome annotation to the other transcript sequencing technologies. PMID- 29495966 TI - The consensus on indications, conditioning regimen, and donor selection of allogeneic hematopoietic cell transplantation for hematological diseases in China recommendations from the Chinese Society of Hematology. AB - Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is widely used to treat malignant hematological neoplasms and non-malignant hematological disorders. Approximately, 5000 allo-HSCT procedures are performed in China annually. Substantial progress has been made in haploidentical HSCT (HID-HSCT), pre-transplantation risk stratification, and donor selection in allo-HSCT, especially after the establishment of the "Beijing Protocol" HID-HSCT system. Transplant indications for selected subgroups in low-risk leukemia or severe aplastic anemia (SAA) differ from those in the Western world. These unique systems developed by Chinese doctors may inspire the refining of global clinical practice. We reviewed the efficacy of allo-HSCT practice from available Chinese studies on behalf of the HSCT workgroup of the Chinese Society of Hematology, Chinese Medical Association and compared these studies to the consensus or guideline outside China. We summarized the consensus on routine practices of all HSCT in China and focused on the recommendations of indications, conditioning regimen, and donor selection. PMID- 29495967 TI - Hypoxia mimetic activity of VCE-004.8, a cannabidiol quinone derivative: implications for multiple sclerosis therapy. AB - BACKGROUND: Multiple sclerosis (MS) is characterized by a combination of inflammatory and neurodegenerative processes variously dominant in different stages of the disease. Thus, immunosuppression is the goal standard for the inflammatory stage, and novel remyelination therapies are pursued to restore lost function. Cannabinoids such as 9Delta-THC and CBD are multi-target compounds already introduced in the clinical practice for multiple sclerosis (MS). Semisynthetic cannabinoids are designed to improve bioactivities and druggability of their natural precursors. VCE-004.8, an aminoquinone derivative of cannabidiol (CBD), is a dual PPARgamma and CB2 agonist with potent anti-inflammatory activity. Activation of the hypoxia-inducible factor (HIF) can have a beneficial role in MS by modulating the immune response and favoring neuroprotection and axonal regeneration. METHODS: We investigated the effects of VCE-004.8 on the HIF pathway in different cell types. The effect of VCE-004.8 on macrophage polarization and arginase 1 expression was analyzed in RAW264.7 and BV2 cells. COX-2 expression and PGE2 synthesis induced by lipopolysaccharide (LPS) was studied in primary microglia cultures. The efficacy of VCE-004.8 in vivo was evaluated in two murine models of MS such as experimental autoimmune encephalomyelitis (EAE) and Theiler's virus-induced encephalopathy (TMEV). RESULTS: Herein, we provide evidence that VCE-004.8 stabilizes HIF-1alpha and HIF 2alpha and activates the HIF pathway in human microvascular endothelial cells, oligodendrocytes, and microglia cells. The stabilization of HIF-1alpha is produced by the inhibition of the prolyl-4-hydrolase activity of PHD1 and PDH2. VCE-004.8 upregulates the expression of HIF-dependent genes such as erythropoietin and VEGFA, induces angiogenesis, and enhances migration of oligodendrocytes. Moreover, VCE-004.8 blunts IL-17-induced M1 polarization, inhibits LPS-induced COX-2 expression and PGE2 synthesis, and induces expression of arginase 1 in macrophages and microglia. In vivo experiments showed efficacy of VCE-004.8 in EAE and TMEV. Histopathological analysis revealed that VCE-004.8 treatments prevented demyelination, axonal damage, and immune cells infiltration. In addition, VCE-004.8 downregulated the expression of several genes closely associated with MS physiopathology, including those underlying the production of chemokines, cytokines, and adhesion molecules. CONCLUSIONS: This study provides new significant insights about the potential role of VCE-004.8 for MS treatment by ameliorating neuroinflammation and demyelination. PMID- 29495969 TI - Reconstruction of a chronically ruptured Achilles tendon using an internal brace: a case report. AB - BACKGROUND: We reconstructed a chronically ruptured Achilles tendon and the associated scar tissue using braided polyblend polyethylene sutures (FiberWire; Arthrex Inc.; Naples, FL, USA) and anchors. CASE PRESENTATION: A 68-year-old Japanese man, who was being treated for right Achilles tendinosis, felt pain in his Achilles tendon when walking and started to find plantar flexion of his ankle joint difficult. As his symptoms persisted, he visited us after 4 weeks. Surgery and orthotic therapy were recommended, but he did not want to undergo these treatments. However, he began to find walking difficult and so underwent surgery 6 months after suffering the injury. The interior of the tendon was curetted, and the ruptured region was subjected to plication using the surrounding scar tissue. Using the percutaneous Achilles repair system (Arthrex Inc.), FiberWire sutures were inserted, and two skin incisions were made on the medial and lateral sides of his calcaneus in the region surrounding the Achilles tendon attachment. SutureLasso (Arthrex Inc.) was passed through, and the proximal FiberWire suture was relayed and fixed with 4.75-mm SwiveLock (Arthrex Inc.). After surgery, his foot was fixed in plaster at 20 degrees plantar flexion of his ankle joint. The plaster was removed 1 week after surgery, and after-treatment was initiated with active dorsiflexion training. No orthosis was used after surgery. As of 16 postoperative months, no re-rupture had occurred. CONCLUSIONS: This method might allow post-treatment rehabilitation, and so on, to occur earlier, and, hence, could become an option for the reconstruction of chronically ruptured Achilles tendons. PMID- 29495968 TI - PATTERNA: transcriptome-wide search for functional RNA elements via structural data signatures. AB - Establishing a link between RNA structure and function remains a great challenge in RNA biology. The emergence of high-throughput structure profiling experiments is revolutionizing our ability to decipher structure, yet principled approaches for extracting information on structural elements directly from these data sets are lacking. We present PATTERNA, an unsupervised pattern recognition algorithm that rapidly mines RNA structure motifs from profiling data. We demonstrate that PATTERNA detects motifs with an accuracy comparable to commonly used thermodynamic models and highlight its utility in automating data-directed structure modeling from large data sets. PATTERNA is versatile and compatible with diverse profiling techniques and experimental conditions. PMID- 29495971 TI - Locals don't have accents: children weigh phonological proficiency over syntactic or semantic proficiency when categorizing individuals. AB - Children categorize native-accented speakers as local and non-native-accented speakers as foreign, suggesting they use accent (i.e., phonological proficiency) to determine social group membership. However, it is unclear if accent is the strongest - and only - group marker children use to determine social group membership, or whether other aspects of language, such as syntax and semantics, are also important markers. To test this, five- to eight-year-old monolingual English-speaking children were asked to judge whether individuals who varied in phonological, syntactic, and semantic proficiency were local or foreign. Children were also asked which individual they wanted as a friend. Children prioritized phonological proficiency over syntactic and semantic proficiency to determine social group membership. However, with age, children begin to shift toward prioritizing syntactic and semantic proficiency over phonological proficiency in their friendship decisions, suggesting that the capacity to integrate different aspects of a speaker's linguistic proficiency changes with development. PMID- 29495972 TI - MicroRNA-342 prohibits proliferation and invasion of melanoma cells by directly targeting Zinc-finger E-box binding homeobox 1. AB - As documented in numerous studies, microRNAs (miRNAs) play key roles in various biological processes associated with melanoma occurrence and development. In this study, we found that miRNA-342 (miR-342) was significantly down-regulated in melanoma tissues and cell lines. Additionally, the ectopic expression of miR-342 prohibited the cell proliferation and invasion of melanoma. Moreover, Zinc-finger Ebox binding homeobox 1 (ZEB1) was identified as a direct target gene of miR-342 in melanoma. Similar with the results induced by miR-342 overexpression, ZEB1 knockdown attenuated cell proliferation and invasion in melanoma. Furthermore, the restoration of ZEB1 expression reversed the suppressive effects of miR-342 on the proliferation and invasion of melanoma cells. These findings suggest that miR 342 may play tumour-suppressing roles in melanoma, at least partially, by directly inhibiting ZEB1 expression. Therefore, miR-342 may be developed as a potential candidate for the treatment of patients with this aggressive type of cancer. PMID- 29495973 TI - microRNA-623 targets cyclin D1 to inhibit cell proliferation and enhance the chemosensitivity of cells to 5-fluorouracil in gastric cancer. AB - The dysregulation of microRNAs (miRNAs) plays an important function in the onset and progression of gastric cancer (GC). In addition, aberrantly expressed miRNAs affect the chemosensitivity of GC cells to chemotherapeutic drugs. Hence, miRNA based targeted therapy might be applied to treat patients with GC exhibiting chemotherapeutic resistance. In this study, miRNA-623 (miR-623) expression was downregulated in GC tissues and cell lines. Functional analysis showed that the restored miR-623 expression could inhibit the proliferation of GC cells and enhance their chemosensitivity to 5-FU via the cell apoptosis pathway. Cyclin D1 (CCND1) was identified as a direct target gene of miR-623 in GC. The overexpressed CCND1 in GC tissues was negatively correlated with miR-623 level. The recovered CCND1 expression counteracted the effects of miR-623 on GC cell proliferation, chemosensitivity and 5-FU induced apoptosis. Thus, our results suggest that miR-623 might function as a tumor suppressor in GC and could be a promising therapeutic target for patients with GC, especially those with chemotherapeutic resistance. PMID- 29495970 TI - Large-scale external validation and comparison of prognostic models: an application to chronic obstructive pulmonary disease. AB - BACKGROUND: External validations and comparisons of prognostic models or scores are a prerequisite for their use in routine clinical care but are lacking in most medical fields including chronic obstructive pulmonary disease (COPD). Our aim was to externally validate and concurrently compare prognostic scores for 3-year all-cause mortality in mostly multimorbid patients with COPD. METHODS: We relied on 24 cohort studies of the COPD Cohorts Collaborative International Assessment consortium, corresponding to primary, secondary, and tertiary care in Europe, the Americas, and Japan. These studies include globally 15,762 patients with COPD (1871 deaths and 42,203 person years of follow-up). We used network meta-analysis adapted to multiple score comparison (MSC), following a frequentist two-stage approach; thus, we were able to compare all scores in a single analytical framework accounting for correlations among scores within cohorts. We assessed transitivity, heterogeneity, and inconsistency and provided a performance ranking of the prognostic scores. RESULTS: Depending on data availability, between two and nine prognostic scores could be calculated for each cohort. The BODE score (body mass index, airflow obstruction, dyspnea, and exercise capacity) had a median area under the curve (AUC) of 0.679 [1st quartile-3rd quartile = 0.655 0.733] across cohorts. The ADO score (age, dyspnea, and airflow obstruction) showed the best performance for predicting mortality (difference AUCADO - AUCBODE = 0.015 [95% confidence interval (CI) = -0.002 to 0.032]; p = 0.08) followed by the updated BODE (AUCBODE updated - AUCBODE = 0.008 [95% CI = -0.005 to +0.022]; p = 0.23). The assumption of transitivity was not violated. Heterogeneity across direct comparisons was small, and we did not identify any local or global inconsistency. CONCLUSIONS: Our analyses showed best discriminatory performance for the ADO and updated BODE scores in patients with COPD. A limitation to be addressed in future studies is the extension of MSC network meta-analysis to measures of calibration. MSC network meta-analysis can be applied to prognostic scores in any medical field to identify the best scores, possibly paving the way for stratified medicine, public health, and research. PMID- 29495974 TI - MicroRNA-664 targets Insulin receptor substrate 1 to suppress cell proliferation and invasion in breast cancer. AB - A large number of microRNAs (miRNAs) have been previously demonstrated to be dysregulated in breast cancer (BC), and alterations in miRNA expression may affect the initiation and progression of BC. This study showed that miR-664 expression was obviously reduced in BC tissues and cell lines. Resumption expression of miR-664 attenuated the proliferation and invasion of BC cells. The molecular mechanism underlying the inhibitory effects of BC cell proliferation and invasion by miR-664 was also studied. Insulin receptor substrate 1 (IRS1) was identified as a novel and direct target of miR-664. In addition, siRNA-mediated silencing of IRS1 expression mimicked the suppressive effects of miR-664 overexpression in BC cells. Rescue experiments demonstrated that recovered IRS1 expression partially antagonized the inhibition of proliferation and invasion of BC cells caused by miR-664 overexpression. Thus, miR664 may serve as a tumor suppressor in BC by directly targeting IRS1. Moreover, miR664 down-regulation in BC may contribute to the occurrence and development of BC, suggesting that miR 664 may be a novel therapeutic target for patients with BC. PMID- 29495975 TI - Long non-coding RNA XIST regulates miR-137-EZH2 axis to promote tumor metastasis in colorectal cancer. AB - We aimed to investigate the significant role of long non-coding RNA X Inactive Specific Transcript (XIST) in regulatingtumor metastasis in colorectal cancer (CRC), as well as its possible mechanism. Expression of lncRNA XIST in CRC tissues and CRC cells was detected. CRC cells were transfected with pc-XIST, blank control si-XIST or si-control, and then the effects of lncRNA XIST on CRC cell migration and invasion were investigated, along with the interaction between lncRNA XIST and miR-137. LncRNA XIST was upregulated in CRC tissues. Compared with HT29 cells that had low metastatic potential, XIST was markedly higher expressed in LoVo cells that had higher metastatic potential. Overexpression of XIST promoted the migratory and invasive potential of HT29 cells, while knockdown of XIST inhibited the migratory and invasive potential of LoVo cells. Moreover, epithelial-mesenchymal transition (EMT) markers, including Ecadherin, N-cadherin, and Vimentin, exhibited corresponding expression changes. In addition, miR-137 was inhibited by XIST and inhibition of miR-137 could reverse the effects of knockdown of XIST on the migratory and invasive potential of LoVo cells. Furthermore, enhancer of zeste homolog 2 (EZH2) was confirmed as a target of miR 137. Our data reveal that lncRNA XIST may promote tumor metastasis in CRC possible through regulating miR-137-EZH2 axis. LncRNA XIST may sever as a prognostic indicator for CRC progression. PMID- 29495976 TI - Knockdown of Long noncoding RNA ENST457720 inhibits proliferation of non-small cell lung cancer cells in vitro and in vivo. AB - Non-small cell lung cancer (NSCLC) represents the leading cause of cancer-related mortality worldwide. More and more reports have identified important roles for long noncoding RNAs (lncRNAs) in cancer development. ENST457720 expression was upregulated in lung adenocarcinoma in a microarray-based lncRNA screen. We determined the expression levels of ENST457720 in NSCLC tissues with quantitative real-time PCR and then studied their clinical significance. We explored the biological significance of ENST457720 with gain- and loss-of-function analyses in vitro and in vivo. In this study, ENST457720 was expressed at higher levels in NSCLC tissues than in paired normal tissues. Higher ENST457720 expression was associated with larger tumor sizes, lymph node metastasis and advanced TNM stage. ENST457720 silencing suppressed NSCLC cell proliferation in vitro and in vivo. Moreover, ENST457720 knockdown inhibited NSCLC invasion and reversed the epithelial-to-mesenchymal transition. ENST457720 promoted NSCLC proliferation and invasion, which may be a novel potential therapeutic target for NSCLC. PMID- 29495977 TI - MiR-30c impedes glioblastoma cell proliferation and migration by targeting SOX9. AB - MiR-30c has been acknowledged as a tumor suppressor in various human cancers, such as ovarian cancer, gastric cancer and prostate cancer. However, the role of miR-30c in glioblastoma (GBM) needs to be investigated. In our study, we found that the expression of miR-30c was significantly downregulated in GBM tissues and cell lines. We found that overexpression of miR-30c inhibited cellular proliferation of GBM cells in vitro and in vivo. More GBM cells were arrested in G0 phase after miR-30c overexpression. Moreover, we showed that miR-30c overexpression suppressed the migration and invasion of GBM cells. In mechanism, we found that SOX9 was a direct target of miR-30c in GBM cells. Overexpression of miR-30c inhibited the mRNA and protein levels of SOX9 in GBM cells. Moreover, there was a negative correlation between the expression of miR-30c and SOX9 in GBM tissues. Finally, we showed that restoration of SOX9 in GBM cells reversed the proliferation, migration and invasion of GBM cells transfected with miR-30c mimics. Collectively, our results demonstrated that miR-30c suppressed the proliferation, migration and invasion of GBM cells via targeting SOX9. PMID- 29495978 TI - Exploring the experiences of Aboriginal and Torres Strait Islander patients admitted to a metropolitan health service. AB - Objective There continue to be disparate health outcomes for people who are Aboriginal and Torres Strait Islander. The aim of the present study was to measure whether there were any differences in in-patient experiences between Aboriginal and Torres Strait Islander people and those without an Aboriginal or Torres Strait Islander background.Methods Random samples of people were invited to complete a survey following admission at the hospitals at Peninsula Health, Victoria, Australia. This survey was based on the Victorian Patient Satisfaction Monitor. Open-ended questions were also asked to gauge perspectives on how the services could better meet needs of Aboriginal and Torres Strait Islander patients.Results A total of 154 responses was obtained. There were differences between the two groups of participants in the following variables: respect of privacy, representation of culture, assistance with meals and access to a culturally specific worker if needed. This was reflected in thematic analysis, with three main themes identified: (1) interactions with staff; (2) the challenging environment; and (3) not just about me, but my family too.Conclusion There were systemic differences in in-patient experiences. Healthcare services have a responsibility to make systemic changes to improve the health care of all Australians by understanding and reforming how services can be appropriately delivered.What is known about the topic? There is a disparity in health outcomes between Aboriginal and Torres Strait Islander Australians and those who do not identify as Aboriginal and/or Torres Strait Islander. In addition, Aboriginal and Torres Strait Islanders have different interactions within healthcare services. Many rural health services have models that aim to deliver culturally appropriate services, but it is unknown whether the same challenges apply for this group of Australians within metropolitan health services.What does this paper add? This paper identifies the structural supports that are required to help close the gap in health care provision inequality. Many of the key issues identified are not people but system based. Healthcare administrators should consider the factors identified and address these at a whole-of-service level.What are the implications for practitioners? Many practitioners are aware of the challenges of providing culturally appropriate services. This research raises awareness of how traditional healthcare is not a one size fits all and flexibility is required to improve health outcomes. PMID- 29495979 TI - Treating Gout in Patients With Cardiovascular Disease: Mutual Benefit or Unintended Consequences? PMID- 29495980 TI - Clinical Outcomes in Adolescents and Adults After the Fontan Procedure. AB - BACKGROUND: Long-term outcomes of Fontan patients who survive to age >=16 years have not been well characterized. The Australian and New Zealand Fontan Registry (ANZFR) provides a unique opportunity to understand survival and complication rates in Fontan patients who transition to adult congenital heart disease centers. OBJECTIVES: This study sought to describe the survival and complications of adult patients who have had a Fontan procedure. METHODS: The study analyzed outcomes in patients >=16 years of age who were prospectively enrolled in the ANZFR. RESULTS: Data from all 683 adult survivors from the ANZFR were analyzed. Mortality status was confirmed from the National Death Index. There were 201 atriopulmonary (AP) connections and 482 total cavopulmonary connections (249 lateral tunnels and 233 extracardiac conduits). For these subjects, the survival rate at age 30 years was 90% (95% CI: 87% to 93%), and it was 80% (95% CI: 75% to 87%) at 40 years of age. Survival at age 30 years was significantly worse for the patients with AP connections (p = 0.03). At latest follow-up, only 53% of patients were in New York Heart Association functional class I. After the age of 16 years, 136 (20%) had experienced at least 1 new arrhythmia, 42 (6%) required a permanent pacemaker, 45 (7%) had a thromboembolic event, and 135 (21%) required a surgical reintervention. Only 41% (95% CI: 33% to 51%) of Fontan patients were free of serious adverse events at 40 years of age. CONCLUSIONS: This comprehensively followed cohort showed that a variety of morbid complications is common in Fontan adults, and that there is a substantial incidence of premature death, particularly in patients with AP connections. PMID- 29495981 TI - The Adolescent and Adult With a Fontan Circulation: "Unnatural" Selection and Survival of the Fittest. PMID- 29495983 TI - Cryptogenic Stroke and Patent Foramen Ovale. AB - Nearly one-half of patients with cryptogenic stroke have a patent foramen ovale (PFO). The dilemma of whether to close these PFOs percutaneously, in an effort to reduce the risk of recurrent paradoxical embolism, has been a matter of ongoing debate for more than a decade. Early randomized clinical trials failed to demonstrate a significant benefit of percutaneous PFO closure for secondary prevention of cryptogenic stroke in an intention-to-treat analysis. The long-term follow-up data from the RESPECT trial and 2 new randomized trials (CLOSE and REDUCE) have clarified these findings. They showed that with good patient selection, transcatheter PFO closure significantly reduces the risk of recurrent stroke compared with medical therapy in patients with cryptogenic stroke, with no increased risk of serious adverse events or influence on major bleeding. PMID- 29495984 TI - Social Media and Cardiology. PMID- 29495985 TI - Rivaroxaban and Post-Stroke Neurological Outcomes in Patients With Acute Coronary Syndrome. PMID- 29495982 TI - 2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials. AB - This publication describes uniform definitions for cardiovascular and stroke outcomes developed by the Standardized Data Collection for Cardiovascular Trials Initiative and the U.S. Food and Drug Administration (FDA). The FDA established the Standardized Data Collection for Cardiovascular Trials Initiative in 2009 to simplify the design and conduct of clinical trials intended to support marketing applications. The writing committee recognizes that these definitions may be used in other types of clinical trials and clinical care processes where appropriate. Use of these definitions at the FDA has enhanced the ability to aggregate data within and across medical product development programs, conduct meta-analyses to evaluate cardiovascular safety, integrate data from multiple trials, and compare effectiveness of drugs and devices. Further study is needed to determine whether prospective data collection using these common definitions improves the design, conduct, and interpretability of the results of clinical trials. PMID- 29495986 TI - Association Between Medicaid Expansion and Cardiovascular Interventions in Michigan. PMID- 29495987 TI - Consent for Pragmatic Trials in Acute Myocardial Infarction. PMID- 29495988 TI - What Is the Biological Relationship Between Left Atrial Fibrosis and Stroke in Atrial Fibrillation? PMID- 29495989 TI - Reply: What Is the Biological Relationship Between Left Atrial Fibrosis and Stroke in Atrial Fibrillation? PMID- 29495991 TI - Subclinical Thrombotic Events as a Mechanism for Troponin Release? PMID- 29495990 TI - Reply: Subclinical Thrombotic Events as a Mechanism for Troponin Release? PMID- 29495992 TI - Correction. PMID- 29495994 TI - Correction. PMID- 29495993 TI - Correction. PMID- 29495995 TI - Gadolinium-Free Cardiac MR Stress T1-Mapping to Distinguish Epicardial From Microvascular Coronary Disease. AB - BACKGROUND: Novel cardiac magnetic resonance (CMR) stress T1 mapping can detect ischemia and myocardial blood volume changes without contrast agents and may be a more comprehensive ischemia biomarker than myocardial blood flow. OBJECTIVES: This study describes the performance of the first prospective validation of stress T1 mapping against invasive coronary measurements for detecting obstructive epicardial coronary artery disease (CAD), defined by fractional flow reserve (FFR <0.8), and coronary microvascular dysfunction, defined by FFR >=0.8 and the index of microcirculatory resistance (IMR >=25 U), compared with first pass perfusion imaging. METHODS: Ninety subjects (60 patients with angina; 30 healthy control subjects) underwent CMR (1.5- and 3-T) to assess left ventricular function (cine), ischemia (adenosine stress/rest T1 mapping and perfusion), and infarction (late gadolinium enhancement). FFR and IMR were assessed <=7 days post CMR. Stress and rest images were analyzed blinded to other information. RESULTS: Normal myocardial T1 reactivity (DeltaT1) was 6.2 +/- 0.4% (1.5-T) and 6.2 +/- 1.3% (3-T). Ischemic viable myocardium downstream of obstructive CAD showed near abolished T1 reactivity (DeltaT1 = 0.7 +/- 0.7%). Myocardium downstream of nonobstructive coronary arteries with microvascular dysfunction showed less blunted T1 reactivity (DeltaT1 = 3.0 +/- 0.9%). Stress T1 mapping significantly outperformed gadolinium-based first-pass perfusion, including absolute quantification of myocardial blood flow, for detecting obstructive CAD (area under the receiver-operating characteristic curve: 0.97 +/- 0.02 vs. 0.91 +/- 0.03, respectively; p < 0.001). A DeltaT1 of 1.5% accurately detected obstructive CAD (sensitivity: 93%; specificity: 95%; p < 0.001), whereas a less-blunted DeltaT1 of 4.0% accurately detected microvascular dysfunction (area under the receiver-operating characteristic curve: 0.95 +/- 0.03; sensitivity: 94%; specificity: 94%: p < 0.001). CONCLUSIONS: CMR stress T1 mapping accurately detected and differentiated between obstructive epicardial CAD and microvascular dysfunction, without contrast agents or radiation. PMID- 29495997 TI - Mapping the Future of Myocardial Ischemia Testing With Cardiac Magnetic Resonance. PMID- 29495996 TI - Diagnosis of Microvascular Angina Using Cardiac Magnetic Resonance. AB - BACKGROUND: In patients with angina and nonobstructive coronary artery disease (NOCAD), confirming symptoms due to coronary microvascular dysfunction (CMD) remains challenging. Cardiac magnetic resonance (CMR) assesses myocardial perfusion with high spatial resolution and is widely used for diagnosing obstructive coronary artery disease (CAD). OBJECTIVES: The goal of this study was to validate CMR for diagnosing microvascular angina in patients with NOCAD, compared with patients with obstructive CAD and correlated to the index of microcirculatory resistance (IMR) during invasive coronary angiography. METHODS: Fifty patients with angina (65 +/- 9 years of age) and 20 age-matched healthy control subjects underwent adenosine stress CMR (1.5- and 3-T) to assess left ventricular function, inducible ischemia (myocardial perfusion reserve index [MPRI]; myocardial blood flow [MBF]), and infarction (late gadolinium enhancement). During subsequent angiography within 7 days, 28 patients had obstructive CAD (fractional flow reserve [FFR] <=0.8) and 22 patients had NOCAD (FFR >0.8) who underwent 3-vessel IMR measurements. RESULTS: In patients with NOCAD, myocardium with IMR <25 U had normal MPRI (1.9 +/- 0.4 vs. controls 2.0 +/ 0.3; p = 0.49); myocardium with IMR >=25 U had significantly impaired MPRI, similar to ischemic myocardium downstream of obstructive CAD (1.2 +/- 0.3 vs. 1.2 +/- 0.4; p = 0.61). An MPRI of 1.4 accurately detected impaired perfusion related to CMD (IMR >=25 U; FFR >0.8) (area under the curve: 0.90; specificity: 95%; sensitivity: 89%; p < 0.001). Impaired MPRI in patients with NOCAD was driven by impaired augmentation of MBF during stress, with normal resting MBF. Myocardium with FFR >0.8 and normal IMR (<25 U) still had blunted stress MBF, suggesting mild CMD, which was distinguishable from control subjects by using a stress MBF threshold of 2.3 ml/min/g with 100% positive predictive value. CONCLUSIONS: In angina patients with NOCAD, CMR can objectively and noninvasively assess microvascular angina. A CMR-based combined diagnostic pathway for both epicardial and microvascular CAD deserves further clinical validation. PMID- 29495998 TI - Long-Term Outcomes of On- Versus Off-Pump Coronary Artery Bypass Grafting. AB - BACKGROUND: When comparing effects of on- versus off-pump coronary artery bypass grafting (CABG), it is important to assess the long-term clinical outcomes. However, most research conducted thus far has concentrated on short-term outcomes and ignored the long-term clinical outcomes, especially the 5-year outcomes of the largest randomized controlled trials. OBJECTIVES: The aim of this systematic review and meta-analysis was to investigate the long-term clinical outcomes of on versus off-pump CABG. METHODS: To identify potential studies systematic searches were carried out using various databases. The search strategy included the key concepts of cardiopulmonary bypass AND off-pump AND long term OR 5-year outcomes. This was followed by a meta-analysis investigating mortality, incidence of myocardial infarction, incidence of angina, need for revascularization, and incidence of stroke. RESULTS: Six studies totaling 8,145 participants were analyzed. In the on-pump group mortality was 12.3%, compared with 13.9% in the off-pump group. The odds ratio (OR) for this comparison was 1.16 (95% confidence interval [CI]: 1.02 to 1.32; p = 0.03; 13.9% vs. 12.3%). In contrast, there were no differences in the incidence of myocardial infarction (OR: 1.06: 95% CI: 0.91 to 1.25; p = 0.45; 8.4% vs. 7.9%), incidence of angina (OR: 1.09; 95% CI: 0.75 to 1.57; p = 0.65; 2.3% vs. 2.1%), need for revascularization (OR: 1.15; 95% CI: 0.95 to 1.40; p = 0.16; 5.9% vs. 5.1%), and the incidence of stroke (OR: 0.78; 95% CI: 0.56 to 1.10; p = 0.16; 2.2% vs. 2.8%). CONCLUSIONS: Statistically, on pump CABG appeared to offer superior long-term survival, although the clinical significance of this may be more uncertain. PMID- 29495999 TI - On-Pump CABG in 2018: Still the Gold Standard. PMID- 29496000 TI - Cardiovascular Risks of Probenecid Versus Allopurinol in Older Patients With Gout. AB - BACKGROUND: Patients with gout are at an increased risk of cardiovascular (CV) disease including myocardial infarction (MI), stroke, and heart failure (HF). OBJECTIVES: The authors conducted a cohort study to examine comparative CV safety of the 2 gout treatments-probenecid and allopurinol-in patients with gout. METHODS: Among gout patients >=65 years of age and enrolled in Medicare (2008 to 2013), those who initiated probenecid or allopurinol were identified. The primary outcome was a composite CV endpoint of hospitalization for MI or stroke. MI, stroke, coronary revascularization, HF, and mortality were assessed separately as secondary outcomes. The authors estimated the incidence rate and hazard ratio of the primary and secondary outcomes in the 1:3 propensity score-matched cohort of probenecid and allopurinol initiators. RESULTS: A total of 9,722 probenecid initiators propensity score-matched to 29,166 allopurinol initiators with mean age of 76 +/- 7 years, and 54% males were included. The incidence rate of the primary composite endpoint of MI or stroke per 100 person-years was 2.36 in probenecid and 2.83 in allopurinol initiators with a hazard ratio of 0.80 (95% confidence interval: 0.69 to 0.93). In the secondary analyses, probenecid was associated with a decreased risk of MI, stroke, HF exacerbation, and mortality versus allopurinol. These results were consistent in the subgroup analyses of patients without baseline CV disease or those without baseline chronic kidney disease. CONCLUSIONS: In this large cohort of 38,888 elderly gout patients, treatment with probenecid appears to be associated with a modestly decreased risk of CV events including MI, stroke, and HF exacerbation compared with allopurinol. PMID- 29496001 TI - Daily rhythm of skin temperature of women evaluated by infrared thermal imaging. AB - It is well known that skin temperature varies due to circadian rhythm. Although there is information available for men, little is known about women's circadian rhythm in the analysis of skin temperature (Tsk) using infrared thermography. The objective of this study is to identify Tsk variations on different body regions in women through infrared thermography during the day. The sample consisted of 20 female (mean age of 20.5 +/- 1.3 years, body weight of 62.2 +/- 9.2kg and height of 165.0 +/- 4.7cm). Oneway ANOVA for repeated measures, and Cosinor analysis was used to determine the MESOR, amplitude and acrophase of Tsk. The regions of the forearm, upper arm and anterior and posterior legs in the lower limbs, as well as the chest and scapulae in the upper limbs showed higher variability throughout the day. In general, distal regions had lower values compared with the central regions, and the pectoral region had the lowest standard deviation values. Tsk of the analyzed regions at different times show significant differences between periods of the day in young active women, showing the minimum absolute values for both Tsk in the early morning. These results highlight the need to consider the time of day when analyzing women's skin temperature. Future studies should report the time of day when the images were collected, as well as consider the circadian rhythm when making comparisons. PMID- 29496002 TI - An optimal two-bout strategy with phase change material cooling vests to improve comfort in hot environment. AB - Cooling vests incorporating phase change material (PCM) packets are used to improve comfort of workers in hot environments. This work aims to investigate by modeling and experimentation the effect of dividing the working duration into two bouts, where different PCM melting temperatures are used in each bout. An integrated bio-heat and fabric-PCM model predictions of physiological and subjective votes are validated via active human subject testing at hot conditions. A parametric study is performed to select, at two conditions (40 degrees C and 45 degrees C), the optimal PCM melting temperatures of the two bouts that would result with similar thermal comfort and sensation to the optimal single-bout case. The optimal case achieves most reductions in energy use for PCM regeneration, PCM carried weight and material cost. The results of the parametric study showed that heat storage is reduced in the second bout due to wearing the second vest with lower PCM melting temperature, thus thermal comfort and sensation are significantly improved. The optimal case at the 40 degrees C environment uses a vest with 21 degrees C PCMs in the first bout and a vest with 21 degrees C PCMs in the second bout (V21->V21). At 45 degrees C, the optimal case is V18->V10 with significant PCM weight reductions from the reference single bout case by a minimum of 47%. Thus, the issue of extra carried weight that affect metabolism and ease of movement when applying continuous cooling during work have been mitigated by using the two-bout strategy. PMID- 29496003 TI - Bursty spike trains of antennal thermo- and bimodal hygro-thermoreceptor neurons encode noxious heat in elaterid beetles. AB - The main purpose of this study was to explain the internal fine structure of potential antennal thermo- and hygroreceptive sensilla, their innervation specifics, and responses of the sensory neurons to thermal and humidity stimuli in an elaterid beetle using focused ion beam scanning electron microscopy and electrophysiology, respectively. Several essential, high temperature induced turning points in the locomotion were determined using automated video tracking. Our results showed that the sensilla under study, morphologically, are identical to the dome-shaped sensilla (DSS) of carabids. A cold-hot neuron and two bimodal hygro-thermoreceptor neurons, the moist-hot and dry-hot neuron, innervate them. Above 25-30 degrees C, all the three neurons, at different threshold temperatures, switch from regular spiking to temperature dependent spike bursting. The percentage of bursty DSS neurons on the antenna increases with temperature increase suggesting that this parameter of the neurons may encode noxious heat in a graded manner. Thus, we show that besides carabid beetles, elaterids are another large group of insects with this ability. The threshold temperature of the beetles for onset of elevated locomotor activity (OELA) was lower by 11.9 degrees C compared to that of critical thermal maximum (39.4 degrees C). Total paralysis occurred at 41.8 degrees C. The threshold temperatures for spike bursting of the sensory neurons in DSS and OELA of the beetles coincide suggesting that probably the spike bursts are responsible for encoding noxious heat when confronted. In behavioural thermoregulation, spike bursting DSS neurons serve as a fast and firm three-fold early warning system for the beetles to avoid overheating and death. PMID- 29496004 TI - Influence of extreme heat or cold stresses on body pigmentation of Drosophila melanogaster. AB - Thoracic and abdominal pigmentation were measured in Drosophila melanogaster under a cold circadian stress (8-25 degrees C) and a heat one (18-33 degrees C) and compared to the phenotypes observed under similar but constant temperatures of 17 or 25 degrees C respectively. An isofemale line design permitted to submit each line (full sibs) to the four thermal regimes. Under cold stress, the pigmentation was similar to the value observed at constant 25 degrees C, suggesting a kind of functional dominance of the high temperature phase. In all cases, thermal stresses increased the individual environmental variance, i.e., increased the developmental instability. Genetic correlations between lines were not modified by the stresses but provided some unexpected and surprising results, which should be confirmed by further investigations: for example, negative correlations between pigmentation and body size or sternopleural bristle number. As a whole, the data do not confirm the hypothesis that under stressing conditions a hidden genetic variability could be unravelled, permitting a faster adaptation to environmental changes. PMID- 29496005 TI - Estimation of the optimum number and location of nanoparticle injections and the specific loss power for ideal hyperthermia. AB - Hyperthermia is one of the most appealing methods of cancer treatment in which the temperature of tumor is elevated to reach a desired temperature. One of the methods of increasing tissue temperature is injection of nanoparticle fluids to tumor and applying alternative magnetic field, which is called magnetic nanoparticle hyperthermia method. The total number of injection points, as well as the their location within a tissue play a significant role in this method. Furthermore, the power of heating of a magnetic material per gram or specific loss power (SLP) is another important factor which needs to be investigated. As the uniform temperature of 43 degrees C is effective enough for a tumor regression in certain specific tissues, the inverse method is applied to find out both the number of injection points and their location. Furthermore, the effective amount of heat generated by nanoparticles is investigated by this technique. Two-dimensional cancerous brain tissue was considered, zero gradients on boundary conditions were assumed, and diffusion equation and Pennes equation, which is regarded as energy equation, were solved, respectively. Conjugate gradient technique as a one way of inverse methods is applied, and unknowns are investigated. The results illustrate that three-point injection with the best injection sites cannot induce a uniform temperate distribution of 43 degrees C, and although four-point injection can create a uniform temperature elevation, the amount of it cannot reach the 43 degrees C. Finally, the optimum locations of five-point injection which are ((0.80,3.24), (0.80,0.84), (2.00,2.00), (3.20,3.24), (3.32,0.84)) (all dimensions are in mm) in the studied domain with special loss power of 420 W/g, all of which are obtained after 36 iterations, demonstrate that these conditions can meet the requirements of the magnetic fluid hyperthermia and can be considered for the future usage of researchers and investigators. PMID- 29496007 TI - The effect of ice slurry ingestion on body temperature and cycling performance in competitive athletes. AB - The effects of pre cooling on endurance performance are widely known. In contrast, the approach of cooling during endurance exercise in combination with pre-exercise cooling has been poorly understood. The purpose of the present study was to determine whether the effects of precooling and cooling during exercise enhance exercise performance compared to the ingestion of a thermo-neutral beverage (20 degrees C) or precooling alone in cycling performance. This was an experimental study using a randomised crossover design in which 7 cyclists underwent three trials comprising of 45 min steady state cycling (SS) at 70% VO2 max and a subsequent 10 km time trial (TT) in hot conditions (32 degrees C, 50% relative humidity). Rectal temperature (Tre), heat storage (HS), heart rate (HR), blood lactate concentration (BLA) and thermal sensation (TS) were measured. The intervention consisted of: (1) ingestion of thermo-neutral beverage before and during SS cycling (TN), (2) ingestion of ice slurry beverage and application of iced towels (precooling) prior to exercise, and then ingestion of thermo-neutral beverage during SS (PRE) and (3) precooling strategy as above plus ice slurry ingestion during SS cycling (PRE + MID). The intake of thermo-neutral or ice slurry beverage (14 g/kg) occurred over 30 min before and every 15 min during SS cycling. There was no significant difference in TT performance between all the conditions (P =0.72). However, PRE and PRE + MID caused a significant decrease in Tre (P < 0.05) from TN during exercise. Accordingly, both precooling and a combination of precooling and mid-cooling during exercise in hot conditions may be a practical and effective way of reducing core temperature. Future studies should investigate longer distance events and timing of ice slurry ingestion. PMID- 29496008 TI - The influence of lifestyle and swimming behavior on metabolic rate and thermal tolerance of twelve Amazon forest stream fish species. AB - The metabolism of fishes is profoundly affected by environmental factors such as temperature, oxygen concentration, and pH levels. Also, biotic elements, for instance, activity levels of species, have been suggested to affect the energy demand, driving their capacity to support environmental challenges. The present work aims to investigate the effects of the lifestyle and swimming activities levels of fishes living in Amazon forest stream on the aerobic metabolism and thermal tolerance. Intermittent flow respirometry was used to measure routine metabolic rate and thermal maximum metabolic rate with a thermal ramp methodology. Critical thermal tolerance, thermal aerobic scope, and thermal factorial aerobic scope were calculated for twelve species belonging to different families. Our findings showed a correlation between routine and thermal maximum metabolic rate and, between metabolic rate and activity levels. Species belonging to Characidae and Crenuchidae families have high resting metabolic rates, which decrease their factorial aerobic scope and reduce their abilities to cope with warming events. Therefore, these species have low thermal tolerance. Instead, species from families Rivulidae and Cichlidae showed opposite metabolic results and larger thermal windows. We hypothesize that these responses are related to an evolutionary trade-off between lifestyle and energetic requirements and warming will favor species with low activity performance. PMID- 29496006 TI - Heterologous expression of AgsA enhances Escherichia coli tolerance to the combined effect of elevated temperature and Zinc toxicity. AB - Small heat shock proteins (sHSPs) are ubiquitous stress proteins that are able to protect the cells against cellular insults from temperature, heavy metal etc. However, the molecular chaperone roles of sHSPs in enhancing growth and adaptation under combined temperature and metal stresses in Escherichia coli cells have been poorly understood. Here, we analyze the function of recombinant AgsA, a small heat shock protein from Salmonella enterica serovar Typhimurium under combined temperature and zinc stress in E. coli. Our results show that the heterologous expression of AgsA significantly increases the tolerance of E. coli cells to the combined effect of temperature stress and zinc toxicity by maintaining the stability of soluble proteins. Furthermore, there was remarkable and significant difference in the half effect concentration (EC50) of zinc at all temperatures treatments in both test cells. The EC50s of zinc at 37 degrees C, 42 degrees C and 50 degrees C were 15.24 mg/L, 29.30 mg/L, and 5.98 mg/L respectively in the AgsA-transformed E. coli cells, and 3.03 mg/L, 2.38 mg/L, and 0.373 mg/L, respectively in the control cells lacking AgsA. Together, our data indicate a good concentration-response relationship between all three temperatures treatment and zinc toxicity in E. coli, and establish for the first time the combined effects of temperature and zinc toxicity on E. coli cells. Also, the AgsA protein response to combined thermal and metal stress could serve as a molecular biomarker for the assessment of interactive stress damage to the cells. PMID- 29496009 TI - Effects of temperature on activities of antioxidant enzymes and Na+/K+-ATPase, and hormone levels in Schizothorax prenanti. AB - This study evaluated the effects of temperature on the activities of antioxidant enzymes and hormone levels in Schizothorax prenanti. Schizothorax prenanti were acutely suffered from increasing temperature at a rate of 1 degrees C h-1. The temperature started from 11 degrees C and the critical thermal maximum (CTMax) was measured to evaluated thermal tolerance of Schizothorax prenanti. Antioxidant parameters including superoxide dismutase (SOD), catalase (CAT), Na+/K+-ATPase and malondialdehyde (MDA) in gills, liver and muscle were measured at five temperature groups (11 degrees C, 16 degrees C, 21 degrees C, 26 degrees C and 31 degrees C). The plasma hormone including acetylcholine (ACh) and cortisol were also measured at five temperature groups. Our results showed that the CTMax of Schizothorax prenanti under acute heat stress was 31 degrees C.The activities of SOD and CAT in liver and muscle at 11 degrees C, 16 degrees C, 26 degrees C and 31 degrees C groups were significantly higher than 21 degrees C group, as well as Na+/K+-ATPase in gills and MDA concentrations in gills and liver. However, plasma ACh and cortisol levels were significantly increased with increasing temperature. The results indicate that oxidative stress parameters could respons to increase of temperatur, altogether reflect that Schizothorax prenanti has higher susceptibility of temperature. Thus, the effect of long-term high temperature on Schizothorax prenanti should be studied further. PMID- 29496010 TI - Effect of altered ambient temperature through shelter modifications on physiological indicators of Malpura lambs reared in semi-arid region during winter. AB - Microclimatic factors are of crucial aspect for the welfare of animals. Therefore, a study was conducted to assess the effect of altered ambient temperature through shelter modifications on physiological indicators of Malpura lambs reared in the semi-arid region during winter. Twenty-one Malpura lambs of 3 5 week age and average body weight 9.97 +/- 0.51 kg were used in the present study. The lambs were divided into three groups (eg. G1, G2, and G3) and were kept in the different microenvironment by manipulation of shelter design. The G1 lambs were maintained at lower minimum temperature (8.59 +/- 0.71 degrees C) in asbestos roofed shed, while G2 lambs were maintained at higher minimum temperature (14.59 +/- 0.54 degrees C) in local handmade bamboo dome structure, and G3 lambs were kept at a medium minimum temperature (11.84 +/- 0.64 degrees C) in thermocol insulated roofed shed from evening 18:30 h to morning 07:00 h. The study was carried out for one month between January and February. The parameters studied were physiological response (respiration rate, pulse rate, rectal temperature), skin temperature, blood metabolites and endocrine profile. The data were analyzed by general linear models. Higher average daily weight gain was recorded in the lambs kept in higher minimum temperature groups (20.54% higher in G2 and 24.68% higher in G3) as compared to G1 lambs. Microenvironment manipulation had no significant (P > 0.05) effect on most of the physiological response and skin temperature except morning respiration rate within low temperature range. The present study reveals that Hb, PCV, T3, and cortisol level were significantly (P < 0.05) influenced by microenvironment manipulation. The results of the study indicated that altered ambient temperature through altered shelter design of housing for raising of lambs in the semi-arid tropical region may support animal welfare during chilling nights of the winter. PMID- 29496011 TI - The effect of temperature and light on embryogenesis and post-embryogenesis of the spider Eratigena atrica (Araneae, Agelenidae). AB - Embryogenesis and post-embryogenesis of spiders depend on several environmental factors including light and temperature. This study was aimed at evaluating the impact of different thermal and lighting conditions on embryonic and early post embryonic development of Eratigena atrica. Embryos, larvae, nymphs I and II were incubated at constant temperatures of 12, 22, 25 and 32 degrees C under three different light regimes: light, dark, light/dark. Extreme temperatures (12 and 32 degrees C) significantly increased mortality of embryos (to 100%) and nymphs II, whereas larvae and nymphs I suffered reduced survival only at the lowest temperature. Moreover, the lowest temperature reduced the development rate of all stages. The impact of light conditions was less pronounced and more variable: constant light reduced the survival of nymphs I at lower temperatures, but increased that of larvae. Moreover, light increased the time of embryonic development and duration of nymphal stages, particularly at lower temperatures (12-22 degrees C). Thus, the most optimal locations for spiders seem to be dark (though except larval stage) and warm (25 degrees C) sites, where their development is fastest and mortality lowest. PMID- 29496012 TI - Investigating factors affecting the body temperature of dogs competing in cross country (canicross) races in the UK. AB - Increasing numbers of people are running with their dogs, particularly in harness through the sport canicross. Whilst canicross races are typically held in the winter months, some human centred events are encouraging running with dogs in summer months, potentially putting dogs at risk of heat related injuries, including heatstroke. The aim of this project was to investigate the effects of ambient conditions and running speed on post-race temperature of canicross dogs in the UK, and investigate the potential risk of heatstroke to canicross racing dogs. The effects of canine characteristics (e.g. gender, coat colour) were explored in order to identify factors that could increase the risk of exercise induced hyperthermia (defined as body temperature exceeding the upper normal limit of 38.8 degrees C).108 dogs were recruited from 10 race days, where ambient conditions ranged from - 5 to 11 degrees C measured as universal thermal comfort index (UTCI). 281 post race tympanic membrane temperatures were recorded, ranging from 37.0-42.5 degrees C. There was a weak correlation between speed and post race temperature (r = 0.269, P < 0.001). Whilst no correlation between any single environmental factor or UTCI and post-race temperature was found, the proportion of dogs developing exercise-induced hyperthermia during the race increased with UTCI (r = 0.688, P = 0.028). Male dogs (chi(1) = 18.286, P < 0.001), and dark coated dogs (chi(2) = 8.234, P = 0.014), were significantly more likely to finish the race with a temperature exceeding 40.6 degrees C. Prolonged elevati degrees n of body temperature above this temperature is likely to cause heatstroke. At every race dogs exceeded this critical temperature, with 10.7% (n = 30) of the overall study population exceeding this temperature throughout the study period. The results suggest male dogs, dark coloured dogs, and increased speed of running all increase the risk of heatstroke in racing canicross dogs. Further research is required to investigate the impact of environmental conditions on post-race cooling, to better understand safe running conditions for dogs. PMID- 29496013 TI - Latitudinal patterns in temperature-dependent growth rates of a forest pathogen. AB - Direct effects of temperature on plant pathogens can be crucial to determine the onset and epidemiology of disease. The pinewood nematode Bursaphelenchus xylophilus, the causal agent of the pine wilt disease (PWD), has a wide geographical distribution in Eurasia and East Asia, and local temperatures are considered determinant for the onset of the PWD. However, direct effects of temperature on this pathogen are never considered when forecasting its distribution and impact. In the present study we assessed: 1) at which temperatures is the development of wild populations of the pinewood nematode optimized; 2) if there is niche divergence on different populations from its wide distribution area. For this we studied two populations originated from different latitudes in eastern North America (NA), and used multi-model inference to evaluate the contributions of temperature, diet, and nematode population toward the growth rates of B. xylophilus. Although population origin had some effect on the predictive models, there seems to be niche conservatism, with temperatures of 28-29 degrees C maximizing the growth rates of the pathogen. Thus, the use of the number of days in the summer with temperatures between 25 and 31 degrees C would probably help to improve models forecasting B. xylophilus dispersion and PWD. The present work highlight the importance of considering adaptations to temperatures in forest pathogens with large geographical distributions, when building models forecasting the impact of climate on these organisms. PMID- 29496014 TI - Estimation of metabolic energy expenditure from core temperature using a human thermoregulatory model. AB - Human metabolic energy expenditure is critical to many scientific disciplines but can only be measured using expensive and/or restrictive equipment. The aim of this work is to determine whether the SCENARIO thermoregulatory model can be adapted to estimate metabolic rate (M) from core body temperature (TC). To validate this method of M estimation, data were collected from fifteen test volunteers (age = 23 +/- 3yr, height = 1.73 +/- 0.07m, mass = 68.6 +/- 8.7kg, body fat = 16.7 +/- 7.3%; mean +/- SD) who wore long sleeved nylon jackets and pants (Itot,clo = 1.22, Im = 0.41) during treadmill exercise tasks (32 trials; 7.8 +/- 0.5km in 1h; air temp. = 22 degrees C, 50% RH, wind speed = 0.35ms-1). Core body temperatures were recorded by ingested thermometer pill and M data were measured via whole room indirect calorimetry. Metabolic rate was estimated for 5min epochs in a two-step process. First, for a given epoch, a range of M values were input to the SCENARIO model and a corresponding range of TC values were output. Second, the output TC range value with the lowest absolute error relative to the observed TC for the given epoch was identified and its corresponding M range input was selected as the estimated M for that epoch. This process was then repeated for each subsequent remaining epoch. Root mean square error (RMSE), mean absolute error (MAE), and bias between observed and estimated M were 186W, 130 +/ 174W, and 33 +/- 183W, respectively. The RMSE for total energy expenditure by exercise period was 0.30 MJ. These results indicate that the SCENARIO model is useful for estimating M from TC when measurement is otherwise impractical. PMID- 29496015 TI - The aphid Acyrthosiphon pisum exhibits a greater survival after a heat shock when parasitized by the wasp Aphidius ervi. AB - The pea aphid Acyrthosiphon pisum is a common pest of many species of legumes and its parasitoid Aphidius ervi is regarded as a successful biocontrol agent. In this study, we report a greater survival rate of parasitized aphids compared with unparasitized ones, after exposure to a very high temperature (39 degrees C for 30min). After the heat shock, the survival of unparasitized aphids decreases according to their age at the heat shock treatment, suggesting a different adaptation of the aphid life stage to the different microclimatic conditions they experience. Survival of parasitized aphids does not change according to the time of the heat shock treatment, but it is always significantly higher compared with the unparasitized ones. Parasitized aphids are very quickly subjected to a wide range of physiological modifications and the observed increased survival could be a consequence of these modifications before the heat shock treatment. The possible explanations as well as the possible adaptive nature of the observed phenomenon are discussed. PMID- 29496016 TI - High competition between ant species at intermediate temperatures. AB - Living organisms have been moving rapidly toward their favorable thermal regions as climate warms. Their competitive interactions will change significantly as a result of changes in distribution, abundance, and species composition. This study examines the relationship of competition intensity (frequency of competitive interactions) with temperature and the influence of competition on the occurrence of ant species. Competition between ants was surveyed at six different temperature sites using baits and the abundance of ants was surveyed using pitfall traps. The intensity of interspecific competition (abundance-corrected bait species displacement) was high at intermediate temperature sites (unimodal). Ant species are hierarchically organized in behavioral dominance. Two low temperature ant species had decreased in the rank of behavioral dominance at warmer temperature sites because of the abundance of dominant intermediate temperature ant species. Ant species co-occurred randomly at the local scale. However, they were segregated at regional scale because of environmental filtering (temperature). Ant competition did not influence the occurrence of ant species at local or regional scale. These results suggest that the influence of changes in interspecific competition because of climate warming might not be great for ants in temperate regions. PMID- 29496017 TI - Circadian rhythms of body temperature and locomotor activity in the antelope ground squirrel, Ammospermophilus leucurus. AB - We studied circadian rhythms of body temperature and locomotor activity in antelope ground squirrels (Ammospermophilus leucurus) under laboratory conditions of a 12L:12D light-dark cycle and in constant darkness. Antelope ground squirrels are diurnally active and, exceptionally among ground squirrels and other closely related members of the squirrel family in general, they do not hibernate. Daily oscillations in body temperature consisted of a rise in temperature during the daytime activity phase of the circadian cycle and a decrease in temperature during the nighttime rest phase. The body temperature rhythms were robust (71% of maximal strength) with a daily range of oscillation of 4.6 degrees C, a daytime mean of 38.7 degrees C, and a nighttime mean of 34.1 degrees C (24-h overall mean 36.4 degrees C). The body temperature rhythm persisted in continuous darkness with a free-running period of 24.2h. This pattern is similar to that of hibernating species of ground squirrels but with a wave form more similar to that of non-hibernating rodents. Daily oscillations in body temperature were correlated with individual bouts of activity, but daytime temperatures were higher than nighttime temperatures even when comparing short episodes of nocturnal activity that were as intense as diurnal activity. This suggests that although muscular thermogenesis associated with locomotor activity can modify the level of body temperature, the circadian rhythm of body temperature is not simply a consequence of the circadian rhythm of activity. PMID- 29496018 TI - Short-term heat stress results in increased apoptotic signaling and autophagy in oxidative skeletal muscle in Sus scrofa. AB - Prolonged environment-induced hyperthermia causes morbidities and mortality in humans and animals and appears to cause organ-specific injury and dysfunction. We have previously determined autophagic dysfunction and apoptotic signaling in oxidative skeletal muscle following prolonged hyperthermia. The aim of this investigation was to extend our knowledge regarding the early chronology of heat stress-mediated apoptotic and autophagic signaling in oxidative skeletal muscle. We hypothesized that 2, 4, and 6 h of hyperthermia would increase apoptosis and autophagy in oxidative skeletal muscle compared to thermoneutral (TN) conditions. Pigs were assigned to four groups (n = 8/group) and exposed to environmental heat stress (37 degrees C) for 0, 2, 4, or 6 h. Immediately following environmental exposure animals were euthanized and the red portion of the semitendinosus was collected. Markers of apoptotic signaling were increased following 2 h of heating but returned to baseline thereafter, while caspase 3 activity remained elevated 2 3 fold (p < .05) throughout the hyperthermic period. Heat stress increased (p < .05) markers of autophagic activation, and nucleation as well as autophagosome formation and degradation linearly throughout the heating intervention. In addition, 6 h of hyperthermia increased (p < .05) markers of mitophagy. These data suggest that apoptotic signaling precedes increased autophagy during acute heat stress in oxidative skeletal muscle. PMID- 29496019 TI - Insights on the thermal impacts of wing colorization of migrating birds on their skin friction drag and the choice of their flight route. AB - The thermal effects of wing color in flight is investigated in four species of birds with respect to their flight routes, migration time, and geometric and behavioral characteristics. Considering the marine and atmospheric characteristics of these flight routes, a thermal analysis of the birds' wings is performed during their migration. The surrounding fluxes including the ocean flux and the solar irradiance are considered in an energy balance in order to determine the skin temperature of both sides of the wing. Applying the Blasius solution for heated boundary layers, it is shown that the color configuration of these migrating birds, namely black on the top side of the wings and white on the bottom side of the wings ("countershading"), results in a skin drag reduction, if compared to some other configurations, when both day and night are taken into consideration. This drag reduction can be considered as one of the effective factors for long endurance of these migrating birds. This research can provide the evolutionary perspective behind the colorization of these migrating birds. PMID- 29496020 TI - A simulated heat wave shortens the telomere length and lifespan of a desert lizard. AB - Understanding how organisms respond to warming contributes important information to the conservation of biodiversity that is threatened by climate warming. Here, we conducted experiments on a desert agama (Phrynocephalus przewalskii) to test the hypothesis that climate warming (an increase in both mean temperature and heat waves) would induce oxidative stress, shortening telomere length, and thereby decreasing survival. Our results demonstrated that one week of exposure to a simulated heat wave significantly shortened telomere length, and decreased the overwinter survival of lizards, but mean temperature increase did not affect the survival of lizards. However, the antioxidant capacity (anti-oxidative enzyme) was not affected by the warming treatments. Therefore, heat waves might have negative impacts on the desert agama, with shortened telomeres likely causing the lifespan of lizards to decrease under climate warming. PMID- 29496021 TI - Post-Myocardial Infarction Heart Failure. AB - Heart failure (HF) complicating myocardial infarction (MI) is common and may be present at admission or develop during the hospitalization. Among patients with MI, there is a strong relationship between degree of HF and mortality. The optimal management of the patient with HF complicating MI varies according to time since the onset of infarction. Medical therapy for HF after MI includes early (within 24 h) initiation of angiotensin-converting enzyme inhibitors and early (within 7 days) use of aldosterone antagonists. Alternatively, in patients with MI and ongoing HF, early use (<24 h) of beta-blockers is associated with an increased risk of cardiogenic shock and death. Long-term beta-blocker use after MI is associated with a reduced risk of reinfarction and death. Thus, it is critical to frequently re-evaluate beta-blocker eligibility among patients after MI with HF. Cardiogenic shock is an extreme presentation of HF after MI and is a leading cause of death in the MI setting. The only therapy proven to reduce mortality for patients with cardiogenic shock is early revascularization. Several studies are examining new approaches to mitigate the occurrence and adverse impact of post-MI HF. These studies are testing drugs for HF and diabetes and are evaluating mechanical support devices to bridge patients to recovery or transplantation. PMID- 29496022 TI - Clinical Characteristics and Outcome of Methamphetamine-Associated Pulmonary Arterial Hypertension and Dilated Cardiomyopathy. AB - OBJECTIVES: This study sought to characterize patients with methamphetamine associated pulmonary arterial hypertension (MA-PAH) and cardiomyopathy (MA-CMP), to compare with MA controls (MA-CTL), users with structurally normal hearts, with the aim of identifying risk factors for these conditions. BACKGROUND: MA-PAH and MA-CMP are 2 poorly understood cardiac complications in MA users. METHODS: We retrospectively studied the clinical characteristics and outcomes of 50 MA-PAH, 296 MA-CMP, and 356 MA-CTL patients, whom we evaluated between 2010 and 2017. RESULTS: After a median follow-up of 20.0 months (interquartile range [IQR]: 7.6 to 42.6 months), all-cause mortality was 18.0% for MA-PAH, 15.2% for MA-CMP, and 4.5% for MA-CTL group (p < 0.001). More women (58%) were in the MA-PAH group than in the MA-CMP (14%; p < 0.001) and MA-CTL (42%; p = 0.028) groups, whereas the MA CMP group was predominantly male (86% vs. 58% in the MA-CTL group; p < 0.001). More MA-CMP patients had hypertension (p < 0.001) or alcoholism (p < 0.001) than MA-CTL patients. Logistic regression analyses identified male sex, alcoholism, and hypertension as independent factors associated with MA-CMP with the following respective adjusted odds ratios (OR) of 3.791 (95% confidence interval [CI]: 2.508 to 5.730), OR of 2.959 (95% CI: 2.084 to 4.203), and OR of 2.111 (95% CI: 1.486 to 2.999), whereas female sex was the only factor associated with MA-PAH. CONCLUSIONS: Both MA-PAH and MA-CMP patients carried significant disease burden and mortality risk. Male sex, hypertension, and alcoholism were strongly associated with MA-CMP, whereas female sex and other unknown factors may influence development of MA-PAH. This study adds to the understanding of MA associated cardiac complications and highlights directions for future investigation. PMID- 29496025 TI - Heart Failure Health Care 2018: Challenges and Opportunities. PMID- 29496024 TI - My Heart Failure Journey. PMID- 29496023 TI - Crystal Methamphetamine: A Drug and Cardiovascular Epidemic. PMID- 29496026 TI - Reply: The Mediterranean Diet to Treat Heart Failure: A Potential Powerful Tool in the Hand of Providers. PMID- 29496027 TI - The Mediterranean Diet to Treat Heart Failure: A Potentially Powerful Tool in the Hands of Providers. PMID- 29496028 TI - Efficacy of Subcutaneous Versus Intravenous Administration of Furosemide in Patients With Worsening Heart Failure: The Devil Is in the Details. PMID- 29496029 TI - Mechanisms of Discrepancy Between Pulmonary Artery Wedge Pressure and Left Ventricular End-Diastolic Pressure in Heart Failure With Preserved Ejection Fraction. PMID- 29496030 TI - Reply: Efficacy of Subcutaneous vs. Intravenous Administration of Furosemide in Patients With Worsening Heart Failure: The Devil Is in the Details. PMID- 29496031 TI - Reply: Mechanisms of Discrepancy Between Pulmonary Artery Wedge Pressure and Left Ventricular End-Diastolic Pressure in Heart Failure With Preserved Ejection Fraction. PMID- 29496032 TI - Reply: Diabetes and Heart Failure: Are We in the Right Direction to Find the Right Morsel for Success? PMID- 29496033 TI - Diabetes and Heart Failure: Are We in the Right Direction to Find the Right Morsel for Success? PMID- 29496034 TI - Erratum to 'Gene therapy for neurodegenerative diseases' [Trends in Molecular Medicine 21 (2015) 504-512]. PMID- 29496035 TI - Detecting tumour-positive resection margins after oral cancer surgery by spraying a fluorescent tracer activated by gamma-glutamyltranspeptidase. AB - OBJECTIVES: Tumour-positive resection margins are a major problem during oral cancer surgery. gGlu-HMRG is a tracer that becomes fluorescent upon activation by gamma-glutamyltranspeptidase (GGT). This study aims to investigate the combination of gGlu-HMRG and a clinical fluorescence imaging system for the detection of tumour-positive resection margins. MATERIALS AND METHODS: The preclinical Maestro and clinical Artemis imaging systems were compared in vitro and ex vivo with cultured human head and neck cancer cells (OSC19, GGT-positive; and FaDu, GGT negative) and tumour-bearing nude mice. Subsequently, frozen sections of normal and oral cancer tissues were ex vivo sprayed with gGlu-HMRG to determine the sensitivity and specificity. Finally, resection margins of patients with suspected oral cancer were ex vivo sprayed with gGlu-HMRG to detect tumour positive resection margins. RESULTS: Both systems could be used to detect gGlu HMRG activation in vitro and ex vivo in GGT positive cancer cells. Sensitivity and specificity of gGlu-HMRG and the Artemis on frozen tissue samples was 80% and 87%, respectively. Seven patients undergoing surgery for suspected oral cancer were included. In three patients fluorescence was observed at the resection margin. Those margins were either tumour-positive or within 1 mm of tumour. The margins of the other patients were clear (>=8 mm). CONCLUSION: This study demonstrates the feasibility to detect tumour-positive resection margins with gGlu-HMRG and a clinical fluorescence imaging system. Applying this technique would enable intraoperative screening of the entire resection margin and allow direct re-resection in case of tumour-positivity. PMID- 29496036 TI - Combination of post-operative radiotherapy and cetuximab for high-risk cutaneous squamous cell cancer of the head and neck: A propensity score analysis. AB - OBJECTIVES: The objective of this study was to investigate the safety, tolerability and preliminary efficacy of radiotherapy plus cetuximab in high risk CSCC patients. MATERIALS AND METHODS: Patients with high-risk CSCC diagnosed between 2006 and 2013 were analyzed. Patients were divided into two groups: radiotherapy alone versus radiotherapy plus cetuximab. Among 68 patients meeting study criteria, we identified 29 treated with cetuximab plus RT and 39 with RT alone. Primary analysis examined disease-free and overall survival, freedom from local and distant recurrence in the propensity score matched cohort. Propensity score analysis was performed with weighted factors including: Charlson Comorbidity Index score, age. KPS, primary location, T and N stage, recurrent status, margin status, LVSI, PNI and grade. Toxicity was assessed using the CTCAE v4.0. RESULTS: Median follow-up for living patients was 30 months. Patients in the cetuximab group were more likely to have advanced N stage, positive margins and recurrent disease. After propensity score matching the groups were well balanced. Six patients experienced >= grade 3 acute toxicity in the cetuximab group. The 1-year, 2-year and 5-year progression free survival (PFS) for patients in the cetuximab group were 86%, 72% and 66%, respectively. The 1-year, 2-year and 5-year overall survival (OS) for patients in the cetuximab group was 98%, 80% and 80%, respectively. CONCLUSIONS: Although limited by small numbers, the combination of cetuximab and radiotherapy in CSCC appears well tolerated there were more long-term survivors and less distant metastasis in the cetuximab group. These promising finding warrant further studies. PMID- 29496037 TI - Pitfalls of post-treatment PET after de-intensified chemoradiotherapy for HPV associated oropharynx cancer: Secondary analysis of a phase 2 trial. AB - OBJECTIVES: We evaluated patterns of nodal response and positive predictive value (PPV) of 3 month post-treatment PET in patients with HPV-associated oropharyngeal cancer treated on a multi-institutional de-intensification trial. MATERIALS AND METHODS: Eligibility criteria included: (1) T0-3, N0-2c, M0, (2) HPV+/p16+ oropharyngeal squamous cell carcinoma, and (3) <=10 pack-years smoking or <=30 pack-years and abstinent >=5 years. Patients received 60 Gy radiation alone (T0 2, N0-1) or with concurrent weekly cisplatin 30 mg/m2 and surveillance PET three months post-radiation. Nodal responses were categorized as complete (CR), equivocal (ER), or incomplete (IR) using both local and central radiographic review. A "true positive" was ER/IR with clinical/radiographic progression or positive pathology. RESULTS: 79 node-positive pts (84% N2) were analyzed. Distribution of nodal CR, ER, and IR was 44 (56%), 27 (34%), and 8 (10%), respectively. 29 (37%) had ER/IR in pre-treatment node-positive neck levels, whereas 14 (18%) had ER/IR in pre-treatment node-negative levels. Of patients with ER/IR, 5 were observed clinically, 19 received repeat imaging, and 11 received either biopsy (1) or neck dissection (10). The PPV was 9% for ER/IR and 13% for IR, with 3 patients found to have persistent disease on neck dissection. There was no difference in nodal relapse rate in patients with nodal CR vs. nodal ER/IR. CONCLUSION: Post-treatment PET may not accurately predict the presence of persistent disease in patients with favorable-risk oropharynx cancer. These results support close surveillance rather than surgical evaluation in most favorable-risk patients. PMID- 29496038 TI - Comparison between magnetic resonance and computed tomography in detecting mandibular invasion in oral cancer: A systematic review and diagnostic meta analysis: MRI x CT in mandibular invasion. AB - BACKGROUND: Suspicion of mandibular invasion directly influences perioperative strategy, requiring marginal or segmental mandibulectomy, or reconstruction in some cases. This has a considerable impact on outcome and quality of life. The aim of this study was to evaluate the accuracy of magnetic resonance and computed tomography in the prediction of mandibular invasion in patients with oral cavity cancer. METHOD: A systematic review was conducted, including diagnostic studies comparing magnetic resonance imaging with computed tomography in the prediction of bone invasion. Sensitivity, specificity, positive and negative likelihood values and summary receiver operating characteristic (sROC) curves were calculated. RESULTS: The electronic and manual search identified 346 articles. Of these, 11 studies were included in the systematic review for a total of 477 patients. The sensitivity, specificity, and positive and negative likelihood values for MRI were 78%, 86%, 5.29 and 0.23, respectively. For CT, they were 76%, 89%, 6.00 and 0.28, respectively. The sROC curves for MRI and CT were 82.3% and 82.5%, respectively. CONCLUSION: No superiority was observed between the diagnostic methods regarding mandibular invasion detection. PMID- 29496040 TI - Podoplanin emerges as a functionally relevant oral cancer biomarker and therapeutic target. AB - Oral cancer has become one of the most aggressive types of cancer, killing 140,000 people worldwide every year. Current treatments for oral cancer include surgery and radiation therapies. These procedures can be very effective; however, they can also drastically decrease the quality of life for survivors. New chemotherapeutic treatments are needed to more effectively combat oral cancer. The transmembrane receptor podoplanin (PDPN) has emerged as a functionally relevant oral cancer biomarker and chemotherapeutic target. PDPN expression promotes tumor cell migration leading to oral cancer invasion and metastasis. Here, we describe the role of PDPN in oral squamous cell carcinoma progression, and how it may be exploited to prevent and treat oral cancer. PMID- 29496039 TI - Characterization of epithelial oral dysplasia in non-smokers: First steps towards precision medicine. AB - OBJECTIVES: Tobacco usage is the strongest risk factor in the development of oral squamous cell carcinoma (OSCC), which mandates careful screening for oral cancers in smokers. However, there are indications that oral potentially malignant lesions, such as oral epithelial dysplasia (OED), in non-smokers (NS) have a higher cancer risk than those in smokers. Without tobacco as an etiology, the development of these lesions in NS may suggest genetic susceptibility. The increasing incidence of OSCC in NS calls for a better understanding of the natural history of OED in NS as compared to that of smokers. MATERIALS AND METHODS: Patients from a population-based longitudinal study with more than 10 years of follow up were analyzed. Of the 455 patients with primary OED (233 mild and 212 moderate dysplasia), 139 were NS and 306 were smokers. Demographic and habit information, clinical information (lesion site, size and appearance; toluidine blue and fluorescent visualization), microsatellite analysis for loss of heterozygosity (LOH) and outcome (progression) were compared between the two groups. RESULTS AND CONCLUSIONS: The majority of patients with OED were smokers. Of these, more were males, non-Caucasians and heavy drinkers. A significantly higher number of OED in NS were in the tongue, whereas a significantly higher number of OED in smokers were in the floor of mouth (FOM). OED in NS showed a greater than 2-fold increase in cancer progression. Strikingly, OED located in the FOM in NS showed a 38-fold increase in cancer progression as compared to those in smokers. PMID- 29496041 TI - Double positivity for HPV-DNA/p16ink4a is the biomarker with strongest diagnostic accuracy and prognostic value for human papillomavirus related oropharyngeal cancer patients. AB - BACKGROUND: The etiologic role of human papillomaviruses (HPV) in oropharyngeal cancer (OPC) is well established. Nevertheless, information on survival differences by anatomic sub-site or treatment remains scarce, and it is still unclear the HPV-relatedness definition with best diagnostic accuracy and prognostic value. METHODS: We conducted a retrospective cohort study of all patients diagnosed with a primary OPC in four Catalonian hospitals from 1990 to 2013. Formalin-fixed, paraffin-embedded cancer tissues were subjected to histopathological evaluation, DNA quality control, HPV-DNA detection, and p16INK4a/pRb/p53/Cyclin-D1 immunohistochemistry. HPV-DNA positive and a random sample of HPV-DNA negative cases were subjected to HPV-E6*I mRNA detection. Demographic, tobacco/alcohol use, clinical and follow-up data were collected. Multivariate models were used to evaluate factors associated with HPV positivity as defined by four different HPV-relatedness definitions. Proportional-hazards models were used to compare the risk of death and recurrence among HPV-related and non-related OPC. RESULTS: 788 patients yielded a valid HPV-DNA result. The percentage of positive cases was 10.9%, 10.2%, 8.5% and 7.4% for p16INK4a, HPV DNA, HPV-DNA/HPV-E6*I mRNA, and HPV-DNA/p16INK4a, respectively. Being non-smoker or non-drinker was consistently associated across HPV-relatedness definitions with HPV positivity. A suggestion of survival differences between anatomic sub sites and treatments was observed. Double positivity for HPV-DNA/p16INK4a showed strongest diagnostic accuracy and prognostic value. CONCLUSIONS: Double positivity for HPV-DNA/p16INK4a, a test that can be easily implemented in the clinical practice, has optimal diagnostic accuracy and prognostic value. Our results have strong clinical implications for patients' classification and handling and also suggest that not all the HPV-related OPC behave similarly. PMID- 29496042 TI - CD70 as a target for chimeric antigen receptor T cells in head and neck squamous cell carcinoma. AB - OBJECTIVES: In accordance with the Precision Medicine Initiative, new treatment strategies for head and neck squamous cell carcinoma (HNSCC) are needed to yield better therapeutic outcomes. The purpose of this study was to establish and validate chimeric antigen receptor (CAR)-T cells targets in HNSCC. METHODS: Putative CAR-T antigens were identified in The Cancer Genome Atlas database. To validate antigen suitability, quantitative RT-PCR, flow cytometry, and immunofluorescent staining were performed. A retroviral human CD70 CAR construct, using truncated CD27 conjugated with 4-1BB and CD3-zeta costimulatory molecules, was used to transduce activated human T cells to generate CD70 CAR-T cells. Cell based cytotoxicity and cytokine ELISAs were used to measure efficacy of killing. RESULTS: Nine potential CAR-T targets (CD276, EGFR, MICA, MICB, MAGE-A4, FAP, EPCAM, CD70, B4GALNT1) were identified based on their high expression in tumors compared to flanking control tissues. CD70 was selected for further proof-of principle analysis based on its differential expression in several tumor subtypes, and showed substantial heterogeneity in individual tumors analyzed. Cell surface CD70 protein and CD70 mRNA were detected from low to high levels in established HNSCC cancer cell lines. CD70 was highly expressed in 4 of 21 tumor biopsies (19%), and 3 of 4 specimens showed strong CD70 expression on the tumor cell surface. CD70-specific CAR-T cells were generated and further demonstrated to recognize and kill CD70-positive HNSCC cells efficiently, but not CD70 negative cancer cells. CONCLUSION: CD70-specific CAR-T cells specifically recognized and efficiently eliminated CD70-positive HNSCC cells. This study provides the basis for further investigation into CD70 and other CAR-T targets. PMID- 29496043 TI - Induction chemotherapy followed by concurrent chemoradiation versus concurrent chemoradiation alone in the definitive management of p16-positive oropharyngeal squamous cell carcinoma with low-neck or N3 disease. AB - OBJECTIVE: The addition of induction chemotherapy (ICT) to concurrent chemoradiation (CCRT) has been investigated as a method of improving outcomes among patients with locally advanced head and neck squamous cell carcinoma. Previous studies have consisted of heterogeneous populations with both p16 positive and p16-negative disease and varying extent of nodal disease burden. We evaluated the role of ICT in p16-positive oropharyngeal squamous cell carcinoma (OPSCC) at high-risk of distant failure. MATERIALS AND METHODS: A retrospective review was conducted of 88 consecutive patients with p16-positive OPSCC with low neck and/or N3 lymphadenopathy. Among these patients, 44 received ICT followed by CCRT, and 44 received CCRT alone with concurrent agents including Cisplatin, Carboplatin, and Cetuximab. Disease control and survival outcomes were reported after adjusting for age, T stage, N stage, and smoking status. RESULTS: Median follow-up for surviving patients was 47 (range: 13-115) months. Patients who received CCRT alone were older than those who received ICT (61 years vs. 56 years; p = 0.02); the groups were otherwise similarly balanced. 3-year distant metastasis: 38% vs. 18% (adjusted hazard ratio (HR) = 0.32 [0.13-0.82]; p = 0.02). 3-year progression-free survival: 49% vs. 74% (adjusted HR = 0.46 [0.22 0.93]; p = 0.03). 3-year overall survival: 67% vs. 83% (adjusted HR = 0.48 [0.21 1.12]; p = 0.09). CONCLUSION: Among patients with p16-positive OPSCC with low neck and/or N3 lymphadenopathy, ICT followed by CCRT may reduce the risk for distant failure over CCRT alone and lead to improved progression-free survival. Future trials should concentrate on patients at the highest risk of distant metastasis in order to appropriately assess the benefit of ICT. PMID- 29496044 TI - Heterogeneity and irregularity of pretreatment 18F-fluorodeoxyglucose positron emission tomography improved prognostic stratification of p16-negative high-risk squamous cell carcinoma of the oropharynx. AB - OBJECTIVES: Human papillomavirus-negative oropharyngeal squamous cell carcinoma (OPSCC) has unfavorable survival outcomes. Two outcomes have been identified based on smoking history and tumor stage. We investigate the prognostic role of pre-treatment positron emission tomography (PET) in high-risk OPSCC. MATERIALS AND METHODS: We enrolled 147 M0 OPSCC patients with p16-negative staining and a history of heavy smoking (>10 pack-years) or T4 disease. All patients completed primary chemoradiotherapy, and 42% maximum standard uptake values (SUVmax) were used as the threshold for primary tumor. Patients were classified into training and validation cohorts with a ratio of 1:1.5 according to the PET date. Heterogeneity and irregularity indices were obtained. PET parameters with significant impact on progression-free survival (PFS) in receiver operating characteristic curves and univariate Cox models were identified and included in recursive partitioning analysis (RPA) for constructing a prognostic model. The RPA-based prognostic model was further tested in the validation cohort using multivariate Cox models. RESULTS: Fifty-eight and 89 patients were in the training and validation groups, respectively. Heterogeneity parameter, SUV entropy (derived from histogram analysis), and irregularity index, and asphericity were significantly associated with PFS. The RPA model revealed that patients with both high SUV-entropy and high asphericity experienced the worst PFS. Results were confirmed in the validation group. The overall concordance index for PFS of the model was 0.75, which was higher than the clinical stages, performance status, SUVmax, and metabolic tumor volume of PET. CONCLUSIONS: PET prognostic model provided useful prediction of PFS for patients with high-risk OPSCC. PMID- 29496045 TI - Does volumetric measurement serve as an imaging biomarker for tumor aggressiveness of ameloblastomas? PMID- 29496046 TI - Comparison of clinical, radiological and morphological features including the distribution of HPV E6/E7 oncogenes in resection specimens of oropharyngeal squamous cell carcinoma. AB - BACKGROUND: Human papillomavirus (HPV)-driven oropharyngeal squamous cell carcinoma (OPSCC) represents a distinct tumour entity in comparison to HPV negative OPSCC. The clinical, radiological, morphological features and distribution of HPV E6/E7 mRNA were investigated in resected specimens of OPSCC. METHODS: We retrieved formalin-fixed, paraffin-embedded whole section slides from 24 p16/HPV-DNA positive and 18 p16/HPV-DNA negative primary tumours and 16 corresponding metastases in patients with early-stage OPSCC who underwent planned curative or diagnostic primary transoral robotic surgery. A detailed clinicoradiological and histopathological investigation of the tumours was performed along with detection of HPV E6/E7 mRNA by in situ hybridisation. RESULTS: HPV-driven OPSCC was characterised by non-keratinising morphology and was dominated by a cohesive invasion pattern at the leading edge of the tumour. Dysplastic zones of the squamous epithelium were strictly located in the tonsillar crypts in contrast to HPV-negative OPSCC which predominantly arised from the dysplastic surface epithelium. Thirteen HPV-driven OPSCC invaded through the tonsillar lymphoid compartment and into soft tissue, causing a stromal desmoplastic reaction. HPV mRNA was consistently but inhomogenously expressed in the entire tumour area and in the dysplastic squamous epithelium. There was no HPV expression in the adjacent normal epithelium and in the non-neoplastic tissues. CONCLUSIONS: This study enhances the current understanding of HPV-driven OPSCC. Only tumours that invade through the lymphoid compartment induce a stromal desmoplastic reaction. A consistent but inhomogenous expression of E6 and E7 mRNA was found in tumour and dysplastic areas, emphasizing that the E6/E7 oncogenes are the driving factors in HPV-driven OPSCC. PMID- 29496047 TI - Oncologic and functional outcomes of pretreatment tracheotomy in advanced laryngeal squamous cell carcinoma: A multi-institutional analysis. AB - OBJECTIVES: Describe the influence of pretreatment tracheotomy and treatment modality (surgical versus non-surgical) on oncologic and functional outcomes. MATERIALS AND METHODS: Retrospective study of previously untreated advanced-stage laryngeal squamous cell carcinoma patients at two academic tertiary care institutions from 1995 to 2014. RESULTS: Primary outcomes evaluated were disease free survival, disease-specific survival, and overall survival of pretreatment tracheotomy versus no pretreatment tracheotomy cohorts. Functional status, measured by tracheotomy decannulation and gastrostomy tube placement/removal, was assessed. Of the 226 patients, 31.4% underwent pretreatment tracheotomy. Five year disease-specific survival was 72.9%, and overall survival was 48.8% for entire cohort. There was a statistically significant decrease in overall survival (p = .03) and disease-free survival (p = .02) for the pretreatment tracheotomy group compared to no pretreatment tracheotomy, which was largely explained by primary tumor stage. Pretreatment tracheotomy was associated with gastrostomy tube placement and was an independent predictor of worse odds of gastrostomy tube removal. Disease stage, distant metastasis, and age independently conferred worse odds of gastrostomy tube removal. CONCLUSION: Patients undergoing pretreatment tracheotomy for primary T4 laryngeal cancer had decreased overall survival compared to patients without pretreatment tracheotomy. There was no difference in local recurrence rates based on tracheotomy status. Organ preservation with chemotherapy and radiation did not result in better functional outcomes than surgery in the pretreatment tracheotomy group as nearly half of patients treated with organ preservation remained tracheotomy dependent. Based on this data, pretreatment tracheotomy may impact oncologic and functional outcomes in advanced disease, and it should be a consideration in an informed decision-making process. PMID- 29496048 TI - Evaluating oropharyngeal carcinoma with transcervical ultrasound, CT, and MRI. AB - OBJECTIVE: To compare transcervical ultrasonography (US) to standard cross sectional imaging for the visualization of human papillomavirus-related oropharyngeal cancer (HPV-OPC). MATERIALS AND METHODS: Patients with HPV-OPC and available standard imaging (CT and/or MRI) were identified in clinic and prospectively enrolled. US was performed to visualize the oropharynx and lymph nodes. Tumor characteristics across imaging modalities were evaluated (CT versus MRI, and US versus standard imaging (SI)). RESULTS: Forty-three patients were included. The overall blinded detection rates for CT and MRI were 83% and 71%, respectively. The unblinded detection rate for US was 98%. Agreement of tumor anatomic subsite was moderate for both CT vs MRI (kappa = 0.59) and US vs SI (kappa = 0.47). Comparison of tumor size by CT and MRI showed statistically significant correlations in craniocaudal (CC), anteroposterior (AP), and mediolateral (ML) dimensions (RhoCC = 0.51, pCC = 0.038; RhoAP = 0.81, pAP < 0.0001; RhoML = 0.57, pML = 0.012). Tumor size estimates by US and SI showed statistically significant correlations in CC and AP, but not ML (RhoCC = 0.60, pCC = 0.003; RhoAP = 0.71, pAP < 0.0001; RhoML = 0.30, pML = 0.08). Tumor volume estimates improved correlations between US and SI (Rho = 0.66, p < 0.0001). Stratification of US patients into early and late imaging studies demonstrated an increase in correlation strength from early (Rho = 0.32, p = 0.32) to late groups (Rho = 0.77, p < 0.0001) demonstrating that ultrasound accuracy improved with experience. CONCLUSIONS: Our findings suggest that transcervical ultrasonography is a sensitive and relatively accurate adjunct to standard imaging for the evaluation of oropharyngeal tumors. Its cost, portability, and potential for in clinic and serial imaging render US an attractive modality to further develop for imaging oropharyngeal tumors. PMID- 29496049 TI - STING activation enhances cetuximab-mediated NK cell activation and DC maturation and correlates with HPV+ status in head and neck cancer. AB - OBJECTIVES: The intracellular DNA sensor stimulator of interferon genes (STING) has recently been shown to play a vital role in anti-viral and anti-tumor immune responses stimulating cytokine production. While human papillomavirus (HPV) is a causative agent for a subset of head and neck squamous cell carcinoma (HNSCC) with unique etiology and clinical outcome, how the STING pathway is regulated in a virus-induced tumor microenvironment is not well understood. Since STING inactivation likely reflects immunoescape via innate immunity, we hypothesized that its restoration would improve efficacy of the immune modulatory monoclonal antibody (mAb), cetuximab. MATERIALS AND METHODS: We correlated STING protein expression with clinical parameters by immunohistochemistry (n = 106) and its mRNA expression from The Cancer Genome Atlas (TCGA) in HNSCC tissue specimens. STING protein expression was tested for association with cancer-specific survival (CSS). We further examined the impact of STING activation on cetuximab-mediated immunity using an in vitro NK:DC:tumor cells co-culture system. RESULTS: In this study, we found that expression of STING both at the protein and mRNA level was higher in HPV positive (HPV+) specimens but unrelated to TNM stage or cancer specific survival. Our in vitro studies verified that STING activation enhanced cetuximab mediated NK cell activation and DC maturation. CONCLUSION: Our findings suggest a novel role of STING in HPV-related carcinogenesis, in which activation of the STING signaling pathway may facilitate anti-tumor response in HNSCC patients, particularly in combination with therapeutic monoclonal antibodies (mAbs) such as cetuximab, an epidermal growth factor receptor (EGFR) inhibitor. PMID- 29496050 TI - Submental artery island flap versus free flap reconstruction of lateral facial soft tissue and parotidectomy defects: Comparison of outcomes and patient factors. AB - OBJECTIVES: The submental artery island flap (SIF) has recently been described in temporal bone defects. At our institution we have broadened the application of the SIF and modified the harvest technique for complex lateral facial and skull base defects. Our primary aim is to evaluate the outcomes of patients undergoing complex lateral facial soft tissue, parotidectomy, and temporal bone defects who are reconstructed with the SIF to a similar cohort undergoing free tissue transfer reconstruction. MATERIALS AND METHODS: Nineteen patients undergoing SIF and 54 patients undergoing free tissue flaps for oncologic lateral facial, parotidectomy and temporal bone defects were retrospectively identified. Comparative statistics were used to analyze variables between the two cohorts, specifically operative time, flap size, length of stay, regional recurrence, disease free survival, and overall survival. RESULTS: No significant difference in demographic and disease related variables was observed. Operative time was significantly lower in SIF group with mean of 412.9 (SD 93.4) minutes compared to 544.1 (SD 139.9) minutes in free flap group. Flap size was significantly larger in free tissue transfer, 32.4 (SD 17.5) cm2 (SIF) compared to mean area of 105.2 (SD 53.2) cm2 (Free tissue transfer). A significant difference in length of stay was also noted between groups. There was no regional recurrence of disease in level I-III in SIF group. There was no significant difference in DFS or OS between the two groups. CONCLUSION: SIF is an oncologically sound option for reconstruction of lateral facial soft tissue, parotidectomy, and temporal bone defects. PMID- 29496051 TI - Baseline peripheral blood leukocytosis: Biological marker predicts outcome in oropharyngeal cancer, regardless of HPV-status. AB - OBJECTIVES: To study the prognostic value of abnormalities in baseline complete blood count in patients with oropharyngeal cancer (OPC) treated with (chemo) radiation. METHODS AND MATERIALS: The prognostic value of baseline complete blood count on outcome in 234 patients with OPC treated between 2010 and 2015 was examined in multivariate analysis together with other conventional prognostic variables including HPV-status, tumor stage, tumor and nodal size. RESULTS: The 3 year overall survival (OS), disease-free survival (DFS), locoregional control (LRC), and distant control (DC) of the whole group were 74%, 64%, 79%, and 88%, respectively. Leukocytosis and HPV-status were the only significant prognosticators for OS and DFS at the multivariate analysis. Patients without leukocytosis had a significantly better DC compared to those with leukocytosis (92% and 70%, respectively, p < 0.001). Patients with HPV-negative OPC had significantly worse LRC compared to HPV-positive patients (67% and 90%, respectively, p < 0.001). The 3-year OS in HPV-positive group with leukocytosis compared to those without leukocytosis were 69% and 95%, respectively (p < 0.001). The figures for HPV-negative patients were 41% vs. 61%, respectively (p = 0.010). CONCLUSIONS: This is the first study to date reporting the independent impact of leukocytosis and HPV-status on outcome of patients with OPC. The poor outcome of patients with leukocytosis is mainly caused by the worse DC. The significant impact of leukocytosis on outcome was even more pronounced in HPV positive patients. These biomarkers could help identifying patients with poor prognosis at baseline requiring intensification of local and/or systemic treatment while treatment de-intensification might be offered to the low-risk group. PMID- 29496052 TI - Proteome analysis reveals that de novo regenerated mucosa over fibula flap reconstructed mandibles resembles mature keratinized oral mucosa. AB - AIM: The aim of this study was to determine whether intra-oral de novo regenerated mucosa (D) that grew over free fibula flap reconstructed-mandibles resembled the donor tissue i.e. external skin (S) of the lateral leg, or the recipient site tissue, i.e. keratinized oral mucosa (K). MATERIALS AND METHODS: Differential proteome analysis was performed with ten tissue samples from each of the three groups: de novo regenerated mucosa (D), external skin (S), and keratinized oral mucosa (K). Expression differences of cornulin and involucrin were validated by Western blot analysis and their spatial distributions in the respective tissues were ascertained by immunohistochemistry. RESULTS: From all three investigated tissue types a total of 1188 proteins were identified, 930 of which were reproducibly and robustly quantified by proteome analysis. The best differentiating proteins were assembled in an oral mucosa proteome signature that encompasses 56 differentially expressed proteins. Principal component analysis of both, the 930 quantifiable proteins and the 56 oral mucosa signature proteins revealed that the de novo regenerated mucosa resembles keratinized oral mucosa much closer than extra-oral skin. Differentially expressed cornification-related proteins comprise proteins from all subclasses of the cornified cell envelope. Prominently expressed in intra-oral mucosa tissues were (i) cornifin-A, cornifin B, SPRR3, and involucrin from the cornified-cell-envelope precursor group, (ii) S100A9, S100A8 and S100A2 from the S100 group, and (iii) cornulin which belongs to the fused-gene-protein group. CONCLUSION: According to its proteome signature de novo regenerated mucosa over the free fibula flap not only presents a passive structural surface layer but has adopted active tissue function. PMID- 29496053 TI - RETRACTED: Systemic therapy in the management of metastatic or advanced salivary gland cancers. PMID- 29496054 TI - Influence of anemia and BMI on prognosis of laryngeal squamous cell carcinoma: Development of an updated prognostic model. AB - OBJECTIVE: evaluating the impact of anemia and body mass index (BMI) on survival, and development of a prognostic model for overall survival for patients with laryngeal squamous cell carcinoma (LSCC). MATERIALS AND METHODS: A retrospective cohort study was performed including all consecutive patients with LSCC diagnosed and treated at the Erasmus Medical Center between January 2006 and December 2013. Patient- and tumor-specific data were collected using data from the Netherlands Comprehensive Cancer Organization and supplemented with data from patient records available in the Erasmus MC. All comorbidities were scored at the time of diagnosis. RESULTS: in total 788 patients were included. Mean follow-up time was 50 months (SD: +/-30), during which 298 patients (37.8%) died. In both univariate and multivariate analysis BMI and anemia were significant predictors for overall survival. Multivariate analysis was performed using known predictors such as age, TNM-stage and comorbidity (ACE-27). The hazard ratio of anemia was 1.41 (95% CI: 1.05-1.90) and of BMI was 0.97 (95% CI: 0.94-0.99). BMI had an inverse association with overall survival in both univariate and multivariate survival analysis. Updating and validating an existing prognostic model with addition of anemia and BMI enhanced the performance of the prognostic model (C-statistic) from 0.77 (95% CI: 0.74-0.79) to 0.79 (95% CI: 0.77-0.82). CONCLUSION: anemia and BMI are predictors of overall survival for LSCC, independent of other known predictors of overall survival. Adding anemia and BMI to an existing prognostic model provides better prediction of overall survival. PMID- 29496055 TI - Three-dimensional printing of patient-specific surgical plates in head and neck reconstruction: A prospective pilot study. AB - BACKGROUND: Surgical plates have been extensively used in head and neck reconstruction and conventional plates are mass-produced with universal configurations. To overcome disadvantages of conventional surgical plates, we have been exploring patient-specific surgical plates using the three-dimensional (3D) printing technology. We hypothesized that the application of 3D-printed patient-specific surgical plates in head and neck reconstruction is feasible, safe and precise. METHODS: We are conducting a prospective clinical trial to assess the feasibility, safety and accuracy of applying 3D-printed patient specific surgical plates in head and neck reconstruction. The primary endpoint was the intraoperative success rate. Secondary endpoints included the incidence and severity of postoperative adverse events within six months postoperatively. The accuracy of surgical outcomes was also explored by comparing the planned and final positions of the maxilla, mandible and grafted bone segments. RESULTS: From December 2016 to October 2017, ten patients were enrolled and underwent head and neck reconstruction using 3D-printed patient-specific surgical plates. The patient-specific surgical plates adapted to bone surface precisely and no plate bending was performed. The intraoperative success rate was 100%. The average follow-up period was 6.5 months. No major adverse events were observed. The mean absolute distance deviation of integral mandible or maxilla was 1.40 +/- 0.63 mm, which showed a high accuracy of reconstruction. CONCLUSIONS: The 3D printing of patient-specific surgical plates could be effective in head and neck reconstruction. Surgical procedures were simplified. The precise jaw reconstruction was achieved with high accuracy. Long-term results with a larger sample size are warranted to support a final conclusion. The study protocol has been registered in ClinicalTrials.gov with a No. of NCT03057223. PMID- 29496056 TI - Role of sequential chemoradiotherapy in stage II and low-risk stage III-IV nasopharyngeal carcinoma in the era of intensity-modulated radiotherapy: A propensity score-matched analysis. AB - OBJECTIVES: To investigate the role of sequential chemoradiotherapy (SCRT; induction chemotherapy [IC] followed by intensity-modulated radiotherapy [IMRT]) in stage II and low-risk stage III-IV nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: Four well-matched groups were individually generated using propensity score matching in patients (n = 689) with stage II (SCRT vs. concurrent chemoradiotherapy [CCRT], SCRT vs. IMRT alone) and low-risk stage III IV NPC (SCRT vs. CCRT, SCRT vs. IC + CCRT). Five-year overall/disease free/locoregional relapse-free/distant metastasis-free survival (OS/DFS/LRRFS/DMFS) and acute hematological toxicities were compared between groups. The value of SCRT was further investigated in multivariate analysis and subgroup analysis by adjusting for covariates and limiting IC-to-IMRT time interval, respectively. RESULTS: SCRT led to equivalent survival outcomes compared to CCRT/IMRT alone and CCRT/IC + CCRT in stage II and low-risk stage III IV NPC, respectively (all P > .050). In multivariate analysis, patients with stage II NPC treated by SCRT obtained higher DMFS (AHR = 0.22, 95% CI = 0.05 1.00, P = .050), but not OS, DFS or LRRFS, compared to patients receiving CCRT; non-significant differences were observed between SCRT and other treatments. SCRT with short IC-to-IMRT time interval (<=70 days) achieved higher 5-year survival rates than IMRT alone (DMFS: P = .046), CCRT (stage II NPC; OS: P = .047; DMFS: P = .020) and IC + CCRT (DFS: P = .041). Moreover, SCRT was associated with higher, equivalent and lower frequencies of acute hematological toxicities than IMRT alone, CCRT and IC + CCRT, respectively. CONCLUSION: SCRT is mainly beneficial in stage II NPC, leading to better DMFS and/or equivalent acute hematological toxicities compared to CCRT/IMRT alone. CCRT is still the best choice for low risk stage III-IV NPC. PMID- 29496058 TI - Real time indocyanin green near infrared lymphangiography for the reduction of drainage volume after neck dissection. AB - BACKGROUND: To investigate the role of indocyanine green (ICG) lymphangiography in the reduction of drainage after neck dissection. METHODS: Patients with oral cavity squamous cell carcinoma were randomized into Group A (study group) and Group B (control). In the study group, upon the completion of neck dissection, a total of 2.5 mg of ICG was injected submucosally at the four quadrants around the tumour. Another 2.5 mg of ICG was injected subdermally in the groin bilaterally. The neck was screened using Near Infrared fluorescence. The presence of lymphatic leakage was noted and plicated with silk stitches. The total drainage volume of post-operative day 1, day 2 and the total accumulated volume until drain removal was measured. RESULTS: Twenty-two patients (Group A, n = 12; Group B, n = 10) were recruited. All patients in Group A had at least one site of lymphatic leakage identified. One patient in Group B developed chylous fistula and was excluded from analysis. The mean total drain output for day 1 and 2 after surgery, as well as the mean total output before drain removal, were significantly lower in Group A (22.4 ml vs. 86.2 ml [p = .02]; 14.2 ml vs. 72.8 ml [p = .02]; and 58.4 ml vs. 392 ml [p = .01], respectively), allowing earlier drain removal (2.2 days vs. 7.2 days, p = .02). CONCLUSIONS: Intra-operative ICG lymphangiography is useful in the reduction of drainage volume after neck dissection for caners in the head and neck region. PMID- 29496057 TI - Effect of adjuvant radiotherapy treatment center volume on overall survival. AB - OBJECTIVES: to examine the impact of radiotherapy center volume on overall survival in patients with oral cavity and oropharyngeal squamous cell carcinoma getting adjuvant radiation therapy after receiving surgery at a high-volume center. MATERIALS AND METHODS: a retrospective study was conducted on patients with oral cavity squamous cell carcinoma or oropharyngeal squamous cell carcinoma treated surgically at a tertiary institution from 2000 to 2012 who received adjuvant radiotherapy. The outcome variable was overall survival and the independent variable was location of adjuvant radiation therapy: high-volume center (HVC) versus low-volume center (LVC). Cox proportional hazards models were used to assess associations between predictors of death. Variables that were found to be significant at the alpha = 0.10 were included in a multivariable model. RESULTS: 336 patients met inclusion criteria. One-hundred thirty-nine patients received adjuvant radiation therapy at HVC and 197 patients received adjuvant radiation therapy at LVC. A univariate Cox proportional hazards model identified the variables location, age, marital status, subsite, T stage, extracapsular extension, and smoking status to include in a multivariable model. Age, subsite, T stage, and extracapsular extension were independent predictors of overall survival (p < .05). Location (p = .55), marital status (p = .29), and smoking status (p = .22) were not statistically significant predictors of survival. CONCLUSION: After surgery at a HVC, the volume of adjuvant radiation therapy center was not significantly associated with overall survival. Significant predictors of survival included age, subsite, T stage, and extracapsular extension. PMID- 29496059 TI - Phosphorylation of PI3K regulatory subunit p85 contributes to resistance against PI3K inhibitors in radioresistant head and neck cancer. AB - OBJECTIVES: PI3K/Akt/mTOR pathway is commonly activated in most cancers and is correlated with resistance to anticancer therapies such as radiotherapy. Therefore, PI3K is an attractive target for treating PI3K-associated cancers. MATERIAL AND METHODS: We investigated the basal expression and the expression after treatment of PI3K inhibitor or Src inhibitor of PI3K/Akt pathway-related proteins in AMC-HN3, AMC-HN3R, HN30 and HN31 cells by performing immunoblotting analysis. The sensitivity to PI3K inhibitors or Src inhibitor was analyzed by MTT assay and clonogenic assay. To determine the antitumoral activity of combination treatment with PI3K inhibitor and Src inhibitor, we used using xenograft mouse model. RESULTS: We found that PI3K regulatory subunit p85 was predominantly phosphorylated in radioresistant head and neck cancer cell line (HN31), which showed resistance to PI3K inhibitors. Next, we investigated mechanism through which PI3K p85 phosphorylation modulated response to PI3K inhibitors. Of note, constitutive activation of Src was found in HN31 cells and upon PI3K inhibitor treatment, restoration of p-Src was occurred. Src inhibitor improved the efficacy of PI3K inhibitor treatment and suppressed the reactivation of both Src and PI3K p85 in HN31 cells. Furthermore, downregulation of PI3K p85 expression by using a specific siRNA suppressed Src phosphorylation. CONCLUSIONS: Together, our results imply the novel role of the PI3K regulatory subunit p85 in the development of resistance to PI3K inhibitors and suggest the presence of a regulatory loop between PI3K p85 and Src in radioresistant head and neck cancers with constitutively active PI3K/Akt pathway. PMID- 29496060 TI - Do we need a different staging system for tongue and gingivobuccal complex squamous cell cancers? AB - OBJECTIVES: To determine the need for a separate staging system for gingivobuccal complex squamous cell cancers (GBCSCC) based on 5-year overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) data from one institution. PATIENTS AND METHODS: An Institutional Review Board (IRB)-approved retrospective analysis was performed on an oral cavity cancer patient database. Patients from 1985 to 2012 with primary surgical treatment for biopsy-proven squamous cell cancer (SCC) from either the oral tongue (TSCC Group) or gingivobuccal complex (GBCSCC Group), were selected as two separate subgroups. The clinicopathologic data were used to stage the patients based on the American Joint Committee on Cancer 7th edition. Survival outcomes including 5-year OS, RFS, and DSS were calculated and analyzed. A multivariate analysis was performed to identify if subsite was an independent predictor for the survival outcomes, adjusting for other variables. A p-value of less than .05 was considered statistically significant. RESULTS: 936 patients with TSCC and 486 patients with GBCSCC were considered eligible for the analysis. Patients with GBCSCC were more likely to be older (p < .001) and presented with more advanced disease (p < .001) compared to patients with TSCC. Unadjusted hazard ratio (HR) suggested GBCSCC had poor OS compared to TSCC. However, after adjusting for other variables, the adjusted HR was not significant (p = .593). There was no difference in 5-year DSS or RFS in either of the study groups. CONCLUSION: With similar survival outcomes by stage, there is no justification for using a different staging system for GBCSCC. PMID- 29496061 TI - Identification of a gene expression signature predicting survival in oral cavity squamous cell carcinoma using Monte Carlo cross validation. AB - OBJECTIVES: This study aims to identify a robust signature that performs well in predicting overall survival across tumor phenotypes and treatment strata, and validates the application of Monte Carlo cross validation (MCCV) as a means of identifying molecular signatures when utilizing small and highly heterogeneous datasets. MATERIALS AND METHODS: RNA sequence gene expression data for 264 patient tumors were acquired from The Cancer Genome Atlas (TCGA). 100 iterations of Monte Carlo cross validation were applied to differential expression and Cox model validation. The association between the gene signature risk score and overall survival was measured using Kaplan-Meier survival curves, univariate, and multivariable Cox regression analyses. RESULTS: Pathway analysis findings indicate that ligand-gated ion channel pathways are the most significantly enriched with the genes in the aggregated signature. The aggregated signature described in this study is predictive of overall survival in oral cancer patients across demographic and treatment strata. CONCLUSION: This study reinforces previous findings supporting the role of ion channel gating, interleukin, calcitonin receptor, and keratinization pathways in tumor progression and treatment response in oral cancer. These results strengthen the argument that differential expression of genes within these pathways reduces tumor susceptibility to treatment. Conducting differential gene expression (DGE) with Monte Carlo cross validation, as this study describes, offers a potential solution to decreasing the variability in DGE results across future studies that are reliant upon highly heterogeneous datasets. This improves the ability of studies reliant upon similarly structured datasets to reach results that are reproducible. PMID- 29496062 TI - Analysis of images for detection of oral epithelial dysplasia: A review. AB - This paper provides a review of various image analysis approaches that have been previously used for recognition of dysplasia in images of the epithelium of the oral cavity. This domain has become especially admissible with the uncovering of the importance of image analysis which can probably be an aid to subjective diagnosis by histopathologists. Oral malignancy is a rampant form of cancer found among people of the Indian subcontinent due to various deleterious habits like consumption of tobacco, areca nut, betel leaf etc. Oral Submucous Fibrosis, a precancer, whose pathological category falls between normal epithelium and epithelial dysplasia, is caused because of these habits and can ultimately lead to oral cancer. Hence early detection of this condition is necessary. Image analysis methods for this purpose have an enormous potential which can also reduce the heavy workload of pathologists and to refine the criterion of interpretation. This paper starts with a critique of statistics of oral carcinoma in India and distribution of cancer in intra-oral sites and moves on to its causes and diagnostic approaches including causative agents, problems in curative approach and importance of image analysis in cancer detection. The various image analysis methods to appraise the cytological and architectural changes accompanied by Oral Epithelial Dysplasia in the images of the oral epithelial region have been described in relation to 2005 WHO Classification System and it was found that in future, analysis of images based on the mentioned methods has the potential in better interpretation and diagnosis of oral carcinoma. PMID- 29496063 TI - Refining the eighth edition AJCC TNM classification and prognostic groups for papillary thyroid cancer with lateral nodal metastasis. AB - BACKGROUND: In the eighth edition, TNM staging system omits location of nodal metastasis as a criterion for staging patients with papillary thyroid cancer (PTC). Accordingly, all of non-metastatic N1b PTC patients are classified as stage I or II solely according to an age-cutoff of 55 years. We hypothesized that incorporating other lymph node (LN) factors into TNM staging system would better predict cancer-specific mortality (CSM) in N1b patients. METHODS: We enrolled 745 N1b PTC patients without distant metastasis. Alternative prognostic LN factors and cut-off points were assessed using Cox regression and time-dependent ROC analysis. Alternative prognostic groupings were derived based on minimal hazard differences for CSM among groups stratified by LN risk and age. We assessed accuracy of CSM prediction. RESULTS: Lateral LN ratio (LNR) >0.3 and largest LN size >3 cm were prognostic factors for CSM. Stage II patients (eighth edition) with LN risk (lateral LNR >0.3 or largest LN size >3 cm) had a much higher CSM rate (20.9%) than those in the same stage without LN risk (3.2%). Alternative prognostic grouping (Group 1, <55 years without LN risk; Group 2, <55 years with LN risk or >=55 years without LN risk; and Group 3, >=55 with LN risk) achieved higher proportions of variance explained (PVEs) for predicting CSM (10.7%) than those of the eighth edition TNM staging system (4.8%). CONCLUSIONS: The proposed grouping for N1b patients using LN risk can distinguish patients with poor prognosis from those with good prognosis better than the eighth edition TNM staging system. PMID- 29496064 TI - Prognostic significance and optimal candidates of primary tumor resection in major salivary gland carcinoma patients with distant metastases at initial presentation: A population-based study. AB - OBJECTIVES: To investigate the prognostic significance and identify optimal candidates of primary tumor resection (PTR) for patients with metastatic major salivary gland carcinoma (MaSGC) at diagnosis. MATERIALS AND METHODS: Patients with metastatic MaSGC were identified from the Surveillance, Epidemiology and End Results (SEER) database. Kaplan-Meier analyses, log-rank tests and multivariate Cox regression models were employed to evaluate the therapeutic roles of PTR in the overall cohort and different subgroups. RESULTS: Overall, 255 patients were included in our study, among whom 80 (31.4%) received PTR. PTR was associated with decreased overall mortality (OM) and cancer-specific mortality (CSM) in the overall cohort (PTR vs No-PTR, HR: 0.363, 95%CI: 0.204-0.646, p = .001 for OM; HR: 0.439, 95%CI: 0.243-0.794, p = .006 for CSM). When we focused on site specific metastases, receipt of PTR significantly reduced the risk of OM for patients with lung, bone or distant lymph node involvement (all p < .05), whereas this surgical procedure not only failed to bring survival benefit, but even seemed to insignificantly increase the mortality risk once liver metastases were presented (PTR vs No-PTR, HR: 1.109, 95%CI: 0.279-4.412 for OM; HR: 1.596, 95%CI: 0.364-7.004 for CSM). In addition, subgroup analyses showed that patients with stage T1-3 disease, younger age (<65), single-site metastases and high-risk pathologies might benefit from PTR. CONCLUSION: Our study for the first time verifies the favorable prognostic impact of PTR for highly-selected patients with metastatic MaSGC at diagnosis and has the potential to be adopted in future clinical practice, although long-term prospective studies are warranted. PMID- 29496065 TI - Neck recurrence in clinically node-negative oral cancer: 27-year experience at a single institution. AB - OBJECTIVES: Neck failure in patients with oral squamous cell carcinoma (OSCC) carries a poor outcome, yet the management of patients who initially present with clinically node-negative (cN0) neck is not clearly defined. PATIENTS AND METHODS: Retrospective review of patients with cN0 OSCC treated at Memorial Sloan Kettering Cancer Center from 1985 to 2012, focusing on rate, pattern and predictors of neck failure, salvage treatment, and survival outcomes. RESULTS: Of 1,302 patients, 806 (62%) underwent elective neck dissection (END) and 496 (38%) had observation. 190 patients (15%) developed neck recurrence. Median follow-up was 58.5 months (range 1-343); 5-year neck recurrence-free survival (NRFS) was 85% and 80% for the END and observation group respectively (p = .06). Patients with neck failure had poorer outcomes than patients without neck failure (5-year overall survival, 37% vs. 74% [p < .001]; disease-specific survival [DSS], 41% vs. 91% [p < .001]). Independent predictors of neck failure were smoking, primary tumor subsite (hard palate and upper gum), and extranodal extension. 87% of patients underwent salvage treatment (END: 81.1%; observation: 94%). Salvage surgery with adjuvant (chemo) radiation had better DSS than surgery alone or nonsurgical salvage. CONCLUSIONS: In our cohort of patients with initially cN0 OSCC triaged to END vs. observation using clinical parameters, 15% developed neck failure. Salvage treatment was feasible in most cases but survival was poorer compared to patients without neck failure. Surgery followed by adjuvant (chemo) radiation resulted in the best outcome. PMID- 29496066 TI - Impact of low dose settings on radiation exposure during pediatric fluoroscopic guided interventions. AB - PURPOSE: To evaluate the effects of lowering the detector entrance exposure in children undergoing interventional radiology procedures. MATERIALS AND METHODS: The study retrospectively investigated radiation dose levels in pediatric patients aged 0-18 years before (n = 39) and after (n = 26) lowering detector entrance dose, undergoing embolization of peripheral Arteriovenous malformations, Portal Vein Interventions or Percutaneous Transhepatic Cholangio Drainage (PTCD) between 2014 and 2017. Patient characteristics, fluoroscopy time, protocols used as well as resulting Skin Dose and Dose Area Product (DAP) were compared in each cohort. Image quality was assessed by two independent readers. RESULTS: The two patient cohorts did not differ in terms of patient demographics. Similarly, fluoroscopy time did not differ before and after implementation of the low dose settings. An overall reduction of skin dose of 75.1% for AVM embolizations, 80.5% for Portal Vein Interventions and 85.3% for PTCD placement was observed. The DAP decrease was 82.5% for AVM embolizations, 72.2% for Portal Vein Interventions and 79.8% for PTCD placement. Image quality was generally considered to be good with an insignificant difference between pre and post implementation of the low dose approach and good agreement between the two readers. Manual inroom-switching to higher dose levels was possible, however this was not performed more frequently after implementation of the low dose settings. CONCLUSION: Lowering the detector entrance dose in pediatric interventional radiology procedures results in a significant decrease of the radiation dose burden. PMID- 29496067 TI - Quantitative CT density histogram values and standardized uptake values of FDG PET/CT with respiratory gating can distinguish solid adenocarcinomas from squamous cell carcinomas of the lung. AB - PURPOSE: To assess the ability of parameters derived from computed tomography (CT) histograms and the maximum standardized uptake value (SUVmax) of 18F fludeoxyglucose-positron emission tomography/CT (FDG-PET/CT) images to distinguish solid lung adenocarcinomas from squamous cell carcinomas and to determine if these parameters are correlated. METHODS: This study comprised 43 consecutive patients with solid lung cancer (<3 cm in diameter), who underwent both plain chest CT and FDG-PET/CT (adenocarcinoma, n = 25; squamous cell carcinoma, n = 18). Density histograms of targeted lung cancers were created from chest CT images, and kurtosis and skewness were calculated. On FDG-PET/CT, the SUVmax without/with respiratory gating (RG) were calculated for each lesion. The values for the 4 parameters determined for patients in each diagnostic group were compared by the Mann-Whitney test. The diagnostic characteristics of the parameters were assessed by receiver operating characteristic (ROC) curve analysis. Differences between these parameters were assessed by the chi-square test. SUVmax with RG, kurtosis, and skewness were combined for binary logistic regression analysis, and the differences between the combined parameters and SUVmax with RG were also assessed. Spearman rank correlation analysis was used to determine the correlations for kurtosis or for skewness with SUVmax without/with RG. RESULTS: The differences in kurtosis and SUVmax without/with RG between the diagnostic groups were significant (kurtosis, P < 0.004; SUVmax without/with RG both P < 0.0001). ROC curve analysis indicated that each parameter (kurtosis value, skewness value, SUVmax, without/with RG) provided low-high ability to differentiate between 2 groups (area under the curve [AUC]: 0.760, 0.593, 0.900, 0.931, respectively). The ROC of the combined parameters provided the highest ability (AUC: 0.949). Both kurtosis and skewness were significantly correlated with SUVmax without/with RG. Kurtosis and SUVmax with RG were most strongly correlated (rho = 0.618). CONCLUSION: Quantitative CT histogram values and SUV assessment can differentiate solid lung adenocarcinomas from squamous cell carcinomas. Kurtosis and SUVmax values were strongly correlated. The addition of RG and further combination of the parameters improved the results. PMID- 29496068 TI - CT-guided radiofrequency ablation in patients with aneurysmal bone cysts. AB - INTRODUCTION: Aneurysmal bone cyst (ABC) is one of most therapeutic challenging lesions for orthopedic surgeons specially in large-sized lesions and lesions, which are very close to important neurovascular structures. In the present study, we express our experience in the treatment of aneurysmal bone cyst by radiofrequency thermal ablation (RFTA). METHODS: In the last two years, we have treated 20 cases (12 males & 8 females) presented with painful aneurysmal bone cysts in different anatomical locations, the age mean (+/-SD) is 18.95 +/- 8.02 years and median is 17.5 years, the mean size of the lesions (+/-SD) is: 32.25 +/ 7.15 mm & the median (range) is 33.5 mm (18.0-43.0) mm. The treatment was done by (RFTA) only in 11 cases and by (RFTA) with cementation in the other 9 cases, then the patients underwent close clinical follow-up for clinical symptoms by using visual analogue scale (VAS) pain score & radiological follow-up for one month, six months & one year after the procedure. RESULTS: Close follow-up for the patients proved that (RFTA) is a clinically successful &curative treatment as there was significant reduction in the mean (+/-SD) of the (VAS) pain score in all treated cases from 8.40 +/- 1.23 before the intervention to 0.20 +/- 0.41 at the end of follow-up period. No recorded post-procedural complications or recurrence during or at the end of the follow-up period. PMID- 29496069 TI - Prognostic value of radiologically enlarged lymph nodes in patients with metastatic colorectal cancer: Subgroup findings of the randomized, open-label FIRE-3/AIO KRK0306 trial. AB - PURPOSE: To determine the prognostic impact of radiologically enlarged lymph nodes >= 10 mm on the survival of patients with metastatic colorectal cancer. MATERIALS AND METHODS: The prospective, randomized, open-label FIRE-3/AIO KRK0306 trial evaluated the first-line therapy of patients with KRAS exon 2 wild-type metastatic colorectal cancer with fluorouracil, folinic acid and irinotecan plus either cetuximab or bevacizumab. In the RAS wild-type population (n = 400), adequately evaluable baseline computed tomographies (n = 339) were reviewed for enlarged regional and distant lymph nodes. Their prognostic relevance was retrospectively analyzed in uni- and multivariable Cox proportional hazard regressions. RESULTS: Median overall survival was 21.7 months in patients with enlarged lymph nodes and 33.2 months in patients without (hazard rate ratio [HR] = 1.61, 95% confidence interval [CI], 1.23-2.09; P < 0.001). This was confirmed in multivariable analysis (HR = 1.37, 95% CI, 1.02-1.83; P = 0.036). Progression free survival of patients with enlarged lymph nodes showed a consistent but insignificant trend (9.9 vs. 11.1 months; HR = 1.23, 95% CI, 0.98-1.54; P = 0.072). Enlarged lymph nodes were also associated with BRAF-mutations (P = 0.004). CONCLUSION: The presence of radiologically enlarged lymph nodes in baseline staging has a negative prognostic value beyond established and potential prognostic parameters. PMID- 29496070 TI - Correlation of size-dependent conversion factor and body-mass-index using size specific dose estimates formalism in CT examinations. AB - PURPOSE: The aim of this investigation is to establish the relationship between the size-dependent conversion factor (fsize) and the body-mass-index (BMI) and to test whether BMI can be substituted for the conventionally used patients' anterior-posterior (AP) and lateral (LAT) dimensions for calculation of fsize. By calculating fsize on the basis of BMI instead of the AP and LAT measurements, size-specific dose estimates (SSDE) could be determined prior to image acquisition. METHODS: Our institute utilizes a dose monitoring software to record radiation exposure during CT examinations. The datasets gathered during each examination contain information regarding the scan protocol, the volumetric computed tomography dose index (CTDIvol), SSDE and BMI. fsize is traditionally calculated through measurement of AP and LAT dimensions. In this work, the dose monitoring system calculates AP and LAT diameters at the middle of scout views. For purpose of this investigation, we used data from 13544 patients who underwent CT examinations of the torso, head or knee (both) to compare fsize as calculated from the AP and LAT dimensions to fsize calculated as a function of BMI. RESULTS: In the examinations of the torso, we observed an exponentially decreasing correlation between fsize and BMI. In the examinations of the head and knee (both), fsize reflected an almost independent behavior to BMI. CONCLUSION: This study demonstrates that it is possible to estimate fsize by using the patients' BMI for the torso as well as the head and knee CT, thereby enabling calculation of the probable SSDE prior to image acquisition on the basis of the presumed CTDIvol provided by the scanner. By providing information on the expected patient dose prior to image acquisition, this method is advantageous over the traditional calculation of fsize via the AP and LAT dimensions. PMID- 29496071 TI - MR imaging of hepatocellular adenomas on genotype-phenotype classification: A report from China. AB - PURPOSE: To investigate and compare the MR features between hepatocellular adenoma (HCA) subtypes in China, including preliminary observations on diffusion weighted imaging (DWI). METHODS: Thirty-six patients with 39 pathologically proven HCAs underwent gadopentetate dimeglumine enhanced MRI. The morphological and imaging features on T1, T2-weighted, dynamic-enhanced imaging and DWI were retrospectively evaluated and compared between four HCA subtypes, using Kruskal Wallis test, Fisher's exact test and Dunn-Bonferroni post hoc test. RESULTS: HCA frequently occurred in male (n = 19, 52.8%), lacked an association with oral contraceptives (n = 0), and had a relatively high incidence of coexistent Hepatitis B infection (n = 6, 16.7%). Signals on T1 and T2-weighted imaging, enhancement pattern and intensity, lesion heterogeneity, as well as accompanying findings including lesion steatosis, necrosis or cystic component, central scar, and pseudocapsule were different between HCA subtypes (P < .0001 to P = .019). Apparent diffusion coefficient (ADC) values among HCA subtypes were different as a whole (P = .029), within which beta-catenin-mutated HCA had the lowest ADCs; but post hoc comparisons demonstrated no significant differences between groups (P = .066-1.000). CONCLUSION: Both clinical and MR imaging presentation of HCA in China had some specific characteristics, and a good relationship existed between MR data and genotype-phenotype classification. Furthermore, ADC value may provide a potential indicator of malignant transformation. PMID- 29496072 TI - Image-guided percutaneous renal cryoablation: Five years experience, results and follow-up. AB - OBJECTIVES: To describe the experience of our institution in image-guided renal nodules percutaneous cryoablation, evaluating demographic and technical aspects as well as efficacy, safety and follow up. MATERIALS AND METHODS: Retrospective study approved by our institutional review board. Seventy-one renal tumors evaluated in 60 patients treated with image guided percutaneous renal cryoablation from January 2009 to December 2015. No patient was excluded from study, even those who were lost on follow up. All the procedures were guided both by ultrasound and tomography. An argon and helium based cryoablation machine was used for all treatments. Hydrodissection was performed when the bowel or ureters were within 1 cm (iodinated contrast media in dextrose solution). Complications were assessed by the terminology criteria of the National Institutes of Health (NIH). Patients were monitored and evaluated by ultrasound, tomography, MRI and/or PET-CT. RESULTS: In most procedures (91.9%) only one nodule was treated. Nodules had a median size of 1.6 cm. Most nodules (61,9%) were exophytic. Hydrodissection and retrograde warm pyeloperfusion were performed in most procedures. Among all variables evaluated in univariate analysis, nearness of nodule to collecting system and anterior/posterior location were significantly associated with PRCA complications. No other factor evaluated was significantly associated with complications. CONCLUSION: PRCA is solid alternative to traditional surgical therapies for treatment of small renal tumors in wide subset of patients. Medium term evidence shows excellent long-term oncological results, similar to nephrectomy, with minimal risk of major complications. PMID- 29496073 TI - The impact of reconstruction techniques on observer performance for the detection and characterization of small pulmonary nodules in chest CT of children under 13 years. AB - OBJECTIVE: To compare three different reconstruction techniques of CT data for the detection of pulmonary nodules in children under 13 years. Secondly to assess the prevalence of perifissural nodular opacities. MATERIALS AND METHODS: The study consisted of chest CTs of 31 children (median age 6.9 years, range 2.1 12.7), of whom 17 had known extra-thoracic malignancies. Four observers assessed three techniques for the presence of nodules: axial 5 mm maximum intensity projections (MIPs) used in conjunction with 1 mm slices (mode A), 1 mm slices alone (mode B) and 3 mm slices (mode C). All modes were available in 3D. Per mode sensitivities were determined above a certain threshold of reader agreement. Confidence level and reader agreement for identification of an opacity as nodule served as surrogate for quality of nodule characterization. RESULTS: 103 nodules (median size 2.0 mm) were detected. Mode A yielded the highest interreader agreement (kappa 0.336) and a superior sensitivity (71%, p = 0.003) compared to mode B and C (kappa 0.218, sensitivity 57% and kappa 0.247, sensitivity 56%, respectively). Mode B provided the highest confidence level and interreader agreement with respect to nodule identification (mean 4.3/5, kappaw 0.508). Double reading improved and evened interreader agreement for all modes (kappa 0.450), mode A maintained the highest sensitivity (89.1%, p = 0.05-0.08). A median of 1 intrapulmonary lymph node/patient was seen in children with and without malignancy. CONCLUSION: MIP improves the detection of pulmonary nodules in chest CTs of children, but overall interreader agreement is only fair. Double reading represents a powerful tool to increase diagnostic reliability in chest CTs of children with a malignancy. Nodule characterization is best with 1 mm slices. Intrapulmonary lymph nodes occur in children with and without malignancy. PMID- 29496074 TI - Computed tomographic thoracic morphologic indices in normal subjects and patients with chronic obstructive pulmonary disease: Comparison with spiral CT densitometry and pulmonary function tests. AB - OBJECTIVES: To determine what computed tomographic (CT) dimensions can predict obstructive lung disease on routine chest CT scans by comparing morphological and densitometric CT findings with pulmonary function test (PFT) in normal subjects and patients with chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS: Consecutive patients (n = 646; 260 females and 386 males; mean age 54.9 years, ranged 20-90 years) who received chest CT scans with densitometry during a 3-month period were retrospectively analyzed in single center. PFT was undertaken in 235 patients (152 males, 83 females) at same times of CT scanning. The patients were grouped by age (<30 years, 31-45 years, 46-60 years, and >61 years). CT parameters including tracheal, azygoesophageal, thoracic vertical, anterior-posterior (AP), transverse diameters, transverse cardiac diameter, diameters of main, right, and left pulmonary arteries, and CT densitometric values including lung volume and density (-900 to -1000 Hounsfield Units, HU), low attenuation value cluster (default threshold: -950 HU) were compared with PFT values. Spearman correlation coefficients was used to evaluate the relationship between the CT indices and PFT. RESULTS: Ninety of 235 patients with PFT were smokers (76 males, 14 females). Obstructive PFT was detected in 65 patients (27.7%: 46 males, 19 females). Male smokers with obstructive PFT displayed significantly larger thoracic anterior-posterior (mean: normal, 172.3 cm versus COPD, 185.9 cm, p = 0.0001) and smaller transverse diameters (mean: normal, 247.0 cm vs. COPD, 235.8 cm, p = 0.01), and increased right pulmonary artery diameter (mean: normal, 20.3 cm v s. COPD, 22.1 cm, p < 0.001), and increased left pulmonary artery diameter (mean: normal, 19.7 cm vs. COPD, 20.6 cm, p < 0.025). The lung parenchyma density (-1000 to -900 HU) and greater concentration of largest cluster on densitometry were significantly different between normal and obstructive PFT pattern in male smoker. Residual volume and total lung capacity are positively correlated with lung volume and lung density (-1000 to -800) of densitometry. CONCLUSIONS: CT findings of the overexpansion of the lungs, such as increases in the vertical diameter of the lung and decreases in the transverse diameter of the heart, can be significant as indirect findings of early chronic obstructive diseases. However, despite the significant CT findings in male smokers, particularly those in their 40s, most lung function parameters were not decidedly abnormal. PMID- 29496075 TI - Yttrium-90 radioembolization for unresectable metastatic neuroendocrine liver tumor: A systematic review. AB - OBJECTIVE: To evaluate the value of yttrium-90 (90Y) microspheres in the management of unresectable liver metastases secondary to neuroendocrine tumors (NETs). MATERIALS AND METHODS: PubMed, EMBASE, the Cochrane Database of Systematic Reviews, and the "gray" literature (Google Scholar) were searched for all studies related to 90Y therapy for unresectable liver metastases of NETs. RESULTS: A total of 11 studies and 7 abstracts involving 870 patients were included in the final analysis. In 11 of these studies, 19.8% (77/388) of patients had undergone transarterial bland embolization (TABE) or transarterial chemoembolization (TACE) before 90Y therapy. The median disease control rate among all patients was 86% at 3 months after 90Y therapy. The median survival was 28 months, with 1-, 2-, and 3-year survival rates of 72.5%, 57%, and 45%, respectively. The median survival values for patients who received resin- and glass-based 90Y treatment were 27.6 and 31.7 months, respectively. The survival values for patients with carcinoid, pancreatic, and unclassified origin of NETs were 56, 31, and 28 months, respectively; the survival values for patients with grade I, II, and III NETs were 71, 56, and 28 months, respectively. Carcinoid syndrome was reported in 52.4% (55/105) of patients, and 69.1% of those with clinical symptoms demonstrated improvement in symptoms after 90Y radioembolization. Complications were reported in 9 studies, including radiation gastritis (n = 4), duodenal ulcer (n = 2), death due to liver failure (n = 1), and radiation cholecystitis (n = 1). The most common side effects were abdominal pain (median, 32.6%), nausea/vomiting (median, 32.5%), and fatigue (median, 30.4%). CONCLUSIONS: 90Y radioembolization can be used as an alternative therapy for unresectable liver metastases of NETs, with an improved survival rate and tumor response. This treatment is also effective for patients who have undergone unsuccessful TABE/TACE therapy and for the relief of symptoms in patients with carcinoid syndrome. PMID- 29496076 TI - Measurement of normal fetal cerebellar vermis at 24-32 weeks of gestation by transabdominal ultrasound and magnetic resonance imaging: A prospective comparative study. AB - OBJECTIVES: Fetal cerebellar vermis may be assessed by ultrasound (US) or magnetic resonance imaging (MRI), and median-plane views are best for evaluation. The purpose of this study was to compare measurements of normal fetal vermis at 24-32 weeks of gestation obtained in median plane by transabdominal 2D-US, 3D-US, and MRI. METHODS: A prospective study was conducted, examining normal singleton fetuses between 24 and 32 weeks of gestation. Within a 24-h period, median-plane views of posterior fossa were generated using 2D-US, 3D-US, and MRI. Measurements of anteroposterior (AP) diameter, craniocaudal (CC) diameter, mid-sagittal surface area, brainstem-vermis (BV) angle and brainstem-tentorium (BT) angle were obtained to compare these imaging modalities. RESULTS: A total of 180 fetuses were studied. Correlation among imaging methods was good, marked by the following intraclass correlation coefficients: AP diameter, 0.955; CC diameter, 0.956; mid sagittal surface area, 0.982; BV angle, 0.810; and BT angle, 0.865 (p < 0.001). CONCLUSIONS: Visualization rates of MRI, 3D-US, and transabdominal 2D-US were decremental, MRI being superior in this regard. However, these three imaging modalities correlated well in measuring cerebellar vermis and its surroundings. PMID- 29496077 TI - Improved depiction of atherosclerotic carotid artery stenosis in virtual monoenergetic reconstructions of venous phase dual-layer computed tomography in comparison to polyenergetic reconstructions. AB - OBJECTIVES: To compare virtual monoenergetic images (VMI) reconstructed from venous phase Dual-Layer CT (DLCT) with polyenergetic images (PI) of DLCT Angiography (DLCT-A) regarding vessel contrast and image quality especially in sight to atherosclerotic carotid artery stenosis. METHODS & MATERIALS: 25 DLCT-A and 55 venous phase DLCT were analyzed in this retrospective study. For objective analysis PI and VMI (40-120 keV) were assessed comparing attenuation, standard deviation, signal-/contrast- to noise ratios (SNR, CNR) in the common carotid artery (CCA), vertebral artery, sternocleidomastoid muscle and air. For subjective analysis, vessel contrast, delineation of the superficial temporal artery, depiction of calcified plaque as well as vessel patency within the atherosclerotic stenosis of the internal carotid artery were rated and the extent of the calcified plaque and remaining vessel lumen were measured in venous phase DLCT. RESULTS: In venous phase DLCT, attenuation, SNR and CNR in the CCA increased with lower keV. Attenuation, SNR and CNR at 40 keV in the CCA were comparable to PI of DLCT-A (all: p > 0.05). Subjective image contrast, assessment of vessel patency within a stenosis as well as delineation of the superficial temporal artery were rated superior at 40-60 keV in comparison to PI of venous phase DLCT (all: p <= 0.05). Slightly more blooming of the atherosclerotic plaque was found in VMI at 40-60 keV. There was no difference of NASCET-criteria of carotid stenosis between VMI at different keV-levels and PI (p = 1.0). CONCLUSION: VMI at 40 keV reconstructed from venous phase DLCT yield an image quality equal to CT-Angiography, especially regarding vessel contrast. Perception and assessment of the carotid artery within an atherosclerotic stenosis are not impaired at low keV. PMID- 29496078 TI - Radiographic patterns of osteoporotic proximal humerus fractures. AB - OBJECTIVE: The objectives of the study were: a) to identify osteoporotic proximal humerus fractures in a large consecutive series of patients; b) to identify radiographic fracture patterns among osteoporotic and non-osteoporotic proximal humerus fractures; and c) to calculate intra- and inter-observer reliability of assessment of osteoporosis and of radiographic fracture patterns. METHODS: This was a prospective observational study of patients admitted to the emergency department affected by a proximal humerus fracture between June 2014 and June 2016. Three researchers evaluated demographic data and comorbidities, x-rays and CT-scans. A new evaluation method for assessment of osteoporosis was proposed; 7 radiographic fracture patterns were studied. Reliabilities between intra- and inter-tester evaluations, and correlations between the presence of osteoporosis and the 7 radiologic fracture patterns were calculated. RESULTS: Two hundred twenty-five patients with a humeral fracture were recruited. Their mean (26-95, 32) age was 58. Of those, 163 (72.4%) were identified as osteoporotic. Among the three raters, the intra- and inter-observer agreement using the proposed methods were high or excellent. Significant correlations with diagnosis of osteoporosis were found with Codman-Lego type 12(p = 0.041), metaphyseal comminution(p < 0.001), impaction of fragments(p = 0.023), comminution of tuberosities(p = 0.037), inferior subluxation(p = 0.029). Intra- and inter-tester reliability of evaluation of these osteoporotic fracture patterns were high. CONCLUSIONS: Osteoporosis of the proximal humerus was identified in 72% of patients during a two year period; most of these patients were elderly females sustaining low energy trauma. These fractures showed to have specific radiographic patterns, as comminution of metaphysis and tuberosities, impaction of fragments, and inferior subluxation of the humeral head. These patterns can be assessed with the simple observation of a 2-plan view of a radiograph, without the use of specific software. PMID- 29496079 TI - Comparison of computer-aided detection (CADe) capability for pulmonary nodules among standard-, reduced- and ultra-low-dose CTs with and without hybrid type iterative reconstruction technique. AB - PURPOSE: To directly compare the effect of a reconstruction algorithm on nodule detection capability of the computer-aided detection (CADe) system using standard dose, reduced-dose and ultra-low dose chest CTs with and without adaptive iterative dose reduction 3D (AIDR 3D). MATERIALS AND METHODS: Our institutional review board approved this study, and written informed consent was obtained from each patient. Standard-, reduced- and ultra-low-dose chest CTs (250 mA, 50 mA and 10 mA) were used to examine 40 patients, 21 males (mean age +/- standard deviation: 63.1 +/- 11.0 years) and 19 females (mean age, 65.1 +/- 12.7 years), and reconstructed as 1 mm-thick sections. Detection of nodule equal to more than 4 mm in dimeter was automatically performed by our proprietary CADe software. The utility of iterative reconstruction method for improving nodule detection capability, sensitivity and false positive rate (/case) of the CADe system using all protocols were compared by means of McNemar's test or signed rank test. RESULTS: Sensitivity (SE: 0.43) and false-positive rate (FPR: 7.88) of ultra-low dose CT without AIDR 3D was significantly inferior to those of standard-dose CTs (with AIDR 3D: SE, 0.78, p < .0001, FPR, 3.05, p < .0001; and without AIDR 3D: SE, 0.80, p < .0001, FPR: 2.63, p < .0001), reduced-dose CTs (with AIDR 3D: SE, 0.81, p < .0001, FPR, 3.05, p < .0001; and without AIDR 3D: SE, 0.62, p < .0001, FPR: 2.95, p < .0001) and ultra-low-dose CT with AIDR 3D (SE, 0.79, p < .0001, FPR, 4.88, p = .0001). CONCLUSION: The AIDR 3D has a significant positive effect on nodule detection capability of the CADe system even when radiation dose is reduced. PMID- 29496080 TI - Improving the prediction of lung adenocarcinoma invasive component on CT: Value of a vessel removal algorithm during software segmentation of subsolid nodules. AB - PURPOSE: To evaluate the value of a vessel removal algorithm in segmentation of subsolid nodules by comparing the software solid component measurement on CT, before and after vessel removal, with the measurement of the invasive component on pathology in lung adenocarcinomas manifesting as subsolid nodules. MATERIALS AND METHODS: Between January 2014 and June 2015, 73 subsolid nodules with an invasive component of <=10 mm on pathology were selected for analyses. For each nodule, semi-automated segmentation was performed by 2 radiologists and 3 dimensional (D) longest, axial longest and effective diameters of solid component were obtained from software, before and after using a vessel removal tool. These measurements were compared with the invasive component diameter on pathology using the paired t-test and Pearson's correlation test. RESULTS: Sixty-eight successfully segmented subsolid nodules were included. The mean maximal diameter of the invasive component on pathology was 4.6 mm (range, 0-10 mm). The correlation between software and pathology measurements was significant (p < 0.01) and the correlation after vessel removal (r = 0.49-0.54) was better than before vessel removal (r = 0.27-0.41). The mean measurement difference between solid component on CT and invasive tumor on pathology was significantly larger before vessel removal than after vessel removal in all measurements. The smallest mean measurement difference was obtained with 3D longest diameter of solid component after vessel removal in both readers (-0.26 mm to 0.10 mm), with no significant difference from pathology (p = 0.53-0.83). CONCLUSION: By adding a vessel removal algorithm in software segmentation of subsolid nodules, the prediction of invasive component in lung adenocarcinomas can be improved. PMID- 29496081 TI - The endovascular management of neurofibromatosis-associated aneurysms: A systematic review. AB - BACKGROUND: Neurofibroblastoma (NF) or Von Recklinghausen disease, is an autosomal dominant disorder affecting one in 3000 individuals. Cardinal features of NF include multiple cafe-au-lait macules, benign neurofibromas, and iris hamartomas. Albeit less common, vascular lesions of medium and large-sized arteries and veins are a well-recognized complication, which can lead to fatal consequences such as rupture. METHOD: A systematic review was conducted as per the Preferred Reporting Instructions for Systematic Reviews and Meta-analysis (PRISMA) guidelines utilizing PubMed, EMBASE, and Cochrane databases. RESULTS: There were 59 articles identified involving 66 patients (mean age 44.3 +/- 30 years), of which 89% had neurofibromatosis type 1. There were 63.6% of patients who presented with aneurysm rupture, 33.3% presented with intact symptomatic aneurysms, and 3.1% presented with intact asymptomatic aneurysms. Anatomically, 4.5% of patients suffered from intracranial aneurysms; 12.1% suffered from visceral artery aneurysms (including hepatic, superior mesenteric, gastroduodenal and renal arteries), and other patients suffered from aneurysms within the chest, abdomen, pelvis, upper limbs and neck. Amongst the various endovascular procedures, coiling was performed in 83.3% of cases. There were 12 covered stents employed in 10 patients (18.2%), of which 7 were balloon-expandable grafts; 2 were self-expandable graft; 3 were not mentioned. The rates of major and minor complications were 15% and 6% respectively, with 4 cases (6%) of perioperative death. On a mean follow-up of 15 months (range 1.5-72 months), two patients developed a distant vascular lesion from the treated lesion. CONCLUSION: Endovascular management is safe and effective even in hemodynamically unstable neurofibroblastoma patients at all ages. Vascular tree screening should be conducted in clinically suspicious patients to prevent fatal aneurysmal complications. A formal meta-analysis could not be performed due to the lack of randomized controlled trials. PMID- 29496082 TI - Preoperative detection of malignant liver tumors: Comparison of 3D-T2-weighted sequences with T2-weighted turbo spin-echo and single shot T2 at 1.5 T. AB - PURPOSE: To assess the performances of three-dimensional (3D)-T2-weighted sequences compared to standard T2-weighted turbo spin echo (T2-TSE), T2-half Fourier acquisition single-shot turbo spin-echo (T2-HASTE), diffusion weighted imaging (DWI) and 3D-T1-weighted VIBE sequences in the preoperative detection of malignant liver tumors. METHODS: From 2012 to 2015, all patients of our institution undergoing magnetic resonance imaging (MRI) examination for suspected malignant liver tumors were prospectively included. Patients had contrast enhanced 3D-T1-weighted, DWI, 3D-T2-SPACE, T2-HASTE and T2-TSE sequences. Imaging findings were compared with those obtained at follow-up, surgery and histopathological analysis. Sensitivities for the detection of malignant liver tumors were compared for each sequence using McNemar test. A subgroup analysis was conducted for HCCs. Image artifacts were analyzed and compared using Wilcoxon paired signed rank-test. RESULTS: Thirty-three patients were included: 13 patients had 40 hepatocellular carcinomas (HCC) and 20 had 54 liver metastases. 3D-T2-weighted sequences had a higher sensitivity than T2-weighted TSE sequences for the detection of malignant liver tumors (79.8% versus 68.1%; P < 0.001). The difference did not reach significance for HCC. T1-weighted VIBE and DWI had a higher sensitivity than T2-weighted sequences. 3D-T2-weighted-SPACE sequences showed significantly less artifacts than T2-weitghted TSE. CONCLUSION: 3D-T2 weighted sequences show very promising performances for the detection of liver malignant tumors compared to T2-weighted TSE sequences. PMID- 29496083 TI - Mammography image quality and evidence based practice: Analysis of the demonstration of the inframammary angle in the digital setting. AB - AIM: The aim of this study is to determine the clinical rates of the demonstration of the inframammary angle (IMA) on the mediolateral oblique (MLO) view of the breast on digital mammograms and to compare the outcomes with current accreditation standards for compliance. Relationships between the IMA, age, the posterior nipple line (PNL) and compressed breast thickness will be identified and the study outcomes validated using appropriate analyses of inter-reader and inter-rater reliability and variability. Differences in left versus right data were also investigated. METHOD: A quantitative retrospective study of 2270 randomly selected paired digital mammograms performed by BreastScreen NSW was undertaken. Data was collected by direct measurement and visual analysis. Intra class correlation analyses were used to evaluate inter- and intra-rater reliability. RESULTS: The IMA was demonstrated on 52.4% of individual and 42.6% of paired mammograms. A linear relationship was found between the posterior nipple line (PNL) and age (p-value <0.001). The PNL was predicted to increase by 0.48 mm for every one year increment in age. The odds of demonstrating the IMA reduced by 2% for every one year increase in age (p-value = 0.001); are 0.4% higher for every 1 mm increase in PNL (p-value = 0.001) and 1.6% lower for every 1 mm increase in compressed breast thickness, (p-value<0.001). There was high inter- and intra-rater reliability for the PNL while there was 100% agreement for the demonstration of the IMA. CONCLUSION: Analysis of the demonstration of the IMA indicates clinically achievable rates (42.6%) well below that required for compliance (50%-75%) to known worldwide accreditation standards for screening mammography. These standards should be aligned to the reported evidence base. Visualisation of the IMA is impacted negatively by increasing age and compressed breast thickness but positively by breast size (PNL). PMID- 29496084 TI - Quantitative computed tomography texture analyses for anterior mediastinal masses: Differentiation between solid masses and cysts. AB - OBJECTIVES: To investigate whether solid anterior mediastinal masses could be differentiated from cysts using quantitative computed tomography (CT) texture analyses in unenhanced CT (UECT) or contrast enhanced CT (CECT). MATERIALS AND METHODS: This clinical retrospective study included 76 UECT images (40 men and 36 women, 28 cystic (mean diameter, 29.5 mm) and 48 solid (mean diameter, 48.2 mm)) and 84 CECT images (45 men and 39 women, 26 cystic (mean diameter, 31.4 mm) and 58 solid (mean diameter, 51.4 mm)) of anterior mediastinal masses, which were diagnosed histopathologically or using imaging criteria. Polygonal regions of interest were placed on these masses. CT histogram analyses for images of masses with or without filtration (Laplacian of Gaussian filters with various spatial scaling factors) were performed. DeLong's test was performed to compare areas under the curve (AUC) with receiver operating characteristic analyses. RESULTS: From logistic regression analyses with a stepwise procedure, a combination of the mean in unfiltered images (mean0; i.e., CT attenuation) and mean in filtered images featuring coarse texture for UECT (AUC = 0.869) and the combination of mean0 and entropy in filtered images featuring fine texture for CECT (AUC = 0.997) were found to predict better the internal characteristics of anterior mediastinal masses. In UECT and CECT, diagnostic performance using these combinations tended to be high compared to mean0 alone (AUC = 0.780 [p = 0.033] and AUC = 0.983 [p = 0.130], respectively). CONCLUSION: Solid anterior mediastinal masses can be differentiated from cysts using quantitative CT texture analyses with moderate and high diagnostic performance in UECT and CECT, respectively. PMID- 29496085 TI - Efficacy and safety of radiofrequency ablation for lung cancers: A systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the efficacy and safety of radiofrequency ablation(RFA) for patients with lung cancers using meta-analysis. METHODS AND MATERIALS: A literature search (PubMed, Embase, Web of science and China National Knowledge Infrastructure) was undertaken until August 2017 to identify sufficient studies evaluating the efficacy and safety of RFA. Pooled proportions of estimates were calculated by performing the random effect model, including technical success rate, recurrence rate, local tumor progression rate and complications. RESULTS: A total of 25 eligible studies were collected, giving a sample size of 1989 patients with 3025 lung tumors. In the present series, the pooled technical success rate was 96%(95%CIs: 93%-100%). Further, we observed pooled recurrence rate of 35%(95%CIs: 12%-59%) following RFA. Additionally, the pooled rate of local tumor progression was 26%(95%CIs: 20%-32%). One hundred and ninety major complications of RFA were reported in 20 studies, giving a pooled proportion of 6% (95%CIs: 3%-8%) for major RFA complications. Pooled rate of minor complications was 27% (95%CIs:14%-41%). CONCLUSION: In this meta-analysis, RFA was found to be a safe and efficient treatment for the patients with lung cancers. The efficacy and safety of RFA for lung cancer deserve future investigation in further well-designed randomized controlled trials. PMID- 29496086 TI - Quantitative computed tomography applied to interstitial lung diseases. AB - OBJECTIVES: To evaluate a new image marker that retrieves information from computed tomography (CT) density histograms, with respect to classification properties between different lung parenchyma groups. Furthermore, to conduct a comparison of the new image marker with conventional markers. MATERIALS AND METHODS: Density histograms from 220 different subjects (normal = 71; emphysema = 73; fibrotic = 76) were used to compare the conventionally applied emphysema index (EI), 15th percentile value (PV), mean value (MV), variance (V), skewness (S), kurtosis (K), with a new histogram's functional shape (HFS) method. Multinomial logistic regression (MLR) analyses was performed to calculate predictions of different lung parenchyma group membership using the individual methods, as well as combinations thereof, as covariates. Overall correct assigned subjects (OCA), sensitivity (sens), specificity (spec), and Nagelkerke's pseudo R2 (NR2) effect size were estimated. NR2 was used to set up a ranking list of the different methods. RESULTS: MLR indicates the highest classification power (OCA of 92%; sens 0.95; spec 0.89; NR2 0.95) when all histogram analyses methods were applied together in the MLR. Highest classification power among individually applied methods was found using the HFS concept (OCA 86%; sens 0.93; spec 0.79; NR2 0.80). Conventional methods achieved lower classification potential on their own: EI (OCA 69%; sens 0.95; spec 0.26; NR2 0.52); PV (OCA 69%; sens 0.90; spec 0.37; NR2 0.57); MV (OCA 65%; sens 0.71; spec 0.58; NR2 0.61); V (OCA 66%; sens 0.72; spec 0.53; NR2 0.66); S (OCA 65%; sens 0.88; spec 0.26; NR2 0.55); and K (OCA 63%; sens 0.90; spec 0.16; NR2 0.48). CONCLUSION: The HFS method, which was so far applied to a CT bone density curve analysis, is also a remarkable information extraction tool for lung density histograms. Presumably, being a principle mathematical approach, the HFS method can extract valuable health related information also from histograms from complete different areas. PMID- 29496087 TI - Systemic Therapy for Colon Cancer. AB - Systemic treatments for patients with colon cancer has expanded broadly beyond 5 fluorouracil based chemotherapy. For early stage colon cancer patients who are considering adjuvant chemotherapy, multiple factors such as the risk of disease recurrence, absolute survival benefit of chemotherapy, treatment toxicity, and patient comorbid medical conditions must be taken into account. In the metastatic setting, biomarkers such as KRAS/NRAS/BRAF mutation, microsatellite instability status, and left- versus right-sided colon cancer have helped oncologists to tailor systemic treatment regimens, which include chemotherapy, targeted therapy, and immunotherapy. PMID- 29496091 TI - Minimally Invasive Surgical Approaches to Colon Cancer. AB - Colon cancer remains the most common abdominal visceral malignancy affecting both men and women in America. Open colectomy has been the standard of care for colon cancer patients the past 100 years; although highly effective, the major trauma associated with it has a significant morbidity rate and represents a large operation for patients to recover from. Minimally invasive colon surgery was developed as a new and alternative option, and surgeons aim to continue to make it simpler, more reproducible, and easier to teach and learn. We describe herein the current state of minimally invasive colorectal surgery for colon cancer and compare it with open surgery to offer insights to future directions. PMID- 29496090 TI - Colorectal Cancer:: Imaging Conundrums. AB - Progressive technological advancements in imaging have significantly improved the preoperative sensitivity for the detection of very small foci of regionally- or hematogenously-metastatic colorectal cancer. Unfortunately, this information has not translated to continued linear gains in patient survival, and might even result in the false-positive upstaging of some cases: these are two conundrums in the imaging of colorectal cancer. Both conundrums might be resolved by the widespread use of real-time imaging guidance during operative procedures. This might open the way for the widespread use of fluorodeoxyglucose PET/CT for the initial staging of patients with colorectal cancer. PMID- 29496092 TI - Population Screening for Hereditary Colorectal Cancer. AB - Colorectal cancer can be caused by hereditary cancer syndromes such as Lynch syndrome and the polyposis syndromes. Tumor screening for Lynch syndrome has been recommended by several professional organizations. In addition, it has been shown that patients with microsatellite unstable colorectal cancer can benefit from immunotherapy. Unfortunately, universal tumor screening for Lynch syndrome has not been implemented at all hospitals yet. More recent studies have found that the prevalence of all hereditary cancer syndromes is around 10%, and for those diagnosed under age 50, it is closer to 16%. It may be time to consider offering genetic counseling and testing to all colorectal cancer patients. PMID- 29496089 TI - Colon Cancer: Inflammation-Associated Cancer. AB - Colitis-associated cancer is a relatively rare form of cancer with an unclear pathogenesis. Colitis-associated cancer serves as a prototype of inflammation associated cancers. Advanced colonoscopic techniques are considered standard of care for surveillance in patients with long-standing colitis, especially those with other risk factors, including sclerosing cholangitis and a family history of colorectal cancer. When colitis-associated cancer is diagnosed, the standard operation involves total proctocolectomy. Restorative procedures and surveillance after colectomy require special considerations. In these contexts, new 3 dimensional human models may be used to usher in personalized medicine. PMID- 29496088 TI - Colon Cancer: What We Eat. AB - A higher incidence of colorectal cancer (CRC) is observed in Oceania and Europe, whereas Africa and Asia have a lower incidence. CRC is largely preventable by adapting a healthy lifestyle, such as healthy diet, adequate physical activity, and avoiding obesity. This review summarizes the latest work available, mainly epidemiologic studies, to examine the relationship between diet and CRC. Higher intake of red/processed meat could increase the CRC risk, whereas fibers, especially from whole grains and cereals, as well as fruit and vegetables may decrease the CRC risk. Heterogeneity and inconsistency among studies or individuals, however, need to be taken into consideration. PMID- 29496093 TI - The Economics of Colon Cancer. AB - The economic burden of cancer on the national health expenditure is billions of dollars. The economic cost is measured on direct and indirect medical costs, which vary depending on stage at diagnosis, patient age, type of medical services, and site of service. Costs vary by region, physician behavior, and patient preferences. When analyzing the economic burden of survivors of colon cancer, we cannot forget the societal burden. Post-acute care and readmissions are major economic burdens. People with colon cancer have to be followed for their lifetime. Economic models are being studied to give cost-effective solutions to this problem. PMID- 29496095 TI - Maximizing the Effectiveness of Colonoscopy in the Prevention of Colorectal Cancer. AB - Colonoscopy is a proven screening test for colorectal cancer; maximizing its effectiveness is the best way to decrease interval colorectal cancer. The adenoma detection rate can be improved by monitoring physician detection rates. Assistive devices and innovative endoscopic equipment may also decrease adenoma miss rates. Complete polypectomy of adenomatous lesions and recommending the proper date for the next examination are important considerations. Advanced polypectomy techniques including endoscopic mucosal resection and endoscopic mucosal dissection have a clear role in the nonsurgical management of large laterally spreading adenomatous polyps that previously would have required surgical resection. PMID- 29496094 TI - Clinical Trials and Progress in Metastatic Colon Cancer. AB - Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide but associated mortality has declined in recent decades. Genomic profiling of the disease has resulted in the definition of subsets of patients-for example, KRAS, NRAS, or BRAF mutated; Her2 amplified; and mismatch repair deficient-which has enabled personalization of therapeutic decision making. These subsets are guiding drug development and combination therapy approaches using both targeted therapies and immunotherapies. Further refinement based on molecular discoveries and the emergence of newer technologies to enable new discoveries allow for great optimism for the future on behalf of patients with colon cancer. PMID- 29496096 TI - Surgical Treatment of Metastatic Colorectal Cancer. AB - Surgical treatment of metastatic colorectal cancer offers a chance for cure or prolonged survival, particularly for those with more favorable prognostic factors and limited tumor burden. The treatment plan requires multidisciplinary evaluation because multiple therapy options exist. Advanced surgical techniques, adjuncts to resection, and modern chemotherapy all contribute to best outcomes for patients with hepatic metastases. Although cure is less common for patients with metastasis to lung or peritoneum, surgical resection for the former and cytoreduction and intraperitoneal chemotherapy for the latter may help to achieve cancer control in selected patients. PMID- 29496097 TI - Lymph Node Metastasis in Colorectal Cancer. AB - Pathologic examination of lymph nodes in patients with cancer remains crucial for postoperative treatment and prognosis prediction. In this article, the authors aim to review several important and challenging issues regarding lymph node metastasis in colorectal cancer using the AJCC staging manual, College of American Pathologists cancer protocol, as well as the literature. These topics include lymph node staging, the definition and controversies in tumor deposits, isolated tumor cells in lymph node and micrometastasis, lymph node ratio as a prognostic stratification factor, and neoadjuvant treatment effect in rectal cancer. Updates from the most recent AJCC 8th edition are included. PMID- 29496098 TI - Colon Cancer. PMID- 29496099 TI - Colon Cancer: The Road Traveled. PMID- 29496100 TI - Pilot study of the financial and practice protocol impacts of canine influenza virus (H3N2) outbreaks in example veterinary practices. AB - Since March 2015, canine influenza virus (CIV) H3N2 has caused widespread outbreaks in dogs across the USA. The effects of local H3N2 outbreaks on veterinary practices were investigated using an online interface and followed with phone calls to respondents when necessary. An outbreak was defined as confirmed diagnosis of H3N2 by either PCR or serology in at least four dogs. Of 30 practices invited to participate, five met the entry criteria: at least one documented H3N2 outbreak in the previous 12 months, a predominantly (>=70%) small animal caseload, and adequate financial records to complete the survey. Respondents reported 1-3 H3N2 outbreaks/practice over the last 12 months, with 4 8 dogs diagnosed/outbreak. For each participating practice, self-reported direct financial impact data was collected from the single H3N2 outbreak that involved the most dogs. The two most substantial categories of self-reported financial loss occurred due to boarding facility closure (estimated cost per practice: median $5000), and treatment costs borne by the practice (estimated cost per practice: median $2850). Median extra biosecurity costs were $300/practice. Median total direct costs of an H3N2 outbreak were $8945/practice. Lost foot traffic included cancelled appointments, appointments redirected to other veterinary hospitals for the duration of the outbreak, and loss of revenue from ancillary services provided during usual business (calculated cost per practice: median $450). Cost/practice normalized by the number of fulltime veterinarians in each practice was calculated and additional effects, such as interruptions to daily practice routine, reduced productivity, reputation loss and poor staff morale, were also reported. Vaccination against H3N2 was introduced as part of routine practice vaccination protocols or was made mandatory before boarding in three of five practices. In the remaining two practices, a focus on client education about canine infectious disease, especially H3N2, emerged in response to outbreaks. H3N2 outbreaks had substantial impacts on veterinary practice finances, daily routines and staff morale, and was associated with enhancements in vaccination, biosecurity and client education protocols. PMID- 29496101 TI - Seroprevalence and risk factors related to small ruminant lentivirus infections in Belgian sheep and goats. AB - Maedi-Visna virus (MVV) and caprine arthritis encephalitis virus (CAEV) are two prototype members of the group of small ruminant lentiviruses (SRLVs). Both result in progressive and persistent infections of sheep and goats that impact animal health and cause economic losses. In Belgium, the sheep and goat sector is small and consists mostly of hobbyist farmers keeping few animals. A voluntary control program however exists, but less than 2% of the farmers participate to the program. The current lack of SRLV seroprevalence data and knowledge on risk factors related to SRLV seropositivity in this hobbyist sector makes it difficult to evaluate the risk of SRLV transmission from non-certified to SRLV free certified farms. We performed a nationwide SRLV seroprevalence study based on a stratified sampling proportional to the number of sheep and goat holders per province. Randomly selected sheep and goat owners were invited to participate and subject to a short questionnaire to collect information about flock size, animal health condition, age, flock constitution and housing conditions. Samples were collected from maximum 7 animals per farm and tested in a commercial ELISA. In total, we received samples from 87 sheep and 76 goat farms. Sheep flocks showed an overall seroprevalence of 9% (CI 95%: 5-15) and a between-herd seroprevalence of 17% (CI 95%:11-27). Seroprevalence at animal level in goat flocks was 6% (CI 95%: 3-12) and the between-herd seroprevalence was 13% (CI 95%: 7-23). Multiple sheep and goat breeds were found SRLV seropositive. Answers provided during the questionnaire confirmed the mostly hobbyist nature of the sector and showed that more than 65% of sheep and goat farmers had never heard of the disease. The only risk factor found to be related to SRLV seroprevalence was flock size. Herds of more than 10 goats had significantly higher chance to harbor seropositive animals (OR: 4.36; CI: 1.07; 17.73). In conclusion, it was shown that participants to the SRLV free certification program are at risk for reintroduction of the disease in their herds since SRLVs are present on about 15%-20% of non-certified farms. Except from flock size, no clear risk factors were found that are helpfull to identify flocks at risk. Greater effort should be made to inform sheep and goat farmers about the existence and consequences of this disease in order to promote the voluntary control program and further reduce the disease prevalence. PMID- 29496102 TI - Estimating the potential for disease spread in horses associated with an equestrian show in Ontario, Canada using an agent-based model. AB - Participation in equestrian shows provides opportunities for contact between horses, increasing the risk of disease introduction and spread within the population. The magnitude of a potential outbreak, and the impact of disease prevention and control strategies, can be estimated using simulation modeling. The objectives of this study were to (1) examine the potential spread of equine influenza in a network of horses associated with a 2-day equestrian show in Ontario, Canada; and (2) determine the effectiveness of several interventions during a simulated outbreak. A discrete-event, continuous-time, stochastic agent based simulation model was constructed to represent horses associated with the show, including those in attendance at the show, and those that were not in attendance but co-boarded with attending horses at their home facilities. At the beginning of each simulation run, one random horse in attendance at the show was infected with equine influenza. In the absence of interventions, the median attack rate was 0.029 (IQR: 0.016-0.056; mean: 0.043; 95% CI: 0.040-0.044) and the average outbreak duration was 19.58 days (95% CI: 19.31-19.85). The most effective intervention was the implementation of either a 5-day or 14-day quarantine period, which both resulted in the same median attack rate of 0.0026 (IQR: 0.0013-0.0039), although the mean attack rates differed (mean: 0.0043, 95% CI: 0.0039-0.0046; and mean: 0.0029, 95% CI: 0.0028-0.0029; respectively). In instances where implementing either a 5-day or 14-day quarantine period would not be feasible, quarantine for shorter time periods was effective when combined with targeted increases in initial facility-level vaccine coverage. The combined implementation of a 2-day quarantine period and an increased vaccine coverage of 75% in facilities with four or more owners resulted in a median attack rate of 0.013 (IQR: 0.0052-0.026; mean: 0.022; 95% CI: 0.020-0.024). This study demonstrates a relative comparison of intervention effectiveness during a simulated outbreak of equine influenza in a population of horses associated with an equestrian show. The results have the potential to inform and improve the current strategies used to prevent the introduction and spread of disease within the equine population. PMID- 29496103 TI - African swine fever control and market integration in Ugandan peri-urban smallholder pig value chains: An ex-ante impact assessment of interventions and their interaction. AB - Pig production in peri-urban smallholder value chains in Uganda is severely constrained by impact of disease, particularly African swine fever (ASF), and the economic consequences of an inefficient pig value chain. Interventions in the form of biosecurity to control ASF disease outbreaks and pig business hub models to better link smallholder farmers to pig markets have the potential to address the constraints. However, there is a dearth of evidence of the effects of the interventions on performance and distribution of outcomes along the pig value chain. An ex-ante impact assessment utilising System Dynamics model was used to assess the impact of the interventions in peri-urban pig value chains in Masaka district. The results showed that although implementation of biosecurity interventions results in reduction of ASF outbreaks, it also leads to a 6.3% reduction in farmer profit margins per year but more than 7% increase in other value chain actors' margins. The pig business hub intervention alone results in positive margins for all value chain actors but minimal reduction in ASF outbreaks. When biosecurity and the pig business hub interventions are implemented together, the interaction effects of the interventions result in positive outcomes for both the control of ASF and improvement in farmers' margins. Farmers may therefore be unwilling to adopt biosecurity practices if implemented alone to control ASF outbreaks unless there is a corresponding financial incentive to compensate for the high costs. This has implications for policy or developing institutions to facilitate cost sharing arrangement among chain actors and/or third party subsidy to provide incentives for producers to adopt biosecurity measures. PMID- 29496104 TI - Validity of a two-stage cluster sampling design to estimate the total number of owned dogs. AB - Estimates of owned dog population size are necessary to calculate measures of disease frequency and to plan and evaluate population management programs. We calculated the error and bias of estimates of the total number of owned dogs using a two-stage cluster sampling design. The estimates were conditioned on sample composition as well as on size and heterogeneity of the spatial distribution of owned dog populations. For this, we simulated nine cities that differed systematically in size (number of census tracts) and heterogeneity (variance of the number of dogs per census tract). Then, we defined 16 scenarios to calculate the sample composition using an algorithm that incorporated data from a pilot sample, estimates of cost, and prior specifications of the expected error and confidence level. In three additional scenarios of predefined sample composition, the numbers of primary and secondary sampling units were: 30 * 30, 50 * 20 and 65 * 15. Finally, for each city and sample composition, we selected primary sampling units (census tracts) with probability proportional to its size and with replacement, and secondary sampling units (households) by simple random sampling. For each city and composition we selected 500 samples, totaling 85500 samples. The distribution of errors conditioned on the sample composition and city showed that estimates were accurate (average mean bias = 0.006%, maximum mean bias = 0.3%). All sample compositions resulted in errors between 4% and 7% in cities with low heterogeneity. In cities with high heterogeneity, the errors for the various compositions ranged as follows: 8-11% (calculated), 11-13% (65 * 15), 12-14% (50 * 20) and 15-17% (30 * 30). The sample size of predefined compositions was between 33% and 87% lower than the sample size of calculated compositions. Therefore, the predefined compositions have an operational advantage (reduced sampling effort) and simplify the sampling design (calculation of sample composition is not needed). Furthermore, the expected error of estimates under different scenarios is known for each predefined composition. In the absence of information about the heterogeneity of the cities, the 65 * 15 is the more conservative composition. PMID- 29496105 TI - Influence of phytogenic feed additive on Lawsonia intracellularis infection in pigs. AB - Lawsonia intracellularis is known to cause proliferative enteropathy (PE), one of the economically most important swine diseases with global distribution. Not unlike other enteric diseases, PE is a frequent indication for antibiotic therapy. However, their unjustified use leads to an emerging problem - antimicrobial resistance. Thus, the aim of this research was to assess if a phytogenic additive may replace antibiotics in the control of PE in 144 weaned piglets (72 treated and 72 controls) naturally infected with L. intracellularis. The quantity of L. intracellularis faecal shedding was monitored by real-time polymerase chain reaction (PCR) assay in faecal samples on day 0, 14 and 28, whilst the level of the ileum damage was determined by immunohistochemistry (IHC) assay performed on gut sections. Real-time PCR assay revealed that cycle threshold (Ct) values in the treatment group increased significantly over time and were higher than in the control. These results indicate that the use of the phytogenic additive decreases the faecal excretion of L. intracellularis both throughout the experiment and in comparison to the control. The expression of the L. intracellularis antigen in IHC assay was lower in treated animals, implying that the additive leads to the decrease in the pathogen quantity in the ileum. Significantly higher feed conversion ratio was recorded in the treatment group. The results indicate that the phytogenic additive may be beneficial in the control of PE, but additional research is necessary to assess its use in various pig categories and define the optimum concentrations. PMID- 29496106 TI - Economic impact of university veterinary diagnostic laboratories: A case study. AB - Veterinary diagnostic laboratories (VDLs) play a significant role in the prevention and mitigation of endemic animal diseases and serve an important role in surveillance of, and the response to, outbreaks of transboundary and emerging animal diseases. They also allow for business continuity in livestock operations and help improve human health. Despite these critical societal roles, there is no academic literature on the economic impact of VDLs. We present a case study on the economic impact of the Iowa State University Veterinary Diagnostic Laboratory (ISUVDL). We use economic contribution analysis coupled with a stakeholder survey to estimate the impact. Results suggest that the ISUVDL is responsible for $2,162.46 million in direct output, $2,832.45 million in total output, $1,158.19 million in total value added, and $31.79 million in state taxes in normal years. In an animal health emergency this increases to $8,446.21 million in direct output, $11,063.06 million in total output, $4,523.70 million in total value added, and $124.15 million in state taxes. The ISUVDL receives $4 million annually as a direct state government appropriation for operating purposes. The $31.79 million in state taxes in normal years and the $124.15 million in state taxes in an animal health emergency equates to a 795% and 3104% return on investment, respectively. Estimates of the economic impact of the ISUVDL provide information to scientists, administrators, and policymakers regarding the efficacy and return on investment of VDLs. PMID- 29496107 TI - Epidemiological survey of equine influenza in Andalusia, Spain. AB - Equine influenza is a highly contagious respiratory disease considered the most important respiratory disease in equids. Although influenza A virus (IAV) has caused outbreaks in equids worldwide, surveillance in these species in Spain has not been conducted. A cross-sectional study was carried out to determine the individual and herd prevalence of antibodies against H3N8 and H7N7 IAV in equids in Andalusia (southern Spain). Antibodies againsts IAV were measured by the single radial haemolysis assay. A spatial scan statistical analysis was carried out using a Bernoulli model. Risk factors associated with IAV infection were assessed by multivariate analysis. Antibodies to H3N8 IAV were detected in 241 out of 464 unvaccinated equids (51.9%; 95% CI: 47.4-56.5). Seropositivity against the H7N7 subtype IAV was not found in any of the analysed animals. Significantly higher seropositivity was found in geriatric (OR = 6.1, P = 0.008, 95% CI = 1.6 23.1) and adult (OR = 4.8, P < 0.001, 95% CI = 2.5-9.0) equids compared to young animals. Specific antibodies against A/equine/Shropshire/2010 (H3N8) or A/equine/Newmarket/5/2003 (H3N8) only were confirmed in 11 and 45 of the animals, respectively. The spatial analysis showed a statistically significant cluster centred in the west part of Andalusia. The results confirmed widespread H3N8 subtype IAV exposure in equine species in Andalusia. Conversely, the absence of seropositivity against H7N7 IAV obtained in the present study suggests that this subtype has not circulated in southern Spain in recent years. Because of the animal health and economic consequences of IAV in equids, further surveillance and molecular studies are required to monitor and characterize the most prevalent IAV circulating in these species in Spain. PMID- 29496108 TI - A systematic review of current immunological tests for the diagnosis of cattle brucellosis. AB - Brucellosis is a worldwide extended zoonosis with a heavy economic and public health impact. Cattle, sheep and goats are infected by smooth Brucella abortus and Brucella melitensis, and represent a common source of the human disease. Brucellosis diagnosis in these animals is largely based on detection of a specific immunoresponse. We review here the immunological tests used for the diagnosis of cattle brucellosis. First, we discuss how the diagnostic sensitivity (DSe) and specificity (DSp), balance should be adjusted for brucellosis diagnosis, and the difficulties that brucellosis tests specifically present for the estimation of DSe/DSp in frequentistic (gold standard) and Bayesian analyses. Then, we present a systematic review (PubMed, GoogleScholar and CABdirect) of works (154 out of 991; years 1960-August 2017) identified (by title and Abstract content) as DSe and DSp studies of smooth lipopolysaccharide, O-polysaccharide core, native hapten and protein diagnostic tests. We summarize data of gold standard studies (n = 23) complying with strict inclusion and exclusion criteria with regards to test methodology and definition of the animals studied (infected and S19 or RB51 vaccinated cattle, and Brucella-free cattle affected or not by false positive serological reactions). We also discuss some studies (smooth lipopolysaccharide tests, protein antibody and delayed type hypersensitivity [skin] tests) that do not meet the criteria and yet fill some of the gaps in information. We review Bayesian studies (n = 5) and report that in most cases priors and assumptions on conditional dependence/independence are not coherent with the variable serological picture of the disease in different epidemiological scenarios and the bases (antigen, isotype and immunoglobulin properties involved) of brucellosis tests, practical experience and the results of gold standard studies. We conclude that very useful lipopolysaccharide (buffered plate antigen and indirect ELISA) and native hapten polysaccharide and soluble protein tests exist, provided they are applied taking into account the means available and the epidemiological contexts of this disease: i) mass vaccination; ii) elimination based on vaccination combined with test-and-slaughter; and iii) surveillance and existence of false positive serological reactions. We also conclude that the insistence in recent literature on the lack of usefulness of all smooth lipopolysaccharide or native hapten polysaccharide tests in areas where S19 vaccination is implemented is a misinterpretation that overlooks scientific and practical evidence. PMID- 29496109 TI - Detection and characterization of Cryptosporidium species and genotypes in three chicken production systems in Brazil using different molecular diagnosis protocols. AB - The objective of this study was to determine the occurrence of Cryptosporidium spp. in domestic chickens raised in different chicken production systems in Brazil using three nested PCR protocols. The purification and concentration of oocysts present in 190 fecal samples from chickens raised in extensive, semi intensive and intensive production systems were accomplished by centrifugal flotation in Sheather's solution and were followed by the extraction of genomic DNA. The detection and molecular characterization of Cryptosporidium species and genotypes were performed using three nested polymerase chain reaction (nested PCR) protocols targeting the 18S rRNA gene followed by sequencing of the amplified fragments. Subgenotyping of C. meleagridis was performed using a nested PCR reaction targeting the gp60 gene. Sample identified as Cryptosporidium sp. genetically similar to Cryptosporidium xiaoi and Cryptosporidium bovis by 18S rRNA gene sequencing were further analyzed by nested PCR targeting the actin gene and subsequent sequencing of the amplified fragment. Positive amplification for Cryptosporidium spp. was observed in 12.6% (24/190) of the samples, including C. baileyi (9.8%; 18/190), C. meleagridis (0.5%, 1/190), C. parvum (2.1%; 4/190) and Cryptosporidium sp. (0.5%; 1/190). Subgenotyping of C. meleagridis revealed the presence of the zoonotic subtype IIIgA23G3R1. Sequencing of the 18S rRNA gene and the actin gene fragments revealed a Cryptosporidium genotype in an extensive poultry system genetically related to C. xiaoi and C. bovis. There was no significant difference in the frequency of positive results obtained by the three nested PCR protocols (p > 0.05); additionally, the agreement obtained by Kappa index ranged from substantial (0.70) to almost perfect (0.9). PMID- 29496110 TI - Cow- and herd-level factors associated with lameness in small-scale grazing dairy herds in Brazil. AB - This cross-sectional study aimed to assess lameness occurrence and to identify the associated risk factors in small-scale grazing dairy herds. Forty four farms (mean lactating herd size was 42 cows, SD = 11.2, range: 28-74) located in the south of Brazil were visited twice, approximately 4 months apart, in 2015. Locomotion was scored in 1633 and 1836 cows at the first and second visit, respectively. Potential risk factors for lameness were assessed through inspection of cows and facilities, and a questionnaire for farmers about herd management practices. Multilevel logistic regressions, using herd as random effect, were fitted to investigate the cow-level risk factors for accumulated incident (not lame at the first visit but lame on the second), chronic (lame on both visits) and recovered (lame at the first visit but sound on the second) cases of lameness. A multilevel linear regression, using municipality as a random effect, was fitted for herd-level analysis. Cumulative lameness incidence between two visits (1110 cows in 41 herds) was 29.6% (range: 0-80); lameness prevalence (n = 44 herds) was 31% (10-70) and 35% (5-76) at the first and second visits, respectively. The odds of incident cases were greater in Holstein cows [odds ratio (OR) = 4.0, 95% confidence interval 2.1-7.6] compared with Jerseys, in cows in parities 2-3 (OR 2.5, 1.4-4.4) or >3 (OR 6.6, 3.3-13.1) relative to parity 1, in cows having a low body condition score (BCS) of 2-2.75 or 3 on the first visit (OR 2, 1.1-3.7), and in cows with observed hoof abnormalities (OR 2.5, 1.3-4.7). Similar associations were found for chronic cases, with Holstein and crossbred cows having greater odds of lameness, compared to Jersey, and chronic cases being more likely in cows with increasing parity, with BCS at first visit of 2-2.75, and with presence of hoof abnormalities. Jersey or crossbred cows (OR 3.2, 1.3 8.1) and cows in parity 1-2 (OR 3.6, 1.6-8.4) had higher probability of recovery from lameness. Having a herd composed of Holstein cows was associated with 13.5% (CI 4.3-22.8) greater incidence of lameness (n = 35). For every 1 km/h increase in the average speed of movement of the herd to or from milking, lameness incidence increased by 5% (CI 0.1-10). Given that the occurrence of lameness was high there is great opportunity to reduce lameness in this population. This study highlights some management and prevention practices that may reduce lameness in these grazing herds. PMID- 29496111 TI - Interactions between the Immune and Nervous systems in Nervous System Development, Diseases and Repair Processes. PMID- 29496112 TI - Special issue on computational models of hearing. PMID- 29496114 TI - Erratum. PMID- 29496113 TI - Toxoplasma secretory granules: one population or more? PMID- 29496115 TI - Erratum. PMID- 29496116 TI - Is Predilation Necessary to Help the Lotus Bloom? PMID- 29496117 TI - Erratum to 'Ltb4r1 inhibitor: A pivotal insulin sensitizer?': [Trends in Endocrinology and Metabolism, May 2015, Vol. 26, No. 5, 221-222]. PMID- 29496118 TI - Erratum to 'Tyrosine Kinase Inhibitors and Diabetes: A Novel Treatment Paradigm?': [Trends in Endocrinology & Metabolism 26 (2015) 643-656]. PMID- 29496119 TI - Because That's Where the Kids Are: Willie Sutton's First-Grade Teacher on Why She Taught School. PMID- 29496120 TI - Adults With Childhood-Onset Schizophrenia and Their Siblings: Do Age of Onset and Familiality Affect Performance on and the Neural Signature of Working Memory Tasks? PMID- 29496121 TI - Executive Function and Genomic Risk for Attention-Deficit/Hyperactivity Disorder: Testing Intermediate Phenotypes in the Context of Polygenic Risk. PMID- 29496122 TI - Pediatric Irritability Comes of Age. PMID- 29496123 TI - Prenatal Selective Serotonin Reuptake Inhibitor Exposure and Child Neurodevelopment: The Importance of Maternal Mental Illness. PMID- 29496124 TI - The Effectiveness of School-Based Mental Health Services for Elementary-Aged Children: A Meta-Analysis. AB - OBJECTIVE: Given problems and disparities in the use of community-based mental health services for youth, school personnel have assumed frontline mental health service roles. To date, most research on school-based services has evaluated analog educational contexts with services implemented by highly trained study staff, and little is known about the effectiveness of school-based mental health services when implemented by school professionals. METHOD: Random-effects meta analytic procedures were used to synthesize effects of school-based mental health services for elementary school-age children delivered by school personnel and potential moderators of treatment response. Forty-three controlled trials evaluating 49,941 elementary school-age children met the selection criteria (mean grade 2.86, 60.3% boys). RESULTS: Overall, school-based services demonstrated a small-to-medium effect (Hedges g = 0.39) in decreasing mental health problems, with the largest effects found for targeted intervention (Hedges g = 0.76), followed by selective prevention (Hedges g = 0.67), compared with universal prevention (Hedges g = 0.29). Mental health services integrated into students' academic instruction (Hedges g = 0.59), those targeting externalizing problems (Hedges g = 0.50), those incorporating contingency management (Hedges g = 0.57), and those implemented multiple times per week (Hedges g = 0.50) showed particularly strong effects. CONCLUSION: Considering serious barriers precluding youth from accessing necessary mental health care, the present meta-analysis suggests child psychiatrists and other mental health professionals are wise to recognize the important role that school personnel, who are naturally in children's lives, can play in decreasing child mental health problems. PMID- 29496126 TI - Working Memory and Vigilance as Multivariate Endophenotypes Related to Common Genetic Risk for Attention-Deficit/Hyperactivity Disorder. AB - OBJECTIVE: Understanding the role of endophenotypes is essential for process models of psychopathology. This study examined which candidate cognitive endophenotypes statistically mediate common variant genetic risk for attention deficit/hyperactivity disorder (ADHD). METHOD: A case-control design using community-recruited volunteer children 7 to 11 years of age (n = 656, n = 435 ADHD), of whom 514 were of homogenous European ancestry for the primary models (n = 337 ADHD, 177 non-ADHD). Children were assessed with a multi-informant, best estimate diagnostic procedure and laboratory measures of working memory, response inhibition, executive functioning, arousal/attention, temporal information processing, and processing speed. Latent variables were created for the candidate cognitive measures and for parent- and teacher-rated ADHD dimensions. Polygenic risk scores (PGS) were computed using a discovery sample of 20,183 individuals with ADHD and 35,191 controls from the Psychiatric Genetics Consortium. Cognitive measures that survived multiple testing correction for association with the PGS were evaluated for mediation with ADHD using structural equation models. RESULTS: Results were essentially identical in the homogeneous European ancestry subgroup (n = 514) and in the full sample (N = 656). For the European population, the PGS was associated with ADHD diagnosis (Nagelkerke R2 = 0.045; beta = 0.233, SE = 0.053, p = .000011) and multi-indicator dimensional ADHD latent variables by parent report (beta = 0.185, SE = 0.043) and teacher report (beta = 0.165, SE = 0.042). The PGS effect was statistically mediated by working memory (indirect effect, beta = 0.101, SE = 0.029, 95% CI = 0.05, 0.16, p = .00049, 43% of genetic effect accounted for) and arousal/alertness (indirect effect beta = 0.115, 95% CI = 0.04, 0.20, SE = 0.041, p = .005, 49% of genetic effect accounted for). CONCLUSION: This is the first clear demonstration from molecular genetic data that working memory and arousal regulation are promising cognitive endophenotypes for ADHD with regard to mediating genetic risk from common genetic variants. PMID- 29496125 TI - Reduced Functional Brain Activation and Connectivity During a Working Memory Task in Childhood-Onset Schizophrenia. AB - OBJECTIVE: Working memory (WM) deficits are consistently reported in schizophrenia and are related to poor functional outcomes. Functional magnetic resonance imaging studies of adult-onset schizophrenia have reported decreased functional activations and connectivity in the WM network, but no prior functional magnetic resonance imaging study has examined WM in childhood-onset schizophrenia (COS). The aim of this study was to examine the neural correlates of WM in COS. METHOD: Adult patients with COS (n = 32, 21.3 +/- 1.1 years), nonpsychotic siblings of patients with COS (n = 30, 19.4 +/- 0.8 years), and healthy controls (n = 39, 20.0 +/- 0.7 years) completed 1- and 2-back WM tasks during 3-T functional magnetic resonance imaging. Functional activation and connectivity analyses were conducted. A separate group of 23 younger patients with COS (17.9 +/- 7.4 years) could not perform the tasks after twice completing a standard training and are not included in this report. RESULTS: Patients with COS who were included scored significantly lower than controls on all tasks (p < .001). Patients with COS showed significantly lower activations in the dorsolateral prefrontal cortices, posterior parietal cortices, cerebellum, and caudate and decreased frontoparietal and corticostriatal functional connectivity compared with controls (p < .05, corrected). Siblings had functional activations and connectivity intermediate between those of patients and controls in a similar set of regions (p < .05, corrected). In patients, functional connectivity strength in the left frontoparietal network correlated positively with accuracy scores during the 1-back task (p = .0023, corrected). CONCLUSION: Decreased functional activation and connectivity in the WM network in COS supports pathophysiologic continuity with adult-onset schizophrenia. The low participation rate and accuracy of the patients highlights the disease severity of COS. Hypo activations and hypo-connectivity were shared by siblings of patients with COS, suggesting COS as a potential endophenotype. CLINICAL TRIAL REGISTRATION INFORMATION: Evaluating Genetic Risk Factors for Childhood-Onset Schizophrenia; http://ClinicalTrials.gov;NCT00001198. PMID- 29496127 TI - Early Childhood Adverse Experiences, Inferior Frontal Gyrus Connectivity, and the Trajectory of Externalizing Psychopathology. AB - OBJECTIVE: Early adverse childhood experiences (ACEs) have been linked to the development of both internalizing and externalizing psychopathology. In our prior work, we found that ACEs predicted reductions in the volume of the inferior frontal gyrus (IFG), a brain region important for impulse control and emotion regulation. Here we tested the hypothesis that ACEs might influence child behavioral outcomes through an impact on IFG functional connectivity, which may influence impulsive or risk-taking behavior. METHOD: We examined the effects of prospectively assessed ACEs on IFG connectivity in childhood, and their relationship to the trajectory of subsequent psychopathology from late school age and early adolescence, using data from an 11-year longitudinal study of children starting in preschool that included 3 waves of resting state functional connectivity across childhood and early adolescence. RESULTS: ACEs predicted functional connectivity of both left and right IFG. Multi-level modeling of symptoms across 3 waves of assessments indicated that more ACEs predicted both internalizing and externalizing symptoms. However, altered IFG connectivity specifically predicted greater externalizing symptoms over time in middle childhood and early adolescence, as compared to internalizing symptoms. Longitudinal modeling indicating that the relationships between externalizing and functional connectivity were maintained across 3 waves of functional connectivity assessment. CONCLUSION: These findings underscore the relationship of ACEs to later psychopathology, and suggest that connectivity of the IFG, a region known to play an important role in impulse control and emotion regulation, may play a key role in the risk trajectory of ACEs to externalizing problems. However, further work is needed to understand whether these relationships reflect a direct effect of ACEs or whether ACEs are a marker for other environmental or genetic factors that may also influence brain development and behavior. PMID- 29496128 TI - Identifying Clinically Significant Irritability in Early Childhood. AB - OBJECTIVE: Advances in developmentally sensitive measurement have enabled differentiation of normative versus clinically salient irritability in early childhood. However, clinical application of these measures is still nascent. The authors developed an optimized model of clinically salient irritable behaviors at preschool age. Based on this model, the authors derived an empirically based cutoff in relation to concurrent DSM-5 irritability-related disorders (i.e., oppositional defiant disorder, disruptive mood dysregulation disorder, other depressive disorders) and used longitudinal models to test the predictive validity of the cutoff for impairment and irritability trajectories and later DSM disorders. METHOD: Preschool children oversampled for irritability were followed over 3 time points into early school age (N = 425; mean age at baseline 4.7 years, mean follow-up 2.9 years). Mothers reported on children's irritability using the developmentally validated Multidimensional Assessment of Profile of Disruptive Behavior (MAP-DB) Temper Loss scale, impairment using the Family Life Impairment Scale, and DSM categories using the Preschool Age Psychiatric Assessment and the Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version. RESULTS: Of 22 MAP-DB Temper Loss behaviors, 2 behaviors-1 normative (easily frustrated) and 1 rare dysregulated (destructive tantrums)-were uniquely related to cross-domain impairment. At baseline, these 2 irritability items identified diagnostic status (oppositional defiant disorder, disruptive mood dysregulation disorder, other depressive disorders) with good sensitivity (70-73%) and specificity (74-83%). Children above the irritability cutoff at baseline also exhibited more persistent irritability and impairment and greater likelihood of DSM disorders in early school age. CONCLUSION: Clinical identification of early-onset irritability can be enhanced using brief, developmentally optimized indicators. Further research to apply these findings to tiered early intervention is important. PMID- 29496130 TI - Mental Health in Syrian Refugee Children Resettling in the United States: War Trauma, Migration, and the Role of Parental Stress. PMID- 29496129 TI - Effect of Time-Dependent Selective Serotonin Reuptake Inhibitor Antidepressants During Pregnancy on Behavioral, Emotional, and Social Development in Preschool Aged Children. AB - OBJECTIVE: To evaluate the effect of prenatal exposure to selective serotonin reuptake inhibitors (SSRIs) on children's behavioral, emotional, and social development by age 5 years, and over time since age 1.5 years. METHOD: The prospective Norwegian Mother and Child Cohort Study was linked to the Medical Birth Registry of Norway. We included women who reported depressive/anxiety disorders before and/or during pregnancy. Children born to women who used SSRIs in early (weeks 0-16), mid- (weeks 17-28), or late (> week 29) pregnancy were compared to those who were unexposed. Children's internalizing and externalizing behaviors (Child Behavior Checklist) and temperament traits (Emotionality, Activity and Shyness Temperament Questionnaire) were measured at 1.5, 3, and 5 years. Mean scores were calculated and standardized. General linear marginal structural models were fitted to account for time-varying exposure and confounders, and censoring; 3-level growth-curve models were used. RESULTS: A total of 8,359 mother-child dyads were included, and 4,128 children had complete outcome data at age 5 years. Children exposed to SSRIs in late pregnancy had an increased risk of anxious/depressed behaviors by age 5 years compared with unexposed children (adjusted beta = 0.50, 95% CI = 0.04, 0.96). Such risk was not evident for earlier timings of exposure. There was no evidence for a substantial prenatal SSRI effect on externalizing, social, and emotional problems. CONCLUSION: These findings suggest no substantial increased risk for externalizing, emotional, or social problems in preschool-aged children following prenatal SSRI exposure. Although the role of chance and potential unmeasured confounding cannot be ruled out, late-pregnancy SSRI exposure was associated with greater anxious/depressed behaviors in the offspring. PMID- 29496131 TI - Tools for Teaching, Room for Debate: The DSM-5. PMID- 29496132 TI - Corrigendum. PMID- 29496133 TI - Corrigendum. PMID- 29496134 TI - The New York Brain Bank of Columbia University: practical highlights of 35 years of experience. AB - The New York Brain Bank processes brains and organs of clinically well characterized patients with age-related neurodegenerative diseases, and for comparison, from individuals without neurologic or psychiatric impairments. The donors, either patients or individuals, were evaluated at healthcare facilities of the Columbia University of New York. Each source brain yields four categories of samples: fresh frozen blocks and crushed parenchyma, and formalin-fixed wet blocks and histology sections. A source brain is thoroughly evaluated to determine qualitatively and quantitatively any changes it might harbor using conventional neuropathologic techniques. The clinical and pathologic diagnoses are integrated to determine the distributive diagnosis assigned to the samples obtained from a source brain. The gradual standardization of the protocol was developed in 1981 in response to the evolving requirements of basic investigations on neurodegeneration. The methods assimilate long-standing experience from multiple centers. The resulting and current protocol includes a constant central core applied to all brains with conditional flexibility around it. The New York Brain Bank is an integral part of the department of pathology, where the expertise, teaching duties, and hardware are shared. Since details of the protocols are available online, this chapter focuses on practical issues in professionalizing brain banking. PMID- 29496135 TI - Neurochemical markers as potential indicators of postmortem tissue quality. AB - Premortem, postmortem, and storage conditions are parameters that can influence the quality and interpretation of data from studies of postmortem tissue. While many neurochemicals in the brain are relatively stable for several hours after death if stored at 4 degrees C, the postmortem delay nevertheless becomes an important variable when examining the disease state because neurochemical levels may change with extended postmortem delay. Moreover, in the postmortem brain, neurochemical levels may also play a key role in determining the diagnosis. This is particularly true for some neurodegenerative disorders where many of the clinical features of the disease are not exclusive to one illness. It is therefore imperative to employ brain tissue of the highest quality from both nondiseased (control) and diseased brain tissue to ascertain the specific molecular and genetic mechanisms particular to the disease pathogenesis. Consequently, it would be very useful if specific markers could be employed to demonstrate and determine the quality of postmortem brain tissue that is suitable for such studies. In this chapter, the following neurochemical markers are critically reviewed as potential candidates to assess the quality of postmortem brain tissue: tryptophan levels, glutathione levels (and glutathione metabolic enzymes), enzymatic activities (glutamate decarboxylase, phosphofructokinase-1), epigenetic enzymes (acetyltransferase, methyltransferase), and tissue pH. In conclusion, the neurochemical tryptophan appears to be the most suitable candidate for assessing the integrity and quality of postmortem brain tissue. However, to optimize the quality of the samples, neuropathologic diagnostic characterization must also be employed in the interpretation and understanding of the data generated. It would also be judicious to consider as many premortem and postmortem conditions as possible as they can also affect the genetic and molecular integrity of the brain tissue. PMID- 29496136 TI - Minimal neuropathologic diagnosis for brain banking in the normal middle-aged and aged brain and in neurodegenerative disorders. AB - Research on human brain diseases is currently often conducted on cell cultures and animals. Several questions however can only be addressed by studying human postmortem brain tissue. However, brain tissue obtained postmortem almost always displays pathology that is often related to the aging phenomenon. Thus, in order to be certain that the answers obtained are reliable, a systematic and thorough assessment of the brain tissue to be studied should be carried out. We are currently aware of several protein alterations that are found in middle-aged and aged brains that are obtained from neurologically unimpaired subjects. The most common alteration is hyperphosphorylation of tau, observed in both neurons and glial cells, in certain brain regions, followed by beta-amyloid aggregation in the neuropil and vessel walls. Less common protein alterations are those noted for alpha-synuclein and Tar DNA-binding protein 43. It is noteworthy that these alterations, when found in excess, are diagnostic for various neurodegenerative diseases, such as Alzheimer disease, Pick disease, progressive supranuclear palsy, corticobasal degeneration, Parkinson disease, Lewy body dementia, and frontotemporal lobar degeneration. Since 1990, the neuropathology community has been aware that these protein alterations tend to progress in an orderly neuroanatomically defined manner and have thus designed a method to define a stage or a phase of the protein alteration. The neuropathology community has defined an initiation site, or neuroanatomic area that they presume the alteration originates from, and defined a presumed pattern of progression from the initiation site to other brain areas. Thus a reliable and reproducible description of each case regarding these alterations can be achieved. In addition to the above alterations, the brain tissue is also prone to various vascular alterations that should be registered as seen or not seen even if the significance of these alterations is still unclear. PMID- 29496137 TI - Brain donation at autopsy: clinical characterization and toxicologic analyses. AB - The study of postmortem human brain tissue is central to the advancement of neurobiologic studies of psychiatric and neurologic illnesses, particularly the study of brain-specific isoforms and molecules. Due to tissue demands, especially pertaining to brain regions strongly implicated in the pathophysiology of neuropsychiatric disorders, the success and future of this research depend on the availability of high-quality brain specimens from large numbers of subjects, including nonpsychiatric controls, both of which may be obtained from brain banks. In this chapter, we elaborate on the need for and acquisition of well curated and properly diagnosed postmortem human brains, relying upon our experience with the Human Brain and Tissue Repository located at the Lieber Institute for Brain Development in Baltimore, MD. We explain the advantages of sourcing postmortem human tissue from medical examiner offices, which provide access to cases of all ages, both with and without central nervous system disorders. Neuropathology analyses and toxicologic screenings, along with autopsy reports and extensive interviews with family members and treating physicians, are invaluable to the diagnoses of postmortem cases. Ultimately, the study of psychiatric and neurologic disorders is the study of brain disease, and accordingly, there is no substitution for human brain tissue. PMID- 29496138 TI - Information technology for brain banking. AB - Implementing and maintaining the information technology (IT) infrastructure of a brain bank can be a daunting task for any brain bank coordinator, particularly when access to both funds and IT professionals is limited. Many questions arise when attempting to determine which IT products are most suitable for a brain bank. The requirements of each brain bank must be assessed carefully to ensure that the chosen IT infrastructure will be able to meet those requirements successfully and will be able to expand and adapt as the size of the brain bank increases. This chapter provides some valuable insights to be considered when implementing the IT infrastructure for a brain bank and discusses the pros and cons of various approaches and products. PMID- 29496139 TI - Collecting, storing, and mining research data in a brain bank. AB - The Stanley Medical Research Institute Brain Collection distributes samples from specified cohorts that contain demographically matched groups of subjects with mental illnesses such as schizophrenia, bipolar disorder, and major depression, as well as unaffected controls. The groups are matched by age, sex, race, postmortem interval, pH, side of brain, and mRNA quality. The samples are distributed coded so that all data must be returned in order to obtain the demographic information. The database contains more than 5000 individual data sets, as well as data from high-throughput microarray, sequencing, and proteomic studies. While most data were generated from the frontal cortex and hippocampus, the cerebellum has the most data sets that differ significantly between diagnostic groups and controls. The database contains interactive features and statistical tools that enable online data mining and real-time data analysis. The decrease in density of parvalbumin-positive neurons in schizophrenia, one of the most replicated findings in the field, is used to illustrate features of the brain bank. We describe how this finding can be replicated and validated in this database. We also show how the density of parvalbumin-positive neurons is correlated with markers of immune activation in the neuropathology data sets, how it is correlated with immune-related genes in a microarray data set, and how it is associated with a single-nucleotide polymorphism in the immune complement system. PMID- 29496140 TI - Brain donation procedures in the Sudden Death Brain Bank in Edinburgh. AB - Brain banks typically receive donations through premortem consent procedures, often through disease-specific patient cohorts, such as dementia. While some control cases can be obtained through this route, access to age-matched control tissues, and some chronic neurologic conditions, particularly psychiatric disorders, can be challenging. The Edinburgh Sudden Death Brain Bank was established to try and increase access to control cases across all ages, and also access to psychiatric disorders through suicides. This chapter outlines the processes for establishing donations through medicolegal postmortems, which, although often with a prolonged postmortem interval, can provide high-quality well-characterized postmortem brain tissue to the neuroscience research community. PMID- 29496141 TI - What can we learn about brain donors? Use of clinical information in human postmortem brain research. AB - Postmortem studies on the human brain reside at the core of investigations on neurologic and psychiatric disorders. Ground-breaking advances continue to be made on the pathologic basis of many of these disorders, at molecular, cellular, and neural connectivity levels. In parallel, there is increasing emphasis on improving methods to extract relevant demographic and clinical information about brain donors and, importantly, translate it into measures that can reliably and effectively be incorporated in the design and data analysis of postmortem human investigations. Here, we review the main source of information typically available to brain banks and provide examples on how this information can be processed. In particular, we discuss approaches to establish primary and secondary diagnoses, estimate exposure to therapeutic treatment and substance abuse, assess agonal status, and use time of death as a proxy in investigations on circadian rhythms. Although far from exhaustive, these considerations are intended as a contribution to ongoing efforts from tissue banks and investigators aimed at establishing robust, well-validated methods for collecting and standardizing information about brain donors, further strengthening the scientific rigor of human postmortem studies. PMID- 29496142 TI - The art of matching brain tissue from patients and controls for postmortem research. AB - The quality of postmortem research depends strongly on a thorough clinical investigation and documentation of the patient's disorder and therapies. In addition, a systematic and professional neuropathologic investigation of both cases and controls is absolutely crucial. In the experience of the Netherlands Brain Bank (NBB), about 20% of clinical neurologic diagnoses, despite being made in first-rate clinics, have to be revised or require an extra diagnosis after a complete and thorough review by the NBB. The neuropathology examination may reveal for instance that the "controls" already have preclinical neurodegenerative alterations. In postmortem studies the patient and control groups must be matched for as many of the known confounding factors as possible. This is necessary to make the groups as similar as possible, except for the topic being investigated. Confounding factors are present before, during, and after death. They are respectively: (1) genetic background, systemic diseases, duration and gravity of illness, medicines and addictive compounds used, age, sex, gender identity, sexual orientation, circadian and seasonal fluctuations, lateralization; (2) agonal state, stress of dying; and (3) postmortem delay, freezing procedures, fixation and storage time. Consequently, a brain bank should have a large number of controls at its disposal for appropriate matching. If matching fails for some confounders, then their influence may be determined by statistical methods such as analysis of variance or regression models. PMID- 29496143 TI - Considerations for optimal use of postmortem human brains for molecular psychiatry: lessons from schizophrenia. AB - Schizophrenia is a disabling disease impacting millions of people around the world, for which there is no known cure. Current antipsychotic treatments for schizophrenia mainly target psychotic symptoms, do little to ameliorate social or cognitive deficits, have side-effects that cause weight gain, and diabetes and 30% of people do not respond. Thus, better therapeutics for schizophrenia aimed at the route biologic changes are needed and discovering the underlying neurobiology is key to this quest. Postmortem brain studies provide the most direct and detailed way to determine the pathophysiology of schizophrenia. This chapter outlines steps that can be taken to ensure the best-quality molecular data from postmortem brain tissue are obtained. In this chapter, we also discuss targeted and high-throughput methods for examining gene and protein expression and some of the strengths and limitations of each method. We briefly consider why gene and protein expression changes may not always concur within brain tissue. We conclude that postmortem brain research that investigates gene and protein expression in well-characterized and matched brain cohorts provides an important foundation to be considered when interpreting data obtained from studies of living schizophrenia patients. PMID- 29496144 TI - Epigenetic analysis of human postmortem brain tissue. AB - Epigenomic profiles have been mapped across a broad range of brain regions and developmental contexts in postmortem human brain tissues, illuminating our understanding of epigenetic regulation in neural function and plasticity across the life course. Importantly, disease-associated epigenetic alterations in postmortem brain have provided compelling insights into the gene-regulatory architecture underlying neurobiologic disease susceptibility and pathogenesis. However, the use of postmortem brain tissues for molecular analyses warrants careful consideration of key technical and biologic factors that may confound epigenetic analyses. In this chapter, we describe the predominant forms of epigenetic regulation (DNA modifications, chromatin structure, and noncoding RNA expression) and discuss the various methodologies used to assess each epigenetic mark. In addition, we provide an overview of existing epigenetic studies using human brain tissues as well as highlight the various challenges and considerations for epigenomic profiling in human postmortem brain samples. PMID- 29496145 TI - Laser microdissection and gene expression profiling in the human postmortem brain. AB - Laser microdissection in combination with gene expression profiling using postmortem human brain tissue provides a powerful approach to interrogating cell type-specific pathologies within neural circuits that are known to be dysfunctional in neuropsychiatric disorders. The success of these experiments critically depends on a number of factors, such as the cellular purity of the sample, the quality of the RNA, the methodologies of data normalization and computational data analysis, and how data are interpreted. Data obtained from these experiments should be validated at the protein level. Furthermore, from the perspective of disease mechanism discovery, it would be ideal to investigate whether manipulation of the expression of genes identified as differentially expressed can rescue or ameliorate the neurobiologic or behavioral phenotypes associated with the specific disease. Thus, the ultimate value of this approach rests upon the fact that the generation of novel disease-related pathophysiologic hypotheses may lead to deeper understanding of disease mechanisms and possible development of effective targeted treatments. PMID- 29496146 TI - Purification of cells from fresh human brain tissue: primary human glial cells. AB - In order to translate the findings obtained from postmortem brain tissue samples to functional biologic mechanisms of central nervous system disease, it will be necessary to understand how these findings affect the different cell populations in the brain. The acute isolation and analysis of pure glial cell populations are common practice in animal models for neurologic diseases, but are not yet regularly applied to human postmortem brain material. The development of novel cell isolation techniques and methods for transcriptomic and proteomic analysis have made it possible to isolate and phenotype primary human cell populations from the central nervous system. The psychiatric program of the Netherlands Brain Bank has considerable experience with the purification of glial cells. This chapter will review the rapid isolation and phenotyping procedures for two major glia cell populations in the human brain, microglia and astrocytes, and will also discuss the potential for biobanking these cells, as well as the possible alternatives to cell isolations. The acute isolation of glial cells without culture-based adherence steps allows the analysis of glial alterations that underlie, or are the result of, disease neuropathology of the donor. PMID- 29496147 TI - Proteomics and lipidomics in the human brain. AB - Proteomics and lipidomics are powerful tools to the large-scale study of proteins and lipids, respectively. Several methods can be employed with particular benefits and limitations in the study of human brain. This is a review of the rationale use of current techniques with particular attention to limitations and pitfalls inherent to each one of the techniques, and more importantly, to their use in the study of post-mortem brain tissue. These aspects are cardinal to avoid false interpretations, errors and unreal expectancies. Other points are also stressed as exemplified in the analysis of human neurodegenerative diseases which are manifested by disease-, region-, and stage-specific modifications commonly in the context of aging. Information about certain altered protein clusters and proteins oxidatively damaged is summarized for Alzheimer and Parkinson diseases. PMID- 29496148 TI - The Netherlands Brain Bank for Psychiatry. AB - The Netherlands Brain Bank (NBB) performs rapid autopsies of donors who gave written informed consent during life for the use of their brain tissue and medical files for research. The NBB initiated the Netherlands Brain Bank for Psychiatry (NBB-Psy), a prospective donor program for psychiatric diseases. NBB Psy wants to expand the tissue collections in order to provide a strong incentive to increase research in psychiatry. The ultimate goal of NBB-Psy is to reduce the burden of psychiatric disorders for patients, their families, and for society as a whole. NBB-Psy consists of an antemortem and postmortem donor program. This chapter focuses on the design of NBB-Psy and the antemortem donor program, where patients and relatives are actively informed on the possibility to become a brain donor. Since the initiation of NBB-Psy, the number of registered donors with a psychiatric diagnosis has increased from 149 in 2010 to 1018 in May 2016. PMID- 29496149 TI - 3D imaging in the postmortem human brain with CLARITY and CUBIC. AB - Recent innovations in tissue clearing and imaging technologies have enabled us to analyse biological systems directly in three-dimensions using thick samples. In this review, we discuss two of these recently reported tissue-clearing technologies (CLARITY and CUBIC) that are compatible with archival formalin-fixed human brain materials that have been fixed in formalin for a long period of time. We will discuss the pros and cons of these two technologies, examples of visualisation of Alzheimer neuropathological hallmarks and the exact protocols that we regularly use in the laboratory. PMID- 29496150 TI - Autism BrainNet: A network of postmortem brain banks established to facilitate autism research. AB - Autism spectrum disorder (ASD or autism) is a neurodevelopmental condition that affects over 1% of the population worldwide. Developing effective preventions and treatments for autism will depend on understanding the genetic perturbations and underlying neuropathology of the disorder. While evidence from magnetic resonance imaging and other noninvasive techniques points to altered development and organization of the autistic brain, these tools lack the resolution for identifying the cellular and molecular underpinnings of the disorder. Postmortem studies of high-quality human brain tissue currently represent the only viable option to pursuing these types of studies. However, the availability of high quality ASD brain tissue has been extremely limited. Here we describe the establishment of a privately funded tissue bank, Autism BrainNet, a network of brain collection sites that work in a coordinated fashion to develop an adequate library of human postmortem brain tissues. Autism BrainNet was initiated as a collaboration between the Simons Foundation and Autism Speaks, and is currently funded by the Simons Foundation Autism Research Initiative. Autism BrainNet has collection sites (nodes) in California, Texas, New York, and Massachusetts; an affiliated, international node is located in Oxford, England. All donations to this network become part of a consolidated pool of tissue that is distributed to qualified investigators worldwide to carry out autism research. An essential component of this program is a widespread outreach program that highlights the need for postmortem brain donations to families affected by autism, led by the Autism Science Foundation. Challenges include an outreach campaign that deals with a disorder beginning in early childhood, collecting an adequate number of donations to deal with the high level of biologic heterogeneity of autism, and preparing this limited resource for optimal distribution to the greatest number of investigators. PMID- 29496151 TI - Neuronal life after death: electrophysiologic recordings from neurons in adult human brain tissue obtained through surgical resection or postmortem. AB - Recordings from fresh human brain slices derived from surgically resected brain tissue are being used to unravel mechanisms underlying human neurophysiology and for the evaluation of potential therapeutic targets and compounds. Data resulting from these studies provide unique insights into physiologic properties of human neuronal microcircuits. However, substantial limitations still remain with this approach. First, the tissue is always resected from patients, never from healthy controls. Second, the patient population undergoing brain surgery with tissue resection is limited to epilepsy and tumor patients - never from patients with other neurologic disorders. Third, the vast majority of tissue resected is limited largely to temporal cortex and hippocampus, occasionally amygdala. Therefore, the possibility to study brain tissue: (1) from healthy controls; (2) from patients with different neuropathologies; (3) from different brain areas; and (4) from a wide spectrum of ages only exists through autopsy-derived brain tissue. Here we describe methods and results from physiologic recordings of adult human neurons and microcircuits in both surgically derived brain tissue as well as in tissue derived from autopsies. We define postmortem time windows during which physiologic recordings could match data obtained from surgical tissue. PMID- 29496152 TI - Postmortem magnetic resonance imaging. AB - This chapter provides a brief overview of studies that combine postmortem magnetic resonance imaging (MRI) and histopathology. We touch upon the logistics of setting up a protocol that limits unwanted postmortem delays and explain how combining postmortem MRI and histopathology can elucidate the histologic substrate of signal changes that appear on MRI. This is demonstrated by exemplary studies in multiple sclerosis, and includes various histopathologic techniques and a wide range of conventional and advanced MRI sequences at various field strengths. We cover topics such as how to visualize white-matter pathology and repair with conventional and advanced MRI sequences, describe the history of visualizing pathology of the gray matter (with newly developed MRI and immunohistopathology techniques), and how advanced methods have aided research in other neurologic diseases. We conclude with several suggestions for future development, such as bridging the gap between postmortem and in vivo research and the importance of collecting non-neurological control tissue. PMID- 29496153 TI - Cyto- and receptor architectonic mapping of the human brain. AB - Mapping of the human brain is more than the generation of an atlas-based parcellation of brain regions using histologic or histochemical criteria. It is the attempt to provide a topographically informed model of the structural and functional organization of the brain. To achieve this goal a multimodal atlas of the detailed microscopic and neurochemical structure of the brain must be registered to a stereotaxic reference space or brain, which also serves as reference for topographic assignment of functional data, e.g., functional magnet resonance imaging, electroencephalography, or magnetoencephalography, as well as metabolic imaging, e.g., positron emission tomography. Although classic maps remain pioneering steps, they do not match recent concepts of the functional organization in many regions, and suffer from methodic drawbacks. This chapter provides a summary of the recent status of human brain mapping, which is based on multimodal approaches integrating results of quantitative cyto- and receptor architectonic studies with focus on the cerebral cortex in a widely used reference brain. Descriptions of the methods for observer-independent and statistically testable cytoarchitectonic parcellations, quantitative multireceptor mapping, and registration to the reference brain, including the concept of probability maps and a toolbox for using the maps in functional neuroimaging studies, are provided. PMID- 29496154 TI - Mapping pathologic circuitry in schizophrenia. AB - Schizophrenia is a complex disorder lacking an effective treatment option for the pervasive and debilitating cognitive impairments experienced by patients. Working memory is a core cognitive function impaired in schizophrenia that depends upon activation of distributed neural network, including the circuitry of the dorsolateral prefrontal cortex (DLPFC). Accordingly, individuals diagnosed with schizophrenia show reduced DLPFC activation while performing working-memory tasks. This lower DLPFC activation appears to be an integral part of the disease pathophysiology, and not simply a reflection of poor performance. Thus, the cellular and circuitry alterations that underlie lower DLPFC neuronal activity in schizophrenia must be determined in order to identify appropriate therapeutic targets. Studies using human postmortem brain tissue provide a robust way to investigate and characterize these cellular and circuitry alterations at multiple levels of resolution, and such studies provide essential information that cannot be obtained either through in vivo studies in humans or through experimental animal models. Studies examining neuronal morphology, protein expression and localization, and transcript levels indicate that a microcircuit composed of excitatory pyramidal cells and inhibitory interneurons containing the calcium binding protein parvalbumin is altered in the DLPFC of subjects with schizophrenia and likely contributes to DLPFC dysfunction. PMID- 29496155 TI - The NIH NeuroBioBank: creating opportunities for human brain research. AB - The National Institutes of Health (NIH) NeuroBioBank is a federally funded research resource for human neurologic diseases and disorders. This chapter will discuss the principles that guided the creation of the NIH NeuroBioBank and the rationale for the resource model selected. In addition, we will describe some performance metrics in the first 2 years and highlight recent advances in biomedical neuroscience that could only have been achieved using postmortem human tissues. The NIH NeuroBioBank was created in order to increase availability of high-quality postmortem human brain tissues to the research community across a broad spectrum of neurologic diseases and disorders, and to achieve economies of scale over previous funding and organizational models. In addition, we aim to increase public awareness about the value of human tissue donation for research by providing web-based information to the public and through active outreach to disease advocacy communities. Studies with human brain tissue have led to a rapid increase in our knowledge of the biologic differences between humans and are bridging the divide between humans and model organisms. Studies of human brain are beginning to give us a glimpse not only into what makes us uniquely human as well as how individual biology may be connected to health and disease. PMID- 29496156 TI - Design of a European code of conduct for brain banking. AB - The BrainNet Europe consortium, which is a consortium of 19 European brain banks, took the initiative to draft a series of documents to provide an ethical framework for brain banks to follow. The framework includes an ethical code of conduct, a model for brain bank regulations, and a toolkit containing several documents. The sources for the information included came from the laws, regulations, and guidelines (declarations, conventions, recommendations, guidelines, and directives) that had been issued by international key organizations, such as the Council of Europe, European Commission, World Medical Association, and World Health Organization. The code of conduct addresses fundamental topics such as the rights of the persons donating their tissue, the obligations of the brain bank with regard to respect and observance of such rights, informed consent, confidentiality, protection of personal data, collections of human biologic material and their management, and transparency and accountability within the organization of a brain bank. The code of conduct was ratified by all European brain banks in 2009. This chapter describes the process of establishing the code of conduct within the BrainNet Europe consortium and elaborates on three key aspects of the code of conduct, namely informed consent, genetics, and financial aspects in brain banking. PMID- 29496157 TI - A review of brain biorepository management and operations. AB - Brain biospecimen banking requires centralized resources, national networks for referral of donors, trained personnel to interact with grieving families, and scientific staff to process the biospecimens. Process development of quality control standards is needed to meet the specific requirements of emerging genomic and proteomic technologies. Attention has to be paid to agonal factors and postmortem interval, tissue processing, neuropathology review, and long-term storage. Samples of both diseased and unaffected normal tissues are required with age- and gender-matched control tissues. Data management is vital to store and retrieve quality control measures, clinical and pathologic data linked to the biospecimens. Customized solutions for managing the acquisition and long-term storage of high-quality brain and tissue biospecimens is necessary to support neuroscience research programs, biomarker discovery and genome scale technologies. Biorepositories that operate according to best-practice policies and procedures guarantee the final wish of the families who donate tissue to support neuroscience research and discovery science. PMID- 29496158 TI - A new viewpoint: running a nonprofit brain bank as a business. AB - It has become clear over the past decades that studying postmortem human brain tissue is one of the most effective ways to increase our knowledge of the pathogenesis and etiology of neuropathologic and psychiatric diseases. Many breakthroughs in neuroscience have depended on the availability of human brain tissue. However, the process of brain banking presents many different challenges, including the high cost that is associated with collecting the samples and with providing the diagnostics, storage, and distribution. Funding is generally from research and facility grants and donations but all are irregular, uncertain, and only cover the costs for a determined period of time. For professional brain banks with extensive prospective donor programs and that are open-access it can be very beneficial to draft a business plan to achieve long-term sustainability. Such a business plan should identify the interests of the stakeholders and address the implementation of cost efficiency and cost recovery systems. PMID- 29496159 TI - Preface. PMID- 29496160 TI - Foreword. PMID- 29496161 TI - Effects of bioactive constituents in the Traditional Chinese Medicinal formula Si Wu-Tang on Nrf2 signaling and neoplastic cellular transformation. AB - BACKGROUND: The nuclear factor erythroid 2-related factor 2 (Nrf2) is a potential molecular target for cancer chemoprevention. Si-Wu-Tang (SWT), a popular traditional Chinese medicine for women's health, was reported with a novel activity of cancer prevention. PURPOSE: The present study was aimed to identify the bioactive constituents in SWT responsible for the Nrf2 activating and cancer preventive activity and explore the pharmacological mechanisms. METHODS: Nine compounds detectable from various batches of SWT were ranked using in silico molecular docking based on their ability to interfere the forming of Nrf2-Keap1 complex. The predicted Nrf2 activating effect was validated using the antioxidant response element (ARE) luciferase reporter assay and quantitative RT-PCR analysis for select Nrf2 regulated genes Hmox1, Nqo1 and Slc7a11. The antimutagenic activity of the compounds were determined by the Ames test. The chemopreventive activity of these compounds were assessed on EGF-induced neoplastic transformation of JB6 P+ cells, an established non-cancerous murine epidermal model for studying tumor promotion and identifying cancer preventive agents. These compounds were further characterized using luciferase reporter assay on EGF induced activation of AP-1, a known transcription factor mediating carcinogenesis. RESULTS: Three of the nine compounds predicted as Nrf2 activators by molecular docking, gallic acid (GA), Z-liguistilide (LIG), and senkyunolide A (SA), were confirmed with highest potency of increasing the Nrf2/ARE promoter activity and upregulating the expression of Hmox1, Nqo1 and Slc7a11. In addition, GA, LIG and SA exhibited an antimutagenic activity against the direct mutagen 2 nitrofluorene while no mutagenic effects were observed at the same time in Ames test. At nontoxic concentrations, GA, LIG, and SA inhibited EGF-induced neoplastic transformation of JB6 P+ cells. Combined treatment of GA, LIG and SA, in the same ratio as detected in SWT, showed enhanced effect against JB6 transformation compared with that of the single compound alone. GA, LIG and SA, alone or in combination, suppressed EGF-induced activation of AP-1. CONCLUSION: We identified three bioactive constituents in SWT responsible for the Nrf2 activating and cancer preventive activity. This study provides evidence supporting novel molecular basis of SWT in cancer prevention. PMID- 29496162 TI - Tamarix hohenackeri Bunge exerts anti-inflammatory effects on lipopolysaccharide activated microglia in vitro. AB - BACKGROUND: Tamarix species are well known as the main host plants of Herba Cistanches, a valuable Traditional Chinese Medicine. They are also traditional medicinal plants themselves and are used to treat spleen problems, leucoderma and ocular conditions. PURPOSE: The aim of the present study was to investigate the anti-inflammatory effect of Tamarix hohenackeri Bunge. METHODS: In the present study, BV-2 microglial cells were used and stimulated with lipopolysaccharide (LPS). Cell viability was tested using the MTT assay. The release of nitric oxide (NO) was determined using the Griess assay. The mRNA level of inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-alpha), interleukin (IL) 1beta and IL-6 were investigated by quantitative real-time PCR (qRT-PCR). The protein levels of phosphorylated of IkappaBalpha, ERK and MEK, as well as the cytoplasmic and nuclear NF-kappaB p65 were tested by Western blot analysis. The translocation of the NF-kappaB p65 subunit from the cytosol to the nucleus was investigated by immunofluorescence staining. RESULTS: Ethyl acetate (EtOAc) extract of Tamarix hohenackeri Bunge significantly inhibited the release of NO. Phytochemical research was performed to produce 13 main constituents. Among them, compounds 6, 7, 10 and 13 were identified to be the effective components with anti-inflammatory activity. These compounds significantly inhibited the production of NO by LPS-activated BV-2 microglial cells. qRT-PCR showed that compounds 6 and 7 significantly suppressed the LPS-induced transcription of genes encoding pro-inflammatory mediators, including iNOS, TNF-alpha, IL-1beta and IL 6. Western blot analysis showed that compound 7 inhibited the LPS-induced phosphorylation of IkappaBalpha and antagonized the LPS-induced reduction of cytoplasmic NF-kappaB p65 and the increase of nuclear NF-kappaB p65. Immunofluorescence staining showed that nuclear translocation of NF-kappaB p65 was suppressed by compound 7. Western blot analysis showed that compound 7 inhibited the LPS-induced phosphorylation of ERK and MEK. CONCLUSION: The present study revealed, for the first time, the effective anti-inflammatory agents from T. Hohenackeri. Compound 7 exerted potent anti-inflammatory effects and its underlying mechanism may be associated with its capacity to inhibit NF-kappaB signaling pathway and the MEK/ERK activation in activated microglia. The compound may be potential candidate therapeutic agent for neurodegenerative diseases. PMID- 29496163 TI - Acetonic extracts of the endolichenic fungus EL002332 isolated from Endocarpon pusillum exhibits anticancer activity in human gastric cancer cells. AB - BACKGROUND: Endolichenic fungi are microbes that inhabit the thalli of lichens and produce various unique chemicals that can be used for pharmaceutical purposes. PURPOSE: This study screened a library of endolichenic fungal extracts to identify novel anticancer agents capable of suppressing the tumorigenicity of human cancer cells. METHODS: Active compounds were isolated from extracts of endolichenic fungi by column chromatography and reverse-phase HPLC. The anticancer effects of the extracts on cell viability was assessed with the use of MTT assay, Western blotting, fluorescence labeling of apoptotic cell, and flow cytometric analysis; and cell motility with the use of migration, invasion and soft agar colony-formation assay in vitro; and on skin and intraperitoneal mouse xenograft tumors in vivo were investigated. The therapeutic effects of the extract alone or in combination with the conventional chemoreagent docetaxel were analyzed by sulforhodamine B assay. RESULTS: Acetone extracts of EL002332, isolated from Endocarpon pusillum collected in the China desert in 2010, showed selective cytotoxicity against AGS human gastric cancer cells and CT26 mouse colon cancer cells. An active pure compound named myC was isolated from mycelium acetone extracts in a liquid culture system and showed more potent cytotoxicity than crude extracts in the AGS cell line. Especially, myC greatly increased the apoptotic cell population at the IC50 concentration and activated apoptotic signaling by regulating Bcl2 family protein expression and caspase pathway activity. EL002332 crude extracts and myC decreased AGS cell motility at sub lethal concentrations. In vivo skin and intraperitoneal xenograft tumor experiments showed that the size of tumors and the tumor score were significantly smaller in EL002332 crude extract-treated groups than in control groups. EL002332 crude extracts showed synergistic effects with docetaxel on the AGS and TMK1 cell lines. CONCLUSION: The endolichenic fungus EL002332 has potential anticancer activity in gastric cancer and peritoneal carcinomatosis. PMID- 29496164 TI - Dietary isoflavone daidzein synergizes centchroman action via induction of apoptosis and inhibition of PI3K/Akt pathway in MCF-7/MDA MB-231 human breast cancer cells. AB - BACKGROUND: Despite advancements in the prognosis and management of breast cancer, it remains a major cause of mortality in women worldwide. Centchroman (CC), an oral contraceptive has been found to exhibit anti-cancer potential against a wide range of cancer including breast cancer. PURPOSE: The present study is intended to evaluate the ability of soy isoflavone Daidzein (DZ) in enhancing the efficacy of CC in Human Breast Cancer Cells (HBCCs). METHODS/STUDY DESIGN: Sulforhodamine B assay was employed to determine the cytotoxicity induced by 10 uM CC & 50 uM DZ separately and together in MCF-7/MDA MB-231 HBCCs and non tumorigenic Human Mammary Epithelial Cells (HMECs) MCF-10A as a control. Combination Index (CI) analysis was executed using CompuSyn software. Further, apoptosis was assessed using Annexin V/PI, AO/PI staining and tunel assay. Cell cycle, reactive oxygen species generation and mitochondrial membrane potential alteration was determined using flow cytometry. Western blot analysis was performed to check the expression of respective proteins. RESULTS: The results suggest that the combination exerts elevated toxicity as compared to control and each drug per se without affecting HMECs MCF-10A. This therefore implies cancer cell specific action of CC plus DZ administered together. Additionally, combination index analysis suggests synergistic action of CC and DZ combination in HBCCs. Cell cycle analysis, Annexin V/PI staining, tunel assay and western blot analysis confirms the induction of apoptosis by combination in HBCCs. Interestingly, western blot analysis also revealed that the combination down regulated the expression of proteins involved in cell survival i.e. PI3K, Akt and mTOR, suggesting inhibition of cell survival pathway. CONCLUSION: The results overall demonstrate that CC plus DZ has higher anticancer efficacy as compared to either drug alone. Hence, the combination of CC plus DZ may offer a novel strategy for the management of breast cancer. PMID- 29496165 TI - Recent progress in doxorubicin-induced cardiotoxicity and protective potential of natural products. AB - BACKGROUND: As an anthracycline antibiotic, doxorubicin (DOX) is one of the most potent and widely used chemotherapeutic agents for various types of solid tumors. Unfortunately, clinical application of this drug results in severe side effects of cardiotoxicity. PURPOSE: We aim to review the research focused on elimination or reduction of DOX cardiotoxicity without affecting its anticancer efficacy by natural products. METHODS: This study is based on pertinent papers that were retrieved by a selective search using relevant keywords in PubMed and ScienceDirect. The literature mainly focusing on natural products and herb extracts with therapeutic efficacies against experimental models both in vitro and in vivo was identified. RESULTS: Current evidence revealed that multiple molecules and signaling pathways, such as oxidative stress, iron metabolism, and inflammation, are associated with DOX-induced cardiotoxicity. Based on these knowledge, various strategies were proposed, and thousands of compounds were screened. A number of natural products and herb extracts demonstrated potency in limiting DOX cardiotoxicity toward cultured cells and experimental animal models. CONCLUSIONS: Though a panel of natural products and herb extracts demonstrate protective effects on DOX-induced cardiotoxicity in cells and animal models, their therapeutic potentials for clinical needs further investigation. PMID- 29496166 TI - Pristimerin exhibits in vitro and in vivo anticancer activities through inhibition of nuclear factor-kB signaling pathway in colorectal cancer cells. AB - BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies associated with high mortality rate worldwide. We previously reported that pristimerin inhibits cell growth and induces apoptosis in CRC cells. HYPOTHESIS/PURPOSE: To further understand the molecular mechanism by which pristimerin elicits its anticancer activities on colon cancer cells, we investigated its effect on nuclear factor-kappaB (NF-kappaB) signaling pathway. STUDY DESIGN: This study consisted of both in vitro and in vivo experiments involving HCT-116 cell line and xenograft mouse model. Molecular techniques such as qRT-PCR, western blotting and immunofluorescence were used to demonstrate pristimerin in vitro effect on NF-kappaB signaling pathway; whereas it's in vivo activity was analyzed by western blot and immunohistochemistry on tumor tissues. RESULTS: Our in vitro results on HCT-116 cells showed that pristimerin inhibited IKK phosphorylation, IkB-alpha degradations and IkB-alpha phosphorylation in both dose- and time- dependent manners, which caused suppression of NF-kB p65 phosphorylation, nuclear translocation and accumulation of NF-kB. Moreover, pristimerin was found to inhibit both constitutive activated-NF-kB and tumor necrosis factor-alpha (TNF-alpha)- and lipopolysaccharide (LPS)-induced activation of NF-kB signaling pathway. Furthermore, our in vivo results on xenograft animal model revealed that pristimerin inhibited tumor growth mainly through suppressing NF-kB activity in tumor tissues. CONCLUSION: Pristimerin antitumor activities were mainly mediated through inhibition of NF-kB signaling pathway in colon tumor cells. These findings further explain that pristimerin has the therapeutic potential for targeting colon cancer. PMID- 29496167 TI - Piscroside C inhibits TNF-alpha/NF-kappaB pathway by the suppression of PKCdelta activity for TNF-RSC formation in human airway epithelial cells. AB - BACKGROUND: Piscroside C, isolated from Pseudolysimachion rotundum var. subintegrum, is a novel iridoid glycoside with therapeutic efficacy in a mouse model of chronic obstructive pulmonary disease (COPD). Piscroside C has been reported as a constituent of YPL-001 (under Phase 2a study, ClinicalTrials.gov identifier NCT02272634). PURPOSE: To investigate the mechanisms behind piscroside C therapeutic effects on COPD in human airway epithelial NCI-H292 cells. METHODS: We tested if piscroside C effectively suppresses MUC5AC gene expression and TNF RSC/IKK/NF-kappaB cascades in TNF-alpha-stimulated NCI-H292 cells by employing, reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, luciferase reporter assays, chromatin immunoprecipitation assays and immunoprecipitation. RESULTS: Piscroside C markedly suppressed the expression of TNF-alpha-induced MUC5AC mucus protein by inhibiting the transcriptional activity of NF-kappaB in NCI-H292 cells. Indeed, piscroside C negatively regulated the function of TNF receptor 1 signaling complex (TNF-RSC, an upstream regulator of the NF-kappaB pathway) without affecting its extracellular interaction with the TNF-alpha ligand. This inhibitory effect by piscroside C is mediated by the inactivation of protein kinase C (PKC), an essential regulator of TNF-RSC. PKC inactivation by piscroside C results in decreased PKCdelta binding to a TRAF2 subunit of TNF-RSC and subsequent reduced IKK phosphorylation, resulting in NF kappaB inactivation. CONCLUSION: We propose that piscroside C is a promising therapeutic constituent of YPL-001 through its inhibition of PKCdelta activity in the TNF-RSC/IKK/NF-kappaB/MUC5AC signaling cascade. PMID- 29496168 TI - St John's wort (Hypericum perforatum) products - an assessment of their authenticity and quality. AB - BACKGROUND: St John's wort products (Hypericum perforatum L.) are widely available for sale in many countries including the UK via the internet. In the UK, these products are required to hold either a marketing authorisation or Traditional herbal registration (THR) to be sold legally. The THR and other regulatory schemes help to ensure product safety and quality providing an example of best practice but there is a risk if both regulated and un-regulated products continue to be available to consumers. AIMS: The project is embedded in a larger study aiming to investigate the quality of different herbal medicinal products along diverse value chains. Here we focus on a comparison of the quality of the finished products and assess phytochemical variation between registered products (THRs) and products obtained from the market without any registration. METHODS: 47 commercial products (granulated powders and extracts) were sourced from different suppliers. We analysed these samples using high performance thin layer chromatography (HPTLC) and 1H NMR spectroscopy coupled with multi-variate analysis software following a method previously developed by our group. RESULTS: The consistency of the products varies significantly. Adulteration of the products (36%), possibly with other Hypericum species obtained from China or use of chemically distinct H. perforatum cultivars or chemotypes, and adulteration of the products (19%) with food dyes (tartrazine, amaranth, brilliant blue, sunset yellow) were the principle findings of this study. CONCLUSIONS: There is significant compositional variation among commercial finished products and two main causative quality problems were identified as adulteration by incorrect species or adulteration with food dyes. Generally, food supplements and unlicensed products were found to be of poorer quality than the regulated ones including THRs. PMID- 29496169 TI - Ophiopogonin D modulates multiple oncogenic signaling pathways, leading to suppression of proliferation and chemosensitization of human lung cancer cells. AB - BACKGROUND: Ophiopogonin D (OP-D), a steroidal glycoside obtained from the Chinese medicinal plant Ophiopogonin japonicas (the root portion), has been traditionally used to treat fever, inflammation, cough, sputum etc. However, the detailed molecular mechanism(s) underlying its therapeutic actions is still unknown. HYPOTHESIS: Because nuclear factor-kappaB (NF-kappaB), PI3K/AKT, and activator protein-1 (AP-1) signaling cascades have significant functions in cell proliferation, inflammation, and angiogenesis in tumor cells, we hypothesized that OP-D may disrupt these signaling cascades to exert its anticancer effects in human lung-cancer cells. METHODS: We evaluated the effect of OP-D on multiple signaling cascades and its regulated functional responses in lung cancer cells. RESULTS: OP-D blocked both basal and cytokine-induced proliferation of human lung cancer cells and caused down-regulation of the expression of diverse oncogenic gene products through the suppression of NF-kappaB, PI3K/AKT, and AP-1 pathways; but did not affect JNK, p38 and ERK MAP kinases. Interestingly, OP-D suppressed constitutive NF-kappaB activation in lung cancer cells via interfering with the IkappaB kinase activation, which inhibited phosphorylation and caused degradation of IkappaB-alpha. OP-D also blocked phosphorylation and the nuclear translocation of p65, thereby suppressing NF-kappaB reporter activity in lung cancer cells. Besides, OP-D could augment cell death induced by paclitaxel in lung-cancer cells. CONCLUSION: Overall, the data indicates that OP-D may abrogate diverse signaling cascades linked to tumorigenesis, and can be used in combination with chemotherapeutic agents for cancer therapy. PMID- 29496170 TI - Studies on detection and analysis of proteases in leaf extract of medicinally important plants. AB - ETHNO-PHARMACOLOGICAL RELEVANCE: The whole plant or the extracts obtained from them have long been used as medicine to treat various human diseases and disorders. Notably, those plants endowed with protease activity have been traditionally used as the agents for treating tumors, digestion disorders, swelling, blood coagulation, fibrinolysis and also for immune-modulation. AIM OF THE STUDY: Proteases occupy a pivotal position in enzyme based industries. Plant proteases have been increasingly exploited for pharmaceutical, food, leather and textile processing industries. Earlier investigations have focused on the occurrence of proteases in medicinally unimportant plants. Therefore it has been aimed to study the occurrence of proteolytic enzymes from medicinally important plants establish any correlation exists between protease activity and medicinal use of individual plants. METHODS: Crude extract were obtained from the leaves of 80 different medicinal plants. Tris-HCl buffer was used as the extraction buffer and the supernatants obtained were used for determination of total protein and protease activity using spectrophotometric methods. Qualitative screening for the presence of protease was carried out with agar diffusion method by incorporating the substrate. SDS-PAGE was used to analyse the isoforms of protease and for determination of relative molecular mass. RESULTS: Relatively higher protease activities were observed in the extracts of leaves of Pongamia pinnata (Fabaceae), Wrightia tinctoria (Apocyanaceae) Acalypha indica (Euphorbiaceae), Adhatoda vasica (Acanthaceae) and Curcuma longa (Zingiberaceae). No correlation was found between the total protein content and protease activity in individual plant species. SDS-PAGE analysis indicated the presence of multiple forms of protease of higher molecular weight range in several plant species. We found a strong correlation between the protease activity and medicinal application of the plant CONCLUSION: The present study has unequivocally revealed that the leaves of medicinal plants could serve as excellent sources of proteases which could be exploited for various industrial, food and pharmaceutical applications. PMID- 29496171 TI - Resveratrol combined with total flavones of hawthorn alleviate the endothelial cells injury after coronary bypass graft surgery. AB - OBJECTIVE: To explore the preventive and therapeutic effects of Resveratrol combined with total flavones of hawthorn, compatibility of traditional Chinese medicines, on the endothelial cells injury after artery bypass graft surgery. METHODS: The animal model of coronary artery bypass grafting (CABG) was prepared by transplanting a segment of autologous jugular vein onto the transected common carotid artery in rabbits. After CABG surgery, the rabbits were administrated with saline (model group), aspirin (Aspirin group), resveratrol (Res group), total flavones of hawthorn (Haw group) and resveratrol combined with total flavones of hawthorn (Res+Haw group) once a day for eight weeks, respectively. Eight weeks later, the grafting arteries from all group were obtained for the pathomorphism observation, peripheral blood was collected to detect circulating endothelial cells (CECs) by flow cytometry. And the concentration of albumen and mRNA of ICAM-1 in the serum were measured by western blot and quantitative real time polymerase chain reaction, respectively. RESULTS: Compared with the model group, the level of CECs density and the expressions of albumen and mRNA of ICAM 1 were significantly decreased in the aspirin,resveratrol,total flavones of hawthorn and resveratrol combined with total flavones of hawthorn groups (P < .05). Of note, above all parameters were lower in Res group than aspirin group. CONCLUSION: The Resveratrol combined with total flavones of hawthorn could protect the endothelial cells after coronary artery bypass graft. PMID- 29496173 TI - Bavachalcone from Cullen corylifolium induces apoptosis and autophagy in HepG2 cells. AB - BACKGROUND: Cullen corylifolium is a plant widely used in traditional Chinese medicine for its stomachic, anthelmintic, and diuretic properties. Bavachalcone, which is known as a component of C. corylifolium has been reported to inhibit osteoclast differentiation. However, the anticancer efficacy and mechanism of C. corylifolium and bavachalcone have not been studied. HYPOTHESIS/PURPOSE: Our aim is to determine whether C. corylifolium has an anticancer effect and to identify the apoptosis and autophagy mechanism of bavachalcone. STUDY DESIGN/METHOD: The anti-proliferative activity of C. corylifolium and bavachalcone was measured with MTT assay. Apoptosis was analyzed using Annexin V and propidium iodide staining. The expression of apoptosis, cell cycle and autophagy related gene was evaluated by western blot. Cell cycle stage was investigated with TaliR image-based cytometer. Autophagic activity was assessed using monodansylcadaverine (MDC) staining. RESULT: C. corylifolium exhibited potent effect on apoptosis in HepG2 cells. To identify which compound in C. corylifolium is responsible for this effect, we determined the effects of psoralen, psoralidin, bavachalcone, and isobavachalcone on the activity of bid, caspase 3, and PARP. Of all the studied compounds, bavachalcone was the most potent inducer of apoptosis and acted via crosstalk between the intrinsic and extrinsic pathways. In addition, bavachalcone caused cell cycle arrest and decreased the levels of early cell cycle regulatory proteins such as CDK 4 and CDK 2, whereas p21 and p27 levels were increased. We also investigated the extent to which bavachalcone-induced autophagy and apoptosis were related. Phosphorylation and expression of Akt and mTOR were decreased, while the LC3 II to LC3I ratio was increased in bavachalcone-treated cells. These results suggest that bavachalcone has anticancer activity by promoting both autophagy and apoptosis in HepG2 cells. CONCLUSION: C. corylifolium has an anticancer effect. Especially, bavachalcone has excellent anticancer ability among other components of C. corylifolium by inducing apoptosis and autophagy. PMID- 29496172 TI - Inhibition of human monoamine oxidase A and B by flavonoids isolated from two Algerian medicinal plants. AB - BACKGROUND: Monoamine oxidases (MAOs) are outer mitochondrial membrane flavoenzymes. They catalyze the oxidative deamination of a variety of neurotransmitters. MAO-A and MAO-B may be considered as targets for inhibitors to treat neurodegenerative diseases and depression and for managing symptoms associated with Parkinson's and Alzheimer's diseases. PURPOSE: The objective was to evaluate the inhibitory effect of Hypericum afrum and Cytisus villosus against MAO-A and B and to isolate the compounds responsible for the MAO-inhibitory activity. METHODS: The inhibitory effect of extracts and purified constituents of H. afrum and C. villosus were investigated in vitro using recombinant human MAO-A and B, and through bioassay-guided fractionation of ethyl acetate fractions of areal parts of the two plants collected in northeastern Algeria. In addition, computational protein-ligand docking and molecular dynamics simulations were carried out to explain the MAO binding at the molecular level. RESULTS: The ethyl acetate (EtOAc) fractions of H. afrum and C. villosus showed the highest MAO inhibition activity against MAO A and B with IC50 values of 3.37 ug/ml and 13.50 ug/ml as well as 5.62 and 1.87 ug/ml, respectively. Bioassay-guided fractionation of the EtOAc fractions resulted in the purification and identification of the known flavonoids quercetin, myricetin, genistein and chrysin as the principal MAO inhibitory constituents. Their structures were established by extensive 1 and 2D NMR studies and mass spectrometry. Quercetin, myricetin and chrysin showed potent inhibitory activity towards MAO-A with IC50 values of 1.52, 9.93 and 0.25 uM, respectively, while genistein more efficiently inhibited MAO-B (IC50 value: 0.65 uM). The kinetics of the inhibition and the study of dialysis dissociation of the complex of quercetin and myricetin and the isoenzyme MAO-A showed competitive and mixed inhibition, respectively. Both compounds showed reversible binding. Molecular docking experiments and molecular dynamics simulations allowed to estimate the binding poses and to identify the most important residues involved in the selective recognition of molecules in the MAOs enzymatic clefts. CONCLUSION: Quercetin and myricetin isolated from H. afrum together with genistein and chrysin isolated from C. villosus have been identified as potent MAO-A and -B inhibitors. H. afrum and C. villosus have properties indicative of potential neuroprotective ability and may be new candidates for selective MAO-A and B inhibitors. PMID- 29496174 TI - Fabrication of surfactant-stabilized nanosuspension of naringenin to surpass its poor physiochemical properties and low oral bioavailability. AB - BACKGROUND: Nanosuspension is a biphasic system consisting of native drug particles dispersed in an aqueous surfactant or polymeric solution with a particle size between 10 to 1000 nm. In contrast to other drug delivery systems, nanosuspension offer the unique advantage of increasing solubility of the native drug resulting into faster drug absorption and hence achieving faster maximum plasma concentration. HYPOTHESIS/PURPOSE: The present study aims to evaluate surfactants/polymer stabilized nanosuspensions of naringenin (NN), a phytomedicine, to surpass its poor physiochemical properties and low oral bioavailability. STUDY DESIGN: Optimization and characterization (DLS, SEM, PXRD and DSC) of nanosuspensions followed by in-vitro drug dissolution studies and pharmacokinetic study in male Sprague-Dawley rats were performed. METHODS: Nanosuspensions were prepared by precipitation-ultrasonication method with varying concentrations of different surfactants and polymer such as sodium cholate (SC), sodium lauryl sulphate (SLS), poly ethylene glycol 4000 (PEG), polysorbate 80 (Tween(r) 80), poloxomer-188 and D-alpha-Tocopherol polyethylene glycol 1000 succinate (TPGS or Vitamin E-TPGS). RESULTS: Nanosuspension prepared with 0.5% w/v d-alpha-Tocopherol polyethylene glycol 1000 succinate (TPNS) and 7.5 mg NN, showed the smallest size of 118.1 +/- 2.7 nm. TPNS showed increase in drug dissolution in simulated gastric fluid pH 1.2 (SGF) and phosphate buffer pH 6.8 (PB). TPNS demonstrated an improved pharmacokinetic profile compared to pure NN resulting 2.14 and 3.76 folds increase in Cmax and AUC, respectively. In addition, TPNS were stable over a period of six months. CONCLUSION: The developed formulation strategy of nanosuspension could be exploited to improve the solubility and bio-availability of poorly soluble NN and other phytomedicines. PMID- 29496175 TI - Caffeic acid phenethyl ester synergistically enhances the antifungal activity of fluconazole against resistant Candida albicans. AB - BACKGROUND: Owing to the increased morbidity and mortality associated with invasive fungal infections, treatments with a combination of antifungal agents are often considered. Caffeic acid phenethyl ester (CAPE), a major active component of propolis, possesses many biological activities, including antibacterial, antiviral, antioxidant, anti-inflammatory, and anticancer effects. PURPOSE: This study aimed to evaluate the interaction between CAPE and fluconazole (FLC) against Candida albicans. METHODS: Microdilution checkerboard and time-kill assays were employed to evaluate the in vitro interaction between CAPE and FLC. The data obtained from the checkerboard tests were analyzed by the fractional inhibitory concentration index (FICI).The antifungal activity of the CAPE and FLC combination was evaluated in vivo in a Caenorhabditis elegans model of infection. RESULTS: We observed that when used in combination, CAPE acted synergistically with FLC against FLC-resistant clinical isolates of C. albicans. In addition, the CAPE-FLC combination significantly extended the longevity and reduced fungal burden in C. elegans when compared with treatment with FLC or CAPE alone. CONCLUSION: These results indicate that the use of CAPE and FLC in combination has considerable therapeutic potential against resistant C. albicans. PMID- 29496176 TI - Rosmarinic acid attenuates development and existing pain in a rat model of neuropathic pain: An evidence of anti-oxidative and anti-inflammatory effects. AB - BACKGROUND: We aimed to investigate the potential prophylactic and curative effects of rosmarinic acid, one of the main constituents of rosemary, on the neuropathic pain induced by chronic constriction injury (CCI) in rats. MATERIALS AND METHODS: CCI was used to induce peripheral neuropathic pain. In prophylactic groups, rosmarinic acid (10, 20, and 40 mg/kg, i.p.) was administered from the day of surgery (day 0) for 14 days. In treatment group, rosmarinic acid (40 mg/kg) was given from day 5 (after the pain was established), for 7 days. The degree of mechanical allodynia, cold allodynia, and heat hyperalgesia were measured on days 0, 3, 5, 7, 10 and 14 post-surgery. The open field test was carried out to assess locomotor activity of animals. Lumbar spinal cord levels of astroglia activation marker, glial fibrillary acidic protein (GFAP), microglial activation marker, ionized calcium-binding adapter molecule 1 (Iba-1), toll-like receptor 4 (TLR-4), tumor necrosis factor alpha (TNF-alpha), inducible isoform of nitric oxide synthase enzyme (iNOS) and apoptotic factors were quantified via western blot on days 7 and 14. RESULTS: CCI rats showed a significant mechanical allodynia, cold allodynia and thermal hyperalgesia, compared to sham ones on day 3, persisted up to day 14 post-CCI. Rosmarinic acid was able to prevent and also attenuate CCI-induced behavioral features in prophylactic as well as treatment groups, respectively. A significant increase in the levels of TNF-alpha, iNOS, apoptotic factors (Bax, caspases 3, 9), Iba-1, TLR-4, and GFAP was observed on both days 7 and 14, which was suppressed by 14 days administration of rosmarinic acid. CONCLUSION: These findings further support the use of rosemary in traditional medicine to alleviate pain. Rosmarinic acid could be a promising compound in prophylaxis and treatment of neuropathic pain. Anti-apoptotic and anti-inflammatory effects of rosmarinic acid may have important roles in the observed antinociceptive properties. PMID- 29496177 TI - Berberine reinforces Sertoli cells niche and accelerates spermatogonial stem cells renewal in experimentally-induced varicocele condition in rats. AB - BACKGROUND: Varicocele is present in 10-20% of the male infertile population. PURPOSE: Present study was done to demonstrate the reinforcing effect of berberine (BBR), as an antioxidant and anti-inflammatory agent, on Sertoli cells related niche and spermatogonial stem cells (SSCs) self-renewal in experimentally induced VCL condition. STUDY DESIGN: 50 mature male Wistar rats were divided into control, control-sham, non-treated VCL-induced, 50 mg kg-1 and 100 mg kg-1 BBR treated VCL-induced groups. METHODS: The Leydig and Sertoli cells distribution and Leydig cells steroidogenic activity, expression of glial cell line-derived neurotrophic factor (GDNF), proto-oncogene Rearranged during Transfection (c-RET) receptor, Ets variant gene 5 (Etv5) and B-cell chronic lymphocytic leukemia (CLL)/lymphoma 6, member B (Bcl-6b) at mRNA and protein levels were analyzed. The mRNA integrity and DNA fragmentation were assessed. Finally, the serum levels of testosterone, inhibin B and testicular total antioxidant capacity, total thiol molecules, catalase, and malondialdehyde were evaluated. RESULTS: Observations revealed that, the BBR significantly enhanced VCL-reduced Leydig and Sertoli cells population, maintained Leydig-Sertoli cells network, enhanced GDNF, c-RET Etv5 and Bcl6b expression, up-regulated testicular antioxidant and endocrine status. CONCLUSION: The BBR by boosting Leydig-Sertoli cells network up-regulates the GDNF, Etv5 and Bcl-6b expression/synthesis in SSCs, which in turn improves SSCs self-renewal activities. Thus, the BBR could be considered as an appropriate agent for antioxidant therapy of VCLs. However, more studies with bigger sample number and focus on BBR-induced effects on other genes involving in the self renewal process are needed to have more deterministic results. PMID- 29496178 TI - Eisenia bicyclis (brown alga) modulates platelet function and inhibits thrombus formation via impaired P2Y12 receptor signaling pathway. AB - BACKGROUND AND PURPOSE: Sea weeds have been used since ancient times in Asian countries, especially in Korea, Japan, and China, as both edible sea vegetables and traditional medicinal tonics due to their health benefits. Eisenia bicyclis has been studied for anti-allergic and anti-cancer effects; however, its effects on the cardiovascular system, especially on platelet function, are yet to be explored. Therefore, we examined the effect of E. bicyclis on platelet function. STUDY DESIGN AND METHODS: E. bicyclis extract (EBE) was prepared and in vitro effects on ADP-induced platelet aggregation, granule secretion, intracellular calcium ion ([Ca2+]i) mobilization, fibrinogen binding to integrin alphaIIbbeta3 and clot retraction were evaluated. Phosphorylation levels of MAPK signaling molecules and P2Y12 receptor downstream signaling pathway components were studied. In vivo effects were studied using an arteriovenous (AV) shunt model. RESULTS: EBE markedly inhibited in vitro ADP-induced platelet aggregation, granule secretion (ATP release and P-selectin expression), [Ca2+]i mobilization, fibrinogen binding to integrin alphaIIbbeta3, and clot retraction; attenuated MAPK pathway activation; and inhibited phosphorylation of PI3K/Akt, PLCgamma2, and Src. The extract significantly inhibited in vivo thrombus weight in an AV shunt model. CONCLUSION: E. bicyclis inhibits agonist-induced platelet activation and thrombus formation through modulation of the P2Y12 receptor downstream signaling pathway, suggesting its therapeutic potential in ethnomedicinal applications as an anti-platelet and anti-thrombotic compound to prevent cardiovascular diseases. PMID- 29496179 TI - Protective effects of total flavonoids from Clinopodium chinense (Benth.) O. Ktze on myocardial injury in vivo and in vitro via regulation of Akt/Nrf2/HO-1 pathway. AB - BACKGROUND: Clinopodium chinense (Benth.) O. Ktze is a traditional Chinese herbal medicine, which comprises the plant's total flavonoids. TFCC plays an important role in the treatment of cardiovascular disease. PURPOSE: The aim of the study was to study the protective effects and possible mechanism of TFCC against isoproterenol (ISO)-mediated myocardial injury in vivo and anoxia/reoxygenation (A/R)-induced H9c2 cell injury in vitro. METHODS: Male Sprague-Dawley (SD) rats were intragastrically pretreated with TFCC for 15 days. After 2 h of TFCC administration on days 14 and 15, a myocardial injury model was established with intragastric administration of 120 mg/kg of ISO daily for 2 days. The experiment was stopped 12 h after the last administration of the drugs. ECG recordings were taken after the treatment. Serum samples were assayed to determine the serum cardiac enzymes (e.g., creatine kinase, aspartate aminotransferase, and lactate dehydrogenase). The left ventricle was excised for histopathological examination, and myocardial homogenates were prepared to detection catalase, glutathione peroxidase, and superoxide dismutase. Reactive oxygen species (ROS), heme oxygenase-1(HO-1),and peroxidase were detected by the corresponding ELISA kits. H9c2 cells were pretreated with different concentrations of TFCC for 12 h before A/R exposure. Afterward, cell viability, LDH release, hoechst 33,342, and peromide iodine (PI) double staining, JC-1 staining, and ROS examination were determined. Western blot analyses of B-cell lymphoma-2, Bcl-2associated X protein, cleaved cysteinylaspartate specific protease-3 and-9, nuclear factor 2(Nrf2), HO-1 and serine/threonine protein kinase (AKT), and P-AKT were conducted. RESULTS: The pretreatment of TFCC (10, 20, and 40 mg/kg) daily for 15 days prevented ISO-induced myocardial damage, including the decrease in serum cardiac enzymes and cardiomyocyte apoptotic index and improvement in the heart rate and vacuolation. TFCC also improved the free radical scavenging and antioxidant potential, thereby suggesting that one possible mechanism of TFCC induced cardio protection is mediated by blocking the oxidative stress. To clarify these mechanisms, we performed the in vitro study by A/R-induced cytotoxicity model in H9c2 cells. TFCC pretreatment prevented apoptosis, increased the expression of HO-1, and enhanced the nuclear translocation of Nrf2. TFCC also activated phosphorylation of AKT, whereas the addition of LY294002, which is the pharmacologic inhibitor of PI3K, blocked the TFCC-induced Nrf2/HO-1 activation and cytoprotective effect. CONCLUSIONS: TFCC protects against myocardial injury and enhances cellular antioxidant defense capacity by inducing the phosphorylation of AKT, which subsequently activated the Nrf2/HO-1 signaling pathway. PMID- 29496180 TI - Early LC3 lipidation induced by d-limonene does not rely on mTOR inhibition, ERK activation and ROS production and it is associated with reduced clonogenic capacity of SH-SY5Y neuroblastoma cells. AB - BACKGROUND: d-Limonene is a natural monoterpene abundant in Citrus essential oils. It is endowed with several biological activities, including inhibition of carcinogenesis and promotion of tumour regression. Recently, d-limonene has been shown to modulate autophagic markers in vitro at concentrations found in vivo, in clinical pharmacokinetic studies. Autophagy is an intracellular catabolic process serving as both an adaptive metabolic response and a quality control mechanism. Because autophagy defects have been linked to a wide range of human pathologies, including neurodegeneration and cancer, there is a need for new pharmacological tools to control deregulated autophagy. PURPOSE: To better understand the effects of d-limonene on autophagy, to identify the molecular mechanisms through which this monoterpene rapidly triggers LC3 lipidation and to evaluate the role for autophagy in long-term effects of d-limonene. METHODS: Human SH-SY5Y neuroblastoma, HepG2 hepatocellular carcinoma and MCF7 breast cancer cells were used. Endogenous LC3-II levels were evaluated by western blotting. Autophagic flux assay was performed using bafilomycin A1 and chloroquine. Intracellular distribution of LC3 protein was studied by confocal microscopy analysis of LC3B GFP transduced cells. Expression of lysosomal-membrane protein LAMP-1 was assessed by immunofluorescence analysis. Phosphorylated levels of downstream substrates of mTOR kinase (p70S6 kinase, 4E-BP1, and ULK1) and ERK were analyzed by western blotting. Production of reactive oxygen species (ROS) was assessed by live confocal microscopy of cells loaded with CellROX(r) Green Reagent. Clonogenic assay was used to evaluate the ability of treated cells to proliferate and form colonies. RESULTS: LC3 lipidation promoted by d-limonene correlates with autophagosome formation and stimulation of basal autophagy. LC3 lipidation does not rely on inhibition of mTOR kinase, which instead appears to be transiently activated. In addition, d-limonene rapidly activates ERK and stimulates ROS generation, yet none of these events is implicated in lipidation of LC3, which was only partly reduced by chelation of intracellular calcium. The early LC3 lipidation induced by d-limonene is associated with inhibition of clonogenic capacity which is reverted by the autophagy inhibitor chloroquine. CONCLUSIONS: d Limonene rapidly stimulates the autophagic flux in cultured cancer cells, which could be usefully exploited for therapeutic purposes. PMID- 29496185 TI - Strengthening preparedness for (re-) emerging arboviruses in Europe. PMID- 29496186 TI - A comparative study of rail-pedestrian trespassing crash injury severity between highway-rail grade crossings and non-crossings. AB - Rail-trespassing crashes that involve various levels of injuries to pedestrians are under-researched. Rail trespassing could occur at crossings where pedestrians are present at the wrong time and at non-crossings where pedestrians are not legally allowed to be present. This paper presents a comparative study examining rail-trespassing crashes in two contexts: highway-rail grade crossings vs. non crossings. How pre-crash trespassing behaviors and other factors (e.g., crash time, locations, and socio-demographics) differ between grade crossings and non crossings are explored. The analysis relies on a ten-year (2006-2015) database of rail-pedestrian trespassing crash records extracted from a Federal Railroad Administration safety database. Of these 7157 rail-pedestrian trespassing crashes, 6236 (87%) occurred at non-crossings, while 921 (13%) occurred at grade crossings. About 60% of the crashes were fatal at both crossings and non crossings. The most prevalent pre-crash trespassing behavior is running or walking, 63% at grade crossings and 44% at non-crossings. Lying or sleeping account for 29% of non-crossing crashes, whereas they are 3.6% at grade crossings. A unique aspect of the study is that a diverse set of variables based on geographic variations across counties along with crash or injury data are modeled. Considering the data structure and heterogeneity that may exist due to unobserved factors, the multilevel mixed-effect ordered logistic regressions models are estimated. The results show that the correlates of injury severity differ across highway-rail grade crossings and non-crossings. For example, lying or sleeping on or near tracks contributed to higher chances of fatal injury in both contexts, however, they were relatively more injurious at grade crossings. The analytical results can provide guidance on railway safety improvement plans. PMID- 29496187 TI - Risk perception and the warning strategy based on microscopic driving state. AB - The paper aimed to explore the relationship between risks and individuals' driving states and then design an efficient method to help drivers avoid high risks. The relationship between risks and individuals' driving states was deeply studied first. Microscopic driving states were categorized into different clusters, and it was found that the risks are distinct in different clusters and a specific driver might experience different risks in car-following process. Then, according to these findings, a risk warning strategy was designed to help drivers avoid high risks. The risk warning is active when the risk is higher than its threshold. The Helly models were used to mimic the drivers' reaction to study the influence of the warning strategy. Simulation results showed that with the consideration of the risk warning, the spacing obviously increases, and the oscillations of velocity and acceleration are significantly shrunk, and risks in the driving process dampen down. Because drivers can perceive high risks during the driving process, and then appropriately change their car-following decisions to avoid high risks. These findings are helpful to improve driving behaviors and promote traffic safety. PMID- 29496188 TI - Evaluation of supercritical fluid chromatography coupled to tandem mass spectrometry for pesticide residues in food. AB - Supercritical fluid chromatography coupled to triple quadrupole mass spectrometry has been evaluated for pesticide residues in food. In order to check its advantages and limitations it was developed a method to identify and quantify 164 pesticides in three different matrices (tomato, orange and leek). A carbon dioxide gradient with methanol (containing 1 mM ammonium formate) was used allowing a flow rate of 1.5 mL/min that made the total run time of 12 min without any problem of overpressure. Addition of a post column flow 150 MUL/min of Methanol with ammonium formate/formic acid was necessary to improve the ionization. The matrix effect study revealed that the percentages of pesticides with irrelevant matrix effect (suppression lower than 20%) was 99% in tomato, 87% in orange and 62% in leek, whereas significant suppression (higher than 50%) was not found in tomato and only 1% of the compounds in orange and 3% in leek.These results compare favorably with that typically obtained in LC-MS/MS. The absence of water in the mobile phase, also provided some important advantages regarding LC-MS/MS as (i) higher retention of polar compounds in the column, which elute with high sensitivity and good peak shape and (ii) a general increase of the sensitivity of the analysis, consequence of the high ionization and ion extraction efficiency. Pesticides evaluated were identified following the SANTE/11813/2017. At the spiking concentration of 5 MUg/kg, 98% of the pesticides were identified in tomato, 98% in orange and 94% in leek, whereas for the concentration of 10 MUg/kg all the compounds were identified in tomato and only spiromesifen was not identified in orange and leek. At the concentration of 20 MUg/kg, spiromesifen was also identified in these two matrices. The linearity and reproducibility of the method were evaluated with results which guarantee high quality in the analytical measurements. Even though only 2 MUL of final extract were injected, the sensitivity of the SFC method was enough to achieve stringent LOQs.Real samples, including 6 different fruits and vegetables, were analyzed by the SFC-MS/MS proposed method, the results being similar to those obtained by LC MS/MS. The method was also applied to a proficiency test of fipronil in eggs with good results in all the cases. Carbon dioxide as mobile phase with methanol as modifier can represent a good alternative to LC-MS/MS with reduction of matrix effects and shorter run times. PMID- 29496189 TI - Optimization and application of parallel solid-phase extraction coupled with ultra-high performance liquid chromatography-tandem mass spectrometry for the determination of 11 aminoglycoside residues in honey and royal jelly. AB - A robust and sensitive method of solid-phase extraction followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) was established and performed for the simultaneous determination of eleven aminoglycosides (AGs) in royal jelly and honey. After sample extraction by a phosphate buffer containing trichloroacetic acid (TCA) and ethylenediaminetetracetic acid disodium salt (Na2EDTA), the extraction solution was subjected to a parallel solid-phase extraction for clean-up prior to the LC-MS/MS analysis. The same method was applied to analyze two completely different matrices, honey and royal jelly. Good sensitivity, repeatability, and recovery were obtained by using the mobile phase without an ion-pairing reagent such as heptafluorobutyric acid (HFBA) or sodium heptanesulfonate. The calibration curves of the honey and royal jelly samples exhibited a good linear response (R2 > 0.99) at six concentrations in the range of 10-1000 MUg/mL. The limit of quantification (LOQ) of the AGs ranged from 10 to 25 MUg/kg in the honey and from 12.5 to 25 MUg/kg in the royal jelly. The recoveries of the AGs for the honey and royal jelly samples were in the range of 79.48% to 108.95% and 74.61% to 113.70% respectively and the relative standard deviations (RSDs) were between 1.23% and 9.59%, and between 1.51% and 9.98%, respectively. The proposed approach has been allowed in China as a reference method for the simultaneous determination of eleven AGs in honey and royal jelly. PMID- 29496190 TI - Advances in covalent organic frameworks in separation science. AB - Covalent organic frameworks (COFs) are a new class of multifunctional crystalline organic polymer constructed with organic monomers via robust covalent bonds. The unique properties such as convenient modification, low densities, large specific surface areas, good stability and permanent porosity make COFs great potential in separation science. This review shows the state-of-the art for the application of COFs and their composites in analytical separation science. COFs and their composites have been explored as promising sorbents for solid phase extraction, potential coatings for solid phase microextraction, and novel stationary phases for gas chromatography, high-performance liquid chromatography and capillary electrochromatography. The prospects of COFs for separation science are also presented, which can offer an outlook and reference for further study on the applications of COFs. PMID- 29496191 TI - Ultra-high performance liquid chromatography with fluorescence detection following salting-out assisted liquid-liquid extraction for the analysis of benzimidazole residues in farm fish samples. AB - Ultra-high performance liquid chromatography (UHPLC) coupled with fluorescence detection (FL) has been proposed for the first time to determine thirteen benzimidazoles (BZs) in farmed fish samples. In order to optimize the chromatographic separation, parameters such as mobile phase composition and flow rate were carefully studied, establishing a gradient mode with a mobile phase consisted of water (solvent A) and acetonitrile (solvent B) at a flow rate of 0.4 mL/min. The separation was performed on a Zorbax Eclipse Plus RRHD C18 column (50 * 2.1 mm, 1.8 MUm), involving a total analysis time lower than 12 min. Salting out assisted liquid-liquid extraction (SALLE) was applied as sample treatment to different types of farmed fish (trout, sea bream and sea bass). To obtain satisfactory extraction efficiencies for the studied analytes, several parameters affecting the SALLE procedure were optimized including the amount of sample, type and volume of the extraction solvent, and the nature and amount of the salt used. Characterization of the method in terms of performance characteristics was carried out, obtaining satisfactory results for the linearity (R2 >= 0.997), repeatability (RSD <= 6.1%), reproducibility (RSD <= 10.8%) and recoveries (R >= 79%; RSD <= 7.8%). Detection limits between 0.04-29.9 MUg kg-1 were obtained, demonstrating the applicability of this fast, simple and environmentally friendly method. PMID- 29496192 TI - Impact of Advanced Therapies for Improving Survival to Heart Transplant in Patients with Hypertrophic Cardiomyopathy. AB - Heart transplant has become an increasingly important option for patients with end-stage nonobstructive hypertrophic cardiomyopathy (HC). However, clinical details related specifically to the overall HC transplant experience remain sparse. We assessed outcomes of HC heart transplants, from 2002 to 2016, at Tufts Medical Center. Fifty-two nonobstructive severely symptomatic patients underwent evaluation at 47 +/- 13 years; 11 (21%) declined or failed to qualify, most commonly because of co-morbidities (n = 7). Of the remaining 41 patients ultimately listed, 6 (15%) died of heart failure awaiting transplant (11%/year), 26 underwent transplant, and 9 remained active on the list. Survival rates on the waiting list depended on >=1 treatment intervention: inotropic medications (n = 20), ventricular assist devices (n = 7), or implantable defibrillators terminating ventricular tachyarrhythmias (n = 7). Of the 26 transplanted patients, 24 survived for 4.8 +/- 3.4 years (up to 12), including 23 who are currently alive. The survival rate 5 years post transplant is 92%. Compared with heart transplants for other cardiomyopathies, patients with HC had similar mortality while wait-listed and post transplant (p = 0.77 and 0.13, respectively). In conclusion, a large proportion of patients with HC considered for transplant ultimately received hearts and experienced excellent short- and long-term survival rates. The survival rate on the waiting list was directly attributable to major interventions: implantable cardioverter-defibrillators, inotropic drugs, and ventricular assist devices, and the perception that patients with HC have low wait-list mortality risk does not appear justified. Neither normal ejection fraction nor peak oxygen consumption > 14 ml/kg/min should exclude drug refractory severely symptomatic patients with HC from heart transplant consideration. PMID- 29496193 TI - Relative Prognostic Value of Cardiac Troponin I and C-Reactive Protein in the General Population (from the Nord-Trondelag Health [HUNT] Study). AB - C-reactive protein and cardiac troponin I measured with high-sensitivity assays (high-sensitivity C-reactive protein [hs-CRP] and high-sensitivity troponin I [hs TnI]) have been associated with risk of fatal and nonfatal cardiovascular events in the general population. The relative prognostic merits of hs-CRP and hs-TnI, and whether these markers of inflammation and subclinical myocardial injury provide incremental information to established cardiovascular risk prediction models, remain unclear. hs-CRP and hs-TnI were measured in 9,005 participants from the prospective observational Nord-Trondelag Health (HUNT) study. All study subjects were free from known cardiovascular disease at baseline. During a median follow-up period of 13.9 years, 733 participants reached the composite end point of hospitalization for acute myocardial infarction or heart failure, or cardiovascular death. In adjusted models, increased hs-TnI concentrations (>10 ng/L for women and >12 ng/L for men) were associated with the incidence of the composite end point (hazard ratio 3.61, 95% confidence interval [CI] 2.89 to 4.51]), whereas the risk associated with increased hs-CRP concentrations (>3 mg/L for both genders) appeared to be weaker (HR 1.71, 95% CI 1.40 to 2.10). The addition of hs-TnI to established cardiovascular risk prediction models led to a net reclassification improvement of 0.35 (95% CI 0.27 to 0.42), superior to that of hs-CRP (0.21, 95% CI 0.13 to 0.28). The prognostic accuracy of hs-TnI, assessed by C-statistics, was significantly greater than that of hs-CRP (0.753, 95% CI 0.735 to 0.772, vs 0.644, 95% CI 0.625 to 0.663). In conclusion, in subjects from the general population without a history of cardiovascular disease, hs-TnI provides prognostic information superior to that provided by hs-CRP and may therefore be a preferred marker for targeted prevention. PMID- 29496194 TI - [Dramatic evolution of a bilateral femoral artery aneurysm in a 16-year-old girl]. AB - Femoral artery aneurysm is a rare entity among the vascular complications of Takayasu's disease. It is sometimes characterized by the risk of serious local complications with hemorrhagic or ischemic event, as well as by a big therapeutic handling difficulty. We report a case of bilateral femoral artery aneurysm in a 16-year-old girl having a dramatic evolution turn after surgical treatment and irreversible limb ischemia. PMID- 29496195 TI - High Throughput Phenotyping for Dimensional Psychopathology in Electronic Health Records. AB - BACKGROUND: Relying on diagnostic categories of neuropsychiatric illness obscures the complexity of these disorders. Capturing multiple dimensional measures of neuropathology could facilitate the clinical and neurobiological investigation of cognitive and behavioral phenotypes. METHODS: We developed a natural language processing-based approach to extract five symptom dimensions, based on the National Institute of Mental Health Research Domain Criteria definitions, from narrative clinical notes. Estimates of Research Domain Criteria loading were derived from a cohort of 3619 individuals with 4623 hospital admissions. We applied this tool to a large corpus of psychiatric inpatient admission and discharge notes (2010-2015), and using the same cohort we examined face validity, predictive validity, and convergent validity with gold standard annotations. RESULTS: In mixed-effect models adjusted for sociodemographic and clinical features, greater negative and positive symptom domains were associated with a shorter length of stay (beta = -.88, p = .001 and beta = -1.22, p < .001, respectively), while greater social and arousal domain scores were associated with a longer length of stay (beta = .93, p < .001 and beta = .81, p = .007, respectively). In fully adjusted Cox regression models, a greater positive domain score at discharge was also associated with a significant increase in readmission risk (hazard ratio = 1.22, p < .001). Positive and negative valence domains were correlated with expert annotation (by analysis of variance [df = 3], R2 = .13 and .19, respectively). Likewise, in a subset of patients, neurocognitive testing was correlated with cognitive performance scores (p < .008 for three of six measures). CONCLUSIONS: This shows that natural language processing can be used to efficiently and transparently score clinical notes in terms of cognitive and psychopathologic domains. PMID- 29496197 TI - Allergic Contact Dermatitis Due to Paraphenylenediamine: An Update. AB - Paraphenylenediamine (PPD) is an amine that is mainly used as an ingredient in hair dyes and henna tattoos. The incidence of allergic contact dermatitis to PPD is increasing, particularly in younger patients. In this article, we review the main sources of PPD and the substances with which it can interact and present a practical algorithm for diagnosing and treating suspected cases of PPD allergy. PMID- 29496196 TI - Genome-wide Association Study of Dimensional Psychopathology Using Electronic Health Records. AB - BACKGROUND: Genetic studies of neuropsychiatric disease strongly suggest an overlap in liability. There are growing efforts to characterize these diseases dimensionally rather than categorically, but the extent to which such dimensional models correspond to biology is unknown. METHODS: We applied a newly developed natural language processing method to extract five symptom dimensions based on the National Institute of Mental Health Research Domain Criteria definitions from narrative hospital discharge notes in a large biobank. We conducted a genome-wide association study to examine whether common variants were associated with each of these dimensions as quantitative traits. RESULTS: Among 4687 individuals, loci in three of five domains exceeded a genome-wide threshold for statistical significance. These included a locus spanning the neocortical development genes RFPL3 and RFPL3S for arousal (p = 2.29 * 10-8) and one spanning the FPR3 gene for cognition (p = 3.22 * 10-8). CONCLUSIONS: Natural language processing identifies dimensional phenotypes that may facilitate the discovery of common genetic variation that is relevant to psychopathology. PMID- 29496198 TI - Lymphadenectomy After a Positive Sentinel Lymph Node Biopsy in Melanoma: A Paradigm Shift. PMID- 29496199 TI - Influence of Article Type on the Impact Factor of Dermatology Journals. AB - BACKGROUND AND OBJECTIVE: For scientific journals, achieving a high impact factor (IF) has become a goal in its own right. Our aim was to describe the influence of article type on the IF of dermatology journals. MATERIAL AND METHODS: We used the Scopus database to calculate an IF for Actas Dermo-Sifiliograficas and the major dermatology journals, excluding articles without abstracts, letters to the editor, and conference proceedings. Included articles were classified into 4 categories: case reports, original articles, narrative reviews, and other. We also calculated the mean IF for each article type. We then compared our results with IFs published by the Institute for Scientific Information. RESULTS: The proportion of each type of article differed between journals. Original articles carried the greatest weight in the major journals (BJD, 76.8%; Contact, 81.1%; JAAD, 63.4%; JAMA Dermatol, 63.7%.) but not in Actas Dermo-Sifiliograficas, where only 31.7% were original research articles. A higher IF was associated with the publication of reviews and original articles; a lower IF was associated with the publication of case reports and other article types. CONCLUSIONS: Publishing case reports, which have lower citation rates, leads to a lower IF. Publishing reviews and original articles will lead to a higher IF. Journals that seek a higher IF should probably publish more reviews and original articles and fewer case reports. Editorial boards should seek a balance between the interests of their clinician readers and the journal's need for a higher IF. PMID- 29496200 TI - 'Why don't they ever call?' Expectations of clinicians and pathologists regarding the communication of critical diagnoses in dermatopathology. AB - Certain diagnoses in dermatopathology have significant implications for patient management and on occasion appropriate clinical care may be facilitated by a phone call from the reporting dermatopathologist to the referring doctor. Whether this is appropriate depends on a number of factors. The concept of 'critical diagnoses' is now well established in surgical pathology, having evolved from critical value policies in clinical pathology and haematology. However, only limited attempts have been made to assess perceptions among different clinical groups. We designed a survey to assess the attitudes of pathologists, dermatologists, surgeons and general practitioners as to what circumstances warrant telephone contact in addition to a standard written report, as well as their approaches to routine histology follow-up. The survey was distributed Australia-wide via a combination of specialist colleges, medical forums and collegiate contacts. A total of 262 responses were received, encompassing representations from all of the targeted specialties. Approximately 20% of respondents were aware of adverse outcomes or 'near misses' which they felt had been due in some part to inadequate communication of histopathology results. While most practitioners have formal systems in place to review histopathology reports, this practice is not universal. There were a number clinical situations where there was a discrepancy between the expectations of clinicians and those of pathologists, in particular with regard to a diagnosis of cutaneous melanoma as well as cutaneous lesions which might be associated with inherited cancer syndromes. It is our hope that the results of this study will facilitate discussion between pathologists and referring clinicians at a local level to minimise the potential for miscommunication. PMID- 29496201 TI - Localised lymphoedema forming a papillated lesion on the scalp. PMID- 29496203 TI - The Halifax Explosion a century later: Lessons for our time. AB - A brief historical account of the Halifax Explosion, one of North America's greatest mass urban trauma casualty events of the 20th century. This disaster, in Halifax, Nova Scotia, was the result of the cataclysmic explosion of a fully loaded World War I munitions ship on the densely waterfront of that city, resulting in nearly 2000 fatalities and 9000 injured. It remains a case study in response to disasters which overwhelm local medical capabilities. PMID- 29496202 TI - Inflammatory angiomyolipoma of the liver: a diagnostic pitfall. PMID- 29496204 TI - Uptake and impact of synoptic reporting in a community care setting. AB - BACKGROUND: Breast cancer surgeries have traditionally been documented in narrative reports. Narrative reports have been shown to be incomplete. Synoptic reports utilize standardized templates to record data and have emerged as an alternative to narrative reports. This study evaluates the uptake and impact of synoptic reporting for breast cancer surgery in a community care setting. METHODS: A retrospective review of operative reports documenting breast cancer surgeries over a consecutive 3-year period. RESULTS: 772 narrative reports and 158 synoptic reports were reviewed. Synoptic reports were associated with a higher degree of overall completeness (60% vs 45%) when compared to narrative reports. 6 out of 7 surgeons that produced at least 5 synoptic and 5 narrative reports had increases in completeness with use of synoptic reporting. CONCLUSIONS: Use of synoptic reporting improves breast cancer operative report completeness and decreases superfluous content when compared to narrative reports. While synoptic report uptake during the study period was suboptimal there exists several means by which it can be improved, including investment in information technology infrastructure and emphasis on stakeholder engagement. PMID- 29496205 TI - Mollusc diversity associated with the non-indigenous macroalga Asparagopsis armata Harvey, 1855 along the Atlantic coast of the Iberian Peninsula. AB - The aims of this study were to explore mollusc assemblages associated with the non-indigenous macroalga Asparagopsis armata, to compare them with those on other macroalgae at the study region and to explore potential differences on mollusc assemblages between two regions in the Atlantic coast of the Iberian Peninsula, where A. armata is present. To achieve this, at each region, four intertidal shores were sampled. Twenty-nine mollusc species were reported and thus, A. armata harboured similar or higher diversity than other annual macroalgae in this area. When compared with perennial macroalgae, results depend on the species and studied area. Moreover, significant differences in structure of mollusc assemblages between the two studied regions were found. However, these were due to differences in the relative abundance of species rather than the presence of exclusive species at each region. PMID- 29496206 TI - A juvenile with compromised osteogenesis provides insights into past hunter gatherer lives. AB - The Late Archaic in northeastern North America (4500-2800 B.P.) pre-dates reliance on pottery and domesticated plants. It is thought to reflect a highly mobile, seasonal migratory foraging/hunting regimen. A juvenile skeleton with pervasive bone wasting and fragile jaws from the Hind Site (AdHk-1), ca. 3000 B.P., southwestern Ontario, provides evidence of the social context of her family group, including aspects of mobility and food management. The well-preserved bones and teeth are considered in bioarchaeological context. Radiographic, osteometric and cross-sectional geometric approaches to assessing musculoskeletal function are presented, plus differential diagnosis of the bone wasting condition. All bones of the probable female (aged approx. 16yr) show stunting and wasting. Wedged lower vertebral bodies, porous trabeculae, undeveloped bicondylar angles (femur) and abnormally low cortical long bone mass are consistent with chronically reduced ambulation. Few teeth remain in the dramatically resorbed alveoli; slight tooth wear and substantial calculus suggest a modified (soft) diet. Osteogenesis imperfecta type IV is the most probable etiology. The extended survival of this juvenile who may never have walked reflects collective care. The case provides evidence of a past lifeway that appears to have been organized around logistic mobility, including occupational stability and food storage. PMID- 29496207 TI - A case of Paget from a Northern Italy medieval necropolis. AB - An excavation conducted in 2002 by the Lombardy Archaeological Heritage in the St. Giulio Church (Cassano Magnago-Northern Italy) revealed an adult skeleton with an important alteration of the left femur. The femur, longer than the contralateral, exhibited an expansion of the full diaphysis; the surface was coarsened and porous. In cross section, it appeared that almost all the cortical bone had been converted into cancellous bone. Macroscopic and radiological alterations are suggestive of the monostotic form of Paget's disease, a chronic disorder, characterized by focal areas of excessive osteoclastic bone resorption followed by a secondary increase in osteoblastic bone formation. Differential diagnosis is complex for Paget's disease, requiring histological analysis, which revealed a thickened and disorganized trabecular pattern with thick cement lines. Such features, resembling to a mosaic pattern, are typical of Paget's disease. PMID- 29496208 TI - Developmental dysplasia of the hip in female adult individual: Site Tres Cruces I, Salta, Argentina (Superior formative period, 400-1000 AD). AB - Developmental dysplasia of the hip (DDH) is a developmental defect that prevents normal articulation between the acetabulum and the femoral head. This is an unusual condition, with a prevalence of 1-2 per thousand, and with only two poorly described skeletons documented in South American paleopathological literature. In this work we report an individual with such a condition, from the archeological site Tres Cruces I (Quebrada del Toro, Salta, Argentina). Several radiocarbon dates and associated materials date it to the Superior Formative (400 1000 AD). The remains are of an adult female, who also has tabular oblique cranial modification. Through detection of abnormalities in the morphology of the femora and ossa coxae, a differential diagnosis was carried out. On the left hip joint the formation of a well-defined false acetabulum, without connection with the true one, was observed. The latter was shallow, triangular, with an irregular base. The left os coxae showed a wider greater sciatic notch angle. The right os coxae exhibited a false acetabulum connected with the true one. Both femora presented a small femoral head, flat and mushroom-shaped, with shortening of the neck. These features were more pronounced on the right-side elements. On the basis of the aforementioned, a presumptive diagnosis of bilateral developmental dysplasia of the hip with complete dislocation on both sides was established. PMID- 29496209 TI - Comment upon "Basilar portion porosity: A pathological lesion possibly associated with infantile scurvy". PMID- 29496210 TI - Response to Gonzalez et al.'s comment upon "Basilar portion porosity: A pathological lesion possibly associated with infantile scurvy". PMID- 29496211 TI - How should we diagnose disease in palaeopathology? Some epistemological considerations. AB - This paper analyses some of the epistemological frameworks that underpin diagnosis in palaeopathology. Currently, the dominant approach is comparative: relationships between skeletal lesions and disease in a reference group in which there is independent evidence of the diseases present in individuals are used to identify disease in unknown archaeological skeletons on the basis of the lesions present. This is essentially a reference sample - target sample approach, analogous to that used to develop methodology in other areas of biological anthropology (e.g. age estimation in palaeodemography). As well as considerable strengths, this approach also has significant weaknesses. Many of these arise from the nature of the reference material (mainly pathology museum and other skeletal collections, and published collations of medical imaging data) used to develop diagnostic criteria. There may also be a tendency toward over-emphasis on pattern-matching between reference and target material, and an under-emphasis on developing our understanding of the biology of bone lesions. Despite its shortcomings, the comparative approach is likely to remain the foundation of most palaeopathological work, but we should increasingly augment it with other diagnostic approaches, especially those grounded in the pathophysiology of bony responses to disease. PMID- 29496212 TI - Horse-riding accidents and injuries in historical records of Joseon Dynasty, Korea. AB - Only a few osteological reports describe bone injuries thought to have been caused by falls from horses. Nevertheless, anthropological study alone is insufficient for establishing the correlates of such equestrian accidents. We therefore reviewed the records in Seungjeongwon ilgi (Diaries of the Royal Secretariat) and Joseon wangjo silrok (Annals of the Joseon Dynasty) of the Korea's Joseon period (1392-1910 CE). Although the mechanisms of trauma were diverse, the Joseon documents recorded many injuries caused by horse-riding accidents. During 1625-1872 CE, equestrian-related accidents occurred almost every year, overwhelming other causes of trauma. In all horse-riding accidents (n=142), 37.77% of the records offer detailed data about the traumatic mechanism. Injuries occurred most frequently to the extremities (79.58%), which were followed by the trunk (34.5%) and head (4.92%). Although we do not think that this attempt can explain every paleopathological case, our historical review shows that equestrian-related injuries could be considered as one of the major causes for the bone trauma observed among ancient equestrian people. PMID- 29496213 TI - Is differential diagnosis attainable in disarticulated pathological bone remains? A case-study from a late 19th/early 20th century necropolis from Juncal (Porto de Mos, Portugal). AB - Differential diagnosis is a fundamental step in every palaeopathological study. It is a challenging exercise since many intrinsic and extrinsic factors may negatively impact the accurate interpretation of bone changes in human skeletal remains. Among these, the completeness and preservation of skeletal elements plays a significant role. This study aims to explore the limits of differential diagnosis in the analysis of disarticulated, fragmented bones. The sample consists of twelve adult bone fragments with noticeable changes. The remains were identified in a dis-articulated skeletal assemblage from the former necropolis of Juncal (Porto de Mos, Portugal), which probably closed in the late 19th century/early 20th century. They were analysed visually and with X-radiography, and the changes carefully described prior to differential diagnosis. Six bones presented signs of healed bone trauma and one showed features compatible with leg amputation. Periosteal reactions were observed in several bones, one of them resembling changes consistent with an overlying skin ulcer. Two bone fragments were identified as belonging to the same individual due to the matching bone changes. Despite the incomplete remains, a broader diagnosis was possible for most cases, which facilitated a discussion of health, medical and social care among the inhabitants of the region. PMID- 29496214 TI - Smaller long bone cross-sectional size in people who died of tuberculosis: Insights on frailty factors from a 19th and early 20th century Finnish population. AB - There is little research on how individuals suffering from tuberculosis may differ from those not infected in terms of overall skeletal morphology. Tuberculosis was endemic in 19th and early 20th century Finland making documented skeletal collections of Finns ideal to study effects of the disease on bone. The present study compares long bone cross-sectional total area between individuals who died of tuberculosis and those with another recorded cause of death in a Finnish sample. Adult male individuals (N = 105) were selected for analysis. Complete humeri (N = 56), femora (N = 66) and tibiae (N = 64) were 3D scanned using a laser scanner and total cross-sectional areas calculated with AsciiSection software. Individuals who died of tuberculosis (N = 24, 15 humeri, 14 femora, 13 tibiae) had, when standardized for body size, significantly smaller total cross-sectional femoral and humeral, but not tibial, areas. The mechanisms behind the observed relationship may reflect a combination of biological 'frailty' in terms of susceptibility to infection, reduced childhood activity and/or vitamin D deficiency, which possibly influenced both subperiosteal development during adolescence and, later, susceptibility to contracting and dying of TB. Due to the relatively small sample future studies are needed to further investigate the relationship between TB and bone cross-sectional size. PMID- 29496215 TI - A recording form for differential diagnosis of arthropathies. AB - The present study is focused on a group of arthropathies that may have very similar bone manifestations (rheumatoid arthritis, ankylosing spondylitis, reactive arthritis, psoriatic arthritis, osteoarthritis and diffuse idiopathic skeletal hyperostosis), which makes it more difficult to diagnose them in human remains from archaeological contexts. A stepwise recording form was designed in order to improve the identification and differential diagnosis of these pathological conditions in bone remains, particularly in joint manifestations of the spine, pelvis, hands, feet and other limb joints. This recording form was applied in the analysis of two medieval individuals from the Basque Country (Spain) who presented very severe arthropathic manifestations. The use of this recording form allowed the researchers the diagnosis of ankylosing spondylitis in one of them and diffuse idiopathic skeletal hyperostosis in the other. PMID- 29496216 TI - CT checklist and scoring system for the assessment of soft tissue preservation in human mummies: application to catacomb mummies from Palermo, Sicily. AB - In this study we applied the recently developed "Checklist and Scoring System for the Assessment of Soft Tissue Preservation in Human Mummies" to catacomb mummies from Palermo, Sicily. Data from twenty-three full-body computed tomography (CT) examinations were available. These consisted of seventeen adults and six children dating from the late 18th to the late 19th centuries AD. Seventeen of these mummies were anthropogenically mummified, and six spontaneously. Based on the checklist and scoring system, soft tissue preservation varied between both mummification groups, among mummies with the same type of mummification, and within individual mummies at different anatomical locations. Checkpoints of the main category "A. Soft Tissues of Head and Musculoskeletal System" were clearly more frequent than checkpoints of the main category "B. Organs and Organ Systems". Among the anthropogenic mummies, intra-arterial filling achieved the highest preservation status of organs and organ systems. Despite the small sample size, the statistical evaluation showed significant differences between mummification types, with the highest soft tissue preservation found in anthropogenic mummies. Application of the "Checklist" allowed a standardized assessment and documentation of the soft tissue preservation of these mummies. The "Scoring System" facilitated a comparison among mummification groups and mummies by means of numeric values. PMID- 29496217 TI - Paleopathological evidence of paranasal lesions: Two cases of frontal sinus osteomata from Imperial Rome. AB - The archaeological excavations carried out in 1999 in the Collatina necropolis of the Roman Imperial Age (1st-3rd centuries AD) (Rome, Italy) discovered the skeletal remains of two adult males with evidence of paranasal lesions. Both individuals showed postmortem damage in the frontal bone, through which it was possible to macroscopically detect an oblong new bone formation. In both specimens, radiological examination of the defects' morphology showed new pediculated-based bone formations. Radiology also confirmed the presence of benign osseous masses arising from the right frontal sinus and interpreted as osteomata. Their dimensions did not exceed 10 mm, so that mechanical complications and compression of the adjacent structures could be ruled out. The osteomata of paranasal sinuses are rarely reported in paleopathology, since they can be discovered only incidental to bone breakage or radiography. Hence, the evaluation of their occurrence in past populations represents an important challenge. The two cases presented here show direct and rare evidence of frontal sinus osteomata dating back to the Roman Imperial Age. PMID- 29496218 TI - Trabecular bone microarchitecture analysis, a way for an early detection of genetic dwarfism? Case study of a dwarf mother's offspring. AB - A 66 year-old woman with a disproportionate dwarfism and who bore seven children was discovered at the Middenbeemster archaeological site (The Netherlands). Three are perinates and show no macroscopic or radiological evidence for a FGFR3 mutation causing hypo-or achondroplasia. This mutation induces dysfunction of the growth cartilage, leading to abnormalities in the development of trabecular bone. Because the mutation is autosomal dominant, these perinates have a 50% risk of having been affected. This study determines whether trabecular bone microarchitecture (TBMA) analysis is useful for detecting genetic dwarfism. Proximal metaphyses of humeri were MUCT-scanned with a resolution of 7-12 MUm. Three volumes of interest were segmented from each bone with TIVMI(c) software. The TBMA was quantified in BoneJ(c) using six parameters on which a multivariate analysis was then performed. Two of the Middenbeemster perinates show a quantitatively different TBMA organization. These results and the family's medical history suggest a diagnosis of genetic dwarfism for this two perinates. This study provides evidence to support the efficacy of MUCT for diagnosing early stage bone disease. PMID- 29496219 TI - Secondary hypertrophic osteoarthropathy in a male from the Early Medieval settlement of Lauchheim, Germany. AB - Hypertrophic osteoarthropathy (HOA) is rarely diagnosed in archaeological human skeletons. Here, we report on the well-preserved skeleton of a middle-adult man from the early Medieval settlement site of Lauchheim (Germany) that exhibits pronounced multi-layered shell-like periosteal new bone formation in a bilaterally symmetric fashion on the long bones, the skeletal elements of the pelvis and those of the pectoral girdle. In addition, the two distal phalanges recovered show signs of osteoclastic resorption on their distal tuberosities. The distribution and morphology of the observed lesions are consistent with a diagnosis of HOA. The adult age at death of the individual and the co-occurrence of "healed" and "active" lesions suggest a secondary form of HOA. Given that only skeletal remains were available for study, the underlying (pulmonary or non pulmonary) primary disease cannot be definitively ascertained in the present case. No osseous changes were found on the ribs, but signs of osteoclastic resorption were observed on the dorsal surface of the sternal body, which might indicate a retrosternal or mediastinal location of the primary disease. Thus far, only a few archaeological case studies of secondary HOA reported signs of the presumed underlying primary disease, which was of a pulmonary nature in each of the individuals. PMID- 29496220 TI - Fusion of cervical vertebrae from a basal archosauromorph from the Middle Triassic Denwa Formation, Satpura Gondwana Basin, India. AB - This report describes two adjacent, longitudinally-fused anterior cervical vertebrae from a basal archosauromorph. The specimen was collected from the Denwa Formation, Satpura Gondwana Basin, India. The differential diagnosis of the fusion includes genetic or environmentally-mediated congenital malformations, nonspecific spondyloarthopathy, and various infectious agents. These observations represent the first published recognition of archosauromorph vertebral pathology from specimens that were discovered in India. The observations affirm that basal archosauromorphs suffered from disorders that have been observed in later dinosaurs and modern-day vertebrates. Considering the process of orderly differential diagnosis is an important aspect of understanding lesions of ancient bones. PMID- 29496221 TI - A case of enchondroma from Carolingian necropolis of St. Pere De Terrassa (Spain): An insight into the archaeological record. AB - Enchondromas occur with an estimated modern incidence rate of 27.7% of benign bone tumors (Hauben and Hogendoorn, 2010), but few are represented in the paleopathological record. The medieval site of St. Pere in Spain has produced a convincing case. The diagnosis was confirmed by X-Ray, CT-scan and MU-CT scan. Therefore UF 755 from St. Pere - a male of more than 60 years old - can be confirmed as a femoral case of enchondroma, supported by evidence, in the paleopathological record. PMID- 29496222 TI - Benign fibro-osseous lesion of the mandible in a Middle Bronze Age skeleton from Southern Russia. AB - A discrete dysplastic lesion of the mandible found in a skeleton of a young adult male of the Middle Bronze Age in the Northern Caucasus/Russia is described. The periapical lesion of the right lower canine alveolus was examined by digital microscopy, plain radiology, and plain and polarizing microscopy. Its macroscopic, radiologic and microscopic characteristics are discussed in reference to different fibro-osseous lesions arising from the odontogenic apparatus and maxillofacial skeleton. Periapical osseous dysplasia was considered to be the most likely diagnosis. PMID- 29496223 TI - A truncated temporal styloid process from the Jordanian Ottoman Period: Developmental variant or fracture? AB - Styloid process (SP) development and its role in an individual's lived experience plays a negligible role in paleopathological research, although a handful of possible Eagle's syndrome cases have been reported. Here, the development of the stylohyoid chain and the medical research of SP variants are reviewed to inform the differential diagnosis of a probable SP fracture in a young adult male associated with the Ottoman Period (13-19thC) in Jordan. The fracture surface of the right SP is smooth rather than irregular, the coloration is uniform with the surrounding cortical bone staining, and no new bone formation is visible. All features are consistent with a perimortem injury. An unossified stylohyal is a differential diagnosis, while the left elongated SP suggests a predisposition to intrinsic injury. The implications of SP fractures are considered. PMID- 29496224 TI - Controlled release of chlorhexidine from a HEMA-UDMA resin using a magnetic field. AB - OBJECTIVES: To functionalize novel chlorhexidine (CHX) particles with iron oxide (Fe3O4) nanoparticles and control their release kinetics in a dental resin using an external magnetic field. METHODS: Fe3O4 nanoparticles were synthesized and incorporated into spherical CHX particles and the powder was freeze dried. Resin disc specimens were produced using a UDMA-HEMA resin mixed with freeze dried spherical Fe3O4-CHX particles (5wt.%), which were placed into a Teflon mould (10mm diameter*1mm depth) and covered with a Mylar strip. A MACS magnet was left in contact for 0min (Group 1), 5min (Group 2) or 10min (Group 3) and the resin discs subsequently light cured (Bluedent LED pen, Bulgaria) for 60s per side. The resin discs were immersed in deionized water at various time points up to 650h. UV-Vis absorbance was used to determine the CHX content. CHX released for each time point was determined. The functionalized CHX particles and resin discs were characterized using TEM, TGA, EDX and SEM. RESULTS: Fe3O4 nanoparticles (20nm) incorporated into the spherical CHX particles led to a mean (SD) particle size reduction from 17.15 (1.99)MUm to 10.39 (2.61)MUm. The presence of Fe3O4 nanoparticles in the spherical CHX particles was confirmed with SEM, EDX, and TGA. SEM of Group 1 resin discs (no magnetic exposure) showed functionalized CHX spheres were homogeneously distributed within the resin discs. For resin discs which had magnetic exposure (5 or 10min) the particles started to cluster nearer the surface (Group 2: 43.7%, Group 3: 57.3%), to a depth of 94MUm. UV-Vis absorbance revealed Group 1 resin discs had a cumulative CHX release of 4.4% compared to 5.9% for Group 2 and 7.4% for Group 3 resin discs, which had magnetic exposure (5, 10min). SIGNIFICANCE: Fe3O4 nanoparticle functionalized CHX spheres demonstrated a magnetic field responsive property. A magnetic field responsive release of CHX may be useful in clinical situations where the drug can be directed to give a tailored release at the site of infection. PMID- 29496226 TI - How is symptom flare defined in musculoskeletal conditions: A systematic review. AB - OBJECTIVE: To systematically review the definitions for "flare" in musculoskeletal conditions, the derivation processes, and validation of definitions for the 12 most burdensome musculoskeletal conditions. METHODS: A literature search was conducted in MEDLINE, EMBASE, CINAHL, AMED, PsycInfo and Lilacs to identify studies that investigated derivation or validation of a flare definition, which we considered as a phrase or group of domains. RESULTS: Reports of derivation of flare definitions were identified for 9/12 musculoskeletal conditions. Validation of flare definitions was initiated for 4/12. For each condition, different derivation and validation methods have been used, with variable levels of consumer involvement, and in some cases different groups have worked on the process in parallel. Although some flare definitions began simply as "symptom worsening" or "change in treatment", most evolved into multidimensional definitions that include: pain, impact on function, joint symptoms, and emotional elements. Frequently initial attempts to create phrase to define the term flare evolved into consensus on the breadth of domains involved. Validation has compared flare definitions/domains against measures of disease activity, clinicians' diagnosis, response to drug therapy, or a combination. CONCLUSION: This review suggests that greater characterisation and definition of flares in musculoskeletal conditions are linked to the inclusion of multiple perspectives, multifaceted domains and compound comparators for their validation. Further work is required to optimise and test the derived definitions for most musculoskeletal conditions. As some elements are disease-specific, flare definitions cannot be extrapolated to other conditions. Research regarding flare in back pain (most burdensome disease) is limited. PMID- 29496225 TI - Do out-of-pocket costs affect medication adherence in adults with rheumatoid arthritis? A systematic review. AB - INTRODUCTION: For individuals with a chronic condition, long-term management of their medication can be difficult and as a result non-adherence is common among this cohort. In patients with rheumatoid arthritis (RA), the introduction of biologic agents was a revolutionary treatment but the high costs of this medication might limit their utilisation. OBJECTIVE: This systematic review aimed to determine whether out-of-pocket (OOP) costs affect adherence to RA medications in adults with a diagnosis of RA. METHODS: Twelve databases were searched to identify primary peer-reviewed articles, written in English from inception to April 2016 that referred to the relationship between adherence to RA medication and OOP costs. The CASP check list was used to assess the quality rating of the included studies. RESULTS: Six articles were identified in the review and all were considered as high quality studies. Among them, three directly considered the association between OOP costs and medication adherence as their main objective. Although the population and the methods of the studies varied widely, there was an inverse relationship between OOP costs and medication adherence in patients with RA. CONCLUSION: The findings of this review suggest that OOP costs can contribute to non-adherence to RA medication in patients with RA. Therefore, health policy makers globally should identify the appropriate OOP amount so these costs do not affect adherence whilst simultaneously ensuring that costs are not an intolerable burden for governments, providers and insurers. PMID- 29496227 TI - Efficacy and safety of repeated courses of hyaluronic acid injections for knee osteoarthritis: A systematic review. AB - INTRODUCTION: Hyaluronic acid (HA) is a commonly prescribed intra-articular (IA) therapy for knee osteoarthritis (OA). While a single series of IA-HA has been well studied, the efficacy and safety of repeated courses of IA-HA injection therapy in knee OA patients have not been evaluated as frequently. METHODS: A literature search was conducted using MEDLINE, EMBASE and PubMed databases. The primary outcome measure was knee pain reduction after each treatment course and/or last reported follow-up visit. Secondary outcomes were treatment-related adverse events (AEs) and serious adverse events (SAEs). RESULTS: A total of 17 articles (7 RCTs and 10 cohort studies) met the pre-defined inclusion criteria. Of the RCTs, six were double-blind with two trials including open label extension studies, and one was single-blind. Studies ranged from investigating a single reinjection cycle to four repeat injection cycles. Eleven studies evaluated one reinjection, five studies evaluated >=2 repeated courses of IA-HA, and one study allowed either one or two repeated courses. All studies reported pain reduction from baseline in the IA-HA treatment group throughout the initial treatment cycle, and either sustained or further reduced pain throughout the repeated courses of treatment. The study with the longest follow-up repeated IA-HA injection every 6 months for 25 months. Pain decreased after the first course and continued to decrease until the end of the study, with an approximate 55% reduction in pain compared to baseline. Common AEs were joint swelling and arthralgia; there were no reported SAEs. All repeated courses were well tolerated, and the number of documented AEs and SAEs was similar to the primary injection regimens. CONCLUSION: Repeated courses of IA-HA injections are an effective and safe treatment for knee OA. Repeat courses were demonstrated to maintain or further improve pain reduction while introducing no increased safety risk. PMID- 29496228 TI - Treatments for giant cell arteritis: Meta-analysis and assessment of estimates reliability using the fragility index. AB - BACKGROUND: To better communicate the results of randomized controlled trials (RCTs) of giant cell arteritis (GCA), we propose the use of the fragility index (FI), which is an intuitive measure defined as the minimum number of subjects whose status would have to change (e.g., from having the outcome to not) to render a statistically significant result nonsignificant, or vice-versa. METHODS: We conducted a systematic review and random-effects meta-analysis of RCTs of glucocorticoid (GC) sparing strategies for relapse-free maintenance in GCA, and used the FI to simplify the presentation of results. RESULTS: Ten RCTs (nine phase II and one phase III enrolling 645 subjects) were included. Tocilizumab, IV GC and methotrexate significantly improved the likelihood of being relapse free with relative risks and 95% confidence intervals of 3.54 (2.28, 5.51), 5.11 (1.39, 18.81) and 1.54 (1.02, 2.30); respectively. The median FI was 4.5 (range, 1-28), and was generally higher for negative RCTs (n = 6; median FI 4.5) than for positive RCTs (n = 4; median FI 3.5). The range of FI per treatment was (1-8) for methotrexate, (2-6) for anti-TNF agents, 4 for abatacept, 3 for IV GC pulses and (4-28) for tocilizumab. CONCLUSION: Tocilizumab, IV GC and methotrexate improve the likelihood of being relapse-free in subjects with GCA. Assessment of GC sparing strategies in GCA has long depended on imprecise trials that would change significance if outcomes were reversed for a handful of subjects. FI may be used in rheumatology to simplify communication of statistical significance and overcome limitations of p-value. PMID- 29496229 TI - Intravenous lidocaine infusion. AB - Systemic lidocaine used in continuous infusion during the peri-operative period has analgesic, anti-hyperalgesic, as well as anti-inflammatory properties. This makes it capable of reducing the use of opioids and inhalational anaesthetics, and the early return of bowel function, and patient hospital stay. The aim of this narrative review was to highlight the pharmacology and indications for clinical application, along with new and interesting research areas. The clinical applications of peri-operative lidocaine infusion have been reviewed in several recent systematic reviews and meta-analyses in patients undergoing open and laparoscopic abdominal procedures, ambulatory procedures, and other types of surgery. Peri-operative lidocaine infusion may be a useful analgesic adjunct in enhanced recovery protocols. Potential benefits of intravenous lidocaine in chronic post-surgical pain, post-operative cognitive dysfunction, and cancer recurrence are under investigation. Due to its immunomodulation properties over surgical stress, current evidence suggests that intravenous lidocaine could be used in the context of multimodal analgesia. PMID- 29496230 TI - Role of voltage-gated sodium channel blockers in the treatment of chronic pain: Potential uses in clinical practice based on available evidence. AB - Once patients have failed first line therapy, there is an apparent lack of knowledge on how to proceed with choosing subsequent therapy. To choose amongst alternative agents, an understanding of pharmacology, pharmacokinetics, and available evidence in targeting various pain conditions is necessary. This article focuses on the use of the carboxamide class of voltage-gated sodium channel blockers (carbamazepine, oxcarbazepine, eslicarbazepine acetate) for adjunct pain medication management; including research updates in pharmacology, pharmacokinetics, and evidence for pain along on this therapeutic group with promising future areas of research. Although evidence for voltage-gated sodium channel blockers in chronic pain management is limited, emerging research has identified this area as promising for additional clinical trials to better guide clinical practice. PMID- 29496231 TI - Multimodality imaging in the study of fundus flavimaculatus. PMID- 29496232 TI - Intestinal malrotation: A rare cause of chronic recurrent abdominal pain. PMID- 29496233 TI - Portal hypertension as a complication of hepatic hydatidosis. PMID- 29496234 TI - Parental confusion may result when primary health care professionals show heterogeneity in their knowledge, attitudes, and perceptions regarding infant nutrition, food allergy, and atopic dermatitis. AB - INTRODUCTION AND OBJECTIVES: Whether the guidelines on infant nutrition, food allergy and atopic dermatitis confer real health benefits in practice at the population level has not been deeply studied. We aimed here to characterize the knowledge, attitudes, and perceptions regarding these issues among primary health care professionals. In addition, we surveyed available parent-reported information sources and the incidence of food-related symptoms, dietary restrictions, food allergy, and atopic dermatitis among one-year-old children in the general population. MATERIALS AND METHODS: An online questionnaire was designed for public health nurses and general practitioners. In addition, parents of one-year-old children were recruited to a separate survey at the time of their regular check-up visit. RESULTS: Altogether, 80 professionals took part. The median overall knowledge score was 77% and significantly higher among the general practitioners than among the nurses (p=0.004). However, only 35% of all the professionals recognized either severe airway or cardiovascular symptoms as potential food allergy-related symptoms. Moisturizers and emollients were thought to be adequate treatment for atopic dermatitis by 56%. Among 248 one-year-old children, the incidence of food allergy was 4% and atopic dermatitis 13%. During this period, parents intentionally avoided giving at least one food to 23% of the children, yet more than 80% of these restrictions can be regarded as unnecessary. CONCLUSION: The knowledge, attitudes and beliefs regarding infant feeding, food allergy, and atopic dermatitis varied significantly among the primary care professionals. This will likely result in heterogeneous guidance practices and confusion among the families at the population level. PMID- 29496235 TI - Angor and heart failure as first manifestation of lymphoma. PMID- 29496236 TI - Arterial hypertension in a 17-year-old male. PMID- 29496237 TI - Symptomatic central nervous system viral escape in patient on darunavir monotherapy. PMID- 29496238 TI - Biomedical research at the crossroads and ways through. PMID- 29496239 TI - Hemoglobin Yuda: First case reported in Spain. PMID- 29496240 TI - Intoxication by the synthetic cannabinoid 5-fluoro-ABD, acquired as ketamine. PMID- 29496241 TI - How long should we continue to use the Cockcroft-Gault formula for dose adjustment of drugs in renal failure? PMID- 29496242 TI - Efficacy and safety of topical tranexamic acid in knee arthroplasty. AB - INTRODUCTION AND OBJECTIVE: Tranexamic acid (TXA) is commonly used to control postoperative blood loss in total knee arthroplasty. In order to avoid adverse effects associated with intravenous administration, topical use has been proposed as an alternative. Our aim was to evaluate the efficacy and safety of topical TXA in total knee arthroplasty. MATERIAL AND METHODS: A total of 90 patients scheduled for unilateral total knee arthroplasty were included in a prospective randomised study. All surgeries were performed under spinal anaesthesia, tourniquet and the same postoperative protocol. Patients were allocated to one of the 3 groups according to the application of TXA: group A (n=30) 1g of topical TXA; group B (n=30) 1g of TXA intravenous and in group C or the control group (n=30) no drug was administrated. Parameters related to blood loss and drain outputs were compared between the 3 groups. RESULTS: The results revealed that post-operative decrease in haemoglobin level was significantly lower in group A (1.95g/dL) than group B (2.25g/dL) and group C (2.96g/dL), P<.01. Total postoperative blood loss was lower in group A (195mL) than group B (466mL) and group C (718mL), P<.01. There was no significant difference in complications and allogenic blood transfusion rate between the 3 groups. CONCLUSIONS: According to the results, topical application of 1g TXA significantly reduced blood loss in patients undergoing total knee arthroplasty more than intravenous or no administration of TXA. PMID- 29496243 TI - Extramedullary plasmacytoma. PMID- 29496244 TI - New pharmacological approaches for cardiovascular risk. PMID- 29496245 TI - Usefulness of abdominal ultrasound and biomarkers in screening for occult cancer in patients with idiopathic venous thromboembolism. PMID- 29496246 TI - Azathioprine-induced hepatic sinusoidal obstruction syndrome. PMID- 29496247 TI - Vitamin B12-induced acne. PMID- 29496248 TI - Complete heart block by lacosamide. PMID- 29496249 TI - High ratio of T790M to EGFR activating mutations correlate with the osimertinib response in non-small-cell lung cancer. AB - OBJECTIVES: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that can overcome resistance due to the Thr790Met (T790M) mutation. However, osimertinib occasionally shows limited efficacy in a small population of patients. We investigated the correlation between the ratio of T790M to EGFR activating mutation and the response to osimertinib. MATERIALS AND METHODS: Between April 2016 and April 2017, 44 patients started osimertinib therapy at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. We performed EGFR mutation analysis of cytological samples from 33 patients using droplet digital PCR. We calculated the ratio of T790M to EGFR activating mutations and correlated it with the systemic response to osimertinib. RESULTS: In tumors from the 33 patients, the average ratio of T790M to EGFR activating mutations was 0.420. Twenty-one of the 33 patients had tumors with a T790M ratio of >=0.4. The osimertinib response rate was significantly higher (92.3%) in patients with a T790M ratio of >=0.4 than in those with a T790M ratio of <0.4 (52.6%; p = 0.0237). We examined the correlation between the T790M ratio and the tumor reduction rate and obtained a coefficient of r = 0.417 (p = 0.0175). In patients with a T790M ratio of >=0.4, the median progression-free survival was 355 days, which was longer, but not significant, than that in patients with a T790M ratio of <0.4 (median: 264 days). In patients with a T790M ratio of >=0.4, the median treatment duration from first-line therapy onward was 931 days, which was significantly longer than that in patients with a T790M ratio of <0.4 (median, 567.5 days) (p = 0.044). CONCLUSION: The T790M ratio to EGFR activating mutation in tumor may correlate with the response to osimertinib, and patients with a higher T790M ratio have a longer treatment history. PMID- 29496250 TI - Real world treatment and outcomes in EGFR mutation-positive non-small cell lung cancer: Long-term follow-up of a large patient cohort. AB - OBJECTIVES: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) have been shown to be effective for the treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC) in clinical trials. However, there is a lack of data from routine clinical practice. This study determined treatment and outcomes in patients with EGFR mutation-positive NSCLC treated in a real world setting. MATERIALS AND METHODS: Clinical characteristics, information about NSCLC treatment regimens and survival outcomes data were obtained retrospectively from 17 medical centers across Japan. In addition to overall survival (OS), subgroup analyses were conducted based on first- and second-line treatments and combinations, and for patients who had survived >5 years from initiation of first line treatment. RESULTS: The full analysis set comprised 1656 patients (mean 67 years, 80.6% with performance status 0 or 1). Median follow-up was 29.5 months and median OS was 29.7 months; 3- and 5-year survival rates were 41.2% and 21.5%, respectively. Significant predictors of OS were younger age, no smoking history, histological diagnosis of adenocarcinoma, less advanced clinical stage, good performance status and major EGFR-activating mutation. Despite some imbalances in baseline characteristics, patients who received first-line chemotherapy had numerically higher 5-year survival rates than those who received first-line EGFR TKIs. CONCLUSIONS: This large, long-term analysis of EGFR mutation-positive NSCLC patients provides useful information about treatment outcomes in clinical practice. Updated analyses are required to determine real world outcomes for NSCLC patients treated with the latest available agents, including immunotherapies. PMID- 29496251 TI - Community-based lung cancer screening with low-dose CT in China: Results of the baseline screening. AB - OBJECTIVES: To investigate whether low-dose computed tomography (LDCT) screening is capable of enhancing the detection rate of early-stage lung cancer in high risk population of China with both smoking and non-smoking related factors. METHODS: From 2013-2014, eligible participants with high-risk factors of lung cancer were randomly assigned to a screening group or a control group with questionnaire inquiries. Any non-calcified nodules or masses with longest diameters of >=4 mm identified on LDCT images were considered as positive. RESULTS: A total of 6717 eligible participants were randomly enrolled to a study group (3550 to LDCT screening and 3167 to standard care). 3512 participants (98.9%) underwent LDCT screening, and 3145 participants (99.3%) received questionnaire inquiries. A positive screening result was observed in 804 participants (22.9%). In the two-year follow-up period, lung cancer was detected in 51 participants (1.5%) in the LDCT group versus 10 (0.3%) in the control group (stage I: 48 vs 2; stage II to IV or limited stage: 3 vs 8), respectively. Early stage lung cancer was found in 94.1% vs 20%, respectively. CONCLUSIONS: Compared to usual care, LDCT led to a 74.1% increase in detecting early-stage lung cancer. This study provides insights about the non-smoking related risk factors of lung cancer in the Chinese population. PMID- 29496252 TI - Coexistence of sensitive and resistant epidermal growth factor receptor (EGFR) mutations in pretreatment non-small cell lung cancer (NSCLC) patients: First or third generation tyrosine kinase inhibitors (TKIs)? AB - OBJECTIVES: Occasionally, primary 20 T790M/insertion plus sensitive mutations can be detected within a single tumor sample by routine molecular testing, but the optimal clinical management for these patients is unclear. Herein, we determined the optimal treatment strategy for these patients. MATERIALS AND METHODS: From January 2011 to January 2017, patients diagnosed with epidermal growth factor receptor (EGFR) mutation were screened. For these harboring primary 20 T790M/insertion plus sensitive mutations, the effectiveness of the first or third generation tyrosine kinase inhibitors (TKIs) were retrospectively analyzed. RESULTS: 16,842 individuals were screened during the study period with 5900 positive patients identified. Sixty-one patients were confirmed to have primary 20 T790M/insertion plus sensitive mutations (1% of all EGFR-mutant patients, 95% CI, 0.8%-1.3%). Among them, 31 eligible patients were included for survival analyses. The median progression-free survival (PFS) of the 15 osimertinib treated patients was 18.0 months (95% CI, 15.1-20.9 months), which was greatly longer than the 16 patients who were treated with first generation TKIs (1.2 months, 95% CI, 0.9-1.6, P < 0.001). Similar results were also observed in overall survival (OS) with 25.1 months (95% CI, not calculable) in the osimertinib group and 17.3 months (95% CI, 9.3-25.4 months) in the first generation TKI group (P = 0.02). CONCLUSIONS: For patients harboring primary resistant and sensitive mutations detected by routine clinical methods, first generation TKIs are ineffective even with the presence of sensitive mutations. However, osimertinib shows great survival benefit, and thus, should be considered during the whole clinical management. PMID- 29496253 TI - A phase III randomised study comparing concomitant radiochemotherapy with cisplatin and docetaxel as induction versus consolidation treatment in patients with locally advanced unresectable non-small cell lung cancer. AB - OBJECTIVES: To assess if induction radiochemotherapy followed by consolidation chemotherapy (arm A) will improve survival in comparison with the same chemotherapy given as induction followed by consolidation concurrent radiochemotherapy (arm B) in patients with unresectable non-metastatic non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy consisted in a combination of cisplatin with docetaxel, with one initial course for each patient, two courses in single modality therapy and weekly administration during chest irradiation (66 Gy). RESULTS: A total of 125 patients were randomised before early closure of the study because of poor accrual and an unplanned blind interim analysis which suggested that the continuation of the study would have been futile. Mature survival results showed no significant difference between both modalities with median survival times, respectively in arms A and B, of 19.6 months and 18.3 months, two years survival rates of 44% and 44% and five years survival rates of 23% and 26%. Toxicity was acceptable. CONCLUSIONS: Our randomised study did not demonstrate survival difference between induction concurrent radiochemotherapy followed by consolidation chemotherapy and induction chemotherapy followed by consolidation concurrent radiochemotherapy. PMID- 29496254 TI - Amrubicin and carboplatin with pegfilgrastim in patients with extensive stage small cell lung cancer: A phase II trial of the Sarah Cannon Oncology Research Consortium. AB - PURPOSE: First-line treatment for patients with extensive-stage small cell lung cancer (SCLC) includes treatment with platinum-based combination chemotherapy. Amrubicin is a synthetic anthracycline with single-agent activity in relapsed/refractory SCLC. In an attempt to improve treatment efficacy, we evaluated amrubicin/carboplatin as first-line therapy for extensive-stage SCLC. PATIENTS AND METHODS: In this multicenter phase II trial, patients received amrubicin (30 mg/m2 daily on Days 1, 2, and 3) and carboplatin (AUC = 5 on Day 1); cycles were repeated every 21 days for 4 cycles. Pegfilgrastim (6 mg subcutaneously) was administered on Day 4 of all cycles. Overall survival (OS) proportion at 1 year was the primary endpoint. The target 1-year OS rate was 47%, an improvement of 35% from historical results with carboplatin/etoposide. RESULTS: Eighty patients received study treatment, and 62% completed the planned 4 courses. The overall response rate was 74% (13% complete responses). The 1-year survival rate was 38% (95% CI: 25, 50). The median survival was 10 months. Myelosuppression was severe but manageable. CONCLUSIONS: The combination of amrubicin/carboplatin was an active first-line treatment for extensive stage SCLC, but showed no indication of increased efficacy compared to standard treatments. Severe myelosuppression was common with this regimen, in spite of prophylactic pegfilgrastim. These results are consistent with those of other trials in showing no role for amrubicin in the first-line treatment of SCLC. PMID- 29496256 TI - Temporal and regional distribution of initial recurrence site in completely resected N1-stage II lung adenocarcinoma: The effect of postoperative adjuvant chemotherapy. AB - OBJECTIVES: Understanding the timing and pattern of cancer recurrence is essential to explain the causes of treatment failure. We investigated the recurrence pattern and rate over time in patients with completely resected N1 stage II lung adenocarcinoma. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 333 patients who underwent complete surgical resection for N1-stage II lung adenocarcinoma. RESULTS: The median recurrence-free survival (RFS) was 38.8 months and the 5-year RFS rate was 39.6%. Left-sided tumors, large tumor size, and lymph node (LN) ratio higher than 0.15 were significantly correlated with a worse RFS, whereas female sex, direct LN involvement, and adjuvant chemotherapy were significantly correlated with a better RFS. Among the 182 patients who experienced recurrences, 46 (25.3%) had only loco-regional recurrences and 136 (74.7%) had distant metastases. The organs most commonly involved in initial recurrence were the lungs (n = 89, 48.9%), followed by bone (n = 41, 22.5%) and the brain (n = 38, 20.9%). The recurrence hazard curve for the entire study population demonstrated a similarly shaped and sized initial and second peak at 15 and 23 months, and a third smaller peak during the fourth year. The recurrence hazard curve of patients who received adjuvant chemotherapy exhibited a more delayed and smaller first peak than those who did not receive adjuvant chemotherapy. The patients treated with adjuvant chemotherapy had a lower rate of distant metastasis (p = 0.037); adjuvant chemotherapy had no effect on brain metastasis (p = 0.640). CONCLUSION: In the present cohort, the hazard curves suggested that bone and brain recurrences exhibited an earlier first peak, while lung recurrences presented later. Adjuvant chemotherapy not only reduced the recurrence hazard but also delayed the recurrence and altered the pattern of recurrence. However, these results need to be confirmed in a prospective study. PMID- 29496255 TI - Randomized phase 2 study of tivantinib plus erlotinib versus single-agent chemotherapy in previously treated KRAS mutant advanced non-small cell lung cancer. AB - BACKGROUND: KRAS mutations are identified in approximately 25% of non-small cell lung cancer (NSCLC) cases and are associated with resistance to currently available targeted therapies. The MET oncogene may be implicated in malignant progression of KRAS-mutant tumors. In a pre-specified subset analysis of KRAS mutant cancers in an earlier phase 2 study of erlotinib plus the oral MET inhibitor tivantinib, combination therapy was associated with substantial clinical benefit compared to erlotinib alone (progression-free survival [PFS] HR 0.18; P < 0.01). The current study was conducted to evaluate this combination further in KRAS mutant non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Previously treated patients with advanced KRAS mutant NSCLC were randomized to receive either oral tivantinib (360 mg twice daily) plus erlotinib (150 mg daily) (ET) or single-agent chemotherapy (investigator's choice of pemetrexed, docetaxel, or gemcitabine) (C). The primary endpoint was PFS. At progression, crossover from C to ET was permitted. RESULTS: Ninety-six patients were randomly assigned to ET (n = 51) or to C (n = 45). Median PFS was 1.7 months (mos) for ET and 4.3 mos for C (HR 1.19; 95% CI, 0.71-1.97; P = 0.50). There was no difference in overall survival (HR 1.20; 95% CI, 0.76-1.88; P = 0.44). There were 4 partial responses in the C arm, and none in the ET arm. Overall, adverse events occurred more frequently in the C arm, with more cytopenias, nausea, fatigue, and alopecia. Dermatologic toxicities were more common in the ET arm. CONCLUSION: In previously treated patients with advanced KRAS mutant NSCLC, the combination of the MET inhibitor tivantinib and erlotinib is not superior to conventional single agent chemotherapy. PMID- 29496257 TI - Workforce Considerations, Training, and Diseases in Africa. AB - Surgeons in sub-Saharan Africa face different challenges than those in developed countries: extreme shortages of otolaryngologists, speech pathologists, and audiologists; lack of training opportunities; and a paucity of otolaryngology services aggravated by population growth and aging. In addition to common Western diseases, patients have otolaryngology complications related to the human immunodeficiency virus, tuberculosis, malaria, and trauma. Less than 5% of the population has access to timely, safe, affordable surgery; 29 out of 52 African countries have no radiotherapy services. Discussion focuses on education and training, which can be achieved in several ways, some complimentary. PMID- 29496258 TI - Progress toward understanding pelvic organ prolapse. PMID- 29496259 TI - A randomized clinical trial of knotless barbed suture vs conventional suture for closure of the uterine incision at cesarean delivery. AB - BACKGROUND: Knotless barbed sutures are monofilament sutures with barbs cut into them. These sutures self-anchor, maintaining tissue approximation without the need for surgical knots. OBJECTIVE: The hypothesis of this study was that knotless barbed suture could be used on the myometrium to close the hysterotomy at cesarean delivery. The objective was to compare uterine closure time, need for additional sutures, and blood loss between this and a conventional suture. STUDY DESIGN: This was a prospective, unblinded, randomized controlled trial conducted at the Ziv Medical Center, Zefat, Israel. The primary outcome was the length of time needed to close the uterine incision, which was measured from the start of the first suture on the uterus until obtaining uterine hemostasis. To minimize provider bias, women were randomized by sealed envelopes that were opened in the operating room just prior to uterine closure with either a bidirectional knotless barbed suture or conventional suture. Secondary outcomes included the number of additional hemostatic sutures needed and blood loss during incision closure. RESULTS: Patients were enrolled from August 2016 until March 2017. One hundred two women were randomized. Fifty-one had uterine closure with knotless barbed suture and 51 with conventional suture. The groups were similar for demographics as well as number of previous cesarean deliveries. Uterine closure time using the knotless barbed suture was significantly shorter than the conventional suture by a mean of 1 minute 43 seconds (P < .001, 95% confidence interval, 67.69-138.47 seconds). Knotless barbed sutures were associated with a lower need for hemostatic sutures (median 0 vs 1, P < .001), and blood loss measured during incision closure was significantly lower (mean 221 mL vs 268 mL, P < .005). CONCLUSION: The use of a knotless barbed suture is a reasonable alternative to conventional sutures because it reduced the closure time of the uterine incision. There was also less need for additional hemostatic sutures and slightly reduced estimated blood loss. PMID- 29496260 TI - Hyperuricemia, Acute and Chronic Kidney Disease, Hypertension, and Cardiovascular Disease: Report of a Scientific Workshop Organized by the National Kidney Foundation. AB - Urate is a cause of gout, kidney stones, and acute kidney injury from tumor lysis syndrome, but its relationship to kidney disease, cardiovascular disease, and diabetes remains controversial. A scientific workshop organized by the National Kidney Foundation was held in September 2016 to review current evidence. Cell culture studies and animal models suggest that elevated serum urate concentrations can contribute to kidney disease, hypertension, and metabolic syndrome. Epidemiologic evidence also supports elevated serum urate concentrations as a risk factor for the development of kidney disease, hypertension, and diabetes, but differences in methodologies and inpacts on serum urate concentrations by even subtle changes in kidney function render conclusions uncertain. Mendelian randomization studies generally do not support a causal role of serum urate in kidney disease, hypertension, or diabetes, although interpretation is complicated by nonhomogeneous populations, a failure to consider environmental interactions, and a lack of understanding of how the genetic polymorphisms affect biological mechanisms related to urate. Although several small clinical trials suggest benefits of urate-lowering therapies on kidney function, blood pressure, and insulin resistance, others have been negative, with many trials having design limitations and insufficient power. Thus, whether uric acid has a causal role in kidney and cardiovascular diseases requires further study. PMID- 29496261 TI - When embodiment breaks down: Language deficits as novel avenues into movement disorders. PMID- 29496262 TI - Colorectal cancer cell-derived exosomes containing miR-10b regulate fibroblast cells via the PI3K/Akt pathway. AB - BACKGROUND: Cancer-associated fibroblasts (CAFs) contribute to the proliferation of colorectal cancer(CRC) cells. However, the mechanism by which CAFs develop in the tumor microenvironment remains unknown. Exosomes may be involved in activating CAFs. METHODS: Using a miRNA expression profiling array, we determined the miRNA expression profile of secretory exosomes in CRC cells and then identified potential miRNAs with significant differential expression compared to normal cells via enrichment analysis. Predicted targets of candidate miRNAs were then assessed via bioinformatics analysis. Realtime qPCR, western blot, and cell cycle analyses were performed to evaluate the role of candidate exosomal miRNAs. Luciferase reporter assays were applied to confirm whether candidate exosomal miRNAs control target pathway expression. A CRC xenograft mouse model was constructed to evaluate tumor growth in vivo. RESULTS: Exosomes from CRC cells contained significantly higher levels of miR-10b than did exosomes from normal colorectal epithelial cells. Moreover, exosomes containing miR-10b were transferred to fibroblasts. Bioinformatics analysis identified PIK3CA, as a potential target of miR-10b. Luciferase reporter assays confirmed that miR-10b directly inhibited PIK3CA expression. Co-culturing fibroblasts with exosomes containing miR-10b significantly suppressed PIK3CA expression and decreased PI3K/Akt/mTOR pathway activity. Finally, exosomes containing miR-10b reduced fibroblast proliferation but promoted expression of TGF-beta and SM alpha-actin, suggesting that exosomal miR-10b may activate fibroblasts to become CAFs that express myofibroblast markers. These activated fibroblasts were able to promote CRC growth in vitro and in vivo. CONCLUSION: CRC-derived exosomes actively promote disease progression by modulating surrounding stromal cells, which subsequently acquire features of CAFs. PMID- 29496263 TI - Evaluating the effect of three newly approved overactive bladder syndrome treating agents on parotid and submandibular salivary glands: Modulation of CXCL10 expression. AB - BACKGROUND: Despite enormous progresses in understanding pathophysiology of the lower urinary tract, antimuscarinics remain the chief clinically well-established approach for improving symptoms of overactive bladder (OAB). Dry mouth on the other hand remains one of the most untolerated systemic side effects of these drugs that limits their uses and results in high discontinuation rate. Three novel drugs have been recently approved by US Food and Drug Administration for treatment of OAB: trospium, darifenacin, and solifenacin. AIMS: This study has been conducted to provide clear head to head comparative studying of histological and ultrastructural effect of those newly emerging drugs on parotid and submandibular salivary glands and to demonstrate the differential expression of CXCL10 to make a cogent structural and molecular assessment of the relative tolerability of these drugs and the potential mechanisms of occurrence of dry mouth. METHODS: Fifty male Sprague Dawley rats were equally divided into five groups: Group I (control), Group II (oxybutynin-treated), Group III (trospium treated), Group IV (darifenacin-treated) and Group V (solifenacin-treated). Histological and ultrastructural studies were performed on parotid and submandibular glands. Measurement of salivary flow, PCR analysis and immunohistochemical assessment of CXCL10 expression have been carried-out. RESULTS: Muscarinic receptor antagonists led to various histological, morphometric and ultrastructural changes together with diminished salivary secretion and up-regulation of CXCL10 expression with the mildest alterations observed with solifenacin. CONCLUSIONS: Solifenacin has shown the least adverse effects to salivary glands. CXCL10 is involved in degenerative changes of salivary glands induced by muscarinic antagonists. PMID- 29496264 TI - Localization of EFA6 (exchange factor for ARF6) isoform D in steroidogenic testicular Leydig cells of adult mice. AB - EFA6 (exchange factor for ARF6) activates Arf6 (ADP ribosylation factor 6) by exchanging ADP to ATP and the resulting activated form of Arf6 is involved in the membrane trafficking and actin remodeling of cells. Our previous study has shown the selective expression/localization of EFA6D in steroidogenic adrenocortical cells in situ of adult mice. In view of the previous finding, the present study was undertaken to examine its localization in mouse Leydig cells representing another steroidogenic cell species in order to further support the possible involvement of the EFA6/Arf6 cascade via membrane trafficking in the regulation of steroidogenesis and/or secretion. A distinct band for EFA6D with the same size as that of the brain was detected in the testis of adult mice. In immuno-light microscopy, immunoreactivity for EFA6D was seen throughout the cytoplasm in most Leydig cells without any distinct accumulation along the plasmalemma. Lack of immunoreactivity for EFA6D was seen in the seminiferous tubular epithelium. In immuno-electron microscopy, the immune-labeling was seen in sporadic/focal patterns on plasma membranes and some vesicles and vacuoles subjacent to the plasma membranes. More constant and rather predominant is the labeling on numerous mitochondria. No immuno-labeling was seen in lipid droplets. The present study suggests that EFA6D is somehow involved in regulation of the synthesis and/or secretion of testosterone through the membrane-traffic by activation of Arf6. In addition, EFA6D is suggested to play in mitochondria some yet unidentified roles rather independent of Arf6-activation, which remains to be elucidated. PMID- 29496265 TI - Localization of orexin B and orexin-2 receptor in the rat epididymis. AB - The peptides orexin A (OXA) and orexin B (OXB) derived from the proteolytic cleavage of a common precursor molecule, prepro-orexin, were originally described in the rat hypothalamus. Successively, they have been found in many other brain regions as well as in peripheral organs of mammals and other less evolved animals. The widespread localization of orexins accounts for the multiple activities that they exert in the body, including the regulation of energy homeostasis, feeding, metabolism, sleep and arousal, stress, addiction, and cardiovascular and endocrine functions. Both OXA and OXB peptides bind to two G coupled receptors, orexin-1 (OX1R) and orexin-2 (OX2R) receptor, though with different binding affinity. Altered expression/activity of orexins and their receptors has been associated with a large number of human diseases. Though at present evidence highlighted a role for orexins and cognate receptors in mammalian reproduction, their central and/or local effects on gonadal functions remain poorly known. Here, we investigated the localization of OXB and OX2R in the rat epididymis. Immunohistochemical staining of sections from caput, corpus and cauda segments of the organ showed intense signals for both OXB and OX2R in the principal cells of the lining epithelium, while no staining was detected in the other cell types. Negative results were obtained from immunohistochemical analysis of hypothalamic and testicular tissues from OX2R knock-out mice (OX2R-/ ) and OX1R/OX2R double knock-out (OX1R-/-; OX2R-/-) mice, thus demonstrating the specificity of the rabbit polyclonal anti-OX2R antibody used in our study. On contrary, the same antibody clearly showed the presence of OX2R in sections from hypothalamus and testis of normal mice and rats which are well known to express the receptor. Thus, our results provide the first definite evidence for the immunohistochemical localization of OXB and OX2R in the principal cells of rat epididymis. PMID- 29496266 TI - Tetrazolium salts and formazan products in Cell Biology: Viability assessment, fluorescence imaging, and labeling perspectives. AB - For many years various tetrazolium salts and their formazan products have been employed in histochemistry and for assessing cell viability. For the latter application, the most widely used are 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl 2H-tetrazolium bromide (MTT), and 5-cyano-2,3-di-(p-tolyl)-tetrazolium chloride (CTC) for viability assays of eukaryotic cells and bacteria, respectively. In these cases, the nicotinamide-adenine-dinucleotide (NAD(P)H) coenzyme and dehydrogenases from metabolically active cells reduce tetrazolium salts to strongly colored and lipophilic formazan products, which are then quantified by absorbance (MTT) or fluorescence (CTC). More recently, certain sulfonated tetrazolium, which give rise to water-soluble formazans, have also proved useful for cytotoxicity assays. We describe several aspects of the application of tetrazolium salts and formazans in biomedical cell biology research, mainly regarding formazan-based colorimetric assays, cellular reduction of MTT, and localization and fluorescence of the MTT formazan in lipidic cell structures. In addition, some pharmacological and labeling perspectives of these compounds are also described. PMID- 29496267 TI - Elements of molecular machinery of GABAergic signaling in the vertebrate cholinergic neuromuscular junction. AB - It is generally accepted that gamma-aminobutyric acid (GABA) is a signaling molecule abundant in central synapses. In a number of studies though, it has been shown that GABA signaling functions in the peripheral nervous system as well, in particular, in the synapses of sympathetic ganglia. However, there exists no firm evidence on the presence of GABAergic signaling cascade in the intercellular junctions of the somatic nerve system. By the use of immunohistochemistry methods, in the synaptic area of cholinergic neuromuscular contact in rat diaphragm, we have detected glutamate decarboxylase, the enzyme involved in synthesis of GABA, molecules of GABA, and also GAT-2, a protein responsible for transmembrane transport of GABA. Earlier we have also shown that metabotropic GABAB receptors have overlapping localization in the same compartment. Moreover, activation of GABAB receptors affects the intensity of acetylcholine release. These data taken together, allows us to suggest that in the mammalian cholinergic neuromuscular junction, GABA is synthesized and performs certain synaptic signaling function. PMID- 29496268 TI - Peroral endoscopic myotomy for the treatment of achalasia and other esophageal motor disorders: Short-term and medium-term results at a Mexican tertiary care center. AB - INTRODUCTION AND AIMS: Achalasia is characterized by the absence of lower esophageal sphincter relaxation and esophageal aperistalsis. Diagnosis is confirmed through high-resolution esophageal manometry. Laparoscopic myotomy is the standard treatment, but peroral endoscopic myotomy (POEM) is a safe and effective alternative, with good short-term and medium-term results. Our aim was to describe the short-term and medium-term experience with POEM at a tertiary care center. MATERIALS AND METHODS: The study was conducted within the time frame of November 2014 and February 2017. Treatment-naive achalasia patients and previously-treated achalasia patients that were candidates for POEM were included. A protocolized 24-month follow-up was carried out. RESULTS: Fifty procedures were included and 31 (68%) were performed on women. Forty-one (82%) of the procedures were carried out on previously untreated patients, 7 (14%) were performed on previously treated patients, and 2 (4%) of the patients had redo POEM. The mean age of the patients was 48.8+/-14.1 years. The pre-POEM Eckardt score was 9 and the integrated relaxation pressure was 24.4mmHg. Sixty-eight percent of the patients had type ii achalasia. Procedure time was 80min and myotomy length was 12.6cm. Hospital stay was 3 days and subcutaneous emphysema was the most common adverse event (30%). A total of 22/50 (44%) patients reached the 24-month follow-up, maintaining the Eckardt score and the decrease in the integrated relaxation pressure. There were no deaths. A total of 47.5% of the patients had a positive pH-study at 6 months, 15% had clinical reflux, and 35% presented with mild esophagitis. All the patients were adequately controlled with proton pump inhibitors. CONCLUSION: POEM is safe and effective in the short term and medium term for the treatment of achalasia and other esophageal motor disorders in Mexican patients. PMID- 29496269 TI - Fully covered stents versus partially covered stents for palliative treatment of esophageal cancer: Is there a difference? AB - INTRODUCTION AND AIMS: Malignant dysphagia is difficulty swallowing resulting from esophageal obstruction due to cancer. The goal of palliative treatment is to reduce the dysphagia and improve oral dietary intake. Self-expandable metallic stents are the current treatment of choice, given that they enable the immediate restoration of oral intake. The aim of the present study was to describe the results of using totally covered and partially covered esophageal stents for palliating esophageal cancer. MATERIALS AND METHODS: A retrospective study was conducted on patients with inoperable esophageal cancer treated with self expandable metallic stents. The 2 groups formed were: group A, which consisted of patients with a fully covered self-expandable stent (SX-ELLA(r)), and group B, which was made up of patients with a partially covered self-expandable stent (Ultraflex(r)). RESULTS: Of the 69-patient total, 50 were included in the study. Group A had 19 men and 2 women and their mean age was 63.6 years (range 41-84). Technical success was achieved in 100% (n=21) of the cases and clinical success in 90.4% (n=19). Group B had 24 men and 5 women and their mean age was 67.5 years (range 43-92). Technical success was achieved in 100% (n=29) of the cases and clinical success in 89.6% (n=26). Complications were similar in both groups (33.3 vs. 51.7%). CONCLUSION: There was no difference between the 2 types of stent for the palliative treatment of esophageal cancer with respect to technical success, clinical success, or complications. PMID- 29496270 TI - [Scleritis and systemic diseases: What should know the internist?] AB - Scleritis is an inflammatory disease of the sclera; outer tunic of the eye on which the oculomotor muscles are inserted. It can be associated with a systemic disease up to one time out of 3. These associated diseases are mainly rheumatoid arthritis, vasculitis, including granulomatosis with polyangiitis in the first line and spondyloarthropathies. Before mentioning such an etiology, it is necessary to eliminate an infectious cause, mainly herpetic, which is regularly underestimated. The classification of scleritis is clinical. We distinguish between anterior scleritis and posterior scleritis. Anterior scleritis is diffuse or nodular, usually of good prognosis. Anterior necrotizing scleritis with inflammation is often associated with an autoimmune disease, necrotizing scleritis without inflammation usually reflects advanced rheumatoid arthritis. The treatment of these conditions requires close collaboration between internists and ophthalmologists to decide on the use of corticosteroid therapy with or without immunosuppressors or biotherapies. PMID- 29496271 TI - [Antimalarial drug retinopathy]. AB - INTRODUCTION: Antimalarial drugs are largely used for the treatment of various systemic diseases. They can cause toxic retinopathy, which can lead to blindness. OBSERVATION: We report the case of a 32-year-old male with a systemic lupus erythematosus treated with hydroxychloroquine 400mg per day and then chloroquine 300mg per day during 8 and 9years respectively. Eighteen months after his latest visual examination, the patient experienced bilateral vision loss. Fundus examination revealed a bull's eye maculopathy. Additional tests including multifocal electroretinogram showed severe bilateral functional impairment in the parafoveal area leading to diagnosis of severe toxic retinopathy induced by antimalarial drugs. DISCUSSION: In 2016, the American Academy of Ophthalmology revised the previous 2011 recommendations concerning early retinal toxicity screening strategy which should be first based on both automated 10-2 visual fields and spectral-domain optical coherence tomography (SD OCT). Multifocal electroretinogram can be more helpful for diagnostic confirmation rather than screening. Although these recommendations are essential, they are not well known in clinical practice. PMID- 29496272 TI - [Management of vertigo and dizziness]. AB - Balance disorders presenting with symptoms of dizziness and vertigo are due to various diseases. Clinical approach gives the opportunity to identify emergency situations and most common causes, among them the first one being the benign paroxysmal positional vertigo. Oculomotor assessment is pertinent as major clinical orientation, particularly between peripheral and central diseases. These clinical findings support the respective indication of modern imaging and/or vestibular tests, focused on the direction of presupposed diagnosis. On elderly the risk of falls and their complications needs a specific evaluation. PMID- 29496273 TI - [NLRC4 associated autoinflammatory diseases: A systematic review of the current literature]. AB - The auto-inflammatory diseases linked to NLRC4 mutations are recently described entities. Transmission is autosomal dominant in 80 % of cases; cases of somatic mutation have already been reported. The disease may display two very different clinical phenotypes: the phenotype 1 (30 %), severe, is dominated by a multisystemic inflammation starting in the first year of life with symptoms of chronic inflammatory bowel disease (IBD), macrophagic actication syndrome (MAS), or even a presentation suggesting a cryopyrinopathy in its CINCA form; the mortality of this phenotype is high (25 %). The phenotype 2 (70 %), mild, usually starts after the age of 3 and is characterized by cold urticaria, arthralgia, ocular features and fever in 50 % of cases without visceral failure. Anti interleukin-1 inhibitors are effective in most cases (83 %). Interleukin-18 (IL 18) levels are very high in both clinical forms. Interleukin-18 inhibitors and anti-interferon-gamma inhibitors were remarkably effective in two very severe phenotype 1 patients. Thus, NLRC4 mutations can induce various clinical manifestations with two distinct phenotypes. Although still rare, because very recently described, this group of diseases could be evoked by an internist in front of cold familial urticarial; probably more and more cases will be diagnosed thanks to the major progresses of genetic diagnostic tools such as next generation sequencing. PMID- 29496274 TI - Gut microbiota alterations and dietary modulation in childhood malnutrition - The role of short chain fatty acids. AB - The gut microbiome affects the health status of the host through different mechanisms and is associated with a wide variety of diseases. Both childhood undernutrition and obesity are linked to alterations in composition and functionality of the gut microbiome. One of the possible mechanisms underlying the interplay between microbiota and host metabolism is through appetite regulating hormones (including leptin, ghrelin, glucagon-like peptide-1). Short chain fatty acids, the end product of bacterial fermentation of non-digestible carbohydrates, might be able to alter energy harvest and metabolism through enteroendocrine cell signaling, adipogenesis and insulin-like growth factor-1 production. Elucidating these mechanisms may lead to development of new modulation practices of the gut microbiota as a potential prevention and treatment strategy for childhood malnutrition. The present overview will briefly outline the gut microbiota development in the early life, gut microbiota alterations in childhood undernutrition and obesity, and whether this relationship is causal. Further we will discuss possible underlying mechanisms in relation to the gut-brain axis and short chain fatty acids, and the potential of probiotics, prebiotics and synbiotics for modulating the gut microbiota during childhood as a prevention and treatment strategy against undernutrition and obesity. PMID- 29496275 TI - Vitamin E status and associations in maternal-infant Dyads in the Midwestern United States. AB - BACKGROUND: Oxidative stress has been associated with adverse neonatal outcomes, and vitamin E has powerful anti-oxidant properties. Vitamin E occurs in several different isoforms which differ in their ability to modulate inflammation and oxidative stress. Therefore, the purpose of this study was to evaluate the status of alpha-, gamma- and delta-tocopherol in maternal-infant pairs, and the impact on maternal-newborn outcomes. METHODS: Vitamin E status was evaluated in 189 mother-infant pairs. Concentrations of alpha-, gamma- and delta-tocopherol were measured using HPLC. Descriptive statistics were calculated and Spearman coefficients were used to assess correlations between maternal and cord measurements. Linear and logistic regression models were used to adjust for relevant confounders. A p < 0.05 was considered statistically significant. RESULTS: Maternal and cord serum tocopherol concentrations were positively correlated for gamma-tocopherol (r = 0.32, p ? 0.001) and delta-tocopherol (r = 0.46, p ? 0.001) but not for alpha-tocopherol. After adjustment for confounders, maternal concentrations of tocopherols were positively associated with Apgar scores (p = 0.02) and infant growth parameters at birth. Conversely, cord tocopherol levels were inversely associated with Apgar scores (p = 0.02) and infant growth. Cord concentrations of alpha-tocopherol were higher in infants born to mothers with a diagnosis of pre-eclampsia (p = 0.04). CONCLUSION: Maternal-fetal transfer of gamma- and delta-tocopherols is higher than alpha tocopherol and may be mediated by either different or more efficient methods, conversely tissue uptake of alpha-tocopherol by the developing fetus may be higher. As serum levels of maternal tocopherols are positively associated with outcomes while higher cord levels show a negative impact, uptake and tissue deposition of vitamin E by the fetus may be crucial in growth and development. More research into the role of maternal diet, placental regulation, and fetal uptake of vitamin E tocopherols in relation to clinical outcomes is warranted. PMID- 29496276 TI - Prevalence and incidence of hyperkalaemia in the Spanish population with heart failure with reduced ejection fraction: a systematic review and populational relevance. AB - BACKGROUND AND OBJECTIVES: Hyperkalaemia (K+ levels>=5.5mmol/L) is a severe ion imbalance that occurs in patients who have heart failure (HF) with reduced ejection fraction (HFrEF) and increases the risk of ventricular fibrillation. Given that there are no estimates on the number of patients with this complication, the aim of this study was to estimate the prevalence and incidence of hyperkalaemia in patients with HFrEF in Spain. MATERIAL AND METHODS: Based on a systematic literature search and through a meta-analysis, we calculated an HFrEF prevalence of <=40% in the European and U.S. POPULATION: Based on another systematic literature search, we calculated the prevalence of hyperkalaemia in patients with HF and its annual incidence rate. Considering the previous values and the Spanish population pyramid in 2016, we estimated the number of individuals with HFrEF who currently have hyperkalaemia and those who develop it each year in Spain. RESULTS: Approximately 17,100 (10,000 men and 7100 women) of the 508,000 patients with HFrEF in Spain have hyperkalaemia. Furthermore, approximately 14,900 patients with HFrEF (9500 men and 5400 women) develop hyperkalaemia each year. CONCLUSIONS: Approximately 1 of every 30 patients with HFrEF has plasma potassium values >5.5 mmol/L. PMID- 29496278 TI - Department of Error. PMID- 29496277 TI - Death and suffering in Eastern Ghouta, Syria: a call for action to protect civilians and health care. PMID- 29496279 TI - ESTRO ACROP consensus guideline on CT- and MRI-based target volume delineation for primary radiation therapy of localized prostate cancer. AB - BACKGROUND AND PURPOSE: Delineation of clinical target volumes (CTVs) remains a weak link in radiation therapy (RT), and large inter-observer variation is seen. Guidelines for target and organs at risk delineation for prostate cancer in the primary setting are scarce. The aim was to develop a delineation guideline obtained by consensus between a broad European group of radiation oncologists. MATERIAL AND METHODS: An ESTRO contouring consensus panel consisting of leading radiation oncologists and one radiologist with known subspecialty expertise in prostate cancer was asked to delineate the prostate, seminal vesicles and rectum on co-registered CT and MRI scans. After evaluation of the different contours, literature review and multiple informal discussions by electronic mail a CTV definition was defined and a guide for contouring the CTV of the prostate and the rectum was developed. RESULTS: The panel achieved consensus CTV contouring definitions to be used as guideline for primary RT of localized prostate cancer. CONCLUSION: The ESTRO consensus on CT/MRI based CTV delineation for primary RT of localized prostate cancer, endorsed by a broad base of the radiation oncology community, is presented to improve consistency and reliability. PMID- 29496282 TI - Bronchial Laceration as a Complication of Transbronchial Lung Cryobiopsy. PMID- 29496280 TI - Two decades of high dose rate brachytherapy with external beam radiotherapy for prostate cancer. AB - BACKGROUND: High-dose-rate brachytherapy (HDR-BT) has optimal prerequisites in radiotherapy of prostate cancer (PC) with a conformal dose distribution and high doses per fraction giving a biological dose escalation. We report the outcome after HDR-BT and external beam radiotherapy (EBRT) after 20 years of experience. MATERIAL AND METHODS: The study includes 623 patients, median age of 66 years, treated from 1995 to 2008 and a median follow up of 11 years (range 2-266 months). Androgen deprivation therapy was given to 429 patients (69%). The HDR-BT was given with two 10 Gy fractions and the EBRT with 2 Gy fractions to 50 Gy. RESULTS: The 10-year PC-specific survival was 100%, 92%, 91%, and 75% for low-, intermediate-, high- and very high-risk patients respectively, and the 10-year probability of PSA relapse was 0%, 21%, 33%, and 65% respectively. The 10-year actuarial prevalence for >=grade 2 GU- and GI-toxicities were 28% and 12% respectively and for >=grade 3, 4% and 1% respectively. Urethral stricture was the most frequent GU complication with a 10-year actuarial incidence of 10%. Treatment without dose constraints for the urethra conferred a higher incidence 18%, compared to 5% after 2003 (p < 0.001). Sixteen patients experienced grade 4 GU toxicity, of which 13 were treated before 2003. No grade 4 rectal toxicity was seen. CONCLUSION: The combination of EBRT and HDR-BT with adequate dose constraints to risk organs provides satisfactory long-term tumour control even in high-risk patients. GI toxicity stabilised but GU toxicity progressed during the 10-year follow up. PMID- 29496281 TI - A model combining age, equivalent uniform dose and IL-8 may predict radiation esophagitis in patients with non-small cell lung cancer. AB - BACKGROUND AND PURPOSE: To study whether cytokine markers may improve predictive accuracy of radiation esophagitis (RE) in non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: A total of 129 patients with stage I-III NSCLC treated with radiotherapy (RT) from prospective studies were included. Thirty inflammatory cytokines were measured in platelet-poor plasma samples. Logistic regression was performed to evaluate the risk factors of RE. Stepwise Akaike information criterion (AIC) and likelihood ratio test were used to assess model predictions. RESULTS: Forty-nine of 129 patients (38.0%) developed grade >=2 RE. Univariate analysis showed that age, stage, concurrent chemotherapy, and eight dosimetric parameters were significantly associated with grade >=2 RE (p < 0.05). IL-4, IL-5, IL-8, IL-13, IL-15, IL-1alpha, TGFalpha and eotaxin were also associated with grade >=2 RE (p < 0.1). Age, esophagus generalized equivalent uniform dose (EUD), and baseline IL-8 were independently associated grade >=2 RE. The combination of these three factors had significantly higher predictive power than any single factor alone. Addition of IL-8 to toxicity model significantly improves RE predictive accuracy (p = 0.019). CONCLUSIONS: Combining baseline level of IL-8, age and esophagus EUD may predict RE more accurately. Refinement of this model with larger sample sizes and validation from multicenter database are warranted. PMID- 29496283 TI - Factors Affecting Lung Function: A Review of the Literature. AB - Lung function reference values are traditionally based on anthropometric factors, such as weight, height, sex, and age. FVC and FEV1 decline with age, while volumes and capacities, such as RV and FRC, increase. TLC, VC, RV, FVC and FEV1 are affected by height, since they are proportional to body size. This means that a tall individual will experience greater decrease in lung volumes as they get older. Some variables, such as FRC and ERV, decline exponentially with an increase in weight, to the extent that tidal volume in morbidly obese patients can be close to that of RV. Men have longer airways than women, causing greater specific resistance in the respiratory tract. The increased work of breathing to increase ventilation among women means that their consumption of oxygen is higher than men under similar conditions of physical intensity. Lung volumes are higher when the subject is standing than in other positions. DLCO is significantly higher in supine positions than in sitting or standing positions, but the difference between sitting and standing positions is not significant. Anthropometric characteristics are insufficient to explain differences in lung function between different ethnic groups, underlining the importance of considering other factors in addition to the conventional anthropometric measurements. PMID- 29496284 TI - Safety of a Modified Protocol of Bronchial Thermoplasty. PMID- 29496285 TI - Leptomeningeal Carcinomatosis in a Patient With Clinical Stage III Lung Adenocarcinoma and Sudden Neurological Impairment. PMID- 29496286 TI - Prostatic Brachytherapy Seed Embolization to the Lung. PMID- 29496287 TI - Pembrolizumab-Induced Rhabdomyolysis With Myositis in a Patient With Lung Adenocarcinoma. PMID- 29496288 TI - Detection of Pleural Fluid Biochemistry Changes in Two Consecutive Thoracenteses for Differentiating Malignant from Benign Effusions. AB - OBJECTIVE: To assess whether changes in pleural fluid (PF) biochemistries between two consecutive thoracenteses enable clinicians to predict malignant or benign pleural effusions (PE). METHODS: Retrospective study of patients with lymphocytic exudates and negative PF cytology, who underwent a second thoracentesis in our center in the last 15 years in whom a final diagnosis was reached (derivation sample). Absolute (Deltaa) and percentage differences (Deltap) in PF biochemistries which predicted a malignant or benign PE in the derivation sample were evaluated in an independent population (validation sample). RESULTS: The derivation sample included 214 PE patients (70 malignant and 144 benign PE). Deltap lactate dehydrogenase (LDH) >0%, Deltap neutrophils >-10% (any increase or less than 10% decrease) and Deltaa protein <0.1g/dL (any increase or less than 0.1g/dL decrease) between the second and the first thoracentesis had an odds ratio of 6.4, 3.9 and 2.1, respectively, to discriminate malignant from benign PE. The presence of the three conditions together had a positive likelihood ratio of 5.6, whereas the absence of any of the 3 parameters had a likelihood ratio of 0.04 for predicting malignancy. These results were reproduced in the validation sample. CONCLUSION: An increase in LDH and neutrophils along with a decrease in protein in a second thoracentesis increase the probability of malignant PE, while the opposite reduces it significantly. PMID- 29496289 TI - Assessment of Midazolam Sedation in Ultrasound-Guided Percutaneous Biopsy of Peripheral Lung Lesions. PMID- 29496290 TI - Pulmonary Hydatid Cyst: A Characteristic Computed Tomography Finding. PMID- 29496291 TI - Lung Re-Transplantation: In Favour of a Second Chance. PMID- 29496292 TI - Control of Mechanotransduction by Molecular Clutch Dynamics. AB - The linkage of cells to their microenvironment is mediated by a series of bonds that dynamically engage and disengage, in what has been conceptualized as the molecular clutch model. Whereas this model has long been employed to describe actin cytoskeleton and cell migration dynamics, it has recently been proposed to also explain mechanotransduction (i.e., the process by which cells convert mechanical signals from their environment into biochemical signals). Here we review the current understanding on how cell dynamics and mechanotransduction are driven by molecular clutch dynamics and its master regulator, the force loading rate. Throughout this Review, we place a specific emphasis on the quantitative prediction of cell response enabled by combined experimental and theoretical approaches. PMID- 29496293 TI - Estimating potential for savings for low risk endometrial cancer using the Endometrial Cancer Alternative Payment Model (ECAP): A companion paper to the Society of Gynecologic Oncology Report on the Endometrial Cancer Alternative Payment Model. AB - OBJECTIVE: To design an endometrial cancer (EC) alternative payment (ECAP) model focused on surgical management of EC, as well as identify drivers of cost in order to develop opportunities for cost-savings while maintaining quality of care. METHODS: National practice patterns and reimbursements were compared between private payers (MarketScan data, years 2009-13) and public payers (Medicare, year 2014) of EC patients who underwent hysterectomy. An episode of care for EC included the hysterectomy, stratified by surgical approach (laparotomy versus robotic versus laparoscopy), and in- and outpatient reimbursements from 30days preoperatively to 60days postoperatively. Reimbursements were categorized into cost centers. A decision model informed modifiable components influencing overall reimbursements for EC surgical care. Variations in length of stay (LOS), emergency department (ED visits), and readmissions were analyzed to create an optimal care model. RESULTS: A total of MarketScan (n=29,558) and Medicare (n=377) patients were included. Mean total reimbursement for an episode of care was $19,183 (SD $10,844) for Medicare and $30,839 (SD $19,911) for MarketScan. Mean reimbursements were greatest for abdominal cases in Medicare ($25,553; SD $11,870) and MarketScan ($35,357; SD $21,670), followed by robotic and laparoscopic. Among MarketScan patients, 7.6% of women were readmitted within 60days after surgery and 11.7% had an evaluation in the ED. The median reimbursement per patient for readmission was $14,474 (IQR $8584 to $26,149), and for ED visit was $6327 (IQR $1369 to $29,153). In an optimized care model, increasing the rate of minimally invasive surgery by 5% while reducing LOS by 10% and ED visits/readmissions by 10%, lowered the average case reimbursement by $903 (2.9%) for MarketScan and $1243 (5.9%) for Medicare. CONCLUSION: An ECAP model demonstrates that reimbursements vary by public versus commercial payers in the U.S. for the surgical management of endometrial cancer patients, and that opportunities for cost savings exist. Nominal increases in the rate of minimally invasive surgery and reduction in the rate of ED visits/readmissions and length of stay can result in substantial savings for endometrial cancer care. PMID- 29496295 TI - Digital version of the European Atlas of natural radiation. AB - The European Atlas of Natural Radiation is a collection of maps displaying the levels of natural radioactivity caused by different sources. It has been developed and is being maintained by the Joint Research Centre (JRC) of the European Commission, in line with its mission, based on the Euratom Treaty: to collect, validate and report information on radioactivity levels in the environment of the EU Member States. This work describes the first version of the European Atlas of Natural Radiation, available in digital format through a web portal, as well as the methodology and results for the maps already developed. So far the digital Atlas contains: an annual cosmic-ray dose map; a map of indoor radon concentration; maps of uranium, thorium and potassium concentration in soil and in bedrock; a terrestrial gamma dose rate map; and a map of soil permeability. Through these maps, the public will be able to: familiarize itself with natural environmental radioactivity; be informed about the levels of natural radioactivity caused by different sources; have a more balanced view of the annual dose received by the European population, to which natural radioactivity is the largest contributor; and make direct comparisons between doses from natural sources of ionizing radiation and those from man-made (artificial) ones, hence, to better assess the latter. Work will continue on the European Geogenic Radon Map and on estimating the annual dose that the public may receive from natural radioactivity, by combining all the information from the different maps. More maps could be added to the Atlas, such us radon in outdoor air and in water and concentration of radionuclides in water, even if these sources usually contribute less to the total exposure. PMID- 29496294 TI - Mismatch repair deficiency is associated with MSI phenotype, increased tumor infiltrating lymphocytes and PD-L1 expression in immune cells in ovarian cancer. AB - OBJECTIVE: The role of mismatch repair (MMR) deficiency in ovarian cancer (OC) pathogenesis and its association with other clinicopathologic features, such as microsatellite instability (MSI) and expression of checkpoint proteins, remain largely elusive. METHODS: We performed Immunohistochemistry (IHC) for MLH1, MSH2, MSH6 and PMS2 on full-section slides from 419 OCs to assess the MMR status. The clinical relevance of MMR deficiency was analyzed in combination with clinical data. The MSI status (by MSI assay) and expression of CD3, CD8, PD-1 and PD-L1 (by IHC) were compared in OCs with different MMR status. RESULTS: We found that 2.6% OCs were MMR-negative, 4.3% OCs were MMR-low, and 63.6% of MMR-negative OCs were of endometrioid subtype. A significantly higher proportion of MMR-negative OCs were diagnosed at stage I or II compared to MMR-proficient OCs (p=0.0041). MSI was observed in all tested MMR-negative OCs, 14.3% of tested MMR-low OCs and 3.2% of tested MMR-proficient OCs. In addition, MMR-negative OCs had better progression free survival compared to MMR-proficient and MMR-low OCs (p=0.0046). Furthermore, the majority of OCs were PD-1-positive in intratumoral lymphocytes regardless of MMR status; while MMR-negative OCs exhibited significantly increased CD3+ and CD8+ tumor-infiltrating lymphocytes, and PD-L1+ intratumoral immune cells compared to MMR-proficient OCs. CONCLUSION: Our data suggests that MMR deficient OC is a unique molecular subgroup, characterized by early stage of diagnosis, MSI phenotype, and increased tumor-infiltrating lymphocytes. These patients may be good candidates for anti-PD-1/PD-L1 therapy. PMID- 29496296 TI - Reduction in exposure of interventional cardiologists to ionising radiation over a 10-year period. AB - Exposure of operators to ionising radiation in interventional cardiology has likely diminished, but data confirming the magnitude of the reduction are lacking. The aim of this study was to compare the dose of radiation received by interventional cardiology operators at 11 years interval (2006 vs 2017). The study population comprised all interventional coronary procedures performed by a single operator in one catheterization laboratory (cathlab) of a large university hospital in north-eastern France. Exposure was compared between two periods, namely period 1 (from October 2005 to March 2006) and period 2 (from March 2017 to June 2017). The primary endpoint was the dose of radiation received by the operator, measured using an electronic dosimeter placed on the operator's left arm. In 2017, the dose of radiation received by the operators was, on average, 95% lower than the dose received in 2006 (p < 0.0001), even though the average fluoroscopy time increased by 73% over the same period (p < 0.0001). By multivariable analysis including body mass index, fluoroscopy time and performance of at least one (1) coronary angioplasty, the reduction in the operator's exposure to radiation remained significant. The dose of radiation received by interventional cardiology operators has decreased by 95% over the last ten years. PMID- 29496297 TI - The relationship between progestin hormonal contraception and depression: a systematic review. AB - OBJECTIVE: We performed a systematic review to look for an association between progestin-only contraception and depression. METHODS: We searched PubMed, Ovid and Web of Science for English-language articles including progestin-only contraception and depression from database inception to September 2016. We evaluated study quality with the procedures guiding reviews for the United States Preventive Services Task Force and the Cochrane Risk of Bias Tools. We included studies that evaluated progestin-only contraception and depression, focusing on externally validated depression measures. We excluded case studies, review articles and other psychiatric disorders. RESULTS: We identified 26 studies that met the inclusion criteria, including 5 randomized controlled trials, 11 cohort studies and 10 cross-sectional studies. We found minimal association between progestin-only methods and depression. No correlation with depression was found in five low-quality, high-risk-of-bias progestin subdermal implant studies and four out of five varying-quality and medium-risk-of-bias levonorgestrel intrauterine device studies. Three medroxyprogesterone acetate intramuscular injection trials with varying levels of quality and bias show no difference in depression. Two progestin-only contraceptive pill studies with varying levels of quality and bias indicate no increase in depression scores, while one good quality, medium-bias study shows an association between progestin-only pills, the intrauterine device and depression. CONCLUSION: Despite perceptions in the community of increased depression following the initiation of progestin contraceptives, the preponderance of evidence does not support an association based on validated measures (mostly level II-1 evidence, moderate quality, low risk of bias). PMID- 29496298 TI - Effects of Intracordal Estradiol and Dexamethasone Injection on Wound Healing in Vocal Fold Injuries. AB - OBJECTIVE: The aim of this study was to investigate the effects of intracordal estradiol and dexamethasone injection on wound healing in vocal fold injuries. STUDY DESIGN: A prospective controlled animal study was carried out. SETTING: This study was conducted at a tertiary center. SUBJECTS-METHODS: Ten rabbits were randomly divided into two groups. As surgical procedure, cordotomy technique was performed in the middle third of the vocal folds bilaterally. In the first group, 0.1 mL of dexamethasone was injected into the right side, and 0.1 mL of saline was injected into the left side. In the second group, 0.1 mL of estradiol was injected into the right side, and 0.1 mL of saline was injected into the left side. Animals were sacrificed after 1 month and laryngeal specimens were evaluated histopathologically. RESULTS: No statistically significant difference was observed in terms of inflammatory response, epithelial thickness, type I and III collagen, and hyaluronic acid parameters in dexamethasone and estradiol injections compared to the saline injection. In terms of elastin level, estradiol injection demonstrated statistically higher values compared to the saline injection. Elastin level of dexamethasone injected vocal folds was not statistically different compared to the saline injection. No significant differences were observed in terms of inflammatory response, epithelial thickness, type I and III collagen, and hyaluronic acid parameters between the estradiol and dexamethasone injected vocal folds. CONCLUSION: It is thought that the effects of estradiol or dexamethasone injections may have similar effects on wound healing in vocal fold injuries. Intracordal estradiol injection has positive effects on tissue elastin levels. PMID- 29496299 TI - [Efficacy of a multidisciplinary care management program for patients admitted at hospital because of heart failure (ProMIC)]. AB - OBJECTIVE: To assess the efficacy of the ProMIC, multidisciplinary program for patients admitted at hospital because of heart failure (HF) programme, in reducing the HF-related readmission rate. DESING: Quasi-experimental research with control group. SETTINGS: Twelve primary health care centres and 3 hospitals from the Basque Country. PARTICIPANTS: Aged 40 years old or above patients admitted for HF with a New York Heart Association functional class II to IV. INTERVENTIONS: Patients in the intervention group carried out the ProMIC programme, a structured clinical intervention based on clinical guidelines and on the chronic care model. Control group received usual care. MAIN MEASUREMENTS: The rate of readmission for HF and health-related quality of life RESULTS: One hundred fifty five patients were included in ProMIC group and 129 in control group. 45 rehospitalisation due to heart failure happened in ProMIC versus 75 in control group (adjusted hazard ratio=0.59, CI 95%: 0.36-0.98; P=.049). There were significant differences in specific quality of life al 6 months. No significant differences were found in rehospitalisation due to all causes, due to cardiovascular causes, visits to emergency room, mortality, the combined variable of these events, the functional capacity or quality of life at 12 months of follow up. CONCLUSIONS: ProMIC reduces significantly heart failure rehospitalisation and improve quality of life al 6 months of follow up. No significant differences were found in the rests of variables. PMID- 29496302 TI - Corrections. PMID- 29496301 TI - [Presentation of a case of primary cerebral lymphoma diagnosed in an immunocompetent patient during a dementia study]. PMID- 29496303 TI - Two steps forward for myelin repair in multiple sclerosis. PMID- 29496300 TI - A retrospective analysis of factors associated with anesthetic case duration for cesarean deliveries. AB - INTRODUCTION: Accurately predicting cesarean delivery case duration is an integral component of designing appropriate workflow protocols and ensuring adequate provider availability. Our primary objective was to describe the variability of case duration, based on factors that we hypothesized would be influential, such as hospital facility type, United States region, time of day, case volume, and patient and provider characteristics. METHODS: We analyzed hospital-, patient-, and provider-level variables from the National Anesthesia Clinical Outcomes Registry, a voluntary registry created to share anesthesia related data and outcomes. Multivariable linear regression was performed to assess the association of these variables to case duration. RESULTS: A total of 205332 cases were included in the final analysis. The majority of these cases came from medium-sized community hospitals (50.8%). Mean and median case duration were 115 and 79 minutes, respectively. Mean duration was longest for cases performed at university hospitals (143 min, standard deviation 136 min). Case duration varied in clinically meaningful ways based on hospital facility type, United States region, presence of a Certified Registered Nurse Anesthetist, and anesthesia type. Differences were not clinically significant with respect to other variables studied. CONCLUSION: This study analyzed national cesarean delivery data and determined factors associated with cesarean delivery duration. We showed that case durations varied in meaningful ways according to facility type, United States region, presence of a Certified Registered Nurse Anesthetist, and anesthesia type. Our work contributes to a small but growing body of research on optimal staffing models for anesthesia practices. PMID- 29496304 TI - [Community health assessment of the programme "Barcelona Health in the Neighbourhoods". Methodology for a participatory process]. AB - This paper describes the methodology used for the assessment of health needs within a programme aimed at promoting health equity in disadvantaged neighbourhoods in the city of Barcelona (Spain). The assessment process involves the use of mixed methods (quantitative and qualitative) in order to obtain information regarding the health of the community, its determinants, and the availability of health-related assets. Quantitative data consists of indicators from different sources. Qualitative data collects the community's perspectives through interviews, focal groups and nominal groups. The combination of several data collection methods yields more complete information about the community, its needs and the resources available to meet them. Participation of community members in the process strengthens links between the community and the agents responsible for implementing the actions to address prioritised issues and favours community empowerment. PMID- 29496305 TI - Juvenile myelomonocytic leukemia with t(3;5)(q25;q35), Auer rods and marked myelodysplasia. AB - Juvenile myelomonocytic leukemia (JMML) is a rare aggressive childhood leukemia characterized by an excess proliferation of cells of granulocytic and monocytic lineages. The WHO classifies JMML with the myelodysplastic/myeloproliferative neoplasms. Myelodysplasia in JMML is usually minimal to mild. Auer rods have never been reported in JMML. We present a 2-year-old boy with splenomegaly, leukocytosis, thrombocytopenia, anemia, and excess myeloblasts with easily seen Auer rods, and marked dysgranulopoiesis and dyserythropoiesis. Conventional cytogenetic analysis showed a sole abnormality of t(3;5)(q25;q35). Microarray analysis showed a terminal 21 Mb region of copy-neutral loss of heterozygosity on 19q. Disease-related somatic NRAS mutation was detected. This case represents an unusual JMML with Auer rods and marked myelodysplasia. These unusual histopathologic features may be related to the t(3;5)(q25;q35). A t(3;5) with variable breakpoints has been reported in a small proportion of acute myeloid leukemias and myelodysplastic syndromes. To our knowledge, this is the first JMML case reported with this translocation. PMID- 29496306 TI - Mutational intratumoral heterogeneity of a putative tumor suppressor gene RARRES3 in colorectal cancers. PMID- 29496307 TI - Infracentimetric parathyroid cysts in hyperparathyroidemia. AB - Parathyroid cysts are rare, more frequently functional. Here we report 2 cases of infracentimetric parathyroid cysts identified in parathyroid adenomas resected for hyperparathyroidemia and hypercalcemia. Chronic parathyroiditis was associated. Chromogranin and E-cadherin/uvomorulin were expressed heterogeneously in the cyst lining and in parathyroid cells. In one of the cases, CD10 and CD56 were expressed by the luminal membrane of parathyroid cells. CD31 was expressed in interparathyroid cell monocyte/macrophage membrane as well as CD68, several cells showing also CD10 and/or CD56 expression. Ki67 was expressed in sparse parathyroid cells, some of binucleated cells or with nuclear clumps. In conclusion, heterogeneous E-cadherin expression in parathyroid cells may only indirectly related to cyst formation while CD56 and CD10 seem not to relate at all. The relevance of nuclear clumps and Azzopardi phenomenon as well as of the presence of disperse monocyte/macrophage-type cells for the parathyroiditis lesions remains to be further investigated. PMID- 29496308 TI - Overexpression of CTNNB1: Clinical implication in Chinese de novo acute myeloid leukemia. AB - Activation of Wnt/beta-catenin signaling played a crucial role in tumorigenesis, and beta-catenin (CTNNB1) overexpression has been identified in numerous solid tumors. The present study was designed to determine CTNNB1 expression and its clinical significance in Chinese de novo acute myeloid leukemia (AML) patients. Real-time quantitative PCR was carried out to detect the pattern of CTNNB1 expression in 140 AML patients and 46 controls. The level of CTNNB1 transcript in AML patients was significantly up-regulated compared with controls (P < 0.001). CTNNB1high patients showed significantly older age than CTNNB1low patients (P < 0.05). The frequency of high CTNNB1 expression was significantly observed in patients with intermediate/poor karyotypes. CTNNB1high patients had a significantly lower complete remission (CR) rate than CTNNB1low patients (P = 0.004). Among cytogenetically normal AML (CN-AML), CTNNB1high patients presented significantly shorter overall survival (OS, P = 0.004) and leukemia-free survival (LFS, P = 0.038) than CTNNB1low patients. Multivariate analysis confirmed that CTNNB1 expression was an independent prognostic factor for OS among CN-AML. Moreover, CTNNB1 expression level significantly decreased after CR stage (P = 0.032) and increased in relapsed stage (P = 0.015). Our findings suggest that CTNNB1 is overexpressed and confers a poor prognosis in AML, and could be used as a biomarker in monitoring disease recurrence. PMID- 29496309 TI - Investigation of relationship between precursor of miRNA-944 and its mature form in lung squamous-cell carcinoma - the diagnostic value. AB - INTRODUCTION: MicroRNA (miRNA) are attractive markers of lung cancer, due to their regulatory role in cell cycle. However, we know more about function of miRNA in cancer development, there is still little known about role of their precursors (primary miRNA; pri-miRNA) in tumorgenesis. In present study we investigated potential role of miRNA-944 and its precursor pri-miRNA-944 in development of squamous-cell lung cancer (SCC) and explored interdependence between miRNA precursor and its mature form. This is a first available literature report analyzing pri-miRNA as a cancer diagnostic marker. MATERIAL AND METHODS: Expression of miRNA-944 and its precursor was analyzed in 58 fresh-frozen tissues of non-small cell lung cancer and corresponding adjacent non-cancerous tissues using qRT-PCR. Expression of pri-miRNA-944 was correlated with TP63 and miRNA 944. Using ROC analysis diagnostic accuracy of studied markers was evaluated. RESULTS: miRNA-944 and its precursor were significantly overexspressed in SCC compared to adenocarcinoma (AC) and non-cancerous tissue. pri-miRNA-944 strongly and positively correlated with TP63 (r = 0.739, p < 0.001) and with mature miRNA 944 expression (r = 0.691, p < 0.001). Also, TP63 expression significantly correlated with mature miRNA (r = 0.785, p < 0.001). Combined analysis of pri miRNA-944 and mature miRNA-944 allowed to distinguish SCC tissue form AC with sensitivity of 93.3% and specificity of 100% (AUC = 0.978), and SCC from non cancerous tissue with 92.9% sensitivity and 100% specificity (AUC = 0.992). CONCLUSION: We assumed that pri-miRNA-944 and miRNA-944 may be involved in early squamous-type differentiation of lung tumors. Moreover, analysis of both markers provided high diagnostic accuracy for SCC detection. PMID- 29496310 TI - Wnt/beta-catenin signal alteration and its diagnostic utility in basal cell adenoma and histologically similar tumors of the salivary gland. AB - Differential diagnosis among basal cell adenoma (BCA), basal cell adenocarcinoma (BCAC), adenoid cystic carcinoma (ACC) and pleomorphic adenoma (PA) of the salivary gland can be challenging due to their similar histological appearance. Although frequent nuclear beta-catenin expression and CTNNB1 mutations have been reported in BCA, further details of the Wnt/beta-catenin signal alterations are unclear. The aim of this study was to assess the diagnostic utility of Wnt/beta catenin signal alteration in BCA and morphological mimics. We performed immunohistochemical staining for beta-catenin and mutation analysis for Wnt/beta catenin-related genes (CTNNB1, APC, AXIN1 and AXIN2) in BCA (n = 34), BCAC (n = 3), ACC (n = 67) and PA (n = 31). We also analyzed ACC-specific MYB and MYBL1 gene rearrangements by fluorescence in situ hybridization (FISH). Nuclear beta catenin expression (>=3%) was present in 32/34 cases (94.1%) of BCA, and the nuclear beta-catenin labeling index was significantly higher than in other tumor types (p = < 0.0001). In BCA, we found mutations in CTNNB1, APC and AXIN1 genes (41.1%, 2.9% and 8.8%, respectively). In BCAC, nuclear beta-catenin expression with CTNNB1 mutation was present in 1/3 cases (33.3%). As for ACC, nuclear beta catenin expression was observed in 3/67 cases (4.4%), but all 3 cases harbored either MYB or MYBL1 gene rearrangement. The results suggest that nuclear beta catenin immunoreactivity with appropriate criteria may be helpful to distinguish BCA from histologically similar tumors. However, a minor subset of ACCs with nuclear beta-catenin expression require careful diagnosis. In addition, Wnt/beta catenin signal alteration may play a role in the pathogenesis of BCA and BCAC. PMID- 29496311 TI - The relationship between EGFR mutation status and clinic-pathologic features in pulmonary adenocarcinoma. AB - To detect the relationship of the epidermal growth factor receptor (EGFR) mutation status and the clinicopathologic features. Six hundred thirty-three patients with pathologically confirmed lung adenocarcinoma who underwent lung cancer resection surgery at the Fourth Hospital of Hebei Medical University between April 2012 and April 2015 were selected for the study. The 32 types of mutations in exons 18-21 of the EGFR gene were detected. The total EGFR mutation rate among patients with lung adenocarcinoma was 56.9%. The mutation rates were 71.2% among females and 42.8% among males (P < 0.05). Among patients with TNM stage I, II, III, and IV disease, the EGFR mutation rates were significant differences (P < 0.05). Concerning different subtypes of lung adenocarcinoma, the EGFR mutation rates were differences, and these differences were statistically significant (P < 0.05). Cox multivariate regression model analysis considering EGFR mutation status revealed that differences in TNM stage (P < 0.01), smoker status, and tumor size were statistically significant predictors. Patients with minimally invasive and lepidic adenocarcinomas were categorized as low-risk group with high EGFR mutation rate; Patients with micro-papillary and solid adenocarcinomas were categorized as high-risk with lower EGFR mutation rate, so there are different mechanisms in different types of adenocarcinomas. PMID- 29496312 TI - Expression of miR-200c and its clinicopathological significance in patients with colorectal cancer. AB - MicroRNA-200c (miR-200c) is known to play a pivotal role in the regulation of epithelial-to-mesenchymal and mesenchymal-to-epithelial transition processes. However, the biological function of miR-200c in human carcinogenesis remains controversial. We examined the association of miR-200c expression with various clinicopathological factors, including KRAS mutation status and survival, in patients with colorectal cancer (CRC). The expression level of miR-200c was evaluated in 109 paired CRC and normal tissue samples using quantitative reverse transcription polymerase chain reaction. The KRAS mutation status of the CRC samples was determined using the PNAClampTM KRAS Mutation Detection kit. Compared with the normal tissue group, miR-200c expression was significantly upregulated in the CRCs (P < .001). The expression of miR-200c was increased in CRCs with higher grade (P = .009), advanced stage (P = .042), and lymphovascular invasion (P = .003). Thirty-one CRCs (28.4%) had KRAS mutations in codon 12 or 13. CRCs with KRAS mutations had significantly higher miR-200c expression than CRCs with wild-type KRAS (P = .003). In survival analysis, high miR-200c expression was correlated with worse overall survival (P = .017) and recurrence-free survival (P = .048). Our results indicate that miR-200c is involved in tumor progression and aggressiveness in CRCs, and this oncogenic role of miR-200c may be triggered by activation of the KRAS signaling pathway. PMID- 29496313 TI - The role of echocardiography as a risk-stratification tool in infective endocarditis. PMID- 29496314 TI - Evolution of bendopnea during admission in patients with decompensated heart failure. PMID- 29496315 TI - Purple urine bag syndrome. PMID- 29496316 TI - How to quantify the 'auditory gain' of a bone-conduction device; comment to the systematic review by Bezdjian et al. (2017). PMID- 29496317 TI - The effect of time to post-operative weightbearing on functional and clinical outcomes in adults with a displaced intra-articular calcaneal fracture; A systematic review and pooled analysis. AB - BACKGROUND: Post-operative weightbearing guidelines for displaced intra-articular calcaneal fractures (DIACF) have been pragmatically developed in the past, however hardly adapted to current health care insights. A period of six to nine weeks of non-weightbearing is usually recommended. It is unknown whether an earlier start of weightbearing is advisable. OBJECTIVES: The primary aim was to evaluate the effect of time to post-operative weightbearing on Bohler's angle. Secondary aims were to determine the effect on functional outcome (e.g., The American Orthopedic Foot and Ankle Society Scale), post-operative pain score, complications (e.g., infections, nonunion, implant removal), and revision surgeries. Finally, the effect of bone void filling on these outcomes was investigated. DATA SOURCE: A literature search was performed on January 24, 2017 in the Cochrane Library, Medline Ovid, Embase, Web of Science, Google Scholar, and CINAHL. LITERATURE SELECTION: Studies reporting on operatively treated patients with a DIACF and time to weightbearing were eligible for inclusion. Studies were excluded when not reporting primary data, solely reporting on open fractures, bilateral fractures, or polytrauma patients. Based upon the time to starting partial weightbearing, patient cohorts were stratified into very early (0-4 weeks), early (4-6 weeks), intermediate (6-8 weeks), or late (8-12 weeks) start of partial weightbearing. DATA EXTRACTION: Two investigators extracted data independently using a predefined data sheet. RESULTS: After applying exclusion criteria, 72 studies remained eligible for analysis. Bohler's and Gissane's angles, calcaneal height, AOFAS, pain scores, and complications had overlapping confidence intervals in all weightbearing groups. CONCLUSION: The adverse sequelae which are assumed to be associated with starting partial weightbearing already within six weeks after internal fixation of calcaneal fractures, is not supported by literature data. This systematic review suggests that early weightbearing does not result in impaired outcomes compared with more conservative weightbearing regimes. PMID- 29496318 TI - Technical tip: Removal of a broken tri-cortical syndesmotic screw using a "perfect circle" technique. AB - While broken or loose syndesmotic screws are typically of no clinical consequence, occasionally breakage can result in pain, metal fretting, or bony erosion. Despite quad-cortical syndesmotic screws being relatively easy to remove due to the prominent screw tip penetrating the medial tibial cortex, removal of a broken tri-cortical screw can be technically challenging. The purpose of this manuscript is to describe a safe technique for removing the buried, broken tri cortical screw fragment via a minimally invasive medial tibial approach by verifying the screw location using intra-operative fluoroscopy. PMID- 29496320 TI - Limited Sampling Strategy for Accurate Prediction of Pharmacokinetics of Saroglitazar: A 3-point Linear Regression Model Development and Successful Prediction of Human Exposure. AB - PURPOSE: Our aim was to develop and validate the extrapolative performance of a regression model using a limited sampling strategy for accurate estimation of the area under the plasma concentration versus time curve for saroglitazar. METHODS: Healthy subject pharmacokinetic data from a well-powered food-effect study (fasted vs fed treatments; n = 50) was used in this work. The first 25 subjects' serial plasma concentration data up to 72 hours and corresponding AUC0-t (ie, 72 hours) from the fasting group comprised a training dataset to develop the limited sampling model. The internal datasets for prediction included the remaining 25 subjects from the fasting group and all 50 subjects from the fed condition of the same study. The external datasets included pharmacokinetic data for saroglitazar from previous single-dose clinical studies. Limited sampling models were composed of 1-, 2-, and 3-concentration-time points' correlation with AUC0-t of saroglitazar. Only models with regression coefficients (R2) >0.90 were screened for further evaluation. The best R2 model was validated for its utility based on mean prediction error, mean absolute prediction error, and root mean square error. Both correlations between predicted and observed AUC0-t of saroglitazar and verification of precision and bias using Bland-Altman plot were carried out. FINDINGS: None of the evaluated 1- and 2-concentration-time points models achieved R2 > 0.90. Among the various 3-concentration-time points models, only 4 equations passed the predefined criterion of R2 > 0.90. Limited sampling models with time points 0.5, 2, and 8 hours (R2 = 0.9323) and 0.75, 2, and 8 hours (R2 = 0.9375) were validated. Mean prediction error, mean absolute prediction error, and root mean square error were <30% (predefined criterion) and correlation (r) was at least 0.7950 for the consolidated internal and external datasets of 102 healthy subjects for the AUC0-t prediction of saroglitazar. The same models, when applied to the AUC0-t prediction of saroglitazar sulfoxide, showed mean prediction error, mean absolute prediction error, and root mean square error <30% and correlation (r) was at least 0.9339 in the same pool of healthy subjects. IMPLICATIONS: A 3-concentration-time points limited sampling model predicts the exposure of saroglitazar (ie, AUC0-t) within predefined acceptable bias and imprecision limit. Same model was also used to predict AUC0-infinity. The same limited sampling model was found to predict the exposure of saroglitazar sulfoxide within predefined criteria. This model can find utility during late phase clinical development of saroglitazar in the patient population. PMID- 29496319 TI - Bias and misleading concepts in an Arnica research study. Comments to improve experimental Homeopathy. AB - Basic experimental models in Homeopathy are of major interest because they could get insightful data about the ability of high dilutions to work in a biological system. Due to the extreme difficulty in the highlighting any possible effect and trusting its reliability, methods should be particularly stringent and highly standardized. Confounders, handling process, pre-analytical errors, misleading statistics and misinterpretations may lead to experimental biases. This article tries to elucidate those factors causing bias, taking into account some recent reported evidence in the field. PMID- 29496321 TI - Stability of Cefazolin in Polyisoprene Elastomeric Infusion Devices. AB - PURPOSE: The aim was to investigate the stability of cefazolin in elastomeric infusion devices. METHODS: Elastomeric devices (Infusor LV) that contain cefazolin (3 g/240 mL and 6 g/240 mL) were prepared and stored at 4 degrees C for 72 hours and then at 35 degrees C for 12 hours, followed by 25 degrees C for 12 hours. An aliquot was withdrawn at predefined time points and analyzed for the concentration of cefazolin. Samples were also assessed for changes in pH, solution color, and particle content. FINDINGS: Cefazolin retained acceptable chemical and physical stability over the studied storage period and conditions. IMPLICATIONS: These findings will allow the administration of cefazolin by the Infusor LV elastomeric device in the outpatient and remote settings. PMID- 29496322 TI - The costal skeleton of the Regourdou 1 Neandertal. AB - The morphology and size of the Neandertal thorax is a subject of growing interest due to its link to general aspects of body size and shape, including physiological aspects related to bioenergetics and activity budgets. However, the number of well-preserved adult Neandertal costal remains is still low. The recent finding of new additional costal remains from the Regourdou 1 (R1) skeleton has rendered this skeleton as one of the most complete Neandertal costal skeletons with a minimum of 18 ribs represented, five of which are complete or virtually complete. Here we describe for the first time all the rib remains from R1 and compare them to a large modern Euroamerican male sample as well as to other published Neandertal individuals. The costal skeleton of this individual shows significant metric and morphological differences from our modern human male comparative sample. The perceived differences include: dorsoventrally large 1st and 2nd ribs, 3rd ribs with a very closed dorsal curvature and large maximum diameters at the posterior angle, a large tubercle-iliocostal line distance in the 4th rib, thick shafts at the dorsal end of its 6th ribs, thick mid-shafts of the 8th ribs, large articular tubercles at the 9th ribs, and thick shafts of the 11th and 12th ribs. Here we also describe a new mesosternal fragment: the left lateral half of sternebral segments 4 and 5. This portion reveals that the mesosternum of R1 had a sternal foramen in its inferiormost preserved sternal segment and supports previous estimation of the total length of this mesosternum. The new costal remains from R1 support the view that Neandertals, when compared with modern humans, show a significantly different thorax, consistent with differences found in other anatomical regions such as the vertebral column and pelvis. PMID- 29496323 TI - Treatment Outcomes in Male Breast Cancer: A Retrospective Analysis of 161 Patients. AB - AIMS: Male breast cancer is a rare disease with limited evidence-based guidelines for treatment. This study aimed to identify demographic, pathological and clinical factors associated with its prognosis. MATERIALS AND METHODS: A retrospective review of 161 male breast cancer patients diagnosed at a single institution from 1987 to June 2017 was conducted. Patient demographics, disease characteristics, treatment and outcome were extracted and included in competing risk analysis and the univariate Cox proportional hazard model for univariate analysis. Factors with P < 0.10 were included in multivariable analysis. RESULTS: The mean age at diagnosis was 67 years (standard deviation = 11.2) and the median follow-up duration was 5.3 years (range 0-25 years). There were 48 deaths, including 23 cancer-specific deaths. The actuarial median survival was 19.9 years. In multivariable analysis, factors associated with overall survival were size of tumours (hazard ratio 2.0; 95% confidence interval 1.4-2.7, P < 0.0001) and diagnosis of metastatic disease (hazard ratio 8.7; 95% confidence interval 1.9-40.6; P = 0.006). Of 138 patients without metastases at diagnoses, 11 had local-regional recurrence and 26 had distant metastases. In the multivariable model for local-regional recurrence, a more recent year of diagnosis was associated with reduced risk (hazard ratio 0.9, 95% confidence interval 0.8-1.0, P = 0.008), whereas more positive lymph nodes was associated with higher risk (hazard ratio 2.2, 95% confidence interval 1.2-4.0, P = 0.01). A higher risk of metastases was associated with more positive lymph nodes (hazard ratio 1.9; 95% confidence interval 1.1-3.3; P = 0.03) and tumour size (hazard ratio 1.8; 95% confidence interval 1.1-2.9; P = 0.01). A higher risk of any recurrence or metastases was associated with the number of positive nodes (hazard ratio 1.9; 95% confidence interval 1.2-3.0; P = 0.005) and tumour size (hazard ratio 1.6; 95% confidence interval 1.1-2.2; P = 0.01). CONCLUSION: In general, tumour size and more positive lymph nodes were associated with worse prognosis. Larger powered studies are needed to identify prognostic factors with smaller effect sizes. PMID- 29496324 TI - Surface marker profiles on lung lymphocytes may predict the mechanism of immune mediated pneumonitis triggered by tumor-infiltrating lymphocytes in lung cancer patients treated with pembrolizumab. PMID- 29496325 TI - End-of-Life Care for Unauthorized Immigrants in the U.S. AB - The Universal Declaration of Human Rights recognizes the inherent dignity, the equal and unalienable rights to be universally protected for all humans irrespective of race, color, gender, language, religion, political or other opinion, national or social origin, property, birth or other status. Though this includes the right to dignity-conserving care for terminally ill unauthorized immigrants, access to quality end-of-life care eludes them. Most of the estimated 11.3 million unauthorized immigrants either entered the country without the knowledge of the U.S. Immigration and Customs Enforcement, or were admitted on a temporary visa and stayed past its expiration date. Unsafe living conditions, occupational hazards, lack of access to routine healthcare, scarceness of a social and financial support system, fear of deportation, discrimination and incarceration limit healthcare access of unauthorized immigrants. Lack of access to preventative primary care encounters often results in this population's dependence on acute emergency services for treatment. Lack of opportunity for advance care planning discussions and lack of eligibility to hospice services commonly contributes to poor end of life care. As unauthorized immigrants approach the last days of life, they may often die alone, away from their loved ones, with little-to-no psychosocial support in their final moments. This article provides an overview on end-of-life care for unauthorized immigrants and makes recommendations for potential strategies to providing humane care and support to this vulnerable population. PMID- 29496326 TI - Demand for and availability of specialist chemsex services in the UK: A cross sectional survey of sexual health clinics. AB - BACKGROUND/INTRODUCTION: Chemsex amongst men who have sex with men (MSM) is well documented in major cities within the United Kingdom (UK), but few data from less urban areas exist. We undertook a survey of sexual health clinic (SHC) healthcare workers (HCWs) to explore demand for and availability of chemsex services to understand training needs and inform service planning. METHODS: An online survey was distributed to HCWs in all SHCs across the UK. For English clinics, we explored associations between responses and geo-demographic region using national surveillance data and population statistics. RESULTS: Responses were received from 56% (150/270) of SHC's in the UK (89% (133/150) from English clinics). 80% (103/129) of UK clinics reported chemsex consultations and in 50% (65/129) these occurred at least monthly, with no significant difference found when analysed by the geo-demographic characteristics of England (p=0.38). Respondents from most clinics (99% (117/118)) wanted chemsex training, 81 %(103/129) felt there was a local clinical need for a chemsex service and 33% (14/43) had chemsex care pathways for referrals in place. DISCUSSION/CONCLUSION: Patients reporting chemsex regularly present to SHCs throughout the UK including rural areas. Given the potential negative health outcomes associated with chemsex, there is a need for local, high quality, appropriate services and training to minimise harm. PMID- 29496327 TI - The influence of limbal and scleral shape on scleral lens design. AB - PURPOSE: To summarize the research findings on the ocular surface profile, to provide a definition and a classification of the corneoscleral shape, and to offer guidelines in selecting scleral lens design. METHODS: The definition of rotational symmetry and rotational asymmetry was inquired and PubMed searches were conducted. RESULTS: The better understanding of the scleral contact lens comportment on the eye and the introduction of new diagnostic instruments to measure the anterior ocular surface have led to improve comprehension of corneoscleral contour formulating new scleral lens designs. The scleral lens landing zone is influenced by corneoscleral profile which may be rotationally symmetric and rotationally asymmetric. Corneal sagittal height, limbal shape, corneoscleral junction profile, corneal, limbal, and conjunctival angles, and scleral shape should be taken in consideration to prevent and manage fitting problems, such as air bubble formation, midday fogging, localized blanching, impingement, conjunctival prolapse, lens decentration, lens flexure, and to increase comfort, wearing time, overall satisfaction, and visual quality. CONCLUSION: Corneoscleral shape may be considered rotationally symmetric including spherical, aspherical and toric profiles, and rotationally asymmetric including regular and irregular quadrants profiles. Each ocular surface contour requires a different landing zone design for an optimal fitting, vaulting properly over the cornea and limbus, and ideal alignment on the sclera. Further studies are still necessary to clarify many aspects of scleral lenses which are little known yet. PMID- 29496328 TI - Trends in Contact Lens Prescribing in Japan (2003-2016). AB - PURPOSE: To review contact lens prescribing trends in Japan between 2003 and 2016. METHODS: An annual survey of contact lens prescribing trends was conducted each year between 2003 and 2016. Japanese ophthalmologists were asked to provide information relating to ten consecutive contact lens fittings between January and March every year. RESULTS: Over the 14 years of the annual survey, data from a total of 64,122 contact lens fits were returned by ophthalmologists. The mean age (+/-SD) of lens wearers was 30 +/- 13 years, and 68% were female. The proportion of rigid lens fits decreased over time, from 35.4% in 2003 to 14.7% in 2016. Across this period, daily disposable lens fits increased, representing 46% in 2016. The proportion of toric lenses and multifocal lenses gradually increased, from 6.6% and 1.9% to 12.3% and 5.8%, respectively. Silicone hydrogel material use grew from 0% to 43.2%, while mid and low water content lens materials declined from 54.1% and 28.2% to 36.1% and 8.3%, respectively. Multi-purpose lens care solutions dominated the market over the 14 year survey period. CONCLUSIONS: This survey has revealed prescribing trends and preferences in Japan over the past 14 years, with the main changes observed being a decrease in rigid lens use and an increase in the use of silicone hydrogel materials and daily disposable lenses. PMID- 29496329 TI - Mild hypoxic ischaemic encephalopathy and long term neurodevelopmental outcome - A systematic review. AB - AIMS: Hypoxic ischaemic encephalopathy (HIE) remains a significant cause of long term neurodisability despite therapeutic hypothermia (TH). Infants with mild HIE, representing 50% of those with HIE, are perceived as low risk and are currently not eligible for TH [1]. This review examines the available evidence of outcome in term infants with mild HIE. METHODS: Medline, Embase and Cochrane Clinical Trials databases were searched in March 2017. Studies with well-defined HIE grading at birth and standardised neurodevelopmental assessment at >=18 months were included. Abnormal outcome was defined as death, cerebral palsy or standardised neurodevelopmental test score more than 1 standard deviation below the mean. RESULT: Twenty studies were included. Abnormal outcome was reported in 86/341 (25%) of infants. There was insufficient evidence to examine the effect of TH on outcome. CONCLUSION: A significant proportion of infants with mild HIE have abnormal outcome at follow up. PMID- 29496330 TI - WASP (Write a Scientific Paper) using Excel - 7: The t-distribution. AB - The calculation of descriptive statistics after data collection provides researchers with an overview of the shape and nature of their datasets, along with basic descriptors, and may help identify true or incorrect outlier values. This exercise should always precede inferential statistics, when possible. This paper provides some pointers for doing so in Microsoft Excel, both statically and dynamically, with Excel's functions, including the calculation of standard deviation and variance and the relevance of the t-distribution. PMID- 29496331 TI - Mothers with acute and chronic postpartum psychoses and impact on the mother infant interaction. AB - BACKGROUND: Maternal postpartum psychoses pose a serious risk to the mother infant interaction. It is unclear how different subtypes of postpartum psychosis, including acute and chronic, might differentially affect the mother-infant interaction. METHOD: A systematic search of electronic journal databases was performed. RESULTS: This systematic review yielded 17 studies with adequate overall study quality. They focused on child custody and involvement of social services as indirect indicators of the mother-infant interaction, observed mother infant interactions as direct indicators, or potential transitional mechanisms, including memory processing, mind-mindedness, and affect recognition, that may partially explain the effects of psychotic disorders. An acute onset of psychosis during the postpartum period (de novo or relapse) was typically related to better mother-infant interactions. Mothers with schizophrenia have the highest risk of child displacement, and interventions by social services were more likely. However, mothers with postpartum schizophrenia did not exhibit more harm to the child or self-harm than mothers with postpartum depression. Heterogeneity of methodology, case definitions, and assessments characterized the studies; hence, they were not pooled. CONCLUSIONS: In addition to evaluating social risk factors in patients with acute onset and chronic psychoses during the postpartum period, negative preconceptions about motherhood and schizophrenia have to be carefully examined. Clinical research on postpartum psychoses should consider the onset criteria, prevalence of self-harm or harm to the child, significance of specific (e.g., religious) delusions and expressed hostility toward the child. More studies on the impact of first-onset (de novo) postpartum psychoses on the mother infant interaction are needed. PMID- 29496333 TI - Modified triceps fascial tongue approach for primary total elbow arthroplasty. AB - BACKGROUND: Triceps weakness is a common complication of total elbow arthroplasty (TEA). Many posterior approaches for TEA have been introduced to maintain triceps function. The present study evaluated the clinical outcomes and extensor strengths of primary TEA with modified triceps fascial tongue approach. METHODS: Twenty-one primary TEAs performed in 20 patients by a single surgeon were reviewed with a mean of 64.2 months (range, 24-127 months) of follow-up. Every TEA was performed using the modified triceps fascial tongue approach, with the Coonrad-Morrey prosthesis. Patient demographics, range of motion, pain visual analog scale, and triceps strength (Medical Research Council [MRC] scale) were compared before and after the operation. The Mayo Elbow Performance Score was evaluated at the latest follow-up. RESULTS: Triceps strength was normal (MRC grade V) in 10 elbows (48%) and good (MRC grade IV) in 11 (52%). Triceps strength after arthroplasty was significantly improved compared with the preoperative strength (P < .001). Mean flexion arc was improved from 78 degrees to 100 degrees after arthroplasty (P = .004). However, mean flexion contracture (preoperative; 29 degrees , postoperative; 26 degrees ) was not improved after surgery (P = .377). The mean visual analog scale pain score improved from 7.7 preoperatively to 2.4 postoperatively (P < .001). Postoperative Mayo Elbow Performance Scores were excellent in 13 elbows, good in 6, and fair in 2. The only complications were 3 intraoperative condylar fractures. CONCLUSIONS: Modified triceps fascial tongue approach is an easy and effective approach for primary TEA. PMID- 29496332 TI - Abnormal expression of ER quality control and ER associated degradation proteins in the dorsolateral prefrontal cortex in schizophrenia. AB - Abnormalities in posttranslational protein modifications (PTMs) that regulate protein targeting, trafficking, synthesis, and function have been implicated in the pathophysiology of schizophrenia. The endoplasmic reticulum (ER) contains specialized machinery that facilitate protein synthesis, ER entry and exit, quality control, and post-translational processing, steps required for protein maturation. Dysregulation of these systems could represent potential mechanisms for abnormalities of neurotransmitter associated proteins in schizophrenia. We hypothesized that expression of ER processing pathways is dysregulated in schizophrenia. We characterized protein and complex expression of essential components from protein folding, ER quality control (ERQC), and ER associated degradation (ERAD) processes in the dorsolateral prefrontal cortex of 12 matched pairs of elderly schizophrenia and comparison subjects. We found increased expression of proteins associated with recognizing and modifying misfolded proteins, including UDP-glucose/glycoprotein glucosyltransferase 2 (UGGT2), ER degradation enhancing alpha-mannosidase like protein 2 (EDEM2), and synoviolin (SYVN1)/HRD1. As SYVN1/HRD1 is a component of the ubiquitin ligase HRD1-SEL1L complex that facilitates ERAD, we immunoprecipitated SEL1L and measured expression of other proteins in this complex. In schizophrenia, SYVN1/HRD1 and OS 9, ERAD promoters, have increased association with SEL1L, while XTP3-B, which can prevent ERAD of substrates, has decreased association. Abnormal expression of proteins associated with ERQC and ERAD suggests dysregulation in ER localized protein processing pathways in schizophrenia. Interestingly, the deficits we found are not in the protein processing machinery itself, but in proteins that recognize and target incompletely or misfolded proteins. These changes may reflect potential mechanisms of abnormal neurotransmitter associated protein expression previously observed in schizophrenia. PMID- 29496334 TI - Whole genome analysis of a multidrug-resistant Streptococcus pneumoniae isolate from a patient with invasive pneumococcal infection developing disseminated intravascular coagulation. AB - Multidrug-resistant Streptococcus pneumoniae strains were isolated from blood and sputum of a patient with disseminated intravascular coagulation in Sapporo city, Japan. These antibiograms were only susceptible to vancomycin, linezolid, daptomycin, some carbapenems, and some fluoroquinolones. Identical antibiograms, serotypes (19F), and sequence types (ST10017) suggested a shared origin of these isolates. Only one ST10017 strain has been isolated in the same city in Japan previously (2014), and the 2014 isolate is still susceptible to macrolides. The whole genome of the blood-derived isolate was sequenced. The strain harbored resistance mutations in parC, gyrA, pbp1a, pbp2a, pbp2b, and pbp2x, and harbored the resistance genes, ermB and tetM. The nucleotide sequences of parC and pbp2x genes of strain MDRSPN001 were clearly different from those of other S. pneumoniae strains and were similar to those of oral streptococci strains. These findings suggest that strain MDRSPN001 has been rapidly and drastically evolving multidrug resistance by gene replacement and accumulation of genes originating from other strains, such as oral streptococci, Streptococcus mitis. PMID- 29496335 TI - The reduction of l-cystine to l-cysteine in the supernatant of A549 cell culture causes imipenem inactivation. AB - In the course of measuring the intracellular antibacterial activity of antibiotics using a human alveolar epithelial cell line A549, we discovered that the antimicrobial activity of several carbapenems (CPs) decreased in the supernatant of the cells cultured with fetal calf serum (FCS)-free RPMI1640 medium (RPMI). Further investigation revealed A549 culture supernatant inhibited the antibacterial activity of CPs but did not inactivate other types of antibiotics. CE-TOFMS and LC-TOFMS metabolomics analysis of the supernatant revealed the presence of l-cysteine (Cys), which is not an original component in RPMI. Cys is known to hydrolyze and inactivate CPs in a time- and concentration dependent manner. In this study, the inactivating effects of A549 culture supernatant on the imipenem (IPM) were examined. Antimicrobial activity of 100 MUg/mL IPM decreased to 25% with two-fold dilution of A549 supernatant incubated for 3 h. l-Cystine (CS), the Cys oxide, and an original component in RPMI did not inactivate IPM. However, the inactivating effects of A549 supernatant on IPM corresponds with the Cys concentration and depends on the CS content of the culture medium. Addition of FCS to the culture medium decreased the Cys concentration and reduced inactivation of IPM in a dose-dependent manner. Our data suggest that IPM were inactivated by Cys reduced from CS, and this CS-to-Cys conversion must be considered when evaluating the antimicrobial activity of CPs in cell culture. Further studies are needed to understand if the same inactivation occurs around the cells in the human body. PMID- 29496336 TI - Relationship between the prognostic nutritional index and long-term clinical outcomes in patients with stable coronary artery disease. AB - BACKGROUND: Malnutrition has recently been reported to correlate with prognosis in patients with heart failure. However, the prognostic significance of nutritional status in patients with stable coronary artery disease (CAD) is unknown. The present study sought to examine the association between nutritional status assessed by the prognostic nutritional index (PNI) and cardiovascular outcomes in patients with stable CAD. METHODS: A total of 1988 patients with stable CAD who underwent elective percutaneous coronary intervention (PCI) between 2000 and 2011 were examined. The PNI was calculated as 10*serum albumin (g/dL)+0.005*total lymphocyte count (per mm3). Patients were assigned to tertiles based on their PNI. The incidence of major adverse cardiac events (MACE), including all-cause death and non-fatal myocardial infarction, was evaluated. RESULTS: The median PNI was 48.9 (interquartile range: 45.5-52.1). During the median follow-up of 7.5 years, Kaplan-Meier analysis showed that patients with lower PNI tertiles had higher rates of MACE (PNI <46.7: 35.5%; 46.7-50.8: 22.3%; >50.8: 16.0%; log-rank p<0.0001). After adjusting for other risk factors, the PNI was independently associated with MACE (hazard ratio 2.05 per 10 PNI decrease, 95% confidence interval: 1.66-2.54, p<0.0001). Adding the PNI to a baseline model with established risk factors improved the C-index (p=0.03), net reclassification improvement (p=0.03), and integrated discrimination improvement (p=0.0001). CONCLUSIONS: The PNI was significantly associated with long-term cardiovascular outcomes in patients with stable CAD. Assessing PNI may be useful for risk stratification of CAD patients undergoing elective PCI. PMID- 29496337 TI - Characteristics of dormant pulmonary vein conduction induced by adenosine triphosphate in patients with atrial fibrillation undergoing cryoballoon ablation. AB - BACKGROUND: Adenosine triphosphate (ATP) can provoke acute reconnections after pulmonary vein isolation (PVI). This study aimed to investigate dormant conduction (DC) after ablation with second-generation cryoballoon (CB). METHODS: Two hundred sixteen patients (148 male; age 64+/-9 years) with atrial fibrillation (AF) were included. After a successful PVI with the CB, 20mg of ATP was administered. All patients were followed up for 425+/-56 days. RESULTS: Seven hundred ninety-five out of 864 (92%) PVs were successfully isolated solely by the CB. DCs were revealed in 8 (3.7%) after ATP injections. AF recurrences occurred in 2 out of 8 patients, while no AF recurrences could be documented in 6 out of 8 patients with DCs after a blanking period of 3 months (25% vs. 75%). In contrast, 29 (13.9%) patients without DCs had AF recurrences, and there was no significant difference between those with and without DCs regarding the recurrence rate of AF (p=0.38). There were no reliable predictors of DCs after the PVI with the CB. CONCLUSION: The present study demonstrated a low rate of transient PV reconnection after adenosine infusion following successful PVI with the CB. There was no reliable predictor of DCs. Further studies will be needed in order to appreciate the prognostic value of adenosine testing after successful PVI with the CB. PMID- 29496338 TI - Googling your hand hygiene data: Using Google Forms, Google Sheets, and R to collect and automate analysis of hand hygiene compliance monitoring. AB - BACKGROUND: Hand hygiene is one of the most important interventions in the quest to eliminate healthcare-associated infections, and rates in healthcare facilities are markedly low. Since hand hygiene observation and feedback are critical to improve adherence, we created an easy-to-use, platform-independent hand hygiene data collection process and an automated, on-demand reporting engine. METHODS: A 3-step approach was used for this project: 1) creation of a data collection form using Google Forms, 2) transfer of data from the form to a spreadsheet using Google Spreadsheets, and 3) creation of an automated, cloud-based analytics platform for report generation using R and RStudio Shiny software. RESULTS: A video tutorial of all steps in the creation and use of this free tool can be found on our YouTube channel: https://www.youtube.com/watch?v=uFatMR1rXqU&t. The on-demand reporting tool can be accessed at: https://crsp.louisville.edu/shiny/handhygiene. CONCLUSIONS: This data collection and automated analytics engine provides an easy-to-use environment for evaluating hand hygiene data; it also provides rapid feedback to healthcare workers. By reducing some of the data management workload required of the infection preventionist, more focused interventions may be instituted to increase global hand hygiene rates and reduce infection. PMID- 29496339 TI - Expansion or Invasion? A Response to Nackley et al. PMID- 29496340 TI - Evolutionary Community Ecology: Time to Think Outside the (Taxonomic) Box. AB - Ecologists and evolutionary biologists have long been interested in the role of interspecific competition in the diversification of clades. These studies often focus on a single taxonomic group, making the implicit assumption that important competitive interactions occur only between closely related taxa, despite abundant documentation of intense competition between species that are distantly related. Specifically, this assumption ignores convergence of distantly related competitors on limiting niche axes and thus may miss cryptic effects of distantly related competitors on the evolution of focal clades. For example, distantly related competitors may act as important drivers of niche conservatism within clades, a pattern commonly ascribed to evolutionary constraints or the abiotic environment. Here we propose an alternative model of how niche similarity evolves when the functional traits of interest are mediated by unrelated phenotypic traits, as is often the case for distantly related competitors. This model represents an important conceptual step towards a more accurate, taxonomically inclusive understanding of the role that competition plays in the micro- and macroevolution of interacting species. PMID- 29496341 TI - Comparison of plant- and egg yolk-based semen diluents on in vitro sperm kinematics and in vivo fertility of frozen-thawed bull semen. AB - Diluents using components of plant origin have been developed as an alternative to animal based extenders for the dilution of bull semen, however, it is unclear if use of these diluents results in in vivo fertility rates similar to those that occur with use of traditional egg yolk-based diluents. The aim of this study was to assess the effect of semen diluent on 60-day non-return rate (NRR) following artificial insemination (AI) with frozen-thawed bull semen. The effect of semen dilution in one of three different commercial diluents (BullXcell - egg yolk based, OptiXcell - plant-based or AndroMed - plant-based) on post-thaw total and progressive motility as well as kinematic parameters (Experiment 1) and field fertility (Experiment 2, n = 1,480 inseminations) was assessed. Semen stored in OptiXcell had greater post-thaw total and progressive motility than AndroMed (P < 0.05) but did not differ from BullXcell. Semen stored in BullXcell had a greater beat cross frequency and straight line velocity compared to semen stored in AndroMed (P < 0.05) but did not differ when compared with use of OptiXcell; while values for these variables when using OptiXcell and AndroMed did not differ from each other (P > 0.05). There was no difference in any other sperm kinematic parameters (P > 0.05). There was no effect of diluent on 60-day NRR (71.5%, 67.8% and 70.6% for BullXcell, OptiXcell and AndroMed, respectively). In conclusion, while diluent significantly affected post-thaw sperm motility and kinematics, no effect on 60-day NRR was observed. Given that OptiXcell and AndroMed are animal protein-free media these diluents may be a suitable alternative to BullXcell for the storage of frozen-thawed bull semen. PMID- 29496342 TI - Climatic factors affecting quantity and quality grade of in vivo derived embryos of cattle. AB - The present study investigated the effects of climatic variables on the quality grade and quantity of in vivo derived cattle embryos in the Midwestern United States. Climatic information included greatest and least daily temperature, average daily wind speed and average temperature-humidity index for each of the 765 records. The response variables included the number of ovarian structures, viable embryos, quality grade 1 embryos, quality grade 2 embryos, quality grade 3 embryos, freezable embryos (sum of quality grade 1 and quality grade 2 embryos), transferable embryos (sum of quality grade 1-3 embryos), degenerate embryos and unfertilized ova. Measures for variables among the breeds of donors and sires grouped by geographical origin were compared. A negative effect of greater temperatures during the early embryonic development stage tended (P < 0.10) to be associated with a decrease in the quality of embryos recovered. Interestingly, the greater the Temperature-Humidity Index (THI) during the early ovarian antral follicular development stage 40-45 days prior to ovulation was associated with a tendency for greater numbers of total number of freezable and transferable embryos recovered per uterine flushing (P < 0.10). Increased wind speed at the early antral follicular phase 40-45 days prior to ovulation was associated with an increase in the percentage of quality grade 1 embryos recovered (P < 0.05). Wind speed during the estrous synchronization period was also associated with a lesser number of embryos recovered (P < 0.05). This retrospective study confirms that climatic variables have significant effects on the in vivo production of cattle embryos and that wind speed should be considered in future analyses of factors affecting embryo quality. PMID- 29496343 TI - Semen evaluation and in vivo fertility in a Northern Italian pig farm: Can advanced statistical approaches compensate for low sample size? An observational study. AB - The evaluation of sperm functionality and morphology allows discerning between high and low quality ejaculates, but does not give detailed predictive information regarding in vivo fertility. The current developments in statistical modeling have helped in carrying out reproductive studies, but their biggest limitation is in the size of the dataset to be used. The aim of the present observational study was to evaluate whether advanced statistical approaches, such as mixed effects regression models and bootstrap resampling, can help in assessing the predictive ability of semen parameters in terms of in vivo fertility (farrowing rate and litter size), on a small/medium farm with a limited number of animals. Data regarding 33 ejaculates, including viability, subjective motility and acrosome reaction, were collected. Two hundred and thirty-five sows were inseminated with an outcome of 167 deliveries and 1734 newborn piglets. In order to evaluate the relationships among the parameters measured and fertility, mixed effects regression statistical models were used. Once the covariates to be included in the final models were identified, non-parametric bootstrapping was used. The results showed that the farrowing rate was highly associated with the total number of spermatozoa and subjective motility, while litter size was associated with percentage of acrosome reaction. In conclusion, the proposed statistical approach seemed to be suitable for studies regarding reproduction and fertility, even for relatively small sample sizes. Nonetheless, larger data sets are still preferable and required in order to achieve higher reliability. PMID- 29496344 TI - Decline in the perceived risk of cigarette smoking between 2006 and 2015: Findings from a U.S. nationally representative sample. AB - INTRODUCTION: Perceived risk of smoking is associated with smoking status, interest in quitting, quit attempts, and sustained quitting. Tracking and reporting of risk perceptions is integral to inform regulation and education. However, no research describes temporal changes in perceived great risk of smoking in the U.S. using nationally representative data. METHODS: Data came from the 2006-2015 National Survey on Drug Use and Health (NSDUH). Time trends were assessed for the population overall, stratified by smoking status and by sociodemographic characteristics. Linear time trends of perceived great risk (versus other risk) were assessed using logistic regression, with survey year as the predictor. RESULTS: Perceived great risk of smoking declined significantly among the entire population between 2006 and 2015 (73.89% versus 72.89%). Perceived great risk also decreased among all smoking statuses: daily (51.16% versus 48.19%), non-daily (64.12% versus 58.44%, former (79.57% versus 77.12%), and non-smokers (79.32% versus 77.10%). The prevalence of perceived great risk declined between 2006 and 2015 among both males and females; the rate of decline was more rapid among females (aOR = 0.98, 95% CI = 0.97, 0.98 versus aOR = 0.99, 95% CI = 0.98, 0.99). Older age, African American and Hispanic race/ethnicity, educational attainment, and non-daily, former, and never smoking statuses were positively associated with perceived great risk of smoking. DISCUSSION: Perceived risk of smoking has declined over a 10-year period in the U.S. Declines in perceived risk indicate the need for innovative interventions to reinforce the harms associated with smoking. Differential rates of decline among males and females indicate the need for sex-specific interventions. PMID- 29496345 TI - Practical management of diabetes patients before, during and after surgery: A joint French diabetology and anaesthesiology position statement. PMID- 29496346 TI - Attenuation, safety, and efficacy of a QX-like infectious bronchitis virus serotype vaccine. AB - Avian infectious bronchitis (IB) is a highly contagious disease caused by avian infectious bronchitis virus (IBV), which is a considerable economic threat to the poultry industry. QX-like IBV strains have increasingly emerged in China in recent years. Hence, development of a specific vaccine to guard against their potential threat is important. In this study, we sought to develop an attenuated vaccine strain. First, attenuated QX-like IBV strain SZ130 was created by continuous passage in chicken embryos for 130 generations, and then its safety was tested. We also evaluated the protective efficacy of different doses of SZ130 against challenge with QX-like IBV field strain SD in chickens. SZ130-infected birds did not experience IB-like signs and organ lesions. Additionally, an excellent protective effect of SZ130 vaccination was observed when vaccinated birds were challenged with SD, with no clinical signs or gross lesions, decreased target tissue replication rates, and lower ciliostasis scores in all immunized groups. These findings indicate that attenuated IBV strain SZ130 is highly safe in chicks and may serve as an effective vaccine against the threat posed by QX like IBV strains. PMID- 29496348 TI - It could have been much worse: The Minnesota measles outbreak of 2017. AB - In 2017, Minnesota battled its largest measles outbreak in nearly 30 years, with 79 cases, most of them Somali-American children. In this study, we gathered vaccination and enrollment data for incoming kindergarteners in Minnesota over fall 2012-2016 from the Minnesota Department of Health. We also gathered the number of measles cases by county in 2017. We found that MMR coverage has substantial variation across districts and district types. The minimum MMR coverage is 58.3% and the maximum is 100%. Private schools, which represent approximately six percent of Minnesota's kindergarten enrollment, have a substantially lower coverage rate, with an overall coverage of 83.00%. The 2017 outbreak was relatively isolated. However, the MMR coverage data suggests that other communities could have been at risk given their geographic proximity to the outbreak and modest coverage rates. PMID- 29496347 TI - Engineering a stable CHO cell line for the expression of a MERS-coronavirus vaccine antigen. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) has infected at least 2040 patients and caused 712 deaths since its first appearance in 2012, yet neither pathogen-specific therapeutics nor approved vaccines are available. To address this need, we are developing a subunit recombinant protein vaccine comprising residues 377-588 of the MERS-CoV spike protein receptor-binding domain (RBD), which, when formulated with the AddaVax adjuvant, it induces a significant neutralizing antibody response and protection against MERS-CoV challenge in vaccinated animals. To prepare for the manufacture and first-in-human testing of the vaccine, we have developed a process to stably produce the recombinant MERS S377-588 protein in Chinese hamster ovary (CHO) cells. To accomplish this, we transfected an adherent dihydrofolate reductase-deficient CHO cell line (adCHO) with a plasmid encoding S377-588 fused with the human IgG Fc fragment (S377-588 Fc). We then demonstrated the interleukin-2 signal peptide-directed secretion of the recombinant protein into extracellular milieu. Using a gradually increasing methotrexate (MTX) concentration to 5 MUM, we increased protein yield by a factor of 40. The adCHO-expressed S377-588-Fc recombinant protein demonstrated functionality and binding specificity identical to those of the protein from transiently transfected HEK293T cells. In addition, hCD26/dipeptidyl peptidase-4 (DPP4) transgenic mice vaccinated with AddaVax-adjuvanted S377-588-Fc could produce neutralizing antibodies against MERS-CoV and survived for at least 21 days after challenge with live MERS-CoV with no evidence of immunological toxicity or eosinophilic immune enhancement. To prepare for large scale manufacture of the vaccine antigen, we have further developed a high-yield monoclonal suspension CHO cell line. PMID- 29496349 TI - WHO/IVI global stakeholder consultation on group A Streptococcus vaccine development: Report from a meeting held on 12-13 December 2016. AB - While progress towards a Group A Streptococcus (GAS) vaccine has been stalled by a combination of scientific, regulatory, and commercial barriers, the problem persists. The high and globally-distributed burden of disease attributable to GAS makes vaccination an imperative global public health goal. Advances across a range of scientific disciplines in understanding GAS diseases have made the goal a realistic one and focused attention on the need for coordinated global action. With a view to accelerating GAS vaccine development, the World Health Organization (WHO) and the International Vaccine Institute (IVI) convened a global stakeholder consultation on the 12th and 13th of December 2016, in Seoul, South Korea. Topics discussed included: (1) gaps in current knowledge of global GAS epidemiology, burden of disease, and molecular epidemiology; (2) contribution of pre-clinical models to candidate vaccine evaluation and new immunological assays to address GAS immunology knowledge gaps; (3) status and future of the GAS vaccine development pipeline; and (4) defining a pathway to licensure, policy recommendations and availability of a vaccine. The meeting determined to establish a GAS vaccine working group to coordinate preparation of a global vaccine values proposition, preferred product characteristics, and a technical research and development roadmap. A new global GAS vaccine consortium will drive strategic planning to anticipate requirements for licensure, prequalification, and policy recommendations. PMID- 29496351 TI - Efficacy and safety of infliximab biosimilar Inflectra(r) in severe sarcoidosis. AB - BACKGROUND: Infliximab, a monoclonal antibody against tumor necrosis factor alpha (TNF-alpha) is effective third-line therapy in severe sarcoidosis. The originator product of Infliximab, Remicade(r), is expensive, limiting universal access. Recently, a less expensive biosimilar of infliximab, Inflectra(r), has become available, but the efficacy and tolerability has not been studied in sarcoidosis. METHODS: In this retrospective cohort study, 29 patients treated with the infliximab biosimilar Inflectra(r), were analysed. Patients received Inflectra(r) intravenously monthly at a dose of 5 mg/kg. We measured trough levels before every infusion. Before and after 6 months of induction therapy pulmonary function and disease activity were evaluated using Standardised Uptake Value (SUV) of the 18F-fluorodeoxyglucose by positron emission tomography (18F-FDG PET), soluble interleukin-2 receptor (sIL-2R), angiotensin converting enzyme (ACE) and health related quality of life (HRQOL). RESULTS: In patients with pulmonary sarcoidosis as main treatment indication (n = 15) the predicted FVC improved with 8.1%, p < 0.05. Furthermore, in the whole group HRQoL improved significantly (p < 0.001), whereas SUVmax and sIL-2R significantly reduced (p < 0.001 and p = 0.001 respectively). Hospitalisation due to infections occurred in four patients. None of the patients discontinued Inflectra(r) due to side-effects. Furthermore, all patients had detectable trough levels indicating development of neutralizing antibodies. CONCLUSION: Infliximab biosimilar Inflectra(r) seems effective in the treatment of refractory sarcoidosis with a comparable safety profile to the reference product Remicade(r). Inflectra(r) can be considered as an alternative and less expensive option for patients with refractory sarcoidosis. PMID- 29496350 TI - Immunization education for internal medicine residents: A cluster-randomized controlled trial. AB - PURPOSE: The aims of this study are to evaluate the impact of a novel immunization curriculum based on the Preferred Cognitive Styles and Decision Making Model (PCSDM) on internal medicine (IM) resident continuity clinic patient panel immunization rates, as well as resident immunization knowledge, attitudes, and practices (KAP). METHODS: A cluster-randomized controlled trial was performed among 143 IM residents at Mayo Clinic to evaluate the PCSDM curriculum plus fact based immunization curriculum (intervention) compared to fact-based immunization curriculum alone (control) on the outcomes of resident continuity clinic patient panel immunization rates for influenza, pneumococcal, tetanus, pertussis, and zoster vaccines. Pre-study and post-study immunization KAP surveys were administered to IM residents. RESULTS: Ninety-nine residents participated in the study. Eighty-two residents completed pre-study and post-study surveys. Influenza and pertussis immunization rates improved for both intervention and control groups. There was no significant difference in immunization rate improvement between the groups. Influenza immunization rates improved significantly by 33.4% and 32.3% in the intervention and control groups, respectively. The odds of receiving influenza immunization at the end of the study relative to pre-study for the entire study cohort was 4.6 (p < 0.0001). The odds of having received pertussis immunization at the end of the study relative to pre-study for the entire study cohort was 1.2 (p = 0.0002). Both groups had significant improvements in immunization knowledge. The intervention group had significant improvements in multiple domains that assessed confidence in counseling patients on immunizations. CONCLUSIONS: Fact-based immunization education was useful in improving IM resident immunization rates for influenza and pertussis. The PCSDM immunization curriculum did not lead to increases in immunization rates compared with the fact-based curriculum, but it did significantly increase resident confidence in communicating with patients about vaccines. PMID- 29496352 TI - Patient prioritisation in HCC treatment: All (good) things come in threes. PMID- 29496353 TI - Primary synovial sarcoma (SS) of larynx: An unusual site. AB - Soft tissue sarcomas (STSs) are heterogeneous disorders comprises myriad subtypes originated from mesenchymal stem cells. Synovial sarcomas (SSs) are belligerent malignant tumours included in this group affecting extremities of patients' age ranging between 15 and 35 years. SS taking place in head and neck region is rare event and primary laryngeal involvement is even rarer happening. There are 20 odd published cases documented in world literature so far. Here we are presenting primary laryngeal SS occurred in 31 year old male patient initially mimicking laryngeal carcinoma as patient was chronic smoker and classic symptom of hoarseness of voice. PMID- 29496354 TI - Expression of the gene coading for PGC-1alpha in peripheral blood leukocytes and related gene variants in patients with Parkinson's disease. AB - INTRODUCTION: Peroxisome proliferator-activated receptor (PPAR)-gamma coactivator 1alpha (PGC-1alpha) plays an important role in Parkinson's disease (PD). The aim of the study was to evaluate PGC-1alpha gene expression in the peripheral blood of PD patients. We also investigated PGC-1alpha-related gene variants and identified whether they are associated with PGC-1alpha gene expression. METHODS: 259 PD patients and 253 healthy controls were included in this study. PPARGC1A (the gene encoding PGC-1alpha) expression levels were tested using real-time PCR. Single nucleotide polymorphisms (SNPs) of the PGC-1alpha-related genes (PPARGC1A, PPARG and SIRT1) were genotyped by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). RESULTS: PPARGC1A levels were significantly decreased in PD patients (P = 0.000) and negatively correlated with the patients' H&Y stage (r = -0.212, P = 0.039) and UPDRS-III score (r = -0.208, P = 0.044), after correcting, these correlations disappeared. The genotype frequencies of PGC-1alpha-related gene variants were not associated with the risk of PD. PPARGC1A rs2970870 variant was associated with the NMS score (P = 0.026), SIRT1 rs7895833 variant was associated with HAMA score (P = 0.029). PPARG rs4684847 variant was associated with MMSE score (P = 0.031). PPARG rs1801282, rs4684847, rs3856806 variants were associated with MoCA score. After correcting, only the association between PPARG rs4684847 and MoCA score remained significant (FDR = 0.048). PGC-1alpha-related gene variants had no effect on PGC-1alpha gene expression. CONCLUSION: The decreased expression of PGC-1alpha may not be due to its related gene variants. PGC-1alpha could become a candidate blood-based biomarker for diagnosis and monitoring disease progression. PMID- 29496355 TI - Cortical thickness, stance control, and arithmetic skill: An exploratory study in premanifest Huntington disease. AB - BACKGROUND: Huntington disease (HD) is an inherited neurodegenerative disorder most commonly manifesting in adulthood. Identification of biomarkers tracking neurodegeneration before the onset of motor symptoms is important for future interventional studies. Our study aimed to contribute in the phenotypic characterization of the premanifest HD phase. METHODS: 28 premanifest subjects (preHD), 25 age-matched controls, and 12 manifest HD patients were enrolled for the study. The participants underwent a multimodal protocol including cognitive evaluations, arithmetic ability test, posturography, composite cerebellar functional test (CCFS), and brain 3T-MRI. PreHD were divided at the group median for predicted years to expected onset into "far-from-onset" (>15 years, PreHD far), and "close-to-onset" (<=15 years, preHD-close). Basal ganglia volumes and cortical thickness were computed using FreeSurfer. RESULTS: PreHD-close showed significantly lower scores than controls in Symbol Digit Modalities Test (p = 0.017), Arithmetic subtraction task (p = 0.04), and MMSE (p < 0.006). At posturography, preHD-close showed increased sway velocity (<0.04) and distance (p < 0.02) compared to controls. PreHD-close had reduced striatum and globus pallidus volumes and left occipital cortical thinning compared to controls. Compared to PreHD far-from-onset, PreHD-close showed bilateral cortical thinning in occipital and parahippocampal regions, inversely correlating with burden score and prognostic index for HD. CCFS only differed between controls and manifest HD. PreHD far-from-onset did not show significant differences in comparison with controls. CONCLUSIONS: We confirmed that quantitative brain MRI represents a valid biomarker of neurodegeneration in preHD. Posturography and Arithmentic tests seem promising tools for detecting early changes in premanifest HD, but need to be further confirmed in large cohorts. PMID- 29496356 TI - Standing up to the cardiometabolic consequences of hematological cancers. AB - Hematological cancer survivors are highly vulnerable to cardiometabolic complications impacting long-term health status, quality of life and survival. Elevated risk of diabetes and cardiovascular disease arises not only from the effects of the cancers themselves, but also from the toxic effects of cancer therapies, and deconditioning arising from reduced physical activity levels. Regular physical activity can circumvent or reverse adverse effects on the heart, skeletal muscle, vasculature and blood cells, through a combination of systemic and molecular mechanisms. We review the link between hematological cancers and cardiometabolic risk with a focus on adult survivors, including the contributing mechanisms and discuss the potential for physical activity interventions, which may act to oppose the negative effects of both physical deconditioning and therapies (conventional and targeted) on metabolic and growth signaling (kinase) pathways in the heart and beyond. In this context, we focus particularly on strategies targeting reducing and breaking up sedentary time and provide recommendations for future research. PMID- 29496357 TI - Pancreatic Walled-Off Necrosis Eroding into the Inferior Vena Cava. AB - Walled-off necrosis (WON) is a well-known delayed local complication of acute necrotizing pancreatitis. Occasionally, WON may spontaneously rupture into the gastrointestinal tract or peritoneal cavity. However, erosion of a WON to a systemic vein has not been reported in literature so far. We report an unusual case of a 63-year-old male with acute necrotizing pancreatitis in whom WON was eroding into the inferior vena cava resulting in its thrombosis. Our patient also had a bunch of other well-described complications of pancreatitis including splanchnic venous thrombosis. PMID- 29496359 TI - The UVA-induced long non-coding RNA GS1-600G8.5 regulates the expression of IL-8. PMID- 29496358 TI - MITF-M regulates melanogenesis in mouse melanocytes. AB - BACKGROUND: Although the impact of the microphthalamia-associated transcription factor (Mitf) signaling pathway on melanocytes progression has been extensively studied, the specific molecular mechanisms behind MITF-M-enhanced melanin production in melanocytes still need to be clarified. METHODS: In this study, we analyzed the levels of Mitf-M in skin tissues of different coat mice in order to further reveal the relationship between Mitf-M and skin pigmentation. To address the function of Mitf-M on melanogenesis, we have used an overexpression system and combined morphological and biochemical methods to investigate its localization in different coat color mice and pigmentation-related genes' expression in mouse melanocytes. RESULTS: The qRT-PCR assay and Western blotting analysis revealed that Mitf-M mRNA and protein were synthesized in all tested mice skin samples, with the highest expression level in brown skin, a moderate expression level in grey skin and the lowest expression level in black skin. Simultaneously, immunofluorescence staining revealed that MITF-M was mainly expressed in the hair follicle matrix and inner and outer root sheath in the skin tissues with different coat colors. Furthermore, overexpression of MITF-M led to increased melanin content and variable pigmentation-related gene expression. CONCLUSION: These results directly demonstrate that MITF-M not only influences melanogenesis, but also determines the progression of melanosomal protein in mouse melanocytes. PMID- 29496360 TI - Glyoxal-induced exacerbation of pruritus and dermatitis is associated with staphylococcus aureus colonization in the skin of a rat model of atopic dermatitis. AB - BACKGROUND: Atopic dermatitis (AD) is a highly pruritic, chronic inflammatory skin disease associated with hyperreactivity to environmental triggers. Among those, outdoor air pollutants such as particulate matter (PM) have been reported to aggravate pre-existing AD. However, underlying mechanisms of air pollution induced aggravation of AD have hardly been studied. OBJECTIVE: To investigate the molecular mechanisms by which glyoxal, a PM-forming organic compound, exacerbates the symptoms of AD induced by neonatal capsaicin treatment. METHODS: Naive and AD rats had been exposed to either fresh air or vaporized glyoxal for 5 weeks (2 h/day and 5 days/week) since one week of age. Pruritus and dermatitis were measured every week. The skin and blood were collected and immunological traits such as Staphylococcus aureus skin colonization, production of antimicrobial peptides and immunoglobulin, and mRNA expression of inflammatory cytokines were analyzed. RESULTS: Exposure to glyoxal aggravated pruritus and dermatitis in AD rats, but did not induce any symptoms in naive rats. Staphylococcus aureus skin colonization was increased in the skin of both naive and AD rats. Expression of antimicrobial peptides such as LL-37 and beta-defensin-2 was also increased by exposure to glyoxal in the skin of both naive and AD rats. The mRNA expression of Th1-related cytokines was elevated on exposure to glyoxal. However, serum immunoglobulin production was not significantly changed by exposure to glyoxal. CONCLUSION: In AD rats, exposure to glyoxal exacerbated pruritus and cutaneous inflammation, which was associated with increased colonization of S. aureus and subsequent immunological alterations in the skin. PMID- 29496361 TI - High-Fidelity Emergency Department Thoracotomy Simulator With Beating-Heart Technology and OSATS Tool Improves Trainee Confidence and Distinguishes Level of Skill. AB - OBJECTIVE: Resuscitative Thoracotomy or Emergency Department Thoracotomy (EDT) is a time-sensitive and potentially life-saving procedure. Yet, trainee experience with this procedure is often limited in both clinical and simulation settings. We sought to develop a high-fidelity EDT simulation module and assessment tool to facilitate trainee education. DESIGN: Using the Kern model for curricular development, a group of expert trauma surgeons identified EDT as a high-stakes, low-frequency procedure. Task analysis identified 5 key steps of EDT: (1) opening chest/rib spreader utilization; (2) pericardiotomy/cardiac repair; (3) open cardiac massage; (4) clamping aorta; and (5) control of pulmonary hilum. A high fidelity simulator with beating-heart technology was built. The previously validated Objective Structured Assessment of Technical Skills (OSATS) was adapted to create the "EDT-OSATS" which assessed performance along several domains: (1) Surgical technique (key steps); (2) general skills; and (3) global rating. A pilot test was performed to compare board-certified trauma surgeons (i.e., Experts) with categorical general surgery interns (i.e., Novices). Each subject received preparatory materials, completed a presimulation quiz, performed a videotaped procedure on the EDT simulator, and completed a postmodule survey. Two independent raters scored performances using the EDT-OSATS. Groups were compared in descriptive and unadjusted analyses. We hypothesized that our EDT simulation module would distinguish between expert vs novice performance and improve trainee confidence. SETTING: Simulation laboratory at Massachusetts General Hospital in Boston, MA. PARTICIPANTS: Trauma surgeons (Experts, n = 6) and categorical general surgery interns (Novices, n = 8). RESULTS: Experts scored significantly higher than Novices on nearly all components of the EDT-OSATS, including: (1) surgical technique: pericardiotomy (4.2 vs 3.4, p = 0.040), cardiac massage (3.6 vs 2.4, p = 0.028), clamping aorta (4.1 vs 3.3, p = 0.035), control of pulmonary hilum (4.8 vs 3.4, p < 0.001); (2) general skills: time/motion (4.1 vs 2.9, p = 0.011), knowledge and handling of instruments (4.3 vs 3.1, p = 0.004), and (3) global rating (3.9 vs 2.9, p = 0.026). There was no statistical difference between groups on opening chest/rib spreader utilization (3.8 vs 3.3, p = 0.352) or procedure time (204sec vs 227sec, p = 0.401), though Experts scored numerically higher than Novices on every measure. Novices reported significantly increased confidence after the simulation (3.1 vs 1.4, p = 0.001). Ninety-three percent (13/14) of participants found the simulator realistic. CONCLUSIONS: Our novel high-fidelity beating-heart EDT simulator is realistic and improves trainee confidence in this low-frequency, high-stakes emergency procedure. The EDT-OSATS tool differentiates between performances of experienced surgeons vs novice trainees on the beating-heart simulator. This training module and accompanying assessment instrument hold promise as a learning tool for clinicians who may perform emergency department thoracotomy. PMID- 29496362 TI - Skewed Groups, Implicit Sex Bias, and Trainee Evaluations. PMID- 29496364 TI - The impact of non-severe hypoglycemia on quality of life in patients with type 2 diabetes. AB - AIMS: To determine the impact of frequency of non-severe hypoglycemic events (NSHE) and the perceived burden of NSHE on quality of life (QOL) over time. METHODS: T2D adults (n = 424) were re-contacted two years after initial QOL assessment. Responding subjects (n = 290) reported the frequency and burden of NSHE over time and completed six generic and diabetes-specific QOL measures. RESULTS: Most subjects (86%) reported >= one NSHE over time. Higher frequency of NSHE was significantly associated with decrements in QOL. Greater perceived burden of NSHE was significantly linked to decreases in QOL over time for all six QOL measures. Interaction terms indicated that participants with a higher frequency of NSHE and higher perceived burden reported the greatest decrease in QOL; participants who experienced frequent NSHE but did not perceive these events as burdensome evidenced little worsening in QOL over time. CONCLUSIONS: NSHE have a negative impact on QOL over time in T2D adults. However, it is not just the occurrence of NSHE that affects QOL; it is the individual's felt burden of these events that is critical. The greatest reductions in QOL are seen among those subjects reporting a higher frequency of NSHE and indicating that such events are burdensome. PMID- 29496363 TI - Simulated auditory nerve axon demyelination alters sensitivity and response timing to extracellular stimulation. AB - Since cochlear implant function involves direct depolarization of spiral ganglion neurons (SGNs) by applied current, SGN physiological health must be an important factor in cochlear implant (CI) outcomes. This expected relationship has, however, been difficult to confirm in implant recipients. Suggestively, animal studies have demonstrated both acute and progressive SGN ultrastructural changes (notably axon demyelination), even in the absence of soma death, and corresponding altered physiology following sensorineural deafening. Whether such demyelination occurs in humans and how such changes might impact CI function remains unknown. To approach this problem, we incorporated SGN demyelination into a biophysical model of extracellular stimulation of SGN fibers. Our approach enabled exploration of the entire parameter space corresponding to simulated myelin diameter and extent of fiber affected. All simulated fibers were stimulated distally with anodic monophasic, cathodic monophasic, anode-phase first (AF) biphasic, and cathode-phase-first (CF) biphasic pulses from an extracellular disc electrode and monitored for spikes centrally. Not surprisingly, axon sensitivity generally decreased with demyelination, resulting in elevated thresholds, however, this effect was strongly non-uniform. Fibers with severe demyelination affecting only the most peripheral nodes responded nearly identically to normally myelinated fibers. Additionally, partial demyelination (<50%) yielded only minimal increases in threshold even when the entire fiber was impacted. The temporal effects of demyelination were more unexpected. Both latency and jitter of responses demonstrated resilience to modest changes but exhibited strongly non-monotonic and stimulus-dependent relationships to more profound demyelination. Normal, and modestly demyelinated fibers, were more sensitive to cathodic than anodic monophasic pulses and to CF than AF biphasic pulses, however, when demyelination was more severe these relative sensitivities were reversed. Comparison of threshold crossing between nodal segments demonstrated stimulus-dependent shifts in action potential initiation with different fiber demyelination states. For some demyelination scenarios, both phases of biphasic pulses could initiate action potentials at threshold resulting in bimodal latency and initiation site distributions and dramatically increased jitter. In summary, simulated demyelination leads to complex changes in fiber sensitivity and spike timing, mediated by alterations in action potential initiation site and slowed action potential conduction due to non-uniformities in the electrical properties of axons. Such demyelination induced changes, if present in implantees, would have profound implications for the detection of fine temporal cues but not disrupt cues on the time scale of speech envelopes. These simulation results highlight the importance of exploring the SGN ultrastructural changes caused by a given etiology of hearing loss to more accurately predict cochlear implantation outcomes. PMID- 29496365 TI - Impact of the severity of hypoglycemia on health - Related quality of life, productivity, resource use, and costs among US patients with type 2 diabetes. AB - AIMS: To explore the association between hypoglycemia severity and health-related quality of life (HRQoL), productivity, health care resource utilization (HCRU), and costs among patients with type 2 diabetes mellitus (T2DM). METHODS: Data were from the 2013 US National Health and Wellness Survey. This analysis included adults with treated T2DM. Participants were categorized based upon their self reported experience in the previous 3 months: no hypoglycemia, non-severe hypoglycemia, or severe hypoglycemia. Validated instruments were used to measure HRQoL and productivity; HCRU was based on participant-reported health care provider (HCP) and emergency department (ED) visits and hospitalizations. Multivariable models tested for trends across the severity groups. RESULTS: The analysis included 3630 participants-1729 (47.6%) with non-severe hypoglycemia and 172 (4.7%) with severe hypoglycemia. Mental and physical component scores and utility scores were significantly associated with hypoglycemia severity (P < 0.001 for each). Similar trends were observed for absenteeism (P < 0.001), presenteeism (P = 0.005), HCP and ED visits (P <= 0.002), and hospitalizations (P < 0.001). Annual HCRU costs associated with increasingly severe hypoglycemia were $6908, $7132, and $15,410, respectively (P < 0.001), and productivity costs were $7248, $7493, and $12,167, respectively (P = 0.008). CONCLUSION: Hypoglycemia severity appears to be related to reduced HRQoL and productivity, which are mirrored by increased direct and indirect costs. PMID- 29496366 TI - Comparison of Macintosh and Miller laryngoscopes during pediatric resuscitation. PMID- 29496367 TI - Novel polyamine-based Histone deacetylases-Lysine demethylase 1 dual binding inhibitors. AB - Epigenetic modulators Histone deacetylases (HDACs) and Lysine demethylase (LSD1) are validated targets for anticancer therapy. Both HDAC1/2 and LSD1 are found in association with the repressor protein CoREST in a transcriptional co-repressor complex, which is responsible for gene silencing. Combined modulation of both targets results in a synergistic antiproliferative activity. In the present investigation, we report about the design and synthesis of a series of polyamine based HDACs-LSD1 dual binding inhibitors obtained by coupling Vorinostat and Tranylcypromine. Compound 4 emerged as the most promising of the synthesized series, showing good inhibitory activity towards HDAC1 and LSD1 either in vitro and in cell-based assay (Ki = 42.52 +/- 8.94 nM and IC50 = 3.85 MUM, respectively). Furthermore, at 70.0 uM compound 4 induced a more pronounced cytotoxic effect than Vorinostat (68.6% vs 56.6% of dead cells) in MCF7 cancer cell line. PMID- 29496368 TI - Bioactivity and structure-activity relationship of cinnamic acid derivatives and its heteroaromatic ring analogues as potential high-efficient acaricides against Psoroptes cuniculi. AB - A series of cinnamic acid derivatives and its heteroaromatic ring analogues were synthesized and evaluated for acaricidal activity in vitro against Psoroptes cuniculi, a mange mite. Among them, eight compounds showed the higher activity with median lethal concentrations (LC50) of 0.36-1.07mM (60.4-192.1ug/mL) and great potential for the development of novel acaricidal agent. Compound 40 showed both the lowest LC50 value of 0.36mM (60.4ug/mL) and the smallest median lethal time (LT50) of 2.6h at 4.5mM, comparable with ivermectin [LC50=0.28mM (247.4ug/mL), LT50=8.9h], an acaricidal drug standard. SAR analysis showed that the carbonyl group is crucial for the activity. The type and chain length of the alkoxy in the ester moiety and the steric hindrance near the ester group significantly influence the activity. The esters were more active than the corresponding thiol esters, amides, ketones or acids. Replacement of the phenyl group of cinnamic esters with alpha-pyridyl or alpha-furanyl significantly increase the activity. Thus, a series of cinnamic esters and its heteroaromatic ring analogues with excellent acaricidal activity emerged. PMID- 29496369 TI - Cochlear implant revision surgeries in children. AB - INTRODUCTION: The surgery during which the cochlear implant internal device is implanted is not entirely free of risks and may produce problems that will require revision surgeries. OBJECTIVE: To verify the indications for cochlear implantation revision surgery for the cochlear implant internal device, its effectiveness and its correlation with certain variables related to language and hearing. METHODS: A retrospective study of patients under 18 years submitted to cochlear implant Surgery from 2004 to 2015 in a public hospital in Brazil. Data collected were: age at the time of implantation, gender, etiology of the hearing loss, audiological and oral language characteristics of each patient before and after Cochlear Implant surgery and any need for surgical revision and the reason for it. RESULTS: Two hundred and sixty-five surgeries were performed in 236 patients. Eight patients received a bilateral cochlear implant and 10 patients required revision surgery. Thirty-two surgeries were necessary for these 10 children (1 bilateral cochlear implant), of which 21 were revision surgeries. In 2 children, cochlear implant removal was necessary, without reimplantation, one with cochlear malformation due to incomplete partition type I and another due to trauma. With respect to the cause for revision surgery, of the 8 children who were successfully reimplanted, four had cochlear calcification following meningitis, one followed trauma, one exhibited a facial nerve malformation, one experienced a failure of the cochlear implant internal device and one revision surgery was necessary because the electrode was twisted. CONCLUSION: The incidence of the cochlear implant revision surgery was 4.23%. The period following the revision surgeries revealed an improvement in the subject's hearing and language performance, indicating that these surgeries are valid in most cases. PMID- 29496370 TI - Pesticide behavior in paddy fields and development of azole-resistant Aspergillus fumigatus: Should we be concerned? AB - Tricyclazole as a common fungicide wildly used to control rice blast disease in the Asian country may induce azole resistance in Aspergillus fumigatus isolates. The main reason of the acquired azole resistance is probably environmental exposure through wide fungicide use in agriculture. The present study was conducted with the aim of investigating the current status of the azole-resistant A. fumigatus obtained from the paddy fields with exposure to tricyclazole. A total of 108 soil samples were collected from four different locations of paddy fields in Mazandaran Province, Iran. Pure fungal colonies were initially identified based on the conventional tools, and then reconfirmed by using DNA sequencing of the partial beta-tubulin gene. In addition, the in vitro antifungal susceptibility was determined using the Clinical and Laboratory Standards Institute document (CLSI) M38-A2. The identification of the mutations in the CYP51A gene was accomplished by the implementation of the polymerase chain reaction amplification assay on the selected isolates. Overall, 31 of 108 (28.7%) isolates were identified as A. fumigatus, four (3.7%) of which were recognized as azole-resistant with MICs of itraconazole >=8MUg/ml and voriconazole >=4MUg/ml. Only two out of the four azole-resistant A. fumigatus isolates harboured TR34/L98H variant and the other two isolates were identified as azole-resistant without any CYP51A gene mutations. However, other point mutations (TR46/Y121F/T289A) were not detected in the CYP51A gene. The high molecular structure similarity between environmental and medical triazoles may result in the selection of resistance mechanisms. Nonetheless, one might conclude that tricyclazole with different molecular structures against medical azoles induces azole-resistance in A. fumigatus isolates. The behavior of such pesticides as tricyclazole in the rice paddy fields would have an effective role in the development of azole-resistance that requires detailed information. PMID- 29496371 TI - Effects of bimaxillary orthognathic surgery on pharyngeal airway and respiratory function at sleep in patients with class III skeletal relationship. AB - PURPOSE: The aim of this study was to examine the effects of bimaxillary orthognathic surgery on pharyngeal airway space (PAS) and respiratory function during sleep. MATERIALS AND METHODS: The subjects were 21 patients with class III skeletal relationship, and all of the patients underwent bimaxillary surgery (Le Fort I advancement and bilateral sagittal split ramus setback osteotomies simultaneously). Pharyngeal volumes of nasopharyngeal (V-NPA), retropalatal (V RPA), retrolingual (V-RLA), oropharyngeal (V-ORO) and total pharyngeal airways (V TOT); minimum axial areas of retropalatal (MA-RPA), retrolingual (MA-RLA) and oropharyngeal airways (MA-ORO); and position of the hyoid were studied in order to detect dimensional PAS changes using cone-beam computed tomography (CBCT) with Dolphin 11.8 software immediately before surgery (T1) and during a period of 6-12 months postoperatively (T2) in all of the patients. Apnea-hypopnea index (AHI), respiratory disturbance index (RDI) and apnea in supine position (SupAHI) parameters were measured with a Compumedics E series full polysomnography system. RESULTS: In volumetric measurements, the V-ORO parameter decreased significantly (p < 0,05) while there was no statistically significant change in the rest of the volumetric parameters (p > 0,05). All of the minimum axial area parameters were decreased significantly (p < 0,01). Hyoid bone moved inferiorly (p < 0,05) and posteriorly (p < 0,05). None of the polysomnographic parameters changed significantly (p > 0,05). CONCLUSION: Bimaxillary orthognathic surgery significantly narrowed PAS dimensions but did not cause an increase in AHI, which is a critical determinant parameter for obstructive sleep apnea syndrome. PMID- 29496372 TI - Recommendations for follow-up of muscle-invasive bladder cancer patients: A consensus by the international bladder cancer network. AB - RATIONALE: Several guidelines exist that address treatment of patients with nonmetastatic muscle-invasive bladder cancer (MIBC). However, most only briefly mention follow-up strategies for patients and hence the treating physician is often left to infer on what the preferred follow-up schema would be for an individual patient. Herein, we aim to synthesize recommendations for follow-up of patients with MIBC for easy reference. METHODS: A multidisciplinary MIBC expert panel from the International Bladder Cancer Network was assembled to critically assess currently available major guidelines on surveillance of MIBC patients. Recommendations for follow-up were extracted and critically evaluated. Important considerations for guideline assessment included both aspects of oncological and functional follow-up-frequency of visits, the use of different imaging modalities, the role of cytology and molecular markers, and the duration of follow-up. OUTCOME: An International Bladder Cancer Network expert consensus recommendation was constructed for the follow-up of patients with MIBC based on the currently available evidence-based data. PMID- 29496373 TI - Major publications in the critical care pharmacotherapy literature: January December 2017. AB - PURPOSE: To summarize selected meta-analyses and trials related to critical care pharmacotherapy published in 2017. The Critical Care Pharmacotherapy Literature Update (CCPLU) Group screened 32 journals monthly for impactful articles and reviewed 115 during 2017. Two meta-analyses and eight original research trials were reviewed here from those included in the monthly CCPLU. Meta-analyses on early, goal-directed therapy for septic shock and statin therapy for acute respiratory distress syndrome were summarized. Original research trials that were included evaluate thrombolytic therapy in severe stroke, hyperoxia and hypertonic saline in septic shock, intraoperative ketamine for prevention of post-operative delirium, intravenous ketorolac dosing regimens for acute pain, angiotensin II for vasodilatory shock, dabigatran reversal with idarucizumab, bivalirudin versus heparin monotherapy for myocardial infarction, and balanced crystalloids versus saline fluid resuscitation. CONCLUSION: This clinical review provides perspectives on impactful critical care pharmacotherapy publications in 2017. PMID- 29496374 TI - Sustained response to lenalidomide for early relapsed marginal zone lymphoma. PMID- 29496375 TI - Expression of aberrantly spliced oncogenic Ikaros isoforms coupled with clonal IKZF1 deletions and chimeric oncogenes in acute lymphoblastic leukemia. PMID- 29496376 TI - [Atrial natriuretic hormones and metabolic syndrome: recent advances]. AB - Natriuretic peptides are a group of hormones including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C type (CNP), urodilatin and guanilyn. ANP (half-life: 2-4 min), is secreted by the atrium, BNP (half-life: 20 min) by the ventricle, CNP by the vascular endothelium, urodilatin by the kidney and guanylin by the intestine. These natriuretic peptides prevent water and salt retention through renal action, vasodilatation and hormonal inhibition of aldosterone, vasopressin and cortisol. These peptides also have a recently demonstrated metabolic effect through an increase of lipolysis, thermogenesis, beta cell proliferation and muscular sensitivity to insulin. Blood levels of these natriuretic peptides depend on "active NPR-A receptors/clearance NPR-C receptors", the last ones being abundant on adipocytes. Therefore, natriuretic peptides act as adipose tissue regulator and constitute a link between blood pressure and metabolic syndrome. They are used as markers and treatment of cardiac failure. Other applications are on going. BNP and NT-proBNP (inactive portion de la pro-hormone) are used as markers of cardiac failure since they have a longer half-life than ANP. BNP decrease is quicker and more important than that one of NT-ProBNP in case of improvement of cardiac failure. Chronic renal insufficiency and beta-blockers increase BNP levels. BNP measurement is useless under treatment with neprilysine inhibitors such as sacubitril, one of the neutral endopeptidases involved in catabolism of natriuretic peptides. The association sacubitril/valsartan is a new treatment of chronic cardiac failure, acting through the decrease of ANP catabolism. PMID- 29496377 TI - Factors associated with sputum culture conversion in patients with pulmonary tuberculosis. AB - OBJECTIVE: The aim of this study was to determine what factors are associated with sputum culture conversion after 1 month of tuberculosis (TB) treatment. MATERIALS AND METHODS: A total of 52 patients with new drug susceptible pulmonary TB were included in the study. Patients completed St. George respiratory questionnaire (SGRQ), they were asked about smoking, alcohol use, living conditions and education. Body mass index (BMI) measurements, laboratory tests (C reactive protein [CRP], vitamin D, albumin) were performed, and chest X-ray was done. After 1 month of treatment sputum culture was repeated. RESULTS: Culture conversion after 1 month of treatment was found in 38.5% cases. None of investigated social factors appeared to have an effect on conversion, but worse overall health status (as reported in SGRQ) and longer duration of tobacco smoking were detected in the "no conversion" group. Concentrations of albumin, CRP, X-ray score and the time it took Mycobacterium tuberculosis culture to grow also differed. Patients who scored 30 or more on SGRQ were more than 7 times as likely to have no conversion. However, the most important factor predicting sputum culture conversion was sputum smear grade at the beginning of treatment: patients with grade of 2+ or more had more than 20-fold higher relative risk for no conversion. Using receiver operating characteristic curve analysis, we also developed a risk score for no conversion. CONCLUSIONS: The most important factors in predicting sputum culture conversion after 1 month of treatment were grades of acid-fast bacilli in sputum smears at time of diagnosis and scores of SGRQ. PMID- 29496378 TI - Prognostic role of neurophysiological testing 3-7 days after onset of acute unilateral Bell's palsy. AB - OBJECTIVE: Recovery from acute Bell's palsy (BP) is variable and there are few predictors of response. We evaluated the usefulness of a range of neurophysiological parameters to predict outcome in BP. METHODS: Fifty-nine patients (age: 33.7+/-15.4 years) with acute unilateral BP were recruited within 3-7 days of onset. They were evaluated with electroneurography, facial nerve excitability, and the blink reflex. House-Brackmann (HB) clinical scores were obtained at the same time and three months later. All patients received prednisolone treatment and regular rehabilitation. RESULTS: At three months, 41 patients (69.5%) had good recovery, while 18 patients (30.5%) had poor recovery according to the HB scale. The facial nerve excitability threshold and threshold difference between sides were significantly lower in patients with good recovery than those with poor recovery (P values=0.022 and 0.006 respectively). Facial nerve degeneration rate (1 - affected/unaffected amplitude of CMAP of muscle *100%) recorded in frontalis (P=0.002) and orbicularis oris (P=0.038) were also smaller in good recovery than poor recovery patients. There were no differences in latency and amplitude of CMAPs recorded from frontalis or orbicularis oris muscle, nor in latencies of the components of the blink reflex. ROC analysis showed that patients who had a threshold side difference <13mA (35 cases), had a higher chance of good recovery (85.7% versus 14.3% poor recovery). Patients who had a degeneration rate<50% (38 cases) also had a higher chance of good recovery (78.9%) versus 21.1% who had poor recovery, while patients with a degeneration rate>50% (21 cases) had a 47.8% chance of good recovery versus 52.2% poor recovery (P=0.004). Logistic regression analysis showed that the most significant predictive indicator of BP recovery was the facial nerve degeneration rate of frontalis muscle (P=0.011). CONCLUSION: Facial nerve degeneration rate of frontalis muscle provides the most sensitive prognostic indicator of recovery from acute BP and may provide useful management strategies. PMID- 29496379 TI - How sensitive are temperate tadpoles to climate change? The use of thermal physiology and niche model tools to assess vulnerability. AB - Ectotherms are vulnerable to climate change, given their dependence on temperature, and amphibians are particularly interesting because of their complex life cycle. Tadpoles may regulate their body temperature by using suitable thermal microhabitats. Thus, their physiological responses are the result of adjustment to the local thermal limits experienced in their ponds. We studied three anuran tadpole species present in Argentina and Chile: Pleurodema thaul and Pleurodema bufoninum that are seasonal and have broad geographic ranges, and Batrachyla taeniata, a geographically restricted species with overwintering tadpoles. Species with restricted distribution are more susceptible to climate change than species with broader distribution that may cope with potential climatic changes in the environments in which they occur. We aim to test whether these species can buffer the potential effects of climate warming. We used ecological niche models and the outcomes of their thermal attributes (critical thermal limits, optimal temperature, and locomotor performance breadth) as empirical evidence of their capacity. We found that Pleurodema species show broader performance curves, related to their occurrence, while the geographically restricted B. taeniata shows a narrower thermal breadth, but is faster in warmer conditions. The modeled distributions and empirical physiological results suggest no severe threats for these three anurans. However, the risk level is increasing and a retraction of their distribution range might be possible for Pleurodema species, and some local population extinctions may happen, particularly for the narrowly distributed B. taeniata. PMID- 29496380 TI - A culture medium for screening 16S rRNA methylase-producing pan-aminoglycoside resistant Gram-negative bacteria. AB - The amikacin plus gentamicin-containing SuperAminoglycoside medium was developed for screening multiple-aminoglycoside resistance in Gram-negative bacteria (Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii). It was evaluated using aminoglycoside-susceptible (n=12) and aminoglycoside-resistant (n=59) Gram-negative isolates, including 16S rRNA methylase producers (n=20). Its sensitivity and specificity of detection were, respectively, of 95% and 96% for detecting multiple aminoglycoside-resistant methylase producers. PMID- 29496381 TI - Prolonged linezolid use is associated with the development of linezolid-resistant Enterococcus faecium. AB - We assessed risk factors for and outcomes of linezolid-resistant vancomycin resistant Enterococcus faecium (LRVREF) bacteremia over 7 years. Thirty-four LRVREF cases were matched to 68 linezolid-susceptible VREF controls. The odds of bacteremia with LRVREF increased by 7% for each additional day of prior linezolid exposure. PMID- 29496382 TI - Improving the work environment in the fluorescent lamp recycling sector by optimizing mercury elimination. AB - One of the main issues in the fluorescent lamp recycling sector is the mercury contamination of output fractions and occupational exposure associated with recycling operations. The aim of this study is to carry out effective mercury mass balance determinations and improve mercury recovery by finding the optimal levels for the recycling process parameters. These optimizations will allow upstream mercury emissions to be reduced, which will help to avoid mercury exposure among WEEE recycling workers. Firstly, the distribution of mercury was assessed in new and spent lamps. For new fluorescent tubes, the mean percentage of mercury in the solid phase is lower in new fluorescent tubes (19.5% with 5.5% in glass, 9.7% in end caps and 4.3% in luminescent powder) than in spent tubes (33.3% with 8.3% in glass, 12.9% in end caps and 12.1% in luminescent powder). The parametric study also shows that the finer the grains of glass, the higher the concentration of mercury (1.2 ug Hg/g for glass size particle >1000 um and 152.0 ug Hg/g for glass size particle <100 um); the crushing time required for the optimal removal of mercury from spent tubes is 24 h; on average 71% of the mercury is desorbed at a temperature of 400 degrees C. The effects of air flow rate, rotation speed and number of balls could not be determined due to wide variations in the results. It is recommended that recycling companies employ processes combining as heating and mixing techniques for the recovery of mercury from lamps in order to both (i) remove as much of the mercury as possible in vapor form and (ii) avoid adsorption of the mercury at new sites created during the crushing process. PMID- 29496383 TI - The influence of the total solid content on the stability of dry-thermophilic anaerobic digestion of rice straw and pig manure. AB - Dry anaerobic digestion is a promising technology for the recycling of agricultural waste to produce energy and fertilizer. Adding water to the substrate enables better handling and avoid inhibition caused by high total solid (TS) content in the reactor; however, it also increases leachate and operational costs. To assess the extent to which the amount of water added can be reduced, it was examined how the TS content in the reactor influenced the production of biogas. A semi-batch dry thermophilic anaerobic digester was fed with substrate (rice straw and pig manure) at a constant organic loading rate, and varied the TS contents (27%, 32%, 37%, and 42%) of the substrate by adding different amounts of water (representing 0-36% of the total substrate). During incubation, the TS content in the reactor gradually increased from 18% to 31%. Biogas production was stable and high (564 +/- 13-580 +/- 36 N m3 t-1 VS), and there was no accumulation of volatile fatty acids when the TS content of the reactor was between 18% and 27%. However, the rate decreased sharply and propionate and acetate were also produced when the TS content of the reactor exceeded 28%. By applying a simple TS balance model, it was found that stable biogas production could be achieved at a substrate TS content of 32%, at which reactor TS content reached 23% at steady-state condition. PMID- 29496384 TI - Unilateral asymmetrical anterior bellies of the digastric muscle in coexistence with accessory muscle bundles in the submental triangle: A rare case report. AB - A three-headed anterior belly of the digastric muscle (ABDM) on the right side of a 54-year old Greek male cadaver coexisted with two accessory muscle bundles (AMB) in the submental region. The left ABDM was typical. Typical ABDM was attached to the digastric fossa, while the accessory right anterior bellies to the lower border of the mandible. A muscle bundle arising from the attachment of the left ABDM to the hyoid bone was also observed fusing with the AMB of the ipsilateral side. It is of extreme importance to be aware of the submental region anatomical variations during surgery, imaging interpretation or differential diagnosis of neck masses. PMID- 29496385 TI - Who owns the baby? A video ethnography of skin-to-skin contact after a caesarean section. AB - PROBLEM: Providing skin-to-skin contact in the operating theatre and recovery is challenging. BACKGROUND: Barriers are reported in the provision of uninterrupted skin-to-skin contact following a caesarean section. AIM: To explore how health professionals' practice impacts the facilitation of skin-to-skin contact within the first 2h following a caesarean section. METHODS: Video ethnographic research was conducted utilising video recordings, observations, field notes, focus groups and interviews. FINDINGS: The maternal body was divided in the operating theatre and mothers were perceived as 'separate' from their baby in the operating theatre and recovery. Obstetricians' were viewed to 'own' the lower half of women; anaesthetists were viewed to 'own' the top half and midwives were viewed to 'own' the baby after birth. Midwives' responsibility for the baby either negatively or positively affected the mother's ability to 'own' her baby, because midwives controlled what maternal-infant contact occurred. Mothers desired closeness with their baby, including skin-to-skin contact, however they realised that 'owning' their baby in the surgical environment could be challenging. DISCUSSION: Health professionals' actions are influenced by their environment and institutional regulations. Further education can improve the provision of skin-to-skin contact after caesarean sections. Skin-to-skin contact can help women remain with their baby and obtain a sense of control after their caesarean section. CONCLUSION: Providing skin-to-skin contact in the first 2h after caesarean sections has challenges. Despite this, health professionals can meet the mother's desire to 'own' her baby by realising they are one entity, encouraging skin-to-skin contact and avoiding maternal and infant separation. PMID- 29496386 TI - Renal failure in decompensated heart failure patients: Double trouble. PMID- 29496387 TI - Retinal microvascular damage and nocturnal hypertension: Therapeutic targets to bear in mind. PMID- 29496388 TI - Multivessel revascularization in non-ST-elevation acute coronary syndrome: Should it become the rule in all patients? PMID- 29496389 TI - Congenital anomalies of the coronary arteries. AB - Congenital coronary artery anomalies are modifications of their origin, course or structure and its incidence varies between 0,2 and 5,6% of the general population. Although the majority is asymptomatic, they are the second leading cause of sudden cardiac death in young athletes. The aim of this study is to highlight the main anomalies with hemodynamic significance, including the anomalous origin of a coronary artery from the opposite sinus and anomalous origin of the left coronary artery from pulmonary artery. The anomalous aortic origin of a coronary artery from the opposite sinus accounts for 14-16% of all cardiac deaths, that unexpectedly occur in healthy children or young athletes during or immediately after exercise. The mechanism responsible for the compression/occlusion of the coronary artery originating from the opposite sinus is still unclear and there are several proposed mechanisms. The clinical presentation of these patients is variable and physical examination is normal in most individuals. Transthoracic echocardiogram is the diagnostic test most commonly used. Treatment and management are controversial topic. The anomalous origin of the left coronary artery from pulmonary artery is a very rare condition and without surgery, most infants die within the first 12 months of life. The echocardiogram is also the method of choice for diagnostic confirmation. The diagnosis of this congenital anomaly in an infant, usually seriously ill, is an indication for urgent surgery. Because these anomalies produce hemodynamic changes, it is important an early diagnosis and treatment. PMID- 29496390 TI - An Unusual Polypoid Symptomatic Carotid Plaque. PMID- 29496391 TI - Structure of LNX1:Ubc13~Ubiquitin Complex Reveals the Role of Additional Motifs for the E3 Ligase Activity of LNX1. AB - LNX1 (ligand of numb protein-X1) is a RING and PDZ domain-containing E3 ubiquitin ligase that ubiquitinates human c-Src kinase. Here, we report the identification and structure of the ubiquitination domain of LNX1, the identification of Ubc13/Ube2V2 as a functional E2 in vitro, and the structural and functional studies of the Ubc13~Ub intermediate in complex with the ubiquitination domain of LNX1. The RING domain of LNX1 is embedded between two zinc-finger motifs (Zn-RING Zn), both of which are crucial for its ubiquitination activity. In the heterodimeric complex, the ubiquitin of one monomer shares more buried surface area with LNX1 of the other monomer and these interactions are unique and essential for catalysis. This study reveals how the LNX1 RING domain is structurally and mechanistically dependent on other motifs for its E3 ligase activity, and describes how dimeric LNX1 recruits ubiquitin-loaded Ubc13 for Ub transfer via E3 ligase-mediated catalysis. PMID- 29496392 TI - Corrigendum to "Evaluation and management of skeletal disease in cancer care" [Crit. Rev. Oncol./Hematol. 120 (December 2017) 217-226]. PMID- 29496393 TI - Morin inhibits proliferation and self-renewal of CD133+ melanoma cells by upregulating miR-216a. AB - Melanoma is one of the most malignant skin tumors with high mortality rate. Morin has been reported to treat several cancers. However, whether or how Morin affects melanoma progression is still poorly understood. Either Morin treatment or miR 216a overexpression reduced cell viability, sphere formation ability and expressions of stem cell marker genes CD20, CD44, CD133 and Wnt-3A. MiR-216a was induced by Morin treatment in CD133+ melanoma cells. Melanoma xenograft model treated by Morin showed reduced tumor size, weight as well as expressions of stemness markers and Wnt-3A. Inhibition of the stemness marker gene expressions in CD133+ melanoma cells is mediated by downregulating Wnt-3A through miR-216a. MiR-216a and Wnt-3A may potentially serve as clinical biomarkers of melanoma, and Morin may contribute to the treatment of melanoma. PMID- 29496394 TI - Engineered biosynthesis of bacteriochlorophyll gF in Rhodobacter sphaeroides. AB - Engineering photosynthetic bacteria to utilize a heterologous reaction center that contains a different (bacterio) chlorophyll could improve solar energy conversion efficiency by allowing cells to absorb a broader range of the solar spectrum. One promising candidate is the homodimeric type I reaction center from Heliobacterium modesticaldum. It is the simplest known reaction center and uses bacteriochlorophyll (BChl) g, which absorbs in the near-infrared region of the spectrum. Like the more common BChls a and b, BChl g is a true bacteriochlorin. It carries characteristic C3-vinyl and C8-ethylidene groups, the latter shared with BChl b. The purple phototrophic bacterium Rhodobacter (Rba.) sphaeroides was chosen as the platform into which the engineered production of BChl gF, where F is farnesyl, was attempted. Using a strain of Rba. sphaeroides that produces BChl bP, where P is phytyl, rather than the native BChl aP, we deleted bchF, a gene that encodes an enzyme responsible for the hydration of the C3-vinyl group of a precursor of BChls. This led to the production of BChl gP. Next, the crtE gene was deleted, thereby producing BChl g carrying a THF (tetrahydrofarnesol) moiety. Additionally, the bchGRs gene from Rba. sphaeroides was replaced with bchGHm from Hba. modesticaldum. To prevent reduction of the tail, bchP was deleted, which yielded BChl gF. The construction of a strain producing BChl gF validates the biosynthetic pathway established for its synthesis and satisfies a precondition for assembling the simplest reaction center in a heterologous organism, namely the biosynthesis of its native pigment, BChl gF. PMID- 29496395 TI - [On the extinction of populations with several types in a random environment]. AB - This study focuses on the extinction rate of a population that follows a continuous-time multi-type branching process in a random environment. Numerical computations in a particular example inspired by an epidemic model suggest an explicit formula for this extinction rate, but only for certain parameter values. PMID- 29496396 TI - 10-10 electrode system for EEG recording. PMID- 29496397 TI - Effect of electrical dyssynchrony on left and right ventricular mechanics in children with pulmonary arterial hypertension. AB - BACKGROUND: Electrical and right ventricular (RV) mechanical dyssynchrony has been previously described in pediatric pulmonary arterial hypertension (PAH), but less is known about the relationship between electrical dyssynchrony and biventricular function. In this study we applied cardiac magnetic resonance (CMR) imaging to evaluate biventricular size and function with a focus on left ventricular (LV) strain mechanics in pediatric PAH patients with and without electrical dyssynchrony. METHODS: Fifty-six children with PAH and comprehensive CMR evaluation were stratified based on QRS duration z-score, with electrical dyssynchrony defined as z-score >=2. Comprehensive biventricular volumetric, dyssynchrony, and strain analysis was performed. RESULTS: Nineteen PAH patients had or developed electrical dyssynchrony. Patients with electrical dyssynchrony had significantly reduced RV ejection fraction (35% vs 50%, p = 0.003) and greater end-diastolic (168 vs 112 ml/m2, p = 0.041) and end-systolic (119 vs 57, ml/m2, p = 0.026) volumes. Patients with electrical dyssynchrony had reduced RV longitudinal strain (-14% vs -19%, p = 0.007), LV circumferential strain measured at the free wall (-19% vs -22%, p = 0.047), and the LV longitudinal strain in the septal region (-10% vs -15%, p = 0.0268). LV mechanical intraventricular dyssynchrony was reduced in patients with electrical dyssynchrony at the LV free wall (43 vs 19 ms, p = 0.019). CONCLUSIONS: The electrical dyssynchrony is associated with the reduced LV strain, enlarged RV volumes, and reduced biventricular function in children with PAH. CMR assessment of biventricular mechanical function with respect to QRS duration may help to detect pathophysiologic processes associated with progressed PAH. PMID- 29496398 TI - A Census of Midsize to Large Supermarkets in Toronto: A Cross-Sectional Analysis of the Consumer Nutrition Environment. AB - OBJECTIVE: Assess the consumer nutrition environment in midsize to large supermarkets by supermarket type and area-level socioeconomic variables. DESIGN: Cross-sectional census of 257 supermarkets using the Toronto Nutrition Environment Measures Survey in Stores. SETTING: Toronto, Canada. VARIABLES MEASURED: Availability; price and linear shelf space of fruits and vegetables vs energy-dense snack foods by supermarket type; after-tax, low-income measure; and neighborhood improvement area. ANALYSIS: Multivariate linear regression. RESULTS: There was a high availability of fruits (7.7 of 8) and vegetables (9.5 of 11). There was similar linear shelf space for fruits and vegetables vs energy-dense snack foods (ratio, 1.1 m). Adjusted fruit prices were lowest in quintiles 1 (beta = -$1.30; P = .008), 2 (beta = -$1.41; P = .005), and 3 (beta = -$1.89; P < .001) vs quintile 5 (lowest percentage of people living with low income) and in ethnic (beta = -$3.47; P < .001) and discount stores (beta = -$5.64; P < .001) vs conventional. Adjusted vegetable prices were lowest in quintiles 2 (beta = $1.87; P = .04), 3 (beta = -$1.78; P = .03), and 4 (beta = -$2.65; P = .001) vs quintile 5 and in ethnic (beta = -$7.10; P < .001) and discount (beta = -$5.49; P < .001) stores. They were highest in other (beta = + $3.08; P = .003) vs conventional stores. Adjusted soda and chips prices were lower in discount (beta = -$1.16; P < .001) and higher in other stores (beta = + $0.67; P < .001) vs conventional. CONCLUSIONS AND IMPLICATIONS: Findings do not indicate inequities in shelf space, availability, or price across diverse neighborhoods. Practitioners can use findings to help consumers navigate supermarkets to make healthy choices. PMID- 29496399 TI - Brain Metastases in Pancreatic Ductal Adenocarcinoma: Assessment of Molecular Genotype-Phenotype Features-An Entity With an Increasing Incidence? AB - PURPOSE: To assess clinical characteristics of patients with metastatic pancreas ductal adenocarcinoma (PDAC) and brain metastases (BM), and to assess somatic and germ-line molecular profiles where performed. PATIENTS AND METHODS: Patients with PDAC and BM between January 1990 and January 2016 were identified. Molecular characteristics of somatic and germ-line testing where performed in the subset of patients who had provided informed consent. Somatic alterations were assessed by either MSK-IMPACT testing (>340 key cancer genes) or Sequenom testing (8-gene panel). Overall survival was calculated from date of diagnosis to either date of last follow-up or death. Survival after BM was calculated from date of diagnosis of BM by radiology or pathology to either date of last follow-up or death. RESULTS: From a total of 5824 patients with PDAC identified from January 2000 to January 2016, twenty-five patients (0.4%) had BM. Median age at PDAC diagnosis was 58 years. Median time to the development of BM from initial PDAC diagnosis was 17 months (range, 0-79 months). Median overall survival after BM diagnosis was 1.5 months (range, 1-31 months). Overall survival for patients who had craniotomy (n = 4) was 11 months (range, 1-31 months), with 2 long-term survivors at 21 and 31 months, respectively. Four patients had leptomeningeal disease. Six of 25 patients had germ-line testing, and 3 had BRCA mutations (2 BRCA1 and 1 BRCA2). Somatic profiling identified KRAS mutations in 100% (4 G12D, 2 G12V, and 1 Q61K). CONCLUSION: BM from PDAC is a rare event. We identified a speculative association of germ-line BRCA1/2 alterations with BM in PDAC, which requires corroboration. Survival after BM development is poor; prolonged survival occurred in selected patients via a multidisciplinary approach. PMID- 29496400 TI - Nanoparticles synthesis by Agaricus soil basidiomycetes. AB - We examined the effect of various concentrations of HAuCl4, AgNO3, Na2SeO3, Na2SiO3, and GeO2 on mycelial growth of the soil basidiomycetes Agaricus bisporus and A. arvensis in submerged and solid media. Fungal mycelial extracts and cell free culture filtrates were able to reduce ions of Au, Ag, Se, Si, and Ge compounds, forming Au0, Ag0, Se0, Si0/SiO2 and Ge0/GeO2 nanoparticles. The physical characteristics of the mycogenic nanoparticles differed depending on the species of Agaricus and the type of extract. Au nanospheres obtained with cell free culture filtrates were of 2-5 nm diameter in A. bisporus and of 2-10 nm in A. arvensis. Nanoparticles produced by extracts of mycelia were several times larger and highly heterogenous. Ag nanoparticles produced by cell-free culture filtrates were spherical or irregular-shaped and agglomerated, whereas with extracts of mycelia, small homogenous nanospheres of 1-10 nm were formed. Se nanospheres obtained with cell-free culture filtrates were of 100-250 nm diameter in A. bisporus and of 150-550 nm diameter in A. arvensis. The particles synthesized with extracts of mycelia were of 40-140 nm in A. bisporus and of 100 250 nm in A. arvensis. Incubation of Na2SiO3 with cell-free culture filtrates resulted in porous Si nanoparticles of 30-65 nm in A. bisporus and of 50-200 nm in A. arvensis. Ge nanoparticles synthesized by both Agaricus species were mostly spheres of 50-250 nm diameter. PMID- 29496401 TI - Solvent-Detergent Plasma for the Treatment of Thrombotic Microangiopathies: A Canadian Tertiary Care Centre Experience. AB - Solvent detergent-treated plasma (SDP) is a pathogen-inactivated blood plasma, which in comparison to frozen plasma is associated with lower rates of allergic reaction, transfusion-associated lung injury, and viral transmission. SDP has been available in Canada since 2012. Data on SDP use in Canada remains limited. We present a review of subjects receiving SDP at a large tertiary care centre primarily for thrombotic thrombocytopenic purpura and atypical hemolytic uremic syndrome, demonstrating the tolerability and safety of SDP. PMID- 29496402 TI - Cardiac 18F-FDG PET/CT procedure for the diagnosis of prosthetic endocarditis and intracardiac devices. AB - Infective endocarditis (IE) is a serious condition with a poor prognosis, its mortality unchanged significantly despite diagnostic and therapeutic advances in the last 30years. The diagnostic ability of the modified Duke criteria in prosthetic endocarditis and/or devices does not exceed 50%, so new tools are necessary for the diagnosis of this entity in this context. The 18F-FDG PET/CTA combines a highly sensitive technique to detect inflammatory-infectious activity with a technique with high anatomical resolution to assess the structural lesions associated with endocarditis. With a diagnostic sensitivity between 91-97%, this hybrid technique has become a useful diagnostic tool for patients with prosthetic valves or devices and suspicion of IE, becoming a major criterion in the diagnostic algorithm of current guidelines. This excellent diagnostic ability depends directly on the quality of the obtained exploration and the knowledge at the time of interpreting the images. The aim of this review is to describe and standardize the methodology of cardiac 18F-FDG PET/CTA in the diagnosis of endocarditis in prosthetic valves and intracardiac devices, with special emphasis on the particularities of the patient's preparation, the PET and CT acquisition procedures, and the subsequent imaging postprocessing and interpretation. PMID- 29496403 TI - [Solitary fibrous tumor: A clinical case]. AB - INTRODUCTION: Solitary fibrous tumor (TFS) is a rare tumor of mesenchymal origin, located mainly in the pleura. It is extraordinarily infrequent find it at the intraespinal level, being the thoracic region the most frequent. CASE PRESENTATION: We present the case of a 48-year-old patient with progressive ascending lower limb and myelopathy of one month of evolution, with intraspinal location at the D3-D4 level. It was surgically operated by posterior dorsal approach and D3-D4 laminoplasty, with an intradural tumor with an intramedullary component of approximately 18*12mm. The resection was complete and the pathological anatomy gave the diagnosis of solitary fibrous tumor. The patient is currently asymptomatic. DISCUSSION: Complete tumor resection and histopathological features are the main prognostic factors. Surgery have a main role in this type of neoplasia. CONCLUSION: There are few case published of solitary fibrous tumor with intraspinal localization. We apport another case to the literature. PMID- 29496404 TI - Analysis of cosmetic residues on a single human hair by ATR FT-IR microspectroscopy. AB - In this work, ATR FT-IR spectra of single human hair and cosmetic residues on hair surface are successfully collected using a homemade dome-shaped Ge MUIRE accessary installed on an infrared microscope. By collecting ATR spectra of hairs from the same person, the spectral patterns are identical and superimposed while different spectral features are observed from ATR spectra of hairs collected from different persons. The spectral differences depend on individual hair characteristics, chemical treatments, and cosmetics on hair surface. The "Contact and-Collect" technique that transfers remarkable materials on the hair surface to the tip of the Ge MUIRE enables an identification of cosmetics on a single hair. Moreover, the differences between un-split and split hairs are also studied in this report. These highly specific spectral features can be employed for unique identification or for differentiation of hairs based on the molecular structures of hairs and cosmetics on hairs. PMID- 29496406 TI - Surface enhanced Raman spectroscopy: A review of recent applications in forensic science. AB - Surface enhanced Raman spectroscopy has many advantages over its parent technique of Raman spectroscopy. Some of these advantages such as increased sensitivity and selectivity and therefore the possibility of small sample sizes and detection of small concentrations are invaluable in the field of forensics. A variety of new SERS surfaces and novel approaches are presented here on a wide range of forensically relevant topics. PMID- 29496407 TI - Multicomponent exercise decreases blood pressure, heart rate and double product in normotensive and hypertensive older patients with high blood pressure. AB - OBJECTIVE: The present study aimed to investigate the effects of a 6-month multicomponent exercise program on blood pressure, heart rate, and double product of uncontrolled and controlled normotensive and hypertensive older patients. METHODS: The study included 183 subjects, 97 normotensives, of which 53 were controlled normotensives (CNS), and 44 uncontrolled normotensives (UNS), as well as 86 hypertensives, of which 43 were controlled hypertensives (CHS), and 43 uncontrolled hypertensives (UHS). Volunteers were recruited and blood pressure and heart rate measurements were made before and after a 6-month multicomponent exercise program. The program of physical exercise was performed twice a week for 26 weeks. The physical exercises program was based on functional and walking exercises. Exercise sessions were performed at moderate intensity. RESULTS: The results indicated that UHS showed a marked decrease in systolic (-8.0mmHg), diastolic (-11.1mmHg), mean (-10.1mmHg), and pulse pressures, heart rate ( 6.8bpm), and double product (-1640bpmmmHg), when compared to baseline. Similarly, diastolic (-5.5mmHg) and mean arterial (-4.8mmHg) pressures were significantly decreased in UNS. Concomitantly, significant changes could be observed in the body mass index (-0.9kg/m2; -1.5kg/m2) and waist circumference (-3.3cm; only UHS) of UNS and UHS, which may be associated with the changes observed in blood pressure. CONCLUSIONS: In conclusion, the data of the present study indicate that a 6-month multicomponent exercise program may lead to significant reductions in blood pressure, heart rate, and double product of normotensive and hypertensive patients with high blood pressure values. PMID- 29496408 TI - Proteomic response of Streptococcus pneumoniae to iron limitation. AB - Iron is an essential trace element and involved in various key metabolic pathways in bacterial lifestyle. Within the human host, iron is extremely limited. Hence, the ability of bacteria to acquire iron from the environment is critical for a successful infection. Streptococcus pneumoniae (the pneumococcus) is a human pathobiont colonizing symptomless the human respiratory tract, but can also cause various local and invasive infections. To survive and proliferate pneumococci have therefore to adapt their metabolism and virulence factor repertoire to different host compartments. In this study, the response of S. pneumoniae to iron limitation as infection-relevant condition was investigated on the proteome level. The iron limitation was induced by application of the iron chelator 2,2' bipyridine (BIP) in two different media mimicking different physiological traits. Under these conditions, the influence of the initial iron concentration on pneumococcal protein expression in response to limited iron availability was analyzed. Interestingly, one major difference between these two iron limitation experiments is the regulation of proteins involved in pneumococcal pathogenesis. In iron-poor medium several proteins of this group were downregulated whereas these proteins are upregulated in iron-rich medium. However, iron limitation in both environments led to a strong upregulation of the iron uptake protein PiuA and the significant downregulation of the non-heme iron-containing ferritin Dpr. Based on the results, it is shown that the pneumococcal proteome response to iron limitation is strongly dependent on the initial iron concentration in the medium or the environment. PMID- 29496409 TI - Editorial commentary: Epigenetics and cardiovascular disease-From concept to reality. PMID- 29496410 TI - Plant-based diets and cardiovascular health. AB - Plant-based diets, defined in terms of low frequency of animal food consumption, have been increasingly recommended for their health benefits. Numerous studies have found plant-based diets, especially when rich in high quality plant foods such as whole grains, fruits, vegetables, and nuts, to be associated with lower risk of cardiovascular outcomes and intermediate risk factors. This review summarizes the current evidence base examining the associations of plant-based diets with cardiovascular endpoints, and discusses the potential biological mechanisms underlying their health effects, practical recommendations and applications of this research, and directions for future research. Healthful plant-based diets should be recommended as an environmentally sustainable dietary option for improved cardiovascular health. PMID- 29496411 TI - Discovery and optimization of tetrahydropyrido[4,3-d]pyrimidine derivatives as novel ATX and EGFR dual inhibitors. AB - In order to discovery autotaxin (ATX) and EGFR dual inhibitors with potential therapeutic effect on IPF-LC, a series of novel tetrahydropyrido[4,3-d]pyrimidine derivatives possessing semicarbazones moiety were designed and synthesized. The preliminary investigation at the cellular level indicated six compounds (7h, 8a, 8c, 8d, 9a and 9d) displayed preferable anti-tumor activities against A549, H1975, MKN-45 and SGC cancer cells. Further enzymatic assay against EGFR kinase identified 8a and 9a as promising hits with IC50 values of 18.0 nM and 24.2 nM. Meanwhile, anti-inflammatory assessment against cardiac fibroblasts (CFs) cell and RAW264.7 macrophages led to the discovery of candidate 9a, which exhibited considerable potency both on inhibition rate of 77% towards CFs and on reducing NO production to 1.05 MUM at 10 MUg/mL. Simultaneously, 9a indicated preferable potency towards ATX with IC50 value of 29.1 nM. Significantly, a RT-PCR study revealed the function of 9a to down-regulate the mRNA expression of TGF-beta and TNF-alpha in a dose-dependent manner. The molecular docking analysis together with the pharmacological studies validated 9a as a potential ATX and EGFR dual inhibitor for IPF-LC treatments. PMID- 29496412 TI - Synthesis and evaluation of 1H-pyrrole-2,5-dione derivatives as cholesterol absorption inhibitors for suppressing the formation of foam cells and inflammatory response. AB - Excess lipid accumulation in the arterial intima and formation of macrophage derived foam cells in the plaque could cause atherosclerotic lesion. Cholesterol absorption inhibitors could suppress the lipid accumulation of human macrophage, inflammatory response and the development of atherosclerosis. In this research, a series of 1H-pyrrole-2,5-dione derivatives were synthesized as cholesterol absorption inhibitor and tested in in vitro experiments. One of the most active inhibitors, compound 20 exhibited stronger in vitro cholesterol absorption activity than ezetimibe, no cytotoxicity in HEK293 and RAW264.7 cell lines and satisfied lipophilicity. The further study indicated that 20 could inhibit lipid accumulation of macrophage and reduce the secretion of LDH, MDA, TNF-alpha and ROS in a concentration-dependent manner. In conclusion, as a novel and potent cholesterol absorption inhibitor, compound 20 could suppress the formation of foam cells and inflammatory response. PMID- 29496413 TI - Structural basis of the broad substrate tolerance of the antibody 7B9-catalyzed hydrolysis of p-nitrobenzyl esters. AB - Catalytic antibody 7B9, which was elicited against p-nitrobenzyl phosphonate transition-state analogue (TSA) 1, hydrolyzes a wide range of p-nitrobenzyl monoesters and thus shows broad substrate tolerance. To reveal the molecular basis of this substrate tolerance, the 7B9 Fab fragment complexed with p nitrobenzyl ethylphosphonate 2 was crystallized and the three-dimensional structure was determined. The crystal structure showed that the strongly antigenic p-nitrobenzyl moiety occupied a relatively shallow antigen-combining site and therefore the alkyl moiety was located outside the pocket. These results support the observed broad substrate tolerance of 7B9 and help rationalize how 7B9 can catalyze various p-nitrobenzyl ester derivatives. The crystal structure also showed that three amino acid residues (AsnH33, SerH95, and ArgL96) were placed in key positions to form hydrogen bonds with the phosphonate oxygens of the transitions-state analogue. In addition, the role of these amino acid residues was examined by site-directed mutagenesis to alanine: all mutants (AsnH33Ala, SerH95Ala, and ArgL96Ala) showed no detectable catalytic activity. Coupling the findings from our structural studies with these mutagenesis results clarified the structural basis of the observed broad substrate tolerance of antibody 7B9-catalyzed hydrolyses. Our findings provide new strategies for the generation of catalytic antibodies that accept a broad range of substrates, aiding their practical application in synthetic organic chemistry. PMID- 29496414 TI - Synthesis, photophysical properties, and photodynamic activity of positional isomers of TFPP-glucose conjugates. AB - The synthesis and characterization of a 'complete set' of positional isomers of tetrakis(perfluorophenyl)porphyrins (TFPP)-glucose conjugates (1OH, 2OH, 3OH, 4OH, and 6OH) are reported herein. The cellular uptake and photocytotoxicity of these conjugates were examined in order to investigate the influence of location of the TFPP moiety on the d-glucose molecule on the biological activity of the conjugates. An In vitro biological evaluation revealed that the certain of these isomers have a greater effect on cellular uptake and cytotoxicity than others. The TFPP-glucose conjugates 1OH, 3OH, and 4OH were found to exert exceptional photocytotoxicity in several types of cancer cells compared to 2OH and 6OH substituted isomers. PMID- 29496415 TI - Synthesis of enantiopure antiobesity drug lorcaserin. AB - Acylation of enantiomerically pure (R)-2-(3-chlorophenyl)propan-1-amine using chloroacetyl chloride, followed by borane reduction and aluminum chloride catalyzed cyclization yielded enantiopure lorcaserin. PMID- 29496416 TI - Aluminium (Al) speciation in serum and urine after subcutaneous venom immunotherapy with Al as adjuvant. AB - BACKGROUND: Aluminium is associated with disorders and is the commonly used vaccine adjuvant. Understanding the mechanisms of how Al is transported, metabolized or of its toxicity depends on the knowledge of Al-interactions with bioligands, i.e. Al-species. Al-speciation in serum is difficult because of low concentration and the risk of exogenous Al contamination. Furthermore, Al measurements may be hampered according to various interferences. This study aims for developing quality controlled protocols for reliable Al- and Al-species determination and for investigating probable differences in Al (-speciation) after Al-containing subcutaneous immunotherapy (SIT). METHODS: Sample donors were recruited either for the control group ("class-0", they never had been treated with SIT containing an Al-depot extract) or for the SIT-group ("class-1", they previously had been treated with SIT for insect venom allergy with an Al-depot extract). Blood was drawn for medical reasons and serum prepared. Additionally, some sample donors collected 24-h-urine. They had been informed (and they consented) about the scientific use of their samples. The study was approved by the ethic committee of the "Medical Association Westphalia-Lippe" and of the University of Munster, evaluating the study positively (No. 2013-667-f-S). We applied quality controlled sample preparation and interference-free Al detection by ICP sectorfield-mass spectrometry. Al-species were analysed using size exclusion-chromatography-ICP-qMS. FINDINGS: Al-concentrations or speciation in urine samples showed no differences between class-0 and class-1. Al-citrate was the main uric Al-species. In serum elevated Al-concentrations were found for both classes, with class-1 samples being significantly higher than class-0 (p = 0.041), but class-0 samples being approximately 10-fold too high compared to reference values from non-exposed persons. We identified gel-monovettes as contamination source. In contamination-free samples from HNO3-prewashed gel-free monovettes (n = 27) there was no difference in the serum Al concentration between the two patient groups (p = 0.669) INTERPRETATION: Thorough cleaning of sample preparation ware and use of gel-free monovettes is decisive for an accurate Al analysis in serum. Without these steps, wrong analysis and wrong conclusions are likely. We conclude that gel-monovettes are unsuitable for blood sampling with subsequent Al-analysis. Whether Al in serum is elevated after SIT treatment containing an Al-depot extract, or not, remains inconclusive as the non contaminated sample size was small. PMID- 29496417 TI - Effect of zinc and vitamin E supplementation on hormones and blood biochemicals in peri-partum Sahiwal cows. AB - Thirty-two advanced pregnant multiparous Sahiwal cows were used to study the effect of additional zinc (Zn) and vitamin E (VE) supplementation on hormonal and biochemical changes. Cows were randomly assigned to four groups and fed a basal diet of compounded concentrate, berseem fodder, and wheat straw in a ratio of 60:20:20. The groups were: (1) the basal diet with no supplement (control treatment); (2) the basal diet supplemented with 60 mg/kg DM/cow daily of Zn (Zn treatment); (3) the basal diet supplemented with 1000 IU/cow daily of vitamin E (VE treatment); and (4) the basal diet supplemented with a combination of 60 mg Zn/kg DM/cow and 1000 IU vitamin E/cow/d (Zn + VE treatment). Blood samples were collected on -60, -45, -30, -15, -7, -3, 0, 3, 7, 15, 30, 45, 60, 90, and 120 d in relation to expected date of calving and were analyzed for endocrine variables and biochemical changes. Plasma concentrations of leptin, insulin, insulin like growth factor-1 (IGF-1), triidothyronine (T3), and tetraiodothyronine (T4) were decreased toward calving and observed lowest (P < 0.05) on 3 d post-partum. However, plasma levels of growth hormone (GH) and cortisol increased toward calving and were found highest (P < 0.05) on 3 d post-partum. Pre-partum concentrations of leptin and IGF-1 were higher (P < 0.05) than its respective concentration observed during post-partum. Post-partum concentrations of GH and cortisol were higher (P < 0.05) than its respective pre-partum concentration. Pre partum concentrations of urea, triglycerides, Zn, and VE were higher (P < 0.05) and total cholesterol and HDL cholesterol were lower than its values observed in post-partum among all the groups. Treatments had significant (P < 0.05) effect on plasma hormonal levels and levels of Zn and VE but no effect on biochemical attributes. Cows fed on diet supplemented with Zn + VE had highest (P < 0.05) pre as well as post-calving concentrations of leptin (6.38 vs 5.01 ng/ml), insulin (1.39 vs 1.33 ng/ml), GH (9.29 vs 13.72 ng/ml), IGF-1 (14.55 vs 12.59 nmol/l), T3 (1.45 vs 1.40 ng/ml), T4 (32.44 vs 31.79 ng/ml) whereas as lowest concentration of cortisol hormone (3.05 vs 3.44 ng/ml). Cows supplemented with combination of Zn and VE showed minimum decline in plasma concentration of leptin, insulin, GH, IGF-1, T3, and T4, and minimum increase in cortisol concentration. In conclusion, dairy cows around parturition faces various endocrine and biochemical alterations and supplementation of Zn in combination with VE can ameliorate adverse effect of calving stress by maintaining circulatory concentration of hormone and biochemicals towards the basal levels. PMID- 29496418 TI - A short 18 items food frequency questionnaire biochemically validated to estimate zinc status in humans. AB - Inadequate dietary zinc intake is wide-spread in the world's population. Despite the clinical significance of zinc deficiency there is no established method or biomarker to reliably evaluate the zinc status. The aim of our study was to develop a biochemically validated questionnaire as a clinically useful tool that can predict the risk of an individual being zinc deficient. From 71 subjects aged 18-55 years blood and urine samples were collected. Zinc concentrations in serum and urine were determined by atomic absorption spectrometry. A food frequency questionnaire (FFQ) including 38 items was filled out representing the consumption during the last 6 months obtaining nutrient diet scores. Latter were calculated by multiplication of the particular frequency of consumption, the nutrient intake of the respective portion size and the extent of the consumed quantity. Results from the FFQ were compared with nutrient intake information gathered in 24-h dietary recalls. A hemogram was performed and cytokine concentrations were obtained using Enzyme-linked Immunosorbent Assay. Reducing the items of the primary FFQ from 38 to 18 did not result in a significant variance between both calculated scores. Zinc diet scores showed highly significant correlation with serum zinc (r = 0.37; p < 0.01) and urine zinc concentrations (r = 0.34; p < 0.01). Serum zinc concentrations and zinc diet scores showed a significant positive correlation with animal protein intake (r = 0.37; p < 0.01/r = 0.54; p < 0.0001). Higher zinc diet scores were found in omnivores compared to vegetarians (213.5 vs. 111.9; p < 0.0001). The 18 items FFQ seems to be a sufficient tool to provide a good estimation of the zinc status. Moreover, shortening of the questionnaire to 18 items without a loss of predictive efficiency enables a facilitated and resource-saving routine use. A validation of the questionnaire in other cohorts could enable the progression towards clinical utilization of this promising tool. PMID- 29496419 TI - Rheumatoid factor testing in Spanish primary care: A population-based cohort study including 4.8 million subjects and almost half a million measurements. AB - OBJECTIVE: Rheumatoid factor (RF) testing is used in primary care in the diagnosis of rheumatoid arthritis (RA); however a positive RF may occur without RA. Incorrect use of RF testing may lead to increased costs and delayed diagnoses. The aim was to assess the performance of RF as a test for RA and to estimate the costs associated with its use in a primary care setting. MATERIAL AND METHODS: A retrospective cohort study using the Information System for the Development of Research in Primary Care database (contains primary care records and laboratory results of >80% of the Catalonian population, Spain). Participants were patients >=18 years with >=1 RF test performed between 01/01/2006 and 31/12/2011, without a pre-existing diagnosis of RA. Outcome measures were an incident diagnosis of RA within 1 year of testing, and the cost of testing per case of RA. RESULTS: 495,434/4,796,498 (10.3%) patients were tested at least once. 107,362 (21.7%) of those tested were sero-positive of which 2768 (2.6%) were diagnosed with RA within 1 year as were 1141/388,072 (0.3%) sero-negative participants. The sensitivity of RF was 70.8% (95% CI 69.4-72.2), specificity 78.7% (78.6-78.8), and positive and negative predictive values 2.6% (2.5-2.7) and 99.7% (99.6-99.7) respectively. Approximately ?3,963,472 was spent, with a cost of ?1432 per true positive case. CONCLUSIONS: Although 10% of patients were tested for RF, most did not have RA. Limiting testing to patients with a higher pre-test probability would significantly reduce the cost of testing. PMID- 29496421 TI - Ureteral tunnel length versus ureteral orifice configuration in the determination of ureterovesical junction competence: A computer simulation model. AB - INTRODUCTION: The long-held belief that a ureteral re-implant tunnel should be five times the diameter of the ureter, as proposed by Paquin in 1959, ignores the effect of the orifice on the occurrence of reflux. In 1969, Lyon proposed that the shape of the ureteral orifice (UO) is more important than the intravesical tunnel. However, both theories missed quantitative evidence from principles of physics. The goal of the current study was to test Lyon's theory through numerical models (i.e. to quantify the sensitivity of ureterovesical junction (UVJ) competence to intravesical tunnel length and to the UO). MATERIALS AND METHODS: The closure of a three-dimensional spatial configuration of ureter, constrained within a bladder, was simulated. Two common UO shapes (i.e. golf type vs 2-mm volcano type (Summary Fig.)), and two different intravesical ureteral tunnel length/diameter ratios (3:1 and 5:1) were examined. The required closure pressures were then compared. RESULTS: The UO was a significant factor in determining closure pressure. Given the same intravesical ureteral tunnel length/diameter ratio, the required closure pressure for the volcanic orifice was 78% less than that for the golf orifice. On the other hand, the intravesical ureteral tunnel length/diameter ratio had minimal effect on the required closure pressure. As the intravesical ureteral tunnel length/diameter ratio changed from 3:1 to 5:1, the required closure pressure was reduced by less than 7%, regardless of the orifice shape. CONCLUSIONS: The simulation results showed that UVJ competence was more sensitive to a 2-mm protrusion of the UO compared to an increase in the intravesical tunnel length from 3:1 to 5:1. This agrees with Lyon's theory, and at the same time challenges Paquin's 5:1 rule. Researchers could use this information to consider the UO configuration in further animal, human, computer or material models. PMID- 29496420 TI - Current Status of Multidisciplinary Care in Psoriatic Arthritis in Spain: NEXUS 2.0 Project. AB - OBJECTIVE: 1) To analyze the implementation of multidisciplinary care models in psoriatic arthritis (PsA) patients, 2) To define minimum and excellent standards of care. METHODS: A survey was sent to clinicians who already performed multidisciplinary care or were in the process of undertaking it, asking: 1) Type of multidisciplinary care model implemented; 2) Degree, priority and feasibility of the implementation of quality standards in the structure, process and result for care. In 6 regional meetings the results of the survey were presented and discussed, and the ultimate priority of quality standards for care was defined. At a nominal meeting group, 11 experts (rheumatologists and dermatologists) analyzed the results of the survey and the regional meetings. With this information, they defined which standards of care are currently considered as minimum and which are excellent. RESULTS: The simultaneous and parallel models of multidisciplinary care are those most widely implemented, but the implementation of quality standards is highly variable. In terms of structure it ranges from 22% to 74%, in those related to process from 17% to 54% and in the results from 2% to 28%. Of the 25 original quality standards for care, 9 were considered only minimum, 4 were excellent and 12 defined criteria for minimum level and others for excellence. CONCLUSIONS: The definition of minimum and excellent quality standards for care will help achieve the goal of multidisciplinary care for patients with PAs, which is the best healthcare possible. PMID- 29496422 TI - Bladder contractility index in posterior urethral valve: A new marker for early prediction of progression to renal failure. AB - INTRODUCTION: Posterior urethral valve (PUV) is the most common cause of pediatric end stage renal disease (ESRD), imposing a major health burden on medical community caregivers and adversely affecting the quality of life of patients. Chronic kidney disease (CKD) stage III or estimated GFR of <60 mL/min/1.73 m2 is known to be associated with more adverse renal, cardiovascular, and clinical outcomes. Thus, it is desirable to identify factors predicting the rapid and early progression of disease. In the present study, baseline characteristics and urodynamic study (UDS) parameters of boys with PUV are correlated with CKD progression to IIIB or more. AIMS AND OBJECTIVES: To study the correlation of bladder contractility index (BCI) with development of CKD stage IIIB (eGFR of <45 mL/min/1.73 m2) or more in boys with PUV. METHODOLOGY: Baseline characteristics and demographical variables of 270 boys with PUV who underwent valve fulguration at the hospital between 2000 and 2010 were recorded and certain UDS parameters in follow-up were noted such as bladder contractility index (BCI = PdetQmax + 5 Qmax), end filling pressure (EFP), compliance (DeltaC), bladder outlet obstruction index (BOOI = Pdet Qmax - 2 Qmax), and bladder volume efficiency (BVE = Voided volume/total capacity). Fate of patients in follow-up was checked in December 2015. RESULTS: Mean follow-up period was 8.5 years (range 5-15) and median age of patients at the time of evaluation was 5.8 years. At the end of the study, 21.8% (59/270) of patients had progressed to CKD stage IIIB or more (primary end point). Cox regression analysis was applied to risk factors predicting development of CKD stage IIIB. In the multivariate model, bladder contractility index (BCI) (HR 0.8; p = 0.004), end filling pressure (EFP) (HR 2.1; p = 0.010), and compliance (DeltaC) (p = 0.020) were significantly associated with the event (i.e. an eGFR of <45 mL/min/1.73 m2), whereas BOOI (p = 0.053) and bladder BVE (p = 0.267) were not. ROC cut-off level for BCI predicting the primary end point was 75 (AUC +/- SE, 0.73 +/- 0.03, sensitivity of 78.2%, and specificity of 62.5%). CONCLUSION: In a well performed UDS, BCI may be a useful tool for early detection of boys with PUV who are likely to progress to CKD stage IIIB or more. PMID- 29496423 TI - Quality of life up to 10 years after external beam radiotherapy and/or brachytherapy for prostate cancer. AB - PURPOSE: The aim of this study was to evaluate quality-of-life changes up to 10 years following three different radiotherapy concepts. METHODS AND MATERIALS: In the years 2000-2003, 295 patients were treated with external beam radiotherapy (EBRT; n = 135; 70.2 Gy in 1.8 Gy fractions), low-dose-rate brachytherapy (LDR-BT with I-125; n = 94; 145 Gy), and high-dose-rate brachytherapy (HDR-BT with Ir 192; n = 66; 18 Gy in two fractions using 4-6 needles) as a boost to EBRT (50.4 Gy in 1.8 Gy fractions). Quality of life was assessed using the Expanded Prostate Cancer Index Composite at median time of 2, 6, and 10 years after treatment. RESULTS: The urinary function score 2 years after EBRT (mean 93 points) was significantly higher in comparison to HDR-BT + EBRT (80 points, higher doses to the urethra relevant) and LDR-BT (88 points). After 10 years, only HDR-BT + EBRT (75 points) remained worse (LDR-BT 92 points; EBRT 91 points). Urinary incontinence score decreased from 83 to 76 points in the HDR-BT + EBRT group. No significant differences or changes resulted in the bowel domain. The mean sexual function score (i.e., sexuality score) was significantly higher after LDR-BT versus HDR-BT + EBRT and EBRT (30 vs. 19 and 24 points after 2 years and 25 vs. 13 and 15 points after 10 years, respectively)-a lower patient age and a lower percentage with hormonal treatment need to be considered. CONCLUSION: Apart from decreasing sexual function for all patients, decreasing urinary scores were found in the HDR-BT + EBRT group predominantly as a result of increasing incontinence. This study demonstrates the need for optimum BT treatment planning. PMID- 29496424 TI - Appropriate timing for postimplant imaging in permanent breast seed implant: Results from a serial CT study. AB - PURPOSE: Postimplant analysis in permanent breast seed implant (PBSI) is performed at inconsistent times subsequent to seed implantation across cancer centers, creating challenges in the interpretation of dosimetric data and ultimately the correlation with clinical outcomes. The purpose of this study is to determine the most appropriate time postimplant to perform this analysis. METHODS AND MATERIALS: Nine patients treated at our institution with PBSI were included in this analysis. Each underwent 4 postimplant CT scans: 0, 15, 30, and 60 days postimplant. A model of the accumulated dose was created by deformably registering the Day 15, 30, and 60 postimplant CT scans and dose matrices to the Day 0 scan, scaling for seed decay. The results from this model were compared to each individual postplan by integral comparison of dose-volume histogram curves for a dose evaluation volume. RESULTS: The Day 30 postplan showed the best agreement with the accumulated dose model and the smallest interpatient variability across the patient cohort. The mean (+/-SD) for the dose evaluation volume V90, V100, V150, and V200 for the accumulated dose model was 90 +/- 7%, 86 +/- 8%, 66 +/- 14%, and 41 +/- 16%, respectively. CONCLUSIONS: Based on the results of this patient cohort, we recommend that postimplant dosimetric analysis for PBSI be performed approximately 30 days following the implant. PMID- 29496425 TI - Endoluminal high-dose-rate brachytherapy for locally recurrent or persistent esophageal cancer. AB - PURPOSE: Management of locally recurrent or persistent esophageal cancer (EC) after standard chemoradiation is challenging. This study updates our experience of treating medically inoperable EC patients with endoluminal high-dose-rate brachytherapy (EHDRBT) including the patients treated with a novel multiballoon channel centering esophageal applicator. METHODS AND MATERIALS: Thirty-three consecutive patients with early-stage primary (n = 7), posttreatment persistent (n = 7), and recurrent (n = 19) EC treated with EHDRBT at our institution were included. Median dose and treatment lengths were 14 Gy (range 10-17.5 Gy) and 6 cm (3.5-9.0 cm), respectively. Endoscopy and biopsy were performed 3 months after EHDRBT and then every 3-6 months thereafter. RESULTS: Median followup was 17.4 months (range 5.0-88.3). Grade 1 and 2 toxicities were observed in 13 (44.8%) and 11 (37.9%) patients, respectively. Grade 3 toxicity (tracheoesophageal fistula) was observed in 1 patient who had previously received two courses of external beam radiotherapy as well as a stent insertion. Median overall survival (OS) for entire cohort was 20.9 months, and 1-year OS was 78%. Complete response was achieved in 58.6% of patients with median time to failure and 1-year disease-free survival of 10.3 months (range 5.4-28.2) and 27%, respectively. CONCLUSIONS: For medically inoperable patients with early-stage primary or local posttreatment residual or recurrent EC, EHDRBT is a well-tolerated treatment option with minimal Grade >=3 toxicity. Brachytherapy in our hands continues to be a safe treatment option. Although 58.6% of patients achieved a complete response and the OS of this cohort is relatively good, long-term local control and cure remains a challenge. PMID- 29496426 TI - [Recommendations for the creation and operation of maternal milk banks in Spain]. AB - It is widely agreed that the best source of nutrition for the newborn is the milk of their own mothers. In those cases where it is not available, especially in very premature and/or very low birth weight infants, as well as other sick newborns, the preferred choice before formula is the human milk provided by selected donors. This indication is supported by the highest international bodies dedicated to the health of the child population, including the World Health Organisation as well as the main national and international scientific societies in the field of Paediatrics. Milk banks are health institutions responsible for the collection, processing and distribution of donated human milk. Currently, there are 14 human milk banks operating in Spain, grouped in the Spanish Association of Human Milk Banks, created in September 2008. In order to homogenise the criteria and to unify the working methods of the different milk banks, the Spanish Association of Human Milk Banks has developed standards to harmonise the protocols, and to serve as a guide for the start-up of new milk banks in the Spanish territory. These standards, set out in the present article, range from the donor selection and the evaluation process to the collection, processing, storage, and distribution of donor human milk. PMID- 29496427 TI - CT-derived left ventricular global strain in aortic valve stenosis patients: A comparative analysis pre and post transcatheter aortic valve implantation. AB - INTRODUCTION: We assessed the potential of CT strain to detect changes in myocardial function in patients referred for TAVI pre and post intervention. PATIENTS AND METHODS: 25 consecutive patients with symptomatic aortic valve stenosis in whom TAVI had been performed were included in this analysis. Functional CT data sets acquired before and 3 to 6 months after TAVI were available. Multiphase reconstructions in increments of 10% of the cardiac cycle were rendered and transferred to a dedicated workstation (Ziostation2, Ziosoft Inc., Tokyo, Japan). For quantification of left ventricular strain, multiplanar reconstructions of the left ventricle in standard 4 chamber, 2 chamber as well as apical 3 chamber views were rendered. The perimeter of the left ventricle was traced dynamically through the cardiac cycle. Peak strain was calculated for each patient pre and post intervention. Furthermore, for quantification of 3 dimensional maximum principal strain, 2 volumetric regions of interests (VOI) were placed per each basal, mid and apical segment of the previously mentioned MPRs and peak maximal principal strain was calculated. Maximum principal strain as well as perimeter-derived longitudinal strain values in the three standard windows were averaged to obtain global strain. RESULTS: 25 patients were included in this analysis (mean age 78 +/- 9 years, 13 males). Peak global maximum principal strain was significantly higher at follow-up compared to baseline (0.46 +/- 0.19 vs. 0.59 +/- 0.18, respectively, p = 0.001). Similarly global longitudinal strain derived by perimeter was significantly lower - implying better contraction - compared to baseline (-8.6% +/- 2.8% vs. -9.8% +/- 2.6%, respectively, p = 0.006). CONCLUSION: Using dedicated software, assessment of CT derived left ventricular strain is feasible. In patients treated with transcatheter aortic valve replacement, CT-derived parameters of global myocardial strain improve onshort-term follow-up. PMID- 29496429 TI - Evaluation of the immunogenicity of a recombinant HSV-1 vector expressing human group C rotavirus VP6 protein. AB - Group C Rotavirus (RVC) has been associated globally with sporadic outbreaks of gastroenteritis in children and adults. RVC also infects animals, and interspecies transmission has been reported as well as its zoonotic potential. Considering its genetic diversity and the absence of effective vaccines, it is important and necessary to develop new generation vaccines against RVC for both humans and animals. The aim of the present study was to develop and characterize an HSV-1-based amplicon vector expressing a human RVC-VP6 protein and evaluate the humoral immune response induced after immunizing BALB/c mice. Local fecal samples positive for RVC were used for isolation and sequencing of the vp6 gene, which phylogenetically belongs to the I2 genotype. We show here that cells infected with the HSV[VP6C] amplicon vector efficiently express the VP6 protein, and induced specific anti-RVC antibodies in mice immunized with HSV[VP6C], in a prime-boost schedule. This work highlights that amplicon vectors are an attractive platform for the generation of safe genetic immunogens against RVC, without the addition of external adjuvants. PMID- 29496430 TI - Non-invasive vagus nerve stimulation reduces blood-brain barrier disruption in a rat model of ischemic stroke. AB - BACKGROUND: Vagus nerve stimulation (VNS) significantly reduces infarct volume in rat models of cerebral ischemia, but the mechanism of this protective effect remains open. HYPOTHESIS: This study tested the hypothesis that non-invasive VNS (nVNS), during transient middle cerebral artery occlusion (MCAO), protects the blood-brain barrier (BBB), leading to reduced infarct size in ischemic brain. METHODS: Spontaneous hypertensive rats (SHRs) were subjected to a 90 min MCAO. nVNS treated rats received 5 stimulations (duration: 2 min; every 10 min) on the skin overlying the cervical vagus nerve in the neck beginning 30 min after MCAO onset. Control rats received the same stimulations on the quadriceps femoris muscle. Twenty-four hours after MCAO onset, MRI and immunohistochemistry (IHC) were performed for analyses of infarct size and BBB leakage. RESULTS: Compared with the control group, anatomic MRI T2-weighted images showed significantly smaller infarct sizes in the nVNS group. Dynamic contrast-enhanced (DCE)-MRI showed a significantly decreased BBB transfer rate (Ki map) in the lesion area in the nVNS group, which was spatially correlated with the attenuation of the infarct size. Furthermore, significantly lower serum IgG leakage, visualized by IHC, was seen in the ischemic hemisphere in nVNS treated rats. nVNS also protected vascular tight junction proteins from disruption in microvessels, and reduced expression of matrix metalloproteinases-2/9 in reactive astrocytes surrounding the compromised vessels in the ischemic hemispheres. CONCLUSION: Our data suggest that the neuroprotective role of a series of nVNS administrations during MCA occlusion, spatially correlates with protection of BBB integrity from damage and reduction of infarct extent induced by ischemic stroke. PMID- 29496432 TI - Revisiting the Functional Impact of NK Cells. AB - Immune responses are critical for the maintenance of homeostasis but can also upset the equilibrium, depending on the context and magnitude of the response. Natural killer (NK) cells are well known for their important roles in antiviral and antitumor immune responses, and they are currently used, mostly under optimized forms, as immunotherapeutic agents against cancer. Nevertheless, with accumulating examples of deleterious effects of NK cells, it is paramount to consider their negative contributions. Here, we critically review and comment on the literature surrounding undesirable aspects of NK cell activity, focusing on situations where they play a harmful rather than a protective role. PMID- 29496431 TI - [In the case of premature live birth, is very early rupture of the membranes an additional risk factor for morbidity and mortality?] AB - OBJECTIVE: To describe survival rate after preterm premature rupture of membranes (PPROM) before 25 weeks of gestation and compare neonatal morbidity and mortality among those born alive with a control group of infants born at a similar gestational age without premature rupture of membranes. METHODS: We conducted a retrospective single-centre study at Port-Royal maternity, from 2007 to 2015, comparing neonatal outcomes between liveborninfants exposed to PPROM prior to 25 weeks of gestation (WG) and a control group not exposed to premature rupture of the membranes. For each live-born child, the next child born after spontaneous labor without PPROM was matched for gestational age at birth, sex, and whether or not they received antenatal corticosteroid therapy. The primary endpoint was severe neonatal complications assessed by a composite endpoint including neonatal deaths, grade 3-4 HIV, bronchopulmonary dysplasia, leukomalacia and stade 3-4 retinopathies. RESULTS: Among 77 cases of very premature rupture of the membranes, 55 children were born alive. Among these, the average gestational age at birth was 28 WG and 1 day. The rate of severe neonatal complications did not differ between the two groups (43.6% in the PPROM group vs. 36.4%, P=0.44) and the survival rate at discharge was also similar in the two groups (85.5% vs. 83.6%, P=0.98). CONCLUSIONS: In our cohort and among livebirths after 24 WG, PPROM before 25 WG was not associated with an increased risk of morbidity and mortality compared to children born at the same gestational age after a spontaneous labor with intact membranes. PMID- 29496433 TI - Fifty-Fourth Annual Meeting, The Society of Thoracic Surgeons. PMID- 29496428 TI - DNA methylation in the pathogenesis of type 2 diabetes in humans. AB - BACKGROUND: Type 2 diabetes (T2D) is a multifactorial, polygenic disease caused by impaired insulin secretion and insulin resistance. Genome-wide association studies (GWAS) were expected to resolve a large part of the genetic component of diabetes; yet, the single nucleotide polymorphisms identified by GWAS explain less than 20% of the estimated heritability for T2D. There was subsequently a need to look elsewhere to find disease-causing factors. Mechanisms mediating the interaction between environmental factors and the genome, such as epigenetics, may be of particular importance in the pathogenesis of T2D. SCOPE OF REVIEW: This review summarizes knowledge of the impact of epigenetics on the pathogenesis of T2D in humans. In particular, the review will focus on alterations in DNA methylation in four human tissues of importance for the disease; pancreatic islets, skeletal muscle, adipose tissue, and the liver. Case-control studies and studies examining the impact of non-genetic and genetic risk factors on DNA methylation in humans will be considered. These studies identified epigenetic changes in tissues from subjects with T2D versus non-diabetic controls. They also demonstrate that non-genetic factors associated with T2D such as age, obesity, energy rich diets, physical activity and the intrauterine environment impact the epigenome in humans. Additionally, interactions between genetics and epigenetics seem to influence the pathogenesis of T2D. CONCLUSIONS: Overall, previous studies by our group and others support a key role for epigenetics in the growing incidence of T2D. PMID- 29496434 TI - Mid-Term Results After Sternal Reconstruction Using Titanium Plates: Is It Worth It to Plate? AB - BACKGROUND: Sternal dehiscence after median sternotomy is a challenging problem in situations of frail bone, fractures, or complete sternectomy. Plate osteosynthesis offers a promising approach to restore sternal integrity. However, there is only scarce data on mid-term outcome. METHODS: Mid-term data on 34 patients with unstable thorax after open heart operation, requiring sternal refixation with the Synthes Titanium Sternal Fixation System (Oberdorf, Switzerland) between 2005 and 2011, were analyzed. The Titanium Sternal Fixation System was used if conventional rewiring had failed or if failure of rewiring was expected because of risk factors. Follow-up examinations included clinical tests, computed tomographic scans, and pain assessment to evaluate sternal integrity and persistent pain. RESULTS: Median follow-up time was 1.4 years (range, 0.3 to 6.6 years). Clinical examination showed thoracic stability in all patients. Computed tomographic scans demonstrated complete bone consolidation in 25.8%, nearly complete in 38.7%, partial in 9.7%, and missing in 25.8% of patients. Pain assessment revealed no sternal pain in 16 patients (48.5%), mild pain in 9 (27.3%), moderate pain in 3 (9.1%), and severe pain in 5 patients (15.1%). Pain on movement was reported in 12 patients and 5 patients had chronic pain. A total of 13 patients (38%) required plate removal due to pain (n = 8) or infection (n = 5) after a median of 10.9 and 2 months, respectively. CONCLUSIONS: With the use of plates, it was possible to achieve thoracic stabilization in complicated dehiscence. However, the rate of postoperative infection and pain is not negligible. Thus, we recommend plate reconstruction only in sternal high-risk patients, who are unsuitable for standard reclosure. PMID- 29496435 TI - Coronary Sinus Rupture Repair: Patency Is Important. AB - We report a case of coronary sinus (CS) injury with a retrograde cardioplegia catheter and repair that compromised CS patency. This resulted in acute global cardiac dysfunction shortly after weaning from bypass, which reversed after patch repair with confirmed CS patency. The case report shows that acute CS occlusion may not be tolerated in some humans. PMID- 29496436 TI - Myectomy and Left Atrial-to-Left Ventricular Conduit for Severe Calcific Mitral Stenosis and Hypertrophic Cardiomyopathy. AB - Severe calcific mitral valve stenosis can rarely occur concomitantly with obstructive hypertrophic cardiomyopathy. In these patients, surgical decalcification of the stenotic mitral valve followed by mitral valve replacement carries substantial operative risk and may result in paravalvular leakage, atrioventricular groove disruption, and excessive bleeding. We report two cases of obstructive hypertrophic cardiomyopathy with severe calcific mitral valve stenosis successfully treated with concomitant transaortic septal myectomy and bypass of the stenotic mitral valve with the use of a valved left atrial-to-left ventricular conduit. PMID- 29496437 TI - Natural polymer functionalized graphene oxide for co-delivery of anticancer drugs: In-vitro and in-vivo. AB - The present study focuses on the development of a chitosan functionalized nanobiocomposite for the co-delivery of two anti-cancer drugs camptothecin (CPT) and 3,3'-Diindolylmethane (DIM). The difference in the mechanism of action of the two drugs makes them a promising candidate to produce a synergistic effect against breast cancer. Herein a nanobiocomposite was developed by functionalizing a natural polymer chitosan to graphene oxide nanoparticles and decorated with folic acid. The nanobiocomposite thus synthesized was loaded with camptothecin and 3,3'-Diindolylmethane and characterized by X-ray diffractometer (XRD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), UV-visible spectroscopy (UV) and atomic force microscopy (AFM).Biocompatibility was assayed by hemolysis and anti inflammatory assay. The cellular toxicity was measured by 3-(4,5-Dimethylthiazol 2-yl)-2,5-Diphenyltetrazolium Bromide (MTT), Sulforhodamine B (SRB) and cell death assay against MCF-7 cell lines. Further in vivo studies were carried out to analyze the biodistribution of the drug, blood biochemical analysis and bioavailability of the drug. The data revealed a significant increase in anticancer activity after co-loading of CPT and DIM to the nanocarrier. Also in vivo studies revealed that DIM successfully masked the toxic effects produced by CPT. PMID- 29496438 TI - Morphological and functional changes of chronic pancreatitis in patients with dyspepsia: A prospective, observational, cross-sectional study. AB - OBJECTIVE: Whether chronic pancreatitis (CP) may present with dyspepsia is controversial. We aimed at evaluating the frequency and risk factors of changes of CP in patients presenting with epigastric pain syndrome (EPS)-like symptoms. DESIGN: A prospective, observational, cross-sectional study was carried out in patients with EPS-like symptoms. Patients underwent endoscopic ultrasound (EUS) evaluation of the pancreas, and changes of CP were defined as the presence of five or more EUS criteria of the disease. In patients with 3 or 4 EUS criteria, magnetic resonance dynamic evaluation of the pancreas (MRI/sMRCP) and endoscopic pancreatic function test (ePFT) were carried out to confirm or exclude the presence of changes of CP. A multivariate logistic regression analysis was performed to evaluate factors associated with CP findings, and results are shown as odds ratio (OR) and 95% confidence interval (CI). RESULTS: 213 patients were included. Changes of CP were confirmed by EUS (>=5 criteria) in 18 patients (8.4%). Thirty-four patients had 3-4 EUS criteria, and changes of CP were confirmed in 27 of them by MRI/sMRCP and ePFT (12.7%). Morphological and functional findings of CP were then present in 45 patients (21.1%). Male gender (OR 2.97; 95%CI 1.39-6.37) and alcohol and tobacco consumption (OR 6.56; 95%CI 1.97-21.85) were associated with the presence of changes of CP. CONCLUSION: Morphological and functional changes of CP are frequent in patients with EPS-like symptoms. Whether these pancreatic changes explain EPS-like symptoms requires further investigation. PMID- 29496439 TI - Patient perspectives on emergency department self-referral after bariatric surgery. AB - BACKGROUND: Reducing avoidable emergency department (ED) visits is an increasingly important target of quality improvement and cost containment efforts in bariatric surgery. Administrative and clinical registry data provide an incomplete picture of the factors contributing to postoperative ED utilization. Patient-centered interviews can help identify intervention opportunities. OBJECTIVES: We sought to understand the circumstances surrounding patient self referral to the ED after elective, primary bariatric surgery. SETTING: A quality improvement collaborative in Michigan. METHODS: A prospective review of clinically abstracted data and patient interviews was completed across 40 hospitals participating in a statewide quality improvement collaborative. Trained nurses collected data on the circumstances surrounding patients' 30-day postoperative ED visits using a previously validated interview tool. Over a year, 201 of 633 total ED visits met the inclusion criteria, with 78% of those patients being interviewed. RESULTS: The most common reported chief complaints were abdominal pain and nausea/vomiting. Patients reported high compliance with provider-driven perioperative measures to reduce ED visits. One third of patients stated urgency as the reason for not contacting their surgeon prior to their visit. A majority of patients believed their ED visit was both necessary and unavoidable. CONCLUSIONS: Most patients experienced non-life-threatening symptoms but believed their concerns required immediate medical attention in an ED. Patients did not seek lower acuity alternatives despite the increasing availability of these lower cost options. Urgent care centers are one practical alternative for patients who need expeditious professional evaluation. Focused, patient-centered education and promotion of appropriate lower acuity options may decrease nonurgent ED utilization among postoperative bariatric patients. PMID- 29496440 TI - Rate of revisions or conversion after bariatric surgery over 10 years in the state of New York. AB - BACKGROUND: A primary measure of the success of a procedure is the whether or not additional surgery may be necessary. Multi-institutional studies regarding the need for reoperation after bariatric surgery are scarce. OBJECTIVES: The purpose of this study is to evaluate the rate of revisions/conversions (RC) after 3 common bariatric procedures over 10 years in the state of New York. SETTING: University Hospital, involving a large database in New York State. METHODS: The Statewide Planning and Research Cooperative System database was used to identify all patients undergoing laparoscopic adjustable gastric banding (LAGB), sleeve gastrectomy (SG), and Roux-en-Y gastric bypass (RYGB) between 2004 and 2010. Patients were followed for RC to other bariatric procedures for at least 4 years (up to 2014). Multivariable cox proportional hazard regression analysis was performed to identify risk factors for additional surgery after each common bariatric procedure. Multivariable logistic regression was used to check the factors associated with having >=2 follow-up procedures. RESULTS: There were 40,994 bariatric procedures with 16,444 LAGB, 22,769 RYGB, and 1781 SG. Rate of RC was 26.0% for LAGB, 9.8% for SG, and 4.9% for RYGB. Multiple RC ( = />2) were more common for LAGB (5.7% for LAGB, .5% for RYGB, and .2% for LSG). Band revision/replacements required further procedures compared with patients who underwent conversion to RYGB/SG (939 compared with 48 procedures). Majority of RC were not performed at initial institution (68.2% of LAGB patients, 75.9% for RYGB, 63.7% of SG). Risk factors for multiple procedures included surgery type, as LAGB was more likely to have multiple RC. CONCLUSIONS: Reoperation was common for LAGB, but less common for RYGB (4.9%) and SG (9.8%). RC rate are almost twice after SG than after RYGB. LAGB had the highest rate (5.7%) of multiple reoperations. Conversion was the procedure of choice after a failed LAGB. PMID- 29496441 TI - Adjustments to warfarin dosing after gastric bypass and sleeve gastrectomy. AB - BACKGROUND: Warfarin dosing after bariatric surgery may be influenced by alterations in gastrointestinal pH, transit time, absorptive surface area, gut microbiota, food intake, and adipose tissue. OBJECTIVES: The aim of this study was to describe trends in warfarin dosing after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). SETTING: Single academic center. METHODS: All patients chronically on warfarin anticoagulation before RYGB or SG were retrospectively identified. Indications for anticoagulation, history of bleeding or thrombotic events, perioperative complications, and warfarin dosing were collected. RESULTS: Fifty-three patients (RYGB n = 31, SG n = 22) on chronic warfarin therapy were identified (56.6% female, mean 54.4 +/- 11.7 yr of age). Of this cohort, 34.0% had prior venous thromboembolic events, 43.4% had atrial fibrillation, and 5.7% had mechanical cardiac valves. Preoperatively, the average daily dose of warfarin was similar in the RYGB group (8.3 +/- 4.1 mg) and SG group (6.9 +/- 2.8 mg). One month after surgery, mean daily dose of warfarin was reduced 24.1% in the RYGB group (P<.001) and 23.2% in the SG group (P = .002). At 12 months postoperatively, the required daily warfarin dose compared with baseline remained statistically different (RYGB: 6.8 +/- 3.8 mg; SG: 6.1 +/- 2.0 mg). CONCLUSIONS: The warfarin dose is expected to be decreased by approximately 25% from preoperative levels after both RYGB and SG. Lower dose requirement within the first month after bariatric surgery is followed by a trend toward increased warfarin dose requirements, but remain less than baseline. Because dose requirements change constantly over time, frequent postoperative monitoring of the international normalized ratio is recommended. PMID- 29496442 TI - Comment on: short-term changes in affective, behavioral, and cognitive components of body image after bariatric surgery. PMID- 29496443 TI - Does Andrews facial analysis predict esthetic sagittal maxillary position? AB - OBJECTIVE: Cephalometric analyses have limited utility in planning maxillary sagittal position for orthognathic surgery. In Six Elements of Orofacial Harmony, Andrews quantified maxillary position relative to forehead projection and angulation and proposed an ideal relationship. The purpose of this study was to investigate the ability of this technique to predict esthetic sagittal maxillary position. STUDY DESIGN: Survey study including a male and female with straight facial profiles, normal maxillary incisor angulations, and Angle's Class I. Maxillary position was modified on lateral photographs to create 5 images for each participant with incisor-goal anterior limit line (GALL) distances of -4, 2, 0, +2, and +4 mm. A series of health care professionals and laypeople were asked to rate each photo in order of attractiveness. RESULTS: A total of 100 complete responses were received. Incisor-GALL distances of +4 mm (41%) and +2 mm (40%) were most commonly considered "most esthetic" for the female volunteer (P < .001). For the male volunteer, there were 2 peak "most esthetic" responses: incisor-GALL distances of 0 mm (37%) and -4 mm (32%) (P < .001). CONCLUSION: Respondents considered maxillary incisor position 2 to 4 mm anterior to GALL most attractive in a woman and 0 to 4 mm posterior to GALL most esthetic in a man. Using these modified target distances, this analysis may be useful for orthognathic surgery planning. PMID- 29496444 TI - Adrenergic receptor-mediated activation of FGF-21-adiponectin axis exerts atheroprotective effects in brown adipose tissue-transplanted apoE-/- mice. AB - Brown adipose tissue (BAT) has been found as an endocrine organ that maintains metabolic homeostasis; however, the effects on atherosclerosis remain undefined. Here, we investigated the effect of experimental BAT transplantation on atherosclerosis. Interscapular BAT was dissected from wild-type mice and transplanted into the visceral cavity of 12-week-old apoE-/- mice. Oil-red O staining of whole aortas after 3 months of a high-cholesterol diet showed a significant decrease in atherosclerotic lesion area in BAT-transplanted mice by 32% compared with the sham control mice. Lipid profiles, except for serum triglyceride level, showed no difference between the 2 groups. BAT-transplanted mice showed higher concentrations of serum noradrenalin, fibroblast growth factor 21 (FGF-21), and adiponectin. Treatment with the beta3-adrenergic receptor (AR) blocker completely abrogated the atheroprotective effects of BAT transplantation, with serum concentrations of FGF-21 and adiponectin being equivalent between the 2 groups. Homologous transplantation of BAT from apoE-/- mice also showed a significant decrease in atherosclerotic lesion area by 28% without affecting lipid profiles, while epidydimal white adipose tissue transplantation did not affect atherosclerosis. Serum and endogenous BAT concentrations of FGF-21 were significantly higher in BAT-transplanted mice than sham control mice. Concomitantly, serum adiponectin levels were elevated in BAT-transplanted mice and showed a significant inverse correlation with atherosclerotic lesion area. Our findings show for the first time that atheroprotective effect of BAT transplantation is BAT-specific and independent of lipid-lowering effect, accompanied by AR-mediated activation of the FGF-21-adiponectin axis. PMID- 29496445 TI - Deficiency of Atg6 impairs beneficial effect of metformin on intestinal stem cell aging in Drosophila. AB - Age-related changes of adult stem cell are crucial for tissue aging and age related diseases. Thus, clarifying mechanisms to prevent adult stem cell aging is indispensable for healthy aging. Metformin, a drug for type 2 diabetes, has been highlighted for its anti-aging and anti-cancer effect. In Drosophila intestinal stem cell (ISC), we previously reported the inhibitory effect of metformin on age related phenotypes of ISC. Here, we showed that knockdown of Atg6, a crucial autophagy-related factor, in ISC induces age-related phenotypes of ISC such as hyperproliferation, centrosome amplification, and DNA damage accumulation. Then, we revealed that metformin inhibits ISC aging phenotypes in Atg6-dependent manner. Taken together, our study suggests that Atg6 is required for the inhibitory effect of metformin on ISC aging, providing an intervention mechanism of metformin on adult stem cell aging. PMID- 29496446 TI - Notch1 regulates PTEN expression to exacerbate renal tubulointerstitial fibrosis in diabetic nephropathy by inhibiting autophagy via interactions with Hes1. AB - Diabetic nephropathy (DN) is a serious clinical microvascular complication of diabetes mellitus. DN is characterized by the accumulation of extracellular matrix, resulting in progressive fibrosis leading to the loss of renal function. Notch1 and phosphatase and tensin homolog deleted on chromosome ten (PTEN) signaling have been associated with fibrosis. Autophagy serves as an essential regulator of tubular cellular homeostasis. However, how these molecules control the balance between fibrosis and autophagy, the main homeostatic mechanism regulating fibrosis, is not well understood. This association was confirmed using Notch1-siRNA in vitro, which prevented the increase in Hes1 and restored PTEN expression. In contrast, transfection with pHAGE-Hes1 repressed PTEN promoter driven luciferase activity, implying a direct relationship between Hes1 and PTEN. The expression of Notch1 and Hes1 was increased in diabetic db/db mice by western blotting; in contrast, the expression of PTEN was decreased. Importantly, the dysregulation of these signaling molecules was associated with an increase in extracellular matrix proteins (Collagen-I and III) and the inhibition of autophagy. Similar results were evident in response to high glucose concentrations in vitro in the NRK-52e cells. Therefore, the high glucose concentrations present in diabetes promote fibrosis through the Notch1 pathway via Hes1, while inhibiting the PTEN and autophagy. In conclusion, the inhibition of PTEN by Notch1/Hes1 in response to high glucose concentration inhibits autophagy, which is associated with the progression of fibrosis. Therefore, these signaling molecules may represent novel therapeutic targets in diabetic nephropathy. PMID- 29496447 TI - Hypothalamic AMPK-induced autophagy ameliorates hypercatabolism in septic rats by regulating POMC expression. AB - Hypercatabolism plays a critical role in the pathogenesis of post-critical care debility in critical patients. Central nervous system may exerte a critical role in the regulation of hypercatabolism. However, little is known about the exact mechanisms of the central role. Here, we reported that actived hypothalamic AMP activated protein kinase (AMPK)-induced autophagy modulated the expression of POMC to ameliorate hypercatabolism in septic rats. Firstly, rats were i.c.v. injected with the lentiviral vector containing shRNA against POMC. Two weeks after injections, rats were intraperitoneally injected with LPS or saline. Twenty four hours later, blood, skeletal muscle and hypothalamus tissues were obtained. Hypercatabolism markers and neuropeptides expression were detected. Then, rats were injected with AICAR or saline into third ventricle and promptly intraperitoneally injected with LPS or saline. Twenty-four hours after infection, blood, skeletal muscle and hypothalamus tissues were obtained. Hypercatabolism, hypothalamic AMPK-induced autophagy markers and neuropeptides expression were also detected. Results showed that sepsis would decrease the level of hypothalamic autophagy accompany with the alterations of POMC expression and hypercatabolism. Knocking out hypothalamus POMC expression could significantly ameliorate hypercatabolism. Moreover, Central activation of AMPK-induced autophagy pathway via third ventricle injection of AICAR, an AMPK activator, could efficiently ameliorate hypercatabolism as well as attenuate the elevated POMC expression rather than other neuropeptides. Taken together, these results suggested that hypothalamic AMPK-autophagy pathway as a regulatory pathway for POMC expression was essential for hypercatabolism during sepsis. And hypothalamic AMPK-autophagy activation could attenuate the POMC expression to ameliorate hypercatabolism. Pharmaceuticals with the ability of activating hypothalamic AMPK autophagy pathway may be a therapeutic potential for hypercatabolism in septic patients. PMID- 29496448 TI - The inhibitory effect of Cordycepin on the proliferation of cisplatin-resistant A549 lung cancer cells. AB - The goal of this study is to determine the anti-cancer mechanism of Cordycepin in A549 Cisplatin-Resistance (CR) lung cancer cells. Cordycepin inhibited the viability of A549CR cells in a dose-dependent manner. The cell inhibition was due to induction of apoptosis in the cells treated with Cordycepin by activation of caspase -3, -8 and -9 activities. The cell cycle analysis showed that accumulation of Sub G1 was observed in Cordycepin-treated with A549CR lung cancer cells. Based on the data of expression profile analysis of cell signaling proteins using IPS-FPAA, H-Ras was down-regulated in Cordycepin-treated A549CR cells. Collectively, anti-proliferative function of Cordycepin was due to stimulation of the cell apoptosis and the cell cycle arrest via caspases activation and down-regulation of H-Ras. PMID- 29496449 TI - Effect of tamoxifen on the sphingolipid biosynthetic pathway in the different intraerythrocytic stages of the apicomplexa Plasmodium falciparum. AB - Parasites of the genus Plasmodium responsible for Malaria are obligate intracellular pathogens residing in mammalian red blood cells, hepatocytes, or mosquito midgut epithelial cells. Regarding that detailed knowledge on the sphingolipid biosynthetic pathway of the apicomplexan protozoan parasites is scarce, different stages of Plasmodium falciparum were treated with tamoxifen in order to evaluate the effects of this drug on the glycosphingolipid biosynthesis. Thin layer chromatography, High performance reverse phase chromatography and UV MALDI-TOF mass spectrometry were the tools used for the analysis. In the ring forms, the increase of NBD-phosphatidyl inositol biosynthesis was notorious but differences at NBD-GlcCer levels were undetectable. In trophozoite forms, an abrupt decrease of NBD-acylated GlcDHCer and NBD-GlcDHCer in addition to an increase of NBD-PC biosynthesis was observed. On the contrary, in schizonts, tamoxifen seems not to be producing substantial changes in lipid biosynthesis. Our findings indicate that in this parasite, tamoxifen is exerting an inhibitory action on Glucosylceramidesynthase and sphingomyelin synthase levels. Moreover, regarding that Plasmodium does not biosynthesize inositolphosphoceramides, the accumulation of phosphatidylinositol should indicate an inhibitory action on glycosylinositol phospholipid synthesis. PMID- 29496450 TI - A unified mechanism for plant polyketide biosynthesis derived from in silico modeling. AB - The polyketide synthases found in a variety of plants and fungi provide a varied source of biologically active compounds of pharmacological and medicinal interest. Stilbene synthase and chalcone synthase catalyze the formation of a common tetraketide intermediate, but use different cyclization mechanisms to produce distinct and separate natural products. While key structural differences have been identified to explain this functional diversity, a fuller explication of the factors responsible for this mechanistic disparity is required. Based on the energetics of our models of the bound tetraketides, and our structural analysis of the active sites we propose that a key tautomeric conversion provides a mechanistic framework common to both cyclizations. A previously unidentified active water molecule facilitates cyclization in chalcone synthase through a Claisen mechanism. Such a "Claisen switch" is comparable to the previously characterized "aldol switch" mechanism proposed for the biosynthesis of resveratrol in stilbene synthase. PMID- 29496451 TI - Multiscale modeling on biological systems. PMID- 29496452 TI - Structural and dynamical characteristics of tropomyosin epitopes as the major allergens in shrimp. AB - Ingestion of marine invertebrates often causes food allergy, where the major allergens have been reported to be derived from tropomyosin (TM). Intact or the digestive fragments of food allergens generally show resistance to digestion, which is usually attributable to the structural stability (or rigidity). The difference in the structural and dynamical characteristics between the epitope and the non-epitope regions in TM has not yet been well understood. In the present study, molecular dynamics simulation was performed at constant pHs for shrimp TM. By analyzing the main-chain dihedral angle fluctuations and local alpha-helix contents, we found that the epitope regions are more stable than the non-epitope counterparts, providing a possible physical reason for the resistance to digestion in the epitopes regions. The difference of the structural stability between the epitope and the non-epitope regions was largest at low pHs, even though pH dependence of the structural stability in itself was not significant in both regions. The lower content of the Ala cluster in the epitope region is considered to cause the higher stability of the epitope region. PMID- 29496453 TI - Crystal structure of the apurinic/apyrimidinic endonuclease IV from Mycobacterium tuberculosis. AB - Endonuclease IV is a typical endonuclease of the apurinic-apyrimidinic (AP) or abasic endonuclease superfamily. It repairs damaged DNA through base excision repair by cleaving the DNA backbone immediately 5' of an AP site. In Mycobacterium tuberculosis, endonuclease IV is the major AP endonuclease. This enzyme is absent from mammalian cells, making it an attractive target for anti tuberculosis drug development. In this study, the structure of the recombinant endonuclease IV from M. tuberculosis (MtbEndo IV) was determined at a high resolution of 1.18 A. MtbEndo IV was found to have a classical alpha8beta8-fold TIM barrel with loops on its surface connecting the alpha-helices and beta strands that constitute a groove for DNA binding. Three zinc ions were identified at the active site. A comparison between the structures of MtbEndo IV and Escherichia coli End IV suggested that Gln32 of MtbEndo IV may plays a role in regulating substrate binding. PMID- 29496454 TI - Potential use of TIA-1, MFF, microRNA-200a-3p, and microRNA-27 as a novel marker for hepatocellular carcinoma. AB - Precise and early diagnosis is critical to improve the survival rate of hepatocellular carcinoma (HCC) patients. Although several genetic and protein markers have been developed and are currently used for diagnosis, prognosis, risk stratification, and therapeutic monitoring, application of these markers still needs to be improved for better specificity and efficacy. In this study, we investigated the relative expression of mitochondrial dynamics-regulating factors including T-cell intercellular antigen protein-1 (TIA-1), mitochondrial fission factor (MFF), microRNA (miR)-200a-3p, and miR-27a/b in the liver tissues from HCC patients. The expressions of TIA-1 and MFF were augmented in the cancerous liver tissues compared to the corresponding non-tumor tissues at mRNA and protein level, while the levels of miR-200a-3p and miR-27a/b were relatively lower in the cancerous liver tissues. In addition, high levels of TIA-1 and MFF mRNA were related to the poor survival rate of HCC patients. Our results indicated that the expressions of TIA-1, MFF, miR-200a-3p, and miR-27a/b in the cancerous liver tissues differed to these in non-cancerous tissues of HCC patients, demonstrating that these gene expressions could be potential markers for the diagnosis and prognosis of HCC. PMID- 29496455 TI - Reverse transcription-quantitative PCR assays for genotype-specific detection of human noroviruses in clinical and environmental samples. AB - Circulation of human noroviruses in water environments is suspected to be genotype-dependent, but the established primer and probe sets for noroviruses are usually genogroup-specific, which do not allow to compare the genotype-specific properties, such as persistence in water environments and resistance to disinfectants. In this study, quantitative PCR assays were designed for genotype specific quantification of four epidemiologically important genotypes, GII.3, GII.4, GII.6, and GII.17. Developed assays were tested using norovirus positive stool samples which were previously confirmed to present target genotypes of this study. The results were 100% in accordance with the previous results. Effect of the co-existence of multiple genotypes in a sample on the target genotype quantification was evaluated using composite stool samples and wastewater samples containing multiple genotypes and the presence of non-target genotypes didn't affect the quantification of target genotype. Sensitivity and specificity was 100% for all four assays developed in this study with no cross-reactions between genotypes demonstrating the validity of our assays and their applicability to clinical and environmental samples. PMID- 29496456 TI - Formulation of a poorly water-soluble drug in sustained-release hollow granules with a high viscosity water-soluble polymer using a fluidized bed rotor granulator. AB - Water-soluble polymers with high viscosity are frequently used in the design of sustained-release formulations of poorly water-soluble drugs to enable complete release of the drug in the gastrointestinal tract. Tablets containing matrix granules with a water-soluble polymer are preferred because tablets are easier to handle and the multiple drug-release units of the matrix granules decreases the influences of the physiological environment on the drug. However, matrix granules with a particle size of over 800 MUm sometimes cause a content uniformity problem in the tableting process because of the large particle size. An effective method of manufacturing controlled-release matrix granules with a smaller particle size is desired. The aim of this study was to develop tablets containing matrix granules with a smaller size and good controlled-release properties, using phenytoin as a model poorly water-soluble drug. We adapted the recently developed hollow spherical granule granulation technology, using water-soluble polymers with different viscosities. The prepared granules had an average particle size of 300 MUm and sharp particle size distribution (relative width: 0.52-0.64). The values for the particle strength of the granules were 1.86-1.97 N/mm2, and the dissolution profiles of the granules were not affected by the tableting process. The dissolution profiles and the blood concentration levels of drug released from the granules depended on the viscosity of the polymer contained in the granules. We succeeded in developing the desired controlled-release granules, and this study should be valuable in the development of sustained-release formulations of poorly water-soluble drugs. PMID- 29496457 TI - Size-based anti-tumoral effect of paclitaxel loaded albumin microparticle dry powders for inhalation to treat metastatic lung cancer in a mouse model. AB - In this study, we prepared paclitaxel (PTX) loaded bovine serum albumin (BSA) microparticles (MPs) of different sizes (0.5, 1.0, and 3.0 um) and converted them into dry powders (DPs) of a uniform size (~5.0 um) through spray-drying techniques. The aim of preparing different sized PTX-MPs is to investigate the size-based in vivo biodistribution and retention of PTX in the lungs after intratracheal administration. Following the in vitro characterizations, the anti tumor efficacy of the DPs containing differently sized PTX-BSA-MPs administered through intratracheal insufflation was compared with intravenously administered PTX solution (Taxol). While the fastest drug release was found for the 0.5 um group, the 1.0 and 3.0 MUm groups showed the highest anti-tumor efficiency in vivo. Taken together, our results demonstrate that the initial particle size of the incorporated particles, i.e., MPs, is crucial for the anti-tumor efficacy of DPs administered by inhalation, and the initial particle size should be regarded as one of the key factors in the development and quality control of such preparations. PMID- 29496458 TI - Aerosol characterisation of nebulised liposomes co-loaded with erlotinib and genistein using an abbreviated cascade impactor method. AB - Erlotinib and genistein co-loaded liposomes were prepared by the thin-film hydration method. The effect of probe sonication as a size reduction method on drug incorporation and the properties of aerosols generated using air-jet and vibrating-mesh nebulisers was studied. The use of the Next Generation Impactor (NGI) to characterise inhaler formulations is limited by the need accurately to quantify drug deposited across 8 stages and is labour intensive to use. The Fast Screening Impactor (FSI) comprising two impaction stages was compared with the NGI to evaluate its applicability as a simple screening and labour-saving tool to characterise nebulised systems. For the developed liposomal formulations, an air jet nebuliser generated a two-fold higher fine particle fraction (FPF) than a vibrating-mesh nebuliser. The findings demonstrated that the cooled FSI (5 degrees C) operated at 15 L/min was effective in differentiating the aerosol properties of the nebulised liposome formulations investigated. Overall, the optimised co-loaded liposomes were more effectively delivered by an air-jet nebuliser, than from a vibrating-mesh nebuliser over a 10 min period as determined using the abbreviated impactor. PMID- 29496459 TI - Mesenchymal Stem Cell-derived Neural Progenitor Cells in Progressive Multiple Sclerosis: Great Expectations. PMID- 29496461 TI - Adenovirus-specific T-lymphocyte efficacy in the presence of methylprednisolone: An in vitro study. AB - Virus-specific T-cell (VST) infusion becomes a promising alternative treatment for refractory viral infections after hematopoietic stem cell transplantation (HSCT). However, VSTs are often infused during an immunosuppressive treatment course, especially corticosteroids, which are a first-line curative treatment of graft-versus-host disease (GVHD). We were interested in whether corticosteroids could affect adenovirus (ADV)-VST functions. After interferon (IFN)-gamma based immunomagnetic selection, ADV-VSTs were in vitro expanded according to three different culture conditions: without methylprednisolone (MP; n = 7), with a final concentration of MP 1 ug/mL (n = 7) or MP 2 ug/mL (n = 7) during 28 +/- 11 days. Efficacy and alloreactivity of expanded ADV-VSTs was controlled in vitro. MP transitorily inhibited ADV-VST early expansion. No impairment of specific IFN gamma secretion capacity and cytotoxicity of ADV-VSTs was observed in the presence of MP. However, specific proliferation and alloreactivity of ADV-VSTs were decreased in the presence of MP. Altogether, these results and the preliminary encouraging clinical experiences of co-administration of MP 1 mg/kg and ADV-VSTs will contribute to safe and efficient use of anti-viral immunotherapy. PMID- 29496460 TI - Performance and precision of double digestion RAD (ddRAD) genotyping in large multiplexed datasets of marine fish species. AB - The development of Genotyping-By-Sequencing (GBS) technologies enables cost effective analysis of large numbers of Single Nucleotide Polymorphisms (SNPs), especially in "non-model" species. Nevertheless, as such technologies enter a mature phase, biases and errors inherent to GBS are becoming evident. Here, we evaluated the performance of double digest Restriction enzyme Associated DNA (ddRAD) sequencing in SNP genotyping studies including high number of samples. Datasets of sequence data were generated from three marine teleost species (>5500 samples, >2.5 * 1012 bases in total), using a standardized protocol. A common bioinformatics pipeline based on STACKS was established, with and without the use of a reference genome. We performed analyses throughout the production and analysis of ddRAD data in order to explore (i) the loss of information due to heterogeneous raw read number across samples; (ii) the discrepancy between expected and observed tag length and coverage; (iii) the performances of reference based vs. de novo approaches; (iv) the sources of potential genotyping errors of the library preparation/bioinformatics protocol, by comparing technical replicates. Our results showed use of a reference genome and a posteriori genotype correction improved genotyping precision. Individual read coverage was a key variable for reproducibility; variance in sequencing depth between loci in the same individual was also identified as an important factor and found to correlate to tag length. A comparison of downstream analysis carried out with ddRAD vs single SNP allele specific assay genotypes provided information about the levels of genotyping imprecision that can have a significant impact on allele frequency estimations and population assignment. The results and insights presented here will help to select and improve approaches to the analysis of large datasets based on RAD-like methodologies. PMID- 29496462 TI - Completely serum-free and chemically defined adipocyte development and maintenance. AB - BACKGROUND AIMS: In vitro engineered adipose tissue is in great demand to treat lost or damaged soft tissue or to screen for new drugs, among other applications. However, today most attempts depend on the use of animal-derived sera. To pave the way for the application of adipose tissue-engineered products in clinical trials or as reliable and robust in vitro test systems, sera should be completely excluded from the production process. In this study, we aimed to develop an in vitro adipose tissue model in the absence of sera and maintain its function long term. METHODS: Human adipose tissue-derived stem cells were expanded and characterized in a xeno- and serum-free environment. Adipogenic differentiation was induced using a completely defined medium. Developed adipocytes were maintained in a completely defined maturation medium for additional 28 days. In addition to cell viability and adherence, adipocyte-specific markers such as perilipin A expression or leptin release were evaluated. RESULTS: The defined differentiation medium enhanced cell adherence and lipid accumulation at a significant level compared with the corresponding negative control. The defined maturation medium also significantly supported cell adherence and functional adipocyte maturation during the long-term culture period. CONCLUSIONS: The process described here enables functional adipocyte generation and maintenance without the addition of unknown or animal-derived constituents, achieving an important milestone in the introduction of adipose tissue-engineered products into clinical trials or in vitro screening. PMID- 29496463 TI - Atopic dermatitis is an important comorbidity in severe asthma. PMID- 29496464 TI - Bronchiectasis in severe asthma: Clinical features and outcomes. AB - BACKGROUND: Bronchiectasis is increasingly being identified in patients with severe asthma and could contribute to disease severity. OBJECTIVE: To determine the prevalence of bronchiectasis in a population of patients with severe asthma and to better characterize the clinical features of these patients and their outcomes. METHODS: We retrospectively reviewed the medical files of 184 subjects with confirmed severe asthma who had undergone high-resolution thoracic computed tomography and compared the characteristics and outcomes of subjects with and without bronchiectasis. RESULTS: Bronchiectasis was identified in 86 patients (47%). These patients had concomitant hypersensitivity to nonsteroidal anti inflammatory drugs (odds ratio [OR] 2.24, 95% confidence interval [CI] 1.00-5.03) and gastroesophageal reflux disease (OR 1.89, 95% CI 1.05-3.41) more frequently than subjects without bronchiectasis, but had less atopic dermatitis (OR 0.188, 95% CI 0.04-0.88). Subjects with bronchiectasis were more frequently hospitalized for asthma exacerbations (OR 2.09, 95% CI 1.08-4.05) and had higher blood eosinophil levels (464 vs 338; P = .005) than subjects without bronchiectasis. CONCLUSION: Our study suggests that in subjects with severe asthma, the presence of bronchiectasis is associated with more frequent hospitalizations, concomitant gastroesophageal reflux disease, hypersensitivity to nonsteroidal anti inflammatory drugs, and higher blood eosinophil counts. Bronchiectasis could represent an additional phenotypic feature of severe eosinophilic asthma. PMID- 29496465 TI - Treatment of hypereosinophilic syndrome and eosinophilic dermatitis with reslizumab. PMID- 29496466 TI - Risk factors and outcomes of pyogenic liver abscess in adult liver recipients: a matched case-control study. AB - BACKGROUND: Adult liver recipients (ALR) differ from the general population with pyogenic liver abscess (PLA) as they exhibit: reconstructed biliary anatomy, recurrent hospitalizations, poor clinical condition and are subjected to immunosuppression. The aim of this study was to identify risk factors associated with PLA in ALR and to analyze the management experience of these patients. METHODS: Between 1996 and 2016, 879 adult patients underwent liver transplantation (LT), 26 of whom developed PLA. Patients and controls were matched according to the time from transplant to abscess in a 1 to 5 relation. A logistic regression model was performed to establish PLA risk factors considering clusters for matched cases and controls. Risk factors were identified and a multivariate regression analysis performed. RESULTS: Patients with post-LT PLA were more likely to have lower BMI (p = 0.006), renal failure (p = 0.031) and to have undergone retransplantation (p = 0.002). A history of hepatic artery thrombosis (p = 0.010), the presence of Roux en-Y hepatojejunostomy (p < 0.001) and longer organ ischemia time (p = 0.009) were independent predictors for the development of post-LT PLA. Five-year survival was 49% (95%CI 28-67%) and 89% (95%CI 78%-94%) for post-LT PLA and no post-LT PLA, respectively (p < 0.001). CONCLUSION: history of hepatic artery thrombosis, the presence of hepatojejunostomy and a longer ischemia time represent independent predictors for the development of post-LT PLA. There was a significantly poorer survival in patients who developed post-LT PLA compared with those who did not. PMID- 29496467 TI - Manufacturing of a novel double-function ssDNA aptamer for sensitive diagnosis and efficient neutralization of SEA. AB - Staphylococcal enterotoxin A (SEA) is an enterotoxin produced mainly by Staphylococcus aureus. In recent years, it has become the most prevalent compound for staphylococcal food poisoning (SFP) around the world. In this study, we isolate new dual-function single-stranded DNA (ssDNA) aptamers by using some new methods, such as the Taguchi method, by focusing on the detection and neutralization of SEA enterotoxin in food and clinical samples. For the asymmetric polymerase chain reaction (PCR) optimization of each round of systematic evolution of ligands by exponential enrichment (SELEX), we use Taguchi L9 orthogonal arrays, and the aptamer mobility shift assay (AMSA) is used for initial evaluation of the protein-DNA interactions on the last SELEX round. In our investigation the dissociation constant (KD) value and the limit of detection (LOD) of the candidate aptamer were found to be 8.5 +/- 0.91 of nM and 5 ng/ml using surface plasmon resonance (SPR). In the current study, the Taguchi and mobility shift assay methods were innovatively harnessed to improve the selection process and evaluate the protein-aptamer interactions. To the best of our knowledge, this is the first report on employing these two methods in aptamer technology especially against bacterial toxin. PMID- 29496468 TI - Exercise and other nonpharmacological strategies to reduce blood pressure in older adults: a systematic review and meta-analysis. AB - The incidence of hypertension increases with advancing age and represents a significant burden of disease. Lifestyle modification represents the first-line intervention in treatment algorithms; however, the majority of evidence for this comes from studies involving young participants using interventions that may not always be feasible in the elderly. This manuscript presents a systematic review of all randomized controlled trials involving participants with a mean age of 65 or over investigating nonpharmacological strategies to reduce blood pressure (BP). Fifty-three randomized controlled trials were included. The majority of interventions described aerobic exercise training, dynamic resistance exercise training, or combined aerobic and dynamic resistance exercise training (COM), with limited studies reporting isometric exercise training or alternative lifestyle strategies. Aerobic exercise training, dynamic resistance exercise training, COM, and isometric exercise training all elicited significant reductions in both systolic and diastolic BP, with no additional benefit of COM compared with single modality exercise training. Three months of traditional exercise-based lifestyle intervention may produce a reduction in BP of approximately 5 mmHg systolic and 3 mmHg diastolic in older individuals, similar to that expected in younger individuals. PMID- 29496469 TI - In-ovo exposed carbon black nanoparticles altered mRNA gene transcripts of antioxidants, proinflammatory and apoptotic pathways in the brain of chicken embryos. AB - With ubiquitous applications of nanotechnology, there are increasing probabilities of exposure to manufactured nanoparticles (NPs), which might be posing emerging health concerns on the next generation. Recent data suggest that generation of reactive oxygen species may play an integral role in the carbon black nanoparticles (CBNPs)-induced oxidative injury; however, the exact molecular mechanism has not been clarified. Hence, the role of oxidative stress, inflammation and apoptosis pathways in the CBNPs-induced neuronal toxicity following in-ovo exposure of chicken embryo was elucidated. Specific pathogen free fertilized Sasso eggs were inoculated with 4.8, 9.5 and 14 MUg CBNPs/egg at the 3rd day of incubation alongside vehicle controls. In a concentration dependent manner, CBNPs inoculation induced oxidative stress, which was ascertained by enhancement of lipid peroxides and diminishing total antioxidant capacity and glutathione levels, and catalase activity in brain tissues. mRNA transcript levels of antioxidant genes showed up-regulation of heme oxygenase-1 and superoxide dismutase-1, with marked down-regulation of glutathione S transferase-alpha. Additionally, the pro-inflammatory genes; nuclear factor kappaB1 was up-regulated, while interferon-gamma was down-regulated. There is also a clear down-regulation in apoptotic markers caspase-8, caspase-3, cytochrome c and B-cell CLL/lymphoma 2 at the different concentrations, while caspase-2 is up-regulated only at higher concentration. Collectively, these results show that CBNPs exposure-mediated overproduction of the free radicals, particularly at higher concentration contributes to inflammation and subsequent cellular apoptosis at the gene expression level, thus unveiling possible molecular relationship between CBNPs and genes linked to the oxidant, inflammatory and apoptotic responses. PMID- 29496471 TI - When Clinical Trials Disagree. PMID- 29496470 TI - Cystic Renal Cell Carcinoma: A Report on Outcomes of Surgery and Active Surveillance in Patients Retrospectively Identified on Pretreatment Imaging. AB - PURPOSE: We evaluated the outcomes of surgical intervention and active surveillance in patients diagnosed with cystic renal cell carcinoma at our hypothesized radiological cutoff of greater than 50% cystic. MATERIALS AND METHODS: We identified all 430 patients with a pathologically confirmed cystic renal mass that fit our criteria from 2000 to 2015. The 292 patients with a lack of computerized tomography, tumors less than 50% cystic on imaging, multifocal tumors and prior renal cell carcinoma were excluded from study. Patients were stratified into benign or malignant subgroups, and radiological, clinicopathological and oncologic features were determined. Univariate and multivariate associations between clinicoradiological parameters in each group were analyzed. We similarly reviewed the records of a separate cohort of patients treated with active surveillance for cystic renal cell carcinoma. RESULTS: Of the 138 identified cases of cystic renal cell carcinoma 102 (73.9%) were renal cell carcinoma and 36 (26.1%) were benign masses. Of the tumors 77.5% were Fuhrman grade 1-2, 83.4% were stage pT2 or less and 65.9% showed clear cell histology. On univariate analysis male gender, a solid component and increasing Bosniak classification were significant for malignancy. In a separate cohort we identified 38 patients on active surveillance. The growth rate was 1.0 mm per year overall and 2.3 mm per year for the solid component. At a median followup of more than 4 years in all cohorts there was no evidence of recurrence or metastasis of cystic renal cell carcinoma. CONCLUSIONS: Patients with unifocal cystic renal cell carcinoma evaluated using a standardized radiological threshold of greater than 50% cystic had an excellent prognosis on active surveillance and after surgical resection. PMID- 29496473 TI - Etonogestrel implant use in women primarily choosing a combined oral contraceptive pill: A proof-of-concept trial. AB - OBJECTIVE: We evaluated a novel concept of initiating the etonogestrel implant as a "back-up" method in women who desire using combined oral contraceptives (COC) but want to decrease their risk of unintended pregnancy with a more effective method. STUDY DESIGN: In this prospective cohort study, we planned to include 20 women as a proof-of-concept. We enrolled both new COC starters and continuing COC users and placed an etonogestrel implant. Participants completed daily bleeding diaries and attended follow-up visits at 1, 3, and 6 months. We assessed implant continuation through six months of study participation and side effects with dual hormonal contraceptive use. RESULTS: Between September and December 2016, we enrolled 10 new starters and 10 current COC users. All participants completed 1 month follow-up, and 18 (90%) subjects completed the 3- and 6-month follow-up assessments. Two current COC users had the implant removed for mood changes before 6 months. At the 6-month follow-up visit, 10 women were using both pills and implant, seven relied on the implant only, and one was using a COC only. Three new starters chose implant removal at end of study participation; one for weight gain and acne, another for mood changes, and one for decreased libido. No subjects discontinued the implant for bleeding complaints. CONCLUSION: In this proof-of-concept study, women using COCs were willing to initiate the implant as a "back-up" method to improve pregnancy prevention. Most women continued the implant through 6 months and after completing study participation. IMPLICATIONS: Initiating the etonogestrel implant as a "back-up" method may be an option for women who desire more effective pregnancy prevention while using combined oral contraceptive pills for its bleeding profile or non-contraceptive benefits. PMID- 29496472 TI - Effect of fenofibrate on uric acid and gout in type 2 diabetes: a post-hoc analysis of the randomised, controlled FIELD study. AB - BACKGROUND: Gout is a painful disorder and is common in type 2 diabetes. Fenofibrate lowers uric acid and reduces gout attacks in small, short-term studies. Whether fenofibrate produces sustained reductions in uric acid and gout attacks is unknown. METHODS: In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial, participants aged 50-75 years with type 2 diabetes were randomly assigned to receive either co-micronised fenofibrate 200 mg once per day or matching placebo for a median of 5 years follow-up. We did a post-hoc analysis of recorded on-study gout attacks and plasma uric acid concentrations according to treatment allocation. The outcomes of this analysis were change in uric acid concentrations and risk of on-study gout attacks. The FIELD study is registered with ISRCTN, number ISRCTN64783481. FINDINGS: Between Feb 23, 1998, and Nov 3, 2000, 9795 patients were randomly assigned to fenofibrate (n=4895) or placebo (n=4900) in the FIELD study. Uric acid concentrations fell by 20.2% (95% CI 19.9-20.5) during the 6-week active fenofibrate run-in period immediately pre randomisation (a reduction of 0.06 mmol/L or 1 mg/dL) and remained -20.1% (18.5 21.7, p<0.0001) lower in patients taking fenofibrate than in those on placebo in a random subset re-measured at 1 year. With placebo allocation, there were 151 (3%) first gout events over 5 years, compared with 81 (2%) among those allocated fenofibrate (HR with treatment 0.54, 95% CI 0.41-0.70; p<0.0001). In the placebo group, the cumulative proportion of patients with first gout events was 7.7% in patients with baseline uric acid concentration higher than 0.36 mmol/L and 13.9% in those with baseline uric acid concentration higher than 0.42 mmol/L, compared with 3.4% and 5.7%, respectively, in the fenofibrate group. Risk reductions were similar among men and women and those with dyslipidaemia, on diuretics, and with elevated uric acid concentrations. For participants with elevated baseline uric acid concentrations despite taking allopurinol at study entry, there was no heterogeneity of the treatment effect of fenofibrate on gout risk. Taking account of all gout events, fenofibrate treatment halved the risk (HR 0.48, 95% CI 0.37 0.60; p<0.0001) compared with placebo. INTERPRETATION: Fenofibrate lowered uric acid concentrations by 20%, and almost halved first on-study gout events over 5 years of treatment. Fenofibrate could be a useful adjunct for preventing gout in diabetes. FUNDING: None. PMID- 29496474 TI - Generation of variation and a modified mean fitness principle: Necessity is the mother of genetic invention. AB - Generation of variation may be detrimental in well-adapted populations evolving under constant selection. In a constant environment, genetic modifiers that reduce the rate at which variation is generated by processes such as mutation and migration, succeed. However, departures from this reduction principle have been demonstrated. Here we analyze a general model of evolution under constant selection where the rate at which variation is generated depends on the individual. We find that if a modifier allele increases the rate at which individuals of below-average fitness generate variation, then it will increase in frequency and increase the population mean fitness. This principle applies to phenomena such as stress-induced mutagenesis and condition-dependent dispersal, and exemplifies "Necessity is the mother of genetic invention." PMID- 29496475 TI - PI3K signaling pathways modulated white spot syndrome virus (WSSV) replication in Procambarus clarkii. AB - The PI3K/AKT signaling pathway is commonly exploited to regulate viral replication and affect the fate of infected cells. In the present study, a PI3K specific inhibitor (LY294002) was employed to pretreat crayfish to evaluate the effects of PI3K/AKT signaling pathway in WSSV replication. The results showed that the WSSV copy numbers in crayfish pretreated with LY294002 were significantly lower than those in Tris-HCl pretreatment crayfish on the sixth and tenth day after WSSV infection. In semigranular cells, the apoptosis rates were up-regulated on the third day post-WSSV infection, and a significantly lower proportion of apoptosis cells were observed in LY294002-pretreatment group. The expression level of Bax, Bax inhibitor-1 and lectin mRNA in haemocytes of crayfish were increased after WSSV infection. After the secondary stimulation with Tris-HCl, the Bax expression level in LY294002-pretreatment crayfish was significantly higher than that of crayfish pretreated with Tris-HCl on the third or sixth day, but the Toll and lectin mRNA expression decreased significantly on the third, sixth and tenth day. The Bax mRNA expression levels in LY294002-WSSV group were significantly higher than those in Tris-HCl-WSSV group on the third and tenth day. The Bax inhibitor-1 mRNA expression levels in LY294002-WSSV group were significantly lower than those in Tris-HCl-WSSV crayfish on the third day. These results together indicated that the hosts PI3K/AKT signaling pathway play positive roles in WSSV replication through the balance between host cell apoptois and innate immune responses. This information is helpful to further understand the role of PI3K/AKT signaling pathway on WSSV replication in Decapoda crustaceans. PMID- 29496476 TI - Introduction. AB - The Adolescent Brain Cognitive Development (ABCD) Study is a longitudinal, observational study of over 10,000 youth recruited at 21 sites throughout the United States. Comprehensive biennial assessments and more limited interim assessments measure health, mental health, neurocognition, family, cultural and environmental variables, substance use, genetic and other biomarkers, and structural and functional brain development. Within this Special Issue, readers will find much information about the rationale and objectives of the study, the broad ranging assessment protocols and new as well as traditional methodologies applied at baseline, the recruitment and retention strategies, and the anticipated final composition of the cohort. Information is also provided about how the study is coordinated and conducted, how decisions are made, how data quality is monitored, and how ethical standards are protected. In this introduction we will focus instead on the position of the ABCD Study in the changing landscape of biomedical research. PMID- 29496477 TI - Activation of immediate early genes by nicotine after chronic neonatal nicotine exposure in brain areas involved in stress and anxiety responses. AB - Maternal smoking has negative long-term consequences on affective behaviors, and in rodents, chronic neonatal nicotine exposure (CNN) results in increased anxiety. In rat pups, acute nicotine stimulation activates brain regions associated with stress and anxiety, but chronic nicotine exposure could desensitize of nicotinic acetylcholine receptors, the molecular target of nicotine. Here, we determined whether CNN affected neuronal activation by an acute nicotine challenge. Using in situ hybridization, we analyzed mRNA expression of the immediate-early genes (IEGs) c-Fos, Arc, Egr-1 and Npas4, which are markers for neuronal activation and implicated in synaptic plasticity. Following CNN (6 mg/kg/day) or control treatment from postnatal day (P)1 to P7, an acute i.p. nicotine (0.7 mg/kg) or saline injection (control) was administered on P8, and brains collected after 30 min. In drug-naive pups, acute nicotine stimulated IEGs expression specifically in brain areas associated with innate anxiety including the paraventricular hypothalamic nucleus, central nucleus of the amygdala (CeA), and locus coeruleus (LC). Following CNN, acute nicotine stimulated IEG expression in all three areas, but activation was significantly reduced in the LC (c-Fos, Egr-1, Npas4), and CeA (c-Fos). Notably, nicotine induced Npas4 expression was greatly diminished in the LC, which may affect inhibitory synapse formation in noradrenergic neurons. Thus, after CNN, neurons located in areas associated with anxiety brain circuitry maintained responsiveness to nicotine, but tolerance differentially developed to nicotine. In the developing brain, repeated activation by nicotine of areas related to limbic pathways could alter circuit connectivity and increase responsiveness to stress and anxiety later in life. PMID- 29496478 TI - Non-pharmacological treatment affects neuropeptide expression in neuropathic pain model. AB - Chronic constriction injury (CCI) of the sciatic nerve elicits changes in neuropeptide expression on the dorsal root ganglia (DRG). The neural mobilization (NM) technique is a noninvasive method that has been proven clinically effective in reducing pain. The aim of this study was to analyze the expression of substance P, transient receptor potential vanilloid 1 (TRPV1) and opioid receptors in the DRG of rats with chronic constriction injury and to compare it to animals that received NM treatment. CCI was performed on adult male rats. Each animal was submitted to 10 sessions of neural mobilization every other day, starting 14 days after the CCI injury. At the end of the sessions, the DRG (L4 L6) were analyzed using Western blot assays for substance P, TRPV1 and opioid receptors (u-opioid receptor, delta-opioid receptor and kappa-opioid receptor). We observed a decreased substance P and TRPV1 expression (48% and 35%, respectively) and an important increase of u-opioid receptor expression (200%) in the DRG after NM treatment compared to control animals. The data provide evidence that NM promotes substantial changes in neuropeptide expression in the DRG; these results may provide new options for treating neuropathic pain. PMID- 29496479 TI - Multisensory cortical processing and dysfunction across the neuropsychiatric spectrum. AB - Sensory processing is affected in multiple neuropsychiatric disorders like schizophrenia and autism spectrum disorders. Genetic and environmental factors guide the formation and fine-tuning of brain circuitry necessary to receive, organize, and respond to sensory input in order to behave in a meaningful and consistent manner. During certain developmental stages the brain is sensitive to intrinsic and external factors. For example, disturbed expression levels of certain risk genes during critical neurodevelopmental periods may lead to exaggerated brain plasticity processes within the sensory circuits, and sensory stimulation immediately after birth contributes to fine-tuning of these circuits. Here, the neurodevelopmental trajectory of sensory circuit development will be described and related to some example risk gene mutations that are found in neuropsychiatric disorders. Subsequently, the flow of sensory information through these circuits and the relationship to synaptic plasticity will be described. Research focusing on the combined analyses of neural circuit development and functioning are necessary to expand our understanding of sensory processing and behavioral deficits that are relevant across the neuropsychiatric spectrum. PMID- 29496480 TI - Coordinate regulation of retinoic acid synthesis by pbx genes and fibroblast growth factor signaling by hoxb1b is required for hindbrain patterning and development. AB - The vertebrate hindbrain is composed of a series of lineage-restricted segments termed rhombomeres. Segment-specific gene expression drives unique programs of neuronal differentiation. Two critical embryonic signaling pathways, Fibroblast Growth Factor (FGF) and Retinoic Acid (RA), regulate early embryonic rhombomere patterning. The earliest expressed hox genes, hoxb1b and hoxb1a in zebrafish, are logical candidates for establishing signaling networks that specify segmental identity. We sought to determine the mechanism by which hox genes regulate hindbrain patterning in zebrafish. We demonstrate that hoxb1a regulates r4 specific patterning, while hoxb1b regulates rhombomere segmentation and size. Hoxb1a and hoxb1b redundantly regulate vhnf1 expression. Loss of hoxb1b together with pbx4 reverts the hindbrain to a groundstate identity, demonstrating the importance of hox genes in patterning nearly the entire hindbrain, and a key requirement for Pbx in this process. Additionally, we provide evidence that while pbx genes regulate RA signaling, hoxb1b regulates hindbrain identity through complex regulation of FGF signaling. PMID- 29496481 TI - Risk of thromboembolic events in patients treated with thalidomide for cutaneous lupus erythematosus: A multicenter retrospective study. PMID- 29496482 TI - The HLA-DQB1*03:01 Is Associated with Bullous Pemphigoid in the Han Chinese Population. PMID- 29496483 TI - Epigenetic plasticity of eosinophils and other immune cell subsets in childhood asthma. PMID- 29496484 TI - COPD beyond smoking: new paradigm, novel opportunities. PMID- 29496487 TI - Neural correlates of dietary self-control in healthy adults: A meta-analysis of functional brain imaging studies. AB - Self-control is known to influence food intake and body weight. Neuroimaging studies have used tasks that tap into different aspects of self-control. Here we conducted a coordinate-based meta-analysis on functional magnetic resonance imaging studies to identify brain regions associated with dietary self-control. Additionally, we tested the effect of task by comparing two widely used paradigms that require either (1) voluntary suppression of an appetitive response to cues, predominantly assessing inhibitory control or (2) food decision-making, where cognitive value modulation is targeted. Core brain regions related to dietary self-control included the anterior insula, inferior and middle frontal gyrus, supplementary motor cortex and parietal cortices. Dorsolateral prefrontal cortex was among regions that showed reduced activation during self-control as a function of body mass index. In addition, the two types of dietary self-control tasks recruited common brain regions making up the core self-control network as well as distinctive regions belonging predominantly to cingulo-opercular or fronto-parietal network. Taken together, our findings provide evidence for the presence of core brain regions related to dietary self-control as well as the involvement of distinct areas depending on the target process of self-control. PMID- 29496485 TI - DNA methylation in childhood asthma: an epigenome-wide meta-analysis. AB - BACKGROUND: DNA methylation profiles associated with childhood asthma might provide novel insights into disease pathogenesis. We did an epigenome-wide association study to assess methylation profiles associated with childhood asthma. METHODS: We did a large-scale epigenome-wide association study (EWAS) within the Mechanisms of the Development of ALLergy (MeDALL) project. We examined epigenome-wide methylation using Illumina Infinium Human Methylation450 BeadChips (450K) in whole blood in 207 children with asthma and 610 controls at age 4-5 years, and 185 children with asthma and 546 controls at age 8 years using a cross sectional case-control design. After identification of differentially methylated CpG sites in the discovery analysis, we did a validation study in children (4-16 years; 247 cases and 2949 controls) from six additional European cohorts and meta analysed the results. We next investigated whether replicated CpG sites in cord blood predict later asthma in 1316 children. We subsequently investigated cell type-specific methylation of the identified CpG sites in eosinophils and respiratory epithelial cells and their related gene-expression signatures. We studied cell-type specificity of the asthma association of the replicated CpG sites in 455 respiratory epithelial cell samples, collected by nasal brushing of 16-year-old children as well as in DNA isolated from blood eosinophils (16 with asthma, eight controls [age 2-56 years]) and compared this with whole-blood DNA samples of 74 individuals with asthma and 93 controls (age 1-79 years). Whole blood transcriptional profiles associated with replicated CpG sites were annotated using RNA-seq data of subsets of peripheral blood mononuclear cells sorted by fluorescence-activated cell sorting. FINDINGS: 27 methylated CpG sites were identified in the discovery analysis. 14 of these CpG sites were replicated and passed genome-wide significance (p<1.14 * 10-7) after meta-analysis. Consistently lower methylation levels were observed at all associated loci across childhood from age 4 to 16 years in participants with asthma, but not in cord blood at birth. All 14 CpG sites were significantly associated with asthma in the second replication study using whole-blood DNA, and were strongly associated with asthma in purified eosinophils. Whole-blood transcriptional signatures associated with these CpG sites indicated increased activation of eosinophils, effector and memory CD8 T cells and natural killer cells, and reduced number of naive T cells. Five of the 14 CpG sites were associated with asthma in respiratory epithelial cells, indicating cross-tissue epigenetic effects. INTERPRETATION: Reduced whole blood DNA methylation at 14 CpG sites acquired after birth was strongly associated with childhood asthma. These CpG sites and their associated transcriptional profiles indicate activation of eosinophils and cytotoxic T cells in childhood asthma. Our findings merit further investigations of the role of epigenetics in a clinical context. FUNDING: EU and the Seventh Framework Programme (the MeDALL project). PMID- 29496486 TI - Developing DNA methylation-based diagnostic biomarkers. AB - An emerging paradigm shift for disease diagnosis is to rely on molecular characterization beyond traditional clinical and symptom-based examinations. Although genetic alterations and transcription signature were first introduced as potential biomarkers, clinical implementations of these markers are limited due to low reproducibility and accuracy. Instead, epigenetic changes are considered as an alternative approach to disease diagnosis. Complex epigenetic regulation is required for normal biological functions and it has been shown that distinctive epigenetic disruptions could contribute to disease pathogenesis. Disease-specific epigenetic changes, especially DNA methylation, have been observed, suggesting its potential as disease biomarkers for diagnosis. In addition to specificity, the feasibility of detecting disease-associated methylation marks in the biological specimens collected noninvasively, such as blood samples, has driven the clinical studies to validate disease-specific DNA methylation changes as a diagnostic biomarker. Here, we highlight the advantages of DNA methylation signature for diagnosis in different diseases and discuss the statistical and technical challenges to be overcome before clinical implementation. PMID- 29496488 TI - Clinical transplant tolerance: Coming of age. PMID- 29496489 TI - Xenobiotic metabolism in the fish hepatic cell lines Hepa-E1 and RTH-149, and the gill cell lines RTgill-W1 and G1B: Biomarkers of CYP450 activity and oxidative stress. AB - The use of fish cell cultures has proven to be an effective tool in the study of environmental and aquatic toxicology. Valuable information can be obtained from comparisons between cell lines from different species and organs. In the present study, specific chemicals were used and biomarkers (e.g. 7-Ethoxyresorufin-O deethylase (EROD) activity and reactive oxygen species (ROS)) were measured to assess the metabolic capabilities and cytotoxicity of the fish hepatic cell lines Hepa-E1 and RTH-149, and the fish gill cell lines RTgill-W1 and G1B. These cell lines were exposed to beta-naphthoflavone (BNF) and benzo[a]pyrene (BaP), the pharmaceutical tamoxifen (TMX), and the organic peroxide tert-butylhydroperoxide (tBHP). Cytotoxicity in gill cell lines was significantly higher than in hepatic cells, with BNF and TMX being the most toxic compounds. CYP1-like associated activity, measured through EROD activity, was only detected in hepatic cells; Hepa-E1 cells showed the highest activity after exposure to both BNF and BaP. Significantly higher levels of CYP3A-like activity were also observed in Hepa-E1 cells exposed to TMX, while gill cell lines presented the lowest levels. Measurements of ROS and antioxidant enzymes indicated that peroxide levels were higher in gill cell lines in general. However, levels of superoxide were significantly higher in RTH-149 cells, where no distinctive increase of superoxide-related antioxidants was observed. The present study demonstrates the importance of selecting adequate cell lines in measuring specific metabolic parameters and provides strong evidence for the fish hepatocarcinoma Hepa-E1 cells to be an excellent alternative in assessing metabolism of xenobiotics, and in expanding the applicability of fish cell lines for in vitro studies. PMID- 29496490 TI - A matrix metalloproteinase 9 (MMP9) gene single nucleotide polymorphism is associated with predisposition to tick-borne encephalitis virus-induced severe central nervous system disease. AB - The progression of infectious diseases depends on causative agents, the environment and the host's genetic susceptibility. To date, human genetic susceptibility to tick-borne encephalitis (TBE) virus-induced disease has not been sufficiently studied. We have combined whole-exome sequencing with a candidate gene approach to identify genes that are involved in the development of predisposition to TBE in a Russian population. Initially, six exomes from TBE patients with severe central nervous system (CNS) disease and seven exomes from control individuals were sequenced. Despite the small sample size, two nonsynonymous single nucleotide polymorphisms (SNPs) were significantly associated with TBE virus-induced severe CNS disease. One of these SNPs is rs6558394 (G/A, Pro422Leu) in the scribbled planar cell polarity protein (SCRIB) gene and the other SNP is rs17576 (A/G, Gln279Arg) in the matrix metalloproteinase 9 (MMP9) gene. Subsequently, these SNPs were genotyped in DNA samples of 150 non-immunized TBE patients with different clinical forms of the disease from two cities and 228 control randomly selected samples from the same populations. There were no statistically significant differences in genotype and allele frequencies between the case and control groups for rs6558394. However, the frequency of the rs17576 G allele was significantly higher in TBE patients with severe CNS diseases such as meningo-encephalitis (43.5%) when compared with TBE patients with milder meningitis (26.3%; P = 0.01), as well as with the population control group (32.5%; P = 0.042). The results suggest that the MMP9 gene may affect genetic predisposition to TBE in a Russian population. PMID- 29496491 TI - A fatal case of Babesia divergens infection in Northwestern Spain. AB - We describe a fatal case caused by the intra-erythrocytic Babesia divergens parasite in an elderly woman. This is the third case of fatal babesiosis reported in the last 15 years in Europe, and the only one in a patient with an intact spleen. PMID- 29496492 TI - Quantitative proteomics of CSF reveals potential predicted biomarkers for extranodal NK-/T-cell lymphoma of nasal-type with ethmoidal sinus metastasis. AB - AIM: Extranodal natural killer cell/T-cell lymphoma of nasal-type (NKTCL) is an aggressive human lymphoma, but its predicted biomarkers after chemotherapy are less known. The aim of this study is to find some potential predicted biomarkers in cerebrospinal fluid (CSF) of NKTCL patients with ethmoidal sinus metastasis (NESM). MATERIALS AND METHODS: The CSF samples were obtained from NKTCL patients with NESM before and after chemotherapy from Cancer Center of West China Hospital. Comparative proteomic profiling using label-free method was performed to characterize the fold change of proteins in NESM patients. KEY FINDING: In this study, 102 proteins with <1% false discovery rate in CSF of NKTCL with NESM patients were quantified. Furthermore, significantly reduced IGFBP2, SERP1NC1, AMBP and GPX3, as well as dramatically increased CPE levels were observed in the CSF of NKTCL patients after cytarabine chemotherapy. SIGNIFICANCE: IGFBP2, SERP1NC1, AMBP, GPX3 and CPE together or alone have a potential to be predicted indicators of NKTCL with NESM in response to chemotherapy. PMID- 29496493 TI - Axl inhibitors as novel cancer therapeutic agents. AB - Overexpression and activation of Axl receptor tyrosine kinase have been widely accepted to promote cell proliferation, chemotherapy resistance, invasion, and metastasis in several human cancers, such as lung, breast, and pancreatic cancers. Axl, a member of the TAM (Tyro3, Axl, Mer) family, and its inhibitors can specifically break the kinase signaling nodes, allowing advanced patients to regain drug sensitivity with improved therapeutic efficacy. Therefore, the research on Axl is promising and it is worthy of further investigations. In this review, we present an update on the Axl inhibitors and provide new insights into their latent application. PMID- 29496494 TI - Cilostazol alleviates streptozotocin-induced testicular injury in rats via PI3K/Akt pathway. AB - AIMS: Male infertility prevalence is higher in diabetic patients. Those patients exhibit testicular oxidative damage due to sustained hyperglycemia and inflammation. The study has investigated the efficacy of cilostazol, a phosphodiesterase 3 inhibitor, on testicular damage of diabetic rats. MAIN METHODS: Streptozotocin-induced diabetes in rats was used as a model. Six control male rats and 24 diabetic male rats were divided into the following: diabetic, cilostazol at low dose, cilostazol at high dose, and sildenafil treated rat groups. Treatment period was 4 weeks. Then, serum testosterone, testicular oxidative parameters, and testicular oxidant defenses were assayed. Real time PCR was done for quantification of Phosphoinositide 3-kinase (PI3K), Akt, and nuclear factor (NF)-kappaB mRNA. Expression of testicular inducible nitric oxide synthase (iNOS) was assessed. KEY FINDINGS: Diabetes negatively affected the testicular tissue as evident by biochemical analysis and histopathology. Four weeks of cilostazol or sildenafil treatment improved anti-oxidative capacity, ameliorated lipid peroxidation and the pro-inflammatory iNOS expression in testicular tissue. Testosterone level and the spermatogenesis showed marked improvement. Quantitative mRNA expression showed an elevation in PI3K and Akt by cilostazol with decreasing in NF-kappaB level by both drugs. SIGNIFICANCE: Our findings suggest the beneficial role of cilostazol and sildenafil in diabetic testicular damage dependent on anti-inflammatory and anti-oxidant effects. PMID- 29496495 TI - Assessment of the TRPM8 inhibitor AMTB in breast cancer cells and its identification as an inhibitor of voltage gated sodium channels. AB - AIMS: To assess levels of the calcium permeable transient receptor potential cation channel, subfamily melastatin, member 8 (TRPM8) in breast cancer molecular subtypes and to assess the consequences of TRPM8 pharmacological inhibition with AMTB (an inhibitor of TRPM8) on breast cancer cell lines. MATERIALS AND METHODS: Cell viability and migration of breast cancer cells was determined using MTS assays and wound healing assays, respectively. RNA-Seq analysis of breast tumours and qPCR in breast cancer cell lines were used to assess mRNA levels of ion channels. Membrane potential assays were employed to assess the effects of AMTB against specific voltage gated sodium channels (NaV). KEY FINDINGS: TRPM8 levels were significantly higher in breast cancers of the basal molecular subtype. AMTB decreased viable cell number in MDA-MB-231 and SK-BR-3 breast cancer cell lines (30 and 100 MUM), and also reduced the migration of MDA-MB-231 cells (30 MUM). However, these effects were independent of TRPM8, as no TRPM8 mRNA was detected in MDA-MB-231 cells. AMTB was identified as an inhibitor of NaV isoforms. NaV1.1 1.9 were expressed in a number of breast cancer cell lines, with NaV1.5 mRNA highest in MDA-MB-231 cells compared to the other breast cancer cell lines assessed. SIGNIFICANCE: TRPM8 levels may be elevated in basal breast cancers, however, TRPM8 expression appears to be lost in many breast cancer cell lines. Some of the effects of AMTB attributed to TRPM8 may be due to effects on NaV channels. PMID- 29496496 TI - N-methyl-N-nitro-N-nitrosoguanidine-mediated ING4 downregulation contributed to the angiogenesis of transformed human gastric epithelial cells. AB - AIMS: Angiogenesis is associated with the progression and mortality of gastric cancer. Epidemiological evidences indicate that long-term N-nitroso compounds (NOCs) exposure predominantly contributes to the mortality of gastric cancer. Therefore, further reduced mortality of gastric cancer demands to explore the exact mechanisms of NOCs induced angiogenesis. As a tumor suppressor gene, inhibitor of growth protein 4 (ING4) plays an important role in pathological angiogenesis. In this study, we will investigate ING4 expression level in human gastric epithelial cells after the long-term low dose exposure of N-methyl-N nitro-N-nitrosoguanidine (MNNG) and the pathological impact of MNNG-reduced ING4 on angiogenesis of transformed cells. MAIN METHODS: The soft agar colony formation assay, Western blotting, immunofluorescence and wound healing assay were used to evaluate the characteristics of transformed cells. HUVEC growth and tube formation assays were performed to test the angiogenic abilities. EMSA, luciferase reporter gene assay, real-time PCR and Western blotting were used to explore the exact mechanism. KEY FINDINGS: By establishing transformed human gastric epithelial cells via chronic low dose treatment, a gradually ING4 downregulation was observed in the later-stage of MNNG-induced cell transformation. Moreover, we demonstrated that MNNG exposure-reduced ING4 expression significantly resulted into aggravating angiogenesis through increasing the phosphorylation level of NF-kappaB p65 and subsequently DAN binding activity and regulating the expressions of NF-kappaB p65 downstream pro angiogenic genes, MMP-2 and MMP-9. SIGNIFICANCE: Our findings provided a significant mechanistic insight into angiogenesis of MNNG-transformed human gastric epithelial cell and supported the concept that ING4 may be a relevant therapeutic target for gastric cancer. PMID- 29496498 TI - The complement factor H (CFH) and its related protein 2 (CFHR2) mediating immune response in large yellow croaker Larimichthys crocea. AB - Complement is a complex innate immune surveillance system, playing a key role in host homeostasis, inflammation, and in the defense against pathogens. Complement regulators are crucial to prevent the injudicious production of these mediators and potential injury to self tissues. Here, we identified the complement factor H (CFH) and its related gene 2 (CFHR2) homologs from large yellow croaker (Larimichthys crocea), named LcCfh and LcCfhr2, respectively. The deduced LcCfh and LcCfhr2 proteins shared significant structural similarities and identified codes for a polypeptide consisting of various numbers of highly conserved SCR domains. LcCfh, LcCfhr1 and LcCfhr2 genes were detected in all examined tissues with predominantly expressions in liver, spleen and kidney, and their expressions all increased upon Vibrio alginolyticus challenge. In vitro assays showed that recombinant LcCfh was likely to act as a cofactor of CFI and played a negative regulation role in complement system, when recombinant LcCfhr2 seemed to play mechanisms independent of the activity of CFH. Both recombinant LcCfh and LcCfhr2 took participate in inflammatory reaction despite of the inequal ability to mediate pro-inflammation response. These data provide a new insight into the functional activities of teleost complement system. PMID- 29496497 TI - Monoacylglycerol lipase inhibitor, JZL-184, confers neuroprotection in the mice middle cerebral artery occlusion model of stroke. AB - INTRODUCTION: Investigators are searching to find new therapeutic strategies to reduce stroke secondary injury. JZL-184 (JZL) is an inhibitory factor for production of arachidonic acid (AA). Thus, it suppresses production of AA metabolites which are the cause of inflammation and tissue edema. Therefore, JZL may be considered for suppression of stroke secondary injury in mice middle cerebral artery occlusion (MCAO) model. Additionally, Aspirin is a known anti inflammatory factor which is used to reduce pro-inflammatory secondary injury. The aim of this study was to determine the effects of JZL on the reduction of stroke secondary injury and to compare them with Aspirin effects. MATERIAL AND METHODS: MCAO model has been induced and accordingly 83 male MCAO induced mice have been introduced to the study. The animals were divided to seven groups including intact, controls, vehicle, Aspirin, JZL 4, 8 and 16 mg/kg administrated groups. Brain edema and infarction, behavioral functions and brain levels of IL 10, TNF-alpha and matrix metaloperoteinase-9 (MMP9) have been examined in the evaluated groups. RESULTS: The results revealed that JZL reduced brain edema, infarction, brain levels of TNF-alpha and MMP9 and also increased brain levels of IL-10 as well as improved behavioral functions in all three concentrations. The therapeutic effects of JZL were observed as well as Aspirin. DISCUSSION: Based on the results, it seems that JZL can be considered as a good candidate for inhibition of stroke secondary injury in the case of delayed treatment. PMID- 29496500 TI - Update in Outpatient General Internal Medicine: Practice-Changing Evidence Published in 2017. AB - Clinicians are challenged to identify new practice-changing articles in the medical literature. To identify the practice-changing articles published in 2017 most relevant to outpatient general internal medicine, 5 internists reviewed the following sources: 1) titles and abstracts from internal medicine journals with the 7 highest impact factors, including New England Journal of Medicine, Lancet, Journal of the American Medical Association, British Medical Journal, Public Library of Science Medicine, Annals of Internal Medicine, and JAMA Internal Medicine; 2) synopses and syntheses of individual studies, including collections in the American College of Physicians Journal Club, Journal Watch, and Evidence Based Medicine; 3) databases of synthesis, including Evidence Updates and the Cochrane Library. Inclusion criteria were perceived clinical relevance to outpatient general medicine, potential for practice change, and strength of evidence. This process yielded 140 articles. Clusters of important articles around one topic were considered as a single-candidate series. A modified Delphi method was utilized by the 5 authors to reach consensus on 7 topics to highlight and appraise from the 2017 literature. PMID- 29496499 TI - Assessment of Plasma Proteomics Biomarker's Ability to Distinguish Benign From Malignant Lung Nodules: Results of the PANOPTIC (Pulmonary Nodule Plasma Proteomic Classifier) Trial. AB - BACKGROUND: Lung nodules are a diagnostic challenge, with an estimated yearly incidence of 1.6 million in the United States. This study evaluated the accuracy of an integrated proteomic classifier in identifying benign nodules in patients with a pretest probability of cancer (pCA) <= 50%. METHODS: A prospective, multicenter observational trial of 685 patients with 8- to 30-mm lung nodules was conducted. Multiple reaction monitoring mass spectrometry was used to measure the relative abundance of two plasma proteins, LG3BP and C163A. Results were integrated with a clinical risk prediction model to identify likely benign nodules. Sensitivity, specificity, and negative predictive value were calculated. Estimates of potential changes in invasive testing had the integrated classifier results been available and acted on were made. RESULTS: A subgroup of 178 patients with a clinician-assessed pCA <= 50% had a 16% prevalence of lung cancer. The integrated classifier demonstrated a sensitivity of 97% (CI, 82-100), a specificity of 44% (CI, 36-52), and a negative predictive value of 98% (CI, 92 100) in distinguishing benign from malignant nodules. The classifier performed better than PET, validated lung nodule risk models, and physician cancer probability estimates (P < .001). If the integrated classifier results were used to direct care, 40% fewer procedures would be performed on benign nodules, and 3% of malignant nodules would be misclassified. CONCLUSIONS: When used in patients with lung nodules with a pCA <= 50%, the integrated classifier accurately identifies benign lung nodules with good performance characteristics. If used in clinical practice, invasive procedures could be reduced by diverting benign nodules to surveillance. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01752114; URL: www.clinicaltrials.gov). PMID- 29496502 TI - Vena Cava Compression Syndrome in Obesity is Reversed by Bariatric Surgery. PMID- 29496501 TI - Geographic Variability in Liver Disease-Related Mortality Rates in the United States. AB - PURPOSE: Liver disease is an important cause of morbidity and mortality in the United States. Geographic variations in the burden of chronic liver disease may have significant impact on public health policies but have not been explored at the national level. The objective of this study is to examine interstate variability in liver disease mortality in the United States. METHODS: We compared liver disease mortality from the 2010 National Vital Statistics Report on a state level. States in each quartile of liver disease mortality were compared with regard to viral hepatitis death rates, alcohol consumption, obesity, ethnic and racial composition, and household income. Race, ethnicity, and median household income data were derived from the 2010 US Census. Alcohol consumption and obesity data were obtained from the 2010 Behavioral Risk Factor Surveillance System Survey. RESULTS AND CONCLUSION: We found significant interstate variability in liver disease mortality, ranging from 6.4 to 17.0 per 100,000. The South and the West carry some of the highest rates of liver disease mortality. In addition to viral hepatitis death rates, there is a strong correlation between higher percentage of Hispanic population and a state's liver disease mortality rate (r = 0.538, P < .001). Lower household income (r = 0.405, P = .003) was also associated with the higher liver disease mortality. While there was a trend between higher obesity rates and higher liver disease mortality, the correlation was not strong and there was no clear association between alcohol consumption and liver disease mortality rates. PMID- 29496503 TI - New Injectable Agents for the Treatment of Type 2 Diabetes Part 1 - Injectable Insulins. AB - The United States Food and Drug Administration has recently approved several new insulin products and new formulations of existing insulin products. These new products may provide advantages over older products, such as a lower risk of nocturnal hypoglycemia and ease of dosing; however, they are costly. The first of 2 articles in a series, this review will describe the potential advantages and disadvantages of these new insulin products. PMID- 29496504 TI - Moments of Wonder. PMID- 29496506 TI - Targeted muscle reinnervation: Advances and opportunities. PMID- 29496505 TI - Hypoxia modulates the development of a corneal stromal matrix model. AB - Deposition of matrix proteins during development and repair is critical to the transparency of the cornea. While many cells respond to a hypoxic state that can occur in a tumor, the cornea is exposed to hypoxia during development prior to eyelid opening and during the diurnal sleep cycle where oxygen levels can drop from 21% to 8%. In this study, we used 2 three-dimensional (3-D) models to examine how stromal cells respond to periods of acute hypoxic states. The first model, a stromal construct model, is a 3-D stroma-like construct that consists of human corneal fibroblasts (HCFs) stimulated by a stable form of ascorbate for 1, 2, and 4 weeks to self-assemble their own extracellular matrix. The second model, a corneal organ culture model, is a corneal wound-healing model, which consists of wounded adult rat corneas that were removed and placed in culture to heal. Both models were exposed to either normoxic or hypoxic conditions for varying time periods, and the expression and/or localization of matrix proteins was assessed. No significant changes were detected in Type V collagen, which is associated with Type I collagen fibrils; however, significant changes were detected in the expression of both the small leucine-rich repeating proteoglycans and the larger heparan sulfate proteoglycan, perlecan. Also, hypoxia decreased both the number of Cuprolinic blue-positive glycosaminoglycan chains along collagen fibrils and Sulfatase 1, which modulates the effect of heparan sulfate by removing the 6-O-sulfate groups. In the stromal construct model, alterations were seen in fibronectin, similar to those that occur in development and after injury. These changes in fibronectin after injury were accompanied by changes in proteoglycans. Together these findings indicate that acute hypoxic changes alter the physiology of the cornea, and these models will allow us to manipulate the conditions in the extracellular environment in order to study corneal development and trauma. PMID- 29496507 TI - IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. AB - INTRODUCTION: Since the year 2000, IDF has been measuring the prevalence of diabetes nationally, regionally and globally. AIM: To produce estimates of the global burden of diabetes and its impact for 2017 and projections for 2045. METHODS: A systematic literature review was conducted to identify published studies on the prevalence of diabetes, impaired glucose tolerance and hyperglycaemia in pregnancy in the period from 1990 to 2016. The highest quality studies on diabetes prevalence were selected for each country. A logistic regression model was used to generate age-specific prevalence estimates or each country. Estimates for countries without data were extrapolated from similar countries. RESULTS: It was estimated that in 2017 there are 451 million (age 18 99 years) people with diabetes worldwide. These figures were expected to increase to 693 million) by 2045. It was estimated that almost half of all people (49.7%) living with diabetes are undiagnosed. Moreover, there was an estimated 374 million people with impaired glucose tolerance (IGT) and it was projected that almost 21.3 million live births to women were affected by some form of hyperglycaemia in pregnancy. In 2017, approximately 5 million deaths worldwide were attributable to diabetes in the 20-99 years age range. The global healthcare expenditure on people with diabetes was estimated to be USD 850 billion in 2017. CONCLUSION: The new estimates of diabetes prevalence, deaths attributable to diabetes and healthcare expenditure due to diabetes present a large social, financial and health system burden across the world. PMID- 29496508 TI - Decreased the creatinine to cystatin C ratio is a surrogate marker of sarcopenia in patients with type 2 diabetes. AB - AIMS: Sarcopenia has recently been shown to affect quality of life and mortality in patients with diabetes. However, early detection requires an expensive equipment. We hypothesized that the ratio of the creatinine/cystatin (Cre/CysC) could be used as a marker for sarcopenia. METHODS: We investigated the association between the Cre/CysC ratio and sarcopenia in a cross-sectional study of patients with type 2 diabetes. Skeletal muscle mass (SMM) was estimated by bioelectrical impedance. The skeletal muscle index (SMI) was defined as the appendicular SMM divided by the square of the height. Sarcopenia was defined with SMI and a grip strength. RESULTS: We identified 285 patients with type 2 diabetes, of whom 25 (8.8%) had sarcopenia. The Cre/CysC ratio was associated with an increased risk of sarcopenia [odds ratio per 0.01 increment, 1.05; 95% confidence interval (CI), 1.01-1.09] after adjusting for covariates. Receiver operating characteristic curve analysis indicated that the optimal the Cre/CysC ratio cut-off point for identifying sarcopenia was 0.9, with an area under the curve, sensitivity, and specificity of 0.683 (95% CI, 0.573-0.793), 0.80, and 0.48, respectively. CONCLUSIONS: We recommend the Cre/CysC ratio as a practical screening marker for sarcopenia in patients with type 2 diabetes. PMID- 29496509 TI - Can electrical stimulation enhance effects of a functional training program in hospitalized geriatric patients? AB - BACKGROUND: Hospitalization of older medical patients may lead to functional decline. This study investigated whether simultaneously applied neuromuscular electrical stimulation (NMES) can enhance the effects of a functional training program in hospitalized geriatric patients. METHOD: This was a quasi-randomized controlled trial in geriatric hospitalized patients (N = 16, age = 83.1 +/- 8.1 years, mean +/- SD). The patients performed a simple and time efficient chair stand based functional exercise program daily, either with (FT + NMES, N = 8) or without (FT, N = 8) simultaneous NMES to the knee extensor muscles. Physical function was assessed at day 2 and 6-10 of the hospitalization with the De Morton Mobility Index (DEMMI), a 30-second chair stand test (30 s-CST) and a 4-meter gait speed test (4 m-GST). Additionally, the pooled results of training from the two training groups (TRAINING, N = 16) was compared to a similar historical control-group (CON, N = 48) receiving only standard-care. RESULTS: Eight patients were assigned to FT, 12 to FT+NMES with 4 dropouts during intervention. During the 6-10 days of hospitalization, both groups improved in all functional measures (p < 0.05), but with no difference between groups (p > 0.05). The training sessions within the FT+NMES-group were more time consuming (~11 vs ~7 min) and entailed higher levels of discomfort than FT-training sessions. Compared to standard-care, training resulted in significantly larger improvements in the 30 s CST (TRAINING: +3.8 repetitions; CON: +1.4 repetitions, p < 0.01), but not in the DEMMI-test and the 4 m-GST. CONCLUSION: A short-duration daily functional training program improves chair stand performance in hospitalized geriatric patients, with no additional effect of simultaneous electrical muscle stimulation. PMID- 29496510 TI - Modifiable stroke risk factors in Africa: lessons from SIREN. PMID- 29496513 TI - Expression-dependent susceptibility to face distortions in processing of facial expressions of emotion. AB - Our capability of recognizing facial expressions of emotion under different viewing conditions implies the existence of an invariant expression representation. As natural visual signals are often distorted and our perceptual strategy changes with external noise level, it is essential to understand how expression perception is susceptible to face distortion and whether the same facial cues are used to process high- and low-quality face images. We systematically manipulated face image resolution (experiment 1) and blur (experiment 2), and measured participants' expression categorization accuracy, perceived expression intensity and associated gaze patterns. Our analysis revealed a reasonable tolerance to face distortion in expression perception. Reducing image resolution up to 48 * 64 pixels or increasing image blur up to 15 cycles/image had little impact on expression assessment and associated gaze behaviour. Further distortion led to decreased expression categorization accuracy and intensity rating, increased reaction time and fixation duration, and stronger central fixation bias which was not driven by distortion-induced changes in local image saliency. Interestingly, the observed distortion effects were expression dependent with less deterioration impact on happy and surprise expressions, suggesting this distortion-invariant facial expression perception might be achieved through the categorical model involving a non-linear configural combination of local facial features. PMID- 29496512 TI - Pharmacological analysis of zebrafish lphn3.1 morphant larvae suggests that saturated dopaminergic signaling could underlie the ADHD-like locomotor hyperactivity. AB - Polymorphisms in the gene coding for the adhesion G-protein coupled receptor LPHN3 are a risk factor for attention-deficit/hyperactivity disorder (ADHD). Transient down-regulation of latrophilin3.1 (lphn3.1), the zebrafish LPHN3 homologue, causes hyperactivity. Zebrafish injected with a lphn3.1-specific morpholino are hyperactive and display an impairment in dopaminergic neuron development. In the present study we used lphn3.1 morphants to further characterize the changes to dopaminergic signaling that trigger hyperactivity. We applied dopamine agonists (Apomorphine, Quinpirole, SKF-38393) and antagonists (Haloperidol, Eticlopride, SCH-23390) to Lphn3.1 morpholino-injected or control injected animals. The percentage of change in locomotor activity was then determined at three different time periods (10-20 min, 30-40 min and 60-70 min). Our results show that drugs targeting dopamine receptors appear to elicit similar effects on locomotion in zebrafish larvae and mammals. In addition, we observed that lphn3.1 morphants have an overall hyposensitivity to dopamine agonists and antagonists compared to control fish. These results are compatible with a model whereby dopaminergic neurotransmission is saturated in lphn3.1 morphants. PMID- 29496514 TI - Genome-wide analysis of long non-coding RNAs in Pichia pastoris during stress by RNA sequencing. AB - Long non-coding RNAs play significant roles in many biological processes. The roles of lncRNAs in Pichia pastoris remain unclear. In this work, we focused on the identification of lncRNAs in P. pastoris and exploration of their potential roles in stress response to PLA2 overexpression and methanol induction. By strand specific RNA sequencing, 208 novel long non-coding RNAs were identified and analyzed. Bioinformatic analysis showed potential trans-target genes and cis regulated genes of 39 differential lncRNAs. Functional annotation and sequence motif analysis indicated that lncRNAs participate in pathways related to methanol degradation and production of the recombinant protein. The differential expression of lncRNAs was validated by qRT-PCR. Lastly, the potential functions of three lncRNAs were evaluated by knockdown of their expression and analysis of the expression levels of target genes. Our study identifies novel lncRNAs in P. pastoris induced during use as a bioreactor, facilitating future functional research. PMID- 29496511 TI - Dominant modifiable risk factors for stroke in Ghana and Nigeria (SIREN): a case control study. AB - BACKGROUND: Sub-Saharan Africa has the highest incidence, prevalence, and fatality from stroke globally. Yet, only little information about context specific risk factors for prioritising interventions to reduce the stroke burden in sub-Saharan Africa is available. We aimed to identify and characterise the effect of the top modifiable risk factors for stroke in sub-Saharan Africa. METHODS: The Stroke Investigative Research and Educational Network (SIREN) study is a multicentre, case-control study done at 15 sites in Nigeria and Ghana. Cases were adults (aged >=18 years) with stroke confirmed by CT or MRI. Controls were age-matched and gender-matched stroke-free adults (aged >=18 years) recruited from the communities in catchment areas of cases. Comprehensive assessment for vascular, lifestyle, and psychosocial factors was done using standard instruments. We used conditional logistic regression to estimate odds ratios (ORs) and population-attributable risks (PARs) with 95% CIs. FINDINGS: Between Aug 28, 2014, and June 15, 2017, we enrolled 2118 case-control pairs (1192 [56%] men) with mean ages of 59.0 years (SD 13.8) for cases and 57.8 years (13.7) for controls. 1430 (68%) had ischaemic stoke, 682 (32%) had haemorrhagic stroke, and six (<1%) had discrete ischaemic and haemorrhagic lesions. 98.2% (95% CI 97.2 99.0) of adjusted PAR of stroke was associated with 11 potentially modifiable risk factors with ORs and PARs in descending order of PAR of 19.36 (95% CI 12.11 30.93) and 90.8% (95% CI 87.9-93.7) for hypertension, 1.85 (1.44-2.38) and 35.8% (25.3-46.2) for dyslipidaemia, 1.59 (1.19-2.13) and 31.1% (13.3-48.9) for regular meat consumption, 1.48 (1.13-1.94) and 26.5% (12.9-40.2) for elevated waist-to hip ratio, 2.58 (1.98-3.37) and 22.1% (17.8-26.4) for diabetes, 2.43 (1.81-3.26) and 18.2% (14.1-22.3) for low green leafy vegetable consumption, 1.89 (1.40-2.54) and 11.6% (6.6-16.7) for stress, 2.14 (1.34-3.43) and 5.3% (3.3-7.3) for added salt at the table, 1.65 (1.09-2.49) and 4.3% (0.6-7.9) for cardiac disease, 2.13 (1.12-4.05) and 2.4% (0.7-4.1) for physical inactivity, and 4.42 (1.75-11.16) and 2.3% (1.5-3.1) for current cigarette smoking. Ten of these factors were associated with ischaemic stroke and six with haemorrhagic stroke occurrence. INTERPRETATION: Implementation of interventions targeting these leading risk factors at the population level should substantially curtail the burden of stroke among Africans. FUNDING: National Institutes of Health. PMID- 29496515 TI - Mytilus trossulus and hybrid (M. edulis-M. trossulus) - New hosts organisms for pathogenic microalgae Coccomyxa sp. from the Estuary and northwestern Gulf of St. Lawrence, Canada. AB - During summer 2014-2017, wild mytilid mussels, highly infested with the pathogenic Coccomyxa-like microalgae, were collected along the Estuary and northwestern part of Gulf of St. Lawrence (Quebec, Canada). Molecular identification showed that algae can be assigned to a single taxon, Coccomyxa sp. (KJ372210), whereas hosts are represented by Mytilus edulis, M. trossulus and hybrid between these two species. This is the first record of M. trossulus and hybrid among hosts of this pathogenic alga. Our results are indicative of a possible widespread distribution of Coccomyxa sp. in the Lower St. Lawrence Estuary and along coastal waters of Canadian Maritime provinces. PMID- 29496516 TI - Magnetic resonance imaging and spectroscopy evidence of efficacy for adrenal and gonadal hormone replacement therapy in anorexia nervosa. AB - PURPOSE: Dehydroepiandrosterone (DHEA)+estrogen/progestin therapy for adolescent girls with anorexia nervosa (AN) has the potential to arrest bone loss. The primary aim of this study was to test the effects of DHEA+estrogen/progestin therapy in adolescent girls with AN on bone marrow in the distal femur using magnetic resonance imaging (MRI) and spectroscopy. METHODS: Seventy adolescent girls with AN were enrolled in a double blind, randomized, placebo-controlled trial at two urban hospital-based programs. INTERVENTION: Seventy-six girls were randomly assigned to receive 12months of either oral micronized DHEA or placebo. DHEA was administered with conjugated equine estrogens (0.3mg daily) for 3months, then an oral contraceptive (20MUg ethinyl estradiol/ 0.1mg levonorgestrel) for 9months. The primary outcome measure was bone marrow fat by MRI and magnetic resonance spectroscopy (MRS). RESULTS: T2 of the water resonance dropped significantly less in the active vs. placebo group over 12months at both the medial and lateral distal femur (p=0.02). Body mass index (BMI) was a significant effect modifier for T1 and for T2 of unsaturated (T2unsat) and saturated fat (T2sat) in the lateral distal femur. Positive effects of the treatment of DHEA+estrogen/progestin were seen primarily for girls above a BMI of about 18kg/m2. CONCLUSIONS: These findings suggest treatment with oral DHEA+estrogen/progestin arrests the age- and disease-related changes in marrow fat composition in the lateral distal femur reported previously in this population. PMID- 29496517 TI - Parallels between hematopoietic stem cell and prostate cancer disseminated tumor cell regulation. AB - The bone marrow is the primary site of hematopoiesis and the home for hematopoietic stem cells (HSCs) in adult mammals. Prostate cancer commonly metastasizes to the bone and forms bone metastases in almost all patients who die of the disease. Prostate cancer bone metastases are thought to develop after rare bone marrow disseminated tumor cells (DTCs) escape a dormant state and reactivate. Prostate cancer DTCs and normal HSCs have been shown to compete for residence in the bone marrow and share many of same regulatory mechanisms for survival, proliferation and homing. In this review, we highlight these parallels in order to help our readers use the literature in HSC and DTC biology to inform their research and generate hypotheses in both fields. PMID- 29496519 TI - Cardiopulmonary Exercise Measures of Men and Women with HFrEF Differ in Their Relationship to Prognosis: The Henry Ford Hospital Cardiopulmonary Exercise Testing (FIT-CPX) Project. AB - BACKGROUND: This study evaluated if different prognostic characteristics exist for peak oxygen consumption (VO2), percent predicted peak VO2 (ppVO2), and the slope of the change in minute ventilation to volume of carbon dioxide produced (VE-VCO2) slope between men and women with heart failure and reduced ejection fraction (HFrEF). METHODS: Analysis of the Henry Ford Hospital Cardiopulmonary Exercise Testing database (n = 1085; 33% women, 55% black) of individuals with HFrEF who completed a physician-referred cardiopulmonary exercise testing (CPX) between 1997 and 2010. Primary outcome was a composite of all-cause death, left ventricular assist device placement, and orthotopic heart transplant . Logistic and Cox regressions were performed and Kaplan-Meier survival curves were developed to describe relationships of the CPX variables and the composite outcome within and between men and women. RESULTS: All patients were followed-up for a minimum of 5 years, during which there were 643 combined events (62%; 499 deaths, 64 left ventricular assist device implants, 80 orthotopic heart transplant). Each CPX variable was significantly related to event-free survival among both men and women. Log-rank assessment of Kaplan-Meier curves noted survival differences for peak VO2 and VE-VCO2 slope (p <= .002), but not ppVO2 (P = .32), between men and women. CONCLUSIONS: Prognostic values for peak VO2 and the VE-VCO2 slope might be considered separately for men and women, whereas the ppVO2 value corresponding to 1- and 3-year survival rates may not be different between the sexes. PMID- 29496518 TI - Based on an analysis of mode of action, styrene-induced mouse lung tumors are not a human cancer concern. AB - Based on 13 chronic studies, styrene exposure causes lung tumors in mice, but no tumor increases in other organs in mice or rats. Extensive research into the mode of action demonstrates the key events and human relevance. Key events are: metabolism of styrene by CYP2F2 in mouse lung club cells to ring-oxidized metabolites; changes in gene expression for metabolism of lipids and lipoproteins, cell cycle and mitotic M-M/G1 phases; cytotoxicity and mitogenesis in club cells; and progression to preneoplastic/neoplastic lesions in lung. Although styrene-7,8-oxide (SO) is a common genotoxic styrene metabolite in in vitro studies, the data clearly demonstrate that SO is not the proximate toxicant and that styrene does not induce a genotoxic mode of action. Based on complete attenuation of styrene short-term and chronic toxicity in CYP2F2 knockout mice and similar attenuation in CYP2F1 (humanized) transgenic mice, limited metabolism of styrene in human lung by CYP2F1, 2 + orders of magnitude lower SO levels in human lung compared to mouse lung, and lack of styrene-related increase in lung cancer in humans, styrene does not present a risk of cancer to humans. PMID- 29496520 TI - EYA1 promotes tumor angiogenesis by activating the PI3K pathway in colorectal cancer. AB - Blood vessels are one of the major routes for the dissemination of cancer cells. Malignant tumors release growth factors such as vascular endothelial growth factor(VEGF) to induce angiogenesis, thereby promoting metastasis. Here, we report that The Drosophila Eyes Absent Homologue 1 (EYA1), which is overexpressed in colorectal tumor cells, can promote colorectal tumor angiogenesis by coordinating with the hypoxia-inducible factor 1 (HIF-1alpha) to increase the expression of VEGF-A. Moreover, data indicated that the enhancement of HIF-1alpha expression by Eya1 depended on its ability to activate the phosphatidylinositol 3 kinase (PI3K) signaling pathways to increase the phosphorylation of AKT subunits. Overexpression of Eya1 increased tumor angiogenesis in vivo and in vitro. Our study suggested that Eya1 is essential in regulating cancer cell-mediated angiogenesis and contributes to tumor growth, and that Eya1 provides a potential and specific target for new anti-angiogenesis drug development. PMID- 29496521 TI - A stakeholder visioning exercise to enhance chronic care and the integration of community pharmacy services. AB - BACKGROUND: Collaboration between relevant stakeholders in health service planning enables service contextualization and facilitates its success and integration into practice. Although community pharmacy services (CPSs) aim to improve patients' health and quality of life, their integration in primary care is far from ideal. Key stakeholders for the development of a CPS intended at preventing cardiovascular disease were identified in a previous stakeholder analysis. Engaging these stakeholders to create a shared vision is the subsequent step to focus planning directions and lay sound foundations for future work. OBJECTIVES: This study aims to develop a stakeholder-shared vision of a cardiovascular care model which integrates community pharmacists and to identify initiatives to achieve this vision. METHODS: A participatory visioning exercise involving 13 stakeholders across the healthcare system was performed. A facilitated workshop, structured in three parts (i.e., introduction; developing the vision; defining the initiatives towards the vision), was designed. The Chronic Care Model inspired the questions that guided the development of the vision. Workshop transcripts, researchers' notes and materials produced by participants were analyzed using qualitative content analysis. RESULTS: Stakeholders broadened the objective of the vision to focus on the management of chronic diseases. Their vision yielded 7 principles for advanced chronic care: patient-centered care; multidisciplinary team approach; shared goals; long-term care relationships; evidence-based practice; ease of access to healthcare settings and services by patients; and good communication and coordination. Stakeholders also delineated six environmental factors that can influence their implementation. Twenty-four initiatives to achieve the developed vision were defined. CONCLUSIONS: The principles and factors identified as part of the stakeholder shared-vision were combined in a preliminary model for chronic care. This model and initiatives can guide policy makers as well as healthcare planners and researchers to develop and integrate chronic disease services, namely CPSs, in real-world settings. PMID- 29496522 TI - Dihydrotanshinone I, a natural product, ameliorates DSS-induced experimental ulcerative colitis in mice. AB - Ulcerative colitis (UC) is a chronic and relapsing inflammatory disorder of the colon and rectum with increasing morbidity in recent years. 15,16 dihydrotanshinone ? (DHT) is a natural product with multiple bioactivities. In this study, we aimed to investigate the protective effect and potential mechanisms of DHT on UC. Dextran sulfate sodium salt (DSS) was administrated in drinking water for 7 days to induce UC in mice. DHT (10 and 25 mg/kg) significantly alleviated DSS-induced body weight loss, disease activity index (DAI) scores, and improved histological alterations of colon tissues. DHT inhibited the myeloperoxidase (MPO) activity, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in colon tissues and decreased serum levels of TNF-alpha, IL-1beta, IL-6, and high-mobility group box 1 (HMGB1). Furthermore, increased expression of kinases receptor-interacting protein 1 (RIP1), RIP3, mixed lineage kinase domain-like protein (MLKL) and decreased expression of caspase-8 in colon tissues were partially restored by DHT. In LPS stimulated RAW264.7 macrophages, DHT significantly inhibited generation of nitric oxide, IL-6, TNF-alpha and protein expression of iNOS, COX-2. In addition, increased expression of iNOS, COX-2, and phosphorylated RIP1, RIP3, MLKL in response to LPS plus Z-VAD (LZ) were also suppressed by DHT. DHT had no effect on TNF-alpha + BV6 + Z-VAD (TBZ) induced phosphorylation of RIPs and MLKL in HT29 cells. Especially, DHT showed no effect on LZ and TBZ-induced necroptosis in RAW264.7 and HT29 cells, respectively. In summary, DHT alleviated DSS-induced UC in mice by suppressing pro-inflammatory mediators and regulating RIPs-MLKL caspase-8 axis. PMID- 29496523 TI - Ultraestructural study of effects of alkylphospholipid analogs against nematodes. AB - Alkylphospholipid analogs were initially developed as anticancer agents and were later found to antiparasitic activity. Miltefosine is the prototype alkylphosphocholine and is the first oral treatment against visceral leishmaniasis. Here we investigated the effects of miltefosine and two ring substituted alkylphosphocholine derivatives, TCAN26 and TC70, on the viability, morphology, and ultrastructure of the life stages of Caenorhabditis elegans and infective larvae of the parasite Strongyloides venezuelensis. Miltefosine displayed activity against C. elegans adults at low concentrations and was more effective than TCAN26 and TC70. Miltefosine inhibited the hatching of eggs, leading to embryonic lethality, and showed larvicidal activity against C. elegans and S. venezuelensis larvae after 24 h. Mitelfosine also induced alterations in the reproductive system of hermaphrodites, causing vulvar prolapse and general effects in the body wall. Electron microscopy analysis showed that miltefosine induced selective embryonic lethality, leading to cell death. Our results suggest that alkylphospholipid analogs are a potential new alternative for anti-nematode chemotherapy. PMID- 29496524 TI - Characterization of a putative glutathione S-transferase of the parasitic nematode Trichinella spiralis. AB - The aim of this study was to identify the biological characteristics and functions of a putative Trichinella spiralis glutathione S-transferase (TspGST). The results of real-time PCR and immunofluorescent test (IFT) showed that the TspGST gene was expressed at all of T. spiralis different developmental stages (muscle larvae, intestinal infective larvae, adult worms and newborn larvae). When anti-rTspGST serum, mouse infection serum, and pre-immune serum were added to the medium, the inhibition rate of the larvae penetrated into the intestinal epithelial cells (IECs) was 25.72%, 49.55%, and 4.51%, respectively (P < 0.01). The inhibition of anti-rTspGST serum on larval invasion of IECs was dose dependent (P < 0.05). Anti-rTspGST antibodies killed T. spiralis newborn larvae by an ADCC-mediated mechanism. Our results showed that the TspGST seemed to be an indispensable protein for T. spiralis invasion, growth and survival in host. PMID- 29496525 TI - Vitamin D receptor regulates intestinal inflammatory response in mice infected with blood stage malaria. AB - Malaria is a harmful disease affecting both tropical and subtropical countries and causing sometimes fatal complications. The effects of malaria-related complications on the intestine have been relatively neglected, and the reasons for the intestinal damage caused by malaria infection are not yet clear. The present study aims to evaluate the influence of intestinal vitamin D receptor on host-pathogen interactions during malaria induced in mice by Plasmodium chabaudi. To induce the infection, animals were infected with 106P. chabaudi-parasitized erythrocytes. Mice were sacrificed on day 8 post-infection. The infected mice experienced a significant body weight loss and parasitaemia affecting about 46% of RBCs. Infection caused marked pathological changes in the intestinal tissue indicated by shortening of the intestine and villi. Moreover, the phagocytic activity of macrophages increased significantly (P < 0.01) in the infected villi compared to the non-infected ones. Infection by the parasite also induced marked upregulation of nuclear factor-kappa B, inducible nitric oxide synthase, Vitamin D Receptor, interleukin-1beta, tumour necrosis factor alpha and interferon gamma mRNA. It can be implied from this that vitamin D receptor has a role in regulating malarial infection. PMID- 29496526 TI - The correlation between the mutual deletions of amino acids within porcine circovirus rep protein and the discrepancy of replication. AB - Porcine circovirus (PCV) has two potential open reading frames, ORF1 and ORF2. ORF1 is predicted to encode a replication-associated protein (Rep) essential for replication of viral DNA. In some studies, PCV1 replicated more efficiently in PK 15 cells than PCV2 was elucidated. PCV1 compared with PCV2; there is some amino acids' deficiency on Rep protein. To identify whether the above amino acids deletion affects the replication of PCV1 and PCV2, we constructed three double copy clones by overlap extension PCR. The 2PCV2(vV) clone deleted the valine of Rep protein in the backbone of PCV2 genome. The 2PCV2(dSGR) clone inserted serine, glycine and arginine of Rep protein successively in the backbone of PCV2 genome. The 2PCV2(dSGR&vV) clone inserted serine, glycine and arginine as well as deleted the valine of Rep protein in the backbone of PCV2 genome. These clones we constructed with amino acid mutations and parental DNA clones were all transfected in PK-15 cells that free of PCV contamination, and their growth characteristics in vitro were determined and compared, to evaluating the replication of the mutant infectious DNA clones. Our results showed that the double copy infectious clones with amino acid mutations could be rescued in vitro. The 2PCV2(vV) replicated more efficiently than parental viruses 2PCV2 and 2PCV1 but the replicated ability of 2PCV2(dSGR) and 2PCV2(dSGR&vV) is attenuated than parental viruses 2PCV2 and 2PCV1. We can determine the valine is the important amino acid that cause PCV1 replicated more efficiently in PK-15 cells than PCV2 primarily. These findings are benefit for exploring the mechanisms of viral replication in pigs and important implications for PCV2 vaccine development. PMID- 29496527 TI - Cytogenetic tests reveal no toxicity in lymphocytes of rabbit (Oryctolagus cuniculus, 2n=44) feed in presence of verbascoside and/or lycopene. AB - Phenylpropanoid glycosides (PPG), like other phenolic compounds, are a powerful antioxidants and the Verbascoside (VB) is one of the most active of them. A previous study, by using in vitro exposure of blood human lymphocytes to Verbascoside, reported a significant increasings of chromosome fragility compared to control. In the present study, four homogeneous groups of rabbits were used to test in vivo the VB and/or Lycopene (LP) by feeding the animals without VB and LP (control), in presence of VB or/and LP for 80 days. Lymphocyte cell cultures were performed in three different times: 0, 40 and 80 days of the experiment and the cytogenetic tests that we used [CA-test (Chromosome Abnormalities in terms of chromosome and chromatid breaks) and Sister Chromatid Exchange (SCE-test)] have revealed no mutagenic effects on chromosomes. Indeed, mean values/cell of CA and SCE decreased during the experiment with some difference among and within groups, with significant decreasing value only for some group. The study shows clear evidence that diets rich in Verbascoside (and/or Lycopene) do not originate any mutagenic activity, resulting no cytotoxic for the animals and, suggesting a possible their use in both animal and human diets. PMID- 29496528 TI - Modulation of pre-neoplastic biomarkers induced by sequential aflatoxin B1 and fumonisin B1 exposure in F344 rats treated with UPSN clay. AB - Populations consuming aflatoxin (AF) and fumonisin (FN)-contaminated foods may be at increased risk for hepatocellular carcinoma (HCC) and developmental disorders; consequently, development of intervention strategies to reduce AF/FN-induced liver disease and adverse health effects in humans could be very useful. Calcium montmorillonite clay (NovaSil) has been shown to absorb AF in vitro, in multiple animal models, as well as in human studies. In the present study, we aimed to evaluate whether uniform particle size NovaSil (UPSN) possessed an ability to modulate the co-carcinogenic potentials of aflatoxin B1 (AFB1) and fumonisin B1 (FB1) in F344 rats. Sequential treatment of FB1 following AFB1 synergistically induces preneoplastic alterations as well as liver damage, indicating that AFB1 acts as an initiator while FB1 as a promoter in the carcinogenesis model, confirming findings from previous studies. The enterosorbent agent UPSN clay at dose of up to 0.5% in diet was shown to be effective in modulating the toxicity and carcinogenicity of co-exposure to AFB1 and FB1, as demonstrated by significant reduction in number and size of hepatic GST-P+ foci, in alterations indicative of liver toxicity, and in levels of AFB1 and FB1 biomarkers. PMID- 29496529 TI - Valorization of onion solid waste and their flavonols for assessment of cytotoxicity, enzyme inhibitory and antioxidant activities. AB - Onion (Allium cepa L.) is rich with flavonols which perceived benefits to human health. Flavonols like quercetin and quercetin glycosides from onion solid waste (OSW) have been extracted and tested against enzymes of clinical importance in Alzheimer's disease and diabetes and be shown to have cytotoxic and antioxidant effects. A simple high-performance liquid chromatography-diode array detector method using a Zorbax Eclipse XDB C18 column was developed to separate quercetin 3, 4'-O-diglucoside, quercetin-4'-O-monoglucoside, and quercetin from OSW. These compounds were identified using infrared, ultra-violet, 1H, and 13C nuclear magnetic resonance spectroscopic techniques. The OSW solvent fractions and flavonols showed significant antioxidant activities using DPPH (1, 1-diphenyl-2 picrylhydrazyl), FRAP (ferric reducing antioxidant power), and ABTS (2,2'-azino bis-3-ethylbenzthiazoline-6-sulphonic acid) radical scavenging assays. The samples exhibited significant in vitro anti-cholinesterase activity with strong antidiabetic effects. OSW extracted with methanol and ethanol showed greater in vitro anti-cholinesterase and hypoglycemic effects than QDG, QMG, and Q possibly due to interactions between multiple compounds and/or complex multivariate interactions with other factors in OSW. In addition, cytotoxicity assays showed that OSW and QDG, QMG, and Q could inhibit the proliferation of selected cancer cell lines. Results indicate that OSW and flavonol glycosides are potential antioxidant, antidiabetic, anticancer, and sedative agents. PMID- 29496530 TI - Antithrombotic components of Malus halliana Koehne flowers. AB - Flowers of Malus halliana (M. halliana) Koehne have been used as a Chinese traditional medicine to treat metrorrhagia and in our study, its chemical composition and anticoagulant effect were investigated. Five compounds were isolated and identified from M. halliana flowers, including limocitrin-3-O glucoside (1), baohuoside II (2), kaempferol-3-O-alpha-L-furan arabinoside (3), phloretin-4'-O-glycosidase (4) and afzeloside (5). Compound 1-3 were isolated for the first time from this genus. The anticoagulant effect of the compounds and extracts of M. halliana flowers were evaluated by APTT, PT, TT and FIB on plasma of rabbit in vitro. The results indicated that several fractions of M. halliana flowers and compounds 2-5 exhibited anticoagulant activity in vitro. Subsequently, afzeloside (5), the abundant component in M. halliana flowers, was investigated further for its antithrombotic effect in vivo and its antithrombotic mechanisms were evaluated on rats acute blood-stasis model. The antithrombotic effect was evaluated by WBV, PV, HCT, ESR, APTT, PT, TT, FIB, 6-keto-PGF1alpha, TXB2, ET-1 and eNOS in vivo. Afzeloside demonstrated inhibitory effect of thrombus formation, and its underlying antithrombotic mechanism was found to be related to the regulation of vascular endothelium active substance, activating blood flow and anticoagulant effect. Hence, we postulate that flavonoids may be the active ingredients of the plant. PMID- 29496532 TI - Deficiency in the DNA glycosylases UNG1 and OGG1 does not potentiate c-Myc induced B-cell lymphomagenesis. AB - C-Myc overexpression mediates lymphomagenesis; however, secondary genetic lesions are required for its full oncogenic potential. The origin and the mechanism of formation of these mutations are unclear. Using the lacI mutation detection system, we show that secondary mutations occur early in B-cell development and are repaired by Msh2. The mutations at the lacI gene were predominantly at C:G base pairs and CpG motifs, suggesting that they were formed due to cytosine deamination or oxidative damage of G. Therefore, we investigated the role of Ogg1 and UNG glycosylases in c-Myc-driven lymphomagenesis but found that their deficiencies did not influence disease outcome in the Eu c-Myc mouse model. We also show that Rag proteins do not contribute to secondary lesions in this model. Our work suggests that mutations at C:G base pairs that are repaired primarily by the mismatch repair system arise early in B-cell ontogeny to promote c-Myc-driven lymphomagenesis. PMID- 29496531 TI - Effects of Danshen capsules on the pharmacokinetics and pharmacodynamics of clopidogrel in healthy volunteers. AB - Nowadays, the Herb-drug combination is becoming increasingly popular in China. However, the possible interaction induced by their combination was examined rarely. The aim of this study was to investigate the effect of multi-dose administration of Danshen capsules on clopidogrel pharmacokinetics and pharmacodynamics in healthy volunteers. A sequential, open-label, and two-period pharmacokinetic drug interaction study was designed to compare clopidogrel pharmacokinetic parameters before and after 7 days of administration of Danshen capsules in twenty healthy male volunteers. Co-administration of multiple doses of Danshen capsules caused increases in apparent oral clearance of clopidogrel and its metabolite by 96.5% and 73.7% and apparent volume of distribution by 94.2% and 75.1%, corresponding declines in Cmax by 41.7% and 32.9%, AUC0-t by 50.3% and 41.8%, and AUC0-infinity by 49.3% and 41.5% in human volunteers, respectively. Corresponding pharmacokinetic findings, co-administration of Danshen capsules with clopidogrel decreased the antiplatelet activity compared with individual agents. The results suggested that multiple dose administration of Danshen capsules could induce cytochrome P450 (CYP) isoenzymes, thereby increasing the clearance of clopidogrel. Therefore, caution should be taken when Danshen products containing lipophilic components are used in combination with therapeutic drugs metabolized by CYP3A4. PMID- 29496533 TI - A CCR5 antagonist-based HIV entry inhibitor exhibited potent spermicidal activity: Potential application for contraception and prevention of HIV sexual transmission. AB - B07 is a small-molecule CCR5 antagonist-based HIV-1 entry inhibitor that is being developed as an anti-HIV microbicide for preventing sexual transmission of HIV. Here we evaluated its spermicidal and contraceptive potential, including sperm motility, plasma membrane integrity, and contraceptive efficacy tested in rabbits. We found that B07 inhibited sperm motility and movement patterns in a concentration- and time-dependent manner. Within 30 min, B07 induced sperm immobilization with the minimum 100% effective concentration and median effective concentration of 640.0 and 64.4 MUg/mL, respectively. The hypo-osmotic swelling test showed that plasma membranes of B07-treated sperms exhibited slight disruption, as verified by electron micrographs. In both B07 gel and N-9 gel groups, not a single implantation site or embryo was observed based on the contraceptive efficacy test in rabbits, indicating that B07 could effectively block the potential of sperm to reach and/or fertilize oocytes. The safety profile of B07 in vivo was evaluated by use of an optimized rabbit vaginal irritation test. While the pathological scores of the N-9 gel group was 14.67 +/- 1.21, those of the blank control and B07 gel groups were 2.17 +/- 0.76 and 4.00 +/- 0.89, respectively, which were within the clinically acceptable range (<8). The proportion of inflammatory cells and CD45+ cells in the cervicovaginal lavages of the B07 gel group showed no significant change compared to those of the control group. Therefore, our results confirmed that B07 exhibited significant spermicidal and contraceptive effects, suggesting its potential for development as a microbicidal spermicide for contraception and prevention of HIV sexual transmission. PMID- 29496534 TI - Patient-Reported Functional Status in Outpatients With Advanced Cancer: Correlation With Physician-Reported Scores and Survival. AB - CONTEXT: Performance status measures are increasingly completed by patients in outpatient cancer settings, but are not well validated for this use. OBJECTIVES: We assessed performance of a patient-reported functional status measure (PRFS, based on the Eastern Cooperative Oncology Group [ECOG]), compared with the physician-completed ECOG, in terms of agreement in ratings and prediction of survival. METHODS: Patients and physicians independently completed five-point PRFS (lay version of ECOG) and ECOG measures on first consultation at an oncology palliative care clinic. We assessed agreement between PRFS and ECOG using weighted Kappa statistics, and used linear regression to determine factors associated with the difference between PRFS and ECOG ratings. We used the Kaplan Meier method to estimate the patients' median survival, categorized by PRFS and ECOG, and assessed predictive accuracy of these measures using the C-statistic. RESULTS: For the 949 patients, there was moderate agreement between PRFS and ECOG (weighted Kappa 0.32; 95% CI: 0.28-0.36). On average, patients' ratings of performance status were worse by 0.31 points (95% CI: 0.25-0.37, P < 0.0001); this tendency was greater for younger patients (P = 0.002) and those with worse symptoms (P < 0.0001). Both PRFS and ECOG scores correlated well with overall survival; the C-statistic was higher for the average of PRFS and ECOG scores (0.619) than when reported individually (0.596 and 0.604, respectively). CONCLUSION: Patients tend to rate their performance status worse than physicians, particularly if they are younger or have greater symptom burden. Prognostic ability of performance status could be improved by using the average of patients and physician scores. PMID- 29496535 TI - Refractory Schizophrenia, Attempted Suicide, and Withdrawal of Life Support: A Clinical Ethics Case Report. AB - BACKGROUND: Withdrawal of life support for an individual with refractory schizophrenia after attempted suicide remains controversial. Discussion regarding prognosis of mental illness and the distinction between somatic and mental illness brings out many ethical issues. This article will examine the role and weight of severe persistent mental illness in the withdrawal of life support after attempted suicide. CASE DESCRIPTION: A 30-year-old gentleman with deafness and schizophrenia was admitted with multiple self-inflicted visceral stab wounds. He developed postoperative complications necessitating ongoing critical care. The parties involved were as follows: the patient, his parents, the critical care trauma service, the palliative and psychiatry consult services, and the ethics committee. Over the patient's hospital course, his parents struggled to reconcile his poor preinjury quality of life with his ongoing need for intensive medical intervention. The primary and consulting teams were required to integrate differing perspectives on the patient's past responsiveness to treatment and the extent to which additional efforts might advance his quality of life and limit his future suffering and suicidality. The patient's surrogate decision makers unanimously requested withdrawal of life support. An ethics committee convened to address the question of whether refractory schizophrenia can produce so poor a quality of life as to merit the withdrawal of life-sustaining measures after a suicide attempt. Consensus was achieved, and life-sustaining measures were subsequently withdrawn, allowing the patient to pass away peacefully in an inpatient hospice facility. PMID- 29496536 TI - Cognitive Impairment and Pain Among Nursing Home Residents With Cancer. AB - CONTEXT: The prevalence of pain and its management has been shown to be inversely associated with greater levels of cognitive impairment. OBJECTIVES: To evaluate whether the documentation and management of pain varies by level of cognitive impairment among nursing home residents with cancer. METHODS: Using a cross sectional study, we identified all newly admitted U.S. nursing home residents with a cancer diagnosis in 2011-2012 (n = 367,462). Minimum Data Set 3.0 admission assessment was used to evaluate pain/pain management in the past five days and cognitive impairment (assessed via the Brief Interview for Mental Status or the Cognitive Performance Scale for 91.6% and 8.4%, respectively). Adjusted prevalence ratios with 95% CI were estimated from robust Poisson regression models. RESULTS: For those with staff-assessed pain, pain prevalence was 55.5% with no/mild cognitive impairment and 50.5% in those severely impaired. Pain was common in those able to self-report (67.9% no/mild, 55.9% moderate, and 41.8% severe cognitive impairment). Greater cognitive impairment was associated with reduced prevalence of any pain (adjusted prevalence ratio severe vs. no/mild cognitive impairment; self-assessed pain 0.77; 95% CI 0.76-0.78; staff-assessed pain 0.96; 95% CI 0.93-0.99). Pharmacologic pain management was less prevalent in those with severe cognitive impairment (59.4% vs. 74.9% in those with no/mild cognitive impairment). CONCLUSION: In nursing home residents with cancer, pain was less frequently documented in those with severe cognitive impairment, which may lead to less frequent use of treatments for pain. Techniques to improve documentation and treatment of pain in nursing home residents with cognitive impairment are needed. PMID- 29496537 TI - Machine Learning Methods to Extract Documentation of Breast Cancer Symptoms From Electronic Health Records. AB - CONTEXT: Clinicians document cancer patients' symptoms in free-text format within electronic health record visit notes. Although symptoms are critically important to quality of life and often herald clinical status changes, computational methods to assess the trajectory of symptoms over time are woefully underdeveloped. OBJECTIVES: To create machine learning algorithms capable of extracting patient-reported symptoms from free-text electronic health record notes. METHODS: The data set included 103,564 sentences obtained from the electronic clinical notes of 2695 breast cancer patients receiving paclitaxel containing chemotherapy at two academic cancer centers between May 1996 and May 2015. We manually annotated 10,000 sentences and trained a conditional random field model to predict words indicating an active symptom (positive label), absence of a symptom (negative label), or no symptom at all (neutral label). Sentences labeled by human coder were divided into training, validation, and test data sets. Final model performance was determined on 20% test data unused in model development or tuning. RESULTS: The final model achieved precision of 0.82, 0.86, and 0.99 and recall of 0.56, 0.69, and 1.00 for positive, negative, and neutral symptom labels, respectively. The most common positive symptoms were pain, fatigue, and nausea. Machine-based labeling of 103,564 sentences took two minutes. CONCLUSION: We demonstrate the potential of machine learning to gather, track, and analyze symptoms experienced by cancer patients during chemotherapy. Although our initial model requires further optimization to improve the performance, further model building may yield machine learning methods suitable to be deployed in routine clinical care, quality improvement, and research applications. PMID- 29496538 TI - A positive feedback loop of IL-17B-IL-17RB activates ERK/beta-catenin to promote lung cancer metastasis. AB - Inflammation contributes to the development and progression of cancer. Interleukin-17 (IL-17) is an inflammatory cytokine that functions in inflammation and cancer, as well as several other cellular processes. In this study, we investigated the roles and the prognostic value of IL-17 and the IL-17 receptor (IL-17R) in lung cancer. Gene expression microarray analysis followed by Kaplan Meier survival curve showed that IL-17B was associated with poor patient survival, and IL-17B receptor (IL-17RB) was up-regulated in lung cancer tissue compared with normal tissue. Expression of IL-17RB was associated with lymph node metastasis and distant metastasis, as well as poor patient survival. IL-17RB overexpression significantly increased cancer cell invasion/migration and metastasis in vitro and in vivo. IL-17RB induced ERK phosphorylation, resulting in GSK3beta inactivation and leading to beta-catenin up-regulation. IL-17RB also participated in IL-17B synthesis via the ERK pathway. IL-17RB activation is required for IL-17B-mediated ERK phosphorylation. Taken together, IL-17B-IL-17RB signaling and ERK participate in a positive feedback loop that enhances invasion/migration ability in lung cancer cell lines. IL-17RB may therefore serve as an independent prognostic factor and a therapeutic target for lung cancer. PMID- 29496539 TI - Sabutoclax, pan-active BCL-2 protein family antagonist, overcomes drug resistance and eliminates cancer stem cells in breast cancer. AB - Misregulation of BCL-2 family of proteins renders a survival signal to withstand cytotoxic anticancer drugs and is often found in drug resistant cells. The drug resistance phenotype is also associated with an enhancement of cancer stem cell like (CSC) characteristics. Thus, inhibition of anti-apoptotic BCL-2 family proteins has been proposed as a possible antineoplastic strategy, and BCL-2 inhibitors are currently being clinically trailed in patients with leukemia, lymphoma or non-small cell lung cancer. However, the effects of BCL-2 inhibitors on drug resistant breast cancer have not yet been elucidated. In the present study, the effect of sabutoclax, a pan-active BCL-2 protein family antagonist, on two chemoresistant breast cancer cell lines was assessed. We found that sabutoclax showed a significant cytotoxic activity on chemoresistant breast cancer cells both in vitro and in vivo. When chemotherapeutic agents were combined with sabutoclax, strong synergistic antiproliferative effects were observed. Sabutoclax induced the blockage of BCL-2, MCL-1, BCL-xL and BFL-1, which in turn led to caspase-3/7 and caspase-9 activation and modulation of Bax, Bim, PUMA and survivin expression. Furthermore, sabutoclax effectively eliminated the CSC subpopulation and reduced sphere formation of drug-resistant cells through down-regulation of the IL-6/STAT3 signaling pathway. A similar effect was observed in a small panel of nine breast tumors ex vivo. Our findings indicate that sabutoclax partially overcomes the drug resistance phenotype of breast cancer cells by reactivation of apoptosis, mediated by the inhibition of several anti-apoptotic BCL-2 family proteins, and eliminates CSCs by abolition of the IL 6/STAT3 pathway. This offers a strong rationale to explore the therapeutic strategy of using sabutoclax alone or in combination for chemotherapy nonresponsive breast cancer patients. PMID- 29496541 TI - Pseudo-parallel patterns of disjunctions in an Arctic-alpine plant lineage. AB - Disjunct distributions have intrigued biologists for centuries. Investigating these biogeographic patterns provides insight into speciation and biodiversity at multiple spatial and phylogenetic scales. Some disjunctions have been intensively studied, yet others have been largely overlooked and remain poorly understood. Among the lesser-known disjunction patterns is that between the mountain ranges of western North America. Flora and fauna endemic to the mountains of this region provide important systems for investigating causes and results of disjunctions, given the relatively recent geological formation of this area and the intense climatic fluctuations that have occurred since its formation. In Micranthes (Saxifragaceae), which has high rates of montane endemism, two species, M. bryophora and M. tolmiei, show this biogeographical pattern. By reconstructing a time-calibrated phylogeny based on 518 low-copy nuclear markers and including multiple populations of each species from the Coast Ranges, Cascades, Sierra Nevada, and Rocky Mountains, this study provides a biogeographical and temporal framework for the evolution of Micranthes in western North America. Strongly supported east-west differentiated clades are recovered for M. bryophora and M. tolmiei in both maximum likelihood and coalescent-based species tree reconstructions. Biogeographic analysis suggests different patterns of dispersal for both taxa and the dating analyses recovered contrasting ages for each clade. Due to both the different geographic patterns and the timing of the initial diversification of each taxon corresponding to different geologic and climatic events, the disjunction patterns shown for these taxa are suggested to be an example of biogeographical pseudocongruence. PMID- 29496540 TI - Stable incorporation of GM-CSF into dissolvable microneedle patch improves skin vaccination against influenza. AB - The widely used influenza subunit vaccine would benefit from increased protection rates in vulnerable populations. Skin immunization by microneedle (MN) patch can increase vaccine immunogenicity, as well as increase vaccination coverage due to simplified administration. To further increase immunogenicity, we used granulocyte-macrophage colony stimulating factor (GM-CSF), an immunomodulatory cytokine already approved for skin cancer therapy and cancer support treatment. GM-CSF has been shown to be upregulated in skin following MN insertion. The GM CSF-adjuvanted vaccine induced robust and long-lived antibody responses cross reactive to homosubtypic and heterosubtypic influenza viruses. Addition of GM-CSF resulted in increased memory B cell persistence relative to groups given influenza vaccine alone and led to rapid lung viral clearance following lethal infection with homologous virus in the mouse model. Here we demonstrate that successful incorporation of the thermolabile cytokine GM-CSF into MN resulted in improved vaccine-induced protective immunity holding promise as a novel approach to improved influenza vaccination. To our knowledge, this is the first successful incorporation of a cytokine adjuvant into dissolvable MNs, thus advancing and diversifying the rapidly developing field of MN vaccination technology. PMID- 29496542 TI - Synchronous diversification of parachuting frogs (Genus Rhacophorus) on Sumatra and Java. AB - Geological and climatological processes can drive the synchronous diversification of co-distributed species. The islands of Sumatra and Java have experienced complex geological and climatological histories, including extensive sea-level changes and the formation of valleys between northern, central, and southern components of the Barisan Mountain Range, which may have promoted diversification of their resident species. We investigate diversification on these islands using 13 species of the parachuting frog genus Rhacophorus. We use both mitochondrial and nuclear sequence data, along with genome-wide SNPs to estimate phylogenetic structure and divergence times, and to test for synchronous diversification. We find support for synchronous divergence among sister-species pairs from Sumatra and Java ~9 Ma, as well as of populations of four co-distributed taxa on Sumatra ~5.6 Ma. We found that sister species diverged in allopatry on Sumatra and conclude that divergence on Sumatra and Java was affected by sea-level fluctuations that promoted isolation in allopatry. PMID- 29496543 TI - beta- Adrenoceptors activate hepatic glutathione efflux through an unreported pathway. AB - The physiological regulation of hepatic glutathione efflux by catecholamines is poorly understood. The purpose of this work was to review the role of adrenergic receptors (AR) on total glutathione (GT) efflux in rat liver. Two models were used: isolated hepatocytes and perfused livers. In hepatocytes 10 MUM adrenaline (Adr), but not isoproterenol (Iso) a beta-AR agonist, or phenylephrine (Phe) an alpha1-AR agonist, (in a Krebs-Henseleit buffer (KHB) enriched with Ca2+ and some aminoacids) increased in 13% GT efflux. In livers perfused with KHB, Adr or Iso at 1 MUmolar doses (but not Phe) stimulated 11-fold initial velocity of GT release, but only during the first 2 min of perfusion. This immediate response progressively disappeared during the following 15 min of perfusion. A second phase of GT efflux, observed between 2 and 14 min of perfusion, mimics the one reported earlier in isolated hepatocytes. The ED50 for Adr and Iso activation are in the range of 320 nM and 10 nM, respectively. Iso-mediated GT release requires Ca2+ to work, and was prevented by H89, glibenclamide, cystic fibrosis transmembrane regulator (CFTR) antibodies, and a direct CFTR inhibitor. This short-lived GT release system is associated to PKA activation and probably operates through CFTR. PMID- 29496544 TI - Frontotemporal dysregulation of the SNARE protein interactome is associated with faster cognitive decline in old age. AB - The molecular underpinnings associated with cognitive reserve remain poorly understood. Because animal models fail to fully recapitulate the complexity of human brain aging, postmortem studies from well-designed cohorts are crucial to unmask mechanisms conferring cognitive resistance against cumulative neuropathologies. We tested the hypothesis that functionality of the SNARE protein interactome might be an important resilience factor preserving cognitive abilities in old age. Cognition was assessed annually in participants from the Rush "Memory and Aging Project" (MAP), a community-dwelling cohort representative of the overall aging population. Associations between cognition and postmortem neurochemical data were evaluated in functional assays quantifying various species of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) machinery in samples from the inferior temporal (IT, n = 154) and middle-frontal (MF, n = 174) gyri. Using blue-native gel electrophoresis, we isolated and quantified several types of complexes containing the three SNARE proteins (syntaxin-1, SNAP25, VAMP), as well as the GABAergic/glutamatergic selectively expressed complexins-I/II (CPLX1/2), in brain tissue homogenates and reconstitution assays with recombinant proteins. Multivariate analyses revealed significant associations between IT and MF neurochemical data (SNARE proteins and/or complexes), and multiple age-related neuropathologies, as well as with multiple cognitive domains of MAP participants. Controlling for demographic variables, neuropathologic indices and total synapse density, we found that temporal 150-kDa SNARE species (representative of pan-synaptic functionality) and frontal CPLX1/CPLX2 ratio of 500-kDa heteromeric species (representative of inhibitory/excitatory input functionality) were, among all the immunocharacterized complexes, the strongest predictors of cognitive function nearest death. Interestingly, these two neurochemical variables were associated with different cognitive domains. In addition, linear mixed effect models of global cognitive decline estimated that both 150-kDa SNARE levels and CPLX1/CPLX2 ratio were associated with better cognition and less decline over time. The results are consistent with previous studies reporting that synapse dysfunction (i.e. dysplasticity) may be initiated early, and relatively independent of neuropathology-driven synapse loss. Frontotemporal dysregulation of the GABAergic/glutamatergic stimuli might be a target for future drug development. PMID- 29496545 TI - Calculating a Continuous Metabolic Syndrome Score Using Nationally Representative Reference Values. AB - OBJECTIVE: The prevalence of metabolic syndrome in youth varies on the basis of the classification system used, prompting implementation of continuous scores; however, the use of these scores is limited to the sample from which they were derived. We sought to describe the derivation of the continuous metabolic syndrome score using nationally representative reference values in a sample of obese adolescents and a national sample obtained from National Health and Nutrition Examination Survey (NHANES) 2011-2012. METHODS: Clinical data were collected from 50 adolescents seeking obesity treatment at a stage 3 weight management center. A second analysis relied on data from adolescents included in NHANES 2011-2012, performed for illustrative purposes. The continuous metabolic syndrome score was calculated by regressing individual values onto nationally representative age- and sex-specific standards (NHANES III). Resultant z scores were summed to create a total score. RESULTS: The final sample included 42 obese adolescents (15 male and 35 female subjects; mean age, 14.8 +/- 1.9 years) and an additional 445 participants from NHANES 2011-2012. Among the clinical sample, the mean continuous metabolic syndrome score was 4.16 +/- 4.30, while the NHANES sample mean was quite a bit lower, at -0.24 +/- 2.8. CONCLUSIONS: We provide a method to calculate the continuous metabolic syndrome by comparing individual risk factor values to age- and sex-specific percentiles from a nationally representative sample. PMID- 29496546 TI - Development and Validation of the Pediatric Medical Complexity Algorithm (PMCA) Version 3.0. AB - OBJECTIVE: To modify the Pediatric Medical Complexity Algorithm (PMCA) to include both International Classification of Diseases, Ninth and Tenth Revisions, Clinical Modification (ICD-9/10-CM) codes for classifying children with chronic disease (CD) by level of medical complexity and to assess the sensitivity and specificity of the new PMCA version 3.0 for correctly identifying level of medical complexity. METHODS: To create version 3.0, PMCA version 2.0 was modified to include ICD-10-CM codes. We applied PMCA version 3.0 to Seattle Children's Hospital data for children with >=1 emergency department (ED), day surgery, and/or inpatient encounter from January 1, 2016, to June 30, 2017. Starting with the encounter date, up to 3 years of retrospective discharge data were used to classify children as having complex chronic disease (C-CD), noncomplex chronic disease (NC-CD), and no CD. We then selected a random sample of 300 children (100 per CD group). Blinded medical record review was conducted to ascertain the levels of medical complexity for these 300 children. The sensitivity and specificity of PMCA version 3.0 was assessed. RESULTS: PMCA version 3.0 identified children with C-CD with 86% sensitivity and 86% specificity, children with NC-CD with 65% sensitivity and 84% specificity, and children without CD with 77% sensitivity and 93% specificity. CONCLUSIONS: PMCA version 3.0 is an updated publicly available algorithm that identifies children with C-CD, who have accessed tertiary hospital emergency department, day surgery, or inpatient care, with very good sensitivity and specificity when applied to hospital discharge data and with performance to earlier versions of PMCA. PMID- 29496547 TI - Evaluation of Over-the-Counter Medication Knowledge and Literacy in Adolescent Students. AB - OBJECTIVE: To 1) assess and compare knowledge and literacy of over-the-counter (OTC) medications among middle school (MS) and high school (HS) students, and 2) to assess student self-identified lack of knowledge regarding OTC medications. METHODS: A convenience sample of suburban adolescent students completed a 2-part survey about OTC medications: part 1 included demographics and baseline knowledge of OTCs, and part 2 included medication label interpretation (literacy). Descriptive statistics and chi-square test were used to summarize and compare responses among MS and HS students. RESULTS: Students (n = 309) were in MS (46.2%) and HS (53.8%), with a mean age of 14 +/- 1.8 years, 61.4% male, 81.2% white, and 84.3% non-Hispanic. A majority of students (68.5%) agreed that they always speak with an adult before taking medication. Students responded correctly to 19% of brand versus generic knowledge questions; conversely, 65% selected "I don't know." Similar trends were seen for questions about medication indications (26% correct, 59% didn't know), side-effects (8% correct, 67% didn't know), and combining medications (21% correct, 63% didn't know). When students referenced a medication label, 55% answered label interpretation questions correctly and 30% reported "I don't know." HS students answered more questions correctly and were less likely to report "I don't know" to questions about common OTC medications (eg, ibuprofen, Tylenol, etc) compared with MS students (P < .05). DISCUSSION: Overall, baseline knowledge of OTC medications was low; however, students were better at interpretation of drug labels. MS students self-reported less knowledge about common OTC medications compared with HS students. This study provides an important foundation for future OTC medication educational programs for adolescents. PMID- 29496548 TI - Sclerosed Hemangioma of the Liver in a 17-Year-Old. PMID- 29496549 TI - Studying microRNAs in osteoarthritis: Critical overview of different analytical approaches. AB - MicroRNAs are small non-coding RNA species with the ability to post transcriptionally control the expression of multiple genes, that have gained substantial interest because of their expression alterations that accompanies aging and possible age-related pathologies. Given the constant rise in the number of patients suffering from age-related diseases -due to the increase of the aging population in the western world- the exploration of the role of specific microRNAs in the etiopathology of these diseases is expected to have great impact. Degenerative arthritis or osteoarthritis is of the most common age related diseases and possible the one with the most limited therapeutic options. In this review therefore, we highlight recent advances considering the implication of microRNAs in processes known to contribute to the development of this disease. We also critically present the analytical approaches adopted so far, in an attempt to facilitate the acknowledgment of the necessary experimental tactic that will lead to the establishment of microRNAs as biomarkers and/or therapeutic agents for this age-related pathology. PMID- 29496550 TI - Seasonal variation of pituitary gonadotropin subunit, brain-type aromatase and sex steroid receptor mRNAs, and plasma steroids during gametogenesis in wild sablefish. AB - Pituitary-hormone signaling plays critical roles in the onset and progression of gametogenesis in vertebrates. This study characterized expression patterns of pituitary gonadotropin beta-subunits (fshb and lhb), brain-type aromatase (cyp19a1b), androgen (ar1, ar2) and estrogen receptors (esr1, esr2a, esr2b), and changes in plasma steroid levels by liquid chromatography/tandem mass spectrometry in wild sablefish (Anoplopoma fimbria, order Scorpaeniformes) during a complete reproductive cycle. Transcripts for fshb increased during early gametogenesis and peaked in late vitellogenic females and late recrudescent males, while expression of lhb reached maximum levels in periovulatory and spermiating fish. Pituitary levels of cyp19a1b and ar1 were strongly correlated with those of lhb in females and males, increasing during gametogenesis and reaching maximum levels prior to spawning. By contrast, expression of ar2, and the three estrogen receptors differed between female and male sablefish. 17beta estradiol (E2) was the dominant steroid in females during vitellogenesis, while a range of at least 6 steroids (11beta-hydroxyandrostenedione, testosterone [T], E2, 11-ketotestosterone [11KT], 11-deoxycortisol, and 17alpha,20beta,21 trihydroxyprogesterone) were detected at similar levels in males during testicular development. Prior to spawning, a marked increase in 4 androstenedione, T, 11KT and E2 was found in both periovulatory females and spermiating males. In conclusion, the concomitant changes in plasma androgen levels and pituitary ar1 expression during gametogenesis suggest a specific role for androgens in pituitary hormone regulation of reproduction in sablefish. Further, our data highlight the importance of E2 during final stages of maturation in this species, which may regulate the transcription of pituitary lhb in a paracrine fashion. PMID- 29496551 TI - A brief update on physical and optical disector applications and sectioning staining methods in neuroscience. AB - A quantitative description of a three-dimensional (3D) object based on two dimensional images can be made using stereological methods These methods involve unbiased approaches and provide reliable results with quantitative data. The quantitative morphology of the nervous system has been thoroughly researched in this context. In particular, various novel methods such as design-based stereological approaches have been applied in neuoromorphological studies. The main foundations of these methods are systematic random sampling and a 3D approach to structures such as tissues and organs. One key point in these methods is that selected samples should represent the entire structure. Quantification of neurons, i.e. particles, is important for revealing degrees of neurodegeneration and regeneration in an organ or system. One of the most crucial morphometric parameters in biological studies is thus the "number". The disector counting method introduced by Sterio in 1984 is an efficient and reliable solution for particle number estimation. In order to obtain precise results by means of stereological analysis, counting items should be seen clearly in the tissue. If an item in the tissue cannot be seen, these cannot be analyzed even using unbiased stereological techniques. Staining and sectioning processes therefore play a critical role in stereological analysis. The purpose of this review is to evaluate current neuroscientific studies using optical and physical disector counting methods and to discuss their definitions and methodological characteristics. Although the efficiency of the optical disector method in light microscopic studies has been revealed in recent years, the physical disector method is more easily performed in electron microscopic studies. Also, we offered to readers summaries of some common basic staining and sectioning methods, which can be used for stereological techniques in this review. PMID- 29496552 TI - Identification of a tyrosinase gene and its functional analysis in melanin synthesis of Pteria penguin. AB - Tyrosinase is a key rate-limiting enzyme in melanin synthesis. In this study, a new tyrosinase gene (Tyr) was identified from Pteria penguin and its effect on melanin synthesis was deliberated by RNA interference (RNAi). The cDNA of PpTyr was 1728 bp long, containing a 5'untranslated region (UTR) of 11 bp, a 3'UTR of 295 bp, and an open reading fragment of 1422 bp encoding 473 amino acids. Amino acid alignment showed PpTyr had the highest (50%) identity to tyrosinase-like protein 1 from Pinctada fucata. Phylogenetic tree analysis classified PpTyr into alpha-subclass of type-3 copper protein. Tissue expression analysis indicated that PpTyr was highly expressed in mantle, a nacre formation related tissue. After PpTyr RNA interference, PpTyr mRNA was significantly inhibited by 71.0% (P < 0.05). For other melanin-related genes, PpCreb2 and PpPax3 expression showed no significant change, but PpBcl2 was obviously increased. By liquid chromatograph tandem mass spectrometer (LC-MS/MS) analysis, the total content of PDCA (pyrrole 2, 3-dicarboxylic acid) and PTCA (pyrrole-2,3,5-tricarboxylic acid), as main markers for eumelanin, was sharply decreased by 66.6% after PpTyr RNAi (P < 0.05). The percentage of PDCA was also obviously decreased from 20.1% to 13.9%. This indicated that tyrosinase played a key role in melanin synthesis and color formation of P. penguin. PMID- 29496553 TI - Polymorphism in promoter of SIX4 gene shows association with its transcription and body measurement traits in Qinchuan cattle. AB - The sine oculis homeobox homolog 4 (SIX4) gene belongs to the SIX gene family, which plays a critical role in muscle regeneration and early stages of ontogeny. This study aimed to detect promoter variations of bovine SIX4 genes in Qinchuan cattle, and to evaluate the effect of transcription regulations and body measurement traits. Quantitative real-time PCR (qPCR) results showed that the mRNA expression levels of SIX4 gene were found significantly highest in longissimus thoracis tissue and individual before attaining the stage of physiological maturity. Using sequencing technology on a total of 428 Qinchuan cattle, seven single nucleotide polymorphisms (SNPs) were identified in the promoter region of SIX4, and seven haplotypes representing 18 potential transcription factor compositions of polymorphic potential cis-acting elements. Association analysis indicated that the H3-H3 diplotype performed greater withers height, chest depth, chest circumference, back fat thickness and ultrasound loin muscle area (P < 0.05) than H5-H6, which were consistent with the promoter activity of Hap3 haplotype was higher than the Hap5 and Hap6 haplotype in vitro. These potential transcription factor information and combined genotypes H3-H3 of the SIX4 gene can be used as a molecular marker for selection of economic traits in Qinchuan cattle. PMID- 29496554 TI - Congenital hypoplastic bone marrow failure associated with a de novo partial deletion of the MECOM gene at 3q26.2. AB - Congenital hypoplastic bone marrow failure is a rare condition in neonates. The genetics and mechanisms behind are largely obscure. Here we characterize a neonate presenting with congenital thrombocytopenia and anemia. During the first 2-4 weeks after birth the neonate developed severe neutropenia while the lymphoid lineages were unaffected. The neonate was without dysmorphic signs. A de novo mono-allelic constitutional microdeletion of 175.1 kb at 3q26.2 affecting exon 2 of MECOM, involving MDS1 but not EVI1, was identified as the only copy number alteration by oligo-based array-CGH analysis. Expression analysis showed profoundly reduced expression of multiple MECOM transcripts in the bone marrow cells. Whole exome sequencing detected no pathogenic mutations in genes known to be associated with inherited bone marrow failure syndromes. The patient was successfully treated with hematopoietic stem cell transplantation at 5 months of age. Interstitial deletions encompassing the 3q26.2 region are very rare. A literature search revealed two previous cases with microdeletions involving this region, and the cases were associated with congenital thrombocytopenia and anemia, but unaffected lymphopoiesis. Together these data indicate that MECOM may be important for normal myeloid hematopoiesis in humans but dispensable for lymphoid differentiation. We suggest that partial deletion in MECOM may be a primary event associated with congenital pancytopenia. PMID- 29496555 TI - Comprehensive analysis of miRNAs expression profiles revealed potential key miRNA/mRNAs regulating colorectal cancer stem cell self-renewal. AB - Self-renewal is essential for the malignant biological behaviors of colorectal cancer stem cells. While the self-renewal molecular mechanisms of colorectal cancer stem cells are not yet fully understood. Recently, miRNAs are reported to be relevant to the self-renewal ability of cancer stem cells. In this study, we first isolated colorectal cancer stem cell from colorectal cancer cell line HCT 116 by 1% low serum culture. Then we conducted a comprehensive analysis based on the miRNAs profiles data of both colorectal cancer stem cells and normal cultured colorectal cancer cells. Pathway analysis revealed multiple pathways including Jak-STAT, TGF-beta, PI3K-Akt and MAPK signaling pathway that are correlated to colorectal cancer. Further, we constructed a miRNA-mRNA network, based on which, several miRNA/mRNA pairs were ranked according to their impact index to the self renewal of colorectal cancer stem cells. Further biological experiment showed that up-regulation of miR-92a-3p led to cell cycle arrest and reduced colony formation. This work provides clues to find the new potential biomarkers for colorectal cancer stem cell diagnosis and select effective miRNAs for targeted therapy. PMID- 29496556 TI - Molecular characterization of a novel algal glutamine synthetase (GS) and an algal glutamate synthase (GOGAT) from the colorful outer mantle of the giant clam, Tridacna squamosa, and the putative GS-GOGAT cycle in its symbiotic zooxanthellae. AB - Giant clams harbor symbiotic zooxanthellae (Symbiodinium), which are nitrogen deficient, mainly in the fleshy and colorful outer mantle. This study aimed to sequence and characterize the algal Glutamine Synthetase (GS) and Glutamate Synthase (GLT), which constitute the glutamate synthase cycle (or GS-GOGAT cycle, whereby GOGAT is the protein acronym of GLT) of nitrogen assimilation, from the outer mantle of the fluted giant clam, Tridacna squamosa. We had identified a novel GS-like cDNA coding sequence of 2325 bp, and named it as T. squamosa Symbiodinium GS1 (TSSGS1). The deduced TSSGS1 sequence had 774 amino acids with a molecular mass of 85 kDa, and displayed the characteristics of GS1 and Nucleotide Diphosphate Kinase. The cDNA coding sequence of the algal GLT, named as T. squamosa Symbiodinium GLT (TSSGLT), comprised 6399 bp, encoding a protein of 2133 amino acids and 232.4 kDa. The zooxanthellal origin of TSSGS1 and TSSGOGAT was confirmed by sequence comparison and phylogenetic analyses. Indeed, TSSGS1 and TSSGOGAT were expressed predominately in the outer mantle, which contained the majority of the zooxanthellae. Immunofluorescence microscopy confirmed the expression of TSSGS1 and TSSGOGAT in the cytoplasm and the plastids, respectively, of the zooxanthellae in the outer mantle. It can be concluded that the symbiotic zooxanthellae of T. squamosa possesses a glutamate synthase (TSSGS1 TSSGOGAT) cycle that can assimilate endogenous ammonia produced by the host clam into glutamate, which can act as a substrate for amino acid syntheses. Thus, our results provide insights into why intact giant clam-zooxanthellae associations do not excrete ammonia under normal circumstances. PMID- 29496557 TI - Human catalase gene promoter haplotype and cardiometabolic improvement after bariatric surgery. AB - Although its powerful impact on most co-morbidities has been widely demonstrated, the metabolic outcomes of bariatric surgery (BS) show a great heterogeneity among patients. Haplotypes of one of the major antioxidant enzyme, catalase (CAT), are associated with hypertension, dyslipidemia, and diabetes. The haplotype referred to as CAT1 includes homozygous carriers of CATH1 [-844G,-89A,-20T], whereas CAT2 haplotype includes heterozygous carriers (CATH1/CATH2) and CATH2 homozygous [ 844A,-89T,-20C]. The aim of our study was to evaluate the impact of CAT1 and CAT2 haplotypes on traditional cardiovascular and metabolic markers one year after BS in a women population. The 294 women with a body mass index (BMI) >35 kg/m2 were followed-up for one year after BS, monitoring their anthropometric, metabolic and inflammatory parameters. CAT1 patients had significantly improved diastolic blood pressure (DBP) and Creactive protein (CRP) levels compared to CAT2 one year after BS. In untreated women at baseline, the change of CRP one year after BS was higher in CAT1 patients. In the population of women receiving at least one anti lipidic, anti-hypertensive or anti-diabetic treatment at baseline, DBP and fat mass were lower one year after BS in CAT1 patients and the greater change of fat mass was associated with a higher change of adiponectin. The results highlight the beneficial impact of the CAT1 haplotype on traditional cardiovascular and metabolic parameters after BS. Our findings suggest that the CAT1 haplotype could be implicated in the level of metabolic and cardiovascular improvement after BS. PMID- 29496558 TI - Diagnosis and therapy with CRISPR advanced CRISPR based tools for point of care diagnostics and early therapies. AB - Molecular diagnostics is of critical importance to public health worldwide. It facilitates not only detection and characterization of diseases, but also monitors drug responses, assists in the identification of genetic modifiers and disease susceptibility. Based upon DNA variation, a wide range of molecular-based tests are available to assess/diagnose diseases. The CRISPR-Cas9 system has recently emerged as a versatile tool for biological and medical research. In this system, a single guide RNA (sgRNA) directs the endonuclease Cas9 to a targeted DNA sequence for site-specific manipulation. As designing CRISPR-guided nucleases can be done easily and relatively fast, the CRISPR/Cas9 system has evolved as widely used DNA editing tool. This technique led to a large number of gene editing studies in variety of organisms. CRISPR/Cas9-mediated diagnosis and therapy has picked up pace due to specificity and accuracy of CRISPR. The aim is not only to identify specific pathogens, especially virus but also to repair disease-causing alleles by changing the DNA sequence at the exact location on the chromosome. At present, PCR-based molecular diagnostic testing predominates; however, alternative technologies aimed at reducing genome complexity without PCR are anticipated to gain momentum in the coming years. Furthermore, development of integrated chip devices should allow point-of-care testing and facilitate genetic readouts from single cells and molecules. Together with molecular based therapy CRISPR based diagnostic testing will be a revolution in modern health care settings. In this review, we emphasize on current developing diagnostic techniques based upon CRISPR Cas approach along with short insights on its therapeutic usage. PMID- 29496559 TI - Functional effects of substitutions I92T and V95A in actin-binding period 3 of tropomyosin. PMID- 29496560 TI - Capreomycin inhibits the initiation of amyloid fibrillation and suppresses amyloid induced cell toxicity. AB - Protein aggregation and amyloid fibrillation are responsible for several serious pathological conditions (like type II diabetes, Alzheimer's and Parkinson's diseases etc.) and protein drugs ineffectiveness. Therefore, a molecule that can inhibit the amyloid fibrillation and potentially clear amyloid fibrils is of great therapeutic value. In this manuscript, we investigated the antiamyloidogenic, fibril disaggregating, as well as cell protective effect of an anti-tuberculosis drug, Capreomycin (CN). Aggregation kinetics data, as monitored by ThT fluorescence, inferred that CN retards the insulin amyloid fibrillation by primarily targeting the fibril elongation step with little effect on lag time. Increasing the dose of CN boosted its inhibitory potency. Strikingly, CN arrested the growth of fibrils when added during the elongation phase, and disaggregated mature insulin fibrils. Our Circular Dichroism (CD) results showed that, although CN is not able to maintain the alpha helical structure of protein during fibrillation, reduces the formation of beta sheet rich structure. Furthermore, Dynamic Light Scattering (DLS) and Transmission Electronic Microscopy (TEM) analysis confirmed that CN treated samples exhibited different size distribution and morphology, respectively. In addition, molecular docking results revealed that CN interacts with insulin through hydrophobic interactions as well as hydrogen bonding, and the Hemolytic assay confirmed the non-hemolytic activity of CN on human RBCs. For future research, this study may assist in the rational designing of molecules against amyloid formation. PMID- 29496561 TI - Evolution of Body Composition Following Autologous and Allogeneic Hematopoietic Cell Transplantation: Incidence of Sarcopenia and Association with Clinical Outcomes. AB - Sarcopenia, the loss of muscle mass, has been identified as a potential risk factor for adverse outcomes in hematopoietic cell transplantation (HCT) recipients. However, much remains unknown about change in body composition following HCT. We retrospectively evaluated computed tomography (CT) imaging from 315 lymphoma patients undergoing HCT at our institution between 2000 and 2014. Cross-sectional areas of lean muscle, subcutaneous adipose tissue, and visceral adipose tissue were measured on CT at the level of the third lumbar vertebral body before HCT, 1-year post-HCT, and 2.5 years post-HCT. The incidence of sarcopenia before HCT was 47% in the autologous HCT (auto-HCT) cohort (n = 218) and 55% in the allogeneic HCT (allo-HCT) cohort (n = 97). Older age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.01 to 1.04; P < .001) and male sex (OR, 4.59; 95% CI, 1.42 to 4.93; P < .001) were associated with sarcopenia before HCT. Increasing body mass index (OR, .78; 95% CI, .73 to .84; P < .001) was protective against sarcopenia before HCT. A significant decline in total lean body mass (beta = 1.96; 95% CI, .79 to 3.13; P = .001) and increased sarcopenia incidence (OR, 1.72; 95% CI, 1.13 to 2.62, P = .012) was observed over time for patients in the allo-HCT cohort when compared with the trend in the auto-HCT cohort. Both auto-HCT and allo-HCT recipients experienced an increase in total body fat mass over time (beta = 3.75; 95% CI, 2.77 to 4.73; P < .001). In multivariate analysis of patients undergoing allo-HCT, the presence of sarcopenia on baseline imaging before HCT was associated with a lower risk of acute graft versus-host disease (OR, .30; 95% CI, .09 to .98; P = .047). In conclusion, we found that total body fat mass increases after both auto-HCT and allo-HCT. Following allo-HCT, total lean body mass significantly decreases corresponding to increased incidence of sarcopenia. Future studies are needed to further characterize changes in body composition in HCT recipients and investigate its impact on HCT outcomes. PMID- 29496562 TI - Impaired Bone Mineral Density in Pediatric Patients with Chronic Graft-versus Host Disease. AB - Pediatric allogeneic hematopoietic stem cell transplantation (AHSCT) recipients with chronic graft-versus-host disease (cGVHD) are at high risk for endocrinopathies, particularly impaired bone mineral density (BMD). However, rates of BMD impairment in pediatric AHSCT recipients with cGVHD have not been well documented. We report 33 patients with cGVHD who were referred to the National Institutes of Health (NIH) for the Natural History of Clinical and Biological Factors Determining Outcomes in Chronic Graft-versus-Host Disease Study (NCT 0092235) and underwent formal BMD assessment via dual-energy X-ray absorptiometry (DEXA). Not surprisingly, we found much higher rates of BMD impairment than previously reported for pediatric AHSCT recipients who were not stratified by the presence or absence of cGVHD. Most of these patients (73%) had a z-score <=-2 in at least 1 anatomic site. Although we expected the rate to be higher than that observed for pediatric AHSCT recipients in studies that did not analyze patients with cGVHD separately, this rate is nonetheless extremely high. Furthermore, the overall rate of occult vertebral compression fractures (VCFs) in our cohort was 17%, and the rate was 23% in patients with at least 1 z-score of <=-2. The rates of BMD impairment and VCF in our pediatric cohort were significantly higher than those seen in the adult AHSCT recipients who were concurrently enrolled on the same study at the NIH and had similar cGVHD severity. We found that older age at cGVHD diagnosis and a greater number of systemic therapies were associated with occult VCF. Moreover, the intensity of current immunosuppression negatively impacted lumbar spine and total hip BMD in this cohort. Our study, although limited by small patient numbers and lack of a control AHSCT recipient group without cGVHD, indicates that children with cGVHD are at a greater risk for BMD impairment than previously appreciated. Given the rising incidence of cGVHD in AHSCT recipients and our findings, we recommend that pre-AHSCT DEXA be incorporated into routine pediatric pretransplantation screening studies. A baseline DEXA study could facilitate longitudinal monitoring of BMD in children, who may be more susceptible than adults to the negative effects of AHSCT on BMD. In addition, given the high risk of BMD impairment in pediatric AHSCT recipients with cGVHD, such patients should undergo BMD evaluation upon developing cGVHD, with continued monitoring thereafter to allow intervention before progression of the BMD impairment to its severe manifestation, VCF. PMID- 29496563 TI - Antiadhesive hydroalcoholic extract from Apium graveolens fruits prevents bladder and kidney infection against uropathogenic E. coli. AB - Fruits from Apium graveolens (Celery) are used traditionally in Persian and European medicine for the treatment of uncomplicated urinary tract infections. No data are available on A. graveolens extract on the interplay between uropathogenic E. coli and the eukaryotic host cells and on quorum sensing of the bacteria. The present study aimed to characterize an antiadhesive and anti quorum sensing effect of a characterized A. graveolens extract by specific in vitro assays and to correlate these effects with in vivo data obtained by an animal infection model. Hydroalcoholic extract CSE (EtOH-water, 1:1) from A. graveolens fruits was characterized by UHPLC/+ESI-QTOF-MS and investigated on antiproliferative activity against UPEC (strain NU14) and human T24 bladder cells. Antiadhesive properties of CSE were investigated within two different in vitro adhesion assays. For in vivo studies BALB/c mice were used in an UPEC infection model. The effect of CSE on bacterial load in bladder tissue was monitored within a 4- and 7 days pretreatment (200, 500 mg/kg) of the animals. CSE was dominated by the presence of luteolin-glycosides and related flavons besides furocoumarins. CSE had no cytotoxic effects against UPEC and bladder cells. CSE exerts a dose dependent antiadhesive activity against UPEC strains NU14 and UTI89. CSE inhibited in a concentration-dependent manner bacterial quorum sensing. 4- and 7-day pretreatment of animals with CSE transurethrally infected with UPEC NU14, significantly reduced the bacterial load in bladder tissue. CSE is assessed as an antiadhesive extract for which the traditional use in phytotherapy for UTI is justified. PMID- 29496564 TI - Cassaine diterpenoids from the seeds of Erythrophleum fordii and their cytotoxic activities. AB - Six new cassaine diterpenoids (1, 3-7), along with three known ones (2, 8-9) were isolated from the seeds of Erythrophleum fordii. Their structures were elucidated by extensive spectroscopic methods and acid hydrolysis. Compound 2 was tested to be the most potent one and showed more sensitive activities on MCF-7 and A549 cancer cells with IC50 values of 3.66 +/- 1.20 and 2.87 +/- 0.46 MUM, respectively. Furthermore, compound 2 reduced the number of cell colonies significantly in a dose-dependent manner in the colony formation assay and triggered apoptosis of MCF-7 cell. PMID- 29496565 TI - Endothelial nitric oxide synthase polymorphisms affect the changes in blood pressure and nitric oxide bioavailability induced by propofol. AB - Propofol anesthesia is usually accompanied by hypotension, which is at least in part related to enhanced endothelial nitric oxide synthase (NOS3)-derived NO bioavailability. We examined here whether NOS3 polymorphisms (rs2070744, 4b/4a VNTR, rs3918226 and rs1799983) and haplotypes affect the changes in blood pressure and NO bioavailability induced by propofol. Venous blood samples were collected from 168 patients at baseline and after 10 min of anesthesia with propofol 2 mg/kg administered intravenously by bolus injection. Genotypes were determined by polymerase chain reaction and haplotype frequencies were estimated. Nitrite concentrations were measured by using an ozone-based chemiluminescence assay, while NOx (nitrites + nitrates) levels were determined by using the Griess reaction. We found that CT + TT genotypes for the rs3918226 polymorphism, the ba + aa genotypes for the 4b/4a VNTR and the CTbT haplotype were associated with lower decreases in blood pressure and lower increases in nitrite levels after propofol anesthesia. On the other hand, the TCbT and CCbT haplotypes were associated with more intense decreases in blood pressure and higher increases in nitrite levels in response to propofol. Our results suggest that NOS3 polymorphisms and haplotypes influence the hypotensive responses to propofol, possibly by affecting NO bioavailability. PMID- 29496566 TI - Effects of repeated potassium iodide administration on genes involved in synthesis and secretion of thyroid hormone in adult male rat. AB - BACKGROUND: A single dose of potassium iodide (KI) is recommended to reduce the risk of thyroid cancer during nuclear accidents. However in case of prolonged radioiodine exposure, more than one dose of KI may be necessary. This work aims to evaluate the potential toxic effect of repeated administration of KI. METHODS: Adult Wistar rats received an optimal dose of KI 1 mg/kg over a period of 1, 4 or 8 days. RESULTS: hormonal status (TSH, FT4) of treated rats was unaffected. Contrariwise, a sequential Wolff-Chaikoff effect was observed, resulting in a prompt decrease of NIS and MCT8 mRNA expression (-58% and -26% respectively), followed by a delayed decrease of TPO mRNA expression (-33%) in conjunction with a stimulation of PDS mRNA expression (+62%). CONCLUSION: we show for the first time that repeated administration of KI at 1 mg/kg/24h doesn't cause modification of thyroid hormones level, but leads to a reversible modification of the expression of genes involved in the synthesis and secretion of thyroid hormones. PMID- 29496567 TI - Carnosine protects pancreatic beta cells and islets against oxidative stress damage. AB - Islet transplantation is a valid therapeutic option for type 1 diabetes treatment. However, in this procedure one of the major problems is the oxidative stress produced during pancreatic islet isolation. The aim of our study was to evaluate potential protective effects of L-carnosine and its isomer D-carnosine against oxidative stress. We evaluated the carnosine effect on cell growth, cell death, insulin production, and the main markers of oxidative stress in rat and murine stressed beta cell lines as well as in human pancreatic islets. Both isomers clearly inhibited hydrogen peroxide induced cytotoxicity, with a decrease in intracellular reactive oxygen and nitrogen species, prevented hydrogen peroxide induced apoptosis/necrosis, nitrite production, and reduced glucose induced insulin secretion. In addition, NF-kappaB expression/translocation and nitrated protein induced in stressed cells was significantly reduced. Furthermore, both isomers improved survival and function, and decreased reactive oxygen and nitrogen species, and nitrite and nitrotyrosine production in human islets cultured for 1, 3, and 7 days. These results seem to indicate that both L and D-carnosine have a significant cytoprotective effect by reducing oxidative stress in beta cell lines and human islets, suggesting their potential use to improve islet survival during the islet transplantation procedure. PMID- 29496568 TI - The Midterm Effect of Iliac Vein Stenting following Catheter-directed Thrombolysis for the Treatment of Deep Vein Thrombosis. AB - BACKGROUND: When following catheter-directed thrombolysis (CDT) for deep vein thrombosis (DVT), the stenosed iliac veins is controversy. To evaluate the mid term outcomes of CDT with or without stent implantation for DVT in the presence of iliac vein compression. METHODS: Seventy-three patients with iliac vein compression following CDT for acute lower extremity DVT from January 2009 to December 2014 were retrospectively analyzed. There were 32 males and 41 females, with average age of 53.57 +/- 15.60 years (median: 45 years, range: 20-79 years). After CDT, patients with iliac vein compression were divided into 2 groups: the stenting group (n = 40) and the nonstenting group (n = 33). Patency rate of the deep vein, chronic change of vessels, clinical, etiological, anatomical, and pathological elements (CEAP) classification, venous clinical severity score, and Villalta scale were chosen to evaluate the midterm and long-term outcomes. RESULTS: Eighty-eight limbs among the patients (58 unilateral and 15 bilateral) were followed with mean time of 38.38 +/- 14.91 months. The difference in vein patency between 2 groups (85.17 +/- 25.62 vs. 54.61 +/- 40.42) was statistically significant (P < 0.05). According to the C in CEAP classification, the difference in clinical manifestations between the 2 groups was statistically significant (P < 0.05). In addition, the Villalta scale scores were also significantly different between the 2 groups (1.73 +/- 2.86 vs. 4.39 +/- 5.16, P < 0.05). CONCLUSIONS: Stent implantation in severely stenosed iliac segments following CDT for lower extremity DVT increased the patency of deep veins and improved midterm quality of life compared with that of nonstenting. PMID- 29496569 TI - Preoperative Embolization May Increase Intraoperative Bleeding in Carotid Body Tumor Surgery. PMID- 29496570 TI - Spatial resolution for EEG source reconstruction-A simulation study on SEPs. AB - BACKGROUND: The accuracy of source reconstruction depends on the spatial configuration of the neural sources underlying encephalographic signals, the temporal distance of the source activity, the level and structure of noise in the recordings, and - of course - on the employed inverse method. This plenitude of factors renders a definition of 'spatial resolution' of the electro-encephalogram (EEG) a challenge. NEW METHOD: A proper definition of spatial resolution requires a ground truth. We used data from numerical simulations of two dipoles changed with waveforms resembling somatosensory evoked potentials peaking at 20, 30, 50, 100 ms. We varied inter-dipole distances and added noise to the simulated scalp recordings with distinct signal-to-noise ratios (SNRs). Prior to inverse modeling we pre-whitened the simulated data and the leadfield. We tested a two-dipole fit, sc-MUSIC, and sc-eLORETA and assessed their accuracy via the distance between the simulated and estimated sources. RESULTS: To quantify the spatial resolution of EEG, we introduced the notion of separability, i.e. the separation of two dipolar sources with a certain inter-dipole distance. Our results indicate separability of two sources in the presence of realistic noise with SNR up to 3 if they are 11 mm or further apart. COMPARISON WITH EXISTING METHODS: In the presence of realistic noise, spatial pre-whitening appears mandatory preprocessing step irrespective of the inverse method employed. CONCLUSIONS: Separability is a legitimate measure to quantify EEG's spatial resolution. An optimal resolution in source reconstruction requires spatial pre-whitening as a crucial pre-processing step. PMID- 29496571 TI - Unusual findings in Peutz-Jeghers syndrome: endoscopic and histologic appearance of gastric hamartomatous polyposis with foveolar dysplasia. PMID- 29496572 TI - Colonoscopy-induced hemoscrotum. PMID- 29496573 TI - Symptomatic large ampullary gastric heterotopia. PMID- 29496574 TI - Narrow-band imaging of a gastric carcinoma with lymphoid stroma associated with Epstein-Barr virus. PMID- 29496575 TI - Tracing the coevolution between Triatoma infestans and its fungal pathogen Beauveria bassiana. AB - The chemical control of Triatoma infestans, the major Chagas disease vector in southern South America, has been threatened in the last years by the emergence of pyrethroid-resistant bug populations. As an alternative approach, the efficacy of the entomopathogenic fungus Beauveria bassiana to control T. infestans populations (regardless their pyrethroid susceptibility) has been demonstrated. Growing research efforts on the interaction between T. infestans and B. bassiana by molecular, ecological, biochemical and behavioral traits has allowed framing such interaction as an evolutionary arms race. This review will focus on the relationships established in this particular host-pathogen system, compiling available data on the relevance of fungal pathogenesis, insect behavior, population dynamics and human intervention to favor fungal dissemination in bug populations. The current snapshot shows the fungus ahead in the evolutionary arms race and predicts a promissory landscape for the biological control of Chagas disease vectors. PMID- 29496576 TI - A water-soluble derivative of propolis augments the cytotoxic activity of natural killer cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Propolis, a resinous material collected from numerous plants by honeybees, has historically been used as a health-promoting food. Recently, due to its potential anti-tumor effects, use of propolis has been proposed as an adjuvant therapy to chemotherapy; however, the effects of propolis on immune responses remain unclear. AIM OF THE STUDY: In this study, we examined the effects of the oral ingestion of propolis on natural killer (NK) cell activity, which is important in immune surveillance against cancer and viral infections. In addition, we assessed the effects of the major components of the water-soluble powder derivative of propolis (WPP). MATERIALS AND METHODS: C57BL/6 (B6) wild-type (WT) and RAG 2-deficient (RAG-/-) mice and BALB/c WT, interferon (IFN)-gamma-deficient (IFN-gamma-/-), IFN-gamma receptor-deficient (IFN-gammaR-/ ) and RAG-/- mice were orally administered WPP or its major components. NK cell populations and cytotoxic activity were then examined by flow cytometry and 51Cr release assay, respectively. RESULTS: While the cytotoxic activity of NK cells was increased following administration of 100 mg/kg/day of WPP for 7 days or 200 or 500 mg/kg/day of WPP for 4 days in WT mice, the proportions of NK cell populations were unaltered. Similar activation of NK cell cytotoxicity was observed when RAG-/-, but not IFN-gamma-/- or IFN-gammaR-/-, mice were orally administered 200 mg/kg/day of WPP for 4 days. Oral ingestion of artepillin C or p coumaric acid, but not drupanin, augmented NK cell cytotoxicity in a manner similar to WPP and to the mixture of these three components. CONCLUSION: These results suggest that oral ingestion of WPP enhances NK cell cytotoxic activity, but not proliferation, in a manner dependent on IFN-gamma and without the contribution of acquired immune responses. Further, artepillin C or p-coumaric acid, but not drupanin, may be the components responsible for this augmentation of NK cell cytotoxicity. These findings suggest the possible utility of WPP as a therapeutic for prevention of cancer development and against viral infection through NK cell activation. PMID- 29496577 TI - Effects of indole alkaloids from leaf of Alstonia scholaris on post-infectious cough in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Leaf of Alstonia scholaris (L.) R. Br. (Apocynaceae), a wide used ethic-medicine in many Asia and Africa counties, has also been recorded as the common traditional Chinese medicine for treatment of illnesses in respiratory system by Dai people. AIM OF THE STUDY: To provide experimental data of clinical adaption of total indole alkaloids (TA) from leaf of A. scholaris for treating post-infectious cough in phase II clinical trial. MATERIALS AND METHODS: To model post-infectious cough, all animals except control group were instilled intra-tracheal with lipopolysaccharide (LPS) (80 MUg/50 uL/mouse), followed by subsequent exposure to cigarette smoke (CS) for 30 min per day for a total of 30 days. Mice were orally given TA at dose of 10, 25, 50 mg/kg, and four main alkaloids (Sch: scholaricine, Epi: 19-epischolaricine, Val: vallesamine, Pic: picrinine) once daily. Cellular infiltration was assessed in the broncho-alveolar lavage fluid (BALF). Expression of interleukin-6 (IL-6) and C-reactive protein (CRP) in the serum was determined, the superoxide dismutase (SOD) activity as well as malondialdehyde (MDA) content in the serum and homogenate were examined. Finally, histopathological examination in the lungs was assessed by H. E. staining. RESULTS: After administration of TA and four major alkaloids respectively, the symptoms of cough in mice were obviously attenuated. Total white blood cells (WBC) and neutrophils (NEU) amounts in BALF were reduced obviously and the pathological damage of lung was also attenuated. There was also significant reduction in IL-6, CRP, MDA and a marked improvement in SOD. CONCLUSIONS: The efficacy of indole alkaloids against post-infectious cough (PIC) was shown in the down-regulation of inflammatory cells, cytokines, and the balance of antioxidants. What's more, the pharmacological effects of TA were better than single indole alkaloid, which might be related to the synergic effect of four major alkaloids. PMID- 29496578 TI - Molecular cloning, expression pattern of follistatin gene and association analysis with growth traits in bighead carp (Hypophthalmichthys nobilis). AB - Follistatin (FST) is a single-chain gonadal protein involving in various biological effects. FST plays important roles in not only ovary development but also body growth, whereas myostatin (MSTN) negatively regulates muscle growth. In this study, FST gene in bighead carp (HynFST) was cloned and characterized. A 5797 bp genomic sequence of HynFST, consisting six exons and five introns were cloned. The full-length cDNA of HynFST (2134 bp) has an open reading fragment encoding a polypeptide of 349 amino acids. Sequence comparison and phylogenetic analysis confirmed that FSTs are conserved throughout the vertebrates and HynFST belongs to FST-1 isoform. Nine single nucleotide polymorphisms (SNPs) of the HynFST were identified and three of them (g.2443 T > C, g.2852 T > C and g.5483A > G) were significantly associated with four growth-related traits. The average body weight of those fish with the combined genotype (CC CC GG) was 12.15-22.63% higher than that of triplotype (TT TT AA) in two bighead carp populations. HynFST was expressed in most of the development stages and various tissues with highest level in ovary. The co-expression results for FST and MSTN in brain and muscle of divergent weight groups showed that FST may inhibit MSTN expression, thus enhancing growth in bighead carp. Our results suggest that FST has significant genetic effects on the regulation of early growth in bighead carp. This study would facilitate the elucidation of multiple functions of FST gene in fish and exploration of the potentials as a gene marker in selective breeding programs for growth of bighead carp. PMID- 29496579 TI - Visual pigment genes and absorbance spectra in the Japanese sardine Sardinops melanostictus (Teleostei: Clupeiformes). AB - The spectral absorbance of photoreceptor visual pigments and the opsin gene class of the visual pigments was investigated in Sardinops melanostictus. Microspectrophotometric (MSP) measurements showed that the rod photoreceptors had peak absorbance spectra (lambdamax) at 502 nm. The spectral sensitivity of single cones was centered at 393 nm. Double cones had a lambdamax of 493/522 nm, but a few displayed a red-shifted absorbance of the long-wave member at 542 nm. The mRNAs of six different opsins were isolated from the retina, retrotranscribed, cloned, and sequenced. Three genes encoded opsins in the green-sensitive class (RH2), and three genes encoded opsins in the red-sensitive class (LWS), the ultraviolet (UV)-sensitive (SWS1) class, and the rod class (RH1). A Southern blot analysis showed that the blue-sensitive (SWS2) opsin gene is absent from this species, hence it was concluded that the lambdamax of 393 nm was generated from the SWS1 opsin. Phylogenetic analyses of S. melanostictus RH1, LWS, and SWS1 sequences placed them with orthologs from other species (e.g., the cyprinids Danio rerio and Carrasius auratus) in Otomorpha. However, unexpectedly, the RH2 sequences were more similar to orthologs in members of the Euteleosteomorpha (e.g., Oryzias latipes and Takifugu rubripes) than to cyprinid RH2 opsins. PMID- 29496580 TI - Pediatric Supratentorial Ganglioneuroblastoma: Case Report and Review of Literature. AB - BACKGROUND: Pediatric cerebral ganglioneuroblastoma is an exceedingly rare tumor. CASE DESCRIPTION: We describe the case of a 4-year-old boy with sudden mental status decline who was found to have a large intracranial lesion with intraventricular extension. CONCLUSION: Management of the case and pathologic findings are discussed, along with a review of the literature on this rare entity. PMID- 29496582 TI - Laparoscopic Management of Gossypiboma. PMID- 29496581 TI - Effect of Age on Cerebral Arteriovenous Malformation Draining Vein Stenosis. AB - OBJECTIVE: The pathogenesis of venous intimal hyperplasia and venous outflow stenosis associated with cerebral arteriovenous malformation (AVM) draining veins is poorly understood. We sought to determine the relationship between venous stenosis and age. METHODS: All patients with an AVM seen at our institution between 1990 and 2016 who underwent a diagnostic cerebral angiogram were retrospectively reviewed. Draining vein stenosis was measured from angiograms before any treatment. The relationship between venous stenosis and age was assessed. RESULTS: We included 281 patients (mean age 39 years, age range 3-83 years, 55% male). Venous stenosis measuring >=50% was present in 59 patients (21% of cohort). Peak age at presentation was 25-29 years, whereas peak frequency of venous stenosis >=50% was 50-54 years. Venous stenosis was present in a significantly higher proportion of patients >=50 years versus <50 years (P = 0.03). Mean percentage stenosis was significantly higher in patients >=50 years versus <50 years (32% vs. 22%, P = 0.001). CONCLUSIONS: Clinically significant cerebral AVM draining vein stenosis appears to be associated with older age, suggesting that venous stenosis is a progressive disease that occurs by the same process that leads to intimal hyperplasia. These results should be confirmed with a population-based longitudinal study. PMID- 29496583 TI - Effect of Surgical Trainee Presence on Vaginal Hysterectomy Outcomes. AB - STUDY OBJECTIVE: Because of the rapid decline in vaginal hysterectomy (VH) cases in recent years, there is concern regarding gynecologic surgical training and proficiency for VH. The objective of this study is to determine the effect of surgical trainee involvement on surgical outcomes in VH cases performed for benign indications. DESIGN: Retrospective, multicenter, cohort study (Canadian Task Force classification II-2). SETTING: Participating hospitals in the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) at various international sites. PATIENTS: Women who underwent VH for benign indication enrolled from the ACS-NSQIP from 2006 to 2012. INTERVENTION: ACS-NSQIP database. MEASUREMENTS AND MAIN RESULTS: Our study included 5756 patients who underwent VH, and surgical trainees were present in 2276 cases (39.5%). Patients who had a trainee present during VH were more likely to be older, nonsmoking, have comorbidities, and be classified as American Society of Anesthesiologists class III or IV. They were also more likely to be admitted as inpatients, undergo concomitant adnexal surgery, and have uterine weight greater than 250 g. Trainee presence during VH was associated with increased rates of overall complications (5.1% vs 3.19%, p < .001), urinary tract infection (5.27% vs 2.64%, p < .001), and operative time (124.25 +/- 59.29 minutes vs 88.64 +/- 50.9 minutes, p < .001). After controlling for baseline characteristics, trainee presence was associated with increased odds of overall complications (adjusted odds ratio, 1.63; 95% confidence interval, 1.25-2.13), urinary tract infection (adjusted odds ratio, 2.02; 95% confidence interval, 1.51-2.69), and prolonged operative time (adjusted odds ratio, 3.65; 95% confidence interval, 3.20-4.15). No differences were observed for other measures of surgical morbidity or mortality. CONCLUSION: Despite the increased patient complexity and operative time associated with teaching cases, the involvement of surgical trainees is associated with urinary tract infection but not with any major surgical morbidity or mortality. These findings have important implications for gynecologic surgical training for VH. PMID- 29496585 TI - An Interpretative Study on Nurses' Perspectives of Working in an Overcrowded Emergency Department in Taiwan. AB - PURPOSE: This study aims to gain in-depth understanding of nurses' perspectives of working in an overcrowded emergency. METHODS: Symbolic interactionism and Charmaz's construction of grounded theory were used. Purposive sampling at the start of the study and a further theoretical sampling by snowball technique were used to recruit 40 registered nurses (RN) to participate in in-depth, semi structured interviews between May and November, 2014. Data analysis included analytic techniques of initial, focused and theoretical coding. RESULTS: Study findings showed searching for work role is derived by the themes of Finding the role of positioning in Emergency Department (ED), Recognizing causes of ED overcrowding, and Confined working environment. Nurses' work experience which represents the RNs not gained control over their work, as care actions influenced by the problematic overcrowded circumstance of the ED environment. CONCLUSION: The findings fill a gap in knowledge about how RNs experience their work role in the context of an overcrowded Emergency Department in Taiwan. Arising from the study result include taking account of nurses' perspectives when planning staff/patient ratios, strategies to reduce waiting time and ensure that clients receive appropriate care. PMID- 29496584 TI - Acetic acid induces Sch9p-dependent translocation of Isc1p from the endoplasmic reticulum into mitochondria. AB - Changes in sphingolipid metabolism have been linked to modulation of cell fate in both yeast and mammalian cells. We previously assessed the role of sphingolipids in cell death regulation using a well characterized yeast model of acetic acid induced regulated cell death, finding that Isc1p, inositol phosphosphingolipid phospholipase C, plays a pro-death role in this process. Indeed, isc1? mutants exhibited a higher resistance to acetic acid associated with reduced mitochondrial alterations. Here, we show that Isc1p is regulated by Sch9p under acetic acid stress, since both single and double mutants lacking Isc1p or/and Sch9p have the same resistant phenotype, and SCH9 deletion leads to a higher retention of Isc1p in the endoplasmic reticulum upon acetic acid exposure. We also found that the higher resistance of all mutants correlates with higher levels of endogenous mitochondrial phosphorylated long chain bases (LCBPs), suggesting that changing the sphingolipid balance in favour of LCBPs in mitochondria results in increased survival to acetic acid. In conclusion, our results suggest that Sch9p pathways modulate acetic acid-induced cell death, through the regulation of Isc1p cellular distribution, thus affecting the sphingolipid balance that regulates cell fate. PMID- 29496586 TI - Microglia and major depression: not yet a clear picture. PMID- 29496588 TI - Corrections. PMID- 29496587 TI - Traumatic brain injury: a potential cause of violent crime? AB - Traumatic brain injury (TBI) is the biggest cause of death and disability in children and young people. TBI compromises important neurological functions for self-regulation and social behaviour and increases risk of behavioural disorder and psychiatric morbidity. Crime in young people is a major social issue. So called early starters often continue for a lifetime. A substantial majority of young offenders are reconvicted soon after release. Multiple factors play a role in crime. We show how TBI is a risk factor for earlier, more violent, offending. TBI is linked to poor engagement in treatment, in-custody infractions, and reconviction. Schemes to assess and manage TBI are under development. These might improve engagement of offenders in forensic psychotherapeutic rehabilitation and reduce crime. PMID- 29496589 TI - Association of translocator protein total distribution volume with duration of untreated major depressive disorder: a cross-sectional study. AB - BACKGROUND: People with major depressive disorder frequently exhibit increasing persistence of major depressive episodes. However, evidence for neuroprogression (ie, increasing brain pathology with longer duration of illness) is scarce. Microglial activation, which is an important component of neuroinflammation, is implicated in neuroprogression. We examined the relationship of translocator protein (TSPO) total distribution volume (VT), a marker of microglial activation, with duration of untreated major depressive disorder, and with total illness duration and antidepressant exposure. METHODS: In this cross-sectional study, we recruited participants aged 18-75 years from the Toronto area and the Centre for Addiction and Mental Health (Toronto, ON, Canada). Participants either had major depressive episodes secondary to major depressive disorder or were healthy, as confirmed with a structured clinical interview and consultation with a study psychiatrist. To be enrolled, participants with major depressive episodes had to score a minimum of 17 on the 17-item Hamilton Depression Rating Scale, and had to be medication free or taking a stable dose of medication for at least 4 weeks before PET scanning. Eligible participants were non-smokers; had no history of or concurrent alcohol or substance dependence, neurological illness, autoimmune disorder, or severe medical problems; and were free from acute medical illnesses for the previous 2 weeks before PET scanning. Participants were excluded if they had used brain stimulation treatments within the 6 months before scanning, had used anti-inflammatory drugs lasting at least 1 week within the past month, were taking hormone replacement therapy, had psychotic symptoms, had bipolar disorder (type I or II) or borderline antisocial personality disorder, or were pregnant or breastfeeding. We scanned three primary grey-matter regions of interest (prefrontal cortex, anterior cingulate cortex, and insula) and 12 additional regions and subregions using 18F-FEPPA PET to measure TSPO VT. We investigated the duration of untreated major depressive disorder, and the combination of total duration of disease and duration of antidepressant treatment, as predictor variables of TSPO VT, assessing their significance. FINDINGS: Between Sept 1, 2009, and July 6, 2017, we screened 134 participants for eligibility, of whom 81 were included in the study (current major depressive episode n=51, healthy n=30). We excluded one participant with a major depressive episode from the analysis because of unreliable information about previous medication use. Duration of untreated major depressive disorder was a strong predictor of TSPO VT (p<0.0001), as were total illness duration (p=0.0021) and duration of antidepressant exposure (p=0.037). The combination of these predictors accounted for about 50% of variance in TSPO VT in the prefrontal cortex, anterior cingulate cortex, and insula. In participants who had untreated major depressive disorder for 10 years or longer, TSPO VT was 29-33% greater in the prefrontal cortex, anterior cingulate cortex, and insula than in participants who were untreated for 9 years or less. TSPO VT was also 31-39% greater in the three primary grey-matter regions of participants with long duration of untreated major depressive disorder compared with healthy participants (p=0.00047). INTERPRETATION: Microglial activation, as shown by TSPO VT, is greater in patients with chronologically advanced major depressive disorder with long periods of no antidepressant treatment than in patients with major depressive disorder with short periods of no antidepressant treatment, which is strongly suggestive of a different illness phase. Consistent with this, the yearly increase in microglial activation is no longer evident when antidepressant treatment is given. FUNDING: Canadian Institutes of Health Research and Neuroscience Catalyst Fund. PMID- 29496590 TI - The immunopathogenesis of chronic and relapsing autoimmune uveitis - Lessons from experimental rat models. AB - Autoimmune diseases usually follow a relapsing-remitting or a chronic progressive course. To understand the underlying immunopathogenesis we investigated experimental Lewis rat models displaying both disease types, which were only dependent on the autoantigen peptide used for immunization. Retinal S-Antigen peptide PDSAg induces chronic, monophasic disease, whilst interphotoreceptor retinoid-binding protein (IRBP)-peptide R14 causes a spontaneously relapsing remitting course. R14-mediated uveitis can be re-induced by immunization; PDSAg induced disease is even preventable by prior CFA-injection. T cells with different antigen specificities preferentially infiltrate the eyes from different sites, e.g. choroid or retinal vessels, they remain in the retina after resolution of inflammation for many weeks. The major inflammatory cell populations in the eyes during rat uveitis are CD4+ or CD8+ monocytes/macrophages. Chemokine mutants only suppress PDSAg-mediated EAU, while IFN-alpha-treatment ameliorated R14-, but worsened PDSAg-induced disease. Comparison of T cells revealed upregulated expression of 26 genes related to various signal transduction pathways upstream and downstream of IFN-gamma only in T cells causing relapsing EAU. Intraocular injection of IFN-gamma induces synchronized relapses in R14-mediated uveitis, while VEGF-expression of PDSAg specific T cells causing chronic disease induced chorioretinal neovascularization that is suppressed by anti-CD146 antibody. Intraocular T cells from rat eyes during EAU express IL-17, IFN-gamma or IL-10, with dynamic changes of the cell populations during the disease course, differing in both disease types. Immunization of animals with a mixture of both antigens suppressed relapses, indicating a dominance of the monophasic disease. Understanding the exact pathogenesis of both disease courses is key to developing novel therapies for autoimmune diseases. PMID- 29496591 TI - Lessons Learned as President of the Institute for Systems Biology (2000-2018). PMID- 29496592 TI - Tocotrienols: The promising analogues of vitamin E for cancer therapeutics. AB - Despite the significant advancements in the diagnosis and treatment of cancer, it still remains one of the most fatal diseases in the world due to the lack of sensitive diagnosis methods and effective drugs. Therefore, discovering novel therapies that are safe, efficacious and affordable are required for the better management of this disease. Tocotrienols, analogues of vitamin E have gained increased attention due to their safety and efficacy. Extensive research over the past several years has strongly indicated that tocotrienols can efficiently prevent/inhibit the growth of different cancers such as cancers of blood, brain, breast, cervical, colon, liver, lung, pancreas, prostate, skin, stomach etc. This is mainly accredited to their ability to modulate various molecular targets involved in cancer cell proliferation, survival, invasion, angiogenesis, and metastasis such as NF-kappaB, STAT3, Akt/mTOR, etc. In addition, increasing lines of evidence has shown that tocotrienols can sensitize cancer cells to chemotherapeutic agents such as celecoxib, doxorubicin, erlotinib, gefitinib, gemcitabine, paclitaxel, statin etc. Moreover, several clinical trials have confirmed the safety and tolerability of tocotrienols in humans. This review summarizes the potential of tocotrienols for the prevention and treatment of different cancers based on the available in vitro, in vivo and clinical studies. PMID- 29496593 TI - Gut microbiota in kidney disease and hypertension. AB - The human gut microbiota is being composed of more than one hundred trillion microbial cells, including aerobic and anaerobic species as well as gram-positive and negative species. Animal based evidence suggests that the change of normal gut microbiota is responsible for several clinical implications including blood pressure increase and kidney function reduction. Trimethylamine-N-Oxide, short chain fatty acids and inflammatory factors are originated from the gut microbes and may induce changes in arteries, kidneys and blood pressure. Prebiotics and probiotics change the gut microbiota and may reduce high blood pressure and ameliorate chronic kidney disease suggesting a new treatment target in patients for the initial stages of hypertension concomitant with other life style changes such as increased physical exercise and weight reduction to reduce cardiovascular disease complications. PMID- 29496595 TI - Inflammatory disorders mimicking periprosthetic joint infections may result in false-positive alpha-defensin. AB - OBJECTIVES: The antimicrobial peptide alpha-defensin has recently been introduced as a potential 'single' biomarker with a high sensitivity and specificity for the preoperative diagnosis of periprosthetic joint infections (PJIs). However, most studies assessed the benefits of the test with exclusion of patients with rheumatic diseases. We aimed to evaluate the alpha-defensin test in a cohort study without exclusion of people with inflammatory diseases. METHODS: Between June 2016 and June 2017, we prospectively included cases with a suspected PJI and an available lateral flow test alpha-defensin (Synovasure(r)) in synovial fluid. We compared the test result to the diagnostic criteria for PJIs published by an International Consensus Group in 2013. RESULTS: We included 109 cases (49 hips, 60 knees) in which preoperative alpha-defensin tests had been performed. Among these, 20 PJIs (16 hips, four knees) were diagnosed. Preoperative alpha-defensin tests were positive in 25 cases (22.9%) with a test sensitivity and specificity of 90% and 92.1% (95% CI 68.3%-98.8% and 84.5%-96.8%, respectively), and a high negative predictive value of 97.6% (95% CI 91.7%-99.4%). We interpreted seven alpha-defensin tests as false positive, mainly in cases with inflammatory rheumatic diseases, including crystal deposition diseases. CONCLUSIONS: A negative synovial alpha-defensin test can reliably rule out a PJI. However, the test can be false positive in conjunction with an underlying non-infectious inflammatory disease. We therefore propose to use the alpha-defensin test only in combination with Musculoskeletal Infection Society criteria and assessment for crystals in synovial aspirates. PMID- 29496594 TI - blaIMP-27 on transferable plasmids in Proteus mirabilis and Providencia rettgeri. AB - OBJECTIVES: A carbapenem-resistant Providencia rettgeri (PR1) isolate was recovered from a wound infection in Missouri, USA. This isolate possessed an EDTA inhibitable carbapenemase that was unidentified using the Xpert CARBA-R assay. Our objective was to elucidate the molecular determinant of carbapenem resistance in this isolate. We then sought to test the transmissibility of blaIMP-27 loci in clinical P. rettgeri and Proteus mirabilis isolates. METHODS: In October 2016 the novel ambler Class B carbapenemase blaIMP-27, was reported in two different Proteus mirabilis (PM185 and PM187) isolates. Broth mating assays for transfer of carbapenemase activity were performed for the three clinical isolates with recipient sodium azide-resistant Escherichia coli J53. Antibiotic susceptibility testing and phenotypic carbapenemase activity testing were performed on the clinical isolates, J53 and transconjugants using the Kirby-Bauer disc diffusion method according to CLSI guidelines. Plasmid DNA from PM187, PR1 and their transconjugants were used as input for Nextera Illumina sequencing libraries and sequenced on a NextSeq platform. RESULTS: PR1 was resistant to both imipenem and meropenem. PM187 and PR1 could transfer resistance to E. coli through plasmid conjugation (pPM187 and pPR1). pPM187 had a virB/virD4 type IV secretion system whereas pPR1 had a traB/traD type IV secretion system. CONCLUSION: Two of three blaIMP-27-bearing clinical isolates tested could conjugate resistance into E. coli. The resulting transconjugants became positive for phenotypic carbapenemase production but did not pass clinical resistance breakpoints. blaIMP-27 can be transmitted on different plasmid replicon types that rely on distinct classes of type IV secretion system for horizontal transfer. PMID- 29496596 TI - Are cirrhotic patients awaiting liver transplantation protected against vaccine preventable diseases? PMID- 29496598 TI - Culture-confirmed cryptococcal meningitis not detected by Cryptococcus PCR on the Biofire meningitis/encephalitis panel(r). PMID- 29496599 TI - "It's in your hands - prevent sepsis in health care"; World Health Organization SAVE LIVES: Clean Your Hands campaign. PMID- 29496600 TI - Images in CMI. PMID- 29496601 TI - Development and validation of the Food Disgust Picture Scale. AB - The present set of studies developed and tested the Food Disgust Picture Scale (FDPS). This is a tool for the assessment of food disgust sensitivity that will measure disgust and predict possible reactions. This eight-picture tool can be used in complement to or as a replacement for currently available text-based measures. In an exploratory Study 1 (N = 57), we constructed a scale consisting of eight pictures. Most of them were taken from validated picture databases. They proved powerful in the assessment of food disgust sensitivity. Study 2 built on these results and refined the scale by substituting pictures from Study 1 with freely available images displaying similar content. The basic structure of the FDPS was then replicated in a bigger sample of Swiss adults (N = 538). Correlational analyses using the eight-item Food Disgust Scale (FDS short), the revised version of the Disgust Scale (DS-R), and the food neophobia scale (FNS) supported the convergent validity of the FDPS. In Study 3 (N = 226), we used a test-retest design to demonstrate the short-term stability of the FDPS. As a result of these studies, the present work provides a short and comprehensive measure of food disgust sensitivity. This novel approach of using pictures to induce a disgust response independently of language significantly facilitates intercultural research on disgust. The FDPS will further contribute to the understanding of food-related disgust and its impact on our food choices. PMID- 29496597 TI - Antimicrobial resistance in leprosy: results of the first prospective open survey conducted by a WHO surveillance network for the period 2009-15. AB - OBJECTIVES: Antimicrobial resistance (AMR) is a priority for surveillance in bacterial infections. For leprosy, AMR has not been assessed because Mycobacterium leprae does not grow in vitro. We aim to obtain AMR data using molecular detection of resistance genes and to conduct a prospective open survey of resistance to antileprosy drugs in countries where leprosy is endemic through a WHO surveillance network. METHODS: From 2009 to 2015, multi-bacillary leprosy cases at sentinel sites of 19 countries were studied for resistance to rifampicin, dapsone and ofloxacin by PCR sequencing of the drug-resistance determining regions of the genes rpoB, folP1 and gyrA. RESULTS: Among 1932 (1143 relapse and 789 new) cases studied, 154 (8.0%) M. leprae strains were found with mutations conferring resistance showing 182 resistance traits (74 for rifampicin, 87 for dapsone and 21 for ofloxacin). Twenty cases showed rifampicin and dapsone resistance, four showed ofloxacin and dapsone resistance, but no cases were resistant to rifampicin and ofloxacin. Rifampicin resistance was observed among relapse (58/1143, 5.1%) and new (16/789, 2.0%) cases in 12 countries. India, Brazil and Colombia reported more than five rifampicin-resistant cases. CONCLUSIONS: This is the first study reporting global data on AMR in leprosy. Rifampicin resistance emerged, stressing the need for expansion of surveillance. This is also a call for vigilance on the global use of antimicrobial agents, because ofloxacin resistance probably developed in relation to the general intake of antibiotics for other infections as it is not part of the multidrug combination used to treat leprosy. PMID- 29496602 TI - Children's self-regulation of eating provides no defense against television and online food marketing. AB - Exposure to unhealthy food marketing stimulates children's food consumption. A child's responsiveness is influenced by individual factors, resulting in an increased vulnerability to advertising effects among some children. Whether these differential responses may be altered by different parental feeding behaviours is unclear. The purpose of this study was to determine the relationship between parental feeding practices and children's food intake responses to food advertising exposure. A randomised, crossover, counterbalanced, within subject trial was conducted across four, six-day holiday camps in New South Wales, Australia between April 2016 and January 2017 with 160 children (7-12 years, n = 40/camp). Children were randomised to either a multiple media (TV and Internet) or single media (TV) condition and exposed to food (3 days) and non-food (3 days) advertising in an online game and/or a cartoon. Children's food consumption (kilojoules (kJ)) was measured at a snack immediately after advertising exposure and then at lunch later in the day. Parents completed the Child Feeding Questionnaire, and 'restriction' and 'pressure to eat' subscale scores were calculated. While food advertising affected all children in the multiple media condition, there was an increased effect on snack intake among children whose parents reported pressuring them to eat, with children consuming an additional 356 kJ after food advertising compared with non-food advertising. This was 209 kJ more than children whose parents did not pressure them to eat. In the single media condition, only children whose parents reported restrictive feeding practices ate more at lunch on food advertising days than non-food advertising days (240 kJ). These data highlight an increased susceptibility to food advertising among children whose parents report controlling feeding practices. PMID- 29496603 TI - Picky eating and food neophobia: Resemblance and agreement in parent/young adult dyads. AB - OBJECTIVE: To explore selective eating in two samples: young adults and their middle aged parents, including the relationship between food neophobia and picky eating in each, resemblance between children and parents in these eating behaviors, agreement between child self-report and parent report on children's eating, and the relationship between parent eating behavior and parent-report on children's eating. We also explored the relationship between socioeconomic status and picky eating and food neophobia in each sample. METHOD: University students responded to questionnaires assessing picky eating and food neophobia. Their parents were contacted and asked to complete the same measure about their own picky- and food neophobic behaviors and to report on their child's current picky eating and food neophobia. The final sample included 109 biological parent-child pairs. RESULTS: There were large positive correlations between food neophobia and picky eating in both samples. There were positive associations between parents' and children's self-reported selective eating behaviors. There was evidence of parent-child agreement in reporting on the child's selective eating, but also considerable variability between raters. This variability between child self report and parent report was partially accounted for by parental selective eating. Finally, young adults from a lower-SES background (e.g., lower parent educational attainment and income) reported higher levels of pickiness and food neophobia. CONCLUSIONS: Young adult children and their parents resemble each other in pickiness and food neophobia. PMID- 29496604 TI - Comparison of two front-of-package nutrition labeling schemes, and their explanation, on consumers' perception of product healthfulness and food choice. AB - OBJECTIVE: Front-of-package (FOP) nutrition labels are increasingly used to present nutritional information to consumers. A variety of FOP nutrition schemes exist for presenting condensed nutrition information. The present study directly compared two symbolic FOP labeling systems - traffic light and star-based schemes - with specific regard to healthfulness perception and purchase intention for a variety of products. Additionally, this study investigated which method of message framing (gain, loss, gain + loss) would best enable individuals to effectively utilize the FOP labels. METHOD: College students (n = 306) viewed food packages featuring either star or traffic light FOP labels and rated the healthfulness of each product and their likelihood of purchasing the product. Within each label type, participants were presented with differently-framed instructions regarding how to use the labels. RESULTS: Participants who viewed the star labels rated products with the lowest healthfulness as significantly less healthful and rated products with the highest healthfulness as significantly more healthful compared to participants who viewed those same products with traffic light labels. Purchase intention did not differ by label type. Additionally, including any type of framing (gain, loss, or gain + loss) assisted consumers in differentiating between foods with mid-range vs. low nutritional value. CONCLUSIONS: Star-based labels led more healthful foods to be seen as even more healthful and less healthful foods to be seen as even less healthful compared to the same foods with traffic light labels. Additionally, results indicate a benefit of including framing information for FOP nutrition label instructions; however, no individual frame led to significantly different behavior compared to the other frames. While ratings of product healthfulness were influenced by the framing and the label type, purchase intention was not impacted by either of these factors. PMID- 29496605 TI - Effect of ventricular pacing lead position on tricuspid regurgitation: A randomized prospective trial. AB - BACKGROUND: Pacing lead-related tricuspid regurgitation (TR), a recognized complication of ventricular pacing lead implantation, may be affected by lead position or diameter. OBJECTIVE: This study sought to determine the effect of ventricular pacing lead position and diameter on pacing lead-related TR. METHODS: A randomized prospective trial compared pacing leads in the right ventricular apex (RVA), right ventricular septum (RVS), or left ventricle via the coronary sinus (LV-CS) in a 1:1:1 fashion. Patients undergoing implantable cardioverter defibrillator lead implantation in the RVA (RVA-ICD) were enrolled in a comparison group. Patients with preexisting moderate or greater TR were excluded. Prospective clinical evaluation, transthoracic echocardiograms, and device interrogation occurred 24 hours and 12 months after device implantation. RESULTS: Sixty-three patients undergoing pacemaker implantation were randomized to RVA, RVS, or LV-CS pacing, and 48 RVA-ICD patients were enrolled as a comparison group. At 12 months, 6 patients (6.4%) developed moderate or greater TR. Moderate or greater TR was not significantly different between groups if analyzed by intention to treat (RVA 5.9%, RVS 10.0%, LV-CS 6.7%, and RVA-ICD 4.8%) or if analyzed by final lead location (RVA 4.8%, RVS 10.5%, LV-CS 8.3%, and RVA-ICD 5.1%). Ventricular lead-related complications occurred in 3 patients with right ventricular leads (3.2%) and 2 patients with LV-CS leads (11.1%) (P = .184). CONCLUSION: Neither pacing lead position nor diameter appears to affect TR development significantly. LV-CS leads failed to achieve a statistically significant reduction in TR as compared with right ventricular leads. PMID- 29496606 TI - Safety and feasibility of leadless pacemaker in patients undergoing atrioventricular node ablation for atrial fibrillation. AB - BACKGROUND: Atrioventricular node (AVN) ablation and permanent pacing is an established strategy for rate control in the management of symptomatic atrial fibrillation (AF). Leadless pacemakers (LPs) can overcome some of the short-term and long-term limitations of conventional transvenous pacemakers (CTPs). OBJECTIVES: The purpose of this study was to compare the feasibility and safety of LP with those of single-chamber CTP in patients with AF undergoing AVN ablation. METHODS: We conducted a multicenter observational study of patients undergoing AVN ablation and pacemaker implantation (LP vs single-chamber CTP) between February 1, 2014 and November 15, 2016. The primary efficacy end points were acceptable sensing (R wave amplitude >=5.0 mV) and pacing thresholds (<=2.0 V at 0.4 ms) at follow-up. Safety end points included device-related major and minor (early <1 month, late >1 month) adverse events. RESULTS: A total of 127 patients with LP (n = 60) and CTP (n = 67) were studied. The median follow-up was 12 months (interquartile range 12-18 months). Ninety-five percent of the LP group and 97% of the CTP group met the primary efficacy end point at follow-up (57 of 60 vs 65 of 67; P = .66). There was 1 major adverse event (loss of pacing and sensing) in the LP group and 2 (lead dislodgement) in the CTP group (1 of 60 vs 2 of 67; P = 1.00). There were 6 minor adverse events (5 early and 1 late) in the LP group and 3 (early) in the CTP group (6 of 60 vs 3 of 67; P = .30). CONCLUSION: Our results demonstrate the feasibility and safety of LP compared with CTP in patients undergoing AVN ablation for AF. PMID- 29496607 TI - A novel modelling mechanism of PAEL receptor and GABARAPL2 interaction involved in Parkinson's disease. AB - Parkin associated endothelin like receptor (PAELR) is G-protein coupled and ubiquitinated by parkin, promoting its degradation. In autosomal recessive Parkinson's disease, mutations in parkin lead to PAELR aggregation in the endoplasmic reticulum (ER), ER stress, neurotoxicity and cell death. We have identified previously that the protein kinase C interacting protein (PICK1) interacts with and regulates the expression and cell toxicity of PAELR. Here, we experimentally identify and provide in-silico modelling of a novel interaction between PAELR and GABARAPL2 (gamma-aminobutyrate type A receptor associated protein like 2), which is an autophagosome-specific Ub-like protein implicated in vesicle trafficking and autophagy. We show that the family of GABARAPs interact with the carboxy terminal (ct) of PAELR and find the cysteine rich region ( CCCCCC-EEC) of ct-PAELR interacts with the GABAA binding site of GABARAPL2. This interaction is modelled by in-slico analysis and confirmed using affinity chromatography, showing Myc-tagged GABARAPL2 is retained by a GST fusion of the ct-PAELR. We also demonstrate that transient transfection of GABARAPL2 in HEK293 cells reduces PAELR expression. This study supports the idea that protein levels of PAELR are likely regulated by a multitude of proteins including parkin, PICK1 and GABARAPL2 via mechanisms that include ubiquitination, proteasomal degradagtion and autophagy. PMID- 29496608 TI - Effects of mesyl salvinorin B alone and in combination with naltrexone on alcohol deprivation effect in male and female mice. AB - Alcohol relapse plays a major role in alcohol dependence and is an important focus for the treatment of alcoholism. The alcohol deprivation effect (ADE) is a widely used paradigm in rodents to model the relapse episodes that occur in human alcoholics. Mesyl Salvinorin B (MSB) is a potent and selective kappa opioid receptor (KOP-r) full agonist, with fewer side effects (e.g., sedation or anhedonia) than classic KOP-r full agonists and a longer duration of action in mice than the structurally similar salvinorin A. We have recently found that MSB prevents cocaine seeking in a rat self-administration model and reduces excessive alcohol drinking in a mouse escalation model via a KOP-r-mediated mechanism. Here, we further investigated whether MSB alone (0.3-3 mg/kg) or in combination with naltrexone (mu-opioid receptor antagonist at 1 mg/kg) altered alcohol "relapse" drinking using a mouse ADE paradigm. Both male and female mice, exposed to 3-week intermittent access alcohol drinking in a two-bottle choice paradigm with 24-h access every other day, developed excessive alcohol intake and then displayed pronounced ADE after 1-week abstinence. Acute administration of MSB prevented the ADE at 3 mg/kg in both male and female mice. Upon investigation of potential synergistic effects between naltrexone and MSB, we found that acute administration of a combination of MSB (0.3 mg/kg) and naltrexone (1 mg/kg) reduced the ADE at doses lower than those individual effective doses, with no sex difference. Our study suggests that the KOP-r full agonist MSB both alone and in combination with naltrexone shows potential in alcohol "relapse" treatment models. PMID- 29496609 TI - The dorsal striatum and the dynamics of the consensus connectomes in the frontal lobe of the human brain. AB - In the applications of the graph theory, it is unusual that one considers numerous, pairwise different graphs on the very same set of vertices. In the case of human braingraphs or connectomes, however, this is the standard situation: the nodes correspond to anatomically identified cerebral regions, and two vertices are connected by an edge if a diffusion MRI-based workflow identifies a fiber of axons, running between the two regions, corresponding to the two vertices. Therefore, if we examine the braingraphs of n subjects, then we have n graphs on the very same, anatomically identified vertex set. It is a natural idea to describe the k-frequently appearing edges in these graphs: the edges that are present between the same two vertices in at least k out of the n graphs. Based on the NIH-funded large Human Connectome Project's public data release, we have reported the construction of the Budapest Reference Connectome Server http://www.connectome.pitgroup.org that generates and visualizes these k frequently appearing edges. We call the graphs of the k-frequently appearing edges "k-consensus connectomes" since an edge could be included only if it is present in at least k graphs out of n. Considering the whole human brain, we have reported a surprising property of these consensus connectomes earlier. In the present work we are focusing on the frontal lobe of the brain, and we report here a similarly surprising dynamical property of the consensus connectomes when k is gradually changed from k = n to k = 1: the connections between the nodes of the frontal lobe are seemingly emanating from those nodes that were connected to sub cortical structures of the dorsal striatum: the caudate nucleus, and the putamen. We hypothesize that this dynamic behavior copies the axonal fiber development of the frontal lobe. An animation of the phenomenon is presented at https://youtu.be/wBciB2eW6_8. PMID- 29496610 TI - Integration of reward with cost anticipation during performance monitoring revealed by ERPs and EEG spectral perturbations. AB - Effort expenditure has an aversive connotation and it can lower hedonic feelings. In this study, we explored the electrophysiological correlates of the complex interplay of reward processing with cost anticipation. To this aim, healthy adult participants performed a gambling task where the outcome (monetary reward vs. no reward) and its expectancy were manipulated on a trial by trial basis while 64 channel EEG was recorded. Crucially, on some trials, the no-reward outcome could be transformed to a rewarding one, pending effort expenditure by means of an orthogonal dot clicking task, enabling us to compare at the electrophysiological level reward processing when cost was anticipated or not. We extracted and compared different markers of reward processing at the feedback level using both classical ERPs and EEG spectral perturbations in specific bands (theta, delta and beta-gamma). At the behavioral level, participants reported enhanced pleasure and relief when the outcome was rewarding but effort expenditure could be avoided, relative to a control condition where the outcome was rewarding but no extra effort was anticipated. In this condition, EEG results showed a larger Reward Positivity ERP component and increased power in the Delta and Beta-gamma bands. By comparison, cost anticipation did not influence the processing of the no reward outcome at the FRN and frontal midline theta levels. All together, these neurophysiological results suggest that effort avoidance is associated with increased reward processing. PMID- 29496613 TI - Neural substrates of the emotion-word and emotional counting Stroop tasks in healthy and clinical populations: A meta-analysis of functional brain imaging studies. AB - The emotional Stroop task (EST) is among the most influential paradigms used to probe attention-related or cognitive control-related emotional processing in healthy subjects and clinical populations. The neuropsychological mechanism underlying the emotional Stroop effect has attracted extensive and long-lasting attention in both cognitive and clinical psychology and neuroscience; however, a precise characterization of the neural substrates underlying the EST in healthy and clinical populations remains elusive. Here, we implemented a coordinate-based meta-analysis covering functional imaging studies that employed the emotion-word or emotional counting Stroop paradigms to determine the underlying neural networks in healthy subjects and the trans-diagnostic alterations across clinical populations. Forty-six publications were identified that reported relevant contrasts (negative > neutral; positive > neutral) for healthy or clinical populations as well as for hyper- or hypo-activation of patients compared to controls. We demonstrate consistent involvement of the vlPFC and dmPFC in healthy subjects and consistent involvement of the vlPFC in patients. We further identify a trans-diagnostic pattern of hyper-activation in the prefrontal and parietal regions. These findings underscore the critical roles of cognitive control processes in the EST and implicate trans-diagnostic cognitive control deficits. Unlike the current models that emphasize the roles of the amygdala and rACC, our findings implicate novel mechanisms underlying the EST for both healthy and clinical populations. PMID- 29496611 TI - Optogenetic fMRI and electrophysiological identification of region-specific connectivity between the cerebellar cortex and forebrain. AB - Complex animal behavior is produced by dynamic interactions between discrete regions of the brain. As such, defining functional connections between brain regions is critical in gaining a full understanding of how the brain generates behavior. Evidence suggests that discrete regions of the cerebellar cortex functionally project to the forebrain, mediating long-range communication potentially important in motor and non-motor behaviors. However, the connectivity map remains largely incomplete owing to the challenge of driving both reliable and selective output from the cerebellar cortex, as well as the need for methods to detect region specific activation across the entire forebrain. Here we utilize a paired optogenetic and fMRI (ofMRI) approach to elucidate the downstream forebrain regions modulated by activating a region of the cerebellum that induces stereotypical, ipsilateral forelimb movements. We demonstrate with ofMRI, that activating this forelimb motor region of the cerebellar cortex results in functional activation of a variety of forebrain and midbrain areas of the brain, including the hippocampus and primary motor, retrosplenial and anterior cingulate cortices. We further validate these findings using optogenetic stimulation paired with multi-electrode array recordings and post-hoc staining for molecular markers of activated neurons (i.e. c-Fos). Together, these findings demonstrate that a single discrete region of the cerebellar cortex is capable of influencing motor output and the activity of a number of downstream forebrain as well as midbrain regions thought to be involved in different aspects of behavior. PMID- 29496614 TI - Segregation of the human basal forebrain using resting state functional MRI. AB - The basal forebrain (BF) is poised to play an important neuromodulatory role in brain regions important to cognition due to its broad projections and complex neurochemistry. While significant in vivo work has been done to elaborate BF function in nonhuman rodents and primates, comparatively limited work has examined the in vivo function of the human BF. In the current study we used multi echo resting state functional magnetic resonance imaging (rs-fMRI) from 100 young adults (18-34 years) to assess the potential segregation of human BF nuclei as well as their associated projections. Multi-echo processing provided significant gains in SNR throughout the brain as compared to traditional single-echo processing, with some of the largest increases observed in the BF. Bottom-up clustering of voxel-wise BF functional connectivity maps yielded adjacent functional clusters within the BF that closely aligned with the distinct, hypothesized nuclei important to cognition: the nucleus basalis of Meynert (NBM) and the medial septum/diagonal band of Broca (MS/DB). Examining their separate functional connections, the NBM and MS/DB revealed distinct projection patterns, suggesting a conservation of nuclei-specific functional connectivity with homologous regions known to be anatomically innervated by the BF. Specifically, the NBM demonstrated coupling with a widespread cortical network as well as the amygdala, whereas the MS/DB revealed coupling with a more circumscribed network, including the orbitofrontal cortex and hippocampal complex. Collectively, these in vivo rs-fMRI data demonstrate that the human BF nuclei support distinct aspects of resting-state functional networks, suggesting that the human BF may be a neuromodulatory hub important for orchestrating network dynamics. PMID- 29496612 TI - Microstructural parcellation of the human brain. AB - The human cerebral cortex is composed of a mosaic of areas thought to subserve different functions. The parcellation of the cortex into areas has a long history and has been carried out using different combinations of structural, connectional, receptotopic, and functional properties. Here we give a brief overview of the history of cortical parcellation, and explore different microstructural properties and analysis techniques that can be used to define the borders between different regions. We show that accounting for the 3D geometry of the highly folded human cortex is especially critical for accurate parcellation. We close with some thoughts on future directions and best practices for combining modalities. PMID- 29496615 TI - Systematic review of interventions for promoting active school transport. AB - Active commuting to school has been recognized as a potential avenue to increase physical activity in children and adolescents. However, active commuting to school has declined over time, and interventions are needed to reverse this trend. The main aim in the current study was to update a previous systematic review on interventions focused on active travel to school, following the same methodology and addressing the quality and effectiveness of new studies detected in the more recent scientific literature. A systematic review was conducted to identify intervention studies of active commuting to school published from February 2010 to December 2016. Five electronic databases and a manual search were conducted. Detailed information was extracted, including a quantitative assessment comparing the effect sizes, with Cohen's d, and a qualitative assessment using the Evaluation of Public Health Practice Projects tool. We identified 23 interventions that focused on active commuting to school. Among the 23 interventions, three were randomized control trials, 22 had a pre/post design, and 12 used control groups. Most interventions reported a small effect size on active commuting to school (14/23) (d: from -1.45 to 2.37). The quality assessment was rated as weak in most studies (21/23). Government funding continues investing in public policies to promote active commuting to school. However, even though seven years have passed since the last systematic review, research with high quality designs with randomization, greater sample size, and the use of valid and reliable instruments are needed. PMID- 29496616 TI - Post-transcriptional regulation of the oxidative stress response in plants. AB - Due to their sessile lifestyle, plants can be exposed to several kinds of stresses that will increase the production of reactive oxygen species (ROS), such as hydrogen peroxide, singlet oxygen, and hydroxyl radicals, in the plant cells and activate several signaling pathways that cause alterations in the cellular metabolism. Nevertheless, when ROS production outreaches a certain level, oxidative damage to nucleic acids, lipids, metabolites, and proteins will occur, finally leading to cell death. Until now, the most comprehensive and detailed readout of oxidative stress responses is undoubtedly obtained at the transcriptome level. However, transcript levels often do not correlate with the corresponding protein levels. Indeed, together with transcriptional regulations, post-transcriptional, translational, and/or post-translational regulations will shape the active proteome. Here, we review the current knowledge on the post transcriptional gene regulation during the oxidative stress responses in planta. PMID- 29496617 TI - FOXO1 cysteine-612 mediates stimulatory effects of the coregulators CBP and PGC1alpha on FOXO1 basal transcriptional activity. AB - Hepatic production and release of metabolites, nutrients and micronutrient transporters is tightly regulated at the level of gene expression. In this regard, transcription factor FOXO1 modulates the expression of genes such as G6PC and SELENOP, encoding the catalytic subunit of glucose 6-phosphatase and the plasma selenium transporter selenoprotein P, respectively. Here, we analyzed the role of cysteine residues in FOXO1 in controlling its activity with respect to regulation of G6PC and SELENOP in HepG2 human hepatoma cells. None of the seven FOXO1 cysteines affected FOXO1 binding to DNA or its basal subcellular distribution. Whereas overexpression of wildtype FOXO1 caused a strong induction of both G6PC and SELENOP promoter activities and mRNA levels, the induction was lowered by approx. 50% if cysteine-deficient FOXO1 was overexpressed instead. Only the most C-terminal of the seven FOXO1 cysteines, Cys612, was required and sufficient to ensure full FOXO1 transactivation activity. Coexpression of FOXO1 coregulators, CBP or PGC1alpha, had a strong synergistic effect in stimulating G6PC promoter activity and expression, fully relying on the presence of FOXO1 Cys612. Similarly, a synergistic effect of FOXO1 and CBP was observed for SELENOP. In contrast, stimulation of SELENOP by PGC1alpha was independent of FOXO1-Cys612, due to the close proximity of a hepatocyte nuclear factor-4alpha binding site to the FOXO1 binding site within the SELENOP promoter, as demonstrated using mutant SELENOP promoter constructs. In summary, full basal FOXO1 transactivation activity relies on Cys612, which mediates synergistic effects of coregulators, CBP or PGC1alpha, on FOXO1 transcriptional activity. The extent of Cys612 contribution depends on the promoter context of FOXO1 target genes. PMID- 29496618 TI - Superoxide radicals react with peptide-derived tryptophan radicals with very high rate constants to give hydroperoxides as major products. AB - Oxidative damage is a common process in many biological systems and proteins are major targets for damage due to their high abundance and very high rate constants for reaction with many oxidants (both radicals and two-electron species). Tryptophan (Trp) residues on peptides and proteins are a major sink for a large range of biological oxidants as these side-chains have low radical reduction potentials. The resulting Trp-derived indolyl radicals (Trp*) have long lifetimes in some circumstances due to their delocalized structures, and undergo only slow reaction with molecular oxygen, unlike most other biological radicals. In contrast, we have shown previously that Trp* undergo rapid dimerization. In the current study, we show that Trp* also undergo very fast reaction with superoxide radicals, O2*-, with k 1-2 * 109 M-1 s-1. These values do not alter dramatically with peptide structure, but the values of k correlate with overall peptide positive charge, consistent with positive electrostatic interactions. These reactions compete favourably with Trp* dimerization and O2 addition, indicating that this may be a major fate in some circumstances. The Trp* + O2*- reactions occur primarily by addition, rather than electron transfer, with this resulting in high yields of Trp-derived hydroperoxides. Subsequent degradation of these species, both stimulated and native decay, gives rise to N-formylkynurenine, kynurenine, alcohols and diols. These data indicate that reaction of O2*- with Trp* should be considered as a major pathway to Trp degradation on peptides and proteins subjected to oxidative damage. PMID- 29496619 TI - Association between antiretroviral therapy and antitubercular drug resistance in TB treatment outcome among Kazakh TB/HIV co-infected patients. AB - OBJECTIVES: Drug-resistant tuberculosis (TB) poses a serious threat to public health in Kazakhstan. This paper presents findings related to TB treatment outcome and drug resistance status among people co-infected with human immunodeficiency virus (HIV) and TB in Kazakhstan. METHODS: A cohort study using data provided by the Kazakhstan Ministry of Health's National Tuberculosis Program for 2014 and 2015 was performed. The chi2 test and logistical regression were performed to understand factors associated with drug-resistant TB status and TB treatment outcome. RESULTS: In the bivariate analysis, drug-resistant TB status was significantly associated with year of TB diagnosis (P=0.001) and viral load (P=0.03). TB treatment outcome was significantly associated with age at diagnosis (p=0.01), antiretroviral (ARV) treatment (P<0.0001) and drug-resistant TB status (P=0.02). In the adjusted analysis, drug-resistant TB status was associated with an increased likelihood of successful completion of treatment with a successful outcome compared with treatment failure (odds ratio=6.94, 95% confidence interval 1.39-34.44). CONCLUSIONS: These results suggest that having drug-resistant TB is associated with a higher likelihood of completing treatment with successful outcome, even when controlling for receipt of ARV therapy. PMID- 29496620 TI - Superior calvarial bone regeneration using pentenoate-functionalized hyaluronic acid hydrogels with devitalized tendon particles. AB - : Traumatic brain injury (TBI) is a life-threatening condition defined by internal brain herniation. Severe TBI is commonly treated by a two-stage surgical intervention, where decompressive craniectomy is first conducted to remove a large portion of calvarial bone and allow unimpeded brain swelling. In the second surgery, spaced weeks to months after the first, cranioplasty is performed to restore the cranial bone. Hydrogels with paste-like precursor solutions for surgical placement may potentially revolutionize TBI treatment by permitting a single-stage surgical intervention, capable of being implanted with the initial surgery, remaining pliable during brain swelling, and tuned to regenerate calvarial bone after brain swelling has subsided. The current study evaluated the use of photocrosslinkable pentenoate-functionalized hyaluronic acid (PHA) and non crosslinking hyaluronic acid (HA) hydrogels encapsulating naturally derived tissue particles of demineralized bone matrix (DBM), devitalized cartilage (DVC), devitalized meniscus (DVM), or devitalized tendon (DVT) for bone regeneration in critical-size rat calvarial defects. All hydrogel precursors exhibited a yield stress for placement and addition of particles increased the average material compressive modulus. The HA-DBM (4-30%), PHA (4%), and PHA-DVT (4-30%) groups had 5 (p < 0.0001), 3.1, and 3.2 (p < 0.05) times greater regenerated bone volume compared to the sham (untreated defect) group, respectively. In vitro cell studies suggested that the PHA-DVT (4-10%) group would have the most desirable performance. Overall, hydrogels containing DVT particles outperformed other materials in terms of bone regeneration in vivo and calcium deposition in vitro. Hydrogels containing DVT will be further evaluated in future rat TBI studies. STATEMENT OF SIGNIFICANCE: Traumatic brain injury (TBI) is a life-threatening condition characterized by severe brain swelling and is currently treated by a two-stage surgical procedure. Complications associated with the two-stage surgical intervention include the occurrence of the condition termed syndrome of the trephined; however, the condition is completely reversible once the secondary surgery is performed. A desirable TBI treatment would include a single surgical intervention to avoid syndrome of the trephined altogether. The first hurdle in reaching the overall goal is to develop a pliable hydrogel material that can regenerate the patient's bone. The development of a pliable hydrogel technology would greatly impact the field of bone regeneration for TBI application and other areas of bone regeneration. PMID- 29496622 TI - Variation in costs among surgeons for lumbar spinal stenosis. AB - BACKGROUND CONTEXT: Lumbar spinal stenosis is a common condition in the elderly for which costs vary substantially by region. Comparing differences between surgeons from a single institution, thereby omitting regional variation, could aid in identifying factors associated with higher costs and individual drivers of costs. The use of decision aids (DAs) has been suggested as one of the possible tools for diminishing costs and cost variation. PURPOSE: (1) To determine factors associated with higher costs for treatment of spinal stenosis in the first year after diagnosis in a single institution; (2) to find individual drivers of costs for providers with higher costs; and (3) to determine if the use of DAs can decrease costs and cost variability. STUDY DESIGN: Retrospective cohort study. PATIENT SAMPLE: A total of 10,858 patients in 18 different practices diagnosed with lumbar spinal stenosis between January 2003 and July 2015 in three associated hospitals of a single institution. OUTCOME MEASURES: Mean cost for a patient per provider in US dollars within 1 year after diagnosis of lumbar spinal stenosis. METHODS: We collected all diagnostic testing, office visits, injections, surgery, and occupational or physical therapy related to lumbar spinal stenosis within 1 year after initial diagnosis. We used multivariable linear regression to determine independent predictors for costs. Providers were grouped in tiers based on mean total costs per patient to find drivers of costs. To assess the DAs effect on costs and cost variability, we matched DA patients one-to-one with non-DA patients. RESULTS: Male gender (beta 0.10, 95% confidence interval [CI] 0.05-0.15, p<.001), seeing an additional provider (beta 0.77, 95% CI 0.69-0.86, p<.001), and having an additional spine diagnosis (beta 0.79, 95% CI 0.74-0.84, p<.001) were associated with higher costs. Providers in the high cost tier had more office visits (p<.001), more imaging procedures (p<.001), less occupational or physical therapy (p=.002), and less surgery (p=.001) compared with the middle tier. Eighty-two patients (0.76%) received a DA as part of their care; there was no statistically significant difference between the DA group and the matched group in costs (p=.975). CONCLUSIONS: Male gender, seeing an additional provider, and having an additional spine diagnosis were independently associated with higher costs. The main targets for cost reduction we found are imaging procedures and number of office visits. Decision aids were not found to affect cost. PMID- 29496621 TI - Esterase from a cariogenic bacterium hydrolyzes dental resins. AB - OBJECTIVES: To identify and characterize specific esterases from S. mutans with degradative activity toward methacrylate-based resin monomers. METHODS: Out of several putative esterases, an esterase encoded in an Open Reading Frame as SMU_118c (The National Center for Biotechnology Information, NCBI), was found to have true hydrolase activities. SMU_118c was cloned, expressed, purified and further characterized for its respective hydrolytic activity towards ester containing nitrophenyl substrates and the universal resin monomers bis-phenyl glycidyl-dimethacrylate (bisGMA) and triethyleneglycol dimethacrylate (TEGDMA) at neutral (7.0) or cariogenic (5.5) pH. Mass spectrometry (MS) was used to verify the expression of SMU_118c protein in S. mutans UA159. RESULTS: Similar to the whole cell activity of S. mutans, SMU_118c showed the highest affinity toward para-nitrophenyl acetate (pNPA) and para-nitrophenyl butyrate (pNPB) vs. ortho nitrophenyl butyrate (oNPB) and butyrylthiocholine iodide (BTC) (p < 0.05). The esterase retained 60% of its activity after 21 days and hydrolyzed bisGMA at a higher rate than TEGDMA at both neutral and cariogenic pH (p < 0.001), similarly to the predominant human salivary esterase degradative activity. MS confirmed that SMU_118c is an intracellular protein in S. mutans UA159 and expressed under pathogenic (pH 5.5) growth conditions. SIGNIFICANCE: The similarity in the activity profile to the whole S. mutans bacterial cell, the stability over time at cariogenic pH, the preference to hydrolyze bisGMA and confirmed expression profile suggest that SMU_118c could be a significant contributor to the whole bacterial degradative activity of S. mutans toward the degradation of resin composites, adhesives and the restoration-tooth interface, potentially accelerating restoration's failure. STATEMENT OF SIGNIFICANCE: The current study builds upon our highly-cited previous study by Bourbia et al., (JDR, 2013) that reported on that the cariogenic bacterium, S. mutans has esterase-like activities that enable the bacterium to degrade dental composites and adhesives. The current submission is the first to report on the isolation and characterization of the specific esterase activity (SMU_118c) from S. mutans that is a significant contributor to the whole bacterial degradative activity toward the hydrolysis of dental resins. This activity compromises the restoration-tooth interface, increases interfacial bacterial microleakage (Kermanshahi et al., JDR 2010), potentially contributing to the pathogenesis of recurrent caries around resin composite restorations. This represent a significant contribution to the field of biomaterials and their clinical performance. PMID- 29496623 TI - Clinical outcomes of percutaneous suction aspiration and drainage for the treatment of infective spondylodiscitis with paravertebral or epidural abscess. AB - BACKGROUND CONTEXT: Patients with infective spondylodiscitis who failed conservative treatment are generally indicated for open surgery. However, some patients are poor candidates for standard surgery, hence the need to evaluate less invasive approaches. Good outcomes were previously reported for percutaneous suction aspiration and drainage (PSAD) in the treatment of infective spondylodiscitis resistant to conservative therapy. We recently extended the surgical approach of PSAD to allow drainage of paravertebral or epidural abscesses in patients with progressive infective spondylodiscitis. PURPOSE: To evaluate the clinical outcomes of PSAD for infective spondylodiscitis with paravertebral or epidural abscess. DESIGN: Retrospective case series. PATIENT SAMPLE: Patients with infective spondylodiscitis and associated epidural or paravertebral abscess treated using PSAD at our institution, between 1998 and 2014. OUTCOME MEASURES: Serum levels of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and imaging data obtained via plain radiography, computed tomography, and magnetic resonance imaging were analyzed. Serum measurements were taken preoperatively and at several time points postoperatively. Clinical outcomes were evaluated using the modified MacNab criteria for overall functional mobility. METHODS: Data were obtained from the patients' case notes, radiological images, and medical records. Student t test was used to assess the relevance of changes in serum levels of CRP and ESR at each evaluated time point, as well as the change in sagittal Cobb angle between the preoperative state and the state at final follow-up. RESULTS: Fifty-two patients (31 men and 21 women; average age, 70.6 years) were included in our analysis. The median (range) CRP levels and ESR values at the time of diagnosis were 6.86 (0.04-20.15) mg/dL and 78.8 (26-120) mm/h, respectively. At 1 year postoperatively, these values had decreased to 0.18 (0.0-1.2) mg/dL and 13.8 (4 28) mm/h for CRP and ESR, respectively. At final follow-up, bone union was observed in 80.8% (42 of 52) of patients, with instability identified in five patients. Regarding functional mobility, excellent outcomes were obtained in 26.9% (14 of 52) of patients, whereas good, fair, and poor outcomes were noted in 42.3% (22 of 52), 3.9% (2 of 52), and 26.9% (14 of 52) of patients, respectively. Overall, treatment was considered effective in 69.2% (36 of 52) of patients. CONCLUSIONS: Percutaneous suction aspiration and drainage can serve as an effective alternative to open surgery for the treatment of patients with progressive infective spondylodiscitis and associated paravertebral or epidural abscess. PMID- 29496624 TI - Bony ingrowth potential of 3D-printed porous titanium alloy: a direct comparison of interbody cage materials in an in vivo ovine lumbar fusion model. AB - BACKGROUND CONTEXT: There is significant variability in the materials commonly used for interbody cages in spine surgery. It is theorized that three-dimensional (3D)-printed interbody cages using porous titanium material can provide more consistent bone ingrowth and biological fixation. PURPOSE: The purpose of this study was to provide an evidence-based approach to decision-making regarding interbody materials for spinal fusion. STUDY DESIGN: A comparative animal study was performed. METHODS: A skeletally mature ovine lumbar fusion model was used for this study. Interbody fusions were performed at L2-L3 and L4-L5 in 27 mature sheep using three different interbody cages (ie, polyetheretherketone [PEEK], plasma sprayed porous titanium-coated PEEK [PSP], and 3D-printed porous titanium alloy cage [PTA]). Non-destructive kinematic testing was performed in the three primary directions of motion. The specimens were then analyzed using micro computed tomography (u-CT); quantitative measures of the bony fusion were performed. Histomorphometric analyses were also performed in the sagittal plane through the interbody device. Outcome parameters were compared between cage designs and time points. RESULTS: Flexion-extension range of motion (ROM) was statistically reduced for the PTA group compared with the PEEK cages at 16 weeks (p-value=.02). Only the PTA cages demonstrated a statistically significant decrease in ROM and increase in stiffness across all three loading directions between the 8-week and 16-week sacrifice time points (p-value<=.01). Micro-CT data demonstrated significantly greater total bone volume within the graft window for the PTA cages at both 8 weeks and 16 weeks compared with the PEEK cages (p value<.01). CONCLUSIONS: A direct comparison of interbody implants demonstrates significant and measurable differences in biomechanical, u-CT, and histologic performance in an ovine model. The 3D-printed porous titanium interbody cage resulted in statistically significant reductions in ROM, increases in the bone ingrowth profile, as well as average construct stiffness compared with PEEK and PSP. PMID- 29496625 TI - The in vivo response to a novel Ti coating compared with polyether ether ketone: evaluation of the periphery and inner surfaces of an implant. AB - BACKGROUND CONTEXT: Increasing bone ongrowth and ingrowth of polyether ether ketone (PEEK) interbody fusion devices has the potential to improve clinical outcomes. PURPOSE: This study evaluated the in vivo response of promoting new bone growth and bone apposition with NanoMetalene (NM) compared with PEEK alone in a cancellous implantation site with an empty aperture. STUDY DESIGN: This is a randomized control animal study. METHODS: Implants and funding for this study were provided by SeaSpine (60,000 USD). Cylindrical dowels with two apertures were prepared as PEEK with a sub-micron layer of the titanium (NM). The titanium coating was applied over the entire implant (Group 1) or just the apertures (Group 2). Polyether ether ketone implants with no coating served as controls (Group 3). Implants were placed in the cancellous bone of the distal femur or proximal tibia with no graft material placed in the apertures in eight adult sheep. Bone ongrowth to the surface of the implant and ingrowth into the apertures was assessed at 4 and 8 weeks after surgery with micro-computed tomography (CT) and undecalcified histology. RESULTS: The apertures in the implants were notably empty in the PEEK group at 4 and 8 weeks. In contrast, new bone formation into the apertures was found in samples coated with NM even though no graft material was placed into the defect. The bone growing into the aperture tracked along the titanium layer. Apertures with the titanium coating demonstrated significantly more bone by micro-CT qualitative grading compared with PEEK with average bone coverage scores of Group 1 (NM) 1.62+/-0.89, Group 2 (NM apertures only) 1.62+/-0.77, and Group 3 (PEEK) 0.43+/-0.51, respectively, at 4 weeks (p<.01) and Group 1 (NM) 1.79+/-1.19, Group 2 (NM apertures only) 1.98+/ 1.18, and Group 3 (PEEK) 0.69+/-0.87, respectively, at 8 weeks (p<.05). The amount of bone in the apertures (ingrowth) quantified using the volumetric data from the micro-CT supported an overall increase in bone volume inside the apertures with the titanium coating compared with PEEK. Histology showed newly formed woven bone tracked along the surface of the titanium in the apertures. The PEEK interface presented the typical nonreactive fibrous tissue inside the apertures at 4 weeks and some focal contact with bone on the outside at 4 weeks and 8 weeks. CONCLUSIONS: Micro-CT and histology demonstrated bone ongrowth to the surfaces coated with NM where the newly formed bone tracked along the thin titanium-coated surfaces. Polyether ether ketone surfaces presented the nonreactive fibrous tissue at the interface as previously reported in preclinical scenarios. PMID- 29496626 TI - A novel anterior decompression technique (vertebral body sliding osteotomy) for ossification of posterior longitudinal ligament of the cervical spine. AB - BACKGROUND CONTEXT: Conventional anterior decompression surgery for cervical myelopathy, including anterior corpectomy and fusion, is technically demanding and is known to be associated with a higher incidence of surgery-related complications, including cerebrospinal fluid (CSF) leakage, neurologic deterioration, and graft failure compared with posterior surgery. PURPOSE: We introduce a novel anterior decompression technique (vertebral body sliding osteotomy [VBSO]) for cervical myelopathy caused by ossification of posterior longitudinal ligament (OPLL) and evaluate the efficacy and safety of this procedure. STUDY DESIGN: This is a case series for novel surgical technique. PATIENT SAMPLE: Fourteen patients (M:F=11:3, mean age 56.9+/-10) with cervical myelopathy caused by OPLL who underwent VBSO by a single surgeon were included. OUTCOME MEASURES: The surgical outcome was evaluated according to the Japanese Orthopaedic Association score for cervical myelopathy (C-JOA score), and the recovery rate of the C-JOA score was calculated. Patients were also evaluated radiographically with plain and dynamic cervical spine radiographs and pre- and postoperative computed tomography images. METHODS: Fourteen patients were followed up for more than 24 months, and operation time, estimated blood loss, neurologic outcomes, and surgery-related complications were investigated. Radiological measurements were also performed to analyze the following parameters: (1) canal-occupying ratio and postoperative canal widening, and (2) pre- and postoperative sagittal alignment. RESULTS: The mean recovery rate of C JOA score at the final follow-up was 68.65+/-17.8%. There were no perioperative complications, including neurologic deterioration, vertebral artery injury, esophageal injury, graft dislodgement, and CSF leaks, after surgery except for pseudarthrosis in one case. An average spinal canal compromised ratio by OPLL decreased from 61.5+/-8.1% preoperatively to 16.5+/-11.2% postoperatively. An average postoperative canal widening was 5.15+/-1.39 mm, and improvement of cervical alignment was observed in all patients, with average recovery angle of 7.3+/-6.1 degrees postoperatively. CONCLUSIONS: The VBSO allows sufficient decompression of spinal cord and provides excellent neurologic outcomes. Because surgeons do not need to manipulate the OPLL mass directly, this technique could significantly decrease surgery-related complications. Furthermore, as VBSO is based on the multilevel discectomy and fusion technique, it would be more helpful to restore a physiological lordosis. PMID- 29496628 TI - NOX4-driven ROS formation regulates proliferation and apoptosis of gastric cancer cells through the GLI1 pathway. AB - NADPH Oxidase 4 (NOX4), a member of the NOX family, has emerged as a significant source of reactive oxygen species, playing an important role in tumor cell proliferation, apoptosis, and other physiological processes. However, the potential function of NOX4 in gastric cancer (GC) cell proliferation is yet unknown. The aim of this study was to illustrate whether NOX4 plays a role in regulating gastric cancer cell growth. First, the clinical information from 90 patients was utilized to explore the clinical value of NOX4 as a predictive tool for tumor size and prognosis. Results showed that NOX4 expression was correlated with tumor size and prognosis. In vitro assays confirmed that knockdown of NOX4 expression blocked cell proliferation and the expression of Cyclin D1, BAX, and so on. Interestingly, NOX4 promoted cell proliferation via activation of the GLI1 pathway. GLI1, a well-known transcription factor in the Hedgehog signaling pathway, was overexpressed to test whether NOX4 activates downstream signaling via GLI1. Overexpression of GLI1 reversed the inhibition of proliferation induced by NOX4 knockdown. In addition, overexpression of NOX4 increased GLI1 expression, and depletion of GLI1 expression decreased the effects induced by NOX4 overexpression. Further, ROS generated by NOX4 was required for GLI1 expression, as shown by use of the ROS inhibitor, diphenylene iodonium (DPI). In summary, the findings indicate that NOX4 plays an important role in gastric cancer cell growth and apoptosis through the generation of ROS and subsequent activation of GLI1 signaling. Hence, the targeting of NOX4 may be an attractive therapeutic strategy for blocking gastric cancer cell proliferation. PMID- 29496629 TI - OBO to UML: Support for the development of conceptual models in the biomedical domain. AB - A conceptual model abstractly defines a number of concepts and their relationships for the purposes of understanding and communication. Once a conceptual model is available, it can also be used as a starting point for the development of a software system. The development of conceptual models using the Unified Modeling Language (UML) facilitates the representation of modeled concepts and allows software developers to directly reuse these concepts in the design of a software system. The OBO Foundry represents the most relevant collaborative effort towards the development of ontologies in the biomedical domain. The development of UML conceptual models in the biomedical domain may benefit from the use of domain-specific semantics and notation. Further, the development of these models may also benefit from the reuse of knowledge contained in OBO ontologies. This paper investigates the support for the development of conceptual models in the biomedical domain using UML as a conceptual modeling language and using the support provided by the OBO Foundry for the development of biomedical ontologies, namely entity kind and relationship types definitions provided by the Basic Formal Ontology (BFO) and the OBO Core Relations Ontology (OBO Core), respectively. Further, the paper investigates the support for the reuse of biomedical knowledge currently available in OBOFFF ontologies in the development these conceptual models. The paper describes a UML profile for the OBO Core Relations Ontology, which basically defines a number of stereotypes to represent BFO entity kinds and OBO Core relationship types definitions. The paper also presents a support toolset consisting of a graphical editor named OBO-RO Editor, which directly supports the development of UML models using the extensions defined by our profile, and a command-line tool named OBO2UML, which directly converts an OBOFFF ontology into a UML model. PMID- 29496627 TI - Jumping mechanisms and performance in beetles. II. Weevils (Coleoptera: Curculionidae: Rhamphini). AB - We describe the kinematics and performance of the natural jump in the weevil Orchestes fagi (Fabricius, 1801) (Coleoptera: Curculionidae) and its jumping apparatus with underlying anatomy and functional morphology. In weevils, jumping is performed by the hind legs and involves the extension of the hind tibia. The principal structural elements of the jumping apparatus are (1) the femoro-tibial joint, (2) the metafemoral extensor tendon, (3) the extensor ligament, (4) the flexor ligament, (5) the tibial flexor sclerite and (6) the extensor and flexor muscles. The kinematic parameters of the jump (from minimum to maximum) are 530 1965 m s-2 (acceleration), 0.7-2.0 m s-1 (velocity), 1.5-3.0 ms (time to take off), 0.3-4.4 MUJ (kinetic energy) and 54-200 (g-force). The specific joint power as calculated for the femoro-tibial joint during the jumping movement is 0.97 W g 1. The full extension of the hind tibia during the jump was reached within up to 1.8-2.5 ms. The kinematic parameters, the specific joint power and the time for the full extension of the hind tibia suggest that the jump is performed via a catapult mechanism with an input of elastic strain energy. A resilin-bearing elastic extensor ligament that connects the extensor tendon and the tibial base is considered to be the structure that accumulates the elastic strain energy for the jump. According to our functional model, the extensor ligament is loaded by the contraction of the extensor muscle, while the co-contraction of the antagonistic extensor and flexor muscles prevents the early extension of the tibia. This is attributable to the leverage factors of the femoro-tibial joint providing a mechanical advantage for the flexor muscles over the extensor muscles in the fully flexed position. The release of the accumulated energy is performed by the rapid relaxation of the flexor muscles resulting in the fast extension of the hind tibia propelling the body into air. PMID- 29496630 TI - Deep neural models for ICD-10 coding of death certificates and autopsy reports in free-text. AB - We address the assignment of ICD-10 codes for causes of death by analyzing free text descriptions in death certificates, together with the associated autopsy reports and clinical bulletins, from the Portuguese Ministry of Health. We leverage a deep neural network that combines word embeddings, recurrent units, and neural attention, for the generation of intermediate representations of the textual contents. The neural network also explores the hierarchical nature of the input data, by building representations from the sequences of words within individual fields, which are then combined according to the sequences of fields that compose the inputs. Moreover, we explore innovative mechanisms for initializing the weights of the final nodes of the network, leveraging co occurrences between classes together with the hierarchical structure of ICD-10. Experimental results attest to the contribution of the different neural network components. Our best model achieves accuracy scores over 89%, 81%, and 76%, respectively for ICD-10 chapters, blocks, and full-codes. Through examples, we also show that our method can produce interpretable results, useful for public health surveillance. PMID- 29496631 TI - The utility of LASSO-based models for real time forecasts of endemic infectious diseases: A cross country comparison. AB - INTRODUCTION: Accurate and timely prediction for endemic infectious diseases is vital for public health agencies to plan and carry out any control methods at an early stage of disease outbreaks. Climatic variables has been identified as important predictors in models for infectious disease forecasts. Various approaches have been proposed in the literature to produce accurate and timely predictions and potentially improve public health response. METHODS: We assessed how the machine learning LASSO method may be useful in providing useful forecasts for different pathogens in countries with different climates. Separate LASSO models were constructed for different disease/country/forecast window with different model complexity by including different sets of predictors to assess the importance of different predictors under various conditions. RESULTS: There was a more apparent cyclicity for both climatic variables and incidence in regions further away from the equator. For most diseases, predictions made beyond 4 weeks ahead were increasingly discrepant from the actual scenario. Prediction models were more accurate in capturing the outbreak but less sensitive to predict the outbreak size. In different situations, climatic variables have different levels of importance in prediction accuracy. CONCLUSIONS: For LASSO models used for prediction, including different sets of predictors has varying effect in different situations. Short term predictions generally perform better than longer term predictions, suggesting public health agencies may need the capacity to respond at short-notice to early warnings. PMID- 29496633 TI - Comment on "Role of Choroid Plexus in Cerebrospinal Fluid Hydrodynamics". PMID- 29496632 TI - Stereological Analysis of Microglia in Aged Male and Female Fischer 344 Rats in Socially Relevant Brain Regions. AB - Aging is associated with a substantial decline in the expression of social behavior as well as increased neuroinflammation. Since immune activation and subsequent increased expression of cytokines can suppress social behavior in young rodents, we examined age and sex differences in microglia within brain regions critical to social behavior regulation (PVN, BNST, and MEA) as well as in the hippocampus. Adult (3-month) and aged (18-month) male and female F344 (N = 26, n = 5-8/group) rats were perfused and Iba-1 immunopositive microglia were assessed using unbiased stereology and optical density. For stereology, microglia were classified based on the following criteria: (1) thin ramified processes, (2) thick long processes, (3) stout processes, or (4) round/ameboid shape. Among the structures examined, the highest density of microglia was evident in the BNST and MEA. Aged rats of both sexes displayed increased total number of microglia number exclusively in the MEA. Sex differences also emerged, whereby aged females (but not males) displayed greater total number of microglia in the BNST relative to their young adult counterparts. When morphological features of microglia were assessed, aged rats exhibited increased soma size in the BNST, MEA, and CA3. Together, these findings provide a comprehensive characterization of microglia number and morphology under ambient conditions in CNS sites critical for the normal expression of social processes. To the extent that microglia morphology is predictive of reactivity and subsequent cytokine release, these data suggest that the expression of social behavior in late aging may be adversely influenced by heightened inflammation. PMID- 29496634 TI - MEN1 Tumor Suppressor Gene is Required for Long-term Memory Formation in an Aversive Operant Conditioning Model of Lymnaea stagnalis. AB - Activity-dependent transcription factors critically coordinate the gene expression program underlying memory formation. The tumor suppressor gene, MEN1, encodes a ubiquitously expressed transcription regulator required for synaptogenesis and synaptic plasticity in invertebrate and vertebrate central neurons. In this study, we investigated the role of MEN1 in long-term memory (LTM) formation in an aversive operant conditioning paradigm in the freshwater pond snail Lymnaea stagnalis (L. stagnalis). We demonstrated that LTM formation is associated with an increased expression of MEN1 coinciding with an up regulation of creb1 gene expression. In vivo knockdown of MEN1 prevented LTM formation and conditioning-induced changes in neuronal activity in the identified pacemaker neuron RPeD1. Our findings suggest the involvement of a new pathway in LTM consolidation that requires MEN1-mediated gene regulation. PMID- 29496635 TI - Quantitative Analysis of Catecholamines in the Pink1 -/- Rat Model of Early-onset Parkinson's Disease. AB - Parkinson's disease (PD) related to homozygous mutations in the Pink1 gene is associated with nigrostriatal dopamine depletion and a wide range of sensorimotor deficits. In humans and animal models of PD, not all sensorimotor deficits are levodopa-responsive. We hypothesized that the underlying mechanisms of locomotion, limb control, and vocal communication behavior include other pathologies. Here, Pink1 -/- rats were treated with an oral dose of levodopa and limb motor and vocal communication behaviors were measured. Levodopa significantly improved some aspects of locomotion but did not improve ultrasonic vocalization intensity or frequency. Catecholamine concentrations in the striatum (SR), substantia nigra (SN), and locus coeruleus (LC) were analyzed to test the hypothesis that behavioral deficits would correlate to altered protein levels. There were no differences in dopamine concentrations in the SR and SN of Pink1 -/ animals compared to wild-type controls. There was a significant increase in norepinephrine concentration in the SN of Pink1 -/- animals. Moreover, an observed decrease in norepinephrine concentrations in the LC is consistent with the hypothesis that early-stage PD includes noradrenergic loss in the brainstem, and is congruent with a significant increase in catechol-O-methyltransferase expression in the LC of Pink1 -/- animals. Pearson's correlations showed that increases in time to traverse a tapered balance beam are significantly associated with reductions in striatal dopamine. Ultrasonic vocalization complexity was positively correlated with LC norepinephrine concentrations. These data support the evolving hypothesis that differences in neural substrates and early-onset noradrenergic mechanisms in the brainstem may contribute to pathogenesis in the Pink1 -/- rat. PMID- 29496637 TI - Longitudinal Treatment Outcomes for an Interdisciplinary Pain Rehabilitation Program: Comparisons of Subjective and Objective Outcomes on the Basis of Opioid Use Status. AB - : Chronic pain is a major public health concern, and widespread use of prescription opioids for chronic pain has contributed to the escalating problem of opioid use disorder. Interdisciplinary pain rehabilitation programs (IPRPs) can be highly effective in discontinuing opioids in patients with chronic pain while also improving functional status. This study sought to examine self-report and performance-based functional outcomes of 2 cohorts of patients enrolled in a 3-week IPRP: patients engaged in interdisciplinary pain treatment and physician supervised opioid taper versus nonopioid users engaged in interdisciplinary treatment. Immediate and long-term treatment outcomes were assessed using a series of 2 (group: opioid use, no opioid use) * 2 (period: pretreatment, post treatment) and 2 (group: opioid use, no opioid use) * 2 (period: pretreatment, 6 months post-treatment) mixed model analyses of variance. Group * Period interactions were nonsignificant whereas period effects were significant for all outcomes in directions indicating improvement (Ps < .001) at discharge from the program and at 6 months, irrespective of opioid use status. Results support the assertion that IPRPs lead to significant improvements in subjective as well as objective indices of function, irrespective of opioid use status. Implications for our findings are discussed. PERSPECTIVE: This article provides support for the effectiveness of interdisciplinary, rehabilitative models of care in improving physical and emotional functioning of patients with chronic pain while simultaneously discontinuing opioid use. The reach of this work is substantial, because opioid dependency and chronic pain are public health problems in the United States. PMID- 29496638 TI - Neuropsychological Functioning and Treatment Outcomes in Acceptance and Commitment Therapy for Chronic Pain. AB - : Neuropsychological (NP) performance has been associated with psychosocial treatment outcomes in nonpain conditions, but has never been investigated in chronic pain. We performed a secondary analysis on the association of baseline NP performance with treatment outcomes among veterans with chronic pain (N = 117) undergoing an 8-week acceptance and commitment therapy (ACT) intervention. Participants completed measures of pain interference, pain severity, quality of life, activity levels, depression, and pain-related anxiety at baseline, midtreatment, and post-treatment. Executive functioning, working memory, processing speed, learning, and verbal memory were assessed at baseline. All study measures significantly improved from baseline to post-treatment. NP performance was related to changes in depression and pain-related anxiety during treatment. Specifically, relatively lower executive functioning and processing speed was associated with greater decreases in depressive symptoms, and relatively lower processing speed was associated with greater decreases in pain related anxiety. Consistent with research in nonpain conditions, those with relatively lower NP functioning received greater benefit from psychosocial treatment, although most study outcomes did not differ as a function of NP performance. Our results suggest relatively lower NP functioning is not contraindicated for participation in psychosocial interventions like ACT but instead may be associated with greater relief. PERSPECTIVE: This study suggests that NP functioning is unrelated to changes in pain interference associated with ACT, and that those with relatively lower NP functioning may experience greater reductions in depressive symptoms and pain-related anxiety. This article contains important information for researchers and clinicians interested in cognition and chronic pain. PMID- 29496636 TI - Within-Person Pain Variability and Mental Health in Older Adults With Osteoarthritis: An Analysis Across 6 European Cohorts. AB - : Pain is a key symptom of osteoarthritis (OA) and has been linked to poor mental health. Pain fluctuates over time within individuals, but a paucity of studies have considered day-to-day fluctuations of joint pain in relation to affective symptoms in older persons with OA. This study investigated the relationship of pain severity as well as within-person pain variability with anxiety and depression symptoms in 832 older adults with OA who participated in the European Project on OSteoArthritis (EPOSA): a 6-country cohort study. Affective symptoms were examined with the Hospital Anxiety and Depression Scale, pain severity was assessed with the Western Ontario and McMaster Universities OA Index and the Australian/Canadian Hand Osteoarthritis Index, and intraindividual pain variability was measured using pain calendars assessed at baseline, 6, and 12 to 18 months. Age-stratified multiple linear regression analyses adjusted for relevant confounders showed that more pain was associated with more affective symptoms in older-old participants (74.1-85 years). Moreover, older-old participants experienced fewer symptoms of anxiety (ratio = .85, 95% confidence interval [CI], .77-.94), depression (ratio = .90, 95% CI, .82-.98), and total affective symptoms (ratio = .87, 95% CI, .79-.94) if their pain fluctuated more. No such association was evident in younger-old participants (65-74.0 years). These findings imply that stable pain levels are more detrimental to mental health than fluctuating pain levels in older persons. PERSPECTIVE: This study showed that more severe and stable joint pain levels were associated with anxiety and depressive symptoms in older persons with OA. These findings emphasize the importance of measuring pain in OA at multiple time points, because joint pain fluctuations may be an indicator for the presence of affective symptoms. PMID- 29496639 TI - The Long-Term Footprint of Endometriosis: Population-Based Cohort Analysis Reveals Increased Pain Symptoms and Decreased Pain Tolerance at Age 46 Years. AB - : Previous studies have shown increased pain sensitivity in fertile-aged women with endometriosis in response to mechanical stimuli. As yet, population-based studies on the association of endometriosis with pain sensation and pain symptoms in late fertile age are lacking. The main objective of this population-based cohort study was to investigate whether a history of endometriosis is associated with altered pain sensation and musculoskeletal pain symptoms at age 46 years. Our data are derived from the Northern Finland Birth Cohort 1966, which contains postal questionnaire data (72% response rate) as well as clinical data assessing pressure-pain threshold and maximal pain tolerance. The study population consisted of 284 women with endometriosis and 3,390 controls. Our results showed that at age 46 women with a history of endometriosis had a 5.3% lower pressure pain threshold and 5.1% lower maximal pain tolerance compared with controls. The most significant contributors besides endometriosis were anxiety, depression, and current smoking status. Women with endometriosis also reported an increased number of pain sites (0 pain sites, 9.6 vs 17.9%; 5-8 pain sites, 24.8 vs 19.1%, endometriosis vs controls respectively; P < .001), and their pain was more troublesome and intense. The results were adjusted for body mass index, smoking, depressive/anxiety symptoms, education, and use of hormonal contraceptives. These unique data revealed an altered pain sensation and a greater likelihood of reporting musculoskeletal pain at age 46 years among women with a history of endometriosis. The results imply that endometriosis has a long-term footprint on affected women, thus underlying the need for psychological support and medical treatment beyond fertile age. PERSPECTIVE: This population-based cohort study showed decreased pain threshold and maximal pain tolerance in women with endometriosis in the late fertile age of 46 years. The pain was also found to be more bothersome and intense compared with controls. PMID- 29496641 TI - Potential use of methane fermentation digested slurry as a low-cost, environmentally-friendly nutrient for bioethanol production from crude glycerol by Klebsiella variicola TB-83D. AB - A methane fermentation digested slurry (MFDS) was evaluated as a substitute for the commercial nutrient, yeast extract (YE), in ethanol production from glycerol by Klebsiella variicola strain TB-83D. In pH-controlled fed-batch cultures, partial replacement of YE by MFDS did not reduce ethanol productivity significantly. However, non-sterilized MFDS had negative effects on glycerol fermentation by this strain. Although ethanol production decreased when YE was completely replaced by sterilized MFDS, the use of crude glycerol and sterilized MFDS achieved a yield of 14.6 g/L ethanol. This is the first study to report the use of MFDS as the sole nutrient for ethanol production from glycerol, which contributes to the development of a low-cost glycerol biorefinery derived from the biodiesel fuel industry. PMID- 29496642 TI - A novel PADRE-Kv1.3 vaccine effectively induces therapeutic antibodies and ameliorates experimental autoimmune encephalomyelitis in rats. AB - Previous studies have confirmed that selective blockade of Kv1.3 channels could modulate the activities of pathogenic T cells and microglia/macrophages, which play key roles in experimental autoimmune encephalomyelitis (EAE). In this study, we designed an anti-Kv1.3 vaccine (PADRE-Kv1.3) to explore its protective role in EAE rat models. When the vaccine was applied in EAE rats, clinical scores and several staining techniques were used to evaluate the severity of the disease. T cell subtypes and related cytokines, as well as microglia/macrophage activation were assayed through flow cytometry, qRT-PCR or immunofluorescence staining, respectively. We herein showed that rats and mice developed high titers of anti Kv1.3 antibodies and appeared no abnormal manifestations after the PADRE-Kv1.3 vaccine treatment. In EAE models, the vaccine treatment effectively alleviated the clinical severity and lessened pathological damages in the central nervous system (CNS). In addition, we found the vaccine significantly decreased the number of pathogenic T cells (Th17 and IFN-gamma-producing T cells) and the production of related pro-inflammatory cytokines (IL-17A, IFN-gamma and IL 1beta), but increased the number of protective T subsets (CD4+IL-10+ T cells and Treg cells) in the spleen or CNS. Moreover, the infiltration of microglia/macrophages significantly reduced and these cells shifted toward anti inflammatory M2 subtype in the CNS after the vaccine treatment. Thus, we demonstrated that the PADRE-Kv1.3 vaccine could induce therapeutic anti-Kv1.3 antibodies and ameliorate EAE in rats effectively and safely, which provides a new field of vision for the protection and therapy of multiple sclerosis. PMID- 29496640 TI - Opposing Roles of Estradiol and Testosterone on Stress-Induced Visceral Hypersensitivity in Rats. AB - : Chronic stress produces maladaptive pain responses, manifested as alterations in pain processing and exacerbation of chronic pain conditions including irritable bowel syndrome. Female predominance, especially during reproductive years, strongly suggests a role of gonadal hormones. However, gonadal hormone modulation of stress-induced pain hypersensitivity is not well understood. In the present study, we tested the hypothesis that estradiol is pronociceptive and testosterone is antinociceptive in a model of stress-induced visceral hypersensitivity (SIVH) in rats by recording the visceromotor response to colorectal distention after a 3-day forced swim (FS) stress paradigm. FS induced visceral hypersensitivity that persisted at least 2 weeks in female, but only 2 days in male rats. Ovariectomy blocked and orchiectomy facilitated SIVH. Furthermore, estradiol injection in intact male rats increased SIVH and testosterone in intact female rats attenuated SIVH. Western blot analyses indicated estradiol increased excitatory glutamate ionotropic receptor NMDA type subunit 1 expression and decreased inhibitory metabotropic glutamate receptor 2 expression after FS in male thoracolumbar spinal cord. In addition, the presence of estradiol during stress increased spinal brain-derived neurotrophic factor (BDNF) expression independent of sex. In contrast, testosterone blocked the stress-induced increase in BDNF expression in female rats. These data suggest that estradiol facilitates and testosterone attenuates SIVH by modulating spinal excitatory and inhibitory glutamatergic receptor expression. PERSPECTIVE: SIVH is more robust in female rats. Estradiol facilitates whereas testosterone dampens the development of SIVH. This could partially explain the greater prevalence of certain chronic visceral pain conditions in women. An increase in spinal BDNF is concomitant with increased stress-induced pain. Pharmaceutical interventions targeting this molecule could provide promising alleviation of SIVH in women. PMID- 29496643 TI - Distinct recruitment of the hippocampal, thalamic, and amygdalar neurons projecting to the prelimbic cortex in male and female rats during context mediated renewal of responding to food cues. AB - Persistent responding to food cues may underlie the difficulty to resist palatable foods and to maintain healthy eating habits. Renewal of responding after extinction is a model of persistent food seeking that can be used to study the underlying neural mechanisms. In context-mediated renewal, a return to the context in which the initial cue-food learning occurred induces robust responding to the cues that were extinguished elsewhere. Previous work found sex differences in context-mediated renewal and in the recruitment of the ventromedial prefrontal cortex (vmPFC) during that behavior. Males exhibited renewal of responding to food cues and had higher Fos induction in the prelimbic area (PL) of the vmPFC, while females failed to exhibit renewal of responding and had lower Fos induction in the PL. The main aim of the current study was to determine key components of the PL circuitry mediating renewal. The focus was on inputs from three areas important in appetitive associative learning and contextual processing: the amygdala, ventral hippocampal formation, and the paraventricular nucleus of the thalamus. The goal was to determine whether neurons from these areas that send direct projections to the PL (identified with a retrograde tracer) are selectively activated (Fos induction) during renewal and whether they are differently recruited in males and females. The Fos induction patterns demonstrated that the PL-projecting neurons in each of these areas were recruited in a sex-specific way that corresponded to the behavioral differences between males and females. These pathways were selectively activated in the male experimental group-the only group that showed renewal behavior. The findings suggest the pathways from the ventral hippocampal formation, paraventricular nucleus of the thalamus, and basolateral amygdala to the PL mediate renewal in males. The lack of recruitment in females suggests that under activation of these pathways may underlie their lack of renewal. PMID- 29496644 TI - Staufen2 deficiency leads to impaired response to novelty in mice. AB - Staufen2 (Stau2) is a double-stranded RNA-binding protein (RBP) involved in posttranscriptional gene expression control in neurons. In flies, staufen contributes to learning and long-term memory formation. To study the impact of mammalian Stau2 on behavior, we generated a novel gene-trap mouse model that yields significant constitutive downregulation of Stau2 (Stau2GT). In order to investigate the effect of Stau2 downregulation on hippocampus-dependent behavior, we performed a battery of behavioral assays, i.e. open field, novel object recognition/location (NOR/L) and Barnes maze. Stau2GT mice displayed reduced locomotor activity in the open field and altered novelty preference in the NOR and NOL paradigms. Adult Stau2GT male mice failed to discriminate between familiar and newly introduced objects but showed enhanced spatial novelty detection. Additionally, we observed deficits in discriminating different spatial contexts in a Barnes maze assay. Together, our data suggest that Stau2 contributes to novelty preference and explorative behavior that is a driver for proper spatial learning in mice. PMID- 29496646 TI - Viral etiology of prostate cancer: Genetic alterations and immune response. A literature review. AB - Prostate cancer is one of the most common cancers in men. Recent estimates suggest that over a million men are diagnosed with the disease annually. Prostate cancer pathogenesis involves both heritable and environmental factors. The molecular events involved in the development or progression of prostate cancer are still unclear. Recent body of literature highlights the role of viral infections in initiation or progression of prostate cancer. In this regard, certain viruses have been reported to interact with host proteins and bring about changes in genetic, immunological and inflammatory events that lead to initiation or progression of prostate cancer. We conducted a comprehensive PubMed database search to identify publications relevant to viruses associated with prostate cancer. In this review, we discuss the possible viral etiology of prostate cancer and evidence of viral-mediated genetic changes, and immune dysregulation involved in initiation or progression of prostate cancer. PMID- 29496645 TI - Memory allocation mechanisms underlie memory linking across time. AB - Memories are dynamic in nature. A cohesive representation of the world requires memories to be altered over time, linked with other memories and eventually integrated into a larger framework of sematic knowledge. Although there is a considerable literature on how single memories are encoded, retrieved and updated, little is known about the mechanisms that govern memory linking, e.g., linking and integration of various memories across hours or days. In this review, we present evidence that specific memory allocation mechanisms, such as changes in CREB and intrinsic excitability, ensure memory storage in ways that facilitate effective recall and linking at a later time. Beyond CREB and intrinsic excitability, we also review a number of other phenomena with potential roles in memory linking. PMID- 29496647 TI - Trends of international medical graduates in surgical and non-surgical residency programs in the US. PMID- 29496648 TI - Adjuvant systemic therapy after resection of node positive gallbladder cancer: Time for a well-designed trial? (Results of a US-national retrospective cohort study). AB - BACKGROUND: Ideal oncologic management of gallbladder carcinoma (GBCA) after complete surgical resection is unclear. We sought to define benefit of post resection adjuvant systemic chemotherapy alone in T2 or greater gallbladder carcinoma utilising a large national dataset. STUDY DESIGN: The National Cancer Data Base (NCDB) 2004-2012 cohort was retrospectively reviewed for patients with GBCA (T2+) undergoing curative-intent resection and surviving at least 6 weeks. Univariate group comparisons, unadjusted Kaplan-Meier and adjusted Cox proportional hazards analyzed overall survival. RESULTS: 4373 patients were included (N = 2479 T2, N = 1894 T3/4). Overall, 22.1% of patients received adjuvant chemotherapy. Use of multi-agent chemotherapy increased during the study period. Patients receiving adjuvant therapy were younger, had fewer comorbidities, more often node-positive and more likely R1-margins than those receiving surgery alone. Unadjusted overall survival was improved in all patients with node-positive disease as well as for those with inadequate nodal staging. The benefit of chemotherapy persisted after adjustment for patient and tumor factors. CONCLUSION: Adjuvant systemic chemotherapy is associated with survival benefit in patients with T2 or greater GBCA with node positive disease. We recommend a multidisciplinary approach in these patients as less than 1-in-4 of them currently receive adjuvant chemotherapy. Future clinical trials should address adjuvant chemotherapy in node positive GBCA. PMID- 29496649 TI - Comparison of the prognosis of primary and progressive muscle-invasive bladder cancer after radical cystectomy: A systematic review and meta-analysis. AB - OBJECTIVE: The aim of the study was to systematically review the relevant studies to evaluate the prognosis of primary and progressive muscle-invasive bladder cancer (MIBC) after radical cystectomy (RC) and provide a clue for the timing of RC in patients with progressive MIBC early at the time of high-risk non-muscle invasive bladder cancer (NMIBC). MATERIAL AND METHODS: PubMed, MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched for eligible studies. We extracted hazard ratios (HRs) of overall survival (OS) and cancer specific survival (CSS) and deaths at 5 and 10 years for each study and performed the meta-analysis using Review Manager 5.3. RESULTS: A total of 11 retrospective studies with 4102 patients were included in the meta-analysis. The pooled analysis suggested a similar CSS (HR: 1.18; 95% CI, 0.74, 1.87; p = 0.50) and OS (HR: 1.15; 95% CI, 0.82, 1.61; p = 0.43) between primary and progressive MIBC patients treated with RC. The results further indicated no significant differences between the two populations in terms of 5-year CSS rate (OR: 1.32; 95% CI, 0.90, 1.95; p = 0.16), 10-year CSS rate (OR: 0.83; 95% CI, 0.37, 1.83; p = 0.64) as well as 5-year OS rate (OR: 1.02; 95% CI, 0.66, 1.56; p = 0.94). Subgroup analysis according to the starting point of follow-up showed similar outcomes. CONCLUSION: The meta-analysis demonstrates comparable CSS and OS in patients with primary and progressive MIBC following RC. Novel risk stratifications and prospective trials are urgently needed to investigate the prognosis after RC of these two groups of patients, which could finally aid clinician decision making and select patients who would actually benefit from early RC. PMID- 29496650 TI - Oral & Maxillofacial Surgery; A historical review of the development of the surgical discipline. PMID- 29496651 TI - Experiences of Indian Health Workers Using WhatsApp for Improving Aseptic Practices With Newborns: Exploratory Qualitative Study. AB - BACKGROUND: Quality improvement (QI) involves the following 4 steps: (1) forming a team to work on a specific aim, (2) analyzing the reasons for current underperformance, (3) developing changes that could improve care and testing these changes using plan-do-study-act cycles (PDSA), and (4) implementing successful interventions to sustain improvements. Teamwork and group discussion are key for effective QI, but convening in-person meetings with all staff can be challenging due to workload and shift changes. Mobile technologies can support communication within a team when face-to-face meetings are not possible. WhatsApp, a mobile messaging platform, was implemented as a communication tool by a neonatal intensive care unit (NICU) team in an Indian tertiary hospital seeking to reduce nosocomial infections in newborns. OBJECTIVE: This exploratory qualitative study aimed to examine experiences with WhatsApp as a communication tool among improvement team members and an external coach to improve adherence to aseptic protocols. METHODS: Ten QI team members and the external coach were interviewed on communication processes and approaches and thematically analyzed. The WhatsApp transcript for the implementation period was also included in the analysis. RESULTS: WhatsApp was effective for disseminating information, including guidance on QI and clinical practice, and data on performance indicators. It was not effective as a platform for group discussion to generate change ideas or analyze the performance indicator data. The decision of who to include in the WhatsApp group and how members engaged in the group may have reinforced existing hierarchies. Using WhatsApp created a work environment in which members were accessible all the time, breaking down barriers between personal and professional time. The continual influx of messages was distracting to some respondents, and how respondents managed these messages (eg, using the silent function) may have influenced their perceptions of WhatsApp. The coach used WhatsApp to share information, schedule site visits, and prompt action on behalf of the team. CONCLUSIONS: WhatsApp is a productive communication tool that can be used by teams and coaches to disseminate information and prompt action to improve the quality of care, but cannot replace in-person meetings. PMID- 29496652 TI - Optimizing Tailored Communications for Health Risk Assessment: A Randomized Factorial Experiment of the Effects of Expectancy Priming, Autonomy Support, and Exemplification. AB - BACKGROUND: Health risk assessments with tailored feedback plus health education have been shown to be effective for promoting health behavior change. However, there is limited evidence to guide the development and delivery of online automated tailored feedback. OBJECTIVE: The goal of this study was to optimize tailored feedback messages for an online health risk assessment to promote enhanced user engagement, self-efficacy, and behavioral intentions for engaging in healthy behaviors. We examined the effects of three theory-based message factors used in developing tailored feedback messages on levels of engagement, self-efficacy, and behavioral intentions. METHODS: We conducted a randomized factorial experiment to test three different components of tailored feedback messages: tailored expectancy priming, autonomy support, and use of an exemplar. Individuals (N=1945) were recruited via Amazon Mechanical Turk and randomly assigned to one of eight different experimental conditions within one of four behavioral assessment and feedback modules (tobacco use, physical activity [PA], eating habits, and weight). Participants reported self-efficacy and behavioral intentions pre- and postcompletion of an online health behavior assessment with tailored feedback. Engagement and message perceptions were assessed at follow-up. RESULTS: For the tobacco module, there was a significant main effect of the exemplar factor (P=.04); participants who received exemplar messages (mean 3.31, SE 0.060) rated their self-efficacy to quit tobacco higher than those who did not receive exemplar messages (mean 3.14, SE 0.057). There was a three-way interaction between the effect of message conditions on self-efficacy to quit tobacco (P=.02), such that messages with tailored priming and an exemplar had the greatest impact on self-efficacy to quit tobacco. Across PA, eating habits, and weight modules, there was a three-way interaction among conditions on self efficacy (P=.048). The highest self-efficacy scores were reported among those who were in the standard priming condition and received both autonomy supportive and exemplar messages. In the PA module, autonomy supportive messages had a stronger effect on self-efficacy for PA in the standard priming condition. For PA, eating habits, and weight-related behaviors, the main effect of exemplar messages on behavioral intentions was in the hypothesized direction but did not reach statistical significance (P=.08). When comparing the main effects of different message conditions, there were no differences in engagement and message perceptions. CONCLUSIONS: Findings suggest that tailored feedback messages that use exemplars helped improve self-efficacy related to tobacco cessation, PA, eating habits, and weight control. Combining standard priming and autonomy supportive message components shows potential for optimizing tailored feedback for tobacco cessation and PA behaviors. PMID- 29496653 TI - Toward Timely Data for Cancer Research: Assessment and Reengineering of the Cancer Reporting Process. AB - BACKGROUND: Cancer registries systematically collect cancer-related data to support cancer surveillance activities. However, cancer data are often unavailable for months to years after diagnosis, limiting its utility. OBJECTIVE: The objective of this study was to identify the barriers to rapid cancer reporting and identify ways to shorten the turnaround time. METHODS: Certified cancer registrars reporting to the Indiana State Department of Health cancer registry participated in a semistructured interview. Registrars were asked to describe the reporting process, estimate the duration of each step, and identify any barriers that may impact the reporting speed. Qualitative data analysis was performed with the intent of generating recommendations for workflow redesign. The existing and redesigned workflows were simulated for comparison. RESULTS: Barriers to rapid reporting included access to medical records from multiple facilities and the waiting period from diagnosis to treatment. The redesigned workflow focused on facilitating data sharing between registrars and applying a more efficient queuing technique while registrars await the delivery of treatment. The simulation results demonstrated that our recommendations to reduce the waiting period and share information could potentially improve the average reporting speed by 87 days. CONCLUSIONS: Knowing the time elapsing at each step within the reporting process helps in prioritizing the needs and estimating the impact of future interventions. Where some previous studies focused on automating some of the cancer reporting activities, we anticipate much shorter reporting by leveraging health information technologies to target this waiting period. PMID- 29496654 TI - Uterine Artery Embolization Versus Hysterectomy in the Treatment of Symptomatic Adenomyosis: Protocol for the Randomized QUESTA Trial. AB - BACKGROUND: Adenomyosis is a benign uterine disease characterized by invasion of endometrium into the myometrium resulting in heavy menstrual bleeding and pain (dysmenorrhea). Hysterectomy is established as the final treatment option when conservative treatment fails. Uterine artery embolization (UAE) in patients with symptomatic adenomyosis has demonstrated to reduce symptoms and improve quality of life. However, randomized controlled trials are lacking. OBJECTIVE: With this study, we aim to evaluate the impact of UAE on Health-Related Quality of Life (HRQOL) in a randomized comparison to hysterectomy in patients with symptomatic adenomyosis. METHODS: This is a multicenter non-blinded randomized controlled trial comparing UAE and hysterectomy. Eligible patients are symptomatic premenopausal women without the desire to conceive and who have symptomatic magnetic resonance imaging (MRI)-confirmed pure adenomyosis or dominant adenomyosis accompanied by fibroids. After obtaining informed consent, patients will be randomly allocated to treatment in a 2:1 UAE versus hysterectomy ratio. The primary objective is HRQOL at 6 months following the assigned intervention. Secondary outcomes are technical results, pain management, clinical outcomes, HRQOL, and cost effectiveness during 2 years of follow-up. In addition, transvaginal ultrasound (TVUS) and MRI will be performed at regular intervals after UAE. RESULTS: Patient enrollment started November 2015. The follow-up period will be completed two years after inclusion of the last patient. At the time of submission of this article, data cleaning and analyses have not yet started. CONCLUSIONS: This trial will provide insight for caretakers and future patients about the effect of UAE compared to the gold standard hysterectomy in the treatment of symptomatic adenomyosis and is therefore expected to improve patients' wellbeing and quality of life. TRIAL REGISTRATION: Netherlands Trial Register NTR5615; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=5615 (Archived by WebCite at http://www.webcitation.org/6xZRyXeIF). PMID- 29496655 TI - Patient Involvement With Home-Based Exercise Programs: Can Connected Health Interventions Influence Adherence? AB - Adherence to home exercise in rehabilitation is a significant problem, with estimates of nonadherence as high as 50%, potentially having a detrimental effect on clinical outcomes. In this viewpoint, we discuss the many reasons why patients may not adhere to a prescribed exercise program and explore how connected health technologies have the ability to offer numerous interventions to enhance adherence; however, it is hard to judge the efficacy of these interventions without a robust measurement tool. We highlight how well-designed connected health technologies, such as the use of mobile devices, including mobile phones and tablets, as well as inertial measurement units, provide us with the opportunity to better support the patient and clinician, with a data-driven approach that incorporates features designed to increase adherence to exercise such as coaching, self-monitoring and education, as well as remotely monitor adherence rates more objectively. PMID- 29496656 TI - Reliability of Self-Reported Mobile Phone Ownership in Rural North-Central Nigeria: Cross-Sectional Study. AB - BACKGROUND: mHealth practitioners seek to leverage the ubiquity of the mobile phone to increase the impact and robustness of their interventions, particularly in resource-limited settings. However, data on the reliability of self-reported mobile phone access is minimal. OBJECTIVE: We sought to ascertain the reliability of self-reported ownership of and access to mobile phones among a population of rural dwellers in north-central Nigeria. METHODS: We contacted participants in a community-based HIV testing program by phone to determine actual as opposed to self-reported mobile phone access. A phone script was designed to conduct these calls and descriptive analyses conducted on the findings. RESULTS: We dialed 349 numbers: 110 (31.5%) were answered by participants who self-reported ownership of the mobile phone; 123 (35.2%) of the phone numbers did not ring at all; 28 (8.0%) rang but were not answered; and 88 (25.2%) were answered by someone other than the participant. We reached a higher proportion of male participants (68/133, 51.1%) than female participants (42/216, 19.4%; P<.001). CONCLUSIONS: Self reported access to mobile phones in rural and low-income areas in north-central Nigeria is higher than actual access. This has implications for mHealth programming, particularly for women's health. mHealth program implementers and researchers need to be cognizant of the low reliability of self-reported mobile phone access. These observations should therefore affect sample-size calculations and, where possible, alternative means of reaching research participants and program beneficiaries should be established. PMID- 29496657 TI - Augmenting Outpatient Alcohol Treatment as Usual With Online Alcohol Avoidance Training: Protocol for a Double-Blind Randomized Controlled Trial. AB - BACKGROUND: Recent theoretical models emphasize the role of impulsive processes in alcohol addiction, which can be retrained with computerized Cognitive Bias Modification (CBM) training. In this study, the focus is on action tendencies that are activated relatively automatically. OBJECTIVE: The aim of the study is to examine the effectiveness of online CBM Alcohol Avoidance Training using an adapted Approach-Avoidance Task as a supplement to treatment as usual (TAU) in an outpatient treatment setting. METHODS: The effectiveness of 8 online sessions of CBM Alcohol Avoidance Training added to TAU is tested in a double-blind, randomized controlled trial with pre- and postassessments, plus follow-up assessments after 3 and 6 months. Participants are adult patients (age 18 years or over) currently following Web-based or face-to-face TAU to reduce or stop drinking. These patients are randomly assigned to a CBM Alcohol Avoidance or a placebo training. The primary outcome measure is a reduction in alcohol consumption. We hypothesize that TAU + CBM will result in up to a 13-percentage point incremental effect in the number of patients reaching the safe drinking guidelines compared to TAU + placebo CBM. Secondary outcome measures include an improvement in health status and a decrease in depression, anxiety, stress, and possible mediation by the change in approach bias. Finally, patients' adherence, acceptability, and credibility will be examined. RESULTS: The trial was funded in 2014 and is currently in the active participant recruitment phase (since May 2015). Enrolment will be completed in 2019. First results are expected to be submitted for publication in 2020. CONCLUSIONS: The main purpose of this study is to increase our knowledge about the added value of online Alcohol Avoidance Training as a supplement to TAU in an outpatient treatment setting. If the added effectiveness of the training is proven, the next step could be to incorporate the intervention into current treatment. TRIAL REGISTRATION: Netherlands Trial Register NTR5087; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=5087 (Archived at WebCite http://www.webcitation.org/6wuS4i1tH). PMID- 29496658 TI - Self-Swabbing for Virological Confirmation of Influenza-Like Illness Among an Internet-Based Cohort in the UK During the 2014-2015 Flu Season: Pilot Study. AB - BACKGROUND: Routine influenza surveillance, based on laboratory confirmation of viral infection, often fails to estimate the true burden of influenza-like illness (ILI) in the community because those with ILI often manage their own symptoms without visiting a health professional. Internet-based surveillance can complement this traditional surveillance by measuring symptoms and health behavior of a population with minimal time delay. Flusurvey, the UK's largest crowd-sourced platform for surveillance of influenza, collects routine data on more than 6000 voluntary participants and offers real-time estimates of ILI circulation. However, one criticism of this method of surveillance is that it is only able to assess ILI, rather than virologically confirmed influenza. OBJECTIVE: We designed a pilot study to see if it was feasible to ask individuals from the Flusurvey platform to perform a self-swabbing task and to assess whether they were able to collect samples with a suitable viral content to detect an influenza virus in the laboratory. METHODS: Virological swabbing kits were sent to pilot study participants, who then monitored their ILI symptoms over the influenza season (2014-2015) through the Flusurvey platform. If they reported ILI, they were asked to undertake self-swabbing and return the swabs to a Public Health England laboratory for multiplex respiratory virus polymerase chain reaction testing. RESULTS: A total of 700 swab kits were distributed at the start of the study; from these, 66 participants met the definition for ILI and were asked to return samples. In all, 51 samples were received in the laboratory, 18 of which tested positive for a viral cause of ILI (35%). CONCLUSIONS: This demonstrated proof of concept that it is possible to apply self-swabbing for virological laboratory testing to an online cohort study. This pilot does not have significant numbers to validate whether Flusurvey surveillance accurately reflects influenza infection in the community, but highlights that the methodology is feasible. Self-swabbing could be expanded to larger online surveillance activities, such as during the initial stages of a pandemic, to understand community transmission or to better assess interseasonal activity. PMID- 29496659 TI - Inhibition of Local Macrophage Growth Ameliorates Focal Inflammation and Suppresses Atherosclerosis. AB - OBJECTIVE: Macrophages play a central role in various stages of atherosclerotic plaque formation and progression. The local macrophages reportedly proliferate during atherosclerosis, but the pathophysiological significance of macrophage proliferation in this context remains unclear. Here, we investigated the involvement of local macrophage proliferation during atherosclerosis formation and progression using transgenic mice, in which macrophage proliferation was specifically suppressed. APPROACH AND RESULTS: Inhibition of macrophage proliferation was achieved by inducing the expression of cyclin-dependent kinase inhibitor 1B, also known as p27kip, under the regulation of a scavenger receptor promoter/enhancer. The macrophage-specific human p27kip Tg mice were subsequently crossed with apolipoprotein E-deficient mice for the atherosclerotic plaque study. Results showed that a reduced number of local macrophages resulted in marked suppression of atherosclerotic plaque formation and inflammatory response in the plaque. Moreover, fewer local macrophages in macrophage-specific human p27kip Tg mice helped stabilize the plaque, as evidenced by a reduced necrotic core area, increased collagenous extracellular matrix, and thickened fibrous cap. CONCLUSIONS: These results provide direct evidence of the involvement of local macrophage proliferation in formation and progression of atherosclerotic plaques and plaque stability. Thus, control of macrophage proliferation might represent a therapeutic target for treating atherosclerotic diseases. PMID- 29496660 TI - Role of Sympathetic Nerves and Adipocyte Catecholamine Uptake in the Vasorelaxant Function of Perivascular Adipose Tissue. AB - OBJECTIVE: Healthy perivascular adipose tissue (PVAT) exerts an anticontractile effect on resistance arteries which is vital in regulating arterial tone. Activation of beta3-adrenoceptors by sympathetic nerve-derived NA (noradrenaline) may be implicated in this effect and may stimulate the release of the vasodilator adiponectin from adipocytes. Understanding the mechanisms responsible is vital for determining how PVAT may modify vascular resistance in vivo. APPROACH AND RESULTS: Electrical field stimulation profiles of healthy C57BL/6J mouse mesenteric resistance arteries were characterized using wire myography. During electrical field stimulation, PVAT elicits a reproducible anticontractile effect, which is endothelium independent. To demonstrate the release of an anticontractile factor, the solution surrounding stimulated exogenous PVAT was transferred to a PVAT-denuded vessel. Post-transfer contractility was significantly reduced confirming that stimulated PVAT releases a transferable anticontractile factor. Sympathetic denervation of PVAT using tetrodotoxin or 6 hydroxydopamine completely abolished the anticontractile effect. beta3 adrenoceptor antagonist SR59203A reduced the anticontractile effect, although the PVAT remained overall anticontractile. When the antagonist was used in combination with an OCT3 (organic cation transporter 3) inhibitor, corticosterone, the anticontractile effect was completely abolished. Application of an adiponectin receptor-1 blocking peptide significantly reduced the anticontractile effect in +PVAT arteries. When used in combination with the beta3 adrenoceptor antagonist, there was no further reduction. In adiponectin knockout mice, the anticontractile effect is absent. CONCLUSIONS: The roles of PVAT are 2 fold. First, sympathetic stimulation in PVAT triggers the release of adiponectin via beta3-adrenoceptor activation. Second, PVAT acts as a reservoir for NA, preventing it from reaching the vessel and causing contraction. PMID- 29496662 TI - Tuition fees for medical school: what is the effect on students? PMID- 29496661 TI - Ly6CHi Blood Monocyte/Macrophage Drive Chronic Inflammation and Impair Wound Healing in Diabetes Mellitus. AB - OBJECTIVE: Wound monocyte-derived macrophage plasticity controls the initiation and resolution of inflammation that is critical for proper healing, however, in diabetes mellitus, the resolution of inflammation fails to occur. In diabetic wounds, the kinetics of blood monocyte recruitment and the mechanisms that control in vivo monocyte/macrophage differentiation remain unknown. APPROACH AND RESULTS: Here, we characterized the kinetics and function of Ly6CHi [Lin- (CD3 CD19-NK1.1-Ter-119-) Ly6G-CD11b+] and Ly6CLo [Lin- (CD3-CD19-NK1.1-Ter-119-) Ly6G CD11b+] monocyte/macrophage subsets in normal and diabetic wounds. Using flow sorted tdTomato-labeled Ly6CHi monocyte/macrophages, we show Ly6CHi cells transition to a Ly6CLo phenotype in normal wounds, whereas in diabetic wounds, there is a late, second influx of Ly6CHi cells that fail transition to Ly6CLo. The second wave of Ly6CHi cells in diabetic wounds corresponded to a spike in MCP 1 (monocyte chemoattractant protein-1) and selective administration of anti-MCP-1 reversed the second Ly6CHi influx and improved wound healing. To examine the in vivo phenotype of wound monocyte/macrophages, RNA-seq-based transcriptome profiling was performed on flow-sorted Ly6CHi [Lin-Ly6G-CD11b+] and Ly6CLo [Lin Ly6G-CD11b+] cells from normal and diabetic wounds. Gene transcriptome profiling of diabetic wound Ly6CHi cells demonstrated differences in proinflammatory and profibrotic genes compared with controls. CONCLUSIONS: Collectively, these data identify kinetic and functional differences in diabetic wound monocyte/macrophages and demonstrate that selective targeting of CD11b+Ly6CHi monocyte/macrophages is a viable therapeutic strategy for inflammation in diabetic wounds. PMID- 29496663 TI - HOXA9 Cooperates with Activated JAK/STAT Signaling to Drive Leukemia Development. AB - Leukemia is caused by the accumulation of multiple genomic lesions in hematopoietic precursor cells. However, how these events cooperate during oncogenic transformation remains poorly understood. We studied the cooperation between activated JAK3/STAT5 signaling and HOXA9 overexpression, two events identified as significantly co-occurring in T-cell acute lymphoblastic leukemia. Expression of mutant JAK3 and HOXA9 led to a rapid development of leukemia originating from multipotent or lymphoid-committed progenitors, with a significant decrease in disease latency compared with JAK3 or HOXA9 alone. Integrated RNA sequencing, chromatin immunoprecipitation sequencing, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) revealed that STAT5 and HOXA9 have co-occupancy across the genome, resulting in enhanced STAT5 transcriptional activity and ectopic activation of FOS/JUN (AP1). Our data suggest that oncogenic transcription factors such as HOXA9 provide a fertile ground for specific signaling pathways to thrive, explaining why JAK/STAT pathway mutations accumulate in HOXA9-expressing cells.Significance: The mechanism of oncogene cooperation in cancer development remains poorly characterized. In this study, we model the cooperation between activated JAK/STAT signaling and ectopic HOXA9 expression during T-cell leukemia development. We identify a direct cooperation between STAT5 and HOXA9 at the transcriptional level and identify PIM1 kinase as a possible drug target in mutant JAK/STAT/HOXA9-positive leukemia cases. Cancer Discov; 8(5); 616-31. (c)2018 AACR.This article is highlighted in the In This Issue feature, p. 517. PMID- 29496664 TI - In Vivo E2F Reporting Reveals Efficacious Schedules of MEK1/2-CDK4/6 Targeting and mTOR-S6 Resistance Mechanisms. AB - Targeting cyclin-dependent kinases 4/6 (CDK4/6) represents a therapeutic option in combination with BRAF inhibitor and/or MEK inhibitor (MEKi) in melanoma; however, continuous dosing elicits toxicities in patients. Using quantitative and temporal in vivo reporting, we show that continuous MEKi with intermittent CDK4/6 inhibitor (CDK4/6i) led to more complete tumor responses versus other combination schedules. Nevertheless, some tumors acquired resistance that was associated with enhanced phosphorylation of ribosomal S6 protein. These data were supported by phospho-S6 staining of melanoma biopsies from patients treated with CDK4/6i plus targeted inhibitors. Enhanced phospho-S6 in resistant tumors provided a therapeutic window for the mTORC1/2 inhibitor AZD2014. Mechanistically, upregulation or mutation of NRAS was associated with resistance in in vivo models and patient samples, respectively, and mutant NRAS was sufficient to enhance resistance. This study utilizes an in vivo reporter model to optimize schedules and supports targeting mTORC1/2 to overcome MEKi plus CDK4/6i resistance.Significance: Mutant BRAF and NRAS melanomas acquire resistance to combined MEK and CDK4/6 inhibition via upregulation of mTOR pathway signaling. This resistance mechanism provides the preclinical basis to utilize mTORC1/2 inhibitors to improve MEKi plus CDK4/6i drug regimens. Cancer Discov; 8(5); 568 81. (c)2018 AACR.See related commentary by Sullivan, p. 532See related article by Romano et al., p. 556This article is highlighted in the In This Issue feature, p. 517. PMID- 29496666 TI - Optimising sleep for night shifts. PMID- 29496665 TI - A Preexisting Rare PIK3CAE545K Subpopulation Confers Clinical Resistance to MEK plus CDK4/6 Inhibition in NRAS Melanoma and Is Dependent on S6K1 Signaling. AB - Combined MEK and CDK4/6 inhibition (MEKi + CDK4i) has shown promising clinical outcomes in patients with NRAS-mutant melanoma. Here, we interrogated longitudinal biopsies from a patient who initially responded to MEKi + CDK4i therapy but subsequently developed resistance. Whole-exome sequencing and functional validation identified an acquired PIK3CAE545K mutation as conferring drug resistance. We demonstrate that PIK3CAE545K preexisted in a rare subpopulation that was missed by both clinical and research testing, but was revealed upon multiregion sampling due to PIK3CAE545K being nonuniformly distributed. This resistant population rapidly expanded after the initiation of MEKi + CDK4i therapy and persisted in all successive samples even after immune checkpoint therapy and distant metastasis. Functional studies identified activated S6K1 as both a key marker and specific therapeutic vulnerability downstream of PIK3CAE545K-induced resistance. These results demonstrate that difficult-to-detect preexisting resistance mutations may exist more often than previously appreciated and also posit S6K1 as a common downstream therapeutic nexus for the MAPK, CDK4/6, and PI3K pathways.Significance: We report the first characterization of clinical acquired resistance to MEKi + CDK4i, identifying a rare preexisting PIK3CAE545K subpopulation that expands upon therapy and exhibits drug resistance. We suggest that single-region pretreatment biopsy is insufficient to detect rare, spatially segregated drug-resistant subclones. Inhibition of S6K1 is able to resensitize PIK3CAE545K-expressing NRAS-mutant melanoma cells to MEKi + CDK4i. Cancer Discov; 8(5); 556-67. (c)2018 AACR.See related commentary by Sullivan, p. 532See related article by Teh et al., p. 568This article is highlighted in the In This Issue feature, p. 517. PMID- 29496667 TI - Staff must be trained to speak clearly for those with hearing difficulties. PMID- 29496668 TI - Is Textbook Outcome a valuable composite measure for short-term outcomes of gastrointestinal treatments in the Netherlands using hospital information system data? A retrospective cohort study. AB - OBJECTIVE: To develop a feasible model for monitoring short-term outcome of clinical care trajectories for hospitals in the Netherlands using data obtained from hospital information systems for identifying hospital variation. STUDY DESIGN: Retrospective analysis of collected data from hospital information systems combined with clinical indicator definitions to define and compare short term outcomes for three gastrointestinal pathways using the concept of Textbook Outcome. SETTING: 62 Dutch hospitals. PARTICIPANTS: 45 848 unique gastrointestinal patients discharged in 2015. MAIN OUTCOME MEASURE: A broad range of clinical outcomes including length of stay, reintervention, readmission and doctor-patient counselling. RESULTS: Patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) for gallstone disease (n=4369), colonoscopy for inflammatory bowel disease (IBD; n=19 330) and colonoscopy for colorectal cancer screening (n=22 149) were submitted to five suitable clinical indicators per treatment. The percentage of all patients who met all five criteria was 54%+/-9% (SD) for ERCP treatment. For IBD this was 47%+/-7% of the patients, and for colon cancer screening this number was 85%+/-14%. CONCLUSION: This study shows that reusing data obtained from hospital information systems combined with clinical indicator definitions can be used to express short-term outcomes using the concept of Textbook Outcome without any excess registration. This information can provide meaningful insight into the clinical care trajectory on the level of individual patient care. Furthermore, this concept can be applied to many clinical trajectories within gastroenterology and beyond for monitoring and improving the clinical pathway and outcome for patients. PMID- 29496669 TI - Next-generation sequencing of idiopathic multicentric and unicentric Castleman disease and follicular dendritic cell sarcomas. AB - Castleman disease (CD) is a rare lymphoproliferative disorder subclassified as unicentric CD (UCD) or multicentric CD (MCD) based on clinical features and the distribution of enlarged lymph nodes with characteristic histopathology. MCD can be further subtyped based on human herpes virus 8 (HHV8) infection into HHV8 associated MCD, HHV8-/idiopathic MCD (iMCD), and polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin change (POEMS)-associated MCD. In a subset of cases of UCD, an associated follicular dendritic cell sarcoma (FDCS) may be seen. Although numerous reports of the clinical and histologic features of UCD, MCD, and FDCS exist, an understanding of the genetic and epigenetic landscape of these rare diseases is lacking. Given this paucity of knowledge, we analyzed 15 cases of UCD and 3 cases of iMCD by targeted next-generation sequencing (NGS; 405 genes) and 3 cases of FDCS associated with UCD hyaline vascular variant (UCD-HVV) by whole-exome sequencing. Common amplifications of ETS1, PTPN6, and TGFBR2 were seen in 1 iMCD and 1 UCD case; the iMCD case also had a somatic DNMT3A L295Q mutation. This iMCD patient also showed clinicopathologic features consistent with a specific subtype known as Castleman Kojima disease (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly [TAFRO] clinical subtype). Additionally, 1 case of UCD-HVV showed amplification of the cluster of histone genes on chromosome 6p. FDCS associated with UCD-HVV showed mutations and copy number changes in known oncogenes, tumor suppressors, and chromatin structural-remodeling proteins. PMID- 29496672 TI - Majority of juniors take a break from training, survey finds. PMID- 29496670 TI - IMiD compounds affect CD34+ cell fate and maturation via CRBN-induced IKZF1 degradation. AB - We have previously shown that immunomodulatory drug (IMiD) compounds induce a shift into immature myeloid precursors with a maturational arrest and subsequent neutropenia. The mechanism of action is unknown. Here we found that IMiD compounds cause selective ubiquitination and degradation of the transcription factor IKZF1 in CD34+ cells by the Cereblon (CRBN) E3 ubiquitin ligase. Loss of IKZF1 is associated with a decrease of the IKZF1-dependent transcription factor PU.1, critical for the development and maturation of neutrophils. Using a thalidomide analog bead pull-down assay, we showed that IMiD compounds directly bind CRBN in CD34+ cells. Knockdown of CRBN in CD34+ cells resulted in resistance to POM-induced IKZF1 downregulation and reversed the POM-induced lineage shift in colony-formation assays, suggesting that the POM-induced degradation of IKZF1 in CD34+ cells requires CRBN. Chromatin immunoprecipitation assays revealed that IKZF1 binds to the promoter region of PU.1, suggesting that PU.1 is a direct downstream target of IKZF1 in CD34+ cells. POM failed to induce IKZF1 degradation in IKZF1-Q146H-OE CD34+ cells, indicating that CRBN binding to IKZF1 and subsequent IKZF1 ubiquitination is critical in this process. Using the NOD/SCID/gamma-c KO mouse model, we confirmed the induction of myeloid progenitor cells by IMiD compounds at the expense of common lymphoid progenitors. These results demonstrate a novel mechanism of action of IMiD compounds in hematopoietic progenitor cells, leading to selective degradation of transcription factors critical for myeloid maturation, and explain the occurrence of neutropenia associated with treatment by IMiD compounds. PMID- 29496674 TI - Colleges work to improve the "med reg" role. PMID- 29496671 TI - BTKCys481Ser drives ibrutinib resistance via ERK1/2 and protects BTKwild-type MYD88-mutated cells by a paracrine mechanism. AB - Acquired ibrutinib resistance due to BTKCys481 mutations occurs in B-cell malignancies, including those with MYD88 mutations. BTKCys481 mutations are usually subclonal, and their relevance to clinical progression remains unclear. Moreover, the signaling pathways that promote ibrutinib resistance remain to be clarified. We therefore engineered BTKCys481Ser and BTKWT expressing MYD88 mutated Waldenstrom macroglobulinemia (WM) and activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL) cells and observed reactivation of BTK-PLCgamma2 ERK1/2 signaling in the presence of ibrutinib in only the former. Use of ERK1/2 inhibitors triggered apoptosis in BTKCys481Ser-expressing cells and showed synergistic cytotoxicity with ibrutinib. ERK1/2 reactivation in ibrutinib-treated BTKCys481Ser cells was accompanied by release of many prosurvival and inflammatory cytokines, including interleukin-6 (IL-6) and IL-10 that were also blocked by ERK1/2 inhibition. To clarify if cytokine release by ibrutinib-treated BTKCys481Ser cells could protect BTKWT MYD88-mutated malignant cells, we used a Transwell coculture system and showed that nontransduced BTKWT MYD88-mutated WM or ABC DLBCL cells were rescued from ibrutinib-induced killing when cocultured with BTKCys481Ser but not their BTKWT-expressing counterparts. Use of IL-6 and/or IL-10 blocking antibodies abolished the protective effect conferred on nontransduced BTKWT by coculture with BTKCys481Ser expressing WM or ABC DLBCL cell counterparts. Rebound of IL-6 and IL-10 serum levels also accompanied disease progression in WM patients with acquired BTKCys481 mutations. Our findings show that the BTKCys481Ser mutation drives ibrutinib resistance in MYD88 mutated WM and ABC DLBCL cells through reactivation of ERK1/2 and can confer a protective effect on BTKWT cells through a paracrine mechanism. PMID- 29496673 TI - Should universal distribution of high dose vitamin A to children cease? PMID- 29496675 TI - Helping Practitioners and Researchers Identify and Use Education Research Literature. AB - Evidence-based teaching practices are being encouraged to increase student skills and understanding in the sciences. Finding, interpreting, and applying education literature to a specific context are barriers to adopting these evidence-based practices. Here, we introduce a new feature, Evidence-Based Teaching Guides This feature identifies literature associated with specific pedagogies, which we distill to practical recommendations for teaching. The goals of the feature are: to provide instructors with tools to make research-supported choices to implement the pedagogy in question, to articulate the reasons for their choices, and to develop increased awareness of biology education research. We think these guides may also be useful for biology education researchers in identifying critical components, adaptations, and contextual features that could be investigated for a given pedagogy. Each guide consists of a website with a visual map of instructional choices associated with the topic and linked pages that summarize findings from the literature and provide additional links to and summaries of key articles. Each guide will include an instructor checklist of recommendations consolidated from the entire guide in order to provide instructors with a snapshot of instructional choices and actionable advice. PMID- 29496676 TI - Language Matters: Considering Microaggressions in Science. PMID- 29496678 TI - Seven days in medicine: 21-27 February 2018. PMID- 29496677 TI - Correction for Collectively Improving Our Teaching: Attempting Biology Department wide Professional Development in Scientific Teaching. PMID- 29496679 TI - Acupuncture for lumbar disc herniation: a systematic review and meta-analysis. AB - OBJECTIVE: To evaluate evidence for the effectiveness of acupuncture in the treatment of lumbar disc herniation (LDH). METHODS: Electronic databases were searched to identify randomised controlled trials (RCTs) of acupuncture for LDH. A meta-analysis was conducted using RevMan 5.3 and the evidence level was assessed using GRADE methodology. RESULTS: Thirty RCTs involving 3503 participants were included in the study. Meta-analysis showed that acupuncture had a higher total effective rate than lumbar traction (RR=1.1, 95% CI 1.05 to 1.15; p<0.001), ibuprofen (RR=1.24, 95% CI 1.03 to 1.48; p=0.02), diclofenac sodium (RR=1.44, 95% CI 1.24 to 1.67; p<0.001) and meloxicam (RR=1.16, 95% CI 1.03 to 1.31; p=0.01). Acupuncture was also better than lumbar traction (SMD 1.33, 95% CI -1.82 to -0.84; p<0.001) and diclofenac sodium (SMD -1.36, 95% CI 2.59 to -0.13; p=0.03) in terms of visual analogue scale (VAS) scores, and better than lumbar traction (SMD 0.96, 95% CI 0.48 to 1.45; p=0.0001) with respect to Japanese Orthopaedic Association (JOA) scores. In addition, the total effective rate in five individual trials was greater for acupuncture than for mannitol plus dexamethasone and mecobalamin, ibuprofen plus fugui gutong capsule, loxoprofen, mannitol plus dexamethasone and huoxue zhitong decoction, respectively. Additionally, two individual trials showed a superior effect of acupuncture in VAS scores comparedwith ibuprofen or mannitol plus dexamethasone, respectively. CONCLUSIONS: Acupuncture showed a more favourable effect in the treatment of LDH than lumbar traction, ibuprofen, diclofenac sodium, meloxicam, mannitol plus dexamethasone and mecobalamin, fugui gutong capsule plus ibuprofen, mannitol plus dexamethasone, loxoprofen and huoxue zhitong decoction. However, further rigorously designed, large-scale RCTs are needed to confirm these findings. PMID- 29496681 TI - National network of vascular surgery units will improve patient outcomes, says NHS Improvement. PMID- 29496682 TI - Inequalities in life expectancy are widening, data confirm. PMID- 29496680 TI - Global ECG Measures and Cardiac Structure and Function: The ARIC Study (Atherosclerosis Risk in Communities). AB - BACKGROUND: Electric excitation initiates myocardial mechanical contraction and coordinates myocardial pumping. We hypothesized that ECG global electric heterogeneity (GEH) and its longitudinal changes are associated with cardiac structure and function. METHODS AND RESULTS: Participants from the ARIC study (Atherosclerosis Risk in Communities) (N=5114; 58% female; 22% blacks) with resting 12-lead ECGs (visits 1-5) and echocardiographic assessment of left ventricular (LV) ejection fraction, LV global longitudinal strain, LV mass index, LV end-diastolic volume index, and LV end-systolic volume index at visit 5 were included. Longitudinal analysis included ARIC participants (N=14 609) with measured GEH at visits 1 to 4. GEH was quantified by spatial ventricular gradient, QRS-T angle, and sum absolute QRS-T integral. Cross-sectional and longitudinal regressions were adjusted for manifest and subclinical cardiovascular disease. Having 4 abnormal GEH parameters was associated with a 6.4% (95% confidence interval, 5.5-7.3) LV ejection fraction decline, a 24.2 g/m2 (95% confidence interval, 21.5-26.9) increase in LV mass index, a 10.3 mL/m2 (95% confidence interval, 8.9-11.7) increase in LV end-diastolic volume index, and a 7.8 mL/m2 (95% confidence interval, 6.9-8.6) increase in LV end-systolic volume index. Altogether, clinical and ECG parameters accounted for approximately one third of LV volume and 20% of systolic function variability. The associations were significantly stronger in cardiovascular disease. Sum absolute QRS-T integral increased by 20 mV*ms for each 3-year period in participants who demonstrated LV dilatation at visit 5. Sudden cardiac death victims demonstrated rapid GEH worsening, whereas those with LV dysfunction demonstrated slow GEH worsening. Healthy aging was associated with a distinct pattern of spatial ventricular gradient azimuth decrement. CONCLUSIONS: GEH is a marker of subclinical abnormalities in cardiac structure and function. PMID- 29496683 TI - Downstream Microvascular Thrombosis in Cortical Venules Is an Early Response to Proximal Cerebral Arterial Occlusion. AB - BACKGROUND: Previous experimental studies have shown that downstream microvascular thromboinflammation is involved in brain damage from acute ischemic stroke. Using intravital microscopy, we investigated and characterized the sequence of downstream microvascular thromboinflammation in an ischemia/reperfusion acute ischemic stroke model. METHODS AND RESULTS: Rats underwent transient monofilament middle cerebral artery (MCA) occlusion. Cerebral microcirculation in the MCA territory was exposed through a craniotomy and analyzed using real-time intravital imaging coupled with laser Doppler interferometry. Leukocytes, platelets, fibrinogen, and blood-brain barrier permeability were analyzed by intravenous injection of fluorescent antibodies and bovine serum albumin. MCA occlusion induced a sudden and profound drop in downstream microvascular blood flow associated with leukocyte margination in the venous compartment. Leukocyte margination fostered fibrinogen deposition and thrombosis in postcapillary venules. Either in venules or arterioles, blood flow was not fully restored after MCA recanalization. Furthermore, venular thrombi persisted despite MCA recanalization, and leukocyte extravasation continued to develop in venules in association with blood-brain barrier disruption. Finally, microhemorrhages were occasionally observed, colocalizing with thrombosed venules characterized by marked leukocyte margination. CONCLUSIONS: We showed that microvascular thrombosis in transient monofilament MCA occlusion and blood-brain barrier disruption are initiated immediately after occlusion and are propagated through the venous compartment in close association with marginating leukocytes. MCA occlusion-induced downstream microvascular thromboinflammation response was responsible for incomplete reperfusion after MCA recanalization and delayed microhemorrhages. PMID- 29496684 TI - Unique simultaneous avulsion fracture of both the proximal and distal insertion sites of the anterior cruciate ligament. AB - February is a busy month for the ambulance skiing patrol at the skiing resorts in Norway and on this day, a call regarding an 11-year-old boy on one of the hills reached the team. What no one knew at that moment was that this boy had suffered a unique injury and that his X-rays would reveal something that, prior to this, had never been described in the history of mankind. This patient had suffered a simultaneous avulsion fracture of both the femoral and tibial insertion sites of the anterior cruciate ligament without suffering any other injuries to the knee. The injury was treated conservatively and at 1-year follow-up, the patient was completely recovered. PMID- 29496685 TI - An 88-year-old woman with flushing, alopecia and hirsutism and a Sertoli-Leydig cell tumour. AB - Sertoli-Leydig cell tumour (SLCT) is a rare, androgen-secreting sex cord-stromal tumour of the ovary that usually occurs in young premenopausal women. The major clinical manifestations are virilisation and defeminisation. The following case describes an 88-year-old G1P1 woman, 40 years after menopause, who presented with flushing, hirsutism, voice changes and alopecia along with significantly elevated levels of testosterone. Postoperative report revealed a well-differentiated SLCT in the left ovary. This case is unique in that SLCT is a very rare cancer and even more so in an 88-year-old woman. Taking this case into consideration, it becomes reasonable to check androgen and oestrogen levels in postmenopausal women, not only in patients with signs of virilisation, but also in those with non-classical presentations, such as flushing or heat spells. PMID- 29496686 TI - Chronic osteomyelitis of the tibia in a runner: catastrophic consequences of shin splints. AB - Medial tibial stress syndrome and chronic osteomyelitis are conditions that are traditionally thought to affect very different patient groups. We present a case of shin splints in a recreational long-distance runner, complicated by chronic osteomyelitis of the tibia. This is a unique case in which the microtrauma resulting from shin splints was implicated as an entry point for bacterial infection into the bone. Clinical evaluation and bone biopsy culture results indicated haematogenous spread of bacteria originating from the oral cavity. The patient required surgical resection of the affected bone and a prolonged course of intravenous antibiotic treatment. We illustrate that when shin splints show signs of acute inflammation with delayed recovery, the possibility of osteomyelitis should be kept in mind. PMID- 29496687 TI - Painful torticollis following adenotonsillectomy: a cardinal sign of atlantoaxial subluxation. AB - An 11-year-old boy with a history of autism spectrum disorder attended the emergency department with his mother 8 days after an adenotonsillectomy reporting postoperative bleeding. Detailed physical examination revealed no active bleeding, but a rigid neck posture was noted. A head and neck CT scan demonstrated unilateral rotatory atlantoaxial subluxation and possible damage to the anterior spinal ligament. He was reviewed by neurosurgeons who performed manipulation under anaesthetic and successfully realigned the occipital cervical tract. Non-traumatic atlantoaxial subluxation (Grisel's syndrome) is a rare but serious complication of routine ear, nose and throat (ENT) procedures. An awareness of this complication among paediatricians, otolaryngologists and emergency physicians, and a high index of suspicion in any patient presenting with torticollis following ENT surgery is essential in preventing significant neurological morbidity. PMID- 29496688 TI - Pericallosal lipoma in children: a rare case. PMID- 29496690 TI - Novel Germline PTEN Mutation Associated with Cowden Syndrome and Osteosarcoma. AB - BACKGROUND: Cowden syndrome (CS) is a rare autosomal-dominant inherited disorder characterized by multiple hamartomas. While the hamartomas are benign, patients with CS have increased risk of osteosarcoma and of breast, thyroid, endometrial, soft-tissue and colonic neoplasms. Germline mutations of phosphatase and tensin homolog (PTEN) are implicated in CS and in the development of osteosarcoma. We report a patient with CS who presented with osteosarcoma, ganglioneuromatosis and a benign breast mass. Osteosarcoma, as presentation of CS, is rare (only one report in the English literature). Genomic DNA from the patient's peripheral blood was quantified by spectrophotometry, then underwent sequence enrichment, polymerase chain reaction and next-generation sequencing. Molecular analysis revealed a non-synonymous c.17_18delAA frameshift mutation in exon 1 of PTEN and a c.116G>T (p.R39L) missense mutation of serine/threonine kinase 11 (STK11) of unknown significance. CONCLUSION: We report a patient with CS presenting with ganglioneuromatosis, benign breast mass and osteosarcoma, harboring a novel molecular alteration in PTEN which to our knowledge has not been previously reported. PMID- 29496689 TI - Characterization of Camptothecin-induced Genomic Changes in the Camptothecin resistant T-ALL-derived Cell Line CPT-K5. AB - Acquisition of resistance to topoisomerase I (TOP1)-targeting camptothecin (CPT) derivatives is a major clinical problem. Little is known about the underlying chromosomal and genomic mechanisms. We characterized the CPT-K5 cell line expressing mutant CPT-resistant TOP1 and its parental T-cell derived acute lymphoblastic leukemia CPT-sensitive RPMI-8402 cell line by karyotyping and molecular genetic methods, including subtractive oligo-based array comparative genomic hybridization (soaCGH) analysis. Karyotyping revealed that CPT-K5 cells had acquired additional structural aberrations and a reduced modal chromosomal number compared to RPMI-8402. soaCGH analysis identified vast copy number alterations and >200 unbalanced DNA breakpoints distributed unevenly across the chromosomal complement in CPT-K5. In addition, the short tandem repeat alleles were found to be highly different between CPT-K5 and its parental cell line. We identified copy number alterations affecting genes important for maintaining genome integrity and reducing CPT-induced DNA damage. We show for the first time that short tandem repeats are targets for TOP1 cleavage, that can be differentially stimulated by CPT. PMID- 29496691 TI - Genetic Landscape of Acute Myeloid Leukemia Interrogated by Next-generation Sequencing: A Large Cancer Center Experience. AB - BACKGROUND/AIM: Acute myeloid leukemia (AML) represents a heterogeneous disease with varying morphologic, immunophenotypic, and genetic features, along with varying patient outcomes. The genomic tractability of AML makes it amenable for targeted next-generation sequencing (NGS) testing clinically. MATERIALS AND METHODS: One hundred eights-seven unique patients with a diagnosis of acute myeloid leukemia between May 2011 and Oct 2014 and with mutational analysis by NGS were included in this study. The distribution of gene mutations was investigated in different subcategories of AML. RESULTS: Most patients in this study (n=182) received Genoptix testing (either 5-gene panel or 21-gene panel). In 130/187 (70%) cases, there was an average of 2.3 mutations per case (range=0-7 mutations). We specifically mention mutations in 32 genes, their significance and co-occurrence as detected in different types of AML. CONCLUSION: The genetic heterogeneity of AML signifies the importance of taking a personalized-medicine approach to the management of patients with AML. PMID- 29496692 TI - ILK Expression in Colorectal Cancer Is Associated with EMT, Cancer Stem Cell Markers and Chemoresistance. AB - BACKGROUND/AIM: Epithelial-mesenchymal transition (EMT) and cancer stem cells (CSC) are critically implicated in cancer metastasis and chemoresistance. Herein, we investigated integrin-linked kinase (ILK)'s role in human colon cancer (CRC) progression and chemoresistance in relation to EMT and CSC markers. PATIENTS AND METHODS: Expression of ILK, EMT and CSC markers were evaluated by immunohistochemistry in 149 CRC samples. We also generated colon cancer cells resistant to 5-FU and oxaliplatin and studied the effect of ILK inhibition on drug response by MTT assay and on EMT and CSC markers' expression. RESULTS: ILK expression in human CRC correlates with EMT and CSC markers and is associated with metastasis and chemoresistance. ILK inhibition increases sensitivity of resistant cells to 5-FU and oxaliplatin and reduces the levels of EMT and CSC markers in 5-FU resistant cells. CONCLUSION: ILK overexpression in human CRC associates with EMT and CSC traits, contributing to tumor progression and chemoresistance. PMID- 29496693 TI - LINE-1 ORF1 Protein Is Up-regulated by Reactive Oxygen Species and Associated with Bladder Urothelial Carcinoma Progression. AB - BACKGROUND/AIM: Reactivation of long interspersed nuclear element-1 (LINE-1) and oxidative stress are suggested to have oncogenic potential to drive tumorigenesis and cancer progression. We previously demonstrated that reactive oxygen species (ROS) caused hypomethylation of LINE-1 elements in bladder cancer cells. In this study, we investigated the expression of LINE-1-encoded protein (ORF1p) and oxidative stress marker 4-hydroxynonenal (4-HNE) in human bladder cancer tissues, as well as induction of ORF1p expression by ROS in bladder cancer cell lines. MATERIALS AND METHODS: Thirty-six cancerous and 15 non-cancerous adjacent tissues were immunohistochemically stained for ORF1p and 4-HNE. ORF1p expression and cell migration were determined in bladder cancer cells exposed to H2O2 Results: ORF1p and 4-HNE expression was higher in cancerous than non-cancerous tissues. Elevated ORF1p expression was associated with increased 4-HNE expression and with advanced tumors. H2O2 provoked oxidative stress and up-regulated ORF1p expression in VM CUB-1 compared to the untreated control, and to a lesser degree in TCCSUP. H2O2 exposure enhanced cell migration in UM-UC-3, TCCSUP and VM-CUB-1. CONCLUSION: Elevated ORF1p expression is associated with tumor progression. ROS experimentally induce ORF1p expression and promote migration in bladder cancer cells. PMID- 29496695 TI - Heat stress and fetal risk. Environmental limits for exercise and passive heat stress during pregnancy: a systematic review with best evidence synthesis. AB - OBJECTIVE: Pregnant women are advised to avoid heat stress (eg, excessive exercise and/or heat exposure) due to the risk of teratogenicity associated with maternal hyperthermia; defined as a core temperature (Tcore) >=39.0 degrees C. However, guidelines are ambiguous in terms of critical combinations of climate and activity to avoid and may therefore unnecessarily discourage physical activity during pregnancy. Thus, the primary aim was to assess Tcore elevations with different characteristics defining exercise and passive heat stress (intensity, mode, ambient conditions, duration) during pregnancy relative to the critical maternal Tcore of >=39.0 degrees C. DESIGN: Systematic review with best evidence synthesis. DATA SOURCES: EMBASE, MEDLINE, SCOPUS, CINAHL and Web of Science were searched from inception to 12 July 2017. STUDY ELIGIBILITY CRITERIA: Studies reporting the Tcore response of pregnant women, at any period of gestation, to exercise or passive heat stress, were included. RESULTS: 12 studies satisfied our inclusion criteria (n=347). No woman exceeded a Tcore of 39.0 degrees C. The highest Tcore was 38.9 degrees C, reported during land-based exercise. The highest mean end-trial Tcore was 38.3 degrees C (95% CI 37.7 degrees C to 38.9 degrees C) for land-based exercise, 37.5 degrees C (95% CI 37.3 degrees C to 37.7 degrees C) for water immersion exercise, 36.9 degrees C (95% CI 36.8 degrees C to 37.0 degrees C) for hot water bathing and 37.6 degrees C (95% CI 37.5 degrees C to 37.7 degrees C) for sauna exposure. CONCLUSION: The highest individual core temperature reported was 38.9 degrees C. Immediately after exercise (either land based or water immersion), the highest mean core temperature was 38.3 degrees C; 0.7 degrees C below the proposed teratogenic threshold. Pregnant women can safely engage in: (1) exercise for up to 35 min at 80%-90% of their maximum heart rate in 25 degrees C and 45% relative humidity (RH); (2) water immersion (<=33.4 degrees C) exercise for up to 45 min; and (3) sitting in hot baths (40 degrees C) or hot/dry saunas (70 degrees C; 15% RH) for up to 20 min, irrespective of pregnancy stage, without reaching a core temperature exceeding the teratogenic threshold. PMID- 29496697 TI - MRD negativity as a surrogate for PFS in CLL? PMID- 29496696 TI - Do the benefits of folic acid fortification outweigh the risk of masking vitamin B12 deficiency? PMID- 29496694 TI - Insights into Novel Prognostic and Possible Predictive Biomarkers of Lung Neuroendocrine Tumors. AB - Primary lung neuroendocrine tumors (NETs) consist of typical and atypical carcinoids, large-cell neuroendocrine carcinomas and small-cell lung carcinomas. NETs are highly heterogeneous in histological characteristics, clinical presentation and natural history. While there are morphological and immunohistochemical criteria to establish diagnosis, there is a lack of universal consensus for prognostic factors or therapeutic targets for personalized treatment of the disease. Thus, identifying potential markers of neuroendocrine differentiation and prognostic factors remains of high importance. This review provides an insight into promising molecules and genes that are implicated in NET carcinogenesis, cell-cycle regulation, chromatin remodeling, apoptosis, intracellular cascades and cell-cell interactions. Additionally it supports a basis for classifying these tumors into categories that distinct molecular characteristics and disease natural history, which may have a direct impact on treatment options. In light of the recent approval of everolimus, mammalian target of rapamycin pathway inhibition and related biomarkers may play a central role in the treatment of pulmonary NETs. Future clinical trials that integrate molecular profiling are deemed necessary in order to treat patients with NET on a personalized basis. PMID- 29496698 TI - The elusive pathogenesis of Schnitzler syndrome. PMID- 29496699 TI - R-spondin(g) to syndecan-1 in myeloma. PMID- 29496700 TI - "Dar"-ing to target CD38 in T-ALL. PMID- 29496701 TI - BEACHcombing for alpha-granules. PMID- 29496702 TI - Unwinding the path from anemia to stroke. PMID- 29496703 TI - Hemophilia gene therapy is effective and safe. PMID- 29496704 TI - Myelophthisic marrow involved by breast cancer and acute myeloid leukemia. PMID- 29496705 TI - Lin RJ, Behera M, Diefenbach CS, Flowers CR. Role of anthracycline and comprehensive geriatric assessment for elderly patients with diffuse large B-cell lymphoma. Blood. 2017;130(20):2180-2185. PMID- 29496706 TI - Erratum for Song et al., "CRISPR-Cas9D10A Nickase-Assisted Genome Editing in Lactobacillus casei". PMID- 29496707 TI - Management of Nosocomial Pneumonia. PMID- 29496708 TI - Exponential Technology. PMID- 29496709 TI - Residual Neuromuscular Blockade in the Critical Care Setting. AB - Residual neuromuscular blockade is a widespread challenge for providers in the acute care setting that, if left unrecognized or untreated, places patients at higher risk for morbidity and mortality. The condition is estimated to occur in 26% to 88% of patients undergoing general anesthesia. The role of the advanced practice nurse in the acute care setting is to facilitate a safe recovery process by identifying early signs of deterioration and supporting the patient until full muscular strength has returned. This article discusses the prevalence of residual neuromuscular blockade and associated complications and patient risk factors. A review is included of the current uses for neuromuscular blockade, pathophysiology of the neuromuscular junction, pharmacologic characteristics of neuromuscular blocking agents (including drug-drug interactions), monitoring modalities, and effectiveness of reversal agents. Treatment recommendations pertinent to residual neuromuscular blockade are outlined. PMID- 29496710 TI - Genomics and Precision Medicine. PMID- 29496711 TI - Genomics and Precision Medicine: Implications for Critical Care. AB - A new paradigm for disease diagnosis and treatment is emerging that will bring about changes in health care delivery in and out of the hospital setting. Over the past several decades, genomic medicine has been one of the fastest growing fields in acute and chronic health care. This quick growth has created a lag in genomics knowledge and preparation among nurses and health care providers. Genomic medicine may lead to more precise evaluation, diagnosis, and management of selected acute care conditions. This article reviews the current state of genetic and genomics science and looks at the expanding field of genomic medicine's integration into precision medicine. The aim of this article is to raise awareness and spark further inquiry to the remarkable field of genomics and precision medicine. PMID- 29496712 TI - Pharmacogenomics in Critical Care. AB - Since the successful completion of the Human Genome Project in 2003, extensive genomic research has continued to alter pathophysiology at the molecular level. This research includes investigation of the specific receptors and metabolizing enzymes in drug pharmacodynamics and pharmacokinetics, specifically the cytochrome P450 system located primarily in the liver. In this article, pharmacogenomics and the role of the cytochrome P450 system in metabolism of various drugs are discussed. Specifically, drugs that are used in the critical care setting and are of clinical significance to the bedside critical care nurse are examined. PMID- 29496713 TI - Cardiac Channelopathies: Recognition, Treatment, Management. AB - The discovery of the human genome has ushered in a new era of molecular testing, advancing our knowledge and ability to identify cardiac channelopathies. Genetic variations can affect the opening and closing of the potassium, sodium, and calcium channels, resulting in arrhythmias and sudden death. Cardiac arrhythmias caused by disorders of ion channels are known as cardiac channelopathies. Nurses are important members of many interdisciplinary teams and must have a general understanding of the pathophysiology of the most commonly encountered cardiac channelopathies, electrocardiogram characteristics, approaches to treatment, and care for patients and their families. This article provides an overview of cardiac channelopathies that nurses might encounter in an array of clinical and research settings, focusing on the clinically relevant features of long QT syndrome, short QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and arrhythmogenic right ventricular dysplasia/cardiomyopathy. PMID- 29496714 TI - Genetics and Genomics of Acute Neurologic Disorders. AB - Neurologic diseases and injuries are complex and multifactorial, making risk prediction, targeted treatment modalities, and outcome prognostication difficult and elusive. Genetics and genomics have affected clinical practice in many aspects in medicine, particularly cancer treatment. Advancements in knowledge of genetic and genomic variability in neurologic disease and injury are growing rapidly. Although these data are not yet ready for use in clinical practice, research continues to progress and elucidate information that eventually will provide answers to complex neurologic questions and serve as a platform to provide individualized care plans aimed at improving outcomes. This article provides a focused review of relevant literature on genetics, genomics, and common complex neurologic disease and injury likely to be seen in the acute care setting. PMID- 29496715 TI - Lung Disease and Genomics. AB - Research and application of genomic medicine in lung disease during the past century has clarified our understanding and focus on specific phenotypes, helping clinicians tailor treatment for individual patients. Cystic fibrosis and lung cancer have been researched extensively; specific genotypes have been instrumental in precision medicine to treat these lung diseases. Asthma and chronic obstructive pulmonary disease are more complex and heterogeneous in their pathogenesis, genotypic profile, and phenotypic expression, making treatment more difficult with increasing disease severity. This article focuses on the evolving state of the science of precision medicine in lung cancer, chronic obstructive pulmonary disease, asthma, and cystic fibrosis. The body of knowledge in lung disease is growing related to pharmacogenomics, clinical guidelines, genome editing, and approaches to genomic health that will guide clinical treatment options, reduce risk, and promote health. PMID- 29496716 TI - Clinical Nurse Specialists Fostering Palliative Care Skills. PMID- 29496717 TI - Ketogenic Therapy: First-Line Management of Intractable Seizures in Children. PMID- 29496718 TI - Risk of preterm delivery and small-for-gestational-age births in women with autoimmune disease using biologics before or during pregnancy: a population-based cohort study. AB - OBJECTIVES: To assess the risk of preterm delivery and small-for-gestational-age (SGA) births in women with autoimmune diseases using biologics before or during pregnancy. METHODS: Using population-based administrative data in British Columbia, Canada, women with one or more autoimmune diseases who had pregnancies between 1 January 2002 and 31 December 2012 were included. Exposure to biologics was defined as having at least one biologic prescription 3 months before or during pregnancy. Each exposed pregnancy was matched with five unexposed pregnancies using high-dimensional propensity scores (HDPS). Logistic regression modelling was used to evaluate the association between biologics use and preterm delivery and SGA. RESULTS: There were 6218 women with 8607 pregnancies who had an autoimmune disease diagnosis; of which 109 women with 120 pregnancies were exposed to biologics 3 months before or during pregnancy. In unadjusted analyses, the ORs for the association of biologics exposure with preterm deliveries were 1.64 (95% CI 1.02 to 2.63) and 1.34 (95% CI 0.72 to 2.51) for SGA. After HDPS matching with 600 unexposed pregnancies, the ORs for the association of biologics exposure and preterm deliveries were 1.13 (95% CI 0.67 to 1.90) and 0.91 (95% CI 0.46 to 1.78) for SGA. Sensitivity analyses using HDPS deciles, continuous HDPS covariate or longer exposure window did not result in marked changes in point estimates and CIs. CONCLUSIONS: These population-based data suggest that the use of biologics before and during pregnancy is not associated with an increased risk of preterm delivery or SGA births. PMID- 29496719 TI - Transmission of rheumatoid arthritis through blood transfusion: a retrospective cohort study. PMID- 29496720 TI - Dual-energy CT: a new imaging modality for bone marrow oedema in rheumatoid arthritis. PMID- 29496721 TI - Navigating Transporter Sciences in Pharmacokinetics Characterization Using the Extended Clearance Classification System. AB - Membrane transporters play an important role in the absorption, distribution, clearance, and elimination of drugs. Supported by the pharmacokinetics data in human, several transporters including organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)2, multidrug and toxin extrusion (MATE) proteins, P-glycoprotein and breast cancer resistance protein are suggested to be of clinical relevance. An early understanding of the transporter role in drug disposition and clearance allows reliable prediction/evaluation of pharmacokinetics and changes due to drug drug interactions (DDIs) or genetic polymorphisms. We recently proposed an extended clearance classification system (ECCS) based on simple drug properties (i.e., ionization, permeability, and molecular weight) to predict the predominant clearance mechanism. According to this framework, systemic clearance of class 1B and 3B drugs is likely determined by the OATP-mediated hepatic uptake. Class 3A and 4 drugs, and certain class 3B drugs, are predominantly cleared by renal, wherein, OAT1, OAT3, OCT2, and MATE proteins could contribute to their active renal secretion. Intestinal efflux and uptake transporters largely influence the oral pharmacokinetics of class 3A, 3B, and 4 drugs. We discuss the paradigm of applying the ECCS framework in mapping the role of clinically relevant drug transporters in early discovery and development; thereby implementing the right strategy to allow optimization of drug exposure and evaluation of clinical risk due to DDIs and pharmacogenomics. PMID- 29496722 TI - Calcium and vitamin D supplementation and increased risk of serrated polyps: results from a randomised clinical trial. AB - OBJECTIVE: Serrated lesions such as sessile serrated adenomas or polyps (SSA/Ps) are important colorectal cancer precursors, but aetiological factors for these lesions are largely unknown. We aimed to determine the effects of calcium and vitamin D supplementation on the incidence of serrated polyps (SPs) in general and hyperplastic polyps and SSA/Ps specifically. DESIGN: Participants with one or more adenoma at baseline were randomised to receive 1200 mg/day of elemental calcium, 1000 IU/day of vitamin D3, both or neither agent. Treatment continued for 3 or 5 years, when risk of polyps was determined from surveillance colonoscopy (treatment phase). Outcomes after treatment ceased were also assessed (observational phase). Adjusted risk ratios (aRRs) of SPs were determined via multivariable generalised linear models. RESULTS: SPs were diagnosed in 565 of 2058 (27.5%) participants during the treatment phase and 329/1108 (29.7%) during the observational phase. In total, 211 SSA/Ps were identified during follow-up. In the treatment phase, there was no effect of either calcium or vitamin D on incidence of SSA/Ps. However, during the later observational phase, we observed elevated risks of SSA/Ps associated with calcium alone and calcium+vitamin D treatment (aRR (95% CI): 2.65 (1.43 to 4.91) and 3.81 (1.25 to 11.64), respectively). CONCLUSION: In a large multicentre chemoprevention study, we found evidence that calcium and vitamin D supplementation increased the risk of SSA/Ps. This appeared to be a late effect: 6-10 years after supplementation began. These possible risks must be weighed against the benefits of calcium and vitamin D supplementation. TRIAL REGISTRATION NUMBER: NCT00153816; Results. PMID- 29496723 TI - Normal Values of Magnetic Relaxation Parameters of Spine Components with the Synthetic MRI Sequence. AB - BACKGROUND AND PURPOSE: SyMRI is a technique developed to perform quantitative MR imaging. Our aim was to analyze its potential use for measuring relaxation times of normal components of the spine and to compare them with values found in the literature using relaxometry and other techniques. MATERIALS AND METHODS: Thirty two spine MR imaging studies (10 cervical, 5 dorsal, 17 lumbosacral) were included. A modified multiple-dynamic multiple-echo sequence was added and processed to obtain quantitative T1 (millisecond), T2 (millisecond), and proton density (percentage units [pu]) maps for each patient. An ROI was placed on representative areas for CSF, spinal cord, intervertebral discs, and vertebral bodies, to measure their relaxation. RESULTS: Relaxation time means are reported for CSF (T1 = 4273.4 ms; T2 = 1577.6 ms; proton density = 107.5 pu), spinal cord (T1 = 780.2 ms; T2 = 101.6 ms; proton density = 58.7 pu), normal disc (T1 = 1164.9 ms; T2 = 101.9 ms; proton density = 78.9 pu), intermediately hydrated disc (T1 = 723 ms; T2 = 66.8 ms; proton density = 60.8 pu), desiccated disc (T1 = 554.4 ms; T2 = 55.6 ms; proton density = 47.6 ms), and vertebral body (T1 = 515.3 ms; T2 = 100.8 ms; proton density = 91.1 pu). Comparisons among the mean T1, T2, and proton density values showed significant differences between different spinal levels (cervical, dorsal, lumbar, and sacral) for CSF (proton density), spinal cord (T2 and proton density), normal disc (T1, T2, and proton density), and vertebral bodies (T1 and proton density). Significant differences were found among mean T1, T2, and proton density values of normal, intermediately hydrated, and desiccated discs. CONCLUSIONS: Measurements can be easily obtained on SyMRI and correlated with previously published values obtained using conventional relaxometry techniques. PMID- 29496724 TI - Altered Regional Homogeneity in Chronic Insomnia Disorder with or without Cognitive Impairment. AB - BACKGROUND AND PURPOSE: Many studies have shown that insomnia is an independent factor in cognitive impairment, but the involved neurobiological mechanisms remain unclear. We used regional homogeneity to explore the specific neurobiologic indicators of chronic insomnia disorder with mild cognitive impairment. MATERIALS AND METHODS: Thirty-nine patients with insomnia were divided into a group with and without cognitive impairment; we also included a control group (n = 28). Abnormalities in brain functional activity were identified by comparing the regional homogeneity values for each brain region among the groups. RESULTS: Subjective insomnia scores were negatively correlated with cognitive impairment after controlling for age, sex, and educational effects. Regions with significant differences in regional homogeneity values in the 3 groups were concentrated in the right medial prefrontal cortex, the right superior frontal gyrus, and the left superior occipital gyrus. Meanwhile, subjective insomnia scores were negatively correlated with the strength of the decreased regional homogeneity in the right medial prefrontal cortex. The increased regional homogeneity value in the right superior frontal gyrus was positively correlated with the Montreal Cognitive Assessment score in patients. CONCLUSIONS: Our results indicate that decreased regional homogeneity values in the medial prefrontal cortex and increased regional homogeneity values in the cuneus may be important neurobiologic indicators of chronic insomnia disorder and accompanying cognitive impairment. Overall, our study described the regional homogeneity of the whole brain in chronic insomnia disorder with mild cognitive impairment and could be the basis for future studies. PMID- 29496725 TI - Radiation Dosimetry of 3D Rotational Neuroangiography and 2D-DSA in Children. AB - BACKGROUND AND PURPOSE: The benefit-risk assessment concerning radiation use in pediatric neuroangiography requires an extensive understanding of the doses delivered. This work evaluated the effective dose of 3D rotational angiography in a cohort of pediatric patients with complex neurovascular lesions and directly compared it with conventional 2D-biplane DSA. MATERIALS AND METHODS: Thirty-three 3D rotational angiography acquisitions were acquired in 24 pediatric patients (mean age, 10.4 years). When clinically indicated, following 2D-biplane DSA, 3D rotational angiography was performed with 1 of 3 technical protocols (2 subtracted, 1 unsubtracted). The protocols consisted of 1 factory and 2 customized techniques, with images subsequently reconstructed into CT volumes for clinical management. Raw projections and quantitative dose metrics were evaluated, and the effective dose was calculated. RESULTS: All 3D rotational angiography acquisitions were of diagnostic quality and assisted in patient management. The mean effective doses were 0.5, 0.12, and 0.06 mSv for the factory subtracted, customized-subtracted, and customized-unsubtracted protocols, respectively. The mean effective dose for 2D-biplane DSA was 0.9 mSv. A direct intraprocedural comparison between 3D and 2D acquisitions indicated that customized 3D rotational angiography protocols delivered mean relative doses of 9% and 15% in unsubtracted and subtracted acquisitions, respectively, compared with biplane DSA, whereas the factory subtracted protocol delivered 68%. CONCLUSIONS: In pediatric neuroangiography, the effective dose for 3D rotational angiography can be significantly lower than for 2D-biplane DSA and can be an essential adjunct in the evaluation of neurovascular lesions. Additionally, available 3D rotational angiography protocols have significant room to be tailored for effectiveness and dose optimization, depending on the clinical question. PMID- 29496726 TI - Utility of Repeat Head CT in Patients with Blunt Traumatic Brain Injury Presenting with Small Isolated Falcine or Tentorial Subdural Hematomas. AB - BACKGROUND AND PURPOSE: In blunt traumatic brain injury with isolated falcotentorial subdural hematoma not amenable to neurosurgical intervention, the routinely performed, nonvalidated practice of serial head CT scans frequently necessitates increased hospital resources and exposure to ionizing radiation. The study goal was to evaluate clinical and imaging features of isolated falcotentorial subdural hematoma at presentation and short-term follow-up. MATERIALS AND METHODS: We performed a retrospective analysis of patients presenting to a level 1 trauma center from January 2013 to March 2015 undergoing initial and short-term follow-up CT with initial findings positive for isolated subdural hematoma along the falx and/or tentorium. Patients with penetrating trauma, other sites of intracranial hemorrhage, or depressed skull fractures were excluded. Patient sex, age, Glasgow Coma Scale score, and anticoagulation history were obtained through review of the electronic medical records. RESULTS: Eighty patients met the inclusion criteria (53 males; 27 females; median age, 61 years). Of subdural hematomas, 57.1% were falcine, 33.8% were tentorial, and 9.1% were mixed. The mean initial Glasgow Coma Scale score was 14.2 (range, 6-15). Isolated falcotentorial subdural hematomas were small (mean, 2.8 mm; range, 1-8 mm) without mass effect and significant change on follow-up CT (mean, 2.7 mm; range, 0-8 mm; P = .06), with an average follow-up time of 10.3 hours (range, 3.9-192 hours). All repeat CTs demonstrated no change or decreased size of the initial subdural hematoma. No new intracranial hemorrhages were seen on follow-up CT. CONCLUSIONS: Isolated falcotentorial subdural hematomas in blunt traumatic brain injury average 2.8 mm in thickness and do not increase in size on short-term follow-up CT. Present data suggest that repeat CT in patients with mild traumatic brain injury with isolated falcotentorial subdural hematoma may not be necessary. PMID- 29496727 TI - Reply. PMID- 29496728 TI - Pacemakers in MRI for the Neuroradiologist: Revisited. PMID- 29496729 TI - Contraception for Adolescents and Young Adults in the Inpatient Setting: The Providers' Perspective. AB - OBJECTIVES: To assess pediatric providers' attitudes and barriers to initiating a contraceptive method in the inpatient setting. METHODS: Pediatric attending physicians and trainees from 5 academic institutions were surveyed about contraceptive prescribing practices, attitudes, and potential barriers to initiating contraception in the inpatient setting. RESULTS: In 2016, 271 pediatric providers (34.0% were attending physicians, 18.1% fellows, and 47.9% residents) completed the survey; the response rate was 19.2%. Most participants practiced in both inpatient and outpatient settings (95.7% and 85.0%, respectively). More providers felt confident screening for sexual activity among young adults as compared with adolescents (71.9% vs 65.6%). The same was true for discussing contraceptive options (44.0% vs 38.8%, respectively). Inpatient providers reported seeing adolescents and young adults privately, discussing confidentiality, and asking about sex less than half of the time. More than 80% of providers agreed that it would be appropriate to initiate a contraceptive method for inpatients; 35.8% had done so, and 85.2% indicated that having additional consultation would increase initiation of a contraceptive method in the hospital (88.1% felt similarly for long-active reversible contraception methods). General barriers to initiating contraception included insufficient training, insufficient exposure to adolescents and young adults to maintain skills, and lack of time. Barriers specific to the inpatient setting included concerns about follow-up, confidentiality, and interference with the treatment plan. CONCLUSIONS: Initiation of a contraceptive method in the inpatient setting is acceptable to providers. In our findings, it is suggested that strategies are needed to enhance provision of these services by addressing confidentiality concerns and educating providers. PMID- 29496732 TI - Treat the lungs, fool the brain and appease the mind: towards holistic care of patients who suffer from chronic respiratory diseases. PMID- 29496730 TI - Genome-reconstruction for eukaryotes from complex natural microbial communities. AB - Microbial eukaryotes are integral components of natural microbial communities, and their inclusion is critical for many ecosystem studies, yet the majority of published metagenome analyses ignore eukaryotes. In order to include eukaryotes in environmental studies, we propose a method to recover eukaryotic genomes from complex metagenomic samples. A key step for genome recovery is separation of eukaryotic and prokaryotic fragments. We developed a k-mer-based strategy, EukRep, for eukaryotic sequence identification and applied it to environmental samples to show that it enables genome recovery, genome completeness evaluation, and prediction of metabolic potential. We used this approach to test the effect of addition of organic carbon on a geyser-associated microbial community and detected a substantial change of the community metabolism, with selection against almost all candidate phyla bacteria and archaea and for eukaryotes. Near complete genomes were reconstructed for three fungi placed within the Eurotiomycetes and an arthropod. While carbon fixation and sulfur oxidation were important functions in the geyser community prior to carbon addition, the organic carbon-impacted community showed enrichment for secreted proteases, secreted lipases, cellulose targeting CAZymes, and methanol oxidation. We demonstrate the broader utility of EukRep by reconstructing and evaluating relatively high-quality fungal, protist, and rotifer genomes from complex environmental samples. This approach opens the way for cultivation-independent analyses of whole microbial communities. PMID- 29496731 TI - Selective maternal seeding and environment shape the human gut microbiome. AB - Vertical transmission of bacteria from mother to infant at birth is postulated to initiate a life-long host-microbe symbiosis, playing an important role in early infant development. However, only the tracking of strictly defined unique microbial strains can clarify where the intestinal bacteria come from, how long the initial colonizers persist, and whether colonization by other strains from the environment can replace existing ones. Using rare single nucleotide variants in fecal metagenomes of infants and their family members, we show strong evidence of selective and persistent transmission of maternal strain populations to the vaginally born infant and their occasional replacement by strains from the environment, including those from family members, in later childhood. Only strains from the classes Actinobacteria and Bacteroidia, which are essential components of the infant microbiome, are transmitted from the mother and persist for at least 1 yr. In contrast, maternal strains of Clostridia, a dominant class in the mother's gut microbiome, are not observed in the infant. Caesarean-born infants show a striking lack of maternal transmission at birth. After the first year, strain influx from the family environment occurs and continues even in adulthood. Fathers appear to be more frequently donors of novel strains to other family members than receivers. Thus, the infant gut is seeded by selected maternal bacteria, which expand to form a stable community, with a rare but stable continuing strain influx over time. PMID- 29496733 TI - 'So why didn't you think this baby was ill?' Decision-making in acute paediatrics. AB - Determining severity of illness and undertaking an adequate risk assessment is a fundamental part of acute paediatric practice. This review highlights physiology, communication, heuristics and external elements as factors which influence decision-making and discusses how incidence of disease and seniority of clinician impact might influence outcomes. PMID- 29496734 TI - Let's Stop Trying to Quantify Household Vulnerability: The Problem With Simple Scales for Targeting and Evaluating Economic Strengthening Programs. AB - INTRODUCTION: Economic strengthening practitioners are increasingly seeking data collection tools that will help them target households vulnerable to HIV and poor child well-being outcomes, match households to appropriate interventions, monitor their status, and determine readiness for graduation from project support. This article discusses efforts in 3 countries to develop simple, valid tools to quantify and classify economic vulnerability status. METHODS AND FINDINGS: In Cote d'Ivoire, we conducted a cross-sectional survey with 3,749 households to develop a scale based on the definition of HIV-related economic vulnerability from the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) for the purpose of targeting vulnerable households for PEPFAR-funded programs for orphans and vulnerable children. The vulnerability measures examined did not cluster in ways that would allow for the creation of a small number of composite measures, and thus we were unable to develop a scale. In Uganda, we assessed the validity of a vulnerability index developed to classify households according to donor classifications of economic status by measuring its association with a validated poverty measure, finding only a modest correlation. In South Africa, we developed monitoring and evaluation tools to assess economic status of individual adolescent girls and their households. We found no significant correlation with our validation measures, which included a validated measure of girls' vulnerability to HIV, a validated poverty measure, and subjective classifications generated by the community, data collector, and respondent. Overall, none of the measures of economic vulnerability used in the 3 countries varied significantly with their proposed validation items. CONCLUSION: Our findings suggest that broad constructs of economic vulnerability cannot be readily captured using simple scales to classify households and individuals in a way that accounts for a substantial amount of variance at locally defined vulnerability levels. We recommend that researchers and implementers design monitoring and evaluation instruments to capture narrower definitions of vulnerability based on characteristics programs intend to affect. We also recommend using separate tools for targeting based on context-specific indicators with evidence-based links to negative outcomes. Policy makers and donors should avoid reliance on simplified metrics of economic vulnerability in the programs they support. PMID- 29496735 TI - Education needed to enhance inclusive, non-discriminatory nursing practice towards lesbian, gay and bisexual parents. PMID- 29496736 TI - SIRFing the replication fork: Assessing protein interactions with nascent DNA. AB - Roy et al. (2018. J. Cell. Biol. https://doi.org/10.1083/jcb.201709121) describe an ingenious single-cell assay system, in situ analysis of protein interactions at DNA replication forks (SIRF), for the quantitative analysis of protein interactions with nascent DNA at active and stalled replication forks. The sensitive and accurate SIRF methodology is suitable for multiparameter measurements in cell populations. PMID- 29496737 TI - Kindlin-2 regulates mesenchymal stem cell differentiation through control of YAP1/TAZ. AB - Precise control of mesenchymal stem cell (MSC) differentiation is critical for tissue development and regeneration. We show here that kindlin-2 is a key determinant of MSC fate decision. Depletion of kindlin-2 in MSCs is sufficient to induce adipogenesis and inhibit osteogenesis in vitro and in vivo. Mechanistically, kindlin-2 regulates MSC differentiation through controlling YAP1/TAZ at both the transcript and protein levels. Kindlin-2 physically associates with myosin light-chain kinase in response to mechanical cues of cell microenvironment and intracellular signaling events and promotes myosin light chain phosphorylation. Loss of kindlin-2 inhibits RhoA activation and reduces myosin light-chain phosphorylation, stress fiber formation, and focal adhesion assembly, resulting in increased Ser127 phosphorylation, nuclear exclusion, and ubiquitin ligase atrophin-1 interacting protein 4-mediated degradation of YAP1/TAZ. Our findings reveal a novel kindlin-2 signaling axis that senses the mechanical cues of cell microenvironment and controls MSC fate decision, and they suggest a new strategy to regulate MSC differentiation, tissue repair, and regeneration. PMID- 29496738 TI - An ordered pattern of Ana2 phosphorylation by Plk4 is required for centriole assembly. AB - Polo-like kinase 4 (Plk4) initiates an early step in centriole assembly by phosphorylating Ana2/STIL, a structural component of the procentriole. Here, we show that Plk4 binding to the central coiled-coil (CC) of Ana2 is a conserved event involving Polo-box 3 and a previously unidentified putative CC located adjacent to the kinase domain. Ana2 is then phosphorylated along its length. Previous studies showed that Plk4 phosphorylates the C-terminal STil/ANa2 (STAN) domain of Ana2/STIL, triggering binding and recruitment of the cartwheel protein Sas6 to the procentriole assembly site. However, the physiological relevance of N terminal phosphorylation was unknown. We found that Plk4 first phosphorylates the extreme N terminus of Ana2, which is critical for subsequent STAN domain modification. Phosphorylation of the central region then breaks the Plk4-Ana2 interaction. This phosphorylation pattern is important for centriole assembly and integrity because replacement of endogenous Ana2 with phospho-Ana2 mutants disrupts distinct steps in Ana2 function and inhibits centriole duplication. PMID- 29496739 TI - Feedback inhibition of actin on Rho mediates content release from large secretory vesicles. AB - Secretion of adhesive glycoproteins to the lumen of Drosophila melanogaster larval salivary glands is performed by contraction of an actomyosin network assembled around large secretory vesicles, after their fusion to the apical membranes. We have identified a cycle of actin coat nucleation and disassembly that is independent of myosin. Recruitment of active Rho1 to the fused vesicle triggers activation of the formin Diaphanous and actin nucleation. This leads to actin-dependent localization of a RhoGAP protein that locally shuts off Rho1, promoting disassembly of the actin coat. When contraction of vesicles is blocked, the strict temporal order of the recruited elements generates repeated oscillations of actin coat formation and disassembly. Interestingly, different blocks to actin coat disassembly arrested vesicle contraction, indicating that actin turnover is an integral part of the actomyosin contraction cycle. The capacity of F-actin to trigger a negative feedback on its own production may be widely used to coordinate a succession of morphogenetic events or maintain homeostasis. PMID- 29496740 TI - Prion-like protein aggregates exploit the RHO GTPase to cofilin-1 signaling pathway to enter cells. AB - Protein aggregation is a hallmark of diverse neurodegenerative diseases. Multiple lines of evidence have revealed that protein aggregates can penetrate inside cells and spread like prions. How such aggregates enter cells remains elusive. Through a focused siRNA screen targeting genes involved in membrane trafficking, we discovered that mutant SOD1 aggregates, like viruses, exploit cofilin-1 to remodel cortical actin and enter cells. Upstream of cofilin-1, signalling from the RHO GTPase and the ROCK1 and LIMK1 kinases controls cofilin-1 activity to remodel actin and modulate aggregate entry. In the spinal cord of symptomatic SOD1G93A transgenic mice, cofilin-1 phosphorylation is increased and actin dynamics altered. Importantly, the RHO to cofilin-1 signalling pathway also modulates entry of tau and alpha-synuclein aggregates. Our results identify a common host cell signalling pathway that diverse protein aggregates exploit to remodel actin and enter cells. PMID- 29496741 TI - Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent autophagy pathway activated by TBK1. AB - Negative regulation of immune pathways is essential to achieve resolution of immune responses and to avoid excess inflammation. DNA stimulates type I IFN expression through the DNA sensor cGAS, the second messenger cGAMP, and the adaptor molecule STING Here, we report that STING degradation following activation of the pathway occurs through autophagy and is mediated by p62/SQSTM1, which is phosphorylated by TBK1 to direct ubiquitinated STING to autophagosomes. Degradation of STING was impaired in p62-deficient cells, which responded with elevated IFN production to foreign DNA and DNA pathogens. In the absence of p62, STING failed to traffic to autophagy-associated vesicles. Thus, DNA sensing induces the cGAS-STING pathway to activate TBK1, which phosphorylates IRF3 to induce IFN expression, but also phosphorylates p62 to stimulate STING degradation and attenuation of the response. PMID- 29496743 TI - Improving the auditory environment for patients with intellectual disabilities and hearing loss. PMID- 29496742 TI - Racial/Ethnic Minority Youth With Recent-Onset Type 1 Diabetes Have Poor Prognostic Factors. AB - OBJECTIVE: To compare races/ethnicities for characteristics, at type 1 diabetes diagnosis and during the first 3 years postdiagnosis, known to influence long term health outcomes. RESEARCH DESIGN AND METHODS: We analyzed 927 Pediatric Diabetes Consortium (PDC) participants <19 years old (631 non-Hispanic white [NHW], 216 Hispanic, and 80 African American [AA]) diagnosed with type 1 diabetes and followed for a median of 3.0 years (interquartile range 2.2-3.6). Demographic and clinical data were collected from medical records and patient/parent interviews. Partial remission period or "honeymoon" was defined as insulin dose adjusted hemoglobin A1c (IDAA1c) <=9.0%. We used logistic, linear, and multinomial regression models, as well as repeated-measures logistic and linear regression models. Models were adjusted for known confounders. RESULTS: AA subjects, compared with NHW, at diagnosis, were in a higher age- and sex-adjusted BMI percentile (BMI%), had more advanced pubertal development, and had higher frequency of presentation in diabetic ketoacidosis, largely explained by socioeconomic factors. During the first 3 years, AA subjects were more likely to have hypertension and severe hypoglycemia events; had trajectories with higher hemoglobin A1c, BMI%, insulin doses, and IDAA1c; and were less likely to enter the partial remission period. Hispanics, compared with NHWs, had higher BMI% at diagnosis and over the three subsequent years. During the 3 years postdiagnosis, Hispanics had higher prevalence of dyslipidemia and maintained trajectories of higher insulin doses and IDAA1c. CONCLUSIONS: Youth of minority race/ethnicity have increased markers of poor prognosis of type 1 diabetes at diagnosis and 3 years postdiagnosis, possibly contributing to higher risk of long-term diabetes complications compared with NHWs. PMID- 29496744 TI - Loss of OcaB Prevents Age-Induced Fat Accretion and Insulin Resistance by Altering B-Lymphocyte Transition and Promoting Energy Expenditure. AB - The current demographic shift toward an aging population has led to a robust increase in the prevalence of age-associated metabolic disorders. Recent studies have demonstrated that the etiology of obesity-related insulin resistance that develops with aging differs from that induced by high-calorie diets. Whereas the role of adaptive immunity in changes in energy metabolism driven by nutritional challenges has recently gained attention, its impact on aging remains mostly unknown. Here we found that the number of follicular B2 lymphocytes and expression of the B-cell-specific transcriptional coactivator OcaB increase with age in spleen and in intra-abdominal epididymal white adipose tissue (eWAT), concomitantly with higher circulating levels of IgG and impaired glucose homeostasis. Reduction of B-cell maturation and Ig production-especially that of IgG2c-by ablation of OcaB prevented age-induced glucose intolerance and insulin resistance and promoted energy expenditure by stimulating fatty acid utilization in eWAT and brown adipose tissue. Transfer of wild-type bone marrow in OcaB-/- mice replenished the eWAT B2-cell population and IgG levels, which diminished glucose tolerance, insulin sensitivity, and energy expenditure while increasing body weight gain in aged mice. Thus these findings demonstrate that upon aging, modifications in B-cell-driven adaptive immunity contribute to glucose intolerance and fat accretion. PMID- 29496745 TI - Mito-Nuclear Interactions Affecting Lifespan and Neurodegeneration in a Drosophila Model of Leigh Syndrome. AB - Proper mitochondrial activity depends upon proteins encoded by genes in the nuclear and mitochondrial genomes that must interact functionally and physically in a precisely coordinated manner. Consequently, mito-nuclear allelic interactions are thought to be of crucial importance on an evolutionary scale, as well as for manifestation of essential biological phenotypes, including those directly relevant to human disease. Nonetheless, detailed molecular understanding of mito-nuclear interactions is still lacking, and definitive examples of such interactions in vivo are sparse. Here we describe the characterization of a mutation in Drosophila ND23, a nuclear gene encoding a highly conserved subunit of mitochondrial complex 1. This characterization led to the discovery of a mito nuclear interaction that affects the ND23 mutant phenotype. ND23 mutants exhibit reduced lifespan, neurodegeneration, abnormal mitochondrial morphology, and decreased ATP levels. These phenotypes are similar to those observed in patients with Leigh syndrome, which is caused by mutations in a number of nuclear genes that encode mitochondrial proteins, including the human ortholog of ND23 A key feature of Leigh syndrome, and other mitochondrial disorders, is unexpected and unexplained phenotypic variability. We discovered that the phenotypic severity of ND23 mutations varies depending on the maternally inherited mitochondrial background. Sequence analysis of the relevant mitochondrial genomes identified several variants that are likely candidates for the phenotypic interaction with mutant ND23, including a variant affecting a mitochondrially encoded component of complex I. Thus, our work provides an in vivo demonstration of the phenotypic importance of mito-nuclear interactions in the context of mitochondrial disease. PMID- 29496746 TI - Plasticity of Meiotic Recombination Rates in Response to Temperature in Arabidopsis. AB - Meiotic recombination shuffles genetic information from sexual species into gametes to create novel combinations in offspring. Thus, recombination is an important factor in inheritance, adaptation, and responses to selection. However, recombination is not a static parameter; meiotic recombination rate is sensitive to variation in the environment, especially temperature. That recombination rates change in response to both increases and decreases in temperature was reported in Drosophila a century ago, and since then in several other species. But it is still unclear what the underlying mechanism is, and whether low- and high temperature effects are mechanistically equivalent. Here, we show that, as in Drosophila, both high and low temperatures increase meiotic crossovers in Arabidopsis thaliana We show that, from a nadir at 18 degrees , both lower and higher temperatures increase recombination through additional class I (interfering) crossovers. However, the increase in crossovers at high and low temperatures appears to be mechanistically at least somewhat distinct, as they differ in their association with the DNA repair protein MLH1. We also find that, in contrast to what has been reported in barley, synaptonemal complex length is negatively correlated with temperature; thus, an increase in chromosome axis length may account for increased crossovers at low temperature in A. thaliana, but cannot explain the increased crossovers observed at high temperature. The plasticity of recombination has important implications for evolution and breeding, and also for the interpretation of observations of recombination rate variation among natural populations. PMID- 29496747 TI - Variant Linkage Analysis Using de Novo Transcriptome Sequencing Identifies a Conserved Phosphine Resistance Gene in Insects. AB - Next-generation sequencing methods enable identification of the genetic basis of traits in species that have no prior genomic information available. The combination of next-generation sequencing, variant analysis, and linkage is a powerful way of identifying candidate genes for a trait of interest. Here, we used a comparative transcriptomics [RNA sequencing (RNAseq)] and genetic linkage analysis approach to identify the rph1 gene. rph1 variants are responsible for resistance to the fumigant phosphine (PH3) that is used to control insect pests of stored grain. In each of the four major species of pest insect of grain we have investigated, there are two major resistance genes, rph1 and rph2, which interact synergistically to produce strongly phosphine-resistant insects. Using RNAseq and genetic linkage analyses, we identified candidate resistance (rph1) genes in phosphine-resistant strains of three species: Rhyzopertha dominica (129 candidates), Sitophilus oryzae (206 candidates), and Cryptolestes ferrugineus (645 candidates). We then compared these candidate genes to 17 candidate resistance genes previously mapped in Tribolium castaneum and found only one orthologous gene, a cytochrome b5 fatty acid desaturase (Cyt-b5-r), to be associated with the rph1 locus in all four species. This gene had either missense amino acid substitutions and/or insertion/deletions/frameshift variants in each of 18 phosphine-resistant strains that were not observed in the susceptible strains of the four species. We propose a model of phosphine action and resistance in which phosphine induces lipid peroxidation through reactive oxygen species generated by dihydrolipoamide dehydrogenase, whereas disruption of Cyt-b5 r in resistant insects decreases the polyunsaturated fatty acid content of membranes, thereby limiting the potential for lipid peroxidation. PMID- 29496748 TI - The Limits to Parapatric Speciation II: Strengthening a Preexisting Genetic Barrier to Gene Flow in Parapatry. AB - By encompassing the whole continuum between allopatric and sympatric scenarios, parapatric speciation includes many potential scenarios for the evolution of new species. Here, we investigate how a genetic barrier to gene flow, that relies on a single postzygotic genetic incompatibility, may further evolve under ongoing migration. We consider a continent island model with three loci involved in pairwise Dobzhansky-Muller incompatibilities (DMIs). Using an analytic approach, we derive the conditions for invasion of a new mutation and its consequences for the strength and stability of the initial genetic barrier. Our results show that the accumulation of genetic incompatibilities in the presence of gene flow is under strong selective constraints. In particular, preexisting incompatibilities do not always facilitate the invasion of further barrier genes. If new mutations do invade, they will often weaken or destroy the barrier rather than strengthening it. We conclude that migration is highly effective at disrupting the so-called "snowball effect", the accelerated accumulation of DMIs that has been described for allopatric populations en route to reproductive isolation. PMID- 29496750 TI - A localised skin reaction after chemotherapy. PMID- 29496751 TI - Towards a national genomics medicine service: the challenges facing clinical research hybrid practices and the case of the 100 000 genomes project. AB - Clinical practice and research are governed by distinct rules and regulations and have different approaches to, for example, consent and providing results. However, genomics is an example of where research and clinical practice have become codependent. The 100 000 genomes project (100kGP) is a hybrid venture where a person can obtain a clinical investigation only if he or she agrees to also participate in ongoing research-including research by industry and commercial companies. In this paper, which draws on 20 interviews with professional stakeholders involved in 100kGP, we investigate the ethical issues raised by this project's hybrid nature. While some interviewees thought the hybrid nature of 100kGP was its vanguard, interviewees identified several tensions around hybrid practice: how to decide who should be able to participate; how to determine whether offering results might unduly influence participation into wide-ranging but often as yet unknown research and how to ensure that patients/families do not develop false expectations about receiving results. These areas require further debate as 100kGP moves into routine healthcare in the form of the national genomic medicine service. To address the tensions identified, we explore the appropriateness of Faden et al.'s framework of ethical obligations for when research and clinical care are completely integrated. We also argue that enabling ongoing transparent and trustworthy communication between patients/families and professionals around the kinds of research that should be permitted in 100kGP will help to understand and ensure that expectations remain realistic. Our paper aims to encourage a focused discussion about these issues and to inform a new 'social contract' for research and clinical care in the health service. PMID- 29496749 TI - Genetic Basis of Body Color and Spotting Pattern in Redheaded Pine Sawfly Larvae (Neodiprion lecontei). AB - Pigmentation has emerged as a premier model for understanding the genetic basis of phenotypic evolution, and a growing catalog of color loci is starting to reveal biases in the mutations, genes, and genetic architectures underlying color variation in the wild. However, existing studies have sampled a limited subset of taxa, color traits, and developmental stages. To expand the existing sample of color loci, we performed QTL mapping analyses on two types of larval pigmentation traits that vary among populations of the redheaded pine sawfly (Neodiprion lecontei): carotenoid-based yellow body color and melanin-based spotting pattern. For both traits, our QTL models explained a substantial proportion of phenotypic variation and suggested a genetic architecture that is neither monogenic nor highly polygenic. Additionally, we used our linkage map to anchor the current N. lecontei genome assembly. With these data, we identified promising candidate genes underlying (1) a loss of yellow pigmentation in populations in the mid Atlantic/northeastern United States [C locus-associated membrane protein homologous to a mammalian HDL receptor-2 gene (Cameo2) and lipid transfer particle apolipoproteins II and I gene (apoLTP-II/I)], and (2) a pronounced reduction in black spotting in Great Lakes populations [members of the yellow gene family, tyrosine hydroxylase gene (pale), and dopamine N-acetyltransferase gene (Dat)]. Several of these genes also contribute to color variation in other wild and domesticated taxa. Overall, our findings are consistent with the hypothesis that predictable genes of large effect contribute to color evolution in nature. PMID- 29496752 TI - Role of a clinical prediction score in a chronic thromboembolic pulmonary hypertension rule-out strategy. PMID- 29496753 TI - Information and education provision in bronchiectasis: co-development and evaluation of a novel patient-driven resource in a digital era. PMID- 29496754 TI - Low prevalence of fluoroquinolone resistance among patients with tuberculosis in the Philippines: results of a national survey. PMID- 29496756 TI - Evaluation of VTE-BLEED for predicting intracranial or fatal bleeding in stable anticoagulated patients with venous thromboembolism. PMID- 29496755 TI - Observing dyspnoea in others elicits dyspnoea, negative affect and brain responses. AB - Dyspnoea is usually caused by diagnosable cardiorespiratory mechanisms. However, frequently dyspnoea relates only weakly or not at all to cardiorespiratory functioning, suggesting that additional neuropsychosocial processes contribute to its experience. We tested whether the mere observation of dyspnoea in others constitutes such a process and would elicit dyspnoea, negative affect and increased brain responses in the observer.In three studies, series of pictures and videos were presented, which either depicted persons suffering from dyspnoea or nondyspnoeic control stimuli. Self-reports of dyspnoea and affective state were obtained in all studies. Additionally, respiratory variables and brain responses during picture viewing (late positive potentials in electroencephalograms) were measured in one study.In all studies, dyspnoea related pictures and videos elicited mild-to-moderate dyspnoea and increased negative affect compared to control stimuli. This was paralleled by increased late positive potentials for dyspnoea-related pictures while respiratory variables did not change. Moreover, increased dyspnoea correlated modestly with higher levels of empathy in observers.The present results demonstrate that observing dyspnoea in others elicits mild-to-moderate dyspnoea, negative affect, and increased brain responses in the absence of respiratory changes. This vicarious dyspnoea has clinical relevance, as it might increase suffering in the family and medical caregivers of dyspnoeic patients. PMID- 29496757 TI - Aspergillus-induced pneumonia in adult without obvious immunodeficiency: test the burst! PMID- 29496758 TI - Cyclophosphamide in steroid refractory unclassifiable idiopathic interstitial pneumonia and interstitial pneumonia with autoimmune features (IPAF). PMID- 29496759 TI - The RNA-binding Protein MEX3B Mediates Resistance to Cancer Immunotherapy by Downregulating HLA-A Expression. AB - Purpose: Cancer immunotherapy has shown promising clinical outcomes in many patients. However, some patients still fail to respond, and new strategies are needed to overcome resistance. The purpose of this study was to identify novel genes and understand the mechanisms that confer resistance to cancer immunotherapy.Experimental Design: To identify genes mediating resistance to T cell killing, we performed an open reading frame (ORF) screen of a kinome library to study whether overexpression of a gene in patient-derived melanoma cells could inhibit their susceptibility to killing by autologous tumor-infiltrating lymphocytes (TIL).Results: The RNA-binding protein MEX3B was identified as a top candidate that decreased the susceptibility of melanoma cells to killing by TILs. Further analyses of anti-PD-1-treated melanoma patient tumor samples suggested that higher MEX3B expression is associated with resistance to PD-1 blockade. In addition, significantly decreased levels of IFNgamma were secreted from TILs incubated with MEX3B-overexpressing tumor cells. Interestingly, this phenotype was rescued upon overexpression of exogenous HLA-A2. Consistent with this, we observed decreased HLA-A expression in MEX3B-overexpressing tumor cells. Finally, luciferase reporter assays and RNA-binding protein immunoprecipitation assays suggest that this is due to MEX3B binding to the 3' untranslated region (UTR) of HLA-A to destabilize the mRNA.Conclusions: MEX3B mediates resistance to cancer immunotherapy by binding to the 3' UTR of HLA-A to destabilize the HLA-A mRNA and thus downregulate HLA-A expression on the surface of tumor cells, thereby making the tumor cells unable to be recognized and killed by T cells. Clin Cancer Res; 24(14); 3366-76. (c)2018 AACRSee related commentary by Kalbasi and Ribas, p. 3239. PMID- 29496760 TI - HER2 Deregulation in Lung Cancer: Right Time to Adopt an Orphan? AB - HER2-deregulated non-small cell lung cancer is an orphan of any specific therapy, probably because of lack of both accurate patient selection and effective drugs. Recent evidence suggests that osimertinib could be effective in HER2-amplified or mutated lung cancer as a single agent or in combination. Clin Cancer Res; 24(11); 2470-2. (c)2018 AACRSee related article by Liu et al., p. 2594. PMID- 29496761 TI - The Twin. PMID- 29496762 TI - Aggressive Care AND Palliative Care. PMID- 29496764 TI - Validation of a Postextubation Dysphagia Screening Tool for Patients After Prolonged Endotracheal Intubation. AB - BACKGROUND: Patients who receive prolonged endotracheal intubation (> 48 hours) are at risk for dysphagia. Nurses should conduct swallowing assessments after extubation because of the high likelihood of aspiration pneumonia developing. No valid and reliable postextubation dysphagia screening tools are available. OBJECTIVES: To establish content validity, analyze interrater reliability, and determine sensitivity and specificity of an evidence-based postextubation dysphagia screening tool developed by a multidisciplinary team. METHODS: A prospective nonexperimental study was conducted in 4 medical-surgical intensive care units in 4 hospitals. The study was conducted in 3 phases: (1) establishing content validity with clinical experts who participated in a Delphi survey, (2) establishing inter-rater reliability by agreement with nurses who simultaneously and independently completed the tool, and (3) establishing sensitivity and specificity with speech language pathologists and nurses who independently and blindly completed the tool for eligible patients. RESULTS: Individual item scores were > 0.82 and the overall content validity index was 0.93, indicating content validity. Interrater reliability was established (Cohen kappa = 0.92). In 66 eligible patients, the prevalence of postextubation dysphagia was 56%, sensitivity of the postextubation dysphagia screening tool was 81%, and specificity was 69%. CONCLUSION: The reliability and validity of a postextubation dysphagia screening tool that can help nurses determine an extubated patient's ability to swallow after prolonged endotracheal intubation were established. PMID- 29496765 TI - Early Rehabilitation and In-Hospital Mortality in Intensive Care Patients With Community-Acquired Pneumonia. AB - BACKGROUND: Community-acquired pneumonia is one of the most common infectious diseases and can be fatal. The benefits of early rehabilitation in intensive care units are known, but the association between early rehabilitation and in-hospital mortality of patients with community-acquired pneumonia admitted to intensive care units has not been studied. OBJECTIVES: To study the association between early rehabilitation and the in-hospital mortality of patients with community- acquired pneumonia admitted to intensive care units, effects of early rehabilitation on unit and hospital lengths of stay, and total costs of hospitalization. METHODS: A retrospective observational cohort study using a national inpatient database of patients with community-acquired pneumonia admitted to intensive care units in acute care hospitals in Japan from July 2011 through March 2014. Propensity score-matching analysis was used to compare outcomes between patients with and without early rehabilitation (within 2 days of admission). RESULTS: Among 8732 eligible patients, propensity score matching created 972 pairs of patients with and without early rehabilitation. The early rehabilitation group had significantly lower in-hospital mortality than did the group without early rehabilitation (17.9% vs 21.9%, respectively; P = .03). The groups did not differ significantly in intensive care unit or hospital lengths of stay or in total costs of hospitalization. CONCLUSIONS: Early rehabilitation within 2 days of admission was associated with reduced in-hospital mortality of patients with community-acquired pneumonia admitted to intensive care units. PMID- 29496766 TI - Lack of Association of High Backrest With Sacral Tissue Changes in Adults Receiving Mechanical Ventilation. AB - BACKGROUND: Although higher backrest elevation may be a theoretical risk for integrity of sacral tissues, few data support use of high backrest elevation. OBJECTIVE: To describe the effect of backrest elevation on the integrity of sacral tissue in critically ill adults receiving mechanical ventilation. METHODS: Patients from 3 critical care units (surgical trauma, medical respiratory, and neuroscience) who were expected to have mechanical ventilation for at least 24 hours were intubated and mechanical ventilation was started. Participants were enrolled in the study within 24 hours of intubation. Backrest elevation was continuously measured by using mechanical system- based accelerometers. Integrity of sacral tissue was evaluated by using high-frequency sonography. RESULTS: Data for 84 patients who had measurements of both backrest elevation and skin integrity were available for analysis. General linear models indicated no significant difference among the proportions of time spent at less than 20 degrees (P values: .57 the first 24 hours, .17 the first 48 hours, .81 the first 72 hours), 20 degrees to 30 degrees (P values: .25 the first 24 hours, .08 the first 48 hours, .25 the first 72 hours), or greater than 30 degrees (P values: .62 the first 24 hours, .28 the first 48 hours, .68 the first 72 hours) among participants with no injury, no change in injury, improvement in injury, or injury that worsened. CONCLUSIONS: Level of backrest elevation is not associated with changes in tissue integrity. Body positioning in critically ill patients receiving mechanical ventilation may not be as important or as effective as once thought. PMID- 29496767 TI - Attitudes and Practices Related to Clinical Alarms: A Follow-up Survey. AB - BACKGROUND: Alarm fatigue is a widely acknowledged patient safety concern in hospitals. In 2013, The Joint Commission issued a National Patient Safety Goal on Alarm Management, making addressing alarm management a priority. To capture changes in attitudes and practices related to alarms, the Healthcare Technology Foundation conducted and reported findings from national online surveys in 2006 and 2011 and completed a third survey in 2016. OBJECTIVES: The goal of the 2016 survey was to identify how hospital practices and clinicians' perceptions of alarms have changed since 2006. METHODS: The online survey was distributed via national health care organizations during a 2-month period. Results of the 2016 survey (N = 1241) were compared with results of the 2006 and 2011 surveys by using chi2 and Kruskal-Wallis analyses. RESULTS: Responses were significantly different for almost all items across the 3 surveys. Respondents in 2016 were more likely to agree that nuisance alarms occur frequently and disrupt patient care and were less likely to agree that clinical staff responds quickly to alarms. Compared with respondents in 2011, those in 2016 were almost twice as likely to report that their hospitals had experienced adverse events related to alarms in the past 2 years. However, in 2016 a much higher proportion of respondents indicated that their hospitals had implemented alarm improvement initiatives. CONCLUSIONS: Although survey findings show disappointing trends in the past 10 years, including worsening perceptions of nuisance alarms and more alarm-related adverse events, the increase in alarm improvement initiatives is encouraging. PMID- 29496768 TI - Correction. PMID- 29496769 TI - Feasibility of Cognitive Training in Critically Ill Patients: A Pilot Study. AB - BACKGROUND: Delirium occurs frequently in the intensive care unit and is associated with detrimental consequences. Cognitive training is a promising, nonpharmacologic, preventive intervention, but it is unknown whether cognitive training is feasible for patients in intensive care units. OBJECTIVES: To examine the feasibility for both nurses and patients of using cognitive training exercises for intensive care unit patients. METHODS: A pilot study of a set of cognitive training exercises in a large, academic intensive care unit. Feasibility of the exercises, operationalized as practicability and burden for the patient and the nurse, was tested in multiple rounds and evaluated using Likert scales and open-ended questions, patients' vital signs, and time investment. RESULTS: In total, 75 patients were included. During the first round, 11 exercises were separately tested by nursing researchers in 44 cooperative patients (50% with delirium). Four exercises were evaluated as burdensome and were excluded. Vital signs did not alter during execution. In a second round, the remaining exercises were tested in 31 patients (52% with delirium) by their attending nurse. All exercises were rated as practicable and not burdensome by the patients and the nurses. Total time investment per exercise was a median 4.5 (interquartile range, 3.0-5.0) minutes. CONCLUSION: Cognitive training exercises used in this study were feasible for intensive care unit patients (including cooperative patients with delirium) and their nurses. More research is needed to determine the clinical effect of the exercises on delirium outcome. PMID- 29496771 TI - Nutrition is Critical. PMID- 29496770 TI - Association Between Enteral Feeding, Weight Status, and Mortality in a Medical Intensive Care Unit. AB - BACKGROUND: Clinical practice guidelines recommend enteral nutrition for most patients receiving mechanical ventilation. However, recently published evidence on the effect of enteral nutrition on mortality, particularly for patients who are well nourished, is conflicting. OBJECTIVES: To examine the association between enteral feeding and hospital mortality in critically ill patients receiving mechanical ventilation and to determine if body mass index mediates this relationship. METHODS: A retrospective cohort study of patients receiving mechanical ventilation admitted to a medical intensive care unit in 2013. Demographic and clinical variables were collected. Cox proportional hazards regression was used to examine the relationship between an enteral feeding order and hospital mortality and to determine if the relationship was mediated by body mass index. RESULTS: Of 777 patients who had 811 hospitalizations requiring mechanical ventilation, 182 (23.4%) died in the hospital. A total of 478 patients (61.5%) received an order for enteral tube feeding, which was associated with a lower risk of death (hazard ratio, 0.41; 95% CI, 0.29-0.59). Body mass index did not mediate the relationship between mortality and receipt of an order for enteral feeding. Median stay in the unit was 3.6 days. Most deaths (72.0%) occurred more than 48 hours after admission. CONCLUSION: The finding of a positive association between an order for enteral feeding and survival supports enteral feeding of patients in medical intensive care units. Furthermore, the beneficial effect of enteral feeding appears to apply to patients regardless of body mass index. PMID- 29496772 TI - Electrocardiographic Correlates of Acute Allograft Rejection Among Heart Transplant Recipients. AB - BACKGROUND: Acute allograft rejection appears to be associated with increases in QT/QTc intervals. OBJECTIVES: To determine the relationship between acute allograft rejection and electrocardiogram changes in patients undergoing an orthotopic heart transplant. METHODS: The study population comprised 220 adult patients undergoing heart transplant and enrolled in the NEW HEART study. Electrocardiograms obtained within 72 hours of endomyocardial biopsy were analyzed; electrocardiograms obtained fewer than 10 days after transplant surgery were excluded. Repeated-measures analysis was performed with statistical models including effects for rejection severity (mild and moderate/severe) and time trends independent of rejection status. RESULTS: The 151 male and 69 female transplant recipients (mean age [SD], 54 [13] years) had 969 biopsy/electrocardiogram pairs: 677 with no rejection, 280 with mild rejection, and 12 with moderate/severe rejection. Moderate to severe organ rejection was associated with significant increases in QRS duration (P < .001), QT (P = .009), QTc (P = .003), and PR interval (P = .03), as well as increased odds of right bundle block branch (P = .002) and fascicular block (P = .009) occurring. CONCLUSIONS: Moderate to severe acute allograft rejection was associated with electrocardiographic changes after transplant surgery. Studies are needed to assess the value of computerized electrocardiogram measurement algorithms for detecting acute allograft rejection. PMID- 29496773 TI - No Time to Be Nice in the Intensive Care Unit. PMID- 29496774 TI - Night Shift Naps Improve Patient and Workforce Safety. PMID- 29496775 TI - Managing Older Persons with Multiple ECG Features. PMID- 29496778 TI - Fight, fatigue and flight: narrowing of attention to a threat compensates for decreased anti-predator vigilance. AB - Fighting carries a predation risk because animals have limited attention, constraining their ability to simultaneously engage in aggression and anti predator vigilance. However, the influence of interspecific aggression and fatigue on the predation cost of fighting is seldom examined, although both are unignorable aspects of fighting. Here, I incorporated both factors in a series of field experiments on the cichlid Lamprologus ocellatus. If territorial males respond more strongly to conspecific territorial intruders than to heterospecific intruders, then they should delay escape more frequently during intraspecific fighting than during interspecific fighting. Consequently, although I predicted that vigilance would be decreased as fighting progresses in both cases, intraspecific aggression should decrease vigilance more than interspecific aggression. Males were also exposed to a predator approaching at different (slow or fast) speeds during these fighting bouts. Delays in predator detection and flight initiation were quantified and these predictions were tested. As predicted, males responded more strongly to intraspecific intruders, resulting in slower predator detection and fleeing times than when encountering interspecific intruders. Furthermore, flight latency decreased with increasing fight duration, suggesting that fatigue negatively influenced escape responses. However, contrary to the prediction, the vigilance decrement rate was faster in response to slow predators than in response to rapid predators, and was not influenced by intruder identity. This suggests that fighting males reserve their attention for information critical to their survival and are less vigilant toward a less threatening (slowly approaching) predator. This cognitive allocation may be an adaptive compensation for fatigue-related low vigilance during fighting. PMID- 29496777 TI - Loci That Control Nonlinear, Interdependent Responses to Combinations of Drought and Nitrogen Limitation. AB - Crop improvement must accelerate to feed an increasing human population in the face of environmental changes. Including anticipated climatic changes with genetic architecture in breeding programs could better optimize improvement strategies. Combinations of drought and nitrogen limitation already occur world wide. We therefore analyzed the genetic architecture underlying the response of Zea mays to combinations of water and nitrogen stresses. Recombinant inbreds were subjected to nine combinations of the two stresses using an optimized response surface design, and their growth was measured. Three-dimensional response surfaces were fit globally and to each polymorphic allele to determine which genetic markers were associated with different response surfaces. Three quantitative trait loci that produced nonlinear surfaces were mapped. To better understand the physiology of the response, we developed a model that reproduced the shapes of the surfaces, their most characteristic feature. The model contains two components that each combine the nitrogen and water inputs. The relative weighting of the two components and the inputs is governed by five parameters, and each QTL affects all five parameters.We estimated the model's parameter values for the experimental surfaces using a mesh of points that covered the surfaces' most distinctive regions. Surfaces computed using these values reproduced the experimental surfaces well, as judged by three different criteria at the mesh points. The modeling and shape comparison techniques used here can be extended to other complex, high-dimensional, nonlinear phenotypes. We encourage the application of our findings and methods to experiments that mix crop protection measures, stresses, or both, on elite and landrace germplasm. PMID- 29496776 TI - Genomic Locus Modulating IOP in the BXD RI Mouse Strains. AB - Intraocular pressure (IOP) is the primary risk factor for developing glaucoma, yet little is known about the contribution of genomic background to IOP regulation. The present study leverages an array of systems genetics tools to study genomic factors modulating normal IOP in the mouse. The BXD recombinant inbred (RI) strain set was used to identify genomic loci modulating IOP. We measured the IOP in a total of 506 eyes from 38 different strains. Strain averages were subjected to conventional quantitative trait analysis by means of composite interval mapping. Candidate genes were defined, and immunohistochemistry and quantitative PCR (qPCR) were used for validation. Of the 38 BXD strains examined the mean IOP ranged from a low of 13.2mmHg to a high of 17.1mmHg. The means for each strain were used to calculate a genome wide interval map. One significant quantitative trait locus (QTL) was found on Chr.8 (96 to 103 Mb). Within this 7 Mb region only 4 annotated genes were found: Gm15679, Cdh8, Cdh11 and Gm8730 Only two genes (Cdh8 and Cdh11) were candidates for modulating IOP based on the presence of non-synonymous SNPs. Further examination using SIFT (Sorting Intolerant From Tolerant) analysis revealed that the SNPs in Cdh8 (Cadherin 8) were predicted to not change protein function; while the SNPs in Cdh11 (Cadherin 11) would not be tolerated, affecting protein function. Furthermore, immunohistochemistry demonstrated that CDH11 is expressed in the trabecular meshwork of the mouse. We have examined the genomic regulation of IOP in the BXD RI strain set and found one significant QTL on Chr. 8. Within this QTL, there is one good candidate gene, Cdh11. PMID- 29496779 TI - Anti-diuretic action of a CAPA neuropeptide against a subset of diuretic hormones in the disease vector Aedes aegypti. AB - The mosquito Aedes aegypti is a vector responsible for transmitting various pathogens to humans, and their prominence as chief vectors of human disease is largely due to their anthropophilic blood feeding behaviour. Larval stage mosquitoes must deal with the potential dilution of their haemolymph in freshwater, whereas the haematophagus A. aegypti female faces the challenge of excess ion and water intake after a blood meal. The excretory system, composed of the Malpighian tubules (MTs) and hindgut, is strictly controlled by neuroendocrine factors, responsible for the regulation of diuresis across all developmental stages. The highly studied insect MTs are influenced by a variety of diuretic hormones and, in some insects, anti-diuretic factors. In the present study, we investigated the effects of AedaeCAPA-1 neuropeptide on larval and adult female A. aegypti MTs stimulated with various diuretic factors including serotonin (5-HT), a corticotropin-related factor (CRF) diuretic peptide, a calcitonin-related diuretic hormone (DH31) and a kinin-related diuretic peptide. Overall, our findings establish that AedaeCAPA-1 specifically inhibits secretion of larval and adult MTs stimulated by 5-HT and DH31, whilst having no activity on MTs stimulated by other diuretic factors. Furthermore, although AedaeCAPA-1 acts as an anti-diuretic, it does not influence the relative proportions of cations transported by adult MTs, thus maintaining the kaliuretic activity of 5-HT and natriuretic activity of DH31 In addition, we tested the effects of the second messenger cGMP in adult MTs. We established that cGMP has similar effects to AedaeCAPA-1, strongly inhibiting 5-HT- and DH31-stimulated fluid secretion, but with only minor effects on CRF-stimulated diuresis. Interestingly, although AedaeCAPA-1 has no inhibitory activity on kinin-stimulated fluid secretion, cGMP strongly inhibited fluid secretion by this diuretic hormone, which targets stellate cells specifically. Collectively, these results support that AedaeCAPA-1 inhibits select diuretic factors acting on the principal cells and this probably involves cGMP as a second messenger. Kinin-stimulated diuresis, which targets stellate cells, is also inhibited by cGMP, suggesting that another anti-diuretic factor in addition to AedaeCAPA-1 exists and may utilize cGMP as a second messenger. PMID- 29496780 TI - Food consumption increases cell proliferation in the python brain. AB - Pythons are model organisms for investigating physiological responses to food intake. While systemic growth in response to food consumption is well documented, what occurs in the brain is currently unexplored. In this study, male ball pythons (Python regius) were used to test the hypothesis that food consumption stimulates cell proliferation in the brain. We used 5-bromo-12'-deoxyuridine (BrdU) as a cell-birth marker to quantify and compare cell proliferation in the brain of fasted snakes and those at 2 and 6 days after a meal. Throughout the telencephalon, cell proliferation was significantly increased in the 6 day group, with no difference between the 2 day group and controls. Systemic postprandial plasticity occurs quickly after a meal is ingested, during the period of active digestion; however, the brain displays a surge of cell proliferation after most digestion and absorption is complete. PMID- 29496781 TI - Thermal analysis of ice and glass transitions in insects that do and do not survive freezing. AB - Some insects rely on the strategy of freeze tolerance for winter survival. During freezing, extracellular body water transitions from the liquid to the solid phase and cells undergo freeze-induced dehydration. Here, we present results of a thermal analysis (from differential scanning calorimetry) of ice fraction dynamics during gradual cooling after inoculative freezing in variously acclimated larvae of two drosophilid flies, Drosophila melanogaster and Chymomyza costata Although the species and variants ranged broadly between 0 and close to 100% survival of freezing, there were relatively small differences in ice fraction dynamics. For instance, the maximum ice fraction (IFmax) ranged between 67.9% and 77.7% total body water (TBW). Chymomyza costata larvae showed statistically significant phenotypic shifts in parameters of ice fraction dynamics (melting point and IFmax) upon entry into diapause, cold acclimation and feeding on a proline-augmented diet. These differences were mostly driven by colligative effects of accumulated proline (ranging between 6 and 487 mmol kg-1 TBW) and other metabolites. Our data suggest that these colligative effects per se do not represent a sufficient mechanistic explanation for high freeze tolerance observed in diapausing, cold-acclimated C. costata larvae. Instead, we hypothesize that accumulated proline exerts its protective role via a combination of mechanisms. Specifically, we found a tight association between proline-induced stimulation of glass transition in partially frozen body liquids (vitrification) and survival of cryopreservation in liquid nitrogen. PMID- 29496782 TI - Brain mitochondrial bioenergetics change with rapid and prolonged shifts in aggression in the honey bee, Apis mellifera. AB - Neuronal function demands high-level energy production, and as such, a decline in mitochondrial respiration characterizes brain injury and disease. A growing number of studies, however, link brain mitochondrial function to behavioral modulation in non-diseased contexts. In the honey bee, we show for the first time that an acute social interaction, which invokes an aggressive response, may also cause a rapid decline in brain mitochondrial bioenergetics. The degree and speed of this decline has only been previously observed in the context of brain injury. Furthermore, in the honey bee, age-related increases in aggressive tendency are associated with increased baseline brain mitochondrial respiration, as well as increased plasticity in response to metabolic fuel type in vitro Similarly, diet restriction and ketone body feeding, which commonly enhance mammalian brain mitochondrial function in vivo, cause increased aggression. Thus, even in normal behavioral contexts, brain mitochondria show a surprising degree of variation in function over both rapid and prolonged time scales, with age predicting both baseline function and plasticity in function. These results suggest that mitochondrial function is integral to modulating aggression-related neuronal signaling. We hypothesize that variation in function reflects mitochondrial calcium buffering activity, and that shifts in mitochondrial function signal to the neuronal soma to regulate gene expression and neural energetic state. Modulating brain energetic state is emerging as a critical component of the regulation of behavior in non-diseased contexts. PMID- 29496784 TI - Effects of long-term sucrose overfeeding on rat brown adipose tissue: a structural and immunohistochemical study. AB - The aim of this study was to determine the effects of long-term sucrose overfeeding on functional capacity and ultrastructural characteristics of the rat brown adipose tissue (BAT). For the study, 16 male Wistar rats, chow-fed and kept under standard laboratory conditions, were divided into 2 equal groups. The rats from a control group drank tap water, whereas those from a sucrose overfed group were allowed to drink 10% sucrose solution for 21 days. Structural changes of BAT were analysed at the level of light and electron microscopy on routinely prepared tissue sections or using immunohistochemical staining, in combination with stereological methods. Obtained results have shown that the significantly increased energy intake in sucrose overfed rats did not result in a higher gain of body mass compared with controls. The light microscopy analysis revealed that the BAT acquired the appearance of a thermogenically active tissue, with intensified vascularisation, reduced size of brown adipocytes and increased multilocularity. At the ultrastructural level, mitochondria of brown adipocytes became more abundant, enlarged and contained more cristae in comparison to control animals. The immunoexpression of uncoupling protein 1 (UCP1) and noradrenaline, as markers of BAT thermogenic status, was increased, whereas the pattern of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1alpha) was slightly modified. Taken together, the results of this investigation indicated that BAT possesses the ability to increase thermogenic capacity/activity in response to high energy intake and to prevent body mass gain. These findings are particularly relevant in view of recent reports on the existence of functional BAT in adult humans and its potential use to combat obesity. PMID- 29496783 TI - Suppression of reactive oxygen species generation in heart mitochondria from anoxic turtles: the role of complex I S-nitrosation. AB - Freshwater turtles (Trachemys scripta) are among the very few vertebrates capable of tolerating severe hypoxia and re-oxygenation without suffering from damage to the heart. As myocardial ischemia and reperfusion causes a burst of mitochondrial reactive oxygen species (ROS) in mammals, the question arises as to whether, and if so how, this ROS burst is prevented in the turtle heart. We find that heart mitochondria isolated from turtles acclimated to anoxia produce less ROS than mitochondria from normoxic turtles when consuming succinate. As succinate accumulates in the hypoxic heart and is oxidized when oxygen returns, this suggests an adaptation to lessen ROS production. Specific S-nitrosation of complex I can lower ROS in mammals and here we show that turtle complex I activity and ROS production can also be strongly depressed in vitro by S nitrosation. We detect in vivo endogenous S-nitrosated complex I in turtle heart mitochondria, but these levels are unaffected upon anoxia acclimation. Thus, while heart mitochondria from anoxia-acclimated turtles generate less ROS and have a lower aerobic capacity than those from normoxic turtles, this is not due to decreases in complex I activity or expression levels. Interestingly, in-gel activity staining reveals that most complex I of heart mitochondria from normoxic and anoxic turtles forms stable super-complexes with other respiratory enzymes and, in contrast to mammals, these are not disrupted by dodecyl maltoside. Taken together, these results show that although S-nitrosation of complex I is a potent mechanism to prevent ROS formation upon re-oxygenation after anoxia in vitro, this is not a major cause of the suppression of ROS production by anoxic turtle heart mitochondria. PMID- 29496785 TI - CSF1R inhibition prevents radiation pulmonary fibrosis by depletion of interstitial macrophages. AB - Radiation-induced lung fibrosis (RIF) is a delayed side-effect of chest radiotherapy, frequently associated with macrophage infiltration.We aimed to characterise the role of pulmonary macrophages in RIF using human lung biopsies from patients receiving radiotherapy for thorax malignancies and a RIF model developed in C57BL/6 mice after 16-Gy thorax irradiation.High numbers of macrophages (both interstitial and alveolar) were detected in clinical and preclinical RIF. In the preclinical model, upregulation of T-helper (Th)2 cytokines was measured, whereas Th1 cytokines were downregulated in RIF tissue lysate. Bronchoalveolar lavage demonstrated upregulation of both types of cytokines. At steady state, tissue-infiltrating macrophages (IMs) expressed 10 fold more arginase (Arg)-1 than alveolar macrophages (AMs), and a 40-fold upregulation of Arg-1 was found in IMs isolated from RIF. IMs, but not AMs, were able to induce myofibroblast activation in vitro In addition, whereas depletion of AMs using Clodrosome didn't affect RIF score, depletion of IMs using a clinically available colony-stimulating factor receptor-1 (CSF1R) neutralising antibody was antifibrotic.These findings suggest differential contributions of alveolar versus interstitial macrophages in RIF, highlighting the fibrogenic role of IMs. The CSF1/CSF1R pathway was identified as a new therapeutic target to inhibit RIF. PMID- 29496786 TI - Adverse respiratory effects of opioids for chronic breathlessness: learning lessons from chronic pain. PMID- 29496787 TI - Achoo, achis, ATCHIN! Vaccine you.... PMID- 29496788 TI - Reassessing Th1 versus Th17.1 in sarcoidosis: new tricks for old dogma. PMID- 29496790 TI - Meet the First Authors. PMID- 29496789 TI - Location or origin? What is critical for macrophage propagation of lung fibrosis? PMID- 29496791 TI - Does Multicolor Lineage Tracing of Endothelial Cells Provide a Black and White Answer on Clonal Expansion in Post-Natal Angiogenesis? PMID- 29496792 TI - Gaming Aging in the "Omic" Era. PMID- 29496793 TI - Regulating Renewable Energy: Connecting AMPKalpha2 to PINK1/Parkin-Mediated Mitophagy in the Heart. PMID- 29496795 TI - Passion and Determination Are the Genesis of Research. PMID- 29496794 TI - Revisiting Old Friends: Sortilin-1, Low-Density Lipoprotein Receptor, and Prorenin Receptor as Modulators of Lipoprotein and Energy Metabolism. PMID- 29496796 TI - Cardiovascular Research in France. PMID- 29496797 TI - Induced Pluripotent Stem Cell (iPSC)-Derived Exosomes for Precision Medicine in Heart Failure. PMID- 29496798 TI - Translational Challenges in Atrial Fibrillation. AB - Atrial fibrillation (AF) is the most common sustained heart rhythm disorder and is associated with substantial morbidity and mortality. Current treatment options for AF have significant limitations. Basic research has provided information on mechanisms relevant to the management of AF and promises to contribute significantly to future advances, yet many important translational challenges remain. Here, we analyze the therapeutic limitations for which improvement is needed, consider the translational opportunities presented by recent scientific and technological developments, and attempt to look into the future of where these may lead. We first review the limitations of current AF management, with a focus on rhythm control therapy. These include arrhythmia complications, progression to advanced treatment-resistant forms, insufficient effectiveness of available therapeutic options, adverse consequences of therapy, and difficulties in new therapeutic development. The translational challenges in addressing these shortcomings are then addressed, including (1) defining actionable patient specific arrhythmia mechanisms to enable personalized therapy; (2) identifying and treating key dynamic modulators controlling AF initiation and progression; (3) achieving atrial-restricted targeting of specific molecular arrhythmia mechanisms; and (4) clarifying the response of the substrate to interventions. For each of these, we describe the translational goal and the opportunities created by recent advances in cardiac imaging, computational modeling, rhythm monitoring, ablation technology, and preclinical studies in human samples and animal models. Finally, we consider the prospects for future solutions that might appreciably improve our ability to understand and manage the arrhythmia over the years to come. PMID- 29496800 TI - Social Determinants of Health: An Essential Element in Dental Education. PMID- 29496799 TI - Endocardial Cell Plasticity in Cardiac Development, Diseases and Regeneration. AB - Endocardial cells are specialized endothelial cells that form the innermost layer of the heart wall. By virtue of genetic lineage-tracing technology, many of the unexpected roles of endocardium during murine heart development, diseases, and regeneration have been identified recently. In addition to heart valves developed from the well-known endothelial to mesenchymal transition, recent fate-mapping studies using mouse models reveal that multiple cardiac cell lineages are also originated from the endocardium. This review focuses on a variety of different cell types that are recently reported to be endocardium derived during murine heart development, diseases, and regeneration. These multiple cell fates underpin the unprecedented roles of endocardial progenitors in function, pathological progression, and regeneration of the heart. Because emerging studies suggest that developmental mechanisms can be redeployed and recapitulated in promoting heart disease development and also cardiac repair and regeneration, understanding the mechanistic regulation of endocardial plasticity and modulation of their cell fate conversion may uncover new therapeutic potential in facilitating heart regeneration. PMID- 29496801 TI - Integrating Social Determinants of Health into Dental Curricula: An Interprofessional Approach. AB - Approaching patient care from a holistic perspective, incorporating not only the patient's medical and dental history but also psychosocial history, improves patient outcomes. Practitioners should be trained to provide this style of care through inclusive education, including training working on interprofessional teams. A component of this education must incorporate social determinants of health into the treatment plan. Social determinants of health include income, race/ethnicity, education level, work opportunities, living conditions, and access to health care. Education regarding social determinants of health should be woven throughout dental curricula, including hands-on application opportunities. This education must extend to patient care situations rather than be limited to didactic settings. This article explains the need to incorporate social determinants of health into dental education and illustrates how social determinants education is being addressed in two U.S. dental schools' curricula, including how to weave social determinants of health into interprofessional education. These descriptions may serve as a model for curricular innovation and faculty development across the dental education community. PMID- 29496802 TI - Should Live Patient Licensing Examinations in Dentistry Be Discontinued? Two Viewpoints: Viewpoint 1: Alternative Assessment Models Are Not Yet Viable Replacements for Live Patients in Clinical Licensure Exams and Viewpoint 2: Ethical and Patient Care Concerns About Live Patient Exams Require Full Acceptance of Justifiable Alternatives. AB - This Point/Counterpoint article addresses a long-standing but still-unresolved debate on the advantages and disadvantages of using live patients in dental licensure exams. Two contrasting viewpoints are presented. Viewpoint 1 supports the traditional use of live patients, arguing that other assessment models have not yet been demonstrated to be viable alternatives to the actual treatment of patients in the clinical licensure process. This viewpoint also contends that the use of live patients and inherent variances in live patient treatment represent the realities of daily private practice. Viewpoint 2 argues that the use of live patients in licensure exams needs to be discontinued considering those exams' ethical dilemmas of exposing patients to potential harm, as well as their lack of reliability and validity and limited scope. According to this viewpoint, the current presence of viable alternatives means that the risk of harm inherent in live patient exams can finally be eliminated and those exams replaced with other means to confirm that candidates are qualified for licensure to practice. PMID- 29496803 TI - U.S. Dental Schools' Preparation for the Integrated National Board Dental Examination. AB - An Integrated National Board Dental Examination (INBDE) combining basic, behavioral, and clinical sciences will be implemented in 2020 to replace the current two-part National Board Dental Examination required for all candidates who seek to practice dentistry in the U.S. The aims of this study were to determine how U.S. dental schools are preparing for implementation of the INBDE and to assess their top administrators' attitudes about the new exam. A total of 150 deans, academic deans, and other administrators at all 64 U.S. dental schools with graduating classes in 2016 were emailed a 19-question electronic survey. The survey questions addressed the respondents' level of support, perceived benefits and challenges, and planned preparation strategies for the INBDE. The individual response rate was 59%, representing 57 of the 64 schools. Approximately 60% of the respondents either agreed or strongly agreed that they support the integrated exam, while roughly 25% either somewhat or strongly disagreed. While most respondents (72%) reported that their institutions would be prepared for the INBDE, 74% reported that the merged exam created additional strain for their institutions. Respondents reported viewing content integration and clinical applicability as benefits of the INBDE, while required curriculum changes and student preparedness and stress were seen as challenges. Most of the respondents reported their schools were currently employing strategies to prepare for the INBDE including meetings with faculty and students and changes to curricula and course content. The beginning of the fourth year and the end of the third year were the most frequently reported times when schools planned to require students to take the INBDE, although almost half of the respondents did not yet know what it would be required at their school. Several schools were reconsidering using the boards as a passing requirement. This study found that support for the INBDE was not universal, but strategies are under way to prepare students, faculty, and curricula for this new means of assessment. PMID- 29496804 TI - Analyzing Dental Students' Clinic Production Using Time-Based Relative Value Units: Ten-Year Cross-Cohort Mapping. AB - The analysis of dental students' clinical production/participation has been used to assess whether a prospective graduate is capable of unsupervised and independent practice (that is, competent to perform that practice). This method and others have inherent biases that may not accurately reflect whether the student has mastered the associated concepts and techniques required for dentistry. The aim of this study was to assess an informatics system that assigned curriculum meta-tags with time-based relative educational value units (ReVUs) to each clinical procedure performed by Medical University of South Carolina (MUSC) students. The system has been used since 1998, but for this study the complete data sets for the MUSC graduating classes of 2007 through 2016 were mapped using microcompetency codes for the dental procedures. In total, 421,494 procedures were formatted and analyzed using software developed to aggregate disparate data sets from clinical activities into a common format for evaluation. The results showed that the ten classes (cohorts) were very consistent with cohort high ReVUs averaging 7,317.1 points, cohort mean ReVUs being 5,180.2 points, and cohort low ReVUs averaging 3,381 points. A detailed analysis of student effort by dental subspecialty found that preventive activities represented 13.4%, patient assessment 32.6%, periodontology 2.8%, restorative dentistry 16.3%, prosthodontics 21.9%, endodontics 6.7%, and oral surgery 5.7% of the total points in the clinical part of the curriculum. In this system, point thresholds can be easily generated to monitor students' progress towards competence for each defined competency and thus assess their progress towards acquiring the skills required for unsupervised, independent practice. PMID- 29496805 TI - The Dental School Interview As a Predictor of Dental Students' OSCE Performance. AB - The aim of this study was to evaluate the use of the dental school admissions interview score as a noncognitive indicator of performance in predoctoral dental education, with specific attention to whether a correlation existed between the admissions interview scores and performance on the objective structured clinical examination (OSCE). The study population consisted of all 175 students in the Harvard School of Dental Medicine (HSDM) DMD Classes of 2012 through 2016. Data on students' gender and age on entering dental school were self-reported using their applications for admission to the HSDM DMD program. Data on students' OSCE scores for three examination sessions were collected from the Office of Dental Education. The results showed that the students' interview scores did not significantly correlate with OSCE performance on any of the three exams. Performance on the first and second OSCEs did, however, correlate with performance on the third OSCE (p<0.05). Age on entering dental school was not significantly associated with performance on any of the three OSCEs; however, among male students, there was a significant negative correlation (p<0.05) between entering age and performance on the second and third OSCEs. There was no significant association between gender and OSCE or interview score. These results suggest that although the admissions interview scores can serve as an important resource in student selection, with the lack of association between interview and OSCE scores, it is possible that the communication skills required for the interview do not directly overlap with those required for OSCE success. PMID- 29496806 TI - A Scoring System for Assessing Learning Progression of Dental Students' Clinical Skills Using Haptic Virtual Workstations. AB - The aim of this study was to develop and test a scoring system to assess the learning progression of novice dental students using haptic virtual workstations. For the study, 101 first-year dental students at a UK dental school conducted one practice task (task 1) and four simulated cavity removal tasks (tasks 2-5) of increasing difficulty over two laboratory sessions in 2015. Performance data on the students' attempts were recorded as haptic technology-enhanced learning (hapTEL) log-files showing the percentage of caries, healthy tissue, and pulp removed. On-screen results were photographed and submitted by the students to the tutors. A scoring system named the Accuracy of Caries Excavation (ACE) score was devised to score these results and achieve an even distribution of scores and a calculated combined score. A total of 127 individual logged attempts by 80% of the students over sessions 1 and 2 were recorded and submitted to the tutors. The mean ACE scores for both sessions for tasks 2 through 5 were 9.2, 11.6, 6.4, and 4.9, respectively; for Session 2 (tasks 3-5), scores were 12.4, 6.7, and 5.0, respectively (p<0.001). The average performance on task 3, which was attempted in similar numbers during both sessions, improved from the first to the second session (8.14 vs. 12.38; p=0.009). Using the HapTEL system in a first-year BDS curriculum improved the students' performance of simulated cavity preparation after practicing over two sessions. Use of the ACE scoring system enabled tutors to make consistent assessments across a large student cohort and provided an objective method of formative assessment. PMID- 29496807 TI - Methods and Purposes for Conducting Students' Course Evaluations Reported by North American Dental School and Dental Hygiene Program Leaders: A Preliminary Survey Study. AB - The aim of this preliminary survey study was to determine the perceptions of leaders of dental schools and dental hygiene programs regarding methods of and purposes for conducting students' course evaluations and their role in course improvement, curriculum design, and faculty assessment. A short electronic survey was distributed in 2016 to the academic deans of all 76 dental schools in the U.S. and Canada and a convenience sample of program directors of 232 of the total 332 accredited dental hygiene programs. Individuals from 93 institutions responded for an overall response rate of 30%: 30 of 76 dental schools (39.5% response rate) and 63 of the 232 dental hygiene programs (27% response rate). All of the respondents (100%) reported that their institutions' full-time faculty members were assessed by students in course evaluations for each course and semester they taught. However, only 78% reported that their part-time faculty members were evaluated by students. Course evaluations were mandatory in 62% (n=58) of the responding institutions, with the remaining 38% (n=35) optional. Respondents indicated course directors received the evaluation results for purposes of annual review (n=73, 78%) and instructional review (n=70, 75%). Further investigation of the use and effects of student evaluations is needed to better understand their role in faculty assessment and other aspects of the administration of dental schools and dental hygiene programs. PMID- 29496808 TI - Periodontal Diagnosis and Treatment Planning Among Indiana Dental Faculty, Periodontists, and General Practice Dentists: A Multi-Group Comparison. AB - Diagnosis and treatment planning for periodontal disease are fraught with challenges because of the complex and multifactorial nature of the disease as well as the inherent variability in interpretation of clinical findings. It is important for all practitioners to be accurate and consistent in formulating diagnoses based on the American Academy of Periodontology classification guidelines and to implement treatment plans to adequately address patients' needs. The aim of this study was to compare diagnoses and treatment plans among four groups of participants: full-time and part-time periodontology faculty at Indiana University School of Dentistry (IUSD), full-time and part-time IUSD general practice faculty, full-time periodontists in private practice, and full time general practitioners in private practice. The study, conducted September 2016 to February 2017, also sought to determine if the calibrated participants had more correct diagnoses and treatment plans than those who had not received calibration training. Each of the four groups had 20 participants each. Participants evaluated ten de-identified case records and selected a diagnosis and treatment plan for each case. In the results, the 20 IUSD periodontal faculty members, most of whom had participated in calibration sessions, had overall better agreement and more correct responses for diagnoses and treatment plans than the IUSD general practice faculty members, private practice general practitioners, and private practice periodontists (only one of those 60 participants had participated in calibration sessions). The results supported the notion that periodic calibration is needed to standardize faculty criteria, facilitate better agreement and accuracy, and enhance consistency in the use of clinical criteria during training for dental students and in practice. PMID- 29496809 TI - Teaching Dental Students About Incarceration and Correctional Dentistry: Results from a National Survey. AB - People who are incarcerated or have a history of incarceration have high rates of dental disease, but access to dental treatment is often a challenge during and after incarceration. Dental students' exposure to this population is unknown: no data exist regarding the number of schools that provide didactic and clinical training in correctional dentistry. The aim of this study was to assess the extent of instruction in correctional dentistry and clinical opportunities at correctional facilities for dental students in the U.S. A survey was distributed to the academic deans at all 66 U.S. dental schools in 2017. Respondents were asked if their institutions had curricular content on correctional health and if they provided clinical opportunities in the correctional setting. Respondents from 30 schools completed the survey, for a response rate of 45%. Nearly two thirds of the respondents said their institutions offered didactic instruction on the impact of incarceration on health, and eight schools offered a clinical experience at a correctional facility. The most common format was a community based dental externship involving fourth-year dental students. Oral exams, prophylaxis, and extractions were the most common procedures performed. Respondents from schools that offered a clinical experience agreed more strongly than those that did not that exposure to correctional health care was important and that their students believed incarceration to be a social determinant of health. This study found that a substantial proportion of dental schools offered didactic education on correctional health, but a much smaller number offered student rotations in correctional facilities. PMID- 29496810 TI - Effect of Lecture Attendance and Prerequisite Academic Outcomes on Dental Students' Oral Pathology Performance. AB - Decreased lecture attendance in undergraduate and health science professions education has been noted throughout the world. The limited study of the effect of lecture attendance on dental students' performance has yielded mixed results, with some studies finding a positive effect and others reporting no association. The aim of this study was to evaluate the effect of lecture attendance on dental students' final grades in an oral pathology course at one U.S. dental school. Due to a curriculum change, second- and third-year students (N=233) were concurrently enrolled in the spring 2016 oral pathology (OP) course. Students' course grades were compared to attendance percentage (Att), grades in prerequisite basic science (PBS) courses, and Academic Average and Total Science (TS) scores on the Dental Admission Test. The results showed that both Att (p=0.011) and TS score (p<0.001) were significant predictors of OP grade, while race, gender, and age were not. Students' grades in OP were moderately to strongly correlated with their grades in all PBS courses (p<0.001). These results suggest that lecture attendance in OP should be encouraged but viewed in light of the finding that it was not as strongly correlated as PBS course performance and was a weaker predictor than TS score. Students with lower TS scores and PBS course grades should be encouraged to use additional supports such as tutoring to improve their performance in OP. PMID- 29496811 TI - Dental Students' Interpretations of Digital Panoramic Radiographs on Completely Edentate Patients. AB - The ability of dental students to interpret digital panoramic radiographs (PANs) of edentulous patients has not been documented. The aim of this retrospective study was to compare the ability of second-year (D2) dental students with that of third- and fourth-year (D3-D4) dental students to interpret and identify positional errors in digital PANs obtained from patients with complete edentulism. A total of 169 digital PANs from edentulous patients were assessed by D2 (n=84) and D3-D4 (n=85) dental students at one Canadian dental school. The correctness of the students' interpretations was determined by comparison to a gold standard established by assessments of the same PANs by two experts (a graduate student in prosthodontics and an oral and maxillofacial radiologist). Data collected were from September 1, 2006, when digital radiography was implemented at the university, to December 31, 2012. Nearly all (95%) of the PANs were acceptable diagnostically despite a high proportion (92%) of positional errors detected. A total of 301 positional errors were identified in the sample. The D2 students identified significantly more (p=0.002) positional errors than the D3-D4 students. There was no significant difference (p=0.059) in the distribution of radiographic interpretation errors between the two student groups when compared to the gold standard. Overall, the category of extragnathic findings had the highest number of false negatives (43) reported. In this study, dental students interpreted digital PANs of edentulous patients satisfactorily, but they were more adept at identifying radiographic findings compared to positional errors. Students should be reminded to examine the entire radiograph thoroughly to ensure extragnathic findings are not missed and to recognize and report patient positional errors. PMID- 29496812 TI - Teaching Cell Biology to Dental Students with a Project-Based Learning Approach. AB - Although the discipline of cell biology (CB) is part of the curricula of predoctoral dental schools, students often fail to recognize its practical relevance. The aim of this study was to assess the effectiveness of a practical theoretical project-based course in closing the gaps among CB, scientific research, and dentistry for dental students. A project-based learning course was developed with nine sequential lessons to evaluate 108 undergraduate dental students enrolled in CB classes of a Brazilian school of dentistry during 2013 16. To highlight the relevance of in vitro studies in the preclinical evaluation of dental materials at the cellular level, the students were challenged to complete the process of drafting a protocol and performing a cytocompatibility assay for a bone substitute used in dentistry. Class activities included small group discussions, scientific database search and article presentations, protocol development, lab experimentation, and writing of a final scientific report. A control group of 31 students attended only one laboratory class on the same theme, and the final reports were compared between the two groups. The results showed that the project-based learning students had superior outcomes in acknowledging the relevance of in vitro methods during biocompatibility testing. Moreover, they produced scientifically sound reports with more content on methodological issues, the relationship with dentistry, and the scientific literature than the control group (p<0.05). The project-based learning students also recognized a higher relevance of scientific research and CB to dental practice. These results suggest that a project-based approach can help contextualize scientific research in dental curricula. PMID- 29496814 TI - Visualization of Fluorescent Protein Expression in Whole-Mount Postimplantation Stage Mouse Embryos. AB - Fluorescent protein (FP)-expressing transgenic mice are powerful genetic resources for marking both live and fixed cells and tissues. Expression in live embryos requires only dissection and visualization using an appropriate microscope. Fixation can compromise FP activity. A simple tissue-clearing agent called Scale preserves FP activity while rendering the embryo or organ optically transparent. PMID- 29496815 TI - Microinjecting Lentivirus into Mouse Embryos. AB - This protocol describes the injection of lentivirus into the perivitelline space of fertilized oocytes. Embryos usually survive lentiviral injection well because only the zona is pierced. PMID- 29496816 TI - Infecting Mouse Embryos by Coculturing with Lentivirus. AB - Lentiviral vectors make it possible to produce transgenic animals without the need to purchase expensive microinjection equipment because integration of the transgene is possible by coculture of embryos with virus. This protocol describes the infection of fertilized oocytes with lentivirus by coculture. PMID- 29496817 TI - Whole-Mount In Situ Hybridization of Xenopus Oocytes. AB - Whole-mount in situ hybridization (WMISH) is a common approach that is used to visualize spatial and temporal gene expression in embryos. In this process, digoxygenin-labeled antisense RNA is hybridized to the complementary transcript of interest and RNA hybrids are immunohistochemically detected using an alkaline phosphatase-conjugated antibody against digoxigenin. During Xenopus laevis oogenesis, certain RNAs localize to the animal or vegetal pole laying the foundation for germ cell development and germ layer formation of the future embryo. Here we present a WMISH protocol for Xenopus laevis oocytes allowing for the efficient detection of localized RNAs in a large number of oocytes during different stages of oogenesis. The application of this approach might be combined with microinjection of tagged reporter RNAs and/or a gain- or loss-of-function background, allowing for the functional analysis of single protein factors involved in RNA localization. PMID- 29496818 TI - Random Mutagenesis Using Error-Prone DNA Polymerases. AB - "Random mutagenesis" is a technique that allows researchers to develop large libraries of variants of a particular DNA sequence. Once developed, these libraries can then be used for several purposes, including structure-function and directed evolution studies. Random mutagenesis is different from other mutagenesis techniques in that it does not require the researcher to have any prior knowledge about the structural properties of the DNA sequence being targeted, thus allowing for the unbiased discovery of novel or beneficial mutations. For this reason, random mutagenesis is especially useful for protein evolution studies. This protocol describes mutagenic replication in vitro by a low-fidelity DNA polymerase followed by selective polymerase chain reaction (PCR) amplification of the newly mutated sequences. The initial mutagenic DNA replication step is accomplished by heat-denaturing the template DNA and annealing primers possessing 5' extensions that are not complementary to the template. The purpose of the noncomplementary extensions on the primers is to allow for future selection of only the mutant strands. DNA replication is then performed by a low-fidelity DNA polymerase of choice (polymerase beta, eta, or iota, or any combination of the three). After mutations have been incorporated into the template, the mutagenized strands are then selectively amplified using PCR. Selective amplification of the mutant strands is accomplished by performing a PCR procedure consisting of a first cycle with a low hybridization temperature followed by subsequent selection cycles under higher hybridization temperatures that do not allow amplification of the original unmutagenized template. PMID- 29496819 TI - In Vitro Mutagenesis Using Double-Stranded DNA Templates: Selection of Mutants with DpnI. AB - In this protocol, two oligonucleotides are used to prime DNA synthesis by a high fidelity polymerase on a denatured plasmid template. The two oligonucleotides both contain the desired mutation and have the same starting and ending positions on opposite strands of the plasmid DNA. The entire lengths of both strands of the plasmid DNA are amplified in a linear fashion during several rounds of thermal cycling, generating a mutated plasmid containing staggered nicks on opposite strands. Because of the amount of template DNA used in the amplification reaction, the background of transformed colonies containing wild-type plasmid DNA can be quite high unless steps are taken to enrich for mutant molecules. In this protocol, the products of the linear amplification reaction are treated with the restriction enzyme DpnI, which specifically cleaves fully methylated GMe6ATC sequences. DpnI will therefore digest the bacterially generated DNA used as template for amplification, but it will not digest DNA synthesized during the course of the reaction in vitro. DpnI-resistant molecules, which are rich in the desired mutants, are recovered by transforming E. coli cells to antibiotic resistance. Because the method works well with virtually any plasmid of moderate size (<7 kb), it can be used to introduce mutations directly into full-length cDNAs and eliminates the need for subcloning into specialized vectors. PMID- 29496820 TI - The Hanahan Method for Preparation and Transformation of Competent Escherichia coli: High-Efficiency Transformation. AB - Chemical transformation is a highly efficient, commonly used method to transform Escherichia coli with plasmid DNA. Hanahan's procedure works well with many strains of E. coli commonly used in molecular cloning. Many variations on the basic technique have been described, all directed toward optimizing the efficiency of transformation. It is now possible on a routine basis to achieve transformation frequencies ranging from 106 to 109 transformants/ug of superhelical plasmid DNA. PMID- 29496821 TI - Screening for Good Batches of Fetal Bovine Serum for Myeloma and Hybridoma Growth. AB - Not all lots of fetal bovine serum (FBS) are good at supporting hybridoma growth at low density. The key constituents that distinguish good batches of serum from bad are not known. It is necessary to order test batches from several suppliers and screen them as described here or purchase prescreened serum directly from the distributor. PMID- 29496822 TI - Polyethylene Glycol Fusion for Hybridoma Production. AB - Once a good immune response has developed in an animal and an appropriate screening procedure has been developed, the construction of hybridomas is ready to begin. Polyethylene glycol (PEG) is the fusing agent of choice for hybridoma production, allowing the rapid and manageable fusion of mammalian cells. PEG fuses the plasma membranes of adjacent myeloma and/or antibody-secreting cells, forming a single cell with two or more nuclei. This heterokaryon retains these nuclei until the nuclear membranes dissolve before mitosis. In this protocol, antibody-secreting cells are isolated from the appropriate lymphoid tissue (mouse spleen and lymph nodes), mixed with myeloma cells, centrifuged to generate good cell-to-cell contacts, and fused with PEG. The fused cells are then diluted into selective medium and plated in multiwell tissue culture dishes. Beginning ~1 wk later, samples of the tissue culture supernatants are removed from wells that contain growing hybridomas and tested for the presence of the appropriate antibodies. Cells from positive wells are grown, single-cell-cloned, and frozen. A procedure for screening batches of PEG for efficacy before hybridoma fusion is also included. PMID- 29496823 TI - Myosin-Driven Intracellular Transport. AB - The delivery of intracellular material within cells is crucial for maintaining normal function. Myosins transport a wide variety of cargo, ranging from vesicles to ribonuclear protein particles (RNPs), in plants, fungi, and metazoa. The properties of a given myosin transporter are adapted to move on different actin filament tracks, either on the disordered actin networks at the cell cortex or along highly organized actin bundles to distribute their cargo in a localized manner or move it across long distances in the cell. Transport is controlled by selective recruitment of the myosin to its cargo that also plays a role in activation of the motor. PMID- 29496824 TI - Draft Genome Sequence of Plant Growth-Promoting and Drought-Tolerant Bacillus altitudinis FD48, Isolated from Rice Phylloplane. AB - The genome sequence of a temperature-tolerant strain, Bacillus altitudinis FD48, is described here. The reads were assembled into contigs with a total size of 3.7 Mb. The genome information will aid in understanding its role in alleviating stress in crop plants as a potential bioinoculant for agricultural applications. PMID- 29496825 TI - Whole-Genome Characterization of Prunus necrotic ringspot virus Infecting Sweet Cherry in China. AB - Prunus necrotic ringspot virus (PNRSV) causes yield loss in most cultivated stone fruits, including sweet cherry. Using a small RNA deep-sequencing approach combined with end-genome sequence cloning, we identified the complete genomes of all three PNRSV strands from PNRSV-infected sweet cherry trees and compared them with those of two previously reported isolates. PMID- 29496826 TI - Complete Genome Sequence of Temperate Stenotrophomonas maltophilia Bacteriophage DLP5. AB - Stenotrophomonas maltophilia bacteriophage DLP5 is a temperate phage with Siphoviridae family morphotype. DLP5 (vB_SmaS_DLP_5) is the first S. maltophilia phage shown to exist as a phagemid. The DLP5 genome is 96,542 bp, encoding 149 open reading frames (ORFs), including four tRNAs. Genomic characterization reveals moron genes potentially involved in host cell membrane modification. PMID- 29496827 TI - Complete Genome Sequence of Escherichia albertii Strain 1551-2, a Potential Extracellular and Intracellular Pathogen. AB - Escherichia albertii has recently been recognized as an emerging human and bird enteric pathogen. Here, we report the complete chromosome sequence of a clinical isolate of E. albertii strain 1551-2, which may provide information about the pathogenic potential of this new species and the mechanisms of evolution of Escherichia species. PMID- 29496828 TI - Draft Genome Sequence of the Radioresistant Bacterium Deinococcus aerius TR0125, Isolated from the High Atmosphere above Japan. AB - Deinococcus aerius strain TR0125 is a bacterium isolated from the high atmosphere above Japan that shows strong resistance to desiccation, UV-C, and gamma radiation. Here, we report the draft genome sequence of D. aerius (4.5 Mb), which may provide useful genetic information supporting its biochemical features. PMID- 29496829 TI - Finished Genome Sequence of a Polyurethane-Degrading Pseudomonas Isolate. AB - Pseudomonas sp. strain WP001 is a laboratory isolate capable of polyurethane polymer degradation and harbors a predicted lipase precursor gene. The genome of strain WP001 is 6.15 Mb in size and is composed of seven scaffolds with a G+C content of 60.54%. Strain WP001 is closely related to Pseudomonas fluorescens based on ribosomal DNA comparisons. PMID- 29496830 TI - Genome Sequence of a Byssochlamys sp. Strain Isolated from Fouled B20 Biodiesel. AB - Byssochlamys sp. strain AF001 is a filamentous fungus isolated from fouled B20 biodiesel. Its growth on B20 biodiesel results in the degradation and fouling of the fuel and higher rates of corrosion in affected storage tanks. The genome of Byssochlamys sp. AF001 is 35.9 Mbp and is composed of 10 scaffolds, with a G+C content of 45.89%. PMID- 29496831 TI - Closed Genome Sequence of Vibrio cholerae O1 El Tor Inaba Strain A1552. AB - Vibrio cholerae is a Gram-negative waterborne human pathogen and the causative agent of cholera. Here, we present the complete genome sequence of the seventh pandemic O1 biovar El Tor Inaba strain A1552 isolated in 1992. This clinical strain has served as an important model strain for studying cholera pathogenicity traits. PMID- 29496832 TI - Complete Genome Sequence of Streptomyces lavendulae subsp. lavendulae CCM 3239 (Formerly "Streptomyces aureofaciens CCM 3239"), a Producer of the Angucycline Type Antibiotic Auricin. AB - Streptomyces lavendulae subsp. lavendulae CCM 3239 produces the angucycline antibiotic auricin and was thought to be the type strain of Streptomyces aureofaciens We report the complete genome sequence of this strain, which consists of a linear chromosome and the linear plasmid pSA3239, and demonstrate it to be S. lavendulae subsp. lavendulae. PMID- 29496833 TI - Genome Sequences of Two Single-Stranded DNA Viruses Identified in Varroa destructor. AB - Varroa destructor is a ubiquitous and parasitic mite of honey bees, infecting them with pathogenic viruses having a major impact on apiculture. We identified two novel circular replication-associated protein (Rep)-encoding single-stranded (CRESS) DNA viruses from V. destructor sampled from a honey bee hive near Christchurch in New Zealand. PMID- 29496834 TI - Draft Genome Sequence of Streptomyces sp. Strain DH-12, a Soilborne Isolate from the Thar Desert with Broad-Spectrum Antibacterial Activity. AB - Strain DH-12 exhibits broad-spectrum antibacterial activity toward Gram-positive and Gram-negative pathogens. The 7.6-Mb draft genome sequence gives insight into the complete secondary metabolite production capacity and reveals genes putatively responsible for its antibacterial activity, as well as genes which enable the survival of the organism in an extreme arid environment. PMID- 29496835 TI - Draft Genome Sequence of Enterobacter sp. Strain EA-1, an Electrochemically Active Microorganism Isolated from Tropical Sediment. AB - Enterobacter sp. strain EA-1 is an electrochemically active bacterium isolated from tropical sediment in Singapore. Here, the annotated draft genome assembly of the bacterium is reported. Whole-genome comparison indicates that Enterobacter sp. EA-1, along with a previously sequenced Enterobacter isolate from East Asia, forms a distinct clade within the Enterobacter genus. PMID- 29496836 TI - Complete Genome Sequence of a Swiss Hepatitis E Virus Isolate from the Liver of a Fattening Pig. AB - We present here the full-length genome sequence of a hepatitis E genotype 3 virus (HEV-3) isolate, CH_VW117, from the liver of a healthy fattening pig collected at the slaughter level. Sequence analysis implies that this strain belongs to the newly proposed HEV subtype 3s. PMID- 29496837 TI - Complete Genome Sequence of a New Zealand Isolate of the Bovine Pathogen Streptococcus uberis. AB - Streptococcus uberis forms part of the native microbiota of cattle and is able to opportunistically infect the mammary gland; as such, it is a leading cause of bovine mastitis globally. Here, we report the complete genome sequence of S. uberis NZ01, isolated in New Zealand from a cow with a clinical case of bovine mastitis. PMID- 29496838 TI - Draft Genome Sequence of Multidrug-Resistant Strain Citrobacter portucalensis MBTC-1222, Isolated from Uziza (Piper guineense) Leaves in Nigeria. AB - In this work, we report the draft whole-genome sequence of the multiply antibiotic-resistant Citrobacter portucalensis strain MBTC-1222 isolated from the uziza leafy vegetable in Nigeria. Sequence analysis showed the assembled genome size to be 4,881,935 bp, containing 4,603 protein-coding genes, 131 pseudogenes, 7 rRNAs, 74 tRNAs, and 9 noncoding RNAs (ncRNAs). PMID- 29496839 TI - Complete Genome Sequence of a Ciprofloxacin-Resistant Salmonella enterica subsp. enterica Serovar Kentucky Sequence Type 198 Strain, PU131, Isolated from a Human Patient in Washington State. AB - Strains of the ciprofloxacin-resistant (Cipr) Salmonella enterica subsp. enterica serovar Kentucky sequence type 198 (ST198) have rapidly and extensively disseminated globally to become a major food safety and public health concern. Here, we report the complete genome sequence of a CiprS. Kentucky ST198 strain, PU131, isolated from a human patient in Washington State (USA). PMID- 29496840 TI - Complete Genome Sequence of Ehrlichia canis Strain YZ-1, Isolated from a Beagle with Fever and Thrombocytopenia. AB - We report the complete genome sequence of Ehrlichia canis strain YZ-1, which was isolated from a beagle with fever, anorexia, depression, lethargy, weight loss, and thrombocytopenia. E. canis is the tick-borne agent of canine and human monocytic ehrlichiosis. PMID- 29496841 TI - Metagenome Sequencing of Prokaryotic Microbiota from Two Hypersaline Soils of the Odiel Salt Marshes in Huelva, Southwestern Spain. AB - Two 454 shotgun metagenomes were sequenced from hypersaline soil samples collected in the Odiel salt marsh area in Huelva, southwestern Spain. Analysis of contigs and 16S rRNA-related sequences showed that Halobacteria, Balneolaeota, and Bacteroidetes were the dominant groups. Rhodothermaeota and Nanohaloarchaeota were also abundant. PMID- 29496842 TI - Draft Genome Sequence of Sphingorhabdus sp. Strain EL138, a Metabolically Versatile Alphaproteobacterium Isolated from the Gorgonian Coral Eunicella labiata. AB - Here, we report the draft genome sequence of Sphingorhabdus sp. strain EL138, an alphaproteobacterium that shows potential to degrade polycyclic aromatic compounds and to cope with various heavy metals and antibiotics. Moreover, the strain, isolated from the gorgonian coral Eunicella labiata, possesses several genes involved in the biosynthesis of polyphosphates, polyketides, and terpenoids. PMID- 29496843 TI - Draft Genome Sequence of Ezakiella peruensis Strain M6.X2, a Human Gut Gram Positive Anaerobic Coccus. AB - We report here the draft genome sequence of Ezakiella peruensis strain M6.X2T The draft genome is 1,672,788 bp long and harbors 1,589 predicted protein-encoding genes, including 26 antibiotic resistance genes with 1 gene encoding vancomycin resistance. The genome also exhibits 1 clustered regularly interspaced short palindromic repeat region and 333 genes acquired by horizontal gene transfer. PMID- 29496844 TI - Complete Genome Sequence of a Pepper mild mottle virus Isolate from Northeast China. AB - The complete genome sequence of a Pepper mild mottle virus (PMMoV) isolate obtained from Northeast China was determined by reverse transcription-PCR (RT PCR) and rapid amplification of cDNA ends (RACE). Phylogenetic analysis showed that the virus isolate is closely related to Japanese, Chinese, Spanish, and U.S. isolates. PMID- 29496845 TI - Complete Genome Sequence of a Circulating Hepatitis B Virus Genotype C Strain Isolated from a Chronically Infected Patient Identified at an Outdoor Hospital in Bangladesh. AB - Hepatitis B virus (HBV) causes significant global health problems despite the presence of a potential vaccine. HBV chronic cases are increasing rapidly in developing countries like Bangladesh. Here, we report the complete genome sequence of an HBV genotype C strain isolated from a chronic patient identified at an outdoor hospital section. PMID- 29496847 TI - Transparent author credit. PMID- 29496848 TI - News at a glance. PMID- 29496846 TI - Science of science. AB - Identifying fundamental drivers of science and developing predictive models to capture its evolution are instrumental for the design of policies that can improve the scientific enterprise-for example, through enhanced career paths for scientists, better performance evaluation for organizations hosting research, discovery of novel effective funding vehicles, and even identification of promising regions along the scientific frontier. The science of science uses large-scale data on the production of science to search for universal and domain specific patterns. Here, we review recent developments in this transdisciplinary field. PMID- 29496850 TI - Arecibo telescope saved by university consortium. PMID- 29496849 TI - Asia's hunger for sand takes toll on ecology. PMID- 29496851 TI - Restraining immunity could lower high blood pressure. PMID- 29496852 TI - Genome editor gets more versatile and precise. PMID- 29496853 TI - Better atomic clocks herald new era of timekeeping. PMID- 29496854 TI - Cosmic dawn signal holds clue to dark matter. PMID- 29496855 TI - The roots of resilience. PMID- 29496856 TI - After the deluge. PMID- 29496857 TI - Nature's strategies: Fish that switch sex to thrive. PMID- 29496858 TI - Lessons in resilience. PMID- 29496859 TI - Nature's strategies: Resilience by regeneration. PMID- 29496860 TI - Nature's strategies: Stealing genes to survive. PMID- 29496861 TI - Bending to the water's will. PMID- 29496862 TI - Nature's strategies: Squirrels with a rainy day fund. PMID- 29496863 TI - Nature's strategies: A plant that stands and fights. PMID- 29496864 TI - Seeking resilience in marine ecosystems. PMID- 29496865 TI - What makes a terrestrial ecosystem resilient? PMID- 29496866 TI - Engineering a designer immunotherapy. PMID- 29496867 TI - pHirst sour taste channels pHound? PMID- 29496868 TI - Microbial warfare against viruses. PMID- 29496869 TI - Early plants and the rise of mud. PMID- 29496870 TI - Fermi arcs connect topological degeneracies. PMID- 29496871 TI - Linking climate policies to advance global mitigation. PMID- 29496872 TI - Agricultural policy can reduce wildfires. PMID- 29496873 TI - Rethinking wildfires and forest watersheds. PMID- 29496874 TI - Invest long term in Canada's wilderness. PMID- 29496875 TI - Selective formation of gamma-lactams via C-H amidation enabled by tailored iridium catalysts. AB - Intramolecular insertion of metal nitrenes into carbon-hydrogen bonds to form gamma-lactam rings has traditionally been hindered by competing isocyanate formation. We report the application of theory and mechanism studies to optimize a class of pentamethylcyclopentadienyl iridium(III) catalysts for suppression of this competing pathway. Modulation of the stereoelectronic properties of the auxiliary bidentate ligands to be more electron-donating was suggested by density functional theory calculations to lower the C-H insertion barrier favoring the desired reaction. These catalysts transform a wide range of 1,4,2-dioxazol-5 ones, carbonylnitrene precursors easily accessible from carboxylic acids, into the corresponding gamma-lactams via sp3 and sp2 C-H amidation with exceptional selectivity. The power of this method was further demonstrated by the successful late-stage functionalization of amino acid derivatives and other bioactive molecules. PMID- 29496876 TI - Evolution of alluvial mudrock forced by early land plants. AB - Mudrocks are a primary archive of Earth's history from the Archean eon to recent times, and their source-to-sink production and deposition play a central role in long-term ocean chemistry and climate regulation. Using original and published stratigraphic data from all 704 of Earth's known alluvial formations from the Archean eon (3.5 billion years ago) to the Carboniferous period (0.3 billion years ago), we prove contentions of an upsurge in the proportion of mud retained on land coeval with vegetation evolution. We constrain the onset of the upsurge to the Ordovician-Silurian and show that alluvium deposited after land plant evolution contains a proportion of mudrock that is, on average, 1.4 orders of magnitude greater than the proportion contained in alluvium from the preceding 90% of Earth's history. We attribute this shift to the ways in which vegetation revolutionized mud production and sediment flux from continental interiors. PMID- 29496877 TI - Evidence for a neural law of effect. AB - Thorndike's law of effect states that actions that lead to reinforcements tend to be repeated more often. Accordingly, neural activity patterns leading to reinforcement are also reentered more frequently. Reinforcement relies on dopaminergic activity in the ventral tegmental area (VTA), and animals shape their behavior to receive dopaminergic stimulation. Seeking evidence for a neural law of effect, we found that mice learn to reenter more frequently motor cortical activity patterns that trigger optogenetic VTA self-stimulation. Learning was accompanied by gradual shaping of these patterns, with participating neurons progressively increasing and aligning their covariance to that of the target pattern. Motor cortex patterns that lead to phasic dopaminergic VTA activity are progressively reinforced and shaped, suggesting a mechanism by which animals select and shape actions to reliably achieve reinforcement. PMID- 29496878 TI - Incomplete host immunity favors the evolution of virulence in an emergent pathogen. AB - Immune memory evolved to protect hosts from reinfection, but incomplete responses that allow future reinfection may inadvertently select for more-harmful pathogens. We present empirical and modeling evidence that incomplete immunity promotes the evolution of higher virulence in a natural host-pathogen system. We performed sequential infections of house finches with Mycoplasma gallisepticum strains of various levels of virulence. Virulent bacterial strains generated stronger host protection against reinfection than less virulent strains and thus excluded less virulent strains from infecting previously exposed hosts. In a two strain model, the resulting fitness advantage selected for an almost twofold increase in pathogen virulence. Thus, the same immune systems that protect hosts from infection can concomitantly drive the evolution of more-harmful pathogens in nature. PMID- 29496880 TI - Accurate computational design of multipass transmembrane proteins. AB - The computational design of transmembrane proteins with more than one membrane spanning region remains a major challenge. We report the design of transmembrane monomers, homodimers, trimers, and tetramers with 76 to 215 residue subunits containing two to four membrane-spanning regions and up to 860 total residues that adopt the target oligomerization state in detergent solution. The designed proteins localize to the plasma membrane in bacteria and in mammalian cells, and magnetic tweezer unfolding experiments in the membrane indicate that they are very stable. Crystal structures of the designed dimer and tetramer-a rocket shaped structure with a wide cytoplasmic base that funnels into eight transmembrane helices-are very close to the design models. Our results pave the way for the design of multispan membrane proteins with new functions. PMID- 29496879 TI - Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptor complexes. AB - Interleukin-2 (IL-2) is a cytokine required for effector T cell expansion, survival, and function, especially for engineered T cells in adoptive cell immunotherapy, but its pleiotropy leads to simultaneous stimulation and suppression of immune responses as well as systemic toxicity, limiting its therapeutic use. We engineered IL-2 cytokine-receptor orthogonal (ortho) pairs that interact with one another, transmitting native IL-2 signals, but do not interact with their natural cytokine and receptor counterparts. Introduction of orthoIL-2Rbeta into T cells enabled the selective cellular targeting of orthoIL-2 to engineered CD4+ and CD8+ T cells in vitro and in vivo, with limited off-target effects and negligible toxicity. OrthoIL-2 pairs were efficacious in a preclinical mouse cancer model of adoptive cell therapy and may therefore represent a synthetic approach to achieving selective potentiation of engineered cells. PMID- 29496882 TI - My year as a fed. PMID- 29496881 TI - beta2-adrenergic receptor-mediated negative regulation of group 2 innate lymphoid cell responses. AB - The type 2 inflammatory response is induced by various environmental and infectious stimuli. Although recent studies identified group 2 innate lymphoid cells (ILC2s) as potent sources of type 2 cytokines, the molecular pathways controlling ILC2 responses are incompletely defined. Here we demonstrate that murine ILC2s express the beta2-adrenergic receptor (beta2AR) and colocalize with adrenergic neurons in the intestine. beta2AR deficiency resulted in exaggerated ILC2 responses and type 2 inflammation in intestinal and lung tissues. Conversely, beta2AR agonist treatment was associated with impaired ILC2 responses and reduced inflammation in vivo. Mechanistically, we demonstrate that the beta2AR pathway is a cell-intrinsic negative regulator of ILC2 responses through inhibition of cell proliferation and effector function. Collectively, these data provide the first evidence of a neuronal-derived regulatory circuit that limits ILC2-dependent type 2 inflammation. PMID- 29496883 TI - Subcellular Compartmentation of Alternatively Spliced Transcripts Defines SERINE/ARGININE-RICH PROTEIN30 Expression. AB - Alternative splicing (AS) is prevalent in higher eukaryotes, and generation of different AS variants is tightly regulated. Widespread AS occurs in response to altered light conditions and plays a critical role in seedling photomorphogenesis, but despite its frequency and effect on plant development, the functional role of AS remains unknown for most splicing variants. Here, we characterized the light-dependent AS variants of the gene encoding the splicing regulator Ser/Arg-rich protein SR30 in Arabidopsis (Arabidopsis thaliana). We demonstrated that the splicing variant SR30.2, which is predominantly produced in darkness, is enriched within the nucleus and strongly depleted from ribosomes. Light-induced AS from a downstream 3' splice site gives rise to SR30.1, which is exported to the cytosol and translated, coinciding with SR30 protein accumulation upon seedling illumination. Constitutive expression of SR30.1 and SR30.2 fused to fluorescent proteins revealed their identical subcellular localization in the nucleoplasm and nuclear speckles. Furthermore, expression of either variant shifted splicing of a genomic SR30 reporter toward SR30.2, suggesting that an autoregulatory feedback loop affects SR30 splicing. We provide evidence that SR30.2 can be further spliced and, unlike SR30.2, the resulting cassette exon variant SR30.3 is sensitive to nonsense-mediated decay. Our work delivers insight into the complex and compartmentalized RNA processing mechanisms that control the expression of the splicing regulator SR30 in a light-dependent manner. PMID- 29496884 TI - Jasmonate Negatively Regulates Stomatal Development in Arabidopsis Cotyledons. AB - Stomata are ports that facilitate gas and water vapor exchange between plants and their environment. Stomatal development is strictly regulated by endogenous signals and environmental cues. Jasmonate is an important signal that modulates multiple physiological processes in plants, yet the molecular mechanisms underlying its interactions with other developmental signaling pathways remain poorly understood. Here, we show that jasmonate negatively regulates stomatal development in Arabidopsis (Arabidopsis thaliana) cotyledons. Cotyledons of the wild type and stomata-overproliferating mutants (such as too many mouths-1 and stomatal density and distribution1-1) treated with methyl jasmonate exhibit a clear reduction in stomata number. By contrast, blocking endogenous jasmonate biosynthesis or perception enhanced stomatal development. Moreover, three MYC transcription factors involved in jasmonate signaling, MYC2, MYC3, and MYC4, were found to redundantly modulate jasmonate-inhibited stomatal development. A genetic analysis showed that these MYC proteins act upstream of the SPEECHLESS and FAMA transcription factors to mediate stomatal development. Furthermore, jasmonate repression of stomatal development is dependent on these three MYC transcription factors, as stomatal development of the myc2 myc3 myc4 triple mutant was insensitive to methyl jasmonate treatment. Collectively, our study demonstrates that jasmonate and MYC transcription factors negatively regulate stomatal development in Arabidopsis cotyledons. PMID- 29496886 TI - Statin-related myopathies. AB - Statins are the Marmite ('You either love it or hate it!') of the drug world, both in terms of therapeutic benefit and risk of side effects. Proponents think that they are potential life-savers, opponents that their main benefit is lining the pockets of pharma. Some consider side effects to be a major issue, outweighing any therapeutic benefit, others that they are rare and essentially innocuous. Statin-induced myalgia is relatively common but often mild and for most people does not limit treatment. In others, reducing the dose or changing the preparation may help. In all, withdrawal of the statin leads to resolution. Statin-induced rhabdomyolysis, most often precipitated by drug-drug interaction, affects only a tiny proportion of statin users, but because of the widespread prescribing of statins is an important clinical problem. Statin-induced immune mediated necrotising myopathy represents a novel disease mechanism and clinically mimics forms of myositis. Resolution often requires immunosuppressant drug treatment, as well as statin withdrawal. PMID- 29496885 TI - Photoperiodic control of the Arabidopsis proteome reveals a translational coincidence mechanism. AB - Plants respond to seasonal cues such as the photoperiod, to adapt to current conditions and to prepare for environmental changes in the season to come. To assess photoperiodic responses at the protein level, we quantified the proteome of the model plant Arabidopsis thaliana by mass spectrometry across four photoperiods. This revealed coordinated changes of abundance in proteins of photosynthesis, primary and secondary metabolism, including pigment biosynthesis, consistent with higher metabolic activity in long photoperiods. Higher translation rates in the day than the night likely contribute to these changes, via an interaction with rhythmic changes in RNA abundance. Photoperiodic control of protein levels might be greatest only if high translation rates coincide with high transcript levels in some photoperiods. We term this proposed mechanism "translational coincidence", mathematically model its components, and demonstrate its effect on the Arabidopsis proteome. Datasets from a green alga and a cyanobacterium suggest that translational coincidence contributes to seasonal control of the proteome in many phototrophic organisms. This may explain why many transcripts but not their cognate proteins exhibit diurnal rhythms. PMID- 29496887 TI - The Real Yield Deal? Nitrate Transporter Expression Boosts Yield and Accelerates Maturation. PMID- 29496888 TI - Hemodialysis Induces an Acute Decline in Cerebral Blood Flow in Elderly Patients. AB - The initiation of hemodialysis is associated with an accelerated decline of cognitive function and an increased incidence of cerebrovascular accidents and white matter lesions. Investigators have hypothesized that the repetitive circulatory stress of hemodialysis induces ischemic cerebral injury, but the mechanism is unclear. We studied the acute effect of conventional hemodialysis on cerebral blood flow (CBF), measured by [15O]H2O positron emission tomography computed tomography (PET-CT). During a single hemodialysis session, three [15O]H2O PET-CT scans were performed: before, early after the start of, and at the end of hemodialysis. We used linear mixed models to study global and regional CBF change during hemodialysis. Twelve patients aged >=65 years (five women, seven men), with a median dialysis vintage of 46 months, completed the study. Mean (+/-SD) arterial BP declined from 101+/-11 mm Hg before hemodialysis to 93+/ 17 mm Hg at the end of hemodialysis. From before the start to the end of hemodialysis, global CBF declined significantly by 10%+/-15%, from a mean of 34.5 to 30.5 ml/100g per minute (difference, -4.1 ml/100 g per minute; 95% confidence interval, -7.3 to -0.9 ml/100 g per minute; P=0.03). CBF decline (20%) was symptomatic in one patient. Regional CBF declined in all volumes of interest, including the frontal, parietal, temporal, and occipital lobes; cerebellum; and thalamus. Higher tympanic temperature, ultrafiltration volume, ultrafiltration rate, and pH significantly associated with lower CBF. Thus, conventional hemodialysis induces a significant reduction in global and regional CBF in elderly patients. Repetitive intradialytic decreases in CBF may be one mechanism by which hemodialysis induces cerebral ischemic injury. PMID- 29496889 TI - Filtering the Evidence: Is There a Cognitive Cost of Hemodialysis? PMID- 29496891 TI - Development of the Mechanisms Governing Midbrain Multisensory Integration. AB - The ability to integrate information across multiple senses enhances the brain's ability to detect, localize, and identify external events. This process has been well documented in single neurons in the superior colliculus (SC), which synthesize concordant combinations of visual, auditory, and/or somatosensory signals to enhance the vigor of their responses. This increases the physiological salience of crossmodal events and, in turn, the speed and accuracy of SC-mediated behavioral responses to them. However, this capability is not an innate feature of the circuit and only develops postnatally after the animal acquires sufficient experience with covariant crossmodal events to form links between their modality specific components. Of critical importance in this process are tectopetal influences from association cortex. Recent findings suggest that, despite its intuitive appeal, a simple generic associative rule cannot explain how this circuit develops its ability to integrate those crossmodal inputs to produce enhanced multisensory responses. The present neurocomputational model explains how this development can be understood as a transition from a default state in which crossmodal SC inputs interact competitively to one in which they interact cooperatively. Crucial to this transition is the operation of a learning rule requiring coactivation among tectopetal afferents for engagement. The model successfully replicates findings of multisensory development in normal cats and cats of either sex reared with special experience. In doing so, it explains how the cortico-SC projections can use crossmodal experience to craft the multisensory integration capabilities of the SC and adapt them to the environment in which they will be used.SIGNIFICANCE STATEMENT The brain's remarkable ability to integrate information across the senses is not present at birth, but typically develops in early life as experience with crossmodal cues is acquired. Recent empirical findings suggest that the mechanisms supporting this development must be more complex than previously believed. The present work integrates these data with what is already known about the underlying circuit in the midbrain to create and test a mechanistic model of multisensory development. This model represents a novel and comprehensive framework that explains how midbrain circuits acquire multisensory experience and reveals how disruptions in this neurotypic developmental trajectory yield divergent outcomes that will affect the multisensory processing capabilities of the mature brain. PMID- 29496892 TI - Renal Remission Status and Longterm Renal Survival in Patients with Lupus Nephritis: A Retrospective Cohort Analysis. AB - OBJECTIVE: This observational study was a retrospective analysis of prospectively collected Hopkins Lupus Cohort data to compare longterm renal survival in patients with lupus nephritis (LN) who achieved complete (CR), partial (PR), or no remission following standard-of-care LN induction therapy. METHODS: Eligible patients with biopsy-proven LN (revised American College of Rheumatology or Systemic Lupus Collaborating Clinics criteria) were identified and categorized into ordinal (CR, PR, or no remission) or binary (response or no response) renal remission categories at 24 months post-diagnosis [modified Aspreva Lupus Management Study (mALMS) and modified Belimumab International Lupus Nephritis Study (mBLISS-LN) criteria]. The primary endpoint was longterm renal survival [without endstage renal disease (ESRD) or death]. RESULTS: In total, 176 patients met the inclusion criteria. At Month 24 postbiopsy, more patients met mALMS remission criteria (CR = 59.1%, PR = 30.1%) than mBLISS-LN criteria (CR = 40.9%, PR = 16.5%). During subsequent followup, 18 patients developed ESRD or died. Kaplan-Meier plots suggested patients with no remission at Month 24 were more likely than those with PR or CR to develop the outcome using either mALMS (p = 0.0038) and mBLISS-LN (p = 0.0097) criteria for remission. Based on Cox regression models adjusted for key confounders, those in CR according to the mBLISS-LN (HR 0.254, 95% CI 0.082-0.787; p = 0.0176) and mALMS criteria (HR 0.228, 95% CI 0.063-0.828; p = 0.0246) were significantly less likely to experience ESRD/mortality than those not in remission. CONCLUSION: Renal remission status at 24 months following LN diagnosis is a significant predictor of longterm renal survival, and a clinically relevant endpoint. PMID- 29496893 TI - One-year Predictors of Presenteeism in Workers with Rheumatoid Arthritis: Disease related Factors and Characteristics of General Health and Work. AB - OBJECTIVE: Rheumatoid arthritis (RA) affects adults of working age and leads to productivity losses because of presenteeism that results from limitations while at work. The aim of our study was to gain insight into disease-related factors, general health, and work characteristics as predictors of presenteeism in workers with RA. METHODS: Workers with RA (n = 150) recruited by rheumatologists completed questionnaires at baseline and after 1 year. Medical information was retrieved from patient records. Presenteeism was measured by the Work Limitations Questionnaire. Disease [28-joint Disease Activity Score (DAS28), Health Assessment Questionnaire (HAQ), pain, fatigue], general health (mental, physical, deterioration of health), and work characteristics (work instability, social support, workload) were assessed as predictors of presenteeism after 1 year using linear regression analyses. RESULTS: Presenteeism was 4.0 h over a 2-week period based on an average work week of 28.7 hours. More RA-related disability (HAQ; B = -1.20, 95% CI -2.12 to -0.28), poorer mental health (B = -0.04, 95% CI -0.08 to 0.01), and health deterioration over a 1-year period (B: -0.02, 95% CI -0.04 to 0.01) were associated with more presenteeism. Work characteristics were not associated with presenteeism. CONCLUSION: Disease-related factors and general health characteristics were significantly associated with presenteeism at 1-year followup, although the effects of the general health characteristics were considered not to be relevant. To reduce presenteeism and improve functioning at work, it is important to pay attention to reducing RA-related disability in addition to reducing disease activity. A broader perspective is needed and should also take into account the level of RA-related disability. PMID- 29496894 TI - Is healthy children surveillance being duplicated by family physicians and paediatricians? A cross-sectional study in Portugal. AB - OBJECTIVES: To determine if children attend the family physician (FP) or the FP/paediatrician for their surveillance medical appointments, as well as analyse the variables associated with the parents' choice between the two physicians. DESIGN: Cross-sectional study. SETTING: Public, semiprivate and private kindergartens in the city of Vila Nova de Famalicao (Portugal). PARTICIPANTS: Parents of children aged 6 years or less without chronic diseases, enrolled in the selected kindergartens. MAIN OUTCOME MEASURES: Proportion of children attending the FP or FP/paediatrician for their surveillance appointments; association between the chosen physician and sociodemographic and household variables (parents' age, educational level, professional situation and marital status; household net income; number of children; the child's age; presence of private health insurance), assessment of the parents' perception of clinical knowledge and accessibility regarding the FP and the paediatrician. RESULTS: A total of 697 children were included in the analysis: 30.6% attended only the FP and 69.4% attended both the FP and the paediatrician. Using a Poisson regression, the mother's age (PR=1.02, 95% CI 1.00 to 1.03), higher educational level (prevalence ratio (PR=1.15, 95% CI 1.00 to 1.33), private health insurance (PR=1.30, 95% CI 1.15 to 1.46), number of children (PR=0.86, 95% CI 0.78 to 0.94) and the child's age (PR=0.95, 95% CI 0.91 to 0.98) were statistically associated with attending both the FP and the paediatrician; parents of children who attended only FP rated the FP with a higher accessibility and knowledge mean score than those who consulted both physicians (2.91vs2.38, P<0.001, and 4.11vs3.85, P<0.001). CONCLUSIONS: Our data show that 70% of our sample simultaneously attended an FP and a paediatrician. FPs are equally qualified to provide medical care to healthy children but this information is not properly transmitted to the general population. PMID- 29496896 TI - Prospective registration trends, reasons for retrospective registration and mechanisms to increase prospective registration compliance: descriptive analysis and survey. AB - OBJECTIVES: To analyse prospective versus retrospective trial registration trends on the Australian New Zealand Clinical Trials Registry (ANZCTR) and to evaluate the reasons for non-compliance with prospective registration. DESIGN: Part 1: Descriptive analysis of trial registration trends from 2006 to 2015. Part 2: Online registrant survey. PARTICIPANTS: Part 1: All interventional trials registered on ANZCTR from 2006 to 2015. Part 2: Random sample of those who had retrospectively registered a trial on ANZCTR between 2010 and 2015. MAIN OUTCOME MEASURES: Part 1: Proportion of prospective versus retrospective clinical trial registrations (ie, registration before versus after enrolment of the first participant) on the ANZCTR overall and by various key metrics, such as sponsor, funder, recruitment country and sample size. Part 2: Reasons for non-compliance with prospective registration and perceived usefulness of various proposed mechanisms to improve prospective registration compliance. RESULTS: Part 1: Analysis of the complete dataset of 9450 trials revealed that compliance with prospective registration increased from 48% (216 out of 446 trials) in 2006 to 63% (723/1148) in 2012 and has since plateaued at around 64%. Patterns of compliance were relatively consistent across sponsor and funder types (industry vs non-industry), type of intervention (drug vs non-drug) and size of trial (n<100, 100-500, >500). However, primary sponsors from Australia/New Zealand were almost twice as likely to register prospectively (62%; 4613/7452) compared with sponsors from other countries with a WHO Network Registry (35%; 377/1084) or sponsors from countries without a WHO Registry (29%; 230/781). Part 2: The majority (56%; 84/149) of survey respondents cited lack of awareness as a reason for not registering their study prospectively. Seventy-four per cent (111/149) stated that linking registration to ethics approval would facilitate prospective registration. CONCLUSIONS: Despite some progress, compliance with prospective registration remains suboptimal. Linking registration to ethics approval was the favoured strategy among those sampled for improving compliance. PMID- 29496895 TI - Prevalence of frailty and prefrailty among community-dwelling older adults in low income and middle-income countries: a systematic review and meta-analysis. AB - OBJECTIVE: To systematically review the research conducted on prevalence of frailty and prefrailty among community-dwelling older adults in low-income and middle-income countries (LMICs) and to estimate the pooled prevalence of frailty and prefrailty in community-dwelling older adults in LMICs. DESIGN: Systematic review and meta-analysis. PROSPERO registration number is CRD42016036083. DATA SOURCES: MEDLINE, EMBASE, AMED, Web of Science, CINAHL and WHO Global Health Library were searched from their inception to 12 September 2017. SETTING: Low income and middle-income countries. PARTICIPANTS: Community-dwelling older adults aged >=60 years. RESULTS: We screened 7057 citations and 56 studies were included. Forty-seven and 42 studies were included in the frailty and prefrailty meta-analysis, respectively. The majority of studies were from upper middle income countries. One study was available from low-income countries. The prevalence of frailty varied from 3.9% (China) to 51.4% (Cuba) and prevalence of prefrailty ranged from 13.4% (Tanzania) to 71.6% (Brazil). The pooled prevalence of frailty was 17.4% (95% CI 14.4% to 20.7%, I2=99.2%) and prefrailty was 49.3% (95% CI 46.4% to 52.2%, I2=97.5%). The wide variation in prevalence rates across studies was largely explained by differences in frailty assessment method and the geographic region. These findings are for the studies with a minimum recruitment age 60, 65 and 70 years. CONCLUSION: The prevalence of frailty and prefrailty appears higher in community-dwelling older adults in upper middle-income countries compared with high-income countries, which has important implications for healthcare planning. There is limited evidence on frailty prevalence in lower middle-income and low-income countries. PROSPERO REGISTRATION NUMBER: CRD42016036083. PMID- 29496899 TI - Role of the EDA-fibronectin splice variant in fibrosis. PMID- 29496897 TI - Audit of HIV counselling and testing services among primary healthcare facilities in Cameroon: a protocol for a multicentre national cross-sectional study. AB - INTRODUCTION: HIV testing is an invaluable entry point to prevention, care and treatment services for people living with HIV and AIDS. Poor adherence to recommended protocols and guidelines reduces the performance of rapid diagnostic tests, leading to misdiagnosis and poor estimation of HIV seroprevalence. This study seeks to evaluate the adherence of primary healthcare facilities in Cameroon to recommended HIV counselling and testing (HCT) procedures and the impact this may have on the reliability of HIV test results. METHODS AND ANALYSIS: This will be an analytical cross-sectional study involving primary healthcare facilities from all the 10 regions of Cameroon, selected by a multistaged random sampling of primary care facilities in each region. The study will last for 9 months. A structured questionnaire will be used to collect general information concerning the health facility, laboratory and other departments involved in the HCT process. The investigators will directly observe at least 10 HIV testing processes in each facility and fill out the checklist accordingly. ETHICS AND DISSEMINATION: Clearance has been obtained from the National Ethical Committee to carry out the study. Informed consent will be sought from the patients to observe the HIV testing process. The final study will be published in a peer-reviewed journal and the findings presented to health policy-makers and the general public. PMID- 29496898 TI - Meeting Report - proteostasis in Ericeira. AB - It was a sunny Ericeira, in Portugal, that received the participants of the EMBO Workshop on Proteostasis, from 17 to 21 November 2017. Most participants gave talks or presented posters concerning their most recent research results, and lively scientific discussions occurred against the backdrop of the beautiful Atlantic Ocean.Proteostasis is the portmanteau of the words protein and homeostasis, and it refers to the biological mechanisms controlling the biogenesis, folding, trafficking and degradation of proteins in cells. An imbalance in proteostasis can lead to the accumulation of misfolded proteins or excessive protein degradation, and is associated with many human diseases. A wide variety of research approaches are used to identify the mechanisms that regulate proteostasis, typically involving different model organisms (yeast, invertebrates or mammalian systems) and different methodologies (genetics, biochemistry, biophysics, structural biology, cell biology and organismal biology). Around 140 researchers in the proteostasis field met in the Hotel Vila Gale, Ericeira, Portugal for the EMBO Workshop in Proteostasis, organized by Pedro Domingos (ITQB NOVA, Oeiras, Portugal) and Colin Adrain (IGC, Oeiras, Portugal). In this report, we attempt to review and integrate the ideas that emerged at the workshop. Owing to space restrictions, we could not cover all talks or posters and we apologize to the colleagues whose presentations could not be discussed. PMID- 29496900 TI - Is bioprosthetic leaflet thrombosis a trigger to valve degeneration? PMID- 29496901 TI - Evaluation of human coronary vasodilator function predicts future coronary atheroma progression. AB - OBJECTIVE: Coronary vasodilator function and atherosclerotic plaque progression have both been shown to be associated with adverse cardiovascular events. However, the relationship between these factors and the lipid burden of coronary plaque remains unknown. These experiments focus on investigating the relationship between impaired coronary vasodilator function (endothelium dependent (salbutamol) and endothelium independent (glyceryl trinitrate)) and the natural history of atheroma plaque progression and lipid burden using dual modality intravascular ultrasound (IVUS) and near-infrared spectroscopy (NIRS) imaging. METHODS: 33 patients with stable chest pain or acute coronary syndrome underwent serial assessment of coronary vasodilator function and intracoronary plaque IVUS and NIRS imaging. Coronary segmental macrovascular response (% change segmental lumen volume (DeltaSLV)), plaque burden (per cent atheroma volume (PAV)), lipid core (lipid-rich plaque (LRP) and lipid core burden index (LCBI)) were measured at baseline and after an interval of 12-18 months (n=520 segments). RESULTS: Lipid-negative coronary segments which develop into LRP over the study time period demonstrated impaired endothelial-dependent function (-0.24+/-2.96 vs 5.60+/-1.47%, P=0.04) and endothelial-independent function (13.91+/-4.45 vs 21.19+/-3.19%, P=0.036), at baseline. By multivariate analysis, endothelial dependent function predicted ?LCBI (beta coefficient: -3.03, 95% CI (-5.81 to 0.25), P=0.033) whereas endothelial-independent function predicted ?PAV (beta coefficient: 0.07, 95% CI (0.04 to 0.10), P<0.0001). CONCLUSIONS: Epicardial coronary vasodilator function is a determinant of future atheroma progression and composition irrespective of the nature of clinical presentation. TRIAL REGISTRATION NUMBER: ACTRN12612000594820, Post-results. PMID- 29496902 TI - Chronic total occlusion percutaneous coronary intervention in clinical practice: novel grounds to be EXPLOREd. PMID- 29496890 TI - Neuroimmune Axes of the Blood-Brain Barriers and Blood-Brain Interfaces: Bases for Physiological Regulation, Disease States, and Pharmacological Interventions. AB - Central nervous system (CNS) barriers predominantly mediate the immune-privileged status of the brain, and are also important regulators of neuroimmune communication. It is increasingly appreciated that communication between the brain and immune system contributes to physiologic processes, adaptive responses, and disease states. In this review, we discuss the highly specialized features of brain barriers that regulate neuroimmune communication in health and disease. In section I, we discuss the concept of immune privilege, provide working definitions of brain barriers, and outline the historical work that contributed to the understanding of CNS barrier functions. In section II, we discuss the unique anatomic, cellular, and molecular characteristics of the vascular blood brain barrier (BBB), blood-cerebrospinal fluid barrier, and tanycytic barriers that confer their functions as neuroimmune interfaces. In section III, we consider BBB-mediated neuroimmune functions and interactions categorized as five neuroimmune axes: disruption, responses to immune stimuli, uptake and transport of immunoactive substances, immune cell trafficking, and secretions of immunoactive substances. In section IV, we discuss neuroimmune functions of CNS barriers in physiologic and disease states, as well as pharmacological interventions for CNS diseases. Throughout this review, we highlight many recent advances that have contributed to the modern understanding of CNS barriers and their interface functions. PMID- 29496903 TI - Youth Gun Violence Prevention in a Digital Age. PMID- 29496904 TI - Hypothyroidism and Iodine Deficiency in Children on Chronic Parenteral Nutrition. AB - BACKGROUND AND OBJECTIVES: Iodine is an essential trace element for maintenance of normal thyroid function. Normal thyroid function is a prerequisite for neurocognitive development and growth in children. In the United States, iodine is not routinely added as a trace element in parenteral nutrition (PN). Our objective was to determine the prevalence of iodine deficiency and hypothyroidism in children on chronic PN. METHODS: This was a cross-sectional study of children <17 years of age and using PN for >6 months at a tertiary children's hospital. Primary outcomes were spot urine iodine concentration (UIC), serum thyrotropin, and free thyroxine levels. RESULTS: Twenty-seven patients were identified (74% male). The median age at screening was 48 months (range: 7-213 months). The median duration on PN was 27 months (range: 11-77 months). Seventeen out of 20 patients (85%) were iodine deficient (spot UIC <100 MUg/L), whereas 11 out of 20 patients (55%) were severely iodine deficient (spot UIC <20 MUg/L). The prevalence of acquired hypothyroidism (elevated thyrotropin, low free thyroxine, and UIC <100 MUg/L) was 33% (n = 8). None of the children with hypothyroidism screened for autoimmune thyroiditis had positive test results. There was no statistically significant association between duration of PN use and development of iodine deficiency (P = .08) or hypothyroidism (P = .96). CONCLUSIONS: Children on chronic PN are at risk for developing iodine deficiency and resultant hypothyroidism; hence, these children should be screened for these outcomes. Further studies are needed to define the temporal onset of iodine deficiency and timing to thyroid dysfunction related to PN. PMID- 29496905 TI - Control of hyperglycemia in male mice by leflunomide: mechanisms of action. AB - p70 S6 kinase (S6K1) is a serine/threonine kinase that phosphorylates the insulin receptor substrate-1 (IRS-1) at serine 1101 and desensitizes insulin receptor signaling. S6K1 hyperactivation due to overnutrition leads to hyperglycemia and type 2 diabetes. Our recent study showed that A77 1726, the active metabolite of the anti-rheumatoid arthritis (RA) drug leflunomide, is an inhibitor of S6K1. Whether leflunomide can control hyperglycemia and sensitize the insulin receptor has not been tested. Here we report that A77 1726 increased AKTS473/T308 and S6K1T389 phosphorylation but decreased S6S235/236 and IRS-1S1101 phosphorylation in 3T3-L1 adipocytes, C2C12 and L6 myotubes. A77 1726 increased insulin receptor tyrosine phosphorylation and binding of the p85 subunit of the PI-3 kinase to IRS 1. A77 1726 enhanced insulin-stimulated glucose uptake in L6 myotubes and 3T3-L1 adipocytes, and enhanced insulin-stimulated glucose transporter type 4 (GLUT4) translocation to the plasma membrane of L6 cells. Finally, we investigated the anti-hyperglycemic effect of leflunomide on ob/ob and high-fat diet (HFD)-induced diabetes mouse models. Leflunomide treatment normalized blood glucose levels and overcame insulin resistance in glucose and insulin tolerance tests in ob/ob and HFD-fed mice but had no effect on mice fed a normal chow diet (NCD). Leflunomide treatment increased AKTS473/T308 phosphorylation in the fat and muscle of ob/ob mice but not in normal mice. Our results suggest that leflunomide sensitizes the insulin receptor by inhibiting S6K1 activity in vitro, and that leflunomide could be potentially useful for treating patients with both RA and diabetes. PMID- 29496906 TI - Comprehensive Redox Profiling of the Thiol Proteome of Clostridium difficile. AB - The strictly anaerobic bacterium C. difficile has become one of the most problematic hospital acquired pathogens and a major burden for health care systems. Although antibiotics work effectively in most C. difficile infections (CDIs), their detrimental effect on the intestinal microbiome paves the way for recurrent episodes of CDI. To develop alternative, non-antibiotics-based treatment strategies, deeper knowledge on the physiology of C. difficile, stress adaptation mechanisms and regulation of virulence factors is mandatory. The focus of this work was to tackle the thiol proteome of C. difficile and its stress induced alterations, because recent research has reported that the amino acid cysteine plays a central role in the metabolism of this pathogen. We have developed a novel cysteine labeling approach to determine the redox state of protein thiols on a global scale. Applicability of this technique was demonstrated by inducing disulfide stress using the chemical diamide. The method can be transferred to any kind of redox challenge and was applied in this work to assess the effect of bile acids on the thiol proteome of C. difficile We present redox-quantification for more than 1,500 thiol peptides and discuss the general difficulty of redox analyses of peptides possessing more than a single cysteine residue. The presented method will be especially useful not only when determining redox status, but also for providing information on protein quantity. Additionally, our comprehensive data set reveals protein cysteine sites particularly susceptible to oxidation and builds a groundwork for redox proteomics studies in C. difficile. PMID- 29496909 TI - Probing the causes of cleft lip. PMID- 29496910 TI - Editorial focus on the current MCP Mission Statement and Scope. PMID- 29496907 TI - Phosphoproteomics Analysis Identifies Novel Candidate Substrates of the Nonreceptor Tyrosine Kinase, Src-related Kinase Lacking C-terminal Regulatory Tyrosine and N-terminal Myristoylation Sites (SRMS). AB - SRMS (Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristoylation sites), also known as PTK 70 (Protein tyrosine kinase 70), is a non-receptor tyrosine kinase that belongs to the BRK family of kinases (BFKs). To date less is known about the cellular role of SRMS primarily because of the unidentified substrates or signaling intermediates regulated by the kinase. In this study, we used phosphotyrosine antibody-based immunoaffinity purification in large-scale label-free quantitative phosphoproteomics to identify novel candidate substrates of SRMS. Our analyses led to the identification of 1258 tyrosine phosphorylated peptides which mapped to 663 phosphoproteins, exclusively from SRMS-expressing cells. DOK1, a previously characterized SRMS substrate, was also identified in our analyses. Functional enrichment analyses revealed that the candidate SRMS substrates were enriched in various biological processes including protein ubiquitination, mitotic cell cycle, energy metabolism and RNA processing, as well as Wnt and TNF signaling. Analyses of the sequence surrounding the phospho-sites in these proteins revealed novel candidate SRMS consensus substrate motifs. We utilized customized high-throughput peptide arrays to validate a subset of the candidate SRMS substrates identified in our MS-based analyses. Finally, we independently validated Vimentin and Sam68, as bona fide SRMS substrates through in vitro and in vivo assays. Overall, our study identified a number of novel and biologically relevant SRMS candidate substrates, which suggests the involvement of the kinase in a vast array of unexplored cellular functions. PMID- 29496911 TI - Announcing New Editorial Leadership in Clinical Proteomics and Biomarker Discovery. PMID- 29496908 TI - Quantitative Phosphoproteomic and Metabolomic Analyses Reveal GmMYB173 Optimizes Flavonoid Metabolism in Soybean under Salt Stress. AB - Salinity causes osmotic stress to crops and limits their productivity. To understand the mechanism underlying soybean salt tolerance, proteomics approach was used to identify phosphoproteins altered by NaCl treatment. Results revealed that 412 of the 4698 quantitatively analyzed phosphopeptides were significantly up-regulated on salt treatment, including a phosphopeptide covering the serine 59 in the transcription factor GmMYB173. Our data showed that GmMYB173 is one of the three MYB proteins differentially phosphorylated on salt treatment, and a substrate of the casein kinase-II. MYB recognition sites exist in the promoter of flavonoid synthase gene GmCHS5 and one was found to mediate its recognition by GmMYB173, an event facilitated by phosphorylation. Because GmCHS5 catalyzes the synthesis of chalcone, flavonoids derived from chalcone were monitored using metabolomics approach. Results revealed that 24 flavonoids of 6745 metabolites were significantly up-regulated after salt treatment. We further compared the salt tolerance and flavonoid accumulation in soybean transgenic roots expressing the 35S promoter driven cds and RNAi constructs of GmMYB173 and GmCHS5, as well as phospho-mimic (GmMYB173S59D ) and phospho-ablative (GmMYB173S59A ) mutants of GmMYB173 Overexpression of GmMYB173S59D and GmCHS5 resulted in the highest increase in salt tolerance and accumulation of cyaniding-3-arabinoside chloride, a dihydroxy B-ring flavonoid. The dihydroxy B-ring flavonoids are more effective as anti-oxidative agents when compared with monohydroxy B-ring flavonoids, such as formononetin. Hence the salt-triggered phosphorylation of GmMYB173, subsequent increase in its affinity to GmCHS5 promoter and the elevated transcription of GmCHS5 likely contribute to soybean salt tolerance by enhancing the accumulation of dihydroxy B-ring flavonoids. PMID- 29496912 TI - Extended linkers improve the detection of protein-protein interactions (PPIs) by dihydrofolate reductase protein-fragment complementation assay (DHFR PCA) in living cells. PMID- 29496913 TI - Glucocorticoids Are Always Under Suspicion - Is the Perception of Their Risks Unbiased? PMID- 29496914 TI - Successful Trial Design and Planning in Systemic Sclerosis: Does It Take a Village? PMID- 29496915 TI - Arthroscopy in Rheumatology: Time for a New Look? PMID- 29496916 TI - Koebner Phenomenon in Juvenile Dermatomyositis. PMID- 29496917 TI - Diagnostic Utility of Anticarbamylated Protein Antibodies as Measured Using Carbamylated Fetal Calf Serum. PMID- 29496918 TI - Drs. Nakabo and Ohmura reply. PMID- 29496919 TI - Ultrasound: A Potential Tool for Detecting of Fasciitis in Dermatomyositis and Polymyositis. PMID- 29496920 TI - Dr. Noda, et al reply. PMID- 29496921 TI - Human Osteoblast-like Cells Are Permissive for Zika Virus Replication. PMID- 29496922 TI - The Antinuclear Antibody Test in the Diagnosis of Antisynthetase Syndrome and Other Autoimmune Myopathies. PMID- 29496923 TI - Dr. Roimicher, et al, reply. PMID- 29496924 TI - Drs. Aggarwal and Oddis reply. PMID- 29496925 TI - Trends for 'pet parents' and 'happy cows' are driving investment in animal health. PMID- 29496926 TI - Live animal exports: should they be banned? PMID- 29496928 TI - Threat of post-Brexit tariffs prompts concern. PMID- 29496929 TI - CCTV in slaughterhouses becomes law. PMID- 29496930 TI - Showcasing crucial work in animal welfare. PMID- 29496932 TI - Disease surveillance in England and Wales, February 2018. PMID- 29496933 TI - Problems that can arise in cattle before and after turnout. AB - This article has been prepared by Arthur Otter of the APHA Cattle Expert Group. PMID- 29496934 TI - Improving the impact of disease control strategies with limited resources: where to invest? PMID- 29496935 TI - Correction: The trends of raw-meat based diets: risks to people and animals. PMID- 29496937 TI - Religious communities and animal welfare. PMID- 29496938 TI - Responsible use of antimicrobials during lambing season. PMID- 29496939 TI - Religious communities and animal welfare. PMID- 29496940 TI - Join the approved list for contagious equine metritis control protocol. PMID- 29496941 TI - Owner-directed cat pelvic fracture survey. PMID- 29496942 TI - Tackling the recruitment crisis. PMID- 29496944 TI - My 10 years as UK chief vet. PMID- 29496945 TI - Ian Cunningham. AB - A gifted scientist and a natural leader, Ian Cunningham was one of Scotland's pre eminent biological scientists; he also directed and chaired a number of key research and educational organisations. PMID- 29496957 TI - Quantitative analysis of population-scale family trees with millions of relatives. AB - Family trees have vast applications in fields as diverse as genetics, anthropology, and economics. However, the collection of extended family trees is tedious and usually relies on resources with limited geographical scope and complex data usage restrictions. We collected 86 million profiles from publicly available online data shared by genealogy enthusiasts. After extensive cleaning and validation, we obtained population-scale family trees, including a single pedigree of 13 million individuals. We leveraged the data to partition the genetic architecture of human longevity and to provide insights into the geographical dispersion of families. We also report a simple digital procedure to overlay other data sets with our resource. PMID- 29496958 TI - Observation of fractional Chern insulators in a van der Waals heterostructure. AB - Topologically ordered phases are characterized by long-range quantum entanglement and fractional statistics rather than by symmetry breaking. First observed in a fractionally filled continuum Landau level, topological order has since been proposed to arise more generally at fractional fillings of topologically nontrivial Chern bands. Here we report the observation of gapped states at fractional fillings of Harper-Hofstadter bands arising from the interplay of a magnetic field and a superlattice potential in a bilayer graphene-hexagonal boron nitride heterostructure. We observed phases at fractional filling of bands with Chern indices [Formula: see text] Some of these phases, in [Formula: see text] and [Formula: see text] bands, are characterized by fractional Hall conductance that is, they are known as fractional Chern insulators and constitute an example of topological order beyond Landau levels. PMID- 29496959 TI - Deciphering how HIV-1 weakens and cracks the bone. PMID- 29496960 TI - Modeling environmentally mediated rotavirus transmission: The role of temperature and hydrologic factors. AB - Rotavirus is considered a directly transmitted disease due to its high infectivity. Environmental pathways have, therefore, largely been ignored. Rotavirus, however, persists in water sources, and both its surface water concentrations and infection incidence vary with temperature. Here, we examine the potential for waterborne rotavirus transmission. We use a mechanistic model that incorporates both direct and waterborne transmission pathways, coupled with a hydrological model, and we simulate rotavirus transmission between two communities with interconnected water sources. To parameterize temperature dependency, we estimated temperature-dependent decay rates in water through a meta-analysis. Our meta-analysis suggests that rotavirus decay rates are positively associated with temperature (n = 39, P [Formula: see text] 0.001). This association is stronger at higher temperatures (over 20 degrees C), consistent with tropical climate conditions. Our model analysis demonstrates that water could disseminate rotavirus between the two communities for all modeled temperatures. While direct transmission was important for disease amplification within communities, waterborne transmission could also amplify transmission. In standing-water systems, the modeled increase in decay led to decreased disease, with every 1 degrees C increase in temperature leading to up to a 2.4% decrease in incidence. These effect sizes are consistent with prior meta-analyses, suggesting that environmental transmission through water sources may partially explain the observed associations between temperature and rotavirus incidence. Waterborne rotavirus transmission is likely most important in cooler seasons and in communities that use slow-moving or stagnant water sources. Even when indirect transmission through water cannot sustain outbreaks, it can seed outbreaks that are maintained by high direct transmission rates. PMID- 29496962 TI - Following sugar patterns in search of galectin function. PMID- 29496961 TI - MAPK signaling couples SCF-mediated degradation of translational regulators to oocyte meiotic progression. AB - RNA-binding proteins (RBPs) are important regulators of gene expression programs, especially during gametogenesis. How the abundance of particular RBPs is restricted to defined stages of meiosis remains largely elusive. Here, we report a molecular pathway that subjects two nonrelated but broadly evolutionarily conserved translational regulators (CPB-3/CPEB and GLD-1/STAR) to proteosomal degradation in Caenorhabditis elegans germ cells at the transition from pachytene to diplotene of meiotic prophase. Both RBPs are recognized by the same ubiquitin ligase complex, containing the molecular scaffold Cullin-1 and the tumor suppressor SEL-10/FBXW7 as its substrate recognition subunit. Destabilization of either RBP through this Skp, Cullin, F-box-containing complex (SCF) ubiquitin ligase appears to loosen its negative control over established target mRNAs, and presumably depends on a prior phosphorylation of CPB-3 and GLD-1 by MAPK (MPK-1), whose activity increases in mid- to late pachytene to promote meiotic progression and oocyte differentiation. Thus, we propose that the orchestrated degradation of RBPs via MAPK-signaling cascades during germ cell development may act to synchronize meiotic with sexual differentiation gene expression changes. PMID- 29496963 TI - Quantitative proteomic and phosphoproteomic comparison of human colon cancer DLD 1 cells differing in ploidy and chromosome stability. AB - Although aneuploidy is poorly tolerated during embryogenesis, aneuploidy and whole chromosomal instability (CIN) are common hallmarks of cancer, raising the question of how cancer cells can thrive in spite of chromosome aberrations. Here we present a comprehensive and quantitative proteomics analysis of isogenic DLD-1 colorectal adenocarcinoma cells lines, aimed at identifying cellular responses to changes in ploidy and/or CIN. Specifically, we compared diploid (2N) and tetraploid (4N) cells with posttetraploid aneuploid (PTA) clones and engineered trisomic clones. Our study provides a comparative data set on the proteomes and phosphoproteomes of the above cell lines, comprising several thousand proteins and phosphopeptides. In comparison to the parental 2N line, we observed changes in proteins associated with stress responses and with interferon signaling. Although we did not detect a conspicuous protein signature associated with CIN, we observed many changes in phosphopeptides that relate to fundamental cellular processes, including mitotic progression and spindle function. Most importantly, we found that most changes detectable in PTA cells were already present in the 4N progenitor line. This suggests that activation of mitotic pathways through hyper phosphorylation likely constitutes an important response to chromosomal burden. In line with this conclusion, cells with extensive chromosome gains showed differential sensitivity toward a number of inhibitors targeting cell cycle kinases, suggesting that the efficacy of anti-mitotic drugs may depend on the karyotype of cancer cells. PMID- 29496964 TI - Involvement in surface antigen expression by a moonlighting FG-repeat nucleoporin in trypanosomes. AB - Components of the nuclear periphery coordinate a multitude of activities, including macromolecular transport, cell-cycle progression, and chromatin organization. Nuclear pore complexes (NPCs) mediate nucleocytoplasmic transport, mRNA processing, and transcriptional regulation, and NPC components can define regions of high transcriptional activity in some organisms at the nuclear periphery and nucleoplasm. Lineage-specific features underpin several core nuclear functions and in trypanosomatids, which branched very early from other eukaryotes, unique protein components constitute the lamina, kinetochores, and parts of the NPCs. Here we describe a phenylalanine-glycine (FG)-repeat nucleoporin, TbNup53b, that has dual localizations within the nucleoplasm and NPC. In addition to association with nucleoporins, TbNup53b interacts with a known trans-splicing component, TSR1, and has a role in controlling expression of surface proteins including the nucleolar periphery-located, procyclin genes. Significantly, while several nucleoporins are implicated in intranuclear transcriptional regulation in metazoa, TbNup53b appears orthologous to components of the yeast/human Nup49/Nup58 complex, for which no transcriptional functions are known. These data suggest that FG-Nups are frequently co-opted to transcriptional functions during evolution and extend the presence of FG-repeat nucleoporin control of gene expression to trypanosomes, suggesting that this is a widespread and ancient eukaryotic feature, as well as underscoring once more flexibility within nucleoporin function. PMID- 29496968 TI - Foreword. PMID- 29496965 TI - Tropomyosin isoforms differentially affect muscle contractility in the head and body regions of the nematode Caenorhabditis elegans. AB - Tropomyosin, one of the major actin filament-binding proteins, regulates actin myosin interaction and actin-filament stability. Multicellular organisms express a number of tropomyosin isoforms, but understanding of isoform-specific tropomyosin functions is incomplete. The nematode Caenorhabditis elegans has a single tropomyosin gene, lev-11, which has been reported to express four isoforms by using two separate promoters and alternative splicing. Here, we report a fifth tropomyosin isoform, LEV-11O, which is produced by alternative splicing that includes a newly identified seventh exon, exon 7a. By visualizing specific splicing events in vivo, we find that exon 7a is predominantly selected in a subset of the body wall muscles in the head, while exon 7b, which is the alternative to exon 7a, is utilized in the rest of the body. Point mutations in exon 7a and exon 7b cause resistance to levamisole--induced muscle contraction specifically in the head and the main body, respectively. Overexpression of LEV 11O, but not LEV-11A, in the main body results in weak levamisole resistance. These results demonstrate that specific tropomyosin isoforms are expressed in the head and body regions of the muscles and contribute differentially to the regulation of muscle contractility. PMID- 29496969 TI - Building Systems That Work for Children With Complex Health Care Needs: Editor's Note. PMID- 29496966 TI - C3G dynamically associates with nuclear speckles and regulates mRNA splicing. AB - C3G (Crk SH3 domain binding guanine nucleotide releasing factor) (Rap guanine nucleotide exchange factor 1), essential for mammalian embryonic development, is ubiquitously expressed and undergoes regulated nucleocytoplasmic exchange. Here we show that C3G localizes to SC35-positive nuclear speckles and regulates splicing activity. Reversible association of C3G with speckles was seen on inhibition of transcription and splicing. C3G shows partial colocalization with SC35 and is recruited to a chromatin and RNase-sensitive fraction of speckles. Its presence in speckles is dependent on intact cellular actin cytoskeleton and is lost on expression of the kinase Clk1. Rap1, a substrate of C3G, is also present in nuclear speckles, and inactivation of Rap signaling by expression of GFP-Rap1GAP alters speckle morphology and number. Enhanced association of C3G with speckles is seen on glycogen synthase kinase 3 beta inhibition or differentiation of C2C12 cells to myotubes. CRISPR/Cas9-mediated knockdown of C3G resulted in altered splicing activity of an artificial gene as well as endogenous CD44. C3G knockout clones of C2C12 as well as MDA-MB-231 cells showed reduced protein levels of several splicing factors compared with control cells. Our results identify C3G and Rap1 as novel components of nuclear speckles and a role for C3G in regulating cellular RNA splicing activity. PMID- 29496970 TI - Families of Children With Medical Complexity: A View From the Front Lines. AB - This article, written by a group of experienced parents of children with medical complexity (CMC), provides an overview of the demands of managing care from their unique perspective. The article articulates why attention to understanding the challenges that families of CMC face with a fragmented health care system, inadequate health insurance coverage, deficits in the delivery of medical care, and problems accessing other critical services (as well as lack of support for children and adolescents in developing and exercising self-management skills) are vital to efforts to improve the current system and positively impact the life course of vulnerable populations. The authors discuss the financial and intangible costs experienced by families of CMC and other stakeholders (including providers, payers, and others), as well as the benefits that can result when effective, flexible, comanaged team-based care coordination is provided within the environment that is the most natural locus of care for the family. The authors detail the role of policy strategies that provide protections for CMC and the importance of family-led advocacy and support organizations in helping families "on the front lines." Throughout the article, the case is made that families authentically involved at every level of health care systems are critical partners in designing policies and systems that will improve care for CMC. The experiences of families of CMC should inform and guide efforts to improve systems of care, thus positively impacting the life course of this vulnerable population. PMID- 29496971 TI - Status Complexicus? The Emergence of Pediatric Complex Care. AB - Discourse about childhood chronic conditions has transitioned in the last decade from focusing primarily on broad groups of children with special health care needs to concentrating in large part on smaller groups of children with medical complexity (CMC). Although a variety of definitions have been applied, the term CMC has most commonly been defined as children and youth with serious chronic conditions, substantial functional limitations, increased health and other service needs, and increased health care costs. The increasing attention paid to CMC has occurred because these children are growing in impact, represent a disproportionate share of health system costs, and require policy and programmatic interventions that differ in many ways from broader groups of children with special health care needs. But will this change in focus lead to meaningful changes in outcomes for children with serious chronic diseases, or is the pediatric community simply adopting terminology with resonance in adult focused health systems? In this article, we will explore the implications of the rapid emergence of pediatric complex care in child health services practice and research. As an emerging field, pediatric care systems should thoughtfully and rapidly develop evidence-based solutions to the new challenges of caring for CMC, including (1) clearer definitions of the target population, (2) a more appropriate incorporation of components of care that occur outside of hospitals, and (3) a more comprehensive outcomes measurement framework, including the recognition of potential limitations of cost containment as a target for improved care for CMC. PMID- 29496972 TI - Models of Care Delivery for Children With Medical Complexity. AB - Children with medical complexity (CMC) are a subset of children and youth with special health care needs with high resource use and health care costs. Novel care delivery models in which care coordination and other services to CMC are provided are a focus of national and local health care and policy initiatives. Current models of care for CMC can be grouped into 3 main categories: (1) primary care-centered models, (2) consultative- or comanagement-centered models, and (3) episode-based models. Each model has unique advantages and disadvantages. Evaluations of these models have demonstrated positive outcomes, but most studies have limited generalizability for broader populations of CMC. A lack of standardized outcomes and population definitions for CMC hinders assessment of the comparative effectiveness of different models of care and identification of which components of the models lead to positive outcomes. Ongoing challenges include inadequate support for family caregivers and threats to the sustainability of models of care. Collaboration among key stakeholders (patients, families, providers, payers, and policy makers) is needed to address the gaps in care and create best practice guidelines to ensure the delivery of high-value care for CMC. PMID- 29496973 TI - Care Coordination for Children With Medical Complexity: Whose Care Is It, Anyway? AB - Children with medical complexity (CMC) have multiple chronic conditions and require an array of medical- and community-based providers. Dedicated care coordination is increasingly seen as key to addressing the fragmented care that CMC often encounter. Often conceptually misunderstood, care coordination is a team-driven activity that organizes and drives service integration. In this article, we examine models of care coordination and clarify related terms such as care integration and case management. The location of care coordination resources for CMC may range from direct practice provision to external organizations such as hospitals and accountable care organizations. We discuss the need for infrastructure building, design and implementation leadership, use of care coordination tools and training modules, and appropriate resource allocation under new payment models. PMID- 29496974 TI - Supporting Self-Management in Children and Adolescents With Complex Chronic Conditions. AB - Self-management improves health outcomes in chronic illness not only by improving adherence to the treatment plan but also by building the individual's capacity to navigate challenges and solve problems. Support for self-management is a critical need among children and adolescents with (medically and/or socially) complex chronic conditions. Self-management support refers to services that health systems and community agencies provide to persons with chronic illness and their families to facilitate self-management; it is a collaboration between the patient, family, and care providers. Evidence has guided the development of self management support approaches and tools for adults and has led to an increased adoption of best practices in adult chronic illness care. However, adult models fail to account for some key differences between children and adults, namely, the integral role of parents and/or caregivers and youth development over time. There is a need for self-management support models that take into account the developmental trajectory across the pediatric age range. Effective approaches must also recognize that in pediatrics, self-management is really shared management between the youth and the parent(s) and/or caregiver(s). Health systems should design care to address self-management for pediatric patients. Although clinicians recognize the importance of self-management in youth with complex chronic conditions, they need standardized approaches and tools to do the following: assess the self-management skills of youth and families, assess modifiable environmental influences on chronic conditions, collaboratively set self-management goals, promote competence and eventual autonomy in youth, share the responsibility for self-management support among nonphysician members of the health care team, and leverage community resources for self-management support. PMID- 29496975 TI - Protecting Rights of Children With Medical Complexity in an Era of Spending Reduction. AB - Children with medical complexity (CMC) often require multiple services across the continuum of care, such as therapies and home nursing. However, sufficient access to needed services is not assured and varies considerably by payer, many of whom who face pressures to control health spending. In this article, we review the rights of CMC in Medicaid, the Children's Health Insurance Program, and various forms of private health insurance to receive services that are necessary to promote optimal health, development, and family functioning. Controlling laws such as the Americans with Disabilities Act and the Early and Periodic Screening, Diagnostic, and Treatment provisions of the Medicaid Act are discussed, and precedential court decisions affecting CMC are reviewed. Implications for policy, advocacy, and payment model design are explored in the context of current emphasis on spending reduction. PMID- 29496976 TI - Ethical Framework for Risk Stratification and Mitigation Programs for Children With Medical Complexity. AB - Those in hospitals and health care systems, when designing clinical programs for children with medical complexity, often talk about needing to develop and implement a system of risk stratification. In this article, we use the framework of an ethical evaluation of a health care program to examine what this task of risk stratification might entail by identifying specific and detailed issues that require particular attention and making a series of recommendations to help ensure that programs for children with medical complexity avoid potentially ethically problematic situations and practices. PMID- 29496977 TI - Evolving Federal and State Health Care Policy: Toward a More Integrated and Comprehensive Care-Delivery System for Children With Medical Complexity. AB - Irrespective of any future changes in federal health policy, the momentum to shift from fee-for-service to value-based payment systems is likely to persist. Public and private payers continue to move toward alternative payment models that promote novel care-delivery systems and greater accountability for health outcomes. With a focus on population health, patient-centered medical homes, and care coordination, alternative payment models hold the potential to promote care delivery systems that address the unique needs of children with medical complexity (CMC), including nonmedical needs and the social determinants of health. Notwithstanding, the implementation of care systems with meaningful quality measures for CMC poses unique and substantive challenges. Stakeholders must view policy options for CMC in the context of transformation within the overall health system to understand how broader health system changes impact care delivery for CMC. PMID- 29496979 TI - Hormonal, metabolic and skeletal phenotype of Schaaf-Yang syndrome: a comparison to Prader-Willi syndrome. AB - BACKGROUND: Nonsense and frameshift mutations in the maternally imprinted, paternally expressed gene MAGEL2, located in the Prader-Willi critical region 15q11-15q13, have been reported to cause Schaaf-Yang syndrome (SYS), a genetic disorder that manifests as developmental delay/intellectual disability, hypotonia, feeding difficulties and autism spectrum disorder. Prader-Willi syndrome (PWS) is a genetic disorder characterised by severe infantile hypotonia, hypogonadotrophic hypogonadism, early childhood onset obesity/hyperphagia, developmental delay/intellectual disability and short stature. Scoliosis and growth hormone insufficiency are also prevalent in PWS.There is extensive documentation of the endocrine and metabolic phenotypes for PWS, but not for SYS. This study served to investigate the hormonal, metabolic and body composition phenotype of SYS and its potential overlap with PWS. METHODS: In nine individuals with SYS (5 female/4 male; aged 5-17 years), we measured serum ghrelin, glucose, insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3, follicle-stimulating hormone, luteinising hormone, thyroid-stimulating hormone, free T4, uric acid and testosterone, and performed a comprehensive lipid panel. Patients also underwent X-ray and dual-energy X-ray absorptiometry analyses to assess for scoliosis and bone mineral density. RESULTS: Low IGF-1 levels despite normal weight/adequate nutrition were observed in six patients, suggesting growth hormone deficiency similar to PWS. Fasting ghrelin levels were elevated, as seen in individuals with PWS. X-rays revealed scoliosis >10 degrees in three patients, and abnormal bone mineral density in six patients, indicated by Z-scores of below -2 SDs. CONCLUSION: This is the first analysis of the hormonal, metabolic and body composition phenotype of SYS. Our findings suggest that there is marked, but not complete overlap between PWS and SYS. PMID- 29496978 TI - Practice guideline: joint CCMG-SOGC recommendations for the use of chromosomal microarray analysis for prenatal diagnosis and assessment of fetal loss in Canada. AB - BACKGROUND: The aim of this guideline is to provide updated recommendations for Canadian genetic counsellors, medical geneticists, maternal fetal medicine specialists, clinical laboratory geneticists and other practitioners regarding the use of chromosomal microarray analysis (CMA) for prenatal diagnosis. This guideline replaces the 2011 Society of Obstetricians and Gynaecologists of Canada (SOGC)-Canadian College of Medical Geneticists (CCMG) Joint Technical Update. METHODS: A multidisciplinary group consisting of medical geneticists, genetic counsellors, maternal fetal medicine specialists and clinical laboratory geneticists was assembled to review existing literature and guidelines for use of CMA in prenatal care and to make recommendations relevant to the Canadian context. The statement was circulated for comment to the CCMG membership-at-large for feedback and, following incorporation of feedback, was approved by the CCMG Board of Directors on 5 June 2017 and the SOGC Board of Directors on 19 June 2017. RESULTS AND CONCLUSIONS: Recommendations include but are not limited to: (1) CMA should be offered following a normal rapid aneuploidy screen when multiple fetal malformations are detected (II-1A) or for nuchal translucency (NT) >=3.5 mm (II-2B) (recommendation 1); (2) a professional with expertise in prenatal chromosomal microarray analysis should provide genetic counselling to obtain informed consent, discuss the limitations of the methodology, obtain the parental decisions for return of incidental findings (II-2A) (recommendation 4) and provide post-test counselling for reporting of test results (III-A) (recommendation 9); (3) the resolution of chromosomal microarray analysis should be similar to postnatal microarray platforms to ensure small pathogenic variants are detected. To minimise the reporting of uncertain findings, it is recommended that variants of unknown significance (VOUS) smaller than 500 Kb deletion or 1 Mb duplication not be routinely reported in the prenatal context. Additionally, VOUS above these cut-offs should only be reported if there is significant supporting evidence that deletion or duplication of the region may be pathogenic (III-B) (recommendation 5); (4) secondary findings associated with a medically actionable disorder with childhood onset should be reported, whereas variants associated with adult-onset conditions should not be reported unless requested by the parents or disclosure can prevent serious harm to family members (III-A) (recommendation 8).The working group recognises that there is variability across Canada in delivery of prenatal testing, and these recommendations were developed to promote consistency and provide a minimum standard for all provinces and territories across the country (recommendation 9). PMID- 29496981 TI - Advanced Ultrasound Technologies for Diagnosis and Therapy. AB - Ultrasound is among the most rapidly advancing imaging techniques. Functional methods such as elastography have been clinically introduced, and tissue characterization is improved by contrast-enhanced scans. Here, novel superresolution techniques provide unique morphologic and functional insights into tissue vascularization. Functional analyses are complemented by molecular ultrasound imaging, to visualize markers of inflammation and angiogenesis. The full potential of diagnostic ultrasound may become apparent by integrating these multiple imaging features in radiomics approaches. Emerging interest in ultrasound also results from its therapeutic potential. Various applications of tumor ablation with high-intensity focused ultrasound are being clinically evaluated, and its performance strongly benefits from the integration into MRI. Additionally, oscillating microbubbles mediate sonoporation to open biologic barriers, thus improving the delivery of drugs or nucleic acids that are coadministered or coformulated with microbubbles. This article provides an overview of recent developments in diagnostic and therapeutic ultrasound, highlighting multiple innovation tracks and their translational potential. PMID- 29496980 TI - Dominant ELOVL1 mutation causes neurological disorder with ichthyotic keratoderma, spasticity, hypomyelination and dysmorphic features. AB - BACKGROUND: Ichthyosis and neurological involvement occur in relatively few known Mendelian disorders caused by mutations in genes relevant both for epidermis and neural function. OBJECTIVES: To identify the cause of a similar phenotype of ichthyotic keratoderma, spasticity, mild hypomyelination (on MRI) and dysmorphic features (IKSHD) observed in two unrelated paediatric probands without family history of disease. METHODS: Whole exome sequencing was performed in both patients. The functional effect of prioritised variant in ELOVL1 (very-long-chain fatty acids (VLCFAs) elongase) was analysed by VLCFA profiling by gas chromatography-mass spectrometry in stably transfected HEK2932 cells and in cultured patient's fibroblasts. RESULTS: Probands shared novel heterozygous ELOVL1 p.Ser165Phe mutation (de novo in one family, while in the other family, father could not be tested). In transfected cells p.Ser165Phe: (1) reduced levels of FAs C24:0-C28:0 and C26:1 with the most pronounced effect for C26:0 (P=7.8*10 6 vs HEK293 cells with wild type (wt) construct, no difference vs naive HEK293) and (2) increased levels of C20:0 and C22:0 (P=6.3*10-7, P=1.2*10-5, for C20:0 and C22:0, respectively, comparison vs HEK293 cells with wt construct; P=2.2*10 7, P=1.9*10-4, respectively, comparison vs naive HEK293). In skin fibroblasts, there was decrease of C26:1 (P=0.014), C28:0 (P=0.001) and increase of C20:0 (P=0.033) in the patient versus controls. There was a strong correlation (r=0.92, P=0.008) between the FAs profile of patient's fibroblasts and that of p.Ser165Phe transfected HEK293 cells. Serum levels of C20:0-C26:0 FAs were normal, but the C24:0/C22:0 ratio was decreased. CONCLUSION: The ELOVL1 p.Ser165Phe mutation is a likely cause of IKSHD. PMID- 29496982 TI - Joint Reconstruction of Activity and Attenuation in Time-of-Flight PET: A Quantitative Analysis. AB - Methods for joint activity reconstruction and attenuation reconstruction of time of-flight (TOF) PET data provide an effective solution to attenuation correction when no (or incomplete or inaccurate) information on attenuation is available. One of the main barriers limiting use of these methods in clinical practice is their lack of validation in a relatively large patient database. In this contribution, we aim to validate reconstruction performed with maximum-likelihood activity reconstruction and attenuation registration (MLRR) in a whole-body patient dataset. Furthermore, a partial validation (because the scale problem of the algorithm is avoided for now) of reconstruction performed with maximum likelihood activity and attenuation (MLAA) is also provided. We present a quantitative comparison between these 2 methods of joint reconstruction and the current clinical gold standard, maximum-likelihood expectation maximization (MLEM) with CT-based attenuation correction. Methods: The whole-body TOF PET emission data of each patient dataset were processed as a whole to reconstruct an activity volume covering all the acquired bed positions, helping reduce the problem of a scale per bed position in MLAA to a global scale for the entire activity volume. Three reconstruction algorithms were used: MLEM, MLRR, and MLAA. A maximum-likelihood scaling of the single-scatter simulation estimate to the emission data was used for scatter correction. The reconstruction results for various regions of interest were then analyzed. Results: The joint reconstructions of the whole-body patient dataset provided better quantification than the gold standard in cases of PET and CT misalignment caused by patient or organ motion. Our quantitative analysis showed a difference of -4.2% +/- 2.3% between MLRR and MLEM and a difference of -7.5% +/- 4.6% between MLAA and MLEM, averaged over all regions of interest. Conclusion: Joint reconstruction of activity and attenuation provides a useful means to estimate tracer distribution when CT-based-attenuation images are subject to misalignment or are not available. With an accurate estimate of the scatter contribution in the emission measurements, the joint reconstructions of TOF PET data are within clinically acceptable accuracy. PMID- 29496983 TI - Effects of Fasting on 18F-DCFPyL Uptake in Prostate Cancer Lesions and Tissues with Known High Physiologic Uptake. AB - In the literature, a 4- to 6-h fast is recommended before a patient undergoes PET/CT with 2-(3-(1-carboxy-5-[(6-18F-fluoro-pyridine-3-carbonyl)-amino]-pentyl) ureido)-pentanedioic acid (18F-DCFPyL); however, a scientific underpinning for this recommendation is lacking. Therefore, we performed a study to determine the impact of fasting on 18F-DCFPyL uptake. Methods: The study included 50 patients who fasted at least 6 h before 18F-DCFPyL administration and 50 patients who did not. Activity (SUVmax) was measured in lesions characteristic of prostate cancer and in normal tissues known to express high physiologic uptake. Results: Uptake in suspected lesions did not differ between the cohorts. 18F-DCFPyL uptake in the submandibular gland, liver, and spleen was significantly higher in the fasting than the nonfasting cohort. Conclusion: Our data show that fasting does not significantly affect 18F-DCFPyL uptake in suspected malignant lesions but does result in significantly lower 18F-DCFPyL uptake in tissues with high physiologic uptake. The absolute differences in uptake were relatively small; therefore, the effects of fasting on the diagnostic performance can be considered negligible. PMID- 29496984 TI - alpha-Emitters for Radiotherapy: From Basic Radiochemistry to Clinical Studies Part 2. AB - The use of radioactive sources to deliver cytotoxic ionizing radiation to disease sites dates back to the early 20th century, with the discovery of radium and its physiologic effects. alpha-emitters are of particular interest in the field of clinical oncology for radiotherapy applications. The first part of this review explored the basic radiochemistry, high cell-killing potency, and availability of alpha-emitting radionuclides, together with hurdles such as radiolabeling methods and daughter redistribution. The second part of this review will give an overview of the most promising and current uses of alpha-emitters in preclinical and clinical studies. PMID- 29496985 TI - Reply: Comparison of 68Ga-PSMA-11 and 18F-Fluciclovine PET/CT in a Case Series of 10 Patients with Prostate Cancer Recurrence: Prospective Trial Is on Its Way. PMID- 29496986 TI - In Vivo Characterization of Platinum(II)-Based Linker Technology for the Development of Antibody-Drug Conjugates: Taking Advantage of Dual Labeling with 195mPt and 89Zr. AB - Linker instability and impaired tumor targeting can affect the tolerability and efficacy of antibody-drug conjugates (ADCs). To improve these ADC characteristics, we recently described the use of a metal-organic linker, [ethylenediamineplatinum(II)]2+, herein called Lx Initial therapy studies in xenograft-bearing mice revealed that trastuzumab-Lx-auristatin F (AF) outperformed its maleimide benchmark trastuzumab-mal-AF and the Food and Drug Administration-approved ado-trastuzumab emtansine, both containing conventional linkers. In this study, we aimed to characterize Lx-based ADCs for in vivo stability and tumor targeting using 195mPt and 89Zr. Methods: The gamma-emitter 195mPt was used to produce the radiolabeled Lx [195mPt]Lx89Zr-Desferrioxamine (89Zr-DFO) was conjugated to trastuzumab either via [195mPt]Lx (to histidine residues) or conventionally (to lysine residues) in order to monitor the biodistribution of antibody, payload, and linker separately. Linker stability was determined by evaluating the following ADCs for biodistribution in NCI-N87 xenograft-bearing nude mice 72 h after injection: trastuzumab-[195mPt]Lx-DFO 89Zr, trastuzumab-[195mPt]Lx-AF, and 89Zr-DFO-(Lys)trastuzumab (control), all having drug-to-antibody ratios (DARs) of 2.2-2.5. To assess the influence of DAR on biodistribution, 89Zr-DFO-(Lys)trastuzumab-Lx-AF with an AF-to-antibody ratio of 0, 2.6, or 5.2 was evaluated 96 h after injection. Results: Similar biodistributions were observed for trastuzumab-[195mPt]Lx-DFO-89Zr, trastuzumab [195mPt]Lx-AF, and 89Zr-DFO-(Lys)trastuzumab irrespective of the isotope used for biodistribution assessment. The fact that Lx follows the antibody biodistribution indicates that the payload-Lx bond is stable in vivo. Uptake of the 3 conjugates, as percentage injected dose (%ID) per gram of tissue, was about 30 %ID/g in tumor tissue but less than 10 %ID/g in most healthy tissues. Trastuzumab-[195mPt]Lx-AF (DAR 2.2) showed a tendency toward faster blood clearance and an elevated liver uptake, which increased significantly to 28.1 +/- 4.2 %ID/g at a higher DAR of 5.2, as revealed from the biodistribution and PET imaging studies. Conclusion: As shown by 195mPt/89Zr labeling, ADCs containing the Lx linker are stable in vivo. In the case of trastuzumab-Lx-AF (DARs 2.2 and 2.6), an unimpaired biodistribution was demonstrated. PMID- 29496988 TI - Glutamatergic Biomarkers for Cocaine Addiction: A Longitudinal Study Using MR Spectroscopy and mGluR5 PET in Self-Administering Rats. AB - Cocaine addiction is a disorder that still lacks diagnostic biomarkers or effective pharmacotherapy. We present findings on a rat model of cocaine self administration that was followed up longitudinally using the metabotropic glutamate receptor type 5 (mGluR5) tracer 18F-3-fluoro-5-[(pyridin-3 yl)ethynyl]benzonitrile (18F-FPEB) PET, proton MR spectroscopy (1H-MRS), and behavioral tests. Methods: Forty-two Wistar rats were scanned with 18F-FPEB PET and 1H-MRS before and after sucrose or intravenous cocaine self-administration, during withdrawal, and during relapse. All animals performed a rodent Iowa Gambling Task (rIGT) at baseline to evaluate decision making. Baseline values were used in a mixed model to assess associations with later cocaine use, and follow-up measurements were compared with the values before drug exposure. Results: Preexposure rIGT scores were significantly related to both cocaine and sucrose use during the drug-exposure phase. However, only cocaine self administration induced a decrease in 18F-FPEB binding. This decrease was most pronounced bilaterally in the hippocampus, where mGluR5 availability correlated with the amount of cocaine used during relapse. Compared with the sucrose group, a larger decrease was observed in the hippocampo-prefrontal cortex pathway. Preexposure glutamate and glycine concentrations in the prefrontal cortex were significantly associated with cocaine use during the drug-exposure phase. Moreover, prefrontal glutamate exhibited a distinct, reversible decrease when animals had access to cocaine but not sucrose. Conclusion: Baseline values of prefrontal glutamate and glycine are associated with future cocaine use. Furthermore, baseline rIGT scores are associated with both sucrose and cocaine. Finally, both glutamate concentration and mGluR5 availability decrease during exposure to cocaine. PMID- 29496987 TI - 18F-XTRA PET for Enhanced Imaging of the Extrathalamic alpha4beta2 Nicotinic Acetylcholine Receptor. AB - Reduced density of the alpha4beta2 nicotinic acetylcholine receptor (alpha4beta2 nAChR) in the cortex and hippocampus of the human brain has been reported in aging and patients with neurodegenerative disease. This study assessed the pharmacokinetic behavior of 18F-(-)-JHU86428 (18F-XTRA), a new radiotracer for in vivo PET imaging of the alpha4beta2-nAChR, particularly in extrathalamic regions of interest in which the alpha4beta2-nAChR is less densely expressed than in thalamus. 18F-XTRA was also used to evaluate the alpha4beta2-nAChR in the hippocampus in human aging. Methods: Seventeen healthy nonsmoker adults (11 men, 6 women; age, 30-82 y) underwent PET neuroimaging over 90 or 180 min in a high resolution research tomograph after bolus injection of 18F-XTRA. Methods to quantify binding of 18F-XTRA to the alpha4beta2-nAChR in the human brain were compared, and the relationship between age and binding in the hippocampus was tested. Results: 18F-XTRA rapidly entered the brain, and time-activity curves peaked within 10 min after injection for extrathalamic regions and at approximately 70 min in the thalamus. The 2-tissue-compartment model (2TCM) predicted the regional time-activity curves better than the 1-tissue-compartment model, and total distribution volume (VT) was well identified by the 2TCM in all ROIs. VT values estimated using Logan analysis with metabolite-corrected arterial input were highly correlated with those from the 2TCM in all regions, and values from 90-min scan duration were on average within 5% of those values from 180 min of data. Parametric images of VT were consistent with the known distribution of the alpha4beta2-nAChR across the brain. Finally, an inverse correlation between VT in the hippocampus and age was observed. Conclusion: Our results extend support for use of 18F-XTRA with 90 min of emission scanning in quantitative human neuroimaging of the extrathalamic alpha4beta2-nAChR, including in studies of aging. PMID- 29496989 TI - Impact of Novel Antidepressants on Cardiac 123I-Metaiodobenzylguanidine Uptake: Experimental Studies on SK-N-SH Cells and Healthy Rabbits. AB - 123I-metaiodobenzylguanidine (123I-MIBG) has independent prognostic value for risk stratification among heart failure patients, but the use of concomitant medication should not affect its quantitative information. We evaluated whether the 4 classes of antidepressants currently most prescribed as first-line treatment for major depressive disorder (MDD) have the potential to alter 123I MIBG imaging results. Methods: The inhibition effect of desipramine, escitalopram, venlafaxine, and bupropion on 131I-MIBG uptake was assessed by in vitro uptake assays using human neuroblastoma SK-N-SH cells. The half-maximal inhibitory concentration of tracer uptake was determined from dose-response curves. To evaluate the effect of intravenous pretreatment with desipramine (1.5 mg/kg) and escitalopram (2.5 or 15 mg/kg) on 123I-MIBG cardiac uptake, in vivo planar 123I-MIBG scanning of healthy New Zealand White rabbits was performed. Results: The half-maximal inhibitory concentrations of desipramine, escitalopram, venlafaxine, and bupropion on 131I-MIBG cellular uptake were 11.9 nM, 7.5 MUM, 4.92 MUM, and 12.9 MUM, respectively. At the maximum serum concentration (as derived by previous clinical trials), the inhibition rates of 131I-MIBG uptake were 90.6% for desipramine, 25.5% for venlafaxine, 11.7% for bupropion, and 0.72% for escitalopram. A low inhibition rate for escitalopram in the cell uptake study triggered investigation of an in vivo rabbit model: with a dosage considerably higher than used in clinical practice, the noninhibitory effect of escitalopram was confirmed. Furthermore, pretreatment with desipramine markedly reduced cardiac 123I-MIBG uptake. Conclusion: In the present in vitro binding assay and in vivo rabbit study, the selective serotonin reuptake inhibitor escitalopram had no major impact on neuronal cardiac 123I-MIBG uptake within therapeutic dose ranges, whereas other types of first-line antidepressants for MDD treatment led to a significant decrease. These preliminary results warrant further confirmatory clinical trials regarding the reliability of cardiac 123I-MIBG imaging, in particular, if the patient's neuropsychiatric status would not tolerate withdrawal of a potentially norepinephrine-interfering antidepressant. PMID- 29496990 TI - Role of Diagnostic 131I SPECT/CT in Long-Term Follow-up of Patients with Papillary Thyroid Microcarcinoma. AB - Papillary thyroid microcarcinoma (PTMC) usually has a favorable prognosis but can also be aggressive, with neck and distant metastases. We evaluated the diagnostic role of 131I SPECT/CT in detecting metastases in PTMC patients during long-term follow-up and whether the procedure should be included in the current diagnostic protocol. Methods: We retrospectively studied 351 consecutive PTMC patients who had undergone thyroidectomy and radioiodine therapy; 21 were at high risk, 94 at low risk, and 236 at very low risk. During follow-up, the patients underwent diagnostic 131I whole-body scanning (WBS) followed by SPECT/CT. Results: WBS found 248 radioiodine-avid foci in 126 patients, and SPECT/CT found 298 in 139 patients, confirming all foci found on WBS. SPECT/CT also correctly classified 76 of the avid foci as unclear or wrongly classified on WBS. Globally, SPECT/CT detected and correctly classified 64 neoplastic lesions in 27 of 30 patients with metastases, and WBS evidenced 39 of 64 lesions, 28 of which were unclear or wrongly classified, in 16 of the 30 patients. Nineteen of 27 patients, including 13 at very low risk, had only neck metastases, 9 of 19 being T1aN0M0 with an undetectable thyroglobulin level. Three of 27 patients, including 1 at very low risk, had only distant metastases with an undetectable or very low thyroglobulin level. Five of 27 patients had neck and distant metastases with a thyroglobulin level <2.5 ng/mL in 1 case, between 2.5 and 10 in 3 cases, and >10 in the remaining case. SPECT/CT also reduced WBS false-positive results in 15 of 139 patients (10.8%). SPECT/CT had an incremental value over WBS in 38.1% of patients with positive findings and changed the classification and therapeutic management in 21.6%. Conclusion: Metastases occurred in 8.5% of patients during long-term follow-up. SPECT/CT performed better than WBS, particularly in patients at very low risk with inconclusive WBS results, a TNM stage of T1aN0M0, and an undetectable or very low level of thyroglobulin. Prolonged surveillance is justified in PTMC patients, and wider use of 131I SPECT/CT in the diagnostic protocol is suggested. PMID- 29496991 TI - Noninvasive Imaging of Drug-Induced Liver Injury with 18F-DFA PET. AB - Drug-induced liver failure is a significant indication for a liver transplant, and unexpected liver toxicity is a major reason that otherwise effective therapies are removed from the market. Various methods exist for monitoring liver injury but are often inadequate to predict liver failure. New diagnostic tools are needed. Methods: We evaluate in a preclinical model whether 18F-2-deoxy-2 fluoroarabinose (18F-DFA), a PET radiotracer that measures the ribose salvage pathway, can be used to monitor acetaminophen-induced liver injury and failure. Mice treated with vehicle, 100, 300, or 500 mg/kg acetaminophen for 7 or 21 h were imaged with 18F-FDG and 18F-DFA PET. Hepatic radiotracer accumulation was correlated to survival and percentage of nonnecrotic tissue in the liver. Mice treated with acetaminophen and vehicle or N-acetylcysteine were imaged with 18F DFA PET. 18F-DFA accumulation was evaluated in human hepatocytes engrafted into the mouse liver. Results: We show that hepatic 18F-DFA accumulation is 49%-52% lower in mice treated with high-dose acetaminophen than in mice treated with low dose acetaminophen or vehicle. Under these same conditions, hepatic 18F-FDG accumulation was unaffected. At 21 h after acetaminophen treatment, hepatic 18F DFA accumulation can distinguish mice that will succumb to the liver injury from those that will survive it (6.2 vs. 9.7 signal to background, respectively). Hepatic 18F-DFA accumulation in this model provides a tomographic representation of hepatocyte density in the liver, with a R2 between hepatic 18F-DFA accumulation and percentage of nonnecrotic tissue of 0.70. PET imaging with 18F DFA can be used to distinguish effective from ineffective resolution of acetaminophen-induced liver injury with N-acetylcysteine (15.6 vs. 6.2 signal to background, respectively). Human hepatocytes, in culture or engrafted into a mouse liver, have levels of ribose salvage activity similar to those of mouse hepatocytes. Conclusion: Our findings suggest that PET imaging with 18F-DFA can be used to visualize and quantify drug-induced acute liver injury and may provide information on the progression from liver injury to hepatic failure. PMID- 29496993 TI - Signaling between pancreatic beta cells and macrophages via S100 calcium-binding protein A8 exacerbates beta-cell apoptosis and islet inflammation. AB - Chronic low-grade inflammation in the pancreatic islets is observed in individuals with type 2 diabetes, and macrophage levels are elevated in the islets of these individuals. However, the molecular mechanisms underlying the interactions between the pancreatic beta cells and macrophages and their involvement in inflammation are not fully understood. Here, we investigated the role of S100 calcium-binding protein A8 (S100A8), a member of the damage associated molecular pattern molecules (DAMPs), in beta-cell inflammation. Co cultivation of pancreatic islets with unstimulated peritoneal macrophages in the presence of palmitate (to induce lipotoxicity) and high glucose (to induce glucotoxicity) synergistically increased the expression and release of islet produced S100A8 in a Toll-like receptor 4 (TLR4)-independent manner. Consistently, a significant increase in the expression of the S100a8 gene was observed in the islets of diabetic db/db mice. Furthermore, the islet-derived S100A8 induced TLR4-mediated inflammatory cytokine production by migrating macrophages. When human islet cells were co-cultured with U937 human monocyte cells, the palmitate treatment up-regulated S100A8 expression. This S100A8 mediated interaction between islets and macrophages evoked beta-cell apoptosis, which was ameliorated by TLR4 inhibition in the macrophages or S100A8 neutralization in the pancreatic islets. Of note, both glucotoxicity and lipotoxicity triggered S100A8 secretion from the pancreatic islets, which in turn promoted macrophage infiltration of the islets. Taken together, a positive feedback loop between islet-derived S100A8 and macrophages drives beta-cell apoptosis and pancreatic islet inflammation. We conclude that developing therapeutic approaches to inhibit S100A8 may serve to prevent beta-cell loss in patients with diabetes. PMID- 29496992 TI - Distinct functions for the membrane-proximal ectodomain region (MPER) of HIV-1 gp41 in cell-free and cell-cell viral transmission and cell-cell fusion. AB - HIV-1 is spread by cell-free virions and by cell-cell viral transfer. We asked whether the structure and function of a broad neutralizing antibody (bNAb) epitope, the membrane-proximal ectodomain region (MPER) of the viral gp41 transmembrane glycoprotein, differ in cell-free and cell-cell-transmitted viruses and whether this difference could be related to Ab neutralization sensitivity. Whereas cell-free viruses bearing W666A and I675A substitutions in the MPER lacked infectivity, cell-associated mutant viruses were able to initiate robust spreading infection. Infectivity was restored to cell-free viruses by additional substitutions in the cytoplasmic tail (CT) of gp41 known to disrupt interactions with the viral matrix protein. We observed contrasting effects on cell-free virus infectivity when W666A was introduced to two transmitted/founder isolates, but both mutants could still mediate cell-cell spread. Domain swapping indicated that the disparate W666A phenotypes of the cell-free transmitted/founder viruses are controlled by sequences in variable regions 1, 2, and 4 of gp120. The sequential passaging of an MPER mutant (W672A) in peripheral blood mononuclear cells enabled selection of viral revertants with loss-of-glycan suppressor mutations in variable region 1, suggesting a functional interaction between variable region 1 and the MPER. An MPER-directed bNAb neutralized cell-free virus but not cell-cell viral spread. Our results suggest that the MPER of cell-cell-transmitted virions has a malleable structure that tolerates mutagenic disruption but is not accessible to bNAbs. In cell-free virions, interactions mediated by the CT impose an alternative MPER structure that is less tolerant of mutagenic alteration and is efficiently targeted by bNAbs. PMID- 29496994 TI - Fascin1 suppresses RIG-I-like receptor signaling and interferon-beta production by associating with IkappaB kinase epsilon (IKKepsilon) in colon cancer. AB - Fascin1 is an actin-bundling protein involved in cancer cell migration and has recently been shown also to have roles in virus-mediated immune cell responses. Because viral infection has been shown to activate immune cells and to induce interferon-beta expression in human cancer cells, we evaluated the effects of fascin1 on virus-dependent signaling via the membrane- and actin-associated protein RIG-I (retinoic acid-inducible gene I) in colon cancer cells. We knocked down fascin1 expression with shRNA retrovirally transduced into a DLD-1 colon cancer and L929 fibroblast-like cell lines and used luciferase reporter assays and co-immunoprecipitation to identify fascin1 targets. We found that intracellular poly(I.C) transfection to mimic viral infection enhances the RIG I/MDA5 (melanoma differentiation-associated gene 5)-mediated dimerization of interferon regulatory factor 3 (IRF-3). The transfection also significantly increased the expression levels of IRF-7, interferon-beta, and interferon inducible cytokine IP-10 in fascin1-deleted cells compared with controls while significantly suppressing cell growth, migration, and invasion. We also found that fascin1 constitutively interacts with IkappaB kinase epsilon (IKKepsilon) in the RIG-I signaling pathway. In summary, we have identified fascin1 as a suppressor of the RIG-I signaling pathway associating with IkappaB kinase epsilon in DLD-1 colon cancer cells to suppress immune responses to viral infection. PMID- 29496995 TI - Myeloperoxidase-catalyzed oxidation of cyanide to cyanate: A potential carbamylation route involved in the formation of atherosclerotic plaques? AB - Protein carbamylation by cyanate is a post-translational modification associated with several (patho)physiological conditions, including cardiovascular disorders. However, the biochemical pathways leading to protein carbamylation are incompletely characterized. This work demonstrates that the heme protein myeloperoxidase (MPO), which is secreted at high concentrations at inflammatory sites from stimulated neutrophils and monocytes, is able to catalyze the two electron oxidation of cyanide to cyanate and promote the carbamylation of taurine, lysine, and low-density lipoproteins. We probed the role of cyanide as both electron donor and low-spin ligand by pre-steady-state and steady-state kinetic analyses and analyzed reaction products by MS. Moreover, we present two further pathways of carbamylation that involve reaction products of MPO, namely oxidation of cyanide by hypochlorous acid and reaction of thiocyanate with chloramines. Finally, using an in vivo approach with mice on a high-fat diet and carrying the human MPO gene, we found that during chronic exposure to cyanide, mimicking exposure to pollution and smoking, MPO promotes protein-bound accumulation of carbamyllysine (homocitrulline) in atheroma plaque, demonstrating a link between cyanide exposure and atheroma. In summary, our findings indicate that cyanide is a substrate for MPO and suggest an additional pathway for in vivo cyanate formation and protein carbamylation that involves MPO either directly or via its reaction products hypochlorous acid or chloramines. They also suggest that chronic cyanide exposure could promote the accumulation of carbamylated proteins in atherosclerotic plaques. PMID- 29496996 TI - Interferon down-regulation of miR-1225-3p as an antiviral mechanism through modulating Grb2-associated binding protein 3 expression. AB - Induction of interferons (IFNs) is a central event of antiviral innate immunity. As crucial posttranscriptional regulators, microRNAs (miRNAs) are important for IFN-mediated host defense. Although screening has indicated a substantial number of miRNAs to be differentially expressed after IFN stimulation, the detailed mechanisms of these miRNAs in the antiviral response are underexplored and of great significance. Here, we show that hsa-miR-1225-3p is specifically down regulated by type I IFN through the IFN/JAK/STAT signaling pathway. Silencing endogenous miR-1225-3p inhibited infection by multiple IFN-susceptible viruses, including hepatitis C virus, Sendai virus, and Newcastle disease virus. In contrast, overexpression of miR-1225-3p impaired the antiviral effect of IFNs and facilitated viral infection. Regarding the mechanism, we identified growth factor receptor-bound protein 2-associated binding protein 3 (GAB3) as a direct target of miR-1225-3p. GAB3 expression was up-regulated by IFN, and overexpression of GAB3 demonstrated potent antiviral effects through enhancing IFN response and virus-triggered innate immune activation. Taken together, our findings reveal the biological function of miR-1225-3p for the first time and propose a novel antiviral regulation pathway in which miRNA and GAB3 participate. This study contributes to the understanding of host miRNA participation in antiviral processes of IFN. PMID- 29496997 TI - Uncovering the mechanistic basis for specific recognition of monomethylated H3K4 by the CW domain of Arabidopsis histone methyltransferase SDG8. AB - Chromatin consists of DNA and histones, and specific histone modifications that determine chromatin structure and activity are regulated by three types of proteins, called writer, reader, and eraser. Histone reader proteins from vertebrates, vertebrate-infecting parasites, and higher plants possess a CW domain, which has been reported to read histone H3 lysine 4 (H3K4). The CW domain of Arabidopsis SDG8 (also called ASHH2), a histone H3 lysine 36 methyltransferase, preferentially binds monomethylated H3K4 (H3K4me1), unlike the mammalian CW domain protein, which binds trimethylated H3K4 (H3K4me3). However, the molecular basis of the selective binding by the CW domain of SDG8 (SDG8-CW) remains unclear. Here, we solved the 1.6-A-resolution structure of SDG8-CW in complex with H3K4me1, which revealed that residues in the C-terminal alpha-helix of SDG8-CW determine binding specificity for low methylation levels at H3K4. Moreover, substitutions of key residues, specifically Ile-915 and Asn-916, converted SDG8-CW binding preference from H3K4me1 to H3K4me3. Sequence alignment and mutagenesis studies revealed that the CW domain of SDG725, the homolog of SDG8 in rice, shares the same binding preference with SDG8-CW, indicating that preference for low methylated H3K4 by the CW domain of ASHH2 homologs is conserved among higher-order plants. Our findings provide first structural insights into the molecular basis for specific recognition of monomethylated H3K4 by the H3K4me1 reader protein SDG8 from Arabidopsis. PMID- 29497001 TI - The National Oncologic PET Registry (NOPR): A Monumental Effort by a Few Leaders. PMID- 29496998 TI - Islet proteomics reveals genetic variation in dopamine production resulting in altered insulin secretion. AB - The mouse is a critical model in diabetes research, but most research in mice has been limited to a small number of mouse strains and limited genetic variation. Using the eight founder strains and both sexes of the Collaborative Cross (C57BL/6J (B6), A/J, 129S1/SvImJ (129), NOD/ShiLtJ (NOD), NZO/HILtJ (NZO), PWK/PhJ (PWK), WSB/EiJ (WSB), and CAST/EiJ (CAST)), we investigated the genetic dependence of diabetes-related metabolic phenotypes and insulin secretion. We found that strain background is associated with an extraordinary range in body weight, plasma glucose, insulin, triglycerides, and insulin secretion. Our whole islet proteomic analysis of the eight mouse strains demonstrates that genetic background exerts a strong influence on the islet proteome that can be linked to the differences in diabetes-related metabolic phenotypes and insulin secretion. We computed protein modules consisting of highly correlated proteins that enrich for biological pathways and provide a searchable database of the islet protein expression profiles. To validate the data resource, we identified tyrosine hydroxylase (Th), a key enzyme in catecholamine synthesis, as a protein that is highly expressed in beta-cells of PWK and CAST islets. We show that CAST islets synthesize elevated levels of dopamine, which suppresses insulin secretion. Prior studies, using only the B6 strain, concluded that adult mouse islets do not synthesize l-3,4-dihydroxyphenylalanine (l-DOPA), the product of Th and precursor of dopamine. Thus, the choice of the CAST strain, guided by our islet proteomic survey, was crucial for these discoveries. In summary, we provide a valuable data resource to the research community, and show that proteomic analysis identified a strain-specific pathway by which dopamine synthesized in beta-cells inhibits insulin secretion. PMID- 29497000 TI - A potent complement factor C3-specific nanobody inhibiting multiple functions in the alternative pathway of human and murine complement. AB - The complement system is a complex, carefully regulated proteolytic cascade for which suppression of aberrant activation is of increasing clinical relevance, and inhibition of the complement alternative pathway is a subject of intense research. Here, we describe the nanobody hC3Nb1 that binds to multiple functional states of C3 with subnanomolar affinity. The nanobody causes a complete shutdown of alternative pathway activity in human and murine serum when present in concentrations comparable with that of C3, and hC3Nb1 is shown to prevent proconvertase assembly, as well as binding of the C3 substrate to C3 convertases. Our crystal structure of the C3b-hC3Nb1 complex and functional experiments demonstrate that proconvertase formation is blocked by steric hindrance between the nanobody and an Asn-linked glycan on complement factor B. In addition, hC3Nb1 is shown to prevent factor H binding to C3b, rationalizing its inhibition of factor I activity. Our results identify hC3Nb1 as a versatile, inexpensive, and powerful inhibitor of the alternative pathway in both human and murine in vitro model systems of complement activation. PMID- 29497003 TI - Erratum. PMID- 29497002 TI - The Injustice of Being Judged by the Errors of Others: The Tragic Tale of the Battle for PET Reimbursement. PMID- 29496999 TI - LysMD3 is a type II membrane protein without an in vivo role in the response to a range of pathogens. AB - Germline-encoded receptors recognizing common pathogen-associated molecular patterns are a central element of the innate immune system and play an important role in shaping the host response to infection. Many of the innate immune molecules central to these signaling pathways are evolutionarily conserved. LysMD3 is a novel molecule containing a putative peptidoglycan-binding domain that has orthologs in humans, mice, zebrafish, flies, and worms. We found that the lysin motif (LysM) of LysMD3 is likely related to a previously described peptidoglycan-binding LysM found in bacteria. Mouse LysMD3 is a type II integral membrane protein that co-localizes with GM130+ structures, consistent with localization to the Golgi apparatus. We describe here two lines of mLysMD3 deficient mice for in vivo characterization of mLysMD3 function. We found that mLysMD3-deficient mice were born at Mendelian ratios and had no obvious pathological abnormalities. They also exhibited no obvious immune response deficiencies in a number of models of infection and inflammation. mLysMD3 deficient mice exhibited no signs of intestinal dysbiosis by 16S analysis or alterations in intestinal gene expression by RNA sequencing. We conclude that mLysMD3 contains a LysM with cytoplasmic orientation, but we were unable to define a physiological role for the molecule in vivo. PMID- 29497005 TI - Image Gently Alliance 2017 Butterfly Award. PMID- 29497004 TI - Erratum. PMID- 29497006 TI - Thomas Named Editor of the Journal of Nuclear Medicine Technology. PMID- 29497007 TI - New NIA/NIH Alzheimer Disease Consortium. PMID- 29497008 TI - ABNM Launches CertLink Longitudinal Assessment Program. PMID- 29497012 TI - FDA Releases Drafts on Device Review and on Targeted Therapies. PMID- 29497009 TI - SNMMI Leadership Update: Advancing Research and Discovery. PMID- 29497013 TI - Genetic basis of channelopathies and cardiomyopathies in Hong Kong Chinese patients: a 10-year regional laboratory experience. AB - INTRODUCTION: Hereditary channelopathies and cardiomyopathies are potentially lethal and are clinically and genetically heterogeneous, involving at least 90 genes. Genetic testing can provide an accurate diagnosis, guide treatment, and enable cascade screening. The genetic basis among the Hong Kong Chinese population is largely unknown. We aimed to report on 28 unrelated patients with positive genetic findings detected from January 2006 to December 2015. METHODS: Sanger sequencing was performed for 28 unrelated patients with a clinical diagnosis of channelopathies or cardiomyopathies, testing for the following genes: KCNQ1,KCNH2,KCNE1,KCNE2, and SCN5A, for long QT syndrome; SCN5A for Brugada syndrome; RYR2 for catecholaminergic polymorphic ventricular tachycardia; MYH7 and MYBPC3 for hypertrophic cardiomyopathy; LMNA for dilated cardiomyopathy; and PKP2 and DSP for arrhythmogenic right ventricular dysplasia/cardiomyopathy. RESULTS: There were 17 males and 11 females; their mean age at diagnosis was 39 years (range, 1-80 years). The major clinical presentations included syncope, palpitations, and abnormal electrocardiography findings. A family history was present in 13 (46%) patients. There were 26 different heterozygous mutations detected, of which six were novel-two in SCN5A (NM_198056.2:c.429del and c.2024 11T>A), two in MYBPC3 (NM_000256.3:c.906-22G>A and c.2105_2106del), and two in LMNA (NM_170707.3:c.73C>A and c.1209_1213dup). CONCLUSIONS: We have characterised the genetic heterogeneity in channelopathies and cardiomyopathies among Hong Kong Chinese patients in a 10-year case series. Correct interpretation of genetic findings is difficult and requires expertise and experience. Caution regarding issues of non-penetrance, variable expressivity, phenotype-genotype correlation, susceptibility risk, and digenic inheritance is necessary for genetic counselling and cascade screening. PMID- 29497014 TI - High-resolution structure of the Influenza A virus PB2cap binding domain illuminates the changes induced by ligand binding. AB - In the face of increasing drug resistance and the rapidly increasing necessity for practicality in clinical settings, drugs targeting different viral proteins are needed in order to control influenza A and B. A small molecule that tenaciously adheres to the PB2cap binding domain, part of the heterotrimeric RNA polymerase machinery of influenza A virus and influenza B virus, is a promising drug candidate. Understanding the anatomic behavior of PB2cap upon ligand binding will aid in the development of a more robust inhibitor. In this report, the anatomic behavior of the influenza A virus PB2cap domain is established by solving the crystal structure of native influenza A virus PB2cap at 1.52 A resolution. By comparing it with the ligand-bound structure, the dissociation and rotation of the ligand-binding domain in PB2cap from the C-terminal domain is identified. This domain movement is present in many PB2cap structures, suggesting its functional relevance for polymerase activity. PMID- 29497015 TI - YopT domain of the PfhB2 toxin from Pasteurella multocida: protein expression, characterization, crystallization and crystallographic analysis. AB - Pasteurella multocida causes respiratory-tract infections in a broad range of animals, as well as opportunistic infections in humans. P. multocida secretes a multidomain toxin called PfhB2, which contains a YopT-like cysteine protease domain at its C-terminus. The YopT domain of PfhB2 contains a well conserved Cys His-Asp catalytic triad that defines YopT family members, and shares high sequence similarity with the prototype YopT from Yersinia sp. To date, only one crystal structure of a YopT family member has been reported; however, additional structural information is needed to help characterize the varied substrate specificity and enzymatic action of this large protease family. Here, a catalytically inactive C3733S mutant of PfhB2 YopT that provides enhanced protein stability was used with the aim of gaining structural insight into the diversity within the YopT protein family. To this end, the C3733S mutant of PfhB2 YopT has been successfully cloned, overexpressed, purified and crystallized. Diffraction data sets were collected from native crystals to 3.5 A resolution and a single wavelength anomalous data set was collected from an iodide-derivative crystal to 3.2 A resolution. Data pertaining to crystals belonging to space group P31, with unit-cell parameters a = 136.9, b = 136.9, c = 74.7 A for the native crystals and a = 139.2, b = 139.2, c = 74.7 A for the iodide-derivative crystals, are discussed. PMID- 29497016 TI - The first crystal structure of manganese superoxide dismutase from the genus Staphylococcus. AB - A recombinant Staphylococcus equorum manganese superoxide dismutase (MnSOD) with an Asp13Arg substitution displays activity over a wide range of pH, at high temperature and in the presence of chaotropic agents, and retains 50% of its activity after irradiation with UVC for up to 45 min. Interestingly, Bacillus subtilis MnSOD does not have the same stability, despite having a closely similar primary structure and thus presumably also tertiary structure. Here, the crystal structure of S. equorum MnSOD at 1.4 A resolution is reported that may explain these differences. The crystal belonged to space group P3221, with unit-cell parameters a = 57.36, b = 57.36, c = 105.76 A, and contained one molecule in the asymmetric unit. The symmetry operation indicates that the enzyme has a dimeric structure, as found in nature and in B. subtilis MnSOD. As expected, their overall structures are nearly identical. However, the loop connecting the helical and alpha/beta domains of S. equorum MnSOD is shorter than that in B. subtilis MnSOD, and adopts a conformation that allows more direct water-mediated hydrogen bond interactions between the amino-acid side chains of the first and last alpha helices in the latter domain. Furthermore, S. equorum MnSOD has a slightly larger buried area compared with the dimer surface area than that in B. subtilis MnSOD, while the residues that form the interaction in the dimer-interface region are highly conserved. Thus, the stability of S. equorum MnSOD may not originate from the dimeric form alone. Furthermore, an additional water molecule was found in the active site. This allows an alternative geometry for the coordination of the Mn atom in the active site of the apo form. This is the first structure of MnSOD from the genus Staphylococcus and may provide a template for the structural study of other MnSODs from this genus. PMID- 29497018 TI - Enhancement of the thermostability of mouse claudin-3 on complex formation with the carboxyl-terminal region of Clostridium perfringens enterotoxin improves crystal quality. AB - Tight junctions regulate substance permeation through intercellular spaces as a physical barrier or a paracellular pathway, and play an important role in maintaining the internal environment. Claudins, which are tetraspan-transmembrane proteins, are pivotal components of tight junctions. In mammals 27 claudin subtypes have been identified, each of which interacts with specific subtypes. Although the crystal structures of several subtypes have been determined, the molecular mechanisms underlying subtype specificity remain unclear. Here, mouse claudin-3 (mCldn3) was crystallized in complex with the C-terminal region of Clostridium perfringens enterotoxin (C-CPE) for the structural analysis of an additional claudin subtype. mCldn3 alone was difficult to crystallize, but complex formation with C-CPE enhanced the thermostability of mCldn3 and facilitated its crystallization. The introduction of an S313A mutation into C-CPE further improved its thermostability, and the resolution limits of the diffraction data sets improved from 8 A for the wild-type complex to 4.7 A for the S313A mutant complex. PMID- 29497017 TI - Cloning, purification and structure determination of the HIV integrase-binding domain of lens epithelium-derived growth factor. AB - Lens epithelium-derived growth factor (LEDGF)/p75 is the dominant binding partner of HIV-1 integrase in human cells. The crystal structure of the HIV integrase binding domain (IBD) of LEDGF has been determined in the absence of ligand. IBD was overexpressed in Escherichia coli, purified and crystallized by sitting-drop vapour diffusion. X-ray diffraction data were collected at Diamond Light Source to a resolution of 2.05 A. The crystals belonged to space group P21, with eight polypeptide chains in the asymmetric unit arranged as an unusual octamer composed of four domain-swapped IBD dimers. IBD exists as a mixture of monomers and dimers in concentrated solutions, but the dimers are unlikely to be biologically relevant. PMID- 29497019 TI - A novel inhibitor stabilizes the inactive conformation of MAPK-interacting kinase 1. AB - Mitogen-activated protein kinase (MAPK)-interacting kinases 1 (Mnk1) and 2 (Mnk2) modulate translation initiation through the phosphorylation of eukaryotic translation initiation factor 4E, which promotes tumorigenesis. However, Mnk1 and Mnk2 are dispensable in normal cells, suggesting that the inhibition of Mnk1 and Mnk2 could be effective in cancer therapy. To provide a structural basis for Mnk1 inhibition, a novel Mnk1 inhibitor was discovered and the crystal structure of Mnk1 in complex with this inhibitor was determined. The crystal structure revealed that the inhibitor binds to the autoinhibited state of Mnk1, stabilizing the Mnk-specific DFD motif in the DFD-out conformation, thus preventing Mnk1 from switching to the active conformation and thereby inhibiting the kinase activity. These results provide a valuable platform for the structure-guided design of Mnk1 inhibitors. PMID- 29497020 TI - Expression, purification and crystallization of phosphoribosyl transferase from a mycobacteriophage. AB - Tuberculosis (TB) continues to remain a leading cause of death globally. Of particular concern is the emergence and rise in incidence of multidrug-resistant and extremely drug-resistant cases of TB. To counter this threat, it is important to explore alternative therapies, including phage therapy. Phage BTCU-1 specifically infects Mycobacterium spp. and kills the majority of them. Intriguingly, many proteins from the phage do not share high amino-acid sequence identity with proteins from species other than phages. Here, the expression, purification and crystallization of one such protein, a putative phosphoribosyl transferase from phage BTCU-1, is reported. The crystals belonged to space group C2221, with unit-cell parameters a = 59.71, b = 64.42, c = 65.32 A, alpha = beta = gamma = 90 degrees . The crystals diffracted X-rays to 2.2 A resolution. PMID- 29497021 TI - Crystal structure of the MSMEG_4306 gene product from Mycobacterium smegmatis. AB - The MSMEG_4306 gene from Mycobacterium smegmatis encodes a protein of unknown function with 242 amino-acid residues that contains a conserved zinc-ribbon domain at its C-terminus. Here, the crystal structure of MSMEG_4306 determined by the single-wavelength anomalous dispersion method using just one zinc ion co purified with the protein is reported. The crystal structure of MSMEG_4306 shows a coiled-coil helix domain in the N-terminal region and a zinc-ribbon domain in the C-terminal region. A structural similarity search against the Protein Data Bank using MSMEG_4306 as a query revealed two similar structures, namely CT398 from Chlamydia trachomatis and HP0958 from Helicobacter pylori, although they share only ~15% sequence identity with MSMEG_4306. Based on comparative analysis, it is predicted that MSMEG_4306 may be involved in secretion systems, possibly by interacting with multiple proteins or nucleic acids. PMID- 29497022 TI - Crystal structure of the Kelch domain of human NS1-binding protein at 1.98 A resolution. AB - NS1-binding protein (NS1-BP), which belongs to the Kelch protein superfamily, was first identified as a novel human 70 kDa protein that interacts with NS1 of Influenza A virus. It is involved in many cell functions, including pre-mRNA splicing, the ERK signalling pathway, the aryl hydrocarbon receptor (AHR) pathway, F-actin organization and protein ubiquitylation. However, the structure of NS1-BP is still unknown, which may impede functional studies. Here, the structure of the C-terminal Kelch domain of NS1-BP (NS1-BP-C; residues 330-642) was determined at 1.98 A resolution. The Kelch domain adopts a highly symmetric six-bladed beta-propeller fold structure. Each blade of the beta-propeller is composed of four antiparallel beta-strands. Comparison of the Kelch-domain structures of NS1-BP and its homologues showed that the Gly-Gly pair in beta strand B and the hydrophobic Trp residue in beta-strand D are highly conserved, while the B-C loops in blades 2 and 6 are variable. This structure of the Kelch domain of NS1-BP extends the understanding of NS1-BP. PMID- 29497024 TI - Atypical chemokine receptor CCRL2 is overexpressed in prostate cancer cells. AB - Atypical chemokine receptors have recently emerged as important molecular players in health and diseases; they affect chemokine availability and function and impact a multitude of pathophysiological events, including the tumorigenesis process. This family of atypical receptors comprises five members: ACKR1/DARC, ACKR2/D6, ACKR3/CXCR7, ACKR4/CCRL1, and ACKR5/CCRL2. This work evaluated the differential expression of these receptors in prostate cancer using quantitative PCR. Further evaluation of CCRL2 at the protein level confirmed its overexpression in a metastatic cell line and in malignant prostatic tissues from patients. CCRL2, a presumed member of the atypical chemokine receptor family, plays a key role in lung dendritic cell trafficking to peripheral lymph nodes. Recent studies have reported the expression of CCRL2 in different human cancer cell lines and tissues. However, its function and expression in prostate cancer has not been previously addressed. PMID- 29497023 TI - Crystal structure of an inferred ancestral bacterial pyruvate decarboxylase. AB - Pyruvate decarboxylase (PDC; EC 4.1.1.1) is a key enzyme in homofermentative metabolism where ethanol is the major product. PDCs are thiamine pyrophosphate- and Mg2+ ion-dependent enzymes that catalyse the non-oxidative decarboxylation of pyruvate to acetaldehyde and carbon dioxide. As this enzyme class is rare in bacteria, current knowledge of bacterial PDCs is extremely limited. One approach to further the understanding of bacterial PDCs is to exploit the diversity provided by evolution. Ancestral sequence reconstruction (ASR) is a method of computational molecular evolution to infer extinct ancestral protein sequences, which can then be synthesized and experimentally characterized. Through ASR a novel PDC was generated, designated ANC27, that shares only 78% amino-acid sequence identity with its closest extant homologue (Komagataeibacter medellinensis PDC, GenBank accession No. WP_014105323.1), yet is fully functional. Crystals of this PDC diffracted to 3.5 A resolution. The data were merged in space group P3221, with unit-cell parameters a = b = 108.33, c = 322.65 A, and contained two dimers (two tetramer halves) in the asymmetric unit. The structure was solved by molecular replacement using PDB entry 2wvg as a model, and the final R values were Rwork = 0.246 (0.3671 in the highest resolution bin) and Rfree = 0.319 (0.4482 in the highest resolution bin). Comparison with extant bacterial PDCs supports the previously observed correlation between decreased tetramer interface area (and number of interactions) and decreased thermostability. PMID- 29497025 TI - In silico prediction of monovalent and chimeric tetravalent vaccines for prevention and treatment of dengue fever. AB - Reverse vaccinology method was used to predict the monovalent peptide vaccine candidate to produce antibodies for therapeutic purpose and to predict tetravalent vaccine candidate to act as a common vaccine to cover all the fever dengue virus serotypes. Envelope (E)-proteins of DENV-1-4 serotypes were used for vaccine prediction using NCBI, Uniprot/Swissprot, Swiss-prot viewer, VaxiJen V2.0, TMHMM, BCPREDS, Propred-1, Propred and MHC Pred,. E-proteins of DENV-1-4 serotypes were identified as antigen from which T cell epitopes, through B cell epitopes, were predicted to act as peptide vaccine candidates. Each selected T cell epitope of E-protein was confirmed to act as vaccine and to induce complementary antibody against particular serotype of dengue virus. Chimeric tetravalent vaccine was formed by the conjugation of four vaccines, each from four dengue serotypes to act as a common vaccine candidate for all the four dengue serotypes. It can be justifiably concluded that the monovalent 9-mer T cell epitope for each DENV serotypes can be used to produce specific antibody agaomst dengue virus and a chimeric common tetravalent vaccine candidate to yield a comparative vaccine to cover any of the four dengue virus serotype. This vaccine is expected to act as highly immunogenic against preventing dengue fever. PMID- 29497026 TI - Right Ventricular Heart Failure from a Cardiac Yolk Sac Tumor. AB - BACKGROUND Cardiac involvement by a malignant tumor is rare. However, this is a case of right heart failure due to cardiac metastasis from a yolk sac tumor. Although a few case reports of cardiac metastasis from yolk sac tumors have been published, to our knowledge this is the first instance of multiple metastases to the right ventricular of yolk sac tumor in an adult male. CASE REPORT The patient is a 46-year-old male with a history of testicular cancer that presented with dyspnea on exertion. He was found to have two large right sided intracardiac masses on echocardiography. Cardiac magnetic resonance imaging (MRI) was obtained to further investigate these masses. Right ventricular function was decreased and concern for right ventricular outflow tract (RVOT) obstruction was present. The patient was taken to the operating room (OR) for resection of the cardiac masses. Pathology revealed the masses to be yolk sac tumors. Despite urgent resection of the tumors, the patient deteriorated clinically, ultimately succumbing to heart failure. CONCLUSIONS This unique presentation of a yolk sac tumor emphasizes the need to keep a broad differential and complete a thorough workup for any cardiac mass. Early diagnosis and treatment of intra-cardiac masses is imperative due to their high rates of mortality. Albeit an uncommon etiology for heart failure, germ cell tumors can potentially metastasize to the heart and present with such a clinical picture. PMID- 29497027 TI - Preoperative Computed Tomography (CT) Evaluation of Anatomical Abnormalities in Endonasal Transsphenoidal Approach in Pituitary Adenoma. AB - BACKGROUND This study aimed to retrospectively analyze patient clinical data to investigate the effects of computed tomography (CT) reconstruction and the measurement of abnormal structures in the endonasal sphenoidal sinus approach on the operative effects in patients undergoing pituitary adenoma resection. MATERIAL AND METHODS The records of 53 patients who underwent pituitary adenoma resection via the endonasal transsphenoidal approach in the Neurosurgery Department of Tai'an City Central Hospital from December 2010 to June 2016 were analyzed retrospectively. All cases showed anatomical abnormalities in the endonasal transsphenoidal approach that were detected by conventional CT scans. The clinical data of the patients were reviewed. After review, 26 patients who underwent preoperative CT reconstruction and measurement of abnormal structures before surgery were included in the observation group (CT reconstruction group), and 27 patients who did not undergo CT reconstruction and measurement of abnormal structures were included in the control group. Data on intraoperative blood loss, surgical time, hospital stay, and postoperative complications were collected to assess the quality of the surgery. RESULTS Compared with the control group, the observation group showed less blood loss (p<0.001), a shorter operation time (p<0.001), fewer postoperative complications (p<0.001), and a shorter hospital stay (p<0.001). CONCLUSIONS Preoperative CT reconstruction and measurement of abnormal structures in patients undergoing pituitary adenoma resection by the endonasal transsphenoidal approach can improve operative quality and reduce complications. PMID- 29497028 TI - Nonsteroidal Anti-Inflammatory Drugs and Analgesics Use by Kidney Transplant Recipients. AB - BACKGROUND Nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics are the most commonly used drugs and are increasingly available over-the-counter (OTC). In certain groups of patients, including kidney transplant recipients, their use may be complicated by adverse effects or drug interactions. The aim of our study was to assess the causes and frequency of OTC NSAIDs or analgesics use, as well as the awareness of related side effects. MATERIAL AND METHODS We enrolled 94 randomly selected kidney transplant recipients, who represented 5% of all kidney transplant recipients at our center. An anonymous survey consisting of 23 multiple-choice questions was administered voluntarily and anonymously. RESULTS In all, 63% of study patients confirmed taking the OTC painkillers; 22% of these patients took these drugs at least several times a week, and 4% took these drugs daily. For 38% of the study kidney transplant recipients, NSAIDs or analgesics were reported to be the only way to manage their pain. In addition, 30% of study patients were unaware of the risks associated with these drugs, despite the fact that 89% of the study patients consider physicians the best source of information. CONCLUSIONS Our study found that 63% of kidney transplant recipients regularly took OTC painkillers and 30% were unaware of the potential adverse effects. This necessitates continuous, ongoing education of kidney transplant recipients about the risks of OTC NSAIDs or analgesics use. PMID- 29497029 TI - Ischemic preconditioning attenuates ischemia/reperfusion-induced kidney injury by activating autophagy via the SGK1 signaling pathway. AB - Ischemic preconditioning (IPC) has a strong renoprotective effect during renal ischemia/reperfusion (I/R) injury that is thought to relate to autophagy. However, the role of autophagy during IPC-afforded renoprotection and the precise mechanisms involved are unknown. In this study, an in vitro hypoxia/reoxygenation (H/R) model was established in which oxygen and glucose deprivation (OGD) was applied to renal cells for 15 h followed by reoxygenation under normal conditions for 30 min, 2 h or 6 h; transient OGD and subsequent reoxygenation were implemented before prolonged H/R injury to achieve hypoxic preconditioning (HPC). 3-Methyladenine (3-MA) was used to inhibit autophagy. In a renal I/R injury model, rats were subjected to 40 min of renal ischemia followed by 6 h, 12 h or 24 h of reperfusion. IPC was produced by four cycles of ischemia (8 min each) followed by 5 min of reperfusion prior to sustained ischemia. We found that IPC increased LC3II and Beclin-1 levels and decreased SQSTM/p62 and cleaved caspase-3 levels in a time-dependent manner during renal I/R injury, as well as increased the number of intracellular double-membrane vesicles in injured renal cells. IPC induced renal protection was efficiently attenuated by pretreatment with 5 mM 3 MA. Pretreatment with IPC also dynamically affected the expression of SGK1/FOXO3a/HIF-1alpha signaling components. Moreover, knocking down SGK1 expression significantly downregulated phosphorylated-FOXO3a (p-FOXO3a)/FOXO3 and HIF-1alpha, suppressed LC3II and Beclin-1 levels, increased SQSTM/p62 and cleaved caspase-3 levels, and abolished the protective effect of IPC against I/R-induced renal damage. SGK1 overexpression efficiently increased p-FOXO3a/FOXO3 and HIF 1alpha levels, promoted the autophagy flux and enhanced the protective effect mediated by HPC. Furthermore, FOXO3a overexpression decreased HIF-1alpha protein levels, inhibited HIF-1alpha transcriptional activity and reduced the protective effect of IPC. Our study indicates that IPC can ameliorate renal I/R injury by promoting autophagy through the SGK1 pathway. PMID- 29497030 TI - Molecular probes reveal deviations from Amontons' law in multi-asperity frictional contacts. AB - Amontons' law defines the friction coefficient as the ratio between friction force and normal force, and assumes that both these forces depend linearly on the real contact area between the two sliding surfaces. However, experimental testing of frictional contact models has proven difficult, because few in situ experiments are able to resolve this real contact area. Here, we present a contact detection method with molecular-level sensitivity. We find that while the friction force is proportional to the real contact area, the real contact area does not increase linearly with normal force. Contact simulations show that this is due to both elastic interactions between asperities on the surface and contact plasticity of the asperities. We reproduce the contact area and fine details of the measured contact geometry by including plastic hardening into the simulations. These new insights will pave the way for a quantitative microscopic understanding of contact mechanics and tribology. PMID- 29497031 TI - WW domain-binding protein 2 acts as an oncogene by modulating the activity of the glycolytic enzyme ENO1 in glioma. AB - WW domain-binding protein 2 (WBP2) has been demonstrated as oncogenic in breast cancer. Many studies have revealed the WBP2 gene as a high-risk gene for leukoariaosis and cerebral white matter lesions is important in the pathologic stage of glioma development. This study aimed to illustrate the underlying mechanism by which WBP2 regulates the process of glioma development. The expression pattern of WBP2 in several tumor cells was determined, clarifying the carcinogenic action of WBP2 in glioma cells. Overexpression of WBP2 in glioma cells promoted cell proliferation and migration, and the number of S-phase cells, whereas the depletion of WBP2 by RNAi-mediated knockdown restrained cell growth and cell cycle progression. Upregulation of WBP2 significantly enhanced the tumorigenic ability of U251 cells in vivo. MS/GST pulldown assay identified alpha enolase (ENO1) and Homer protein homolog 3 (Homer3) as novel potent interaction partners of WBP2. Knockdown of ENO1 or Homer3 allowed cell growth and migration to return to normal levels. Furthermore, in vitro and in vivo experiments indicated that the oncogenic role of WBP2 in glioma was through modulating ENO1 and glycolysis activity via the ENO1-PI3K/Akt signaling pathway. Collectively, these results reveal that WBP2 plays a vital role in the occurrence and development of glioma, indicating a target gene for glioblastoma treatment. PMID- 29497032 TI - De novo adipocyte differentiation from Pdgfrbeta+ preadipocytes protects against pathologic visceral adipose expansion in obesity. AB - Pathologic expansion of white adipose tissue (WAT) in obesity is characterized by adipocyte hypertrophy, inflammation, and fibrosis; however, factors triggering this maladaptive remodeling are largely unknown. Here, we test the hypothesis that the potential to recruit new adipocytes from Pdgfrbeta+ preadipocytes determines visceral WAT health in obesity. We manipulate levels of Pparg, the master regulator of adipogenesis, in Pdgfrbeta+ precursors of adult mice. Increasing the adipogenic capacity of Pdgfrbeta+ precursors through Pparg overexpression results in healthy visceral WAT expansion in obesity and adiponectin-dependent improvements in glucose homeostasis. Loss of mural cell Pparg triggers pathologic visceral WAT expansion upon high-fat diet feeding. Moreover, the ability of the TZD class of anti-diabetic drugs to promote healthy visceral WAT remodeling is dependent on mural cell Pparg. These data highlight the protective effects of de novo visceral adipocyte differentiation in these settings, and suggest Pdgfrbeta+ adipocyte precursors as targets for therapeutic intervention in diabetes. PMID- 29497033 TI - Sei-1 promotes double minute chromosomes formation through activation of the PI3K/Akt/BRCA1-Abraxas pathway and induces double-strand breaks in NIH-3T3 fibroblasts. AB - Sei-1 is a potential oncogene that plays an important role in promoting genomic instability. Double minute chromosomes (DMs) are hallmarks of gene amplification and contribute to tumorigenesis. Defects in the DNA double-strand break (DSB) repairing pathways can lead to gene amplification. To date, the mechanisms governing the formation of DMs induced by Sei-1 are not fully understood. We established DMs induced by Sei-1 in the NIH-3T3 cell line. RNA-sequencing was used to identify key characteristics of differentially expressed genes. Metaphase spreads were used to calculate DM numbers. Immunofluorescence was employed to detect gammaH2AX foci. Western blot and Akt pathway inhibition experiments were performed to reveal the role of the PI3K/Akt/BRCA1-Abraxas pathway in Sei-1 induced DMs. Luciferase reporter assay was employed to explore the regulatory mechanisms between Sei-1 and BRCA1. DM formation was associated with a deficiency in DSB repair. Based on this finding, activation of the PI3K/Akt/BRCA1-Abraxas pathway was found to increase the DM population with passage in vivo, and inhibition resulted in a reduction of DMs. Apart from this, it was shown for the first time that Sei-1 could directly regulate the expression of BRCA1. Our results suggest that the PI3K/Akt/BRCA1-Abraxas pathway is responsible for the formation of DMs induced by Sei-1. PMID- 29497034 TI - Proteasome inhibition blocks necroptosis by attenuating death complex aggregation. AB - Proteasome inhibitors have achieved clinical success because they trigger intrinsic and extrinsic cell death to eliminate susceptible human cancers. The ubiquitin-proteasome protein degradation system regulates signaling pathways by controlling levels of components such as cellular inhibitor of apoptosis (cIAP)1 and cIAP2 in TNF-mediated cell death. Here, we sought to evaluate the contribution of necroptosis to the cell death pattern induced by the specific proteasome inhibitor Carfilzomib (Cf). Proteasome inhibitor-sensitive multiple myeloma cell lines die in response to Cf by apoptosis in combination with serine protease-dependent death, without any contribution of RIPK3-dependent necroptosis. Proteasome inhibition leads to the induction of apoptotic markers such as activated caspase-3 rather than necroptotic markers such as phosphorylated-MLKL in all cell lines tested. In HT-29 cells, Cf attenuates the late RIPK1 interaction with TNFR1 during TNF-induced necroptosis without altering the sensitivity of cIAP antagonists. Cf treatment results in decreased translocation of death signaling components RIPK1, FADD, caspase-8, cFLIP, and RIPK3 to detergent insoluble fractions. Our results show that proteasome inhibition with Cf impairs necroptosis and favors apoptosis even in cells with intact necroptotic machinery. Following the induction of TNFR1-mediated necroptosis, proteasome activity stabilizes effective aggregation and activation of ripoptosome/necrosome complexes. PMID- 29497035 TI - TET-mediated epimutagenesis of the Arabidopsis thaliana methylome. AB - DNA methylation in the promoters of plant genes sometimes leads to transcriptional repression, and the loss of DNA methylation in methyltransferase mutants results in altered gene expression and severe developmental defects. However, many cases of naturally occurring DNA methylation variations have been reported, whereby altered expression of differentially methylated genes is responsible for agronomically important traits. The ability to manipulate plant methylomes to generate epigenetically distinct individuals could be invaluable for breeding and research purposes. Here, we describe "epimutagenesis," a method to rapidly generate DNA methylation variation through random demethylation of the Arabidopsis thaliana genome. This method involves the expression of a human ten eleven translocation (TET) enzyme, and results in widespread hypomethylation that can be inherited to subsequent generations, mimicking mutants in the maintenance of DNA methyltransferase met1. Application of epimutagenesis to agriculturally significant plants may result in differential expression of alleles normally silenced by DNA methylation, uncovering previously hidden phenotypic variations. PMID- 29497036 TI - Reconstruction of complex single-cell trajectories using CellRouter. AB - A better understanding of the cell-fate transitions that occur in complex cellular ecosystems in normal development and disease could inform cell engineering efforts and lead to improved therapies. However, a major challenge is to simultaneously identify new cell states, and their transitions, to elucidate the gene expression dynamics governing cell-type diversification. Here, we present CellRouter, a multifaceted single-cell analysis platform that identifies complex cell-state transition trajectories by using flow networks to explore the subpopulation structure of multi-dimensional, single-cell omics data. We demonstrate its versatility by applying CellRouter to single-cell RNA sequencing data sets to reconstruct cell-state transition trajectories during hematopoietic stem and progenitor cell (HSPC) differentiation to the erythroid, myeloid and lymphoid lineages, as well as during re-specification of cell identity by cellular reprogramming of monocytes and B-cells to HSPCs. CellRouter opens previously undescribed paths for in-depth characterization of complex cellular ecosystems and establishment of enhanced cell engineering approaches. PMID- 29497037 TI - Rapid measurement of inhibitor binding kinetics by isothermal titration calorimetry. AB - Although drug development typically focuses on binding thermodynamics, recent studies suggest that kinetic properties can strongly impact a drug candidate's efficacy. Robust techniques for measuring inhibitor association and dissociation rates are therefore essential. To address this need, we have developed a pair of complementary isothermal titration calorimetry (ITC) techniques for measuring the kinetics of enzyme inhibition. The advantages of ITC over standard techniques include speed, generality, and versatility; ITC also measures the rate of catalysis directly, making it ideal for quantifying rapid, inhibitor-dependent changes in enzyme activity. We used our methods to study the reversible covalent and non-covalent inhibitors of prolyl oligopeptidase (POP). We extracted kinetics spanning three orders of magnitude, including those too rapid for standard methods, and measured sub-nM binding affinities below the typical ITC limit. These results shed light on the inhibition of POP and demonstrate the general utility of ITC-based enzyme inhibition kinetic measurements. PMID- 29497038 TI - The distinct roles of mesenchymal stem cells in the initial and progressive stage of hepatocarcinoma. AB - Increasing evidences suggest that mesenchymal stem cells (MSCs) could migrate to the tumor site and play a vital role in tumorigenesis and progression. However, it is still a lively debate whether MSCs exert a pro- or anticancer action. Cancer development and progression is a multistep process. Therefore, we investigated the effect of MSCs on hepatocarcinoma and whether the role of MSCs depends on the stage of cancer development. In our study, chronically exposing rats to N-diethylnitrosamine (DEN) was employed as hepatocarcinoma model. And to evaluate the effect of MSCs on hepatocarcinoma, the animals were divided into three groups: rats were injected with MSCs in the initial (DEN + MSC (Is) group) or progressive stage (DEN + MSC (Ps) group) of hepatocarcinoma, respectively. Rats injected with PBS were used as control (DEN group). Interestingly, we found that MSCs had a tumor-suppressive effect in the Is of hepatocarcinoma, yet a tumor-promotive effect in the Ps. In the Is, MSCs showed a protective role against drug damage, possibly through reducing DNA damage and ROS accumulation. Meanwhile, MSCs in the Is also exhibited anti-inflammatory and anti-liver fibrosis effect. Further, in the Ps, MSCs facilitated tumor formation not only by enhancing cancer cell proliferation but also through promoting stem cell-like properties and epithelial-mesenchymal transition of liver cancer cells. Taken together, MSCs have a paradoxical role in the different stages of hepatocarcinogenesis, which sheds new light on the role of MSCs in hepatocarcinoma and cautions the therapeutic application of MSCs for liver cancer. PMID- 29497040 TI - Podocyte-specific Rac1 deficiency ameliorates podocyte damage and proteinuria in STZ-induced diabetic nephropathy in mice. AB - Activation of Ras-related C3 botulinum toxin substrate 1 (Rac1) has been implicated in diverse kidney diseases, yet its in vivo significance in diabetic nephropathy (DN) is largely unknown. In the present study, we demonstrated a podocyte-specific Rac1-deficient mouse strain and showed that specific inhibition of Rac1 was able to attenuate diabetic podocyte injury and proteinuria by the blockade of Rac1/PAK1/p38/beta-catenin signaling cascade, which reinstated the integrity of podocyte slit diaphragms (SD), rectified the effacement of foot processes (FPs), and prevented the dedifferentiation of podocytes. In vitro, we showed Rac1/PAK1 physically bound to beta-catenin and had a direct phosphorylation modification on its C-terminal Ser675, leading to less ubiquitylated beta-catenin, namely more stabilized beta-catenin, and its nuclear migration under high-glucose conditions; further, p38 activation might be responsible for beta-catenin nuclear accumulation via potentiating myocyte specific enhancer factor 2C (MEF2c) phosphorylation. These findings provided evidence for a potential renoprotective and therapeutic strategy of cell-specific Rac1 deficiency for DN and other proteinuric diseases. PMID- 29497039 TI - ER-mitochondria signaling in Parkinson's disease. AB - Mitochondria form close physical contacts with a specialized domain of the endoplasmic reticulum (ER), known as the mitochondria-associated membrane (MAM). This association constitutes a key signaling hub to regulate several fundamental cellular processes. Alterations in ER-mitochondria signaling have pleiotropic effects on a variety of intracellular events resulting in mitochondrial damage, Ca2+ dyshomeostasis, ER stress and defects in lipid metabolism and autophagy. Intriguingly, many of these cellular processes are perturbed in neurodegenerative diseases. Furthermore, increasing evidence highlights that ER-mitochondria signaling contributes to these diseases, including Parkinson's disease (PD). PD is the second most common neurodegenerative disorder, for which effective mechanism-based treatments remain elusive. Several PD-related proteins localize at mitochondria or MAM and have been shown to participate in ER-mitochondria signaling regulation. Likewise, PD-related mutations have been shown to damage this signaling. Could ER-mitochondria associations be the link between pathogenic mechanisms involved in PD, providing a common mechanism? Would this provide a pharmacological target for treating this devastating disease? In this review, we aim to summarize the current knowledge of ER-mitochondria signaling and the recent evidence concerning damage to this signaling in PD. PMID- 29497041 TI - MTSS1 and SCAMP1 cooperate to prevent invasion in breast cancer. AB - Cell-cell adhesions constitute the structural "glue" that retains cells together and contributes to tissue organisation and physiological function. The integrity of these structures is regulated by extracellular and intracellular signals and pathways that act on the functional units of cell adhesion such as the cell adhesion molecules/adhesion receptors, the extracellular matrix (ECM) proteins and the cytoplasmic plaque/peripheral membrane proteins. In advanced cancer, these regulatory pathways are dysregulated and lead to cell-cell adhesion disassembly, increased invasion and metastasis. The Metastasis suppressor protein 1 (MTSS1) plays a key role in the maintenance of cell-cell adhesions and its loss correlates with tumour progression in a variety of cancers. However, the mechanisms that regulate its function are not well-known. Using a system biology approach, we unravelled potential interacting partners of MTSS1. We found that the secretory carrier-associated membrane protein 1 (SCAMP1), a molecule involved in post-Golgi recycling pathways and in endosome cell membrane recycling, enhances Mtss1 anti-invasive function in HER2+/ER-/PR- breast cancer, by promoting its protein trafficking leading to elevated levels of RAC1-GTP and increased cell-cell adhesions. This was clinically tested in HER2 breast cancer tissue and shown that loss of MTSS1 and SCAMP1 correlates with reduced disease specific survival. In summary, we provide evidence of the cooperative roles of MTSS1 and SCAMP1 in preventing HER2+/ER-/PR- breast cancer invasion and we show that the loss of Mtss1 and Scamp1 results in a more aggressive cancer cell phenotype. PMID- 29497042 TI - Genetic study links components of the autonomous nervous system to heart-rate profile during exercise. AB - Heart rate (HR) responds to exercise by increasing during exercise and recovering after exercise. As such, HR is an important predictor of mortality that researchers believe is modulated by the autonomic nervous system. However, the mechanistic basis underlying inter-individual differences has yet to be explained. Here, we perform a large-scale genome-wide analysis of HR increase and HR recovery in 58,818 UK Biobank individuals. Twenty-five independent SNPs in 23 loci are identified to be associated (p < 8.3 * 10-9) with HR increase or HR recovery. A total of 36 candidate causal genes are prioritized that are enriched for pathways related to neuron biology. No evidence is found of a causal relationship with mortality or cardiovascular diseases. However, a nominal association with parental lifespan requires further study. In conclusion, the findings provide new biological and clinical insight into the mechanistic underpinnings of HR response to exercise. The results also underscore the role of the autonomous nervous system in HR recovery. PMID- 29497043 TI - Vangl2 regulates spermatid planar cell polarity through microtubule (MT)-based cytoskeleton in the rat testis. AB - During spermatogenesis, developing elongating/elongated spermatids are highly polarized cells, displaying unique apico-basal polarity. For instance, the heads of spermatids align perpendicular to the basement membrane with their tails pointing to the tubule lumen. Thus, the maximal number of spermatids are packed within the limited space of the seminiferous epithelium to support spermatogenesis. Herein, we reported findings that elongating/elongated spermatids displayed planar cell polarity (PCP) in adult rat testes in which the proximal end of polarized spermatid heads were aligned uniformly across the plane of the seminiferous epithelium based on studies using confocal microscopy and 3 dimensional (D) reconstruction of the seminiferous tubules. We also discovered that spermatid PCP was regulated by PCP protein Vangl2 (Van Gogh-like protein 2) since Vangl2 knockdown by RNAi was found to perturb spermatid PCP. More important, Vangl2 exerted its regulatory effects through changes in the organization of the microtubule (MT)-based cytoskeleton in the seminiferous epithelium. These changes were mediated via the downstream signaling proteins atypical protein kinase C xi (PKCzeta) and MT-associated protein (MAP)/microtubule affinity-regulating kinase 2 (MARK2). These findings thus provide new insights regarding the biology of spermatid PCP during spermiogenesis. PMID- 29497045 TI - Preparation and Imaging Investigation of Dual-targeted C3F8-filled PLGA Nanobubbles as a Novel Ultrasound Contrast Agent for Breast Cancer. AB - Molecularly-targeted contrast enhanced ultrasound (US) imaging is a promising imaging strategy with large potential for improving diagnostic accuracy of conventional US imaging in breast cancer detection. Therefore, we constructed a novel dual-targeted nanosized US contrast agent (UCA) directed at both vascular endothelial growth factor receptor 2 (VEGFR2) and human epidermal growth factor receptor 2 (HER2) based on perfluoropropane (C3F8)-filled poly(lactic-co-glycolic acid) (PLGA) (NBs) for breast cancer detection. In vitro, single- or dual targeted PLGA NBs showed high target specificities and better effects of target enhancement in VEGFR2 or HER2-positive cells. In vivo, US imaging signal in the murine breast cancer model was significantly higher (P < 0.01) for dual-targeted NBs than single-targeted and non-targeted NBs. Small animal fluorescence imaging further confirmed the special affinity of the dual-targeted nanosized contrast agent to both VEGFR2 and HER2. Immunofluorescence and immunohistochemistry staining confirmed the expressions of VEGFR2 and HER2 on tumor neovasculature and tumor cells of breast cancer. In conclusions, the feasibility of using dual targeted PLGA NBs to enhance ultrasonic images is demonstrated in vitro and in vivo. This may be a promising approach to target biomarkers of breast cancer for two site-specific US molecular imaging. PMID- 29497046 TI - Electron heating and thermal relaxation of gold nanorods revealed by two dimensional electronic spectroscopy. AB - To elucidate the complex interplay between the size and shape of gold nanorods and their electronic, photothermal, and optical properties for molecular imaging, photothermal therapy, and optoelectronic devices, it is a prerequisite to characterize ultrafast electron dynamics in gold nanorods. Time-resolved transient absorption (TA) studies of plasmonic electrons in various nanostructures have revealed the time scales for electron heating, lattice vibrational excitation, and phonon relaxation processes in condensed phases. However, because linear spectroscopic and time-resolved TA signals are vulnerable to inhomogeneous line-broadening, pure dephasing and direct electron heating effects are difficult to observe. Here we show that femtosecond two-dimensional electronic spectroscopy, with its unprecedented time resolution and phase sensitivity, can be used to collect direct experimental evidence for ultrafast electron heating, anomalously strong coherent and transient electronic plasmonic responses, and homogenous dephasing processes resulting from electron-vibration couplings even for polydisperse gold nanorods. PMID- 29497044 TI - Elongator and codon bias regulate protein levels in mammalian peripheral neurons. AB - Familial dysautonomia (FD) results from mutation in IKBKAP/ELP1, a gene encoding the scaffolding protein for the Elongator complex. This highly conserved complex is required for the translation of codon-biased genes in lower organisms. Here we investigate whether Elongator serves a similar function in mammalian peripheral neurons, the population devastated in FD. Using codon-biased eGFP sensors, and multiplexing of codon usage with transcriptome and proteome analyses of over 6,000 genes, we identify two categories of genes, as well as specific gene identities that depend on Elongator for normal expression. Moreover, we show that multiple genes in the DNA damage repair pathway are codon-biased, and that with Elongator loss, their misregulation is correlated with elevated levels of DNA damage. These findings link Elongator's function in the translation of codon biased genes with both the developmental and neurodegenerative phenotypes of FD, and also clarify the increased risk of cancer associated with the disease. PMID- 29497047 TI - Adenovirus-prime and baculovirus-boost heterologous immunization achieves sterile protection against malaria sporozoite challenge in a murine model. AB - With the increasing prevalence of artemisinin-resistant malaria parasites, a highly efficacious and durable vaccine for malaria is urgently required. We have developed an experimental virus-vectored vaccine platform based on an envelope modified baculovirus dual-expression system (emBDES). Here, we show a conceptually new vaccine platform based on an adenovirus-prime/emBDES-boost heterologous immunization regimen expressing the Plasmodium falciparum circumsporozoite protein (PfCSP). A human adenovirus 5-prime/emBDES-boost heterologous immunization regimen consistently achieved higher sterile protection against transgenic P. berghei sporozoites expressing PfCSP after a mosquito-bite challenge than reverse-ordered or homologous immunization. This high protective efficacy was also achieved with a chimpanzee adenovirus 63-prime/emBDES-boost heterologous immunization regimen against an intravenous sporozoite challenge. Thus, we show that the adenovirus-prime/emBDES-boost heterologous immunization regimen confers sterile protection against sporozoite challenge by two individual routes, providing a promising new malaria vaccine platform for future clinical use. PMID- 29497048 TI - Reducing group delay spread using uniform long-period gratings. AB - Despite the promise of an orders-of-magnitude increase in transmission capacity, practical implementation of mode-division multiplexing faces a number of challenges. The most important among them is the complexity of digital signal processing (DSP) for compensating mode crosstalk and modal dispersion. The most promising method proposed so far for reducing this DSP complexity is strong mode coupling. We propose and demonstrate, for the first time, a method of inducing strong mode coupling and reducing group delay spread using uniform long-period gratings (LPGs). Even though the LPGs have a fixed grating period, mode coupling is effective among all mode groups and over a broad wavelength range. Both insertion loss and mode-dependent loss can be significantly reduced by optimizing the index profile of and the number of modes supported by the fiber in which the LPG is applied. PMID- 29497051 TI - DAX1 promotes cervical cancer cell growth and tumorigenicity through activation of Wnt/beta-catenin pathway via GSK3beta. AB - DAX1 is well known for its fundamental role in several types of cancer, while its biological role in cervical cancer remains largely unexplored. The expression of DAX1 in cervical carcinoma tissue was examined using immunohistochemistry and western blot. The effects of DAX1 silencing on the cell growth, tumor formation, and CSC (cancer stem cell) characteristics were also investigated. DAX1 expressed a gradual increase from normal cervix to high-grade squamous intraepithelial lesions, and consequently to cervical cancer. Silence of DAX1 significantly inhibited the cell growth, tumorigenicity, and tumorsphere formation. Furthermore, the TOP/FOP-Flash reporter assay revealed that Wnt/beta-catenin pathway was significantly inactivated in DAX1-silenced cervical cancer cells with the downregulation of Wnt/beta-catenin targeting genes, including cyclinD1 and c myc. Moreover, dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assay confirmed that DAX1 transcriptionally repressed glycogen synthase kinase 3beta (GSK3beta), an inhibitor of the Wnt/beta-catenin pathway, by physically interacting with -666~-444 motif on the GSK3beta promoter. Additionally, the blockage of GSK3beta by CHIR-99021 resulted in a significant increase of CSC characteristics induced by the silence of DAX1. Our data demonstrated that DAX1 is overexpressed in cervical cancer, and that it promotes cell growth and tumorigenicity through activating Wnt/beta-catenin pathway mediated by GSK3beta. PMID- 29497052 TI - Introgression of a functional epigenetic OsSPL14WFP allele into elite indica rice genomes greatly improved panicle traits and grain yield. AB - Rice yield potential has been stagnant since the Green Revolution in the late 1960s, especially in tropical rice cultivars. We evaluated the effect of two major genes that regulate grain number, Gn1a/OsCKX2 and IPA1/WFP/OsSPL14, in elite indica cultivar backgrounds. The yield-positive Gn1a-type 3 and OsSPL14WFP alleles were introgressed respectively through marker-assisted selection (MAS). The grain numbers per panicle (GNPP) were compared between the recipient allele and the donor allele groups using segregating plants in BC3F2 and BC3F3 generations. There was no significant difference in GNPP between the two Gn1a alleles, suggesting that the Gn1a-type 3 allele was not effective in indica cultivars. However, the OsSPL14WFP allele dramatically increased GNPP by 10.6 59.3% in all four different backgrounds across cropping seasons and generations, indicating that this allele provides strong genetic gain to elite indica cultivars. Eventually, five high-yielding breeding lines were bred using the OsSPL14WFP allele by MAS with a conventional breeding approach that showed increased grain yield by 28.4-83.5% (7.87-12.89 t/ha) vis-a-vis the recipient cultivars and exhibited higher yield (~64.7%) than the top-yielding check cultivar, IRRI 156 (7.82 t/ha). We demonstrated a strong possibility to increase the genetic yield potential of indica rice varieties through allele mining and its application. PMID- 29497050 TI - Whole-exome sequencing reveals the origin and evolution of hepato cholangiocarcinoma. AB - Hepatocellular-cholangiocarcinoma (H-ChC) is a rare subtype of liver cancer with clinicopathological features of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). To date, molecular mechanisms underlying the co-existence of HCC and iCCA components in a single tumor remain elusive. Here, we show that H-ChC samples contain substantial private mutations from WES analyses, ranging from 33.1 to 86.4%, indicative of substantive intratumor heterogeneity (ITH). However, on the other hand, numerous ubiquitous mutations shared by HCC and iCCA suggest the monoclonal origin of H-ChC. Mutated genes identified herein, e.g., VCAN, ACVR2A, and FCGBP, are speculated to contribute to distinct differentiation of HCC and iCCA within H-ChC. Moreover, immunohistochemistry demonstrates that EpCAM is highly expressed in 80% of H-ChC, implying the stemness of such liver cancer. In summary, our data highlight the monoclonal origin and stemness of H-ChC, as well as substantial intratumoral heterogeneity. PMID- 29497049 TI - Redox metals homeostasis in multiple sclerosis and amyotrophic lateral sclerosis: a review. AB - The effect of redox metals such as iron and copper on multiple sclerosis and amyotrophic lateral sclerosis has been intensively studied. However, the origin of these disorders remains uncertain. This review article critically describes the physiology of redox metals that produce oxidative stress, which in turn leads to cascades of immunomodulatory alteration of neurons in multiple sclerosis and amyotrophic lateral sclerosis. Iron and copper overload has been well established in motor neurons of these diseases' lesions. On the other hand, the role of other metals like cadmium participating indirectly in the redox cascade of neurobiological mechanism is less studied. In the second part of this review, we focus on this less conspicuous correlation between cadmium as an inactive-redox metal and multiple sclerosis and amyotrophic lateral sclerosis, providing novel treatment modalities and approaches as future prospects. PMID- 29497053 TI - Exogenous hydrogen sulfide gas does not induce hypothermia in normoxic mice. AB - Hydrogen sulfide (H2S, 80 ppm) gas in an atmosphere of 17.5% oxygen reportedly induces suspended animation in mice; a state analogous to hibernation that entails hypothermia and hypometabolism. However, exogenous H2S in combination with 17.5% oxygen is able to induce hypoxia, which in itself is a trigger of hypometabolism/hypothermia. Using non-invasive thermographic imaging, we demonstrated that mice exposed to hypoxia (5% oxygen) reduce their body temperature to ambient temperature. In contrast, animals exposed to 80 ppm H2S under normoxic conditions did not exhibit a reduction in body temperature compared to normoxic controls. In conclusion, mice induce hypothermia in response to hypoxia but not H2S gas, which contradicts the reported findings and putative contentions. PMID- 29497055 TI - Author Correction: Well-being, problematic alcohol consumption and acute subjective drug effects in past-year ayahuasca users: a large, international, self-selecting online survey. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29497054 TI - Multipotent Adult Progenitor Cells Support Lymphatic Regeneration at Multiple Anatomical Levels during Wound Healing and Lymphedema. AB - Lymphatic capillary growth is an integral part of wound healing, yet, the combined effectiveness of stem/progenitor cells on lymphatic and blood vascular regeneration in wounds needs further exploration. Stem/progenitor cell transplantation also emerged as an approach to cure lymphedema, a condition caused by lymphatic system deficiency. While lymphedema treatment requires lymphatic system restoration from the capillary to the collector level, it remains undetermined whether stem/progenitor cells support a complex regenerative response across the entire anatomical spectrum of the system. Here, we demonstrate that, although multipotent adult progenitor cells (MAPCs) showed potential to differentiate down the lymphatic endothelial lineage, they mainly trophically supported lymphatic endothelial cell behaviour in vitro. In vivo, MAPC transplantation supported blood vessel and lymphatic capillary growth in wounds and restored lymph drainage across skin flaps by stimulating capillary and pre-collector vessel regeneration. Finally, human MAPCs mediated survival and functional reconnection of transplanted lymph nodes to the host lymphatic network by improving their (lymph)vascular supply and restoring collector vessels. Thus, MAPC transplantation represents a promising remedy for lymphatic system restoration at different anatomical levels and hence an appealing treatment for lymphedema. Furthermore, its combined efficacy on lymphatic and blood vascular growth is an important asset for wound healing. PMID- 29497056 TI - Dioscin inhibits stem-cell-like properties and tumor growth of osteosarcoma through Akt/GSK3/beta-catenin signaling pathway. AB - Osteosarcoma is the most common primary bone tumor in children and adolescents. Many patients with osteosarcoma always develop drug resistance to current chemotherapy regimens, which induces a poor prognosis. And cancer stem cells (CSCs) have been reported to possess the properties to self-renew and maintain the phenotype of tumor, which may lead to clinical treatment failure. Thus, it is an urgent task to develop several potentially useful therapeutic agents, which could target CSCs in osteosarcoma. This study aims to clarify the in vitro and in vivo anti-osteosarcoma effects of dioscin, the primary component derived from Discorea nipponica Makino, and its molecular mechanism of action. In this study, all the ten human osteosarcoma cell lines were sensitive to dioscin treatment in a dose- and time-dependent manner. Dioscin inhibits proliferation and induces cell cycle arrest as well as apoptotic cell death in osteosarcoma cells. More importantly, oral administration of dioscin (60 mg/kg) showed significant therapeutic effect on osteosarcoma growth without obvious side effects in vivo. In addition, dioscin possesses the ability to suppress stem-cell-like phenotype of osteosarcoma cells. Mechanistically, dioscin inhibits osteosarcoma stem-cell like properties and tumor growth through repression of Akt/GSK3/beta-catenin pathway. Moreover, beta-catenin expression in osteosarcoma patients was associated with clinical prognosis. Conclusively, the present study provides comprehensive evidence for the inhibition of dioscin on osteosarcoma stem-cell like properties and tumor growth through repression of Akt/GSK3/beta-catenin pathway, which suggests dioscin as a promising therapeutic regimen. And beta catenin may be a potential therapeutic target as well as a significant prognostic marker for osteosarcoma patients in clinic. PMID- 29497058 TI - Author Correction: Micro-Doppler measurement of insect wing-beat frequencies with W-band coherent radar. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29497057 TI - Conserved roles of C. elegans and human MANFs in sulfatide binding and cytoprotection. AB - Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) protein that can be secreted and protects dopamine neurons and cardiomyocytes from ER stress and apoptosis. The mechanism of action of extracellular MANF has long been elusive. From a genetic screen for mutants with abnormal ER stress response, we identified the gene Y54G2A.23 as the evolutionarily conserved C. elegans MANF orthologue. We find that MANF binds to the lipid sulfatide, also known as 3-O-sulfogalactosylceramide present in serum and outer-cell membrane leaflets, directly in isolated forms and in reconstituted lipid micelles. Sulfatide binding promotes cellular MANF uptake and cytoprotection from hypoxia-induced cell death. Heightened ER stress responses of MANF-null C. elegans mutants and mammalian cells are alleviated by human MANF in a sulfatide-dependent manner. Our results demonstrate conserved roles of MANF in sulfatide binding and ER stress response, supporting sulfatide as a long-sought lipid mediator of MANF's cytoprotection. PMID- 29497059 TI - Author Correction: Comparative analysis of molecular and physiological traits between perennial Arabis alpina Pajares and annual Arabidopsis thaliana Sy-0. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29497060 TI - Frontal cortex function as derived from hierarchical predictive coding. AB - The frontal lobes are essential for human volition and goal-directed behavior, yet their function remains unclear. While various models have highlighted working memory, reinforcement learning, and cognitive control as key functions, a single framework for interpreting the range of effects observed in prefrontal cortex has yet to emerge. Here we show that a simple computational motif based on predictive coding can be stacked hierarchically to learn and perform arbitrarily complex goal-directed behavior. The resulting Hierarchical Error Representation (HER) model simulates a wide array of findings from fMRI, ERP, single-units, and neuropsychological studies of both lateral and medial prefrontal cortex. By reconceptualizing lateral prefrontal activity as anticipating prediction errors, the HER model provides a novel unifying account of prefrontal cortex function with broad implications for understanding the frontal cortex across multiple levels of description, from the level of single neurons to behavior. PMID- 29497061 TI - Influence of glass-based dental ceramic type and thickness with identical shade on the light transmittance and the degree of conversion of resin cement. AB - The purpose of this study was to assess the influence of the types and thicknesses of glass ceramic plates on light transmittance and compare the degrees of conversion (DC) of resin cement under the ceramic materials. Three ceramic plates with thicknesses of 0.5, 1.0, 2.0, and 4.0 mm were fabricated from each of five commercial ceramic blocks in shade A2: high-translucency and low translucency IPS Empress CAD (Emp_HT and Emp_LT); high-translucency and low translucency IPS e.max CAD (Emx_HT and Emx_LT); and Vita Mark II (Vita). The translucency parameter was obtained using a colorimeter. The light transmittance rate was measured using a photodetector attached to an optical power meter. The DC of a resin cement (Variolink N) underneath the ceramic plates was examined by Fourier transform infrared spectroscopy. The translucency parameter, light transmittance rate, and DC showed significant differences by ceramic type and thickness (P < 0.05). The Emp_HT specimens showed the highest light transmission and DCs, and the Emx_LT showed the least light transmission and the lowest DCs. The high-translucency Empress showed significantly higher DCs than the low translucency types (P < 0.05), but there was no significant difference in e.max (P > 0.05). Both type and thickness of the glass ceramics significantly influenced the light transmittance and DC of the light-cured resin cement beneath the ceramic of the same shade. PMID- 29497062 TI - Large XPF-dependent deletions following misrepair of a DNA double strand break are prevented by the RNA:DNA helicase Senataxin. AB - Deletions and chromosome re-arrangements are common features of cancer cells. We have established a new two-component system reporting on epigenetic silencing or deletion of an actively transcribed gene adjacent to a double-strand break (DSB). Unexpectedly, we find that a targeted DSB results in a minority (<10%) misrepair event of kilobase deletions encompassing the DSB site and transcribed gene. Deletions are reduced upon RNaseH1 over-expression and increased after knockdown of the DNA:RNA helicase Senataxin, implicating a role for DNA:RNA hybrids. We further demonstrate that the majority of these large deletions are dependent on the 3' flap endonuclease XPF. DNA:RNA hybrids were detected by DNA:RNA immunoprecipitation in our system after DSB generation. These hybrids were reduced by RNaseH1 over-expression and increased by Senataxin knock-down, consistent with a role in deletions. Overall, these data are consistent with DNA:RNA hybrid generation at the site of a DSB, mis-processing of which results in genome instability in the form of large deletions. PMID- 29497063 TI - Lack of effects of simvastatin on smoking cessation in humans: A double-blind, randomized, placebo-controlled clinical study. AB - A recent pre-clinical study has shown that brain-penetrating statins can reduce risks of relapse to cocaine and nicotine addiction in rats. Based on this information, we conducted a randomized, double-blind, placebo-controlled, proof of-concept trial to assess the efficacy of simvastatin in smoking cessation. After informed consent, 118 participants received behavioral cessation support and were randomly assigned to a 3-month treatment with simvastatin or placebo. The primary outcome was biochemically verified abstinence or smoking reduction at 3-month post-target quit date (TQD). Secondary outcomes were abstinence during weeks 9-12 post-TQD, prolonged abstinence or reduction at months 6 and 12 post TQD, safety and craving assessed at each visit during the 3-month period of treatment. Simvastatin treatment was not associated with higher 3-month abstinence or smoking reduction compared to placebo. There was no significant difference in any of the secondary outcomes. Simvastatin was well tolerated. Over 3 and 9 months follow-up period, 78% simvastatin and 69% placebo participants were retained in the study. At 6 and 12 months, smoking remained significantly reduced from baseline in both groups. Our results demonstrate that a 3-month simvastatin treatment (40 mg/day), added to individual behavioral cessation support, does not improve significantly smoking cessation compared to placebo in humans. PMID- 29497064 TI - Author Correction: Facile single-stranded DNA sequencing of human plasma DNA via thermostable group II intron reverse transcriptase template switching. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29497065 TI - Author Correction: Giant pandas can discriminate the emotions of human facial pictures. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29497066 TI - Fat accretion measurements strengthen the relationship between feed conversion efficiency and Nitrogen isotopic discrimination while rumen microbial genes contribute little. AB - The use of biomarkers for feed conversion efficiency (FCE), such as Nitrogen isotopic discrimination (Delta15N), facilitates easier measurement and may be useful in breeding strategies. However, we need to better understand the relationship between FCE and Delta15N, particularly the effects of differences in the composition of liveweight gain and rumen N metabolism. Alongside measurements of FCE and Delta15N, we estimated changes in body composition and used dietary treatments with and without nitrates, and rumen metagenomics to explore these effects. Nitrate fed steers had reduced FCE and higher Delta15N in plasma compared to steers offered non-nitrate containing diets. The negative relationship between FCE and Delta15N was strengthened with the inclusion of fat depth change at the 3rd lumbar vertebrae, but not with average daily gain. We identified 1,700 microbial genes with a relative abundance >0.01% of which, 26 were associated with Delta15N. These genes explained 69% of variation in Delta15N and showed clustering in two distinct functional networks. However, there was no clear relationship between their relative abundances and Delta15N, suggesting that rumen microbial genes contribute little to Delta15N. Conversely, we show that changes in the composition of gain (fat accretion) provide additional strength to the relationship between FCE and Delta15N. PMID- 29497067 TI - The use of SWATH to analyse the dynamic changes of bacterial proteome of carbapanemase-producing Escherichia coli under antibiotic pressure. AB - Antibiotic resistance associated with the clinically significant carbapenemases KPC, NDM and OXA-48 in Enterobacteriaceae is emerging as worldwide. In Australia, IMP-producing Enterobacteriaceae are the most prevalent carbapenemase-producing Enterobacteriaceae (CPE). Genomic characteristics of such CPE are well described, but the corresponding proteome is poorly characterised. We have thus developed a method to analyse dynamic changes in the proteome of CPE under antibiotic pressure. Specifically, we have investigated the effect of meropenem at sub lethal concentrations to develop a better understanding of how antibiotic pressure leads to resistance. Escherichia coli strains producing either NDM-, IMP or KPC-type carbapenemases were included in this study, and their proteomes were analysed in growth conditions with or without meropenem. The most significant difference in the bacterial proteomes upon the addition of meropenem was triggered amongst NDM-producers and to a lower extent amongst KPC-producers. In particular, HU DNA-binding proteins, the GroEL/GroES chaperonin complex and GrpE proteins were overexpressed. These proteins may thus contribute to the better adaptability of NDM- and KPC-producers to meropenem. A significant meropenem induced increase in the expression of the outer membrane protein A was only observed in IMP-producers, thus demonstrating that carbapenemase-mediated resistance relies on far more complex mechanisms than simple inactivation of the antibiotic. PMID- 29497068 TI - Functionally distinct smiles elicit different physiological responses in an evaluative context. AB - When people are being evaluated, their whole body responds. Verbal feedback causes robust activation in the hypothalamic-pituitary-adrenal (HPA) axis. What about nonverbal evaluative feedback? Recent discoveries about the social functions of facial expression have documented three morphologically distinct smiles, which serve the functions of reinforcement, social smoothing, and social challenge. In the present study, participants saw instances of one of three smile types from an evaluator during a modified social stress test. We find evidence in support of the claim that functionally different smiles are sufficient to augment or dampen HPA axis activity. We also find that responses to the meanings of smiles as evaluative feedback are more differentiated in individuals with higher baseline high-frequency heart rate variability (HF-HRV), which is associated with facial expression recognition accuracy. The differentiation is especially evident in response to smiles that are more ambiguous in context. Findings suggest that facial expressions have deep physiological implications and that smiles regulate the social world in a highly nuanced fashion. PMID- 29497069 TI - A Highly Sensitive Detection System based on Proximity-dependent Hybridization with Computer-aided Affinity Maturation of a scFv Antibody. AB - The hepatitis B virus (HBV) infection is a critical health problem worldwide, and HBV preS1 is an important biomarker for monitoring HBV infection. Previously, we found that a murine monoclonal antibody, mAb-D8, targets the preS1 (aa91-107) fragment of HBV. To improve its performance, we prepared the single-chain variable region of mAb-D8 (scFvD8) and constructed the three-dimensional structure of the scFvD8-preS1 (aa91-107) complex by computer modelling. The affinity of scFvD8 was markedly increased by the introduction of mutations L96Tyr to Ser and H98Asp to Ser. Furthermore, a highly sensitive immunosensor was designed based on a proximity-dependent hybridization strategy in which the preS1 antigen competitively reacts with an antibody labelled with DNA, resulting in decreased proximity-dependent hybridization and increased electrochemical signal from the Fc fragment, which can be used for the quantisation of preS1. The results showed a wide detection range from 1 pM to 50 pM with a detection limit of 0.1 pM. The sensitivity and specificity of this immunosensor in clinical serum samples were 100% and 96%, respectively. This study provides a novel system based on proximity-dependent hybridization and the scFv antibody fragment for the rapid quantisation of antigens of interest with a high sensitivity. PMID- 29497070 TI - Landscape of the spliced leader trans-splicing mechanism in Schistosoma mansoni. AB - Spliced leader dependent trans-splicing (SLTS) has been described as an important RNA regulatory process that occurs in different organisms, including the trematode Schistosoma mansoni. We identified more than seven thousand putative SLTS sites in the parasite, comprising genes with a wide spectrum of functional classes, which underlines the SLTS as a ubiquitous mechanism in the parasite. Also, SLTS gene expression levels span several orders of magnitude, showing that SLTS frequency is not determined by the expression level of the target gene, but by the presence of particular gene features facilitating or hindering the trans splicing mechanism. Our in-depth investigation of SLTS events demonstrates widespread alternative trans-splicing (ATS) acceptor sites occurring in different regions along the entire gene body, highlighting another important role of SLTS generating alternative RNA isoforms in the parasite, besides the polycistron resolution. Particularly for introns where SLTS directly competes for the same acceptor substrate with cis-splicing, we identified for the first time additional and important features that might determine the type of splicing. Our study substantially extends the current knowledge of RNA processing by SLTS in S. mansoni, and provide basis for future studies on the trans-splicing mechanism in other eukaryotes. PMID- 29497071 TI - Mapping the refractive index with single plasmonic nanoantenna. AB - As the size of the state-of-the-art optical devices shrinks to nanoscale, the need for tools allowing mapping the local optical properties at deep sub diffraction resolution increases. Here we demonstrate successful mapping the variations of the refractive index of a smooth dielectric surface by detecting spectral response of a single spherical-shape Ag nanoparticle optically aligned with a supporting optical fiber axicon microlens. We propose and examine various excitation schemes of the plasmonic nanoantenna to provide efficient interaction of its dipolar and quadrupolar modes with the underlying sample surface and to optimize the mapping resolution and sensitivity. Moreover, we demonstrate an lithography-free approach for fabrication of the scanning probe combining the high-quality fiber microaxicon with the Ag spherical nanoparticle atop. Supporting finite-difference time-domain calculations are undertaken to tailor the interaction of the plasmonic nanoantenna and the underlying dielectric substrate upon various excitation conditions demonstrating good agreement with our experimental findings and explaining the obtained results. PMID- 29497073 TI - Publisher Correction: IgG1 memory B cells keep the memory of IgE responses. AB - The originally published version of this Article contained errors in Fig. 4 that were introduced during the production process. In panel c, the two uppermost labels 'IgE spleen' and 'IgE BM' incorrectly read 'IgG1 spleen' and 'IgE1 BM', respectively. These errors have now been corrected in both the PDF and HTML versions of the Article. PMID- 29497072 TI - Preoperative Heart Rate Variability as Predictors of Vagus Nerve Stimulation Outcome in Patients with Drug-resistant Epilepsy. AB - Vagus nerve stimulation (VNS) is an adjunctive treatment for drug-resistant epilepsy (DRE). However, it is still difficult to predict which patients will respond to VNS treatment and to what extent. We aim to explore the relationship between preoperative heart rate variability (HRV) and VNS outcome. 50 healthy control subjects and 63 DRE patients who had received VNS implants and had at least one year of follow up were included. The preoperative HRV were analyzed by traditional linear methods and heart rhythm complexity analyses with multiscale entropy (MSE). DRE patients had significantly lower complexity indices (CI) as well as traditional linear HRV measurements than healthy controls. We also found that non-responders0 had significantly lower preoperative CI including Area 1-5, Area 6-15 and Area 6-20 than those in the responders0 while those of the non responders50 had significantly lower RMSSD, pNN50, VLF, LF, HF, TP and LF/HF than the responders50. In receiver operating characteristic (ROC) curve analysis, Area 6-20 and RMSSD had the greatest discriminatory power for the responders0 and non responders0, responders50 and non-responders50, respectively. Our results suggest that preoperative assessment of HRV by linear and MSE analysis can help in predicting VNS outcomes in patients with DRE. PMID- 29497074 TI - Metabolic characterization of directly reprogrammed renal tubular epithelial cells (iRECs). AB - Fibroblasts can be directly reprogrammed to induced renal tubular epithelial cells (iRECs) using four transcription factors. These engineered cells may be used for disease modeling, cell replacement therapy or drug and toxicity testing. Direct reprogramming induces drastic changes in the transcriptional landscape, protein expression, morphological and functional properties of cells. However, how the metabolome is changed by reprogramming and to what degree it resembles the target cell type remains unknown. Using untargeted gas chromatography-mass spectrometry (GC-MS) and targeted liquid chromatography-MS, we characterized the metabolome of mouse embryonic fibroblasts (MEFs), iRECs, mIMCD-3 cells, and whole kidneys. Metabolic fingerprinting can distinguish each cell type reliably, revealing iRECs are most similar to mIMCD-3 cells and clearly separate from MEFs used for reprogramming. Treatment with the cytotoxic drug cisplatin induced typical changes in the metabolic profile of iRECs commonly occurring in acute renal injury. Interestingly, metabolites in the medium of iRECs, but not of mIMCD 3 cells or fibroblast could distinguish treated and non-treated cells by cluster analysis. In conclusion, direct reprogramming of fibroblasts into renal tubular epithelial cells strongly influences the metabolome of engineered cells, suggesting that metabolic profiling may aid in establishing iRECs as in vitro models for nephrotoxicity testing in the future. PMID- 29497075 TI - Cellulose Nanocrystal Templated Graphene Nanoscrolls for High Performance Supercapacitors and Hydrogen Storage: An Experimental and Molecular Simulation Study. AB - Graphene nanoscrolls (GNS), due to their remarkably interesting properties, have attracted significant interest with applications in various engineering sectors. However, uncontrolled morphologies, poor yield and low quality GNS produced through traditional routes are major challenges associated. We demonstrate sustainable approach of utilizing bio-derived cellulose nanocrystals (CNCs) as template for fabrication of GNS with tunable morphological dimensions ranging from micron-to-nanoscale(controlled length < 1 MUm or >1 MUm), alongwith encapsulation of catalytically active metallic-species in scroll interlayers. The surface-modified magnetic CNCs acts as structural-directing agents which provides enough momentum to initiate self-scrolling phenomenon of graphene through van der Waals forces and pi-pi interactions, mechanism of which is demonstrated through experimental and molecular simulation studies. The proposed approach of GNS fabrication provides flexibility to tune physico-chemical properties of GNS by simply varying interlayer spacing, scrolling density and fraction of encapsulated metallic nanoparticles. The hybrid GNS with confined palladium or platinum nanoparticles (at lower loading ~1 wt.%) shows enhanced hydrogen storage capacity (~0.2 wt.% at~20 bar and ~273 K) and excellent supercapacitance behavior (~223 357 F/g) for prolonged cycles (retention ~93.5-96.4% at ~10000 cycles). The current strategy of utilizing bio-based templates can be further extended to incorporate complex architectures or nanomaterials in GNS core or inter-layers, which will potentially broaden its applications in fabrication of high performance devices. PMID- 29497077 TI - Author Correction: Effects of habitat constraints on soil microbial community function. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29497076 TI - Bufalin suppresses hepatocarcinogenesis by targeting beta-catenin/TCF signaling via cell cycle-related kinase. AB - Hepatocellular carcinoma (HCC) is one of the most aggressive malignant tumors, of which treatment options are limited especially in advanced stage. Bufalin, the major digoxin-like component of the traditional Chinese medicine Chansu, exhibits significant antitumor activities in hepatoma cells, but the potential mechanism is obscure. Cell cycle-related kinase (CCRK) is recently identified to be a crucial oncogenic master regulator to drive hepatocarcinogenesis. Here we investigated the molecular function of bufalin on CCRK-regulated signaling pathway, and expounded the underlying mechanism in HCC suppression. In vitro with PLC5 HCC cells and human immortal LO2 cells, proliferation, malignant transformation and cell cycle progression assays were performed to evaluate the antitumor effect of bufalin. In vivo with xenograft and orthotopic mice models, tumor growths with weight and volume change were assessed with or without bufalin treatment. Western blot, RT-qPCR, immunofluorescence and immunohistochemistry were conducted to examine the expression level of CCRK and beta-catenin/TCF signaling cascade. We revealed that bufalin suppresses PLC5 HCC cell proliferation, transformation and cell cycle progression rather than LO2 cells, which is correlated with CCRK-mediated beta-catenin/TCF signaling. It was also confirmed in mice model. Thus, bufalin is a potential anti-HCC therapeutic candidate through the inhibition of CCRK-driven beta-catenin/TCF oncogenic signaling pathway. PMID- 29497079 TI - Individualistic values are related to an increase in the outbreaks of infectious diseases and zoonotic diseases. AB - Collectivist versus individualistic values are important attributes of intercultural variation. Collectivist values favour in-group members over out group members and may have evolved to protect in-group members against pathogen transmission. As predicted by the pathogen stress theory of cultural values, more collectivist countries are associated with a higher historical pathogen burden. However, if lifestyles of collectivist countries indeed function as a social defence which decreases pathogen transmission, then these countries should also have experienced fewer disease outbreaks in recent times. We tested this novel hypothesis by correlating the values of collectivism-individualism for 66 countries against their historical pathogen burden, recent number of infectious disease outbreaks and zoonotic disease outbreaks and emerging infectious disease events, and four potentially confounding variables. We confirmed the previously established negative relationship between individualism and historical pathogen burden with new data. While we did not find a correlation for emerging infectious disease events, we found significant positive correlations between individualism and the number of infectious disease outbreaks and zoonotic disease outbreaks. Therefore, one possible cost for individualistic cultures may be their higher susceptibility to disease outbreaks. We support further studies into the exact protective behaviours and mechanisms of collectivist societies which may inhibit disease outbreaks. PMID- 29497080 TI - Quantum Secure Group Communication. AB - We propose a quantum secure group communication protocol for the purpose of sharing the same message among multiple authorized users. Our protocol can remove the need for key management that is needed for the quantum network built on quantum key distribution. Comparing with the secure quantum network based on BB84, we show our protocol is more efficient and securer. Particularly, in the security analysis, we introduce a new way of attack, i.e., the counterfactual quantum attack, which can steal information by "invisible" photons. This invisible photon can reveal a single-photon detector in the photon path without triggering the detector. Moreover, the photon can identify phase operations applied to itself, thereby stealing information. To defeat this counterfactual quantum attack, we propose a quantum multi-user authorization system. It allows us to precisely control the communication time so that the attack can not be completed in time. PMID- 29497078 TI - Novel and Haplotype Specific MicroRNAs Encoded by the Major Histocompatibility Complex. AB - The MHC is recognized for its importance in human health and disease. However, many disease-associated variants throughout the region remain of unknown significance, residing predominantly within non-coding regions of the MHC. The characterization of non-coding RNA transcripts throughout the MHC is thus central to understanding the genetic contribution of these variants. Therefore, we characterize novel miRNA transcripts throughout the MHC by performing deep RNA sequencing of two B lymphoblastoid cell lines with completely characterized MHC haplotypes. Our analysis identifies 89 novel miRNA transcripts, 48 of which undergo Dicer-dependent biogenesis and are loaded onto the Argonaute silencing complex. Several of the identified mature miRNA and pre-miRNA transcripts are unique to specific MHC haplotypes and overlap common SNPs. Furthermore, 43 of the 89 identified novel miRNA transcripts lie within linkage disequilibrium blocks that contain a disease-associated SNP. These disease associated SNPs are associated with 65 unique disease phenotypes, suggesting that these transcripts may play a role in the etiology of numerous diseases associated with the MHC. Additional in silico analysis reveals the potential for thousands of putative pre miRNA encoding loci within the MHC that may be expressed by different cell types and at different developmental stages. PMID- 29497081 TI - Hypoxia-induced exosome secretion promotes survival of African-American and Caucasian prostate cancer cells. AB - African American men in the United States have higher mortality due to prostate cancer (PCa) compared to other races. One reason for this disparity is the lack of in-depth understanding of the PCa biology in African Americans. For example, hypoxia in prostate tumor microenvironment is associated with adverse prognosis; still, no hypoxia-related studies have been reported in African Americans. Here, we compared African-American and Caucasian PCa cells for exosome secretion under normoxic (21% O2) and hypoxic (1% O2) conditions. All cell lines showed higher exosome secretion under hypoxia but it was clearly more prominent in African American PCa cells. Further, under hypoxia, Rab5 (a biomarker for early endosome) was clustered in perinuclear region; and CD63 (a biomarker for exosomes and multivesicular endosomes) showed greater co-localization with actin cytoskeleton especially in African American PCa cells. Importantly, exosome biogenesis inhibitors GW4869 (10-20 uM) or DMA (10-20 ug/ml) significantly decreased cell viability and clonogenicity in PCa cells. Interestingly, we also observed higher level of lactic acid loaded in exosomes secreted under hypoxia. Overall, under chronic hypoxia, PCa cells secrete more exosomes as a survival mechanism to remove metabolic waste. PMID- 29497082 TI - Sonoporation-induced cell membrane permeabilization and cytoskeleton disassembly at varied acoustic and microbubble-cell parameters. AB - Sonoporation mediated by microbubbles has being extensively studied as a promising technique to facilitate gene/drug delivery to cells. Previous studies mainly explored the membrane-level responses to sonoporation. To provide in-depth understanding on this process, various sonoporation-induced cellular responses (e.g., membrane permeabilization and cytoskeleton disassembly) generated at different impact parameters (e.g., acoustic driving pressure and microbubble-cell distances) were systemically investigated in the present work. HeLa cells, whose alpha-tubulin cytoskeleton was labeled by incorporation of a green fluorescence protein (GFP)-alpha-tubulin fusion protein, were exposed to a single ultrasound pulse (1 MHz, 20 cycles) in the presence of microbubbles. Intracellular transport via sonoporation was assessed in real time using propidium iodide and the disassembly of alpha-tubulin cytoskeleton was observed by fluorescence microscope. Meanwhile, the dynamics of an interacting bubble-cell pair was theoretically simulated by boundary element method. Both the experimental observations and numerical simulations showed that, by increasing the acoustic pressure or reducing the bubble-cell distance, intensified deformation could be induced in the cellular membrane, which could result in enhanced intracellular delivery and cytoskeleton disassembly. The current results suggest that more tailored therapeutic strategies could be designed for ultrasound gene/drug delivery by adopting optimal bubble-cell distances and/or better controlling incident acoustic energy. PMID- 29497083 TI - Author Correction: Divergent effects of Wnt/beta-catenin signaling modifiers on the preservation of human limbal epithelial progenitors according to culture condition. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29497084 TI - The energy sensor OsSnRK1a confers broad-spectrum disease resistance in rice. AB - Sucrose non-fermenting-1-related protein kinase-1 (SnRK1) belongs to a family of evolutionary conserved kinases with orthologs in all eukaryotes, ranging from yeasts (SnF1) to mammals (AMP-Activated kinase). These kinases sense energy deficits caused by nutrient limitation or stress and coordinate the required adaptations to maintain energy homeostasis and survival. In plants, SnRK1 is a global regulator of plant metabolism and is also involved in abiotic stress responses. Its role in the response to biotic stress, however, is only starting to be uncovered. Here we studied the effect of altered SnRK1a expression on growth and plant defense in rice. OsSnRK1a overexpression interfered with normal growth and development and increased resistance against both (hemi)biotrophic and necrotrophic pathogens, while OsSnRK1a silencing in RNAi lines increased susceptibility. OsSnRK1a overexpression positively affected the salicylic acid pathway and boosted the jasmonate-mediated defense response after inoculation with the blast fungus Pyricularia oryzae. Together these findings strongly suggest OsSnRK1a to be involved in plant basal immunity and favor a model whereby OsSnRK1a acts as a master switch that regulates growth-immunity trade-offs. PMID- 29497085 TI - Recognition motif and mechanism of ripening inhibitory peptides in plant hormone receptor ETR1. AB - Synthetic peptides derived from ethylene-insensitive protein 2 (EIN2), a central regulator of ethylene signalling, were recently shown to delay fruit ripening by interrupting protein-protein interactions in the ethylene signalling pathway. Here, we show that the inhibitory peptide NOP-1 binds to the GAF domain of ETR1 - the prototype of the plant ethylene receptor family. Site-directed mutagenesis and computational studies reveal the peptide interaction site and a plausible molecular mechanism for the ripening inhibition. PMID- 29497086 TI - An allosteric link connecting the lipid-protein interface to the gating of the nicotinic acetylcholine receptor. AB - The mechanisms underlying lipid-sensing by membrane proteins is of considerable biological importance. A unifying mechanistic question is how a change in structure at the lipid-protein interface is translated through the transmembrane domain to influence structures critical to protein function. Gating of the nicotinic acetylcholine receptor (nAChR) is sensitive to its lipid environment. To understand how changes at the lipid-protein interface influence gating, we examined how a mutation at position 418 on the lipid-facing surface of the outer most M4 transmembrane alpha-helix alters the energetic couplings between M4 and the remainder of the transmembrane domain. Human muscle nAChR is sensitive to mutations at position 418, with the Cys-to-Trp mutation resulting in a 16-fold potentiation in function that leads to a congenital myasthenic syndrome. Energetic coupling between M4 and the Cys-loop, a key structure implicated in gating, do not change with C418W. Instead, Trp418 and an adjacent residue couple energetically with residues on the M1 transmembrane alpha-helix, leading to a reorientation of M1 that stabilizes the open state. We thus identify an allosteric link connecting the lipid-protein interface of the nAChR to altered channel function. PMID- 29497087 TI - Degradation shaped bacterial and archaeal communities with predictable taxa and their association patterns in Zoige wetland at Tibet plateau. AB - Soil microbes provide important ecosystem services. Zoige Plateau wetland, the largest alpine peat wetland in the world, has suffered from serious degradation in the past 30 years. We studied the composition of the Zoige Plateau alpine wetland soil microbiota and relations among specific taxa using 16S rRNA amplicon sequencing combined with association network analysis. Compared to the pristine swamp soil, taxons DA101, Aeromicrobium, Bradyrhizobium, and Candidatus Nitrososphaera were enriched and several methanogenic Euryarchaeota were depleted in the moderately degraded meadow soil and highly degraded sandy soil. Soil total potassium contents in soils with different degradation levels were significantly different, being the highest in meadow soil and lowest in swamp soil. The association network analysis showed that total potassium positively correlated with specific bacterial and archaeal taxa. Jiangella, Anaerolinea, Desulfobulbus, Geobacter, Flavobacterium, Methanobacterium and Methanosaeta were identified as the keystone genera in the networks. Soil degradation affected soil properties, and caused changes in the bacterial and archaeal community composition and the association patterns of community members. The changes could serve as early warning signals of soil degradation in alpine wetlands. PMID- 29497088 TI - A multiscale model of the effect of Ir thickness on the static and dynamic properties of Fe/Ir/Fe films. AB - The complex magnetic properties of Fe/Ir/Fe sandwiches are studied using a hierarchical multi-scale model. The approach uses first principles calculations and thermodynamic models to reveal the equilibrium spinwave, magnetization and dynamic demagnetisation properties. Finite temperature calculations show a complex spinwave dispersion and an initially counter-intuitive, increasing exchange stiffness with temperature (a key quantity for device applications) due to the effects of frustration at the interface, which then decreases due to magnon softening. Finally, the demagnetisation process in these structures is shown to be much slower at the interface as compared with the bulk, a key insight to interpret ultrafast laser-induced demagnetization processes in layered or interface materials. PMID- 29497089 TI - Author Correction: Immune-checkpoint protein VISTA critically regulates the IL 23/IL-17 inflammatory axis. AB - A correction has been published and is linked to the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29497090 TI - Application of Bld-1-Embedded Elastin-Like Polypeptides in Tumor Targeting. AB - Expression of various molecules on the surface of cancer cells compared to normal cells creates a platform for the generation of various drug vehicles for targeted therapy. Multiple interactions between ligands and their receptors mediated by targeting peptide-modified polymer could enable simultaneous delivery of a drug selectively to target tumor cells, thus limiting side effects resulting from non specific drug delivery. In this study, we synthesized a novel tumor targeting system by using two key elements: (1) Bld-1 peptide (SNRDARRC), a recently reported bladder tumor targeting peptide identified by using a phage-displayed peptide library, and (2) ELP, a thermally responsive polypeptide. B5V60 containing five Bld-1 peptides and non-targeted ELP77 with a thermal phase transition over 37 degrees C were analyzed to determine their bioactivities. Further studies confirmed the superior binding ability of B5V60 to bladder tumor cells and the cellular accumulation of B5V60 in cancer cells was dependent on the expression level of sialyl-Tn antigen (STn), a tumor-associated carbohydrate antigen. Additionally, B5V60 displayed excellent localization in bladder tumor xenograft mice after intravenous injection and was strictly confined to sialyl-Tn antigen-overexpressing tumor tissue. Thus, our newly designed B5V60 showed high potential as a novel carrier for STn-specific targeted cancer therapy or other therapeutic applications. PMID- 29497092 TI - Author Correction: A genome scan for milk production traits in dairy goats reveals two new mutations in Dgat1 reducing milk fat content. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29497091 TI - Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer. AB - CDK4/6 inhibition substantially improves progression-free survival (PFS) for women with advanced estrogen receptor-positive breast cancer, although there are no predictive biomarkers. Early changes in circulating tumor DNA (ctDNA) level may provide early response prediction, but the impact of tumor heterogeneity is unknown. Here we use plasma samples from patients in the randomized phase III PALOMA-3 study of CDK4/6 inhibitor palbociclib and fulvestrant for women with advanced breast cancer and show that relative change in PIK3CA ctDNA level after 15 days treatment strongly predicts PFS on palbociclib and fulvestrant (hazard ratio 3.94, log-rank p = 0.0013). ESR1 mutations selected by prior hormone therapy are shown to be frequently sub clonal, with ESR1 ctDNA dynamics offering limited prediction of clinical outcome. These results suggest that early ctDNA dynamics may provide a robust biomarker for CDK4/6 inhibitors, with early ctDNA dynamics demonstrating divergent response of tumor sub clones to treatment. PMID- 29497093 TI - Lateral attachment of kinetochores to microtubules is enriched in prometaphase rosette and facilitates chromosome alignment and bi-orientation establishment. AB - Faithful chromosome segregation is ensured by the establishment of bi orientation; the attachment of sister kinetochores to the end of microtubules extending from opposite spindle poles. In addition, kinetochores can also attach to lateral surfaces of microtubules; called lateral attachment, which plays a role in chromosome capture and transport. However, molecular basis and biological significance of lateral attachment are not fully understood. We have addressed these questions by focusing on the prometaphase rosette, a typical chromosome configuration in early prometaphase. We found that kinetochores form uniform lateral attachments in the prometaphase rosette. Many transient kinetochore components are maximally enriched, in an Aurora B activity-dependent manner, when the prometaphase rosette is formed. We revealed that rosette formation is driven by rapid poleward motion of dynein, but can occur even in its absence, through slow kinetochore movements caused by microtubule depolymerization that is supposedly dependent on kinetochore tethering at microtubule ends by CENP-E. We also found that chromosome connection to microtubules is extensively lost when lateral attachment is perturbed in cells defective in end-on attachment. Our findings demonstrate that lateral attachment is an important intermediate in bi orientation establishment and chromosome alignment, playing a crucial role in incorporating chromosomes into the nascent spindle. PMID- 29497095 TI - The combined influence of body size and density on cohesive sediment resuspension by bioturbators. AB - We propose an empirical framework to scale the effects of bioturbation on sediment resuspension to population bioturbation activity, approximated as population metabolic rate. Individual metabolic rates have been estimated as functions of body size and extrapolated to population level. We used experimental flumes to test this approach across different types of marine, soft-sediment bioturbators. We observed that a large part of the variance in biota-mediated sediment resuspension can be explained by a positive relationship with population metabolic rate. Other mechanisms can strongly influence the outcome, such as bioturbation of deep sediment strata, biotic interactions with hydrodynamic stress and overlapping areas of influence must be further investigated. By relating the biota-mediated changes in resuspended sediment to metabolism, we can place our observations within the broader context of the metabolic theory of ecology and to formulate general expectations about changes in biota-mediated sediment resuspension in response to changes in population structure and climate change. PMID- 29497094 TI - Conditional knockout of NaV1.6 in adult mice ameliorates neuropathic pain. AB - Voltage-gated sodium channels NaV1.7, NaV1.8 and NaV1.9 have been the focus for pain studies because their mutations are associated with human pain disorders, but the role of NaV1.6 in pain is less understood. In this study, we selectively knocked out NaV1.6 in dorsal root ganglion (DRG) neurons, using NaV1.8-Cre directed or adeno-associated virus (AAV)-Cre mediated approaches, and examined the specific contribution of NaV1.6 to the tetrodotoxin-sensitive (TTX-S) current in these neurons and its role in neuropathic pain. We report here that NaV1.6 contributes up to 60% of the TTX-S current in large, and 34% in small DRG neurons. We also show NaV1.6 accumulates at nodes of Ranvier within the neuroma following spared nerve injury (SNI). Although NaV1.8-Cre driven NaV1.6 knockout does not alter acute, inflammatory or neuropathic pain behaviors, AAV-Cre mediated NaV1.6 knockout in adult mice partially attenuates SNI-induced mechanical allodynia. Additionally, AAV-Cre mediated NaV1.6 knockout, mostly in large DRG neurons, significantly attenuates excitability of these neurons after SNI and reduces NaV1.6 accumulation at nodes of Ranvier at the neuroma. Together, NaV1.6 in NaV1.8-positive neurons does not influence pain thresholds under normal or pathological conditions, but NaV1.6 in large NaV1.8-negative DRG neurons plays an important role in neuropathic pain. PMID- 29497096 TI - Fatty Acid Supplementation Reverses the Small Colony Variant Phenotype in Triclosan-Adapted Staphylococcus aureus: Genetic, Proteomic and Phenotypic Analyses. AB - Staphylococcus aureus can develop a small colony variant (SCV) phenotype in response to sub-lethal exposure to the biocide triclosan. In the current study, whole genome sequencing was performed and changes in virulence were investigated in five Staphylococcus aureus strains following repeated exposure to triclosan. Following exposure, 4/5 formed SCV and exhibited point mutations in the triclosan target gene fabI with 2/4 SCVs showing mutations in both fabI and fabD. The SCV phenotype was in all cases immediately reversed by nutritional supplementation with fatty acids or by repeated growth in the absence of triclosan, although fabI mutations persisted in 3/4 reverted SCVs. Virulence, determined using keratinocyte invasion and Galleria mellonella pathogenicity assays was significantly (p < 0.05) attenuated in 3/4 SCVs and in the non-SCV triclosan adapted bacterium. Proteomic analysis revealed elevated FabI in 2/3 SCV and down regulation in a protein associated with virulence in 1/3 SCV. In summary, attenuated keratinocyte invasion and larval virulence in triclosan-induced SCVs was associated with decreases in growth rate and virulence factor expression. Mutation occurred in fabI, which encodes the main triclosan target in all SCVs and the phenotype was reversed by fatty acid supplementation, demonstrating an association between fatty acid metabolism and triclosan-induced SCV. PMID- 29497097 TI - Boat noise impacts risk assessment in a coral reef fish but effects depend on engine type. AB - Human noise pollution has increased markedly since the start of industrialization and there is international concern about how this may impact wildlife. Here we determined whether real motorboat noise affected the behavior, space use and escape response of a juvenile damselfish (Pomacentrus wardi) in the wild, and explored whether fish respond effectively to chemical and visual threats in the presence of two common types of motorboat noise. Noise from 30 hp 2-stroke outboard motors reduced boldness and activity of fish on habitat patches compared to ambient reef-sound controls. Fish also no longer responded to alarm odours with an antipredator response, instead increasing activity and space use, and fewer fish responded appropriately to a looming threat. In contrast, while there was a minor influence of noise from a 30 hp 4-stroke outboard on space use, there was no influence on their ability to respond to alarm odours, and no impact on their escape response. Evidence suggests that anthropogenic noise impacts the way juvenile fish assess risk, which will reduce individual fitness and survival, however, not all engine types cause major effects. This finding may give managers options by which they can reduce the impact of motorboat noise on inshore fish communities. PMID- 29497098 TI - Disturbance Regimes Drive The Diversity of Regional Floristic Pools Across Guianan Rainforest Landscapes. AB - Disturbances control rainforest dynamics, and, according to the intermediate disturbance hypothesis (IDH), disturbance regime is a key driver of local diversity. Variations in disturbance regimes and their consequences on regional diversity at broad spatiotemporal scales are still poorly understood. Using multidisciplinary large-scale inventories and LiDAR acquisitions, we developed a robust indicator of disturbance regimes based on the frequency of a few early successional and widely distributed pioneer species. We demonstrate at the landscape scale that tree-species diversity and disturbance regimes vary with climate and relief. Significant relationships between the disturbance indicator, tree-species diversity and soil phosphorus content agree with the hypothesis that rainforest diversity is controlled both by disturbance regimes and long-term ecosystem stability. These effects explain the broad-scale patterns of floristic diversity observed between landscapes. In fact, species-rich forests in highlands, which have benefited from long-term stability combined with a moderate and regular regime of local disturbances, contrast with less diversified forests on recently shaped lowlands, which have undergone more recent changes and irregular dynamics. These results suggest that taking the current disturbance regime into account and including geomorphological stratifications in climate vegetation models may be an effective way to improve the prediction of changes in species diversity under climate change. PMID- 29497099 TI - Association of clinicopathological features and prognosis of TERT alterations in phyllodes tumor of breast. AB - Phyllodes tumor (PT) of the breast is a rare but clinically important fibroepithelial tumor with potential risks of recurrence and metastasis. Recent studies identified recurrent TERT promoter mutations in PTs. However, the clinical significance of this alteration has not been fully examined. Two hundred and seven PTs from two intuitions were included. All cases were subjected to immunohistochemical analysis for TERT expression. Analysis of TERT promoter mutations was further performed by Sanger sequencing targeting the hotspot mutation region on cases from one of the involved institutions. The expression of TERT was correlated with clinicopathologic features, mutation status and recurrence. There was an association of TERT expression and its promoter mutation. Both stromal TERT expression and its promoter mutation correlated with PT grading and older patient age. Recurrence free survival (RFS) of PT patients with high stromal TERT expression was shorter if the excision margin was positive. Our findings suggested a possible pathogenic role of TERT alteration in PT malignancy. Currently there is no consensus for re-excision for PT patients with positive surgical margin, particularly for low grade cases. Stromal TERT expression could be potentially useful to guide management patients with benign PTs. PMID- 29497101 TI - Author Correction: Low oxygen eddies in the eastern tropical North Atlantic: Implications for N2O cycling. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29497100 TI - Intramembranous ossification and endochondral ossification are impaired differently between glucocorticoid-induced osteoporosis and estrogen deficiency induced osteoporosis. AB - A fracture is the most dangerous complication of osteoporosis in patients because the associated disability and mortality rates are high. Osteoporosis impairs fracture healing and prognosis, but how intramembranous ossification (IO) or endochondral ossification (EO) during fracture healing are affected and whether these two kinds of ossification are different between glucocorticoid-induced osteoporosis (GIOP) and estrogen deficiency-induced osteoporosis (EDOP) are poorly understood. In this study, we established two bone repair models that exhibited repair via IO or EO and compared the pathological progress of each under GIOP and EDOP. In the cortical drill-hole model, which is repaired through IO, osteogenic differentiation was more seriously impaired in EDOP at the early stage than in GIOP. In the periosteum scratch model, in which EO is replicated, chondrocyte hypertrophy progression was delayed in both GIOP and EDOP. The in vitro results were consistent with the in vivo results. Our study is the first to establish bone repair models in which IO and EO occur separately, and the results strongly describe the differences in bone repair between GIOP and EDOP. PMID- 29497102 TI - Risk assessment of deoxynivalenol in high-risk area of China by human biomonitoring using an improved high throughput UPLC-MS/MS method. AB - A risk assessment of deoxynivalenol (DON) was recently conducted for the residents in Henan province, China, where wheat as the staple food are highly consumed. A high-throughput sensitive UPLC-MS/MS method following 96-well MUElution solid-phase extraction (SPE) were developed and validated for the determination of DON biomarkers in human urine. Isotope labelled internal standard, 13C-DON, was used for accurate quantification. Urinary samples collected from 151 healthy Chinese aged 2-78 years were processed with and without enzyme hydrolysis to determine total and free biomarkers, respectively. DON, and de-epoxy-deoxynivalenol (DOM-1) to a lesser extent, can be frequently detected in these samples both with and without enzyme hydrolysis. Free DOM-1 was detected at low level in human urine for the first time. Total DON was detected in all samples with a mean concentration at 47.6 ng mL-1. The mean and median probable daily intakes (PDI) for the whole participants, estimated to be 1.61 MUg/kg bw and 1.10 MUg/kg bw, both exceeded the PMTDI (1 MUg/kg bw/day), indicating a potential risk for the residents in this area, especially for children and adolescents. PMID- 29497103 TI - Author Correction: Long-range Stripe Nanodomains in Epitaxial (110) BiFeO3 Thin Films on (100) NdGaO3 Substrate. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29497104 TI - Large-scale patterning of single cells and cell clusters in hydrogels. AB - Biophysical properties of the extracellular matrix (ECM) are known to play a significant role in cell behavior. To gain a better understanding of the effects of the biophysical microenvironment on cell behavior, the practical challenge is longitudinally monitoring behavioral variations within a population to make statistically powerful assessments. Population-level measurements mask heterogeneity in cell responses, and large-scale individual cell measurements are often performed in a one-time, snapshot manner after removing cells from their matrix. Here we present an easy and low-cost method for large-scale, longitudinal studies of heterogeneous cell behavior in 3D hydrogel matrices. Using a platform we term "the drop-patterning chip", thousands of cells were simultaneously transferred from microwell arrays and fully embedded, only using the force of gravity, in precise patterns in 3D collagen I or Matrigel. This method allows for throughputs approaching 2D patterning methods that lack phenotypic information on cell-matrix interactions, and does not rely on special equipment and cell treatments that may result in a proximal stiff surface. With a large and yet well organized group of cells captured in 3D matrices, we demonstrated the capability of locating selected individual cells and monitoring cell division, migration, and proliferation for multiple days. PMID- 29497105 TI - Association between homocysteine and conventional predisposing factors on risk of stroke in patients with hypertension. AB - Previous studies have focused mostly on independent effects of the stroke risk factors, whereas little attention has been paid to interactions between individual factors which may be important for stroke prevention. We collected data related to the patients' demographic characteristics, history of chronic diseases and lifestyle factors in 2258 patients with primary hypertension. Logistic regression models based on odds ratio (OR) with their associated 95% confidence interval (CI) were used to estimate an independent effect of homocysteine (Hcy) on the risk of stroke but also include the interactions between Hcy and other risk factors. Hcy was associated with an increased OR of the risk of stroke in both hypertension patients (OR, 1.027; 95% CI, 1.016-1.038; P < 0.001) and H-type hypertension patients (OR, 1.026; 95% CI, 1.014-1.037; P < 0.001), after adjustment for potential confounding factors. Among the hypertension participants, three tests of interactions between Hcy and other risk factors were statistically significant: sex, systolic blood pressure and diastolic blood pressure. In conclusion, complexities of the interactions of Hcy stratified by sex and blood pressure need to be considered in predicting overall risk and selecting certain treatments for stroke prevention. PMID- 29497106 TI - Support for viral persistence in bats from age-specific serology and models of maternal immunity. AB - Spatiotemporally-localised prediction of virus emergence from wildlife requires focused studies on the ecology and immunology of reservoir hosts in their native habitat. Reliable predictions from mathematical models remain difficult in most systems due to a dearth of appropriate empirical data. Our goal was to study the circulation and immune dynamics of zoonotic viruses in bat populations and investigate the effects of maternally-derived and acquired immunity on viral persistence. Using rare age-specific serological data from wild-caught Eidolon helvum fruit bats as a case study, we estimated viral transmission parameters for a stochastic infection model. We estimated mean durations of around 6 months for maternally-derived immunity to Lagos bat virus and African henipavirus, whereas acquired immunity was long-lasting (Lagos bat virus: mean 12 years, henipavirus: mean 4 years). In the presence of a seasonal birth pulse, the effect of maternally-derived immunity on virus persistence within modelled bat populations was highly dependent on transmission characteristics. To explain previous reports of viral persistence within small natural and captive E. helvum populations, we hypothesise that some bats must experience prolonged infectious periods or within host latency. By further elucidating plausible mechanisms of virus persistence in bat populations, we contribute to guidance of future field studies. PMID- 29497107 TI - Engineering Axl specific CAR and SynNotch receptor for cancer therapy. AB - Axl is a tyrosine kinase receptor that is commonly overexpressed in many cancers. As such, Axl represents an attractive therapeutic target. The transfer of engineered T cell expressing chimeric antigen receptor (CAR) is an exciting cancer therapeutic approach that shows high efficacy against cancers in clinical trials, especially for B cell malignancies. Furthermore, recently developed synthetic Notch (synNotch) receptor has demonstrated potential in enhancing the specificity of CAR T cell therapy and delivering therapeutic payloads to tumors in an antigen-dependent manner. Therefore, a CAR or synNotch against Axl could be a valuable therapeutic reagent against many cancers. Here, we develop a single chain variable fragment from a humanized monoclonal antibody against Axl. The scFv is attached to CD3zeta, CD28, and 4-1BB signaling domains to generate an anti-Axl CAR. When introduced into human primary T cells, the anti-Axl CAR can lead to cytokine production and cell killing in response to tumor cells expressing Axl. Moreover, an anti-Axl synNotch generated using the same scFv can be activated with Axl expressing tumor cells. Given the fact that Axl is an important cancer therapeutic target, these receptors could be valuable reagents for developing anti-Axl therapies. PMID- 29497108 TI - Human milk oligosaccharides protect against the development of autoimmune diabetes in NOD-mice. AB - Development of Type 1 diabetes (T1D) is influenced by non-genetic factors, such as optimal microbiome development during early life that "programs" the immune system. Exclusive and prolonged breastfeeding is an independent protective factor against the development of T1D, likely via bioactive components. Human Milk Oligosaccharides (HMOS) are microbiota modulators, known to regulate immune responses directly. Here we show that early life provision (only for a period of six weeks) of 1% authentic HMOS (consisting of both long-chain, as well as short chain structures), delayed and suppressed T1D development in non-obese diabetic mice and reduced development of severe pancreatic insulitis in later life. These protective effects were associated with i) beneficial alterations in fecal microbiota composition, ii) anti-inflammatory microbiota-generating metabolite (i.e. short chain fatty acids (SCFAs)) changes in fecal, as well as cecum content, and iii) induction of anti-diabetogenic cytokine profiles. Moreover, in vitro HMOS combined with SCFAs induced development of tolerogenic dendritic cells (tDCs), priming of functional regulatory T cells, which support the protective effects detected in vivo. In conclusion, HMOS present in human milk are therefore thought to be vital in the protection of children at risk for T1D, supporting immune and gut microbiota development in early life. PMID- 29497109 TI - Melanopsin photoreception contributes to human visual detection, temporal and colour processing. AB - The visual consequences of melanopsin photoreception in humans are not well understood. Here we studied melanopsin photoreception using a technique of photoreceptor silent substitution with five calibrated spectral lights after minimising the effects of individual differences in optical pre-receptoral filtering and desensitising penumbral cones in the shadow of retinal blood vessels. We demonstrate that putative melanopsin-mediated image-forming vision corresponds to an opponent S-OFF L + M-ON response property, with an average temporal resolution up to approximately 5 Hz, and >10x higher thresholds than red green colour vision. With a capacity for signalling colour and integrating slowly changing lights, melanopsin-expressing intrinsically photosensitive retinal ganglion cells maybe the fifth photoreceptor type for peripheral vision. PMID- 29497110 TI - Room temperature 90 degrees phase-matching in zirconium and magnesium co-doped lithium niobate crystals. AB - Laser has been widely used in many aspects, by now it is difficult to get each frequency that we want, and frequency conversion is an effective way to obtain different frequency laser through a nonlinear optical crystal. MgO-doped LiNbO3 (Mg:LN) crystal has usually been used for second harmonic generation (SHG) through temperature-matching configuration with a stove, till now a room temperature 90 degrees phase-matching is still lacking. Here we find that the SHG of Nd:YAG laser is achieved at 26.1 degrees C while the optical damage resistance is higher than 6.5 MW/cm2 in the ZrO2 and MgO co-doped LiNbO3 (Zr,Mg:LN) crystal. Moreover, the monotonic decrease of phase-matching temperature is firstly found with the increase of doping concentration. These unusual properties may be attributed to the formation of [Formula: see text] + [Formula: see text] defect pairs. Our work suggests that Zr,Mg:LN crystal may be an attractive candidate for nonlinear optical applications. PMID- 29497111 TI - Vacancy assisted He-interstitial clustering and their elemental interaction at fcc-bcc semicoherent metallic interface. AB - Cu-Nb layered nanocomposite system can be considered as a prototype system to investigate stability of the fcc-bcc semicoherent metallic interfaces. Theoretical simulations based on density functional theory have been performed in order to investigate the stability of different defects in such interfaces. The calculations find the interfacial misfit dislocation intersections as the preferred site for defects including a vacancy, He-interstitial, and a vacancy-He complex in good agreement with previous works. Our results suggest that the presence of a metallic vacancy may act as a sink for defect and favour the migration of He interstitials leading to their aggregation at the interface. The potential capability of the vacancy to accommodate He atoms was also predicted with a higher affinity towards Nb. This aggregation of He atoms is driven by local density of electron and strain in a region in the neighbourhood of Nb. Finally, we propose a plausible picture of defect energetics in the vicinity of the interface based on the Voronoi volume and Bader's charge analysis. This analysis may replace the conventional methods used for surface energetics mapping which are extremely tedious for such large systems. PMID- 29497112 TI - Near-infrared laser thermal conjunctivoplasty. AB - Conjunctivochalasis is a common cause of tear dysfunction due to the conjunctiva becoming loose and wrinkly with age. The current solutions to this disease include either surgical excision in the operating room, or thermoreduction of the loose tissue with hot wire in the clinic. We developed a near-infrared laser thermal conjunctivoplasty system. The system utilizes a 1460-nm programmable laser diode system as the light source. At this wavelength, a water absorption peak exists and the blood absorption is minimal, so the heating of redundant conjunctiva is even and there is no bleeding. A miniaturized handheld probe delivers the laser light and reshapes the laser into a 10 * 1 mm2 line on the working plane. A foot pedal is used to deliver a preset number of calibrated laser pulses. A fold of loose conjunctiva is grasped by a pair of forceps. The NIR laser light is delivered through an optical fiber and a laser line is aimed exactly on the conjunctival fold by a cylindrical lens. Ex vivo experiments using porcine eye was performed to investigate the induced shrinkage of conjunctiva and decide the optimal laser parameters. It was found that up to 45% of conjunctiva shrinkage could be achieved. PMID- 29497113 TI - Tolerance of chronic HDACi treatment for neurological, visceral and lung Niemann Pick Type C disease in mice. AB - Histone deacetylase (HDAC) inhibitors are of significant interest as drugs. However, their use to treat neurological disorders has raised concern because HDACs are required for brain function. We have previously shown that a triple combination formulation (TCF) of the pan HDACi vorinostat (Vo), 2-hydroxypropyl beta-cyclodextrin (HPBCD) and polyethylene glycol (PEG) 400 improves pharmacokinetic exposure and entry of Vo into the brain. TCF treatment significantly delayed both neurodegeneration and death in the Npc1 nmf164 murine model of Niemann-Pick Type C (NPC) disease. The TCF induces no metabolic toxicity, but its risk to normal brain functions and potential utility in treating lung disease, a major NPC clinical complication, remain unknown. Here we report that TCF administered in healthy mice for 8-10 months was not detrimental to the brain or neuromuscular functions based on quantitative analyses of Purkinje neurons, neuroinflammation, neurocognitive/muscular disease symptom progression, cerebellar/hippocampal nerve fiber-staining, and Hdac gene expression. The TCF also improved delivery of Vo to lungs and reduced accumulation of foamy macrophages in Npc1 nmf164 mice, with no injury. Together, these data support feasibility of tolerable, chronic administration of an HDACi formulation that treats murine NPC neurological disease and lung pathology, a frequent cause of death in this and possibly additional disorders. PMID- 29497114 TI - Echinacoside Increases Sperm Quantity in Rats by Targeting the Hypothalamic Androgen Receptor. AB - Male infertility is a major health issue with an estimated prevalence of 4.2% of male infertility worldwide. Our early work demonstrated that Cistanche extracts protect against sperm damage in mice and that echinacoside (ECH) is one of the major active components. Here we report an essential role for ECH, a natural product that reverses or protects against oligoasthenospermia in rats. ECH was assayed by HPLC, the quantity and quality of sperm was evaluated and hormone levels were determined by radioimmunosorbent assay. ECH reduced levels of androgen receptor (AR) and key steroidogenic-related genes as determined by Western blot and qPCR analysis. The interaction between ECH and AR were evaluated by indirect ELISA and molecular docking. The results show that ECH combined with hypothalamic AR in the pocket of Met-894 and Val-713 to inhibit transfer of AR from the cytoplasm to nuclei in the hypothalamus. While negative feedback of sex hormone regulation was inhibited, positive feedback was stimulated to increase the secretion of luteinizing hormone and testosterone subsequently enhancing the quantity of sperm. Taken together, these data demonstrate that ECH blocks AR activity in the hypothalamus to increase the quantity of sperm and protect against oligoasthenospermia in rats. PMID- 29497115 TI - Loss of mRNA surveillance pathways results in widespread protein aggregation. AB - Eukaryotic cells contain translation-associated mRNA surveillance pathways which prevent the production of potentially toxic proteins from aberrant mRNA translation events. We found that loss of mRNA surveillance pathways in mutants deficient in nonsense-mediated decay (NMD), no-go decay (NGD) and nonstop decay (NSD) results in increased protein aggregation. We have isolated and identified the proteins that aggregate and our bioinformatic analyses indicates that increased aggregation of aggregation-prone proteins is a general occurrence in mRNA surveillance mutants, rather than being attributable to specific pathways. The proteins that aggregate in mRNA surveillance mutants tend to be more highly expressed, more abundant and more stable proteins compared with the wider proteome. There is also a strong correlation with the proteins that aggregate in response to nascent protein misfolding and an enrichment for proteins that are substrates of ribosome-associated Hsp70 chaperones, consistent with susceptibility for aggregation primarily occurring during translation/folding. We also identified a significant overlap between the aggregated proteins in mRNA surveillance mutants and ageing yeast cells suggesting that translation-dependent protein aggregation may be a feature of the loss of proteostasis that occurs in aged cell populations. PMID- 29497116 TI - Towards spontaneous parametric down conversion from monolayer MoS2. AB - We present a detailed study of the second order nonlinearity of 2D (mono-atomic layer) dichalcogenide MoS2, both in the visible and in the IR regime, and test its potential for spontaneous parametric down-conversion (SPDC), the amplification of vacuum fluctuations mediated by optical nonlinearity. We develop a model of SPDC from a deeply subwavelength nonlinear medium, where phase matching conditions are completely relaxed, and make predictions about the rate of emitted photons, their momentum, polarisation and spectrum. We show that detection in the visible spectral region is hindered by the strong photoluminescence background. Moving to the IR regime we observe indications of SPDC by performing polarization, power dependence and lifetime measurements around 1560 nm. We show that the signal from a single monolayer is qualitatively different from that generated by multi-layer MoS2. Finally, we characterize the latter as a new kind of photo-luminescence emission which is enhanced at the edges of multi-layer MoS2. PMID- 29497117 TI - A complex pattern with hexagonal lattice and white-eye stripe in dielectric barrier discharge. AB - A novel type of white-eye pattern in a dielectric barrier discharge system has been investigated in this paper. It is a superposition of a hexagonal lattice and a white-eye stripe in appearance and evolves from a white-eye square grid state with the applied voltage increasing. Its spatio-temporal dynamics obtained by an intensified charge-coupled device shows that it consists of three transient rectangular sublattices. The spatiotemporally resolved evolutions of the molecular vibrational temperature and electron density of the pattern are measured by optical emission spectra. The evolution of surface charge distribution is given and its effect on the self-organized pattern formation is discussed. PMID- 29497118 TI - Solution structure and dynamics of anti-CRISPR AcrIIA4, the Cas9 inhibitor. AB - The bacterial CRISPR-Cas system provides adaptive immunity against invading phages. Cas9, an RNA-guided endonuclease, specifically cleaves target DNA substrates and constitutes a well-established platform for genome editing. Recently, anti-CRISPR (Acr) proteins that inhibit Cas9 have been discovered, promising a useful off-switch for Cas9 to avoid undesirable off-target effects. Here, we report the solution structure and dynamics of Listeria monocytogenes AcrIIA4 that inhibits Streptococcus pyogenes Cas9 (SpyCas9). AcrIIA4 forms a compact monomeric alphabetabetabetaalphaalpha fold comprising three antiparallel beta strands flanked by three alpha-helices and a short 310-helix. AcrIIA4 exhibits distinct backbone dynamics in fast and slow timescales at loop regions that form interaction surfaces for SpyCas9. In particular, the beta1-beta2 loop that binds to the RuvC domain of SpyCas9 is highly mobile, and the beta1-beta2 and alpha2-alpha3 loops that bind to the RuvC and C-terminal domains of SpyCas9, respectively, undergoes conformational exchanges in microsecond-to-millisecond time scales. AcrIIA4 binds to apo-SpyCas9 with KD ~4.8 MUM, which compares to KD ~0.6 nM for AcrIIA4 binding to sgRNA-bound SpyCas9. Since the binary complex between AcrIIA4 and SpyCas9 does not compete with the target DNA binding, it can effectively disable the Cas9 nuclease activity by forming a tight ternary complex in the presence of sgRNA. PMID- 29497119 TI - Transcriptional activation of zebrafish fads2 promoter and its transient transgene expression in yolk syncytial layer of zebrafish embryos. AB - The front-end desaturases (Fads) are rate-limiting enzymes responsible for production of long-chain polyunsaturated fatty acids (LC-PUFA). The full spectrum of the transcriptional regulation of fads is still incomplete, as cloning of fads promoter is limited to a few species. Here, we described the cloning and characterisation of the zebrafish fads2 promoter. Using 5'-deletion and mutation analysis on this promoter, we identified a specific region containing the sterol regulatory element (SRE) which is responsible for the activation of the fads2 promoter. In tandem, two conserved CCAAT boxes were also present adjacent to the SRE and mutation of either of these binding sites attenuates the transcriptional activation of the fads2 promoter. An in vivo analysis employing GFP reporter gene in transiently transfected zebrafish embryos showed that this 1754 bp upstream region of the fads2 gene specifically directs GFP expression in the yolk syncytial layer (YSL) region. This indicates a role for LC-PUFA in the transport of yolk lipids through this tissue layer. In conclusion, besides identifying novel core elements for transcriptional activation in zebrafish fads2 promoter, we also reveal a potential role for fads2 or LC-PUFA in YSL during development. PMID- 29497120 TI - Spatial summation across the visual field in strabismic and anisometropic amblyopia. AB - Ricco's area (the largest area of visual space in which stimulus area and intensity are inversely proportional at threshold) has previously been hypothesised to be a result of centre/surround antagonism in retinal ganglion cell receptive fields, but recent evidence suggests a sizeable cortical contribution. Here, Ricco's area was measured in amblyopia, a condition in which retinal receptive fields are normal, to better understand its physiological basis. Spatial summation functions were determined at 12 visual field locations in both eyes of 14 amblyopic adults and 15 normal-sighted controls. Ricco's area was significantly larger in amblyopic eyes than in fellow non-amblyopic eyes. Compared to the size of Ricco's area in control eyes, Ricco's area measured significantly larger in amblyopic eyes. Additionally, Ricco's area in the fellow, non-amblyopic eye of amblyopic participants measured significantly smaller than in control eyes. Compared to controls, Ricco's area was larger in amblyopic eyes and smaller in fellow non-amblyopic eyes. Amblyopia type, binocularity, and inter ocular difference in visual acuity were significantly associated with inter ocular differences in Ricco's area in amblyopes. The physiological basis for Ricco's area is unlikely to be confined to the retina, but more likely representative of spatial summation at multiple sites along the visual pathway. PMID- 29497121 TI - A preliminary study on efficacy of rupatadine for the treatment of acute dengue infection. AB - Currently there are no specific treatments available for acute dengue infection. We considered that rupatadine, a platelet-activating factor receptor inhibitor, might modulate dengue-associated vascular leak. The effects of rupatadine were assessed in vitro, and in a dengue model, which showed that rupatadine significantly reduced endothelial permeability by dengue sera in vitro, and significantly inhibited the increased haematocrit in dengue-infected mice with dose-dependency. We conducted a randomised, placebo-controlled trial in 183 adult patients in Sri Lanka with acute dengue, which showed that rupatadine up to 40 mg daily appeared safe and well-tolerated with similar proportions of adverse events with rupatadine and placebo. Although the primary end-point of a significant reduction in fluid leakage (development of pleural effusions or ascites) was not met, post-hoc analyses revealed small but significant differences in several parameters on individual illness days - higher platelet counts and lower aspartate-aminotransferase levels on day 7 in the rupatadine group compared to the placebo group, and smaller effusions on day 8 in the subgroup of patients with pleural effusions. However, due to the small sample size and range of recruitment time, the potential beneficial effects of rupatadine require further evaluation in large studies focused on recruitment during the early febrile phase. PMID- 29497122 TI - Optical properties of dense lithium in electride phases by first-principles calculations. AB - The metal-semiconductor-metal transition in dense lithium is considered as an archetype of interplay between interstitial electron localization and delocalization induced by compression, which leads to exotic electride phases. In this work, the dynamic dielectric response and optical properties of the high pressure electride phases of cI16, oC40 and oC24 in lithium spanning a wide pressure range from 40 to 200 GPa by first-principles calculations are reported. Both interband and intraband contribution to the dielectric function are deliberately treated with the linear response theory. One intraband and two interband plasmons in cI16 at 70 GPa induced by a structural distortion at 2.1, 4.1, and 7.7 eV are discovered, which make the reflectivity of this weak metallic phase abnormally lower than the insulating phase oC40 at the corresponding frequencies. More strikingly, oC24 as a reentrant metallic phase with higher conductivity becomes more transparent than oC40 in infrared and visible light range due to its unique electronic structure around Fermi surface. An intriguing reflectivity anisotropy in both oC40 and oC24 is predicted, with the former being strong enough for experimental detection within the spectrum up to 10 eV. The important role of interstitial localized electrons is highlighted, revealing diversity and rich physics in electrides. PMID- 29497123 TI - Functional innate immunity restricts Hepatitis C Virus infection in induced pluripotent stem cell-derived hepatocytes. AB - Knowledge of activation and interplay between the hepatitis C virus (HCV) and the hosts' innate immunity is essential to understanding the establishment of chronic HCV infection. Human hepatoma cell lines, widely used as HCV cell culture system, display numerous metabolic alterations and a defective innate immunity, hindering the detailed study of virus-host interactions. Here, we analysed the suitability of induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (iHLCs) as a physiologically relevant model to study HCV replication in vitro. Density gradients and triglyceride analysis revealed that iHLCs secreted very-low density lipoprotein (VLDL)-like lipoproteins, providing a putative platform for bona fide lipoviroparticles. iHLCs supported the full HCV life cycle, but in contrast to Huh7 and Huh7.5 cells, replication and viral RNA levels decreased continuously. Following HCV infection, interferon-stimulated gene (ISG)-expression significantly increased in iHLCs, whereas induction was almost absent in Huh7/7.5 cells. However, IFNalpha-stimulation equally induced ISGs in iHLCs and hepatoma cells. JAK-STAT pathway inhibition increased HCV replication in mature iHLCs, but not in Huh7 cells. Additionally, HCV replication levels where higher in STAT2-, but not STAT1-knockdown iHLCs. Our findings support iHLCs as a suitable model for HCV-host interaction regarding a functional innate immunity and lipoprotein synthesis. PMID- 29497124 TI - USP27-mediated Cyclin E stabilization drives cell cycle progression and hepatocellular tumorigenesis. AB - Overexpression of Cyclin E has been seen in many types of cancers. However, the underlying mechanism remains enigmatic. Herein, we identified ubiquitin-specific peptidase 27 (USP27) as a Cyclin E interactor. We found that USP27 promoted Cyclin E stability by negatively regulating its ubiquitination. In addition, suppression of USP27 expression resulted in the inhibition of the growth, migration, and invasion of hepatocellular carcinoma. Furthermore, we detected a positive correlation between USP27 and Cyclin E expression in hepatocellular carcinoma tissues. Finally, we found that USP27 expression is inhibited by 5 fluorouracil (5-FU) treatment and USP27 depletion sensitizes Hep3B cells to 5-FU induced apoptosis. USP27-mediated Cyclin E stabilization is involved in tumorigenesis, suggesting that targeting USP27 may represent a new therapeutic strategy to treat cancers with aberrant overexpression of Cyclin E protein. PMID- 29497125 TI - Critical role of sigma-1 receptors in central neuropathic pain-related behaviours after mild spinal cord injury in mice. AB - Sigma-1 receptor (sigma1R) knockout (KO) CD1 mice, generated by homologous recombination, and separate pharmacological studies in wild type (WT) mice were done to investigate the role of this receptor in the development of pain-related behaviours (thermal hyperalgesia and mechanical allodynia) in mice after spinal cord contusion injury (SCI) - a model of central neuropathic pain. The modulatory effect of sigma1R KO on extracellular mediators and signalling pathways in the spinal cord was also investigated. In particular, changes in the expression of inflammatory cytokines (tumour necrosis factor TNF-alpha, interleukin IL-1beta) and both the expression and activation (phosphorylation) of the N-methyl-D aspartate receptor subunit 2B (NR2B-NMDA) and extracellular signal-regulated kinases (ERK1/2) were analysed. Compared with WT mice, both mechanical and thermal hypersensitivity were attenuated in sigma1R KO mice following SCI. Accordingly, treatment of WT mice with the sigma1R antagonist MR309 (previously developed as E-52862; S1RA) after SCI exerted antinociceptive effects (i.e. reduced mechanical allodynia and thermal hyperalgesia). Attenuated nociceptive responses in sigma1R KO were accompanied by reduced expression of TNF- alpha and IL-1beta as well as decreased activation/phosphorylation of NR2B-NMDA receptors and ERK1/2. These findings suggest that sigma1R may modulate central neuropathic pain and point to regulation of sensitization-related phenomena as a possible mechanism. PMID- 29497126 TI - Depressive symptoms and their association with social determinants and chronic diseases in middle-aged and elderly Chinese people. AB - Depression is one of the most prevalent mental disorders worldwide. Little information is available regarding association of depressive symptoms (DS) with cancer and chronic diseases among middle-aged and elderly Chinese in a population based setting. In this study we evaluated the prevalence and examined correlates of DS in two population-based cohort studies. Included in the analyses were 103,595 people with a mean age of 61.8 years at the DS assessment. The prevalence of DS was 2.4% in men and 5.6% in women. We found elderly participants, those with lower BMI, or chronic diseases were more likely to experience DS. Having a history of stroke (odds ratio (OR) = 2.2 in men and 1.8 in women), cancer (OR = 3.3 in men and 1.9 in women), or Parkinson's disease (OR = 3.1 in men and 2.7 in women) was associated with high DS. In women, high income and high education levels were inversely related to DS. Being a single woman, long-term or heavy female smoker was associated with high prevalence of DS. High BMI was correlated with low prevalence of depression in men. Our data suggests a low prevalence of DS among middle-aged and elderly people in Shanghai, China. Age, education, income, marital status, smoking, BMI, and certain health conditions were associated with DS. PMID- 29497128 TI - Experimental Study of Key Effect Factors and Simulation on Oil Displacement Efficiency for a Novel Modified Polymer BD-HMHEC. AB - A novel synthetic hydrophobically modified hydroxyethyl cellulose (HEC) using bromododecane (BD) was developed in our previous paper, which we denote as BD HMHEC. A series of one dimensional core displacement experiments were continually conducted to evaluate the key effect factors on the resistance factor (FR) and residual resistance factor (FRR) of BD-HMHEC solution, including polymer concentration, core permeability and injection rate. Results have shown that BD HMHEC has higher FR and FRR and has much better oil displacement performance than HEC during oil displacement process. Meanwhile, compared with HEC flooding, the key effects on oil displacement efficiency of BD-HMHEC flooding were investigated, including polymer concentration, injection slug and injection rate. A numerical simulation study has been developed by the Computer Modelling Group (CMG) simulator. Results have shown that BD-HMHEC flooding could cause better oil displacement efficiency than HEC flooding at the same condition. As indicated by one dimensional core displacement experimental results, the further incremental oil recovery of switching to BD-HMHEC flooding could increase by 7.0~8.0% after hydrolyzed polyacryamide (HPAM) flooding. The studies indicate that BD-HMHEC has great potential application during enhanced oil recovery (EOR) processes in oilfields. PMID- 29497127 TI - Genetic variants in two pathways influence serum urate levels and gout risk: a systematic pathway analysis. AB - The aims of this study were to identify candidate pathways associated with serum urate and to explore the genetic effect of those pathways on the risk of gout. Pathway analysis of the loci identified in genome-wide association studies (GWASs) showed that the ion transmembrane transporter activity pathway (GO: 0015075) and the secondary active transmembrane transporter activity pathway (GO: 0015291) were both associated with serum urate concentrations, with PFDR values of 0.004 and 0.007, respectively. In a Chinese population of 4,332 individuals, the two pathways were also found to be associated with serum urate (PFDR = 1.88E 05 and 3.44E-04, separately). In addition, these two pathways were further associated with the pathogenesis of gout (PFDR = 1.08E-08 and 2.66E-03, respectively) in the Chinese population and a novel gout-associated gene, SLC17A2, was identified (OR = 0.83, PFDR = 0.017). The mRNA expression of candidate genes also showed significant differences among different groups at pathway level. The present study identified two transmembrane transporter activity pathways (GO: 0015075 and GO: 0015291) were associations with serum urate concentrations and the risk of gout. SLC17A2 was identified as a novel gene that influenced the risk of gout. PMID- 29497129 TI - Long-term nutrient addition increased CH4 emission from a bog through direct and indirect effects. AB - Peatlands are globally significant sources of atmospheric methane (CH4). While several studies have examined the effects of nutrient addition on CH4 dynamics, there are few long-term peatland fertilization experiments, which are needed to understand the aggregated effects of nutrient deposition on ecosystem functioning. We investigated responses of CH4 flux and production to long-term field treatments with three levels of N (1.6-6.4 g m-2 yr-1 as NH4NO3), potassium and phosphorus (PK, 5.0 g P and 6.3 g K m-2 yr-1 as KH2PO4), and NPK in a temperate bog. Methane fluxes were measured in the field from May to August in 2005 and 2015. In 2015 CH4 flux was higher in the NPK treatment with 16 years of 6.4 g N m-2 yr-1 than in the control (50.5 vs. 8.6 mg CH4 m-2 d-1). The increase in CH4 flux was associated with wetter conditions derived from peat subsidence. Incubation of peat samples, with and without short-term PK amendment, showed that potential CH4 production was enhanced in the PK treatments, both from field application and by amending the incubation. We suggest that changes in this bog ecosystem originate from long-term vegetation change, increased decomposition and direct nutrient effects on microbial dynamics. PMID- 29497130 TI - Ultra-intense laser interaction with nanostructured near-critical plasmas. AB - Near-critical plasmas irradiated at ultra-high laser intensities (I > 1018W/cm2) allow to improve the performances of laser-driven particle and radiation sources and to explore scenarios of great astrophysical interest. Near-critical plasmas with controlled properties can be obtained with nanostructured low-density materials. By means of 3D Particle-In-Cell simulations, we investigate how realistic nanostructures influence the interaction of an ultra-intense laser with a plasma having a near-critical average electron density. We find that the presence of a nanostructure strongly reduces the effect of pulse polarization and enhances the energy absorbed by the ion population, while generally leading to a significant decrease of the electron temperature with respect to a homogeneous near-critical plasma. We also observe an effect of the nanostructure morphology. These results are relevant both for a fundamental understanding and for the foreseen applications of laser-plasma interaction in the near-critical regime. PMID- 29497131 TI - PDE4D regulates Spine Plasticity and Memory in the Retrosplenial Cortex. AB - The retrosplenial cortex (RSC) plays a critical role in episodic memory, but the molecular mechanisms governing plasticity in this structure are poorly understood. Diverse studies have demonstrated a role for RSC in acquisition, early consolidation and retrieval similar to the hippocampus (HC), as well as in systems consolidation similar to the anterior cingulate cortex. Here, we asked whether established molecular and structural substrates of memory consolidation in the HC also engage in RSC shortly after learning. We show striking parallels in training induced gene-activation in HC and RSC following contextual conditioning, which is blocked by systemic administration of an NMDA receptor antagonist. Long-term memory is enhanced by retrosplenial and hippocampal knockdown (KD) of the cAMP specific phosphodiesterase Pde4d. However, while training per se induces lasting spine changes in HC, this does not occur in RSC. Instead, increases in the number of mature dendritic spines are found in the RSC only if cAMP signaling is augmented by Pde4d KD, and spine changes are at least partially independent of training. This research highlights parallels and differences in spine plasticity mechanisms between HC and RSC, and provides evidence for a functional dissociation of the two. PMID- 29497132 TI - Phase transitions of ordered ice in graphene nanocapillaries and carbon nanotubes. AB - New phase diagrams for water confined in graphene nanocapillaries and single walled carbon nanotubes (CNTs) are proposed, identifying ice structures, their melting points and revealing the presence of a solid-liquid critical point. For quasi-2D water in nanocapillaries, we show through molecular-dynamics simulations that AA stacking in multilayer quasi-2D ice arises from interlayer hydrogen bonding and is stable up to three layers, thereby explaining recent experimental observations. Detailed structural and energetic analyses show that quasi-2D water can freeze discontinuously through a first-order phase transition or continuously with a critical point. The first-order transition line extends to a continuous transition line, defined by a sharp transition in diffusivity between solid-like and liquid-like regimes. For quasi-1D water, confined in CNTs, we observe the existence of a similar critical point at intermediate densities. In addition, an end point is identified on the continuous-transition line, above which the solid and liquid phases deform continuously. The solid-liquid phase transition temperatures in CNTs are shown to be substantially higher than 273 K, confirming recent Raman spectroscopy measurements. We observe ultrafast proton and hydroxyl transport in quasi-1D and -2D ice at 300 K, exceeding those of bulk water up to a factor of five, thereby providing possible applications to fuel-cells and electrolyzers. PMID- 29497133 TI - Bilateral acute iris transillumination following systemic administration of antibiotics. AB - OBJECTIVES: To describe the demographic characteristics, clinical features, and potential prognostic factors of bilateral acute iris transillumination (BAIT) following oral antibiotic uptake. METHODS: A retrospective study of 16 consecutive patients who developed BAIT following treatment with systemic antibiotics. Detailed past medical and ocular history was obtained, presenting signs and symptoms were documented and demographic characteristics were analyzed. All patients underwent a complete ocular examination and laboratory investigation. The course of best corrected visual acuity (BCVA), anterior chamber activity, and intraocular pressure (IOP) during the follow-up period were recorded and possible correlations with potential prognosticators were investigated. RESULTS: Fourteen females and two males were included in the present study. The mean age (SD) of the patients was 43 (14) years. All individuals presented conjunctival injection and photophobia and developed bilateral transillumination defects, fixed mid-dilated pupils and pigment dispersion in the anterior chamber. Systemic antibiotics were previously prescribed in all cases (13 patients with moxifloxacin and three patients with clarithromycin) and the mean (SD) interval between onset of symptoms and antibiotic administration was 17 (4) days. Ocular hypertension complicated all eyes and required antiglaucoma medication in 25 eyes. Severe anterior chamber pigment dispersion and higher IOP during the first week after presentation was significantly associated with longer duration of ocular hypertension (OHT) (p = 0.019). CONCLUSIONS: BAIT represents a rare clinical entity with characteristic features. Although etiopathogenesis of this condition remains unclear, a series of cases that indicate a strong correlation between systemic antibiotic administration and BAIT is herein presented. PMID- 29497134 TI - Spontaneous consecutive esotropia. AB - PURPOSE: Although less frequent than consecutive exotropia, consecutive esotropia is a well-known type of strabismus when it follows the surgical correction of an exotropia. Spontaneous conversion from initial constant, large-angle exotropia beyond the age of 3 months to esotropia or orthophoria, however, is not common. We describe a series of infants who presented a spontaneous evolution from a large-angle infantile exotropia to either an orthophoria or a spontaneously consecutive esotropia. METHODS: Cases of infants examined in the pediatric neuro ophthalmology clinic of a tertiary ophthalmology department between 2009 and 2015, and having presented an early large-angle exotropia that spontaneously converted into an esotropia or orthophoria-i.e., without any previous surgery or botulinum toxin injection-were studied. RESULTS: Ten cases (6 M:4 F) were followed up. Median age at first exotropia assessment was 3.88 months (SD = 6.35). Median age at spontaneous conversion to esotropia or orthophoria was 7.23 months (SD = 14.73). Six patients suffered from severe neurologic or metabolic diseases, three had neonatal respiratory distress syndrome, and one was healthy. CONCLUSION: Spontaneous conversion from initial large-angle exotropia to esotropia or orthophoria can be encountered. The cerebral maturation of visual structures probably accounts for this uncommon strabismus sequence. PMID- 29497135 TI - Intraoperative enteroscopy in Peutz-Jeghers syndrome. PMID- 29497136 TI - Multiple lymphomatous polyposis incidentally found after acute sigmoid diverticulitis. PMID- 29497137 TI - Board Review Vignette: Intraductal Papillary Neoplasm of the Bile Duct. PMID- 29497138 TI - Anti-mitotic chemotherapeutics promote apoptosis through TL1A-activated death receptor 3 in cancer cells. AB - The commonly used antimitotic chemotherapeutic agents such as taxol and vinblastine arrest cell cycle progression by disrupting mitotic spindles, and cause cancer cells to undergo apoptosis through 'mitotic catastrophe'. The molecular mechanisms by which these drugs induce apoptosis and their relevance to clinical efficacy are not known. Facilitated by a new spindle poison diazonamide, we found that apoptosis induced by these agents requires death receptor 3 (DR3). Mitotic arrest by these agents induces lysosome-dependent secretion of the DR3 ligand, TL1A. Engagement of TL1A with DR3 stimulates the formation of FADD containing and caspase-8-containing death-inducing signaling complex (DISC), which subsequently activates apoptosis in cells that express DR3. Expression of DR3 and TL1A correlates with the apoptotic response of human tumor xenograft models and human cancer cell lines to antimitotic drugs, providing further evidence that these drugs kill cancer cells through the DR3/TL1A-mediated pathway. These results suggest that TL1A and DR3 may hold promise to be used as biomarkers for predicting clinical response to antimitotic therapeutics. PMID- 29497140 TI - Author Correction: Single-nucleus analysis of accessible chromatin in developing mouse forebrain reveals cell-type-specific transcriptional regulation. AB - In the version of this article initially published online, the accession code was given as GSE1000333. The correct code is GSE100033. The error has been corrected in the print, HTML and PDF versions of the article. PMID- 29497139 TI - Antimicrobial mechanisms due to hyperpolarisation induced by nanoporous Au. AB - Nanomaterials such as nanoparticles exhibit remarkable antimicrobial activities. Nanoparticles directly disturb the cell membrane or cytoplasmic proteins because they pass through the cell wall. Nanoporous Au (NPG) is another antimicrobial nanomaterial, which cannot pass through the cell wall of bacteria but can still kill bacteria, utilising interactions between the surface of NPG and cell wall of bacteria. The origins of antimicrobial activities without direct interactions are unknown. It is necessary to elucidate these mechanisms to ensure safe usage. Here we show that the antimicrobial mechanism of NPG consists of two interactions: between the surface of NPG and cell wall, and between the cell wall and cell membrane. Fluorescent experiments showed that the cell wall was negatively hyperpolarised by NPG, and molecular dynamics simulations and first-principles calculations suggested that the hyperpolarisation of the cell wall leads to delicate structural changes in the membrane proteins, rendering them bactericidal. Thus, the hyperpolarisation induced by NPG plays a critical role in both interactions. The combination of molecular dynamics simulations and first principles calculations allows a deeper understanding of the interactions between metallic surfaces and biomolecules, because charge transfer and exchange interactions are calculated exactly. PMID- 29497141 TI - The somatic FAH C.1061C>A change counteracts the frequent FAH c.1062+5G>A mutation and permits U1snRNA-based splicing correction. AB - In tyrosinaemia type 1(HT1), a mosaic pattern of fumarylacetoacetase (FAH) immunopositive or immunonegative nodules in liver tissue has been reported in many patients. This aspect is generally explained by a spontaneous reversion of the mutation into a normal genotype. In one HT1 patient carrying the frequent FAH c.1062+5G>A mutation, a second somatic change (c.1061C>A) has been reported in the same allele, and found in immunopositive nodules. Here, we demonstrated that the c.1062+5G>A prevents usage of the exon 12 5' splice site (ss), even when forced by an engineered U1snRNA specifically designed on the FAH 5'ss to strengthen its recognition. Noticeably the new somatic c.1061C>A change, in linkage with the c.1062+5G>A mutation, partially rescues the defective 5'ss and is associated to trace level (~5%) of correct transcripts. Interestingly, this combined genetic condition strongly favored the rescue by the engineered U1snRNA, with correct transcripts reaching up to 60%. Altogether, these findings elucidate the molecular basis of HT1 caused by the frequent FAH c.1062+5G>A mutation, and demonstrate the compensatory effect of the c.1061C>A change in promoting exon definition, thus unraveling a rare mechanism leading to FAH immune-reactive mosaicism. PMID- 29497142 TI - Author Correction: Pathogenic p62/SQSTM1 mutations impair energy metabolism through limitation of mitochondrial substrates. AB - A correction has been published and is linked to the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29497143 TI - Evaluation of three methods for biomass estimation in small invertebrates, using three large disparate parasite species as model organisms. AB - Invertebrate biomass is considered one of the main factors driving processes in ecosystems. It can be measured directly, primarily by weighing individuals, but more often indirect estimators are used. We developed two indirect and non destructive approaches to estimate biomass of small invertebrates in a simple manner. The first one was based on clay modelling and the second one was based on image analysis implemented with open-source software. Furthermore, we tested the accuracy of the widely used geometric approximation method (third method). We applied these three different methods to three morphologically disparate model species, an acanthocephalan worm, a crustacean and a flatworm. To validate our indirect estimations and to test their accuracy, we weighed specimens of the three species and calculated their tissue densities. Additionally, we propose an uncomplicated technique to estimate thickness of individuals under a microscope, a required measurement for two of the three indirect methods tested. The indirect methods proposed in this paper provided the best approximation to direct measurements. Despite its wide use, the geometric approximation method showed the lowest accuracy. The approaches developed herein are timely because the recently increasing number of studies requiring reliable biomass estimates for small invertebrates to explain crucial processes in ecosystems. PMID- 29497145 TI - Drug delivery: DNA nanorobots - seek and destroy. PMID- 29497147 TI - Metastasis: Staying organized. PMID- 29497144 TI - The molecular landscape of head and neck cancer. AB - Head and neck squamous cell carcinomas (HNSCCs) arise in the mucosal linings of the upper aerodigestive tract and are unexpectedly heterogeneous in nature. Classical risk factors are smoking and excessive alcohol consumption, and in recent years, the role of human papillomavirus (HPV) has emerged, particularly in oropharyngeal tumours. HPV-induced oropharyngeal tumours are considered a separate disease entity, which recently has manifested in an adapted prognostic staging system while the results of de-intensified treatment trials are awaited. Carcinogenesis caused by HPV in the mucosal linings of the upper aerodigestive tract remains an enigma, but with some recent observations, a model can be proposed. In 2015, The Cancer Genome Atlas (TCGA) consortium published a comprehensive molecular catalogue on HNSCC. Frequent mutations of novel druggable oncogenes were not demonstrated, but the existence of a subgroup of genetically distinct HPV-negative head and neck tumours with favourable prognoses was confirmed. Tumours can be further subclassified based on genomic profiling. However, the amount of molecular data is currently overwhelming and requires detailed biological interpretation. It also became apparent that HNSCC is a disease characterized by frequent mutations that create neoantigens, indicating that immunotherapies might be effective. In 2016, the first results of immunotherapy trials with immune checkpoint inhibitors were published, and these may be considered as a paradigm shift in head and neck oncology. PMID- 29497146 TI - Opportunities and challenges for human papillomavirus vaccination in cancer. AB - The discovery of genotype 16 as the prototype oncogenic human papillomavirus (HPV) initiated a quarter century of laboratory and epidemiological studies that demonstrated their necessary, but not sufficient, aetiological role in cervical and several other anogenital and oropharyngeal cancers. Early virus-induced immune deviation can lead to persistent subclinical infection that brings the risk of progression to cancer. Effective secondary prevention of cervical cancer through cytological and/or HPV screening depends on regular and widespread use in the general population, but coverage is inadequate in low-resource settings. The discovery that the major capsid antigen L1 could self-assemble into empty virus like particles (VLPs) that are both highly immunogenic and protective led to the licensure of several prophylactic VLP-based HPV vaccines for the prevention of cervical cancer. The implementation of vaccination programmes in adolescent females is underway in many countries, but their impact critically depends on the population coverage and is improved by herd immunity. This Review considers how our expanding knowledge of the virology and immunology of HPV infection can be exploited to improve vaccine technologies and delivery of such preventive strategies to maximize reductions in HPV-associated disease, including incorporation of an HPV vaccine covering oncogenic types within a standard multitarget paediatric vaccine. PMID- 29497148 TI - Neuron-specific deficits of bioenergetic processes in the dorsolateral prefrontal cortex in schizophrenia. AB - Schizophrenia is a devastating illness that affects over 2 million people in the United States and costs society billions of dollars annually. New insights into the pathophysiology of schizophrenia are needed to provide the conceptual framework to facilitate development of new treatment strategies. We examined bioenergetic pathways in the dorsolateral prefrontal cortex (DLPFC) of subjects with schizophrenia and control subjects using western blot analysis, quantitative real-time polymerase chain reaction, and enzyme/substrate assays. Laser-capture microdissection-quantitative polymerase chain reaction was used to examine these pathways at the cellular level. We found decreases in hexokinase (HXK) and phosphofructokinase (PFK) activity in the DLPFC, as well as decreased PFK1 mRNA expression. In pyramidal neurons, we found an increase in monocarboxylate transporter 1 mRNA expression, and decreases in HXK1, PFK1, glucose transporter 1 (GLUT1), and GLUT3 mRNA expression. These results suggest abnormal bioenergetic function, as well as a neuron-specific defect in glucose utilization, in the DLPFC in schizophrenia. PMID- 29497149 TI - The DREADD agonist clozapine N-oxide (CNO) is reverse-metabolized to clozapine and produces clozapine-like interoceptive stimulus effects in rats and mice. AB - Clozapine-N-oxide (CNO) has long been the ligand of choice for selectively activating Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). However, recent studies have challenged the long-held assertion that CNO is otherwise pharmacologically inert. The present study aimed to 1) determine whether CNO is reverse-metabolized to its parent compound clozapine in mice (as has recently been reported in rats), and 2) determine whether CNO exerts clozapine-like interoceptive stimulus effects in rats and/or mice. Following administration of 10.0 mg/kg CNO, pharmacokinetic analyses replicated recent reports of back-conversion to clozapine in rats and revealed that this phenomenon also occurs in mice. In rats and mice trained to discriminate 1.25 mg/kg clozapine from vehicle, CNO (1.0-20.0 mg/kg) produced partial substitution for the clozapine stimulus on average, with full substitution being detected in some individual animals of both species at doses frequently used to activate DREADDs. The present demonstration that CNO is converted to clozapine and exerts clozapine like behavioral effects in both mice and rats further emphasizes the need for appropriate control groups in studies employing DREADDs, and highlights the utility of the drug discrimination procedure as a tool with which to screen the off-target effects of novel DREADD agonists. PMID- 29497150 TI - Impact of long-term potassium supplementation on thiazide diuretic-induced abnormalities of glucose and uric acid metabolisms. AB - Treatment of hypertension with thiazide diuretics may trigger hypokalemia, hyperglycemia, and hyperuricemia. Some studies suggest simultaneous potassium supplementation in hypertensive patients using thiazide diuretics. However, few clinical studies have reported the impact of long-term potassium supplementation on thiazide diuretic-induced abnormalities in blood glucose and uric acid (UA) metabolisms. One hundred hypertensive patients meeting the inclusion criteria were equally randomized to two groups: IND group receiving indapamide (1.25-2.5 mg daily) alone, and IND/KCI group receiving IND (1.25-2.5 mg daily) plus potassium chloride (40 mmol daily), both for 24 weeks. At the end of 24-week follow-up, serum K+ level in IND group decreased from 4.27 +/- 0.28 to 3.98 +/- 0.46 mmol/L (P < 0.001), and fasting plasma glucose (FPG) and UA increased from 5.11 +/- 0.52 to 5.31 +/- 0.57 mmol/L (P < 0.05), and from 0.404 +/- 0.078 to 0.433 +/- 0.072 mmol/L (P < 0.05), respectively. Serum K+ level in IND/KCl group decreased from 4.27 +/- 0.36 to 3.89 +/- 0.28 mmol/L (P < 0.001), and FPB and UA increased from 5.10 +/- 0.41 to 5.35 +/- 0.55 mmol/L (P < 0.01), and from 0.391 +/- 0.073 to 0.457 +/- 0.128 mmol/L (P < 0.001), respectively. The difference value between the serum K+ level and FPG before and after treatment was not statistically significant between the two groups. However, the difference value in UA in IND/KCl group was significantly higher than that in IND group (0.066 (95% confidence interval (CI): 0.041-0.090) mmol/L vs. 0.029 (95% CI: 0.006 0.058) mmol/L, P < 0.05). The results showed that long-term routine potassium supplementation could not prevent or attenuate thiazide diuretic-induced abnormalities of glucose metabolism in hypertensive patients; rather, it may aggravate the UA metabolic abnormality. PMID- 29497151 TI - New guidelines with few takers: will the new American guidelines ever be accepted? PMID- 29497153 TI - CNS infections: Hidden consequences of Zika virus infection in pregnancy. PMID- 29497152 TI - Histone H3 lysine 4 monomethylation modulates long-range chromatin interactions at enhancers. AB - This corrects the article DOI: 10.1038/cr.2018.1. PMID- 29497154 TI - Motor neuron disease: Benefits of nusinersen extend to later-onset SMA. PMID- 29497155 TI - Peripheral neuropathies: Nerve damage differs between diabetes types. PMID- 29497157 TI - Working together, apart. PMID- 29497156 TI - Multiple sclerosis: CSF markers predict progression from radiologically isolated syndrome. PMID- 29497158 TI - Ancient nitrogen fixers. PMID- 29497159 TI - Repelling planthoppers. PMID- 29497160 TI - Secondary siRNAs rescue virus-infected plants. PMID- 29497161 TI - Crosstalk between PTGS and TGS pathways in natural antiviral immunity and disease recovery. AB - Virus-induced diseases cause severe damage to cultivated plants, resulting in crop losses. Certain plant-virus interactions allow disease recovery at later stages of infection and have the potential to reveal important molecular targets for achieving disease control. Although recovery is known to involve antiviral RNA silencing1,2, the specific components of the many plant RNA silencing pathways 3 required for recovery are not known. We found that Arabidopsis thaliana plants infected with oilseed rape mosaic virus (ORMV) undergo symptom recovery. The recovered leaves contain infectious, replicating virus, but exhibit a loss of viral suppressor of RNA silencing (VSR) protein activity. We demonstrate that recovery depends on the 21-22 nt siRNA-mediated post transcriptional gene silencing (PTGS) pathway and on components of a transcriptional gene silencing (TGS) pathway that is known to facilitate non-cell autonomous silencing signalling. Collectively, our observations indicate that recovery reflects the establishment of a tolerant state in infected tissues and occurs following robust delivery of antiviral secondary siRNAs from source to sink tissues, and establishment of a dosage able to block the VSR activity involved in the formation of disease symptoms. PMID- 29497162 TI - Alone in the dark. PMID- 29497163 TI - Author Correction: Timing and localization of human dystrophin isoform expression provide insights into the cognitive phenotype of Duchenne muscular dystrophy. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29497164 TI - The OPRM1 A118G polymorphism: converging evidence against associations with alcohol sensitivity and consumption. AB - The endogenous opioid system may be involved in the development and maintenance of alcohol use disorder (AUD) and is a target for existing AUD pharmacotherapies. A functional polymorphism of the mu-opioid receptor gene (OPRM1 A118G, rs1799971) may alter the risk of developing AUD. Human laboratory studies have demonstrated that minor allele carriers self-administer more alcohol, show greater sensitivity to alcohol's effects, and exhibit increased alcohol-induced dopamine release. On the other hand, large genome-wide association studies and meta-analyses of candidate gene studies have not found an association between this genotype and alcohol dependence diagnosis. Given this discrepancy, the present study sought to verify whether OPRM1 A118G was associated with alcohol self-administration, subjective response to alcohol, and craving in a sample of 106 social drinkers of European ancestry who completed an intravenous alcohol self-administration session. We found no relationship between OPRM1 rs1799971 genotype and subjective response to alcohol or craving. OPRM1 genotype was not associated with total alcohol exposure or likelihood of attaining a binge-level exposure (80 mg%) during the intravenous alcohol self-administration session. Analysis of 90-day Timeline Followback interview data in a larger sample of 965 participants of European ancestry found no relationship between OPRM1 genotype and alcohol consumption in either alcohol dependent or non-dependent participants. These findings suggest that there may not be an association between OPRM1 rs1799971 genotype and alcohol consumption or sensitivity in individuals of European ancestry. PMID- 29497165 TI - mTORC2 in the dorsomedial striatum of mice contributes to alcohol-dependent F Actin polymerization, structural modifications, and consumption. AB - Actin is highly enriched at dendritic spines, and actin remodeling plays an essential role in structural plasticity. The mammalian target of rapamycin complex 2 (mTORC2) is a regulator of actin polymerization. Here, we report that alcohol consumption increases F-actin content in the dorsomedial striatum (DMS) of mice, thereby altering dendritic spine morphology in a mechanism that requires mTORC2. Specifically, we found that excessive alcohol consumption increases mTORC2 activity in the DMS, and that knockdown of Rictor, an essential component of mTORC2 signaling, reduces actin polymerization, and attenuates the alcohol dependent alterations in spine head size and the number of mushroom spines. Finally, we show that knockdown of Rictor in the DMS reduces alcohol consumption, whereas intra-DMS infusion of the mTORC2 activator, A-443654, increases alcohol intake. Together, these results suggest that mTORC2 in the DMS facilitates the formation of F-actin, which in turn induces changes in spine structure to promote and/or maintain excessive alcohol intake. PMID- 29497166 TI - Glucagon-like peptide-1 receptor activation in the ventral tegmental area attenuates cocaine seeking in rats. AB - Novel molecular targets are needed to develop new medications for the treatment of cocaine addiction. Here we investigated a role for glucagon-like peptide-1 (GLP-1) receptors in the reinstatement of cocaine-seeking behavior, an animal model of relapse. We showed that peripheral administration of the GLP-1 receptor agonist exendin-4 dose dependently reduced cocaine seeking in rats at doses that did not affect ad libitum food intake, meal patterns or body weight. We also demonstrated that systemic exendin-4 penetrated the brain where it putatively bound receptors on both neurons and astrocytes in the ventral tegmental area (VTA). The effects of systemic exendin-4 on cocaine reinstatement were attenuated in rats pretreated with intra-VTA infusions of the GLP-1 receptor antagonist exendin-(9-39), indicating that the suppressive effects of systemic exendin-4 on cocaine seeking were due, in part, to activation of GLP-1 receptors in the VTA. Consistent with these effects, infusions of exendin-4 directly into the VTA reduced cocaine seeking. Finally, extinction following cocaine self administration was associated with decreased preproglucagon mRNA expression in the caudal brainstem. Thus, our study demonstrated a novel role for GLP-1 receptors in the reinstatement of cocaine-seeking behavior and identified behaviorally relevant doses of a GLP-1 receptor agonist that selectively reduced cocaine seeking and did not produce adverse effects. PMID- 29497167 TI - Photo-induced surface-enhanced Raman spectroscopy from a diphenylalanine peptide nanotube-metal nanoparticle template. AB - UV irradiation of aligned diphenylalanine peptide nanotubes (FF-PNTs) decorated with plasmonic silver nanoparticles (Ag NPs) enables photo-induced surface enhanced Raman spectroscopy. UV-induced charge transfer facilitates a chemical enhancement that provides up to a 10-fold increase in surface-enhanced Raman intensity and allows the detection of a wide range of small molecules and low Raman cross-section molecules at concentrations as low as 10-13 M. The aligned FF PNT/Ag NP template further prevents photodegradation of the molecules under investigation. Our results demonstrate that FF-PNTs can be used as an alternative material to semiconductors such as titanium dioxide for photo-induced surface enhanced Raman spectroscopy applications. PMID- 29497168 TI - Analysis of (CAG)n expansion in ATXN1, ATXN2 and ATXN3 in Chinese patients with multiple system atrophy. AB - Multiple system atrophy (MSA) is a complex and multifactorial neurodegenerative disease, and its pathogenesis remains uncertain. Patients with MSA or spinocerebellar ataxia (SCA) show overlapping clinical phenotypes. Previous studies have reported that intermediate or long CAG expansions in SCA genes have been associated with other neurodegenerative disease. In this study, we screened for the number of CAG repeats in ATXN1, 2 and 3 in 200 patients with MSA and 314 healthy controls to evaluate possible associations between (CAG)n in these three polyQ-related genes and MSA. Our findings indicated that longer repeat lengths in ATXN2 were associated with increased risk for MSA in Chinese individuals. No relationship was observed between CAG repeat length in the three examined genes and age at onset (AO) of MSA. PMID- 29497169 TI - One-step fabrication of robust superhydrophobic and superoleophilic surfaces with self-cleaning and oil/water separation function. AB - Superhydrophobic surfaces have great potential for application in self-cleaning and oil/water separation. However, the large-scale practical applications of superhydrophobic coating surfaces are impeded by many factors, such as complicated fabrication processes, the use of fluorinated reagents and noxious organic solvents and poor mechanical stability. Herein, we describe the successful preparation of a fluorine-free multifunctional coating without noxious organic solvents that was brushed, dipped or sprayed onto glass slides and stainless-steel meshes as substrates. The obtained multifunctional superhydrophobic and superoleophilic surfaces (MSHOs) demonstrated self-cleaning abilities even when contaminated with or immersed in oil. The superhydrophobic surfaces were robust and maintained their water repellency after being scratched with a knife or abraded with sandpaper for 50 cycles. In addition, stainless steel meshes sprayed with the coating quickly separated various oil/water mixtures with a high separation efficiency (>93%). Furthermore, the coated mesh maintained a high separation efficiency above 95% over 20 cycles of separation. This simple and effective strategy will inspire the large-scale fabrication of multifunctional surfaces for practical applications in self-cleaning and oil/water separation. PMID- 29497170 TI - Whither systems medicine? AB - New technologies to generate, store and retrieve medical and research data are inducing a rapid change in clinical and translational research and health care. Systems medicine is the interdisciplinary approach wherein physicians and clinical investigators team up with experts from biology, biostatistics, informatics, mathematics and computational modeling to develop methods to use new and stored data to the benefit of the patient. We here provide a critical assessment of the opportunities and challenges arising out of systems approaches in medicine and from this provide a definition of what systems medicine entails. Based on our analysis of current developments in medicine and healthcare and associated research needs, we emphasize the role of systems medicine as a multilevel and multidisciplinary methodological framework for informed data acquisition and interdisciplinary data analysis to extract previously inaccessible knowledge for the benefit of patients. PMID- 29497171 TI - Sleep deprivation disrupts the lacrimal system and induces dry eye disease. AB - Sleep deficiency is a common public health problem associated with many diseases, such as obesity and cardiovascular disease. In this study, we established a sleep deprivation (SD) mouse model using a 'stick over water' method and observed the effect of sleep deficiency on ocular surface health. We found that SD decreased aqueous tear secretion; increased corneal epithelial cell defects, corneal sensitivity, and apoptosis; and induced squamous metaplasia of the corneal epithelium. These pathological changes mimic the typical features of dry eye. However, there was no obvious corneal inflammation and conjunctival goblet cell change after SD for 10 days. Meanwhile, lacrimal gland hypertrophy along with abnormal lipid metabolites, secretory proteins and free amino-acid profiles became apparent as the SD duration increased. Furthermore, the ocular surface changes induced by SD for 10 days were largely reversed after 14 days of rest. We conclude that SD compromises lacrimal system function and induces dry eye. These findings will benefit the clinical diagnosis and treatment of sleep-disorder related ocular surface diseases. PMID- 29497173 TI - Pirfenidone reduces profibrotic responses in human dermal myofibroblasts, in vitro. AB - Pirfenidone (PFD) is a synthetic small molecule inhibitor with demonstrated anti inflammatory and antifibrotic properties in vitro and in vivo. The exact mechanism(s) of PFD action remain unclear, due in part to the broad effects of this drug on the complex processes involved in inflammation and fibrosis. While PFD is FDA-approved for the treatment of idiopathic pulmonary fibrosis, the efficacy of this compound for the treatment of dermal fibrosis has not yet been fully characterized. Dermal fibrosis is the pathological formation of excess fibrous connective tissue of the skin, usually the result of traumatic cutaneous injury. Fibroproliferative scarring, caused by delayed wound healing and prolonged inflammation, remains a major clinical concern with considerable morbidity. Despite efforts to identify a therapeutic that targets the fibrotic pathways involved in wound healing to mitigate scar formation, no satisfactory dermal antifibrotic has yet been identified. We aim to better elucidate the antifibrotic mechanism(s) of PFD activity using an in vitro model of dermal fibrosis. Briefly, cultured human dermal fibroblasts were stimulated with TGF beta1 to induce differentiation into profibrotic myofibroblast cells. A dose dependent reduction in cellular proliferation and migration was observed in TGF beta1-stimulated cells when treated with PFD. We observed a clear inhibition in the development of essential myofibroblast mechanoregulatory machinery, including contractile F-actin stress fibers containing alpha-SMA and large super-mature focal adhesions. PFD treatment significantly reduced protein levels of major ECM components type I and type III collagen. PFD targeted the p38 MAPK signaling pathway and mitigated profibrotic gene expression profiles. This in vitro data promotes PFD as a potential therapeutic agent for the treatment of dermal fibrosis. PMID- 29497172 TI - Impaired Na+-K+-ATPase signaling in renal proximal tubule contributes to hyperuricemia-induced renal tubular injury. AB - Hyperuricemia contributes to renal inflammation. We aimed to investigate the role of Na+-K+-ATPase (NKA) in hyperuricemia-induced renal tubular injury. Human primary proximal tubular epithelial cells (PTECs) were incubated with uric acid (UA) at increasing doses or for increasing lengths of time. PTECs were then stimulated by pre-incubation with an NKA alpha1 expression vector or small interfering RNA before UA (100 MUg ml-1, 48 h) stimulation. Hyperuricemic rats were induced by gastric oxonic acid and treated with febuxostat (Feb). ATP levels, the activity of NKA and expression of its alpha1 subunit, Src, NOD-like receptor pyrin domain-containing protein 3 (NLRP3) and interleukin 1beta (IL 1beta) were measured both in vitro and in vivo. Beginning at concentrations of 100 MUg ml-1, UA started to dose-dependently reduce NKA activity. UA at a concentration of 100 MUg ml-1 time-dependently affected the NKA activity, with the maximal increased NKA activity at 24 h, but the activity started to decrease after 48 h. This inhibitory effect of UA on NKA activity at 48 h was in addition to a decrease in NKA alpha1 expression in the cell membrane, but an increase in lysosomes. This process also involved the subsequent activation of Src kinase and NLRP3, promoting IL-1beta processing. In hyperuricemic rats, renal cortex NKA activity and its alpha1 expression were upregulated at the 7th week and both decreased at the 10th week, accompanied with increased renal cortex expression of Src, NLRP3 and IL-1beta. The UA levels were reduced and renal tubular injuries in hyperuricemic rats were alleviated in the Feb group. Our data suggested that the impairment of NKA and its consequent regulation of Src, NLRP3 and IL-1beta in the renal proximal tubule contributed to hyperuricemia-induced renal tubular injury. PMID- 29497174 TI - Lack of hepatic stimulator substance expression promotes hepatocellular carcinoma metastasis partly through ERK-activated epithelial-mesenchymal transition. AB - Hepatocellular carcinoma (HCC) is one of the most lethal malignancies due to its high frequency of metastasis via the epithelial-mesenchymal transition (EMT) pathway. Hepatic stimulator substance (HSS) can protect hepatocytes from injury and promote liver growth. Recent studies indicated that HSS expression is increased in HCC tissues; however, whether HSS expression is potentially associated with HCC metastasis, particularly through the EMT pathway, remains largely unknown. In this study, the relationship between HSS expression and HCC metastasis was investigated in clinical samples of HCC. Meanwhile, the regulation of HCC metastasis and EMT progression by HSS were also analyzed in both in vitro and in vivo models. The results showed that the expression of 23 kDa HSS was significantly decreased among HCC tissues with angioinvasion. A decrease in HSS predicted poor prognosis with a lower survival rate. Furthermore, the growth of xenograft tumors after inoculating MHCC97H-HSS-shRNA (HCC) cells into nude mice was notably accelerated compared to those inoculated with HSS-expressing cells. Further analysis revealed that knockdown of HSS expression in both MHCC97H and HepG2 cells could enhance the migration of these HCC cells. Concurrently, interference of HSS expression by shRNA promoted conversion of morphologically epithelial-like HCC cells into mesenchymal-like cells, together with downregulations of epithelial markers (such as E-cadherin and zonula occludens-1) and upregulation of mesenchymal-like makers (such as alpha-SMA, beta-catenin, and fibronectin). Furthermore, it was demonstrated that, as well as promoting EMT, HSS-shRNA induced the phosphorylation of extracellular signal-regulated kinase (ERK) and elevated the expression of the EMT-related transcription factor Snail. Specific inhibition of HSS-shRNA-induced ERK phosphorylation by PD98059 attenuated HCC cell migration in a dose-dependent manner. In conclusion, we demonstrated that downregulation of HSS expression contributes to HCC metastasis partially through the ERK-activated EMT pathway. PMID- 29497175 TI - Circulating tumor DNA measurement provides reliable mutation detection in mice with human lung cancer xenografts. AB - Genotype-directed targeted therapy has become one of the standard treatment options for non-small cell lung cancer (NSCLC). There have been numerous limitations associated with mutation analysis of tissue samples. Consequently, mutational profile analysis of circulating cell-free DNA (cfDNA) by highly sensitive droplet digital PCR (ddPCR) assay has been developed. Possibly due to differences in cfDNA concentrations, previous studies have shown numerous discrepancies in mutation detection consistency between tissue and cfDNA. In order to rigorously analyze the amount of cfDNA needed, we constructed 72 athymic nude mice xenografted with NCI-H1975 (harboring a EGFR T790M mutation) or NCI H460 (harboring a KRAS Q61H mutation) human NSCLC. We thoroughly investigated the relationship between plasma cfDNA using Q-PCR targeting human long interspersed nuclear element-1 (LINE-1) retrotransposon and the mouse ACTB gene, and the accuracy of mutation detection by ddPCR at different times post-graft. Our results show that the concentration and fragmentation of human (tumor) derived cfDNA (hctDNA) were positively correlated with tumor weight, but not with mouse derived cfDNA (mcfDNA). Quantification of cfDNA by Q-PCR depends on the amplified target length. Mutation copies in plasma of per milliliter were positively linked to tumor weight, hctDNA level and hctDNA/mcfDNA ratio, respectively. Furthermore, tumor weight, hctDNA level and ratio of hctDNA/mcfDNA were significantly higher in cfDNA mutation-positive mice than in negative mice. Also, our data indicate that when plasma hctDNA level and hctDNA/mcfDNA ratio reach a certain level in xenografted mice, plasma cfDNA mutation can be detected. In summary, the present study suggests that determination of ctDNA levels may be essential for reliable mutation detection by analysis of cfDNA. PMID- 29497176 TI - Acrylic Acid Plasma Coated 3D Scaffolds for Cartilage tissue engineering applications. AB - The current generation of tissue engineered additive manufactured scaffolds for cartilage repair shows high potential for growing adult cartilage tissue. This study proposes two surface modification strategies based on non-thermal plasma technology for the modification of poly(ethylene oxide terephthalate/poly(butylene terephthalate) additive manufactured scaffolds to enhance their cell-material interactions. The first, plasma activation in a helium discharge, introduced non-specific polar functionalities. In the second approach, a carboxylic acid plasma polymer coating, using acrylic acid as precursor, was deposited throughout the scaffolds. Both surface modifications were characterized by significant changes in wettability, linked to the incorporation of new oxygen-containing functional groups. Their capacity for chondrogenesis was studied using ATDC5 chondroblasts as a model cell-line. The results demonstrate that the carboxylic acid-rich plasma coating had a positive effect on the generation of the glucoaminoglycans (GAG) matrix and stimulated the migration of cells throughout the scaffold. He plasma activation stimulated the formation of GAGs but did not stimulate the migration of chondroblasts throughout the scaffolds. Both plasma treatments spurred chondrogenesis by favoring GAG deposition. This leads to the overall conclusion that acrylic acid based plasma coatings exhibit potential as a surface modification technique for cartilage tissue engineering applications. PMID- 29497177 TI - Intermittent mild negative pressure applied to the lower limb in patients with spinal cord injury and chronic lower limb ulcers: a crossover pilot study. AB - STUDY DESIGN: Randomized, assessor-blinded crossover pilot study. OBJECTIVES: To explore the use of an intermittent negative pressure (INP) device for home use in addition to standard wound care (SWC) for patients with spinal cord injury (SCI) and chronic leg and foot ulcers before conducting a superiority trial. SETTING: Patient homes and outpatient clinic. METHODS: A 16-week crossover trial on 9 SCI patients (median age: 57 years, interquartile range [IQR] 52-66), with leg ulcers for 52 of weeks (IQR: 12-82) duration. At baseline, patients were allocated to treatment with INP + SWC or SWC alone. After 8 weeks, the ulcers were evaluated. To assess protocol adherence, the patients were then crossed over to the other group and were evaluated again after another 8 weeks. Lower limb INP treatment consisted of an airtight pressure chamber connected to an INP generator (alternating 10 s -40mmHg/7 s atmospheric pressure) used 2 h/day at home. Ulcer healing was assessed using a photographic wound assessment tool (PWAT) and by measuring changes in wound surface area (WSA). RESULTS: Seven of nine recruited patients adhered to a median of 90% (IQR: 80-96) of the prescribed 8-week INP protocol, and completed the study without side effects. PWAT improvement was observed in 4/4 patients for INP + SWC vs. 2/5 patients for SWC alone (P = 0.13). WSA improved in 3/4 patients allocated to INP + SWC vs. 3/5 patients in SWC alone (P = 0.72). CONCLUSIONS: INP can be used as a home-based treatment for patients with SCI, and its efficacy should be tested in an adequately sized, preferably multicenter randomized trial. PMID- 29497180 TI - Biotin supplements and laboratory test results in neuropsychiatric practice and research. PMID- 29497179 TI - Social structure as a strategy to mitigate the costs of group living: a comparison of gelada and guereza monkeys. AB - In mammals, and especially primates, group size and social complexity are typically correlated. However, we have no general explanation why this is so. I suggest that the answer may lie in one of the costs of group living: mammalian reproductive endocrinology is extremely sensitive to stress, and forms one of the hidden costs of living in groups. Fertility declines with group size widely across the social mammals, including primates, and will ultimately place a constraint on group size. However, some species seem to have been able to mitigate this cost by forming bonded relationships that reduce the impact of experienced aggression, even if rates of aggression remain high. The downside is that they reduce network connectivity and hence risk fragmenting the group by providing fracture lines for group fission. To explore this, I compare network indices and fertility patterns across the same range of group sizes for two species of Old World monkeys, Colobus guereza and Theropithecus gelada: the former relatively unsocial, the latter intensely social with frequent use of grooming-based alliances. Compared to those of the guereza, gelada social networks lose density more slowly, maintain connectedness more effectively and are less likely to fragment as they increase in size. Although fertility declines with group size in both species, in gelada the impact of this effect is deferred to larger group sizes. The differences in fertility and network structure both predict the very different maximum group sizes typical of these two species, as well as the typical sizes at which their groups undergo fission. This finding may explain aspects of wider mammalian sociality. PMID- 29497181 TI - A Magna Carta in psychosocial rehabilitation: The long road traveled. PMID- 29497178 TI - In cervical spondylotic myelopathy spinal cord motion is focally increased at the level of stenosis: a controlled cross-sectional study. AB - STUDY DESIGN: Level-, age-, and gender-matched controlled cross-sectional cohort study. OBJECTIVES: To investigate alterations of spinal cord (SC) motion within cervical spondylotic myelopathy (CSM) across the cervical spinal segments and its relation to cerebrospinal fluid (CSF)-flow, anatomic conditions, and clinical parameters. SETTING: University Hospital Balgrist, Zurich, Switzerland. METHODS: Overall, 12 patients suffering from CSM at level C5 and 12 controls underwent cardiac-gated 2D phase-contrast-MRI at level C2 and C5 and standard MRI sequences. Parameters of interest: Velocity measurements of SC and CSF (area under the curve = total displacement (normalization for duration of the heart cycle), total displacement ratio (C5/C2; intraindividual normalization for confounders)), spinal canal diameters, clinical motor- and sensory scores, and performance measures. RESULTS: Interrater reliability was excellent for SC motion at both levels and for CSF flow at C2, but not reliable for CSF flow at C5. Within controls, SC motion at C2 positively correlated with SC motion at C5 (p = 0.000); this correlation diminished in patients (p = 0.860). SC total displacement ratio was significantly increased in patients (p = 0.029) and correlated with clinical impairment (p = 0.017). Morphometric measures of the extent of stenosis were not related to SC motion or clinical symptoms. CONCLUSION: The findings revealed physiological interactions of CSF flow and SC motion across the cervical spine in healthy controls while being diminished in CSM patients. Findings of focally increased SC motion at the level of stenosis were related to clinical impairment and might be promising as a diagnostic and prognostic marker in CSM. SPONSORSHIP: CRPP Neurorehab of the University of Zurich, Switzerland. PMID- 29497182 TI - Rebuilding the brain with psychotherapy. AB - Brain has been the most fascinating and mysterious organ of the human body. Researchers have tried to explore into each and every function of different parts of the human brain linking it up with various mental and neural processes, some of which are phylogenetically shared and many are unshared. It has been hypothesized that brain is built during development and can be rebuilt during psychotherapy. Recent research in neuroscience of socioemotional cognition, developmental neuroscience, coupled with advances in investigative techniques of brain functions has provided tremendous opportunities for the study of brain and the mind. In this article, in the initial part, we have tried to explain the developmental processes involved in building of the human brain and what changes occur when an individual develops a psychiatric disorder. Later on, we have tried to postulate from different researches available that how psychotherapy can bring about a change in the neural mechanisms of the brain producing long-lasting effects. Several changes in the neural architecture of the brain occur during the process of psychotherapy. Further, we would like to elaborate on the hypothesis based on available literature that if psychiatric disorders can debuild the brain, then psychotherapy can help in rebuilding it again. PMID- 29497183 TI - Religiosity among patients with schizophrenia: An exploratory study. AB - Aim: This study aimed to compare the religiosity and religious coping of patients with schizophrenia with a healthy control group and to assess the correlation between the level of religiosity and religious coping with residual psychopathology, level of functioning, and quality of life (QOL). Methodology: Patients of schizophrenia were assessed on religiousness measure scale, duke religion index (DUREL), brief religious coping scale (RCOPE), positive and negative symptom scale, and World Health Organization QOL-BREF version. Results: Of the 100 patients of schizophrenia, 99% reported that they believed in God. About 60% of patients attended religious places either once a week or more and 56% of patients indulged in private religious activity at least once a day. Two third of the participants had high intrinsic religiosity score. The mean score of positive religious coping (PRC) subscale was 14.56 and that for negative religious coping (NRC) subscale was 8.31. No significant difference was noted in the various domains of religious measure scale, DUREL, and PRC between patients with schizophrenia and healthy controls. However, compared to healthy controls, patients more often used NRC. Various aspects of religiosity (except for negative RCOPE score) correlated negatively with residual psychopathology and positively with functioning and QOL. Conclusion: Findings of this study suggest that high proportions of patients with schizophrenia are religious and this is similar to healthy controls in the community. Higher level of religiosity and more frequent use of religious coping are associated with lower level of psychopathology and better QOL. PMID- 29497184 TI - How patients' characteristics influence the use of coercive measures. AB - Background: Coercive measures are applied in psychiatry as a last resort to control self- and hetero-aggressive behaviors in situations where all other possible strategies have failed. For ethical and clinical reasons, the number of instances of coercion should be reduced as far as possible. Aim: The aim of the study was to identify sociodemographic and clinical characteristics of patients that were associated with coercion during hospital treatment. Materials and Methods: The study has a descriptive, longitudinal design, based on a 1 year prospective observation of patients admitted to a psychiatric hospital consisting of six inpatient psychiatric wards with a total of 236 beds. Results: In the 12 month period covered by the study, 1476 people (778 men and 698 women) were treated in the hospital; 226 of them (15%) were subjected to coercion on a total of 405 occasions. The most frequently implemented form of direct coercion was mechanical restraint. The following factors involved in the use of direct coercion were identified: Male gender, young age, mental disorders resulting from the abuse of psychoactive drugs, involuntary admission to the hospital and the use of direct coercion in the past. Conclusion: Assessments of patients' sociodemographic and clinical characteristics can help clinicians recognize patients who are particularly at risk of being subjected to coercive measures. PMID- 29497185 TI - The investigation of the relationship between probability of suicide and reasons for living in psychiatric inpatients. AB - Aim: This study was carried out to determine the reasons of the suicide probability and reasons for living of the inpatients hospitalized at the psychiatry clinic and to analyze the relationship between them. Materials and Methods: The sample of the study consisted of 192 patients who were hospitalized in psychiatric clinics between February and May 2016 and who agreed to participate in the study. In collecting data, personal information form, suicide probability scale (SPS), reasons for living inventory (RFL), and Beck's depression inventory (BDI) were used. Stepwise regression method was used to determine the factors that predict suicide probability. Results: In the study, as a result of analyses made, the median score on the SPS was found 76.0, the median score on the RFL was found 137.0, the median score on the BDI of the patients was found 13.5, and it was found that patients with a high probability of suicide had less reasons for living and that their depression levels were very high. As a result of stepwise regression analysis, it was determined that suicidal ideation, reasons for living, maltreatment, education level, age, and income status were the predictors of suicide probability (F = 61.125; P < 0.001). Discussion: It was found that the patients who hospitalized in the psychiatric clinic have high suicide probability and the reasons of living are strong predictors of suicide probability in accordance with the literature. PMID- 29497186 TI - Posttraumatic growth and its correlates in primary caregivers of schizophrenic patients. AB - Context: The concept of posttraumatic growth (PTG) is important to focus on positive outcomes of a challenging process like caregiving. Aims: The aim of the present study is to investigate the factors inclusively considered to be related to PTG in primary caregivers of schizophrenic patients. Settings and Design: This cross-sectional study was conducted with caregivers of patients with schizophrenia between January 2013 and February 2014 at a mental health hospital. Materials and Methods: The study was carried out on 109 schizophrenic patients followed up at Bakirkoy Prof. Dr. Mazhar Osman Research and Training Hospital for Psychiatry, Neurology, and Neurosurgery, and 109 family members who are the primary caregivers of the patients. All caregivers were evaluated with Posttraumatic Growth Inventory, Multidimensional Scale of Perceived Social Support, Ways of Coping Inventory, and the Basic Personality Traits Inventory and Religious Orientation Scale. Statistical Analysis: Kruskal-Wallis and Mann Whitney U-test were used in quantitative analysis of data. Spearman's correlation analysis was used in the determination of correlation between variables. Linear regression analysis was used in the determination of predictors of PTG. Results: Optimistic and problem-focused coping, perceived social support (total and all three - family, friends, significant others - domains), personality traits such as extraversion, conscientiousness, and openness to experience, and religiousness were found to be related with PTG. Religiousness, perceived social support, and openness to experience were independent predictors of PTG. Conclusions: Interventions to caregivers of schizophrenic patients on the domains of social support and coping strategies may contribute to caring process in a positive change. PMID- 29497187 TI - Comparison of efficacy of haloperidol and olanzapine in the treatment of delirium. AB - Objective: Till date, typical antipsychotic haloperidol is the treatment of choice for delirium. But, due to higher side effects with haloperidol, newer atypical antipsychotics (e.g., olanzapine) are increasingly being used in the treatment of delirious patients. The aim of the current research was to study the efficacy and tolerability of haloperidol and olanzapine in the treatment of delirium. Materials and Methods: This was an open-label, randomized controlled study carried out in a tertiary care hospital at Chandigarh, India. A total of 100 patients admitted in medicine, surgery, and orthopedic wards and diagnosed as having delirium on Confusion Assessment Method scale were included in the study. Patients were given either haloperidol (1-4 mg/day either orally or by nasogastric tube) or olanzapine (2.5-10 mg/day either orally or by nasogastric tube). Severity of delirium and pattern of symptom improvement were assessed by Memorial Delirium Assessment Scale (MDAS). Extrapyramidal side effects were assessed by Simpson-Angus Scale. Results: There was an improvement in delirium severity in both groups with treatment. Mean daily dose of haloperidol and olanzapine used per patient was 2.10 and 5.49 mg, respectively, and the mean duration of treatment in olanzapine group and haloperidol group was 3.57 days and 3.37 days, respectively. There was no significant difference in the mean duration of treatment in both groups. At the end of study period, the MDAS scores in olanzapine and haloperidol groups were 8.43 and 8.00, respectively, and the difference was not significant statistically with P = 0.765. Five patients experienced drug-related mild side effects. Conclusion: Low-dose haloperidol and olanzapine were equally efficacious and well tolerated in delirium. PMID- 29497188 TI - Intervention for phantom limb pain: A randomized single crossover study of mirror therapy. AB - Introduction: Mirror therapy suggested to help relieve phantom limb pain (PLP) by resolving the visual- proprioceptive dissociation in the brain, but studies so far either had shorter follow-up or smaller sample size. Materials and Methods: In this randomized single crossover trial, 64 amputees with PLP in the age group of 15-75 years of age were distributed into test and control groups by simple randomization method. Of these 28 in control and 32 in test groups, respectively, completed the 4 weeks of mirror therapy and 12 weeks of follow-up assessments. A standardized set of exercises for 15 min/day for 4 and 8 weeks in test and control groups (in the first 4 weeks, the mirror was covered), respectively, was administered under supervision of one of the authors. All were assessed using the visual analog scale and Short-Form McGill Pain Questionnaire on day 0 and at 4, 8, and 12 weeks after therapy. In control group for the initial 4 weeks, the mirror was covered. The assessing author was blinded to the group to which the participants belonged. Results: Significant reduction in PLP was noted in the test group at 4 weeks compared to the control group (P < 0.0001). Significant reduction was seen in control group also after the switchover and sustained for 12 weeks in both. No harm was reported. Conclusion: Mirror therapy is effective in relieving the intensity, duration, frequency, and overall PLP, and improvement is maintained up to 12 weeks' posttherapy. PMID- 29497189 TI - Psychiatric morbidity among female commercial sex workers. AB - Context: Psychological distress is higher in women working in sex industry. The various psycho social issues are associated with female commercial sex workers (FCSWs). The host of psychosocial vulnerabilities including, childhood sexual abuse, exposure to childhood physical abuse, poverty, interpersonal violence in adulthood, sexually transmitted diseases, and substance use, forms a fertile ground for psychiatric morbidity. Aim: This study aims to assess the psychiatric morbidity among FCSWs in Shillong, India. Materials and Methods: In the present study, 100 FCSWs were selected. For the recruitment of sample, simple random sampling procedure was followed; sociodemographic data sheet and the Mini International Neuropsychiatric Interview were administered. Results: In the study, it was found that 9% of the respondents reported having major depressive episode (current), 25% of the respondents reported major depressive episode (past), 3% were having major depressive episode with melancholic features (current), 21% of the respondents reported posttraumatic stress disorder (PTSD), 8% of the respondents reported to have alcohol dependence, 3% of the respondents reported to have nonalcohol psychoactive substance use disorder, 8% of the respondents were found to have generalized anxiety disorder, and 9% of the respondents were found to have antisocial personality disorder. Conclusions: There is a prevalence of mental health problems in the FCSW. Assessment of the psychiatric morbidity in FCSW is significant in developing health policy and interventions to reduce their impact on their well-being. It is the immediate need that the governmental and nongovernmental agencies, mental health professionals, and workers in this area need to be sensitized to the issue of mental health status of the commercial sex workers. PMID- 29497190 TI - Early stages of Alzheimer's disease are alarming signs in injury deaths caused by traffic accidents in elderly people (>=60 years of age): A neuropathological study. AB - Background: There is little information available in the literature concerning the contribution of dementia in injury deaths in elderly people (>=60 years). Aim: This study was intended to investigate the extent of dementia-related pathologies in the brains of elderly people who died in traffic accidents or by suicide and to compare our findings with age- and sex-matched natural deaths in an elderly population. Materials and Methods: Autopsy-derived human brain samples from nine injury death victims (5 suicide and 4 traffic accidents) and nine age- and sex-matched natural death victims were screened for neurodegenerative and cerebrovascular pathologies using histopathological and immunohistochemical techniques. For the analysis, Statistical Package for the Social Sciences (SPSS) version 16.0 was used. Results: There was a greater likelihood for Alzheimer's disease (AD)-related changes in the elders who succumbed to traffic accidents (1 out of 4) compared to age- and sex-matched suicides (0 out of 5) or natural deaths (0 out of 9) as assessed by the National Institute on Aging - Alzheimer's Association guidelines. Actual burden of both neurofibrillary tangles (NFTs) and (SPs) was comparatively higher in the brains of traffic accidents, and the mean NFT counts were significantly higher in the region of entorhinal cortex (P < 0.05). However, associations obtained for other dementia-related pathologies were not statistically important. Conclusion: Our findings suggest that early Alzheimer stages may be a contributing factor to injury deaths caused by traffic accidents in elderly people whereas suicidal brain neuropathologies resembled natural deaths. PMID- 29497191 TI - Serum cholesterol and Suicide in first episode psychosis: A preliminary study. AB - Background: Low levels of cholesterol have been described in suicide behavior including among those individuals who have an increased tendency for impulsivity. Violent suicide attempters show significantly lower cholesterol levels than nonviolent suicide attempters. The suicide rate is particularly high in the prodromal and early phase of schizophrenia. It is unclear if there is a psychopathological relationship between early psychosis, suicide, and cholesterol levels. The present study examines levels of cholesterol and suicide behavior in a cohort of early psychosis. Methodology: Sixty admitted patients with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of nonaffective schizophrenia spectrum disorder (early psychosis) were assessed in a naturalistic cross-sectional, cohort study. Psychopathology was assessed with the Positive and Negative Symptom Scale for Schizophrenia (PANSS), Hamilton Depression Rating Scale, and Scale for Impact of Suicidality-Management, Assessment and Planning of Care (SIS-MAP). Serum levels of cholesterol were estimated in the cohort as well. The findings were analyzed for a clinical correlation of cholesterol levels, suicidal attempters, and psychopathology. Results: Out of 60 patients, 13 patients had a suicide attempt in the recent past. No serum cholesterol abnormality (3.7 +/- 1.2 mmol/L) was observed in patients as a group and those with low suicidality (SIS-MAP <17, serum cholesterol: 4.1 +/- 1.3 mmol/L). However, low levels of cholesterol were observed in a subgroup with severe suicidality (SIS-MAP >33; serum cholesterol: 3.5 +/- 1.4 mmol/L). Females with moderate suicidality showed statistically significant lower cholesterol levels than males (P = 0.047). Conclusions: The study suggests lower levels of cholesterol in patients of psychosis with severe suicidal thoughts and depression in early psychosis. More research is required in this field to determine the neurochemistry of suicide behavior in psychosis and its significance in the prediction of suicidal behavior. PMID- 29497193 TI - Use of modified bilateral electroconvulsive therapy during pregnancy: A case series. AB - There is limited literature on the use of electroconvulsive therapy (ECT) during pregnancy. ECT is considered as a treatment of last resort during pregnancy. In this case series, we present the data of five patients who were administered ECT during pregnancy. The use of ECT required multidisciplinary approach involving psychiatrist, gynecologist, anesthetist and neonatologist. Two patients received ECT during the second trimester and three patients received ECT during the third trimester. In all the patients, ECT was administered by placing the patients in the left lateral position, glycopyrrolate was used for premedication, thiopentone was used for induction, and succinylcholine was used for muscle relaxation. Patients who were administered ECT close to the full-term were given injection betamethasone 12 mg intramuscularly on two consecutive days before starting of first ECT to promote fetal lung maturity. In all the five cases, no adverse maternal and fetal outcomes were encountered except for possible precipitation of labor in one case. PMID- 29497192 TI - No genetic association between A118G polymorphism of MU-opioid receptor gene and schizophrenia and bipolar disorders. AB - Background: Schizophrenia (SZ) and bipolar disorder (BD) are chronic and multifactorial psychiatric disorders that might be affected by different genes in combination with environmental factors. There is evidence of association between polymorphisms of MU-opioid receptor gene (OPRM1) with these disorders. Objectives: The aim of this study was to investigate the genetic association between OPRM1 A118G SNP in SZ and BD patients in comparison with healthy controls (HCs). Materials and Methods: One single-nucleotide polymorphism in OPRM1 was genotyped using TaqMan real-time PCR assay in 203 SZ and BD patients and 389 HCs. Results: There was no statistically significant difference in genotypic and allelic frequencies of OPRM1 A118G SNP between HCs and SZ/BD patients. Conclusions: To find the underlying genetic factors associated with these complex disorders, further studies need to be conducted using larger sample size, different genetic populations, and different gene variations. PMID- 29497194 TI - Electroconvulsive therapy for medication-refractory depression in a patient with ruptured intracranial dermoid cyst, meningioma, and neurofibromatosis. AB - Electroconvulsive therapy (ECT) is considered relatively contraindicated in patients with intracranial space-occupying lesions. A 53-year-old male presented with a 5-year history of medication-refractory major depressive disorder. Brain imaging findings suggested the presence of a ruptured dermoid cyst in the transverse sinus and a calcified meningioma in the temporal lobe sulcal space. There was no evidence of mass effect. Neurofibromatosis was the only other clinical condition present. The patient had no clinical neurological deficits. Since the depression was severe and he was suicidal, ECT was advised. There was a substantial improvement after four bilateral and then eight right unilateral brief-pulse ECTs administered on alternate days, thrice weekly. There were no complications associated with ECT. The treatment gains were maintained with maintenance antidepressant medication at a 1-year follow-up. This is probably the first reported case of the use of ECT in a medication-refractory, severely depressed patient with a ruptured intracranial dermoid cyst and with a calcifying meningioma. The results testify to the safety of ECT even in high-risk patients. PMID- 29497195 TI - Prolonged Wahnstimmung (delusional mood) without development of a psychotic illness in a 50-year-old male. AB - Delusional mood, or Wahnstimmung, is a prodromal feature of an impending psychotic illness. In this case, the patient reports experiencing this sensation persistently since early childhood. This case suggests that Wahnstimmung may persist for years without developing into full psychosis. This is the first reported case of prolonged and persistent delusional mood in literature. It should be of interest to psychiatry professionals looking to investigate the prodromal phase of psychosis. This case is regarding a 50-year-old, Caucasian male. He presented to clinic with a feeling of excitement. Despite being referred for suicidal ideation, he described himself as "the happiest guy that I know. I wake up every morning feeling excited." This original case should highlight the possibility of this phenomenon in other patients. Ultimately, an understanding of why patients may not progress to full psychotic illness may improve our understanding of protective factors in psychotic illnesses. PMID- 29497196 TI - Oculogyric crisis with atypical antipsychotics: A case series. AB - Oculogyric crisis (OGC) is an acute dystonic reaction, commonly seen with the administration of typical antipsychotics, and rarely reported with atypical antipsychotics. Here, we report five cases of oculogyric crisis, developed after administration of atypical antipsychotics. The first case developed OGC on quetiapine 800 mg/day and the second case on olanzapine 20 mg/day. Both the patients did not improve on adding anticholinergic agents and finally stabilized by switching to clozapine. The third case developed OGC on amisulpride 400 mg and lurasidone 40 mg/day and improved by reducing amisulpride dose to 200 mg and stopping lurasidone. The fourth case developed OGC on aripiprazole 30 mg/day and improved by dose reduction. The fifth case developed OGC on amisulpride 400 mg/day and improved by switching to risperidone and anticholinergic combination. Oculogyric crisis is a potential side effect of antipsychotic medications (mostly with typical and rarely with atypical) and generally respond to oral anticholinergics, but in some cases, dose reduction or discontinuation of antipsychotic agent and switching to safer alternatives or clozapine is required. PMID- 29497197 TI - Stress among medical students: A cross-sectional study from a North Indian Medical University. AB - Aims: The aim is to study stress among medical students and the relationship of stress to the year of study and gender. Materials and Methods: A single-point, cross-sectional, observational study of students of a medical university in North India divided on the basis of the semester of their course. The study was done using the higher education stress inventory. Results: A total of 251 students were included in the study. Worry about future endurance and capacity was rated the highest by the final year students while faculty shortcomings and insufficient feedback were rated highest by the 2nd-year students and financial concerns the highest by the 1st-year students. Males rated financial concerns higher than females. Discussion: The study would provide insight to the university authorities to make remedies based on the expectations and feedback of the students. Conclusion: the current study shows that stress amongst medical students is a dynamic process as the reasons of stress vary depending on the stage of curriculum. The college/university administration can mitigate this by taking appropriate steps as needed. PMID- 29497199 TI - Primary prevention in psychiatry in general hospitals in South Asia. AB - The focus of primary prevention is on reducing the disease incidence. Primary prevention in mental health has been given minimal priority in low-resource settings with no significant investments. General hospitals are one of the main providers of mental health services in South Asia. This paper focuses on primary prevention activities, which can be undertaken in a general hospital in South Asia with abysmally low-mental health resources. For implementing primary prevention in psychiatry, a general hospital may be conceptualized as a population unit, located in a well-populated area with easy accessibility where different kinds of communities, for example, students and resident doctors, consultants, patients and their caregivers, and paramedical, nursing, administrative and other supportive staff, coexist and have varied functions. All the functional components of the general hospital psychiatric units (GHPUs) offer scope for introducing primary preventive psychiatry services. Psychiatrists in GHPUs can lead efforts for primary prevention in mental health in the hospital by employing strategies in the framework of universal, selective, and indicated prevention. The preventive strategies could be targeted at the patients visiting the hospital for various health services and their caregivers, employees, and the trainees. Similar principles can be employed in teaching and training. PMID- 29497198 TI - Understanding the schizophrenia prodrome. AB - Schizophrenia is a neurodevelopmental disorder and its course is said to have an onset much before the presentation with psychotic symptoms. Even though the concept of prodrome in schizophrenia has been accepted, there is still an existence of a diagnostic dilemma. Various imaging studies and biomarkers have also been studied for confirmation of this diagnosis. The critical period of intervention when identified clarifies the doubts about faster and better outcomes. PMID- 29497200 TI - Goodness of fit. PMID- 29497201 TI - Feedback of students to aligned teaching -learning and assessment. PMID- 29497202 TI - Postinjection delirium/sedation syndrome with long-acting olanzapine pamoate in a middle-aged female. PMID- 29497203 TI - Antidepressant compliance in a rural setting. PMID- 29497204 TI - Major depressive disorder comorbid severe hydrocephalus caused by Arnold-Chiari malformation. PMID- 29497205 TI - Does exposure to a seclusion and restraint event during clerkship influence medical student's attitudes toward psychiatry? PMID- 29497206 TI - Tourette's syndrome and schizophrenia: About a case report. PMID- 29497207 TI - Age as a variable: Continuous or categorical? PMID- 29497208 TI - An innovative concept book guide for MBBS students. PMID- 29497209 TI - One year of innovative services: Library for patients and their caregivers in the psychiatry ward. PMID- 29497210 TI - Iron Catalyzed Dehydrocoupling of Amine- and Phosphine-Boranes. AB - Catalytic dehydrocoupling methodologies, whereby dihydrogen is released from a substrate (or intermolecularly from two substrates) is a mild and efficient method to construct main group element-main group element bonds, the products of which can be used in advanced materials, and also for the development of hydrogen storage materials. With growing interest in the potential of compounds such as ammonia-borane to act as hydrogen storage materials which contain a high weight% of H2, along with the current heightened interest in base metal catalyzed processes, this review covers recent developments in amine and phosphine dehydrocoupling catalyzed by iron complexes. The complexes employed, products formed and mechanistic proposals will be discussed. PMID- 29497211 TI - Population density shapes patterns of survival and reproduction in Eleutheria dichotoma (Hydrozoa: Anthoathecata). AB - Budding hydromedusae have high reproductive rates due to asexual reproduction and can occur in high population densities along the coasts, specifically in tidal pools. In laboratory experiments, we investigated the effects of population density on the survival and reproductive strategies of a single clone of Eleutheria dichotoma. We found that sexual reproduction occurs with the highest rate at medium population densities. Increased sexual reproduction was associated with lower budding (asexual reproduction) and survival probability. Sexual reproduction results in the production of motile larvae that can, in contrast to medusae, seek to escape unfavorable conditions by actively looking for better environments. The successful settlement of a larva results in starting the polyp stage, which is probably more resistant to environmental conditions. This is the first study that has examined the life-history strategies of the budding hydromedusa E. dichotoma by conducting a long-term experiment with a relatively large sample size that allowed for the examination of age-specific mortality and reproductive rates. We found that most sexual and asexual reproduction occurred at the beginning of life following a very rapid process of maturation. The parametric models fitted to the mortality data showed that population density was associated with an increase in the rate of aging, an increase in the level of late-life mortality plateau, and a decrease in the hidden heterogeneity in individual mortality rates. The effects of population density on life-history traits are discussed in the context of resource allocation and the r/K strategies' continuum concept. PMID- 29497212 TI - Spontaneous bending of pre-stretched bilayers. AB - We discuss spontaneously bent configurations of pre-stretched bilayer sheets that can be obtained by tuning the pre-stretches in the two layers. The two dimensional nonlinear plate model we use for this purpose is an adaptation of the one recently obtained for thin sheets of nematic elastomers, by means of a rigorous dimensional reduction argument based on the theory of Gamma-convergence (Agostiniani and DeSimone in Meccanica. doi:10.1007/s11012-017-0630-4, 2017, Math Mech Solids. doi:10.1177/1081286517699991, arXiv:1509.07003, 2017). We argue that pre-stretched bilayer sheets provide us with an interesting model system to study shape programming and morphing of surfaces in other, more complex systems, where spontaneous deformations are induced by swelling due to the absorption of a liquid, phase transformations, thermal or electro-magnetic stimuli. These include bio-mimetic structures inspired by biological systems from both the plant and the animal kingdoms. PMID- 29497213 TI - Low temperature heat capacities and thermodynamic functions described by Debye Einstein integrals. AB - Abstract: Thermodynamic data of various crystalline solids are assessed from low temperature heat capacity measurements, i.e., from almost absolute zero to 300 K by means of semi-empirical models. Previous studies frequently present fit functions with a large amount of coefficients resulting in almost perfect agreement with experimental data. It is, however, pointed out in this work that special care is required to avoid overfitting. Apart from anomalies like phase transformations, it is likely that data from calorimetric measurements can be fitted by a relatively simple Debye-Einstein integral with sufficient precision. Thereby, reliable values for the heat capacities, standard enthalpies, and standard entropies at T = 298.15 K are obtained. Standard thermodynamic functions of various compounds strongly differing in the number of atoms in the formula unit can be derived from this fitting procedure and are compared to the results of previous fitting procedures. The residuals are of course larger when the Debye Einstein integral is applied instead of using a high number of fit coefficients or connected splines, but the semi-empiric fit coefficients keep their meaning with respect to physics. It is suggested to use the Debye-Einstein integral fit as a standard method to describe heat capacities in the range between 0 and 300 K so that the derived thermodynamic functions are obtained on the same theory related semi-empiric basis. Additional fitting is recommended when a precise description for data at ultra-low temperatures (0-20 K) is requested. Graphical abstract: PMID- 29497214 TI - Syntheses, characterization, and biological activity of novel mono- and binuclear transition metal complexes with a hydrazone Schiff base derived from a coumarin derivative and oxalyldihydrazine. AB - Abstract: A hydrazone Schiff base ligand was synthesized by the condensation of 3 formyl-4-hydroxycoumarin and oxalyldihydrazide in the molar ratio 2:1. The Schiff base ligand acts as a mono-, bi-, tri- or even tetradentate ligand with metal cations in the molar ratios 1:1 or 2:1 (M:L) to yield either mono- or binuclear complexes as keto or enol isomers, where M = Co(II), Ni(II), Cu(II), VO(IV), and Fe(III). The ligand and its metal complexes were characterized by elemental analyses, IR, 1H NMR, mass, and UV-Vis spectroscopy. Furthermore, the magnetic moments were calculated from the measured electric conductivities of the complexes. According to the received data, the dihydrazone ligand contains one or two units of ONO domains and can bind to the metal ions via the azomethine nitrogen, the carbonyl oxygen atoms, and/or the phenolic oxygen atoms. Electronic spectra and the magnetic moments of all complexes show that the complexes' geometries are either octahedral, tetrahedral, square planar, or square pyramidal. Cyclic voltammograms of the mononuclear Co(II) and Ni(II) complexes show quasi-reversible peaks. Tests against two pathogenic bacteria as Gram positive and Gram-negative bacteria for both, the Schiff base ligand and its metal complexes were carried out. In addition, also one kind of fungi was tested. The synthesized complexes demonstrate mild antibacterial and antifungal activities against these organisms. Graphical abstract: PMID- 29497215 TI - Differentiation between pine woods according to species and growing location using FTIR-ATR. AB - Attenuated total reflectance-Fourier transform infrared (FTIR-ATR) spectroscopy was applied to 120 samples of heartwood rings from eight individual pine trees from different locations in Spain. Pinus sylvestris cores were collected at the Artikutza natural park (Ps-ART). Pinus nigra cores were collected in Sierra de Cazorla (Pn-LIN) and in La Sagra Mountain (Pn-LSA). Three discriminant analysis tests were performed using all bands (DFT), lignin bands only (DFL) and polysaccharides bands only (DFP), to explore the ability of FTIR-ATR to separate between species and growing location. The DFL model enabled a good separation between pine species, whereas the DFP model enabled differentiation for both species and growing location. The DFT model enabled virtually perfect separation, based on two functions involving twelve FTIR bands. Discrimination between species was related to bands at 860 and 1655 cm-1, which were more intense in P. sylvestris samples, and bands at 1425 and 1635 cm-1, more intense in P. nigra samples. These vibrations were related to differences in lignin structure and polysaccharide linear chains. Discrimination between growing locations was mainly related to polysaccharide absorptions: at 900, 1085 and 1335 cm-1 more representative of Pn-LIN samples, and at 1105 and 1315 cm-1 mostly associated to Pn-LSA samples. These absorptions are related to beta-glycosidic linkages (900 cm 1), cellulose and hemicellulose (C-O bonds, 1085 and 1105 cm-1) and content in amorphous/crystalline cellulose (1315 and 1335 cm-1). These results show that FTIR-ATR in combination with multivariate statistics can be a useful tool for species identification and provenancing for pine wood samples of unknown origin. PMID- 29497216 TI - Chemistry of Sulfur-Contaminated Soil Substrate from a Former Frasch Extraction Method Sulfur Mine Leachate with Various Forms of Litter in a Controlled Experiment. AB - The impact of tree litter on soil chemistry leachate and sulfurous substrates of mine soils from former Jeziorko sulfur mine was investigated. Composites were used: soil substrate (less contaminated at mean 5090 mg kg-1 S or high contaminated at 42,500 mg kg-1 S) + birch or pine litter and control substrate (no litter). The composites were rinsed with distilled water over 12 weeks. In the obtained leachate, pH, EC, dissolved organic carbon, N, Ca, Mg, Al, and S were determined. Physicochemical parameters of the substrates and their basal respiration rate were determined. Rinsing and litter application lowered sulfur concentration in high contamination substrates. Pine litter application decreased EC and increased pH of the low-contaminated substrate. The substrate pH remained at low phytotoxic level (i.e., below 3.0), resulting in the low biological activity of the composites. Birch litter application increased leaching of N and Mg, indicating the possibility of an intensification of soil-forming processes in contaminated sites. PMID- 29497217 TI - On Reciprocal Causation in the Evolutionary Process. AB - Recent calls for a revision of standard evolutionary theory (SET) are based partly on arguments about the reciprocal causation. Reciprocal causation means that cause-effect relationships are bi-directional, as a cause could later become an effect and vice versa. Such dynamic cause-effect relationships raise questions about the distinction between proximate and ultimate causes, as originally formulated by Ernst Mayr. They have also motivated some biologists and philosophers to argue for an Extended Evolutionary Synthesis (EES). The EES will supposedly expand the scope of the Modern Synthesis (MS) and SET, which has been characterized as gene-centred, relying primarily on natural selection and largely neglecting reciprocal causation. Here, I critically examine these claims, with a special focus on the last conjecture. I conclude that reciprocal causation has long been recognized as important by naturalists, ecologists and evolutionary biologists working in the in the MS tradition, although it it could be explored even further. Numerous empirical examples of reciprocal causation in the form of positive and negative feedback are now well known from both natural and laboratory systems. Reciprocal causation have also been explicitly incorporated in mathematical models of coevolutionary arms races, frequency-dependent selection, eco-evolutionary dynamics and sexual selection. Such dynamic feedback were already recognized by Richard Levins and Richard Lewontin in their bok The Dialectical Biologist. Reciprocal causation and dynamic feedback might also be one of the few contributions of dialectical thinking and Marxist philosophy in evolutionary theory. I discuss some promising empirical and analytical tools to study reciprocal causation and the implications for the EES. Finally, I briefly discuss how quantitative genetics can be adapated to studies of reciprocal causation, constructive inheritance and phenotypic plasticity and suggest that the flexibility of this approach might have been underestimated by critics of contemporary evolutionary biology. PMID- 29497219 TI - Design and operation of a low-cost and compact autonomous buoy system for use in coastal aquaculture and water quality monitoring. AB - The need to ensure future food security and issues of varying estuarine water quality is driving the expansion of aquaculture into near-shore coastal waters. It is prudent to fully evaluate new or proposed aquaculture sites, prior to any substantial financial investment in infrastructure and staffing. Measurements of water temperature, salinity and dissolved oxygen can be used to gain insight into the physical, chemical and biological water quality conditions within a farm site, towards identifying its suitability for farming, both for the stock species of interest and for assessing the potential risk from harmful or toxic algae. The latter can cause closure of shellfish harvesting. Unfortunately, commercial scientific monitoring systems can be cost prohibitive for small organisations and companies to purchase and operate. Here we describe the design, construction and deployment of a low cost (10 in the season, were taken into account. The following meteorological parameters were analyzed: air temperature, relative humidity, precipitation and wind speed. Effects of individual weather parameters on hourly and daily concentrations of different fungal spore types were examined using Spearman's rank association test, whereas effects of complex of meteorological factors on hourly and daily compositions of spore were assessed using detrended correspondence analysis (DCA) and redundancy analysis (RDA). Airborne fungal spore distribution patterns in relation to meteorological variables were determined by RDA, after DCA results detected a linear structure of the spore data. The RDA results obtained indicated that all the applied variables accounted for 20 and 22% of the total variance in the hourly and daily spore data, respectively. The results of stepwise forward selection of variables revealed all included hourly and daily meteorological variables were statistically significant. The largest amount of the total variance in the spore composition was explained by the air temperature in both cases (16%). Multivariate ordination did not show large differences between the hourly and daily relationships (with exception of wind speed impact), while the differences between simple hourly and daily correlations were more clear. Correlations between daily values of variables were in most cases higher than between hourly values of variables. PMID- 29497242 TI - Airborne fungi as indicators of ecosystem disturbance: an example from selected Tatra Mountains caves (Poland). AB - We report on the determination of the spore concentration and the species composition of the airborne fungi in selected caves of the Tatra Mountains, Poland. The following caves were surveyed: Mylna, Oblazkowa, Mrozna, Zimna and Naciekowa. The sampling was carried out in July 2015 and in January 2016. The aeromycological analyses were performed with the impact method, using the Air Ideal 3P apparatus and potato dextrose agar (PDA, Biocorp) culture medium. In the course of the July 2015 analysis, 17 species of fungi were isolated and 11 species were isolated in January 2016. In Mylna and Naciekowa caves, the dominant species were Cladosporium cladosporioides and Stachybotrys cylindrospora. In Oblazkowa cave, Rhizoctonia predominated and in Zimna cave-the colonies of the yeast-like fungi, along with S. cylindrospora. In Mrozna cave, Penicillium notatum was the most abundant taxon. In the winter time, in the majority of the caves Penicillium spp. predominated, with the exception of Mrozna and Naciekowa caves where Aspergillus niger was dominant. We propose that aeromycological monitoring be performed regularly in the following caves: Mrozna, Naciekowa and Zimna. PMID- 29497243 TI - The completeness of the fossil record of plesiosaurs, marine reptiles from the Mesozoic. AB - Plesiosaurs were a highly successful group of marine reptiles occurring worldwide in the Jurassic and Cretaceous, but to date few studies have focused on their preservation through time. Here, we conduct the first detailed assessment of the quality of the plesiosaur fossil record. Data was compiled for 178 specimens representing 114 valid species. For each species we calculated the character completeness metric (CCM: percentage of phylogenetic characters from a cladistic dataset that can be scored for that species) and the skeletal completeness metric (SCM: percentage of the overall skeleton that is preserved for that species). Average CCM and SCM values were calculated for individual geological stages. A strong significant positive correlation was recovered between CCM and SCM, suggesting that the two metrics are recording the same signal, at least for this clade. Although a significant correlation between changes in sea level and changes in plesiosaur completeness was not recovered, an underlying negative relationship may be present but obscured by poorly sampled time bins. Plesiosaur completeness though time is not significantly correlated with that for contemporary terrestrial groups (sauropods, pterosaurs, birds), but is significantly correlated with that for ichthyosaurs, suggesting common controls on skeletal preservation in the marine realm. Significantly higher median completeness values in plesiosaurs and ichthyosaurs than in contemporary terrestrial groups support the hypothesis that the marine tetrapod fossil record is more complete than that of terrestrial tetrapods. A collector's curve for plesiosaurs shows a generally slow constant rate of discovery from the latter part of the 19th century until the 1990s, at which point the rate of discovery increased substantially and shows no sign of slowing. A significant but very weak negative correlation between SCM and the year in which a taxon was named suggests a weak tendency for more recently named species to have less complete skeletons. PMID- 29497244 TI - Do ancient types of wheat have health benefits compared with modern bread wheat? AB - A number of studies have suggested that ancient wheats have health benefits compared with modern bread wheat. However, the mechanisms are unclear and limited numbers of genotypes have been studied, with a particular focus on Kamut(r) (Khorasan wheat). This is important because published analyses have shown wide variation in composition between genotypes, with further effects of growth conditions. The present article therefore critically reviews published comparisons of the health benefits of ancient and modern wheats, in relation to the selection and growth of the lines, including dietary interventions and comparisons of adverse effects (allergy, intolerance, sensitivity). It is concluded that further studies are urgently required, particularly from a wider range of research groups, but also on a wider range of genotypes of ancient and modern wheat species. Furthermore, although most published studies have made efforts to ensure the comparability of material in terms of growth conditions and processing, it is essential that these are standardised in future studies and this should perhaps be a condition of publication. PMID- 29497245 TI - Baseline risk and marginal willingness to pay for health risk reduction. AB - Empirical results presented in this paper suggest that parents' marginal willingness to pay (MWTP) for a reduction in morbidity risk from heart disease is inversely related to baseline risk (i.e., the amount of risk initially faced) both for themselves and for their children. For instance, a 40% reduction from the mean of baseline risk results in an increase in MWTP by 70% or more. Thus, estimates of monetary benefits of public programs to reduce heart disease risk would be understated if the standard practice is followed of evaluating MWTP at initial risk levels and then multiplying this value by the number of cases avoided. Estimates are supported by: (1) unique quantitative information on perceptions of the risk of getting heart disease that allow baseline risk to be defined at an individual level and (2) improved econometric procedures to control for well-known difficulties associated with stated preference data. PMID- 29497246 TI - Methadone is Now Available in India: Is the Long Battle Over? AB - Context: Morphine and fentanyl had so far been the only available opioids in India in step three of the World Health Organization analgesic ladder. Especially for those not tolerating morphine and particularly for those developing neurotoxicity, an inexpensive alternative was essential. Many years of advocacy by palliative care activists have resulted in methadone being now available for sale in India for pain management. However, the characteristic pharmacokinetics and pharmacodynamics of methadone raise potential issues of safety. Aims: This study aimed to recommend the essential steps for ensuring availability of methadone for improved pain relief in India, while at the same time ensuring safe use. Conclusions: Two steps are suggested. Firstly, the palliative care community in India must launch an educational program on methadone freely available to all potential prescribers of this medicine. Secondly, we must advocate with drug controllers of states and union territories for making methadone available only through recognized medical institutions and for ensuring that indiscriminate sale through pharmacies is avoided. PMID- 29497247 TI - Safe Use of Methadone for Cancer Pain using "Opioid Circle of Safety". PMID- 29497248 TI - Methadone for Pain Management: Past, Present and Future. AB - Methadone for pain management in this article describes briefly pain, methadone as a Level 3 World Health Organization ladder opioid in the context of India and rest of the world, as well as the relationship to past, present, and future possibilities of pain management. Acute pain is proportional to the injury most of the times, and such proportionality may not exist in chronic pain. Pain management over decades has changed because of knowledge and availability of molecules and compounds to reduce chronic pain. Naturally occurring opioids from "poppy" such as morphine and heroin were available through cultivation and trade for pain management and recreational use in different parts of the world for centuries. Methadone has been a synthetic molecule discovered in the 1930s in Germany. It has been used for harm reduction for opioid use disorder in the form of "methadone maintenance treatment". This program exists since the 1950s while pain management started around the late 1970s in Europe and North America. More recently, the knowledge of acute and chronic pain at a molecular level, including ion channel modification, allowed the use of coanalgesics and opioids prudently. The concept of "total pain, neuroplasticity, and neurotransmitters" how they could be modified for better pain management with pharmaceuticals and nonpharmacological methods are being investigated, and evidence is being practiced clinically. In the present context, education for physicians, allied health professionals, patients, and family caregivers is important. Education to the physicians can skill and capacity build in the community and can be associated with educational research and peer-reviewed publications. The future remains promising, as innovations such as pharmacogenomics, nanotechnology, molecular, and quantum biology may create evidence, along with physical and psychological rehabilitation, to prevent and holistically better pain management. PMID- 29497249 TI - Practical Pharmacology of Methadone: A Long-acting Opioid. AB - Methadone is a naturally long-acting analgesic with unique pharmacodynamic and pharmacokinetic properties compared to other opioids, available now in India, to treat severe pain. It has the potential to dramatically relieve suffering among patients with serious illness who are living with persistent physical pain. However, clinicians must appreciate its unique pharmacologic properties and its use in clinical practice safely and effectively. The available formulation in India is a racemic mixture of the S- and R-enantiomers, and as such, it will have a propensity for drug-drug and drug-genetic interactions that can increase the risk of Torsades de Point and respiratory depression. Appropriate patient selection, careful dosing and thorough monitoring of methadone will mitigate these risks. PMID- 29497250 TI - When to Use Methadone for pain: A Case-Based Approach. AB - The case studies are written in this article to illustrate how methadone might be used for pain in the Indian context. These cases might be used for discussion in a multidisciplinary team, or for individual study. It is important to understand that pain requires a multidisciplinary approach as opioids will assist only with physical, i.e. neuropathic and nociceptive pain, but not emotional, spiritual, or relational pain or the pain of immobility. The social determinants of pain were included to demonstrate how emotional, relational, and psychological dimensions of pain amplify the physical aspects of pain. The case studies follow a practical step-wise approach to pain while undergoing cancer treatment, pain toward the end of-life and needing longer acting opioid. Methadone in children, and methadone in conditions of opioid toxicity or where there is a need for absorption in the proximal intestine cases are included. PMID- 29497251 TI - Practical Guide for Using Methadone in Pain and Palliative Care Practice. AB - Since the 2014 Amendment to the NDPS Act methadone has been released in India for pain management. The methadone is supplied as racemic mixture with R & S methadone with benefit in pain management and associated adverse effects. Physicians need to be aware of adverse effects so that methadone can be administered safely. Similarly, patients and families need to store and use methadone carefully and experience the benefits and not increase the risk of further morbidity. Considerable amount of literature on methadone is available and sometimes conflicting, hence the article is attempting to guide a physician to use methadone safely to acquire experience and expertise over time. PMID- 29497252 TI - Challenges of Using Methadone in the Indian Pain and Palliative Care Practice. AB - Palliative care providers across India lobbied to gain access to methadone for pain relief and this has finally been achieved. Palliative care activists will count on the numerous strengths for introducing methadone in India, including the various national and state government initiatives that have been introduced recognizing the importance of palliative care as a specialty in addition to improving opioid accessibility and training. Adding to the support are the Non Governmental Organizations (NGOs), the medical fraternity and the international interactive and innovative programs such as the Project Extension for Community Health Outcome. As compelling as the need for methadone is, many challenges await. This article outlines the challenges of procuring methadone and also discusses the challenges specific to methadone. Balancing the availability and diversion in a setting of opioid phobia, implementing the amended laws to improve availability and accessibility in a country with diverse health-care practices are the major challenges in implementing methadone for relief of pain. The unique pharmacology of the drug requires meticulous patient selection, vigilant monitoring, and excellent communication and collaboration with a multidisciplinary team and caregivers. The psychological acceptance of the patient, the professional training of the team and the place where care is provided are also challenges which need to be overcome. These challenges could well be the catalyst for a more diligent and vigilant approach to opioid prescribing practices. Start low, go slow could well be the way forward with caregiver education to prescribe methadone safely in the Indian palliative care setting. PMID- 29497253 TI - Towards the design of anti-amyloid short peptide helices. AB - A set of short peptide sequences susceptible to fibrillar aggregation produces sequneces capable of arresting elongation of amyloid fibrils. The "stop" signals are short helices customized for each individual target. Such a helix should exhibit high amphiphilicity, with differing conditions present on each side (one side should be highly hydrophilic to enable water to interact with the aggregate, while the other side must retain a local distribution of hydrophobicity which matches that of the terminal portion of the fibril). The emergence and elongation of fibrillary forms resulting from linear propagation of local hydrophobicity peaks is shown using the fuzzy oil drop model. PMID- 29497254 TI - Identification of coding sequence and its use for functional and structural characterization of catalase from Phyllanthus emblica. AB - Catalase is an essential antioxidant enzyme that is well characterized from microbial and animal sources. The structure of plant catalase is unknown. Therefore, it is of interest to understand the functional and structural characteristics of catalase from an Indian gooseberry, Phyllanthus emblica (or Emblica officinalis). Hence, catalase from P. emblica was cloned in pUC18 plasmid, sequenced and submitted to GenBank with the accession numbers "MF979112" and "ATO98311.1". InterProScan showed that the coding sequence is monofunctional and haem-dependent catalase-like superfamily. Multiple sequence alignment (MSA) followed by phylogenetic analysis showed that the P. emblica catalase groups with soybean catalase. We further report the characteristics of structural model of the enzyme for functional characterization. PMID- 29497255 TI - Molecular docking based screening of Noggin inhibitors. AB - Noggin (NOG) a BMP (bone morphogenetic protein) antagonist plays a key role in preferentially driving a subset of breast cancer cells towards the bone and causing osteolytic lesions leading to severe pain and discomfort in the patients. Owing to its role in bone metastasis, NOG could be promising molecular target in bone metastasis and that identifying small molecule inhibitors could aid in the treatment. Towards identifying cognate inhibitors of NOG, structure based virtual screen was employed. A total of 8.5 million ligands from e-molecule database were screened at a novel binding site on NOG identified by the Sitemap tool, employing GLIDE algorithm. Potential eight molecules were selected based on the Glide score, binding mode and H-bond interactions. Free energy of binding was calculated using Molecular mechanics based MMGBSA and the obtained energy was used in the prioritizing the compounds with the similar structures and glide score. Further, the compounds were evaluated for their druggability employing physico-chemical property analysis. Our study helped in identifying novel potential NOG inhibitors that can further be validated using in-vivo and in-vitro studies and these molecules can also be employed as tool compounds to study the functions of BMP. PMID- 29497256 TI - Identification and characterization of sodium and chloride-dependent gamma aminobutyric acid (GABA) transporters from eukaryotic pathogens as a potential drug target. AB - We explored 285 completed eukaryotic pathogen genomes for GABA transporter proteins as effective chemotherapy targets. We identified 8 GABA proteins that spread across 4 phyla with 5 different pathogen species; Eimeria mitis Houghton, Neospora caninum Liverpool, S. mansoni, S. haematobium and Trichinella spiralis. Sub-cellular localization prediction revealed that these proteins are integral membrane and are mostly insoluble. It is found that about 81% of these proteins are non-crystallizable and 15% are crystallizable. Transmembrane helices predictions show that the GABA transporters have 10, 11, 12 and 14 TMHs with 15, 23, 31 and 11%, respectively. It is further observed that most of these GABA transporters are from several parasites'genomes. PMID- 29497257 TI - Current Bioinformatics resources in combating infectious diseases. AB - Bioinformatics tools and techniques analyzing next-generation sequencing (NGS) data are increasingly used for the diagnosis and monitoring of infectious diseases. It is of interest to review the application of bioinformatics tools, commonly used databases and NGS data in clinical microbiology, focusing on molecular identification, genotypic, microbiome research, antimicrobial resistance analysis and detection of unknown disease-associated pathogens in clinical specimens. This review documents available bioinformatics resources and databases that are used by medical microbiology scientists and physicians to control emerging infectious pathogens. PMID- 29497258 TI - Odorant Binding Proteins: a key player in the sense of smell. AB - Olfaction is an important mechanism by which humans and animals communicate with environment. Odorant-binding proteins (OBPs) play crucial role in the olfactory mechanism. Here, we briefly discuss about the role of OBPs and their importance in industrial, pest management and therapeutic developments. PMID- 29497260 TI - A note on some identities of derangement polynomials. AB - The problem of counting derangements was initiated by Pierre Remond de Montmort in 1708 (see Carlitz in Fibonacci Q. 16(3):255-258, 1978, Clarke and Sved in Math. Mag. 66(5):299-303, 1993, Kim, Kim and Kwon in Adv. Stud. Contemp. Math. (Kyungshang) 28(1):1-11 2018. A derangement is a permutation that has no fixed points, and the derangement number [Formula: see text] is the number of fixed point-free permutations on an n element set. In this paper, we study the derangement polynomials and investigate some interesting properties which are related to derangement numbers. Also, we study two generalizations of derangement polynomials, namely higher-order and r-derangement polynomials, and show some relations between them. In addition, we express several special polynomials in terms of the higher-order derangement polynomials by using umbral calculus. PMID- 29497261 TI - Solution of the inverse problem for Bessel operator on an interval [Formula: see text]. AB - In this note, we solve the inverse nodal problem for Bessel-type p-Laplacian problem [Formula: see text] on a special interval. We obtain some nodal parameters like nodal points and nodal lengths. In addition, we reconstruct the potential function by nodal points. Results obtained in this paper are similar to the classical Sturm-Liouville problem. However, equations of this type are considered with the condition defined at the origin. We solve the problem on the interval [Formula: see text], that problem is not singular. PMID- 29497259 TI - Artificial Intelligence and brain. AB - From the start, Kurt Godel observed that computer and brain paradigms were considered on a par by researchers and that researchers had misunderstood his theorems. He hailed with displeasure that the brain transcends computers. In this brief article, we point out that Artificial Intelligence (AI) comprises multitudes of human-made methodologies, systems, and languages, and implemented with computer technology. These advances enhance development in the electron and quantum realms. In the biological realm, animal neurons function, also utilizing electron flow, and are products of evolution. Mirror neurons are an important paradigm in neuroscience research. Moreover, the paradigm shift proposed here - 'hall of mirror neurons' - is a potentially further productive research tactic. These concepts further expand AI and brain research. PMID- 29497262 TI - Existence of nontrivial weak solutions for a quasilinear Choquard equation. AB - We are concerned with the following quasilinear Choquard equation: [Formula: see text] where [Formula: see text], [Formula: see text] is the p-Laplacian operator, the potential function [Formula: see text] is continuous and [Formula: see text]. Here, [Formula: see text] is the Riesz potential of order [Formula: see text]. We study the existence of weak solutions for the problem above via the mountain pass theorem and the fountain theorem. Furthermore, we address the behavior of weak solutions to the problem near the origin under suitable assumptions for the nonlinear term f. PMID- 29497264 TI - Fractional Herglotz variational problems with Atangana-Baleanu fractional derivatives. AB - The purpose of this paper is to solve fractional calculus of variational Herglotz problem depending on an Atangana-Baleanu fractional derivative. Since the new Atangana-Baleanu fractional derivative is non-singular and non-local, the Euler Lagrange equations are proposed for the problems of Herglotz. Fractional variational Herglotz problems of variable order are considered and two cases are shown. The Noether-type theorem with this new fractional derivative is proved. Several typical examples of the results of this paper are expressed in this paper. PMID- 29497263 TI - The bounds estimate of sub-band operators for multi-band wavelets. AB - A concept of the sub-band operator of multi-band wavelets is introduced, the theory of d-circular matrices is developed and the upper bound and the lower bound of the norm of the sub-band operator are obtained. Examples are provided to illustrate the results proposed in this paper. PMID- 29497265 TI - Comparing the excepted values of atom-bond connectivity and geometric-arithmetic indices in random spiro chains. AB - The atom-bond connectivity (ABC) index and geometric-arithmetic (GA) index are two well-studied topological indices, which are useful tools in QSPR and QSAR investigations. In this paper, we first obtain explicit formulae for the expected values of ABC and GA indices in random spiro chains, which are graphs of a class of unbranched polycyclic aromatic hydrocarbons. Based on these formulae, we then present the average values of ABC and GA indices with respect to the set of all spiro chains with n hexagons and make a comparison between the expected values of ABC and GA indices in random spiro chains. PMID- 29497267 TI - New limiting variants of the classical reiteration theorem for the K interpolation method. AB - We establish some reiteration theorems for limiting K-interpolation methods, thereby obtaining new limiting variants of the classical reiteration theorem. An application to the Fourier transform is given. PMID- 29497266 TI - On approximation and energy estimates for delta 6-convex functions. AB - The smooth approximation and weighted energy estimates for delta 6-convex functions are derived in this research. Moreover, we conclude that if 6-convex functions are closed in uniform norm, then their third derivatives are closed in weighted [Formula: see text]-norm. PMID- 29497268 TI - Alternating proximal penalization algorithm for the modified multiple-sets split feasibility problems. AB - In this paper, we present an extended alternating proximal penalization algorithm for the modified multiple-sets feasibility problem. For this method, we first show that the sequences generated by the algorithm are summable, which guarantees that the distance between two adjacent iterates converges to zero, and then we establish the global convergence of the algorithm provided that the penalty parameter tends to zero. PMID- 29497269 TI - Oral microbiota transplant: a potential new therapy for oral diseases. AB - Dental caries and periodontitis are amongst the most common diseases affecting humans worldwide. There is an evolving trend for dental and medical research to share knowledge on the etiology and promising therapies for human diseases. Inspired by the success of fecal microbiota transplant to manage gastro intestinal disordes, oral microbiome transplant has been proposed but not yet tested in humans. This article critically reviews the potential of oral microbiome transplant for managing oral diseases. PMID- 29497270 TI - Economic Conditions of Young Adults Before and After the Great Recession. AB - Transition to adulthood has undoubtedly changed in the last few decades. For youth today, an important marker of adulthood is self-actualization in their professional career, and, consequently, also the achievement of stable financial conditions. Economic conditions of youth are greatly subject to fluctuations in the economy, and the subsequent governmental response. Using the Luxembourg Income Study, this work investigates the trends in income from work of young adults before and after the Great Recession of 2008 in five countries-US, UK, Norway, Germany, and Spain. The findings showed deterioration in economic conditions of young men, but with differences across countries. Young women suffered less from the crisis, and in some countries, their economic situation improved. The general negative trend was especially pronounced for those with high education, which is primarily because they stayed in education longer. PMID- 29497271 TI - A Couple-Based Psychological Treatment for Chronic Pain and Relationship Distress. AB - Chronic pain impacts individuals with pain as well as their loved ones. Yet, there has been little attention to the social context in individual psychological treatment approaches to chronic pain management. With this need in mind, we developed a couple-based treatment, "Mindful Living and Relating," aimed at alleviating pain and suffering by promoting couples' psychological and relational flexibility skills. Currently, there is no integrative treatment that fully harnesses the power of the couple, treating both the individual with chronic pain and the spouse as two individuals who are each in need of developing greater psychological and relational flexibility to improve their own and their partners' health. Mindfulness, acceptance, and values-based action exercises were used to promote psychological flexibility. The intervention also targets relational flexibility, which we define as the ability to interact with one's partner, fully attending to the present moment, and responding empathically in a way that serves one's own and one's partner's values. To this end, the intervention also included exercises aimed at applying psychological flexibility skills to social interactions as well as emotional disclosure and empathic responding exercises to enhance relational flexibility. The case presented demonstrates that healthy coping with pain and stress may be most successful and sustainable when one is involved in a supportive relationship with someone who also practices psychological flexibility skills and when both partners use relational flexibility skills during their interactions. PMID- 29497272 TI - Clinician Telephone Training to Reduce Family Tobacco Use: Analysis of Transcribed Recordings. AB - Background: Family tobacco use and exposure are significant threats to the health of children and their families. However, few pediatric clinicians address family tobacco use and exposure in a routine and effective manner. The Clinical Effort Against Secondhand Smoke Exposure (CEASE) intervention was developed to tackle this gap between clinical need and clinical practice. Objective: To review the main considerations and questions that clinicians and office staff expressed during telephone training to participate in CEASE. Methods: This study was conducted in pediatric practices in 5 US states. Practices were recruited by the American Academy of Pediatrics (10 intervention, 10 control). Ten training calls were recorded and transcribed. The data was then coded inductively based on themes found in the transcripts. Results: The data revealed that clinicians and staff were concerned about prescribing, dosing, and insurance coverage of nicotine replacement therapy; motivation for and methods to help families become tobacco-free; and the impact of the intervention on practice operations. Conclusion: While the majority of clinicians and office staff were interested and enthusiastic about helping families become tobacco-free, they expressed concerns that could threaten implementation of family tobacco control strategies. PMID- 29497273 TI - Long-term outcomes of the aphakic snap-on Boston type I keratoprosthesis at the Bascom Palmer Eye Institute. AB - Purpose: To determine the indications, long-term clinical and visual outcomes, and complications of the aphakic snap-on type I Boston keratoprosthesis (KPro). Design: Retrospective, non-comparative case series. Methods: Forty-five eyes of 43 patients with type I aphakic snap-on KPros with at least 1 year of follow-up were included. The past medical histories, preoperative indications, best corrected visual acuities (BCVAs), postoperative complications, and retention rates were analyzed. Results: The most common indication for KPro implantation was a failed corneal graft (89%). The mean preoperative BCVA was count fingers hand motion (2.14+/-0.45 logarithm of minimum angle of resolution [logMAR]), which initially improved to 20/200 (1.04+/-0.85 logMAR; P<0.0001). At the last examination, 24 eyes (53%) maintained some visual gain, 22% retained their preoperative visual acuity, and 24% lost vision due to postoperative events and underlying ocular comorbidities. Postoperative complications included retroprosthetic membranes (8/45, 18%), corneal melts (5/45, 11%), glaucoma progression (6/45, 13%), and endophthalmitis or sterile vitritis (6/45, 13%). The KPro retention rate was 89%, with a mean follow-up of 51 months. The mean BCVA at the last visit was 20/1,400 (1.82+/-0.92 logMAR). Conclusion: Most patients experienced improved visual acuity after the implantation of the aphakic, snap-on type I KPro; however, the visual gains were not sustained over time, correlating with the onset of postoperative complications. PMID- 29497274 TI - Evaluation of visual function in preschool-age children using a vision screening protocol. AB - Purpose: To evaluate the relationship between uncorrected visual acuity and refraction and binocular function using a vision screening protocol. Methods: In total, 760 children (3-6 years old) who were enrolled in 4 nursery schools in Otawara, Japan, were recruited; a total of 1,520 eyes were examined. We assessed uncorrected near visual acuity, manifest refraction, stereopsis, and eye position. Subjects were divided into 4 subgroups according to the lowest uncorrected near visual acuity value compared between the 2 eyes: group 1 (visual acuity [VA] <=0.00 [logarithm of the minimum angle of resolution]), group 2 (VA 0.15-0.05), group 3 (VA 0.52-0.22), and group 4 (VA >0.52). These parameters were compared among the groups. Results: The sample number of each of the 4 sub-groups was as follows: group 1, 608; group 2, 114; group 3, 27; and group 4, 11. The median spherical equivalent values were -1.13 diopter (D) in group 1 and -1.00 in group 2, which were more myopic than group 4. Median cylindrical power in group 1 was 0.25 D, and was the lowest among all groups. In group 1, median anisometropia was 0.38 D and median corneal astigmatism value was 1.13 D; both values were lowest in group 1. With regard to binocular function, 89.6% of the subjects in group 1 had 60 arcseconds or better in near stereopsis and 98.8% had no detectable strabismus, which were significantly different from the findings in the other groups. The percentage of subjects in group 1 who had 80 arcseconds or worse in near stereopsis was 10.4%. In contrast, 90.9% of the subjects in group 4 had 80 arcseconds or worse in near stereopsis, and 18.2% had intermittent or manifest strabismus. Conclusion: We suggest that examination of refraction and stereopsis in preschool-age children undergoing vision screening is an important supplement to visual acuity testing. PMID- 29497276 TI - The 24-hour intraocular pressure control by tafluprost/timolol fixed combination after switching from the concomitant use of tafluprost and timolol gel-forming solution, in patients with primary open-angle glaucoma. AB - Objective: The aim of this study was to evaluate the 24-hour intraocular pressure (IOP)-control effect of the tafluprost/timolol fixed combination (TAF/TIM-FC) in patients with primary open-angle glaucoma after they switched from the concomitant use of tafluprost and timolol gel-forming solution. Patients and methods: Twenty patients with primary open-angle glaucoma (12 male and 8 female; mean +/- SD age, 57.0+/-7.1 years) were included in this study. The patients were treated for 8 weeks with the concomitant administration of tafluprost and timolol gel-forming solution (evening dosing). At the end of this period, the patients underwent 24-hour IOP monitoring (measured at 21:00, 01:00, 05:00, 09:00, 13:00 and 17:00). IOP was measured with Goldmann applanation tonometer (GAT) and Icare PRO at sitting position at all timepoints and additionally, at supine position with Icare PRO tonometer at 01:00 and 05:00. The patients were then all switched to TAF/TIM-FC treatment (evening dosing). After 8 weeks, the 24-hour IOP monitoring was repeated. Results: Nineteen patients completed the study. The mean 24-hour IOPs in the concomitant and TAF/TIM-FC phases were 13.8+/-2.7 vs 13.3+/ 2.8 mmHg (P=0.0033) with the GAT in the sitting position and 13.96+/-2.56 vs 13.48+/-2.56 mmHg (P=0.0120) with the Icare PRO in habitual positions. In comparison with the concomitant phase, significantly lower IOP was observed for the TAF/TIM-FC phase at 21:00 and 01:00 with the GAT and at 01:00 with the Icare PRO. In addition, the maximum IOP and fluctuations in IOP in habitual positions were lower for the TAF/TIM-FC phase than for the concomitant phase. Conclusion: TAF/TIM-FC showed a stable 24-hour IOP-lowering effect and was equally or more effective than the concomitant use of tafluprost and timolol gel, both when sitting and when in habitual positions. PMID- 29497275 TI - Peripheral refraction and image blur in four meridians in emmetropes and myopes. AB - Introduction: The peripheral refractive error of the human eye has been hypothesized to be a major stimulus for the development of its central refractive error. Aim: The purpose of this study was to investigate the changes in the peripheral refractive error across horizontal, vertical and two diagonal meridians in emmetropic and low, moderate and high myopic adults. Subjects and methods: Thirty-four adult subjects were recruited and aberration was measured using a modified commercial aberrometer. We then computed the refractive error in power vector notation from second-order Zernike terms. Statistical analysis was performed to evaluate the statistical differences in refractive error profiles between the subject groups and across all measured visual field meridians. Results: Small amounts of relative myopic shift were observed in emmetropic and low myopic subjects. However, moderate and high myopic subjects exhibited a relative hyperopic shift in all four meridians. Astigmatism J0 and J45 had quadratic or linear changes dependent on the visual field meridians. Peripheral Sphero-Cylindrical Retinal Image Blur increased in emmetropic eyes in most of the measured visual fields. Conclusion: The findings indicate an overall emmetropic or slightly relative myopic periphery (spherical or oblate retinal shape) formed in emmetropes and low myopes, while moderate and high myopes form relative hyperopic periphery (prolate, or less oblate, retinal shape). In general, human emmetropic eyes demonstrate higher amount of peripheral retinal image blur. PMID- 29497277 TI - Review of deutetrabenazine: a novel treatment for chorea associated with Huntington's disease. AB - Deutetrabenazine was recently approved for the treatment of chorea in Huntington's disease (HD) and is the first deuterated medication that has been US Food and Drug Administration (FDA)-approved for therapeutic use. In this article, we review deutetrabenazine's drug design, pharmacokinetics, drug interactions, efficacy, adverse events, comparison with tetrabenazine, dosage, and administration. Deutetrabenazine is a deuterated form of tetrabenazine and is a vesicular monoamine transporter 2 (VMAT2) inhibitor. The substitution of deuterium for hydrogen at key positions in the tetrabenazine molecule allows a longer drug half-life and less frequent daily dosing. Deutetrabenazine is administered twice daily up to a maximum daily dose of 48 mg, which corresponds to a similar daily dose of 100 mg of tetrabenazine. In a Phase III clinical trial (First-HD), there was a statistically significant improvement of chorea in HD subjects, as well as improvements in global impression of change as assessed by both patients and clinicians. This improvement was seen without significant adverse effects as the overall tolerability profile of deutetrabenazine was similar to placebo. Somnolence was the most commonly reported symptom in the deutetrabenazine group. In a study where subjects converted from tetrabenazine to deutetrabenazine in an open-label fashion (ARC-HD) and indirect comparison studies between tetrabenazine and deutetrabenazine, there is a suggestion that while efficacy for chorea is similar, the data may slightly favor tetrabenazine, but adverse effects and tolerability strongly favor deutetrabenazine. These data have not been replicated in true head-to-head studies. Current evidence supports that deutetrabenazine is an effective therapeutic treatment option for chorea in HD and may provide a more favorable adverse effect profile than tetrabenazine. However, more data are needed, particularly in the form of head-to-head studies between deutetrabenazine and other treatment options as well as longer term clinical experience with deutetrabenazine. PMID- 29497278 TI - Abemaciclib: a CDK4/6 inhibitor for the treatment of HR+/HER2- advanced breast cancer. AB - Although early breast cancer (BC) is highly curable, advanced or metastatic disease poses numerous challenges in terms of medical management and treatment decisions and is associated with significantly worse prognosis. Among the new targeted agents, anticancer drugs exploiting the cell-cycle machinery have shown great potential in preclinical studies. CDK4/6 inhibitors target the cyclin D/CDK/retinoblastoma signaling pathway, inducing cell-cycle arrest, reduced cell viability and tumor shrinking. As the cyclin D/CDK complex is activated downstream of estrogen signaling, the combination of CDK4/6 inhibitors with standard endocrine therapies represents a rational approach to elicit synergic antitumor activity in hormone receptor-positive BC. The results of clinical trials have indeed confirmed the superiority of the combination of CDK4/6 inhibitors plus endocrine therapies over endocrine therapy alone. Currently approved are three compounds that exhibit similar structural characteristics as well as biological and clinical activities. Abemaciclib is the latest CDK4/6 inhibitor approved by the US Food and Drug Administration (FDA) in view of the results of the MONARCH 1 and 2 trials. Further trials are ongoing as other important questions await response. In this review, we focus on abemaciclib to examine preclinical and clinical results, describing current therapeutic indications, open questions and ongoing clinical trials. PMID- 29497280 TI - Short-term efficacy of intravitreal conbercept in treatment-naive patients with polypoidal choroidal vasculopathy. AB - Introduction: To evaluate the functional and morphological outcomes of intravitreal conbercept monotherapy in patients with polypoidal choroidal vasculopathy (PCV). Materials and methods: In this retrospective, observational case series study, we reviewed medical records of 48 eyes (48 patients) with naive PCV that were treated with a series of 3 monthly intravitreal injections of 0.5 mg of conbercept followed by as-needed injections (3+pro re nata). All patients completed at least 6 months of monthly follow-up. Changes in the best corrected visual acuity, optical coherence tomography, and indocyanine green angiography were retrospectively evaluated. Results: At 6 months, the mean best corrected visual acuity significantly improved from 0.89+/-0.35 (20/160 in Snellen equivalent) at baseline to 0.58+/-0.26 (Snellen equivalent of 20/80; P<0.001), and 60.42% (29/48) of eyes had an improvement of three lines of vision; the mean central retinal thickness significantly decreased from 333.56+/-171.04 MUm at baseline to 187.65+/-54.46 MUm (P<0.001), and 93.75% (45/48) achieved a dry macula. At 3 months, 6 of 32 eyes (18.75%) showed partial regression of branching vascular network, 14 of 32 (43.75%) patients showed complete resolution of polyps. The mean number of injections was 3.4+/-0.9 through 6 months. No conbercept-related systemic or ocular adverse effects were observed. Conclusion: Intravitreal injection of conbercept using "3+pro re nata" regimen significantly improved visual acuity and anatomical outcomes in treatment-naive patients with PCV. PMID- 29497279 TI - Pharmacokinetics and tolerability of eletriptan hydrobromide in healthy Korean subjects. AB - Background: Migraine is one of the most common headache disorders that greatly affect the quality of life. Selective serotonin (5-HT) receptor agonists such as triptamine-based drugs called triptans are used for treatment of migraine. Purpose: This study aimed to evaluate the pharmacokinetic (PK) and tolerability profiles of eletriptan hydrobromide (eletriptan HBr), a selective 5 hydroxytryptamine (also known as serotonin) 1B/1D receptor agonist, in Koreans and compare the results to those observed in non-Koreans in a previously published study. Patients and methods: A randomized, open-label, single, and repeated-dose study was conducted in 16 healthy Korean male subjects using a four treatment, four-period, and four-sequence crossover design (NCT01139515). The subjects received one of the following four treatments in each period: a single dose of 20, 40, 80 mg eletriptan HBr or a repeated oral dose of 40 mg 2 h apart. Blood samples were collected before and up to 26 h after dosing for quantification of plasma eletriptan concentration by high-performance liquid chromatography tandem-mass spectrometry. The PK parameters were estimated using noncompartmental methods. Ethnicity differences between Korean and non-Korean subjects were identified using geometric mean ratios and 90% confidence intervals (CIs) of dose-normalized maximum plasma concentration (Cmax) and dose-normalized area under the plasma concentration versus time curve from 0 h to the last measurable concentration (AUC0-t). Results: After single-dose administration of eletriptan HBr to Korean subjects, the mean Cmax and AUC0-t increased linearly with dose. Comparable total systemic exposures were observed in the 2 h apart 40 mg repeated and single 80 mg dose. The geometric mean ratios (90% CIs) of the dose-normalized Cmax and AUC0-t of Korean subjects were similar to those of non Korean subjects reported in the literature. The adverse events observed were transient and mild in severity. Conclusion: Eletriptan HBr showed linear PK and was well tolerated in Korean subjects. The PK and tolerability of eletriptan HBr did not differ between Korean and non-Korean subjects. PMID- 29497281 TI - The evaluation of pharmaceutical pictograms among elderly patients in community pharmacy settings - a multicenter pilot study. AB - Introduction: The search for new ways to optimize the use of medications by patients has led the pharmaceutical community to promote the idea of introducing pictograms into routine practice. The main intention of pictograms is to ease patient adherence and to reduce potential risks or errors associated with the use of medications. Purpose: To evaluate a series of pharmaceutical pictograms for patient comprehension. Patients and methods: The study was conducted in community pharmacies within a European Union country that belongs to the professional research network. Structured interviews were used to evaluate the pictograms for patient comprehension. This consisted of an assessment of the following: the transparency and translucency of the pictograms, health literacy, and pictogram recall. Participants were also given the opportunity to provide feedback on how to improve the pictograms. The primary endpoint was pictogram comprehension. Secondary outcomes included recall of the pictograms and pictogram translucency. Results: The study included 68 patients with whom face-to-face interviews were performed. Low transparency results (<=25%) and extensive patient feedback in initial interviews led to the withdrawal of certain pictograms (n=15) from the evaluation. Among the pictograms included in the final stage of our research, 22 pictograms (62.8%) obtained an acceptable transparency level >=66%. All pictograms passed the short-term recall test with positive results. Conclusion: A majority of the designed and modified pictograms reached satisfactory guess ability scores. Feedback from patients enabled modification of the pictograms and proved that patients have an important voice in the discussion regarding the design of additional pictograms. PMID- 29497282 TI - Satisfaction with oral anticoagulants in patients with atrial fibrillation. AB - Background: Although, by itself, atrial fibrillation is associated with an impairment of quality of life antithrombotic therapy may play a role. Objective: To evaluate the satisfaction with anticoagulant treatment in patients with nonvalvular atrial fibrillation who attended internal medicine departments in Spain. Methods: Patients from two different cross-sectional studies were combined. To measure the satisfaction with anticoagulant treatment, the Anti-Clot Treatment Scale (ACTS) questionnaire was completed by every patient. A multivariate analysis was performed to determine the variables associated with satisfaction of patients receiving oral anticoagulants. Results: A total of 1,309 patients (mean age 78.5+/-8.4 years; 49.3% men; CHA2DS2VASC 4.9+/-1.5; HAS-BLED 2.0+/-0.9) were included in the study, of whom 902 (68.9%) were taking vitamin K antagonists (VKA) and 407 (31.1%) direct oral anticoagulants (DOACs). Overall, satisfaction with oral anticoagulation was high (ACTS Burdens scale 49.69+/-9.45; ACTS Benefits scale 11.35+/-2.61). The perceived burdens with anticoagulant treatment were lower in men, as well as in patients with no dependency, normal renal function, who were not polymedicated, or who had moderate bleeding risk. Among patients taking VKA, those subjects with a lower number of International Normalized Ratio (INR) determinations in the last 6 months or with an optimal time in the therapeutic range exhibited a lower perceived burden. Patients taking DOACs (vs VKA) showed a lower perceived burden with anticoagulation. Benefits with anti-coagulation were higher in men, younger patients, those with no dependency, or low bleeding risk. Perceived benefits were higher in patients taking DOACs (vs VKA). Conclusion: Satisfaction with oral anticoagulation was high in patients with nonvalvular atrial fibrillation, who were attending internal medicine departments daily in Spain. Among patients taking VKA, those subjects with a lower number of INR determinations in the last 6 months or with an optimal time in the therapeutic range exhibited a lower perceived burden with anticoagulant therapy. Patients taking DOACs (vs VKA) showed lower perceived burdens and higher perceived benefits with anticoagulation. PMID- 29497283 TI - Targeting "hardly reached" people with chronic illness: a feasibility study of a person-centered self-management education approach. AB - Background: Self-management education is critical to the development of successful health behavior changes related to chronic illness. However, people in high-risk groups attend less frequently or benefit less from patient education programs than do people with more socioeconomic advantages. Aim: The aim was to test the feasibility of a participatory person-centered education approach and tool-kit targeting self-management of chronic illness in hardly reached people. Methods: After participating in a training program, educators (n=77) tested the approach in practice. Data collection included online questionnaires for educators (n=65), observations of education sessions (n=7), and interviews with educators (n=11) and participants (n=22). Descriptive statistics were calculated. Transcripts of interviews and observations were analyzed using systematic text condensation. Feasibility was examined in terms of practicality, integration, suitability, and efficacy. Results: Educators had a positive response to the approach and found that the tools supported involving participants in education and support. Participant satisfaction varied, depending on the ability of educators to integrate the tools into programs in a meaningful way. The tools provided time for reflection in the education process that benefited participants and educators alike. Educators found it challenging to allow participants to help set the agenda and to exchange experiences without educator control. Barriers to use reported by educators included lack of time for both training and preparation. Limitations: The testing included varied groups of participants, some groups included members of hardly reached populations and others did not. Also, some tools were only tried in practice by a few educators. Conclusion: The approach was feasible in terms of practicality, integration, acceptability, and efficacy and perceived by educators as suitable for both hardly reached participants and those who are less disadvantaged. Implementation of the approach requires time for training and preparation. PMID- 29497284 TI - Adjuvant endocrine therapy after breast cancer: a qualitative study of factors associated with adherence. AB - Introduction: Despite evidence of the efficacy of adjuvant endocrine therapy (AET) in reducing the risk of recurrence and mortality after treatment for primary breast cancer, adherence to AET is suboptimal. This study aimed to explore factors that influence adherence and nonadherence to AET following breast cancer to inform the development of supportive interventions. Methods: Interviews were conducted with 32 women who had been prescribed AET, 2-4 years following their diagnosis of breast cancer. Both adherers (n=19) and nonadherers (n=13) were recruited. The analysis was conducted using the Framework approach. Results: Factors associated with adherence were as follows: managing side effects including information and advice on side effects and taking control of side effects, supportive relationships, and personal influences. Factors associated with nonadherence were as follows: burden of side effects, feeling unsupported, concerns about long-term AET use, regaining normality, including valuing the quality of life over length of life, and risk perception. Conclusion: Provision of timely information to prepare women for the potential side effects of AET and education on medication management strategies are needed, including provision of timely and accurate information on the efficacy of AET in reducing breast cancer recurrence and on potential side effects and ways to manage these should they arise. Trust in the doctor-patient relationship and clear patient pathways for bothersome side effects and concerns with AET are important. Training and education on AET for GPs should be considered alongside novel care pathways such as primary care nurse cancer care review and community pharmacist follow-up. PMID- 29497285 TI - Review of Statistical Learning Methods in Integrated Omics Studies (An Integrated Information Science). AB - Integrated omics is becoming a new channel for investigating the complex molecular system in modern biological science and sets a foundation for systematic learning for precision medicine. The statistical/machine learning methods that have emerged in the past decade for integrated omics are not only innovative but also multidisciplinary with integrated knowledge in biology, medicine, statistics, machine learning, and artificial intelligence. Here, we review the nontrivial classes of learning methods from the statistical aspects and streamline these learning methods within the statistical learning framework. The intriguing findings from the review are that the methods used are generalizable to other disciplines with complex systematic structure, and the integrated omics is part of an integrated information science which has collated and integrated different types of information for inferences and decision making. We review the statistical learning methods of exploratory and supervised learning from 42 publications. We also discuss the strengths and limitations of the extended principal component analysis, cluster analysis, network analysis, and regression methods. Statistical techniques such as penalization for sparsity induction when there are fewer observations than the number of features and using Bayesian approach when there are prior knowledge to be integrated are also included in the commentary. For the completeness of the review, a table of currently available software and packages from 23 publications for omics are summarized in the appendix. PMID- 29497286 TI - The effect of flat and textured insoles on the balance of primary care elderly people: a randomized controlled clinical trial. AB - Background: Aging is associated with reduced postural stability and increased fall risk. Foot orthoses have been reported as an adjuvant intervention to improve balance by stimulating foot plantar mechanical receptors and thus increasing somatosensory input. Purpose: The aim of this study is to evaluate the effect of flat and textured insoles on the balance of primary care elderly people. Design: Prospective, parallel, randomized, and single-blind trial. Methods: A total of 100 subjects from a primary care unit, aged >=65 years, were randomly assigned to intervention groups with flat insoles (n=33), textured insoles (n=33), or control group (n=34) without insoles. The Berg Balance Scale and the Timed Up and Go test were assessed at baseline and after 4 weeks. Results: Improvements in the Berg Balance Scale and the Timed Up and Go test were noted only in intervention groups with insoles but not in control group. No significant difference was found between flat and textured insoles. Minor adverse effects were noted only in the group with textured insoles. Conclusion: The results suggest that foot orthoses (both flat and textured insoles) are effective in improving balance in primary care elderly people. They may represent a low cost and high-availability adjuvant strategy to improve balance and prevent falls in this population. PMID- 29497288 TI - Erratum: Reduced nuclear translocation of serum response factor is associated with skeletal muscle atrophy in a cigarette smoke-induced mouse model of COPD [Corrigendum]. AB - [This corrects the article on p. 581 in vol. 12, PMID: 28260872.]. PMID- 29497287 TI - Beneficial effects of natural eggshell membrane versus placebo in exercise induced joint pain, stiffness, and cartilage turnover in healthy, postmenopausal women. AB - Purpose: Despite its many health benefits, moderate exercise can induce joint discomfort when done infrequently or too intensely even in individuals with healthy joints. This study was designed to evaluate whether NEM(r) (natural eggshell membrane) would reduce exercise-induced cartilage turnover or alleviate joint pain or stiffness, either directly following exercise or 12 hours post exercise, versus placebo. Patients and methods: Sixty healthy, postmenopausal women were randomly assigned to receive either oral NEM 500 mg (n=30) or placebo (n=30) once daily for two consecutive weeks while performing an exercise regimen (50-100 steps per leg) on alternating days. The primary endpoint was any statistically significant reduction in exercise-induced cartilage turnover via the biomarker C-terminal cross-linked telopeptide of type-II collagen (CTX-II) versus placebo, evaluated at 1 and 2 weeks of treatment. Secondary endpoints were any reductions in either exercise-induced joint pain or stiffness versus placebo, evaluated daily via participant questionnaire. The clinical assessment was performed on the per protocol population. Results: NEM produced a significant absolute treatment effect (TEabs) versus placebo for CTX-II after both 1 week (TEabs -17.2%, P=0.002) and 2 weeks of exercise (TEabs -9.9%, P=0.042). Immediate pain was not significantly different; however, rapid treatment responses were observed for immediate stiffness (Day 7) and recovery pain (Day 8) and recovery stiffness (Day 4). No serious adverse events occurred and the treatment was reported to be well tolerated by study participants. Conclusion: NEM rapidly improved recovery from exercise-induced joint pain (Day 8) and stiffness (Day 4) and reduced discomfort immediately following exercise (stiffness, Day 7). Moreover, a substantial chondroprotective effect was demonstrated via a decrease in the cartilage degradation biomarker CTX-II. Clinical Trial Registration number: NCT02751944. PMID- 29497289 TI - Seasonal variations in exacerbations and deaths in patients with COPD during the TIOSPIR(r) trial. AB - Background: Although COPD exacerbations are known to occur more frequently in winter, there is little information on hospitalizations and cause-specific mortality. This study aimed to examine seasonal variations in mortality and exacerbations in patients with COPD during the TIOtropium Safety and Performance In Respimat(r) (TIOSPIR(r)) trial. Patients and methods: TIOSPIR was a large scale, multicenter trial, which assessed the safety and efficacy of tiotropium delivered via HandiHaler(r) (18 MUg once daily) or Respimat(r) Soft MistTM (2.5 or 5 MUg once daily) inhaler in patients with COPD. Patients were aged >=40 years, with a smoking history >=10 pack-years, and post-bronchodilator forced expiratory volume in 1 second <=70% and forced expiratory volume in 1 second/forced vital capacity <=0.70. COPD exacerbations and deaths were monitored throughout the trial. The data were pooled to examine seasonal patterns. Southern hemisphere data were shifted by 6 months to align with northern hemisphere seasons. Results: TIOSPIR was conducted in 43 northern (n=15,968) and 7 southern (n=1,148) hemisphere (n=1,148) countries. The median duration of treatment was 835 days, with a mean follow-up of 2.3 years. Among 19,494 exacerbations, there were clear seasonal differences (winter, 6,646 [34.1%]; spring, 4,515 [23.2%]; summer, 3,198 [16.4%]; autumn, 5,135 [26.3%]). Exacerbations peaked in early winter (December in the northern hemisphere and June in the southern hemisphere), respiratory hospitalizations in midwinter, and respiratory deaths in early spring. Conclusion: Although winter poses a 2-fold hazard for COPD exacerbations vs summer, respiratory deaths peak in early spring. These data suggest that seasonal intensification of preventive treatments may impact COPD morbidity and mortality. Trial registration number: NCT01126437. PMID- 29497290 TI - Safety and effectiveness of the high-frequency chest wall oscillation vs intrapulmonary percussive ventilation in patients with severe COPD. AB - Purpose: Chest physiotherapy is an important tool in the treatment of COPD. Intrapulmonary percussive ventilation (IPV) and high-frequency chest wall oscillation (HFCWO) are techniques designed to create a global percussion of the lung which removes secretions and probably clears the peripheral bronchial tree. We tested the hypothesis that adding IPV or HFCWO to the best pharmacological therapy (PT) may provide additional clinical benefit over chest physiotherapy in patients with severe COPD. Methods: Sixty patients were randomized into three groups (20 patients in each group): IPV group (treated with PT and IPV), PT group with (treated with PT and HFCWO), and control group (treated with PT alone). Primary outcome measures included results on the dyspnea scale (modified Medical Research Council) and Breathlessness, Cough, and Sputum scale (BCSS), as well as an evaluation of daily life activity (COPD Assessment Test [CAT]). Secondary outcome measures were pulmonary function testing, arterial blood gas analysis, and hematological examinations. Moreover, sputum cell counts were performed at the beginning and at the end of the study. Results: Patients in both the IPV group and the HFCWO group showed a significant improvement in the tests of dyspnea and daily life activity evaluations (modified Medical Research Council scale, BCSS, and CAT) compared to the control group, as well as in pulmonary function tests (forced vital capacity, forced expiratory volume in 1 second, forced expiratory volume in 1 second/forced vital capacity%, total lung capacity, residual volume, diffusing lung capacity monoxide, maximal inspiratory pressure, maximal expiratory pressure) and arterial blood gas values. However, in the group comparison analysis for the same variables between IPV group and HFCWO group, we observed a significant improvement in the IPV group maximal inspiratory pressure, maximal expiratory pressure, BCSS, and CAT. Similar results were observed in changes of sputum cytology with reduction of inflammatory cells (neutrophils and macrophages). Conclusion: The two techniques improved daily life activities and lung function in patients with severe COPD. IPV demonstrated a significantly greater effectiveness in improving some pulmonary function tests linked to the small bronchial airways obstruction and respiratory muscle strength and scores on health status assessment scales (BCSS and CAT) as well as a reduction of sputum inflammatory cells compared with HFCWO. PMID- 29497291 TI - TNF promoter polymorphisms are associated with genetic susceptibility in COPD secondary to tobacco smoking and biomass burning. AB - Background: Smoking and smoke from biomass burning (BB) are the main environmental risk factors for COPD. Clinical differences have been described between COPD related to smoking and related to wood smoke, but no studies have shown genetic differences between patients exposed to these two risk factors. Methods: To investigate a possible association of tumor necrosis factor (TNF) promoter polymorphisms, we conducted a case-control study. A total of 1,322 subjects were included in four groups: patients with a diagnosis of COPD secondary to smoking (COPD-S, n=384), patients with COPD secondary to biomass burning (COPD-BB, n=168), smokers without COPD (SWOC, n=674), and biomass burning exposed subjects (BBES n=96). Additionally, a group of 950 Mexican mestizos (MMs) was included as a population control. Three single nucleotide polymorphisms (SNPs) were selected in the TNF gene (rs1800629, rs361525, and rs1800750) and one SNP in the lymphotoxin alpha gene (rs909253). Results: Statistically significant differences were found with genotype GA of the rs1800629: COPD-S vs SWOC, (p<0.001, odds ratio [OR] =2.55, 95% CI=1.53-4.27); COPD-S vs COPD-BB (p,0.01). When performing the comparison of the less severe (G1: I + II) and the more severe (G2: III + IV) levels, differences were identified in G1 (p<0.05, OR=1.94, 95% CI=1.04-3.63) and G2 (p<0.001, OR=3.68, 95% CI=1.94-3.07) compared with SWOC. Regarding genotype GA of rs361525, it has been associated when comparing COPD-BB vs BBES (p=0.0079, OR=5.99, 95% CI=1.38-53.98). Conclusion: The heterozygous genotype GA of polymorphisms rs1800629 and rs361525 in the TNF promoter are associated with the risk of COPD. PMID- 29497292 TI - Poly(lactic-co-glycolic acid)-loaded nanoparticles of betulinic acid for improved treatment of hepatic cancer: characterization, in vitro and in vivo evaluations. AB - Purpose: The application of betulinic acid (B), a potent antineoplastic agent, is limited due to poor bioavailability, short plasma half-life and inappropriate tissue distribution. Thus, we aimed to prepare novel 50:50 poly(lactic-co glycolic acid) (PLGA)-loaded B nanoparticles (BNP) and to compare its anti hepatocellular carcinoma (HCC) activity with parent B. Methods: BNP were synthesized and characterized using different methods such as scanning electron microscopy (SEM), fourier-transform infrared (FTIR) spectrometry and particle size analyses. Particle size of BNP was optimized through the application of the stabilizer, polyvinyl alcohol (PVA). The anti-HCC response was evaluated through in vitro cell line study using Hep-G2 cells, confocal microscopy, in vivo oral pharmacokinetics and animal studies. Further, quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis was conducted to observe the changes in the expression of specific genes. Results: Particle size of BNP was optimized through the application of the stabilizer, polyvinyl alcohol. Physicochemical characterization exhibited particle size of 257.1 nm with zeta potential -0.170 mV (optimized batch B, BNP). SEM and FTIR analyses of BNP showed that cylindrical particles of B converted to spherical particles in BNP and there were no interaction between B and used polymers. The release study of optimized BNP was highest (>=80%) than any other formulation. Later, in vitro cell culture analysis using Hep-G2 cells and confocal microscopy studies revealed that BNP had the highest inhibition and penetration properties than parent B. Oral pharmacokinetics studies using albino Wistar rats at single 100 mg dose again exhibited BNP had the higher 50% of plasma concentration (t1/2), a higher maximum plasma concentration (Cmax) and took longer to reach the maximum plasma concentration (Tmax) than parent B. Next, our in vivo study using nitrosodiethyl amine (NDEA)-induced HCC model documented BNP decreased in number of nodules, restored body weight, oxidative stress parameters, liver marker enzymes and histological architecture than parent B. Lastly, qRT-PCR studies further demonstrated that anti-HCC properties of BNP may be due to over expression of antiapoptotic caspases i.e., caspase 3 and 8. Conclusion: The prepared BNP showed a better therapeutic response against HCC and could be attributed as future candidate molecule for HCC treatment. PMID- 29497293 TI - Tannic acid-modified silver nanoparticles for wound healing: the importance of size. AB - Introduction: Silver nanoparticles (AgNPs) have been shown to promote wound healing and to exhibit antimicrobial properties against a broad range of bacteria. In our previous study, we prepared tannic acid (TA)-modified AgNPs showing a good toxicological profile and immunomodulatory properties useful for potential dermal applications. Methods: In this study, in vitro scratch assay, antimicrobial tests, modified lymph node assay as well as a mouse splint wound model were used to access the wound healing potential of TA-modified and unmodified AgNPs. Results: TA-modified but not unmodified AgNPs exhibited effective antibacterial activity against Pseudomonas aeruginosa, Staphylococcus aureus and Escherichia coli and stimulated migration of keratinocytes in vitro. The tests using the mouse splint wound model showed that TA-modified 33 and 46 nm AgNPs promoted better wound closure, epithelialization, angiogenesis and formation of the granulation tissue. Additionally, AgNPs elicited expression of VEGF-alpha, PDGF-beta and TGF-beta1 cytokines involved in wound healing more efficiently in comparison to control and TA-treated wounds. However, both the lymph node assay and the wound model showed that TA-modified AgNPs sized 13 nm can elicit strong inflammatory response not only during wound healing but also when applied to the damaged skin. Conclusion: TA-modified AgNPs sized >26 nm promote wound healing better than TA-modified or unmodified AgNPs. These findings suggest that TA-modified AgNPs sized >26 nm may have a promising application in wound management. PMID- 29497297 TI - Relationships between clinical scales and binge eating days in adults with moderate to severe binge eating disorder in two Phase III studies. AB - Objectives: In two Phase III studies, lisdexamfetamine dimesylate (LDX) reduced binge eating (BE) days/week in adults with moderate to severe binge eating disorder (BED) and was associated with improvement based on the Clinical Global Impressions-Improvement (CGI-I) scale. In this study, post hoc analyses examined the relationships between clinical observations and clinical rating scales in individuals with BED. Clinical trial registration: NCT01718483 (ClinicalTrials.gov/ct2/show/NCT01718483); NCT01718509 (ClinicalTrials.gov/ct2/show/NCT01718509). Methods: Two 12-week, double-blind, placebo-controlled studies randomized (1:1) adults meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, BED criteria and with protocol-defined moderate to severe BED (study 1, N=383; study 2, N=390) to placebo or dose-optimized LDX (50 or 70 mg). Assessments included the number of BE days/week, CGI-Severity (CGI-S) and CGI-I scores, and Yale-Brown Obsessive Compulsive Scale modified for Binge Eating (Y-BOCS-BE) total scores. For these post hoc analyses, data were pooled across studies and treatment arms. Statistical assessments included Spearman correlations and equipercentile linking analyses (ELA). Reported P-values are nominal (descriptive and not adjusted for multiplicity). Results: At baseline, nominally significant correlations with CGI S scores were reported for BE days/week (r=0.374; P<0.0001) and Y-BOCS-BE total scores (r=0.319; P<0.0001). Baseline ELA for CGI-S further characterized this relationship: a CGI-S score of 4 (moderately ill) corresponding to 3.504 BE days/week and a Y-BOCS-BE total score of 18.6. Nominally significant correlations with CGI-I scores were reported for changes from baseline at study endpoint for BE days/week (r=0.647; P<0.0001) and Y-BOCS-BE total scores (r=0.741; P<0.0001). ELA for CGI-I scores at study endpoint showed that a CGI-I score of 1 (very much improved) corresponds to a reduction from baseline of 4.504 BE days/week and 19.4 points for Y-BOCS-BE total score. Conclusion: These post hoc analyses suggest that indices of global disease severity and improvement positively correlate with BE behavior and with obsessive and compulsive features of BED, measured by the Y BOCS-BE, supporting the clinical relevance of BED treatment outcomes. PMID- 29497294 TI - Polymeric micelles for potentiated antiulcer and anticancer activities of naringin. AB - Naringin is one of the most interesting phytopharmaceuticals that has been widely investigated for various biological actions. Yet, its low water solubility, limited permeability, and suboptimal bioavailability limited its use. Therefore, in this study, polymeric micelles of naringin based on pluronic F68 (PF68) were developed, fully characterized, and optimized. The optimized formula was investigated regarding in vitro release, storage stability, and in vitro cytotoxicity vs different cell lines. Also, cytoprotection against ethanol induced ulcer in rats and antitumor activity against Ehrlich ascites carcinoma in mice were investigated. Nanoscopic and nearly spherical 1:50 micelles with the mean diameter of 74.80+/-6.56 nm and narrow size distribution were obtained. These micelles showed the highest entrapment efficiency (EE%; 96.14+/-2.29). The micelles exhibited prolonged release up to 48 vs 10 h for free naringin. The stability of micelles was confirmed by insignificant changes in drug entrapment, particle size, and retention (%) (91.99+/-3.24). At lower dose than free naringin, effective cytoprotection of 1:50 micelles against ethanol-induced ulcer in rat model has been indicated by significant reduction in mucosal damage, gastric level of malondialdehyde, gastric expression of tumor necrosis factor alpha, caspase-3, nuclear factor kappa-light-chain-enhancer of activated B cells, and interleukin-6 with the elevation of gastric reduced glutathione and superoxide dismutase when compared with the positive control group. As well, these micelles provoked pronounced antitumor activity assessed by potentiated in vitro cytotoxicity particularly against colorectal carcinoma cells and tumor growth inhibition when compared with free naringin. In conclusion, 1:50 naringin PF68 micelles can be represented as a potential stable nanodrug delivery system with prolonged release and enhanced antiulcer as well as antitumor activities. PMID- 29497295 TI - Polyaspartic acid-anchored mesoporous silica nanoparticles for pH-responsive doxorubicin release. AB - Background: Nanotechnology-based drug delivery systems exhibit promising therapeutic efficacy in cancer chemotherapy. However, ideal nano drug carriers are supposed to be sufficiently internalized into cancer cells and then release therapeutic cargoes in response to certain intracellular stimuli, which has never been an easy task to achieve. Objective: This study is to design mesoporous silica nanoparticles (MSNs)-based pH-responsive nano drug delivery system that is effectively internalized into cancer cells and then release drug in response to lysosomal/endosomal acidified environment. Methods: We synthesized MSNs by sol gel method. Doxorubicin (DOX) was encapsulated into the pores as a model drug. Polyaspartic acid (PAsA) was anchored on the surface of mesoporous MSNs (P-MSNs) as a gatekeeper via amide linkage and endowed MSNs with positive charge. Results: In vitro release analysis demonstrated enhanced DOX release from DOX-loaded PAsA anchored MSNs (DOX@P-MSNs) under endosomal/lysosomal acidic pH condition. Moreover, more DOX@P-MSNs were internalized into HepG2 cells than DOX-loaded MSNs (DOX@MSNs) and free DOX revealed by flow cytometry. Likewise, confocal microscopic images revealed that DOX@P-MSNs effectively released DOX and translocated to the nucleus. Much stronger cytotoxicity of DOX@P-MSNs against HepG2 cells was observed compared with DOX@MSNs and free DOX. Conclusion: DOX@P MSNs were successfully fabricated and achieved pH-responsive DOX release. We anticipated this nanotherapeutics might be suitable contenders for future in vivo cancer chemotherapeutic applications. PMID- 29497298 TI - Agomelatine versus paroxetine in treating depressive and anxiety symptoms in patients with chronic kidney disease. AB - Objective: Depressive and anxiety symptoms could affect the quality of life and prognostic outcomes in chronic kidney disease (CKD) patients, but only a few studies focus on the interventions to manage or prevent these symptoms in CKD patients. Therefore, this study was conducted to compare the efficacy and acceptability of agomelatine versus paroxetine in treating depressive and anxiety symptoms in CKD patients. Methods: CKD stage 2-4 patients with depressive and anxiety symptoms were included. The first patient was randomized in April 2013 and the last clinic visit occurred in March 2017. The included patients were randomly assigned to receive paroxetine 20-40 mg/day or agomelatine 25-50 mg/day. The treatment was continued for 12 weeks. The Hamilton Depression Rating Scale (HDRS) (17-item) and Hamilton Anxiety Rating Scale (HARS) were the primary outcome measures, and the response rate, remission rate, and Activities of Daily Living (ADL) scale were the secondary outcome measures. Meanwhile, the adverse events were recorded during the whole treatment period. Results: At baseline and week 4, both groups had similar average HDRS and HARS scores. But at week 8 and 12, compared to the patients receiving paroxetine, the patients receiving agomelatine had significantly lower average HDRS scores (p=0.002, p=0.001, respectively) and HARS scores (p<0.00001, p<0.00001, respectively). At week 12, the patients receiving agomelatine had a non-significantly lower average ADL score, and non-significantly higher response and remission rates. The adverse events in both groups were mild and transient. Conclusion: These results demonstrated that the agomelatine had some advantages over par-oxetine in treating CKD stage 2-4 patients with depressive and anxiety symptoms, and future studies are needed to further explore its efficacy and acceptability. PMID- 29497296 TI - Anti-TNF-alpha antibody attenuates subarachnoid hemorrhage-induced apoptosis in the hypothalamus by inhibiting the activation of Erk. AB - Background: Subarachnoid hemorrhage (SAH) can induce apoptosis in many regions of the brain including the cortex and hippocampus. However, few studies have focused on apoptosis in the hypothalamus after SAH. Although some antiapoptotic strategies have been developed for SAH, such as anti-tumor necrosis factor-alpha (TNF-alpha) antibody, the molecular mechanisms underlying this condition have yet to be elucidated. Therefore, the purpose of this study was to evaluate whether SAH could induce apoptosis in the hypothalamus and identify the potential molecular mechanisms underlying the actions of anti-TNF-alpha antibody, as a therapeutic regimen, upon apoptosis. Materials and methods: SAH was induced in a rat model. Thirty minutes prior to SAH, anti-TNF-alpha antibody or U0126, an extracellular signal-regulated kinase (Erk) inhibitor, was microinjected into the left lateral cerebral ventricle. In addition, phorbol-12-myristate-13-acetate was injected intraperitoneally immediately after the anti-TNF-alpha antibody microinjection. Then, real-time polymerase chain reaction, Western blotting and immunohistochemistry were used to detect the expression of caspase-3, bax, bcl-2, phosphorylated Erk (p-Erk) and Erk. Finally, anxiety-like behavior was identified by using open field. Results: Levels of caspase-3, bax and bcl-2, all showed a temporary rise after SAH in the hypothalamus, indicating the induction of apoptosis in this brain region. Interestingly, we found that the microinjection of anti-TNF-alpha antibody could selectively block the elevated levels of bax, suggesting the potential role of anti-TNF-alpha antibody in the inhibition of SAH induced apoptosis in the hypothalamus. Moreover, we found that Erk activation was necessary for apoptosis after SAH and that the microinfusion of anti-TNF-alpha antibody could inhibit apoptosis by suppressing the increase of p-Erk in the hypothalamus. Finally, our data indicated that the infusion of anti-TNF-alpha antibody could improve anxiety-like behavior. Conclusion: Collectively, our data demonstrate that anti-TNF-alpha antibody attenuates apoptosis in the hypothalamus by inhibiting the activation of Erk, which plays an important role in the treatment of SAH. PMID- 29497299 TI - Human factors evaluation of a novel digital medicine system in psychiatry. AB - Background: The digital medicine system (DMS), a drug-device combination developed for patients with serious mental illness, integrates adherence measurement with pharmacologic treatment by embedding an ingestible sensor in a pill, allowing for information sharing among patients, health care providers (HCPs), and caregivers via a mobile interface. Studies conducted during the DMS development process aimed to minimize cognitive burden and use-related risks and demonstrated effective use of the technology. Methods: Human factors (HF) studies assessed the system's safe and effective use by the intended users for the intended uses. The patient interface was tested in six formative HF studies followed by a validation study. The HCP/caregiver interface was tested in one study before validation. All tasks critical to safety or necessary for effective use were included. Formative studies identified use-related risks and the causes of use problems to guide design modification. Validation of the patient and HCP/caregiver interfaces assessed risks of the final product. Results: During the patient formative studies, design improvements were made to address problems and mitigate risks thought to be associated with a suboptimal system design or patient understanding of the system. In the validation study of the patient interface, 35 patients attempted 23 performance tasks, for a total of 805 attempts; 783/805 attempts were completed with success. One close call, 15 failures, and 6 difficulties occurred on these user tasks; only 3 of these were on a critical task. Residual risks resistant to mitigation were found to be of low severity based on the US Food and Drug Administration 2016 guidance. Conclusion: The final design of the DMS reflects input by the intended user populations through a comprehensive development methodology. In alignment with the US Food and Drug Administration goals for HF studies, the system was found to be safe and effective for the intended users, uses, and use environments. PMID- 29497301 TI - Vitamin D and vitamin D receptor levels in children with attention deficit/hyperactivity disorder. AB - Objective: In this study, we aimed to evaluate vitamin D and vitamin D receptor levels in children with attention-deficit/hyperactivity disorder (ADHD). Patients and methods: In this cross-sectional study, a total of 80 children including 40 ADHD patients (aged 6-12 years; 28 males and 12 females) and 40 age-, sex-, and season of blood collection-matched controls (aged 6-12 years; 25 males and 15 females) were enrolled. Serum vitamin D and vitamin D receptor levels and calcium, phosphorus, and alkaline phosphatase were measured. The vitamin D receptor levels in the serum were measured using the quantitative sandwich enzyme immunoassay technique. Results: Serum vitamin D and vitamin D receptor levels were found to be significantly lower in children with ADHD compared to healthy controls. No significant differences were found in serum calcium, phosphorus, and alkaline phosphatase levels. No significant differences were found among the ADHD subtypes in terms of serum vitamin D, vitamin D receptor, calcium, phosphorus and alkaline phosphatase levels. Conclusion: This study suggests that children with ADHD have lower levels of vitamin D and vitamin D receptor. According to the authors' knowledge, this is the first study to describe vitamin D receptor levels in ADHD. PMID- 29497300 TI - Drug-drug interactions involving antidepressants: focus on desvenlafaxine. AB - Psychiatric and physical conditions often coexist, and there is robust evidence that associates the frequency of depression with single and multiple physical conditions. More than half of patients with depression may have at least one chronic physical condition. Therefore, antidepressants are often used in cotherapy with other medications for the management of both psychiatric and chronic physical illnesses. The risk of drug-drug interactions (DDIs) is augmented by complex polypharmacy regimens and extended periods of treatment required, of which possible outcomes range from tolerability issues to lack of efficacy and serious adverse events. Optimal patient outcomes may be achieved through drug selection with minimal potential for DDIs. Desvenlafaxine is a serotonin-norepinephrine reuptake inhibitor approved for the treatment of adults with major depressive disorder. Pharmacokinetic studies of desvenlafaxine have shown a simple metabolic profile unique among antidepressants. This review examines the DDI profiles of antidepressants, particularly desvenlafaxine, in relation to drugs of different therapeutic areas. The summary and comparison of information available is meant to help clinicians in making informed decisions when using desvenlafaxine in patients with depression and comorbid chronic conditions. PMID- 29497303 TI - Red blood cell distribution width and the risk of being in poor glycemic control among patients with established type 2 diabetes. AB - Background: The red cell distribution width (RDW) has been shown to be associated with the incidence and complications of type 2 diabetes (T2D). However, the relevance of RDW with the risk of being in poor glycemic control among patients with established T2D is largely overlooked. Methods: A total of 702 T2D participants from the REACTION study were enrolled in this study. Blood routine index, fasting plasma glucose, hemoglobin A1c and lipid profile data were available for all of the enrolled population. Results: The univariate logistic analysis revealed a significant association between RDW and the risk of being in poor glycemic control among T2D subjects with an odds ratio (OR) and a 95% confidence interval (CI) of 0.5 and 0.3-0.8, respectively, for the fourth vs the first quartile of RDW. The association strengthened after multivariable adjustment (OR [95% CI]: 0.3 [0.2-0.7]). Interaction and stratified analyses indicated that this association was seen only among T2D subjects with lower body mass index and/or serum lipid levels. Conclusion: T2D patients with higher RDW had significantly lower risk of being in poor glycemic control. RDW may contribute to risk assessment for T2D individuals at risk of being in poor glycemic control. PMID- 29497302 TI - High serum levels of 8-OHdG are an independent predictor of post-stroke depression in Chinese stroke survivors. AB - Purpose: Although previous studies have investigated oxidative stress biomarkers in association with depression in non-stroke subjects, the association between oxidative deoxyribonucleic acid damage and post-stroke depression (PSD) remains unelucidated. Patients and methods: Two hundred forty-one first-ever ischemic stroke patients were consecutively recruited within the first 24 h of stroke onset and were followed up at 1 month. Serum 8-hydroxy-2'-deoxyguanosine (8-OHdG) and catalase (CAT) levels were measured within 24 h of admission using a commercially available enzyme-linked immunosorbent assay. The 17-item Hamilton Depression Scale was used to evaluate depressive symptoms. Diagnosis of PSD was made in line with the Diagnostic and Statistical Manual of Mental Disorders, 4th edition criteria for depression. Results: Serum levels of 8-OHdG (P<0.001) and CAT (P=0.025) increased in depressed patients at admission. A positive correlation was found between the 8-OHdG and CAT levels in both the total stroke patients (r=0.320, P<0.001) and the depressed patients (r=0.300, P=0.012). The 8 OHdG levels were positively correlated with the 17-item Hamilton Depression Scale scores (r=0.129, P=0.046) in depressed patients. Multivariate analyses found that 8-OHdG levels >=200.0 ng/L were independently associated with PSD (odds ratio, 7.477; 95% CI, 3.342-16.289, P<0.001) after adjusting for possible relevant confounders. Conclusion: Higher serum 8-OHdG levels at admission were found to be correlated with PSD 1 month after stroke. PMID- 29497304 TI - Insulin treatment reverses the increase in atrogin-1 expression in atrophied skeletal muscles of diabetic rats with acute joint inflammation. AB - Background: The aim of this study was to evaluate the changes in biomarkers of skeletal muscle proteolysis (atrogin-1, muscle RING finger-1 protein [MuRF-1]) and inflammation (nuclear factor kappa-B) in skeletal muscles of rats under two catabolic conditions, diabetes mellitus (DM) and acute joint inflammation, and the effects of insulin therapy. Materials and methods: Male Wistar rats were divided into groups without diabetes - normal (N), saline (NS), or iota carrageenan (NCa) injection into the tibiotarsal joint - and groups with diabetes - diabetes (D), plus insulin (DI), saline (DS), or iota-carrageenan (DCa) injection into the tibiotarsal joint, or iota-carrageenan injection and treatment with insulin (DCaI). Three days after iota-carrageenan injection (17 days after diabetes induction), tibialis anterior (TA) and soleus (SO) skeletal muscles were used for analysis. Results: DM alone caused a significant decrease in the mass of TA and SO muscles, even with low levels of atrogenes (atrogin-1, MuRF-1), which could be interpreted as an adaptive mechanism to spare muscle proteins under this catabolic condition. The loss of muscle mass was exacerbated when iota carrageenan was administered in the joints of diabetic rats, in association with increased expression of atrogin-1, MuRF-1, and nuclear factor kappa-B. Treatment with insulin prevented the increase in atrogin-1 (TA, SO) and the loss of muscle mass (SO) in diabetic-carrageenan rats; in comparison with TA, SO muscle was more responsive to the anabolic actions of insulin. Conclusion: Acute joint inflammation overcame the adaptive mechanism in diabetic rats to prevent excessive loss of muscle mass, worsening the catabolic state. The treatment of diabetic-carrageenan rats with insulin prevented the loss of skeletal muscle mass mainly via atrogin-1 inhibition. Under the condition of DM and inflammation, muscles with the prevalence of slow-twitch, type 1 fibers were more responsive to insulin treatment, recovering the ability to grow. PMID- 29497305 TI - Intraoperative dexmedetomidine attenuates postoperative systemic inflammatory response syndrome in patients who underwent percutaneous nephrolithotomy: a retrospective cohort study. AB - Purpose: Dexmedetomidine (DEX) has been reported to attenuate inflammation in rats. The present retrospective cohort study aimed to investigate whether intraoperative administration with DEX could reduce the incidence of postoperative systemic inflammatory response syndrome (SIRS) in patients following percutaneous nephrolithotomy (PCNL). Patients and methods: A total of 251 patients were included in the analysis. Among these patients, 175 received intravenous DEX infusion during the intraoperative period and 76 did not. The primary outcome measures were the incidences of postoperative SIRS and fever. Secondary outcomes included patient-controlled analgesia (tramadol) requirements, length of postoperative hospitalization stay, serum creatinine (Scr) and serum blood urea nitrogen (BUN) concentration, and adverse events (bradycardia, hypotension, renal artery thrombosis). Results: Administration of DEX not only significantly attenuated the incidence of SIRS and fever (P=0.029, P=0.042, respectively), but also reduced analgesia requirements (P=0.028). The length of postoperative hospitalization stay, Scr and BUN concentration, and adverse events did not differ significantly between the two groups. Further univariate and multivariate logistic regression analysis indicated that intraoperative DEX administration was a protective factor against SIRS after PCNL (OR 0.476 [95% CI: 0.257-0.835]; P=0.019). Conclusion: Intraoperative administration of DEX might be associated with reductions in the incidences of SIRS and fever after PCNL. PMID- 29497307 TI - Pain Management: Time to Minimize Variations in Practice. AB - There continue to be great variations in the management of pain in palliative care. Efforts need to be made within the field develop strategies to address this to avoid undue distress in patients. PMID- 29497306 TI - New developments in the management of head and neck cancer - impact of pembrolizumab. AB - Head and neck squamous cell carcinoma (HNSCC), a heterogeneous group of upper aerodigestive tract malignancies, is the seventh most common cancer worldwide. Tobacco use and alcohol consumption were the most identified risk factors of HNSCC. However, human papilloma virus, a sexually transmitted infection, has been determined as another primary cause of HNSCC. Early-stage disease is treated with surgery or radiotherapy. Recurrent or metastatic HNSCC is associated with poor prognosis with a median overall survival of 10 months. The EXTREME protocol is commonly used in first-line setting. Recently, pembrolizumab, an anti-programmed death-1 agent, has been approved by the US Food and Drug Administration for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck with disease progression on or after a platinum-based therapy. It demonstrated a durable objective response rate with a good safety profile and quality of life. Many ongoing trials are evaluating the use of pembrolizumab for the treatment of HNSCC in various indications such as adjuvant and neoadjuvant setting, maintenance and recurrent disease, alone or in combination with chemotherapy, radiation and targeted therapy. Finding those biomarkers predictive of response to immune checkpoints inhibitors has been a major concern. However, markers have been identified, such as PD-L1 expression, human papilloma virus infection, interferon-gamma signature score, microsatellite instability and neoantigen production. PMID- 29497308 TI - Insights Into the Environmental Health Burden of Childhood Asthma. PMID- 29497309 TI - An Operational Evaluation of 3 Methoprene Larvicide Formulations for Use Against Mosquitoes in Catch Basins. AB - Effectiveness in controlling mosquitoes in storm water catch basins in the North Shore Mosquito Abatement District (northeastern Cook County, Illinois) was determined for 3 formulations of methoprene-based larvicides (Altosid XR 150-day Briquets, Altosid 30-day Pellets, Altosid 30-day Granules) in 2017 using a pass/fail evaluation criterion, in which emergence of a single adult from pupae collected from the basin constituted a control failure. Over the course of the 16 week study, basins receiving the 150-day briquets were treated once and basins receiving the pellet and granular formulations were treated every 4 weeks, with the first treatment occurring during the last week of May. Untreated basins were also observed for comparison with the treated basins. Over the course of the study, adult mosquitoes emerged from pupae collected in 94.2% of the untreated basins that contained pupae. All of the formulations evaluated in the study demonstrated some degree of control compared with the untreated basins, with pupae successfully emerging as adults in 64.6%, 55.5%, and 21.8% of samples from 150-day briquet, 30-day tablet, and 30-day pellet-treated basins that contained pupae, respectively. Pellets reapplied every 28 days provided significantly more effective control than the other formulations. The simple pass/fail criterion for evaluating control effectiveness proved to be a useful procedure for comparing effectiveness to untreated basins and among treatments. PMID- 29497310 TI - ISL1 is upregulated in breast cancer and promotes cell proliferation, invasion, and angiogenesis. AB - ISL1 plays a key role in several cancers, including pheochromocytoma, gastrointestinal, pancreatic, and lung tumors and bile duct carcinoma. In order to elucidate the role of ISL1 in breast cancer, we performed quantitative real time polymerase chain reaction and Western blotting analysis, and we found that ISL1 was upregulated in breast cancer cells and tissues. Moreover, high expression of ISL1 was correlated with tumor size, metastasis, and poor prognosis. Colony formation analysis and CCK-8 analysis revealed that ISL1 facilitated breast cancer cell proliferation. In addition, wound healing analysis and transwell invasion analysis demonstrated that ISL1 played a role in cell migration and invasion. Interestingly, the expression of ISL1 was also associated with the expression of vascular endothelial growth factor (VEGF) in breast cancer, and ISL1 promoted angiogenesis in breast cancer. In conclusion, reducing the expression of ISL1 suppresses proliferation, migration, invasion, and angiogenesis in breast cancer, suggesting that ISL1 might serve as a novel molecular therapy target in breast cancer. PMID- 29497311 TI - The association between HOTAIR polymorphisms and cancer susceptibility: an updated systemic review and meta-analysis. AB - Objectives: This work aims to explore whether HOX transcript antisense intergenic RNA (HOTAIR) polymorphisms are associated with cancer susceptibility. Materials and methods: A comprehensive search was conducted for literature published from January 2007 to July 2017. The pooled odds ratios (ORs) and the corresponding 95% CIs were calculated using the Revman 5.2 software. Eighteen articles of 36 case control studies were enrolled including six HOTAIR polymorphisms and 10 cancer types. Results: The results showed that cancer risk was elevated in recessive mutation of rs12826786 (TT vs CC+CT: OR =1.55, 95% CI =1.19, 2.03; TT+CT vs CC: OR =1.23, 95% CI =1.04, 1.46; TT vs CC: OR =1.67, 95% CI =1.24, 2.24; T vs C: OR =1.24, 95% CI =1.09, 1.40) and rs920778 (TT vs CC+CT: OR =1.73, 95% CI =1.30, 2.30; TT+CT vs CC: OR =1.40, 95% CI =1.16, 1.70; TT vs CC: OR =1.83, 95% CI =1.25, 2.68; T vs C: OR =1.37, 95% CI =1.18, 1.59), while the results for polymorphisms of rs7958904, rs4759314, rs874945, and rs1899663 were insignificant. The stratified results for Chinese population were consistent with the overall group analysis. Conclusion: Our meta-analysis showed that HOTAIR polymorphisms of rs12826786 and rs920778 were correlated with increased cancer risk, while rs7958904, rs4759314, rs874945, and rs1899663 were not. More studies with different types of cancer are needed to confirm the findings. PMID- 29497312 TI - Clinical significance of quantitative HER2 gene amplification as related to its predictive value in breast cancer patients in neoadjuvant setting. AB - Background: The aims of this study were to determine whether the quantitative HER2 gene amplification level is related to the key clinicopathological features that represent the aggressiveness of breast cancer (BC) and to determine whether the quantitative HER2 gene amplification level could predict the treatment response in the subset of HER2-positive patients who received neoadjuvant targeted therapy. Materials and methods: Patients treated with weekly cisplatin- and paclitaxel-based neoadjuvant chemotherapy, who had undergone both immunohistochemistry and the fluorescence in situ hybridization test for HER2, were included in the study (n=103). For HER2-positive patients, defined as immunohistochemistry score 3+ or fluorescence in situ hybridization ratio >=2.0, trastuzumab was recommended with neoadjuvant chemotherapy (n=45). Pathological complete response was defined as complete pathological remission of tumor cells both in breast and axillary lymph nodes postoperation. Results: In all patients enrolled in the study, a higher HER2 amplification level was significantly correlated with larger tumor size and the absence of ER and PR expression. In HER2-positive patients treated with neoadjuvant trastuzumab concurrent with chemotherapy, both univariate and multivariate logistic regression showed that a higher HER2/CEP17 ratio and HER2 gene copy number were associated with a higher pathological complete response rate. When calculated by receiver operating characteristics analysis, an optimal cutoff of 4.5 for the HER2/CEP17 ratio was expected to distinguish the most sensitive candidate for treatment with a combination of trastuzumab and neoadjuvant chemotherapy. Conclusion: A higher HER2 amplification level was correlated with larger tumor size and reduced ER and PR expression, which may indicate more aggressive tumor behavior. For HER2 positive patients, the HER2/CEP17 ratio and HER2 gene copy number may be good predictive factors for concurrent neoadjuvant trastuzumab and chemotherapy. PMID- 29497313 TI - Knockdown of KLK11 reverses oxaliplatin resistance by inhibiting proliferation and activating apoptosis via suppressing the PI3K/AKT signal pathway in colorectal cancer cell. AB - Introduction: Kallikrein 11 (KLK11) plays a crucial role in drug-resistance to oxaliplatin (L-OHP) in the treatment of metastatic colorectal cancer (mCRC). The study aimed to investigate the role of KLK11 in chemoresistance, and to clarify the mechanism underlying reverse of L-OHP resistance by knockdown of KLK11. Materials and Methods: Resistance to oxaliplatin was induced in HCT-8 (HCT-8/L OHP) colorectal adenocarcinoma cell lines by exposing cells to increasing concentrations of L-OHP. MTT, RT-qPCR, and Western blot were used to evaluate the resistance to L-OHP. We then knocked down KLK11 in HCT-8/L-OHP cells to explore the mechanism through which KLK11 reverses L-OHP resistance. The mRNA and protein expression of KLK11 in tissues from mCRC patients were detected by RT-qPCR and immunohistochemistry. Results: The drug resistance index (RI) of HCT-8/L-OHP cell line to L-OHP, 5-Fluorouracil (5-FU), Irinotecan (CPT-11), Vincristine (VCR) and Cis-diamminedichloroplatinum (CDDP) were 10, 5.35, 3.23, 1.28, and 6.64, respectively. Increased expression of multi-drug resistant genes ABCC1, ABCB1, GSTP1 and ERCC1 were detected in HCT-8/L-OHP cell line. Moreover, the activated PI3K/AKT pathway was related to L-OHP-resistance. Knockdown of KLK11 in HCT-8/L OHP cell reversed L-OHP-resistance by inhibiting cell growth and activating apoptosis via suppressing the PI3K/AKT signaling pathway. Moreover, high expression of KLK11 in chemoresistant-patients was associated with lymph node metastases and histopathology. Conclusion: KLK11 was highly expressed in chemoresistant-patients and L-OHP-resistant cell lines. Moreover, L-OHP resistance was associated with activated PI3K/AKT signal pathway. Knockdown of KLK11 can reverse L-OHP resistance by blocking PI3K/AKT signaling pathway. PMID- 29497314 TI - MiR-1180-5p regulates apoptosis of Wilms' tumor by targeting p73. AB - Introduction: Wilms' tumor (WT), the most common childhood tumor, occurs in sporadic or familial forms. Recent findings reported that abnormal expression in microRNA (miRNA) suggests an important role of miRNAs during WT progress. MiRNAs are endogenous short-chain noncoding RNAs, which have been reported as key biomarkers for detecting tumor onset and progression. However, the functional role of miR-1180 in WT has remained unknown. Materials and methods: MTT and clonogenic survival assays were used to detect WT cell proliferation. Flow cytometry Annexin V-FITC was used to measure apoptosis. In addition, proteins expressions in the cells were determined by Western blotting. Results: In the present study, we demonstrated that miR-1180 is upregulated in WT when compared with adjacent tissues by quantitative reverse-transcription polymerase chain reaction. In addition, the inhibition of miR-1180 induced apoptosis in SK-NEP-1 cell line in vitro. Moreover, luciferase reporter assay showed that p73 protein was the target of miR-1180, which was confirmed by the results of Western blotting. Finally, in vivo data indicated that the tumor growth in mice was significantly inhibited by miR-1180 inhibitor. Conclusion: Our results indicate that miR-1180 might serve as a therapeutic target for future WT therapy. PMID- 29497315 TI - Developments in the management of advanced soft-tissue sarcoma - olaratumab in context. AB - Lartruvo(r) (olaratumab) is a fully human immunoglobulin G subclass 1 (IgG1) monoclonal antibody that inhibits platelet-derived growth factor receptor alpha (PDGFRalpha). The antitumor activity of olaratumab has been tested in vitro and in vivo, and inhibition of tumor growth has been observed in cancer cell lines, including glioblastoma and leiomyosarcoma cells. It represents the first-in-class antibody to be approved by regulatory authorities for the treatment of advanced soft-tissue sarcomas (STSs) in combination with doxorubicin, based on the results of the Phase Ib/II trial by Tap et al. The median progression-free survival (PFS), which was the primary end point of the study, was improved for patients treated with olaratumab plus doxorubicin compared to those treated with doxorubicin monotherapy (6.6 vs 4.1 months, respectively; HR 0.672, 95% CI 0.442 1.021, p=0.0615). Moreover, final analysis of overall survival (OS) showed a median OS of 26.5 months with olaratumab plus doxorubicin vs 14.7 months with doxorubicin, with a gain of 11.8 months (HR 0.46, 95% CI 0.30-0.71, p=0.0003). In October 2016, olaratumab was admitted in the Accelerated Approval Program by the US Food and Drug Administration (FDA) for use in combination with doxorubicin for the treatment of adult patients with STSs. In November 2016, the European Medicines Agency (EMA) granted conditional approval for olaratumab in the same indication under its Accelerated Assessment Program. A double-blind, placebo controlled, randomized Phase III study (ANNOUNCE trial, NCT02451943) is being performed in order to confirm the survival advantage of olaratumab and to provide definitive drug confirmation by regulators. The study is ongoing, but enrollment is closed. The purpose of this review was to evaluate the rationale of olaratumab in the treatment of advanced STSs and its emerging role in clinical practice. PMID- 29497316 TI - Interleukin-33 enhanced the migration and invasiveness of human lung cancer cells. AB - Aim: Interleukin-33 (IL-33), belonging to IL-1 family cytokines, has been reported to participate in cancer growth and metastasis. The clinical values of IL-33 in lung cancer have been previously investigated. We aimed to elucidate the probable role of IL-33 in the migration and invasion of lung cancer cells. Methods: Cell migration and invasiveness were tested by Transwell assay. Western blotting analysis was performed to detect protein expression. Results: We found that IL-33 treatment in human lung A549 cells dose-dependently enhanced their migratory and invasive ability, accompanied by elevated expression of matrix metallo-proteinase (MMP) 2 and MMP9. Meanwhile, IL-33-induced cell migration and invasion were significantly abolished by small interfering RNA-targeting ST2, the specific receptor of IL-33. Furthermore, IL-33 exposure induced the phosphorylation of AKT. Pretreatment with an AKT inhibitor LY294002 markedly attenuated IL-33-induced cell migration and invasion. Conclusion: IL-33/ST2 promoted the migration and invasiveness of lung cancer cells through AKT pathway. Our findings strongly suggest that IL-33 may serve as a promising therapeutic strategy for lung cancer. PMID- 29497317 TI - Effects of four single nucleotide polymorphisms of EZH2 on cancer risk: a systematic review and meta-analysis. AB - Background: Although the relationship between several single nucleotide polymorphisms (SNPs) of the oncogene EZH2 and cancer risk has been assessed by some case-control studies, results of subsequent studies are controversial. Sample sizes from single-center studies are also limited, thereby providing unreliable findings. Hence, we conducted a comprehensive search and meta-analysis to evaluate the associations between EZH2 SNPs and cancer risk. Materials and methods: A comprehensive literature search for studies focusing on EZH2 SNPs and cancer risk was conducted on PubMed, Web of Science, Embase, and China National Knowledge Infrastructure online databases. Genotype data were extracted and examined through a meta-analysis, and pooled odds ratios (ORs) with 95% CIs were used to assess the corresponding associations. Sensitivity analysis, publication bias assessment, and heterogeneity test were performed using STATA 12.0. Results: Twelve eligible studies were included in this meta-analysis. The association of 4 SNPs, namely, rs887569, rs2302427, rs3757441, and rs41277434, in the EZH2 locus with cancer risk was evaluated. Five studies (1,794 cases and 1,878 controls) indicated that rs887569 was related to a decreased cancer risk (CTTT/CC: OR =0.849, 95% CI: [0.740 to 0.973], P=0.019; TT/CCCT: OR =0.793, 95% CI: [0.654 to 0.962], P=0.019). Seven studies (2,408 cases and 2,910 controls) showed that rs2302427 was linked to a decreased cancer risk (GG/CC: OR =0.562, 95% CI: [0.400 to 0.792], P=0.001; CGGG/CC: OR =0.856, 95% CI: [0.748 to 0.980], P=0.024; GG/CCCG: OR =0.733, 95% CI: [0.571 to 0.940], P=0.015). No relationships were observed between rs3757441 or rs41277434 and cancer risk. Conclusion: rs887569 and rs2302427 in EZH2 may be correlated with a decreased cancer risk. Although rs3757441 and rs41277434 are independent risk factors of cancer, further large scale and functional studies are warranted to validate our findings. PMID- 29497318 TI - Klotho ameliorates sepsis-induced acute kidney injury but is irrelevant to autophagy. AB - Background: The role of Klotho (KL) in sepsis-induced acute kidney injury (AKI) and the potential relationship between KL and autophagy in septic AKI were investigated. Materials and methods: A murine model of sepsis-induced AKI was established by cecal ligation and puncture (CLP). Mice undergoing CLP and immortalized proximal tubular epithelial human HK-2 cells that were exposed to lipopolysaccharide (LPS) were treated with recombinant KL, autophagy stimulator rapamycin (Rap), and autophagy suppressor 3-methyladenine (3-MA). Results: Autophagy activation and KL reduction reached maximum levels in mice 24 hours after CLP. Recombinant KL and/or Rap significantly attenuated CLP-induced renal dysfunction (P<0.05) and partially restored endogenous renal KL expression (P<0.05). Recombinant KL had no impact on CLP-induced autophagy and apoptosis, whereas Rap significantly stimulated autophagy and reduced apoptosis in mice. 3 MA significantly exacerbated renal dysfunction, increased apoptosis, and inhibited autophagy in mice with CLP-induced AKI (all P<0.05). In LPS-treated HK 2 cells, Rap significantly enhanced autophagy and reduced apoptosis (all P<0.05), whereas recombinant KL had no impact, and 3-MA inhibited autophagy and significantly increased apoptosis (P<0.05). Conclusion: Recombinant KL alleviates renal dysfunction and restores renal KL expression in mice with sepsis-induced AKI, but the underlying mechanism may not be related to autophagy induction. PMID- 29497319 TI - Successful treatment of metastatic colorectal cancer with apatinib: report of two cases and literature review. AB - Apatinib, a novel small molecule tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor-2, was approved for metastatic gastric adenocarcinoma in China in Oct 2014. This is the first report on its use for advanced colorectal cancer as a kind of third-line therapy to date. Here we report two Chinese patients who presented with metastatic colorectal cancer who received apatinib 850 mg daily as a third-line therapy. Both the patients achieved favorable benefits in outcomes after the administration of apatinib. Patient 1 benefited 4 months progression-free survival and 11 months overall survival, while patient 2's progression-free survival was over 10 months. Both the patients presented hand-foot syndrome, and one of them suffered a slight impairment of liver function, mild elevated blood pressure, and proteinuria. But these adverse events were manageable with symptomatic treatment and dose reduction or a short-time drug withdrawal. PMID- 29497320 TI - Bone marrow mesenchymal stem cells as nuclear donors improve viability and health of cloned horses. AB - Introduction: Cell plasticity is crucial in cloning to allow an efficient nuclear reprogramming and healthy offspring. Hence, cells with high plasticity, such as multipotent mesenchymal stem cells (MSCs), may be a promising alternative for horse cloning. In this study, we evaluated the use of bone marrow-MSCs (BM-MSCs) as nuclear donors in horse cloning, and we compared the in vitro and in vivo embryo development with respect to fibroblasts. Materials and methods: Zona-free nuclear transfer was performed using BM-MSCs (MSC group, n=3432) or adult fibroblasts (AF group, n=4527). Embryos produced by artificial insemination (AI) recovered by uterine flushing and transferred to recipient mares were used as controls (AI group). Results: Blastocyst development was higher in the MSC group than in the AF group (18.1% vs 10.9%, respectively; p<0.05). However, pregnancy rates and delivery rates were similar in both cloning groups, although they were lower than in the AI group (pregnancy rates: 17.7% [41/232] for MSC, 12.5% [37/297] for AF and 80.7% [71/88] for AI; delivery rates: 56.8% [21/37], 41.5% [17/41] and 90.1% [64/71], respectively). Remarkably, the gestation length of the AF group was significantly longer than the control (361.7+/-10.9 vs 333.9+/-8.7 days), in contrast to the MSC group (340.6+/-8.89 days). Of the total deliveries, 95.2% (20/21) of the MSC-foals were viable, compared to 52.9% (9/17) of the AF foals (p<0.05). In addition, the AF-foals had more physiological abnormalities at birth than the MSC-foals; 90.5% (19/21) of the MSC-delivered foals were completely normal and healthy, compared to 35.3% (6/17) in the AF group. The abnormalities included flexural or angular limb deformities, umbilical cord enlargement, placental alterations and signs of syndrome of neonatal maladjustment, which were treated in most cases. Conclusion: In summary, we obtained 29 viable cloned foals and found that MSCs are suitable donor cells in horse cloning. Even more, these cells could be more efficiently reprogrammed compared to fibroblasts. PMID- 29497321 TI - A cost-utility analysis of small bite sutures versus large bite sutures in the closure of midline laparotomies in the United Kingdom National Health Service. AB - Purpose: This study aimed to perform an economic evaluation of small bite sutures versus large bite sutures in the closure of midline laparotomies in the United Kingdom National Health Service (NHS). Methods: A cost-utility analysis was conducted using data from a systematic literature review. Large bite sutures placed 10 mm from the wound edge were compared to small bite sutures 3-6 mm from the wound edge. The analysis used a 3-year time horizon in order to take into account complications including incisional hernias and surgical site infections (SSIs). Cost and benefit data were considered from the perspective of the NHS. A two-way sensitivity analysis was conducted to assess the impact of a variation in the clinical effectiveness of small bite sutures. Results: The incremental cost effectiveness ratio was calculated to be -L482.61 per quality-adjusted life year (QALY) using the proposed small bite suture technique, indicating a cost saving to the NHS. Sensitivity analysis demonstrated that small bites are a cost-neutral technique provided that the cost of using small bites is less than L98 per patient. Small bites cost less than L20,000/QALY when they reduce either the rate of SSIs by more than 15% or the rate of hernias by more than 3.4%. Conclusion: This study proposes that small bite sutures should become the mainstay suturing technique in the closure of midline laparotomies, replacing large bite sutures, which dominate current practice. The financial savings accompanied by the decrease in SSI rates and herniation warrant the use of this new technique. The sensitivity analysis demonstrates that findings hold true for a wide range of levels of clinical effectiveness for small bites. PMID- 29497322 TI - Early laparoscopic cholecystectomy is more cost-effective than delayed laparoscopic cholecystectomy in the treatment of acute cholecystitis. AB - Background: This economic evaluation quantifies the cost-effectiveness of early laparoscopic cholecystectomy (ELC) versus delayed laparoscopic cholecystectomy (DLC) in the management of acute cholecystitis. The two interventions were assessed in terms of outcome measures, including utilities, to derive quality adjusted life years (QALYs) as a unit of effectiveness. This study hypothesizes that ELC is more cost-effective than DLC. Materials and methods: In this economic evaluation, existing literature was compiled and analyzed to estimate the incremental cost-effectiveness of ELC versus DLC. Six randomized controlled trials were used to schematically represent the probabilities of each decision tree branch. To calculate health outcomes, quality of life scores were sourced from three articles and multiplied by the expected length of life postintervention to give QALYs. From an National Health Service (NHS) perspective, one QALY may be sacrificed if the incremental cost-effectiveness ratio is above L20,000-L30,0000 in cost savings. Results: This economic evaluation calculated the average net present values of ELC to be L3920 and DLC to be L4565, demonstrating that ELC is the less-expensive intervention, with potential cost savings of L645 per operation. When scaling these savings up to a population approximately comparable to the size of the UK, full-scale implementation of ELC rather than DLC will potentially save the NHS L30,000,000 per annum. Conclusion: ELCs are cost-effective from the perspective of the NHS. As such, policy should review existing guidelines and consider the merits of ELC versus DLC, improving resource allocation. The findings of this article advocate that ELC should become a standard practice. PMID- 29497323 TI - Bouveret syndrome: current management strategies. AB - Bouveret syndrome is a rare complication of cholelithiasis that usually presents with signs and symptoms of gastric outlet obstruction. Given the relative rarity of this condition, there are no standardized guidelines for the management of this condition. In this paper, we review the diagnosis and management options (endoscopic, laparoscopic, and open approaches) of patients with Bouveret syndrome, including a report of one case to illustrate some of the endoscopic and surgical principles of management. PMID- 29497324 TI - Inflammation and oxidative stress markers in diabetes and hypertension. AB - Background: Inflammation and oxidative stress are important factors associated with chronic disease such as essential hypertension (HTN) and type 2 diabetes mellitus (T2DM). However, the association of inflammation and oxidative stress in HTN with T2DM as a comorbidity is inconclusive due to the multifactorial nature of these cardiometabolic diseases. Methodology: The influence of pathophysiological factors include genetics, age of patient, and disease progression change throughout the lifespan and require further investigation. The study population included 256 participants attending a rural health screening program who were tested for markers of inflammation, oxidative stress, and coagulation/fibrinolysis. Demographic and clinical variables included, age, gender, systolic and diastolic blood pressures, blood glucose, hemoglobin A1c, estimated glomerular filtration rate, and cholesterol profile. Data were tested for normality, and nonparametric statistics were applied to analyze the sample with significance set at p<0.05. Results: Of the inflammatory markers, interleukin-1beta (IL-1beta) and IL-10 were significantly different between the control and hypertensive group (p<0.03) and between the HTN+T2DM compared to the HTN group (p<0.05). Significant results for oxidative stress were observed for urinary 8-iso-PGF2alpha and insulin-like growth factor 1 (IGF-1) between the control and the HTN+T2DM group (p<0.01). Glutathione (GSH) was also significant between the HTN and HTN+T2DM group (p<0.05). Investigation of the progression of HTN also found significant changes in the inflammatory markers IGF-1, monocyte chemoattractant protein 1 (MCP-1), and (MCP-1/IGF-1)*IL-6 (p<0.05). Conclusion: This study demonstrated that 8-iso-PGF2alpha and erythrocyte GSH may be clinically useful for assessing HTN and HTN with T2DM as a comorbidity, while significant changes in the inflammatory profile were also observed with HTN progression. PMID- 29497326 TI - Which attributes of whole genome sequencing tests are most important to the general population? Results from a German preference study. AB - Objective: The aim of this study was to identify the preferences for whole genome sequencing (WGS) tests without genetic counseling. Methods: A discrete choice experiment was conducted where participants chose between two hypothetical alternatives consisting of the following attributes: test accuracy, test costs, identified diseases, probability of disease occurrence, and data access. People from the general German population aged >=18 years were eligible to participate in the survey. We estimated generalized linear mixed effects models, latent class mixed-logit models, and the marginal willingness to pay. Results: Three hundred and one participants were included in the final analysis. Overall, the most favored WGS testing attributes were 95% test accuracy, report of severe hereditary diseases and 40% probability of disease development, test costs of ?1,000, and access to test results for researchers. Subgroup analysis, however, showed differences in these preferences between males and females. For example, males preferred reporting of results at a 10% probability of disease development and females preferred reporting of results at a 40% probability. The test cost, participant's educational level, and access to data influenced the willingness to participate in WGS testing in reality. Conclusion: The German general population was aware of the importance of genetic research and preferred to provide their own genetic data for researchers. However, among others, the reporting of results with a comparatively relatively low probability of disease development at a level of 40%, and the test accuracy of 95% had a high preference. This shows that the results and consequences of WGS testing without genetic counseling are hard to assess for individuals. Therefore, WGS testing should be supported by qualified genetic counseling, where the attributes and consequences are explained. PMID- 29497327 TI - Erratum: Perirenal fat stranding is not a powerful diagnostic tool for acute pyelonephritis [Corrigendum]. AB - [This corrects the article on p. 137 in vol. 10, PMID: 28507449.]. PMID- 29497325 TI - The importance of the thick ascending limb of Henle's loop in renal physiology and pathophysiology. AB - The thick ascending limb (TAL) of Henle's loop is a crucial segment for many tasks of the nephron. Indeed, the TAL is not only a mainstay for reabsorption of sodium (Na+), potassium (K+), and divalent cations such as calcium (Ca2+) and magnesium (Mg2+) from the luminal fluid, but also has an important role in urine concentration, overall acid-base homeostasis, and ammonia cycle. Transcellular Na+ transport along the TAL is a prerequisite for Na+, K+, Ca2+, Mg2+ homeostasis, and water reabsorption, the latter through its contribution in the generation of the cortico-medullar osmotic gradient. The role of this nephron site in acid-base balance, via bicarbonate reabsorption and acid secretion, is sometimes misunderstood by clinicians. This review describes in detail these functions, reporting in addition to the well-known molecular mechanisms, some novel findings from the current literature; moreover, the pathophysiology and the clinical relevance of primary or acquired conditions caused by TAL dysfunction are discussed. Knowing the physiology of the TAL is fundamental for clinicians, for a better understanding and management of rare and common conditions, such as tubulopathies, hypertension, and loop diuretics abuse. PMID- 29497328 TI - Managing cluster headache with sphenopalatine ganglion stimulation: a review. AB - Cluster headache (CH) is a primary headache and considered as one of the worst pains known to man. The sphenopalatine ganglion (SPG) plays a pivotal role in cranial autonomic symptoms associated with pain. Lesioning procedures involving the SPG and experimental acute SPG stimulation have shown some degree of efficacy with regard to CH. A neuromodulation device, chronically implanted in the pterygopalatine fossa, has been specifically designed for acute on-demand SPG stimulation. In a pilot placebo-controlled study in 28 patients suffering from refractory chronic CH, alleviation of pain was achieved in 67.1% of full stimulation-treated attacks compared to 7% of sham stimulation-treated attacks (p<0.0001). Long-term results (24 months; 33 patients) confirmed the efficacy of SPG stimulation as an abortive treatment for CH attacks. Moreover, 35% of the patients observed a >50% reduction in attack frequency, suggesting that repeated use of SPG stimulation might act as a CH-preventive treatment. Globally, 61% of the patients were acute responders, frequency responders, or both, and 39% did not respond to SPG stimulation. The safety of SPG microstimulator implantation procedure was evaluated in a cohort of 99 patients; facial sensory disturbances were observed in 67% of the patients (46% of them being transient), transient allodynia in 3%, and infection in 5%. SPG stimulation appears as a promising innovative, efficient, and safe therapeutic solution for patients suffering from severe CH. It has shown its efficacy in aborting CH attacks compared to placebo stimulation, suggesting that it is particularly adapted for CH patients who are not sufficiently improved by abortive treatments such as sumatriptan and oxygen. However, further studies comparing SPG stimulation with standard abortive and/or preventive CH treatments will be necessary to define more precisely its place within the management of severe chronic and/or episodic CH. PMID- 29497329 TI - Evaluation of the safety and efficacy of an intravenous nanocrystal formulation of meloxicam in the management of moderate-to-severe pain after bunionectomy. AB - Objective: This randomized, double-blind, placebo-controlled study evaluated the safety and efficacy of an intravenous (IV) nanocrystal formulation of meloxicam in subjects with moderate-to-severe pain following a standardized unilateral bunionectomy. Methods: Fifty-nine subjects aged 18-72 years were randomized to receive doses of either 30 mg (n=20) or 60 mg (n=20) meloxicam IV or placebo (n=19), administered once daily as bolus IV injections over 15-30 seconds (two or three doses). Safety, the primary objective, was assessed by physical examination, clinical laboratory tests, and the incidence of adverse events (AEs). Efficacy was evaluated by examining summed pain intensity differences over the first 48 hours (SPID48) using analysis of covariance models. Use of opioid rescue analgesic agents was evaluated. Results: Generally, AEs were mild-to moderate in intensity, and their incidence was similar across the three treatment groups. No serious AEs were reported; there were no withdrawals due to AEs, including injection-related AEs. The estimated effect size for SPID48 versus placebo was 1.15 and 1.01 for meloxicam IV doses 30 mg and 60 mg, respectively (P<=0.01). Both doses produced significantly greater pain reductions versus placebo (P<=0.05) at all evaluated times/ intervals during the 48-hour period. The proportions of subjects with >=30% and >=50% overall reduction in pain from baseline after 6 and 24 hours were significantly higher with meloxicam IV 30 mg doses versus placebo, but not with meloxicam IV 60 mg doses. The time to first use of rescue medication was significantly longer versus placebo with meloxicam IV 60 mg (P<0.05), but not with meloxicam IV 30 mg doses. Conclusion: Meloxicam IV was generally safe and well tolerated in subjects with moderate-to-severe post bunionectomy pain. Once-daily administration of meloxicam IV 30 mg and 60 mg exhibited rapid onset of analgesia (as early as 15 minutes) with maintenance of analgesic effect for two consecutive 24-hour periods. PMID- 29497331 TI - The role of calgranulin B gene on the biological behavior of squamous cervical cancer in vitro and in vivo. AB - Objective: The objective of the study was to explore the role of calgranulin B gene on the biological behavior of squamous cervical cancer. Methods: Differential transcription in calgranulin B gene between human papillomavirus (HPV)-positive and negative cervical cancer groups was identified, and the relationship between calgranulin B gene and matrix metalloproteinase (MMP) genes were explored using The Cancer Genome Atlas database. Subsequently, the role of calgranulin B on the cell proliferation, apoptosis, invasion and migration was investigated, through overexpression and/or underexpression of calgranulin B in cervical cancer cells. In addition, the effect of calgranulin B on the growth of the cervical cancer was studied via constructing xenograft model in BALB/c nude mice that either overexpressed or underexpressed calgranulin B. Results: Calgranulin B gene transcription in cervical cancer was highly correlated with the high-risk HPV-16 and HPV-45. In addition, overexpression of calgranulin B increased cell proliferation, invasion and migration, whereas it did not significantly affect cell apoptosis. This effect was also confirmed by calgranulin B knockdown assay. Additionally, we found that the transcription of calgranulin B gene was negatively correlated with MMP15 and MMP24 genes, but positively associated with MMP25 genes in cervical cancer. Furthermore, calgranulin B significantly promoted the growth of cervical cancer in vivo. Conclusion: Calgranulin B promotes cell proliferation, migration and invasion of squamous cervical cancer, possibly via regulation of MMPs. Whether there are synergistic actions between calgranulin B and HPV-16/HPV-45 infection on the squamous cervical carcinogenesis or progression need further study. PMID- 29497330 TI - Does pain hypervigilance further impact the lack of habituation to pain in individuals with chronic pain? A cross-sectional pain ERP study. AB - Aim: In chronic pain, habituation is believed to be impaired, and pain hypervigilance can enhance the pain experience. The goal of this study was to determine whether pain hypervigilance further worsens habituation of event related potentials, measured in a pain-rating protocol of 25 painful somatosensory electrical stimuli, in patients with chronic pain. Methods: Pain hypervigilance was assessed with the Pain Vigilance Awareness Questionnaire and analyzed using the event-related fixed interval areas multilevel technique, which enables one to study within-session habituation. In a cohort of 111 participants, 33 reported chronic pain. This chronic pain group was compared with 33 pain-free individuals, matched for age and sex. Results: The relationship between pain status and habituation was not moderated by pain hypervigilance. Chronic pain status affected linear habituation and dishabituation (quadratic function) from 220 to 260 ms for nearly all electrodes, and from 580 to 640 ms for frontal electrodes. The effect of pain hypervigilance on habituation was observed primarily from 480 to 820 ms poststimulus for right-sided and central electrodes. Conclusion: Pain hypervigilance and chronic pain independently influence habituation to painful stimuli - although not synergistically. To confirm that these effects are mediated by separate pathways, further research is required, in which electroencephalography is combined with other modalities with adequate spatial resolution, such as functional magnetic resonance imaging. PMID- 29497333 TI - Patients with osteosarcoma and soft tissue sarcoma might become "cancer refugees" in some Japanese regional cities. AB - Purpose: "Rare cancer" is defined as malignancy with a disease prevalence (age adjusted incidence rate) of less than six per 100,000 population. Proper treatments which these patients need cannot always be performed unless they find dedicated facilities. Patients tend to be desperate, searching for advice and care. Thus, they are called "cancer refugees". Osteosarcoma and soft tissue sarcoma (OS/STS) are representative rare cancers in Japan. We conducted a retrospective analysis of patients with OS/STS to improve the current treatment modalities in a Japanese regional city. Patients and methods: Twenty-one patients with OS/STS who were hospitalized to receive standard chemotherapy or palliative treatment were enrolled between October 2011 and January 2017. Patients with non Hodgkin's lymphoma (NHL) and advanced cancer who were treated in the palliative care unit (PCU) of the Kawasaki Medical School General Medical Center were recruited as the control groups. We analyzed the difference in residential area between patients with OS/STS and the control groups. Results: Approximately one third of patients with OS/STS were referred from hospitals outside of Okayama prefecture. The ratio of patients with OS/STS referred from Okayama city and/or the same medical administration area of Okayama prefecture was lower than that of patients with NHL and advanced cancer who were treated in the PCU. Conclusion: Because the medical environment of patients with OS/STS in Japanese local cities has not been consolidated, completing medical care within the patient's own medical administration area is difficult. Thus, some patients with OS/STS may become "cancer refugees" who are unable to receive standard therapy near their residence. PMID- 29497332 TI - MicroRNA-mRNA expression profiles associated with medulloblastoma subgroup 4. AB - Purpose: Medulloblastoma (MB), the most common malignant brain tumor in children, is divided into four tumor subgroups: wingless-type (WNT), sonic hedgehog (SHH), Group 3, and Group 4. Ideally, clinical practice and treatment design should be subgroup specific. While WNT and SHH subgroups have well-defined biomarkers, distinguishing Group 3 from Group 4 is not straightforward. MicroRNAs (miRNAs), which regulate posttranscriptional gene expression, are involved in MB tumorigenesis. However, the miRNA-messenger RNA (mRNA) regulatory network in MB is far from being fully understood. Our aims were to investigate miRNA expression regulation in MB subgroups, to assess miRNA target relationships, and to identify miRNAs that can distinguish Group 3 from Group 4. Patients and methods: With these aims, integrated transcriptome mRNA and miRNA expression analysis was performed on primary tumor samples collected from 18 children with MB, using miRNA sequencing (miRNA-seq), RNA sequencing (RNA-seq), and quantitative PCR. Results: Of all the expressed miRNAs, 19 appeared to be significantly differentially expressed (DE) between Group 4 and non-Group 4 subgroups (false discovery rate [FDR] <0.05), including 10 miRNAs, which, for the first time, are reported to be in conjunction with MB. RNA-seq analysis identified 165 genes that were DE between Group 4 and the other subgroups (FDR <0.05), among which seven are predicted targets of five DE miRNAs and exhibit inverse expression pattern. Conclusion: This study identified miRNA molecules that may be involved in Group 4 etiology, in general, and can distinguish between Group 3 and Group 4, in particular. In addition, understanding the involvement of miRNAs and their targets in MB may improve diagnosis and advance the development of targeted treatment for MB. PMID- 29497334 TI - Marginal accuracy of computer-aided design- and computer-aided manufacturing fabricated full-arch zirconia restoration. AB - Objective: This study evaluated marginal accuracy of full-arch zirconia restoration fabricated from two digital computer-aided design and computer-aided manufacturing (CAD-CAM) systems (Trios-3 and CS3500) in comparison to conventional cast metal restoration. Materials and methods: A stainless steel model comprising two canine and two molar abutments was used as a master model for full-arch reconstruction. The canine and molar abutments were machined in a cylindrical shape with 5 degrees taper and chamfer margin. The CAD-CAM systems based on the digital approach were used to construct the full-arch zirconia restoration. The conventional cast metal restoration was fabricated according to a conventional lost-wax technique using nickel-chromium alloys. Ten restorations were fabricated from each system. The marginal accuracy of each restoration was determined at four locations for each abutment. An analysis of variance (ANOVA) and Tukey's honest significant difference (HSD) multiple comparisons were used to determine statistically significant difference at 95% confidence interval. Results: The mean values of marginal accuracy of restorations fabricated from conventional casting, Trios-3, and CS3500 were 48.59+/-4.16 MUm, 53.50+/-5.66 MUm, and 56.47+/-5.52 MUm, respectively. ANOVA indicated significant difference in marginal fit of restorations among various systems. The marginal discrepancy of zirconia restoration fabricated from the CS3500 system demonstrated significantly larger gap than that fabricated from the 3Shape system (p<0.05). Tukey's HSD multiple comparisons indicated that the zirconia restoration fabricated from either CS3500 or Trios-3 demonstrated a significantly larger marginal gap than the conventional cast metal restoration (p<0.05). Conclusion: Full-arch zirconia restoration fabricated from the Trios-3 illustrated better marginal fits than that from the CS3500, although, both were slightly less accurate than the conventional cast restoration. However, the marginal discrepancies of restoration produced by both CAD-CAM systems were within the clinically acceptable range and satisfactorily precise to be suggested for construction full-arch zirconia restoration. PMID- 29497336 TI - Increased proportions of HIV-infected women met cervical cancer screening guideline in 2016. AB - Background: HIV-infected women are five times more likely to develop invasive cervical cancer. Routine screening can detect early signs of cancer and provide an opportunity for treatment. However, suboptimal screening rates are reported in this population. This retrospective study examined the rates of cervical cancer screening in HIV-positive women, conducted according to the current guidelines, from 2014 to 2016 in an inner-city clinic. Materials and methods: We implemented focused scheduling for eligible women by a designated medical assistant. Testing was conducted using Thin PrepTM and Cervista HPV HRTM. Chi-square tests and logistic regression models were used to assess predictors of cervical cancer screening in 2016. Results: A total of 360 adult HIV-infected women were active in medical care, as of December 31, 2016. Most were African American (77%) and aged 51-60 years (38%). In 2016, 75% of women met the guidelines for cervical cancer screening, compared to 48% in 2014. There was a significant association between receipt of cervical cancer screening in the prior 3 years and screening in 2016. In an adjusted model, those with a prior screening were 6.88 times (95% CI, 3.47-13.67) more likely to be screened in 2016, compared to those who were never previously screened. Conclusion: Focused scheduling and implementation of the updated cervical cancer screening guideline extending the period of rescreening, after 3 yearly negative results or negative Papanicolaou/human papilloma virus testing, resulted in an increased proportion of women meeting the current guideline. PMID- 29497335 TI - Fertility intentions of prenatal and postpartum HIV-positive women in primary care in Mpumalanga province, South Africa: a longitudinal study. AB - Introduction: This study aimed to assess fertility intentions (planning to have more children in the future) and associated factors among pregnant and postpartum HIV positive women in rural South Africa. Methods: In a longitudinal study, as part of a prevention of mother to child transmission (PMTCT) intervention trial, 699 HIV positive prenatal women, were systematically recruited and followed up at 6 months and 12 months postpartum (retention rate = 59.5%). Results: At baseline, 32.9% of the women indicated fertility intentions and at 12 months postnatal, 120 (28.0%) reported fertility intentions. In longitudinal analyses, which included time-invariant baseline characteristics predicting fertility intention over time, not having children, having a partner with unknown/HIV-negative status, and having disclosed their HIV status to their partner, were associated with fertility intentions. In a model with time-varying covariates, decreased family planning knowledge, talking to a provider about a future pregnancy, and increased male involvement were associated with fertility intentions. Conclusion: Results support ongoing perinatal family planning and PMTCT education. PMID- 29497337 TI - Atypical metastasis of renal cell carcinoma to the uvula: case report and review of literature. AB - Renal cell carcinoma (RCC) is a common malignancy with high metastatic potential, primarily due to its extensive vascularity. Common sites of metastasis include lungs, bone, lymph nodes, liver, and brain. However, rare cases of metastasis to other sites including inguinal lymph nodes, peritoneum/mesentery, and orbit have been published in the literature. Herein, a unique case involving metastasis of RCC to the uvula is presented. The patient is a 55-year-old White female with a past medical history of stage 3 (T3aN0M0) RCC s/p nephrectomy 3 years prior to presentation. She had symptoms of a foreign body sensation at the back of her throat, and oropharyngeal examination revealed uvular erythematous mass with vascularity. Uvular biopsy and complete excision were performed, which revealed metastatic RCC. Palate biopsy was negative and revealed only squamous mucosa with mild chronic inflammation. To our knowledge, there is only one other documented case of RCC metastasis to the uvula in the literature. PMID- 29497338 TI - Adult patient with Becker dystrophy undergoing orthopedic surgery: an anesthesia challenge. AB - Muscular dystrophies are considered to be a series of neuromuscular diseases with genetic causes and are characterized by progressive muscle weakness and degeneration of the skeletal muscle. The case of an adult man with Becker dystrophy referred for repair of the patella tendon tearing and patella fracture is described. He underwent successful surgery using total intravenous anesthesia without any complications. PMID- 29497339 TI - Quality of life and burden of morbidity in primary care users with multimorbidity. AB - Purpose: The aim of this study was to assess the quality of life, number of diseases and burden of morbidity of multimorbid primary care users and whether a simple disease count or a multimorbidity burden score is more predictive of quality of life. Patients and methods: Primary care patients with at least 1 of 11 specified chronic conditions were invited to participate in a postal survey. Participants completed the Disease Burden Impact Scale (DBIS) questionnaire, the five dimension-five level Euro-Qol (EQ-5D-5L) and standard demographics questions. The DBIS asks participants to self-report chronic conditions and to rate the impact of each condition. Descriptive statistics and analysis of variance were used to determine quality of life, count of diseases and burden of morbidity. Multiple linear regression analyses determined whether disease count or the DBIS, adjusted for demographics, was more predictive of the EQ-5D-5L scores. Results: Thirty-one percent (n=917) responded, from which 69 were excluded as they reported no or only one condition, leaving 848 (92%) in the analysis. Slightly more women (50.9%) participated; the mean age was 67.0 (SD 13.9) and the mean number of conditions was 6.5 (SD 3.49). The mean scores were: DBIS 15.5 (SD 12.00; score range 0-140, with higher scores indicating higher multimorbidity burden), EQ-5D-5L score 0.69 (SD 0.28; score range -0.28 [a state worse than death] to 1 [best possible health state]) and EQ-5D Visual Analog Scale (EQ-VAS) 65.44 (SD 23.66; score range 0-100 with higher scores meaning better health). The model using the DBIS score was more predictive of the EQ-5D 5L score and EQ-VAS than the model using the disease count (R2adj=0.53 using DBIS and R2adj=0.42 using disease count for EQ-5D-5L score, and R2adj=0.44 using DBIS versus R2adj=0.34 using disease count for EQ-VAS). All models were statistically significant (p<0.001). Conclusion: The DBIS is a useful measure for assessing multimorbidity from the perspective of primary care users in particular, as it is more predictive of health outcomes than a simple count of conditions. PMID- 29497341 TI - Cardiovascular Risk Factors and Atherogenic Indices in an Iranian Population: Birjand East of Iran. AB - Introduction: The alteration in serum lipid profile; increase in total cholesterol (TC), triacylglycerol (TAG), and low-density lipoprotein cholesterol (LDL-C); and reduction in high-density lipoprotein cholesterol (HDL-C) are key factors in cardiovascular disease progression. The high prevalence and severity of cardiovascular diseases require new screening tools for better evaluation. Atherogenic index (AI) (LDL-C/HDL-C) and coronary risk index (CRI) (TC/HDL-C) can be strong markers for predicting the risk of atherosclerosis and coronary heart disease and disclose the presence of LDL or TAG in the serum of related patients. To implement this strategy, the AIs and CRIs in our population were assessed. In this study, a total of 5207 subjects were recruited and AIs and CRIs were calculated for all of them. According to our data, age, body mass index, sex, as well as CRI and AI had affirmative correlation with TC, LDL-C, TAG, systolic blood pressure, and diastolic blood pressure. By increasing these factors, AIs and CRIs were augmented. Moreover, in situations where all atherogenic parameters are normal, these parameters may be the alternative screening tool. PMID- 29497342 TI - Hemostasis After Brachial Artery Access With the MynxGrip Device: A Case Report. AB - Purpose: Brachial access is occasionally used for endovascular procedures when other more established or safer ones (eg, femoral or radial) are contraindicated. Although manual compression is the standard of care after brachial arteriotomy, suboptimal compression may lead to bleeding or thrombosis. Arteriotomy closure devices have thus been proposed as an alternative means to achieve hemostasis after brachial arteriotomy. Yet, there is a paucity of evidence and a limited spectrum of devices suitable for brachial arteriotomy closure. We present the use of the MynxGrip closure device after brachial arteriotomy. Case: A 70-year-old gentleman underwent brachial arteriotomy followed by iliac artery stenting with a 7F compatible device. Hemostasis was then achieved with the MynxGrip device, uneventfully. Conclusions: This clinical vignette highlights the feasibility and safety of brachial use of the MynxGrip device in experienced hands, suggesting that it can represent a useful adjunct to the armamentarium of the endovascular specialist. PMID- 29497340 TI - Data Mining of Small RNA-Seq Suggests an Association Between Prostate Cancer and Altered Abundance of 5' Transfer RNA Halves in Seminal Fluid and Prostatic Tissues. AB - Extracellular RNAs are gaining clinical interest as biofluid-based noninvasive markers for diseases, especially cancer. In particular, derivatives of transfer RNA (tRNA) are emerging as a new class of small-noncoding RNAs with high biomarker potential. We and others previously reported alterations in serum levels of specific tRNA halves in disease states including cancer. Here, we explored seminal fluid for tRNA halves as potential markers of prostate cancer. We found that 5' tRNA halves are abundant in seminal fluid and are elevated in prostate cancer relative to noncancer patients. Importantly, most of these tRNA halves are also detectable in prostatic tissues, and a subset were increased in malignant relative to adjacent normal tissue. These findings emphasize the potential of 5' tRNA halves as noninvasive markers for prostate cancer screening and diagnosis and provide leads for future work to elucidate a putative role of the 5' tRNA halves in carcinogenesis. PMID- 29497343 TI - On the Diagnosis of Mycotic Aortic Aneurysms. AB - Objective: There is striking paucity in consensus on the terminology, definition, and diagnostic criteria of mycotic aortic aneurysms. This literature study aims to elucidate this scientific omission, discuss its consequences, and present a proposition for reporting items on this disease. Methods: A systematic literature review on PubMed and Medline using mycotic and infected aortic aneurysms between 1850 and 2017 was performed. Articles were assessed according to a protocol regarding terminology, definition, and diagnostic criteria. Case series with less than 5 patients were excluded. Results: A total of 49 articles were included. The most prevalent term was mycotic aortic aneurysm but there was no widely accepted definition. Most modern publications used a diagnostic workup based on a combination on clinical presentation, laboratory results, imaging findings, and intraoperative findings. How these protean variables should be balanced was unclear. A proposition of reporting items was framed and consisted of definition of disease used, basis of diagnostic workup, exclusion criteria, patient characteristics, laboratory and imaging findings, aneurysm anatomy, details on treatment, pre/postoperative antibiotic treatment, and details on follow-up. Conclusions: This article emphasizes the need to standardize definition, terminology, and diagnostic criteria for mycotic aortic aneurysms and proposes reporting items enhancing comparability between studies. PMID- 29497344 TI - Orbital Inflammatory Complications of Crohn's Disease: A Rare Case Series. AB - Orbital inflammatory disease is a rare ophthalmic manifestation of Crohn's disease. Inflammation is characteristically nonspecific, involving one or multiple structures of the orbit. Mechanisms of disease and optimal methods of treatment are poorly understood. The aim of this report is to present 3 cases of orbital involvement in Crohn's disease. A retrospective case note review of patients with orbital inflammatory disease and Crohn's disease was performed at our academic center to determine the clinical, imaging, and histopathologic features of this condition and its relationship to intestinal Crohn's disease. Three patients were identified with orbital inflammatory manifestations complicating Crohn's disease. All patients described were women with active intestinal disease and had a history of treatment with immunosuppressive therapies. Similarities were observed in clinical presentations with variance noted in radiologic and histopathologic findings. In all cases, symptoms improved with oral corticosteroids or nonsteroidal drugs in combination with anti-tumor necrosis factor agents. Inflammatory bowel disease-related orbital complications are rare but potentially vision-threatening. It is important to consider mimics of orbital inflammatory disease such as systemic inflammatory disease, malignancy, congenital malformations, infection, and trauma when formulating a comprehensive differential diagnosis. Therapeutic intervention is directed toward preservation of vision and orbital function and reducing the acute inflammatory process. Corticosteroids are typically the initial treatment of choice for moderate-to-severe disease, although several classes of immunomodulatory agents have been variably useful in treating this condition. Heightened awareness and close cooperation between gastroenterologists and ophthalmologists are mandatory. PMID- 29497345 TI - Overcoming barriers to interprofessional education in gerontology: the Interprofessional Curriculum for the Care of Older Adults. AB - A fragmented workforce consisting of multiple disciplines with varying levels of training and limited ability to work as a team often provides care to older adults. Interprofessional education (IPE) is essential for preparing practitioners for the effective teamwork required for community-based, holistic, person-centered care of the older adults. Despite numerous programs and offerings to advance education and interdisciplinary patient care, there is an unmet need for geriatric IPE, especially as it relates to community-dwelling older adults and caregivers in medically underserved areas. A core group of university faculty from multiple disciplines received funding from the Health Resources and Services Administration Geriatric Workforce Enhancement Program to collaborate with community-based providers from several Area Agencies on Aging in the creation and implementation of the Interprofessional Curriculum for the Care of Older Adults (iCCOA). This geriatric curriculum is interprofessional, comprehensive, and community-based. Learners include third-year nursing students, nurse practitioner students, third-year medical students, internal medicine and family medicine residents, master's level social work students, third-year pharmacy students, pharmacy residents, third-year dental students, dental hygiene students, community-based organization professionals, practicing community organizers, and community health navigators. This article describes the efforts, successes, and challenges experienced with this endeavor, including securing funding, ensuring equal representation of the disciplines, adding new components to already crowded curricula, building curriculum on best practices, improving faculty expertise in IPE, managing logistics, and ensuring comprehensive evaluation. The results summarize the iCCOA components, as well as the interprofessional domains, knowledge, and competencies. PMID- 29497346 TI - UK medical students' perceptions, attitudes, and interest toward medical leadership and clinician managers. AB - Background: We aimed to determine UK medical students' perceptions and attitudes and interest toward medical leadership and clinician managers. Methods: A cross sectional study was conducted during the academic year 2015-2016. An online questionnaire was distributed to 2,349 final-year students from 10 UK medical schools. Participants were asked to complete a 5-point Likert scale on their current perceptions, attitudes, and interest toward medical leadership and clinician managers. They were also asked to self-rate their leadership competences set by the Medical Leadership Competency Framework and to rate the quality of management and leadership training they received from their medical school. Results: In total, we received 114 complete responses. Only 7.9% of respondents were in agreement (strongly agree or agree) when asked whether they felt they were well informed about what a managerial position in medicine entails. When asked whether clinicians should influence managerial decisions within a clinical setting, 94.7% of respondents were in agreement with the statement. About 85% of respondents were in agreement that it is important for clinicians to have managerial or leadership responsibilities, with 63.2% of students in agreement that they would have liked more management or leadership training during medical school. Over half the respondents rated their management and leadership training they received during medical school as "very poor" or "poor" (54.4%). Conclusion: Our study suggests that UK medical students have an appetite for management and leadership training and appreciate its importance but feel that the training they are receiving is poor. This suggests that there is a gap between the demand for management and leadership training and the quality of training supplied by UK medical schools. PMID- 29497347 TI - Particle release and control of worker exposure during laboratory-scale synthesis, handling and simulated spills of manufactured nanomaterials in fume hoods. AB - Fume hoods are one of the most common types of equipment applied to reduce the potential of particle exposure in laboratory environments. A number of previous studies have shown particle release during work with nanomaterials under fume hoods. Here, we assessed laboratory workers' inhalation exposure during synthesis and handling of CuO, TiO2 and ZnO in a fume hood. In addition, we tested the capacity of a fume hood to prevent particle release to laboratory air during simulated spillage of different powders (silica fume, zirconia TZ-3Y and TiO2). Airborne particle concentrations were measured in near field, far field, and in the breathing zone of the worker. Handling CuO nanoparticles increased the concentration of small particles (< 58 nm) inside the fume hood (up to 1 * 105 cm 3). Synthesis, handling and packaging of ZnO and TiO2 nanoparticles did not result in detectable particle release to the laboratory air. Simulated powder spills showed a systematic increase in the particle concentrations inside the fume hood with increasing amount of material and drop height. Despite powder spills were sometimes observed to eject into the laboratory room, the spill events were rarely associated with notable release of particles from the fume hood. Overall, this study shows that a fume hood generally offers sufficient exposure control during synthesis and handling of nanomaterials. An appropriate fume hood with adequate sash height and face velocity prevents 98.3% of particles release into the surrounding environment. Care should still be made to consider spills and high cleanliness to prevent exposure via resuspension and inadvertent exposure by secondary routes. PMID- 29497348 TI - Quinuclidine and DABCO Enhance the Radiofluorinations of 5-Substituted 2 Halopyridines. AB - Positron emission tomography (PET) is an important molecular imaging technique for medical diagnosis, biomedical research and drug development. PET tracers for molecular imaging contain beta+-emitting radionuclides, such as carbon-11 (t1/2 = 20.4 min) or fluorine-18 (t1/2 = 109.8 min). The [18F]2-fluoro-pyridyl moiety features in a few prominent PET radiotracers, not least because this moiety is usually resistant to unwanted radiodefluorination in vivo. Various methods have been developed for labeling these radiotracers from cyclotron-produced no-carrier added [18F]fluoride ion, mainly based on substitution of a leaving group, such as halide (Cl or Br), or preferably a better leaving group, such as nitro or trimethylammonium. However, precursors with a good leaving group are sometimes more challenging or lengthy to prepare. Methods for enhancing the reactivity of more readily accessible 2-halopyridyl precursors are therefore desirable, especially for early radiotracer screening programs that may require the quick labeling of several homologous radiotracer candidates. In this work, we explored a wide range of additives for beneficial effect on nucleophilic substitution by [18F]fluoride ion in 5-subsituted 2-halopyridines (halo = Cl or Br). The nucleophilic cyclic tertiary amines, quinuclidine and DABCO, proved effective for increasing yields to practically useful levels (> 15%). Quinuclidine and DABCO likely promote radiofluorination through reversible formation of quaternary ammonium intermediates. PMID- 29497349 TI - Calculations with off-shell matrix elements, TMD parton densities and TMD parton showers. AB - A new calculation using off-shell matrix elements with TMD parton densities supplemented with a newly developed initial state TMD parton shower is described. The calculation is based on the KaTie package for an automated calculation of the partonic process in high-energy factorization, making use of TMD parton densities implemented in TMDlib. The partonic events are stored in an LHE file, similar to the conventional LHE files, but now containing the transverse momenta of the initial partons. The LHE files are read in by the Cascade package for the full TMD parton shower, final state shower and hadronization from Pythia where events in HEPMC format are produced. We have determined a full set of TMD parton densities and developed an initial state TMD parton shower, including all flavors following the TMD distribution. As an example of application we have calculated the azimuthal de-correlation of high [Formula: see text] dijets as measured at the LHC and found very good agreement with the measurement when including initial state TMD parton showers together with conventional final state parton showers and hadronization. PMID- 29497350 TI - Interleukin-10 attenuates impairment of the blood-brain barrier in a severe acute pancreatitis rat model. AB - Background: Impairment of the blood-brain barrier (BBB) in severe acute pancreatitis (SAP) could result in life-threatening pancreatic encephalopathy. Interleukin-10 (IL-10) is a classical cytokine that is well-known for its strong immunoregulatory and anti-inflammatory abilities. However, whether and how IL-10 protects the BBB in SAP are still unclear. Methods: This study includes in vivo experiments using a SAP rat model and in vitro experiments using an in vitro BBB model consisting of a monolayer of brain microvascular endothelial cells (BMECs). The study groups are divided into the control, SAP (in vivo)/TNF-alpha (in vitro), IL-10 treatment, IL-10 + signal transducer and activator of transcription 3 (STAT3) inhibitor S3I-201 treatment groups. Pancreatic pathological scores, serum amylase, serum TNF-alpha levels and BBB permeability by Evan's blue assay in SAP rat models were evaluated. BMEC apoptosis in SAP rats or induced by TNF alphain vitro was detected by terminal-deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) and flow cytometry, separately. Expression levels of claudin 5 and proteins involved in the STAT3 signaling pathway were measured by Western blotting. Location and changes of junctional structure of claudin-5 on BMECs were assessed by immunohistochemistry and immunofluorescence. Results: In vivo, IL-10 alleviated the severity of inflammation, attenuated the increased BBB permeability in SAP rat models by reducing BMEC apoptosis via the STAT3 pathway and ameliorated the down-regulation of claudin-5 expression in BMECs; in vitro, IL-10 improved BBB integrity against TNF-alpha by attenuating BMEC apoptosis via the STAT3 pathway, the impairment of tight junction structure and the down regulation of claudin-5 expression in BMECs. Conclusions: IL-10 improves BBB properties in SAP by attenuating the down-regulation of claudin-5 expression and the impairment of tight junctions and by STAT3 pathway-mediated anti-apoptotic effects on BMECs. PMID- 29497351 TI - Controlling Stochasticity in Epithelial-Mesenchymal Transition Through Multiple Intermediate Cellular States. AB - Epithelial-mesenchymal transition (EMT) is an instance of cellular plasticity that plays critical roles in development, regeneration and cancer progression. Recent studies indicate that the transition between epithelial and mesenchymal states is a multi-step and reversible process in which several intermediate phenotypes might coexist. These intermediate states correspond to various forms of stem-like cells in the EMT system, but the function of the multi-step transition or the multiple stem cell phenotypes is unclear. Here, we use mathematical models to show that multiple intermediate phenotypes in the EMT system help to attenuate the overall fluctuations of the cell population in terms of phenotypic compositions, thereby stabilizing a heterogeneous cell population in the EMT spectrum. We found that the ability of the system to attenuate noise on the intermediate states depends on the number of intermediate states, indicating the stem-cell population is more stable when it has more sub-states. Our study reveals a novel advantage of multiple intermediate EMT phenotypes in terms of systems design, and it sheds light on the general design principle of heterogeneous stem cell population. PMID- 29497352 TI - Personal and Professional Knowledge of and Experience With Suicide and Suicide Prevention Among Stakeholders in Clinical and Community Practice. AB - Community-dwelling veterans at risk for suicide may be in contact with a variety of providers in agency-based settings that offer health and human services. The study aim is to describe the perspective of agency-based clinical and community providers who may come into contact with veterans in need of suicide prevention services and to examine the nature of their personal and professional relationships to individuals at risk for suicide among this sample. This study reports on qualitative data from a sample of Veterans' Affairs (VA) and community providers serving veterans and military families in one Midwestern state (N = 70). Providers completed a survey assessing exposure to suicide, including contact with and relationship to someone suicidal, and organizational characteristics of the providers' employing agencies. Semi-structured interview questions probed for the nature of how they would react with suicidal individuals. Most providers (94%) had some prior contact with someone who was suicidal, and nearly three quarters (77%) knew someone who had died by suicide. Providers reported powerful emotional responses of sadness and remorse to suicidal experiences. While these providers interact with veterans and military families as part of their jobs, they may have their own history of being exposed to suicide, both professionally and personally. PMID- 29497354 TI - Correction Notice. AB - [This corrects the article DOI: 10.1177/1559325817690849.]. PMID- 29497353 TI - How much protein can the body use in a single meal for muscle-building? Implications for daily protein distribution. AB - Controversy exists about the maximum amount of protein that can be utilized for lean tissue-building purposes in a single meal for those involved in regimented resistance training. It has been proposed that muscle protein synthesis is maximized in young adults with an intake of ~ 20-25 g of a high-quality protein; anything above this amount is believed to be oxidized for energy or transaminated to form urea and other organic acids. However, these findings are specific to the provision of fast-digesting proteins without the addition of other macronutrients. Consumption of slower-acting protein sources, particularly when consumed in combination with other macronutrients, would delay absorption and thus conceivably enhance the utilization of the constituent amino acids. The purpose of this paper was twofold: 1) to objectively review the literature in an effort to determine an upper anabolic threshold for per-meal protein intake; 2) draw relevant conclusions based on the current data so as to elucidate guidelines for per-meal daily protein distribution to optimize lean tissue accretion. Both acute and long-term studies on the topic were evaluated and their findings placed into context with respect to per-meal utilization of protein and the associated implications to distribution of protein feedings across the course of a day. The preponderance of data indicate that while consumption of higher protein doses (> 20 g) results in greater AA oxidation, this is not the fate for all the additional ingested AAs as some are utilized for tissue-building purposes. Based on the current evidence, we conclude that to maximize anabolism one should consume protein at a target intake of 0.4 g/kg/meal across a minimum of four meals in order to reach a minimum of 1.6 g/kg/day. Using the upper daily intake of 2.2 g/kg/day reported in the literature spread out over the same four meals would necessitate a maximum of 0.55 g/kg/meal. PMID- 29497355 TI - Cell-free production of pore forming toxins: Functional analysis of thermostable direct hemolysin from Vibrio parahaemolyticus. AB - The pore forming characteristic of TDH1 and TDH2 variants of thermostable direct hemolysin (TDH), a major toxin involved in the pathogenesis of Vibrio parahaemolyticus, was studied on a planar lipid bilayer painted over individual picoliter cavities containing microelectrodes assembled in a multiarray. Both proteins formed pores upon insertion into the lipid bilayer which was shown as a shift in the conductance from the baseline current. TDH2 protein was able to produce stable currents and the currents were influenced by external factors like concentration, type of salt and voltage. The pore currents were influenced and showed a detectable response in the presence of polymers which makes them suitable for biotechnology applications. PMID- 29497357 TI - Inter-subject Registration of Functional Images: Do We Need Anatomical Images? AB - In Echo-Planar Imaging (EPI)-based Magnetic Resonance Imaging (MRI), inter subject registration typically uses the subject's T1-weighted (T1w) anatomical image to learn deformations of the subject's brain onto a template. The estimated deformation fields are then applied to the subject's EPI scans (functional or diffusion-weighted images) to warp the latter to a template space. Historically, such indirect T1w-based registration was motivated by the lack of clear anatomical details in low-resolution EPI images: a direct registration of the EPI scans to template space would be futile. A central prerequisite in such indirect methods is that the anatomical (aka the T1w) image of each subject is well aligned with their EPI images via rigid coregistration. We provide experimental evidence that things have changed: nowadays, there is a decent amount of anatomical contrast in high-resolution EPI data. That notwithstanding, EPI distortions due to B0 inhomogeneities cannot be fully corrected. Residual uncorrected distortions induce non-rigid deformations between the EPI scans and the same subject's anatomical scan. In this manuscript, we contribute a computationally cheap pipeline that leverages the high spatial resolution of modern EPI scans for direct inter-subject matching. Our pipeline is direct and does not rely on the T1w scan to estimate the inter-subject deformation. Results on a large dataset show that this new pipeline outperforms the classical indirect T1w-based registration scheme, across a variety of post-registration quality assessment metrics including: Normalized Mutual Information, relative variance (variance-to-mean ratio), and to a lesser extent, improved peaks of group-level General Linear Model (GLM) activation maps. PMID- 29497356 TI - Role of mTORC1 Controlling Proteostasis after Brain Ischemia. AB - Intense efforts are being undertaken to understand the pathophysiological mechanisms triggered after brain ischemia and to develop effective pharmacological treatments. However, the underlying molecular mechanisms are complex and not completely understood. One of the main problems is the fact that the ischemic damage is time-dependent and ranges from negligible to massive, involving different cell types such as neurons, astrocytes, microglia, endothelial cells, and some blood-derived cells (neutrophils, lymphocytes, etc.). Thus, approaching such a complicated cellular response generates a more complex combination of molecular mechanisms, in which cell death, cellular damage, stress and repair are intermixed. For this reason, animal and cellular model systems are needed in order to dissect and clarify which molecular mechanisms have to be promoted and/or blocked. Brain ischemia may be analyzed from two different perspectives: that of oxygen deprivation (hypoxic damage per se) and that of deprivation of glucose/serum factors. For investigations of ischemic stroke, middle cerebral artery occlusion (MCAO) is the preferred in vivo model, and uses two different approaches: transient (tMCAO), where reperfusion is permitted; or permanent (pMCAO). As a complement to this model, many laboratories expose different primary cortical neuron or neuronal cell lines to oxygen-glucose deprivation (OGD). This ex vivo model permits the analysis of the impact of hypoxic damage and the specific response of different cell types implicated in vivo, such as neurons, glia or endothelial cells. Using in vivo and neuronal OGD models, it was recently established that mTORC1 (mammalian Target of Rapamycin Complex-1), a protein complex downstream of PI3K-Akt pathway, is one of the players deregulated after ischemia and OGD. In addition, neuroprotective intervention either by estradiol or by specific AT2R agonists shows an important regulatory role for the mTORC1 activity, for instance regulating vascular endothelial growth factor (VEGF) levels. This evidence highlights the importance of understanding the role of mTORC1 in neuronal death/survival processes, as it could be a potential therapeutic target. This review summarizes the state-of-the art of the complex kinase mTORC1 focusing in upstream and downstream pathways, their role in central nervous system and their relationship with autophagy, apoptosis and neuroprotection/neurodegeneration after ischemia/hypoxia. PMID- 29497359 TI - Domestic Use of the Exoskeleton for Gait Training in Patients with Spinal Cord Injuries: Ethical Dilemmas in Clinical Practice. PMID- 29497358 TI - Diffusion Basis Spectrum and Diffusion Tensor Imaging Detect Hippocampal Inflammation and Dendritic Injury in a Virus-Induced Mouse Model of Epilepsy. AB - Hippocampal CA1 inflammation and dendritic loss are common in epilepsy. Quantitative detection of coexisting brain inflammation and injury could be beneficial in monitoring disease progression and assessing therapeutic efficacy. In this work, we used conventional diffusion tensor imaging (DTI, known to detect axonal injury and demyelination) and a novel diffusion basis spectrum imaging (DBSI, known to detect axonal injury, demyelination, and inflammation) to detect hippocampal CA1 lesions resulting from neuronal dendritic injury/loss and concomitant inflammation in Theiler's murine encephalomyelitis virus (TMEV) induced seizure mice. Following the cross-sectional ex vivo diffusion magnetic resonance imaging measurements, immunohistochemistry was performed to validate DTI and DBSI findings. Both DTI and DBSI detected immunohistochemistry-confirmed dendritic injury in the hippocampal CA1 region. Additionally, DBSI-derived restricted isotropic diffusion tensor fraction correlated with 4',6-diamidine-2' phenylindole dihydrochloride (DAPI)-positive nucleus counts, and DBSI-derived fiber fraction correlated with dendrite density assessed by microtubule associated protein 2 staining. DTI-derived fractional anisotropy (FA) correlated with dendrite density and negatively correlated with DAPI-positive nucleus counts. Although both DTI and DBSI detected hippocampal injury/inflammation, DTI FA was less specific than DBSI-derived pathological metrics for hippocampal CA1 dendritic injury and inflammation in TMEV-induced seizure mice. PMID- 29497360 TI - Effects of Distracting Task with Different Mental Workload on Steady-State Visual Evoked Potential Based Brain Computer Interfaces-an Offline Study. AB - Brain-computer interfaces (BCIs), independent of the brain's normal output pathways, are attracting an increasing amount of attention as devices that extract neural information. As a typical type of BCI system, the steady-state visual evoked potential (SSVEP)-based BCIs possess a high signal-to-noise ratio and information transfer rate. However, the current high speed SSVEP-BCIs were implemented with subjects concentrating on stimuli, and intentionally avoided additional tasks as distractors. This paper aimed to investigate how a distracting simultaneous task, a verbal n-back task with different mental workload, would affect the performance of SSVEP-BCI. The results from fifteen subjects revealed that the recognition accuracy of SSVEP-BCI was significantly impaired by the distracting task, especially under a high mental workload. The average classification accuracy across all subjects dropped by 8.67% at most from 1- to 4-back, and there was a significant negative correlation (maximum r = 0.48, p < 0.001) between accuracy and subjective mental workload evaluation of the distracting task. This study suggests a potential hindrance for the SSVEP-BCI daily use, and then improvements should be investigated in the future studies. PMID- 29497361 TI - Silencing Alpha Synuclein in Mature Nigral Neurons Results in Rapid Neuroinflammation and Subsequent Toxicity. AB - Human studies and preclinical models of Parkinson's disease implicate the involvement of both the innate and adaptive immune systems in disease progression. Further, pro-inflammatory markers are highly enriched near neurons containing pathological forms of alpha synuclein (alpha-syn), and alpha-syn overexpression recapitulates neuroinflammatory changes in models of Parkinson's disease. These data suggest that alpha-syn may initiate a pathological inflammatory response, however the mechanism by which alpha-syn initiates neuroinflammation is poorly understood. Silencing endogenous alpha-syn results in a similar pattern of nigral degeneration observed following alpha-syn overexpression. Here we aimed to test the hypothesis that loss of alpha-syn function within nigrostriatal neurons results in neuronal dysfunction, which subsequently stimulates neuroinflammation. Adeno-associated virus (AAV) expressing an short hairpin RNA (shRNA) targeting endogenous alpha-syn was unilaterally injected into the substantia nigra pars compacta (SNc) of adult rats, after which nigrostriatal pathology and indices of neuroinflammation were examined at 7, 10, 14 and 21 days post-surgery. Removing endogenous alpha-syn from nigrostriatal neurons resulted in a rapid up-regulation of the major histocompatibility complex class 1 (MHC-1) within transduced nigral neurons. Nigral MHC-1 expression occurred prior to any overt cell death and coincided with the recruitment of reactive microglia and T-cells to affected neurons. Following the induction of neuroinflammation, alpha-syn knockdown resulted in a 50% loss of nigrostriatal neurons in the SNc and a corresponding loss of nigrostriatal terminals and dopamine (DA) concentrations within the striatum. Expression of a control shRNA did not elicit any pathological changes. Silencing alpha-syn within glutamatergic neurons of the cerebellum did not elicit inflammation or cell death, suggesting that toxicity initiated by alpha-syn silencing is specific to DA neurons. These data provide evidence that loss of alpha-syn function within nigrostriatal neurons initiates a neuronal-mediated neuroinflammatory cascade, involving both the innate and adaptive immune systems, which ultimately results in the death of affected neurons. PMID- 29497362 TI - Repeated Clozapine Increases the Level of Serotonin 5-HT1AR Heterodimerization with 5-HT2A or Dopamine D2 Receptors in the Mouse Cortex. AB - G-protein-coupled receptor (GPCR) heterodimers are new targets for the treatment of schizophrenia. Dopamine D2 receptors and serotonin 5-HT1A and 5-HT2A receptors play an important role in neurotransmission and have been implicated in many human psychiatric disorders, including schizophrenia. Therefore, in this study, we investigated whether antipsychotic drugs (clozapine (CLZ) and haloperidol (HAL)) affected the formation of heterodimers of D2-5-HT1A receptors as well as 5 HT1A-5-HT2A receptors. Proximity ligation assay (PLA) was used to accurately visualize, for the first time, GPCR heterodimers both at in vitro and ex vivo levels. In line with our previous behavioral studies, we used ketamine to induce cognitive deficits in mice. Our study confirmed the co-localization of D2/5-HT1A and 5-HT1A/5-HT2A receptors in the mouse cortex. Low-dose CLZ (0.3 mg/kg) administered repeatedly, but not CLZ at 1 mg/kg, increased the level of D2-5-HT1A and 5-HT1A-5-HT2A heterodimers in the mouse prefrontal and frontal cortex. On the other hand, HAL decreased the level of GPCR heterodimers. Ketamine affected the formation of 5-HT1A-5-HT2A, but not D2-5-HT1A, heterodimers. PMID- 29497364 TI - Vulnerable Parkin Loss-of-Function Drosophila Dopaminergic Neurons Have Advanced Mitochondrial Aging, Mitochondrial Network Loss and Transiently Reduced Autophagosome Recruitment. AB - Selective degeneration of substantia nigra dopaminergic (DA) neurons is a hallmark pathology of familial Parkinson's disease (PD). While the mechanism of degeneration is elusive, abnormalities in mitochondrial function and turnover are strongly implicated. An Autosomal Recessive-Juvenile Parkinsonism (AR-JP) Drosophila melanogaster model exhibits DA neurodegeneration as well as aberrant mitochondrial dynamics and function. Disruptions in mitophagy have been observed in parkin loss-of-function models, and changes in mitochondrial respiration have been reported in patient fibroblasts. Whether loss of parkin causes selective DA neurodegeneration in vivo as a result of lost or decreased mitophagy is unknown. This study employs the use of fluorescent constructs expressed in Drosophila DA neurons that are functionally homologous to those of the mammalian substantia nigra. We provide evidence that degenerating DA neurons in parkin loss-of function mutant flies have advanced mitochondrial aging, and that mitochondrial networks are fragmented and contain swollen organelles. We also found that mitophagy initiation is decreased in park (Drosophila parkin/PARK2 ortholog) homozygous mutants, but autophagosome formation is unaffected, and mitochondrial network volumes are decreased. As the fly ages, autophagosome recruitment becomes similar to control, while mitochondria continue to show signs of damage, and climbing deficits persist. Interestingly, aberrant mitochondrial morphology, aging and mitophagy initiation were not observed in DA neurons that do not degenerate. Our results suggest that parkin is important for mitochondrial homeostasis in vulnerable Drosophila DA neurons, and that loss of parkin-mediated mitophagy may play a role in degeneration of relevant DA neurons or motor deficits in this model. PMID- 29497363 TI - Parathyroid Hormone-Related Peptide Elicits Peripheral TRPV1-dependent Mechanical Hypersensitivity. AB - Bone metastasis in breast, prostate and lung cancers often leads to chronic pain, which is poorly managed by existing analgesics. The neurobiological mechanisms that underlie chronic pain associated with bone-metastasized cancers are not well understood, but sensitization of peripheral nociceptors by tumor microenvironment factors has been demonstrated to be important. Parathyroid hormone-related peptide (PTHrP) is highly expressed in bone-metastasized breast and prostate cancers, and is critical to growth and proliferation of these tumors in the bone tumor microenvironment. Previous studies have suggested that PTHrP could sensitize nociceptive sensory neurons, resulting in peripheral pain hypersensitivity. In this study, we found that PTHrP induces both heat and mechanical hypersensitivity, that are dependent on the pain-transducing transient receptor potential channel family vanilloid, member-1 (TRPV1), but not the mechano-transducing TRPV4 and TRPA1 ion channels. Functional ratiometric Ca2+ imaging and voltage-clamp electrophysiological analysis of cultured mouse DRG neurons show significant potentiation of TRPV1, but not TRPA1 or TRPV4 channel activation by PTHrP. Interestingly, PTHrP exposure led to the slow and sustained activation of TRPV1, in the absence of any exogenous channel agonist, and is dependent on the expression of the type-1 parathyroid hormone receptor (PTH1), as well as on downstream phosphorylation of the channel by protein kinase C (PKC). Accordingly, local administration of specific small-molecule antagonists of TRPV1 to mouse hindpaws after the development of PTHrP-induced mechanical hypersensitivity led to its significant attenuation. Collectively, our findings suggest that PTHrP/PTH1-mediated flow activation of TRPV1 channel contributes at least in part to the development and maintenance of peripheral mechanical pain hypersensitivity, and could therefore constitute a mechanism for nociceptor sensitization in the context of metastatic bone cancer pain. PMID- 29497365 TI - Olig2-Lineage Astrocytes: A Distinct Subtype of Astrocytes That Differs from GFAP Astrocytes. AB - Astrocytes are the most abundant glia cell type in the central nervous system (CNS), and are known to constitute heterogeneous populations that differ in their morphology, gene expression and function. Although glial fibrillary acidic protein (GFAP) is the cardinal cytological marker of CNS astrocytes, GFAP negative astrocytes can easily be found in the adult CNS. Astrocytes are also allocated to spatially distinct regional domains during development. This regional heterogeneity suggests that they help to coordinate post-natal neural circuit formation and thereby to regulate eventual neuronal activity. Here, during lineage-tracing studies of cells expressing Olig2 using Olig2CreER; Rosa CAG-LSL-eNpHR3.0-EYFP transgenic mice, we found Olig2-lineage mature astrocytes in the adult forebrain. Long-term administration of tamoxifen resulted in sufficient recombinant induction, and Olig2-lineage cells were found to be preferentially clustered in some adult brain nuclei. We then made distribution map of Olig2-lineage astrocytes in the adult mouse brain, and further compared the map with the distribution of GFAP-positive astrocytes visualized in GFAPCre; Rosa-CAG-LSL-eNpHR3.0-EYFP mice. Brain regions rich in Olig2-lineage astrocytes (e.g., basal forebrain, thalamic nuclei, and deep cerebellar nuclei) tended to lack GFAP-positive astrocytes, and vice versa. Even within a single brain nucleus, Olig2-lineage astrocytes and GFAP astrocytes frequently occupied mutually exclusive territories. These findings strongly suggest that there is a subpopulation of astrocytes (Olig2-lineage astrocytes) in the adult brain, and that it differs from GFAP-positive astrocytes in its distribution pattern and perhaps also in its function. Interestingly, the brain nuclei rich in Olig2 lineage astrocytes strongly expressed GABA-transporter 3 in astrocytes and vesicular GABA transporter in neurons, suggesting that Olig2-lineage astrocytes are involved in inhibitory neuronal transmission. PMID- 29497367 TI - Functional Connectomes in Time Domain from Simulated Neurotransmitter Release Based on Electrocorticograms. AB - This paper uses a newly defined functional connectome and connectome values calculated in time domain of simulated neurotransmitter release (NTR) from an electrocorticogram (ECoG) to distinguish between conditioned and unconditioned stimuli. The NTR derived from multiple channels releasing one quantum at the same time suggests that one functional connectome occurs across those channels at that time. During the first 600 ms after conditional stimulation, the connectome indexes of the 64-channel NTR trains were sorted from the 8 to 20 Hz band obtained from filtered rabbit ECoGs recorded from the visual cortices. In the small scale visual cortex area, this association was significantly larger than the habituation, even though the trial-to-trail variability of large scale synchrony after conditional stimulation is increased, which is also consistent with the hypothesis that attention decreases coherence of lower frequency within each cortical area. The increased conectome index suggests that the stimuli related to association are able to generate stronger substantial responses in the small scale visual cortex than habituation. That is, besides of the background cortical states as well as attention-related decreases in synchrony of lower frequency, the increased part of neurotransmitters released simultaneously from the pre-synaptic terminals of small scale visual cortex for association is larger than habituation. PMID- 29497366 TI - Confocal Synaptology: Synaptic Rearrangements in Neurodegenerative Disorders and upon Nervous System Injury. AB - The nervous system is a notable exception to the rule that the cell is the structural and functional unit of tissue systems and organs. The functional unit of the nervous system is the synapse, the contact between two nerve cells. As such, synapses are the foci of investigations of nervous system organization and function, as well as a potential readout for the progression of various disorders of the nervous system. In the past decade the development of antibodies specific to presynaptic terminals has enabled us to assess, at the optical, laser scanning microscopy level, these subcellular structures, and has provided a simple method for the quantification of various synapses. Indeed, excitatory (glutamatergic) and inhibitory synapses can be visualized using antibodies against the respective vesicular transporters, and choline-acetyl transferase (ChAT) immunoreactivity identifies cholinergic synapses throughout the central nervous system. Here we review the results of several studies in which these methods were used to estimate synaptic numbers as the structural equivalent of functional outcome measures in spinal cord and femoral nerve injuries, as well as in genetic mouse models of neurodegeneration, including Alzheimer's disease (AD). The results implicate disease- and brain region-specific changes in specific types of synapses, which correlate well with the degree of functional deficit caused by the disease process. Additionally, results are reproducible between various studies and experimental paradigms, supporting the reliability of the method. To conclude, this quantitative approach enables fast and reliable estimation of the degree of the progression of neurodegenerative changes and can be used as a parameter of recovery in experimental models. PMID- 29497368 TI - Meta-Analysis of the Structural Equation Models' Parameters for the Estimation of Brain Connectivity with fMRI. AB - Structural Equation Models (SEM) is among of the most extensively applied statistical techniques in the study of human behavior in the fields of Neuroscience and Cognitive Neuroscience. This paper reviews the application of SEM to estimate functional and effective connectivity models in work published since 2001. The articles analyzed were compiled from Journal Citation Reports, PsycInfo, Pubmed, and Scopus, after searching with the following keywords: fMRI, SEMs, and Connectivity. Results: A 100 papers were found, of which 25 were rejected due to a lack of sufficient data on basic aspects of the construction of SEM. The other 75 were included and contained a total of 160 models to analyze, since most papers included more than one model. The analysis of the explained variance (R2) of each model yields an effect of the type of design used, the type of population studied, the type of study, the existence of recursive effects in the model, and the number of paths defined in the model. Along with these comments, a series of recommendations are included for the use of SEM to estimate of functional and effective connectivity models. PMID- 29497370 TI - User's Self-Prediction of Performance in Motor Imagery Brain-Computer Interface. AB - Performance variation is a critical issue in motor imagery brain-computer interface (MI-BCI), and various neurophysiological, psychological, and anatomical correlates have been reported in the literature. Although the main aim of such studies is to predict MI-BCI performance for the prescreening of poor performers, studies which focus on the user's sense of the motor imagery process and directly estimate MI-BCI performance through the user's self-prediction are lacking. In this study, we first test each user's self-prediction idea regarding motor imagery experimental datasets. Fifty-two subjects participated in a classical, two-class motor imagery experiment and were asked to evaluate their easiness with motor imagery and to predict their own MI-BCI performance. During the motor imagery experiment, an electroencephalogram (EEG) was recorded; however, no feedback on motor imagery was given to subjects. From EEG recordings, the offline classification accuracy was estimated and compared with several questionnaire scores of subjects, as well as with each subject's self-prediction of MI-BCI performance. The subjects' performance predictions during motor imagery task showed a high positive correlation (r = 0.64, p < 0.01). Interestingly, it was observed that the self-prediction became more accurate as the subjects conducted more motor imagery tasks in the Correlation coefficient (pre-task to 2nd run: r = 0.02 to r = 0.54, p < 0.01) and root mean square error (pre-task to 3rd run: 17.7% to 10%, p < 0.01). We demonstrated that subjects may accurately predict their MI-BCI performance even without feedback information. This implies that the human brain is an active learning system and, by self-experiencing the endogenous motor imagery process, it can sense and adopt the quality of the process. Thus, it is believed that users may be able to predict MI-BCI performance and results may contribute to a better understanding of low performance and advancing BCI. PMID- 29497369 TI - Reduced Orbitofrontal Gray Matter Concentration as a Marker of Premorbid Childhood Trauma in Cocaine Use Disorder. AB - Background: Childhood trauma affects neurodevelopment and promotes vulnerability to impaired constraint, depression, and addiction. Reduced gray matter concentration (GMC) in the mesocorticolimbic regions implicated in reward processing and cognitive control may be an underlying substrate, as documented separately in addiction and for childhood trauma. The purpose of this study was to understand the contribution of childhood maltreatment to GMC effects in individuals with cocaine use disorder. Methods: Individuals with cocaine use disorder were partitioned into groups of low vs. high childhood trauma based on median split of the total score of the Childhood Trauma Questionnaire (CTQ; CUD L, N = 23; CUD-H, N = 24) and compared with age, race, and gender matched healthy controls with low trauma (N = 29). GMC was obtained using voxel-based morphometry applied to T1-weighted MRI scans. Drug use, depression and constraint were assessed with standardized instruments. Results: Whole-brain group comparisons showed reduced GMC in the right lateral orbitofrontal cortex (OFC) in CUD-H as compared with controls (cluster-level pFWE-corr < 0.001) and CUD-L (cluster-level pFWE-corr = 0.035); there were no significant differences between CUD-L and controls. A hierarchical regression analysis across both CUD groups revealed that childhood trauma, but not demographics and drug use, and beyond constraint and depression, accounted for 37.7% of the variance in the GMC in the right lateral OFC (p < 0.001). Conclusions: Beyond other contributing factors, childhood trauma predicted GMC reductions in the OFC in individuals with cocaine use disorder. These findings underscore a link between premorbid environmental stress and morphological integrity of a brain region central for behaviors underlying drug addiction. These results further highlight the importance of accounting for childhood trauma, potentially as a factor predisposing to addiction, when examining and interpreting neural alterations in cocaine addicted individuals. PMID- 29497371 TI - Transcranial Static Magnetic Field Stimulation over the Primary Motor Cortex Induces Plastic Changes in Cortical Nociceptive Processing. AB - Transcranial static magnetic field stimulation (tSMS) is a novel and inexpensive, non-invasive brain stimulation (NIBS) technique. Here, we performed non-invasive modulation of intra-epidermal electrical stimulation-evoked potentials (IES-EPs) by applying tSMS or sham stimulation over the primary motor (M1) and somatosensory (S1) cortices in 18 healthy volunteers for 15 min. We recorded EPs after IES before, right after, and 10 min after tSMS. The IES-EP amplitude was significantly reduced immediately after tSMS over M1, whereas tSMS over S1 and sham stimulation did not affect the IES-EP amplitude. Thus, tSMS may affect cortical nociceptive processing. Although the results of intervention for experimental acute pain in healthy subjects cannot be directly translated into the clinical situation, tSMS may be a potentially useful NIBS method for managing chronic pain, in addition to standard of care treatments. PMID- 29497372 TI - The Influence of Preprocessing Steps on Graph Theory Measures Derived from Resting State fMRI. AB - Resting state functional MRI (rs-fMRI) is an imaging technique that allows the spontaneous activity of the brain to be measured. Measures of functional connectivity highly depend on the quality of the BOLD signal data processing. In this study, our aim was to study the influence of preprocessing steps and their order of application on small-world topology and their efficiency in resting state fMRI data analysis using graph theory. We applied the most standard preprocessing steps: slice-timing, realign, smoothing, filtering, and the tCompCor method. In particular, we were interested in how preprocessing can retain the small-world economic properties and how to maximize the local and global efficiency of a network while minimizing the cost. Tests that we conducted in 54 healthy subjects showed that the choice and ordering of preprocessing steps impacted the graph measures. We found that the csr (where we applied realignment, smoothing, and tCompCor as a final step) and the scr (where we applied realignment, tCompCor and smoothing as a final step) strategies had the highest mean values of global efficiency (eg) . Furthermore, we found that the fscr strategy (where we applied realignment, tCompCor, smoothing, and filtering as a final step), had the highest mean local efficiency (el) values. These results confirm that the graph theory measures of functional connectivity depend on the ordering of the processing steps, with the best results being obtained using smoothing and tCompCor as the final steps for global efficiency with additional filtering for local efficiency. PMID- 29497373 TI - The Complement System Is Critical in Maintaining Retinal Integrity during Aging. AB - The complement system is a key component of innate immunity comprised of soluble components that form a proteolytic cascade leading to the generation of effector molecules involved in cellular clearance. This system is highly activated not only under general inflammatory conditions such as infections, collagen diseases, nephritis, and liver diseases, but also in focal ocular diseases. However, little is known about the role of the complement system in retinal homeostasis during aging. Using young (6-week-old) and adult (6-month-old) mice in wild type (C57BL/6) and complement knockout strains (C1q-/-, Mbl a/c-/-, Fb-/-, C3-/-, and C5-/-), we compared amplitudes of electroretinograms (ERG) and thicknesses of retinal layers in spectral domain optical coherence tomography between young and adult mice. The ERG amplitudes in adult mice were significantly decreased (p < 0.001, p < 0.0001) compared to that of young mice in all complement knockout strains, and there were significant decreases in the inner nuclear layer (INL) thickness in adult mice compared to young mice in all complement knockout strains (p < 0.0001). There were no significant differences in ERG amplitude or thickness of the INL between young and adult control mice. These data suggest that the complement system plays an important role in maintaining normal retinal integrity over time. PMID- 29497374 TI - Are Hypometric Anticipatory Postural Adjustments Contributing to Freezing of Gait in Parkinson's Disease? AB - Introduction: This study aims at investigating whether impaired anticipatory postural adjustments (APA) during gait initiation contribute to the occurrence of freezing of gait (FOG) or whether altered APAs compensate for FOG in Parkinson's disease (PD). Methods: Gait initiation after 30 s quiet stance was analyzed without and with a cognitive dual task (DT) in 33 PD subjects with FOG (PD+FOG), 30 PD subjects without FOG (PD-FOG), and 32 healthy controls (HC). APAs were characterized with inertial sensors and muscle activity of the tensor fasciae latae (TFL), gastrocnemius, and tibialis anterior was captured with electromyography recordings. Nine trials (of 190) were associated with start hesitation/FOG and analyzed separately. Results: PD+FOG and PD-FOG did not differ in disease duration, disease severity, age, or gender. PD+FOG had significantly smaller medio-lateral (ML) and anterio-posterior APAs compared to PD-FOG (DT, p < 0.05). PD+FOG had more co-contraction of left and right TFL during APAs compared to PD-FOG (p < 0.01). Within the PD+FOG, the ML size of APA (DT) was positively correlated with the severity of FOG history (NFOG-Q), with larger APAs associated with worse FOG (rho = 0.477, p = 0.025). ML APAs were larger during trials with observed FOG compared to trials of PD+FOG without FOG. Conclusions: People with PD who have a history of FOG have smaller ML APAs (weight shifting) during gait initiation compared to PD-FOG and HC. However, start hesitation (FOG) is not caused by an inability to sufficiently displace the center of mass toward the stance leg because APAs were larger during trials with observed FOG. We speculate that reducing the acceleration of the body center of mass with hip abductor co contraction for APAs might be a compensatory strategy in PD+FOG, to address postural control deficits and enable step initiation. PMID- 29497375 TI - Endogenous Antioxidant and LOX-Mediated Systems Contribute to the Hepatoprotective Activity of Aqueous Partition of Methanol Extract of Muntingia calabura L. Leaves against Paracetamol Intoxication. AB - Methanol extract of Muntingia calabura L. (family Muntingiaceae) leaf has been reported to exert various pharmacological activities including hepatoprotection. The present study was carried out to identify the most effective hepatoprotective partition derived from the extract and to determine the mechanisms of action involved. The extract was partitioned using solvents with different polarity to yield petroleum ether (PEMC), ethyl acetate (EAMC), and aqueous (AQMC) extracts. Each extract, at 250 mg/kg, was subjected to the paracetamol (PCM)-induced hepatotoxic assay and several parameters such as liver weight, liver/body weight ratio, serum liver enzymes' level, and histopathological examinations were determined. Each partition was also tested for their antioxidant and anti inflammatory potentials. The most effective extract (AQMC) was prepared in additional dose of 50 and 500 mg/kg, and then subjected to the same liver toxicity test in addition to the endogenous antioxidant enzymes assay. Moreover, AQMC was also subjected to the phytochemical screening and HPLC analysis. Overall, from the results obtained: AQMC exerted significant (p < 0.05): (i) antioxidant activity when assessed using the DPPH, SOD and ORAC assays with high TPC detected; (ii) anti-inflammatory activity via LOX, but not XO pathway; (iii) hepatoprotective activity indicated by its ability to reverse the effect of PCM on the liver weight and liver/body weight ratio, the level of serum liver enzymes (ALT, AST, and ALP), and activity of several endogenous antioxidant enzymes (SOD and CAT). Phytochemicals analyses demonstrated the presence of several flavonoid based bioactive compounds such as gallic acid and quercetin, which were reported to possess hepatoprotective activity. In conclusion, AQMC exerts hepatoprotective activity against the PCM-induced toxicity possibly by having a remarkable antioxidant potential and ability to activate the endogenous antioxidant system possibly via the synergistic action of its phytoconstituents. PMID- 29497376 TI - The Flavonoid Quercetin Ameliorates Liver Inflammation and Fibrosis by Regulating Hepatic Macrophages Activation and Polarization in Mice. AB - At present, there are no effective antifibrotic drugs for patients with chronic liver disease; hence, the development of antifibrotic therapies is urgently needed. Here, we performed an experimental and translational study to investigate the potential and underlying mechanism of quercetin treatment in liver fibrosis, mainly focusing on the impact of quercetin on macrophages activation and polarization. BALB/c mice were induced liver fibrosis by carbon tetrachloride (CCl4) for 8 weeks and concomitantly treated with quercetin (50 mg/kg) or vehicle by daily gavage. Liver inflammation, fibrosis, and hepatic stellate cells (HSCs) activation were examined. Moreover, massive macrophages accumulation, M1 macrophages and their related markers, such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and monocyte chemotactic protein-1 (MCP-1) in livers were analyzed. In vitro, we used Raw 264.7 cells to examine the effect of quercetin on M1-polarized macrophages activation. Our results showed that quercetin dramatically ameliorated liver inflammation, fibrosis, and inhibited HSCs activation. These results were attributed to the reductive recruitment of macrophages (F4/80+ and CD68+) into the liver in quercetin-treated fibrotic mice confirmed by immunostaining and expression levels of marker molecules. Importantly, quercetin strongly inhibited M1 polarization and M1-related inflammatory cytokines in fibrotic livers when compared with vehicle-treated mice. In vitro, studies further revealed that quercetin efficiently inhibited macrophages activation and M1 polarization, as well as decreased the mRNA expression of M1 macrophage markers such as TNF-alpha, IL-1beta, IL-6, and nitric oxide synthase 2. Mechanistically, the inhibition of M1 macrophages by quercetin was associated with the decreased levels of Notch1 expression on macrophages both in vivo and in vitro. Taken together, our data indicated that quercetin attenuated CCl4-induced liver inflammation and fibrosis in mice through inhibiting macrophages infiltration and modulating M1 macrophages polarization via targeting Notch1 pathway. Hence, quercetin holds promise as potential therapeutic agent for human fibrotic liver disease. PMID- 29497377 TI - Long-term Treatment with Low-Dose Caffeine Worsens BPSD-Like Profile in 3xTg-AD Mice Model of Alzheimer's Disease and Affects Mice with Normal Aging. AB - Coffee or caffeine has recently been suggested as prophylaxis for dementia. Although memory problems are hallmarks of Alzheimer's disease, this dementia is also characterized by neuropsychiatric symptoms called Behavioral and Psychological Symptoms of Dementia (BPSD). The impact of preventive/therapeutic strategies on both cognitive and non-cognitive symptoms can be addressed in the 3xTg-AD mice, since they exhibit cognitive but also BPSD-like profiles. Here, we studied the long-term effects of a low dose of caffeine in male 3xTg-AD mice and as compared to age-matched non-transgenic (NTg) counterparts with normal aging. Animals were treated (water or caffeine in drinking water) from adulthood (6 months of age) until middle-aged (13 months of age), that in 3xTg-AD mice correspond to onset of cognitive impairment and advanced stages, respectively. The low caffeine dosing used (0.3 mg/ml) was previously found to give a plasma concentration profile in mice roughly equivalent to that of a human coffee drinker. There were significant effects of caffeine on most behavioral variables, especially those related to neophobia and other anxiety-like behaviors, emotionality, and cognitive flexibility. The 3xTg-AD and NTg mice were differently influenced by caffeine. Overall, the increase of neophobia and other anxiety-related behaviors resulted in an exacerbation of BPSD-like profile in 3xTg-AD mice. Learning and memory, strongly influenced by anxiety in 3xTg-AD mice, got little benefit from caffeine, only shown after a detailed analysis of navigation strategies. The worsened pattern in NTg mice and the use of search strategies in 3xTg-AD mice make both groups more similar. Circadian motor activity showed genotype differences, which were found to be enhanced by caffeine. Selective effects of caffeine on NTg were found in the modulation of behaviors related to emotional profile and risk assessment. Caffeine normalized splenomegaly of 3xTg-AD mice, a physical indicator of their impaired peripheral immune system, and trended to increase their corticosterone levels. Our observations of adverse caffeine effects in an Alzheimer's disease model together with previous clinical observations suggest that an exacerbation of BPSD-like symptoms may partly interfere with the beneficial cognitive effects of caffeine. These results are relevant when coffee-derived new potential treatments for dementia are to be devised and tested. PMID- 29497378 TI - Anti-inflammatory Mechanism of Geniposide: Inhibiting the Hyperpermeability of Fibroblast-Like Synoviocytes via the RhoA/p38MAPK/NF-kappaB/F-Actin Signal Pathway. AB - Geniposide (GE) is the extraction and purification of iridoid glycosides from the Gardenia jasminoides Ellis, which is a promising anti-inflammatory drug, but its mechanism of actions on rheumatoid arthritis (RA) has not been clarified. This study investigated the molecular mechanism behind GE reduced the high permeability of fibroblast-like synoviocytes (FLSs) derived from SD rats with adjuvant arthritis (AA), with the aims of observing the action of GE in AA rats and exploring new therapeutic strategies for RA treatment. The CCK-8 method was used to detect FLSs proliferation. The pro-inflammatory cytokines levels and anti inflammatory cytokines levels in FLSs were determined by ELISA kits. FLSs permeability assay was performed on Transwell. Immunofluorescence was used to assay the arrangement and morphology of F-actin. The expression of the key molecules related to FLSs permeability (RhoA, p-p38MAPK, NF-kappaB p-p65 and F actin) was detected by western blotting. After treatment with lipopolysaccharide (LPS), the proliferation and the permeability of the cells increased significantly (all P < 0.05). The expression of RhoA, p-p38MAPK, NF-kappaB p-p65 and F-actin in FLSs was higher compared with the control group, and F-actin was redistributed, with the formation of additional stress fibers. But, these conditions were moderated after treatment with GE. We demonstrated that the treatment of different concentrations of GE (25, 50, and 100 MUg/mL) had a significant inhibitory effect on the proliferation and permeability of FLSs in vitro. Furthermore, the levels of interleukin (IL)-1beta and IL-17 secreted by FLSs were decreased in different doses of GE groups, and the levels of anti inflammatory cytokines (IL-4, TGF-beta1) were increased. Under treatment with GE, low expression of RhoA downregulated expression of p-p38MAPK, NF-kappaB p-p65, and F-actin while compared with control group, and restored the hyperpermeability of FLSs due to LPS treatment. Taken together, GE might play its anti-inflammatory and immunoregulatory effects via regulating the relative equilibrium of pro inflammatory cytokines and anti-inflammatory cytokines. GE attenuated the hyperpermeability of FLSs. The down-regulation of the conduction of RhoA/p38MAPK/NF-kappaB/F-actin signal may play a critical role in the mechanisms of GE on RA. GE could be an effective therapeutic agent for the treatment of RA. PMID- 29497380 TI - Triple-Gene Therapy for Stroke: A Proof-of-Concept in Vivo Study in Rats. AB - Natural brain repair after stroke is extremely limited, and current therapeutic options are even more scarce with no clinical break-through in sight. Despite restricted regeneration in the central nervous system, we have previously proved that human umbilical cord blood mono-nuclear cells (UCB-MC) transduced with adenoviral vectors carrying genes encoding vascular endothelial growth factor (VEGF), glial cell-derived neurotrophic factor (GDNF), and neural cell adhesion molecule (NCAM) successfully rescued neurons in amyotrophic lateral sclerosis and spinal cord injury. This proof-of-principle project was aimed at evaluating the beneficial effects of the same triple-gene approach in stroke. Rats subjected to distal occlusion of the middle cerebral artery were treated intrathecally with a combination of these genes either directly or using our cell-based (UCB-MC) approach. Various techniques and markers were employed to evaluate brain injury and subsequent recovery after treatment. Brain repair was most prominent when therapeutic genes were delivered via adenoviral vector- or UCB-MC-mediated approach. Remodeling of brain cortex in the stroke area was confirmed by reduction of infarct volume and attenuated neural cell death, depletion of astrocytes and microglial cells, and increase in the number of oligodendroglial cells and synaptic proteins expression. These results imply that intrathecal injection of genetically engineered UCB-MC over-expressing therapeutic molecules (VEGF, GDNF, and NCAM) following cerebral blood vessel occlusion might represent a novel avenue for future research into treating stroke. PMID- 29497381 TI - Delipidation of Plasma Has Minimal Effects on Human Butyrylcholinesterase. AB - Human butyrylcholinesterase (BChE) is purified in large quantities from Cohn fraction IV-4 to use for protection against the toxicity of chemical warfare agents. Small scale preliminary experiments use outdated plasma from the American Red Cross as the starting material for purifying BChE (P06276). Many of the volunteer donor plasma samples are turbid with fat, the donor having eaten fatty food before the blood draw. The turbid fat interferes with enzyme assays performed in the spectrophotometer and with column chromatography. Our goal was to find a method to remove fat from plasma without loss of BChE activity. Satisfactory delipidation was achieved by adding a solution of 10% dextran sulfate and calcium chloride to fatty plasma, followed by centrifugation, and filtration through a 0.8 MUm filter. Treatment with Aerosil also delipidated fatty plasma, but was accompanied by loss of 50% of the plasma volume. BChE activity and the BChE isozyme pattern on nondenaturing gel electrophoresis were unaffected by delipidation. BChE in delipidated plasma was efficiently captured by immobilized monoclonal antibodies B2 18-5 and mAb2. The immunopurified BChE was released from antibody binding with acid and visualized as a highly enriched, denatured BChE preparation by SDS gel electrophoresis. In conclusion, delipidation with dextran sulfate/CaCl2 preserves BChE activity and the tetramer structure of BChE. PMID- 29497379 TI - Molecular Evidence of Adenosine Deaminase Linking Adenosine A2A Receptor and CD26 Proteins. AB - Adenosine is an endogenous purine nucleoside that acts in all living systems as a homeostatic network regulator through many pathways, which are adenosine receptor (AR)-dependent and -independent. From a metabolic point of view, adenosine deaminase (ADA) is an essential protein in the regulation of the total intracellular and extracellular adenosine in a tissue. In addition to its cytosolic localization, ADA is also expressed as an ecto-enzyme on the surface of different cells. Dipeptidyl peptidase IV (CD26) and some ARs act as binding proteins for extracellular ADA in humans. Since CD26 and ARs interact with ADA at opposite sites, we have investigated if ADA can function as a cell-to-cell communication molecule by bridging the anchoring molecules CD26 and A2AR present on the surfaces of the interacting cells. By combining site-directed mutagenesis of ADA amino acids involved in binding to A2AR and a modification of the bioluminescence resonance energy transfer (BRET) technique that allows detection of interactions between two proteins expressed in different cell populations with low steric hindrance (NanoBRET), we show direct evidence of the specific formation of trimeric complexes CD26-ADA-A2AR involving two cells. By dynamic mass redistribution assays and ligand binding experiments, we also demonstrate that A2AR-NanoLuc fusion proteins are functional. The existence of this ternary complex is in good agreement with the hypothesis that ADA could bridge T-cells (expressing CD26) and dendritic cells (expressing A2AR). This is a new metabolic function for ecto-ADA that, being a single chain protein, it has been considered as an example of moonlighting protein, because it performs more than one functional role (as a catalyst, a costimulator, an allosteric modulator and a cell-to-cell connector) without partitioning these functions in different subunits. PMID- 29497383 TI - TRIM31 Deficiency Is Associated with Impaired Glucose Metabolism and Disrupted Gut Microbiota in Mice. AB - Tripartite motif-containing protein 31 (TRIM31), an E3 ubiquitin ligase of the tripartite motif family, plays an important role in the innate immune response. It can reduce the activity of the nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome. However, little information is about glucose metabolic health of TRIM31-deficient mice, and investigations about gut microbiota in TRIM31-deficient mice is limited. Thus, we aimed to compare glucose metabolic parameters, gut microbiota composition and inflammatory cytokine levels between TRIM31-/- and wild-type (WT) mice, and further investigate whether or not certain gut microbiota taxon correlates with specific metabolic parameters and inflammation cytokines in TRIM31-deficient mice. TRIM31-/- mice showed glucose intolerance and insulin resistance, with a significant difference in gut microbiota composition, characterized by increased abundance of Prevotellaceae and Veillonellaceae. TRIM31-/- mice with impaired glucose metabolism was accompanied by elevated serum tumor necrosis factor-alpha (TNF-alpha) and interleukin 1beta (IL-1beta) concentrations, as well as upregulated caecal TNF-alpha, IL-1beta, caspase-1, and NLRP3 expressions. Furthermore, elevated p-IRS-1/IRS-1 protein expression, and decreased Akt Thr308 phosphorylation were observed in TRIM31-/- mice. Prevotellaceae abundance was positively associated with caecal IL-1beta mRNA expression, and Veillonellaceae was associated with higher TNF-alpha mRNA expression and serum insulin concentration. In conclusion, our study is novel in showing that TRIM31 deficiency is associated with impaired glucose metabolism and disrupted gut microbiota in mice. This study contributes to the theoretical foundation on the potential relationship between TRIM31 deficiency and the development of abnormal glucose metabolism. PMID- 29497382 TI - Therapeutic Potential of Polyphenols in Cardiac Fibrosis. AB - Cardiac fibrosis, in response to injury and stress, is central to a broad constellation of cardiovascular diseases. Fibrosis decreases myocardial wall compliance due to extracellular matrix (ECM) accumulation, leading to impaired systolic and diastolic function and causing arrhythmogenesis. Although some conventional drugs, such as beta-blockers and renin-angiotensin-aldosterone system (RAAS) inhibitors, have been shown to alleviate cardiac fibrosis in clinical trials, these traditional therapies do not tend to target all the fibrosis-associated mechanisms, and do not hamper the progression of cardiac fibrosis in patients with heart failure. Polyphenols are present in vegetables, fruits, and beverages and had been proposed as attenuators of cardiac fibrosis in different models of cardiovascular diseases. Together with results found in the literature, we can show that some polyphenols exert anti-fibrotic and myocardial protective effects by mediating inflammation, oxidative stress, and fibrotic molecular signals. This review considers an overview of the mechanisms of cardiac fibrosis, illustrates their involvement in different animal models of cardiac fibrosis treated with some polyphenols and projects the future direction and therapeutic potential of polyphenols on cardiac fibrosis. PMID- 29497384 TI - Identification and Expression Patterns of Anoplophora chinensis (Forster) Chemosensory Receptor Genes from the Antennal Transcriptome. AB - The citrus long-horned beetle (CLB), Anoplophora chinensis (Forster) is a destructive native pest in China. Chemosensory receptors including odorant receptors (ORs), gustatory receptors (GRs), and ionotropic receptors (IRs) function to interface the insect with its chemical environment. In the current study, we assembled the antennal transcriptome of A. chinensis by next-generation sequencing. We assembled 44,938 unigenes from 64,787,784 clean reads and annotated their putative gene functions based on gene ontology (GO) and Clusters of Orthologous Groups of proteins (COG). Overall, 74 putative receptor genes from chemosensory receptor gene families, including 53 ORs, 17 GRs, and 4 IRs were identified. Expression patterns of these receptors on the antennae, maxillary and labial palps, and remaining body segments of both male and female A. chinensis were performed using quantitative real time-PCR (RT-qPCR). The results revealed that 23 ORs, 6 GRs, and 1 IR showed male-biased expression profiles, suggesting that they may play a significant role in sensing female-produced sex pheromones; whereas 8 ORs, 5 GRs, and 1 IR showed female-biased expression profiles, indicating that these receptors may be involved in some female-specific behaviors such as oviposition site seeking. These results lay a solid foundation for deeply understanding CLB olfactory processing mechanisms. Moreover, by comparing our results with those from chemosensory receptor studies in other cerambycid species, several highly probable pheromone receptor candidates were highlighted, which may facilitate the identification of additional pheromone and/or host attractants in CLB. PMID- 29497385 TI - Validation and Trustworthiness of Multiscale Models of Cardiac Electrophysiology. AB - Computational models of cardiac electrophysiology have a long history in basic science applications and device design and evaluation, but have significant potential for clinical applications in all areas of cardiovascular medicine, including functional imaging and mapping, drug safety evaluation, disease diagnosis, patient selection, and therapy optimisation or personalisation. For all stakeholders to be confident in model-based clinical decisions, cardiac electrophysiological (CEP) models must be demonstrated to be trustworthy and reliable. Credibility, that is, the belief in the predictive capability, of a computational model is primarily established by performing validation, in which model predictions are compared to experimental or clinical data. However, there are numerous challenges to performing validation for highly complex multi-scale physiological models such as CEP models. As a result, credibility of CEP model predictions is usually founded upon a wide range of distinct factors, including various types of validation results, underlying theory, evidence supporting model assumptions, evidence from model calibration, all at a variety of scales from ion channel to cell to organ. Consequently, it is often unclear, or a matter for debate, the extent to which a CEP model can be trusted for a given application. The aim of this article is to clarify potential rationale for the trustworthiness of CEP models by reviewing evidence that has been (or could be) presented to support their credibility. We specifically address the complexity and multi-scale nature of CEP models which makes traditional model evaluation difficult. In addition, we make explicit some of the credibility justification that we believe is implicitly embedded in the CEP modeling literature. Overall, we provide a fresh perspective to CEP model credibility, and build a depiction and categorisation of the wide-ranging body of credibility evidence for CEP models. This paper also represents a step toward the extension of model evaluation methodologies that are currently being developed by the medical device community, to physiological models. PMID- 29497386 TI - Psychosocial Variables Associated with Immunosuppressive Medication Non-Adherence after Renal Transplantation. AB - Introduction: Non-adherence to immunosuppressive medication is regarded as an important factor for graft rejection and loss after successful renal transplantation. Yet, results on prevalence and relationship with psychosocial parameters are heterogeneous. The main aim of this study was to investigate the association of immunosuppressive medication non-adherence and psychosocial factors. Methods: In 330 adult renal transplant recipients (>=12 months posttransplantation), health-related quality of life, depression, anxiety, social support, and subjective medication experiences were assessed, and their associations with patient-reported non-adherence was evaluated. Results: 33.6% of the patients admitted to be partially non-adherent. Non-adherence was associated with younger age, poorer social support, lower mental, but higher physical health related quality of life. There was no association with depression and anxiety. However, high proportions of clinically relevant depression and anxiety symptoms were apparent in both adherent and non-adherent patients. Conclusion: In the posttransplant follow-up, kidney recipients with lower perceived social support, lower mental and higher physical health-related quality of life, and younger age can be regarded as a risk group for immunosuppressive medication non-adherence. In follow-up contacts with kidney transplant patients, physicians may pay attention to these factors. Furthermore, psychosocial interventions to optimize immunosuppressive medication adherence can be designed on the basis of this information, especially including subjectively perceived physical health-related quality of life and fostering social support seems to be of importance. PMID- 29497388 TI - The Associations between Self-Reported Exposure to the Chernobyl Nuclear Disaster Zone and Mental Health Disorders in Ukraine. AB - Background: In 1986, Reactor 4 of the Chernobyl nuclear power plant near Pripyat, Ukraine exploded, releasing highly-radioactive materials into the surrounding environment. Although the physical effects of the disaster have been well documented, a limited amount of research has been conducted on association of the disaster with long-term, clinically-diagnosable mental health disorders. According to the diathesis-stress model, the stress of potential and unknown exposure to radioactive materials and the ensuing changes to ones life or environment due to the disaster might lead those with previous vulnerabilities to fall into a poor state of mental health. Previous studies of this disaster have found elevated symptoms of stress, substance abuse, anxiety, and depression in exposed populations, though often at a subclinical level. Materials and methods: With data from The World Mental Health Composite International Diagnostic Interview, a cross-sectional large mental health survey conducted in Ukraine by the World Health Organization, the mental health of Ukrainians was modeled with multivariable logistic regression techniques to determine if any long-term mental health disorders were association with reporting having lived in the zone affected by the Chernobyl nuclear disaster. Common classes of psychiatric disorders were examined as well as self-report ratings of physical and mental health. Results: Reporting that one lived in the Chernobyl-affected disaster zone was associated with a higher rate of alcohol disorders among men and higher rates of intermittent explosive disorders among women in a prevalence model. Subjects who lived in the disaster zone also had lower ratings of personal physical and mental health when compared to controls. Discussion: Stress resulting from disaster exposure, whether or not such exposure actually occurred or was merely feared, and ensuing changes in life circumstances is associated with increased rates of mental health disorders. Professionals assisting populations that are coping with the consequences of disaster should be aware of possible increases in psychiatric disorders as well as poorer perceptions regarding personal physical and mental health. PMID- 29497387 TI - Evaluation of Alcohol Preference and Drinking in msP Rats Bearing a Crhr1 Promoter Polymorphism. AB - Alcoholism is a pervasive societal problem, yet available pharmacotherapies fail to treat most sufferers. The type 1 corticotropin-releasing factor (CRF1) receptor has received much attention for its putative role in the progression to alcohol dependence, although at present its success in clinical trials has been limited. Two single-nucleotide polymorphisms in the rat Crhr1 promoter have been identified in the Marchigian substrain of Sardinian alcohol-preferring (msP) rats. Unlike other Wistar-derived alcohol-preferring lines, nondependent msP rats reduce their alcohol self-administration in response to CRF1 antagonists and show increased brain CRF1 expression. The current study tested the hypotheses that the A alleles in the Crhr1 promoter polymorphisms are: (1) unique to msP (vs. CRF1 antagonist-insensitive) alcohol-preferring lines and (2) associate with greater alcohol preference or intake. Two related polymorphisms were observed in which both loci on a given chromosome were either mutant variant (A) or wild-type (G) alleles within the distal Crhr1 promoter of 17/25 msP rats (68%), as compared to 0/23 Indiana P rats, 0/20 Sardinian alcohol-preferring rats bred at Scripps (Scr:sP) and 0/21 outbred Wistar rats. Alcohol consumption in msP rats did not differ according to the presence of Crhr1 A alleles, but greater alcohol preference (98%) was observed in A allele homozygous msP rats (AA) compared to msP rats with wild-type (GG, 91%) or heterozygous (GA, 91%) genotypes. The greater alcohol preference reflected decreased water intake, accompanied by reduced total calories consumed by AA rats. The data show that msP rats differentially possess mutant A variant alleles in the polymorphic promoter region of the Crhr1 gene that may differentially regulate consumption. PMID- 29497389 TI - Whole-Body Roll Tilt Influences Goal-Directed Upper Limb Movements through the Perceptual Tilt of Egocentric Reference Frame. AB - In our day-to-day life, we can accurately reach for an object in our gravitational environment without any effort. This can be achieved even when the body is tilted relative to gravity. This is accomplished by the central nervous system (CNS) compensation for gravitational forces and torque acting on the upper limbs, based on the magnitude of body tilt. The present study investigated how performance of upper limb movements was influenced by the alteration of body orientation relative to gravity. We observed the spatial trajectory of the index finger while the upper limb reached for a memorized target with the body tilted in roll plane. Results showed that the terminal location of the fingertip shifted toward the direction of body tilt away from the actual target location. The subsequent experiment examined if the perceived direction of the body longitudinal axis shifted relative to the true direction in roll plane. The results showed that the perceived direction of the body longitudinal axis shifted toward the direction of the body tilt, which correlated with the shift of the terminal location in the first experiment. These results suggest that the dissociation between the egocentric and gravitational coordinates induced by whole-body tilt leads to systematic shifts of the egocentric reference frame for action, which in turn influences the motor performance of goal-directed upper limb movements. PMID- 29497390 TI - Editorial: Multitasking: Executive Functioning in Dual-Task and Task Switching Situations. PMID- 29497391 TI - A Model to Predict Psychological- and Health-Related Adjustment in Men with Prostate Cancer: The Role of Post Traumatic Growth, Physical Post Traumatic Growth, Resilience and Mindfulness. AB - Background: Post traumatic growth (PTG) can be defined as positive change following a traumatic event. The current conceptualization of PTG encompasses five main dimensions, however, there is no dimension which accounts for the distinct effect of a physical trauma on PTG. The purpose of the present research was to test the role of PTG, physical post traumatic growth (PPTG), resilience and mindfulness in predicting psychological and health related adjustment. Method: Ethical approval was obtained from relevant institutional ethics committees. Participants (N = 241), who were at least 1 year post prostate cancer treatment, were invited to complete a battery of questionnaires either through an online survey or a paper and pencil package received in the post The sample ranged in age from 44 to 88 years (M = 64.02, SD = 7.76). Data were analysis using confirmatory factor analysis and structural equation modeling. Results: The physical post traumatic growth inventory (P-PTGI) was used to evaluate the role of PPTG in predicting adjustment using structural equation modeling. P-PTGI predicted lower distress and improvement of quality of life, whereas conversely, the traditional PTG measure was linked with poor adjustment. The relationship between resilience and adjustment was found to be mediated by P-PTGI. Conclusion: Findings suggest the central role of PTG in the prostate cancer survivorship experience is enhanced by the inclusion of PPTG. Adjusting to a physical trauma such as illness (internal transgressor) is unlike a trauma with an external transgressor as the physical trauma creates an entirely different framework for adjustment. The current study demonstrates the impact of PPTG on adjustment. This significantly adds to the theory of the development of PTG by highlighting the interplay of resilience with PTG, PPTG, and adjustment. PMID- 29497392 TI - Monitoring Processes in Visual Search Enhanced by Professional Experience: The Case of Orange Quality-Control Workers. AB - Visual search tasks have often been used to investigate how cognitive processes change with expertise. Several studies have shown visual experts' advantages in detecting objects related to their expertise. Here, we tried to extend these findings by investigating whether professional search experience could boost top down monitoring processes involved in visual search, independently of advantages specific to objects of expertise. To this aim, we recruited a group of quality control workers employed in citrus farms. Given the specific features of this type of job, we expected that the extensive employment of monitoring mechanisms during orange selection could enhance these mechanisms even in search situations in which orange-related expertise is not suitable. To test this hypothesis, we compared performance of our experimental group and of a well-matched control group on a computerized visual search task. In one block the target was an orange (expertise target) while in the other block the target was a Smurfette doll (neutral target). The a priori hypothesis was to find an advantage for quality controllers in those situations in which monitoring was especially involved, that is, when deciding the presence/absence of the target required a more extensive inspection of the search array. Results were consistent with our hypothesis. Quality-controllers were faster in those conditions that extensively required monitoring processes, specifically, the Smurfette-present and both target-absent conditions. No differences emerged in the orange-present condition, which resulted to mainly rely on bottom-up processes. These results suggest that top down processes in visual search can be enhanced through immersive real-life experience beyond visual expertise advantages. PMID- 29497393 TI - Is Social Categorization Spatially Organized in a "Mental Line"? Empirical Evidences for Spatial Bias in Intergroup Differentiation. AB - Social categorization is the differentiation between the self and others and between one's own group and other groups and it is such a natural and spontaneous process that often we are not aware of it. The way in which the brain organizes social categorization remains an unresolved issue. We present three experiments investigating the hypothesis that social categories are mentally ordered from left to right on an ingroup-outgroup continuum when membership is salient. To substantiate our hypothesis, we consider empirical evidence from two areas of psychology: research on differences in processing of ingroups and outgroups and research on the effects of spatial biases on processing of quantitative information (e.g., time; numbers) which appears to be arranged from left to right on a small-large continuum, an effect known as the spatial-numerical association of response codes (SNARC). In Experiments 1 and 2 we tested the hypothesis that when membership of a social category is activated, people implicitly locate ingroup categories to the left of a mental line whereas outgroup categories are located on the far right of the same mental line. This spatial organization persists even when stimuli are presented on one of the two sides of the screen and their (explicit) position is spatially incompatible with the implicit mental spatial organization of social categories (Experiment 3). Overall the results indicate that ingroups and outgroups are processed differently. The results are discussed with respect to social categorization theory, spatial agency bias, i.e., the effect observed in Western cultures whereby the agent of an action is mentally represented on the left and the recipient on the right, and the SNARC effect. PMID- 29497394 TI - ULTRA: Universal Grammar as a Universal Parser. AB - A central concern of generative grammar is the relationship between hierarchy and word order, traditionally understood as two dimensions of a single syntactic representation. A related concern is directionality in the grammar. Traditional approaches posit process-neutral grammars, embodying knowledge of language, put to use with infinite facility both for production and comprehension. This has crystallized in the view of Merge as the central property of syntax, perhaps its only novel feature. A growing number of approaches explore grammars with different directionalities, often with more direct connections to performance mechanisms. This paper describes a novel model of universal grammar as a one directional, universal parser. Mismatch between word order and interpretation order is pervasive in comprehension; in the present model, word order is language particular and interpretation order (i.e., hierarchy) is universal. These orders are not two dimensions of a unified abstract object (e.g., precedence and dominance in a single tree); rather, both are temporal sequences, and UG is an invariant real-time procedure (based on Knuth's stack-sorting algorithm) transforming word order into hierarchical order. This shift in perspective has several desirable consequences. It collapses linearization, displacement, and composition into a single performance process. The architecture provides a novel source of brackets (labeled unambiguously and without search), which are understood not as part-whole constituency relations, but as storage and retrieval routines in parsing. It also explains why neutral word order within single syntactic cycles avoids 213-like permutations. The model identifies cycles as extended projections of lexical heads, grounding the notion of phase. This is achieved with a universal processor, dispensing with parameters. The empirical focus is word order in noun phrases. This domain provides some of the clearest evidence for 213-avoidance as a cross-linguistic word order generalization. Importantly, recursive phrase structure "bottoms out" in noun phrases, which are typically a single cycle (though further cycles may be embedded, e.g., relative clauses). By contrast, a simple transitive clause plausibly involves two cycles (vP and CP), embedding further nominal cycles. In the present theory, recursion is fundamentally distinct from structure-building within a single cycle, and different word order restrictions might emerge in larger domains like clauses. PMID- 29497395 TI - Consequences of Disregarding Metric Invariance on Diagnosis and Prognosis Using Psychological Tests. PMID- 29497396 TI - The Fallacy of the Theoretical Meaning of Formative Constructs. PMID- 29497397 TI - Elevated Plasma Chemokines for Eosinophils in Neuromyelitis Optica Spectrum Disorders during Remission. AB - Background: A prominent pathological feature of neuromyelitis optica spectrum disorders (NMOSD) is markedly greater eosinophilic infiltration than that seen in other demyelinating diseases, like multiple sclerosis (MS). Eosinophils express the chemokine receptor CCR3, which is activated by eotaxins (CCL11/eotaxin-1, CCL24/eotaxin-2, CCL26/eotaxin-3) and CCL13 [monocyte chemoattractant protein (MCP)-4]. Moreover, CCL13 is part of the chemokine set that activates CCR2. The present study aimed to evaluate plasma levels of eotaxins (CCL11, CCL24, and CCL26) and MCPs (CCL13, CCL2, CCL8, and CCL7) in patients with NMOSD during remission. Methods: Healthy controls (HC; n = 30) and patients with MS (n = 47) and NMOSD (n = 58) in remission were consecutively enrolled in this study between January 2016 and August 2017. Plasma CCL11, CCL24, CCL26, CCL2, CCL8, CCL7, CCL13, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1beta levels were detected using the human cytokine multiplex assay. Results: Plasma CCL13, CCL11, and CCL26 levels were all significantly higher in patients with NMOSD than in HC and patients with MS. No significant differences were found in the CCL13, CCL11, or CCL26 levels between patients with NMOSD receiving and not receiving immunosuppressive therapy. The plasma levels of TNF-alpha and IL-1beta, which stimulate the above chemokines, were higher in patients with NMOSD than in HC. There was no difference in CCL24 levels among the three groups. In most cases, the CCL7 levels were below the threshold value of the human cytokine multiplex assay, which is in line with other studies. Adjusted multiple regression analyses showed a positive association of CCL13 levels with the number of relapses after controlling gender, age, body mass index, and disease duration in patients with NMOSD. Conclusion: The study indicates that in NMOSD, the overproduction of cytokines such as IL-1beta and TNF-alpha during remission stimulates eosinophilic chemoattractants such as CCL13, CCL11, and CCL26, which in turn bind to their receptor (CCR3); this could lead to eosinophil hypersensitivity. These findings suggest that the elevated secretion of CCL13, CCL11, and CCL26 may be a critical step in eosinophil recruitment during NMOSD remission. PMID- 29497398 TI - Cerebrospinal Fluid Presepsin As a Marker of Nosocomial Infections of the Central Nervous System: A Prospective Observational Study. AB - Background: Nosocomial CNS infection (NI-CNS) is a common and serious complication in neurocritical care patients. Timely, accurate diagnosis of NI-CNS is crucial, yet current infection markers lack specificity and/or sensitivity. Presepsin (PSP) is a novel biomarker of macrophage activation. Its utility in NI CNS has not been explored. We first determined the normal range of cerebrospinal fluid (CSF) PSP in a control group without brain injury before collecting data on CSF PSP levels in neurocritical care patients. Samples were analyzed in four groups defined by systemic and neurological infection status. Results: CSF PSP levels in 15 control patients without neurological injury were 50-100 pg/ml. Ninety-seven CSF samples were collected from 21 neurocritical care patients. In patients without NI-CNS or systemic infection, CSF PSP was 340.4 +/- 201.1 pg/ml. Isolated NI-CNS was associated with CSF PSP levels of 640.8 +/- 235.5 pg/ml, while levels in systemic infection without NI-CNS were 580.1 +/- 329.7 pg/ml. Patients with both NI-CNS and systemic infection had CSF PSP levels of 1,047.7 +/ 166.2 pg/ml. In neurocritical care patients without systemic infection, a cut off value of 321 pg/ml gives sensitivity and specificity for NI-CNS of 100 and 58.3%, respectively. Conclusion: CSF PSP may prove useful in diagnosing NI-CNS, but its current utility is as an additional marker only. PMID- 29497399 TI - Tau Filaments and the Development of Positron Emission Tomography Tracers. AB - A pathological pathway leading from soluble, monomeric to insoluble, filamentous Tau, is believed to underlie human Tauopathies. Cases of frontotemporal dementia are caused by dominantly inherited mutations in MAPT, the Tau gene. They show that dysfunction of Tau protein is sufficient to cause neurodegeneration and dementia. Extrapolation to the more common sporadic Tauopathies leads one to conclude that the pathological pathway is central to the development of all cases of disease, even if there are multiple reasons for Tau assembly. These findings are conceptually similar to those reported for beta-amyloid, alpha-synuclein and prion protein. Here, we provide an overview of Tau filaments and their positron emission tomography ligands. PMID- 29497400 TI - Luteal Coasting and Individualization of Human Chorionic Gonadotropin Dose after Gonadotropin-Releasing Hormone Agonist Triggering for Final Oocyte Maturation-A Retrospective Proof-of-Concept Study. AB - Ovarian stimulation in a gonadotropin-releasing hormone (GnRH) antagonist protocol with the use of GnRH agonist for final oocyte maturation is the state-of the-art treatment in patients with an expected or known high response to avoid or at least reduce significantly the risk for development of ovarian hyperstimulation syndrome (OHSS). Due to a shortened LH surge after administration of GnRH agonist in most patients, the luteal phase will be characterized by luteolysis and luteal phase insufficiency. Maintaining a sufficient luteal phase is crucial for achievement of a pregnancy; however, the optimal approach is still under debate. Administration of human chorionic gonadotropin (hCG) within 72 h rescues the corpora lutea function; however, the so far often used 1,500 IU still bear the risk for development of OHSS. The recently introduced concept of "luteal coasting" individualizes the luteal phase support by monitoring the progesterone concentrations and administering a rescue dosage of hCG when progesterone concentrations drop significantly. This retrospective proof-of-concept study explored the correlation between hCG dosages ranging from 375 up to 1,500 IU and the progesterone levels in the early and mid luteal phases as well as the likelihood of pregnancy, both early and ongoing. The chance of pregnancy is highest with progesterone level >=13 ng/ml at 48 h postoocyte retrieval. Among the small sample size of 52 women studied, it appears that appropriate progesterone levels can be achieved with hCG dosages as low as 375 IU. This may well optimize the chance of pregnancy while reducing the risk of OHSS associated with higher doses of hCG supplementation in the luteal phase. PMID- 29497401 TI - Indirect Basal Metabolism Estimation in Tailoring Recombinant Human TSH Administration in Patients Affected by Differentiated Thyroid Cancer: A Hypothesis-Generating Study. AB - Purpose: Recombinant human TSH (rhTSH) is currently used in follow-up of patients affected by differentiated thyroid cancer (DTC). Age, sex, weight, body mass index, body surface area (BSA) and renal function are known factors affecting serum TSH peak levels, but the proper rhTSH dose to deliver to single patient remains elusive. In this study, the correlations of basal metabolic rates with serum TSH peak following rhTSH administration were investigated. Methods: We evaluated 221 patients affected by thyroid cancer that received a standard dose rhTSH. Blood samples were collected at pre-established time points. Data on body weight, height, and BSA were collected. The Mifflin-St Jeor and Fleisch equations were used to assess basal metabolism. Results: The median value (range) of serum TSH peaks was 142 +/- 53 MUU/ml. Serum TSH peaks were significantly lower in males than in females (p = 0.04). TSH values also increased with age. Data showed a significant decrease of TSH peak levels at day 3 from the administration of rhTSH when basal metabolic rates increased (p = 0.002 and p = 0.009, respectively). Similar findings were observed at day 5 (p = 0.004 and p = 0.04, respectively). A multivariate analysis of several factors revealed that patients' basal metabolism (obtained using the Mifflin-St Jeor but not Fleisch equation) predicts serum TSH level peak at day 3 (p < 0.001). These results were used to generate a new formula based on Mifflin-StJeor equation which reveals as a promising tool in tailoring rhTSH dose. Conclusion: Basal metabolism appears an improving factor in tailoring diagnostic rhTSH dose in patients affected by DTC. PMID- 29497403 TI - Compatible Solute Synthesis and Import by the Moderate Halophile Spiribacter salinus: Physiology and Genomics. AB - Members of the genus Spiribacter are found worldwide and are abundant in ecosystems possessing intermediate salinities between seawater and saturated salt concentrations. Spiribacter salinus M19-40 is the type species of this genus and its first cultivated representative. In the habitats of S. salinus M19-40, high salinity is a key determinant for growth and we therefore focused on the cellular adjustment strategy to this persistent environmental challenge. We coupled these experimental studies to the in silico mining of the genome sequence of this moderate halophile with respect to systems allowing this bacterium to control its potassium and sodium pools, and its ability to import and synthesize compatible solutes. S. salinus M19-40 produces enhanced levels of the compatible solute ectoine, both under optimal and growth-challenging salt concentrations, but the genes encoding the corresponding biosynthetic enzymes are not organized in a canonical ectABC operon. Instead, they are scrambled (ectAC; ectB) and are physically separated from each other on the S. salinus M19-40 genome. Genomes of many phylogenetically related bacteria also exhibit a non-canonical organization of the ect genes. S. salinus M19-40 also synthesizes trehalose, but this compatible solute seems to make only a minor contribution to the cytoplasmic solute pool under osmotic stress conditions. However, its cellular levels increase substantially in stationary phase cells grown under optimal salt concentrations. In silico genome mining revealed that S. salinus M19-40 possesses different types of uptake systems for compatible solutes. Among the set of compatible solutes tested in an osmostress protection growth assay, glycine betaine and arsenobetaine were the most effective. Transport studies with radiolabeled glycine betaine showed that S. salinus M19-40 increases the pool size of this osmolyte in a fashion that is sensitively tied to the prevalent salinity of the growth medium. It was amassed in salt-stressed cells in unmodified form and suppressed the synthesis of ectoine. In conclusion, the data presented here allow us to derive a genome-scale picture of the cellular adjustment strategy of a species that represents an environmentally abundant group of ecophysiologically important halophilic microorganisms. PMID- 29497404 TI - Ammonia-Oxidizing Archaea Show More Distinct Biogeographic Distribution Patterns than Ammonia-Oxidizing Bacteria across the Black Soil Zone of Northeast China. AB - Black soils (Mollisols) of northeast China are highly productive and agriculturally important for food production. Ammonia-oxidizing microbes play an important role in N cycling in the black soils. However, the information related to the composition and distribution of ammonia-oxidizing microbes in the black soils has not yet been addressed. In this study, we used the amoA gene to quantify the abundance and community composition of ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB) across the black soil zone. The amoA abundance of AOA was remarkably larger than that of AOB, with ratios of AOA/AOB in the range from 3.1 to 91.0 across all soil samples. The abundance of AOA amoA was positively correlated with total soil C content (p < 0.001) but not with soil pH (p > 0.05). In contrast, the abundance of AOB amoA positively correlated with soil pH (p = 0.009) but not with total soil C. Alpha diversity of AOA did not correlate with any soil parameter, however, alpha diversity of AOB was affected by multiple soil factors, such as soil pH, total P, N, and C, available K content, and soil water content. Canonical correspondence analysis indicated that the AOA community was mainly affected by the sampling latitude, followed by soil pH, total P and C; while the AOB community was mainly determined by soil pH, as well as total P, C and N, water content, and sampling latitude, which highlighted that the AOA community was more geographically distributed in the black soil zone of northeast China than AOB community. In addition, the pairwise analyses showed that the potential nitrification rate (PNR) was not correlated with alpha diversity but weakly positively with the abundance of the AOA community (p = 0.048), whereas PNR significantly correlated positively with the richness (p = 0.003), diversity (p = 0.001) and abundance (p < 0.001) of the AOB community, which suggested that AOB community might make a greater contribution to nitrification than AOA community in the black soils when ammonium is readily available. PMID- 29497405 TI - Surveillance Data Highlights Feed Form, Biosecurity, and Disease Control as Significant Factors Associated with Salmonella Infection on Farrow-to-Finish Pig Farms. AB - Among the zoonotic pathogens affecting pigs, Salmonella stands out due to the high number of human cases linked to pork consumption. In the last two decades many countries have put considerable effort into the control of the infection by surveillance and control strategies on farm. Despite this effort, many herds still have a high Salmonella prevalence and they require guidance to address this problem. The present study, using the serological surveillance data of finishing pigs from the Irish National pig Salmonella Control Programme, aimed to highlight factors associated with increased risk or that might mitigate Salmonella occurrence on farm. A questionnaire with 33 questions regarding herd characteristics, management, feeding, biosecurity, and health was completed for 61 individual herds. After the multivariate analysis by linear regression, nine variables were retained in the final model and linked to herd seroprevalence. Home produced-feed linked to the use of meal showed an eight points reduction in Salmonella prevalence compared to purchased feed (p = 0.042). Different biosecurity measures were associated to lower seroprevalence. Changing of footwear from outside to inside the farm decreased seroprevalence nearly 20 units (p = 0.014) and policies not permitting access to the farmyard to feed trucks (p = 0.048) or avoiding the presence of cats on the farm (p = 0.05) were estimated in 10 units less of seroprevalence. In contrast, the lack of perimeter fence increased the chance to have higher seroprevalence in five units (p = 0.05). Finally, intestinal diseases such as swine dysentery (p = 0.044) and E. coli diarrhea (p = 0.1) were estimated to increase Salmonella prevalence in ~20 and 10 units, respectively, demonstrating the importance of controlling other enteric pathogens in an on-farm Salmonella control programme. These results show the usefulness of surveillance data to improve on-farm control and confirm that Salmonella infection in pigs is multi-factorial and the approach to its control should be multifaceted. PMID- 29497402 TI - Phylogenomics and Comparative Genomic Studies Robustly Support Division of the Genus Mycobacterium into an Emended Genus Mycobacterium and Four Novel Genera. AB - The genus Mycobacterium contains 188 species including several major human pathogens as well as numerous other environmental species. We report here comprehensive phylogenomics and comparative genomic analyses on 150 genomes of Mycobacterium species to understand their interrelationships. Phylogenetic trees were constructed for the 150 species based on 1941 core proteins for the genus Mycobacterium, 136 core proteins for the phylum Actinobacteria and 8 other conserved proteins. Additionally, the overall genome similarity amongst the Mycobacterium species was determined based on average amino acid identity of the conserved protein families. The results from these analyses consistently support the existence of five distinct monophyletic groups within the genus Mycobacterium at the highest level, which are designated as the "Tuberculosis-Simiae," "Terrae," "Triviale," "Fortuitum-Vaccae," and "Abscessus-Chelonae" clades. Some of these clades have also been observed in earlier phylogenetic studies. Of these clades, the "Abscessus-Chelonae" clade forms the deepest branching lineage and does not form a monophyletic grouping with the "Fortuitum-Vaccae" clade of fast growing species. In parallel, our comparative analyses of proteins from mycobacterial genomes have identified 172 molecular signatures in the form of conserved signature indels and conserved signature proteins, which are uniquely shared by either all Mycobacterium species or by members of the five identified clades. The identified molecular signatures (or synapomorphies) provide strong independent evidence for the monophyly of the genus Mycobacterium and the five described clades and they provide reliable means for the demarcation of these clades and for their diagnostics. Based on the results of our comprehensive phylogenomic analyses and numerous identified molecular signatures, which consistently and strongly support the division of known mycobacterial species into the five described clades, we propose here division of the genus Mycobacterium into an emended genus Mycobacterium encompassing the "Tuberculosis Simiae" clade, which includes all of the major human pathogens, and four novel genera viz. Mycolicibacterium gen. nov., Mycolicibacter gen. nov., Mycolicibacillus gen. nov. and Mycobacteroides gen. nov. corresponding to the "Fortuitum-Vaccae," "Terrae," "Triviale," and "Abscessus-Chelonae" clades, respectively. With the division of mycobacterial species into these five distinct groups, attention can now be focused on unique genetic and molecular characteristics that differentiate members of these groups. PMID- 29497406 TI - Detection and Characterization of Enteropathogenic and Shiga Toxin-Producing Escherichia coli Strains in Rattus spp. from Buenos Aires. AB - Enteropathogenic Escherichia coli (EPEC) and Shiga toxin-producing E. coli (STEC) are pathovars of E. coli that impact human health by causing childhood diseases. In this work, 118 synanthropic rodents of the genus Rattus from Buenos Aires, Argentina were evaluated as EPEC and STEC carriers. Rectal swab samples from captured animals were evaluated by conventional PCR to detect the presence of the eae, stx1, stx2, and rfbO157 genes. Twenty-one isolates were obtained (17 EPEC isolates from seven animals and four STEC isolates from the same animal). All EPEC isolates tested negative for the presence of the bfpA gene. One EPEC isolate carried the iha gene, and five EPEC isolates carried the toxB gene. STEC isolates exhibited two different virulence profiles: stx1a/stx2a/stx2c/stx2d/saa/ehxA/subA (3/4) and stx1a/stx2a/saa/ehxA/subA (1/4). EPEC isolate serotypes included O109:H46 (7), O71:H40 (4), O71:NM (2), O138:H40 (1), O108:H21 (1), O88:H25 (1), and O76:NM (1), and STEC isolates belonged to the O108:H11 (4) serotype. Antimicrobial susceptibility testing was carried out, and resistance to tetracycline was observed in one EPEC strain. Our results demonstrate that Rattus spp. may act as carriers of EPEC and STEC strains and may be involved in the epidemiology of diarrheal disease in infancy. PMID- 29497407 TI - Peste des Petits Ruminants Virus Enters Caprine Endometrial Epithelial Cells via the Caveolae-Mediated Endocytosis Pathway. AB - Peste des petits ruminants virus (PPRV) causes an acute and highly contagious disease of sheep and goats and has spread with alarming speed around the world. The pathology of Peste des petits ruminants is linked to retrogressive changes and necrotic lesions in lymphoid tissues and epithelial cells. However, the process of PPRV entry into host epithelial cells remains largely unknown. Here, we performed a comprehensive study of the entry mechanism of PPRV into caprine endometrial epithelial cells (EECs). We clearly demonstrated that PPRV internalization was inhibited by chloroquine and ammonium chloride, which elevate the pH of various organelles. However, PPRV entry was not affected by chlorpromazine and knockdown of the clathrin heavy chain in EECs. In addition, we found that the internalization of PPRV was dependent on dynamin and membrane cholesterol and was suppressed by silencing of caveolin-1. Macropinocytosis did not play a role, but phosphatidylinositol 3-kinase (PI3K) was required for PPRV internalization. Cell type and receptor-dependent differences indicated that PPRV entry into caprine fetal fibroblast cells (FFCs) occurred via a different route. Taken together, our findings demonstrate that PPRV enters EECs through a cholesterol-dependent caveolae-mediated uptake mechanism that is pH-dependent and requires dynamin and PI3K but is independent of clathrin. This potentially provides insight into the entry mechanisms of other morbilliviruses. PMID- 29497408 TI - Recent Insights on Biological and Ecological Aspects of Ectomycorrhizal Fungi and Their Interactions. AB - The roots of most terrestrial plants are colonized by mycorrhizal fungi. They play a key role in terrestrial environments influencing soil structure and ecosystem functionality. Around them a peculiar region, the mycorrhizosphere, develops. This is a very dynamic environment where plants, soil and microorganisms interact. Interest in this fascinating environment has increased over the years. For a long period the knowledge of the microbial populations in the rhizosphere has been limited, because they have always been studied by traditional culture-based techniques. These methods, which only allow the study of cultured microorganisms, do not allow the characterization of most organisms existing in nature. The introduction in the last few years of methodologies that are independent of culture techniques has bypassed this limitation. This together with the development of high-throughput molecular tools has given new insights into the biology, evolution, and biodiversity of mycorrhizal associations, as well as, the molecular dialog between plants and fungi. The genomes of many mycorrhizal fungal species have been sequenced so far allowing to better understanding the lifestyle of these fungi, their sexual reproduction modalities and metabolic functions. The possibility to detect the mycelium and the mycorrhizae of heterothallic fungi has also allowed to follow the spatial and temporal distributional patterns of strains of different mating types. On the other hand, the availability of the genome sequencing from several mycorrhizal fungi with a different lifestyle, or belonging to different groups, allowed to verify the common feature of the mycorrhizal symbiosis as well as the differences on how different mycorrhizal species interact and dialog with the plant. Here, we will consider the aspects described before, mainly focusing on ectomycorrhizal fungi and their interactions with plants and other soil microorganisms. PMID- 29497409 TI - Verticillium dahliae-Arabidopsis Interaction Causes Changes in Gene Expression Profiles and Jasmonate Levels on Different Time Scales. AB - Verticillium dahliae is a soil-borne vascular pathogen that causes severe wilt symptoms in a wide range of plants. Co-culture of the fungus with Arabidopsis roots for 24 h induces many changes in the gene expression profiles of both partners, even before defense-related phytohormone levels are induced in the plant. Both partners reprogram sugar and amino acid metabolism, activate genes for signal perception and transduction, and induce defense- and stress-responsive genes. Furthermore, analysis of Arabidopsis expression profiles suggests a redirection from growth to defense. After 3 weeks, severe disease symptoms can be detected for wild-type plants while mutants impaired in jasmonate synthesis and perception perform much better. Thus, plant jasmonates have an important influence on the interaction, which is already visible at the mRNA level before hormone changes occur. The plant and fungal genes that rapidly respond to the presence of the partner might be crucial for early recognition steps and the future development of the interaction. Thus they are potential targets for the control of V. dahliae-induced wilt diseases. PMID- 29497410 TI - A Novel Antimicrobial Coating Represses Biofilm and Virulence-Related Genes in Methicillin-Resistant Staphylococcus aureus. AB - Methicillin-resistant Staphylococcus aureus (MRSA) has become an important cause of hospital-acquired infections worldwide. It is one of the most threatening pathogens due to its multi-drug resistance and strong biofilm-forming capacity. Thus, there is an urgent need for novel alternative strategies to combat bacterial infections. Recently, we demonstrated that a novel antimicrobial surface coating, AGXX(r), consisting of micro-galvanic elements of the two noble metals, silver and ruthenium, surface-conditioned with ascorbic acid, efficiently inhibits MRSA growth. In this study, we demonstrated that the antimicrobial coating caused a significant reduction in biofilm formation (46%) of the clinical MRSA isolate, S. aureus 04-02981. To understand the molecular mechanism of the antimicrobial coating, we exposed S. aureus 04-02981 for different time-periods to the coating and investigated its molecular response via next-generation RNA sequencing. A conventional antimicrobial silver coating served as a control. RNA sequencing demonstrated down-regulation of many biofilm-associated genes and of genes related to virulence of S. aureus. The antimicrobial substance also down regulated the two-component quorum-sensing system agr suggesting that it might interfere with quorum-sensing while diminishing biofilm formation in S. aureus 04 02981. PMID- 29497411 TI - Structural and Biochemical Characterization of BdsA from Bacillus subtilis WU S2B, a Key Enzyme in the "4S" Desulfurization Pathway. AB - Dibenzothiophene (DBT) and their derivatives, accounting for the major part of the sulfur components in crude oil, make one of the most significant pollution sources. The DBT sulfone monooxygenase BdsA, one of the key enzymes in the "4S" desulfurization pathway, catalyzes the oxidation of DBT sulfone to 2' hydroxybiphenyl 2-sulfonic acid (HBPSi). Here, we determined the crystal structure of BdsA from Bacillus subtilis WU-S2B, at the resolution of 2.2 A, and the structure of the BdsA-FMN complex at 2.4 A. BdsA and the BdsA-FMN complex exist as tetramers. DBT sulfone was placed into the active site by molecular docking. Seven residues (Phe12, His20, Phe56, Phe246, Val248, His316, and Val372) are found to be involved in the binding of DBT sulfone. The importance of these residues is supported by the study of the catalytic activity of the active site variants. Structural analysis and enzyme activity assay confirmed the importance of the right position and orientation of FMN and DBT sulfone, as well as the involvement of Ser139 as a nucleophile in catalysis. This work combined with our previous structure of DszC provides a systematic structural basis for the development of engineered desulfurization enzymes with higher efficiency and stability. PMID- 29497412 TI - Metagenomic Analysis of a Biphenyl-Degrading Soil Bacterial Consortium Reveals the Metabolic Roles of Specific Populations. AB - Polychlorinated biphenyls (PCBs) are widespread persistent pollutants that cause several adverse health effects. Aerobic bioremediation of PCBs involves the activity of either one bacterial species or a microbial consortium. Using multiple species will enhance the range of PCB congeners co-metabolized since different PCB-degrading microorganisms exhibit different substrate specificity. We have isolated a bacterial consortium by successive enrichment culture using biphenyl (analog of PCBs) as the sole carbon and energy source. This consortium is able to grow on biphenyl, benzoate, and protocatechuate. Whole-community DNA extracted from the consortium was used to analyze biodiversity by Illumina sequencing of a 16S rRNA gene amplicon library and to determine the metagenome by whole-genome shotgun Illumina sequencing. Biodiversity analysis shows that the consortium consists of 24 operational taxonomic units (>=97% identity). The consortium is dominated by strains belonging to the genus Pseudomonas, but also contains betaproteobacteria and Rhodococcus strains. whole-genome shotgun (WGS) analysis resulted in contigs containing 78.3 Mbp of sequenced DNA, representing around 65% of the expected DNA in the consortium. Bioinformatic analysis of this metagenome has identified the genes encoding the enzymes implicated in three pathways for the conversion of biphenyl to benzoate and five pathways from benzoate to tricarboxylic acid (TCA) cycle intermediates, allowing us to model the whole biodegradation network. By genus assignment of coding sequences, we have also been able to determine that the three biphenyl to benzoate pathways are carried out by Rhodococcus strains. In turn, strains belonging to Pseudomonas and Bordetella are the main responsible of three of the benzoate to TCA pathways while the benzoate conversion into TCA cycle intermediates via benzoyl-CoA and the catechol meta-cleavage pathways are carried out by beta proteobacteria belonging to genera such as Achromobacter and Variovorax. We have isolated a Rhodococcus strain WAY2 from the consortium which contains the genes encoding the three biphenyl to benzoate pathways indicating that this strain is responsible for all the biphenyl to benzoate transformations. The presented results show that metagenomic analysis of consortia allows the identification of bacteria active in biodegradation processes and the assignment of specific reactions and pathways to specific bacterial groups. PMID- 29497413 TI - The Small RNA ErsA of Pseudomonas aeruginosa Contributes to Biofilm Development and Motility through Post-transcriptional Modulation of AmrZ. AB - The small RNA ErsA of Pseudomonas aeruginosa was previously suggested to be involved in biofilm formation via negative post-transcriptional regulation of the algC gene that encodes the virulence-associated enzyme AlgC, which provides sugar precursors for the synthesis of several polysaccharides. In this study, we show that a knock-out ersA mutant strain forms a flat and uniform biofilm, not characterized by mushroom-multicellular structures typical of a mature biofilm. Conversely, the knock-out mutant strain showed enhanced swarming and twitching motilities. To assess the influence of ErsA on the P. aeruginosa transcriptome, we performed RNA-seq experiments comparing the knock-out mutant with the wild type. More than 160 genes were found differentially expressed in the knock-out mutant. Parts of these genes, important for biofilm formation and motility regulation, are known to belong also to the AmrZ transcriptional regulator regulon. Here, we show that ErsA binds in vitro and positively regulates amrZ mRNA at post-transcriptional level in vivo suggesting an interesting contribution of the ErsA-amrZ mRNA interaction in biofilm development at several regulatory levels. PMID- 29497414 TI - Survival of Listeria monocytogenes and Staphylococcus aureus in Synthetic Brines. Studying the Effects of Salt, Temperature and Sugar through the Approach of the Design of Experiments. AB - The fermentation of table olives relies on a complex microbiota of lactic acid bacteria (LAB), yeasts, and enterobacteria. Producers often add sugar to increase the growth rate of LAB, "but this practice could also increase the survival rate of some pathogens. Therefore, the main topic of this paper was to study the effect of sugar, salt and temperature on the survival of Staphylococcus aureus and Listeria monocytogenes in a synthetic brine through the theory of the Design of Experiments (simplex centroid). The addition of sugar could prolong the survival time of L. monocytogenes by 40 days, whereas an increase of the temperature caused a decrease of survival from 18 to 3 days. The survival time of S. aureus was prolonged by 50 days by combining sugar (2-4 g/l) and low temperatures (5-15 degrees C). The use of desirability approach and prediction profiles suggests that the prolongation of the survival time of L. monocytogenes could be related to a shift in the geometrical shape of the death kinetic. This paper offers a structured statistical approach on the variables acting on the survival of two pathogens in brines and represents the first step to set up and design a predictive approach for olive producers. PMID- 29497415 TI - Yeast Immobilization Systems for Alcoholic Wine Fermentations: Actual Trends and Future Perspectives. AB - Yeast immobilization is defined as the physical confinement of intact cells to a region of space with conservation of biological activity. The use of these methodologies for alcoholic fermentation (AF) offers many advantages over the use of the conventional free yeast cell method and different immobilization systems have been proposed so far for different applications, like winemaking. The most studied methods for yeast immobilization include the use of natural supports (e.g., fruit pieces), organic supports (e.g., alginate), inorganic (e.g., porous ceramics), membrane systems, and multi-functional agents. Some advantages of the yeast-immobilization systems include: high cell densities, product yield improvement, lowered risk of microbial contamination, better control and reproducibility of the processes, as well as reuse of the immobilization system for batch fermentations and continuous fermentation technologies. However, these methods have some consequences on the behavior of the yeasts, affecting the final products of the fermentative metabolism. This review compiles current information about cell immobilizer requirements for winemaking purposes, the immobilization methods applied to the production of fermented beverages to date, and yeast physiological consequences of immobilization strategies. Finally, a recent inter species immobilization methodology has been revised, where yeast cells are attached to the hyphae of a Generally Recognized As Safe fungus and remain adhered following loss of viability of the fungus. The bio-capsules formed with this method open new and promising strategies for alcoholic beverage production (wine and low ethanol content beverages). PMID- 29497416 TI - Epigallocatechin Gallate-Mediated Cell Death Is Triggered by Accumulation of Reactive Oxygen Species Induced via the Cpx Two-Component System in Escherichia coli. AB - The high antimicrobial activity of epigallocatechin gallate (EGCG), the most bioactive component of tea polyphenol with a number of health benefits, is well known. However, little is known about the mechanism involved. Here, we discovered the relationship between reactive oxygen species (ROS), the Cpx system, and EGCG mediated cell death. We first found an increase in ampicillin resistance as well as the transcription level of a LD-transpeptidase (LD-TPase) involved in cell wall synthesis; ycbB transcription was upregulated whereas that of another LD TPase, ynhG, appeared to be constant after a short exposure of Escherichia coli to sub-inhibitory doses of EGCG. Additionally, the transcription level of cpxP, a downstream gene belonging to the Cpx regulon, was positively correlated with the concentration of EGCG, and significant upregulation was detected when cells were treated with high doses of EGCG. Through analysis of a cpxR deletion strain (DeltacpxR), we identified a constant ROS level and a notable increase in the survival rate of DeltacpxR, while the ROS level increased and the survival rate decreased remarkably in the wild-type strain. Furthermore, thiourea, which is an antioxidant, reduced the ROS level and antimicrobial activity of EGCG. Taken together, these results suggest that EGCG induces ROS formation by activating the Cpx system and mediates cell death. PMID- 29497417 TI - The Possible Effect of B-Cell Epitopes of Epstein-Barr Virus Early Antigen, Membrane Antigen, Latent Membrane Protein-1, and -2A on Systemic Lupus Erythematosus. AB - This study was aimed to evaluate the role of B-cell epitopes of Epstein-Barr virus (EBV) Early antigen protein D (EA), envelope glycoprotein GP340/membrane antigen (MA), latent membrane protein (LMP)-1, and LMP-2A in systemic lupus erythematosus (SLE). B-cell epitopes were predicted by analyzing secondary structure, transmembrane domains, surface properties, and homological comparison. 60 female mice were randomized equally into 12 groups: 1-10 groups were immunized by epitope peptides (EPs) 1-10, respectively, while 11 and 12 groups were PBS and Keyhole limpet hemocyanin (KLH) control groups. Immunoglobulin G (IgG) and autoantibody to nuclear antigen (ANA) concentrations in mice serum were determined at week 8. Indirect levels of EP1-10 were further detected by enzyme linked immuno sorbent assay (ELISA) in 119 SLE patients and 64 age- and gender matched health controls (HCs). 10 probable EBV EA, MA, LMP-1, and LMP-2A B-cell epitopes related to SLE self-antigens were predicted and corresponding EP1-10 were synthesized. IgG concentrations at week 8 were increased in EP1-10 and KLH groups compared with PBS group in mice; while ANA levels were elevated in only EP1-4, EP6-7, and EP10 groups compared to KLH group by ELISA, and ANA-positive rates were increased in only EP1, EP2, EP4, EP6, and EP10 groups by indirect immunofluorescence assay. EP1-4, EP6, and EP10 indirect levels were increased in SLE patients than HCs, while EP1, EP3, EP6, and EP9 were correlated with SLE disease activity index score. In conclusion, EBV EA, MA, LMP-1, and LMP-2A B-cell EPs increased SLE-related autoantibodies in mice, and their indirect levels might be served as potential biomarkers for SLE diagnosis and disease severity. PMID- 29497418 TI - African Trypanosomiasis-Associated Anemia: The Contribution of the Interplay between Parasites and the Mononuclear Phagocyte System. AB - African trypanosomosis (AT) is a chronically debilitating parasitic disease of medical and economic importance for the development of sub-Saharan Africa. The trypanosomes that cause this disease are extracellular protozoan parasites that have developed efficient immune escape mechanisms to manipulate the entire host immune response to allow parasite survival and transmission. During the early stage of infection, a profound pro-inflammatory type 1 activation of the mononuclear phagocyte system (MPS), involving classically activated macrophages (i.e., M1), is required for initial parasite control. Yet, the persistence of this M1-type MPS activation in trypanosusceptible animals causes immunopathology with anemia as the most prominent pathological feature. By contrast, in trypanotolerant animals, there is an induction of IL-10 that promotes the induction of alternatively activated macrophages (M2) and collectively dampens tissue damage. A comparative gene expression analysis between M1 and M2 cells identified galectin-3 (Gal-3) and macrophage migration inhibitory factor (MIF) as novel M1-promoting factors, possibly acting synergistically and in concert with TNF-alpha during anemia development. While Gal-3 enhances erythrophagocytosis, MIF promotes both myeloid cell recruitment and iron retention within the MPS, thereby depriving iron for erythropoiesis. Hence, the enhanced erythrophagocytosis and suppressed erythropoiesis lead to anemia. Moreover, a thorough investigation using MIF-deficient mice revealed that the underlying mechanisms in AT-associated anemia development in trypanosusceptible and tolerant animals are quite distinct. In trypanosusceptible animals, anemia resembles anemia of inflammation, while in trypanotolerant animals' hemodilution, mainly caused by hepatosplenomegaly, is an additional factor contributing to anemia. In this review, we give an overview of how trypanosome- and host-derived factors can contribute to trypanosomosis-associated anemia development with a focus on the MPS system. Finally, we will discuss potential intervention strategies to alleviate AT-associated anemia that might also have therapeutic potential. PMID- 29497419 TI - C-Type Lectin-Like Receptors As Emerging Orchestrators of Sterile Inflammation Represent Potential Therapeutic Targets. AB - Over the last decade, C-type lectin-like receptors (CTLRs), expressed mostly by myeloid cells, have gained increasing attention for their role in the fine tuning of both innate and adaptive immunity. Not only CTLRs recognize pathogen-derived ligands to protect against infection but also endogenous ligands such as self carbohydrates, proteins, or lipids to control homeostasis and tissue injury. Interestingly, CTLRs act as antigen-uptake receptors via their carbohydrate recognition domain for internalization and subsequent presentation to T-cells. Furthermore, CTLRs signal through a complex intracellular network leading to the secretion of a particular set of cytokines that differently polarizes downstream effector T-cell responses according to the ligand and pattern recognition receptor co-engagement. Thus, by orchestrating the balance between inflammatory and resolution pathways, CTLRs are now considered as driving players of sterile inflammation whose dysregulation leads to the development of various pathologies such as autoimmune diseases, allergy, or cancer. For examples, the macrophage inducible C-type lectin (MINCLE), by sensing glycolipids released during cell damage, promotes skin allergy and the pathogenesis of experimental autoimmune uveoretinitis. Besides, recent studies described that tumors use physiological process of the CTLRs' dendritic cell-associated C-type lectin-1 (DECTIN-1) and MINCLE to locally suppress myeloid cell activation and promote immune evasion. Therefore, we aim here to overview the current knowledge of the pivotal role of CTLRs in sterile inflammation with special attention given to the "Dectin-1" and "Dectin-2" families. Moreover, we will discuss the potential of these receptors as promising therapeutic targets to treat a wide range of acute and chronic diseases. PMID- 29497421 TI - Engineered T Regulatory Type 1 Cells for Clinical Application. AB - T regulatory cells, a specialized subset of T cells, are key players in modulating antigen (Ag)-specific immune responses in vivo. Inducible T regulatory type 1 (Tr1) cells are characterized by the co-expression of CD49b and lymphocyte activation gene 3 (LAG-3) and the ability to secrete IL-10, TGF-beta, and granzyme (Gz) B, in the absence of IL-4 and IL-17. The chief mechanisms by which Tr1 cells control immune responses are secretion of IL-10 and TGF-beta and killing of myeloid cells via GzB. Tr1 cells, first described in peripheral blood of patients who developed tolerance after HLA-mismatched fetal liver hematopoietic stem cell transplantation, have been proven to modulate inflammatory and effector T cell responses in several immune-mediated diseases. The possibility to generate and expand Tr1 cells in vitro in an Ag-specific manner has led to their clinical use as cell therapy in patients. Clinical grade protocols to generate or to enrich and expand Tr1 cell medicinal products have been established. Proof-of-concept clinical trials with Tr1 cell products have demonstrated the safety and the feasibility of this approach and indicated some clinical benefit. In the present review, we provide an overview on protocols established to induce/expand Tr1 cells in vitro for clinical application and on results obtained in Tr1 cell-based clinical trials. Moreover, we will discuss a recently developed protocol to efficient convert human CD4+ T cells into a homogeneous population of Tr1-like cells by lentiviral vector-mediated IL-10 gene transfer. PMID- 29497422 TI - Respiratory Influenza A Virus Infection Triggers Local and Systemic Natural Killer Cell Activation via Toll-Like Receptor 7. AB - The innate immune system senses influenza A virus (IAV) through different pathogen-recognition receptors including Toll-like receptor 7 (TLR7). Downstream of viral recognition natural killer (NK) cells are activated as part of the anti IAV immune response. Despite the known decisive role of TLR7 for NK cell activation by therapeutic immunostimulatory RNAs, the contribution of TLR7 to the NK cell response following IAV infection has not been addressed. We have analyzed lung cytokine responses as well as the activation, interferon (IFN)-gamma production, and cytotoxicity of lung and splenic NK cells following sublethal respiratory IAV infection in wild-type and TLR7ko mice. Early airway IFN-gamma levels as well as the induction of lung NK cell CD69 expression and IFN-gamma production in response to IAV infection were significantly attenuated in TLR7 deficient hosts. Strikingly, respiratory IAV infection also primed splenic NK cells for IFN-gamma production, degranulation, and target cell lysis, all of which were fully dependent on TLR7. At the same time, lung type I IFN levels were significantly reduced in TLR7ko mice early following IAV infection, displaying a potential upstream mechanism of the attenuated NK cell activation observed. Taken together, our data clearly demonstrate a specific role for TLR7 signaling in local and systemic NK cell activation following respiratory IAV infection despite the presence of redundant innate IAV-recognition pathways. PMID- 29497424 TI - Interleukin (IL)-6 Inhibits IL-27- and IL-30-Mediated Inflammatory Responses in Human Monocytes. AB - Interleukin (IL)-30, the IL-27p28 subunit of the heterodimeric cytokine IL-27, acts as an antagonist of IL-27 and IL-6 signaling in murine cells via glycoprotein 130 (gp130) receptor and additional binding partners. Thus far, functions of IL-30 have not been fully elucidated in human cells. We demonstrate that like IL-27, IL-30 upregulated TLR4 expression to enhance lipopolysaccharide induced TNF-alpha production in human monocytes; however, these IL-30-mediated activities did not reach the same levels of cytokine induction compared to IL-27. Interestingly, IL-30- and IL-27-mediated interferon-gamma-induced protein 10 (IP 10) production required WSX-1 engagement and signal transducer and activator of transcription (STAT) 3 phosphorylation; furthermore, IL-30 induced STAT phosphorylation after 16 h, whereas IL-27 induced STAT phosphorylation within 30 min. This prompted us to examine if a secondary mediator was required for IL-30 induced pro-inflammatory functions, and hence we examined IL-6-related molecules. Combined with inhibition of soluble IL-6 receptor alpha (sIL-6Ralpha) and data showing that IL-6 inhibited IL-30/IL-27-induced IP-10 expression, we demonstrate a role for sIL-6Ralpha and gp130 in IL-30-mediated activity in human cells. PMID- 29497423 TI - Whole-Genome Expression Profiling in Skin Reveals SYK As a Key Regulator of Inflammation in Experimental Epidermolysis Bullosa Acquisita. AB - Because of the morbidity and limited therapeutic options of autoimmune diseases, there is a high, and thus far, unmet medical need for development of novel treatments. Pemphigoid diseases, such as epidermolysis bullosa acquisita (EBA), are prototypical autoimmune diseases that are caused by autoantibodies targeting structural proteins of the skin, leading to inflammation, mediated by myeloid cells. To identify novel treatment targets, we performed cutaneous genome-wide mRNA expression profiling in 190 outbred mice after EBA induction. Comparison of genome-wide mRNA expression profiles in diseased and healthy mice, and construction of a co-expression network identified Sykb (spleen tyrosine kinase, SYK) as a major hub gene. Aligned, pharmacological SYK inhibition protected mice from experimental EBA. Using lineage-specific SYK-deficient mice, we identified SYK expression on myeloid cells to be required to induce EBA. Within the predicted co-expression network, interactions of Sykb with several partners (e.g., Tlr13, Jdp2, and Nfkbid) were validated by curated databases. Additionally, novel gene interaction partners of SYK were experimentally validated. Collectively, our results identify SYK expression in myeloid cells as a requirement to promote inflammation in autoantibody-driven pathologies. This should encourage exploitation of SYK and SYK-regulated genes as potential therapeutic targets for EBA and potentially other autoantibody-mediated diseases. PMID- 29497420 TI - Infection Elicited Autoimmunity and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Explanatory Model. AB - Myalgic encephalomyelitis (ME) often also called chronic fatigue syndrome (ME/CFS) is a common, debilitating, disease of unknown origin. Although a subject of controversy and a considerable scientific literature, we think that a solid understanding of ME/CFS pathogenesis is emerging. In this study, we compiled recent findings and placed them in the context of the clinical picture and natural history of the disease. A pattern emerged, giving rise to an explanatory model. ME/CFS often starts after or during an infection. A logical explanation is that the infection initiates an autoreactive process, which affects several functions, including brain and energy metabolism. According to our model for ME/CFS pathogenesis, patients with a genetic predisposition and dysbiosis experience a gradual development of B cell clones prone to autoreactivity. Under normal circumstances these B cell offsprings would have led to tolerance. Subsequent exogenous microbial exposition (triggering) can lead to comorbidities such as fibromyalgia, thyroid disorder, and orthostatic hypotension. A decisive infectious trigger may then lead to immunization against autoantigens involved in aerobic energy production and/or hormone receptors and ion channel proteins, producing postexertional malaise and ME/CFS, affecting both muscle and brain. In principle, cloning and sequencing of immunoglobulin variable domains could reveal the evolution of pathogenic clones. Although evidence consistent with the model accumulated in recent years, there are several missing links in it. Hopefully, the hypothesis generates testable propositions that can augment the understanding of the pathogenesis of ME/CFS. PMID- 29497425 TI - Histopathological Correlations between Mediastinal Fat-Associated Lymphoid Clusters and the Development of Lung Inflammation and Fibrosis following Bleomycin Administration in Mice. AB - Bleomycin (BLM) has been reported to induce lung inflammation and fibrosis in human and mice and showed genetic susceptibility. Interestingly, the C57BL/6 (B6) mice had prominent mediastinal fat-associated lymphoid cluster (MFALCs) under healthy condition, and showed susceptibility to development of lung fibrosis following BLM administration. However, the pathogenesis of lung lesion progression, and their correlation with MFALC morphologies, remain to be clarified. To investigate the correlations between MFALC structures and lung injuries in B6 mice, histopathological examination of mediastinal fat tissues and lungs was examined at 7 and 21 days (d) following a single 50 MUL intranasal (i.n.) instillation of either BLM sulfate (5 mg/kg) (BLM group) or phosphate buffered saline (control group). The lung fibrosis was examined by Masson's trichrome (MT) stain of paraffin sections and mRNA expression levels of Col1a1, Col3a1, and Acta2 in different frozen lung samples. Furthermore, immunohistochemistry for CD3, B220, Iba1, Gr1, BrdU, LYVE-1, and peripheral node addressin (PNAd) was performed to detect T- and B-cells, macrophages, granulocytes, proliferating cells, lymph vessels (LVs), and high endothelial venules (HEVs). We found that MFALCs were more abundant in the BLM group as compared to the control group. The lung of BLM group developed pneumonitis with severe cellular infiltrations at 7 days and significant collagen deposition (MT) and higher expression of Col1a1, and Col3a1 at 21 days post-administration. Numerous immune cells, proliferating cells, HEVs, and LVs were observed in both MFALCs and lungs of the BLM group. Interestingly, PNAd + HEVs were observed in the lungs of the BLM group, but not the control group. Moreover, numerous Gr1 + polymorphonuclear and mononuclear-like ring cells were found in the MFALCs and lungs of the BLM group. Interestingly, flow cytometric analysis revealed a significant increase of B-cell populations within the MFALCs of BLM group suggesting a potential proliferative induction of B-cells following inflammation. Furthermore, significant positive correlations were observed between quantitative parameters of these immune cells in both the lungs and MFALCs. Thus, we suggest a potentially important role for MFALCs and HEVs in the progression of lung disease, especially in inflammatory lung disease. PMID- 29497426 TI - Dexamethasone-Induced Myeloid-Derived Suppressor Cells Prolong Allo Cardiac Graft Survival through iNOS- and Glucocorticoid Receptor-Dependent Mechanism. AB - How to induce immune tolerance without long-term need for immunosuppressive drugs has always been a central problem in solid organ transplantation. Modulating immunoregulatory cells represents a potential target to resolve this problem. Myeloid-derived suppressor cells (MDSCs) are novel key immunoregulatory cells in the context of tumor development or transplantation, and can be generated in vitro. However, none of current systems for in vitro differentiation of MDSCs have successfully achieved long-term immune tolerance. Herein, we combined dexamethasone (Dex), which is a classic immune regulatory drug in the clinic, with common MDSCs inducing cytokine granulocyte macrophage colony stimulating factor (GM-CSF) to generate MDSCs in vitro. Addition of Dex into GM-CSF system specifically increased the number of CD11b+ Gr-1int/low MDSCs with an enhanced immunosuppressive function in vitro. Adoptive transfer of these MDSCs significantly prolonged heart allograft survival and also favored the expansion of regulatory T cells in vivo. Mechanistic studies showed that inducible nitric oxide sythase (iNOS) signaling was required for MDSCs in the control of T-cell response and glucocorticoid receptor (GR) signaling played a critical role in the recruitment of transferred MDSCs into allograft through upregulating CXCR2 expression on MDSCs. Blockade of GR signaling with its specific inhibitor or genetic deletion of iNOS reversed the protective effect of Dex-induced MDSCs on allograft rejection. Together, our results indicated that co-application of Dex and GM-CSF may be a new and important strategy for the induction of potent MDSCs to achieve immune tolerance in organ transplantation. PMID- 29497429 TI - Functional Characterization of a Flavonoid Glycosyltransferase in Sweet Orange (Citrus sinensis). AB - Fruits of sweet orange (Citrus sinensis), a popular commercial Citrus species, contain high concentrations of flavonoids beneficial to human health. These fruits predominantly accumulate O-glycosylated flavonoids, in which the disaccharides [neohesperidose (rhamnosyl-alpha-1,2-glucose) or rutinose (rhamnosyl-alpha-1,6-glucose)] are linked to the flavonoid aglycones through the 3- or 7-hydroxyl sites. The biotransformation of the flavonoid aglycones into O rutinosides or O-neohesperidosides in the Citrus plants usually consists of two glycosylation reactions involving a series of uridine diphosphate-sugar dependent glycosyltransferases (UGTs). Although several genes encoding flavonoid UGTs have been functionally characterized in the Citrus plants, full elucidation of the flavonoid glycosylation process remains elusive. Based on the available genomic and transcriptome data, we isolated a UGT with a high expression level in the sweet orange fruits that possibly encodes a flavonoid glucosyltransferase and/or rhamnosyltransferase. Biochemical analyses revealed that a broad range of flavonoid substrates could be glucosylated at their 3- and/or 7-hydrogen sites by the recombinant enzyme, including hesperetin, naringenin, diosmetin, quercetin, and kaempferol. Furthermore, overexpression of the gene could significantly increase the accumulations of quercetin 7-O-rhamnoside, quercetin 7-O-glucoside, and kaempferol 7-O-glucoside, implying that the enzyme has flavonoid 7-O glucosyltransferase and 7-O-rhamnosyltransferase activities in vivo. PMID- 29497428 TI - Proteomic Analysis of Kiwifruit in Response to the Postharvest Pathogen, Botrytis cinerea. AB - Gray mold, caused by the fungus Botrytis cinerea, is the most significant postharvest disease of kiwifruit. In the present study, iTRAQ with LC-ESI-MS/MS was used to identify the kiwifruit proteins associated with the response to B. cinerea. A total of 2,487 proteins in kiwifruit were identified. Among them, 292 represented differentially accumulated proteins (DAPs), with 196 DAPs having increased, and 96 DAPs having decreased in accumulation in B. cinerea-inoculated vs. water-inoculated, control kiwifruits. DAPs were associated with penetration site reorganization, cell wall degradation, MAPK cascades, ROS signaling, and PR proteins. In order to examine the corresponding transcriptional levels of the DAPs, RT-qPCR was conducted on a subset of 9 DAPs. In addition, virus-induced gene silencing was used to examine the role of myosin 10 in kiwifruit, a gene modulating host penetration resistance to fungal infection, in response to B. cinerea infection. The present study provides new insight on the understanding of the interaction between kiwifruit and B. cinerea. PMID- 29497430 TI - A High-Density Integrated DArTseq SNP-Based Genetic Map of Pisum fulvum and Identification of QTLs Controlling Rust Resistance. AB - Pisum fulvum, a wild relative of pea is an important source of allelic diversity to improve the genetic resistance of cultivated species against fungal diseases of economic importance like the pea rust caused by Uromyces pisi. To unravel the genetic control underlying resistance to this fungal disease, a recombinant inbred line (RIL) population was generated from a cross between two P. fulvum accessions, IFPI3260 and IFPI3251, and genotyped using Diversity Arrays Technology. A total of 9,569 high-quality DArT-Seq and 8,514 SNPs markers were generated. Finally, a total of 12,058 markers were assembled into seven linkage groups, equivalent to the number of haploid chromosomes of P. fulvum and P. sativum. The newly constructed integrated genetic linkage map of P. fulvum covered an accumulated distance of 1,877.45 cM, an average density of 1.19 markers cM-1 and an average distance between adjacent markers of 1.85 cM. The composite interval mapping revealed three QTLs distributed over two linkage groups that were associated with the percentage of rust disease severity (DS%). QTLs UpDSII and UpDSIV were located in the LGs II and IV respectively and were consistently identified both in adult plants over 3 years at the field (Cordoba, Spain) and in seedling plants under controlled conditions. Whenever they were detected, their contribution to the total phenotypic variance varied between 19.8 and 29.2. A third QTL (UpDSIV.2) was also located in the LGIVand was environmentally specific as was only detected for DS % in seedlings under controlled conditions. It accounted more than 14% of the phenotypic variation studied. Taking together the data obtained in the study, it could be concluded that the expression of resistance to fungal diseases in P. fulvum originates from the resistant parent IFPI3260. PMID- 29497427 TI - Chimeric Antigen Receptor Expressing Natural Killer Cells for the Immunotherapy of Cancer. AB - Adoptive cell therapy has emerged as a powerful treatment for advanced cancers resistant to conventional agents. Most notable are the remarkable responses seen in patients receiving autologous CD19-redirected chimeric antigen receptor (CAR) T cells for the treatment of B lymphoid malignancies; however, the generation of autologous products for each patient is logistically cumbersome and has restricted widespread clinical use. A banked allogeneic product has the potential to overcome these limitations, yet allogeneic T-cells (even if human leukocyte antigen-matched) carry a major risk of graft-versus-host disease (GVHD). Natural killer (NK) cells are bone marrow-derived innate lymphocytes that can eliminate tumors directly, with their activity governed by the integration of signals from activating and inhibitory receptors and from cytokines including IL-15, IL-12, and IL-18. NK cells do not cause GVHD or other alloimmune or autoimmune toxicities and thus, can provide a potential source of allogeneic "off-the-shelf" cellular therapy, mediating major anti-tumor effects without inducing potentially lethal alloreactivity such as GVHD. Given the multiple unique advantages of NK cells, researchers are now exploring the use of CAR-engineered NK cells for the treatment of various hematological and non-hematological malignancies. Herein, we review preclinical data on the development of CAR-NK cells, advantages, disadvantages, and current obstacles to their clinical use. PMID- 29497431 TI - Cell Death Is Not Sufficient for the Restriction of Potato Virus Y Spread in Hypersensitive Response-Conferred Resistance in Potato. AB - Hypersensitive response (HR)-conferred resistance to viral infection restricts the virus spread and is accompanied by the induction of cell death, manifested as the formation of necrotic lesions. While it is known that salicylic acid is the key component in the orchestration of the events restricting viral spread in HR, the exact function of the cell death in resistance is still unknown. We show that potato virus Y (PVY) can be detected outside the cell death zone in Ny-1-mediated HR in potato plants (cv. Rywal), observed as individual infected cells or small clusters of infected cells outside the cell death zone. By exploiting the features of temperature dependent Ny-1-mediated resistance, we confirmed that the cells at the border of the cell death zone are alive and harbor viable PVY that is able to reinitiate infection. To get additional insights into this phenomenon we further studied the dynamics of both cell death zone expansion and occurrence of viral infected cell islands outside it. We compared the response of Rywal plants to their transgenic counterparts, impaired in SA accumulation (NahG Rywal), where the lesions occur but the spread of the virus is not restricted. We show that the virus is detected outside the cell death zone in all lesion developmental stages of HR lesions. We also measured the dynamics of lesions expansion in both genotypes. We show that while rapid lesion expansion is observed in SA-depleted plants, virus spread is even faster. On the other hand the majority of analyzed lesions slowly expand also in HR-conferred resistance opening the possibility that the infected cells are eventually engulfed by cell death zone. Taken altogether, we suggest that the HR cell death is separated from the resistance mechanisms which lead to PVY restriction in Ny-1 genetic background. We propose that HR should be regarded as a process where the dynamics of events is crucial for effectiveness of viral arrest albeit the exact mechanism conferring this resistance remains unknown. PMID- 29497433 TI - Preliminary Evidences of Biofortification with Iodine of "Carota di Polignano", An Italian Carrot Landrace. AB - The "Carota di Polignano" (Polignano Carrot - PC, Daucus carota L.) is a multi colored landrace, cultivated in the Southern Italy, whose colors range from yellow to purple. Iodine is an essential micronutrient for humans, since it is a key component of thyroid hormones, which regulate the growth and development of the human body. The main source for iodine assumption is represented by diet, but its concentration in the vegetables is usually limited with respect to human needs. To this purpose, two experimental trials (in open field and in greenhouse with a soil-less system) were carried out to enrich PC with iodine. Three levels of iodine (control treatment, C - 0 mg.L-1; low, L - 50 mg.L-1; and high, H - 500 mg.L-1), distributed with foliar spray fertilizations (in both open field and greenhouse) or with nutrient solution (in greenhouse, at the level of 50 mg.L-1) in the form of KIO3 were compared. In open field, the H treatment showed a biofortification that was double and triple respect to L and C treatments, respectively, without influencing color and biometric parameters, such as the fresh and dry weight of roots and DM percentage. In greenhouse, the biofortification done with foliar spray fertilization followed the same trend of open field, while the biofortification by means of nutrient solution was more effective but reached very high levels that had toxic effects on the plants and could be too high for human nutrition. However, the concentrations of iodine into biofortified carrots in open field can allow to satisfy the recommended daily allowance (RDA) by consuming 100 and 200 g of fresh product for the treatment H and L, respectively. Regarding the greenhouse biofortification, the RDA would be satisfied by consuming 200 g of fresh carrots (with the high level of foliar fertilization). PMID- 29497432 TI - Acropetal Auxin Transport Inhibition Is Involved in Indeterminate But Not Determinate Nodule Formation. AB - Legumes enter into a symbiotic relationship with nitrogen-fixing rhizobia, leading to nodule development. Two main types of nodules have been widely studied, indeterminate and determinate, which differ in the location of the first cell division in the root cortex, and persistency of the nodule meristem. Here, we compared the control of auxin transport, content, and response during the early stages of indeterminate and determinate nodule development in the model legumes Medicago truncatula and Lotus japonicus, respectively, to investigate whether differences in auxin transport control could explain the differences in the location of cortical cell divisions. While auxin responses were activated in dividing cortical cells during nodulation of both nodule types, auxin (indole-3 acetic acid) content at the nodule initiation site was transiently increased in M. truncatula, but transiently reduced in L. japonicus. Root acropetal auxin transport was reduced in M. truncatula at the very start of nodule initiation, in contrast to a prolonged increase in acropetal auxin transport in L. japonicus. The auxin transport inhibitors 2,3,5-triiodobenzoic acid and 1-N naphthylphthalamic acid (NPA) only induced pseudonodules in legume species forming indeterminate nodules, but failed to elicit such structures in a range of species forming determinate nodules. The development of these pseudonodules in M. truncatula exhibited increased auxin responses in a small primordium formed from the pericycle, endodermis, and inner cortex, similar to rhizobia-induced nodule primordia. In contrast, a diffuse cortical auxin response and no associated cortical cell divisions were found in L. japonicus. Collectively, we hypothesize that a step of acropetal auxin transport inhibition is unique to the process of indeterminate nodule development, leading to auxin responses in pericycle, endodermis, and inner cortex cells, while increased auxin responses in outer cortex cells likely require a different mechanism during the formation of determinate nodules. PMID- 29497434 TI - Dormant Flower Buds Actively Accumulate Starch over Winter in Sweet Cherry. AB - Temperate woody perennials survive to low temperatures in winter entering a dormant stage. Dormancy is not just a survival strategy, since chilling accumulation is required for proper flowering and arbitrates species adaptation to different latitudes. In spite of the fact that chilling requirements have been known for two centuries, the biological basis behind remain elusive. Since chilling accumulation is required for the normal growth of flower buds, it is tempting to hypothesize that something might be going on at this particular stage during winter dormancy. Here, we characterized flower bud development in relation to dormancy, quantifying changes in starch in the flower primordia in two sweet cherry cultivars over a cold and a mild year. Results show that, along the winter, flower buds remain at the same phenological stage with flower primordia at the very same developmental stage. But, surprisingly, important variation in the starch content of the ovary primordia cells occurs. Starch accumulated following the same pattern than chilling accumulation and reaching a maximum at chilling fulfillment. This starch subsequently vanished during ecodormancy concomitantly with ovary development before budbreak. These results showed that, along the apparent inactivity during endodormancy, flower primordia were physiologically active accumulating starch, providing a biological basis to understand chilling requirements. PMID- 29497435 TI - Biomass Accumulation, Photosynthetic Traits and Root Development of Cotton as Affected by Irrigation and Nitrogen-Fertilization. AB - Limitations of soil water and nitrogen (N) are factors which cause a substantial reduction in cotton (Gossypium hirsutum L.) yield, especially in an arid environment. Suitable management decisions like irrigation method and nitrogen fertilization are the key yield improvement technologies in cotton production systems. Therefore, we hypothesized that optimal water-N supply can increase cotton plant biomass accumulation by maintaining leaf photosynthetic capacity and improving root growth. An outdoor polyvinyl chloride (PVC) tube study was conducted to investigate the effects of two water-N application depths, i.e., 20 cm (H20) or 40 cm (H40) from soil surface and four water-N combinations [deficit irrigation (W55) and no N (N0) (W55N0), W55 and moderate N (N1) (W55N1), moderate irrigation (W75) and N0 (W75N0), W75N1] on the roots growth, leaf photosynthetic traits and dry mass accumulation of cotton crops. H20W55N1 combination increased total dry mass production by 29-82% and reproductive organs biomass by 47-101% compared with other counterparts. Root protective enzyme and nitrate reductase (NR) activity, potential quantum yield of photosystem (PS) II (Fv/Fm), PSII quantum yield in the light [Y(II)] and electron transport rate of PSII were significantly higher in H20W55N1 prior to 82 days after emergence. Root NR activity and protective enzyme were significantly correlated with chlorophyll, Fv/Fm, Y(II) and stomatal conductance. Hence, shallow irrigation (20 cm) with moderate irrigation and N-fertilization application could increase cotton root NR activity and protective enzyme leading to enhance light capture and photochemical energy conversion of PSII before the full flowering stage. This enhanced photoassimilate to reproductive organs. PMID- 29497436 TI - Structure and Distribution of Centromeric Retrotransposons at Diploid and Allotetraploid Coffea Centromeric and Pericentromeric Regions. AB - Centromeric regions of plants are generally composed of large array of satellites from a specific lineage of Gypsy LTR-retrotransposons, called Centromeric Retrotransposons. Repeated sequences interact with a specific H3 histone, playing a crucial function on kinetochore formation. To study the structure and composition of centromeric regions in the genus Coffea, we annotated and classified Centromeric Retrotransposons sequences from the allotetraploid C. arabica genome and its two diploid ancestors: Coffea canephora and C. eugenioides. Ten distinct CRC (Centromeric Retrotransposons in Coffea) families were found. The sequence mapping and FISH experiments of CRC Reverse Transcriptase domains in C. canephora, C. eugenioides, and C. arabica clearly indicate a strong and specific targeting mainly onto proximal chromosome regions, which can be associated also with heterochromatin. PacBio genome sequence analyses of putative centromeric regions on C. arabica and C. canephora chromosomes showed an exceptional density of one family of CRC elements, and the complete absence of satellite arrays, contrasting with usual structure of plant centromeres. Altogether, our data suggest a specific centromere organization in Coffea, contrasting with other plant genomes. PMID- 29497437 TI - Shifts in Plant Community Assembly Processes across Growth Forms along a Habitat Severity Gradient: A Test of the Plant Functional Trait Approach. AB - Species respond to changes in their environments. A core goal in ecology is to understand the process of plant community assembly in response to a changing climate. Examining the performance of functional traits and trait-based assembly patterns across species among different growth forms is a useful way to explore the assembly process. In this study, we constructed a habitat severity gradient including several environment factors along a 2300 m wide elevational range at Taibai Mountain, central China. Then we assessed the shift on functional trait values and community assembly patterns along this gradient across species among different growth forms. We found that (1) although habitat-severity values closely covaried with elevation in this study, an examined communities along a habitat severity gradient might reveal community dynamics and species responses under future climate change. (2) the occurrence of trait values along the habitat severity gradient across different growth forms were similar, whereas the assembly pattern of herbaceous species was inconsistent with the community and woody species. (3) the trait-trait relationships of herbaceous species were dissimilar to those of the community and woody species. These results suggest that (1) community would re-assemble along habitat severity gradient through environmental filtering, regardless of any growth forms and that (2) different growth forms' species exhibiting similar trait values' shift but different trait trait relationship by different trait combinations. PMID- 29497439 TI - Human-Mediated Gene Flow Contributes to Metapopulation Genetic Structure of the Pathogenic Fungus Alternaria alternata from Potato. AB - Metapopulation structure generated by recurrent extinctions and recolonizations plays an important role in the evolution of species but is rarely considered in agricultural systems. In this study, generation and mechanism of metapopulation structure were investigated by microsatellite assaying 725 isolates of Alternaria alternata sampled from potato hosts at 16 locations across China. We found a single major cluster, no isolate-geography associations and no bottlenecks in the A. alternata isolates, suggesting a metapopulation genetic structure of the pathogen. We also found weak isolation-by-distance, lower among than within cropping region population differentiation, concordant moving directions of potato products and net gene flow and the highest gene diversity in the region with the most potato imports. These results indicate that in addition to natural dispersal, human-mediated gene flow also contributes to the generation and dynamics of the metapopulation genetic structure of A. alternata in China. Metapopulation structure increases the adaptive capacity of the plant pathogen as a result of enhanced genetic variation and reduced population fragmentation. Consequently, rigid quarantine regulations may be required to reduce population connectivity and the evolutionary potential of A. alternata and other pathogens with a similar population dynamics for a sustainable plant disease management. PMID- 29497438 TI - The ERA-Related GTPase AtERG2 Associated with Mitochondria 18S RNA Is Essential for Early Embryo Development in Arabidopsis. AB - The ERA (E. coli RAS-like protein)-related GTPase (ERG) is a nuclear-encoded GTPase with two conserved domains: a GTPase domain and a K Homology (KH) domain. ERG plays a vital role in early seed development in Antirrhinum majus. However, the mechanism that regulates seed development remains unclear. Blasting the genome sequence revealed two homologies of ERG, AtERG1, and AtERG2 in Arabidopsis. In this study, we found that AtERG2 is localized in the mitochondria and binds mitochondrial 18S RNA. Promoter and transcript analyses indicated that AtERG2 was mainly expressed in the leaf vein, trichome, and ovule. The T-DNA insertion lines of AtERG2 showed silique shortage, early seed abortion, and sporophytic maternal effects (SME), in which some seeds arrested in the zygotic stage at 1.5 days after pollination (DAP) and aborted at 2.0 DAP in aterg2-1 +/-. We further showed that the ovules of these arrested seeds presented unusual tissue degradation inside the embryo sacs. Reactive oxygen species (ROS) accumulated at 1.0 and 1.5 DAP in the arrested seeds, and the transcription of several ROS-responsive genes, WRKY40, ANAC017, and AOX1a, was up-regulated in the aterg2-1 +/- arrested seeds at 1.5 and 2.0 DAP, but not in wild-type (WT) and aterg2-1 +/- developed seeds. The cell death-related gene BAG6 was also transcriptionally activated in aterg2-1 +/- seeds arrested at 2.0 DAP. Additionally, the protein level of mitochondria protein ATPase Subunit 6 was lower in 2-DAP siliques of aterg2-1 +/- than it was in those of WT. These results suggested that AtERG2 promotes early seed development by affecting the maturation of the mitochondria ribosome small subunit and mitochondrial protein translation in Arabidopsis. PMID- 29497440 TI - Molecular Evidences of a Hidden Complex Scenario in Leporinus cf. friderici. AB - The megadiversity of the neotropical ichthyofauna has been associated to recent diversification processes, reflecting in subtle or lacking morphological differentiation between species, challenging the classical taxonomic identification. Leporinus friderici occurs in several river basins of South America, and its nominal taxonomic validity has been questioned. Its wide distribution within the Brazilian Shield suggests that this species could be genetically structured among the hydrographic basins, despite a sharp morphological similarity. In this study, we performed phylogenetic analyses, based on three nuclear (recombination activating gene 1, RAG1, recombination activating gene 2, RAG2, and myosin heavy chain 6 cardiac muscle alpha gene, Myh6) and two mitochondrial (COI and Cytochrome b, Cytb) markers, in specimens morphologically similar to L. friderici and related species from different hydrographic basins in South America. Our phylogenetic tree identified four well supported clades, which point out to the existence of taxonomic inconsistencies within this fish group. A clade named L. cf. friderici sensu stricto included eight Molecular Operational Taxonomic Units recently diversified in the Brazilian Shield basins. These results were also confirmed by a single-gene species delimitation analysis. It is suggested that this clade includes a species complex, characterizing taxonomic uncertainties. Another clade recovered only L. friderici from the Suriname rivers, validating this nominal species in its type locality. A third no-named clade, characterized by deeper species divergence, recovered five different nominal species interleaved with other undescribed forms previously also recognized as L. cf. friderici, indicating taxonomic errors. The fourth clade only included L. taeniatus. Our results showed a complex scenario involving the morphotype L. cf. friderici and allowed us to address aspects related to evolutionary diversification of this fish group and historical processes involved with, highlighting the importance of revealing hidden biodiversity for the taxonomy and conservationist action plans of these fish. PMID- 29497441 TI - Prevalence of orthodontic treatment need in permanent dentition of Iranian population: A systematic review and meta-analysis of observational studies. AB - Background: Malocclusion is a common oral health problem and can affect the psychosocial well-being in the long term. Therefore, in the recent decades, demand for orthodontic treatment to correct malocclusion has greatly increased worldwide. This systematic review and meta-analysis was undertaken to assess existing evidence on the prevalence of orthodontic treatment need in Iran. Materials and Methods: National and international databases were searched for articles on the prevalence of orthodontic treatment need using index of orthodontic treatment need (IOTN) and dental aesthetic index (DAI). The required data were completed by hand-searching. After applying the inclusion and exclusion criteria, the quality of articles was checked by a professional checklist. Data extraction and meta-analysis were performed. A random effects model was employed, and publication bias was checked. Results: From a total of 443 articles that reported orthodontic treatment need in Iran, 24 articles were included in the meta-analysis process. Meta-analysis was performed on components of IOTN and DAI. The pooled prevalence of orthodontic treatment need based on Dental Health Component and Aesthetic Component of IOTN and DAI was 23.8% (19.5%-28.7%), 4.8% (3.3%-7%), and 16.1% (12.3%-20.8%). The results were found to be heterogeneous (P < 0.05). Conclusion: The results of this study revealed that orthodontic treatment need was not high in the Iranian population. Considering the differing prevalence of orthodontic treatment need based on normative index and self perceived index, it is essential to improve the people's awareness of malocclusion and its side effects on their oral and general health. PMID- 29497442 TI - Clinical evaluation of Class II and Class III gingival recession defects of maxillary posterior teeth treated with pedicled buccal fat pad: A pilot study. AB - Background: Buccal fat pad (BFP) is a specialized vascular tissue adequately present in buccal space and is close to the maxillary posterior quadrant. The aim of this clinical study was to evaluate the utility of pedicled BFP (PBFP) in the treatment of Class II and III gingival recession. Materials and Methods: Ten systemically healthy patients with age ranging from 35 to 55 years with Class II and Class III gingival recession in the maxillary molars were selected. Before the surgical phase, patients were enrolled in a strict maintenance program including oral hygiene instructions and scaling and root planing. A horizontal incision of 1-1.5 cm was made in the buccal sulcus of the maxillary molar region; buccinator muscle was separated bluntly to expose the BFP. The fat was then teased out from its bed and spread to cover defects adequately. It was then secured and sutured without tension. Clinical parameters such as probing depth, recession width, recession length (RL), and width of keratinized gingiva were recorded at baseline and at 6 months postoperatively, and weekly assessment was done at 1 week, 2 weeks, 3 weeks, and after 4 weeks for observations during the postoperative healing. Results: Treated recession defects healed successfully without any significant postoperative complications. Decreased gingival recession horizontal width values from 4.65 +/- 0.4327 to 0.94 +/- 1.350 and RL from 6.4 +/ 1.075 to 0.7 +/- 0.6750 were observed postoperatively (P < 0.05). Percentage of root coverage average was 89.3%. There was a statistically significant decrease in the width and depth of recession. Conclusion: Pedicled buccal fat showed promising results as the treatment modality in the management of Class II and Class III gingival recession of maxillary posterior teeth. PMID- 29497443 TI - Effect of ceramic cooling protocols and zirconia coloring on fracture load of zirconia-based restorations. AB - Background: Residual thermal stresses in dental porcelains can cause clinical failure. Porcelain cooling protocols may affect the amount of residual stresses within porcelain and also porcelain-zirconia bond strength. The objective of this study was to assess the effect of cooling protocols on the fracture load of porcelain veneered zirconia restorations. Materials and Methods: Forty zirconia bars (31 mm * 6.5 mm * 1.35 mm +/- 0.1 mm) were fabricated by computer-aided design and computer-aided manufacturing technology. Half of the specimens were immersed in the coloring agent for 2 min before sintering (yellow group). Thus, the specimens were divided into two groups of white (W) and yellow (Y) samples (n = 20). Heat-pressed ceramic was applied to all bars. After pressing, half of the samples in each group were immediately removed from the oven (fast cooling) while the other specimens remained in the partially open door (30%) oven until the temperature reached to 500 degrees C. Samples were thermocycled for 5000 cycles and subjected to modified four-point flexural strength test by a universal testing machine at a crosshead speed of 0.5 mm/min. Two-way ANOVA, One-way ANOVA followed by post hoc Tukey honest significant difference tests were used for data analysis (alpha = 0.05). Results: Fractures were cohesive in all samples (within the porcelain adjacent to the interface). Two-way ANOVA showed that the effect of cooling protocol on the fracture load of samples was statistically significant (P < 0.001). In addition, the fracture load of W and Y groups was significantly different (P < 0.001). The white slow group showed the highest fracture load (179.88 +/- 23.43 N). Conclusion: Slow cooling protocol should be preferably applied for zirconia restorations. Coloring agent used in this study had a significant negative effect on fracture load. PMID- 29497444 TI - Effects of ethanol concentrations of acrylate-based dental adhesives on microtensile composite-dentin bond strength and hybrid layer structure of a 10 wt% polyhedral oligomeric silsesquioxane (POSS)-incorporated bonding agent. AB - Background: The aim of this study was to assess for the first time the effects of different amounts of ethanol solvent on the microtensile bond strength of composite bonded to dentin using a polyhedral oligomeric silsesquioxane (POSS) incorporated adhesive. Materials and Methods: This experimental study was performed on 120 specimens divided into six groups (in accordance with the ISO TR11405 standard requiring at least 15 specimens per group). Occlusal dentin of thirty human molar teeth was exposed by removing its enamel. Five teeth were assigned to each of six groups and were converted to 20 microtensile rods (with square cross-sections of 1 mm * 1 mm) per group. The "Prime and Bond NT" (as a common commercial adhesive) was used as the control group. Experimental acrylate based bonding agents containing 10 wt% POSS were produced with five concentrations of ethanol as solvent (0, 20, 31, 39, and 46 wt%). After application of adhesives on dentin surface, composite cylinders (height = 6 mm) were bonded to dentin surface. The microtensile bond strength of composite to dentin was measured. The fractured surfaces of specimens were evaluated under a scanning electron microscope to assess the morphology of hybrid layer. Data were analyzed using one-sample t-test, one-way analysis of variance (ANOVA), and Tukey tests (alpha = 0.05). Results: the mean bond strength in the groups: "control, ethanol-free, and 20%, 31%, 39%, and 46% ethanol" was, respectively, 46.5 +/- 5.6, 29.4 +/- 5.7, 33.6 +/- 4.1, 59.0 +/- 5.5, 41.9 +/- 6.2, and 18.7 +/- 4.6 MPa. Overall difference was significant (ANOVA, P < 0.0001). Pairwise differences were all significant (Tukey P < 0.05) except those of "ethanol 0% versus 20%" and "20% versus 31%." All groups except "0% and 46% ethanol" had bond strengths above 30 MPa (t-test P < 0.05). Conclusion: Incorporation of 31% ethanol as solvent into a 10 wt% POSS-incorporated experimental dental adhesive might increase the bond strength of composite to dentin and improve the quality and morphology of the hybrid layer. However, higher concentrations of the solvent might not improve the bond strength or quality of the hybrid layer. PMID- 29497445 TI - Evaluation of cavity size, kind, and filling technique of composite shrinkage by finite element. AB - Background: Cavity preparation reduces the rigidity of tooth and its resistance to deformation. The purpose of this study was to evaluate the dimensional changes of the repaired teeth using two types of light cure composite and two methods of incremental and bulk filling by the use of finite element method. Materials and Methods: In this computerized in vitro experimental study, an intact maxillary premolar was scanned using cone beam computed tomography instrument (SCANORA, Switzerland), then each section of tooth image was transmitted to Ansys software using AUTOCAD. Then, eight sizes of cavity preparations and two methods of restoration (bulk and incremental) using two different types of composite resin materials (Heliomolar, Brilliant) were proposed on software and analysis was completed with Ansys software. Results: Dimensional change increased by widening and deepening of the cavities. It was also increased using Brilliant composite resin and incremental filling technique. Conclusion: Increase in depth and type of filling technique has the greatest role of dimensional change after curing, but the type of composite resin does not have a significant role. PMID- 29497446 TI - Innovative evaluation of local injective gel of curcumin on the orthodontic tooth movement in rats. AB - Background: Curcumin is the most active compound in turmeric. It can suppress the nuclear factor kappa-light-chain-enhancer of activated B cells pathway and prevent the osteoclastogenesis procedure. This study aimed to be the first to evaluate the effect of curcumin on the rate of orthodontic tooth movement (OTM). Materials and Methods: Forty rats were used as follows in each group: (1) negative control: Did not receive any appliance or injection; (2) positive control: received 0.03 cc normal saline and appliance; (3) gelatin plus curcumin (G): Received 0.03 cc hydrogel and appliance; and (4) chitosan plus curcumin (Ch): Received 0.03 cc hydrogel and appliance. They were anesthetized and closed nickel-titanium coil springs were installed between the first molars and central incisors unilaterally as the orthodontic appliance. After 21 days, the rats were decapitated, and the distance between the first and second molars was measured by a leaf gauge. Howship's lacunae, blood vessels, osteoclast-like cells, and root resorption lacunae were evaluated in the histological analysis. Data were analyzed by one-way ANOVA, Tukey's test, and t-test (P < 0.05 consider significant). Results: No significant difference was found in OTM between groups delivered orthodontic forces. Curcumin inhibited root and bone resorption, osteoclastic recruitment, and angiogenesis significantly. Conclusion: Curcumin had no significant inhibitory effect on OTM. While it had a significant role on decreasing bone or root resorption (P > 0.05). PMID- 29497447 TI - Assessment of palatal rugae pattern for sex and ethnicity identification in an iranian population. AB - Background: Palatal rugoscopy is a reliable method in the forensic personal identification and racial group specification. the aim of the present study is to use palatal rugae pattern in sex and ethnicity identification applications. Materials and Methods: Four hundred individual dental casts from four different ethnic populations of Iran were randomly selected. The pattern of the palatal rugae (shape, length, and number) investigated and its reliability to classify sex and minor ethnicity for each individual cast was evaluated. (P < 0.05) considered significant. Results: The most common rugae shapes were straight, followed by wavy and curved types. The least frequent shapes were converging and circular types. Palatal rugae patterns were unique to each person. However, they could not differentiate males and females and had low abilities to classify the racial subsets. Conclusion: The palatal rugae pattern was unique to each individual and palatal rugoscopy can be considered as a reliable forensic identification tool where utilizing other methods such as DNA profiling, fingerprint, and dental record comparison is impossible or difficult. In this study, palatal rugoscopy was not a reliable method to classify the sex of an individual and to differentiate between different racial subsets. PMID- 29497448 TI - Comparison of apical transportation and centering ability of Mtwo and Reciproc R25 in severely curved canals using cone-beam computed tomography. AB - Background: Apical transportation (AT) of the root canal moves the physiologic canal terminus to a new location on the external root surface and results in the accumulation of debris and residual microorganisms due to inadequate cleaning and shaping of the canal end. This study aimed to assess the prevalence of AT following canal preparation with Mtwo and Reciproc R25 using cone-beam computed tomographic (CBCT). Materials and Methods: In this in vitro study, 40 mesiobuccal root canals of the maxillary molars with 19-22 mm length and (>40 degrees ) taper were prepared in two groups using Mtwo and Reciproc R25 rotary systems along with irrigation with 2.5% NaOCl. CBCT scans were obtained of the canals before and after preparation under similar conditions, and the values were measured using the device software. The amount of AT was measured according to Gambill et al. Data were analyzed using SPSS 17 and Chi-square and t-tests. P < 0.05 was considered significant. Results: Both systems caused some degrees of AT. No significant difference was found between the two systems in terms of the amount and direction of AT (P > 0.05); overall, the frequency of AT toward the mesial wall was greater than that toward the distal direction. However, this difference was not statistically significant. Conclusion: The mean amount of AT and the ability to keep the instruments in severely curved canals were not significantly different in canals prepared by Mtwo and Reciproc rotary systems. Thus, these systems can be used in the clinical setting with the lowest risk of AT. PMID- 29497449 TI - Bond strength of self-adhesive resin cement to base metal alloys having different surface treatments. AB - Background: This study aimed to assess and compare the shear bond strength of self-etch and self-adhesive resin cement to nickel-chromium-cobalt alloy with different surface treatments. Materials and Methods: In this in vitro study, a total of 120 disks were fabricated of VeraBond II base metal alloy. Specimens were divided into 15 groups of 8 based on the type of cement and surface treatment. The five surface treatments studied included sandblasting alone, application of Alloy Primer with and without sandblasting, and application of Metal Primer II with and without sandblasting. The three cement tested included Panavia F2.0, RelyX Unicem (RU), and G-Cem (GC). After receiving the respective surface treatments, the specimens were thermocycled for 1500 cycles and underwent shear bond strength testing. Data were analyzed using SPSS 20.0 and three-way analysis of variance. P values of the significant level of 0.05 were reported. Results: The results exhibited that the mean bond strengths in sandblasted groups were higher than nonsandblasted one. These differences were significantly higher in the sandblasted groups of Panavia F2.0 and RU cement (P < 0.05). The mean bond strength values between GC and Panavia F2.0 were not statistically significant (P > 0.05). The highest bond strength was recorded for Panavia F2.0 with the surface treatment of both sandblasting and Metal Primer II. Conclusion: Based on the results, sandblasting improves the shear bond strength of self-etch and self adhesive resin cement to base metal alloys. The best results can be achieved with a combination of sandblasting and metal primers. The performance of resin cement depends on to their chemical composition, not to the type of system. PMID- 29497450 TI - Analysis of interleukin-10 gene polymorphisms in patients with chronic periodontitis and healthy controls. AB - Background: Interleukin-10 (IL-10) is an anti-inflammatory cytokine that has important roles in the periodontal diseases. The IL10-1082, -819, and -592 polymorphisms in the promoter region of IL-10 gene have been associated with various IL-10 expressions. The aim of this study was to investigate the association between these gene polymorphisms with chronic periodontitis in a sample of Iranian populations from Southeast of Iran. Materials and Methods: IL 10 single nucleotide polymorphisms were analyzed in 210 patients with chronic periodontitis (CP) and 100 individuals without CP by polymerase chain reaction restriction fragment length polymorphism method. Statistical analysis of data was performed using the Chi-square test. The risk associated with single alleles, genotypes, and haplotypes were calculated by performing a multiple logistic regression analysis to estimate the odds ratio (OR) and 95% confidence interval (CI). P < 0.05 for statistical significance. Results: The prevalences of AG and GG genotypes of IL10-1082 were significantly different between CP and control groups in comparison to AA genotype (OR = 2.671; CI = 1.482-4.815; P = 0.001 for AG vs. AA, OR = 4.151; CI = 2.128-8.097; P < 0.001 for GG vs. AA). In addition, subjects with at least one IL10-1082-G allele were significantly had an increased risk for CP (OR = 2.157; CI = 1.531-3.038; P < 0.001). The distribution of the IL10-819 and IL10-592 genotypes was not different between CP and control subjects (P = 0.109 and P = 0.139, respectively). The combination of different genotypes showed that GCC haplotype was significantly different between groups (OR = 4.379; CI = 1.077-17.807; P = 0.039). Conclusion: The results demonstrated that IL10 1082 polymorphism was a putative risk factor for chronic periodontitis and associated with increased susceptibility to CP. PMID- 29497451 TI - Rhabdomyosarcoma of the maxillary gingiva. AB - Rhabdomyosarcoma is a malignant skeletal muscle neoplasm. The tumor is much more common in children, and the most frequent site is head and neck region. Since this tumor is less frequent than other neoplasms in oral cavity, the clinicians sometimes ignore it, working the patients up. Rhabdomyosarcoma is a high-grade malignancy with poor prognosis. Considering the aggressive behavior and various clinical or histopathologic presentations of the tumor, early diagnosis has a significant impact on the treatment outcome and prognosis of the patients. We highlight the importance of combining the clinical, radiographic, and histopathologic examination to obtain a definitive diagnosis in sarcomas of the head and neck region, especially rhabdomyosarcoma. A case of rhabdomyosarcoma of the maxillary gingiva is presented in a 32-year-old woman in which the primary incisional biopsy was erroneously interpreted as an inflammatory process and consequently, the accurate diagnosis postponed for about 10 months. PMID- 29497454 TI - Fine-needle aspiration of a slowly enlarging neck mass in a 61-year-old woman: An interesting adult blue cell tumor in an unusual location. PMID- 29497452 TI - The latest evidence for possible HIV-1 curative strategies. AB - Human immunodeficiency virus type 1 (HIV-1) infection remains a major health issue worldwide. In developed countries, antiretroviral therapy has extended its reach from treatment of people living with HIV-1 to post-exposure prophylaxis, treatment as prevention, and, more recently, pre-exposure prophylaxis. These healthcare strategies offer the epidemiological tools to curve the epidemic in rich settings and will be concomitantly implemented in developing countries. One of the remaining challenges is to identify an efficacious curative strategy. This review manuscript will focus on some of the current curative strategies aiming at providing a sterilizing or functional cure to HIV-1-positive individuals. These include the following: early treatment initiation in post-treatment controllers as a long-term HIV-1 remission strategy, latency reversal, gene editing with or without stem cell transplantation, and antibodies against either the viral envelope protein or the host integrin alpha4beta7. PMID- 29497453 TI - Gene and protein expression of CXCR4 in adult and elderly patients with chronic rhinitis, pharyngitis or sinusitis undergoing thermal water nasal inhalations. AB - Background: Chronic rhinitis, pharyngitis and sinusitis are common health problems with a significant impact on public health, and are suspected to be influenced by ageing factors. Nasal inhalation with thermal water may be used to reduce symptoms, inflammation and drug intake. A pre-post clinical study was conducted in 183 consecutive adult and elderly patients with chronic rhinitis, pharyngitis or sinusitis, to evaluate whether thermal water nasal inhalations could improve their symptoms, clinical signs and rhinomanometry measurements, and influence inflammatory biomarkers levels in nasal epithelial cells. Results: Participants profile revealed that they were aged on average (mean age and SD 60.6 +/- 15.2 years, median 65, range 20-86, 86 aged <= 65 years (47%), 96 aged > 65 years (53%)) and extremely concerned about wellbeing. Older age was associated with better compliance to inhalation treatment. Total symptom and clinical evaluation scores were significantly ameliorated after treatment (p < 0.001), with no substantial difference according to age, while rhinomanometry results were inconsistent. Persistence of symptom improvement was confirmed at phone follow up 1 year later (n = 74). The training set of 48 inflammatory genes (40 patients) revealed a strong increase of CXCR4 gene expression after nasal inhalations, confirmed both in the validation set (143 patients; 1.2 +/- 0.68 vs 3.3 +/- 1.2; p < 0.0001) and by evaluation of CXCR4 protein expression (40 patients; 1.0 +/- 0.39 vs 2.6 +/- 0.66; p < 0.0001). CXCR4 expression was consistently changed in patients with rhinitis, pharyngitis or sinusitis. The increase was smaller in current smokers compared to non-smokers. Results were substantially unchanged when comparing aged subjects (>= 65 years) or the eldest quartile (>= 71 years) to the others. Other genes showed weaker variations (e.g. FLT1 was reduced only in patients with sinusitis). Conclusions: These results confirm the clinical impact of thermal water nasal inhalations on upper respiratory diseases both in adults and elders, and emphasize the role of genes activating tissue repair and inflammatory pathways. Future studies should evaluate CXCR4 as possible therapeutic target or response predictor in patients with chronic rhinitis, pharyngitis or sinusitis. Trial registration: Communication to Italian Ministry of Health - ICPOM 000461. Registered 10/11/2014. PMID- 29497455 TI - Primary cutaneous non-Hodgkin's lymphoma, clinically mimicking a soft tissue sarcoma. AB - Primary cutaneous B-cell lymphomas (PCBCL) are a heterogeneous group of neoplasms with distinct biology and clinical course when compared to their nodal counterparts. They usually present as violaceous, erythematous plaques, and nonulcerated nodules, which are confined to skin at the time of presentation. We present an unusual case of primary cutaneous diffuse large B-cell lymphoma, clinically mimicking a sarcoma. This case highlights the uncommon aggressive behavior and ulcerated type of nodular lesions seen in PCBCL and also revisits the cytomorphological findings of the same. PMID- 29497456 TI - Diagnostic importance of CD56 with fine-needle aspiration cytology in suspected papillary thyroid carcinoma cases. AB - Background: Palpable thyroid nodules can be found in 4%-7% of the adult population; however, <5% of thyroid nodules are malignant. Immunohistochemical markers, such as CD56, can be used to make a differential diagnosis between benign and malignant lesions. To increase the accuracy of the diagnosis and distinguish the malignant aspirates from the benign ones, chose to evaluate CD56, which is normally found in benign thyroid tissue. Methods: A total of 53 fine needle aspirate samples from patients diagnosed with suspected papillary thyroid carcinoma (PTC) were included prospectively. These aspirates were immunocytochemically stained for CD56. Results: In histopathological examination, the fine-needle aspiration cytopathology specimens suspicious for PTC (after undergoing surgery) showed that 32 (60.4%) were benign and 21 (39.6%) were malignant. Thirty-one of the benign cases (96.87%) were CD56-positive, whereas the last case (3.13%) was CD56-negative. Staining was not seen in any of the malignant cases. Conclusions: We believe that CD56 is an important marker in the definitive diagnosis of suspected PTC cases, with CD56-positivity being interpreted in favor of benignity. PMID- 29497457 TI - Neurogenic Thoracic Outlet Syndrome Caused by Vascular Compression of the Brachial Plexus: A Report of Two Cases. AB - Thoracic outlet syndrome (TOS) is caused by compression of the brachial plexus and/or subclavian vessels as they pass through the cervicothoracobrachial region, exiting the chest. There are three main types of TOS: neurogenic TOS, arterial TOS, and venous TOS. Neurogenic TOS accounts for approximately 95% of all cases, and it is usually caused by physical trauma (posttraumatic etiology), chronic repetitive motion (functional etiology), or bone or muscle anomalies (congenital etiology). We present two cases in which neurogenic TOS was elicited by vascular compression of the inferior portion of the brachial plexus. PMID- 29497458 TI - Consensus, uncertainties and challenges for perennial bioenergy crops and land use. AB - Perennial bioenergy crops have significant potential to reduce greenhouse gas (GHG) emissions and contribute to climate change mitigation by substituting for fossil fuels; yet delivering significant GHG savings will require substantial land-use change, globally. Over the last decade, research has delivered improved understanding of the environmental benefits and risks of this transition to perennial bioenergy crops, addressing concerns that the impacts of land conversion to perennial bioenergy crops could result in increased rather than decreased GHG emissions. For policymakers to assess the most cost-effective and sustainable options for deployment and climate change mitigation, synthesis of these studies is needed to support evidence-based decision making. In 2015, a workshop was convened with researchers, policymakers and industry/business representatives from the UK, EU and internationally. Outcomes from global research on bioenergy land-use change were compared to identify areas of consensus, key uncertainties, and research priorities. Here, we discuss the strength of evidence for and against six consensus statements summarising the effects of land-use change to perennial bioenergy crops on the cycling of carbon, nitrogen and water, in the context of the whole life-cycle of bioenergy production. Our analysis suggests that the direct impacts of dedicated perennial bioenergy crops on soil carbon and nitrous oxide are increasingly well understood and are often consistent with significant life cycle GHG mitigation from bioenergy relative to conventional energy sources. We conclude that the GHG balance of perennial bioenergy crop cultivation will often be favourable, with maximum GHG savings achieved where crops are grown on soils with low carbon stocks and conservative nutrient application, accruing additional environmental benefits such as improved water quality. The analysis reported here demonstrates there is a mature and increasingly comprehensive evidence base on the environmental benefits and risks of bioenergy cultivation which can support the development of a sustainable bioenergy industry. PMID- 29497459 TI - Treatment of uveal melanoma: where are we now? AB - Uveal melanoma, a rare subset of melanoma, is the most common primary intraocular malignancy in adults. Despite effective primary therapy, nearly 50% of patients will develop metastatic disease. Outcomes for those with metastatic disease remain dismal due to a lack of effective therapies. The unique biology and immunology of uveal melanoma necessitates the development of dedicated management and treatment approaches. Ongoing efforts seek to optimize the efficacy of targeted therapy and immunotherapy in both the adjuvant and metastatic setting. This review provides a comprehensive, updated overview of disease biology and risk stratification, the management of primary disease, options for adjuvant therapy, and the current status of treatment strategies for metastatic disease. PMID- 29497460 TI - Ontology for Semantic Data Integration in the Domain of IT Benchmarking. AB - A domain-specific ontology for IT benchmarking has been developed to bridge the gap between a systematic characterization of IT services and their data-based valuation. Since information is generally collected during a benchmark exercise using questionnaires on a broad range of topics, such as employee costs, software licensing costs, and quantities of hardware, it is commonly stored as natural language text; thus, this information is stored in an intrinsically unstructured form. Although these data form the basis for identifying potentials for IT cost reductions, neither a uniform description of any measured parameters nor the relationship between such parameters exists. Hence, this work proposes an ontology for the domain of IT benchmarking, available at https://w3id.org/bmontology. The design of this ontology is based on requirements mainly elicited from a domain analysis, which considers analyzing documents and interviews with representatives from Small- and Medium-Sized Enterprises and Information and Communications Technology companies over the last eight years. The development of the ontology and its main concepts is described in detail (i.e., the conceptualization of benchmarking events, questionnaires, IT services, indicators and their values) together with its alignment with the DOLCE-UltraLite foundational ontology. PMID- 29497461 TI - Performance Survey and Comparison Between Rapid Sterility Testing Method and Pharmacopoeia Sterility Test. AB - The sterility test described in pharmacopoeial compendia requires a 14-day incubation period to obtain a valid analytical result. Therefore, the use of alternative methods to evaluate the sterility of pharmaceuticals, such as the BacT/Alert(r) 3D system, is particularly interesting, because it allows a reduced incubation period and lower associated costs. Considering that the BacT/Alert(r) 3D system offers several culture media formulations developed for this microbial detection system, the present study was aimed to evaluate and compare the performance of BacT/Alert(r) 3D with the pharmacopoeial sterility test. There was no significant difference between the ability of the culture media to allow detection of microbial contamination. However, the rapid sterility testing method allowed a more rapid detection of the challenge microorganisms, which indicates that the system is a viable alternative for assessing the sterility of injectable products. PMID- 29497462 TI - Transdermal Delivery of Ibuprofen Utilizing a Novel Solvent-Free Pressure sensitive Adhesive (PSA): TEPI(r) Technology. AB - Purpose: The main objective of this present study was the investigation of potential novel transdermal patch technology (TEPI(r)) delivering ibuprofen as the active pharmaceutical ingredient (API) using a novel poly(ether-urethane) silicone crosslinked pressure-sensitive adhesive (PSA) as the drug reservoir in a solvent-free manufacturing process. Methods: The patch was synthesized utilizing the hot-melt crosslinking technique without the addition of solvents at 80 degrees C in 100% relative humidity. Dissolution and permeation studies performed utilizing diffusion cells and subsequently HPLC validated methods were employed to determine the API content in the acceptor solution. Accelerated stability studies were also performed at 40 degrees C and 70% relative humidity. The adhesive performance of the fabricated patch was evaluated utilizing loop tack adhesion tests. Results: In vitro permeation experiments across both Strat-M(r) and human skin demonstrated that ibuprofen can easily be released from the adhesive matrix and penetrate through the studied membrane. A comparison on the permeation rates of the API across the two membranes indicated that there is not a strong correlation between the obtained data. The presence of chemical enhancers facilitated an increased flux of the API higher than observed in the basic formulation. Initial stability studies of the optimized formulation showed no degradation with respect to the drug content. Adhesion studies were also performed indicating higher values when compared with commercially available products. Conclusions: The present study demonstrated the fabrication of an ibuprofen patch utilizing a versatile, solvent-free drug delivery platform. Upon optimization of the final system, the resulting patch offers many advantages compared to commercially available formulations including high drug loading (up to 25 wt%), good adhesion, and painless removal leaving no residues on the skin. This PSA offers many advantages over existing adhesive technology. Graphical Abstract?. PMID- 29497464 TI - How are Immigrant Children in Sweden Faring? Mean Income, Affluence and Poverty Since the 1980s. AB - This article presents new research on income-based child indicators for immigrant children from 17 different national backgrounds and children of parents born in Sweden observed during the 3-year periods 1983-85, 1995-97 and 2008-10. This research examines mean household income, representation at the top of the income distribution and relative poverty differ for immigrant children from the corresponding levels among children with native born parents. Most of the analysis is concentrated on the second generation of immigrant children. It is shown that the relative position of immigrant children deteriorated between 1983 85 and 1995-97 when the labour market situation of immigrant parents weakened more than among native born parents. Changes thereafter were more complex. Children born in Sweden to parents from Denmark, Norway or Germany were as likely as children of native born parents to be observed at the top of the income distribution in contrast to children of parents from countries with middle or low human development. Poverty rates among immigrant children were higher among all categories of immigrant children in 2008-10 than among children of native born parents. These cross origin differences in income-based child indicators can be attributed to the reasons and qualifications parents had when they entered Sweden and the number of years since their immigration. A majority of children living in Sweden that are classified as poor in 2008-10 were immigrant children of various categories. PMID- 29497463 TI - 'They Say HIV is a Punishment from God or from Ancestors': Cross-Cultural Adaptation and Psychometric Assessment of an HIV Stigma Scale for South African Adolescents Living with HIV (ALHIV-SS). AB - Sub-Saharan Africa is home to 90 % of the world's adolescents living with HIV (ALHIV). HIV-stigma and the resultant fear of being identified as HIV-positive can compromise the survival of these youth by undermining anti-retroviral treatment initiation and adherence. To date, no HIV-stigma measures have been validated for use with ALHIV in Sub-Saharan Africa. This paper reports on a two stage study in the Eastern Cape, South Africa. Firstly, we conducted a cross cultural adaptation of an HIV stigma scale, previously used with US ALHIV. One-on one semi-structured cognitive interviews were conducted with 9 urban and rural ALHIV. Three main themes emerged: 1) participants spoke about experiences of HIV stigma specific to a Southern African context, such as anticipating stigma from community members due to 'punishment from God or ancestors'; 2) participants' responses uncovered discrepancies between what the items intended to capture and how they understood them and 3) participants' interpretation of wording uncovered redundant items. Items were revised or removed in consultation with participants. Secondly, we psychometrically assessed and validated this adapted ALHIV stigma scale (ALHIV-SS). We used total population sampling in 53 public healthcare facilities with community tracing. 721 ALHIV who were fully aware of their status were identified and interviewed for the psychometric assessment. Confirmatory factor analysis confirmed a 3-factor structure of enacted, anticipated and internalized stigma. The removal of 3 items resulted in a significant improvement in model fit (Chi2(df) = 189.83 (33), p < .001) and the restricted model fitted the data well (RMSEA = .017; CFI/TLI = .985/.980; SRMR = .032). Standardized factor loadings of indicators onto the latent variable were acceptable for all three measures (.41-.96). Concurrent criterion validity confirmed hypothesized relationships. Enacted stigma was associated with higher AIDS symptomatology (r = .146, p < .01) and depression (r = .092, p < .01). Internalized stigma was correlated with higher depression (r = .340, p < .01), higher AIDS symptomatology (r = .228, p < .01) and low social support (r = -.265, p < .01). Anticipated stigma was associated with higher depression (r = .203, p < .01) and lower social support (r = -.142, p < .01). The resulting ALHIV-SS has 10 items capturing all three HIV stigma mechanisms experienced by ALHIV. ALHIV-SS will be valuable for evaluating rates and types of stigma, as well as effectiveness of stigma reduction interventions among ALHIV in Southern Africa. PMID- 29497466 TI - ADT-G as a promising biomarker for peripheral hyperandrogenism in adult female acne. AB - Acne vulgaris is a chronic inflammatory disease that affects the pilosebaceous unit. Recent studies have shown an increasing number of cases of acne in adult women. These cases are predominantly normoandrogenic and present some clinical differences compared to adolescent acne. Local glandular metabolism turns some weak hormonal precursors into more active substances that increase the production of sebum, leaving these areas more prone to an increasing the colonization by Propionibacterium acnes (P. acnes). Our objective was to evaluate the usefulness of an androgenic metabolite as an adult female acne biomarker. The study population consisted of 38 adult women with acne without any features of hyperandrogenism and a control group. They were recruited from the clinic of Dermatology Hospital Division of Sao Paulo, Federal University of Sao Paulo from January 2012 to September 2014. After the first hormonal dosages, patients with acne were randomized into two different groups: one receiving a combined oral contraceptive (COC) containing 0,02 mg of ethinylestradiol and 3 mg drospirenone in a regimen of 24 days of medication, and the other group was treated with a topical gel containing 15% azelaic acid (AA), twice daily, both for six months. With the end of treatment new dosages were performed. Regarding the hormones, total and free testosterone and dehydroepiandrosterone sultate were quantified. In addition, the detection and quantification of androsterone glucuronate (ADT G), an androgenic metabolite, has been developed. Only ADT-G was sensitive in detecting differences between the control and acne groups, and presented reduction of their values with systemic treatment. Therefore, only ADT-G was able to analyze the peripheral hyperandrogenism in cases of adult female acne. PMID- 29497465 TI - Piezoelectric smart biomaterials for bone and cartilage tissue engineering. AB - Tissues like bone and cartilage are remodeled dynamically for their functional requirements by signaling pathways. The signals are controlled by the cells and extracellular matrix and transmitted through an electrical and chemical synapse. Scaffold-based tissue engineering therapies largely disturb the natural signaling pathways, due to their rigidity towards signal conduction, despite their therapeutic advantages. Thus, there is a high need of smart biomaterials, which can conveniently generate and transfer the bioelectric signals analogous to native tissues for appropriate physiological functions. Piezoelectric materials can generate electrical signals in response to the applied stress. Furthermore, they can stimulate the signaling pathways and thereby enhance the tissue regeneration at the impaired site. The piezoelectric scaffolds can act as sensitive mechanoelectrical transduction systems. Hence, it is applicable to the regions, where mechanical loads are predominant. The present review is mainly concentrated on the mechanism related to the electrical stimulation in a biological system and the different piezoelectric materials suitable for bone and cartilage tissue engineering. PMID- 29497467 TI - Characterizing Cardiac Involvement in Chronic Kidney Disease Using CMR-a Systematic Review. AB - Purpose of Review: The aim of the review was to identify and describe recent advances (over the last 3 years) in cardiac magnetic resonance (CMR) imaging in patients with chronic kidney disease (CKD). We conducted a literature review in line with current guidelines. Recent Findings: The authors identified 22 studies. Patients with CKD had left ventricular global and regional dysfunction and adverse remodeling. Stress testing with CMR revealed a reduced stress-response in CKD patients. Native T1 relaxation times (as a surrogate markers of fibrosis) are elevated in CKD patients, proportional to disease duration. Patients with CKD have reduced strain magnitudes and reduced aortic distensibility. Summary: CMR has diagnostic utility to identify and characterize cardiac involvement in this patient group. A number of papers have described novel findings over the last 3 years, suggesting that CMR has potential to become more widely used in studies in this patient group. PMID- 29497468 TI - Nicotinamide treatment robustly protects from inherited mouse glaucoma. AB - Nicotinamide adenine dinucleotide (NAD) is a key molecule in several cellular processes and is essential for healthy mitochondrial metabolism. We recently reported that mitochondrial dysfunction is among the very first changes to occur within retinal ganglion cells during initiation of glaucoma in DBA/2J mice. Furthermore, we demonstrated that an age-dependent decline of NAD contributes to mitochondrial dysfunction and vulnerability to glaucoma. The decrease in NAD renders retinal ganglion cells vulnerable to a metabolic crisis following periods of high intraocular pressure. Treating mice with the NAD precursor nicotinamide (the amide form of vitamin B3) inhibited many age- and high intraocular pressure- dependent changes with the highest tested dose decreasing the likelihood of developing glaucoma by ~10-fold. In this communication, we present further evidence of the neuroprotective effects of nicotinamide against glaucoma in mice, including its prevention of optic nerve excavation and axon loss as assessed by histologic analysis and axon counting. We also show analyses of age- and intraocular pressure- dependent changes in transcripts of NAD producing enzymes within retinal ganglion cells and that nicotinamide treatment prevents these transcriptomic changes. PMID- 29497470 TI - Identifying the transition to the maturation zone in three ecotypes of Arabidopsis thaliana roots. AB - The Arabidopsis thaliana (hereafter Arabidopsis) root has become a useful model for studying how organ morphogenesis emerge from the coordination and balance of cell proliferation and differentiation, as both processes may be observed and quantified in the root at different stages of development. Hence, being able to objectively identify and delimit the different stages of root development has been very important. Up to now, three different zones along the longitudinal axis of the primary root of Arabidopsis, have been identified: the root apical meristematic zone (RAM) with two domains [the proliferative (PD) and the transition domain (TD)], the elongation zone (EZ) and the maturation zone (MZ). We previously reported a method to quantify the length of the cells of the meristematic and the elongation zone, as well as the boundaries or transitions between the root domains along the growing part of the Arabidopsis root. In this study, we provide a more accurate criterion to identify the MZ. Traditionally, the transition between the EZ to the MZ has been established by the emergence of the first root-hair bulge in the epidermis, because this emergence coincides with cell maturation in this cell type. But we have found here that after the emergence of the first root-hair bulge some cells continue to elongate and we have confirmed this in three different Arabidopsis ecotypes. We established the limit between the EZ and the MZ by looking for the closest cortical cell with a longer length than the average cell length of 10 cells after the cortical cell closest to the epidermal cell with the first root-hair bulge in these three ecotypes. In Col-0 and Ws this cell is four cells above the one with the root hair bulge and, in the Ler ecotype, this cell is five cells above. To unambiguously identifying the site at which cells stop elongating and attain their final length and fate at the MZ, we propose to calculate the length of completely elongated cortical cells counting 10 cells starting from the sixth cell above the cortical cell closest to the epidermal cell with the first root hair bulge. We validated this proposal in the three ecotypes analyzed and consider that this proposal may aid at having a more objective way to characterize root phenotypes and compare among them. PMID- 29497469 TI - The complex world of plant protease inhibitors: Insights into a Kunitz-type cysteine protease inhibitor of Arabidopsis thaliana. AB - Plants have evolved an intricate regulatory network of proteases and corresponding protease inhibitors (PI), which operate in various biological pathways and serve diverse spatiotemporal functions during the sedentary life of a plant. Intricacy of the regulatory network can be anticipated from the observation that, depending on the developmental stage and environmental cue(s), either a single PI or multiple PIs regulate the activity of a given protease. On the other hand, the same PI often interacts with different targets at different places, necessitating another level of fine control to be added in planta. Here, it is reported on how the activity of a papain-like cysteine protease dubbed RD21 (RESPONSIVE TO DESICCATION 21) is differentially regulated by serpin and Kunitz PIs over plant development and how this mechanism contributes to defenses against herbivorous arthropods and microbial pests. PMID- 29497471 TI - Common effects of attractive and repulsive signaling: Further analysis of Mical mediated F-actin disassembly and regulation by Abl. AB - To change their size, shape, and connectivity, cells require actin and tubulin proteins to assemble together into long polymers - and numerous extracellular stimuli have now been identified that alter the assembly and organization of these cytoskeletal structures. Yet, there remains a lack of defined signaling pathways from the cell surface to the cytoskeleton for many of these extracellular signals, and so we still know little of how they exert their precise structural effects. These extracellular cues may be soluble or substrate bound and have historically been classified into two independently acting and antagonistic groups: growth-promoting/attractants (inducing turning toward the source of the factor/positive chemotropism) or growth-preventing/repellents (turning away from the source of the factor/negative chemotropism). Paradoxically, our recent results directly link the action of growth factors/chemoattractants and their signaling pathways to the promotion of the disassembly of the F-actin cytoskeleton (a defined readout of repellents/repulsive signaling). Herein, we add to this by simply driving a constitutively active form of Mical, which strongly disassembles F-actin/remodels cells in vivo independent of repulsive cues - and find that loss of Abl, which mediates growth factor signaling in these cells, decreases Mical's F-actin disassembly/cellular remodeling effects. Thus, our results are consistent with a hypothesis that cues defined as positive effectors of movement (growth factors/chemoattractants) can at least in some contexts enhance the F-actin disassembly and remodeling activity of repellents. PMID- 29497472 TI - Only two sex forms but multiple gender variants: How to explain? AB - Are sex and gender interchangeable terms? In classical biology, both are sometimes but not always used on an equal basis for some groups of animals. However, for our own species the Homo sapiens, they are not. A major question is why are there only two types of gametes (sperm- and egg cells), two types of sex steroids, (androgens and estrogens in vertebrates, and two types of ecdysteroids in insects), while the reproduction-related behaviour of the gamete producers displays a much greater variability than just two prominent forms, namely heterosexual males and heterosexual females? It indicates that in addition to a few sex-determining genes ( = the first pillar), other factors play a role. A second possible pillar is the still poorly understood cognitive memory system in which electrical phenomena and its association with the plasma membrane membrane cytoskeletal complex of cells play a major role (learning, imitation and imprinting). This paper advances a third pillar, that hitherto has been almost completely ignored, namely the cellular Ca2+-homeostasis system, more specifically its sex-specific differences. Differential male-female genetics- and hormone-based Ca2+-homeostasis with effects on gender-related processes has been named Calcigender before. It will be argued that it follows from the principles of Ca2+- physiology and homeostasis that all individuals of a sexually reproducing animal population have a personalized gender behaviour. Thus, subdividing gender-behaviours in hetero-, homo-, bi-, trans- etc. which all result from a differential use of the very same basic physiological principles, is too primitive a system that may yield false sociological interpretations. PMID- 29497473 TI - Booting up the organism during development: Pre-behavioral functions of the vertebrate brain in guiding body morphogenesis. AB - A recent study in Xenopus laevis embryos showed that the very early brain has important functions long before behavior. While the nascent brain is being constructed, it is required for normal patterning of the muscle and peripheral nerve networks, including those far away from the head. In addition to providing important developmental signals to remote tissues in normal embryogenesis, its presence is also able to render harmless exposure to specific chemicals that normally act as teratogens. These activities of the early brain can be partially compensated for in a brainless embryo by experimental modulation of neurotransmitter and ion channel signaling. Here, we discuss the major findings of this paper in the broader context of developmental physiology, neuroscience, and biomedicine. This novel function of the embryonic brain has significant implications, especially for understanding developmental toxicology and teratogenesis in the context of pharmaceutical and environmental reagents. PMID- 29497475 TI - Assessment of bacterial endosymbionts and the host, Bemisia tabaci (Hemiptera: Aleyrodidae), using rRNA and mitochondrial cytochrome oxidase I gene sequences. AB - Endosymbionts are vital factor for arthropod ecology. The whitefly Bemisia tabaci (Hemiptera: Aleyrodidae) is a cryptic species complex composed of more than 34 putative species. Moreover to the primary endosymbiont Portiera aleyrodidarum, six secondary endosymbionts Cardinium, Arsenophonus, Rickettsia, Wolbachia, Hamiltonella and Fritschea are known in B. tabaci. Here, we tested four of the six secondary endosymbiont lineages (excluding Fritschea and Hamiltonella) from 180 whitely individuals collected from six host plants belonging to families Solanaceae (Brinjal, Tomato and Potato) and Fabaceae (Soyabean, Mungbean and Subabool). Phylogenetic studies grounded on the mitochondrial cytochrome I gene revealed the presence of Asia 1, Asia II 1 and Asia II 7 genetic groups for B. tabaci. Specific primers targeting 16S rRNA and 23S rRNA gene were used for estimating the bacterial endosymbionts. As a primary endosymbiont Portiera aleyrodidarum was present in all the studied samples; whereas, an uneven distribution of secondary endosymbionts were recorded. Overall our finding exposes the variation and diversity of endosymbionts within the B. tabaci collected from different host plants and outlines the genetic groups of the insect pest. The study delivers a significant information concerning the circulation of secondary endosymbionts with host preferences of B. tabaci and provides suggestion for progressive studies on targeting the specific endosymbionts with respect to host for the control measures. PMID- 29497474 TI - Multiple lines of inhibitory feedback on AKT kinase in Schwann cells lacking TSC1/2 hint at distinct functions of mTORC1 and AKT in nerve development. AB - During nerve development, Schwann cells (SCs) build multilayered myelin sheaths around axons to accelerate nerve conduction. The mechanistic target of rapamycin complex 1 (mTORC1) downstream of PI3K/AKT signaling lately emerged as a central anabolic regulator of myelination. Using mutant mice with sustained mTORC1 hyperactivity in developing SCs we recently uncovered that mTORC1 impedes developmental myelination by promoting proliferation of immature SCs while antagonizing SC differentiation. In contrast, mTORC1 stimulates myelin production, rather than SC proliferation, in already differentiated SCs. Importantly, these diametrical mTORC1 functions were unmasked under settings of greatly suppressed AKT signaling. Here we demonstrate, inter alia, additional mechanisms of feedback inhibition of AKT by mTORC1, such as strikingly elevated PTEN levels in SCs with disruption of the mTORC1 inhibitory complex, TSC1/2. These data lead us to propose a model wherein mTORC1 and AKT have distinct roles in developing SCs that have to be precisely coordinated for normal myelinogenesis. PMID- 29497477 TI - Characterization of Moist Processes Associated With Changes in the Propagation of the MJO With Increasing CO2. AB - The processes that lead to changes in the propagation and maintenance of the Madden-Julian Oscillation (MJO) as a response to increasing CO2 are examined by analyzing moist static energy budget of the MJO in a series of NASA GISS model simulations. It is found changes in MJO propagation is dominated by several key processes. Horizontal moisture advection, a key process for MJO propagation, is found to enhance predominantly due to an increase in the mean horizontal moisture gradients. The terms that determine the strength of the advecting wind anomalies, the MJO horizontal scale and the dry static stability, are found to exhibit opposing trends that largely cancel out. Furthermore, reduced sensitivity of precipitation to changes in column moisture, i.e., a lengthening in the convective moisture adjustment time scale, also opposes enhanced propagation. The dispersion relationship of Adames and Kim, which accounts for all these processes, predicts an acceleration of the MJO at a rate of ~3.5% K-1, which is consistent with the actual phase speed changes in the simulation. For the processes that contribute to MJO maintenance, it is found that damping by vertical MSE advection is reduced due to the increasing vertical moisture gradient. This weaker damping is nearly canceled by weaker maintenance by cloud radiative feedbacks, yielding the growth rate from the linear moisture mode theory nearly unchanged with the warming. Furthermore, the estimated growth rates are found to be a small, negative values, suggesting that the MJO in the simulation is a weakly damped mode. PMID- 29497476 TI - Green tea and cocoa enhance cognition in Lymnaea. AB - A flavonoid, (-)-epicatechi (Epi), enhances long-term memory (LTM) formation in Lymnaea and reverses memory obstruction caused by stress. Many foods contain substantial amounts of Epi, (e.g. green tea and cocoa). In humans eating such foods may directly or indirectly enhance cognition. We directly test whether operant conditioning training Lymnaea in these natural foods result in the same effects as training snails in pure Epi. We found that exposure to products containing high concentrations of Epi (e.g. green tea and cocoa) during training enhanced memory formation and could even reverse a learning and memory deficit brought about by stress. Epi can be photo-inactivated by exposure to ultraviolet light. We found that following photo-inactivation of Epi, memory enhancement did not occur. Photo-inactivation of foods containing Epi (e,g. green tea) blocked their ability to enhance LTM. Our data are thus consistent with the hypothesis that dietary sources of Epi can have positive benefits on cognitive ability and be able to reverse memory aversive states. PMID- 29497478 TI - Chemical Mechanisms and Their Applications in the Goddard Earth Observing System (GEOS) Earth System Model. AB - NASA's Goddard Earth Observing System (GEOS) Earth System Model (ESM) is a modular, general circulation model (GCM), and data assimilation system (DAS) that is used to simulate and study the coupled dynamics, physics, chemistry, and biology of our planet. GEOS is developed by the Global Modeling and Assimilation Office (GMAO) at NASA Goddard Space Flight Center. It generates near-real-time analyzed data products, reanalyses, and weather and seasonal forecasts to support research targeted to understanding interactions among Earth System processes. For chemistry, our efforts are focused on ozone and its influence on the state of the atmosphere and oceans, and on trace gas data assimilation and global forecasting at mesoscale discretization. Several chemistry and aerosol modules are coupled to the GCM, which enables GEOS to address topics pertinent to NASA's Earth Science Mission. This paper describes the atmospheric chemistry components of GEOS and provides an overview of its Earth System Modeling Framework (ESMF)-based software infrastructure, which promotes a rich spectrum of feedbacks that influence circulation and climate, and impact human and ecosystem health. We detail how GEOS allows model users to select chemical mechanisms and emission scenarios at run time, establish the extent to which the aerosol and chemical components communicate, and decide whether either or both influence the radiative transfer calculations. A variety of resolutions facilitates research on spatial and temporal scales relevant to problems ranging from hourly changes in air quality to trace gas trends in a changing climate. Samples of recent GEOS chemistry applications are provided. PMID- 29497479 TI - Inclusion of Solar Elevation Angle in Land Surface Albedo Parameterization Over Bare Soil Surface. AB - Land surface albedo is a significant parameter for maintaining a balance in surface energy. It is also an important parameter of bare soil surface albedo for developing land surface process models that accurately reflect diurnal variation characteristics and the mechanism behind the solar spectral radiation albedo on bare soil surfaces and for understanding the relationships between climate factors and spectral radiation albedo. Using a data set of field observations, we conducted experiments to analyze the variation characteristics of land surface solar spectral radiation and the corresponding albedo over a typical Gobi bare soil underlying surface and to investigate the relationships between the land surface solar spectral radiation albedo, solar elevation angle, and soil moisture. Based on both solar elevation angle and soil moisture measurements simultaneously, we propose a new two-factor parameterization scheme for spectral radiation albedo over bare soil underlying surfaces. The results of numerical simulation experiments show that the new parameterization scheme can more accurately depict the diurnal variation characteristics of bare soil surface albedo than the previous schemes. Solar elevation angle is one of the most important factors for parameterizing bare soil surface albedo and must be considered in the parameterization scheme, especially in arid and semiarid areas with low soil moisture content. This study reveals the characteristics and mechanism of the diurnal variation of bare soil surface solar spectral radiation albedo and is helpful in developing land surface process models, weather models, and climate models. PMID- 29497480 TI - Differentiation in native as well as introduced ranges: germination reflects mean and variance in cover of surrounding vegetation. AB - Germination, a crucial phase in the life cycle of a plant, can be significantly influenced by competition and facilitation. The aim of this study was to test whether differences in cover of surrounding vegetation can lead to population differentiation in germination behaviour of an annual grassland species, and if so, whether such a differentiation can be found in the native as well as in the introduced range. We used maternal progeny of Erodium cicutarium previously propagated under uniform conditions that had been collected in multiple populations in the native and two introduced ranges, in populations representing extremes in terms of mean and variability of the cover of surrounding vegetation. In the first experiment, we tested the effect of germination temperature and mean cover at the source site on germination, and found interlinked effects of these factors. In seeds from one of the introduced ranges (California), we found indication for a 2-fold dormancy, hindering germination at high temperatures even if physical dormancy was broken and water was available. This behaviour was less strong in high cover populations, indicating cross-generational facilitating effects of dense vegetation. In the second experiment, we tested whether spatial variation in cover of surrounding vegetation has an effect on the proportion of dormant seeds. Contrary to our expectations, we found that across source regions, high variance in cover was associated with higher proportions of seeds germinating directly after storage. In all three regions, germination seemed to match the local environment in terms of climate and vegetation cover. We suggest that this is due to a combined effect of introduction of preadapted genotypes and local evolutionary processes. PMID- 29497481 TI - Increasing Perspectival Obliqueness Increases the Leaning Tower Illusion. AB - The leaning tower illusion is a perceptual illusion in which two identical images of a tower photographed from below appear to diverge when juxtaposed. We manipulated the perceived obliqueness of the (upright) St Mark bell tower in Venice by modifying two parameters both related to the position of the camera with respect to the tower: (a) increasing the peripherality of the tower and (b) reducing the distance between the camera and the tower. The resulting images clearly show that the illusory leaning effect increases as a function of the obliqueness. Another crucial condition for the leaning tower effect must be that the twin images are perceived as parts of a unitary display: The illusion increases when the distance between the photos is progressively increased, but beyond a certain level of separation, the integration of the images should, of course, break down, and the illusion vanish. PMID- 29497482 TI - Exposure to 60% oxygen promotes migration and upregulates angiogenesis factor secretion in breast cancer cells. AB - Peri-operative factors, including anaesthetic drugs and techniques, may affect cancer cell biology and clinical recurrence. In breast cancer cells, we demonstrated that sevoflurane promotes migration and angiogenesis in high fractional oxygen but not in air. Follow-up analysis of the peri-operative oxygen fraction trial found an association between high inspired oxygen during cancer surgery and reduced tumor-free survival. Here we evaluated effects of acute, high oxygen exposure on breast cancer cell viability, migration and secretion of angiogenesis factors in vitro. MDA-MB-231 and MCF-7 breast cancer cells were exposed to 21%, 30%, 60%, or 80% v/v O2 for 3 hours. Cell viability at 24 hours was determined by MTT and migration at 24 hours with the OrisTM Cell Migration Assay. Secretion of angiogenesis factors at 24 hours was measured via membrane based immunoarray. Exposure to 30%, 60% or 80% oxygen did not affect cell viability. Migration of MDA-MB-231 and MCF-7 cells was increased by 60% oxygen (P = 0.012 and P = 0.007, respectively) while 30% oxygen increased migration in MCF 7 cells (P = 0.011). These effects were reversed by dimethyloxaloylglycine. In MDA-MB-231 cells high fractional oxygen increased secretion of angiogenesis factors monocyte chemotactic protein 1, regulated on activation normal T-cell expressed and vascular endothelial growth factor. In MCF-7 cells, interleukin-8, angiogenin and vascular endothelial growth factor secretion was significantly increased by high fractional oxygen. High oxygen exposure stimulates migration and secretion of angiogenesis factors in breast cancer cells in vitro. PMID- 29497483 TI - Polarization of macrophages in the blood after decompression in mice. AB - The veins are a major site of bubble formation after decompression and the lung is a target organ of bubbles. Bubble-induced inflammation has been implicated in the pathogenesis of decompression sickness (DCS). Macrophages play a central role in the inflammation, and macrophage polarization is closely related to the pathogenesis of some lung diseases. This study aimed to investigate the blood macrophage polarization in mice after decompression. BALB/c mice were exposed to hyperbaric air for 60 minutes, and rapid decompression was performed to induce DCS. Slow decompression and hyperoxia (150 kPa, 60 minutes) served as control groups, and hyperbaric oxygen (HBO; 250 kPa, 60 minutes) was employed for DCS treatment. Macrophage phenotype was determined by flow cytometry, and cytokines related to macrophage polarization were measured by enzyme-linked immunosorbent assay. Our results showed rapid decompression significantly induced the shift to M1 phenotype, which was not observed in slow decompression group, HBO and hyperoxia groups. These changes were consistent with the change in blood tumor necrosis factor alpha level. Moreover, any treatment could significantly increase the M2 macrophages, but blood interleukin-10 remained unchanged after different treatments. In addition, the blood and lung levels of monocyte chemoattractant protein-1 and intercellular adhesion molecule-1 increased significantly after rapid decompression, but reduced markedly after HBO treatment. Taken together, rapid decompression is able to induce the shift to M1 phenotype in blood macrophages, which may then migrate into the lung involving decompression-induced lung injury. PMID- 29497484 TI - Comparing the efficacy and safety of laryngeal mask airway, streamlined liner of the pharyngeal airway and I-gel following tracheal extubation. AB - Adverse events following surgical operations are common complications due to removal of tracheal tube in contrast to the tracheal intubation. Awareness about the new methods and strategies for tracheal tube extubation is necessary for a safe and successful extubation. Therefore, we aimed to assess the safety and efficacy of laryngeal mask airway (LMA), streamlined liner of the pharyngeal airway (SLIPA) and I-gel in extubation time of tracheal tube. A one-single randomized clinical trial was conducted in 105 eligible patients in three groups including LMA, SLIPA and I-gel. The patients were under surgery after general anesthesia with propofol (2-3 mg/kg) and fentanyl (1-2 MUg/kg). Hemodynamic responses and extubation consequences including coughing rate, laryngospasm, airway obstruction, apnea, breath holding and straining of patients, vomiting, and need for re-intubation were recorded every 5 minutes since inserting of supraglottic airway devices (SADs) until patients restore consciousness. Analysis of data was conducted in SPSS software by analysis of variance (ANOVA) and ANOVA for repeated measurements tests. The overall successful insertion was 100% for LMA and I-Gel and this rate was 97.1% for SLIPA method. A significant decrease was observed in trend of hemodynamic responses in all three groups. Nevertheless, the MBP was lower in LMA group and lower HR was observed in I-Gel and higher HR occurred in SLIPA (P < 0.05). Three groups was same statistically regarding sore throat, vomiting, coughing, breath holding, apnea, laryngospasm, and re intubation need (P > 0.05). However, the incidence rate of apnea, and laryngospasm, as well as re-intubation need in SLIPA group was 2.9%, respectively. LMA, I-GEL and SLIPA could be considered as useful and safe devices for ventilation control after tracheal tube removal at the end of operation. Three devices were same regarding to sore throat, vomiting, coughing, and breath holding. However, LMA showed lower side effects while SLIPA was related to more occurrences of apnea, laryngospasm, and re-intubation need. PMID- 29497486 TI - A physiologically based model for denitrogenation kinetics. AB - Under normal conditions we continuously breathe 78% nitrogen (N2) such that the body tissues and fluids are saturated with dissolved N2. For normobaric medical gas administration at high concentrations, the N2 concentration must be less than that in the ambient atmosphere; therefore, nitrogen will begin to be released by the body tissues. There is a need to estimate the time needed for denitrogenation in the planning of surgical procedures. In this paper we will describe the application of a physiologically based pharmacokinetic model to denitrogenation kinetics. The results are compared to the data resulting from experiments in the literature that measured the end tidal N2 concentration while breathing 100% oxygen in the form of moderately rapid and slow compartment time constants. It is shown that the model is in general agreement with published experimental data. Correlations for denitrogenation as a function of subject weight are provided. PMID- 29497485 TI - Hydrogen-rich water for improvements of mood, anxiety, and autonomic nerve function in daily life. AB - Health and a vibrant life are sought by everyone. To improve quality of life (QOL), maintain a healthy state, and prevent various diseases, evaluations of the effects of potentially QOL-increasing factors are important. Chronic oxidative stress and inflammation cause deteriorations in central nervous system function, leading to low QOL. In healthy individuals, aging, job stress, and cognitive load over several hours also induce increases in oxidative stress, suggesting that preventing the accumulation of oxidative stress caused by daily stress and daily work contributes to maintaining QOL and ameliorating the effects of aging. Hydrogen has anti-oxidant activity and can prevent inflammation, and may thus contribute to improve QOL. The present study aimed to investigate the effects of drinking hydrogen-rich water (HRW) on the QOL of adult volunteers using psychophysiological tests, including questionnaires and tests of autonomic nerve function and cognitive function. In this double-blinded, placebo-controlled study with a two-way crossover design, 26 volunteers (13 females, 13 males; mean age, 34.4 +/- 9.9 years) were randomized to either a group administered oral HRW (600 mL/d) or placebo water (PLW, 600 mL/d) for 4 weeks. Change ratios (post treatment/pre-treatment) for K6 score and sympathetic nerve activity during the resting state were significantly lower after HRW administration than after PLW administration. These results suggest that HRW may reinforce QOL through effects that increase central nervous system functions involving mood, anxiety, and autonomic nerve function. PMID- 29497487 TI - The influence of ZnO-SnO2 nanoparticles and activated carbon on the photocatalytic degradation of toluene using continuous flow mode. AB - The present study examined the gas-phase photocatalytic degradation of toluene using ZnO-SnO2 nanocomposite supported on activated carbon in a photocatalytic reactor. Toluene was selected as a model pollutant from volatile organic compounds to determine the pathway of photocatalytic degradation and the factors influencing this degradation. The ZnO-SnO2 nanocomposite was synthesized through co-precipitation method in a ratio of 2:1 and then supported on activated carbon. The immobilization of ZnO-SnO2 nanocomposite on activated carbon was determined by the surface area and scanning electron micrograph technique proposed by Brunauer, Emmett, and Teller. The laboratory findings showed that the highest efficiency was 40% for photocatalytic degradation of toluene. The results also indicated that ZnO-SnO2 nano-oxides immobilization on activated carbon had a synergic effect on photocatalytic degradation of toluene. Use of a hybrid photocatalytic system (ZnO/SnO2 nano coupled oxide) and application of absorbent (activated carbon) may be efficient and effective technique for refinement of toluene from air flow. PMID- 29497488 TI - The transfer of hydrogen from inert gas to therapeutic gas. AB - Hydrogen is the most abundant chemical element in the universe, and has been used as an inert gas for a long time. More recent studies have shown that molecular hydrogen as a kind of antioxidant, anti-inflammatory, anti-apoptosis, gene expression and signal modulation molecule, can be used for the treatment of many diseases. This review mainly focuses on the research progresses of hydrogen in various medical fields and the possible action mechanisms. PMID- 29497490 TI - Renal responses to sevoflurane and isoflurane in patients undergoing donor nephrectomy. PMID- 29497489 TI - The role of nitrous oxide in stroke. AB - Stroke that is caused by poor blood flow into the brain results in cell death, including ischemia stroke due to lack of blood into brain tissue, and hemorrhage due to bleeding. Both of them will give rise to the dysfunction of brain. In general, the signs and symptoms of stroke are the inability of feeling or moving on one side of body, sometimes loss of vision to one side. Above symptoms will appear soon after the stroke has happened. If the symptoms and signs happen in 1 or 2 hours, we often call them as transient ischemic attack. Moreover, hemorrhagic stroke often leads to severe headache. It is known that neuronal death can happen after stroke, and it depends upon the activation of N-methyl-D aspartate (NMDA) excitatory glutamate receptor which is the goal for a lot of neuroprotective agents. Nitrous oxide was discovered by Joseph Priestley in 1772, and then he and his friends, including the poet Coleridge and Robert Sauce, experimented with the gas. They found this gas could make patients loss the sense of pain and still maintain consciousness after inhalation. Shortly the gas was used as an anesthetic, especially in the field of dentists. Now, accroding to theme of Helene N. David and other scientists, both of nitrous oxide at 75 vol% and xenon at 50 vol% could reduce ischemic neuronal death in the cortex by 70% and decrease NMDA-induced Ca2+ influx by 30%. Therefore, more clinical and experimental studies are important to illuminate the mechanisms of how nitrous oxide protects brain tissue and to explore the best protocol of this gas in stroke treatment. PMID- 29497491 TI - Ozone therapy in dentistry: revisited. PMID- 29487738 TI - A multi-tool recipe to identify regions of protein-DNA binding and their influence on associated gene expression. AB - One commonly performed bioinformatics task is to infer functional regulation of transcription factors by observing differential expression under a knockout, and integrating DNA binding information of that transcription factor. However, until now, this task has required dedicated bioinformatics support to perform the necessary data integration. GenomeSpace provides a protocol, or "recipe", and a user interface with inter-operating software tools to identify protein occupancies along the genome from a ChIP-seq experiment and associated differentially regulated genes from a RNA-Seq experiment. By integrating RNA-Seq and ChIP-seq analyses, a user is easily able to associate differing expression phenotypes with changing epigenetic landscapes. PMID- 29497493 TI - CellMap visualizes protein-protein interactions and subcellular localization. AB - Many tools visualize protein-protein interaction (PPI) networks. The tool introduced here, CellMap, adds one crucial novelty by visualizing PPI networks in the context of subcellular localization, i.e. the location in the cell or cellular component in which a PPI happens. Users can upload images of cells and define areas of interest against which PPIs for selected proteins are displayed (by default on a cartoon of a cell). Annotations of localization are provided by the user or through our in-house database. The visualizer and server are written in JavaScript, making CellMap easy to customize and to extend by researchers and developers. PMID- 29487740 TI - Tuition reduction is the key factor determining tax burden of graduate students under the Tax Cuts and Job Act. AB - Background: The proposed Tax Cuts and Jobs Act (H.R.1) has stirred significant public debate on the future of American economics. While supporters of the plan have championed it as a necessity for economic revitalization, detractors have pointed out areas of serious concern, particularly for low- and middle-income Americans. One particularly alarming facet of the plan is the radical change to education finance programs and taxation of students in higher education. Methods: By analyzing actual income and tuition of a public and a private university student, as well as the 'average' graduate student, we investigated the effect of both the House and Senate versions of H.R. 1 on taxation of students of various family structures. Results: Our findings indicate that taxable tuition would be the greatest contributor to graduate student tax burden across all four categories of filing status. However, when tuition reduction is upheld or a student is on sustaining fees rather than full tuition, graduate students would realize decreases in taxation. Conclusions: Overall, we conclude that removal of tuition reduction would result in enormous tax burdens for graduate students and their families and that these effects are dependent not only on the status of the student in their degree program but also on their tuition and stipend, and therefore the institution they attend. PMID- 29497495 TI - Improving the biomedical research literature: insights from authors' editors can help journal editors define and refine their core competencies. AB - A team of stakeholders in biomedical publishing recently proposed a set of core competencies for journal editors, as a resource that can inform training programs for editors and ultimately improve the quality of the biomedical research literature. This initiative, still in its early stages, would benefit from additional sources of expert information. Based on our experiences as authors' editors, we offer two suggestions on how to strengthen these competencies so that they better respond to the needs of readers and authors - the main users of and contributors to research journals. First, journal editors should be able to ensure that authors are given useful feedback on the language and writing in submitted manuscripts, beyond a (possibly incorrect) blanket judgement of whether the English is "acceptable" or not. Second, journal editors should be able to deal effectively with inappropriate text re-use and plagiarism. These additional competencies would, we believe, be valued by other stakeholders in biomedical research publication as markers of editorial quality. PMID- 29497496 TI - Recent advances in neuromuscular block during anesthesia. AB - Muscle relaxation is a routine part of anesthesia and has important advantages. However, the lingering effects of muscle relaxants in the postoperative period have historically been associated with postoperative adverse events. Neuromuscular reversal, together with neuromuscular monitoring, is a recognized strategy to reduce the rate of postoperative residual relaxation but has only marginally improved outcome in the past few decades. Sugammadex, a novel reversal agent with unique encapsulating properties, has changed the landscape of neuromuscular reversal and opened up new opportunities to improve patient care. By quickly and completely reversing any depth of neuromuscular block, it may reduce the rate of residual relaxation and improve respiratory recovery. In addition, sugammadex has made the use of deep neuromuscular block possible during surgery. Deep neuromuscular block may improve surgical working conditions and allow for a reduction in insufflation pressures during selected laparoscopic procedures. However, whether and how this may impact outcomes is not well established. PMID- 29497497 TI - The role of NAFLD in cardiometabolic disease: an update. AB - Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the world, yet the complex pathogenesis remains to be fully elucidated. The prevalence of NAFLD has risen precipitously in recent years and is now a leading indication for liver transplantation. New waitlist registrants with non-alcoholic steatohepatitis-induced cirrhosis increased by 170% from 2004 to 2013. In addition, patients with NAFLD are at increased risk of both cardiovascular disease and type II diabetes. In this update, recent studies contributing to the understanding of the place of NAFLD in cardiometabolic disease will be discussed. PMID- 29497499 TI - World Peace in One Hour?Peace is Profitable?Roadmap to Peace. PMID- 29497498 TI - Psychosocial and pharmacological interventions for the treatment of cannabis use disorder. AB - Cannabis use has been continuously increasing, and cannabis use disorder (CUD) has become a public health issue. Some psychosocial interventions have demonstrated the ability to reduce cannabis use; however, there are no pharmacotherapies approved for the treatment of CUD. Some drugs have shown limited positive effects on use and withdrawal symptoms, but no controlled studies have been able to show strong and persistent effects on clinically meaningful outcomes. The aim of this review is to synthesize the evidence from the available literature regarding the effectiveness of psychosocial and pharmacological treatments for CUD among adults (that is, 18 years old or older). An analysis of the evidence shows that the current best psychosocial intervention to reduce cannabis use is the combination of motivational enhancement therapy and cognitive-behavioral therapy, preferably accompanied by a contingency management approach. In regard to pharmacological interventions, there are mostly unclear findings. Some drugs, such as CB1 agonists, gabapentin, and N-acetylcysteine, have been shown to produce improvements in some symptoms of CUD in single studies, but these have not been replicated. Other classes of medications, including antidepressants and antipsychotics, have been unsuccessful in producing such effects. There is an imminent need for more clinical trials to develop more effective treatments for CUD. PMID- 29497500 TI - Motivation and satisfaction among community health workers administering rapid diagnostic tests for malaria in Western Kenya. AB - Background: The continued success of community case management (CCM) programs in low-resource settings depends on the ability of these programs to retain the community health workers (CHWs), many of whom are volunteers, and maintain their high-quality performance. This study aims to identify factors related to the motivation and satisfaction of CHWs working in a malaria CCM program in two sub counties in Western Kenya. Methods: We interviewed 70 CHWs who were trained to administer malaria rapid diagnostic tests as part of a broader study evaluating a malaria CCM program. We identified factors related to CHWs' motivation and their satisfaction with participation in the program, as well as the feasibility of program scale-up. We used principal components analysis to develop an overall CHW satisfaction score and assessed associations between this score and individual CHW characteristics as well as their experiences in the program. Results: The majority of CHWs reported that they were motivated to perform their role in this malaria CCM program by a personal desire to help their community (69%). The most common challenge CHWs reported was a lack of community understanding about malaria diagnostic testing and CHWs' role in the program (39%). Most CHWs (89%) reported that their involvement in the diagnostic testing intervention had either a neutral or a net positive effect on their other CHW activities, including improving skills applicable to other tasks. CHWs who said they strongly agreed with the statement that their work with the malaria program was appreciated by the community had a 0.76 standard deviation (SD) increase in their overall satisfaction score (95% confidence interval CI = 0.10-1.24, P = 0.03). Almost all CHWs (99%) strongly agreed that they wanted to continue their role in the malaria program. Conclusions: Overall, CHWs reported high satisfaction with their role in community-based malaria diagnosis, though they faced challenges primarily related to community understanding and appreciation of the services they provided. CHWs' perceptions that the malaria program generally did not interfere with their other activities is encouraging for the sustainability and scale-up of similar CHW programs. PMID- 29497501 TI - Implementing health care reform: implications for performance of public hospitals in central Ethiopia. AB - Background: Understanding the way health care reforms have succeeded or failed thus far would help policy makers cater continued reform efforts in the future and provides insight into possible levels of improvement in the health care system. This work aims to assess and describe the implications of health care reform on the performance of public hospitals in central Ethiopia. Methods: A facility-based, cross-sectional study was carried out in five public hospitals with different operational characteristics that have been implementing health care reform in central Ethiopia. The reform documents were reviewed to assess the nature and targets of the reform for interpretive analysis. Adopting dimensions of health system performance as the theoretical framework, a self-administered questionnaire was developed. Consenting health care professionals who have been involved in the reform from inception to implementation filled the questionnaire. Cronbach's alpha was measured to ensure internal consistency of the instrument. Descriptive statistics, weighted median score, chi2, and Mann-Whitney U and Kruskal-Wallis tests were used for data analysis. Result: s Despite implementation of the reform, the health care system in public hospitals was still fragmented as confirmed by 50% of respondents. Limited effects were reported in favour of quality (48%), access (50%), efficiency (51%), sustainability (53%), and equity (61%) of care, while poor effects were reported in patient-provider (41%) and provider-management (32%) interactions. Though there was substantial gain in infrastructure and workspace, stewardship of health care resources was less benefited. The predominant hindrances of the reform were the working environment (adjusted Odds Ratio (aOR) = 2.27, 95% confidence interval (CI): 1.15-4.47), financial resources (aOR = 3.54, 95%CI = 1.97-6.33), management (aOR = 2.27, 95% CI = 1.15-4.47), and information technology system (aOR = 3.15, 95% CI = 1.57-6.32). Conclusion: s The Ethiopian health care reform has laid the groundwork for health system improvement, but progress was slow and the health care delivery system was still fragile. Healthcare reform efforts in such settings are feasible, but with regular mapping of programmatic outcomes and bringing a common understanding of the reform among stakeholders. PMID- 29497502 TI - Association of obstructive sleep apnea with hypertension: A systematic review and meta-analysis. AB - Background: Obstructive sleep apnea (OSA) is a sleep disorder characterized as complete or partial upper airflow cessation during sleep. Although it has been widely accepted that OSA is a risk factor for the development of hypertension, the studies focusing on this topic revealed inconsistent results. We aimed to clarify the association between OSA and hypertension, including essential and medication-resistant hypertension. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was followed. PubMed and Embase databases were used for searching the relevant studies published up to December 31, 2016. A quantitative approach of meta-analysis was performed to estimate the pooled odds ratio (OR) and 95% confidence interval (CI). Results: Twenty-six studies with 51 623 participants (28 314 men, 23 309 women; mean age 51.8 years) met inclusion criteria and were included in this study. Among them, six studies showed a significant association between OSA and resistant hypertension (pooled OR = 2.842, 95% CI = 1.703-3.980, P < 0.05). Meanwhile, the combination of 20 original studies on the association of OSA with essential hypertension also presented significant results with the pooled ORs of 1.184 (95% CI = 1.093-1.274, P < 0.05) for mild OSA, 1.316 (95% CI = 1.197-1.433, P < 0.05) for moderate OSA and 1.561 (95% CI = 1.287-1.835, P < 0.05) for severe OSA. Conclusions: Our findings indicated that OSA is related to an increased risk of resistant hypertension. Mild, moderate and severe OSA are associated essential hypertension, as well a dose-response manner relationship is manifested. The associations are relatively stronger among Caucasians and male OSA patients. PMID- 29497503 TI - Carrying water may be a major contributor to disability from musculoskeletal disorders in low income countries: a cross-sectional survey in South Africa, Ghana and Vietnam. AB - Background: The Sustainable Development Goals include commitments to end poverty, and promote education for all, gender equality, the availability of water and decent work for all. An important constraint is the fact that each day, many millions of women and children, and much less frequently men, carry their household's water home from off-plot sources. The burden of fetching water exacerbates gender inequality by keeping women out of education and paid employment. Despite speculation about the potential health impacts of fetching water, there is very little empirical evidence. We report the first large study of the health impacts of carrying water on women and children. Methods: A cross sectional survey was conducted in South Africa, Ghana and Vietnam during 2012. It investigated water carrying methods and health status. Because areas of self reported pain were correlated we undertook factor analysis of sites of reported pain, to interpret patterns of pain reporting. Regression analysis using Generalised Estimating Equations (GEE) investigated water carrying as a risk factor for general health and self-reported pain. Results: People who previously carried water had increased relative risk of reporting pain in the hands (risk ratio RR 3.62, 95% confidence interval CI 1.34 to 9.75) and upper back (RR 2.27, 95% CI 1.17 to 4.40), as did people who currently carry water (RR hand pain 3.11, 95% CI 1.34 to 7.23; RR upper back pain 2.16, 95% CI 1.25 to 3.73). The factor analysis results indicate that factor 1, 'axial compression', which is correlated with pain in the head and upper back, chest/ribs, hands, feet and abdomen/stomach, is associated with currently (0.30, 95% CI 0.17 to 0.43) or previously (0.21, 95% CI 0.01 to 0.42) carrying water. Factor 2, 'soft tissue strain', which is correlated with pain in the neck, shoulders/arms, lower back and hips/pelvis or legs, is marginally negatively associated with currently ( 0.18, 95% CI -0.32 to -0.04) carrying water. The factor 'axial compression' was more strongly associated with carrying water containers on the head. Conclusions: Participants who reported a history of current or past water carrying more frequently reported pain in locations most likely to be associated with sustained spinal axial compression in the cervical region. Given the fact that cervical spinal conditions are globally one of the more common causes of disability, our findings suggest that water carrying, especially by head loading is a major contributing factor in musculoskeletal disease burden in low income countries. Our findings support the proposed indicator for monitoring SDG6.1: "Percentage of population using safely managed drinking water services at home." PMID- 29497504 TI - An observational study of monitoring of vital signs in children admitted to Kenyan hospitals: an insight into the quality of nursing care? AB - Background: Measurement and correct interpretation of vital signs is part of routine clinical care. Repeated measurement enhances early recognition of deterioration, may help prevent morbidity and mortality and is a standard of care in most countries. Objective: To examine documentation of vital signs by clinicians for admissions to paediatric wards in Kenyan hospitals, to describe monitoring frequency by nurses and explore factors influencing frequency. Methods: Vital signs information (temperature, respiratory and pulse rate) for the first 48 hours of admission was collected from case records of children admitted with non-surgical conditions to 13 Kenyan county hospitals between September 2013 and April 2016. A mixed effect negative binomial regression model was used to explore whether the severity of illness (indicated by danger signs or severe diagnostic episodes) is associated with increased vital signs observation frequency. Results: We examined 54 800 admission episodes with an overall mortality 6.1%. Nurse to bed ratios were very low (1:10 to 1:41 across hospitals). Admitting clinicians documented all or no vital signs in 57.0% and 8.4% cases respectively. For respiratory and pulse rates there was pronounced even end-digit preference (an indicator of incorrect information) and high frequency recording of specific values (P < 0.001) suggesting approximation. Monitoring frequency was explored in 41 738 children. Those with inpatient stays >=48 hours were expected to have a vital signs count of 18, hospitals varied but most did not achieve this benchmark (median 9, range 2-30). There were clinically small but significant associations between vital signs count and presence of multiple severe illnesses or presence of severe pallor (adjusted relative risk ratio = 1.04, P < 0.01, 95% confidence interval CI = 1.02-1.06 and 1.05, P = 0.02, 95% CI = 1.01-1.09, respectively). Conclusions: Data suggest accurate admission measures are sometimes missing especially for pulse and respiratory rates, possibly linked to manual measurement. Monitoring frequency is often low in the high risk population studied probably indicating how quality of nursing care is undermined by considerable human resource shortages. PMID- 29497505 TI - An emergency cash transfer program promotes weight gain and reduces acute malnutrition risk among children 6-24 months old during a food crisis in Niger. AB - Background: Assessment of the impact of emergency cash transfer programs on child nutritional status has been difficult to achieve due to the considerable logistic and ethical constraints that characterize humanitarian settings. Methods: We present the findings from a quasi-experimental longitudinal study of a conditional emergency cash transfer program implemented by Concern Worldwide in 2012 during a food crisis in Tahoua, Niger, in which the use of a concurrent control group permits estimation of the program's impact on child weight gain. Program beneficiaries received three transfers totaling approximately 65% of Niger's gross national per capita income; mothers attended mandatory sessions on child and infant feeding and care practices. Dietary and anthropometric data from 211 vulnerable households and children targeted by the intervention were compared with 212 similarly vulnerable control households and children from the same 21 villages. We used multilevel mixed effects regression to estimate changes in weight and weight-for-height Z scores (WHZ) over time, and logistic regression to estimate the probability of acute malnutrition. Results: We found the intervention to be associated with a 1.27 kg greater overall weight gain (P < 0.001) and a 1.82 greater overall gain in WHZ (P < 0.001). The odds of having acute malnutrition at the end of the intervention were 25 times higher among children in the comparison group than those in households receiving cash (P < 0.001). Conclusions: We conclude that this emergency cash transfer program promoted child weight gain and reduced the risk of acute malnutrition among children in the context of a food crisis. We suspect that the use of strategic conditional terms and a valuable transfer size were key features in achieving this result. Limitations in study design prevent us from attributing impact to particular aspects of the program, and preclude a precise estimation of impact. Future studies of this nature would benefit from pre-baseline measurements, more exhaustive data collection on household characteristics and transfer use, and further investigation into the use of conditional terms in emergency settings. PMID- 29497506 TI - Behavioural and clinical predictors for Loiasis. AB - Background: Loiasis is a vector-borne disease in Central and West Africa. While there is still uncertainty to what extent loiasis is responsible for population morbidity, individuals having both loiasis and onchocerciasis have a high risk of fatal encephalopathy when treatment (ie, ivermectin) for onchocerciasis is given. Therefore it is current policy that communities of high loiasis-burden are excluded from mass drug administration programmes of ivermectin. To address this treatment gap we present diagnostic scores, based on clinical and behavioural predictors that may help to rapidly identify sub-groups with loiasis within high burden communities. Methods: A cross-sectional survey was performed in the province of la Ngounie, Gabon between December 2015 and Februrary 2016 and 947 participants of all ages were recruited. Clinical parameters and behavioural exposure factors were ascertained by questionnaire-based interviews. Parasitological analysis of blood samples was performed for L. loa detection. Diagnostic scores consisting of clinical and behavioural factors were modelled to predict loiasis in sub-groups residing in endemic regions. Results: Increasing sylvan exposure was identified as important risk factor for loiasis with adjusted odds ratios of 5.1 (95% confidence interval CI 2.6-9.9) for occasional forest exposure, 11.1 (95% CI 5.4-22.6) for frequent forest exposure and 25.7 (95% CI 12.5-52.9) for intensive forest exposure. Individuals with loiasis were 7.7 (95% CI 5.4-11.0) times more likely to report recurrent pruritus than those without loiasis. Reporting of regular daily exposure to the deep rain forest and recurrent pruritus was 9-fold (positive likelihood ratio 9.18; 95% CI: 6.39 13.18) more prevalent in individuals with loiasis than in controls. Concordantly, the absence of regular weekly forest exposure was associated with extremely low disease-likelihood (negative likelihood ratio 0.09; 95% CI 0.05-0.16). Conclusions: These composite scores may serve as a simple tool to rapidly identify both those most and those least at risk of disease and may simplify loiasis control activities as well as screening procedures for studies on loiasis. Further, they may aid policy-makers to tailor the delivery of ivermectin mass drug administration for onchocerciasis control programmes more effectively and safely in regions of high loiasis-burden. PMID- 29497507 TI - Research priorities for adolescent health in low- and middle-income countries: A mixed-methods synthesis of two separate exercises. AB - Background: In order to clarify priorities and stimulate research in adolescent health in low- and middle-income countries (LMICs), the World Health Organization (WHO) conducted two priority-setting exercises based on the Child Health and Nutrition Research Initiative (CHNRI) methodology related to 1) adolescent sexual and reproductive health and 2) eight areas of adolescent health including communicable diseases prevention and management, injuries and violence, mental health, non-communicable diseases management, nutrition, physical activity, substance use, and health policy. Although the CHNRI methodology has been utilized in over 50 separate research priority setting exercises, none have qualitatively synthesized the ultimate findings across studies. The purpose of this study was to conduct a mixed-method synthesis of two research priority setting exercises for adolescent health in LMICs based on the CHNRI methodology and to situate the priority questions within the current global health agenda. Methods: All of the 116 top-ranked questions presented in each exercise were analyzed by two independent reviewers. Word clouds were generated based on keywords from the top-ranked questions. Questions were coded and content analysis was conducted based on type of delivery platform, vulnerable populations, and the Survive, Thrive, and Transform framework from the United Nations Global Strategy for Women's, Children's, and Adolescents' Health, 2016-2030. Findings: Within the 53 top-ranked intervention-related questions that specified a delivery platform, the platforms specified were schools (n = 17), primary care (n = 12), community (n = 11), parenting (n = 6), virtual media (n = 5), and peers (n = 2). Twenty questions specifically focused on vulnerable adolescents, including those living with HIV, tuberculosis, mental illness, or neurodevelopmental disorders; victims of gender-based violence; refugees; young persons who inject drugs; sex workers; slum dwellers; out-of-school youth; and youth in armed conflict. A majority of the top-ranked questions (108/116) aligned with one or a combination of the Survive (n = 39), Thrive (n = 67), and Transform (n = 28) agendas. Conclusions: This study advances the CHNRI methodology by conducting the first mixed-methods synthesis of multiple research priority-setting exercises by analyzing keywords (using word clouds) and themes (using content analysis). PMID- 29497508 TI - Linking data sources for measurement of effective coverage in maternal and newborn health: what do we learn from individual- vs ecological-linking methods? AB - Background: Improving maternal and newborn health requires improvements in the quality of facility-based care. This is challenging to measure: routine data may be unreliable; respondents in population surveys may be unable to accurately report on quality indicators; and facility assessments lack population level denominators. We explored methods for linking access to skilled birth attendance (SBA) from household surveys to data on provision of care from facility surveys with the aim of estimating population level effective coverage reflecting access to quality care. Methods: We used data from Mayuge District, Uganda. Data from household surveys on access to SBA were linked to health facility assessment census data on readiness to provide basic emergency obstetric and newborn care (BEmONC) in the same district. One individual- and two ecological-linking methods were applied. All methods used household survey reports on where care at birth was accessed. The individual-linking method linked this to data about facility readiness from the specific facility where each woman delivered. The first ecological-linking approach used a district-wide mean estimate of facility readiness. The second used an estimate of facility readiness adjusted by level of health facility accessed. Absolute differences between estimates derived from the different linking methods were calculated, and agreement examined using Lin's concordance correlation coefficient. Results: A total of 1177 women resident in Mayuge reported a birth during 2012-13. Of these, 664 took place in facilities within Mayuge, and were eligible for linking to the census of the district's 38 facilities. 55% were assisted by a SBA in a facility. Using the individual linking method, effective coverage of births that took place with an SBA in a facility ready to provide BEmONC was just 10% (95% confidence interval CI 3-17). The absolute difference between the individual- and ecological-level linking method adjusting for facility level was one percentage point (11%), and tests suggested good agreement. The ecological method using the district-wide estimate demonstrated poor agreement. Conclusions: The proportion of women accessing appropriately equipped facilities for care at birth is far lower than the coverage of facility delivery. To realise the life-saving potential of health services, countries need evidence to inform actions that address gaps in the provision of quality care. Linking household and facility-based information provides a simple but innovative method for estimating quality of care at the population level. These encouraging findings suggest that linking data sets can result in meaningful evidence even when the exact location of care seeking is not known. PMID- 29497509 TI - Kangaroo mother care for clinically unstable neonates weighing <=2000 g: Is it feasible at a hospital in Uganda? AB - Background: Kangaroo mother care (KMC) for stable neonates <=2000 g (g) is associated with decreased mortality, sepsis, hypothermia, and length of stay compared to conventional care. The World Health Organization states that KMC "should be initiated... as soon as newborns are clinically stable" [12]. However, the majority of deaths occur in unstable neonates. We aimed to determine the proportion of admitted neonates meeting proposed instability criteria, assess the feasibility of providing KMC to unstable neonates, and evaluate the acceptability of this intervention to parents and providers at Jinja Regional Referral Hospital in Uganda. Methods: This was a mixed-methods study. We recorded data including birthweight, chronological age, and treatments administered from medical charts, and calculated the percentage of clinically unstable neonates, defined as the need for >=2 medical therapies in the first 48 hours of admission. We enrolled a sample of neonates meeting pre-defined instability criteria. Mothers were counselled to provide KMC as close to continuously as possible. We calculated the median duration of KMC per episode and per day. To explore acceptability, we conducted semi-structured interviews with parents and newborn unit care providers, and analysed data using the thematic content approach. Findings: We included 254 neonates in the audit, 10 neonates in the feasibility sub-study, and 20 participants in the acceptability sub-study. Instability criteria were easily implementable, identifying 89% of neonates as unstable in the audit. The median duration of individual KMC episodes ranged from 115 to 134 minutes. The median daily duration ranged from 4.5 to 9.7 hours. Seventy-five percent of interviewees felt KMC could be used in neonates concurrently receiving other medical therapies. Barriers included lack of resources (beds/space, monitoring devices), privacy issues, inadequate education, and difficulties motivating mothers to devote time to KMC. Recommendations included staff/peer counselling, resources, family support, and community outreach. Conclusions: There remains a need for an evidence-based approach to consistently define stability criteria for KMC to improve care. We found that KMC for unstable neonates weighing <=2000g was feasible and acceptable at Jinja Hospital in Uganda. Randomised controlled trials are needed to demonstrate the effect of KMC on survival among unstable neonates in low-resource settings. PMID- 29497510 TI - Pathophysiological lessons from rare associations of autoimmune diseases. PMID- 29497512 TI - Renal replacement therapy in Europe-a summary of the 2009 ERA-EDTA Registry Annual Report. AB - Introduction: This study provides a summary of the 2009 ERA-EDTA Registry Report, with a focus on the differences in the incidence and prevalence of haemodialysis (HD), peritoneal dialysis (PD) and renal transplantation between countries and over time. Methods: For this report, 56 data sets on renal replacement therapy (RRT) from national and regional registries in 30 countries in Europe and bordering the Mediterranean Sea were available. Data sets with individual patient data were received from 26 registries, whereas 19 registries contributed data in aggregated form. For both types of registries, we present incidence, prevalence and transplant rates. Survival analysis is based on individual patient records. Results: In 2009, the overall incidence rate of RRT for end-stage renal disease (ESRD) among all registries reporting to the ERA-EDTA Registry was 125 per million population (p.m.p.). Incidence rates varied from 259 p.m.p. in Turkey to 19 p.m.p. in Ukraine and the mean age of patients starting RRT in 2009 ranged from 47.6 years in Russia to 69.5 year in Dutch-speaking Belgium. When examining the relative change of the HD, PD and transplantation distribution (at Day 91 after the start of RRT) between 2005 and 2009, we found overall a 0.5% decrease in HD, 1.4% decrease in PD utilization and an 1.8% increase of the share of patients living on a functioning graft. The overall prevalence of RRT for ESRD as of 31 December 2009 was 730 p.m.p. The highest prevalence was reported by Portugal (1507 p.m.p.) and the lowest by Ukraine (101 p.m.p.). In Norway, 70% of the patients on RRT were living with a functioning graft (591 p.m.p.) at 31 December 2009. The number of transplants performed p.m.p. in 2009 was highest in Spain (Cantabria) (78 p.m.p.). For the cohort 2000-04, the adjusted 1-, 2- and 5 year survival of patients on RRT was 87.4% (95% confidence interval: 87.2-87.7), 78.5% (95% confidence interval: 78.2-78.8) and 56.3% (95% confidence interval: 55.9-56.7), respectively. PMID- 29497511 TI - Non-muscle myosins and the podocyte. AB - Proteinuria is often accompanied by a pathological change in the glomerulus that is refereed as effacement of the podocyte foot processes. The highly dynamic podocyte foot processes contain an actin-based contractile apparatus comparable to that of pericytes, which needs to be precisely and temporally controlled to withstand high pressure in the capillaries and to maintain intact glomerular filtration properties. This review outlines the most recent concepts on the function of the podocyte contractile apparatus with a focus on the role of non muscle myosins as they have been highlighted by studies in monogenic hereditary proteinuric diseases. PMID- 29497513 TI - Amyloid proximal tubulopathy: a novel form of light chain proximal tubulopathy. AB - Light chain proximal tubulopathy is a paraproteinemic-related kidney disease most commonly seen in patients with a plasma cell dyscrasia. The classic description is that of proximal tubules with kappa-restricted intracytoplasmic crystals in a patient with a clinical Fanconi's syndrome. Recently, other variants of light chain proximal tubulopathy have been described including those without crystal formation. We expand the morphologic spectrum in this report of a patient who presented with acute renal failure, proteinuria and hematuria. Biopsy revealed proximal tubulopathy in which the proximal tubules show intracytoplasmic amyloid formation. This is the first description, to our knowledge, of amyloid proximal tubulopathy. PMID- 29497514 TI - Anti-factor H antibody affecting factor H cofactor activity in a patient with dense deposit disease. AB - Complement alternative pathway dysregulation seems to be the pathophysiological basis of Dense Deposit Disease (DDD). Here, we describe a monoclonal anti-factor H (FH) autoantibody in a woman diagnosed with DDD with a monoclonal gammapathy. Enzyme-linked immunosorbent assays evidenced the presence of anti-FH antibodies in the patient's serum and showed that they were associated with the monoclonal IgG-lambda fraction. These autoantibodies recognize the N-terminal region of FH and interfere with its regulatory function. In summary, in the DDD patient described here, the activation of complement alternative pathway was favoured by the presence of anti-FH autoantibodies that recognize the regulatory region of this protein and impede its function and which could ultimately cause the glomerulopathy. PMID- 29497515 TI - A deaf mother and son with diabetes and renal failure. AB - Chronic renal failure is a well-known complication of long-standing diabetes. Moreover, audiological abnormalities are a common feature of patients with end stage renal disease. Severe deafness, however, is not a typical symptom in most patients with chronic renal failure and likewise in patients with diabetes mellitus. In this case report, we describe a young patient with insulin-dependant diabetes mellitus, severe deafness requiring hearing aid and chronic renal failure outlining typical clinical features of the maternally inherited diabetes with deafness syndrome. Genetic testing confirmed the presence of the m.3243A>G mutation. PMID- 29497516 TI - Ischaemic monomelic neuropathy (IMN) following vascular access surgery for haemodialysis: an under-recognized complication in non-diabetics. AB - Ischaemic monomelic neuropathy (IMN) is an infrequently recognized type of neuropathy, produced after acute arterial occlusion or reduced blood flow to an extremity. In the upper limb, it usually occurs after vascular access surgery for haemodialysis. IMN has been reported largely in diabetics with peripheral neuropathy and atherosclerotic vascular disease. We report a case of IMN following arteriovenous (AV) fistula formation in a patient with advanced chronic renal failure, who did not have diabetes mellitus and symptoms of peripheral neuropathy or features of atherosclerotic vascular disease. Symptoms improved immediately after the distal revascularization and interval ligation procedure to the AV fistula. PMID- 29497517 TI - Extramedullary haematopoiesis in the kidney. AB - Extramedullary haematopoiesis (EMH) is the development of haematopoietic tissue outside the bone marrow and it most often occurs in the liver and spleen. Renal EMH is quite rare and there are very few case reports concerning the kidney. We describe two cases of 'renal histologically documented EMH' and, in particular, in the second of these two, the EMH tissue coexists with a clear cell renal carcinoma. Although rare, these clinical pictures raise some questions about the role of needle biopsy in the management of renal masses that present a diagnostic dilemma, especially in cases without involvement of other abdominal or intrathoracic organs. PMID- 29497518 TI - Haemodialysis in massive caffeine intoxication. AB - Caffeine is the most widely consumed psychoactive substance worldwide. Intoxication causes central nervous system and haemodynamic complications, which have significant mortality rates. We report the case of a 39-year-old woman who ingested ~0.5 mol (100 g) of pure caffeine, leading to a peak serum concentration of 2.95 mmol/L (574 mg/L). Three consecutive haemodialysis sessions caused serum caffeine reduction rates of 66, 46 and 45%, indicating that the unbound caffeine fraction is not dose linear in this high serum caffeine concentration range. Aggressive and repeated haemodialysis sessions may be of benefit in cases of severe caffeine intoxication. PMID- 29497519 TI - Renal ablation using bilateral ureteral ligation for nephrotic syndrome due to renal amyloidosis. AB - Nephrotic syndrome is common in immunoglobulin light chain amyloidosis (AL). In patients who do not achieve renal recovery, renal ablation has been reported for intractable proteinuria. We describe a patient with renal-limited AL who failed therapy and developed disabling proteinuria. He underwent laparoscopic ligation of the native ureters. Post-operatively, blood pressure improved. Hemodialysis was initiated. We conclude that bilateral ureteral ligation is a novel and minimally invasive method of renal ablation and may be considered for patients with refractory nephrotic syndrome. PMID- 29497520 TI - Acute renal failure following multiple hornet stings. AB - Hornet stings are medically important stings which can cause allergic manifestations and, in severe cases, may lead to the unusual complication of acute renal failure (ARF) and other systemic complications. ARF results from toxic or ischaemic acute tubular necrosis in a setting of haemolysis or rhabdomyolysis or both and acute allergic interstitial nephritis. Venom from hornet stings can also contribute to myocardial injury or liver impairment. Here, we report three cases of hornet stings leading to ARF. Case #1 and Case #3 recovered their renal function and body physiology after a 38-day and 15-day stay in the hospital, respectively, whereas Case #2 died. They were meticulously supported by haemodialysis along with the combination of various drug regimens. PMID- 29497521 TI - Episodic electrolyte disorders and renal failure due to a rare disease: the McKittrick-Wheelock syndrome. AB - We describe a patient with intermittent bouts of malaise and muscle weakness due to profound electrolyte disturbances. Colonoscopy showed a giant villous adenoma of the sigmoid. The patient was diagnosed with a McKittrick-Wheelock syndrome with pre-renal disease and electrolyte disorders due to periodic rectal fluid loss. The diagnosis was delayed by the patient's misinterpretation of the doctor's questions. In cases where the patient's history is contrary to what the data reveal, the expected culprit organ should be investigated early in the course of the disease. Extracting relevant and guiding information out of the patient's history remains an important skill. PMID- 29497523 TI - More than shingles. PMID- 29497522 TI - Hepatitis in a renal transplant patient-beyond the usual. PMID- 29497524 TI - Unusual abdominal masses. PMID- 29497525 TI - Tackling the 'brown' frown. PMID- 29497526 TI - The history of the ERA/EDTA. Memories of a former president. PMID- 29497528 TI - Erratum. AB - [This corrects the article on p. 418 in vol. 4.]. PMID- 29497527 TI - The meaning of the blood urea nitrogen/creatinine ratio in acute kidney injury. AB - Background: A blood urea nitrogen (BUN)/creatinine ratio (BCR) >20 (0.081 in international unit) is used to distinguish pre-renal azotemia (PRA) and acute tubular necrosis (ATN). However, there is little evidence that BCR can distinguish between these two conditions and/or is clinically useful. Methods: We conducted a retrospective study using a large hospital database. Patients were divided into three groups: 'low BCR' (if BCR when acute kidney injury (AKI) developed was <=20), 'high BCR' (if BCR when AKI developed was >20) and 'no AKI' if patients did not satisfy any of the Risk, Injury, Failure, Loss and End-stage kidney disease criteria for AKI during hospitalization. Results: Among 20 126 study patients, 3641 (18.1%) had AKI. Among these patients, 1704 (46.8%) had a BCR <20 at AKI diagnosis ('low BCR') and 1937 (53.2%) had a BCR >20 ('high BCR'). The average BCR for the two groups was 15.8 versus 26.1 (P < 0.001). Hospital mortality was significantly less in the 'low-BCR' group (18.4 versus 29.9%, P < 0.001). Multivariable logistic regression analysis for hospital mortality ('no AKI' as a reference) showed that the odds ratio of 'high BCR' (5.73) was higher than that of 'low BCR' (3.32). Conclusions: Approximately half of the patients with AKI have a BCR >20, the traditional threshold of diagnosing PRA. Unlike PRA patients who have a lower mortality than ATN patients, high BCR patients had higher hospital mortality compared with low BCR patients, which was confirmed with multivariable analysis. These findings do not support BCR as a marker of PRA. PMID- 29497529 TI - Singular case of the driving instructor: Temporal and topographical disorientation. AB - Lesions of the medio-parietal lobes are linked with topographical and temporal disorientation, and are of interest to understanding mental time. We examined a 39-year-old man who worked as a driving instructor before cerebral hemorrhage, and followed his case for 8 years including neuropsychological testing and brain imaging. The patient had mild anterograde episodic amnesia, but no semantic amnesia. He felt that time passed too quickly, and developed a compulsive routine to compensate, although he was able to count time at a normal speed. Furthermore, he was unable to accurately sketch the layout of his house and to make a cross reference type timetable for the future. Brain magnetic resonance imaging showed lesions of the left anterior-posterior cingulate gyrus, and N-isopropyl-[123I] p iodoamphetamine single-photon emission computed tomography showed decreased blood flow mainly of the left medio-parietal lobe. PMID- 29497531 TI - Blood patch for the treatment of post-dural puncture tinnitus. AB - Audiometric disturbances are recognised as potential complications after spinal or epidural anaesthesia; however, incidences of tinnitus occur less frequently. We report a case of a patient with severe bilateral tinnitus post-lumbar puncture who was treated with an epidural blood patch. A 40-year-old ASA I lady (a medically fit patient with no known medical problem) presented with ongoing bilateral severe tinnitus for 6 days after a lumbar puncture. Venous blood (18 mL) was injected into the epidural space using a 16G needle. The patient completed the Tinnitus Handicap Inventory Questionnaire before the blood patch, 3 h, 24 h and 1-month post-procedure. An audiogram was also conducted before and 1 month after the blood patch. The patient scored 84 (grade 5) on the Tinnitus Handicap Inventory before the blood patch. Three hours post-procedure, her score improved to 16 (grade 1), with complete resolution by 24 h. Audiogram revealed a low-frequency mild sensorineural hearing loss in the left ear prior to the procedure. By her 1-month follow-up, her hearing loss was back to normal. In our experience, an epidural blood patch is an effective treatment for post-dural puncture tinnitus. Its effects are instantaneous and complete resolution is achieved by 24 h. PMID- 29497530 TI - Unravelling the molecular basis for regulatory T-cell plasticity and loss of function in disease. AB - Regulatory T cells (Treg) are critical for preventing autoimmunity and curtailing responses of conventional effector T cells (Tconv). The reprogramming of T-cell fate and function to generate Treg requires switching on and off of key gene regulatory networks, which may be initiated by a subtle shift in expression levels of specific genes. This can be achieved by intermediary regulatory processes that include microRNA and long noncoding RNA-based regulation of gene expression. There are well-documented microRNA profiles in Treg and Tconv, and these can operate to either reinforce or reduce expression of a specific set of target genes, including FOXP3 itself. This type of feedforward/feedback regulatory loop is normally stable in the steady state, but can alter in response to local cues or genetic risk. This may go some way to explaining T-cell plasticity. In addition, in chronic inflammation or autoimmunity, altered Treg/Tconv function may be influenced by changes in enhancer-promoter interactions, which are highly cell type-specific. These interactions are impacted by genetic risk based on genome-wide association studies and may cause subtle alterations to the gene regulatory networks controlled by or controlling FOXP3 and its target genes. Recent insights into the 3D organisation of chromatin and the mapping of noncoding regulatory regions to the genes they control are shedding new light on the direct impact of genetic risk on T-cell function and susceptibility to inflammatory and autoimmune conditions. PMID- 29497532 TI - Bright X-ray and up-conversion nanophosphors annealed using encapsulated sintering agents for bioimaging applications. AB - Nanophosphors are promising contrast agents for deep tissue optical imaging applications because they can be excited by X-ray and near infrared light that penetrates deeply through tissue and generates almost no autofluorescence background in the tissue. For these bioimaging applications, the nanophosophors should ideally be small, monodispersed and brightly luminescent. However, most methods used to improve luminescence yield by annealing the particles to reduce crystal and surface defects (e.g. using flux or sintering agents) also cause particle fusion or require multiple component core-shell structures. Here, we report a novel method to prepare bright, uniformly sized X-ray nanophosphors (Gd2O2S:Eu or Tb) and upconversion nanophosphors (Y2O2S: Yb/Er, or Yb/Tm) with large crystal domain size without causing aggregation. A core-shell nanoparticle is formed, with NaF only in the core. We observe that increasing the NaF sintering agent concentration up to 7.6 mol% increases both crystal domain size and luminescence intensity (up to 40% of commercial microphosphors) without affecting the physical particticle diameter. Above 7.6 mol%, particle fusion is observed. The annealing is insensitive to the cation (Na+ or K+) but varies strongly with anion, with F->Cl->CO32->Br->I-. The luminescence depends strongly on crystal domain size. The data agree reasonably well with a simple domain surface quenching model, although the size-dependence suggests additional quenching mechanisms within small domains. The prepared bright nanophosphors were subsequently functionalized with PEG-folic acid to target MCF-7 breast cancer cells which overexpress folic acid receptors. Both X-ray and upconversion nanophosphors provided low background and bright luminescence which was imaged through 1 cm chicken breast tissue at a low dose of nanophosphors 200 uL (0.1 mg/mL). We anticipate these highly monodispersed and bright X-ray and upconversion nanophosphors will have significant potential for tumor targeted imaging. PMID- 29497533 TI - Narrow-band imaging thoracoscopy in pleural amyloidosis. AB - We report the case of a 68-year-old male non-smoker suffering from shortness of breath for 1 year. He was referred to our institution for a definitive diagnosis. Both chest X-ray and computed tomography scans showed bilateral hydrothorax with no pleural thickening. We performed flexi-rigid thoracoscopic pleural biopsy on the right side with a single port under local anaesthesia. Multiple white nodules were seen in parietal and visceral pleura, and these nodules were small and flat under white light. Narrow-band imaging demonstrated pathognostic findings on parietal pleura. Irregular dilative vessels were seen around these nodules. Subsequently, we performed parietal pleural biopsy for these nodules. Pathological examination with haematoxylin and eosin staining revealed eosinophilic matrix material depositions present in the pleural parenchyma and the vessel wall. These depositions were positive for Congo red stain and showed apple-green birefringence under polarized light. These findings were compatible with pleural amyloidosis. PMID- 29497534 TI - Intravenous immunoglobulin fails to improve ARDS in patients undergoing ECMO therapy. AB - Background: Acute respiratory distress syndrome (ARDS) is associated with high mortality rates. ARDS patients suffer from severe hypoxemia, and extracorporeal membrane oxygenation (ECMO) therapy may be necessary to ensure oxygenation. ARDS has various etiologies, including trauma, ischemia-reperfusion injury or infections of various origins, and the associated immunological responses may vary. To support the immunological response in this patient collective, we used intravenous IgM immunoglobulin therapy to enhance the likelihood of pulmonary recovery. Methods: ARDS patients admitted to the intensive care unit (ICU) who were placed on ECMO and treated with (IVIG group; n = 29) or without (control group; n = 28) intravenous IgM-enriched immunoglobulins for 3 days in the initial stages of ARDS were analyzed retrospectively. Results: The baseline characteristics did not differ between the groups, although the IVIG group showed a significantly reduced oxygenation index compared to the control group. We found no differences in the length of ICU stay or ventilation parameters. We did not find a significant difference between the groups for the extent of inflammation or for overall survival. Conclusion: We conclude that administration of IgM enriched immunoglobulins as an additional therapy did not have a beneficial effect in patients with severe ARDS requiring ECMO support. Trial registration: Clinical Trials: NCT02961166; retrospectively registered. PMID- 29497536 TI - Hypoinsulinemic hypoglycemia triggered by liver injury in elderly subjects with low body weight: case reports. AB - : Hypoglycemia is induced by many causes, especially over-dose of insulin or oral hypoglycemic agents in diabetic subjects. In such a case, hyperinsulinemic hypoglycemia is usually observed. On the other hand, it is important to classify secondary hypoglycemia and hypoinsulinemic hypoglycemia. Liver injury-induced hypoglycemia is one of the causes of hypoinsulinemic hypoglycemia but rarely observed in clinical practice. Herein, we experienced similar 2 cases of non diabetic hypoinsulinemic hypoglycemia. Both of them were elderly subjects with low body weight. Furthermore, it is likely that hypoinsulinemic hypoglycemia in both subjects was triggered by severe liver injury, at least in part, due to possible limited liver glycogen store. In elderly subjects with low body weight and/or malnutrition, metabolism in the liver is reduced and glycogen accumulation is decreased. Such alteration brings out acute and marked liver injury, which finally leads to the onset of severe hypoglycemia. It is known that not only liver injury but also multiple organ failure could be induced due to extreme emaciation in subjects. It is likely that in elderly subjects with low body weight and/or malnutrition, multiple organ failure including liver failure could be induced due to the similar reason. Therefore, we should be very careful of such subjects in order to avoid the development of multiple organ failure which leads to life-threatening situations. In conclusion, we should keep in mind the possibility of hypoinsulinemic hypoglycemia when we examine severe liver injury, especially in elderly or starving subjects with low body weight and limited liver glycogen stores. Learning points: It is important to classify secondary hypoglycemia and hypoinsulinemic hypoglycemia.Liver injury-induced hypoglycemia is one of the causes of hypoinsulinemic hypoglycemia but rarely observed in everyday clinical practice.Herein, we reported similar 2 cases of hypoinsulinemic hypoglycemia without diabetes presumably triggered by severe liver injury.In both cases, hypoglycemia was improved by glucose infusion, although their liver injury was not improved.We should keep in mind the possibility of hypoinsulinemic hypoglycemia when we examine severe liver injury, especially in elderly subjects with low body weight. PMID- 29497535 TI - Effect of norepinephrine dosage on mortality in patients with septic shock. AB - Background: Use of high-dose norepinephrine is thought to have an immunosuppressive action that increases mortality. This study aimed to evaluate the correlation between norepinephrine dosage and prognosis of patients with septic shock. Methods: This study was a nested cohort of the DExmedetomidine for Sepsis in Intensive Care Unit Randomized Evaluation (DESIRE) trial. We evaluated 112 patients with septic shock and an initial Sequential Organ Failure Assessment Cardiovascular (SOFA-C) category score > 2 and initial lactate level > 2 mmol/L. We divided the patients into two groups according to the norepinephrine dosage administered over the initial 7 days: high dose (>= 416 MUg/kg/week) (H group, n = 56) and low dose (< 416 MUg/kg/week) (L group, n = 56). The primary outcome of interest was 28-day mortality. Secondary outcomes were ventilator-free days, initial 24-h infusion volume, initial 24- to 48-h infusion volume, and the need for renal replacement therapy. For comparisons between the H group and L group, we used the chi-square test or Fisher's exact test for categorical variables and the t test or Wilcoxon rank sum test for continuous variables. For time-to-event outcomes, Cox proportional hazards models were used. Kaplan-Meier survival curves were created for graphical representation. Results: Patient characteristics appeared to be similar between the two groups except for the SOFA-C score and fibrinogen degradation product level. The cumulative incidence of death at 28 days was 29.9% (16 patients) in the L group and 29.7% (15 patients) in the H group (p = 0.99). The median number of 28-day ventilator-free days was 20 (0, 25) in the L group and 16 (0, 22) in the H group (p < 0.05). Initial infusion volume at 0-24 h in the H group was significantly higher than that in the L group (p = 0.004). Infusion volume at 24-48 h in the H group was also significantly higher than that in the L group (p = 0.03). Conclusions: No statistically significant difference was observed in 28-day mortality between patients with septic shock treated with high-dose norepinephrine compared with those treated with low-dose norepinephrine. However, the number of ventilator-free days in the L group was higher than that in the H group. Trial registration: clinicaltrials.gov Identifier: NCT01760967 Date of trial registration: January 4, 2013. PMID- 29497537 TI - Recurrent pituitary abscess: case report and review of the literature. AB - : A 26-year-old woman presented with severe postpartum headaches. Magnetic resonance imaging (MRI) revealed a symmetric, heterogeneous enlargement of the pituitary gland. Three months later, she developed central diabetes insipidus. A diagnosis of postpartum hypophysitis was suspected and corticosteroids were prescribed. Six months later, the pituitary mass showed further enlargement and characteristics of a necrotic abscess with a peripheral shell and infiltration of the hypothalamus. Transsphenoidal surgery was performed, disclosing a pus-filled cavity which was drained. No bacterial growth was observed, except a single positive blood culture for Staphylococcus aureus, considered at that time as a potential contaminant. A short antibiotic course was, however, administered together with hormonal substitution for panhypopituitarism. Four months after her discharge, severe headaches recurred. Pituitary MRI was suggestive of a persistent inflammatory mass of the sellar region. She underwent a new transsphenoidal resection of a residual abscess. At that time, the sellar aspiration fluid was positive for Staphylococcus aureus and she was treated with antibiotics for 6 weeks, after which she had complete resolution of her infection. The possibility of a pituitary abscess, although rare, should be kept in mind during evaluation for a necrotic inflammatory pituitary mass with severe headaches and hormonal deficiencies. Learning points: The possibility of a pituitary abscess, although rare, should be kept in mind during evaluation for a necrotic inflammatory pituitary mass with severe headaches and hormonal deficiencies.In a significant proportion of cases no pathogenic organism can be isolated.A close follow-up is necessary given the risk of recurrence and the high rate of postoperative pituitary deficiencies. PMID- 29497538 TI - Difficulties in cerebrospinal fluid betahCG interpretation in a patient with an infundibular lesion. AB - : A variety of neoplastic, inflammatory and congenital conditions can cause pituitary stalk thickening. Differentiating between these causes is important as targeted treatment may be offered. Diagnostic work-up consists of a thorough history, examination, biochemical analysis and imaging. We present the case of a 33-year-old male who presented with diabetes insipidus and had pituitary stalk thickening on magnetic resonance imaging. Further investigations revealed an elevated CSF betahCG, which raised the possibility of an intracranial germ cell tumor. However, when repeated on four different assays, the betahCG levels were discordant. On serial imaging, the pituitary stalk thickening reduced slightly, which would be unexpected for a germ cell tumor. This case raises the difficulties interpreting CSF betahCG, as not all immunoassays for betahCG have been validated for use in CSF. The Roche Diagnostics Elecsys and Siemens Centaur assays have been validated for CSF betahCG, and so we advocate using one of these methods. If unavailable or serum/CSF results are ambiguous, serial MRI is appropriate, with pituitary stalk biopsy considered if the stalk measures >6.5 mm or other imaging abnormalities are present. Learning points: Most adult patients with central diabetes insipidus have imaging abnormalities on a pituitary MRI. The most common abnormalities are loss of the posterior pituitary bright spot and pituitary stalk thickening, both of which are non-specific.Causes of pituitary stalk thickening include neoplastic, inflammatory, infective and congenital lesions.Investigation of pituitary stalk thickening should encompass the many possible causes and include biochemical analyses as well as imaging of the chest, abdomen and pelvis. Further investigations should be guided by the clinical context, but may include testicular ultrasound, CSF analysis and pituitary stalk biopsy.Germ cell tumors involving the pituitary stalk may be suspected on clinical grounds, but in the absence of a tissue diagnosis (biopsy) confirmation may be difficult and relies on biochemical assessment of blood and possibly CSF as well as serial MRI imaging.CSF betahCG levels should be analyzed on an instrument validated for use in CSF or on multiple instruments, and the pitfalls of testing this marker (false negative in some germ cell tumors, false positives in other conditions, lack of internationally agreed reference ranges for diagnosing germ cell tumors) should be considered when interpreting the results. PMID- 29497539 TI - Treatment of congenital hypothyroidism in a newborn with malabsorption after subtotal ileum resection. AB - : Congenital hypothyroidism requires prompt treatment to prevent adverse health outcomes. Poor intestinal levothyroxine absorption can complicate management. We present a case of a term female newborn with necrotizing enterocolitis (NEC) requiring subtotal ileum resection. Congenital hypothyroidism was diagnosed by newborn screening. Treatment was complicated by intestinal malabsorption of levothyroxine. Intravenous levothyroxine substitution restored euthyroidism and supraphysiologic PO doses subsequently maintained a euthyroid state. After several months, the required levothyroxine dose was weaned down to typical recommended dosing. In conclusion, small bowel resection secondary to NEC may lead to malabsorption of oral levothyroxine. An intravenous levothyroxine dose of approximately 50% typical PO dosing is effective in providing rapid normalization of free T4 and TSH. High PO doses may be required to maintain euthyroidism. Close thyroid function monitoring and immediate therapy adjustment are essential as the individual absorption may vary widely. Normal absorption levels may be regained due to adaption of the neonatal intestines. Learning points: In neonates with malabsorption after ileum resection intravenous levothyroxine replacement should be used to provide normalization of free T4 and TSH.Very high doses of up to 500% usual oral levothyroxine may be required to maintain euthyroidism. The estimated degree of malabsorption can be used to determine the initial dose.Close thyroid function monitoring and immediate therapy adjustment are essential as the absorption and intestinal adaption may vary widely. PMID- 29497540 TI - Lower limb onset Parry-Romberg syndrome: an unusual presentation of a rare disease. AB - Parry-Romberg syndrome (PRS) is characterized by progressive degeneration and atrophy of the cutaneous, subcutaneous connective tissues, muscles and bones. Classically, PRS is restricted to unilateral face but in 20% of patients may extend to other parts of the body including ipsilateral or contralateral arms, trunk and legs. We report a case of 24-year-old male who presented with insidious onset, gradually progressive deformity and muscle wasting of right lower limb followed by right side of face and chest for 8 years. The right side of the face showed hemiatrophy, coup de sabre and deviation of nose and chin toward the same side. The magnetic resonance imaging showed atrophy of right lower limb. Computed tomography with 3D facial reconstruction revealed atrophy of facial bones on right side. He was managed with physiotherapy and symptomatic treatment and planned for facial and ankle reconstructive surgery on follow-up. PMID- 29497541 TI - Klebsiella pyomyositis with complications: a quadriceps quandary in a dialysis patient. AB - The authors report an extremely rare case of Klebsiella pneumoniae pyomyositis of the left thigh in a patient with type II diabetes mellitus on renal replacement therapy (haemodialysis), with untreated hepatitis C. This patient presented via the dialysis unit with fevers, rigors and a swollen left thigh and knee. Initial differential diagnoses included deep vein thrombosis with systemic inflammatory response syndrome, septic arthritis and crystal arthropathy-all of which were subsequently excluded. Although missed on ultrasound duplex scan, lower limb magnetic resonance imaging (MRI) revealed communicating abscesses in the anterior and medial compartments of the left thigh, with associated inflammation of the muscle. Blood cultures on admission and cultures from direct aspiration of the abscesses grew Klebsiella pneumoniae. The abscesses were managed with a computed tomography-guided drain and combination antibiotic therapy. PMID- 29497543 TI - Congenital agenesis of the gallbladder: a UK case report. AB - Congenital absence of the gallbladder has a reported incidence between 0.013 and 0.075% (Singh et al., Congenital absence of the gallbladder. Surg Radiol Anat 1999; 21: 221-4). With fewer than 500 cases reported in the literature, it is a well-recognised yet rare embryological malformation. Gallbladder agenesis becomes symptomatic in almost a quarter of cases mostly presenting as cholecystitis or cholecystolithiasis. In this case report, a 24-year-old Caucasian male presented with intermittent right-sided abdominal pain with no associated symptoms. On a background of no past medical history, his pain was presumed to be biliary colic. The rarity of these case reports shows that there is a lack of awareness of gallbladder agenesis when thinking of differential diagnoses. There has also been no conclusive gold standard investigation decided, upon which results are satisfactory enough to avoid surgery. Therefore, as in this case report, this group of patients often undergo unnecessary operations as often the condition is not considered and precise diagnosis pre-operatively is very difficult. PMID- 29497542 TI - Isolated scapular involvement: uncommon presentation of childhood tuberculosis. AB - Scapular involvement in childhood tuberculosis (TB) is rare. To date, only eight cases are reported in the literature in children aged <18 years. We report a case of isolated scapular TB in a 7-year-old boy who presented with swelling and pain over right shoulder and was suspected to have malignancy based on the X-ray findings. Magnetic resonance imaging was suggestive of erosive lesion of whole scapula with normal shoulder joint, humerus and spine and conglomerate axillary lymph nodes. Histopathology and TB culture were diagnostics of TB. Patient was started on anti-TB treatment and doing well on follow-up. PMID- 29497544 TI - IL-5 in the plasma-cell-dominant Castleman disease: a nosological entity. AB - A 40-year-old male presented with a history of low-grade fever, weight loss, night sweats and breathlessness of 3 months duration. On examination, the patient had freely mobile lump in left lumbar region. The lump was surgically excised. Histological examination and immunohistochemistry of the specimen were consistent with the diagnosis of plasma cell variant of the Castleman disease. The patient had polyclonal hypergammaglobulinemia, anemia, eosinophilia and elevated interleukin (IL)-6 level. The level of IL-5 was not measured; however, the presence of eosinophilia indirectly suggests an increased IL-5 level. He obtained complete remission after resection of lump and 20 months of surgery had no signs and symptoms of diseases recurrence with normal hematological parameters. We discuss the role of IL-5 in the pathophysiology of the Castleman disease along with dysregulated overproduction of IL-6. PMID- 29497545 TI - Thymic carcinoma with metastasis in a 29-year-old male causing radiculopathy. AB - Thymic carcinoma is a rare, aggressive neoplasm with low 5-year survival rates ranging from 28 to 67%. Initial presentation with spinal or bone metastasis in primary thymic carcinoma is extremely rare. Thymic carcinoma, compared with thymoma, has higher recurrence rates and worse survival. We report one patient, a 29-year-old African-American male, with thymic carcinoma with metastasis to the epidural space (with cord compression), multiple bony structures (T10-L1) and left supraclavicular lymph node. Immunohistochemical staining was CD5 and c-Kit positive, consistent with thymic carcinoma. Patient underwent T12-L1 laminectomy with tumor resection to relieve cord compression and leg numbness/weakness. Patient was deemed a good candidate for rehabilitation. Soon after starting a rehabilitation program, he quickly demonstrated gains in gait distance with little to no assistance. Follow-up appointments with oncology were scheduled, and further planning of radiation and chemotherapy treatments were discussed. PMID- 29497546 TI - The role of nitrous oxide remains uncertain. PMID- 29497548 TI - Large laryngeal polyp causing airway obstruction. PMID- 29497547 TI - Pacemaker malfunction associated with proton beam therapy: a report of two cases and review of literature-does field-to-generator distance matter? AB - It is well known that radiotherapy causes malfunctions of cardiac implantable electronic devices such as pacemaker (PM) and implantable cardioverter defibrillator because of incidental neutron production. Here, we report our experience with two cases of PM reset among seven patients with PM who underwent proton beam therapy (PBT) from January 2011 to April 2015 at our centre. Our experience shows PM reset can occur also with abdominal PBT. In both cases, PM reset was not detected by electrocardiogram (ECG) monitoring but was rather discovered by post-treatment programmer analysis. Our cases suggest that PM malfunction may not always be detected by ECG monitoring and emphasize the importance of daily programmer analysis. PMID- 29497549 TI - Pyomyelia presenting as acute flaccid paralysis. AB - We report an unusual case of a 10-month-old girl with intramedullary spinal cord abscess who presented with fever and acute flaccid paraplegia. Nerve conduction study showed demyelinating neuropathy after which she received intravenous immunoglobulin therapy. This was followed by ascending paralysis and left-sided ptosis. Lumbar puncture revealed purulent cerebrospinal fluid and magnetic resonance imaging (MRI) with gadolinium showed intramedullary holocord abscess with a dermal sinus tract extending from skin to intramedullary canal in the lumbosacral region. This tract was excised completely along with drainage of pus. She was treated with broad-spectrum antibiotics for 6 weeks and underwent neurorehabilitation after which there was significant neurological improvement. Follow-up MRI shows good resolution of the intramedullary abscess. PMID- 29497550 TI - Non-surgical bleeding in cardiac surgery. AB - Bleeding is an occurrence stemming from complex interactions encountered in cardiac surgery and is often attributed to the perioperative administration of anti-thrombotic products if inadequate surgical haemostasis is excluded. Very occasionally, bleeding does not fit the norm and the aetiology is not a lack of surgical prolene or an iatrogenic-induced coagulopathy. Patients who present for cardiac surgery should be questioned carefully for a history of bleeding; however, patients at risk are not always identified. This case presents a series of haemorrhagic events incorrectly labelled as surgical complications resulting from an uncommon but not insignificant undiagnosed condition. The existing literature outlining protocols to safely manage patients with haemophilia during the perioperative cardiac surgical period is discussed in this report. This case explicitly demonstrates the importance of preoperative identification to avoid the morbidity that can result from cardiac surgery in an undiagnosed haemophilic patient. PMID- 29497551 TI - A case of reversible hyperoxaluria nephropathy early after roux-en-y-gastric bypass induced by vitamin C intake. AB - Roux-en-y-gastric bypass (RYGB) is the most commonly performed bariatric procedure worldwide which is taking the lead in resolving of comorbid conditions. Short- and long-term complications of RYGB procedure have been recognized, including osteopenia, osteomalacia and more rarely neurological disorders. Oxalate nephropathy is a complication of RYGB that has been described earlier in the literature and may end with renal failure and dialysis if not recognized and treated early. The etiology of this phenomenon is still unclear, but the length of common limb remains the theory that mostly contributed to its development. We believe that this limb should be more than 100 cm to prevent severe malabsorption. Here, we report a reversible case of oxalate nephropathy 3 months after RYGB in a 51-year-old patient. PMID- 29497552 TI - Temporomandibular joint dislocation during status epilepticus. AB - Dislocation of temporomandibular joint (TMJ) secondary to a seizure is rare. We report the case of a 32-year-old woman, who presented with a left TMJ dislocation during a status epilepticus. The airway was protected until reduction. A bimanual relocation by Nelaton's manoeuvre was attempted successfully. PMID- 29497553 TI - Essential rhythmic palatal myoclonus in a 51-year-old man. AB - Essential palatal myoclonus is a rare movement disorder consisting of continuous rhythmic jerks of the soft palate; it usually develops secondary to brainstem or cerebellar disease called symptomatic rhythmic palatal myoclonus. Diagnosis is usually clinical, and some patients, however, fail to show evidence of a structural lesion like our patient called essential rhythmic palatal myoclonus. We report a 51-year-old man who has suffered from the condition and showed improvements on treatments. PMID- 29497554 TI - Ibuprofen-induced renal tubular acidosis-a rare cause of rhabdomyolysis: a case report. AB - Ibuprofen is widely used in the community to manage pain, inflammation and fever. In cases of prolonged and supratherapeutic ingestion of ibuprofen, renal tubular acidosis (RTA) with profound hypokalemia may occur. Although hypokalemia is known to cause rhabdomyolysis, rhabdomyolysis occurring in the setting of ibuprofen induced RTA is rare. We present an unusual case of a 34-year-old male who presented with rhabdomyolysis in the setting of profound hypokalemia as a result of ibuprofen-induced RTA. The patient was successfully treated with fluid resuscitation, electrolyte replacement and supportive therapy. This case demonstrates a serious complication of ibuprofen and the importance of monitoring in nonprescription medications. PMID- 29497555 TI - Diagnose Kearns-Sayre syndrome genetically and investigate the phenotype comprehensively. PMID- 29497556 TI - Case of intersurgical acute massive pulmonary embolism with successful thrombolysis therapy. AB - A 56-year-old man underwent surgery to repair an open left tibial fracture. At the end of the surgery, he exhibited haemodynamic instability requiring an increased epinephrine dose. The situation was life-threatening, and the patient was at risk for pulmonary thromboembolism. Although surgery is a contraindication to thrombolysis, we performed intravenous thrombolysis with alteplase and used a femoral tourniquet to decrease blood loss. Once the patient was haemodynamically stable, he was taken to the intensive care unit. The patient recovered and was discharged with a long-term anticoagulation plan. In conclusion, thrombolysis can successfully treat life-threatening pulmonary thromboembolism during the early postoperative period. PMID- 29497557 TI - Protocol for a Systematic Review of Effect Sizes and Statistical Power in the Rodent Fear Conditioning Literature. AB - The concepts of effect size and statistical power are often disregarded in basic neuroscience, and most articles in the field draw their conclusions solely based on the arbitrary significance thresholds of statistical inference tests. Moreover, studies are often underpowered, making conclusions from significance tests less reliable. With this in mind, we present the protocol of a systematic review to study the distribution of effect sizes and statistical power in the rodent fear conditioning literature, and to analyze how these factors influence the description and publication of results. To do this we will conduct a search in PubMed for "fear conditioning" AND ("mouse" OR "mice" OR "rat" OR "rats") and obtain all articles published online in 2013. Experiments will be included if they: (a) describe the effect(s) of a single intervention on fear conditioning acquisition or consolidation; (b) have a control group to which the experimental group is compared; (c) use freezing as a measure of conditioned fear; and (d) have available data on mean freezing, standard deviation and sample size of each group and on the statistical significance of the comparison. We will use the extracted data to calculate the distribution of effect sizes in these experiments, as well as the distribution of statistical power curves for detecting a range of differences at a threshold of alpha=0.05. We will assess correlations between these variables and (a) the chances of a result being statistically significant, (b) the way the result is described in the article text, (c) measures to reduce risk of bias in the article and (d) the impact factor of the journal and the number of citations of the article. We will also perform analyses to see whether effect sizes vary systematically across species, gender, conditioning protocols or intervention types. PMID- 29497558 TI - Risk factors for fingolimod-induced lymphopenia in multiple sclerosis. AB - Background: Lymphopenia is a well-known adverse event of fingolimod, a disease modifying drug for multiple sclerosis (MS). Objectives: The objective of this paper is to investigate risk factors for predicting fingolimod-induced lymphopenia in MS by frequent hematological monitoring. Methods: We retrospectively reviewed data of fingolimod-treated MS patients. Data assessed were sex, age, disease duration, medication history, body mass index, all attacks, Kurtzke's Expanded Disability Status Scale score, and absolute lymphocyte count (ALC) within two days before initiating fingolimod (baseline), on the day after first administration (day 2), and at least every other month after initiating fingolimod therapy. Results: Of 41 MS patients, marked lymphopenia (ALC <200/ul) was confirmed in 12 patients (lymphopenia group) within one year. A significantly more frequent history of treatment with any interferon beta and lower median baseline ALC was observed in the lymphopenia group than in the non-lymphopenia group (n = 29) (91.7% vs. 44.8%; p = 0.006 and 1469/ul vs. 1879/ul; p = 0.005). An ALC of <=952/MUl on day 2 was the most responsible risk factor for predicting marked lymphopenia (sensitivity, 92%; specificity, 76%; area under the curve, 0.823; p < 0.001). Conclusions: Low baseline ALC and treatment history with any interferon-beta were risk factors for fingolimod induced lymphopenia, possibly predicted from ALC on day 2. PMID- 29497559 TI - Treadmill walking exercise training and brain function in multiple sclerosis: Preliminary evidence setting the stage for a network-based approach to rehabilitation. AB - Exercise training has been identified as a highly promising approach for managing the cognitive consequences of multiple sclerosis (MS). This study represents a secondary analysis of resting-state functional connectivity (RSFC) magnetic resonance imaging data from a pilot treadmill walking exercise training intervention for improving cognitive processing speed (CPS) in MS. There were large intervention effects on RSFC between the thalamus and right superior frontal gyrus (d = 1.92) and left medial frontal gyrus (d = 1.70). There further were moderate-to-large intervention effects on CPS (d = 0.72). Such preliminary data highlight FC within thalamocortical circuitry as a potential target for rehabilitation interventions for improving CPS in cognitively impaired individuals with MS. PMID- 29497560 TI - Acceptability of mindfulness from the perspective of stroke survivors and caregivers: a qualitative study. AB - Background: Depression is very common among stroke survivors with estimated prevalence rates of approximately 33% among stroke survivors, but treatment options are limited. Mindfulness-Based Stress Reduction (MBSR) is an effective treatment for depression generally, but benefits in stroke patients are unclear. The aim of this study was to determine the feasibility of delivering MBSR to stroke survivors and their caregivers in the community. We conducted a study to gain views of MBSR as a potential treatment option among stroke survivors and their caregivers in the community. Methods: Participants were recruited from an urban community in Scotland (UK) using newspaper adverts, social media and support groups run by health charities. A 2-h MBSR taster session was delivered by two experienced mindfulness instructors, followed by focus group sessions with all participants on their user experience and suggestions for MBSR modifications for stroke survivors. The focus group sessions were audio recorded and transcribed verbatim. Transcript data were analysed thematically using the framework approach. Results: The study sample consisted of 28 participants (16 females); there were 21 stroke survivors (11 females) and 7 caregivers (5 females). The median age for participants was 60 years.Most participants described the MBSR taster session as a positive experience. The main challenge reported was trying to maintain focus and concentration throughout the MBSR session. Some participants expressed reservations about the duration of standard mindfulness course sessions, suggesting a preference for shorter sessions. The potential for achieving better control over negative thoughts and emotions was viewed as a potential facilitator for future MBSR participation. Participants suggested having an orientation session prior to starting an 8-week course as a means of developing familiarity with the MBSR instructor and other participants. Conclusion: It was feasible to recruit 21 stroke survivors and 7 caregivers for MBSR taster sessions in the community. A shorter MBSR session and an orientation session prior to the full course are suggestions for potential MBSR modifications for stroke survivors, which needs further research and evaluation. PMID- 29497561 TI - The Patient Reported Outcomes, Burdens and Experiences (PROBE) Project: development and evaluation of a questionnaire assessing patient reported outcomes in people with haemophilia. AB - Background: The interest of health care agencies, private payers and policy makers for patient-reported outcomes (PRO) is continuously increasing. There is a substantial need to improve capacity to collect and interpret relevant PRO data to support implementation of patient-centered research and optimal care in haemophilia. The Patient Reported Outcomes, Burdens and Experiences (PROBE) Project aims to develop a patient-led research network, to develop a standardized questionnaire to gather patient-reported outcomes and to perform a feasibility study of implementing the PROBE questionnaire. Methods: A pilot questionnaire was developed using focus group methodology. Content and face validity were assessed by a pool of persons living with haemophilia (PWH) and content experts through interactive workshops. The PROBE questionnaire was translated with the forward backward approach. PROBE recruited national haemophilia patient non-governmental organizations (NGOs) to administer the questionnaire to people with and without haemophilia. PROBE measured the time to complete the questionnaire and gathered feedback on its content and clarity; staff time and cost required to implement the questionnaire were also collected. Results: The PROBE questionnaire is comprised of four major sections (demographic data, general health problems, haemophilia-related health problems and health-related quality of life using EQ 5D-5L and EQ-VAS). Seventeen NGOs participated in the pilot study of the PROBE Project, recruiting 656 participants. Of these, 71% completed the questionnaire within 15 min, and all participants completed within 30 min. The median total staff and volunteer time required for the NGOs to carry out the study within their country was 9 h (range 2 to 40 h). NGO costs ranged from $22.00 to $543.00 USD per country, with printing and postage being the most commonly reported expenditures. Conclusions: The PROBE questionnaire assesses patient-important reported outcomes in PWH and control participants, with a demonstrated short completion time. PROBE proved the feasibility to engage diverse patient communities in the structured generation of real-world outcome research at all stages. Trial registration: Trial registration: NCT02439710. PMID- 29497563 TI - Rasch analysis of the patient-rated wrist evaluation questionnaire. AB - Background: The Patient-Rated Wrist Evaluation (PRWE) was developed as a wrist joint specific measure of pain and disability and evidence of sound validity has been accumulated through classical psychometric methods. Rasch analysis (RA) has been endorsed as a newer method for analyzing the clinical measurement properties of self-report outcome measures. The purpose of this study was to evaluate the PRWE using Rasch modeling. Methods: We employed the Rasch model to assess overall fit, response scaling, individual item fit, differential item functioning (DIF), local dependency, unidimensionality and person separation index (PSI). A convenience sample of 382 patients with distal radius fracture was recruited from the hand and upper limb clinic at large academic healthcare organization, London, Ontario, Canada, 6-month post-injury scores of the PRWE was used. RA was conducted on the 3 subscales (pain, specific activities, and usual activities) of the PRWE separately. Results: The pain subscale adequately fit the Rasch model when item 4 "Pain - When it is at its worst" was deleted to eliminate non-uniform DIF by age group, and item 5 "How often do you have pain" was rescored by collapsing into 8 intervals to eliminate disordered thresholds. Uniform DIF for "Use my affected hand to push up from the chair" (by work status) and "Use bathroom tissue with my affected hand" (by injured hand) was addressed by splitting the items for analysis. After background rescoring of 2 items in pain subscale, 2 items in specific activities and 3 items in usual activities, all three subscales of the PRWE were well targeted and had high reliability (PSI = 0.86). These changes provided a unidimensional, interval-level scaled measure. Conclusion: Like a previous analysis of the Patient-Rated Wrist and Hand Evaluation, this study found the PRWE could be fit to the Rasch model with rescoring of multiple items. However, the modifications required to achieve fit were not the same across studies, our fit statistics also suggested one of the pain items should be deleted. This study adds to the pool of evidence supporting the PRWE, but cannot confidently provide a Rasch-based scoring algorithm. PMID- 29497562 TI - Ferritin nanoparticles for improved self-renewal and differentiation of human neural stem cells. AB - Background: Biomaterials that promote the self-renewal ability and differentiation capacity of neural stem cells (NSCs) are desirable for improving stem cell therapy to treat neurodegenerative diseases. Incorporation of micro- and nanoparticles into stem cell culture has gained great attention for the control of stem cell behaviors, including proliferation and differentiation. Method: In this study, ferritin, an iron-containing natural protein nanoparticle, was applied as a biomaterial to improve the self-renewal and differentiation of NSCs and neural progenitor cells (NPCs). Ferritin nanoparticles were added to NSC or NPC culture during cell growth, allowing for incorporation of ferritin nanoparticles during neurosphere formation. Results: Compared to neurospheres without ferritin treatment, neurospheres with ferritin nanoparticles showed significantly promoted self-renewal and cell-cell interactions. When spontaneous differentiation of neurospheres was induced during culture without mitogenic factors, neuronal differentiation was enhanced in the ferritin-treated neurospheres. Conclusions: In conclusion, we found that natural nanoparticles can be used to improve the self-renewal ability and differentiation potential of NSCs and NPCs, which can be applied in neural tissue engineering and cell therapy for neurodegenerative diseases. PMID- 29497564 TI - Full-genome dengue virus sequencing in mosquito saliva shows lack of convergent positive selection during transmission by Aedes aegypti. AB - Like other pathogens with high mutation and replication rates, within-host dengue virus (DENV) populations evolve during infection of their main mosquito vector, Aedes aegypti. Within-host DENV evolution during transmission provides opportunities for adaptation and emergence of novel virus variants. Recent studies of DENV genetic diversity failed to detect convergent evolution of adaptive mutations in mosquito tissues such as midgut and salivary glands, suggesting that convergent positive selection is not a major driver of within host DENV evolution in the vector. However, it is unknown whether this conclusion extends to the transmitted viral subpopulation because it is technically difficult to sequence DENV genomes in mosquito saliva. Here, we achieved DENV full-genome sequencing by pooling saliva samples collected non-sacrificially from 49 to 163 individual Ae. aegypti mosquitoes previously infected with one of two DENV-1 genotypes. We compared the transmitted viral subpopulations found in the pooled saliva samples collected in time series with the input viral population present in the infectious blood meal. In all pooled saliva samples examined, the full-genome consensus sequence of the input viral population was unchanged. Although the pooling strategy prevents analysis of individual saliva samples, our results demonstrate the lack of strong convergent positive selection during a single round of DENV transmission by Ae. aegypti. This finding reinforces the idea that genetic drift and purifying selection are the dominant evolutionary forces shaping within-host DENV genetic diversity during transmission by mosquitoes. PMID- 29497565 TI - Assessment of pazopanib-related hypertension, cardiac dysfunction and identification of clinical risk factors for their development. AB - Background: Antineoplastic therapy with the tyrosine kinase inhibitor pazopanib in patients with advanced/metastatic renal cell carcinoma (mRCC) has been associated with hypertension (HTN), cardiomyopathy, and cardiac dysrhythmias. We therefore assessed the cardiovascular (CV) risk with pazopanib in a clinical setting. Methods: Medical records of 35 antineoplastic-naive mRCC patients newly started on pazopanib were retrospectively reviewed at a single academic medical center. Assessment of the hypertensive response and adverse cardiac events associated with pazopanib was the primary objective. Outcomes were defined using the National Cancer Institute's Common Terminology Criteria for Adverse Events v4.0. Potential clinical risk factors were investigated with univariate and multivariable logistic regression. Results: Pazopanib-induced HTN was observed in 57% of patients. Median maximal systolic blood pressure (SBP) during pazopanib treatment was 167.5 mmHg with median time to event of 24.5 days. New-onset HTN occurred in 6/14 (43%) patients. Baseline SBP > 130 mmHg (odds ratio [OR]: 5.32; 95% confidence interval [CI]: 0.94-29.99; p = 0.058) and ACEi/ARB use (OR: 4.88; 95% CI: 1.05 22.84; p = 0.044) were risk factors for pazopanib-induced HTN. When HTN was excluded, 34% of patients developed a CV adverse event. Age >= 60 years (OR: 8.72; 95% CI: 0.74-513.26; p = 0.105) trended towards being a predictor for a non-HTN CV adverse event. Conclusions: Our findings suggest that pazopanib has a broad CV toxicity profile in treatment-naive mRCC patients headlined by a rapid and striking hypertensive response. More intensive BP control prior to starting pazopanib and standardization of CV surveillance particularly in older patients may optimize oncologic care while minimizing CV risk. PMID- 29497566 TI - Prioritization in medical school simulation curriculum development using survey tools and desirability function: a pilot experiment. AB - Background: In Italy, there is no framework of procedural skills that all medical students should be able to perform autonomously at graduation. The study aims at identifying (1) a set of essential procedural skills and (2) which abilities could be potentially taught with simulation. Desirability score was calculated for each procedure to determine the most effective manner to proceed with simulation curriculum development. Methods: A web poll was conducted at the School of Medicine in Novara, looking at the level of expected and self-perceived competency for common medical procedures. Three groups were enrolled: (1) faculty, (2) junior doctors in their first years of practice, and (3) recently graduated medical students. Level of importance of procedural skills for independent practice expressed by teachers, level of mastery self-perceived by learners (students and junior doctors) and suitability of simulation training for the given technical skills were measured. Desirability function was used to set priorities for future learning. Results: The overall mean expected level of competency for the procedural skills was 7.9/9. Mean level of self reported competency was 4.7/9 for junior doctors and 4.4/9 for recently graduated students. The highest priority skills according to the desirability function were urinary catheter placement, nasogastric tube insertion, and incision and drainage of superficial abscesses. Conclusions: This study identifies those technical competencies thought by faculty to be important and assessed the junior doctors and recent graduates level of self-perceived confidence in performing these skills. The study also identifies the perceived utility of teaching these skills by simulation. The study prioritizes those skills that have a gap between expected and observed competency and are also thought to be amenable to teaching by simulation. This allows immediate priorities for simulation curriculum development in the most effective manner. This methodology may be useful to researchers in other centers to prioritize simulation training. PMID- 29497567 TI - C1-C2 arthrodesis after spontaneous Propionibacterium acnes spondylodiscitis: Case report and literature analysis. AB - Background: Propionibacterium acnes (P. acnes) is a microaerophilic anaerobic Gram-positive rod responsible for acne vulgaris. Although it is often considered to be a skin contaminant, it may act as a virulent agent in implant-associated infections. Conversely, spontaneous infectious processes have been rarely described. Case Description: Here, we describe a 43-year-old female with C1-C2 spondylodiscitis attributed to P. acnes infection. Despite long-term antibiotic treatment, computed tomography demonstrated erosion of the C1 and C2 vertebral complex that later warranted a fusion. One year postoperatively, the patient was asymptomatic. Conclusions: Clinical knowledge of P. acnes virulence in spontaneous cervical spondylodiscitis allows early diagnosis, which is necessary to prevent or reduce complications such as cervical deformity with myelopathy or mediastinitis. PMID- 29497569 TI - Benefits of spinal meningioma resection. AB - Background: Spinal meningiomas account for approximately 40% of intradural extramedullary tumors. As they are usually slow growing, some patients are often diagnosed late in the clinical course when they have developed myelopathy. Methods: Here, we retrospectively studied a cohort of 51 patients undergoing surgery for spinal meningiomas. The median follow-up period was 45.9 months (range, 1-168 months). Assessment included evaluation of functional outcomes (e.g., comparison of the pre and postoperative status using the modified McCormick Functional Scale) and identification of prognostic factors. Results: Seventeen patients with grade IV (McCormick Scale) neurological deficits on admission underwent surgical resection; 4 of 5 grade III (McCormick Scale) and 14 patients (Grade IV) improved within 2.11 months (mean time) postoperatively. There was no surgical mortality and the morbidity rate was 16%. Conclusion: Patients with advanced neurological deficits/myelopathy (Grades III or IV on the McCormick Scale) improved following surgical resection of spinal meningiomas. PMID- 29497568 TI - Suprasellar keratinous cyst: A case report and review on its radiological features and treatment outcome. AB - Background: Keratinous or epidermoid cysts (ECs) are encapsulated lesions lined by squamous cell epithelium. They comprise approximately 1% of intracranial lesions. Contrary to dermoid cysts, they lack dermal elements such as sebaceous or apocrine glands and hair follicles. The sellar region is the second most common intracranial site following the cerebellopontine angle. Here, we report a case of EC in a patient who complained of endocrine disturbances. We also performed a systematic review on previously published cases to analyze clinical and radiological characteristics and report the treatment outcomes of suprasellar ECs. Case Description: A 42-year-old woman presented with a one-year history of amenorrhea, weight gain, severe headache, and visual disturbances for 6 months. Work-up identified an elevated prolactin level and a temporal field defect of the right eye. Magnetic resonance imaging (MRI) showed a cystic suprasellar lesion pushing on the optic chiasm. She underwent endoscopic trans-sphenoidal surgery, which confirmed a keratinous cyst on histology. Postoperatively, complete resection was confirmed on imaging. She did well although her hospital stay was prolonged due to diabetes insipidus and hypocortisolism. Conclusion: Chronic endocrine disturbances can be the presenting complaints of a suprasellar EC, whose T1-weighted MRI appearance can be non-specific, mimicking other differential diagnoses, such as a Rathke's cleft cyst. However, the T2-weighted MRI appearances of ECs are generally hyper-intense and lesions show diffusion restriction. Treatment is surgical and yields good outcomes in most cases reported. PMID- 29497570 TI - Diagnostic efficacy of clinical tests for lumbar spinal instability. AB - Background: Although various clinical tests are utilized to assess lumbar spine instability (LSI), few have documented diagnostic efficacy. We assessed the diagnostic efficacy of four clinical and one radiographic test for LSI in patients with degenerative lumbar disease. Methods: A cohort of 52 patients with pain attributed to lumbar spine stenosis and degenerative spondylolisthesis were prospectively evaluated utilizing dynamic X-rays, the passive lumbar extension (PLE) test, instability catch sign, painful catch sign, and the apprehension sign. The results of these preoperative tests were compared with spinal surgeons' intraoperative documentation of spinal instability considered in this study as the "gold" standard. Results: Intraoperatively, 33 patients demonstrated instability (63.5%) whereas 28 had motion documented on preoperative dynamic radiography. The sensitivity, specificity, positive, and negative predictive value and accuracy of dynamic radiography were 84.8%, 100%, 100%, 79.1%, and 90.4%, respectively. The diagnostic efficiency of PLE was higher than other additional studies - sensitivity 78.8%, specificity 94.7%, positive predictive value 96.3%, negative predictive value 72%, and accuracy rate 84.6%. Conclusion: Dynamic radiography was more reliable than any of the clinical tests in diagnosing LSI. Among the latter, PLE had the highest diagnostic value for establishing LSI. PMID- 29497571 TI - Gamma knife radiosurgery in the management of endolymphatic sac tumors. AB - Background: Although widely regarded as rare epithelial tumors with a low grade of malignancy, endolymphatic sac tumors (ELST) often lead to disabling petrous bone destruction and significantly impairing symptoms at the time of primary diagnosis and/or recurrence. ELST is not uncommon in von Hippel Lindau (VHL) patients. Although open surgery is regarded as the best treatment option, recurrence remains a challenge, particularly when gross tumor resection (GTR) is deemed unachievable due to topographic conditions. Tumor recurrence successfully treated with fractionated radiotherapy and radiosurgery have been reported in selected cases. We present the case of a patient with recurrent ELST treated with salvage gamma knife radiosurgery (GKRS) adding a review of current literature. Case Description: A 65-year-old patient underwent GKRS of an unresectable, recurrent ELST. Tumor volumetric analysis showed almost 15% increase in tumor volume in the 4 months between the pre-GKRS magnetic resonance imaging (MRI) and the stereotactic MRI (s-MRI) at treatment. Follow-up MRI at 12 and 20 months showed significant decrease in local tumor volume, decreased contrast enhancement and no perifocal edema. The patient's general and neurological status remains stable to the present day. Conclusion: In the present case, GKRS was effective in the management of a recurrent ELST over the course of 20 months. Because of ELSTs recurrence potential, long-term follow up is required. The present case as well as previous reports might suggest a possible salvage/adjunctive role of radiosurgery in the management of ELST. Further studies are deemed necessary. PMID- 29497573 TI - Nonoperative Treatment of Appendicitis during Pregnancy in a Remote Area. AB - Appendicitis is the most common nonobstetric surgical disease during pregnancy. Appendicitis during pregnancy is associated with an increased risk of morbidity and perforation compared with the general population. Furthermore, it may cause preterm birth and fetal loss, and quick surgical intervention is the established treatment option in pregnant women with appendicitis. In Greenland, geographical distances are very large, and weather conditions can be extreme, and surgical care is not always immediately available. Hence, antibiotic treatment is often initiated as a bridge-to-surgery. We report on a pregnant Greenlandic Inuit woman with appendicitis who was treated with intravenous antibiotics. Antibiotic treatment was successful before surgical care became available and the patient was not operated. No complications occurred, and further pregnancy was uneventful. Our case suggests that antibiotic treatment of appendicitis during pregnancy as a bridge-to-surgery may be a sensible treatment option in remote areas, where no surgical care is immediately available. In some cases, antibiotic treatment may turn out to be definitive treatment. PMID- 29497572 TI - Engraftment, neuroglial transdifferentiation and behavioral recovery after complete spinal cord transection in rats. AB - Background: Proof of the efficacy and safety of a xenogeneic mesenchymal stem cell (MSCs) transplant for spinal cord injury (SCI) may theoretically widen the spectrum of possible grafts for neuroregeneration. Methods: Twenty rats were submitted to complete spinal cord transection. Ovine bone marrow MSCs, retrovirally transfected with red fluorescent protein and not previously induced for neuroglial differentiation, were applied in 10 study rats (MSCG). Fibrin glue was injected in 10 control rats (FGG). All rats were evaluated on a weekly basis and scored using the Basso-Beattie-Bresnahan (BBB) locomotor scale for 10 weeks, when the collected data were statistically analyzed. The spinal cords were then harvested and analyzed with light microscopy, immunohistochemistry, and immunofluorescence. Results: Ovine MSCs culture showed positivity for Nestin. MSCG had a significant and durable recovery of motor functions (P <.001). Red fluorescence was found at the injury sites in MSCG. Positivity for Nestin, tubulin betaIII, NG2 glia, neuron-specific enolase, vimentin, and 200 kD neurofilament were also found at the same sites. Conclusions: Xenogeneic ovine bone marrow MSCs proved capable of engrafting into the injured rat spinal cord. Transdifferentiation into a neuroglial phenotype was able to support partial functional recovery. PMID- 29497574 TI - Stroke Telerehabilitation in Sicily: a Cost-Effective Approach to Reduce Disability? PMID- 29497576 TI - Effectiveness of Electroconvulsive Therapy (ECT) in Parkinsonian Symptoms: A Case Series. AB - Depression is a common comorbidity in patients suffering from Parkinson's disease (PD). Available evidence suggests that electroconvulsive therapy (ECT) is an effective treatment for depression and also improves symptoms of PD. However, literature on usefulness of ECT in parkinsonian symptoms is limited. A review of records of all patients receiving ECT from 2010 to April 2017 in the authors' clinic yielded six cases (0.63% of all patients who received ECT at the authors' center over last 7 years) of depression with PD who were treated with ECT. All six patients had improvement in both depression and symptoms of PD following ECT treatment. The improvement achieved with ECT was sustained in four patients. Worsening of PD symptoms 3 to 4 months post-treatment was seen in two patients. ECT appears to be an effective treatment option for management of motoric symptoms in patients with PD, especially those with comorbid psychiatric disorders. PMID- 29497575 TI - Pimavanserin: A Novel Drug Approved to Treat Parkinson's Disease Psychosis. AB - Objective: Pimavanserin is the first United States Food and Drug Administration (FDA)-approved treatment for Parkinson's disease psychosis (PDP). This article reviews the safety, efficacy, and pharmacology data for pimavanserin and its role in therapy. Method of Research: Initial literature sources were identified via MEDLINE search (1946-September 2016) of pimavanserin and ACP-103 (original molecular designation). Reference review and search of FDA.gov and clinicaltrials.gov yielded additional studies. English-language studies of pimavanserin for PDP were evaluated. Animal studies were excluded. Randomized, controlled trials (RCTs) were prioritized. Results: Four RCTs were identified. In each, pimavanserin was well-tolerated with few adverse effects and no worsening of motor symptoms. A Phase II trial displayed a nonsignificant trend toward Scale for Assessment of Positive Symptoms (SAPS) improvement (p=0.09), with significant benefits in secondary efficacy markers. However, two Phase III trials, including one that was terminated early, failed to show significant SAPS improvement. A third Phase III trial with an improved research design utilized a nine-item subset of the SAPS, the SAPS-PD, as the primary outcome and demonstrated that pimavanserin 40mg was effective in improving PDP compared to placebo (p=0.0014, effect size=0.50). Secondary outcomes were also significantly improved: Clinical Global Impression of Severity (CGI-S) (p=0.0007, effect size=0.52) and Clinical Global Impression of Improvement (CGI-I) (p=0.0011, effect size=0.51), caregiver burden (p=0.0016, effect size=0.50), nighttime sleep (p=0.0446, effect size=0.31), and daytime wakefulness (p=0.012, effect size=0.39). Conclusion: Evidence suggests pimavanserin attenuates PDP symptoms with few adverse effects and little risk of worsening motor function. With limited treatment options for PDP, pimavanserin represents an important therapeutic innovation. PMID- 29497577 TI - Lower-extremity Dynamometry as a Novel Outcome Measure in a Double-blind, Placebo controlled, Feasibility Trial of Intravenous Immunoglobulin (IVIG) for HIV associated Myelopathy. AB - Objective: Open-label data suggest that intravenous immunoglobulin (IVIG) might improve lower-extremity strength in human immunodeficiency virus (HIV)-associated myelopathy (HIVM), a rare but debilitating neurologic complication of HIV. We sought to determine the feasibility of testing the efficacy of IVIG for HIVM more rigorously. Design: We conducted a randomized, double-blind, placebo-controlled feasibility trial of IVIG for HIVM, using dynamometry as an outcome measure (Clinical Trial No. NCT01561755). Setting: The study took place in an academic medical center in New York, New York Participants: Only 12 participants were enrolled in four years; critical impediments to the study were the rarity of patients with new HIVM diagnoses and prior exposure to IVIG in patients with an established diagnosis. Measurements: Dynamometry of hip flexion, knee flexion, and ankle dorsiflexion were measured; the HIV Dementia Motor Score (HDMS); and the two-minute timed walk test were utilized. Results: Recruitment was the major feasibility issue. Dynamometry was generally well-tolerated, had good test-retest reliability (r=0.71-0.86, p<0.02 for all muscle groups), and good inter-item reliability as judged by the correlations between the muscle groups (r=0.76-0.81, p=0.001-0.005). Dynamometry was valid and clinically meaningful based on its correlations with the HDMS and the two-minute timed walk test. Conclusion: We conclude that an adequately powered clinical trial of IVIG for HIVM would likely require a prolonged recruitment period and multiple participating sites. Lower limb dynamometry is a useful outcome measure for HIVM, which might also be useful in other HIV-related gait disorders. PMID- 29497578 TI - The Benefit of Mirtazapine in the Treatment of Progressive Multifocal Leukoencephalopathy in a Young HIV-positive Patient: A Case Report. AB - Highly active antiretroviral therapy is well-established in the treatment of human immunodeficiency virus (HIV)-positive patients. Nonadherence with therapy regimens often leads to the occurrence of opportunistic infections that further complicate treatment and challenge the treating physician. We report a young HIV positive patient who suffered from progressive multifocal leukoencephalopathy caused by the human John Cunningham virus and showed objective clinical improvement after adding mirtazapine to the treatment regimen, an observation that is supported by the emerging literature. PMID- 29497580 TI - Wants Talk Psychotherapy but Cannot Talk: EMDR for Post-stroke Depression with Expressive Aphasia. AB - While post-stroke depression (PSD) is a common sequelae of stroke, many stroke survivors also have expressive aphasia (i.e., the inability to produce spoken or written language), which limits or prevents treating depression with talk psychotherapy. Unlike most psychotherapy modalities, eye movement desensitization and reprocessing (EMDR) does not require extensive verbal communication to therapists, which might make EMDR an ideal treatment modality for aphasic patients with mental health concerns. The authors present the first known case reporting EMDR in aphasia, describing the treatment of a 50-year-old woman with a history of depression following a left middle cerebral artery stroke. Left frontal lobe strokes are independently associated with both PSD and expressive aphasia. EMDR began two years following the stroke, at which point the patient continued to have persistent expressive aphasia despite previously completing more than a year of speech therapy. Using the Blind to Therapist Protocol, EMDR successfully led to improvement in depressive symptoms and, surprisingly, improvement in aphasia. This case report suggests that EMDR might be beneficial for those with mental health concerns who have expressive communication impairments that might prevent treatment with other psychotherapy modalities. We discuss potential challenges and technical workarounds with EMDR in aphasia, we speculate about potential biopsychosocial explanations for our results, and we recommend future research on EMDR for PSD and other mental health concerns in the context of aphasia, as well as possibly for aphasia itself. PMID- 29497579 TI - Cognitive Impairment Associated with Cancer: A Brief Review. AB - This brief review explores the areas of cognitive impairment that have been observed in cancer patients and survivors, the cognitive assessment tools used, and the management of the observed cognitive changes. Cognitive changes and impairment observed in patients with cancer and those in remission can be related to the direct effects of cancer itself, nonspecific factors or comorbid conditions that are independent of the actual disease, and/or the treatments or combination of treatments administered. Attention, memory, and executive functioning are the most frequently identified cognitive domains impacted by cancer. However, the prevalence and extent of impairment remains largely unknown due to marked differences in methodology, definitions of cognitive impairment, and the assessment measures used. Assessment of cognitive functioning is an important and necessary part of a comprehensive oncological care plan. Research is needed to establish a better understanding of cognitive changes and impairments associated with cancer so that optimal patient outcomes can be achieved. PMID- 29497581 TI - Detecting Glaucomatous Progression With a Region-of-Interest Approach on Optical Coherence Tomography: A Signal-to-Noise Evaluation. AB - Purpose: To compare two region-of-interest (ROI) approaches and a global thickness approach for capturing progressive circumpapillary retinal nerve fiber layer (cpRNFL) changes on optical coherence tomography (OCT) imaging. Methods: Progressive cpRNFL thickness changes were evaluated in 164 eyes with a clinical diagnosis of glaucoma or suspected glaucoma; all eyes underwent optic disc OCT imaging on two visits at least 1 year apart. Such changes were evaluated with a manual ROI approach (ROIM), which involved manual identification of region(s) of observed or suspected glaucomatous damage. The ROIM was compared with an automatic ROI approach (ROIA), where regions were automatically identified if the cpRNFL thickness fell below the 1% lower normative limits, and to global cpRNFL thickness. These methods were compared using longitudinal signal-to-noise ratios (SNRs), calculated based upon individualized estimates of measurement variability and age-related changes for each ROI, obtained from 321 glaucoma eyes and 394 healthy eyes, respectively. Results: The average longitudinal SNR of the ROIM, ROIA and global thickness methods were -0.46, -0.39, and -0.30 y-1, respectively. The average longitudinal SNR for the ROIM was significantly more negative compared with both the ROIA and global thickness methods (P = 0.005 for both). Conclusions: A manual ROI approach was the optimal method for detecting progressive cpRNFL loss compared with an automatic ROI approach and the global cpRNFL thickness measure. Translational Relevance: These findings highlight the potential advantages conferred by a careful qualitative evaluation of OCT imaging for detecting glaucoma progression. PMID- 29497582 TI - New Normative Database of Inner Macular Layer Thickness Measured by Spectralis OCT Used as Reference Standard for Glaucoma Detection. AB - Purpose: This study examines the capacity to detect glaucoma of inner macular layer thickness measured by spectral-domain optical coherence tomography (SD-OCT) using a new normative database as the reference standard. Methods: Participants (N = 148) were recruited from Leuven (Belgium) and Zaragoza (Spain): 74 patients with early/moderate glaucoma and 74 age-matched healthy controls. One eye was randomly selected for a macular scan using the Spectralis SD-OCT. The variables measured with the instrument's segmentation software were: macular nerve fiber layer (mRNFL), ganglion cell layer (GCL), and inner plexiform layer (IPL) volume and thickness along with circumpapillary RNFL thickness (cpRNFL). The new normative database of macular variables was used to define the cutoff of normality as the fifth percentile by age group. Sensitivity, specificity, and area under the receiver operating characteristic curve (AUROC) of each macular measurement and of cpRNFL were used to distinguish between patients and controls. Results: Overall sensitivity and specificity to detect early-moderate glaucoma were 42.2% and 88.9% for mRNFL, 42.4% and 95.6% for GCL, 42.2% and 94.5% for IPL, and 53% and 94.6% for RNFL, respectively. The best macular variable to discriminate between the two groups of subjects was outer temporal GCL thickness as indicated by an AUROC of 0.903. This variable performed similarly to mean cpRNFL thickness (AUROC = 0.845; P = 0.29). Conclusions: Using our normative database as reference, the diagnostic power of inner macular layer thickness proved comparable to that of peripapillary RNFL thickness. Translational Relevance: Spectralis SD-OCT, cpRNFL thickness, and individual macular inner layer thicknesses show comparable diagnostic capacity for glaucoma and RNFL, GCL, and IPL thickness may be useful as an alternative diagnostic test when the measure of cpRNFL shows artifacts. PMID- 29497583 TI - Further Enhancement of Intraocular Open-Capsule Devices for Prevention of Posterior Capsule Opacification. AB - Purpose: We improve the intraocular open-capsule devices (IOCD) for the prevention of posterior capsule opacification (PCO). Methods: A total of 45 New Zealand rabbit eyes were divided into six similar groups after crystalline lens evacuation. Each group was implanted with a hydrophilic intraocular lens (IOL) and a hydrophilic IOCD of different designs. In the first experiment (Part A), a square design ring with and without large apertures was compared to a round design ring without apertures. In the second experiment (Part B), a square design ring with large apertures was compared to square design IOCDs with small apertures of high and low density. PCO and Soemmering's ring were evaluated clinically, by the Miyake Apple view, and histologically. The results were compared to a control group of eyes implanted with a hydrophilic IOL only. Results: All devices showed significant prevention of PCO and Soemmering's ring compared to the control group. Part A: the square design with apertures had the lowest level of peripheral lens epithelial cells proliferation (protrusions). Part B: modifying the size and density of the apertures had no influence on those protrusions. Conclusions: The IOCD significantly reduced the rate of PCO and its precursor, Soemmering's ring. The rings with the square edges and apertures produced the best results. The study was underpowered to determine the influence of the apertures design. Translational Relevance: The IOCD has the potential to prevent up to 80% of the PCO cases; the most common complication after cataract surgery. The design of the ring is important for its success. PMID- 29497584 TI - A New Graphical Tool for Assessing Visual Field Progression in Clinical Populations. AB - Purpose: We demonstrate a new approach for assessing and visualizing visual field (VF) progression in clinics. Methods: Two summary measures for VF progression, Rate of Progression (RP) and Loss of Sight Years (LSY), are combined with a novel visualization (Hedgehog Plots). RP is calculated per eye using linear regression of mean deviation (MD) against time of follow-up. LSY is a novel parameter, linked to actuarial data, which estimates the number of years that a patient will have advanced bilateral VF loss in their predicted remaining lifetime. Every eye is given a rank within the sample based on RP and LSY allowing for "priority" patients to be identified. We illustrate differences between the parameters with an experiment comparing the cases flagged as "priority" by each method using data from 1263 VF records. Results: RP for every eye in a "clinic" can be visualized and assessed using a Hedgehog Plot. Eyes are ranked against all other eyes by RP and LSY; these parameters provide different and complementary information on a patient's VF progression status. A purpose written interactive application demonstrating the techniques is available in the public domain at https://crabblab.shinyapps.io/hedgehog. Conclusion: Hedgehog Plots provide a tool for visualizing VF progression in groups of patients and can be used potentially to prioritize monitoring resources. Translational Relevance: This study illustrates a novel visualization technique and an interactive application that can be used to help determine VF progression in large groups of patients. PMID- 29497585 TI - Spiritually Integrated Cognitive Processing Therapy: A New Treatment for Post traumatic Stress Disorder That Targets Moral Injury. AB - Background: Post-traumatic stress disorder (PTSD) is a debilitating disorder, and current treatments leave the majority of patients with unresolved symptoms. Moral injury (MI) may be one of the barriers that interfere with recovery from PTSD, particularly among current or former military service members. Objective: Given the psychological and spiritual aspects of MI, an intervention that addresses MI using spiritual resources in addition to psychological resources may be particularly effective in treating PTSD. To date, there are no existing empirically based individual treatments for PTSD and MI that make explicit use of a patient's spiritual resources, despite the evidence that spiritual beliefs/activities predict faster recovery from PTSD. Method: To address this gap, we adapted Cognitive Processing Therapy (CPT), an empirically validated treatment for PTSD, to integrate clients' spiritual beliefs, practices, values, and motivations. We call this treatment Spiritually Integrated CPT (SICPT). Results: This article describes this novel manualized therapeutic approach for treating MI in the setting of PTSD for spiritual/religious clients. We provide a description of SICPT and a brief summary of the 12 sessions. Then, we describe a case study in which the therapist helps a client use his spiritual resources to resolve MI and assist in the recovery from PTSD. Conclusion: SICPT may be a helpful way to reduce PTSD by targeting MI, addressing spiritual distress, and using a client's spiritual resources. In addition to the spiritual version (applicable for those of any religion and those who do not identify as religious), we have also developed 5 religion-specific manuals (Christianity, Judaism, Islam, Buddhism, and Hinduism) for clients who desire a more religion specific approach. PMID- 29497586 TI - Advanced Metrics for Assessing Holistic Care: The "Epidaurus 2" Project. AB - In response to the challenge of military traumatic brain injury and posttraumatic stress disorder, the US military developed a wide range of holistic care modalities at the new Walter Reed National Military Medical Center, Bethesda, MD, from 2001 to 2017, guided by civilian expert consultation via the Epidaurus Project. These projects spanned a range from healing buildings to wellness initiatives and healing through nature, spirituality, and the arts. The next challenge was to develop whole-body metrics to guide the use of these therapies in clinical care. Under the "Epidaurus 2" Project, a national search produced 5 advanced metrics for measuring whole-body therapeutic effects: genomics, integrated stress biomarkers, language analysis, machine learning, and "Star Glyphs." This article describes the metrics, their current use in guiding holistic care at Walter Reed, and their potential for operationalizing personalized care, patient self-management, and the improvement of public health. Development of these metrics allows the scientific integration of holistic therapies with organ-system-based care, expanding the powers of medicine. PMID- 29497588 TI - In-Flight Observation of Gamma Ray Glows by ILDAS. AB - An Airbus A340 aircraft flew over Northern Australia with the In-Flight Lightning Damage Assessment System (ILDAS) installed onboard. A long-duration gamma ray emission was detected. The most intense emission was observed at 12 km altitude and lasted for 20 s. Its intensity was 20 times the background counts, and it was abruptly terminated by a distant lightning flash. In this work we reconstruct the aircraft path and event timeline. The glow-terminating flash triggered a discharge from the aircraft wing that was recorded by a video camera operating onboard. Another count rate increase was observed 6 min later and lasted for 30 s. The lightning activity as reported by ground networks in this region was analyzed. The measured spectra characteristics of the emission were estimated. PMID- 29497587 TI - A striking new genus and species of cave-dwelling frog (Amphibia: Anura: Microhylidae: Asterophryinae) from Thailand. AB - We report on a discovery of Siamophryne troglodytesGen. et sp. nov., a new troglophilous genus and species of microhylid frog from a limestone cave in the tropical forests of western Thailand. To assess its phylogenetic relationships we studied the 12S rRNA-16S rRNA mtDNA fragment with final alignment comprising up to 2,591 bp for 56 microhylid species. Morphological characterization of the new genus is based on examination of external morphology and analysis of osteological characteristics using microCT-scanning. Phylogenetic analyses place the new genus into the mainly Australasian subfamily Asterophryinae as a sister taxon to the genus Gastrophrynoides, the only member of the subfamily known from Sundaland. The new genus markedly differs from all other Asterophryinae members by a number of diagnostic morphological characters and demonstrates significant mtDNA sequence divergence. We provide a preliminary description of a tadpole of the new genus. Thus, it represents the only asterophryine taxon with documented free living larval stage and troglophilous life style. Our work demonstrates that S. troglodytesGen. et sp. nov. represents an old lineage of the initial radiation of Asterophryinae which took place in the mainland Southeast Asia. Our results strongly support the "out of Indo-Eurasia" biogeographic scenario for this group of frogs. To date, the new frog is only known from a single limestone cave system in Sai Yok District of Kanchanaburi Province of Thailand; its habitat is affected by illegal bat guano mining and other human activities. As such, S. troglodytesGen. et sp. nov. is likely to be at high risk of habitat loss. Considering high ecological specialization and a small known range of the new taxon, we propose a IUCN Red List status of endangered for it. PMID- 29497590 TI - Sedimentary processes of the Bagnold Dunes: Implications for the eolian rock record of Mars. AB - The Mars Science Laboratory rover Curiosity visited two active wind-blown sand dunes within Gale crater, Mars, which provided the first ground-based opportunity to compare Martian and terrestrial eolian dune sedimentary processes and study a modern analog for the Martian eolian rock record. Orbital and rover images of these dunes reveal terrestrial-like and uniquely Martian processes. The presence of grainfall, grainflow, and impact ripples resembled terrestrial dunes. Impact ripples were present on all dune slopes and had a size and shape similar to their terrestrial counterpart. Grainfall and grainflow occurred on dune and large ripple lee slopes. Lee slopes were ~29 degrees where grainflows were present and ~33 degrees where grainfall was present. These slopes are interpreted as the dynamic and static angles of repose, respectively. Grain size measured on an undisturbed impact ripple ranges between 50 MUm and 350 MUm with an intermediate axis mean size of 113 MUm (median: 103 MUm). Dissimilar to dune eolian processes on Earth, large, meter-scale ripples were present on all dune slopes. Large ripples had nearly symmetric to strongly asymmetric topographic profiles and heights ranging between 12 cm and 28 cm. The composite observations of the modern sedimentary processes highlight that the Martian eolian rock record is likely different from its terrestrial counterpart because of the large ripples, which are expected to engender a unique scale of cross stratification. More broadly, however, in the Bagnold Dune Field as on Earth, dune-field pattern dynamics and basin-scale boundary conditions will dictate the style and distribution of sedimentary processes. PMID- 29497589 TI - Chemistry, mineralogy, and grain properties at Namib and High dunes, Bagnold dune field, Gale crater, Mars: A synthesis of Curiosity rover observations. AB - The Mars Science Laboratory Curiosity rover performed coordinated measurements to examine the textures and compositions of aeolian sands in the active Bagnold dune field. The Bagnold sands are rounded to subrounded, very fine to medium sized (~45-500 MUm) with >=6 distinct grain colors. In contrast to sands examined by Curiosity in a dust-covered, inactive bedform called Rocknest and soils at other landing sites, Bagnold sands are darker, less red, better sorted, have fewer silt sized or smaller grains, and show no evidence for cohesion. Nevertheless, Bagnold mineralogy and Rocknest mineralogy are similar with plagioclase, olivine, and pyroxenes in similar proportions comprising >90% of crystalline phases, along with a substantial amorphous component (35% +/- 15%). Yet Bagnold and Rocknest bulk chemistry differ. Bagnold sands are Si enriched relative to other soils at Gale crater, and H2O, S, and Cl are lower relative to all previously measured Martian soils and most Gale crater rocks. Mg, Ni, Fe, and Mn are enriched in the coarse-sieved fraction of Bagnold sands, corroborated by visible/near-infrared spectra that suggest enrichment of olivine. Collectively, patterns in major element chemistry and volatile release data indicate two distinctive volatile reservoirs in Martian soils: (1) amorphous components in the sand-sized fraction (represented by Bagnold) that are Si-enriched, hydroxylated alteration products and/or H2O- or OH-bearing impact or volcanic glasses and (2) amorphous components in the fine fraction (<40 MUm; represented by Rocknest and other bright soils) that are Fe, S, and Cl enriched with low Si and adsorbed and structural H2O. PMID- 29497591 TI - Thirty-Three Years of Ocean Benthic Warming Along the U.S. Northeast Continental Shelf and Slope: Patterns, Drivers, and Ecological Consequences. AB - The U.S. Northeast Continental Shelf is experiencing rapid warming, with potentially profound consequences to marine ecosystems. While satellites document multiple scales of spatial and temporal variability on the surface, our understanding of the status, trends, and drivers of the benthic environmental change remains limited. We interpolated sparse benthic temperature data along the New England Shelf and upper Slope using a seasonally dynamic, regionally specific multiple linear regression model that merged in situ and remote sensing data. The statistical model predicted nearly 90% of the variability of the data, resulting in a synoptic time series spanning over three decades from 1982 to 2014. Benthic temperatures increased throughout the domain, including in the Gulf of Maine. Rates of benthic warming ranged from 0.1 to 0.4 degrees C per decade, with fastest rates occurring in shallow, nearshore regions and on Georges Bank, the latter exceeding rates observed in the surface. Rates of benthic warming were up to 1.6 times faster in winter than the rest of the year in many regions, with important implications for disease occurrence and energetics of overwintering species. Drivers of warming varied over the domain. In southern New England and the mid-Atlantic shallow Shelf regions, benthic warming was tightly coupled to changes in SST, whereas both regional and basin-scale changes in ocean circulation affect temperatures in the Gulf of Maine, the Continental Shelf, and Georges Banks. These results highlight data gaps, the current feasibility of prediction from remotely sensed variables, and the need for improved understanding on how climate may affect seasonally specific ecological processes. PMID- 29497592 TI - Synthesis of Aryl Triflones through the Trifluoromethanesulfonylation of Benzynes. AB - The direct synthesis of aryl triflones, that is, trifluoromethanesulfonyl arenes, was achieved through the trifluoromethanesulfonylation of benzynes. The trifluoromethanesulfonyl group, one of the fluorinated functional groups, is a highly electron-negative and mild lipophilic substituent. Aryl triflones have high potential in the synthesis of bioactive compounds and specialty materials. The treatment of 2-(trimethylsilyl)aryl trifluoromethanesulfonates with cesium fluoride in the presence of 15-crown-5 generated benzynes, which reacted with sodium trifluoromethanesulfinate followed by protonation with tBuOH under heating conditions, provided aryl triflones in moderated to good yields. Both symmetrical and unsymmetrical triflones were nicely accessed under the same reaction conditions. Interestingly, the trifluoromethanesulfonylation of unsymmetrical benzyne precursors proceeded smoothly to furnish corresponding aryl triflones in good yields with good to high regioselectivities. The balance of polarization of electric charge as well as steric hindrance of the benzyne intermediates are central factors to control the outcome of regioselectivity. PMID- 29497593 TI - Gender and Menthol Cigarette Use in the United States: A Systematic Review of the Recent Literature (2011 - May 2017). AB - Purpose of review: To summarize current research on gender differences in mentholated cigarette use and related outcomes. Secondarily, to summarize literature on gender differences in mentholated cigarette use and related outcomes among Black smokers. Recent findings: Women smokers are more likely to use menthol cigarettes than men. Other than prevalence, there is a paucity of research on gender differences in menthol related outcomes (e.g., cessation, disease). Among both women and men, menthol preference is stable during adolescence and young adulthood. A substantial portion of both women and men who smoke menthol report an expectation of quitting should menthol be banned. We did not identify any studies of gender differences in mentholated cigarette use among Black smokers. Summary: Despite public health relevance, there is little current research on gender differences in mentholated cigarette use, other than studies of prevalence, and very little research on gender differences among Black smokers, including prevalence. PMID- 29497594 TI - The Importance of the Left Occipitotemporal Cortex in Developmental Dyslexia. AB - Purpose of Review: Developmental dyslexia is characterized by an impaired acquisition of fluent and skilled reading ability. Numerous studies have explored the neural correlates of this neurodevelopmental disorder, with most classic accounts strongly focussing on left temporoparietal regions. We will review recent findings from structural and functional MRI studies that suggest a more important role of occipitotemporal cortex abnormalities in dyslexia. Recent Findings: Recent findings highlight the role of the occipitotemporal cortex which exhibits functional as well as structural abnormalities in dyslexic readers and in children at risk for dyslexia and suggest a more central role for the occipitotemporal cortex in the pathophysiology of dyslexia. Summary: We demonstrate the importance of the occipitotemporal cortex in for understanding impaired reading acquisition and point out how future research might enhance our understanding of functional and structural impairments in the reading network via large-scale data analysis approaches. PMID- 29497595 TI - Understanding the Functional Mobility of Adults with Developmental Coordination Disorder (DCD) Through the International Classification of Functioning (ICF). AB - Purpose of Review: This phenomenological study explored the lived experience of six adults with developmental coordination disorder (DCD) and its potential impact on functional mobility. Utilising the International Classification of Functioning (World Health Organisation, 2001), the data derived from interviews were analysed to consider how persistent motor impairments impact on activity engagement and participation. Recent Findings: Much of the research evidence pertaining to DCD focuses on children. However, there is increasing acknowledgment that for some, the motor impairments synonymous with DCD continue into adulthood. Summary: The findings from this study suggest that for this group of participants, functional mobility can be compromised, restricting activity and participation. At a body structure/function level, participants identified additional impairments that moved beyond mobility, suggesting that the secondary consequences of fatigue and anxiety were disabling. However, personal factors were seen to mitigate some difficulties encountered to allow participants to remain actively engaged in a range of adult roles. PMID- 29497596 TI - Understanding Organisational Ability and Self-Regulation in Children with Developmental Coordination Disorder. AB - Purpose of the Review: This paper examines physical and emotional coherence in young people with developmental coordination disorder (DCD). Specifically, the transactional relationship between motor and non-motor/executive dysfunction in children with DCD and its impact on psychosocial functioning is explored. Recent Findings: This paper integrates the subjective reported experiences of young people with DCD with objective measurements and findings from neuroimaging studies. Summary: Consideration of the transactional relationship between the person, the activity and the environment, whether these factors be physical, social, attitudinal or virtual, will be fundamental to our understanding of the mechanisms underpinning organisational and emotional issues presenting in DCD. Integrating the experiences of young people with research evidence will be essential to improve outcomes for young people with DCD in clinical practice. PMID- 29497597 TI - Understanding, Recognising and Treating Co-occurring Anxiety in Autism. AB - Purpose of Review: Autistic people are at increased risk of anxiety, with around 50% of autistic adults and children experiencing this debilitating mental health condition. The purpose of this review is to consider some contemporary ideas about underlying mechanisms for anxiety in autism, explore issues in the identification and assessment of anxiety and discuss emerging trends in anxiety interventions for autistic people, before identifying some important next steps in the field. Recent Findings: Emerging evidence suggests that anxiety may present differently in autism compared to the general population and that whilst CBT holds promise, there may be important differences in neurobiological, affective and cognitive responses to stressors for autistic people, which warrant tailored anxiety models, assessments and interventions. Summary: We conclude that research is needed to develop and evaluate theoretical frameworks, assessment methods and interventions for anxiety in autism, particularly for autistic adults and those with co-occurring intellectual disability. PMID- 29497598 TI - Differentiating the structure of PtNi octahedral nanoparticles through combined ADF-EDX simulations. AB - Advances in catalysis rely on the synthesis and characterisation of nanoparticles that have tailored structures and compositions. Although energy-dispersive X-ray (EDX) spectroscopy can be used to study local variations in the compositions of individual supported nanoparticles on the atomic-scale in the scanning transmission electron microscope, electron beam induced damage and contamination can preclude the use of long exposure times and tomographic approaches. Here, we perform simulations of EDX maps of seven different octahedral PtNi nanoparticles for a selection of crystallographic orientations and tilts, to evaluate which of them can be distinguished from elemental mapping performed in only one orientation. PMID- 29497599 TI - The Role of Intestinal Stem Cells in Epithelial Regeneration Following Radiation Induced Gut Injury. AB - Purpose of Review: Intestinal epithelial cells show remarkable plasticity in regenerating the epithelium following radiation injury. In this review, we explore the regenerative capacity and mechanisms of various populations of intestinal stem cells (ISCs) in response to ionizing radiation. Recent Findings: Ionizing radiation targets mitotic cells that include "active" ISCs and progenitor cells. Lineage-tracing experiments showed that several different cell types identified by a single or combination of markers are capable of regenerating the epithelium, confirming that ISCs exhibit a high degree of plasticity. However, the identities of the contributing cells marked by various markers require further validation. Summary: Following radiation injury, quiescent and/or radioresistant cells become active stem cells to regenerate the epithelium. Looking forward, understanding the mechanisms by which ISCs govern tissue regeneration is crucial to determine therapeutic approaches to promote intestinal epithelial regeneration following injury. PMID- 29497600 TI - Olfactory Receptors as Biomarkers in Human Breast Carcinoma Tissues. AB - Olfactory receptors (ORs) are known to be expressed in a variety of human tissues and act on different physiological processes, such as cell migration, proliferation, or secretion and have been found to function as biomarkers for carcinoma tissues of prostate, lung, and small intestine. In this study, we analyzed the OR expression profiles of several different carcinoma tissues, with a focus on breast cancer. The expression of OR2B6 was detectable in breast carcinoma tissues; here, transcripts of OR2B6 were detected in 73% of all breast carcinoma cell lines and in over 80% of all of the breast carcinoma tissues analyzed. Interestingly, there was no expression of OR2B6 observed in healthy tissues. Immunohistochemical staining of OR2B6 in breast carcinoma tissues revealed a distinct staining pattern of carcinoma cells. Furthermore, we detected a fusion transcript containing part of the coding exon of OR2B6 as a part of a splice variant of the histone HIST1H2BO transcript. In addition, in cancer tissues and cell lines derived from lung, pancreas, and brain, OR expression patterns were compared to that of corresponding healthy tissues. The number of ORs detected in lung carcinoma tissues was significantly reduced in comparison to the surrounding healthy tissues. In pancreatic carcinoma tissues, OR4C6 was considerably more highly expressed in comparison to the respective healthy tissues. We detected OR2B6 as a potential biomarker for breast carcinoma tissues. PMID- 29497601 TI - Ecological Shifts of Supragingival Microbiota in Association with Pregnancy. AB - Pregnancy is a physiological process with pronounced hormonal fluctuations in females, and relatively little is known regarding how pregnancy influences the ecological shifts of supragingival microbiota. In this study, supragingival plaques and salivary hormones were collected from 11 pregnant women during pregnancy (P1, <=14 weeks; P2, 20-25 weeks; P3, 33-37 weeks) and the postpartum period (P4, 6 weeks after childbirth). Seven non-pregnant volunteers were sampled at the same time intervals. The microbial genetic repertoire was obtained by 16S rDNA sequencing. Our results indicated that the Shannon diversity in P3 was significantly higher than in the non-pregnant group. The principal coordinates analysis showed distinct clustering according to gestational status, and the partial least squares discriminant analysis identified 33 genera that may contribute to this difference. There were differentially distributed genera, among which Neisseria, Porphyromonas, and Treponema were over-represented in the pregnant group, while Streptococcus and Veillonella were more abundant in the non pregnant group. In addition, 53 operational taxonomic units were observed to have positive correlations with sex hormones in a redundancy analysis, with Prevotella spp. and Treponema spp. being most abundant. The ecological events suggest that pregnancy has a role in shaping an at-risk-for-harm microbiota and provide a basis for etiological studies of pregnancy-associated oral dysbiosis. PMID- 29497602 TI - Protective Capacity of Statins during Pneumonia Is Dependent on Etiological Agent and Obesity. AB - Acute respiratory infections are a leading cause of death worldwide. Clinical data is conflicted regarding whether statins improve outcomes for pneumonia. Potential confounding factors including specific etiology of pneumonia as well as obesity could potentially mask protective benefit. Obesity is a risk factor for high cholesterol, the main target for statin therapy. We demonstrate that statin intervention conferred no protective benefit in the context of wild-type mice regardless of infectious agent. Statin intervention conferred either a protective benefit, during influenza infection, or detrimental effect, in the case of pneumococcal infection, in obese animals. These data suggest etiology of pneumonia in the context of obesity could be dramatically altered by the protective effects of statin therapy during bacterial and viral pneumonia. PMID- 29497603 TI - High-Throughput Quantification of Bacterial-Cell Interactions Using Virtual Colony Counts. AB - The quantification of bacteria in cell culture infection models is of paramount importance for the characterization of host-pathogen interactions and pathogenicity factors involved. The standard to enumerate bacteria in these assays is plating of a dilution series on solid agar and counting of the resulting colony forming units (CFU). In contrast, the virtual colony count (VCC) method is a high-throughput compatible alternative with minimized manual input. Based on the recording of quantitative growth kinetics, VCC relates the time to reach a given absorbance threshold to the initial cell count using a series of calibration curves. Here, we adapted the VCC method using the model organism Salmonella enterica sv. Typhimurium (S. Typhimurium) in combination with established cell culture-based infection models. For HeLa infections, a direct side-by-side comparison showed a good correlation of VCC with CFU counting after plating. For MDCK cells and RAW macrophages we found that VCC reproduced the expected phenotypes of different S. Typhimurium mutants. Furthermore, we demonstrated the use of VCC to test the inhibition of Salmonella invasion by the probiotic E. coli strain Nissle 1917. Taken together, VCC provides a flexible, label-free, automation-compatible methodology to quantify bacteria in in vitro infection assays. PMID- 29497604 TI - Antibody-Dependent Enhancement and Zika: Real Threat or Phantom Menace? PMID- 29497605 TI - Enzalutamide and blocking androgen receptor in advanced prostate cancer: lessons learnt from the history of drug development of antiandrogens. AB - Enzalutamide is a nonsteroidal antiandrogen for the treatment of metastatic castration-resistant prostate cancer (mCRPC) both before and after chemotherapy. Enzalutamide is more effective than its predecessor bicalutamide, which was analyzed in head-to-head studies of patients with CRPC. This family of nonsteroidal antiandrogens is now comprised of four drugs approved by the US Food and Drug Administration with two investigational drugs in clinical trials. Antiandrogens have been employed clinically for more than five decades to provide a rich resource of information. Steady-state concentration minimums (Cmin or trough) in the range of ~1-13 MUg/mL are measured in patients at therapeutic doses. Interestingly, enzalutamide which is considered to have strong affinity for the androgen receptor (AR) requires Cmin levels >10 MUg/mL. The sequence of antiandrogens and the clinical order of application in regard to other drugs that target the androgen axis remain of high interest. One novel first-in-class drug, called ralaniten, which binds to a unique region in the N-terminus domain of both the full-length and the truncated constitutively active splice variants of the AR, is currently in clinical trials for patients who previously received abiraterone, enzalutamide, or both. This highlights the trend to develop drugs with novel mechanisms of action and potentially differing mechanisms of resistance compared with antiandrogens. Better and more complete inhibition of the transcriptional activity of the AR appears to continue to provide improvements in the clinical management of mCRPC. PMID- 29497607 TI - Regulation of Internet-based Genetic Testing: Challenges for Australia and Other Jurisdictions. AB - The Internet currently enables unprecedented ease of access for direct-to consumer (DTC) genetic testing, with saliva collection kits posted directly to consumer homes from anywhere in the world. This poses new challenges for local jurisdictions in regulating genetic testing, traditionally a tightly-regulated industry. Some Internet-based genetic tests have the capacity to cause significant confusion or harm to consumers who are unaware of the risks or potential variability in quality. The emergence of some online products of questionable content, unsupported by adequate scientific evidence, is a cause for concern. Proliferation of such products in the absence of regulation has the potential to damage public trust in accredited and established clinical genetic testing during a critical period of evidence generation for genomics. Here, we explore the challenges arising from the emergence of Internet-based DTC genetic testing. In particular, there are challenges in regulating unaccredited or potentially harmful Internet-based DTC genetic testing products. In Australia, challenges exist for the Therapeutic Goods Administration, which oversees regulation of the genetic testing sector. Concerns and challenges faced in Australia are likely to reflect those of other comparable non-US jurisdictions. Here, we summarize current Australian regulation, highlight concerns, and offer recommendations on how Australia and other comparable jurisdictions might be more proactive in addressing this emerging public health issue. PMID- 29497606 TI - Network for Early Onset Cystic Kidney Diseases-A Comprehensive Multidisciplinary Approach to Hereditary Cystic Kidney Diseases in Childhood. AB - Hereditary cystic kidney diseases comprise a complex group of genetic disorders representing one of the most common causes of end-stage renal failure in childhood. The main representatives are autosomal recessive polycystic kidney disease, nephronophthisis, Bardet-Biedl syndrome, and hepatocyte nuclear factor 1beta nephropathy. Within the last years, genetic efforts have brought tremendous progress for the molecular understanding of hereditary cystic kidney diseases identifying more than 70 genes. Yet, genetic heterogeneity, phenotypic variability, a lack of reliable genotype-phenotype correlations and the absence of disease-specific biomarkers remain major challenges for physicians treating children with cystic kidney diseases. To tackle these challenges comprehensive scientific approaches are urgently needed that match the ongoing "revolution" in genetics and molecular biology with an improved efficacy of clinical data collection. Network for early onset cystic kidney diseases (NEOCYST) is a multidisciplinary, multicenter collaborative combining a detailed collection of clinical data with translational scientific approaches addressing the genetic, molecular, and functional background of hereditary cystic kidney diseases. Consisting of seven work packages, including an international registry as well as a biobank, NEOCYST is not only dedicated to current scientific questions, but also provides a platform for longitudinal clinical surveillance and provides precious sources for high-quality research projects and future clinical trials. Funded by the German Federal Government, the NEOCYST collaborative started in February 2016. Here, we would like to introduce the rationale, design, and objectives of the network followed by a short overview on the current state of progress. PMID- 29497608 TI - Indigenous Youth Peer-Led Health Promotion in Canada, New Zealand, Australia, and the United States: A Systematic Review of the Approaches, Study Designs, and Effectiveness. AB - Background: Youth peer-led interventions have become a popular way of sharing health information with young people and appear well suited to Indigenous community contexts. However, no systematic reviews focusing on Indigenous youth have been published. We conducted a systematic review to understand the range and characteristics of Indigenous youth-led health promotion projects implemented and their effectiveness. Methods: A systematic search of Medline, Embase, and ProQuest Social Sciences databases was conducted, supplemented by gray literature searches. Included studies focused on interventions where young Indigenous people delivered health information to age-matched peers. Results: Twenty-four studies were identified for inclusion, based on 20 interventions (9 Australian, 4 Canadian, and 7 from the United States of America). Only one intervention was evaluated using a randomized controlled study design. The majority of evaluations took the form of pre-post studies. Methodological limitations were identified in a majority of studies. Study outcomes included improved knowledge, attitude, and behaviors. Conclusion: Currently, there is limited high quality evidence for the effectiveness of peer-led health interventions with Indigenous young people, and the literature is dominated by Australian-based sexual health interventions. More systematic research investigating the effectiveness of peer-led inventions is required, specifically with Indigenous populations. To improve health outcomes for Indigenous youth, greater knowledge of the mechanisms and context under which peer-delivered health promotion is effective in comparison to other methods of health promotion is needed. PMID- 29497609 TI - Heat: A Highly Efficient Skin Enhancer for Transdermal Drug Delivery. AB - Advances in materials science and bionanotechnology have allowed the refinements of current drug delivery systems, expected to facilitate the development of personalized medicine. While dermatological topical pharmaceutical formulations such as foams, creams, lotions, gels, etc., have been proposed for decades, these systems target mainly skin-based diseases. To treat systemic medical conditions as well as localized problems such as joint or muscle concerns, transdermal delivery systems (TDDSs), which use the skin as the main route of drug delivery, are very appealing. Over the years, these systems have shown to offer important advantages over oral as well as intravenous drug delivery routes. Besides being non-invasive and painless, TDDSs are able to deliver drugs with a short-half-life time more easily and are well adapted to eliminate frequent administrations to maintain constant drug delivery. The possibility of self-administration of a predetermined drug dose at defined time intervals makes it also the most convenient personalized point-of-care approach. The transdermal market still remains limited to a narrow range of drugs. While small and lipophilic drugs have been successfully delivered using TDDSs, this approach fails to deliver therapeutic macromolecules due to size-limited transport across the stratum corneum, the outermost layer of the epidermis. The low permeability of the stratum corneum to water-soluble drugs as well as macromolecules poses important challenges to transdermal administration. To widen the scope of drugs for transdermal delivery, new procedures to enhance skin permeation to hydrophilic drugs and macromolecules are under development. Next to iontophoresis and microneedle-based concepts, thermal-based approaches have shown great promise to enhance transdermal drug delivery of different therapeutics. In this inaugural article for the section "Frontiers in Bioengineering and Biotechnology," the advances in this field and the handful of examples of thermal technologies for local and systemic transdermal drug delivery will be discussed and put into perspective. PMID- 29497610 TI - Cancer Chemoprevention and Piperine: Molecular Mechanisms and Therapeutic Opportunities. AB - Cancer is a genetic disease characterized by unregulated growth and dissemination of malignantly transformed neoplastic cells. The process of cancer development goes through several stages of biochemical and genetic alterations in a target cell. Several dietary alkaloids have been found to inhibit the molecular events and signaling pathways associated with various stages of cancer development and therefore are useful in cancer chemoprevention. Cancer chemoprevention has long been recognized as an important prophylactic strategy to reduce the burden of cancer on health care system. Cancer chemoprevention assumes the use of one or more pharmacologically active agents to block, suppress, prevent, or reverse the development of invasive cancer. Piperine is an active alkaloid with an excellent spectrum of therapeutic activities such as anti-oxidant, anti-inflammatory, immunomodulatory, anti-asthmatic, anti-convulsant, anti-mutagenic, antimycobacterial, anti-amoebic, and anti-cancer activities. In this article, we made an attempt to sum up the current knowledge on piperine that supports the chemopreventive potential of this dietary phytochemical. Many mechanisms have been purported to understand the chemopreventive action of piperine. Piperine has been reported to inhibit the proliferation and survival of many types of cancer cells through its influence on activation of apoptotic signaling and inhibition of cell cycle progression. Piperine is known to affect cancer cells in variety of other ways such as influencing the redox homeostasis, inhibiting cancer stem cell (CSC) self-renewal and modulation of ER stress and autophagy. Piperine can modify activity of many enzymes and transcription factors to inhibit invasion, metastasis, and angiogenesis. Piperine is a potent inhibitor of p-glycoprotein (P gp) and has a significant effect on the drug metabolizing enzyme (DME) system. Because of its inhibitory influence on P-gp activity, piperine can reverse multidrug resistance (MDR) in cancer cells and acts as bioavailability enhancer for many chemotherapeutic agents. In this article, we emphasize the potential of piperine as a promising cancer chemopreventive agent and the knowledge we collected in this review can be applied in the strategic design of future researches particularly human intervention trials with piperine. PMID- 29497611 TI - Subcellular Localization and Dynamics of the Bcl-2 Family of Proteins. AB - Bcl-2 family proteins are recognized as major regulators of the mitochondrial pathway of apoptosis. They control the mitochondrial outer membrane permeabilization (MOMP) by directly localizing to this organelle. Further investigations demonstrated that Bcl-2 related proteins are also found in other intracellular compartments such as the endoplasmic reticulum, the Golgi apparatus, the nucleus and the peroxisomes. At the level of these organelles, Bcl 2 family proteins not only regulate MOMP in a remote fashion but also participate in major cellular processes including calcium homeostasis, cell cycle control and cell migration. With the advances of live cell imaging techniques and the generation of fluorescent recombinant proteins, it became clear that the distribution of Bcl-2 proteins inside the cell is a dynamic process which is profoundly affected by changes in the cellular microenvironment. Here, we describe the current knowledge related to the subcellular distribution of the Bcl 2 family of proteins and further emphasize on the emerging concept that this highly dynamic process is critical for cell fate determination. PMID- 29497612 TI - Cardiovascular Imaging Techniques in Systemic Rheumatic Diseases. AB - The risk of cardiovascular (CV) events and mortality is significantly higher in patients with systemic rheumatic diseases than in the general population. Although CV involvement in such patients is highly heterogeneous and may affect various structures of the heart, it can now be diagnosed earlier and promptly treated. Various types of assessments are employed for the evaluation of CV risk such as transthoracic or transesophageal echocardiography, magnetic resonance imaging (MRI), and computed tomography (CT) to investigate valve abnormalities, pericardial disease, and ventricular wall motion defects. The diameter of coronary arteries can be assessed using invasive quantitative coronarography or intravascular ultrasound, and coronary flow reserve can be assessed using non invasive transesophageal or transthoracic ultrasonography (US), MRI, CT, or positron emission tomography (PET) after endothelium-dependent vasodilation. Finally, peripheral circulation can be measured invasively using strain-gauge plethysmography in an arm after the arterial infusion of an endothelium-dependent vasodilator or non-invasively by means of US or MRI measurements of flow-mediated vasodilation of the brachial artery. All of the above are reliable methods of investigating CV involvement, but more recently, introduced use of speckle tracking echocardiography and 3-dimensional US are diagnostically more accurate. PMID- 29497613 TI - ZnJ2 Is a Member of a Large Chaperone Family in the Chloroplast of Photosynthetic Organisms that Features a DnaJ-Like Zn-Finger Domain. AB - Photosynthesis is performed by large complexes, composed of subunits encoded by the nuclear and chloroplast genomes. Assembly is assisted by general and target specific chaperones, but their mode of action is yet unclear. We formerly showed that ZnJ2 is an algal chaperone resembling BSD2 from land plants. In algae, it co migrates with the rbcL transcript on chloroplast polysomes, suggesting it contributes to the de-novo synthesis of RbcL (Doron et al., 2014). ZnJ2 contains four CXXCXGXG motifs, comprising a canonical domain typical also of DnaJ-type I (DNAJA). It contributes to the binding of protein substrates to DnaK and promotes an independent oxidoreductase activity (Mattoo et al., 2014). To examine whether ZnJ2 has oxidoreductase activity, we used the RNaseA assay, which measures the oxidation-dependent reactivation of reduced-denatured RNaseA. Although ZnJ2 assisted the native refolding of reduced-denatured RNaseA, its activity was restricted to an oxidizing environment. Thus, ZnJ2 did not carry the exclusive responsibility for the formation of disulfide bridges, but contributed to the stabilization of its target polypeptides, until they reached their native state. A ZnJ2 cysteine deficient mutant maintained a similar holding chaperone activity as the wild-type and did not induce the formation of disulfide bonds. ZnJ2 is devoid of a J-domain. It thus does not belong to the J-domain co-chaperones that target protein substrates to DnaK. As expected, in vitro, its aggregation prevention activity was not synergic to the ATP-fueled action of DnaK/DnaJ/GrpE in assisting the native refolding of denatured malate dehydrogenase, nor did it show an independent refolding activity. A phylogenetic analysis showed that ZnJ2 and BSD2 from land plants, are two different proteins belonging to a larger group containing a cysteine-rich domain, that also includes the DNAJAs. Members of this family are apparently involved in specific assembly of photosynthetic complexes in the chloroplast. PMID- 29497614 TI - Bias due to Preanalytical Dilution of Rodent Serum for Biochemical Analysis on the Siemens Dimension Xpand Plus. AB - Clinical pathology testing of rodents is often challenging due to insufficient sample volume. One solution in clinical veterinary and exploratory research environments is dilution of samples prior to analysis. However, published information on the impact of preanalytical sample dilution on rodent biochemical data is incomplete. The objective of this study was to evaluate the effects of preanalytical sample dilution on biochemical analysis of mouse and rat serum samples utilizing the Siemens Dimension Xpand Plus. Rats were obtained from end of study research projects. Mice were obtained from sentinel testing programs. For both, whole blood was collected via terminal cardiocentesis into empty tubes and serum was harvested. Biochemical parameters were measured on fresh and thawed frozen samples run straight and at dilution factors 2-10. Dilutions were performed manually, utilizing either ultrapure water or enzyme diluent per manufacturer recommendations. All diluted samples were generated directly from the undiluted sample. Preanalytical dilution caused clinically unacceptable bias in most analytes at dilution factors four and above. Dilution-induced bias in total calcium, creatinine, total bilirubin, and uric acid was considered unacceptable with any degree of dilution, based on the more conservative of two definitions of acceptability. Dilution often caused electrolyte values to fall below assay range precluding evaluation of bias. Dilution-induced bias occurred in most biochemical parameters to varying degrees and may render dilution unacceptable in the exploratory research and clinical veterinary environments. Additionally, differences between results obtained at different dilution factors may confound statistical comparisons in research settings. Comparison of data obtained at a single dilution factor is highly recommended. PMID- 29497615 TI - Prevalence and Risk Factors Associated with Gross Pulmonary Lesions in Slaughtered Pigs in Smallholder and Commercial Farms in Two Provinces in the Philippines. AB - A cross-sectional study of lungs from 1,887 randomly selected pigs from 471 farms from two provinces in the Philippines was carried out to estimate the prevalence of gross pathological lesions, identify potential risk factors and spatial clustering associated with high lung or pleurisy score farms. Lungs from pigs were scored at slaughter. Interviews with the farm managers were conducted to collect information about farm management and biosecurity practices. Of lungs examined, 48% had a lung score above 6 (maximum was 55) and 22% showed pleurisy. When data were aggregated at the farm level, commercial farms were at higher risk of being high lung score farms and high pleurisy farms compared to smallholder farms (P < 0.01). Variables that were associated with an increased risk of a farm being a high lung score farm included the presence of a market pen on the farm, not vaccinating against hog cholera and the presence of another piggery within 500 m. Practicing "feedback" (feeding pig manure, viscera or aborted material to pigs), presence of another piggery within 500 m, and allowing commercial livestock vehicles on farm were all associated with an increased risk of being a high pleurisy farm. Spatial analyses revealed a primary 9.6 km-radius cluster of 39 farms with high lung and pleurisy scores in the southeast of Bulacan province. High lung and pleurisy score farms could be targeted to improve on-farm disease control programs to reduce the risk of respiratory diseases. Clusters of high scoring farms could be prioritized for further investigations or for coordinating intervention efforts. PMID- 29497616 TI - Magnetic Resonance Imaging Signal Alterations in Paraspinal Muscles in Dogs with Acute Thoracolumbar Intervertebral Disk Extrusion. AB - Muscle signal alteration detected on MRI is seen in diverse pathologic conditions. We observed signal alterations within the paraspinal muscles in dogs with acute thoracolumbar intervertebral disk extrusion. The aim of this retrospective study was to describe MRI features of paraspinal muscle signal alteration in dogs with acute thoracolumbar intervertebral disk extrusion and to investigate an association of the signal alterations with neurological grade, type and location of intervertebral disk extrusion, degree of spinal cord compression, and presence of epidural hemorrhage. Medical records of dogs undergoing MRI because of thoracolumbar intervertebral disk extrusion between August 2014 and June 2016 were reviewed. MRI was evaluated for SI changes within the paravertebral musculature, their location, extension, affected muscles, contrast enhancement, and signal void in T2* sequences. Intervertebral disk herniation was categorized as acute non-compressive nucleus pulposus extrusion (ANNPE) or compressive intervertebral disk disease. In five patients, muscle biopsies of areas with signal intensity changes were taken during surgery. In total, 103 dogs were enrolled in the study. Paraspinal muscle signal alterations were visible in 37 dogs (36%) affecting the epaxial musculature (n = 17), hypaxial musculature (n = 12), or both (n = 8). All signal alterations were hyperintense on T2-weighted images and iso- or hypointense in T1-weighted images. Signal void in T2* was not observed in any dog. Postcontrast sequences were available in 30 of the 37 dogs and showed enhancement in 45%. There was neither an association with degree of compression nor epidural hemorrhage. Intervertebral disk extrusion caudal to L1 and a higher neurological grade was associated with the presence of muscle changes. Histopathology revealed mild to moderate acute muscle fiber degeneration with edema and necrosis in three of five samples. The MRI, as well as the muscle samples, show rather unspecific changes. The underlying pathomechanism might be related to ischemia or muscle spasm, but also denervation edema may explain the signal alteration. PMID- 29497617 TI - Factors influencing readthrough therapy for frequent cystic fibrosis premature termination codons. AB - Premature termination codons (PTCs) are generally associated with severe forms of genetic diseases. Readthrough of in-frame PTCs using small molecules is a promising therapeutic approach. Nonetheless, the outcome of preclinical studies has been low and variable. Treatment efficacy depends on: 1) the level of drug induced readthrough, 2) the amount of target transcripts, and 3) the activity of the recoded protein. The aim of the present study was to identify, in the cystic fibrosis transmembrane conductance regulator (CFTR) model, recoded channels from readthrough therapy that may be enhanced using CFTR modulators. First, drug induced readthrough of 15 PTCs was measured using a dual reporter system under basal conditions and in response to gentamicin and negamycin. Secondly, exon skipping associated with these PTCs was evaluated with a minigene system. Finally, incorporated amino acids were identified by mass spectrometry and the function of the predicted recoded CFTR channels corresponding to these 15 PTCs was measured. Nonfunctional channels were subjected to CFTR-directed ivacaftor lumacaftor treatments. The results demonstrated that CFTR modulators increased activity of recoded channels, which could also be confirmed in cells derived from a patient. In conclusion, this work will provide a framework to adapt treatments to the patient's genotype by identifying the most efficient molecule for each PTC and the recoded channels needing co-therapies to rescue channel function. PMID- 29497618 TI - Leaks during multiple-breath washout: characterisation and influence on outcomes. AB - Nitrogen multiple-breath washout (N2MBW) is increasingly used in patients with cystic fibrosis. The current European Respiratory Society/American Thoracic Society consensus statement for MBW recommends the rejection of measurements with leaks. However, it is unclear whether this is necessary for all types of leaks. Here, our aim was to 1) model and 2) apply air leaks, and 3) to assess their influence on the primary MBW outcomes of lung clearance index and functional residual capacity. We investigated the influence of air leaks at various locations (pre-, intra- and post-capillary), sizes, durations and stages of the washout. Modelled leaks were applied to existing N2MBW data from 10 children by modifying breath tables. In addition, leaks were applied to the equipment during N2MBW measurements performed by one healthy adolescent. All modelled and applied leaks resulted in statistically significant but heterogeneous effects on lung clearance index and functional residual capacity. In all types of continuous inspiratory leaks exceeding a certain size, the end of the washout was not reached. For practical application, we illustrated six different "red flags", i.e. signs that enable easy identification of leaks during measurements. Air leaks during measurement significantly influence N2MBW outcomes. The influence of leaks on MBW outcomes is dependent on the location, relation to breath cycle, duration, stage of washout and size of the leak. We identified a range of signs to help distinguish leaks from physiological noise. PMID- 29497619 TI - The validation study on a three-dimensional burn estimation smart-phone application: accurate, free and fast? AB - Background: Accurate total body surface area burned (TBSAB) estimation is a crucial aspect of early burn management. It helps guide resuscitation and is essential in the calculation of fluid requirements. Conventional methods of estimation can often lead to large discrepancies in burn percentage estimation. We aim to compare a new method of TBSAB estimation using a three-dimensional smart-phone application named 3D Burn Resuscitation (3D Burn) against conventional methods of estimation-Rule of Palm, Rule of Nines and the Lund and Browder chart. Methods: Three volunteer subjects were moulaged with simulated burn injuries of 25%, 30% and 35% total body surface area (TBSA), respectively. Various healthcare workers were invited to use both the 3D Burn application as well as the conventional methods stated above to estimate the volunteer subjects' burn percentages. Results: Collective relative estimations across the groups showed that when used, the Rule of Palm, Rule of Nines and the Lund and Browder chart all over-estimated burns area by an average of 10.6%, 19.7%, and 8.3% TBSA, respectively, while the 3D Burn application under-estimated burns by an average of 1.9%. There was a statistically significant difference between the 3D Burn application estimations versus all three other modalities (p < 0.05). Time of using the application was found to be significantly longer than traditional methods of estimation. Conclusions: The 3D Burn application, although slower, allowed more accurate TBSAB measurements when compared to conventional methods. The validation study has shown that the 3D Burn application is useful in improving the accuracy of TBSAB measurement. Further studies are warranted, and there are plans to repeat the above study in a different centre overseas as part of a multi-centre study, with a view of progressing to a prospective study that compares the accuracy of the 3D Burn application against conventional methods on actual burn patients. PMID- 29497621 TI - Management of Elbow Dislocations in the National Football League. AB - Background: Although much literature exists regarding the treatment and management of elbow dislocations in the general population, little information is available regarding management in the athletic population. Furthermore, no literature is available regarding the postinjury treatment and timing of return to play in the contact or professional athlete. Purpose: To review the clinical course of elbow dislocations in professional football players and determine the timing of return to full participation. Study Design: Case series; Level of evidence, 4. Methods: All National Football League (NFL) athletes with elbow dislocations from 2000 through 2011 who returned to play during the season were identified from the NFL Injury Surveillance System (NFL ISS). Roster position, player activity, use of external bracing, and clinical course were reviewed. Mean number of days lost until full return to play was determined for players with elbow dislocations who returned in the same season. Results: From 2000 to 2011, a total of 62 elbow dislocations out of 35,324 injuries were recorded (0.17%); 40 (64.5%) dislocations occurred in defensive players, 12 (19.4%) were in offensive players; and 10 (16.1%) were during special teams play. Over half of the injuries (33/62, 53.2%) were sustained while tackling, and 4 (6.5%) patients required surgery. A total of 47 (75.8%) players who sustained this injury were able to return in the same season. For this group, the mean number of days lost in players treated conservatively (45/47) was 25.1 days (median, 23.0 days; range, 0.0-118 days), while that for players treated operatively (2/47) was 46.5 days (median, 46.5 days; range, 29-64 days). Mean return to play based on player position was 25.8 days for defensive players (n = 28; median, 21.5 days; range, 3.0-118 days), 24.1 days for offensive players (n = 11; median, 19 days; range, 2.0-59 days), and 25.6 days for special teams players (n = 8; median, 25.5 days; range, 0-44 days). Conclusion: Elbow dislocations comprise less than a half of a percent of all injuries sustained in the NFL. Most injuries occur during the act of tackling, with the majority of injured athletes playing a defensive position. Players treated nonoperatively missed a mean of 25.1 days, whereas those managed operatively missed a mean of 46.5 days. PMID- 29497620 TI - Anterior Cruciate Ligament Reconstruction in Skeletally Immature Patients: Early Results Using a Hybrid Physeal-Sparing Technique. AB - Background: Reconstruction of the anterior cruciate ligament (ACL) in the skeletally immature patient is frequently performed in hopes of preventing new or additional chondral damage and meniscal injuries. Patients within a few years of skeletal maturity are more at risk for ACL injuries than prepubescent patients, about whom several physeal-sparing techniques have been described. Reconstruction techniques in the former higher risk group need to be better understood. Purpose: To review a series of adolescent patients with ACL injuries surgically treated with the hybrid physeal-sparing technique. Study Design: Case series; Level of evidence, 4. Methods: Surgical logs of ACL reconstructions (ACLRs) performed at a single pediatric/adolescent sports medicine center over a 6-year period were reviewed. Patients with open physes who had undergone ACLR with a femoral physeal sparing tunnel and transphyseal tibial tunnel were identified. Their demographics, operative reports, rehabilitative course, time to return to play, outcome scores, and postoperative radiographs were collected and analyzed. Results: Twenty-three patients with a mean chronological age and bone age of 13.0 and 13.6 years, respectively, were identified. Examination and subjective outcome scores were obtained at a mean of 19 months and overall demonstrated positive results, with a mean Pediatric International Knee Documentation Committee (Pedi IKDC) score of 96.0 and a mean Anterior Cruciate Ligament-Return to Sport after Injury (ACL-RSI) score of 89.1. Full-length mechanical axis films obtained at a mean 21 months postoperatively demonstrated no leg-length discrepancies or angular deformities in 21 of 23 patients. Two patients had an identified growth disturbance in the form of femoral and tibial growth acceleration on the ACL reconstructed limb. Conclusion: The femoral physeal-sparing with transphyseal tibial drilling "hybrid" technique in skeletally maturing patients appears to have a high rate of success with low morbidity. However, the possibility of physeal abnormalities does exist, which demonstrates the importance of a close postoperative follow-up and evaluation until skeletal maturity is achieved. ACLR in skeletally immature patients is performed on an increasingly regular basis. Establishing the best and safest technique to do so is therefore important. PMID- 29497622 TI - Back to Sports After Arthroscopic Revision Bankart Repair. AB - Background: Recurrent instability following primary arthroscopic stabilization of the shoulder is a common complication. Young, athletic patients are at the greatest risk of recurring instability. To date, the literature contains insufficient description regarding whether return to sports is possible after revision arthroscopic Bankart repair. Hypothesis: Patients presenting with recurrent instability after primary arthroscopic stabilization should expect limitations in terms of their ability to partake in sporting activities after revision surgery. Study Design: Case series; Level of evidence, 4. Methods: Twenty athletes who underwent arthroscopic revision stabilization of the shoulder after failed primary arthroscopic Bankart repair were included in the study after completing inclusion and exclusion criteria surveys. Athletic Shoulder Outcome Scoring System (ASOSS), Shoulder Sport Activity Score (SSAS), and the Subjective Patient Outcome for Return to Sports (SPORTS) scores were determined to assess the participants' ability to partake in sporting activities. Furthermore, sport type and sport level were classified and recorded. To assess function and stability, Rowe, American Shoulder and Elbow Surgeons, Constant-Murley, and Walch Duplay scores were measured and recorded. Results: Follow-up consultations were carried out after a mean of 28.7 months. The mean age at follow-up examination was 27.75 years. At the time of follow-up, 70% of the patients were able to return to their original sporting activities at the same level. However, 90% of patients described a limitation in their shoulder when participating in their sports. At 28.7 months after surgery, the mean ASOSS score was 76.8; the SSAS score decreased from 7.85 before first-time dislocation to 5.35 at follow-up (P < .005). The SPORTS score was 5.2 out of 10 at the follow-up consultation. Function and instability-specific scores showed good to excellent results. The mean external rotational deficit for high external rotation was 9.25 degrees , and for low external rotation it was 12 degrees . Conclusion: Patients can return to their original type and level of sport after arthroscopic revision Bankart repair, but they must expect persistent deficits and limitations to the shoulder when put under the strains of sporting activity. Patients with shoulder injuries who partake in sports that put greater demand on the shoulder show the smallest probabilities of returning to sporting activity. PMID- 29497623 TI - Significantly Increased Odds of Reporting Previous Shoulder Injuries in Female Marines Based on Larger Magnitude Shoulder Rotator Bilateral Strength Differences. AB - Background: Musculoskeletal injuries to the extremities are a primary concern for the United States (US) military. One possible injury risk factor in this population is side-to-side strength imbalance. Purpose: To examine the odds of reporting a previous shoulder injury in US Marine Corps Ground Combat Element Integrated Task Force volunteers based on side-to-side strength differences in isokinetic shoulder strength. Study Design: Cohort study; Level of evidence, 3. Methods: Male (n = 219) and female (n = 91) Marines were included in this analysis. Peak torque values from 5 shoulder internal/external rotation repetitions were averaged and normalized to body weight. The difference in side to-side strength measurements was calculated as the absolute value of the limb difference divided by the mean peak torque of the dominant limb. Participants were placed into groups based on the magnitude of these differences: <10%, 10% to 20%, and >20%. Odds ratios (ORs) and 95% CIs were calculated. Results: When separated by sex, 13.2% of men reported an injury, while 5.5% of women reported an injury. Female Marines with >20% internal rotation side-to-side strength differences demonstrated increased odds of reporting a previous shoulder injury compared with female Marines with <10% strength differences (OR, 15.4; 95% CI, 1.4-167.2; P = .03 ) and female Marines with 10% to 20% strength differences (OR, 13.9; 95% CI, 1.3-151.2; P = .04). No significant ORs were demonstrated in male Marines. Conclusion: Marines with larger magnitude internal rotation strength differences demonstrated increased odds of reporting a previous shoulder injury compared with those with lesser magnitude differences. Additionally, female sex appears to drastically affect the increased odds of reporting shoulder injuries (OR, 13.9-15.4) with larger magnitude differences (ie, >20%) compared with those with lesser magnitude differences (ie, <10% and 10%-20%). The retrospective cohort design of this study cannot delineate cause and effect but establishes a relationship between female Marines and greater odds of larger magnitude strength differences after returning from an injury. PMID- 29497625 TI - Immunogenicity and Safety of a 13-Valent Pneumococcal Conjugate Vaccine Coadministered with a Quadrivalent Influenza Vaccine in Adults 50 Years and Older Previously Vaccinated With 23-Valent Pneumococcal Polysaccharide Vaccine. PMID- 29497624 TI - Scleral surgery for the treatment of presbyopia: where are we today? AB - Presbyopia corrections traditionally have been approached with attempts to exchange power, either at the cornea or the lens planes, inducing multifocality, or altering asphericity to impact the optical system. Treatments that affect the visual axis, such as spectacle and contact lens correction, refractive surgeries, corneal onlays and inlays, and intraocular lenses are typically unable to restore true accommodation to the presbyopic eye. Their aim is instead to enhance 'pseudoaccommodation' by facilitating an extended depth-of-focus for which vision is sufficient. There is a true lack of technology that approaches presbyopia from a treatment based or therapy based solution, rather than a 'vision correction' solution that compromises other components of the optical system. Scleral surgical procedures seek to restore true accommodation combined with pseudoaccommodation and have several advantages over other more invasive options to treat presbyopia. While the theoretical justification of scleral surgical procedures remains controversial, there has nevertheless been increasing interest and evidence to support scleral surgical and therapeutic approaches to treat presbyopia. Enormous progress in scleral surgery techniques and understanding of the mechanisms of action have been achieved since the 1970s, and this remains an active area of research. In this article, we discuss the historic scleral surgical procedures, the two scleral procedures currently available, as well as an outlook of the future for the scleral surgical space for treating presbyopia. PMID- 29497626 TI - Association Between Cytomegalovirus Reactivation and Clinical Outcomes in Immunocompetent Critically Ill Patients: A Systematic Review and Meta-Analysis. AB - Background: The aim of our systematic review was to investigate the association between cytomegalovirus (CMV) reactivation and outcomes in immunocompetent critically ill patients. Methods: We searched electronic databases and gray literature for original studies and abstracts published between 1990 and October 2016. The review was limited to studies including critically ill immunocompetent patients. Cytomegalovirus reactivation was defined as positive polymerase chain reaction, pp65 antigenemia, or viral culture from blood or bronchoalveolar lavage. Selected patient-centered outcomes included mortality, duration of mechanical ventilation, need for renal replacement therapy (RRT), and nosocomial infections. Health resource utilization outcomes included intensive care unit and hospital lengths of stay. Results: Twenty-two studies were included. In our primary analysis, CMV reactivation was associated with increased ICU mortality (odds ratio [OR], 2.55; 95% confidence interval [CI], 1.87-3.47), overall mortality (OR, 2.02; 95% CI, 1.60-2.56), duration of mechanical ventilation (mean difference 6.60 days; 95% CI, 3.09-10.12), nosocomial infections (OR, 3.20; 95% CI, 2.05-4.98), need for RRT (OR, 2.37; 95% CI, 1.31-4.31), and ICU length of stay (mean difference 8.18 days; 95% CI, 6.14-10.22). In addition, numerous sensitivity analyses were performed. Conclusions: In this meta-analysis, CMV reactivation was associated with worse clinical outcomes and greater health resource utilization in critically ill patients. However, it remains unclear whether CMV reactivation plays a causal role or if it is a surrogate for more severe illness. PMID- 29497628 TI - Improving Management of Hospitalized Adults With Uncomplicated Cellulitis or Cutaneous Abscess. AB - Implementation of a guideline for the management of hospitalized adults with uncomplicated skin and soft-tissue infections may decrease unnecessary antibiotic use. For cellulitis, treatment with vancomycin and broad-spectrum antibiotics decreased significantly. For cutaneous abscess, treatment with broad-spectrum antibiotics decreased significantly. There were no differences in rates of treatment failure, recurrence, or adverse events. PMID- 29497627 TI - Treatment Outcomes Among Older Human Immunodeficiency Virus-Infected Adults in Nigeria. AB - Background: Older age at initiation of combination antiretroviral therapy (cART) has been associated with poorer clinical outcomes. Our objectives were to compare outcomes between older and younger patients in our clinical cohort in Jos, Nigeria. Methods: This retrospective cohort study evaluated patients enrolled on cART at the Jos University Teaching Hospital, Nigeria between 2004 and 2012. We compared baseline and treatment differences between older (>=50 years) and younger (15-49 years) patients. Kaplan-Meier analysis and Cox proportional hazard models estimated survival and loss to follow-up (LTFU) and determined factors associated with these outcomes at 24 months. Results: Of 8352 patients, 643 (7.7%) were aged >=50 years. The median change in CD4 count from baseline was 151 vs 132 (P = .0005) at 12 months and 185 vs 151 cells/mm3 (P = .03) at 24 months for younger and older patients, respectively. A total of 68.9% vs 71.6% (P = .13) and 69.6% vs 74.8% (P = .005) of younger and older patients achieved viral suppression at 12 and 24 months, with similar incidence of mortality and LTFU. In adjusted hazard models, factors associated with increased risk of mortality were male sex, World Health Organization (WHO) stage III/IV, and having a gap in care, whereas being fully suppressed was protective. The risk of being LTFU was lower for older patients, those fully suppressed virologically and with adherence rates >95%. Male sex, lack of education, WHO stage III/IV, body mass index <18.5 kg/m2, and having a gap in care independently predicted LTFU. Conclusions: Older patients achieved better viral suppression, and older age was not associated with increased mortality or LTFU in this study. PMID- 29497629 TI - Seasonal Influenza Forecasting in Real Time Using the Incidence Decay With Exponential Adjustment Model. AB - Background: Seasonal influenza epidemics occur frequently. Rapid characterization of seasonal dynamics and forecasting of epidemic peaks and final sizes could help support real-time decision-making related to vaccination and other control measures. Real-time forecasting remains challenging. Methods: We used the previously described "incidence decay with exponential adjustment" (IDEA) model, a 2-parameter phenomenological model, to evaluate the characteristics of the 2015 2016 influenza season in 4 Canadian jurisdictions: the Provinces of Alberta, Nova Scotia and Ontario, and the City of Ottawa. Model fits were updated weekly with receipt of incident virologically confirmed case counts. Best-fit models were used to project seasonal influenza peaks and epidemic final sizes. Results: The 2015-2016 influenza season was mild and late-peaking. Parameter estimates generated through fitting were consistent in the 2 largest jurisdictions (Ontario and Alberta) and with pooled data including Nova Scotia counts (R0 approximately 1.4 for all fits). Lower R0 estimates were generated in Nova Scotia and Ottawa. Final size projections that made use of complete time series were accurate to within 6% of true final sizes, but final size was using pre-peak data. Projections of epidemic peaks stabilized before the true epidemic peak, but these were persistently early (~2 weeks) relative to the true peak. Conclusions: A simple, 2-parameter influenza model provided reasonably accurate real-time projections of influenza seasonal dynamics in an atypically late, mild influenza season. Challenges are similar to those seen with more complex forecasting methodologies. Future work includes identification of seasonal characteristics associated with variability in model performance. PMID- 29497630 TI - A NATURAL BODY WINDOW TO STUDY HUMAN PANCREATIC ISLET CELL FUNCTION AND SURVIVAL. AB - The World Health Organization projects diabetes prevalence worldwide to be at 4.4% in 2030 compared to 2.8% in the year 2000. These alarming predictions come amid vigorous efforts in diabetes research which have failed so far to deliver effective therapies. Our incomplete understanding of the pathogenesis of diabetes is likely to contribute to the "disconnect" between our research efforts and their translation into successful therapies. Technically, studying the pathophysiology of the pancreatic islets is hindered by the anatomical location of the pancreas, which is deeply embedded in the body, and by lack of experimental tools that enable comprehensive interrogation of the pancreatic islets with sufficient resolution in the context of the natural in vivo environment non-invasively and longitudinally. Emerging evidence also indicates that challenges in successful translation of findings in animal models to the human setting are complicated by some inherent structural and functional differences between the mouse and human islets. In this review, we briefly describe the advantages and shortcomings of existing intravital imaging approaches used to study the pancreatic islet biology in vivo, and we contrast such techniques with a recently established intravital approach using pancreatic islet transplantation into the anterior chamber of the eye. We also provide a summary of recent structure-function studies in the human pancreas to reveal distinctive features of human islets compared with mouse islets. We finally touch on a recently renewed discussion of the validity of animal models in studying human health and disease, and we highlight the potential utility of "humanized" animal models in studying different aspects of human islet biology and improving our understanding of diabetes. PMID- 29497632 TI - Inflammation and genetic factors in stroke pathogenesis. PMID- 29497631 TI - Clinical intraocular islet transplantation is not a number issue. AB - It is now well established that beta cell replacement through pancreatic islet transplantation results in significant improvement in the quality-of-life of type 1 diabetes (T1D) patients. This is achieved through improved control and prevention of severe drops in blood sugar levels. Islet transplant therapy is on the verge of becoming standard-of-care in the USA. Yet, as with other established transplantation therapies, there remain hurdles to overcome to bring islet transplantation to full fruition as a long-lasting therapy of T1D. One of these hurdles is establishing reliable new sites, other than the liver, where durable efficacy and survival of transplanted islets can be achieved. In this article, we discuss the anterior chamber of the eye as a new site for clinical islet transplantation in the treatment of T1D. We specifically focus on the common conceptions, and preconceptions, on the requirements of islet mass, and whether or not the anterior chamber can accommodate sufficient islets to achieve meaningful efficacy and significant impact on hyperglycemia in clinical application. PMID- 29497633 TI - Successful resuscitation of amniotic fluid embolism applying a new classification and management strategy. AB - Amniotic fluid embolism (AFE) is a rare but life-threatening maternal emergency caused by the entry of amniotic fluid contents into the maternal circulation. The clinical manifestations of AFE are heterogeneous, leading to misdiagnosis or treatment delay. Kanayama and colleagues distinguished the cardiopulmonary collapse type (or classic type) from the disseminated intravascular coagulation (DIC) type of AFE on the basis of the presence of uterine atony and DIC in the latter prior to cardiopulmonary failure. We report a case of DIC-type AFE successfully treated by blood volume replacement and coagulation therapy. The patient was scheduled for elective cesarean delivery because of a previous cesarean section and moyamoya disease. Delivery was uneventful, but massive vaginal bleeding without clotting and ensuing hypovolemic shock occurred 4 h later. She was transferred to the operating room for emergency laparotomy, but sustained a cardiac arrest. The patient was successfully resuscitated and a hysterectomy performed. During surgery, the patient received fresh frozen plasma, platelets, fibrinogen, and antithrombin concentrate. In cardiopulmonary collapse type AFE, cardiopulmonary resuscitation without delay is important. In the present case of DIC-type AFE, however, early supplementation of clotting factors and platelets was critical for patient survival. PMID- 29497634 TI - Persistent left superior vena cava with absent right superior vena cava detected during emergent coronary artery bypass grafting surgery. AB - Although persistent left superior vena cava (PLSVC) itself is a common venous anomaly in congenital heart disease, PLSVC with absent right superior vena cava (RSVC) is a rare venous congenital malformation. Due to the lack of symptoms, this malformation is often detected fortuitously when patients undergo central venous catheter placement, pacemaker implantation, or open cardiac surgery. This particular venous malformation is rare, but clinicians in many fields should be well aware of its variations and management techniques to avoid complications. Anesthesiologists should know that patients with PLSVC rarely have absent RSVC. TEE was helpful in the diagnosis of PLSVC with absent RSVC during emergent surgery. PMID- 29497635 TI - Intrathecal morphine versus epidural ropivacaine infusion for analgesia after Cesarean section: a retrospective study. AB - Background: Analgesia after Cesarean delivery (CD) requires early ambulation to prevent thromboembolic disease and to facilitate baby care. We retrospectively reviewed anesthesia charts and medical records of patients who underwent CD to compare the efficacy of spinal anesthesia supplemented with intrathecal morphine hydrochloride (ITM) and combined spinal-epidural anesthesia followed by opioid free epidural analgesia (CSEA-EDA). Findings: All subjects underwent CD at Nagaoka Chuo General Hospital between February 2012 and January 2013. Patient characteristics, time to first analgesic rescue after CD, and analgesic use after CD were examined. Incidences of postural hypotension, lower extremity numbness/weakness, postoperative nausea/vomiting (PONV), and pruritus were also examined for 48 h after CD. Average time to first analgesic use after CD (ITM 25.13 +/- 16.07 h, CSEA-EDA 22.42 +/- 16.27 h, p = 0.521) and cumulative probability of rescue analgesic use (p = 0.139 by log-rank test) were comparable between groups. However, average analgesic use within 24 h was lower in the ITM group (0.75 +/- 1.05 times) than in the CSEA-EDA group (1.52 +/- 1.72 times, p = 0.0497). Numbness or motor weakness in lower extremities only occurred in the CSEA-EDA group, and pruritus only occurred in the ITM group. Conclusions: The results of this study suggest that ITM is better than CSEA-EDA for anesthesia following CD with regard to pain control. Also, ITM would be advantageous for early ambulation following CD because of lower incidence of numbness and motor weakness in lower extremities compared to CSEA-EDA. PMID- 29497636 TI - Acute transverse myelitis arising after combined general and thoracic epidural anesthesia. AB - Acute transverse myelitis after surgery is a rare condition, but this complication is devastating. The relationship between anesthetic procedures and acute transverse myelitis is controversial. A 46-year-old woman was scheduled a colostomy closure, and general anesthesia with thoracic epidural anesthesia was performed. Epidural catheter was inserted at the T10-11 interspace, and insertion was smooth, and no blood or cerebrospinal fluid leakage was seen. However, 28 h after the surgery, the patient complained motor, sensory, and autonomic dysfunction. Two days after onset, a magnetic resonance imaging study demonstrated intramedullary hyperintensity, particularly in the gray matter, extending from T5-T9 and then diagnosed with acute transverse myelitis followed by the several examinations. High-dose IV methylprednisolone treatment was initiated and neurologic function restored 2 months after onset. Transverse myelitis may unpredictably occur following surgery. We are not able to determine the pathogenic relationship between anesthesia and myelitis with certainty, but proper diagnostic approach to myelitis may improve the prognosis. PMID- 29497637 TI - Optical surgical navigation system causes pulse oximeter malfunction. AB - An optical surgical navigation system is used as a navigator to facilitate surgical approaches, and pulse oximeters provide valuable information for anesthetic management. However, saw-tooth waves on the monitor of a pulse oximeter and the inability of the pulse oximeter to accurately record the saturation of a percutaneous artery were observed when a surgeon started an optical navigation system. The current case is thought to be the first report of this navigation system interfering with pulse oximetry. The causes of pulse jamming and how to manage an optical navigation system are discussed. PMID- 29497638 TI - Petechial and subcutaneous hemorrhage with blister formations in right upper extremity during cardiopulmonary bypass by axillary artery cannulation. AB - A 72-year-old man underwent aortic valve replacement and coronary artery bypass graft using cardiopulmonary bypass with right axillary artery cannulation. After undraping, petechial and subcutaneous hemorrhage with blister formations were found in right upper extremity. Axillary artery cannula was considered to compress right subclavian and disturb venous return in the right subclavian vein, which caused an acute compartment syndrome during cardiopulmary bypass. This case was a rare,but severe complication of cardiopulmonary bypass with right axillary artery cannulation. PMID- 29497639 TI - Comparison between succinylcholine and rocuronium as neuromuscular blocking agents for electroconvulsive therapy in a patient with pseudocholinesterase deficiency. AB - We report here the anesthetic management of a patient with schizophrenia and pseudocholinesterase deficiency. Electroconvulsive therapy was performed using succinylcholine and rocuronium as the neuromuscular blocking agents in the first seven and latter six treatments, respectively. The recovery time from muscle relaxation after succinylcholine administration was remarkably longer than that after rocuronium-sugammadex administration. Rocuronium and sugammadex appear to be useful in situations in which succinylcholine is contraindicated. PMID- 29497640 TI - Journal of Anesthesia (JA) clinical reports. PMID- 29497641 TI - Successful use of recombinant activated factor VII (eptacog alfa, Novoseven(r)) in a refractory bleeding during pediatric cardiac surgery: a case report. AB - A 2-year-and-7-month-old boy underwent an emergent reconstruction surgery of the right ventricle-pulmonary artery (RV-PA) conduit. Although he was successfully weaned from cardiopulmonary bypass (CPB) after reconstruction of the RV-PA conduit, the bleeding continued despite the massive transfusion of red blood cell (RBC), fresh frozen plasma (FFP), and platelets. Because of persistent bleeding and abnormal coagulation laboratory results, we administered the recombinant activated factor VII (rFVIIa), which was not approved for use in the treatment of post-CPB coagulopathy. After administration of rFVIIa, his coagulation data dramatically improved, the bleeding decreased, and the operation was able to be finished. PMID- 29497642 TI - Anesthetic management for abdominal aortic surgery in a patient with a left ventricular assist device: a case report. AB - Left ventricular assist devices (LVAD) are a currently established destination and bridge therapy until cardiac transplantation; hence, this patient population continues to increase. Here, we present the first report of abdominal aortic cross-clamping (ACC) in a LVAD patient undergoing emergency aneurysm repair. Anticoagulation was continued pre-and intra-operatively to avoid pump thrombosis. The pumping function of the LVAD is highly dependent on both preload and afterload. In this case, abdominal ACC, which increases the afterload, did not significantly influence circulatory dynamics. However, when the abdominal ACC was released, mean atrial pressure (MAP) fell to 42 mmHg, because preload reduction due to massive bleeding (3532 g) secondary to anticoagulation and afterload reduction by abdominal ACC release combined to cause critical hypotension. Maintenance of MAP required rapid infusion and use of an alpha-adrenergic agent. Surgical and anesthesia times were 411 and 525 min, respectively. Total blood loss was 5389 g, respectively. The patient was discharged after 25 postoperative days with no major complications. ACC release, with its accompanying decrease in preload and afterload, and massive bleeding due to anticoagulation in these patients require careful management. PMID- 29497643 TI - Airway management for patients with ossification of the anterior longitudinal ligament of the cervical spine. AB - Ossification of the anterior longitudinal ligament (OALL), also called Forestier's disease or diffuse idiopathic skeletal hyperostosis, is characterized by anterior bridging osteophytes of unknown etiology. OALL may cause dysphagia, dyspnea, dysphonia, and acute airway obstruction. We report difficulty in tracheal intubation during anesthesia induction in two OALL patients. In an 82 year-old man, anterior bridging osteophytes (of the cervical region) were observed on preoperative lateral radiograph after several attempts of tracheal intubation for the operation of the anterior fusion of cervical spine. During the same procedure in another 69-year-old man, fiberoptic-assisted awake intubation was extremely difficult because of posterior hypopharyngeal wall protuberance by osteophytes of cervical spine; although tracheal intubation for anesthesia was uneventful on two previous occasions over the months. OALL is usually asymptomatic, but it has been found in 12 % of autopsies and may exaggerate with age. Dysphagia, difficulties with tracheal and/or gastric intubation, acute respiratory compromise, and sleep apnea result from the presence of cervical osteophytes. Anesthesiologists should be aware that tracheal intubation for such patients may be difficult, and thus the preoperative evaluation and airway management need careful consideration. PMID- 29497645 TI - Hypercapnic respiratory distress and loss of consciousness: a complication of supraclavicular brachial plexus block. AB - Supraclavicular brachial plexus block is a common anesthetic technique performed for surgery of the upper extremities. We experienced a case of acute hypercapnic respiratory distress with loss of consciousness during creation of an arteriovenous fistula under ultrasound-guided supraclavicular brachial plexus block using 30 mL of 0.75 % ropivacaine. We detected ipsilateral hemidiaphragmatic paralysis by means of M-mode ultrasonography of the block. We thus speculate that phrenic nerve palsy caused by supraclavicular brachial plexus block was the underlying mechanism of the event. Bedside ultrasonography played a pivotal role in making a differential diagnosis and in managing this patient. PMID- 29497644 TI - Accelerated idioventricular rhythm observed under total intravenous anesthesia using remifentanil, propofol, and rocuronium. AB - Accelerated idioventricular rhythm (AIVR) during anesthesia has been described in several drug toxicity such as from cocaine, halothane, desflurane, and propofol. We present the case of a man who developed episodes of AIVR observed under total intravenous anesthesia (TIVA) using remifentanil, propofol, and rocuronium. AIVR during anesthesia was a benign phenomenon, and further examinations after surgery showed no structural heart disease and the daily occurrence of idioventricular arrhythmias. This case suggests that the suppression of sinus and atrioventricular nodal function and the autonomic imbalance caused by propofol and remifentanil may induce AIVR with greater frequency. PMID- 29497646 TI - Management of general anesthesia in a child with Miller-Dieker syndrome: a case report. AB - Miller-Dieker syndrome (MDS) is a rare disorder characterized by type I lissencephaly and a distinctive facial appearance that may include prominent forehead, bitemporal hollowing, and micrognathia. MDS is associated with epilepsy. We here report an 18-month-old girl with MDS who required general anesthesia. The child had an extremely low Bispectral Index (BIS) value prior to undergoing general anesthesia. Her perioperative course was uneventful. This case highlights some of the important anesthetic concerns in patients with MDS, which include potentially difficult airways and extremely low BIS values. PMID- 29497647 TI - Pectoral nerve block combined with general anesthesia for breast cancer surgery: a retrospective comparison. AB - Background: Acute postoperative pain is an integral risk factor in the development of chronic pain after breast cancer surgery (BCS). Pectoral nerve block (PECSB) has been recently reported as an analgesic method for BCS. Here, we retrospectively compared intraoperative opioid requirement, postoperative pain after BCS, and incidence of postoperative nausea and vomiting (PONV) in patients who underwent BCS under total intravenous anesthesia (TIVA) with or without PECSB. Findings: We reviewed anesthesia charts and medical records of 146 patients who underwent BCS at Niigata University Medical and Dental Hospital from January 2013 to March 2014; 36 patients were included in the TIVA group, and 35 patients were included in the TIVA + PECSB group. Intraoperative remifentanil requirements were significantly lower in the TIVA + PECSB group than in the TIVA group, and the cumulative distribution of remifentanil was reduced in patients who received PECSB (TIVA: 10.9 +/- 2.9 MUg/kg/h; TIVA + PECSB: 7.3 +/- 3.3 MUg/kg/h; p < 0.001). Postoperative pain scores during the 48 h after surgery were significantly lower in the TIVA + PECSB group than in the TIVA group (TIVA: 2 [1-5]; TIVA + PECSB: 1 [0-5]; p = 0.03). However, administration of fentanyl during operation, percentage of patients requiring supplemental analgesics, and incidence of PONV were not significantly different between groups. Conclusions: PECSB significantly reduced intraoperative remifentanil usage and postoperative pain. However, the requirement for postoperative supplemental analgesics and the incidence of PONV did not differ. These data suggested that PECSB may be useful for perioperative pain management in patients undergoing BCS. PMID- 29497648 TI - Elective use of surgical cricothyroidotomy for maxillofacial fracture fixation with contraindication of nasotracheal intubation: a case report. AB - We report three cases of airway management with elective surgical cricothyroidotomy (SCT) for anesthetic management during surgical repair of maxillofacial injury involving basal skull fracture or nasal-bone fracture. In all patients, general anesthesia was induced, a supraglottic airway (SGA) device inserted, and SCT performed. Tracheal intubation was performed through SCT site, and the SGA device was removed. After surgery of maxillofacial fixation, the SGA device was re-inserted and the tracheal tube was removed. No major complications, such as subglottic stenosis or voice change, occurred. SCT holds potential as an alternative to tracheostomy because of ease of performance, fewer complications, and better cosmetic outcomes. PMID- 29497649 TI - Life-threatening check valve formation due to tracheobronchial aspergillosis. AB - A 12-year-old girl receiving chemotherapy for acute myeloid leukemia had a fever of unknown origin in spite of administration of micafungin. Her respiratory condition suddenly deteriorated. Her trachea was intubated, and positive pressure ventilation was initiated; however, her respiratory condition further deteriorated. Expiratory volume was considerably lower than inspiratory volume. Simultaneously, she developed severe hypotension and bradycardia, and tension pneumothorax was suspected. Emergent chest decompression was subsequently performed; however, her airway resistance was still high. Bronchoscopy was performed to remove a foreign body in the carina. Subsequently, her respiratory status improved. Histopathological examination revealed that the foreign body was a fibrinous blood clot mixed with fungal hyphae of Aspergillus niger. Life threatening check valve formation due to tracheobronchial aspergillosis under positive-pressure ventilation may be rare; however, once it occurs, prompt establishment of an escape route for trapped air, such as thoracentesis, may be required. PMID- 29497650 TI - The management of difficult intubation in infants: a retrospective review of anesthesia record database. AB - We retrospectively reviewed the anesthesia records of infants < 1 year of age for elucidating the incidence of difficult intubation and airway management in a single general hospital. The electronic data records from a total of 753 consecutive anesthesiological procedures in 513 different infants were analyzed. After excluding data with a lack of records of laryngoscopic findings, a total of 497 procedures (389 different infants) with either remarks of difficult intubation (requiring > 10 min for tracheal intubation) or records of Cormack Lehane grade were included. Demographic data are median age 5 (range, 0-11) months, height 61 (33-84) cm, body weight 6.0 (1.1 - 11.8) kg. The number of cases with ASA physical status I, II, III and IV was 182 (36.6 %), 135 (27.3 %), 177 (35.5 %) and 3 (0.6 %), respectively. Cormack-Lehane grade 1, 2, 3 and 4 was seen in 450 (90.5 %), 32 (6.4 %), 6 (1.2 %) and 6 (1.2 %) cases, respectively. Document of difficult intubation was found in 12 cases (2.4 %, 10 different infants) with a lack of record of Cormack-Lehane grade in 3 cases. Of these 10 infants, nine had multiple congenital anomalies including heart diseases and cleft palate. Without premedication, general anesthesia was induced with intravenous midazolam or sevoflurane in the 12 cases. Tracheal intubation was performed after disappearance of spontaneous respiration except three cases who were intubated in the awake state or under sedation. Elapsed time from induction of anesthesia to intubation was 17 (14-29) min. Although mask ventilation was adequate in all cases, two cases (one infant) developed hypoxia and bradycardia during tracheal intubation. No remarkable decrease of SpO2 or bradycardia less than 100 bpm was detected in other cases. In conclusion, we found difficult intubation in 2.4 % of infants undergoing general anesthesia. Although muscle relaxants are useful for facilitating tracheal intubation, it should be carefully used with the preparation of other airway devices in infants with predicted difficult intubation. PMID- 29497651 TI - Thoracic paravertebral block reduced the incidence of chronic postoperative pain for more than 1 year after breast cancer surgery. AB - Background: Thoracic paravertebral block (TPVB) is used to reduce pain after breast cancer surgery (BCS), but the pain-reduction effects more than 1 year after surgery are unclear. Findings: Fifty-one patients underwent BCS at the Niigata City General Hospital from December 2009 through March 2010. To evaluate the long-term effects of TPVB in the reduction of chronic pain after BCS, we retrospectively reviewed the anesthesia charts and medical records of these patients and conducted telephone surveys regarding postoperative pain 13-17 months after surgery in 46 of these patients. Among the 46 patients enrolled in this study, 17 experienced chronic pain. There was a significant difference in the percentage of patients that received TPVB among those with and without chronic pain (patients with chronic pain 5/17 (29.4 %), patients without chronic pain 18/29 (62.1 %), p = 0.039). The pain score 3-6 h after surgery was significantly higher in the patients with chronic pain than without (p = 0.016). Bivariate logistic regression revealed that TPVB and pain score 3-6 h after surgery were independent predictive factors of chronic pain after BCS. Conclusions: These results indicate that TPVB has the potential to reduce chronic pain for more than 1 year after BCS. PMID- 29497652 TI - A case requiring tracheal stenting due to superior vena cava syndrome developing after craniotomy. AB - We report a patient who developed sustained hypotension during craniotomy; further, owing to a mediastinal mass, critical tracheal stenosis and brain edema were observed after craniotomy, despite the absence of preoperative symptomatic superior vena cava (SVC) syndrome. A 62-year-old man underwent removal of a suspected metastatic brain tumor. The main brain tumor was speculated to be a metastatic tumor from lung cancer. A subsequent chest CT revealed a large solid tumor in the mediastinum. The maximum reduction in the cross-sectional area of the trachea was estimated to be 50 %. In addition, bilateral innominate veins were completely obstructed, and the superior vena cava was involved in the mass and was completely compressed. The patient did not show any cardiopulmonary symptoms or upper body edema. Intravenous lines were secured at the right extremity. General anesthesia was induced without any complications and was maintained with sevoflurane, remifentanil, and rocuronium. During the surgery, hemodynamic status fluctuated and was unstable. To maintain systolic blood pressure, continuous, massive infusion of noradrenaline was required. After the surgery, the patient was turned to the supine position. Massive facial edema was apparent. In addition, the bilateral upper extremities were significantly swollen. Despite the removal of the main lesion, brain edema was still observed on head CT. Chest CT revealed that the maximum reduction in the cross-sectional area of the trachea was estimated to be >90 %, which necessitated mechanical ventilation with tracheal intubation. On the day following craniotomy, tracheal stenting was performed uneventfully. The patient's trachea was finally extubated, and his respiratory condition did not deteriorate. Although he did not develop SVC syndrome, the patient died from asphyxiation after coughing up blood at home 5 months after the procedure. It was suggested that fluid infusion from the upper extremities owing to the mediastinal tumor caused critical SVC syndrome. PMID- 29497654 TI - A case of myocardial infarction caused by obstruction of a drug-eluting stent during the perioperative period. AB - We report a patient who developed drug-eluting stent (DES) thrombosis induced by discontinuation of dual antiplatelet therapy (DAPT) and subsequently had a massive surgical site bleed caused by restarting heparin and DAPT during the perioperative period. An 85-year-old man visited a local hospital owing to complaints dyspnea. He was diagnosed with laryngeal cancer and was scheduled for a total laryngectomy. Preoperative examinations showed an anteroseptal myocardial infarction. A DES was placed at segment 6 of the coronary artery and DAPT was initiated 27 days before surgery. After admission to our hospital, DAPT was replaced with unfractionated heparin. On the operation day, heparin was discontinued, and a tracheotomy, total laryngectomy and right hemi-thyroidectomy were performed. While recovering from anesthesia, ischemic ST elevation appeared. Cardiac catheterization revealed complete obstruction of the DES by a white thrombus. After recanalization, heparin and DAPT were restarted, and bleeding occurred. The next day, total blood loss was 2755 mL and surgical hemostasis was performed. Because his serum creatine kinase value was elevated at the cessation of heparin, anticoagulation by unfractionated heparin could not have prevented platelet thrombosis. Therefore, we should performed the tracheostomy to secure the patient's airway under DAPT or only aspirin therapy a month after the DES implantation, and performed the laryngectomy and right hemi-thyroidectomy five months after the first surgery. This case is serious warnings of perioperative major adverse cardiac events induced by discontinuation of DAPT; unfractionated heparin was an insufficient safeguard against platelet thrombosis, and perioperative massive bleeding induced by restarting antiplatelet and anticoagulation therapy. In addition, a series of human errors, which the cardiologist chosen DES regardless of scheduled total larygectomy, the discontinuation of antiplatelet therapy shortly after a DES placement, and the surgical staffs failed to share the elevated serum CK and CK-MB values, caused life-threatening complications. PMID- 29497653 TI - Transversus abdominis plane block for bilateral orchiopexy in an 8-year-old patient with Eisenmenger's syndrome. AB - Non-cardiac surgery should only be performed in patients with Eisenmenger's syndrome if absolutely mandatory because these patients are at high risk of perioperative mortality. Proper anesthetic and perioperative pain management in these patients remains a controversial topic. Transversus abdominis plane (TAP) block provides safe and beneficial perioperative analgesia in adults and children; however, no report has described the performance of TAP block in a child with Eisenmenger's syndrome. Herein, we describe the performance of bilateral orchiopexy for cryptorchidism in an 8-year-old boy with Eisenmenger's syndrome due to an uncorrected muscular ventricular septal defect (mVSD). Anesthesia induction and maintenance were uneventful. Subsequently, the patient received ultrasound-guided bilateral TAP block by using 10 mL of 0.25 % levobupivacaine shortly before recovery from anesthesia. The TAP block provided pain relief and maintenance of stable hemodynamics during the postoperative period. We successfully used a TAP block in a child with Eisenmenger's syndrome to provide postoperative analgesia. No side effects were apparent during the perioperative period. TAP block can be considered a beneficial pain management technique for analgesia in children with Eisenmenger's syndrome. PMID- 29497655 TI - Ventricular tachycardia observed during cesarean section in a patient without structural cardiac disease. AB - A 32-year-old gravida 2, para 1 woman without structural cardiac disease was scheduled for her second cesarean section under combined spinal and epidural anesthesia (CSEA). She had stable hemodynamics after delivery; however, 16 min after the application of uterotonics, ventricular tachycardia (VT) with a heart rate (HR) of 150 bpm appeared. VT lasted for <30 s, and her hemodynamics remained stable. Ventricular arrhythmia frequently appeared for 3 min, and the HR at sinus rhythm was approximately 90 bpm. After the discontinuation of oxytocin, VT did not reappear. A postoperative 12-lead electrocardiogram showed first-degree atrioventricular block, but echocardiography performed 2 days later did not reveal any structural abnormalities. Autonomic nervous imbalance induced by CSEA, ephedrine, and oxytocin, as well as ergometrine may cause intraoperative VT during cesarean section in patients without structural cardiac disease. PMID- 29497656 TI - Large myxoma causing cardiac arrest during surgery. AB - The patient was a 67-year-old woman with a history of worsening dyspnea over several months. Cardiac echocardiography showed a large, mobile left atrial myxoma. Emergency surgery was performed. Cardiac arrest occurred during repositioning of the heart to cannulate the inferior vena cava and transesophageal echocardiography revealed the large myxoma obstructing the left ventricle. Cardiopulmonary bypass was initiated and spontaneous heartbeat returned shortly afterward. Changing myxoma position and sudden mitral orifice obstruction must be considered in these cases and once the diagnosis is made, patients should be operated on as early as possible. PMID- 29497657 TI - Cardiac arrest after thoracic paravertebral block with ropivacaine in a 6-year old child. AB - We encountered cardiac arrest induced by 0.375 % ropivacaine 7 ml administered via a catheter for continuous thoracic paravertebral block (TPVB) in a 6-year-old female who underwent pacemaker implantation for sick sinus syndrome (SSS). She was successfully resuscitated with adrenaline and lipid emulsion. Plasma concentration of ropivacaine was 5.2 MUg/ml, suggesting intravascular administration of ropivacaine. Inadvertent intravascular administration is a crucial complication of TPVB. PMID- 29497658 TI - Ligation of the internal jugular vein increased regional cerebral oxygen saturation but decreased the bispectral index in a 72-year-old man: a case report. AB - Regional cerebral oxygen saturation (rSO2) and the bispectral index (BIS) are used to detect cerebral perfusion abnormalities. However, whether rSO2 and BIS values change during ligation of the internal jugular vein (IJV) is unknown. We report a case in which BIS values were decreased, despite increased rSO2 during ligation of the IJV. A 72-year-old man was diagnosed with metastasis of renal cancer to the thyroid associated with tumor embolism in the right IJV. Thyroidectomy with total laryngectomy was performed. After right IJV ligation, right rSO2 was increased from 73 to 78 %, while the right BIS value was decreased from 40 to 27. Contralateral rSO2 and BIS values were unchanged. Right rSO2 and BIS values returned to pre-ligation values in 10 min. Ligation of the IJV might increase cerebral blood flow and ipsilateral rSO2. Physicians should use BIS values with caution during IJV ligation because a sudden decrease in the BIS value is not always associated with cerebral hypoperfusion. PMID- 29497659 TI - A case of unexpectedly difficult intubation caused by a large asymptomatic choanal polyp. AB - We report a case of unexpectedly difficult intubation in a patient with a huge but asymptomatic choanal polyp. A 77-year-old man with invasive bladder cancer was scheduled for total cystectomy under general anesthesia. However, tracheal intubation with a Macintosh laryngoscope proved impossible due to obstruction by a large oropharyngeal tumor. Using a video laryngoscope, intubation was successfully achieved. Choanal polyps are not uncommon, but large choanal polyps reaching the oropharynx appear relatively rare. Anesthesia and airway management for large oropharyngeal tumor has not been sufficiently discussed. PMID- 29497661 TI - Rapid sequence spinal anesthesia for the most urgent cesarean section: a simulation and clinical application. AB - Rapid sequence spinal anesthesia is a recently developed technique for the most urgent, category-1 cesarean section. To successfully perform this technique, it is important to multi-disciplinarily discuss with all staffs related to delivery, make a local protocol in each hospital and simulate the procedure with them. Owing to the above preparation, we were able to perform the technique smoothly also in the real patient. Considering possible benefits of rapid sequence spinal anesthesia, we should prepare enough before we use it in the actual clinical situations. PMID- 29497660 TI - Reiterative ventricular fibrillation caused by R-on-T during temporary epicardial pacing: a case report. AB - Epicardial pacemaker wire insertion is standard following cardiothoracic surgery. However, undersensing of pacing wires may cause the R-on-T phenomenon, which induces ventricular fibrillation. We report a case of a male patient with severe mitral regurgitation scheduled for mitral valve replacement who experienced two ventricular fibrillation episodes related to the R-on-T phenomenon caused by undersensing of the epicardial pacing wire. Both undersensing events happened despite an appropriately low sensing threshold. Notably, the stimulated T wave followed the QRS of the premature ventricular contraction (PVC). This case suggests that a PVC's R wave may be undersensed despite a low sensing threshold. This critical complication may have occurred because pacemakers sense R waves using a slew rate, which is the quotient of voltage over time. As a result, pacemakers may undersense wide QRS waves such as PVCs. Avoiding this dangerous phenomenon completely is not possible using epicardial pacemakers; therefore we recommend carefully adapting epicardial pacing especially when PVC waves occur frequently. PMID- 29497662 TI - Successful recovery without any neurological complication after intraoperative cardiopulmonary resuscitation for an extended period of time in the lateral position: a case report. AB - No successful resuscitation has ever been reported about intraoperative cardiopulmonary resuscitation (CPR) for an extended period of time in the lateral position. Here we report a case of successful resuscitation without any neurological complication after cardiac arrest due to massive hemorrhage and 25 min of CPR in the lateral position. The patient was a 65-year-old man. During open hemostasis for the postoperative hemorrhage, the patient's rhythm changed sinus to ventricular fibrillation (VF), followed by asystole. We started CPR immediately with the patient in the left lateral position. Chest compression was performed by two practitioners, one pressing patient's sternum and the other pressing simultaneously patient's mid-thoracic spine from his back. During CPR, though the value of end-tidal CO2 (EtCO2) was significantly low (around 5-20 mmHg), the value of systolic arterial pressure was kept about 35-50 mmHg, and diastolic pressure about 20-30 mmHg. After the 25 min of lateral CPR, he achieved the return of spontaneous circulation (ROSC). He was hemodynamically stable after ROSC. He regained his consciousness at the next postoperative day. He was discharged from our hospital on the 60th day of operation without any cardiac and neurological complication. Successful neurological outcome suggests that we may expect satisfactory neurological outcome even in the case of lateral position and prolonged CPR if we perform effective CPR with the feedback of arterial blood pressure and EtCO2 and with the immediate intervention to culprit injuries. PMID- 29497663 TI - A case of malignant hyperthermia that was difficult to be differentiated from oral antipsychotic polypharmacy-associated neuroleptic malignant syndrome. AB - Malignant hyperthermia (MH) occurred during anesthesia with volatile inhalation anesthetics in a patient under treatment with multiple oral antipsychotic drugs and with a history of multi-acting receptor-targeted antipsychotic drug (MARTA) induced elevation of serum creatine kinase (CK). Since the patient was considered to be at high risk for neuroleptic malignant syndrome (NMS) based on this history, differential diagnosis between MH and NMS was difficult at the time of onset. Later, the patient was found to be predisposed to MH based on abnormal high rate of the Ca2+-induced Ca2+ release (CICR). We concluded that MH was induced by the volatile inhalation anesthetics. PMID- 29497664 TI - Plasma substance P concentrations in patients undergoing general anesthesia: an objective marker associated with postoperative nausea and vomiting. AB - Background: This study investigated plasma concentrations of substance P (SP) in patients undergoing general anesthesia (GA) and postoperative nausea and vomiting (PONV). This prospective, observational, cohort study included 23 patients who underwent scheduled surgery under general anesthesia. Blood was collected from the radial artery at predetermined time points (15-30 mins prior anesthesia, 15 30 mins after surgery/GA, and 24 h after surgery). PONV, SP concentrations, risk factors, and analgesics used were measured. Findings: Nine of 23 patients experienced PONV. In patients without PONV, SP concentrations significantly decreased (P < 0.0001) at the end of surgery/GA, compared to baseline, and recovered at 24 h after surgery/GA (452.9 +/- 146.2 vs. 666.9 +/- 176.5 vs. 580.7 +/- 168.6 pg/mL, respectively), whereas SP levels were unchanged during surgery/GA and increased at 24 hours after surgery (P = 0.020) in patients with PONV (726.1 +/- 167.8 vs. 655.8 +/- 168.0 vs. 779.7 +/- 220.7 pg/mL, respectively). Conclusions: These finding suggest that SP levels may be utilized as an objective marker for PONV. PMID- 29497665 TI - Unanticipated difficult airway due to undiagnosed oropharyngeal stenosis: a case report. AB - Unanticipated difficult airway is a challenging problem for anesthesiologists. Oropharyngeal stenosis (OPS) is a rare complication of upper airway surgery which may cause difficult airway. We present a patient whose postsurgical OPS was revealed during the induction of general anesthesia, and necessitated reschedule of surgery and tracheotomy. We also discuss the etiology and risk factors of postsurgical OPS. PMID- 29497666 TI - General anesthesia of a Japanese infant with Barber-Say syndrome: a case report. AB - Background: Barber-Say syndrome (BSS) is a very rare congenital disorder characterized by macrostomia, cutis laxa, and other features. We report our experience of performing general anesthesia on a Japanese child with BSS. Case presentation: A bilateral repair of the corners of the mouth under general anesthesia was planned for an 18-month-old male with macrostomia; the child was 75 cm in height and weighed 9.9 kg. As insertion of the peripheral intravenous catheter was difficult, it was inserted before the surgery by a pediatrician. The patient wore a mask and was ventilated manually after loss of consciousness with intravenous anesthesia. A mask for adults provided a superior fit and was effective in preventing air leakage from the corners of the mouth. After rocuronium was administered, the larynx was spread with a Macintosh laryngoscope. There was no laryngeal anatomical abnormality, and tracheal intubation was readily possible. The operation was completed without incident. Stiffening of both arms occurred for several seconds one hour after the operation ended, but the patient did not develop other complications. Conclusions: Mask ventilation and the insertion of an intravenous catheter may be difficult in the general anesthesia of patients with BSS, and anesthetic management requires caution. PMID- 29497667 TI - Duodenal ulcer accompanied by intractable right lateral chest pain (T6/T7 dermatomal segments). AB - A 48-year-old man who complained of a severe throbbing pain in his right lateral chest was referred to our department. His chest computed tomography (CT) and X ray, abdominal CT and ultrasonography had revealed no abnormalities. Four days after admission to our ward the patient vomited and he requested upper gastrointestinal (GI) endoscopy: this showed duodenal ulcer. Treatment with omeprazole and sucralfate improved the duodenal ulcer; concurrently, the symptoms of chest pain were relieved. PMID- 29497668 TI - Anesthetic management in an adult moyamoya disease patient undergoing mitral valve plasty for severe mitral regurgitation. AB - Background: Despite several previous reports, there are no established procedures for intraoperative management in moyamoya disease patients requiring cardiac surgery. Case presentation: Herein, we report the case of a 42-year-old man who was scheduled to undergo mitral valve plasty for severe mitral regurgitation. He had been diagnosed with moyamoya disease on the onset of cerebral ischemia at 41 years of age. During the cardiac surgical procedure, the patient was maintained on inhalation anesthesia with 1 to 1.5 % sevoflurane. Sevoflurane causes cerebral vasodilation followed by increased cerebral blood flow, and moreover we expected a sevoflurane preconditioning-induced neuroprotective effect. In addition, we used pulsatile perfusion support to maintain cerebral circulation with intra aortic balloon pumping during the cardiopulmonary bypass. We aimed to keep the mean arterial pressure constantly above 70 mmHg. We were able to maintain regional cerebral oxygen saturation at 80 % of the baseline value, and could not detect the progression of neurological deficits using follow-up brain single photon emission computed tomography. The patient was discharged 16 days after admission. Conclusions: The details of the clinical course of his case will add to our knowledge regarding intraoperative management options in moyamoya disease patients requiring cardiac surgery. We suggest that pulsatile blood flow supported by intra-aortic balloon pumping and sevoflurane anesthesia for increasing cerebral blood flow and for possible neuroprotection may be efficacious for anesthetic management of moyamoya disease patients. PMID- 29497669 TI - Failure of lumbar puncture in a patient with spinal epidural lipomatosis: a case report. AB - We report a case of difficult lumbar puncture due to the inability to obtain adequate cerebrospinal fluid (CSF) in a patient later diagnosed with spinal epidural lipomatosis (SEL). A 76-year-old man with a body mass index (BMI) of 24.1 kg/m2 was scheduled for transurethral resection of a bladder tumor for superficial bladder cancer under spinal anesthesia. The patient had a 3-year history of inhaled steroid use for the management of chronic obstructive pulmonary disease. After placing the patient in the right lateral position, a lumbar puncture was performed via the median approach. However, CSF could not be tapped adequately despite repeated attempts at lumbar puncture, so general anesthetic was administered instead. Subsequently, both anesthesia and surgery proceeded uneventfully. On the first postoperative day, the patient developed mild postdural puncture headache (PDPH), which was treated conservatively. No postoperative neurological complications related to spinal anesthesia were observed. Approximately 2 months after discharge, the patient reported progressive lower back pain and was diagnosed with SEL by magnetic resonance imaging (MRI). A lumbar laminectomy and removal of excessive adipose tissue was performed. After surgery, the patient's symptoms resolved. The pathogenesis of SEL involves excess fat tissue deposition in the spinal canal, which can lead to obliteration of the spinal subarachnoid space. Therefore, in this patient, the SEL was thought to have caused the inability to obtain adequate CSF during lumbar puncture, and was associated with difficult spinal anesthesia. PMID- 29497670 TI - Perioperative management of esophagectomy in a patient who previously underwent bilateral lung transplantation. AB - Background: General theory of anesthetic managements for nontransplant procedures in lung transplant patients was proposed. However, there are few literatures reporting the perioperative management of thoracoabdominal major surgery following lung transplantation in detail. Herein, we scrupulously report a perioperative management of esophagectomy in a patient who previously underwent bilateral lung transplantation (BLTx), focusing on protection of the transplanted lungs and the respiratory function of the patient. Case presentation: A 50-year old woman was listed for cadaveric BLTx for severe respiratory failure due to end stage diffuse panbronchiolitis. She underwent BLTx under veno-arterial extracorporeal membranous oxygenation support. Blood loss during the BLTx was 13,675 mL, and mild lung edema developed. She was weaned from the ventilator on the sixth postoperative day (POD) and discharged on the 65th POD. Two years after the BLTx, respiratory function improved markedly, but she was diagnosed with esophageal cancer and was scheduled for thoracoscopic esophagectomy with radical lymph node dissection, hand-assisted laparoscopic gastric mobilization, and anastomosis of the gastric conduit to the cervical esophagus via posterior mediastinum. We were concerned that impaired lymphatic drainage could cause pulmonary edema or lymphangiogenesis could cause a severe immunologic response against the lung grafts. To avoid graft injury and rejection, we addressed lung protective ventilation, reduced transfusion volume, continued immunosuppressive agents, administered volatile anesthetics, and prevented dynamic pain by epidural analgesia. These factors and the improved respiratory function may have contributed to successful management of esophagectomy. During the perioperative period, the major respiratory problems were a slight right lung edema and a persistent pulmonary air leak due to the division of thoracic adhesions, which resolved on 13th POD. Conclusions: Cancer surgeries in lung transplant recipients become more common. When such patients undergo thoracoabdominal major surgery, we should pay special attention to respiratory function, operative stress, immunosuppressive therapy, transfusion volume for the prevention of lung edema, and thoracic adhesions. PMID- 29497671 TI - A case of hemothorax due to traumatic bleeding managed effectively by Sonoclot(r) guided blood transfusion. AB - A 71-year-old woman was transported to our hospital due to traumatic bleeding, and an operation was immediately performed for achieving hemostasis. We decided to perform Sonoclot(r)-guided blood transfusion. When Sonoclot signatures had returned normal values, further bleeding did not occur. We experienced the first case of traumatic bleeding managed effectively by using Sonoclot. We suggest that a Sonoclot analyzer may be useful for the management of severe coagulopathy due to traumatic bleeding like ROTEM and TEG. PMID- 29497672 TI - Anesthetic management using peripheral nerve block in patients with factor XI deficiency: a case report. AB - Factor XI deficiency is rare but may cause life-threatening bleeding during the perioperative period. The clinical manifestation of factor XI deficiency is characterized by bleeding tendency. This unpredictable bleeding tendency makes anesthetic management difficult. We report a case of a partial duodenectomy in a patient with factor XI deficiency. The patient was scheduled for duodenectomy because of a duodenal tumor. When checked for coagulation before surgery, the patient was found to have a remarkably prolonged activated partial thrombin time, and further investigation revealed factor XI deficiency. Fresh frozen plasma was transfused before surgery, and general anesthesia and peripheral nerve block were performed. In the present case of factor XI deficiency, supplementation with clotting factor and proper anesthetic management were important to prevent severe complications. PMID- 29497673 TI - Transient cardiac arrest in a child with Down syndrome during anesthesia induction with sevoflurane: a case report. AB - Background: This report describes a case of transient cardiac arrest in a child with Down syndrome. The cardiac arrest occurred during induction of anesthesia with sevoflurane. To the best of our knowledge, this is the first such report. Case presentation: A 14-year-old boy was scheduled to undergo dental treatment under general anesthesia because of his mental disorder. He had congenital atrial and ventricular septal defects and patent ductus arteriosus, which had been repaired previously. Therefore, we anticipated no problems with his cardiovascular system during the perioperative period. Because the sedation administered before the insertion of an intravenous catheter and arterial line was insufficient to induce an anesthetic effect, general anesthesia was induced by using a mixture of sevoflurane (5 %) with oxygen in nitrous oxide. A few minutes after the induction of anesthesia, the patient unexpectedly experienced bradycardia (heart rate <30 beats/min), and his electrocardiography findings indicated asystole. After a few minutes of cardiopulmonary resuscitation, the patient's heart rate returned to normal. Conclusions: We postulated that the asystole was triggered by a dysfunction in the autonomic cardiac regulation and sympathetic activation, which often occurs in patients with Down syndrome, and due to the use of high concentrations of sevoflurane. In future cases of pediatric patients with Down syndrome, with or without heart disease, the concentration of sevoflurane administered during surgery should be increased gradually. Moreover, an intravenous catheter should be promptly inserted to administer anticholinergic drugs as quickly as possible in order to prevent transient cardiac arrest. PMID- 29497674 TI - Accidental administration of the remifentanil formulation UltivaTM into the epidural space and the complete time course of its consequences: a case report. AB - Background: UltivaTM contains the potent short-acting MU-opioid receptor agonist remifentanil hydrochloride, and it is commonly administered intravenously during general anesthesia. It is not approved for epidural or intrathecal use in clinical practice because it contains glycine as an acidic buffer. However, at this moment, very limited information is available on epidural administration of UltivaTM. Case presentation: We report the accidental administration of 300 MUg of remifentanil and 2.25 mg of glycine into the epidural space after emergence from general anesthesia for distal pancreatectomy and the complete time course of its consequences. The respiratory depression occurred at 5 min after the administration, and complete loss of consciousness was observed at 8 min. The patient was re-intubated and underwent mechanical respiration. At 45 min (33 min after re-intubation), spontaneous respiration resumed, she was responsive to commands, and her orientation returned. She was extubated successfully. Conclusions: These consequences might have resulted from the diffusion of the components of UltivaTM into not only systemic circulation but also the cerebrospinal fluid. Moreover, the complex pathophysiology might be associated with remifentanil, as well as glycine present in UltivaTM. PMID- 29497675 TI - Failure of a "foolproof" pin-index medical pipeline system. AB - Background: The pin-index medical gas pipeline system, which complies with Japan Industrial Standard (JIS), is considered to be "foolproof" and is widely used in Japan to avoid medical gas misconnections. Case presentation: The wall-mounted gas outlet used in our hospital (NSV outlet, CENTRAL UNI, Co., Ltd., Tokyo, Japan) contains multiple sockets, which connect to hoses with gas-specific pins. Each socket is covered with a gas-specific plastic pin guide, which is considered to make the system foolproof; i.e., to prevent misconnections. However, while checking an anesthesia machine in accordance with the guidelines developed by the Japanese Society of Anesthesiologists, an anesthesiologist found that one of the gas-specific plastic pin guides covering the wall-mounted gas outlets had disappeared; and hence, the gas outlet system was no longer foolproof. A subsequent verification test performed by engineers of the system's manufacturer revealed that the plastic pin guides could be dislodged by applying 29.4 N of vertical force. Conclusions: It is important to check that gas outlet systems are functioning in a gas-specific manner when they are used for clinical purposes. PMID- 29497676 TI - Successful perinatal management of a ruptured brain arteriovenous malformation in a pregnant patient by endovascular embolization followed by elective cesarean section: a single-case experience. AB - Background: Although brain arteriovenous malformations (AVM) usually remain asymptomatic during pregnancy, they can cause intracranial hemorrhage and lead to serious neurological deficits. Nowadays, it is accepted that treatment of a ruptured brain AVM during pregnancy should be based on neurologic, not obstetric, indications.Recently, endovascular treatment has been recognized as a treatment option associated in pregnant patients with brain AVMs. Case presentation: A 34 year-old woman presented at 25 weeks of gestation with a history of severe headache followed by severe consciousness disturbance. Brain CT showed a subcortical hematoma in the right occipital lobe along with bilateral intraventricular hematomas. A cerebral angiogram was performed to confirm the diagnosis, which revealed right occipital AVM. At 27 weeks of gestation, endovascular embolization of the AVM was attempted under general anesthesia. The feeding artery and the nidus were simultaneously obliterated by injection of 50 % n-butyl-cyanoacrylate. As a result, the blood flow into the nidus was drastically decreased and the risk of re-bleeding was substantially reduced. At 38 weeks of gestation, elective cesarean section was performed to deliver the baby under combined spinal-epidural anesthesia (CSEA). An infant weighing 3665 g was delivered, with Apgar scores of 8 and 9 at 1 and 5 min, respectively.Postoperative analgesia was provided by a continuous infusion of ropivacaine via the epidural catheter. The infant was confirmed as not having any congenital anomalies.On POD 5, both of the patient and the infant were discharged home without any medical problems. The mother has shown no evidence of re bleeding from the intracranial lesion since, and the infant is thriving well. Conclusions: Endovascular treatment in pregnant women is associated with various unique concerns. However, it can be carried out safely and effectively and is useful not only for saving the mother's life but also for allowing the pregnancy to continue to term. PMID- 29497677 TI - Anti-NMDA receptor encephalitis presenting as an acute psychotic episode misdiagnosed as dissociative disorder: a case report. AB - Background: In 2005, "anti-N-methyl-d-aspartate (NMDA) receptor encephalitis," a syndrome with prominent psychiatric symptoms, memory loss, decrease in level of consciousness, and central hypoventilation, was described in young women with ovarian teratomas and antibodies against an antigen highly expressed in the hippocampus. This report highlights the growing need for increased awareness among psychiatrists and other relevant medical professionals about this under diagnosed disorder, which should be considered in differential diagnoses. Case presentation: A 19-year-old female with no psychiatric history presented to a district general hospital with acute psychosis, emotional lability, memory deficit, fluctuating behavioral changes such as wandering and babbling, and seizure. She was admitted to the hospital with a provisional diagnosis of dissociative disorder. Soon after admission, she developed aspiration pneumonia and was intubated for mechanical ventilation. She was transferred to our hospital for further assessment and admitted to the intensive care unit for ventilation. Laboratory test results were unremarkable, but her EEG showed non-specific slowing with no epileptiform activity, and brain computed tomography (CT) and MRI also showed no remarkable findings. Cerebrospinal fluid (CSF) analysis showed an elevated white blood cell count (15 cells/hpf; 70 % lymphocytes), and blood serum and CSF samples tested positive for NMDA receptor antibodies. Abdominal contrast enhanced CT revealed an ovarian teratoma, which was subsequently removed laparoscopically. Postoperative immunotherapy (steroids, intravenous immunoglobulin, and plasmapheresis) led to gradual improvement. On day 25 of hospitalization, neuropsychological assessment demonstrated that overall, she had returned to her premorbid level of functioning. Her condition substantially improved over several months of cognitive rehabilitation, and she was eventually discharged on day 75. Conclusions: Anti-NMDA receptor encephalitis, a form of autoimmune encephalitis, is commonly associated with tumors and often misdiagnosed. Diagnosis can be confirmed by detecting NMDA receptor antibodies in the patient's serum or CSF. Management can be achieved with immunosuppressive therapy and tumor resection. PMID- 29497678 TI - Sudden onset of severe pulmonary edema after emergency cesarean section. AB - Mitral valve stenosis (MS) associated with rheumatic disease no longer represents a major heart problem during the perinatal period in Japan. Here we present a case of acute heart failure due to MS after emergency cesarean section (CS). The patient was transferred due to the development of fetal distress at 36 weeks gestation and underwent an emergency CS under general anesthesia. She developed acute heart failure immediately postoperatively and was diagnosed with MS associated with pulmonary artery hypertension for the first time. She underwent percutaneous transvenous mitral commissurotomy and was discharged from our hospital in good condition. PMID- 29497679 TI - Management of a centenarian who underwent emergency laparoscopic cholecystectomy under general anesthesia with subcostal transversus abdominis plane block. AB - The anesthetic management of centenarians is challenging, since they have loss of functional reserve in all organs. The mortality rate of 25 % is reported in patients over 100 years old who underwent emergency surgery. The transversus abdominis plane block has been shown to provide effective analgesia in laparoscopic cholecystectomy. A 101-year-old woman was diagnosed with grade I (mild) acute cholecystitis with gallstones. An emergency laparoscopic cholecystectomy was scheduled. The patient had a history of hypertension. The patient's laboratory data showed that she had mild coagulopathy, anemia, thrombocytopenia, and decreased renal function. After induction of general anesthesia, an ultrasound-guided, bilateral subcostal transversus abdominis plane block was performed. Her postoperative course was uneventful. Using the preoperative subcostal transversus abdominis plane block, we were able to avoid hemodynamic instability and to reduce opioid dosage in a centenarian who underwent emergency laparoscopic cholecystectomy under general anesthesia. PMID- 29497680 TI - Difficult tracheal intubation in a patient with maternal uniparental disomy 14. AB - Background: Maternal uniparental disomy 14 (UPD(14)mat) is an imprinting disorder. It is a rare disease, but there is the possibility that more undiagnosed patients might exist because the clinical features of UPD(14)mat resemble those of the Prader-Willi syndrome or other congenital diseases. We performed anesthetic management for an 8-year-old girl with UPD(14)mat. Case presentations: She was admitted to undergo correction surgery due to symptomatic scoliosis. Preoperative examination revealed that she had a restricted mouth opening and retrognathia, as well as some typical characteristics of UPD(14)mat, such as small hands, growth retardation, and precocious puberty. We induced general anesthesia using sevoflurane without any problems. However, the tracheal intubation was difficult because of the restricted mouth opening. We used the McGRATHR MAC videolaryngoscope to overcome this problem. Conclusions: We speculate that the craniofacial deformity in case of UPD(14)mat patients may lead to difficulty in tracheal intubation. PMID- 29497681 TI - A postoperative left ventricular-right atrial shunt due to infectious endocarditis after aortic repair with aortic valve replacement detected by transesophageal echocardiography. AB - Infectious endocarditis (IE) with acute heart failure is a medical emergency. In particular, postoperative IE after aortic repair with an artificial vascular graft is a life-threatening matter. We present a case in which a mobile abscess appeared on the aortic valve annulus with an intra-cardiac shunt in the left ventricle (LV) to the right atrium (RA) after ascending aortic repair with aortic valve replacement (AVR) for acute type A aortic dissection. It was diagnosed with transesophageal echocardiography (TEE), which prompted further exploration. PMID- 29497682 TI - What range of extra-cardiac conduit flow velocity is detectable intraoperatively following the completion of a total cavo-pulmonary connection? AB - Background: Very few studies have investigated the blood flow velocity from the inferior vena cava (IVC) to the pulmonary artery following the Fontan operation using an extra-cardiac conduit (ECC). No studies at all have investigated the velocity immediately after the circulation is established. The purpose of this retrospective study was to find an acceptable flow velocity at the ECC following the completion of a total cavo-pulmonary connection (TCPC) via transesophageal echocardiography. Findings: We measured the mean velocity (m-V) of the blood flow proximal to the anastomosis between the IVC and ECC in eight patients and compared the results with theoretically predicted values based on assumptions regarding the cardiac output, the ratio of the IVC flow to the superior vena cava flow, and the cross-sectional form of the ECC. Mean velocities ranging from about 15 to 60 cm/s were detected in the absence of any observable stenosis. The measured m-V was significantly faster than the predicted value in our study, both collectively and in every patient individually. The shrinking and compression of the ECC might account for the faster velocities measured in our cases. Conclusion: The observed range of m-V at the ECC, about 15-60cm/s, may be acceptable for the establishment of TCPC circulation. PMID- 29497683 TI - Subdural hematoma after cesarean delivery without symptoms: a case report. AB - Background: Subdural hematoma (SDH) after accidental dural puncture (ADP) is rare but may be lethal. We experienced a patient who developed SDH after combined spinal and epidural anesthesia without a headache. Case presentation: A 41-year old parturient female with an unruptured cerebral aneurysm, was scheduled to undergo elective cesarean delivery. Cerebrospinal fluid leakage was identified during puncture of the epidural space, and a catheter was placed after re puncture. The postoperative course was normal except for incisional pain. The patient complained of slight neck stiffness on the second postoperative day. Magnetic resonance imaging (MRI) was performed to ensure that there was no intracranial problem on the fourth postoperative day and showed a bilateral subdural hematoma. Increase in size of hematoma was shown on computed tomography (CT) on the ninth postoperative day. Epidural blood patch was performed. A decrease in the size of the hematoma was confirmed on the CT images on the 11th postoperative day, and the patient was discharged. The patient has not developed any additional symptoms. Conclusions: We experienced a patient who developed a SDH without a remarkable headache. It may be better to perform brain imaging studies, even if the patient does not complain of headache. PMID- 29497684 TI - Multicenter experience from the UK and Ireland of use of lumen-apposing metal stent for transluminal drainage of pancreatic fluid collections. AB - Background and study aims: Pancreatic fluid collection (PFC) is a common complication of pancreatitis for which endoscopic ultrasound-guided drainage is first-line treatment. A new single-device, lumen-apposing, covered self-expanding metal stent (LAMS) has been licensed for PFC drainage. We therefore present our multicenter experience with the LAMS for PFC drainage in a multicenter prospective case series to assess success and complication rates. Patients and methods: All adult patients from 11 tertiary centers who had LAMS placement for PFC from July 2015 to July 2016 were included. Data including indications, technical success, clinical success, collection resolution, stent removal, early and late adverse events (AEs), mortality and recurrence at 6 months were collected. Results: 116 patients, median age 52.5 years (range 16 - 80) and 67 % male, were treated with a single LAMS in each case. The indication was walled off necrosis (WON) in 70 and pseudocyst in 46. Median size of the PFC was 11 cm (5 - 21 cm) and the estimated median necrotic volume in WON was 30 % (5 % - 90 %). Stent insertion was technically successful in 115 (99.1 %) and clinically successful in 109 (94 %). Early serious AEs (SAEs): n = 7 sepsis, n = 1 stent blockage with food, n = 1 stent migration requiring laparotomy, n = 1 stent dislodgement and n = 1 bleeding requiring emboliZation. Late AEs: n = 1 buried stent and n = 1 esophageal fistula. Non-procedure-related deaths: n = 3 (2.5 %). Conclusion: This multicenter case series demonstrates that use of the new LAMS is feasible, effective and relatively safe in draining PFC with a technical success rate of 99 % and cumulative SAE rate of 11.2 %. PMID- 29497685 TI - Radiofrequency ablation (RFA) vs. argon plasma coagulation (APC) for the management of gastric antral vascular ectasia (GAVE) in patients with and without cirrhosis: results from a retrospective analysis of a large cohort of patients treated at a single center. AB - Introduction and study aims: Gastric antral vascular ectasia (GAVE) is a mucosal abnormality associated with multiple conditions, most notably cirrhosis and systemic sclerosis, that causes indolent gastrointestinal bleeding. It is primarily managed with endoscopic therapy. Traditionally, GAVE is endoscopically ablated using argon plasma coagulation (APC) but radiofrequency ablation (RFA) is emerging as an alternative modality. No prior comparison of the 2 modalities has been published. Patients and methods: After receiving IRB approval, we reviewed our electronic health records to identify all patients who underwent endoscopic evaluation for GAVE between January, 2011 and October, 2016. We compared important variables between APC and RFA, as well as between cirrhosis and non cirrhosis, using the Chi-square test and the Wilcoxon two-sample test as appropriate. Results: During our study period, 81 patients were endoscopically evaluated for GAVE. 24 patients were treated with APC alone, 28 with RFA alone and 25 patients received both treatment modalities. Conclusions: RFA and APC were both effective in treating bleeding from GAVE. Though we found subtle differences, patients underwent a similar number of treatment sessions and had similar procedure times and a similar time between sessions no matter the treatment modality used. PMID- 29497686 TI - Etiologies and risks of splenic decapsulation after endoscopic retrograde cholangiopancreatography: case report and literature review. AB - Background and study aims Endoscopic retrograde cholangiopancreatography (ERCP) is an invasive diagnostic and interventional procedure used in conditions related to the pancreas and biliary tract. It has a complication rate ranging from 4 % to 10 %. Severe complications are few with the most common of them being post-ERCP pancreatitis, post-sphincterotomy bleeding, and perforation. A rare, but potentially life-threatening complication of ERCP is splenic injury. We report the case of a 60-year-old female with choledocholithiasis who sustained splenic decapsulation following ERCP. The exact causes of splenic injury are unknown, although several mechanisms are postulated. A literature review of splenic injuries post-ERCP shows that there are only 3 cases with post-ERCP splenic decapsulation. Our patient is the first one in whom splenic decapsulation occurred without any risk factors or technical difficulties during the procedure. A high index of suspicion for splenic injury is required in any patient who has severe pain, anemia, or hemorrhagic shock after ERCP. PMID- 29497687 TI - Endoscopic necrosectomy of walled-off pancreatic necrosis by large-bore percutaneus metal stent: a new opportunity? AB - Background and study aims Endoscopic drainage of walled-off pancreatic necrosis (WOPN) is feasible when contact with the gastric or duodenal wall is present; when WOPN cannot be accessed endoscopically, a percutaneous approach can be considered. Percutaneous use of esophageal self-expandable metal stents (SEMS) to establish access to a WOPN cavity was evaluated. PMID- 29497688 TI - Redundant-target processing is robust against changes to task load. AB - Monitoring visual displays while performing other tasks is commonplace in many operational environments. Although dividing attention between tasks can impair monitoring accuracy and response times, it is unclear whether it also reduces processing efficiency for visual targets. Thus, the current three experiments examined the effects of dual-tasking on target processing in the visual periphery. A total of 120 undergraduate students performed a redundant-target task either by itself (Experiment 1a) or in conjunction with a manual tracking task (Experiments 1b-3). Target processing efficiency was assessed using measures of workload resilience. Processing of redundant targets in Experiments 1-2 was less efficient than predicted by a standard parallel race model, giving evidence for limited-capacity, parallel processing. However, when stimulus characteristics forced participants to process targets in serial (Experiment 3), processing efficiency became super-capacity. Across the three experiments, dual-tasking had no effect on target processing efficiency. Results suggest that a central task slows target detection in the display periphery, but does not change the efficiency with which multiple concurrent targets are processed. PMID- 29497689 TI - Color inference in visual communication: the meaning of colors in recycling. AB - People interpret abstract meanings from colors, which makes color a useful perceptual feature for visual communication. This process is complicated, however, because there is seldom a one-to-one correspondence between colors and meanings. One color can be associated with many different concepts (one-to-many mapping) and many colors can be associated with the same concept (many-to-one mapping). We propose that to interpret color-coding systems, people perform assignment inference to determine how colors map onto concepts. We studied assignment inference in the domain of recycling. Participants saw images of colored but unlabeled bins and were asked to indicate which bins they would use to discard different kinds of recyclables and trash. In Experiment 1, we tested two hypotheses for how people perform assignment inference. The local assignment hypothesis predicts that people simply match objects with their most strongly associated color. The global assignment hypothesis predicts that people also account for the association strengths between all other objects and colors within the scope of the color-coding system. Participants discarded objects in bins that optimized the color-object associations of the entire set, which is consistent with the global assignment hypothesis. This sometimes resulted in discarding objects in bins whose colors were weakly associated with the object, even when there was a stronger associated option available. In Experiment 2, we tested different methods for encoding color-coding systems and found that people were better at assignment inference when color sets simultaneously maximized the association strength between assigned color-object parings while minimizing associations between unassigned pairings. Our study provides an approach for designing intuitive color-coding systems that facilitate communication through visual media such as graphs, maps, signs, and artifacts. PMID- 29497690 TI - Interprofessional teaching and learning in the health occupations - A conference developed by and for young scientists in the field of education. PMID- 29497691 TI - Competency-based learning in an ambulatory care setting: Implementation of simulation training in the Ambulatory Care Rotation during the final year of the MaReCuM model curriculum. AB - Aim: As part of the MaReCuM model curriculum at Medical Faculty Mannheim Heidelberg University, a final year rotation in ambulatory care was implemented and augmented to include ambulatory care simulation. In this paper we describe this ambulatory care simulation, the designated competency-based learning objectives, and evaluate the educational effect of the ambulatory care simulation training. Method: Seventy-five final year medical students participated in the survey (response rate: 83%). The control group completed the ambulatory rotation prior to the implementation of the ambulatory care simulation. The experimental group was required to participate in the simulation at the beginning of the final year rotation in ambulatory care. A survey of both groups was conducted at the beginning and at the end of the rotation. The learning objectives were taken from the National Competency-based Catalogue of Learning Objectives for Undergraduate Medical Education (NKLM). Results: The ambulatory care simulation had no measurable influence on students' subjectively perceived learning progress, the evaluation of the ambulatory care rotation, or working in an ambulatory care setting. At the end of the rotation participants in both groups reported having gained better insight into treating outpatients. At the beginning of the rotation members of both groups assessed their competencies to be at the same level. The simulated ambulatory scenarios were evaluated by the participating students as being well structured and easy to understand. The scenarios successfully created a sense of time pressure for those confronted with them. The ability to correctly fill out a narcotic prescription form as required was rated significantly higher by those who participated in the simulation. Participation in the ambulatory care simulation had no effect on the other competencies covered by the survey. Discussion: The effect of the four instructional units comprising the ambulatory care simulation was not measurable due to the current form or the measurement point at the end of the 12-week rotation. The reasons for this could be the many and statistically elusive factors relevant to the individual and the wide variety among final year rotation placements, the late point in time of the final survey, and the selection of simulated scenarios. The course is slated to undergo specific further development and should be supplemented with additional learning opportunities to ensure that the main learning objectives are covered. The description of the teaching format is meant to contribute to the ongoing development of medical education with an emphasis on competency in the areas of ambulatory care, communication, prevention and health promotion. PMID- 29497692 TI - Peer-mentoring Program during the Preclinical Years of Medical School at Bonn University: a Project Description. AB - Introduction: To better prepare young medical students in a thorough and competent manner for the ever increasing clinical, scientific, as well as psychosocial requirements, universities should enable a close, personal transfer of experience and knowledge. Structured mentoring programs are a promising approach to incorporate clinical subjects earlier into the preclinical training. Such a mentoring program facilitates the prioritization of concepts from a broad, theory-heavy syllabus. Here we report the experiences and results of the preclinical mentoring program of Bonn University, which was introduced in the winter semester of 2012/2013. Project desciption: The program is characterized by the concept of peer-to-peer teaching during the preclinical semesters of medical school. Regular, voluntary course meetings with different clinical case examples provide students the opportunity to apply knowledge acquired from the basic science curricula; furthermore, a personal contact for advice and support is ensured. Thus, an informal exchange of experiences is made possible, which provides to the students motivational and learning aids, in particular for the oral examination at the end of the premedical semesters as well as for other examinations during medical school. Results: Over the course of the preceding three years the number of participants and the interest in the program grew steadily. The analysis of collected evaluations confirms very good communication between mentors and students (>80%), as well as consistently good to very good quality and usefulness in terms of the mentors' subject-specific and other advice. The overall final evaluation of the mentoring program was always good to very good (winter semester: very good 64.8+/-5.0%, good 35.2+/-5.0%, summer semester: very good 83.9+/-7.5%, good 16.1+/-7.5%) Summary: In summary, it has been shown that the mentoring program had a positive impact on the development, education and satisfaction of students beginning their preclinical semesters at Bonn University. PMID- 29497694 TI - Effect of data self-collection as an activating teaching method in a statistical software course in medical biometry - a pilot study. AB - Background: Biostatistics is an integral part of the studies of human medicine. Students learn the basics of analyzing and interpreting study results. It is important to demonstrate the subject's relevance by means of appropriate measures to maximize learning success. We investigated whether an active involvement of students in the process of data collection may improve test performance and motivation among medical students. Methods: We conducted a pilot study comparing active involvement of students (n1=45) in the process of data collection and standard education (n2=26). All students of this pilot study participated in an observational study assessing their preferences regarding sweets or salty munchies, and students of the experimental group subsequently used this data set during the exercises throughout the semester. Primary and secondary endpoints were examination success and motivation respectively. Results: Superiority of the activating teaching method could not be demonstrated (intervention: 109.0 points (SD 8.8), control: 113.8 points (SD 6.5)). The course ratings were superior in the intervention group (median grade 1 vs. median grade 2 in the control group), although this was not a significant improvement (p=0.487). Conclusions: Biostatistics education should incorporate approaches contributing to a better understanding of learning contents. Possible reasons why this pilot study failed to prove superiority of the intervention were a lack of sample size as well as the good grades in the control group. The presented teaching concept has to be evaluated by means of a larger sample enabling more valid conclusions. Furthermore, the considered research question in the experimental group may be changed to a more relevant one for medical practice. PMID- 29497693 TI - Factors that Affect the National Student Performance Examination Grades of Brazilian Undergraduate Medical Programs. AB - Background: The Brazilian National Student Performance Examination - ENADE is an instrument used to measure the quality of undergraduate courses. The identification of factors that influence the result of this examination can contribute to providing support necessary to improve the quality of medical courses. The purpose of this work was to evaluate the factors that affect the National Student Performance Examination grades of Brazilian undergraduate medical programs. Methods: Factors that influenced the 2010 ENADE grades of 100 undergraduate medical programs were studied. Data collection was performed using public databases. Academic and healthcare infrastructure variables were investigated. The data analysis was based on the performance of the medical programs on the 2010 ENADE, whereby the programs were divided into two groups: ENADE 1-2 (unsatisfactory grade) versus ENADE 4-5 (satisfactory grade). Results: One hundred schools were included in this analysis. In the univariate analysis the university variables (p=0.037), public institution (p<0.001), lower number of openings per course (p=0.036), lower number of specialist professors (p=0.003) and higher number of doctors (p=0.010), strictu sensu post-graduation program (p<0.001), higher course lifetime (p<0.001) were associated to best results in ENADE. In the multivariate analysis of logistic binary regression four variables remained independently associated to a better performance in ENADE: public institution (OR 9.9; 95%CI 1.03 to 95.5), lower number of openings per course (OR 0.984; 95% CI 0.969 to 0.999), strictu sensu post-graduation program (OR 8.189; 95% CI 1.459 to 45.971) and longer course lifetime (OR 1.058; 95% CI 1.013 to 1.105). Conclusions: The satisfactory score of this evaluation (ENADE 4-5) was associated to the public administration category of higher degree institutions, lower number of openings offered per course, the presence of a strictu sensu and longer course lifetime. PMID- 29497695 TI - Case-oriented selection of investigation methods in direct access: A comparison between physiotherapy trainees at professional colleges and in bachelor's study courses. AB - Objective: Direct access to physiotherapy services is currently discussed in Germany. Its introduction would mean that initial diagnoses must be made in physiotherapy practices as well. However, it was not yet investigated whether the current training in physiotherapy is sufficient for this, and whether there are differences between the training systems. This study aims to answer the question of whether trainees at the end of Bachelor's studies (BS) are more reliably able to assess the case-related suitability of examination methods than professional college students (FS). Methodology: Questionnaires were developed to assess the suitability of examination methods for diagnostic inquiries. All professional colleges and bachelor's study courses listed with the German Physiotherapy Association were asked to present the questionnaires to their final classes. Results: In 216 addressed professional colleges and 24 bachelor's study courses, the return rate was 9.26% for professional colleges and 33.33% for study courses. One hundred thirty-eight questionnaires from students in 8 study courses and 368 questionnaires from students at 20 professional colleges were evaluated. The mean of correct decisions in total (of max. 54) was 19.01 (BS) or 15.73 (FS); in structure-related and function-related examination methods (of max. 42), it was 17.22 (BS) and 14.8 (FS); in activity-related methods (of max. 12), it was 1.97 (BS) and 0.89 (FS). Out of a max. of 49 examination methods, 23.45 (BS) and 26.72 (FS) were stated as unknown. Conclusion: The university students made correct decisions on the suitability of examination methods significantly more frequently than the professional college students. However, the determined group difference is low. Overall, the results do not appear sufficient for direct access. Training would have to be adapted for this purpose. PMID- 29497696 TI - Integrating teaching into routine outpatient care: The design and evaluation of an ambulatory training concept (HeiSA). AB - Background: Direct patient contact is crucial in learning important interactional and examination skills. However, medical students have limited opportunity to self-responsibly practise these skills in authentic clinical settings and typically receive insufficient feedback on their performance. We developed a novel single-session ambulatory teaching concept (Heidelberg Student Ambulatory training, "HeiSA") to prepare students more adequately for clinical-practical responsibilities. Methods: To identify challenges and target group needs, we reviewed current literature and consulted an expert group of faculty lecturers and training researchers. The resulting course concept was put into practice at the University Hospital's general-internistic outpatient department and evaluated in a pilot phase (winter term 2010, ten participants) and a main project phase (summer and winter terms 2011, 14 and 21 participants, respectively). Third and fourth-year students autonomously take a new patient's medical history and conduct a complete physical examination in one hour under supervision, followed by extensive preceptor feedback. To assess learning achievements, participants and a control group self-rated their communication and examination skills before and (participants only) after the session on six-point Likert scales (1=completely able, 6=completely unable). The preceptor also evaluated the participants' performance. Finally, all stakeholders re-evaluated the course concept. Results: HeiSA is a feasible training concept and accepted by staff members and students. It provides opportunities to practise clinical skills in a relevant, authentic learning environment with extensive feedback. Participants report improved anamnesis (0.27+/-0.51, p=.003) and physical examination (0.25+/ 0.41, p=.008) skills. The preceptor evaluated students' performance to be generally high, with ratings ranging from 1.40+/-0.55 (item: the student does not interrupt the patient) to 2.51+/-0.89 (item: psychosocial anamnesis). Conclusions: HeiSA is a viable course concept for teaching anamnesis and physical examination skills. It integrates student teaching into routine care and can potentially be adapted to other outpatient departments. PMID- 29497697 TI - Advancing clinical reasoning in virtual patients - development and application of a conceptual framework. AB - Background: Clinical reasoning is a complex skill students have to acquire during their education. For educators it is difficult to explain their reasoning to students, because it is partly an automatic and unconscious process. Virtual Patients (VPs) are used to support the acquisition of clinical reasoning skills in healthcare education. However, until now it remains unclear which features or settings of VPs optimally foster clinical reasoning. Therefore, our aims were to identify key concepts of the clinical reasoning process in a qualitative approach and draw conclusions on how each concept can be enhanced to advance the learning of clinical reasoning with virtual patients. Methods: We chose a grounded theory approach to identify key categories and concepts of learning clinical reasoning and develop a framework. Throughout this process, the emerging codes were discussed with a panel of interdisciplinary experts. In a second step we applied the framework to virtual patients. Results: Based on the data we identified the core category as the "multifactorial nature of learning clinical reasoning". This category is reflected in the following five main categories: Psychological Theories, Patient-centeredness, Context, Learner-centeredness, and Teaching/Assessment. Each category encompasses between four and six related concepts. Conclusions: With our approach we were able to elaborate how key categories and concepts of clinical reasoning can be applied to virtual patients. This includes aspects such as allowing learners to access a large number of VPs with adaptable levels of complexity and feedback or emphasizing dual processing, errors, and uncertainty. PMID- 29497698 TI - A model of interprofessional problem-based learning for medical and nursing students: Implementation, evaluation and implications for future implementation. AB - Objective: In Germany there is little evidence of interprofessional problem-based learning (PBL) to date. For this reason a corresponding course for medical and nursing students was implemented. The goal was to analyse the feasibility and usefulness from the point of view of the students. Method: For the purposes of evaluation a quantitative observational study was conducted with a pre-course survey, a teaching evaluation and a post-course survey. The pre- and post-course surveys took place before the commencement of and after the conclusion of learning. The teaching evaluation was carried out after the conclusion of the interprofessional course. In total there were five medical students and five nursing students who took part. The descriptive data analysis was carried out using the statistics software package SPSS. The data from the open text fields was transcribed and evaluated using qualitative content analysis. Results: The students' assessment of the interprofessional PBL was predominantly positive. They stated that they were able to expand their knowledge of the roles of the other profession, that the interprofessional course had a positive effect in terms of mutual appreciation and that the tutor had a positive influence on the interprofessional PBL due to his cooperative learning support. Suggestions for improvement were concerned with the expansion of the interprofessional exchange and the establishment of a set timetable for the tutorials. Conclusion: The first study results of the Bildungscluster study can be used to make adjustments to the interprofessional PBL in order to be able to implement the course with a greater number of participants. Further studies are needed in order to comprehensively examine the learning effects and the impact on daily practice. PMID- 29497700 TI - How could the topic patient safety be embedded in the curriculum? A recommendation by the Committee for Patient Safety and Error Management of the GMA. AB - The topic of patient safety is of fundamental interest for the health care sector. In view of the realisation of the National Competence-Based Learning Objectives Catalogue for Undergraduate Medical Education (NKLM) this topic now has to be prepared for medical education. For a disciplinary and content-related orientation the GMA Committee developed the Learning Objectives Catalogue Patient Safety for Undergraduate Medical Education (GMA-LZK). To ensure an optimal implementation of the GMA-LZK we recommend a longitudinal embedding into the existing curriculum. This position paper supports the implementation of the GMA LZK and is aimed at everyone who wants to establish teaching courses on the topic patient safety and embed them in the curriculum. In light of this, we will initially describe the key features for a structured analysis of the current situation. Based on three best-practice-examples, as seen in the faculties of Freiburg, Bonn and Munich, different approaches to the implementation of the GMA LZK will be illustrated. Lastly, we will outline the methodical requirements regarding the curriculum development as well as the disciplinary and methodical competences that the lecturers will have to hold or develop to fulfil the requirements. PMID- 29497699 TI - How the Start into the Clinical Elective Year Could be Improved: Qualitative Results and Recommendations from Student Interviews. AB - Background: Entering the Clinical Elective Year (CEY) is a challenging transition phase for undergraduate medical students. Students become members of a professional team, thereby taking over certain tasks, which are executed more or less independently. Factors which facilitate (or impede) this transition in the perception of students are not well described. We therefore wanted to explore, what students perceived to be helpful during the first phase of the CEY and possibly derive respective recommendations. Methods: We conducted semi-structured interviews with 5th year medical students after they had completed the first two months of their CEY. Students were asked which problems they had faced and how they felt prepared for the CEY. Interviews were audio-recorded, transcribed, and analysed by qualitative content analysis. Results: From 34 interviews, we included 28 into analysis. Overall, 24 students were satisfied or very satisfied with their start into the CEY. Satisfaction was expressed with respect to workplace experiences, learning progress, responsibilities and team integration. Especially, students appreciated if they were integrated as active members of the team, were given responsibility for certain units of work, and received well structured formal teaching and supervision. Students had divergent opinions about the quality of teaching and supervision, about their own achievements, and the recognition they received. Students recommended improvements in respect to formal teaching and supervision by clinical supervisors, preparation of the CEY by university, and supporting structures in the hosting institution. Conclusion: Students in this study were generally satisfied with the first two months of their CEY. Facilitating factors were active and responsible involvement into routine patient care, and high quality formal teaching and supervision. Findings may inform universities, teaching hospitals, and students how to better shape the first phase of the CEY. PMID- 29497701 TI - Vitronectin as a Micromanager of Cell Response in Material-Driven Fibronectin Nanonetworks. AB - Surface functionalization strategies of synthetic materials for regenerative medicine applications comprise the development of microenvironments that recapitulate the physical and biochemical cues of physiological extracellular matrices. In this context, material-driven fibronectin (FN) nanonetworks obtained from the adsorption of the protein on poly(ethyl acrylate) provide a robust system to control cell behavior, particularly to enhance differentiation. This study aims at augmenting the complexity of these fibrillar matrices by introducing vitronectin, a lower-molecular-weight multifunctional glycoprotein and main adhesive component of serum. A cooperative effect during co-adsorption of the proteins is observed, as the addition of vitronectin leads to increased fibronectin adsorption, improved fibril formation, and enhanced vitronectin exposure. The mobility of the protein at the material interface increases, and this, in turn, facilitates the reorganization of the adsorbed FN by cells. Furthermore, the interplay between interface mobility and engagement of vitronectin receptors controls the level of cell fusion and the degree of cell differentiation. Ultimately, this work reveals that substrate-induced protein interfaces resulting from the cooperative adsorption of fibronectin and vitronectin fine-tune cell behavior, as vitronectin micromanages the local properties of the microenvironment and consequently short-term cell response to the protein interface and higher order cellular functions such as differentiation. PMID- 29497702 TI - alpha-Tubulin Acetyltransferase Is a Novel Target Mediating Neurite Growth Inhibitory Effects of Chondroitin Sulfate Proteoglycans and Myelin-Associated Glycoprotein. AB - Damage to the CNS results in neuronal and axonal degeneration, and subsequent neurological dysfunction. Endogenous repair in the CNS is impeded by inhibitory chemical and physical barriers, such as chondroitin sulfate proteoglycans (CSPGs) and myelin-associated glycoprotein (MAG), which prevent axon regeneration. Previously, it has been demonstrated that the inhibition of axonal histone deacetylase-6 (HDAC6) can promote microtubule alpha-tubulin acetylation and restore the growth of CSPGs- and MAG-inhibited axons. Since the acetylation of alpha-tubulin is regulated by two opposing enzymes, HDAC6 (deacetylation) and alpha-tubulin acetyltransferase-1 (alphaTAT1; acetylation), we have investigated the regulation of these enzymes downstream of a growth inhibitory signal. Our findings show that exposure of primary mouse cortical neurons to soluble CSPGs and MAG substrates cause an acute and RhoA-kinase-dependent reduction in alpha tubulin acetylation and alphaTAT1 protein levels, without changes to either HDAC6 levels or HDAC6 activity. The CSPGs- and MAG-induced reduction in alphaTAT1 occurs primarily in the distal and middle regions of neurites and reconstitution of alphaTAT1, either by Rho-associated kinase (ROCK) inhibition or lentiviral mediated alphaTAT1 overexpression, can restore neurite growth. Lastly, we demonstrate that CSPGs and MAG signaling decreases alphaTAT1 levels posttranscriptionally via a ROCK-dependent increase in alphaTAT1 protein turnover. Together, these findings define alphaTAT1 as a novel potential therapeutic target for ameliorating CNS injury characterized by growth inhibitory substrates that are prohibitive to axonal regeneration. PMID- 29497703 TI - Neural Determinants of Task Performance during Feature-Based Attention in Human Cortex. AB - Studies of feature-based attention have associated activity in a dorsal frontoparietal network with putative attentional priority signals. Yet, how this neural activity mediates attentional selection and whether it guides behavior are fundamental questions that require investigation. We reasoned that endogenous fluctuations in the quality of attentional priority should influence task performance. Human subjects detected a speed increment while viewing clockwise (CW) or counterclockwise (CCW) motion (baseline task) or while attending to either direction amid distracters (attention task). In an fMRI experiment, direction-specific neural pattern similarity between the baseline task and the attention task revealed a higher level of similarity for correct than incorrect trials in frontoparietal regions. Using transcranial magnetic stimulation (TMS), we disrupted posterior parietal cortex (PPC) and found a selective deficit in the attention task, but not in the baseline task, demonstrating the necessity of this cortical area during feature-based attention. These results reveal that frontoparietal areas maintain attentional priority that facilitates successful behavioral selection. PMID- 29497706 TI - Plexiform Neurofibroma of the Posterior Tibial Nerve Misdiagnosed as Proximal Tarsal Tunnel Syndrome: A Case Report. AB - Plexiform neurofibromas of the foot are rare, benign tumors of the peripheral nerves. Diagnosis can be challenging if they present with symptoms mimicking other peripheral nerve pathologies. Tarsal tunnel syndrome is an entrapment syndrome of the entire tibial nerve behind the medial malleolus and under the flexor retinaculum. The clinical presentation typically includes posteromedial pain, positive Tinel's sign, and neurogenic signs, including both the sensation of numbness and the actual hypoesthesia and clawing of the toes. Here, we report the case of a 59-year-old female patient with plexiform neurofibroma with symptoms similar to those of tarsal tunnel syndrome. The plexiform neurofibroma was surgically excised and the nerve function was partially preserved. PMID- 29497707 TI - Mentoring Clinical-Year Medical Students: Factors Contributing to Effective Mentoring. AB - Theory: Academic mentoring is an effective method of enhancing undergraduate medical student academic performance, research productivity, career planning, and overall satisfaction. Hypotheses: This study investigates the relationship between mentor characteristics and mentee academic performance, with an emphasis on identifying students who need special support. Methods: A cross-sectional study was conducted among fourth-year medical students at King Abdulaziz University Faculty of Medicine undertaking the clinical skills module (CSM) rotation. Mentors included senior and junior faculty members from the Department of Internal Medicine and the Department of Family Medicine. King Abdulaziz University Faculty of Medicine assigned 1 mentor for every 10 medical students. We organized our mentoring program in the following format: (1) an initial group meeting (mentor with all 10 medical students) and (2) subsequent one-on-one meetings (mentor with each mentee alone). We assessed mentor characteristics, student academic performance and satisfaction, and the rate of mentees referred for special support. Results: A total of 184 students completed the CSM rotation. Among these, 90 students responded to the preprogram survey, with 83% reporting that mentoring was important to them. Group meetings and one-on-one meetings were attended by 60% and 49% of all students, respectively. The most frequent type of support required by the participating students was psychological support (12% of mentees). Participation in the mentoring program had no significant effect on student academic performance. Mentor seniority (P = .024) and motivation (P = .002) were significantly associated with the rate of student referral for special support. Conclusions: This study demonstrated that academic mentoring can be effective in enhancing student outcomes and promoting special support for students. Moreover, mentor and mentee motivation were found to be essential elements of a successful mentoring program. PMID- 29497704 TI - Atypical Localization and Dissociation between Glucose Uptake and Amyloid Deposition in Cognitively Normal APOE*E4 Homozygotic Elders Compared with Patients with Late-Onset Alzheimer's Disease. AB - Alzheimer's disease (AD) progresses insidiously over decades. Therefore, study of preclinical AD is critical to identify early pathophysiological changes as potential targets for prevention or treatment. The brain processes at the preclinical stage remain minimally understood. Aside from age, the E4 allele of APOE flags a group at particularly high risk of late-onset AD (LOAD). Studies of these individuals could provide insights about the ontogenesis of AD offering clues for novel treatment strategies. To this end, cognitively normal, APOE*E4 homozygotes from the Alzheimer's Diseases Neuroimaging Research Initiative database (ADNI-LONI) provided fluorodeoxyglucose and amyloid (florbetapir) PET scans (n = 8 and 7, respectively; mean age 76 years). Their scans were compared to those of matched cognitively normal elders who were not E4 carriers. There was dissociation in the distribution between glucose uptake and amyloid deposition in the homozygotes. Peak hypometabolism localized bilaterally along the medial temporal cortex. In contrast, peak amyloid deposition localized principally to the putamen, a finding also seen in preclinical carriers of autosomal dominant AD mutations and preclinical AD associated with Down syndrome. Additional regions of amyloid deposition in homozygotes were medial prefrontal cortices including the anterior cingulate, middle and inferior frontal cortices, and middle and inferior occipital cortices. These findings contrast with those reported for LOAD. These data begin to characterize elders with normal cognition despite high AD risk in comparison to the known phenotypes of patients with LOAD. PMID- 29497708 TI - TelePain: Primary Care Chronic Pain Management through Weekly Didactic and Case based Telementoring. AB - Chronic pain is a significant problem among military personnel and a priority of the military health system. The U.S. Army Surgeon General's Pain Management Task Force recommends using telehealth capabilities to enhance pain management. This article describes the development and evaluation of a telehealth intervention (TelePain) designed to improve access to pain specialist consultation in the military health system. The study uses a wait-list controlled clinical trial to test: 1) effectiveness of the intervention, and 2) interviews to assess barriers and facilitators of the intervention implementation. The intervention involves a didactic presentation based on the Joint Pain Education Curriculum followed by patient case presentations and multi-disciplinary discussion via videoconference by clinicians working in the military health system. A panel of pain specialists representing pain medicine, internal medicine, anesthesiology, rehabilitation medicine, psychiatry, addiction medicine, health psychology, pharmacology, nursing, and complementary and integrative pain management provide pain management recommendations for each patient case. We use the Pain Assessment Screening Tool and Outcomes Registry (PASTOR) to measure patient outcomes, including pain, sleep, fatigue, anxiety, and depression. This article reports some of the challenges and lessons learned during early implementation of the TelePain intervention. Weekly telephone meetings among the multisite research team were instrumental in problem solving, identifying problem areas, and developing solutions. Solutions for recruitment challenges included additional outreach and networking to military health providers, both building on. PMID- 29497705 TI - Amygdala Adaptation and Temporal Dynamics of the Salience Network in Conditioned Fear: A Single-Trial fMRI Study. AB - Research in rodents has established the role of the amygdaloid complex in defensive responses to conditioned threat. In human imaging studies, however, activation of the amygdala by conditioned threat cues is often not observed. One hypothesis states that this finding reflects adaptation of amygdaloid responses over time. We tested this hypothesis by estimating single-trial neural responses over a large number of conditioning trials. Functional MRI (fMRI) was recorded from 18 participants during classical differential fear conditioning: Participants viewed oriented grayscale grating stimuli (45 degrees or 135 degrees ) presented centrally in random order. In the acquisition block, one grating (the CS+) was paired with a noxious noise, the unconditioned stimulus (US), on 25% of trials. The other grating, denoted CS-, was never paired with the US. Consistent with previous reports, BOLD in dorsal anterior cingulate cortex (dACC) and insula, but not the amygdala, was heightened when viewing CS+ stimuli that were not paired with US compared to CS- stimuli. Trial-by-trial analysis showed that over the course of acquisition, activity in the amygdala attenuated. Interestingly, activity in the dACC and insula also declined. Representational similarity analysis (RSA) corroborated these results, indicating that the voxel patterns evoked by CS+ and CS- in these brain regions became less distinguishable over time. Together, the present findings support the hypothesis that the lack of BOLD differences in the amygdaloid complex in many studies of classical conditioning is due to adaptation, and the adaptation effects may reflect changes in large-scale networks mediating aversive conditioning, particularly the salience network. PMID- 29497710 TI - Towards reliable references for electron paramagnetic resonance parameters based on quantum chemistry: the case of verdazyl radicals. AB - We present an efficient and accurate computational procedure to calculate properties measurable by EPR spectroscopy. We simulate a molecular dynamics (MD) trajectory by employing the quantum mechanically derived force field (QMDFF) [S. Grimme, J. Chem. Theory Comput., 2014, 10, 4497] and sample the trajectory at different time steps. For each snapshot EPR properties are calculated with a hybrid density functional theory (DFT) method. EPR spectra are simulated based on the averaged results. We applied the strategy to a number of previously published and novel verdazyl radicals, for which we recorded EPR spectra. The resulting simulated spectra are compatible with experiment already before employing an additional fitting step, in contrast to those from single point electronic structure calculations. After the refinement, the experimental data are excellently reproduced, and the fitted EPR parameters do not deviate much from the calculated ones. This provides confidence in ascribing a direct physical meaning to the refined data in terms of experimental EPR parameters rather than merely considering them as mathematical fit parameters. We also find that couplings to hydrogen nuclei have a significant influence on the spectra of verdazyl radicals. PMID- 29497711 TI - Al-Doped Ni2P nanosheet array: a superior and durable electrocatalyst for alkaline hydrogen evolution. AB - It is highly desired to develop high-efficiency and low-cost catalysts for the hydrogen evolution reaction (HER). Herein, we report the development of an Al doped Ni2P nanosheet array on Ti mesh as a high-performance and durable electrocatalyst for the HER in 1.0 M KOH. Such a catalyst demands an overpotential of 129 mV to afford 10 mA cm-2 and maintains its catalytic activity for at least 20 h. This work offers us a promising cost-effective catalyst for large-scale electrolytic production of hydrogen fuels. PMID- 29497709 TI - A Protective Role for NKG2D-H60a Interaction via Homotypic T Cell Contact in Nonobese Diabetic Autoimmune Diabetes Pathogenesis. AB - The NK group 2 member D (NKG2D) immune receptor is implicated in both human and mouse autoimmune diabetes. However, the significance of NKG2D in diabetes pathogenesis has been unclear due to conflicting reports as to the importance of this receptor in the NOD mouse model. In this study we demonstrate that NKG2D expression affects NOD diabetes development by at least two previously undescribed, and opposing, mechanisms. First, we demonstrate that the NKG2D ligand H60a is induced on activated NOD T cells, and that NKG2D-H60a interaction during CD8+ T cell differentiation into CTLs generally decreases the subsequent CTL effector cytokine response. This corresponds to an increase in diabetes development in NKG2D-deficient compared with wild-type NOD mice under microbiota depleted conditions. Second, we demonstrate that NKG2D promotes NOD diabetes development through interaction with the microbiota. Together these findings reveal a previously undescribed role for NKG2D ligand expression by activated T cells in CTL development. Further, they demonstrate that NKG2D has both diabetogenic and antidiabetogenic roles in NOD diabetes development. PMID- 29497712 TI - Systematic exploitation of thermotropic bicontinuous cubic phase families from 1,2-bis(aryloyl)hydrazine-based molecules. AB - Rational design of molecules that exhibit a thermotropic bicontinuous cubic (Cub) phase has been earnestly desired. In this work, we describe the suitable selection of a molecular motif that has enabled the systematic exploitation of eight new series of Cub-phase molecules with symmetric molecular cores, N-n (1), PB-n (2), S-n (3), and PEB-n (4), and unsymmetric cores, B-N-n (5), B-PB-n (6), B S-n (7), and B-PEB-n (8). These eight series all originate from achiral chain core-chain type rod-like molecules that exhibit two types of Cub phases, an achiral Ia3d phase, and a chiral phase. All the Ia3d phases formed were found to be isomorphous structures, with their cell dimensions being proportional to the core size, and the same was true for the latter chiral phase. We demonstrated that the formation is mainly governed by the segregation between core and alkyl moieties of the molecules, and thus, by the weight fraction of the core portion fcore. This work also demonstrates that the central dicarbonylhydrazine linkage bearing intermolecular hydrogen bonding ability exhibits a pinning effect that prevents slippage of pi-stacks of molecules, which is critical for the formation of the two Cub phases that are composed of chiral networks with twisted molecular arrangements. In each series, the emergence of spontaneous chirality formation that occurred in the chiral phase was limited to between 0.36 and 0.50 in the range of fcore. An interesting insight was that the introduced unsymmetry of the molecular core strongly influenced the phase behavior, which lowered the temperature range of Cub phases to around that of the smallest core series B-n, while the high temperature limit (Tc) was roughly proportional to the core size, as determined by the strength of intermolecular pi-pi interactions. PMID- 29497713 TI - Protein cage assembly across multiple length scales. AB - Within the materials science community, proteins with cage-like architectures are being developed as versatile nanoscale platforms for use in protein nanotechnology. Much effort has been focused on the functionalization of protein cages with biological and non-biological moieties to bring about new properties of not only individual protein cages, but collective bulk-scale assemblies of protein cages. In this review, we report on the current understanding of protein cage assembly, both of the cages themselves from individual subunits, and the assembly of the individual protein cages into higher order structures. We start by discussing the key properties of natural protein cages (for example: size, shape and structure) followed by a review of some of the mechanisms of protein cage assembly and the factors that influence it. We then explore the current approaches for functionalizing protein cages, on the interior or exterior surfaces of the capsids. Lastly, we explore the emerging area of higher order assemblies created from individual protein cages and their potential for new and exciting collective properties. PMID- 29497714 TI - Bimetallic junction mediated synthesis of multilayer graphene edges towards ultrahigh capacity for lithium ion batteries. AB - In this work, we report on a novel strategy to synthesize high-density graphene edges on a vertically-aligned nanorod array substrate based on multiple segmented Ni-Au units. The growth of graphene layers on Ni and Au was performed by chemical vapor deposition (CVD) leading to the effective generation of edge-rich multilayer graphene due to the distinct carbon solubility. The composite material was applied as an anode in a lithium ion battery (LIB) whose discharging capacity was found to closely depend on the total number of Ni-Au junctions within the vertical nanorods. Graphene deposited on the 19-junction composite Ni-(Au-Ni)9 exhibited an ultrahigh capacity of 86.3 MUAh cm-2 at 50 MUA cm-2 which was much higher than graphene deposited on 1-junction, 2-junction and pure Ni nanorods. This ultrahigh capacity was mainly ascribed to the generation of high-density graphene edges engineered by the bimetallic junction. The proposed strategy opens new appealing routes to synthesize high-density graphene edges using bimetallic junctions, which is promising for increasing the performance of LIBs and other electrochemical energy systems (supercapacitors, fuel cells, etc.). PMID- 29497715 TI - SypHer3s: a genetically encoded fluorescent ratiometric probe with enhanced brightness and an improved dynamic range. AB - We designed a genetically encoded ratiometric fluorescent probe, SypHer3s, with enhanced brightness and optimized pKa, which responds to pH changes in different cellular compartments. SypHer3s was successfully utilized for imaging the pH dynamics in mitochondria of living neurons and in quantitative pH measurement in zebrafish embryos. PMID- 29497716 TI - A computational study of high pressure polymorphic transformations in monazite type LaPO4. AB - Polymorphic transformations in LaPO4 are investigated as a function of pressure using density functional theory (DFT) based calculations under the generalized gradient approximation. The monazite-type (P21/n) -> barite-type (Pbnm) structural transformation is identified at 16.2 GPa and experimentally, no transformation is observed near this pressure. A discontinuity in the pressure volume relation (of 4.16% volume discontinuity compared to the monazite structure at the same pressure) and unit-cell dimensions is observed around 28 GPa, which matches well with the previous experimental results. The pressure of discontinuity matches the DFT calculated monazite-type (P21/n) -> post barite type (P212121) structural transformation pressure. The equation of state, single crystal elastic constants and phonon dispersion curves of the different polymorphs as a function of pressure are determined. Both the barite-type (Pbnm) and post barite-type (P212121) structures are mechanically and dynamically stable at 27 GPa indicating that the monazite-type (P21/n) -> barite-type (Pbnm) phase transformation may be hindered by a kinetic barrier. The phase transformation in monazite-type LaPO4 is driven by a softening of the C25 single crystal elastic constant. Moreover, a small displacement and tilting of PO4 tetrahedra as a function of pressure leads to a change in the La chemical environment and creates space for the construction of LaO12 polyhedra from LaO9 due to a phase transformation. PMID- 29497717 TI - Gas-generating reactions for point-of-care testing. AB - Gas generation-based measurement is an attractive alternative approach for POC (Point-of-care) testing, which relies on the amount of generated gas to detect the corresponding target concentrations. In gas generation-based POC testing, the integration of a target recognition component and a catalyzed gas-generating reaction initiated by the target introduction can lead to greatly amplified signals, which can be highly sensitive measured via distance readout or simple hand-held devices. More importantly, numerous gas-generating reactions are environment-friendly since their products such as oxygen and nitrogen are nontoxic and odourless, which makes gas generation-based POC testing safe and secure for inexperienced staff. Researchers have demonstrated that gas generation based measurements enable the rapid and highly sensitive POC detection of a variety of analytes. In this review, we focus on the recent developments in gas generation-based POC testing systems. The common types of gas-generating reactions are first listed and the translation of gas signals to different signal readouts for POC testing are then summarized, including distance readouts and hand-held devices. Moreover, we introduce gas bubbles as actuators to power microfluidic devices. We finally provide the applications and future perspective of gas generation-based POC testing systems. PMID- 29497718 TI - Deciphering the biochemical similarities and differences among mouse embryonic stem cells, somatic and cancer cells using ATR-FTIR spectroscopy. AB - Cellular macromolecules play important roles in cellular behaviors and biological processes. In the current work, cancer (KLN205), normal (MSFs) and mouse embryonic stem cells (mESCs) are compared using ATR-FTIR spectroscopy. Modifications in the composition, concentration, structure and function-related changes in the cellular components were deciphered using the infrared spectra. Our results revealed that cancer and embryonic stem cells are very similar but highly different from the normal cells based on the spectral variations in the protein, lipid, carbohydrate and nucleic acid components. The longest lipid acyl chains exist in mESCs, while cancer cells harbor the lowest lipid amount, short lipid acyl chains, a high content of branched fatty acids and thin cell membranes. The highest cellular growth rate and accelerated cell divisions were observed in the cancer cells. However, the normal cells harbor low nucleic acid and glycogen amounts but have a higher lipid composition. Any defect in the signaling pathways and/or biosynthesis of these cellular parameters during the embryonic-to-somatic cell transition may lead to physiological and molecular events that promote cancer initiation, progression and drug resistance. We conclude that an improved understanding of both similarities and differences in the cellular mechanisms among the cancer, normal and mESCs is crucial to develop a potential clinical relevance, and ATR-FITR can be successfully used as a novel approach to gain new insights into the stem cell and cancer research. We suggest that targeting the cellular metabolisms (glycogen and lipid) can provide new strategies for cancer treatment. PMID- 29497719 TI - In situ plasma-assisted atmospheric nitrogen fixation using water and spray-type jet plasma. AB - In this study, a sustainable nitrogen fixation process was presented under atmospheric conditions and without introducing hydrogen or any catalyst. The novel in situ synthesis in this study used an advanced spray-type jet plasma, which significantly improved the fixation rate of nitrite, nitrate, and ammonium. Furthermore, the mechanism focusing on the co-synthesis of the abovementioned three nitrogen compounds was proposed based on the synergistic interactions between the gas-phase plasma and liquid surface dissociation. PMID- 29497720 TI - Doping effect of non-metal group in porous ultrathin g-C3N4 nanosheets towards synergistically improved photocatalytic hydrogen evolution. AB - Searching for effective approaches of accelerating charge separation and broadening optical absorption is critical for designing a high-performance photocatalytic system. Herein, a photocatalyst based on the non-metal group doped porous ultrathin g-C3N4 nanosheets (CNB NS) was prepared through a combined methodology of precursor reforming and thermal condensation. The synergistic effect of non-metal group doping and porous ultrathin nanosheet-architecture not only endow the material with improved light harvesting and regulated band structure, but also facilitate the electron-hole pair separation, supplying numerous active reactive sites and electron diffusion channels. As a result, the CNB NS photocatalyst exhibits a highly efficient photocatalytic H2 performance (the apparent quantum efficiency is 7.45% at 420 nm) and stability in water under the visible light, which is approximately 13 times higher than that of pure g C3N4. This study may open a new perspective for designing the non-metal group doped g-C3N4 photocatalyst and further fabricate other advanced photocatalytic materials. PMID- 29497721 TI - Computational engineering of cellulase Cel9A-68 functional motions through mutations in its linker region. AB - Microbial cellulosic degradation by cellulases has become a complementary approach for biofuel production. However, its efficiency is hindered by the recalcitrance of cellulose fibres. In this context, computational protein design methods may offer an efficient way to obtain variants with improved enzymatic activity. Cel9A-68 is a cellulase from Thermobifida fusca that is still active at high temperatures. In a previous work, we described a collective bending motion, which governs the overall cellulase dynamics. This movement promotes the approximation of its CBM and CD structural domains (that are connected by a flexible linker). We have identified two residues (G460 and P461) located at the linker that act as a hinge point. Herein, we applied a new level of protein design, focusing on the modulation of this collective motion to obtain cellulase variants with enhanced functional dynamics. We probed whether specific linker mutations would affect Cel9A-68 dynamics through computational simulations. We assumed that P461G and G460+ (with an extra glycine) constructs would present enhanced interdomain motions, while the G460P mutant would be rigid. From our results, the P461G mutation resulted in a broader exploration of the conformational space, as confirmed by clustering and free energy analyses. The WT enzyme was the most rigid system. However, G460P and P460+ explored distinct conformational states described by opposite directions of low-frequency normal modes; they sampled preferentially closed and open conformations, respectively. Overall, we highlight two significant findings: (i) all mutants explored larger conformational spaces than the WT; (ii) the selection of distinct conformational populations was intimately associated with the mutation considered. Thus, the engineering of Cel9A-68 motions through linker mutations may constitute an efficient way to improve cellulase activity, facilitating the disruption of cellulose fibres. PMID- 29497722 TI - Peptide-based nanoprobes for molecular imaging and disease diagnostics. AB - Pathological changes in a diseased site are often accompanied by abnormal activities of various biomolecules in and around the involved cells. Identifying the location and expression levels of these biomolecules could enable early-stage diagnosis of the related disease, the design of an appropriate treatment strategy, and the accurate assessment of the treatment outcomes. Over the past two decades, a great diversity of peptide-based nanoprobes (PBNs) have been developed, aiming to improve the in vitro and in vivo performances of water soluble molecular probes through engineering of their primary chemical structures as well as the physicochemical properties of their resultant assemblies. In this review, we introduce strategies and approaches adopted for the identification of functional peptides in the context of molecular imaging and disease diagnostics, and then focus our discussion on the design and construction of PBNs capable of navigating through physiological barriers for targeted delivery and improved specificity and sensitivity in recognizing target biomolecules. We highlight the biological and structural roles that low-molecular-weight peptides play in PBN design and provide our perspectives on the future development of PBNs for clinical translation. PMID- 29497723 TI - Different antitumor effects of quercetin, quercetin-3'-sulfate and quercetin-3 glucuronide in human breast cancer MCF-7 cells. AB - This study was designed to investigate the tumor-inhibitory effects of quercetin (Que) and its water-soluble metabolites, quercetin-3'-sulfate (Q3'S) and quercetin-3-glucuronide (Q3G), as well as to make the molecular mechanism and structure-antitumor relationship clear. It was found that Que, Q3'S, and Q3G could inhibit the growth of human breast cancer MCF-7 cells in a dose-dependent manner, with the IC50 values of 23.1, 27.6, and 73.2 MUM, respectively, and their anticancer effect was ranked as Que > Q3'S > Q3G. Furthermore, flow cytometric assay revealed that Que, Q3'S, and Q3G mediated the cell-cycle arrest principally at the S phase and decreased the number of G0/G1 and G2/M after a 48 h treatment with human breast MCF-7 cells. Moreover, it was found that 70.8%, 58.2%, and 48.0% of MCF-7 cancer cells entered the early phase of apoptosis when treated with 100 MUM Que, Q3'S, and Q3G for 48 h, respectively. In addition, induction of apoptosis by Que, Q3'S, and Q3G was accompanied by marginal generation of intracellular reactive oxygen species (ROS) in the MCF-7 cancer cells. Overall, these results demonstrate that Que, Q3'S, and Q3G possess strong antitumor effects through induction of an ROS-dependent apoptosis pathway in MCF-7 cells. PMID- 29497724 TI - Vibrational spectra of small methylamine clusters accessed by an ab initio anharmonic approach. AB - Methylamine (MMA) is one of the simplest amines, and the vibrational spectra of its dimer have recently been obtained experimentally. The vibrational spectra of NH stretch modes were well resolved, but the complex features of the CH3 group could not be fully accounted for even with the assistance of ab initio molecular dynamics (AIMD) with various density functional methods. In this study, we carried out anharmonic vibrational calculations on MMA clusters up to tetramers using MP2/aug-cc-pVDZ to examine vibrational coupling among CH/NH and compute the vibrational spectra of these clusters between 2800 and 3500 cm-1. We found that the main origin of the complexity between 2800 and 3000 cm-1 was caused by Fermi resonance (FR) between the stretching and bending overtones of the CH3 group. This spectral feature becomes simpler in trimers and tetramers. Furthermore, Fermi resonance in the NH2 group is found to be very strong. In the MMA dimer, no noticeable FR features can be found; however, in its trimers and tetramers, the enhancement of hydrogen bond strength due to the cooperative effect will cause the N-H stretching mode to red-shift to revert the energy order of the fundamental of the N-H stretch and overtone of N-H bending between n = 3 and n = 4. Therefore, significant re-distribution of the intensities of the bands at 3200 and 3300 cm-1 should be seen. PMID- 29497725 TI - Modified optical properties via induced cation disorder in self-activated NaMg2V3O10. AB - Cation disorder in the phosphor lattice could be one of the effective approaches to modify the luminescence efficiency. In this work, cation substitutions of (Mo6+-> V5+) and (Na+-> Mg2+) were conducted in the self-activated NaMg2V3O10. All the samples of Na1+xMg2-xV3-xMoxO10 (x = 0, 0.01, 0.05, 0.1, 0.2, 0.3) were prepared via solid-state reaction. The morphological properties were measured via SEM and EDS analyses. Structural Rietveld refinement was performed to investigate the microstructure in the lattices. The cation substitution brings about structural disorder in the phosphor, which exerts great modifications in the luminescence properties. NaMg2V3O10 presents an intrinsic indirect transition with a band gap of 3.22 eV. The incorporation of Mo6+ and Na+ in the lattices moves the optical absorption to a longer wavelength bringing about a narrower band gap. The luminescence intensity, thermal stability and corresponding lifetime were modified by the cation disorder in the self-activated phosphor. PMID- 29497726 TI - Formation and reactions of active five-membered phosphane/borane frustrated Lewis pair ring systems. AB - The reactive five-membered frustrated P/B Lewis pair 6a was generated from Tipp P(vinyl)2 (Tipp: 2,4,6-triisopropylphenyl) by a series of anti-Markovnikov and Markovnikov hydroboration reactions. The in situ generated compound dimerized to give 7a under kinetic control and the dimer pair 8a/9a under thermodynamic control. The Mes*-P(vinyl)2 analogue (Mes*: 2,4,6-tri-tert-butylphenyl) reacts in a similar way, but in this case the thermodynamic dimers are observed at r.t. whereas the monomer 6b is the dominant species at 80 degrees C in solution. It is an active dihydrogen splitting reagent. The in situ generated monomeric five membered P/B FLPs undergo addition reactions to various organic pi-reagents. With benzaldehyde or phenylacetylene this gave the respective zwitterionic heteronorbornene or -norbornadiene type products, the latter with liberation of ethylene. PMID- 29497727 TI - High efficiency two-photon uncaging coupled by the correction of spontaneous hydrolysis. AB - Two-photon (TP) uncaging of neurotransmitter molecules is the method of choice to mimic and study the subtleties of neuronal communication either in the intact brain or in slice preparations. However, the currently available caged materials are just at the limit of their usability and have several drawbacks. The local and focal nature of their use may for example be jeopardized by a high spontaneous hydrolysis rate of the commercially available compounds with increased photochemical release rate. Here, using quantum chemical modelling we show the mechanisms of hydrolysis and two-photon activation, and synthesized more effective caged compounds. Furthermore, we have developed a new enzymatic elimination method removing neurotransmitters inadvertently escaping from their compound during experiment. This method, usable both in one and two-photon experiments, allows for the use of materials with an increased rate of photochemical release. The efficiency of the new compound and the enzymatic method and of the new compound are demonstrated in neurophysiological experiments. PMID- 29497728 TI - Giant exchange coupling and field-induced slow relaxation of magnetization in Gd2@C79N with a single-electron Gd-Gd bond. AB - Magnetic properties of the azafullerene Gd2@C79N are studied by SQUID magnetometry. The effective exchange coupling constant jGd,e between the Gd spins and the spin of unpaired electron residing on the single-electron Gd-Gd bond is determined to be 170 +/- 10 cm-1. Low temperature AC measurements revealed field induced millisecond-long relaxation of magnetization. PMID- 29497729 TI - The impact of lactation and gestational age on the composition of branched-chain fatty acids in human breast milk. AB - Breast milk consumption reduces the incidence of necrotizing enterocolitis (NEC) in preterm infants compared to formula. Branched-chain fatty acids (BCFAs) are present in breast milk but not in most formulas intended for preterm infants. We aimed to determine the composition of BCFAs in the breast milk of mothers with preterm infants, and to understand the impact of gestational age at birth and stage of lactation on BCFA content. The main BCFAs in preterm breast milk were iso-14:0, iso-15:0, anteiso-15:0, iso-16:0, iso-17:0, and anteiso-17:0. Breast milk BCFAs as a percent of total fatty acids (g per 100 g, %) were significantly different across lactation stages, with the highest concentration in colostrum, followed by transitional and mature breast milk (median: 0.41, 0.31, and 0.28%, respectively, p < 0.05). Lower BCFAs in preterm breast milk compared to term breast milk may have been related to maternal intake, or the ability of the mammary gland to extract BCFA from plasma, or differences in mammary gland BCFA synthesis. BCFAs were mainly in the sn-2 position (52-65%), similar to palmitic acid. Overall, preterm and term breast milk BCFAs were similar and showed specific concentration patterns, resembling 16:0 with respect to sn-2 positional distribution. BCFAs were reduced with lactation stage, similar to highly unsaturated fatty acids. PMID- 29497730 TI - Infrared ion spectroscopy: an analytical tool for the study of metabolites. AB - Vibrational ion spectroscopy techniques coupled with mass spectrometry are applied to standard metabolites as a proof-of-principle demonstration for the structural identification of unknown metabolites. The traditional room temperature infrared multiple photon dissociation (IRMPD) spectroscopy technique is shown to differentiate chemical moieties in isobaric and isomeric variants. These results are compared to infrared spectra of cryogenically cooled analyte ions, showing enhanced spectral resolution, and thus also improved differentiation between closely related molecules, such as isomers. The cryogenic spectroscopy is effected in a recently developed mass-selective cryogenic linear ion trap, which is capable of high sensitivity and the ability to measure the IR spectra of multiple analytes simultaneously. PMID- 29497731 TI - Metal-coordination crosslinked N-polyindoles as recyclable high-performance thermosets and nondestructive detection for their tensile strength and glass transition temperature. AB - Metal coordination crosslinking between stiff N-polyindole chains was constructed, and the crosslinked films exhibited high tensile strength, high heat resistance and excellent polar solvent resistance. The noncovalent crosslinking can be further removed via external pyrophosphate, which endows the crosslinked polymer with a recyclable behavior. The tensile strength and glass transition temperature of the polymers can be nondestructively detected by taking advantage of the fluorescence quenching effect of metal coordination to the adjacent bipyridine structure. PMID- 29497732 TI - Target-guided screening of fragments (TGSOF) in the discovery of inhibitors against EV-A71 3C protease. AB - Target-guided screening of fragments (TGSOF) was developed and employed in the identification of EV-A71 3C protease (3Cpro) inhibitors. We identified 4 acetylpyridine and 3-acetylpyridine as effective P3 fragments of an inhibitor and obtained the corresponding irreversible inhibitors 12c and 12fvia this method. Furthermore, based on 12c and 12f, we have obtained reversible inhibitors 17c and 17f. These results demonstrated that TGSOF is a useful strategy for identifying suitable fragments in developing leads in drug discovery. PMID- 29497733 TI - Theoretical characterization of sulfur-to-selenium substitution in an emissive RNA alphabet: impact on H-bonding potential and photophysical properties. AB - We employ density functional theory (DFT) and time-dependent DFT (TDDFT) calculations to investigate the structural, energetic and optical properties of a new computationally designed RNA alphabet, where the nucleobases, tsA, tsG, tsC, and tsU (ts-bases), have been derived by replacing sulfur with selenium in the previously reported tz-bases, based on the isothiazolo[4,3-d]pyrimidine heterocycle core. We find out that the modeled non-natural bases have minimal impact on the geometry and energetics of the classical Watson-Crick base pairs, thus potentially mimicking the natural bases in a RNA duplex in terms of H bonding. In contrast, our calculations indicate that H-bonded base pairs involving the Hoogsteen edge of purines are destabilized as compared to their natural counterparts. We also focus on the photophysical properties of the non natural bases and correlate their absorption/emission peaks to the strong impact of the modification on the energy of the lowest unoccupied molecular orbital. It is indeed stabilized by roughly 1.1-1.6 eV as compared to the natural analogues, resulting in a reduction of the gap between the highest occupied and the lowest unoccupied molecular orbital from 5.3-5.5 eV in the natural bases to 3.9-4.2 eV in the modified ones, with a consequent bathochromic shift in the absorption and emission spectra. Overall, our analysis clearly indicates that the newly modelled ts-bases are expected to exhibit better fluorescent properties as compared to the previously reported tz-bases, while retaining similar H-bonding properties. In addition, we show that a new RNA alphabet based on size-extended benzo homologated ts-bases can also form stable Watson-Crick base pairs with the natural complementary nucleobases. PMID- 29497734 TI - Half-metallic and magnetic semiconducting behaviors of metal-doped blue phosphorus nanoribbons from first-principles calculations. AB - We investigate the electronic and magnetic properties of substitutional metal atom impurities in two-dimensional (2D) blue phosphorene nanoribbons using first principles calculations. In impure zigzag blue phosphorene nanoribbons (zBPNRs), a metal atom substitutes for a P atom at position "A/B". The V-"B"structure shows half-metallic properties, while the Mn-"A/B", V-"A", Fe-"B", and Cr-"A/B" structures show magnetic semiconductor properties. In addition, the Fe-"A" system shows magnetic metallic properties. On the other hand, for metal-doped armchair blue phosphorene nanoribbons (aBPNRs), the Mn-"A/B", V-"A", Fe-"A/B", and Cr "A/B" structures show magnetic semiconductor properties, while the V-"B" structure shows nonmagnetic properties. We find that the magnetic properties of such substitutional impurities can be understood by regarding the exchange splitting of the metal 3d orbitals. And from analyzing the electron orbitals, we conclude that the main contribution of the DOS for every system comes from the d and p orbitals. These results suggest excellent candidates for new magnetic semiconductors and half-metals for spintronic devices based on blue phosphorenes. PMID- 29497735 TI - Thermodynamic description of Tc(iv) solubility and carbonate complexation in alkaline NaHCO3-Na2CO3-NaCl systems. AB - The solubility of 99Tc(iv) was investigated in dilute to concentrated carbonate solutions (0.01 M <= Ctot<= 1.0 M, with Ctot = [HCO3-] + [CO32-]) under systematic variation of ionic strength (I = 0.3-5.0 M NaHCO3-Na2CO3-NaCl-NaOH) and pHm (-log[H+] = 8.5-14.5). Strongly reducing conditions (pe + pHm~ 2) were set with Sn(ii). Carbonate enhances the solubility of Tc(iv) in alkaline conditions by up to 3.5 log10-units compared to carbonate-free systems. Solvent extraction and XANES confirmed that Tc was kept as +IV during the timeframe of the experiments (<= 650 days). Solid phase characterization performed by XAFS, XRD, SEM-EDS, chemical analysis and TG-DTA confirmed that TcO2.0.6H2O(am) controls the solubility of Tc(iv) under the conditions investigated. Slope analysis of the solubility data in combination with solid/aqueous phase characterization and DFT calculations indicate the predominance of the species Tc(OH)3CO3- at pHm<= 11 and Ctot>= 0.01 M, for which thermodynamic and activity models are derived. Solubility data obtained above pHm~ 11 indicates the formation of previously unreported Tc(iv)-carbonate species, possibly Tc(OH)4CO32 , although the likely formation of additional complexes prevents deriving a thermodynamic model valid for this pHm-region. This work provides the most comprehensive thermodynamic dataset available for the system Tc4+-Na+-Cl--OH- HCO3--CO32--H2O(l) valid under a range of conditions relevant for nuclear waste disposal. PMID- 29497736 TI - Correction: Four new carbazole alkaloids from Murraya koenigii that display anti inflammatory and anti-microbial activities. AB - Correction for 'Four new carbazole alkaloids from Murraya koenigii that display anti-inflammatory and anti-microbial activities' by Yedukondalu Nalli et al., Org. Biomol. Chem., 2016, 14, 3322-3332. PMID- 29497737 TI - Computational prediction of a high ZT of n-type Mg3Sb2-based compounds with isotropic thermoelectric conduction performance. AB - N-type Mg3Sb2-based Zintl compounds are proved to be high-performance thermoelectric materials with multiple degenerate valleys and low lattice thermal conductivity. Here, we investigate the electronic band structure and the thermoelectric properties of n-type Mg3Sb2 using first-principles density functional theory. A high ZT of 3.1 at 725 K is obtained when the minimum lattice thermal conductivity and the optimal carrier concentration are reached. The calculated thermoelectric performance demonstrates that Mg3Sb2 possesses an isotropic character in thermoelectric transport. Furthermore, the calculated lattice thermal conductivity kappaL reveals that the unusually low kappaL in Mg3Sb2 predominantly originates from the large Gruneisen parameter gamma. PMID- 29497738 TI - Dual emissive bodipy-benzodithiophene-bodipy TICT triad with a remarkable Stokes shift of 194 nm. AB - An acceptor-donor-acceptor (A-D-A) triad based on a BODIPY acceptor and a benzodithiophene donor exhibited dual fluorescence and pronounced fluorescence solvatochromism because of twisted intramolecular charge transfer (TICT) state formation. Furthermore, it showed a Stokes shift of ~194 nm which is the highest known for any BODIPY compound with a readily tunable fluorescence and a high charge carrier mobility of 4.46 * 10-4 cm2 V-1 s-1. PMID- 29497739 TI - Combining sonicated cold development and pulsed electrodeposition for high aspect ratio sub-10 nm gap gold dimers for sensing applications in the visible spectrum. AB - Strong interactions between localized surface plasmons and nanoscale objects have led to the development of highly sensitive biochemical sensing in planar metallic nanostructures with sensing performance mainly dependent on the interaction volume and the local electric field. However, the sensitivity and the interaction volume of these planar structures have been limited by the achievable aspect ratios based on the standard lift-off process. We propose a new technique which involves cold sonicated development and pulsed electrodeposition to overcome this limitation, and demonstrate robust gold square dimers with sub-10 nm gaps and a gap aspect ratio of ~8. We show that smooth gold surfaces can be achieved by growing the gold film directly on a transparent ITO substrate without a gold seed layer, and demonstrate a significant improvement in Q factors and resonance contrast in electrodeposited dimers compared to dimers fabricated by physical vapor deposition. We demonstrate that the electrodeposited dimers exhibit near 50% higher bulk refractive index sensitivity than their planar counterparts. The technique may be used to grow a variety of metals of arbitrary geometries and spatial arrangements. PMID- 29497740 TI - Unusual strain response of thermal transport in dimerized three-dimensional graphene. AB - Newly synthesized 3D graphene with large porosity and hollow structure holds great potential in many applications. However, there is still controversy over the stable structure of the observed 3D graphene and the relevant physical and chemical properties are still lacking. From first-principles lattice dynamics and ab initio molecular dynamics simulation, we found that the previously proposed model for experimentally synthesized 3D graphene is not stable due to the dangling bonds along the connection junctions. We show that reconstruction of equidistant carbon atoms along the junctions, i.e. dimerization, can make the structure more energetically favorable and thermodynamically stable. More intriguingly, an anomalous non-monotonic response of strain-engineered lattice thermal conductivity is observed for the new 3D graphene structure with the highest thermal conductivity achieved at 3% strain. Upon analyzing individual phonon modes, it is found that the anomalous change is dominated by an overwhelming increase of the phonon relaxation time and the governing physics is unraveled using root mean-square displacement, Gruneisen parameter and local potential well in forming the dimerization of the C-C linkage. The fundamental mechanism would be very beneficial for the relevant applications of 3D graphene, such as thermal management of high power density energy storage. PMID- 29497741 TI - Sentence Diversity in Early Language Development: Recommendations for Target Selection and Progress Monitoring. AB - Purpose: This clinical focus article describes how to assess and when to target diverse, simple sentences as part of early language intervention. Method: The theoretical foundations and clinical motivations for assessing sentence diversity based on unique combinations of subjects and verbs are explained, followed by a description of how to compute the measure. Sentence diversity is then related to familiar developmental measures of lexical diversity, utterance length, and grammatical complexity in a sample of 40 typically developing toddlers at 30 months of age. Descriptive and correlational analyses are used to demonstrate how sentences become more diverse as utterances also become longer and more complex. Conclusions: The ability to produce simple sentences with diverse subject-verb combinations is proposed as a general developmental expectation for toddlers at 30 months of age. All 40 children produced at least 10 different subject-verb combinations in 30 min of parent-toddler conversation. Sentence diversity is also associated with familiar developmental measures. Recommendations are provided for using the measure of sentence diversity to inform treatment planning and monitor progress for young children with language disorders. Supplemental Material: https://doi.org/10.23641/asha.5895976. PMID- 29497743 TI - Contribution of global and local biological motion information to speed perception and discrimination. AB - To respond to movements of others and understand the intention of others' actions, it is important to accurately extract motion information from body movements. Here, using original and spatially scrambled point-light biological motions in upright and inverted orientations, we investigated the effect of global and local biological motion information on speed perception and sensitivity. The speed discrimination task revealed that speed sensitivity was higher for the original than for scrambled stimuli (Experiment 1) and higher for upright than for inverted stimuli (Experiment 2). Perceived motion speed was slower for the original than for scrambled stimuli (Experiment 2), but regardless of the orientation of the display (Experiment 1). A subsequent experiment comparing different scrambled stimuli of the same actions showed that the higher speed discrimination sensitivity to upright stimuli was preserved even in the scrambled biological motions (Experiment 3). Taken together, our findings suggest that perception of the speed of biological movements emanates from both global and local biological motion signals. PMID- 29497742 TI - Recent cross-modal statistical learning influences visual perceptual selection. AB - Incoming sensory signals are often ambiguous and consistent with multiple perceptual interpretations. Information from one sensory modality can help to resolve ambiguity in another modality, but the mechanisms by which multisensory associations come to influence the contents of conscious perception are unclear. We asked whether and how novel statistical information about the coupling between sounds and images influences the early stages of awareness of visual stimuli. We exposed subjects to consistent, arbitrary pairings of sounds and images and then measured the impact of this recent passive statistical learning on subjects' initial conscious perception of a stimulus by employing binocular rivalry, a phenomenon in which incompatible images presented separately to the two eyes result in a perceptual alternation between the two images. On each trial of the rivalry test, subjects were presented with a pair of rivalrous images (one of which had been consistently paired with a specific sound during exposure while the other had not) and an accompanying sound. We found that, at the onset of binocular rivalry, an image was significantly more likely to be perceived, and was perceived for a longer duration, when it was presented with its paired sound than when presented with other sounds. Our results indicate that recently acquired multisensory information helps resolve sensory ambiguity, and they demonstrate that statistical learning is a fast, flexible mechanism that facilitates this process. PMID- 29497744 TI - Speech Adaptation to Kinematic Recording Sensors: Perceptual and Acoustic Findings. AB - Purpose: This study used perceptual and acoustic measures to examine the time course of speech adaptation after the attachment of electromagnetic sensor coils to the tongue, lips, and jaw. Method: Twenty native English speakers read aloud stimulus sentences before the attachment of the sensors, immediately after attachment, and again 5, 10, 15, and 20 min later. They read aloud continuously between recordings to encourage adaptation. Sentence recordings were perceptually evaluated by 20 native English listeners, who rated 150 stimuli (which included 31 samples that were repeated to assess rater reliability) using a visual analog scale with the end points labeled as "precise" and "imprecise." Acoustic analysis began by segmenting and measuring the duration of the fricatives /s/ and /?/ as well as the whole sentence. The spectral center of gravity and spectral standard deviation of the 2 fricatives were measured using Praat. These phonetic targets were selected because the standard placement of sensor coils on the lingual surface was anticipated to interfere with normal fricative production, causing them to become distorted. Results: Perceptual ratings revealed a decrease in speech precision after sensor attachment and evidence of adaptation over time; there was little perceptual change beyond the 10-min recording. The spectral center of gravity for /s/ decreased, and the spectral standard deviation for /?/ increased after sensor attachment, but the acoustic measures showed no evidence of adaptation over time. Conclusion: The findings suggest that 10 min may be sufficient time to allow speakers to adapt before experimental data collection with Northern Digital Instruments Wave electromagnetic sensors. PMID- 29497745 TI - Considerations for the Use of Neuroimaging Technologies for Predicting Recovery of Speech and Language in Aphasia. AB - Purpose: The number of research articles aimed at identifying neuroimaging biomarkers for predicting recovery from aphasia continues to grow. Although the clinical use of these biomarkers to determine prognosis has been proposed, there has been little discussion of how this would be accomplished. This is an important issue because the best translational science occurs when translation is considered early in the research process. The purpose of this clinical focus article is to present a framework to guide the discussion of how neuroimaging biomarkers for recovery from aphasia could be implemented clinically. Method: The genomics literature reveals that implementing genetic testing in the real-world poses both opportunities and challenges. There is much similarity between these opportunities and challenges and those related to implementing neuroimaging testing to predict recovery in aphasia. Therefore, the Center for Disease Control's model list of questions aimed at guiding the review of genetic testing has been adapted to guide the discussion of using neuroimaging biomarkers as predictors of recovery in aphasia. Conclusion: The adapted model list presented here is a first and useful step toward initiating a discussion of how neuroimaging biomarkers of recovery could be employed clinically to provide improved quality of care for individuals with aphasia. PMID- 29497746 TI - Effects of Treatment Intensity on Outcomes in Acquired Apraxia of Speech. AB - Purpose: This investigation was designed to examine the effects of treatment intensity (i.e., dose frequency) on the outcomes of Sound Production Treatment (SPT) for acquired apraxia of speech. Method: Five men with chronic apraxia of speech and aphasia received both intense SPT (3 hr per day/3 days per week) and nonintense/traditional SPT (SPT-T; 1 hr per day/3 days per week) in the context of single-case experimental designs. Each treatment was applied separately to a designated set of experimental words with 1 treatment applied at a time. Twenty seven treatment sessions were conducted with each phase of treatment. Accuracy of articulation of target sounds within treated and untreated experimental words was measured during the course of the investigation. Results: All participants demonstrated improved articulation with both treatment intensities. Better maintenance of gains for treated items was found with SPT-T for 2 participants as measured at an 8-week posttreatment retention probe. Superior maintenance of increased accuracy of production of untreated items was also observed with SPT-T for all participants. Conclusion: A less intense (distributed) application of SPT facilitated better maintenance of improved articulatory accuracy for untreated items, and in some cases treated items, than intense SPT. Supplemental Materials: https://doi.org/10.23641/asha.5734053. PMID- 29497747 TI - Language Changes Following Combined Aphasia and Apraxia of Speech Treatment. AB - Purpose: Combined Aphasia and Apraxia of Speech Treatment (CAAST) is a newly developed treatment shown to increase production of accurate content in narrative discourse for persons with aphasia and apraxia of speech. The purpose of this post hoc study was to further describe lexical and morphosyntactic changes associated with changes in content production. Method: Existing probe data from 8 persons with aphasia who had completed CAAST were used to complete analyses of morphosyntactic production, lexical diversity, and novelty of content. Language analyses were completed using discourse samples obtained at numerous pretreatment and posttreatment intervals. Results: All participants demonstrated gains in morphosyntactic language output for treated items, which extended to untreated sets for 7 participants. All 8 increased in production of novel content. Lexical diversity increases were evident for most participants. Although there were some similarities in language changes, there was substantial variability across response profiles. Conclusion: CAAST, previously associated with positive treatment effects for production of accurate content, also appears to facilitate acquisition and generalization of morphosyntactic complexity, lexical diversity, and novelty of content for individuals with nonfluent aphasia. Further investigation is needed to determine causality and appropriate clinical application. Supplemental Material: https://doi.org/10.23641/asha.5912530. PMID- 29497748 TI - Describing Phonological Paraphasias in Three Variants of Primary Progressive Aphasia. AB - Purpose: The purpose of this study was to describe the linguistic environment of phonological paraphasias in 3 variants of primary progressive aphasia (semantic, logopenic, and nonfluent) and to describe the profiles of paraphasia production for each of these variants. Method: Discourse samples of 26 individuals diagnosed with primary progressive aphasia were investigated for phonological paraphasias using the criteria established for the Philadelphia Naming Test (Moss Rehabilitation Research Institute, 2013). Phonological paraphasias were coded for paraphasia type, part of speech of the target word, target word frequency, type of segment in error, word position of consonant errors, type of error, and degree of change in consonant errors. Results: Eighteen individuals across the 3 variants produced phonological paraphasias. Most paraphasias were nonword, followed by formal, and then mixed, with errors primarily occurring on nouns and verbs, with relatively few on function words. Most errors were substitutions, followed by addition and deletion errors, and few sequencing errors. Errors were evenly distributed across vowels, consonant singletons, and clusters, with more errors occurring in initial and medial positions of words than in the final position of words. Most consonant errors consisted of only a single-feature change, with few 2- or 3-feature changes. Importantly, paraphasia productions by variant differed from these aggregate results, with unique production patterns for each variant. Conclusions: These results suggest that a system where paraphasias are coded as present versus absent may be insufficient to adequately distinguish between the 3 subtypes of PPA. The 3 variants demonstrate patterns that may be used to improve phenotyping and diagnostic sensitivity. These results should be integrated with recent findings on phonological processing and speech rate. Future research should attempt to replicate these results in a larger sample of participants with longer speech samples and varied elicitation tasks. Supplemental Materials: https://doi.org/10.23641/asha.5558107. PMID- 29497749 TI - Effects of Epilepsy on Language Functions: Scoping Review and Data Mining Findings. AB - Purpose: This study involved a scoping review to identify possible gaps in the empirical description of language functioning in epilepsy in adults. With access to social network data, data mining was used to determine if individuals with epilepsy are expressing language-related concerns. Method: For the scoping review, scientific databases were explored to identify pertinent articles. Findings regarding the nature of epilepsy etiologies, patient characteristics, tested language modalities, and language measures were compiled. Data mining focused on social network databases to obtain a set of relevant language-related posts. Results: The search yielded 66 articles. Epilepsy etiologies except temporal lobe epilepsy and older adults were underrepresented. Most studies utilized aphasia tests and primarily assessed single-word productions; few studies included healthy control groups. Data mining revealed several posts regarding epilepsy-related language problems, including word retrieval, reading, writing, verbal memory difficulties, and negative effects of epilepsy treatment on language. Conclusion: Our findings underscore the need for future specification of the integrity of language in epilepsy, particularly with respect to discourse and high-level language abilities. Increased awareness of epilepsy related language issues and understanding the patients' perspectives about their language concerns will allow researchers and speech-language pathologists to utilize appropriate assessments and improve quality of care. PMID- 29497751 TI - Attentive Reading With Constrained Summarization Adapted to Address Written Discourse in People With Mild Aphasia. AB - Purpose: The purpose of this study was to examine the preliminary efficacy of Attentive Reading and Constrained Summarization-Written (ARCS-W) in people with mild aphasia. ARCS-W adapts an existing treatment, ARCS (Rogalski & Edmonds, 2008), to address discourse level writing in mild aphasia. ARCS-W focuses on the cognitive and linguistic skills required for discourse production. Method: This study was a within-subject pre-postdesign. Three people with mild aphasia participated. ARCS-W integrates attentive reading or listening with constrained summarization of discourse level material in spoken and written modalities. Outcomes included macro- (main concepts) and microlinguistic (correct information units, complete utterances) discourse measures, confrontation naming, aphasia severity, and functional communication. Results: All 3 participants demonstrated some generalization to untrained spoken and written discourse at the word, sentence, and text levels. Reduced aphasia severity and/or increased functional communication and confrontation naming were also observed in some participants. Conclusions: The findings of this study provide preliminary evidence of the efficacy of ARCS-W to improve spoken and written discourse in mild aphasia. Different generalization patterns suggest different mechanisms of improvement. Further research and replication are required to better understand how ARCS-W can impact discourse abilities. PMID- 29497750 TI - Links Between Short-Term Memory and Word Retrieval in Aphasia. AB - Purpose: This study explored the relationship between anomia and verbal short term memory (STM) in the context of an interactive activation language processing model. Method: Twenty-four individuals with aphasia and reduced STM spans (i.e., impaired immediate serial recall of words) completed a picture-naming task and a word pair repetition task (a measure of verbal STM). Correlations between verbal STM and word retrieval errors made on the picture-naming task were examined. Results: A significant positive correlation between naming accuracy and verbal span length was found. More intricate verbal STM analyses examined the relationship between picture-naming error types (i.e., semantic vs. phonological) and 2 measures of verbal STM: (a) location of errors on the word pair repetition task and (b) imageability and frequency effects on the word pair repetition task. Results indicated that, as phonological word retrieval errors (relative to semantic) increase, bias toward correct repetition of high-imageability words increases. Conclusions: Results suggest that word retrieval and verbal STM tasks likely rely on a partially shared temporary linguistic activation process. PMID- 29497752 TI - The Relationship Between Confrontation Naming and Story Gist Production in Aphasia. AB - Purpose: The purpose of this study was to examine the relationship between picture naming performance and the ability to communicate the gist, or essential elements, of a story. We also sought to determine if this relationship varied according to Western Aphasia Battery-Revised (WAB-R; Kertesz, 2007) aphasia subtype. Method: Demographic information, test scores, and transcripts of 258 individuals with aphasia completing 3 narrative tasks were retrieved from the AphasiaBank database. Narratives were subjected to a main concept analysis to determine gist production. A correlation analysis was used to investigate the relationship between naming scores and main concept production for the whole group of persons with aphasia and for WAB-R subtypes separately. Results: We found strong correlations between naming test scores and narrative gist production for the large sample of persons with aphasia. However, the strength of the correlations varied by WAB-R subtype. Conclusions: Picture naming may accurately predict gist production for individuals with Broca's and Wernicke's aphasia, but not for other WAB-R subtypes. Given the current reprioritization of outcome measurement, picture naming may not be an appropriate surrogate measure for functional communication for all persons with aphasia. Supplemental Materials: https://doi.org/10.23641/asha.5851848. PMID- 29497753 TI - Reading for Meaning: What Influences Paragraph Understanding in Aphasia? AB - Purpose: The current study investigated the effect of text variables including length, readability, propositional content, and type of information on the reading comprehension of people with aphasia. Method: The performance of 75 people with aphasia was compared with 87 healthy, age-matched control participants. Reading comprehension was considered in terms of both accuracy in responding to questions tapping comprehension and reading time. Participants with aphasia (PWA) were divided into 2 groups (no reading impairment [PWA:NRI] and reading impairment [PWA:RI]) depending on whether their performance fell within the 5th percentile of control participants. Results: As groups, both PWA:NRI and PWA:RI differed significantly from control participants in terms of reading time and comprehension accuracy. PWA:NRI and PWA:RI differed from each other in terms of accuracy but not reading time. There was no significant effect of readability or propositional density on comprehension accuracy or reading time for any of the groups. There was a significant effect of length on reading time but not on comprehension accuracy. All groups found main ideas easier than details, stated information easier than inferred, and had particular difficulty with questions that required integration of information across paragraphs (gist). Conclusions: Both accuracy of comprehension and reading speed need to be considered when characterizing reading difficulties in people with aphasia. PMID- 29497754 TI - What Matters in Semantic Feature Analysis: Practice-Related Predictors of Treatment Response in Aphasia. AB - Purpose: This study investigated the predictive value of practice-related variables-number of treatment trials delivered, total treatment time, average number of trials per hour, and average number of participant-generated features per trial-in response to semantic feature analysis (SFA) treatment. Method: SFA was administered to 17 participants with chronic aphasia daily for 4 weeks. Individualized treatment and semantically related probe lists were generated from items that participants were unable to name consistently during baseline testing. Treatment was administered to each list sequentially in a multiple-baseline design. Naming accuracy for treated and untreated items was obtained at study entry, exit, and 1-month follow-up. Results: Item-level naming accuracy was analyzed using logistic mixed-effect regression models. The average number of features generated per trial positively predicted naming accuracy for both treated and untreated items, at exit and follow-up. In contrast, total treatment time and average trials per hour did not significantly predict treatment response. The predictive effect of number of treatment trials on naming accuracy trended toward significance at exit, although this relationship held for treated items only. Conclusions: These results suggest that the number of patient generated features may be more strongly associated with SFA-related naming outcomes, particularly generalization and maintenance, than other practice related variables. Supplemental Materials: https://doi.org/10.23641/asha.5734113. PMID- 29497755 TI - Exploring Treatment Fidelity in Persons With Aphasia Autonomously Practicing With Computerized Therapy Materials. AB - Purpose: Current computer technologies permit independent practice for people with cognitive-communicative disorders. Previous research has investigated compliance rates and outcome changes but not treatment fidelity per se during practice. Our aim was to examine adherence to procedures (treatment fidelity) and accuracy while persons with aphasia independently practiced word production using interactive, multimodal, user-controlled, word-level icons on computers. Method: Four persons with aphasia independently practiced single-word production after stimulation via user-initiated interactions in 3 conditions: (I) auditory stimulus with static representational drawing; (II) auditory stimulus with synchronized articulation video; and (III) users' choice between the 2 prior conditions. Sessions were video-recorded for subsequent analysis, which established emergently refined behavioral taxonomies using an iterative, mixed methods approach. Results: In independent practice, users only sometimes adhere to modeled behaviors, other times improvising novel behaviors. The latter sometimes co-occurred with successful productions. Differences in success rates were noted between Conditions I and II across behaviors with Condition II generally favored. In Condition III, participants tended to choose the stimulus that resulted in highest success rates. Conclusions: During independent practice with technology, persons with aphasia do not necessarily comply with clinicians' practice instructions, and treatment fidelity does not determine success. Autonomy and choice in practice may reveal unanticipated dimensions for computerized aphasia treatment. PMID- 29497756 TI - More Than a Story: My Life Came Back to Life. AB - Purpose: Social models of aphasia rehabilitation emphasize the importance of supporting identity renegotiation, which can be accomplished in part through personal narrative construction. The purpose of this study was to examine the experiences of persons who had engaged in a project to coconstruct personal narratives about life with aphasia. Method: Qualitative interviews were conducted with 3 participants with aphasia who completed a 4-week personal narrative coconstruction project, which included preadministration and postadministration of the Communication Confidence Rating Scale for Aphasia (Cherney & Babbitt, 2011). Results were analyzed using interpretative phenomenological analysis. Results: Three themes were revealed: (a) More than a story: It changed my life validated the idea that the narrative coconstruction process supported a positive view of identity; (b) A positive experience captured the participants' enjoyment in coconstructing and sharing their story; (c) Hope engendered by the coconstruction experience empowered participants with new levels of confidence not only in their communication skills but also in themselves. Conclusions: This study provided insight into the experience of coconstructing personal narratives using a structured protocol. Participants experienced the project as a positive, meaningful opportunity to actively contemplate their life and look forward. The study has implications for clinicians considering support of identity renegotiation in aphasia rehabilitation. PMID- 29497757 TI - Response Time Inconsistencies in Object and Action Naming in Anomic Aphasia. AB - Purpose: The effect of repeated naming on both object and action picture naming in individuals with anomic aphasia is explored. We asked whether repeatedly naming the same items leads to improved accuracy and reduced response latency. Method: Ten individuals with anomic aphasia and 6 healthy adults, 3 young and 3 old, named a set of 27 object pictures and a set of 27 action pictures presented 1 at a time on a computer screen. We examined accuracy and response times (RTs) across the 2 blocks of 10 repeated trials. Results: Results demonstrated higher accuracy and faster RTs for object than for action naming for all participants, with lower accuracy rates and slower RTs for the people with aphasia (PWA) compared with the healthy individuals, and diverging patterns of change across trials. Unlike the healthy participants, whose RTs decreased across trials, PWA continued to demonstrate variability in response latencies across the trials. Conclusions: Our preliminary results suggest that measuring RT may be useful in characterizing retrieval difficulty in anomic aphasia and that the retrieval processes in PWA, even in those who experience mild anomia, may be less efficient or different from those processes in neurologically healthy individuals. PMID- 29497759 TI - Tau-U: A Quantitative Approach for Analysis of Single-Case Experimental Data in Aphasia. AB - Purpose: Tau-U is a quantitative approach for analyzing single-case experimental design (SCED) data. It combines nonoverlap between phases with intervention phase trend and can correct for a baseline trend (Parker, Vannest, & Davis, 2011). We demonstrate the utility of Tau-U by comparing it with the standardized mean difference approach (Busk & Serlin, 1992) that is widely reported within the aphasia SCED literature. Method: Repeated writing measures from 3 participants with chronic aphasia who received computer-based writing treatment are analyzed visually and quantitatively using both Tau-U and the standardized mean difference approach. Results: Visual analysis alone was insufficient for determining an effect between the intervention and writing improvement. The standardized mean difference yielded effect sizes ranging from 4.18 to 26.72 for trained items and 1.25 to 3.20 for untrained items. Tau-U yielded significant (p < .05) effect sizes for 2 of 3 participants for trained probes and 1 of 3 participants for untrained probes. A baseline trend correction was applied to data from 2 of 3 participants. Conclusions: Tau-U has the unique advantage of allowing for the correction of an undesirable baseline trend. Although further study is needed, Tau-U shows promise as a quantitative approach to augment visual analysis of SCED data in aphasia. PMID- 29497758 TI - Analysis of Story Recall in Military Veterans With and Without Mild Traumatic Brain Injury: Preliminary Results. AB - Purpose: The purpose of this study was to determine whether detailed analysis of story recall performance reveals significant differences between veterans with and without history of mild traumatic brain injury (mTBI). Method: Twenty-one military veterans participated, with 7 reporting history of mTBI. All participants were administered the Logical Memory I and II subtests from the Wechsler Memory Scale-Fourth Edition (Wechsler, 2009). Responses were scored for total correct ideas (TCI) and total words produced (TWP). Results: Although the groups did not differ in scaled scores, other measures did reveal significant differences. After a delay, the mTBI group showed a greater drop in TCI relative to the control group. Additionally, the control group showed an increase in TWP when the recall was delayed versus immediate; a pattern not observed for the mTBI group. Conclusions: The mTBI and control groups did not significantly differ in scaled scores. However, group differences were observed in TCI and TWP. The findings suggest that, relative to the control group, the mTBI group were less successful in retrieving episodic information and eliciting self-cueing. Small sample size limited data interpretation, and larger sample sizes are needed to confirm the findings. The results indicate that veterans with mTBI may present with symptoms persisting beyond the acute state of the injury. PMID- 29497760 TI - Using Images With Individuals With Aphasia: Current Research and Clinical Trends. AB - Purpose: Visuographic supports in the form of images are utilized during assessment and treatment for individuals with aphasia to supplement speech, language, and cognitive losses limiting communication. Clinicians rely on prior experience and intuition to make decisions regarding image-based support design and selection (e.g., augmentative and alternative communication strategies). Researchers have begun to focus on the relationship between the images and the benefits they provide for adults with aphasia. Method: The aim of this review resulting from a roundtable discussion at the 2016 Clinical Aphasiology Conference-was to disseminate summaries of current and past researches regarding image use by individuals with aphasia and to highlight areas of need within research and practice. Results: Review of the literature illuminated 4 major themes: (a) image creation, capture, and sharing; (b) image characteristics; (c) image use across linguistic domains and contexts; and (d) implications for clinical and research practices. Conclusions: Reviewing current knowledge and practice regarding the use of visual supports for individuals with aphasia is essential to advancing therapeutic practices and providing evidence-based protocols for creating, selecting, and implementing images within augmentative and alternative communication strategies. Several gaps in knowledge were identified as future research needs (e.g., caregiver training and enhanced image feature investigation). PMID- 29497762 TI - Pharmacological inhibition of IL-6 trans-signaling improves compromised fracture healing after severe trauma. AB - Patients with multiple injuries frequently suffer bone fractures and are at high risk to develop fracture healing complications. Because of its key role both in systemic posttraumatic inflammation and fracture healing, the pleiotropic cytokine interleukin-6 (IL-6) may be involved in the pathomechanisms of trauma induced compromised fracture healing. IL-6 signals are transmitted by two different mechanisms: classic signaling via the membrane-bound receptor (mIL-6R) and trans-signaling via its soluble form (sIL-6R). Herein, we investigated whether IL-6 classic and trans-signaling play different roles in bone regeneration after severe injury. Twelve-week-old C57BL/6J mice underwent combined femur osteotomy and thoracic trauma. To study the function of IL-6, either an anti-IL-6 antibody, which inhibits both IL-6 classic and trans signaling, or a soluble glycoprotein 130 fusion protein (sgp130Fc), which selectively blocks trans-signaling, were injected 30 min and 48 h after surgery. Bone healing was assessed using cytokine analyses, flow cytometry, histology, micro-computed tomography, and biomechanical testing. Selective inhibition of IL 6 trans-signaling significantly improved the fracture healing outcome after combined injury, as confirmed by accelerated cartilage-to-bone transformation, enhanced bony bridging of the fracture gap and improved mechanical callus properties. In contrast, global IL-6 inhibition did not affect compromised fracture healing. These data suggest that classic signaling may mediate beneficial effects on bone repair after severe injury. Selective inhibition of IL 6 trans-signaling might have therapeutic potential to treat fracture healing complications in patients with concomitant injuries. PMID- 29497763 TI - [Deep neuromuscular blockade : Benefits and risks]. AB - Neuromuscular blockade (TOF count = 0) can improve tracheal intubation and microlaryngeal surgery. It is also frequently used in many surgical fields including both nonlaparoscopic and laparoscopic surgery to improve surgical conditions and to prevent sudden muscle contractions. Currently there is a controversy regarding the need and the clinical benefits of deep neuromuscular blockade for different surgical procedures. Deep neuromuscular relaxation improves laparoscopic surgical space conditions only marginally when using low intra-abdominal pressure. There is no outcome-relevant advantage of low compared to higher intra-abdominal pressures, but worsen the surgical conditions. Postoperative, residual curarisation can be avoided by algorithm-based pharmacological reversing and quantitative neuromuscular monitoring. PMID- 29497764 TI - Novel approach for the rapid screening of banned aromatic amines in dyed textiles using a chromogenic method. AB - A novel and simple method utilizing a chromogenic reaction on filter paper is introduced for the rapid screening of banned aromatic amines released from azo dyes. The proposed method involves the sample preparation protocols outlined by the current standard method and the chromogenic reaction of extracted aromatic amines on filter paper. Based on the principle of the reaction between primary amines and aldehydes, p-dimethylaminobenzaldehyde (DMAB) was used as the chromogenic reagent for the rapid screening of 24 carcinogenic aromatic amines and aniline without any chromatographic instruments under optimized experimental conditions. The detection limit for all the aromatic amines in this study was less than 15 mg/kg. A total of 727 dyed textile samples were analyzed using both the present standard method and the proposed method simultaneously. Using the proposed method, a total of 471 samples did not require further instrumental analysis, which can dramatically save instrumental detection time (61.2%), can decrease instrumental detection costs, and can avoid the use of large amounts of toxic reagents. The proposed method has been applied to detect banned aromatic amines in some inspection institutions and dye factories and has large social and economic benefits. Graphical abstract Chromogenic reaction methods. PMID- 29497765 TI - Development and application of a UHPLC-MS/MS metabolomics based comprehensive systemic and tissue-specific screening method for inflammatory, oxidative and nitrosative stress. AB - Oxidative stress and inflammation are underlying pathogenic mechanisms associated with the progression of several pathological conditions and immunological responses. Elucidating the role of signalling lipid classes, which include, among others, the isoprostanes, nitro fatty acids, prostanoids, sphingoid bases and lysophosphatidic acids, will create a snapshot of the cause and effect of inflammation and oxidative stress at the metabolic level. Here we describe a fast, sensitive, and targeted ultra-high-performance liquid chromatography-tandem mass spectrometry metabolomics method that allows the quantitative measurement and biological elucidation of 17 isoprostanes as well as their respective isomeric prostanoid mediators, three nitro fatty acids, four sphingoid mediators, and 24 lysophosphatidic acid species from serum as well as organ tissues, including liver, lung, heart, spleen, kidney and brain. Application of this method to paired mouse serum and tissue samples revealed tissue- and serum specific stress and inflammatory readouts. Little correlation was found between localized (tissue) metabolite levels compared with the systemic (serum) circulation in a homeostatic model. The application of this method in future studies will enable us to explore the role of signalling lipids in the metabolic pathogenicity of stress and inflammation during health and disease. PMID- 29497766 TI - Long-Term Harvest Residue Retention Could Decrease Soil Bacterial Diversities Probably Due to Favouring Oligotrophic Lineages. AB - Harvest residues contain large stores of carbon (C) and nitrogen (N) in forest plantations. Decomposing residues can release labile C and N into soil and thus provide substrates for soil bacterial communities. Previous studies showed that residue retention could increase soil C and N pools and activate bacterial communities in the short term (<= 10 years). The current study examined the effects of a long-term (19-year) harvest residue retention on soil total and water and hot water extractable C and N pools, as well as bacterial communities via Illumina MiSeq sequencing. The experiment was established in a randomised complete block design with four replications, southeast Queensland of Australia, including no (R0), single (R1, 51 to 74 t ha-1 dry matter) and double quantities (R2, 140 t ha-1 dry matter) of residues retained. Generally, no significant differences existed in total C and N, as well as C and N pools extracted by water and hot water among the three treatments, probably due to negligible amounts of labile C and N released from harvest residues. Soil delta15N significantly decreased from R0 to R1 to R2, probably due to reduced N leaching with residue retention (P < 0.001). Residue retention increased the relative abundances of Actinobacteria (P = 0.016) and Spartobacteria (P < 0.001), whereas decreased Betaproteobacteria (P = 0.050). This favour for the oligotrophic groups probably caused the decrease in the bacterial diversity as revealed by Shannon index (P = 0.025). Hence, our study suggests that residue retention is not an appropriate management practice in the long term. PMID- 29497768 TI - The "all-seeing needle" micro-PCNL versus flexible ureterorenoscopy for lower calyceal stones of <= 2 cm. AB - The objectives of the study are to compare the safety and efficacy of "all-seeing needle" optical puncture system micro-percutaneous nephrolithotomy (micro-PCNL) and flexible ureterorenoscopy (FURS) for the treatment of lower calyceal stones of <= 2 cm and to determine the advantages and disadvantages of each. 116 patients in total with lower calyceal stones of <= 2 cm were randomly divided into two equal groups, "all-seeing needle" optical puncture system micro-PCNL and FURS. In both groups, holmium laser was utilized for lithotripsy. The perioperative parameters were compared between the two groups. Compared to the "all-seeing needle" micro-PCNL group, the mean operative time was significantly longer in the FURS group (P = 0.000). However, there was no significant difference between the two groups with respect to mean hemoglobin reduction (P = 0.087), complications (P = 0.731) and LOS (P = 0.856). The overall SFR of the "all-seeing needle" micro-PCNL group and FURS group was 84.5% (49/58) and 79.3% (46/58), respectively, without any significant difference between the groups (P = 0.469). For treating lower calyceal stones of <= 2 cm, the "all-seeing needle" micro-PCNL group had shorter operative time than FURS, while no significant differences between the two groups with respect to mean hemoglobin reduction, complications, LOS and SFR were found. PMID- 29497767 TI - Genome-wide association study identified genetic variations and candidate genes for plant architecture component traits in Chinese upland cotton. AB - KEY MESSAGE: Thirty significant associations between 22 SNPs and five plant architecture component traits in Chinese upland cotton were identified via GWAS. Four peak SNP loci located on chromosome D03 were simultaneously associated with more plant architecture component traits. A candidate gene, Gh_D03G0922, might be responsible for plant height in upland cotton. A compact plant architecture is increasingly required for mechanized harvesting processes in China. Therefore, cotton plant architecture is an important trait, and its components, such as plant height, fruit branch length and fruit branch angle, affect the suitability of a cultivar for mechanized harvesting. To determine the genetic basis of cotton plant architecture, a genome-wide association study (GWAS) was performed using a panel composed of 355 accessions and 93,250 single nucleotide polymorphisms (SNPs) identified using the specific-locus amplified fragment sequencing method. Thirty significant associations between 22 SNPs and five plant architecture component traits were identified via GWAS. Most importantly, four peak SNP loci located on chromosome D03 were simultaneously associated with more plant architecture component traits, and these SNPs were harbored in one linkage disequilibrium block. Furthermore, 21 candidate genes for plant architecture were predicted in a 0.95-Mb region including the four peak SNPs. One of these genes (Gh_D03G0922) was near the significant SNP D03_31584163 (8.40 kb), and its Arabidopsis homologs contain MADS-box domains that might be involved in plant growth and development. qRT-PCR showed that the expression of Gh_D03G0922 was upregulated in the apical buds and young leaves of the short and compact cotton varieties, and virus-induced gene silencing (VIGS) proved that the silenced plants exhibited increased PH. These results indicate that Gh_D03G0922 is likely the candidate gene for PH in cotton. The genetic variations and candidate genes identified in this study lay a foundation for cultivating moderately short and compact varieties in future Chinese cotton-breeding programs. PMID- 29497769 TI - Studies on Manfred Eigen's model for the self-organization of information processing. AB - In 1971, Manfred Eigen extended the principles of Darwinian evolution to chemical processes, from catalytic networks to the emergence of information processing at the molecular level, leading to the emergence of life. In this paper, we investigate some very general characteristics of this scenario, such as the valuation process of phenotypic traits in a high-dimensional fitness landscape, the effect of spatial compartmentation on the valuation, and the self-organized transition from structural to symbolic genetic information of replicating chain molecules. In the first part, we perform an analysis of typical dynamical properties of continuous dynamical models of evolutionary processes. In particular, we study the mapping of genotype to continuous phenotype spaces following the ideas of Wright and Conrad. We investigate typical features of a Schrodinger-like dynamics, the consequences of the high dimensionality, the leading role of saddle points, and Conrad's extra-dimensional bypass. In the last part, we discuss in brief the valuation of compartment models and the self organized emergence of molecular symbols at the beginning of life. PMID- 29497770 TI - Dynamic surface tension and adsorption mechanism of surfactin biosurfactant at the air-water interface. AB - The dynamic adsorption of the anionic biosurfactant, surfactin, at the air-water interface has been investigated in this work and compared to those of two synthetic surfactants: the anionic sodium dodecylbenzenesulfonate (SDBS) and the nonionic octaethylene glycol monotetradecyl ether (C14E8). The results revealed that surfactin adsorption at the air-water interface is purely controlled by diffusion mechanism at the initial stage of the adsorption process (i.e., [Formula: see text]), but shifts towards a mixed diffusion-barrier mechanism when surface tension approaches equilibrium (i.e., [Formula: see text]) due to the development of an energy barrier for adsorption. Such energy barrier has been found to be a function of the surfactin bulk concentration (increases with increasing surfactin concentration) and it is estimated to be in the range of 1.8 9.5 kJ/mol. Interestingly, such a trend (pure diffusion-controlled mechanism at [Formula: see text] and mixed diffusion-barrier mechanism at [Formula: see text]) has been also observed for the nonionic C14E8 surfactant. Unlike the pure diffusion-controlled mechanism of the initial surfactin adsorption, which was the case in the presence and the absence of the sodium ion (Na+), SDBS showed a mixed diffusion-barrier controlled at both short and long time, with an energy barrier of 3.0-9.0 and 3.8-18.0 kJ/mol, respectively. Such finding highlights the nonionic-like adsorption mechanism of surfactin despite its negative charge. PMID- 29497771 TI - Cerebral Blood Flow Following Hybrid Stage I Palliation in Infants with Hypoplastic Left Heart Syndrome. AB - Hypoplastic left heart syndrome (HLHS) palliation may result in altered cerebral blood flow with subsequent neurodevelopmental implications. The purpose of the study was to assess blood flow in the middle cerebral artery (MCA) and investigate the relationship with early neurodevelopmental outcomes in infants with HLHS after hybrid stage I. Transcranial Doppler (TCD) was performed to obtain peak systolic, end-diastolic, and mean velocities, as well as pulsatility index of the MCA in infants with HLHS (n = 18) at baseline and at 2, 4, and 6 months of age. Developmental assessment was performed at 6 months of age. Results of TCD and development were compared to healthy control subjects (n = 6) and normative data. Overall, peak systolic velocity (p = 0.0031), end-diastolic velocity (p < 0.0001), and mean velocity (p < 0.0001) were significantly lower and pulsatility index (p = 0.0011) significantly higher in the HLHS group compared to the control group. A significant increase in change over time was noted for peak systolic velocity (p < 0.0016) and mean velocity (p < 0.0046). There was no significant correlation between TCD variables and development scores. TCD values in 5-6 months old infants with HLHS who undergo hybrid stage I palliation had consistently lower blood flow velocities than control infants; however, pulsatility index was slightly higher. No correlation between TCD measurements and measures of cognitive, language, and motor skills were noted. PMID- 29497772 TI - Sirtuins in the Cardiovascular System: Potential Targets in Pediatric Cardiology. AB - Cardiovascular diseases represent a major cause of death and morbidity. Cardiac and vascular pathologies develop predominantly in the aged population in part due to lifelong exposure to numerous risk factors but are also found in children and during adolescence. In comparison to adults, much has to be learned about the molecular pathways driving cardiovascular diseases in the pediatric population. Sirtuins are highly conserved enzymes that play pivotal roles in ensuring cardiac homeostasis under physiological and stress conditions. In this review, we discuss novel findings about the biological functions of these molecules in the cardiovascular system and their possible involvement in pediatric cardiovascular diseases. PMID- 29497774 TI - Radiographic morphology of normal ring apophyses in the immature cervical spine. AB - BACKGROUND: The ring apophyses of the cervical spine have a variable appearance that changes with age. The times at which they appear and fuse at each level are not fixed. In this study, we aim to detail normal ranges of appearance of these ossification centers for each age group. MATERIALS AND METHODS: One hundred and eighty patients under the age of 21 attending the Royal Stoke University Hospital for cervical spine radiographs were retrospectively identified. The presence or absence of ring apophyses at each cervical level and whether these had undergone fusion was reported, as were the thickness, length, and craniocaudal and anteroposterior distance of the apophysis from the vertebral body. The angulation of the apophysis relative to the endplate was also noted. RESULTS: The youngest patient in which apophyses were seen was aged 3, but apophyses were otherwise rarely seen before the age of 6. All apophyses were present from age 14, and the superior apophyses fused by the age of 18, although unfused inferior apophyses were still seen in the 20-year age group. It was observed that apophyses were rarely separated from the vertebral body by greater than 1 mm in craniocaudal distance (1%) or 2.5 mm in anteroposterior distance (2.6%) and the anterior apophysis was angulated towards the endplate in only 1% of cases. CONCLUSIONS: We have detailed the range of normal appearances of the ring apophyses of the developing cervical spine. Cervical spine apophyseal injury is thought to be rare, but knowledge of normative morphological features should help in this diagnosis. PMID- 29497773 TI - Luteolin activates ERK1/2- and Ca2+-dependent HO-1 induction that reduces LPS induced HMGB1, iNOS/NO, and COX-2 expression in RAW264.7 cells and mitigates acute lung injury of endotoxin mice. AB - OBJECTIVE: Although luteolin has shown to have anti-inflammatory action, no report is available whether luteolin inhibits HMGB1 and protects acute lung injury (ALI) in endotoxin rodents. We hypothesized that HO-1 induction by luteolin might play a crucial role for inhibition of pro-inflammatory mediators including HMGB1 through MAPK signaling in LPS-induced RAW264.7 cells, and it ameliorates ALI of endotoxin mice. METHODS: The effects of luteolin on the production of pro-inflammatory mediators in LPS-activated RAW264.7 cells and LPS injected mice were evaluated. The mechanisms were investigated using various signal inhibitors. RESULTS: Luteolin significantly increased HO-1 expression through ERK1/2 signaling in a time- and concentration-dependent manner. Indeed, luteolin inhibited pro-inflammatory mediators (HMGB1, iNOS/NO, COX-2, and NF kappaB activity) in LPS-activated RAW264.7 cells. In addition, PD98059, an ERK1/2 inhibitor, treatment failed to inhibit production of these pro-inflammatory mediators by luteolin. Interestingly, luteolin augmented HO-1 induction through Ca2+ influx in RAW264.7 cells. Administration of luteolin significantly inhibited plasma HMGB1 level, and iNOS expression in the lung that resulted in a significant reduction of ALI in endotoxin mice that was reversed by a HO-1 inhibitor, ZnPPIX. CONCLUSION: Therefore, we conclude that luteolin has a great potential for treatment of ALI and related diseases, where HMGB1 is a therapeutic target. PMID- 29497775 TI - Texture analysis of paraspinal musculature in MRI of the lumbar spine: analysis of the lumbar stenosis outcome study (LSOS) data. AB - OBJECTIVE: To evaluate association of fatty infiltration in paraspinal musculature with clinical outcomes in patients suffering from lumbar spinal stenosis (LSS) using qualitative and quantitative grading in magnetic resonance imaging (MRI). MATERIALS AND METHODS: In this retrospective study, texture analysis (TA) was performed on postprocessed axial T2 weighted (w) MR images at level L3/4 using dedicated software (MaZda) in 62 patients with LSS. Associations in fatty infiltration between qualitative Goutallier and quantitative TA findings with two clinical outcome measures, Spinal stenosis measure (SSM) score and walking distance, at baseline and regarding change over time were assessed using machine learning algorithms and multiple logistic regression models. RESULTS: Quantitative assessment of fatty infiltration using the histogram TA feature "mean" showed higher interreader reliability (ICC 0.83-0.97) compared to the Goutallier staging (kappa = 0.69-0.93). No correlation between Goutallier staging and clinical outcome measures was observed. Among 151 TA features, only TA feature "mean" of the spinotransverse group showed a significant but weak correlation with worsened SSM (p = 0.046). TA feature "S(3,3) entropy" showed a significant but weak association with worsened WD over 12 months (p = 0.046). CONCLUSION: MR TA is a reproducible tool to quantitatively assess paraspinal fatty infiltration, but there is no clear association with the clinical outcome in asymptomatic LSS patients. PMID- 29497777 TI - [Correction to: Drug therapy of acne inversa]. PMID- 29497776 TI - [Current drug treatment of hepatitis C : Useful therapy algorithms taking into consideration economical aspects]. AB - Treatment of chronic hepatitis C (HCV) has changed dramatically since the approval of the direct-acting antivirals (DAA). Depending on the HCV genotype and the stage of liver disease, sustained HCV clearance can be achieved in more than 95% of patients with a treatment duration of 8-12 weeks in most of the cases. The selection and combination of the drugs depends on previous antivirals therapies, the stage of liver fibrosis, HCV genotype and subtype, viral load at baseline, and renal function. Nowadays, potent antiviral therapy with minimal side effects can be offered to almost every patient. In the real-world setting, a high quality of HCV therapy considering economic aspects has been documented in the German Hepatitis C Registry. A reduction of clinical complications of chronic liver disease by clearance of HCV has already been documented. PMID- 29497778 TI - Is my patient's respiratory drive (too) high? PMID- 29497779 TI - Impacts of Agricultural Practices and Individual Life Characteristics on Ecosystem Services: A Case Study on Family Farmers in the Context of an Amazonian Pioneer Front. AB - In tropical forests farmers are among the most important agents of deforestation. At the interface between societies and their environment, ecosystem services (ES) is an integrated working framework through which natural and anthropogenic dimensions can be addressed. Here, we aimed to understand to what extent farmers impact ES availability. Based on case studies in three locations in the Brazilian Amazon rainforest, we performed statistical analyses at 135 sampling points and 110 farms to link socioeconomic and ES data, both derived from field work. The socioeconomic data characterized agricultural production, sociological characteristics, and quality of life. ES data were obtained from statistical analyses that yielded a multiple ES indicator for each sampling point and farm. Our results produced three main findings: first, the establishment of ES associations is due more to agricultural production characteristics than to sociological and quality-of-life factors. Second, the impact of agricultural production on ES availability depends on the level of total incomes. An increase in incomes causes a decrease in the forest cover that provides many ES and an increase in other areas that provide fewer ES. Finally, our analyses show a very strong site effect that probably expresses the heterogeneity of the biophysical contexts, but also the importance for ES availability of the historical depth of deforestation and/or the role of specific public policies. Finding ways of producing an alternative impact on ES availability and establishing specific ES associations will therefore depend more on changes in the global political context than in individual practices. PMID- 29497780 TI - Early detection of hepatocellular carcinoma using autoantibody profiles from a panel of tumor-associated antigens. AB - BACKGROUND: Multiple antigen miniarrays used for detecting autoantibodies to tumor-associated antigens (TAAs) can be a useful approach for cancer detection and diagnosis. We here address a very specific question: might there be autoimmune responses to TAAs which precede clinical detection of hepatocellular carcinoma (HCC) in HBV and HCV chronic liver disease patients under continuous medical surveillance, and if so, could these anti-TAAs be added to the armamentarium of diagnostic tests? METHODS: We here examine the utility of a panel of 12 TAAs for the diagnosis of hepatocellular carcinoma (HCC). We derived a predictive rule for the presence of HCC based on the panel, from a cohort comprising 160 HCC patients and 90 normals. We then applied this rule to sequential anti-TAA data from a cohort of 17 HCC patients, from whom this information was available prior to diagnosis. RESULTS: The predictors (autoantibodies to HCC1, P16, P53, P90, and survivin) indicated the presence of HCC prior to diagnosis in 16 of the 17 patients, at a median lead time of 0.75 year. CONCLUSIONS: We believe these findings warrant further study of anti-TAA profiles as biomarkers for primary or early diagnosis of HCC. PMID- 29497782 TI - Do daily fluctuations in inhibitory control predict alcohol consumption? An ecological momentary assessment study. AB - RATIONALE: Deficient inhibitory control is predictive of increased alcohol consumption in the laboratory; however, little is known about this relationship in naturalistic, real-world settings. OBJECTIVES: In the present study, we implemented ecological momentary assessment methods to investigate the relationship between inhibitory control and alcohol consumption in the real world. METHODS: Heavy drinkers who were motivated to reduce their alcohol consumption (N = 100) were loaned a smartphone which administered a stop signal task twice per day at random intervals between 10 a.m. and 6 p.m. for 2 weeks. Each day, participants also recorded their planned and actual alcohol consumption and their subjective craving and mood. We hypothesised that day-to-day fluctuations in inhibitory control (stop signal reaction time) would predict alcohol consumption, over and above planned consumption and craving. RESULTS: Multilevel modelling demonstrated that daily alcohol consumption was predicted by planned consumption (beta = .816; 95% CI .762-.870) and craving (beta = .022; 95% CI .013-.031), but inhibitory control did not predict any additional variance in alcohol consumption. However, secondary analyses demonstrated that the magnitude of deterioration in inhibitory control across the day was a significant predictor of increased alcohol consumption on that day (beta = .007; 95% CI .004-.011), after controlling for planned consumption and craving. CONCLUSIONS: These findings demonstrate that short-term fluctuations in inhibitory control predict alcohol consumption, which suggests that transient fluctuations in inhibition may be a risk factor for heavy drinking episodes. PMID- 29497781 TI - From gene networks to drugs: systems pharmacology approaches for AUD. AB - The alcohol research field has amassed an impressive number of gene expression datasets spanning key brain areas for addiction, species (humans as well as multiple animal models), and stages in the addiction cycle (binge/intoxication, withdrawal/negative effect, and preoccupation/anticipation). These data have improved our understanding of the molecular adaptations that eventually lead to dysregulation of brain function and the chronic, relapsing disorder of addiction. Identification of new medications to treat alcohol use disorder (AUD) will likely benefit from the integration of genetic, genomic, and behavioral information included in these important datasets. Systems pharmacology considers drug effects as the outcome of the complex network of interactions a drug has rather than a single drug-molecule interaction. Computational strategies based on this principle that integrate gene expression signatures of pharmaceuticals and disease states have shown promise for identifying treatments that ameliorate disease symptoms (called in silico gene mapping or connectivity mapping). In this review, we suggest that gene expression profiling for in silico mapping is critical to improve drug repurposing and discovery for AUD and other psychiatric illnesses. We highlight studies that successfully apply gene mapping computational approaches to identify or repurpose pharmaceutical treatments for psychiatric illnesses. Furthermore, we address important challenges that must be overcome to maximize the potential of these strategies to translate to the clinic and improve healthcare outcomes. PMID- 29497783 TI - Angptl8 antisense oligonucleotide improves adipose lipid metabolism and prevents diet-induced NAFLD and hepatic insulin resistance in rodents. AB - AIMS/HYPOTHESIS: Targeting regulators of adipose tissue lipoprotein lipase could enhance adipose lipid clearance, prevent ectopic lipid accumulation and consequently ameliorate insulin resistance and type 2 diabetes. Angiopoietin-like 8 (ANGPTL8) is an insulin-regulated lipoprotein lipase inhibitor strongly expressed in murine adipose tissue. However, Angptl8 knockout mice do not have improved insulin resistance. We hypothesised that pharmacological inhibition, using a second-generation antisense oligonucleotide (ASO) against Angptl8 in adult high-fat-fed rodents, would prevent ectopic lipid accumulation and insulin resistance by promoting adipose lipid uptake. METHODS: ANGPTL8 expression was assessed by quantitative PCR in omental adipose tissue of bariatric surgery patients. High-fat-fed Sprague Dawley rats and C57BL/6 mice were treated with ASO against Angptl8 and insulin sensitivity was assessed by hyperinsulinaemic euglycaemic clamps in rats and glucose tolerance tests in mice. Factors mediating lipid-induced hepatic insulin resistance were assessed, including lipid content, protein kinase Cepsilon (PKCepsilon) activation and insulin-stimulated Akt phosphorylation. Rat adipose lipid uptake was assessed by mixed meal tolerance tests. Murine energy balance was assessed by indirect calorimetry. RESULTS: Omental fat ANGPTL8 mRNA expression is higher in obese individuals with fatty liver and insulin resistance compared with BMI-matched insulin-sensitive individuals. Angptl8 ASO prevented hepatic steatosis, PKCepsilon activation and hepatic insulin resistance in high-fat-fed rats. Postprandial triacylglycerol uptake in white adipose tissue was increased in Angptl8 ASO-treated rats. Angptl8 ASO protected high-fat-fed mice from glucose intolerance. Although there was no change in net energy balance, Angptl8 ASO increased fat mass in high-fat-fed mice. CONCLUSIONS/INTERPRETATION: Disinhibition of adipose tissue lipoprotein lipase is a novel therapeutic modality to enhance adipose lipid uptake and treat non-alcoholic fatty liver disease and insulin resistance. In line with this, adipose ANGPTL8 is a candidate therapeutic target for these conditions. PMID- 29497785 TI - Transcervical access via direct neck exposure for neurointerventional procedures in the hybrid angiosuite. AB - PURPOSE: A complicated course of the femoral route for neurointervention can prevent approaching the target. Thus, we determined whether transcervical access in the hybrid angiosuite is applicable and beneficial in real practice. METHODS: From January 2014 to March 2017, this approach was used in 17 of 453 (3.75%) cases: 11 cerebral aneurysms (4 ruptured, 7 unruptured), 4 acute occlusions of the large cerebral artery, 1 proximal internal carotid artery (ICA) stenosis, and 1 direct carotid cavernous fistula (CCF). RESULTS: All patients were elderly (mean age, 78.1 years). The main cause was severe tortuosity of the supra-aortic course or the supra-aortic and infra-aortic courses (eight and five cases, respectively), orifice disturbance (three cases), and femoral occlusion (one case). Through neck dissection, 6-8Fr guiding catheters were placed via subcutaneous tunneling to enhance device stability and support. All cerebral aneurysms were embolized (eight complete and three neck remnants) using the combination of several additional devices. Mechanical stent retrieval with an 8Fr balloon guiding catheter was successfully achieved in a few runs (mean, 2 times; range, 1-3) within the proper time window (mean skin to puncture, 17 +/- 4 min; puncture to recanalization, 25 +/- 4 min). Each stent was satisfactorily deployed in the proximal ICA and direct CCF without catheter kick-back. All puncture sites were closed through direct suturing without complications. CONCLUSIONS: In the hybrid angiosuite, transcervical access via direct neck exposure is feasible in terms of device profile and support when the femoral route has an unfavorable anatomy. PMID- 29497786 TI - Safety of cerebral angiography and neuroendovascular therapy in patients with chronic kidney disease. AB - PURPOSE: Contrast-induced nephropathy is a common clinical concern in patients undergoing neuroendovascular procedures, especially in those with pre-existent kidney disease. We aimed to define the incidence of contrast-induced nephropathy in these high-risk patients in our practice. METHODS: We analyzed data retrospectively from patients undergoing neuroendovascular procedures at two academic medical centers over a 4-year period. Contrast-induced nephropathy was determined by an absolute increase in serum creatinine of 0.5 mg/dL or a rise from its baseline value by >= 25%, at 48-72 h after exposure to contrast agent after excluding other causes of renal impairment. High-risk patients were identified as those with pre-procedural estimated glomerular filtration rate < 60 mL/min irrespective of creatinine level, corresponding to stages 3-5 of chronic kidney disease. RESULTS: One hundred eighty-five high-risk patients undergoing conventional cerebral angiography and neuroendovascular interventions were identified. Only 1 out of 184 (0.54%) high-risk patients developed contrast induced nephropathy. That one patient had stage 5 chronic kidney disease and multiple other risk factors. CONCLUSION: We have observed a very low rate of renal injury in patients with chronic kidney disease, traditionally considered high risk for neuroendovascular procedures. Multiple factors may be responsible in the risk reduction of contrast-induced nephropathy in this patient population. PMID- 29497787 TI - Letter in response to editorials Goyal et al. and von Kummer. PMID- 29497784 TI - Absence of cannabinoid 1 receptor in beta cells protects against high-fat/high sugar diet-induced beta cell dysfunction and inflammation in murine islets. AB - AIMS/HYPOTHESIS: The cannabinoid 1 receptor (CB1R) regulates insulin sensitivity and glucose metabolism in peripheral tissues. CB1R is expressed on pancreatic beta cells and is coupled to the G protein Galphai, suggesting a negative regulation of endogenous signalling in the beta cell. Deciphering the exact function of CB1R in beta cells has been confounded by the expression of this receptor on multiple tissues involved in regulating metabolism. Thus, in models of global genetic or pharmacological CB1R blockade, it is difficult to distinguish the indirect effects of improved insulin sensitivity in peripheral tissues from the direct effects of inhibiting CB1R in beta cells per se. To assess the direct contribution of beta cell CB1R to metabolism, we designed a mouse model that allows us to determine the role of CB1R specifically in beta cells in the context of whole-body metabolism. METHODS: We generated a beta cell specific Cnr1 (CB1R) knockout mouse (beta-CB1R-/-) to study the long-term consequences of CB1R ablation on beta cell function in adult mice. We measured beta cell function, proliferation and viability in these mice in response to a high-fat/high-sugar diet and induction of acute insulin resistance with the insulin receptor antagonist S961. RESULTS: beta-CB1R-/- mice had increased fasting (153 +/- 23% increase at 10 weeks of age) and stimulated insulin secretion and increased intra-islet cAMP levels (217 +/- 33% increase at 10 weeks of age), resulting in primary hyperinsulinaemia, as well as increased beta cell viability, proliferation and islet area (1.9-fold increase at 10 weeks of age). Hyperinsulinaemia led to insulin resistance, which was aggravated by a high fat/high-sugar diet and weight gain, although beta cells maintained their insulin secretory capacity in response to glucose. Strikingly, islets from beta-CB1R-/- mice were protected from diet-induced inflammation. Mechanistically, we show that this is a consequence of curtailment of oxidative stress and reduced activation of the NLRP3 inflammasome in beta cells. CONCLUSIONS/INTERPRETATION: Our data demonstrate CB1R to be a negative regulator of beta cell function and a mediator of islet inflammation under conditions of metabolic stress. Our findings point to beta cell CB1R as a therapeutic target, and broaden its potential to include anti inflammatory effects in both major forms of diabetes. DATA AVAILABILITY: Microarray data have been deposited at GEO (GSE102027). PMID- 29497788 TI - Combined Amendments of Nano-hydroxyapatite Immobilized Cadmium in Contaminated Soil-Potato (Solanum tuberosum L.) System. AB - The toxicity of cadmium (Cd) has posed major public health concern in crops grown in the Cd-contaminated soils. The effects of five amendments, nano-hydroxyapatite (n-HA) and it combined with lime, zeolite, bone mill and fly ash on Cd immobilization in soils and uptake in potatoes, were investigated in a contaminated soil by pot experiments. The result showed that the applications of combined amendments significantly decreased the bioavailable Cd concentrations extracted by TCLP, DTPA-TEA and MgCl2 in the contaminated soils, and changed the soluble and exchangeable and specifically sorbed fractions to oxide-bound and organic-bound fractions. Compared to the control group, the concentrations of Cd in the potato tubers grown in n-HA, n-HA + Fly ash, n-HA + Lime, n-HA + Bone mill and n-HA + Zeolite soil were reduced 17.4%, 20.7%, 15.2%, 32.6% and 39.1%, respectively. Nano-hydroxyapatite combined amendments was more effective in reducing bioavailable Cd concentrations and Cd accumulations in potatoes, especially for n-HA + Z. PMID- 29497789 TI - Testicular Oxidative Stress and Cellular Deformities in Clarias gariepinus (Burchell) from River Yamuna in Delhi Region, India. AB - River Yamuna is under constant menace due to pollution levels beyond limit, ensuing chronic poisoning of aquatic biota. Induction of oxidative stress and cellular deformities is a common effect in fish. The present study aimed in assessing impact of environmental pollutants on gonad (testis) of Clarias gariepinus from Wazirabad barrage (entry site) and Okhla barrage (exit site) of river Yamuna in Delhi segment. Antioxidant enzymes assays viz. Super oxide dismutase (SOD), catalase (CAT) and ferric reducing antioxidant power (FRAP); thiobarbituric acid reactive substance assay (TBARS) for determining level of lipid peroxidation and histology for analysis of degenerative changes were employed as biomarkers. The results depicted signs of environmental contamination, hallmarked by significant increase (p < 0.001) in TBARs level (umol/g wet tissue); significant decrease (p < 0.001) in SOD, CAT (U/mg protein) and FRAP value (U/mg tissue) in response to greater pollution at Okhla barrage as compared to Wazirabad barrage. Degenerative changes viz. unorganized seminiferous tubules, extensive vacuolization in germ cells, inflammatory lesions, greater vacant spaces and condensation of tubular cells prevailed in 75%, 85%, 80%, 80%, and 65% specimens respectively from Okhla barrage. Hence, the selected biomarkers highlighted the existence of greater prooxidative compounds at the exit site resulting in stressful condition for fish in river basin. PMID- 29497790 TI - Trace Metal Inference on Seaweeds in Wandoor Area, Southern Andaman Island. AB - Trace metals concentrations were studied for three different seasons on four seaweed species (Halimeda gracilis, Padina pavonica, Sargassum swartzii and Turbinaria ornata) from Wandoor area of southern Andaman Island. Though diversified seaweed population records in the study area, the studied four species were predominantly present in all the seasons. The observed average levels on trace metals concentrations were Cd 0-0.311 ug/g, Cr 0.002-0.334 ug/g, Cu 0.003-0.291 ug/g, Mn 0.118-7.736 ug/g, Pb 0-0.165 ug/g and Zn 0.019-5.537 ug/g respectively. Brown seaweed P. pavonica showed higher level of Mn concentration as 7.73 ug/g during northeast monsoon reflects physiological properties and sequestrative nature. Our result suggests, the metal concentrations were not higher with reference to Dadolahi's metal pollution index. Based on univariate analysis of variance, there is no significant variation found in both species and seasons. To maintain the tradition of the study area, continues monitoring is essential for better understanding and ecosystem conservation. PMID- 29497793 TI - Genome-scale biological models for industrial microbial systems. AB - The primary aims and challenges associated with microbial fermentation include achieving faster cell growth, higher productivity, and more robust production processes. Genome-scale biological models, predicting the formation of an interaction among genetic materials, enzymes, and metabolites, constitute a systematic and comprehensive platform to analyze and optimize the microbial growth and production of biological products. Genome-scale biological models can help optimize microbial growth-associated traits by simulating biomass formation, predicting growth rates, and identifying the requirements for cell growth. With regard to microbial product biosynthesis, genome-scale biological models can be used to design product biosynthetic pathways, accelerate production efficiency, and reduce metabolic side effects, leading to improved production performance. The present review discusses the development of microbial genome-scale biological models since their emergence and emphasizes their pertinent application in improving industrial microbial fermentation of biological products. PMID- 29497792 TI - Protective effects of systemic dermatan sulfate treatment in a preclinical model of radiation-induced oral mucositis. AB - PURPOSE: Oral mucositis is a frequent, dose-limiting side effect of radio(chemo)therapy of head-and-neck malignancies. The epithelial radiation response is based on multiple tissue changes, which could offer targets for a biologically tailored treatment. The potential of dermatan sulfate (DS) to modulate radiation-induced oral mucositis was tested in an established preclinical mucositis model. METHODS: Irradiation was either applied alone or in combination with daily DS treatment (4 mg/kg, subcutaneously) over varying time intervals. Irradiation comprised single dose irradiation with graded doses to the lower tongue surface or daily fractionated irradiation of the whole tongue. Fractionation protocols (5 * 3 Gy/week) over one (days 0-4) or two weeks (days 0 4, 7-11) were terminated by an additional local single dose irradiation to a defined treatment field on the lower tongue surface to induce the mucosal radiation response. The additional single dose irradiation (top-up) on day 7 (after one week of fractionation) or day 14 (after 2 weeks of fractionation) comprised graded doses in order to generate full dose-effect curves. Ulceration of the epithelium of the lower tongue, corresponding to confluent mucositis, was analysed as clinically relevant endpoint. Additionally, the time course parameters, latent time and ulcer duration were analysed. RESULTS: DS treatment significantly reduced the incidence of ulcerations. DS application over longer time intervals resulted in a more pronounced reduction of ulcer frequency, increased latent times and reduced ulcer duration. CONCLUSION: DS has a significant mucositis-ameliorating activity with pronounced effects on mucositis frequency as well as on time course parameters. PMID- 29497791 TI - Nonmetastatic pancreatic cancer : Improved survival with chemoradiotherapy > 40 Gy after systemic treatment. AB - PURPOSE: The role of radiotherapy (RT) for nonmetastatic pancreatic cancer is still a matter of debate since randomized control trials have shown inconsistent results. The current retrospective single-institution study includes both resected and unresected patients with nonmetastasized pancreatic cancer. The aim is to analyze overall survival (OS) after irradiation combined with induction chemotherapy. PATIENTS AND METHODS: Of the 73 patients with nonmetastatic pancreatic cancer eligible for the present analysis, 42 (58%) patients had adjuvant chemoradiotherapy (CRT), while 31 (42%) received CRT as primary treatment. In all, 65 (89%) had chemotherapy at any time before, during, or after RT, and 39 (53%) received concomitant CRT. The median total dose was 50 Gy (range 12-77 Gy), while 61 (84%) patients received >40 Gy. RESULTS: With a median follow up of 22 months (range 1.2-179.8 months), 14 (19%) are still alive and 59 (81%) of the patients have died, whereby 51 (70%) were cancer-related deaths. Median OS and the 2-year survival rate were 22.9 months (1.2-179.8 months) and 44%, respectively. In addition, 61 (84%) patients treated with >40 Gy had a survival advantage (median OS 23.7 vs. 17.3 months, p = 0.026), as had patients with 4 months minimum of systemic treatment (median OS 27.5 vs. 14.3 months, p = 0.0004). CONCLUSION: CRT with total doses >40 Gy after induction chemotherapy leads to improved OS in patients with nonmetastatic pancreatic cancer. PMID- 29497794 TI - Rational designed mutagenesis of levansucrase from Bacillus licheniformis 8-37-0 1 for product specificity study. AB - Levansucrases, which belong to the glycoside hydrolase family 68 (GH68), synthesize beta (2-6)-linked fructan levan with sucrose as substrate. We described the use of a levansucrase (Bl_SacB) from Bacillus licheniformis 8-37-0 1 for catalysis of fructosyl transfer to obtain high levan yield previously. In the present study, six variants (Y246A, N251A, K372A, R369A, R369S, and R369K) were constructed through sequence alignment and structural analysis to explore the synthesis mechanism of Bl_SacB. The selected residues were predicted to localize to the substrate-entering channel of the active cavity and close to or remote from the catalytic triad. The products of these variants ranged from homopolymers levan to fructo-oligosaccharides (FOSs). The primary FOSs were identified through MS and NMR analyses as neolevan-type neokestose [beta-D-Fru-(2 6)-alpha-D-Glc-(1-2)-beta-D-Fru], levan-type 6-kestose [beta-D-Fru-(2-6)-beta-D Fru-(2-1)-alpha-D-Glc], and inulin-type 1-kestose [beta-D-Fru-(2-1)-beta-D-Fru-(2 1)-alpha-D-Glc]. The mutation at Tyr246 located remote from the catalytic triad led to the production of short-chain oligosaccharides with degree of polymerization (DP) of up to 25. The replaced Arg369 located close to the catalytic triad resulted in either elimination of polysaccharide synthesis or complete change in the dominant linkage of the products. The Michaelis constants (Km) of Y246A, N251A, K372A, and R369K were found to be similar to that of the wild type (WT). However, the turnover number (kcat) and the value of transfructosylation versus hydrolysis activity of the six variants decreased compared with those of the WT. Hence, the residues located on the surface of the substrate-entering channel of Bl_SacB can be critical in product linkage type and/or elongation mechanism. PMID- 29497795 TI - Methanogens in humans: potentially beneficial or harmful for health. AB - Methanogens are anaerobic prokaryotes from the domain archaea that utilize hydrogen to reduce carbon dioxide, acetate, and a variety of methyl compounds into methane. Earlier believed to inhabit only the extreme environments, these organisms are now reported to be found in various environments including mesophilic habitats and the human body. The biological significance of methanogens for humans has been re-evaluated in the last few decades. Their contribution towards pathogenicity has received much less attention than their bacterial counterparts. In humans, methanogens have been studied in the gastrointestinal tract, mouth, and vagina, and considerable focus has shifted towards elucidating their possible role in the progression of disease conditions in humans. Methanoarchaea are also part of the human skin microbiome and proposed to play a role in ammonia turnover. Compared to hundreds of different bacterial species, the human body harbors only a handful of methanogen species represented by Methanobrevibacter smithii, Methanobrevibacter oralis, Methanosphaera stadtmanae, Methanomassiliicoccus luminyensis, Candidatus Methanomassiliicoccus intestinalis, and Candidatus Methanomethylophilus alvus. Their presence in the human gut suggests an indirect correlation with severe diseases of the colon. In this review, we examine the current knowledge about the methanoarchaea in the human body and possible beneficial or less favorable interactions. PMID- 29497796 TI - Quantitative prediction of shrimp disease incidence via the profiles of gut eukaryotic microbiota. AB - One common notion is emerging that gut eukaryotes are commensal or beneficial, rather than detrimental. To date, however, surprisingly few studies have been taken to discern the factors that govern the assembly of gut eukaryotes, despite growing interest in the dysbiosis of gut microbiota-disease relationship. Herein, we firstly explored how the gut eukaryotic microbiotas were assembled over shrimp postlarval to adult stages and a disease progression. The gut eukaryotic communities changed markedly as healthy shrimp aged, and converged toward an adult-microbiota configuration. However, the adult-like stability was distorted by disease exacerbation. A null model untangled that the deterministic processes that governed the gut eukaryotic assembly tended to be more important over healthy shrimp development, whereas this trend was inverted as the disease progressed. After ruling out the baseline of gut eukaryotes over shrimp ages, we identified disease-discriminatory taxa (species level afforded the highest accuracy of prediction) that characteristic of shrimp health status. The profiles of these taxa contributed an overall 92.4% accuracy in predicting shrimp health status. Notably, this model can accurately diagnose the onset of shrimp disease. Interspecies interaction analysis depicted how the disease-discriminatory taxa interacted with one another in sustaining shrimp health. Taken together, our findings offer novel insights into the underlying ecological processes that govern the assembly of gut eukaryotes over shrimp postlarval to adult stages and a disease progression. Intriguingly, the established model can quantitatively and accurately predict the incidences of shrimp disease. PMID- 29497797 TI - Development and optimization of a tumor targeting system based on microbial synthesized PHA biopolymers and PhaP mediated functional modification. AB - Polyhydroxyalkanoate (PHA) is a class of microbial synthesized biodegradable and biocompatible aliphatic polymer which has been developed into nanoparticles (NPs) for sustained release of hydrophobic compounds. Taking advantage of the natural PHA binding protein PhaP which could be steadily adsorbed onto PHA NPs through hydrophobic interaction, a tumor targeting system was developed in this study by presenting an epidermal growth factor receptor (EGFR)-targeting peptide (ETP) on the surface of PHA NPs, via PhaP mediated adsorption. To reveal the effects of residual emulsifiers on PhaP mediated ETP modification and optimize the tumor targeting capacity of the system, a novel emulsifier-free PHA NPs (EF-NPs) was fabricated together with other two kinds of conventional emulsifier-required PHA NPs (PVA-NPs and P68-NPs, which were prepared with poly(vinyl alcohol) (PVA) and Pluronic F68 as emulsifiers, respectively). By analyzing the surface hydrophobicity, the amount of adsorbed fusion protein, and the cellular uptake of all kinds of PHA NPs, our results demonstrated that EF-NPs with stronger surface hydrophobicity were the most proper formulation for further PhaP mediated ETP functionalization. The residual PVA and Pluronic F68 affected the modification efficiency and secondary structure of ETP-PhaP fusion protein, and finally obstructed the targeting effect of ETP-PhaP modified PVA-NPs and P68-NPs to EGFR over-expressed tumor cells. The animal experiment further confirmed the effectiveness and feasibility of in vivo application of ETP-PhaP functionalized EF-NPs, indicating that it could be served as a promising tumor targeting system with satisfactory EGFR targeting ability. This PhaP mediated bio-modification process also opens a wide way for developing various PHA-based targeting systems by presenting different tumor or other tissue-specific targeting peptides. PMID- 29497798 TI - State of the art on granular sludge by using bibliometric analysis. AB - With rapid industrialization and urbanization in the nineteenth century, the activated sludge process (ASP) has experienced significant steps forward in the face of greater awareness of and sensitivity toward water-related environmental problems. Compared with conventional flocculent ASP, the major advantages of granular sludge are characterized by space saving and resource recovery, where the methane and hydrogen recovery in anaerobic granular and 50% more space saving, 30-50% of energy consumption reduction, 75% of footprint cutting, and even alginate recovery in aerobic granular. Numerous engineers and scientists have made great efforts to explore the superiority over the last 40 years. Therefore, a bibliometric analysis was desired to trace the global trends of granular sludge research from 1992 to 2016 indexed in the SCI-EXPANDED. Articles were published in 276 journals across 44 subject categories spanning 1420 institutes across 68 countries. Bioresource Technology (293, 11.9%), Water Research (235, 9.6%), and Applied Microbiology and Biotechnology (127, 5.2%) dominated in top three journals. The Engineering (991, 40.3%), China (906, 36.9%), and Harbin Inst Technol, China (114, 4.6%) were the most productive subject category, country, and institution, respectively. The hotspot is the emerging techniques depended on granular reactors in response to the desired removal requirements and bio-energy production (primarily in anaerobic granular sludge). In view of advanced and novel bio-analytical methods, the characteristics, functions, and mechanisms for microbial granular were further revealed in improving and innovating the granulation techniques. Therefore, a promising technique armed with strengthened treatment efficiency and efficient resource and bio-energy recovery can be achieved. PMID- 29497799 TI - Molecular and functional characterization of two pyruvate decarboxylase genes, PDC1 and PDC5, in the thermotolerant yeast Kluyveromyces marxianus. AB - Pyruvate decarboxylase (Pdc) is a cytosolic enzyme located at the branch point between fermentative and respiratory sugar catabolism. Here, we identified and functionally characterized KmPDC1 and KmPDC5 encoding two homologs of Pdc in the thermotolerant yeast Kluyveromyces marxianus KCTC 17555. Despite the conservation of important Pdc domains, a few amino acid sequences essential for enzymatic activity are not conserved in KmPdc5p. Deletion of KmPDC1 alone eliminated most of Pdc activity, but the growth of the Kmpdc1Delta strain on glucose was comparable to that of the wild type (WT) strain under aerobic conditions. In contrast to the WT, Kmpdc1Delta could not grow on glucose under oxygen-limited conditions. The KmPDC5 deletion did not generate any apparent change in Pdc activity or growth patterns under several tested conditions. Whereas the expression of KmPDC1 was enhanced by glucose, the basic expression levels of KmPDC5 were very low, without a detectable difference between glucose and nonfermentable carbon sources. Moreover, KmPDC5 overexpression was unable to complement the growth defect of Kmpdc1Delta in the presence of antimycin A, and the purified recombinant KmPdc5p was inactive in Pdc activity assay, supporting the notion that KmPdc5p may lack Pdc enzymatic activity. Notably, compared to the WT, Kmpdc1Delta single and Kmpdc1Deltapdc5Delta double mutants produced significantly less glycerol, acetate, and ethanol while accumulating pyruvate. Altogether, our data indicate that a single deletion of KmPDC1 is sufficient in Crabtree-negative K. marxianus strains to generate a starting host strain for engineering of production of high-value biomaterials derived from pyruvate without byproduct formation. PMID- 29497800 TI - Dominant role of ammonia-oxidizing bacteria in nitrification due to ammonia accumulation in sediments of Danjiangkou reservoir, China. AB - Surface sediments are the inner source of contaminations in aquatic systems and usually maintain aerobic conditions. As the key participators of nitrification process, little is known about the activities and contributions of ammonia oxidizing archaea (AOA) and bacteria (AOB) in the surface sediments. In this study, we determined the net and potential nitrification rates and used 1-octyne as an AOB specific inhibitor to detect the contributions of AOA and AOB to nitrification in surface sediments of Danjiangkou reservoir, which is the water source area of the middle route of South-to-North Water Diversion Project in China. Quantitative PCR and Illumina high-throughput sequencing were used to evaluate the abundance and diversity of the amoA gene. The net and potential nitrification rates ranged from 0.42 to 1.93 and 2.06 to 8.79 mg N kg-1 dry sediments d-1, respectively. AOB dominated in both net and potential nitrification, whose contribution accounted for 52.7-78.6% and 59.9-88.1%, respectively. The cell-specific ammonia oxidation rate calculation also revealed the cell-specific rates of AOB were higher than that of AOA. The Spearman's rank correlation analysis suggested that ammonia accumulation led to the AOB predominant role in net nitrification activity, and AOB abundance played the key role in potential nitrification activity. Furthermore, phylogenetic analysis suggested AOB were predominantly characterized by the Nitrosospira cluster, while AOA by the Nitrososphaera and Nitrososphaera sister clusters. This study will help us to better understand the contributions and characteristics of AOA and AOB in aquatic sediments and provide improved strategies for nitrogen control in large reservoirs. PMID- 29497801 TI - First validation of myocardial flow reserve assessed by dynamic 99mTc-sestamibi CZT-SPECT camera: head to head comparison with 15O-water PET and fractional flow reserve in patients with suspected coronary artery disease. The WATERDAY study. AB - PURPOSE: We assessed the feasibility of myocardial blood flow (MBF) and flow reserve (MFR) estimation using dynamic SPECT with a novel CZT camera in patients with stable CAD, in comparison with 15O-water PET and fractional flow reserve (FFR). METHODS: Thirty patients were prospectively included and underwent FFR measurements in the main coronary arteries (LAD, LCx, RCA). A stenosis >=50% was considered obstructive and a FFR abnormal if <=0.8. All patients underwent a dynamic rest/stress 99mTc-sestamibi CZT-SPECT and 15O-water PET for MBF and MFR calculation. Net retention kinetic modeling was applied to SPECT data to estimate global uptake values, and MBF was derived using Leppo correction. Ischemia by PET and CZT-SPECT was considered present if MFR was lower than 2 and 2.1, respectively. RESULTS: CZT-SPECT yielded higher stress and rest MBF compared to PET for global and LAD and LCx territories, but not in RCA territory. MFR was similar in global and each vessel territory for both modalities. The sensitivity, specificity, accuracy, positive and negative predictive value of CZT-SPECT were, respectively, 83.3, 95.8, 93.3, 100 and 85.7% for the detection of ischemia and 58.3, 84.6, 81.1, 36.8 and 93% for the detection of hemodynamically significant stenosis (FFR <= 0.8). CONCLUSIONS: Dynamic 99mTc-sestamibi CZT-SPECT was technically feasible and provided similar MFR compared to 15O-water PET and high diagnostic value for detecting impaired MFR and abnormal FFR in patients with stable CAD. PMID- 29497802 TI - Tracer uptake in mediastinal and paraaortal thoracic lymph nodes as a potential pitfall in image interpretation of PSMA ligand PET/CT. AB - PURPOSE: Since the introduction of 68Ga-PSMA-11 PET/CT for imaging prostate cancer (PC) we have frequently observed mediastinal lymph nodes (LN) showing tracer uptake despite being classified as benign. The aim of this evaluation was to further analyze such LN. METHODS: Two patient groups with biphasic 68Ga-PSMA 11 PET/CT at 1 h and 3 h p.i. were included in this retrospective evaluation. Group A (n = 38) included patients without LN metastases, and group B (n = 43) patients with LN metastases of PC. SUV of mediastinal/paraaortal LN of group A (n = 100) were compared to SUV of LN metastases of group B (n = 91). Additionally, 22 randomly selected mediastinal and paraaortal LN of patients without PC were immunohistochemically (IHC) analyzed for PSMA expression. RESULTS: In group A, 7/38 patients (18.4%) presented with at least one PSMA-positive mediastinal LN at 1 h p.i. and 3/38 (7.9%) positive LN at 3 h p.i. with a SUVmax of 2.3 +/- 0.7 at 1 h p.i. (2.0 +/- 0.7 at 3 h p.i.). A total of 11 PSMA-positive mediastinal/paraaortal LN were detected in nine patients considering both imaging timing points. SUVmax of LN-metastases was 12.5 +/- 13.2 at 1 h p.i. (15.8 +/- 17.0 at 3 h p.i.). SUVmax increased clearly (> 10%) between 1 h and 3 h p.i. in 76.9% of the LN metastases, and decreased significantly in 72.7% of the mediastinal/paraaortal LN. By IHC, PSMA-expression was observed in intranodal vascular endothelia of all investigated LN groups and to differing degrees within germinal centers of 15/22 of them (68.1%). Expression was stronger in mediastinal nodes (p = 0.038) and when follicular hyperplasia was present (p = 0.050). CONCLUSION: PSMA-positive mediastinal/paraaortal benign LN were visible in a notable proportion of patients. PSMA-positivity on the histopathological level was associated with the activation state of the LN. However, in contrast to LN metastases of PC, they presented with significantly lower uptake, which, in addition, usually decreased over time. PMID- 29497804 TI - Correction to: A Novel Classification and Staged Approach for Dissection Along the Celiac and Hepatic Artery During Pancreaticoduodenectomy. AB - In the original article, the captions for Figs. 2 and 3 were erroneously interchanged. The original article has been corrected. PMID- 29497803 TI - Prospective observational study of 177Lu-DOTA-octreotate therapy in 200 patients with advanced metastasized neuroendocrine tumours (NETs): feasibility and impact of a dosimetry-guided study protocol on outcome and toxicity. AB - PURPOSE: Peptide receptor radionuclide therapy in patients with neuroendocrine tumours has yielded promising results. This prospective study investigated the feasibility of dosimetry of the kidneys and bone marrow during therapy and its impact on efficacy and outcome. METHODS: The study group comprised 200 consecutive patients with metastasized somatostatin receptor-positive neuroendocrine tumours progressing on standard therapy or not suitable for other therapeutic options. A treatment cycle consisted of 7.4 GBq 177Lu-DOTA-octreotate with co-infusion of a mixed amino acid solution, and cycles were repeated until the absorbed dose to the kidneys reached 23 Gy or there were other reasons for stopping therapy. The Ki-67 index was <=2% in 47 patients (23.5%), 3-20% in 121 (60.5%) and >20% in 16 (8%). RESULTS: In 123 patients (61.5%) the absorbed dose to the kidneys reached 23 Gy with three to nine cycles during first-line therapy; in no patient was a dose to the bone marrow of 2 Gy reached. The best responses (according to RECIST 1.1) were a complete response (CR) in 1 patient (0.5%), a partial response (PR) in 47 (23.5%), stable disease (SD) in 135 (67.5%) and progressive disease (PD) in 7 (3.5%). Median progression-free survival was 27 months (95% CI 22-30 months) in all patients, 33 months in those in whom the absorbed dose to the kidneys reached 23 Gy and 15 months in those in whom it did not. Median overall survival (OS) was 43 months (95% CI 39-53 months) in all patients, 54 months in those in whom the absorbed dose to the kidneys reached 23 Gy and 25 months in those in whom it did not. Median OS was 60 months in patients with a best response of PR or CR, 42 months in those with SD and 16 months in those with PD. Three patients (1.5%) developed acute leukaemia, 1 patient (0.5%) chronic leukaemia (unconfirmed) and 30 patients (15%) grade 3 or 4 bone marrow toxicity. Eight patients (4%) developed grade 2 kidney toxicity and one patient (0.5%) grade 4 kidney toxicity. CONCLUSIONS: Dosimetry-based therapy with 177Lu DOTA-octreotate is feasible. Patients in whom the absorbed dose to the kidneys reached 23 Gy had a longer OS than those in whom it did not. Patients with CR/PR had a longer OS than those with SD. Bone marrow dosimetry did not predict toxicity. PMID- 29497805 TI - Intraoperative Parathyroid Hormone Assay Remains Predictive of Cure in Renal Impairment in Patients with Single Parathyroid Adenomas. AB - BACKGROUND: Parathyroid hormone (PTH) has a short half-life and is cleared by the liver and kidneys. This study examined whether declining estimated glomerular filtration rate (eGFR) affects application of the Miami criterion for intraoperative PTH (ioPTH) decline during parathyroidectomy for primary hyperparathyroidism (pHPT). METHODS: A retrospective review of consecutive patients undergoes parathyroidectomy for pHPT. Patients with multi-gland disease, without ioPTH, failure-to-cure and those <18 years were excluded. Baseline demographics, pre-operative PTH, ioPTH and 6-month follow-up data were available. Patients were categorised into normal or chronic kidney disease (CKD stage 2-5) based on pre-operative eGFR. Nonparametric data were compared using Mann-Whitney U test/Kruskal-Wallis test. The primary outcome measure was to assess whether CKD affected ioPTH decline in parathyroidectomy for pHPT. RESULTS: A total of 476 patients were included [75.4% women; median age 63.8 years (18-92)]. CKD was present in 362 (76%) (CKD2:289; CKD3:66; CKD4/5:7). Increasing CKD stage was associated with advancing age [normal 53 years (41-61); CKD2 65 (57-73); CKD3 73.5 (66-78); CKD4/5 74(63-81); p < 0.001] and higher pre-operative PTH [16.6 pmol/L (11.1-22.9); 13.1 (10.4-17.7); 22.6 (13.8-33.7); 33.8(12.4-41.7); p < 0.001]. Baseline and post-excision ioPTH were significantly higher in those with CKD4/5 (p < 0.05). The Miami criterion was met in all patients, but median fall in ioPTH at 10-min varied between groups [normal:0.78 (0.71-0.82); CKD2:0.76 (0.69-0.83); CKD3:0.75 (0.69-0.82); CKD4/5:0.69 (0.61-0.70); p = 0.048)]. It was significantly lower in those with CKD4/5 compared with the remainder of patients [0.69 (0.61-0.70) vs. 0.76 (0.70-0.82); p = 0.008]. CONCLUSIONS: Although the reduction in ioPTH after successful parathyroidectomy is lower in severe CKD, the Miami criterion remains predictive of cure. Differences in absolute levels of PTH and tumour weight suggest that renal HPT may be a confounding factor. PMID- 29497806 TI - Progressive transformation of germinal centers: an illustration of two clinical cases. PMID- 29497807 TI - Clinical impact of underweight status at diagnosis on elderly patients with acute myeloid leukemia: a retrospective study of JALSG GML200. PMID- 29497808 TI - Novel anatomic variation: heptafurcation of the celiac trunk. AB - We report here anatomic variants which were found during a retrospective study of a male patient, 54 years old, evaluated in computed tomography: heptafurcation of the celiac trunk (CT) and bilateral double renal arteries. The seven branches of the heptafurcated CT were the (1) left and (2) right inferior phrenic arteries, the (3) splenic and (4) left gastric artery, the (5) common hepatic artery, further sending off the (a) proper, continued as left, hepatic artery and (b) the gastroduodenal artery, (6) a replaced right hepatic artery and (7) the dorsal pancreatic artery. To our knowledge, heptafurcation of the CT was not reported previously. The arterial variants have great importance during various surgical and interventional procedures and should be documented prior to respective procedures. PMID- 29497810 TI - New digital methods: remodelling the harms tangent scale setting. AB - PURPOSE: The aim of this study is to present a feasibility study to evaluate and compare a self-constructed, digital-based tangent scale using the Harms tangent screen test for the examination of patients' strabismus angles. METHODS: The documented strabismus angles of 10 patients were measured at nine gaze-positions and compared using the Harms tangent screen test (Harms Screen) and a self constructed digital screen test (Digital Screen). The primary outcome is the difference in the measured angles between both methods. Secondary outcomes include the duration of the examinations and the diagnostic conclusion based on the results of the measurements. RESULTS: The datasets from 10 of 13 patients were used for comparisons (median age 52 years; females 5; males 5). All measurements showed a mean of 1.77 degrees (SD 2.95 degrees ) in horizontal deviations and 1.11 degrees (SD 2.23 degrees ) in vertical deviations. The two methods showed differences (> 5 degrees ) in 12 cases (13.3%) for horizontal angle measurements and in four cases (4.4%) for vertical angle measurements. The median examination time was 238 s (range 60-430 s) for the Harms Screen and 150 s (range 120-600 s) for the Digital Screen tests. The diagnostic conclusions were identical for both methods. CONCLUSIONS: The feasibility of the experimental digital setup in principle is shown. Despite some deviations in the measured strabismus angles, the resulting diagnosis of the paresis was identical. The new method showed a reduction of examination time. PMID- 29497809 TI - Maintenance of genome stability: the unifying role of interconnections between the DNA damage response and RNA-processing pathways. AB - Endogenous and exogenous factors can severely affect the integrity of genetic information by inducing DNA damage and impairing genome stability. The protection of genome integrity is ensured by the so-called "DNA damage response" (DDR), a set of evolutionary-conserved events that, triggered upon DNA damage detection, arrests the cell cycle, and attempts DNA repair. Here, we review the role of the DDR proteins as post-transcriptional regulators of gene expression, in addition to their roles in DNA damage recognition, signaling, and repair. At the same time, we discuss recent insights into how pre-mRNA splicing factors go beyond their splicing activities and play direct functions in detecting, signaling, and repairing DNA damage. The importance of extensive two-way crosstalk and interaction between the RNA processing and the DDR stems from growing evidence that the defects of their communication lead to genomic instability. PMID- 29497811 TI - The genome sequence of 'Kurodagosun', a major carrot variety in Japan and China, reveals insights into biological research and carrot breeding. AB - Carrot (Daucus carota L.) is one of the most economically important root vegetables in the world, providing numerous nutrients for human health. China is the largest country of carrot production in the world, and 'Kurodagosun' has been a major carrot variety in China. Carrot material used in this study was the inbred line 'DC-27', which was derived by forced selfing from 'Kurodagosun'. To understand the genetic system and plant-specific genes of 'Kurodagosun', we report the draft genome sequence of carrot 'DC-27' assembled using a combination of Roche454 and HiSeq 2000 sequencing technologies to achieve 32-fold genome coverage. A total of 31,891 predicted genes were identified. These assembled sequences provide candidate genes involved in biological processes including stress response and carotenoid biosynthesis. Genomic sequences corresponding to 371.6 Mb was less than 473 Mb, which is the estimated genome size. The availability of a draft sequence of the 'DC-27' genome advances knowledge on the biological research and breeding of carrot, as well as other Apiaceae plants. The 'DC-27' genome sequence data also provide a new resource to explore the evolution of other higher plants. PMID- 29497812 TI - Efficacy and tolerability of 2-L polyethylene glycol with ascorbic acid versus sodium picosulfate with magnesium citrate: a randomized controlled trial. AB - BACKGROUND/AIM: Previous studies comparing 2-L polyethylene glycol (PEG)-based solution with ascorbic acid (PEG/Asc) with sodium picosulfate/magnesium citrate (SP/MC) drew inconclusive results. This study aimed to compare a 2-L-PEG/Asc with SP/MC by split method in bowel cleansing efficacy, tolerability, and safety and to identify factors influencing inadequate bowel preparation. METHOD: We performed a prospective randomized, endoscopist-blinded, single-center, controlled trial. The Aronchick scale and Ottawa bowel preparation scale (OBPS) were used to evaluate the bowel cleansing efficacy, and patients' tolerability and preferences were assessed by questionnaire. RESULTS: In total, 223 patients were randomized to receive 2-L-PEG/Asc (n = 109) or SP/MC (n = 114). There was no significant difference in overall bowel cleansing efficacy between the two groups; however, when analyzing by individual segment, mean bowel cleansing efficacy of right colon showed a trend in favor of SP/MC group than in PEG/Asc group (OBPS; 1.55 +/- 0.66 vs. 1.74 +/- 0.88, P = 0.08). Furthermore, SP/MC was better tolerated than PEG/Asc based on ease of consumption and preference to receive the agents again in the future. Total adverse events were significantly lower in SP/MC group than PEG/Asc group (47.4 vs. 62.4%, P = 0.031). In multivariate analysis, later colonoscopic starting time was the only independent factor predicting inadequate bowel preparation (OR 1.39, 95% CI 1.156-1.692, P = 0.001). CONCLUSIONS: There was no significant difference in overall bowel cleansing efficacy between PEG/Asc and SP/MC; however, SP/MC showed better tolerability and safety profile than PEG/Asc. The independent factor for inadequate bowel preparation was later colonoscopic starting time when applied split method. PMID- 29497813 TI - A novel way to manage trastuzumab cardiotoxicity. AB - PURPOSE: Trastuzumab is the most widely prescribed anti-HER2 humanized monoclonal antibody. Cardiac toxicity is the only limiting toxicity of trastuzumab and it is of particular concern in patients with complete response, since the drug needs to be stopped, with a risk of disease relapse. To date, no pharmacological data on trastuzumab cardiotoxicity in patients have been made available. Here, we provide proof of concept, demonstrating that it was possible to prevent trastuzumab induced cardiotoxicity by modifying the drug administration schedule. METHODS: In this paper, we report the case of a patient with metastatic breast cancer responding to trastuzumab, who developed severe cardiac toxicity twice using a 3 weekly regimen. Considering preclinical pharmacological data on trastuzumab cardiotoxicity, we hypothesized that a weekly schedule of trastuzumab with lower peaks of serum concentration could be safe while remaining efficient. With the patient's consent, we started a weekly combination of carboplatin (AUC2) and trastuzumab (2 mg/kg) with close monitoring of trastuzumab concentrations. RESULTS: We successfully controlled the disease for an additional 6 months with relevant trough concentrations of trastuzumab of around 50 mg/L. Another important aspect is that, with this weekly schedule, we observed no cardiac toxicity, and the left ventricular ejection fraction remained stabilized, at over 50%. CONCLUSIONS: Trastuzumab is the most widely prescribed anti-HER2 monoclonal antibody for the treatment of HER2 metastatic breast cancer, and it is the only drug that has been approved for the treatment of localized HER2 breast cancer, 1 year treatment being required after surgery. In case of cardiac toxicity, particularly in women over 60 years of age, a weekly regimen with lower peaks of concentration could be an alternative to the standard 3-weekly regimen. PMID- 29497815 TI - Effects of patient navigation on satisfaction with cancer care: a systematic review and meta-analysis. AB - PURPOSE: Patient navigation (PN) is a model of healthcare coordination designed to reduce barriers to achieving optimal health outcomes. Systematic reviews evaluating whether PN is associated with higher patient satisfaction with cancer care are lacking. METHODS: We conducted a systematic review to synthesize evidence of comparative studies evaluating the effectiveness of PN programs to improve satisfaction with cancer-related care. We included studies reported in English that: (1) evaluated a PN intervention designed to increase satisfaction with cancer care; and (2) involved a randomized controlled trial (RCT) or non-RCT approach. Standardized forms were used to abstract data from studies. These data were evaluated for methodological quality, summarized qualitatively, and synthesized under a random effects model. RESULTS: The initial search yielded 831 citations. Nine met inclusion criteria. Five had adequate data (1 RCT and 4 non RCTs) to include in the meta-analysis. Methodological quality of included studies ranged from weak to strong, with half rated as weak. Findings of the RCTs showed a statistically significant increase in satisfaction with cancer care involving PN (standardized mean difference (SMD) = 2.30; 95% confidence interval 1.79, 2.80, p < 0.001). Pooled results from non-RCTs showed no significant association between PN and satisfaction with cancer-related care (standardized mean difference = 0.39; 95% confidence interval - 0.02, 0.80, p = 0.06). CONCLUSIONS: Although PN has been widely implemented to improve cancer care, high-quality studies are needed to characterize the relationship between PN and satisfaction with cancer-related care. PMID- 29497816 TI - Selected reaction monitoring for colorectal cancer diagnosis using a set of five serum peptides identified by BLOTCHIP(r)-MS analysis. AB - BACKGROUND: Colorectal cancer (CRC) is one of the most predominant types of cancer, and it is the fourth most common cause of cancer-related death and it is important to diagnose CRC in early stage to decrease the mortality by CRC. In our previous study, we identified a combination of five peptides as a biomarker candidate to diagnose CRC by BLOTCHIP(r)-MS analysis using a set of healthy control subjects and CRC patients (stage II-IV). The aim of the present study was to validate the serum biomarker peptides reported in our previous study using a second cohort and to establish their potential usefulness in CRC diagnosis. METHODS: A total of 56 patients with CRC (n = 14 each of stages I-IV), 60 healthy controls, and 60 patients with colonic adenoma were included in this study. The five peptides were extracted and analyzed by selected reaction monitoring using ProtoKey(r) Colorectal Cancer Risk Test Kit (Protosera, Inc., Amagasaki, Japan). RESULTS: The results clearly showed that the four CRC groups, stages I-IV, could be sufficiently discriminated from the control group and colonic polyp group. This five-peptide set could identify CRC at each stage compared to the control population in this validation cohort, including those with early-stage disease. The AUC values for each stage of CRC compared to the control population were 0.779, 0.946, 0.852, and 0.973 for stages I, II, III, and IV, respectively. CONCLUSIONS: In this case-control validation study, we confirmed high diagnostic performance for CRC using five peptides that were identified in our previous study as serum biomarker candidates for the detection of CRC. PMID- 29497817 TI - Primary 'dehydration' and acute stroke: a systematic research review. AB - BACKGROUND AND PURPOSE: Hydration status at the time of stroke has been acknowledged as an important determinant in early stroke recovery. However, the diagnosis of dehydration, or more accurately, a volume-contracted state, at the time of stroke is challenging since there are currently no consensus diagnostic criteria. In this systematic review, we gather the available evidence about diagnosis and treatment of dehydration after stroke. METHODS: Studies of hospitalized ischemic stroke patients that reported rates of dehydration from January 1997 to March 2017 were screened for inclusion via a systematic search of PubMed, CINAHL, Cochrane, and Scopus using keywords hydration, dehydration, hemodilution, viscosity, volume status, and thirst. RESULTS: Twenty-five studies of 8699 acute stroke patients were included. Nineteen studies reported on the diagnostic approach to dehydration. Findings are synthesized into four main categories of available research including studies that specify: (1) biological mechanisms using animal models to investigate the relationship between dehydration and stroke; (2) measures of dehydration in the acute human stroke population; (3) rehydration therapies after stroke; and (4) outcomes after stroke in dehydrated patients. CONCLUSIONS: We found considerable variation in terminology specific to hydration status, diagnostic approach to dehydration, and few prospective studies of treatment strategies with varying results. This review supports the need for consensus development of operational diagnostic criteria, standardization of language, and the opportunity for prospective study of rehydration strategies to impact outcome after stroke. PMID- 29497819 TI - cIMPACT-NOW update 2: diagnostic clarifications for diffuse midline glioma, H3 K27M-mutant and diffuse astrocytoma/anaplastic astrocytoma, IDH-mutant. PMID- 29497818 TI - [18F] AV-1451 uptake in corticobasal syndrome: the influence of beta-amyloid and clinical presentation. AB - Corticobasal syndrome (CBS) is a phenotypic manifestation of diverse pathologies, including Alzheimer's disease and 4-repeat tauopathies. Predicting pathology in CBS is unreliable and, hence, molecular neuroimaging may prove to be useful. The aim of this study was to assess regional patterns of uptake on [18F] AV-1451 PET in CBS and determine whether patterns of uptake differ according to beta-amyloid deposition or differing clinical presentations. Fourteen patients meeting criteria for CBS underwent Pittsburgh Compound B (PiB) and [18F] AV-1451 PET. Seven patients presented as CBS and seven presented with apraxia of speech (AOS) and later evolved into CBS. A global PiB summary was calculated and used to classify patients as PiB (-) or PiB (+). AV-1451 uptake was calculated in fourteen regions-of-interest, with values divided by uptake in cerebellar crus grey matter to generate standard uptake value ratios. AV-1451 uptake was considered elevated if it fell above the 95th percentile from a group of 476 cognitively unimpaired normal controls. Six of the 14 CBS patients (43%) were PiB (+), with three of these patients showing strikingly elevated AV-1451 uptake across many cortical regions. Of the eight PiB (-) patients, only those with AOS showed elevated AV-1451 uptake in supplementary motor area and precentral cortex compared to controls. No region of elevated AV-1451 uptake were observed in PiB ( ) typical CBS patients without AOS. These results suggest that regional [18F] AV 1451 is variable in CBS and depends on the presence of beta-amyloid as well as clinical presentation such as AOS. PiB (+) CBS does not necessarily reflect underlying Alzheimer's disease; however, the possibility some of these patients will evolve into Alzheimer's disease over time cannot be excluded. PMID- 29497820 TI - Analysis of a model microswimmer with applications to blebbing cells and mini robots. AB - Recent research has shown that motile cells can adapt their mode of propulsion depending on the environment in which they find themselves. One mode is swimming by blebbing or other shape changes, and in this paper we analyze a class of models for movement of cells by blebbing and of nano-robots in a viscous fluid at low Reynolds number. At the level of individuals, the shape changes comprise volume exchanges between connected spheres that can control their separation, which are simple enough that significant analytical results can be obtained. Our goal is to understand how the efficiency of movement depends on the amplitude and period of the volume exchanges when the spheres approach closely during a cycle. Previous analyses were predicated on wide separation, and we show that the speed increases significantly as the separation decreases due to the strong hydrodynamic interactions between spheres in close proximity. The scallop theorem asserts that at least two degrees of freedom are needed to produce net motion in a cyclic sequence of shape changes, and we show that these degrees can reside in different swimmers whose collective motion is studied. We also show that different combinations of mode sharing can lead to significant differences in the translation and performance of pairs of swimmers. PMID- 29497821 TI - Birth prevalence of congenital malformations in singleton pregnancies resulting from in vitro fertilization/intracytoplasmic sperm injection worldwide: a systematic review and meta-analysis. AB - PURPOSE: We conducted a systematic review and meta-analysis to estimate the worldwide birth prevalence of total congenital malformations (CMs), major CMs, and specific CMs according to organs and systems classification associated with IVF/ICSI singleton pregnancies. METHODS: Unrestricted searches were conducted, with an end-date parameter of 1 June 2017, of PubMed, Embase, Google Scholar, Cochrane Libraries, and Chinese databases, to identify cohort studies assessing CMs associated with IVF/ICSI singleton pregnancies. The prevalence estimates were summarized and analyzed by meta-analysis. RESULTS: Thirty-four cohort studies comprising 159,021 IVF/ICSI and 6704,405 spontaneously conceived singleton pregnancies met the inclusion criteria. Among IVF/ICSI singleton pregnancies, pooled estimates of total CMs and major CMs (per 10,000) were 484.3 (95% CI 363.8 641.9) and 475.8 (95% CI 304.9-735.2), respectively; for specific CMs, pooled estimates 13.04 (95% CI 9.90-17.18) for cleft lip and/or palate, 17.01 (95% CI 8.01-36.06) for eye, ear, face, and neck malformations, 16.51(95% CI 11.56-23.57) for nervous system malformations, 36.21 (95% CI 26.20-50.02) for chromosomal defects, 8.31 (95% CI 4.21-16.40) for respiratory system malformations, 38.01 (95% CI 24.06-60.00) for digestive system malformations, 110.25 (95% CI 66.92 181.12) for musculoskeletal system malformations, 108.92 (95% CI 68.73-172.21) for urogenital system malformations, and 77.20 (95% CI 53.25-111.80) for circulatory system malformations. The IVF/ICSI singleton pregnancies compared with those conceived naturally experienced higher prevalence of total CMs, major CMs, and most specific CMs. Significant differences across continents, countries, types of assisted conception, and diagnose time of CMs were observed for total CMs birth prevalence among IVF/ICSI singleton pregnancies. CONCLUSIONS: The IVF/ICSI singleton pregnancies were significantly associated with high birth prevalence of CMs, representing a major global health burden. Significant differences across continents, countries, types of ART, and diagnose time of CMs were found. However, it remains uncertain whether detected differences represent true or methodological differences. In the future, population wide prospective CMs' registries covering the entire world population are needed to determine the exact birth prevalence. PMID- 29497822 TI - A retrospective comparative study evaluating the efficacy of adding intra arterial methotrexate infusion to uterine artery embolisation followed by curettage for cesarean scar pregnancy. AB - PURPOSE: The study aimed to compare the efficacy of intra-arterial methotrexate (MTX) infusion combined with uterine artery embolisation (UAE) and uterine curettage with that of UAE and curettage without MTX infusion for the treatment of cesarean scar pregnancy (CSP). METHODS: In this retrospective study, data of CSP patients admitted from January 2011 to July 2015 were obtained from electronic patient records. Clinical information at baseline and after treatment were extracted and analyzed. RESULTS: A total of 93 CSP patients were included, with 57 patients receiving UAE followed by curettage (UC) and 36 patients receiving intra-arterial MTX infusion followed by UAE and curettage (MUC). The baseline characteristics were not significantly different between the two groups. Without additional intervention, 32 (88.9%) patients were successfully treated by MUC, and 49 (86.0%) patients were successfully treated by UC, defined by discontinued ectopic conceptus growth, normalized serum beta-human chorionic gonadotropin (beta-hCG) level, ceased vaginal bleeding and preservation of uterus, with no significant difference between the two groups. Additionally, intra-operative blood loss volume and post-operative bleeding events were not significantly different between the two groups. However, serum beta-hCG decline on the first day after surgery was significantly promoted, and the hospitalization length and the time needed for serum beta-hCG normalization were significantly shortened by addition of intra-arterial MTX infusion. CONCLUSIONS: Adding intra-arterial MTX to UAE and curettage significantly promoted post operative recovery, though success rate and bleeding events were not significantly affected, suggesting that addition of intra-arterial MTX might not be necessary. PMID- 29497823 TI - What we do and do not know about women and kidney diseases: Questions unanswered and answers unquestioned : Reflection on World Kidney Day and International Woman's Day. PMID- 29497825 TI - Development of the Mitsucal computer system to identify causal mutation with a high-throughput sequencer. AB - KEY MESSAGE: Development of Mitsucal. Recent advances in DNA sequencing technology have facilitated whole-genome sequencing of mutants and variants. However, the analyses of large sequence datasets using a computer remain more difficult than operating a sequencer. Forward genetic approach is powerful even in sexual reproduction to identify key genes. Therefore, we developed the Mitsucal computer system for identifying causal genes of mutants, using whole genome sequence data. Mitsucal includes a user-friendly web interface to configure analysis variables, such as background and crossed strains. Other than configuration, users are only required to upload short reads. All results are presented through a web interface where users can easily obtain a short list of candidate mutations. In the present study, we present three examples of Arabidopsis mutants defective in sexual reproduction in which Mitsucal is used to identify causal mutation. One mutant was screened from seeds of a transgenic line with a reporter gene to elucidate the mechanisms involved in the regulation of seed oil storage. The identified gene codes for a protein may be involved in mRNA splicing. Other two mutants had defects in the surface walls on pollen termed exine. Both causal genes were identified, and mutants were found to be allele of known mutants. These results show that Mitsucal could facilitate identification of causal genes. PMID- 29497824 TI - Acute kidney injury in children with chronic liver disease. AB - Acute kidney injury (AKI) is a common accompaniment in patients with liver disease. The causes, risk factors, manifestations and management of AKI in these patients vary according to the liver disease in question (acute liver failure, acute-on-chronic liver failure, post-liver transplantation or metabolic liver disease). There are multiple causes of AKI in patients with liver disease-pre renal, acute tubular necrosis, post-renal, drug-induced renal failure and hepatorenal syndrome (HRS). Definitions of AKI in liver failure are periodically revised and updated, but pediatric definitions have still to see the light of the day. As our understanding of the pathophysiology of liver disease and renal involvement improves, treatment modalities have become more advanced and rationalized. Treatment includes reversing precipitating factors, such as infections and gastrointestinal bleeding, volume expansion, paracentesis and vasoconstrictors. This approach is tried and tested in adults. A pediatric tailored approach is still lacking due to inadequate numbers of patients, differences in causes of AKI and paucity of literature. In this review, we attempt to explore the pathophysiological basis, treatment modalities and controversies in the diagnosis and treatment of AKI in pediatric patients with chronic liver disease and discuss our own personal practice. We recognize that, although it is not a very commonly encountered entity in pediatric population, HRS has specific diagnostic criteria and treatment modalities that differ from other causes of AKI in patients with chronic liver disease; hence among the etiologies of kidney injury in patients with chronic liver disease, we focus here on HRS. PMID- 29497827 TI - SAGES Foregut Surgery Masters Program: a surgeon's social media resource for collaboration, education, and professional development. AB - BACKGROUND: Facebook is a popular online social networking platform increasingly used for professional collaboration. Literature regarding use of Facebook for surgeon professional development and education is limited. The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) has established a Facebook group dedicated to discussion of surgery of the esophagus, stomach, and small intestine-the "SAGES Foregut Surgery Masters Program." The aim of this study is to examine how this forum is used for professional development, education, and quality improvement. METHODS: Member and post statistics were obtained from https://grytics.com , a Facebook group analytics service. All posts added to the Foregut forum since its creation in April 2015 through December 2016 were reviewed and categorized for content and topic. Posts were reviewed for potential identifiable protected health information. RESULTS: As of December 2016, there were 649 total members in the group. There have been a total of 411 posts and 4116 comments with a median of 10.1 comments/post (range 0-72). Posts were categorized as operative technique (64%), patient management (52%), continuing education (10%), networking (10%), or other (6%). Video and/or photos were included in 53% of posts with 4% of posts depicting radiologic studies and 13% with intraoperative photos or videos. An additional 40 posts included links to other pages, such as YouTube, journal articles, or the SAGES website. One post (0.2%) contained identifiable protected health information and was deleted once recognized by the moderators of the group. CONCLUSION: Social media is a unique, real-time platform where surgeons can learn, discuss, and collaborate towards the goal of optimal treatment of surgical disease. Active online surgical communities such as the SAGES Foregut Surgery Masters Program have the potential to enhance communication between surgeons and are a potential innovative adjunct to traditional methods of continuing surgical education. Surgical societies should adopt and promote professional and responsible use of social media. PMID- 29497826 TI - Comparison of propofol and desflurane for postanaesthetic morbidity in patients undergoing surgery for aneurysmal SAH: a randomized clinical trial. AB - PURPOSE: Surgery for aneurysmal clipping after subarachnoid haemorrhage (SAH) poses a unique anaesthetic challenge. However, data on the influence of anaesthetic agents in these patients are lacking. The study aims to evaluate the superiority of propofol over desflurane for postanaesthetic morbidity in patients undergoing surgery following aneurysmal SAH. METHODS: Seventy World Federation of Neurosurgeons Grade I and II patients were randomized into propofol (n = 35) and desflurane groups (n = 35). Anaesthesia was maintained with propofol/fentanyl in propofol group and desflurane/fentanyl in the desflurane group. Jugular venous oxygen saturation (SjVO2) and brain relaxation were assessed intraoperatively. Time to eye opening, response to verbal commands, and extubation were noted from the time of discontinuing the anaesthetic agent. Duration of postoperative hospital stay and modified Rankin score (MRS) at discharge were subsequently compared. RESULTS: Median postoperative hospital stay was 9 (6, 14) days with use of propofol and 9 (7, 12) days in desflurane group (P = 0.671). 18 patients in the propofol group and 14 patients in the desflurane group had good outcome (modified Rankin score 0-1; P = 0.453). Both the anaesthetics were similar in terms of intraoperative haemodynamics, brain relaxation, time to eye opening, response to verbal commands, and extubation time (P > 0.05). Emergence hypertension was more in the desflurane group (P = 0.007). The intraoperative SjVO2 values were significantly higher in the desflurane group (P < 0.05). CONCLUSION: Propofol and desflurane are comparable in terms of postoperative morbidity in patients undergoing aneurysm neck clipping following SAH. PMID- 29497828 TI - Quality of life after robot-assisted transmediastinal radical surgery for esophageal cancer. AB - BACKGROUND: The aim of this retrospective study was to assess postoperative quality of life (QOL) after robot-assisted radical transmediastinal esophagectomy, defined as a nontransthoracic esophagectomy with radical mediastinal lymphadenectomy combining a robotic transhiatal approach and a video assisted cervical approach. The results were compared to those of transthoracic esophagectomy. METHODS: In this study, all consecutive patients who underwent robot-assisted radical transmediastinal esophagectomy or transthoracic esophagectomy for esophageal cancer at University of Tokyo between January 2010 and December 2014 were included. The European Organization for Research and Treatment of Cancer (EORTC)'s quality of life questionnaires QLQ-C30 and QLQ OES18 were sent to all patients that were still living, had no recurrence or other malignancy, and had not undergone a reoperation because of complications after esophagectomy. RESULTS: We were able to survey 63 (98.4%) of 64 eligible patients. We assessed and compared the QOL scores of both groups of patients. Compared to transthoracic esophagectomy, transmediastinal esophagectomy was associated with better QOL. Global health status and the physical, role, and cognitive function scale scores were significantly superior in the transmediastinal esophagectomy group (P = 0.004, < 0.0001, 0.007, 0.002, respectively). Fatigue, nausea and vomiting, pain, appetite loss, reflux, and taste scores were significant lower (superior) in the transmediastinal esophagectomy group (P = 0.003, 0.032, 0.025, 0.018, 0.001, 0.041, respectively). CONCLUSIONS: This study indicates that robot-assisted radical transmediastinal esophagectomy is associated with better postoperative QOL compared to transthoracic esophagectomy. A larger study and prospective analyses are needed to confirm the current results. PMID- 29497829 TI - The safe use of surgical energy devices by surgeons may be overestimated. AB - BACKGROUND: Surgical energy injuries are an underappreciated phenomenon. Improper use of surgical energy or poor attention to patient safety can result in operating room fires, tissue injuries, and interferences with other electronic devices, while rare complications can be devastatingly severe. Despite this, there is no current standard requirement for educating surgeons on the safe use of energy-based devices or evaluation of electrosurgery (ES) education in residency training, credentialing, or practice. The study aimed to assess the current baseline knowledge of surgeons and surgical trainees with regards to ES across varying experiences at a tertiary level care center. METHODS: Surgeons and surgical trainees from seven surgical specialties (General Surgery, Cardiothoracic Surgery, Vascular Surgery, Obstetrics/Gynecology, Orthopedic Surgery, Urology, and Otorhinolaryngology) at a tertiary level care hospital were tested. Testing included an evaluation regarding their background training and experiences with ES-related adverse events and a 15 multiple-choice-question exam testing critical knowledge of ES. RESULTS: A total of 134 surveys were sent out with 72 responses (53.7%). The mean quiz score was 51.5 +/- 15.5% (passing score was 80%). Of staff surgeons, 33/65 (50.8%) completed the survey with mean and median scores of 54.9 and 53.3%, respectively (range 33.3-86.7%). Of surgical trainees, 39/69 (56.5%) completed the survey with mean and median scores of 48.6 and 46.7%, respectively (range 13.3-80.0%). There were no statistically significant differences based on training status (p = 0.08), previous training (p = 0.24), number of cases (p = 0.06), or specialty (p = 0.689). CONCLUSION: Surgeons and surgical trainees both have a significant knowledge gap in the safe and effective use of surgical energy devices, regardless of surgical specialty and despite what they feel was adequate training. The knowledge gap is not improved with experience. A formal surgical energy education program should be a requirement for residency training or credentialing. PMID- 29497830 TI - Screening for Dysphagia in Adult Patients with Stroke: Assessing the Accuracy of Informal Detection. AB - Early identification of dysphagia by screening is recommended best practice for patients admitted to hospital with acute stroke. Screening can reduce the risk of pneumonia and promote stroke recovery, yet some institutions do not utilize a formal screening protocol. This study assessed the accuracy of informal dysphagia detection prior to implementation of a formal screening protocol. We conducted a secondary analysis of data captured between 2003 and 2008 from a sample of 250 adult stroke survivors admitted to a tertiary care centre. Using a priori criteria, patient medical records were reviewed for notation about dysphagia; if present, the date/time of notation, writer's profession, and suggestion of dysphagia presence. To assess accuracy of notations indicating dysphagia presence, we used speech language pathology (SLP) assessments as the criterion reference. There were 221 patient medical records available for review. Patients were male (56%), averaged 68 years (SD = 15.0), with a mean Canadian Neurological Scale score of 8.1 (SD = 3.0). First notations of swallowing by SLP were excluded. Of the remaining 170 patients, 147 (87%) had first notations (104 by nurses; 40 by physicians) within a median of 24.3 h from admission. Accuracy of detecting dysphagia from informal notations was low, with a sensitivity of 36.7% [95% CI, 24.9, 50.1], but specificity was high (94.2% [95% CI, 86.5, 97.9]). Informal identification methods, although timely, are suboptimal in their accuracy to detect dysphagia and leave patients with stroke at risk for poor health outcomes. Given these findings, we encourage the use of psychometrically validated formal screening protocols to identify dysphagia. PMID- 29497831 TI - Factors Contributing to Hydration, Fluid Intake and Health Status of Inpatients With and Without Dysphagia Post Stroke. AB - Dysphagia has been strongly associated with poor hydration in acute stroke settings. However, in sub-acute settings, the contribution to dehydration of dysphagia in combination with other common stroke comorbidities has not been explored. The aim of this study was to investigate which demographic and stroke comorbidities, including dysphagia, contribute most significantly to oral fluid intake, hydration status and specific adverse health outcomes for patients in sub acute rehabilitation following stroke. Data from 100 inpatients from three Australian rehabilitation facilities (14 with confirmed dysphagia and 86 without dysphagia) were analysed. Hierarchical multiple regressions were conducted to determine which demographic or stroke comorbidities were most predictive of each outcome: average daily fluid intake; Blood urea nitrogen/creatinine (BUN/Cr) ratio as an index of hydration and medically diagnosed adverse events of pneumonia, dehydration, urinary tract infection or constipation. Average daily beverage intake (M = 1448 ml, SD 369 ml) was significantly and independently predicted by Functional Independence Measure (FIM) at admission (F change = 9.212, p = 0.004). BUN/Cr ratio (M = 20, SD 5.16) was predicted only by age (F change = 4.026, p = 0.049). Adverse health events, diagnosed for 20% of participants, were significantly predicted by Admission FIM (OR 1.040, 95% CI 1.001, 1.081, p = 0.047). Dysphagia was not a significant predictor of any of the outcomes measured. Rather, overall functional dependency was the most significant predictor of poor oral fluid intake and fluid-related adverse health outcomes in sub-acute stroke. Clinical Trial number: Data for the post hoc analysis presented in this article came from the registered trial ACTRN12610000752066. PMID- 29497832 TI - Ischemic stroke associated with ankylosing spondylitis: an integral part of disease spectrum, or a natural consequence of progressive infirmity? PMID- 29497833 TI - Micro-decomposer communities and decomposition processes in tropical lowlands as affected by land use and litter type. AB - We investigated how the land-use change from rainforest into jungle rubber, intensive rubber and oil palm plantations affects decomposers and litter decomposition in Sumatra, Indonesia. Litterbags containing three litter types were placed into four land-use systems and harvested after 6 and 12 months. Litter mass loss and litter element concentrations were measured, and different microbial groups including bacteria, fungi and testate amoebae were studied. After 12 months 81, 65, 63 and 53% of litter exposed in rainforest, jungle rubber in oil palm and rubber plantations was decomposed. In addition to land use, litter decomposition varied strongly with litter type and short-term effects differed markedly from long-term effects. After 6 months, oil palm and rubber litter decomposed faster than rainforest litter, but after 12 months, decomposition of rainforest litter exceeded that of oil palm and rubber litter, reflecting adaptation of bacteria and fungi to decompose structural compounds in rainforest litter but not (or less) in rubber and oil palm litter. Bacterial and fungal community composition and testate amoeba species number and density varied strongly with litter type, but little with land use. However, community composition of testate amoebae was mainly affected by land use. Generally, changes in bacteria, fungi and testate amoebae were linked to changes in litter element concentrations, suggesting that element ratios of litter material as basal resource for the decomposer food web shape the structure of decomposer communities and decomposition processes via bottom-up forces. Overall, changing rainforest to monoculture plantations shifts the decomposer community structure and negatively affects litter decomposition. PMID- 29497834 TI - Microspatial ecotone dynamics at a shifting range limit: plant-soil variation across salt marsh-mangrove interfaces. AB - Ecotone dynamics and shifting range limits can be used to advance our understanding of the ecological implications of future range expansions in response to climate change. In the northern Gulf of Mexico, the salt marsh mangrove ecotone is an area where range limits and ecotone dynamics can be studied in tandem as recent decreases in winter temperature extremes have allowed for mangrove expansion at the expense of salt marsh. In this study, we assessed aboveground and belowground plant-soil dynamics across the salt marsh-mangrove ecotone quantifying micro-spatial patterns in horizontal extent. Specifically, we studied vegetation and rooting dynamics of large and small trees, the impact of salt marshes (e.g. species and structure) on mangroves, and the influence of vegetation on soil properties along transects from underneath the mangrove canopy into the surrounding salt marsh. Vegetation and rooting dynamics differed in horizontal reach, and there was a positive relationship between mangrove tree height and rooting extent. We found that the horizontal expansion of mangrove roots into salt marsh extended up to eight meters beyond the aboveground boundary. Variation in vegetation structure and local hydrology appear to control mangrove seedling dynamics. Finally, soil carbon density and organic matter did not differ within locations across the salt marsh-mangrove interface. By studying aboveground and belowground variation across the ecotone, we can better predict the ecological effects of continued range expansion in response to climate change. PMID- 29497835 TI - Strong among population variation in frugivory strength by functional diverse frugivores: a 'reciprocal translocation' experiment. AB - Fruit-frugivore interactions are critical for the dynamics and evolution of many plant communities. The strength of the interactions between a given plant species and different frugivore guilds (e.g., seed dispersers, seed predators) often vary in space due to changes in plant extrinsic factors (e.g., frugivore abundances) and plant traits (e.g., fruit size and reward). By reciprocally translocating Pyrus bourgaeana ripe fruits representative of five Mediterranean localities during 2 consecutive years, we experimentally quantified guild-specific variations among populations in frugivory strength, while accounted for plant intrinsic and- extrinsic factors. Though overall fruit removal did not differ among localities, there were strong guild-specific differences in fruit removal strength. Fruit removal by pulp feeders, seed dispersers, and fruit predators varied among populations up to 8.5-, 5.6-, and 4.0-folds, respectively. These strong variations seemed mediated by changes in frugivore relative abundances rather than on availability of alternative fruits. As expected, all fruit traits considered (e.g., fruit size, pulp amount) markedly varied among tree populations. However, no frugivore guild showed preference for fruits from any locality, suggesting that fruit traits did not contribute much to differences in frugivory strength among populations. Since the functional diverse frugivore guilds played contrasting roles in P. bourgaeana dynamics (e.g., seed dispersal vs. seed predation), our study highlights the importance of accounting for functional diversity in frugivore guilds when estimating spatial variations in the strenght of seed dispersal. This investigation also illustrates a neglected but widely applicable experimental approach to identify the relative importance of extrinsic factors and fruit traits in mediating fruit-frugivore interactions. PMID- 29497836 TI - The influence of the carotid baroreflex on dynamic regulation of cerebral blood flow and cerebral tissue oxygenation in humans at rest and during exercise. AB - PURPOSE: This preliminary study tested the hypothesis that the carotid baroreflex (CBR) mediated sympathoexcitation regulates cerebral blood flow (CBF) at rest and during dynamic exercise. METHODS: In seven healthy subjects (26 +/- 1 years), oscillatory neck pressure (NP) stimuli of + 40 mmHg were applied to the carotid baroreceptors at a pre-determined frequency of 0.1 Hz at rest, low (10 +/- 1W), and heavy (30 +/- 3W) exercise workloads (WLs) without (control) and with alpha - 1 adrenoreceptor blockade (prazosin). Spectral power analysis of the mean arterial blood pressure (MAP), mean middle cerebral artery blood velocity (MCAV), and cerebral tissue oxygenation index (ScO2) in the low-frequency range (0.07 0.20 Hz) was estimated to examine NP stimuli responses. RESULTS: From rest to heavy exercise, WLs resulted in a greater than three-fold increase in MCAV power (42 +/- 23.8-145.2 +/- 78, p < 0.01) and an almost three-fold increase in ScO2 power (0.51 +/- 0.3-1.53 +/- 0.8, p = 0.01), even though there were no changes in MAP power (from 24.5 +/- 21 to 22.9 +/- 11.9) with NP stimuli. With prazosin, the overall MAP (p = 0.0017), MCAV (p = 0.019), and ScO2 (p = 0.049) power was blunted regardless of the exercise conditions. Prazosin blockade resulted in increases in the Tf gain index between MAP and MCAV compared to the control (p = 0.03). CONCLUSION: CBR-mediated changes in sympathetic activity contribute to dynamic regulation of the cerebral vasculature and CBF at rest and during dynamic exercise in humans. PMID- 29497837 TI - Progression of diabetic retinopathy severity after treatment with dexamethasone implant: a 24-month cohort study the 'DR-Pro-DEX Study'. AB - PURPOSE: Intravitreal anti-vascular endothelial growth factor agents have been shown to reduce diabetic retinopathy (DR) progression; data on the effects of intravitreal corticosteroids on modifying disease severity are limited. This study evaluates the long-term effect of intravitreal dexamethasone implant (DEX) on the severity and progression of non-proliferative DR (NPDR). METHODS: This was a retrospective cohort study. Sixty eyes from 60 consecutive patients with NPDR and diabetic macular edema (DME) treated with dexamethasone implant (DEX group) and 49 eyes from consecutive 49 patients without DME requiring observation only. Fundus angiography images from baseline and after 24 months were graded by two masked assessors into mild, moderate and severe NPDR and PDR, according to the ETDRS classification. Patients were followed up 1-3 and 4-6 months after each DEX implant. Re-treatment with DEX implant was on a pro re nata basis. Records were reviewed for performance of panretinal photocoagulation. Main outcome was as follows: change of DR >= 1 grade and progression to proliferative diabetic retinopathy (PDR). RESULTS: Three eyes (5%) in the DEX group and 43 (87.8%) eyes in the control group progressed to PDR (P < 0.0001). Twenty-five eyes (41.7%) in the DEX group but none in the control group demonstrated an improvement in DR severity (P < 0.0001). CONCLUSION: This study provides the first long-term evidence that DEX implant has the potential to not only delay progression of DR and PDR development, but may also improve DR severity over 24 months. Better understanding of the effects of corticosteroids will help guide its use in the treatment pathway of DR. PMID- 29497838 TI - Substance P-expressing excitatory interneurons in the mouse superficial dorsal horn provide a propriospinal input to the lateral spinal nucleus. AB - The superficial dorsal horn (laminae I and II) of the spinal cord contains numerous excitatory and inhibitory interneurons, and recent studies have shown that each of these groups can be divided into several neurochemically distinct populations. Although it has long been known that some neurons in this region have intersegmental (propriospinal) axonal projections, there have been conflicting reports concerning the number of propriospinal cells and the extent of their axons. In addition, little is known about the neurochemical phenotype of propriospinal neurons or about the termination pattern of their axons. In the present study we show, using retrograde tracing, that around a third of lamina I II neurons in the lumbar enlargement project at least five segments cranially. Substance P-expressing excitatory neurons are over-represented among these cells, accounting for one-third of the propriospinal neurons. In contrast, inhibitory interneurons and excitatory PKCgamma neurons are both under-represented among the retrogradely labelled cells. By combining viral vector-mediated Cre-dependent anterograde tracing with immunocytochemistry, we provide evidence that the lateral spinal nucleus (LSN), rather than the superficial dorsal horn, is the main target for axons belonging to propriospinal substance P-expressing neurons. These findings help to resolve the discrepancies between earlier studies and have implications for the role of the LSN in pain mechanisms. PMID- 29497839 TI - Virtual surgery simulation versus traditional approaches in training of residents in cervical pedicle screw placement. AB - INTRODUCTION: The cervical screw placement is one of the most difficult procedures in spine surgery, which often needs a long period of repeated practices and could cause screw placement-related complications. We performed this cadaver study to investigate the effectiveness of virtual surgical training system (VSTS) on cervical pedicle screw instrumentation for residents. MATERIALS AND METHODS: A total of ten novice residents were randomly assigned to two groups: the simulation training (ST) group (n = 5) and control group (n = 5). The ST group received a surgical training of cervical pedicle screw placement on VSTS and the control group was given an introductory teaching session before cadaver test. Ten fresh adult spine specimens including 6 males and 4 females were collected, and were randomly allocated to the two groups. The bilateral C3-C6 pedicle screw instrumentation was performed in the specimens of the two groups, respectively. After instrumentation, screw positions of the two groups were evaluated by image examinations. RESULTS: There was significantly statistical difference in screw penetration rates between the ST (10%) and control group (62.5%, P < 0.05). The acceptable rates of screws were 100 and 50% in the ST and control groups with significant difference between each other (P < 0.05). In addition, the average screw penetration distance in the ST group (1.12 +/- 0.47 mm) was significantly lower than the control group (2.08 +/- 0.39 mm, P < 0.05). CONCLUSIONS: This study demonstrated that the VSTS as an advanced training tool exhibited promising effects on improving performance of novice residents in cervical pedicle screw placement compared with the traditional teaching methods. PMID- 29497840 TI - IL-17 inhibition: is it the long-awaited savior for alopecia areata? AB - Interleukin-17 (IL-17) has been implicated in the pathogenesis of a large number of inflammatory and autoimmune conditions, including skin disorders such as psoriasis. Recently, much data have accumulated on the possible role of IL-17 in the pathogenesis of alopecia areata (AA). In this review, the available information on the connection between AA and IL-17 is described. While IL-17 levels are consistently reported to be elevated in the serum and lesional skin of AA patients, there is no clear connection between IL-17 levels and disease severity or duration. Some evidence has suggested an association between IL-17 and an early-onset disease, although this awaits further confirmation. While there is enough information to support clinical trials with IL-17-targeted treatments, it is possible that they will be effective only in a subset of AA patients. Further studies are warranted to better delineate the exact role of IL 17 in AA pathogenesis. PMID- 29497841 TI - Airflow in Tracheobronchial Tree of Subjects with Tracheal Bronchus Simulated Using CT Image Based Models and CFD Method. AB - Tracheal Bronchus (TB) is a rare congenital anomaly characterized by the presence of an abnormal bronchus originating from the trachea or main bronchi and directed toward the upper lobe. The airflow pattern in tracheobronchial trees of TB subjects is critical, but has not been systemically studied. This study proposes to simulate the airflow using CT image based models and the computational fluid dynamics (CFD) method. Six TB subjects and three health controls (HC) are included. After the geometric model of tracheobronchial tree is extracted from CT images, the spatial distribution of velocity, wall pressure, wall shear stress (WSS) is obtained through CFD simulation, and the lobar distribution of air, flow pattern and global pressure drop are investigated. Compared with HC subjects, the main bronchus angle of TB subjects and the variation of volume are large, while the cross-sectional growth rate is small. High airflow velocity, wall pressure, and WSS are observed locally at the tracheal bronchus, but the global patterns of these measures are still similar to those of HC. The ratio of airflow into the tracheal bronchus accounts for 6.6-15.6% of the inhaled airflow, decreasing the ratio to the right upper lobe from 15.7-21.4% (HC) to 4.9-13.6%. The air into tracheal bronchus originates from the right dorsal near-wall region of the trachea. Tracheal bronchus does not change the global pressure drop which is dependent on multiple variables. Though the tracheobronchial trees of TB subjects present individualized features, several commonalities on the structural and airflow characteristics can be revealed. The observed local alternations might provide new insight into the reason of recurrent local infections, cough and acute respiratory distress related to TB. PMID- 29497842 TI - A series of new E. coli-Thermococcus shuttle vectors compatible with previously existing vectors. AB - Hyperthermophilic microorganisms are an important asset in the toolkits of biotechnologists, biochemists and evolutionary biologists. The anaerobic archaeon, Thermococcus kodakarensis, has become one of the most useful hyperthermophilic model species, not least due to its natural competence and genetic tractability. Despite this, the range of genetic tools available for T. kodakarensis remains limited. Using sequencing and phylogenetic analyses, we determined that the rolling-circle replication origin of the cryptic mini-plasmid pTP2 from T. prieurii is suitable for plasmid replication in T. kodakarensis. Based on this replication origin, we present a novel series of replicative E. coli-T. kodakarensis shuttle vectors. These shuttle vectors have been constructed with three different selectable markers, allowing selection in a range of T. kodakarensis backgrounds. Moreover, these pTP2-derived plasmids are compatible with the single-existing E. coli-T. kodakarensis shuttle vector, pLC70. We show that both pTP2-derived and pLC70-derived plasmids replicate faithfully while cohabitating in T. kodakarensis cells. These plasmids open the door for new areas of research in plasmid segregation, DNA replication and gene expression. PMID- 29497843 TI - Identification and characterization of a novel cold-tolerant extracellular protease from Planococcus sp. CGMCC 8088. AB - A psychrophilic extracellular protease was isolated from the marine bacterium Planococcus sp. M7 found in the deep-sea mud of the Southern Indian Ocean. The mature protease is about 43 kDa and contains 389 amino acids. Sequence alignment revealed that the protease whose catalytic triad was comprised of Ser224, Lys249, and Gln253 contains a catalytic module belonging to the serralysin-type protease family 41, and displays 46.55% identity with the experimentally verified serine protease from Bacillus subtilis str. 168. The enzyme displayed an alkaline mesophilic preference with an optimum pH of 10.0 and an optimum temperature of 35 degrees C. The enzyme retained its activity from 5 to 35 degrees C and was resistant to repeated freezing and thawing, but was completely inactivated at 55 degrees C. Calcium ions had a protective effect against thermal denaturation. More than 60% of the maximum activity was retained at pH values in the range of 5.0-11.0. Almost no activity loss was detected after 1 h of incubation at pH 8.0 10.0 and 20 degrees C, or with 1.0% SDS. Most important, this protease also showed good stability and compatibility with the standard enzyme-free detergent, which indicates its special interest for applications in detergent industry. PMID- 29497844 TI - Pain, fatigue and functional disability are associated with higher educational needs in systemic sclerosis: a cross-sectional study. AB - In the process of the planned and systematic education of patients/families, it is extremely important to identify patients' health problems as well as their needs and expectations. The objective of this study was to determine the relationship between functional disability, health problems and perceived educational needs in people with systemic sclerosis (SSc). This was a cross sectional analytic study conducted in six rheumatology centers in Poland. Functional disability was measured using HAQ-DI, and the magnitude of other health problems (pain, fatigue, intestinal problems, breathing problems, Raynaud's phenomenon, finger ulcerations) was measured using 0-100 mm visual analogue scales. The educational needs were measured using the Polish version of the Educational Needs Assessment Tool (Pol-ENAT). Spearman's correlation coefficient (rs) was used to report associations. The sample comprised 140 patients, 125 (89.28%) were women. They had a mean (SD) age of 54 (14.23) and disease duration of 11 (10.27) years. The median (IQR) HAQ-DI was 1.12 (0.62 1.62) and mean ENAT score was 71.54 (SD 27.72). Patients needed to know more about the disease process, self-help measures and managing pain. All health problems had significant correlations with the overall educational needs, pain, functional disability and fatigue having the highest rs = 0.359, p < 0.0001; rs = 0.314, p < 0.001 and rs = 0.270, p = 0.001, respectively. Health problems in people with SSc are associated with considerable educational needs; therefore, health professionals should take this into account when planning patient education. Group interventions should consider providing patient education related to disease process as a minimum. PMID- 29497845 TI - Low- and high-anxious hypermobile Ehlers-Danlos syndrome patients: comparison of psychosocial and health variables. AB - Despite the frequent co-ocurrence of hypermobile Ehler-Danlos syndrome (hEDS) and pathological anxiety, little is known about the psychosocial and health implications of such comorbidity. Our aim was to explore the association between high levels of anxiety and psychosocial (catastrophizing, kinesiophobia, somatosensory amplification, social support and functioning), health (pain, fatigue, BMI, tobacco/alcohol use, depression, diagnosis delay, general health), and sociodemographic factors in people with hEDS. In this cross-sectional study, 80 hEDS patients were divided into two groups according to self-reported anxiety levels: low and high. Psychosocial, sociodemographic and health variables were compared between the groups. Forty-one participants reported a high level of anxiety (51.2%). No differences were found in the sociodemographic variables between high-anxious and low-anxious patients. The percentage of participants with severe fatigue and high depressive symptomatology was significantly higher in the high-anxious group (80.5 vs 56.4; 26.8 vs 12.8%, respectively). High anxious hEDS patients also showed significantly higher levels of pain catastrophizing, somatosensory amplification as well as a poorer social functioning and general health. Multivariate analyses showed that somatosensory amplification, pain catastrophizing and poor social functioning are variables that increase the probability of belonging to the high-anxious group. Despite limitations, this first study comparing high-anxious versus low-anxious hEDS patients with respect to health aspects, highlight the importance of considering the psychosocial factors (many susceptible to modification), to improve the adjustment to this chronic condition and provide support to those affected through a biopsychosocial approach. PMID- 29497847 TI - The effect of a massive wastewater discharge on nearshore ocean chemistry. AB - An opportunity to study the effect of a massive wastewater discharge on a nearshore ocean environment arose in 2015 over a 42-day period when the City of Los Angeles diverted 9.4 billion gal of treated wastewater effluent from an outfall located 5 mi in the Pacific Ocean to a 1-mi backup in the Santa Monica Bay (SMB). SMB is a heavily used waterbody and is home to many marine organisms. To understand the impact of this diversion on human health and on SMB ecosystem, samples of the wastewater effluent, the receiving seawater, and sediments from around the backup outfall were analyzed, among others, for metals, semivolatile organic compounds (SVOC), nutrients, and total organic carbon (TOC) during the diversion project. Results show that these parameters were present at levels below local water quality guidelines (i.e., not enough to cause health or environmental concerns). In the effluent, metal levels were < 10 MUg/L except Zn (23 +/- 9.9 MUg/L); phosphate, ammonia-nitrogen, organic-nitrogen, and TOC levels were 3.48 +/- 0.37, 42.7 +/- 5.3, 4.7 +/- 1.4, and 19.0 +/- 4.9 mg/L, respectively. In seawater and sediments around the backup outfall, metal levels were < 1.5 MUg/L and < 25 mg/kg, respectively. Apart from 4,4'-DDE, SVOCs were not detected in sediments. To assess whether changes to native levels of pollutants in SMB occurred due to the diversion project, pre-diversion and post diversion datasets were compared statistically. No significant differences were found between the two datasets (p > .05, paired t test), meaning the diversion did not change the SMB chemistry. PMID- 29497846 TI - Imaging to Assess Ischemic Heart Disease in Women. AB - PURPOSE OF REVIEW: Ischemic heart disease is a leading cause of morbidity and mortality for women and men around the world. However, traditional cardiovascular risk factors do not fully capture cardiac risk in women. This review summarizes sex-based differences in the clinical presentation, pathophysiology, and risk assessment of ischemic heart disease. We also examine the use of anatomic and functional imaging modalities in the diagnosis of ischemic heart disease in women. RECENT FINDINGS: Recent studies with women subjects have bolstered the predictive value of the coronary artery calcium (CAC) score in predicting atherosclerotic cardiovascular disease risk and major adverse cardiac events in a graded fashion. In addition, combined CAC scoring and coronary computed tomography (CCTA) has shown promise in excluding coronary artery disease (CAD). Using CCTA, data have suggested that increasing cardiovascular risk factors are associated with an increase in noncalcified coronary plaque in women compared with an increase in both calcified and noncalcified plaque in men with cardiac risk factors. Some data have suggested that women obtain greater prognostic benefit from CCTA than from other noninvasive tests. Fractional flow reserve obtained from a CCTA (FFRCT) is a new mathematical assessment of coronary blood flow that determines the presence of lesion-specific myocardial ischemia. Prevention and identification of ischemic heart disease remains a foundation of cardiology and public health. In women, atypical symptoms and limitations in traditional risk factor assessment lead to challenges in the identification of ischemic heart disease. With improvements in technologies such as CAC scoring, CCTA, instantaneous flow reserve (iFR), optical coherence tomography (OCT), and FFRCT, there is great promise for identification of ischemic heart disease, and the future of prevention in women. Future studies with strong female representation should investigate the role of novel imaging techniques in women. PMID- 29497848 TI - Characterization of the interactome of the porcine reproductive and respiratory syndrome virus glycoprotein-5. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most important pathogens in the swine industry, causing reproductive failure in sows and respiratory disorders in piglets. Glycosylated protein 5 (GP5) is a major envelope protein of the virus. It is essential for virus particle assembly and involved in viral pathogenesis. In the present study, we identified the host cellular proteins that interact with GP5 by performing immunoprecipitation in MARC-145 cells infected by a recombinant PRRSV containing a FLAG-tag insertion in GP5. In total, 122 cellular proteins were identified by LC-MS/MS. Gene Ontology and KEGG databases were used to map these proteins to different cellular processes, locations and functions. Interestingly, 10.24% of identified cellular proteins were involved in the process of translation. Follow up experiments demonstrated that expression of GP5 in transfected cells led to inhibition of translation of reporter genes. Interaction between GP5 and ATP synthase subunit alpha (ATP5A) was further confirmed by co-immunoprecipitation suggesting a possible role of GP5 in regulation of ATP production in cells. These data contribute to a better understanding of GP5's role in viral pathogenesis and virus-host interactions. PMID- 29497849 TI - Anti-influenza virus activity of a salcomine derivative mediated by inhibition of viral RNA synthesis. AB - Influenza virus infection is a major threat to global health. Although vaccines and anti-influenza virus drugs are available, annual influenza virus epidemics result in severe illness, and an influenza pandemic occurs every 20-30 years. To identify candidate anti-influenza virus compounds, we screened approximately 5,000 compounds in an in-house library. We identified MZ7465, a salcomine derivative, as a potent inhibitor of influenza virus propagation. We analyzed the antiviral propagation mechanism of the hit compound by determining the amounts of viral proteins and RNA in infected cells treated with or without the hit compound. Treatment of infected cells with MZ7465 decreased both viral protein and RNA synthesis. In addition, an in vitro assay showed that viral RNA synthesis was directly inhibited by MZ7465. These results suggest that salcomine and its derivatives are potential candidates for the treatment of influenza virus infections. PMID- 29497850 TI - Complete genome sequence of SRT8, a novel T1-like Escherichia coli bacteriophage. AB - In this study, an Escherichia coli virulent phage, SRT8, was isolated from sewage sludge samples collected from Jinan, Shandong Province, China. The genome of phage SRT8 consists of 49,579 bp with 47.83% G+C content. The phage genome contains 84 putative protein-coding genes, and no rRNA or tRNA genes. Comparative genomics analysis showed that the E. coli phage SRT8 is a member of a new species and belongs to the subfamily Tunavirinae, which includes T1-like phages. PMID- 29497851 TI - Resolution of traumatic bilateral vertebral artery injury. AB - PURPOSE: Cerebrovascular ischaemia is a rare but serious complication of damage to the carotid or vertebral arteries in the neck caused by blunt injury to the neck. Screening for blunt cerebrovascular injury should be performed in patients with certain signs or symptoms and risk factors. We described a case of traumatic bilateral vertebral artery injury (VAI) including unilateral vertebral arterial occlusion that resolved 3 months post-injury with antiplatelet and direct oral anticoagulant therapy. This resolution of traumatic bilateral VAI is very rare. Vertebral artery injury should be suspected in patients with displaced fracture dislocation of the cervical spine, particularly in the elder and those with ankylosing spondylitis, and therefore imaging of these patients should include a modality to look at the patency of the vertebral arteries. CASE DESCRIPTION: A 70 year-old man who was diagnosed with ankylosing spondylitis collapsed and presented with tetraplegia. Computed tomography showed C3 fracture dislocation, and magnetic resonance imaging showed a high-signal intensity and intense compression of the spinal cord from C2 to C3. Cerebral angiogram showed left vertebral artery occlusion and right vertebral artery stenosis. Heparin was administered to prevent posterior circulation stroke and he underwent posterior fixation. Three months post-injury, a cerebral angiogram showed the resolution of the bilateral VAI. PMID- 29497852 TI - Pedicle screw anchorage of carbon fiber-reinforced PEEK screws under cyclic loading. AB - PURPOSE: Pedicle screw loosening is a common and significant complication after posterior spinal instrumentation, particularly in osteoporosis. Radiolucent carbon fiber-reinforced polyetheretherketone (CF/PEEK) pedicle screws have been developed recently to overcome drawbacks of conventional metallic screws, such as metal-induced imaging artifacts and interference with postoperative radiotherapy. Beyond radiolucency, CF/PEEK may also be advantageous over standard titanium in terms of pedicle screw loosening due to its unique material properties. However, screw anchorage and loosening of CF/PEEK pedicle screws have not been evaluated yet. The aim of this biomechanical study therefore was to evaluate whether the use of this alternative nonmetallic pedicle screw material affects screw loosening. The hypotheses tested were that (1) nonmetallic CF/PEEK pedicle screws resist an equal or higher number of load cycles until loosening than standard titanium screws and that (2) PMMA cement augmentation further increases the number of load cycles until loosening of CF/PEEK screws. METHODS: In the first part of the study, left and right pedicles of ten cadaveric lumbar vertebrae (BMD 70.8 mg/cm3 +/- 14.5) were randomly instrumented with either CF/PEEK or standard titanium pedicle screws. In the second part, left and right pedicles of ten vertebrae (BMD 56.3 mg/cm3 +/- 15.8) were randomly instrumented with either PMMA augmented or nonaugmented CF/PEEK pedicle screws. Each pedicle screw was subjected to cyclic cranio-caudal loading (initial load ranging from - 50 N to + 50 N) with stepwise increasing compressive loads (5 N every 100 cycles) until loosening or a maximum of 10,000 cycles. Angular screw motion ("screw toggling") within the vertebra was measured with a 3D motion analysis system every 100 cycles and by stress fluoroscopy every 500 cycles. RESULTS: The nonmetallic CF/PEEK pedicle screws resisted a similar number of load cycles until loosening as the contralateral standard titanium screws (3701 +/- 1228 vs. 3751 +/- 1614 load cycles, p = 0.89). PMMA cement augmentation of CF/PEEK pedicle screws furthermore significantly increased the mean number of load cycles until loosening by 1.63-fold (5100 +/- 1933 in augmented vs. 3130 +/- 2132 in nonaugmented CF/PEEK screws, p = 0.015). In addition, angular screw motion assessed by stress fluoroscopy was significantly smaller in augmented than in nonaugmented CF/PEEK screws before as well as after failure. CONCLUSIONS: Using nonmetallic CF/PEEK instead of standard titanium as pedicle screw material did not affect screw loosening in the chosen test setup, whereas cement augmentation enhanced screw anchorage of CF/PEEK screws. While comparable to titanium screws in terms of screw loosening, radiolucent CF/PEEK pedicle screws offer the significant advantage of not interfering with postoperative imaging and radiotherapy. These slides can be retrieved under Electronic Supplementary Material. PMID- 29497854 TI - A Review of Buccal Mucosa Graft Ureteroplasty. AB - PURPOSE OF REVIEW: We review the buccal mucosa graft (BMG) ureteroplasty literature to evaluate its utility in the management of ureteral strictures, identify indications for which it is particularly useful, and highlight refinements in surgical technique. RECENT FINDINGS: Recent reports have described the efficacy of robotic BMG ureteroplasty and the utilization of near-infrared fluorescence to assist with precise identification of the ureteral stricture margins. BMG ureteroplasty is well-suited for ureteral reconstruction as it allows for minimal disruption of the delicate ureteral blood supply and facilitates a tension-free anastomosis. This technique is particularly useful in patients with long ureteral strictures not amenable to ureteroureterostomy and in patients with a recurrent ureteral stricture after a previously failed ureteral reconstruction. PMID- 29497853 TI - Complications in adult spine deformity surgery: a systematic review of the recent literature with reporting of aggregated incidences. AB - PURPOSE: To review the incidence of perioperative and late complications of surgery for spinal deformity (ASD). METHODS: Review of the literature. We reviewed recent literature in English to investigate the incidence of complications in ASD surgery in the perioperative (<= 3 months post-operative) and late (> 3 months post-operative) periods. Randomized-controlled trials, non randomized trials, cohort studies, case-control studies, and case series published in 2005 or later were included. We divided articles according to surgical technique: open procedures (OP), minimally invasive surgery (MIS), and hybrid procedures (HP). Complications were recorded, grouped by surgical technique, and then classified according to a proposed Grading of Incidence of Complications (IOC). RESULTS: Ninety-six publications reporting on 12,168 patients were included; 68 were level IV of evidence studies, 24 were level III, and 4 level II. Perioperative IOC was 26.5% in OP, 36.4% in HP, and 24.2% in MIS. Late IOC was 11.1% in OP, 15.4% in HP, and 14.0% in MIS. IOC was significantly higher for hybrid procedures compared to both open and MIS procedures. CONCLUSIONS: Reported complications of surgery for ASD in the recent literature are frequent (24-36% perioperative plus 11-15% late). Open procedures were the most extensively reported in the literature. Complication rates are similar for OP and MIS. HP presented higher IOC likely due to the combination of OP and MIS respective complications. Small number of studies and heterogeneity in reporting could result in risk of bias in these results. Large-scale registry-based studies can fill this gap in the future. These slides can be retrieved under Electronic Supplementary Material. PMID- 29497855 TI - Geospatial assessment of tourism impact on land environment of Dehradun, Uttarakhand, India. AB - India's tourism industry has emerged as a leading industry with a potential to grow further in the next few decades. Dehradun, one of the famous tourist places in India located in the state of Uttarakhand, attracts tourist from all over the country and abroad. The surge in tourist number paved the way for new infrastructure projects like roads, buildings, and hotels, which in turn affects the topography of the mountainous region. In this study, remote sensing and GIS techniques have been used to assess the impact of tourism on the land environment of Dehradun. Satellite images of the years 1972, 2000, and 2016 were analyzed using object-based image analysis (OBIA) to derive land use and land cover (LULC) and ASTER-DEM (Digital Elevation Model) was used to determine the topography of the study area. LULC classification includes built-up, vegetation, forest, scrub, agriculture, plantation, and water body. The slope of the region was categorized as gentle, moderate, strong, extreme, steep, and very steep. To assess the sprawl of built-up on high terrain land, built-up class of LULC was overlaid on slope classes. The overlay analysis reveals that due to increase in tourism, the land use in terms of the built-up area has been extended from gentle slope to very steep slope. The haphazard construction on the extreme, steep, and very steep slope is prone to landslide and other natural disasters. For this, landslide susceptibility maps have also been generated using multicriteria evaluation (MCE) techniques to prevent haphazard construction and to assist in further planning of Dehradun City. This study suggests that a proper developmental plan of the city is essential which follows the principles of optimum use of land and sustainable tourism. PMID- 29497856 TI - Variation in Frequency of Intraoperative Arterial, Central Venous and Pulmonary Artery Catheter Placement During Kidney Transplantation: An Analysis of Invasive Monitoring Trends. AB - The rapidly increasing number of kidney transplantations warrants assessment of anesthesia care in this patient population. We explored the frequency of arterial catheter (AC), central venous catheter (CVC) and pulmonary artery catheter (PAC) placement during kidney transplantation in the USA using data from the National Anesthesia Clinical Outcomes Registry (NACOR) and assessed the between-facility variation in the frequency of catheter placement. We defined cases of kidney transplantation using Agency for Healthcare Research and Quality Clinical Classification Software. Placement of AC, CVC and PAC was defined by respective Current Procedural Terminology codes. The frequency of vascular catheter placement across facility types was compared using Pearson chi2 test. We identified 10,580 cases of kidney transplantation performed in 100 facilities from January 1, 2010 to December 31, 2014. Placement of an AC was reported in 1700 (16.1%), CVC in 2580 (24.4%) and PAC in 50 (0.5%) of cases. The frequency of placement of specific types of catheters was statistically different across facility types (p < 0.001). Within individual facilities that reported at least 50 cases of kidney transplantation, the percentages of cases performed with AC, CVC and PAC ranged from 0% to 86%, 0% to 90% and 0% to 3%, respectively. Considerable between-facility variation in the frequency of AC, CVC and PAC placement during kidney transplantation raises concerns about the need for better practice standardization. Excess invasive monitoring may represent a safety risk as well as unnecessary additional cost. If kidney transplantation can be safely performed without an AC, CVC or PAC in most patients, facilities with above average catheter placement rates may have an opportunity for measurable reduction in catheter-related perioperative complications. Optimizing perioperative monitoring is an important component of ensuring high functioning, high-value medical systems. PMID- 29497857 TI - Sex-specific trajectories of ADHD symptoms from adolescence to young adulthood. AB - Reports of current ADHD symptoms in adults with a childhood diagnosis of ADHD are often discrepant: While one subgroup reports a particularly high level of current ADHD symptoms, another reports-in contrast-a very low level. The reasons for this difference remain unclear. Although sex might play a moderating role, it has not yet been examined in this regard. In an epidemiological cohort study from birth to young adulthood, childhood ADHD diagnoses were assessed at the ages of 4.5, 8, and 11 years based on parent ratings. Sex-specific development of ADHD symptoms was analyzed from the age of 15 to 25 years via self-reported ADHD symptoms in participants with (n = 47) and without childhood ADHD (n = 289) using a random coefficient regression model. The congruence between parent reports and adolescents' self-ratings was examined, and the role of childhood ADHD diagnosis, childhood OCC/CD, and childhood internalizing disorder as possible sex-specific predictors of self-reported ADHD symptoms at age 25 years was investigated. With regard to self-reported ADHD symptoms, females with a childhood ADHD diagnosis reported significantly more ADHD symptoms compared to females without childhood ADHD and males with and without ADHD throughout adolescence and young adulthood. In contrast, males with childhood ADHD did not differ from control males either at age 15 or at age 25 years. Only in females did a childhood diagnosis of an externalizing disorder (ADHD and CD/ODD) predict self-reported ADHD symptoms by age 25 years. Our findings suggest that self-reports of young adults with a childhood diagnosis of ADHD are influenced by sex. Specifically, females with childhood ADHD report increased levels of ADHD symptoms upon reaching adulthood. To correctly evaluate symptoms and impairment in this subgroup, other, more objective, sources of information may be advisable, such as neurophysiological measures. PMID- 29497858 TI - Predictors for the detection of prostate cancer and clinically significant prostate cancer using TRUS-guided biopsy in patients with negative initial biopsy results. AB - PURPOSE: We aimed to determine the predictors for the detection of prostate cancer and clinically significant prostate cancer in the setting of repeat prostate biopsy using trans-rectal ultrasonography-guided biopsy. METHODS: A total of 636 patients who underwent repeat prostate biopsy were included. The patients were divided into two groups according to the repeat biopsy results (with vs. without prostate cancer). A multivariable analysis was performed to assess the predictors for the detection of prostate cancer and clinically significant prostate cancer. RESULTS: Prostate cancer was detected in 98 patients (15.4%). Although there was no difference in the prostate-specific antigen velocity, the prostate-specific antigen density was higher in the patients with prostate cancer at the initial (0.14 vs. 0.17 ng/mL/cc, p = 0.049) and repeat biopsies (0.17 vs. 0.26 ng/mL/cc, p < 0.001). The proportions of the patients who met the active surveillance criteria were as follows: 22.4% (Johns Hopkins), 30.6% (University of Toronto), 32.7% (University of California at San Francisco), 30.6% (Prostate Cancer Research International Active Surveillance), 27.6% (Memorial Sloan Kettering Cancer Center), and 13.3% (University of Miami). In the multivariable analysis, age, hypoechoic lesion on trans-rectal ultrasonography, and prostate-specific antigen density at the repeat biopsy were the significant predictors for prostate cancer and clinically significant prostate cancer. CONCLUSIONS: Trans-rectal ultrasonography before repeat prostate biopsy and the prostate-specific antigen density are useful for selecting patients with a high probability for prostate cancer if repeat trans-rectal ultrasonography-guided biopsy is considered. In addition, these are also helpful for detecting clinically significant prostate cancer. PMID- 29497859 TI - Transurethral resection of bladder cancer on the lateral bladder wall without obturator nerve block: extent of adductor spasms using the monopolar versus bipolar technique-a prospective randomised study. AB - PURPOSE: To establish whether bipolar transurethral resection of tumours (bTURB) on the lateral bladder wall is superior to monopolar transurethral resection (mTURB) of such tumours. To our knowledge, this is the first prospective randomised study, which defines complete resection depending on obturator jerk as primary endpoint. METHODS: In a prospective, randomised, single centre study, 52 patients with newly diagnosed or recurrent bladder tumour on the lateral bladder wall were enrolled and randomised to undergo mTURB or bTURB; 44 patients were eligible for analysis, of whom 21 underwent mTURB and 23 bTURB. Any differences between the two techniques related to the incidence of unwanted stimulation of the obturator nerve and subsequent adductor spasms were evaluated. All procedures were carried out under laryngeal mask anaesthesia without obturator nerve block (ONB) and without drug-induced relaxation. RESULTS: Baseline characteristics of the two study groups did not differ statistically significantly. The success rate defined as complete resection of the bladder tumour without any clinically relevant adductor spasm was 61.9% in the monopolar group and 82.6% in the bipolar group (p = 0.18). CONCLUSIONS: Complete, undisturbed resection of tumours of the lateral bladder wall is feasible with mTURB and bTURB. Adductor spasms due to obturator jerk can occur suddenly with the risk of bladder perforation. We therefore support ONB when using spinal anaesthesia and drug-induced relaxation when using general anaesthesia when performing TURB on the lateral bladder wall. PMID- 29497860 TI - Are 10-, 10-12-, or > 12-mm prostate biopsy core quality control cutoffs reasonable? AB - PURPOSE: To explore the role of prostate biopsy core length on prediction of index tumor clinical significance and localization on radical prostatectomy (RP) and time to recurrence, hypothesizing 10-, 10-12-, or > 12-mm minimum core as potential biopsy quality control. METHODS: Assessed 2424 prostate biopsy cores and corresponding RP of 202 patients submitted to the first set of 12 cores prostate biopsy between 2010 and 2015. Analyzed biopsy core length, age, prostate volume (PV), free and total PSA ratio, PSA density, RP index tumor clinical significance, extension, localization, surgical margins, and cancer control. Prostate biopsy confronted to surgical specimens defined Gleason grade-grouping system (1-5) agreement. RESULTS: Median age was 63.7 years, PSA 10.1 ng/dl, PSA density 28%, and mean follow-up 5 years. Recurrence was identified in 64 (31.7%) patients and predicted by PSA > 10 at time of diagnosis (p = 0.008), seminal vesicle invasion (p = 0.0019), core tumor percentage (p = 0.033), and tumor localization predominantly in the prostate base (p = 0017). The mean core length was longer in index tumor positive cores (p = 0.043) and in tumors classified as clinically insignificant (p = 0.011), without impact on tumor localization (basal vs apical p = 0.592; left vs. right p = 0.320). Biopsy core length categories (<= 10, 10-12 and > 12 mm) did not significantly impact Gleason grade-grouping agreement or time to recurrence (p > 0.05). Core length was not significantly different in all Gleason grade-groupings 1-5 (p = 0.312). CONCLUSION: Prostate biopsy core length impacts tumor characterization; however, 10 mm minimum core length and even 10-12- and > 12-mm categories failed as a biopsy quality control in our data. PMID- 29497861 TI - Obesity paradox in prostate cancer: increased body mass index was associated with decreased risk of metastases after surgery in 13,667 patients. AB - INTRODUCTION: Obesity might negatively affect prostate cancer (PCa) outcomes. However, evidence according to the associations between obesity and metastases free survival after radical prostatectomy (RP) is still inconsistent. METHODS: We relied on PCa patients treated with RP at the Martini-Klinik Prostate Cancer Center between 2004 and 2015. First, multivariable Cox regression analyses examined the impact of obesity on metastases after RP. Last, in a propensity score matched cohort, Kaplan-Meier analyses assessed metastases-free survival according to body mass index (kg/m2) (BMI) strata (>= 30 vs. < 25). RESULTS: Of 13,667 individuals, 1990 (14.6%) men were obese (BMI >= 30). Median follow-up was 36.4 month (IQR 13.3-60.8). Obese patients were less likely to exhibit metastases after RP (HR 0.7, 95% CI 0.5-0.97, p = 0.03). Similarly, after propensity score adjustment, obesity was associated with increased metastases-free survival (log rank p = 0.001). CONCLUSION: We recorded the obesity paradox phenomenon in PCa patients. In particular, high BMI (>= 30) was associated with decreased risk of metastases after RP, despite an increased risk being anticipated. Whether statin use might have affected the results was not assessed. Further research is needed to unravel the controversially debated association between obesity and PCa. PMID- 29497862 TI - Cardiovascular Concerns in BRCA1 and BRCA2 Mutation Carriers. AB - PURPOSE OF REVIEW: BRCA1 and BRCA2 mutation carriers can be at increased cardiovascular risk. The goal of this review is to provide information about factors associated with increased cardiovascular risk, methods to prevent cardiovascular toxicities, and recommended screening guidelines. RECENT FINDINGS: BRCA1/2 mutation carriers who are diagnosed with cancer are often exposed to chemotherapy, chest radiotherapy, and/or HER2 directed therapies, all of which can be cardiotoxic. In addition, BRCA1/2 carriers often undergo prophylactic salpingoopherectomies, which may also increase cardiovascular risks. Understanding the potential for increased cardiovascular risk in individuals with a BRCA1 or BRCA2 mutation, as well as gold standard practices for prevention, detection, and treatment of cardiac concerns in this population, is important. PMID- 29497864 TI - Nonintrusive Remote Monitoring of Sleep in Home-Based Situation. AB - Sleep deprivation can lead to loss of concentration, and risky decision-making. Nevertheless, some people may underestimate the importance of getting quality sleep. The standard health care systems might not be suitable for long-term monitoring of sleep. As an example, the polysomnography, i.e., the gold standard for assessing sleep disorders is cumbersome, expensive, and time-consuming. As a result, portable, nonintrusive and inexpensive systems for monitoring quality of sleep are greatly needed. This paper demonstrates a novel nonintrusive system for monitoring quality of sleep using an optical fiber embedded sensor mat. The proposed system is deployed in real-life conditions over a one-month period. Three senior female residents were enrolled for the study, where the sensor mat is placed under the bed mattress. Sleep quality is assessed based on several parameters, such as duration of sleep, sleep interruption, vital signs (heart rate and respiration). The proposed system shows an agreement with a user's survey collected before the study. Furthermore, the system is integrated within an existing ambient assisted living platform with a user-friendly interface to make it more convenient for the caregivers to follow-up the sleep parameters of the residents. PMID- 29497863 TI - Does Altered Uric Acid Metabolism Contribute to Diabetic Kidney Disease Pathophysiology? AB - PURPOSE OF REVIEW: Multiple experimental and clinical studies have identified pathways by which uric acid may facilitate the development and progression of chronic kidney disease (CKD) in people with diabetes. However, it remains uncertain if the association of uric acid with CKD represents a pathogenic effect or merely reflects renal impairment. RECENT FINDINGS: In contrast to many published reports, a recent Mendelian randomization study did not identify a causal link between uric acid and CKD in people with type 1 diabetes. Two recent multicenter randomized control trials, Preventing Early Renal Function Loss in Diabetes (PERL) and FEbuxostat versus placebo rAndomized controlled Trial regarding reduced renal function in patients with Hyperuricemia complicated by chRonic kidney disease stage 3 (FEATHER), were recently designed to assess if uric acid lowering slows progression of CKD. We review the evidence supporting a role for uric acid in the pathogenesis of CKD in people with diabetes and the putative benefits of uric acid lowering. PMID- 29497865 TI - Assessment of Psychophysiological Response and Specific Fine Motor Skills in Combat Units. AB - : Soldiers' training and experience can influence the outcome of the missions, as well as their own physical integrity. The objective of this research was to analyze the psycho-physiological response and specific motor skills in an urban combat simulation with two units of infantry with different training and experience. MATERIAL AND METHODS: psychophysiological parameters -Heart Rate, blood oxygen saturation, glucose and blood lactate, cortical activation, anxiety and heart rate variability-, as well as fine motor skills were analyzed in 31 male soldiers of the Spanish Army, 19 belonging to the Light Infantry Brigade, and 12 to the Heavy Forces Infantry Brigade, before and after an urban combat simulation. RESULTS AND CONCLUSION: A combat simulation provokes an alteration of the psycho-physiological basal state in soldiers and a great unbalance in the sympathetic-vagal interaction. The specific training of Light Infantry unit involves lower metabolic, cardiovascular, and anxiogenic response not only previous, but mainly after a combat maneuver, than Heavy Infantry unit's. No differences were found in relation with fine motor skills, improving in both cases after the maneuver. This fact should be taken into account for betterment units' deployment preparation in current theaters of operations. PMID- 29497866 TI - Exploring the differences and similarities between urea and thermally driven denaturation of bovine serum albumin: intermolecular forces and solvation preferences. AB - The interactions of bovine serum albumin (BSA) with urea/water were investigated by computer simulation. It was revealed that the BSA-hydrophobic residues in urea solutions favored contact with urea more than with water. Energy decomposition analysis showed that van der Waals energy was the dominant driving force behind urea affinity for hydrophobic residues, whereas coulombic attraction was largely responsible for water affinity for these residues. Meanwhile, urea-BSA hydrogen bond energies were found to be weaker than water-BSA hydrogen bond energies. The greater strength of water-BSA hydrogen bonds than urea-BSA hydrogen bonds, and the opposing preferential interaction between the BSA and urea suggest that disruption of hydrophobic interaction predominates urea-protein denaturation. In pure water, hydrophobic residues showed aggregation tendencies at 323 K, suggesting an increase in hydrophobicity, while at 353 K the residues were partly denatured due to loss of hydrogen bonds; thus, disruption of hydrophobic interactions appeared to contribute less to thermal denaturation. PMID- 29497868 TI - Density functional theory modeling of chromate adsorption onto ferrihydrite nanoparticles. AB - Density functional theory (DFT) calculations were performed on a model of a ferrihydrite nanoparticle interacting with chromate ([Formula: see text]) in water. Two configurations each of monodentate and bidentate adsorbed chromate as well as an outer-sphere and a dissolved bichromate ([Formula: see text]) were simulated. In addition to the 3-D periodic planewave DFT models, molecular clusters were extracted from the energy-minimized structures. Calculated interatomic distances from the periodic and cluster models compare favorably with Extended X-ray Absorption Fine Structure spectroscopy values, with larger discrepancies seen for the clusters due to over-relaxation of the model substrate. Relative potential energies were derived from the periodic models and Gibbs free energies from the cluster models. A key result is that the bidentate binuclear configuration is the lowest in potential energy in the periodic models followed by the outer-sphere complex. This result is consistent with observations of the predominance of bidentate chromate adsorption on ferrihydrite under conditions of high surface coverage (Johnston Environ Sci Technol 46:5851-5858, 2012). Cluster models were also used to perform frequency analyses for comparison with observed ATR FTIR spectra. Calculated frequencies on monodentate, bidentate binuclear, and outer-sphere complexes each have infrared (IR)-active modes consistent with experiment. Inconsistencies between the thermodynamic predictions and the IR-frequency analysis suggest that the 3-D periodic models are not capturing key components of the system that influence the adsorption equilibria under varying conditions of pH, ionic strength and electrolyte composition. Model equilibration via molecular dynamics (MD) simulations is necessary to escape metastable states created during DFT energy minimizations based on the initial classical force field MD-derived starting configurations. PMID- 29497867 TI - Relapse after Le Fort I surgery in oral cleft patients: a 2-year follow-up using digitized and 3D models. AB - This retrospective observational study aimed to evaluate and identify the relapse rate after orthognathic surgery for maxillary advancement (Le Fort I maxillary osteotomy) in oral cleft patients through digitized cephalograms and 3D dental models, following 2 years. Lateral cephalograms and dental casts of 17 individuals, enrolled in Orthodontics Department in Hospital of Rehabilitation of Craniofacial Anomalies, were carried out. The digital cephalometric tracings were evaluated in: T1-before surgery, T2-immediate after surgery, T3-6-month to 1-year after surgery. The dental study casts were digitized and evaluated in: F1-before surgery; F2-3-month to 1-year after surgery; F3-1 to 2 years after surgery. The analyses of the dental arches were performed directly on the scanned images. A single examiner previously trained and calibrated performed all the assessments. Repeated measures ANOVA was applied to study the variables and compare the periods, followed by Tukey test to evaluate the statistically significant differences, with level of significance of 5%. The digital cephalogram results showed that the vertical movement statistically differed from T2 to T3 (p = 0.002). The right and left premolar relationship in digitized models revealed that at F2 the individuals exhibited 1/4 Class II and Class I, in 29.4 and 23.5% of the cases, respectively; and at F3, Class I, 58.8 and 70.6% of the cases, respectively. The cephalometry showed the relapse in the vertical movement after orthognathic surgery for maxillary advancement, but no relapse in the other evaluated parameters. PMID- 29497870 TI - Use of antibiotic disks to evolve drug-resistant bacteria. AB - The methods used to generate antibiotic-resistant bacterial strains can be labour intensive, costly, lengthy and/or prone to plate-to-plate variation. We propose a simple, inexpensive and easily replicated method to expose bacteria to a continuous gradient of antibiotic concentration, providing an environment of positive selective pressure for evolution of antibiotic-resistant strains. PMID- 29497869 TI - Differences in gut microbiota composition in finishing Landrace pigs with low and high feed conversion ratios. AB - The goal of this study was to evaluate the microbial communities in the gut and feces from female finishing Landrace pigs with high and low feed conversion ratio (FCR) by 16S rRNA gene amplicon sequencing. Many potential biomarkers can distinguish between high and low FCR groups in the duodenum, ileum, cecum, colon, and rectum, according to linear discriminant analysis effect sizes. The relative abundance of microbes were tested by Mann-Whitney test between the high and low FCR groups in different organs: Campylobacter, Prevotella and Sphaerochaeta were different in the duodenum (P < 0.05); Sanguibacter, Kingella and Anaeroplasma in jejunum; Anaeroplasma, Arthrobacter, Kingella, Megasphaera and SMB53 in the ileum; Butyricicoccus, Campylobacter, Mitsuokella, and Coprobacillus in the cecum; Lactococcus and Peptococcus in the colon; Staphylococcus in the rectum; and Rothia in feces. The prevalence of microbial genera in certain locations could potentially be used as biomarkers to distinguish between high and low FCR. Functional prediction clustering analysis suggested that bacteria in the hindgut mainly participated in carbohydrate metabolism and amino acid metabolism, and different in the relative abundance of metabolic pathways, as predicted from the microbial taxa present, were identified by comparing the high and low groups of each location. The results may provide insights for the alteration of the intestinal microbial communities to improve the growth rate of pigs. PMID- 29497871 TI - Correction to: A holistic view of cancer bioenergetics: mitochondrial function and respiration play fundamental roles in the development and progression of diverse tumors. AB - In this Correction, the authors would like to acknowledge that the original publication of the article "A holistic view of cancer bioenergetics: mitochondrial function and respiration play fundamental roles in the development and progression of diverse tumors" [1] was supported by CPRIT (Cancer Prevention & Research Institute of Texas) Grant RP160617. PMID- 29497872 TI - Morphometric semi-quantitative assessment of vertebral fractures in postmenopausal black women in Central Africa. AB - : This prospective and multi-centric study assessed the lacking of pattern in fractured patients and features of vertebral fractures in postmenopausal black women living in central Africa. INTRODUCTION: Patients with osteoporosis commonly collapsed their vertebral body. This has been widely studied in Caucasians, Asians, and Americans and studies in black African are lacking. Our study was designed to establish a pattern of patients with fractures and determine the features of vertebral fractures in postmenopausal black women living in Central Africa. METHODS: A prospective and multi-centric study was conducted from June 2011 to June 2016, to assess the thoraco-lumbar-computed tomographic images of women. The menopausal statuses and anthropometric parameters (age, height, and weight) were collected. The body mass index and the Asset Poverty Index were evaluated. The reviews included a morphometric analysis of each vertebra that was rated according to the visual semi-quantitative system proposed by Genant et al. RESULTS: Four hundred thirty women aged 47-87 years old were included in this study. The mean age was 57 years old, and the mean menopause duration was 11.45 +/- 6.6 years with extremes ranging from 2 to 37 years. The body mass indices were rated as overweight and obese in 80.8% of subjects and 54, 3% had high-API indices. Among the 4730 vertebrae analyzed, 529 (11.12%) were fractured, with 68.7% exhibited a cup-shaped deformation (biconcave), 19.8% had a wedge-shaped deformation, and 11.4% exhibited a cake (crush) deformation. Of the vertebras, 88.8% were grade 0, 5.5% grade 1, 5% grade 2, and 0.57% were grade 3. Of the women, 68.8% had one vertebra fractured and 31.2% had more than one fractured vertebrae. CONCLUSION: This study seemed to determine the pattern and features of vertebral fractures in black African women which may be useful for comparisons with the pattern of worldwide populations. PMID- 29497873 TI - Safety of long-term anticoagulation in patients with brain metastases. AB - Anticoagulation is thought to be associated with the risk of intracranial hemorrhage (ICH) in patients with brain metastases; however, the data on this topic are limited. This study was conducted to determine the incidence of ICH associated with anticoagulant use in adult patients with brain metastases. Consecutive patients with brain metastases occurring from 2006 to 2014 were identified from a single-institution database. Long-term anticoagulant therapy was defined as outpatient anticoagulation therapy of > 1 month. Chi-square tests and Fisher's exact test were used to compare rates of ICH by groups. This cohort included 125 patients with brain metastases. Of these, 64 had primary of non small cell lung cancer (51.2%). Of these patients, 12/125 (9.6%) patients developed ICH. Neither the primary tumor site nor the number of brain metastases was associated with the development of ICH. ICH incidence was not associated with the use of anticoagulant therapy, with 8/67 (11.94%) patients on outpatient anticoagulation and 4/58 (6.9%) not on anticoagulation experiencing ICH (p = 0.33). The type of treatment did not significantly influence ICH, although those having combined WBRT and SRS were numerically more likely to experience ICH (4/15; 26.67%) of this cohort. In patients on enoxaparin, there was no difference in the incidence of ICH for daily versus twice-daily dosing (p = 1.0). Long-term anticoagulant use is not associated with an increased incidence of ICH in patients with intracranial metastases. PMID- 29497875 TI - Water leakage management by district metered areas at water distribution networks. AB - The aim of this study is to design a district metered area (DMA) at water distribution network (WDN) for determination and reduction of water losses in the city of Malatya, Turkey. In the application area, a pilot DMA zone was built by analyzing the existing WDN, topographic map, length of pipes, number of customers, service connections, and valves. In the DMA, International Water Association standard water balance was calculated considering inflow rates and billing records. The ratio of water losses in DMAs was determined as 82%. Moreover, 3124 water meters of 2805 customers were examined while 50% of water meters were detected as faulty. This study revealed that DMA application is useful for the determination of water loss rate in WDNs and identify a cost effective leakage reduction program. PMID- 29497876 TI - Characterisation and immunosuppressive activity of human cartilage-derived mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) exert potent immuno-regulatory activities on various immune cells and also differentiate into various mesodermal lineages besides retaining a distinct self-renewal ability. Such exclusive characteristics had enabled MSCs to be recognised as an ideal source for cell-based treatment in regenerative medicine and immunotherapy. Thus, considering MSCs for treating degenerative disease of organs with limited regenerative potential such as cartilage would serve as an ideal therapy. This study explored the feasibility of generating human cartilage-derived MSCs (hC-MSCs) from sports injured patients and characterised based on multipotent differentiation and immunosuppressive activities. Cartilage tissues harvested from a non-weight bearing region during an arthroscopy procedure were used to generate MSCs. Despite the classic morphology of fibroblast-like cells and a defined immunophenotyping, MSCs expressed early embryonic transcriptional markers (SOX2, REX1, OCT4 and NANOG) and differentiated into chondrocytes, adipocytes and osteocytes when induced accordingly. Upon co-culture with PHA-L activated T-cells, hC-MSCs suppressed the proliferation of the T-cells in a dose-dependent manner. Although, hC-MSCs did not alter the activation profile of T cells significantly, yet prevented the entering of activated T cells into S phase of the cell cycle by cell cycle arrest. The present study has strengthened the evidence of tissue-resident mesenchymal stem cells in human cartilage tissue. The endogenous MSCs could be an excellent tool in treating dysregulated immune response that associated with cartilage since hC-MSCs exerted both immunosuppressive and regenerative capabilities. PMID- 29497877 TI - Anti-inflammatory effect of lysozyme from hen egg white on mouse peritoneal macrophages. AB - Lysozyme from hen egg has been reported to possess an anti-inflammatory effect. However, little is known about its detailed mechanism. The mechanism of anti inflammatory effect of lysozyme was examined in this study. When mouse macrophage like cell line RAW264.7 cells and mouse peritoneal macrophages were activated with lipopolysaccharide (LPS) and then treated with lysozyme, the production of tumor necrosis factor-alpha and interleukin-6 was significantly suppressed. The effect was induced by suppressing the gene expression levels of both cytokines. Phagocytosis activity of peritoneal macrophages was not altered by the treatment with lysozyme, suggesting that lysozyme shows the anti-inflammatory effect without inhibiting the phagocytotic response of macrophages. In addition, lysozyme inhibited phosphorylation of c-jun N-terminal kinase (JNK) and was taken up by macrophages within 1 h after treatment of the cells with lysozyme. Overall results suggest that lysozyme is taken up intracellularly and suppresses LPS induced inflammatory responses by inhibiting JNK phosphorylation. PMID- 29497874 TI - Visualizing the Human Subcortex Using Ultra-high Field Magnetic Resonance Imaging. AB - With the recent increased availability of ultra-high field (UHF) magnetic resonance imaging (MRI), substantial progress has been made in visualizing the human brain, which can now be done in extraordinary detail. This review provides an extensive overview of the use of UHF MRI in visualizing the human subcortex for both healthy and patient populations. The high inter-subject variability in size and location of subcortical structures limits the usability of atlases in the midbrain. Fortunately, the combined results of this review indicate that a large number of subcortical areas can be visualized in individual space using UHF MRI. Current limitations and potential solutions of UHF MRI for visualizing the subcortex are also discussed. PMID- 29497879 TI - Community-acquired Clostridium difficile infection in Serbian pediatric population. AB - Carriage of Clostridium (C.) difficile in the intestinum of children, as well as its role in the disease (diarrhea) onset, is still controversial. The aim of this study is to investigate the community-acquired Clostridium difficile infection (CA-CDI) in Serbian pediatric population and to describe the basic clinical characteristics and risk factors for CA-CDI occurrence in Serbian pediatric population. The data obtained from 63 Serbian pediatric patients with CA-CDI and from control group of 126 children with community-acquired diarrhea, whose stool specimens were negative for C. difficile and toxins A/B, were mutually compared. In the current work, we found that children with CA-CDI display a significantly less severe disease clinical presentation than children with diarrheas of other origin. Lethal outcome was noted in two cases, but in children with severe underlying diseases (Crohn's disease and leukemia). By using the multivariate statistical regression model, the following statistically significant risk factors for community-acquired C. difficile-associated diarrhea development were determined: previous application of laxatives (OR = 0.199, CI 0.55-0.79, p = 0.015), general antibiotic use during the previous 2 months (OR = 0.05, CI 0.02 0.17, p < 0.001), and specifically the use of penicillins (OR = 0.112, CI 0.04 0.31, p < 0.0001) and cephalosporins (OR = 0.16, CI 40.06-0.44, p < 0.0001). Antibiotics from the groups of cephalosporins and penicillins were found to be the most important independent risk factors. Laxative application plays a significant role in the community-acquired Clostridium difficile infections in children, with mechanisms that are not completely understood. PMID- 29497878 TI - Spasticity Treatment Ameliorates the Efficacy of Melatonin Therapy in Experimental Autoimmune Encephalomyelitis (EAE) Mouse Model of Multiple Sclerosis. AB - Multiple sclerosis (MS) is a progressive inflammatory demyelinating disease in the central nervous system (CNS). Melatonin is an effective treatment in MS patients and experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Melatonin secretion peaks at 2 AM, concomitant with the time at which the muscles are resting and the body is exerting its antioxidant activity. The current study was designed to investigate combination treatment of baclofen, a muscle relaxant drug, and melatonin in EAE mice. Results showed that melatonin (Mel) alone or in combination with baclofen (Bac + Mel) reduced clinical scores and demyelination by significantly increasing myelin oligodendrocyte glycoprotein (MOG) levels, a marker for mature oligodendrocytes, compared to EAE mice. Moreover, Mel or Bac + Mel therapy caused a significant increase in IL-4 serum levels, an anti-inflammatory cytokine, whereas IFN-gamma serum levels, a pro inflammatory cytokine, were significantly reduced. On the other hand, Mel or Bac + Mel caused a significant reduction in malondialdehyde (MDA) levels, a marker of oxidative stress, in comparison to EAE mice. In contrast, the activity of antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD) was significantly increased in Mel and Bac + Mel groups. In summary, combination therapy improved clinical scores and tend to enhance the efficiency of melatonin treatment by further promoting remyelination, decreasing inflammation, and stimulating the activity of antioxidant enzymes, which suggests that prior spasticity treatment increases the efficacy of melatonin therapy in EAE mouse model of MS. Further experimental and clinical studies are needed to ensure the beneficial role of this combination strategy. PMID- 29497881 TI - 5-aminolevulinic acid fluorescence in tumefactive demyelinating lesion. PMID- 29497880 TI - Trypanosoma cruzi Transmission Among Captive Nonhuman Primates, Wildlife, and Vectors. AB - Natural infection of captive nonhuman primates (NHPs) with Trypanosoma cruzi (agent of Chagas disease) is an increasingly recognized problem in facilities across the southern USA, with negative consequences for NHP health and biomedical research. We explored a central Texas NHP facility as a nidus of transmission by characterizing parasite discrete typing units (DTU) in seropositive rhesus macaques (Macaca mulatta), identifying the wildlife reservoirs, and characterizing vector infection. In seropositive NHPs, we documented low and intermittent concentrations of circulating T. cruzi DNA, with two DTUs in equal proportions, TcI and TcIV. In contrast, consistently high concentrations of T. cruzi DNA were found in wild mesomammals at the facility, yet rodents were PCR negative. Strong wildlife host associations were found in which raccoons (Procyon lotor) harbored TcIV and opossums (Didelphis virginiana) harbored TcI, while skunks (Mephitis mephitis) were infected with both DTUs. Active and passive vector surveillance yielded three species of triatomines from the facility and in proximity to the NHP enclosures, with 17% T. cruzi infection prevalence. Interventions to protect NHP and human health must focus on interrupting spillover from the robust sylvatic transmission in the surrounding environment. PMID- 29497883 TI - Trends of two HPV-associated cancers in Massachusetts: cervical and oropharyngeal cancer. AB - PURPOSE: To understand trends in the incidence and mortality of two human papillomavirus (HPV)-associated cancers, cervical and oropharyngeal cancer, in Massachusetts. METHODS: From 2004 to 2014, the Massachusetts Cancer Registry recorded 3,996 incident cases of oropharyngeal cancer and 2,193 incident cases of cervical cancer. Mortality data were obtained from the Massachusetts Registry of Vital Records and Statistics from 2008 to 2014. Rates were age-standardized to the 2000 U.S. population and trends were assessed using joinpoint regression. RESULTS: While the incidence rate of cervical cancer (5.46 per 100,000) decreased by 2.41% annually (p = 0.004), the incidence rate of oropharyngeal cancer among males (7.85 per 100,000) increased by 2.82% annually (p = 0.0002). Mortality rates for both cancers decreased from 2008 to 2014 but were not statistically significant (cervical - 3.73% annually, p = 0.29; oropharyngeal - 1.94% annually, p = 0.44). CONCLUSION: The rising incidence rate of oropharyngeal cancer in men and the decreasing, but relatively high, incidence rate of cervical cancer in women highlight the need for further screening and prevention by HPV vaccination in Massachusetts. PMID- 29497882 TI - Clinical glycomics for the diagnosis of congenital disorders of glycosylation. AB - Clinical glycomics comprises a spectrum of different analytical methodologies to analyze glycan structures, which provides insights into the mechanisms of glycosylation. Within clinical diagnostics, glycomics serves as a functional readout of genetic variants, and can form a basis for therapy development, as was described for PGM1-CDG. Integration of glycomics with genomics has resulted in the elucidation of previously unknown disorders of glycosylation, namely CCDC115 CDG, TMEM199-CDG, ATP6AP1-CDG, MAN1B1-CDG, and PGM1-CDG. This review provides an introduction into protein glycosylation and presents the different glycomics methodologies ranging from gel electrophoresis to mass spectrometry (MS) and from free glycans to intact glycoproteins. The role of glycomics in the diagnosis of congenital disorders of glycosylation (CDG) is presented, including a diagnostic flow chart and an overview of glycomics data of known CDG subtypes. The review ends with some future perspectives, showing upcoming technologies as system wide mapping of the N- and O-glycoproteome, intact glycoprotein profiling and analysis of sugar metabolism. These new advances will provide additional insights and opportunities to develop personalized therapy. This is especially true for inborn errors of metabolism, which are amenable to causal therapy, because interventions through supplementation therapy can directly target the pathogenesis at the molecular level. PMID- 29497884 TI - Hysterectomy-corrected rates of endometrial cancer among women younger than age 50 in the United States. AB - PURPOSE: This analysis describes the impact of hysterectomy on incidence rates and trends in endometrioid endometrial cancer in the United States among women of reproductive age. METHODS: Hysterectomy prevalence for states containing Surveillance, Epidemiology, and End Results (SEER) registry was estimated using data from the Behavioral Risk Factor Surveillance System (BRFSS) between 1992 and 2010. The population was adjusted for age, race, and calendar year strata. Age adjusted incidence rates and trends of endometrial cancer among women age 20-49 corrected for hysterectomy were estimated. RESULTS: Hysterectomy prevalence varied by age, race, and ethnicity. Increasing incidence trends were observed, and were attenuated after correcting for hysterectomy. Among all women, the incidence was increasing 1.6% annually (95% CI 0.9, 2.3) and this increase was no longer significant after correction for hysterectomy (+ 0.7; 95% CI - 0.1, 1.5). Stage at diagnosis was similar with and without correction for hysterectomy. The largest increase in incidence over time was among Hispanic women; even after correction for hysterectomy, incidence was increasing (1.8%; 95% CI 0.2, 3.4) annually. CONCLUSION: Overall, endometrioid endometrial cancer incidence rates in the US remain stable among women of reproductive age. Routine reporting of endometrial cancer incidence does not accurately measure incidence among racial and ethnic minorities. PMID- 29497885 TI - Application of beta-glucuronidase-immobilised silica gel formulation to microfluidic platform for biotransformation of beta-glucuronides. AB - OBJECTIVE: To improve the efficiency of reactions of beta-glucuronidase (GUS) assisted glucuronic acid (GluA) removal within a microfluidic system. RESULTS: beta-glucuronidase from Helix pomatia was immobilised and characterised in silica based sol-gel monoliths. Efficiency of the GUS-doped silica monoliths was tested for hydrolysis of p-Nitrophenyl-beta-D-glucuronide (pNP-GluA) in both ml-scaled medium via batch reactions and microfluidic environment via continuous-flow reactions. In the microfluidic platform, within a duration of 150 min of continuous operation (flow rate: 1 uL/min), the obtained highest pNP yield was almost 50% higher than that of the corresponding batchwise reaction. However, increased flow rates (3, 5, and 10 uL/min) resulted in lower conversion yields compared to 1 uL/min. The microfluidic platform demonstrated continuous hydrolytic activity for 7 days with considerable reaction yields while using a small amount of the enzyme. CONCLUSION: These results revealed that usage of the microreactors has considerable potential to efficiently obtain bioactive GluA free aglycons from various plant-derived beta-glucuronides for pharmaceutical applications. PMID- 29497886 TI - Selenium and hazardous elements distribution in plant-soil-water system and human health risk assessment of Lower Cambrian, Southern Shaanxi, China. AB - The natural selenium poisoning due to toxic Se levels in food chain had been observed in humans and animals in Lower Cambrian outcrop areas in Southern Shaanxi, China. To find out the distribution pattern of selenium and other hazardous elements in the plant, soil and water of Lower Cambrian in Southern Shaanxi, China, and their possible potential health risk, a total of 30 elements were analyzed and the health risk assessment of 18 elements was calculated. Results showed that the soil, plant and natural water of Lower Cambrian all had relatively high Se levels. In Lower Cambrian, the soil was enriched with Se, As, Ba, Cu, Mo, Ni, Zn, Ga, Cd and Cr (1.68 < Igeo < 4.48, Igeo; geo-accumulation index). In same plants, the contents of Se, Cd and Zn (except Cd in corn and rice, Zn in potato and corn) of Lower Cambrian were higher than that of the other strata. Ba and Ga in natural water were higher than that of the other strata, while K and Cs were opposite. The health risk assessment results showed that the people living in outcrop areas of Lower Cambrian had both high total non carcinogenic risk of 18 elements (HI = 16.12, acceptable range: < 1) and carcinogenic risk of As (3.98E-04, acceptable range: 10-6-10-4). High contents of Se, As, Mo and Tl of Lower Cambrian may pose a health risk to local people, and food intake was the major pathway. For minimizing potential health risk, the local inhabitants should use the mix-imported food with local growing foods. PMID- 29497887 TI - Autonomic symptoms following Zika virus infection. AB - PURPOSE: To determine if autonomic symptoms are associated with previous Zika virus infection. METHODS: Case-control study including 35 patients with Zika virus infection without evidence of neurological disease and 105 controls. Symptoms of autonomic dysfunction were assessed with the composite autonomic symptom scale 31 (COMPASS-31). RESULTS: Patients with previous Zika virus infection had significantly higher COMPASS-31 score than controls regardless of age and sex (p = 0.007). The main drivers for the higher scores where orthostatic intolerance (p = 0.003), secretomotor (p = 0.04) and bladder symptoms (p < 0.001). CONCLUSION: Zika virus infection is associated with autonomic dysfunction. The mechanisms remain to be elucidated. PMID- 29497888 TI - Assessment of focal laser photocoagulations' early effect on polypoidal choroidal vasculopathy with optical coherence tomography angiography. AB - Polypoidal choroidal vasculopathy (PCV) is seen with polypoidal lesions and branching vascular networks (BVNs) (Spaide et al. in Retina 15(2):100-110, 1995; Yannuzzi et al. in Retina 10(1):1-8, 1990). There are reports about laser photocoagulation for PCV (Yuzawa et al. in Japan J Ophthalmol 47(4):379-384, 2003; Lee et al. in Eye 23(1):145-148, 2009); however, all these reports are about final vision and frequent relapses. Therefore, this treatment merits rigorous scrutiny using optical coherence tomography angiography (OCTA). PMID- 29497889 TI - Influence of exercise on oxidative stress in patients with heart failure. AB - Reactive oxygen species play an important role in the pathophysiology of heart failure (HF). In contrast, regular physical exercise can promote adaptations to reactive oxygen species that are beneficial for patients with HF. We completed a systematic review of randomized controlled trials that evaluate the influence of exercise on oxidative stress in patients with HF. Articles were searched in the PubMed, Cochrane, SciELO, and LILACS databases. The search was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines. The quality of the included studies was assessed using the Physiotherapy Evidence Database scale. We selected 12 studies with a total of 353 participants. The included patients had a left ventricle ejection fraction of < 52% and New York Heart Association functional class II or III disease. A significant increase was observed in peak oxygen consumption (between 10 and 46%) in the group that underwent training (TG). There was an improvement in the oxidative capacity of skeletal muscles in the TG, related to the positive activity of mitochondrial cytochrome c oxidase (between 27 and 41%). An increase in the expression of the enzymes glutathione peroxidase (41%), catalase (between 14 and 42%), and superoxide dismutase (74.5%), and a decrease in lipid peroxidation (between 28.8 and 58.5%) were observed in the TG. Physical training positively influenced the cardiorespiratory capacity and enhanced the benefits of oxidant and antioxidant biomarkers in patients with HF. High-intensity training promoted a 15% increase in the plasma total antioxidant capacity, whereas moderate training had no effect. PMID- 29497890 TI - Experience adjusted life years and critical medical allocations within the British context: which patient should live? AB - Medical resource allocation is a controversial topic, because in the end it prioritises some peoples' medical problems over those of others. This is less controversial when there is a clear clinical reason for such a prioritisation, but when such a reason is not available people might perceive it as deeming certain individuals more important than others. This article looks at the role of social utility in medical resource allocation, in a situation where the clinical outcome would be identical if either person received the treatment. This situation is explored with a focus on the United Kingdom, but its conclusions have wider applications to any system where healthcare is tax-payer funded. The article proposes an experience adjusted life years system, and discusses its strengths and weaknesses. PMID- 29497892 TI - TURP in the era of UroLift. PMID- 29497893 TI - The Importance of the Scalp in Head Impact Kinematics. AB - The best way to reduce the risk of head injury (up to 69% reduction) is to wear a helmet. In recent years, the improvement of helmet standard tests focused on reproducing realistic impact conditions and including the effect of rotational acceleration. However, less importance has been given to the development of a realistic headform. The goal of this work was to evaluate the role of scalp tissue in head impact kinematics; both with respect to its mechanical properties and with respect to its sliding properties. An EN960 and HIII headform were subjected to linear and oblique impacts, respectively, both with and without porcine scalp attached. Different speeds, impact locations and impact surfaces were tested. Standard linear drop tests (EN960) showed that the scalp reduced the impact energy by up to 68.7% (rear impact). Oblique head impact tests showed how the headform-anvil friction coefficient changes when the HIII is covered with scalp, affecting linear and rotational accelerations. Therefore, the scalp plays an important role in head impacts and it should be realistically represented in headforms used for impact tests and in numerical models of the human head. PMID- 29497891 TI - The relationship between female sexual function index domains and premature ejaculation. AB - PURPOSE: The aim of this prospective, observational study was to investigate the relationship between premature ejaculation (PE) and female sexual response cycle, using the female sexual function index (FSFI). The FSFI evaluates female sexual function in six domains: desire, arousal, lubrication, orgasm, satisfaction, and pain. METHODS: All men were considered to have PE if they fulfilled the criteria of the second Ad Hoc International Society for Sexual Medicine (ISSM) Committee. All men were also assessed by the Premature Ejaculation Diagnostic Tool (PEDT) and intravaginal ejaculatory latency time (IELT) using stopwatch which was held by the partner. All women completed the FSFI. RESULTS: A total of 181 couples who had regular sexual intercourse with one partner for the past 6 months were enrolled the study. By the definition of ISSM Committee, there were 117 men with PE and 64 men without PE. Partners of men with PE had significantly lower total FSFI scores than did partners of men without PE (21.8 +/- 3.5 for PE and 26.4 +/- 3.1 for non-PE, p < 0.001). Moreover, all the domains of the FSFI scoring system were separately associated with PE. According to the mean FSFI scores, the 48.43% of women had sexual dysfunction in the non-PE group, and all women had sexual dysfunction in PE group. CONCLUSION: PE is associated with female sexual dysfunction and all of the female sexual dysfunction domains, as determined by FSFI scores. PMID- 29497895 TI - Preclinical investigation of a potent geranylgeranyl diphosphate synthase inhibitor. AB - Geranylgeranyl diphosphate synthase (GGDPS) is the enzyme in the isoprenoid biosynthesis pathway that catalyzes the synthesis of the 20-carbon isoprenoid GGPP, which serves as the isoprenoid donor for protein geranylgeranylation reactions. Rab proteins mediate vesicle trafficking within the cell and their activity is dependent on geranylgeranylation. Our prior work has demonstrated that agents that disrupt Rab geranylgeranylation disrupt monoclonal protein trafficking in myeloma cells, resulting in induction of the unfolded protein response pathway and apoptosis. VSW1198 is a potent GGDPS inhibitor with measurable cellular activity at concentrations as low as 30 nM. Due to its potent activity against myeloma cells in vitro, we were interested in evaluating the toxicology profile, pharmacokinetic (PK) profile, tissue distribution pattern and metabolic stability of VSW1198 in preparation for in vivo efficacy studies. Single dose testing via IV administration in CD-1 mice revealed a maximum tolerated dose of 0.5 mg/kg. Doses >=1 mg/kg resulted in liver toxicity that peaked around 6-7 days post-injection. Disruption of protein geranylgeranylation following repeat dosing of VSW1198 was confirmed via immunoblot analysis of unmodified Rap1a in multiple organs. The PK studies revealed a half-life of 47.7 +/- 7.4 h. VSW1198 was present in all tested tissues with the highest levels in the liver. In both human liver microsomes and mouse S9 studies VSW1198 showed complete stability, suggesting no phase I or phase II metabolism. In summary, these studies demonstrate systemic distribution, on-target disruption of protein geranylgeranylation, and metabolic stability of a potent GGDPS inhibitor VSW1198 and form the basis for future efficacy studies in mouse models of myeloma. PMID- 29497894 TI - The PanCareSurFup cohort of 83,333 five-year survivors of childhood cancer: a cohort from 12 European countries. AB - Childhood cancer survivors face risks from a variety of late effects, including cardiac events, second cancers, and late mortality. The aim of the pan-European PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies (PanCareSurFup) Consortium was to collect data on incidence and risk factors for these late effects among childhood cancer survivors in Europe. This paper describes the methodology of the data collection for the overall PanCareSurFup cohort and the outcome-related cohorts. In PanCareSurFup 13 data providers from 12 countries delivered data to the data centre in Mainz. Data providers used a single variable list that covered all three outcomes. After validity and plausibility checks data was provided to the outcome-specific working groups. In total, we collected data on 115,596 patients diagnosed with cancer from 1940 to 2011, of whom 83,333 had survived 5 years or more. Due to the eligibility criteria and other requirements different numbers of survivors were eligible for the analysis of each of the outcomes. Thus, 1014 patients with at least one cardiac event were identified from a cohort of 39,152 5-year survivors; for second cancers 3995 survivors developed at least one second cancer from a cohort of 71,494 individuals, and from the late mortality cohort of 79,441 who had survived at least 5 years, 9247 died subsequently. Through the close cooperation of many European countries and the establishment of one central data collection and harmonising centre, the project succeeded in generating the largest cohort of children with cancer to date. PMID- 29497896 TI - Neuromyelitis optical spectrum disorders presenting with isolated "inverted V" sign in area postrema. PMID- 29497897 TI - Expanding the spectrum of movement disorders in Klinefelter syndrome. PMID- 29497900 TI - Correction to: Comparison of glycyrrhizin content in 25 major kinds of Kampo extracts containing Glycyrrhizae Radix used clinically in Japan. AB - The article Comparison of glycyrrhizin content in 25 major kinds of Kampo extracts containing Glycyrrhizae Radix used clinically in Japan, written by Mitsuhiko Nose, Momoka Tada, Rika Kojima, Kumiko Nagata, Shinsuke Hisaka, Sayaka Masada, Masato Homma and Takashi Hakamatsuka, was originally published Online First without open access. After publication in volume 71, issue 4, page 711-722 the author decided to opt for Open Choice and to make the article an open access publication. Therefore, the copyright of the article has been changed to PMID- 29497899 TI - Predictive value of microRNA-132 and its target gene NAG-1 in evaluating therapeutic efficacy of non-steroidal anti-inflammatory drugs treatment in patients with ankylosing spondylitis. AB - Ankylosing spondylitis (AS) is a common chronic rheumatic disorder, accompanied by the differential expression of various microRNAs (miRNAs) in patients suffering from the condition, some of which have the potential to serve as novel complementary AS biomarkers. During this study, AS patients were recruited in connection with our investigation into the correlation of microRNA-132 (miR-132) in peripheral blood and its target gene NAG-1 expressions in relation with the clinical efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) treatment in patients with AS. A total of 218 AS patients who had been previously treated with oral diclofenac sodium and were placed into either the response (n = 175) or non response groups (n = 43) following a 16-week period of therapeutic evaluation. An additional 113 healthy patients were also recruited for the purposes of the study. AS patient peripheral blood samples were obtained at the 0th, 8th, and 16th week, with the corresponding samples of the healthy patients collected at week 0. The expressions of miR-132 and NAG-1 were detected by RT-qPCR and analyzed using a ROC curve for the elucidation of the diagnostic value of peripheral blood miR-132 expressions as well as their predictive value among AS patients undergoing NSAIDs treatment. The targeting relations of miR-132 and NAG 1 were validated by microRNA.org and luciferase assay. Greater levels of peripheral blood miR-132 expression were observed among AS patients prior to treatment, in comparison to the healthy patients in the study. Prior to treatment, the area under the miR-132 ROC curve (AUC) of AS patients was 0.965, with a critical point of 2.605. The sensitivity and specificity of miR-132 were 91.7 and 97.3%, respectively, in regard to the AS diagnostic clinical efficacy. In comparison with the non-response group, the miR-132 expression of patients in the response group exhibited descended levels while the mRNA expression of NAG-1 increased. The ROC results indicated that the AUC of miR-132 was 0.876 with its sensitivity and specificity observed to be 95.3 and 80.0%, respectively. The AUC of NAG-1 was 0.912 with its sensitivity and specificity observed to be 76.6 and 79.1%, respectively. In comparison with the high miR-132 expression group and the low NAG-1 mRNA expression group, significantly improved blood biochemistry indexes, sign indexes, blood indexes, and adverse reaction rate were observed among the low miR-132 expression group and the high NAG-1 mRNA expression group. The microRNA.org and luciferase assay revealed NAG-1 to be a target of miR-132. Based on the results of this study, it was concluded that the expressions of MiR 132 and NAG-1 could serve as biological markers in the prediction of the therapeutic efficiency of NSAID treatment in AS patients. PMID- 29497901 TI - Correction to: Ephedra Herb extract activates/desensitizes transient receptor potential vanilloid 1 and reduces capsaicin-induced pain. AB - The article Ephedra Herb extract activates/desensitizes transient receptor potential vanilloid 1 and reduces capsaicin-induced pain, written by Shunsuke Nakamori, Jun Takahashi, Sumiko Hyuga, Toshiko Tanaka-Kagawa, Hideto Jinno, Masashi Hyuga, Takashi Hakamatsuka, Hiroshi Odaguchi, Yukihiro Goda, Toshihiko Hanawa and Yoshinori Kobayashi, was originally published Online First without open access. After publication in volume 71, issue 1, page 105-113 the author decided to opt for Open Choice and to make the article an open access publication. Therefore, the copyright of the article has been changed to PMID- 29497902 TI - Sexual Migration and HIV Risk in a Sample of Brazilian, Colombian and Dominican Immigrant MSM Living in New York City. AB - We examined motivations for migration to the United States (US) among 482 Brazilian, Colombian, and Dominican men who have sex with men (MSM). Participants' most common reason for migration was to improve their financial situation (49%), followed by sexual migration in order to affirm their sexual orientation (40%). Fewer endorsed sexual migration motivated by avoiding persecution due to being gay (13%). We conducted further analyses among 276 participants who migrated after age 15 and were HIV-negative at the time of migration. We hypothesized that sexual migration would be associated with greater likelihood of HIV acquisition post-migration. Hierarchical logistic regression analysis indicated that sexual migration motivated by avoiding persecution due to being gay was associated with increased odds of contracting HIV after arrival in the US whereas sexual migration to lead a gay life was not. Our findings highlight the importance of addressing the negative impact of anti-gay discrimination in countries of origin. PMID- 29497903 TI - 2R,4R-APDC, a Metabotropic Glutamate Receptor Agonist, Reduced Neuronal Apoptosis by Upregulating MicroRNA-128 in a Rat Model After Seizures. AB - This study aimed to study the protective effect of (2R,4R)-4-aminopyrrolidine-2,4 dicarboxylate (2R,4R-APDC), a selective metabotropic glutamate receptor agonist, against hippocampal neuronal apoptosis induced by seizures in a rat model of pilocarpine-induced epilepsy. The Morris water maze test was used to assess the spatial memory abilities of epileptic rats with or without 2R,4R-APDC treatment. TUNEL assay was performed to examine neuronal apoptosis in hippocampus. Western blot was conducted to evaluate changes in the levels of caspase-3 and caspase-9 in hippocampus. Real-time PCR was used to determine the levels of microRNA-128 (miR-128) in hippocampus. The results of the Morris water maze test showed that the 2R,4R-APDC treatment reduced the escape latencies and swimming lengths of rats after seizures. The TUNEL assay showed that 2R,4R-APDC significantly counteracted seizure-induced cell apoptosis. The western blot confirmed this finding, demonstrating that the levels of cleaved caspase-3 and cleaved caspase-9 were potently decreased by 2R,4R-APDC in rat hippocampus after seizures. In addition, 2R,4R-APDC upregulated miR-128 expression levels in the hippocampus. A miR-128 mimic or inhibitor decreased or increased the percentage of TUNEL positive cells in rats after seizures and 2R,4R-APDC treatment, respectively. The levels of both cleaved caspase-3 and cleaved caspase-9 were decreased in hippocampus exposed to the miR-128 mimic, whereas they were markedly increased in miR-128 inhibitor-treated hippocampus. In conclusion, 2R,4R-APDC protected hippocampal cells from cell apoptosis after seizures, possibly by upregulating miR-128. PMID- 29497904 TI - Chrysophanol Relieves Cognition Deficits and Neuronal Loss Through Inhibition of Inflammation in Diabetic Mice. AB - Patients with diabetes mellitus are easy to experience diabetic encephalopathy (DE) and other cognition dysfunction, whereas the neural alterations in developing this disease are unknown yet. Chrysophanol (CHR) is one of traditional Chinese medicine which was reported to show protective effects in cognition dysfunction and inflammatory in previously studies. In this current study, whether CHR protects learning and memory dysfunctions induced by diabetes disease or not and underlying mechanisms were studied. DE model was induced by streptozotocin (STZ, i.p.) in ICR mice. CHR was administrated 3 days after STZ treated mice which was confirmed with diabetes for consecutive 6 days. Learning and memory function was tested by Morris water maze after the CHR injection. The morphology of neuronal cells in hippocampus CA3 region was stained by HE staining. ELISA and Western blot assay were used to determine the levels of pro inflammation cytokines (IL-1beta, IL-4, IL-6, TNF-alpha) in hippocampus. Here, we demonstrated that mice harboring diabetes mellitus induced by STZ exhibit high blood glucose, learning and memory deficits detected by Morris water maze behavior tests. Application with CHR right after developing diabetes disease rescues partial blood sugar increasing, learning and memory deficits. The data also indicated that the death rate of neurons and the number of astrocytes in hippocampus CA3 region was significantly improved in diabetic mice. Moreover, the underlying mechanisms of CHR's protective effect are likely associated with anti inflammation by downregulating the expression of pro-inflammation cytokines (IL 1beta, IL-4, IL-6, TNF-alpha) in hippocampus and inhibiting the over-activation of astrocytes in hippocampus CA3 region. Therefore, application with CHR contributes to the learning and memory deficits induced by diabetes disease via inhibitory expressions of inflammatory in hippocampus region. PMID- 29497905 TI - Magnetic Resonance Imaging: The Nuclear Option. PMID- 29497906 TI - Adherence to a Low FODMAP Diet in Relation to Symptoms of Irritable Bowel Syndrome in Iranian Adults. AB - BACKGROUND: Most studies assessing the influence of a low fermentable oligo-, di , monosaccharides and polyols (FODMAP) diet on irritable bowel syndrome (IBS) symptoms were clinical trials with a small sample size. OBJECTIVE: This study was done to examine the association between adherence to a low FODMAP diet and symptoms of irritable bowel syndrome in Iranian adults. METHODS: In this cross sectional study, data on 3362 Iranian adults were collected. Dietary intakes of study participants were assessed using a validated 106-item self-administered dish-based, semi-quantitative food frequency questionnaire. Based on earlier studies, we identified all foods with a high FODMAP content in our dataset. Participants were categorized into quartiles in terms of dietary intakes of these foods. Total FODMAP score for each individual was computed by summing up the scores of all foods. Individuals in the highest quintile of FODMAP score were defined as those with the greatest adherence to the low FODMAP diet. A modified Persian version of the ROME III questionnaire was used for assessment of IBS, which was defined according to ROME III criteria. RESULTS: Adherence to the low FODMAP diet was significantly associated with low intakes of macro- and micro nutrients as well as all food groups (P < 0.001 for all). Participants with the greatest adherence to the low FODMAP diet, compared to those with the lowest adherence, had not significantly lower odds for having IBS, either before (95% CI 0.93, 1.58, P < 0.05) or after adjustment for potential confounders (95% CI 0.80, 1.60, P < 0.05). This was also the case for IBS subtypes; such that those with the greatest adherence to the low FODMAP diet, compared to those with the lowest adherence, were not less likely to have these types of IBS. CONCLUSION: In conclusion, we did not find any significant association between adherence to the low FODMAP diet and IBS. Further studies are required to reach a definite conclusion in this regard. PMID- 29497908 TI - Prediction of Overall Survival and Novel Classification of Patients with Gastric Cancer Using the Survival Recurrent Network. AB - BACKGROUND: Artificial neural networks (ANNs) have been applied to many prediction and classification problems, and could also be used to develop a prediction model of survival outcomes for cancer patients. OBJECTIVE: The aim of this study is to develop a prediction model of survival outcomes for patients with gastric cancer using an ANN. METHODS: This study enrolled 1243 patients with stage IIA-IV gastric cancer who underwent D2 gastrectomy from January 2007 to June 2010. We used a recurrent neural network (RNN) to make the survival recurrent network (SRN), and patients were randomly sorted into a training set (80%) and a test set (20%). Fivefold cross-validation was performed with the training set, and the optimized model was evaluated with the test set. Receiver operating characteristic (ROC) curves and area under the curves (AUCs) were evaluated, and we compared the survival curves of the American Joint Committee on Cancer (AJCC) 8th stage groups with those of the groups classified by the SRN predicted survival probability. RESULTS: The test data showed that the ROC AUC of the SRN was 0.81 at the fifth year. The SRN-predicted survival corresponded closely with the actual survival in the calibration curve, and the survival outcome could be more discriminately classified by using the SRN than by using the AJCC staging system. CONCLUSION: SRN was a more powerful tool for predicting the survival rates of gastric cancer patients than conventional TNM staging, and may also provide a more flexible and expandable method when compared with fixed prediction models such as nomograms. PMID- 29497907 TI - Co-expression Network Analysis Identified COL8A1 Is Associated with the Progression and Prognosis in Human Colon Adenocarcinoma. AB - BACKGROUNDS AND AIMS: Human colon adenocarcinoma is one of the major causes of tumor-induced death worldwide. A complicated gene interconnection network significantly regulates its progression and prognosis. The aim of our study was to find hub genes associated with the progression and prognosis of colon adenocarcinoma and to illustrate the underlying mechanisms. METHODS: A weighted gene co-expression network analysis was performed in our study to identify significant gene modules and hub genes associated with the TNM stage of colon adenocarcinoma (n = 441). RESULTS: In the turquoise module of interest, 23 hub genes were initially selected, and 10 of them were identified as "real" hub genes with high connectivity in the protein-protein interaction network. In the terms of validation, COL8A1 had the highest correlation with clinical traits among all of the hub genes. Data obtained from the Oncomine and GEPIA databases showed a higher expression of COL8A1 in colon adenocarcinoma tissues compared with normal colon tissues. Kaplan-Meier survival curves showed that higher expression of COL8A1 resulted in a shorter overall survival time and disease-free survival time. Univariate and multivariate Cox proportional hazards analyses indicated that the COL8A1 expression was an independent prognostic factor for survival in colon adenocarcinoma patients. Finally, gene set enrichment analysis indicated that the gene sets associated with focal adhesion were significantly enriched in colon adenocarcinoma samples with COL8A1 highly expressed. CONCLUSIONS: COL8A1 was identified and proved to be correlated with the progression and prognosis of human colon adenocarcinoma, probably through regulating focal adhesion-related pathways. PMID- 29497909 TI - Vertical Rectus Abdominis Musculocutaneous Flap Repair Improves Perineal Wound Healing after Abdominoperineal Resection for Irradiated Locally Advanced Rectal Cancer. AB - BACKGROUND: Radiotherapy (RT) and subsequent abdominoperineal resection (APR) for locally advanced rectal cancer (LARC) is associated with significant perineal wound morbidity. The aim of the present study was to investigate if vertical rectus abdominis musculocutaneous (VRAM) flap repair after APR in LARC patients improves perineal wound healing compared with direct perineal wound closure (non VRAM). METHODS: LARC patients (n = 329) operated with APR between January 2006 and December 2015 after neoadjuvant RT of >= 25 Gy were identified, including 260 and 69 patients in the non-VRAM and VRAM groups, respectively. Perineal wound healing was assessed 3 months postoperatively, and risk factors for perineal wound complications and associations with short- and long-term outcome were analyzed. RESULTS: Delayed perineal wound healing after 3 months was more frequent in the non-VRAM group (31.5%) compared with the VRAM group (10.4%) (p < 0.01). In the non-VRAM group, 26.9% of patients developed pelvic abscess, compared with 10.1% in the VRAM group (p < 0.01). Significant risk factors for perineal wound morbidity were non-VRAM (odds ratio [OR] 3.94, 95% confidence interval [CI] 1.72-9.00; p = 0.02), positive circumferential resection margin (R1; OR 3.64, 95% CI 1.91-6.93; p < 0.01), pelvic abscess (OR 3.27, 95% CI 1.90 5.63; p < 0.01), and short-course RT (OR 3.81, 95% CI 1.75-8.30; p < 0.01). Perineal wound morbidity was not associated with impaired long-term oncologic outcome. CONCLUSIONS: VRAM flap reconstruction of the perineum is associated with an increased wound healing rate and may protect against pelvic abscess development. However, procedure-related long-term morbidity is incompletely studied and the procedure should be reserved for selected patients. PMID- 29497911 TI - Internal Mammary Lymph Node Biopsy During Free-Flap Breast Reconstruction: Optimizing Adjuvant Breast Cancer Treatment Through Comprehensive Staging. AB - BACKGROUND: Accurate breast cancer staging is essential for optimal management of adjuvant therapies. While breast lymphatic drainage involves both axillary and internal mammary (IM) lymph node (LN) basins, IM LN sampling is not routinely advocated. The current study analyzes the incidence of IM LN metastases sampled during free flap breast reconstruction and subsequent changes in adjuvant treatment. METHODS: A retrospective analysis of patients with positive IM LN biopsies during free flap breast reconstruction was performed. Pre-reconstruction surgical and adjuvant therapies as well as staging and prognostic data were recorded. Change in adjuvant therapies based solely on IM LN positivity was determined. RESULTS: IM LN metastases were found on 28 (1.3%) out of 2057 patients and comprised the study population. Mean age was 49 years with pre reconstruction chemotherapy or radiation administered in 50 or 54% of cases, respectively. Five (18%) patients had previously undergone lumpectomy with axillary sampling. Mean tumor size was 3.1 cm with tumor location evenly distributed among all four quadrants. Ten (36%) patients had isolated IM LN metastases Patients with both axillary and IM disease had larger lesions, increased prevalence of pre-reconstruction chemotherapy and radiation. Based exclusively on positive IM LN disease, 17 (63%) patients had a change in adjuvant therapy. CONCLUSION: Despite the low incidence of IM LN metastases, IM LN biopsy during free flap breast reconstruction is recommended. In 36% of cases, nodal metastases were isolated to the IM nodes. Identification of IM metastases influenced adjuvant therapies in a majority of cases. PMID- 29497910 TI - Risk of Regional Recurrence After Negative Repeat Sentinel Lymph Node Biopsy in Patients with Ipsilateral Breast Tumor Recurrence. AB - BACKGROUND: Repeat sentinel lymph node biopsy (rSLNB) has increasingly been used in patients with ipsilateral breast tumor recurrence (IBTR). The safety in terms of regional disease control after this procedure remains unclear. This study evaluates occurrence of regional recurrence as first event in patients with IBTR and negative rSLNB, treated without additional lymph node dissection. PATIENTS AND METHODS: Data were obtained from the Sentinel Node and Recurrent Breast Cancer (SNARB) study. In 201 patients, tumor-negative rSLNB was obtained without performing additional lymph node dissections. RESULTS: With median follow-up of 4.7 (range 0.9-12.7) years, regional recurrence occurred after median time of 3.0 (range 0.4-6.7) years in 4.5% (N = 9) of patients as first event after IBTR and rSLNB. In four of these nine patients, the site of recurrence was in concordance with the anatomical location of rSLNB. Two of the nine recurrences were reported in the ipsilateral axilla, resulting in an ipsilateral axillary regional recurrence rate of 1.0%. In the other seven patients, regional recurrence occurred in aberrant basins. Univariable analysis showed that triple-negative IBTR and lower amount of radioactive-labeled tracer (99mtechnetium) used during rSLNB were associated with developing regional recurrence as first event after negative rSLNB (P < 0.05). CONCLUSIONS: The risk of developing regional recurrence after negative rSLNB is low. The low relapse rate supports the safety of rSLNB as primary nodal staging tool in IBTR. The time has come for clinical guidelines to adopt rSLNB as axillary staging tool in patients with IBTR. PMID- 29497913 TI - Design of shared unit-dose drug distribution network using multi-level particle swarm optimization. AB - Unit-dose drug distribution systems provide optimal choices in terms of medication security and efficiency for organizing the drug-use process in large hospitals. As small hospitals have to share such automatic systems for economic reasons, the structure of their logistic organization becomes a very sensitive issue. In the research reported here, we develop a generalized multi-level optimization method - multi-level particle swarm optimization (MLPSO) - to design a shared unit-dose drug distribution network. Structurally, the problem studied can be considered as a type of capacitated location-routing problem (CLRP) with new constraints related to specific production planning. This kind of problem implies that a multi-level optimization should be performed in order to minimize logistic operating costs. Our results show that with the proposed algorithm, a more suitable modeling framework, as well as computational time savings and better optimization performance are obtained than that reported in the literature on this subject. PMID- 29497912 TI - Unique Genes in Tumor-Positive Sentinel Lymph Nodes Associated with Nonsentinel Lymph Node Metastases in Melanoma. AB - BACKGROUND: Current risk assessment tools to estimate the risk of nonsentinel lymph node metastases after completion lymphadenectomy for a positive sentinel lymph node (SLN) biopsy in cutaneous melanoma are based on clinical and pathologic factors. We identified a novel genetic signature that can predict non SLN metastases in patients with cutaneous melanoma staged with a SLN biopsy. METHODS: RNA was collected for tumor-positive SLNs in patients staged by SLN biopsy for cutaneous melanoma. All patients with a tumor-positive SLN biopsy underwent completion lymphadenectomy. A 1:10 case:control series of positive and negative non-SLN patients was analyzed by microarray and quantitative RT-PCR. Candidate differentially expressed genes were validated in a 1:3 case:control separate cohort of positive and negative non-SLN patients. RESULTS: The 1:10 case:control discovery set consisted of 7 positive non-SLN cases matched to 70 negative non-SLN controls. The cases and controls were similar with regards to important clinicopathologic factors, such as gender, primary tumor site, age, ulceration, and thickness. Microarray and RT-PCR identified six potential differentially expressed genes for validation. In the 40-patient separate validation set, 10 positive non-SLN patients were matched to 30 negative non-SLN controls based on gender, ulceration, age, and thickness. Five of the six genes were differentially expressed. The five gene panel identified patients at low (7.1%) and high risk (66.7%) for non-SLN metastases. CONCLUSIONS: A novel, non SLN gene score based on differential expressed genes in a tumor-positive SLN can identify patients at high and low risk for non-SLN metastases. PMID- 29497914 TI - Exploring the Link Between Daily Relationship Quality, Sexual Desire, and Sexual Activity in Couples. AB - Current models of sexual responding emphasize the role of contextual and relational factors in shaping sexual behavior. The present study used a prospective diary design to examine the temporal sequence and variability of the link between sexual and relationship variables in a sample of couples. Studying sexual responding in the everyday context of the relationship is necessary to get research more aligned with the complex reality of having sex in a relationship, thereby increasing ecological validity and taking into account the dyadic interplay between partners. Over the course of 21 days, 66 couples reported every day on their sexual desire, sexual activity (every morning), and relationship quality (every evening). In addition, we examined whether the link between these daily variables was moderated by relationship duration, having children, general relationship satisfaction, and sexual functioning. Results showed that the sexual responses of women depended on the relationship context, mainly when having children and being in a longer relationship. Male sexual responding depended less on contextual factors but did vary by level of sexual functioning. Several cross partner effects were found as well. These results verify that relational and sexual variables feed forward into each other, indicating the need to incorporate interpersonal dynamics into current models of sexual responding and to take into account variability and dyadic influences between partners. PMID- 29497915 TI - Gender Variance and Sexual Orientation Among Male Spirit Mediums in Myanmar. AB - This article describes the gender identity, gender expression, and sexual orientation of male spirit mediums in Myanmar. Our analysis is based on ethnographic work, field observation, and 10 semi-structured interviews. These observations were conducted from 2010 to 2015, mostly in Mandalay, with some fieldwork in Yangon and Bagan. The focus of this investigation was specifically on achout (gender variant individuals) who were spirit mediums (nat kadaw). Semi structured interviews explored the ways that participants understood their gender identity, gender expression, and sexuality in relation to their work as spirit mediums and broader social life. Myanmar remains quite a homophobic and transphobic culture but is undergoing rapid economic and social change. Therefore, it provides an interesting context to study how safe spaces are produced for sexual/gender minorities amidst broader social change. We find that, through the animistic belief structure, there is a growing space for gender nonconforming people, gender variant, and same-sex-oriented individuals (achout) to neutralize their stigmatized status and attain a level of respect and economic advantage. Their ability to become nat kadaw (mediums of spirits) mitigates or trumps their stigmatized status. PMID- 29497916 TI - Strategizing to Make Pornography Worthwhile: A Qualitative Exploration of Women's Agentic Engagement with Sexual Media. AB - Women often expect to encounter negative, problematic content when they consume pornography, yet many women use and enjoy pornography anyway. Some research has centered content type (e.g., sexist/violent vs. nonsexist/women-focused) as a key determinant of women's pornography experiences, but this precludes the notion that women are active, engaged consumers of pornography and minimizes women's role in shaping their own experiences. In the present study, we explored how a sample of sexually diverse women in the U.S. (aged 18-64; N = 73) worked toward positive experiences with pornography via active negotiation with negative content, using a secondary analysis of focus group data on women's sexual pleasure. We found that, although women often experienced pornography as risky, many women used it anyway and actively employed strategies to increase the likelihood of having a positive experience. Women's strategies were similar across sexual identity and age groups, but the heteronormative, youth-oriented portrayals of sexuality in mainstream pornography presented unique concerns for heterosexual, queer, and older women. Results have implications for how women can be conceptualized as active, rather than passive, consumers of pornography as well as for how women's agency might influence women's arousal responses to sexually explicit stimuli in research. PMID- 29497917 TI - Pesticide-induced oxidative stress and antioxidant responses in tomato (Solanum lycopersicum) seedlings. AB - Excessive use of pesticides can adversely affect the growth of non-target host plants in different ways. Pesticide-induced stress can affect non-target plants through elevated levels of reactive oxygen species (ROS) responsible for detrimental effects on cell metabolism, biochemical and other physiological activities. In response to oxidative stress, plant activates antioxidant defense system consisting of both enzymatic and non-enzymatic components. In the present investigation, three commonly used pesticides, emamectin benzoate, alpha cypermethrin and imidacloprid, were assessed for causing oxidative stress in tomato. The oxidative damage induced by these pesticides at five different concentrations i.e. 1/4X, 1/2X, recommended application dose (X), 2X and 4X in the root and shoot tissues of tomato plant/seedlings were evaluated. Following pesticide exposure for 35 days, cell viability, cell injury, total soluble sugar (TSS) and total soluble proteins (TSP) were measured. Antioxidant activities were estimated by measuring activity levels of superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR) peroxidase (POD), ascorbate peroxidase (APX) and proline. Hydrogen peroxide (H2O2) levels were analysed as ROS, lipid peroxidation was measured in term of thiobarbituric acid reactive substances (TBARS) as membrane damage caused by ROS was also assessed. Analysis of the data revealed that pesticides application at higher concentrations significantly elevated ROS levels and caused membrane damage by the formation of TBARS, increased cell injury and reduced cell viability both in root and shoot tissues compared with non-treated plants. Moreover, a gradual decrease in the levels of TSS and TSP was observed in plants subjected to increasing doses of pesticides. To cope with pesticide-induced oxidative stress, a significant increase in levels of antioxidants was observed in the plants exposed to higher doses of pesticides. Shoot tissues responded more drastically by producing higher levels of antioxidants as compared to root tissues indicating the direct exposure of shoots to foliar application of pesticides. Taken together, these results strongly suggested that the application of pesticides above the recommended dose can provoke the state of oxidative stress and can cause oxidative damages in non target host plants. PMID- 29497918 TI - Response of digestive enzymes and esterases of ecotoxicological concern in earthworms exposed to chlorpyrifos-treated soils. AB - Assessment of organophosphorus (OP) pesticide exposure in non-target organisms rarely involves non-neural molecular targets. Here we performed a 30-d microcosm experiment with Lumbricus terrestris to determine whether the activity of digestive enzymes (phosphatase, beta-glucosidase, carboxylesterase and lipase) was sensitive to chlorpyrifos (5 mg kg-1 wet soil). Likewise, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities were measured in the wall muscle and gastrointestinal tissues as indicators of OP exposure. Chlorpyrifos inhibited the acid phosphatase (34% of controls), carboxylesterase (25.6%) and lipase activities (31%) in the gastrointestinal content. However, in the gastrointestinal tissue, only the carboxylesterase and lipase activities were significantly depressed (42-67% carboxylesterase inhibition in the foregut and crop/gizzard, and 15% lipase inhibition in the foregut). Chlorpyrifos inhibited the activity of both cholinesterases in the gastrointestinal tissues, whereas the AChE activity was affected in the wall muscle. These results suggested chlorpyrifos was widely distributed throughout the earthworm body after 30 d of incubation. Interestingly, we found muscle carboxylesterase activity strongly inhibited (92% of control) compared with that detected in the gastrointestinal tissues of the same OP-exposed individuals. This finding was explained by the occurrence of pesticide-resistant esterases in the gastrointestinal tissues, which were evidenced by zymography. Our results suggest that digestive processes of L. terrestris may be altered by chlorpyrifos, as a consequence of the inhibitory action of the insecticide on some digestive enzymes. PMID- 29497919 TI - VEGF-A regulates sFlt-1 production in trophoblasts through both Flt-1 and KDR receptors. AB - Studies have shown that sFlt-1 overproduction stimulated by excess VEGF of deciduous origin in trophoblasts can cause preeclampsia. However, the mechanism underlying how VEGF regulates sFtl-1 expression in trophoblasts remains unknown. To address this issue, JEG3 and HTR-8/SV neo (HTR8) trophoblast cell lines were used to investigate the signaling pathways involved in the regulation of sFlt-1 production via VEGF overexpression in vitro. JEG3 (VEGF-GFP-JEG3, V-J) and HTR8 (VEGF-GFP-HTR8, V-H) cells overexpressing VEGF165 were established by infecting the JEG3 and HTR8 cell lines with lentivirus expressing VEGF165. Both the mRNA and protein levels of VEGF and sFlt-1 were dramatically up-regulated in the V-J and V-H cells compared to the JEG3 and HTR8 cells, and they were significantly decreased after treatment with an Flt-1 receptor inhibitor (MK-2461), a KDR receptor inhibitor (XL-184), or an Flt-1 and KDR receptor inhibitor (ABT-869). The mRNA levels of sFlt-1, Flt-1, and KDR were increased in V-H cells after treatment, and the VEGF-A mRNA levels were also elevated. The migration and invasion abilities of JEG3 and HTR8 cells were decreased after VEGF overexpression, and this reduction could be reversed with VEGF receptor inhibitor treatment. In addition, after the different treatments, the cell migration rates of V-J cells were significantly increased compared with the control treatment. Taken together, these results indicate that sFlt-1 up-regulation by VEGF may be mediated by the VEGF/Flt-1 and/or VEGF/KDR signaling pathways. However, elucidating which pathway plays this key role requires further investigation. PMID- 29497920 TI - Identification and Sensitivity Analysis for Average Causal Mediation Effects with Time-Varying Treatments and Mediators: Investigating the Underlying Mechanisms of Kindergarten Retention Policy. AB - Considering that causal mechanisms unfold over time, it is important to investigate the mechanisms over time, taking into account the time-varying features of treatments and mediators. However, identification of the average causal mediation effect in the presence of time-varying treatments and mediators is often complicated by time-varying confounding. This article aims to provide a novel approach to uncovering causal mechanisms in time-varying treatments and mediators in the presence of time-varying confounding. We provide different strategies for identification and sensitivity analysis under homogeneous and heterogeneous effects. Homogeneous effects are those in which each individual experiences the same effect, and heterogeneous effects are those in which the effects vary over individuals. Most importantly, we provide an alternative definition of average causal mediation effects that evaluates a partial mediation effect; the effect that is mediated by paths other than through an intermediate confounding variable. We argue that this alternative definition allows us to better assess at least a part of the mediated effect and provides meaningful and unique interpretations. A case study using ECLS-K data that evaluates kindergarten retention policy is offered to illustrate our proposed approach. PMID- 29497921 TI - Exosomal miR-9 Released from HIV Tat Stimulated Astrocytes Mediates Microglial Migration. AB - Chronic neuroinflammation still remains a common underlying feature of HIV infected patients on combined anti-retroviral therapy (cART). Previous studies have reported that despite near complete suppression of virus replication by cART, cytotoxic viral proteins such as HIV trans-activating regulatory protein (Tat) continue to persist in tissues such as the brain and the lymph nodes, thereby contributing, in part, to chronic glial activation observed in HIV associated neurological disorders (HAND). Understanding how the glial cells cross talk to mediate neuropathology is thus of paramount importance. MicroRNAs (miR) also known as regulators of gene expression, have emerged as key paracrine signaling mediators that regulate disease pathogenesis and cellular crosstalk, through their transfer via the extracellular vesicles (EV). In the current study we have identified a novel function of miR-9, that of mediating microglial migration. We demonstrate that miR-9 released from Tat-stimulated astrocytes can be taken up by microglia resulting in their migratory phenotype. Exposure of human astrocytoma (A172) cells to HIV Tat resulted in induction and release of miR-9 in the EVs, which, was taken up by microglia, leading in turn, increased migration of the latter cells, a process that could be blocked by both an exosome inhibitor GW4869 or a specific target protector of miR-9. Furthermore, it was also demonstrated that EV miR-9 mediated inhibition of the expression of target PTEN, via its binding to the 3'UTR seed sequence of the PTEN mRNA, was critical for microglial migration. To validate the role of miR-9 in this process, microglial cells were treated with EVs loaded with miR-9, which resulted in significant downregulation of PTEN expression with a concomitant increase in microglial migration. These findings were corroborated by transfecting microglia with a specific target protector of PTEN, that blocked miR-9-mediated downregulation of PTEN as well as microglial migration. In vivo studies wherein the miR-9 precursor-transduced microglia were transplanted into the striatum of mice, followed by assessing their migration in response to a stimulus administered distally, further validated the role of miR-9 in mediating microglial migration. Collectively, our findings provide evidence that glial crosstalk via miRs released from EVs play a vital role in mediating disease pathogenesis and could provide new avenues for development of novel therapeutic strategies aimed at dampening neuropathogenesis. PMID- 29497922 TI - Why Patients Decline Genomic Sequencing Studies: Experiences from the CSER Consortium. AB - Clinical and research settings are increasingly incorporating genomic sequencing (GS) technologies. Previous research has explored reasons for declining genetic testing and participation in genetic studies; however, there is a dearth of literature regarding why potential participants decline participation in GS research, and if any of these reasons are unique to GS. This knowledge is essential to promote informed decision-making and identify potential barriers to research participation and clinical implementation. We aggregated data from seven sites across the National Institutes of Health's Clinical Sequencing Exploratory Research (CSER) consortium on each project's procedures for recruitment, and rates of and reasons for decline. Data were analyzed using descriptive statistics. The decline rate for enrollment at the seven CSER sites ranged from 12 to 64% (median 28%) and varied based on age and disease status. Projects differed in their protocols for approaching potential participants and obtaining informed consent. Reasons for declining GS research were reported for 1088 potential participants. Commonly cited reasons were similar to those reported for clinical single gene testing and non-GS genetic research. The most frequently cited reason for decline was study logistics (35%); thus, addressing logistical barriers to enrollment may positively impact GS study recruitment. Privacy and discrimination concerns were cited by 13% of decliners, highlighting the need for researchers and providers to focus educational efforts in this area. The potential psychological burden of pursuing and receiving results from GS and not wanting to receive secondary findings, a concern specific to GS, have been cited as concerns in the literature. A minority of potential participants cited psychological impact (8%) or not wanting to receive secondary findings (2%) as reasons for decline, suggesting that these concerns were not major barriers to participation in these GS studies. Further research is necessary to explore the impact, if any, of different participant groups or study protocols on rates of decline for GS studies. Future studies exploring GS implementation should consider using standardized collection methods to examine reasons for decline in larger populations and more diverse healthcare settings. PMID- 29497923 TI - Understanding Adult Participant and Parent Empowerment Prior to Evaluation in the Undiagnosed Diseases Network. AB - The burden of living with an undiagnosed condition is high and includes physical and emotional suffering, frustrations, and uncertainty. For patients and families experiencing these stressors, higher levels of empowerment may be associated with better outcomes. Thus, it is important to understand the experiences of patients with undiagnosed conditions and their families affected by undiagnosed conditions in order to identify strategies for fostering empowerment. In this study, we used the Genetic Counseling Outcome Scale (GCOS-24) to assess levels of empowerment and support group participation in 35 adult participants and 67 parents of child participants in the Undiagnosed Diseases Network (UDN) prior to their UDN in person evaluation. Our results revealed significantly lower empowerment scores on the GCOS-24 in adult participants compared to parents of child participants [t(100) = - 3.01, p = 0.003, average difference = - 11.12, 95% CI (- 3.78, - 18.46)] and no significant association between support group participation and empowerment scores. The majority of participants (84.3%, 86/102) are not currently participating in any support groups, and participation rates were not significantly different for adult participants and parents of child participants (11.4 vs. 19.7%, respectively, FE p = 0.40). Open-ended responses provided additional insight into support group participation, the challenges of living with undiagnosed conditions, and positive coping strategies. Future research will evaluate the extent to which empowerment scores change as participation in the UDN unfolds. PMID- 29497924 TI - Introduction to the "Technology in Practice" Special Issue. PMID- 29497925 TI - Recovery Within Injury Compensation Schemes: A System Mapping Study. AB - Purpose Many industrialised nations have systems of injury compensation and rehabilitation that are designed to support injury recovery and return to work. Despite their intention, there is now substantial evidence that injured people, employers and healthcare providers can experience those systems as difficult to navigate, and that this can affect injury recovery. This study sought to characterise the relationships and interactions occurring between actors in three Australian injury compensation systems, to identify the range of factors that impact on injury recovery, and the interactions and inter-relationships between these factors. Methods This study uses data collected directly from injured workers and their family members via qualitative interviews, analysed for major themes and interactions between themes, and then mapped to a system level model. Results Multiple factors across multiple system levels were reported by participants as influencing injury recovery. Factors at the level of the injured person's immediate environment, the organisations and personnel involved in rehabilitation and compensation processes were more commonly cited than governmental or societal factors as influencing physical function, psychological function and work participation. Conclusions The study demonstrates that injury recovery is a complex process influenced by the decisions and actions of organisations and individuals operating across multiple levels of the compensation system. Changes occurring 'upstream', for instance at the level of governmental or organisational policy, can impact injury recovery through both direct and diffuse pathways. PMID- 29497927 TI - Recent Advances in Understanding Bisphosphonate Effects on Bone Mechanical Properties. AB - PURPOSE OF THE REVIEW: Bisphosphonates have well-established effects on suppressing bone resorption and slowing bone loss, yet the effects on bone mechanical properties are less clear. We review recent data from pre-clinical and clinical experiments that assessed mechanical properties of bisphosphonate treated specimens. RECENT FINDINGS: Pre-clinical work has utilized new techniques to show reduced fatigue life and transfer of stress from the mineral to collagen. Several notable studies have examined mechanical properties of tissue from patients treated with bisphosphonates with mixed results. Pre-clinical data suggest effects on mechanics may be independent of remodeling suppression. The direct effect of bisphosphonates on bone mechanics remains unclear but recent work has set a solid foundation for the coming years. PMID- 29497928 TI - Outcomes of Definitive Chemoradiotherapy for Cervical and Upper Thoracic Esophageal Cancers: a Single-Institution Experience of a Rare Cancer. AB - PURPOSE: Upper esophageal carcinomas are uncommon but confer a poor prognosis. However, there is scarcity of data regarding outcomes of definitive chemoradiotherapy for cervical and upper thoracic esophageal squamous cell carcinoma in Iran. METHODS: In this retrospective cohort study, we analyzed data of patients with squamous cell carcinoma of cervical and upper thoracic esophagus (at 16 to 25 cm from incisors) treated by definitive chemoradiotherapy in our institution between 2007 and 2015. The primary outcome was overall survival and secondary endpoints were predictors of overall survival. RESULTS: From 2007 to 2015, 40 patients were entered to final analysis. The mean age of patients was 59.7 +/- 14.3 (range 24-85 years). Sixteen (40%) were node-positive. The median follow-up time was 15.3 months. Twenty-seven patients (67.5%) died during post treatment period. Thirty-five percent and 25% of patients suffered from local and distant recurrences, respectively. The actuarial median overall survival was 19.2 (CI 95% 14.2-24.2) months. The 1- and 2-year overall survival rates were 76 and 38%, respectively. The overall survival was higher among patients who were younger than 50 years, of female gender, had stage II tumor, grades I to II, who received induction chemotherapy, and whom treated with doses < 60 Gy. However, none of the differences was statistically significant. CONCLUSIONS: Cervical and upper thoracic esophageal squamous cell carcinomas are associated with bad outcome. Studies with bigger sample sizes are required to define best treatment strategies. PMID- 29497929 TI - Prognostic Value of Cyclin D1 and CD44 Expression in Gastric Adenocarcinoma. AB - BACKGROUND: Worldwide, gastric carcinoma (GC) is the 5th most common malignancies in both sexes representing 6.8% of the total fatalities and is the 3rd leading cause of cancer death representing 8.8% of total fatalities. In Egypt, GC considers the 12th leading cause of cancer death representing 2.2% of the total cancer mortality. A growing body of evidence supports that cancer stem cells (CSCs) are resistant to chemotherapy or radiation, and the cell adhesion molecule CD44 has been identified as a cell surface marker associated with cancer stem cell in several types of tumors including gastric cancer. CD44 regulates gastric stem cell proliferation by increasing cyclin D1 expression which represents an important regulatory protein in the cell cycle transition from G1 phase to S phase. This study aimed to investigate whether cyclin D1 and CD44 can be used as prognostic indicators in gastric cancer. MATERIAL AND METHODS: Forty formalin fixed and paraffin-embedded gastric tissues, obtained from patients who underwent endoscopic resection or surgical resection, constituted the group of our study. The immunohistochemical expression of cyclin D1 and CD44 was examined and correlated with clinical-pathological parameters and outcome of the patients. RESULTS: Overexpression of CD44 and cyclin D1 was noted (in of 55 and 50% respectively). Cyclin D1 and CD44 positive expressions in GC were positively correlated with tumor differentiation (p = 0.020, p = 0.004 respectively), TNM stage (p < 0.001 for both), poor survival (p < 0.001 for both), and with increased rate of recurrence (p = 0.020, p = 0.005 respectively). CONCLUSION: CD44 and cyclin D1 were associated with poor prognosis in gastric cancer, and so, they comprise an attractive target for anticancer drug development. PMID- 29497930 TI - Hyperammonemia and lactic acidosis in adults: Differential diagnoses with a focus on inborn errors of metabolism. AB - The adult endocrinologist may be asked to consult on a patient for unexplained biochemical disturbances that could be caused by an underlying inborn error of metabolism. A genetic disorder is generally less likely to be the cause as these disorders are individually rare, however inborn errors of metabolism are collectively not infrequent and important to consider as they may be treatable and tragic outcomes avoided. Hyperammonemia or lactic acidosis are most often secondary markers of an acquired primary disease process, but they may be a clue to the presence of a genetic disorder. Herein is presented an approach to the differential diagnosis of elevated ammonia and lactate, and a brief discussion of management for when an inborn error is diagnosed. PMID- 29497926 TI - Antifungal Activity of Chitosan-Coated Poly(lactic-co-glycolic) Acid Nanoparticles Containing Amphotericin B. AB - Amphotericin B (AmB) is one of the most used drugs for the treatment of systemic fungal infections; however, the treatment causes several toxic manifestations, including nephrotoxicity and hemolytic anemia. Chitosan-coated poly(lactide-co glycolide) (PLGA) nanoparticles containing AmB were developed with the aim to decrease AmB toxicity and propose the oral route for AmB delivery. In this work, the antifungal efficacy of chitosan-coated PLGA nanoparticles containing AmB was evaluated in 20 strains of fungus isolates from patients with vulvovaginal candidiasis (01 Candida glabrata and 03 Candida albicans), bloodstream infections (04 C. albicans and 01 C. tropicalis) and patients with urinary tract infection (04 Candida albicans, 02 Trichosporon asahii, 01 C. guilhermondii, 03 C. glabrata) and 01 Candida albicans ATCC 90028. Moreover, the cytotoxicity over erythrocytes was evaluated. The single-emulsion solvent evaporation method was suitable for obtaining chitosan-coated PGLA nanoparticles containing AmB. Nanoparticles were spherical in shape, presented mean particle size about 460 nm, positive zeta potential and encapsulation efficiency of 42%. Moreover, nanoparticles prolonged the AmB release. All the strains were susceptible to plain AmB and nanostructured AmB, according to EUCAST breakpoint version 8.1 (resistant > 1 MUg/mL), using broth microdilution method. In C. albicans (urine, blood, and vulvovaginal secretion isolates, and 1 ATCC), the MIC value of AmB loaded nanoparticles varied from 0.25 to 0.5 MUg/mL and EUCAST varied from 0.03 to 0.5 MUg/mL. In urine and vulvovaginal secretion isolates of C. glabrata, the MIC value of AmB-loaded nanoparticles varied from 0.25 to 0.5 MUg/mL and EUCAST varied from 0.03 to 0.015 MUg/mL. In urine isolates of C. guilhermondii, the MIC value of AmB-loaded nanoparticles was 0.12 MUg/mL and EUCAST was 0.06 MUg/mL. In blood isolates of C. tropicalis, the MIC value of AmB-loaded nanoparticles was 0.5 MUg/mL and EUCAST was 0.25 MUg/mL. Finally, in urine isolates of T asahii, the MIC value of AmB-loaded nanoparticles was 1 MUg/mL and EUCAST varied from 0.5 to 1 MUg/mL. In the cytotoxicity assay, plain AmB was highly hemolytic (100% in 24 h) while AmB-loaded chitosan/PLGA nanoparticles presented negligible hemolysis. PMID- 29497931 TI - An effective feature extraction method by power spectral density of EEG signal for 2-class motor imagery-based BCI. AB - EEG signals have weak intensity, low signal-to-noise ratio, non-stationary, non linear, time-frequency-spatial characteristics. Therefore, it is important to extract adaptive and robust features that reflect time, frequency and spatial characteristics. This paper proposes an effective feature extraction method WDPSD (feature extraction from the Weighted Difference of Power Spectral Density in an optimal channel couple) that can reflect time, frequency and spatial characteristics for 2-class motor imagery-based BCI system. In the WDPSD method, firstly, Power Spectral Density (PSD) matrices of EEG signals are calculated in all channels, and an optimal channel couple is selected from all possible channel couples by checking non-stationary and class separability, and then a weight matrix which reflects non-stationary of PSD difference matrix in selected channel couple is calculated; finally, the robust and adaptive features are extracted from the PSD difference matrix weighted by the weight matrix. The proposed method is evaluated from EEG signals of BCI Competition IV Dataset 2a and Dataset 2b. The experimental results show a good classification accuracy in single session, session-to-session, and the different types of 2-class motor imagery for different subjects. PMID- 29497933 TI - Evaluation of a Crib Distribution and Safe Sleep Educational Program to Reduce Risk of Sleep-Related Infant Death. AB - To increase access to safe infant sleep surfaces and reduce risk of sleep-related infant deaths, the Georgia Department of Public Health implemented a portable crib distribution and safe sleep educational program. The aim of this evaluation was to compare parental knowledge and practices related to infant sleep before and after receipt of the safe sleep educational program and crib. A prospective, matched pre- and post-test cohort design with a follow-up survey was utilized to evaluate changes in knowledge and practices. Female participants were recruited through the county health department and met the following criteria: (1) between 32 and 40 weeks pregnant or within 3 months postpartum, and (2) demonstrated financial need. Participants completed a survey prior to the start of a group educational program and upon program completion. For those who agreed, a follow up phone survey was conducted approximately 10 weeks after program completion or after the infant's birth. McNemar's Chi square tests were conducted to detect significant differences between specific items on pre-test, post-test, and follow up surveys, and paired sample t tests were conducted to compare differences in knowledge and practice scores. A total of 132 participants completed matched pre- and post-test surveys and 76 completed follow-up surveys. Knowledge of recommendations regarding position, surface, environment, smoking, breastfeeding, and pacifier use increased significantly between pre- and post-test, with most participants maintaining knowledge at follow-up. The proportion of recommended practices also increased significantly. A group-based safe sleep educational program can be effective in reducing risky infant sleep practices. PMID- 29497934 TI - The Value of Community Health Workers in Diabetes Management in Low-Income Populations: A Qualitative Study. AB - To describe community health workers (CHWs) roles in a diabetes self-management intervention. Retrospective qualitative inductive analysis of open text home visit encounter form from Peer Support for Achieving Independence in Diabetes (Peer AID), a randomized controlled trial in which low-income individuals with poorly controlled diabetes received either CHW home visits or usual care. Following visits, CHWs completed encounter forms documenting the health goal of the visit, the self-management strategies discussed and participant concerns. 634 encounter reports were completed for the 145 intervention participants. CHW notes revealed three main obstacles to optimal disease control: gaps in diabetes knowledge and self-management skills; socioeconomic conditions; and the complexity of the healthcare system. CHWs helped participants overcome these obstacles through extensive, hands-on education, connecting participants to community resources, and assistance navigating the medical system. In addition, the CHWs offered uncomplicated accessibility and availability to their clients. CHWs can be a valuable asset for low-income patients with chronic health conditions who may require more support than what can provided in a typical primary care visit. PMID- 29497932 TI - In the search for reliable biomarkers for the early diagnosis of autism spectrum disorder: the role of vitamin D. AB - Autism spectrum disorder (ASD) affects about 1% of the world's population. Vitamin D is thought to be essential for normal brain development and modulation of the immune system. Worldwide about 1 billion people are affected by vitamin D deficiency. High-sensitivity C-reactive protein (hs-CRP), cytochrome P450 2E1 (CYP2E1) and 8-hydroxy-2'-deoxyguanosine (8-OH-dG) are biomarkers related to inflammation and oxidative stress. In the present study, these biomarkers were together with serum 25-hydroxyvitamin D (25(OH)D3) analyzed in 28 (mean age seven years) Saudi male patients with ASD. The study was conducted to determine if there is any relationship between vitamin D levels, the tested biomarkers and the presence and severity of ASD. The hope was to identify if these biomarkers may be useful for early ASD diagnosis. The Childhood Autism Rating Scale (CARS) and the Social Responsiveness Scale (SRS) were used to measure autism severity. The results of the ASD children were compared with 27 age and gender-matched neurotypical controls. The data indicated that Saudi patients with ASD have significantly lower plasma levels of 25(OH)D3 than neurotypical controls (38 ng/ml compared to 56 ng/ml, respectively; [P = 0.001]). Surprisingly, the levels of CYP2E1 were lower in the children with ASD than the neurotypical controls (0.48 +/- 0.08 vs. 69 +/- 0.07 ng/ml, respectively; P = 0.001). The ASD children also had significantly higher levels of hs-CRP (0.79 +/- 0.09 vs. 0.59 +/- 0.09 ng/ml, respectively; P = 0.001) and 8-OH-dG (8.17 +/- 1.04 vs. 4.13 +/- 1.01 ng/ml, respectively; P = 0.001, compared to neurotypical age and gender-matched controls. The values for hs-CRP and 8-OH-dG did not correlate [P < 0.001] with autism severity. There was found a relationship between autism severity on the CARS scale and the levels of 25(OH)D3 and CYP1B1. But this was not found for SRS. All four biomarkers seemed to have good sensitivity and specificity, but the sample size of the present study was too small to determine clinical usefulness. The findings also indicate that inadequate levels of vitamin D play a role in the etiology and severity of autism. Furthermore, the results of the present study suggest the possibility of using 25(OH)D3, CYP1B1, hs-CRP and 8-OH-dG, preferably in combination, as biomarkers for the early diagnosis of ASD. However, further research is needed to evaluate this hypothesis. PMID- 29497935 TI - Simultaneous determination of myricetrin, quercitrin and afzelin in leaves of Cercis chinensis by a fast and effective method of ionic liquid microextraction coupled with HPLC. AB - In this study, the contents of myricetrin, quercitrin and afzelin in Cercis chinensis leaves were determined simultaneously by 1-butyl-3-methylimidazolium tetrafluoroborate [BMIM] BF4/70% ethanol microextraction combined with High Performance Liquid Chromatograph (HPLC) analysis. The mobile phase was eluted with an Agilent ZORBAX SB-C18 column (4.6 mm*5 mm, 5 MUm), B was methanol and C was 0.1% glacial acetic acid-water as the mobile phase. The flow rate was 0.8 mL min-1, eluents was detected at 245 nm at column temperature of 30 degrees C. The orthogonal experiment and variance analysis were used to determine the optimum process of C. chinensis leaves by the comprehensive evaluation of the contents of myricetrin, quercitrin and afzelin. The results showed that the injection rates of myricetrin, quercitrin and afzelin were in the range of 0.4997-18.73 MUg (r = 0.9997), 0.1392-5.218 MUg (r = 0.9998) and 0.04582-1.718 MUg (r = 0.9998), respectively. The optimum conditions were determined as follows: the concentration of extraction, 0.9 mol/L; the ultrasonic time, 50 min; the solid liquid ratio, 1:30; the centrifugal speed, 5000 r/min, and the crushing ratio, 90 mesh. Under these optimal conditions, the average levels of myricetrin, quercitrin and afzelin were 8.6915, 1.5865 and 1.0920 (mg/g), respectively. PMID- 29497936 TI - Special issue: developments in water management technologies and systems. PMID- 29497937 TI - Correction to: Effects-based spatial assessment of contaminated estuarine sediments from Bear Creek, Baltimore Harbor, MD, USA. AB - The authors of the article have informed the Journal that an author, Dr. Sacoby Wilson of the University of Maryland School of Public Health, was inadvertently omitted from the published version of their manuscript due to a miscommunication regarding authorship criteria. PMID- 29497938 TI - First evidence of anticoagulant rodenticides in fish and suspended particulate matter: spatial and temporal distribution in German freshwater aquatic systems. AB - Anticoagulant rodenticides (ARs) have been used for decades for rodent control worldwide. Research on the exposure of the environment and accumulation of these active substances in biota has been focused on terrestrial food webs, but few data are available on the impact of ARs on aquatic systems and water organisms. To fill this gap, we analyzed liver samples of bream (Abramis brama) and co located suspended particulate matter (SPM) from the German Environmental Specimen Bank (ESB). An appropriate method was developed for the determination of eight different ARs, including first- and second-generation ARs, in fish liver and SPM. Applying this method to bream liver samples from 17 and 18 sampling locations of the years 2011 and 2015, respectively, five ARs were found at levels above limits of quantifications (LOQs, 0.2 to 2 MUg kg-1). For 2015, brodifacoum was detected in 88% of the samples with a maximum concentration of 12.5 MUg kg-1. Moreover, difenacoum, bromadiolone, difethialone, and flocoumafen were detected in some samples above LOQ. In contrast, no first generation AR was detected in the ESB samples. In SPM, only bromadiolone could be detected in 56% of the samples at levels up to 9.24 MUg kg-1. A temporal trend analysis of bream liver from two sampling locations over a period of up to 23 years revealed a significant trend for brodifacoum at one of the sampling locations. PMID- 29497939 TI - Ecotoxicological assessment of oil-based paint using three-dimensional multi species bio-testing model: pre- and post-bioremediation analysis. AB - The present study validates the oil-based paint bioremediation potential of Bacillus subtilis NAP1 for ecotoxicological assessment using a three-dimensional multi-species bio-testing model. The model included bioassays to determine phytotoxic effect, cytotoxic effect, and antimicrobial effect of oil-based paint. Additionally, the antioxidant activity of pre- and post-bioremediation samples was also detected to confirm its detoxification. Although, the pre-bioremediation samples of oil-based paint displayed significant toxicity against all the life forms. However, post-bioremediation, the cytotoxic effect against Artemia salina revealed substantial detoxification of oil-based paint with LD50 of 121 MUl ml-1 (without glucose) and > 400 MUl ml-1 (with glucose). Similarly, the reduction in toxicity against Raphanus raphanistrum seeds germination (%FG = 98 to 100%) was also evident of successful detoxification under experimental conditions. Moreover, the toxicity against test bacterial strains and fungal strains was completely removed after bioremediation. In addition, the post-bioremediation samples showed reduced antioxidant activities (% scavenging = 23.5 +/- 0.35 and 28.9 +/- 2.7) without and with glucose, respectively. Convincingly, the present multi-species bio-testing model in addition to antioxidant studies could be suggested as a validation tool for bioremediation experiments, especially for middle and low-income countries. Graphical abstract ?. PMID- 29497940 TI - Change of heavy metal speciation, mobility, bioavailability, and ecological risk during potassium ferrate treatment of waste-activated sludge. AB - The effects of potassium ferrate treatment on the heavy metal concentrations, speciation, mobility, bioavailability, and environmental risk in waste-activated sludge (WAS) at various dosages of potassium ferrate and different treatment times were investigated. Results showed that the total concentrations of all metals (except Cd) were decreased slightly after treatment and the order of metal concentrations in WAS and treated waste-activated sludge (TWAS) was Mg > Zn > Cu > Cr > Pb > Ni > Cd. Most heavy metals in WAS remained in TWAS after potassium ferrate treatment with metal residual rates over 67.8% in TWAS. The distribution of metal speciation in WAS was affected by potassium ferrate treatment. The bioavailability and the mobility of heavy metals (except Mg) in TWAS were mitigated, compared to those in WAS. Meanwhile, the environmental risk of heavy metals (except Pb and Cu) was alleviated after potassium ferrate treatment. PMID- 29497941 TI - Phosphorus release from cyanobacterial blooms during their decline period in eutrophic Dianchi Lake, China. AB - The phosphorus (P) release from bloom-cyanobacterium during its decline period is one of the most important parts involved in lake P-biogeochemical cycle, which is an important nutrient self-regulating process to sustain eutrophic status in lakes. An in situ experiment was set up to study the phosphorus release mechanisms of cyanobacterial blooms in Dianchi Lake during its decline period. In the enclosure, the cyanobacteria were dying out gradually and this process further affected the water quality parameters and lead to P release from bloom cyanobacteria. The pH and electric conductivity (EC) increased substantially, while the redox potential (ORP) decreased during the whole experimental period. Among all the released P forms, the orthophosphate (ortho-P) was the main released P form and accounted for 96.7 and 67.8% of the total phosphorus (TP) increment in the water and the TP reduction in algae respectively. According to the TP in sediment and lost P of overlying water column, it could be concluded that the ortho-P released from algae was absorbed by sediment as well. The release of TP, organic P (OP), and ortho-P from bloom-cyanobacteria all followed the first-order kinetics, and the release rate of ortho-P was much higher than that of OP (p < 0.05). Furthermore, according to the total extracellular polysaccharide (EPS) determination and related Pearson's correlation analysis, the release of TP and ortho-P from bloom-cyanobacteria would probably depend on the reduction of capsular polysaccharide (CPS) and colonial sheath disaggregation. In conclusion, a large amount of ortho-P was released and adsorbed by sediment gradually during cyanobacterial bloom decline period, and these bioavailable P could provide the sufficient nutrient for newborn cyanobacteria and could contribute to the construction of a new internal P cycle among sediment, water, and cyanobacterial bloom. PMID- 29497942 TI - Is there any association between phthalate exposure and precocious puberty in girls? AB - Considerable increase in the prevalence of precocious puberty (PP) during the last decade has raised a lot of concerns. Some environmental endocrine disruptor chemicals (EDCs), such as phthalate esters, have intrinsic estrogen activity or increase endogenous sex hormone levels leading to PP. This study was conducted to investigate the association between exposure to phthalate esters and PP in a sample of girls. Plasma levels of seven phthalate ester metabolites were measured in 87 girls with PP and 63 age- and sex-matched controls by dispersive liquid liquid microextraction and GC/MS analysis. History of exposure to main sources of phthalates was obtained by a checklist. Diethyl hexyl phthalate (DEHP) metabolite levels were significantly higher in those with PP than that in controls (p < 0.05), but this difference was not significant for other phthalate metabolites. 30.1% girls with PP and 12.2% of controls had played for more than 2 h/day with plastic toys in their childhood. 65.1% girls with PP and 32.8% of controls have regularly used some cosmetic products. Consumption of bottled water and beverages by those with PP was about twofold higher than that in the control group. A positive correlation was found between bottled ware consumption and plasma concentrations of four phthalate metabolites. The frequency of seafood consumption was not significantly different between the groups studied. Our findings confirm positive association between phthalate exposure and incidence of PP in girls. Control and reduction of children exposure to phthalate esters should be considered as a health priority. PMID- 29497943 TI - Impact assessment of meteorological and environmental parameters on PM2.5 concentrations using remote sensing data and GWR analysis (case study of Tehran). AB - The PM2.5 as one of the main pollutants in Tehran city has a devastating effect on human health. Knowing the key parameters associated with PM2.5 concentration is essential to take effective actions to reduce the concentration of these particles. This study assesses the relationship between meteorological (humidity, pressure, temperature, precipitation, and wind speed) and environmental parameters (normalize difference vegetation index and land surface temperature of MODIS satellite data) on PM2.5 concentration in Tehran city. The Geographically Weighted Regression (GWR) was employed to assess the impact of key parameters on PM2.5 concentrations in winter and summer. For this purpose, first the seasonal average of meteorological data were extracted and synchronized to satellite data. Then, using the ordinary least square model, the important parameters related to PM2.5 concentration were determined and evaluated. Finally, using the GWR model, the relationships between parameters related to PM2.5 concentration were analyzed. The results of this study indicate that meteorological and environmental parameters in winter season (71%) have a much higher ability to explain PM2.5 concentration than summer season (40%). In winter, PM2.5 concentration has a negative correlation with vegetation at most parts of the study area, a negative correlation with LST in the western and a positive correlation in the eastern part of the study area, a positive correlation with temperature, and a negative correlation with wind speed in the northeastern part of the study area. Precipitation has a positive correlation with PM2.5 concentration in most parts of the study area in both seasons. But, it was investigated in case of higher precipitation (more than 2 mm), PM2.5 concentration decreases. But, there is no negative relationship in any of the dependent parameters with PM2.5 concentration in summer. In this season, the air temperature parameter showed a high correlation with PM2.5 concentration. Also, spatial variations of the local coefficients for all parameters are higher in winter than in summer. PMID- 29497944 TI - Assessing hydrothermal groundwater flow path using Kohonen's SOM, geochemical data, and groundwater temperature cooling trend. AB - Assessing groundwater flow path in a thermal aquifer, such as El Hamma aquifer, southeastern Tunisia, and its lateral communication with the adjacent Jeffara Gabes aquifers, is a very complex operation which requires the integration of several approaches to understand and explain the reality of phenomenon. In this study, geochemical and isotopic data, Kohonen self-organizing map, temperature cooling trend, and kriging techniques were used to assess groundwater flow path in hydrothermal aquifer of El Hamma-Gabes, Tunisia. For this objective, 32 sampled wells are analyzed for major ions, electric conductivity, pH, total dissolved solids, and stables isotopes (delta2H and delta18O). Geochemical diagrams reveal that groundwater chemistry was controlled by evaporation, and rock-water interaction with a dominant water facies was Cl.SO4-Na.Ca-Mg. Kriging techniques were used to highlight groundwater flow path. Kohonen self-organizing map shows that the waters are clustered into three classes according to chemical and isotopic composition. These clusters represent a hydrothermal groundwater class from the Continental Intercalaire aquifer, a shallow groundwater class corresponding to Jeffara-Gabes aquifer and mixed water class. Groundwater cooling trend and stable isotopes indicate that groundwater flow is toward west to east part of study area, indicating a recharge of Jeffara aquifer from El Hamma thermal aquifer. PMID- 29497945 TI - Cleaner emissions from a DI diesel engine fueled with waste plastic oil derived from municipal solid waste under the influence of n-pentanol addition, cold EGR, and injection timing. AB - Urban planning and development is a decisive factor that increases the automobile numbers which leads to increased energy demand across the globe. In order to meet the escalating requirements of energy, it is necessary to find viable alternatives. Waste plastic oil (WPO) is one such alternative which has dual benefits as it reduces the environmental pollution caused by plastic waste and it could possibly meet the energy requirement along with fossil fuels. The study attempted to reduce emissions from a DI diesel engine fueled with WPO using 30% by volume of n-pentanol with fossil diesel (WPO70P30). EGR (10, 20, and 30%) and injection timing modifications were made with the intention to find optimum engine operating conditions. The experimental results indicated that addition of renewable component like n-pentanol had improved the combustion characteristics by igniting WPO more homogeneously producing a higher premixed combustion phase. Smoke density for WPO70P30 was found to be twice lower than that of neat WPO at standard injection timing of 23 degrees CA bTDC at any given EGR rate, NOx emissions were slightly on the higher side about 12% for WPO70P30 blend against WPO at same operating conditions. WPO70P30 showed lowest smoke and carbon monoxide emissions than diesel and WPO while delivering BTE's higher than WPO and closer to diesel at all EGR and injection timings. However NOx and HC emissions increased with n-pentanol addition. The use of EGR reduced NOx emissions but was found to aggravate other emissions. It was concluded WPO70P30 can be favorably used in a DI diesel engine at the engines advanced injection timing for better performance than diesel with a slight penalty in NOx emissions. PMID- 29497946 TI - Reproducibility of right-to-left shunt quantification using transthoracic contrast echocardiography in hereditary haemorrhagic telangiectasia. AB - AIM: Transthoracic contrast echocardiography (TTCE) is recommended for screening of pulmonary arteriovenous malformations (PAVMs) in hereditary haemorrhagic telangiectasia. Shunt quantification is used to find treatable PAVMs. So far, there has been no study investigating the reproducibility of this diagnostic test. Therefore, this study aimed to describe inter-observer and inter-injection variability of TTCE. METHODS: We conducted a prospective single centre study. We included all consecutive persons screened for presence of PAVMs in association with hereditary haemorrhagic telangiectasia in 2015. The videos of two contrast injections per patient were divided and reviewed by two cardiologists blinded for patient data. Pulmonary right-to-left shunts were graded using a three-grade scale. Inter-observer and inter-injection agreement was calculated with kappa statistics for the presence and grade of pulmonary right-to-left shunts. RESULTS: We included 107 persons (accounting for 214 injections) (49.5% male, mean age 45.0 +/- 16.6 years). A pulmonary right-to-left shunt was present in 136 (63.6%) and 131 (61.2%) injections for observer 1 and 2, respectively. Inter-injection agreement for the presence of pulmonary right-to-left shunts was 0.96 (95% confidence interval (CI) 0.9-1.0) and 0.98 (95% CI 0.94-1.00) for observer 1 and 2, respectively. Inter-injection agreement for pulmonary right-to-left shunt grade was 0.96 (95% CI 0.93-0.99) and 0.95 (95% CI 0.92-0.98) respectively. There was disagreement in right-to-left shunt grade between the contrast injections in 11 patients (10.3%). Inter-observer variability for presence and grade of the pulmonary right-to-left shunt was 0.95 (95% CI 0.91-0.99) and 0.97 (95% CI 0.95 0.99) respectively. CONCLUSION: TTCE has an excellent inter-injection and inter observer agreement for both the presence and grade of pulmonary right-to-left shunts. PMID- 29497947 TI - Protective Effect of Hydroxytyrosol Against Oxidative Stress Mediated by Arsenic Induced Neurotoxicity in Rats. AB - The present study reports beneficial effect of hydroxytyrosol (HT) against arsenic (As)-induced oxidative stress in the rat brain. Rats were orally administered with sodium arsenite dissolved in distilled water (25 ppm, by oral gavage) for 8 weeks or HT (10 mg/kg b. wt.) in combination with As. Results showed increase in protein oxidation and lipid peroxidation, while catalase and superoxide dismutase (SOD) activities as well as GSH content were decreased after As exposure in rat brain. Fourier transform infrared analysis showed significant alteration in peak area values that also validated the oxidative damage to lipids and proteins. In addition, As exposure caused increase in protein expression of caspase-3 and Bax, while Bcl-2 expression was downregulated resulting in translocation of cytochrome c from mitochondria to cytosol. Treatment of HT with As reversed protein oxidation, lipid peroxidation, and increased GSH content as well as catalase and SOD activities. Administration of HT also prevented translocation of cytochrome c from mitochondria and increased mitochondria/cytosol ratio of cytochrome c. Hence, treatment of HT with As improved antioxidant system and efficiently lowered the generation of oxidative stress in rat brain. PMID- 29497948 TI - The effect of unilateral forced nostril breathing on sleep in healthy right handed men: a preliminary report. AB - PURPOSE: Although we spend about one-third of our lives in sleep and recognize its necessity for good health, sleep has only been partially elucidated in the last century. The nasal cycle of congestion and decongestion during sleep has various effects on human physiology. The aim of the present study was to investigate the effect of unilateral forced nostril breathing on sleep. METHODS: Twenty-one healthy male volunteers aged 18-24 years were included in the study. Only individuals with right-hand dominance were included. Subjects were observed during sleep for three nights under different conditions: no obstruction (normal sleep) on the first night, right nasal obstruction on the second night, and left nasal obstruction on the third night. RESULTS: The main findings of our study are that sleep efficiency, NREM stage III, and total sleep duration were greater during left nasal obstruction (right nostril dominant respiration), while apnea hypopnea index (AHI), frequency of periodic limb movements, and oxygen desaturation were higher during right nasal obstruction (left nostril dominant respiration). CONCLUSION: The nasal cycle has a significant impact on sleep which is reflected in sleep recordings. Our result supports that nasal obstructions, due to deviations, concha hypertrophy, or congestion/decongestion, might affect the physiology of respiration and sleep. Nasal obstruction should be taken into consideration when evaluating patients in sleep laboratories and further studies are required to elucidate the situation in the patients with nasal obstruction. PMID- 29497949 TI - Pulmonary functions and sleep-related breathing disorders in lipid storage disease. AB - PURPOSE: Pulmonary function abnormalities and sleep-related breathing disorders (SRBD) are frequent in subjects with several neuromuscular diseases but there is no data about lipid storage diseases (LSD). Therefore, we aimed to evaluate pulmonary functions and SRBD in adults with LSD. METHODS: Pulmonary functions (forced expiratory volume (FEV1), forced vital capacity (FVC), supine FVC, upright-supine FVC% change, maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), peak cough flow (PCF)), arterial blood gases, and polysomnographic data of all subjects were evaluated. RESULTS: Twenty-five subjects with LSD were evaluated [17 males, 8 females; age 34.9 +/- 15 years; BMI 26.5 +/- 3.4 kg/m2]. MIP was - 72.2 +/- 32.7 cmH2O (< - 80 cmH2O in 13 subjects), MEP was 80.9 +/- 39.1 cmH2O (< 80 cmH2O in 9 subjects, < 40 cmH2O in 6 subjects), and PCF was 441.3 +/- 190.9 L/min (< 360 L/min in 11 subjects). FVC was 87.8% +/- 25.7 and 6 subjects had FVC < 80%. Seven subjects had diaphragm dysfunction (four upright-supine FVC% >= 15, three dyspnea in supine position with paradoxical abdominal respiration). Five subjects had hypoxemia (PaO2 < 80 mmHg) and 8 subjects had hypercapnia (PaCO2 > 45 mmHg). REM sleep had decreased in all subjects (10.2% +/- 6.1). Obstructive sleep apnea (OSA) was found in 80% of the subjects (n = 20; 9 mild, 9 moderate, 2 severe). For subjects with OSA, apnea hypopnea index (AHI) was 20.8 +/- 15.9/h, oxygen desaturation index (ODI) was 11.9 +/- 15.4/h, AHIREM was 30.6 +/- 19.7/h, AHINREM was 19.7 +/- 16.6/h, ODIREM was 27.2 +/- 26.1/h, and ODINREM was 11.4 +/- 15/h. Five subjects (20%) diagnosed as REM-related OSA. Nocturnal mean SpO2 was 94.9% +/- 1.7, lowest SpO2 was 73.3% +/- 13.9, and time spent with SpO2 < 90% was 2.4% +/- 7.2. CONCLUSION: In subjects with LSD, pulmonary function impairment, daytime hypercapnia and hypoxemia, and OSA, especially REM-related OSA, are frequent. Therefore, pulmonary functions and polysomnography should be performed routinely. PMID- 29497951 TI - Expression of inhibitor proteins that control primordial follicle reserve decreases in cryopreserved ovaries after autotransplantation. AB - PURPOSE: Even with 86 live births reported globally so far, the mechanism of primordial follicle loss following autotransplantation of the frozen-thawed ovarian tissue needs further evaluation. Pten, Tsc1, p27, and Amh are the inhibitor proteins that play crucial roles in suppressing the transition from the primordial follicle to primary state, maintaining the primordial follicle reserve. In this study, we aimed to evaluate whether the expression patterns of these proteins change and it may be related to the global primordial follicle loss after autotransplantation of the frozen-thawed ovarian tissue. METHODS: Four groups were established in rats: fresh-control, frozen/thawed, fresh transplanted, and frozen/thawed and transplanted. After slow freezing and thawing process, two ovarian pieces were transplanted into the back muscle of the same rat. After 2 weeks, grafts were harvested, fixed, and embedded into the paraffin block. Normal and atretic primordial/growing follicle count was performed in all groups. Ovarian tissues were evaluated for the dynamic expressions of the Pten, Tsc1, p27, and Amh proteins using immunohistochemistry, and H-score analyses were done. RESULTS: Ovarian tissue cryopreservation does not change the expression patterns of inhibitory proteins that control ovarian reserve. Both in fresh and frozen/thawed autotransplanted groups, the expression of inhibitory proteins and Amh decreased significantly in primordial follicles and in growing follicles, respectively. In control group and in frozen/thawed group, primordial follicle counts were similar but decreased by almost half in both fresh-transplanted and frozen/thawed and transplanted groups. CONCLUSIONS: One of the causes of primordial follicle loss after transplantation of ovarian graft may be decreased expression of the inhibitory proteins that guard the ovarian reserve and transplantation itself seems to be the major cause for disruption of inhibitory molecular signaling. Our findings highlight important molecular aspects for future clinical applications for fertility preservation in humans. PMID- 29497952 TI - Maternal carriers of the ANXA5 M2 haplotype are exposed to a greater risk for placenta-mediated pregnancy complications. AB - PURPOSE: Annexin A5 (ANXA5) is a protein abundantly expressed in normal placenta where it contributes to the healthy outcome of a pregnancy. Lower ANXA5 levels have been observed in M2/ANXA5 haplotype carrying chorion. Consequently, this study aimed to assess the potential association of M2 maternal carrier status with the risk of recurrent pregnancy loss (RPL), the timing of miscarriages, and other obstetric complications, for the first time in a population from Latin America. METHODS: This study was designed as a prospective recruitment of RPL patients with post hoc analysis. The distribution of the M2/ANXA5 haplotype was compared between a group of 229 Argentine women with RPL and 100 parous controls, and was further analyzed in subgroups of patients stratified according to the timing of miscarriages and in relation to other obstetric complications. RESULTS: No significant differences were found in the distribution of M2 haplotype among either RPL patients or the subgroups with embryonic, early fetal, or late fetal losses compared to parous controls. Notwithstanding, maternal M2/ANXA5 was found to be independently associated with a higher risk of suffering intrauterine growth restriction (IUGR) and/or preeclampsia (PE). Simultaneously, the presence of inherited and/or acquired thrombophilia also proved to be an independent risk factor for these. CONCLUSIONS: The association found between the maternal carriage of the M2/ANXA5 haplotype and an elevated risk of IUGR and/or PE supports the hypothesis that carrier status of this haplotype and the consequently reduced placental ANXA5 expression might be responsible, at least partially, for the onset of these gestational vascular complications. PMID- 29497953 TI - Transplantation of frozen-thawed ovarian tissue: an update on worldwide activity published in peer-reviewed papers and on the Danish cohort. AB - PURPOSE: The purpose of the study is to review all peer-reviewed published reports of women receiving ovarian tissue transplantation (OTT) with frozen/thawed tissue (OTC) with respect to age, diagnosis, transplantation site, fertility outcome, and potential side effects, including data from all women in the Danish program. METHODS: A systematic review of the literature was performed in PubMed combined with results from all patients who had received OTT in Denmark up to December 2017. RESULTS: OTT has been reported from 21 different countries comprising a total of 360 OTT procedures in 318 women. In nine women, malignancy was diagnosed after OTT; none were considered to be directly caused by the OTT. Despite a potential under reporting of cancer recurrence, there is currently no evidence to suggest that OTT causes reseeding of the original cancer. Renewed ovarian endocrine function was reported in 95% of the women. Half of all children born following OTT resulted from natural conception, and newborns were reported to be healthy except for one neonate with a chromosome anomaly with a family disposition. Women who conceived after OTT were significantly younger than those who failed. CONCLUSION: This study found no indications of sufficient numbers of malignant cells present in the ovarian tissue to cause recurrence of cancer after OTT. Further, it is unlikely that OTC affects the well-being of children born. OTC is now an established method of fertility preservation in Denmark with public reimbursement. The current data encourage that women who require gonadotoxic treatment should be offered an individual evaluation considering fertility preservation. PMID- 29497955 TI - Synthesis, structural determination and antimicrobial evaluation of two novel CoII and ZnII halogenometallates as efficient catalysts for the acetalization reaction of aldehydes. AB - BACKGROUND: Complexes of imidazole derivatives with transition metal ions have attracted much attention because of their biological and pharmacological activities, such as antimicrobial, antifungal, antiallergic, antitumoural and antimetastatic properties. In addition, imidazoles occupy an important place owing to their meaningful catalytic activity in several processes, such as in hydroamination, hydrosilylation, Heck reaction and Henry reaction. In this work, we describe the crystallization of two halogenometallate based on 2 methylimidazole. Their IR, thermal analysis, catalytic properties and antibacterial activities have also been investigated. RESULTS: Two new isostructural organic-inorganic hybrid materials, based on 2-methyl-1H-imidazole, 1 and 2, were synthesized and fully structurally characterized. The analysis of their crystal packing reveals non-covalent interactions, including C/N-H...Cl hydrogen bonds and pi...pi stacking interactions, to be the main factor governing the supramolecular assembly of the crystalline complexes. The thermal decomposition of the complexes is a mono-stage process, confirmed by the three dimensional representation of the powder diffraction patterns (TDXD). The catalytic structure exhibited promising activity using MeOH as solvent and as the unique source of acetalization. Moreover, the antimicrobial results suggested that metal-complexes exhibit significant antimicrobial activity. CONCLUSION: This study highlights again the structural and the biological diversities within the field of inorganic-organic hybrids. PMID- 29497954 TI - Influence of follicular fluid and cumulus cells on oocyte quality: clinical implications. AB - An equilibrium needs to be established by the cellular and acellular components of the ovarian follicle if developmental competence is to be acquired by the oocyte. Both cumulus cells (CCs) and follicular fluid (FF) are critical determinants for oocyte quality. Understanding how CCs and FF influence oocyte quality in the presence of deleterious systemic or pelvic conditions may impact clinical decisions in the course of managing infertility. Given that the functional integrities of FF and CCs are susceptible to concurrent pathological conditions, it is important to understand how pathophysiological factors influence natural fertility and the outcomes of pregnancy arising from the use of assisted reproduction technologies (ARTs). Accordingly, this review discusses the roles of CCs and FF in ensuring oocyte competence and present new insights on pathological conditions that may interfere with oocyte quality by altering the intrafollicular environment. PMID- 29497956 TI - Comparison of [99mTc]3PRGD2 Imaging and [18F]FDG PET/CT in Breast Cancer and Expression of Integrin alphavbeta3 in Breast Cancer Vascular Endothelial Cells. AB - PURPOSE: This study aimed to investigate the value of 99mtechnetium-three polyethylene glycol spacers-arginine-glycine-aspartic acid ([99mTc]3PRGD2) imaging in diagnosis and staging of breast cancer compared with 2-deoxy-2 [18F]fluoro-D-glucose ([18F]FDG) imaging, and to explore the expression of integrin alphavbeta3 in tumor vascular endothelial cells. PROCEDURES: Forty-two women with suspected breast cancer underwent both [99mTc]3PRGD2 imaging and [18F]FDG imaging. Visual analysis was used to assess primary breast lesion, axillary lymph node, and distant metastasis. The tumor-blood (T/B) ratios from [99mTc]3PRGD2 imaging and the maximum standardized uptake value (SUVmax) from [18F]FDG imaging were analyzed for breast lesions. Integrin alphavbeta3 was analyzed through immunohistochemistry. RESULTS: Forty-five breast lesions were found (malignant, n = 38; benign, n = 7). The sensitivity, specificity, and accuracy of [99mTc]3PRGD2 and [18F]FDG imaging in visual analysis for the breast lesion were 97.4, 87.5, and 95.6 % and 97.4, 71.4, and 93.3 %, respectively (P > 0.05). For semi-quantitative analysis, no significant difference of the area under the curves (AUC) was found in the imaging using the two radiopharmaceuticals (0.880 and 0.955; Z = 0.88, P > 0.05). The sensitivity, specificity, and accuracy for axillary lymph node metastasis with [99mTc]3PRGD2 and [18F]FDG were 78.05, 99.36, and 94.92 % and 85.37, 98.72, and 95.64 %, respectively (P > 0.05). Nine patients with distant metastases were all detected with the two radiopharmaceuticals. The expression of integrin alphavbeta3 was correlated with [99mTc]3PRGD2 uptake (r = 0.582, P = 0.001), which were significantly higher in the HER2-positive and stage III-IV patients (P < 0.05). CONCLUSIONS: The prospective study demonstrated that [99mTc]3PRGD2 imaging seems to be valuable for diagnosis of breast cancer and its staging. It may be less sensitive for detecting small lymph node metastatic lesions when compared with [18F]FDG imaging. Integrin alphavbeta3 in tumor microvessels was associated with the breast cancer subtype and its staging. PMID- 29497957 TI - Chemotherapy drugs induce pyroptosis through caspase-3-dependent cleavage of GSDME. PMID- 29497959 TI - Erratum to: Traffic injury data, policy, and public health: Lessons from Boston Chinatown. AB - In the March 2002 issue, the following credit line was omitted from Fig. 1(a) on p. 90 (Brugge D, Lai Z, Hill, C, Rand W. Traffic Injury Data, Policy, and Public Health: Lessons from Boston Chinatown. J Urban Health. 2002;79(1):87-103): "This figure is reprinted with permission from Brugge D, A Leong, Z Lai. Can a community inject public health values into transportation questions? Public Health Rep. 1999:114:44." PMID- 29497960 TI - Systemic Inflammation in Severe Obese Patients Undergoing Surgery for Obesity and Weight-Related Diseases. AB - BACKGROUND: Obesity is a worldwide disease related to genetic, environmental, and behavioral factors, and it is associated with high rates of morbidity and mortality. Recently, obesity has been characterized by a low-grade inflammatory state known as inflammome indicated by chronic increases in circulating concentrations of inflammatory markers. The purpose of this study was to evaluate the effect of weight loss induced by surgery for obesity and weight-related diseases on pro-inflammatory cytokine (TNF-alpha) and anti-inflammatory adipokine (adiponectin) levels, and on an adipose-derived hormone (leptin) in severely obese subjects. METHODS: This randomized, controlled trial involved 55 severe obese patients (50 women, age 18-63 years, and body mass index of 35.7-63 kg/m2) who underwent bariatric surgery (BS). Patients with a BMI > 65 kg/m2 and clinical and mental instability, or significant and unrealistic expectations of surgery were excluded. Blood samples were collected during the fasting period to analyze tumor necrosis factor alpha (TNF-alpha), adiponectin, and leptin levels by enzyme linked immunosorbent assay. RESULTS: At baseline, no significant difference was observed in the anthropometric, demographic, clinical characteristics and biochemistry and inflammatory markers between the control group (CG) and bariatric surgery group (BSG). The same finding was also observed when we compared the baseline variables to those at the 6-month follow-up in the CG. However, the same variables in the BSG group were significantly different between baseline and the 6-month follow-up after BS. CONCLUSIONS: Weight loss induced by surgery for obesity and weight-related diseases reduced the inflammome state in severely obese patients. PMID- 29497961 TI - Long-term Metabolic Effects of Laparoscopic Sleeve Gastrectomy. AB - OBJECTIVE: Obesity is one of the major health challenges throughout the world. The association between obesity and diabetes is well established because 90% of patients with type 2 diabetes mellitus (T2DM) show excess body weight. The aim of the study was to evaluate the effect of laparoscopic sleeve gastrectomy (LSG) on morbid obesity and type 2 diabetes (T2DM) in the long-term follow-up. METHODS: One hundred ninety-five obese patients, 78 with T2DM, were evaluated before and after LSG up to 10 years, to identify complete diabetes remission (FPG < 100 mg/dl, A1c < 6.0%), partial remission (FPG 100-125 mg/dl, A1c < 6.5%), or relapse. RESULTS: Before surgery, body weight and BMI were 123 +/- 21 kg and 44.6 +/- 6.8 kg/m2 respectively; at a mean follow-up of 7 years (range 4-10), body weight was 104.9 +/- 18 kg and BMI 37 +/- 6 kg/m2. Minimum weight was reached after 2 years. T2DM remission was observed in 66, 57, and 52% at short (< 2 years), medium (2-5 years), and long-term (> 5 years) follow-up respectively. Furthermore, 45.2% maintained complete remission for at least 5 years and about 36% showed a persistent but improved diabetes. None of the patients cured from diabetes had a duration disease greater than 8 years and a glycemic control requiring insulin. The prevalence of hypertension and dyslipidemia significantly decreased from 49 to 35% and from 51 to 40% respectively. CONCLUSIONS: LSG significantly improves body weight, diabetes, hypertension, and dyslipidemia in long-term follow-up. PMID- 29497962 TI - Intragastric Balloons for Overweight Populations-1 Year Post Removal. AB - BACKGROUND: Endoscopic balloons have been used for years to treat obese seeking weight loss. This study evaluated the safety and effectiveness of our lifestyle modification program. METHODS: Retrospective analysis of prospectively collected data from patients who underwent End-ball(r) (Endalis) intragastric balloon insertion with a multidisciplinary follow-up program. Demographic data, weight loss complications, and satisfaction rates were assessed. RESULTS: In total, 114 overweight/obese individuals from July 2012 to December 2015 were included. Mean age 36.5 years (72% females). Initial body mass index (BMI) was 33.5 kg/m2. Twelve early removals (10.52%) due to intolerance (n = 7), dissatisfaction (n = 4), and esophagitis (n = 1); 102 patients completed the program. BMI reduction ranged 5.5-6.4 at balloon removal and 4.1 1-year post removal. Average excess BMI loss (EBMIL) was 46-48% at balloon removal and 39.1% after 1 year; 75% of participants maintained > 60% of their weight loss 1 year after removal. EBMIL was 17 and 48% when initial BMI > 35 and <= 35 kg/m2, respectively. At removal, 80% of patients were satisfied with the process. CONCLUSION: The End-ball(r) program resulted in significant weight loss that continued for 1 year after balloon removal, with minimal complications. When treating overweight/obese populations, the main principles of the balloon insertion process should be no complications, high safety, and significant effectiveness. The process was most beneficial in the overweight and class I obese populations since average BMI was 33 and the class II obese had less weight loss and can possibly prevent future bariatric surgery. PMID- 29497963 TI - Long-term effectiveness and cost-effectiveness of high versus low-to-moderate intensity resistance and endurance exercise interventions among cancer survivors. AB - PURPOSE: This study aimed to evaluate the long-term effectiveness and cost effectiveness of high intensity (HI) versus low-to-moderate intensity (LMI) exercise on physical fitness, fatigue, and health-related quality of life (HRQoL) in cancer survivors. METHODS: Two hundred seventy-seven cancer survivors participated in the Resistance and Endurance exercise After ChemoTherapy (REACT) study and were randomized to 12 weeks of HI (n = 139) or LMI exercise (n = 138) that had similar exercise types, durations, and frequencies, but different intensities. Measurements were performed at baseline (4-6 weeks after primary treatment), and 12 (i.e., short term) and 64 (i.e., longer term) weeks later. Outcomes included cardiorespiratory fitness, muscle strength, self-reported fatigue, HRQoL, quality-adjusted life years (QALYs) and societal costs. Linear mixed models were conducted to study (a) differences in effects between HI and LMI exercise at longer term, (b) within-group changes from short term to longer term, and (c) the cost-effectiveness from a societal perspective. RESULTS: At longer term, intervention effects on role (beta = 5.9, 95% CI = 0.5; 11.3) and social functioning (beta = 5.7, 95%CI = 1.7; 9.6) were larger for HI compared to those for LMI exercise. No significant between-group differences were found for physical fitness and fatigue. Intervention-induced improvements in cardiorespiratory fitness and HRQoL were maintained between weeks 12 and 64, but not for fatigue. From a societal perspective, the probability that HI was cost effective compared to LMI exercise was 0.91 at 20,000?/QALY and 0.95 at 52,000?/QALY gained, mostly due to significant lower healthcare costs in HI exrcise. CONCLUSIONS: At longer term, we found larger intervention effects on role and social functioning for HI than for LMI exercise. Furthermore, HI exercise was cost-effective with regard to QALYs compared to LMI exercise. TRIAL REGISTRATION: This study is registered at the Netherlands Trial Register [NTR2153 [ http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2153 ]] on the 5th of January 2010. IMPLICATIONS FOR CANCER SURVIVORS: Exercise is recommended to be part of standard cancer care, and HI may be preferred over LMI exercise. PMID- 29497965 TI - Pressure and Flow Rate Changes During Contrast Injections in Cerebral Angiography: Correlation to Reflux Length. AB - Cerebral angiography involves the antegrade injection of contrast media through a catheter into the vasculature to visualize the region of interest under X-ray imaging. Depending on the injection and blood flow parameters, the bolus of contrast can propagate in the upstream direction and proximal to the catheter tip, at which point contrast is said to have refluxed. In this in vitro study, we investigate the relationship of fundamental hemodynamic variables to this phenomenon. Contrast injections were carried out under steady and pulsatile flow using various vessel diameters, catheter sizes, working fluid flow rates, and injection rates. The distance from the catheter tip to the proximal edge of the contrast bolus, called reflux length, was measured on the angiograms; the relation of this reflux length to different hemodynamic parameters was evaluated. Results show that contrast reflux occurs when the pressure distal to the catheter tip increases to be greater than the pressure proximal to the catheter tip. The ratio of this pressure difference to the baseline flow rate, called reflux resistance here, was linearly correlated to the normalized reflux length (reflux length/vessel diameter). Further, the ratio of blood flow to contrast fluid momentums, called the Craya-Curtet number, was correlated to the normalized reflux length via a sigmoid function. A sigmoid function was also found to be representative of the relationship between the ratio of the Reynolds numbers of blood flow to contrast and the normalized reflux length. As described by previous reports, catheter based contrast injections cause substantial increases in local flow and pressure. Contrast reflux should generally be avoided during standard antegrade angiography. Our study shows two specific correlations between contrast reflux length and baseline and intra-injection parameters that have not been published previously. Further studies need to be conducted to fully characterize the phenomena and to extract reliable indicators of clinical utility. Parameters relevant to cerebral angiography are studied here, but the essential principles are applicable to all angiographic procedures involving antegrade catheter injections. PMID- 29497964 TI - Adjuvant radiotherapy following pancreaticoduodenectomy for ampullary adenocarcinoma improves survival in node-positive patients: a propensity score analysis. AB - INTRODUCTION: This study aimed to evaluate the impact of adjuvant radiotherapy in patients undergoing pancreaticoduodenectomy (PD) for ampullary adenocarcinoma. METHODS: Using the Surveillance, Epidemiology, and End Results, patients with non metastatic ampullary adenocarcinoma between 2004 and 2013 were identified. Cancer specific survival and overall survival were estimated using Kaplan-Meier and Cox regression to obtain adjusted hazard ratio of survival. RESULTS: In this study, 1106 patients with ampullary adenocarcinoma were identified, of which 27% received adjuvant radiotherapy and the remaining 73% (803/1106) patients did not receive any adjuvant radiotherapy. In the matched cohort, there were still no significant difference in CSS (median 41 vs 35, p = 0.28) and OS (median 32 vs 30, p = 0.26) between patients receiving adjuvant radiotherapy and those under observation alone. However, in patients with N2 (Fig. 4) disease, both CSS (median 27 vs 19 months, p = 0.0044) and OS (median 23 vs 17 months, p = 0.0091) were significantly longer for patients receiving adjuvant radiotherapy. CONCLUSION: In summary, adjuvant radiotherapy following PD for ampullary adenocarcinoma significantly improves survival in patients with N2 disease. Future studies defining "high-risk" groups using larger cohorts will enable reliable appraisal on the benefit of adjuvant radiotherapy to allow for a more personalized approach in treating patients. PMID- 29497967 TI - Re: Time to consider integration of a formal robotic-assisted surgical training program. PMID- 29497966 TI - Coating and Pharmacokinetic Evaluation of Air Spray Coated Drug Coated Balloons. AB - Drug coated balloons (DCB) are becoming the standard-care treatment for peripheral arterial disease (PAD). DCB use excipients to transfer and retain anti proliferative drugs, such as paclitaxel. Excipients thus play a vital role in the design and function of DCB, however methods to coat balloons with excipients and anti-proliferative drugs remain unknown. The goal of this study was to thus develop an approach to coat and evaluate DCB for various excipients. An air sprayer method was developed to deposit paclitaxel and various excipients onto non-coated commercially available angioplasty balloons. The coating of the angioplasty balloons was evaluated for drug deposition and coating efficiency using high performance liquid chromatography tandem mass spectrometry. Drug transfer and retention of the coated angioplasty balloons into arterial segments were evaluated ex vivo using harvested pig arteries in a pulsatile flow bioreactor. The air sprayer method successfully delivered varying excipients including bovine serum albumin (BSA), urea and iohexol. The air spray method was configured to coat four angioplasty balloons simultaneously with paclitaxel and iohexol with an average paclitaxel load of 4.0 +/- 0.70 ug/mm2. The intra-day (within) and inter-day (between) coating precisions, defined as relative standard deviation (RSD), was 17.2 and 15.5%, respectively. Ex vivo deployment of iohexol paclitaxel DCB yielded an arterial paclitaxel concentration of 123.4 +/- 44.68 ng/mg (n = 3) at 1 h, 126.7 +/- 25.27 ng/mg (n = 3) at 1 day, and 12.9 +/- 12.88 ng/mg (n = 3) at 7 days. This work provides proof-of-concept of a quick, inexpensive approach to coat commercially available angioplasty balloons with paclitaxel and various excipients. PMID- 29497968 TI - Identification of Bactrian camel cell lines using genetic markers. AB - Iranian Bactrian camel population is less than 100 animals. Iranian biological resource center produced more than 50 Bactrian camel fibroblast cell lines as a somatic cell bank for conservation animal genetic resources. We compared two type markers performance, including 14 random amplified polymorphic DNA (RAPDs) (dominant) and eight microsatellite (co-dominant) for cell line identification, individual identification and investigation genetic structure of these samples. Based on clarity, polymorphism, and repeatability, four RAPD primers were selected for future analysis. Four RAPD primers and eight microsatellite markers have generated a total of 21 fragments and 45 alleles, respectively. RAPD primers revealed fragment size between 150 to 2000 bp and gene diversity since 0.27 (IBRD) to 0.46 (GC10), with an average of 0.37. Microsatellite markers generated number of alleles per locus ranged from 3 to 11, with an average of 5.62 alleles. The observed heterozygosity ranged from 0.359 (IBRC02) to 0.978 (YWLL08), and expected heterozygosity ranged from 0.449 (IBRC02) to 0.879 (YWLL08). Bottleneck analysis and curve showed that Bactrian camel population did not experience a low diversity. RAPD profiles were especially suitable for investigation population genetics. All primers generated novel and polymorphic fragments. Briefly, our results show that a multiplex PCR based on these markers can still be valuable and suitable for authentication of cell lines, investigating gene diversity and conservation genetic resources in Bactrian camel, while new technologies are continuously developed. PMID- 29497969 TI - The Ethics of Smart Stadia: A Stakeholder Analysis of the Croke Park Project. AB - The development of "smart stadia", i.e. the use of "smart technologies" in the way sports stadia are designed and managed, promises to enhance the experience of attending a live match through innovative and improved services for the audience, as well as for the players, vendors and other stadium stakeholders. These developments offer us a timely opportunity to reflect on the ethical implications of the use of smart technologies and the emerging Internet of Things (IoT). The IoT has the potential to radically transform society and is representative of the ways that novel technologies will alter human life. We use Dublin's Croke Park stadium smart project as a case study for examining the development of smart stadia. PMID- 29497970 TI - Science, Technology and Innovation as Social Goods for Development: Rethinking Research Capacity Building from Sen's Capabilities Approach. AB - Science and technology are key to economic and social development, yet the capacity for scientific innovation remains globally unequally distributed. Although a priority for development cooperation, building or developing research capacity is often reduced in practice to promoting knowledge transfers, for example through North-South partnerships. Research capacity building/development tends to focus on developing scientists' technical competencies through training, without parallel investments to develop and sustain the socioeconomic and political structures that facilitate knowledge creation. This, the paper argues, significantly contributes to the scientific divide between developed and developing countries more than any skills shortage. Using Charles Taylor's concept of irreducibly social goods, the paper extends Sen's Capabilities Approach beyond its traditional focus on individual entitlements to present a view of scientific knowledge as a social good and the capability to produce it as a social capability. Expanding this capability requires going beyond current fragmented approaches to research capacity building to holistically strengthen the different social, political and economic structures that make up a nation's innovation system. This has implications for the interpretation of human rights instruments beyond their current focus on access to knowledge and for focusing science policy and global research partnerships to design approaches to capacity building/development beyond individual training/skills building. PMID- 29497971 TI - Predicting an adrenal crisis: can we do it? PMID- 29497972 TI - Copeptin in hyponatremia: is there a role for this biomarker in the diagnostic workup? PMID- 29497973 TI - Multiple endocrine neoplasia type 1: analysis of germline MEN1 mutations in the Italian multicenter MEN1 patient database. AB - PURPOSE: Multiple endocrine neoplasia type 1 (MEN1) is caused by germline inactivating mutations of the MEN1 gene. Currently, no direct genotype-phenotype correlation is identified. We aim to analyze MEN1 mutation site and features, and possible correlations between the mutation type and/or the affected menin functional domain and clinical presentation in patients from the Italian multicenter MEN1 database, one of the largest worldwide MEN1 mutation series published to date. METHODS: The study included the analysis of MEN1 mutation profile in 410 MEN1 patients [370 familial cases from 123 different pedigrees (48 still asymptomatic at the time of this study) and 40 single cases]. RESULTS: We identified 99 different mutations: 41 frameshift [small intra-exon deletions (28) or insertions (13)], 13 nonsense, 26 missense and 11 splicing site mutations, 4 in-frame small deletions, and 4 intragenic large deletions spanning more than one exon. One family had two different inactivating MEN1 mutations on the same allele. Gastro-entero-pancreatic tumors resulted more frequent in patients with a nonsense mutation, and thoracic neuroendocrine tumors in individuals bearing a splicing-site mutation. CONCLUSIONS: Our data regarding mutation type frequency and distribution are in accordance with previously published data: MEN1 mutations are scattered through the entire coding region, and truncating mutations are the most common in MEN1 syndrome. A specific direct correlation between MEN1 genotype and clinical phenotype was not found in all our families, and wide intra-familial clinical variability and variable disease penetrance were both confirmed, suggesting a role for modifying, still undetermined, factors, explaining the variable MEN1 tumorigenesis. PMID- 29497975 TI - Plasma concentration of urokinase plasminogen activator receptor is a marker of kidney allograft function. AB - BACKGROUND: Urokinase-type plasminogen activator receptor (uPAR) is found in a variety of cell types including monocytes, lymphocytes, macrophages, and endothelial cells and plays an important role in fibrinolysis and in the activation and chemotaxis of neutrophils and lymphocytes. In this study, we examined the correlation between uPAR plasma concentration and kidney allograft function. AIMS: This study enrolled 78 Caucasian deceased-donor renal transplant recipients. METHODS: Plasma concentrations of uPAR were measured using commercially available enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: We observed elevated with borderline significance (p = 0.095) uPAR plasma concentrations in patients with tubular atrophy. Plasma concentrations of uPAR showed strong statistically significant positive correlations with serum creatinine or urea and strong negative correlation with estimated glomerular filtration rate (eGFR). There was also a borderline positive correlation between uPAR plasma concentration and protein concentration in urine as well as the duration of hemodialysis. CONCLUSIONS: The results of our study indicate that uPAR plasma concentrations in kidney allograft recipients are significantly negatively correlated with graft function and may be elevated in patients with tubular atrophy. PMID- 29497977 TI - Five-year postsurgical monitoring of serum p53 antibody for locally advanced esophageal squamous cell carcinoma. AB - Serum p53 antibody (s-p53-Ab) titers were postoperatively monitored for over 5 years in a 67-year-old man with locally advanced esophageal squamous cell carcinoma. The tumor stage was classified as clinical stage II (cT3N0M0). Serum SCC antigen (s-SCC-Ag; 6.2 ng/mL) and s-p53-Ab (3.83 U/mL) were noted to be positive before surgery. Radical esophagectomy with three-field lymph node dissection was performed without neoadjuvant therapy. Pathological findings of the surgically resected specimens revealed a stage II tumor (pT3N0M0). Postoperatively, the patients did not receive any adjuvant therapy. Although the s-SCC-Ag was found to be negative at 2 months postoperatively, s-SCC-Ag was found to be six times positive despite no signs of recurrence. The s-p53-Ab titers constantly decreased to less than the cutoff value at 6 months postoperatively and continuously decreased over 5 years postoperatively. Finally, s-p53-Ab titers became less than the detection limit value at 60 months postoperatively. No recurrence was observed throughout the postoperative course. This case report is the first to describe the five-year monitoring of postoperative changes in s-p53 Ab titers in a patient with locally advanced esophageal squamous cell carcinoma without recurrence. s-p53-Ab titers seemed to be more useful than s-SCC-Ag for disease monitoring in this case. PMID- 29497978 TI - Repeated Clostridium difficile infection after living donor liver transplantation. AB - Liver transplant recipients are considered to be at high risk for Clostridium difficile infection, with an incidence of 2.7-8.0%, which is three times higher than that among other patients. A case of a patient who suffered from pseudomembranous colitis five times after living donor liver transplantation is reported. A 60-year-old woman underwent splenectomy and living donor liver transplantation using the left lobe of her spouse for primary biliary cirrhosis. The patient made a satisfactory recovery, except for splenic vein thrombosis. She was discharged on postoperative day 36; however, she developed pseudomembranous colitis due to Clostridium difficile infection five times within 6 months after transplant and was treated with oral vancomycin each time. At the fifth recurrence of pseudomembranous colitis, the patient received vancomycin taper treatment, dietary counseling, and repeat instructions regarding hand hygiene and house cleaning. The patient recovered and is currently well without recurrence of Clostridium difficile infection 36 months after living donor liver transplantation. PMID- 29497979 TI - A Novel Frameshift CACNA1A Mutation Causing Episodic Ataxia Type 2. PMID- 29497980 TI - Prevalence of Depressive Disorders in Individuals with Autism Spectrum Disorder: a Meta-Analysis. AB - Substantial uncertainty exists about the prevalence of depressive disorders in individuals with autism spectrum disorder (ASD). This meta-analysis quantitatively summarized studies that assessed the lifetime and current prevalence of unipolar depressive disorders in children, adolescents, and adults with ASD. We also examined demographic, methodological, and study moderators. This meta-analysis adhered to PRISMA guidelines. A total of 7857 articles were identified through 5 databases (PubMed, Web of Science, PYSCInfo, CINAHL, ProQuest Dissertations and Theses), forward searches, and backward searches. Two reviewers independently screened articles and extracted data. Sixty-six articles met inclusion criteria. Results indicated that the pooled lifetime and current prevalence was 14.4% (95% CI 10.3-19.8) and 12.3% (95% CI 9.7-15.5), respectively. Rates of depressive disorders were highest among studies that used a standardized interview to assess depressive disorders (lifetime = 28.5%, 95% CI 20.1-38.8; current = 15.3%, 95% CI 11.0-20.9) and required participants to report on their own depressive symptoms (lifetime = 48.6%, 95% CI 33.3-64.2; current = 25.9%, 95% CI 17.0-37.3). Rates were also higher in studies that included participants with higher intelligence. Lifetime, but not current, prevalence was positively associated with age and the proportion of the sample that was White. In conclusion, we found that the rates of depressive disorders are high among individuals with ASD. Compared to typically developing individuals, individuals with ASD are 4-times more likely to experience depression in their lifetime. These results suggest that individuals with ASD should be regularly screened and offered treatment for depression. PMID- 29497981 TI - Bioprospecting of Diaporthe terebinthifolii LGMF907 for antimicrobial compounds. AB - Antibiotic-resistant bacteria have been observed with increasing frequency over the past decades, driving the search for new drugs and stimulating the interest in natural products sources. Endophytic fungi from medicinal plants represent a great source of novel bioactive compounds useful to pharmaceutical and agronomical purposes. Diaporthe terebinthifolii is an endophytic species isolated from Schinus terebinthifolius, a plant used in popular medicine for several health problems. The strain D. terebinthifolii LGMF907 was previously reported by our group to produce secondary metabolites with biological activity against phytopathogens. Based on these data, strain LGMF907 was chosen for bioprospecting against microorganisms of clinical importance and for characterization of major secondary metabolites. In this study, different culture conditions were evaluated and the biological activity of this strain was expanded. The crude extracts demonstrated high antibacterial activity against Escherichia coli, Micrococcus luteus, Saccharomyces cerevisiae, methicillin-sensitive Staphylococcus aureus, and methicillin-resistant S. aureus. The compounds diaporthin and orthosporin were characterized and also showed activity against the clinical microorganisms evaluated. This study discloses the first isolation of diaporthin and orthosporin from D. terebinthifolii, and revealed the potential of this endophytic fungus to produce secondary metabolites with antimicrobial activity. PMID- 29497982 TI - PET imaging of tau protein targets: a methodology perspective. AB - The two neuropathological hallmarks of Alzheimer's disease (AD) are amyloid [Formula: see text] plaques and neurofibrillary tangles of tau protein. Fifteen years ago, Positron Emission Tomography (PET) with Pittsburgh Compound B (11C PiB) enabled selective in-vivo visualization of amyloid-[Formula: see text] plaque deposits and has since provided valuable information about the role of amyloid-[Formula: see text] deposition in AD. The progression of tau deposition has been shown to be highly associated with neuronal loss, neurodegeneration, and cognitive decline. Until recently it was not possible to visualize tau deposition in-vivo, but several tau PET tracers are now available in different stages of clinical development. To date, no tau tracer has been approved by the Food and Drug Administration for use in the evaluation of AD or other tauopathies, despite very active research efforts. In this paper we review the recent developments in tau PET imaging with a focus on in-vivo findings in AD and discuss the challenges associated with tau tracer development, the status of development and validation of different tau tracers, and the clinical information these provide. PMID- 29497983 TI - Caring for Children with Special Health Care Needs: Profiling Pediatricians and Their Health Care Resources. AB - Background and Objectives Pediatricians face numerous challenges in providing care for children with special health care needs (CSHCN). Few studies have described health care resources available to support pediatricians to care for CSHCN. This study investigated available resources to care for CSHCN and factors associated with having a greater proportion of CSHCN in practice. Methods We conducted a statewide survey of active members of the American Academy of Pediatrics in California to study pediatric subspecialty care access, community and office resources and practice barriers. We performed a logistic regression model on having an "above average proportion" of CSHCN in practice, adjusting for demographics, practice type (rural vs. suburban/urban) and medical resources, care satisfaction, and ease of subspecialty access. Results Our response rate was 50.2% (n = 1290); 75% of respondents reported providing some primary care services, with many primary care pediatricians caring for a high proportion of CSHCN. Pediatricians reported an average of 28% CSHCN in their practices. Rural pediatricians lacked subspecialty access (10-59% reporting no access to the various subspecialties). Factors relating to higher CSHCN in practice included being in academic medical centers and satisfaction in caring for CSHCN. Conclusions Pediatricians report lack of access to mental health services, care coordination and case management. Academic medical centers and higher physician satisfaction in care delivery for CSHCN are associated with more CSHCN in practice. Promoting ways to support pediatricians, such as practice collaboration with behavioral specialists, may be necessary to encourage primary care pediatricians to provide medical homes for CSHCN. PMID- 29497984 TI - Impact of Maternal Infant Weight Perception on Infant Feeding and Dietary Intake. AB - Introduction Obesity is a global problem that is challenging to prevent and expensive to treat. Early childhood interventions show promise in establishing lifelong healthy eating patterns, however a better understanding of how parental feeding practices develop is needed. The study aimed to investigate maternal perception of infant weight and its relationship to feeding practices and infant dietary intake. Methods A questionnaire was completed by 263 Queensland mothers of infants aged between 5 and 13 months. Logistic regression was used to describe the association between maternal feeding practices (restriction, pressure-to-eat, monitoring), parenting style (warmth, hostility), infant weight concern and infant dietary intake. Correlation and linear regression were used to identify relationships between maternal feeding practices, parenting style, infant weight concern and infant weight. Results Mothers were found to be more concerned about underweight than overweight, misjudge infants as being underweight and failed to recognise overweight infants. Underweight concern was associated with infant weight (r = -0.27, p < 0.01), early introduction of solids (OR 0.24, CI 0.11 0.51) and pressure-to-eat (r = 0.19, p < 0.01). Pressure-to-eat was associated to maternal perception of infant weight (r = - 0.21, p < 0.01), infant weight (r = - 0.17, p < 0.05) and lower fruit and vegetable intake (OR 0.50, CI 0.27-0.92). Restrictive feeding practices were correlated to overweight concern (r = 0.08, p < 0.05). Discussion Maternal infant weight perception and concerns are related to control feeding practices which can be detrimental to infant dietary intake. Inability to recognise healthy weight may ignite these concerns or fail to address infant feeding risk factors. Discussing healthy growth should be a fundamental component of strategies to support healthy infant feeding and eating. PMID- 29497985 TI - Optimal Gestational Weight Gain for Women with Gestational Diabetes and Morbid Obesity. AB - OBJECTIVES: Our aim was to investigate the greatest gestational weight gain (GWG) without adverse pregnancy complications in women with gestational diabetes mellitus (GDM) and morbid obesity. METHODS: An observational retrospective study including 3284 patients with single pregnancies and GDM was completed. Of the patients, 131 (4.0%) were classified as having pre-pregnancy morbid obesity (BMI >= 35 kg/m2). Perinatal complications were compared among BMI groups. In the group with morbid obesity, GWG threshold values to predict outcomes were examined based on sensitivity and specificity values under the receiver operating characteristic curve. RESULTS: GWG was higher in mothers with morbid obesity and macrosomic neonates: 11.3 (4.4-15.7) versus 4.8 (1.5-8.2) kg (p = 0.033). The GWG and neonatal ponderal index were positively correlated (r = 0.305, p = 0.001). The GWG was 7.0 (2.9-11.6) kg in women with hypertensive disorder versus 4.5 (1.0 7.5) kg in normotensive women (p = 0.017). A GWG above 5 kg was a risk factor for macrosomia (87.8% sensitivity, 54.7% specificity) and hypertensive disorder (70.0% sensitivity, 48.4% specificity). GWG associations were maintained after controlling for glycemic control, maternal and gestational age, parity, smoking and neonatal sex. CONCLUSIONS FOR PRACTICE: A GWG below 5 kg is recommended for women with GDM and morbid obesity. In these women, adequate GWG may prevent macrosomia, fetal overgrowth and hypertensive disorder. PMID- 29497986 TI - Liver cirrhosis and cancer: comparison of mortality. AB - BACKGROUND: Liver cirrhosis is known to have low survival rate, and its assessment in relation with other fatal diseases will help us design appropriate health interventions. This study compares the mortality of liver cirrhosis with that of five major cancers (lung, colorectal, stomach, liver, and breast cancers). METHODS AND RESULTS: We used the National Health Insurance Service National Sample Cohort (NHIS-NSC) which provides data for 1,025,340 representative samples of the 46,605,433 people in Korea from 2002 to 2010. During the 8 years, 800 out of 2609 liver cirrhosis patients died and 1316 out of 4852 patients with the five major cancers died. When we estimated the mortality between liver cirrhosis and five major cancers, the relative mortality for liver cirrhosis was greater [hazard ratio 1.47 (95% CI 1.28-1.67) after age, gender, area of residence, type of insurance, insurance premium level (proxy for income level), and comorbidities were adjusted for]. When a sensitivity analysis was performed by excluding patients with both liver cirrhosis and one of the five cancers, the relative mortality was still greater for liver cirrhosis [hazard ratio 1.27 (95% CI 1.10-1.47)]. Furthermore, when we limited liver cirrhosis patients to those with decompensated liver cirrhosis, the relative mortality of decompensated liver cirrhosis was even greater than that of the five cancers [hazard ratio 1.82 (95% CI 1.51-2.20)]. CONCLUSIONS: The mortality of liver cirrhosis is greater than that of the five major cancers. This implies the need to prioritize appropriate health interventions for liver cirrhosis. PMID- 29497987 TI - Right Care in Hospital Medicine: Co-creation of Ten Opportunities in Overuse and Underuse for Improving Value in Hospital Medicine. PMID- 29497988 TI - Gender Differences During Toddlerhood in Autism Spectrum Disorder: A Prospective Community-Based Longitudinal Follow-Up Study. AB - Relatively few studies have examined gender differences in infants and toddlers, and most focus on clinically referred samples or high-risk infant cohorts. The current study aimed to examine gender differences in early autism manifestations and cognitive development in a community-ascertained sample. In total, 46 males and 21 females with ASD were seen at approximately 24 and 48 months of age. No significant gender differences were observed on overall cognitive ability, verbal skills, non-verbal skills, overall autism severity, or restricted repetitive behaviours. However, females were found to exhibit more social communication impairments than males. These findings may indicate that female toddlers with less severe or different, social communication impairments may be more likely to be missed during routine surveillance during toddlerhood. PMID- 29497990 TI - Transmembrane domain dependent inhibitory function of FcgammaRIIB. AB - FcgammaRIIB, the only inhibitory IgG Fc receptor, functions to suppress the hyper activation of immune cells. Numerous studies have illustrated its inhibitory function through the ITIM motif in the cytoplasmic tail of FcgammaRIIB. However, later studies revealed that in addition to the ITIM, the transmembrane (TM) domain of FcgammaRIIB is also indispensable for its inhibitory function. Indeed, recent epidemiological studies revealed that a non-synonymous single nucleotide polymorphism (rs1050501) within the TM domain of FcgammaRIIB, responsible for the I232T substitution, is associated with the susceptibility to systemic lupus erythematosus (SLE). In this review, we will summarize these epidemiological and functional studies of FcgammaRIIB-I232T in the past few years, and will further discuss the mechanisms accounting for the functional loss of FcgammaRIIB-I232T. Our review will help the reader gain a deeper understanding of the importance of the TM domain in mediating the inhibitory function of FcgammaRIIB and may provide insights to a new therapeutic target for the associated diseases. PMID- 29497989 TI - SCFbeta-TRCP E3 ubiquitin ligase targets the tumor suppressor ZNRF3 for ubiquitination and degradation. AB - Wnt signaling has emerged as a major regulator of tissue development by governing the self-renewal and maintenance of stem cells in most tissue types. As a key upstream regulator of the Wnt pathway, the transmembrane E3 ligase ZNRF3 has recently been established to play a role in negative regulation of Wnt signaling by targeting Frizzled (FZD) receptor for ubiquitination and degradation. However, the upstream regulation of ZNRF3, in particular the turnover of ZNRF3, is still unclear. Here we report that ZNRF3 is accumulated in the presence of proteasome inhibitor treatment independent of its E3-ubiquitin ligase activity. Furthermore, the Cullin 1-specific SCF complex containing beta-TRCP has been identified to directly interact with and ubiquitinate ZNRF3 thereby regulating its protein stability. Similar with the degradation of beta-catenin by beta-TRCP, ZNRF3 is ubiquitinated by beta-TRCP in both CKI-phosphorylation- and degron-dependent manners. Thus, our findings not only identify a novel substrate for beta-TRCP oncogenic regulation, but also highlight the dual regulation of Wnt signaling by beta-TRCP in a context-dependent manner where beta-TRCP negatively regulates Wnt signaling by targeting beta-catenin, and positively regulates Wnt signaling by targeting ZNRF3. PMID- 29497991 TI - Cancer-associated fibroblasts affect breast cancer cell gene expression, invasion and angiogenesis. AB - PURPOSE: It has been reported that stromal cell features may affect the clinical outcome of breast cancer patients. Cancer associated fibroblasts (CAFs) represent one of the most abundant cell types within the breast cancer stroma. Here, we aimed to explore the influence of CAFs on breast cancer gene expression, as well as on invasion and angiogenesis. METHODS: qRT-PCR was used to evaluate the expression of several cancer progression related genes (S100A4, TGFbeta, FGF2, FGF7, PDGFA, PDGFB, VEGFA, IL-6, IL-8, uPA, MMP2, MMP9, MMP11 and TIMP1) in the human breast cancer-derived cell lines MCF-7 and MDA-MB-231, before and after co culture with CAFs. Stromal mononuclear inflammatory cell (MIC) MMP11 expression was used to stratify primary tumors. In addition, we assessed the in vitro effects of CAFs on both MDA-MB-231 breast cancer cell invasion and endothelial cell (HUVEC) tube formation. RESULTS: We found that the expression levels of most of the genes tested were significantly increased in both breast cancer-derived cell lines after co-culture with CAFs from either MMP11+ or MMP11- MIC tumors. IL 6 and IL-8 showed an increased expression in both cancer-derived cell lines after co-culture with CAFs from MMP11+ MIC tumors. We also found that the invasive and angiogenic capacities of, respectively, MDA-MB-231 and HUVEC cells were increased after co-culture with CAFs, especially those from MMP11+ MIC tumors. CONCLUSIONS: Our data indicate that tumor-derived CAFs can induce up-regulation of genes involved in breast cancer progression. Our data additionally indicate that CAFs, especially those derived from MMP11+ MIC tumors, can promote breast cancer cell invasion and angiogenesis. PMID- 29497994 TI - The use of extracorporeal membrane oxygenation in the anticipated difficult airway: a case report and systematic review. AB - While extracorporeal membrane oxygenation (ECMO) is an effective method of oxygenation for patients with respiratory failure, further refinement of its incorporation into airway guidelines is needed. We present a case of severe glottic stenosis from advanced thyroid carcinoma in which gas exchange was facilitated by veno-arterial ECMO prior to achieving a definitive airway. We also conducted a systematic review of the MEDLINE, EMBASE, CINAHL, and Web of Science databases, using the keywords "airway/ tracheal obstruction", "anesthesia", "extracorporeal", and "cardiopulmonary bypass" to identify reports where ECMO was initiated as the a priori method of oxygenation during difficult airway management.Thirty-six papers were retrieved discussing the use of ECMO or cardiopulmonary bypass (CPB) for the management of critical airway obstruction. Forty-five patients underwent pre-induction of anesthesia institution of CPB or ECMO for airway obstruction. The patients presenting with critical airway obstruction had a range of airway pathologies with tracheal tumours (31%), tracheal stenosis (20%), and head and neck cancers (20%) being the most common. All cases reported a favourable patient outcome with all patients surviving to hospital discharge without significant complications.While most practitioners are familiar with the fundamental airway techniques of bag-mask ventilation, supraglottic airway use, tracheal intubation, and front-of-neck airway access for oxygenation, these techniques have limitations in managing patients with pre existing severe airway obstruction. The use of ECMO should be considered in patients with severe (or near-complete) airway obstruction secondary to anterior neck or tracheal disease. This approach can provide essential tissue oxygenation while attempts to secure a definitive airway are carried out in a controlled environment. PMID- 29497992 TI - The Management of Paediatric Functional Abdominal Pain Disorders: Latest Evidence. AB - Recurrent abdominal pain (RAP) is one of the most common health complaints in both children and adults. Although RAP is considered a functional disorder rather than an organic disease, affected children and their families can still experience anxiety and concerns that can interfere with school, sports, and regular daily activities and lead to frequent attendances at pediatric emergency departments or pediatric gastroenterology clinics. Our review shows experts do not agree on a universally proven management that will work on every child presenting with functional abdominal pain (FAP). Treatment strategies include both non-pharmacological and pharmacological options. Non-pharmacological treatments are usually very well accepted by both children and their parents and are free from medication side effects. Nevertheless, they may be as effective as the pharmacological interventions; therefore, according to many experts and based on the majority of current evidence, a non-pharmacological approach should be the first intervention attempt in children with RAP. In particular, the importance of the bio-psychosocial approach is highlighted, as a majority of children will improve with counselling and reassurance that no serious organic pathologies are suspected, especially when the physician establishes a trustful relationship with both the child and their family. Placebo and pharmacological interventions could be attempted when the bio-psychosocial approach is not applicable or not efficacious. In some difficult cases, finding an effective treatment for FAP can be a challenge, and a number of strategies may need to be tried before symptoms are controlled. In these cases, a multidisciplinary team, comprising a pediatric gastroenterologist, dietician, psychologist, and psychotherapist, is likely to be successful. PMID- 29497995 TI - Raising Rates of Childhood Vaccination: The Trade-off Between Coercion and Trust. AB - Vaccination is a highly effective public health strategy that provides protection to both individuals and communities from a range of infectious diseases. Governments monitor vaccination rates carefully, as widespread use of a vaccine within a population is required to extend protection to the general population through "herd immunity," which is important for protecting infants who are not yet fully vaccinated and others who are unable to undergo vaccination for medical or other reasons. Australia is unique in employing financial incentives to increase vaccination uptake, mainly in the form of various childcare payments and tax benefits linked to timely, age-appropriate vaccination. Despite relatively high compliance with the childhood vaccination schedule, however, the Australian government has determined that rates should be higher and has recently introduced policy that includes removing certain tax and childcare benefits for non vaccinators and formally disallowing conscientious objection to vaccination ("No Jab No Pay"). In addition, it has raised the possibility of banning unvaccinated children from childcare centres ("No Jab No Play"). This article examines the impact of coercive approaches to childhood vaccination and raises the question of the ethical justification of health policy initiatives based on coercion. We consider the current evidence regarding childhood vaccination in Australia, the small but real risks associated with vaccination, the ethical requirement for consent for medical procedures, and the potential social harms of targeting non vaccinators. We conclude that the evidence does not support a move to an increasingly mandatory approach that could only be delivered through paternalistic, coercive clinical practices. PMID- 29497996 TI - Defective activation of the MAPK/ERK pathway, leading to PARP1 and DNMT1 dysregulation, is a common defect in IgA nephropathy and Henoch-Schonlein purpura. AB - Studies on IgA nephropathy (IgAN) have identified, through GWAS, linkage analysis, and pathway scanning, molecular defects in familial and sporadic IgAN patients. In our previous study, we identified a novel variant in the SPRY2 gene that segregates with the disease in one large family. The functional characterization of this variant led us to discover that the MAPK/ERK pathway was defective not only in this family, but also in two sporadic IgAN patients wild type for SPRY2. In the present study, we have deepened the molecular analysis of the MAPK/ERK pathway and extended our evaluation to a larger cohort of sporadic patients and to one additional family. We found that the ERK pathway is defective in IgAN patients and in patients affected by another IgA-mediated disorder, Henoch-Schonlein purpura (HSP). Furthermore, we found that two other proteins, PARP1 and DNMT1, respectively involved in DNA repair and in antibody class switching and methylation maintenance duties, were critically downregulated in IgAN and HSP patients. This study opens up the possibility that defective ERK activation, in some patients, leads to PARP1 and DNMT1 downregulation suggesting that IgAN could be the consequence of a dysregulated epigenetic maintenance leading to the upregulation of several genes. In particular, PARP1 could be used as a potential biomarker for the disease. PMID- 29497997 TI - Association Between Chronic Exposure to Tobacco Smoke and Accumulation of Toxic Metals in Hair Among Pregnant Women. AB - Tobacco smoke contains various toxic heavy metals that individuals are exposed to when they smoke. Despite the presence of heavy metals in tobacco smoke, the relationship between smoking and the accumulation of toxic metals in pregnant women after long-term exposure remains under discussion. We examined the association between long-term exposure to tobacco smoke and the accumulation of toxic metals in the hair of female participants. Our study recruited 252 women from the Shanxi and Hebei provinces of Northern China; these participants were self-reported non-active smokers, and had previously delivered healthy babies without birth defects. Scalp hair was collected and analyzed for nicotine and cotinine and five potentially toxic metals (specifically, silver, chromium, cadmium, mercury, and lead). Our results showed significant positive correlations between cotinine and four metals, including silver (r = 0.369, p < 0.001), cadmium (r = 0.185, p < 0.01), mercury (r = 0.161, p < 0.05), and lead (r = 0.243, p < 0.001). Significant positive correlations were also found between nicotine and three metals-specifically silver (r = 0.331, p < 0.001), cadmium (r = 0.176, p < 0.01), and lead (r = 0.316, p < 0.001). A logistic regression model showed significant associations between cotinine and potentially toxic metals including mercury, silver, and lead (with or without adjusting for potential confounders). We thus conclude that long-term passive smoking could potentially increase the exposure level of toxic metals including lead, silver, and mercury in our study, which are especially harmful for pregnant women and their unborn fetus. PMID- 29497998 TI - Hair Trace Elements in Overweight and Obese Adults in Association with Metabolic Parameters. AB - The objective of the present study was to investigate the level of toxic and essential trace elements in hair of adult overweight and obese persons as well as its association with metabolic parameters. Hair trace element levels were assessed using inductively coupled plasma mass-spectrometry in 112 overweight and obese patients and 106 lean controls. Serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), glucose, uric acid (UA) levels, and cholinesterase (CE) and gamma-glutamyltransferase (GGT) activity were also assessed. Excessive body weight significantly affected hair trace element levels. In particular, hair Co (33%), Cu (13%), I (30%), Mg (2-fold), Mn (25%), Zn (17%), and Ni (21%) levels were lower, whereas Al (14%) and As levels were higher in comparison to those in the control group. Correlation analysis demonstrated the most significant correlations for hair Mg with body weight, BMI, systolic and diastolic blood pressure, and UA, and for hair Al with body weight, BMI, TC, glucose, TG, CE, GGT, and UA. Multiple regression analysis demonstrated that trace elements were not associated with TC and LDL-C levels neither in crude nor in adjusted models. In turn, crude and adjusted models accounted for 25 and 43% of serum TG variance. The most significant associations were observed for hair Al, Fe, Si, and V in adjusted model. The obtained data demonstrate that obesity-related metabolic disorders may be at least partially mediated by altered trace element and mineral levels. PMID- 29497999 TI - Supplementation of Cr Methionine During Dry Period of Dairy Cows and Its Effect on Some Production and Biochemical Parameters During Early Lactation and on Immunity of Their Offspring. AB - This study aimed to investigate the effect of dietary chromium methionine (Cr Met) supplementation on the production and immunological parameters of dairy cows during the dry and postpartum period and their offspring. Forty-five Holstein transition cows were randomly assigned to experimental groups with control, positive control (levamisole-injected cows), and treatment groups (5 g dietary Cr Met/day/cow). Production, immunological, and biochemical parameters were analyzed during the dry and postpartum period. Result revealed that in dry cows, monocyte count and serum glucose level significantly (p < 0.05) decrease in Cr supplemented cows over control. Similarly, after parturition, the numbers of all immune cells (except monocytes) decreased significantly (p < 0.05); however, serum IgG, ALT, AST, glucose levels, and total leucocyte, neutrophil, and leucocyte count were increased significantly (p < 0.05) in Cr-supplemented cows over the control group. Days in milk (DIM) of treatment cows were significantly (p < 0.05) decreased over the control group; however, no significant (p > 0.05) differences were observed on milk production, colostrum, and IgG concentrations. As a conclusion, the supplementation of Cr had positive effects on immune cells of cows after parturition; however, serum biochemical parameters remained unaffected. Also, there were significant differences on the number of total leucocyte and neutrophil, on the activity of ALT at birthday, and on the number of total leucocyte at postpartum for calves. PMID- 29498000 TI - Economic Analysis of First-Line Treatment with Cetuximab or Panitumumab for RAS Wild-Type Metastatic Colorectal Cancer in England. AB - BACKGROUND: Combination therapies with cetuximab (Erbitux(r); Merck Serono UK Ltd) and panitumumab (Vectibix(r); Amgen UK Ltd) are shown to be less effective in adults with metastatic colorectal cancer who have mutations in exons 2, 3 and 4 of KRAS and NRAS oncogenes from the rat sarcoma (RAS) family. OBJECTIVE: The objective of the study was to estimate the cost effectiveness of these drugs in patients with previously untreated RAS wild-type (i.e. non-mutated) metastatic colorectal cancer, not eligible for liver resection at baseline, from the UK National Health Service and Personal Social Services perspective. METHODS: We constructed a partitioned survival model to evaluate the long-term costs and benefits of cetuximab and panitumumab combined with either FOLFOX (folinic acid, fluorouracil and oxaliplatin) or FOLFIRI (folinic acid, fluorouracil and irinotecan) vs. FOLFOX or FOLFIRI alone. The economic analysis was based on three randomised controlled trials. Costs and quality-adjusted life-years were discounted at 3.5% per annum. RESULTS: Based on the evidence available, both drugs fulfil the National Institute for Health and Care Excellence's end-of-life criteria. In the analysis, assuming discount prices for the drugs from patient access schemes agreed by the drug manufacturers with the Department of Health, predicted mean incremental cost-effectiveness ratios for cetuximab + FOLFOX, panitumumab + FOLFOX and cetuximab + FOLFIRI compared with chemotherapy alone appeared cost-effective at the National Institute for Health and Care Excellence's threshold of L50,000 per quality-adjusted life-year gained, applicable to end-of-life treatments. CONCLUSION: Cetuximab and panitumumab were recommended by the National Institute for Health and Care Excellence for patients with previously untreated RAS wild-type metastatic colorectal cancer, not eligible for liver resection at baseline, for use within the National Health Service in England. Both treatments are available via the UK Cancer Drugs Fund. PMID- 29498001 TI - Once Bitten Twice Shy: Thinking Carefully Before Adopting the EQ-5D-5L. PMID- 29498002 TI - The Determinants of Household Out-of-Pocket (OOP) Medical Expenditure in Rural Bangladesh. AB - BACKGROUND: The Government of Bangladesh has a National Healthcare Strategy 2012 2032 that reiterates a goal to achieve universal health coverage (UHC) by the year 2032. To achieve the goal, the government has set up a strategy to reduce the share of out-of-pocket (OOP) expenditure from the current 64% of the total household healthcare costs to 32% at the national level. As the majority of the people live in the rural areas, and the rural people are generally poor, the success of the strategy relies predominantly on any type of pro-poor healthcare policy and strategy. OBJECTIVE: To estimate if there is any feedback effect in the healthcare costs model and to estimate relative contributions of various determinants to OOP medical expenditure in rural Bangladesh. METHODS: This study used an econometric approach and a system of simultaneous equations models. The OOP expenditure was measured by household medical expenditure, which is a sum of expenditures for medicine, ayurvedic, various kinds of tests, hospitalization, and dental-related, incidental and other health-related costs. The feedback effect hypothesis is tested by the level of statistically significant dependent variables of the three equations used in the system of simultaneous equations model. The relative importance of the determinants of OOP expenditures was measured by the size of standardised coefficients of the determinants. RESULTS: There is a feedback effect between the three dependent variables-medical expenditure, sickness of the household members and the selection of healthcare provider. We also find that although the selection of private healthcare facilities is relatively the most important determinant of OOP expenditures in the rural areas, the sickness of the members of a household and the selection of healthcare provider together have a real effect on the OOP expenditure in rural Bangladesh. CONCLUSIONS: Bangladesh needs a holistic approach to undertake any strategy; private healthcare facilities are relatively the most important source of high medicine costs; hence, the supply of medicine and its price should be given attention on a priority basis for pro-poor policy framing in conjunction with healthcare insurance and motivation to consult doctors rather than pharmacists in case of sickness. PMID- 29498003 TI - Phenolic acid-tethered isoniazid for abrogation of drug-induced hepatotoxicity: design, synthesis, kinetics and pharmacological evaluation. AB - Morphological and metabolic aberrations in the liver caused by long-term use of anti-tubercular agent isoniazid (INH) have been an issue of great concern in tuberculosis treatment. To resolve this issue, a novel hepatoprotective prodrug strategy was developed by combining the antioxidant property of phenolic acids with INH moiety for probable synergistic effect. In this work, INH was conjugated with phenolic antioxidants using Schotten-Baumann reaction through biocleavable amide linkage. Synthesized prodrugs were characterized by spectral analysis and in vitro release studies were carried out using HPLC. They were found to be stable in acidic (pH 1.2), basic (pH 7.4) buffers, stomach homogenates of rat whereas hydrolyzed significantly (56.03-88.62%) in intestinal homogenates over a period of 6 h. Further their hepatoprotective potential was evaluated in male Wistar rats by performing liver function tests, oxidative stress markers, and histopathology studies. All the prodrugs were effective in abating oxidative stress and re-establishing normal hepatic physiology. Especially the effect of prodrugs of INH with gallic acid and syringic acid in restoring levels of enzymes superoxide dismutase and glutathione peroxidase and abrogating liver damage was noteworthy. The findings of this investigation demonstrated that reported prodrugs can add safety and efficacy to future clinical protocols of tuberculosis treatment. PMID- 29498004 TI - Sustained-release amorphous solid dispersions. AB - The use of amorphous solid dispersions (ASD) to overcome poor drug solubility has gained interest in the pharmaceutical industry over the past decade. ASDs are challenging to formulate because they are thermodynamically unstable, and the dispersed drugs tend to recrystallize. Until now, most research on ASDs has focused on immediate-release formulations, supersaturation, and stability; only a few studies have recently reported on the manufacturing of sustained-release ASDs. Sustained-release ASDs can minimize the frequency of administration and prevent high concentrations that can lead to toxicity. Sustained-release ASDs can also decrease the reprecipitation rate in the medium, which can lead to increased bioavailability. However, sustained-release ASDs also pose some significant challenges, such as intramatrix recrystallization, inhibition of drug release as a result of drug-polymer gelling, and low supersaturation due to a slow dissolution rate. This review details the challenges and the formulation approaches that have been investigated to manufacture sustained-release ASDs. In particular, the advantages and drawbacks of hydrophilic polymers, hydrophobic polymers, and lipid-based systems are discussed. PMID- 29498005 TI - Soluble Factors from Human Olfactory Neural Stem/Progenitor Cells Influence the Fate Decisions of Hippocampal Neural Precursor Cells. AB - Neurogenesis plays a significant role during adulthood, and the observation that neural stem cells reside in the central nervous system and the olfactory epithelium has attracted attention due to their importance in neuronal regeneration. In addition, soluble factors (SFs) release by neural stem cells may modulate the neurogenic process. Thus, in this study, we identified the SFs released by olfactory human neural stem/progenitor cells (hNS/PCs-OE). These cells express Ki67, nestin, and betaIII-tubulin, indicating their neural lineage. The hNS/PCs-OE also express PSD95 and tau proteins during proliferation, but increased levels are observed after differentiation. Thus, we evaluated the effects of SFs from hNS/PCs-OE on the viability, proliferation, and differentiation potential of adult murine hippocampal neural precursor cells (AHPCs). SFs from hNS/PCs-OE maintain cells in the precursor and proliferative stages and mainly promote the astrocytic differentiation of AHPCs. These effects involved the activation, as measured by phosphorylation, of several proteins (Erk1/2; Akt/PRAS40/GSK3beta and JAK/STAT) involved in key events of the neurogenic process. Moreover, according to the results from the antibody-based microarray approach, among the soluble factors, hNS/PCs-OE produce interleukin-6 (IL-6) and neurotrophin 4 (NT4). However, residual epidermal growth factor (EGF) was also detected. These proteins partially reproduced the effects of SFs from hNS/PCs-OE on AHPCs, and the mechanism underlying these effects is mediated by Src proteins, which have been implicated in EGF-induced transactivation of TrkB receptor. The results of the present study suggest the potential use of SFs from hNS/PCs-OE in controlling the differentiation potential of AHPCs. Thus, the potential clinical relevance of hNS/PCs-OE is worth pursuing. PMID- 29498006 TI - Inhibition of Cyclooxygenase-2 (COX-2) Initiates Autophagy and Potentiates MPTP Induced Autophagic Cell Death of Human Neuroblastoma Cells, SH-SY5Y: an Inside in the Pathology of Parkinson's Disease. AB - Cyclooxygenase-2 or COX-2 has been known to be crucial for Parkinson's disease (PD) pathogenesis; however, its exact role is still not known. We first time report that inhibition of COX-2 promotes 1-methyl-4-phenyl 1,2,3,6 tetrahydropyridine (MPTP)-induced neuronal cell death via induction of autophagic mechanisms. We found that treatment with MPTP induced cell death of neuroblastoma cells SH-SY5Y in a dose dependent manner. Treatment of MPTP has also upregulated the expressions of autophagic proteins such as LC3, beclin, ATG-5, and p62. Interestingly, nimesulide, a preferential COX-2 inhibitor, further potentiated the MPTP-induced cell death of human neuroblastoma cells. Treatment of nimesulide with MPTP further potentiated expressions of p62, ATG-5, beclin-1, LC3 autophagic proteins. Furthermore, nimesulide with MPTP increased apoptotic protein cleaved caspase-3 and also induced expression of p53 gene. Interestingly, it was observed that Akt inhibitor significantly increased MPTP-induced cell death of neuroblastoma cells. However, (-) deprenyl, a monoamine oxidase B (MAO B) inhibitor, attenuated MPTP-induced autophagic response and protected cell death. The prior treatment with prostaglandin E2 protected against nimesulide induced death of neuronal cells. This study confirms that neuroinflammation is associated to the autophagy and may be one of the main pathological mechanisms in Parkinson's disease and other inflammation-associated disorders. PMID- 29498007 TI - Erythropoietin Upregulates Brain Hemoglobin Expression and Supports Neuronal Mitochondrial Activity. AB - Multiple sclerosis (MS) is a neuro-inflammatory and demyelinating disease. Downregulation of neuronal mitochondrial gene expression and activity have been reported in several studies of MS. We have previously shown that hemoglobin-beta (Hbb) signals to the nucleus of neurons and upregulates H3K4me3, a histone mark involved in regulating cellular metabolism and differentiation. The present study was undertaken to evaluate the effect of erythropoietin (EPO) on the upregulation of hemoglobin and mitochondrial-associated neuroprotection. We found that administering EPO (5000 IU/kg intraperitoneally) to mice upregulated brain Hbb expression, levels of H3K4me3, expression of mitochondrial complex III, complex V, and mitochondrial respiration. We also found that the neuronal mitochondrial metabolite N-acetylaspartate (NAA), a marker of neuronal mitochondrial activity, was increased with EPO treatment. Further, we measured the effects of EPO on preventing mitochondrial deficits in the cuprizone toxic demyelinating mouse model of MS. We found that EPO prevented cuprizone-mediated decreases in Hbb, complex III, and NAA. Our data suggest that EPO mediated regulation of Hbb supports neuronal energetics and may provide neuroprotection in MS and other neurodegenerative diseases where a dysfunction of mitochondria contributes to disease. PMID- 29498008 TI - Histamine Excites Striatal Dopamine D1 and D2 Receptor-Expressing Neurons via Postsynaptic H1 and H2 Receptors. AB - The central histaminergic nervous system, originating from the tuberomammillary nucleus (TMN) of the hypothalamus, widely innervates almost the whole brain, including the basal ganglia. Intriguingly, the histaminergic system is altered in parkinsonian patients. Yet, little is known about the effect and mechanisms of histamine on different types of neurons in the basal ganglia circuitry. Here, by using anterograde tracing, immunostaining, patch clamp recording, and single-cell qPCR techniques, we investigate the histaminergic afferents in the striatum, the major input structure of the basal ganglia, as well as the effect of histamine on the striatal GABAergic medium spiny projection neurons (MSNs). We report a direct histaminergic projection from the hypothalamic TMN to the striatum in rats. Furthermore, histamine exerts a strong postsynaptic excitatory effect on both dopamine D1 and D2 receptor-expressing MSNs. The concentration-response curves and the EC50 values for histamine on these two types of MSNs are similar. In addition, dopamine D1 and D2 receptor-expressing MSNs co-express histamine H1 and H2 receptor mRNAs. Both histamine H1 and H2 receptors are co-localized on dopamine D1 and D2 receptor-expressing MSNs and co-mediate the histamine-induced excitation on the two types of neurons. These results suggest that the histaminergic afferent inputs in the striatum may modulate both dopamine D1 and D2 receptor-expressing MSNs by activation of postsynaptic histamine H1 and H2 receptors and thus serve as an important extrastriatal modulator for biasing the direct and indirect pathways to actively regulate functions of the basal ganglia and participate in the pathogenesis and pathophysiology of basal ganglia diseases. PMID- 29498009 TI - Using the Symmetry Analysis Design to Screen for Adverse Effects of Non-vitamin K Antagonist Oral Anticoagulants. AB - INTRODUCTION: Knowledge on adverse effects (AEs) related to non-vitamin K antagonist oral anticoagulants (NOACs) in real-world populations is sparse. OBJECTIVE: Our objective was to identify signals of potential AEs in patients with atrial fibrillation (AF) initiating NOAC treatment using a hypothesis-free screening approach. METHODS: Using the nationwide Danish registries, we identified patients with AF initiating dabigatran, rivaroxaban, or apixaban between 2011 and 2015 (n = 50,627). Applying a symmetry analysis design, we screened for AEs of NOAC, as reflected by new drug treatments, incident diagnoses, or procedures. For signals with the lowest number needed for one additional patient to be harmed (NNTH), we evaluated whether they likely represented genuine AEs or other types of associations. Signals assessed as potential AEs were grouped into five categories for analysis of effect modification according to patient and drug characteristics. RESULTS: Of the identified signals, 61 were classified as potential AEs. Most signals could be categorized as the following types of AEs: bleedings, non-bleeding gastrointestinal symptoms, mental disease, urinary tract disorders, and musculoskeletal symptoms. Older age and first-ever use of anticoagulants was associated with strengthening of all "NOAC-adverse effect" associations. Conversely, use of low-dose NOAC and apixaban led to attenuation of most associations. CONCLUSION: Through a symmetry analysis-based hypothesis-free screening of large-scale healthcare databases, we were able to confirm well established AEs of NOAC therapy in clinical practice as well as potential AEs that deserve further investigation. PMID- 29498010 TI - Therapeutic oligonucleotides in cardiovascular and metabolic diseases: insights for the internist. AB - The idea of using small RNA fragments (oligonucleotides) for therapeutic purposes dates back to the 1990s, following the landmark discoveries on the mechanisms of gene silencing and RNA-interference (RNA-i). However, the first applications in medicine were hampered by difficulties in chemical stabilization and efficient delivery to target tissues. Recent advances in chemical manipulation of oligonucleotides have, at least partially, bypassed such obstacles. In particular, conjugation with ligands for specific receptors allows the selective uptake of oligonucleotides by critical cells (e.g., hepatocytes), where they inhibit the synthesis of the target protein by binding the complementary mRNA and inducing its degradation. In parallel, next-generation sequencing (NGS) studies at population levels have identified a number of key molecular targets, mainly through the discovery of "human knock-outs," i.e., subjects lacking a given protein because of nonsense mutations in the corresponding gene. Such highly informative individuals are often healthy, or even protected from the development of certain diseases. Indeed, subjects with null mutations in certain genes controlling lipoprotein metabolism like PCSK9 or ANGPTL-3 have a lower risk of cardiovascular disease. Since the complete absence of such proteins does not appear to carry any negative health effect, the corresponding genes are ideal candidates for the silencing approach. Pilot clinical trials with long acting anti-PCSK9 or anti-ANGPTL-3 oligonucleotides have yielded very promising results, so that their use as "vaccines" against atherosclerosis has been suggested in the future. As therapeutic oligonucleotides can virtually target innumerable proteins, their increasing development is predicted to substantially expand the repertoire of the "biological drugs," in addition to, or even substituting, more consolidated approaches like monoclonal antibodies. PMID- 29498011 TI - Trying to prolong life no matter what, or to dignify it till the end: the dilemma of modern medicine-comment. PMID- 29498012 TI - Attempted suicide as a trigger of Takotsubo syndrome: a minireview of available case reports. PMID- 29498013 TI - Aristolochia, a nephrotoxic herb, still surfs on the Web, 15 years later. PMID- 29498014 TI - The Relationships Between Depressive Symptoms, Functional Health Status, Physical Activity, and the Availability of Recreational Facilities: a Rural-Urban Comparison in Middle-Aged and Older Chinese Adults. AB - PURPOSE: This study drew upon the ecological system theory to demonstrate rural urban differences in the relationships between the availability of recreational facilities, physical activity (PA), functional health status, and depressive symptoms in middle-aged and older Chinese adults. METHODS: Nationally representative data (n = 5949) from the Chinese Health and Retirement Longitudinal Study (CHARLS, 2011-2013) were examined using the multigroup structural equation modeling approach. RESULTS: The results suggest that higher availability of recreational facilities in the urban communities was associated with higher levels of leisure time physical activity (LTPA), better functional capacity, and less occurrence of depressive symptoms among urban participants. In contrast, LTPA engagement among rural participants was low and had negligible mitigating effects on functional decline and depressive symptoms. The findings also show that functional health status mediated the association between total PA and depressive symptoms in both rural and urban participants. However, high levels of total PA were directly associated with elevated depressive symptoms, suggesting that the context of PA and related socioeconomic factors might explain this association after the non-LTPA components were included. CONCLUSIONS: The findings highlight how complex patterns of intrapersonal, behavioral, and environmental correlates influence depressive symptoms in middle-aged and older Chinese adults. The context of PA should be considered when creating targeted strategies to prevent depressive symptoms. As an inactive lifestyle evolves with China's rapid urbanization, joint efforts from public health and urban planning should be made to promote LTPA and develop active living communities for achieving optimal health in later life. PMID- 29498015 TI - Enhanced Penetration for Axial Length Measurement of Eyes with Dense Cataracts Using Swept Source Optical Coherence Tomography: A Consecutive Observational Study. AB - INTRODUCTION: The aim of this study was to find cases in which the axial eye length could not be measured with partial coherence interferometry (PCI) technology and to assess if it could be measured using swept source optical coherence tomography (ss-OCT) technology. METHODS: All patients were measured at their pre-assessment visit 1 week prior to cataract surgery using conventional optical biometry (PCI technology, IOLMaster 500, Carl Zeiss Meditec AG, Jena, Germany). Patients in whom one or both eyes could not be measured using PCI technology were invited to participate in the study and to be measured with the ss-OCT (IOL Master 700, Carl Zeiss Meditec AG, Jena, Germany) device. RESULTS: Altogether, 1226 eyes of 613 patients were measured consecutively, and 78 eyes were not measured successfully with PCI technology. Among those with unsuccessfully measured eyes, 23 patients were willing to participate in the study, and two of those were also unsuccessfully measured with the ss-OCT device (8.7%, 2/23). However, 91.3% (21/23) of the eyes that were unsuccessfully scanned with PCI technology were measurable with the ss-OCT device. The estimated overall rate of unsuccessful scans with the ss-OCT device was 0.5% (6/1226) ([Formula: see text] < 0.01). CONCLUSION: ss-OCT technology significantly improves the rate of attainable axial eye length measurements, especially in eyes with posterior subcapsular cataracts, but also in eyes with dense nuclear cataracts, except for white cataracts. PMID- 29498016 TI - Using a Summer REU to Help Develop the Next Generation of Mathematical Ecologists. AB - Understanding the complexities of environmental issues requires individuals to bring together ideas and data from different disciplines, including ecology and mathematics. With funding from the national science foundation (NSF), scientists from the University of Wisconsin-La Crosse and the US geological survey held a research experience for undergraduates (REU) program in the summer of 2016. The goals of the program were to expose students to open problems in the area of mathematical ecology, motivate students to pursue STEM-related positions, and to prepare students for research within interdisciplinary, collaborative settings. Based on backgrounds and interests, eight students were selected to participate in one of two research projects: wind energy and wildlife conservation or the establishment and spread of waterfowl diseases. Each research program was overseen by a mathematician and a biologist. Regardless of the research focus, the program first began with formal lectures to provide students with foundational knowledge followed by student-driven research projects. Throughout this period, student teams worked in close association with their mentors to create, parameterize and evaluate ecological models to better understand their systems of interest. Students then disseminated their results at local, regional, and international meetings and through publications (one in press and one in progress). Direct and indirect measures of student development revealed that our REU program fostered a deep appreciation for and understanding of mathematical ecology. Finally, the program allowed students to gain experiences working with individuals with different backgrounds and perspectives. Taken together, this REU program allowed us to successfully excite, motivate and prepare students for future positions in the area of mathematical biology, and because of this it can be used as a model for interdisciplinary programs at other institutions. PMID- 29498017 TI - Deep learning with convolutional neural network in radiology. AB - Deep learning with a convolutional neural network (CNN) is gaining attention recently for its high performance in image recognition. Images themselves can be utilized in a learning process with this technique, and feature extraction in advance of the learning process is not required. Important features can be automatically learned. Thanks to the development of hardware and software in addition to techniques regarding deep learning, application of this technique to radiological images for predicting clinically useful information, such as the detection and the evaluation of lesions, etc., are beginning to be investigated. This article illustrates basic technical knowledge regarding deep learning with CNNs along the actual course (collecting data, implementing CNNs, and training and testing phases). Pitfalls regarding this technique and how to manage them are also illustrated. We also described some advanced topics of deep learning, results of recent clinical studies, and the future directions of clinical application of deep learning techniques. PMID- 29498018 TI - Effectiveness of a Fixed-Dose, Single-Pill Combination of Perindopril and Amlodipine in Patients with Hypertension: A Non-Interventional Study. AB - INTRODUCTION: We conducted a prospective, non-interventional, multicenter study to examine the effect of a fixed-dose combination of perindopril/amlodipine in patients with arterial hypertension. METHODS: Patients who were previously untreated or required a change in medication were treated with a fixed combination of perindopril/amlodipine (3.5/2.5 or 7.0/5.0 mg) for 12 weeks. Changes in office, home and ambulatory blood pressure (BP) were recorded. Adherence was assessed by the Hill-Bone medication adherence scale. RESULTS: Overall, 1814 patients (mean age 60.0 +/- 13.4 years) were included in 614 German practices, and data of 1770 patients were analyzed. At study entry, 97.7% of patients received perindopril/amlodipine at a daily dose of 3.5 mg/2.5 mg, and 47.9% of patients remained on this dose during the study period. Treatment with perindopril/amlodipine decreased mean office BP from 163.7/95.4 to 133.6/80.3 mmHg (p < 0.0001), resulting in a hypertension control rate of 69.1%. Blood pressure control was comparable in previously untreated and treated patients (70.3 vs. 68.1%), and in younger and older patients (70.6 < 65 vs. 66.3% >= 65 years). Ambulatory BP measurements were available in a subgroup of patients (n = 167), and mean 24 h ambulatory BP decreased from 150.6 +/- 12.6/88.9 +/- 8.8 to 132.4 +/- 11.9/79.4 +/- 8.5 mmHg (p < 0.0001). Furthermore, the proportion of patients with severe hypertension European Society of Hypertension/European Society of Cardiology (ESH/ESC) grade II or III decreased from 64.4 to 3.9%, and patients with pre-existing isolated systolic hypertension (n = 284) converted to normal BP in 67.6% of cases. Nearly half of the patients (47.2%) were perfectly adherent during the study. In previously treated patients, the percentage of patients with perfect adherence increased from 20.6% prior to study to 43.5% at final visit (p < 0.0001). Adverse drug reactions were documented for 4.9% of patients. CONCLUSION: A fixed-dose combination of perindopril/amlodipine shows significant blood pressure reduction and improvement in medication adherence in a primary care setting. TRIAL REGISTRATION: ISRCTN26323538. FUNDING: Servier Deutschland GmbH. PMID- 29498020 TI - Botulinum Toxin: Does it have a Place in the Management of Depression? PMID- 29498022 TI - Correction to: Interior Immigration Enforcement and Political Participation of U.S. Citizens in Mixed-Status Households. AB - Ruggles, S., Genadek, K., Goeken, R., Grover, J., & and Sobek, M. (2017). Integrated Public Use Microdata Series: Version 7.0 [Data set]. Minneapolis: University of Minnesota. https://doi.org/10.18128/D010.V7.0. PMID- 29498021 TI - Prescribed Dose of Opioids and Overdose: A Systematic Review and Meta-Analysis of Unintentional Prescription Opioid Overdose. AB - BACKGROUND: The rate of an unintentional drug overdose involving prescription opioids continues to rise. An understanding of the threshold dose and dose(s) associated with unintentional prescription opioid overdose will help to mitigate this epidemic. OBJECTIVE: The objective of this systematic review is to systematically synthesise and meta-analyse studies on doses of prescription opioids and ascertain the doses of opioids that are associated with increased risk of severe opioid poisoning or mortality. DATA SOURCES: A search of PubMed, EMBASE, CINAHL and Web of Science from inception to 16 January 2017 was conducted using search strategies and the MeSH (Medical Subject Headings) terms for studies of adult patients using prescription opioids who experienced an accidental overdose. STUDY SELECTION: Of the 1332 studies identified, 117 were selected for full article review. Ten met the inclusion criteria for qualitative analysis, but only seven studies were meta-analysed. The included studies were in English, and participants met predetermined International Classification of Diseases (ICD) codes. Studies were excluded if they included only paediatric participants or the participants met the ICD code for intentional self-harm. DATA EXTRACTION AND SYNTHESIS: Two researchers elaborated and validated a data extraction form. Data were then independently extracted by both reviewers as per this form. We assessed study quality using the Newcastle-Ottawa Scale (NOS) for non-randomised studies in meta-analyses. We performed a meta-regression using a random-effect model and summarised the results using relative risk (RR) and 95% confidence intervals (CIs). The threshold dose for an unintentional overdose is 20 morphine milligram equivalents (MME)/day. There were higher risks with larger doses: (1) <= 20 versus >= 21 MME/day: RR 2.81, 95% CI 1.09-7.22, p < 0.001; (2) <= 50 versus > 50 MME/day: RR 3.87, 95% CI 2.36-6.33, p < 0.001; (3) <= 100 versus > 100 MME/day: RR 4.28, 95% CI 2.61-7.1, p < 0.001; and (4) <= 50 versus > 50-100 MME/day: RR 3.09, 95% CI 1.84-5.18, p < 0.001). Heterogeneity was explained by the type of overdose event, inpatient or outpatient status, and length of observation. Type of pain (cancer or non-cancer pain) had no impact on heterogeneity. LIMITATIONS: The definition of exposure in studies included in the meta-analysis was heterogeneous. Some studies defined exposure as the filling of a prescription while others defined exposure as the prescription of an opioid to the patient, and all studies assumed that patients took the prescribed opioid. Medications that may contribute to overdose, such as benzodiazepines and other drugs, were not considered. CONCLUSIONS: A significantly increased risk of inadvertent prescription opioid overdose was found with 20-50 MME/day, with fatality more likely with opioid doses above 50 MME/day, although extensive heterogeneity was found with the dose comparisons. Clinicians should inform patients of this risk and monitor them closely. PROTOCOL REGISTRATION: This protocol was registered with PROSPERO 2017: CRD42017058426. PMID- 29498019 TI - A Review of Microbiota and Irritable Bowel Syndrome: Future in Therapies. AB - Irritable bowel syndrome (IBS), one of the most frequent digestive disorders, is characterized by chronic and recurrent abdominal pain and altered bowel habit. The origin seems to be multifactorial and is still not well defined for the different subtypes. Genetic, epigenetic and sex-related modifications of the functioning of the nervous and immune-endocrine supersystems and regulation of brain-gut physiology and bile acid production and absorption are certainly involved. Acquired predisposition may act in conjunction with infectious, toxic, dietary and life event-related factors to enhance epithelial permeability and elicit mucosal microinflammation, immune activation and dysbiosis. Notably, strong evidence supports the role of bacterial, viral and parasitic infections in triggering IBS, and targeting microbiota seems promising in view of the positive response to microbiota-related therapies in some patients. However, the lack of highly predictive diagnostic biomarkers and the complexity and heterogeneity of IBS patients make management difficult and unsatisfactory in many cases, reducing patient health-related quality of life and increasing the sanitary burden. This article reviews specific alterations and interventions targeting the gut microbiota in IBS, including prebiotics, probiotics, synbiotics, non-absorbable antibiotics, diets, fecal transplantation and other potential future approaches useful for the diagnosis, prevention and treatment of IBS. PMID- 29498023 TI - Treatment of Heart Failure with Preserved Ejection Fraction. AB - Heart failure with preserved ejection fraction (HFpEF) is a growing epidemiologic problem affecting more than half of the patients with heart failure (HF). HFpEF has a significant morbidity and mortality and so far no treatment has been clearly demonstrated to improve the outcomes in HFpEF, in contrast to the efficacy of treatment in heart failure with reduced ejection fraction (HFrEF).The failure of proven beneficial drugs in HFrEF to influence the outcome of patients with HFpEF could be related to the heterogeneity of the disease, its various phenotypes and multifactorial pathophysiology, incompletely elucidated yet. The diagnosis of HFpEF could be demanding or even inaccurate. Moreover, the therapeutic strategies were influenced by different cut-offs used to define preserved ejection fraction (EF). From this perspective, the current guidelines have classified HFpEF by an EF >= 50%, together with a distinct entity, heart failure with mid-range ejection fraction (HFmrEF), defined by an EF ranging from 41-49%.New therapies have been developed to interfere with the mediator pathways of HFpEF at the cellular and molecular level, including mineralocorticoid receptor antagonists, soluble guanylate cyclase stimulators, or angiotensin receptor-neprilysin inhibitors. A number of antidiabetic drugs, such as sodium/glucose cotransporter 2 inhibitors and dipeptidyl peptidase-4 inhibitors are promising options, being under research in large clinical trials. Until the results of ongoing trials shed light on these therapies, guidelines recommend empirical treatment for established HFpEF, and emphasize the crucial role of addressing cardiovascular comorbidities leading to HFpEF, in particular arterial hypertension. PMID- 29498024 TI - Advanced Non-invasive Imaging Techniques in Chronic Heart Failure and Cardiomyopathies : Focus on Cardiac Magnetic Resonance Imaging and Computed Tomographic. AB - Cardiomyopathies (Cs) are a heterogeneous group of myocardial diseases with structural and/or functional abnormalities.The aetiology is due to genetic-family substrate in most cases, however, the correct and detailed analysis of morphofunctional abnormalities (severity and distribution of hypertrophy, ventricular dilatation, ventricular dysfunction) and tissue characteristics (myocardial fibrosis, myocardial infiltration) are a crucial element for a definite diagnosis.Among the different diagnostic imaging modalities applied in clinical practice (echocardiography, nuclear medicine), cardiac magnetic resonance (CMR) has emerged as a non-invasive diagnostic tool having high ability to quantify systolic function and tissue abnormalities that represent the substrates of many Cs.The main added value of CMR is the ability to identify cardiomyopathies with respect to ischemic heart disease and, above all, to discriminate the major types of cardiomyopathies based on morpho-functional presentation patterns and the presence and location of myocardial fibrosis.Many CMR elements allow increasing diagnostic accuracy but CMR data should be integrated with an appropriate clinical and instrumental context.Computed Tomographic (CT) scan technology has showed a complementary role in patients having Cs and HF.In this chapter, the diagnostic, pathophysiologic and prognostic value of CMR and CT in heart failure due to the most common cardiomyopathies will be discussed. PMID- 29498025 TI - Dental Stem Cells in Bone Tissue Engineering: Current Overview and Challenges. AB - The treatment of bone that is impaired due to disease, trauma or tumor resection creates a challenge for both clinicians and researchers. Critical size bone defects are conventionally treated with autografts which are associated with risks such as donor site morbidity and limitations like donor shortage. Bone tissue engineering has become a promising area for the management of critical size bone defects by the employment of biocompatible materials and the discovery of novel stem cell sources. Mesenchymal stem cells (MSCs) can be isolated with ease from various dental tissues including dental pulp stem cells, stem cells from apical papilla, dental follicle stem cells, stem cells from human exfoliated deciduous teeth, periodontal ligament stem cells, gingival stem cells and tooth germ derived stem cells. Outcomes of dental MSC mediated bone tissue engineering is explored in various in vivo and in vitro preclinical studies. However, there are still obscurities regarding the mechanisms underlying in MSC mediated bone regeneration and challenges in applications of dental stem cells. In this review, we summarized dental stem cell sources and their characterizations, along with currently used biomaterials for cell delivery and future perspectives for dental MSCs in the field of bone tissue engineering. Further efforts are necessary before moving to clinical trials for future applications. PMID- 29498026 TI - Comment on: "The General Adaptation Syndrome: A Foundation for the Concept of Periodization". PMID- 29498027 TI - Trading Health Risks for Glory: A Reformulation of the Goldman Dilemma. AB - BACKGROUND: The Goldman dilemma presented athletes with a Faustian bargain that guaranteed winning an Olympic gold medal in their sport but resulted in certain death 5 years later. Athletes' responses to Goldman's bargain were reported from 1982 to 1995. Several studies subsequently evaluated people's willingness to accept the bargain proposed in the Goldman question. Our study updates Goldman's question using contingent-behavior questions, a preference-elicitation method widely applied in economics, marketing and psychology to understand people's choice behavior. Contingent-behavior questions ask people to evaluate hypothetical tradeoffs between outcomes when real-world decisions are unobservable, nonexistent, or unreliable. METHODS: A web-enabled survey was conducted with athletes in 50 sports between June, 2012 and April, 2013. Athletes were invited by their sport governing bodies in the United States to complete the online survey. Responses from 2888 athletes were collected. Our reformulation elicited athletes' willingness to accept a performance-enhancing drug (PED) associated with the risk of a realistic fatal event, not certain death. A double bounded dichotomous-choice question format was used to elicit athletes' maximum acceptable mortality risk (MAMR) for winning an Olympic gold medal. Data were analyzed using an interval regression model to estimate the implicit probability of accepting a continuous risk level. MAMR was defined as the mortality risk level with a 0.50 probability of acceptance. RESULTS: Estimated mean MAMRs varied between 7 and 14% across athletes in different ranks and sports. Elite athletes were generally the most willing to accept a fatal cardiovascular risk to win a gold medal in the Olympics. This range was similar to the levels of risk that patients accept for life-changing interventions. CONCLUSIONS: Results suggest that very few athletes would be expected to accept a PED in the bargain postulated by the Goldman dilemma. Risk tolerance among elite athletes suggest they may be more aware of the potential financial and nonfinancial benefits of such a win, and/or less optimistic about their potential to move up in the level of competition without the use of PEDs. PMID- 29498029 TI - Authors' Reply to Buckner et al.: 'Comment on: "The General Adaptation Syndrome: A Foundation for the Concept of Periodization". PMID- 29498028 TI - A New Direction to Athletic Performance: Understanding the Acute and Longitudinal Responses to Backward Running. AB - Backward running (BR) is a form of locomotion that occurs in short bursts during many overground field and court sports. It has also traditionally been used in clinical settings as a method to rehabilitate lower body injuries. Comparisons between BR and forward running (FR) have led to the discovery that both may be generated by the same neural circuitry. Comparisons of the acute responses to FR reveal that BR is characterised by a smaller ratio of braking to propulsive forces, increased step frequency, decreased step length, increased muscle activity and reliance on isometric and concentric muscle actions. These biomechanical differences have been critical in informing recent scientific explorations which have discovered that BR can be used as a method for reducing injury and improving a variety of physical attributes deemed advantageous to sports performance. This includes improved lower body strength and power, decreased injury prevalence and improvements in change of direction performance following BR training. The current findings from research help improve our understanding of BR biomechanics and provide evidence which supports BR as a useful method to improve athlete performance. However, further acute and longitudinal research is needed to better understand the utility of BR in athletic performance programs. PMID- 29498031 TI - Patterns and predictors of conversion to bipolar disorder in 91 587 individuals diagnosed with unipolar depression. AB - OBJECTIVE: Conversion from unipolar depression (UD) to bipolar disorder (BD) is a clinically important event that should lead to treatment modifications. Unfortunately, recognition of this transition is often delayed. Therefore, the objective of this study was to identify predictors of diagnostic conversion from UD to BD. METHOD: Historical prospective cohort study based on 91 587 individuals diagnosed with UD in Danish hospital psychiatry between 1995 and 2016. The association between a series of potential predictors and the conversion from UD to BD during follow-up (702 710 person-years) was estimated by means of Cox regression with death as competing risk. RESULTS: During follow-up, 3910 individuals with UD developed BD. The cumulative incidence of conversion was slightly higher in females (8.7%, 95% CI: 8.2-9.3) compared to males (7.7%, 95% CI: 7.0-8.4). The strongest predictor of conversion from UD to BD was parental history of BD (adjusted hazard ratio (aHR) = 2.60, 95% CI: 2.20-3.07)). Other predictors included psychotic depression at the index UD episode (aHR = 1.73, 95% CI: 1.48-2.02), a prior/concomitant non-affective psychosis (aHR = 1.73, 95% CI: 1.51-1.99), and in-patient treatment at the index episode (aHR = 1.76, 95% CI: 1.63-1.91). CONCLUSION: Diagnostic conversion from UD to BD is predicted by severe depression requiring in-patient treatment, psychotic symptomatology, and parental history of BD. PMID- 29498030 TI - Baseline Performance of NCAA Athletes on a Concussion Assessment Battery: A Report from the CARE Consortium. AB - BACKGROUND: Sport-related concussion and repetitive head impact exposure in contact sports continue to receive increased attention in public and medical spheres. The Concussion Assessment, Research and Education (CARE) Consortium, a multicenter cooperative, was established to study the natural history of concussion in National Collegiate Athletic Association (NCAA) collegiate student athletes across 29 colleges and universities in the United States. The purpose of this investigation is to provide normative data from the CARE Consortium and evaluate for differences between sport categories. METHODS: NCAA student-athletes were evaluated annually for general demographics and sport-specific characteristics before the start of the competitive season. We collected demographic and medical history information and evaluated each student-athlete's neurocognitive function, neurological status, postural stability, and self reported symptoms. Sports were categorized by the amount of contact typically associated with the sport (i.e., contact, limited contact, non-contact). Comparisons between the three sport categories for the evaluated variables were made using linear or zero inflated negative binomial regression models adjusted for gender, concussion history, and household income. RESULTS: Over a 2-year period (August 2014-July 2016), 15,681 NCAA athletes completed preseason evaluations. Overall, 53% of the athletes were in the contact sport group, 31% were in the limited contact group and 17% were in the non-contact group. After adjusting for covariates, there were statistically significant differences found between athlete groups, although the differences and effect sizes were small and not clinically significant. The contact sport group had better scores on Immediate Post-Concussion Assessment Testing (ImPACT(r)) visual and verbal memory, Sport Concussion Assessment Tool (SCAT) symptom checklist, and Brief Symptom Inventory-18 (BSI-18), but slower ImPACT reaction time and worse scores on Standardized Assessment of Concussion (SAC). Further, the data indicate that some ImPACT score distributions were noticeably different from those presented in the technical manual. CONCLUSIONS: In this large, racially and socio-economically diverse cohort of male and female college athletes, we found no evidence that student-athletes participating in contact sports have clinically meaningful deficits in pre-season cognitive and balance testing. They also did not report significantly more symptoms of psychological distress when compared with student athletes in non-contact or limited contact sports. In addition, the data suggest potential limitations when using published ImPACT norms when evaluating injured athletes. PMID- 29498032 TI - Genomic Variation and Pharmacokinetics in Old Age: A Quantitative Review of Age- vs. Genotype-Related Differences. AB - Older persons may particularly benefit from pharmacogenetic diagnostics, but there is little clinical evidence on that question. We quantitatively analyzed the effects of age and genotype in drugs with consensus on a therapeutically relevant impact of a genotype. Assuming additive effects of age and genotype, drugs may be classified in groups with different priorities to consider either age, or genotype, or both, in therapy. Particularly interesting were those studies specifically analyzing the age-by-genotype interaction. PMID- 29498033 TI - Media exposure to terrorism and people's risk perception: The role of environmental sensitivity and psychophysiological response to stress. AB - Terrorist attacks have a destabilizing impact on the general population, causing distress and fear. However, not all individuals are equally susceptible to the effects of terror threat. This study aimed to examine whether exposure to terrorism-related pictures interacted with individual differences in environmental sensitivity and psychophysiological response to stress to explain people's risk perception, operationalized as perceived likelihood of a terrorist attack and willingness to trade off one's privacy to increase national security. Ninety-five university students were randomly assigned to one of two conditions (terrorism-related vs. neutral pictures). After watching the pictures, they answered questions concerning risk perception and completed questionnaires. Stress was induced by the Mannheim Multicomponent Stress Test, during which heart rate was recorded. Results showed that the perceived likelihood of future attacks was affected by the interaction between exposure to terrorism pictures and psychophysiological reactivity to stress, whereas willingness to trade off one's privacy to improve national security was influenced by the interaction between exposure to terrorism pictures and environmental sensitivity. The study suggests that individuals high in sensitivity and psychophysiological stress reactivity are particularly affected by terrorism-related pictures. Psychologists should direct their efforts to raise general awareness of the negative effects, especially for some people, of such media coverage. PMID- 29498034 TI - Perceived benefits and barriers of implementing nursing residency programs in Jordan. AB - AIMS: To explore the challenges that face Jordanian nurses in the first year of employment; and understand the benefits and barriers of implementing a Nursing Residency Program from the perspectives of nurses and key informants. BACKGROUND: Many researchers reported that novice nurses do not have an adequate level of competence needed in the real clinical practice to meet the increasing demands of healthcare systems. METHODS: A descriptive qualitative approach using individual interviews and focus group discussions was utilized. The sample was a purposive one that consisted of 30 Jordanian nurses and six key informants. Data were recorded and then transcribed. Content analysis was used to analyze the data. FINDINGS: The results revealed several challenges that face nurses in their first year of experience such as reality shock, lack of self-confidence, and burnout and intent to leave. Some of the perceived barriers of implementing the Program were issues concerned with the responsible regulatory body, payment, and monitoring and evaluation. CONCLUSION: The findings asserted that the implementation of the Nursing Residency Program for new practicing nurses would enhance their competencies and self- confidence; and decrease the rate of reality shock and turnover within the first year of employment. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Policy makers, nurse educators, and nurse administrators and clinical nurses need to collaborate to develop a formal system with binding policies and regulations concerning the implementation of Nursing Residency Program. There is also a need to address and modify current orientation programmes offered by hospitals for novice nurses to enhance their transition into clinical practice. PMID- 29498035 TI - Variations in internal structure, composition and protein distribution between intra- and extra-articular knee ligaments and tendons. AB - Tendons and ligaments play key roles in the musculoskeletal system in both man and animals. Both tissues can undergo traumatic injury, age-related degeneration and chronic disease, causing discomfort, pain and increased susceptibility to wider degenerative joint disease. To date, tendon and ligament ultrastructural biology is relatively under-studied in healthy, non-diseased tissues. This information is essential to understand the pathology of these tissues with regard to function-related injury and to assist with the future development of tissue engineered tendon and ligament structures. This study investigated the morphological, compositional and extracellular matrix protein distribution differences between tendons and ligaments around the non-diseased canine stifle joint. The morphological, structural characteristics of different regions of the periarticular tendons and ligaments (the intra-articular anterior cruciate ligament, the extra-articular medial collateral ligament, the positional long digital extensor tendon and energy-storing superficial digital flexor tendons) were identified using a novel semi-objective histological scoring analysis and by determining their biochemical composition. Protein distribution of extracellular matrix collagens, proteoglycans and elastic fibre proteins in anterior cruciate ligament and long digital extensor tendon were also determined using immunostaining techniques. The anterior cruciate ligament was found to have significant morphological differences in comparison with the other three tissues, including less compact collagen architecture, differences in cell nuclei phenotype and increased glycosaminoglycan and elastin content. Intra- and interobserver differences of histology scoring resulted in an average score 0.7, indicative of good agreement between observers. Statistically significant differences were also found in the extracellular matrix composition in terms of glycosaminoglycan and elastin content, being more prominent in the anterior cruciate ligament than in the other three tissues. A different distribution of several extracellular matrix proteins was also found between long digital extensor tendon and anterior cruciate ligament, with a significantly increased immunostaining of aggrecan and versican in the anterior cruciate ligament. These findings directly relate to the different functions of tendon and ligament and indicate that the intra-articular anterior cruciate ligament is subjected to more compressive forces, reflecting an adaptive response to normal or increased loads and resulting in different extracellular matrix composition and arrangement to protect the tissue from damage. PMID- 29498037 TI - Prenatal diagnosis of persistent right umbilical vein - Incidence and clinical impact. A prospective study. AB - BACKGROUND: Persistent right umbilical vein (PRUV) is usually an isolated finding but it may be accompanied by other fetal malformations. AIMS: We aimed to determine the incidence of prenatally diagnosed PRUV in a referral population, assess the neonatal outcome and discuss the findings together with those from previous publications. MATERIALS AND METHODS: A total of 2360 women with low-risk singleton pregnancies were examined in the second and third trimesters. A transabdominal convex volume transducer was used. B-mode was applied in each patient. Scanning of the venous system included imaging of the target vessels with two-dimensional colour Doppler mapping. The diagnosis of PRUV was made in a transverse section of the fetal abdomen. Three-dimensional ultrasounds were performed as necessary, when anomalous cases were encountered. RESULTS: The incidence of PRUV in our population was 12/2360 = 0.5%, and it was higher than in other retrospective studies. In 75% (n = 9), PRUV was an isolated finding where delivery was uneventful and the postnatal outcome was favourable. In two cases PRUV was accompanied by omphalocele, and in one case by tetralogy of Fallot and single umbilical artery. CONCLUSIONS: PRUV is an uncommon prenatal finding. Screening for this anomaly can be easily performed in all pregnant patients. A diagnosis of PRUV should be followed by a thorough fetal morphology scan in order to exclude any other malformations, especially those of the cardiovascular system. PMID- 29498036 TI - Yoda1 analogue (Dooku1) which antagonizes Yoda1-evoked activation of Piezo1 and aortic relaxation. AB - BACKGROUND AND PURPOSE: The mechanosensitive Piezo1 channel has important roles in vascular physiology and disease. Yoda1 is a small-molecule agonist, but the pharmacology of these channels is otherwise limited. EXPERIMENTAL APPROACH: Yoda1 analogues were generated by synthetic chemistry. Intracellular Ca2+ and Tl+ measurements were made in HEK 293 or CHO cell lines overexpressing channel subunits and in HUVECs, which natively express Piezo1. Isometric tension recordings were made from rings of mouse thoracic aorta. KEY RESULTS: Modification of the pyrazine ring of Yoda1 yielded an analogue, which lacked agonist activity but reversibly antagonized Yoda1. The analogue is referred to as Dooku1. Dooku1 inhibited 2 MUM Yoda1-induced Ca2+ -entry with IC50 s of 1.3 MUM (HEK 293 cells) and 1.5 MUM (HUVECs) yet failed to inhibit constitutive Piezo1 channel activity. It had no effect on endogenous ATP-evoked Ca2+ elevation or store-operated Ca2+ entry in HEK 293 cells or Ca2+ entry through TRPV4 or TRPC4 channels overexpressed in CHO and HEK 293 cells. Yoda1 caused dose-dependent relaxation of aortic rings, which was mediated by an endothelium- and NO dependent mechanism and which was antagonized by Dooku1 and analogues of Dooku1. CONCLUSION AND IMPLICATIONS: Chemical antagonism of Yoda1-evoked Piezo1 channel activity is possible, and the existence of a specific chemical interaction site is suggested with distinct binding and efficacy domains. PMID- 29498038 TI - Evaluation of Potential Disease-Mediated Drug-Drug Interaction in Patients With Moderate-to-Severe Atopic Dermatitis Receiving Dupilumab. AB - This open-label drug-drug interaction study assessed whether blockade by dupilumab of interleukin (IL)-4 and IL-13 signaling affects the pharmacokinetics of drugs metabolized by cytochrome P450 (CYP450) enzymes. The pharmacokinetics of five CYP450 substrates given orally (midazolam, omeprazole, S-warfarin, caffeine, and metoprolol, metabolized by CYP3A, CYP2C19, CYP2C9, CYP1A2, and CYP2D6, respectively) were evaluated before and 28 days after initiation of dupilumab treatment (subcutaneous 300 mg weekly) in 14 patients with moderate-to-severe atopic dermatitis. Dupilumab had no clinically relevant effects on the pharmacokinetics of CYP450 substrates, provided substantial clinical benefit, and was generally well tolerated. Only one serious adverse event was reported, an episode of systemic inflammatory response syndrome that resolved after treatment was discontinued. In summary, blockade of IL-4/IL-13 signaling in patients with type 2 inflammation does not appear to significantly affect CYP450 enzyme activities; the use of dupilumab in atopic dermatitis patients is unlikely to influence the pharmacokinetics of CYP450 substrates. PMID- 29498039 TI - Retrospective cohort study comparing the adverse reactions and efficacy of intravenous iron polymaltose with ferric carboxymaltose for iron deficiency anemia. AB - OBJECTIVE: To examine the adverse drug reactions (ADRs) and the efficacy of intravenous iron polymaltose and ferric carboxymaltose (FCM) among gynecology/obstetric patients with anemia. METHODS: The present retrospective observational study examined data from anemic obstetrics and gynecology patients who received either iron polymaltose or FCM between January 1, 2011, and April 30, 2015, at The Royal Women's Hospital, Victoria, Australia. Patient demographic data, dosage, ADR documentation, and hemoglobin levels were collected from medical records and compared. RESULTS: The study included 221 patients; 111 and 110 received iron polymaltose and FCM, respectively. ADRs were documented for 18 (16.2%) patients in the iron polymaltose group and 2 (1.8%) in the FCM group (P<0.001), with no incidences of anaphylaxis. Both formulations achieved increased hemoglobin levels within 12 weeks (P<0.001 for both). Mean hemoglobin level increases were similar in both groups among non-pregnant patients (P=0.186), but were greater in the iron polymaltose cohort among pregnant patients (P=0.005). FCM dose compliance was suboptimal, with 8 of 57 (14%) patients who required second visits for doses greater than 1000 mg returning for the infusion. CONCLUSION: FCM was associated with a lower incidence of ADRs than iron polymaltose. Patients receiving FCM infusions were less likely to receive their total required iron dose. Further randomized prospective studies are required to compare clinical efficacy of iron polymaltose versus FCM. PMID- 29498040 TI - The educational preparation of nurses in a developing economy and patient mortality. AB - BACKGROUND: Most studies have reported that higher levels (baccalaureate degree) of educational attainment by nurses are associated with lower levels of patient mortality. Researchers working in developed economies (e.g. North America and Europe) have almost exclusively conducted these studies. The value of baccalaureate nurse education has not been tested in countries with a developing economy. METHOD: A retrospective observational study conducted in seven hospitals. Patient mortality was the main outcome of interest. Anonymized data were extracted from nurses and patients from two different administrative sources and linked using the staff identification number that exists in both systems. We used bivariate logistic regression models to test the association between mortality and the educational attainment of the admitting nurse (responsible for assessment and care planning). RESULTS: Data were extracted for 11 918 (12, 830 admissions) patients and 7415 nurses over the first 6 months of 2015. The majority of nurses were educated in South Asia and just over half were educated to at least bachelor degree level. After adjusting for confounding and clustering, nurse education was not found to be associated with mortality. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Our observations may suggest that in a developing economy, the academic level of nurses' education is not associated with a reduction in patient mortality. Findings should be interpreted with considerable caution but do challenge widely held assumptions about the value of baccalaureate-prepared nurses. Further research focused on nursing education in developing economies is required to inform health policy and planning. PMID- 29498042 TI - Prefer feeling bad? Subcultural differences in emotional preferences between Han Chinese and Mongolian Chinese. AB - As a multi-ethnic country that is comprised of diverse cultural systems, there has been little research on the subcultural differences in emotional preferences in China. Also, little attention has been paid to examine how explicit and implicit attitudes towards emotions influence emotional preferences interactively. In this study, we manipulated explicit attitudes towards emotions among Han (N = 62) and Mongolian Chinese individuals (N = 70). We assessed participants' implicit attitudes towards emotions to explore their contributions to emotional preferences. (a) Han Chinese had lower preferences for pleasant emotions than Mongolian Chinese after inducing contra-hedonic attitudes towards emotions, and (b) after priming contra-hedonic attitudes towards emotions, the more Han Chinese participants evaluated pleasant emotions as negative implicitly, the less they preferred to engage in pleasant emotional activities. These findings contribute to the growing literature of subcultural differences and demonstrate that explicit and implicit attitudes towards emotions interactively influence individuals' emotional preferences between different subculture groups. PMID- 29498041 TI - Novel long-acting antagonists of muscarinic ACh receptors. AB - BACKGROUND AND PURPOSE: The aim of this study was to develop potent and long acting antagonists of muscarinic ACh receptors. The 4-hexyloxy and 4-butyloxy derivatives of 1-[2-(4-oxidobenzoyloxy)ethyl]-1,2,3,6-tetrahydropyridin-1-ium were synthesized and tested for biological activity. Antagonists with long residence time at receptors are therapeutic targets for the treatment of several neurological and psychiatric human diseases. Their long-acting effects allow for reduced daily doses and adverse effects. EXPERIMENTAL APPROACH: The binding and antagonism of functional responses to the agonist carbachol mediated by 4 hexyloxy compounds were investigated in CHO cells expressing individual subtypes of muscarinic receptors and compared with 4-butyloxy analogues. KEY RESULTS: The 4-hexyloxy derivatives were found to bind muscarinic receptors with micromolar affinity and antagonized the functional response to carbachol with a potency ranging from 30 nM at M1 to 4 MUM at M3 receptors. Under washing conditions to reverse antagonism, the half-life of their antagonistic action ranged from 1.7 h at M2 to 5 h at M5 receptors. CONCLUSIONS AND IMPLICATIONS: The 4-hexyloxy derivatives were found to be potent long-acting M1 -preferring antagonists. In view of current literature, M1 -selective antagonists may have therapeutic potential for striatal cholinergic dystonia, delaying epileptic seizure after organophosphate intoxication or relieving depression. These compounds may also serve as a tool for research into cognitive deficits. PMID- 29498043 TI - Distribution of non-native suckermouth armoured catfish Pterygoplichthys ambrosettii in the upper Parana River basin, Brazil. AB - This study describes the invasion of the upper Parana River basin by Pterygoplichthys ambrosettii based on a literature review and field samples. Pterygoplichthys ambrosettii has been reported in 42 localities throughout the upper Parana River basin, including the Tiete, Paranapanema, Parana, Grande and Aguapei rivers. The ascent of P. ambrosettii after the inundation of the Sete Quedas Falls on the Parana River and the release of individuals by aquarium hobbyists were the primary drivers of this invasion. PMID- 29498044 TI - New remarkable sexually dimorphic miniature species of Hyphessobrycon (Characiformes: Characidae) from the upper Rio Tapajos basin. AB - A new miniature species of Hyphessobrycon is described from an affluent of the Rio Papagaio, tributary of the Rio Juruena, upper Rio Tapajos basin, Mato Grosso State, Brazil. The new species can be distinguished from its congeners by having a remarkable secondary sexual dimorphism in its live colouration (males are red and females yellow), well-defined and relatively narrow dark midlateral stripe extending from tip of snout to tip of middle caudal-fin rays, absence of humeral blotch, 15-18 branched anal-fin rays and five or six branched pelvic-fin rays. The sexually dimorphic colouration of the new species is briefly discussed regarding its temporal variation. PMID- 29498045 TI - Rice leaf hydrophobicity and gas films are conferred by a wax synthesis gene (LGF1) and contribute to flood tolerance. AB - Floods impede gas (O2 and CO2 ) exchange between plants and the environment. A mechanism to enhance plant gas exchange under water comprises gas films on hydrophobic leaves, but the genetic regulation of this mechanism is unknown. We used a rice mutant (dripping wet leaf 7, drp7) which does not retain gas films on leaves, and its wild-type (Kinmaze), in gene discovery for this trait. Gene complementation was tested in transgenic lines. Functional properties of leaves as related to gas film retention and underwater photosynthesis were evaluated. Leaf Gas Film 1 (LGF1) was identified as the gene determining leaf gas films. LGF1 regulates C30 primary alcohol synthesis, which is necessary for abundant epicuticular wax platelets, leaf hydrophobicity and gas films on submerged leaves. This trait enhanced underwater photosynthesis 8.2-fold and contributes to submergence tolerance. Gene function was verified by a complementation test of LGF1 expressed in the drp7 mutant background, which restored C30 primary alcohol synthesis, wax platelet abundance, leaf hydrophobicity, gas film retention, and underwater photosynthesis. The discovery of LGF1 provides an opportunity to better understand variation amongst rice genotypes for gas film retention ability and to target various alleles in breeding for improved submergence tolerance for yield stability in flood-prone areas. PMID- 29498046 TI - N-myristoylation and S-acylation are common modifications of Ca2+ -regulated Arabidopsis kinases and are required for activation of the SLAC1 anion channel. AB - N-myristoylation and S-acylation promote protein membrane association, allowing regulation of membrane proteins. However, how widespread this targeting mechanism is in plant signaling processes remains unknown. Through bioinformatics analyses, we determined that among plant protein kinase families, the occurrence of motifs indicative for dual lipidation by N-myristoylation and S-acylation is restricted to only five kinase families, including the Ca2+ -regulated CDPK-SnRK and CBL protein families. We demonstrated N-myristoylation of CDPK-SnRKs and CBLs by incorporation of radiolabeled myristic acid. We focused on CPK6 and CBL5 as model cases and examined the impact of dual lipidation on their function by fluorescence microscopy, electrophysiology and functional complementation of Arabidopsis mutants. We found that both lipid modifications were required for proper targeting of CBL5 and CPK6 to the plasma membrane. Moreover, we identified CBL5-CIPK11 complexes as phosphorylating and activating the guard cell anion channel SLAC1. SLAC1 activation by CPK6 or CBL5-CIPK11 was strictly dependent on dual lipid modification, and loss of CPK6 lipid modification prevented functional complementation of cpk3 cpk6 guard cell mutant phenotypes. Our findings establish the general importance of dual lipid modification for Ca2+ signaling processes, and demonstrate their requirement for guard cell anion channel regulation. PMID- 29498048 TI - Somatic hybridization provides segregating populations for the identification of causative mutations in sterile mutants of the moss Physcomitrella patens. AB - Forward genetics is now straightforward in the moss Physcomitrella patens, and large mutant populations can be screened relatively easily. However, perturbation of development before the formation of gametes currently leaves no route to gene discovery. Somatic hybridization has previously been used to rescue sterile mutants and to assign P. patens mutations to complementation groups, but the cellular basis of the fusion process could not be monitored, and there was no tractable way to identify causative mutations. Here we use fluorescently tagged lines to generate somatic hybrids between Gransden (Gd) and Villersexel (Vx) strains of P. patens, and show that hybridization produces fertile diploid gametophytes that form phenotypically normal tetraploid sporophytes. Quantification of genetic variation between the two parental strains reveals single nucleotide polymorphisms at a frequency of 1/286 bp. Given that the genetic distinction between Gd and Vx strains exceeds that found between pairs of strains that are commonly used for genetic mapping in other plant species, the spore populations derived from hybrid sporophytes provide suitable material for bulk segregant analysis and gene identification by genome sequencing. PMID- 29498050 TI - WBC alloimmunization: effects on the laboratory and clinical endpoints of therapeutic granulocyte transfusions. AB - BACKGROUND: Although the subject of many previous studies, the importance of white blood cell (WBC) alloimmunization in granulocyte transfusion therapy has not been settled. In this study, we report the results of the effects of WBC antibodies in the RING (Resolving Infection in Neutropenia with Granulocytes) study, a randomized controlled trial comparing the efficacy of daily granulocyte transfusion therapy plus antimicrobials versus antimicrobials alone; the primary outcome results have been published previously. STUDY DESIGN AND METHODS: One hundred fourteen subjects were enrolled in the study. Serum samples for WBC antibody determination were obtained from each subject at baseline and at 2 and 6 weeks. One hundred subjects had at least one antibody test result. Samples were tested for human leukocyte antigen (HLA) Class I and Class II antibodies as well as for granulocyte-specific antibodies using granulocyte agglutination and immunofluorescence techniques. All testing was performed at a central laboratory. RESULTS: Baseline WBC alloimmunization was modest, depending somewhat on the assay. Seroconversion during the study was slightly higher in the granulocyte transfusion arm, but the differences were not statistically significant. There was no demonstrable effect of the presence of alloimmunization on the primary outcome (survival and microbial response at 42 days), the occurrence of transfusion reactions (either overall or pulmonary), or posttransfusion neutrophil increments. CONCLUSION: The presence or development of WBC antibodies had no demonstrable effect on any clinical aspect of granulocyte transfusion therapy. It appears that, at least in the patient population studied, there is no evidence suggesting need for concern about recipient WBC alloimmunization when prescribing granulocyte transfusions. PMID- 29498049 TI - Red blood cells treated with the amustaline (S-303) pathogen reduction system: a transfusion study in cardiac surgery. AB - BACKGROUND: Nucleic acid-targeted pathogen inactivation technology using amustaline (S-303) and glutathione (GSH) was developed to reduce the risk of transfusion-transmitted infectious disease and transfusion-associated graft versus-host disease with red blood cell (RBC) transfusion. STUDY DESIGN AND METHODS: A randomized, double-blind, controlled study was performed to assess the in vitro characteristics of amustaline-treated RBCs (test) compared with conventional (control) RBCs and to evaluate safety and efficacy of transfusion during and after cardiac surgery. The primary device efficacy endpoint was the postproduction hemoglobin (Hb) content of RBCs. Exploratory clinical outcomes included renal and hepatic failure, the 6-minute walk test (a surrogate for cardiopulmonary function), adverse events (AEs), and the immune response to amustaline-treated RBCs. RESULTS: A total of 774 RBC unis were produced. Mean treatment difference in Hb content was -2.27 g/unit (95% confidence interval, 2.61 to -1.92 g/unit), within the prespecified equivalence margins (+/-5 g/unit) to declare noninferiority. Amustaline-treated RBCs met European guidelines for Hb content, hematocrit, and hemolysis. Fifty-one (25 test and 26 control) patients received study RBCs. There were no significant differences in RBC usage or other clinical outcomes. Observed AEs were within the spectrum expected for patients of similar age undergoing cardiovascular surgery requiring RBCs transfusion. No patients exhibited an immune response specific to amustaline-treated RBCs. CONCLUSION: Amustaline-treated RBCs demonstrated equivalence to control RBCs for Hb content, have appropriate characteristics for transfusion, and were well tolerated when transfused in support of acute anemia. Renal impairment was characterized as a potential efficacy endpoint for pivotal studies of RBC transfusion in cardiac surgery. PMID- 29498051 TI - Host lignin composition affects haustorium induction in the parasitic plants Phtheirospermum japonicum and Striga hermonthica. AB - Parasitic plants in the family Orobanchaceae are destructive weeds of agriculture worldwide. The haustorium, an essential parasitic organ used by these plants to penetrate host tissues, is induced by host-derived phenolic compounds called haustorium-inducing factors (HIFs). The origin of HIFs remains unknown, although the structures of lignin monomers resemble that of HIFs. Lignin is a natural phenylpropanoid polymer, commonly found in secondary cell walls of vascular plants. We therefore investigated the possibility that HIFs are derived from host lignin. Various lignin-related phenolics, quinones and lignin polymers, together with nonhost and host plants that have different lignin compositions, were tested for their haustorium-inducing activity in two Orobanchaceae species, a facultative parasite, Phtheirospermum japonicum, and an obligate parasite, Striga hermonthica. Lignin-related compounds induced haustoria in P. japonicum and S. hermonthica with different specificities. High concentrations of lignin polymers induced haustorium formation. Treatment with laccase, a lignin degradation enzyme, promoted haustorium formation at low concentrations. The distinct lignin compositions of the host and nonhost plants affected haustorium induction, correlating with the response of the different parasitic plants to specific types of lignin-related compounds. Our study provides valuable insights into the important roles of lignin biosynthesis and degradation in the production of HIFs. PMID- 29498052 TI - Abnormalities in flatfishes of the south-west Atlantic Ocean. AB - Five adult paralichthyid specimens with various kinds of abnormalities are reported from the south-west Atlantic Ocean. These abnormal flatfish specimens represent the first records of wholly ambicoloured Paralichthys orbignyanus specimens having a deep notch between the eye and dorsal fin and a partially albinistic specimen having skeletal deformities and only the second record of an almost totally ambicoloured specimen. We also report the first observation of reversal in Paralichthys patagonicus and an almost totally ambicoloured, reversed Xystreurys rasile. PMID- 29498053 TI - Mechanical hemolysis in pediatric patients associated with rapid transfusion and one-way valve. AB - BACKGROUND: Four similar transfusion reactions involving infants were reported in less than 1 year. After transfusion of red blood cells (RBCs) via syringe in the operating room, each patient experienced discolored urine, laboratory evidence of hemolysis, and acute kidney injury. Clerical and serologic investigations were unremarkable. Mechanical hemolysis was considered. STUDY DESIGN AND METHODS: Simulated syringe transfusions were performed. Measurements included hematocrit (Hct), free hemoglobin, and visual hemolysis index. Washed and unwashed RBCs were tested with or without a recently introduced one-way valve, using a 24- or 16 gauge intravenous catheter. Constant manual pressure (1.43 +/- 0.49 mL/sec) or syringe pump (2 mL/min) was used and a subset was timed. RESULTS: The valve increased hemolysis during manual transfusion using both catheters with washed and unwashed RBCs. With the 24-gauge catheter, the change in Hct was -3.53 +/- 0.69% with the valve and 0.22 +/- 0.13% without (p < 0.00001). Comparing the individual valves tested, differences in hemolysis were observed (change in Hct, p < 0.0001). During manual transfusion with 24-gauge catheter and unwashed RBCs, the degree of hemolysis was greater when it took longer to transfuse with a valve (change in Hct versus time, r = -0.75, p < 0.0001) compared to a slight increase in hemolysis for samples that took less time to transfuse without a valve (change in Hct versus time, r = 0.58, p = 0.23). CONCLUSIONS: Mechanical hemolysis should be considered when investigating possible hemolytic transfusion reactions, especially with high rates of transfusion and use of a valve. During rapid manual transfusion with the valve, greater resistance was associated with increased hemolysis. PMID- 29498054 TI - Evaluation of renal oxygen homeostasis in a preclinical animal model to elucidate difference in blood quality after transfusion. AB - BACKGROUND: Red blood cell (RBC) oxygen (O2 ) delivery may be impacted at the tissue, cellular, and molecular levels after storage duration, preservation strategies, and pathogen reduction. Collectively, the preclinical measurement of arterial and venous PO2 , systemic blood flow, tissue hypoxia-inducible factors (HIFs), pimonidazole adduction, and erythropoietin (EPO) regulation can serve to elucidate differential RBC quality after storage and processing. STUDY DESIGN AND METHODS: Donor guinea pig blood was collected, leukoreduced, and stored at 4 degrees C in AS-3 for 1 (fresh) or 14 (stored) days. RBC variables-2,3 diphosphoglycerate, adenosine triphosphate, hemoglobin, morphology, deformability, and in vivo recovery at 24 hours-were measured at each storage duration. Recipient guinea pigs were exchange transfused until 80% volume replacement was achieved. Arterial and venous blood gases, systemic blood flow, renal HIF-1alpha and HIF-2alpha, renal EPO mRNA, plasma EPO, and renal tissue pimonidazole adduction were measured after transfusion. RESULTS: RBC variables declined significantly with storage; however, hemolysis and in vivo recovery remained within the allowable limits for human blood storage. Posttransfusion arterial and venous PO2 and systemic blood flow decreased, and renal HIFs, EPO mRNA, and pimonidazole adducts increased. Subsequently, EPO accumulated in plasma indicating decreased O2 availability in the kidneys. Conversely, all variables remained at basal levels in the fresh blood group. CONCLUSION: The evaluation of renal O2 homeostasis after transfusion represents an effective approach to defining RBC quality between predicate and novel processing. Methods are adapted from standardized techniques and ideal for preclinical evaluation. PMID- 29498055 TI - Cardiac measures of nuclear power plant operator stress during simulated incident and accident scenarios. AB - Maintaining optimal performance in demanding situations is challenged by stress induced alterations in performance. Here, we quantified the stress of nuclear power plant (NPP) operators (N = 20) during a full-scale simulator training for incident and accident scenarios. We compared the ambulatory electrocardiography measurements of heart rate (HR) and heart rate variability (HRV), and self reported stress during baselines and simulated scenarios. Perceived (scale 0-10) and physiologically measured stress were low during baseline after the scenarios and normal NPP operation (means 1.8-2.2, mean HR 75-80 bpm). During a cognitively challenging scenario simulating a sensor malfunction, the operators' stress was mild to moderate (mean 3.4; HR + 12% from baseline). During simulations of severe accidents of fire and radioactive steam leakage, the experienced stress and cardiac activity were on a moderate to high level (means 4.2 and 4.6; HR + 23% and + 14% from baseline, respectively). Cardiac activity paralleled the self reported stress: correlation of self-reported stress to HR was 0.61 (p < .001) and to HRV features RMSSD, HF, LF/HF, SD1, and SD1/SD2 were -0.26, -0.28, 0.35, 0.40, and -0.39 (p < .01), respectively. The low shared variance (22%) between HR and physical activity further support the interpretation that the cardiac activity was strongly linked to the experience of stress and not accountable by operators' movement within the simulator. Cardiac measurements in naturalistic settings can thus reveal relevant information on acute stress with the benefit of not interrupting the primary task. PMID- 29498056 TI - Growth patterns in fetuses with isolated cardiac defects. AB - OBJECTIVES: There is evidence that in fetuses with congenital heart defects (CHDs), head growth is affected. However, scanty data are available on longitudinal growth patterns of other biometric parameters such as abdominal circumference (AC) and femur length (FL). The aim was to evaluate growth patterns in fetuses with isolated CHD diagnosed prenatally in different categories of lesions. METHODS: Fetuses with isolated CHD seen between 2008 and 2013 at the Fetal Medicine Unit of 2 tertiary referral centers were retrospectively included in the study. CHD was classified into 7 categories. Fetal biometry parameters were assessed at 4 variable time points between 18 and 35 weeks' gestation and transformed into Z scores. Linear mixed modeling was performed to analyze repeated measurements and construction of growth models. RESULTS: Two hundred forty-six live births with CHD were analyzed. Linear growth modeling showed a slight decrease in head circumference (HC) in the second half of pregnancy, whereas AC and FL growth were not significantly affected. The model predicted a significantly smaller HC at 36 weeks' gestation in fetuses with conotruncal heart defects. CONCLUSIONS: Fetuses with CHD showed a modest but significant linear decrease in HC growth, whereas AC and FL growth trajectories remained stable. PMID- 29498057 TI - Changes in School Competitive Food Environments after a Health Promotion Campaign. AB - BACKGROUND: Schools can reduce student access to competitive foods and influence healthy food choices by improving the school nutrition environment. This study describes changes in competitive nutrition environments in 100 K-8 schools participating in the Philadelphia Campaign for Healthier Schools. METHODS: Interviews with school staff were used to elicit information about policies, practices, and guidelines to restrict/limit competitive foods in schools, before and 1 year into the campaign. To increase the validity of responses, respondents provided documentation for reported policies and guidelines. Baseline interviews were conducted between April and June 2011 and follow-up interviews were conducted between April and June 2012. RESULTS: At follow-up, significantly more schools reported having policies and/or guidelines in place to regulate food as a reward in the classroom, food served at parties and celebrations, outside foods allowed in school, and the availability of sodas and sugar-sweetened beverages. There were no measurable effects on food available in school stores, fundraisers, or afterschool programs. Availability of concrete documentation of policies was limited, but when provided, it corroborated the interview responses. CONCLUSIONS: In the context of a comprehensive school wellness policy, school wellness councils were associated with increases in school-level policies and practices that improved the competitive nutrition environment. PMID- 29498058 TI - Gender Expression, Violence, and Bullying Victimization: Findings From Probability Samples of High School Students in 4 US School Districts. AB - BACKGROUND: Young people may experience school-based violence and bullying victimization related to their gender expression, independent of sexual orientation identity. However, the associations between gender expression and bullying and violence have not been examined in racially and ethnically diverse population-based samples of high school students. METHODS: This study includes 5469 students (13-18 years) from the 2013 Youth Risk Behavior Surveys conducted in 4 urban school districts. Respondents were 51% Hispanic/Latino, 21% black/African American, 14% white. Generalized additive models were used to examine the functional form of relationships between self-reported gender expression (range: 1 = Most gender conforming, 7 = Most gender nonconforming) and 5 indicators of violence and bullying victimization. We estimated predicted probabilities across gender expression by sex, adjusting for sexual orientation identity and potential confounders. RESULTS: Statistically significant quadratic associations indicated that girls and boys at the most gender conforming and nonconforming ends of the scale had elevated probabilities of fighting and fighting-related injury, compared to those in the middle of the scale (p < .05). There was a significant linear relationship between gender expression and bullying victimization; every unit increase in gender nonconformity was associated with 15% greater odds of experiencing bullying (p < .0001). CONCLUSIONS: School-based victimization is associated with conformity and nonconformity to gender norms. School violence prevention programs should include gender diversity education. PMID- 29498059 TI - Parents' Executive Functioning and Involvement in Their Child's Education: An Integrated Literature Review. AB - BACKGROUND: Parents' involvement in their children's education is integral to academic success. Several education-based organizations have identified recommendations for how parents can best support their children's learning. However, executive functioning (EF), a high-ordered cognitive skill set, contributes to the extent to which parents can follow through with these recommendations. METHOD: This integrative review of the literature describes how executive function can affect parents' ability to facilitate and actively participate in their child's education and provides strategies for all school staff to strengthen parent-school partnerships when parents have limitations in EF. RESULTS: EF skills are fluid and influenced by several factors, including parental age, sleep, stress, and mood/affect. Despite possible limitations in parental EF, there are strategies school personnel can employ to strengthen partnership with parents to support their children's academic success. CONCLUSIONS: As reforms in education call for increased customization and collaboration with families, parental EF is an important consideration for school personnel. Awareness and understanding of how parents' EF affects children's learning will help schools better support parents in supporting their children's academic success. PMID- 29498060 TI - Crime Prevention Through Environmental Design (CPTED) Characteristics Associated With Violence and Safety in Middle Schools. AB - BACKGROUND: This study used a new Crime Prevention Through Environmental Design (CPTED) assessment tool to test the associations between physical attributes of schools and violence-related behaviors and perceptions of students. METHODS: Data were collected from 4717 students from 50 middle schools. Student perceptions of risk and safety, and violence were assessed. Evaluators used the CPTED School Assessment (CSA) to quantify how well the physical elements of each school correspond to ideal CPTED principles. Generalized linear mixed models were used to adjust for school- and student-level characteristics. RESULTS: Higher CSA scores were generally associated with higher perceptions of safety and lower levels of violence perpetration and perceived risk in unadjusted models. Higher CSA scores were also associated with lower odds of missing school because of safety concerns in most adjusted models, with significant adjusted odds ratios (AORs) ranging from 0.32 to 0.63. CSA scores for parking and bus loading areas also remained associated with higher perceived safety (AORs = 1.28 and 1.32, respectively) and lower perceived risk (AORs = 0.73 and 0.66, respectively) in adjusted models. CONCLUSIONS: The CSA is useful for assessing school environments that are associated with violence-related behaviors and perceptions. The CSA might help guide school environmental modifications to reduce violence. PMID- 29498061 TI - The Application of Optimal Defaults to Improve Elementary School Lunch Selections: Proof of Concept. AB - BACKGROUND: In this study, we applied behavioral economics to optimize elementary school lunch choices via parent-driven decisions. Specifically, this experiment tested an optimal defaults paradigm, examining whether strategically manipulating the health value of a default menu could be co-opted to improve school-based lunch selections. METHODS: The design was a randomized comparison of optimal versus suboptimal (standard) default lunch menus for all first-graders in a school district for a period of 1 week. We hypothesized that making the default lunch option healthier, while providing parents the opportunity to access and choose from the standard school menu for their child, would yield more frequent selection of healthier items than when the default option was suboptimal. RESULTS: Overall, 127 (93%) first-grade children's families participated. Among those families randomized to receive the nutritionally optimized default menu, all but one remained with these options; of those parents randomized to the standard menu (suboptimal default), all parents remained with these options (Chi2 = 123.06, df = 1, p < .001). CONCLUSIONS: The mere positioning of choices, without restricting options, significantly affected which menu items the children received during the test period. Results are proof of concept for a strategy to increase health-promoting school lunch content, procedures, and policies. PMID- 29498062 TI - School Connectedness and Chinese Adolescents' Sleep Problems: A Cross-Lagged Panel Analysis. AB - BACKGROUND: Although previous research indicates an association between school connectedness and adolescents' sleep quality, its causal direction has not been determined. This study used a 2-wave cross-lagged panel analysis to explore the likely causal direction between these 2 constructs. METHODS: Participants were 888 Chinese adolescents (43.80% boys; Mage = 15.55) who provided self-report data on school connectedness and sleep quality as well as demographic variables at the beginning and the end of a school year. RESULTS: After controlling for sex and age, we found that sleep problems at the beginning of the school year were a significant and negative predictor of school connectedness at the end of the school year (b2 = -.26, SE = .13, beta2 = -.10, p < .05), but school connectedness at the beginning of the school year did not predict sleep problems at the end of the school year (b1 = .05, SE = .03, beta1 = .09, p > .05). Separate analyses by sex showed that the above pattern of results was mainly driven by the boys. CONCLUSIONS: Our findings demonstrated that sleep problems could be a risk factor for adolescent boys' school connectedness. PMID- 29498063 TI - The Impact of State Legislation and Model Policies on Bullying in Schools. AB - BACKGROUND: The purpose of this study was to determine the impact of the coverage of state legislation and the expansiveness ratings of state model policies on the state-level prevalence of bullying in schools. METHODS: The state-level prevalence of bullying in schools was based on cross-sectional data from the 2013 High School Youth Risk Behavior Survey. Multiple regression was conducted to determine whether the coverage of state legislation and the expansiveness rating of a state model policy affected the state-level prevalence of bullying in schools. RESULTS: The purpose and definition category of components in state legislation and the expansiveness rating of a state model policy were statistically significant predictors of the state-level prevalence of bullying in schools. The other 3 categories of components in state legislation-District Policy Development and Review, District Policy Components, and Additional Components-were not statistically significant predictors in the model. CONCLUSIONS: Extensive coverage in the purpose and definition category of components in state legislation and a high expansiveness rating of a state model policy may be important in efforts to reduce bullying in schools. Improving these areas may reduce the state-level prevalence of bullying in schools. PMID- 29498065 TI - TRENDS IN ATMOSPHERIC OZONE AND ULTRAVIOLET RADIATION: MECHANISMS AND OBSERVATIONS FOR THE NORTHERN HEMISPHERE. PMID- 29498064 TI - Teacher Victimization in Authoritative School Environments. AB - BACKGROUND: Victimization in schools is not limited to students. Teachers increasingly face threats and attacks from their students. An authoritative school environment, characterized by high structure and support, has been associated with lower rates of victimization. The purpose of this study was to explore the relationship between authoritative school environments and teacher victimization rates. METHODS: Researchers examined public school teacher responses (N = 37,497) from the Schools and Staffing Survey regarding rules and issues facing the school community. Descriptive statistics were gathered, and a hierarchical regression technique was employed to assess the impact of a structured, supportive school environment on teacher victimization. RESULTS: Results indicate an authoritative school environment helped reduce rates of teacher victimization. White, female teachers are among the teachers most likely to experience violence from students. Enforcing school rules, by both teachers and administrators, is the most effective way to diminish episodes of teacher victimization. CONCLUSIONS: P-12 school personnel should emphasize the importance of enforcing school rules and reducing negative issues, such as student truancy and apathy within each school. As high levels of structure and support reduce instances of violence, these findings have important implications for school environments and teacher health. PMID- 29498066 TI - RUTHENIUM RED INHIBITION OF OXYGEN EVOLUTION AND SPECIFIC RELEASE OF THE EXTRINSIC 16 kDa POLYPEPTIDE IN A PHOTOSYSTEM II PREPARATION. AB - The inhibitory effect of the dye ruthenium red was studied in photosystem II enriched submembrane fractions. A number of distinct types of interaction were found, which differed in their concentration range and required incubation time. Ruthenium red instantaneously quenches the initial chlorophyll a fluorescence level (F0 ) and the maximum fluorescence level (Fm ) by enhancing radiationless deactivation in the chlorophyll light harvesting complex. Associated with this quenching of fluorescence is an instantaneous decrease in the quantum yield of oxygen evolution. Ruthenium red also inhibited the light saturated rate of oxygen evolution and the variable fluorescence, monitored 80 us after a saturating excitation-flash. These inhibitions increased with incubation time and became greater than 50% within 5 min. Although ruthenium red was known to affect Ca2+ or Cl- sites specifically, the inhibitory action was more pronounced than simple Ca2+ or Cl- depletion. Incubation with ruthenium red for 5 min blocks the Z P680+ -> Z+ P680 charge transfer reaction. Upon mixing with the photosystem II preparation, ruthenium red induced specific release of the extrinsic 16 kDa polypeptide associated with water-splitting without release of Mn. It is proposed that the inhibitor produces an ionic imbalance which alters the configuration of the donor side of photosystem II. PMID- 29498067 TI - THE RESOLUTION OF CHLOROPHYLL a/b BINDING PROTEINS BY A PREPARATIVE METHOD BASED ON FLAT BED ISOELECTRIC FOCUSING. AB - We describe a new fractionation method for intrinsic membrane proteins based on flat bed isoelectric focusing (IEF) in granulated gel. The characteristics of the separation in the presence of the non-ionic detergent dodecylmaltoside are considered. The method has been applied to the fractionation of chlorophyll a/b binding proteins from chloroplast grana membranes. Several Light Harvesting Complexes II (LHC II) have been resolved showing differences in their polypeptide composition. Probing with monoclonal and polyclonal antibodies showed that polypeptides belonging to different [EF fractions with the same mobility in denaturing sodium dodecyl sulphate polyacrylamide gel electrophoresis, are immunologically distinct polypeptides. This is the first report of the presence in the thylakoid membrane of a number of LHCII polypeptides that may reflect the genetic complexity of the Cab genes. Moreover preparative amounts have been obtained of the minor chlorophyll a/b proteins CP 29, CP 26 and CP 24 that have been recently described. The analysis of a currently used LHCII preparation by the present method shows that this fraction is actually contaminated by two minor chlorophyll a/b proteins. PMID- 29498068 TI - PTERIN- AND FLAVIN-LIKE FLUORESCENCE ASSOCIATED WITH ISOLATED FLAGELLA OF Euglena gracilis. AB - Fluorescence excitation- and emission spectra indicate the presence of pterin(s) and flavin(s) in isolated flagella of the phytoflagellate Euglena gracilis. These compounds appear to bind at least in part non-covalently to the molecular framework of the paraflagellar body, which is the presumed photoreceptor organelle and which is attached to the isolated flagella. A compound with pterin like fluorescence excitation and emission spectrum could he extracted with methanol from isolated flagella and could he recovered on thin-layer silica gels. Besides the previously assumed photoreceptor function of flavins, our results suggest also a role for pterins in the photosensory transduction chain of Euglena gracilis. PMID- 29498069 TI - FLAVIN TYPE ACTION SPECTRUM OF NITRATE UTILIZATION BY Monoraphidium braunii. AB - The light-dependent utilization of nitrate by the green alga Monoraphidium braunii, coming from nocturnal dark periods, shows an action spectrum of flavin type with two main bands: one in the blue, peaking at 450 and 480 nm, and the other in the near-UV region with a maximum at 365 nm. Other results indicate that cells growing on nitrate as the only nitrogen source resynthesize nitrate reductase daily, which implies the nocturnal loss of this enzyme. The biosynthesis of nitrate reductase at the beginning of the light periods can proceed under red light. In addition, blue or near-UV light is required for the activation of the previously formed nitrate reductase. PMID- 29498070 TI - Leaf and canopy photosynthesis of a chlorophyll deficient soybean mutant. AB - The photosynthetic, optical, and morphological characteristics of a chlorophyll deficient (Chl-deficient) "yellow" soybean mutant (MinnGold) were examined in comparison with 2 green varieties (MN0095 and Eiko). Despite the large difference in Chl content, similar leaf photosynthesis rates were maintained in the Chl deficient mutant by offsetting the reduced absorption of red photons by a small increase in photochemical efficiency and lower non-photochemical quenching. When grown in the field, at full canopy cover, the mutants reflected a significantly larger proportion of incoming shortwave radiation, but the total canopy light absorption was only slightly reduced, most likely due to a deeper penetration of light into the canopy space. As a consequence, canopy-scale gross primary production and ecosystem respiration were comparable between the Chl-deficient mutant and the green variety. However, total biomass production was lower in the mutant, which indicates that processes other than steady state photosynthesis caused a reduction in biomass accumulation over time. Analysis of non photochemical quenching relaxation and gas exchange in Chl-deficient and green leaves after transitions from high to low light conditions suggested that dynamic photosynthesis might be responsible for the reduced biomass production in the Chl deficient mutant under field conditions. PMID- 29498071 TI - High performance collision cross section calculation-HPCCS. AB - Since the commercial introduction of Ion Mobility coupled with Mass Spectrometry (IM-MS) devices in 2003, a large number of research laboratories have embraced the technique. IM-MS is a fairly rapid experiment used as a molecular separation tool and to obtain structural information. The interpretation of IM-MS data is still challenging and relies heavily on theoretical calculations of the molecule's collision cross section (CCS) against a buffer gas. Here, a new software (HPCCS) is presented, which performs CCS calculations using high perfomance computing techniques. Based on the trajectory method, HPCCS can accurately calculate CCS for a great variety of molecules, ranging from small organic molecules to large protein complexes, using helium or nitrogen as buffer gas with considerable gains in computer time compared to publicly available codes under the same level of theory. HPCCS is available as free software under the Academic Use License at https://github.com/cepid-cces/hpccs. (c) 2018 Wiley Periodicals, Inc. PMID- 29498072 TI - Perinatal Outcomes of Fetal Lower Urinary Tract Obstruction After Vesicoamniotic Shunting Using a Double-Basket Catheter. AB - OBJECTIVES: To evaluate the perinatal survival and renal function of fetuses with lower urinary tract obstruction (LUTO) who underwent vesicoamniotic shunting using a double-basket catheter METHODS: We retrospectively reviewed 32 fetuses with LUTO who underwent vesicoamniotic shunting using a double-basket catheter between 1998 and 2013. RESULTS: Among the 32 fetuses examined, 5 died because of termination of pregnancy, and 2 died in utero. The median gestational age at diagnosis was 15.5 (range, 10.0-27.3) weeks, and that at initial shunting was 17.1 (range, 12.3-32.2) weeks. Shunt dislocation or occlusion occurred in 18 of 42 procedures (42.8%). The median gestational age at delivery for the 25 live births was 35.5 (range, 28-40) weeks. Postnatal diagnosis revealed posterior urethral valves in 15 fetuses, a cloacal anomaly in 7, and urethral stenosis in 3. Three neonatal deaths occurred, resulting in an overall perinatal survival rate of 68.8% (22 of 32). The rates of normal renal function were 40.6% (13 of 32) at 28 days and 40% (10 of 25) at 2 years after birth. The absence of oligohydramnios after shunting was the only prognostic factor for normal renal function at 2 years (P < .05). CONCLUSIONS: Vesicoamniotic shunting may be helpful for fetuses with LUTO. PMID- 29498073 TI - Children's emotion understanding in relation to attachment to mother and father. AB - Although attachment plays a key role in children's socio-emotional development, little attention has been paid to the role of children's attachment to their father. This study examined whether insecure attachment to each parent was associated with reduced emotion understanding in children and whether children showed consistent attachments to their mother and father. We measured children's attachment to each parent using the Manchester Child Attachment Story Task and child emotion understanding using the Test of Emotion Comprehension (children's Mage = 5.64 years, SD = 0.84). The results indicated that insecure father-child attachment and insecure mother-child attachment were each associated with lower emotion understanding in children after controlling for parent's depressive symptoms and children's age. There was significant concordance of child attachment to mother and father. The findings provide support for convergence of children's attachment across parents and suggest that father-child attachment is an important factor to consider when examining children's emotion understanding. Statement of contribution What is already known on this subject Secure mother child attachment is positively associated with children's emotional competence. Children form similar representations of attachment to their mother and father. What the present study adds Both mother-child and father-child attachment are associated with children's emotion understanding. The study's findings highlight the importance of father-child attachment in their children's emotion understanding. The study provides support for concordance of children's attachment across parents. PMID- 29498074 TI - Influence of Ulipristal Acetate Therapy on Uterine Fibroid-Related Symptoms and on Uterine and Fibroid Volumes and Vascularity Indices Assessed by Ultrasound. AB - OBJECTIVES: To investigate the modifications of uterine and fibroid volume, to study Doppler changes in uterine arteries and fibroid-supplying vessels, and to assess possible symptomatic relief after 3 months of treatment with ulipristal acetate. METHODS: Forty-two premenopausal women with symptomatic fibroids were included in the study. They were evaluated clinically for the symptoms reported and underwent ultrasound examinations before starting treatment and after 3 months of therapy with ulipristal acetate. Transvaginal scanning was performed by the same sonographer, who measured the uterine volume and uterine artery pulsatility index and resistive index. Considering that some patients had more than 1 fibroid, the vascularization (supplying vessel pulsatility and resistive indices), locations, and sizes of a total of 73 fibroids were also recorded. RESULTS: After 3 months of ulipristal acetate, patients had a significant improvement of all symptoms (P < .05). The percentage of uterine volume reduction was 14% (P = .03), with fibroid volume reduction of 32.8% (P = .01). Uterine artery vascular indices decreased after treatment, but their reduction did not reach significant results, whereas all fibroid vascular indices decreased significantly after 3 months of ulipristal acetate (P < .05). When the fibroids were divided according to their localization, all had significant volume reduction after therapy, but type 5 had the highest decrease (42%) compared to other fibroid types (P = .03). CONCLUSIONS: Fibroid treatment with ulipristal acetate resulted in a significant improvement of fibroid-related symptoms; moreover, it proved to be effective in decreasing both uterine and fibroid volumes and fibroid vascularization. Type 5 fibroids seem to have the most major response to treatment. PMID- 29498075 TI - Steered molecular dynamics simulations for uncovering the molecular mechanisms of drug dissociation and for drug screening: A test on the focal adhesion kinase. AB - Drug-binding kinetics could play important roles in determining the efficacy of drugs and has caught the attention of more drug designers. Using the dissociation of 1H-pyrrolo[2,3-b]-pyridines from the focal adhesion kinase as an example, this work finds that steered molecular dynamics simulations could help screen compounds with long-residence times. It also reveals a two-step mechanism of ligand dissociation resembling the release of ADP from protein kinase A reported earlier. A phenyl group attaching to the pyrrole prolongs residence time by creating a large activation barrier for transition from the bound to the intermediate state when it becomes exposed to the solvent. Principal component analysis shows that ligand dissociation does not couple with large-scale collective motions of the protein involving many of its amino acids. Rather, a small subset of amino acids dominates. Some of these amino acids do not contact the ligands directly along the dissociation pathways and could exert long-range allosteric effects. (c) 2018 Wiley Periodicals, Inc. PMID- 29498076 TI - Clinical Value of 3-Dimensional Ultrasound in Gynecology. AB - This report provides examples of using 3-dimensional ultrasound diagnostically in gynecology. The cost efficiency it provides and the wide range of applications it has support the routine use of this ultrasound technology in the practice of gynecology. PMID- 29498077 TI - Persistent symptoms and activity changes three months after mild traumatic brain injury. AB - BACKGROUND/AIM: Approximately, 80% of traumatic brain injuries are considered mild in severity. Mild traumatic brain injury (mTBI) may cause temporary or persisting impairments that can adversely affect an individual's ability to participate in daily occupations and life roles. This study aimed to identify symptoms, factors predicting level of symptoms and functional and psycho-social outcomes for participants with mTBI three months following injury. METHOD: Patients discharged from the Emergency Department of a major metropolitan hospital with a diagnosis of mTBI were contacted by telephone three months after injury. An interview with two questionnaires was administered: The Concussion Symptom Inventory (CSI) Scale and the Rivermead Head Injury Follow-Up Questionnaire (RHIFUQ). Data obtained were used to determine the type and prevalence of post-concussion symptoms and their impact on activity change. RESULTS: Sixty-three people with mTBI participated in the study. The majority of participants (81%) reported that all symptoms had resolved within the three-month time frame. Of those still experiencing symptoms, workplace fatigue (22%) and an inability to maintain previous workload/standards (17%) were reported. CONCLUSION: There is a small, but clinically significant, subgroup of patients who continue to experience symptoms three-month post-mTBI. Symptoms experienced beyond the expected three-month recovery timeframe have the potential to adversely affect an individual's ability to participate in daily occupation and return to work. PMID- 29498079 TI - The McConnell Sign is Seen in Patients With Acute Chest Syndrome. AB - Bedside ultrasound is often used as a part of the evaluation of patients who are critically ill. The McConnell sign is an important echocardiographic finding in some critically ill patients with pulmonary embolism and an acute right ventricular infarct. We present 3 critically ill patients with confirmed acute chest syndrome who showed the McConnell sign on echocardiography. In patients with sickle cell disease presenting with chest pain and shortness of breath, the presence of the McConnell sign does not narrow the differential diagnosis between pulmonary embolism, an acute right ventricular infarct, and acute chest syndrome. PMID- 29498080 TI - Erratum. PMID- 29498081 TI - Associations of insulin-like growth factor-I and insulin-like growth factor binding protein-3 with bone quality in the general adult population. AB - OBJECTIVE: Growth hormone (GH) and its main mediator, insulin-like growth factor I (IGF-I), play a significant role in bone metabolism. The relations between IGF I and bone mineral density (BMD) or osteoporosis have been assessed in previous studies but whether the associations are sex-specific remains uncertain. Moreover, only a few studies examined bone quality assessed by quantitative ultrasound (QUS). We aimed to investigate these associations in the general population of north-east Germany. DESIGN AND MEASUREMENTS: Data from 1759 men and 1784 women who participated in the baseline examination of the Study of Health in Pomerania (SHIP)-Trend were used. IGF-I and IGF-binding protein-3 (IGFBP-3) concentrations were measured on the IDS-iSYS multidiscipline automated analyser (Immunodiagnostic Systems Limited). QUS measurements were performed at the heel (Achilles InSight, GE Healthcare). Sex-specific linear and multinomial logistic regression models adjusted for potential confounders were calculated. RESULTS: Linear regression analyses revealed significant positive associations between IGF I and IGF-I/IGFBP-3 ratio, a marker for free IGF-I, with all QUS parameters in men. Among women, we found an inverse association between IGF-I and the QUS-based fracture risk but no association with any other QUS parameter. There was no association between IGFBP-3 and the QUS-based fracture risk. CONCLUSIONS: Our data suggest an important role of IGF-I on bone quality in men. The observed association of IGF-I with the QUS-based stiffness index and QUS-based fracture risk in this study might animate clinicians to refer patients with low IGF-I levels, particularly men, to a further evaluation of risk factors for osteoporosis and a detailed examination of the skeletal system. PMID- 29498082 TI - Heterogeneous hemoglobin lower thresholds in clinical laboratories. PMID- 29498078 TI - Stopping nucleos(t)ide analogue treatment in Caucasian hepatitis B patients after HBeAg seroconversion is associated with high relapse rates and fatal outcomes. AB - BACKGROUND: Stopping nucleos(t)ide analogues (NA) after hepatitis B e antigen (HBeAg) seroconversion is associated with high relapse rates in Asian patients, but data in Caucasian cohorts are scarce. Clinical course, outcomes and immunological aspects of chronic hepatitis B infections differ substantially between distinct ethnicities. AIM: The aim of this study was to determine relapse rates, factors predicting relapse and clinical outcomes after nucleos(t)ide analogue cessation in a large, predominantly Caucasian cohort of chronic hepatitis B patients with nucleos(t)ide analogue-induced HBeAg seroconversion. METHODS: This is a nationwide observational cohort study including HBeAg positive, mono-infected chronic hepatitis B patients with nucleos(t)ide analogue induced HBeAg seroconversion from 18 centres in Belgium. RESULTS: A total of 98 patients with nucleo(s)tide analogue-induced HBeAg seroconversion were included in the study. Of the 62 patients who stopped treatment after a median consolidation treatment of 8 months, 30 relapsed. Higher gamma-glutamyl transferase levels at both treatment initiation (HR 1.004; P = 0.001 per unit increment) and HBeAg seroconversion (HR 1.006; P = 0.013 per unit increment) were associated with an increased risk of clinically significant relapse in a multivariate Cox regression model. Treatment cessation led to liver-related death in 2 patients, of whom one showed a severe flare. Of the patients who continued treatment after HBeAg seroconversion, none relapsed or developed severe hepatic outcomes. CONCLUSION: Treatment withdrawal in Caucasian chronic hepatitis B patients after nucleos(t)ide analogue-induced HBeAg seroconversion results in viral relapses in more than half of patients with potential fatal outcomes. These real-world data further lend support to preferentially continue NA treatment after HBeAg seroconversion until HBsAg loss. PMID- 29498083 TI - Chemical shift magnetic resonance imaging could predict subclinical cortisol production from an incidentally discovered adrenal mass. AB - CONTEXT: To investigate whether any association between chemical shift magnetic resonance (MRI) findings, cortisol secretion and pathological findings exists that could predict subclinical hypercortisolism (SCH) in patients with adrenal incidentalomas (AI). DESIGN: Retrospective, cross-sectional study in a tertiary centre. PATIENTS: Sixty-eight subjects with AIs and 13 patients with Cushing's syndrome (CS). Patients with AIs were categorized according to cortisol levels post 1 mg dexamethasone (post-DST). MEASUREMENTS: Visual inspection of the lipid content of the adrenal tumour and calculation of adrenal-to-spleen ratio (ASR), the signal intensity index (SII), volume and the assessment of the association between pathological, radiological and hormonal findings in surgically treated patients. RESULTS: Percentage of clear cells was correlated with ASR (r = -.525, P = .01), SII (r = .465, P = .025), post-DST cortisol (r = -.711, P < .001) and ACTH (r = .475, P = .046). By ANOVA and post hoc analysis, patients with CS and five subjects with a post-DST cortisol greater than 137 nmol/L differed significantly in ASR and SII from those with a post-DST cortisol less than 50 nmol/L. An ASR level higher than 0.245 (OR 19.7, 95% CI 1.5-257.5; P = .023) and a SII level lower than 78.37 (OR 15.6, 95% CI 1.2-20; P = .034) remained as the independent predictors for SCH while age, presence of arterial hypertension or tumour volume did not make significant contribution to the models. CONCLUSIONS: Cortisol hypersecretion by adrenal adenomas is associated with distinctive MRI characteristics. The quantitative assessment of intracellular lipid in an AI could help distinguish patients with a clear phenotype of SCH. PMID- 29498084 TI - RNAi-mediated reduction of hepatic Tmprss6 diminishes anemia and secondary iron overload in a splenectomized mouse model of beta-thalassemia intermedia. AB - Diminished beta-globin synthesis in beta-thalassemia is associated with ineffective erythropoiesis, leading to secondary iron overload caused by inappropriately low levels of hepcidin and to splenomegaly in the symptomatic thalassemias. Splenectomy is often employed in patients with beta-thalassemia to reduce hemolysis. Expression of the iron regulatory peptide hormone hepcidin is repressed by the serine protease TMPRSS6. Hepcidin induction by RNAi-mediated inhibition of TMPRSS6 expression reduces iron overload and mitigates anemia in murine models of beta-thalassemia intermedia. To interrogate the efficacy of RNAi mediated reduction of Tmprss6 in splenectomized beta-thalassemia, splenectomized beta-thalassemic Hbbth3/+ animals were treated with a GalNAc-conjugated siRNA targeting Tmprss6 (GalNAc-Tmprss6) and their hematological and iron parameters monitored. We demonstrate that treatment with GalNAc-Tmprss6 significantly diminishes Tmprss6 expression and appropriately elevates hepcidin expression in splenectomized Hbbth3/+ animals. Similar to unsplenectomized animals, treated animals have markedly improved anemia due to diminished ineffective erythropoiesis and reduced iron loading in both serum and tissue. These results suggest that RNAi-mediated reduction of Tmprss6 may have positive outcomes even in splenectomized beta-thalassemia patients. PMID- 29498085 TI - What's in a name: are cultured red blood cells 'natural'? AB - The case of cultured red blood cells (RBCs) currently being grown in a laboratory for future use in human transfusion raises questions about the ontological status of such products of modern biotechnology. This paper presents results from a six year ethnographic study involving interviews, focus groups and other forms of engagement with the scientific research team and other stakeholders, including public groups, which sought to understand respondents' reactions to cultured RBCs. These cells, derived from stem cell technology, have the potential to address the global shortage of donated blood. How these blood cells are situated within the spectrum of 'natural' to 'synthetic' will shape expectations and acceptance of this product, both within the scientific community and by wider publics: these blood cells are both novel and yet, at the same time, very familiar. Drawing on discussions related to classification and 'anchoring', we examine the contrasting discourses offered by our respondents on whether these blood cells are 'natural' or not and consider the impact that naming might have on both their future regulation and the eventual uptake of cultured RBCs by society. PMID- 29498086 TI - Gossypol stimulates opening of a Ca2+ - and Na+ -permeable but Ni2+ - and Co2+ impermeable pore in bEND.3 endothelial cells. AB - Gossypol, a polyphenolic dialdehyde toxin isolated from cotton seed, has anti cancer properties and has recently shown some success in the treatment of glioma. Its effects on brain neurons and blood vessels are poorly understood. In this work we examined the effects of gossypol on cytosolic Ca2+ concentration ([Ca2+ ]i ) of mouse brain bEND.3 endothelial cells. Cell viability tests revealed that after 3 hour and 18 hour exposures, 10 umol/L gossypol caused 23% and 65% cell death, respectively; 3 umol/L gossypol caused no and 21% cell death, respectively. [Ca2+ ]i was raised concentration-dependently by 1-10 umol/L gossypol. We then explored the Ca2+ signalling triggered by 3 umol/L gossypol, which inflicted minimal toxicity: the Ca2+ signal was composed largely of Ca2+ influx and to a small extent, intracellular Ca2+ release. Such Ca2+ influx was much larger than store-operated Ca2+ influx triggered by maximal Ca2+ pool depletion. The Ca2+ influx triggered by 3 and 10 umol/L gossypol caused NO release and cell death, respectively. Gossypol also triggered influx of Mn2+ and Na+ , but not Ni2+ and Co2+ . Gossypol-triggered Ca2+ signal was inhibited only by 14% and 37% by 100 umol/L La3+ and 10 umol/L nimodipine, respectively; and not suppressed at all by 5 mmol/L Ni2+ . Gossypol-triggered Ca2+ signal was suppressed by 78% by 30 umol/L ruthenium red, suggesting gossypol may act on TRPV channels. Our results suggest gossypol triggered opening of a non-selective cation pore, possibly a member of the TRPV family. PMID- 29498087 TI - Acute Alcohol Co-Ingestion and Hospital-Treated Deliberate Self-Poisoning: Is There an Effect on Subsequent Self-Harm? AB - The aim of this study was to determine the relationship between alcohol co ingestion in an index deliberate self-poisoning (DSP) episode with repeated DSP and subsequent suicide. A retrospective cohort study was conducted involving 5,669 consecutive index presentations to a toxicology service following DSP between January 1, 1996, and October 31, 2010. Records were probabilistically matched to National Coronial Information System data to identify subsequent suicide. Index DSPs were categorized on co-ingestion of alcohol, and primary outcomes analyzed were repetition of any DSP, rates of repeated DSP, time to first repeat DSP, and subsequent suicide. Co-ingestion of alcohol occurred in 35.9% of index admissions. There was no difference between those who co-ingested alcohol (ALC+) and those who did not co-ingest alcohol (ALC-) in terms of proportion of repeat DSP, number of DSP events, or time to first repeat DSP event. Forty-one (1.0%) cases were probabilistically matched to a suicide death; there was no difference in the proportion of suicide between ALC+ and ALC- at 1 or 3 years. There was no significant relationship between the co-ingestion of alcohol in an index DSP and subsequent repeated DSP or suicide. Clinically, this highlights the importance of mental health assessment of patients that present after DSP, irrespective of alcohol co-ingestion at the time of event. PMID- 29498088 TI - Exclusive breastfeeding in hospital predicts longer breastfeeding duration in Canada: Implications for health equity. AB - BACKGROUND: Breastfeeding has many established health benefits for women and children. We examined the association between maternal education, newborn feeding in hospital, and long-term breastfeeding duration. METHODS: We studied 3195 Canadian mother-infant dyads in the CHILD pregnancy cohort. Newborn feeding was documented from hospital records. Caregivers reported sociodemographic factors and infant feeding at 3, 6, 12, 18, and 24 months. RESULTS: Overall, 97% of newborns initiated breastfeeding and 74% were exclusively breastfed in hospital. Exclusively breastfed newborns were ultimately breastfed longer compared with those who received formula supplementation during their hospital stay (median 11.0 vs 7.0 months, P < .001). After controlling for maternal age, ethnicity, birth mode, and gestational age, exclusively breastfed newborns had a 21% reduced risk of breastfeeding cessation (HR = 0.79, 0.71-0.87). This effect was strongest among women without a postsecondary education (HR = 0.65, 0.53-0.79). DISCUSSION: Exclusive breastfeeding in hospital is associated with longer breastfeeding duration, particularly among women of lower socioeconomic status. Initiatives that support exclusive breastfeeding of newborns in hospital could improve long term breastfeeding rates and help reduce health inequities arising in early life. PMID- 29498089 TI - Predicting Suicide Ideation in the Military: The Independent Role of Aggression. AB - The purpose of this study was to examine the longitudinal relationship between aggression and suicide ideation when controlling for other externalizing (i.e., alcohol misuse and risk-taking) and internalizing (i.e., depression and sleep problems) risk factors in an active duty, military sample. Preexisting data from a longitudinal study were analyzed to assess the wellness of service members across the deployment cycle. Participants were 944 active duty service members (95% male, 48% between 18 and 24 years old) who completed surveys upon initial return from deployment and approximately 3 months later. After controlling for other externalizing (alcohol misuse, risk-taking) and internalizing (depression, sleep problems) risk factors, service members reporting aggression were significantly more likely to report suicide ideation than those reporting no aggression (OR = 3.19; OR 95% CI: 1.16-8.80). The independent nature of the relationship between anger and suicidality suggests aggression may be an important indicator of suicidality for service members. Understanding the role of aggression in suicidality may improve the ability to identify at-risk service members and to develop effective interventions to reduce suicide risk. PMID- 29498090 TI - Increased concentration of serum periostin is associated with poor outcome of patients with aneurysmal subarachnoid hemorrhage. AB - OBJECTIVE: To explore the role of serum periostin in patients with aneurysmal subarachnoid hemorrhage (aSAH). METHOD: We conducted a retrospective study and 124 aSAH patients treated in Shenzhen People's hospital during March 1st 2015 to December 30th 2016 were included. Baseline information, neurological status and clinical outcome were recorded. Blood samples on admission were collected and enzyme linked immunosorbent assay (ELISA) kits were used to detect the serum level of periostin. Spearman's Correlation Analysis was used to analyze the correlation between periostin and clinical severity. Receiver operating characteristic (ROC) curve was performed to investigate variables' prognostic value in patients with aSAH. RESULTS: The average age of patients included was 57.23 years old. Preliminary analysis revealed that serum periostin was significantly correlated with clinical severity. Patients with poor outcome at 12 months had higher level of periostin than patients with good outcome. Multivariate logistic regression analysis showed elevated level of periostin was significantly associated with poor outcome and the AUC was 0.85 for periostin in predicting poor outcome of patient with aSAH. CONCLUSION: Elevated serum periostin concentrations are significantly associated with clinical severity and poor outcome of aSAH patients, which indicate serum periostin can be used as a prognostic biomarker in patients with aSAH. PMID- 29498091 TI - Intramolecular O-H?O and C-H?O hydrogen bond cooperativity in D-glucopyranose and D-galactopyranose-A DFT/GIAO, QTAIM/IQA, and NCI approach. AB - Density functional theory calculations are used to compute proton nuclear magnetic resonance (NMR) chemical shifts, interatomic distances, atom-atom interaction energies, and atomic charges for partial structures and conformers of alpha-D-glucopyranose, beta-D-glucopyranose, and alpha-D-galactopyranose built up by introducing OH groups into 2-methyltetrahydropyran stepwisely. For the counterclockwise conformers, the most marked effects on the NMR shift and the charge on the OH1 proton are produced by OH2, those of OH3 and OH4 being somewhat smaller. This argues for a diminishing cooperative effect. The effect of OH6 depends on the configuration of the hydroxymethyl group and the position, axial or equatorial, of OH4, which controls hydrogen bonding in the 1,3-diol motif. Variations in the interaction energies reveal that a "new" hydrogen bond is sometimes formed at the expense of a preexisting one, probably due to geometrical constraints. Whereas previous work showed that complexing a conformer with pyridine affects only the nearest neighbour, successive OH groups increase the interaction energy of the N?H1 hydrogen bond and reduce its length. Analogous results are obtained for the clockwise conformers. The interaction energies for C H?OH hydrogen bonding between axial CH protons and OH groups in certain conformers are much smaller than for O-H?OH bonds but they are largely covalent, whereas those of the latter are predominantly coulombic. These interactions are modified by complexation with pyridine in the same way as O-H?OH interactions: the computed NMR shifts of the CH protons increase, the atom-atom distances are shorter, and interaction energies are enhanced. PMID- 29498092 TI - Editorial for the Biometrical Journal Special Issue ISCB 2016. PMID- 29498093 TI - Phase-encoded xSPEN: A novel high-resolution volumetric alternative to RARE MRI. AB - PURPOSE: To develop a rapid, non-CPMG high-resolution volumetric imaging approach, exhibiting a speed and in-plane resilience to field inhomogeneities comparable to RARE/turbo-spin-echo (TSE) while endowed with unique downsampling characteristics. METHODS: A multi-scan extension of cross-term spatiotemporal encoding (xSPEN) is introduced and analyzed. The method simultaneously yields ky /kz data containing low and high frequency components, as well as transposed, low resolution z/y images. This dual k-/spatial-domain information is captured by a multi-scan procedure that phase-encodes ky while simultaneously slice-selecting z. A reconstruction scheme converting this information into high resolution 3D images with fully multiplexed volumetric coverage is introduced and exemplified. RESULTS: Phase-encoded xSPEN was tested by human brain imaging at sub-mm resolutions. The method exceeded 2D TSE's sensitivity by factors of ~3-4, while providing similar resolution and SNR as 3D TSE in ~50% acquisition times. The method's contrast is dominated by T2 and is free from "bright-fat" effects associated to spin-echo trains. Further acceleration is enabled by the method's downsampling abilities. Tradeoffs between encoding time, number of measurements, spatial resolution, SNR, and artifact levels are also laid out. CONCLUSION: A new MRI strategy is introduced delivering high in- and through-plane resolutions while enjoying full Fourier multiplexing, leading to fast acquisitions with high SNR. PMID- 29498094 TI - Trouble at teens' fingertips: Youth sexting and the law. AB - The last decade has seen a rapid increase in the use of smartphones among young children and adolescents. One consequence of this phenomenon is sexting. Although researchers of sexting have yet to arrive at a single, cohesive definition for the behavior, it generally involves the transmission of text, pictures, or videos containing sexual material. Different definitions of the behavior have led to widely varying estimates of its prevalence, although some studies have documented relatively high rates of sexting among teenagers. As adolescence is the time period in people's lives where the psychological tasks of identity consolidation and the development of intimate relationships become primary, it is not surprising that many teens utilize sexting as one way of practicing skills associated with successful completion of these tasks. The criminal prosecution of sexting cases, then, raises many legal and ethical questions. Offenders may be prosecuted under state or federal child pornography laws or state-specific sexting laws. Sexting laws, particularly in instances of consensual sext exchange, call into question who they are meant to protect and from what. In this article we review the research on teen sexting, its prevalence, and its association with mental health problems; summarize legal responses to the behavior in the United States; and identify considerations for prosecutors and legal decision-makers facing sexting cases. PMID- 29498095 TI - Melatonin-mediated miR-526b-3p and miR-590-5p upregulation promotes chondrogenic differentiation of human mesenchymal stem cells. AB - Bone marrow-derived mesenchymal stem cells (BMSCs), with inherent chondrogenic differentiation potential appear to be ideally suited for therapeutic use in cartilage regeneration. Accumulating evidence has demonstrated that melatonin can promote chondrogenic differentiation in human BMSCs. However, little is known about the mechanism. MicroRNAs (miRNAs) have been shown to regulate the differentiation of BMSCs, but their roles in melatonin-promoted chondrogenic differentiation have not been characterized. Here, we demonstrate that melatonin promoted chondrogenic differentiation of human BMSCs via upregulation of miR-526b 3p and miR-590-5p. Mechanistically, the elevated miR-526b-3p and miR-590-5p enhanced SMAD1 phosphorylation by targeting SMAD7. Additionally, administration of miR-526b-3p mimics or miR-590-5p mimics successfully promoted the chondrogenic differentiation of human BMSCs. Collectively, our study suggests that modification of BMSCs using melatonin or miRNA transduction could be an effective therapy for cartilage damage and degeneration. PMID- 29498096 TI - The CDKN2A polymorphisms and the susceptibility of HBV-related gestational diabetes mellitus. AB - BACKGROUND: Single-nucleotide polymorphisms (SNPs) were discovered in HBV-related gestational diabetes mellitus, but it still unclear whether these SNPs are associated with the susceptibility of HBV-related gestational diabetes mellitus. METHODS: The investigation of the association between CDKN2A polymorphisms and occurrence of HBV-related gestational diabetes mellitus (GDM) in Chinese was assessed in the case-control study. A total of 480 pregnant patients with HBV and 530 pregnant controls were consecutively recruited from January 2015 to December 2016. Polymerase chain reaction-restriction fragment length polymorphisms (PCR RFLP) method was applied to measure genotyping for the detection of CDKN2A. RESULTS: The significant differences in the frequency of CDKN2A genotype distributions, rs10811661 and rs564398, were found by Chi-square test. Using conditional logistic analysis, individuals carrying the CDKN2A rs10811661 TC and TT genotypes and CDKN2A rs564398 AA and AG genotypes were related to a greater risk of HBV-related GDM compared with the genotype. CONCLUSIONS: In conclusion, the CDKN2A rs10811661 and rs564398 polymorphisms showed association with a greater risk of HBV-related GDM in a Chinese population. PMID- 29498098 TI - Computed Tomographic Angiography of the Pancreas in Cats with Chronic Diabetes Mellitus Compared to Normal Cats. AB - BACKGROUND: Diabetes mellitus (DM) is a common endocrinopathy in cats. No known diagnostic test or patient characteristic at the time of diagnosis can predict likely disease course, unlike in people in whom computed tomographic angiography (CTA) is used. No published data exist regarding the CTA appearance of the pancreas in cats with DM, and thus, it is unknown what if any CTA variables should be further assessed for associations with pancreatic endocrine function. HYPOTHESIS/OBJECTIVES: A significant difference in pancreatic attenuation, volume, and size will be identified between normal cats and those with chronic DM on CTA. ANIMALS: Ten healthy control cats and 15 cats with naturally occurring DM present for >12 months. METHODS: Prospective cross-sectional study comparing pancreatic attenuation, enhancement pattern, size, volume, pancreatic volume-to body weight ratio (V:BW), pancreatic arterial: portal phase ratio (A:P), time-to arterial enhancement, and time-to-peak portal enhancement on CTA between sedated healthy control cats and those with chronic DM. RESULTS: The pancreas in cats with chronic DM was significantly larger, had higher volume, higher V:BW, and shorter time-to-peak portal enhancement on CTA when compared to normal cats. CONCLUSIONS AND CLINICAL IMPORTANCE: Peak portal enhancement time, pancreatic size, pancreatic volume, and V:BW can be used to differentiate normal sedated cats from those with chronic DM by CTA. These variables warrant further investigation to identify possible associations with endocrine function. PMID- 29498099 TI - Large number of cutaneous neurofibromas beyond age-appropriate incidence in a patient with a large deletion of NF1. PMID- 29498097 TI - Non-contrast MR imaging of blood-brain barrier permeability to water. AB - PURPOSE: Many brain diseases are associated with an alteration in blood-brain barrier (BBB) and its permeability. Current methods using contrast agent are primarily sensitive to major leakage of BBB to macromolecules, but may not detect subtle changes in BBB permeability. The present study aims to develop a novel non contrast MRI technique for the assessment of BBB permeability to water. METHODS: The central principle is that by measuring arterially labeled blood spins that are drained into cerebral veins, water extraction fraction (E) and permeability surface-area product (PS) of BBB can be determined. Four studies were performed. We first demonstrated the proof-of-principle using conventional ASL with very long post-labeling delays (PLD). Next, a new sequence, dubbed water-extraction with-phase-contrast-arterial-spin-tagging (WEPCAST), and its Look-Locker (LL) version were developed. Finally, we demonstrated that the sensitivity of the technique can be significantly enhanced by acquiring the data under mild hypercapnia. RESULTS: By combining a strong background suppression with long PLDs (2500-4500 ms), ASL spins were reliably detected in the superior sagittal sinus (SSS), demonstrating the feasibility of measuring this signal. The WEPCAST sequence eliminated partial voluming effects of tissue perfusion and allowed quantitative estimation of E = 95.5 +/- 1.1% and PS = 188.9 +/- 13.4 mL/100 g/min, which were in good agreement with literature reports. LL-WEPCAST sequence shortened the scan time from 19 min to 5 min while providing results consistent with multiple single-PLD acquisitions. Mild hypercapnia increased SNR by 78 +/- 25% without causing a discomfort in participants. CONCLUSION: A new non-contrast technique for the assessment of global BBB permeability was developed, which may have important clinical applications. PMID- 29498101 TI - Correlating the Dermatology Life Quality Index and Skin Discoloration Impact Evaluation Questionnaire tools in disorders of hyperpigmentation. PMID- 29498102 TI - A simple head-sized phantom for realistic static and radiofrequency characterization at high fields. AB - PURPOSE: To demonstrate a simple head-sized phantom for realistic static and RF field characterization in high field systems. METHODS: The head-sized phantom was composed of an ellipsoidal compartment and a spherical cavity to mimic the nasal cavity. The phantom was filled with an aqueous solution of polyvinylpyrrolidone (PVP), to mimic the average dielectric properties of brain tissue. The static and RF field distributions were characterized on a 7T MRI system and compared to in vivo measurements and simulations. MR thermometry was performed, and the results were compared to thermal simulations for RF validation purposes. RESULTS: Accurate reproduction of both static and RF fields patterns observed in vivo was confirmed experimentally and was shown to be strongly affected by the inclusion of the spherical cavity. MR thermometry and transmit efficiency ( B1+) measurements were obtained in close agreement with simulations (peak values agreeing within 0.3 degrees C and 0.02 MUT/?W) as well as fiber optic thermal probes (RMSE < 0.18 degrees C). CONCLUSIONS: A simple head-sized phantom has been presented that produces B0 and B1+ nonuniformities similar to those encountered in the human head and allows for accurate MR thermometry measurements, making this a suitable reference phantom for RF validation and methodological development in high field MRI. PMID- 29498105 TI - Asymmetric Benzylic Allylic Alkylation Reaction of 3-Furfural Derivatives by Dearomatizative Dienamine Activation. AB - The dearomatizative dienamine-type ortho-quinodimethane species are smoothly generated between 2-alkyl-3-furfurals and chiral secondary amine catalysts, which undergo asymmetric benzylic allylic alkylation reactions with 2-nitroallylic acetates efficiently. A spectrum of densely functionalized 3-furfural derivatives are delivered in moderate to high yields with good to excellent diastereo- and enantioselectivity (up to 98 % yield, >19:1 d.r., >99 % ee). The latent transformations allow the facile production of some enantioenriched architectures, such as 1,1,2,2-tetraarylethanes and triarylmethanes, which are not easily available from other protocols. PMID- 29498104 TI - Cardio-hepatic risk assessment by CMR imaging in liver transplant candidates. AB - BACKGROUND: The preoperative workup of orthotopic liver transplantation (OLT) patients is practically complex given the need for multiple imaging modalities. We recently demonstrated in our proof-of-concept study the value of a one-stop shop approach using cardiovascular MRI (CMR) to address this complex problem. However, this approach requires further validation in a larger cohort, as detection of hepatocellular carcinoma (HCC) as well as cardiovascular risk assessment is critically important in these patients. We hypothesized that coronary risk assessment and HCC detectability is acceptable using the one-stop shop CMR approach. METHODS: In this observational study, patients underwent CMRI evaluation including cardiac function, stress CMR, thoracoabdominal MRA, and abdominal MRI on a standard MRI scanner in one examination. RESULTS: Over 8 years, 252 OLT candidates underwent evaluation in the cardiac MRI suit. The completion rates for each segment of the CMR examination were 99% for function, 95% completed stress CMR, 93% completed LGE for viability, 85% for liver MRI, and 87% for MRA. A negative CMR stress examination had 100% CAD event-free survival at 12 months. A total of 63 (29%) patients proceeded to OLT. Explant pathology confirmed detection/exclusion of HCC. CONCLUSIONS: This study further defines the population suitable for the one-stop-shop CMR concept for preop evaluation of OLT candidates providing a road map for integrated testing in this complex patient population for evaluation of cardiac risk and detection of HCC lesions. PMID- 29498106 TI - T-cell replete haploidentical stem cell transplantation attenuates the prognostic impact of FLT3-ITD in acute myeloid leukemia: A report from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. AB - Acute myeloid leukemia (AML) patients harboring the FLT3-ITD mutation are considered a high risk patient subset preferentially allocated for allogeneic stem cell transplantation in first remission. Whether FLT3-ITD retains a prognostic role in haploidentical stem cell transplantation (haplo-SCT) is unknown. To analyze the prognostic impact of FLT3-ITD in haplo-SCT, we performed a retrospective analysis of the multicenter registry of the acute leukemia working party of the European Society for Blood and Marrow Transplantation. We included all adult AML patients with known FLT3 status who underwent a first T cell replete related haplo-HCT in first complete remission from 2005 to 2016. We evaluated 293 patients of whom 202 were FLT3wt and 91 were FLT3-ITD mutated. FLT3 ITD patients were more likely to be NPM1 mutated as well as be in the intermediate risk cytogenetic risk category. In multivariate analysis, patients with FLT3-ITD had comparable rates of relapse incidence [Hazard ratio (HR) = 1.34, confidence interval (CI) 95%, 0.67-2.7; P = .9] and leukemia-free survival (HR = 0.99, CI 95%, 0.62-1.57; P = .9) to those of FLT3wt patients. Overall survival, the incidence of nonrelapse mortality, and graft versus host disease free/relapse-free survival were not significantly impacted by FLT3-ITD status. Furthermore, relapse and overall survival were comparable between FLT3-ITD patients transplanted from various donor pools, namely matched siblings, unrelated donors, haplo-SCT). Finally, subset analysis of patients with intermediate risk cytogenetics confirmed the absence of a prognostic impact of FLT3-ITD also for this patient segment. In AML patients undergoing T-cell replete haplo-SCT, the FLT3-ITD mutation possibly does not retain its prognostic significance. PMID- 29498107 TI - First line treatment of aplastic anemia with thymoglobuline in Europe and Asia: Outcome of 955 patients treated 2001-2012. AB - The aim of this study was to assess the outcome of patients with aplastic anemia (AA), receiving rabbit anti-thymocyte globulin (Thymoglobulin, SANOFI) and cyclosporin, as first line treatment. Eligible were 955 patients with AA, treated first line with Thymoglobulin, between 2001 and 2008 (n = 492), or between 2009 and 2012 (n = 463). The median age of the patients was 21 years (range 1-84). Mortality within 90 days was 5.7% and 2.4%, respectively in the two time periods (P = .007).The actuarial 10-year survival for the entire population was 70%; transplant free survival was 64%. Predictors of survival in multivariate analysis, were severity of the disease, patients age and the interval between diagnosis and treatment. Survival was 87% vs 61% for responders at 6 months versus nonresponders (P < .0001). The 10-year survival of nonresponders at 6 months, undergoing a subsequent transplant (n = 110), was 64%, vs 60% for patient not transplantated (n = 266) (P = .1). The cumulative incidence of response was 37%, 52%, 65% respectively, at 90, 180, and 365 days. In multivariate analysis, negative predictors of response at 6 months, were older age, longer interval diagnosis treatment, and greater severity of the disease. In conclusion, early mortality is low after first line treatment of AA with Thymoglobulin, and has been further reduced after year 2008. Patients age, together with interval diagnosis-treament and severity of the disease, remain strong predictors of response and survival. PMID- 29498103 TI - The neuroprotective role of melatonin in neurological disorders. AB - Melatonin is a neurohormone secreted from the pineal gland and has a wide-ranging regulatory and neuroprotective role. It has been reported that melatonin level is disturbed in some neurological conditions such as stroke, Alzheimer's disease, and Parkinson's disease, which indicates its involvement in the pathophysiology of these diseases. Its properties qualify it to be a promising potential therapeutic neuroprotective agent, with no side effects, for some neurological disorders. This review discusses and localizes the effect of melatonin in the pathophysiology of some diseases. PMID- 29498109 TI - Allogeneic transplantation for myelofibrosis with adverse risk karyotype: Attack on the clones? PMID- 29498108 TI - Evaluation of individual low-dose dexamethasone suppression test patterns in naturally occurring hyperadrenocorticism in dogs. AB - BACKGROUND: Dogs with hyperadrenocorticism (HAC) may be more mildly affected at the time of diagnosis today, which could influence the prevalence of associated clinical and clinicopathological abnormalities and diagnostic test performance. Different low-dose dexamethasone suppression test (LDDST) result patterns have not been evaluated individually. OBJECTIVES: To assess the current features of HAC and evaluate if the diagnostic test performance of individual LDDST result patterns differ. ANIMALS: One hundred and twenty-three dogs undergoing investigation for HAC. METHODS: Retrospective evaluation of dogs in which a LDDST was performed and HAC confirmed or excluded by alternative means. Cases with basal cortisol concentrations (t0 ) < 1 MUg/dL were excluded. Each LDDST result was classified as (a) complete suppression (t3 and t8 < 1 MUg/dL), (b) lack of suppression (t3 and t8 > 1 MUg/dL and both > 50% t0 ), (c) partial suppression (t3 and t8 > 1 MUg/dL but either < 50% t0 ), (d) escape (t8 > 1 MUg/dL and t3 < 1 MUg/dL) or (e) inverse (t3 > 1 MUg/dL and t8 < 1 MUg/dL) pattern. RESULTS: Fifty-nine (48%) dogs were diagnosed with HAC and 64 (52%) with non-adrenal illness. Hyperadrenocorticism cases had similar clinicopathological abnormalities compared to previous reports. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) (95% confidence interval [CI]) of the LDDST for diagnosing HAC were 96.6 (91.9-100)%, 67.2 (55.7-78.7)%, 73.1 (63.2 82.9)%, and 95.6 (89.5-100)%, respectively. Lack of suppression pattern had the highest PPV (93.9 [85.8-100]%) followed by the partial suppression pattern (67.9 [50.6-85.2]%) and escape or inverse pattern (36.8 [15.1-58.5]%). CONCLUSIONS AND CLINICAL IMPORTANCE: A lack of suppression LDDST pattern has the highest PPV for diagnosing HAC followed by a partial suppression pattern. By contrast, the escape or inverse pattern provided limited support of HAC. PMID- 29498110 TI - Dynamic and Tunable Threshold Voltage in Organic Electrochemical Transistors. AB - In recent years, organic electrochemical transistors (OECTs) have found applications in chemical and biological sensing and interfacing, neuromorphic computing, digital logic, and printed electronics. However, the incorporation of OECTs in practical electronic circuits is limited by the relative lack of control over their threshold voltage, which is important for controlling the power consumption and noise margin in complementary and unipolar circuits. Here, the threshold voltage of OECTs is precisely tuned over a range of more than 1 V by chemically controlling the electrochemical potential at the gate electrode. This threshold voltage tunability is exploited to prepare inverters and amplifiers with improved noise margin and gain, respectively. By coupling the gate electrode with an electrochemical oscillator, single-transistor oscillators based on OECTs with dynamic time-varying threshold voltages are prepared. This work highlights the importance of electrochemistry at the gate electrode in determining the electrical properties of OECTs, and opens a path toward the system-level design of low-power OECT-based electronics. PMID- 29498111 TI - Skin lesions in Aubrac cows strongly associated with fly bites (Haematobia irritans). AB - BACKGROUND: The horn fly Haematobia irritans is known to cause problems in cattle including weight loss and decreased milk production; cutaneous lesions have not been widely reported and descriptions of the clinical manifestations are quite variable. HYPOTHESIS/OBJECTIVES: This study describes the clinical and histopathological lesions of several Aubrac cows that presented with focal to confluent areas of alopecia, skin scaling and thickening, suspected to be induced by H. irritans bites. ANIMALS: Twenty seven, three- to six-year-old Aubrac cows, kept in mountain pastures in France, that presented with an apparently asymptomatic alopecic dermatosis. METHODS: Samples for skin cytological evaluation, skin scrapings and trichograms were examined; also, skin biopsy specimens from affected animals were used for histopathological examination. RESULTS: Clinical lesions consisted of focal to coalescing, symmetrical areas of hair loss and scaling, located on the back, flanks, and lateral and caudal aspects of the thighs. Histopathological examination revealed perivascular, oedematous, eosinophilic dermatitis with eosinophilic folliculitis and furunculosis. Species identification of several flies captured on the cows revealed H. irritans. The final clinicopathological diagnosis was eosinophilic dermatitis and folliculitis and furunculosis, suspected to be due to H. irritans fly-bite. CONCLUSION AND CLINICAL IMPORTANCE: Fly-bite (H. irritans) dermatitis should be included in the differential diagnosis of alopecic dermatoses in cows. PMID- 29498112 TI - Phosphorylation control of the ubiquitin ligase Cbl is conserved in choanoflagellates. AB - Cbl proteins are E3 ubiquitin ligases specialized for the regulation of tyrosine kinases by ubiquitylation. Human Cbl proteins are activated by tyrosine phosphorylation, thus setting up a feedback loop whereby the activation of tyrosine kinases triggers their own degradation. Cbl proteins are targeted to their substrates by a phosphotyrosine-binding SH2 domain. Choanoflagellates, unicellular eukaryotes that are closely related to metazoans, also contain Cbl. The tyrosine kinase complement of choanoflagellates is distinct from that of metazoans, and it is unclear if choanoflagellate Cbl is regulated similarly to metazoan Cbl. Here, we performed structure-function studies on Cbl from the choanoflagellate species Salpingoeca rosetta and found that it undergoes phosphorylation-dependent activation. We show that S. rosetta Cbl can be phosphorylated by S. rosetta Src kinase, and that it can ubiquitylate S. rosetta Src. We also compared the substrate selectivity of human and S. rosetta Cbl by measuring ubiquitylation of Src constructs in which Cbl-recruitment sites are placed in different contexts with respect to the kinase domain. Our results indicate that for both human and S. rosetta Cbl, ubiquitylation depends on proximity and accessibility, rather than being targeted toward specific lysine residues. Our results point to an ancient interplay between phosphotyrosine and ubiquitin signaling in the metazoan lineage. PMID- 29498113 TI - Blastocyst production after intracytoplasmic sperm injection with semen from a stallion with testicular degeneration. AB - In horse breeding, intracytoplasmic sperm injection (ICSI) has gained interest to obtain offspring from subfertile individuals. This paper presents a case report of a stallion with severe testicular degeneration. Semen analysis showed very low motility and 83.5% of detached heads. Histology of a testicular biopsy showed severely decreased spermatogenesis, while transmission electron microscopy of the sperm cells revealed no significant abnormalities. A total of 39 oocytes were fertilized by ICSI with frozen-thawed spermatozoa of this stallion: 25 oocytes with intact spermatozoa and 24 with detached heads. When using intact sperm cells, 8 out of the 25 oocytes cleaved, and 1 developed to the blastocyst stage 9 days after ICSI. None of the oocytes injected with a detached sperm head cleaved. Studies on the paternal influence on ICSI outcome are limited in the horse and further research is needed to define which stallion factors may influence ICSI results. Here, we report the possibility to produce a blastocyst by ICSI of a stallion suffering from testicular degeneration with a poor spermiogram, as long as an intact sperm cell containing a centriole is selected. PMID- 29498114 TI - Smoking behaviour and preferences for cessation support among clients of an Indigenous community-controlled health service. AB - INTRODUCTION AND AIMS: Reducing smoking prevalence among Indigenous Australians is a vital part of closing the health gap between Indigenous and non-Indigenous Australians. Community-controlled health clinics are an important setting for delivering smoking cessation advice and assistance. This study measured tobacco and e-cigarette use, knowledge of smoking-related health effects, motivations to quit and interest in cessation aids. DESIGN AND METHODS: Clients of Aboriginal & Torres Strait Islander Community Health Service dental clinics in Southeast Queensland (n = 421) completed a brief written questionnaire while in the waiting room. RESULTS: Nearly half (n = 184, 47%) of the participants currently smoked daily, of which 9% (n = 7) currently used e-cigarettes. Few smokers (8%, n = 13) had no intention to quit smoking. For current smokers, previously used quit methods were abrupt cessation (42%, n = 78), nicotine replacement therapies (NRT; 25%, n = 45), prescription medications (23%, n = 43), e-cigarettes (9%, n = 17) and other methods (3%, n = 6). Current smokers were most interested in cutting down (85%, n = 110), abrupt cessation (75%, n = 98) and free NRT (72%, n = 101). Fewer (34%, n = 36) were interested in purchasing NRT for smoking cessation. DISCUSSION AND CONCLUSIONS: Our study found there was interest in accessing smoking cessation aids among the clients of this community-controlled health clinic, particularly if provided free of charge. Embedding smoking cessation advice and assistance into a range of community-controlled health clinics could provide opportunities for addressing the high smoking prevalence among Indigenous Australians. PMID- 29498115 TI - Materials and Wearable Devices for Autonomous Monitoring of Physiological Markers. AB - Wearable devices are gaining considerable attention owing to the ease with which they can collect crucial information in real-time, both continuously and noninvasively, regarding a wearer's health. A concise summary is given of the three main elements that enable autonomous detection and monitoring of the likelihood or the existence of a health-risk state in continuous and real-time modes, with an emphasis on emerging materials and fabrication techniques in the relevant fields. The first element is the sensing technology used in the noninvasive detection of physiological markers relevant to the state of health. The second element is self-powered devices for longer periods of use by drawing energy from bodily movement and temperature. The third element is the self healing properties of the materials used in the wearable devices to extended usage if they become scratched or cut. Promises and challenges of the separately reviewed parts and the combined parts are presented and discussed. Ideas regarding further improvement of skin-based wearable devices are also presented and discussed. PMID- 29498116 TI - A new technique for evaluating heel xerosis grade and the effects of moisturizer on heel skin dryness. AB - BACKGROUND: Dryness-related heel skin problems are common; however, there are very few studies about heel skin dryness. The objective of this study was to develop new assessment methods for evaluating heel skin dryness, to clarify the characteristics associated with heal skin dryness, and assess the effectiveness of moisturizer use according to dryness severity. MATERIALS AND METHODS: We investigated the heel skin of 150 Korean women (aged 20-78 years). Heel skin images were taken using a DSLR camera and the distribution or severity of flakes, scaling, cracking, and fissures were visually assessed. Skin properties such as hydration, transepidermal water loss (TEWL), amount of dead skin cells, and efficacy of moisturizer were evaluated according to heel xerosis grade. Furthermore, as conventional evaluation methods for desquamation are not appropriate for heel skin, we developed new techniques using binarization of magnified images. RESULTS: Skin hydration tended to decrease and TEWL tended to increase as heel dryness grade increased. The amount of dead skin cells increased with increasing dryness grade using the new technique. Subjects in the severe dryness group achieved similar hydration levels as normal subjects at baseline after 3 hours of moisturizer application. CONCLUSION: Our new methods of visually classifying heel dryness and quantifying dead skin cells using magnified images effectively evaluated heel skin properties. As heel skin is prone to dryness, daily repetitive application of moisturizer might be helpful for hydrating dry heel skin, and ultimately preventing complications. PMID- 29498117 TI - Expression of IL-33 in chronic lesional skin of canine atopic dermatitis. AB - BACKGROUND: In humans, interleukin (IL)-33 plays a critical role in the enhancement of allergic skin inflammation. However, it currently remains unclear whether IL-33 is involved in the pathogenesis of canine atopic dermatitis (cAD). OBJECTIVES: To examine the expression of IL-33 in chronic lesional skin of cAD. ANIMALS: Eight dogs with spontaneous cAD and five healthy dogs were used. METHODS: The transcription of il-33 in chronic lesional skin of cAD was quantified by quantitative reverse transcription PCR. The expression of IL-33 was evaluated immunohistochemically using an anti-human IL-33 monoclonal antibody with cross-reactivity to canine IL-33. RESULTS: The transcription levels of il-33 in chronic lesional skin of cAD were significantly higher than those in normal skin of healthy dogs. Keratinocytes were a major cellular source of IL-33 production in chronic lesional skin of cAD. CONCLUSIONS AND CLINICAL IMPORTANCE: The results indicate that IL-33 is involved in chronic lesional skin of cAD. PMID- 29498119 TI - Managed alcohol programs: Reducing social and injury harm, but what about long term health harm? PMID- 29498118 TI - Inhibition of amyloid beta fibril formation by monomeric human transthyretin. AB - Transthyretin (TTR) is a homotetrameric protein that is found in the plasma and cerebrospinal fluid. Dissociation of TTR tetramers sets off a downhill cascade of amyloid formation through polymerization of monomeric TTR. Interestingly, TTR has an additional, biologically relevant activity, which pertains to its ability to slow the progression of amyloid beta (Abeta) associated pathology in transgenic mice. In vitro, both TTR and a kinetically stable variant of monomeric TTR (M TTR) inhibit the fibril formation of Abeta1-40/42 molecules. Published evidence suggests that tetrameric TTR binds preferentially to Abeta monomers, thus destabilizing fibril formation by depleting the pool of Abeta monomers from aggregating mixtures. Here, we investigate the effects of M-TTR on the in vitro aggregation of Abeta1-42 . Our data confirm previous observations that fibril formation of Abeta is suppressed in the presence of sub-stoichiometric amounts of M-TTR. Despite this, we find that sub-stoichiometric levels of M-TTR are not bona fide inhibitors of aggregation. Instead, they co-aggregate with Abeta to promote the formation of large, micron-scale insoluble, non-fibrillar amorphous deposits. Based on fluorescence correlation spectroscopy measurements, we find that M-TTR does not interact with monomeric Abeta. Two-color coincidence analysis of the fluorescence bursts of Abeta and M-TTR labeled with different fluorophores shows that M-TTR co-assembles with soluble Abeta aggregates and this appears to drive the co-aggregation into amorphous precipitates. Our results suggest that mimicking the co-aggregation activity with protein-based therapeutics might be a worthwhile strategy for rerouting amyloid beta peptides into inert, insoluble, and amorphous deposits. PMID- 29498120 TI - Assessing care-giving demands, resources and costs of family/friend caregivers for persons with mental health disorders: A scoping review. AB - As mental health (MH) care has shifted from institutional settings to the community, families and friends are responsible for providing the majority of the care at home. The substantial literature on the adverse effects experienced by caregivers has focused mainly on psychological morbidity. Less attention has been paid to how caregivers for persons with MH disorders interact with larger social systems and the impacts of factors such as financial strain, lost time from leisure activities, and the availability of health and social services. We conducted a scoping review of MH and other caregiver questionnaires published between 1990 and 2016 to determine whether they addressed four key domains: caregiver work demands, resource needs, resource utilisation and costs. A range of health and social care databases were searched, including MEDLINE and Health and Psychosocial Instruments. After screening for relevance and quality, our search identified 14 instruments addressing elements related to one or more of our domains. Because these instruments covered only a small portion of our domains, we conducted a second targeted search of the general care-giving literature and consulted with experts, identifying an additional 18 instruments. A total of 32 questionnaires were reviewed, 14 specific to care-giving for mental health problems and 18 for other health conditions. Our search identified instruments or items within instruments that assess constructs in each of our domains, but no one instrument covered them completely. Additionally, some constructs were evaluated in detail and others only addressed by single items. While these instruments are helpful for moving measurement beyond the psychological impacts of care-giving, our results serve only as an initial guide. Additional methodological work is needed to more comprehensively measure the impact of care-giving for individuals with MH disorders and to contribute to the development of more meaningful and effective policies and programmes. PMID- 29498121 TI - Preliminary investigation of the variations in root canal morphology of hypomineralised second primary molars. AB - AIM: To investigate the root canal morphology of hypomineralised second primary molars(HSPM) using micro-CT(MUCT) compared with non-hypomineralised second primary molars (non-HSPM). METHODOLOGY: Ten HSPM and 10 non-HSPM were divided into Group 1(maxillary HSPM), Group 2 (mandibular HSPM), Group 3(maxillary non HSPM), and Group 4 (mandibular non-HSPM). All teeth were scanned using MUCT to assess the following parameters: (i) root canal configuration, (ii) pulp volumes, and (iii) the influence of the root canal system landmarks on access cavity outline forms and canal curvature. Two-way ANOVA was employed for descriptive analysis (P < 0.05). RESULTS: At the furcation level, there was minimal variation in the number of canals. In the mesiobuccal root, Group 1 showed higher frequency of multiple canals in the middle (85.7%) and apical (85.7%) thirds compared with Group 3. In the mesial root, Group 4 demonstrated multiple canals at the furcation (60%) compared with Group 2(33.3%). In the distal root, Group 2 demonstrated a higher percentage of multiple canals at the apical level (100%) compared with Group 4. The mean pulp volumes of Group 2 and Group 4 were 54.1 mm3 (16.7) and 30 mm3 (5.12), respectively, which was statistically significant (P < 0.05). The canal curvature values did not differ significantly between HSPM and non-HSPM groups. CONCLUSIONS: HSPM exhibited greater variations in their root canal configuration when compared to non-HSPM. PMID- 29498122 TI - "I would love to have online support but I don't trust it": Positive and negative views of technology from the perspective of those with eating disorders in Canada. AB - This qualitative study aims to explore how individuals who are seeking help and support for eating disorders use various forms of technology. Fifteen participants, recruited from an Eating Disorder Program in a hospital setting and an eating disorder community support centre, voluntarily participated in focus groups and individual interviews in 2015. The authors used thematic analysis to code and analyse the qualitative data, and three themes were identified: safety, connection and technology development. This study identifies the need for technology use to be addressed and integrated into clinical services for eating disorders, as well as for safe and helpful technology tools to be developed for this population. PMID- 29498123 TI - B-mode and power Doppler ultrasonography of the equine suspensory ligament branches: A descriptive study on 13 horses. AB - Ultrasonography is routinely used to achieve the diagnosis of equine suspensory ligament desmopathy. In human medicine, power Doppler ultrasonography has also been found to be useful for the diagnosis of tendon/ligament injuries. The aim of this prospective, pilot study was to assess the presence or absence of power Doppler signal in suspensory ligament branches and compare B-mode findings with power Doppler findings in suspensory ligament branches of lame and non-lame limbs. Thirteen horses were used (eight lame horses, with lameness related to pain in the suspensory ligament branches, and five non-lame horses). Ten lame limbs and 24 sound limbs were assessed by B-mode and power Doppler ultrasonography. The severity of power Doppler signal was scored by two independent readers. The B-mode ultrasonographic examination revealed abnormalities in branches of lame limbs and in branches of sound limbs. Suspensory ligament branches that were considered normal in B-mode showed no power Doppler signal. However, power Doppler signal was detected in suspensory ligament branches that were abnormal in B-mode, both in lame and sound limbs. Power Doppler scores were subjectively higher in suspensory ligament branches of lame limbs and in branches with more severe B-mode changes. Findings supported the use of power Doppler as an adjunctive diagnostic test for lame horses with suspected suspensory desmopathy. PMID- 29498124 TI - Papilla height in relation to the distance between bone crest and interproximal contact point at single-tooth implants: A systematic review. AB - OBJECTIVES: The aim of this systematic review was to investigate the tooth implant papilla formation in correlation with the distance between the interproximal bone level and the prosthetic contact point. MATERIAL AND METHODS: A comprehensive search of the current literature (01/01/2000-01/01/2017) was performed to identify human trials that included 10 patients or more, with at least 12 months follow-up, in need of the replacement of one single tooth in the anterior maxillary region with an implant-supported single crown. To meet the inclusion criteria, studies had to provide both radiographic and clinical data regarding the distance between the interproximal bone level and the prosthetic contact point. RESULTS: The search yielded 136 records. After evaluation of abstracts and full texts, 12 papers were included in the final review, even though various reference points, for the comparison between the vertical distance and the papilla height, were used. The vertical distance between the interproximal bone level and prosthetic contact point ranged between 2 and 11 mm, and the partial or complete papilla fill (Jemt's score 2-3) ranged between 56.5% and 100% of cases. CONCLUSION: There is limited evidence that the vertical distance from the base of the interproximal contact point to the crestal bone level seems to affect the interproximal papilla height; that is, the lower is the distance the higher is the percentage of papilla fill. Complete embrasure fill between an implant restoration and the adjacent tooth seems to be correlated with the integrity of the periodontal ligament of the tooth. To reduce the risk of aesthetic failures, interproximal probing on the adjacent teeth should be encouraged before implant placement. PMID- 29498125 TI - Evidence-based knowledge on the aesthetics and maintenance of peri-implant soft tissues: Osteology Foundation Consensus Report Part 2-Effects of hard tissue augmentation procedures on the maintenance of peri-implant tissues. AB - OBJECTIVES: One task of Working Group 1 at the 2nd Consensus Meeting of the Osteology Foundation was to comprehensively assess the effects of hard tissue augmentation procedures on peri-implant health or disease. MATERIALS AND METHODS: One systematic review and meta-analysis on the effects of hard tissue augmentation procedures included a total of eight studies (n = 12 publications). Consensus statements, clinical recommendations, and implications for future research were based on structured group discussions and plenary session approval. RESULTS: After 1-10 years of follow- up, lateral bone augmentation procedures were associated with peri-implant tissue stability, as evidenced by minimal and non-significant changes in bleeding on probing, probing depth, and marginal bone levels. Case definitions based on clinical and radiographic parameters to differentiate peri-implant health from disease have been inconsistently employed in the studies investigated. CONCLUSIONS: Lateral bone augmentation procedures are associated with peri-implant tissue stability on short-term (1-3 years) and midterm follow-ups to long-term (>3 years) follow-ups. PMID- 29498126 TI - Effects of lateral bone augmentation procedures on peri-implant health or disease: A systematic review and meta-analysis. AB - OBJECTIVES: This systematic review evaluated the evidence on the effect of the interventions aimed for lateral ridge augmentation (both simultaneously with implant placement or as a staged procedure) on peri-implant health or disease. METHODS: A protocol was developed to answer the following PICO question: "In patients with horizontal alveolar ridge deficiencies (population), what is the effect of lateral bone augmentation procedures (intervention and comparison) on peri-implant health (outcome)?" Included studies were randomised controlled trials or controlled clinical trials with a follow-up of at least 12 months after implant loading. Meta-analyses were performed whenever possible, including subgroup analysis based on follow-up. RESULTS: Twelve final publications from eight investigations were included. The results from the meta-analysis indicated that irrespective of the type of intervention, the inflammatory changes, based on bleeding on probing (%) were minimal, both at short- (n = 1; weighted mean difference [WMD] = -1.00; 95% CI [-14.04; 12.04]; p = .881) and long-term (n = 5; WMD = -5.63; 95% CI [-18.42; 7.16]; p = .881). When comparing different treatment modalities, no significant differences were observed (n = 6; WMD = -3.36; 95% CI [-12.49; 5.77]; p < .471). Similarly, changes in probing pocket depth and marginal bone levels were not significantly different among groups. The incidence of peri-implantitis was evaluated in three investigations and varied from 16% to 26% after a follow-up period of 6-8 years. CONCLUSIONS: The results from this systematic review and meta-analysis have shown that lateral ridge augmentation procedures can maintain peri-implant health over time with low mucosal inflammatory changes and a relatively small incidence of peri-implant bone loss. PMID- 29498127 TI - Evidence-based knowledge on the aesthetics and maintenance of peri-implant soft tissues: Osteology Foundation Consensus Report Part 1-Effects of soft tissue augmentation procedures on the maintenance of peri-implant soft tissue health. AB - OBJECTIVES: The goal of Working Group 1 at the 2nd Consensus Meeting of the Osteology Foundation was to comprehensively assess the effects of soft tissue augmentation procedures on peri-implant health or disease. MATERIALS AND METHODS: A systematic review and meta-analysis on the effects of soft tissue augmentation procedures included a total of 10 studies (mucosal thickness: n = 6; keratinized tissue: n = 4). Consensus statements, clinical recommendations, and implications for future research were based on structured group discussions and a plenary session approval. RESULTS: Soft tissue grafting to increase the width of keratinized tissue around implants was associated with greater reductions in gingival and plaque indices when compared to non-augmented sites. Statistically significant differences were noted for final marginal bone levels in favor of an apically positioned flap plus autogenous graft vs. all standard-of-care control treatments investigated. Soft tissue grafting (i.e., autogenous connective tissue) to increase the mucosal thickness around implants in the aesthetic zone was associated with significantly less marginal bone loss over time, but no significant changes in bleeding on probing, probing depths, or plaque scores when compared to sites without grafting. CONCLUSIONS: The limited evidence available supports the use of soft tissue augmentation procedures to promote peri-implant health. PMID- 29498128 TI - A systematic review on the influence of the horizontal distance between two adjacent implants inserted in the anterior maxilla on the inter-implant mucosa fill. AB - OBJECTIVES: To address the following focused question: "Does the horizontal distance between two adjacent implants inserted in the anterior maxilla affect the inter-implant mucosa fill?". MATERIAL AND METHODS: A comprehensive literature screening was performed in MEDLINE and Cochrane databases from January 1, 2000 until July 1, 2017. Clinical human studies including >=10 patients treated with at least two adjacent implant-supported crowns in the anterior maxilla with a minimum of 12 months of follow-up were searched. Studies reporting on inter implant mucosa fill in relation to the radiographic horizontal distance between the two adjacent implants were included. The reporting of this systematic analysis adhered to the Preferred Reporting items for Systematic Review and Meta analyses (PRISMA) statement. RESULTS: The initial search resulted in 208 publications. From 13 full-text articles reviewed, 4 were included in the final analysis. Depending on the reference points used, the horizontal inter-implant distance ranged between 2.01 and 4.0 mm. In 21 to 88.5% of the cases, inter implant-mucosa filled more than half of the inter-implant space. When interpreting results of inter-implant mucosa fill, time of implant placement (immediate or delayed) and restoring (immediate or conventional) were taken into consideration. A tendency towards incomplete inter-implant mucosa fill at a distance of <3 mm was noted in the 3 included papers. One of the studies found this trend to be statistically significant (p = .008). CONCLUSIONS: Based on the available evidence, it is not possible to define a precise threshold for the optimal horizontal distance between two adjacent implants. PMID- 29498129 TI - Effects of soft tissue augmentation procedures on peri-implant health or disease: A systematic review and meta-analysis. AB - OBJECTIVE: To review the dental literature in terms of soft tissue augmentation procedures and their influence on peri-implant health or disease in partially and fully edentulous patients. METHODS: A MEDLINE search from 1966 to 2016 was performed to identify controlled clinical studies comparing soft tissue grafting versus no soft tissue grafting (maintenance) or two types of soft tissue grafting procedures at implant sites. The soft tissue grafting procedures included either an increase of keratinized tissue or an increase of the thickness of the peri implant mucosa. Studies reporting on the peri-implant tissue health, as assessed by bleeding or gingival indices, were included in the review. The search was complemented by an additional hand search of all selected full-text articles and reviews published between 2011 and 2016. The initial search yielded a total number of 2,823 studies. Eligible studies were selected based on the inclusion criteria (finally included: four studies on gain of keratinized tissue; six studies on gain of mucosal thickness) and quality assessments conducted. Meta analyses were applied whenever possible. RESULTS: Soft tissue grafting procedures for gain of keratinized tissue resulted in a significantly greater improvement of gingival index values compared to maintenance groups (with or without keratinized tissue) [n = 2; WMD = 0.863; 95% CI (0.658; 1.067); p < .001]. For final marginal bone levels, statistically significant differences were calculated in favor of an apically positioned flap (APF) plus autogenous grafts versus all control treatments (APF alone; APF plus a collagen matrix; maintenance without intervention [with or without residual keratinized tissue]) [n = 4; WMD = -0.175 mm; 95% CI: (-0.313; -0.037); p = .013]. Soft tissue grafting procedures for gain of mucosal thickness did not result in significant improvements in bleeding indices over time, but in significantly less marginal bone loss over time [WMD = 0.110; 95% CI: 0.067; 0.154; p < .001] and a borderline significance for marginal bone levels at the study endpoints compared to sites without grafting. CONCLUSIONS: Within the limitations of this review, it was concluded that soft tissue grafting procedures result in more favorable peri-implant health: (i) for gain of keratinized mucosa using autogenous grafts with a greater improvement of bleeding indices and higher marginal bone levels; (ii) for gain of mucosal thickness using autogenous grafts with significantly less marginal bone loss. PMID- 29498130 TI - Soft and hard tissue augmentation procedures for promotion of peri-implant health and aesthetics. PMID- 29498132 TI - About the Osteology Foundation. PMID- 29498131 TI - Evidence-based knowledge on the aesthetics and maintenance of peri-implant soft tissues: Osteology Foundation Consensus Report Part 3-Aesthetics of peri-implant soft tissues. AB - OBJECTIVES: Working Group 2 at the 2nd Consensus Meeting of the Osteology Foundation had a focus on the influence of vertical implant placement on papilla height at single implants adjacent to teeth and on the inter-implant mucosa fill at two adjacent implants in the anterior maxilla. MATERIALS AND METHODS: Two systematic reviews were prepared in advance of the consensus meeting. Due to the heterogeneity among the studies with regard to study design, study population, method of assessment, meta-analyses were not possible. Consensus statements, clinical recommendations, and implications for future research were based on structured group discussions until consensus was reached among the entire expert group. RESULTS: The systematic review about single-tooth implants included a total of 12 studies demonstrating that the vertical distance from the crestal bone level to the base of the interproximal contact point varied considerably from 2 mm up to 11 mm, and a partial or complete papilla fill was reached in 56.5% to 100% of the cases. For the systematic review regarding two adjacent implants, only four studies reported on horizontal inter-implant distances which ranged between 2.0 and 4.0 mm. More than half of the papilla presence was indicated in 21% to 88.5% of the cases. CONCLUSIONS: It was concluded that for single-tooth implants, the papilla height between an implant and a tooth is predominantly dependent on the clinical attachment level of the tooth. In cases with two adjacent implants, it was concluded that it is not possible to define the optimal horizontal distance between two adjacent implants restored with fixed dental prosthess. PMID- 29498133 TI - Religion and desistance from substance use among adolescent offenders: The role of cognitive functioning. AB - BACKGROUND: Religious beliefs and practices have been shown to have some association with desistance from offending, as have cognitive processes, including emotion regulation, self-control, reasoning, learning, and empathy. Religious behaviours may, however, be moderated or mediated by cognitive abilities, but few studies take this into account. AIM: The aim of this study was to assess the role of cognitive ability in any relationship between religious beliefs and behaviours and desistance from substance use among adolescents. METHOD: Data were extracted from the Pathways to Desistance Study dataset (n = 1,354). Religious measures were self-rated importance of religion, helpfulness of religion in dealing with problems, and attendance at religious services. Cognitive measures were the Wechsler Abbreviated Scale of Intelligence and Trail Making Tests. A count of numbers of mind-altering substances used constituted the main substance measure. Control variables included sex, age, and age of onset of offending. RESULTS: Mixed-effects longitudinal analyses revealed that religious behaviours did constitute a significant predictor of lower substance use for young people after a criminal conviction, after controlling for changes in employment, social support, and delinquent peer association, but only among those with average or above cognitive function. CONCLUSIONS: These findings may explain why there have been some discrepancies in previous studies of religion and substance misuse. They may also have important implications for the training of anyone delivering programmes to young people in prison that have faith-based elements, including community faith group leaders and volunteers. PMID- 29498134 TI - Tipping the Balance between Ligand and Metal Protonation due to Relativistic Effects: Unusually High Proton Affinity in Gold(I) Pincer Complexes. AB - Quantum theoretical studies show that the extremely high proton affinity at the metal center of the unusual T-shaped (LXL)AuI -pincer complex, consisting of a carbazole framework and two mesoionic carbenes, is caused by relativistic effects. This brings the basicity of the AuI center in line with the electron rich nitrogen atom of the carbazole ring system, resulting in one of the highest proton affinities for a neutral molecule. PMID- 29498135 TI - A preliminary study of serum IgE against cross-reactive carbohydrate determinants (CCD) in client-owned atopic dogs. AB - BACKGROUND: Cross-reactive carbohydrate determinants (CCD) are defined carbohydrate portions of glycoprotein cell surface molecules common to many plant and insect species. Mammalian species recognize CCD as foreign antigens and can mount humoral immune responses against them. Approximately 20-37% of grass and venom allergic people possess circulating IgE against CCD; these antibodies are generally considered clinically irrelevant. Anti-CCD IgE is, however, recognized as a cause of false positive, clinically incongruent serum allergen test results in people; this phenomenon has not been investigated in animals. OBJECTIVE: To determine if anti-CCD IgE could be detected in sera of client-owned atopic dogs and how frequently it is found. ANIMALS: Sera from 38 dogs with a clinical diagnosis of atopic dermatitis and prior serological evidence of IgE antibodies, defined as a positive result to at least one mite and pollen (of any type). METHODS: Sera were analysed for IgE against CCD and environmental allergens with a commercially available multiplex enzyme-labelled allergen-specific IgE assay. RESULTS: Anti-CCD IgE was detected in nine of 38 (24%) of atopic dog sera. As with their human counterparts, all dogs with anti-CCD IgE had strong serological reactivity to grass pollens. CONCLUSIONS AND CLINICAL IMPORTANCE: Anti-CCD IgE can confound serological allergen testing in people; the same might be true in dogs. Further studies are warranted to investigate the clinical implications of anti-CCD IgE in dogs, including the potential for these antibodies to affect serum allergen-specific IgE assays used for clinical diagnosis, and whether they are relevant to clinical disease. PMID- 29498136 TI - Assessing the Effect of a Medical Toxicologist in the Care of Rattlesnake envenomated Patients. AB - BACKGROUND: Rattlesnake envenomation is an important problem in the United States, and the management of these envenomations can be complex. Despite these complexities, however, the majority of such cases are managed without the involvement of a medical toxicologist. The primary objective of this study was to evaluate the impact of a medical toxicology service (MTS) on the length of stay (LOS) of such patients. METHODS: The authors conducted a retrospective study at six centers in California. Patients were included if they were admitted in the 2 years before the establishment of a MTS (pre-MTS) or in the 2 years after the creation of a MTS (post-MTS). RESULTS: A total of 300 subjects were included (169 pre-MTS, 131 post MTS). Baseline characteristics between the pre-MTS and post-MTS groups were very similar. The creation of a MTS was associated with a significant reduction in the mean (95% confidence interval) LOS (69.5 [59.1-79.9] hours vs. 48.1 [41.4-54.8] hours). This reduced LOS was not associated with any statistically significant change in readmission rates. CONCLUSION: Rattlesnake bite patients treated by a medical toxicologist have a significantly reduced LOS compared to those without direct involvement of a medical toxicologist. PMID- 29498137 TI - Impact of perioperative hyperglycemia in patients undergoing microvascular reconstruction. AB - BACKGROUND: The effects of perioperative hyperglycemia on complications and outcomes in microvascular reconstruction have not been reported in the literature. METHODS: A retrospective cohort of 203 patients undergoing microvascular reconstruction was generated. Perioperative glucose levels and clinical factors were tested for associations with complications using simple and multivariate analyses. RESULTS: Hyperglycemia (blood glucose >= 180 mg/dL) occurred in 91 patients (44.8%) perioperatively, and was associated with increased rates of surgical complications, medical complications, surgical site infections, fistulas, and wound dehiscence. On univariate analysis, a more strict definition of hyperglycemia (blood glucose >= 165 mg/dL) was significantly associated with greater rates of venous thrombosis, although this lost statistical significance on multivariate analysis. CONCLUSION: Perioperative hyperglycemia occurs commonly in patients undergoing microvascular reconstruction and is associated with higher rates of complications, independent of a preexisting diagnosis of diabetes mellitus. Further research is needed to define the ideal glycemic target in this population. PMID- 29498138 TI - Systematic Review and Meta-analysis of Outcomes of Patients With Subsegmental Pulmonary Embolism With and Without Anticoagulation Treatment. AB - BACKGROUND: This systematic review addresses the controversy over the decision to anticoagulate patients with subsegmental pulmonary embolism (SSPE). METHODS: We searched Ovid MEDLINE, PubMed, Embase, the Cochrane Library, Scopus, Web of Science, ClinicalTrials.gov, Google Scholar, and bibliographies in March 2017. Two authors reviewed and retained papers with symptomatic patients who underwent computerized tomographic pulmonary angiography and had sufficient information to determine SSPE; decision to treat (or not) with systemic anticoagulation; and outcomes of bleeding, venous thromboembolism (VTE) recurrence, and death. Papers were assessed for selection and publication bias and heterogeneity, with Eggers and the inconsistency indexes (I2 ). RESULTS: From 1,512 papers screened, we included 14 studies comprising 15,563 patients for full-length review and analysis. Pooled data demonstrated I2 = 99% with an Eggers p < 0.001, suggesting significant publication bias. The pooled prevalence of SSPE was 4.6% (95% confidence interval [CI] = 1.8%-8.5%). The frequency of bleeding in SSPE patients treated with anticoagulation (n = 589) was 8.1% (95% CI = 2.8%-15.8%), with no available bleeding data in untreated patients (n = 126). The frequency of VTE recurrence within 90 days was 5.3% (95% CI = 1.6%-10.9%) for treated versus 3.9% (95% CI = 4.8%-13.4%) for untreated, while the frequency of death was 2.1% (95% CI = 3.4%-5.2%) for treated versus 3.0% (95% CI = 2.8%-8.6%) for untreated. CONCLUSION: This systematic review highlights the lack of any clinical trial to make a clear inference about harm or benefit of anticoagulation for SSPE. Comparison of pooled data from uncontrolled outcome studies shows no increase in VTE recurrence or death rates for patients who were not anticoagulated. These data suggest clinical equipoise for decision to anticoagulate or not anticoagulate patients with SSPE. However, this inference is limited by small numbers, imprecision, and the lack of a controlled clinical trial. PMID- 29498139 TI - Evidence-based nursing outputs and hot spot analysis of the last 5 years in mainland China: Results of a bibliometric analysis. AB - BACKGROUND: Evidence-based nursing has been highlighted and highly developed in recent decades in mainland China. Nevertheless, little is known about its overall development. AIMS: To gain insights on the overall development of evidence-based nursing in the most recent 5 years and to inform future evidence-based nursing research in mainland China. METHOD: Four Chinese and four English databases were searched with the search terms "evidence-based practice," "nurse or nursing," and "China or Chinese" from 2012 to 2016. Bibliometric and co-word cluster analysis were conducted with the final included publications. RESULTS: A total of 9036 papers published by 13 808 authors in 606 journals were included. Publication numbers were increasing. None of the top ten journals publishing evidence-based nursing papers were core nursing journals. The research hot spots on evidence based nursing in the recent five years were cardiovascular disease, mental health, and complication prevention. However, little attention has been paid to education for evidence-based nursing. CONCLUSION: Evidence-based nursing has penetrated into various nursing branches in mainland China and become a well recognized and relatively mature research domain. More importance should be attached to the study design, methodological, and reporting quality of evidence based nursing projects. PMID- 29498140 TI - Confronting the Opioid Crisis by Taking a Long Look in the Mirror ... and at Our Peers. PMID- 29498141 TI - Normal values for assessment of anal sphincter morphology, anorectal motion, and pelvic organ prolapse with MRI in healthy women. AB - BACKGROUND: Endoanal MRI and MR defecography are used to identify anal sphincter injury and disordered defecation. However, few studies have evaluated findings in asymptomatic healthy people. The effects of BMI and parity on rectoanal motion and evacuation are unknown. METHODS: In 113 asymptomatic females (age 50 +/- 17 years, Mean +/- SD) without risk factors for anorectal trauma, anal sphincter appearance, anorectal motion, and pelvic organ prolapse were evaluated with MRI. The relationship between age, BMI, and parity and structural findings were evaluated with parametric and non-parametric tests. RESULTS: The anal sphincters and puborectalis appeared normal in over 90% of women. During dynamic MRI, the anorectal angle was 100 +/- 1o (Mean +/- SEM) at rest, 70 +/- 2 degrees at squeeze, and 120 +/- 2 degrees during defecation. The change in anorectal angle during squeeze (r = -.25, P < .005), but not during evacuation (r = .13, P = .25) was associated with age. In the multivariable models, BMI (P < .01) and parity (P < .01) were, respectively, independently associated with the intersubject variation in the anorectal angle at rest and the angle change during squeeze. Ten percent or fewer women had had descent of the bladder base or uterus 4 cm or more below the pubococcygeal line or a rectocele measuring 4 cm or larger. Only 5% had a patulous anal canal. CONCLUSIONS: In addition to age, BMI and parity also affect anorectal motion in asymptomatic women. These findings provide age adjusted normal values for rectoanal anatomy and pelvic floor motion. PMID- 29498142 TI - Non-invasive estimation of 10 B-4-borono-L-phenylalanine-derived boron concentration in tumors by PET using 4-borono-2-18 F-fluoro-phenylalanine. AB - In boron neutron capture therapy (BNCT), 10 B-4-borono-L-phenylalanine (BPA) is commonly used as a 10 B carrier. PET using 4-borono-2-18 F-fluoro-phenylalanine (18 F-FBPA PET) has been performed to estimate boron concentration and predict the therapeutic effects of BNCT; however, the association between tumor uptake of 18 F-FBPA and boron concentration in tumors remains unclear. The present study investigated the transport mechanism of 18 F-FBPA and BPA, and evaluated the utility of 18 F-FBPA PET in predicting boron concentration in tumors. The transporter assay revealed that 2-aminobicyclo-(2.2.1)-heptane-2-carboxylic acid, an inhibitor of the L-type amino acid transporter, significantly inhibited 18 F FBPA and 14 C-4-borono-L-phenylalanine (14 C-BPA) uptake in FaDu and LN-229 human cancer cells. 18 F-FBPA uptake strongly correlated with 14 C-BPA uptake in 7 human tumor cell lines (r = .93; P < .01). PET experiments demonstrated that tumor uptake of 18 F-FBPA was independent of the administration method, and uptake of 18 F-FBPA by bolus injection correlated well with BPA uptake by continuous intravenous infusion. The results of this study revealed that evaluating tumor uptake of 18 F-FBPA by PET was useful for estimating 10 B concentration in tumors. PMID- 29498143 TI - Remembering an amazing scientist and friend, Colin Groves (1942 - 2017). PMID- 29498144 TI - Glioma infiltration sign on high b-value diffusion-weighted imaging in gliomas and its prognostic value. AB - BACKGROUND: Glioma cells may infiltrate beyond the tumor margins revealed on conventional structural images. PURPOSE: To investigate whether the presence of a glioma infiltration sign on high b-value diffusion-weighted imaging (DWI) can predict the prognosis of gliomas. STUDY TYPE: Retrospective cohort. SUBJECTS: Fifty-two patients with gliomas (14 WHO grade II; 13 WHO grade III; 25 WHO grade IV). FIELD STRENGTH/SEQUENCE: 3.0T, including a T1 -weighted contrast-enhanced (T1 w-CE) sequence, contrast-enhanced T2 -flair sequence, and a DWI sequence. ASSESSMENT: T1 w-CE images and contrast-enhanced T2 -flair images were used for identifying the tumor region for enhancing and nonenhancing gliomas, respectively. The glioma infiltration sign was defined as the presence of a peritumoral abnormal high signal region on DWI map, which was adjacent to the tumor region and had higher signal than surrounding areas. This sign was assessed on a high b-value DWI map with b = 3000 s/mm2 . For patients with glioma infiltration sign, DWI3000max , DWI1000max , ADC3000min , and ADC1000min were measured by drawing a region of interest over the peritumoral abnormal high signal region. STATISTICAL TESTS: Survival analysis was conducted by using Cox regression. RESULTS: Glioma infiltration sign was observed in 28 (53.8%) patients. The occurrence rate of this sign was 92.0% in grade IV gliomas, 30.8% in grade III gliomas, and 7.1% in grade II gliomas. The glioma infiltration sign could independently predict both the progression-free survival (hazard ratio [HR], 95% confidence interval [CI] = 8.58 [3.19-23.03], P < 0.001) and overall survival (HR, 95% CI = 11.90 [3.41-41.55], P < 0.001) after adjustment. For patients with glioma infiltration sign, DWI3000max (P = 0.005) and ADC3000min (P = 0.008) were both independent predictors of overall survival after adjustment, while DWI1000max and ADC1000min were not. DATA CONCLUSION: The glioma infiltration sign on high b-value DWI is an independent predictor of poor prognosis in glioma patients. High b-value DWI might be a convenient method to detect glioma infiltration. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. PMID- 29498145 TI - Feasibility of carbon-ion radiotherapy for re-irradiation of locoregionally recurrent, metastatic, or secondary lung tumors. AB - Intrathoracic recurrence after carbon-ion radiotherapy for primary or metastatic lung tumors remains a major cause of cancer-related deaths. However, treatment options are limited. Herein, we report on the toxicity and efficacy of re irradiation with carbon-ion radiotherapy for locoregionally recurrent, metastatic, or secondary lung tumors. Data of 95 patients with prior intrathoracic carbon-ion radiotherapy who were treated with re-irradiation with carbon-ion radiotherapy at our institution between 2006 and 2016 were retrospectively analyzed. Seventy-three patients (76.8%) had primary lung tumors and 22 patients (23.2%) had metastatic lung tumors. The median dose of initial carbon-ion radiotherapy was 52.8 Gy (relative biological effectiveness) and the median dose of re-irradiation was 66.0 Gy (relative biological effectiveness). None of the patients received concurrent chemotherapy. The median follow-up period after re-irradiation was 18 months. In terms of grade >=3 toxicities, one patient experienced each of the following: grade 5 bronchopleural fistula, grade 4 radiation pneumonitis, grade 3 chest pain, and grade 3 radiation pneumonitis. The 2-year local control and overall survival rates were 54.0% and 61.9%, respectively. In conclusion, re-irradiation with carbon-ion radiotherapy was associated with relatively low toxicity and moderate efficacy. Re-irradiation with carbon-ion radiotherapy might be an effective treatment option for patients with locoregionally recurrent, metastatic, or secondary lung tumors. PMID- 29498146 TI - Periostin antisense oligonucleotide suppresses bleomycin-induced formation of a lung premetastatic niche for melanoma. AB - Metastasis is the leading cause of cancer death. A tumor-supportive microenvironment, or premetastatic niche, at potential secondary tumor sites plays an important role in metastasis, especially in tumor cell colonization. Although a fibrotic milieu is known to promote tumorigenesis and metastasis, the underlying molecular contributors to this effect have remained unclear. Here we show that periostin, a component of the extracellular matrix that functions in tissue remodeling, has a key role in formation of a fibrotic environment that promotes tumor metastatic colonization. We found that periostin was widely expressed in fibrotic lesions of mice with bleomycin-induced lung fibrosis, and that up-regulation of periostin expression coincided with activation of myofibroblasts positive for alpha-smooth muscle actin. We established a lung metastasis model for B16 murine melanoma cells and showed that metastatic colonization of the lung by these cells was markedly promoted by bleomycin induced lung fibrosis. Inhibition of periostin expression by giving an intratracheal antisense oligonucleotide targeting periostin mRNA was found to suppress bleomycin-induced lung fibrosis and thereby to attenuate metastatic colonization of the lung by melanoma cells. Our results indicate that periostin is a key player in the development of bleomycin-induced fibrosis and consequent enhancement of tumor cell colonization in the lung. Our results therefore implicate periostin as a potential target for prevention or treatment of lung metastasis. PMID- 29498148 TI - The value of the Modified Early Warning Score for unplanned Intensive Care Unit admissions of patients treated in hospital general wards. AB - AIM: To determine the value of the Modified Early Warning Score (MEWS) for general ward patients and its potential use as an alarm tool for ward nurses. METHODS: A combined prospective-retrospective observational study was conducted with 153 patients in a university hospital (2013-2014). All patients were admitted to the intensive care unit (ICU) from general wards. Parameters retrospectively studied were 5 MEWS values at 4 hourly intervals, up to 20 hours before ICU admission. Parameters prospectively studied were ICU length of stay, ICU mortality, and mortality after ICU discharge. RESULTS: Most frequent severe adverse events were acute respiratory failure (39.9%) and septic shock (20.3%). Modified Early Warning Score increased gradually during the last 20 hours, and most patients remained in the wards, above a cut-off point >=7 recorded at 4 hours before admission. Significant associations between latest MEWS score and ICU mortality and ICU length of stay were found. MEWS score>= 7 hours before admission was highly associated with increased ICU and hospital mortality. CONCLUSION: Patient deterioration in general wards can result in severe adverse events. Modified Early Warning Score is a strong predictor of outcome and may be used as a monitoring tool for potentially avoidable deaths and unplanned admissions to ICU. PMID- 29498147 TI - Subtypes of depression and their overlap in a naturalistic inpatient sample of major depressive disorder. AB - Subtyping depression is important in order to further delineate biological causes of depressive syndromes. The aim of this study was to evaluate clinical and outcome characteristics of distinct subtypes of depression and to assess proportion and features of patients fulfilling criteria for more than one subtype. Melancholic, atypical and anxious subtypes of depression were assessed in a naturalistic sample of 833 inpatients using DSM-IV specifiers based on operationalized criteria. Baseline characteristics and outcome criteria at discharge were compared between distinct subtypes and their overlap. A substantial proportion of patients (16%) were classified with more than one subtype of depression, 28% were of the distinct anxious, 7% of the distinct atypical and 5% of the distinct melancholic subtype. Distinct melancholic patients had shortest duration of episode, highest baseline depression severity, but were more often early improvers; distinct anxious patients had higher NEO Five Factor Inventory (NEO-FFI) neuroticism scores compared with patients with unspecific subtype. Melancholic patients with overlap of anxious features had worse treatment outcome compared to distinct melancholic and distinct anxious subtype. Distinct subtypes differed in only few variables and patients with overlap of depression subtypes may have independent clinical and outcome characteristics. Studies investigating biological causes of subtypes of depression should take influence of features of other subtypes into account. PMID- 29498149 TI - Continuity of care in after-hours house call medical services: An exploration of follow-up patterns in an Australian context. AB - RATIONALE, AIMS AND OBJECTIVES: This study explores the postconsultation follow up behaviours of patients who used the Australian after-hours house-call (AHHC) medical services. These behaviours provide insights into the nature of the continuity of care (CoC) in the industry and are a measure quality in AHHC service delivery. Understanding the patterns of these CoCs and their predictors will enable stakeholders in the industry, both locally and globally, plan and implement higher quality services. METHODS: This is a cross-sectional survey of all 10,838 patients who used AHHC during the last week of January 2016. A validated questionnaire was used, distributed through a mix of online and postal questionnaires. RESULTS: One thousand two hundred twenty-eight questionnaires were returned (11.3%). Had the AHHC not been available, 38.6% of respondents would have gone to their own general practitioners (GPs), 40.1% to an emergency department (ED), 15.9% to an office-based after-hours service, and 5.5% would have done nothing. After the AHHC visits, however, 47.3% followed up with their GPs, 8.4% went to an ED, 4.2% arranged for a further AHHC visit, while 40.0% required no follow-up. Patients who required GP follow-ups were likely to be dissatisfied with aspects of the AHHC care received, while those with no follow ups were generally satisfied. Patients >=65 years were more likely to require no follow-ups (P < .001) and, if they did, were unlikely to do so with their GPs (P = .04). Where required, follow-ups for those aged <=16 years were likely to result in ED attendances (P = .01), while students generally rely on AHHCs for follow-ups (P = .03). Compared to females, males were likely to rely on their GPs (P = .01), and less likely to go to an ED (P = .01). CONCLUSION: Most patients seen by Australian AHHC services either end up requiring no further follow-up, or do so with their own GPs, with few relying on further AHHC visits for follow-up. The real reasons for follow-up differences observed by age and gender may need to be explored further so as to ensure that the AHHC services are better used. PMID- 29498150 TI - Acute Aortic Dissection: Is There Something Better than Physician Gestalt? PMID- 29498151 TI - Estimating correlations among cardiovascular patients' psychiatric and physical symptom indicators: The biplot in correspondence analysis approach. AB - OBJECTIVES: We employed the correspondence analysis (CA) biplot to estimate correlations between gender-age levels of cardiovascular disease patients and their psychiatric and physical symptoms. Utilization of this correlation estimation can inform clinical practice by elucidating associations between certain psychiatric or physical symptoms and specific gender-age levels. METHOD: The CA biplot utilized here was designed to visually inspect row-column category associations in a 2-dimensional plane and then to numerically estimate the category associations with correlations. To do so, we (a) estimated dimensions from row and column categories with CA; (b) verified statistical significance of dimensions with a permutation test; (c) projected row and column categories in a plan constructed with the first 2 dimensions that were statistically significant; (d) visually inspected category associations in the plane; and (e) numerically estimated category associations with correlations. RESULTS: Consistent with the previous results, female cardiovascular disease patients were more likely to experience psychiatric symptoms than the male patients. However, when examining the results by gender and age, both female and male patients in their 50s and 60s tended to experience elevated rates of the psychiatric symptoms. CONCLUSIONS: The CA biplot can be useful for isolating key clinical concerns among any medical populations. PMID- 29498152 TI - Self-perceived educational needs of junior assistant professors in Conservative Dentistry and Endodontics in France. AB - INTRODUCTION: Academic dental educators play a major role in training future dentists. They help students to develop medical knowledge and behavioural skills that improve the quality and rigor of their future practice. Therefore, their experience and knowledge are critical to ensure effective learning. However, a French national workshop revealed that most junior assistant professors lack educational skills at the beginning of their career. The aim of this study was to assess educational training needs of junior assistant professors in the Department of Conservative Dentistry and Endodontics. MATERIALS AND METHODS: An electronic survey was sent to junior assistant professors belonging to Departments of Conservative Dentistry and Endodontics within the 16 French dental schools in 2016. This survey was designed to collect data regarding their motivations, teaching expertise and interest in pedagogy. RESULTS: Sixty of the 69 junior educators turned in their answers, which represents a response rate of 87%. About 86.7% of respondents cited their attraction to teaching as one of the main reasons behind their application. The major difficulty encountered by junior faculty was related to course preparation. Only 15% had received educational training despite the fact that 98.3% were convinced of the usefulness of such a training for junior teachers. CONCLUSION: This study identified the motivations and difficulties encountered by junior assistant professors. This collection of educational needs should be considered when planning a national programme for educational training of dental faculty that will promote the acquisition of teaching skills and improve the education of dental students. PMID- 29498153 TI - A novel mutation in SLC39A14 causing hypermanganesemia associated with infantile onset dystonia. AB - BACKGROUND: Mutations in SLC39A14 cause a recessive disorder of manganese (Mn) metabolism that manifests as childhood onset progressive neurodegeneration characterized by parkinsonism and dystonia. METHODS: The present study genetically investigated a case of hypermanganesemia. We describe a family where an affected child with a history of progressive neurodegeneration showed symptoms of dystonia with increased levels of blood Mn and altered signal intensities in globus pallidus and dentate nucleus. Whole exome sequencing was conducted to genetically investigate the pathology in the child, which allowed us to identify a novel homozygous causal mutation in SLC39A14. RESULTS: Insilico modeling of the novel homozygous causal mutation in SLC39A14 predicted that it was deleterious, affecting Mn binding and transportation of metal by transmembrane instability of the protein structure. The clinical features of other reported mutations in SLC39A14 were also reviewed and the clinical spectrum in our case conforms to the described neurological abnormalities. CONCLUSIONS: We conclude that the mutation identified in SLC39A14 in our case is a novel variation linked to recessive disorders of hypermaganesemia and dystonia. PMID- 29498154 TI - Editorial: Helicobacter pylori and gastric cancer in Alaskan Natives: Time to stop studying H. pylori and to eradicate it. PMID- 29498155 TI - Effect of a Data-driven Intervention on Opioid Prescribing Intensity Among Emergency Department Providers: A Randomized Controlled Trial. AB - OBJECTIVE: Little is known about accuracy of provider self-perception of opioid prescribing. We hypothesized that an intervention asking emergency department (ED) providers to self-identify their opioid prescribing practices compared to group norms-and subsequently providing them with their actual prescribing data would alter future prescribing compared to controls. METHODS: This was a prospective, multicenter randomized trial in which all attending physicians, residents, and advanced practice providers at four EDs were randomly assigned either to no intervention or to a brief data-driven intervention during which providers were: 1) asked to self-identify and explicitly report to research staff their perceived opioid prescribing in comparison to their peers and 2) then given their actual data with peer group norms for comparison. Our primary outcome was the change in each provider's proportion of patients discharged with an opioid prescription at 6 and 12 months. Secondary outcomes were opioid prescriptions per hundred total prescriptions and normalized morphine milligram equivalents prescribed. Our primary comparison stratified intervention providers by those who underestimated their prescribing and those who did not underestimate their prescribing, both compared to controls. RESULTS: Among 109 total participants, 51 were randomized to the intervention, 65% of whom underestimated their opioid prescribing. Intervention participants who underestimated their baseline prescribing had larger-magnitude decreases than controls (Hodges-Lehmann difference = -2.1 prescriptions per hundred patients at 6 months [95% confidence interval {CI} = -3.9 to -0.5] and -2.2 per hundred at 12 months [95% CI = -4.8 to -0.01]). Intervention participants who did not underestimate their prescribing had similar changes to controls. CONCLUSIONS: Self-perception of prescribing was frequently inaccurate. Providing clinicians with their actual opioid prescribing data after querying their self-perception reduced future prescribing among providers who underestimated their baseline prescribing. Our findings suggest that guideline and policy interventions should directly address the potential barrier of inaccurate provider self-awareness. PMID- 29498156 TI - The effect of a regular walking program on dyspnoea severity and quality of life in normal weight, overweight, and obese patients with chronic obstructive pulmonary disease. AB - AIM: The objective was to determine the effect of a regular walking program on physical activity (the number of steps and walking duration), dyspnoea severity, and quality of life in normal weight, overweight, and obese patients with chronic obstructive pulmonary disease. METHOD: An experimental study; 50 patients with chronic obstructive pulmonary disease admitted to the respiratory clinic of a public hospital in Turkey between November 2014 and July 2015 were included. All the patients underwent a regular walking program (at least 30 minutes every day) using a pedometer for 16 weeks under the supervision of a nurse. RESULTS: After the regular walking program, the respiratory function test results of the obese patients were significantly improved. The walking duration, the number of steps taken per day, and the quality of life of all participants improved significantly, and dyspnoea severity was reduced in all participants. CONCLUSION: The regular walking program reduced dyspnoea severity and improved quality of life in all participants. Nurses' efforts to increase activity levels in all patients with chronic obstructive pulmonary disease, and particularly those with obesity, through a regular walking program may contribute to reduce the severity of dyspnoea and improve quality of life. PMID- 29498157 TI - Rubric system for evaluation of crown preparation performed by dental students. AB - OBJECTIVE: This study aimed to investigate the use of an analytic rubric system for the evaluation of all-ceramic crown preparation on the right maxillary central incisor performed by the dental students. MATERIALS AND METHODS: Seventy two-third-year students and 8 faculty members from prosthodontics participated in this double-blind study. The students prepared an ivorine tooth # 11 for all ceramic crown. The students were given clear instructions regarding the all ceramic crown preparation and informed about the criteria for the assessment of the preparation. An analytic rubric based on 10-point scale for assessment of various preparation parameters was used by the 8 examiners. Descriptive statistics, ANOVA and post hoc Tukey tests were used for statistical analysis. RESULTS: One-way analysis of variance indicated significance amongst the examiners for all the parameters except for time management. The overall mean scoring by examiners was 7.60 +/- 1.18, with highest and lowest mean scores for Examiner 1 (8.02 +/- 1.06) and Examiner 4 (6.82 +/- 1.50), respectively. The highest number of interexaminer variation (difference) in scoring was found for two plane reduction, and the least difference amongst the examiners was observed for finishing of margins and walls of the preparation. Examiner 4 had the highest number of significant difference with the rest of the examiners. The students scored least marks in axial reduction (56.33%) and preservation of adjacent teeth (66.9%). CONCLUSIONS: Criteria-based assessment using analytic rubric for crown preparations in pre-clinical fixed prosthodontics is an effective tool for finding the errors/weak areas of dental students. PMID- 29498158 TI - Preclinical evidence for combining the 5-HT2C receptor agonist lorcaserin and varenicline as a treatment for nicotine dependence. AB - Varenicline, a nicotinic acetylcholine receptor partial agonist, is used to treat nicotine dependence. Lorcaserin, a 5-HT2C receptor agonist has been approved in some countries to treat obesity. Based on preclinical and preliminary clinical evidence, lorcaserin may have potential to treat nicotine dependence. These experiments examined in rats the effects of combining varenicline (0.5 or 1 mg/kg) and lorcaserin (0.3, 0.6 and 1 mg/kg) on nicotine self-administration, reinstatement of nicotine seeking, responding for food and impulsive action. Both drugs alone reduced nicotine self-administration. Combining varenicline and 0.6 mg/kg lorcaserin reduced responding to a greater extent than either drug alone. In a relapse model, extinguished nicotine seeking was reinstated by a priming injection of nicotine and nicotine-associated cues. Reinstatement was reduced by varenicline (1 mg/kg) and by lorcaserin (0.3 mg/kg). Combining lorcaserin (0.3 mg/kg) with varenicline (0.5 or 1 mg/kg) reduced reinstatement to a greater degree than either drug alone. Both drugs had minimal effects on responding for food, alone or in combination. In the five-choice serial reaction time test, varenicline (0.5 or 1 mg/kg) increased impulsivity, measured as increased premature responding. This effect was reduced by lorcaserin (0.3 mg/kg). Plasma levels of varenicline or lorcaserin were not altered by co-administration of the other drug. Varenicline and lorcaserin have additive effects on nicotine self administration, and on nicotine seeking. Lorcaserin prevents impulsivity induced by varenicline. This pattern of effects suggests that co-administration of varenicline and lorcaserin has potential as a treatment for nicotine dependence that may exceed the value of either drug alone. PMID- 29498159 TI - Quantifying the HDL proteome by mass spectrometry: how many proteins truly associate with HDL? Reply. PMID- 29498160 TI - Complications in pediatric intestine transplantation in the absence of peri operative donor or recipient bowel decontamination. AB - This study reports the clinical complication and infection rates of an active pediatric IT program that has never utilized bowel decontamination in either the donor or the recipient. All patients undergoing IT from 2003 to 2015 at a single pediatric IT center were reviewed. Post-transplant surgical, infectious, and immunosuppressive complications are reported. There were 52 patients who underwent IT during the study period. Among these patients, 4% developed a postoperative abscess, one developed an enteric fistula (2%), and one had an enteric or anastomotic leak (2%). The rate of any bacterial infection was 90% in the first year, with a wound infection rate of 23%. Any fungal infection occurred in 25% of patients. Any viral infection occurred in 75% of patients. Gastrointestinal viruses were diagnosed in 52% of patients, and cytomegalovirus infections occurred in 17%. Rejection rates were 39% at any time post-transplant (isolated 44% and 35% for multivisceral patients). At this center in which no bowel decontamination was used, rates of surgical complications, infections, and rejection were similar to those reported by other centers. These findings suggest bowel decontamination may provide no significant benefit in this population of high-risk transplant patients. PMID- 29498161 TI - Tailoring the d-Band Centers Enables Co4 N Nanosheets To Be Highly Active for Hydrogen Evolution Catalysis. AB - Endowing materials with specific functions that are not readily available is always of great importance, but extremely challenging. Co4 N, with its beneficial metallic characteristics, has been proved to be highly active for the oxidation of water, while it is notoriously poor for catalyzing the hydrogen evolution reaction (HER), because of its unfavorable d-band energy level. Herein, we successfully endow Co4 N with prominent HER catalytic capability by tailoring the positions of the d-band center through transition-metal doping. The V-doped Co4 N nanosheets display an overpotential of 37 mV at 10 mA cm-2 , which is substantially better than Co4 N and even close to the benchmark Pt/C catalysts. XANES, UPS, and DFT calculations consistently reveal the enhanced performance is attributed to the downshift of the d-band center, which helps facilitate the H desorption. This concept could provide valuable insights into the design of other catalysts for HER and beyond. PMID- 29498162 TI - The mental health of our sovereigns: The case of King Charles VI of France. PMID- 29498163 TI - Bronsted Acid Enabled Nickel-Catalyzed Hydroalkenylation of Aldehydes with Styrene and its Derivatives. AB - A Bronsted acid enabled nickel-catalyzed hydroalkenylation of aldehydes and styrene derivatives has been developed. The Bronsted acid acts as a proton shuttle to transfer a proton from the alkene to the aldehyde, thereby leading to an economical and byproduct-free coupling. A series of synthetically useful allylic alcohols were obtained through one-step reactions from readily available styrene derivatives and aliphatic aldehydes in up to 88 % yield and with high linear selectivity. PMID- 29498164 TI - Halogen-Bond-Mediated Assembly of a Single-Component Supramolecular Triangle and an Enantiomeric Pair of Double Helices from 2-(Iodoethynyl)pyridine Derivatives. AB - Construction of single-component supramolecular triangle and unprecedented spontaneous resolution of pairs of intertwined supramolecular 31 - and 32 -double helices by the self-assembly of achiral 2-(iodoethynyl)pyridine and its derivatives have been achieved through intermolecular ethynyl C-I????N halogen bonds in the crystalline state. Fine-tuning of the molecular structure of the achiral monomer and choice of solvents for crystallization have a dominant effect on the resultant supramolecular architectures. PMID- 29498165 TI - Somatoform disorder in primary care: The influence of co-morbidity with anxiety and depression on health care utilization. AB - RATIONALE, AIMS, AND OBJECTIVES: Patients with somatoform disorders are frequent attenders in primary and secondary care. While co-morbid mental disorders, especially depression and anxiety, are frequently present, there is controversy on whether mental co-morbidity leads to higher health care utilization (HCU). The present paper investigates the influence of co-morbid depressive and anxiety disorders on primary, specialized somatic and mental HCU in primary care patients with somatoform disorders. Additionally, we investigated the predictive value of self-rated health and illness perception on HCU. METHODS: Patients in 19 primary care practices were screened with the Patient Health Questionnaire, and patients at high risk for somatoform disorders were assessed using the Composite International Diagnostic Interview. N = 71 patients with somatoform disorders were analysed. We analysed whether having one vs two co-morbidities (depression and/or anxiety), self-rated health, and illness perception were predictors for primary, specialized somatic and mental HCU using binominal and hierarchical regression analyses. RESULTS: Having both co-morbid depressive and anxiety disorder predicted higher primary HCU (IRR = 1.96, 95% CI, 1.30-2.93), and increased the odds of being in mental health care (OR = 5.16, 95% CI, 1.10 24.20), while only one co-morbidity did not. No differences were found for specialized somatic HCU. Illness perception and self-rated health did not predict HCU. CONCLUSION: Not a single but only the presence of multiple co-morbidities predicts primary and mental HCU in patients with somatoform disorder. Health care utilization might be essentially influenced by the associated psychological distress, which should be considered in treatment. PMID- 29498166 TI - Electrochemical Oxidative C-H Amination of Phenols: Access to Triarylamine Derivatives. AB - Dehydrogenative C-H/N-H cross-coupling serves as one of the most straightforward and atom-economical approaches for C-N bond formation. In this work, an electrochemical reaction protocol has been developed for the oxidative C-H amination of unprotected phenols under undivided electrolytic conditions. Neither metal catalysts nor chemical oxidants are needed to facilitate the dehydrogenation process. A series of triarylamine derivatives could be obtained with good functional-group tolerance. The electrolysis is scalable and can be performed at ambient conditions. PMID- 29498167 TI - Shape-Selective Zeolites Promote Ethylene Formation from Syngas via a Ketene Intermediate. AB - Syngas conversion by Fischer-Tropsch synthesis (FTS) is characterized by a wide distribution of hydrocarbon products ranging from one to a few carbon atoms. Reported here is that the product selectivity is effectively steered toward ethylene by employing the oxide-zeolite (OX-ZEO) catalyst concept with ZnCrOx mordenite (MOR). The selectivity of ethylene alone reaches as high as 73 % among other hydrocarbons at a 26 % CO conversion. This selectivity is significantly higher than those obtained in any other direct syngas conversion or the multistep process methanol-to-olefin conversion. This highly selective pathway is realized over the catalytic sites within the 8-membered ring (8MR) side pockets of MOR via a ketene intermediate rather than methanol in the 8MR or 12MR channels. This study provides substantive evidence for a new type of syngas chemistry with ketene as the key reaction intermediate and enables extraordinary ethylene selectivity within the OX-ZEO catalyst framework. PMID- 29498168 TI - Chelating N-Heterocyclic Carbene Ligands Enable Tuning of Electrocatalytic CO2 Reduction to Formate and Carbon Monoxide: Surface Organometallic Chemistry. AB - Reported here is the chelate effect as a design principle for tuning heterogeneous catalysts for electrochemical CO2 reduction. Palladium functionalized with a chelating tris-N-heterocyclic carbene (NHC) ligand (Pd timtmbMe ) exhibits a 32-fold increase in activity for electrochemical reduction of CO2 to C1 products with high Faradaic efficiency (FEC1 =86 %) compared to the parent unfunctionalized Pd foil (FE=23 %), and with sustained activity relative to a monodentate NHC-ligated Pd electrode (Pd-mimtmbMe ). The results highlight the contributions of the chelate effect for tailoring and maintaining reactivity at molecular-materials interfaces enabled by surface organometallic chemistry. PMID- 29498169 TI - Allosterically Activated Protein Self-Assembly for the Construction of Helical Microfilaments with Tunable Helicity. AB - Protein allostery, a chemical-to-mechanical effect that can precisely regulate protein structure, exists in many proteins. Herein, we demonstrate that protein allostery can be used to drive self-assembly for the construction of tunable protein architectures. Calmodulin (CaM) was chosen as a model allosteric protein. Ca2+ -mediated contraction of CaM to a closed state can activate CaM and its ligand to self-assemble into a 1D protein helical microfilament. Conversely, relaxation of CaM to the open state can unwind and further dissociate the helical assemblies. Fine regulation of the protein conformation by tuning the external Ca2+ level allows us to obtain various protein helical nanostructures with tunable helicity. This study offers a new approach toward chemomechanically controlled protein self-assembly. PMID- 29498170 TI - Pharmacogenetics of Dopamine beta-Hydroxylase in cocaine dependence therapy with doxazosin. AB - The alpha1 -adrenergic antagonist, doxazosin, has improved cocaine use disorder (CUD) presumably by blocking norepinephrine (NE) stimulation and reward from cocaine-induced NE increases. If the NE levels for release were lower, then doxazosin might more readily block this NE stimulation and be more effective. The NE available for release can be lower through a genetic polymorphism in dopamine beta-hydroxylase (DBH) (C-1021T, rs1611115), which reduces DbetaH's conversion of dopamine to NE. We hypothesize that doxazosin would be more effective in CUD patients who have these genetically lower DbetaH levels. This 12-week, double blind, randomized, placebo-controlled trial included 76 CUD patients: 49 with higher DbetaH levels from the DBH CC genotype and 27 with lower DbetaH levels from T-allele carriers (CT or TT). Patients were randomized to doxazosin (8 mg/day, N = 47) or placebo (N = 29) and followed with thrice weekly urine toxicology and once weekly cognitive behavioral psychotherapy. Cocaine use was reduced at a higher rate among patients in the doxazosin than in the placebo arm. We found significantly lower cocaine use rates among patients carrying the T allele (CT/TT) than the CC genotype. The percentage of cocaine positive urines was reduced by 41 percent from baseline in the CT/TT group with low DbetaH and NE levels, as compared with no net reduction in the CC genotype group with normal DbetaH and NE levels. The DBH polymorphism appears play an important role in CUD patients' response to doxazosin treatment, supporting a pharmacogenetic association and potential application for personalized medicine. PMID- 29498171 TI - Severe hypoglycemia and diabetic ketoacidosis in young persons with preschool onset of type 1 diabetes mellitus: An analysis of three nationwide population based surveys. AB - OBJECTIVES: To describe incidence rates and temporal trends of severe hypoglycemia (SH) and of hospitalizations for SH or diabetic ketoacidosis (DKA) in persons with early-onset, long-term type 1 diabetes (T1D) and associations of these short-term complications with potential risk factors. METHODS: This study includes data of 1,875 persons 11.2 to 21.9 years of age with early-onset (<5 years) and long-term (>10 years) T1D from 3 cross-sectional nationwide, population-based surveys conducted in 2009/2010, 2012/2013 and 2015/2016 using standardized questionnaires. Negative binomial regression was used to estimate incidence rates per 100 person-years (py), temporal trends and associations between potential risk factors and outcomes. RESULTS: The crude incidence rate of SH showed a decreasing trend over time (P for trend = .004), disappearing after adjustment for confounders (P for trend = .341). In contrast, adjusted rates of SH- and DKA-associated hospitalizations did not change significantly between 2009 and 2016 (P for trend = .306 and .774, respectively). Associations between sex, diabetes duration, insulin treatment regimen, hypoglycemia awareness as well as physical activity and SH were found, while family structure was associated with hospitalizations for SH. Family structure, socioeconomic status (SES), diabetes duration, and hemoglobin A1c values showed associations with DKA-related hospitalizations. CONCLUSIONS: After adjustment, rates of SH and SH- or DKA associated hospitalization showed no significant changes in recent years. Structured education programs focusing on high-risk groups as, for example, persons with T1D living with 1 biological parent and the parents' partner or those with a low SES, should be implemented to reduce incidence rates of hospitalizations. PMID- 29498172 TI - Substrate-Induced Phase of a Benzothiophene Derivative Detected by Mid-Infrared and Lattice Phonon Raman Spectroscopy. AB - The presence of a substrate-induced polymorph of 2,7-dioctyloxy[1]benzothieno[3,2 b]benzothiophene is probed in microscopic crystals and in thin films. Two experimental techniques are used: lattice phonon Raman and IR spectroscopy. The bulk crystal and substrate-induced phase have an entirely different molecular packing, and therefore, their Raman spectra are characteristic fingerprints of the respective polymorphs. These spectra can be unambiguously assigned to the individual polymorphs. Drop-cast and spin-coated thin films on solid substrates are investigated in the as-prepared state and after solvent-vapor annealing. Because Raman spectroscopy is less sensitive with decreasing film thickness, IR spectroscopy is shown to be a more feasible tool for phase detection. The surface induced phase is mainly present in the as-prepared thin films, whereas the bulk phase is present after solvent-vapor annealing. This result suggests that the surface-induced phase is a metastable polymorph. PMID- 29498173 TI - Quantifying the HDL proteome by mass spectrometry: how many proteins truly associate with HDL? PMID- 29498174 TI - The mind-brain gap and the neuroscience-psychiatry gap. AB - A problem underlying the mind brain gap is the complex integration among the disciplines involved in it: neurosciences, clinical psychiatry and psychology, and philosophy of science. Research in neurosciences and clinical psychiatry requires a positioning in relation to some conceptual/philosophical aspects. These are related to the models of interrelationship of the brain and the mind, to explanatory approaches in psychiatry, and to conceptual issues such as dimensionality versus categories, symptoms versus disorders, and neurobiological correlates versus clinical determination of mental disorder. In this article, we try to address some of these issues that, if taken into account, could reduce the gap between psychiatrists and neuroscientists and turn the research in this area more profitable. PMID- 29498175 TI - How to do a simple laparoscopic jejunostomy. PMID- 29498176 TI - Self-assessment of ergonomics amongst dental students utilising photography: RCT. AB - INTRODUCTION: Dental professionals are at high risk of musculoskeletal disorders (MSDs) due to static working positions for extended periods of time. Musculoskeletal pain has been identified as early as during their entry-level dental education. The purpose of this study was to determine whether feedback involving photography and self-assessment would improve ergonomic scores and the accuracy of ergonomic self-assessments amongst dental students. MATERIALS AND METHODS: The study involved a randomised control design of 135 dental students. At weeks 1 and 4, participants were photographed, and at weeks 1 through 4, participants completed ergonomic self-evaluations, using a Modified-Dental Operator Posture Assessment Instrument (M-DOPAI). During weeks 2 and 3, participants in the training group were photographed and used those photographs to complete ergonomic self-assessments. All participants' pre-training and post training photographs were evaluated for ergonomic scores by two raters. RESULTS: A mixed-design ANOVA of ergonomic scores revealed that ergonomic scores improved for all students who received the ergonomics training (F(1,254)=17.41, P < .001). In addition, a mixed-design ANOVA of kappa coefficient values between student and rater scores revealed that the accuracy of self-assessments improved for all students who received the ergonomics training (F(1,127)=6.33, P < .05). CONCLUSION: The use of photographs and self-assessment provides dental and dental hygiene educators with a pragmatic method to improve self-assessment skills, increase student awareness of any postural deviations from ideal and improve musculoskeletal health. PMID- 29498177 TI - Significant correlation between peripheral blood CD34+ cell count in children prior to aphaeresis and CD34+ cell yield following aphaeresis: A single-center experience. AB - Numerous adults' studies demonstrated that preaphaeresis CD34+ cells significantly correlate with the number of CD34+ cells collected by the aphaeresis procedure. Equivalent studies in children are scarce. We studied retrospectively 92 aphaeresis procedures performed following chemotherapy (44) or in steady state (48) in 60 pediatric patients (40 males, 20 females), median age of 7.5 years. Aphaeresis procedures were performed using a SPECTRA Optica (TERUMOBCT) continuous flow cell separator. CD34+ cell concentrations were assessed using flow cytometry. A highly significant correlation between peripheral CD34 cell count on the day of aphaeresis and CD34 cell yield per kg (R2 = .824, P < .0001) was demonstrated. A higher preaphaeresis CD34 cell count was demonstrated in patients with higher preaphaeresis white blood cell count, in patients with brain tumors, and in patients who received chemotherapy as part of their mobilization protocol. A threshold number of 20 peripheral CD34+ cell/MUL was found to predict harvesting of 3 * 106 stem cells/kg, and 30 peripheral CD34+ cell/MUL for harvesting of 5 * 106 stem cells/kg. This significant correlation between peripheral CD34 cell count and CD34 cell yield, and the threshold number of peripheral CD34 found to predict adequate harvesting can be useful in planning the optimal time for aphaeresis in children. PMID- 29498178 TI - Innovation in dental education: The "On-the-Fly" approach to simultaneous development, implementation and evidence collection. AB - INTRODUCTION: This study outlines an approach for education innovation and addresses the ambivalence between evidence-based and non-evidence-based conditions. The "on-the-fly" approach was described as involving implementation during the development of an innovation for dental education. MATERIALS AND METHODS: The process of designing and implementing cutting-edge technology of the MOOG Simodont Dental Trainer (DT) whilst systematically collecting evidence illustrates the "on-the-fly" approach. RESULTS: Using the "on-the-fly" approach for developing, implementing and collecting evidence simultaneously in an academic environment appears feasible in serving both the professionals, users and developers and system designers. During the implementation of the new technology, growing evidence stepwise strengthened its position; therefore, showing stakeholders that evidence was used to improve the technology seemed to support and increase acceptance of the new technology. CONCLUSIONS: When pioneering an innovative technology in a specialty field, the development stage often precedes evidence for its effectiveness. Consciously choosing the "on-the fly" approach clarifies to stakeholders in advance about the lack of evidence in an innovation and the need of their support to collect such evidence for improvement and in order to facilitate implementation. PMID- 29498179 TI - Is anemia associated with cognitive impairment and delirium among older acute surgical patients? AB - AIM: The determinants of cognitive impairment and delirium during acute illness are poorly understood, despite being common among older people. Anemia is common in older people, and there is ongoing debate regarding the association between anemia, cognitive impairment and delirium, primarily in non-surgical patients. METHODS: Using data from the Older Persons Surgical Outcomes Collaboration 2013 and 2014 audit cycles, we examined the association between anemia and cognitive outcomes in patients aged >=65 years admitted to five UK acute surgical units. On admission, the Confusion Assessment Method was carried out to detect delirium. Cognition was assessed using the Montreal Cognitive Assessment, and two levels of impairment were defined as Montreal Cognitive Assessment <26 and <20. Logistic regression models were constructed to examine these associations in all participants, and individuals aged >=75 years only. RESULTS: A total of 653 patients, with a median age of 76.5 years (interquartile range 73.0-80.0 years) and 53% women, were included. Statistically significant associations were found between anemia and age; polypharmacy; hyperglycemia; and hypoalbuminemia. There was no association between anemia and cognitive impairment or delirium. The adjusted odds ratios of cognitive impairment were 0.95 (95% CI 0.56-1.61) and 1.00 (95% CI 0.61-1.64) for the Montreal Cognitive Assessment <26 and <20, respectively. The adjusted odds ratio of delirium was 1.00 (95% CI 0.48-2.10) in patients with anemia compared with those without. Similar results were observed for the >=75 years age group. CONCLUSIONS: There was no association between anemia and cognitive outcomes among older people in this acute surgical setting. Considering the retrospective nature of the study and possible lack of power, findings should be taken with caution. Geriatr Gerontol Int 2018; 18: 1025-1030. PMID- 29498181 TI - Implementing collaborative care for glaucoma patients and suspects in Australia. PMID- 29498180 TI - Accuracy of intraocular lens power calculation formulas in long eyes: a systematic review and meta-analysis. AB - IMPORTANCE: Visual outcome after intraocular lens (IOL) implantation in long eyes is considerably affected by IOL power calculation. Various formulas have been designed to achieve an accurate IOL power prediction. However, controversy about the accuracy remains. BACKGROUND: To evaluate the accuracy of IOL power calculation formulas in long eyes. DESIGN: Meta-analysis. PARTICIPANTS: Patients with ocular axial length (AL) over 24.5 mm. METHODS: A comprehensive search in PubMed, EMBASE, Cochrane Data Base of Systematic Reviews and the Cochrane Central Register of Controlled Trials were conducted by September, 2017. The weighted mean differences of mean absolute errors (MAE) and the odds ratio of percentage of eyes within +/-0.50D of prediction error among formulas were analysed. MAIN OUTCOMES MEASURES: Between-group differences of MAE among formulas. RESULTS: Eleven observational studies, involving 4047 eyes, were enrolled. Six formulas for IOL power calculation were compared: Barrett Universal II, Haigis, Holladay 2, SRK/T, Hoffer Q and Holladay 1. The MAE of Barrett Universal II was statistically lower than that of Holladay 2 (mean difference, MD = -0.04D, P = 0.0002), SRK/T (MD = -0.05D, P < 0.00001), Hoffer Q (MD = -0.07D, P < 0.00001) and Holladay 1 (MD = -0.07D, P < 0.00001). Barrett Universal II yielded significantly higher percentage of eyes within +/-0.50D of the prediction error than the other formulas. The heterogeneity was minimized through dividing eyes into two groups by the AL of 26 mm. CONCLUSIONS AND RELEVANCE: This study demonstrates the superiority of Barrett Universal II over Holladay 2, SRK/T, Hoffer Q and Holladay 1 in predicting IOL power in long eyes. PMID- 29498182 TI - Use of the malnutrition screening tool by non-dietitians to identify at-risk patients in a rehabilitation setting: A validation study. AB - AIM: Malnutrition is highly prevalent in rehabilitation patients, and screening is important to allow for timely intervention to reduce the incidence of adverse clinical outcomes. We aimed to determine the reliability and validity of the commonly employed malnutrition screening tool by non-dietitian staff in categorising patients at risk of malnutrition in the rehabilitation setting. METHODS: This prospective observational cohort study recruited 100 participants on admission to a rehabilitation ward. The malnutrition screening tool was applied by nursing staff and repeated by nutrition assistants. Results were compared to malnutrition as determined by dietitian-applied subjective global assessment of each patient. Inter-rater reliability tests were conducted with two dietitians, two nutrition assistants and two nurses independently but simultaneously recording malnutrition screening tool scores on a subgroup of 15 participants. RESULTS: Agreement between dietitian-determined malnutrition and risk as identified by nutrition assistant and nursing staff screening tool application was only modest (64% and 51%, respectively). While both professions met the a priori criteria for acceptable specificity (>=60%), neither met the criterion for adequate sensitivity (>=80%). The inter-rater reliability of the tool was excellent, with almost perfect agreement (>=0.89) between ward dietitian and nutrition assistants, and moderate to substantial agreement (0.56-0.65) with nursing staff, when compared to a senior dietitian. CONCLUSIONS: Non-dietitian staff failed to apply the malnutrition screening tool with sufficient sensitivity in normal ward practice to warrant its use in the rehabilitation setting. Alternative options for identification of malnutrition need to be considered to ensure appropriate treatment. PMID- 29498183 TI - IL1A (-889) gene polymorphism is associated with the effect of diet as a risk factor in Acne Vulgaris. AB - BACKGROUND: Despite the several studies suggesting the genetic basis of acne vulgaris, the exact genetic architecture of this very common condition is not yet clear. AIM OF THE WORK: This study aimed to investigate the association between IL-1A (-889) gene polymorphism and acne vulgaris in a sample of patients. SUBJECTS AND METHOD: Blood samples from 100 patients with acne vulgaris and 100 healthy age, sex, and BMI matched controls were obtained. DNA samples were isolated from blood cells, and the PCR-RFLP method was used for genotyping. RESULTS: The genotype distributions of IL-1A (-889) polymorphism were as expected under Hardy-Weinberg equilibrium. T allele was predominant in the patients, while C allele predominated in the control subjects (P value < .001). The frequency of TT genotype in patients was significantly higher than in the control subjects (P value < .001). CT genotype was significantly more frequent in the control subjects compared to patients (P value < .001). Among the 47 patients who reported diet as a risk factor for triggering or exacerbating their lesions, 62.5% had TT genotype (P value = .038). CONCLUSION: IL-1A (-889) gene polymorphism has a role in the pathogenesis of acne vulgaris. We suggest that the triggering or exacerbating effect of diet on acne may be related to IL-1A (-889) gene polymorphism. PMID- 29498185 TI - Collagen type III and elastin genes polymorphism and the risk of nonsyndromic striae. AB - BACKGROUND: Striae have been reported to be one of the most common skin lesions and a commonly encountered esthetic problem. OBJECTIVES: The aim of this research was to examine elastin gene polymorphism (rs7787362, ELN) and collagen type III alpha 1 polymorphism (rs1800255, COL3A1) among polish woman population with SD in comparison with women without the lesions and to verify these polymorphisms as risk factors for SD. METHODS: Seventy female students (35 with striae (the mean age 23.9 years, SD 1.2 years) and 35 without these lesions (22.9 years, SD 1.7 years)) were included in the study. The subjects were asked to fill out a questionnaire including questions concerning risk factors for SD and had a cheek swabbed for cells for DNA isolation. RESULTS: Analysis of polymorphisms of elastin gene (rs7787362) and COL3A1 gene (rs1800255) showed that women with SD and without these lesions did not differ in these aspects. Polymorphism rs7787362 was also analyzed in relation to SD in different locations, and showed no differences. CONCLUSION: In conclusion, we found that there are some clinical factors that reduced the risk of SD: history of intended weight loss, negative family history of SD, and lower BMI. Gene polymorphisms analysis in patients with SD may help to establish the etiology of these lesions and to target the therapy. Analysis of polymorphisms of elastin gene (rs7787362) did not show differences in allele distribution between women with and without SD. Polymorphisms of COL3A1 gene (rs1800255) also did not differ between the examined groups. PMID- 29498184 TI - Sphingosine-1-phosphate receptors and innate immunity. AB - Sphingosine-1-phosphate (S1P) is a signalling lipid that regulates many cellular processes in mammals. One well-studied role of S1P signalling is to modulate T cell trafficking, which has a major impact on adaptive immunity. Compounds that target S1P signalling pathways are of interest for immune system modulation. Recent studies suggest that S1P signalling regulates many more cell types and processes than previously appreciated. This review will summarise current understanding of S1P signalling, focusing on recent novel findings in the roles of S1P receptors in innate immunity. PMID- 29498186 TI - Inter- and intra-rater reliability and agreement in determining subcutaneous tumour margins in dogs. AB - The objective of this prospective study was to evaluate agreement and reliability of calliper-based measurements of locally invasive subcutaneous malignant tumours in dogs. Four raters measured the longest diameter of 12 subcutaneous tumours (7 soft tissue sarcomas and 5 mast cell tumours) from 11 client-owned dogs during 3 randomized, blinded measurement trials, both pre- and post-sedation. Inter- and intra-rater reliability was evaluated using intra-class correlation coefficient (ICC) and agreement was evaluated using Bland-Altman plots. Inter- and intra rater reliability was good (ICC range of 0.8694-0.89520) and excellent (ICC range of 0.9720-0.9966), respectively. For agreement calculations, an a priori clinically relevant limit of agreement of 10 mm was set. Inter- and intra-rater agreement was unacceptable with inter-rater limits of agreement ranging from 15.9 to 55.6 mm and intra-rater limit of agreement ranging from 11.9 to 28.1 mm. Review of the measurement trial photographs revealed that calliper orientation changes were frequent, occurring in 9/12 (75%) and 8/12 (67%) pre- and post sedation cases. No significant correlation was found between inter-rater measurement standard deviations and calliper orientation changes or dog body condition score. These findings suggest veterinarians may have poor agreement in determining the gross edge of tumours, which is expected to introduce bias and inconsistency in tumour staging, assessing response to therapy, and surgical margin planning. Due to the potential consequences for veterinary cancer patients, future studies are needed to validate the present findings. PMID- 29498187 TI - Cervical dilatation over time is a poor predictor of severe adverse birth outcomes: a diagnostic accuracy study. AB - OBJECTIVE: To assess the accuracy of the World Health Organization (WHO) partograph alert line and other candidate predictors in the identification of women at risk of developing severe adverse birth outcomes. DESIGN: A facility based, multicentre, prospective cohort study. SETTING: Thirteen maternity hospitals located in Nigeria and Uganda. POPULATION: A total of 9995 women with spontaneous onset of labour presenting at cervical dilatation of <=6 cm or undergoing induction of labour. METHODS: Research assistants collected data on sociodemographic, anthropometric, obstetric, and medical characteristics of study participants at hospital admission, multiple assessments during labour, and interventions during labour and childbirth. The alert line and action line, intrapartum monitoring parameters, and customised labour curves were assessed using sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratio, and the J statistic. OUTCOMES: Severe adverse birth outcomes. RESULTS: The rate of severe adverse birth outcomes was 2.2% (223 women with severe adverse birth outcomes), the rate of augmentation of labour was 35.1% (3506 women), and the caesarean section rate was 13.2% (1323 women). Forty-nine percent of women in labour crossed the alert line (4163/8489). All reference labour curves had a diagnostic odds ratio ranging from 1.29 to 1.60. The J statistic was less than 10% for all reference curves. CONCLUSIONS: Our findings suggest that labour is an extremely variable phenomenon, and the assessment of cervical dilatation over time is a poor predictor of severe adverse birth outcomes. The validity of a partograph alert line based on the 'one-centimetre per hour' rule should be re-evaluated. FUNDING: Bill & Melinda Gates Foundation, United States Agency for International Development (USAID), UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), and WHO (A65879). TWEETABLE ABSTRACT: The alert line in check: results from a WHO study. PMID- 29498188 TI - Clinical outcomes after Descemet's stripping endothelial keratoplasty using donor corneas from children younger than 3 years. AB - IMPORTANCE: There is limited literature on paediatric donors in endothelial keratoplasty. BACKGROUND: This study investigated the efficacy of and appropriate paediatric donor age for Descemet's stripping endothelial keratoplasty (DSEK). DESIGN: Retrospective and observational case series. PARTICIPANTS: Thirty-eight consecutive patients underwent DSEK with paediatric donor corneas. METHODS: The age of the donors ranged from 32 weeks gestation (premature neonate) to 3 years old. All donor consents were obtained from the parents. The causes of donor death included traffic accident, congenital heart disease and neonatal respiratory distress syndrome. MAIN OUTCOME MEASURES: The outcome measures included best corrected visual acuity, endothelial cell loss and complications. RESULTS: Best corrected visual acuity at last follow-up was >20/40 in 28 of 38 eyes (73.7%). The mean preoperative endothelial cell density of donor corneas was 4682 +/- 520 cells/mm2 . The mean endothelial cell density of grafts was 3977 +/- 556 cells/mm2 at 18 months postoperatively. Three lenticules from premature neonate donors exhibited severe contraction postoperatively. The edge of six lenticules from donors <1-year-old exhibited contraction in the early postoperative period and gradually flattened spontaneously. Graft detachment occurred in one patient. CONCLUSIONS AND RELEVANCE: DSEK with paediatric donor corneas can achieve good clinical outcomes. The corneal lenticules from 1- to 3-year- old donors are suitable for DSEK while those from donors <1-year-old are less suitable due to the possibility of severe postoperative graft contraction. PMID- 29498189 TI - Synthesis and luminescence properties of Ca3 (BO3 )2 :Eu3+ via two-step method. AB - Novel Ca2 B2 O5 .H2 O:Eu3+ nanotubes, constructed with nanobelts, were prepared using a hydrothermal method. The Ca3 (BO3 )2 :Eu3+ nanobelts with a thickness of about 100 nm were made for the first time using a two-step hydrothermal process with Ca2 B2 O5 .H2 O:Eu3+ as the precursor. The samples were characterized by energy dispersive X-ray spectroscopy, X-ray diffraction, Fourier transform infra red spectroscopy, thermogravimetry differential thermal analysis and scanning electron microscopy. The relationship between Ca3 (BO3 )2 :Eu3+ and Ca2 B2 O5 .H2 O:Eu3+ was also studied. Possible reaction and growth mechanisms for Ca2 B2 O5 .H2 O:Eu3+ and Ca3 (BO3 )2 :Eu3+ were proposed. Ca3 (BO3 )2 :Eu3+ preserved the basic microstructure unit of Ca2 B2 O5 .H2 O:Eu3+ . Both Ca2 B2 O5 .H2 O:Eu3+ and Ca3 (BO3 )2 :Eu3+ exhibited red emissions centred at 614 nm, but the maximum excitation peaks for Ca2 B2 O5 .H2 O:Eu3+ and Ca3 (BO3 )2 :Eu3+ differed. Ca3 (BO3 )2 :Eu3+ exhibited higher photoluminescence intensity but a lower R/O value than Ca2 B2 O5 .H2 O:Eu3+ . PMID- 29498190 TI - Deckblatt+Editoren. PMID- 29498191 TI - ABSTRACTBAND der DDG KOMPAKT & PRAXISNAH 02.-03. Marz 2018, Stuttgart. PMID- 29498192 TI - Accuracy of digital radiography: regional scaling factors for trauma. AB - BACKGROUND: Surgical planning in trauma is essential for optimal patient care and best patient outcomes. Digital radiography has improved the availability, convenience and access to radiographs worldwide as used in every trauma centre in Australia. One shortcoming, however, is the variability in magnification error associated with different anatomic regions. Accurate assessment of radiographs is paramount to proper surgical planning. METHODS: A retrospective review of 513 post-operative trauma radiographs of implants at a single centre, collected from January 2015 to August 2016, was measured by the four individual investigators. A comparison of the digital calliper reading with the known implant size, taken from operation reports and company implant data, was conducted. Magnification scales were created for different anatomic regions: femur, tibia, humerus, elbow, wrist and hand, foot and ankle. RESULTS: Precise regional scaling factors increase accuracy of digital radiography. Average magnification for hand, wrist, ankle and forearm is 5% (1-16%). Average magnification for foot, knee, tibia and elbow is 8% (3-11%). Humerus magnification is 10.3% (3-17%) and shoulder and femur approximately 15% (12-18%). Inter-rater Pearson's R reliability testing is 0.985-0.995 and intra-observer reliability is 0.998. DISCUSSION: Applying regional scaling factors improves accuracy of digital imaging, therefore improving clinical decision-making regarding fractures, distance from bony landmarks, component sizing and reduction assessment. Femoral and tibial fracture measurements with appropriate scaling factors allow the accurate estimation of nail diameter required for fixation and screw diameter for fragment fixation. PMID- 29498193 TI - Prevalence and characteristics of choroidal nevi: the Australian National Eye Health Survey. AB - IMPORTANCE: Choroidal nevi are a common incidental finding on fundus examination. The National Eye Health Survey (NEHS, 2015-2016) provides an up-to-date estimate of the prevalence of choroidal nevi in non-Indigenous and Indigenous Australian adults. BACKGROUND: To describe the prevalence and characteristics of choroidal nevi among non-Indigenous and Indigenous Australian adults. DESIGN: Population based cross-sectional study. PARTICIPANTS: This study included 3098 non Indigenous Australians (aged 50-98 years) and 1738 Indigenous Australians (aged 40-92 years) living in 30 randomly selected sites, stratified by remoteness. METHODS: Choroidal nevi were graded from retinal photographs using standard protocols. MAIN OUTCOME MEASURES: Prevalence of choroidal nevi. RESULTS: In the non-Indigenous population aged 50 years and over, the weighted prevalence of choroidal nevi was 2.1% (95% CI: 1.4, 3.3). Among Indigenous Australians aged 40 years and over, the weighted prevalence of choroidal nevi was 0.68% (95% CI: 0.4, 1.3). The average maximum diameter, surface area and distance from the disc of the choroidal nevi was 1730 MUm, 2 766 800 MUm2 and 3400 MUm, respectively. After multivariate adjustments, Indigenous participants (OR = 0.28, P = 0.01) and those of older age (OR = 0.79 per 10 years, P = 0.02) were less likely to have choroidal nevi. Choroidal nevus was not the primary cause of vision loss in any participant. CONCLUSIONS AND RELEVANCE: Choroidal nevi were relatively infrequent among NEHS participants, however non-Indigenous Australians had a significantly higher prevalence than Indigenous Australians. Choroidal nevi did not affect visual acuity and the majority were small. PMID- 29498194 TI - Long-term progression after laser peripheral iridotomy in Caucasian primary angle closure suspects. PMID- 29498195 TI - Robot-assisted duodenum-preserving pancreatic head resection with pancreaticogastrostomy for benign or premalignant pancreatic head lesions: a single-centre experience. AB - BACKGROUND: The purpose of this study was to compare short- and long-term outcomes of modified robot-assisted duodenum-preserving pancreatic head resection (RA-DPPHR) versus robot-assisted pancreaticoduodenectomy (RA-PD). METHODS: Matched for age, sex, ASA classification, tumour size, history of abdominal surgery and pathological type, 34 patients undergoing RA-DPPHR and 34 patients undergoing RA-PD between January 2010 and December 2016 were retrospectively analyzed. RESULTS: The RA-DPPHR group had shorter surgical time (188.2 vs. 386.3 min, p < 0.001) and less blood loss (168.2 vs. 386.3 ml, p = 0.026) but higher complication rate (47.1% vs. 32.4%, p = 0.105) and pancreatic fistula rate (32.4% vs. 17.6%, p = 0.161). Hospital mortality was 2.9%. Exocrine insufficiency was lower in the RA-DPPHR group (3.0% vs. 24.2%, p = 0.027). Endocrine insufficiency was observed in one RA-DPPHR patient and 5 RA-PD patients (p = 0.197). CONCLUSIONS: Modified RA-DPPHR benefits in terms of better conservation of exocrine and endocrine pancreatic functions at the expense of a significant morbidity and non-zero mortality. PMID- 29498197 TI - Hard-to-place kidney offers: Donor- and system-level predictors of discard. AB - Understanding risk factors for deceased-donor kidney nontransplantation is important since discard rates remain high. We analyzed DonorNet(r) data of consecutive deceased-donor nonmandatory share primary kidney-only offers to adult candidates at our center and beyond between July 1, 2015 and March 31, 2016 for donor- and system-level risk factors of discard, defined as nontransplantation at our or subsequent transplant centers. Exclusions were hepatitis C virus/hepatitis B virus core antibody status, blood type AB, and donor <1 year based on low candidate waitlist size. Of 456 individual kidney offers, from 296 donors, 73% were discarded. Most were national (93%) offers from Kidney Donor Profile Index 35-85% (n = 233) or >85% (n = 208) donors late in the allocation sequence with prior refusals logged for numerous candidates. On multivariate regression, factors significantly associated with discard were donor cerebrovascular accident (adjusted odds ratio [aOR]: 3.32), cancer transmission concern (aOR: 6.5), renal artery luminal compromise (aOR: 3.97), biopsy score >=3 (aOR: 5.09), 2-hour pump resistive index >0.4 (aOR: 3.27), absence of pump (aOR: 2.58), nonspecific kidney abnormality (aOR: 2.76), increasing offer cold ischemia time category 11-15, 16 20, and >21 hours (aOR: 2.07, 2.33, 2.82), nighttime notification (aOR: 2.19), and neither kidney placed at time of offer (aOR: 2.74). Many traditional determinants of discard lack discriminatory value when granular factors are assessed. System-level factors also influence discard and warrant further study. PMID- 29498196 TI - Prescription opioid use before and after kidney transplant: Implications for posttransplant outcomes. AB - Evolving literature suggests that the epidemic of prescription opioid use affects the transplant population. We examined a novel database wherein national U.S. transplant registry records were linked to a large pharmaceutical claims warehouse (2007-2015) to characterize prescription opioid use before and after kidney transplant, and associations (adjusted hazard ratio, 95% LCL aHR95% UCL ) with death and graft loss. Among 75 430 eligible patients, 43.1% filled opioids in the year before transplant. Use was more common among recipients who were women, white, unemployed, publicly insured, and with longer pretransplant dialysis. Of those with the highest level of pretransplant opioid use, 60% continued high-level use posttransplant. Pretransplant opioid use had graded associations with one-year posttransplant outcomes; the highest-level use predicted 46% increased risk of death (aHR 1.28 1.461.66 ) and 28% increased risk of all-cause graft failure (aHR 1.17 1.281.41 ). Effects of high-level opioid use in the first year after transplant were stronger, predicting twice the risk of death (aHR 1.93 2.242.60 ) and 68% higher all-cause graft failure risk (aHR 1.50 1.681.89 ) over the subsequent year; increased risk persisted over five years. While associations may, in part, reflect underlying conditions or behaviors, opioid use history is relevant in assessing and providing care to transplant candidates and recipients. PMID- 29498198 TI - In-Plane Heterostructures Enable Internal Stress Assisted Strain Engineering in 2D Materials. AB - Conventional methods to induce strain in 2D materials can hardly catch up with the sharp increase in requirements to design specific strain forms, such as the pseudomagnetic field proposed in graphene, funnel effect of excitons in MoS2 , and also the inverse funnel effect reported in black phosphorus. Therefore, a long-standing challenge in 2D materials strain engineering is to find a feasible scheme that can be used to design given strain forms. In this article, combining the ability of experimentally synthetizing in-plane heterostructures and elegant Eshelby inclusion theory, the possibility of designing strain fields in 2D materials to manipulate physical properties, which is called internal stress assisted strain engineering, is theoretically demonstrated. Particularly, through changing the inclusion's size, the stress or strain gradient can be controlled precisely, which is never achieved. By taking advantage of it, the pseudomagnetic field as well as the funnel effect can be accurately designed, which opens an avenue to practical applications for strain engineering in 2D materials. PMID- 29498199 TI - beta-2 Agonists as Misusing Drugs? Assessment of both Clenbuterol- and Salbutamol related European Medicines Agency Pharmacovigilance Database Reports. AB - A recent years' increase in misusing levels of image- and performance- enhancing drugs (IPEDs) has been observed. Out of these drugs, beta-2 agonists have recently emerged for their potential of misuse, especially for slimming and bodybuilding purposes. To this perspective, clenbuterol ('the size zero pill') has been reported as being both popular and widely available from the illegal market. All clenbuterol and salbutamol misuse/abuse/dependence/withdrawal/overdose/off-label spontaneous reports (2006 2016) from the European Medicines Agency (EMA) EudraVigilance (EV) database were collected and analysed by age range, gender, concomitant therapies and source of information. From the EV database, 55 of a total number of 920 'suspect' misuse/abuse/dependence/withdrawal/overdose/off-label ADRs (e.g. 5.97%; corresponding to 25 of 138 individuals) and 1310 of 62,879 ADRs (e.g. 2.08%; corresponding to 474 of 6923 individuals) were, respectively, associated with clenbuterol (typically ingested in combination with a range of anabolic steroids) and salbutamol. Proportional reporting ratio (PRR) value for misuse/abuse ADRs was higher (PRR = 18.38) for clenbuterol in comparison with salbutamol. Clenbuterol misuse/abuse could be a cause for major concern, especially in vulnerable individuals. PMID- 29498200 TI - Examining clinicians' perceptions of head and neck cancer (HNC) information. AB - BACKGROUND: Providing appropriate educational resources to patients with head and neck cancer (HNC) is important but challenging. The aim of this study was to determine Australian clinicians' perceptions of currently used HNC information resources. METHODS: A purpose-designed questionnaire was disseminated electronically to clinician members of the Australian and New Zealand Head and Neck Cancer Society (ANZHNCS) and The Australian Society of Otolaryngology Head and Neck Surgery (ASOHNS). RESULTS: Of the 648 clinicians invited, 112 responded to the survey (17.3% response rate). Overall, 85% utilized written information as their primary mode of patient education and 49% received information on treatment details. Areas for improvement include information provision, pain management, emerging risk factors, survivorship and side effects. The majority (66%) of clinicians had a preference for internet patient education materials. CONCLUSIONS: Clinicians predominantly utilized written HNC information rather than multimedia or interactive resources. However, they expressed the desire to be able to deliver HNC information resources via an internet-based platform covering the psychosocial effects of treatment. PMID- 29498202 TI - Thriving, not just surviving: Well-being in emergency medicine. PMID- 29498201 TI - Dose modifications in adjuvant chemotherapy for solid organ malignancies: A systematic review of clinical trials. AB - Toxicities of systemic cancer therapies are often less frequently observed in clinical trials than in clinical practice, due to the careful selection of patients with fewer comorbidities. Although guidelines exist for the estimation of chemotherapy dose, clinical factors like age, comorbid illness and extremes of body habitus are not considered in the method of dose calculation, which can result in significant toxicity. We reviewed the referenced clinical trials from which the evidence-based curative-intent cancer treatment protocols were developed for EVIQ, which is an Australian government, online resource. This review shows that a significant proportion of patients in curative-intent clinical trials experience toxicities that result in dose modifications-dose reduction, dose delays or missed doses-despite strict selection criteria and intense monitoring. Thus, even in ideal, clinical-trial settings chemotherapy dose calculation remains imprecise and subject to adjustment as clinically appropriate. In real-world clinical practice, dose alterations or modifications in response to toxicities need to be thoroughly discussed and implemented with clear understanding of the patient with appropriate documentation. This review may be used as a reference in these situations to elaborate the extent of toxicities seen in clinical trials with optimal settings. PMID- 29498203 TI - Directed Vertical Diffusion of Photovoltaic Active Layer Components into Porous ZnO-Based Cathode Buffer Layers. AB - Cathode buffer layers (CBLs) can effectively further the efficiency of polymer solar cells (PSCs), after optimization of the active layer. Hidden between the active layer and cathode of the inverted PSC device configuration is the critical yet often unattended vertical diffusion of the active layer components across CBL. Here, a novel methodology of contrast variation with neutron and anomalous X ray reflectivity to map the multicomponent depth compositions of inverted PSCs, covering from the active layer surface down to the bottom of the ZnO-based CBL, is developed. Uniquely revealed for a high-performance model PSC are the often overlooked porosity distributions of the ZnO-based CBL and the differential diffusions of the polymer PTB7-Th and fullerene derivative PC71 BM of the active layer into the CBL. Interface modification of the ZnO-based CBL with fullerene derivative PCBE?OH for size-selective nanochannels can selectively improve the diffusion of PC71 BM more than that of the polymer. The deeper penetration of PC71 BM establishes a gradient distribution of fullerene derivatives over the ZnO/PCBE-OH CBL, resulting in markedly improved electron mobility and device efficiency of the inverted PSC. The result suggests a new CBL design concept of progressive matching of the conduction bands. PMID- 29498204 TI - Association of impaired endothelial glycocalyx with arterial stiffness, coronary microcirculatory dysfunction, and abnormal myocardial deformation in untreated hypertensives. AB - We investigated the association of endothelial glycocalyx damage with arterial stiffness, impairment of coronary microcirculatory function, and LV myocardial deformation in 320 untreated hypertensives and 160 controls. We measured perfused boundary region (PBR) of the sublingual microvessels, a marker inversely related with glycocalyx thickness, coronary flow reserve (CFR), and Global Longitudinal strain (GLS) by echocardiography, pulse wave velocity (PWV), and central systolic blood pressure (cSBP). Hypertensives had higher PBR, PWV cSBP, and lower CFR and GLS than controls (P < .05). In hypertensives, increased PBR was associated with increased cSBP, PWV, and decreased CFR and GLS after adjustment for age, sex, BMI, smoking LV mass, heart rate, hyperlipidemia, and office SBP (P < .05). PBR had an additive value to PWV, CFR, and office SBP for the prediction of abnormal GLS (x2 = 2.4-3.8, P for change = .03). Endothelial glycocalyx is impaired in untreated hypertensives and is related to arterial stiffness, coronary, and myocardial dysfunction. PMID- 29498205 TI - Hydrothermal growth of Zn2 SnO4 :Eu,Ca for red emission. AB - Zinc stannate (Zn2 SnO4 ) and Zn2 SnO4 codoped with Eu3+ and Ca2+ (ZTO:Eu,Ca) were synthesized by hydrothermal method and characterized with X-ray diffraction (XRD), energy-dispersive X-ray analysis (EDAX), Raman spectrometer, field emission scanning electron microscopy (FESEM), ultraviolet-visible (UV-vis) and photoluminescence (PL) spectrophotometers. PL analysis of Zn2 SnO4 gives broad defect induced emission in the region 500-750 nm. The crystal structure of Zn2 SnO4 was retained even with a nominal doping of Eu, Ca and its combination in the Zn2 SnO4 . The Eu3+ ions were found to occupy the non-centrosymmetric sites of the Zn2 SnO4 and gave emissions at 592, 615 and 702 nm. Zn2 SnO4 :Eu,Ca showed red emission at 615 nm attributed to the electronic transition from the excited state 5 D0 -> 7 F2 of the 4f6 configuration of Eu3+ . Nominal codoping of Eu3+ and Ca2+ ions promoted the quenching of orange emission from Eu3+ in Zn2 SnO4 :Eu,Ca. PMID- 29498206 TI - Wellness, resilience and performance: Translating ideas into action. PMID- 29498207 TI - Strong opioid prescription in cancer patients in their final year of life: A population-based analysis using a Taiwanese health insurance database. AB - AIM: Pain assessment and management have been important criteria in hospital accreditation in Taiwan since 2007. We used a Taiwanese health insurance database to determine factors influencing patterns of strong opioid use in cancer patients in their final 12 months of life. METHODS: Data from patients with cancer in Taiwan outpatient clinics with cancer-related deaths between 2008 and 2011 were included in the analysis. Strong opioid prescription data from the last 12 months of each patient's life, as well as patient, physician, and hospital characteristics, were collected from the National Health Insurance Research Database. RESULTS: Among 162 679 patients, more were male (63.6%) than female (36.4%) and almost half (49.3%) were >=70 years old. Most (44.9%) patients had gastrointestinal cancer. More than one-third (35.4%) of patients were prescribed strong opioids during the 12 months before death, and more than half (53.2%) of those prescribed opioids received them in the 3 months before death. Median duration of strong opioid use was 81 days before death. Patients with head/neck cancer (52.8%) or who were treated in hematology and oncology departments (45.8%) were most likely, and patients with gastrointestinal cancer (hazard ratio = 0.65; 95% confidence interval, 0.64-0.67) or treated in gastroenterology departments (hazard ratio = 0.88; 95% confidence interval, 0.84-0.93) were least likely to be prescribed strong opioids. CONCLUSION: Strong opioid prescriptions varied among patients with different cancer diagnoses and physicians. Information from this study can guide efforts to improve patient and physician education about cancer pain management. PMID- 29498208 TI - Outcomes of Australian patients receiving non-funded anti-PD-1 immune checkpoint inhibitors for non-melanoma cancers. AB - AIM: To characterize the outcomes of patients with nonmelanoma solid tumors receiving anti-PD-1 immunotherapy not funded by the Australian Pharmaceutical Benefits Scheme. METHODS: Medical records of patients with metastatic nonmelanoma tumor diagnoses treated with anti-PD-1 (self-funded pembrolizumab or nivolumab through an access program) from January 1, 2014, to December 31, 2016, at Peter MacCallum Cancer Centre, were retrospectively reviewed. Events after December 31, 2016, were censored. RESULTS: Of 47 patients identified, 27 (57%) had lung cancer. Twenty-six had compassionate access to nivolumab (24 lung, one renal, one gastroesophageal with possible new lung primary). Median overall survival was 5.7 months. Eleven (23%) achieved a partial response; none had complete response. Twenty (43%) had disease progression on first imaging; 16 (48%) of these continued treatment beyond radiological progression, with three achieving subsequent partial responses. Ten (21%) were not re-staged mostly due to rapid deterioration or death. At 6 and 12 months, nine (20%) and two (4%) remained on treatment, respectively. Five (12%) discontinued treatment due to immune-related toxicities. Of 34 patients who died, 71% received treatment within the last month of life; 38% died in an acute hospital. None of 25 patients with poor Eastern Cooperative Oncology Group performance scores of 2-4 responded. CONCLUSION: The response rates and overall survival of patients with NSCLC, renal carcinoma and triple negative breast cancer of good performance status receiving anti-PD-1 therapy outside of a clinical trial are consistent with clinical trial data. However, patients with poor ECOG performance status are unlikely to respond. Careful patient selection and counseling about the potential outcomes of self funding treatment in this setting is needed. PMID- 29498209 TI - An ice-binding and tandem beta-sandwich domain-containing protein in Shewanella frigidimarina is a potential new type of ice adhesin. AB - : Out of the dozen different ice-binding protein (IBP) structures known, the DUF3494 domain is the most widespread, having been passed many times between prokaryotic and eukaryotic microorganisms by horizontal gene transfer. This ~25 kDa beta-solenoid domain with an adjacent parallel alpha-helix is most commonly associated with an N-terminal secretory signal peptide. However, examples of the DUF3494 domain preceded by tandem Bacterial Immunoglobulin-like (BIg) domains are sometimes found, though uncharacterized. Here, we present one such protein (SfIBP_1) from the Antarctic bacterium Shewanella frigidimarina. We have confirmed and characterized the ice-binding activity of its ice-binding domain using thermal hysteresis measurements, fluorescent ice plane affinity analysis, and ice recrystallization inhibition assays. X-ray crystallography was used to solve the structure of the SfIBP_1 ice-binding domain, to further characterize its ice-binding surface and unique method of stabilizing or 'capping' the ends of the solenoid structure. The latter is formed from the interaction of two loops mediated by a combination of tandem prolines and electrostatic interactions. Furthermore, given their domain architecture and membrane association, we propose that these BIg-containing DUF3494 IBPs serve as ice-binding adhesion proteins that are capable of adsorbing their host bacterium onto ice. DATABASE: Submitted new structure to the Protein Data Bank (PDB: 6BG8). PMID- 29498210 TI - A multicenter, observational study of metastatic breast cancer patients who were treated with eribulin mesylate or taxane-based regimens. AB - AIM: This multicenter, observational study aimed to investigate the survival benefit of eribulin as well as that of taxane-based regimens in Japanese patients with metastatic breast cancer (MBC) in a real-world setting. METHODS: This study enrolled women with MBC who received eribulin or taxane-based regimens with or without bevacizumab in routine clinical practice from July 2011 to March 2014. Patients were followed until September 2015. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), post progression survival (PPS) and adverse events. Efficacy findings were adjusted according to demographics. RESULTS: In total, 216 patients receiving eribulin monotherapy (n = 101), taxane monotherapy (n = 73) or taxane plus bevacizumab (n = 42) were followed for a median time of 15.4 months. Median OS, PFS and PPS were 22.3, 8.1 and 14 months in the eribulin monotherapy group; 13.2, 3.6 and 7.6 months in the taxane monotherapy group; and 12.9, 5.7 and 6.3 months, in the taxane plus bevacizumab group, respectively. The incidence of neutropenia was 67.3, 41.1 and 16.7%, and the incidence of grade 4 neutropenia was 1.0, 8.2 and 7.1% in the eribulin monotherapy, taxane monotherapy and taxane plus bevacizumab groups, respectively. One patient (1.0%) discontinued eribulin and 18 patients (15.7%) discontinued taxane-based regimens because of adverse events. CONCLUSION: In Japanese MBC patients in a real-world setting, eribulin showed a survival benefit and tolerability similar to that in previous reports. PMID- 29498211 TI - Producing offspring in Armadillidium vulgare: Effects of genetic diversity and inbreeding. AB - Genetic diversity is known to be correlated to fitness traits, and inbred individuals often display lower values for life history traits. In this study, we attempt to quantify how inbreeding affects such traits in the terrestrial isopod Armadillidium vulgare by performing inbred and non-inbred crosses under laboratory conditions. We estimated genetic characteristics of parents and offspring, and related them to fecundity and fertility measures, as well as offspring growth and survival. Our study shows that a decrease in offspring number might result from mortality around birth, but not to changes in fecundity, fertilization rate, or developmental failure between inbred and non-inbred crosses. More heterozygous females tended to be bigger and had a higher fecundity, which could have implications in mate choice. No effect of inbreeding was detected on offspring growth and survival. These results can be related to previously observed effects of genetic characteristics on mating strategies in A. vulgare, and could shed light on mechanisms of inbreeding avoidance in this species. PMID- 29498212 TI - The transcription factor Dach1 is essential for podocyte function. AB - Dedifferentiation and loss of podocytes are the major cause of chronic kidney disease. Dach1, a transcription factor that is essential for cell fate, was found in genome-wide association studies to be associated with the glomerular filtration rate. We found that podocytes express high levels of Dach1 in vivo and to a much lower extent in vitro. Parietal epithelial cells (PECs) that are still under debate to be a type of progenitor cell for podocytes expressed Dach1 only at low levels. The transfection of PECs with a plasmid encoding for Dach1 induced the expression of synaptopodin, a podocyte-specific protein, demonstrated by immunocytochemistry and Western blot. Furthermore, synaptopodin was located along actin fibres in a punctate pattern in Dach1-expressing PECs comparable with differentiated podocytes. Moreover, dedifferentiating podocytes of isolated glomeruli showed a significant reduction in the expression of Dach1 together with synaptopodin after 9 days in cell culture. To study the role of Dach1 in vivo, we used the zebrafish larva as an animal model. Knockdown of the zebrafish ortholog Dachd by morpholino injection into fertilized eggs resulted in a severe renal phenotype. The glomeruli of the zebrafish larvae showed morphological changes of the glomerulus accompanied by down-regulation of nephrin and leakage of the filtration barrier. Interestingly, glomeruli of biopsies from patients suffering from diabetic nephropathy showed also a significant reduction of Dach1 and synaptopodin in contrast to control biopsies. Taken together, Dach1 is a transcription factor that is important for podocyte differentiation and proper kidney function. PMID- 29498214 TI - Temperature dependence of bulk luminescence from ZnO. AB - X-Ray excited luminescence (radioluminescence, RL) spectra from nominally pure crystalline zinc oxide (ZnO) are reported. The temperature range is from 20 to 673 K. Significant changes of emission band energies and intensities are observed across the temperature range. Photon energies of emission bands linked to the band gap decrease with increasing temperature in RL. This dependence fits the theoretical equations describing the temperature response of the ZnO band gap. Defect related luminescence includes a complex mixture of features at low temperature for RL. Thermoluminescence (TL) signals from 20 to 300 K confirm the presence of an unresolved feature in the RL data. Comments on the possible origin of these bands are summarized. The data underline that it is essential to record the temperature dependence for the luminescence data in order to separate overlapping spectral features. PMID- 29498213 TI - Clinical feasibility of using multiple grafts from a single donor for Quarter DMEK. PMID- 29498215 TI - Iron Phosphate Coated Flexible Carbon Nanotube Fabric as a Multifunctional Cathode for Na-Ion Batteries. AB - Conventional slurry casted electrodes cannot stand high loads or be repeatedly flexed or bent without being fractured, which inhibits their use in flexible batteries. Carbon nanotube (CNT) fabric exhibits a paramount mechanical stability and, due to its porosity, can additionally accommodate an active material within its structure. While solution-based protocols cannot achieve conformal coatings of active materials, chemical vapor deposition (CVD) gives a unique opportunity to control and vary the thickness and homogeneity of the coating. Herein, a conformal CVD coating of amorphous iron (III) phosphate (a-FePO4 , FP) on flexible CNT fabric and its ability to reversibly accommodate large radius Na ions is reported. The freestanding binder-free CNT@FP electrodes exhibit high rate capabilities and exceptional cycle stabilities with 98% of retention of initial capacity after 100 cycles. Such electrodes additionally demonstrate high mechanical stability under high loads, remarkable bending characteristics, and modulus of toughness (12 MJ m-3 ) exceeding that of Al. The presented concept of flexible CNT@FePO4 electrodes with high load-bearing characteristics opens new perspectives toward the formation of light-weight, flexible, multifunctional Na ion battery electrodes based on abundant materials. PMID- 29498216 TI - Hypertension after kidney donation: Incidence, predictors, and correlates. AB - Incidence of postdonation hypertension, risk factors associated with its development, and impact of type of treatment received on renal outcomes were determined in 3700 kidney donors. Using Cox proportional hazard model, adjusted hazard ratios (HRs) for cardiovascular disease (CVD); estimated glomerular filtration rate (eGFR) <60, <45, <30 mL/min/1.73m2 ; end stage renal disease (ESRD); and death in hypertensive donors were determined. After a mean (standard deviation [SD]) of 16.6 (11.9) years of follow-up, 1126 (26.8%) donors developed hypertension and 894 with known antihypertensive medications. Hypertension developed in 4%, 10%, and 51% at 5, 10, and 40 years, respectively, and was associated with proteinuria, eGFR < 30, 45, and 60 mL/min/1.73m2 , CVD, and death. Blood pressure was <140/90 mm Hg at last follow-up in 75% of hypertensive donors. Use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (compared to other antihypertensive agents) was associated with a lower risk for eGFR <45 mL/min/1.73m2, HR 0.64 (95% confidence interval [CI] 0.45-0.9), P = .01, and also less ESRD; HR 0.03 (95% CI 0.001-0.20), P = .004. In this predominantly Caucasian cohort, hypertension is common after donation, well controlled in most donors, and factors associated with its development are similar to those in the general population. PMID- 29498217 TI - NOVA1 acts as an oncogene in melanoma via regulating FOXO3a expression. AB - Increasing studies have suggested that dysregulation of RNA-binding proteins (RBPs) contributes to cancer progression. Neuro-oncological ventral antigen 1 (NOVA1) is a novel RBP and plays an important role in tumour development. However, the expression and role of NOVA1 in melanoma remain unknown. In this study, we indicated that NOVA1 expression was up-regulated in melanoma samples and cell lines. Moreover, we demonstrated that knockdown of NOVA1 suppressed melanoma cell proliferation, migration and invasion in both A375 and A875 cell lines. In addition, we showed that suppressed expression of NOVA1 enhanced forkhead box O3a (FOXO3a) expression while inhibited AKT expression in melanoma cell. Furthermore, we demonstrated that inhibited expression of FoxO3A rescued NOVA1-mediated cell proliferation, migration and invasion in melanoma cell line A375. These results suggested that NOVA1 acted as an oncogene in the development of melanoma partly through regulating FoxO3A expression. PMID- 29498218 TI - Opportunities and Challenges in Implementation of Multiparameter Single Cell Analysis Platforms for Clinical Translation. AB - The high-content interrogation of single cells with platforms optimized for the multiparameter characterization of cells in liquid and solid biopsy samples can enable characterization of heterogeneous populations of cells ex vivo. Doing so will advance the diagnosis, prognosis, and treatment of cancer and other diseases. However, it is important to understand the unique issues in resolving heterogeneity and variability at the single cell level before navigating the validation and regulatory requirements in order for these technologies to impact patient care. Since 2013, leading experts representing industry, academia, and government have been brought together as part of the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium to foster the potential of high content data integration for clinical translation. PMID- 29498219 TI - Combination nivolumab with transcatheter arterial chemoembolization for clinical remission of small cell lung cancer: A case report. AB - The outcome of small cell lung cancer (SCLC) patients is poor because rapid metastasis develops after first-line chemotherapy and few drugs are available for second-line chemotherapy. The median survival rate has not significantly changed in recent years. In this report, we discuss the case of a 71-year-old Chinese female non-smoker diagnosed with extensive-stage SCLC who was treated with nivolumab for a short period and obtained a prolonged clinical benefit. We report the clinical history, clinical features, potential mechanism, benefits, and the best therapeutic window. The patient was treated with transcatheter arterial chemoembolization because of liver metastasis and then with four doses of nivolumab as third-line systemic treatment. There was no disease progression for 15 months. The lesions became larger than before, suggesting disease progression, thus nivolumab treatment was ceased. Immunotherapy has the capacity to turn combined therapy into a feature that may be exploited for clinical benefit. Further research is required to evaluate whether combined treatment is beneficial for patients, affecting the efficacy of immunotherapy, and to determine the best therapeutic window for clinical treatment. PMID- 29498220 TI - ZrMn Oxides for Aqueous-Phase Ketonization of Acetic Acid: Effect of Crystal and Porosity. AB - Aqueous-phase ketonization of bio-based acetic acid is important to improve the conversion efficiency of biomass resources. In this study, ZrMn mixed oxides (ZrMnOx ) with high aqueous-phase ketonization activity are synthetized through a carbonization/oxidation method (COM) and solvothermal method (STM). The results show that ZrMnOx prepared by COM possesses tetragonal ZrO2 , and hausmannite Mn3 O4 is observed only at a high oxidation temperature of 750 degrees C. Low temperature and long oxidation results in decreased crystallinity and crystallite size, which is related to highly dispersed Mnn+ species. The catalysts with improved acid sites possess high ketonization activity. Surface areas and pore size of ZrMnOx synthetized by STM are controlled by the solvents for thermal treatment. Compared with water as solvent, ethanol increases the surface area and pore size, resulting in high ketonization activity. PMID- 29498221 TI - Enhancing the Lithium Storage Performance of Graphene/SnO2 Nanorods by a Carbon Riveting Strategy. AB - Graphene/metal oxide (MO) nanocomposites hold great promise for application as anodes in lithium-ion batteries (LIBs). However, the restacking of graphene during subsequent processing remains a challenge to overcome for enhanced lithium storage properties. Herein, the fabrication of sandwich-architecture carbon riveted graphene/SnO2 nanorods, in which the SnO2 nanorods are confined in the nanospaces formed by the carbon layers on graphene, by a two-step hydrothermal process followed by thermal treatment, is reported. Electrochemical tests show that the carbon-riveted nanolayers significantly improve the lithium storage performance of graphene/SnO2 . The nanocomposite displays a high reversible capacity of 815 mAh g-1 after 150 cycles at 100 mA g-1 and high cycling stability at 1000 mA g-1 . This work provides an efficient way to manipulate graphene/MO based nanocomposites for LIBs with improved performance. PMID- 29498222 TI - Novel cellulose/hydroxyapatite scaffolds for bone tissue regeneration: In vitro and in vivo study. AB - Cellulose scaffolds containing nano- or micro-hydroxyapatite (nHA or MUHA) were prepared by the regeneration of cellulose from its acetylated derivative and the mechanical immobilization of inorganic particles, followed by freeze-drying. Microtomographic (micro-computed tomography) evaluation revealed that both scaffolds presented a highly interconnected porous structure, with a mean pore diameter of 490 +/- 94 and 540 +/- 132 MUm for cellulose/nHA and cellulose/MUHA, respectively. In vitro and in vivo characterizations of the developed scaffolds were investigated. Commercially available bone allograft was used as a control material. For the in vitro characterization, osteoblastic cell cultures were used and characterized over time to evaluate cell adhesion, metabolic activity, and functional output (alkaline phosphatase activity and osteoblastic gene expression). The results revealed greater spreading cell distribution alongside an increased number of filopodia, higher MTT values, and significantly increased expression of osteoblastic genes (Runx-2, alkaline phosphatase, and BMP-2) for cellulose/nHA, compared with cellulose/MUHA and the control. The in vivo biocompatibility was evaluated in a rabbit calvarial defect model. The investigated scaffolds were implanted in circular rabbit calvaria defects. Four- and 12-week bone biopsies were investigated using micro-computed tomography and histological analysis. Although both cellulose/HA scaffolds outperformed the assayed control, a significantly higher amount of newly formed mineralized tissue was found within the defects loaded with cellulose/nHA. Within the limitations of this study, the developed cellulose/HA scaffolds showed promising results for bone regeneration applications. The biological response to the scaffold seems to be greatly dependent on the HA particles' characteristics, with cellulose scaffolds loaded with nHA eliciting an enhanced bone response. PMID- 29498224 TI - Change in BMI Distribution over a 24-Year Period and Associated Socioeconomic Gradients: A Quantile Regression Analysis. AB - OBJECTIVE: This study assessed the change in body mass index (BMI) distribution among 18- or 19-year-olds over 24 years. It also investigated parallel changes in the distribution of birth weight and in the association between birth weight and later risk of overweight and/or obesity. Parental educational variations in the trends and associations were explored. METHODS: The study used data on 606,832 male military conscripts enlisted between 1985 and 2008. Quantile regression was used to assess the temporal change in BMI and birth weight distribution. The association between birth weight and overweight and/or obesity at age 18 or 19 years was quantified by using logistic regression. RESULTS: Increases in BMI over time were found namely in the 90th, 95th, 97th, and 99th percentiles. Socioeconomic differences in this increase were documented in the 75th to 97th percentiles. The distribution of birth weight and the association between birth weight and the risk of overweight and/or obesity at age 18 or 19 years remained stable over time. CONCLUSIONS: The difference in the increase in BMI between low and high percentiles indicates the limited role of mean BMI in reflecting population changes. The results suggest a need to focus on those with low socioeconomic position in the upper ends of the BMI distribution to combat increasing disparities in obesity-related outcomes. PMID- 29498223 TI - Metabolically Healthy Obesity and Risk of Kidney Function Decline. AB - OBJECTIVE: The aim of this study was to examine the association between BMI categories, stratified by metabolic health status, and the risk of kidney function decline (KFD). METHODS: In this study, 42,128 adult patients with a stable BMI were classified over a 3-year baseline window by BMI and metabolic health status (assessed by Adult Treatment Panel-III criteria). KFD was defined as an estimated glomerular filtration rate (eGFR) decline >= 30%, eGFR < 15 mL/min/1.73 m2 , or receipt of dialysis and/or transplant. RESULTS: Over a median of 5.1 years (interquartile range 2.1-8.9), 6,533 (15.5%) individuals developed KFD. Compared with the normal weight, metabolically healthy category, metabolically healthy obesity was associated with a higher risk of KFD (adjusted hazard ratio [aHR] 1.52; 95% CI: 1.22-1.89). aHRs for KFD were 1.17 (95% CI: 0.89 1.53), 2.21 (95% CI: 1.59-3.08), and 2.20 (95% CI: 1.55-3.11) for metabolically healthy obesity with BMI 30 to 34.9, BMI 35 to 39.9, and BMI >= 40 kg/m2 . These associations were consistent among men and women, patients with eGFR >= or < 90 mL/min/1.73 m2 , and age >= or < 55 years. The risk of KFD was highest among metabolically unhealthy individuals with BMI >= 40 (aHR 4.02; 95% CI: 3.40-4.75 vs. metabolically healthy individuals with normal weight). CONCLUSIONS: Obesity, whether in the presence or absence of metabolic health, is a risk factor for KFD. PMID- 29498225 TI - The relationship between increased oxidative stress and visual field defect progression in glaucoma patients with sleep apnoea syndrome. AB - PURPOSE: Sleep apnoea syndrome (SAS) is often associated with glaucoma, and intermittent hypoxia, present in SAS, can contribute to glaucoma pathogenesis. However, the relationships between SAS, high systemic oxidative stress and the speed of glaucoma progression are unclear. Thus, we investigated these relationships in glaucoma patients with and without SAS. METHODS: Peripheral blood samples were collected from 166 eyes of 166 Japanese patients: 42 controls, 109 open-angle glaucoma (OAG) patients without SAS and 15 OAG patients with SAS. Prognostic factors for visual field defect progression were determined with logistic regression. Diacron reactive oxygen metabolites (dROM) and biological antioxidant potential (BAP) were measured with a free radical analyser. Clinical parameters were also recorded. Intergroup comparisons used the Mann-Whitney U test. RESULTS: Multiple regression analysis showed that SAS was a statistically significant contributing factor to fast visual field defect progression, defined as mean deviation (MD) slope <=-2.0 dB/Y (SAS: odds ratio (OR) = 14.48; p = 0.002). The non-SAS and SAS groups had similar age, sex, intraocular pressure (IOP), axial length and antiglaucoma drug use. The SAS group had a significantly higher dROM level (p = 0.001), BAP level (p = 0.038) and steeper MD slope (p = 0.001) than the non-SAS group. CONCLUSION: Glaucoma patients with SAS have higher dROM, as well as steeper MD slope, than patients without SAS, suggesting that SAS may induce systemic oxidative stress and promote glaucomatous visual field defect progression. PMID- 29498226 TI - Low-Cost K4 Fe(CN)6 as a High-Voltage Cathode for Potassium-Ion Batteries. AB - Potassium-ion batteries (KIBs) are of interest for large-scale electrical energy storage, owing to the abundance of K resources and potential high energy density. Low-cost cathodes with high performance are crucial for KIBs. Herein, K4 Fe(CN)6 is shown to be a low-cost and high-voltage cathode for KIBs. It can deliver a high voltage of approximately 3.6 V and a discharge capacity of 65.5 mAh g-1 with a lifespan of 400 cycles of discharge and charge. This is attributed to the strong sigma bonds between C atoms and Fe and to the reduced particle size and good contact with conductive carbon brought about by ball milling, which benefit both the K+ ion and the electronic conduction. The [Fe(CN)6 ]3-/4- redox couple is found to be responsible for charge compensation upon reversible extraction/insertion of K+ from/into K4 Fe(CN)6 . The high voltage and stability of K4 Fe(CN)6 will make it a promising low-cost cathode for KIBs and encourage more investigations into high-performance cathode materials. PMID- 29498227 TI - Boosting the Photocatalytic Activity of P25 for Carbon Dioxide Reduction by using a Surface-Alkalinized Titanium Carbide MXene as Cocatalyst. AB - Although they are widely used as cocatalysts in promoting photocatalysis, practical application of noble metals is limited by their high cost and rarity. Development of noble-metal-free cocatalysts is thus highly demanded. Herein titanium carbide (Ti3 C2 ) MXene is shown to be a highly efficient noble-metal free cocatalyst with commercial titania (P25) for photocatalytic CO2 reduction. Surface alkalinization of Ti3 C2 dramatically enhances the activity; the evolution rates of CO (11.74 MUmol g-1 h-1 ) and CH4 (16.61 MUmol g-1 h-1 ) are 3- and 277-times higher than those of bare P25, respectively. The significantly enhanced activity is attributed to the superior electrical conductivity and charge-carrier separation ability, as well as the abundant CO2 adsorption and activation sites of surface-alkalinized Ti3 C2 MXene, indicating its promise as a highly-active noble-metal-free cocatalysts for photocatalytic CO2 reduction. PMID- 29498228 TI - Coronaviruses in guano from Pteropus medius bats in Peradeniya, Sri Lanka. AB - Bats are a unique group of mammals well suited to be hosts for emerging viruses. With current rates of deforestation and urbanization, redistribution of bat habitats to urban and suburban areas may bring bats into closer contact with livestock and humans. Common flying fox, Pteropus medius (previously known as Pteropus giganteus), forms large communal roosts on treetops, often in close proximity to human habitation in Sri Lanka. This report describes the detection of coronavirus RNA in P. medius bat guano collected in Peradeniya, Sri Lanka. These viruses had >97% nucleotide identity with coronaviruses detected in Cynopterus sphinx, Scotophilus heathii and S. kuhlii bats in Thailand. Pteropus medius is widespread in Asia and appears to excrete group D coronaviruses, which are hitherto confined to bats; however, these findings may have public health implications in the future. PMID- 29498229 TI - Simvastatin improves oral implant osseointegration via enhanced autophagy and osteogenesis of BMSCs and inhibited osteoclast activity. AB - Dental implants have become a widely accepted and successful treatment for fully and partially edentulous patients. Simvastatin has been applied to improve and accelerate the osseointegration of implants by increasing the quantity and quality of bone tissue. However, its potential mechanism has not been elucidated completely. Here, we found that simvastatin significantly enhanced the autophagy level of jaw-derived bone marrow stromal cells (BMSCs) and alleviated production of reactive oxygen species under unfavourable conditions. Simvastatin promoted osteogenic differentiation of BMSCs via enhanced autophagy. Furthermore, simvastatin inhibited the bone resorption activity of osteoclasts. With the use of a rat model of oral implant osseointegration, we found local injection of simvastatin displayed more new bone formation at the interface of the bone and implant compared with that of oral administration. Fluorochrome labelling histomorphometrical analysis and micro-CT also showed that simvastatin promoted the osseointegration of implants. Notably, fewer activated osteoclasts were observed in the region of osseointegration of implants from the simvastatin treatment groups, especially the local delivery of simvastatin. Collectively, our results revealed that simvastatin can increase osteoblastic differentiation of BMSCs via enhanced autophagy and decreased osteoclast activity. Thus, simvastatin could be a viable and promising drug to improve and even accelerate the osseointegration of a dental implant. PMID- 29498230 TI - Optical coherence tomography angiography in patients with retinitis pigmentosa who have normal visual acuity. AB - PURPOSE: To investigate flow area changes measured using optical coherence tomography angiography (OCTA; RTVue XR Avanti(r) ) in patients with retinitis pigmentosa (RP) with preserved visual acuity (VA). METHODS: This was an age- and refraction-matched case-control study. Consecutive patients with a best-corrected visual acuity (BCVA) of >=20/20 and normal subjects were recruited. Fifty eyes (32 patients) and 22 eyes (12 controls) were included. The flow area and foveal avascular zone (FAZ) were measured in both superficial and deep layers within a 3 * 3 mm central area of the fovea. Association between OCTA parameters and the length of the inner segment ellipsoid (ISe) and external limiting membrane (ELM), the area without abnormal fluorescence in fundus autofluorescence (normal FAF area ratio) and the area of I-2e of the Goldmann perimeter were analysed using mixed-effects regression analysis. RESULTS: Foveal avascular zones were significantly smaller in patients with RP than in controls in superficial (p = 0.004) but not in deep layers (p = 0.25). The flow area in superficial (p = 0.007) and deep layers (p = 0.004) was significantly smaller in patients with RP than in controls. In patients with RP, flow areas in the superficial layers, but not in the deep layers, were significantly associated with the lengths of ISe (p = 0.001) and ELM (p = 0.002) and the I-2e area (p = 0.036), but not with the normal FAF area ratio (p = 0.399). CONCLUSION: Optical coherence tomography angiography (OCTA)-measured flow area in superficial layers gradually reduced with RP progression and may be a useful parameter of RP pathogenesis. PMID- 29498231 TI - Body Mass Index and Kidney Disease-Related Mortality in Midlife: A Nationwide Cohort of 2.3 Million Adolescents. AB - OBJECTIVE: This study aimed to evaluate the association of body mass index (BMI) in adolescence with mortality attributed to kidney disease. METHODS: In this study, 2,294,139 Jewish Israeli adolescents with measured weight and height at 17 years old during the military fitness assessment were analyzed with a follow-up extending up to 45 years. All kidney-related outcomes, coded by the Central Bureau of Statistics from death notifications as the underlying cause of death, were obtained by linkage. Cox hazards models were applied. RESULTS: During 42,297,007 person-years of follow-up (median 18.4 years), 226 deaths related to kidney disease were recorded. There was an increased risk for kidney-related death among adolescents with overweight and obesity with adjusted hazard ratios of 2.7 (95% CI: 1.8-3.9) and 8.4 (5.1-13.8), respectively, with BMI between 18.5 and 22.0 kg/m2 as the reference. A 15% increased risk for kidney-related mortality (1.11-1.19) per unit increment in BMI was observed. Furthermore, a multivariable spline model indicated a minimum risk for kidney-related mortality starting at BMI of 18.6 kg/m2 with significantly increased risk seen above values of 22.8 kg/m2 . The results withstood extensive sensitivity analyses, including stratification of kidney-related death attributed to acute, chronic, and total kidney disease. CONCLUSIONS: Adolescent overweight and obesity are risk markers for kidney-related mortality over 4 decades. PMID- 29498232 TI - The current status of treatment-related severe hypoglycemia in Japanese patients with diabetes mellitus: A report from the committee on a survey of severe hypoglycemia in the Japan Diabetes Society. AB - Despite great strides in pharmacotherapy for diabetes, there is increasing concern over the risk of hypoglycemia in patients with diabetes receiving pharmacotherapy as they become increasingly older. This has prompted the Japan Diabetes Society (JDS) to initiate a survey on the current status of severe hypoglycemia in clinical settings. In July 2015, following approval from the JDS Scientific Survey/Research Ethics Committee, the JDS extended an invitation to executive educators, who represented a total of 631 healthcare facilities accredited by the JDS for diabetes education, to participate in the proposed survey. Of these, those who expressed their willingness to participate in the survey were sent an application form required for obtaining ethical approval at these healthcare facilities and were then asked, following approval, to enter relevant clinical data on an unlinked, anonymous basis in a web-based registry. The current survey was fully funded by the JDS Scientific Survey/Research Committee. A case registry (clinical case database) was launched after facility specific information (healthcare facility database) was collected from all participating facilities and after informed consent was obtained from all participating patients. With severe hypoglycemia defined as the "presence of hypoglycemic symptoms requiring assistance from another person to treat and preferably venous plasma glucose levels at onset/diagnosis of disease or at presentation clearly less than 60 mg/dL (capillary whole blood glucose, less than 50 mg/dL)", the current survey was conducted between April 1, 2014 and March 31, 2015, during which facility-specific information was collected from a total of 193 facilities with a total of 798 case reports collected from 113 facilities. Of the 193 respondent facilities, 149 reported having an emergency department as well, with the median number of patients who required emergency transportation services to reach these facilities totaling 4,962 annually, of which those with severe hypoglycemia accounted for 0.34% (17). The respondent facilities accommodated a total of 2,237 patients with severe hypoglycemia annually, with the number of patients thus accommodated being 6.5 patients per site. A total of 1,171 patients were admitted for severe hypoglycemia, with the number of patients thus admitted being 4.0 per site, who accounted for 52.3% of all patients visiting annually for severe hypoglycemia. A review of the 798 case reports collected during the survey revealed that 240, 480 and 78 patients had type 1 diabetes, type 2 diabetes, and other types of diabetes, respectively; those with type 2 diabetes were shown to be significantly older (median [interquartile range], 77.0 [68.0-83.0]) than those with type 1 diabetes (54.0 [41.0-67.0]) (P < 0.001); and the BMI was shown to be significantly higher for those with type 2 diabetes (22.0 [19.5-24.8] kg/m2 ) than for those with type 1 diabetes (21.3 [18.9-24.0] kg/m2 ) (P = 0.003). It was also found that the median estimated glomerular filtration rate (eGFR) was significantly lower among those with type 2 diabetes (50.6 mL [31.8-71.1]/min/1.73 m2 ) than among those with type 1 diabetes (73.3 [53.5-91.1] mL/min/1.73 m2 ) (P < 0.001). Again, the median HbA1c value at onset of severe hypoglycemia was shown to be 7.0 (6.3-8.1)% among all patients examined, 7.5 (6.9-8.6)% among those with type 1 diabetes, and 6.8 (6.1-7.6)% among those with type 2 diabetes, with the HbA1c value at onset of hypoglycemia being significantly lower among those with type 2 diabetes (P < 0.001). Antecedent symptoms of severe hypoglycemia were shown to be present, absent and unknown in 35.5, 35.6, and 28.9% of all patients, respectively, with the incidence of symptomatic hypoglycemia being significantly lower among those with type 1 diabetes (41.0%) than among those with type 2 diabetes (56.9%). The antidiabetic agents used in those with type 2 diabetes were insulin preparations (292 patients including 29 receiving concomitant sulfonylureas [SUs]) (60.8%), SUs (159 insulin-naive patients) (33.1%), and no insulin preparations or SUs (29 patients) (6.0%). Of the 798 patients surveyed, 296 patients (37.2%) were shown to have required emergency transportation services for severe hypoglycemia before. Thus, the survey revealed, for the first time, the current status of treatment-related severe hypoglycemia in Japan and clearly highlights the acute need for implementing preventive measures against hypoglycemia not only through education on hypoglycemia but through optimization of antidiabetic therapy for those at high risk of severe hypoglycemia or those with a history of severe hypoglycemia. PMID- 29498233 TI - Exploratory investigation of Q fever in apparently healthy meat sheep flocks in Belgium. AB - Q fever is a cosmopolitan disease affecting both humans and many animal species. Although sheep are often implicated in human Q fever outbreaks, the disease remains largely underestimated in meat sheep flocks. In order to fulfil this gap, a preliminary study was performed aiming to investigate the serological and molecular aspects of infection with Coxiella burnetii among meat sheep flocks in Belgium. Five Belgian sheep flocks were recruited for this work. Indirect ELISA was used, and in addition, real-time PCR was performed on samples of milk, rectal and vaginal swabs, to understand the dynamics of bacterial shedding. Despite the low overall apparent seroprevalence of 1.39% (95% CI: 0.04-7.5), a high rate of bacterial shedding was found, with 27.7% of tested sheep (N = 72) with a positive result to PCR, especially through the rectal and vaginal routes and in seronegative animals. Furthermore, Coxiella burnetii DNA was detected in 26.76% of seronegative animals. It can be concluded that an overall good clinical condition of the sheep cannot be used to exclude the presence of C. burnetii in a flock. Furthermore in the diagnosis of Q fever in sheep, serology alone was not a sensitive diagnostic tool. On the contrary, molecular biology allowed to detect bacterial shedding, which is an essential element in order to assess the risk due to the contact with shedding animals. At the light of these results, the role of meat sheep flocks in the epidemiology of Q fever in Belgium needs to be better understood. PMID- 29498235 TI - Point-of-Care Identification of Bacteria Using Protein-Encapsulated Gold Nanoclusters. AB - The rapid, simple, and reliable identification of the most prevalent pathogens is essential for clinical diagnostics, biology, and food safety. Herein, four protein-encapsulated gold nanoclusters (protein-AuNCs) are designed and prepared as a sensor array for rapid identification of bacteria. The discrimination of six kinds of bacteria, including two kinds of drug-resistant bacteria, is successfully realized by the as-fabricated sensor array. The strategy presented here shows the advantages of easy synthesis and convenient to use. Furthermore, 100% classification accuracy is achieved by the sensor array consisting of two protein-AuNCs probes, demonstrating the design with sufficient diagnostic capacity. Taken together, the developed sensor array holds great promise for facile diagnosis of bacterial infection in resource-limited settings. PMID- 29498234 TI - Frontloading HIV financing maximizes the achievable impact of HIV prevention. AB - INTRODUCTION: Due to the nature of funding, national planners and international donors typically balance budgets over short time periods when designing HIV programmes (~5-year funding cycles). We aim to explicitly quantify the cost of short-term funding arrangements on the success of future HIV prevention programmes. METHODS: Using mathematical models of HIV transmission in Kenya, we compare the impact of optimized combination prevention strategies under different constraints on investment over time. Each scenario has the same total budget for the 30-year intervention period but the pattern of spending over time is allowed to vary. We look at the impact of programmes with decreasing, increasing or constant spending across 5-year funding cycles for a 30-year period. Interventions are optimized within each funding cycle such that strategies take a short-term view of the epidemic. We compare these with two strategies with no spending pattern constraints: one with static intervention choices and another flexible strategy with interventions changed in year ten. RESULTS AND DISCUSSION: For the same total 30-year budget, greatest impact is achieved if larger initial prevention spending is offset by later treatment savings which leads to accumulating benefits in reduced infections. The impact under funding cycle constraints is determined by the extent to which greater initial spending is permitted. Short-term funding constraints and funds held back to later years may reduce impact by up to 18% relative to the flexible long-term strategy. CONCLUSIONS: Ensuring that funding arrangements are in place to support long-term prevention strategies will make spending most impactful. Greater prevention spending now will bring considerable returns through reductions in new infections, greater population health and reductions in the burden on health services in the future. PMID- 29498236 TI - Measuring Thriving across Nations: Examining the Measurement Equivalence of the Comprehensive Inventory of Thriving (CIT) and the Brief Inventory of Thriving (BIT). AB - BACKGROUND: Positive psychological health is a multifaceted construct and fundamental to individuals' overall mental health. Yet, measures of positive psychological health tend to focus on only a few of these facets. Su, Tay, and Diener () sought to address this by creating the Comprehensive and Brief Inventories of Thriving (CIT/BIT), integrative measures of well-being that assess positive psychological health broadly. METHOD: Given growing interest in cross national comparisons in positive psychological health, the present study expands on this work by examining the measurement invariance of these two measures across 10 countries (N = 3,077). First, a series of single-group confirmatory analyses were run to assess how well the CIT/BIT fit data from each country. Next, multi group confirmatory analyses were run to assess measurement invariance. RESULTS: Single-group confirmatory factor analysis supported the original 18-factor structure of the CIT when compared to alternative models (single factor, seven factor, bi-factor model) in seven of the 10 countries and the single-factor structure of the BIT across all countries. Results from the measurement invariance analysis indicated partial scalar invariance for the remaining seven countries on the CIT as well as partial scalar invariance across all countries for the BIT. CONCLUSION: The present study extends the initial work by Su et al. () by providing evidence of the measurement invariance of the comprehensive and brief inventories of thriving across cultures. Although the factor structure of the CIT was inadmissible in three countries, the results provide a crucial first step for those interested in comparing positive psychological health across nations. Research in both using these measures and cross-cultural comparisons on positive psychological health is growing. We hope that the current efforts help facilitate this work towards furthering the understanding of positive psychological health. PMID- 29498237 TI - The Africa Yoga Project and Well-Being: A Concept Map of Students' Perceptions. AB - BACKGROUND: Concept mapping methodology was used to explore the perceived impact of practicing yoga with the Africa Yoga Project (AYP)-an organisation created to increase health and well-being by providing community-based yoga classes throughout Kenya. AYP's mission fit with theoretical models of well-being is discussed. Anecdotal evidence and initial qualitative research suggested the AYP meaningfully impacted adult students. METHODS: Of the hundreds of AYP's adult students, 56 and 82 students participated in Phases I and II, respectively. Phase I brainstorming resulted in 94 student-generated statements about their perceived change. Phase II participants sorted and rated statements in terms of importance. Multidimensional scaling and hierarchical cluster analysis of sort data was utilised to map and group statements into clusters. RESULTS: Based on statistical and interpretive criteria, a five-cluster solution with the following concepts was identified as the best model of students' change: Personal Growth; Interpersonal Effectiveness (lowest importance); Physical and Social Benefits; Emotional Resiliency; and Improved Self-Concept (highest importance). CONCLUSIONS: Overall, students reported positive perceptions of the AYP. Additional research is needed to quantify students' change, and to compare the AYP outcomes to those of other programs aimed at poverty-related stress reduction and well-being. PMID- 29498238 TI - Synthesis and Biological Evaluation of Imidazole-Bearing alpha Phosphonocarboxylates as Inhibitors of Rab Geranylgeranyl Transferase (RGGT). AB - Rab geranylgeranyl transferase (RGGT) is an interesting therapeutic target, as it ensures proper functioning of Rab GTPases, a class of enzymes responsible for the regulation of vesicle trafficking. Relying on our previous studies, we synthesized a set of new alpha-phosphonocarboxylic acids as potential RGGT inhibitors, with emphasis on the elaboration of imidazole-containing analogues. We identified two compounds with activity similar to that of previously reported RGGT inhibitors, showing structural similarity to imidazo[1,2-a]pyridine containing analogues in terms of their substitution pattern. Interestingly, analogues of the N-series, derived from another phosphonocarboxylate RGGT inhibitor, 2-fluoro-3-(1H-imidazol-1-yl)-2-phosphonopropanoic acid, turned out to be inactive in our model, indicating that an additional substituent localized at positions C2 or C4 of the imidazole ring, may adversely affect the potency against the targeted enzyme. PMID- 29498239 TI - Retinal sensitivity following intraocular silicone oil and gas tamponade for rhegmatogenous retinal detachment. AB - PURPOSE: To investigate whether intraocular silicone oil (SO) tamponade is associated with functional changes in patients with both macula-on and macula-off rhegmatogenous retinal detachments (RRDs). METHODS: Prospective observational cohort study of patients with RRD treated by vitrectomy with gas or SO tamponade at the University Medical Center Utrecht. Outcome was best-corrected visual acuity (BCVA) and retinal sensitivity on microperimetry 2 months after surgery. RESULTS: In total, 40 eyes were included. There are 10 eyes in each of the following groups: macula-on RRD and gas, macula-on RRD and SO, macula-off RRD and gas, and macula-off RRD and SO. Median retinal sensitivity on microperimetry was decreased following SO tamponade compared to gas tamponade for both macula-on and macula-off RRD (p < 0.037). CONCLUSION: Foveal sensitivity was decreased in eyes after SO tamponade compared to gas tamponade. These effects were observed in patients with macula-on as well as macula-off RRD. Although further investigation is warranted to validate our results and to study underlying mechanisms, retinal surgeons need to be aware of these findings after the use of SO tamponade. PMID- 29498240 TI - Attempt of peripheral nerve reconstruction during lung cancer surgery. AB - BACKGROUND: Vagus nerve and recurrent laryngeal nerve (RLN) injury are not rare complications of lung cancer surgery and can cause lethal consequences. Until now, no optimal method other than paying greater attention during surgery has been available. METHODS: Four patients underwent lung surgery that involved RLN or vagus nerve injury. The left RLN or vagus nerve was cut off and then reconstructed immediately during surgery. Two patients underwent direct anastomosis, while the remaining two underwent phrenic nerve replacing tension relieving anastomosis. RESULTS: All patients were able to speak immediately after recovery. No or minimal glottal gap was observed during laryngoscopy conducted on the second day after surgery. Most patients achieved full recovery of voice quality. CONCLUSIONS: Immediate reconstruction of RLN is technically feasible and can be carried out with satisfying short-term and long-term outcomes. PMID- 29498241 TI - Erratum. PMID- 29498242 TI - Cell-Based and Exosome Therapy in Diabetic Stroke. AB - Stroke is a global health concern and it is imperative that therapeutic strategies with wide treatment time frames be developed to improve neurological outcome in patients. Patients with diabetes mellitus who suffer a stroke have worse neurological outcomes and long-term functional recovery than nondiabetic stroke patients. Diabetes induced vascular damage and enhanced inflammatory milieu likely contributes to worse post stroke outcomes. Diabetic stroke patients have an aggravated pathological cascade, and treatments that benefit nondiabetic stroke patients do not necessarily translate to diabetic stroke patients. Therefore, there is a critical need to develop therapeutics for stroke specifically in the diabetic population. Stem cell based therapy for stroke is an emerging treatment option with wide therapeutic time window. Cell-based therapies for stroke promote endogenous central nervous system repair and neurorestorative mechanisms such as angiogenesis, neurogenesis, vascular remodeling, white matter remodeling, and also modulate inflammatory and immune responses at the local and systemic level. Emerging evidence suggests that exosomes and their cargo microRNA mediate cell therapy derived neurorestorative effects. Exosomes are small vesicles containing protein and RNA characteristic of its parent cell. Exosomes are transported by biological fluids and facilitate communication between neighboring and remote cells. MicroRNAs, a class of naturally occurring, small noncoding RNA sequences, contained within exosomes can regulate recipient cell's signaling pathways and alter protein expression either acting alone or in concert with other microRNAs. In this perspective article, we summarize current knowledge and highlight the promising future of cell based and exosome therapy for stroke and specifically for diabetic stroke. Stem Cells Translational Medicine 2018;7:451-455. PMID- 29498243 TI - Nonsyndromic cleft palate: An association study at GWAS candidate loci in a multiethnic sample. AB - BACKGROUND: Nonsyndromic cleft palate only (nsCPO) is a common and multifactorial form of orofacial clefting. In contrast to successes achieved for the other common form of orofacial clefting, that is, nonsyndromic cleft lip with/without cleft palate (nsCL/P), genome wide association studies (GWAS) of nsCPO have identified only one genome wide significant locus. Aim of the present study was to investigate whether common variants contribute to nsCPO and, if so, to identify novel risk loci. METHODS: We genotyped 33 SNPs at 27 candidate loci from 2 previously published nsCPO GWAS in an independent multiethnic sample. It included: (i) a family-based sample of European ancestry (n = 212); and (ii) two case/control samples of Central European (n = 94/339) and Arabian ancestry (n = 38/231), respectively. A separate association analysis was performed for each genotyped dataset, and meta-analyses were performed. RESULTS: After association analysis and meta-analyses, none of the 33 SNPs showed genome-wide significance. Two variants showed nominally significant association in the imputed GWAS dataset and exhibited a further decrease in p-value in a European and an overall meta analysis including imputed GWAS data, respectively (rs395572: PMetaEU = 3.16 * 10-4 ; rs6809420: PMetaAll = 2.80 * 10-4 ). CONCLUSION: Our findings suggest that there is a limited contribution of common variants to nsCPO. However, the individual effect sizes might be too small for detection of further associations in the present sample sizes. Rare variants may play a more substantial role in nsCPO than in nsCL/P, for which GWAS of smaller sample sizes have identified genome-wide significant loci. Whole-exome/genome sequencing studies of nsCPO are now warranted. PMID- 29498244 TI - Novel 3D Hybrid Nanofiber Aerogels Coupled with BMP-2 Peptides for Cranial Bone Regeneration. AB - An ideal synthetic bone graft is a combination of the porous and nanofibrous structure presented by natural bone tissue as well as osteoinductive biochemical factors such as bone morphogenetic protein 2 (BMP-2). In this work, ultralight 3D hybrid nanofiber aerogels composed of electrospun PLGA-collagen-gelatin and Sr-Cu codoped bioactive glass fibers with incorporation of heptaglutamate E7 domain specific BMP-2 peptides have been developed and evaluated for their potential in cranial bone defect healing. The nanofiber aerogels are surgically implanted into 8 mm * 1 mm (diameter * thickness) critical-sized defects created in rat calvariae. A sustained release of E7-BMP-2 peptide from the degradable hybrid aerogels significantly enhances bone healing and defect closure over 8 weeks in comparison to unfilled defects. Histomorphometry and X-ray microcomputed tomography (u-CT) analysis reveal greater bone volume and bone formation area in case of the E7-BMP-2 peptide loaded hybrid nanofiber aerogels. Further, histopathology data divulged a near complete nanofiber aerogel degradation along with enhanced vascularization of the regenerated tissue. Together, this study for the first time demonstrates the fabrication of 3D hybrid nanofiber aerogels from 2D electrospun fibers and their loading with therapeutic osteoinductive BMP-2 mimicking peptide for cranial bone tissue regeneration. PMID- 29498245 TI - Baseline diastolic pressure gradient and pressure reduction in chronic heart failure patients implanted with the CardioMEMSTM HF sensor. AB - AIMS: Remote haemodynamic monitoring (RHM) decreases hospitalization rates in patients with chronic heart failure (HF). Many patients with chronic HF develop pulmonary hypertension (PH) secondary to left heart disease with some acquiring combined pre-capillary and post-capillary PH (Cpc-PH). The efficacy of RHM in achieving pulmonary pressure reductions in patients with Cpc-PH vs. isolated post capillary PH (Ipc-PH) is unknown. The purpose of this study is to evaluate whether a higher baseline diastolic pressure gradient (DPGbaseline ) measured at the time of CardioMEMSTM HF sensor implantation is associated with lower reductions in pulmonary artery diastolic pressures (PADP). METHODS AND RESULTS: This was a retrospective analysis of 32 patients meeting clinical indications for CardioMEMSTM implantation. DPGbaseline categorized patients as Cpc-PH (DPG >= 7 mmHg) or Ipc-PH (DPG < 7 mmHg). Minimum achievable PADP (PADPmin ) and ?PADP (PADPbaseline - PADPmin ) were determined. Pearson's correlation analysis and comparison of mean pressure changes were assessed. Median age was 69 years, and median left ventricular ejection fraction (LVEF) was 25%. Eight patients (25%) had a LVEF >=40%. Twenty-five patients (78%) met criteria for Ipc-PH and seven (22%) for Cpc-PH. Neither PADPmin (rho = 0.27; P = 0.13) nor DeltaPADP (rho = 0.07; P = 0.72) was correlated with DPGbaseline . A trend towards higher DeltaPADP was seen in Cpc-PH vs. Ipc-PH patients (15.2 vs. 9.88 mmHg; P = 0.12). There was a moderate positive correlation between baseline PADP and DeltaPADP [rho = 0.55 (0.26-0.76); P < 0.001]. CONCLUSIONS: Decreased PADP reduction was not seen in Cpc-PH vs. Ipc-PH patients. Higher PADPbaseline was associated with greater DeltaPADP. Larger studies are needed to elaborate our findings. PMID- 29498247 TI - Effect of dehydration on performance and technique of three-point shooting in elite basketball. PMID- 29498246 TI - Editorial: Logos, Ethos and Pathos: Whither academia and public health in a post truth world? AB - Rhetoric tells us there are three approaches to persuasive argument; logos, ethos and pathos (Bernanke, 2010). Logos is the appeal to logic by use of facts, data and analogies. Ethos is ethical appeal, focusing on the author's credibility or character with allied use of audience appropriate language and grammar. Pathos relates to emotional appeal by invoking sympathy, fear and anger. PMID- 29498248 TI - Oxidative stress biomarkers after a single maximal test in blind and non-blind soccer players. AB - BACKGROUND: Compare oxidative stress biomarkers, antioxidant capacity, muscle damage and hormone response between vision impaired and non-vision impaired athletes after a single maximal exercise test. METHODS: Eight vision impaired and fifteen non-vision impaired athletes performed a maximal aerobic test with blood collected before and after. RESULTS: Non-vision impaired athletes displayed greater aerobic capacity than blind individuals (p<0.05). Lactate increased by four-fold, while CK and GGT as well as the oxidative stress biomarkers and antioxidants were unchanged. Cortisol increased, but testosterone and their ratio were not altered. Differences were observed for ALT and AST, which were increased only in non-blind athletes. CONCLUSIONS: Our data suggest that blind soccer players, in comparison to those with vision, experienced less cellular damage. PMID- 29498250 TI - Breast cancer: effectiveness of a one-year unsupervised exercise program. AB - BACKGROUND: Improvements in prevention and therapeutic strategies over the years have increased the numbers of breast cancer survivors considerably. Sedentary behavior is now acknowledged to be a risk factor for cancer and cancer relapse. Currently, there are different approaches to increasing the effectiveness of long term physical activity in these patients. The aim of this study was to verify the long-term effectiveness of a home-based program for active lifestyle change in overweight breast cancer survivors. METHODS: We enrolled 43 women (age 51.5+/-9.9 years), who underwent an evaluation of their spontaneous physical activity levels, their baseline aerobic capacity through a 6-Minute Walking Test (6MWT), their flexibility, grip and lower limb strength, and their body composition. We repeated the measurements of these physical and anthropometric parameters six times during one year of unsupervised exercise. RESULTS: At the beginning of the program the sample showed a moderate level of spontaneous physical activity (physical activity level=1.44+/-0.12, steps/day=7420.3+/-1622.3). After being prescribed an individual exercise program, a significant reduction in BMI (T0=27.9+/-4.3, T5= 25.8+/-3.0 kg/m2; p<0.001) and skinfold sum was observed (T0=99.5+/-25.2, T5=86.2+/-22.7 mm; p=0.019), with a parallel maintenance of cell mass (T0= 21.4+/-3.3, T5= 22.5+/-3.0 kg; p=0.654). The functional parameters showed an increase in lower limb muscle fitness and a reduction in diastolic blood pressure after 6 MWT (T0= 78.4+/-10.1, T5= 72.5+/-14.9 mmhg; p=0.032). CONCLUSIONS: Physical activity is recommended for cancer patients; this model of prescribing unsupervised exercise seems to ensure optimal compliance, thus allowing long-term therapeutic efficacy. PMID- 29498249 TI - A profile of body composition, omega-3 and vitamin D in National Football League players. AB - BACKGROUND: Body composition (%BF), omega-3 and vitamin D (VitD) status are important components of an athlete's individual physiological profile, as each measure has potential to influence performance, inflammation, and injury recovery. The purpose of this study was to characterize %BF, omega-3, and VitD in a subset of professional football athletes. Secondary analyses investigated changes in %BF, omega-3, and VitD, throughout a competitive season, and evaluated the relationship between physiological variables, race, and injury prevalence. METHODS: Forty-two professional football players (Age: 24.0+/-2.4 yrs; Height: 186.8+/-5.9 cm; Weight: 108.8+/-19.4 kg) volunteered to participate. A-mode ultrasonography measured %BF and the percentage of highly unsaturated fatty acid content comprised of omega-3s was determined by an omega-3 bloodspot test. Vitamin D levels and injury prevalence were obtained from the team athletic trainer. RESULTS: Omega-3 was moderately correlated with VitD (R=0.397, p=0.030). Throughout the season there was a significant decrease in omega-3 percentage (?= 2.47+/-5.48%, p=0.030), no change in body composition (?=0.26+/-1.97%, p=0.482) and a significant increase in VitD (?=9.03 +/- 19.46 ng/mL, p=0.015). VitD was significantly higher in white athletes (48.00+/-13.73 ng/mL) than black athletes (27.09+/-9.28 ng/mL; p<0.001) and athletes of other races (23.33+/-4.73 ng/mL; p=0.004). CONCLUSIONS: Throughout the season, %BF was maintained, VitD levels increased, and omega-3 decreased. White athletes had significantly higher VitD levels than athletes of all other races. There were no differences in the physiological variables between injury severity categories. The results from the current study provides support for the potential importance of VitD and omega-3 supplementation for professional football athletes. PMID- 29498251 TI - The effect of acute match play loading on hip adductor strength & flexibility in soccer players. AB - BACKGROUND: Deficits in adductor strength and flexibility are known risk factors for soccer hip/groin injury, yet little is known about the acute effects of soccer match play on these physical features. The aim of this study therefore was to examine the changes in adductor strength and flexibility before; during and immediately after soccer match play. METHODS: Design: Twenty, male university soccer players (age = 22.35 +/- 1.98 years) participated in this field-based, within subject, repeated measures study. Each participant performed three adductor squeeze tests at both 0 degrees and 45 degrees hip flexed test positions alongside a bent knee fall out test. Adductor squeeze scores were quantified using pressure sphygmomanometer and BKFO values recorded in centimetres. Each test was performed before (0 mins) half time (45 mins) and at full time (90 mins) of a competitive match. RESULTS: Adductor strength decreased by 17.7% in 0 degrees test position and 19.1% in 45 degrees test position at 90 minutes of soccer play, whilst BKFO scores increased by 15% indicating a reduction in adductor flexibility. Statistical analysis showed significant effects of time Vs adductor strength and squeeze test position (P=<0.005), Positive correlations between time played and BKFO scores, and BKFO scores vs adductor squeeze scores at 0 and 45 minutes (P=<0.005) were also observed. CONCLUSIONS: University soccer players exhibit decreased adductor squeeze test and BKFO values as soccer match duration increases. These findings may have implications hip/groin injury management and recovery strategies, post or during soccer matches. PMID- 29498252 TI - Effects of a one-week vacation with various activity programs on cardiovascular parameters. AB - OBJECTIVE: A vacation is considered essential to achieve recovery from the stress of work. Knowledge about the potential health effects of holidays is scarce. The East Tyrolean Health Tourism Study is an open comparative study to investigate the cardiovascular effects of a one- week vacation with different activities on healthy vacationers. METHODS: Fifty-two healthy vacationers spending one week in East Tyrol participated in two types of vacation activities (golf vs. Nordic walking or e-biking [nw&eb]). In the former group 30 subjects played golf for 33.5 hours per week, and in the nw&eb group 22 engaged in Nordic walking or e biking for 14.2 hours per week. Cardiovascular parameters such as performance capacity, blood pressure, heart rate profiles and cardiac diastolic function were measured by a cardiopulmonary exercise test, holter ECG and echocardiography performed one day before and after the stay. RESULTS: There was a significant decrease in body weight of 1.0 kg in the nw&eb-group but not in the golf group. In both groups we noted a reduction of blood pressure and heart rate, which was marked and significant only in the golf group. We observed no significant changes in performance capacity, but did note an improvement of cardiac diastolic function in both groups; the improvement was more pronounced in the nw&eb group. CONCLUSIONS: A one-week vacation with an activity program for several hours per week is well tolerated by healthy vacationers and improves cardiovascular parameters. The cardiovascular benefits were homogeneous but differed in their magnitude, depending on the activity group. The benefits were probably due to the enhanced physical activity rather than purely a holiday effect. PMID- 29498253 TI - Individualized dry-land intervention program for an elite Paralympic swimmer: a case report. AB - The aim of this retrospective case study is the longitudinal description of the physical and functional parameters of a top-level Paralympic swimmer class S9-SB8 SM9 during four swimming seasons of training, from the Paralympic games in London 2012 to the Paralympic games in Rio 2016. A 22-year-old male swimmer underwent a specific preventive dry-land training based on diaphragmatic breathing, postural alignment, and slow-velocity resistance training aimed to improve his muscle strength. He was tested by using the Functional Movement ScreenTM, photographic postural assessment and vertical jump. The swimmer improved his functional, postural and strength parameters indicating a better functional movement and muscular power. These results shows that a four-year specific dry-land intervention could be capable of enhancing the functional and physical requirements of a top-level Paralympic swimmer. This approach might be a suitable novel alternative for physical therapists and athletic trainers to integrate their training protocols for athletes with similar impairments. PMID- 29498254 TI - Type 2 diabetes mellitus risk and exercise: is resistin involved? AB - Obesity and associated disorders such as type 2 diabetes mellitus (T2DM) pose an increasing risk to the health of both individuals and society. Adipose tissue is an active endocrine organ, secreting many hormones, known as adipokines. Evidence suggests that one suggest adipokine, resistin, may be elevated in the plasma of individuals with T2DM, and early reports indicated that this may contribute to the impaired glucose tolerance and insulin resistance observed in T2DM, hence its name, resistin, however subsequent evidence suggests it may have a proinflammatory role. Performing regular exercise and dietary interventions improve insulin sensitivity and glucose tolerance in the majority of individuals with T2DM, and we hypothesised that plasma resistin levels may drop in individuals following a long term aerobic and/or resistance exercise intervention programme. Articles analysing the effects of exercise on serum resistin levels were therefore analysed. Articles were selected and analysed based on a minimum aerobic and/or resistance training programme of 2 sessions per week for 12 weeks. Plasma resistin levels decreased following either endurance aerobic exercise and/or resistance training plans in individuals with obesity and/or insulin resistance, although this was not related to BMI change. Exercise intervention programmes generally showed potentially beneficial changes in plasma resistin concentrations. It is possible these effects are mediated through exercise induced decreases in inflammation via anti-inflammatory cytokine release rather than alterations in glucose metabolism and reductions in BMI per se. A possible link between resistin, exercise and T2DM is discussed. PMID- 29498255 TI - Link between body cellular mass and left ventricular hypertrophy in female and male athletes. AB - BACKGROUND: Cardiac adaptation to intense physical training is determined by many factors. Differences between the sexes in the left ventricle parameters are well established, however, both sport activity and body composition seem to reduce them. In order to better explain some heart modifications, a first approach was to eliminate the fat mass from the indexing of the left ventricular parameters. Fat free mass also contains the extracellular mass which does not represent a metabolically active compartment. The aim of this study is to verify the differences between the sexes with a new left ventricular indexation with the metabolically active tissue of the body as body cell mass in elite athletes. METHOD: 25 females were matched with 25 elite male soccer players (females=26.2+/ 1.9 yrs, males=26.5+/-1.8 yrs; p=NS). An accurate body composition analysis (skinfold and bioimpedance) and an echocardiography were performed. RESULTS: Differences between the sexes in body composition were confirmed in fat mass (fat mass index females=3.5+/-0.5 kg/m2, males=2.4+/-0.5 kg/m2, p<0.001), while no differences were found in the extra cellular mass index (females=7.3+/-1.1 kg/m2, males=7.5+/-0.5 kg/m2; p=NS). There are no differences in systo-diastolic parameters between sexes. Greater relationships were found between left ventricular mass and body cells (r=0.829, r2=0.686, COV=401.5) compared to fat free mass (r=0.819, r2=0.675, COV=344.7). Left ventricular dimensions show higher values in males who also have the following body cell indexation (females=128.2+/ 15.8 g/m2, males=143.4+/-14.7 g/m2 ; p<0.001). CONCLUSIONS: Analyzing body composition in three compartments appears a solution that physiologically can explain some aspects of the athlete's heart. These results could be considered as preliminary data which can be used to create a new indexation. PMID- 29498256 TI - BIABooster: Online DNA Concentration and Size Profiling with a Limit of Detection of 10 fg/MUL and Application to High-Sensitivity Characterization of Circulating Cell-Free DNA. AB - We describe a technology to perform sizing and concentration analysis of double stranded DNA with a sensitivity of 10 fg/MUL in an operating time of 20 min. The technology is operated automatically on a commercial capillary electrophoresis instrument using electro-hydrodynamic actuation. It relies on a new capillary device that achieves online concentration of DNA at the junction between two capillaries of different diameters, thanks to viscoelastic lift forces. Using a set of DNA ladders in the range of 100-1500 bp, we report a sizing accuracy and precision better than 3% and a concentration quantification precision of ~20%. When the technology is applied to the analysis of clinical samples of circulating cell-free DNA (cfDNA), the measured cfDNA concentrations are in good correlation with those measured by digital PCR. Furthermore, the cfDNA size profiles indicate that the fraction of low molecular weight cfDNA in the range of 75-240 bp is a candidate biomarker to discriminate between healthy subjects and cancer patients. We conclude that our technology is efficient in analyzing highly diluted DNA samples and suggest that it will be helpful in translational and clinical research involving cfDNA. PMID- 29498257 TI - Improved Thermoelectric Performance in Nonstoichiometric Cu2+deltaMn1-deltaSnSe4 Quaternary Diamondlike Compounds. AB - A novel quaternary Cu2MnSnSe4 diamondlike thermoelectric material was discovered recently based on the pseudocubic structure engineering. In this study, we show that introducing off-stoichiometry in Cu2MnSnSe4 effectively enhances its thermoelectric performance by simultaneously optimizing the carrier concentrations and suppressing the lattice thermal conductivity. A series of nonstoichiometric Cu2+deltaMn1-deltaSnSe4 (delta = 0, 0.025, 0.05, 0.075, and 0.1) samples has been prepared by the melting-annealing method. The X-ray analysis and the scanning electron microscopy measurement show that all nonstoichiometric samples are phase pure. The Rietveld refinement demonstrates that substituting part of Mn by Cu well maintains the structure distortion parameter eta close to 1, but it induces obvious local distortions inside the anion-centered tetrahedrons. Significantly improved carrier concentrations are observed in these nonstoichiometric Cu2+deltaMn1-deltaSnSe4 samples, pushing the power factors to the theoretical maximal value predicted by the single parabolic model. Substituting part of Mn by Cu also reduces the lattice thermal conductivity, which is well interpreted by the Callaway model. Finally, a maximal thermoelectric dimensionless figure-of-merit zT around 0.60 at 800 K has been obtained in Cu2.1Mn0.9SnSe4, which is about 33% higher than that in the Cu2MnSnSe4 matrix compound. PMID- 29498258 TI - Michael Addition Based Chemodosimeter for Serum Creatinine Detection Using ( E)-3 (Pyren-2-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one Chalcone. AB - First, a simple and highly emissive fluorescent chalcone ( E)-3-(pyren-2-yl)-1 (3,4,5-trimethoxyphenyl)prop-2-en-1-one (PTP) was synthesized via simple shaking along with an excellent quantum yield of 0.85, and proved as a stable, highly sensitive, and selective biosensor for creatinine. Owing to its unique photophysical interaction with creatinine through Michael adduct formation, PTP was utilized as a Chemodosimeter for the selective recognition of creatinine in blood serum. Under optimized conditions, a broad range of creatinine detection was achieved from 0.00000113 mg/dL to 15.8 mg/dL along with an excellent limit of detection of 0.00000065 mg/dL (0.058 nM). This biosensor is highly reproducible even for different concentration levels of creatinine. It is the very first creatinine biosensor possessing a wider linear range for clinical applications for creatinine. To ensure its clinical application, blood serum samples of people of different age groups were collected from Alpha Hospital and analyzed for creatinine by using our chemodosimeter method and compared with data obtained using a commercial method in the Alpha hospital. Our data show very good agreement with clinical data. Because clinical protocol involves trienzymes and tedious sample preparation, no doubt, our chemodosimeter will be a cheap and sensitive option compared to the existing clinical methods. PMID- 29498259 TI - Diphenylalanine-Based Microribbons for Piezoelectric Applications via Inkjet Printing. AB - Peptide-based nanostructures are very promising for nanotechnological applications because of their excellent self-assembly properties, biological and chemical flexibility, and unique multifunctional performance. However, one of the limiting factors for the integration of peptide assemblies into functional devices is poor control of their alignment and other geometrical parameters required for device fabrication. In this work, we report a novel method for the controlled deposition of one of the representative self-assembled peptides diphenylalanine (FF)-using a commercial inkjet printer. The initial FF solution, which has been shown to readily self-assemble into different structures such as nano- and microtubes and microrods, was modified to be used as an efficient ink for the printing of aligned FF-based structures. Furthermore, during the development of the suitable ink, we were able to produce a novel type of FF conformation with high piezoelectric response and excellent stability. By using this method, ribbonlike microcrystals based on FF could be formed and precisely patterned on different surfaces. Possible mechanisms of structure formation and piezoelectric effect in printed microribbons are discussed along with the possible applications. PMID- 29498260 TI - Highly Biocompatible Chlorin e6-Loaded Chitosan Nanoparticles for Improved Photodynamic Cancer Therapy. AB - The photosensitizer Chlorin e6 (Ce6) has been frequently employed for photodynamic therapy (PDT) of cancer; however, its nonspecific toxicity has limited its clinical applications. In this study, we prepared chitosan nanoparticles (CNPs), with a mean diameter of approximately 130 nm, by a nonsolvent-aided counterion complexation method in an aqueous solution, into which Ce6 could be physically entrapped during the preparation process. These CNPs and Ce6-loaded CNPs (CNPs-Ce6) were fully characterized by UV-vis, photoluminescence, and Fourier transform infrared spectroscopic analysis, as well as dynamic light scattering and transmission electron microscopy measurements. More importantly, the biocompatibility of the otherwise toxic Ce6 was significantly improved upon its loading into the CNPs, as demonstrated by both confocal laser scanning microscopy analysis and 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assays. Furthermore, the PDT efficiency of Ce6 loaded CNPs was dramatically enhanced, in comparison with that of the free Ce6, as shown by both MTT and flow cytometry assays. This discovery provides a novel strategy for improving the biocompatibility and therapeutic efficacy of PDT agents by using a natural, biocompatible polysaccharide carrier. PMID- 29498261 TI - NIST Standards for Measurement, Instrument Calibration, and Quantification of Gaseous Atmospheric Compounds. AB - There are many gas phase compounds present in the atmosphere that affect and influence the earth's climate. These compounds absorb and emit radiation, a process which is the fundamental cause of the greenhouse effect. The major greenhouse gases in the earth's atmosphere are carbon dioxide, methane, nitrous oxide, and ozone. Some halocarbons are also strong greenhouse gases and are linked to stratospheric ozone depletion. Hydrocarbons and monoterpenes are precursors and contributors to atmospheric photochemical processes, which lead to the formation of particulates and secondary photo-oxidants such as ozone, leading to photochemical smog. Reactive gases such as nitric oxide and sulfur dioxide are also compounds found in the atmosphere and generally lead to the formation of other oxides. These compounds can be oxidized in the air to acidic and corrosive gases and contribute to photochemical smog. Measurements of these compounds in the atmosphere have been ongoing for decades to track growth rates and assist in curbing emissions of these compounds into the atmosphere. To accurately establish mole fraction trends and assess the role of these gas phase compounds in atmospheric chemistry, it is essential to have good calibration standards. The National Institute of Standards and Technology has been developing standards of many of these compounds for over 40 years. This paper discusses the development of these standards. PMID- 29498262 TI - Cellulose Nanocrystal-Based Colored Thin Films for Colorimetric Detection of Aldehyde Gases. AB - We demonstrate a controllable and reliable process for manifesting color patterns on solid substrates using cellulose nanocrystals (CNCs) without the use of any other chemical pigments. The color can be controlled by adjusting the assembly conditions of the CNC solution during a dip-and-pull process while aiding the close packing of CNCs on a solid surface with the help of ionic-liquid (1-butyl-3 methylimidazolium) molecules that screen the repelling electrostatic charges between CNCs. By controlling the pulling speed from 3 to 9 MUm/min during the dip and-pull process, we were able to control the film thickness from 100 to 300 nm, resulting in films with different colors in the visible range. The optical properties were in good agreement with the finite-difference time-domain simulation results. By functionalizing these films with amine groups, we developed colorimetric sensors that can change in color when exposed to aldehyde gases such as formaldehyde or propanal. A principal component analysis showed that we can differentiate between different aldehyde gases and other interfering molecules. We expect that our approach will enable inexpensive and rapid volatile organic compound detection with on-site monitoring capabilities. PMID- 29498263 TI - Impacts of Personal Mobility and Diurnal Concentration Variability on Exposure Misclassification to Ambient Pollutants. AB - Appreciating the uncertainty margins of exposure assessment to air pollution requires good understanding of its variability throughout the daily activities. This study describes a modeling framework for estimating exposure to air pollutants for a representative sample of working Israeli adults ( N ~ 168 000) for which both the residence and workplace addresses were available. Individual daily trajectories were simulated by accounting for five generic daily activities: at home, at work, while in commute from home to work and back, and during out-of-home leisure activities. The integrated daily exposure to nitrogen dioxide (NO2) was estimated for each individual by tracking the daily trajectory through an NO2 concentration map, obtained using a dynamic and highly resolved dispersion-like model (temporal resolution, half-hourly; spatial resolution, 500 m). Accounting for the subjects' daily mobility was found to affect their exposure more significantly than accounting solely for the diurnal concentration variability, yet a synergistic effect was noted when accounting for both factors simultaneously. Exposure misclassification varies along the day, with the work microenvironment found to contribute the most to it. In particular, regardless of the high concentrations encountered during the commute, their contribution to the integrated daily exposure is small due to the relatively short time spent in this activity by most people. PMID- 29498264 TI - Reactive Oxygen Species-Biodegradable Gene Carrier for the Targeting Therapy of Breast Cancer. AB - An ideal gene-carrying vector is supposed to exhibit outstanding gene-condensing capability with positively charged macromolecules to protect the carried gene during in vivo circulation and a rapid dissociation upon microenvironmental stimuli at the aimed sites to release the escorted gene. Currently, it still remains a challenge to develop an ideal gene carrier with efficient transfection ability and low toxicity for clinical applications. Herein, we have innovatively introduced a reactive oxygen species (ROS)-biodegradable boric acid ester linkage in elaborating the design of a gene carrier. In virtue of the featured intracellular characteristics such as the high level of ROS in tumor cells, an ROS-biodegradable electropositive polymer derived from branched polyethylenimine (BPEI) with a low molecular weight (1.2k) through a cross-linking reaction by the boric acid ester bond was developed in this study to achieve condensation and escorting of carried genes. Furthermore, the polymer was modified with substance P (SP) peptide as the targeting ligand through polyethylene glycol. The final fabricated SP-cross-linked BPEI/plasmid DNA nanoparticles exhibit favorable biocompatibility, ROS-cleavability, and fine targeting ability as well as high transfection efficiency compared with parental BPEI1.2k both in vitro and in vivo. SP-cross-linked BPEI/small interfering RNA (pololike kinase 1) polyplex possesses favorable gene-silencing effects in vitro and satisfactory antitumor ability in vivo. Hopefully, this novel cross-linked electropositive polymer may serve well as a safe and efficient gene-delivery vehicle in the clinic. PMID- 29498265 TI - Integration of Biofuel Cell-Based Self-Powered Biosensing and Homogeneous Electrochemical Strategy for Ultrasensitive and Easy-To-Use Bioassays of MicroRNA. AB - Biofuel cell (BFC)-based self-powered biosensors have attracted substantial attentions because of their unique merits such as having no need for power sources (only two electrodes are needed). More importantly, in case it can also work in a homogeneous system, more efficient and easy-to-use bioassays could come true. Thus, herein, we proposed a novel homogeneous self-powered biosensing strategy via the integration of BFCs and a homogeneous electrochemical method, which was further utilized for ultrasensitive microRNA (miRNA) detection. To construct such an assay protocol, the cathodic electron acceptor [Fe(CN)6]3- was entrapped in the pores of positively charged mesoporous silica nanoparticles and capped by the biogate DNAs. Once the target miRNA existed, it would trigger the controlled release of [Fe(CN)6]3-, leading to the dramatic increase of the open circuit voltage. Consequently, the "signal-on" homogeneous self-powered biosensor for the ultrasensitive miRNA assay was realized. Encouragingly, the limit of detection for the miRNA-21 assay was down to 2.7 aM (S/N = 3), obviously superior to those of other analogous reported approaches. This work not only provides an ingenious idea to construct the ultrasensitive and easy-to-use bioassays of miRNA but also exhibits a successful prototype of a portable and on-site biomedical sensor. PMID- 29498266 TI - pH-Dependent Surface Chemistry from First Principles: Application to the BiVO4(010)-Water Interface. AB - We present a theoretical formulation for studying the pH-dependent interfacial coverage of semiconductor-water interfaces through ab initio electronic structure calculations, molecular dynamics simulations, and the thermodynamic integration method. This general methodology allows one to calculate the acidity of the individual adsorption sites on the surface and consequently the pH at the point of zero charge, pHPZC, and the preferential adsorption mode of water molecules, either molecular or dissociative, at the semiconductor-water interface. The proposed method is applied to study the BiVO4(010)-water interface, yields a pHPZC in excellent agreement with the experimental characterization. Furthermore, from the calculated p Ka values of the individual adsorption sites, we construct an ab initio concentration diagram of all adsorbed species at the interface as a function of the pH of the aqueous solution. The diagram clearly illustrates the pH-dependent coverage of the surface and indicates that protons are found to be significantly adsorbed (~1% of available sites) only in highly acidic conditions. The surface is found to be mostly covered by molecularly adsorbed water molecules in a wide interval of pH values ranging from 2 to 8. Hydroxyl ions are identified as the dominant adsorbed species at pH larger than 8.2. PMID- 29498267 TI - Equilibria and Rate Phenomena from Atomistic to Mesoscale: Simulation Studies of Magnetite. AB - Batteries are dynamic devices composed of multiple components that operate far from equilibrium and may operate under extreme stress and varying loads. Studies of isolated battery components are valuable to the fundamental understanding of the physical processes occurring within each constituent element. When the components are integrated into a full device and operated under realistic conditions, it can be difficult to decouple the physical processes that occur across multiple interfaces and multiple length scales. Thus, the physical processes studied in isolated components may change in a full battery setup or may be irrelevant to performance. Simulation studies on many length scales play a key role in the analysis of experiments and in the elucidation of the relevant physical processes impacting performance. In this Account, we aim to highlight the use of modeling on multiple length scales to identify rate limiting phenomena in lithium-ion batteries. To illustrate the utility of modeling, we examine lithium-ion batteries with nanostructured magnetite, Fe3O4, as the positive electrode active material against a solid Li0 negative electrode. Due to continuous operation away from equilibrium, batteries exhibit highly nonideal behavior, and a model that aims to reproduce behavior under realistic operating conditions must be able to capture the physics occurring on the length scales relevant to the performance of the system. It is our experience that limiting behavior in lithium-ion batteries can be observed on the atomic scale and up through the electrode scale and thus, predictive models must be capable of integrating and communicating physics across multiple length scales. Magnetite is studied as an electrode material for lithium-ion batteries, but it is found to suffer from slow solid-state transport of lithium, slow reaction kinetics, and poor cycling. Magnetite (Fe3O4) is a material capable of undergoing multiple electron transfers (MET), and can accept up to eight lithium per formula unit (Li8Fe3O4). Magnetite, (Fe8a3+)[Fe3+Fe2+]16dO4,32e2-, has a close-packed inverse spinel structure and undergoes intercalation, structural rearrangement, and conversion reactions upon full lithiation. (1) To overcome solid-state transport resistances, magnetite can be nanostructured to decrease Li+ diffusion lengths, and this has been shown to increase capacity. Additionally, unique architectures incorporating both carbon and Fe3O4 have shown to alleviate transport and cycling issues in the material. (2) Here, we solely address traditional composite electrodes, in which Fe3O4 is synthesized as nanoparticles and combined with additives to fabricate the electrode. In the case of nanoparticulate magnetite, it has been found that the electrode fabrication process results in the formation of micrometer-sized agglomerates of the Fe3O4 nanoparticles, introducing a secondary structural motif. The agglomerates may form in one or more fabrication processes, and their elimination may not be straightforward or warranted. Here, we highlight the impact of these secondary formations on the performance of the Fe3O4 lithium-ion battery. We illustrate how simulations can be used to design experiments, prioritize research efforts, and predict performance. PMID- 29498268 TI - Unequal Exchange of Air Pollution and Economic Benefits Embodied in China's Exports. AB - As the world's factory, China has enjoyed huge economic benefits from international export but also suffered severe environmental consequences. Most studies investigating unequal environmental exchange associated with trade took China as a homogeneous entity ignoring considerable inequality and outsourcing of pollution within China. This paper traces the regional mismatch of export-induced economic benefits and environmental costs along national supply chains by using the latest multiregional input-output model and emission inventory for 2012. The results indicate that approximately 56% of the national GDP induced by exports has been received by developed coastal regions, while about 72% of air pollution embodied in national exports, measured as aggregated atmospheric pollutant equivalents (APE), has been mainly incurred by less developed central and western regions. For each yuan of export-induced GDP, developed regions only incurred 0.4 0.6 g APE emissions, whereas less developed regions from western or central China had to suffer 4-8 times the amount of emissions. This is due to poorer regions providing lower value added and higher emission-intensive inputs and having lower environmental standards and less efficient technologies. Our results may pave a way to mitigate the unequal relationship between developed and less developed regions from the perspective of environment-economy nexus. PMID- 29498269 TI - Understanding the Improved Kinetics and Cyclability of a Li2MnSiO4 Cathode with Calcium Substitution. AB - Limited practical capacity and poor cyclability caused by sluggish kinetics and structural instability are essential aspects that constrain the potential application of Li2MnSiO4 cathode materials. Herein, Li2Mn1- xCa xSiO4/C nanoplates are synthesized using a diethylene-glycol-assisted solvothermal method, targeting to circumvent its drawbacks. Compared with the pristine material, the Ca-substituted material exhibits enhanced electrochemical kinetics and improved cycle life performance. In combination with experimental studies and first-principles calculations, we reveal that Ca incorporation enhances electronic conductivity and the Li-ion diffusion coefficient of the Ca substituted material, and it improves the structural stability by reducing the lattice distortion. It also shrinks the crystal size and alleviates structure collapse to enhance cycling performance. It is demonstrated that Ca can alleviate the two detrimental factors and shed lights on the further searching for suitable dopants. PMID- 29498270 TI - Postsynthetic Modification of Metal-Organic Frameworks through Nitrile Oxide Alkyne Cycloaddition. AB - Postsynthetic modification of metal-organic frameworks is an important method to tailor their properties. We report on the nitrile oxide-alkyne cycloaddition (NOAC) as a modification tool, a reaction requiring neither strained alkynes nor a catalyst. This is demonstrated with the reaction of nitrile oxides with PEPEP PIZOF-15 and -19 at room temperature. PIZOF-15 and -19 are porous Zr-based MOFs (BET surface areas 1740 and 960 m2 g-1, respectively) consisting of two mutually interpenetrating UiO-type frameworks with linkers of the type -O2C[PE-P(R1,R2) EP]CO2- (P, phenylene; E, ethynylene; R1 and R2, side chains at the central benzene ring with R1 = R2 = OCH2C=CH or R1 = OCH2C=CH and R2 = O(CH2CH2O)3Me). Their syntheses, using benzoic acid as a modulator, and their characterization are reported herein. The propargyloxy (OCH2C=CH) side chains contain the ethyne moieties needed for NOAC. Formation of nitrile oxides through oxidation of oximes in aqueous ethanolic solution in the presence of PEPEP-PIZOF-15 and -19 resulted in the reaction of 96-100% of the ethyne moieties to give isoxazoles. Thereby the framework was preserved. The type of nitrile oxide RCNO was greatly varied with R being isopentyl, tolyl, 2-pyridyl, and pentafluorophenyl. A detailed NMR spectroscopic investigation showed the formation of the 3,5-disubstituted isoxazole to be clearly favored (>=96%) over that of the constitutional isomeric 3,4-disubstituted isoxazole, except for one example. PMID- 29498271 TI - NaNO3/NaCl Oxidant and Polyethylene Glycol (PEG) Capped Gold Nanoparticles (AuNPs) as a Novel Green Route for AuNPs Detection in Electrochemical Biosensors. AB - Gold nanoparticles (AuNPs) have been exploited as signal-producing tags in electrochemical biosensors. However, the electrochemical detection of AuNPs is currently performed using corrosive acid solutions, which may raise health and environmental concerns. Here, oxidant salts, and specifically the environmentally friendly and occupational safe NaNO3/NaCl mixture, have been evaluated for the first time as potential alternatives to the acid solutions traditionally used for AuNPs electrooxidation. In addition, a new strategy to improve the sensitivity of the biosensor through PEG-based ligand exchange to produce less compact and easier to oxidize AuNPs immunoconjugates is presented too. As we show, the electrochemical immunosensor using NaNO3/NaCl measurement solution for AuNPs electrooxidation and detection, coupled to the employment of PEG-capped nanoimmunoconjugates, produced results comparable to classical HCl detection. The procedure developed was next tested for human matrix metallopeptidase-9 (hMMP9) analysis, exhibiting a 0.18-23 ng/mL linear range, a detection limit of 0.06 ng/mL, and recoveries between 95 and 105% in spiked human plasma. These results show that the procedure developed is applicable to the analysis of protein biomarkers in blood plasma and could contribute to the development of more environmentally friendly AuNP-based electrochemical biosensors. PMID- 29498272 TI - Potential Mechanisms of Action of Dietary Phytochemicals for Cancer Prevention by Targeting Cellular Signaling Transduction Pathways. AB - Cancer is a severe health problem that significantly undermines life span and quality. Dietary approach helps provide preventive, nontoxic, and economical strategies against cancer. Increased intake of fruits, vegetables, and whole grains are linked to reduced risk of cancer and other chronic diseases. The anticancer activities of plant-based foods are related to the actions of phytochemicals. One potential mechanism of action of anticancer phytochemicals is that they regulate cellular signal transduction pathways and hence affects cancer cell behaviors such as proliferation, apoptosis, and invasion. Recent publications have reported phytochemicals to have anticancer activities through targeting a wide variety of cell signaling pathways at different levels, such as transcriptional or post-transcriptional regulation, protein activation and intercellular messaging. In this review, we discuss major groups of phytochemicals and their regulation on cell signaling transduction against carcinogenesis via key participators, such as Nrf2, CYP450, MAPK, Akt, JAK/STAT, Wnt/beta-catenin, p53, NF-kappaB, and cancer-related miRNAs. PMID- 29498274 TI - Construction of Layered Structure of Anion-Cations To Tune the Work Function of Aluminum-Doped Zinc Oxide for Inverted Polymer Solar Cells. AB - Suitable work function (WF) of the cathode in polymer solar cells (PSCs) is of essential importance for the efficient electron extraction and collection to boost the power conversion efficiency. Herein, we report a facile and efficient method to tune the surface WF of aluminum-doped zinc oxide (AZO) through building of a definite interfacial dipole, which is realized by the construction of a layered structure of positive and negative ionized species. A cross-linked perylene bisimide (poly-PBI) thin film is deposited onto the AZO surface first, and then it is reduced to the radical anion state (poly-PBI*-) in an electrochemical cell, using tetraoctylammonium (TOA+), a bulky cation, as a counter ion. Owing to the huge volume of TOA+, it is absorbed on the surface of the cross-linked PBI*- thin film through Coulomb force, and thus a definite interface dipole is formed between the two ionized layers. Because of the definite interface dipole, the surface WF of the electrode modified with ionized layers is decreased dramatically to 3.9 eV, which is much lower than that of the electrode modified with the neutral PBI layer (4.5 eV). By using this novel cathode interlayer with a definite interface dipole in PSCs, a significantly increased open-circuit voltage ( VOC) is obtained. The results indicate that it is a facile and unique method by the construction of a definite interface dipole to tune the surface WF of the electrode for the application in organic electronic devices. PMID- 29498273 TI - A Linear Scaling Relation for CO Oxidation on CeO2-Supported Pd. AB - Resolving the structure and composition of supported nanoparticles under reaction conditions remains a challenge in heterogeneous catalysis. Advanced configurational sampling methods at the density functional theory level are used to identify stable structures of a Pd8 cluster on ceria (CeO2) in the absence and presence of O2. A Monte Carlo method in the Gibbs ensemble predicts Pd-oxide particles to be stable on CeO2 during CO oxidation. Computed potential energy diagrams for CO oxidation reaction cycles are used as input for microkinetics simulations. Pd-oxide exhibits a much higher CO oxidation activity than metallic Pd on CeO2. This work presents for the first time a scaling relation for a CeO2 supported metal nanoparticle catalyst in CO oxidation: a higher oxidation degree of the Pd cluster weakens CO binding and facilitates the rate-determining CO oxidation step with a ceria O atom. Our approach provides a new strategy to model supported nanoparticle catalysts. PMID- 29498275 TI - EQE Climbing Over 6% at High Brightness of 14350 cd/m2 in Deep-Blue OLEDs Based on Hybridized Local and Charge-Transfer Fluorescence. AB - Three deep-blue emitters PPi-Pid, PPi-Xid, and PPi-Mid based on a novel conjugated system phenantroimidazole-pi-indolizine have been designed and synthesized. Here, indolizine with appropriate pi-conjugation length was used as the acceptor profited from its high-photoluminescence quantum yield and good electron-withdrawing ability. Fluorescent organic light-emitting diodes (OLEDs) based on PPi-Pid, PPi-Xid, and PPi-Mid achieved deep-blue emissions with the Commission Internationale de L'Eclairage coordinates of (0.151, 0.076), (0.155, 0.052), and (0.153, 0.052); high brightness of 14350, 4377, and 4002 cd/m2; and high external quantum efficiencies (EQEs) of 6.01, 3.90, and 4.28%, respectively. Moreover, it is noticeable that all of the devices exhibited efficiencies increasing with brightness. In particular, the PPi-Pid-based device exhibited high EQE over 6% at a high brightness of 14350 cd/m2. Such high brightness along with high EQE is very rare whether in deep-blue fluorescent or thermally activated delayed fluorescent OLEDs. PMID- 29498276 TI - Kinetic Studies of Copolymerization of Cyclohexene Oxide with CO2 by a Diamino bis(phenolate) Chromium(III) Complex. AB - A diamino-bis(phenolate) chromium(III) complex, CrCl(THF)[L], 1, where [L] = dimethylaminoethylamino- N, N-bis(2-methylene-4,6- tert-butylphenolate), has been synthesized in high yield and characterized by MALDI-TOF mass spectrometry, elemental analysis, UV-vis spectroscopy and single crystal X-ray diffraction. This complex combined with 4-dimethylaminopyridine (DMAP) or bis(triphenylphosphoranylidene)ammonium chloride or azide salts (PPNCl or PPNN3) shows improved activity over previously reported amine-bis(phenolate) chromium(III) complexes for copolymerization of cyclohexene oxide (CHO) and CO2 to yield poly(cyclohexene) carbonate (PCHC). Kinetic studies of the complex/DMAP system showed the activation energy for polycarbonate formation to be 62 kJ/mol. End group analysis of resulting polycarbonates by MALDI-TOF MS reveals either the chloride of the Cr(III) complex or the external nucleophile initiates the copolymerization reaction. PMID- 29498277 TI - Current Strategies for the Detoxification of Jatropha curcas Seed Cake: A Review. AB - Jatropha curcas is an important oilseed plant, with considerable potential in the development of biodiesel. Although Jatropha seed cake, the byproduct of oil extraction, is a residue rich in nitrogen, phosphorus, potassium, and carbon, with high protein content suitable for application in animal feed, the presence of toxic phorbol esters limits its application in feed supplements and fertilizers. This review summarizes the current methods available for detoxification of this residue, based upon chemical, physical, biological, or combined processes. The advantages and disadvantages of each process are discussed, and future directions involving genomic and proteomic approaches for advancing our understanding of biodegradation processes involving microorganisms are highlighted. PMID- 29498278 TI - Bioactivity-Based Molecular Networking for the Discovery of Drug Leads in Natural Product Bioassay-Guided Fractionation. AB - It is a common problem in natural product therapeutic lead discovery programs that despite good bioassay results in the initial extract, the active compound(s) may not be isolated during subsequent bioassay-guided purification. Herein, we present the concept of bioactive molecular networking to find candidate active molecules directly from fractionated bioactive extracts. By employing tandem mass spectrometry, it is possible to accelerate the dereplication of molecules using molecular networking prior to subsequent isolation of the compounds, and it is also possible to expose potentially bioactive molecules using bioactivity score prediction. Indeed, bioactivity score prediction can be calculated with the relative abundance of a molecule in fractions and the bioactivity level of each fraction. For that reason, we have developed a bioinformatic workflow able to map bioactivity score in molecular networks and applied it for discovery of antiviral compounds from a previously investigated extract of Euphorbia dendroides where the bioactive candidate molecules were not discovered following a classical bioassay-guided fractionation procedure. It can be expected that this approach will be implemented as a systematic strategy, not only in current and future bioactive lead discovery from natural extract collections but also for the reinvestigation of the untapped reservoir of bioactive analogues in previous bioassay-guided fractionation efforts. PMID- 29498279 TI - Transition-Metal-Free C-P Bond Formation via Decarboxylative Phosphorylation of Cinnamic Acids with P(O)H Compounds. AB - A novel, transition-metal-free phosphorylation of cinnamic acids with P(O)H compounds has been developed via radical-promoted decarboxylation under mild conditions. This method provides simple, efficient, and versatile access to valuable ( E)-alkenylphosphine oxides in satisfactory yields with a wide variety of substrates. PMID- 29498280 TI - Bioinspired Total Synthesis of Bussealin E. AB - The first total synthesis of bussealin E, a natural product with a unique cycloheptadibenzofuran scaffold, is reported. A strategy inspired by a proposed biosynthesis was employed whereby a diphenylpropane derivative underwent an oxidative phenolic coupling to forge the tetracyclic ring system. The synthesis of the diphenylpropane featured a key sp2-sp3 Hiyama coupling between a vinyldisiloxane and a benzylic bromide. PMID- 29498281 TI - 10-Mesityl-1,8-diphenylanthracene Dimer: Synthesis, Structure, and Properties. AB - Macrocyclic 10-mesityl-1,8-diphenylanthracene dimer 4 was synthesized by using the electron-transfer oxidation of Lipshutz cuprate derived from 1,8-bis(4 bromophenyl)-10-mesityl-anthracene 7 in moderate yield. This dimer 4 is a considerably fluorescent molecule (PhiF 0.40) with high thermal, photo, and air stability. The X-ray analysis of 4 revealed a unique structure with a small inner cavity which can incorporate a small molecule or atom. 1H NMR spectra in solution and emission spectra of 4 in the solid state showed that copper(I) ion was incorporated to form a 1:1 complex 4.CuOTf, whereas silver(I) ion only weakly interacted with 4 under similar conditions. PMID- 29498282 TI - SeCl2-Mediated Approach Toward Indole-Containing Polysubstituted Selenophenes. AB - A novel and efficient SeCl2-mediated chalcogenative cyclization strategy toward 3 selenophen-3-yl-1 H-indoles from readily available and conveniently substituted propargyl indoles is described. It entails an unprecedented selenirenium-induced 1,2-indolyl shift prompted by the electrophilic addition of SeCl2 to the triple bond of the propargyl indole, followed by cyclization through the intermediacy of a 1-seleno-1,3-diene. The reaction takes place at room temperature and shows excellent selectivity, broad substrate scope, and wide functional group tolerance. PMID- 29498283 TI - Indium(III) Triflate-Catalyzed Reactions of Aza-Michael Adducts of Chalcones with Aromatic Amines: Retro-Michael Addition versus Quinoline Formation. AB - The indium(III) triflate-catalyzed reaction of aza-Michael adducts of chalcones with aromatic amines has been investigated. The Michael adducts derived from substituted anilines and chalcones underwent retro-Michael addition to give the original starting materials, whereas the adducts derived from 1-naphthylamines and chalcones afforded quinolines. A six-membered cyclic transition state has been proposed to explain the retro-Michael addition, while a Povarov mechanism has been put forward to explain the quinoline formation. PMID- 29498284 TI - Radical "On Water" Addition to the C?N Bond of Hydrazones: A Synthesis of Isoindolinone Derivatives. AB - A radical "on water" addition to the C?N bond of hydrazones has been described. Hydrazone, diphenylsilane, alkyl iodide, and triethylborane afforded the corresponding addition products "on water" in good yields. A significant solvent effect was observed from the water. The developed protocol can be applied to the synthesis of 3-substituted isoindolinone derivatives. Moreover, the process offers environmentally benign tin-free radical reaction conditions. PMID- 29498285 TI - Synthesis of Triazolodiazepinium Salts: Sequential [3++2] Cycloaddition/Rearrangement Reaction of 1-Aza-2-azoniaallenium Cation Intermediates Generated from Piperidin-4-ones. AB - The bicyclic 1-aza-2-azoniaallenium salt intermediates, generated from the azoester species upon treatment with a Lewis acid, have been demonstrated to participate in Huisgen-type cycloaddition with nitriles to result in the formation of fused 6,7,8,9-tetrahydro-5 H-[1,2,4]triazolo[1,5- d][1,4]diazepinium salts. This transformation is interpreted as a regular [3++2] cycloaddition between intermediates as the reactive 1,3-monopole reactants and nitriles as the nucleophilic reagents followed by spontaneous [1,2]-cationic rearrangement. The azoester precursors were easily accessible via oxidation of the corresponding hydrazones using hypervalent iodine oxidant PhI(OAc)2 under mild conditions. The [1,2,4]triazolodiazepine compounds represent a class of N-containing biologically important heterocycles with a new type of scaffold. PMID- 29498286 TI - A General Synthetic Route to Polycyclic Aromatic Dicarboximides by Palladium Catalyzed Annulation Reaction. AB - Here we report a general method for the synthesis of polycyclic aromatic dicarboximides (PADIs) by palladium-catalyzed annulation of naphthalene dicarboximide to different types of aromatic substrates. Reaction conditions were optimized by systematic variation of ligand, solvent, and additive. It was shown that solvent has a decisive effect on the yield of the reaction products, and thus 1-chloronaphthalene as solvent afforded the highest yield. By applying the optimized reaction conditions, a broad series of planar carbo- and heterocycle containing PADIs were synthesized in up to 97% yield. Moreover, this approach could be applied to curved aromatic scaffold to achieve the respective bowl shaped PADI. Two-fold annulation was accomplished by employing arene diboronic esters, affording polycyclic aromatic bis(dicarboximides). The optical and electrochemical properties of this broad series of PADIs were explored as well. PMID- 29498288 TI - Selectivity in Hydrogenation Catalysis with Unsaturated Aldehydes: Parallel versus Sequential Steps. AB - A high-flux molecular beam setup has been used to characterize the kinetics of the steady-state catalytic hydrogenation of unsaturated aldehydes, specifically of crotonaldehyde, promoted by platinum surfaces under single-collision conditions. Surprisingly, in addition to the hydrogenation of the individual single bonds, to yield the saturated aldehyde and the unsaturated alcohol, the formation of the saturated alcohol, the product of the hydrogenation of both C?C and C?O bonds, was detected as well. This indicates that the dual hydrogenation reaction is a primary pathway and not the result of secondary hydrogenation of the other products as commonly assumed. Moreover, an increase in the partial pressure of the reactant was found to shift the reaction selectivity from the saturated alcohol to the saturated aldehyde without significantly affecting the selectivity toward the production of the unsaturated alcohol. We explain these observations by proposing a mechanism involving the parallel formation of several monohydrogenated intermediates on the surface. PMID- 29498287 TI - Position Accuracy of Gold Nanoparticles on DNA Origami Structures Studied with Small-Angle X-ray Scattering. AB - DNA origami objects allow for accurate positioning of guest molecules in three dimensions. Validation and understanding of design strategies for particle attachment as well as analysis of specific particle arrangements are desirable. Small-angle X-ray scattering (SAXS) is suited to probe distances of nano-objects with subnanometer resolution at physiologically relevant conditions including pH and salt and at varying temperatures. Here, we show that the pair density distribution function (PDDF) obtained from an indirect Fourier transform of SAXS intensities in a model-free way allows to investigate prototypical DNA origami mediated gold nanoparticle (AuNP) assemblies. We analyze the structure of three AuNP-dimers on a DNA origami block, an AuNP trimer constituted by those dimers, and a helical arrangement of nine AuNPs on a DNA origami cylinder. For the dimers, we compare the model-free PDDF and explicit modeling of the SAXS intensity data by superposition of scattering intensities of the scattering objects. The PDDF of the trimer is verified to be a superposition of its dimeric contributions, that is, here AuNP-DNA origami assemblies were used as test boards underlining the validity of the PDDF analysis beyond pairs of AuNPs. We obtain information about AuNP distances with an uncertainty margin of 1.2 nm. This readout accuracy in turn can be used for high precision placement of AuNP by careful design of the AuNP attachment sites on the DNA-structure and by fine tuning of the connector types. PMID- 29498289 TI - Localization of migraine susceptibility genes in human brain by single-cell RNA sequencing. AB - BACKGROUND: Migraine is a debilitating disorder characterized by severe headaches and associated neurological symptoms. A key challenge to understanding migraine has been the cellular complexity of the human brain and the multiple cell types implicated in its pathophysiology. The present study leverages recent advances in single-cell transcriptomics to localize the specific human brain cell types in which putative migraine susceptibility genes are expressed. METHODS: The cell type specific expression of both familial and common migraine-associated genes was determined bioinformatically using data from 2,039 individual human brain cells across two published single-cell RNA sequencing datasets. Enrichment of migraine-associated genes was determined for each brain cell type. RESULTS: Analysis of single-brain cell RNA sequencing data from five major subtypes of cells in the human cortex (neurons, oligodendrocytes, astrocytes, microglia, and endothelial cells) indicates that over 40% of known migraine-associated genes are enriched in the expression profiles of a specific brain cell type. Further analysis of neuronal migraine-associated genes demonstrated that approximately 70% were significantly enriched in inhibitory neurons and 30% in excitatory neurons. CONCLUSIONS: This study takes the next step in understanding the human brain cell types in which putative migraine susceptibility genes are expressed. Both familial and common migraine may arise from dysfunction of discrete cell types within the neurovascular unit, and localization of the affected cell type(s) in an individual patient may provide insight into to their susceptibility to migraine. PMID- 29498291 TI - The prognostic strength of gas analysis measurement during maximal exercise testing. PMID- 29498290 TI - Access to health professionals by children and adolescents with mental disorders: Are we meeting their needs? AB - OBJECTIVE: To identify the percentage of 4-17 year olds with mental disorders in Australia who attended health professionals for single or repeat visits to get help for emotional and behavioural problems during a 12-month period. To identify factors associated with single and repeat visits, and the average length of time between visits. To compare the number of parent-reported visits with visits recorded in the Medicare Benefits Schedule. METHOD: The study used data from the national survey of the mental health and wellbeing of 4-17 year olds conducted in 2013-2014 ( n = 6310). Participants were randomly selected from all 4 to 17 year olds in Australia. Information about visits was available from face-to-face interviews with parents, the Medicare Benefits Schedule and self-reports from 13 to 17 year olds. Mental disorders were assessed using the Diagnostic Interview Schedule for Children Version IV completed by parents. RESULTS: Parents reported that 51.1% of 4-17 year olds with mental disorders had attended a health professional during the previous 12 months. However, 13.6% of these children had attended on only a single occasion, most commonly with a general practitioner. With the exception of occupational therapists, 2-4 visits was the most common number of repeat visits. Children with comorbid disorders and severe functional impairment and those aged 12-17 years were more likely to have repeat visits. Among those with linked Medicare Benefits Schedule data, more children were reported by parents to have attended Medicare Benefits Schedule-funded health professionals (47.9%) than were recorded in Medicare Benefits Schedule data (38.0%). CONCLUSION: The typical number of visits to health professionals by children with mental disorders during a 12-month period is relatively small. Furthermore, parent-reports may overestimate the number of visits during this time. It seems unlikely that current patterns of attendance are of sufficient duration and frequency to allow full implementation of evidence-based treatment programmes for child and adolescent mental disorders. PMID- 29498292 TI - Measuring the effects of Coulomb repulsion via signal decay in an atmospheric pressure laser ionization ion mobility spectrometer. AB - Using lasers in ion mobility spectrometry offers a lot of advantages compared to standard ionization sources. Especially, the ion yield can be drastically increased. It can, however, reach levels where the Coulomb repulsion leads to unwanted side effects. Here, we investigate how the Coulomb repulsion can be detected apart from the typical signal broadening by measuring effects created already in the reaction region and comparing them with corresponding finite element method simulations. PMID- 29498293 TI - Functional Connectivity Changes in Systemic Lupus Erythematosus: A Resting-State Study. AB - To investigate resting-state functional connectivity of lupus patients and associated subgroups according to the ACR NPSLE case definitions (ACR ad hoc). In addition, we investigated whether or not the observed alterations correlated with disease duration, the systemic lupus erythematosus (SLE)-Disease Activity Index 2000 (SLEDAI-2k), and Systemic Lupus International Collaborating Clinical/ACR organ damage index (SDI)-scores. Anatomical 3T magnetic resonance imaging (MRI) and resting-state functional MRI were performed in 61 female lupus patients (mean age = 37.0 years, range = 18.2-52.0 years) and 20 gender- and age-matched controls (mean age = 36.2 years, range = 23.3-52.2 years) in conjunction with clinical examination and laboratory testing. Whole-brain voxelwise functional connectivity analysis with permutation testing was performed to extract network components that differed in lupus patients relative to healthy controls (HCs). Lupus patients exhibited both inter- and intranetwork hypo- and hyperconnectivity involving several crucial networks. We found reduced connectivity within the default mode network (DMN), the central executive network (CEN), and in-between the DMN and CEN in lupus patients. Increased connectivity was primarily observed within and between the sensory motor network in lupus patients when compared to HCs. Comparing lupus patients with and without neuropsychiatric symptoms, hypoconnectivity was more pronounced in the group with neuropsychiatric complaints. The functional connectivity of SLE patients was both positively and negatively correlated to duration of disease. We conclude that SLE patients in general and neuropsychiatric SLE patients in particular experience altered brain connectivity. These patterns may be due both to direct neuronal damage and compensatory mechanisms through neuronal rewiring and recruitment and may partly explain neuropsychiatric symptoms in SLE patients. PMID- 29498295 TI - Challenges faced in daily life by persons with type 2 diabetes: A meta-synthesis. AB - Objectives To derive improved understanding of the implicit meanings of challenges in daily life from the perspective of persons with type 2 diabetes. Methods A meta-synthesis was conducted with an interpretive and constructivist approach. Four databases were searched for articles published between 2007 and 2011, producing 37 articles for analysis. Van Deurzen's life world theory was applied as an analytic grid. Results Challenges in daily life with type 2 diabetes could be understood as living in a tension between opposing forces, implying a struggle with inevitable paradoxes: living in the present and for the future, trusting oneself while relying on others, and being normal while feeling changed and different. Discussion This synthesis adds knowledge to previous understanding of living with type 2 diabetes, revealing the complexity of daily life when struggling with a lifelong illness. Person-centred care could be used to understand what challenges diabetes may cause in family and working life and the ambivalent feelings the illness can lead to. Future research is needed to implement and evaluate a person-centred care in practice. Since new qualitative research is continuously added to this topic, metasyntheses should be undertaken regularly. PMID- 29498294 TI - Asymmetric dimethylarginine levels and diabetes duration: Relationship with measures of subclinical atherosclerosis and cardiac function in children and adolescents with Type 1 diabetes. AB - AIMS: We aimed to evaluate asymmetric dimethylarginine levels in young patients with Type 1 diabetes mellitus according to diabetes duration and to examine the relationship between these levels and measures of atherosclerosis and myocardial function. MATERIALS AND METHODS: In total, 83 patients (8.5-22 years) with Type 1 diabetes mellitus were stratified by diabetes duration: 12-60 months (Group 1, n = 27), >60-120 months (Group 2, n = 29) and >120 months (Group 3, n = 27). Asymmetric dimethylarginine levels were assessed. Carotid intima-media thickness was measured. Myocardial function was assessed by M-mode, conventional Doppler and tissue Doppler echocardiography. RESULTS: Asymmetric dimethylarginine level was significantly higher in Group 1, while carotid intima-media thickness was significantly greater in Group 3 ( p < 0.05). Tissue Doppler echocardiography showed the ratio of peak early to peak late diastolic myocardial annular velocity decreased significantly in Groups 2 and 3 with a negative correlation with duration (r: -0.310, p = 0.004) and HBA1c levels (r = -0.391, p < 0.001). Myocardial performance index in all groups and isovolumic relaxation time in Group 3 increased significantly. Asymmetric dimethylarginine levels were negatively correlated with carotid intima-media thickness and isovolumic relaxation time ( p < 0.05). CONCLUSION: In contrast to adult diabetics, asymmetric dimethylarginine concentration decreases as diabetes duration increases in young Type 1 diabetic patients and is associated with worsening measures of cardiovascular risk and poorer diastolic function. PMID- 29498296 TI - ASP2215 in the treatment of relapsed/refractory acute myeloid leukemia with FLT3 mutation: background and design of the ADMIRAL trial. AB - Acute myeloid leukemia (AML) is a heterogeneous disease with cure rates of only 30-40% in patients <60 years old. Cytogenetic and molecular markers have improved our understanding of the different prognostic entities in AML. FLT3 mutations are present in 30-40% of AML cases, conferring a poor prognosis with reduced survival. AXL activates FLT3, impacting adversely on outcome. Both FLT3 and AXL constitute promising molecular targets. ASP2215 (gilteritinib) is a novel, dual FLT3/AXL inhibitor with promising early phase trial data (NCT02014558). A Phase III randomized multicenter clinical trial, comparing ASP2215 to salvage chemotherapy in relapsed/refractory AML with FLT3-mutations is now open to recruitment (NCT02421939). Trial design and objectives are discussed here. PMID- 29498297 TI - Initial clinical results with a fusion prototype for mammography and three dimensional ultrasound with a standard mammography system and a standard ultrasound probe. AB - BACKGROUND: Combinations *Equal contributors. of different imaging techniques in fusion devices appear to be associated with improvements in diagnostic assessment. PURPOSE: The aim of this study was to test the feasibility of using an automated standard three-dimensional (3D) ultrasound (US) device fused with standard mammography for the first time in breast cancer patients. MATERIAL AND METHODS: Digital mammograms and 3D automated US images were obtained in 23 patients with highly suspicious breast lesions. A recently developed fusion machine consisting of an ABVS 3D US transducer from an Acuson S2000 machine and a conventional Mammomat Inspiration device (both Siemens Healthcare GmbH, Erlangen, Germany) were used for the purpose. The feasibility of the examinations, imaging coverage, and patients' experience of the procedure were examined. RESULTS: In 15 out of 19 patients, the region of interest (ROI) with the tumor marked in the mammogram was visible on US. The examination was experienced positively by the patients, with no unexpected pain or injury. The examination was time-saving and well tolerated. CONCLUSION: In conclusion, we have shown initial clinical feasibility of an US/radiography fusion prototype with good localization and evaluation of the ROIs. The combined examination was well tolerated. The simultaneous evaluation with mammography and US imaging may be able to improve detection and reduce examiner-related variability. PMID- 29498298 TI - Deconstructing autism: from unitary syndrome to contributory developmental endophenotypes. AB - A recent generation of family studies has revealed that autism can be predicted from an array of neurobehavioural susceptibilities that are appreciable before the syndrome is diagnosed, and that each may be traceable to partially independent sets of genetic variation. Some of these liabilities are not necessarily specific to ASD-those that are non-specific could account for a significant share of the 'missing heritability' of autism, would (by definition) contribute to pleiotropy, and relate to so-called 'co-morbidities', which are inappropriately named if they actually contribute to (or exacerbate) the severity of autism itself. Linking genetic variants to these underlying traits rather than to a diagnosis of 'autism' may be more productive in devising personalized approaches to developmental intervention, especially if autism represents an epiphenomenon of earlier-interacting susceptibilities. In this article, the implications of conceptualizing autism as a syndrome of neurobehavioural degeneration is considered, predicated on the notion that it can arise from a critical co-aggregation of earlier-interacting neuropsychiatric liabilities, the phenotypic expression of which-importantly-can be moderated by sex. PMID- 29498299 TI - Cardiovascular outcomes trial with anacetrapib in subjects with high cardiovascular risk - are major benefits REVEALed? AB - INTRODUCTION: The actions of the cholesteryl ester transfer protein (CETP) inhibitors (torcetrapib, dalcetrapib and evacetrapib) include increasing high density lipoprotein (HDL) cholesterol, but they do not reduce cardiovascular outcomes in subjects with high cardiovascular risk. Anacetrapib also inhibits CETP, increases HDL cholesterol and lowers low-density lipoprotein (LDL) cholesterol. Areas covered: This evaluation is of the REVEAL (Randomized Evaluation of the Effects of Anacetrapib through Lipid Modification) trial, which was a cardiovascular outcomes trial with anacetrapib in subjects with high cardiovascular risk. Consideration is given as to whether increasing HDL cholesterol, lowering LDL cholesterol or other mechanisms/factors underlying the positive outcome with this CETP inhibitor. Expert opinion: After three years, the REVEAL trial with anacetrapib, demonstrated cardiovascular benefits, but not a reduction in coronary artery deaths. The reductions were not significant in years one and two. Thus, in my opinion, the benefits of anacetrapib were not major, and may not apply in 'real' world populations where adherence to medicines is lower than in REVEAL. Also, lowering LDL cholesterol and off-target mechanisms of anacetrapib may have contributed to any beneficial and/or toxic effects. Anacetrapib has a good safety profile. PMID- 29498300 TI - Arsenic induces cardiac rhythm dysfunction and acylcarnitines metabolism perturbation in rats. AB - BACKGROUND: Arsenic has been shown to cause various diseases (such as blackfoot disease, cardiovascular diseases, bladder cancer and skin cancer) in many areas of the world. However, the effects of arsenic on cardiac rhythm functions still lack investigation. METHODS: In this study, different concentrations of arsenic were orally applied to Sprague Dawley rats in order to examine the relationship between arsenic and cardiovascular rhythm (i.e. long QT) via electrocardiography measurement. In addition, QT correction formulas were used to correct the QT interval. Linear regression analysis was used to examine the correlation between the QT interval and cardiac cycle length, corrected QT and heart rate. A metabolomic approach was applied to study carnitine-derived metabolites under arsenic exposure by using an ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS) system. RESULTS: The present findings showed that exposure to arsenic causes QT and corrected (QTc) prolongation and heart rate declines. However, the linear correlation analysis showed that there is no significant correlation between cardiac cycle length and the QT interval in both the uncorrected QT and corrected QT. The expression of acylcarnitine metabolites can be used to discriminate the control and arsenic treated groups. CONCLUSIONS: This study provides information concerning the effect of arsenic at different concentrations on cardiac rhythm (such as QT, QTc, and heart rate) but not on cardiac cycle length. The metabolism of acylcarnitine metabolites can be a potential pathway for arsenic-induced cardiac rhythm dysfunction in rats. PMID- 29498301 TI - Comparing an on-site nurse practitioner with telemedicine physician support hospitalist programme with a traditional physician hospitalist programme. AB - Introduction Since 2010, more than 75 rural hospitals have closed in the USA and more than one-third are at risk of closure due to lower patient volumes, lower funding levels, decreased hospital revenue and lower physician employment pools. Telemedicine can provide new models of care delivery that maintain quality and reduce cost of healthcare in rural populations. The purpose of this project was to evaluate a cross-organizational pilot program by comparing a NP/telemedicine physician hospitalist programme with a traditional physician hospitalist model to assess effects on length of patient stay, mortality rates, readmission rate, Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) ratings of provider communication, and total hospital costs. Methods The Standard for Quality Improvement Reporting Excellence (SQUIRE) guidelines were followed. Using a one-year retrospective chart review, average length of stay, mortality rates, 30-day readmission rates and provider communication ratings were compared between hospitalists that were nurse practitioners working with physicians through telemedicine support and physicians alone. Results There was no statistically significant variance in average length of stay, mortality rates, 30-day readmission rates, or provider communication ratings on HCAHPS surveys compared to the NP or physician hospitalist. Discussion This new model of care demonstrates that telemedicine can be used to provide safe and efficient physician support from a regional hub medical centre to nurse practitioners practising as hospitalists in rural Critical Access Hospitals at up to 58% cost savings while maintaining quality of care and increasing access to community based physicians. PMID- 29498302 TI - The microbiome and MS: The influence of the microbiota on MS risk and progression Session chair summary. PMID- 29498303 TI - Design of non-invasive glucose meter using near-infrared technique. AB - Diabetics need to keep track of their blood glucose level and measure it regularly to determine their insulin dose intake and to ensure that glucose level is always within the normal range. In this article, a system that enables the measurement of blood glucose level non-invasively is designed. This article uses a near infra-red (NIR) transmittance spectroscopy, without drawing blood, puncturing the skin, or causing pain. It involves a light source and light detector circuits positioned on a certain region of the body. The attenuated received infra-red signal by the detector is a measure of the blood glucose level of that region. Data are collected from the receiving circuit and sent to a microcontroller using CoolTerm application, then exporting it to Excel Sheet, in which mean values and graphs are obtained. The performance of the circuit with and without Filtering is examined. A downward pattern was noticed, as the glucose concentration in the solution increased, the voltage output decreased, meaning that a less intensity light was detected by the receiving circuit. An improvement in the accuracy of measurements by 17% was achieved, when a notch filter is implemented to cut the voltage components corresponding to the power line noisy signals. PMID- 29498304 TI - Refractory neuromyelitis optica spectrum disorder in systemic lupus erythematosus successfully treated with rituximab. AB - We present a case of a woman with systemic lupus erythematosus (SLE) who had refractory episodes of neuromyelitis optica spectrum disorder (NMOSD) and was successfully treated with rituximab. She was positive for anti-aquaporin-4 (AQP4) antibody and had typical cranial and longitudinally extended spinal lesions but no optic nerve involvement. There is no established treatment for NMOSD/SLE overlap cases. Our experience suggests that rituximab may be effective for patients with combined SLE and anti-AQP4 antibody-positive NMOSD. PMID- 29498306 TI - Journal Honors Samantha Jaglowski, MD, As Recipient of the 2011 JCO Young Investigator Award. PMID- 29498305 TI - Ectopic osteogenesis effect of antigen-extracted xenogeneic cancellous bone graft with chitosan/rhBMP-2/bFGF sequential sustained-release nanocapsules. AB - To explore the ectopic osteogenesis effect of sequential sustained release application of recombinant human bone morphogenic protein-2 (rhBMP-2) and basic fibroblast growth factor (bFGF). Antigen-extracted xenogeneic cancellous bone coupled with growth factor-loaded chitosan nanocapsules were implanted in rats in intramuscular site in accordance with the following experimental pattern: group A: simultaneous burst release of rhBMP-2 and bFGF; group B: simultaneous sustained release of rhBMP-2 and bFGF; group C: preferential burst release of rhBMP-2, then sustained release of bFGF; group D: preferential burst release of bFGF, then sustained release of rhBMP-2; group E: sustained release of rhBMP-2 alone; group F: sustained release of bFGF alone, blank control group G: antigen extracted xenogeneic cancellous bone graft only; negative control group H: not filled with anything. Specimens were obtained after executing the animals at 2 and 4 weeks for general observation and weighing, calcium content detection, micro-CT scanning and bone parameter measurement analysis, H&E staining, ALP staining and CD34 staining. The materials weight of A-2, B-2, C-2, A-4, B-4, C-4, D-4 and E-4 were significantly higher than that of preoperative materials ( P < 0.05). The concentration of calcium of group B-4 was the highest (414.7 +/- 12.03 mg/dl). Micro-CT scanning and bone parameter measurement analysis showed that the values of bone mineral density and trabecular thickness of group A, B, D, E at 4 weeks were both higher than the ones at 2 weeks ( P < 0.05), and both the bone mineral density (367.52 +/- 11.64 mg/cc) and the trabecular thickness (126.17 +/- 11.36 MUm) of group B-4 were the highest. H&E staining showed that a large region of calcified cartilage and haemopoietic tissues were newly formed, especially in group B-4. ALP staining and CD34 staining showed the most positive expression region in group B-4. Therefore, we conclude that simultaneous sustained release of rhBMP-2 and bFGF is the ideal way to release drug, and has better inducement of antigen-extracted xenogeneic cancellous bone graft. PMID- 29498307 TI - Kruppel-like factor 4 mediates cellular migration and invasion by altering RhoA activity. AB - Kruppel like factor 4 (KLF4) is a transcription factor that regulates genes related to differentiation and proliferation. KLF4 also plays a role in metastasis via epithelial to mesenchymal transition. Here, we investigate the function of Klf4 in migration and invasion using mouse embryonic fibroblasts and the RKO human colon cancer cell line. Compared to wild-type, cells lacking Klf4 exhibited increased migration-associated phenotypes. In addition, overexpression of Klf4 in Klf4-/- MEFs attenuated the presence of stress fibers to wild-type levels. An invasion assay suggested that lack of Klf4 resulted in increased invasive capacity. Finally, analysis of RhoA showed elevated RhoA activity in both RKO and MEF cells. Taken together, our results strongly support the novel role of KLF4 in a post-translational regulatory mechanism where KLF4 indirectly modulates the actin cytoskeleton morphology via activity of RhoA in order to inhibit cellular migration and invasion. PMID- 29498308 TI - Inactivation kinetics of food-borne pathogens subjected to thermal treatments: a review. AB - Thermal processing technologies are safe and easy to control methods without leaving residues, and could be used to inactivate food-borne pathogens, ensure food quality and provide the food with sufficient stability during storage. Establishing inactivation kinetics of food-borne pathogens is essential in developing effective pasteurisation protocols without damaging food quality. This study presents a comprehensive review of recent progresses in inactivation kinetics of food-borne pathogens. It covers theoretical bases and experimental methods for developing thermal inactivation kinetics of food-borne pathogens and making comparisons and applications of the common thermal death kinetic models. Finally, it proposes possible recommendations on the future research directions of establishing inactivation kinetic models for food-borne pathogens in thermal processing. PMID- 29498310 TI - An overview of the role of sympathetic regulation of immune responses in infectious disease and autoimmunity. AB - Stress in patients and pre-clinical research animals plays a critical role in disease progression Activation of the sympathetic nervous system (SNS) by stress results in secretion of the catecholamines epinephrine (Epi) and norepinephrine (NE) from the adrenal gland and sympathetic nerve endings. Adrenergic receptors for catecholamines are present on immune cells and their activity is affected by stress and the accompanying changes in levels of these neurotransmitters. In this short review, we discuss how this adrenergic stress impacts two categories of immune responses, infections and autoimmune diseases. Catecholamines signal primarily through the beta2-adrenergic receptors present on innate and adaptive immune cells which are critical in responding to infections caused by pathogens. In general, this adrenergic input, particularly chronic stimulation, suppresses lymphocytes and allows infections to progress. On the other hand, insufficient adrenergic control of immune responses allows progression of several autoimmune diseases. PMID- 29498309 TI - Temperature-sensitive liposomal ciprofloxacin for the treatment of biofilm on infected metal implants using alternating magnetic fields. AB - Implants are commonly used as a replacement for damaged tissue. Many implants, such as pacemakers, chronic electrode implants, bone screws, and prosthetic joints, are made of or contain metal. Infections are one of the difficult to treat complications associated with metal implants due to the formation of biofilm, a thick aggregate of extracellular polymeric substances (EPS) produced by the bacteria. In this study, we treated a metal prosthesis infection model using a combination of ciprofloxacin-loaded temperature-sensitive liposomes (TSL) and alternating magnetic fields (AMF). AMF heating is used to disrupt the biofilm and release the ciprofloxacin-loaded TSL. The three main objectives of this study were to (1) investigate low- and high-temperature-sensitive liposomes (LTSLs and HTSLs) containing the antimicrobial agent ciprofloxacin for temperature-mediated antibiotic release, (2) characterise in vitro ciprofloxacin release and stability and (3) study the efficacy of combining liposomal ciprofloxacin with AMF against Pseudomonas aeruginosa biofilms grown on metal washers. The release of ciprofloxacin from LTSL and HTSL was assessed in physiological buffers. Results demonstrated a lower transition temperature for both LTSL and HTSL formulations when incubated in serum as compared with PBS, with a more pronounced impact on the HTSLs. Upon combining AMF with temperature-sensitive liposomal ciprofloxacin, a 3 log reduction in CFU of Pseudomonas aeruginosa in biofilm was observed. Our initial studies suggest that AMF exposure on metal implants can trigger release of antibiotic from temperature sensitive liposomes for a potent bactericidal effect on biofilm. PMID- 29498311 TI - Heat transfer from nanoparticles for targeted destruction of infectious organisms. AB - Whereas the application of optically or magnetically heated nanoparticles to destroy tumours is now well established, the extension of this concept to target pathogens has barely begun. Here we examine the challenge of targeting pathogens by this means and, in particular, explore the issues of power density and heat transfer. Depending on the rate of heating, either hyperthermia or thermoablation may occur. This division of the field is fundamental and implies very different sources of excitation and heat transfer for the two modes, and different strategies for their clinical application. Heating by isolated nanoparticles and by agglomerates of nanoparticles is compared: hyperthermia is much more readily achieved with agglomerates and for large target volumes, a factor which favours magnetic excitation and moderate power densities. In contrast, destruction of planktonic pathogens is best achieved by localised thermoablation and very high power density, a scenario that is best delivered by pulsed optical excitation. PMID- 29498313 TI - Introduction to the special issue on thermal therapy and infectious diseases. PMID- 29498312 TI - Thermal shock susceptibility and regrowth of Pseudomonas aeruginosa biofilms. AB - Biofilms on implanted medical devices cause thousands of patients each year to undergo multiple surgeries to remove and replace the implant, driving billions of dollars in increased health care costs due to the lack of viable treatment options for in situ biofilm eradication. Remotely activated localised heating is under investigation to mitigate these biofilms; however, little is known about the temperatures required to kill the biofilms. To better understand the required parameters this study investigated the thermal susceptibility of biofilms as a function of their fluidic and chemical environment during growth, as well as their propensity for regrowth following thermal shock. Pseudomonas aeruginosa biofilms were cultured in shaker plate fluidic conditions in four different growth media, then thermally shocked at various temperatures and exposure times. Biofilms were re-incubated to determine their regrowth potential following thermal shocks of various intensities. Results indicate that growth media has little impact on thermal susceptibility, while fluidic conditions strongly influence susceptibility to modest thermal shocks. This effect disappears, however, with increasingly aggressive shocks, reducing biofilm populations by up to 5 orders of magnitude. Regrowth studies indicate a critical post-shock bacterial loading (~103 CFU/cm2) below which the biofilms were no longer viable, while biofilms above that loading slowly regrew to their previous population density. PMID- 29498314 TI - Progress on utilizing hyperthermia for mitigating bacterial infections. AB - Recovery from systemic or local bacterial infections can be lengthy and costly, with the clinical challenges being further complicated when bacteria acquire resistance to current antibiotics. Hyperthermia offers new mechanisms for removing bacteria via ablation, or sensitising them to chemical agents. The first part of this review provides a background on the bacterial biofilms, their response to hyperthermia, and acquired resistance to antibiotics, followed by the clinical challenges they present in managing infections associated with soft tissues and biomedical implants. The second part of the review discusses the thermal modalities used to combat infections, including radiofrequency, ultrasound, high-intensity focussed ultrasound, microwave thermotherapy, and photothermal and magnetic nanoparticles (NP). The overall aim of this review is to demonstrate the tremendous potential of hyperthermia for mitigating bacterial infections and foster new research ventures to help remedy these challenging occurrences. PMID- 29498316 TI - Effect of Perceived Parent-Child Relationship in Childhood on Resilience in Japanese Youth. AB - The present study examined the effect of the perceived parent-child relationship in childhood on resilience in youth. It recruited 268 university students majoring in education and college students majoring in welfare science to investigate the relationship between their perception of parent-child relationship in their childhood and their current resilience by their responses on the Adolescent Resilience Scale and the Children's Perceived Affiliation for Parents Scale. The results indicated that female's positive perception of their relationship with their mothers in childhood had a positive influence on their resilience. On the other hand, the positive influence was inconspicuous and limited with regard to the perception of female's relationship with their fathers in childhood. In contrast, this positive influence was not confirmed in male participants regardless of the perception of their relationship with mothers and fathers in childhood. Although limited to females, these results suggest that youth's perception of their parent-child relationships in childhood significantly affected the development of resilience. In addition, sex difference was observed in this effect. The findings have been discussed with respect to the process of the development of resilience. PMID- 29498315 TI - Lower leg and foot contributions to turnout in female pre-professional dancers: A 3D kinematic analysis. AB - Turnout is a central element of classical ballet which involves sustained external rotation of the lower limbs during dance movements. Lower leg and foot compensation mechanisms which are often used to increase turnout have been attributed to the high incidence of lower limb injury in dancers. Evaluation of dancers' leg posture is needed to provide insight into the lower limb kinematic strategies used to achieve turnout. The primary purpose of this study was to use 3D kinematic analyses to determine the lower leg and foot compensations that are incorporated by female university dancers to accentuate their turnout. Active and passive external tibiofemoral rotation (TFR) was also measured. A moderate-strong negative relationship was observed between hip external rotation (HER) and foot abduction in the three first position conditions. A moderate negative relationship was found between passive TFR and foot abduction in all first position conditions. Our findings suggest dancers are more likely to pronate, than rotate the knee to compensate for limited HER. Dancers with a limited capacity to pronate may force additional rotation via the knee. Ongoing research would benefit from more in-depth analyses of the foot/ankle complex using a multi segment foot model. PMID- 29498317 TI - Management of the Tinnitus Patient. PMID- 29498318 TI - International Multidisciplinary Symposium. PMID- 29498319 TI - Anatomy and Histopathology of the Head and Neck and Temporal Bone. PMID- 29498320 TI - Spanish Society of Otorhinolaryngology Head and Neck Surgery. PMID- 29498321 TI - Controversies and Advances in Head and Neck Surgery. PMID- 29498322 TI - Navigating manuscript assessment: The new practitioner's guide to primary literature peer review. AB - For pharmacists, the first years after graduation are spent developing their knowledge base, advancing as a practitioner, and honing their abilities as healthcare providers and drug information experts. New practitioners encounter many challenges during this time, which for many include publishing original research or reviewing manuscripts for colleagues and medical journals. Inexperience navigating the publication process, from submission to receipt of (and response to) peer review commentary, is often cited as a major barrier to timely publication of resident and new practitioner research. Serving as a peer reviewer in turn provides the new practitioner with insight on this process and can be an enlightening experience used to garner confidence in subsequently submitting their own formal manuscripts. A number of publications describing steps for peer review are available, however, many of these articles address more experienced reviewers or critique the peer review process itself. No definitive resource exists for new pharmacy practitioners interested in developing their peer review skills. The information presented in this summative guide should be used in conjunction with practice opportunities to help new practitioners develop proficiency at peer review. PMID- 29498323 TI - Cystic acne due to imatinib therapy for chronic myelocytic leukemia. AB - Imatinib mesylate is a tyrosine kinase inhibitor used in the treatment of several malignancies. Its use, however, is associated with a number of toxic effects including adverse cutaneous reactions. Herein, we present a case of facial cystic acne in a patient receiving imatinib therapy for chronic myelocytic leukemia. This side effect resolved with cessation of therapy. To the best of our knowledge, this clinical entity has never been previously reported in the medical literature. PMID- 29498324 TI - Everyday memory measures in multiple sclerosis: a systematic review. AB - Everyday memory is one of the most affected cognitive functions in multiple sclerosis (MS). Assessing everyday memory problems is crucial for monitoring the impact of memory deficits on individuals' day-to-day lives and evaluating the effectiveness of interventions that aim to improve cognitive functions. The aim of this systematic review was to identify the research literature on everyday memory measures used with people with MS, describe the types of measures used, and summarise their psychometric properties. Empirical studies of cognitive function in MS using standardised everyday memory measures were included. Online databases (MEDLINE, PsycINFO, PsycARTICLES, Embase) and Google Scholar were searched. Forty-four studies met the inclusion criteria. A total of 12 measures were identified, with varied uses and administration methods. The majority of papers did not report any psychometric properties for MS populations. The few papers that did, reported that the measures have good reliability and appear to have good face, concurrent, and ecological validity, but these need to be evaluated further. This review presents researchers and clinicians with an overview of the various everyday memory measures used in studies with people with MS, to help them choose the appropriate measure for their evaluations. PMID- 29498325 TI - Aerococcus urinae: an underestimated cause of spine infection? Case report and review of the literature. AB - OBJECTIVE AND IMPORTANCE: New methods of microbiology identification as MALDI-TOF MS increased the rate of Aerococci detection in microbiological samples making this germ an emerging pathogen. The purpose of this case report and literature review is to highlight the role of A. urinae in spine infection and discuss the management of this type of infection. CLINICAL PRESENTATION AND INTERVENTION: A 32-year-old man, with a medical history of paraplegia secondary to a relapsing form of multiple sclerosis, was admitted because of lower back-pain following complaints suggestive of urinary tract infection. Spondilodiscitis was diagnosed and Aerococcus urinae was identified from bone culture. The patient improved after surgery and appropriate antibiotherapy. CONCLUSION: A. urinae is currently more frequently identified since the introduction of MALDI-TOF MS in routine laboratories. Serious infections as endocarditis, bacteremia and spondylodiscitis have been reported usually in patients with predisposing conditions. This pathogen can be successfully treated with beta-lactam antibiotics which can be replaced by vancomycin in case of penicillin allergy. PMID- 29498326 TI - Basic visual perceptual processes in children with typical development and cerebral palsy: The processing of surface, length, orientation, and position. AB - The present study aims to assess how the processing of basic visual perceptual (VP) components (length, surface, orientation, and position) develops in typically developing (TD) children (n = 215, 4-14 years old) and adults (n = 20, 20-25 years old), and in children with cerebral palsy (CP) (n = 86, 5-14 years old) using the first four subtests of the Battery for the Evaluation of Visual Perceptual and Spatial processing in children. Experiment 1 showed that these four basic VP processes follow distinct developmental trajectories in typical development. Experiment 2 revealed that children with CP present global and persistent deficits for the processing of basic VP components when compared with TD children matched on chronological age and nonverbal reasoning abilities. PMID- 29498328 TI - [Editorial]. PMID- 29498327 TI - Endovascular management of inferior vena cava filter thrombotic occlusion. AB - Objective Inferior vena cava occlusion is a potentially life-threatening complication related to caval filters. We present our experience with filter induced inferior vena cava occlusion in order to assess the feasibility, safety, and effectiveness of endovascular management. Methods A retrospective review of all patients undergoing inferior vena cava filter placement over a 60-month study period was performed. From this cohort, a total of 10 cases of inferior vena cava occlusion after filter placement were identified. Demographics, clinical data, procedures, and outcomes were extracted. Patients were followed to the last clinic visit or until they died. Results One-hundred eighty filters were placed by our group practice during the study period. Of those, a total of 10 patients were identified. Overall, there were 7 males; the mean age was 57.1 years (25-78 years). The median time between inferior vena cava filter placement and filter occlusion was 105 days (range 5-4745 days). All patients were clinically symptomatic at the time of their presentation. Nine out of 10 patients were successfully managed endovascularly. TrellisTM-8 thrombectomy was the most common endovascular strategy performed ( n = 9). Four patients had balloon angioplasty, two of those with stent placement for chronically occluded inferior vena cava/iliac veins. No thromboembolic complications developed during a median follow-up period of 233 days (range 4-1083 days). Conclusions Endovascular management of inferior vena cava occlusion is feasible, safe, and effective in decreasing thrombus burden in the presence of an inferior vena cava filter. Further studies evaluating long-term inferior vena cava patency and optimal surveillance regimen after endovascular management of filter-related inferior vena cava occlusion are warranted. PMID- 29498329 TI - [Contents]. PMID- 29498330 TI - On Mechanisms of Change in Psychodynamic Therapy. AB - BACKGROUND: There is a growing body of evidence for the efficacy of psychodynamic therapy. Some representatives of other approaches, however, have repeatedly questioned its efficacy. Recently, another line of argumentation emerged, claiming that psychodynamic therapy may work, but that the mechanisms of change underlying its effects were not clear or even could not be tested empirically at all. OBJECTIVE: The present article critically reviews these allegations. RESULTS: The allegations put forward were shown to be mostly untenable. Mechanisms of change of psychodynamic therapy are testable and have been tested empirically. CONCLUSIONS: There is evidence for both the efficacy of psychodynamic therapy and for the assumed mechanisms of change. The repeatedly presented critique by representatives of other approaches seems to be motivated more by political than by scientific reasons. However, further research on both the outcome and process of psychodynamic therapy is required. PMID- 29498332 TI - [Congress dates]. PMID- 29498333 TI - ? PMID- 29498331 TI - Differential Diagnoses of Food-Related Gastrointestinal Symptoms in Patients with Anorexia Nervosa and Bulimia Nervosa: A Review of Literature. AB - OBJECTIVES: The present review investigates the prevalence and medical causes of food-related gastrointestinal symptoms in eating disorder (ED) patients and recommends a diagnostic algorithm based on the current literature. METHODS: A literature search was conducted, which included publications from January 2000 until January 2017 Results: Over 90% of ED patients suffer from food-related symptoms. There is no evidence for a higher prevalence of immunological or structural gastrointestinal disorders in ED patients compared to the healthy population. Most food-related symptoms in ED patients are likely to be functional. CONCLUSIONS: Diagnostic work-up of food-related symptoms in ED patients needs to be based on clinical history. Only if timing and quality of symptoms point towards a disorder independent from the ED is a comprehensive diagnostic work-up necessary. PMID- 29498335 TI - [The authors in this issue]. PMID- 29498334 TI - [News]. PMID- 29498336 TI - ? PMID- 29498337 TI - [Emotional experience of early traumatic experiences and relationship-specific attachment styles in alcohol-dependent patients]. AB - : Emotional experience of early traumatic experiences and relationship-specific attachment styles in alcohol-dependent patients Objectives: The present investigation studied the differences in emotional experiences among alcohol dependent patients in inpatient psychotherapy, taking into account their traumatic experiences and relationship-specific attachment styles. METHODS: Three standardized instruments were used on this clinical sample of 70 patients in inpatient psychotherapy: (1) Scales for Experiencing Emotions (SEE), (2) Childhood Trauma Questionnaire (CTQ), (3) Relationship-Specific Attachment Scales for Adults (RASA). RESULTS: The results showed that traumatic experiences in childhood and adolescence as well as relationship-specific attachment styles were indeed associated with deficits in emotional experience and regulation. Especially emotional abuse was associated with deficits in emotional experience. An insecure attachment style was associated with a lower level of acceptance of emotions, a lower level of self-control, and dysfunctional emotion regulation. In particular, the attachment style to the mother seems to be important. DISCUSSION: These results suggest that a distinction of alcohol-addicted patients, with respect to attachment styles and traumatic experiences in childhood and adolescent, seems to be important in order to define specific interventions to improve the ability to regulate emotions. PMID- 29498338 TI - Surface Disinfection: Treatment Time (Wipes and Sprays) Versus Contact Time (Liquids). PMID- 29498339 TI - Frequency and Nature of Infectious Risk Moments During Acute Care Based on the INFORM Structured Classification Taxonomy. AB - OBJECTIVE In this study, we sought to establish a comprehensive inventory of infectious risk moments (IRMs), defined as seemingly innocuous yet frequently occurring care manipulations potentially resulting in transfer of pathogens to patients. We also aimed to develop and employ an observational taxonomy to quantify the frequency and nature of IRMs in acute-care settings. DESIGN Prospective observational study and establishment of observational taxonomy. SETTING Intensive care unit, general medical ward, and emergency ward of a university-affiliated hospital. PARTICIPANTS Healthcare workers (HCWs) METHODS Exploratory observations were conducted to identify IRMs, which were coded based on the surfaces involved in the transmission pathway to establish a structured taxonomy. Structured observations were performed using this taxonomy to quantify IRMs in all 3 settings. RESULTS Following 129.17 hours of exploratory observations, identified IRMs involved HCW hands, gloves, care devices, mobile objects, and HCW clothing and accessories. A structured taxonomy called INFORM (INFectiOus Risk Moment) was established to classify each IRM according to the source, vector, and endpoint of potential pathogen transfer. We observed 1,138 IRMs during 53.77 hours of structured observations (31.25 active care hours) for an average foundation of 42.8 IRMs per active care hour overall, and average densities of 34.9, 36.8, and 56.3 IRMs in the intensive care, medical, and emergency wards, respectively. CONCLUSIONS Hands and gloves remain among the most important contributors to the transfer of pathogens within the healthcare setting, but medical devices, mobile objects, invasive devices, and HCW clothing and accessories may also contribute to patient colonization and/or infection. The INFORM observational taxonomy and IRM inventory presented may benefit clinical risk assessment, training and education, and future research. Infect Control Hosp Epidemiol 2018;39:272-279. PMID- 29498340 TI - Likelihood of Infectious Outcomes Following Infectious Risk Moments During Patient Care-An International Expert Consensus Study and Quantitative Risk Index. AB - OBJECTIVE To elicit expert consensus on the likelihood of infectious outcomes (patient colonization or infection) following a broad range of infectious risk moments (IRMs) from observations in acute care. DESIGN Expert consensus study using modified Delphi technique. PARTICIPANTS Panel of 40 international experts including nurses, physicians and microbiologists specialized in infectious diseases and infection prevention and control (IPC). METHODS The modified Delphi process consisted of 3 online survey rounds, with feedback of mean ratings and expert comments between rounds. The Delphi survey comprised 52 care scenarios representing observed IRMs organized into 6 sections: hands, gloves, medical devices, mobile objects, invasive procedures, and additional moments. For each scenario, experts indicated the likelihood of both patient colonization and infection on a scale from 0 to 5 (high). Expert ratings were plotted against frequencies of IRMs observed during actual patient care resulting in a risk index. RESULTS Following 3 rounds, consensus was achieved for 92 of 104 items (88.5%). The mean ratings across all scenarios for likelihood of colonization and infection were 2.68 and 2.02, respectively. The likelihood of colonization was rated higher than infection for 48 of 52 scenarios. Ratings were significantly higher for colonization (P=.001) and infection (P<.0005) when the scenario involved transfer of pathogens to critical patient sites. CONCLUSIONS The design of effective IPC strategies requires the selection of behaviors according to their impact on patient outcomes. The IRM index reported here provides a basis for standardizing and prioritizing targets for quality improvement initiatives, training, and future research in acute health care. Infect Control Hosp Epidemiol 2018;39:280-289. PMID- 29498341 TI - Dairy product consumption is associated with pre-diabetes and newly diagnosed type 2 diabetes in the Lifelines Cohort Study. AB - Previous studies show associations between dairy product consumption and type 2 diabetes, but only a few studies conducted detailed analyses for a variety of dairy subgroups. Therefore, we examined cross-sectional associations of a broad variety of dairy subgroups with pre-diabetes and newly diagnosed type 2 diabetes (ND-T2DM) among Dutch adults. In total, 112 086 adults without diabetes completed a semi-quantitative FFQ and donated blood. Pre-diabetes was defined as fasting plasma glucose (FPG) between 5.6 and 6.9 mmol/l or HbA1c% of 5.7-6.4 %. ND-T2DM was defined as FPG >=7.0 mmol/l or HbA1c >=6.5 %. Logistic regression analyses were conducted by 100 g or serving increase and dairy tertiles (T1ref), while adjusting for demographic, lifestyle and dietary covariates. Median dairy product intake was 324 (interquartile range 227) g/d; 25 549 (23 %) participants had pre diabetes; and 1305 (1 %) had ND-T2DM. After full adjustment, inverse associations were observed of skimmed dairy (OR100 g 0.98; 95 % CI 0.97, 1.00), fermented dairy (OR100 g 0.98; 95 % CI 0.97, 0.99) and buttermilk (OR150 g 0.97; 95 % CI 0.94, 1.00) with pre-diabetes. Positive associations were observed for full-fat dairy (OR100 g 1.003; 95 % CI 1.01, 1.06), non-fermented dairy products (OR100 g 1.01; 95 % CI 1.00, 1.02) and custard (ORserving/150 g 1.13; 95 % CI 1.03, 1.24) with pre-diabetes. Moreover, full-fat dairy products (ORT3 1.16; 95 % CI 0.99, 1.35), non-fermented dairy products (OR100 g 1.05; 95 % CI 1.01, 1.09) and milk (ORserving/150 g 1.08; 95 % CI 1.02, 1.15) were positively associated with ND T2DM. In conclusion, our data showed inverse associations of skimmed and fermented dairy products with pre-diabetes. Positive associations were observed for full-fat and non-fermented dairy products with pre-diabetes and ND-T2DM. PMID- 29498342 TI - Effects of synbiotic supplementation on metabolic parameters and apelin in women with polycystic ovary syndrome: a randomised double-blind placebo-controlled trial. AB - Polycystic ovary syndrome (PCOS) is one of the most common causes of infertility in women of reproductive age. Insulin resistance is a main pathophysiologic feature in these patients. According to some studies, the intake of probiotic bacteria may improve glucose homoeostasis. The aim of this study was to investigate the effect of synbiotics on metabolic parameters and apelin in PCOS patients. This randomised double-blind placebo-controlled trial was conducted on eighty-eight PCOS women aged 19-37 years old. The participants were randomly assigned to two groups receiving (1) synbiotic supplement (n 44), and (2) placebo (n 44) for 12 weeks. Fasting blood samples were taken at baseline and after 12 weeks. The two groups showed no difference in fasting blood sugar (adjusted mean difference: 0.60; 95 % CI -3.80, 5.00, P=0.727), plasma glucose fasting 2-h (adjusted mean difference 2.09; 95 % CI -9.96, 14.15, P=0.134), HbA1c (adjusted mean difference 0.06; 95 % CI -0.09, 0.22, P=0.959), homoeostatic model assessment-insulin resistance (HOMA-IR) (adjusted mean difference: 0.02; 95 % CI 0.99, 1.03, P=0.837), quantitative insulin sensitivity check index (QUICKI) (adjusted mean difference: -0.02; 95 % CI -0.33, 0.29, P=0.940) and C-reactive protein (CRP) (adjusted mean difference: 0.24; 95 % CI -1.61, 2.08, P=0.141) by the end of the intervention. A significant difference was observed in the mean apelin 36 before and after the intervention between synbiotic and placebo groups (adjusted mean difference: -4.05; 95 % CI -7.15, -0.96, P=0.004). A 12-week synbiotic supplementation has no significant beneficial effects on HOMA-IR and CRP in PCOS patients, whereas the level of apelin 36 significantly decreased. PMID- 29498343 TI - Serum 25-hydroxyvitamin D, calcium and parathyroid hormone levels in Native and European populations in Greenland. AB - Ca homoeostasis is important to human health and tightly controlled by powerful hormonal mechanisms that display ethnic variation. Ethnic variations could occur also in Arctic populations where the traditional Inuit diet is low in Ca and sun exposure is limited. We aimed to assess factors important to parathyroid hormone (PTH) and Ca in serum in Arctic populations. We included Inuit and Caucasians aged 50-69 years living in the capital city in West or in rural East Greenland. Lifestyle factors were assessed by questionnaires. The intake of Inuit diet was assessed from a FFQ. 25-Hydroxyvitamin D (25OHD2 and 25OHD3) levels were measured in serum as was albumin, Ca and PTH. The participation rate was 95 %, with 101 Caucasians and 434 Inuit. Median serum 25OHD (99.7 % was 25OHD3) in Caucasians/Inuit was 42/64 nmol/l (25, 75 percentiles 25, 54/51, 81) (P<0.001). Total Ca in serum was 2.33/2.29 mmol/l (25, 75 percentiles 2.26, 2.38/2.21, 2.36) (P=0.01) and PTH was 2.7/2.2 pmol/l (25, 75 percentiles 2.2, 4.1/1.7, 2.7) (P<0.001). The 69/97 Caucasians/Inuit with serum 25OHD <50 nmol/l differed in PTH (P=0.001) that rose with lower 25OHD levels in Caucasians, whereas this was not the case in Inuit. Ethnic origin influenced PTH (beta=0.27, P<0.001) and Ca (beta=0.22, P<0.001) in multivariate linear regression models after adjustment for age, sex, BMI, smoking, alcohol and diet. In conclusion, ethnic origin influenced PTH, PTH response to low vitamin D levels and Ca levels in populations in Greenland. Recommendations are to evaluate mechanisms underlying the ethnic influence on Ca homoeostasis and to assess the impact of transition in dietary habits on Ca homoeostasis and skeletal health in Arctic populations. PMID- 29498344 TI - Environmental enteric dysfunction and systemic inflammation predict reduced weight but not length gain in rural Bangladeshi children. AB - Environmental enteric dysfunction (EED) and systemic inflammation (SI) are common in developing countries and may cause stunting. In Bangladesh, >40 % of preschool children are stunted, but EED and SI contributions are unknown. We aimed to determine the impact of EED and SI (assessed with multiple indicators) on growth in children (n 539) enrolled in a community-based randomised food supplementation trial in rural Bangladesh. EED was defined with faecal myeloperoxidase, alpha-1 antitrypsin and neopterin and serum endotoxin core antibody and glucagon-like peptide-2, consolidated into gut inflammation (GI) and permeability (GP) scores, and urinary lactulose:mannitol alpha-1 acid glycoprotein (AGP) characterised SI. Biomarker associations with anthropometry (15-, 18- and 24-month length-for-age (LAZ), weight-for-length (WLZ) and weight-for-age (WAZ) z scores) were examined in pairwise correlations and adjusted mixed-effects regressions. Stunting, wasting and underweight prevalence at 18 months were 45, 15 and 37 %, respectively, with elevated EED and SI markers common. EED and SI were not associated with 15-24-month length trajectory. Elevated (worse) GI and GP scores predicted reduced 18-24-month WLZ change (beta -0.01 (se 0.00) z score/month for both). Elevated GP was also associated with reduced 15-18-month WLZ change (beta 0.03 (se 0.01) z score/month) and greater 15-month WLZ (beta 0.16 (se 0.05)). Higher AGP was associated with reduced prior and increased subsequent WLZ change (beta -0.04 (se 0.01) and beta 0.02 (se 0.00) z score/month for 15-18 and 18-24 months). The hypothesised link from EED to stunting was not observed in this sample of Bangladeshi 18-month-olds, but the effects of EED on constrained weight gain may have consequences for later linear growth or for other health and development outcomes. PMID- 29498345 TI - 20-Week follow-up of hepatic steatosis installation and liver mitochondrial structure and activity and their interrelation in rats fed a high-fat-high fructose diet. AB - The incidence of obesity and its metabolic complications are rapidly increasing and become a major public health issue. This trend is associated with an increase in the prevalence of non-alcoholic fatty liver disease (NAFLD), insulin resistance and diabetes. The sequence of events leading to NAFLD progression and mitochondrial dysfunction and their interrelation remains to be elucidated. This study aimed to explore the installation and progression of NAFLD and its association with the liver mitochondrial structure and activity changes in rats fed an obesogenic diet up to 20 weeks. Male Wistar rats were fed either a standard or high-fat-high-fructose (HFHFR) diet and killed on 4, 8, 12, 16 and 20 weeks of diet intake. Rats fed the HFHFR diet developed mildly overweight, associated with increased adipose tissue weight, hepatic steatosis, hyperglycaemia and hyperinsulinaemia after 8 weeks of HFHFR diet. Hepatic steatosis and many biochemical modifications plateaued at 8-12 weeks of HFHFR diet with slight amelioration afterwards. Interestingly, several biochemical and physiological parameters of mitochondrial function, as well as its phospholipid composition, in particular cardiolipin content, were tightly related to hepatic steatosis installation. These results showed once again the interrelation between hepatic steatosis development and mitochondrial activity alterations without being able to say whether the mitochondrial alterations preceded or followed the installation/progression of hepatic steatosis. Because both hepatic steatosis and mitochondrial alterations occurred as early as 4 weeks of diet, future studies should consider these four 1st weeks to reveal the exact interconnection between these major consequences of obesogenic diet intake. PMID- 29498346 TI - Mother-child dietary behaviours and their observed associations with socio demographic factors: findings from the Healthy Beginnings Trial. AB - Few studies have investigated the effect of maternal factors on child eating practices. Our study aimed to explore mother-child dietary behaviours and their associations with socio-demographic factors. A cross-sectional analysis was conducted using data from control participants (n 243) in the Healthy Beginnings Trial, which involved first-time mothers and their 2-year-old children. Mother child dietary behaviours were assessed using short dietary questions (short FFQ) and their associations with socio-demographic factors were examined using binary logistic regression. The dietary intake of 2-year-old children was characterised by low vegetable consumption and high discretionary food intake. In multivariate analysis, lower-income mothers (0.5 cups/d) AOR 2.93 (95 % CI 1.03, 8.35), compared with older mothers (>=25 years). Non-Australian-born mothers reported their child consumed more fruit juice (>0.5 cups/d) AOR 2.04 (95 % CI 1.02, 4.05), sweet snacks AOR 1.96 (95 % CI 1.02, 3.76) and fast food (>=2 times/week) AOR 3.67 (95 % CI 1.29, 10.43) compared with Australian-born mothers. Significant positive correlations between maternal and child dietary intake were observed for all dietary variables except milk, with the largest association for fast foods (Pearson's r 0.52, P<0.001). This study shows that maternal factors are associated with child dietary behaviours. Targeting young mothers (<25 years) of potential disadvantage, before commencement of early feeding practices, has the potential to improve children's diets. PMID- 29498347 TI - The effect of short-term coenzyme Q10 supplementation and pre-cooling strategy on cardiac damage markers in elite swimmers. AB - Strenuous physical exercise and hyperthermia may paradoxically induce oxidative stress and adverse effects on myocardial function. The purpose of this study was to investigate the effect of 14-d coenzyme Q10 (CoQ10) supplementation and pre cooling on serum creatine kinase-MB (CK-MB), cardiac Troponin I (cTnI), myoglobin (Mb), lactate dehydrogenase (LD), total antioxidant capacity (TAC), lipid peroxidation (LPO) and CoQ10 concentration in elite swimmers. In total, thirty six healthy males (mean age 17 (sd 1) years) were randomly selected and divided into four groups of supplementation, supplementation with pre-cooling, pre cooling and control. During an eighteen-session protocol in the morning and evening, subjects attended speed and endurance swimming training sessions for 5 km in each session. Blood sampling was done before (two stages) and after (two stages) administration of CoQ10 and pre-cooling. ANCOVA and repeated measurement tests with Bonferroni post hoc test were used for the statistical analysis of the data. There was no significant statistical difference among groups for the levels of CK-MB, cTnI, Mb, LD, TAC, LPO and CoQ10 at the presampling (stages 1 and 2) (P>0.05). However, pre-cooling and control groups show a significant increase in the levels of CK-MB, cTnI, Mb, LD and LPO compared with the supplementation and supplementation with pre-cooling groups in the post-sampling (stages 1 and 2) (P<0.05), except for the TAC and CoQ10. Consequently, CoQ10 supplementation prevents adverse changes of myocardial damage and oxidative stress during swimming competition phase. Meanwhile, the pre-cooling strategy individually has no desired effect on the levels of CK-MB, cTnI, Mb, LD, LPO, TAC and CoQ10. PMID- 29498348 TI - 4-Week consumption of anthocyanin-rich blood orange juice does not affect LDL cholesterol or other biomarkers of CVD risk and glycaemia compared with standard orange juice: a randomised controlled trial. AB - Elevated circulating cholesterol levels are a risk factor for CVD which is also associated with sub-optimal vascular function. There is emerging evidence that anthocyanins can cause beneficial cardio-protective effects by favourably modulating lipoprotein profiles. We compared the effects of blood orange juice which is rich in anthocyanins and blonde orange juice without anthocyanins on LDL cholesterol and other biomarkers of CVD risk, vascular function and glycaemia. In all, forty-one participants (aged 25-84 years) with a waist circumference >94 cm (men) and >80 cm (women) completed a randomised, open label, two-arm cross-over trial. For 28 d participants ingested (i) 500 ml blood orange juice providing 50 mg anthocyanins/d and (ii) 500 ml blonde orange juice without anthocyanins. There was a minimum 3-week washout period between treatments. LDL-cholesterol and other biomarkers associated with CVD risk and glycaemia were assessed at the start and end of each treatment period. No significant differences were observed in total, HDL- and LDL-cholesterol, TAG, glucose, fructosamine, nitric oxide, C-reactive protein, aortic systolic blood pressure and diastolic blood pressure or carotid femoral and brachial-ankle pulse wave velocity after 28 d ingestion of blood orange juice compared with standard orange juice. The lack of effect on LDL cholesterol may be due to the modest concentration of anthocyanins in the blood orange juice. PMID- 29498349 TI - Type of dietary fat intakes in relation to all-cause and cause-specific mortality in US adults: an iso-energetic substitution analysis from the American National Health and Nutrition Examination Survey linked to the US mortality registry. AB - Accumulating evidence indicates that saturated fat intake is related to mortality risk increase, whereas unsaturated fat intake is associated with reduced mortality risk. The aim of the present study was to estimate the mortality risk reduction related to a dietary change from saturated fat to mono- or polyunsaturated fat intake. The American National Health and Nutrition Examination Surveys conducted between 1999 and 2010 were linked to the 2011 national US death registry resulting in an observational prospective mortality study. Proportional hazards Cox models were used to evaluate the association between saturated, monounsaturated and polyunsaturated fat with all-cause and cause-specific mortality. Substitution analysis was conducted to estimate an iso energetic substitution of 10 % of the energy from dietary fat intake applied to the substitution of saturated fat with an equal amount of energy from monounsaturated or polyunsaturated fat. The highest tertile intakes of saturated fat resulted in an increased risk (12 %) of all-cause and specific-cause mortality, whereas the highest tertile intakes of polyunsaturated fat resulted in a reduced risk (7 %) of all-cause and specific-cause mortality when compared with the corresponding lowest tertile. Iso-energetic substitution revealed that a substitution of 10 % of energy (from total fat) from saturated fat to an equal amount of energy from monounsaturated or polyunsaturated fat resulted in a significant reduction of the mortality risk ranging from 4 to 8 %. Iso-energetic substitution of saturated fat with monounsaturated and polyunsaturated fat reduced all-cause and specific-cause mortality in US adults. PMID- 29498350 TI - Vitamin D intake, serum 25-hydroxyvitamin D status and response to moderate vitamin D3 supplementation: a randomised controlled trial in East African and Finnish women. AB - Insufficient vitamin D status (serum 25-hydroxyvitamin D (S-25(OH)D)0.05 for differences between ethnic groups). In conclusion, high prevalence of vitamin D insufficiency existed among East African women living in Finland, despite higher vitamin D intake than their Finnish peers. Moderate vitamin D3 supplementation was effective in increasing S-25(OH)D in both groups of women, and no ethnic differences existed in the response to supplementation. PMID- 29498351 TI - Effect of increased calcium consumption from fat-free milk in an energy restricted diet on the metabolic syndrome and cardiometabolic outcomes in adults with type 2 diabetes mellitus: a randomised cross-over clinical trial. AB - We investigated the effects of high-Ca fat-free milk phase (MD) (prescription of approximately 1500 mg of Ca/d) v. low-Ca phase (CD) (prescription of approximately 800 mg of Ca/d) in an energy-restricted diet on the metabolic syndrome (MetS) and cardiometabolic measures in individuals with type 2 diabetes mellitus (T2DM) and low habitual Ca consumption (<600 mg/d). In this randomised cross-over design, fourteen adults with T2DM (49.5 (sd 8.6) years, BMI 29.4 (sd 4.5) kg/m2) consumed either MD or CD for 12 weeks, with a washout of 18 weeks between phases. A breakfast shake containing 700 mg (MD) or 6.4 mg (CD) of Ca was consumed in the laboratory. In addition, energy-restricted diets were prescribed (800 mg of dietary Ca/d). Waist circumference (WC), fasting glucose, fasting TAG, systolic (SBP) and diastolic blood pressure (DBP), fasting total cholesterol, fasting LDL-cholesterol, fasting HDL-cholesterol, HDL:LDL ratio, HDL:TAG ratio and lipid accumulation product (LAP) index were assessed at baseline and after each phase. Ca consumption during the study was equivalent to 1200 mg/d during MD and 525 mg/d during CD. There was a greater reduction in WC, SBP, DBP and LAP index after MD compared with CD. HDL:LDL ratio increased and total cholesterol, LDL-cholesterol, SBP, DBP and LAP index decreased only in MD. The consumption of approximately 1200 mg of Ca/d (700 mg from fat-free milk+500mg from other dietary sources) associated with an energy-restricted diet decreased some of the MetS components and cardiometabolic measures in adults with T2DM. PMID- 29498352 TI - Integrative analysis of transcriptomics and metabolomics profiling on flesh quality of large yellow croaker Larimichthys crocea fed a diet with hydroxyproline supplementation. AB - A previous study showed that flesh quality of large yellow croaker (LYC) was improved by feeding dietary hydroxyproline (Hyp, 0.69 %). The aim of the present study was to explore the underlying mechanisms using transcriptomics and metabolomics analysis. The metabolomics analysis showed that muscle metabolite profiles could be clearly separated between the basal diet and Hyp supplementation diet. Metabolites including betaine, Hyp, lactate, glucose-6 phosphate, trimethylamine N-oxide, taurine, creatine, inosine monophosphate, histamine and serine made significant contribution to the separation. Compared with the control diet, the transcriptomics analysis identified a total of 334 different expressed genes, of which 298 genes were up-regulated and thirty-six genes were down-regulated in the Hyp supplementation group. The altered genes of the Hyp supplementation group were involved in collagen metabolism, lipid metabolism and energy metabolism. The integrated results revealed that the increased muscle collagen content in the Hyp supplementation diet was partly because of its enhancement of biosynthesis and the reduction of degradation. The improvement of muscle quality by dietary Hyp supplementation could also be related to a good utilisation of glucose through enhancement of glycolysis. It was concluded that dietary Hyp supplementation could improve flesh quality because of comprehensive metabolism changes including elevated collagen content, glycolysis, lipid metabolism and flesh flavour of LYC. The present study provided a novel strategy to understand the underlying molecular mechanism of flesh quality of LYC fed diet with Hyp supplementation. PMID- 29498353 TI - A review on cluster estimation methods and their application to neural spike data. AB - The extracellular action potentials recorded on an electrode result from the collective simultaneous electrophysiological activity of an unknown number of neurons. Identifying and assigning these action potentials to their firing neurons-'spike sorting'-is an indispensable step in studying the function and the response of an individual or ensemble of neurons to certain stimuli. Given the task of neural spike sorting, the determination of the number of clusters (neurons) is arguably the most difficult and challenging issue, due to the existence of background noise and the overlap and interactions among neurons in neighbouring regions. It is not surprising that some researchers still rely on visual inspection by experts to estimate the number of clusters in neural spike sorting. Manual inspection, however, is not suitable to processing the vast, ever growing amount of neural data. To address this pressing need, in this paper, thirty-three clustering validity indices have been comprehensively reviewed and implemented to determine the number of clusters in neural datasets. To gauge the suitability of the indices to neural spike data, and inform the selection process, we then calculated the indices by applying k-means clustering to twenty widely used synthetic neural datasets and one empirical dataset, and compared the performance of these indices against pre-existing ground truth labels. The results showed that the top five validity indices work consistently well across variations in noise level, both for the synthetic datasets and the real dataset. Using these top performing indices provides strong support for the determination of the number of neural clusters, which is essential in the spike sorting process. PMID- 29498354 TI - Magnetic and electronic properties of single-walled Mo2C nanotube: a first principles study. AB - The structural, electronic, and magnetic properties of single-walled Mo2C nanotubes are investigated by using first-principles calculations. We establish that single-walled Mo2C nanotubes can be rolled up from a graphene-like Mo2C monolayer with H- or T-type phase, i.e. H-Mo2C and T-Mo2C nanotubes. The armchair type T-Mo2C nanotubes are more energetically stable than H-Mo2C nanotubes with the same diameter, while zigzag-type H-Mo2C nanotubes are more energetically stable than T-Mo2C nanotubes. In particular, (8, 0) H-Mo2C nanotube are more stable than Mo2C monolayer due to structural deformation. All Mo2C nanotubes are magnetic metals, independent of their chirality, and the magnetic moments of Mo atoms in the outer layer are larger than the inner. The ionic and metallic bonds in Mo2C nanotubes and delocalized electrons around Mo atoms lead to the versatile electronic and magnetic properties in them, endowing them potential applications in catalysts and electronics. PMID- 29498355 TI - Two spin-canting textures in the antiferromagnetic phase AF1 of MnWO4 based on the new polar atomistic model in P2. AB - The low temperature antiferromagnetic (AF) phase of MnWO4 (the so-called AF1 phase) exhibits different spin-canting configurations at two Mn2+ sublattices of the (3 + 1)-dimensional magnetic structure. The suggested superspace group [Formula: see text] is a significant consequence of the polar space group [Formula: see text]2 true for the nuclear structure of MnWO4. Density functional theory calculations showed that its ground state prefers this two spin-canting system. The structural difference between two independent atomic sites for Mn (Mn a , Mn b ) is too small to allow microscopically detectable electric polarisation. However, this hidden intrinsic polar character allows AF1 two commensurately modulated spin-canting textures. This is considered as the prerequisite onset of the improper ferroelectricity enhanced by the helical spin order in the multiferroic phase AF2 of MnWO4. PMID- 29498356 TI - Calibration of a thermoluminescent dosimeter worn over lead aprons in fluoroscopy guided procedures. AB - Fluoroscopy guided interventional procedures provide remarkable benefits to patients. However, medical staff working near the scattered radiation field may be exposed to high cumulative equivalent doses, thus requiring shielding devices such as lead aprons and thyroid collars. In this situation, it remains an acceptable practice to derive equivalent doses to the eye lenses or other unprotected soft tissues with a dosimeter placed above these protective devices. Nevertheless, the radiation backscattered by the lead shield differs from that generated during dosimeter calibration with a water phantom. In this study, a passive personal thermoluminescent dosimeter (TLD) was modelled by means of the Monte Carlo (MC) code Penelope. The results obtained were validated against measurements performed in reference conditions in a secondary standard dosimetry laboratory. Next, the MC model was used to evaluate the backscatter correction factor needed for the case where the dosimeter is worn over a lead shield to estimate the personal equivalent dose H p (0.07) to unprotected soft tissues. For this purpose, the TLD was irradiated over a water slab phantom with a photon beam representative of the result of a fluoroscopy beam scattered by a patient. Incident beam angles of 0 degrees and 60 degrees , and lead thicknesses between the TLD and phantom of 0.25 and 0.5 mm Pb were considered. A backscatter correction factor of 1.23 (independent of lead thickness) was calculated comparing the results with those faced in reference conditions (i.e., without lead shield and with an angular incidence of 0 degrees ). The corrected dose algorithm was validated in laboratory conditions with dosimeters irradiated over a thyroid collar and angular incidences of 0 degrees , 40 degrees and 60 degrees , as well as with dosimeters worn by interventional radiologists and cardiologists. The corrected dose algorithm provides a better approach to estimate the equivalent dose to unprotected soft tissues such as eye lenses. Dosimeters that are not shielded from backscatter radiation might underestimate personal equivalent doses when worn over a lead apron and, therefore, should be specifically characterized for this purpose. PMID- 29498357 TI - Correlation between structural change and electrical transport properties of Fe doped chrysotile nanotubes under high pressure. AB - Fe3+ doped chrysotile nanotubes (NTs) have been synthesized under controlled hydrothermal conditions, and have been characteristic of layered-walls and room temperature ferromagnetism. High-pressure in situ impedance spectra and synchrotron XRD measurements are performed on Fe-doped chrysotile NTs to reveal the electrical transport and structural properties under compression. Sample resistance (R sum) was found to increase with the pressure elevation, accompanying the step decrease in the grain boundary relaxation frequency (f gb), which reflects the bandgap broadening and dipoles polarization weakening due to the application of pressure. Furthermore, it is found that both R sum and f gb change their pressure dependences at ~5.0 GPa, which is attributed to the nonlinear compressibility of c-axis and even the underlying lattice distortion of monoclinic structure obtained in the XRD observations. PMID- 29498358 TI - Motor-commands decoding using peripheral nerve signals: a review. AB - During the last few decades, substantial scientific and technological efforts have been focused on the development of neuroprostheses. The major emphasis has been on techniques for connecting the human nervous system with a robotic prosthesis via natural-feeling interfaces. The peripheral nerves provide access to highly processed and segregated neural command signals from the brain that can in principle be used to determine user intent and control muscles. If these signals could be used, they might allow near-natural and intuitive control of prosthetic limbs with multiple degrees of freedom. This review summarizes the history of neuroprosthetic interfaces and their ability to record from and stimulate peripheral nerves. We also discuss the types of interfaces available and their applications, the kinds of peripheral nerve signals that are used, and the algorithms used to decode them. Finally, we explore the prospects for future development in this area. PMID- 29498359 TI - Many-body perturbation theory and non-perturbative approaches: screened interaction as the key ingredient. AB - Many-body perturbation theory is often formulated in terms of an expansion in the dressed instead of the bare Green's function, and in the screened instead of the bare Coulomb interaction. However, screening can be calculated on different levels of approximation, and it is important to define what is the most appropriate choice. We explore this question by studying a zero-dimensional model (so called 'one-point model') that retains the structure of the full equations. We study both linear and non-linear response approximations to the screening. We find that an expansion in terms of the screening in the random phase approximation is the most promising way for an application in real systems. Moreover, by making use of the nonperturbative features of the Kadanoff-Baym equation for the one-body Green's function, we obtain an approximate solution in our model that is very promising, although its applicability to real systems has still to be explored. PMID- 29498360 TI - Low temperature magnetic properties of Nd2Ru2O7. AB - We present magnetic susceptibility, heat capacity, and neutron diffraction measurements of polycrystalline Nd2Ru2O7 down to 0.4 K. Three anomalies in the magnetic susceptibility measurements at 146, 21 and 1.8 K are associated with an antiferromagnetic ordering of the Ru4+ moments, a weak ferromagnetic signal attributed to a canting of the Ru4+ and Nd3+ moments, and a long-range-ordering of the Nd3+ moments, respectively. The long-range order of the Nd3+ moments was observed in all the measurements, indicating that the ground state of the compound is not a spin glass. The magnetic entropy of Rln2 accumulated up to 5 K, suggests the Nd3+ has a doublet ground state. Lattice distortions accompany the transitions, as revealed by neutron diffraction measurements, and in agreement with earlier synchrotron x-ray studies. The magnetic moment of the Nd3+ ion at 0.4 K is estimated to be 1.54(2)u B and the magnetic structure is all-in all-out as determined by our neutron diffraction measurements. PMID- 29498361 TI - Characterization of highly multiplexed monolithic PET / gamma camera detector modules. AB - PET detectors use signal multiplexing to reduce the total number of electronics channels needed to cover a given area. Using measured thin-beam calibration data, we tested a principal component based multiplexing scheme for scintillation detectors. The highly-multiplexed detector signal is no longer amenable to standard calibration methodologies. In this study we report results of a prototype multiplexing circuit, and present a new method for calibrating the detector module with multiplexed data. A [Formula: see text] mm3 LYSO scintillation crystal was affixed to a position-sensitive photomultiplier tube with [Formula: see text] position-outputs and one channel that is the sum of the other 64. The 65-channel signal was multiplexed in a resistive circuit, with 65:5 or 65:7 multiplexing. A 0.9 mm beam of 511 keV photons was scanned across the face of the crystal in a 1.52 mm grid pattern in order to characterize the detector response. New methods are developed to reject scattered events and perform depth-estimation to characterize the detector response of the calibration data. Photon interaction position estimation of the testing data was performed using a Gaussian Maximum Likelihood estimator and the resolution and scatter rejection capabilities of the detector were analyzed. We found that using a 7 channel multiplexing scheme (65:7 compression ratio) with 1.67 mm depth bins had the best performance with a beam-contour of 1.2 mm FWHM (from the 0.9 mm beam) near the center of the crystal and 1.9 mm FWHM near the edge of the crystal. The positioned events followed the expected Beer-Lambert depth distribution. The proposed calibration and positioning method exhibited a scattered photon rejection rate that was a 55% improvement over the summed signal energy-windowing method. PMID- 29498362 TI - Interface structure and composition of MoO3/GaAs(0 0 1). AB - We studied growth, structure, stress, oxidation state as well as surface and interface structure and composition of thermally-evaporated thin MoO3 films on the technologically important III/V-semiconductor substrate GaAs(0 0 1). The MoO3 films grow with Mo in the 6+ oxidation state. The electrical resistance is tunable by the oxygen partial pressure during deposition from transparent insulating to semi-transparant halfmetallic. In the investigated growth temperature range (room temperature to 200 degrees C) no diffraction spots are detected by x-ray diffraction. However, high resolution transmission electron microscopy reveals the formation of MoO3 nanocrystal grains with diameters of 5-8 nm. At the interface a ~3 nm-thick intermediate layer has formed, where the single-crystal lattice of GaAs gradually transforms to the nanocrystalline MoO3 structure. This interpretation is corroborated by our in situ and real-time stress measurements evidencing a two-stage growth process as well as by elemental interface analysis revealing coexistance of Ga, As, Mo, and oxygen in a intermediate layer of 3-4 nm. PMID- 29498363 TI - Anisotropic thermal conductivity in carbon honeycomb. AB - Carbon honeycomb, a new kind of 3D carbon allotrope experimentally synthesized recently, has received much attention for its fascinating applications in electronic device and energy storage. In the present work, we perform equilibrium molecular dynamics (EMD) to study the thermal transport properties of carbon honeycombs with different chirality. It is found that the thermal conductivity along the honeycomb axis ([Formula: see text]) is three times larger than that normal to the axis ([Formula: see text]), which shows strong anisotropy reflecting their geometric anisotropy. Lattice dynamics calculations reveal that this anisotropy stems from the orientation-dependent phonon group velocities. Moreover, when ambient temperature ([Formula: see text]) increases from 200 K to 800 K, the [Formula: see text] dependence of [Formula: see text] is observed due to the enhanced Umklapp scattering. The detailed phonon spectra analyses indicate phonon group velocities are insensitive to the variation of ambient temperature, and the temperature dependence of the relaxation times of low-frequency phonons (<20 THz) follows [Formula: see text] behavior. Our results have a certain guiding significance to develop carbon honeycomb for effective thermal channeling devices. PMID- 29498364 TI - Elevated serum RANTES chemokine levels in autoimmune Addison disease. AB - INTRODUCTION Regulated on activation, normal T-cell expressed and secreted chemokine (RANTES), the product of the CCL5 gene, is involved in trafficking immune cells into the inflammation site. It acts as coactivator of T cells and promotes polarization of the immune response towards the Th1 profile. In autoimmune Addison disease (AAD), the adrenal cortex is gradually destroyed by adrenal-specific immune cell infiltration. RANTES might be implicated in autoimmune adrenal failure through recruitment and activation of the immune cells. Furthermore, the promoter CCL5 variant, rs2107538, seems to be associated with autoimmune endocrine conditions: diabetes and thyroid disease. OBJECTIVES Our analysis was designed to evaluate the prevalence of rs2107538 and serum RANTES levels in AAD. PATIENTS AND METHODS rs2107538 was genotyped using TaqMan technology in 239 individuals with AAD and 542 controls, while serum RANTES levels were evaluated by an enzyme-linked immunosorbent assay in 114 patients with AAD and 111 healthy age- and sex-matched individuals. RESULTS No differences were found in rs2107538 genotype or allele frequencies between patients and controls (P = 0.53 and P = 0.39, respectively), and no association was detected with age at AAD onset (P = 0.14). Serum RANTES levels were elevated in patients with AAD compared with controls (mean [SD], 59.2 [30.3] ng/ml vs 45.5 [20.4] ng/ml, P = 0.001). Healthy carriers of various rs2107538 genotypes demonstrated differences in serum RANTES levels (P = 0.02), whereas AAD patients did not (P = 0.26). No correlation was found between circulating RANTES levels and age, AAD duration, serum autoantibodies, hydrocortisone dose, and body mass (P >0.05). CONCLUSIONS This study demonstrates for the first time elevated serum RANTES levels in AAD and confirms that rs2107538 may affect serum chemokine levels. PMID- 29498365 TI - [Small intestine neoplasms]. AB - Small intestine tumors are rarely diagnosed as they constitute only 0.6% of all malignant tumors, including about 1-3% of malignant neoplasms of the gastrointestinal tract. They also advocate for 0.2% of deaths caused by malignant tumors. Factors that increase the risk of disease include Crohn's disease, familial adenomatous polyposis (FAP), Lynch syndrome (HNPCC - hereditary non polyposis colorectal cancer), Peuz-Jeghers syndrome, celiac disease and acquired immunodeficiency syndrome (AIDS). Diagnosis of small intestinal tumors is difficult because the symptoms reported by patients are not characteristic. In advanced disease, the symptoms of the digestive system dominate in the form of free, bloody stools, as well as jaundice and general weakness resulting from the deepening anemia. Often, the first symptom is gastrointestinal obstruction. In the diagnosis of small intestinal tumors, modern diagnostic techniques are used, starting from imaging (computed tomography, magnetic resonance) through endoscopic examination (gastroscopy, endoscopic capsule, bi-balloon enteroscopy). Due to the rarity of small intestine and duodenum cancer, standards for dealing with patients with these tumors have not been established. In stages I to III according to AJCC, surgical treatment is used. There are no specific standards for adjuvant or palliative chemotherapy. PMID- 29498366 TI - [The analysis of perioperative complications of percutaneous nephrolithotomy in the treatment of nephrolithiasis with the use of modified Clavien-Dindo classification]. AB - : The improvement of surgical care requires transparent, consistent and accurate reports concerning surgical outcomes which are assessed and documented in a standardized manner. No consensus has yet been reached as to how to define and assess postoperative complications with regard to the specificity of urological procedures. Therefore, the comparison of data from different centres is difficult. The modified Clavien-Dindo classification allows for a more uniform analysis of surgical complications. This study analyses the occurrence of perioperative complications after percutaneous nephrolithotomy assessed on the basis of the aforementioned classification. AIM: The aim of this study was to analyse perioperative complications with the use of modified Clavien-Dindo classification. Obtained results were compared with those from the multicentre Endourological Society Percutaneous Nephrolithotomy Global Study. MATERIALS AND METHODS: This retrospective analysis involved 201 patients who underwent percutaneous nephrolithotomy during the period from 01.01.2013 to 31.12.2016. We assessed the frequency of complication and the characteristics of deposits. The modified Clavien- Dindo classification was used here. The surgery was performed by one operator in one centre. RESULTS: In 83.08% of patients normal postoperative course was reported. In case of 12.44%, there were minor deviations from the standard intraoperative and postoperative course. 2,49% of patients required transfusions of red blood cell (Clavien II) after the procedure. Less than 1.5% of patients required surgical, endoscopic or radiological intervention under local anaesthesia (Clavien IIa) and one patient required such intervention under general anaesthesia (Clavien IIb). Serious complications were not reported. The most common complications were as follows: low-grade fever (15.42%), fever (5.97%) and bleeding (3.48%). Among the least frequent complications there were: injuries of renal pelvis or ureter 2.99%, residual stones (1.99%), urinary leakage (1.49%), urinary retention (0.995%), arteriovenous fistula (0.497%). CONCLUSIONS: Percutaneous nephrolithotomy is a highly effective treatment of stones removal from the kidney. It is characterized by a small percentage of serious complications, especially when it is performed by an experienced operator. The modified Clavien-Dindo classification of complications is useful in monitoring and comparing the results obtained for this procedure. PMID- 29498368 TI - [Duodenal adenocarcinoma - a case report]. AB - The diagnosis of duodenal adenocarcinoma is still a complex gastrological and oncological problem. The described case illustrates the unusual character of the course, the reasonableness of the diagnostic procedures and the scope of the therapy undertaken. The causes of anemia, which was the first symptom of the disease, were not revealed in the tests carried out at this stage - gastroscopy, colonoscopy, with normal other basic laboratory tests. At the next episode, after 6 months from the first, the presence of a bleeding lesion within the duodenum was revealed. Further imaging and endoscopic examinations as well as the results of histopathological examinations from duodenum collected material were enabled the diagnosis of adenocarcinoma. In urgent mode, the operation was performed using the Whipplle method, removing the duodenum, the pyloric part of the stomach, the part of the pancreas head and the gallbladder. After 6 weeks, chemotherapy was applied in accordance with accepted standards, obtaining stabilization and gradual improvement of the general condition of the patient, which was confirmed in the performed tests. PMID- 29498367 TI - Takotsubo cardiomyopathy in a young male with lung cancer and neoplastic embolization of the coronary microcirculation. AB - The associations between stress-induced takotsubo cardiomyopathy (TC) and cancer or its therapy have been studied with increasing interest in recent years. Different mechanisms of TC development in neoplastic disease are suggested, including a decreased threshold for stress stimuli or aggravated heart adrenoreceptors sensitivity. The action of cytokines and reactive oxygen species on the myocardium, on the epicardial arteries as well as on the coronary microcirculation is also taken into consideration. The authors describe a case of a 30-year-old male with lung cancer, after immunotherapy with checkpoint inhibitors followed by two lines of chemotherapy and after pericardial and pleural drainage. He was admitted to hospital due to severe heart failure (HF) with echocardiographic features of apical TC. During symptomatic treatment of HF his state temporarily improved and left ventricular function returned to normal. Unfortunately, a few days later, he died. The autopsy revealed histological features of TC (contraction band necrosis), cardiac infiltration by cancer and the presence of cancer cells in the coronary microcirculation, which was not previously reported in TC patients. The authors emphasize that disseminated neoplastic embolization of the coronary microcirculation may be important in TC pathogenesis in some cancer patients. PMID- 29498369 TI - [Abscesses in the lumbo-sacral spine area - a case report]. AB - Infection of the surgical operation site is found in approximately 3% of patients and 20% of patients undergoing urgent surgery. The occurrence of this type of complications is affected both by coexisting diseases and the presence of infection in the environment in which the patient is staying. It should also be taken into account that the bacteria found in the implanted material and surrounding tissues have the ability to adhere to the implant, creating a biofilm structure there. The presented patient is an illustration of such a problem, because after L5 laminectomy and extensive L2-L3 and L3-L4 one-sided fenestration and L2-L3-L4-L5 facetectomy, interbody bone arthrodesis and transpedicular stabilization, he reported for fever and pain in right lumbar area. In the patient, the presence of inflammatory infiltrate in the lumbar region of the lumbar tissues was found in imaging studies, with fluid reservoirs that surrounded pedicle screws and spinous processes, as well as abscesses and inflammatory changes in the spinal canal at the L4-L5 level. Empirical antibiotic therapy was ordered and decision about surgical treatment was made. A large amount of purulent and odorous secretion was evacuated at the site of previously performed laminectomy. In the postoperative period, targeted antibiotic therapy was applied based on the culture result obtained from the surgical site. The culture showed Staphylococcus aureus MSSA (methicillin-susceptible S. aureus) which was sensitive to the majority of antibiotics tested. The low effectiveness of this treatment caused the necessity to broaden the research, blood culture revealed Turicella otitidis, which was sensitive to gentamycin, vancomycin, linezolid and rifampicin. The applied rifampicin caused improvement of the patient's condition and the possibility of starting motor rehabilitation. The described case indicates real difficulties in the treatment of post-operative infections, despite invasive procedures and antibiotic therapy. PMID- 29498370 TI - [Application of physical therapy procedures in the treatment of chronic wounds of palm fingers - a case report]. AB - For many years the increasing number of patients who indulge different accidents and injuries during executing buildings works was observed. The medical help offered to those patients - the most often surgical or orthopedic - in form of surgical debridement of wound should enable its complete healing. However in many cases the healing process of wounds does not run in correct way and chronic wounds come into being, which need complex treatment. Contemporary physical medicine systematically broadens the healing possibilities by introducing to clinical practice new procedures and the therapeutic devices which in many cases accelerate the healing processes of chronic wounds. It this paper the results of the treatment of 44-years old man who experienced the injury of right palm - the cut of two finger tips by the angle grinder, were presented. In the treatment two physical methods were applied: magnetostimulation and local hyperbaric oxygen therapy, with good results resulting in complete healing of wounds, enabling the independent patient's existence, return to professional activity and improvement of quality of his life (Quality of Life). PMID- 29498371 TI - [Cardiovascular disease and trans fatty acids: legal act necessary]. AB - Hydrogenated oils containing trans fatty acids (TFA) are used to produce margarine and various processed foods. TFA affect serum lipid levels, fatty acids metabolism, and endothelial function. High TFA intake is linked to increased all cause mortality, coronary heart disease mortality and cardiovascular disease (CVD) incidence. Denmark was first to introduce law that limited TFA content in food; this action led to lower CVD mortality. Seven European countries have followed this practice until now, in a few others the food industry voluntarily reduced TFA use. The issue remains unaddressed in Poland. Legal TFA limit should be established, as it is the optimal solution considering both CVD prevention and the associated cost savings in public healthcare. PMID- 29498372 TI - Proteflazid(r): Clinical experience in children of young and preschool age - systematic review of postmarketing surveillance. AB - Scientific literature data on the experience of use of Proteflazid(r) (drops) and Immunoflazid(r) (syrup) for the treatment of viral diseases in children of the first six years of life are analysed in the article. A systematic review was conducted on the basis of postmarketing comparative clinical trials and long-term follow-up (during the period of 2002 to 2016) that involved about 1500 children (the intent-to-treat population comprised more than 800 of them). The safety and efficacy of the Proteflazid(r) (drops) and Immunoflazid(r) (syrup) usage in children for the treatment of viral infections have been proven. PMID- 29498373 TI - [The risk of perioperative infections after orthopedic surgery]. AB - Perioperative infections after orthopedic surgery are complications that extend the process of treatment and rehabilitation of patients. The multifactor mechanism of their formation has already been defined, which allows effective control of the threat. In addition to the introduction of ever safer surgical techniques, strict epidemic surveillance and acceptable by the body implanted materials, widely prophylactic perioperative antibiotic therapy is applied. The effects of this action are demonstrated in available clinical analyzes, which indicate a reduction in the scale of the threat. When using antibiotics, pay attention to their spectrum of activity and penetrations to the place of the ongoing inflammatory process. On the basis of these parameters, the dose, time and route of administration should be set so that the prophylaxis is fully effective. PMID- 29498374 TI - Obesity: Link between maternal obesity and offspring is STELLA. PMID- 29498375 TI - Diabetes: Peripheral nerve modulation to treat metabolic disease. PMID- 29498376 TI - Metabolism: Role of bone in glucose metabolism. PMID- 29498377 TI - Dynamic Spectrum Access Algorithms Based on Survival Analysis. AB - In this study, we design and implement two algorithms for dynamic spectrum access that are based on survival analysis. They use a non-parametric estimate of the cumulative hazard function to predict the remaining idle time available for secondary transmission subject to the constraint of a preset probability of successful completion. In addition to theoretical performance analysis of the algorithms, we evaluate them using data collected from a long term evolution band to model primary user activity to demonstrate their effectiveness in real-world scenarios, even at fine time scales. The algorithms are run in different configurations, i.e., they are trained and run on a few combinations of data sets. Our results show that as long as the cumulative hazard functions are fairly similar across datasets, the algorithms can be trained on one dataset and run on that of another without any significant degradation of performance. The algorithms achieve fairly high white space utilization and have a measured probability of interference that is at or below the preset threshold. PMID- 29498378 TI - Erratum: Cannabis: Does it have a medicinal value? AB - [This corrects the article on p. 262 in vol. 59, PMID: 29085083.]. PMID- 29498379 TI - Experiencing visual impairment in a lifetime home: an interpretative phenomenological inquiry. AB - Lifetime home standards (LTHS) are a set of standards aimed at making homes more accessible. Previous research, however, indicates that LTHS do not adequately meet the needs of those with sensory impairments. Now, with visual impairment set to increase globally and acknowledging the recognised link between quality of dwelling and wellbeing, this article aims to examine the experiences of visually impaired people living in lifetime homes. The objectives are to investigate existing lifetime homes and to identify whether LTHS meet occupants' needs. Qualitative semi-structured interviews were carried out with six visually impaired people living in homes designed to LTHS in Northern Ireland. Collected data was analysed using interpretative phenomenological analysis identifying three super-ordinate themes: (1) living with visual impairment; (2) design considerations and (3) coping strategies. A core theme of balance between psychological and physical needs emerged through interconnection of super ordinate themes. Although there are benefits to living in lifetime homes, negative aspects are also apparent with occupants employing several coping strategies to overcome difficulties. Whilst residents experience negative emotions following visual impairment diagnoses, results suggest that occupants still regard their homes as key places of security and comfort in addition to then highlighting the need for greater consideration of specific individual needs within general guidelines. PMID- 29498380 TI - Correction: A microbial survey of the International Space Station (ISS). AB - [This corrects the article DOI: 10.7717/peerj.4029.]. PMID- 29498381 TI - Metal-organic framework-based materials: superior adsorbents for the capture of toxic and radioactive metal ions. AB - Highly efficient removal of metal ion pollutants, such as toxic and nuclear waste related metal ions, remains a serious task from the biological and environmental standpoint because of their harmful effects on human health and the environment. Recently, highly porous metal-organic frameworks (MOFs), with excellent chemical stability and abundant functional groups, have represented a new addition to the area of capturing various types of hazardous metal ion pollutants. This review focuses on recent progress in reported MOFs and MOF-based composites as superior adsorbents for the efficient removal of toxic and nuclear waste-related metal ions. Aspects related to the interaction mechanisms between metal ions and MOF based materials are systematically summarized, including macroscopic batch experiments, microscopic spectroscopy analysis, and theoretical calculations. The adsorption properties of various MOF-based materials are assessed and compared with those of other widely used adsorbents. Finally, we propose our personal insights into future research opportunities and challenges in the hope of stimulating more researchers to engage in this new field of MOF-based materials for environmental pollution management. PMID- 29498382 TI - Inducing microstructural changes in Nafion by incorporating graphitic carbon nitride to enhance the vanadium-blocking effect. AB - Two-dimensional graphitic carbon nitride (g-C3N4) nanosheets are introduced into a Nafion matrix to prepare a 'vanadium-blocking' recast Nafion membrane for vanadium redox flow battery (VRFB) applications. After 0.2 wt% g-C3N4 nanosheets are incorporated, the vanadium ion permeability of the composite membrane decreases from 3.3 * 10-7 cm2 min-1 to 3.8 * 10-9 cm2 min-1, which is a reduction of two orders of magnitude in comparison to the pristine recast Nafion membrane. This satisfactory result contributes to the physical blocking effect as well as the Donnan effect from the 2D morphology and functional amino groups of g-C3N4 nanosheets. Notably, this work reveals that the g-C3N4 nanosheets can help reinforce the vanadium-blocking effect by changing the microstructure of Nafion in addition to the well-known effects mentioned above. The g-C3N4 nanosheets induce shrinkage in the original spherical structure of the ion cluster and generate a new lamellar structure. Correspondingly, the amorphous phase of Nafion is interrupted, and the membrane crystallinity is reduced. The VRFB with an optimized composite membrane achieves a high coulombic efficiency of 97% and an energy efficiency of 83% at a current density of 160 mA cm-2. Meanwhile, the battery exhibited excellent lifetime stability during a 100 charge-discharge cycling test. PMID- 29498383 TI - Self-catalyzed copper-silver complex inks for low-cost fabrication of highly oxidation-resistant and conductive copper-silver hybrid tracks at a low temperature below 100 degrees C. AB - Cu-Ag complex inks are developed for printing conductive tracks of low cost, high stability, and high conductivity on heat-sensitive substrates such as polyethylene terephthalate (PET) substrates. The inks show an obvious self catalyzed characteristic due to the in situ formation of fresh metal nanoparticles which promote rapid decomposition and sintering of the inks at a low temperature below 100 degrees C. The temperature is 40-60 degrees C lower than those of general Cu complex inks and 100-120 degrees C lower than those of general Cu/Ag particle inks. Highly conductive Cu-Ag tracks of 2.80 * 10-5 Omega cm and 6.40 * 10-5 Omega cm have been easily realized at 100 degrees C and 80 degrees C, respectively. In addition, the printed Cu-based tracks not only show high oxidation resistance at high temperatures of up to 140 degrees C (the maximum tolerable temperature of current PET substrate) but also show excellent stability at high humidity of 85% because of the very uniform Cu-Ag hybrid structure. The printable tracks exhibit great potential application in various wearable devices fabricated on textiles, papers, and other heat-sensitive substrates. PMID- 29498384 TI - Virtually imprinted polymers (VIPs): understanding molecularly templated materials via molecular dynamics simulations. AB - Molecularly imprinted polymers are advanced recognition materials selectively rebinding a target molecule present during the synthesis of the polymer matrix. It is commonly understood that the templating process is based on embedding the complex formed between a template and functional monomers into a co-polymer matrix. This happens by a polymerization of the complex with a cross-linker while maintaining their spatial arrangement forming a molecular imprint. Template removal then leads to synthetic recognition sites ready to selectively rebind their targets, which are complementary in functionality, size and shape to the target. In this study, an innovative theoretical concept using fully atomistic molecular dynamics simulations for modeling molecular templating processes is introduced yielding virtually imprinted polymers (VIPs). VIPs created for the template 17-beta-estradiol and applied in modeled chromatography experiments demonstrated selectivity for their template. This evidenced the creation of virtual imprints as a result of a templated synthesis protocol, which represents a theoretical confirmation of the governing imprinting theory. PMID- 29498385 TI - Effect of size confinement on skyrmionic properties of MnSi nanomagnets. AB - Bulk magnetic materials with the noncentrosymmetric cubic B20 structure are fascinating due to skyrmion spin structures associated with Dzyaloshinskii-Moriya interactions, but the size of skyrmions are generally larger than 50 nm. The control of such spin structures in the 10 nm size ranges is essential to explore them for spintronics, ultra-high-density magnetic recording, and other applications. In this study, we have fabricated MnSi nanoparticles with average sizes of 9.7, 13.1 and 17.7 nm and investigated their structural and magnetic properties. X-ray diffraction and transmission electron microscope studies show that the MnSi nanoparticles crystallize in the cubic B20 structure. Field dependent dc susceptibility data of the MnSi samples with average particle sizes of 17.7 and 13.1 nm show anomalies in limited field (about 25-400 Oe) and temperature (25 K-43 K) ranges. These features are similar to the signature of the skyrmion-like spin structures observed below the Curie temperature of MnSi. Our results also show that this anomalous behavior is size-dependent and suppressed in the smallest nanoparticles (9.7 nm), and this suppression is interpreted as a confinement effect that leads to a truncation of the skyrmion structure. PMID- 29498386 TI - Atmospheric chemistry of CH3CHO: the hydrolysis of CH3CHO catalyzed by H2SO4. AB - Elucidating atmospheric oxidation mechanisms and the reaction kinetics of atmospheric compounds is of great importance and necessary for atmospheric modeling and the understanding of the formation of atmospheric organic aerosols. While the hydrolysis of aldehydes has been detected in the presence of sulfuric acid, the reaction mechanism and kinetics remain unclear. Herein, we use electronic structure methods with CCSD(T)/CBS accuracy and canonical variational transition state theory combined with small-curvature tunneling to study the reaction mechanism and kinetics of the hydrolysis of CH3CHO. The calculated results show that the hydrolysis of CH3CHO needs to overcome an energy barrier of 37.21 kcal mol-1, while the energy barrier is decreased to -9.79 kcal mol-1 with a sulfuric acid catalyst. In addition, the calculated kinetic results show that the H2SO4H2O + CH3CHO reaction is faster than H2SO4 + CH3CHOH2O. Additionally, the H2SO4H2O + CH3CHO reaction can play an important role in the sink of CH3CHO below 260 K occurring during the night period when OH, H2SO4, and H2O concentrations are 104, 108, and 1017 molecules cm-3, respectively, because it can compete well with the CH3CHO + OH reaction. There are wide implications in atmospheric chemistry from these findings because of the potential importance of the catalytic effect of H2SO4 on the hydrolysis of CH3CHO in the atmosphere and in the formation of secondary organic aerosols. PMID- 29498387 TI - In situ self-sacrificed template synthesis of vanadium nitride/nitrogen-doped graphene nanocomposites for electrochemical capacitors. AB - Vanadium nitride and graphene have been widely used as pseudo-capacitive and electric double-layer capacitor electrode materials for electrochemical capacitors, respectively. However, the poor cycling stability of vanadium nitride and the low capacitance of graphene impeded their practical applications. Herein, we demonstrated an in situ self-sacrificed template method for the synthesis of vanadium nitride/nitrogen-doped graphene (VN/NGr) nanocomposites by the pyrolysis of a mixture of dicyandiamide, glucose, and NH4VO3. Vanadium nitride nanoparticles of the size in the range of 2 to 7 nm were uniformly embedded into the nitrogen-doped graphene skeleton. Furthermore, the VN/NGr nanocomposites with a high specific surface area and pore volume showed a high specific capacitance of 255 F g-1 at 10 mV s-1, and an excellent cycling stability (94% capacitance retention after 2000 cycles). The excellent capacitive properties were ascribed to the excellent conductivity of nitrogen-doped graphene, high surface area, high pore volume, and the synergistic effect between vanadium nitride and nitrogen doped graphene. PMID- 29498388 TI - From helical supramolecular arrays to gel-forming networks: lattice restructuring and aggregation control in peptide-based sulfamides to integrate new functional attributes. AB - While supramolecular organisation is central to both crystallization and gelation, the latter is more complex considering its dynamic nature and multifactorial dependence. This makes the rational design of gelators an extremely difficult task. In this report, the assembly preference of a group of peptide-based sulfamides was modulated by making them part of an acid-amine two component system to drive the tendency from crystallization to gelation. Here, the peptide core directed the assembly while the long-chain amines, introduced through salt-bridges, promoted layering and anisotropic development of primary aggregates. This proved to be very successful, leading to gelation of a number of solvents. Apart from this, it was possible to fine-tune their aggregation using an amphiphilic polymer like F-127 as an additive to get honey-comb-like 3D molecular architectures. These gels also proved to be excellent matrices for entrapping silver nanoparticles with superior emissive properties. PMID- 29498389 TI - Highly stretchable strain sensors with reduced graphene oxide sensing liquids for wearable electronics. AB - Strain sensors with high sensitivity, broad sensing ranges and excellent durable stability are highly desirable due to their promising potential in electronic skins and human-friendly wearable interactive systems. Herein, we report a high performance strain sensor based on rGO (reduced graphene oxide)/DI (deionized water) sensing elements. The strain sensors were fabricated by using Ecoflex rubber filled with rGO/DI conductive liquids via template methods, making the process simple, low-cost and scalable. The as-assembled strain sensors can be used to reflect both stretching and compressing with high sensitivity (a maximum gauge factor of 31.6 and a pressure sensitivity of 0.122 kPa-1), an ultralow limit of detection (0.1% strain), and excellent reliability and stability (>15 000 cycles for pressuring and >10 000 cycles for stretching). In particular, the maximum sensing range is up to 400%, much wider than that of the sensor recently reported. More significantly, the strain sensors are able to distinguish between touch/compressive (resistance decrease) and tensile (resistance increase) deformation, which has not been explored before. This interesting property of strain sensors is due to the micro-contact of nanomaterials in a liquid environment. The sensing liquid of the device can be refilled when it fails, and this enables the recycling of the materials and reduces the waste rate. Therefore, it is attractive and promising for practical applications in multifunctional wearable electronics such as the detection of acoustic vibration, human vocalization and other human motions. PMID- 29498390 TI - Uncovering reaction sequences on surfaces through graphical methods. AB - ZStruct is a graph-based model that generates an ensemble of plausible reaction pathways starting from a given initial state, without requiring prior knowledge of reaction intermediates. In this article, a surface-reaction oriented implementation (S-ZStruct) is introduced for unimolecular and bimolecular reactions, including sampling of different binding sites and adsorption orientations. To test the unimolecular reaction generation ability and angle sampling feature of S-ZStruct, the propanoic acid to ethylene dissociation network is studied. Starting from multiple initial orientations of two key intermediates, multiple unique reaction pathways, each with different activation energies, were discovered. Atomic layer deposition of TiN on Si(100)-involving a challenging reaction mechanism-is also studied as an example of bimolecular reactions. In addition to locating a number of expected pathways, S-ZStruct found that the little-understood step of reduction of Ti(iv) to Ti(iii) likely occurs through beta-hydride transfer between diamido ligands on neighboring Ti centers. These results suggest that S-ZStruct is a powerful tool for exploring surface chemistry, which will permit discoveries of reaction mechanisms in a wide variety of environments. PMID- 29498391 TI - Efficient continuous-wave and short-pulse Ho3+-doped fluorozirconate glass all fiber lasers operating in the visible spectral range. AB - In this work, efficient visible Ho3+-doped fluorozirconate glass (Ho:ZBLAN) all fiber lasers operating in continuous-wave (CW) and Q-switching regimes are experimentally demonstrated. The combination of a direct blue pump, a highly doped Ho:ZBLAN fiber and the fiber end-facet mirrors contributes to a simple all fiber configuration. A tunable laser emission in the green spectral range of 543 550 nm is achieved with >150 mW output power and a tunable deep-red laser around 754-758 nm is also obtained with about 16 mW output power. Interestingly, stable visible self-Q-switched operation was successfully observed. For the green Q switched all-fiber laser, a maximum single pulse energy of 196 nJ is realized with a repetition rate of 97.66 kHz and a pulse duration of 605 ns. As the pump power is increased, the deep-red Q-switched all-fiber laser has the pulse repetition rate from 59.88 to 100.5 kHz and the pulse duration from 4.85 to 2.02 MUs, corresponding to the maximum pulse energy of 58 nJ. To the best of our knowledge, this work is the first demonstration of Ho:ZBLAN all-fiber lasers emitting in the visible spectral range (i.e., both green and deep-red wavelengths). PMID- 29498392 TI - A metal-free direct C (sp3)-H cyanation reaction with cyanobenziodoxolones. AB - A metal-free protocol of direct C(sp3)-H cyanation with cyanobenziodoxolones functioning as both cyanating reagents and oxidants was developed. Unactivated substrates, such as alkanes, ethers and tertiary amines, were thereby transformed to the corresponding nitriles in moderate to high yields. Mechanistic studies indicated that the cyanation proceeded with two potential pathways, which is highly dependent on the substrates: (1) a free radical case for alkanes and ethers and (2) an oxidative case for tertiary amines. PMID- 29498394 TI - Global Health Nursing: Making Connections by Embracing the Other. PMID- 29498393 TI - Comparison of charge transfer dynamics in polypyridyl ruthenium sensitizers for solar cells and water splitting systems. AB - Standard ruthenium components of dye-sensitized solar cells (sensitizer N719) and dye-sensitized photoelectrochemical cells (sensitizer RuP and water oxidation catalyst RuOEC) are investigated in the same solar cell configuration to compare their photodynamics and charge separation efficiency. The samples are studied on time scales from femtoseconds to seconds by means of transient absorption, time resolved emission and electrochemical impedance measurements. RuP shows significantly slower electron injection into a mesoporous titania electrode and enhanced fast (sub-ns) electron recombination with respect to those of N719. Moreover, RuOEC is found to be responsible for partial light absorption and electron injection with low efficiency. The obtained results reveal new insights into the reasons for the lower charge separation efficiency in water splitting systems with respect to that in solar cells. The important role of the initial processes occurring at the dye-titania interface within the first nanoseconds in this efficiency is emphasized. PMID- 29498395 TI - Identifying and Resolving Conflicts of Interest for Individuals in a Position to Control Educational Content. AB - This article addresses how nurse planners and nursing professional development practitioners can meet Educational Design Process 3 in the American Nurses Credentialing Center Primary Accreditation criteria that also corresponds with the Association for Nursing Professional Development Scope and Standards of Practice7. J Contin Educ Nurs. 2018;49(3):102-104. PMID- 29498396 TI - Beyond High-Fidelity Simulation: Emerging Technologies in Leadership Development. AB - Technology offers educators active learning and new teaching strategies. Five lower cost and scalable technology applications are presented as alternative or complement to high-fidelity simulation. Professional nurse educators should adopt technology when teaching and interact with vendors to generate real-world applications that advance development. J Contin Educ Nurs. 2018;49(3):105-108. PMID- 29498397 TI - Global Health Engagement: At Home and Abroad. AB - Nurses and nurse educators need to be prepared to accelerate progress toward the United Nations' Sustainable Development Goals to improve local and global health in the face of continued poverty, hunger, and disease. This four-part Teaching Tips series will focus on developing nurse educators to prepare nurses for global engagement on the following topics: introduction to global health, systems thinking for global health, strategies for integrating global awareness and engagement into clinical practice, and leading and participating in service trips. The authors offer tips for increasing global awareness and using frameworks, strategies, and resources for both students and nurses to use in their own settings and practice. J Contin Educ Nurs. 2018;49(3):109-110. PMID- 29498398 TI - Preceptor Education for Specialty Community-Based Nurses: A Pre- and Postevaluation. AB - BACKGROUND: Quality preceptorship is an integral aspect of nursing education. Evidence suggests that preceptor education programs can be designed to support RNs in their capacity as preceptors. Little has been reported on the effectiveness of preceptor programs for community-based nurses who provide primary health care for preschool children and their families. METHOD: The project evaluated the effectiveness of a 4-hour face-to-face tailored preceptor education program undertaken by 59 nurses in Victoria, Australia. Pre- and postsurveys were undertaken to evaluate the program. RESULTS: Participants had improved understanding of the role of preceptor after the education program. They had increased confidence in their ability to give feedback, assess clinical skills, and use the clinical assessment tool. They were also surer of the standard of performance expected of students. CONCLUSION: A strategically designed preceptor program was effective in improving some preceptorship skills of community-based nurses who supervise postgraduate nursing students. J Contin Educ Nurs. 2018;49(3):111-118. PMID- 29498399 TI - Peer-Review Competency Assessment Engages Staff and Influences Patient Outcomes. AB - BACKGROUND: Nurse educators must guide competency assessment in a way that influences safe patient care. The goal of this innovative competency assessment was for RNs to demonstrate performance of sound practice related to anticoagulation medication, pressure injuries, and pain management using a peer review format. METHOD: The process was initiated through the unit-based team. The clinical RN was required to bring forth the information that he or she had met the competency requirements. Rubrics provided consistency in evaluation. RESULTS: The process was perceived to have evaluated actual performance and allowed demonstration of performance. For patient outcomes, anticoagulation safety measures were sustained, pressure injury measures were improved, and pain outcome measures were not improved during and after the competency period. CONCLUSION: A peer-review process for clinical RN competency assessment enhanced professionalism through professional practice evaluation, was perceived as favorable, and was associated with positive patient outcomes. J Contin Educ Nurs. 2018;49(3):119-126. PMID- 29498400 TI - Knowledge of Nurses About Preoperative Fasting in a Corporate Hospital. AB - BACKGROUND: Preoperative fasting is a requirement to be made by anesthesiologists, but they generally depend on nurses to ensure it is carried out by patients. Lack of updated knowledge among nurses may cause complications. METHOD: The objective of this study was to understand the knowledge of nurses about preoperative fasting. The multi-unit study was conducted in the units of our hospitals using an Internet-based survey. The responders were anonymous to the authors. RESULTS: The survey was sent to approximately 5,000 nurses, with more than 600 responding to the survey. Most of the respondents were aware of the preoperative fasting guidelines. The understanding regarding preoperative fasting appeared to be insufficient among nurses. The nurses appreciated the concern of the anesthesiologists about fasting. The nurses opined that additional training regarding preoperative fasting might benefit them. CONCLUSION: This survey conveyed to the authors that the nurses of our hospitals were knowledgeable but required further training to update them. J Contin Educ Nurs. 2018;49(3):127-131. PMID- 29498401 TI - A Comparative Study of Newly Licensed Registered Nurses' Stressors: 2003 and 2015. AB - BACKGROUND: Newly licensed nurses are overwhelmed and feel stressed as they transition from student to professional nurse. Health educators are making strides in improving the work environment, yet these nurses continue to feel stressed. Little has been done to track stress-ors to see whether they have changed over time. METHOD: A descriptive qualitative research method was used to identify the stressors of newly licensed nurses. The first focus group interviews were conducted in 2003 with 21 nurses. In 2015, the study was replicated using another group of 22 recently graduated nurses. RESULTS: There were fewer stressors noted in the 2015 group compared with the 2003 group. Six major stress ors were identified in the 2003 group, and only three of these were noted in the 2015 group. CONCLUSION: The decline in work-related stressors could be attributed to changes in health care organizations and in state policies. Nurse educators and leaders should refine orientation and educational programs based on ongoing changes in stressors expressed by newly licensed nurses. J Contin Educ Nurs. 2018;49(3):132-140. PMID- 29498402 TI - Journal Clubs: Engaging Clinical Nurses and Midwives in Research. AB - It is essential that nurses and midwives can understand and critically evaluate research to ensure the delivery of high-quality evidence-based care. Journal clubs are an educational method that helps to develop research capacity and assist with bridging the gap between research and clinical practice. To maintain competence and remain current with the latest evidence, a commitment to continuing professional education is required. This article describes how a successful journal club led to clinical nurses identifying a gap in their own practice, which resulted in a research project being conducted by the members of the journal club. J Contin Educ Nurs. 2018;49(3):141-144. PMID- 29498403 TI - IgG response to MHC class I epitope peptides is a quantitative predictive biomarker in the early course of treatment of colorectal cancer using therapeutic peptides. AB - Cancer vaccines have been developed as a new therapeutic approach, however, their clinical benefit remains limited. We previously performed a phase II study for advanced colorectal cancer (CRC) using five human leukocyte antigen (HLA-A*24:02) restricted peptides derived from kinase of the outer chloroplast membrane 1, translocase of outer mitochondrial membrane 34 (TOMM34), ring finger protein 43 (RNF43), vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2. In the present study the relationship between overall survival (OS) and several biomarkers, including cytotoxic T lymphocyte (CTL) and immunoglobulin G (IgG) responses to these five peptides, was investigated. In 89 advanced CRC patients treated with a combination therapy consisting of these five peptides and oxaliplatin-based chemotherapy, plasma was collected before and after 3 months of vaccine administration. IgGs reactive to each of the five peptides were assessed using the multiplex bead suspension Luminex system. Antigen-specific T-cell responses were estimated by enzyme-linked immunoSpot assay. Plasma levels of TOMM34 IgG (P<0.001), RNF43 IgG (P<0.001) and VEGFR2 IgG (P<0.001) were significantly increased after vaccination and stronger VEGFR2 IgG responses correlated significantly with OS in HLA-matched patients (P=0.034). CTL responses to VEGFR1 and VEGFR2 were also significantly increased in the HLA-matched group (P=0.049 and P<0.001, respectively). However, increased CTL response did not correlate with OS. Multivariate analysis indicated that IgG responses to VEGFR2 were the most significant predictor for OS in the HLA-A*24:02-matched group (P=0.04). Our findings indicated that VEGFR2 IgG responses may be an important immunological biomarker in the early course of treatment for CRC patients treated with therapeutic epitope peptides. PMID- 29498404 TI - Deleted in malignant brain tumor 1 is a novel prognostic marker in colorectal cancer. AB - The gene deleted in malignant brain tumor 1 (DMBT1) encoding a large scavenger receptor cysteine-rich protein was originally identified based on its deletion in a brain tumor cell line. The DMBT1 protein is involved in mucosal immune defense, epithelial differentiation and tumor suppression. In the present study, the clinicopathologic significance of DMBT1 protein expression in stool and tissue samples of colorectal cancer (CRC) patients was evaluated. Western blot analysis of fecal DMBT1 was performed for patients with CRC (n=177), colorectal adenoma (n=61), inflammatory bowel diseases (IBDs; n=54) and healthy individuals as the control group (n=151). Immunohistochemical analysis of tissue expression of DMBT1 was performed in 385 primary CRC tissues. Fecal DMBT1 expression was higher in CRC and IBD patients than in healthy controls or adenoma patients (P<0.0001), but not significantly different between IBD and CRC or between adenoma and healthy control groups. In CRC patients, fecal DMBT1 expression was not associated with the tumor stage or site. The sensitivity of fecal DMBT1 analysis for CRC was 50%, while the specificity and positive predictive value were 86.8 and 81.3%, respectively. Immunohistochemical expression patterns of DMBT1 in CRC tissues varied from loss to overexpression. Loss of expression was observed in 4.7% (18 out of 385 cases) and significantly associated with lymph node metastasis (P=0.016), distant metastasis (P=0.013), advanced stage (P=0.026), and higher histologic grade (P=0.033). In addition, DMBT1 loss was an independent poor prognostic factor for cancer-associated death (hazard ratio, 2.272; P=0.015) and disease recurrence (hazard ratio, 2.689; P=0.009). In conclusion, fecal DMBT1 has limited value as a diagnostic biomarker, while the tissue expression of DMBT1 may serve as an efficient prognostic marker for CRC. Furthermore, DMBT1 may have a role in the progression of CRC. PMID- 29498405 TI - Platelet-derived growth factor receptor-beta gene expression relates to recurrence in colorectal cancer. AB - Platelet-derived growth factor receptor-beta (PDGFR-beta) in epithelial tumors is mainly expressed by stromal cells. High expression of PDGFR-beta has been related to poor prognosis in several cancers, however its significance in colorectal cancer (CRC) remains unknown. The present study aimed to clarify the prognostic impact of PDGFR-beta in CRC patients. The study included 194 patients who underwent surgery for CRC. PDGFR-beta expression was examined by real-time reverse transcription-polymerase chain reaction and immunohistochemistry and the expression levels were correlated with various clinical parameters. The biological significance was evaluated by knockdown experiments in CRC cell lines and the specific PDGFR inhibitor, crenolanib. PDGFR-beta mRNA and protein expression levels were positively correlated with each other. Low PDGFR-beta expression was associated with significantly better disease-free survival after curative surgical resection, than high PDGFR-beta expression, according to univariate and multivariate analyses. The assessment of PDGFR-beta knockdown in two cell lines revealed that small interfering RNA (siRNA) inhibition resulted in statistically significant reductions in cell growth and invasion. PDGFR inhibitor suppressed CRC cell proliferation in vitro in a dose-dependent manner. In conclusion, PDGFR-beta expression was a risk factor for recurrence in patients with CRC and PDGFR inhibitor may be a useful therapeutic agent for CRC. PMID- 29498406 TI - A screening method for gastric cancer by oral microbiome detection. AB - Gastric cancer is the second most common malig-nancy and one of the principal causes of cancer-related mortality worldwide. Early diagnostic and screening methods for gastric cancer are limited at present, most of them involving invasive procedures. We aimed to investigate the characteristics of the oral microbiome in gastric cancer individuals and to conduct a screening method for gastric cancer by oral microbiome detection. We used high-throughput sequencing to examine the total bacterial profile of saliva and plaque samples of 50 subjects, including 37 individuals with gastric cancer and 13 controls. The Venn diagram and species abundance clusters were generated from the data. The results indicated that the oral bacteria were more complex in patients with gastric cancer. Based on the characteristics of the oral microbiome in individuals with gastric cancer, a scoring system was designed to screen gastric cancer. In the present study, 36 out of 37 individuals in the gastric cancer group were identified as a high-risk population, giving a sensitivity rate of 97%. One out of 13 individuals in the control group was identified as a high-risk population, providing a false-positive rate of 7.7%. The scoring system we designed may be a potential method for screening suspected gastric cancer patients by oral microbiome detection. Further calibration of this scoring system is needed by recruiting a larger study population. PMID- 29498407 TI - MicroRNA-26b inhibits the tumor growth of human liver cancer through the PI3K/Akt and NF-kappaB/MMP-9/VEGF pathways. AB - We investigated the role of microRNA-26b signaling in mediating the tumor growth of human liver cancer. MicroRNA-26b expression was observably downregulated in human liver cancer tissue. Forced upregulation of microRNA-26b had anticancer effects, inhibited cell proliferation, induced apoptosis and promoted Bax and caspase-3/-9 protein expression in a liver cancer cell line as determined by MTT assay, flow cytometry and western blot analysis. MicroRNA-26b significantly suppressed the PI3K/Akt and NF-kappaB/MMP-9/VEGF pathways. PI3K inhibitor significantly facilitated the effects of microRNA-26b regarding the suppression of the PI3K/Akt pathway, inhibition of cell proliferation, induction of apoptosis and increases in Bax and caspase-3/-9 protein expression in the liver cancer cell line. NF-kappaB inhibitor also significantly enhanced the effects of microRNA-26b regarding suppression of the NF-kappaB/MMP-9/VEGF pathway, inhibition of cell proliferation, induction of apoptosis, and promotion of Bax and caspase-3/-9 protein expression in the liver cancer cell line. The present study demonstrated that microRNA-26b inhibits the tumor growth of human liver cancer through the PI3K/Akt and NF-kappaB/MMP-9/VEGF pathways. PMID- 29498408 TI - Genetic polymorphisms and protein expression of P53 and BRCA1 in preneoplastic and neoplastic rat mammary glands. AB - Breast cancer is the most common type of cancer and the leading cause of cancer related deaths among women in the United Arab Emirates and worldwide. Although many factors contribute to the high incidence of breast cancer, a considerable number of cases are related to environmental factors. In the present study, breast cancer was induced in female rats using a single dose, 80 mg/kg body wt, of the environmental carcinogen 7,12-dimethylbenz[a]anthracene (DMBA). The aim of the present study, was to characterize some of the molecular changes that occur during breast cancer development in the DMBA-treated rat model. Mammary gland tissues of control and DMBA-treated rats were processed for: i) immunohistochemical probing using anti-BRCA1 antibody to characterize and correlate the localization of this cell cycle protein during progression to cancer, ii) western blotting to analyze the alteration of p53 protein expression in preneoplastic and neoplastic lesions of the mammary glands, and iii) polymerase chain reactions using primers specific for BRCA1 and P53 genes followed by single stranded conformational polymorphism (SSCP) or restriction fragment length polymorphism (RFLP) assays to detect possible mutations in these genes during development of breast cancer. Microscopic examination revealed a wide range of preneoplastic and neoplastic lesions providing a sequence representing the multistep process of breast cancer formation in DMBA-treated rats. Probing for BRCA1 protein revealed a gradual defect in its translocation from the cytoplasm to the nucleus during breast cancer progression. In control rats, BRCA1 was present in the nuclei of terminal duct epithelial cells. However, in the preneoplastic lesions, BRCA1 was localized in both the cytoplasm and nuclei of the epithelial duct cells. In all malignant lesions, BRCA1 was mostly found in the cytoplasm. Western blotting revealed initial downregulation in the expression of p53 protein during breast cancer development. However, with progression towards malignancy, upregulation of p53 was observed. These changes were associated with polymorphism in p53 gene, which was detected in exon 5 using SSCP assay. However, using RFLP and BamHI to digest the PCR products of exon 11 of BRCA1 gene revealed no detectable polymorphisms. In conclusion, molecular characterization of the early changes that occur during development of breast cancer provides some clues for better understanding of its pathogenesis. PMID- 29498409 TI - Identification of antibody reactive proteins in pancreatic cancer using 2D immunoblotting and mass spectrometry. AB - Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by early invasiveness and resistance to treatment. Surgery in early stages is the only effective treatment, thus finding new biomarkers for the early detection of PDAC remains a major challenge. The present study aimed to compare the immunoproteome between PDAC patients and healthy controls using serological proteome analysis method. Firstly, cell lysates from two different pancreatic cancer cell lines were separated by two dimensional (2D) gels, and then transferred onto membranes probed with sera from 20 PDAC patients and 10 healthy controls. Proteins differentially reacting with autoantibodies in PDAC patients and control groups and were identified using mass spectrometry. This process led to the identification of 18 pancreatic immunoreactive antigens such as laminin, superoxide dismutase, ATP synthase, Rho GDP-dissociation inhibitor II, septin, glyceraldehyde 3-phosphate-dehydrogenase, phosphoglycerate mutase B, tubulin beta8 channel and prohibit in. In the present study, we identified 18 immunoreactive proteins in PDAC. While the identified proteins were critically involved in PDAC pathogenesis, further investigation in a large scale population will determine the applicability of these potential biomarkers for the early diagnosis or treatment of the disease. PMID- 29498410 TI - Local application of a gentamicin-loaded thermo-responsive hydrogel allows for fracture healing upon clearance of a high Staphylococcus aureus load in a rabbit model. AB - Antibiotic-loaded biomaterials (ALBs) have emerged as a potential useful adjunctive antimicrobial measure for the prevention of infection in open fracture care. A biodegradable thermo-responsive poly(N-isopropylacrylamide) grafted hyaluronic acid (HApN) hydrogel loaded with gentamicin has recently been shown to prevent implant-related infection in a rabbit osteosynthesis model. The primary aim of this study was to determine the influence of this HApN hydrogel on bone healing at an early stage (4 weeks). A rabbit humeral osteotomy model with plating osteosynthesis was used to compare fracture healing in rabbits receiving the hydrogel as compared with control animals. The secondary aim was to observe fracture healing in groups treated with and without antibiotic-loaded hydrogel in the presence of bacterial contamination. In all groups, outcome measures were mechanical stability and histological score, with additional quantitative bacteriology in the inoculated groups. Application of the HApN hydrogel in non inoculated rabbits did not significantly influence humeral stiffness or histological scores for fracture healing in comparison to controls. In the inoculated groups, animals receiving the bacterial inoculum without hydrogel were culture-positive at euthanasia and found to display lower humeral stiffness values and higher histopathological scores for bacterial presence in comparison with equivalents receiving the gentamicin-loaded HApN hydrogel, which were also infection-free. In summary, our data showed that HApN was an effective antibiotic carrier that did not affect fracture healing. This data supported its suitability for application in fracture care. Addition of osteopromotive compounds could provide further support for accelerating fracture healing in addition to successful infection prophylaxis. PMID- 29498411 TI - RSK1 promotes murine breast cancer growth and metastasis. AB - INTRODUCTION: Triple-negative breast cancer (TNBC), representing over 15% of all breast cancers, has a poorer prognosis than other subtypes. There is no effective targeted treatment available for the TNBC sufferers. Ribosomal S6 kinases (RSKs) have been previously proposed as drug targets for TNBC based on observations that 85% of these tumors express activated RSKs. MATERIALS AND METHODS: Herein we examined an involvement of RSK1 (p90 ribosomal S6 kinase 1) in a regulation of TNBC growth and metastatic spread in an animal model, which closely imitates human disease. Mice were inoculated into mammary fat pad with 4T1 cells or their RSK1-depleted variant. We examined tumor growth and formation of pulmonary metastasis. Boyden chamber, wound healing and soft agarose assays were performed to evaluate cells invasion, migration and anchorage-independent growth. RESULTS: We found that RSK1 promoted tumor growth and metastasis in vivo. After 35 days all animals inoculated with control cells developed tumors while in the group injected with RSK1-negative cells, there were 75% tumor-bearing mice. Average tumor mass was estimated as 1.16 g and 0.37 g for RSK1-positive vs. -negative samples, respectively (p < 0.0001). Quantification of the macroscopic pulmonary metastases indicated that mice with RSK1-negative tumors developed approximately 85% less metastatic foci on the lung surface (p < 0.001). This has been supported by in vitro data presenting that RSK1 promoted anchorage-independent cell growth and migration. Moreover, RSK1 knock-down corresponded with decreased expression of cell cycle regulating proteins, i.e. cyclin D3, CDK6 and CDK4. CONCLUSIONS: We provide evidence that RSK1 supports tumor growth and metastatic spread in vivo as well as in vitro migration and survival in non-adherent conditions. Further studies of RSK1 involvement in TNBC progression may substantiate our findings, laying the foundations for development of anti-RSK1-based therapeutic strategies in the management of patients with TNBC. PMID- 29498412 TI - Unexpected diagnosis of a SHH nonsense variant causing a variable phenotype ranging from familial coloboma and Intellectual disability to isolated microcephaly. PMID- 29498413 TI - Use of hyaluronidase as an adjunct to local anaesthetic eye blocks to reduce intraoperative pain in adults. AB - BACKGROUND: Hyaluronidase has been used over many decades as an adjunct to local anaesthetic solution to improve the speed of onset of eye blocks and to provide better akinesia and analgesia. With the evolution of modern eye surgery techniques, fast onset and akinesia are not essential requirements anymore. The assumption that the addition of hyaluronidase to local anaesthetic injections confers better analgesia for the patient needs to be examined. There has been no recent systematic review to provide evidence that hyaluronidase actually improves analgesia. OBJECTIVES: To ascertain if adding hyaluronidase to local anaesthetic solutions for use in ophthalmic anaesthesia in adults results in a reduction of perceived pain during the operation and to assess harms, participant and surgical satisfaction, and economic impact. SEARCH METHODS: We carried out systematic searches in Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and four other databases in June 2017. We searched the trial registers at www.ISRCTN.com, ClinicalTrials.gov and www.clinicaltrialsregister.eu for relevant trials. We imposed no language restrictions. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that evaluated the effect of hyaluronidase on pain experienced by adults during intraocular surgery using a rating scale. DATA COLLECTION AND ANALYSIS: Two review authors (HR and KA) independently extracted data and assessed methodological quality using standard procedures as expected by Cochrane. MAIN RESULTS: We included seven trials involving 500 participants that studied the effect of hyaluronidase on intraoperative pain. Four of the seven trials with 289 participants reported the primary outcome in a dichotomous manner, and we proceeded to meta-analyse the findings which showed a moderate heterogeneity that could not be explained (I2 = 41% ). The pooled risk ratio (RR) for these four trials was 0.83 with the 95% confidence interval ranging from 0.48 to 1.42. The reduction in intraoperative pain scores in the hyaluronidase group were not statistically significant. Among the three trials that reported the primary outcome in a continuous manner, the presence of missing data made it difficult to conduct a meta-analysis. To further explore the data, we imputed standard deviations for the other studies from another included RCT (Sedghipour 2012). However, this resulted in substantial heterogeneity between study estimates (I2 = 76% ). The lack of reported relevant data in two of the three remaining trials made it difficult to assess the direction of effect in a clinical setting.Overall, there was no statistical difference regarding the intraoperative reduction of pain scores between the hyaluronidase and control group. All seven included trials had a low risk of bias.According to GRADE, we found the quality of evidence was low and downgraded the trials for serious risk of inconsistency and imprecision. Therefore, the results should be analysed with caution.Participant satisfaction scores were significantly higher in the hyaluronidase group in two high quality trials with 122 participants. Surgical satisfaction was also superior in two of three high quality trials involving 141 participants. According to GRADE, the quality of evidence was moderate for participant and surgical satisfaction as the trials were downgraded for imprecision due to the small sample sizes. The risk of bias in these trials was low.There was no reported harm due to the addition of hyaluronidase in any of the studies. No study reported on the cost of hyaluronidase in the context of eye surgery. AUTHORS' CONCLUSIONS: The effects of adding hyaluronidase to local anaesthetic fluid on pain outcomes in people undergoing eye surgery are uncertain due to the low quality of evidence available. A well designed RCT is required to address inconsistency and imprecision among the studies and to determine the benefit of hyaluronidase to improve analgesia during eye surgery. Participant and surgical satisfaction is higher with hyaluronidase compared to the control groups, as demonstrated in moderate quality studies. There was no harm attributed to the use of hyaluronidase in any of the studies. Considering that harm was only rarely defined as an outcome measure, and the overall small number of participants, conclusions cannot be drawn about the incidence of harmful effects of hyaluronidase. None of the studies undertook cost calculations with regards to use of hyaluronidase in local anaesthetic eye blocks. PMID- 29498414 TI - A method for the quantification of biased signalling at constitutively active receptors. AB - BACKGROUND AND PURPOSE: Biased agonism, the ability of an agonist to differentially activate one of several signal transduction pathways when acting at a given receptor, is an increasingly recognized phenomenon at many receptors. The Black and Leff operational model lacks a way to describe constitutive receptor activity and hence inverse agonism. Thus, it is impossible to analyse the biased signalling of inverse agonists using this model. In this theoretical work, we develop and illustrate methods for the analysis of biased inverse agonism. EXPERIMENTAL APPROACH: Methods were derived for quantifying biased signalling in systems that demonstrate constitutive activity using the modified operational model proposed by Slack and Hall. The methods were illustrated using Monte Carlo simulations. KEY RESULTS: The Monte Carlo simulations demonstrated that, with an appropriate experimental design, the model parameters are 'identifiable'. The method is consistent with methods based on the measurement of intrinsic relative activity (RAi ) (DeltaDeltalogR or DeltaDeltalog(tau/Ka )) proposed by Ehlert and Kenakin and their co-workers but has some advantages. In particular, it allows the quantification of ligand bias independently of 'system bias' removing the requirement to normalize to a standard ligand. CONCLUSIONS AND IMPLICATIONS: In systems with constitutive activity, the Slack and Hall model provides methods for quantifying the absolute bias of agonists and inverse agonists. This provides an alternative to methods based on RAi and is complementary to the DeltaDeltalog(tau/Ka ) method of Kenakin et al. in systems where use of that method is inappropriate due to the presence of constitutive activity. PMID- 29498415 TI - Rare compound heterozygous variants in PNKP identified by whole exome sequencing in a German patient with ataxia-oculomotor apraxia 4 and pilocytic astrocytoma. AB - Ataxia-oculomotor apraxia type 4 (AOA4) is a rare autosomal recessive neurologic disorder. The phenotype is characterized by ataxia, oculomotor apraxia, peripheral neuropathy and dystonia. AOA4 is caused by biallelic pathogenic variants in the PNKP gene encoding a polynucleotide kinase 3'-phosphatase with an important function in DNA-damage repair. By whole exome sequencing, we identified 2 variants within the PNKP gene in a 27-year-old German woman with a clinical AOA phenotype combined with a cerebellar pilocytic astrocytoma diagnosed at 23 years of age. One variant, a duplication in exon 14 resulting in the frameshift c.1253_1269dup p.(Thr424fs*49), has previously been described as pathogenic, for example, in cases of AOA4. The second variant, representing a nonsense mutation in exon 17, c.1545C>G p.(Tyr515*), has not yet been described and is predicted to cause a loss of the 7 C-terminal amino acids. This is the first description of AOA4 in a patient with central European descent. Furthermore, the occurrence of a pilocytic astrocytoma has not been described before in an AOA4 patient. Our data demonstrate compound heterozygous PNKP germline variants in a German patient with AOA4 and provide evidence for a possible link with tumor predisposition. Localization of the 2 variants in human PNKP NP_009185.2. NM_007254.3:c.1253_1269dup p.(Thr424fs*49) is predicted to cause a frameshift within the kinase domain, NM_007254.3:c.1545C>G p.(Tyr515*) is predicted to cause loss of 2 C-terminal amino acids of the kinase domain and 5 additional C-terminal amino acids. PMID- 29498416 TI - Workplace lighting for improving alertness and mood in daytime workers. AB - BACKGROUND: Exposure to light plays a crucial role in biological processes, influencing mood and alertness. Daytime workers may be exposed to insufficient or inappropriate light during daytime, leading to mood disturbances and decreases in levels of alertness. OBJECTIVES: To assess the effectiveness and safety of lighting interventions to improve alertness and mood in daytime workers. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, seven other databases; ClinicalTrials.gov and the World Health Organization trials portal up to January 2018. SELECTION CRITERIA: We included randomised controlled trials (RCTs), and non-randomised controlled before-after trials (CBAs) that employed a cross-over or parallel-group design, focusing on any type of lighting interventions applied for daytime workers. DATA COLLECTION AND ANALYSIS: Two review authors independently screened references in two stages, extracted outcome data and assessed risk of bias. We used standardised mean differences (SMDs) and 95% confidence intervals (CI) to pool data from different questionnaires and scales assessing the same outcome across different studies. We combined clinically homogeneous studies in a meta-analysis. We used the GRADE system to rate quality of evidence. MAIN RESULTS: The search yielded 2844 references. After screening titles and abstracts, we considered 34 full text articles for inclusion. We scrutinised reports against the eligibility criteria, resulting in the inclusion of five studies (three RCTs and two CBAs) with 282 participants altogether. These studies evaluated four types of comparisons: cool-white light, technically known as high correlated colour temperature (CCT) light versus standard illumination; different proportions of indirect and direct light; individually applied blue-enriched light versus no treatment; and individually applied morning bright light versus afternoon bright light for subsyndromal seasonal affective disorder.We found no studies comparing one level of illuminance versus another.We found two CBA studies (163 participants) comparing high CCT light with standard illumination. By pooling their results via meta-analysis we found that high CCT light may improve alertness (SMD -0.69, 95% CI -1.28 to -0.10; Columbia Jet Lag Scale and the Karolinska Sleepiness Scale) when compared to standard illumination. In one of the two CBA studies with 94 participants there was no difference in positive mood (mean difference (MD) 2.08, 95% CI -0.1 to 4.26) or negative mood (MD -0.45, 95% CI -1.84 to 0.94) assessed using the Positive and Negative Affect Schedule (PANAS) scale. High CCT light may have fewer adverse events than standard lighting (one CBA; 94 participants). Both studies were sponsored by the industry. We graded the quality of evidence as very low.We found no studies comparing light of a particular illuminance and light spectrum or CCT versus another combination of illuminance and light spectrum or CCT.We found no studies comparing daylight versus artificial light.We found one RCT (64 participants) comparing the effects of different proportions of direct and indirect light: 100% direct lighting, 70% direct lighting plus 30% indirect lighting, 30% direct lighting plus 70% indirect lighting and 100% indirect lighting. There was no substantial difference in mood, as assessed by the Beck Depression Inventory, or in adverse events, such as ocular, reading or concentration problems, in the short or medium term. We graded the quality of evidence as low.We found two RCTs comparing individually administered light versus no treatment. According to one RCT with 25 participants, blue-enriched light individually applied for 30 minutes a day may enhance alertness (MD -3.30, 95% CI -6.28 to -0.32; Epworth Sleepiness Scale) and may improve mood (MD -4.8, 95% CI -9.46 to -0.14; Beck Depression Inventory). We graded the quality of evidence as very low. One RCT with 30 participants compared individually applied morning bright light versus afternoon bright light for subsyndromal seasonal affective disorder. There was no substantial difference in alertness levels (MD 7.00, 95% CI -10.18 to 24.18), seasonal affective disorder symptoms (RR 1.60, 95% CI 0.81, 3.20; number of participants presenting with a decrease of at least 50% in SIGH-SAD scores) or frequency of adverse events (RR 0.53, 95% CI 0.26 to 1.07). Among all participants, 57% had a reduction of at least 50% in their SIGH-SAD score. We graded the quality of evidence as low.Publication bias could not be assessed for any of these comparisons. AUTHORS' CONCLUSIONS: There is very low-quality evidence based on two CBA studies that high CCT light may improve alertness, but not mood, in daytime workers. There is very low-quality evidence based on one CBA study that high CCT light may also cause less irritability, eye discomfort and headache than standard illumination. There is low-quality evidence based on one RCT that different proportions of direct and indirect light in the workplace do not affect alertness or mood. There is very low-quality evidence based on one RCT that individually applied blue enriched light improves both alertness and mood. There is low-quality evidence based on one RCT that individually administered bright light during the afternoon is as effective as morning exposure for improving alertness and mood in subsyndromal seasonal affective disorder. PMID- 29498417 TI - Phosphorus acquisition by citrate- and phytase-exuding Nicotiana tabacum plant mixtures depends on soil phosphorus availability and root intermingling. AB - Citrate and phytase root exudates contribute to improved phosphorus (P) acquisition efficiency in Nicotiana tabacum (tobacco) when both exudates are produced in a P deficient soil. To test the importance of root intermingling in the interaction of citrate and phytase exudates, Nicotiana tabacum plant-lines with constitutive expression of heterologous citrate (Cit) or fungal phytase (Phy) exudation traits were grown under two root treatments (roots separated or intermingled) and in two soils with contrasting soil P availability. Complementarity of plant mixtures varying in citrate efflux rate and mobility of the expressed phytase in soil was determined based on plant biomass and P accumulation. Soil P composition was evaluated using solution 31 P NMR spectroscopy. In the soil with limited available P, positive complementarity occurred in Cit+Phy mixtures with roots intermingled. Root separation eliminated positive interactions in mixtures expressing the less mobile phytase (Aspergillus niger PhyA) whereas positive complementarity persisted in mixtures that expressed the more mobile phytase (Peniophora lycii PhyA). Soils from Cit+Phy mixtures contained less inorganic P and more organic P compared to monocultures. Exudate specific strategies for the acquisition of soil P were most effective in P limited soil and depended on citrate efflux rate and the relative mobility of the expressed phytase in soil. Plant growth and soil P utilization in plant systems with complementary exudation strategies are expected to be greatest where exudates persist in soil and are expressed synchronously in space and time. PMID- 29498418 TI - Papillary Thyroid Carcinoma Recurrence: Low Yield of Neck Ultrasound With an Undetectable Serum Thyroglobulin Level. AB - OBJECTIVES: To assess the yield of neck ultrasound (US) when serum thyroglobulin (Tg) is undetectable (<0.1 ng/mL) compared to elevated serum Tg in patients with differentiated papillary thyroid carcinoma (PTC) treated with thyroidectomy and radioactive iodine 131 (RAI) ablation. METHODS: A retrospective chart review was conducted from 2010 through 2015 at an academic institution evaluating US results in patients with serum Tg levels obtained within 6 months of a neck US examination after thyroidectomy and RAI. The reference standard for recurrence was pathologic results from US-guided fine-needle aspiration (FNA) or follow-up for at least 1 year. RESULTS: Among 76 patients with undetectable serum Tg levels, there were 19 examinations in 18 patients in which US raised the possibility of recurrence. None of these 18 patients had recurrence by FNA (n = 8) or clinical follow-up of at least 1 year (n = 10). Among 65 patients with elevated serum Tg levels, there were 24 examinations in 22 patients in which US raised the possibility of recurrence. Twelve patients underwent FNA, with 9 patients (34.6%) showing PTC; 7 patients had follow-up neck US examinations showing stability of findings; and 3 patients were lost to follow up. The yield of neck US was significantly lower when serum Tg was undetectable compared to when levels were elevated (P = .001). CONCLUSIONS: Neck US did not identify recurrent PTC when the serum Tg level was undetectable in patients who underwent total thyroidectomy and RAI therapy. Eliminating neck US when serum TG levels are undetectable could decrease unnecessary imaging examinations without negatively affecting the ability to detect recurrent disease. PMID- 29498419 TI - Essential oils: effects of application rate and modality on potential for combating northern fowl mite infestations. AB - The northern fowl mite (NFM), Ornithonyssus sylviarum (Mesostigmata: Macronyssidae), is the primary blood-feeding ectoparasite found on poultry in the U.S.A. Three experiments were conducted in vitro to test the acaricidal properties of cade, garlic, lavender, lemongrass, pine and thyme essential oils against NFM, and to evaluate whether these effects are altered by adjusting oil application rates and application modality (direct vs. vapour contact). Applied at the rate of 0.21 mg/cm2 , the essential oils of cade, thyme, lemongrass and garlic resulted in higher NFM mortality at 24 h post-application than lavender and pine oils, and the untreated and ethanol-treated controls. Cade and thyme were the most consistent and fast-acting of the essential oils in terms of toxicity to NFM. Cade applied at 0.21 mg/cm2 and 0.11 mg/cm2 and thyme applied at 0.21 mg/cm2 were effective in eliminating NFM within 2 h through direct contact. The modality of application did not affect the efficacy of cade and thyme essential oils. The results suggest that essential oils may be utilized as alternatives to chemical pesticides and could be used as fumigants for the control of NFM. PMID- 29498420 TI - Identification and molecular characterization of the Brachypodium distachyon NRT2 family, with a major role of BdNRT2.1. AB - The small monocot plant Brachypodium distachyon is rapidly emerging as a powerful model system to study questions unique to the monocot crops. An extensive BLAST search was carried to identify putative orthologues of the Arabidopsis NRT2 genes in the fully sequenced Brachypodium genome. Seven genes encoding putative high affinity nitrate transporters (BdNRT2) were identified. Transcriptional analysis of individual BdNRT2 gene under various nitrogen sources and levels in the wild type and a T-DNA mutant of BdNRT2.1 were performed. A transgenic approach was taken to complement the bdnrt2.1 mutant. BdNRT2.1 and BdNRT2.2 were strongly induced by nitrate resupply to nitrogen-starved plants and were classified as inducible genes. BdNRT2.5 was found to be repressed by nitrate resupply whereas other members were constitutively expressed in the root. Interestingly, higher ammonium concentrations also triggered similar gene expression regulation, suggesting BdNRT2 gene expression was also governed by internal nitrogen status, not just external nitrate concentrations. In bdnrt2.1 mutant, the high-affinity transporter system (HATS) was reduced by 30% and BdNRT2.2 and BdNRT2.6 were differentially regulated. This pioneering research demonstrates that genes in the BdNRT2 family have diverse roles, differing from the Arabidopsis AtNRT2 family, in response to various nitrogen conditions. BdNRT2.1 serves as a key member of the family. PMID- 29498421 TI - Manual dexterity in young and healthy older adults. 2. Association with cognitive abilities. AB - Currently, little is known about the cognitive constraints underlying manual dexterity decline in aging. Here, we assessed the relationship between cognitive function and dexterity in 45 young and 55 healthy older adults. Effects of gender on the cognition-dexterity association were also explored. Cognitive assessment comprised neuropsychological tests of executive function, working memory, attention, and memory. Dexterity assessment included evaluation of movement times and kinematics during performance of unimanual and bimanual tasks of the Purdue Pegboard Test. Cognitive and dexterity group differences were established. Thereafter, regression analyses showed that executive function best predicted movement times and to some extent path lengths for the left hand in the older group. No gender differences were found in older participants. The findings confirm the involvement of executive function in manual dexterity in aging and suggest that movement times and path length may be useful parameters to assess the cognition-dexterity association in older adults. PMID- 29498422 TI - Consistency and stability of narrative coherence: An examination of personal narrative as a domain of adult personality. AB - OBJECTIVE: Narrative theories of personality assume that individual differences in coherence reflect consistent and stable differences in narrative style rather than situational and event-specific differences (e.g., McAdams & McLean, 2013). However, this assumption has received only modest empirical attention. Therefore, we present two studies testing the theoretical assumption of a consistent and stable coherent narrative style. METHOD: Study 1 focused on the two most traumatic and most positive life events of 224 undergraduates. These event specific narratives were coded for three coherence dimensions: theme, context, and chronology (NaCCs; Reese et al., 2011). Study 2 focused on two life narratives told 4 years apart by 98 adults, which were coded for thematic, causal, and temporal coherence (Kober, Schmiedek, & Habermas, 2015). RESULTS: Confirmatory factor analysis in both studies revealed that individual differences in the coherence ratings were best explained by a model including both narrative style and event-/narration-specific latent variables. CONCLUSIONS: The ways in which we tell autobiographical narratives reflect a stable feature of individual differences. Further, they suggest that this stable element of personality is necessary, but not sufficient, in accounting for specific event and life narrative coherence. PMID- 29498423 TI - A comparison of procedures for unpairing conditioned reflexive motivating operations. AB - This study compared the effectiveness of two procedures to reduce behavior evoked by a reflexive conditioned motivating operation (CMO-R). Task demands were shown to evoke escape-maintained problem behavior for 4 students with disabilities. Alternative communication responses were taught as an appropriate method to request escape and this treatment combined with extinction for problem behavior led to decreases in problem behavior for all students. A beeping timer was then arranged to temporally precede the task demand to create a CMO-R that evoked communication responses. When data showed that the sound of the timer was functioning as a CMO-R, two methods to reduce behavior evoked by a CMO-R extinction unpairing and noncontingent unpairing-were evaluated. Results indicated that noncontingent unpairing was an effective method to reduce the evocative effects of the CMO-R. Extinction produced unsystematic effects across participants. Results are discussed in terms of abolishing CMOs and the implications of CMOs. PMID- 29498424 TI - Discounting model selection with area-based measures: A case for numerical integration. AB - A novel method for analyzing delay discounting data is proposed. This newer metric, a model-based Area Under Curve (AUC) combining approximate Bayesian model selection and numerical integration, was compared to the point-based AUC methods developed by Myerson, Green, and Warusawitharana (2001) and extended by Borges, Kuang, Milhorn, and Yi (2016). Using data from computer simulation and a published study, comparisons of these methods indicated that a model-based form of AUC offered a more consistent and statistically robust measurement of area than provided by using point-based methods alone. Beyond providing a form of AUC directly from a discounting model, numerical integration methods permitted a general calculation in cases when the Effective Delay 50 (ED50) measure could not be calculated. This allowed discounting model selection to proceed in conditions where data are traditionally more challenging to model and measure, a situation where point-based AUC methods are often enlisted. Results from simulation and existing data indicated that numerical integration methods extended both the area based interpretation of delay discounting as well as the discounting model selection approach. Limitations of point-based AUC as a first-line analysis of discounting and additional extensions of discounting model selection were also discussed. PMID- 29498425 TI - Associations between informant ratings of personality disorder traits, self reports of personality, and directly observed behavior. AB - OBJECTIVE: Diagnoses of personality disorders (PD) must rely on judgments of observers-either clinicians or acquaintances-because personality disorders are primarily defined in terms of maladaptive interpersonal behavior. Little is known, however, about how closely acquaintances' judgments of PD traits relate to self-reports of theoretically relevant Big Five traits or directly observed behavioral outcomes in interpersonal situations. The present study examines associations between judgments of the 10 PD traits provided by close acquaintances, self-reports of PD-relevant Big Five personality traits, and observed interpersonal behaviors across three different three-person laboratory interactions (i.e., unstructured chat, cooperative task, competitive game). METHOD: The sample consisted of 256 undergraduate students (130 females; Mage = 19.83, SD = 1.25). Four unacquainted observers independently rated participants' behaviors from video recordings. RESULTS: In line with previous work, informant reports of PD traits demonstrate strong convergent validity with relevant self reported Big Five traits (as identified by Lynam & Widiger, 2001). Directly observed behavior is meaningfully associated with acquaintances' judgments and self-reports of PD-relevant traits, and the associations between these judgments and behavior are strongest for traits associated with histrionic and schizoid PD. Vector correlations between behavioral profiles associated with informant and self-reports show that both assessments have similar behavioral correlates. Associations between PD trait ratings and behavior appeared to differ as a function of gender, with males showing more and stronger correlations. CONCLUSIONS: Informants' ratings of PD traits are impressively accurate, converging both with self-reports of relevant traits and directly observed interpersonal behavior. Therefore, a comprehensive understanding of PDs and associated traits can be augmented by information from multiple acquaintances who have the opportunity to observe how an individual interacts with others on a daily basis across diverse contexts. PMID- 29498426 TI - Integrating programme evaluation and strategy: a promising practice. PMID- 29498427 TI - Simulated rounds: a multi-level learner OSCE. PMID- 29498428 TI - Cutaneous squamous cell carcinoma with epidermodysplasia verruciformis-like features in a patient with Schimke immune-osseous dysplasia. PMID- 29498429 TI - Understanding mothers' decision-making needs for autopsy consent after stillbirth: Framework analysis of a large survey. AB - BACKGROUND: Experiencing stillbirth is devastating and leaves parents searching for causes. Autopsy is the gold standard for investigation, but deciding to consent to this procedure is very difficult for parents. Decision support in the form of clear, consistent, and parent-centered information is likely to be helpful. The aims of this study were to understand the influences on parents' decisions about autopsy after stillbirth and to identify attributes of effective decision support that align with parents' needs. METHODS: Framework analysis using the Decision Drivers Model was used to analyze responses from 460 Australian and New Zealand (ANZ) mothers who took part in a multi-country online survey of parents' experiences of stillbirth. The main outcomes examined were factors influencing mothers' decisions to consent to autopsy after stillbirth. RESULTS: Free-text responses from 454 ANZ mothers referenced autopsy, yielding 1221 data segments for analysis. The data confirmed the difficult decision autopsy consent entails. Mothers had a strong need for answers coupled with a strong need to protect their baby. Four "decision drivers" were confirmed: preparedness for the decision; parental responsibility; possible consequences; and role of health professionals. Each had the capacity to influence decisions for or against autopsy. Also prominent were the "aftermath" of the decision: receiving the results; and decisional regret or uncertainty. CONCLUSIONS: The influences on decisions about autopsy are diverse and unpredictable. Effective decision support requires a consistent and structured approach that is built on understanding of parents' needs. PMID- 29498430 TI - Do private hospitals outperform public hospitals regarding efficiency, accessibility, and quality of care in the European Union? A literature review. AB - European countries have enhanced the scope of private provision within their health care systems. Privatizing services have been suggested as a means to improve access, quality, and efficiency in health care. This raises questions about the relative performance of private hospitals compared with public hospitals. Most systematic reviews that scrutinize the performance of the private hospitals originate from the United States. A systematic overview for Europe is nonexisting. We fill this gap with a systematic realist review comparing the performance of public hospitals to private hospitals on efficiency, accessibility, and quality of care in the European Union. This review synthesizes evidence from Italy, Germany, the United Kingdom, France, Greece, Austria, Spain, and Portugal. Most evidence suggests that public hospitals are at least as efficient as or are more efficient than private hospitals. Accessibility to broader populations is often a matter of concern in private provision: Patients with higher social-economic backgrounds hold better access to private hospital provision, especially in private parallel systems such as the United Kingdom and Greece. The existing evidence on quality of care is often too diverse to make a conclusive statement. In conclusion, the growth in private hospital provision seems not related to improvements in performance in Europe. Our evidence further suggests that the private (for-profit) hospital sector seems to react more strongly to (financial) incentives than other provider types. In such cases, policymakers either should very carefully develop adequate incentive structures or be hesitant to accommodate the growth of the private hospital sector. PMID- 29498431 TI - Addition of N-terminal pro-B natriuretic peptide to soluble fms-like tyrosine kinase-1/placental growth factor ratio > 38 improves prediction of pre-eclampsia requiring delivery within 1 week: a longitudinal cohort study. AB - OBJECTIVE: Short-term prediction of pre-eclampsia (PE) using the soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio is characterized by frequent false-positive results. As such, no treatment can be recommended to test-positive patients and multiple measurements are often required. The aim of this study was to evaluate the effectiveness of N-terminal pro-B natriuretic peptide (NT-proBNP), uric acid and the sFlt-1/PlGF ratio for prediction of delivery with PE within 1 week in singleton pregnancies with suspected PE and sFlt-1/PlGF ratio > 38. METHODS: This was a longitudinal prospective cohort study of singleton pregnancies presenting at 24 + 0 to 36 + 6 weeks of gestation with clinically suspected PE and sFlt-1/PlGF ratio > 38, enrolled between January 2015 and June 2017. Multiple samples per patient were allowed but were restricted to one sample per gestational week. From 495 enrolled patients, 270 blood samples from 134 patients were ultimately analyzed. By using generalized estimating equations (GEE), the best-fit model was selected for prediction of delivery with PE within 1 week. The predictive value of this model was then assessed using area under the paired-ROC curve (AUC) analysis. RESULTS: The best-fit model included the sFlt-1/PlGF ratio, NT-proBNP and the gestational week at the time of the measurement. This combined model was compared with the GEE model based on the sFlt-1/PlGF ratio and the gestational week at the time of the measurement (reduced model). The AUC for the combined model was 0.845 (95% CI, 0.787-0.896), which was significantly greater (P = 0.011) than that of the reduced model (0.786 (95% CI, 0.722-0.844)). CONCLUSION: The addition of NT-proBNP assessment improves the short-term prediction of delivery as a result of PE compared with sFlt-1/PlGF ratio alone, when the sFlt-1/PlGF ratio is > 38. This finding should be considered in future research on the assessment of short-term risk of delivery as a result of PE. Copyright (c) 2018 ISUOG. Published by John Wiley & Sons Ltd. PMID- 29498432 TI - The third annual Northeastern Evolutionary Primatologists meeting at Yale University. PMID- 29498433 TI - The influence of clerkship on students' stigma towards mental illness: a meta analysis. AB - CONTEXT: In university programmes preparing students to work with patients with mental illness, clerkship is proposed as a component that may contribute to the battle against stigma, through bringing students into contact with the patients' reality. Yet, the precise contribution of clerkship remains unclear, perhaps because of the variety of university programmes, clerkship characteristics or types of stigma explored. This is the first systematic meta-analysis of available evidence determining the precise effect size of the influence of clerkship on stigma and the potential moderators. METHODS: We carried out a systematic literature review in Eric, PsycINFO, Pubmed, Scopus, UMI and Proquest dissertations, aiming to identify all the studies exploring health care students' stigma of mental illness (measured as overall stigma or as attitudes, affect and behavioural intentions) before and after a clerkship from 2000 to 2017. Twenty two studies were included in the meta-analysis, providing data from 22 independent samples. The total sample consisted of 3161 students. The effects of programme (medicine, nursing, occupational therapy, and their combination), study design (paired-unpaired samples), publication year, sex, age and clerkship context, and inclusion of theoretical training and duration, were examined as potential moderators. RESULTS: Our analyses yielded a highly significant medium effect size for overall stigma (Hedge's g = 0.35; p < 0.001; 95% confidence interval [CI], 0.20, 0.42), attitudes (Hedge's g = 0.308; p = 0.003; 95% CI, 0.10, 0.51) and behavioural intentions (Hedge's g = 0.247; p < 0.001; 95% CI, 0.17, 0.33), indicating a considerable change, whereas there was no significant change in the students' affect. Moderator analyses provided evidence for the distinct nature of each stigma outcome, as they were influenced by different clerkship and student characteristics such as clerkship context, theoretical training, age and sex. CONCLUSIONS: The robust effect of clerkship on students' stigma of mental illness established by the present meta-analysis highlights its role as a crucial curriculum component for experiential learning and as a necessary agent for the battle against stigma. PMID- 29498434 TI - Predictive Movements and Human Reinforcement Learning of Sequential Action. AB - Sequential action makes up the bulk of human daily activity, and yet much remains unknown about how people learn such actions. In one motor learning paradigm, the serial reaction time (SRT) task, people are taught a consistent sequence of button presses by cueing them with the next target response. However, the SRT task only records keypress response times to a cued target, and thus it cannot reveal the full time-course of motion, including predictive movements. This paper describes a mouse movement trajectory SRT task in which the cursor must be moved to a cued location. We replicated keypress SRT results, but also found that predictive movement-before the next cue appears-increased during the experiment. Moreover, trajectory analyses revealed that people developed a centering strategy under uncertainty. In a second experiment, we made prediction explicit, no longer cueing targets. Thus, participants had to explore the response alternatives and learn via reinforcement, receiving rewards and penalties for correct and incorrect actions, respectively. Participants were not told whether the sequence of stimuli was deterministic, nor if it would repeat, nor how long it was. Given the difficulty of the task, it is unsurprising that some learners performed poorly. However, many learners performed remarkably well, and some acquired the full 10-item sequence within 10 repetitions. Comparing the high- and low performers' detailed results in this reinforcement learning (RL) task with the first experiment's cued trajectory SRT task, we found similarities between the two tasks, suggesting that the effects in Experiment 1 are due to predictive, rather than reactive processes. Finally, we found that two standard model-free reinforcement learning models fit the high-performing participants, while the four low-performing participants provide better fit with a simple negative recency bias model. PMID- 29498435 TI - Dental follicle mesenchymal stem cells down-regulate Th2-mediated immune response in asthmatic patients mononuclear cells. AB - BACKGROUND: Asthma is a chronic inflammatory disease in which inflammatory responses have the polarisation of CD4+ T cells to Th2 cells. Dental follicle mesenchymal stem cells (DFSCs) have strong anti-inflammatory properties comparable to other mesenchymal stem cells. OBJECTIVE: We investigated the immunomodulatory effects of DFSCs on CD4+ T helper cell responses of asthmatic patients and compared the results with those obtained with asthmatic subjects on immunotherapy and with healthy individuals. METHOD: Peripheral blood mononuclear cells (PBMC) were isolated from immunotherapy naive asthmatics, asthmatics on subcutaneous Der p1 immunotherapy and from healthy individuals. PBMC were pre conditioned with anti-CD3/anti-CD28 mAbs, Der p1 or IFN-gamma in the presence and absence of DFSCs and analysed for T cell viability and proliferation, CD4+ CD25+ FOXP3+ regulatory T cell frequencies, cytokine expression, and GATA3, T bet and FoxP3 expressions. Neutralisation of TGF-beta and blockade of IDO and PGE2 pathways were performed to determine suppressive signalling pathways of DFSCs. RESULTS: Dental follicle mesenchymal stem cells suppressed proliferative responses of CD4+ T lymphocytes and increased the frequency of Treg cells. DFSCs decreased effector and effector memory CD4+ T cell phenotypes in favour of naive T cell markers. DFSCs decreased IL-4 and GATA3 expression and increased IFN gamma, T-bet and IL-10 expression in asthmatics. Costimulatory molecules were suppressed in monocytes with DFSCs in the cocultures. DFSCs down-regulated inflammatory responses via IDO and TGF-beta pathways in asthmatic patients. CONCLUSION: Dental follicle mesenchymal stem cells suppressed allergen-induced Th2-cell polarisation in favour of Th1 responses and attenuated antigen presenting cell co-stimulatory activities. These studies suggest that DFSC-based cell therapy may provide pro-tolerogenic immunomodulation relevant to allergic diseases such as asthma. PMID- 29498436 TI - A Capping Step During Automated Glycan Assembly Enables Access to Complex Glycans in High Yield. AB - The products of multi-step automated solid phase syntheses are purified after release from the resin. Capping of unreacted nucleophiles is commonplace in automated oligonucleotide synthesis to minimize accumulation of deletion sequences. To date, capping was not used routinely during automated glycan assembly (AGA) since previous capping protocols suffered from long reaction times and conditions incompatible with some protective groups. Here, a method using methanesulfonic acid and acetic anhydride for the fast and quantitative capping of hydroxyl groups that failed to be glycosylated is reported. Commonly used protective groups in AGA are stable under these capping conditions. The introduction of a capping step into the coupling cycle drastically improved overall yields by decreasing side-products and simplifying purification, while reducing building block consumption. To illustrate the method, the biologically important tetrasaccharide Lc4, as well as a 50-mer polymannoside were prepared. PMID- 29498437 TI - Evaluating the Theoretic Adequacy and Applied Potential of Computational Models of the Spacing Effect. AB - The spacing effect is among the most widely replicated empirical phenomena in the learning sciences, and its relevance to education and training is readily apparent. Yet successful applications of spacing effect research to education and training is rare. Computational modeling can provide the crucial link between a century of accumulated experimental data on the spacing effect and the emerging interest in using that research to enable adaptive instruction. In this paper, we review relevant literature and identify 10 criteria for rigorously evaluating computational models of the spacing effect. Five relate to evaluating the theoretic adequacy of a model, and five relate to evaluating its application potential. We use these criteria to evaluate a novel computational model of the spacing effect called the Predictive Performance Equation (PPE). Predictive Performance Equation combines elements of earlier models of learning and memory including the General Performance Equation, Adaptive Control of Thought-Rational, and the New Theory of Disuse, giving rise to a novel computational account of the spacing effect that performs favorably across the complete sets of theoretic and applied criteria. We implemented two other previously published computational models of the spacing effect and compare them to PPE using the theoretic and applied criteria as guides. PMID- 29498438 TI - Redox-triggered chiroptical switching activity of ruthenium(III)-bis-(beta diketonato) complexes bearing a bipyridine-helicene ligand. AB - The charged, electroactive bipyridine-helicene-ruthenium(III) complex [4].+ ,PF6- has been prepared from 3-(2-pyridyl)-4-aza[6]helicene and a Ru-bis-(beta diketonato)-bis-acetonitrile precursor (beta-diketonato: 2,2,6,6-tetramethyl-3,5 heptanedionato). Its chiroptical properties (electronic circular dichroism and optical rotation) were studied both experimentally and theoretically and suggest the presence of 2 diastereoisomers, namely (P,Delta)- and (P,Lambda)-[4].+ ,PF6- (denoted jointly as (P,Delta*)-[4].+ ,PF6- ) and their mirror-images (M,Lambda)- and (M,Delta)-[4].+ ,PF6- ((M,Delta*)-[4].+ ,PF6- ). The electrochemical reduction of (P,Delta*)-[4].+ ,PF6- to neutral complex (P,Delta*)-4 was performed and revealed strong changes in the UV-vis and electronic circular dichroism spectra. A reversible redox-triggered chiroptical switching process was then achieved. PMID- 29498439 TI - Synthetic Regulation of 1,4-Dihydropyridines for the AIE or AIEE Effect: From Rational Design to Mechanistic Views. AB - Aggregation-induced emission/aggregation-induced emission enhancement (AIE/AIEE) has recently attracted intense research, and a large number of AIE/AIEE luminogens (AIE/AIEEgens) have been constructed for application in diverse scientific fields. The AIE and AIEE effects have similar, but not identical, photophysical behaviors, which are closely related to molecular architectures. However, the current understanding of the inherent differences between AIE and AIEE is still obscure. Herein, a rational design strategy is reported for achieving AIE and AIEE effects by simply incorporating different substituents at the periphery of the same core skeleton. Experimental and theoretical studies on the series of compounds indicated that the restriction of intramolecular twisting motions or/and rotations plays an important role in regard to the corresponding AIE or AIEE behaviors. Moreover, compound 1 a (FW=203, PhiF =80.9 %) was discovered as the lowest molecular weight AIEEgen with a high quantum yield in the solid state despite having no rotatable units. Compound 2 a also exhibited an AIEE effect with the minimum necessary structure (a single ring). PMID- 29498440 TI - Molecular enantiorecognition of l-glucose and d-glucose in whole blood samples. AB - In the past years, enantioanalysis became very important for clinical analysis; biomarkers/substances of biomedical importance with chiral structure should be analyzed and their presence correlated with the specific disorder. Therefore, we developed a method for the assay of l- and d-glucose, based on molecular recognition of l- and d-glucose. While for d-glucose there are many methods to assess its quantity, the l-enantiomer is not routinely detected by standard methods. Two stochastic microsensors based on the immobilization of Copper(II)phthalocyanine and Ni(II)phthalocyanine, in natural diamond powder, were proposed for the enantioanalysis of glucose. The proposed methods proved to have high sensitivities and were able to be used for determination of concentrations as low as 2.5 pg mL-1 for d-glucose and as low as 2.5 fg mL-1 for l-glucose. The enatioanalysis was performed with good results in whole blood samples collected from diabetic patients. PMID- 29498441 TI - Release of Isonitrile- and NHC-Stabilized Borylenes from Group VI Terminal Borylene Complexes. AB - A family of doubly isonitrile-stabilized terphenyl borylenes could be obtained by addition of three equivalents of isonitrile to the corresponding Cr and W terminal terphenyl-borylene complexes. The mechanism of isonitrile- and carbon monoxide-induced borylene liberation was investigated computationally and found to be significantly exergonic in both cases. Furthermore, addition of a small N heterocyclic carbene (NHC) to a terminal Cr borylene complex results in release of an NHC-stabilized borylene carbonyl species, whereas the analogous reaction with bulkier phosphines results in metal-centered substitution. PMID- 29498444 TI - Innovations and advancements with prosthetic breast reconstruction. AB - Prosthetic breast reconstruction has evolved over the years to provide results that now mimic that of a natural breast. This is due to a variety of innovations and advancements related to mastectomy techniques, acellular dermal matrices, autologous fat grafting, and improved breast implants. The evolution of prosthetic breast reconstruction has gone full-circle and included prepectoral placement in the 1970s and 80s, partial or total subpectoral placement from 1985 to 2015, and now gradually trending back to prepectoral. There are several techniques and strategies that now allow for patients to achieve results that are superior to any time over the past 50 years. This manuscript will review the salient aspects of prosthetic breast reconstruction and how its evolution has progressed over the years. PMID- 29498443 TI - Outcomes of "one-day" vs "two-day" injection protocols using Tc-99m tilmanocept for sentinel lymph node biopsy in breast cancer. AB - No prior studies have compared Tc-99m tilmanocept (TcTM) one-day and two-day injection protocols for sentinel lymph node (SLN) biopsy in breast cancer (BC). We retrospectively identified patients with clinically node-negative BC undergoing SLN biopsy at our institution. Patients received a single, intradermal peritumoral injection of TcTM on day of surgery or day prior to surgery in addition to an intraoperative injection of isosulfan blue dye. Univariable and multivariable Poisson regression count models were constructed to assess the effects of injection timing, radiologist, patient and surgeon characteristics on the number of removed SLNs. A total of 617 patients underwent SLN biopsy with TcTM and blue dye. Sixty-seven (10.9%) patients were injected with the two-day protocol. Patients in the one-day protocol had a mean of 3.0 (standard deviation (SD) 1.9) SLNs removed compared with 2.7 (SD 1.4) SLNs in the two-day protocol, P value = .13. On multivariable analysis, patient age and operating surgeon significantly affected the number of removed SLNs; however, the injection timing and the nuclear radiologist did not influence the number of removed SLNs. The performance of Tc-99m tilmanocept did not differ significantly between one-day and two-day injection protocols. These results are similar to other radiotracers used for SLN biopsy in BC. PMID- 29498442 TI - Vitis vinifera berry metabolic composition during maturation: Implications of defoliation. AB - Leaves are an important contributor toward berry sugar and nitrogen (N) accumulation, and leaf area, therefore, affects fruit composition during grapevine (Vitis vinifera) berry ripening. The aim of this study was to investigate the impact of leaf presence on key berry quality attributes in conjunction with the accumulation of primary berry metabolites. Shortly after the start of veraison (berry ripening), potted grapevines were defoliated (total defoliation and 25% of the control), and the accumulation of berry soluble solids, N and anthocyanins were compared to that of a full leaf area control. An untargeted approach was undertaken to measure the content in primary metabolites by gas chromatography/mass spectrometry. Partial and full defoliation resulted in reduced berry sugar and anthocyanin accumulation, while total berry N content was unaffected. The juice yeast assimilable N (YAN), however, increased upon partial and full defoliation. Remobilized carbohydrate reserves allowed accumulation of the major berry sugars during the absence of leaf photoassimilation. Berry anthocyanin biosynthesis was strongly inhibited by defoliation, which could relate to the carbon (C) source limitation and/or increased bunch exposure. Arginine accumulation, likely resulting from reserve translocation, contributed to increased YAN upon defoliation. Furthermore, assessing the implications on various products of the shikimate pathway suggests the C flux through this pathway to be largely affected by leaf source limitation during fruit maturation. This study provides a novel investigation of impacts of leaf C and N source presence during berry maturation, on the development of key berry quality parameters as underlined by alterations in primary metabolism. PMID- 29498445 TI - Impact of preoperative BRCA1/2 testing on surgical decision making in patients with newly diagnosed breast cancer. AB - The utility and benefit of integrating germ-line genetic testing into the management of newly diagnosed breast cancer is not fully understood. This study evaluates the impact of preoperative genetic testing on surgical decision making in patients with newly diagnosed breast cancer. Women with newly diagnosed breast cancer were classified into preoperative or postoperative genetic testing group, depending on whether they received their genetic testing results prior to or after their first surgery. Demographics, tumor characteristics, surgical treatment, and results of genetic testing were retrospectively collected. A total of 997 patients were evaluated, 531 (53.3%) in the preoperative genetic testing group and 466 (46.7%) in the postoperative group. Majority (87.2%) of BRCA positive women in the preoperative group underwent bilateral mastectomy as first surgery. Majority (70.6%) of BRCA-positive women in postoperative group underwent partial mastectomy as first surgery prior to receiving their genetic testing result. Nearly half (41.2%) of these women in the postoperative group with partial mastectomy underwent bilateral mastectomy after receiving their BRCA positive result. Time from diagnosis to first surgery was longer in the preoperative genetic testing group. Younger age, bilateral cancer, BRCA1/2 positive results, and preoperative genetic testing were significant predictors of bilateral mastectomy at first surgery. Preoperative genetic testing impacts initial surgical treatment in BRCA1/2-positive patients and reduces the need for additional surgeries. PMID- 29498446 TI - Empyema necessitans mimicking inflammatory breast cancer-An unusual case of breast edema. PMID- 29498447 TI - Common Patterns in Chaperone Interactions with a Native Client Protein. AB - Many molecular chaperones are promiscuous and interact with a wide range of unfolded, quasi-native, and native client proteins. The mechanisms by which chaperones interact with the highly diverse structures of native clients thus remain puzzling. In this work, we investigate at the atomic level how three ATP independent chaperones interact with a beta-sheet-rich protein, the Fyn SH3 domain. The results reveal that the chaperone Spy recognizes the locally frustrated surface of the client Fyn SH3 and that the interaction is transient and highly dynamic, leaving the chaperone-interacting surface on Fyn SH3 solvent accessible. The two alternative molecular chaperones SurA and Skp recognize the same locally frustrated surface of the Fyn SH3 domain. These results indicate dynamic recognition of frustrated segments as a common mechanism underlying the chaperone-native client interaction, which also provides a basis for chaperone promiscuousness. PMID- 29498448 TI - Variations in cancer care for adolescents and young adults (AYAs) with ductal carcinoma in situ. AB - NCCN guidelines recommend tamoxifen (TAM) for adjuvant treatment of ductal carcinoma in situ (DCIS). TAM has side effects that can potentially complicate treatment recommendations and patient acceptance. It is unknown how well-accepted this recommended therapy is for the adolescent and young adult (AYA) patient population with DCIS. The NCDB was used to identify patients aged 15-39 with DCIS treated between 2000 and 2012. Patient demographic, socioeconomic, and treatment data were collected. Chi-squared test and multivariate analysis were used for statistical assessment. A total of 3988 women were identified of which 1795 (45%) were recommended for endocrine therapy. Age > 30 (OR 1.31, 95%CI 1.01-1.70), Black (OR 1.40, 95% CI 1.12-1.65), or Asian (OR 1.45, 95% CI 1.08-1.94) race, treatment at a nonacademic facility (OR 0.71, 95% CI 0.56-0.91), geographic location of treating facility, receipt of radiation (OR 5.30, 95% CI 4.59-6.11), and negative margins (OR 2.14, 95% CI 1.47-3.11) were significant predictors of recommendation for endocrine therapy. Of those recommended, 1484 (83%) accepted treatment. Age, race, and annual income were significant variables affecting acceptance. Overall, only 37.2% (1484 of 3988) of women in this study initiated endocrine therapy for treatment of DCIS. Our results demonstrate that little over a third of patients in the AYA cohort receive endocrine therapy as treatment for DCIS. The bias appears to lie in physician recommendation because when recommended, the majority of patients accept treatment. Factors exist both medical and nonmedical that appear to influence these treatment decisions. PMID- 29498449 TI - HER2 equivocal breast cancer that is positive by alternative probe HER2 FISH are classified as HER2 negative by Oncotype DX. AB - In breast cancer, human epidermal growth factor receptor 2 (HER2) status is determined by immunohistochemistry (IHC) and/or in situ hybridization. Oncotype DX also reports HER2 status by an rt-PCR-based assay. Assay concordance between IHC and fluorescent in situ hybridization (FISH) (including alternative probe HER2 FISH) vs Oncotype DX HER2 rt-PCR has not been described in the post-2013 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) HER2 Guideline revision setting. We performed a retrospective review of HER2 equivocal invasive breast carcinoma from 2014 to 2016 with the Oncotype DX HER2 result. Fifteen patients with HER2 equivocal invasive breast cancer had Oncotype DX performed. Of these, 13 underwent alternative probe HER2 FISH yielding 4 negative, 6 equivocal and 3 positive results. All 15 cases were classified as HER2 negative by Oncotype DX rt-PCR, including the three cases which were positive by alternative probe HER2 FISH, yielding a discordance rate for Oncotype DX rt-PCR HER2 of 20% (3/15). All three patients with HER2-positive breast cancer on the basis of alternative probe HER2 FISH received anti-HER2-targeted therapy. Treatment decisions based on HER2 status should utilize the IHC/FISH result as Oncotype DX results may incorrectly disqualify some patients from being eligible for anti-HER2 therapy based on the current 2013 ASCO/CAP HER2 Guidelines. PMID- 29498450 TI - An updated Meta-Analysis of radioactive seed localization versus wire-guided localization in the treatment of nonpalpable breast lesions. PMID- 29498451 TI - 50 years with Down syndrome: A longitudinal study. AB - BACKGROUND: A population sample of people with Down syndrome, studied from infancy, has now been followed up at the age of 50 years. From the original sample of 54, there were 27 still in the study at the age of 50, all but four of the losses resulting from deaths. METHODS: Intelligence and language skills were tested and daily living skills assessed. Memory/cognitive deterioration was examined using two test instruments. Other aspects of the people's lives were examined via carers' reports. RESULTS: Scores on verbal tests showed little change. Those on a non-verbal test, on self-help skills and on both memory tests showed some decline, even when the scores of those already suffering from dementia were discounted. CONCLUSIONS: At the age of 50, those not already diagnosed with dementia showed some decline on most tests. While this may include scores of people who subsequently develop dementia, it may also reflect the normal ageing process in this population. PMID- 29498452 TI - Ryanodine receptor type 3 (RYR3) as a novel gene associated with a myopathy with nemaline bodies. AB - BACKGROUND AND PURPOSE: Nemaline myopathy (NEM) has been associated with mutations in 12 genes to date. However, for some patients diagnosed with NEM, definitive mutations are not identified in the known genes, suggesting that there are other genes involved. This study describes compound heterozygosity for rare variants in ryanodine receptor type 3 (RYR3) gene in one such patient. METHODS AND RESULTS: Clinical examination of the patient at 22 years of age revealed a long narrow face, high arched palate and bilateral facial weakness. She had proximal weakness in all four limbs, mild scapular winging but no scoliosis. Muscle biopsy revealed wide variation in fibre size with type 1 fibre predominance and atrophy. Abundant nemaline bodies were located in perinuclear and subsarcolemmal areas, and within the cytoplasm. No likely pathogenic mutations in known NEM genes were identified. Copy number variation in known NEM genes was excluded by NEM-targeted comparative genomic hybridization array. Next generation sequencing revealed compound heterozygous missense variants in the RYR3 gene. RYR3 transcripts are expressed in human fetal and adult skeletal muscle as well as in human brain and cauda equina samples. Immunofluorescence of human skeletal muscle revealed a 'single-row' appearance of RYR3, interspersed between the 'double rows' of ryanodine receptor type 1 (RYR1) at each A-I junction. CONCLUSION: The results suggest that variants in RYR3 may cause a recessive muscle disease with pathological features including nemaline bodies. We characterize the expression pattern of RYR3 in human skeletal muscle and brain, and the subcellular localization of RYR1 and RYR3 in human skeletal muscle. PMID- 29498453 TI - Primary tumor resection in metastatic breast cancer: A propensity-matched analysis, 1988-2011 SEER data base. AB - Primary tumor resection (PTR) in metastatic breast cancer is not a standard treatment modality, and its impact on survival is conflicting. The primary objective of this study was to analyze impact of PTR on survival in metastatic patients with breast cancer. A retrospective study of metastatic patients with breast cancer was conducted using the 1988-2011 Surveillance, Epidemiology, and End Results (SEER) data base. Cox proportional hazards regression models were used to evaluate the relationship between PTR and survival and to adjust for the heterogeneity between the groups, and a propensity score-matched analysis was also performed. A total of 29 916 patients with metastatic breast cancer were included in the study, and 15 129 (51%) of patients underwent primary tumor resection, and 14 787 (49%) patients did not undergo surgery. Overall, decreasing trend in PTR for metastatic breast cancer in last decades was noted. Primary tumor resection was associated with a longer median OS (34 vs 18 months). In a propensity score-matched analysis, prognosis was also more favorable in the resected group (P = .0017). Primary tumor resection in metastatic breast cancer was associated with survival improvement, and the improvement persisted in propensity-matched analysis. PMID- 29498454 TI - Sebaceous carcinoma of the breast: Histological, cytological, and ultrastructural features. PMID- 29498455 TI - Ethnicity influences breast cancer stem cells' drug resistance. PMID- 29498456 TI - Severe hyponatremia following cyclophosphamide infusion in breast cancer patients. PMID- 29498458 TI - Do women with dense breasts have higher radiation dose during screening mammography? PMID- 29498457 TI - Rikkunshito simultaneously improves dyspepsia correlated with anxiety in patients with functional dyspepsia: A randomized clinical trial (the DREAM study). AB - BACKGROUND: Functional dyspepsia (FD), a heterogeneous disorder, involves multiple pathogenetic mechanisms. Developing treatments for FD has been challenging. We performed a randomized, placebo-controlled, double-blind clinical trial to determine the efficacy of rikkunshito, a Japanese herbal medicine, in FD patients. METHODS: FD patients (n = 192) who met the Rome III criteria without Helicobacter pylori infection, predominant heartburn, and depression were enrolled at 56 hospitals in Japan. After 2 weeks of single-blind placebo treatment, 128 patients with continuous symptoms were randomly assigned to 8 weeks of rikkunshito (n = 64) or placebo (n = 61). The primary efficacy endpoint was global assessment of overall treatment efficacy (OTE). The secondary efficacy endpoints were improvements in upper gastrointestinal symptoms evaluated by the Patient Assessment of Upper Gastrointestinal Disorders-Symptom Severity Index (PAGI-SYM), the Global Overall Symptom scale (GOS), and the modified Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (m-FSSG), and psychological symptoms evaluated by the Hospital Anxiety and Depression Scale (HADS). KEY RESULTS: Rikkunshito increased OTE compared to placebo at 8 weeks (P = .019). Rikkunshito improved upper gastrointestinal symptoms (PAGI-SYM, GOS, and m-FSSG) at 8 weeks, especially postprandial fullness/early satiety (P = .015 and P = .001) and bloating (P = .007 and P = .002) of the PAGI-SYM subscales at 4 weeks and 8 weeks. Improvement of HADS at 8 weeks (P = .027) correlated with those of PAGI-SYM (r = .302, P = .001), GOS (r = .186, P = .044), and m-FSSG (r = .462, P < .001), postprandial fullness/early satiety (r = .226, P = .014), dyspepsia (r = .215, P = .019), and PDS (r = .221, P = .016). CONCLUSION & INFERENCES: Rikkunshito may be beneficial for FD patients to simultaneously treat gastrointestinal and psychological symptoms. PMID- 29498459 TI - Mental health service user and staff perspectives on tobacco addiction and smoking cessation: A meta-synthesis of published qualitative studies. AB - : WHAT IS KNOWN ON THE SUBJECT?: There are high rates of tobacco smoking in people living with mental illness, and rates are much higher than the general population. People living with mental illness experience high rates of cardiovascular disease and other physical health problems as a result of tobacco smoking. There is a lack of evidence on successful interventions for reducing the rates of smoking in people living with mental illness. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: A meta-synthesis of data from a number of studies to support mental health nurses to access data quickly and support the translation of findings into practice. Studies found staff working in mental health services expressed they did not have the confidence to adequately address smoking cessation for people living with mental illness. People living with mental illness would like support and encouragement support to help them achieve successful smoking cessation. People living with mental illness want support from mental health service staff to increase their confidence in smoking cessation rather than mainstream smoking cessation services. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Existing evidence-based interventions for smoking cessation has had limited impact on the smoking rates of people living with mental illness. Research is needed into innovative smoking cessation interventions and the service delivery of these interventions for people living with mental illness. Interventions to support people living with mental illness in smoking cessation could be part of mainstream mental health service delivery. Opportunities for smoking cessation training for mental health service staff could be provided. ABSTRACT: Introduction People with mental illness are up to three times more likely to smoke and experience greater challenges and less success when trying to quit and therefore have higher risk of smoking-related morbidity and mortality. There is a lack of evidence on successful interventions to reduce the smoking rates in people living with serve mental illness. A meta-synthesis was undertaken to summarize the data from multiple studies to inform the development of future smoking cessation intervention studies. Methods MEDLINE, PsycINFO, Embase and CINAHL were searched in March 2017. A total of 965 titles and abstracts were screened for inclusion with 29 papers reviewed in full and 15 studies that met inclusion criteria. Included studies were assessed for quality using the Critical Appraisal Skills Programme tool. Key data across studies were examined and compared, and a thematic analysis was conducted. Results Analysis and synthesis developed five analytical themes: environmental and social context, living with a mental health illness, health awareness, financial awareness and provision of smoking cessation support. Themes generated the interpretive construct: "Whose role is it anyway?" which highlights tensions between staff perspectives on their role and responsibilities to providing smoking cessation support and support service users would like to receive. Relevance to mental health nursing Routine smoking cessation training for mental health professionals and research on innovative smoking cessation interventions to support people living with mental illness are needed. The Cochrane tobacco group has not found sufficient direct evidence of existing evidence-based interventions that have beneficial effect on smoking in people living with mental illness. With this in mind, mental health professionals should be encouraged to engage in future research into the development of new interventions and consider innovative harm reduction strategies for smoking into their practice, to reduce the morbidity and mortality many people living with mental illness experience from tobacco smoking. PMID- 29498460 TI - Chemical Mapping by Macroscopic X-ray Powder Diffraction (MA-XRPD) of Van Gogh's Sunflowers: Identification of Areas with Higher Degradation Risk. AB - The discoloration rate of chrome yellow (CY), a class of synthetic inorganic pigments (PbCr1-x Sx O4 ) frequently used by Van Gogh and his contemporaries, strongly depends on its sulfate content and on its crystalline structure (either monoclinic or orthorhombic). Macroscopic X-Ray powder diffraction imaging of selected areas on Van Gogh's Sunflowers (Van Gogh Museum, Amsterdam) revealed the presence of two subtypes of CY: the light-fast monoclinic PbCrO4 (LF-CY) and the light-sensitive monoclinic PbCr1-x Sx O4 (x~0.5; LS-CY). The latter was encountered in large parts of the painting (e.g., in the pale-yellow background and the bright-yellow petals, but also in the green stems and flower hearts), thus indicating their higher risk for past or future darkening. Overall, it is present in more than 50 % of the CY regions. Preferred orientation of LS-CY allows observation of a significant ordering of the elongated crystallites along the direction of Van Gogh's brush strokes. PMID- 29498461 TI - Facile Synthesis of Single alpha-tert-Alkylated Acetaldehydes by Hydroxyalkylation of Enamides in Aqueous Solution. AB - In this work, we established a general protocol to synthesize single alpha-tert alkylated acetaldehydes via Cu-catalyzed hydroxyalkylation of enamides in aqueous solutions. The yields of the products were very high and there was excellent functional group compatibility. Our reaction allows easy access to highly functionalized acetaldehydes that can be used to synthesize further useful compounds including spirocycles. The control experiments revealed that this reaction includes hydroxyalkylation processes via radical reactions. PMID- 29498462 TI - Cutaneous metastases from carcinoma breast presenting as vesiculo-bullous lesion. PMID- 29498463 TI - Ruthenium-Catalyzed Cascade Annulation of Indole with Propargyl Alcohols. AB - Cascade transformations forming multiple bonds and one-pot procedures provide rapid access to natural-product-like scaffolds from simple precursors. These atom economic processes are valuable tools in organic synthesis and drug discovery. Herein, we report on ruthenium-catalyzed cascade annulations of indole with readily available propargyl alcohols. These provide rapid access to diverse carbazoles, cyclohepta[b]indoles, and further fused polycycles with high selectivity. A bifunctional ruthenium complex featuring a redox-coupled cyclopentadienone ligand acts as a common catalyst for the different cascade processes. PMID- 29498464 TI - The Site-Assembly Determines Catalytic Activity of Nanoparticles. AB - Heterogeneous catalysts are often designed as metal nanoparticles supported on oxide surfaces. Here, the relation between particle morphology and reaction kinetics is investigated by scaling relation kinetic Monte Carlo simulations using CO oxidation over Pt nanoparticles as a model reaction. We find that different particle morphologies result in vastly different catalytic activities. The activity is strongly affected by kinetic couplings between sites, and a wide site distribution generally enhances the activity. The present study highlights the role of site-assemblies as a concept that, in addition to isolated active sites, can be used to understand catalytic reactions over nanoparticles. PMID- 29498465 TI - Synthesis, Characterization, and Reactivity of Cationic Gold Diarylallenylidene Complexes. AB - Methoxide abstraction from gold acetylide complexes of the form (L)Au[eta1 C=CC(OMe)ArAr'] (L=IPr, P(t Bu)2 (ortho-biphenyl); Ar/Ar'=C6 H4 X where X=H, Cl, Me, OMe) with trimethylsilyl trifluoromethanesulfonate (TMSOTf) at -78 degrees C resulted in the formation of the corresponding cationic gold diarylallenylidene complexes [(L)Au=C=C=CArAr']+ OTf- in >=85+/-5 % yield according to 1 H NMR analysis. 13 C NMR and IR spectroscopic analysis of these complexes established the arene-dependent delocalization of positive charge on both the C1 and C3 allenylidene carbon atoms. The diphenylallenylidene complex [(IPr)Au=C=C=CPh2 ]+ OTf- reacted with heteroatom nucleophiles at the allenylidene C1 and/or C3 carbon atom. PMID- 29498466 TI - Effectiveness of preoperative physical therapy for older patients with hip fracture. AB - AIM: To clarify the effectiveness of preoperative physical therapy for older patients after hip fracture in an acute care hospital. METHODS: In the present retrospective observational study, data from the Japan Rehabilitation Database were analyzed for patients admitted to an acute care hospital with hip fracture between 2005 and 2015. In this study, all eligible patients received surgery within 10 days of admission. Propensity score analysis was used to compare outcomes between patients who underwent preoperative rehabilitation and those who did not. The primary outcome was motor Functional Independence Measure (FIM) gain. RESULTS: Of the 681 patients eligible after applying exclusion criteria, 50% underwent preoperative rehabilitation after hip fracture. Both before and after adjustment by inverse probability weighting, motor FIM gain was significantly higher in patients who underwent preoperative rehabilitation (motor FIM gain 31.1 +/- 18.2 before weighting, 31.1 +/- 18.2 after weighting) than in those who did not (motor FIM gain 24.6 +/- 18.1 before weighting, P < 0.01; 26.2 +/- 17.6 after weighting, P < 0.02). In addition, motor FIM effectiveness and motor FIM at discharge were significantly higher among patients who underwent preoperative rehabilitation. CONCLUSIONS: Our data suggest that preoperative rehabilitation after hip fracture is associated with better rehabilitation outcomes than no preoperative rehabilitation. Geriatr Gerontol Int 2018; 18: 1003 1008. PMID- 29498467 TI - Role of bicarbonate supplementation on urine uric acid crystals and diabetic tubulopathy in adults with type 1 diabetes. AB - Uricosuria and crystallization are increasingly recognized risk factors for diabetic tubulopathy. This pilot clinical trial aimed to determine the acute effect of urinary alkalinization using oral sodium bicarbonate (NaHCO3 ) on UA crystals in adults with type 1 diabetes (T1D). Adults with T1D, ages 18 to 65 years (n = 45, 60% female, HbA1c, 7.5 +/- 1.2%, 20.2 +/- 9.3 years duration) without chronic kidney disease (eGFR >=60 mL/min/1.73 m2 and albumin-to creatinine ratio < 30 mg/g) received 2 doses of 1950 mg oral NaHCO3 over 24 hours. Fasting urine and serum were collected pre- and post-intervention. UA crystals were identified under polarized microscopy. Urine measurements included: osmolality, pH, UA, creatinine and kidney injury molecule-1 (KIM-1). NaHCO3 therapy increased mean +/- SD urine pH from 6.1 +/- 0.7 to 6.5 +/- 0.7 (P < .0001). Prior to therapy, 31.0% of participants had UA crystals vs 6.7% post therapy (P = .005). Change in urine pH inversely correlated with change in urine KIM-1 (r:-0.51, P = .0003). In addition, change in urine UA over 24 hours correlated with change in urine KIM-1 (r:0.37, P = .01). In conclusion, oral NaHCO3 normalized urine pH and decreased UA crystals, and may hold promise as an inexpensive and safe tubulo-protective intervention in individuals with T1D. PMID- 29498468 TI - SrB5 O7 F3 Functionalized with [B5 O9 F3 ]6- Chromophores: Accelerating the Rational Design of Deep-Ultraviolet Nonlinear Optical Materials. AB - Fluorooxoborates, benefiting from the large optical band gap, high anisotropy, and ever-greater possibility to form non-centrosymmetric structures activated by the large polarization of [BOx F4-x ](x+1)- building blocks, have been considered as the new fertile fields for searching the ultraviolet (UV) and deep-UV nonlinear optical (NLO) materials. Herein, we report the first asymmetric alkaline-earth metal fluorooxoborate SrB5 O7 F3 , which is rationally designed by taking the classic Sr2 Be2 B2 O7 (SBBO) as a maternal structure. Its [B5 O9 F3 ]6 fundamental building block with near-planar configuration composed by two edge sharing [B3 O6 F2 ]5- rings in SrB5 O7 F3 has not been reported in any other borates. Solid state 19 F and 11 B magic-angle spinning NMR spectroscopy verifies the presence of covalent B-F bonds in SrB5 O7 F3 . Property characterizations reveal that SrB5 O7 F3 possesses the optical properties required for deep-UV NLO applications, which make SrB5 O7 F3 a promising crystal that could produce deep UV coherent light by the direct SHG process. PMID- 29498469 TI - Different glucagon effects during DPP-4 inhibition versus SGLT-2 inhibition in metformin-treated type 2 diabetes patients. AB - AIMS: Previous studies have shown that dipeptidyl peptidase (DPP)-4 inhibition lowers glucagon levels whereas sodium-glucose co-transporter 2 (SGLT-2) inhibition increases them. This study evaluated the extent of these opposite effects in a direct comparative head-to-head study. METHODS: In a single-centre, randomized study with a cross-over design, 28 metformin-treated patients with type 2 diabetes (T2D) (mean age, 63 years; baseline HbA1c, 6.8%) were treated with vildagliptin (50 mg twice daily) or dapagliflozin (10 mg once daily) for 2 weeks, with a 4-week wash-out period between the two separate treatments. After each treatment period, a meal test was undertaken, with measurements of islet and incretin hormones and 4-hour area under the curve (AUC) levels were estimated. RESULTS: Fasting glucagon (35.6 +/- 2.5 vs 39.4 +/- 3.4 pmoL/L; P = .032) and postprandial glucagon (4-hour AUCglucagon , 32.1 +/- 2.3 vs 37.5 +/- 2.7 nmoL/L min; P = .001) were ~15% lower after vildagliptin compared to dapagliflozin treatment. This was associated with stronger early (15 minute) C-peptide response and higher 4-hour AUCC-peptide (P < .010), higher 4-hour AUC of the intact form of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) (P < .001) and lower 4-hour AUC of total GIP and GLP-1 (P < .001). CONCLUSION: Treatment with DPP-4 inhibition with vildagliptin results in 15% lower fasting and postprandial glucagon levels compared to SGLT-2 inhibition with dapagliflozin. DPP-4 inhibition also induces more rapid insulin secretion and higher levels of intact incretin hormones, resulting in stronger feedback inhibition of incretin hormone secretion than SGLT-2 inhibition. PMID- 29498470 TI - Levels of neuroticism differentially predict individual scores in the depression and anxiety dimensions of the tripartite model: A multiwave longitudinal study. AB - The associations between neuroticism and depression and anxiety symptoms remain unclear possibly due to the lack of specificity and covariation among common symptoms. The current study hypothesized that neuroticism acts as a vulnerability factor for general distress (GD) and specific depression and anxiety symptoms. We investigated this hypothesis using the "tripartite model" (a well-known dimensional model of anxiety and depression). A sample of 644 college students was recruited from Hunan, China. In the initial stage of this investigation, the students completed self-assessment forms to measure their levels of neuroticism and frequency of daily hassles. The students also reported on their levels of GD and specific depression and anxiety symptoms. The same self-assessment procedure was undertaken once a month for the next 6 months. The results of the hierarchical linear model suggest a significant interaction between neuroticism and the level of stress caused by exposure to increased levels of daily hassles, which can be used as a predictor of future levels of GD and specific anxiety symptoms. However, the same interaction was not a significant predictor of specific depression symptoms. The current findings suggest that neuroticism may be a risk factor for specific anxiety but not for specific depression symptoms in face of stress caused by daily hassles. PMID- 29498471 TI - Test of simulator-based assessment of psychomotor skill in transthoracic echo. AB - BACKGROUND: We developed a transthoracic echo simulator that measures technical skill in image acquisition in terms of the deviation angle between an acquired image and the anatomically correct plane for that view. We studied whether this metric reflects the clinical experience of providers. METHODS: Attendees at an echo course or at the annual meeting of the Swedish Heart Association were invited to test themselves on the simulator by scanning a mannequin and acquiring four views in 15 min: parasternal long axis (pLAX) in patient 1, apical four chamber and apical long axis (aLAX) in patient 2 and pLAX in patient 3. Their experience with echo was assessed from duration in years and procedure volume in the past year. Image acquisition error was assessed from the deviation angle. RESULTS: Of 61 participants, there were 37 physicians and 24 non-physicians (22 sonographers and two nurses). Non-physicians had higher procedure volume than physicians (850 +/- 599 versus 312 +/- 393 tests year-1 , P<0.001); both had similar duration of experience (9 +/- 8 versus 12 +/- 11 years, P = NS). The deviation angle for aLAX (55 +/- 37 degrees) was higher than for any other view (P<0.00001). aLAX was the only view whose deviation angle correlated significantly with experience and only with procedure volume (r = -0.357, P = 0.008). CONCLUSIONS: These results demonstrate that deviation angle, a novel metric of technical skill in image acquisition, reflects clinical experience. Simulator-based testing provides objective and quantitative assessment that may be of value in the certification of trainees and for maintenance of certification. PMID- 29498472 TI - Effects of blood flow restriction exercises on bone metabolism: a systematic review. AB - This study analysed the effect of low-intensity (LI) exercises with blood flow restriction (BFR) on bone metabolism compared with high-intensity (HI) exercises without BFR. The following databases were searched using the keywords therapeutic occlusion training OR BFR training OR vascular occlusion training OR KAATSU training OR ischaemia training AND osteogenesis OR bone biomarkers OR bone metabolic marker OR bone mass OR bone turnover OR osteoporosis OR osteopenia: PubMed, Web of Science, SPORTDiscus, CINAHL, Science Direct, Cochrane and Google Scholar. Two researchers, independently and blindly, selected the studies based on established inclusion and exclusion criteria. Electronic and manual searches located 170 articles published in English; after screening, only four studies showed that BFR training increases the expression of bone formation markers (e.g. bone-specific alkaline phosphatase) and decreases bone resorption markers (e.g. the amino-terminal telopeptides of type I collagen) after both aerobic and anaerobic exercise across several populations. The results of this study show that few studies have confirmed the positive effect of exercise with BFR on bone metabolism, formation and resorption. Furthermore, no methodological standardization of the samples, exercise type, intervention frequency or duration was observed. PMID- 29498473 TI - Safety of non-insulin glucose-lowering drugs in pregnant women with pre gestational diabetes: A cohort study. AB - AIMS: To evaluate the association between use of non-insulin antidiabetics in early pregnancy and the risk of miscarriages, stillbirths and major structural malformations. MATERIALS AND METHODS: A cohort of 1511 pregnant women with pre gestational diabetes linked to live births was identified using electronic medical records from The Health Improvement Network (THIN) for the period 1995 to 2012. Information on prescriptions, foetal outcomes and potential confounders was ascertained from both codes and free text in the THIN database. Odds ratios (OR) and 95% confidence intervals (CI) of adverse foetal outcomes in women treated with non-insulin antidiabetics during the first trimester compared to those on insulin were estimated using logistic regression to adjust for type of diabetes, glycaemic control and other maternal characteristics. RESULTS: Among 311 pregnant women on non-insulin antidiabetics, 21.9% had a miscarriage and 1.6% a stillbirth; 1.9% of live births had major malformations. The corresponding frequencies for the 883 women on insulin were 13.3%, 1.7% and 9.6%. Insulin users more often had type 1 diabetes and poor glycaemic control. Compared to women with type 1 diabetes, those with type 2 diabetes had a higher risk of miscarriages (20.5% vs 12.8%) but a lower prevalence of malformations (4.0% vs 9.2%). Compared to women with HbA1c <=7%, those with HbA1c >7% had a higher prevalence of malformations (12.6% vs 2.7%). After adjustment for diabetes type and glycaemic control, compared to insulin, non-insulin antidiabetic patients were associated with an OR for miscarriage of 1.19 (95% CI, 0.75-1.89), for stillbirths of 0.65 (95% CI, 0.16-2.58), and for major malformations of 0.25 (95% CI, 0.08-0.84). CONCLUSION: Among women with diabetes, use of non-insulin antidiabetics early in pregnancy was not associated with greater risks of foetal losses or major malformations than was insulin. PMID- 29498474 TI - The Usefulness of Sperm Kinematics in Drug-Induced Toxicity Assessment. AB - In vitro drug-induced toxicity assessment demands the usability and validation of suitable cell models, obtained non-invasively and pain-free. Sperm suspensions, painlessly and easily obtained from breeding boars, have been proven as suitable biosensors for pre-clinical toxicology screening and ranking of lead compounds in the drug development processes on a kinematics-based assay. Having a limited number of mitochondria and depending on these mitochondria and on cytoplasmic glycolysis for the energy needed for motility and for plasma membrane functionality, spermatozoa become a suitable model for capturing multiple modes of action of drugs and other chemicals acting via measurements of sperm motility. In this MiniReview, the usability of boar spermatozoa as detectors of cytotoxicity based on sperm motility measurements is discussed. PMID- 29498475 TI - 'It's a silver lining': A template analysis of satisfaction and quality of life following post-mastectomy breast reconstruction. AB - OBJECTIVE: In the United Kingdom, the number of women undergoing post-mastectomy breast reconstruction is increasing. Consequently, exploring patient-reported outcomes in breast surgery has become increasingly important. This study investigated satisfaction and quality of life following post-mastectomy breast reconstruction. DESIGN: Qualitative research design. METHODS: In-depth, semi structured telephone interviews were conducted with 25 women (age, M = 53.08, SD = 8.41) following breast reconstruction in the United Kingdom. Data were analysed using template analysis which produced three-first-level, 13 second-level, and 19 third-level themes. RESULTS: Following reconstruction, women reported improved emotional functioning, although this was often accompanied by deterioration in physical, sexual, and/or social functioning. Women positively appraised their breast appearance, although some reported a decline in satisfaction over time, attributing this decline to their chosen reconstructive technique. Many women accepted the inevitability of scarring and most perceived their scars as a representation of their journey, signifying survival. Generally, women were satisfied with the outcome of their reconstruction, although on reflection some would not have opted for reconstruction. Following breast reconstruction, women were increasingly likely to experience the fear of recurrence, attributed to no longer being able to have a mammogram on the affected breast(s). CONCLUSIONS: This study provides new insights into post-mastectomy breast reconstruction and is a novel application of template analysis. The analysis demonstrates only slight variation in some categories of experience among women, despite a heterogeneous sample. The findings allow researchers and clinicians to focus on specific dimensions of satisfaction and quality of life to support the needs of women following reconstruction. Statement of contribution What is already known on this subject? Patient satisfaction and quality of life are key patient reported outcomes of breast reconstruction, although relatively few studies distinguish between types of satisfaction. The number of women electing to undergo reconstructive surgery is steadily increasing. As a consequence, exploring patient-reported outcomes in reconstructive breast surgery has become increasingly important for research and clinical practice. It is often suggested that breast reconstruction offers psychosocial benefits, although within the literature some mixed findings have been reported. Therefore, a qualitative exploration has the potential to add some clarity to the experiences of women following post-mastectomy breast reconstruction. What does this study add? To our knowledge, this is the first study to employ template analysis to explore the experiences of women following post-mastectomy breast reconstruction. Template analysis demonstrated that there was only slight variation in some categories of experience among women, despite a heterogeneous sample. This study distinguishes between the patient-reported outcomes breast satisfaction and outcome satisfaction to identify the key factors that are involved in determining satisfaction. The findings allow researchers and clinicians to focus on specific dimensions of satisfaction and quality of life which require improvement to support the unmet needs of women following breast reconstruction. The study presents two novel findings. Women attributed the fear of cancer recurrence to no longer being able to have a mammogram on the affected breast(s). Women also reported a decline in appearance-related satisfaction over time due to either the ptotic nature of autologous-based reconstruction or the fuller projected breast implant-based reconstruction affords. PMID- 29498476 TI - Orthostatic hypotension and overall mortality in 1050 older patients of the outpatient comprehensive geriatric assessment unit. AB - AIM: Orthostatic hypotension is a common problem in individuals aged >=65 years. Its association with mortality is not clear. The aim of the present study was to evaluate associations between orthostatic hypotension and overall mortality in a sample of individuals aged >=65 years who were seen at the Outpatient Comprehensive Geriatric Assessment Unit, Clalit Health Services, Beer-Sheva, Israel. METHODS: Individuals who were evaluated in the Outpatient Comprehensive Geriatric Assessment Unit between January 2005 and December 2015, and who had data on orthostatic hypotension were included in the study. The database included sociodemographic characteristics, body mass index, functional and cognitive state, geriatric syndromes reached over the course of the assessment, and comorbidity. Data on mortality were also collected. RESULTS: The study sample included 1050 people, of whom 626 underwent comprehensive geriatric assessment and 424 underwent geriatric consultation. The mean age was 77.3 +/- 5.4 years and 35.7% were men. Orthostatic hypotension was diagnosed in 294 patients (28.0%). In univariate analysis, orthostatic hypotension was associated with overall mortality only in patients aged 65-75 years (HR 1.5, 95% CI 1.07-2.2), but in the multivariate model this association disappeared. CONCLUSIONS: In older frail patients, orthostatic hypotension was not an independent risk factor for overall mortality. Geriatr Gerontol Int 2018; 18: 1009-1017. PMID- 29498477 TI - Heterogeneous estimates of influenza virus types A and B in the elderly: Results of a meta-regression analysis. AB - Influenza has many age-dependent characteristics. A previous systematic review of randomized controlled trials showed that the detection rate of influenza B was higher in children than in non-elderly adults. However, no comprehensive reviews have targeted the elderly, who carry the main burden of disease. We aimed to quantify the relative detection rates of virus types A and B among the elderly, to identify factors affecting these proportions, and to compare type distribution among seniors and younger age-classes. A comprehensive literature search was conducted to identify multiseason studies reporting A and B virus type distributions in the elderly. A random-effects meta-analysis was planned to quantify the prevalence of type B among elderly subjects with laboratory confirmed influenza. Meta-regression was then applied to explain the sources of heterogeneity. Across 27 estimates identified, the type B detection rate among seniors varied from 5% to 37%. Meta-analysis was not feasible owing to high heterogeneity (I2 = 98.5%). Meta-regression analysis showed that study characteristics, such as number of seasons included, hemisphere, and setting, could have contributed to the heterogeneity observed. The final adjusted model showed that studies that included both outpatients and inpatients reported a significantly (P = .024) lower proportion than those involving outpatients only. The detection rate of type B among the elderly was generally lower than in children/adolescents, but not non-elderly adults. Influenza virus type B has a relatively low detection rate in older adults, especially in settings covering both inpatients and outpatients. Public health implications are discussed. PMID- 29498478 TI - Interaction of Sulfonylureas with Liver Uptake Transporters OATP1B1 and OATP1B3. AB - Sulfonylureas (SUs) such as glibenclamide, gliclazide, glimepiride, glipizide and gliquidone are one of the first oral medicines available for the treatment of type 2 diabetes and are widely used for the treatment of hyperglycaemia. The hepatic transporters, organic anion transporting polypeptide 1B1 (OATP1B1) and organic anion transporting polypeptide 1B3 (OATP1B3), play an important role in the disposition of a variety of drugs by mediating their uptake from blood into hepatocytes. Drug-drug interactions mediated by OATP1B1/1B3 may result in the hepatic transporting change for drug substrates. The inhibitory effects of glibenclamide and glimepiride on sulfobromophthalein (BSP) uptake have been previously studied, and glibenclamide has been reported as the substrate of OATP1B3, but it remains unclear whether other SUs such as gliclazide, glipizide and gliquidone are substrates of OATP1B1 and OATP1B3. Here, we investigated the relationship between the five most commonly applied SUs (glibenclamide, gliclazide, glimepiride, glipizide, gliquidone) and OATP1B1 and OATP1B3. We performed uptake and inhibition assays in HEK293T cells stably expressing OATP1B1 or OATP1B3, respectively, and established a liquid chromatography-mass spectrometry (LC-MS) method for the simultaneous measurement of five SUs. We demonstrated that gliclazide and glimepiride are substrates of OATP1B1 and glibenclamide and glipizide are substrates of OATP1B3. We also confirmed the interaction between these SUs and rosuvastatin. No transporting was observed for gliquidone, suggesting that it is not a substrate of either transporter. PMID- 29498479 TI - Sociophonetics: The Role of Words, the Role of Context, and the Role of Words in Context. AB - This paper synthesizes a wide range of literature from sociolinguistics and cognitive psychology, to argue for a central role for the "word" as a vehicle of language variation and change. Three crucially interlinked strands of research are reviewed-the role of context in associative learning, the word-level storage of phonetic and contextual detail, and the phonetic consequences of skewed distributions of words across different contexts. I argue that the human capacity for associative learning, combined with attention to fine-phonetic detail at the level of the word, plays a significant role in predicting a range of subtle but systematically robust observed socioindexical patterns in speech production and perception. PMID- 29498481 TI - Predictors of remission during acute treatment of first-episode schizophrenia patients involuntarily hospitalized and treated with algorithm-based pharmacotherapy: Secondary analysis of an observational study. AB - AIM: Early clinical response predicts symptomatic remission and recovery in the maintenance treatment phase of first-episode schizophrenia (FES). However, little is known about predictors of symptomatic remission during acute treatment of severely ill patients with FES. Here, we conducted a secondary analysis of our retrospective observational study, which examined response, remission and treatment-resistance rates in seriously ill patients with FES spectrum disorders involuntarily hospitalized and treated with algorithm-based pharmacotherapy. METHODS: We performed a retrospective chart review of 131 involuntarily admitted patients with schizophrenia or schizoaffective disorder. Our algorithm aimed to delay olanzapine treatment, standardize medications and suggest initiation of clozapine after failure of third-line antipsychotic treatment. The duration of each adequate antipsychotic treatment at an optimal dosage was 4 weeks or more. Remission was defined using the symptom-severity component of consensus remission criteria. A logistic regression model was applied to identify significant predictors of remission at discharge. RESULTS: Overall, 74 patients (56%) were in remission at discharge. Non-remitters were hampered from becoming remitters mainly by the presence of negative symptoms. There were no differences in first line antipsychotics, dosage of antipsychotics at time of response and adherence rates to algorithm-based pharmacotherapy between remitters and non-remitters. Shorter duration of untreated psychosis, favourable early response and less negative symptoms at baseline were identified as independent predictors of remission at discharge. CONCLUSIONS: The importance of early intervention and specific and adequate treatments of negative symptoms is highlighted. PMID- 29498480 TI - The Effect of a Combination of Diclofenac and Methadone Applied as Gel in a Human Experimental Pain Model - A Randomized, Placebo-controlled Trial. AB - Pain involves responses in which both peripheral and central mechanisms contribute to the generation of pain. Pre-clinical laboratory data have supported that a topical formulation of combined diclofenac and methadone (Diclometh) may alleviate local pain, and potentially, the side effect profile should be low. We hypothesized that antiallodynic and antihyperalgesic effects of Diclometh could be demonstrated in a human experimental pain model and that Diclometh would be safe to administer. Thus, the aims were as follows: (i) to compare two doses of Diclometh versus placebo; and (ii) to assess the safety profile of Diclometh. The study was a crossover, randomized, double-blind, placebo-controlled comparison of two doses of Diclometh gel (0.1% and 0.2%) administered topically in healthy participants. Nerve growth factor (NGF) and capsaicin intradermal injections were used as human pain models. Pressure stimulation, contact heat stimulation, hyperalgesia (pinprick stimulation) and allodynia (brush stimulation) to mechanical stimulation were performed in the area where capsaicin and NGF were injected. Side effects were recorded on a four-point Likert scale. Twenty-one men completed the study (mean age 26.14 +/- 5.3). Diclometh 0.2% reduced the capsaicin-induced dynamic mechanical allodynia compared to placebo (primary end point, p = 0.03). No other primary or secondary end-points were found significantly different (all p > 0.05). All side effects were reported as mild with no differences between treatments (p = 0.15). Indication of antiallodynic effect of Diclometh 0.2% was found. Additionally, it was demonstrated that Diclometh was safe to use. PMID- 29498482 TI - Rare imaging appearance of skeletal metastases in a 61-year-old breast cancer patient. PMID- 29498483 TI - Enterovirus D-68 in children presenting for acute care in the hospital setting. AB - BACKGROUND: Severe respiratory disease associated with enterovirus D68 (EV-D68) has been reported in hospitalized pediatric patients. Virologic and clinical characteristics of EV-D68 infections exclusively in patients presenting to a hospital Emergency Department (ED) or urgent care have not been well defined. METHODS: Mid-nasal swabs from pediatric patients with respiratory symptoms presenting to the ED or urgent care were evaluated using a commercial multiplex PCR platform. Specimens positive for rhinovirus/enterovirus (HRV/EV) were subsequently tested using real-time reverse-transcriptase PCR for EV-D68. The PCR cycle threshold (CT) was used as a viral load proxy. Clinical outcomes were compared between patients with EV-D68 and patients without EV-D68 who tested positive for HRV/EV. RESULTS: From August to December 2014, 511 swabs from patients with HRV/EV were available. EV-D68 was detected in 170 (33%) HRV/EV positive samples. In multivariable models adjusted for age and underlying asthma, patients with EV-D68 were more likely to require hospitalization for respiratory reasons (odds ratio (OR): 3.11, CI: 1.85-5.25), require respiratory support (OR: 1.69, CI: 1.09-2.62), have confirmed/probable lower respiratory tract infection (LRTI; OR: 3.78, CI: 2.03-7.04), and require continuous albuterol or steroids (OR: 3.91, CI: 2.22-6.88 and OR: 4.73, CI: 2.65-8.46, respectively). Higher EV D68 viral load was associated with need for respiratory support and LRTI in multivariate models. CONCLUSIONS: Among pediatric patients presenting to the ED or urgent care, EV-D68 causes more severe disease than non-EV-D68 HRV/EV independent of underlying asthma. High viral load was associated with worse clinical outcomes. Rapid and quantitative viral testing may help identify and risk stratify patients. PMID- 29498484 TI - Wavelength-dependent scattering in human eye with cataracts. AB - The gradual process in which the crystalline lens is cloudy due to the appearance of elements giving rise to variations in the refractive index is known as cataract. Clinical assessment is usually complicated because it considers patient's perception, and individuals with similar development have different visual deficits. This work presents a model which considers the fluctuations in the refractive index as spherical particles produce measurable scatter radial profiles patterns on the retina. Measurements for 2 different wavelengths simultaneously provide information on particle size and a quantitative assessment by measurement of the fluctuations of the refractive index. PMID- 29498486 TI - Red blood cell membrane damage by light-induced thermal gradient under optical trap. AB - Rapid membrane damage of optically trapped red blood cells (RBCs) was observed at trapping powers >=280 mW. An excellent agreement between the estimated laser induced thermal gradient across trapped cell's membrane and that typically required for membrane electropermeabilization suggests a mechanism involving temperature gradient-induced electropermeabilization of membrane. Also the rapid collapse of the trapped cell due to membrane rupture was seen to cause shock waves in the surroundings permeabilizing nearby untrapped cells. When the experiments were carried out with RBCs collected from type II diabetic patients, a noticeable change in the damage rate compared to normal RBCs was seen suggesting a novel optical diagnosis method for the disease. PMID- 29498485 TI - In vivo expression of proteases and protease inhibitor, a serpin, by periodontal pathogens at teeth and implants. AB - Porphyromonas gingivalis and Tannerella forsythia secrete proteases, gingipains and KLIKK-proteases. In addition, T. forsythia produces a serpin (miropin) with broad inhibitory spectrum. The aim of this pilot study was to determine the level of expression of miropin and individual proteases in vivo in periodontal and peri implant health and disease conditions. Biofilm and gingival crevicular fluid (GCF)/ peri-implant sulcular fluid (PISF) samples were taken from healthy tooth and implant sites (n = 10), gingivitis and mucositis sites (n = 12), and periodontitis and peri-implantitis sites (n = 10). Concentration of interleukin-8 (IL-8), IL-1beta and IL-10 in GCF was determined by enzyme-linked immunosorbent assay. Loads of P. gingivalis and T. forsythia and the presence of proteases and miropin genes were assessed in biofilm by quantitative PCR, whereas gene expression was estimated by quantitative RT-PCR. The presence of P. gingivalis and T. forsythia, as well as the level of IL-8 and IL-1beta, were associated with disease severity in the periodontal and peri-implant tissues. In biofilm samples harboring T. forsythia, genes encoding proteases were found to be present at 72.4% for karilysin and 100% for other KLIKK-protease genes and miropin. At the same time, detectable mRNA expression of individual genes ranged from 20.7% to 58.6% of samples (for forsylisin and miropsin-1, respectively). In comparison with the T. forsythia proteases, miropin and the gingipains were highly expressed. The level of expression of gingipains was associated with those of miropin and certain T. forsythia proteases around teeth but not implants. Cumulatively, KLIKK-proteases and especially miropin, might play a role in pathogenesis of both periodontal and peri-implant diseases. PMID- 29498487 TI - Plasminogen binding and degradation by Treponema denticola: Identification of the plasminogen binding interface on the FhbB protein. AB - Treponema denticola is a proteolytic-anaerobic spirochete whose abundance in the subgingival crevice correlates with periodontal disease severity. Treponema denticola evades serum-mediated killing through the binding of factor H (FH), a negative regulator of the complement system. The T. denticolaFH receptor has been identified as FhbB, an 11.4kDa immunodominant lipoprotein. Three distinct subfamilies of FhbB proteins have been delineated and designated as FhbB1, FhbB2 and FhbB3. In this study we demonstrate that all FhbB variants bind human plasminogen (Plg). Competitive binding analyses revealed that FH and Plg do not compete for binding. Binding studies with FhbB135405 site-directed amino acid substitution mutants demonstrated that the interaction domains for FH and Plg on FhbB are separable. Inhibition of Plg-FhbB binding by epsilon-aminocaproic acid (a lysine analog) indicates that binding is mediated by electrostatic interactions that presumably occur with Lys binding sites contained within Plg "Kringle" domains 1, 2, 4 or 5. Similar to that demonstrated for FH, Plg can also serve as a substrate for the T. denticola protease, dentilisin. The in vivo consequences of dentilisin-mediated cleavage of Plg remained to be determined. The data presented demonstrate that FhbB is a multi-functional protein that may contribute to virulence through several mechanisms including immune evasion, manipulation of the host immune response, adherence or tissue invasion. PMID- 29498488 TI - Identification of the novel HLA-B*27:103 allele in a Chinese bone marrow donor. AB - HLA-B*27:103 has one nucleotide change from HLA-B*27:04:01 at position 121C > T. PMID- 29498489 TI - Natural history of gastric cancer from a retrospective review of endoscopic images of older patients with interval gastric cancer. AB - AIM: Interval gastric cancers (IGC) are defined as those diagnosed after negative results of endoscopy carried out within the past 10 years. We aimed to investigate the characteristics of IGC and the natural history of gastric cancer (GC) from a retrospective view of endoscopic images of older patients with IGC. METHODS: We retrospectively reviewed endoscopic images of 240 patients with GC who were aged >60 years. We compared past endoscopic images with newer ones, in which GC was diagnosed. IGC were classified into two categories: missed cancers and new cancers. RESULTS: Of the 240 patients with GC, 32 had past endoscopic images that qualified for a precise review. A total of 14 cases involved new cancers, whereas 18 involved missed cancers. Most of the IGC were stage I for at least 2 years; however, a small subset was unresectable at >2 years after a negative endoscopy. Furthermore, the rate of endoscopic treatment was significantly higher for IGC compared with that for non-IGC. CONCLUSIONS: In people aged >60 years, most IGC remain in an early stage for at least 2 years; however, at >2 years after a negative endoscopy, some are unresectable. These results suggest that most early-stage GC will not develop into advanced cancers within 2 years; thus, a 2-year interval might be within the permissible range for patients with negative endoscopy results for any lesions. Geriatr Gerontol Int 2018; 18: 997-1002. PMID- 29498490 TI - Abstract Concepts and Pictures of Real-World Situations Activate One Another. AB - concepts typically are defined in terms of lacking physical or perceptual referents. We argue instead that they are not devoid of perceptual information because knowledge of real-world situations is an important component of learning and using many abstract concepts. Although the relationship between perceptual information and abstract concepts is less straightforward than for concrete concepts, situation-based perceptual knowledge is part of many abstract concepts. In Experiment 1, participants made lexical decisions to abstract words that were preceded by related and unrelated pictures of situations. For example, share was preceded by a picture of two girls sharing a cob of corn. When pictures were presented for 500 ms, latencies did not differ. However, when pictures were presented for 1,000 ms, decision latencies were significantly shorter for abstract words preceded by related versus unrelated pictures. Because the abstract concepts corresponded to the pictured situation as a whole, rather than a single concrete object or entity, the necessary relational processing takes time. In Experiment 2, on each trial, an abstract word was presented for 250 ms, immediately followed by a picture. Participants indicated whether or not the picture showed a normal situation. Decision latencies were significantly shorter for pictures preceded by related versus unrelated abstract words. Our experiments provide evidence that knowledge of events and situations is important for learning and using at least some types of abstract concepts. That is, abstract concepts are grounded in situations, but in a more complex manner than for concrete concepts. Although people's understanding of abstract concepts certainly includes knowledge gained from language describing situations and events for which those concepts are relevant, sensory and motor information experienced during real-life events is important as well. PMID- 29498491 TI - Explore! Dream! Discover! PMID- 29498492 TI - Disease characteristics and causes of early and late death in a group of Croatian patients with systemic lupus erythematosus deceased over a 10-year period. AB - AIM: To assess the causes of early death (ED) and late death (LD) in patients with systemic lupus erythematosus (SLE) and determine the features of deceased SLE patients followed-up in a single Croatian tertiary hospital center, because little if any data on causes of death (CODs) in SLE patients are available for Croatia. METHOD: We identified SLE patients regularly followed-up at the Division of Clinical Immunology and Rheumatology, University Hospital Center Zagreb, who died from 2002 to 2011. Death was ascertained by matching our institutional records with the Croatian National Death Database. Patients were grouped according to their disease duration to ED and LD and compared by demographic characteristics, classification criteria, organ damage, and CODs. RESULTS: We identified 90 patients (68 women), who died at the age of 58+/-15 years. The most frequent COD category was cardiovascular diseases (40%), followed by infections (33%), active SLE (29%), and malignancies (17%). No significant difference was found between the frequencies of causes of ED and LD, except for stroke, which caused only LD>=10 years after the diagnosis. SLE was reported in death certificates of only 41 of 90 patients. CONCLUSION: Although stroke occurred both in the early and late disease course, it was primarily associated with LD. Given the low proportion of SLE recorded in death certificates of deceased SLE patients, matching of institutional and vital statistics records may be required to assess the true impact of SLE on mortality. PMID- 29498493 TI - Effect of antiepileptic drug comedication on lamotrigine concentrations. AB - AIM: To estimate the effect size of concomitant antiepileptic therapy on the concentrations of lamotrigine, a drug often prescribed in combination with other antiepileptic drugs (AED), which can act as enzyme inducers or inhibitors. METHODS: A total of 304 patients with epilepsy, aged 18-70 years, were divided into a lamotrigine monotherapy group and groups receiving lamotrigine with AEDs that act as enzyme inducers, enzyme inhibitors, or both. We compared lamotrigine monotherapy serum concentrations with those where lamotrigine was administered with a metabolic inhibitor valproate, metabolic inducers carbamazepine, oxcarbazepine, phenobarbital, phenytoin, or topiramate, and both an inducer and an inhibitor. RESULTS: Comparison of trough lamotrigine monotherapy concentrations and lamotrigine polytherapy concentrations showed an almost similar median concentration in case of drug-inducers, and higher lamotrigine concentration in case of comedication with valproate as an inhibitor. A significant difference was confirmed after dose correction (P<0.001). Significant positive correlations of lamotrigine trough serum concentrations with valproate were observed before and after the dose correction (r=0.480, P<0.001 and r=0.561, P<0.001, respectively). Positive correlations between the dose-corrected lamotrigine trough concentration and carbamazepine (r=0.439; PP<0.001) or monohydroxy metabolite of oxcarbazepine (MHD) (r=0.675; PP<0.001) were also significant. CONCLUSION: Higher valproate levels resulted in higher inhibition potency and higher lamotrigine levels. Increased dose-corrected concentrations of inducers carbamazepine and MHD, after the process of induction was finished, did not lower lamotrigine concentrations. These findings can be of clinical significance for optimal AED dosing. PMID- 29498494 TI - Potential hot spot for de novo mutations in PTCH1 gene in Gorlin syndrome patients: a case report of twins from Croatia. AB - We describe a case of twins with sporadic Gorlin syndrome. Both twins had common Gorlin syndrome features including calcification of the falx cerebri, multiple jaw keratocysts, and multiple basal cell carcinomas, but with different expressivity. One brother also had benign testicular mesothelioma. We propose this tumor type as a possible new feature of Gorlin syndrome. Gorlin syndrome is a rare autosomal dominant disorder characterized by both developmental abnormalities and cancer predisposition, with variable expression of various developmental abnormalities and different types of tumors. The syndrome is primarily caused by mutations in the Patched 1 (PTCH1) gene, although rare mutations of Patched 2 (PTCH2) or Suppressor of Fused (SUFU) genes have also been found. Neither founder mutations nor hot spot locations have been described for PTCH1 in Gorlin syndrome patients. Although de novo mutations of the PTCH1 gene occur in almost 50% of Gorlin syndrome cases, there are a few recurrent mutations. Our twin patients were carriers of a de novo mutation in the PTCH1 gene, c.3364_3365delAT (p.Met1122ValfsX22). This is, to our knowledge, the first Gorlin syndrome-causing mutation that has been reported four independent times in distant geographical locations. Therefore, we propose the location of the described mutation as a potential hot spot for mutations in PTCH1. PMID- 29498495 TI - H-index in medicine is driven by original research. AB - AIM: To investigate the contribution of selected types of articles to h-indices of medical researchers. METHODS: We used the Web of Science to export the publication records of various members from 26 scientific medical societies (13 European, 13 North American) associated with 13 medical specialties. Those included were presidents (n=26), heads of randomly chosen committees (n=52), and randomly selected members of those committees (n=52). Publications contributing to h-index were categorized as research articles, reviews, guidelines, meta analyses, or other published work. RESULTS: Overall, 3259 items authored by 129 scholars were analyzed. The median h-index was 19.5. The median contribution of research articles to h-index was 84.4%. Researchers in the upper h-index tercile (>=28.5) had a larger share of research articles that contributed to h-index in comparison with those in the lower h-index tercile (<=12.5) (median 87.3% [1st 3rd quartile: 80.0%-93.1%] vs 80.0% [50.0%-88.9%], P=0.015). We observed an analogous difference with regard to guidelines (1.1% [0%-3.7%] vs 0% [0%-0%], P=0.007). CONCLUSIONS: Original research drives h-indices in medicine. Although guidelines contribute to h-indices in medicine, their influence is low. The specific role of randomized controlled trials in building h-index in medicine remains to be assessed. PMID- 29498496 TI - Re-thinking knowledge landscapes in the context of Grounded Aboriginal Theory and online health communication. PMID- 29498497 TI - Progress towards poliomyelitis eradication: Nigeria, January-December 2017. PMID- 29498498 TI - A real voyage of discovery. AB - In an article that first appeared in the March 2016 issue of The Australian Hospital Engineer, Greg Truscott MIHEA, the IHEA (Institute of Hospital Engineering Australia) 'exchange' delegate for 2015, reports on the enjoyable experience and the knowledge he gained as an ANZEX delegate during a recent visit to New Zealand hosted by the NZIHE (the New Zealand Institute of Healthcare Engineering). During the visit, he not only toured 11 different hospital sites, but also presented at the 2015 NZIHE national conference. PMID- 29498499 TI - Saving energy via high-efficiency fans. AB - Thomas Heine, sales and market manager for EC Upgrades, the retrofit arm of global provider of air movement solutions, ebm-papst A&NZ, discusses the retrofitting of high-efficiency fans to existing HVAC equipment to 'drastically reduce energy consumption'. PMID- 29498500 TI - Senior personnel meet to debate key issues. AB - Prior to the start of the second day of April's Hospital Innovations 2016 show at Olympia, London, and immediately before Lord Carter gave an address at the event updating conference delegates on progress with he and his team's review of the 'productivity and efficiency' of English NHS acute hospitals, IHEEM held an 'invitation only' Chief Executives' Breakfast Briefing, at which senior personnel from both the NHS and private sector discussed some of their key concerns against today's difficult economic backdrop for the sector. HEJ editor, Jonathan Baillie, reports. PMID- 29498501 TI - Better protecting staff working alone. AB - Established four and a half years ago as a wholly-owned subsidiary of Dutch headquartered personal security and critical communications solutions provider, Atus BV, Hereford-based Atus Systems has since established a strong UK-wide client base supplying personal pagers, wireless personal alarm units, and the associated infrastructure, predominantly to high secure mental health facilities, prisons, and detention centres. Recent months, however, mark a new chapter for it, with the launch of a 'unique' lone worker protection system able to identify such personnel's location even when they are indoors and out of range of GPS coverage, and a sophisticated two-way enterprise critical messaging system. As HEJ editor, Jonathan Baillie, discovered from MD, Darren Swindlehurst, the company will target both systems squarely at the NHS and private healthcare providers, as well as at its more 'traditional' customers. PMID- 29498502 TI - Managing electrical supplies safely. AB - Few will doubt that electrical supplies in healthcare premises need to be designed and maintained to standards exceeding those encountered in domestic premises. Alongside the need to ensure continuity of electrical supplies--hence the importance of properly maintained emergency standby generators to ensure that vital medical electrical (ME) equipment and building services systems can operate without interruption--patients may be particularly vulnerable to electrical hazards during medical procedures, due to the attachment to the skin of applied parts of ME equipment, and/or their introduction into the body. Here Al Rufaie, BSc CEng MIET FIHEEM, who has 40 years' electrical industry experience, including over 10 years at the Department of Health providing electrical technology and safety guidance to the NHS, covers these elements, and details the patient protection requirements and various classifications of medical locations. PMID- 29498503 TI - Highly Crystalline Layered VS2 Nanosheets for All-Solid-State Lithium Batteries with Enhanced Electrochemical Performances. AB - All-solid-state lithium batteries employing inorganic solid electrolytes have been regarded as an ultimate solution to safety issues because of their features of no leakage as well as incombustibility and they are expected to achieve higher energy densities owing to their simplified structure. Two-dimensional transition metal dichalcogenides exhibit a great potential in energy storage devices because of their unique physical and chemical characteristics. In this work, 50 nm thick highly crystalline layered VS2 (hc-VS2) nanosheets are prepared by a solvothermal method, and their electrochemical performances are evaluated in Li/75% Li2S-24% P2S5-1% P2O5/Li10GeP2S12/hc-VS2 all-solid-state lithium batteries. At 50 mA g-1, hc-VS2 nanosheets show a high reversible capacity of 532.2 mAh g-1 after 30 cycles. Moreover, stable discharge capacities are maintained at 436.8 and 270.4 mAh g-1 at 100 and 500 mA g-1 after 100 cycles, respectively. The superior rate capability and cycling stability are ascribed to the better electronic conductivity and well-developed layered structure. In addition, the electrochemical reaction kinetics and capacity contributions were analyzed via cyclic voltammetry measurements at different scan rates. PMID- 29498504 TI - Intra-molecular Charge Transfer and Electron Delocalization in Non-fullerene Organic Solar Cells. AB - Two types of electron acceptors were synthesized by coupling two kinds of electron-rich cores with four equivalent perylene diimides (PDIs) at the alpha position. With fully aromatic cores, TPB and TPSe have pi-orbitals spread continuously over the whole aromatic conjugated backbone, unlike TPC and TPSi, which contain isolated PDI units due to the use of a tetrahedron carbon or silicon linker. Density functional theory calculations of the projected density of states showed that the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) for TPB are localized in separate regions of space. Further, the LUMO of TPB shows a greater contribution from the orbitals belonging to the connective core of the molecules than that of TPC. Overall, the properties of the HOMO and LUMO point at increased intra-molecular delocalization of negative charge carriers for TPB and TPSe than for TPC and TPSi and hence at a more facile intra-molecular charge transfer for the former. The film absorption and emission spectra showed evidences for the inter-molecular electron delocalization in TPB and TPSe, which is consistent with the network structure revealed by X-ray diffraction studies on single crystals of TPB. These features benefit the formation of charge transfer states and/or facilitate charge transport. Thus, higher electron mobility and higher charge dissociation probabilities under Jsc condition were observed in blend films of TPB:PTB7-Th and TPSe:PTB7-Th than those in TPC:PTB7-Th and TPSi:PTB7-Th blend films. As a result, the Jsc and fill factor values of 15.02 mA/cm2, 0.58 and 14.36 mA/cm2, 0.55 for TPB- and TPSe-based solar cell are observed, whereas those for TPC and TPSi are 11.55 mA/cm2, 0.47 and 10.35 mA/cm2, 0.42, respectively. PMID- 29498505 TI - Molecular Engineered Safer Organic Battery through the Incorporation of Flame Retarding Organophosphonate Moiety. AB - Here, we report the first electrochemical assessment of organophosphonate-based compound as a safe electrode material for lithium-ion batteries, which highlights the reversible redox activity and inherent flame retarding property. Dinickel 1,4 benzenediphosphonate delivers a high reversible capacity of 585 mA h g-1 with stable cycle performance. It expands the scope of organic batteries, which have been mainly dominated by the organic carbonyl family to date. The redox chemistry is elucidated by X-ray absorption spectroscopy and solid-state 31P NMR investigations. Differential scanning calorimetry profiles of the lithiated electrode material exhibit suppressed heat release, delayed onset temperature, and endothermic behavior in the elevated temperature zone. PMID- 29498506 TI - In Situ Embedded Pseudo Pd-Sn Solid Solution in Micropores Silica with Remarkable Catalytic Performance for CO and Propane Oxidation. AB - Most of the industrial and environmental catalytic reactions are operated at high temperature for a long time, and the sintering of the active centers is the main factor leading to catalysts deactivation, especially for noble metal catalysts. Herein we develop a dual confinement (enhanced metal-oxide interaction and the porous shell confinement) strategy to prepare Pd-Sn pseudo solid solution and in situ embedded in microporous silica for the first time and showed superior catalytic performance for CO and propane total oxidation (two main vehicle emission gases), even stored more than 640 days. PMID- 29498507 TI - Update on the Pharmacological Treatment of Tics with Dopamine-Modulating Agents. AB - More than 40 years of research and clinical practice have proven the effectiveness of dopamine receptor antagonists in the pharmacological treatment of tics. A blockade of the striatal dopamine-D2 receptors is mainly responsible for their tic-reducing effect. A broad spectrum of dopamine-modulating agents, such as typical and atypical antipsychotics, but also dopamine receptor agonists are used with an immanent discord between experts about which of them should be considered as first choice. The present Review outlines the state of the art on pharmacological treatment of tics with dopamine-modulating agents by giving an systematic overview of studies on their effectiveness and a critical discussion of their specific adverse effects. It is considered as an update of a previous review of our research group published in 2013. The Review closes with a description of the current resulting treatment recommendations including the results of a first published revised survey on European expert's prescription preferences. Based on the enormously growing evidence on its effectiveness and safety, aripiprazole currently seems to be the most promising agent in the pharmacological treatment of tics. Furthermore, benzamides (especially tiapride), which are commonly used in Europe, have proven their excellent effectiveness tolerability profile over decades in clinical practice and are therefore also highly recommended for the treatment of tics. Nevertheless, pharmacological treatment of tics remains an indiviual choice depending on each patient's own specific needs. PMID- 29498509 TI - Microfluidic Cell Microarray Platform for High Throughput Analysis of Particle Cell Interactions. AB - With advances in nanotechnology, particles with various size, shape, surface chemistry, and composition can be easily produced. Nano- and microparticles have been extensively explored in many industrial and clinical applications. Ensuring that the particles themselves are not possessing toxic effects to the biological system is of paramount importance. This paper describes a proof of concept method, in which a microfluidic system is used in conjunction with a cell microarray technique aiming to streamline the analysis of particle-cell interaction in a high throughput manner. Polymeric microparticles, with different particle surface functionalities, were first used to investigate the efficiency of particle-cell adhesion under dynamic flow. Silver nanoparticles (AgNPs, 10 nm in diameter) perfused at different concentrations (0 to 20 MUg/mL) in parallel streams over the cell microarray exhibited a higher toxicity compared to the static culture in the 96-well-plate format. This developed microfluidic system can be easily scaled up to accommodate a larger number of microchannels for high throughput analysis of the potential toxicity of a wide range of particles in a single experiment. PMID- 29498508 TI - Seeded Growth Synthesis of Gold Nanotriangles: Size Control, SAXS Analysis, and SERS Performance. AB - We studied the controlled growth of triangular prismatic Au nanoparticles with different beveled sides for surface-enhanced Raman spectroscopy (SERS) applications. First, in a seedless synthesis using 3-butenoic acid (3BA) and benzyldimethylammonium chloride (BDAC), gold nanotriangles (AuNTs) were synthesized in a mixture with gold nanooctahedra (AuNOCs) and separated by depletion-induced flocculation. Here, the influence of temperature, pH, and reducing agent on the reaction kinetics was initially investigated by UV-vis and correlated to the size and yield of AuNT seeds. In a second step, the AuNT size was increased by seed-mediated overgrowth with Au. We show for the first time that preformed 3BA-synthesized AuNT seeds can be overgrown up to a final edge length of 175 nm and a thickness of 80 nm while maintaining their triangular shape and tip sharpness. The NT morphology, including edge length, thickness, and tip rounding, was precisely characterized in dispersion by small-angle X-ray scattering and in dry state by transmission electron microscopy and field emission scanning electron microscopy. For sensor purposes, we studied the size dependent SERS performance of AuNTs yielding analytical enhancement factors between 0.9 * 104 and 5.6 * 104 and nanomolar limit of detection (10-8-10-9 M) for 4-mercaptobenzoic acid and BDAC. These results confirm that the 3BA approach allows the fabrication of AuNTs in a whole range of sizes maintaining the NT morphology. This enables tailoring of localized surface plasmon resonances between 590 and 740 nm, even in the near-infrared window of a biological tissue, for use as colloidal SERS sensing agents or for optoelectronic applications. PMID- 29498510 TI - Thermal Driven Giant Spin Dynamics at Three-Dimensional Heteroepitaxial Interface in Ni0.5Zn0.5Fe2O4/BaTiO3-Pillar Nanocomposites. AB - Traditional magnetostrictive/piezoelectric laminated composites rely on the two dimensional interface that transfers stress/strain to achieve the large magnetoelectric (ME) coupling, nevertheless, they suffer from the theoretical limitation of the strain effect and of the substrate clamping effect in real ME applications. In this work, 3D NZFO/BTO-pillar nanocomposite films were grown on SrTiO3 by template-assisted pulsed laser deposition, where BaTiO3 (BTO) nanopillars appeared in an array with distinct phase transitions as the cores were covered by NiZn ferrite (NZFO) layer. The perfect 3D heteroepitaxial interface between BTO and NZFO phases can be identified without any edge dislocations, which allows effective strain transfer at the 3D interface. The 3D structure nanocomposites enable the strong two magnon scattering (TMS) effect that enhances ME coupling at the interface and reduces the clamping effect by strain relaxation. Thereby, a large FMR field shift of 1866 Oe in NZFO/BTO-pillar nanocomposite was obtained at the TMS critical angle near the BTO nanopillars phase transition of 255 K. PMID- 29498511 TI - Highly Efficient Deep Blue Fluorescent Organic Light-Emitting Diodes Boosted by Thermally Activated Delayed Fluorescence Sensitization. AB - Highly efficient deep blue fluorescent material and various thermally activated delayed fluorescent (TADF) blue sensitization materials were synthesized for fluorescent deep blue organic light-emitting diodes (OLEDs). These materials were designed and selected by considering efficient energy transfer conditions (i.e., spectral overlap and quantum efficiency) between sensitizer and acceptor. Energy transfer process from TADF host sensitizers to deep blue fluorescent emitter has been investigated by measuring the energy transfer rate. Measured energy transfer rate was to be 1.24 * 1010 s-1 (mol/dm3)-1 for a prompt decay of fluorescence and 2.61 * 108 s-1 (mol/dm3)-1 for delayed fluorescence, which demonstrated the efficient energy transfer. Indeed, highly efficient deep blue fluorescent OLEDs boosted by the TADF host-sensitization process were successfully fabricated. The maximum external quantum efficiency was 19.0% with color coordinates of (0.14, 0.15) and 15.5% with color coordinates of (0.15, 0.11) in the different host system. The efficiency roll-off characteristic and device operating lifetime were also improved by this efficient sensitization process. PMID- 29498512 TI - In Situ Synthesis of CuCo2S4@N/S-Doped Graphene Composites with Pseudocapacitive Properties for High-Performance Lithium-Ion Batteries. AB - To satisfy the demand of high power application, lithium-ion batteries (LIBs) with high power density have gained extensive research effort. The pseudocapacitive storage of LIBs is considered to offer high power density through fast faradic surface redox reactions rather than the slow diffusion controlled intercalation process. In this work, CuCo2S4 anchored on N/S-doped graphene is in situ synthesized and a typical pseudocapacitive storage behavior is demonstrated when applied in the LIB anode. The pseudocapacitive storage and N/S-doped graphene enable the composite to display a capacity of 453 mA h g-1 after 500 cycles at 2 A g-1 and a ultrahigh rate capability of 328 mA h g-1 at 20 A g-1. We believe that this work could further promote the research on pseudocapacitive storage in transition-metal sulfides for LIBs. PMID- 29498514 TI - Bacteria That Make a Meal of Sulfonamide Antibiotics: Blind Spots and Emerging Opportunities. AB - The release of sulfonamide antibiotics into the environment is alarming because the existence of these antibiotics in the environment may promote resistance in clinically relevant microorganisms, which is a potential threat to the effectiveness of antibiotic therapies. Controllable biodegradation processes are of particular significance for the inexpensive yet effective restoration of sulfonamide-contaminated environments. Cultivation-based techniques have already made great strides in successfully isolating bacteria with promising sulfonamide degradation abilities, but the implementation of these isolates in bioremediation has been limited by unknown microbial diversity, vast population responsiveness, and the impact of perturbations from open and complex environments. Advances in DNA sequencing technologies and metagenomic analyses are being used to complement the information derived from cultivation-based procedures. In this Review, we provide an overview of the growing understanding of isolated sulfonamide degraders and identify shortcomings of the prevalent literature in this field. In addition, we propose a technical paradigm that integrates experimental testing with metagenomic analysis to pave the way for improved understanding and exploitation of these ecologically important isolates. Overall, this Review aims to outline how metagenomic studies of isolated sulfonamide degraders are being applied for the advancement of bioremediation strategies for sulfonamide contamination. PMID- 29498513 TI - Microfluidics-Based Chromosome Conformation Capture (3C) Technology for Examining Chromatin Organization with a Low Quantity of Cells. AB - Detecting three-dimensional (3D) genome organization in the form of physical interactions between various genomic loci is of great importance for understanding transcriptional regulations and cellular fate. Chromosome Conformation Capture (3C) method is the gold standard for examining chromatin organization, but usually requires a large number of cells (>107). This hinders studies of scarce tissue samples from animals and patients using the method. Here we developed a microfluidics-based approach for examining chromosome conformation by 3C technology. Critical 3C steps, such as digestion and religation of BAC DNA and cross-linked chromatin, were implemented on a microfluidic chip using a low quantity of cells (<104). Using this technology, we analyzed the chromatin looping interactions in the human beta-globin. We envision that our method will provide a powerful tool for low-input analysis of chromosome conformation and epigenetic regulations. PMID- 29498515 TI - NiTe2 Nanowire Outperforms Pt/C in High-Rate Hydrogen Evolution at Extreme pH Conditions. AB - Better hydrogen generation with nonprecious electrocatalysts over Pt is highly anticipated in water splitting. Such an outperforming nonprecious electrocatalyst, nickel telluride (NiTe2), has been fabricated on Ni foam for electrocatalytic hydrogen evolution in extreme pH conditions, viz., 0 and 14. The morphological outcome of the fabricated NiTe2 was directed by the choice of the Te precursor. Nanoflakes (NFs) were obtained when NaHTe was used, and nanowires (NWs) were obtained when Te metal powder with hydrazine hydrate was used. Both NiTe2 NWs and NiTe2 NFs were comparatively screened for hydrogen evolution reaction (HER) in extreme pH conditions, viz., 0 and 14. NiTe2 NWs delivered current densities of 10, 100, and 500 mA cm-2 at the overpotentials of 125 +/- 10, 195 +/- 4, and 275 +/- 7 mV in 0.5 M H2SO4. Similarly, in 1 M KOH, overpotentials of 113 +/- 5, 247 +/- 5, and 436 +/- 8 mV were required for the same current densities, respectively. On the other hand, NiTe2 NFs showed relatively poorer HER activity than NiTe2 NWs, which required overpotentials of 193 +/- 7, 289 +/- 5, and 494 +/- 8 mV in 0.5 M H2SO4 for the current densities of 10 and 100 mA cm-2 and 157 +/- 5 and 335 +/- 6 mV in 1 M KOH for the current densities of 10 and 100 mA cm-2, respectively. Notably, NiTe2 NWs outperformed the state-of-the-art Pt/C 20 wt % loaded Ni foam electrode of comparable mass loading. The Pt/C 20 wt % loaded Ni foam electrode reached 500 mA cm-2 at 332 +/- 5 mV, whereas NiTe2 NWs drove the same current density with 57 mV less. These encouraging findings emphasize that a NiTe2 NW could be an alternative to noble and expensive Pt as a nonprecious and high-performance HER electrode for proton exchange membrane and alkaline water electrolyzers. PMID- 29498516 TI - Thermal, Catalytic Conversion of Alkanes to Linear Aldehydes and Linear Amines. AB - Alkanes, the main constituents of petroleum, are attractive feedstocks for producing value-added chemicals. Linear aldehydes and amines are two of the most important building blocks in the chemical industry. To date, there have been no effective methods for directly converting n-alkanes to linear aldehydes and linear amines. Here, we report a molecular dual-catalyst system for production of linear aldehydes via regioselective carbonylation of n-alkanes. The system is comprised of a pincer iridium catalyst for transfer-dehydrogenation of the alkane using t-butylethylene or ethylene as a hydrogen acceptor working sequentially with a rhodium catalyst for olefin isomerization-hydroformylation with syngas. The system exhibits high regioselectivity for linear aldehydes and gives high catalytic turnover numbers when using ethylene as the acceptor. In addition, the direct conversion of light alkanes, n-pentane and n-hexane, to siloxy-terminated alkyl aldehydes through a sequence of Ir/Fe-catalyzed alkane silylation and Ir/Rh catalyzed alkane carbonylation, is described. Finally, the Ir/Rh dual-catalyst strategy has been successfully applied to regioselective alkane aminomethylation to form linear alkyl amines. PMID- 29498518 TI - Using Physical Organic Chemistry To Shape the Course of Electrochemical Reactions. AB - While organic electrochemistry can look quite different to a chemist not familiar with the technique, the reactions are at their core organic reactions. As such, they are developed and optimized using the same physical organic chemistry principles employed during the development of any other organic reaction. Certainly, the electron transfer that triggers the reactions can require a consideration of new "wrinkles" to those principles, but those considerations are typically minimal relative to the more traditional approaches needed to manipulate the pathways available to the reactive intermediates formed downstream of that electron transfer. In this review, three very different synthetic challenges-the generation and trapping of radical cations, the development of site-selective reactions on microelectrode arrays, and the optimization of current in a paired electrolysis-are used to illustrate this point. PMID- 29498517 TI - Fragment-Based Drug Discovery of Inhibitors of Phosphopantetheine Adenylyltransferase from Gram-Negative Bacteria. AB - The discovery and development of new antibiotics capable of curing infections due to multidrug-resistant and pandrug-resistant Gram-negative bacteria are a major challenge with fundamental importance to our global healthcare system. Part of our broad program at Novartis to address this urgent, unmet need includes the search for new agents that inhibit novel bacterial targets. Here we report the discovery and hit-to-lead optimization of new inhibitors of phosphopantetheine adenylyltransferase (PPAT) from Gram-negative bacteria. Utilizing a fragment based screening approach, we discovered a number of unique scaffolds capable of interacting with the pantetheine site of E. coli PPAT and inhibiting enzymatic activity, including triazolopyrimidinone 6. Structure-based optimization resulted in the identification of two lead compounds as selective, small molecule inhibitors of bacterial PPAT: triazolopyrimidinone 53 and azabenzimidazole 54 efficiently inhibited E. coli and P. aeruginosa PPAT and displayed modest cellular potency against the efflux-deficient E. coli Delta tolC mutant strain. PMID- 29498519 TI - Identification of Eukaryotic Translation Elongation Factor 1-alpha 1 Gamendazole Binding Site for Binding of 3-Hydroxy-4(1 H)-quinolinones as Novel Ligands with Anticancer Activity. AB - Here, we have identified the interaction site of the contraceptive drug gamendazole using computational modeling. The drug was previously described as a ligand for eukaryotic translation elongation factor 1-alpha 1 (eEF1A1) and found to be a potential target site for derivatives of 2-phenyl-3-hydroxy-4(1 H) quinolinones (3-HQs), which exhibit anticancer activity. The interaction of this class of derivatives of 3-HQs with eEF1A1 inside cancer cells was confirmed via pull-down assay. We designed and synthesized a new family of 3-HQs and subsequently applied isothermal titration calorimetry to show that these compounds strongly bind to eEF1A1. Further, we found that some of these derivatives possess significant in vitro anticancer activity. PMID- 29498520 TI - Bioinspired Asymmetric Synthesis of (-)-Gymnothelignan V. AB - A bioinspired asymmetric total synthesis of a structurally unique subtype of lignan, namely, (-)-gymnothelignan V, was achieved. The key synthetic sequences involved reduction of the eupomatilone skeleton leading to (-)-gymnothelignan J followed by the formation of the corresponding oxocarbenium ion and stereoselective intramolecular Friedel-Crafts reaction. Our synthetic approach provides the information to support the plausible biosynthetic pathway of this structurally unusual lignan. On a similar basis, other structurally related natural and non-natural gymnothelignans including (-)-gymnothelignan D, 6,9-bis- epi-gymnothelignan V, and 5- epi-gymnothelignans D and J were readily prepared. PMID- 29498521 TI - Theoretical Investigation of the Gas-Phase SN2 Reactions of Anionic and Neutral Nucleophiles with Chloramines. AB - The SN2 reactions at nitrogen center (SN2@N) play a significant role in organic synthesis, carcinogenesis, and the formation of some environmentally toxic compounds. However, the SN2@N reactions specifically for neutral compounds as nucleophiles are less known. In this work, reactions of dimethylamine (DMA) and F with NH2Cl were investigated as model reactions to validate an accurate functional from 24 DFT functionals by comparing with the CCSD(T) reference data. M06-2X functional was found to perform best and applied to systematically explore the trends in reactivity for halides (F- and Cl-) and simple amines toward the substrates NH2Cl and NHCl2 (SN2@N) as well as CH3Cl and CH2Cl2 (SN2@C). The computational results show that the backside inversion channel dominates most the SN2@N reactions except for the case of F- + NHCl2, which reacts preferentially via proton transfer. The overall activation free energies (Delta G?) of the inversion channel for the SN2 reactions of F- and Cl- with chloramines are negative, whereas those for amines as nucleophiles are around 30-44 kcal/mol. The SN2@N reactions for all the nucleophiles investigated here are faster than the corresponding SN2@C. Moreover, amines react faster when they have a higher extent of methyl substitution. Additionally, the energy gap between the HOMO of nucleophile and LUMO of substrate generally correlates well with Delta G? of the corresponding SN2 reactions, which is consistent with previous results. PMID- 29498522 TI - The Discovery of ( S)-1-(6-(3-((4-(1-(Cyclopropanecarbonyl)piperidin-4-yl)-2 methylphenyl)amino)-2,3-dihydro-1 H-inden-4-yl)pyridin-2-yl)-5-methyl-1 H pyrazole-4-carboxylic Acid, a Soluble Guanylate Cyclase Activator Specifically Designed for Topical Ocular Delivery as a Therapy for Glaucoma. AB - Soluble guanylate cyclase (sGC), the endogenous receptor for nitric oxide (NO), has been implicated in several diseases associated with oxidative stress. In a pathological oxidative environment, the heme group of sGC can be oxidized becoming unresponsive to NO leading to a loss in the ability to catalyze the production of cGMP. Recently a dysfunctional sGC/NO/cGMP pathway has been implicated in contributing to elevated intraocular pressure associated with glaucoma. Herein we describe the discovery of molecules specifically designed for topical ocular administration, which can activate oxidized sGC restoring the ability to catalyze the production of cGMP. These efforts culminated in the identification of compound (+)-23, which robustly lowers intraocular pressure in a cynomolgus model of elevated intraocular pressure over 24 h after a single topical ocular drop and has been selected for clinical evaluation. PMID- 29498523 TI - Glass-Transition Temperature of the beta-Relaxation as the Major Predictive Parameter for Recrystallization of Neat Amorphous Drugs. AB - Recrystallization of amorphous drugs is currently limiting the simple approach to improve solubility and bioavailability of poorly water-soluble drugs by amorphization of a crystalline form of the drug. In view of this, molecular mobility, alpha-relaxation and beta-relaxation processes with the associated transition temperatures Tgalpha and Tgbeta, was investigated using dynamic mechanical analysis (DMA). The correlation between the transition temperatures and the onset of recrystallization for nine amorphous drugs, stored under dry conditions at a temperature of 296 K, was determined. From the results obtained, Tgalpha does not correlate with the onset of recrystallization under the experimental storage conditions. However, a clear correlation between Tgbeta and the onset of recrystallization was observed. It is shown that at storage temperature below Tgbeta, amorphous nifedipine retains its amorphous form. On the basis of the correlation, an empirical correlation is proposed for predicting the onset of recrystallization for drugs stored at 0% RH and 296 K. PMID- 29498524 TI - Ruthenium(II)-Catalyzed Redox-Free [3 + 2] Cycloaddition of N-Sulfonyl Aromatic Aldimines with Maleimides. AB - A ruthenium(II)-catalyzed redox-free cycloaddition of N-sulfonyl aromatic aldimines with maleimides providing 1-aminoindanes in good yields is described. Usually, maleimides reacted with substituted aromatics, affording the Michael type ortho alkylated aromatics or 1,1-type cyclized spirosuccinimides. In the present reaction, maleimides provided 1,2-type cycloaddition products. The proposed mechanism was strongly supported by the DFT calculations and isolation of a ruthenacycle intermediate. PMID- 29498525 TI - Copper-Catalyzed One-Pot N-Acylation and C5-H Halogenation of 8-Aminoquinolines: The Dual Role of Acyl Halides. AB - The synthesis of N-acyl-5-halo-8-aminoquinolines has been realized by directly employing 8-aminoquinolines and acyl halides (Cl, Br, I) with copper catalysis. The construction of the target products involves domino N-acylation and C5-H halogenations of the 8-aminoquinoline, wherein the acyl halides act as the donors of both acyl and halide atoms, which enables the first access to the step efficient synthesis of 5-halogenated N-acyl quinlolines. PMID- 29498526 TI - Targeted Metabolomics Reveals a Protective Role for Basal PPARalpha in Cholestasis Induced by alpha-Naphthylisothiocyanate. AB - alpha-Naphthylisothiocyanate (ANIT) is an experimental agent used to induce intrahepatic cholestasis. The Ppara-null mouse line is widely employed to explore the physiological and pathological roles of PPARalpha. However, little is known about how PPARalpha influences the hepatotoxicity of ANIT. In the present study, wild-type and Ppara-null mice were orally treated with ANIT to induce cholestasis. The serum metabolome of wild-type mice segregated from that of the Ppara-null mice, driven by changes of bile acid (BA) metabolites. Alkaline phosphatase and total BAs were elevated preferentially in Ppara-null mice, which correlated with changes in Cyp7a1, Cyp8b1, Mrp3, Cyp3a11, Cyp2b10, Ugt1a2, and Ugt1a5 genes and showed cross-talk between basal PPARalpha and potentially adaptive pathways. Il6, Tnfa, and target genes in the STAT3 pathway ( Socs3, Fga, Fgb, and Fgg) were up-regulated in Ppara-null mice but not in wild-type mice. The JNK pathway was activated in both mouse lines, while NF-kappaB and STAT3 were activated only in Ppara-null mice. These data suggest protection against cholestasis by basal PPARalpha involves regulation of BA metabolism and inhibition of NF-kappaB/STAT3 signaling. Considering studies on the protective effects of both basal and activated PPARalpha, caution should be exercised when one attempts to draw conclusions in which the PPARalpha is modified by genetic manipulation, fasting, or activation in pharmacological and toxicological studies. PMID- 29498527 TI - Influence of Evaporation on Soap Film Rupture. AB - Although soap films are prone to evaporate due to their large surface to volume ratio, the effect of evaporation on macroscopic film features has often been disregarded in the literature. In this work, we experimentally investigate the influence of environmental humidity on soap film stability. An original experiment allows to measure both the maximum length of a film pulled at constant velocity and its thinning dynamics in a controlled atmosphere for various values of the relative humidity [Formula: see text]. At first order, the environmental humidity seems to have almost no impact on most of the film thinning dynamics. However, we find that the film length at rupture increases continuously with [Formula: see text]. To rationalize our observations, we propose that film bursting occurs when the thinning due to evaporation becomes comparable to the thinning due to liquid drainage. This rupture criterion turns out to be in reasonable agreement with an estimation of the evaporation rate in our experiment. PMID- 29498529 TI - NMR Metabolomics Reveals Metabolism-Mediated Protective Effects in Liver (HepG2) Cells Exposed to Subtoxic Levels of Silver Nanoparticles. AB - The expansion of biomedical and therapeutic applications of silver nanoparticles (AgNPs) raises the need to further understand their biological effects on human cells. In this work, NMR metabolomics has been applied to reveal the metabolic effects of AgNPs toward human hepatoma (HepG2) cells, which are relevant with respect to nanoparticle accumulation and detoxification. Cellular responses to widely disseminated citrate-coated AgNPs (Cit30) and to emergent biogenic AgNPs prepared using an aqueous plant extract as reducing and stabilizing agent (GS30) have been compared with a view to assess the influence of nanoparticle coating on the metabolic effects produced. Subtoxic concentrations (IC5 and IC20) of both nanoparticle types caused profound changes in the cellular metabolome, suggesting adaptations in energy production processes (glucose metabolism and the phosphocreatine system), antioxidant defenses, protein degradation and lipid metabolism. These signatures were proposed to reflect mainly metabolism-mediated protective mechanisms and were found to be largely common to Cit30 and GS30 AgNPs, although differences in the magnitude of response, not captured by conventional cytotoxicity assessment, were detected. Overall, this study highlights the value of NMR metabolomics for revealing subtoxic biological effects and helping to understand cell-nanomaterial interactions. PMID- 29498530 TI - Bond Ellipticity Alternation: An Accurate Descriptor of the Nonlinear Optical Properties of pi-Conjugated Chromophores. AB - Well-defined structure-property relationships offer a conceptual basis to afford a priori design principles to develop novel pi-conjugated molecular and polymer materials for nonlinear optical (NLO) applications. Here, we introduce the bond ellipticity alternation (BEA) as a robust parameter to assess the NLO characteristics of organic chromophores and illustrate its effectiveness in the case of streptocyanines. BEA is based on the symmetry of the electron density, a physical observable that can be determined from experimental X-ray electron densities or from quantum-chemical calculations. Through comparisons to the well established bond-length alternation and pi-bond order alternation parameters, we demonstrate the generality of BEA to foreshadow NLO characteristics and underline that, in the case of large electric fields, BEA is a more reliable descriptor. Hence, this study introduces BEA as a prominent descriptor of organic chromophores of interest for NLO applications. PMID- 29498528 TI - A Regulation of Regiodivergent Routes for Enantioselective Aldol Addition of 2 Alkyl Allenoates with Aldehydes: alpha-Addition versus gamma-Addition. AB - A method for the regioselective asymmetric aldol addition of 2-alkyl allenoates with aldehydes to provide an alpha- or gamma-adduct depending on the aldehyde pair is reported. In most cases, except enals, a mixture of a chiral bromoborane with 2-alkyl allenoates in the presence of iPr2NEt can react with aldehydes to provide efficient gamma-addition products as single isomers containing axial and central chirality. On the other hand, observations indicate that enals undergo alpha-addition to yield highly functionalized adducts, including an alpha-carbon quaternary center in high levels of diastereo- and enantioselectivity. PMID- 29498531 TI - Clinical translation of myocardial conditioning. AB - Rapid admission and acute interventional treatment combined with modern antithrombotic pharmacologic therapy have improved outcomes in patients with ST elevation myocardial infarction. The next major target to further advance outcomes needs to address ischemia-reperfusion injury, which may contribute significantly to the final infarct size and hence mortality and postinfarction heart failure. Mechanical conditioning strategies including local and remote ischemic pre-, per-, and postconditioning have demonstrated consistent cardioprotective capacities in experimental models of acute ischemia-reperfusion injury. Their translation to the clinical scenario has been challenging. At present, the most promising mechanical protection strategy of the heart seems to be remote ischemic conditioning, which increases myocardial salvage beyond acute reperfusion therapy. An additional aspect that has gained recent focus is the potential of extended conditioning strategies to improve physical rehabilitation not only after an acute ischemia-reperfusion event such as acute myocardial infarction and cardiac surgery but also in patients with heart failure. Experimental and preliminary clinical evidence suggests that remote ischemic conditioning may modify cardiac remodeling and additionally enhance skeletal muscle strength therapy to prevent muscle waste, known as an inherent component of a postoperative period and in heart failure. Blood flow restriction exercise and enhanced external counterpulsation may represent cardioprotective corollaries. Combined with exercise, remote ischemic conditioning or, alternatively, blood flow restriction exercise may be of aid in optimizing physical rehabilitation in populations that are not able to perform exercise practice at intensity levels required to promote optimal outcomes. PMID- 29498533 TI - Galectin-3 in the pathogenesis of heart failure: a causative mediator or simply a biomarker? PMID- 29498532 TI - Minoxidil improves vascular compliance, restores cerebral blood flow, and alters extracellular matrix gene expression in a model of chronic vascular stiffness. AB - Increased vascular stiffness correlates with a higher risk of cardiovascular complications in aging adults. Elastin (ELN) insufficiency, as observed in patients with Williams-Beuren syndrome or with familial supravalvular aortic stenosis, also increases vascular stiffness and leads to arterial narrowing. We used Eln+/- mice to test the hypothesis that pathologically increased vascular stiffness with concomitant arterial narrowing leads to decreased blood flow to end organs such as the brain. We also hypothesized that drugs that remodel arteries and increase lumen diameter would improve flow. To test these hypotheses, we compared carotid blood flow using ultrasound and cerebral blood flow using MRI-based arterial spin labeling in wild-type (WT) and Eln+/- mice. We then studied how minoxidil, an ATP-sensitive K+ channel opener and vasodilator, affects vessel mechanics, blood flow, and gene expression. Both carotid and cerebral blood flows were lower in Eln+/- mice than in WT mice. Treatment of Eln+/- mice with minoxidil lowered blood pressure and reduced functional arterial stiffness to WT levels. Minoxidil also improved arterial diameter and restored carotid and cerebral blood flows in Eln+/- mice. The beneficial effects persisted for weeks after drug removal. RNA-Seq analysis revealed differential expression of 127 extracellular matrix-related genes among the treatment groups. These results indicate that ELN insufficiency impairs end-organ perfusion, which may contribute to the increased cardiovascular risk. Minoxidil, despite lowering blood pressure, improves end-organ perfusion. Changes in matrix gene expression and persistence of treatment effects after drug withdrawal suggest arterial remodeling. Such remodeling may benefit patients with genetic or age-dependent ELN insufficiency. NEW & NOTEWORTHY Our work with a model of chronic vascular stiffness, the elastin ( Eln)+/- mouse, shows reduced brain perfusion as measured by carotid ultrasound and MRI arterial spin labeling. Vessel caliber, functional stiffness, and blood flow improved with minoxidil. The ATP-sensitive K+ channel opener increased Eln gene expression and altered 126 other matrix-associated genes. PMID- 29498534 TI - Low-Dose Nocturnal Dexmedetomidine Prevents ICU Delirium. A Randomized, Placebo controlled Trial. AB - RATIONALE: Dexmedetomidine is associated with less delirium than benzodiazepines and better sleep architecture than either benzodiazepines or propofol; its effect on delirium and sleep when administered at night to patients requiring sedation remains unclear. OBJECTIVES: To determine if nocturnal dexmedetomidine prevents delirium and improves sleep in critically ill adults. METHODS: This two-center, double-blind, placebo-controlled trial randomized 100 delirium-free critically ill adults receiving sedatives to receive nocturnal (9:30 p.m. to 6:15 a.m.) intravenous dexmedetomidine (0.2 MUg/kg/h, titrated by 0.1 MUg /kg/h every 15 min until a goal Richmond Agitation and Sedation Scale score of -1 or maximum rate of 0.7 MUg/kg/h was reached) or placebo until ICU discharge. During study infusions, all sedatives were halved; opioids were unchanged. Delirium was assessed using the Intensive Care Delirium Screening Checklist every 12 hours throughout the ICU admission. Sleep was evaluated each morning by the Leeds Sleep Evaluation Questionnaire. MEASUREMENTS AND MAIN RESULTS: Nocturnal dexmedetomidine (vs. placebo) was associated with a greater proportion of patients who remained delirium-free during the ICU stay (dexmedetomidine [40 (80%) of 50 patients] vs. placebo [27 (54%) of 50 patients]; relative risk, 0.44; 95% confidence interval, 0.23-0.82; P = 0.006). The average Leeds Sleep Evaluation Questionnaire score was similar (mean difference, 0.02; 95% confidence interval, 0.42-1.92) between the 34 dexmedetomidine (average seven assessments per patient) and 30 placebo (six per patient) group patients able to provide one or more assessments. Incidence of hypotension, bradycardia, or both did not differ significantly between groups. CONCLUSIONS: Nocturnal administration of low-dose dexmedetomidine in critically ill adults reduces the incidence of delirium during the ICU stay; patient reported sleep quality appears unchanged. Clinical trial registered with www.clinicaltrials.gov (NCT01791296). PMID- 29498535 TI - Patient perspectives on repeated MRI and PET/CT examinations during neoadjuvant treatment of esophageal cancer. AB - OBJECTIVE: The perceived burden of diagnostic tests by patients during the assessment of esophageal cancer warrants attention with the current increase in repeated imaging for purposes of disease monitoring during and after treatment. The purpose of this prospective study was to evaluate the experienced burden associated with repeated MRI and positron emission tomography with integrated CT (PET/CT) examinations during neoadjuvant treatment for esophageal cancer from the perspective of the patient. METHODS: In 27 patients receiving neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer MRI and PET/CT examinations were performed before nCRT, during nCRT and before surgery. The experienced burden during repeated MRI and PET/CT examinations was evaluated with a self-report questionnaire addressing discomfort, pain, anxiety and embarrassment, each measured on a 5-point Likert scale (1 = none; up to 5 = very much). In addition, a comparative assessment was used to rank MRI, PET/CT and baseline endoscopy. RESULTS: All scans were performed without the occurrence of an adverse event. Few patients experienced discomfort (mean score +/-SD: 1.9 +/- 1.0 for MRI vs 2.0 +/- 1.0 for PET/CT, p = 0.586), pain (1.1 +/- 0.4 for MRI vs 1.3 +/- 0.7 for PET/CT, p = 0.059), anxiety (1.0 +/- 0.2 for MRI vs 1.0 +/- 0.2 for PET/CT, p = 1.000) and embarrassment (1.0 +/- 0 for MRI vs 1.0 +/- 0.2 for PET/CT, p = 0.317) during both MRI and PET/CT. Patients preferred MRI over PET/CT (67% vs 22%, respectively, p = 0.023), and MRI over endoscopy (59% vs 19%, respectively, p = 0.027). In the comparison between PET/CT and endoscopy, 59% of patients preferred PET/CT and 26% preferred endoscopy (p = 0.093). CONCLUSION: Repeated imaging with both MRI and PET/CT is generally well-tolerated for the assessment of response to treatment in esophageal cancer patients. Shorter acquisition times and altered body positioning during scanning will likely improve patient experience. Advances in knowledge: This paper demonstrates that MRI and PET/CT are generally well-tolerated imaging procedures for the assessment of response to treatment in esophageal cancer patients. When asked to rank different tests, patients preferred MRI over PET/CT and endoscopy. PMID- 29498536 TI - 18F-FDG PET/CT in the management of patients with malignant pleural mesothelioma being considered for multimodality therapy: experience of a tertiary referral center. AB - OBJECTIVE: To compare the N- and M-staging accuracy of PET vs CT, as per the American Joint Committee on Cancer (AJCC) eighth edition in patients with malignant pleural mesothelioma (MPM) being considered for multimodality therapy in a tertiary referral center. A secondary aim was to assess survival outcome of patients chosen for surgical management after PET. METHODS: A retrospective, single institution comparison of PET and CT was performed in patients with histologically proven MPM being considered for multimodality therapy. Performance of each modality in identifying nodal category and presence or absence of distant metastases was abstracted from electronic patient records. The standard of reference was surgical histopathology for nodal stage and histopathology or clinical and imaging follow-up of >3 months for distant metastases. RESULTS: There were 101 eligible patients with complete data sets; 82 males, 19 females with a mean age of 66.6 years (range: 39-85). Most patients (n = 68) had epithelioid histology. Surgery was performed in 61/101 patients (60.4%), most of whom had multimodality therapy. Nodal category was concordant to surgical histopathology in 38/60 patients (63.3%) on PET, compared to 27/60 (45%) on CT (p = 0.001). For detection of >=N1 disease only, PET and CT correctly staged 15/37 patients (40.5%) and 8/37 (21.6%), respectively (p = 0.023). Distant metastases were identified uniquely on PET in eight patients and on CT only in one patient. Overall, PET and CT correctly identified 11/12 (91.6%) and 4/12 (33.3%) patients with distant metastases, respectively (p = 0.0391). CONCLUSION: PET identifies significantly more patients with nodal or distant metastatic disease than CT and may contribute to more appropriate selection of patients with MPM for surgery or multimodality therapy. Advances in knowledge: In patients with MPM, fludeoxyglucose-PET/CT detects significantly more patients with distant metastases than CT. PET/CT can help in the selection of patients with MPM who would benefit from surgery or multimodality therapy. PMID- 29498537 TI - Complementary and Alternative Medicine Usage by Multiple Sclerosis Patients: Results from a Prospective Clinical Study. AB - OBJECTIVES: To investigate the factors associated with complementary and alternative medicine (CAM) usage by multiple sclerosis (MS) patients. Design, Setting/Location: Single-center, prospective clinical study at an academic MS center in the northeastern United States. METHODS: This study included CAM data from 524 MS patients and 304 healthy controls (HC) enrolled in a prospective study of clinical, neuroimaging, and environmental risk factors in MS at an academic MS Center. Clinical, neuroimaging, and disease-modifying treatment data were obtained. In addition, data on usage of CAM modalities, including acupuncture, aromatherapy, Ayurveda, Chinese herbal medicine, chiropractor, electromagnetic therapy, homeopathy, hypnosis, massage, naturopathy, Qi gong, Reiki, therapeutic touch, and bee stings were collected in an in-person interview. RESULTS: The percentages of HC reporting usage of any CAM (32%) was similar to that in MS patients after diagnosis (30.5%). The usage of any CAM was higher in MS patients after MS diagnosis compared to before MS diagnosis (p < 0.001). The three most frequently used CAM for MS patients after MS diagnosis and HC were chiropractor, massage, and acupuncture. The most frequent reasons for CAM use were MS symptom relief, back problems, and pain. In multivariate analysis, female gender, higher education level, MS disease course, and not currently on disease-modifying therapies (DMT) treatment status were associated with CAM usage. CONCLUSIONS: Gender, education level, DMT treatment status, and MS disease course are associated with CAM usage in MS patients. Ever-CAM usage patterns in MS patients are similar to those in HC. PMID- 29498538 TI - Weekend effect in acute coronary syndrome: A meta-analysis of observational studies. AB - BACKGROUND: The effect of a weekend compared with a weekday hospital admission on patient outcomes after an acute coronary syndrome is unclear. This study aims to determine whether collectively there is a weekend effect in acute coronary syndrome. METHOD: We conducted a systematic review and meta-analysis of cohort studies examining the association between weekend compared to weekday admission at any time of the day and early mortality (in-hospital or 30-day). A search was performed on Medline and Embase and relevant studies were pooled using random effects meta-analysis for risk of early mortality. Additional analyses were performed considering only more recent studies (conducted after 2005) and by patient group (ST-elevation myocardial infarction [STEMI] or non-STEMI [NSTEMI]), as well as meta-regression according to starting year and mean year of study. RESULTS: A total of 18 studies were included with over 14 million participants incorporating 3 million weekend and over 11.5 million weekday admissions and the rates of mortality were 19.2% and 23.4%, respectively. The pooled results of all 18 studies suggest that weekend admission was associated with a small increased risk of early mortality (odds ratio [OR] 1.06, 95% confidence interval [CI] 1.03 1.09). The results for subgroups of STEMI and NSTEMI cohorts were not statistically significant and timing of admission after 2005 had minimal influence on the results (OR 1.06, 95% CI 0.95-1.17). CONCLUSIONS: There is a small weekend effect for admission with acute coronary syndrome that has persisted over time. PMID- 29498539 TI - Effect of Postmortem Interval and Years in Storage on RNA Quality of Tissue at a Repository of the NIH NeuroBioBank. AB - Brain tissue from 1068 donors was analyzed for RNA quality as a function of postmortem interval (PMI) and years in storage. Approximately 83% of the cortical and cerebellar samples had an RNA integrity number (RIN) of 6 or greater, indicating their likely suitability for real-time quantitative polymerase chain reaction research. The average RIN value was independent of the PMI, up to at least 36 hours. The RNA quality for specific donated brains could not be predicted based on the PMI. Individual samples with a low PMI could have a poor RIN value, while a sample with a PMI over 36 hours may have a high RIN value. The RIN values for control brain donors, all of whom died suddenly and unexpectedly, were marginally higher than for individuals with clinical brain disorders. Polymerase chain reaction (PCR) analysis of samples confirmed that RIN values were more critical than PMI for determining suitability of tissue for molecular biological studies and samples should be matched by their RIN values rather than PMI. Importantly, PCR analysis established that tissue stored up to 23 years at 80 degrees C yielded high-quality RNA. These results confirm that postmortem human brain tissue collected by brain and tissue banks over decades can serve as high quality material for the study of human disorders. PMID- 29498540 TI - Quantifying changes in nigrosomes using quantitative susceptibility mapping and neuromelanin imaging for the diagnosis of early-stage Parkinson's disease. AB - OBJECTIVE: To quantify nigral changes with a focus on their spatial variation within the substantia nigra pars compacta (SNpc) for diagnosing early-stage Parkinson's disease (PD). METHODS: The study participants were 18 patients with early-stage PD (PD group) and 18 healthy controls (HC group) who underwent quantitative susceptibility mapping (QSM) and neuromelanin imaging. The QSM and neuromelanin values in each whole SNpc containing the entire nigrosome and dorsolateral SNpc containing nigrosome 1 were calculated. The neuromelanin area was defined as the volume with a signal-to-noise ratio higher than that of the background region. The significance of intergroup differences in the QSM value and neuromelanin area in each SNpc region was tested. Logit (p) was used to estimate the probability of PD in relation to the QSM value and the neuromelanin area, and receiver operating characteristic analyses were performed for each value. RESULTS: In both SNpc, QSM values were significantly higher and neuromelanin areas were significantly lower in the PD group compared with the HC group (p < 0.05). The respective areas under the receiver operating characteristic curve for the two groups were 0.70/0.73 for the QSM value, 0.81/0.78 for the neuromelanin area in the whole/dorsolateral SNpc, and 0.86 for logit (p) in relation to the QSM value of the dorsolateral SNpc and the neuromelanin area of the whole SNpc. CONCLUSION: Comprehensive MRI assessment of the abnormality involving the nigrosomes can yield a high diagnostic performance for early-stage PD. Advances in knowledge: Focusing on spatial differences in nigral changes within the SNpc can increase the sensitivity of the detection of PD-related neurodegenerative changes. PMID- 29498542 TI - Routine hospital data - is it good enough for trials? An example using England's Hospital Episode Statistics in the SHIFT trial of Family Therapy vs. Treatment as Usual in adolescents following self-harm. AB - BACKGROUND: Use of routine data sources within clinical research is increasing and is endorsed by the National Institute for Health Research to increase trial efficiencies; however there is limited evidence for its use in clinical trials, especially in relation to self-harm. One source of routine data, Hospital Episode Statistics, is collated and distributed by NHS Digital and contains details of admissions, outpatient, and Accident and Emergency attendances provided periodically by English National Health Service hospitals. We explored the reliability and accuracy of Hospital Episode Statistics, compared to data collected directly from hospital records, to assess whether it would provide complete, accurate, and reliable means of acquiring hospital attendances for self harm - the primary outcome for the SHIFT (Self-Harm Intervention: Family Therapy) trial evaluating Family Therapy for adolescents following self-harm. METHODS: Participant identifiers were linked to Hospital Episode Statistics Accident and Emergency, and Admissions data, and episodes combined to describe participants' complete hospital attendance. Attendance data were initially compared to data previously gathered by trial researchers from pre-identified hospitals. Final comparison was conducted of subsequent attendances collected through Hospital Episode Statistics and researcher follow-up. Consideration was given to linkage rates; number and proportion of attendances retrieved; reliability of Accident and Emergency, and Admissions data; percentage of self-harm episodes recorded and coded appropriately; and percentage of required data items retrieved. RESULTS: Participants were first linked to Hospital Episode Statistics with an acceptable match rate of 95%, identifying a total of 341 complete hospital attendances, compared to 139 reported by the researchers at the time. More than double the proportion of Hospital Episode Statistics Accident and Emergency episodes could not be classified in relation to self-harm (75%) compared to 34.9% of admitted episodes, and of overall attendances, 18% were classified as self-harm related and 20% not related, while ambiguity or insufficient information meant 62% were unclassified. Of 39 self-harm-related attendances reported by the researchers, Hospital Episode Statistics identified 24 (62%) as self-harm related while 15 (38%) were unclassified. Based on final data received, 1490 complete hospital attendances were identified and comparison to researcher follow-up found Hospital Episode Statistics underestimated the number of self-harm attendances by 37.2% (95% confidence interval 32.6%-41.9%). CONCLUSION: Advantages of routine data collection via NHS Digital included the acquisition of more comprehensive and timely trial outcome data, identifying more than double the number of hospital attendances than researchers. Disadvantages included ambiguity in the classification of self-harm relatedness. Our resulting primary outcome data collection strategy used routine data to identify hospital attendances supplemented by targeted researcher data collection for attendances requiring further self-harm classification. PMID- 29498543 TI - The reporting of harms in publications on randomized controlled trials funded by the "Programme Hospitalier de Recherche Clinique," a French academic funding scheme. AB - BACKGROUND/AIMS: Accurate information on harms arising from medical interventions is essential for assessing benefit-risk ratios. Since 2004, there has been an extension of the Consolidated Standards of Reporting Trials statement for reporting harms data in publications on randomized clinical trials. The objective of our study was to assess the quality of this reporting from academic randomized clinical trials on drugs. METHODS: We searched for articles on randomized clinical trials funded between 2004 and 2008 by the "Programme Hospitalier de Recherche Clinique." We included all published randomized clinical trials that assessed drugs. Harm-related data were extracted and compared with the Consolidated Standards of Reporting Trials Harms extension, and the space in the articles devoted to harms data was measured. RESULTS: In total, 37 randomized clinical trials met the inclusion criteria. The median harm score was 9/18. In 73.0% of the randomized clinical trials, the reporting of adverse events was selective. Less than 50% of articles provided information on reasons for drug discontinuation that were related to adverse events. The score and the space allocated to harms were higher in antineoplastic and immunomodulating drugs randomized clinical trials, while the median proportion of the space in the results section allocated to harms was 16.8%. In 67.6% of the articles, the space allocated to the authors' list and affiliations was greater than the space in the results section allocated to descriptions of harms. No significant improvement in the score or the space allocation was observed during the study period. CONCLUSION: Reporting of harms in French academic drug randomized clinical trials is suboptimal; moreover, this shortcoming is a critical barrier to evaluating the benefit-risk ratio of drug randomized clinical trials. Thus, the authors should be encouraged to adhere to the Consolidated Standards of Reporting Trials Harms extension. PMID- 29498541 TI - Staging hand-wrist and cervical vertebrae images: a comparison of reproducibility. AB - OBJECTIVES: The aim of this study was to compare the reproducibility of skeletal maturation assessments by raters with similar orthodontic experience using hand wrist (HW) and cervical vertebral maturation (CVM) methods. METHODS: HW and lateral cephalometric radiographs from 15 subjects (8 males and 7 females; ages, 9-16 years) were selected randomly. HW skeletal maturation was evaluated by the method of Greulich and Pyle, and CVM staging was evaluated by the method of Baccetti et al. Six orthodontic residents evaluated all images at three time periods: T1, initial evaluation; T2, re-evaluation after 7 days and T3, final evaluation after 5 weeks. Intra- and interexaminer reproducibility was evaluated with the intraclass correlation coefficient; the limits of agreement (LoA) were determined by using the Bland-Altman method. RESULTS: The intraexaminer reliability assessed by intraclass correlation coefficient was scored as good for both of methods (T1-T2-T3 HW = 0.89 and CVM = 0.80; T1-T2 HW = 0.87 and CVM = 0.77; T2-T3 HW0 = 0.90 and CVM = 0.81), as well as the interexaminer evaluation, with the exception of HW-T1, which scored excellent (0.92). The width of LoA from Bland-Altman plot of cervical vertebra method was narrower (CVM T1-T2: -2.3 and +1.8; CVM T2-T3: -2.0 and +2.0) than the HW method (HW T1-T2: -3.9 and +4.8; HW T2-T3: -4.0 and +3.5). CONCLUSIONS: Both HW and CVM methods presented good reproducibility for intra- and interexaminer correlation assessments. The small LoA indicated that the CVM is a reproducible method. PMID- 29498546 TI - Thank You and Welcome: Editorial Changes in Current Eye Research. PMID- 29498544 TI - Synthesis and Evaluation of 2-[18F]Fluoroethyltriazolesuberohydroxamine Acid for Histone Deacetylase in a Tumor Model as a Positron Emission Tomography Radiotracer. AB - Histone deacetylases (HDACs) are an important regulator of expression and activity of numerous proteins in terms of epigenetic aberrations. This makes HDACs attractive for antitumor therapy and imaging in certain cancers. The authors report the radiochemical synthesis of 2 [18F]fluoroethyltriazolesuberohydroxamine acid ([18F]FETSAHA) as a HDAC-targeted radiolabel probe for positron imaging tomography/computed tomography. The authors also evaluated the in vivo tumor targeting in subcutaneously implanted RR1022 rats. [18F]FETSAHA was produced in less than 2 h with 31.2% +/- 4.6% (n = 6) decay-corrected yields and specific activity of 21.4 +/- 9.1 GBq/MUmol (n = 6) at end of synthesis. [18F]FETSAHA showed significant radioactivity accumulation in tumors with rapid blood clearance and both gastrointestinal track and renal excretion. Tumor-to-blood and tumor-to-muscle uptake ratios in the RR1022 tumor bearing rat model were 1.21 and 1.83 and 2.75 and 2.76 at 30 and 60 min, respectively. An inhibition study of [18F]FETSAHA in the presence of excess amount of suberanilohydroximic acid (SAHA) revealed receptor specific activity accumulation. [18F]FETSAHA has favorable in vivo tumor imaging properties and may be useful for noninvasive evaluation of the correlation between cancer and HDACs. PMID- 29498545 TI - Food Safety Practices Linked with Proper Refrigerator Temperatures in Retail Delis. AB - Listeria monocytogenes (L. monocytogenes) causes the third highest number of foodborne illness deaths annually. L. monocytogenes contamination of sliced deli meats at the retail level is a significant contributing factor to L. monocytogenes illness. The Centers for Disease Control and Prevention's Environmental Health Specialists Network (EHS-Net) conducted a study to learn more about retail delis' practices concerning L. monocytogenes growth and cross contamination prevention. This article presents data from this study on the frequency with which retail deli refrigerator temperatures exceed 41 degrees F, the Food and Drug Administration (FDA)-recommended maximum temperature for ready to-eat food requiring time and temperature control for safety (TCS) (such as retail deli meat). This provision was designed to control bacterial growth in TCS foods. This article also presents data on deli and staff characteristics related to the frequency with which retail delis refrigerator temperatures exceed 41 degrees F. Data from observations of 445 refrigerators in 245 delis showed that in 17.1% of delis, at least one refrigerator was >41 degrees F. We also found that refrigeration temperatures reported in this study were lower than those reported in a related 2007 study. Delis with more than one refrigerator, that lacked refrigerator temperature recording, and had a manager who had never been food safety certified had greater odds of having a refrigerator temperature >41 degrees F. The data from this study suggest that retail temperature control is improving over time. They also identify a food safety gap: some delis have refrigerator temperatures that exceed 41 degrees F. We also found that two food safety interventions were related to better refrigerated storage practices: kitchen manager certification and recording refrigerated storage temperatures. Regulatory food safety programs and the retail industry may wish to consider encouraging or requiring kitchen manager certification and recording refrigerated storage temperatures. PMID- 29498547 TI - Goal-setting in diabetes self-management: A systematic review and meta-analysis examining content and effectiveness of goal-setting interventions. AB - BACKGROUND: Goal-setting is recommended and widely used within diabetes self management programmes. However, empirical evidence around its effectiveness lacks clarity. This review aims to evaluate the effectiveness of goal-setting interventions on diabetes outcomes and to determine which behaviour change techniques (BCTs) are frequently used within these interventions. METHODS: A systematic search identified 14 studies, describing 12 interventions targeting diabetic-control which incorporated goal-setting as the main intervention strategy. Study characteristics, outcome measures and effect sizes of the included studies were extracted and checked by two authors. The BCT taxonomy v1 was used to identify intervention content. Meta-analyses were conducted to assess intervention effects on the primary outcome of average blood glucose levels (HbA1c) and on body-weight. Psycho-social and behavioural outcomes were summarised in narrative syntheses. RESULTS: Significant post-intervention improvements in HbA1C were found (-.22, 95% CI, -.40, -.04) across studies. No other main effects were identified. The BCT 'goal-setting (behaviour)' was most frequently implemented and was identified in 84% of the interventions. CONCLUSIONS: Goal-setting interventions appear to be associated with reduced HbA1C levels. However, the low numbers of studies identified and the risk biases across studies suggest more research is needed to further explore goal-setting BCTs in diabetes self-management. PMID- 29498548 TI - Evaluation of multikinase inhibitor LDN193189 induced hepatotoxicity in teleost fish Poecilia latipinna. AB - Currently, scientists show keen interest in the drugs that inhibit multiple kinases, LDN193189, being an example. It combats certain cancers in vitro as well as in vivo, making it a prerequisite for researchers to study the toxic potential of this drug in animal models. As most of the drugs metabolized by liver cause hepatic injury, LDN193189-induced hepatotoxicity was examined using a teleost fish, Poecilia latipinna. As a prelude, calculation of LD50 showed a value of 95.22 mg/kg body weight and three doses were decided based on it for further evaluations. All these groups were tested for antioxidant enzyme levels and were significantly raised for mid- and high-dose group. Similar trend was recorded for ALP, AST, and ALT levels. Furthermore, some key indicators of drug metabolism in liver were tested for their expression in response to LDN193189 treatment. Among these, Cyt-C, CYP3A4, CYP1B1 and CYP1A1 were elevated in mid- and high dose, except CYP21A1, which declined remarkably. Moreover, histological profile of the liver reflected high degree of inflammation due to drug treatment, but this was found only at high dose. In summary, LDN193189, at 2.5 mg/kg body weight, did not cause any adverse hepatotoxicity, rendering it safe for use as an anti proliferative agent - an activity for which it has already shown promising results in the same animal model. The low-dose group previously studied for its anti-proliferative property showed no adverse effect in liver, whereas the mid- and high dose induced moderate or severe hepatotoxicity in P. latipinna. PMID- 29498549 TI - Potential of serum soluble CD93 as a biomarker for asthma in an ovalbumin-induced asthma murine model. AB - BACKGROUND: CD93 is a membrane-associated glycoprotein, which can be released in a soluble form (sCD93) into the serum. CD93 has received renewed attention as a candidate biomarker of inflammation in various inflammatory and immune-mediated diseases, including asthma. OBJECTIVE: We aimed to evaluate the effects of airway inflammation on CD93 levels in murine models. METHODS: We established an ovalbumin (OVA)-induced acute asthma murine model (OVA model) and a lipopolysaccharide (LPS)-induced airway inflammation murine model (LPS model). Dexamethasone was administered by gavage to attenuate the airway inflammation. RESULTS: The OVA model demonstrated typical allergic asthma features with increased airway hyper-responsiveness, inflammatory cell infiltration, increased Th2 cytokine levels, compared to the control group. CD93 levels were decreased in lung homogenates and, respiratory epithelial cells, whereas serum sCD93 levels were increased in the OVA model, as compared to the control group. Dexamethasone reversed these effects of OVA. In contrast, in the LPS model, CD93 levels were not affected in neither respiratory epithelial cells nor serum. CONCLUSIONS: Our findings demonstrate the potential of using sCD93 as a biomarker for allergic asthma. PMID- 29498550 TI - High versus Low Intensity Summer Treatment for ADHD Delivered at Secondary School Transitions. AB - Spikes in symptom severity are noted for adolescents with attention deficit/hyperactivity disorder (ADHD) at the transitions to middle and high school that are attributed to developmental maladjustment. This study evaluated the effectiveness of high-intensity (HI; 412 hr, $4,373 per participant) versus low-intensity (LI; 24 hr, $97 per participant) skills-based summer intervention delivered to adolescents with ADHD by local school district staff. Participants were 325 ethnically diverse rising sixth and ninth graders with ADHD randomized to HI versus LI (n = 218) or recruited into an untreated comparison group (n = 107). Group * Time 1-year outcome trajectories were compared using linear mixed models. Both interventions possessed high fidelity and were viewed by families as enjoyable and beneficial. Youth attendance was higher for HI (~80%) versus LI (~45%). Parent training attendance was uniform across groups (~50%). Parent and student attendance did not impact trajectories. Primary benefits of HI over LI were to note taking (d = .50), parent contingency management (d = .43), and parent-rated ADHD symptoms (d = .40-.46; ninth grade only). Secondary analyses suggested that HI may produce additional benefits compared to no treatment for home organization skills (HI vs. untreated d = .54), parent-teen conflict (HI vs. untreated d = .39), and grade point average (HI vs. untreated d = .47, ninth grade only). Summer HI treatment was superior to LI in engagement and uptake of certain skills. However, the extent to which these medium benefits on a limited number of outcomes justify high costs compared to LI remains an open question. Delivering treatment during the summer instead of school year may limit generalizability. PMID- 29498551 TI - Enhancing the apoptotic effect of IL-24/mda-7 on the human hepatic stellate cell through RGD peptide modification. AB - Induction of apoptosis or quiescent hepatic stellate cells (HSCs) can be an attractive molecular strategy due to the importance of activation of HSCs during hepatic fibrogenesis. Interleukin-24/melanoma differentiation-associated gene-7 (IL-24/mda-7) is a cytokine that has attracted a great deal of attention in the tumor killing as well as pathophysiology of the diseases. In this study, the Pro apoptotic and senescence inductive properties of IL-24/mda-7 were assessed in human-derived HSCs. Three plasmids expressing natural mda-7, peptide modified version, mda-7-RGD genes beside a recombinant IL-24 protein, were added or transfected into activated LX-2 cells. Cell viability and the amount of apoptosis were analyzed using MTT and Annexin V staining method, respectively. Hence, the expression levels of apoptotic genes and PPARgamma in different groups were also compared by real-time PCR analysis. Furthermore, the senescence effect of IL 24/mda-7 by a beta-galactosidase (SA-beta-gal) senescence assay, was evaluated. The viability assessment showed that pmda-7-RGD had the most significant growth inhibitory effect when compared to the control group, pcDNA3.1 (P = 0.0002). The apoptosis analysis also revealed a significant impact of different mda-7 forms in apoptosis induction. The measuring of cell senescence also indicated that IL 24/mda-7 in plasmid and protein forms exhibited a senescence inductive activity as determined by an increase in PPARgamma gene expression and beta-galctosidase activity. In conclusion, our findings demonstrated that both endogenous and soluble forms of IL-24/mda-7 induced apoptosis and senescence in activated LX-2 cells and more importantly, fusion of RGD peptide to this cytokine enhanced these activities. So, RGD-modified IL-24/mda-7 could be a suitable candidate for further molecular therapy of fibrosis. PMID- 29498552 TI - Skin subtype categorization based on a new questionnaire for Korean women. AB - BACKGROUND: Several terms have been used to characterize skin types. However, these are not based on evident dermatologic definitions, which usually include subjective and psychological properties. OBJECTIVE: The objective of this study is to establish a new practical questionnaire to classify skin subtypes in Korean women to establish treatment and skin care guidance. METHODS: Eight experts developed consensus statements about skin types and created a questionnaire. The content was categorized into four major subtypes: dry or non-dry; oily or nonoily; sensitive or nonsensitive; and pigmented or nonpigmented. A total of 512 patients completed the questionnaire. Correlations with age, skin Fitzpatrick's phototypes, and dermatologic comorbidities were analyzed. RESULTS: Korean women commonly have oily skin but complain of dryness after cleansing. They are especially sensitive to skin care products and prone to developing pigmentary lesions. There was a trend in the proportion of dry skin subtype that increased as pigmented skin increased and oily skin decreased with advanced age. The proportion of sensitive skin was higher in patients with dermatologic comorbidities. The proportion of the pigmented skin was higher in darker Fitzpatrick skin phototypes. CONCLUSION: This is the first questionnaire established for Korean women to classify practical skin subtypes and may provide a basis for treating various skin conditions. PMID- 29498553 TI - OnabotulinumtoxinA treatment of moderate to severe glabellar lines in Chinese subjects after laser therapy: A prospective, open-label, noncomparative study. AB - INTRODUCTION: This study evaluated safety and efficacy of onabotulinumtoxinA for moderate to severe glabellar lines (GL) following laser therapy in Chinese subjects. MATERIALS AND METHODS: Subjects (n = 173) were followed for 120 days following a single onabotulinumtoxinA (20 U) treatment for GL after recent laser therapy. Subjects completed validated patient-reported outcomes, including Facial Lines Outcome 11-item (FLO-11) Questionnaire and Facial Lines Satisfaction Questionnaire (FLSQ). Physicians and subjects assessed GL severity at maximum frown and at rest using the Facial Wrinkle Scale with Asian Photonumeric Guide (FWS-A). RESULTS: Mean total FLO-11 scores increased from 47.7 (baseline) to 75.9 (day 120) (p < 0.0001), with mean improvement of at least two grades for most items maintained to day 120. Most subjects were mostly or very satisfied, per the FLSQ. Percentages of subjects with at least one-grade improvement in FWS-A (responders) at maximum frown per subjects and physicians were 93.1% and 97.1%, respectively, at day 30, and 72.3% and 81.5% at day 120 (all, p < 0.0001). More than 70% were FWS-A responders at day 120. All adverse events were mild or moderate; none were related to onabotulinumtoxinA. CONCLUSIONS: A single onabotulinumtoxinA (20 U) treatment following laser therapy was safe and effective in correcting GL for up to 120 days. PMID- 29498554 TI - Surgical correction of involutional lower lid entropion with lateral canthal eyelid block excision and imbrication of the capsulopalpebral ligament using non buried non-resorbable imbricating sutures versus buried resorbable imbricating sutures. AB - PURPOSE: To compare the results of surgical correction of involutional lower eyelid entropion using either buried resorbable imbricating sutures or non-buried non-resorbable sutures that were removed after five to seven days. METHODS: Retrospective analysis of a two-surgeon series. Analysis of the charts of patients surgically treated for involutional lower eyelid entropion between January 2011 and December 2014 with a minimum follow-up of 12 months. MAIN OUTCOME MEASURES: Recurrence rate, postoperative complications. RESULTS: We included 281 eyelids of 240 patients. Of these, 89 eyelids had been treated with buried resorbable imbricating sutures (surgeon WvdB) and 192 with non-buried non resorbable sutures (surgeon DP). Of the 281 eyelids, 77 eyelids had undergone previous entropion surgery. In the buried resorbable suture group (group R), the mean follow-up was 30 months (range 12 to 61 months) versus 39 months (range 14 to 60 months) in the non-buried non-resorbable group (group NR) (p = 0.07). With a follow-up of up to 18 months, the recurrence rate was 2.2% in group R and 4.2% in group NR (p = 0.73). With a similar follow-up, the recurrence rate was 3.9% after primary surgery versus 2.6% in recurrent cases (p = 0.73). Minor postoperative complications and side-effects were seen in 5.3% (15/281). CONCLUSION: We found no difference in the recurrence rate between the use of buried resorbable imbricating sutures and non-buried non-resorbable sutures and between primary versus recurrent cases. We conclude that we can safely use buried resorbable imbricating sutures in involutional entropion. It yields comparable results and omits the need for suture removal. PMID- 29498555 TI - Tissue inhibitor of the metalloproteinases-3 gene polymorphisms and carotid plaque susceptibility in the Han Chinese population. AB - Tissue inhibitor of metalloproteinases (TIMPs) are endogenous inhibitors of matrix metalloproteinases that are involved in normal cellular processes and in the development and progression of atherosclerosis. Our purpose was to evaluate the polymorphisms of the TIMP-3 genes for their associations with carotid plaques or with serum protein levels in the Han Chinese population. Two promoter variants, -915A/G (rs2234921) and -1296T/C (rs9619311), were genotyped in 548 subjects with no plaques, 462 subjects with echogenic plaques, and 427 subjects with mixture plaques. The serum TIMP-3 levels were measured using an enzyme linked immunosorbent assay (ELISA). There was a strong linkage disequilibrium between -1296T/C and -915A/G (D' = 1.0, r2 = 0.991). The individuals with the genotype (TC+CC) were 1.8 times more likely to have mixture plaques than the individuals with the TT genotype (P = 0.001, OR: 1.836, 95%CI: 1.269-2.665). The frequency of the C allele in the mixture plaque group was significantly higher than in the no plaque group (P = 0.009, CI: 1.119-2.187). We observed a significant elevation of the TIMP-3 levels in the serum of patients affected with mixture plaques compared to those with no plaques (P = 0.013). The current data suggest that genetic variation in the TIMP-3 genes may contribute to individual differences in mixture plaque susceptibility in the Han Chinese population. PMID- 29498556 TI - Treatment of early stage chronic hepatitis C virus infection. AB - INTRODUCTION: Treatment of Hepatitis C Virus (HCV) with direct acting antivirals (DAAs) is able to achieve the cure of infection in almost the totality of patients, independently of the characteristics of the individual and the virus, using short treatment schedules, and without the need of ribavirin. The high cost of DAAs is the main limiting factor for universal treatment of HCV. However, there is a strong evidence that treatment of infection at the early stage of disease may be the most rewarding approach. Areas covered: This review evaluates the aspects underlying the benefit of treating chronic HCV infection at the early stage of disease. It outlines the considerations that have to be taken into account when planning treatment in patients with HCV and minimal liver disease, assessing the positive reflex of viral eradication on several HCV-associated extra-hepatic conditions such as the risk of lymphoma, insulin-resistance and glycaemic control, and renal function. Lastly, it also covers the improvement of patients' quality of life and the pharmaco-economic aspects associated with early treatment. Expert commentary: Treatment of patients with HCV and minimal liver disease is associated with a beneficial, pleiotropic effect of viral eradication that goes beyond the simplistic consideration of the improvement in liver disease related outcomes. PMID- 29498557 TI - Training students as interprofessional learning facilitators: An exploratory study highlighting the need to build confidence. AB - Interprofessional learning (IPL) aims to equip students for future interprofessional and collaborative practice. Involving students as IPL facilitators is becoming increasingly commonplace as an attempt to catalyse the necessary transformation of our workforce needed to deliver truly integrated and person-centred care. Evidence in the literature highlights the key role of trained facilitators in reaching successful IPL outcomes. Some guidelines are available as to how we train staff facilitators, but little evidence is available that describes how to appropriately prepare student IPL facilitators. The aim of this exploratory study was to investigate whether student IPL facilitators felt that they were sufficiently prepared for their role. Data in the form of open ended text-based responses from student facilitators (n = 9) were collated after an intervention where student facilitators had been given the role of supporting IPL. Data were analysed using principles of thematic analysis. Three main themes emerged: i) building confidence; ii) purpose of IPL; iii) learning moments. Student IPL facilitators who took part in this study felt that they were adequately prepared for their role. Findings show that preparing students for IPL facilitation has similar, yet unique, components compared to the training staff. In particular, this study highlighted a need for student facilitators to receive further preparation to help build their confidence. Involving students as IPL facilitators has great potential in staff and students joining forces to equip students for future interprofessional and collaborative practice that can deliver high-quality care. PMID- 29498558 TI - Few adults with functional limitations advised to exercise more or lose weight in NHANES 2011-14 seek health professional assistance: An opportunity for physical therapists. AB - PURPOSE: Functional limitations are associated with decreased physical activity and increased body mass index. The purpose of this study was to assess the prevalence of functional limitations among adults who reported receiving health professional advice to exercise more or lose weight, and to assess involvement of health professionals, including physical therapists, in weight loss efforts with these individuals. DESIGN: A cross-sectional analysis of U.S. adults from the 2011 to 2014 National Health and Nutrition Examination Survey (n = 5,480). METHODS: Participant demographics, health history, and functional limitations were assessed via self-report and examination. Frequency distributions were calculated using SAS(r) analytical software, accounting for the complex survey design. Population estimates were calculated using the American Community Survey. RESULTS: 31.0% of individuals (n = 1,696), representing a population estimate of 35 million adults, advised to exercise more or lose weight by a health professional reported one or more functional limitation. Of the 31%, 57.6% attempted weight loss, and 40.1% used exercise for weight loss. Few sought health professional assistance. Physical therapists were not mentioned. CONCLUSIONS: Few individuals with functional limitations advised to lose weight or increase exercise seek health professional assistance for weight loss. Physical therapists have an opportunity to assist those with functional limitations with exercise prescription. PMID- 29498559 TI - Prevalence and predictors of symptoms of anxiety and depression, and comorbid symptoms of distress in parents of childhood cancer survivors and bereaved parents five years after end of treatment or a child's death. AB - BACKGROUND: Symptoms of anxiety and depression and their comorbidity in parents of children diagnosed with cancer, particularly later in the cancer trajectory, need further study. The aim was to investigate the prevalence and predictors of symptoms of anxiety and depression in parents of childhood cancer survivors and bereaved parents, five years after end of treatment or a child's death and to investigate comorbidity between symptoms of anxiety, depression and posttraumatic stress. MATERIAL AND METHODS: Participants were 132 parents (68 mothers, 64 fathers) of survivors and 37 bereaved parents (20 mothers, 17 fathers). Chi square test and t-test were used to explore differences in symptoms of anxiety and depression. Comorbidity was explored using Pearson's correlations and Chi square test. Multivariable hierarchical linear regressions were used to identify predictors of symptoms of anxiety and depression. RESULTS: In parents of survivors, 20% reported anxiety and 14% reported depression. Corresponding figures among bereaved parents were 30% and 35%. Among parents of survivors reporting clinically relevant anxiety and depression, a larger proportion were mothers than fathers. No such difference was found among bereaved parents. Symptoms of anxiety, depression and posttraumatic stress were highly correlated (all r >= 0.65, p < .001). Comorbid symptoms were reported by 7-11% of parents of survivors and 14-24% of bereaved parents. In multivariable analyses, more severe symptoms of depression were associated with anxiety, posttraumatic stress and distress related to previous stressful life events. Being a mother, symptoms of depression and posttraumatic stress were associated with more severe symptoms of anxiety. CONCLUSION: A subset of parents report clinically elevated symptoms of anxiety and depression, comorbid anxiety, depression and posttraumatic stress. Experiencing distress related to previous stressful life events as well as concurrent comorbidity were associated with more severe psychological distress at five years after end of treatment/a child's death. These results deserve further attention in research and clinical care. PMID- 29498560 TI - A Novel PspA Protein Vaccine Intranasal Delivered by Bacterium-Like Particles Provides Broad Protection Against Pneumococcal Pneumonia in Mice. AB - BACKGROUND: Streptococcus pneumoniae is a major pathogen accounting for a large number of pneumococcal disease in worldwide. Due to the mucosal immune pathway induces both systemic and mucosal immune responses, the potential strategy to prevent pneumococcal disease may be to develop a mucosal vaccine. METHOD: In this study, we developed an intranasal pneumococcal protein vaccine based on a bacterium-like particle (BLP) delivery system. PspA is expressed and exposed on the surface of all pneumococcal strains, which confers the potential to induce immune responses to protect against pneumococcal infection. We fused one of the pneumococcal surface proteins (PspA, family2 clade4) with the protein anchor (PA) protein in order to display PspA on the surface of BLPs. RESULT: The current results showed that intranasal immunization with BLPs/PspA-PA efficiently induced both PspA-specific IgG in the serum and PspA-specific IgA in mucosal washes. And intranasal immunization of BLPs/PspA-PA could provide complete protection in a mouse challenge model with pneumococci of different two clades of both homologous and heterologous PspA families. DISCUSSION AND CONCLUSION: Thus, targeted delivery of multiple bacterial antigens via BLPs may prevent pneumococcal disease by inducing both systemic and mucosal immune responses. PMID- 29498561 TI - Developmentally linked human DNA hypermethylation is associated with down modulation, repression, and upregulation of transcription. AB - DNA methylation can affect tissue-specific gene transcription in ways that are difficult to discern from studies focused on genome-wide analyses of differentially methylated regions (DMRs). To elucidate the variety of associations between differentiation-related DNA hypermethylation and transcription, we used available epigenomic and transcriptomic profiles from 38 human cell/tissue types to focus on such relationships in 94 genes linked to hypermethylated DMRs in myoblasts (Mb). For 19 of the genes, promoter-region hypermethylation in Mb (and often a few heterologous cell types) was associated with gene repression but, importantly, DNA hypermethylation was absent in many other repressed samples. In another 24 genes, DNA hypermethylation overlapped cryptic enhancers or super-enhancers and correlated with down-modulated, but not silenced, gene expression. However, such methylation was absent, surprisingly, in both non-expressing samples and highly expressing samples. This suggests that some genes need DMR hypermethylation to help repress cryptic enhancer chromatin only when they are actively transcribed. For another 11 genes, we found an association between intergenic hypermethylated DMRs and positive expression of the gene in Mb. DNA hypermethylation/transcription correlations similar to those of Mb were evident sometimes in diverse tissues, such as aorta and brain. Our findings have implications for the possible involvement of methylated DNA in Duchenne's muscular dystrophy, congenital heart malformations, and cancer. This epigenomic analysis suggests that DNA methylation is not simply the inevitable consequence of changes in gene expression but, instead, is often an active agent for fine-tuning transcription in association with development. PMID- 29498563 TI - Pelvic floor outcomes in patients who have undergone general rehabilitation following surgery for colorectal cancer: A pilot study. AB - BACKGROUND: There is a paucity of evidence on changes in pelvic floor outcomes in patients with colorectal cancer (CRC) following general oncology rehabilitation. OBJECTIVE: In patients following surgery for CRC, to explore changes in pelvic floor muscle function before and after a general oncology rehabilitation program; and to compare pelvic floor symptoms in patients undergoing the rehabilitation program to a matched control group. METHODS: This pilot study was conducted as an observational study nested within a prospective study evaluating the feasibility of a general oncology rehabilitation program for patients following surgery for abdomino-pelvic cancer. In this nested study, pelvic floor muscle function was measured in 10 participants with CRC (rehabilitation group) before and immediately after the 8-week rehabilitation program and at 6-month follow-up. Data of 10 matched participants from the prospective study who completed questionnaires only at the same assessment time points were used as a control group. Symptom measurement tools were the Australian Pelvic Floor Questionnaire (APFQ) and the International Consultation on Incontinence Questionnaire-Bowel module (ICIQ-B). Descriptive statistics were used to summarize data on pelvic floor muscle function of the rehabilitation group, and repeated measures analysis of variance was used to assess within- and between-group changes in pelvic floor symptom scores over time in the rehabilitation group and control group matched for gender and level of tumor. RESULTS: Scores in the bowel domain of the APFQ (p = 0.037) and bowel control domain of the ICIQ-B (p = 0.026) improved in the rehabilitation group only and the improvement in ICIQ-B was sustained at 6-month follow-up. There were no significant differences in bladder and bowel symptoms between the rehabilitation and matched control groups (p > 0.05) at any assessment time-point. CONCLUSIONS: Patients undergoing a general rehabilitation program following surgery for CRC demonstrated improved bowel symptoms from pre- to post-rehabilitation program; however, there were no differences when compared with matched controls who did not undertake rehabilitation. Further studies with larger sample sizes and longer-term follow-up are needed confirm these findings. PMID- 29498562 TI - Quantitative blood flow measurement in rat brain with multiphase arterial spin labelling magnetic resonance imaging. AB - Cerebral blood flow is an important parameter in many diseases and functional studies that can be accurately measured in humans using arterial spin labelling (ASL) MRI. However, although rat models are frequently used for preclinical studies of both human disease and brain function, rat CBF measurements show poor consistency between studies. This lack of reproducibility is due, partly, to the smaller size and differing head geometry of rats compared to humans, as well as the differing analysis methodologies employed and higher field strengths used for preclinical MRI. To address these issues, we have implemented, optimised and validated a multiphase pseudo-continuous ASL technique, which overcomes many of the limitations of rat CBF measurement. Three rat strains (Wistar, Sprague Dawley and Berlin Druckrey IX) were used, and CBF values validated against gold-standard autoradiography measurements. Label positioning was found to be optimal at 45 degrees , while post-label delay was optimised to 0.55 s. Whole brain CBF measures were 109 +/- 22, 111 +/- 18 and 100 +/- 15 mL/100 g/min by multiphase pCASL, and 108 +/- 12, 116 +/- 14 and 122 +/- 16 mL/100 g/min by autoradiography in Wistar, SD and BDIX cohorts, respectively. Tumour model analysis shows that the developed methods also apply in disease states. Thus, optimised multiphase pCASL provides robust, reproducible and non-invasive measurement of CBF in rats. PMID- 29498564 TI - 3D printing for low cost, rapid prototyping of eyelid crutches. AB - Blepharoptosis or ptosis is a common and potentially debilitating clinical problem. Long-term surgical treatment for ptosis caused by progressive myopathies can be challenging due to potential recurrence and complications associated with facial muscle weakness. When surgical treatment is no longer effective, an eyelid crutch can be used as an alternative intervention. This report demonstrates how 3D printing was used to rapidly design, prototype, and manufacture new custom-fit eyelid crutches at a low cost. PMID- 29498565 TI - Taxonomically Different Co-Microsymbionts of a Relict Legume, Oxytropis popoviana, Have Complementary Sets of Symbiotic Genes and Together Increase the Efficiency of Plant Nodulation. AB - Ten rhizobial strains were isolated from root nodules of a relict legume Oxytropis popoviana Peschkova. For identification of the isolates, sequencing of rrs, the internal transcribed spacer region, and housekeeping genes recA, glnII, and rpoB was used. Nine fast-growing isolates were Mesorhizobium-related; eight strains were identified as M. japonicum and one isolate belonged to M. kowhaii. The only slow-growing isolate was identified as a Bradyrhizobium sp. Two strains, M. japonicum Opo-242 and Bradyrhizobium sp. strain Opo-243, were isolated from the same nodule. Symbiotic genes of these isolates were searched throughout the whole-genome sequences. The common nodABC genes and other symbiotic genes required for plant nodulation and nitrogen fixation were present in the isolate Opo-242. Strain Opo-243 did not contain the principal nod, nif, and fix genes; however, five genes (nodP, nodQ, nifL, nolK, and noeL) affecting the specificity of plant-rhizobia interactions but absent in isolate Opo-242 were detected. Strain Opo-243 could not induce nodules but significantly accelerated the root nodule formation after coinoculation with isolate Opo-242. Thus, we demonstrated that taxonomically different strains of the archaic symbiotic system can be co microsymbionts infecting the same nodule and promoting the nodulation process due to complementary sets of symbiotic genes. PMID- 29498566 TI - Transcriptional Changes in Mycorrhizal and Nonmycorrhizal Soybean Plants upon Infection with the Fungal Pathogen Macrophomina phaseolina. AB - Macrophomina phaseolina is a soil-borne fungal pathogen with a wide host range that causes charcoal rot in soybean [Glycine max (L.) Merr.]. Control of the disease is a challenge, due to the absence of genetic resistance and effective chemical control. Alternative or complementary measures are needed, such as the use of biological control agents, in an integrated approach. Several studies have demonstrated the role of arbuscular mycorrhizal fungi (AMF) in enhancing plant resistance or tolerance to biotic stresses, decreasing the symptoms and pressure caused by various pests and diseases, including M. phaseolina in soybean. However, the specific contribution of AMF in the regulation of the plant response to M. phaseolina remains unclear. Therefore, the objective of the present study was to investigate, under strict in-vitro culture conditions, the global transcriptional changes in roots of premycorrhized soybean plantlets challenged by M. phaseolina (+AMF+Mp) as compared with nonmycorrhizal soybean plantlets ( AMF+Mp). MapMan software was used to distinguish transcriptional changes, with special emphasis on those related to plant defense responses. Soybean genes identified as strongly upregulated during infection by the pathogen included pathogenesis-related proteins, disease-resistance proteins, transcription factors, and secondary metabolism-related genes, as well as those encoding for signaling hormones. Remarkably, the +AMF+Mp treatment displayed a lower number of upregulated genes as compared with the -AMF+Mp treatment. AMF seemed to counteract or balance costs upon M. phaseolina infection, which could be associated to a negative impact on biomass and seed production. These detailed insights in soybean-AMF interaction help us to understand the complex underlying mechanisms involved in AMF-mediated biocontrol and support the importance of preserving and stimulating the existing plant-AMF associates, via adequate agricultural practices, to optimize their agro-ecological potential. PMID- 29498568 TI - Quality of life following surgical treatment of lesions within the pineal region. AB - OBJECTIVE Pineal region tumors are a rare and heterogeneous group of lesions. The optimal therapeutic approach is currently a topic of controversy, particularly in light of the potential operative risks and complications. The potential beneficial effects of surgery have already been described, but information about neurological outcome and, in particular, health-related quality of life (HRQOL) is still lacking in the literature. The aim of this study was to assess the therapeutic effect of resection of pineal region lesions, emphasizing grade of tumor resection, neurological outcome, quality of life, and the necessity of additional shunt procedures. METHODS The authors performed a prospective study of HRQOL in 32 patients who had undergone surgical treatment of lesions in the pineal region (20 tumors and 12 cysts) between 2008 and 2014. All patients had at least 6 months of follow-up, with reexamination including standardized neurological assessment, an evaluation of dependency using the modified Rankin Scale, and an evaluation of HRQOL. The authors retrospectively examined patient charts and collected information regarding imaging studies, neurological status prior to surgery, surgical strategies used, any complications, and histological diagnoses. RESULTS In this study, there was no surgery-associated mortality or major morbidity. Permanent minor morbidity was reported for 4 patients (13%). Comparing pre- and postoperative neurological symptoms, 75% of tumor patients had either complete resolution or improvement of preoperative symptoms; symptoms were unchanged in 10% of tumor patients and deteriorated in 15%. In patients with pineal cysts, long-term follow-up showed that 42% of patients were free of any symptoms and 58% experienced improvement of their preoperative symptoms. These outcomes were also reflected in the modified Rankin Scale scores, which demonstrated significant improvement following resection of pineal region lesions. Furthermore, significant improvements in HRQOL scores occurred in global health status, in all functional scales, and in pain, nausea and vomiting, fatigue, and insomnia (p < 0.0001). Moreover, a significant reduction in the necessity for permanent shunt procedures was observed after gross-total tumor resection compared with subtotal resection (p = 0.035) of pineal cysts. CONCLUSIONS Despite potential risks, (radical) surgery is a highly effective and safe treatment option for pineal region lesions and should be considered for the majority of patients. PMID- 29498567 TI - The Red Alga Gracilariopsis chorda and Its Active Constituent Arachidonic Acid Promote Spine Dynamics via Dendritic Filopodia and Potentiate Functional Synaptic Plasticity in Hippocampal Neurons. AB - Exogenous neurotrophins can induce neuronal differentiation, outgrowth, survival, and synaptic function in the central nervous system. In primary cultures of rat hippocampal neurons, an ethanol extract of the red alga Gracilariopsis chorda (GCE) and its active compound arachidonic acid (AA) significantly increased the densities of dendritic filopodia and spines, promoted the expression of presynaptic vesicle protein 2 (SV2) and postsynaptic density protein 95 (PSD-95), induced robust synaptogenesis, and increased the expression of cell division control protein 42 (CDC42) and actin-related protein 2 (ARP2), which are important for actin organization in dendritic protrusions, and facilitated presynaptic plasticity by increasing the size of the synaptic vesicle pool at presynaptic nerve terminals. In addition, oral administration of GCE and AA for 10 days, at concentrations of 1 mg/g and 2.2 MUg/g body weight, respectively, significantly protected against scopolamine-induced memory impairment in mice by increasing the latency time in the passive avoidance test. These results provide strong scientific evidence that these natural products can be used as neurotrophic substances and/or dietary supplements for the prevention and treatment of memory-related neurological disorders via the reconstruction of axo dendrites and its synapses. PMID- 29498569 TI - Fifty shades of gradients: does the pressure gradient in venous sinus stenting for idiopathic intracranial hypertension matter? A systematic review. AB - OBJECTIVE The role of venous sinus stenting (VSS) for idiopathic intracranial hypertension (IIH) is not well understood. The aim of this systematic review is to attempt to identify subsets of patients with IIH who will benefit from VSS based on the pressure gradients of their venous sinus stenosis. METHODS MEDLINE/PubMed was searched for studies reporting venous pressure gradients across the stenotic segment of the venous sinus, pre- and post-stent pressure gradients, and clinical outcomes after VSS. Findings are reported according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. RESULTS From 32 eligible studies, a total of 186 patients were included in the analysis. Patients who had favorable outcomes had higher mean pressure gradients (22.8 +/- 11.5 mm Hg vs 17.4 +/- 8.0 mm Hg, p = 0.033) and higher changes in pressure gradients after stent placement (19.4 +/- 10.0 mm Hg vs 12.0 +/- 6.0 mm Hg, p = 0.006) compared with those with unfavorable outcomes. The post-stent pressure gradients between the 2 groups were not significantly different (2.8 +/- 4.0 mm Hg vs 2.7 +/- 2.0 mm Hg, p = 0.934). In a multivariate stepwise logistic regression controlling for age, sex, body mass index, CSF opening pressure, pre-stent pressure gradient, and post-stent pressure gradient, the change in pressure gradient with stent placement was found to be an independent predictor of favorable outcome (p = 0.028). Using a pressure gradient of 21 as a cutoff, 81/86 (94.2%) of patients with a gradient > 21 achieved favorable outcomes, compared with 82/100 (82.0%) of patients with a gradient <= 21 (p = 0.022). CONCLUSIONS There appears to be a relationship between the pressure gradient of venous sinus stenosis and the success of VSS in IIH. A randomized controlled trial would help elucidate this relationship and potentially guide patient selection. PMID- 29498570 TI - Pterional versus superciliary keyhole approach: direct comparison of approach related complaints and satisfaction in the same patient. AB - OBJECTIVE The objective of this study was to evaluate and compare the level of patient satisfaction and approach-related patient complaints between a superciliary keyhole approach and a pterional approach. METHODS Patients who underwent an ipsilateral superciliary keyhole approach and a contralateral pterional approach for bilateral intracranial aneurysms during an 11-year period were contacted and asked to complete a patient satisfaction questionnaire. The questionnaire covered 5 complaint areas related to the surgical approaches: craniotomy-related pain, sensory symptoms in the head, cosmetic complaints, palpable cranial irregularities, and limited mouth opening. The patients were asked to rate the 5 complaint areas on a scale from 0 (asymptomatic or very pleasant) to 4 (severely symptomatic or very unpleasant). Finally, the patients were asked to rate the level of overall satisfaction related to each surgical procedure on a visual analog scale (VAS) from 0 (most unsatisfactory) to 100 (most satisfactory). RESULTS A total of 21 patients completed the patient satisfaction questionnaire during a follow-up clinic visit. For the superciliary procedures, no craniotomy-related pain, palpable irregularities, or limited mouth opening was reported, and only minor sensory symptoms (numbness in the forehead) and cosmetic complaints (short linear operative scar) were reported (score = 1) by 1 (4.8%) and 3 patients (14.3%), respectively. Compared with the pterional approach, the superciliary approach showed better outcomes regarding the incidence of craniotomy-related pain, cosmetic complaints, and palpable irregularities, with a significant between-approach difference (p < 0.05). Furthermore, the VAS score for patient satisfaction was significantly higher for the superciliary approach (mean 95.2 +/- 6.0 [SD], range 80-100) than for the pterional approach (mean 71.4 +/- 10.6, range 50-90). Moreover, for the pterional approach, a multiple linear regression analysis indicated that the crucial factors decreasing the level of patient satisfaction were cosmetic complaints, craniotomy-related pain, and sensory symptoms, in order of importance (p < 0.05). CONCLUSIONS In successful cases in which the primary surgical goal of complete aneurysm clipping without postoperative complications is achieved, a superciliary keyhole approach provides a much higher level of patient satisfaction than a pterional approach, despite a facial wound. For a pterional approach, the patient satisfaction level is affected by the cosmetic results, craniotomy-related pain, and numbness behind the hairline, in order of importance. PMID- 29498571 TI - The role of preoperative deep vein thrombosis screening in neurooncology. AB - OBJECTIVE Venous thromboembolism (VTE) is a major cause of morbidity in patients undergoing neurosurgical intervention. The authors postulate that the introduction of a routine preoperative deep vein thrombosis (DVT) screening protocol for patients undergoing neurosurgical intervention for brain tumors would result in a more effective diagnosis of DVT in this high-risk subgroup, and subsequent appropriate management of the condition would reduce pulmonary embolism (PE) rates and improve patient outcomes. METHODS The authors conducted a prospective study of 115 adult patients who were undergoing surgical intervention for a brain tumor. All patients underwent preoperative lower-limb Doppler ultrasonography scanning for DVT screening. Patients with confirmed DVT underwent a period of anticoagulation therapy, which was stopped prior to surgery. An inferior vena cava (IVC) filter was inserted to cover the perioperative period during which anticoagulation therapy was avoided due to bleeding risk before restarting the therapy at a later date. Patients underwent follow-up performed by a neurooncology multidisciplinary team, and subsequent complications and outcomes were recorded. RESULTS Seven (6%) of the 115 screened patients had DVT. Of these patients, one developed postoperative PE, and another had bilateral DVT postoperatively. None of the patients without preoperative DVT developed VTE postoperatively. Age, symptoms of DVT, and previous history of VTE were significantly higher in the group with preoperative DVT. There were no deaths and no complications from the anticoagulation or IVC filter insertion. CONCLUSIONS Preoperative screening for DVT is a worthwhile endeavor in patients undergoing neurosurgical intervention. A multidisciplinary approach in management of anticoagulation and IVC filter insertion is safe and can minimize further VTE in such patients. PMID- 29498572 TI - Prevalence, management, and outcome of problem residents among neurosurgical training programs in the United States. AB - OBJECTIVE The challenging nature of neurosurgical residency necessitates that appropriate measures are taken by training programs to ensure that residents are properly progressing through their education. Residents who display a pattern of performance deficiencies must be identified and promptly addressed by faculty and program directors to ensure that resident training and patient care are not affected. While studies have been conducted to characterize these so-called "problem residents" in other specialties, no current data regarding the prevalence and management of such residents in neurosurgery exist. The purpose of this study was to determine the rate and the outcome of problem residents in US neurosurgical residency programs and identify predictive risk factors that portend a resident's departure from the program. METHODS An anonymous nationwide survey was sent to all 108 neurosurgical training programs in the US to assess a 20-year history of overall attrition as well as the management course of problem residents, including the specific deficiencies of the resident, management strategies used by faculty, and the eventual outcome of each resident's training. RESULTS Responses were received from 36 centers covering a total of 1573 residents, with the programs providing a mean 17.4 years' worth of data (95% CI 15.3-19.4 years). The mean prevalence of problem residents among training programs was 18.1% (95% CI 14.7%-21.6%). The most common deficiencies recognized by program directors were poor communication skills (59.9%), inefficiency in tasks (40.1%), and poor fund of medical knowledge (39.1%). The most common forms of program intervention were additional meetings to provide detailed feedback (93.9%), verbal warnings (78.7%), and formal written remediation plans (61.4%). Of the identified problem residents whose training status is known, 50% graduated or are on track to graduate, while the remaining 50% ultimately left their residency program for other endeavors. Of the 97 residents who departed their programs, 65% left voluntarily (most commonly for another specialty), and 35% were terminated (often ultimately training in another neurosurgery program). On multivariable logistic regression analysis, the following 3 factors were independently associated with departure of a problem resident from their residency program: dishonesty (OR 3.23, 95% CI 1.67-6.253), poor fund of medical knowledge (OR 2.54, 95% CI 1.47-4.40), and poor technical skill (OR 2.37, 95% CI 1.37-4.12). CONCLUSIONS The authors' findings represent the first study to characterize the nature of problem residents within neurosurgery. Identification of predictive risk factors, such as dishonesty, poor medical knowledge, and/or technical skill, may enable program directors to preemptively act and address such deficiencies in residents before departure from the program occurs. As half of the problem residents departed their programs, there remains an unmet need for further research regarding effective remediation strategies. PMID- 29498573 TI - High rebleeding risk associated with choroidal collateral vessels in hemorrhagic moyamoya disease: analysis of a nonsurgical cohort in the Japan Adult Moyamoya Trial. AB - OBJECTIVE Choroidal collateral vessels typical of moyamoya disease have received attention as a potential bleeding source. The authors' previous angiographic cross-sectional analysis suggested a possible association between choroidal collaterals and posterior hemorrhage, indicating a high risk for rebleeding. The present longitudinal analysis is intended to determine whether choroidal collaterals are a predictor of rebleeding in hemorrhagic moyamoya disease. METHODS The Japan Adult Moyamoya Trial group designed an ancillary cohort study using 5-year follow-up data on 37 patients included in the nonsurgical arm of the original randomized controlled trial and compared the rebleeding rate of those with and those without choroidal collaterals, represented by the connection between the anterior or posterior choroidal arteries and the medullary arteries. An expert panel determined whether a choroidal collateral was present in each patient through the measurement of baseline angiography studies. The rebleeding rate comparison was adjusted for age, diagnosis of hypertension, and involvement of the posterior cerebral artery. RESULTS Choroidal collaterals were present in 21 patients (56.8%). The rebleeding rate was 13.1% per year in the collateral positive group as compared with 1.3% in the negative group (p = 0.008, log-rank test). The adjusted hazard ratio for rebleeding in the collateral-positive group relative to the negative group remained statistically significant (HR 11.10, 95% CI 1.37-89.91). Radiographic assessment of the collateral-positive group revealed good correspondence between the distribution of collaterals and rebleeding sites. CONCLUSIONS Results of this study suggest that choroidal collaterals are a bleeding source with a high risk for hemorrhagic recurrence and a predictor of rebleeding in hemorrhagic moyamoya disease. PMID- 29498574 TI - Letter to the Editor. Prognostic factors in skull base chordoma. PMID- 29498575 TI - Long-term outcome after Gamma Knife radiosurgery for acoustic neuroma of all Koos grades: a single-center study. AB - OBJECTIVE The authors present long-term follow-up data on patients treated with Gamma Knife radiosurgery (GKRS) for acoustic neuroma. METHODS Six hundred eighteen patients were radiosurgically treated for acoustic neuroma between 1992 and 2016 at the Department of Neurosurgery, Medical University Vienna. Patients with neurofibromatosis and patients treated too recently to attain 1 year of follow-up were excluded from this retrospective study. Thus, data on 557 patients with spontaneous acoustic neuroma of any Koos grade are presented, as are long term follow-up data on 426 patients with a minimum follow-up of 2 years. Patients were assessed according to the Gardner-Robertson (GR) hearing scale and the House Brackmann facial nerve function scale, both prior to GKRS and at the times of follow-up. RESULTS Four hundred fifty-two patients (81%) were treated with radiosurgery alone and 105 patients (19%) with combined microsurgery radiosurgery. While the combined treatment was especially favored before 2002, the percentage of cases treated with radiosurgery alone has significantly increased since then. The overall complication rate after GKRS was low and has declined significantly in the last decade. The risk of developing hydrocephalus after GKRS increased with tumor size. One case (0.2%) of malignant transformation after GKRS was diagnosed. Radiological tumor control rates of 92%, 91%, and 91% at 5, 10, and 15 years after GKRS, regardless of the Koos grade or pretreatment, were observed. The overall tumor control rate without the need for additional treatment was even higher at 98%. At the last follow-up, functional hearing was preserved in 55% of patients who had been classified with GR hearing class I or II prior to GKRS. Hearing preservation rates of 53%, 34%, and 34% at 5, 10, and 15 years after GKRS were observed. The multivariate regression model revealed that the GR hearing class prior to GKRS and the median dose to the cochlea were independent predictors of the GR class at follow-up. CONCLUSIONS In small to medium-sized spontaneous acoustic neuromas, radiosurgery should be recognized as the primary treatment at an early stage. Although minimizing the cochlear dose seems beneficial for hearing preservation, the authors, like others before, do not recommend undertreating intracanalicular tumors in favor of low cochlear doses. For larger acoustic neuromas, radiosurgery remains a reliable management option with tumor control rates similar to those for smaller acoustic neuromas; however, careful patient selection and counseling are recommended given the higher risk of side effects. Microsurgery must be considered in acoustic neuromas with significant brainstem compression or hydrocephalus. PMID- 29498576 TI - 3D printing and intraoperative neuronavigation tailoring for skull base reconstruction after extended endoscopic endonasal surgery: proof of concept. AB - OBJECTIVE Endoscopic endonasal approaches are increasingly performed for the surgical treatment of multiple skull base pathologies. Preventing postoperative CSF leaks remains a major challenge, particularly in extended approaches. In this study, the authors assessed the potential use of modern multimaterial 3D printing and neuronavigation to help model these extended defects and develop specifically tailored prostheses for reconstructive purposes. METHODS Extended endoscopic endonasal skull base approaches were performed on 3 human cadaveric heads. Preprocedure and intraprocedure CT scans were completed and were used to segment and design extended and tailored skull base models. Multimaterial models with different core/edge interfaces were 3D printed for implantation trials. A novel application of the intraoperative landmark acquisition method was used to transfer the navigation, helping to tailor the extended models. RESULTS Prostheses were created based on preoperative and intraoperative CT scans. The navigation transfer offered sufficiently accurate data to tailor the preprinted extended skull base defect prostheses. Successful implantation of the skull base prostheses was achieved in all specimens. The progressive flexibility gradient of the models' edges offered the best compromise for easy intranasal maneuverability, anchoring, and structural stability. Prostheses printed based on intraprocedure CT scans were accurate in shape but slightly undersized. CONCLUSIONS Preoperative 3D printing of patient-specific skull base models is achievable for extended endoscopic endonasal surgery. The careful spatial modeling and the use of a flexibility gradient in the design helped achieve the most stable reconstruction. Neuronavigation can help tailor preprinted prostheses. PMID- 29498577 TI - Botulinum toxin to improve vessel graft patency in cerebral revascularization surgery: report of 3 cases. AB - Surgical revascularization continues to play an important role in the management of complex intracranial aneurysms and ischemic cerebrovascular disease. Graft spasm is a common complication of bypass procedures and can result in ischemia or graft thrombosis. The authors here report on the first clinical use of botulinum toxin to prevent graft spasm following extracranial-intracranial (EC-IC) bypass. This technique was used in 3 EC-IC bypass surgeries, 2 for symptomatic carotid artery occlusions and 1 for a ruptured basilar tip aneurysm. In all 3 cases, the harvested graft was treated ex vivo with botulinum toxin before the anastomosis was performed. Post-bypass vascular imaging demonstrated patency and the absence of spasm in all grafts. Histopathological analyses of treated vessels did not show any immediate endothelial or vessel wall damage. Postoperative angiograms were without graft spasm in all cases. Botulinum toxin may be a reasonable option for preventing graft spasm and maintaining patency in cerebral revascularization procedures. PMID- 29498578 TI - Increase in brain atrophy after subdural hematoma to rates greater than associated with dementia. AB - OBJECTIVE Chronic subdural hematoma (cSDH) is a highly morbid condition associated with brain atrophy in the elderly. It has a reported 30% 1-year mortality rate. Approximately half of afflicted individuals report either no or relatively unremarkable trauma preceding their diagnosis, raising the possibility that cSDH is a manifestation of degenerative or inflammatory disease rather than trauma. The purpose of this study was to compare the rates of cerebral atrophy before and after cSDH to determine whether it is more likely that cSDH causes atrophy or that atrophy causes cSDH. The authors also compared atrophy rates in patients with cSDH to the rates in patients with and without dementia. METHODS The authors developed algorithmic segmentation analysis software to measure whole brain, CSF, and intracranial space volumes. They then identified military veterans who had undergone at least 4 brain CT scans over a period of 10 years. Within this database, the authors identified 146 patients with 962 head CT scans who had received diagnoses of either cSDH, dementia, or no known dementia condition. Volumetric analyses of brains in 45 patients with dementia (dementia group) and 73 patients without dementia (nondementia group), in whom 262 and 519 head CT scans were obtained, respectively, were compared with 11 patients in whom 81 CT scans were obtained a mean of 4.21 years before a cSDH diagnosis and 17 patients in whom 100 scans were obtained a mean of 4.24 years after SDH. Longitudinal measures were then related to disease status and the time since first scan by using hierarchical models, and atrophy rates between the groups were compared. RESULTS Head CT scans from patients were obtained for an average time period of 4.21 years (SD 1.69) starting at a mean patient age of 74 years. Absolute brain volume loss for the 17 patients in the post-SDH group (13 were treated surgically) was significantly greater, at 16.32 ml/year, compared with 6.61 ml/year in patients with dementia, 5.33 ml/year in patients without dementia, and 3.57 ml/year in pre-SDH patients. The atrophy rate for these individuals prior to enrollment in the study was 2.32 ml/year (p = 0.001). In terms of brain volume normalized to cranial cavity size, the post-SDH group had an atrophy rate of 0.7801%/year, compared with 0.4467%/year in patients with dementia, 0.3474%/year in patients without dementia, and 0.2135%/year in the pre SDH group. CONCLUSIONS Prior to development of a cSDH, the atrophy rates in patients who ultimately develop cSDH are similar to those of patients without dementia. After development of a cSDH, the atrophy rates increase to more than twice those of patients with dementia. Chronic subdural hematoma is thus associated with a significant increase in brain atrophy rate. These findings suggest the neurotoxic consequences of cSDH and may have implications for better understanding of the pathophysiology of cerebral atrophy and dementia. PMID- 29498579 TI - Functional outcomes and quality of life after microsurgical clipping of unruptured intracranial aneurysms: a prospective cohort study. AB - OBJECTIVE Few studies have examined patients' ability to drive and quality of life (QOL) after microsurgical repair for unruptured intracranial aneurysms (uIAs). However, without a strong evidentiary basis, jurisdictional road transport authorities have recommended driving restrictions following brain surgery. In the present study, authors examined the outcomes of the microsurgical repair of uIAs by measuring patients' perceived QOL and cognitive abilities related to driving. METHODS Between January 2011 and January 2016, patients with a new diagnosis of uIA were prospectively enrolled in this study. Assessments were performed at referral, before surgery, and at 6 weeks and 12 months after surgery in those undergoing microsurgical repair and at referral and at 12 months in conservatively managed patients. Assessments included the Physical Component Summary (PCS) and Mental Component Summary (MCS) of the SF-36, the off-road driver-screening instrument DriveSafe (DS), the modified Barthel Index (mBI), and the modified Rankin Scale (mRS). RESULTS One hundred sixty-nine patients were enrolled in and completed the study, and 112 (66%) of them had microsurgical repair of their aneurysm. In the microsurgical group, there was a trend for improved DS scores: from a mean (+/- standard deviation) score of 108 +/- 10.7 before surgery to 111 +/- 9.7 at 6 weeks after surgery to 112 +/- 10.2 at 12 months after surgery (p = 0.05). Two percent of the microsurgical repair group and 4% of the conservatively managed group whose initial scores indicated competency to drive according to the DS test subsequently had 12-month scores deemed as not competent to drive; the difference between these 2 groups was not statistically significant (p > 0.99). Factors associated with a decline in the DS score among those who had a license at the time of initial assessment were an increasing age (p < 0.01) and mRS score > 0 at one of the assessments (initial, 6 weeks, or 12 months; p < 0.01). Mean PCS scores in the microsurgical repair group were 52 +/- 8.1, 46 +/- 6.8, and 52 +/- 7.1 at the initial, 6-week, and 12-month assessments, respectively (p < 0.01). These values represented a significant decline in the mean PCS score at 6 weeks that recovered by 12 months (p < 0.01). There were no significant changes in the MCS, mBI, or mRS scores in the surgical group. CONCLUSIONS Overall, QOL at 12 months for the microsurgical repair group had not decreased and was comparable to that in the conservatively managed group. Furthermore, as assessed by the DS test, the majority of patients were not affected in their ability to drive. PMID- 29498580 TI - Initial Design and Experimental Evaluation of a Pneumatic Interference Actuator. AB - Substantial device mass and control complexity can hinder the impact of wearable robotic technologies, such as exoskeletons. Thus, despite promising previous research, the development of a simple, lightweight actuator for these systems has not yet been fully realized. The purpose of this study was to derive and demonstrate a proof-of-concept for a pneumatic interference actuator (PIA)-a lightweight, soft actuator able to produce torque by the self-intersection of a fabric balloon that arises from changes in physical geometry. General closed-form equations are derived to express the expected actuator torque and mechanical work as functions of the balloon geometry, pressure, and deflection angle. Hard and soft cylindrical physical prototypes were constructed to assess the accuracy of the mathematical models. The proposed mathematical model was found to agree with the pressure-volume relationship and successfully predict the maximum torque as a function of geometry, pressure, and deflection at nonzero deflection angles. Peak powers up to 122.1 +/- 10.0 W (mean +/- standard deviation), with a resting internal pressure of 158.0 +/- 0.2 kPa, were observed from the hard actuator prototype. For the soft actuator prototype, peak powers of 97.9 +/- 21.1 W were observed at a resting pressure of 166.8 kPa. The work performed was within 3.2% +/- 3.4% and 14.4% +/- 8.2% of theoretical values across all trials, and within 19.1% +/- 4.4% of theoretical values when compared to the torque-angle relationship. This study highlights the promise of utilizing the self intersection of a PIA to perform human-scale mechanical work, and future research will focus on implementations for wearable robotic systems. PMID- 29498581 TI - Primary spinal cord astroblastoma: case report. AB - Astroblastoma is a rare tumor that is thought to occur exclusively in the cerebrum. To the authors' knowledge, no cases of spinal cord astroblastoma have been reported. A 20-year-old woman presented with numbness in her legs. MRI demonstrated a 2-cm intramedullary enhancing lesion in the spinal cord at the T-1 level. The patient declined to undergo resection of the tumor because she was able to walk unassisted; however, she returned for surgery 1 month later because she had developed paraplegia with bladder and rectal dysfunction, and MRI showed enlargement of the tumor. Intraoperatively, the border between the tumor and normal tissue was poorly defined. Biopsy samples were obtained for histopathological examinations, and a diagnosis of astroblastoma with a Ki-67 index of 5% was made. Considering the rapid tumor growth on MRI and remarkable deterioration in her symptoms, the patient was treated with a combination of radiation therapy, temozolomide (TMZ), and bevacizumab. After completion of the combined treatment, she was able to move her toes, and oral TMZ and bevacizumab injections were continued. Six months later, definite tumor shrinkage was identified on MRI, and the patient was able to stand up from a wheelchair without assistance and walk by herself. No therapeutic regimens for residual astroblastoma are established; however, in this case the authors' therapeutic strategy was successful in treating the spinal cord astroblastoma. PMID- 29498582 TI - Letter to the Editor. John F. Kennedy's back: a few supplementary comments. PMID- 29498583 TI - Spinal cord injury below-level neuropathic pain relief with dorsal root entry zone microcoagulation performed caudal to level of complete spinal cord transection. AB - OBJECTIVE Surgically created lesions of the spinal cord dorsal root entry zone (DREZ) to relieve central pain after spinal cord injury (SCI) have historically been performed at and cephalad to, but not below, the level of SCI. This study was initiated to investigate the validity of 3 proposed concepts regarding the DREZ in SCI central pain: 1) The spinal cord DREZ caudal to the level of SCI can be a primary generator of SCI below-level central pain. 2) Neuronal transmission from a DREZ that generates SCI below-level central pain to brain pain centers can be primarily through sympathetic nervous system (SNS) pathways. 3) Perceived SCI below-level central pain follows a unique somatotopic map of DREZ pain generators. METHODS Three unique patients with both intractable SCI below-level central pain and complete spinal cord transection at the level of SCI were identified. All 3 patients had previously undergone surgical intervention to their spinal cords-only cephalad to the level of spinal cord transection-with either DREZ microcoagulation or cyst shunting, in failed attempts to relieve their SCI below-level central pain. Subsequent to these surgeries, DREZ lesioning of the spinal cord solely caudal to the level of complete spinal cord transection was performed using electrical intramedullary guidance. The follow-up period ranged from 1 1/2 to 11 years. RESULTS All 3 patients in this study had complete or near-complete relief of all below-level neuropathic pain. The analyzed electrical data confirmed and enhanced a previously proposed somatotopic map of SCI below-level DREZ pain generators. CONCLUSIONS The results of this study support the following hypotheses. 1) The spinal cord DREZ caudal to the level of SCI can be a primary generator of SCI below-level central pain. 2) Neuronal transmission from a DREZ that generates SCI below-level central pain to brain pain centers can be primarily through SNS pathways. 3) Perceived SCI below-level central pain follows a unique somatotopic map of DREZ pain generators. PMID- 29498584 TI - Letter to the Editor. How and why Hans Kraus, MD, helped President Kennedy's back pain. PMID- 29498585 TI - Letter to the Editor. Thoracolumbar surgery and sarcopenia. PMID- 29498587 TI - Corrigendum. PMID- 29498586 TI - Stiffening Sheaths for Continuum Robots. AB - Added to their high dexterity and ability to conform to complex shapes, continuum robots can be further improved to provide safer interaction with their environment. Indeed, controlling their stiffness is one of the most challenging yet promising research topics. We propose a tubular stiffening sheath as a replaceable cover for small-diameter continuum robots to temporarily increase the stiffness in a certain configuration. In this article, we assess and compare performances of two different stiffening modalities: granular and layer jamming, provide arguments for material selection and experimental results for stiffness with respect to lateral and axial applied forces. Furthermore, we detected empirically additional effects relating sheath stiffness to material parameters and added to recent investigations in the state of the art, which are based exclusively on material roughness. Finally, we integrated the selected layer jamming material in a miniaturized sheath (13 mm outer diameter, 2.5 mm wall thickness) and covered a tendon-actuated continuum robot with it. Experimental characterization of the behavior with respect to applied external forces was performed via stiffness measurements and proved that the initial tendon-actuated continuum robot stiffness can be improved by a factor up to 24. PMID- 29498588 TI - Modelling methane emission mitigation by anaerobic digestion: effect of storage conditions and co-digestion. AB - In this work the methane conversion factor (MCF) of untreated and anaerobically digested cattle manure (CM) as a function of storage temperature, time and co digestion was measured in an in vitro experiment and modelled based on IPCC (2006) methodology (Tier 2). For this, one sample of untreated CM, one sample of mono-digested CM and three samples of CM co-digested with grass were incubated at seven different temperatures (from 5 degrees C to 50 degrees C) over 346 days. The main results showed that ultimate methane yield (B0) of CM is higher than the B0 reported by the IPCC (2006). Two temperature ranges should be considered for MCF evolution, below 15 degrees C very low MCF was measured in this work for untreated CM, mono and co-digested samples. At higher temperatures, MCF obtained in this work and that provided by the IPCC could be comparable depending on storage time. Anaerobic mono-digestion decreased MCF compared to untreated CM at all temperatures and times, except in the temperature range between 20 degrees C and 25 degrees C if storage time is low, due to a lag phase observed in CM. This lag phase would probably not happen in real storage conditions depending on the proportion of old manure remaining in the storage tank. Co-digestion with grass decreased MCF compared to mono-digestion, but increased CH4 production in terms of fresh matter due to the higher B0 of the mixture. Storage time, temperature and co-digestion should be considered in the quantification of CH4 emission from digested material. PMID- 29498589 TI - Lived experience of young widowed individuals: A qualitative study. AB - Young widowhood is a unique experience that has received little in-depth attention in research and clinical settings. The present study examined the lived experiences of young men and women who had lost a spouse. Eleven men and women between the ages of 18 and 49 were interviewed about their experiences postloss using phenomenological methods. After coding the interviews, three themes emerged: (1) relationship prior to death, (2) coping, and (3) concerns. Clinical implications included the need for more accessible resources for young widowed individuals, such as therapeutic services, finances, and childcare. PMID- 29498591 TI - The metaphorical zombie A Review of Zombie Theory: A Reader edited by Sarah Juliet Lauro. PMID- 29498590 TI - Use of a novel drainage flow servo-controlled CPB for mitral valve replacement in a Jehovah's Witness. AB - We developed a novel open cardiopulmonary bypass (CPB) system, a drainage flow servo-controlled CPB system (DS-CPB), in which rotational speed of the main roller pump is servo-controlled to generate the same amount of flow as the systemic venous drainage. It was designed to safely decrease the priming volume while maintaining a constant reservoir level, even during fluctuations of the drainage flow. We report a successful use of a novel DS-CPB system in an elderly Jehovah's Witness patient with dehydration who underwent mitral valve replacement. PMID- 29498592 TI - Art therapist's perceptions of the role of the art medium in the treatment of bereaved clients in art therapy. AB - The exploratory study's aim was to examine how art therapists perceive the role of the art medium in the treatment of bereaved clients. Eight Israeli art therapists reflected on this topic through drawings and interviews. Qualitative analysis identified three major roles, specifically art as: (1) a space for the client's grief work; (2) a communication channel that impacts the art therapist's experience and therapeutic relationship; and (3) a shared space where client and therapist create a new narrative. The discussion deals with the findings and their clinical implications, identifying the central therapeutic processes involved in art therapy with bereaved clients. PMID- 29498594 TI - The Effect of Practice Schedule on Context-Dependent Learning. AB - It is well established that random practice compared to blocked practice enhances motor learning. Additionally, while information in the environment may be incidental, learning is also enhanced when an individual performs a task within the same environmental context in which the task was originally practiced. This study aimed to disentangle the effects of practice schedule and incidental/environmental context on motor learning. Participants practiced three finger sequences under either a random or blocked practice schedule. Each sequence was associated with specific incidental context (i.e., color and location on the computer screen) during practice. The participants were tested under the conditions when the sequence-context associations remained the same or were changed from that of practice. When the sequence-context association was changed, the participants who practiced under blocked schedule demonstrated greater performance decrement than those who practiced under random schedule. The findings suggested that those participants who practiced under random schedule were more resistant to the change of environmental context. PMID- 29498593 TI - Reduction in Thyroid Nodule Biopsies and Improved Accuracy with American College of Radiology Thyroid Imaging Reporting and Data System. AB - Purpose To compare the biopsy rate and diagnostic accuracy before and after applying the American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS) criteria for thyroid nodule evaluation. Materials and Methods In this retrospective study, eight radiologists with 3-32 years experience in thyroid ultrasonography (US) reviewed US features of 100 thyroid nodules that were cytologically proven, pathologically proven, or both in December 2016. The radiologists evaluated nodule features in five US categories and provided biopsy recommendations based on their own practice patterns without knowledge of ACR TI-RADS criteria. Another three expert radiologists served as the reference standard readers for the imaging findings. ACR TI-RADS criteria were retrospectively applied to the features assigned by the eight radiologists to produce biopsy recommendations. Comparison was made for biopsy rate, sensitivity, specificity, and accuracy. Results Fifteen of the 100 nodules (15%) were malignant. The mean number of nodules recommended for biopsy by the eight radiologists was 80 +/- 16 (standard deviation) (range, 38-95 nodules) based on their own practice patterns and 57 +/- 11 (range, 37-73 nodules) with retrospective application of ACR TI-RADS criteria. Without ACR TI-RADS criteria, readers had an overall sensitivity, specificity, and accuracy of 95% (95% confidence interval [CI]: 83%, 99%), 20% (95% CI: 16%, 25%), and 28% (95% CI: 21%, 37%), respectively. After applying ACR TI-RADS criteria, overall sensitivity, specificity, and accuracy were 92% (95% CI: 68%, 98%), 44% (95% CI: 33%, 56%), and 52% (95% CI: 40%, 63%), respectively. Although fewer malignancies were recommended for biopsy with ACR TI-RADS criteria, the majority met the criteria for follow-up US, with only three of 120 (2.5%) malignancy encounters requiring no follow-up or biopsy. Expert consensus recommended biopsy in 55 of 100 nodules with ACR TI-RADS criteria. Their sensitivity, specificity, and accuracy were 87% (95% CI: 48%, 98%), 51% (95% CI: 40%, 62%), and 56% (95% CI: 46%, 66%), respectively. Conclusion ACR TI-RADS criteria offer a meaningful reduction in the number of thyroid nodules recommended for biopsy and significantly improve the accuracy of recommendations for nodule management. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 29498595 TI - A comparative study on subacute toxicity of arsenic trioxide and dimethylarsinic acid on antioxidant status in Crandell Rees feline kidney (CRFK), human hepatocellular carcinoma (PLC/PRF/5), and epithelioma papulosum cyprini (EPC) cell lines. AB - Arsenic (As) is a global contaminant of terrestrial and aquatic environments posing concern for environmental and human health. The effects of subacute concentrations of arsenic trioxide (AsIII) and dimethylarsinic acid (DMAV) were examined using Crandell Rees feline kidney (CRFK), human hepatocellular carcinoma (PLC/PRF/5), and epithelioma papulosum cyprini (EPC). Whole monolayer with suffering cells (confluence 100%, pyknosis and refractive cells; value scale = 2) led to identification of subacute As concentrations for the three cell lines. The selected AsIII concentrations were 1.33 uM for CRFK and 33.37 uM for PLC/PRF/5 and EPC, at 48 hr time point. The selected DMAV concentrations were 0.67 mM for PLC/PRF/5, 1.33 mM for CRFK, and 2.67 mM for EPC for 48 hr. Unlike the AsIII test, the three cell lines did not exhibit marked susceptibility to DMAV-mediated toxicity. Several oxidative stress biomarker levels, directly or indirectly associated with reactive oxygen species (ROS) elimination including superoxide dismutase, catalase, glutathione peroxidases, glutathione reductase, glutathione S-transferase, glyoxalase I, glyoxalase II, and total glutathione, were determined in the three cell lines at 24 and 48 hr. Antioxidant responses in metal-treated cells were significantly altered compared to controls, suggesting a perturbation of redox state. The weakening of antioxidant pathway in either healthy or tumoral cells was greater using AsIII than DMAV. Differences in level of several oxidative stress biomarkers suggest that the oxidative stress mechanism induced by AsIII is distinctly different from DMAV. Multifaceted mechanisms of action underlying ROS generation in tumor and nontumor cells versus AsIII and DMAV exposure are thus involved. Since As-mediated toxicity is quite complex, more data regarding both oxidant-enhancement and oxidant-lowering strategies may be useful to improve knowledge regarding the influence of As on human and animal cells. PMID- 29498596 TI - Level of choice in older women's decisions to retire or continue working and associated well-being. AB - Retirement is a complex life transition. Women's retirement, like their work lives, may be further complicated, for example, by family or financial obligations; they may feel forced to retire or to continue working or feel they have the choice to do so. This study examines the role of voluntary versus involuntary retirement or continued work participation among retirement-age women; specifically, the relationships between choice, work status, and well being. Compared to women forced to retire, women who chose retirement or continuing to work had higher levels of life satisfaction. Findings highlight the importance of examining retirement within the life course context. PMID- 29498597 TI - Reply to: The problem of using standardised base excess. PMID- 29498598 TI - Disposition of methylmercury over time in a 75% nephrectomized rat model. AB - Chronic kidney disease (CKD) is a highly relevant clinical condition that is characterized by the permanent loss of functional nephrons. Individuals with CKD may exhibit impaired renal clearance, which may alter corporal handling of metabolites and xenobiotics. Methylmercury (MeHg) is an important environmental toxicant to which humans are exposed to on a regular basis. Given the prevalence of CKD and ubiquitous presence of MeHg in the environment, it is important to understand how mercuric ions are handled in patients with CKD. Therefore, the purpose of the current study was to characterize the disposition of MeHg over time in a rat model of CKD (i.e., 75% nephrectomized (NPX) rats). Control and NPX rats were exposed intravenously (iv) to a non-nephrotoxic dose of MeHg (5 mg/kg) once daily for1, 2, or 3 d and the amount of MeHg in organs, blood, urine, and feces determined. The accumulation of MeHg in kidneys and blood of controls was significantly greater than that of NPX animals. In contrast, MeHg levels in brain and liver of controls were not markedly different from corresponding NPX rats. In all organs examined, accumulation of MeHg increased over the course of exposure, suggesting that urinary and fecal elimination are not sufficient to fully eliminate all mercuric ions. The current findings are important in that the disposition of mercuric ions in rats with normal renal function versus renal insufficiency following exposure to MeHg for a prolonged period differ and need to be taken into account with respect to therapeutic management. PMID- 29498599 TI - Teaching and evaluating measurement of the ankle-brachial index. PMID- 29498600 TI - Comparative electrophysiological evaluation of hippocampal function following repeated inhalation exposures to JP-8, Jet A, JP-5, and the synthetic Fischer Tropsch fuel. AB - Exposure to fuels continues to be a concern in both military and general populations. The aim of this study was to examine effects of in vivo rat repeated exposures to different types of jet fuel utilizing microelectrode arrays for comparative electrophysiological (EP) measurements in hippocampal slices. Animals were exposed to increasing concentrations of four jet fuels, Jet Propellant (JP) 8, Jet A, JP-5, or synthetic Fischer Tropsch (FT) fuel via whole-body inhalation for 20 d (6 hr/d, 5 d/week for 28 d) and synaptic transmission as well as behavioral performance were assessed. Our behavioral studies indicated no significant changes in behavioral performance in animals exposed to JP-8, Jet A, or JP-5. A significant deviation in learning pattern during the Morris water maze task was observed in rats exposed to the highest concentration of FT (2000 mg/m3). There were also significant differences in the EP profile of hippocampal neurons from animals exposed to JP-8, Jet A, JP-5, or FT compared to control air. However, these differences were not consistent across fuels or dose dependent. As expected, patterns of EP alterations in brain slices from JP-8 and Jet A exposures were more similar compared to those from JP-5 and FT. Further longitudinal investigations are needed to determine if these EP effects are transient or persistent. Such studies may dictate if and how one may use EP measurements to indicate potential susceptibility to neurological impairments, particularly those that result from inhalation exposure to chemicals or mixtures. PMID- 29498601 TI - Edema of the optic tract in patients with tumors of the sellar region: clinical and visual implications in the pediatric population. AB - OBJECTIVE Tumor-related edema of the optic tract (EOT) corresponds to a preferential posterior distribution of peritumoral edema along the white matter tract of the visual system. To date, the consequences of EOT have never been evaluated specifically in the pediatric population. In this study, the authors attempted to identify clinical and radiological features associated with the development of EOT and the specific influence of this edema on visual function. METHODS A retrospective review was performed of data collected from patients younger than 18 years who underwent surgery for a tumor in the sellar region at the authors' institution between January 2005 and January 2016. Data were collected on patient characteristics, ophthalmological evaluations, and neuroimaging findings. To evaluate and compare visual function impairment, ophthalmological data were converted to a global visual function score, which took into account visual acuity, visual field evaluations, and laterality deficiencies. The visual acuity score was defined according to the International Classification of Diseases, 10th Revision. Visual field deficiencies were converted to a score of 0-2. Two opposing groups were then distinguished according to the presence or absence of EOT. Visual acuity, visual field results, and global scores were compared between groups before and after treatment. RESULTS Twenty-six patients were included in the study: 17 patients with craniopharyngioma, 3 patients with pilocytic astrocytoma, 2 patients with ganglioglioma, 2 patients with germ cell tumor, 1 patient with macroprolactinoma, and 1 patient with Rathke's cleft cyst. There were 11 children in the group with edema and 15 children in the group without edema. None of the following criteria were statistically different between the 2 groups: age, sex, clinical symptoms at presentation (endocrine deficiency or intracranial hypertension signs), incidence of hydrocephalus, compression of the optic tracts and mass effect on the optic chiasm, tumor size and localization, presence of intratumoral cysts, treatment, type of tumor, or recurrence. The median global visual function and visual acuity scores were not significantly different between the groups either at presentation or at final evaluation. The visual field score was lower (i.e., more deficiency) in the group with edema than in the group without edema (p < 0.05); 89% of the patients with edema had severe or mild visual field impairment versus only 40% of the patients without edema. At the final examination after treatment, the visual field scores were not different between the 2 groups. Although not significant, the number of patients with optic disc pallor was greater in the group without edema both at diagnosis and at final examination. CONCLUSIONS This study confirms that EOT in the context of sellar region tumor in children is not necessarily associated with a less-favorable visual prognosis. PMID- 29498602 TI - Neonatal intracranial aneurysms: case report and review of the literature. AB - Intracranial aneurysms in the neonate, presenting in the first 4 weeks of life, are exceedingly rare. They appear to have characteristics, including presentation and location, that vary from those found in adults. The authors present a case of a 28-day-old neonate with a ruptured distal middle cerebral artery (MCA) aneurysm. Initial noninvasive imaging with transfontanelle ultrasound and CT confirmed intraparenchymal and subarachnoid hemorrhage. Contrast-enhanced MRI revealed a 14-mm ruptured fusiform MCA aneurysm that was not identified on time of-flight magnetic resonance angiography (MRA). Microsurgical treatment was performed with partial neurological recovery. A comprehensive review of the literature from 1949 to 2017 revealed a total of 40 aneurysms in 37 neonates, including the present case. The most common presenting symptom was seizure. Although subarachnoid hemorrhage was the most common form of hemorrhage, 40% had intraparenchymal hemorrhage. The median aneurysm size was 10 mm (range 2-30 mm) and the most common location was the MCA, with two-thirds of cases involving the distal intracranial vasculature. Over the last 10 years, there has been a trend of increasing noninvasive diagnosis of ruptured cerebral aneurysms in neonates, with CT angiography and contrast-enhanced MRI being the most useful diagnostic modalities. The use of contrast-enhanced MRI may improve sensitivity over time-of flight MRA. Microsurgical treatment was the most common treatment modality overall, with increased use of endovascular treatment in the last decade. Most patients underwent microsurgical vessel ligation or endovascular parent vessel occlusion. There were high rates of neurological recovery after microsurgical or endovascular treatment, particularly for patients with distal aneurysms. PMID- 29498603 TI - Letter to the Editor. Role of dysplastic and genetic mutations during the formation of cerebral aneurysms in infants. PMID- 29498604 TI - Early postnatal cranial vault reduction and fixation surgery for severe hydrocephalic macrocephaly. AB - OBJECTIVE Infants with severe hydrocephalus and extreme macrocephaly typically undergo CSF diversion early in life, which can result in significant cranial deformity due to CSF overdrainage. In this scenario, overlap of the cranial plates can precede the development of secondary synostosis and/or severe, permanent cranial deformity. As a result, extensive cranial vault remodeling is sometimes undertaken later in life, which is often challenging and has been associated with mortality and a high morbidity rate. The authors have previously described a technique for early postnatal cranial vault reduction and fixation (CVRF), in which the calvarial bones are stabilized using absorbable fixation plates in the neonatal period, in an attempt to facilitate patient positioning, simplify hydrocephalus management, and improve cosmesis. Here, the authors describe their institutional experience managing patients with extreme neonatal hydrocephalus with CSF diversion, with and without CVRF, over the past 12 years. METHODS The authors retrospectively reviewed the charts of infants with extreme hydrocephalus (head circumference > 49 cm) treated at their children's hospital with ventriculoperitoneal shunting, with or without CVRF, between 2005 and 2017. Data collected included age, sex, etiology of hydrocephalus, type of CVRF performed (anterior, posterior, or combined), follow-up duration, orbitofrontal circumference, craniometric measurements, intraoperative blood loss, operative duration, and postoperative complications. Developmental data were collected using the third edition of the Ages and Stages Questionnaire. Photographic imaging was used to demonstrate esthetic outcomes, and family questionnaires were used to evaluate satisfaction with the esthetic outcome. RESULTS Eleven patients with extreme neonatal hydrocephalus underwent CSF shunting; 5 underwent shunting alone and 6 patients underwent shunting and CVRF. For patients who underwent shunting and CVRF, the median age at CVRF was 6 days and the median interval between shunt placement and CVRF was 2.5 days. The mean extent of calvarial vault volume reduction was 44.5% (+/- 3.9%). The mean duration of the CVRF procedure was 108 minutes, and 5 of 6 patients required intraoperative transfusion. Of the 5 patients who underwent shunting alone, 3 developed severe cranial deformities. Of 6 patients who underwent shunting and CVRF, 1 had a poor cosmetic outcome. In the shunting-alone group, 2 patients died and 1 required extensive cranial vault correction at 10 years of age. One patient in the shunting and CVRF group also died. CONCLUSIONS CVRF in combination with CSF shunting in the neonatal period can simplify the treatment of the rare case of severe hydrocephalic macrocephaly and leads to cosmetic outcomes that are considered good by their families. PMID- 29498606 TI - Buffalo horn ventricles: case illustration. PMID- 29498605 TI - MynxGrip vascular closure device use in pediatric neurointerventional procedures. AB - OBJECTIVE The aim of this paper was assess the efficacy and safety of using the MynxGrip arterial closure device in pediatric neuroendovascular procedures where the use of closure devices remains off-label despite their validation and widespread use in adults. METHODS A retrospective review of all pediatric patients who underwent diagnostic or interventional neuroendovascular procedures at the authors' institution was performed. MynxGrip use was predicated by an adequate depth of subcutaneous tissue and common femoral artery (CFA) diameter. Patients remained on supine bedrest for 2 hours after diagnostic procedures and for 3 hours after therapeutic procedures. Patient demographics, procedural details, hemostasis status, and complications were recorded. RESULTS Over 36 months, 83 MynxGrip devices were deployed in 53 patients (23 male and 30 female patients; mean age 14 years) who underwent neuroendovascular procedures. The right-side CFA was the main point of access for most procedures. The mean CFA diameter was 6.24 mm and ranged from 4 mm to 8.5 mm. Diagnostic angiography comprised 46% of the procedures. A single device failure occurred without any sequelae; the device was extracted, and hemostasis was achieved by manual compression with the placement of a Safeguard compression device. No other immediate or delayed major complications were recorded. CONCLUSIONS MynxGrip can be used safely in the pediatric population for effective hemostasis and has the advantage of earlier mobilization. PMID- 29498607 TI - Normative human brain volume growth. AB - OBJECTIVE While there is a long history of interest in measuring brain growth, as of yet there is no definitive model for normative human brain volume growth. The goal of this study was to analyze a variety of candidate models for such growth and select the model that provides the most statistically applicable fit. The authors sought to optimize clinically applicable growth charts that would facilitate improved treatment and predictive management for conditions such as hydrocephalus. METHODS The Weibull, two-term power law, West ontogenic, and Gompertz models were chosen as potential models. Normative brain volume data were compiled from the NIH MRI repository, and the data were fit using a nonlinear least squares regression algorithm. Appropriate statistical measures were analyzed for each model, and the best model was characterized with prediction bound curves to provide percentile estimates for clinical use. RESULTS Each model curve fit and the corresponding statistics were presented and analyzed. The Weibull fit had the best statistical results for both males and females, while the two-term power law generated the worst scores. The statistical measures and goodness of fit parameters for each model were provided to assure reproducibility. CONCLUSIONS The authors identified the Weibull model as the most effective growth curve fit for both males and females. Clinically usable growth charts were developed and provided to facilitate further clinical study of brain volume growth in conditions such as hydrocephalus. The authors note that the homogenous population from which the normative MRI data were compiled limits the study. Gaining a better understanding of the dynamics that underlie childhood brain growth would yield more predictive growth curves and improved neurosurgical management of hydrocephalus. PMID- 29498608 TI - Five-factor model in bereaved adults with and without complicated grief. AB - Knowledge about what psychological characteristics underlie complicated grief (CG) is limited. The current study examined the five-factor personality traits in 81 bereaved adults with (n = 51) and without (n = 30) CG. A trained doctoral level clinician evaluated participants using a structured, diagnostic psychiatric interview, and they completed self-report measures of grief and personality. A multiple regression model indicated that higher levels of neuroticism were associated with greater CG symptom severity, implicating neuroticism in the development of CG. Future prospective studies confirming it as a risk factor for the development of CG are warranted. PMID- 29498610 TI - What is the epigenome and is it involved in multiple sclerosis? PMID- 29498611 TI - Community perspectives of end-of-life preparedness. AB - While death is a universal human experience, the process of planning for death can be difficult and may be avoided altogether. To understand community perspectives of end-of-life preparedness, we undertook a multimethod study exploring the experiences of 25 community members and 10 stakeholders engaged in end-of-life planning. In addition, card sorting activities and focused discussions with 97 older adults were undertaken to highlight perspectives and needs. Data were analyzed using descriptive statistics and qualitative description. Overall, the participants perceived many benefits to being end-of life prepared, however, few community members had engaged in formal planning. Key barriers include concerns about the accessibility and accuracy of information, discomfort when engaging in end-of-life conversations, and perceptions about the cost associated with engaging in formal legal or financial preparations. Areas for further research include the need for studies that capture the cultural dimensions of end-of-life planning and explores the implementation and evaluation of community-based interventions to improve preparedness. PMID- 29498612 TI - Pulmonary embolism attenuation is a potential imaging biomarker for pulmonary artery hemodynamic improvement after catheter-directed thrombolysis. AB - This study examined the potential correlation between pulmonary embolism (PE) attenuation on computed tomography pulmonary angiography (CTPA) and pulmonary artery hemodynamic response to catheter-directed thrombolysis (CDT) in 10 patients with submassive PE. Treatment parameters, PE attenuation, clot burden, computed tomography signs of right ventricle dysfunction and right ventricular systolic pressure at echocardiography were retrospectively analyzed to determine correlation with pulmonary artery pressure improvement using Spearman correlation. A single reader, blinded to the treatment results, measured PE attenuation of all patients. There was a significant positive correlation between PE attenuation and absolute pulmonary artery pressure improvement with a Spearman correlation of 0.741, p=0.014. When attenuation was greater than or equal to the median (44.5 HU, n=5), CDT was associated with significantly better pulmonary artery pressure improvement ( p=0.037). Clot attenuation at CTPA may be a potential imaging biomarker for predicting pulmonary artery pressure improvement after CDT. PMID- 29498613 TI - Release behavior of allyl sulfide from cyclodextrin inclusion complex of allyl sulfide under different storage conditions. AB - The stability of allyl sulfide, an organosulfur compound present in garlic oil, in its alpha-, beta-, and gamma-cyclodextrin inclusion complexes was investigated under various storage conditions. The complexes of cyclodextrins and allyl sulfide were prepared by spray drying. The storage temperature, relative humidity, and initial moisture content of the inclusion complex had different effects on the release rate of allyl sulfide. Allyl sulfide in alpha-cyclodextrin complexes had a lower release rate than in beta- and gamma-cyclodextrin complexes at 100 degrees C and at 50 degrees C under 6, 40, 54, and 73% relative humidity. The initial moisture content affected only the release rate of allyl sulfide from alpha-cyclodextrin complexes. The release behavior of allyl sulfide can be correlated with the first-order release rate equation with a normal Gaussian distribution of free energy of activation of release rate constant. The results indicated alpha-cyclodextrin is a suitable material for controlled release of allyl sulfide. PMID- 29498614 TI - Psychosocial standards of care for children with cancer and their families: A national survey of pediatric oncology social workers. AB - In 2015, an interdisciplinary group of psychosocial experts developed The Standards of Psychosocial Care for Children with Cancer and Their Families. This paper presents data from a national survey of pediatric oncology social workers and their experiences in delivering psychosocial care to children and families. In total, 107 social workers from 81 cancer institutions participated in a 25 item online survey that mirrored the 15 Standards for Psychosocial Care. Both closed and open-ended questions were included. Social work participants reported that psychosocial support is being provided at most cancer centers surveyed, primarily by social workers and child life specialists, addressing adaptation to the cancer diagnosis, treatment, and transitions into survivorship or end-of-life care and bereavement. While social workers reported offering comprehensive services throughout the cancer trajectory, many of the 2015 Standards are not being systematically implemented. Areas for improvement include funding for psychosocial support staff and programs, incorporation of standardized assessment measures, assessment for financial burden throughout treatment and beyond, consistent access to psychology and psychiatry, integrated care for parents and siblings, and more inclusion of palliative care services from time of diagnosis. PMID- 29498615 TI - Starmerella camargoi f.a., sp. nov., Starmerella ilheusensis f.a., sp. nov., Starmerella litoralis f.a., sp. nov., Starmerella opuntiae f.a., sp. nov., Starmerella roubikii f.a., sp. nov. and Starmerella vitae f.a., sp. nov., isolated from flowers and bees, and transfer of related Candida species to the genus Starmerella as new combinations. AB - Six novel yeast species, Starmerella camargoi f.a., sp. nov., Starmerella ilheusensis f.a., sp. nov., Starmerella litoralis f.a., Starmerella opuntiae f.a., sp. nov., sp. nov., Starmerella roubikii f.a., sp. nov. and Starmerella vitae f.a, sp. nov. are proposed to accommodate 19 isolates recovered from ephemeral flowers or bees in Brazil, Costa Rica and Belize. Sequence analysis of the ITS-5.8S region (when available) and the D1/D2 domains of the large subunit of the rRNA gene showed that the six novel yeasts are phylogenetically related to several species of the Starmerella clade. The type strains are Starmerella camargoi f.a., sp. nov. UFMG-CM-Y595T (=CBS 14130T; Mycobank number MB 822640), Starmerella ilheusensis f.a., sp. nov. UFMG-CM-Y596T (=CBS CBS14131T; MB 822641), Starmerella litoralis f.a., sp. nov. UFMG-CM-Y603T (=CBS14104T; MB 822642), Starmerella opuntiae f.a., sp. nov. UFMG-CM-Y286T (=CBS 13466T; MB 822643), Starmerella roubikii f.a., sp. nov. UWOPS 01-191.1 (=CBS 15148; MB 822645) and Starmerella vitae f.a., sp. nov. UWOPS 00-107.2 (=CBS 15147T; MB 822646). In addition, 25 species currently assigned to the genus Candida are reassigned formally to the genus Starmerella. PMID- 29498616 TI - Marmoricola silvestris sp. nov., a novel actinobacterium isolated from alpine forest soil. AB - A Gram-stain-positive, flagellated, catalase- and cytochrome c oxidase-positive bacterial strain, designated S20-100T, was isolated from alpine forest soil. Growth occurred at a temperature range of 0-30 degrees C, at pH 6-9 and in the presence of 0-1 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequence showed that strain S20-100T was related to the genus Marmoricola and had the highest 16S rRNA gene sequence similarity to Marmoricola ginsengisoli Gsoil 097T (98.4 %) and Marmoricola solisilvae KIS18-7T (98.3 %). The cell-wall peptidoglycan of strain S20-100T contained ll-diaminopimelic acid (ll-Dpm) as the diagnostic diamino acid and was of the type A3gamma ll-Dpm - Gly. The strain contained MK-8(H4) as the predominant isoprenoid quinone and diphosphatidylglycerol, phosphatidylglycerol, four unidentified phospholipids and three unidentified lipids in lower amounts. The major cellular fatty acids (>10 %) were iso-C16 : 0, C17 : 1omega6c and C18 : 1omega9c. The genomic DNA G+C content was 66.2 mol%. Combined data of phylogenetic, phenotypic and chemotaxonomic analyses demonstrated that strain S20-100T represents a novel species of the genus Marmoricola, for which the name Marmoricola silvestris sp. nov. is proposed. The type strain is S20-100T (=DSM 104694T=LMG 30008T). PMID- 29498617 TI - Amnibacterium endophyticum sp. nov., an endophytic actinobacterium isolated from Aegiceras corniculatum. AB - A Gram-stain-positive, aerobic, non-motile, non-spore-forming and short-rod shaped actinobacterium, designated strain 1T4Z-3T, was isolated from a piece of surface-sterilized branch of Aegiceras corniculatum collected from the Cotai Ecological Zones in Macao, China. Comparative 16S rRNA gene sequence analysis showed that strain 1T4Z-3T was clearly affiliated to the genus Amnibacterium and exhibited 97.9 % gene sequence similarity to Amnibacterium kyonggiense JCM 16463T, 97.3 % gene sequence similarity to Amnibacterium soli JCM 19015T and less than 96.4 % gene sequence similarities to other genera of the family Microbacteriaceae. Strain 1T4Z-3T had L-2,4-diaminobutyric acid as the diagnostic cell-wall diamino acid. The major fatty acids (>10 % of total fatty acids) were iso-C16 : 0 (46.6 %) and anteiso-C15 : 0 (27.3 %). The predominant menaquinones of strain 1T4Z-3T were MK-11 (81.4 %) and MK-12 (14.1 %). The polar lipids comprised diphosphatidylglycerol, phosphatidylglycerol, six unidentified glycolipids, four unidentified phospholipids and two unidentified lipids. The DNA G+C content of strain 1T4Z-3T was 71.4 mol%. Based on the phylogenetic, phenotypic and chemotaxonomic features, strain 1T4Z-3T is considered to represent a novel species of the genus Amnibacterium, for which the name Amnibacterium endophyticum sp. nov. is proposed. The type strain of Amnibacterium endophyticum is 1T4Z-3T (=KCTC 39983T=CGMCC 1.16066T). PMID- 29498618 TI - Flavobacterium fluviatile sp. nov., isolated from a freshwater creek. AB - A yellowish-pink-coloured bacterial strain, TAPY14T, was isolated from a freshwater creek in Taiwan. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain TAPY14T belonged to the genus Flavobacterium and showed the highest similarity (97.3 %) with respect to Flavobacterium reichenbachii WB 3.2-61T, Flavobacterium ginsengisoli DCY54T and Flavobacterium defluvii EMB117T and less than 97 % with other members of the genus. Cells of strain TAPY14T were Gram-stain-negative, strictly aerobic, motile by gliding and rod-shaped. Optimal growth occurred at 20-30 degrees C, pH 6 and in the presence of 0.5 % NaCl. Strain TAPY14T contained iso-C15 : 0 and summed feature 3 (C16 : 1omega6c and/or C16 : 1omega7c) as the predominant fatty acids. The polar lipid profile consisted of phosphatidylethanolamine, four uncharacterized aminophospholipids, one uncharacterized phospholipid and one uncharacterized lipid. The major polyamine was homospermidine. The major isoprenoid quinone was MK-6. The DNA G+C content of the genomic DNA was 38.1 mol%. The DNA-DNA hybridization values for strain TAPY14T with F. reichenbachii DSM 21791T, F. ginsengisoli JCM 17336T and F. defluvii DSM 17963T were less than 30 %. On the basis of the phylogenetic inference and phenotypic data, strain TAPY14T should be classified as a novel species, for which the name Flavobacterium fluviatile sp. nov. is proposed. The type strain is TAPY14T (=BCRC 81012T=LMG 29733T=KCTC 52446T). PMID- 29498619 TI - Genomic survey of Clostridium difficile reservoirs in the East of England implicates environmental contamination of wastewater treatment plants by clinical lineages. AB - There is growing evidence that patients with Clostridiumdifficile-associated diarrhoea often acquire their infecting strain before hospital admission. Wastewater is known to be a potential source of surface water that is contaminated with C. difficile spores. Here, we describe a study that used genome sequencing to compare C. difficile isolated from multiple wastewater treatment plants across the East of England and from patients with clinical disease at a major hospital in the same region. We confirmed that C. difficile from 65 patients were highly diverse and that most cases were not linked to other active cases in the hospital. In total, 186 C. difficile isolates were isolated from effluent water obtained from 18 municipal treatment plants at the point of release into the environment. Whole genome comparisons of clinical and environmental isolates demonstrated highly related populations, and confirmed extensive release of toxigenic C. difficile into surface waters. An analysis based on multilocus sequence types (STs) identified 19 distinct STs in the clinical collection and 38 STs in the wastewater collection, with 13 of 44 STs common to both clinical and wastewater collections. Furthermore, we identified five pairs of highly similar isolates (<=2 SNPs different in the core genome) in clinical and wastewater collections. Strategies to control community acquisition should consider the need for bacterial control of treated wastewater. PMID- 29498622 TI - Characterization of the pixB gene in Xenorhabdus nematophila and discovery of a new gene family. AB - Xenorhabdus nematophila are Gram-negative bacteria that engage in mutualistic associations with entomopathogenic nematodes. To reproduce, the nematodes invade insects and release X. nematophila into the haemolymph where it functions as an insect pathogen. In complex medium, X. nematophila cells produce two distinct types of intracellular crystalline inclusions, one composed of the methionine rich PixA protein and the other composed of the PixB protein. Here we show that PixB crystalline inclusions were neither apparent in X. nematophila cells grown in medium that mimics insect haemolymph (Grace's medium) nor in cells grown directly in the insect haemocoel. The identified pixB gene was regulated by a conserved sigma70 promoter while the pixA promoter was less well conserved. Expression of pixA and pixB under biological conditions was analysed using GFP promoter reporters. Microplate fluorescence detection and flow cytometry analyses revealed that pixB was expressed at high levels in Grace's medium and in insect haemolymph and at lower levels in complex medium, while pixA was expressed at lower levels under all conditions. Although pixB was highly expressed in Grace's medium, PixB crystalline inclusions were not present, suggesting that under biological conditions PixB production may be controlled post-transcriptionally. Although a pixB-minus strain was constructed, the function of PixB remains unresolved. The pixB gene was present in few Xenorhabdus species and pixB-type genes were identified in some Proteobacteria and Gram-positive species, while pixA was only present in Xenorhabdus species. Two conserved sequences were identified in PixB-type proteins that characterize this previously unrecognized gene family. PMID- 29498620 TI - Roles of pyruvate dehydrogenase and branched-chain alpha-keto acid dehydrogenase in branched-chain membrane fatty acid levels and associated functions in Staphylococcus aureus. AB - PURPOSE: Membrane fluidity to a large extent is governed by the presence of branched-chain fatty acids (BCFAs). Branched-chain alpha-keto acid dehydrogenase (BKD) is the key enzyme in BCFA synthesis. A Staphylococcus aureus BKD-deficient strain still produced substantial levels of BCFAs. Pyruvate dehydrogenase (PDH) with structural similarity to BKD has been speculated to contribute to BCFAs in S. aureus. METHODOLOGY: This study was carried out using BKD-, PDH- and BKD : PDH deficient derivatives of methicillin-resistant S. aureus strain JE2. Differences in growth kinetics were evaluated spectrophotometrically, membrane BCFAs using gas chromatography and membrane fluidity by fluorescence polarization. Carotenoid levels were estimated by measuring A465 of methanol extracts from 48 h cultures. MIC values were determined by broth microdilution.Results/Key findings. BCFAs made up 50 % of membrane fatty acids in wild-type but only 31 % in the BKD deficient mutant. BCFA level was ~80 % in the PDH-deficient strain and 38 % in the BKD : PDH-deficient strain. BKD-deficient mutant showed decreased membrane fluidity, the PDH-deficient mutant showed increased membrane fluidity. The BKD- and PDH-deficient strains grew slower and the BKD : PDH-deficient strain grew slowest at 37 degrees C. However at 20 degrees C, the BKD- and BKD : PDH deficient strains grew only a little followed by autolysis of these cells. The BKD-deficient strain produced higher levels of staphyloxanthin. The PDH-deficient and BKD : PDH-deficient strains produced very little staphyloxanthin. The BKD deficient strain showed increased susceptibility to daptomycin. CONCLUSION: The BCFA composition of the cell membrane in S. aureus seems to significantly impact cell growth, membrane fluidity and resistance to daptomycin. PMID- 29498621 TI - Parvibium lacunae gen. nov., sp. nov., a new member of the family Alcaligenaceae isolated from a freshwater pond. AB - A bacterial strain designated KMB9T was isolated from a freshwater pond in Taiwan and characterized using a polyphasic taxonomy approach. Cells of strain KMB9T were Gram-stain-negative, aerobic, poly-beta-hydroxybutyrate-accumulating, motile by means of a monopolar flagellum, non-spore-forming and rods surrounded by a thick capsule and forming white-coloured colonies. Growth occurred at 20-40 degrees C (optimum, 25-37 degrees C), at pH 6.5-7.5 (optimum, pH 7.0) and with 0 0.5 % NaCl (optimum, 0 %). Phylogenetic analyses based on 16S rRNA gene and four housekeeping gene sequences (recA, rpoA, rpoB and atpD) showed that strain KMB9T forms a distinct phyletic line within the family Alcaligenaceae, and the levels of 16S rRNA gene sequence similarity to its closest relatives with validly published names were less than 93.3 %. The predominant fatty acids were summed feature 3 (comprising C16 : 1omega7c and/or C16 : 1omega6c), C16 : 0 and C18 : 1omega7c. The major isoprenoid quinone was Q-8. The major polyamine was putrescine. The polar lipid profile revealed the presence of phosphatidylethanolamine, phosphatidylglycerol and several uncharacterized aminophospholipids, aminolipids, phospholipids and lipids. The genomic DNA G+C content of strain KMB9T was 54.5 mol%. On the basis of the genotypic and phenotypic data, strain KMB9T represents a novel species of a new genus in the family Alcaligenaceae, for which the name Parvibium lacunae gen. nov., sp. nov. is proposed. The type strain is KMB9T (=BCRC 81053T=LMG 30055T=KCTC 52814T). PMID- 29498623 TI - Temperature-dependent Raman spectroscopy studies of the interface coupling effect of monolayer ReSe2 single crystals on Au foils. AB - Rhenium diselenide (ReSe2), which bears in-plane anisotropic optical and electrical properties, is of considerable interest for its excellent applications in novel devices, such as polarization-sensitive photodetectors and integrated polarization-controllers. However, great challenges to date in the controllable synthesis of high-quality ReSe2 have hindered its in-depth investigations and practical applications. Herein, we report a feasible synthesis of monolayer single-crystal ReSe2 flakes on the Au foil substrate by using a chemical vapor deposition route. Particularly, we focus on the temperature-dependent Raman spectroscopy investigations of monolayer ReSe2 grown on Au foils, which present concurrent red shifts of Eg-like and Ag-like modes with increasing measurement temperature from 77-290 K. Linear temperature dependences of both modes are revealed and explained from the anharmonic vibration of the ReSe2 lattice. More importantly, the strong interaction of ReSe2 with Au, with respect to that with SiO2/Si, is further confirmed by temperature-dependent Raman characterization. This work is thus proposed to shed light on the optical and thermal properties of such anisotropic two-dimensional three-atom-thick materials. PMID- 29498624 TI - Preparation and characterization of a supported system of Ni2P/Ni12P5 nanoparticles and their use as the active phase in chemoselective hydrogenation of acetophenone. AB - Ni2P/Ni12P5 nanoparticles were obtained by thermal decomposition of nickel organometallic salt at low temperature. The use of different characterization techniques allowed us to determine that this process produced a mixture of two nickel phosphide phases: Ni2P and Ni12P5. These nickel phosphides nanoparticles, supported on mesoporous silica, showed activity and high selectivity for producing the hydrogenation of the acetophenone carbonyl group to obtain 1 phenylethanol. This is a first report that demonstrates the ability of supported Ni2P/Ni12P5 nanoparticles to produce the chemoselective hydrogenation of acetophenone. We attribute these special catalytic properties to the particular geometry of the Ni-P sites on the surface of the nanoparticles. This is an interesting result because the nickel phosphides have a wide composition range (from Ni3P to NiP3), with different crystallographic structures, therefore we think that different phases could be active and selective to hydrogenate many important molecules with more than one functional group. PMID- 29498625 TI - Thermophoretically driven water droplets on graphene and boron nitride surfaces. AB - We investigate thermally driven water droplet transport on graphene and hexagonal boron nitride (h-BN) surfaces using molecular dynamics simulations. The two surfaces considered here have different wettabilities with a significant difference in the mode of droplet transport. The water droplet travels along a straighter path on the h-BN sheet than on graphene. The h-BN surface produced a higher driving force on the droplet than the graphene surface. The water droplet is found to move faster on h-BN surface compared to graphene surface. The instantaneous contact angle was monitored as a measure of droplet deformation during thermal transport. The characteristics of the droplet motion on both surfaces is determined through the moment scaling spectrum. The water droplet on h-BN surface showed the attributes of the super-diffusive process, whereas it was sub-diffusive on the graphene surface. PMID- 29498626 TI - Characterizing the surface forces between two individual nanowires using optical microscopy based nanomanipulation. AB - The adhesion and friction between two Al2O3 nanowires (NWs) was characterized by the use of optical microscopy based nanomanipulation, with which peeling, shearing and sliding was performed. The elastically deformed shape of the NWs during peeling and shearing was used to calculate the adhesion and frictional forces; force sensing was not required. The obtained adhesion stress between two Al2O3 NWs varied from 0.14 to 0.25 MPa, lower than that observed for carbon nanotube junctions, and was attributed to van der Waals attraction. Stick-slip was observed during the shearing and sliding of two NWs, and was the consequence of discrete contact between surface asperities. The obtained static and kinetic frictional stresses varied from 0.7 to 1.3 MPa and 0.4 to 0.8 MPa, respectively; significantly greater than the obtained adhesion stress. PMID- 29498627 TI - Contemporary Pain Management in Elderly Patients After Hip Fracture Surgery: Cross-sectional Analyses at Baseline of a Randomized Controlled Trial. AB - BACKGROUND: Adequate pain management following hip fracture surgery reduces length of stay, reduces incidence of delirium, promotes recovery, and improves mobility. Previous research suggests that hip fracture pain is undertreated in some patient subgroups, and that hypovitaminosis D can further aggravate pain which could hinder active rehabilitation. We provide a cross-sectional analysis of the baseline characteristics of participants in the REVITAHIP study with the aim of documenting pain intensity and its associations after hip fracture and to explore the characteristics of people who report higher levels of pain. METHOD: We analyzed the baseline characteristics with a focus on pain scores in patients admitted with a hip fracture (undergoing surgery) to 3 teaching hospitals over New South Wales, Australia, between January 2011 and April 2013. Patients were evaluated using the Verbal Rating Scale (VRS). Secondary measures including 25 hydroxyvitamin D levels at baseline, hip fracture subtype, type of surgical intervention, quality of life score, and cognitive and mobility status were correlated with the VRS using the Pearson correlation, ANOVA, and regression analysis. RESULTS: The 218 participants had a mean age of 83.9+/-7.2 years and 77.1% were women of whom 16.0% had a Mini Mental State Examination score of <=23 of 30. The mean and SD VRS pain score was 3.5+/-2.3. More than half (61.9%, n=113) had VRS>=3 and 18.1% (n=52) had VRS>=5. Using the EuroQOL pain subscore, 78.1% had moderate pain or discomfort and 7.9% had extreme pain or discomfort. Using a multivariate regression model, postoperative VRS was significantly higher in persons with a higher comorbidity count, those previously living independently alone, and surgical fixative modality with hemiarthroplasty. CONCLUSIONS: Overall, the levels of pain reported by this cohort are acceptable although approximately 10% to 15% had higher than reasonable levels of pain. This study provides an insight into pain assessment and management by identifying certain patient subtypes who are vulnerable to undertreatment of pain. PMID- 29498628 TI - Baseline Variation in Use of VA/DOD Clinical Practice Guideline Recommended Opioid Prescribing Practices Across VA Health Care Systems. AB - OBJECTIVES: The purpose of this study was to determine baseline adherence to key recommendations from the 2010 VA/DOD Clinical Practice Guideline for Opioid Therapy for Chronic Pain at Veterans Health Administration (VA) facilities. We hoped to understand practice patterns at the time of guideline release to guide quality improvement and implementation efforts. METHODS: Overall practice patterns were examined at each of the 140 VA Health Care Systems based on quality metrics developed to assess adherence to the VA/DOD Clinical Practice Guideline. RESULTS: Clinical practice varied widely across facilities on measures of use of urine drug screens, substance use disorder treatment for diagnosed substance use disorder patients, and use of rehabilitative treatments. Less variation was observed in measures of sedative coprescription and use of adjunctive pharmacotherapy. Use of guideline recommended practices was generally more frequent for patients prescribed long-acting opioid formulations and those with chronic use. Relative facility-level implementation was correlated across most measures. Overall implementation of guideline recommended practices was lower at less complex facilities and facilities in the Western United States. DISCUSSION: In 2010, guideline-recommended practices for opioid prescribing were variably used across VA health care systems. Efforts to disseminate practices used at high performing sites, and increase consistency of use of recommended practices across patients and facilities should be considered to improve pain management and reduce adverse events. PMID- 29498629 TI - Hepatitis B Virus-Associated Hepatocellular Carcinoma and Hepatic Cancer Stem Cells. AB - Chronic Hepatitis B Virus (HBV) infection is linked to hepatocellular carcinoma (HCC) pathogenesis. Despite the availability of a HBV vaccine, current treatments for HCC are inadequate. Globally, 257 million people are chronic HBV carriers, and children born from HBV-infected mothers become chronic carriers, destined to develop liver cancer. Thus, new therapeutic approaches are needed to target essential pathways involved in HCC pathogenesis. Accumulating evidence supports existence of hepatic cancer stem cells (hCSCs), which contribute to chemotherapy resistance and cancer recurrence after treatment or surgery. Understanding how hCSCs form will enable development of therapeutic strategies to prevent their formation. Recent studies have identified an epigenetic mechanism involving the downregulation of the chromatin modifying Polycomb Repressive Complex 2 (PRC2) during HBV infection, which results in re-expression of hCSC marker genes in infected hepatocytes and HBV-associated liver tumors. However, the genesis of hCSCs requires, in addition to the expression of hCSC markers cellular changes, rewiring of metabolism, cell survival, escape from programmed cell death, and immune evasion. How these changes occur in chronically HBV-infected hepatocytes is not yet understood. In this review, we will present the basics about HBV infection and hepatocarcinogenesis. Next, we will discuss studies describing the mutational landscape of liver cancers and how epigenetic mechanisms likely orchestrate cellular reprograming of hepatocytes to enable formation of hCSCs. PMID- 29498631 TI - Microstructures and Mechanical Properties of Commercially Pure Ti Processed by Rotationally Accelerated Shot Peening. AB - Gradient structured materials possess good combinations of strength and ductility, rendering the materials attractive in industrial applications. In this research, a surface nanocrystallization (SNC) technique, rotationally accelerated shot peening (RASP), was employed to produce a gradient nanostructured pure Ti with a deformation layer that had a thickness of 2000 MUm, which is thicker than those processed by conventional SNC techniques. It is possible to fabricate a gradient structured Ti workpiece without delamination. Moreover, based on the microstructural features, the microstructure of the processed sample can be classified into three regions, from the center to the surface of the RASP processed sample: (1) a twinning-dominated core region; (2) a "twin intersection" dominated twin transition region; and (3) the nanostructured region, featuring nanograins. A microhardness gradient was detected from the RASP-processed Ti. The surface hardness was more than twice that of the annealed Ti sample. The RASP processed Ti sample exhibited a good combination of yield strength and uniform elongation, which may be attributed to the high density of deformation twins and a strong back stress effect. PMID- 29498633 TI - Effects of Medium-Term Amendment with Diversely Processed Sewage Sludge on Soil Humification-Mineralization Processes and on Cu, Pb, Ni, and Zn Bioavailability. AB - The organic fraction of sewage sludge administered to agricultural soil can contribute to slowing down the loss of soil's organic carbon and, in some cases, can improve the physical and mechanical properties of the soil. One of the main constraints to the agricultural use of sewage sludge is its heavy metals content. In the long term, agricultural administration of sewage sludge to soil could enhance the concentration of soil heavy metals (as total and bioavailable fractions). The aim of this research was to evaluate the effects of medium-term fertilization with diversely processed sewage sludge on the soil's organic carbon content and humification-mineralization processes, on the physical-mechanical properties of soil and their influence on the pool of potentially bioavailable heavy metals, in order to assess their effectiveness as soil organic amendments. After eight years of sludge administration; an increase in the concentrations of bioavailable form was evidenced in all the heavy metals analyzed; independently of the type of sludge administered. The form of sludge administration (liquid, dehydrated, composted) has differently influenced the soil humification mineralization processes and the physical-mechanical properties of soil. The prolonged amendment with composted sewage sludge contributed to keeping the soil humification-mineralization process in equilibrium and to improving the physical and mechanical qualities of the treated soil. PMID- 29498630 TI - Recent Understandings of Biology, Prophylaxis and Treatment Strategies for Hypertrophic Scars and Keloids. AB - Hypertrophic scars and keloids are fibroproliferative disorders that may arise after any deep cutaneous injury caused by trauma, burns, surgery, etc. Hypertrophic scars and keloids are cosmetically problematic, and in combination with functional problems such as contractures and subjective symptoms including pruritus, these significantly affect patients' quality of life. There have been many studies on hypertrophic scars and keloids; but the mechanisms underlying scar formation have not yet been well established, and prophylactic and treatment strategies remain unsatisfactory. In this review, the authors introduce and summarize classical concepts surrounding wound healing and review recent understandings of the biology, prevention and treatment strategies for hypertrophic scars and keloids. PMID- 29498632 TI - Rapid Determination of Active Compounds and Antioxidant Activity of Okra Seeds Using Fourier Transform Near Infrared (FT-NIR) Spectroscopy. AB - Okra seeds (OSD) have been proved to possess significantly anti-fatigue activity and due to their high contents of flavonoids and polyphenols. While, the quality of OSD is easily affected by harvest time, region and other factors. In this research, the rapid method based on Fourier transform near infrared (FT-NIR) spectroscopy was developed for quality assessment of okra seeds. Firstly, 120 samples' spectra were acquired, and quantification of isoquercitrin, quercetin-3 O-gentiobioside, total phenols (TP) and antioxidant assays including 1-diphenyl-2 picrylhydrazyl (DPPH) scavenging, ferric reducing antioxidant power (FRAP) were conducted. Next, partial least squares (PLS) regression and full cross-validation were applied to develop calibration models for these data, and external validation was used to determine models' quality. The coefficient of determination for calibration ( R c 2 ), the root mean square error of cross validation (RMSECV) and the corresponding determination coefficients for cross validation ( R cv 2 ) proved all these models have excellent precision. Besides, the residual predictive deviation (RPD) of models (4.07 for isoquercitrin, 4.04 for quercetin-3-O-gentiobioside, 9.79 for TP, 4.58 for DPPH and 4.12 for FRAP) also demonstrated that these models possessed good predicative ability. All these results showed that FT-NIR spectroscopy could be used to rapidly determine active compounds and antioxidant activity of okra seeds. PMID- 29498634 TI - Bax Inhibitor-1 Acts as an Anti-Influenza Factor by Inhibiting ROS Mediated Cell Death and Augmenting Heme-Oxygenase 1 Expression in Influenza Virus Infected Cells. AB - Influenza virus remains a major health concern worldwide, and there have been continuous efforts to develop effective antivirals despite the use of annual vaccination programs. The purpose of this study was to determine the anti influenza activity of Bax inhibitor-1 (BI-1). Madin-Darby Canine Kidney (MDCK) cells expressing wild type BI-1 and a non-functional BI-1 mutant, BI-1 ?C (with the C-terminal 14 amino acids deleted) were prepared and infected with A/PR/8/34 influenza virus. BI-1 overexpression led to the suppression of virus-induced cell death and virus production compared to control Mock or BI-1 ?C overexpression. In contrast to BI-1 ?C-overexpressing cells, BI-1-overexpressing cells exhibited markedly reduced virus-induced expression of several viral genes, accompanied by a substantial decrease in ROS production. We found that treatment with a ROS scavenging agent, N-acetyl cysteine (NAC), led to a dramatic decrease in virus production and viral gene expression in control MDCK and BI-1 ?C-overexpressing cells. In contrast, NAC treatment resulted in the slight additional suppression of virus production and viral gene expression in BI-1-overexpressing cells but was statistically significant. Moreover, the expression of heme oxygenase-1 (HO 1) was also significantly increased following virus infection in BI-1 overexpressing cells compared to control cells. Taken together, our data suggest that BI-1 may act as an anti-influenza protein through the suppression of ROS mediated cell death and upregulation of HO-1 expression in influenza virus infected MDCK cells. PMID- 29498636 TI - Development of a Flexible Broadband Rayleigh Waves Comb Transducer with Nonequidistant Comb Interval for Defect Detection of Thick-Walled Pipelines. AB - It is necessary to develop a transducer that can quickly detect the inner and outer wall defects of thick-walled pipes, in order to ensure the safety of such pipes. In this paper, a flexible broadband Rayleigh-waves comb transducer based on PZT (lead zirconate titanate) for defect detection of thick-walled pipes is studied. The multiple resonant coupling theory is used to expand the transducer broadband and the FEA (Finite Element Analysis) method is used to optimize transducer array element parameters. Optimization results show that the best array element parameters of the transducer are when the transducer array element length is 30 mm, the thickness is 1.2 mm, the width of one end of is 1.5 mm, and the other end is 3 mm. Based on the optimization results, such a transducer was fabricated and its performance was tested. The test results were consistent with the finite-element simulation results, and the -3 dB bandwidth of the transducer reached 417 kHz. Transducer directivity test results show that the Theta-3dB beam width was equal to 10 degrees , to meet the defect detection requirements. Finally, defects of thick-walled pipes were detected using the transducer. The results showed that the transducer could detect the inner and outer wall defects of thick-walled pipes within the bandwidth. PMID- 29498635 TI - The Process and Strategy for Developing Selective Histone Deacetylase 3 Inhibitors. AB - Histone deacetylases (HDACs) are epigenetic drug targets that have gained major scientific attention. Inhibition of these important regulatory enzymes is used to treat cancer, and has the potential to treat a host of other diseases. However, currently marketed HDAC inhibitors lack selectivity for the various HDAC isoenzymes. Several studies have shown that HDAC3, in particular, plays an important role in inflammation and degenerative neurological diseases, but the development of selective HDAC3 inhibitors has been challenging. This review provides an up-to-date overview of selective HDAC3 inhibitors, and aims to support the development of novel HDAC3 inhibitors in the future. PMID- 29498637 TI - Recombinant Goose Circoviruses Circulating in Domesticated and Wild Geese in Poland. AB - Circoviruses are circular single-stranded DNA (ssDNA) viruses that infect a variety of animals, both domestic and wild. Circovirus infection in birds is associated with immunosuppression and this in turn predisposes the infected animals to secondary infections that can lead to mortality. Farmed geese (Anser anser) in many parts of the world are infected with circoviruses. The majority of the current genomic information for goose circoviruses (GoCVs) (n = 40) are from birds sampled in China and Taiwan, and only two genome sequences are available from Europe (Germany and Poland). In this study, we sampled 23 wild and 19 domestic geese from the Goplo Lake area in Poland. We determined the genomes of GoCV from 21 geese; 14 domestic Greylag geese (Anser anser), three wild Greylag geese (A. anser), three bean geese (A. fabalis), and one white fronted goose (A. albifrons). These genomes share 83-95% nucleotide pairwise identities with previously identified GoCV genomes, most are recombinants with exchanged fragment sizes up to 50% of the genome. Higher diversity levels can be seen within the genomes from domestic geese compared with those from wild geese. In the GoCV capsid protein (cp) and replication associated protein (rep) gene sequences we found that episodic positive selection appears to largely mirror those of beak and feather disease virus and pigeon circovirus. Analysis of the secondary structure of the ssDNA genome revealed a conserved stem-loop structure with the G C rich stem having a high degree of negative selection on these nucleotides. PMID- 29498638 TI - Ethnic and Gender Differences in Family Social Support among Black Adolescents. AB - This study examines black adolescents' reports of the most helpful types of social support that they receive from and provide to family members, and whether family support exchanges vary by ethnicity (African American vs. Black Caribbean) and gender. Data for this study are from the National Survey of American Life Adolescent Supplement (NSAL-A), a national, probability sample of African American and Black Caribbean youth (ages 13-17). Overall, youth reported financial support, followed by emotional assistance and practical support as the most helpful types of support that they received. Practical and emotional assistance characterized the most commonly reported types of support that they provided to family members. Black Caribbean adolescents were more likely than African American adolescents to report financial and practical assistance as the most helpful types of support that they received from family members; no ethnic differences were observed in the provision of support to relatives. There were no significant gender differences in the receipt of support, but adolescent girls reported greater involvement in providing emotional support and caregiving than adolescent boys. The results of this paper reveal that African American and Black Caribbean adolescents are involved in a complex pattern of reciprocal support exchanges with their extended family members. Study findings also reinforce the importance of research focused on racial/ethnic and gender differences in family support exchanges in order to develop a more nuanced understanding of family support behaviors within these groups. PMID- 29498639 TI - The Oncolytic Virus VSV-GP Is Effective against Malignant Melanoma. AB - Previously, we described VSV-GP, a modified version of the vesicular stomatitis virus, as a non-neurotoxic oncolytic virus that is effective for the treatment of malignant glioblastoma and ovarian cancer. Here, we evaluate the therapeutic efficacy of VSV-GP for malignant melanoma. All of the human, mouse, and canine melanoma cell lines that were tested, alongside most primary human melanoma cultures, were infected by VSV-GP and efficiently killed. Additionally, we found that VSV-GP prolonged the survival of mice in both a xenograft and a syngeneic mouse model. However, only a few mice survived with long-term tumor remission. When we analyzed the factors that might limit VSV-GP's efficacy, we found that vector-neutralizing antibodies did not play a role in this context, as even after eight subsequent immunizations and an observation time of 42 weeks, no vector neutralizing antibodies were induced in VSV-GP immunized mice. In contrast, the type I IFN response might have contributed to the reduced efficacy of the therapy, as both of the cell lines that were used for the mouse models were able to mount a protective IFN response. Nevertheless, early treatment with VSV-GP also reduced the number and size of lung metastases in a syngeneic B16 mouse model. In summary, VSV-GP is a potent candidate for the treatment of malignant melanoma; however, factors limiting the efficacy of the virus need to be further explored. PMID- 29498640 TI - Microginins from a Microcystis sp. Bloom Material Collected from the Kishon Reservoir, Israel. AB - During blooms, cyanobacteria produce diverse modified peptides. Among these are the microginins, which inhibit zinc-containing metalloproteases. Ten microginins, microginins KR767 (1), KR801(2), KR835 (3), KR785 (4), KR604 (5), KR638 (6), KR781 (7), KR815 (8), FR3 (9), and FR4 (10), were isolated from the extract of a bloom material of Microcystis sp. (IL-405) collected from the Kishon Reservoir, Israel in the fall of 2009. The structures of the pure compounds were elucidated using 1D and 2D NMR techniques and high-resolution mass spectrometry. The absolute configuration of the chiral centers of the amino acids were determined by Marfey's and advance Marfey's methods and by comparison of 1H and 13C NMR chemical shifts of the Ahda derivatives with those of known microginins. These microginins differ in sequence and absolute configuration of the chiral centers of the Ahda moieties and by N-methylation of the Ahda amine group and extent of chlorination of the Ahda terminal methyl group. The compounds were evaluated for inhibition of the zinc metalloprotease, aminopeptidase M, and exhibited low- to sub-nanomolar half maximal inhibitory concentration (IC50) values. PMID- 29498641 TI - Security Architecture and Protocol for Trust Verifications Regarding the Integrity of Files Stored in Cloud Services. AB - Cloud computing is considered an interesting paradigm due to its scalability, availability and virtually unlimited storage capacity. However, it is challenging to organize a cloud storage service (CSS) that is safe from the client point-of view and to implement this CSS in public clouds since it is not advisable to blindly consider this configuration as fully trustworthy. Ideally, owners of large amounts of data should trust their data to be in the cloud for a long period of time, without the burden of keeping copies of the original data, nor of accessing the whole content for verifications regarding data preservation. Due to these requirements, integrity, availability, privacy and trust are still challenging issues for the adoption of cloud storage services, especially when losing or leaking information can bring significant damage, be it legal or business-related. With such concerns in mind, this paper proposes an architecture for periodically monitoring both the information stored in the cloud and the service provider behavior. The architecture operates with a proposed protocol based on trust and encryption concepts to ensure cloud data integrity without compromising confidentiality and without overloading storage services. Extensive tests and simulations of the proposed architecture and protocol validate their functional behavior and performance. PMID- 29498644 TI - Digital Analysis of Sit-to-Stand in Masters Athletes, Healthy Old People, and Young Adults Using a Depth Sensor. AB - The aim of this study was to compare the performance between young adults (n = 15), healthy old people (n = 10), and masters athletes (n = 15) using a depth sensor and automated digital assessment framework. Participants were asked to complete a clinically validated assessment of the sit-to-stand technique (five repetitions), which was recorded using a depth sensor. A feature encoding and evaluation framework to assess balance, core, and limb performance using time- and speed-related measurements was applied to markerless motion capture data. The associations between the measurements and participant groups were examined and used to evaluate the assessment framework suitability. The proposed framework could identify phases of sit-to-stand, stability, transition style, and performance between participant groups with a high degree of accuracy. In summary, we found that a depth sensor coupled with the proposed framework could identify performance subtleties between groups. PMID- 29498643 TI - Combining Load and Motor Encoders to Compensate Nonlinear Disturbances for High Precision Tracking Control of Gear-Driven Gimbal. AB - High-performance position control can be improved by the compensation of disturbances for a gear-driven control system. This paper presents a mode-free disturbance observer (DOB) based on sensor-fusion to reduce some errors related disturbances for a gear-driven gimbal. This DOB uses the rate deviation to detect disturbances for implementation of a high-gain compensator. In comparison with the angular position signal the rate deviation between load and motor can exhibits the disturbances exiting in the gear-driven gimbal quickly. Due to high bandwidth of the motor rate closed loop, the inverse model of the plant is not necessary to implement DOB. Besides, this DOB requires neither complex modeling of plant nor the use of additive sensors. Without rate sensors providing angular rate, the rate deviation is easily detected by encoders mounted on the side of motor and load, respectively. Extensive experiments are provided to demonstrate the benefits of the proposed algorithm. PMID- 29498642 TI - Estrogen Receptor Signaling in Radiotherapy: From Molecular Mechanisms to Clinical Studies. AB - Numerous studies have established a proof of concept that abnormal expression and function of estrogen receptors (ER) are crucial processes in initiation and development of hormone-related cancers and also affect the efficacy of anti cancer therapy. Radiotherapy has been applied as one of the most common and potent therapeutic strategies, which is synergistic with surgical excision, chemotherapy and targeted therapy for treating malignant tumors. However, the impact of ionizing radiation on ER expression and ER-related signaling in cancer tissue, as well as the interaction between endocrine and irradiation therapy remains largely elusive. This review will discuss recent findings on ER and ER related signaling, which are relevant for cancer radiotherapy. In addition, we will summarize pre-clinical and clinical studies that evaluate the consequences of anti-estrogen and irradiation therapy in cancer, including emerging studies on head and neck cancer, which might improve the understanding and development of novel therapeutic strategies for estrogen-related cancers. PMID- 29498646 TI - Adjacent Vehicle Number-Triggered Adaptive Transmission for V2V Communications. AB - For vehicle-to-vehicle (V2V) communication, such issues as continuity and reliability still have to be solved. Specifically, it is necessary to consider a more scalable physical layer due to the high-speed mobility of vehicles and the complex channel environment. Adaptive transmission has been adapted in channel dependent scheduling. However, it has been neglected with regards to the physical topology changes in the vehicle network. In this paper, we propose a physical topology-triggered adaptive transmission scheme which adjusts the data rate between vehicles according to the number of connectable vehicles nearby. Also, we investigate the performance of the proposed method using computer simulations and compare it with the conventional methods. The numerical results show that the proposed method can provide more continuous and reliable data transmission for V2V communications. PMID- 29498648 TI - Citizen Science and Community Engagement in Tick Surveillance-A Canadian Case Study. AB - Lyme disease is the most common tick-borne disease in North America and Europe, and on-going surveillance is required to monitor the spread of the tick vectors as their populations expand under the influence of climate change. Active surveillance involves teams of researchers collecting ticks from field locations with the potential to be sites of establishing tick populations. This process is labor- and time-intensive, limiting the number of sites monitored and the frequency of monitoring. Citizen science initiatives are ideally suited to address this logistical problem and generate high-density and complex data from sites of community importance. In 2014, the same region was monitored by academic researchers, public health workers, and citizen scientists, allowing a comparison of the strengths and weaknesses of each type of surveillance effort. Four community members persisted with tick collections over several years, collectively recovering several hundred ticks. Although deviations from standard surveillance protocols and the choice of tick surveillance sites makes the incorporation of community-generated data into conventional surveillance analyses more complex, this citizen science data remains useful in providing high-density longitudinal tick surveillance of a small area in which detailed ecological observations can be made. Most importantly, partnership between community members and researchers has proven a powerful tool in educating communities about of the risk of tick-vectored diseases and in encouraging tick bite prevention. PMID- 29498647 TI - Chemical and Biological Significance of Oenothein B and Related Ellagitannin Oligomers with Macrocyclic Structure. AB - In 1990, Okuda et al. reported the first isolation and characterization of oenothein B, a unique ellagitannin dimer with a macrocyclic structure, from the Oenothera erythrosepala leaves. Since then, a variety of macrocyclic analogs, including trimeric-heptameric oligomers have been isolated from various medicinal plants belonging to Onagraceae, Lythraceae, and Myrtaceae. Among notable in vitro and in vivo biological activities reported for oenothein B are antioxidant, anti inflammatory, enzyme inhibitory, antitumor, antimicrobial, and immunomodulatory activities. Oenothein B and related oligomers, and/or plant extracts containing them have thus attracted increasing interest as promising targets for the development of chemopreventive agents of life-related diseases associated with oxygen stress in human health. In order to better understand the significance of this type of ellagitannin in medicinal plants, this review summarizes (1) the structural characteristics of oenothein B and related dimers; (2) the oxidative metabolites of oenothein B up to heptameric oligomers; (3) the distribution of oenotheins and other macrocyclic analogs in the plant kingdom; and (4) the pharmacological activities hitherto documented for oenothein B, including those recently found by our laboratory. PMID- 29498650 TI - Estimating and Comparing Dam Deformation Using Classical and GNSS Techniques. AB - Global Navigation Satellite Systems (GNSS) receivers are nowadays commonly used in monitoring applications, e.g., in estimating crustal and infrastructure displacements. This is basically due to the recent improvements in GNSS instruments and methodologies that allow high-precision positioning, 24 h availability and semiautomatic data processing. In this paper, GNSS-estimated displacements on a dam structure have been analyzed and compared with pendulum data. This study has been carried out for the Eleonora D'Arborea (Cantoniera) dam, which is in Sardinia. Time series of pendulum and GNSS over a time span of 2.5 years have been aligned so as to be comparable. Analytical models fitting these time series have been estimated and compared. Those models were able to properly fit pendulum data and GNSS data, with standard deviation of residuals smaller than one millimeter. These encouraging results led to the conclusion that GNSS technique can be profitably applied to dam monitoring allowing a denser description, both in space and time, of the dam displacements than the one based on pendulum observations. PMID- 29498645 TI - The Energy Costs of Prematurity and the Neonatal Intensive Care Unit (NICU) Experience. AB - Premature neonates are in an energy deficient state due to (1) oxygen desaturation and hypoxia events, (2) painful and stressful stimuli, (3) illness, and (4) neurodevelopmental energy requirements. Failure to correct energy deficiency in premature infants may lead to adverse effects such as neurodevelopmental delay and negative long-term metabolic and cardiovascular outcomes. The effects of energy dysregulation and the challenges that clinicians in the Neonatal Intensive Care Unit (NICU) face in meeting the premature infant's metabolic demands are discussed. Specifically, the focus is on the effects of pain and stress on energy homeostasis. Energy deficiency is a complex problem and requires a multi-faceted solution to promote optimum development of premature infants. PMID- 29498649 TI - Violent and Non-Violent Criminal Behavior among Young Chinese Drug Users: A Mixed Methods Study. AB - Young drug users are found to be increasingly involved in criminal justice issues. This exploratory and descriptive study aims to analyze the criminal behaviors among young Chinese drug users through a mixed methods research design. Quantitative analysis indicates that young drug users with and without a history of criminality show significant differences in terms of several features. Male drug users, particularly, those who are older, with religious beliefs, and initiated into drug use at younger age were most likely to commit crimes. Among drug users with criminal experiences, those who committed crimes prior to drug initiation have a greater likelihood of committing violent crimes. Furthermore, young drug users with severe depression are more likely to commit crimes, especially violent ones. Qualitative analysis further illustrates that young male drug users often get involved in criminal conduct of the youth gang nature with propensity for engaging in violent crimes as compared to their female counterparts who are more likely to turn into drug dealers and traffickers, in addition to engaging in larceny. The research findings are consistent with developmental theories and "victim to offender cycle". Integrated mental health and substance use services are suggested for crime prevention among young Chinese drug users. PMID- 29498651 TI - Thermogelling 3D Systems towards Stem Cell-Based Tissue Regeneration Therapies. AB - Stem cell culturing and differentiation is a very important research direction for tissue engineering. Thermogels are well suited for encapsulating cells because of their non-biotoxic nature and mild sol-gel transition as temperature increases. In particular, thermogels provide a 3D growth environment for stem cell growth, which is more similar to the extracellular matrix than flat substrates, so thermogels as a medium can overcome many of the cell abnormalities caused by 2D cell growth. In this review, we summarize the applications of thermogels in cell and stem cell culture in recent years. We also elaborate on the methods to induce stem cell differentiation by using thermogel-based 3D scaffolds. In particular, thermogels, encapsulating specific differentiation inducing factor and having specific structures and moduli, can induce the differentiation into the desired tissue cells. Three dimensional thermogel scaffolds that control the growth and differentiation of cells will undoubtedly have a bright future in regenerative medicine. PMID- 29498652 TI - Palladium Supported on Titanium Carbide: A Highly Efficient, Durable, and Recyclable Bifunctional Catalyst for the Transformation of 4-Chlorophenol and 4 Nitrophenol. AB - Developing highly efficient and recyclable catalysts for the transformation of toxic organic contaminates still remains a challenge. Herein, Titanium Carbide (Ti3C2) MXene modified by alkali treatment process was selected as a support (designated as alk-Ti3C2X2, where X represents the surface terminations) for the synthesis of Pd/alk-Ti3C2X2. Results show that the alkali treatment leads to the increase of surface area and surface oxygen-containing groups of Ti3C2X2, thereby facilitating the dispersion and stabilization of Pd species on the surface of alk Ti3C2X2. The Pd/alk-Ti3C2X2 catalyst shows excellent catalytic activity for the hydrodechlorination of 4-chlorophenol and the hydrogenation of 4-nitrophenol in aqueous solution at 25 degrees C and hydrogen balloon pressure. High initial reaction rates of 216.6 and 126.3 min-1. g pd - 1 are observed for the hydrodechlorination of 4-chlorophenol and hydrogenation of 4-nitrophenol, respectively. Most importantly, Pd/alk-Ti3C2X2 exhibits excellent stability and recyclability in both reactions without any promoters. The superior property of Pd/alk-Ti3C2X2 makes it as a potential material for practical applications. PMID- 29498653 TI - A Context-Aware Indoor Air Quality System for Sudden Infant Death Syndrome Prevention. AB - Context-aware monitoring systems designed for e-Health solutions and ambient assisted living (AAL) play an important role in today's personalized health-care services. The majority of these systems are intended for the monitoring of patients' vital signs by means of bio-sensors. At present, there are very few systems that monitor environmental conditions and air quality in the homes of users. A home's environmental conditions can have a significant influence on the state of the health of its residents. Monitoring the environment is the key to preventing possible diseases caused by conditions that do not favor health. This paper presents a context-aware system that monitors air quality to prevent a specific health problem at home. The aim of this system is to reduce the incidence of the Sudden Infant Death Syndrome, which is triggered mainly by environmental factors. In the conducted case study, the system monitored the state of the neonate and the quality of air while it was asleep. The designed proposal is characterized by its low cost and non-intrusive nature. The results are promising. PMID- 29498654 TI - Highly-Bioreactive Silica-Based Mesoporous Bioactive Glasses Enriched with Gallium(III). AB - Beneficial effects in bone cell growth and antibacterial action are currently attributed to Ga3+ ions. Thus, they can be used to upgrade mesoporous bioactive glasses (MBGs), investigated for tissue engineering, whenever they released therapeutic amounts of gallium ions to the surrounding medium. Three gallium enriched MBGs with composition (in mol %) xSiO2-yCaO-zP2O5-5Ga2O3, being x = 70, y = 15, z = 10 for Ga_1; x = 80, y = 12, z = 3 for Ga_2; and x = 80, y = 15, z = 0 for Ga_3, were investigated and compared with the gallium-free 80SiO2-15CaO 5P2O5 MBG (B). 29Si and 31P MAS NMR analyses indicated that Ga3+ acts as network modifier in the glass regions with higher polymerization degree and as network former in the zones with high concentration of classical modifiers (Ca2+ ions). Ga_1 and Ga_2 exhibited a quick in vitro bioactive response because they were coated by an apatite-like layer after 1 and 3 days in simulated body fluid. Although we have not conducted biological tests in this paper (cells or bacteria), Ga_1 released high but non-cytotoxic amounts of Ga3+ ions in Todd Hewitt Broth culture medium that were 140 times higher than the IC90 of Pseudomonas aeruginosa bacteria, demonstrating its potential for tissue engineering applications. PMID- 29498655 TI - Quantitative 1H-NMR Spectroscopy for Profiling Primary Metabolites in Mulberry Leaves. AB - The primary metabolites in aqueous extract of mulberry (Morus alba L.) leaves were characterized by using proton nuclear magnetic resonance (1H-NMR) spectroscopy. With the convenience of resonance assignment, GABA together with the other 10 primary metabolites was simultaneously identified and quantified in one 1H-NMR spectrum. In this study, external calibration curves for metabolites were employed to calculate the concentrations of interests. The proposed quantitative approach was demonstrated with good linearity (r2 ranged in the interval of 0.9965-0.9999), precision, repeatability, stability (RSD values in the ranges of 0.35-4.89%, 0.77-7.13% and 0.28-2.33%, respectively) and accuracy (recovery rates from 89.2% to 118.5%). The established 1H-NMR method was then successfully applied to quantify 11 primary metabolites in mulberry leaves from different geographical regions within a rapid analysis time and a simple sample preparation procedure. PMID- 29498656 TI - Immobilization of Polyoxometalates on Tailored Polymeric Surfaces. AB - Herein we describe the preparation of hybrid polymer-inorganic interfaces by the immobilization of polyoxometalate nanoclusters on functionalized polymer surfaces. The polymeric surfaces were made of polystyrene-b-poly(acrylic acid)/polystyrene (PS-b-PAA/PS) blends by spin coating on a silicon wafer. The functionalization of the polymer film was obtained by interfacial migration of the amphiphilic block copolymer toward the interface upon water vapor annealing. The carboxylic acid functional groups contained in the PAA block were then employed to anchor the [LnIII(alpha-SiW11O39)]5- polyoxometalates (Ln: Ce, Er). This purpose was achieved by immersing the films in aqueous solutions of the in situ-formed inorganic nanoclusters. X-ray photoelectron and confocal Raman spectroscopies, together with atomic force microscopy, confirmed the immobilization of the inorganic species at the interface. PMID- 29498657 TI - Dietary Magnesium Intake and Hyperuricemia among US Adults. AB - To assess the association between dietary magnesium intake and hyperuricemia in United States (US) adults, we extracted 26,796 US adults aged 20-85 years from the National Health and Nutrition Examination Survey (NHANES) in 2001-2014. All dietary intake was measured through 24 h dietary recall method. Multivariable logistic regression analysis was performed to investigate the association between magnesium intake and hyperuricemia after adjusting for several important confounding variables. When compared to the lowest quintile (Q1), for male, adjusted odds ratios (ORs) of hyperuricemia in the second quintile (Q2) to the fifth quintile (Q5) of the magnesium intake were 0.83 (95% CI: 0.72-0.95), 0.74 (0.64-0.85), 0.78 (0.67-0.90), and 0.70 (0.58-0.84, p for trend = 0.0003), respectively. For female, OR was 0.75 (0.62-0.90) in the fourth quintile (Q4) (p for trend = 0.0242). As compared to Q4 of magnesium intake (contains recommended amount), the relative odds of hyperuricemia were increased by 1.29 times in Q1 (OR = 1.29, 1.11-1.50) in male. The ORs were 1.33 (1.11-1.61) in Q1, 1.27 (1.07 1.50) in Q2 in female. Our results indicated that increased magnesium intake was associated with decreased hyperuricemia risk. It also indicated the importance of recommended dietary allowance (RDA) of magnesium and the potential function of magnesium intake in the prevention of hyperuricemia. PMID- 29498658 TI - Enzyme Kinetics and Molecular Docking Studies on Cytochrome 2B6, 2C19, 2E1, and 3A4 Activities by Sauchinone. AB - Sauchinone, an active lignan isolated from the aerial parts of Saururus chinensis (Saururaceae), exhibits anti-inflammatory, anti-obesity, anti-hyperglycemic, and anti-hepatic steatosis effects. As herb-drug interaction (HDI) through cytochrome P450s (CYPs)-mediated metabolism limits clinical application of herbs and drugs in combination, this study sought to explore the enzyme kinetics of sauchinone towards CYP inhibition in in vitro human liver microsomes (HLMs) and in vivo mice studies and computational molecular docking analysis. In in vitro HLMs, sauchinone reversibly inhibited CYP2B6, 2C19, 2E1, and 3A4 activities in non competitive modes, showing inhibition constant (Ki) values of 14.3, 16.8, 41.7, and 6.84 MUM, respectively. Also, sauchinone time-dependently inhibited CYP2B6, 2E1 and 3A4 activities in vitro HLMs. Molecular docking study showed that sauchinone could be bound to a few key amino acid residues in the active site of CYP2B6, 2C19, 2E1, and 3A4. When sibutramine, clopidogrel, or chlorzoxazone was co-administered with sauchinone to mice, the systemic exposure of each drug was increased compared to that without sauchinone, because sauchinone reduced the metabolic clearance of each drug. In conclusion, when sauchinone was co-treated with drugs metabolized via CYP2B6, 2C19, 2E1, or 3A4, sauchinone-drug interactions occurred because sauchinone inhibited the CYP-mediated metabolic activities. PMID- 29498660 TI - Synthetic Lignan Secoisolariciresinol Diglucoside (LGM2605) Reduces Asbestos Induced Cytotoxicity in an Nrf2-Dependent and -Independent Manner. AB - Asbestos exposure triggers inflammatory processes associated with oxidative stress and tissue damage linked to malignancy. LGM2605 is the synthetic lignan secoisolariciresinol diglucoside (SDG) with free radical scavenging, antioxidant, and anti-inflammatory properties in diverse inflammatory cell and mouse models, including exposure to asbestos fibers. Nuclear factor-E2 related factor 2 (Nrf2) activation and boosting of endogenous tissue defenses were associated with the protective action of LGM2605 from asbestos-induced cellular damage. To elucidate the role of Nrf2 induction by LGM2605 in protection from asbestos-induced cellular damage, we evaluated LGM2605 in asbestos-exposed macrophages from wild type (WT) and Nrf2 disrupted (Nrf2-/-) mice. Cells were pretreated with LGM2605 (50 uM and 100 uM) and exposed to asbestos fibers (20 ug/cm2) and evaluated 8 h and 24 h later for inflammasome activation, secreted cytokine levels (interleukin 1beta (IL-1beta), interleukin-18 (IL-18), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNFalpha)), cytotoxicity and cell death, nitrosative stress, and Nrf2-regulated enzyme levels. Asbestos exposure induced robust oxidative and nitrosative stress, cell death and cytotoxicity, which were equally mitigated by LGM2605. Inflammasome activation was significantly attenuated in Nrf2-/- macrophages compared to WT, and the protective action of LGM2605 was seen only in WT cells. In conclusion, in a cell model of asbestos-induced toxicity, LGM2605 acts via protective mechanisms that may not involve Nrf2 activation. PMID- 29498659 TI - Investigation of an 18F-labelled Imidazopyridotriazine for Molecular Imaging of Cyclic Nucleotide Phosphodiesterase 2A. AB - Specific radioligands for in vivo visualization and quantification of cyclic nucleotide phosphodiesterase 2A (PDE2A) by positron emission tomography (PET) are increasingly gaining interest in brain research. Herein we describe the synthesis, the 18F-labelling as well as the biological evaluation of our latest PDE2A (radio-)ligand 9-(5-Butoxy-2-fluorophenyl)-2-(2-([18F])fluoroethoxy)-7 methylimidazo[5,1-c]pyrido[2,3-e][1,2,4]triazine (([18F])TA5). It is the most potent PDE2A ligand out of our series of imidazopyridotriazine-based derivatives so far (IC50 hPDE2A = 3.0 nM; IC50 hPDE10A > 1000 nM). Radiolabelling was performed in a one-step procedure starting from the corresponding tosylate precursor. In vitro autoradiography on rat and pig brain slices displayed a homogenous and non-specific binding of the radioligand. Investigation of stability in vivo by reversed-phase HPLC (RP-HPLC) and micellar liquid chromatography (MLC) analyses of plasma and brain samples obtained from mice revealed a high fraction of one main radiometabolite. Hence, we concluded that [18F]TA5 is not appropriate for molecular imaging of PDE2A neither in vitro nor in vivo. Our ongoing work is focusing on further structurally modified compounds with enhanced metabolic stability. PMID- 29498661 TI - The Regulatory Role of MeAIB in Protein Metabolism and the mTOR Signaling Pathway in Porcine Enterocytes. AB - Amino acid transporters play an important role in cell growth and metabolism. MeAIB, a transporter-selective substrate, often represses the adaptive regulation of sodium-coupled neutral amino acid transporter 2 (SNAT2), which may act as a receptor and regulate cellular amino acid contents, therefore modulating cellular downstream signaling. The aim of this study was to investigate the effects of MeAIB to SNAT2 on cell proliferation, protein turnover, and the mammalian target of rapamycin (mTOR) signaling pathway in porcine enterocytes. Intestinal porcine epithelial cells (IPEC)-J2 cells were cultured in a high-glucose Dulbecco's modified Eagle's (DMEM-H) medium with 0 or 5 mmoL/L System A amino acid analogue (MeAIB) for 48 h. Cells were collected for analysis of proliferation, cell cycle, protein synthesis and degradation, intracellular free amino acids, and the expression of key genes involved in the mTOR signaling pathway. The results showed that SNAT2 inhibition by MeAIB depleted intracellular concentrations of not only SNAT2 amino acid substrates but also of indispensable amino acids (methionine and leucine), and suppressed cell proliferation and impaired protein synthesis. MeAIB inhibited mTOR phosphorylation, which might be involved in three translation regulators, EIF4EBP1, IGFBP3, and DDIT4 from PCR array analysis of the 84 genes related to the mTOR signaling pathway. These results suggest that SNAT2 inhibition treated with MeAIB plays an important role in regulating protein synthesis and mTOR signaling, and provide some information to further clarify its roles in the absorption of amino acids and signal transduction in the porcine small intestine. PMID- 29498663 TI - Capsaicin and Piperine Can Overcome Multidrug Resistance in Cancer Cells to Doxorubicin. AB - BACKGROUND: Multidrug resistance (MDR) can develop in cancer cells after treatment with anticancer drugs, mainly due to the overexpression of the ATP binding cassette (ABC) transporters. We analyzed the ability of two pungent tasting alkaloids-capsaicin and piperine from Capsicum frutescens and Piper nigrum, respectively-to reverse multidrug resistance in the cancer cell lines Caco-2 and CEM/ADR 5000, which overexpress P-glycoprotein (P-gp) and other ABC transporters. METHODS: The MTT assay was first used to determine the cytotoxicity of doxorubicin, the alkaloids, and digitonin alone, and then their combinations. Furthermore, rhodamine (Rho) 123 and calcein-AM were used to detect the effects of alkaloids on the activity of P-gp. RESULTS: Capsaicin and piperine synergistically enhanced the cytotoxicity of doxorubicin in Caco-2 and CEM/ADR 5000 cells. Furthermore, capsaicin and piperine increased the intracellular accumulation of the fluorescent P-glycoprotein (P-gp) substrates rhodamine and calcein and inhibited their efflux from the MDR cell lines. CONCLUSION: Our study has demonstrated that capsaicin and piperine are P-gp substrates and have potential chemosensitizing activity, which might be interesting for the development of novel modulators of multidrug resistance. PMID- 29498662 TI - Wnt Signalling in Intestinal Stem Cells: Lessons from Mice and Flies. AB - Adult stem cells play critical roles in the basal maintenance of tissue integrity, also known as homeostasis, and in tissue regeneration following damage. The highly conserved Wnt signalling pathway is a key regulator of stem cell fate. In the gastrointestinal tract, Wnt signalling activation drives homeostasis and damage-induced repair. Additionally, deregulated Wnt signalling is a common hallmark of age-associated tissue dysfunction and cancer. Studies using mouse and fruit fly models have greatly improved our understanding of the functional contribution of the Wnt signalling pathway in adult intestinal biology. Here, we summarize the latest knowledge acquired from mouse and Drosophila research regarding canonical Wnt signalling and its key functions during stem cell driven intestinal homeostasis, regeneration, ageing and cancer. PMID- 29498664 TI - Calixarenes as High Temperature Matrices for Thermally Activated Delayed Fluorescence: C70 in Dihomooxacalix[4]arene. AB - Thermally activated delayed fluorescence (TADF) of 12C70 and 13C70 was observed up to 140 degrees C in a p-tert-butyldihomooxacalix[4]arene solid matrix, a temperature range significantly higher than that of previous TADF quantitative studies. An effective singlet-triplet energy gap of 29 kJ/mol and triplet formation quantum yields of 0.97 and 0.99 were measured for 12C70 and 13C70, respectively. The photophysical properties of the two fullerenes in this new matrix are comparable to those obtained in polystyrene at a lower temperature range. Calixarenes are proposed to be suitable matrices for high temperature TADF studies and applications. PMID- 29498665 TI - Molecular Reactivity and Absorption Properties of Melanoidin Blue-G1 through Conceptual DFT. AB - This computational study presents the assessment of eleven density functionals that include CAM-B3LYP, LC-wPBE, M11, M11L, MN12L, MN12SX, N12, N12SX, wB97, wB97X and wB97XD related to the Def2TZVP basis sets together with the Solvation Model Density (SMD) solvation model in calculating the molecular properties and structure of the Blue-G1 intermediate melanoidin pigment. The chemical reactivity descriptors for the system are calculated via the conceptual Density Functional Theory (DFT). The choice of the active sites related to the nucleophilic, electrophilic, as well as radical attacks is made by linking them with the Fukui function indices, the electrophilic Parr functions and the condensed dual descriptor Delta f ( r ) . The prediction of the maximum absorption wavelength tends to be considerably accurate relative to its experimental value. The study found the MN12SX and N12SX density functionals to be the most appropriate density functionals in predicting the chemical reactivity of the studied molecule. PMID- 29498666 TI - The High-Throughput Analyses Era: Are We Ready for the Data Struggle? AB - Recent and rapid technological advances in molecular sciences have dramatically increased the ability to carry out high-throughput studies characterized by big data production. This, in turn, led to the consequent negative effect of highlighting the presence of a gap between data yield and their analysis. Indeed, big data management is becoming an increasingly important aspect of many fields of molecular research including the study of human diseases. Now, the challenge is to identify, within the huge amount of data obtained, that which is of clinical relevance. In this context, issues related to data interpretation, sharing and storage need to be assessed and standardized. Once this is achieved, the integration of data from different -omic approaches will improve the diagnosis, monitoring and therapy of diseases by allowing the identification of novel, potentially actionably biomarkers in view of personalized medicine. PMID- 29498667 TI - Long-Term Melatonin Therapy for Adolescents and Young Adults with Chronic Sleep Onset Insomnia and Late Melatonin Onset: Evaluation of Sleep Quality, Chronotype, and Lifestyle Factors Compared to Age-Related Randomly Selected Population Cohorts. AB - The extent of continuance of melatonin therapy initiated in pre-pubertal children with chronic sleep onset insomnia (CSOI) was investigated in young adult life. Sleep timing, sleep quality, adverse events, reasons for cessation of therapy, and patient characteristics with regard to therapy regimen, chronotype and lifestyle factors possibly influencing sleeping behavior were assessed. With an online survey using questionnaires (Pittsburgh Sleep Quality Index, Insomnia Severity Index, Morningness-Eveningness Questionnaire, and Munich Chronotype Questionnaire), outcomes were measured and compared with age-related controls. These controls were extracted from published epidemiological research programs applying the same questionnaires. At the moment of the survey, melatonin was still continued by 27.3% of the patients, with a mean treatment duration of 10.8 years. The overall average treatment duration was 7.1 years. Sleep quality of both discontinued and persistent melatonin users did not deviate from controls. Sleep timing and chronotype scores indicated evening type preference in all responders. Adverse events were scarce but the perceived timing of pubertal development suggested a tendency towards delayed puberty in former and current users of melatonin. This study may underestimate the number of children that are able to stop using melatonin due to the response rate (47.8%) and appeal for continuing users. Sleep timing parameters were based on self-reported estimates. Control populations were predominantly students and were of varying nationalities. The statistical power of this study is low due to the limited sample size. Melatonin therapy sustained for 7.1 years does not result in substantial deviations of sleep quality as compared to controls and appears to be safe. The evening type preference suggests a causal relation with CSOI. This study shows that ten years after initiation of treatment with melatonin for CSOI, approximately 75% of the patients will have normal sleep quality without medication. PMID- 29498668 TI - Investigations on Structural, Optical and X-Radiation Responsive Properties of a Se Thin Films Fabricated by Thermal Evaporation Method at Low Vacuum Degree. AB - Amorphous selenium (a-Se) thin films with a thickness of 1200 nm were successfully fabricated by thermal evaporation at a low vacuum degree of 10-2 Pa. The structural properties involving phase and morphology showed that a-Se thin films could be resistant to 60 degrees C in air. Also, a transformation to polycrystalline Selenium (p-Se) was shown as the annealing temperature rose to 62 degrees C and 65 degrees C, with obvious changes in color and surface morphology. Moreover, as the a-Se transformed to p-Se, the samples' transmittance decreased significantly, and the band gap declined dramatically from 2.15 eV to 1.92 eV. Finally, the X-radiation response of a-Se was investigated as an important property, revealing there is a remarkable response speed of photogeneration current both X-ray on and X-ray off, with a requirement of only a very small electrical field. PMID- 29498669 TI - Using PDX for Preclinical Cancer Drug Discovery: The Evolving Field. AB - The ability to create patient derived xenografts (PDXs) has evolved considerably from the breakthrough of the development of immune compromised mice. How researchers in drug discovery have utilized PDX of certain cancer types has also changed from traditionally selecting a few models to profile a drug, to opting to assess inter-tumor response heterogeneity by screening across a broad range of tumor models, and subsequently to enable clinical stratification strategies. As with all models and methodologies, imperfections with this approach are apparent, and our understanding of the fidelity of these models continues to expand. To date though, they are still viewed as one of the most faithful modeling systems in oncology. Currently, there are many efforts ongoing to increase the utility and translatability of PDXs, including introducing a human immune component to enable immunotherapy studies. PMID- 29498670 TI - Microbiological Sensing Technologies: A Review. AB - Microorganisms have a significant influence on human activities and health, and consequently, there is high demand to develop automated, sensitive, and rapid methods for their detection. These methods might be applicable for clinical, industrial, and environmental applications. Although different techniques have been suggested and employed for the detection of microorganisms, and the majority of these methods are not cost effective and suffer from low sensitivity and low specificity, especially in mixed samples. This paper presents a comprehensive review of microbiological techniques and associated challenges for bioengineering researchers with an engineering background. Also, this paper reports on recent technological advances and their future prospects for a variety of microbiological applications. PMID- 29498671 TI - The Application of Gene Expression Profiling in Predictions of Occult Lymph Node Metastasis in Colorectal Cancer Patients. AB - A key factor in determining the likely outcome for a patient with colorectal cancer is whether or not the tumour has metastasised to the lymph nodes information which is also important in assessing any possibilities of lymph node resection so as to improve survival. In this review we perform a wide-range assessment of literature relating to recent developments in gene expression profiling (GEP) of the primary tumour, to determine their utility in assessing node status. A set of characteristic genes seems to be involved in the prediction of lymph node metastasis (LNM) in colorectal patients. Hence, GEP is applicable in personalised/individualised/tailored therapies and provides insights into developing novel therapeutic targets. Not only is GEP useful in prediction of LNM, but it also allows classification based on differences such as sample size, target gene expression, and examination method. PMID- 29498672 TI - Comparative Transcriptome Profiling of Rice Near-Isogenic Line Carrying Xa23 under Infection of Xanthomonas oryzae pv. oryzae. AB - Bacterial blight, caused by Xanthomonas oryzae pv. oryzae (Xoo), is an overwhelming disease in rice-growing regions worldwide. Our previous studies revealed that the executor R gene Xa23 confers broad-spectrum disease resistance to all naturally occurring biotypes of Xoo. In this study, comparative transcriptomic profiling of two near-isogenic lines (NILs), CBB23 (harboring Xa23) and JG30 (without Xa23), before and after infection of the Xoo strain, PXO99A, was done by RNA sequencing, to identify genes associated with the resistance. After high throughput sequencing, 1645 differentially expressed genes (DEGs) were identified between CBB23 and JG30 at different time points. Gene Ontlogy (GO) analysis categorized the DEGs into biological process, molecular function, and cellular component. KEGG analysis categorized the DEGs into different pathways, and phenylpropanoid biosynthesis was the most prominent pathway, followed by biosynthesis of plant hormones, flavonoid biosynthesis, and glycolysis/gluconeogenesis. Further analysis led to the identification of differentially expressed transcription factors (TFs) and different kinase responsive genes in CBB23, than that in JG30. Besides TFs and kinase responsive genes, DEGs related to ethylene, jasmonic acid, and secondary metabolites were also identified in both genotypes after PXO99A infection. The data of DEGs are a precious resource for further clarifying the network of Xa23-mediated resistance. PMID- 29498674 TI - Molecular Evolution of Chloroplast Genomes of Orchid Species: Insights into Phylogenetic Relationship and Adaptive Evolution. AB - Orchidaceae is the 3rd largest family of angiosperms, an evolved young branch of monocotyledons. This family contains a number of economically-important horticulture and flowering plants. However, the limited availability of genomic information largely hindered the study of molecular evolution and phylogeny of Orchidaceae. In this study, we determined the evolutionary characteristics of whole chloroplast (cp) genomes and the phylogenetic relationships of the family Orchidaceae. We firstly characterized the cp genomes of four orchid species: Cremastra appendiculata, Calanthe davidii, Epipactis mairei, and Platanthera japonica. The size of the chloroplast genome ranged from 153,629 bp (C. davidi) to 160,427 bp (E. mairei). The gene order, GC content, and gene compositions are similar to those of other previously-reported angiosperms. We identified that the genes of ndhC, ndhI, and ndhK were lost in C. appendiculata, in that the ndh I gene was lost in P. japonica and E. mairei. In addition, the four types of repeats (forward, palindromic, reverse, and complement repeats) were examined in orchid species. E. mairei had the highest number of repeats (81), while C. davidii had the lowest number (57). The total number of Simple Sequence Repeats is at least 50 in C. davidii, and, at most, 78 in P. japonica. Interestingly, we identified 16 genes with positive selection sites (the psbH, petD, petL, rpl22, rpl32, rpoC1, rpoC2, rps12, rps15, rps16, accD, ccsA, rbcL, ycf1, ycf2, and ycf4 genes), which might play an important role in the orchid species' adaptation to diverse environments. Additionally, 11 mutational hotspot regions were determined, including five non-coding regions (ndhB intron, ccsA-ndhD, rpl33 rps18, ndhE-ndhG, and ndhF-rpl32) and six coding regions (rps16, ndhC, rpl32, ndhI, ndhK, and ndhF). The phylogenetic analysis based on whole cp genomes showed that C. appendiculata was closely related to C. striata var. vreelandii, while C. davidii and C. triplicate formed a small monophyletic evolutionary clade with a high bootstrap support. In addition, five subfamilies of Orchidaceae, Apostasioideae, Cypripedioideae, Epidendroideae, Orchidoideae, and Vanilloideae, formed a nested evolutionary relationship in the phylogenetic tree. These results provide important insights into the adaptive evolution and phylogeny of Orchidaceae. PMID- 29498673 TI - Regulation of TNF-Related Apoptosis-Inducing Ligand Signaling by Glycosylation. AB - Tumor necrosis-factor related apoptosis-inducing ligand, also known as TRAIL or APO2L (Apo-2 ligand), is a cytokine of the TNF superfamily acknowledged for its ability to trigger selective apoptosis in tumor cells while being relatively safe towards normal cells. Its binding to its cognate agonist receptors, namely death receptor 4 (DR4) and/or DR5, can induce the formation of a membrane-bound macromolecular complex, coined DISC (death-signaling inducing complex), necessary and sufficient to engage the apoptotic machinery. At the very proximal level, TRAIL DISC formation and activation of apoptosis is regulated both by antagonist receptors and by glycosylation. Remarkably, though, despite the fact that all membrane-bound TRAIL receptors harbor putative glycosylation sites, only pro apoptotic signaling through DR4 and DR5 has, so far, been found to be regulated by N- and O-glycosylation, respectively. Because putative N-glycosylation sequons and O-glycosylation sites are also found and conserved in all these receptors throughout all animal species (in which these receptors have been identified), glycosylation is likely to play a more prominent role than anticipated in regulating receptor/receptor interactions or trafficking, ultimately defining cell fate through TRAIL stimulation. This review aims to present and discuss these emerging concepts, the comprehension of which is likely to lead to innovative anticancer therapies. PMID- 29498675 TI - Impact of Supplemental Oxygen on Obstructive Sleep Apnea of Infants. AB - Treatment options may be limited for infants with obstructive sleep apnea when there is no surgically correctable upper airway lesion. We therefore evaluated, retrospectively, the efficacy of low-flow oxygen as a therapeutic option for infant obstructive sleep apnea. We reviewed the medical charts of 23 infants who had undergone a therapeutic trial of low-flow oxygen during polysomnography. Split-night polysomnography was used in 21/23 subjects while 2/23 had undergone two separate, full-night polysomnography sleep architecture and respiratory findings on the baseline polysomnogram segment that was obtained in room air were compared with the segment on low-flow oxygen (0.25-1 L/min). Wilcoxon signed rank or McNemar's test were used as indicated for comparing apnea hypopnea index and measures of sleep architecture at baseline and with oxygen therapy. The mean (+/ SD) age of subjects was 4.8 (+/-2.7) months, with 52% being males. The median apnea hypopnea index fell from a baseline of 18 (range 7-43) to 3 (range 1-19; p = 0.001) on oxygen. The baseline median obstructive/mixed apnea index decreased from 2 (range 1-16) to 1 during oxygen therapy (range 0-1; p = 0.003). Additionally, a significant decrease in central apnea index (median interquartile range (IQR) 1 (0-2) vs. 0 (0-1), p = 0.002) was noted. Sleep efficiency remained unaffected, while O2 saturation (SaO2) average and SaO2 nadir improved on oxygen. We were able to confirm the utility of low-flow oxygen in reducing central, obstructive, and mixed apneas and improving average oxygen saturation in infants with obstructive sleep apnea (OSA). PMID- 29498677 TI - Real-Time Dynamic Observation of Micro-Friction on the Contact Interface of Friction Lining. AB - This paper aims to investigate the microscopic friction mechanism based on in situ microscopic observation in order to record the deformation and contact situation of friction lining during the frictional process. The results show that friction coefficient increased with the shear deformation and energy loss of the surfacee, respectively. Furthermore, the friction mechanism mainly included adhesive friction in the high-pressure and high-speed conditions, whereas hysteresis friction was in the low-pressure and low-speed conditions. The mixed friction mechanism was in the period when the working conditions varied from high pressure and speed to low pressure and speed. PMID- 29498676 TI - Lipid-Coated Zinc Oxide Nanoparticles as Innovative ROS-Generators for Photodynamic Therapy in Cancer Cells. AB - In the present paper, we use zinc oxide nanoparticles under the excitation of ultraviolet (UV) light for the generation of Reactive Oxygen Species (ROS), with the aim of further using these species for fighting cancer cells in vitro. Owing to the difficulties in obtaining highly dispersed nanoparticles (NPs) in biological media, we propose their coating with a double-lipidic layer and we evaluate their colloidal stability in comparison to the pristine zinc oxide NPs. Then, using Electron Paramagnetic Resonance (EPR) coupled with the spin-trapping technique, we demonstrate and characterize the ability of bare and lipid-coated ZnO NPs to generate ROS in water only when remotely actuated via UV light irradiation. Interestingly, our results reveal that the surface chemistry of the NPs greatly influences the type of photo-generated ROS. Finally, we show that lipid-coated ZnO NPs are effectively internalized inside human epithelial carcinoma cells (HeLa) via a lysosomal pathway and that they can generate ROS inside cancer cells, leading to enhanced cell death. The results are promising for the development of ZnO-based therapeutic systems. PMID- 29498678 TI - Isolation and Purification of Two Isoflavones from Hericium erinaceum Mycelium by High-Speed Counter-Current Chromatography. AB - High-speed counter-current chromatography (HSCCC) was used to separate and purify two isoflavones for the first time from Hericium erinaceum (H. erinaceum) mycelium using a two-phase solvent system composed of chloroform-dichloromethane methanol-water (4:2:3:2, v/v/v/v). These two isoflavones were identified as genistein (4',5,7-trihydroxyisoflavone, C15H10O5) and daidzein (4',7 dihydroxyisoflavone, C15H10O4), using infrared spectroscopy (IR), electro-spary ionisation mass (ESI-MS), 1H-nuclear magnetic resonance (NMR) and 13C-NMR spectra. About 23 mg genistein with 95.7% purity and 18 mg daidzein with 97.3% purity were isolated from 150 mg ethanolic extract of H. erinaceum mycelium. The results demonstrated that HSCCC was a feasible method to separate and purify genistein and daidzein from H. erinaceum mycelium. PMID- 29498680 TI - A Semi-Supervised Learning Algorithm for Predicting Four Types MiRNA-Disease Associations by Mutual Information in a Heterogeneous Network. AB - Increasing evidence suggests that dysregulation of microRNAs (miRNAs) may lead to a variety of diseases. Therefore, identifying disease-related miRNAs is a crucial problem. Currently, many computational approaches have been proposed to predict binary miRNA-disease associations. In this study, in order to predict underlying miRNA-disease association types, a semi-supervised model called the network-based label propagation algorithm is proposed to infer multiple types of miRNA-disease associations (NLPMMDA) by mutual information derived from the heterogeneous network. The NLPMMDA method integrates disease semantic similarity, miRNA functional similarity, and Gaussian interaction profile kernel similarity information of miRNAs and diseases to construct a heterogeneous network. NLPMMDA is a semi-supervised model which does not require verified negative samples. Leave-one-out cross validation (LOOCV) was implemented for four known types of miRNA-disease associations and demonstrated the reliable performance of our method. Moreover, case studies of lung cancer and breast cancer confirmed effective performance of NLPMMDA to predict novel miRNA-disease associations and their association types. PMID- 29498681 TI - TrkB-Target Galectin-1 Impairs Immune Activation and Radiation Responses in Neuroblastoma: Implications for Tumour Therapy. AB - Galectin-1 (Gal-1) has been described to promote tumour growth by inducing angiogenesis and to contribute to the tumour immune escape. We had previously identified up-regulation of Gal-1 in preclinical models of aggressive neuroblastoma (NB), the most common extracranial tumour of childhood. While Gal-1 did not confer a survival advantage in the absence of exogenous stressors, Gal-1 contributed to enhanced cell migratory and invasive properties. Here, we review these findings and extend them by analyzing Gal-1 mediated effects on immune cell regulation and radiation resistance. In line with previous results, cell autonomous effects as well as paracrine functions contribute to Gal-1 mediated pro-tumourigenic functions. Interfering with Gal-1 functions in vivo will add to a better understanding of the role of the Gal-1 axis in the complex tumour-host interaction during immune-, chemo- and radiotherapy of neuroblastoma. PMID- 29498682 TI - Empathy Variation in General Practice: A Survey among General Practitioners in Denmark. AB - Background: Previous studies have demonstrated that high levels of physician empathy may be correlated with improved patient health outcomes and high physician job satisfaction. Knowledge about variation in empathy and related general practitioner (GP) characteristics may allow for a more informed approach to improve empathy among GPs. Objective: Our objective is to measure and analyze variation in physician empathy and its association with GP demographic, professional, and job satisfaction characteristics. Methods: 464 Danish GPs responded to a survey containing the Danish version of the Jefferson Scale of Empathy for Health Professionals (JSE-HP) and questions related to their demographic, professional and job satisfaction characteristics. Descriptive statistics and a quantile plot of the ordered empathy scores were used to describe empathy variation. In addition, random-effect logistic regression analysis was performed to explore the association between empathy levels and the included GP characteristics. Results: Empathy scores were negatively skewed with a mean score of 117.9 and a standard deviation of 10.1 within a range from 99 (p5) to 135 (p95). GPs aged 45-54 years and GPs who are not employed outside of their practice were less likely to have high empathy scores (>=120). Neither gender, nor length of time since specialization, length of time in current practice, practice type, practice location, or job satisfaction was associated with odds of having high physician empathy. However, odds of having a high empathy score were higher for GPs who stated that the physician-patient relationship and interaction with colleagues has a high contribution to job satisfaction compared to the reference groups (low and medium contribution of these factors). This was also the trend for GPs who stated a high contribution to job satisfaction from intellectual stimulation. In contrast, high contribution of economic profit and prestige did not contribute to increased odds of having a high empathy score. Conclusions: Albeit generally high, we observed substantial variation in physician empathy levels among this population of Danish GPs. This variation is positively associated with values of interpersonal relationships and interaction with colleagues, and negatively associated with middle age (45-54 years) and lack of outside employment. There is room to increase GP physician empathy via educational and organizational interventions, and consequently, to improve healthcare quality and outcomes. PMID- 29498683 TI - A Modified Distributed Bees Algorithm for Multi-Sensor Task Allocation. AB - Multi-sensor systems can play an important role in monitoring tasks and detecting targets. However, real-time allocation of heterogeneous sensors to dynamic targets/tasks that are unknown a priori in their locations and priorities is a challenge. This paper presents a Modified Distributed Bees Algorithm (MDBA) that is developed to allocate stationary heterogeneous sensors to upcoming unknown tasks using a decentralized, swarm intelligence approach to minimize the task detection times. Sensors are allocated to tasks based on sensors' performance, tasks' priorities, and the distances of the sensors from the locations where the tasks are being executed. The algorithm was compared to a Distributed Bees Algorithm (DBA), a Bees System, and two common multi-sensor algorithms, market based and greedy-based algorithms, which were fitted for the specific task. Simulation analyses revealed that MDBA achieved statistically significant improved performance by 7% with respect to DBA as the second-best algorithm, and by 19% with respect to Greedy algorithm, which was the worst, thus indicating its fitness to provide solutions for heterogeneous multi-sensor systems. PMID- 29498679 TI - Modes of Interaction of KMT2 Histone H3 Lysine 4 Methyltransferase/COMPASS Complexes with Chromatin. AB - Regulation of gene expression is achieved by sequence-specific transcriptional regulators, which convey the information that is contained in the sequence of DNA into RNA polymerase activity. This is achieved by the recruitment of transcriptional co-factors. One of the consequences of co-factor recruitment is the control of specific properties of nucleosomes, the basic units of chromatin, and their protein components, the core histones. The main principles are to regulate the position and the characteristics of nucleosomes. The latter includes modulating the composition of core histones and their variants that are integrated into nucleosomes, and the post-translational modification of these histones referred to as histone marks. One of these marks is the methylation of lysine 4 of the core histone H3 (H3K4). While mono-methylation of H3K4 (H3K4me1) is located preferentially at active enhancers, tri-methylation (H3K4me3) is a mark found at open and potentially active promoters. Thus, H3K4 methylation is typically associated with gene transcription. The class 2 lysine methyltransferases (KMTs) are the main enzymes that methylate H3K4. KMT2 enzymes function in complexes that contain a necessary core complex composed of WDR5, RBBP5, ASH2L, and DPY30, the so-called WRAD complex. Here we discuss recent findings that try to elucidate the important question of how KMT2 complexes are recruited to specific sites on chromatin. This is embedded into short overviews of the biological functions of KMT2 complexes and the consequences of H3K4 methylation. PMID- 29498684 TI - A Lightweight RFID Mutual Authentication Protocol Based on Physical Unclonable Function. AB - With the fast development of the Internet of Things, Radio Frequency Identification (RFID) has been widely applied into many areas. Nevertheless, security problems of the RFID technology are also gradually exposed, when it provides life convenience. In particular, the appearance of a large number of fake and counterfeit goods has caused massive loss for both producers and customers, for which the clone tag is a serious security threat. If attackers acquire the complete information of a tag, they can then obtain the unique identifier of the tag by some technological means. In general, because there is no extra identifier of a tag, it is difficult to distinguish an original tag and its clone one. Once the legal tag data is obtained, attackers can be able to clone this tag. Therefore, this paper shows an efficient RFID mutual verification protocol. This protocol is based on the Physical Unclonable Function (PUF) and the lightweight cryptography to achieve efficient verification of a single tag. The protocol includes three process: tag recognition, mutual verification and update. The tag recognition is that the reader recognizes the tag; mutual verification is that the reader and tag mutually verify the authenticity of each other; update is supposed to maintain the latest secret key for the following verification. Analysis results show that this protocol has a good balance between performance and security. PMID- 29498685 TI - Nonlinear Errors Resulting from Ghost Reflection and Its Coupling with Optical Mixing in Heterodyne Laser Interferometers. AB - Even after the Heydemann correction, residual nonlinear errors, ranging from hundreds of picometers to several nanometers, are still found in heterodyne laser interferometers. This is a crucial factor impeding the realization of picometer level metrology, but its source and mechanism have barely been investigated. To study this problem, a novel nonlinear model based on optical mixing and coupling with ghost reflection is proposed and then verified by experiments. After intense investigation of this new model's influence, results indicate that new additional high-order and negative-order nonlinear harmonics, arising from ghost reflection and its coupling with optical mixing, have only a negligible contribution to the overall nonlinear error. In real applications, any effect on the Lissajous trajectory might be invisible due to the small ghost reflectance. However, even a tiny ghost reflection can significantly worsen the effectiveness of the Heydemann correction, or even make this correction completely ineffective, i.e., compensation makes the error larger rather than smaller. Moreover, the residual nonlinear error after correction is dominated only by ghost reflectance. PMID- 29498686 TI - A Three-Step Resolution-Reconfigurable Hazardous Multi-Gas Sensor Interface for Wireless Air-Quality Monitoring Applications. AB - This paper presents a resolution-reconfigurable wide-range resistive sensor readout interface for wireless multi-gas monitoring applications that displays results on a smartphone. Three types of sensing resolutions were selected to minimize processing power consumption, and a dual-mode front-end structure was proposed to support the detection of a variety of hazardous gases with wide range of characteristic resistance. The readout integrated circuit (ROIC) was fabricated in a 0.18 MUm CMOS process to provide three reconfigurable data conversions that correspond to a low-power resistance-to-digital converter (RDC), a 12-bit successive approximation register (SAR) analog-to-digital converter (ADC), and a 16-bit delta-sigma modulator. For functional feasibility, a wireless sensor system prototype that included in-house microelectromechanical (MEMS) sensing devices and commercial device products was manufactured and experimentally verified to detect a variety of hazardous gases. PMID- 29498687 TI - Wedelolactone Enhances Osteoblastogenesis through ERK- and JNK-mediated BMP2 Expression and Smad/1/5/8 Phosphorylation. AB - Our previous study showed that wedelolactone, a compound isolated from Ecliptae herba, has the potential to enhance osteoblastogenesis. However, the molecular mechanisms by which wedelolactone promoted osteoblastogenesis from bone marrow mesenchymal stem cells (BMSCs) remain largely unknown. In this study, treatment with wedelolactone (2 MUg/mL) for 3, 6, and 9 days resulted in an increase in phosphorylation of extracellular signal-regulated kinases (ERKs), c-Jun N terminal protein kinase (JNK), and p38. Phosphorylation of mitogen-activated protein kinases (MAPKs), ERK and JNK started to increase on day 3 of treatment, and p38 phosphorylation was increased by day 6 of treatment. Expression of bone morphogenetic protein (BMP2) mRNA and phosphorylation of Smad1/5/8 was enhanced after treatment of cells with wedelolactone for 6 and 9 days. The addition of the JNK inhibitor SP600125, ERK inhibitor PD98059, and p38 inhibitor SB203580 suppressed wedelolactone-induced alkaline-phosphatase activity, bone mineralization, and osteoblastogenesis-related marker genes including Runx2, Bglap, and Sp7. Increased expression of BMP2 mRNA and Smad1/5/8 phosphorylation was blocked by SP600125 and PD98059, but not by SB203580. These results suggested that wedelolactone enhanced osteoblastogenesis through induction of JNK- and ERK mediated BMP2 expression and Smad1/5/8 phosphorylation. PMID- 29498689 TI - Novel Wearable Electrodes Based on Conductive Chitosan Fabrics and Their Application in Smart Garments. AB - Smart garments, which can capture electrocardiogram signals at any time or location, can alert others to the risk of heart attacks and prevent sudden cardiac death when people are sleeping, walking, or running. Novel wearable electrodes for smart garments based on conductive chitosan fabrics were fabricated by electroless plating of silver nanoparticles onto the surfaces of the fibers. The electrical resistance, which is related to the silver content of the composite fabrics, can be as low as 0.0332 +/- 0.0041 Omega/sq due to the strong reactivity between amine groups and silver ions. After washing these fabrics eight times, the electrical resistance remained below 1 Omega/sq. The conductive chitosan fabrics were applied to smart garments as wearable electrodes to capture electrocardiogram signals of the human body in static state, jogging state, and running state, which showed good data acquisition ability and sensitivity. PMID- 29498688 TI - Antiangiogenic Potential of Microbial Metabolite Elaiophylin for Targeting Tumor Angiogenesis. AB - Angiogenesis plays a very important role in tumor progression through the creation of new blood vessels. Therefore, angiogenesis inhibitors could contribute to cancer treatment. Here, we show that a microbial metabolite, elaiophylin, exhibits potent antiangiogenic activity from in vitro and in vivo angiogenesis assays. Elaiophylin dramatically suppressed in vitro angiogenic characteristics such as proliferation, migration, adhesion, invasion and tube formation of human umbilical vein endothelial cells (HUVECs) stimulated by vascular endothelial growth factor (VEGF) at non-toxic concentrations. In addition, elaiophylin immensely inhibited in vivo angiogenesis of the chorioallantoic membrane (CAM) from growing chick embryos without cytotoxicity. The activation of VEGF receptor 2 (VEGFR2) in HUVECs by VEGF was inhibited by elaiophylin, resulting in the suppression of VEGF-induced activation of downstream signaling molecules, Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38, nuclear factor-kappaB (NFkappaB), matrix metalloproteinase (MMP)-2 and -9 which are closely associated with VEGF induced angiogenesis. We also found that elaiophylin blocked tumor cell-induced angiogenesis both in vitro and in vivo. Elaiophylin downregulated the expression of VEGF by inhibiting hypoxia inducible factor-1alpha (HIF-1alpha) accumulation in tumor cells. To our knowledge, these results for the first time demonstrate that elaiophylin effectively inhibits angiogenesis and thus may be utilized as a new class of natural antiangiogenic agent for cancer therapy. PMID- 29498690 TI - An Integrated Theatre Production for School Nutrition Promotion Program. AB - In the context of stubbornly high childhood obesity rates, health promotion activities in schools provide a potential avenue to improve children's nutritional behaviours. Theatre production has a rich history as a health behaviour promotion strategy but lacks sound, outcome-based evaluation. This study evaluated the effect of an integrated, two-part, place-based theatre performance program with 212 students in five schools in a regional urban and semi-rural area. The program included a theatre performance and a healthy eating competition. A brief survey assessed student healthy eating knowledge and attitudes at three time points. Nutrition behaviour was measured by scoring the contents of children's lunch boxes before, during and up to six weeks after the intervention. Statistical analysis tested change over time on five variables (Knowledge, Attitude, Sometimes foods, Everyday foods, Overall lunch box score). Results showed that both components of the integrated program improved nutrition knowledge and that the theatre performance improved children's healthy eating attitudes. All three lunch box scores peaked after the integrated program and remained significantly higher than baseline at 4-6 weeks follow-up. Interaction effects were identified for school catchment area on four of the five dependent variables. Evaluation of this integrated theatre production program indicates the potential benefit of taking a "super-setting" approach. It demonstrates an effect from students taking home information they had learned and incorporating it into lunch box preparation. It also showed consistent effects for school geographical catchment. This study suggests that, with careful, theory-based design, theatre productions in schools can improve student nutritional activities. PMID- 29498692 TI - Modification and Characterization of Fe3O4 Nanoparticles for Use in Adsorption of Alkaloids. AB - Magnetite (Fe3O4) is a ferromagnetic iron oxide of both Fe(II) and Fe(III), prepared by FeCl2 and FeCl3. XRD was used for the confirmation of Fe3O4. Via the modification of Tetraethyl orthosilicate (TEOS), (3-Aminopropyl)trimethoxysilane (APTMS), and Alginate (AA), Fe3O4@SiO2, Fe3O4@SiO2-NH2, and Fe3O4@SiO2-NH2-AA nanoparticles could be obtained, and IR and SEM were used for the characterizations. Alkaloid adsorption experiments exhibited that, as for Palmatine and Berberine, the most adsorption could be obtained at pH 8 when the adsorption time was 6 min. The adsorption percentage of Palmatine was 22.2%, and the adsorption percentage of Berberine was 23.6% at pH 8. Considering the effect of adsorption time on liquid phase system, the adsorption conditions of 8 min has been chosen when pH 7 was used. The adsorption percentage of Palmatine was 8.67%, and the adsorption percentage of Berberine was 7.25%. Considering the above conditions, pH 8 and the adsorption time of 8min could be chosen for further uses. PMID- 29498691 TI - Regulation of Muscle Glycogen Metabolism during Exercise: Implications for Endurance Performance and Training Adaptations. AB - Since the introduction of the muscle biopsy technique in the late 1960s, our understanding of the regulation of muscle glycogen storage and metabolism has advanced considerably. Muscle glycogenolysis and rates of carbohydrate (CHO) oxidation are affected by factors such as exercise intensity, duration, training status and substrate availability. Such changes to the global exercise stimulus exert regulatory effects on key enzymes and transport proteins via both hormonal control and local allosteric regulation. Given the well-documented effects of high CHO availability on promoting exercise performance, elite endurance athletes are typically advised to ensure high CHO availability before, during and after high-intensity training sessions or competition. Nonetheless, in recognition that the glycogen granule is more than a simple fuel store, it is now also accepted that glycogen is a potent regulator of the molecular cell signaling pathways that regulate the oxidative phenotype. Accordingly, the concept of deliberately training with low CHO availability has now gained increased popularity amongst athletic circles. In this review, we present an overview of the regulatory control of CHO metabolism during exercise (with a specific emphasis on muscle glycogen utilization) in order to discuss the effects of both high and low CHO availability on modulating exercise performance and training adaptations, respectively. PMID- 29498694 TI - The Performance of a Self-Flocculating Microalga Chlorococcum sp. GD in Wastewater with Different Ammonia Concentrations. AB - The performance of a self-flocculating microalga Chlorococcum sp. GD on the flocculation, growth, and lipid accumulation in wastewater with different ammonia nitrogen concentrations was investigated. It was revealed that relative high ammonia nitrogen concentration (20-50 mg.L-1) was beneficial to the flocculation of Chlorococcum sp. GD, and the highest flocculating efficiency was up to 84.4%. It was also found that the highest flocculating efficiency occurred in the middle of the culture (4-5 days) regardless of initial ammonia concentration in wastewater. It was speculated that high flocculating efficiency was likely related to the production of extracellular proteins. 20 mg.L-1 of ammonia was found to be a preferred concentration for both biomass production and lipid accumulation. 92.8% COD, 98.8% ammonia, and 69.4% phosphorus were removed when Chlorococcum sp. GD was cultivated in wastewater with 20 mg.L-1 ammonia. The novelty and significance of the investigation was the integration of flocculation, biomass production, wastewater treatment, and lipid accumulation, simultaneously, which made Chlorococcum sp. GD a potential candidate for wastewater treatment and biodiesel production if harvested in wastewater with suitable ammonia nitrogen concentration. PMID- 29498693 TI - Diurnal Variation of Sweet Taste Recognition Thresholds Is Absent in Overweight and Obese Humans. AB - Sweet taste thresholds are positively related to plasma leptin levels in normal weight humans: both show parallel diurnal variations and associations with postprandial glucose and insulin rises. Here, we tested whether this relationship also exists in overweight and obese (OW/Ob) individuals with hyperleptinemia. We tested 36 Japanese OW/Ob subjects (body mass index (BMI) > 25 kg/m2) for recognition thresholds for various taste stimuli at seven different time points from 8:00 a.m. to 10:00 p.m. using the staircase methodology, and measured plasma leptin, insulin, and blood glucose levels before each taste threshold measurement. We also used the homeostatic model assessment of insulin resistance (HOMA-IR) to evaluate insulin resistance. The results demonstrated that, unlike normal weight subjects, OW/Ob subjects showed no significant diurnal variations in the recognition thresholds for sweet stimuli but exhibited negative associations between the diurnal variations of both leptin and sweet recognition thresholds and the HOMA-IR scores. These findings suggest that in OW/Ob subjects, the basal leptin levels (~20 ng/mL) may already exceed leptin's effective concentration for the modulation of sweet sensitivity and that this leptin resistance-based attenuation of the diurnal variations of the sweet taste recognition thresholds may also be indirectly linked to insulin resistance in OW/Ob subjects. PMID- 29498695 TI - Prospective Associations of Maternal Dietary Patterns and Postpartum Mental Health in a Multi-Ethnic Asian Cohort: The Growing up in Singapore towards Healthy Outcomes (GUSTO) Study. AB - Diet in the first month postpartum, otherwise known as "the confinement diet" in Asia, has unique characteristics that are influenced by traditions, cultures, and beliefs. We aimed to characterize dietary patterns during confinement period in a multi-ethnic Asian cohort and examined their associations with postpartum depression (PPD) and anxiety (PPA). Dietary intakes of 490 women were ascertained in the first month postpartum using 3-day food diaries and dietary patterns were derived by factor analysis. Participants completed the Edinburgh Postnatal Depression Scale (EPDS) and State-Trait Anxiety Inventory (STAI) at three months' postpartum; higher scores are indicative of more depressive and anxiety symptoms, respectively. Four dietary patterns were identified: Traditional-Chinese Confinement diet, Traditional-Indian-Confinement diet, Eat-Out diet and Soup Vegetables-Fruits diet. The Traditional-Indian-Confinement diet was associated with less PPD symptoms [beta (95% CI) -0.62 (-1.16, -0.09) EPDS score per SD increase in diet score] and a non-significant trend with reduced probable PPD (EPDS scores >= 13) [OR (95% CI) 0.56 (0.31, 1.01)]. The Soup-Vegetables-Fruits diet was associated with less PPA symptoms [beta (95% CI) -1.49 (-2.56, -0.42) STAI-state score]. No associations were observed for other dietary patterns. Independent of ethnicity, adherence to the Traditional-Indian-Confinement diet that is characterized by intake of herbs and legumes, and Soup-Vegetables-Fruits diet high in fruits, vegetables and fish during the postpartum period were associated with less PPD and PPA symptoms, respectively. PMID- 29498696 TI - Synergistic Effects of Salvianolic Acid B and Puerarin on Cerebral Ischemia Reperfusion Injury. AB - Ischemic stroke (IS) is characterized by the sudden loss of blood circulation to an area of the brain, resulting in a corresponding loss of neurologic function. It has been a worldwide critical disease threatening to the health and life of human beings. Despite significant progresses achieved, effective treatment still remains a formidable challenge due to the complexity of the disease. Salvianolic acid B (Sal-B) and Puerarin (Pue) are two active neuroprotectants isolated from traditional Chinese herbs, Salvia miltiorrhiza and Kudzu root respectively, which have been used for the prevention and treatment of IS for thousands of years in China. The activities of two compounds against cerebral ischemia reperfusion injury have been confirmed via various pathways. However, the therapeutic efficacy of any of the two components is still unsatisfied. In the present study, the effect of the combination of Sal-B and Pue on IS was evaluated and validated in vitro and in vivo. The ratio of two compounds was firstly optimized based on the results of CoCl2 damaged PC12 cells model. The co-administration exhibited significantly protective effect in CoCl2 induced PC12 cells injury model by reducing ROS, inhibiting apoptosis and improving mitochondrial membrane potential in vitro. Moreover, Sal-B + Pue significantly relieved neurological deficit scores and infarct area than Sal-B or Pue alone in vivo. The results indicated that neuroprotection mechanism of Sal-B + Pue was related to TLR4/MyD88 and SIRT1 activation signaling pathway to achieve synergistic effect, due to the inhibition of NF-kappaB transcriptional activity and expression of pro-inflammatory cytokine (TNF-alpha, IL-1beta, IL-6). In conclusion, the combination of Sal-B and Pue exerted much stronger neuroprotective effect than Sal-B or Pue alone, which provides a potential new drug and has great significance for the treatment of IS. PMID- 29498697 TI - Incidence and Characteristics of Cataract Surgery in Poland, during 2010-2015. AB - Background: To assess the incidence and characteristic of cataract surgery in Poland from 2010 to 2015 and to interpret these findings. Patients and methods: Data from all patients who underwent cataract surgery alone or in combined procedures in Poland between January 2010 and December 2015 were evaluated. Patient data were from the national database of hospitalizations maintained by National Health Fund. Data on the population of Poland were obtained from Central Statistical Office of Poland. Results: In total, 1,218,777 cataract extractions (alone or combined with other procedures) were performed in 1,081,345 patients during 2010-2015. Overall, the incidence of cataract surgery increased from 5.22/1000 person-years in 2010 to 6.17/1000 person-years in 2015. Phacoemulsification was performed in 97.46% of cataract extractions, and 3.02% of cataract extractions were combined procedures. The rate of one-day procedures increased from 28.3% in 2010 to 43.1% in 2015. The probability of second-eye surgery 12 months after the first-eye surgery increased from 44% in 2010 to 73% in 2015 (log-rank test p < 0.0001). Conclusion: In Poland, from 2010 to 2015, the total incidence of cataract surgery, the number of people who underwent surgery, and the number of one-day cataract surgeries increased significantly. PMID- 29498699 TI - Grey Language Hesitant Fuzzy Group Decision Making Method Based on Kernel and Grey Scale. AB - Based on grey language multi-attribute group decision making, a kernel and grey scale scoring function is put forward according to the definition of grey language and the meaning of the kernel and grey scale. The function introduces grey scale into the decision-making method to avoid information distortion. This method is applied to the grey language hesitant fuzzy group decision making, and the grey correlation degree is used to sort the schemes. The effectiveness and practicability of the decision-making method are further verified by the industry chain sustainable development ability evaluation example of a circular economy. Moreover, its simplicity and feasibility are verified by comparing it with the traditional grey language decision-making method and the grey language hesitant fuzzy weighted arithmetic averaging (GLHWAA) operator integration method after determining the index weight based on the grey correlation. PMID- 29498698 TI - Expression of LRRC8/VRAC Currents in Xenopus Oocytes: Advantages and Caveats. AB - Volume-regulated anion channels (VRACs) play a role in controlling cell volume by opening upon cell swelling. Apart from controlling cell volume, their function is important in many other physiological processes, such as transport of metabolites or drugs, and extracellular signal transduction. VRACs are formed by heteromers of the pannexin homologous protein LRRC8A (also named Swell1) with other LRRC8 members (B, C, D, and E). LRRC8 proteins are difficult to study, since they are expressed in all cells of our body, and the channel stoichiometry can be changed by overexpression, resulting in non-functional heteromers. Two different strategies have been developed to overcome this issue: complementation by transient transfection of LRRC8 genome-edited cell lines, and reconstitution in lipid bilayers. Alternatively, we have used Xenopus oocytes as a simple system to study LRRC8 proteins. Here, we have reviewed all previous experiments that have been performed with VRAC and LRRC8 proteins in Xenopus oocytes. We also discuss future strategies that may be used to perform structure-function analysis of the VRAC in oocytes and other systems, in order to understand its role in controlling multiple physiological functions. PMID- 29498700 TI - Arsenic Concentration in the Surface Water of a Former Mining Area: The La Junta Creek, Baja California Sur, Mexico. AB - The mining activity in the San Antonio-El Triunfo district, located in a mountainous region at 60 km southeast of La Paz, occured for more than 250 years and left behind severe contamination of soils and riverbed sediments which led to elevated concentrations of arsenic and other trace elements in the surface- and groundwater of the region. Although the main mining activity ended around 1911, contamination is still beeing distributed, especially from left behind tailings and mine waste piles. The contamination levels in the groundwater have been reported in several studies, but there is little information available on the surface water quality, and especially the temporal variation. In this study, we analyzed the surface water of the La Junta creek, in the southern part of the San Antonio-El Triunfo mining district. The working hypothesis was that by means of a spatial analysis of surface water and shallow groundwater, in combination with the temporal observation of the concentrations in runoff water, the effects of different sources of arsenic (natural geogene anomalies, due to historic mining activity, and hydrothermal related impact) in the La Junta creek can be recognized. This present study revealed that historic mining activity caused a mojor impact of arsenic but less contamination was observed than in the northern part of the district and elevated arsenic concentrations in stream water generally occurred during times of low streamflow. PMID- 29498701 TI - Energy Efficient Pico Cell Range Expansion and Density Joint Optimization for Heterogeneous Networks with eICIC. AB - Heterogeneous networks, constituted by conventional macro cells and overlaying pico cells, have been deemed a promising paradigm to support the deluge of data traffic with higher spectral efficiency and Energy Efficiency (EE). In order to deploy pico cells in reality, the density of Pico Base Stations (PBSs) and the pico Cell Range Expansion (CRE) are two important factors for the network spectral efficiency as well as EE improvement. However, associated with the range and density evolution, the inter-tier interference within the heterogeneous architecture will be challenging, and the time domain Enhanced Inter-cell Interference Coordination (eICIC) technique becomes necessary. Aiming to improve the network EE, the above factors are jointly considered in this paper. More specifically, we first derive the closed-form expression of the network EE as a function of the density of PBSs and pico CRE bias based on stochastic geometry theory, followed by a linear search algorithm to optimize the pico CRE bias and PBS density, respectively. Moreover, in order to realize the pico CRE bias and PBS density joint optimization, a heuristic algorithm is proposed to achieve the network EE maximization. Numerical simulations show that our proposed pico CRE bias and PBS density joint optimization algorithm can improve the network EE significantly with low computational complexity. PMID- 29498702 TI - High-Precision Phenotyping of Grape Bunch Architecture Using Fast 3D Sensor and Automation. AB - Wine growers prefer cultivars with looser bunch architecture because of the decreased risk for bunch rot. As a consequence, grapevine breeders have to select seedlings and new cultivars with regard to appropriate bunch traits. Bunch architecture is a mosaic of different single traits which makes phenotyping labor intensive and time-consuming. In the present study, a fast and high-precision phenotyping pipeline was developed. The optical sensor Artec Spider 3D scanner (Artec 3D, L-1466, Luxembourg) was used to generate dense 3D point clouds of grapevine bunches under lab conditions and an automated analysis software called 3D-Bunch-Tool was developed to extract different single 3D bunch traits, i.e., the number of berries, berry diameter, single berry volume, total volume of berries, convex hull volume of grapes, bunch width and bunch length. The method was validated on whole bunches of different grapevine cultivars and phenotypic variable breeding material. Reliable phenotypic data were obtained which show high significant correlations (up to r2 = 0.95 for berry number) compared to ground truth data. Moreover, it was shown that the Artec Spider can be used directly in the field where achieved data show comparable precision with regard to the lab application. This non-invasive and non-contact field application facilitates the first high-precision phenotyping pipeline based on 3D bunch traits in large plant sets. PMID- 29498703 TI - Three-Dimensional Reconstruction from Single Image Base on Combination of CNN and Multi-Spectral Photometric Stereo. AB - Multi-spectral photometric stereo can recover pixel-wise surface normal from a single RGB image. The difficulty lies in that the intensity in each channel is the tangle of illumination, albedo and camera response; thus, an initial estimate of the normal is required in optimization-based solutions. In this paper, we propose to make a rough depth estimation using the deep convolutional neural network (CNN) instead of using depth sensors or binocular stereo devices. Since high-resolution ground-truth data is expensive to obtain, we designed a network and trained it with rendered images of synthetic 3D objects. We use the model to predict initial normal of real-world objects and iteratively optimize the fine scale geometry in the multi-spectral photometric stereo framework. The experimental results illustrate the improvement of the proposed method compared with existing methods. PMID- 29498704 TI - A Review of Recent Advances in Research on PM2.5 in China. AB - PM2.5 pollution has become a severe problem in China due to rapid industrialization and high energy consumption. It can cause increases in the incidence of various respiratory diseases and resident mortality rates, as well as increase in the energy consumption in heating, ventilation, and air conditioning (HVAC) systems due to the need for air purification. This paper reviews and studies the sources of indoor and outdoor PM2.5, the impact of PM2.5 pollution on atmospheric visibility, occupational health, and occupants' behaviors. This paper also presents current pollution status in China, the relationship between indoor and outdoor PM2.5, and control of indoor PM2.5, and finally presents analysis and suggestions for future research. PMID- 29498705 TI - E-Nose and GC-MS Reveal a Difference in the Volatile Profiles of White- and Red Fleshed Peach Fruit. AB - First purchases of fruit are mainly dependent on aspects of appearance such as color. However, repeat buys of fruit are determined by internal quality traits such as flavor-related volatiles. Differences in volatile profiles in white- and red-fleshed peach fruit are not well understood. In the present study, peach cultivars with white- and red-fleshed fruit were subjected to sensory analysis using electronic nose (e-nose) to evaluate overview volatile profiles. Approximately 97.3% of the total variation in peach color-volatiles was explained by the first principle component 1 (PC1) and PC2. After analyzing sensory differences between peach fruit samples, 50 volatile compounds were characterized based on GC-MS. Multivariate analysis such as partial least squares discriminant analysis (PLS-DA) was applied to identify volatile compounds that contribute to difference in white- and red-fleshed peach fruit cultivars. A total of 18 volatiles that could separate peach fruit cultivars with different colors in flesh during ripening were identified based on variable importance in projection (VIP) score. Fruity note latone gamma-hexalactone had higher contents in red fleshed cultivars, while grassy note C6 compounds such as hexanal, 2-hexenal, (E) 2-hexenal, 1-hexanol, and (Z)-2-hexen-1-ol showed great accumulation in white fleshed peach fruit. PMID- 29498706 TI - New Drug Candidate Targeting the 4A1 Orphan Nuclear Receptor for Medullary Thyroid Cancer Therapy. AB - Medullary thyroid cancer (MTC) is a relatively rare thyroid cancer responsible for a substantial fraction of thyroid cancer mortality. More effective therapeutic drugs with low toxicity for MTC are urgently needed. Orphan nuclear receptor 4A1 (NR4A1) plays a pivotal role in regulating the proliferation and apoptosis of a variety of tumor cells. Based on the NR4A1 protein structure, 2 imino-6-methoxy-2H-chromene-3-carbothioamide (IMCA) was identified from the Specs compounds database using the protein structure-guided virtual screening approach. Computationally-based molecular modeling studies suggested that IMCA has a high affinity for the ligand binding pocket of NR4A1. MTT [3-(4,5-dimethyl-2 thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide] and apoptosis assays demonstrated that IMCA resulted in significant thyroid cancer cell death. Immunofluorescence assays showed that IMCA induced NR4A1 translocation from the nucleus to the cytoplasm in thyroid cancer cell lines, which may be involved in the cell apoptotic process. In this study, the quantitative polymerase chain reaction results showed that the IMCA-induced upregulation of sestrin1 and sestrin2 was dose-dependent in thyroid cancer cell lines. Western blot showed that IMCA increased phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK) and decreased phosphorylation of ribosomal protein S6 kinase (p70S6K), which is the key enzyme in the mammalian target of rapamycin (mTOR) pathway. The experimental results suggest that IMCA is a drug candidate for MTC therapy and may work by increasing the nuclear export of NR4A1 to the cytoplasm and the tumor protein 53 (p53)-sestrins-AMPK-mTOR signaling pathway. PMID- 29498707 TI - A Novel Class of Schistosoma mansoni Histone Deacetylase 8 (HDAC8) Inhibitors Identified by Structure-Based Virtual Screening and In Vitro Testing. AB - A promising means in the search of new small molecules for the treatment of schistosomiasis (amongst other parasitic ailments) is by targeting the parasitic epigenome. In the present study, a docking based virtual screening procedure using the crystal structure of histone deacetylase 8 from Schistosoma mansoni (smHDAC8) was designed. From the developed screening protocol, we were able to identify eight novel N-(2,5-dioxopyrrolidin-3-yl)-n-alkylhydroxamate derivatives as smHDAC8 inhibitors with IC50 values ranging from 4.4-20.3 uM against smHDAC8. These newly identified inhibitors were further tested against human histone deacetylases (hsHDAC1, 6 and 8), and were found also to be exerting interesting activity against them. In silico prediction of the docking pose of the compounds was confirmed by the resolved crystal structure of one of the identified hits. This confirmed these compounds were able to chelate the catalytic zinc ion in a bidentate fashion, whilst showing an inverted binding mode of the hydroxamate group when compared to the reported smHDAC8/hydroxamates crystal structures. Therefore, they can be considered as new potential scaffold for the development of new smHDAC8 inhibitors by further investigation of their structure-activity relationship. PMID- 29498709 TI - Application of PolyHIPE Membrane with Tricaprylmethylammonium Chloride for Cr(VI) Ion Separation: Parameters and Mechanism of Transport Relating to the Pore Structure. AB - The structural characteristics of membrane support directly affect the performance of carrier facilitated transport membrane. A highly porous PolyHIPE impregnated with Aliquat 336 is proposed for Cr(VI) separation. PolyHIPE consisting of poly(styrene-co-2-ethylhexyl acrylate) copolymer crosslinked with divinylbenzene has the pore structure characteristic of large pore spaces interconnected with small window throats. The unique pore structure provides the membrane with high flux and stability. The experimental results indicate that the effective diffusion coefficient D* of Cr(VI) through Aliquat 336/PolyHIPE membrane is as high as 1.75 * 10-11 m2 s-1. Transport study shows that the diffusion of Cr(VI) through Aliquat 336/PolyHIPE membrane can be attributed to the jumping transport mechanism. The hydraulic stability experiment shows that the membrane is quite stable, with recovery rates remaining at 95%, even after 10 consecutive cycles of operation. The separation study demonstrates the potential application of this new type of membrane for Cr(VI) recovery. PMID- 29498710 TI - Regulating the Emission Spectrum of CsPbBr3 from Green to Blue via Controlling the Temperature and Velocity of Microchannel Reactor. AB - The ability to precisely obtain tunable spectrum of lead halide perovskite quantum dots (QDs) is very important for applications, such as in lighting and display. Herein, we report a microchannel reactor method for synthesis of CsPbBr3 QDs with tunable spectrum. By adjusting the temperature and velocity of the microchannel reactor, the emission peaks of CsPbBr3 QDs ranging from 520 nm to 430 nm were obtained, which is wider than that of QDs obtained in a traditional flask without changing halide component. The mechanism of photoluminescence (PL) spectral shift of CsPbBr3 QDs was investigated, the result shows that the supersaturation control enabled by the superior mass and heat transfer performance in the microchannel is the key to achieve the wide range of PL spectrum, with only a change in the setting of the temperature controller required. The wide spectrum of CsPbBr3 QDs can be applied to light-emitting diodes (LEDs), photoelectric sensors, lasers, etc. PMID- 29498708 TI - Identification and Characterizations of Novel, Selective Histone Methyltransferase SET7 Inhibitors by Scaffold Hopping- and 2D-Molecular Fingerprint-Based Similarity Search. AB - SET7, serving as the only histone methyltransferase that monomethylates 'Lys-4' of histone H3, has been proved to function as a key regulator in diverse biological processes, such as cell proliferation, transcriptional network regulation in embryonic stem cell, cell cycle control, protein stability, heart morphogenesis and development. What's more, SET7 is involved inthe pathogenesis of alopecia aerate, breast cancer, tumor and cancer progression, atherosclerosis in human carotid plaques, chronic renal diseases, diabetes, obesity, ovarian cancer, prostate cancer, hepatocellular carcinoma, and pulmonary fibrosis. Therefore, there is urgent need to develop novel SET7 inhibitors. In this paper, based on DC-S239 which has been previously reported in our group, we employed scaffold hopping- and 2D fingerprint-based similarity searches and identified DC S285 as the new hit compound targeting SET7 (IC50 = 9.3 MUM). Both radioactive tracing and NMR experiments validated the interactions between DC-S285 and SET7 followed by the second-round similarity search leading to the identification ofDC S303 with the IC50 value of 1.1 MUM. In cellular level, DC-S285 retarded tumor cell proliferation and showed selectivity against MCF7 (IC50 = 21.4 MUM), Jurkat (IC50 = 2.2 MUM), THP1 (IC50 = 3.5 MUM), U937 (IC50 = 3.9 MUM) cell lines. Docking calculations suggested that DC-S303 share similar binding mode with the parent compoundDC-S239. What's more, it presented good selectivity against other epigenetic targets, including SETD1B, SETD8, G9a, SMYD2 and EZH2. DC-S303 can serve as a drug-like scaffold which may need further optimization for drug development, and can be used as chemical probe to help the community to better understand the SET7 biology. PMID- 29498711 TI - Search for Fibrous Aggregates Potentially Useful in Regenerative Medicine Formed under Physiological Conditions by Self-Assembling Short Peptides Containing Two Identical Aromatic Amino Acid Residues. AB - This study investigates the propensity of short peptides to self-organize and the influence of aggregates on cell cultures. The dipeptides were derived from both enantiomers of identical aromatic amino acids and tripeptides were prepared from two identical aromatic amino acids with one cysteine or methionine residue in the C-terminal, N-terminal, or central position. The formation or absence of fibrous structures under physiological conditions was established using Congo Red and Thioflavine T assays as well as by microscopic examination using normal and polarized light. The in vitro stability of the aggregates in buffered saline solution was assessed over 30 days. Materials with potential for use in regenerative medicine were selected based on the cytotoxicity of the peptides to the endothelial cell line EA.hy 926 and the wettability of the surfaces of the films, as well as using scanning electron microscopy. The criteria were fulfilled by H-dPhedPhe-OH, H-dCysdPhedPhe-OH, H-CysTyrTyr-OH, H-dPhedPhedCys-OH, H TyrTyrMet-OH, and H-TyrMetTyr-OH. Our preliminary results suggest that the morphology and cell viability of L919 fibroblast cells do not depend on the stereochemistry of the self-organizing peptides. PMID- 29498712 TI - Pyrethroid Resistance in the Major Malaria Vector Anopheles funestus is Exacerbated by Overexpression and Overactivity of the P450 CYP6AA1 Across Africa. AB - Resistance to pyrethroids (the ingredients in bed net insecticides) in the major malaria vector Anopheles funestus is threatening recent gains in the fight against malaria. Here, we established the role of an over-expressed P450, A. funestus CYP6AA1 in insecticides resistance. Transcription profiling of CYP6AA1 across Africa using microarray and quantitative reverse transcription polymerase chain reaction (qRT-PCR) revealed that it is significantly more over-expressed in southern African populations compared to West (Benin) and East African (Uganda). Heterologous expression in Escherichia coli coupled with metabolism assays demonstrated that CYP6AA1 metabolises type I (permethrin) and type II (deltamethrin) pyrethroids, as well as bendiocarb (a carbamate). Transgenic Drosophila melanogaster flies over-expressing CYP6AA1 were significantly more resistant to pyrethroid insecticides, permethrin and deltamethrin compared with control flies not expressing the gene, validating the role of this gene in pyrethroid resistance. In silico modelling and docking simulations predicted the intermolecular receptor-ligand interactions which allow this P450 to metabolise the pyrethroids and bendiocarb. Validation of CYP6AA1 as a pyrethroid resistance gene makes it possible to monitor the spread of resistance in the field where this P450 is over-expressed. Its potential cross-resistance role makes it necessary to monitor the gene closely to inform control programs on molecular basis of multiple resistance in the field. PMID- 29498715 TI - Behavior Analysis of Novel Wearable Indoor Mapping System Based on 3D-SLAM. AB - This paper presents a Wearable Prototype for indoor mapping developed by the University of Vigo. The system is based on a Velodyne LiDAR, acquiring points with 16 rays for a simplistic or low-density 3D representation of reality. With this, a Simultaneous Localization and Mapping (3D-SLAM) method is developed for the mapping and generation of 3D point clouds of scenarios deprived from GNSS signal. The quality of the system presented is validated through the comparison with a commercial indoor mapping system, Zeb-Revo, from the company GeoSLAM and with a terrestrial LiDAR, Faro Focus3D X330. The first is considered as a relative reference with other mobile systems and is chosen due to its use of the same principle for mapping: SLAM techniques based on Robot Operating System (ROS), while the second is taken as ground-truth for the determination of the final accuracy of the system regarding reality. Results show that the accuracy of the system is mainly determined by the accuracy of the sensor, with little increment in the error introduced by the mapping algorithm. PMID- 29498714 TI - Targeting Receptor-Type Protein Tyrosine Phosphatases with Biotherapeutics: Is Outside-in Better than Inside-Out? AB - Protein tyrosine phosphatases (PTPs), of the receptor and non-receptor classes, are key signaling molecules that play critical roles in cellular regulation underlying diverse physiological events. Aberrant signaling as a result of genetic mutation or altered expression levels has been associated with several diseases and treatment via pharmacological intervention at the level of PTPs has been widely explored; however, the challenges associated with development of small molecule phosphatase inhibitors targeting the intracellular phosphatase domain (the "inside-out" approach) have been well documented and as yet there are no clinically approved drugs targeting these enzymes. The alternative approach of targeting receptor PTPs with biotherapeutic agents (such as monoclonal antibodies or engineered fusion proteins; the "outside-in" approach) that interact with the extracellular ectodomain offers many advantages, and there have been a number of exciting recent developments in this field. Here we provide a brief overview of the receptor PTP family and an update on the emerging area of receptor PTP targeted biotherapeutics for CD148, vascular endothelial-protein tyrosine phosphatase (VE-PTP), receptor-type PTPs sigma, gamma, zeta (RPTPsigma, RPTPgamma, RPTPzeta) and CD45, and discussion of future potential in this area. PMID- 29498717 TI - Paroxysmal positional vertigo despite complete vestibular impairment: the role of instrumental assessment. AB - Lindsay and Hemenway syndrome is characterised by a posterior canal benign paroxysmal positional vertigo following a partial unilateral vestibular loss affecting the same side. The syndrome is caused by damage of structures innervated by the superior division of the vestibular nerve and perfused by the anterior vestibular artery; the detached otoconia can cause vertigo in the still intact posterior semicircular canal. The most recent vestibular instrumental techniques allow reaching an accurate topodiagnosis in case of peripheral vestibular failure. We report on two cases of Lindsay-Hemenway syndrome despite complete vestibular failure demonstrated by vestibular instrumental assessment. After making some critical considerations on these findings, we underline the importance of not disregarding the diagnosis of paroxysmal positional vertigo in an established complete labyrinthine loss of function. PMID- 29498716 TI - Association between the increase in incidence of papillary thyroid carcinoma in Crete and exposure to radioactive agents. AB - The mean gamma-ray distribution in Crete during the years after the nuclear accident at Chernobyl and its correlation with the Papillary Thyroid Cancer (PTC) distribution was identified. A total of 4285 patients underwent total thyroidectomy in our centre between 1990 and 2012. Data of gamma-ray (nSv/h) distribution were selected from the Greek Statistical Authorisation. A geo spatial statistical model was used to estimate the expected number of patients with PTC and Kriging interpolation prediction model to estimate their distribution. Geographical weighted regression was performed to estimate the risk of PTC in relation to gamma ray distribution. All factors that were examined were found to be statistically significant for PTC distribution in Crete. Gamma-ray was determined as a significant risk factor (OR = 2.89; 95% CI = 1.682-4.989; p value = 0.03). There is a significant correlation between gamma-ray exposure and the increased prevalence of the PTC suggesting that the former may have been a significant risk factor. PMID- 29498713 TI - Effects of Passage Number and Differentiation Protocol on the Generation of Dopaminergic Neurons from Rat Bone Marrow-Derived Mesenchymal Stem Cells. AB - Multiple studies have demonstrated the ability of mesenchymal stem cells (MSCs) to differentiate into dopamine-producing cells, in vitro and in vivo, indicating their potential to be used in the treatment of Parkinson's disease (PD). However, there are discrepancies among studies regarding the optimal time (i.e., passage number) and method for dopaminergic induction, in vitro. In the current study, we compared the ability of early (P4) and later (P40) passaged bone marrow-derived MSCs to differentiate into dopaminergic neurons using two growth-factor-based approaches. A direct dopaminergic induction (DDI) was used to directly convert MSCs into dopaminergic neurons, and an indirect dopaminergic induction (IDI) was used to direct MSCs toward a neuronal lineage prior to terminal dopaminergic differentiation. Results indicate that both early and later passaged MSCs exhibited positive expression of neuronal and dopaminergic markers following either the DDI or IDI protocols. Additionally, both early and later passaged MSCs released dopamine and exhibited spontaneous neuronal activity following either the DDI or IDI. Still, P4 MSCs exhibited significantly higher spiking and bursting frequencies as compared to P40 MSCs. Findings from this study provide evidence that early passaged MSCs, which have undergone the DDI, are more efficient at generating dopaminergic-like cells in vitro, as compared to later passaged MSCs or MSCs that have undergone the IDI. PMID- 29498718 TI - Principles and applications of EPR spectroscopy in the chemical sciences. AB - Electron spins permeate every aspect of science and influence numerous chemical processes: they underpin transition metal chemistry and biochemistry, mediate photosynthesis and photovoltaics and are paramount in the field of quantum information, to name but a few. Electron paramagnetic resonance (EPR) spectroscopy detects unpaired electrons and provides detailed information on structure and bonding of paramagnetic species. In this tutorial review, aimed at non-specialists, we provide a theoretical framework and examples to illustrate the vast scope of the technique in chemical research. Case studies were chosen to exemplify systematically the different interactions that characterize a paramagnetic centre and to illustrate how EPR spectroscopy may be used to derive chemical information. PMID- 29498719 TI - Facile meltPEGylation of flame-made luminescent Tb3+-doped yttrium oxide particles: hemocompatibility, cellular uptake and comparison to silica. AB - Flame aerosol technology is a versatile method for scalable synthesis of nanoparticles. Since particles are produced and collected in a dry state, dispersibility and further functionalization could pose hurdles to their biomedical use. We report on a one-pot, scalable and robust procedure for the PEGylation of flame-made yttria and silica nanoparticles. We demonstrate improved colloidal stability, attenuated activation of blood coagulation and decreased uptake into phagocytic cells, all of which pave the way for facilitated biomedical use of flame-made oxide nanoparticles. PMID- 29498720 TI - Complexes of gold and imidazole formed in helium nanodroplets. AB - We have studied complexes of gold atoms and imidazole (C3N2H4, abbreviated Im) produced in helium nanodroplets. Following the ionization of the doped droplets we detect a broad range of different AumImn+ complexes, however we find that for specific values of m certain n are "magic" and thus particularly abundant. Our density functional theory calculations indicate that these abundant clusters sizes are partially the result of particularly stable complexes, e.g. AuIm2+, and partially due to a transition in fragmentation patterns from the loss of neutral imidazole molecules for large systems to the loss of neutral gold atoms for smaller systems. PMID- 29498721 TI - Synthesis, crystal structure and reactivity of eta2-thiophyne Ni complexes. AB - The first synthesis and crystal structures of five-membered ring aryne complexes, Ni(dcpe)(eta2-thiophyne) and Ni(dcpe)(eta2-benzo[b]thiophyne), are described. The aryne fragments retain considerable aromatic character and the two coordinated carbon atoms exhibit distinct reactivity due to their asymmetric nature. PMID- 29498722 TI - Super-helical filaments at surfaces: dynamics and elastic responses. AB - Bio-filaments often behave in a way unexpected from the standard semi-flexible polymer chain model (WLC), when squeezed to a surface, confined in microfluidic channels or clamped by their end. This calls for the super-helical filament model, going beyond WLC, where the filament forms a helix much wider than its diameter. We study this model using Brownian dynamics simulations, focusing on filaments confined to a surface by a strong potential. We analyze shapes and shape fluctuations under tension where excited states comprising a number of inflection points (twist-kink) can be stabilized. Pulling/releasing experiments during a cycle of increasing/decreasing tension show hysteresis. We find that the excited state, once established, is long-lived and the life time grows with the filament length cubed. Twist-kink diffusion involves position (filament shape) dependent friction for which we provide analytical expression. Dynamic responses to tension are investigated via numerical simulations and several mechanisms of shape relaxation are found and rationalized. PMID- 29498723 TI - Transfection efficiencies of alpha-tocopherylated cationic gemini lipids with hydroxyethyl bearing headgroups under high serum conditions. AB - Herein, five new alpha-tocopheryl cationic gemini lipids with hydroxyethyl bearing headgroups (THnS, n = 4, 5, 6, 8, 12) have been synthesized for efficient plasmid DNA (pDNA) delivery into cancer cells. Among these gemini lipid formulations, the lipid with an octamethylene [-(CH2)8] spacer (TH8S) showed the highest transfection efficiency (TE) that was comparable to that of the commercial standard lipofectamine 2000 (L2K) in terms of luciferase expression in HepG2 (liver hepatocellular carcinoma) cells. The addition of the helper lipid DOPE (1,2-dioleoyl phosphatidyl ethanolamine) with cationic lipids in mixed liposomes further enhanced the TE and the optimized molar ratio was 2 : 1 (DOPE : cationic lipid). The optimized co-liposomal formulation of TH8S (DOPE : TH8S = 2 : 1) showed a higher TE in HepG2, A549 (human lung carcinoma) and MCF7 (human breast adenocarcinoma) cells than other optimized co-liposomal formulations and was also significantly more potent than L2K. The comparison of the TE of DOPE TH8S (2 : 1) with the gemini lipid T8T (the headgroup devoid of the hydroxyl group) further demonstrated the importance of the hydroxyethyl functionality at the level of the headgroup. Relatively good binding efficiency and easy release of pDNA (pGL3) were also observed with DOPE-TH8S (2 : 1) in the ethidium bromide (EB)-exclusion and re-intercalation assay, which may be the plausible reason for high TE. The lipoplexes were also characterized by atomic force microscopy (AFM), dynamic light scattering (DLS), zeta potential and small angle X-ray diffraction experiments. Greater cellular internalization of fluorescein tagged pDNA was also observed with DOPE-TH8S (2 : 1) lipoplexes compared to that with L2K. Retention of the TE of DOPE-TH8S (2 : 1) lipoplexes under high serum conditions was conferred by the presence of the tocopherol backbone and also the hydroxyethyl functionalities. The cellular internalization pathway of the lipoplexes was characterized by performing transfection experiment in the presence of inhibitors of different endocytic pathways and it was found to be caveolae mediated. An MTT based cell viability assay indicated that the lipoplex mediated gene delivery vectors exhibited low toxicity in all the three cancer cell lines studied. PMID- 29498724 TI - Photolysis of O2 dispersed in solid neon with far-ultraviolet radiation. AB - Irradiation at 173 or 143 nm of samples of 16O2 or 18O2 in solid Ne near 4 K produced many new spectral lines in absorption and emission from the mid-infrared to the near-ultraviolet regions. The major product was ozone, O3, that was identified with its mid-infrared and near-ultraviolet absorption lines. Oxygen atoms were formed on photolysis of O2 and stored in solid neon until the temperature of a sample was increased to 9 K, which enabled their migration and combination to form O3 and likely also O2. O2 in five excited states and O in two excited states detected through the emission spectra indicate that complicated processes occurred in solid Ne after far-ultraviolet excitation. For the transition 1D2 -> 3P1,2 of O, the lifetime was determined to be 5.87 +/- 0.10 s; the lifetime of the upper state of an unidentified transition associated with an emission feature at 701.7 nm was determined to be 2.34 +/- 0.07 s. PMID- 29498725 TI - Hydrolysis of organometallic and metal-amide precursors: synthesis routes to oxo bridged heterometallic complexes, metal-oxo clusters and metal oxide nanoparticles. AB - The hydrolysis reaction between Bronsted basic organometallic or metal-amide reagents with Bronsted acidic OH groups from water or metal-hydroxides may act as a controlled stoichiometric strategy for the formation of M-O-M bonds, if careful consideration of reaction conditions is employed. This article explores the utilisation of highly reactive organometallic and metal-amide complexes from across the periodic table as reagents for the synthesis of metal-oxo clusters, oxo-bridged heterobimetallics and metal oxide nanoparticles. Such reactivity typically occurs at low temperatures with the release of hydrocarbon or amine by products. The impact of ligand coordination, M-C bond strength, M-OH acidity and reaction temperature are discussed. PMID- 29498726 TI - Revealing the fate of the phenylcoumaran linkage during lignin oxidation reactions. AB - The fate of most lignin linkages, other than the beta-O-4, under selective oxidation conditions is largely unknown. In this work we use advanced beta-5 lignin model compounds to identify the fate of phenylcoumaran units in a softwood lignin during oxidation with DDQ. By using model compounds combined with detailed characterisation of the oxidised lignin polymer using HSQC and HMBC NMR we show that phenylcoumarones are a major product, and therefore constitute a novel non native beta-5 linkage in oxidised lignins. Additionally, the reactivity of these units in lignin led us to further investigate their connectivity in lignin, showing that they are found as both phenolic and etherified units. The findings and approach developed here will help improve the efficiency of selective oxidative lignin depolymerisation processes, particularly those aimed at the upgrading of softwood lignin in which phenylcoumarans are a major linkage. PMID- 29498727 TI - Reply to the 'Comment on "Methanol dimer formation drastically enhances hydrogen abstraction from methanol by OH at low temperature"' by D. Heard, R. Shannon, J. Gomez Martin, R. Caravan, M. Blitz, J. Plane, M. Antinolo, M. Agundez, E. Jimenez, B. Ballesteros, A. Canosa, G. El Dib, J. Albaladejo and J. Cernicharo, Phys. Chem. Chem. Phys., 2018, 20, DOI: 10.1039/C7CP04561A. AB - In this Reply we answer the two main arguments raised in the Comment. The first argument is related to the binding energy of the methanol dimer and its influence on the dimerization rate constant. We show that the dimerization rate constants calculated in the Comment are unphysically low. We report values that are about two orders of magnitude higher than the values of the Comment, which confirm the conclusions of the original article that dimers can be present in a small amount. The second argument based on the dependence of the pseudo-first order rates on the methanol concentration was already explained in detail in the Supporting Information of the original article. PMID- 29498728 TI - Minimalistic peptide supramolecular co-assembly: expanding the conformational space for nanotechnology. AB - Molecular self-assembly is a ubiquitous process in nature and central to bottom up nanotechnology. In particular, the organization of peptide building blocks into ordered supramolecular structures has gained much interest due to the unique properties of the products, including biocompatibility, chemical and structural diversity, robustness and ease of large-scale synthesis. In addition, peptides, as short as dipeptides, contain all the molecular information needed to spontaneously form well-ordered structures at both the nano- and the micro-scale. Therefore, peptide supramolecular assembly has been effectively utilized to produce novel materials with tailored properties for various applications in the fields of material science, engineering, medicine, and biology. To further expand the conformational space of peptide assemblies in terms of structural and functional complexity, multicomponent (two or more) peptide supramolecular co assembly has recently evolved as a promising extended approach, similar to the structural diversity of natural sequence-defined biopolymers (proteins) as well as of synthetic covalent co-polymers. The use of this methodology was recently demonstrated in various applications, such as nanostructure physical dimension control, the creation of non-canonical complex topologies, mechanical strength modulation, the design of light harvesting soft materials, fabrication of electrically conducting devices, induced fluorescence, enzymatic catalysis and tissue engineering. In light of these significant advancements in the field of peptide supramolecular co-assembly in the last few years, in this tutorial review, we provide an updated overview and future prospects of this emerging subject. PMID- 29498729 TI - Contact engineering for 2D materials and devices. AB - Over the past decade, the field of two-dimensional (2D) layered materials has surged, promising a new platform for studying diverse physical phenomena that are scientifically intriguing and technologically relevant. Contacts are the communication links between these 2D materials and the three-dimensional world for probing and harnessing their exquisite electronic properties. However, fundamental challenges related to contacts often limit the ultimate performance and potential of 2D materials and devices. This article provides a comprehensive overview of the basic understanding and importance of contacts to 2D materials and various strategies for engineering and improving them. In particular, we elucidate the phenomenon of Fermi level pinning at the metal/2D contact interface, the Schottky versus Ohmic nature of the contacts and various contact engineering approaches including interlayer contacts, phase engineered contacts, and basal versus edge plane contacts, among others. Finally, we also discuss some of the relatively under-addressed and unresolved issues, such as contact scaling, and conclude with a future outlook. PMID- 29498730 TI - Reverse-bias-driven whispering gallery mode lasing from individual ZnO microwire/p-Si heterojunction. AB - In this paper, electrically driven whispering gallery mode (WGM) lasing was observed from ZnO single microwire (SMW)/p-Si heterojunctions operated at reverse bias. Current-voltage curve exhibits a non-ideal rectification characteristic with a turn-on voltage of about 0.8 V. When the reverse current of 20 mA was applied, several sharp lasing peaks with FWHM as narrow as ~2 nm appeared in the spectra, which demonstrated that the gain was now large enough to enable the cavity resonant in ZnO SMW. The resonant process, lasing mode and quality factor (Q) were investigated via experiments and theory. The observed discrete lasing peak positions effectively matched the simulated lasing modes. The carrier transport process and light emission mechanism in heterojunctions are also discussed by energy band theory and interface defect. PMID- 29498731 TI - Probing the shear modulus of two-dimensional multiplanar nanostructures and heterostructures. AB - Generalized high-fidelity closed-form formulae have been developed to predict the shear modulus of hexagonal graphene-like monolayer nanostructures and nano heterostructures based on a physically insightful analytical approach. Hexagonal nano-structural forms (top view) are common for nanomaterials with monoplanar (such as graphene and hBN) and multiplanar (such as stanene and MoS2) configurations. However, a single-layer nanomaterial may not possess a particular property adequately, or multiple desired properties simultaneously. Recently, a new trend has emerged to develop nano-heterostructures by assembling multiple monolayers of different nanostructures to achieve various tunable desired properties simultaneously. Shear modulus assumes an important role in characterizing the applicability of different two-dimensional nanomaterials and heterostructures in various nanoelectromechanical systems such as determining the resonance frequency of vibration modes involving torsion, wrinkling and rippling behavior of two-dimensional materials. We have developed mechanics-based closed form formulae for the shear modulus of monolayer nanostructures and multi-layer nano-heterostructures. New results of shear modulus are presented for different classes of nanostructures (graphene, hBN, stanene and MoS2) and nano heterostructures (graphene-hBN, graphene-MoS2, graphene-stanene and stanene MoS2), which are categorized on the basis of fundamental structural configurations. The numerical values of shear modulus are compared with the results from the scientific literature (as available) and separate molecular dynamics simulations, wherein a good agreement is noticed. The proposed analytical expressions will enable the scientific community to efficiently evaluate shear modulus of a wide range of nanostructures and nanoheterostructures. PMID- 29498732 TI - Methylene-linked bis-phenylbenzimidazoles - a new scaffold to target telomeric DNA/RNA hybrid duplex. AB - We report a series of novel methylene-linked bis-phenylbenzimidazoles intercalators that stabilize telomeric DNA/RNA hybrid (tDRH) structures by up to 7.2 degrees C at a 1 MUM ligand concentration while having negligible affinity for DNA/DNA duplexes, although with a low affinity for quadruplex DNA. We have used molecular modelling studies to rationalize this selectivity, concluding that the methylene spacer between the terminal benzimidazole and phenylene moieties plays a key role in facilitating the bis-intercalating process. This scaffold may be used to develop chemical tools or new therapeutics to selectively target the telomeric DNA/RNA duplex without affecting normal genomic DNA. PMID- 29498734 TI - Neuronal adhesion and growth on nanopatterned EA5-POPC synthetic membranes. AB - Biomimetic membranes create opportunities for various applications, including the possibility of replacing interacting cells in a cell-cell contact. Here we have fractionated synthetic membranes using metal nano-grid structures where EphrinA5 (EA5), a neuronal adhesion promoter, was anchored via its Fc domain (immunoglobulin G (IgG)-domain). FRAP experiments were performed to check the confinement of the synthetic membrane within these nano-structures. Rat cortical primary neurons were cultured and live cell imaging techniques were used to monitor the neuronal interaction with these fractionated synthetic membranes. Computational imaging analysis of the corresponding images elucidated interesting details of the cellular behavior. The phenotypic cellular response on these nano membrane fractions was found to be similar to that on non-fractionated synthetic membranes indicating that although the number of focal adhesion points was low (due to the reduced EA5 number) in the nano-sized membrane patches perhaps some other factors like metal grid boundaries might be playing a role in rendering the similarity. PMID- 29498735 TI - Toward universal protein post-translational modification detection in high throughput format. AB - Post-translational modification (PTM) of proteins plays essential regulatory roles in a variety of pathological conditions. Reliable and practical assays are required to accelerate the discovery of inhibitors and activators for PTM related diseases. Today, methodologies are based on specific or group-specific PTM recognition of e.g. phosphate for kinase activity without extending to other type of PTMs. Here we have established a universal time-resolved luminescence assay on a peptide-break platform for the direct detection of wide variety of PTMs. The developed assay is based on the leucine zipper concept wherein a europium-chelate labeled detection peptide and a non-labeled peptide substrate form a highly luminescent dimer. As an active PTM enzyme at sub or low nanomolar concentration modifies the substrate peptide, the luminescent signal of the detached detection peptide is quenched in the presence of soluble quenchers. The functionality of this universal assay technique has been demonstrated for the monitoring of phosphorylation, dephosphorylation, deacetylation, and citrullination with high applicability also to other PTMs in a high throughput format. PMID- 29498736 TI - First-principles studies of spontaneous polarization in mixed poly(vinylidene fluoride)/2,3,3,3-tetrafluoropropene polymer crystals. AB - Spontaneous polarization P of mixed polymer crystals based on beta poly(vinylidene fluoride) (PVDF, -CH2-CF2-) and 2,3,3,3-tetrafluoropropene (TFP, CH2-CF(CF3)-) was evaluated for beta-PVDF/iso-PTFP, beta-PVDF/P(VDF-alt-iso-TFP) and beta-PVDF/syndio-PTFP. A plane-wave-based density-functional theory (DFT) approach, combined with the Modern Theory of Polarization formalism utilizing maximally-localized Wannier functions for calculating P, indicates that all systems exhibit similarly high or even slightly larger polarization than that of perfectly crystalline beta-PVDF (0.18 C m-2). These properties stem from the substantial dipole moment of the TFP unit, which is estimated to be ~2.3 D in an isolated chain, but is enhanced to ~2.8 D in the crystal. PMID- 29498733 TI - Optogenetically controlled protein kinases for regulation of cellular signaling. AB - Protein kinases are involved in the regulation of many cellular processes including cell differentiation, survival, migration, axon guidance and neuronal plasticity. A growing set of optogenetic tools, termed opto-kinases, allows activation and inhibition of different protein kinases with light. The optogenetic regulation enables fast, reversible and non-invasive manipulation of protein kinase activities, complementing traditional methods, such as treatment with growth factors, protein kinase inhibitors or chemical dimerizers. In this review, we summarize the properties of the existing optogenetic tools for controlling tyrosine kinases and serine-threonine kinases. We discuss how the opto-kinases can be applied for studies of spatial and temporal aspects of protein kinase signaling in cells and organisms. We compare approaches for chemical and optogenetic regulation of protein kinase activity and present guidelines for selection of opto-kinases and equipment to control them with light. We also describe strategies to engineer novel opto-kinases on the basis of various photoreceptors. PMID- 29498737 TI - Photoirradiation-generated radicals in two-component supramolecular gel for polymerization. AB - While supramolecular gels have been attracting great interest due to their easy design and fabrication, development of new applications based on these gels is always a challenging topic. Here, we report a two-component supramolecular gel that can generate and stabilize radicals through photo-irradiation, which can be subsequently used for polymerization. It has been found that the electrostatic interactions between a cationic amphiphile and anionic sulfonate could afford co assembly into a two-component supramolecular gel. Upon photo-irradiation, the gel changed colour and produced the radicals, as verified from the EPR measurements. The radical thus formed in the supramolecular gel is relatively stable and could be used to polymerize acrylic acid directly without deoxygenation. In contrast, acrylic acid could not be polymerized in solution under the same conditions. This work expands the application scope of supramolecular gels. PMID- 29498738 TI - Blastocystis hominis transmission by non-potable water: a case report in Italy. AB - In the reported case, a 41-year-old Italian man came to the clinician's observation reporting cramps, bloating and watery diarrhoea a few days after drinking water indicated as unpotable from a fountain in a farm area. The medical suspicion was directed at both gluten intolerance and enteric infection, eventually of waterborne origin. Gluten intolerance was investigated by intestinal biopsy and excluded, while stool analyses ruled out infective bacteriological or viral agents and parasites. Subsequently, a persistent eosinophilia was revealed and a parasitological analysis was again suggested, planning for a more sensitive molecular method. Therefore, a multiplex-PCR of enteric protozoa species DNA was performed on an intestinal biopsy and faecal samples revealing only Blastocystis hominis protozoa, subsequently typed as subtype 1 by RFLP-PCR method. B. hominis is an anaerobic protozoa found in the human and animal intestinal tract, recently associated with a pathogenic role characterized by chronic development. Since blastocystosis has been demonstrated as a waterborne infection, a sample of water matrix was analysed, revealing the B. hominis subtype 1 DNA inside. A probable water transmission of Blastocystis infection has been demonstrated in this case report. Only a probiotic treatment based on Saccharomyces boulardii was administered to the patient and this apparently resolved the infection. In summary, the case described here is a chronic blastocystosis of possible waterborne origin, controlled by assuming a yeast treatment. PMID- 29498739 TI - Prevalence and antimicrobial resistance of genital Mollicutes in Italy over a two year period. AB - Knowledge of the prevalence and antimicrobial susceptibility of genital Mollicutes is crucial to offer guidelines for empirical treatments. The aim of this study was to investigate the prevalence and the resistance profile of Mycoplasma hominis (MH) and Ureaplasma urealyticum/Ureaplasma parvum (UU/UP) in genital samples over a two-year period in Bologna, Italy. From January 2015 to December 2016, data on all the subjects providing uro-genital specimens for Mollicutes detection by culture were analyzed. A total of 4660 subjects (84.4% females) were enrolled and an overall Mollicutes prevalence of 30.9% was found. Women turned positive for Mollicutes infection twice as often as men (33.3% vs 17.8%) and the detection rate progressively decreased with increasing age. Ureaplasmas represented the commonest species isolated (overall prevalence: 24.2%), whereas mixed infections (6.5%) and MH single infections (3.9%) were far less common. Ureaplasma species showed significant levels of quinolone resistance, especially to ciprofloxacin (77%), whereas MH strains were non susceptible to azithromycin and roxithromycin in about 90% of cases. Mollicutes co-infections showed a more severe resistance pattern than single infections. Over time, the resistance rate for azithromycin and roxithromycin increased significantly. Globally, our results revealed that minocycline and doxycycline can still be first-line drugs for Mollicutes treatment. PMID- 29498740 TI - Varicella-zoster virus infection: natural history, clinical manifestations, immunity and current and future vaccination strategies. AB - Varicella-zoster virus (VZV) is the etiologic agent of varicella (chicken pox), a childhood exanthematic disease that develops as a result of primary infection, and zoster (shingles), caused by reactivation of the virus persisting in a latent form in the dorsal sensory ganglia. Although varicella is generally a mild self limiting illness, in immunocompromised subjects and adults it can have a serious clinical course that can lead to permanent damage of the central nervous system. In these and in most zoster cases, treatment with anti-herpetic drugs and/or immunotherapy is necessary. Because it is highly contagious, varicella is one of the most common exanthematic diseases. It is preventable by vaccination with an attenuated vaccine administered around the first year of age, and with a boost vaccination in school age. This article briefly describes the natural history and pathophysiology of VZV infection and its current epidemiology and provides an overview of current and future vaccine options to protect against varicella and/or zoster. PMID- 29498741 TI - Metagenomic analysis of bacterial community in a travertine depositing hot spring. AB - Several factors influence bacteria biodiversity in hot springs. The impact of biotic and abiotic pathways on travertine deposition plays a key role in microbial ecology and in the final composition of the waterborne microbiota. The metabolism of some bacterial groups such as photoautotrophs or lithoautotrophs influences water chemistry, favoring carbonate precipitation processes. The role of microbial mats in mineral precipitation processes is not fully clarified. For the first time, a comprehensive metagenomic analysis has been undertaken in the historical Bullicame hot spring. Bacterial biodiversity was characterized and biomineralization activities were assigned to different genera. A higher biodiversity in mat samples compared to water samples was observed: Shannon index of 3.34 and 0.86, respectively. Based on the functional assignment of each Operational Taxonomic Unit, the bacteria involved in biologically- induced mineralization are prevalent in mat and released in the water. According to the principle that each geothermal water specimen has distinctive physic-chemical characteristics, our results suggest new interacting bio-actions within these ecosystems. The saturation index and the chemical composition, as the high concentration of sulfur species and HCO3, can be linked to create a selective environment where pioneer communities are able to live and shape the ecosystem. PMID- 29498742 TI - Potential associations between atazanavir exposure and clinical outcome: a pharmacokinetic sub-study from the MODAt randomized trial. AB - The 96-week results of the Monotherapy Once a Day with Atazanavir/r (MODAt) study [NCT01511809] showed an inferior virological efficacy of atazanavir (ATV)/ritonavir monotherapy versus triple therapy, which was promptly retrieved by the reintroduction of nucleoside/nucleotide inhibitors of reverse transcriptase [N(n)RTIs]. We aimed to identify potential relationships between ATV exposure and clinical outcome in HIV-1 subjects treated with ATV/ritonavir monotherapy [ATV/r 300/100 mg] versus ATV/ritonavir triple therapy [ATV/r 300/100 mg+2NRTIs]. A chromatographic method coupled with tandem mass spectrometry was applied to analyze ATV plasma concentrations in a pharmacokinetic sub-study from the MODAt trial. Mixed linear models were used to examine the ATV plasma concentration trend during follow-up and to assess the association between ATV plasma concentrations trajectories with the study arm or the occurrence of treatment failure or drugrelated adverse events or the grading of baseline total bilirubin (<3 vs >=3). The analyses were performed using SAS Software, release 9.4 (SAS Institute, Cary, NC, USA). Overall, ATV plasma Ctrough concentration did not vary during follow-up (slope: +0.75 ng/mL/week, 95%CI: -0.97 to 2.47, p=0.387); trajectories did not differ between study arms (p=0.527). The unadjusted model-based means (95%CI) of ATV Ctrough during follow-up were 835 (95%CI: 657-1012) ng/ml in the ATV/r monotherapy arm as compared to 911 (95%CI: 740-1082) ng/mL in the ATV/r triple therapy arm (p=0.621). Mean ATV Ctrough was similar in subjects with or without adverse events (AEs). Subjects treated with ATV/r monotherapy showed significantly higher ATV concentrations as compared to subjects without adverse events or treated with ATV/r triple therapy. ATV concentrations were associated with the grading of baseline total bilirubin and the occurrence of drug-related AEs but not with HCV infection. Our findings showed a lack of association between ATV concentrations and treatment failure both in ATV/r monotherapy and triple therapy. Conversely, these data emphasized that ATV concentrations are associated with the development of side-effects in both subjects treated with ATV/r monotherapy and subjects treated with ATV/r triple therapy. PMID- 29498743 TI - Amiodarone affects Ebola virus binding and entry into target cells. AB - Ebola Virus Disease is one of the most lethal transmissible infections characterized by a high fatality rate. Several research studies have aimed to identify effective antiviral agents. Amiodarone, a drug used for the treatment of arrhythmias, has been shown to inhibit filovirus infection in vitro by acting at the early step of the viral replication cycle. Here we demonstrate that amiodarone reduces virus binding to target cells and slows down the progression of the viral particles along the endocytic pathway. Overall our data support the notion that amiodarone interferes with Ebola virus infection by affecting cellular pathways/ targets involved in the viral entry process. PMID- 29498744 TI - Behaviour of Bdellovibrio bacteriovorus in the presence of Gram-positive Staphylococcus aureus. AB - The present study aimed to characterize the behavior of Bdellovibrio bacteriovorus in the presence of Staphylococcus aureus. B. bacteriovorus was co cultured with S. aureus or Pseudomonas aeruginosa or Streptococcus mutans, in planktonic and sessile conditions. Co-cultures were studied by Field-Emission Scanning Electron Microscopy (FESEM), Scanning Transmission Electron Microscopy (STEM), turbidimetry, quantitative PCR (qPCR), and sequencing of gene Bd0108 of B. bacteriovorus. Results indicated that B. bacteriovorus comparably inhibited planktonic growth of P. aeruginosa and S. aureus, but not of S. mutans. FESEM and STEM showed that B. bacteriovorus interacts with S. aureus affecting its cell wall and membrane. Sequencing of gene Bd0108 did not reveal any of the mutations that can arise from the host-interaction (hit) locus. Although some Gram-negative species are reported to be B. bacteriovorus prey, it seems that in case of nutrient deficiency this predatory bacterium can also take advantage of some Gram positive species. B. bacteriovorus behaviour in the presence of S. aureus is relevant for its possible therapeutic use in several pathologies, like cystic fibrosis in which S. aureus and P. aeruginosa frequently coexist as infectious agents. PMID- 29498745 TI - Molecular typing of Burkholderia cepacia complex isolated from patients attending an Italian Cystic Fibrosis Centre. AB - Bacteria from the Burkholderia cepacia complex (Bcc) are capable of causing severe infections in patients with cystic fibrosis (CF). Bcc infection is often extremely difficult to treat due to its intrinsic resistance to multiple antibiotics. In addition, it seems to speed up the decline of lung function and is considered a contraindication for lung transplantation in CF. This study investigates the species of the Bcc strains recovered from chronically infected CF subjects by means of: isolation, identification methods and complete recA nucleotide sequences of 151 samples. Molecular typing showed that B. cenocepacia III is the dominant strain found in the group of subjects being treated at the Milan CF Centre (Italy) and that the infection is chronically maintained by the same species. Defining species by means of molecular analysis yields important information for the clinician in order to establish the most appropriate therapy and implement correct measures for prevention of transmission among CF subjects. PMID- 29498746 TI - Self-Management Support and eHealth When Managing Changes in Behavior and Mood of a Relative With Dementia: An Asynchronous Online Focus Group Study of Family Caregivers' Needs. AB - The current article discusses how and by whom family caregivers want to be supported in self-management when managing changes in behavior and mood of relatives with dementia and whether family caregivers consider eHealth a useful tool for self-management support. Four asynchronous online focus groups were held with 32 family caregivers of individuals with dementia. Transcripts of the online focus groups were analyzed using qualitative thematic analysis. Family caregivers need support from professionals or peers in the form of (a) information about dementia and its symptoms, (b) tips and advice on managing changes in behavior and mood, (c) opportunities to discuss experiences and feelings, and (d) appreciation and acknowledgement of caregiving. The opinions of family caregivers about self-management support through eHealth were also reported. Findings suggest a personal approach is essential to self-management support for family caregivers managing changes in behavior and mood of relatives with dementia. In addition, self-management support can be provided to some extent through eHealth, but this medium cannot replace personal contacts entirely. [Res Gerontol Nurs. 2018; 11(3):151-159.]. PMID- 29498748 TI - Feasibility and Pilot Testing of a Mindfulness Intervention for Frail Older Adults and Individuals With Dementia. AB - : Mindfulness interventions have been beneficial for healthy adults and individuals experiencing a stressful medical or mental health diagnosis. The purposes of the current study were to: (a) determine feasibility of mindfulness for older adults in long-term residential settings, and (b) examine differences in outcomes between a mindfulness and cognitive activity. The current study is the first mindfulness study to include individuals in moderate and severe stages of dementia, and included 36 individuals with a range of cognitive abilities. A crossover design was used, and the intervention was feasible for continued practice by individuals with cognitive impairment. Statistically significant short-term changes in agitation, discomfort, anger, and anxiety were found. Nighttime sleep did not improve, but participants slept less during the day. Long term changes in outcomes were not found. Mindfulness may be useful in decreasing emotional reactivity and improving well-being of older adults in long-term care. TARGETS: Individuals with multiple chronic conditions, including cognitive impairment. INTERVENTION DESCRIPTION: The Present in the Now (PIN) intervention is a mindfulness intervention with three components: attentional skill exercises, body awareness activities, and compassion meditation. MECHANISMS OF ACTION: Mindfulness acts to decrease emotional reactivity through cognitive and affective mechanisms of action and neural activation of the cingulate cortex, amygdala, and hippocampus. OUTCOMES: Agitation, affect, stress, sleep, discomfort, and communication of need. [Res Gerontol Nurs. 2018; 11(3):137-150.]. PMID- 29498747 TI - Supporting Transitions in Care for Older Adults With Type 2 Diabetes Mellitus and Obesity. AB - : The aim of the current study was to compare outcomes for older adults with type 2 diabetes mellitus and obesity following participation in a transitional care intervention that included diabetes self-management education (DSME) and homecare. The three groups analyzed comprised an inpatient DSME plus homecare group (n = 35); an inpatient DSME only group (n = 100); and a group who received usual care (n = 45). Outcomes of interest included rehospitalization rates and hemoglobin A1C (A1C) for up to 1-year post hospital discharge. Rates of rehospitalization and A1C improved for older adults who received nurse-led inpatient DSME and homecare during transitions of care from hospital to home. Rehospitalization rates up to 90 days were decreased for the DSME plus homecare group (10%) compared to DSME only (20%) and usual care groups (26.7%) (p < 0.05). A decrease of -0.4 and -2.3 A1C units was observed for the DSME group and DSME plus homecare group, respectively, at 90 days. These results support a transitional care educational intervention for older adults with type 2 diabetes mellitus and obesity. TARGETS: Older adults with type 2 diabetes mellitus and obesity. INTERVENTION DESCRIPTION: Transitional care intervention including diabetes self-management education and homecare. MECHANISMS OF ACTION: Inpatient diabetes education and homecare helps improve rates of rehospitalization and hemoglobin A1C during care transitions from hospital to home. OUTCOMES: Rehospitalization rates, glycemic control (i.e., A1C level). [Res Gerontol Nurs. 2018; 11(2):71-81.]. PMID- 29498749 TI - Falls and Social Isolation of Older Adults in the National Health and Aging Trends Study. AB - A longitudinal secondary analysis of 2 years of data from the National Health and Aging Trends Study was undertaken to determine the extent to which social isolation predicts falls in older adults. Social isolation during Year 1 (baseline) was operationalized as a multiple-indicator measure based on Social Network Index participation domains. Falling during the previous year was self reported using Year 2 data. Logistic regression models revealed social isolation significantly predicted falls (odds ratio [OR] = 1.11; 95% confidence interval [CI] [1.05, 1.17]). The relationship remained significant after adjusting for age, gender, and education (OR = 1.08; 95% CI [1.02, 1.14]). The relationship weakened after adjusting for self-reported general health, depression risk, and worry about falling (OR = 1.02; 95% CI [0.96, 1.08]). Adjusting for Short Physical Performance Battery (SPPB), assistive mobility device, and activities of daily living further weakened the relationship (OR = 0.99; 95% CI [0.94, 1.04]). SPPB demonstrated the strongest correlation with social isolation (r = -0.42; p < 0.01). Fall prevention intervention studies specifically targeting social isolation may incorporate physical performance as a shorter-term and cost effective proxy outcome for falls. [Res Gerontol Nurs. 2018; 11(2):61-70.]. PMID- 29498750 TI - Genetic risk factors for osteochondrosis in various horse breeds. AB - Osteochondrosis (OC) is an injury to cartilage canals with a following necrosis in the growth cartilage, from there it can develop to osteochondrosis dissecans (OCD). Due to its high impact in the equine industry, new insights into predisposing factors and potential high-risk genetic variants are warranted. This article reviews advancements in quantitative and molecular genetics in refining estimation of genetic parameters and identifying predisposing genetic loci. Heritabilities were highest for hock OC with estimates at 0.29-0.46 in Hanoverian warmblood and Norwegian trotters, whereas in Thoroughbreds only very low genetic variation seemed to be present in hock OC lesions. Whole genome scans using the Illumina Equine SNP50 or SNP70 Beadchip were performed in Thoroughbred, Standardbred, French and Norwegian trotter, Hanoverian and Dutch warmblood. Validation studies in Spanish Purebred and Hanoverian warmblood horses corroborated OC risk loci on ECA 3, 14, 27 and 29. Particularly, a strong association with hock-OCD was found for a single nucleotide polymorphism (SNP) on horse chromosome (ECA) 3 upstream to the LCORL gene. Gene expression and microRNA analyses may be helpful to understand pathophysiological processes in equine OC and to connect OCD-associated genomic regions with potential candidate genes. Furthermore progress in elucidating the underlying genetic variants and pathophysiological changes in OC may be expected from whole genome DNA and RNA next-generation sequencing studies. PMID- 29498751 TI - National survey showed that Chinese city children under two years of age had similar feeding patterns to developed countries. AB - AIM: This 2015 study was a part of the National Growth Survey of Children under seven years of age, which has been carried out in nine Chinese cities every 10 years since 1975. Our aim was to assess children's feeding practices and nutritional supplements. METHODS: This was a cross-sectional survey of 89 006 healthy children aged one to 24 months. All data were collected by face-to-face interviews during child health visits, using a questionnaire. RESULTS: The exclusive breastfeeding rate was 53% in infants under six months of age, and the continued breastfeeding rate was 51% among infants who were 10-12 months and 5% when they were 21-24 months. Infants were weaned at a mean of 9.3 months in urban areas and 9.4 months in suburban areas. Cereals were provided as complementary food at a mean age of five months, eggs at six months, meat at eight and a half months and bean products at over 12 months. The most common nutritional supplements given to the children were vitamins A and D and calcium. CONCLUSION: The feeding practices of Chinese city children were similar to those in developed countries, but strategies are needed to promote more rational consumption of nutritional supplements. PMID- 29498752 TI - Why names matter for women: MINOCA/INOCA (myocardial infarction/ischemia and no obstructive coronary artery disease). AB - The syndromes of myocardial infarction/myocardial ischemia with No Obstructive Coronary Artery Disease (MINOCA/INOCA) are increasingly evident. A majority of these patients have coronary microvascular dysfunction. These patients have elevated risk for a cardiovascular event (including acute coronary syndrome, myocardial infarction, stroke, and repeated cardiovascular procedures) and appear to be at higher risk for development of heart failure with preserved ejection fraction. Terminology such as coronary artery disease or coronary heart disease is often synonymous with obstructive atherosclerosis in the clinician's mind, leaving one at a loss to recognize or explain the phenomenon of MINOCA and INOCA with elevated risk. We review the available literature regarding stable and unstable ischemic heart disease that suggests that use of the ischemic heart disease (IHD) terminology matters for women, and should facilitate recognition of risk to provide potential treatment targets and optimized health. PMID- 29498753 TI - Text Messaging to Reduce Alcohol Relapse in Prelisting Liver Transplant Candidates: A Pilot Feasibility Study. AB - BACKGROUND: Many liver transplantation programs require documented alcohol sobriety prior to United Network for Organ Sharing (UNOS) listing. This pilot study examined the feasibility of the first mobile, alcohol relapse prevention intervention for liver transplant patients with alcoholic liver disease (ALD). METHODS: This was a randomized 8-week pilot feasibility trial of a text message based alcohol intervention. In-treatment assessment was conducted at 4 weeks (4W), and immediate posttreatment assessment was conducted at 8W. Participants were liver transplant candidates (N = 15) diagnosed with ALD who reported at least 1 drinking episode in the past year. Primary feasibility outcomes were percent of messages responded to and posttreatment intervention satisfaction ratings. Preliminary clinical efficacy outcomes were any biologically confirmed alcohol consumption, stress, abstinence self-efficacy, and alcohol craving. RESULTS: On feasibility outcomes, participants responded to 81% of messages received and reported high rates of intervention satisfaction, looked forward to receiving the messages, and found it easy to complete the intervention. On preliminary efficacy outcomes, zero participants in the text message (TM) had positive urine alcohol tests at 8W. Two of the 6 participants in standard care (SC) tested positive at 8W. No effects were seen on craving. For stress, a condition * time interaction emerged. TM participants had less stress at 4W and 8W compared with SC at baseline. They maintained their stress level during the intervention. For self-efficacy, a trend for condition effect emerged. TM participants had higher self-efficacy than SC participants. CONCLUSIONS: Participants reported high satisfaction with the intervention, looked forward to the messages, and found it easy to complete. Participants who received the intervention had better treatment outcomes than those who received standard care. They maintained higher levels of self-efficacy and lower stress. Mobile alcohol interventions may hold significant promise to help ALD liver transplant patients maintain sobriety. PMID- 29498754 TI - Association of oral health literacy with oral health behaviors, perception, knowledge, and dental treatment related outcomes: a systematic review and meta analysis. AB - OBJECTIVES: To conduct a systematic review and meta-analysis regarding the association of oral health literacy (OHL) with oral health behaviors, perception, knowledge, and dental treatment related outcomes. METHODS: Eight electronic databases were searched up until June 2017. Studies regarding the aforementioned outcomes measuring OHL through a validated instrument and in which OHL was an explanatory variable were included. Two independent reviewers selected studies, extracted data, and analyzed the risk of bias of the studies. Meta-analysis using random effect modeling was undertaken. Pooled estimates were calculated with 95 percent confidence interval (CI) and odds ratios (OR). RESULTS: Twenty-five studies were included in the systematic review and three in the meta-analysis. Most studies were cross-sectional (n = 21) and had a high risk of bias (n = 17). The meta-analysis showed no association between OHL and frequency of visit to the dentist for adults, either through bivariate analysis (OR = 1.25; 95 percent CI: 0.95-1.63) or multivariate analysis (OR = 1.90; 95 percent CI: 0.77-4.84). Dental anxiety and night bottle-feeding were associated with low OHL (P < 0.05). Most studies regarding tooth brushing frequency found no association with OHL. Most studies regarding oral health knowledge related outcomes reported an association with higher OHL. The literature was inconclusive regarding the association between OHL and dental treatment outcomes, oral health behaviors, and oral health perception. CONCLUSIONS: The current scientific evidence suggests that no association exists between OHL and any of the outcomes investigated. Further prospective studies with a higher methodological quality are necessary to confirm the evidence. PMID- 29498755 TI - Simultaneous determination of residues of thiamethoxam and its metabolite clothianidin in tobacco leaf and soil using liquid chromatography-tandem mass spectrometry. AB - A simple analytical method was developed to simultaneously determine thiamethoxam and its metabolite, clothianidin, in fresh tobacco leaf, soil and cured tobacco leaf using liquid chromatography with tandem mass spectrometry. Thiamethoxam and clothianidin in tobacco and soil samples were extracted with acetonitrile containing 0.1% formic acid and purified using an NH2 -SPE column. The optimized method provided good linearity with coefficients of determination R2 >= 0.9981. The limits of detection and quantification were between 0.006-0.12 and 0.02-0.4 mg/kg, respectively. Intra- and inter-day recovery assays were used to validate the established method. The average recoveries of thiamethoxam and clothianidin in fresh tobacco leaf, soil and cured tobacco leaf were 75.04-100.47%, 75.86 86.40% and 89.83-99.39%, respectively. The intra- and inter-day relative standard deviations were all <9%. The developed method was successfully applied for the analysis of thiamethoxam and clothianidin residues in actual tobacco and soil samples. The results indicated that the established method met the requirements for the analysis of trace amounts of thiamethoxam and clothianidin in fresh tobacco leaf, soil and cured tobacco leaf. PMID- 29498756 TI - Activation of RhoA, Smad2, c-Src, PKC-betaII/delta and JNK in atopic dermatitis. AB - Atopic dermatitis is a multifactorial skin disease characterised by chronic and relapsing inflammation whose pathogenesis is incompletely understood. We found that the expression of TGFbetaR1 and the activation of SMAD2, RhoA, JNK, PKC betaII/delta and c-Src were upregulated in the infiltrated inflammatory cells, fibroblasts and vasculatures in the dermis and epidermis. In addition, increases in the expression of TGFbetaR1 and phosphorylation levels of JNK and c-Src were positively correlated with the inflammatory progression of atopic dermatitis severity. PMID- 29498757 TI - Quantification of amlodipine and atorvastatin in human plasma by UPLC-MS/MS method and its application to a bioequivalence study. AB - A robust, rapid and sensitive UPLC-MS/MS method has been developed, optimized and validated for the determination of amlodipine (AML) and atorvastatin (ATO) in human plasma using eplerenone as an internal standard (IS). Multiple-reaction monitoring in positive electrospray ionization mode was utilized in Xevo TQD LC MS/MS. Double extraction was used in sample preparation using diethyl ether and ethyl acetate. The prepared samples were analyzed using an Acquity UPLC BEH C18 (50 * 2.1 mm, 1.7 MUm) column. Ammonium formate and acetonitrile, pumped isocraticaly at a flow rate of 0.25 mL/min, were used as a mobile phase. Method validation was done as per the US Food and Drug Administration guidelines. Linearity was achieved in the range of 0.1-10 ng/mL for AML and 0.05-50 ng/mL for ATO. Intra-day and inter-day accuracy and precision were calculated and found to be within the acceptable range. A short run time, of <1.5 min, permits analysis of a large number of plasma samples per batch. The developed and validated method was applied to estimate AML and ATO in a bioequivalence study in healthy human volunteers. PMID- 29498759 TI - Lessons learnt from the epidemiology of Helicobacter pylori infection in Malaysia: JGHF Marshall and Warren Lecture 2017. AB - The study of Helicobacter pylori in Malaysia has given several important insights into the epidemiology of the infection and pathogenesis of disease. Malaysia has a multiracial Asian population with three major Asian races living together Malay, Chinese, and Indian. Races remain fairly distinct because of a paucity of interracial marriages. The "Racial Cohort Hypothesis" proposes that the infection occurs within racial groups rather than between. As such, the high prevalence among Indians (> 50%) and Chinese (40-50%) reflects the high prevalence in their countries of origin even though migration had taken place more than two generations before. The Malays have a comparatively low prevalence of about 10 20%. Despite the high prevalence of H. pylori, the Indians have a low gastric cancer incidence of less than 10 per 100 000 per year. This is in contrast to the Chinese who has an incidence in excess of 20 per 100 000 per year. We have called this the "Indian Enigma." The reason for this enigma is unclear and is the result of interaction between bacterial virulence factors, host susceptibility, and environmental factors. Phylogenetically, Chinese bacterial strains are distinct from Indians and Malays and are predominantly hpEastAsia/hsp EAsia. CagA EPIYA motifs among Chinese belong predominantly to the more virulent ABD motif. There is no clear distinguishing profile among host genetic factors. Environmental factors particularly diet may play an important role. Indians consume chilies and curries, which may be gastro protective, whereas Chinese consume more preserved and salted foods, which are thought to be carcinogenic. PMID- 29498758 TI - A review of the growing risk of vitamin D toxicity from inappropriate practice. AB - Vitamin D is a particularly important sterol hormone, with evidence emerging of its beneficial effects well beyond bone. In consequence of this and increased global recognition of vitamin D deficiency in the general population, there has been a resurgence in treatment with vitamin D preparations. However, the increasing use of vitamin D treatments has also seen a substantial increase in the number of reports of vitamin D intoxication, with the majority (75%) of reports published since 2010. Many of these cases are a consequence of inappropriate prescribing, and the use of high-dose over-the-counter preparations or unlicensed preparations. This review highlights that the majority of cases were preventable and discusses the inappropriate use of poorly formulated, and unlicensed vitamin D preparations. PMID- 29498760 TI - Macrocephaly diagnosed during well child visits. AB - BACKGROUND: The measurement of head circumference (HC) provides valuable anthropometric data for a child's growth during well child visits. There are few studies on the characteristics of macrocephaly (MC) diagnosed during well child visits. The aim of this study was to identify the characteristics of children with MC diagnosed during the well-child visits. METHODS: This descriptive clinical study was carried out in the well child unit of a medical faculty hospital. The health records of all children who were followed up between 2004 and 2014 were reviewed. The records of children with the diagnosis of MC were evaluated. All children with MC had cranial ultrasonography, measurement of parental HC, and biochemistry. The HC measurements were carried out until 3 years of age in the unit. RESULTS: Ninety of 9,758 children (0.9%) had the diagnosis of MC. Of these children, 61% were male. Mean age at diagnosis was 2.7 months. The majority of children (63.3%) had familial MC. The other leading findings were isolated MC and hydrocephalus: two of eight children with hydrocephalus had delayed neuromotor development. CONCLUSION: MC was not rare in the present well child unit population. The evaluation of parental HC and cranial ultrasonography might be important for the differential diagnosis. PMID- 29498762 TI - The effects of capillary transit time heterogeneity on the BOLD signal. AB - Neurovascular coupling mechanisms give rise to vasodilation and functional hyperemia upon neural activation, thereby altering blood oxygenation. This blood oxygenation level dependent (BOLD) contrast allows studies of activation patterns in the working human brain by functional MRI (fMRI). The BOLD-weighted fMRI signal shows characteristic transients in relation to functional activation, such as the so-called initial dip, overshoot, and post-stimulus undershoot. These transients are modulated by other physiological stimuli and in disease, but the underlying physiological mechanisms remain incompletely understood. Capillary transit time heterogeneity (CTH) has been shown to affect oxygen extraction, and hence blood oxygenation. Here, we examine how recently reported redistributions of capillary blood flow during functional activation would be expected to affect BOLD signal transients. We developed a three-compartment (hemoglobin, plasma, and tissue) model to predict the BOLD signal, incorporating the effects of dynamic changes in CTH. Our model predicts that the BOLD signal represents the superposition of a positive component resulting from increases in cerebral blood flow (CBF), and a negative component, resulting from elevated tissue metabolism and homogenization of capillary flows (reduced CTH). The model reproduces salient features of BOLD signal dynamics under conditions such as hypercapnia, hyperoxia, and caffeine intake, where both brain physiology and BOLD characteristics are altered. Neuroglial signaling and metabolism could affect CBF and capillary flow patterns differently. Further studies of neurovascular and neuro-capillary coupling mechanisms may help us relate BOLD signals to the firing of certain neuronal populations based on their respective BOLD "fingerprints." PMID- 29498763 TI - The neural correlates of morphological complexity processing: Detecting structure in pseudowords. AB - Morphological complexity is a highly debated issue in visual word recognition. Previous neuroimaging studies have shown that speakers are sensitive to degrees of morphological complexity. Two-step derived complex words (bridging through bridgeN > bridgeV > bridging) led to more enhanced activation in the left inferior frontal gyrus than their 1-step derived counterparts (running through runV > running). However, it remains unclear whether sensitivity to degrees of morphological complexity extends to pseudowords. If this were the case, it would indicate that abstract knowledge of morphological structure is independent of lexicality. We addressed this question by investigating the processing of two sets of pseudowords in German. Both sets contained morphologically viable two step derived pseudowords differing in the number of derivational steps required to access an existing lexical representation and therefore the degree of structural analysis expected during processing. Using a 2 * 2 factorial design, we found lexicality effects to be distinct from processing signatures relating to structural analysis in pseudowords. Semantically-driven processes such as lexical search showed a more frontal distribution while combinatorial processes related to structural analysis engaged more parietal parts of the network. Specifically, more complex pseudowords showed increased activation in parietal regions (right superior parietal lobe and left precuneus) relative to pseudowords that required less structural analysis to arrive at an existing lexical representation. As the two sets were matched on cohort size and surface form, these results highlight the role of internal levels of morphological structure even in forms that do not possess a lexical representation. PMID- 29498761 TI - Aberrant functional network connectivity in psychopathy from a large (N = 985) forensic sample. AB - Psychopathy is a personality disorder characterized by antisocial behavior, lack of remorse and empathy, and impaired decision making. The disproportionate amount of crime committed by psychopaths has severe emotional and economic impacts on society. Here we examine the neural correlates associated with psychopathy to improve early assessment and perhaps inform treatments for this condition. Previous resting-state functional magnetic resonance imaging (fMRI) studies in psychopathy have primarily focused on regions of interest. This study examines whole-brain functional connectivity and its association to psychopathic traits. Psychopathy was hypothesized to be characterized by aberrant functional network connectivity (FNC) in several limbic/paralimbic networks. Group-independent component and regression analyses were applied to a data set of resting-state fMRI from 985 incarcerated adult males. We identified resting-state networks (RSNs), estimated FNC between RSNs, and tested their association to psychopathy factors and total summary scores (Factor 1, interpersonal/affective; Factor 2, lifestyle/antisocial). Factor 1 scores showed both increased and reduced functional connectivity between RSNs from seven brain domains (sensorimotor, cerebellar, visual, salience, default mode, executive control, and attentional). Consistent with hypotheses, RSNs from the paralimbic system-insula, anterior and posterior cingulate cortex, amygdala, orbital frontal cortex, and superior temporal gyrus-were related to Factor 1 scores. No significant FNC associations were found with Factor 2 and total PCL-R scores. In summary, results suggest that the affective and interpersonal symptoms of psychopathy (Factor 1) are associated with aberrant connectivity in multiple brain networks, including paralimbic regions. PMID- 29498765 TI - Noninvasive extraction of microsecond-scale dynamics from human motor cortex. AB - State-of-the-art noninvasive electromagnetic recording techniques allow observing neuronal dynamics down to the millisecond scale. Direct measurement of faster events has been limited to in vitro or invasive recordings. To overcome this limitation, we introduce a new paradigm for transcranial magnetic stimulation. We adjusted the stimulation waveform on the microsecond scale, by varying the duration between the positive and negative phase of the induced electric field, and studied corresponding changes in the elicited motor responses. The magnitude of the electric field needed for given motor-evoked potential amplitude decreased exponentially as a function of this duration with a time constant of 17 us. Our indirect noninvasive measurement paradigm allows studying neuronal kinetics on the microsecond scale in vivo. PMID- 29498764 TI - Recurrent attacks of acute hepatic porphyria: major role of the chronic inflammatory response in the liver. AB - BACKGROUND: Acute intermittent porphyria (AIP) is an inherited disorder of haem metabolism characterized by life-threatening acute neurovisceral attacks due to the induction of hepatic delta-aminolevulinic acid synthase 1 (ALAS1) associated with hydroxymethylbilane synthase (HMBS) deficiency. So far, the treatment of choice is hemin which represses ALAS1. The main issue in the medical care of AIP patients is the occurrence of debilitating recurrent attacks. OBJECTIVE: The aim of this study was to determine whether chronic hemin administration contributes to the recurrence of acute attacks. METHODS: A follow-up study was conducted between 1974 and 2015 and included 602 French AIP patients, of whom 46 had recurrent AIP. Moreover, we studied the hepatic transcriptome, serum proteome, liver macrophage polarization and oxidative and inflammatory profiles of Hmbs-/- mice chronically treated by hemin and extended the investigations to five explanted livers from recurrent AIP patients. RESULTS: The introduction of hemin into the pharmacopeia has coincided with a 4.4-fold increase in the prevalence of chronic patients. Moreover, we showed that both in animal model and in human liver, frequent hemin infusions generate a chronic inflammatory hepatic disease which induces HO1 remotely to hemin treatment and maintains a high ALAS1 level responsible for recurrence. CONCLUSION: Altogether, this study has important impacts on AIP care underlying that hemin needs to be restricted to severe neurovisceral crisis and suggests that alternative treatment targeting the liver such as ALAS1 and HO1 inhibitors, and anti-inflammatory therapies should be considered in patients with recurrent AIP. PMID- 29498766 TI - Morphological Characterizations of Four Species of Parallelostrombidium (Ciliophora, Oligotrichia), with a Note on the Phylogeny of the Genus. AB - The morphology and phylogeny of four oligotrichid ciliates, Parallelostrombidium paraellipticum sp. n., P. dragescoi sp. n., P. jankowskii (Xu et al. 2009) comb. n., and P. kahli (Xu et al. 2009) comb. n., are described or redescribed based on live observation, protargol stained material, and SSU rRNA gene sequences. The new species P. paraellipticum sp. n. is characterized by its obovoidal cell shape, adoral zone composed of 17-21 collar, 9-11 buccal, and two thigmotactic membranelles, and extrusomes attached in one row along the girdle kinety. The new species P. dragescoi sp. n. is distinguished from its congeners by its obovoidal cell shape and a lack of thigmotactic membranelles. Based on ciliary patterns recognizable in the original slides, Omegastrombidium jankowskii Xu et al. 2009 and O. kahli Xu et al. 2009 should be transferred to the genus Parallelostrombidium Agatha 2004. Phylogenetic analyses based on SSU rRNA gene sequence data demonstrate that all four new sequences cluster with previously described congeners. The genus Parallelostrombidium is separated into two clusters, suggesting its non-monophyly and probably corresponding to the two subgenera proposed by Agatha and Struder-Kypke (2014), as well as their morphological difference (cell dorsoventrally flattened vs. unflattened). PMID- 29498767 TI - Dermal fibroblasts can activate matrix metalloproteinase-1 independent of keratinocytes via plasmin in a 3D collagen model. AB - Photoaging of the skin is marked by obvious wrinkles and mainly depends on degradation of the extracellular matrix (ECM) in the dermis. Matrix metalloproteinase (MMP)-1 is one of the most important factors involved in degradation of the ECM; however, its mechanism of activation is not fully understood. It has been thought that MMP-1 is expressed by dermal fibroblasts as an inactive precursor protein that is activated by proteinases produced by keratinocytes in the epidermis. In this study, we constructed a 3D model of the dermis using collagen-embedded fibroblasts with or without ultraviolet (UV)-A exposure to mimic photoaging in the dermis. Collagen lattices embedded with UV-A irradiated fibroblasts miniaturized and collagen was degraded to a greater extent than collagen lattices embedded with non-irradiated fibroblasts. The results demonstrate that fibroblasts in this 3D model express activated MMP-1 in the absence of keratinocytes. Moreover, the results confirm that activation of MMP-1 depends on increased plasmin activity in this model and lattice miniaturization was inhibited by the plasmin inhibitor tranexamic acid. Our results suggest that plasmin acts as an activator of MMP-1 and the inhibition of plasmin prevents collagen degradation. PMID- 29498768 TI - Psychological impact of multigene cancer panel testing in patients with a clinical suspicion of hereditary cancer across Spain. AB - OBJECTIVE: Patients' psychological reactions to multigene cancer panel testing might differ compared with the single-gene testing reactions because of the complexity and uncertainty associated with the different possible results. Understanding patients' preferences and psychological impact of multigene panel testing is important to adapt the genetic counselling model. METHODS: One hundred eighty-seven unrelated patients with clinical suspicion of hereditary cancer undergoing a 25-gene panel test completed questionnaires after pretest genetic counselling and at 1 week, 3 months, and 12 months after results to elicit their preferences regarding results disclosure and to measure their cancer worry and testing-specific distress and uncertainty. RESULTS: A pathogenic variant was identified in 38 patients (34 high penetrance and 4 moderate penetrance variants), and 54 patients had at least one variant of uncertain significance. Overall, cancer panel testing was not associated with an increase in cancer worry after results disclosure (P value = .87). Twelve months after results, carriers of a moderate penetrance variant had higher distress and uncertainty scores compared with carriers of high penetrance variants. Cancer worry prior to genetic testing predicted genetic testing specific distress after results, especially at long term (P value <.001). Most of the patients reported the wish to know all genetic results. CONCLUSIONS: Our results suggest that patients can psychologically cope with cancer panel testing, but distress and uncertainty observed in carriers of moderate penetrance cancer variants in this cohort warrant further research. PMID- 29498769 TI - Contrast coding in the primary visual cortex depends on temporal contexts. AB - Contrast response function in the primary visual cortex (V1) has long been described as following a sigmoid curve. However, this is mainly based on measuring neural responses to drifting contrast grating in a stable stimulation, a model that does not consider the effects of motion or length of stimulus presentation. During natural viewing, the visual system can obtain sufficient information for identifying the shapes defined by contrast from a single glance; acquiring greater knowledge of the neuronal response properties to contrast in such a short timescale is necessary to understand the underlying mechanisms. We investigated responses of cat V1 neurons to contrast presented by static grating for 40 ms without pause compared to drifting grating presented continuously for 2000 ms. The neuronal response to transiently presented contrast could be well described by a linear function. Further examination of the effects of motion and presentation duration on contrast responses demonstrated that motion increased response sensitivity in the low-contrast range, while brief presentation increased response sensitivity in the high-contrast range. Motion and prolonged presentation (adaptation) together resulted in an asymptotic sigmoid curve with a saturation response in the high-contrast range. These results suggest that motion mainly enhance the neural response sensitivity to low-contrast objects, while short and rapid presentation mainly enhance the neural sensitivity to high contrast stimulus. Our findings indicate that multiple factors influence the properties of contrast response functions, suggesting that V1 neuron contrast coding is flexible and depends on the temporal contexts. PMID- 29498771 TI - Single unit activity of periaqueductal gray and deep mesencephalic nucleus neurons involved in sleep stage switching in the mouse. AB - A total of 668 single units were recorded in the mouse periaqueductal gray (PAG) and adjacent deep mesencephalic nucleus (DpMe) to determine their role in the switching of sleep-wake states, that is, wakefulness (W), slow-wave sleep (SWS) and paradoxical (or rapid eye movement) sleep (PS) in general, and, in particular, to determine whether PS-on and PS-off neurons involved in PS state switching are present in these structures and to identify neuronal substrates for the SWS-PS switching mediated by DpMe neurons. Both structures were found to contain similar percentages of W/PS-active neurons, which discharge at a higher rate during W and PS than during SWS, while W-active neurons, which discharge maximally during W, were found mainly in the PAG. Both also contained similar percentages of SWS/PS-active neurons, which discharge at higher rates during SWS and PS than during W, and PS-active neurons, which discharge maximally during PS, while SWS-active neurons, which discharge maximally during SWS, were found almost exclusively in the PAG. Both structures contained virtually no PS-on or PS-off neurons, which, respectively, discharge or cease firing selectively and tonically just prior to, and during, PS. Unlike the PAG, the DpMe contained many SWS/PS-on neurons, which discharge selectively at high rates during SWS and PS, but show a decrease in discharge rate at the transition from SWS to PS. Analysis of discharge profiles and trends in spike activity at the state transitions strongly suggests that PAG and DpMe neurons play an important role in the W-SWS, SWS-PS and/or PS-W switches. PMID- 29498770 TI - Iron-sulfur protein maturation in Helicobacter pylori: identifying a Nfu-type cluster carrier protein and its iron-sulfur protein targets. AB - Helicobacter pylori is anomalous among non nitrogen-fixing bacteria in containing an incomplete NIF system for Fe-S cluster assembly comprising two essential proteins, NifS (cysteine desulfurase) and NifU (scaffold protein). Although nifU deletion strains cannot be obtained via the conventional gene replacement, a NifU depleted strain was constructed and shown to be more sensitive to oxidative stress compared to wild-type (WT) strains. The hp1492 gene, encoding a putative Nfu-type Fe-S cluster carrier protein, was disrupted in three different H. pylori strains, indicating that it is not essential. However, Deltanfu strains have growth deficiency, are more sensitive to oxidative stress and are unable to colonize mouse stomachs. Moreover, Deltanfu strains have lower aconitase activity but higher hydrogenase activity than the WT. Recombinant Nfu was found to bind either one [2Fe-2S] or [4Fe-4S] cluster/dimer, based on analytical, UV-visible absorption/CD and resonance Raman studies. A bacterial two-hybrid system was used to ascertain interactions between Nfu, NifS, NifU and each of 36 putative Fe-S containing target proteins. Nfu, NifS and NifU were found to interact with 15, 6 and 29 putative Fe-S proteins respectively. The results indicate that Nfu, NifS and NifU play a major role in the biosynthesis and/or delivery of Fe-S clusters in H. pylori. PMID- 29498772 TI - SLAM family member 8 is involved in oncogenic KIT-mediated signalling in human mastocytosis. AB - The signalling lymphocytic activation molecule family member 8 (SLAMF8)/CD353 is a member of the CD2 family of proteins. Its ligand has not been identified. SLAMF8 is expressed by macrophages and suppresses cellular functions. No study has yet explored SLAMF8 expression or function in human mastocytosis, which features oncogenic KIT-mediated proliferation of human mast cells. SLAMF8 protein was expressed in human mastocytosis cells, immunohistochemically. SLAMF8 expression was also evident in the human mast cell lines, HMC1.2 (expressing oncogenic KIT) and LAD2 (expressing wild-type KIT) cells. SLAMF8 knock-down significantly reduced the KIT-mediated growth of HMC1.2 cells but not that of LAD2 cells. SLAMF8 knock-down HMC1.2 cells exhibited significant attenuation of SHP-2 activation and oncogenic KIT-mediated RAS-RAF-ERK signalling. An interaction between SLAMF8 and SHP-2 was confirmed in HMC1.2 cells and all pathological mastocytosis specimens examined (19 of 19 cases, 100%). Thus, SLAMF8 is involved in oncogenic KIT-mediated RAS-RAF-ERK signalling and the subsequent growth of human neoplastic mast cells mediated by SHP-2. SLAMF8 is a possible therapeutic target in human mastocytosis patients. PMID- 29498773 TI - Short-Term Interferential Transabdominal Electrical Stimulation Did Not Change Oral-Rectal Transit Time in Piglets. AB - BACKGROUND: Transcutaneous electrical stimulation (TES) using interferential current (IFC) is a new therapeutic treatment for constipation. Clinical studies show that TES-IFC for 3-6 months improves colonic transit, but it is not clear if short-term stimulation affects transit or the effect requires longer to develop. The aim of this study was to determine if TES-IFC for only four days affects oral rectal transit time in healthy pigs. METHODS: Twenty-two 4-5-week old large white female piglets had transit studies during week 4 and week 5 by placing a capsule containing 18 radiopaque plastic markers in the esophagus under anesthetic followed by x-rays at 6, 30, 54, and 78 hours. Animals were randomly assigned to active or control groups. The active group received TES for 30 min daily for four days. Interferential current was applied through four electrodes (4 * 4 cm), with two para-spinal just below the last rib and two on the belly at the same level. Stimulation was at 4000 Hz and 4080-4160 Hz with currents crossing through the abdominal cavity. RESULTS: Whole bowel transit times ranged from 7.7 to 72.2 hours, stomach transit from <1 to 63 hours, and bowel with rectum transit time from 5 to 53 hours. Transit times were the same for the control (median 28.4 hours) and TES-IFC (23.0 hours) groups in the prestimulation and stimulation weeks (control 23.0, TES-IFC 19.8 hours) with no change within or between groups. CONCLUSION: Four days of half-hour TES-IFC daily in healthy 5-week-old piglets did not change oral-rectal transit time. PMID- 29498774 TI - Telephone-based management of chronic pain in older adults in an integrated care program. AB - OBJECTIVE: Few studies have explored behavioral strategies for managing chronic pain in older adults. Pain Care Management (PCM) is a telephone-based behavioral intervention for chronic pain. The present study examined chronic pain characteristics among older adults and tested the delivery of PCM as an adjunct to depression and anxiety care management. METHODS: Participants were drawn from a state-sponsored program offering care management services to community members aged 65 and older who were prescribed a psychotropic medication by a primary care provider. Chronic pain information was collected for all participants in the state program (N = 250) and treatment outcome data were collected for a subset with significant chronic pain. Eighty participants with high chronic pain interference were offered PCM and compared to 80 participants with chronic pain who received monitoring only on depression, anxiety, and pain interference outcomes. RESULTS: Chronic pain was identified in 14% of older adults newly prescribed a psychotropic medication. Compared to monitoring only, PCM participants had higher odds of seeing a reduction of 2 or more points in pain interference at 6 months. Pain care management participants' anxiety scores significantly decreased over the study period. CONCLUSIONS: Older adults treated with psychotropic medications often also experience chronic pain that interferes with daily activities. A telephone-based care management intervention is acceptable and feasible with an older community-based population and can lead to improvements in anxiety symptoms and interference from chronic pain. Further research will help to refine interventions that may help improve symptoms and increase functioning with this population. PMID- 29498775 TI - IL-26 in allergic contact dermatitis: Resource in a state of readiness. AB - In this study, we investigated the role of IL-26 in allergic contact dermatitis (ACD), highlighting its' contribute in the cytotoxic mechanism responsible for the tissue injury. IL-26 is a signature Th17 cytokine, and immune cells are its predominant sources. Recently, it has shown that Th17 cell-derived-IL-26 functions like an antimicrobial peptide. Here, we hypothesized that IL-26 could be involved in cytotoxicity mechanism that underlies ACD. Indeed, we have attributed a role to IL-26 in this context, through PBMC cytotoxicity assays vs HaCat. To demonstrate that IL-26 was effectively involved in this activity, we performed the assay using transfected ACD PBMCs by siRNA for IL-26. Indeed, we demonstrated that these cells were less able to kill keratinocytes compared with ACD PBMCs (P < .01). In conclusion, our findings support the idea that this emergent cytokine, IL-26, is implicated in the killing mechanisms of KC observed during ACD. PMID- 29498776 TI - Deep in the brain: Changes in subcortical function immediately preceding a migraine attack. AB - The neural mechanism responsible for migraine remains unclear. While the role of an external trigger in migraine initiation remains vigorously debated, it is generally assumed that migraineurs display altered brain function between attacks. This idea stems from relatively few brain imaging studies with even fewer studies exploring changes in the 24 h period immediately prior to a migraine attack. Using functional magnetic resonance imaging, we measured infra slow oscillatory activity, regional homogeneity, and connectivity strengths of resting activity in migraineurs directly before (n = 8), after (n = 11), and between migraine attacks (n = 26) and in healthy control subjects (n = 78). Comparisons between controls and each migraine group and between migraine groups were made for each of these measures. Directly prior to a migraine, increased infra-slow oscillatory activity occurred in brainstem and hypothalamic regions that also display altered activity during a migraine itself, that is, the spinal trigeminal nucleus, dorsal pons, and hypothalamus. Furthermore, these midbrain and hypothalamic sites displayed increased connectivity strengths and regional homogeneity directly prior to a migraine. Remarkably, these resting oscillatory and connectivity changes did not occur directly after or between migraine attacks and were significantly different to control subjects. These data provide evidence of altered brainstem and hypothalamic function in the period immediately before a migraine and raise the prospect that such changes contribute to the expression of a migraine attack. PMID- 29498777 TI - Emotional distress with dementia: A systematic review using corpus-based analysis and meta-ethnography. AB - OBJECTIVE: More understanding is needed about the emotional experiences of dementia from the perspective of the individual. This understanding can then inform the provision of health care to meet individual needs. This systematic review aimed to present all available descriptions of emotional distress and explanations for emotional distress experienced by individuals with dementia, articulated personally and by others. METHODS: A systematic mixed-method review identified literature that was screened and quality appraised. Data were analysed quantitatively and qualitatively using corpus-based methods and meta-ethnography. RESULTS: The 121 included studies showed that individuals with dementia have expressed emotional distress comprehensibly. Family, professional caregivers, clinicians, and academic writers have also observed and described extreme emotional experiences. Feeling fearful and lonely were predominant and show the importance of anxiety in dementia. Explanations for emotional distress included threats to universal, human needs for identity, belonging, hope, and predictability. CONCLUSIONS: The variable and personal emotional experiences of individuals with dementia are well described and should not continue to be overlooked. Limitations, future research, and clinical implications are discussed. PMID- 29498778 TI - Normal abdominal aorta diameter in infants, children and adolescents. AB - BACKGROUND: The normal limits of arterial diameters must be known to diagnose pathologies such as dilatation, stenosis and hypoplasia. Thoracic aorta diameter in childhood has been measured in previous studies, but the number of studies in which normal aortic diameter is determined is very small. The aim of this study was therefore to determine the normal standard diameter of the aorta and iliac arteries in children according to gender and level. METHODS: Pediatric abdominal computed tomography carried out for various reasons was retrospectively re evaluated between January 2016 and February 2017. Patients were classified according to age into six groups. Vessel diameter, age, gender and vertebra diameter were evaluated. RESULTS: Mean proximal aorta diameter was 8.84 mm for 12 36 months, 10.02 mm for 37-84 months, 12.32 mm for 85-132 months, 14.45 mm for 133-180 months, and 16.51 mm for 181-204 months. Mean distal aorta diameter was 6.67 mm for 12-36 months, 8.07 mm for 37-84 months, 10.79 mm for 85-132 months, 12.14 mm for 133-180 months, and 14.01 mm for 181-204 months. The lumen diameter of the abdominal aorta, both proximally and distally, correlated linearly with age as an independent predictor. Similarly, the lumen diameter of the right and left common iliac artery correlated linearly with age as an independent predictor. There was no statistically significant difference in vascular diameter according to gender in any age groups. CONCLUSIONS: Optimal evaluation of aortic diameter is possible on computed tomography. Measurement outside the normal range is a sign of aneurysm or hypoplasia. PMID- 29498779 TI - Levodopa has mood-enhancing effects in healthy elderly adults. PMID- 29498780 TI - The association between depression and mild cognitive impairment: A cross sectional study. PMID- 29498781 TI - Are all the former Siberian deportees with posttraumatic stress disorder patients at risk for unsuccessful aging? PMID- 29498782 TI - Factors associated with pain severity, pain interference, and perception of functional abilities independent of joint status in US adults with hemophilia: Multivariable analysis of the Pain, Functional Impairment, and Quality of Life (P FiQ) study. AB - INTRODUCTION: Levels of pain and dysfunction appear to differ among people with hemophilia despite similar levels of joint disease. OBJECTIVE: To determine patient characteristics that influence pain and function independent of joint status. METHODS: US adults with hemophilia completed a survey that included information on clinical characteristics, demographics, and patient-reported outcome instruments assessing pain (Brief Pain Inventory v2 Short Form [BPI]), functional impairment (Hemophilia Activities List [HAL]), and health status (EQ 5D-5L). Additionally, physiotherapists optionally completed a clinical joint evaluation (Hemophilia Joint Health Score [HJHS]). Associations were examined using simple and multiple regression models. RESULTS: Of 381 adults enrolled, 240 had complete HJHS scores (median age, 32 years). After controlling for HJHS and opiate use, anxiety/anxiolytic use was significantly associated with worse pain severity and interference scores. After controlling for HJHS, the most significant predictors of functional impairment were older age, unemployment, more severe hemophilia, and greater pain. EQ-5D-5L pain/discomfort was associated with worse outcomes on most HAL scores. CONCLUSION: Unemployment, anxiety, and depression were each associated with both greater pain and functional disability after controlling for joint status. Continued attention to pain and psychosocial issues will be important in improving clinical care and research efforts in the hemophilia population. PMID- 29498783 TI - Patient-reported outcomes and joint status across subgroups of US adults with hemophilia with varying characteristics: Results from the Pain, Functional Impairment, and Quality of Life (P-FiQ) study. AB - INTRODUCTION: Pain and functional impairment associated with joint disease are major problems for people with hemophilia, and impact on health-related quality of life (HRQoL) may vary across groups defined by demographic and treatment related characteristics. OBJECTIVE: To evaluate differences in overall HRQoL, pain, function, and joint status between P-FiQ study subgroups. METHODS: Adult males with hemophilia and a history of joint pain/bleeding completed a pain history and the patient-reported outcome instruments EQ-5D-5L, Brief Pain Inventory v2 Short Form (BPI), International Physical Activity Questionnaire (IPAQ), and Hemophilia Activities List (HAL); optionally, joint status was assessed (Hemophilia Joint Health Score v2.1 [HJHS]). Scores were analyzed between subgroups across sets of participant characteristics. RESULTS: A total of 381 adult males with hemophilia were enrolled, with median age of 34 years. Worse scores on EQ-5D-5L index, BPI pain severity/interference, HAL overall score, and HJHS were generally associated with being college educated, unemployment, self reporting both acute and chronic pain, and self-reporting anxiety/depression. CONCLUSIONS: Measures of joint status and HRQoL were consistently lower in participants who had higher educational levels, were unemployed, self-reported having both acute and chronic pain, and self-reported having anxiety/depression. A greater understanding of the association of these factors with disease outcomes may improve individualized patient management. PMID- 29498784 TI - Assessments of pain, functional impairment, anxiety, and depression in US adults with hemophilia across patient-reported outcome instruments in the Pain, Functional Impairment, and Quality of Life (P-FiQ) study. AB - INTRODUCTION: Pain, functional impairment, anxiety, and depression associated with joint disease may affect health-related quality of life (HRQoL) in people with hemophilia. OBJECTIVE: To report detailed patient-reported outcomes (PRO) assessments related to HRQoL in participants in the Pain, Functional Impairment, and Quality of Life (P-FiQ) study. METHODS: Pain and HRQoL were assessed via PRO instruments in US adult males with hemophilia A or B and a history of joint pain or bleeding. PRO instruments included EQ-5D-5L with visual analog scale, Brief Pain Inventory v2 Short Form, SF-36v2, and Hemophilia Activities List. Instrument domain and item responses were described. RESULTS: Responses were collected from 381 adult males with a median age of 34 years. Pain was observed across instruments and affected daily activities and quality of life. Respondents reported functional impairment that limited the kind of work and activities they participated in, with activities involving the lower extremities being most affected. A high prevalence of mental health disorders was identified across instruments. CONCLUSIONS: Pain and HRQoL were evaluated using multiple PRO instruments, which vary in timescales of assessment and levels of detail. More consistent clinical assessments and patient dialog regarding pain and aspects of HRQoL may help drive improved outcomes. PMID- 29498785 TI - What can we learn from using formal patient-reported outcome instruments to assess pain, functional impairment, anxiety, and depression in US adults with hemophilia? AB - People with hemophilia frequently suffer from arthropathy that leads to pain and functional impairment, ultimately resulting in reduced quality of life. The impact of pain and functional impairment on the lives of people with hemophilia was explored in the Pain, Functional Impairment, and Quality of Life (P-FiQ) study. Various patient-reported outcome (PRO) instruments were employed to assess the effect of pain and functional impairment on multiple aspects of health in people with hemophilia. The results presented in this supplement include detailed observations from PRO instruments regarding pain, functional impairment, anxiety, and depression, an analysis of the differences in health-related quality of life across subgroups of patients defined by demographic and treatment-related characteristics, and results of a modeling analysis to identify patient factors which influence perceptions of pain and functional impairment, independent of joint status. These data provide insights into how the results from PRO assessments may be used to evaluate outcomes for people with hemophilia in the clinical and research settings. PMID- 29498786 TI - Randomised controlled trial to estimate reduction in pain after laparoscopic surgery when using a combination therapy of intraperitoneal normal saline and the pulmonary recruitment manoeuvre. AB - OBJECTIVE: To evaluate the effect of two manoeuvres at the end of gynaecological laparoscopy on postoperative pain. DESIGN: Randomised controlled trial. SETTING: One teaching and one university hospital in the Netherlands. SAMPLE: Women aged between 18 and 65 years, with American Society of Anaesthesiologists (ASA) classification I-II, scheduled for an elective laparoscopic procedure for a benign gynaecological indication. METHODS: Women were randomly allocated to two groups. In the intervention group, carbon dioxide was removed from the abdomen by a combination treatment of intraperitoneal warm saline and performing a pulmonary recruitment manoeuvre. In the control group, carbon dioxide was removed with gentle abdominal pressure. MAIN OUTCOME MEASURES: Frequency and intensity of post laparoscopic shoulder pain and pain in the upper abdomen at 8, 24, and 48 hours after surgery. RESULTS: A total of 200 women participated, with 100 in each group. No difference was observed in the occurrence of post-laparoscopic shoulder pain during the first 48 hours after surgery between the intervention group (46%) and the control group (55%). The incidence of abdominal pain was not significantly different between the two groups. The mean visual analogue scale (VAS) scores of participants who reported shoulder pain were not statistically different between the groups. The mean VAS score for abdominal pain at 8 hours after surgery was significantly lower in the intervention group compared with the control group (3.2 versus 4.2, P = 0.02). No difference in pain medication between the groups was observed, nor was there any difference in nausea or vomiting. CONCLUSIONS: Combined intervention of intraperitoneal saline and the pulmonary recruitment manoeuvre does not lower post-laparoscopic shoulder pain. FUNDING: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. TWEETABLE ABSTRACT: PRM with intraperitoneal saline does not influence the incidence and intensity of post laparoscopic shoulder pain. PMID- 29498787 TI - Climate change likely to reduce orchid bee abundance even in climatic suitable sites. AB - Studies have tested whether model predictions based on species' occurrence can predict the spatial pattern of population abundance. The relationship between predicted environmental suitability and population abundance varies in shape, strength and predictive power. However, little attention has been paid to the congruence in predictions of different models fed with occurrence or abundance data, in particular when comparing metrics of climate change impact. Here, we used the ecological niche modeling fit with presence-absence and abundance data of orchid bees to predict the effect of climate change on species and assembly level distribution patterns. In addition, we assessed whether predictions of presence-absence models can be used as a proxy to abundance patterns. We obtained georeferenced abundance data of orchid bees (Hymenoptera: Apidae: Euglossina) in the Brazilian Atlantic Forest. Sampling method consisted in attracting male orchid bees to baits of at least five different aromatic compounds and collecting the individuals with entomological nets or bait traps. We limited abundance data to those obtained by similar standard sampling protocol to avoid bias in abundance estimation. We used boosted regression trees to model ecological niches and project them into six climate models and two Representative Concentration Pathways. We found that models based on species occurrences worked as a proxy for changes in population abundance when the output of the models were continuous; results were very different when outputs were discretized to binary predictions. We found an overall trend of diminishing abundance in the future, but a clear retention of climatically suitable sites too. Furthermore, geographic distance to gained climatic suitable areas can be very short, although it embraces great variation. Changes in species richness and turnover would be concentrated in western and southern Atlantic Forest. Our findings offer support to the ongoing debate of suitability-abundance models and can be used to support spatial conservation prioritization schemes and species triage in Atlantic Forest. PMID- 29498788 TI - High IDO-1 expression in tumor endothelial cells is associated with response to immunotherapy in metastatic renal cell carcinoma. AB - Nivolumab belongs to the standard therapy in the second-line setting of metastatic renal cell carcinoma (mRCC). Although deep and long-lasting responses are seen in some patients, the majority of patients will further progress. PD-L1 is still under critical evaluation as a predictive biomarker. Thus, more accurate biomarkers are clearly warranted. Here, we investigated for the first time the predictive role of IDO-1, a negative immune-regulatory molecule, on clear cell RCC tissues of 15 patients undergoing nivolumab therapy. IDO-1 and other immune inhibitory molecules (PD-L1, PD-L2, FOXP3) as well as immune cell subsets (CD3, CD4 and CD8) were measured on formalin-fixed, paraffin-embedded sections of RCC specimens by immunohistochemistry. IDO-1 was predominantly expressed in tumor endothelial cells, and was totally absent from tumor cells itself. IDO-1 overexpression (>10%) could be detected more frequently in responders (100%, n = 6/6) compared to non-responders (33.3%, n = 3/9; P = .028), resulting in a better progression-free survival during immunotherapy (IDO-1 <= 10% vs >10%, median: 3.5 vs not estimated (NE) months, P = .01 by log-rank test). In addition, IDO-1 was positively correlated with CD8+ T cell expression (rs = .691, P = .006). PD-L1 expression on tumor cells was negative in 13 (86.7%) of 15 patients, irrespective of therapeutic response (responders vs non-responders: 83.3% vs 88.9%). No differences were noticed in the PD-L1 expression on tumor-infiltrating immune cells (PD-L1 < 1% in 66.7% of both responders and non-responders). In contrast to PD-L1, these results suggest that IDO-1 may be a more promising predictive biomarker for response to immune-based cancer therapy in mRCC. PMID- 29498790 TI - Differential roles of glucosinolates and camalexin at different stages of Agrobacterium-mediated transformation. AB - Agrobacterium tumefaciens is the causal agent of crown gall disease in a wide range of plants via a unique interkingdom DNA transfer from bacterial cells into the plant genome. Agrobacterium tumefaciens is capable of transferring its T-DNA into different plant parts at different developmental stages for transient and stable transformation. However, the plant genes and mechanisms involved in these transformation processes are not well understood. We used Arabidopsis thaliana Col-0 seedlings to reveal the gene expression profiles at early time points during Agrobacterium infection. Common and differentially expressed genes were found in shoots and roots. A gene ontology analysis showed that the glucosinolate (GS) biosynthesis pathway was an enriched common response. Strikingly, several genes involved in indole glucosinolate (iGS) modification and the camalexin biosynthesis pathway were up-regulated, whereas genes in aliphatic glucosinolate (aGS) biosynthesis were generally down-regulated, on Agrobacterium infection. Thus, we evaluated the impacts of GSs and camalexin during different stages of Agrobacterium-mediated transformation combining Arabidopsis mutant studies, metabolite profiling and exogenous applications of various GS hydrolysis products or camalexin. The results suggest that the iGS hydrolysis pathway plays an inhibitory role on transformation efficiency in Arabidopsis seedlings at the early infection stage. Later in the Agrobacterium infection process, the accumulation of camalexin is a key factor inhibiting tumour development on Arabidopsis inflorescence stalks. In conclusion, this study reveals the differential roles of GSs and camalexin at different stages of Agrobacterium mediated transformation and provides new insights into crown gall disease control and improvement of plant transformation. PMID- 29498789 TI - Impairment of K-Ras signaling networks and increased efficacy of epidermal growth factor receptor inhibitors by a novel synthetic miR-143. AB - Despite considerable research on K-Ras inhibitors, none had been established until now. We synthesized nuclease-resistant synthetic miR-143 (miR-143#12), which strongly silenced K-Ras, its effector signal molecules AKT and ERK, and the K-Ras activator Sos1. We examined the anti-proliferative effect of miR-143#12 and the mechanism in human colon cancer DLD-1 cell (G13D) and other cell types harboring K-Ras mutations. Cell growth was markedly suppressed in a concentration dependent manner by miR-143#12 (IC50 : 1.32 nmol L-1 ) with a decrease in the K Ras mRNA level. Interestingly, this mRNA level was also downregulated by either a PI3K/AKT or MEK inhibitor, which indicates a positive circuit of K-Ras mRNA expression. MiR-143#12 silenced cytoplasmic K-Ras mRNA expression and impaired the positive circuit by directly targeting AKT and ERK mRNA. Combination treatment with miR-143#12 and a low-dose EGFR inhibitor induced a synergistic inhibition of growth with a marked inactivation of both PI3K/AKT and MAPK/ERK signaling pathways. However, silencing K-Ras by siR-KRas instead of miR-143#12 did not induce this synergism through the combined treatment with the EGFR inhibitor. Thus, miR-143#12 perturbed the K-Ras expression system and K-Ras activation by silencing Sos1 and, resultantly, restored the efficacy of the EGFR inhibitors. The in vivo results also supported those of the in vitro experiments. The extremely potent miR-143#12 enabled us to understand K-Ras signaling networks and shut them down by combination treatment with this miRNA and EGFR inhibitor in K-Ras-driven colon cancer cell lines. PMID- 29498792 TI - Using salivary glands to treat serious systemic diseases-Examples of new roles for oral medicine in the healthcare team? PMID- 29498791 TI - Epidemiological observations of Kawasaki disease in Japan, 2013-2014. AB - BACKGROUND: The etiology of Kawasaki disease (KD) is unknown. In Japan, the number of patients and incidence rate of KD has increased continuously since its discovery. The aim of this report was to analyze the latest nationwide epidemiological survey of KD in Japan. METHODS: The 23rd nationwide survey of KD was conducted in 2015. To report on all patients diagnosed with KD in 2013 and 2014, a questionnaire was sent to hospitals with >=100 beds containing pediatric departments, as well as specialized pediatric hospitals. RESULTS: The number of KD patients reported was 15 696 in 2013 and 15 979 in 2014, resulting in an annual incidence rate of 302.5 and 308.0 per 100 000 population aged 0-4 years, respectively. The number of patients and incidence rate of KD in 2014 were the highest ever recorded in Japan. The number of patients diagnosed per month peaked in January, and a gradual increase in summer was also observed. Eight patients died of KD in 2013 and 2014. CONCLUSIONS: The number of patients and incidence rate of KD in Japan continue to increase. Continued surveillance of epidemiological trends of KD is therefore required. PMID- 29498793 TI - Does audiovisual distraction reduce dental anxiety in children under local anesthesia? A systematic review and meta-analysis. AB - OBJECTIVES: To perform a systematic review and meta-analysis on the effects of audiovisual distraction on reducing dental anxiety in children during dental treatment under local anesthesia. METHODS: The authors identified eligible reports published through August 2017 by searching PubMed, EMBASE, and Cochrane Central Register of Controlled Trials. Clinical trials that reported the effects of audiovisual distraction on children's physiological measures, self-reports, and behavior rating scales during dental treatment met the minimum inclusion requirements. The authors extracted data and performed a meta-analysis of appropriate articles. RESULTS: Nine eligible trials were included and qualitatively analyzed; some of these trials were also quantitatively analyzed. Among the physiological measures, heart rate or pulse rate was significantly lower (p = .01) in children subjected to audiovisual distraction during dental treatment under local anesthesia than in those who were not; a significant difference in oxygen saturation was not observed. The majority of the studies using self-reports and behavior rating scales suggested that audiovisual distraction was beneficial in reducing anxiety perception and improving children's cooperation during dental treatment. CONCLUSION: The audiovisual distraction approach effectively reduces dental anxiety among children. Therefore, we suggest the use of audiovisual distraction when children need dental treatment under local anesthesia. PMID- 29498794 TI - Salivary human beta-defensins affected by oral Candida status in Chinese HIV/AIDS patients undergoing ART. AB - OBJECTIVES: To observe relationships between oral Candida status and salivary human beta-defensin 2 and 3 (hBD-2 and hBD-3) levels in HIV/AIDS patients of Guangxi, China during the first year of antiretroviral therapy (ART) dynamically, and to understand the influence of ART on oral Candida status and salivary hBDs expressions. METHODS: A prospective self-controlled study was carried to observe the dynamic changes of CD4+ T cell counts, oral Candida carriages and salivary hBD-2,3 expressions in HIV/AIDS patients during the first year of ART. A total of 90 HIV/AIDS patients were enrolled and were examined at the baseline, 3rd, 6th, 12th month of ART. Thirty healthy individuals were enrolled as control. Peripheral blood, oral rinse sample, and unstimulated whole saliva were collected to test CD4+ T cell counts, oral Candida carriages, and hBD-2,3 expressions. RESULTS: In the first year of ART, CD4+ T cell counts increased significantly. However, oral Candida carriages and oral candidiasis decreased significantly, and salivary hBD-2 expressions in HIV/AIDS patients decreased gradually, salivary hBD 3 levels were highly variable. Salivary hBD-2 concentrations were positively related to oral Candida carriages. CONCLUSIONS: The incidence of oral candidiasis among HIV/AIDS patients gradually decreased due to the immune reconstruction of ART. Salivary defensins might play an important role in Candida-host interaction in HIV/AIDS patients. PMID- 29498795 TI - Antibiotic resistance evolution of Pseudomonas aeruginosa in cystic fibrosis patients (2010-2013). AB - INTRODUCTION: Pseudomonas aeruginosa is the predominant pathogen responsible of chronic colonization of the airways in cystic fibrosis (CF) patients. There are few European data about antibiotic susceptibility evolution of P aeruginosa in CF patients. OBJECTIVES: The aim of this study is to evaluate the evolution of antibiotic resistance in the period 2010-2013 in CF patients chronically colonized by P aeruginosa and to highlight the characteristics of this evolution in patients younger than 20 years. METHODS: Clinical and microbiological data were extracted from two electronic databases and analyzed. Antibiotic resistance was defined according to European Committee of Antimicrobial Susceptibility Testing for levofloxacin, ciprofloxacin, meropenem, amikacin and ceftazidime. The between-group comparison was drawn with the Chi-square test for proportions, with the T-test for unpaired samples for normally distributed data and with Mann Whitney test for non-normally distributed data. Significancy was defined by P < .05. RESULTS: Fifty-seven CF patients, including thirteen subjects aged less than 20 years, were enrolled. P.. aeruginosa antibiotic sensitivity decreased significantly for fluoroquinolones, mainly in patients aged <20 years, while it increased for amikacin and colistin. The analysis of minimum inhibitory concentration confirmed these trends. In pediatric patients treated with more than three antibiotic cycles per year, greater resistance was found, except for amikacin and colistin. CONCLUSION: An evolution in P aeruginosa antibiotic resistances is observed in the 4-year period studied. Responsible and informed use of antibiotics is mandatory in CF. PMID- 29498796 TI - Pregnancy - do we really understand how the immune system tolerates us? PMID- 29498798 TI - Pleural effusion as presenting feature of pulmonary alveolar proteinosis: A rare occurrence. PMID- 29498797 TI - Visceral transplantation in patients with intestinal-failure associated liver disease: Evolving indications, graft selection, and outcomes. AB - Intestinal failure (IF)-associated liver disease (IFALD) is widely recognized as a lethal complication of long-term parenteral nutrition. The pathophysiology of IFALD is poorly understood but appears to be multifactorial and related to the inflammatory state in the patient with IF. Visceral transplant for IFALD includes variants of intestine, liver, or combined liver-intestine allografts. Graft selection for an individual patient depends on the etiology of IF, abdominal and vascular anatomy, severity of IFALD, and potential for intestinal rehabilitation. The past decade has witnessed dramatic improvement in the management of IFALD, principally due to improved lipid emulsion formulations and the multidisciplinary care of the patient with IF. As the recognition and treatment of IFALD continue to improve, the requirement of liver-inclusive visceral grafts appears to be decreasing, representing a paradigm shift in the care of the patient with IF. This review highlights the current indications, graft selection, and outcomes of visceral transplantation for IFALD. PMID- 29498799 TI - Does the severity of interstitial lung disease affect the gains from pulmonary rehabilitation? AB - INTRODUCTION: Reduced exercise capacity is a main feature of Interstitial Lung Diseases (ILDs) and it is related to closely prognosis of these patients. Pulmonary Rehabilitation (PR) results to improve in peak exercise capacity, dyspnea and quality of life in ILDs. OBJECTIVES: We aimed to evaluate the benefits of PR in patients with ILDs and to determine whether there are similar gains in patients with severe ILD. METHODS: We recruited ILD stable patients. All patients were evaluated with pulmonary function test, exercise capacity [6-minute walking test (6MWD)], quality of life [Short Form-36 (SF-36), St. George's Respiratory Questionnare (SGRQ), Hospital anxiety and Depression (HAD)] before and after PR (8 week). RESULTS: Fifty-seven patients who completed PR program, 30 women and 27 men, included in this study. It was determined a significant difference in terms of quality of life and exercise capacity (P < .05) before and after PR. When these patients were divided into 2 groups (DLCO <40% predicted, severe: group-1, and group-2: other >=40], there was no difference between 2 groups except for forced expiratory volume in 1 second, pulse oxygen saturation and partial oxygen pressure (pO2 ). When compared the differences between pre and post values of all variables, there was no difference significantly except 4 variables (SF-36; physical functioning, social functioning, role physical and pO2 ). CONCLUSION: PR led to improvement in quality of life and exercise capacity in ILDs. In addition, PR, irrespective of the severity of the disease, is particularly beneficial in patients with severe ILDs. PMID- 29498800 TI - Syncope as a subject of the risk assessment of pulmonary thromboembolism to be used for: A cross-sectional study. AB - INTRODUCTION: Syncope is infrequent in pulmonary thromboembolism (PTE) yet might be indicative of haemodynamic instability. The prognostic role of syncope in PTE has not been well documented. OBJECTIVES: In this study, the association between risk classification of the European Society of Cardiology and syncope was investigated in the normotensive PTE patients. METHODS: We retrospectively screened electronic medical records of patients who were admitted in 2 tertiary care hospital and diagnosis of PTE with computed tomography pulmonary angiography. Patients with hypotension (high risk) at the time of admission were excluded from the study. RESULTS: Of 5% patients (16/322) had syncope with the proportion of 81.3% (13/16) in the intermediate high risky group, 18.7% (3/16) in intermediate low risk group and 0% in low risk group. Mortality rate was higher in subjects with syncope (25% vs 11.1%) although it was not it was not statistically significant (P = NS). In those with syncope, the central venous thrombus was more frequent than those without it (78.6% vs 30.1%, P = .008). Only heart rate and intermediate high-risk group were retained as independent predictors of syncope selection in the multivariate logistic regression. CONCLUSION: Although syncope is positively correlated with the severity of PTE, it does not predict the prognosis alone. Nonetheless, syncope in patients with PTE can be considered as an important alarming stimulus for clinical course. PMID- 29498801 TI - The role of plasma D-dimer levels for predicting lymph node and mediastinal lymph node involvement in non-small cell lung cancer. AB - INTRODUCTION: Elevated plasma D-dimer levels have been suggested as a predictor of poor prognosis in NSCLC. But rare study showed the relationship between D dimer levels and lymph node involvement. OBJECTIVES: To evaluate the role of plasma D-dimer levels in predicting lymph node and mediastinal lymph node involvement in NSCLC. METHODS: Preoperative plasma D-dimer levels were quantified in 253 NSCLC patients that underwent radical lung resection with systemic lymph node dissection. Patients were classified as lymph node negative (N0) versus lymph node positive (N1 + N2) and mediastinal lymph node negative (N0 + N1) versus mediastinal lymph node positive (N2). RESULTS: Median plasma D-dimer level was significantly lower in Group N0 (94.0 MUg/L) compared to Group N1 + N2 (177.0 MUg/L) and in Group N0 + N1 (122.0 MUg/L) compared to Group N2 (198.0 MUg/L). Similar results were found in patients stratified by age, sex, smoking status and histological type, expect in patients with squamous carcinoma. The Receiver Operating Characteristic (ROC) curve for plasma D-dimer levels of N0 versus N1 + N2 showed an area under the curve (AUC) of 0.757 and when a cutoff value was 124.0 MUg/L DDU, the sensitivity and specificity was 0.80 and 0.68. The ROC curve for plasma D-dimer levels of N0 + N1 versus N2 showed an AUC of 0.720 and when a cutoff value was 147.0 MUg/L DDU, the sensitivity and specificity was 0.75 and 0.67. CONCLUSIONS: Plasma D-dimer level has utility for predicting lymph node and mediastinal lymph node status in patients with operable NSCLC. PMID- 29498803 TI - Structural basis of potassium activation in plant asparaginases. AB - l-asparaginases (EC 3.5.1.1) play an important role in nitrogen mobilization in plants. Here, we investigated the biochemical and biophysical properties of potassium-dependent (PvAspG1) and potassium-independent (PvAspG-T2) l asparaginases from Phaseolus vulgaris. Our previous studies revealed that PvAspG1 requires potassium for catalytic activation and its crystal structure suggested that Ser-118 in the activation loop plays a critical role in coordinating the metal cation. This amino acid residue is replaced by isoleucine in PvAspG-T2. Reciprocal mutants of the enzymes were produced and the effect of the amino acid substitution on the kinetic parameters, allosteric effector binding, secondary structure conformation, and pH profile were studied. Introduction of the serine residue conferred potassium activation in PvAspG-T2. Conversely, the PvAspG1 S118I mutant could no longer be activated by potassium. PvAspG1 and the PvAspG-T2 I117S mutant had a similar half-maximal effective concentration (EC50 ) value for potassium activation, between 0.1 and 0.3 mm. Potassium binding elicited a similar conformational change in PvAspG1 and PvAspG-T2-I117S, as studied by circular dichroism. However, no change in conformation was observed for PvAspG-T2 and PvAspG1-S118I. Analysis of kinetic parameters in function of pH indicated that potassium activation mediated by Ser-118 influences the ionization of specific functional groups in the enzyme-substrate complex. Together, the results indicate that Ser-118 of PvAspG1 is essential and sufficient for potassium activation in plant l-asparaginases. ENZYME: l-Asparaginase (EC 3.5.1.1). PMID- 29498802 TI - Differential effects of Vav-promoter-driven overexpression of BCLX and BFL1 on lymphocyte survival and B cell lymphomagenesis. AB - Overexpression of BCLX and BFL1/A1 has been reported in various human malignancies and is associated with poor prognosis and drug resistance, identifying these prosurvival BCL2 family members as putative drug targets. We have generated transgenic mice that express human BFL1 or human BCLX protein throughout the haematopoietic system under the control of the Vav gene promoter. Haematopoiesis is normal in both the Vav-BFL1 and Vav-BCLX transgenic (TG) mice and susceptibility to spontaneous haematopoietic malignancies is not increased. Lymphoid cells from Vav-BCLX TG mice exhibit increased resistance to apoptosis in vitro while most blood cell types form Vav-BFL1 TG mice were poorly protected. Both transgenes significantly accelerated lymphomagenesis in EMU-MYC TG mice and, surprisingly, the Vav-BFL1 transgene was the more potent. Unexpectedly, expression of transgenic BFL1 RNA and protein is significantly elevated in B lymphoid cells of Vav-BFL1/EMU-MYC double-transgenic compared to Vav-BFL1 mice, even during the preleukaemic phase, providing a rationale for the potent synergy. In contrast, Vav-BCLX expression was not notably different. These mouse models of BFL1 and BCLX overexpression in lymphomas should be useful tools for the testing the efficacy of novel human BFL1- and BCLX-specific inhibitors. PMID- 29498805 TI - New evidence of the need for living kidney donor follow-up. PMID- 29498804 TI - STRENDA DB: enabling the validation and sharing of enzyme kinetics data. AB - Standards for reporting enzymology data (STRENDA) DB is a validation and storage system for enzyme function data that incorporates the STRENDA Guidelines. It provides authors who are preparing a manuscript with a user-friendly, web-based service that checks automatically enzymology data sets entered in the submission form that they are complete and valid before they are submitted as part of a publication to a journal. PMID- 29498806 TI - Nd3+ -Yb3+ /Nd3+ -Yb3+ -Li+ co-doped Gd2 O3 phosphors for up and down conversion luminescence. AB - Frequency up-conversion (UC) emission from the Nd3+ -Yb3+ /Nd3+ -Yb3+ -Li+ co doped gadolinium oxide (Gd2 O3 ) phosphors prepared by the solution combustion technique in the visible range have been studied by using 980 nm near infrared (NIR) laser diode excitation. The crystalline structure and formation of the cubic phase has been confirmed with the help of X-ray diffraction (XRD) studies. XRD peak shifts have been found towards the lower diffraction angle side in the case of the Nd3+ -Yb3+ -Li+ co-doped phosphors. Surface morphology and particle size information have been observed by using field emission scanning electron microscopy (FESEM) and transmission electron microscopy (TEM) analysis. Down conversion emission study under 351 nm excitation in the visible region for the Nd3+ -Yb3+ /Nd3+ -Yb3+ -Li+ co-doped phosphors has been performed. The UC emission bands lying in the green and red region arising from the Nd3+ ions have been enhanced by ~260 times, ~113 times due to incorporation of Li+ ions in the Nd3+ -Yb3+ co-doped phosphors. Photometric characterization has been done for the Nd3+ -Yb3+ /Nd3+ -Yb3+ -Li+ co-doped phosphors. The present study suggests the capability of the synthesized phosphors in near-infrared (NIR) to visible upconverter and luminescent device applications. PMID- 29498808 TI - Highly selective and sensitive coumarin-triazole-based fluorometric 'turn-off' sensor for detection of Pb2+ ions. AB - Exposure to even very low concentrations of Pb2+ is known to cause cardiovascular, neurological, developmental, and reproductive disorders, and affects children in particular more severely. Consequently, much effort has been dedicated to the development of colorimetric and fluorescent sensors that can selectively detect Pb2+ ions. Here, we describe the development of a triazole based fluorescent sensor L5 for Pb2+ ion detection. The fluorescence intensity of chemosensor L5 was selectively quenched by Pb2+ ions and a clear color change from colorless to yellow could be observed by the naked eye. Chemosensor L5 exhibited high sensitivity and selectivity towards Pb2+ ions in phosphate buffered solution [20 mM, 1:9 DMSO/H2 O (v/v), pH 8.0] with a 1:1 binding stoichiometry, a detection limit of 1.9 nM and a 6.76 * 106 M-1 binding constant. Additionally, low-cost and easy-to-prepare test strips impregnated with chemosensor L5 were also produced for efficient of Pb2+ detection and proved the practical use of this test. PMID- 29498809 TI - Antibody-based cell-surface proteome profiling of metastatic breast cancer primary explants and cell lines. AB - Flow cytometric cell surface proteomics provides a new and powerful tool to determine changes accompanying neoplastic transformation and invasion, providing clues to essential interactions with the microenvironment as well as leads for potential therapeutic targets. One of the most important advantages of flow cytometric cell surface proteomics is that it can be performed on living cells that can be sorted for further characterization and functional studies. Here, we document the surface proteome of clonogenic metastatic breast cancer (MBrCa) explants, which was strikingly similar to that of normal mesenchymal stromal cells (P = 0.017, associated with Pearson correlation coefficient) and transformed mammary epithelial cells (P = 0.022). Markers specifically upregulated on MBrCa included CD200 (Ox2), CD51/CD61 (Integrin alpha5/beta3), CD26 (dipeptidyl peptidase-4), CD165 (c-Cbl), and CD54 (ICAM-1). Proteins progressively upregulated in a model of neoplastic transformation and invasion included CD26, CD63 (LAMP3), CD105 (Endoglin), CD107a (LAMP1), CD108 (Semaphorin 7A), CD109 (Integrin beta4), CD151 (Raph blood group), and disialoganglioside G2. The proteome of the commonly used cell lines MDA-MB-231, MCF7, and BT-474 were uncorrelated with that of MBrCa (P = 1.0, 1.0, 0.9, respectively). The comparison has demonstrated the mesenchymal nature of clonogenic cells isolated by short term culture of metastatic breast cancer, provided several leads for biomarkers and potential targets for anti-invasive therapy, including CD200, and highlighted the limitations of breast cancer cell lines for representing the cell surface biology of breast cancer. (c) 2017 International Society for Advancement of Cytometry. PMID- 29498807 TI - Application of area scaling analysis to identify natural killer cell and monocyte involvement in the GranToxiLux antibody dependent cell-mediated cytotoxicity assay. AB - Several different assay methodologies have been described for the evaluation of HIV or SIV-specific antibody-dependent cell-mediated cytotoxicity (ADCC). Commonly used assays measure ADCC by evaluating effector cell functions, or by detecting elimination of target cells. Signaling through Fc receptors, cellular activation, cytotoxic granule exocytosis, or accumulation of cytolytic and immune signaling factors have been used to evaluate ADCC at the level of the effector cells. Alternatively, assays that measure killing or loss of target cells provide a direct assessment of the specific killing activity of antibodies capable of ADCC. Thus, each of these two distinct types of assays provides information on only one of the critical components of an ADCC event; either the effector cells involved, or the resulting effect on the target cell. We have developed a simple modification of our previously described high-throughput ADCC GranToxiLux (GTL) assay that uses area scaling analysis (ASA) to facilitate simultaneous quantification of ADCC activity at the target cell level, and assessment of the contribution of natural killer cells and monocytes to the total observed ADCC activity when whole human peripheral blood mononuclear cells are used as a source of effector cells. The modified analysis method requires no additional reagents and can, therefore, be easily included in prospective studies. Moreover, ASA can also often be applied to pre-existing ADCC-GTL datasets. Thus, incorporation of ASA to the ADCC-GTL assay provides an ancillary assessment of the ability of natural and vaccine-induced antibodies to recruit natural killer cells as well as monocytes against HIV or SIV; or to any other field of research for which this assay is applied. (c) 2018 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of ISAC. PMID- 29498811 TI - Flushing compliance enhanced at St George's. AB - The estates team at St George's Hospital in south London say the deployment of a web-based software system which verifies that 'responsible' staff across the site have regularly flushed low-use water outlets to maintain flow, and thus prevent potentially dangerous waterborne bacteria building up in pipework, has 'very substantially' increased compliance with approved flushing practice--as set out in the HSE's L8 Approved Code of Practice on controlling Legionella bacteria in water systems, and the new HTM 04-01, Safe Water in Healthcare Premises. As HEJ editor, Jonathan Baillie, reports, the hospital's use of Digital Missives' L8guard software system has also saved considerable staff time, eliminated the need to manually input data from thousands of paper flushing return forms, and enabled the Estates team to easily identify departments not undertaking regular flushing. PMID- 29498810 TI - Bioturbation and directionality in Earth's carbon isotope record across the Neoproterozoic-Cambrian transition. AB - Mixing of sediments by moving animals becomes apparent in the trace fossil record from about 550 million years ago (Ma), loosely overlapping with the tail end of the extreme carbonate carbon isotope delta13 Ccarbonate fluctuations that qualitatively distinguish the Proterozoic geochemical record from that of the Phanerozoic. These Precambrian-scale fluctuations in delta13 Ccarbonate (PSF delta13 Ccarbonate ) remain enigmatic, due to their high amplitude and inclusion of global-scale negative delta13 Ccarbonate values, below anything attributable to mantle input. Here, we note that different biogeochemical-model scenarios plausibly explaining globally synchronous PSF-delta13 Ccarbonate converge: via mechanistic requirements for extensive anoxia in marine sediments to support sedimentary build-up of 13 C-depleted carbon. We hypothesize that bioturbation qualitatively reduced marine sediment anoxia by exposing sediments to oxygenated overlying waters, which ultimately contributed to decreasing the carbon cycle's subsequent susceptibility to PSF- delta13 Ccarbonate . Bioturbation may also have reduced the quantity of (isotopically light) organic-derived carbon available to contribute to PSF- delta13 Ccarbonate via ocean crust carbonatization at depth. We conduct a comparative modelling exercise in which we introduce bioturbation to existing model scenarios for PSF- delta13 Ccarbonate : expressing both the anoxic proportion of marine sediments, and the global organic carbon burial efficiency, as a decreasing function of bioturbation. We find that bioturbation's oxygenating impact on sediments has the capacity to prevent PSF- delta13 Ccarbonate caused by authigenic carbonate precipitation or methanogenesis. Bioturbation's impact on the f-ratio via remineralization is partially offset by liberation of organic phosphate, some of which feeds back into new production. We emphasize that this study is semiquantitative, exploratory and intended merely to provide a qualitative theoretical framework within which bioturbation's impact on long term, first-order delta13 Ccarbonate can be assessed (and it is hoped quantified in more detail by future work). With this proviso, we conclude that it is entirely plausible that bioturbation made a decisive contribution to the enigmatic directionality in the delta13 Ccarbonate record, from the Neoproterozoic-Cambrian boundary onwards. PMID- 29498812 TI - Work-based training's 'profound effect'. AB - Klaus Muecher, Higher Education Programmes manager at Eastwood Park Training, examines the benefits of work-based learning. He suggests that, in addition to equipping those undertaking such training with valuable new skills and expertise, 'in a world of continuous quality improvement and change management', work-based degree students can also act as 'the subtle drivers of positive change'. PMID- 29498813 TI - Best practice not being sufficiently replicated. AB - 'Efficient productivity through innovation' was the theme of the first ever Hospital Innovations conference and exhibition at Olympia, London in late April. At the two-day event--supported by organisations including IHEEM, the Legionella Control Association, the Water Management Society, the BRE, and a sizeable number of English NHS Trusts--the Day Two keynote address by Lord Carter very much reflected this theme. Following his address at Healthcare Estates 2015, the Labour Peer focused further in London on his team's recent review of the 'productivity and efficiency' of English NHS Trusts, and explained how the initiative would progress in coming months. One of his key conclusions was that while the NHS consistently rates as one of the world's most efficient public health systems, innovation and good practice are rarely sufficiently shared or widely replicated service-wide, resulting in a considerable 'gap' between the best and worst-performing Trusts. HEJ editor, Jonathan Baillie, reports. PMID- 29498814 TI - Procurement options' 'pros and cons'. AB - The existing ProCure21+ (P21+) framework deal for delivering healthcare construction projects for the NHS is due to end this September, and will be replaced by ProCure22, which could see a spend of L2 bn - L5 bn over four years. Against this backdrop, Ian Nunn ICIOB, a senior associate at multidisciplinary design, property, and construction consultancy solutions business, Pellings, reviews the different types of procurement options open to NHS Trusts, and considers their 'pros and cons'. PMID- 29498815 TI - HTM advocates 'holistic approach'. AB - Dr Nick Hill, a fellow of IHEEM, and chair of the Institute's Water Technical Platform, whose career encompasses over 25 years' experience working on all aspects of water, considers some of the key guidance contained in the new Health Technical Memorandum, HTM 04-01, Safe Water in Healthcare Premises (2016), which was published last month. PMID- 29498816 TI - Act quickly and harness the right expertise. AB - In an article that first appeared in The Australian Hospital Engineer, Jeremy Stamkos, principal indoor environment consultant for Eronmor, a specialist indoor air quality consultancy, advises on some of the key steps that hospitals and other healthcare facilities should take following 'water ingress events'--to both protect property from damage, and safeguard the health of patients, visitors, and staff. The key, he stresses, is to act quickly and, where necessary, to harness specialist external expertise. PMID- 29498817 TI - Naval spell launches voyage of discovery. AB - In an article in the April 2016 issue of HEJ, we highlighted the current UK shortage of female engineers, focused on some of the reasons for the difficulty in recruiting young women, and considered some of the key steps bodies including professional institutes need to take to address the 'gender gap'. Here, in the first of a series of planned follow-up articles on successful women engineers' careers, HEJ editor, Jonathan Baillie, talks to Claire Hennessy FIHEEM, who, as head of Operational Estates and Facilities at Oxford University Hospitals NHS Foundation Trust, is responsible for the smooth day-to-day running of the buildings and plant at four busy hospitals. As she explained, she gained her first engineering experience looking after weaponry in the Royal Navy. PMID- 29498818 TI - Carter Report will be a key focus in Telford. AB - This year's HefmA conference and exhibition--the 2016 HefmA Leadership Forum- will be held at the Telford International Centre from 19-20 May, and themed 'Lean on me--Compassion, Culture & Compliance'. With the findings and recommendations of Lord Carter and his team likely to be fresh in delegates' minds, this year's conference will include an update on the Carter team's work, and a look at 'The challenges ahead for the whole NHS in delivering the Lord Carter Productivity and Efficiency Programme', by Peter Sellars, head of profession, NHS Estates & Facilities, Productivity and Efficiency, at the Department of Health. This will be followed by a panel discussion on this highly topical issue. HEJ editor, Jonathan Bailie, looks ahead to the event. PMID- 29498819 TI - Spectacular views for patients at The Shard. AB - HCA International, the UK division of Healthcare Corporation of America, the world's largest private hospital company, has recently opened the doors to a new, 'state-of-the-art' Diagnostic and Outpatient Centre spanning three floors of one of London's most prominent and iconic buildings--The Shard. HEJ editor, Jonathan Baillie, recently met with the company's senior construction project manager, Stephen Kimp, to find out more about the latest addition to the HCA network, and a new joint venture with Guy's Hospital. PMID- 29498820 TI - Ultrasmall Plasmonic Single Nanoparticle Light Source Driven by a Graphene Tunnel Junction. AB - Metal nanoparticles that can couple light into tightly confined surface plasmons bridge the size mismatch between the wavelength of light and nanostructures are one of the smallest building blocks of nano-optics. However, plasmonic nanoparticles have been primarily studied to concentrate or scatter incident light as an ultrasmall antenna, while studies of their intrinsic plasmonic light emission properties have been limited. Although light emission from plasmonic structures can be achieved by inelastic electron tunneling, this strategy cannot easily be applied to isolated single nanoparticles due to the difficulty in making electrical connections without disrupting the particle plasmon mode. Here, we solve this problem by placing gold nanoparticles on a graphene tunnel junction. The monolayer graphene provides a transparent counter electrode for tunneling while preserving the ultrasmall footprint and plasmonic mode of nanoparticle. The tunneling electrons excite the plasmonic mode, followed by radiative decay of the plasmon. We also demonstrate that a dielectric overlayer atop the graphene tunnel junction can be used to tune the light emission. We show the simplicity and scalability of this approach by achieving electroluminescence from single nanoparticles without bulky contacts as well as millimeter-sized arrays of nanoparticles. PMID- 29498821 TI - Intratumoral Injection of Low-Energy Photon-Emitting Gold Nanoparticles: A Microdosimetric Monte Carlo-Based Model. AB - Gold nanoparticles (Au NPs) distributed in the vicinity of low-dose rate (LDR) brachytherapy seeds could multiply their efficacy thanks to the secondary emissions induced by the photoelectric effect. Injections of radioactive LDR gold nanoparticles (LDR Au NPs), instead of conventional millimeter-size radioactive seeds surrounded by Au NPs, could further enhance the dose by distributing the radioactivity more precisely and homogeneously in tumors. However, the potential of LDR Au NPs as an emerging strategy to treat cancer is strongly dependent on the macroscopic diffusion of the NPs in tumors, as well as on their microscopic internalization within the cells. Understanding the relationship between interstitial and intracellular distribution of NPs, and the outcomes of dose deposition in the cancer tissue is essential for considering future applications of radioactive Au NPs in oncology. Here, LDR Au NPs (103Pd:Pd@Au-PEG NPs) were injected in prostate cancer tumors. The particles were visualized at time-points by computed tomography imaging ( in vivo), transmission electron microscopy ( ex vivo), and optical microscopy ( ex vivo). These data were used in a Monte Carlo based dosimetric model to reveal the dose deposition produced by LDR Au NPs both at tumoral and cellular scales. 103Pd:Pd@Au-PEG NPs injected in tumors produce a strong dose enhancement at the intracellular level. However, energy deposition is mainly confined around vesicles filled with NPs, and not necessarily close to the nuclei. This suggests that indirect damage caused by the production of reactive oxygen species might be the leading therapeutic mechanism of tumor growth control, over direct damage to the DNA. PMID- 29498822 TI - Quasi-Topotactic Transformation of FeOOH Nanorods to Robust Fe2O3 Porous Nanopillars Triggered with a Facile Rapid Dehydration Strategy for Efficient Photoelectrochemical Water Splitting. AB - A facile rapid dehydration (RD) strategy is explored for quasi-topotactic transformation of FeOOH nanorods to robust Fe2O3 porous nanopillars, avoiding collapse, shrink, and coalescence, and compared with a conventional treatment route. Additionally, the so-called RD process is capable of generating a beneficial porous structure for photoelectrochemical water oxidation. The obtained RD-Fe2O3 photoanode exhibits a photocurrent density as high as 2.0 mA cm 2 at 1.23 V versus reversible hydrogen electrode (RHE) and a saturated photocurrent density of 3.5 mA cm-2 at 1.71 V versus RHE without any cocatalysts, which is about 270% improved photocurrent density over Fe2O3 with the conventional temperature-rising route (0.75 mA cm-2 at 1.23 V vs RHE and 1.48 mA cm-2 at 1.71 V vs RHE, respectively). The enhanced photocurrent on RD-Fe2O3 is attributed to a synergistic effect of the following factors: (i) preservation of single crystalline nanopillars decreases the charge-carrier recombination; (ii) formation of long nanopillars enhances light harvesting; and (iii) the porous structure shortens the hole transport distance from the bulk material to the electrode-electrolyte interface. PMID- 29498823 TI - Pharmacogenomics and the Placebo Response. AB - There is perhaps no more important time in the history of placebos to consider their role in clinical trials and in medicine. Increasingly well-designed pharmaceutical and academic clinical trials testing promising and established drug and surgical interventions have failed to "beat" the placebo response. The collateral damage resulting from these failures is staggering; novel treatments, many with compelling mechanisms of action and promising Phase 2 trial results, never reach the patient, adversely affecting small and large pharma alike. Recent evidence suggests that variability in placebo response may be attributed in part to genetic variation. Thus, having a better understanding of the genomic underpinnings of the placebo response, the "placebome", may pave the way to innovatively and more effectively use placebos in drug development. PMID- 29498824 TI - Engineered Production of Short-Chain Acyl-Coenzyme A Esters in Saccharomyces cerevisiae. AB - Short-chain acyl-coenzyme A esters serve as intermediate compounds in fatty acid biosynthesis, and the production of polyketides, biopolymers and other value added chemicals. S. cerevisiae is a model organism that has been utilized for the biosynthesis of such biologically and economically valuable compounds. However, its limited repertoire of short-chain acyl-CoAs effectively prevents its application as a production host for a plethora of natural products. Therefore, we introduced biosynthetic metabolic pathways to five different acyl-CoA esters into S. cerevisiae. Our engineered strains provide the following acyl-CoAs: propionyl-CoA, methylmalonyl-CoA, n-butyryl-CoA, isovaleryl-CoA and n-hexanoyl CoA. We established a yeast-specific metabolite extraction protocol to determine the intracellular acyl-CoA concentrations in the engineered strains. Propionyl CoA was produced at 4-9 MUM; methylmalonyl-CoA at 0.5 MUM; and isovaleryl-CoA, n butyryl-CoA, and n-hexanoyl-CoA at 6 MUM each. The acyl-CoAs produced in this study are common building blocks of secondary metabolites and will enable the engineered production of a variety of natural products in S. cerevisiae. By providing this toolbox of acyl-CoA producing strains, we have laid the foundation to explore S. cerevisiae as a heterologous production host for novel secondary metabolites. PMID- 29498825 TI - A Water-Soluble, Green-Light Triggered, and Photo-Calibrated Nitric Oxide Donor for Biological Applications. AB - Nitric oxide (NO) is a versatile endogenous molecule, involved in various physiological processes and implicated in the progression of many pathological conditions. Therefore, NO donors are valuable tools in NO related basic and applied applications. The traditional spontaneous NO donors are limited in scenarios where flux, localization, and dose of NO could be monitored. This has promoted the development of novel NO donors, whose NO release is not only under control, but also self-calibrated. Herein, we reported a phototriggered and photocalibrated NO donor (NOD565) with an N-nitroso group on a rhodamine dye. NOD565 is nonfluorescent and could release NO efficiently upon irradiation by green light. A bright rhodamine dye is generated as a side-product and its fluorescence can be used to monitor the NO release. The potentials of NOD565 in practical applications are showcased in in vitro studies, e.g., platelet aggregation inhibition and fungi growth suppression. PMID- 29498826 TI - Relationship of Catalysis and Active Site Loop Dynamics in the (betaalpha)8 Barrel Enzyme Indole-3-glycerol Phosphate Synthase. AB - It is important to understand how the catalytic activity of enzymes is related to their conformational flexibility. We have studied this activity-flexibility correlation using the example of indole-3-glycerol phosphate synthase from Sulfolobus solfataricus (ssIGPS), which catalyzes the fifth step in the biosynthesis of tryptophan. ssIGPS is a thermostable representative of enzymes with the frequently encountered and catalytically versatile (betaalpha)8-barrel fold. Four variants of ssIGPS with increased catalytic turnover numbers were analyzed by transient kinetics at 25 degrees C, and wild-type ssIGPS was likewise analyzed both at 25 degrees C and at 60 degrees C. Global fitting with a minimal three-step model provided the individual rate constants for substrate binding, chemical transformation, and product release. The results showed that in both cases, namely, the application of activating mutations and temperature increase, the net increase in the catalytic turnover number is afforded by acceleration of the product release rate relative to the chemical transformation steps. Measurements of the solvent viscosity effect at 25 degrees C versus 60 degrees C confirmed this change in the rate-determining step with temperature, which is in accordance with a kink in the Arrhenius diagram of ssIGPS at ~40 degrees C. When rotational diffusion rates of electron paramagnetic spin-labels attached to active site loop beta1alpha1 are plotted in the form of an Arrhenius diagram, kinks are observed at the same temperature. These findings, together with molecular dynamics simulations, demonstrate that a different degree of loop mobility correlates with different rate-limiting steps in the catalytic mechanism of ssIGPS. PMID- 29498827 TI - Layered Insulator/Molecule/Metal Heterostructures with Molecular Functionality through Porphyrin Intercalation. AB - Intercalation of molecules into layered materials is actively researched in materials science, chemistry, and nanotechnology, holding promise for the synthesis of van der Waals heterostructures and encapsulated nanoreactors. However, the intercalation of organic molecules that exhibit physical or chemical functionality remains a key challenge to date. In this work, we present the synthesis of heterostructures consisting of porphines sandwiched between a Cu(111) substrate and an insulating hexagonal boron nitride ( h-BN) monolayer. We investigated the energetics of the intercalation, as well as the influence of the capping h-BN layer on the behavior of the intercalated molecules using scanning probe microscopy and density functional theory calculations. While the self assembly of the molecules is altered upon intercalation, we show that the intrinsic functionalities, such as switching between different porphine tautomers, are preserved. Such insulator/molecule/metal structures provide opportunities to protect organic materials from deleterious effects of atmospheric environment, can be used to control chemical reactions through spatial confinement, and give access to layered materials based on the ample availability of synthesis protocols provided by organic chemistry. PMID- 29498829 TI - Hemoglobin as a Smart pH-Sensitive Nanocarrier To Achieve Aggregation Enhanced Tumor Retention. AB - Natural proteins have been greatly explored to address unmet medical needs. However, few work has treated proteins as natural pH-sensitive nanoplatforms that make use of the inherent pH gradient of pathogenic sites. Here, hemoglobin is employed as a smart pH-sensitive nanocarrier for near-infrared dye IR780, which disperses well at normal tissue pH and exhibits aggregation at tumor acidic milieu. The pH-sensitive hemoglobin loaded with IR780 shows higher uptake by cancer cells at tumor acidic pH 6.5 than normal tissue pH 7.4. In vivo and ex vivo studies reveal that the hemoglobin nanocarrier exhibits distinct retention kinetics with remarkably prolonged residence time in tumor. Hemoglobin is then proved to be a potent pH-sensitive nanocarrier for cancer diagnosis and treatment. PMID- 29498830 TI - Block Copolymer Micelles for Photonic Fluids and Crystals. AB - Block copolymer micelles (BCMs) are self-assembled nanoparticles in solution with a collapsed core and a brush-like stabilizing corona typically in the size range of tens of nanometers. Despite being widely studied in various fields of science and technology, their ability to form structural colors at visible wavelength has not received attention, mainly due to the stringent length requirements of photonic lattices. Here, we describe the precision assembly of BCMs with superstretched corona, yet with narrow size distribution to qualify as building blocks for tunable and reversible micellar photonic fluids (MPFs) and micellar photonic crystals (MPCs). The BCMs form free-flowing MPFs with an average interparticle distance of 150-300 nm as defined by electrosteric repulsion arising from the highly charged and stretched corona. Under quiescent conditions, millimeter-sized MPCs with classical FCC lattice grow within the photonic fluid medium upon refinement of the positional order of the BCMs. We discuss the generic properties of MPCs with special emphasis on surprisingly narrow reflected wavelengths with full width at half-maximum (fwhm) as small as 1 nm. We expect this concept to open a generic and facile way for self-assembled tunable micellar photonic structures. PMID- 29498831 TI - Synthesis and Evaluation of a New 18F-Labeled Radiotracer for Studying the GABAB Receptor in the Mouse Brain. AB - New GABAB agonists, fluoropyridyl ether analogues of baclofen, have been synthesized as potential PET radiotracers. The compound with highest inhibition binding affinity as well as greatest agonist response, ( R)-4-amino-3-(4-chloro-3 ((2-fluoropyridin-4-yl)methoxy)phenyl)butanoic acid (1b), was radiolabeled with 18F with good radiochemical yield, high radiochemical purity, and high molar radioactivity. The regional brain distribution of the radiolabeled ( R)-4-amino-3 (4-chloro-3-((2-[18F]fluoropyridin-4-yl)methoxy)phenyl)butanoic acid, [18F]1b, was studied in CD-1 male mice. The study demonstrated that [18F]1b enters the mouse brain (1% ID/g tissue). The accumulation of [18F]1b in the mouse brain was inhibited (35%) by preinjection of GABAB agonist 1a, suggesting that the radiotracer brain uptake is partially mediated by GABAB receptors. The presented data demonstrate a feasibility of imaging of GABAB receptors in rodents and justify further development of GABAB PET tracers with improved specific binding and greater blood-brain barrier permeability. PMID- 29498828 TI - Protein-Derived Cofactors Revisited: Empowering Amino Acid Residues with New Functions. AB - A protein-derived cofactor is a catalytic or redox-active site in a protein that is formed by post-translational modification of one or more amino acid residues. These post-translational modifications are irreversible and endow the modified amino acid residues with new functional properties. This Perspective focuses on the following advances in this area that have occurred during recent years. The biosynthesis of the tryptophan tryptophylquinone cofactor is catalyzed by a diheme enzyme, MauG. A bis-FeIV redox state of the hemes performs three two electron oxidations of specific Trp residues via long-range electron transfer. In contrast, a flavoenzyme catalyzes the biosynthesis of the cysteine tryptophylquinone (CTQ) cofactor present in a newly discovered family of CTQ dependent oxidases. Another carbonyl cofactor, the pyruvoyl cofactor found in classes of decarboxylases and reductases, is formed during an apparently autocatalytic cleavage of a precursor protein at the N-terminus of the cleavage product. It has been shown that in at least some cases, the cleavage is facilitated by binding to an accessory protein. Tyrosylquinonine cofactors, topaquinone and lysine tyrosylquinone, are found in copper-containing amine oxidases and lysyl oxidases, respectively. The physiological roles of different families of these enzymes in humans have been more clearly defined and shown to have significant implications with respect to human health. There has also been continued characterization of the roles of covalently cross-linked amino acid side chains that influence the reactivity of redox-active metal centers in proteins. These include Cys-Tyr species in galactose oxidase and cysteine dioxygenase and the Met-Tyr-Trp species in the catalase-peroxidase KatG. PMID- 29498832 TI - How a Lytic Polysaccharide Monooxygenase Binds Crystalline Chitin. AB - Lytic polysaccharide monooxygenases (LPMOs) are major players in biomass conversion, both in Nature and in the biorefining industry. How the monocopper LPMO active site is positioned relative to the crystalline substrate surface to catalyze powerful, but potentially self-destructive, oxidative chemistry is one of the major questions in the field. We have adopted a multidisciplinary approach, combining biochemical, spectroscopic, and molecular modeling methods to study chitin binding by the well-studied LPMO from Serratia marcescens SmAA10A (or CBP21). The orientation of the enzyme on a single-chain substrate was determined by analyzing enzyme cutting patterns. Building on this analysis, molecular dynamics (MD) simulations were performed to study interactions between the LPMO and three different surface topologies of crystalline chitin. The resulting atomistic models showed that most enzyme-substrate interactions involve the polysaccharide chain that is to be cleaved. The models also revealed a constrained active site geometry as well as a tunnel connecting the bulk solvent to the copper site, through which only small molecules such as H2O, O2, and H2O2 can diffuse. Furthermore, MD simulations, quantum mechanics/molecular mechanics calculations, and electron paramagnetic resonance spectroscopy demonstrate that rearrangement of Cu-coordinating water molecules is necessary when binding the substrate and also provide a rationale for the experimentally observed C1 oxidative regiospecificity of SmAA10A. This study provides a first, experimentally supported, atomistic view of the interactions between an LPMO and crystalline chitin. The confinement of the catalytic center is likely crucially important for controlling the oxidative chemistry performed by LPMOs and will help guide future mechanistic studies. PMID- 29498833 TI - Acid-Labile Degradation of Injectable Fiber Fragments to Release Bioreducible Micelles for Targeted Cancer Therapy. AB - Cancer chemotherapy is confronted with difficulties enhancing the tumor accumulation, improving the bioavailability, and relieving the adverse effect of chemotherapeutic agents. To address the challenges, this study proposes a feasible strategy to realize a sustained release of drug-loaded micelles from fiber fragments after intratumoral injection. Camptothecin (CPT) is grafted on hyaluronic acid (HA) via 3,3'-dithiodipropionic acid to obtain reduction sensitive promicelle polymers (PMCPT), which are conjugated with poly(d,l lactide) via 2-propionic-3-methylmaleic anhydride (CDM) to obtain acid-labile copolymers for the preparation of injectable fiber fragments. Fiber fragments show remarkable acid-sensitive degradation, and the released PMCPT are spontaneously self-assembled into micelles, followed by subsequent HA-mediated internalization into tumor cells and reduction-sensitive release of drugs in the cytosol. Compared to fresh micelles prepared by ultrasonication, the micelles released via the degradation of fiber fragments display similar behaviors, such as the size and morphology, glutathione-sensitive drug release, cellular uptake efficiency, and cytotoxicity. Taking advantage of the aggregation-induced emission (AIE) effect of tetraphenylethene (TPE), the micelle release, cellular uptake, and tumor accumulation have been elucidated from the self-assembly induced fluorescence light-up in vitro and after intratumoral injection. Compared to the intratumoral injection of free micelles, sustained micelle release from fiber fragments resulted in significantly higher antitumor efficacy with respect to the inhibition of tumor growths, prolonging of animal survivals, and induction of cell apoptosis in tumor tissues. Thus, the micelle-releasing fiber fragments integrated with double targeting capabilities and double stimuli responsiveness have demonstrated a superior capacity to sustainably deliver chemotherapeutic agents directly within tumor cells. PMID- 29498834 TI - Lanthanide Texaphyrins as Photocatalysts. AB - Here, we report the use of gadolinium(III)-, lutetium(III)-, and lanthanum(III) texaphyrins as bioinspired photocatalysts that promote a novel approach to the degradation of curcumin, a 1,3-diketo-containing natural product. Complexation of curcumin to the lanthanide centers of the texaphyrins yields stable species that display limited reactivity in the dark or under anaerobic conditions. However, upon exposure to mWatt intensity light (pocket flashlight) or simply under standard laboratory illumination in the presence of atmospheric oxygen, substrate oxidation occurs readily to generate curcumin-derived cleavage products. These latter species were identified on the basis of spectroscopic and mass spectrometric analyses. The mild nature of the activation conditions serves to highlight a potential new role for photoactive lanthanide complexes. PMID- 29498835 TI - Stimulus-Responsive Peptide for Effective Delivery and Release of DNA in Plants. AB - For efficient gene delivery in plant systems, nonviral vector and DNA complexes require extracellular stability, cell wall/membrane translocation capability, and the ability to mediate both endosomal escape and intracellular DNA release. Peptides make appealing gene delivery vectors due to their DNA-binding, cell penetrating, and endosome escape properties. However, DNA release within cells has so far been inefficient, which results in poor and delayed gene expression, while the lack of understanding of both internalization and trafficking mechanisms is a further obstacle to the design of efficient peptide gene delivery vectors. Here, we report successful gene delivery into plants using a cellular environment-responsive vector, BPCH7, which is an efficient cell-penetrating peptide with a cyclic DNA-binding domain that is formed by a disulfide bond between two cysteines. The cyclic structure of BPCH7 confers high avidity attachment to DNA in vitro. Following endocytosis into cells, disulfide bond cleavage facilitated by intracellular glutathione induces structural changes within BPCH7 that enable the release of the associated DNA cargo. Comparative studies with BPKH, a cell-penetrating peptide with a linear DNA-binding domain, show that BPCH7 maximized and expedited gene transfer in cells and unveil for the first time the crucial role of plant stomata in the internalization of peptide DNA complexes. PMID- 29498836 TI - Metal (Pb, Cd, and Zn) Binding to Diverse Organic Matter Samples and Implications for Speciation Modeling. AB - This study evaluated the influence of dissolved organic matter (DOM) properties on the speciation of Pb, Zn, and Cd. A total of six DOM samples were categorized into autochthonous and allochthonous sources based on their absorbance and fluorescence properties. The concentration of free metal ions ( CM2+) measured by titration using the absence of gradients and Nernstian equilibrium stripping (AGNES) method was compared with that predicted by the Windermere humic aqueous model (WHAM). At the same binding condition (pH, dissolved organic carbon, ionic strength, and total metal concentration) the allochthonous DOM showed a higher level of Pb binding than the autochthonous DOM (84- to 504-fold CPb2+ variation). This dependency, however, was less pronounced for Zn (12- to 74-fold CZn2+ variation) and least for Cd (2- to 14-fold CCd2+ variation). The WHAM performance was affected by source variation through the active DOM fraction ( F). The commonly used F = 1.3 provided reliable CPb2+ for allochthonous DOMs and acceptable CCd2+ for all DOM, but it significantly under-predicted CPb2+ and CZn2+ for autochthonous DOM. Adjusting F improved CM2+ predictions, but the optimum F values were metal-specific (e.g., 0.03-1.9 for Pb), as shown by linear correlations with specific optical indexes. The results indicate a potential to improve WHAM by incorporating rapid measurement of DOM optical properties for site-specific F. PMID- 29498837 TI - Composite and Low-Cost Approaches for Molecular Crystal Structure Prediction. AB - Molecular crystal structure prediction (CSP) requires evaluating differences in lattice energy between candidate crystal structures accurately and efficiently. In this work, we explore and compare several low-cost alternatives to dispersion corrected density-functional theory (DFT) in the plane-waves/pseudopotential approximation, the most accurate and general approach used for CSP at present. Three types of low-cost methods are considered: DFT with a small basis set of finite-support numerical orbitals (the SIESTA method), dispersion-corrected Gaussian small or minimal-basis-set Hartree-Fock and DFT with additional empirical corrections (HF-3c and PBEh-3c), and self-consistent-charge dispersion corrected density-functional tight binding (SCC-DFTB3-D3). In addition, we study the performance of composite methods that comprise a geometry optimization using a low-cost approach followed by a single-point calculation using the accurate but comparatively expensive B86bPBE-XDM functional. All methods were tested for their abilities to produce absolute lattice energies, relative lattice energies, and crystal geometries. We show that assessing various methods by their ability to produce absolute lattice energies can be misleading and that relative lattice energies are a much better indicator of performance in CSP. The EE14 set of relative solubilities of homochiral and heterochiral chiral crystals is proposed for relative lattice-energy benchmarking. Our results show that PBE-D2 plus a DZP basis set of numerical orbitals coupled with a final B86bPBE-XDM single-point calculation gives excellent performance at a fraction of the cost of a full B86bPBE-XDM calculation, although the results are sensitive to the particular details of the computational protocol. The B86bPBE-XDM//PBE-D2/DZP method was subsequently tested in a practical CSP application from our recent work on the crystal structure of the enantiopure and racemate forms of 1-aza[6]helicene, a chiral organic semiconductor. Our results show that this multilevel method is able to correctly reproduce the energy ranking of both crystal forms. PMID- 29498838 TI - The Influence of Different Air-Drying Conditions on Bioactive Compounds and Antioxidant Activity of Berries. AB - The aim of the present research was to study the effect of convective drying on color, bioactive compounds, and antioxidant activity of berry fruits and to chemically characterize the polyphenolic composition of raspberry, boysenberry, redcurrants, and blackcurrants fruit. Drying berries at 65 degrees C provoked the best conservations of color, particularly for boysenberry and blackcurrant. Drying at 65 degrees C was also the condition that showed higher level of polyphenols, while drying at 50 or 130 degrees C showed above % degradation of them due to the long time or high temperature drying. Radical scavenging activity was the predominant antioxidant mechanism in all samples, with 65 degrees C dried berries being the most active ones possibly because of polyphenol depolymerization. The anthocyanin profile showed that delphinidin and cyanidin derivatives were the most abundant anthocyanidins with different predominance between berry genera. Degradation of anthocyanins was increased with drying temperature been Cy 3-glucoside and Cy 3-rutinoside the most abundant. PMID- 29498839 TI - Water-Stable Metal-Organic Framework with Three Hydrogen-Bond Acceptors: Versatile Theoretical and Experimental Insights into Adsorption Ability and Thermo-Hydrolytic Stability. AB - A new microporous cadmium metal-organic framework was synthesized both mechanochemically and in solution by using a sulfonyl-functionalized dicarboxylate linker and an acylhydrazone colinker. The three-dimensional framework is highly stable upon heating to 300 degrees C as well as in aqueous solutions at elevated temperatures or acidic conditions. The thermally activated material exhibits steep water vapor uptake at low relative pressures at 298 K and excellent recyclability up to 260 degrees C as confirmed by both quasi equilibrated temperature-programmed desorption and adsorption (QE-TPDA) method as well as adsorption isotherm measurements. Reversible isotherms and hysteretic isobars recorded for the desorption-adsorption cycles indicate the maximum uptake of 0.19 g/g (at 298 K, up to p/p0 = 1) or 0.18 g/g (at 1 bar, within 295-375 K range), respectively. The experimental isosteric heat of adsorption (48.9 kJ/mol) indicates noncoordinative interactions of water molecules with the framework. Exchange of the solvent molecules in the as-made material with water, performed in the single-crystal to single-crystal manner, allows direct comparison of both X-ray crystal structures. The single-crystal X-ray diffraction for the water loaded framework demonstrates the orientation of water clusters in the framework cavities and reveals their strong hydrogen bonding with sulfonyl, acyl, and carboxylate groups of the two linkers. The grand canonical Monte Carlo (GCMC) simulations of H2O adsorption corroborate the experimental findings and reveal preferable locations of guest molecules in the framework voids at various pressures. Additionally, both experimental and GCMC simulation insights into the adsorption of CO2 (at 195 K) on the activated framework are presented. PMID- 29498840 TI - Crystal Structures and Electronic Properties of Oxygen-rich Titanium Oxides at High Pressure. AB - Pressure is well-known to significantly change the bonding patterns of materials and lift the reactivity of elements, leading to the synthesis of unconventional compounds with fascinating properties. Titanium-oxygen (Ti-O) compounds (e.g., TiO2) are attracting increasing attention due to their attractive electronic properties and extensive industrial applications (e.g., photocatalysis and solar cells). Using the effective CALYPSO structure searching method combined with first-principles calculations, we theoretically explored various oxygen-rich Ti-O compounds at pressures ranging from 0 to 200 GPa. Our results revealed, unexpectedly, that pressure stabilizes two hitherto unknown stoichiometric oxygen rich Ti2O5 and TiO3 compounds. Ti2O5 crystallized in P-421 c structure, whose remarkable feature is that it contains a peroxide group (O22-) with an O-O distance of 1.38 A at 150 GPa. The trioxide TiO3 is an ionic metal and is the oxygen-richest compound known thus far in the Ti-O system. It adopts a high symmetry (space group Pm-3 n) structure consisting of a 12-fold coordinated face sharing TiO12 icosahedron, where Ti has the highest coordination number with O among all Ti-O structures. The underlying mechanisms for the stabilization of Ti2O5 and TiO3 lie in the higher coordination number and denser structure packing. Our current results unravel the unusual oxygen-rich stoichiometry of Ti O compounds and provide further insight into the diverse electronic properties of Ti oxides under high pressure. PMID- 29498841 TI - Optical Thermometry Based on Vibration Sidebands in Y2MgTiO6:Mn4+ Double Perovskite. AB - Mn4+-doped Y2MgTiO6 phosphors are synthesized by the traditional solid-state method. Powder X-ray diffraction, scanning electron microscope, and energy dispersive X-ray spectrometer are employed to characterize the samples. The Mn4+ doped Y2MgTiO6 phosphors show the far-red emission at ~715 nm, which is assigned to the 2Eg -> 4A2 spin-forbidden transition of Mn4+. The temperature-dependent luminescent dynamics of Mn4+ is described by a complete model associated with electron-lattice interaction and spin-orbit coupling. The noncontact optical thermometry of Y2MgTiO6:Mn4+ is discussed based on the fluorescence intensity ratio of thermally coupled anti-Stokes and Stokes sidebands of the efficient ~715 nm far-red emission in the temperature range of 10-513 K. The maximum sensor sensitivity of Y2MgTiO6:Mn4+ is determined to be as high as 0.001 42 K-1 at 153 K, which demonstrates potential applications for the optical thermometry at low temperature environments. PMID- 29498842 TI - Chirality-Amplifying, Dynamic Induction of Single-Handed Helix by Chiral Guests to Macromolecular Chiral Catalysts Bearing Boronyl Pendants as Receptor Sites. AB - Helical chirality of poly(quinoxaline-2,3-diyl)s bearing a boronyl pendant at the 5-position of the quinoxaline ring was induced by condensation with chiral guests such as a diol, diamine, and amino alcohol. Reversible induction of a single handed helical structure was achieved by using less than an equimolar amount of chiral amino alcohols to the boronyl pendants. Majority-rule-effect-based chiral amplification on the polyquinoxaline main chain was demonstrated with chiral amino alcohols with low enantiomeric excess (ee). The helical macromolecular scaffold whose helicity was thus induced was utilized in palladium-catalyzed asymmetric silaboration of meso-methylenecyclopropane (up to 92% ee) by introducing (diarylphosphino)phenyl pendants at their side chains. PMID- 29498843 TI - Discovery of Trifluoromethyl Glycol Carbamates as Potent and Selective Covalent Monoacylglycerol Lipase (MAGL) Inhibitors for Treatment of Neuroinflammation. AB - Monoacylglycerol lipase (MAGL) inhibition provides a potential treatment approach to neuroinflammation through modulation of both the endocannabinoid pathway and arachidonoyl signaling in the central nervous system (CNS). Herein we report the discovery of compound 15 (PF-06795071), a potent and selective covalent MAGL inhibitor, featuring a novel trifluoromethyl glycol leaving group that confers significant physicochemical property improvements as compared with earlier inhibitor series with more lipophilic leaving groups. The design strategy focused on identifying an optimized leaving group that delivers MAGL potency, serine hydrolase selectivity, and CNS exposure while simultaneously reducing log D, improving solubility, and minimizing chemical lability. Compound 15 achieves excellent CNS exposure, extended 2-AG elevation effect in vivo, and decreased brain inflammatory markers in response to an inflammatory challenge. PMID- 29498844 TI - Isolation and Identification of Three gamma-Glutamyl Tripeptides and Their Putative Production Mechanism in Aged Garlic Extract. AB - We analyzed aged garlic extract (AGE) to understand its complex sulfur chemistry using post-column high-performance liquid chromatography with an iodoplatinate reagent and liquid chromatography high resolution mass spectrometry (LC-MS). We observed unidentified peaks of putative sulfur compounds. Three compounds were isolated and identified as gamma-glutamyl-gamma-glutamyl- S-methylcysteine, gamma glutamyl-gamma-glutamyl- S-allylcysteine (GGSAC) and gamma-glutamyl-gamma glutamyl- S-1-propenyl-cysteine (GGS1PC) by nuclear magnetic resonance and LC-MS analysis based on comparisons with chemically synthesized reference compounds. GGSAC and GGS1PC were novel compounds. Trace amounts of these compounds were detected in raw garlic, but the contents of these compounds increased during the aging process. Production of these compounds was inhibited using a gamma-glutamyl transpeptidase (GGT) inhibitor in the model reaction mixtures. These findings suggest that gamma-glutamyl tripeptides in AGE are produced by GGT during the aging process. PMID- 29498845 TI - Lewis Acid-Catalyzed Diastereoselective Synthesis of Multisubstituted N Acylaziridine-2-carboxamides from 2 H-Azirines via Joullie-Ugi Three-Component Reaction. AB - A ZnCl2-catalyzed diastereoselective Joullie-Ugi three-component reaction from 2 H-azirines, isocyanides, and carboxylic acids was established. The protocol allows the preparation of highly and diversely functionalized N-acylaziridine-2 carboxamide derivatives in up to 82% isolated yields. Moreover, the applicability of N-acylaziridines is demonstrated through a variety of transformations. PMID- 29498846 TI - Unusual Coexistence of Nickel(II) and Nickel(IV) in the Quadruple Perovskite Ba4Ni2Ir2O12 Containing Ir2NiO12 Mixed-Metal-Cation Trimers. AB - The crystal chemistry and magnetic properties of two hexagonal nickel(IV) containing perovskites, Ba4Ni1.94Ir2.06O12 and BaNiO3, are reported. The 12R perovskite, Ba4Ni1.94Ir2.06O12, possesses an unexpected coexistence of nickel(II) and nickel(IV). This quadruple perovskite structure contains Ir2NiO12 mixed-metal cation units in which direct metal-metal bonding between nickel(IV) and iridium(V) is inferred. X-ray absorption near-edge spectroscopy and X-ray photoelectron spectroscopy measurements were conducted to confirm the simultaneous presence of nickel(II) and nickel(IV). PMID- 29498848 TI - Tunable Thermosetting Epoxies Based on Fractionated and Well-Characterized Lignins. AB - Here we report the synthesis of thermosetting resins from low molar mass Kraft lignin fractions of high functionality, refined by solvent extraction. Such fractions were fully characterized by 31P NMR, 2D-HSQC NMR, SEC, and DSC in order to obtain a detailed description of the structures. Reactive oxirane moieties were introduced on the lignin backbone under mild reaction conditions and quantified by simple 1H NMR analysis. The modified fractions were chemically cross-linked with a flexible polyether diamine ( Mn ~ 2000), in order to obtain epoxy thermosets. Epoxies from different lignin fractions, studied by DSC, DMA, tensile tests, and SEM, demonstrated substantial differences in terms of thermo mechanical properties. For the first time, strong relationships between lignin structures and epoxy properties could be demonstrated. The suggested approach provides unprecedented possibilities to tune network structure and properties of thermosets based on real lignin fractions, rather than model compounds. PMID- 29498847 TI - Copper-Catalyzed Chan-Lam Cyclopropylation of Phenols and Azaheterocycles. AB - Small molecules containing cyclopropane-heteroatom linkages are commonly needed in medicinal chemistry campaigns yet are problematic to prepare using existing methods. To address this issue, a scalable Chan-Lam cyclopropylation reaction using potassium cyclopropyl trifluoroborate has been developed. With phenol nucleophiles, the reaction effects O-cyclopropylation, whereas with 2-pyridones, 2-hydroxybenzimidazoles, and 2-aminopyridines the reaction brings about N cyclopropylation. The transformation is catalyzed by Cu(OAc)2 and 1,10 phenanthroline and employs 1 atm of O2 as the terminal oxidant. This method is operationally convenient to perform and provides a simple, strategic disconnection toward the synthesis of cyclopropyl aryl ethers and cyclopropyl amine derivatives bearing an array of functional groups. PMID- 29498849 TI - HSQC-TOCSY Fingerprinting for Prioritization of Polyketide- and Peptide-Producing Microbial Isolates. AB - Microbial products are a promising source for drug leads as a result of their unique structural diversity. However, reisolation of already known natural products significantly hampers the discovery process, and it is therefore important to incorporate effective microbial isolate selection and dereplication protocols early in microbial natural product studies. We have developed a systematic approach for prioritization of microbial isolates for natural product discovery based on heteronuclear single-quantum correlation-total correlation spectroscopy (HSQC-TOCSY) nuclear magnetic resonance profiles in combination with antiplasmodial activity of extracts. The HSQC-TOCSY experiments allowed for unfractionated microbial extracts containing polyketide and peptidic natural products to be rapidly identified. Here, we highlight how this approach was used to prioritize extracts derived from a library of 119 ascidian-associated actinomycetes that possess a higher potential to produce bioactive polyketides and peptides. PMID- 29498850 TI - Saroclides A and B, Cyclic Depsipeptides from the Mangrove-Derived Fungus Sarocladium kiliense HDN11-112. AB - Two new depsipeptides (1 and 2), together with three known related compounds, pestalotin (3), pestalotiopyrone L (4), and PC-2 (5), were discovered in the extract of a mangrove derived fungus Sarocladium kiliense HDN11-112. The structures of saroclides A and B were established by interpretation of extensive NMR spectroscopic data and X-ray crystallographic analysis. Compound 1 was also produced by Simplicillium lamellicola HDN13-430. Compounds 1 and 2 were inactive against five cancer cell lines and four pathogenic microorganisms, while compound 1 showed a lipid-lowering effect. PMID- 29498851 TI - Systematic and Stereoselective Total Synthesis of Mannosylerythritol Lipids and Evaluation of Their Antibacterial Activity. AB - The total synthesis of the 20 homogeneous members of mannosylerythritol lipids (MELs) with different alkyl chain lengths was effectively and systematically accomplished from a strategically designed common key intermediate that was stereoselectively constructed by the borinic acid catalyzed beta-mannosylation reaction. In addition, their antibacterial activities against Gram-positive bacteria were evaluated. Our results demonstrated that not only the length of the alkyl chains but also the pattern of Ac groups on the mannose moiety were important factors for antibacterial activity. PMID- 29498852 TI - Insertion of Ni(I) into Porphyrins at Room Temperature: Preparation of Ni(II)porphyrins, and Ni(II)chlorins and Observation of Hydroporphyrin Intermediates. AB - Reduced Nickel porphyrins play an important role as enzymatic cofactors in the global carbon cycle (cofactor F430), and as powerful catalysts in solar-to-fuel processes such as the hydrogen evolution reaction, and the reduction of CO and CO2. The preparation of Ni(II)porphyrins requires harsh conditions, and characterization of the reduced species is intricate. We present a very mild, convenient, and high yielding method of inserting Ni into electron rich, and electron deficient porphyrins which at the same time gives access to to Ni(II) phlorins and Ni(II)chlorins and Ni(II)porphyrins. PMID- 29498853 TI - Ultrafast Reactive Quantum Dynamics Coupled to Classical Solvent Dynamics Using an Ehrenfest Approach. AB - The inclusion of solvent effects in the theoretical analysis of molecular processes becomes increasingly important. Currently, it is not feasible to directly include the solvent on the quantum level. We use an Ehrenfest approach to study the coupled time evolution of quantum dynamically treated solutes and classical solvents system. The classical dynamics of the solvent is coupled to the wavepacket dynamics of the solute and rotational and translational degrees of freedom of the solute are included classically. This allows quantum dynamics simulations for ultrafast processes that are decided by environment interactions without explicit separation of time scales. We show the application to the dissociation of ICN in liquid Ar as a proof of principal system and to the more applied example of uracil in water. PMID- 29498854 TI - Comment on "The Mayonnaise Effect". PMID- 29498855 TI - Structural Identification of 19 Purified Isomers of the OPV Acceptor Material bisPCBM by 13C NMR and UV-Vis Absorption Spectroscopy and High-Performance Liquid Chromatography. AB - The molecular structures of 19 purified isomers of bis-phenyl-C62-butyric acid methyl ester were identified by a combination of 13C NMR and UV-vis absorption spectroscopies and high-performance liquid chromatography (HPLC) retention time analysis. All 19 isomers are dicyclopropafullerenes (none are homofullerenes). There were seven isomers with C1 molecular point-group symmetry, four with C s, six with C2, one with C2 v, and one with C2 h symmetry. The C2 h, C2 v, and all five nonequatorial C1 isomers were unambiguously assigned to their respective HPLC fractions. For the other 12 isomers, the 13C NMR and UV-vis spectra placed them in six groups of two same-symmetry isomers. On the basis of the widely spaced HPLC retention times of the two isomers within each of these six groups, and the empirical inverse correlation between retention time and addend spacing, each isomer was assigned to its corresponding HPLC fraction. In addition, the missing trans-1 isomer was found, purified, and characterized. PMID- 29498856 TI - New Electrochemical Sensor Based on a Silver-Doped Iron Oxide Nanocomposite Coupled with Polyaniline and Its Sensing Application for Picomolar-Level Detection of Uric Acid in Human Blood and Urine Samples. AB - A simple and very sensitive electrochemical sensor for the detection of uric acid (UA) has been developed based on polyaniline (PANI) merged into a silver-doped iron oxide (Ag-Fe2O3) nanocomposite-modified glassy carbon electrode. The synthesized ternary composite material (Ag-Fe2O3@PANI) was characterized by UV visible spectroscopy, Fourier transform infrared spectroscopy, energy-dispersive X-ray, High-resolution transmission electron microscopy, X-ray diffraction, and thermo gravimetric analysis analyses. The nanocomposite-modified electrode shows an exceptional electrocatalytic activity and reversibility to the oxidation of UA in a 0.1 M phosphate buffer solution (pH 7.0) compared to those in PANI and Ag Fe2O3. The detection limit of UA is found to be 102 pM with a linear dynamic range of 0.001-0.900 MUM. The fabricated UA sensor also exhibits good selectivity, reproducibility, and long-time stability. The limit of detection and linear range attained for the synthesized composite are much greater compared to those of any other composite materials reported in the literature. The proposed method has been successfully applied for the selective detection of UA in various real samples such as human serum and urine with good recoveries. This platform that assimilates such electrocatalytic ternary nanocomposite with high performance can be widely employed for fabricating diverse sensors. PMID- 29498858 TI - Theoretical Study of the Feasibility of Laser Cooling the 24Mg35Cl Molecule Including Hyperfine Structure and Branching Ratios. AB - The possibility of laser cooling the 24Mg35Cl molecule is investigated using the electronic, rovibrational, and hyperfine structure. Twelve low-lying Lambda-S electronic states of the 24Mg35Cl molecule have been calculated at the multireference configuration interaction level of theory. The spin-orbit coupling effects are taken into account in the electronic structure calculations. Spectroscopic constants agree well with previously obtained theoretical and experimental values. On the basis of the potential energy curves and transition dipole moments, the highly diagonally distributed Franck-Condon factors for the A2Pi -> X2Sigma+ transition and short radiative lifetime of the A2Pi state are determined. Then, employing a quantum effective Hamiltonian approach, we investigate the hyperfine manifolds of the X2Sigma+ state and obtain the zero field hyperfine spectrum with the errors relative to the experimental data not exceeding 8-20 kHz. Finally, we design a laser cooling scheme with one cooling main laser beam and two repumping laser beams with modulated sidebands, which is sufficient for the implementation of efficient laser slowing and cooling of the 24Mg35Cl molecule. Moreover, it is important to note that the dissociation energy (2.2593 eV) of the B2Sigma+ state is obtained for the first time at the multireference configuration interaction level. We hope that this can provide a helpful reference for experimental observation. PMID- 29498859 TI - Developing and Standardizing a Protocol for Quantitative Proton Nuclear Magnetic Resonance (1H NMR) Spectroscopy of Saliva. AB - Metabolic profiling by 1H NMR spectroscopy is an underutilized technology in salivary research, although preliminary studies have identified promising results in multiple fields (diagnostics, nutrition, sports physiology). Translation of preliminary findings into validated, clinically approved knowledge is hindered by variability in protocol for the collection, storage, preparation, and analysis of saliva. This study aims to evaluate the effects of differing sample pretreatments on the 1H NMR metabolic profile of saliva. Protocol considerations are highly varied in the current literature base, including centrifugation, freeze-thaw cycles, and different NMR quantification methods. Our findings suggest that the 1H NMR metabolite profile of saliva is resilient to any change resulting from freezing, including freezing of saliva prior to centrifuging. However, centrifugation was necessary to remove an unidentified broad peak between 1.24 and 1.3 ppm, the intensity of which correlated strongly with saliva cellular content. This peak obscured the methyl peak from lactate and significantly affected quantification. Metabolite quantification was similar for saliva centrifuged between 750 g to 15 000 g. Quantification of salivary metabolites was similar whether quantified using internal phosphate-buffered sodium trimethylsilyl-[2,2,3,3-2H4]-propionate (TSP) or external TSP in a coaxial NMR tube placed inside the NMR tube containing the saliva sample. Our results suggest that the existing literature on salivary 1H NMR will not have been adversely affected by variations of the common protocol; however, use of TSP as an internal standard without a buffered medium appears to affect metabolite quantification, notably for acetate and methanol. We include protocol recommendations to facilitate future NMR-based studies of saliva. PMID- 29498857 TI - Chemical Shifts of the Carbohydrate Binding Domain of Galectin-3 from Magic Angle Spinning NMR and Hybrid Quantum Mechanics/Molecular Mechanics Calculations. AB - Magic angle spinning NMR spectroscopy is uniquely suited to probe the structure and dynamics of insoluble proteins and protein assemblies at atomic resolution, with NMR chemical shifts containing rich information about biomolecular structure. Access to this information, however, is problematic, since accurate quantum mechanical calculation of chemical shifts in proteins remains challenging, particularly for 15NH. Here we report on isotropic chemical shift predictions for the carbohydrate recognition domain of microcrystalline galectin 3, obtained from using hybrid quantum mechanics/molecular mechanics (QM/MM) calculations, implemented using an automated fragmentation approach, and using very high resolution (0.86 A lactose-bound and 1.25 A apo form) X-ray crystal structures. The resolution of the X-ray crystal structure used as an input into the AF-NMR program did not affect the accuracy of the chemical shift calculations to any significant extent. Excellent agreement between experimental and computed shifts is obtained for 13Calpha, while larger scatter is observed for 15NH chemical shifts, which are influenced to a greater extent by electrostatic interactions, hydrogen bonding, and solvation. PMID- 29498860 TI - pH-Responsive Nanophotosensitizer for an Enhanced Photodynamic Therapy of Colorectal Cancer Overexpressing EGFR. AB - Photodynamic therapy (PDT) has been shown to kill cancer cells and improve survival and quality of life in cancer patients, and numerous new approaches have been considered for maximizing the efficacy of PDT. In this study, a new multifunctional nanophotosensitizer Ce6/GE11-(pH)micelle was developed to target epidermal growth factor receptor (EGFR) overexpressing colorectal cancer (CRC) cells. This nanophotosensitizer was synthesized using a micelle comprising pH responsive copolymers (PEGMA-PDPA), biodegradable copolymers (mPEG-PCL), and maleimide-modified biodegradable copolymers (Mal-PEG-PCL) to entrap the potential hydrophobic photosensitizer chlorin e6 (Ce6) and to present EGFR-targeting peptides (GE11) on its surface. In the presence of Ce6/GE11-(pH)micelles, Ce6 uptake by EGFR-overexpressing CRC cells significantly increased due to GE11 specificity. Moreover, Ce6 was released from Ce6/GE11-(pH)micelles in tumor environments, leading to improved elimination of cancer cells in PDT. These results indicate enhanced efficacy of PDT using Ce6/GE11-(pH)micelle, which is a powerful nanophotosensitizer with high potential for application to future PDT for CRC. PMID- 29498861 TI - Direct Microscopic Observation of Domain Rearrangement Mechanism of Photo Orientation Process in Azobenzene-Containing Materials. AB - The evolution of the domain structure of two azobenzene-containing materials during irradiation with polarized light was monitored using polarized optical microscopy with additional lambda-waveplate for discerning the domains oriented parallel and perpendicular to irradiating light polarization. It is shown that the process of photo-orientation consists in growth of perpendicularly oriented domains and diminishing of parallel domains via the movement of domain boundaries. These data confirm the mechanism of photo-orientation via domain structure rearrangement. PMID- 29498862 TI - Transition-Metal-Free Formylation of Allylzinc Reagents Leading to alpha Quaternary Aldehydes. AB - The first example of formylation of allylzinc reagents using S-phenyl thioformate is presented. The reaction proceeded under mild conditions without any transition metal catalyst, forming quaternary carbon centers with reactive functionalities, such as formyl and vinyl groups. Moreover, Barbier-type formylation of an allylic bromide with a sterically demanding thioformate was achieved. As a preliminary result, asymmetric formylation was conducted using a menthol-derived chiral thioformate. PMID- 29498863 TI - Self-Assembly of Triblock Copolymers from Cyclic Esters as a Tool for Tuning Their Particle Morphology. AB - This paper presents the effect of end groups, chain structure, and stereocomplexation on the microparticle and nanoparticle morphology and thermal properties of the supramolecular triblock copolyesters. Therefore, the series of the triblock copolymers composed of l,l- and d,d-lactide, trimethylene carbonate (TMC), and epsilon-caprolactone (CL) with isopropyl ( iPr) or 2-ureido-4-[1 H] pyrimidinone (UPy) end groups at both chain ends were synthesized. In addition, these copolymers were intermoleculary stereocomplexed by polylactide (PLA) blocks with an opposite configuration of repeating units to promote their self-assembly in various organic solvents. The combination of two noncovalent interactions of the end groups and PLA enantiomeric chains leads to stronger interactions between macromolecules and allows for alteration of their segmental mobility. The simple tuning of the copolymer microstructure and functionality induced the self assembly of macromolecules at liquid/liquid interfaces, which consequently leads to their phase separation in the form of particles with diameters ranging from 0.1 MUm to 10 MUm. This control is essential for their potential applications in the biomedical field, where biocompatible and well-defined microparticles and nanoparticles are highly desirable. PMID- 29498864 TI - Schinortriterpenoids with Identical Configuration but Distinct ECD Spectra Generated by Nondegenerate Exciton Coupling. AB - Ten schinortriterpenoids with biogenetically related lancischiartane scaffolds, including the first 3-norlancischiartane (1) with unusual configuration inversions occurring at C-1 and C-10, were isolated from Schisandra lancifolia. Unusual ECD curve patterns observed in 6-8 were confirmed to be caused by nondegenerate exciton coupling, suggesting that ECD spectrum empirical comparison should be used with caution in configuration determination. Additionally, structure revision of 2, originally proposed as arisanlactone A, was completed using NMR computation and X-ray diffraction analysis. PMID- 29498865 TI - Regiocontrolled Wacker Oxidation of Cinnamyl Azides. AB - A highly regioselective Wacker oxidation has been developed for the oxidation of cinnamyl azides. The catalytic oxidation tolerates the azide functionality, and more than 15 beta-azido ketones were isolated (25-92% yield). High regioselectivity for the aryl ketone is observed in all cases. A robustness screen was conducted to determine functional group tolerance. The products of the oxidaiton can be readily diversified. PMID- 29498866 TI - Local Observation of Phase Segregation in Mixed-Halide Perovskite. AB - Mixed-halide perovskites have emerged as promising materials for optoelectronics due to their tunable band gap in the entire visible region. A challenge remains, however, in the photoinduced phase segregation, narrowing the band gap of mixed halide perovskites under illumination thus restricting applications. Here, we use a combination of spatially resolved and bulk measurements to give an in-depth insight into this important yet unclear phenomenon. We demonstrate that photoinduced phase segregation in mixed-halide perovskites selectively occurs at the grain boundaries rather than within the grain centers by using shear-force scanning probe microscopy in combination with confocal optical spectroscopy. Such difference is further evidenced by light-biased bulk Fourier-transform photocurrent spectroscopy, which shows the iodine-rich domain as a minority phase coexisting with the homogeneously mixed phase during illumination. By mapping the surface potential of mixed-halide perovskites, we evidence the higher concentration of positive space charge near the grain boundary possibly provides the initial driving force for phase segregation, while entropic mixing dominates the reverse process. Our work offers detailed insight into the microscopic processes occurring at the boundary of crystalline perovskite grains and will support the development of better passivation strategies, ultimately allowing the processing of more environmentally stable perovskite films. PMID- 29498867 TI - Tuning Electron-Phonon Interactions in Nanocrystals through Surface Termination. AB - We perform ab initio molecular dynamics on experimentally relevant-sized lead sulfide (PbS) nanocrystals (NCs) constructed with thiol or Cl, Br, and I anion surfaces to determine their vibrational and dynamic electronic structure. We show that electron-phonon interactions can explain the large thermal broadening and fast carrier cooling rates experimentally observed in Pb-chalcogenide NCs. Furthermore, our simulations reveal that electron-phonon interactions are suppressed in halide-terminated NCs due to reduction of both the thermal displacement of surface atoms and the spatial overlap of the charge carriers with these large atomic vibrations. This work shows how surface engineering, guided by simulations, can be used to systematically control carrier dynamics. PMID- 29498868 TI - Liposomal Codelivery of Doxorubicin and Andrographolide Inhibits Breast Cancer Growth and Metastasis. AB - Effective treatment of metastatic (stage IV) breast cancers remains a formidable challenge. To address this issue, a cell-penetrating peptide-assisted liposomal system was developed for codelivery of doxorubicin and andrographolide. This nanomedicine-based combination therapy showed the ability to inhibit the in vitro migration and invasion of 4T1 cells through the wound healing and transwell invasion assays. Furthermore, this delivery system exhibited the enhanced accumulation in the tumor tissues and deep intratumoral penetration. The synergistic effect of doxorubicin and andrographolide led to an evident inhibition of tumor growth in an orthotopic breast tumor mouse model and efficient prevention of lung metastasis. The therapeutic mechanism was associated with the anti-angiogenesis effect. In conclusion, this nanomedicine-based combination therapy provides a potential method for overcoming metastatic breast cancers. PMID- 29498869 TI - Improved HER Catalysis through Facile, Aqueous Electrochemical Activation of Nanoscale WSe2. AB - In the search for nonprecious metal catalysts for the hydrogen evolution reaction (HER), transition metal dichalcogenides (TMDCs) have been proposed as promising candidates. Here, we present a facile method for significantly decreasing the overpotential required for catalyzing the HER with colloidally synthesized WSe2. Solution phase deposition of 2H WSe2 nanoflowers (NFs) onto carbon fiber electrodes results in low catalytic activity in 0.5 M H2SO4 with an overpotential at -10 mA/cm2 of greater than 600 mV. However, two postdeposition electrode processing steps significantly reduce the overpotential. First, a room temperature treatment of the prepared electrodes with a dilute solution of the alkylating agent Meerwein's salt ([Et3O][BF4]) results in a reduction in overpotential by approximately 130 mV at -10 mA/cm2. Second, we observe a decrease in overpotential of approximately 200-300 mV when the TMDC electrode is exposed to H+, Li+, Na+, or K+ ions under a reducing potential. The combined effect of ligand removal and electrochemical activation results in an improvement in overpotential by as much as 400 mV. Notably, the Li+ activated WSe2 NF deposited carbon fiber electrode requires an overpotential of only 243 mV to generate a current density of -10 mA/cm2. Measurement of changes in the material work function and charge transfer resistance ultimately provide rationale for the catalytic improvement. PMID- 29498870 TI - Sensitized Two-Photon Activation of Coumarin Photocages. AB - Here we report the design of a new coumarin-based photolabile protecting group with enhanced two-photon absorption. Two-photon excited fluorescence (TPEF), color-tuned ultrafast transient absorption spectroscopy and infrared (IR) measurements are employed to photochemically characterize the newly designed ATTO 390-DEACM-cargo triad. Increased two-photon cross-section values of the novel cage in comparison to the widely used protecting group DEACM ([7 (diethylamino)coumarin-4-yl]methyl) are extracted from TPEF experiments. Femtosecond pump-probe experiments reveal a fast intramolecular charge transfer, a finding that is confirmed by quantum chemical calculations. Uncaging of glutamate is monitored in IR measurements by photodecarboxylation of the carbamate linker between the photolabile protecting group and the glutamate, showing the full functionality of the novel two-photon activatable photocage. PMID- 29498871 TI - [Diabetic dyslipidemia and microvascular complications of diabetes]. AB - Diabetic dyslipidemia is one of the main risk factors for atherosclerosis. Although its participation in diabetic microvascular complications is not that dominant, dyslipidemia may play an important role in formation and progression of these complications. Pathophysiological mechanisms by which diabetic dyslipidemia affects the etiopathogenesis of diabetic nephropathy, retinopathy, neuropathy and diabetic foot are presented. The data from clinical studies and treatment possibilities for particular microvascular complications using lipid-lowering therapy are discussed.Key words: diabetes mellitus - diabetic foot - dyslipidemia - nephropathy - neuropathy - retinopathy. PMID- 29498872 TI - [Familial combined hyperlipidemia - the most common genetic dyslipidemia in population and in patients with premature atherothrombotic cardiovascular disease]. AB - Familial combined hyperlipidemia (FCH) is the most frequent genetic dyslipidemia (DLP) with high risk of early atherosclerosis manifestation. It is characterized by elevated both triglycerides 1.5 mmol/l and apolipoprotein B 1.2 g/l (hyper TG/hyper-ApoB fenotype), with at least two affected family members. Despite the fact that plasmatic levels of total cholesterol and LDL-C are usually lower than in familial hypercholesterolemia and full expression of DLP in FCH occurs in adulthood, risk of premature manifestation of atherosclerosis is similar in both these familial DLP. It is probably due to the presence of other atherogenic lipid and non-lipid risk factors, such as increased levels of triglyceride rich lipoprotein remnants, presence of small dense LDL, reduction of HDL-C, presence of insulin resistance with impaired glucose homeostasis, hepatic steatosis, arterial hypertension, hyperuricemia and presence of increased markers of systemic inflammation. The term "familial" usually implicates a monogenic trait. However, FCH is almost always nonmendelian. According to recent knowledge FCH is mostly polygenic with variable presence of large effect mutations, accumulation of several small-effect polymorphisms and some environmental influences. Therefore, FCH is rather a syndrome with common clinical presentation but multigenic causes. The term "familial combined hyperlipidemia" is embedded in clinical practice and so it is not necessary to abandon it, as it nearly urges to examination of first degree relatives. This might help to identify a great number of risk subjects who deserve appropriate management.Key words: apolipoprotein B - familial combined hyperlipidemia - genetics - insulin resistance - premature atherosclerosis - triglycerides. PMID- 29498873 TI - [Epidemiology of hypercholesterolemia]. AB - Hypercholesterolemia is one of the most important risk factors of cardiovascular (CV) disease. Epidemiology follows the prevalence, the incidence and the possibilities of risk factors or diseases intervention. A review of observation epidemiologic studies, pharmacotherapy and treatment perspectives is presented. The first epidemiologic studies, e.g. the Framingham Heart Study or MRFIT showed hyperlipidemia is associated with the incidence of CV disease. The North Karelia Project showed the intervention of CV risk factors is useful on population-based principles. Interventional studies with statins showed the usefulness of LDL cholesterol lowering to decrease CV morbidity and mortality and also total mortality. Anyway, the control of CV risk factors is unsatisfactory.Key words: epidemiology - hypercholesterolemia - intervention. PMID- 29498874 TI - [MedPed - the reality of familial hypercholesterolemia care at the biggest center]. AB - The MedPed project (Make Early Diagnosis to Prevent Early Deaths) aiming at screening, diagnosis and treatment of patients with familial hypercholesterolemia (FH) was initiated more than 19 years ago. More than 60 cooperating centers and a large number of health care professionals have been involved. Till November 15, 2017 the nationwide database has comprised 7 567 entries of individual FH patients, 439 of these being children up to 19 years of age. Given the recently corrected estimated population frequency of FH of 1 to 250 this number represents 18.9 % of the predicted number of 40 000 FH individuals in the Czech Republic. Although the number of patients captured by the database seems to be relatively low, it is the third highest number in the world. This review describes working procedures of one of the national leading centers for FH in the Czech Republic. Additionally, a comparison of the up-to-date data set of 558 FH individuals being actively followed in the center to the original FH cohort (n = 190) as described by prof. Sobra in the late 1960 s. is being discussed.Key words: familial hypercholesterolemia - heterozygous - homozygous - project Medped. PMID- 29498875 TI - [The role of PCSK9-inhibitors and of lipoprotein apheresis in the treatment of homozygous and severe heterozygous familial hypercholesterolemia: A rivalry, or are things quite different?] AB - PCSK9-inhibitors belong to the new class of hypolipidemic agents. They enhance catabolism of low density lipoprotein cholesterol (LDL-C) through inhibiting activity of proprotein convertase subtilisin/kexin type 9 (PCSK9). They are monoclonal antibodies (alirocumab, evolocumab etc). Under clinical development are also other types of PCSK9-inhibitors which act at a subcellular level. The treatment with PCSK9-inhibitors can be beneficially combined with lipoprotein apheresis (LA). If such treatment using PCSK9-inhibitors is possible with regard to an individual patients genotype, the combination of LA and PCSK9-inhibitors leads to slowing the space of LDL-C increase between individual procedures of apheresis and enables attaining of the lowest possible values of LDL cholesterolemia for the longest possible period of time. Due to high efficiency of PCSK9-inhibitors lowering LDL-C, but also their lower cost as compared to therapeutic LA, PCSK9-inhibitors now take precedence over the use of extracorporeal lipoprotein apheresis which, nonetheless, still remains the final method for hypolipidemic treatment of patients with severe hypercholesterolemia, who are resistant to conventional therapy while not reaching the target lipid values and at high cardiovascular risk. They belong to extracorporeal elimination methodologies which remove low density lipoprotein (LDL) cholesterol from circulating blood. LA in combination with higher doses of statins and ezetimib currently represents the most efficient method of treatment of homozygous and statin-refractory heterozygous familial hypercholesterolemia (FH). Residual cardiovascular risk in these patients still remains high, in particular because, despite the aforementioned treatment, the target values for lipids according to present recommendations cannot be reached. The combination of LA with the new drugs is promising, primarily due to its potential for further lowering of LDL cholesterolemia between the individual apheresis procedures. Preliminary results of the ongoing studies indicate that the new hypolipidemic drugs in combination with LA, or when used separately, will substantially enrich and improve the treatment of refractory FH.Key words: alirocumab - atherosclerosis - evolocumab - hypercholesterolemia - cardiovascular disease - lipoprotein apheresis. PMID- 29498876 TI - [Cardiovascular risk in patients with rheumatic disease and its management]. AB - Cardiovascular disease (CVD) risk in patients with rheumatic diseases is increased by 50 % compared to the general population. This is a result of the increased inflammatory activity as well as modification of traditional CVD risk factors by the primary disease. So called lipid paradox, paradoxical decrease of concentrations of atherogenic plasma lipids due to increased inflammatory activity and their rise with successful anti-inflammatory treatment, is of particular importance. CVD risk in rheumatic diseases is further modified by drugs used for their treatment: while some treatment modalities increase the risk (e.g. glucocorticoids), others may act in an opposite direction (methotrexate, biological therapies). CVD risk stratification in patients with rheumatic diseases is uneasy; so far none of the specific scoring systems has been shown superior to traditional ones designed for the general population. Principles of cardiovascular risk intervention remain the same as for the general population: the management starts with lifestyle measures (healthy diet, increase in physical activity and smoking cessation) complemented with pharmacotherapy when indicated. Blood pressure as well as lipid lowering therapies should be led according to the same principles as in the general population and, also, to the same treatment goals. To improve CVD prevention outcomes in patients with rheumatic diseases it seems feasible to work in interdisciplinary teams led by a rheumatologist cooperating with a specialist in CVD prevention strategies (general practitioner, cardiologist, internist, diabetes specialist). A nutritional therapist and a physiotherapist are important members of the team, too. Interdisciplinary and complex CVD prevention in patients with rheumatic diseases decreases CVD morbidity.Key words: cardiovascular risk - intervention - lipid paradox - rheumatic diseases - risk factors - risk stratification. PMID- 29498877 TI - [Examination methods for coronary atherosclerosis regression with special focus on GLAGOV trial]. AB - Authors summarize trials assessing regression of coronary atherosclerosis. Special interest is devoted to imagine techniques. Authors describe in a detail methodology and results of GLAGOV trial.Key words: coronary atherosclerosis - intravascular ultrasound - regression. PMID- 29498878 TI - [Effect of pulsatility on markers of vascular damage in patients with implanted continuous flow mechanical circulatory support]. AB - Ventricular assist devices are an important therapeutic modality in advanced surgical therapy of end-stage heart failure. Previously most frequently used devices generated mainly non-pulsatile blood flow. Despite indisputable clinical success of this therapy, we encounter complications specific to the devices generating continuous flow. Complications are mainly attributed to changes in shear stress and subsequent changes of the blood vessel characteristics, mainly of endothelium. Effect of continuous flow on the vasculature and blood elements, therefore, became a subject of intense recent research. Effect of continuous flow on the vascular bed is subject of intensive research. Widespread methods used in angiology measuring the state of vasculature are based mainly on imaging modalities and on the presence of pulsatile flow; therefore, under circumstances of non-pulsatile flow their use is limited and the attention is shifted also to laboratory methods, namely to detection of circulating indicators of vascular damage. Therefore, in our recent studies of the effect of mechanical ventricular assist devices on the blood flow we exploit combination of imaging and laboratory methods, including measurements of circulating microparticles and endothelial progenitor cells. Based on these studies interesting data were obtained studying the effect of implantation of mechanical cardiac support on the dynamics of vascular changes taking into account also response to changes of blood flow characteristics. In this paper we summarize our observations.Key words: continuous flow - endothelial progenitor cells - mechanical circulatory support - microparticles - vascular damage. PMID- 29498879 TI - [Remarks on biomarkers of cardiovascular risk]. AB - Authors describe state-of-the-art in the routine laboratory diagnostics of cardiovascular risk with special emphasis on metrology, traceability, external quality assessment, biological variation, and reference change value. While analytical quality of total cholesterol, triglycerides, glucose, and HbA1c is satisfactory, improvements are needed for HDL-cholesterol, LDL-cholesterol, apolipoprotein A1, apolipoprotein B, Lp(a), and LpPLA2 measurements. Biological variation is a strong player in the lipid diagnostics, because reference change value is above 20 % for majority of biomarkers. Current methodology for the measurement of remnant cholesterol is far from optimum and standardization is therefore needed.Key words: biological variation - clinical chemistry - interpretation - lipid profile - metrology - remnant cholesterol. PMID- 29498880 TI - [Long non-coding RNAs in the pathophysiology of atherosclerosis]. AB - The human genome contains about 22 000 protein-coding genes that are transcribed to an even larger amount of messenger RNAs (mRNA). Interestingly, the results of the project ENCODE from 2012 show, that despite up to 90 % of our genome being actively transcribed, protein-coding mRNAs make up only 2-3 % of the total amount of the transcribed RNA. The rest of RNA transcripts is not translated to proteins and that is why they are referred to as "non-coding RNAs". Earlier the non-coding RNA was considered "the dark matter of genome", or "the junk", whose genes has accumulated in our DNA during the course of evolution. Today we already know that non-coding RNAs fulfil a variety of regulatory functions in our body - they intervene into epigenetic processes from chromatin remodelling to histone methylation, or into the transcription process itself, or even post-transcription processes. Long non-coding RNAs (lncRNA) are one of the classes of non-coding RNAs that have more than 200 nucleotides in length (non-coding RNAs with less than 200 nucleotides in length are called small non-coding RNAs). lncRNAs represent a widely varied and large group of molecules with diverse regulatory functions. We can identify them in all thinkable cell types or tissues, or even in an extracellular space, which includes blood, specifically plasma. Their levels change during the course of organogenesis, they are specific to different tissues and their changes also occur along with the development of different illnesses, including atherosclerosis. This review article aims to present lncRNAs problematics in general and then focuses on some of their specific representatives in relation to the process of atherosclerosis (i.e. we describe lncRNA involvement in the biology of endothelial cells, vascular smooth muscle cells or immune cells), and we further describe possible clinical potential of lncRNA, whether in diagnostics or therapy of atherosclerosis and its clinical manifestations.Key words: atherosclerosis - lincRNA - lncRNA - MALAT - MIAT. PMID- 29498881 TI - [The current position of hydrochlorothiazide among thiazide and thiazide-like diuretics]. AB - Thiazide and thiazide-like diuretics are an important group of drugs used in the treatment of essential arterial hyper-tension. While their beneficial therapeutic effect in monotherapy is evident, they are increasingly used in fixed combinations, particularly with ACE inhibitors or sartans. The aim of this article was to summarize the current status of hydrochlorothiazide and compare its effects with other substances in this subgroup of diuretics.Key words: diuretics - HCTZ - hydrochlorothiazide - hypertension - chlorthalidone - indapamide - thiazide. PMID- 29498884 TI - Alteration of Knee Kinematics After Anatomic Anterior Cruciate Ligament Reconstruction Is Dependent on Associated Meniscal Injury. AB - BACKGROUND: Limited in vivo kinematic information exists on managing meniscal injury during anterior cruciate ligament reconstruction (ACLR). HYPOTHESIS: Isolated anatomic ACLR restores knee kinematics, whereas ACLR in the presence of medial meniscal injury is associated with altered long-term knee kinematics. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: From March 2011 to December 2012, 49 of 57 participants in a clinical trial underwent anatomic ACLR with successful kinematic testing at 24 months after ACLR. Twenty-five patients had associated meniscal tears: medial (n = 11), lateral (n = 9), or bilateral (n = 5). With a dynamic stereo radiography system with superimposed high-resolution computed tomography scans of patient knees, kinematics were measured during downhill running. The initial single-support phase of the gait cycle (0%-10%) was analyzed. RESULTS: Anterior tibial translation (ATT) was the only kinematic outcome between patients' ACLR and contralateral knees that had significant interactions among meniscal groups ( P = .007). There was significant difference in ATT between patients with intact menisci and medial tears ( P = .036) and with medial tears and lateral tears ( P = .025). Patients with intact menisci had no difference in ATT, with a negligible effect size between the ACLR and contralateral knees (mean +/- SEM: 13.1 +/- 0.7 mm vs 12.6 +/- 0.5 mm, P = .24, Cohen d = 0.15, n = 24), while patients with medial meniscal tears had an increase in ATT, with a medium effect size between the ACLR and contralateral knees (15.4 +/- 1.0 mm vs 13.2 +/- 1.0 mm, P = .024, Cohen d = 0.66, n = 11). CONCLUSION: Associated medial meniscal injury in the setting of ACLR leads to increased ATT at 24-month follow-up. Furthermore, isolated anatomic ACLR in the absence of meniscal injury demonstrated no significant difference from native knee kinematics at 24-month follow-up during rigorous "high demand" knee activity with the current sample size. Patients undergoing anatomic ACLR in the presence of medial meniscal injury remained at a higher likelihood of sustaining altered long-term knee kinematics. PMID- 29498885 TI - Surgical Treatment of Lateral Epicondylitis: A Prospective, Randomized, Double Blinded, Placebo-Controlled Clinical Trial. AB - BACKGROUND: A number of surgical techniques for managing tennis elbow have been described. One of the most frequently performed involves excising the affected portion of the extensor carpi radialis brevis (ECRB). The results of this technique, as well as most other described surgical techniques for this condition, have been reported as excellent, yet none have been compared with placebo surgery. HYPOTHESIS: The surgical excision of the degenerative portion of the ECRB offers no additional benefit over and above placebo surgery for the management of chronic tennis elbow. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: This study investigated surgical excision of the macroscopically degenerated portion of the ECRB (surgery; n = 13) as compared with skin incision and exposure of the ECRB alone (sham; n = 13) to treat patients who had tennis elbow for >6 months and had failed at least 2 nonsurgical modalities. The primary outcome measure was defined as patient-rated frequency of elbow pain with activity at 6 months after surgery. Secondary outcome measures included patient-rated pain and functional outcomes, range of motion, epicondyle tenderness, and strength at 6 months and 2.5 years. All outcome measures up to and including the 6-month follow-up were measured in person; the longer-term questionnaire was conducted in person or over the phone. RESULTS: The 2 groups, surgery and sham, were similar for age, sex, hand dominance, and duration of symptoms. Both procedures improved patient-rated pain frequency and severity, elbow stiffness, difficulty with picking up objects, difficulty with twisting motions, and overall elbow rating >6 months and at 2.5 years ( P < .01). Both procedures also improved epicondyle tenderness, pronation-supination range, grip strength, and modified Orthopaedic Research Institute-Tennis Elbow Testing System at 6 months ( P < .05). No significant difference was observed between the groups in any parameter at any stage. No side effects or complications were reported. The study was stopped before the calculated number of patients were enrolled (40 per group); yet, a post hoc futility analysis was conducted that showed, based on the magnitude of the differences between the groups, >6500 patients would need to be recruited per group to see a significant difference between the groups at 26 weeks in the primary outcome (patient-rated frequency of elbow pain with activity). CONCLUSION: With the number of available participants, this study failed to show additional benefit of the surgical excision of the degenerative portion of the ECRB over placebo surgery for the management of chronic tennis elbow. PMID- 29498886 TI - The impact of forced swimming on expression of RANKL and OPG in a type 2 diabetes mellitus rat model. AB - OBJECTIVE: The importance of swimming in bone metabolism during type 2 diabetes (T2DM) is not well known. Receptor activator of nuclear factor-kB ligand (RANKL)/ osteoprotegerin (OPG) system as a critical pathway in bone remodeling may play a role in pathogenesis of T2DM. Hence, we tested this pathway and the possible beneficial effects of swim training on T2DM. MATERIALS AND METHODS: Forty male rats were assigned to groups (n = 10): control(C), diabetic (D), exercised control (E), and diabetic exercised (DE). One week after the induction of diabetes, animals were subjected to swim. At the end of training, fasting blood sugar, insulin, bone and serum OPG and RANKL levels were measured. RESULTS: Diabetes significantly increased OPG and decreased RANKL mRNAs and proteins in bone and serum and swim training could reverse these changes to control. CONCLUSION: Swim training could partially compensate T2DM associated changes of bone and serum OPG/RANKL in rats. PMID- 29498887 TI - Return to Sports and Physical Work After Arthroscopic Superior Capsule Reconstruction Among Patients With Irreparable Rotator Cuff Tears. AB - BACKGROUND: Although sports participation and heavy physical work can contribute to rotator cuff tears, many patients expect to return to these activities after surgery; however, irreparable rotator cuff tears can preclude this outcome. A new surgical treatment-arthroscopic superior capsule reconstruction (SCR)-restores shoulder stability and muscle balance in patients with irreparable rotator cuff tears; consequently, it improves shoulder function and relieves pain. PURPOSE: To evaluate the rates of return to sports and physical work among patients treated with arthroscopic SCR. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: From 2007 to 2014, we performed arthroscopic SCR in 105 patients with irreparable rotator cuff tears, 5 of whom were lost to follow-up. Consequently, 100 patients (mean age, 66.9 years; range, 43-82 years) were enrolled in the study. Before surgery, 26 patients had participated in sports (2 competitive, 24 recreational), and 34 patients had physical work. Rates of return to sports and physical work, the American Shoulder and Elbow Surgeons (ASES) score, active shoulder range of motion, and rate of graft tear were evaluated. The mean time to final follow-up was 48 months (range, 24-88 months). RESULTS: All 26 patients who played sports before their injuries returned fully to them. In addition, 32 patients returned fully to their previous physical work, whereas the 2 remaining patients returned with reduced hours and workloads. As compared with the nonsports group, the sports group had significantly higher postoperative active elevation (160 degrees +/- 32 degrees vs 146 degrees +/- 39 degrees ; P = .04) and higher postoperative ASES scores (97 +/- 7 vs 91 +/- 12; P = .02). The shoulder range of motion and ASES scores before and after surgery did not differ significantly between the physical and nonphysical work groups ( P = .11-.99). The rate of graft tear did not differ between the sports group (4%) and nonsports group (5%) ( P = .75) and between the physical work group (6%) and nonphysical work group (5%) ( P = .77). CONCLUSION: Arthroscopic SCR restored shoulder function and resulted in high rates of return to recreational sports and physical work. PMID- 29498888 TI - Effect of Visualization Training on Uncertain Spatial Trajectory Predictions. AB - OBJECTIVE: The goal of this study was to explore the ways in which visualizations influence the prediction of uncertain spatial trajectories (e.g., the unknown path of a downed aircraft or future path of a hurricane) and participant overconfidence in such prediction. BACKGROUND: Previous research indicated that spatial predictions of uncertain trajectories are challenging and are often associated with overconfidence. Introducing a visualization aid during training may improve the understanding of uncertainty and reduce overconfidence. METHOD: Two experiments asked participants to predict the location of various trajectories at a future time. Mean and variance estimates were compared for participants who were provided with a visualization and those who were not. RESULTS: In Experiment 1, participants exhibited less error in mean estimations when a linear visualization was present but performed worse than controls once the visualization was removed. Similar results were shown in Experiment 2, with a nonlinear visualization. However, in both experiments, participants who were provided with a visualization did not retain any advantage in their variance estimations once the visualization was removed. CONCLUSIONS: Visualizations may support spatial predictions under uncertainty, but they are associated with benefits and costs for the underlying knowledge being developed. APPLICATION: Visualizations have the potential to influence how people make spatial predictions in the presence of uncertainty. Properly designed and implemented visualizations may help mitigate the cognitive biases related to such predictions. PMID- 29498889 TI - Structural Basis for G Protein-Coupled Receptor Signaling. AB - G protein-coupled receptors (GPCRs), which mediate processes as diverse as olfaction and maintenance of metabolic homeostasis, have become the single most effective class of therapeutic drug targets. As a result, understanding the molecular basis for their activity is of paramount importance. Recent technological advances have made GPCR structural biology increasingly tractable, offering views of these receptors in unprecedented atomic detail. Structural and biophysical data have shown that GPCRs function as complex allosteric machines, communicating ligand-binding events through conformational change. Changes in receptor conformation lead to activation of effector proteins, such as G proteins and arrestins, which are themselves conformational switches. Here, we review how structural biology has illuminated the agonist-induced cascade of conformational changes that culminate in a cellular response to GPCR activation. Expected final online publication date for the Annual Review of Biophysics Volume 47 is May 20, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 29498890 TI - Structure and Dynamics of Membrane Proteins from Solid-State NMR. AB - Solid-state nuclear magnetic resonance (SSNMR) spectroscopy elucidates membrane protein structures and dynamics in atomic detail to yield mechanistic insights. By interrogating membrane proteins in phospholipid bilayers that closely resemble biological membranes, SSNMR spectroscopists have revealed ion conduction mechanisms, substrate transport dynamics, and oligomeric interfaces of seven transmembrane helix proteins. Research has also identified conformational plasticity underlying virus-cell membrane fusions by complex protein machineries, and beta-sheet folding and assembly by amyloidogenic proteins bound to lipid membranes. These studies collectively show that membrane proteins exhibit extensive structural plasticity to carry out their functions. Because of the inherent dependence of NMR frequencies on molecular orientations and the sensitivity of NMR frequencies to dynamical processes on timescales from nanoseconds to seconds, SSNMR spectroscopy is ideally suited to elucidate such structural plasticity, local and global conformational dynamics, protein-lipid and protein-ligand interactions, and protonation states of polar residues. New sensitivity-enhancement techniques, resolution enhancement by ultrahigh magnetic fields, and the advent of 3D and 4D correlation NMR techniques are increasingly aiding these mechanistically important structural studies. PMID- 29498891 TI - MyoScreen, a High-Throughput Phenotypic Screening Platform Enabling Muscle Drug Discovery. AB - Despite the need for more effective drug treatments to address muscle atrophy and disease, physiologically accurate in vitro screening models and higher information content preclinical assays that aid in the discovery and development of novel therapies are lacking. To this end, MyoScreen was developed: a robust and versatile high-throughput high-content screening (HT/HCS) platform that integrates a physiologically and pharmacologically relevant micropatterned human primary skeletal muscle model with a panel of pertinent phenotypic and functional assays. MyoScreen myotubes form aligned, striated myofibers, and they show nerve independent accumulation of acetylcholine receptors (AChRs), excitation contraction coupling (ECC) properties characteristic of adult skeletal muscle and contraction in response to chemical stimulation. Reproducibility and sensitivity of the fully automated MyoScreen platform are highlighted in assays that quantitatively measure myogenesis, hypertrophy and atrophy, AChR clusterization, and intracellular calcium release dynamics, as well as integrating contractility data. A primary screen of 2560 compounds to identify stimulators of myofiber regeneration and repair, followed by further biological characterization of two hits, validates MyoScreen for the discovery and testing of novel therapeutics. MyoScreen is an improvement of current in vitro muscle models, enabling a more predictive screening strategy for preclinical selection of the most efficacious new chemical entities earlier in the discovery pipeline process. PMID- 29498892 TI - A Mechano-Activated Cell Reporter System as a Proxy for Flow-Dependent Endothelial Atheroprotection. AB - The vascular endothelium plays a critical role in the health and disease of the cardiovascular system. Importantly, biomechanical stimuli generated by blood flow and sensed by the endothelium constitute important local inputs that are translated into transcriptional programs and functional endothelial phenotypes. Pulsatile, laminar flow, characteristic of regions in the vasculature that are resistant to atherosclerosis, evokes an atheroprotective endothelial phenotype. This atheroprotective phenotype is integrated by the transcription factor Kruppel like factor-2 (KLF2), and therefore the expression of KLF2 can be used as a proxy for endothelial atheroprotection. Here, we report the generation and characterization of a cellular KLF2 reporter system, based on green fluorescence protein (GFP) expression driven by the human KLF2 promoter. This reporter is induced selectively by an atheroprotective shear stress waveform in human endothelial cells, is regulated by endogenous signaling events, and is activated by the pharmacological inducer of KLF2, simvastatin, in a dose-dependent manner. This reporter system can now be used to probe KLF2 signaling and for the discovery of a novel chemical-biological space capable of acting as the "pharmacomimetics of atheroprotective flow" on the vascular endothelium. PMID- 29498893 TI - The Essential Properties of Yoga Questionnaire (EPYQ): Psychometric Properties. AB - Yoga interventions are heterogeneous and vary along multiple dimensions. These dimensions may affect mental and physical health outcomes in different ways or through different mechanisms. However, most studies of the effects of yoga on health do not adequately describe or quantify the components of the interventions being implemented. This lack of detail prevents researchers from making comparisons across studies and limits our understanding of the relative effects of different aspects of yoga interventions. To address this problem, we developed the Essential Properties of Yoga Questionnaire (EPYQ), which allows researchers to objectively characterize their interventions. We present here the reliability and validity data from the final phases of this measure-development project. Analyses identified fourteen key dimensions of yoga interventions measured by the EPYQ: acceptance/compassion, bandhas, body awareness, breathwork, instructor mention of health benefits, individual attention, meditation and mindfulness, mental and emotional awareness, physicality, active postures, restorative postures, social aspects, spirituality, and yoga philosophy. The EPYQ demonstrated good reliability, as assessed by internal consistency and test retest reliability analysis, and evidence suggests that the EPYQ is a valid measure of multiple dimensions of yoga. The measure is ready for use by clinicians and researchers. Results indicate that, currently, trained objective raters should score interventions to avoid reference frame errors and potential rating bias, but alternative approaches may be developed. The EPYQ will allow researchers to link specific yoga dimensions to identifiable health outcomes and optimize the design of yoga interventions for specific conditions. PMID- 29498894 TI - Trends in herpes zoster epidemiology in Germany based on primary care sentinel surveillance data, 2005-2016. AB - Herpes zoster (HZ) is caused by reactivation of the varicella-zoster-virus (VZV). Childhood varicella vaccination, as recommended in Germany in 2004, may reduce the risk of HZ in vaccinated children but also virus circulation and thus the booster possibility of latent infected persons. In this context we analyzed age specific trends in HZ epidemiology in Germany using data on HZ-associated outpatient consultations in participating sentinel sites and HZ-associated cases in all hospitals since 2005. We analyzed two separate time periods that differed in sentinel management and data integrity. For the period 2005-2010, we found a decrease in HZ-associated outpatient consultations in 1- to 4-year-olds (IRR = 0.72, 95%CI 0.63-0.81, p<0.001). For the period 2013-2016, we observed a decrease in HZ-associated outpatient consultations in 10- to 14-year-olds (IRR = 0.85, 95%CI 0.78-0.93, p<0.01). Moreover, we detected an increase in the age groups 20 years and older except for the group 30-39 years. HZ-associated hospitalizations showed similar trends for the second time period (here 2012-2015). The decrease in HZ-associated outpatient consultations and hospitalizations in children started and continued over cohorts eligible for varicella vaccination and could be a result of their reduced HZ-risk. Whether the observed steady increasing HZ incidences for adults are associated with the varicella vaccination in children remains unclear and could not be investigated with our data. PMID- 29498897 TI - Hypertrophic Osteopathy Associated with Mycotic Pneumonia in a Roe Deer ( Capreolus capreolus). AB - Aspergillus fumigatus is one of the most common Aspergillus species causing disease in individual animals but it rarely affects deer species. We report a case of A. fumigatus infection causing mycotic pneumonia and hypertrophic osteopathy in a roe deer ( Capreolus capreolus). PMID- 29498896 TI - STEROIDAL SAPONIN TOXICITY IN EASTERN GREY KANGAROOS ( MACROPUS GIGANTEUS): A NOVEL CLINICOPATHOLOGIC PRESENTATION OF HEPATOGENOUS PHOTOSENSITIZATION. AB - We describe the clinicopathologic features of a mortality event characterized by blindness and dermatitis affecting eastern grey kangaroos ( Macropus giganteus), secondary to hepatogenous photosensitization. Affected animals exhibited photophobic behavior, blindness, ataxia, recumbency, lethargy, ear shaking, and behavior consistent with distress or depression. The photophobia manifested as abnormal shade-seeking during the day, including finding refuge under or in structures used frequently by people. Severely affected kangaroos were jaundiced and had markedly elevated serum bilirubin and gamma glutamyl-transpeptidase concentrations. Blindness in affected animals was attributed to moderate to severe corneal opacity due to corneal edema and inflammation. Skin lesions were typically subtle on gross examination even in cases which had severe necrotizing dermatitis histologically. Histologic lesions in the liver of affected animals included the presence of acicular clefts typical of steroidal saponins. The outbreak was associated with pasture dominated by the invasive grass, Panicum gilvum, which is a recognized source of saponin-induced photosensitization in livestock. PMID- 29498895 TI - ASSAYS FOR DETECTION AND IDENTIFICATION OF THE CAUSATIVE AGENT OF MANGE IN FREE RANGING BLACK BEARS ( URSUS AMERICANUS). AB - Three mite species ( Demodex ursi, Ursicoptes americanus, and Sarcoptes scabiei) have been associated with mange in black bears ( Ursus americanus). Since the early 1990s, the number and geographic distribution of mange cases in black bears in Pennsylvania, US has increased; however, the causative mites have yet to be completely defined. We evaluated several diagnostic approaches for detection and identification of mites in 72 black bears with severe lesions consistent with mange. Sarcoptes scabiei was morphologically identified in skin scrapes from 66 of the bears; no mites were identified in the remaining six. Histopathologic lesions consistent with sarcoptic mange were observed in 39 of 40 bear skin samples examined, and intralesional mites were observed in samples from 38 of these bears. Samples were collected from a subset of the 72 bears for PCR testing targeting both the internal transcribed spacer (ITS)-2 region and cytochrome c oxidase I ( cox1) gene including 69 skin scrapes ( ITS-2 only), 56 skin biopsies ( ITS-2 and cox1), and 36 fecal samples ( ITS-2 and cox1). Skin scrapes were a more sensitive sample for PCR detection than either skin biopsies or fecal samples, and the ITS-2 primers proved more sensitive than cox1. Using a commercial indirect enzyme-linked immunosorbent assay, antibodies to S. scabiei were detected in 45/49 (92%) black bears with confirmed mange and 0/62 (0%) cubs with no gross lesions suggestive of mange and which were born to seronegative sows. Sarcoptes scabiei was the predominant mite associated with mange in black bears in Pennsylvania. Diagnostically, cytologic examination of skin scrapes was the most effective approach for diagnosing active mite infestations in black bears. The evaluated serologic assay accurately detected antibodies to S. scabiei in most bears with confirmed S. scabiei infestations. Additional research is needed to determine the usefulness of this approach for larger scale surveys and for asymptomatic bears. PMID- 29498898 TI - Infectious Canine Hepatitis in a Brown Bear ( Ursus arctos horribilis) from Alaska, USA. AB - We diagnosed infectious canine hepatitis in a free-ranging brown bear ( Ursus arctos horribilis) cub from Alaska, US, found dead in October 2015. Intranuclear inclusion bodies were present in hepatocytes, and immunohistochemistry showed reactivity to adenoviral antigens. Sequencing of the hexon protein of adenovirus showed 100% identity to canine adenovirus 1. PMID- 29498899 TI - Chlamydia pecorum in Joint Tissue and Synovial Fluid of a Koala ( Phascolarctos cinereus) with Arthritis. AB - A small number of koalas ( Phascolarctos cinereus) presented to wildlife hospitals in Queensland, Australia, with signs of arthritis in one or more joints. Molecular analysis identified Chlamydia pecorum in the tarsal tissue and synovial fluid of an affected joint of a koala, suggesting that in addition to livestock, C. pecorum has the potential to cause arthritis in the koala. PMID- 29498900 TI - EVIDENCE OF TWO COCIRCULATING CANINE DISTEMPER VIRUS STRAINS IN MESOCARNIVORES FROM NORTHERN COLORADO, USA. AB - Canine distemper virus (CDV) is a highly contagious pathogen that principally infects wildlife and domestic carnivores. Peridomestic species such as raccoons ( Procyon lotor) experience outbreaks with high mortality. Clinical signs of infection include anorexia, fever, respiratory infection, and neurologic complications. Although not zoonotic, CDV poses a high risk to unvaccinated domestic animals and the conservation of endangered species. During 2013-16, we opportunistically collected wild and domestic carnivore specimens through a rabies surveillance program in northern Colorado, US. Brainstem and cerebellar tissue samples were independently tested for rabies and CDV by fluorescent antibody test. We tested a total of 478 animals for CDV, comprised of 10 wild and domestic carnivore species. A total of 15% (72/478) of all animals sampled tested positive for CDV, consisting of 24% (71/300) of raccoons and 4% (1/26) of coyotes ( Canis latrans), but coinfection with rabies virus was not observed among CDV positive animals. We extracted RNA from positive tissues, and a reverse transcription PCR was used to create complementary DNA. We amplified and sequenced the hemagglutinin gene from 60 CDV-positive tissues, and a median joining network and maximum likelihood phylogenetic tree revealed two major lineages among samples. Phylogenetic analysis indicated that our sequences were most similar to the America-2 ( n=55) and the America-3 ( n=5) CDV lineages circulating in North America. Our results indicated two distinct and distantly related clades of CDV overlapping geographically and temporally among raccoon populations in northern Colorado. PMID- 29498901 TI - Prevalence of Urogenital Carcinoma in Stranded California Sea Lions ( Zalophus californianus) from 2005-15. AB - Urogenital carcinoma is common in wild California sea lions ( Zalophus californianus) along the west coast of the US. From 1979 to 1994, this cancer was observed in 18% (66/370) of necropsied subadult and adult sea lions at The Marine Mammal Center in Sausalito, California. A retrospective review of records from 1 January 2005 to 31 December 2015 was performed to characterize prevalence and characteristics of cancer over this decade. Fourteen percent (263/1917) of necropsied sea lions had cancer, of which 90% (237/263) were urogenital carcinoma. The prevalence of urogenital carcinoma was significantly higher in adults compared to juveniles and subadults. Advanced-stage disease with metastases was identified histologically in 78% (182/232) of cases and was the cause of death in 95% (172/182) of these cases. Metastases were most common in lung and lymph nodes, and hydronephrosis, secondary to ureter obstruction by metastases, was identified in 62% (114/185) of animals with advanced disease. No significant temporal change in prevalence was detected over the decade, and this highly aggressive, fatal cancer remains common in stranded California sea lions. PMID- 29498902 TI - Co-located perinatal psychiatry clinic: impact of adding a psychologist on clinical quality improvement metrics. AB - PURPOSE: To describe the impact of adding a psychologist (the intervention) to a co-located perinatal psychiatry clinic (PPC) in terms of effects on clinical quality improvement (QI) metrics. METHODS: Six-month pre- and postintervention study design with measurement of QI metrics: number of unique patients treated; number of new and established visits; percent no-shows for new and established visits; and mean wait time to new visit. RESULTS: Number of unique patients treated by the psychiatrist increased by 30%, from 90 preintervention to 118 postintervention (p = .06). Total number of visits completed by the psychiatrist increased by 20% from 174 preintervention to 208 postintervention. Mean wait time for new visits for a physician decreased from 20 days preintervention to 14 days postintervention, with a mean difference of 6.4 days (p = .0015). Percentage of no-shows for new visits increased slightly from 23% preintervention to 26% postintervention (p = .72). The percentage of no-shows for established visits decreased significantly from 22% preintervention to 10% postintervention (p < .005). CONCLUSIONS: By adding a psychologist to the co-located PPC, we improved quality of perinatal mental health care by improving efficiency, timeliness and patient-centered care. The psychiatrist saw a greater number of unique patients, decreased wait time to new visits and decreased no-show rates for established visits, likely by better matching patient needs with provider services. A psychologist could be a valuable addition to a PPC, given the shortage of psychiatrists in the United States. PMID- 29498903 TI - Using Virtual Ridge Augmentation and 3-Dimensional Printing to Fabricate a Titanium Mesh Positioning Device: A Novel Technique Letter. PMID- 29498904 TI - Improved Dental Implant Drill Durability and Performance Using Heat and Wear Resistant Protective Coatings. AB - The dental implant drilling procedure is an essential step for implant surgery, and frictional heat in bone during drilling is a key factor affecting the success of an implant. The aim of this study was to increase the dental implant drill lifetime and performance by using heat- and wear-resistant protective coatings to decrease the alveolar bone temperature caused by the dental implant drilling procedure. Commercially obtained stainless steel drills were coated with titanium aluminum nitride, diamond-like carbon, titanium boron nitride, and boron nitride coatings via magnetron-sputter deposition. Drilling was performed on bovine femoral cortical bone under the conditions mimicking clinical practice. Tests were performed under water-assisted cooling and under the conditions when no cooling was applied. Coated drill performances and durabilities were compared with those of three commonly used commercial drills with surfaces made from zirconia, black diamond. and stainless steel. Protective coatings with boron nitride, titanium boron nitride, and diamond-like carbon have significantly improved drill performance and durability. In particular, boron nitride-coated drills have performed within safe bone temperature limits for 50 drillings even when no cooling is applied. Titanium aluminium nitride coated drills did not show any improvement over commercially obtained stainless steel drills. Surface modification using heat- and wear-resistant coatings is an easy and highly effective way to improve implant drill performance and durability, which can improve the surgical procedure and the postsurgical healing period. The noteworthy success of different types of coatings is novel and likely to be applicable to various other medical systems. PMID- 29498905 TI - Decreased interleukin(IL)-35 Expression is Associated with Active Intraocular Inflammation in Vogt-Koyanagi-Harada(VKH) Disease. AB - PURPOSE: Recent studies have reported that IL-35 has a protective effect in autoimmune disease. In this study, we explored the role of IL-35 in the pathogenesis of Vogt-Koyanagi-Harada (VKH) disease. METHODS: The IL-35/EBI3 and IL-35/P35 mRNA level was assayed by Real-Time PCR. The level of IL-35 in serum was detected by ELISA. PBMCs and monocyte-derived DCs were cultured with or without IL-35 and the concentration of IL-17, IL-10, IFN-gamma, IL-6, TNF-alpha, and IL-1beta in supernatants was tested by ELISA. RESULTS: The serum level of IL 35 is reduced in active VKH patients. The mRNA expression of the two subunits IL 35/EBI3 and IL-35/P35 in PBMCs from patients with active VKH was also decreased. IL-35 significantly inhibited IFN-gamma and IL-17 expression and induced IL-10 production by PBMCs and inhibited IL-6 production by monocyte-derived DCs. CONCLUSION: The current study suggests that a decreased IL-35 expression may be involved in the pathogenesis of VKH disease. PMID- 29498906 TI - P-Curving a More Comprehensive Body of Research on Postural Feedback Reveals Clear Evidential Value for Power-Posing Effects: Reply to Simmons and Simonsohn (2017). PMID- 29498907 TI - VISUAL VIGNETTE. PMID- 29498908 TI - IS MEASUREMENT OF CIRCULATING TUMOR DNA OF DIAGNOSTIC USE IN PATIENTS WITH THYROID NODULES? AB - OBJECTIVE: Circulating tumor DNA (ctDNA), a subset of cell-free DNA (cfDNA), is a potential biomarker for thyroid cancer. We determined the performance of a ctDNA panel for detecting thyroid malignancy in patients with thyroid nodules. METHODS: Sixty-six patients with thyroid nodules without a prior history of cancer enrolled in a prospective, 1-year study in which blood was drawn for ctDNA analysis prior to undergoing fine-needle aspiration biopsy (FNAB) of thyroid nodules. The ctDNA panel consisted of 96-mutations in 9 cancer driver genes. The primary outcome measures were the sensitivity, specificity, and positive and negative predictive values (PPV, NPV) of our ctDNA panel for the diagnosis of thyroid malignancy as determined by pathologic and/or molecular tissue examination. RESULTS: Results from 10 subjects could not be determined due to inadequate volume or technical issues. The final classifications of the thyroid nodules were 13 malignant and 43 benign lesions. A KRAS G12V mutation was detected in the plasma of 1 patient with stage IVA papillary carcinoma whose tissue contained the same mutation. Two of the 43 patients with benign lesions also had ctDNA detected, giving a sensitivity of 7.7%, specificity of 95.35%, PPV of 33.33%, and NPV of 77.35%. There were no significant differences between benign or malignant lesions in cfDNA levels. CONCLUSION: Neither cfDNA measurements nor our panel of ctDNA mutations are sensitive or specific enough to provide valuable information over FNAB. An expanded panel and the inclusion of proteomics may improve sensitivity and specificity for thyroid cancer detection. ABBREVIATIONS: cfDNA = cell-free DNA; ctDNA = circulating tumor DNA; FNAB = fine needle aspiration biopsy; NIFTP = noninvasive follicular thyroid neoplasm with papillary-like nuclear features. PMID- 29498909 TI - Diagnostic Difficulties In a Young Women With Symptoms of Cushing Syndrome. PMID- 29498910 TI - ACUTE PHASE REACTIONS AFTER ZOLEDRONIC ACID INFUSION: PROTECTIVE ROLE OF 25 HYDROXYVITAMIN D AND PREVIOUS ORAL BISPHOSPHONATE THERAPY. AB - OBJECTIVE: The most common adverse reaction to zoledronic acid (ZOL) infusion is the acute phase reaction (APR), characterized by transient, usually mild, flu like symptoms. Previous treatment with oral amino-bisphosphonates (BPs) was reported as an independent protective factor for APR, and an association between APR and 25-hydroxyvitamin D (25(OH)D) levels in BP-naive patients treated with ZOL was identified. The aims of our study were to confirm this association and to see if it was different in patients previously treated with oral BPs compared with BP-naive patients and to investigate the role of 25(OH)D for the time of APR onset. METHODS: We included 153 consecutive patients with postmenopausal osteoporosis undergoing their first ZOL infusion. Sixty-eight had been previously treated with oral BPs. Clinical, demographic, and serologic data were recorded. RESULTS: 25(OH)D levels were significantly lower in patients experiencing APR compared to patients without APR (26.3 +/- 12.7 vs. 37.0 +/- 13.5 ng/mL, respectively; P<.0001). Patients with 25(OH)D <30 ng/mL had a significantly higher risk of APR (odds ratio [OR] 4.2 [95% confidence interval [CI] 2.1-8.2]) occurring in 65%. APR was significantly less frequent in patients previously treated with oral BPs than in BP-naive subjects (33.8% [23/68] vs 52.9% [45/85], P = .018), but only a weak association remained after correction for 25(OH)D (OR 0.5, 95% CI 0.3-1.1, P = .08). CONCLUSION: Higher baseline 25(OH)D levels appear to be protective for APR post-ZOL infusion. The role of previous treatment with oral BPs as an independent protective factor for APR should be evaluated in a larger cohort. ABBREVIATIONS: APR = acute phase reaction; BPs = amino bisphosphonates; CI = confidence interval; 25(OH)D = 25-hydroxyvitamin D; OP = osteoporosis; OR = odds ratio; PTH = parathyroid hormone; ROC = receiver operating characteristic; ZOL = zoledronic acid. PMID- 29498911 TI - HEMOSTATIC AGENT MIMICKING RESIDUAL THYROID TISSUE IN A PATIENT STATUS POST COMPETITION THYROIDECTOMY FOR THYROID CANCER. PMID- 29498912 TI - ONE-YEAR TIME ANALYSIS IN AN ACADEMIC DIABETES CLINIC: QUANTIFYING OUR BURDEN. PMID- 29498914 TI - VISUAL VIGNETTE. PMID- 29498913 TI - ACUTE PANCREATITIS IN PATIENTS WITH SEVERE HYPERTRIGLYCERIDEMIA IN A MULTI-ETHNIC MINORITY POPULATION. AB - OBJECTIVE: To investigate the prevalence and predictors of hypertriglyceridemic acute pancreatitis (HTG-AP) in a multi-ethnic minority population. METHODS: A retrospective, cross-sectional study from 2003 to 2013 of 1,157 adults with a serum triglyceride (TG) level >=1,000 mg/dL comparing baseline characteristics and risk factors between those with and without HTG-AP. RESULTS: Mean study population age was 49.2 +/- 11.5 years; 75.6% were male, 31.6% African American, 38.4% Hispanic, 22.7% Caucasian, 5.7% Asian, and 1.6% Pacific Islander. Prevalence of HTG-AP was 9.2%. Patients with HTG-AP were significantly younger (41.3 years vs. 50.0 years; P<.001) than those without HTG-AP. Excessive alcohol intake (odds ratio [OR], 3.9; 95% confidence interval [CI], 2.5 to 6.0; P<.001), gallstone disease (OR, 3.9; 95% CI, 1.4 to 10.8; P = .008), and TG >2,000 mg/dL (OR, 4.8; 95% CI, 3.1 to 7.4; P<.001) remained significant independent risk factors. TG levels for patients with HTG-AP were higher (median TG, 2,394 mg/dL; interquartile range [IQR], 1,152 to 4,339 mg/dL vs. median TG, 1,406 mg/dL; IQR, 1,180.7 to 1,876.5 mg/dL). TG levels >2,000 mg/dL were associated with higher incidence of AP (22% vs. 5%). Patients with TG levels <2,000 mg/dL and no risk factors had prevalence of 2% compared to 33.6% with one risk factor and TG >2,000 mg/dL. Patients with HTG-AP had higher incidence of diabetic ketoacidosis at admission (7.5% vs. 2.5%; P = .004). CONCLUSION: TG level >=2,000 mg/dL is associated with higher HTG-AP prevalence in ethnic minorities. Presence of excessive alcohol intake and/or gallstones further accentuates risk. ABBREVIATIONS: AP = acute pancreatitis; CT = computed tomography; DM = diabetes mellitus; HbA1c = hemoglobin A1c; HIV = human immunodeficiency virus; HTG = hyper triglyceridemia; HTG-AP = hypertriglyceridemic acute pancreatitis; ROC = receiver operating characteristic; TG = triglyceride. PMID- 29498915 TI - GLUCOCORTICOID-INDUCED ADRENAL INSUFFICIENCY: A STUDY OF THE INCIDENCE IN HOSPITAL PATIENTS AND A REVIEW OF PERI-OPERATIVE MANAGEMENT. AB - OBJECTIVE: Glucocorticoid (GC) pharmacotherapy is an effective treatment for a range of diseases, but exposure can suppress the hypothalamic-pituitary-adrenal axis, leading to glucocorticoid-induced adrenal insufficiency (GC-AI) in some patients. However, the incidence of diagnosed GC-AI and the associated health burden, including the incidence of adrenal crises (ACs), are unknown. Although GC AI treatment is based on well-established principles, there are no agreed protocols regarding the peri-operative management of exposed patients. The aims of this study were to assess the incidence of diagnosed GC-AI in hospital patients and review current approaches to peri-operative management of surgical patients with GC exposure. METHODS: An analysis of hospital admission data concerning adult patients diagnosed with GC-AI and a review of published recommendations for peri-operative GC cover. RESULTS: Between 2001 and 2013, admission with a diagnosis of GC-AI in New South Wales, Australia was rare (annual average of 22.5 admissions/year) and ACs were even more rare (n = 3). Almost two-thirds (64.4%, n = 188) of the patients with diagnosed GC-AI were aged between 50 and 79 years and 45.2% (n = 132) had a comorbid infection. The current approach to peri-operative management of patients with GC exposure appears to be influenced by both the absence of clear guidelines and historic practices. This results in the exposure of some patients to supraphysiologic doses of GCs during the peri-operative period. CONCLUSION: Hospital admission with a diagnosis of GC AI (with or without an AC) is very rare. Clear guidelines on peri-operative GC cover are necessary to avoid overreplacement with supraphysiologic doses in susceptible patients. ABBREVIATIONS: AC = adrenal crisis; ACTH = adrenocorticotropic hormone; AI = adrenal insufficiency; CI = confidence interval; GC = glucocorticoid; GC-AI = glucocorticoid-induced adrenal insufficiency; HPA = hypothalamic-pituitary-adrenal; OR = odds ratio. PMID- 29498916 TI - BROWN TUMOR OF THE PALATE. PMID- 29498917 TI - DIABETES MANAGEMENT "UP IN THE AIR": IT'S TIME FOR CONSENSUS. PMID- 29498918 TI - Goiter as a Red Herring In the Triad of Obesity, Neck Compressive Symptoms, and Goiter. PMID- 29498919 TI - Lateral neck Cystic Mass: The Role of Thyroglobulin Measurement in Fine Needle Aspiration. PMID- 29498920 TI - UPDATE ON THE CLINICOPATHOLOGY OF PITUITARY ADENOMAS. AB - OBJECTIVE: Pituitary adenomas are the third most common central nervous system tumors and arise from the anterior pituitary within the pituitary fossa. METHODS: Literature review and discussion. RESULTS: The signs and symptoms of patients with pituitary adenomas vary from 'mass effects' caused by a large adenoma to features secondary to excess pituitary hormones produced by the functioning pituitary adenoma. Detailed histopathologic assessment, based on novel classifications and the latest World Health Organization guidelines, helps to categorize pituitary adenomas into different subtypes and identify features that, in some cases, help to predict their behavior. Most of the pituitary tumors occur sporadically without known genetic predisposition, but in a significant minority of cases, somatic mutations can be identified in the GNAS and USP8 genes. A small proportion of the cases have germline genetic defects or embryonic mutations leading to mosaicism. Genes with germ-line mutations predisposing to pituitary adenomas include AIP, GPR101, MEN1, CDKN1B, PRKAR1A, PRKAR2A, DICER1, NF1, and SDHx, whereas more recently, CABLES1 has also been implicated. CONCLUSION: Understanding the pathogenesis of pituitary adenomas will allow clinicians to correlate the pathologic and genetic features with clinical data, helping decisions on the best management of these tumors. ABBREVIATIONS: ACTH = adrenocorticotropic hormone; AIP = aryl hydrocarbon receptor-interacting protein; alphaSU = alpha-subunit; EGFR = epithelial growth factor receptor; ER = estrogen receptor; FSH = follicle-stimulating hormone; GH = growth hormone; GHRH = growth hormone-releasing hormone; IGF-1 = insulin-like growth factor 1; LH = luteinizing hormone; MEN1 = multiple endocrine neoplasia 1; MRI = magnetic resonance imaging; NFPA = nonfunctioning pituitary adenoma; PRL = prolactin; TSH = thyroid stimulating hormone; USP8 = ubiquitin-specific peptidase 8; WHO = World Health Organization. PMID- 29498922 TI - Varicell Zoster Virus-Associated Uveitis. PMID- 29498921 TI - ENHANCED BETA-CATENIN EXPRESSION IS ASSOCIATED WITH RECURRENCE OF PAPILLARY THYROID CARCINOMA. AB - OBJECTIVE: A direct role of beta-catenin 1 (beta-cat) in the proliferation of human thyroid tumor cells has been identified. This study aimed to determine if there is an association between beta-cat gene expression and the staging, recurrence, metastasis, and disease-free survival of papillary thyroid cancer. METHODS: A retrospective cohort study was conducted using data from available information in the medical records and paraffin blocks of 81 of 400 patients referred to the endocrine clinic over a 10-year period. Real-time polymerase chain reaction was used to evaluate beta-cat gene expression. Disease-free survival was assessed using the Kaplan-Meier method. RESULTS: The 10-year survival rate in these patients was 98.25%, and disease-free survival was 48.1%. Cumulative dose of radioactive iodine that patients received was significantly and positively correlated with beta-cat gene expression ( r = -0.2; P = .03). Also, in patients with recurrence, beta-cat gene expression was higher and statistically significant (5-fold increase; P = .002). Patients in more advanced stage and those with recurrence/distant metastasis had higher beta-cat gene expression. We found that the patients had a better survival (lower recurrence) if they had a lower beta-cat gene expression (SD, 0.142 to 0.052) (Mantel-Cox test, P = .002). CONCLUSION: We conclude that beta-cat gene expression is positively correlated with recurrence, distant metastasis, and tumor-node metastasis stage. ABBREVIATIONS: beta-cat = beta-catenin 1; CI = confidence interval; PTC = papillary thyroid carcinoma; ROC = receiver operating characteristic. PMID- 29498923 TI - IKZF1plus Defines a New Minimal Residual Disease-Dependent Very-Poor Prognostic Profile in Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia. AB - Purpose Somatic deletions that affect the lymphoid transcription factor-coding gene IKZF1 have previously been reported as independently associated with a poor prognosis in pediatric B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). We have now refined the prognostic strength of IKZF1 deletions by analyzing the effect of co-occurring deletions. Patients and Methods The analysis involved 991 patients with BCP ALL treated in the Associazione Italiana Ematologia ed Oncologia Pediatrica-Berlin-Frankfurt-Muenster (AIEOP-BFM) ALL 2000 trial with complete information for copy number alterations of IKZF1, PAX5, ETV6, RB1, BTG1, EBF1, CDKN2A, CDKN2B, Xp22.33/Yp11.31 (PAR1 region; CRLF2, CSF2RA, and IL3RA), and ERG; replication of findings involved 417 patients from the same trial. Results IKZF1 deletions that co-occurred with deletions in CDKN2A, CDKN2B, PAX5, or PAR1 in the absence of ERG deletion conferred the worst outcome and, consequently, were grouped as IKZF1plus. The IKZF1plus group comprised 6% of patients with BCP ALL, with a 5-year event-free survival of 53 +/- 6% compared with 79 +/- 5% in patients with IKZF1 deletion who did not fulfill the IKZF1plus definition and 87 +/- 1% in patients who lacked an IKZF1 deletion ( P <= .001). Respective 5-year cumulative relapse incidence rates were 44 +/- 6%, 11 +/- 4%, and 10 +/- 1% ( P <= .001). Results were confirmed in the replication cohort, and multivariable analyses demonstrated independence of IKZF1plus. The IKZF1plus prognostic effect differed dramatically in analyses stratified by minimal residual disease (MRD) levels after induction treatment: 5-year event-free survival for MRD standard-risk IKZF1plus patients was 94 +/- 5% versus 40 +/- 10% in MRD intermediate- and 30 +/- 14% in high-risk IKZF1plus patients ( P <= .001). Corresponding 5-year cumulative incidence of relapse rates were 6 +/- 6%, 60 +/- 10%, and 60 +/- 17% ( P <= .001). Conclusion IKZF1plus describes a new MRD dependent very-poor prognostic profile in BCP ALL. Because current AIEOP-BFM treatment is largely ineffective for MRD-positive IKZF1plus patients, new experimental treatment approaches will be evaluated in our upcoming trial AIEOP BFM ALL 2017. PMID- 29498929 TI - Erratum: "Decadal Changes in the Edible Supply of Seafood and Methylmercury Exposure in the United States". AB - [This corrects the article DOI: https://doi.org/10.1289/EHP2644.]. PMID- 29498932 TI - Force plates may be used for dynamic analyses of endoprostheses explantation procedures. AB - The number of hip and knee arthroplasty replacement surgeries is increasing steadily. In combination with demographic aging and the number of periprosthetic complications, this development has lead to the phenomenon where the need for revision surgery is rising. The problem is, that, while implantation procedures of hip arthroplasties are more or less standardized, explantation is a non standardized task for experienced specialists, due to the unpredictability of the adequate loosening method. The surgeon often only gets to decide on which tools and methods may be applied to detach the prosthesis, only after getting access to the operation site. The time taken to detach the prosthesis is hardly predictable and mainly depends on the surgeons' skills. To gain objective data on the mechanics of explantation, new measurement methods are required. One technical base for studies on revision procedures are standard force plates, available in biomechanics laboratories. PMID- 29498928 TI - TB and Tailpipes: Does Traffic-Related Air Pollution Affect Mortality during Tuberculosis Treatment? PMID- 29498925 TI - Dasatinib in Pediatric Patients With Chronic Myeloid Leukemia in Chronic Phase: Results From a Phase II Trial. AB - Purpose Safe, effective treatments are needed for pediatric patients with chronic myeloid leukemia in chronic phase (CML-CP). Dasatinib is approved for treatment of adults and children with CML-CP. A phase I study determined suitable dosing for children with Philadelphia chromosome-positive (Ph+) leukemias. Methods CA180 226/NCT00777036 is a phase II, open-label, nonrandomized prospective trial of patients < 18 years of age receiving dasatinib. There are three cohorts: (1) imatinib-resistant/intolerant CML-CP, (2) imatinib-resistant/intolerant CML in accelerated/blast phase or Ph+ acute lymphoblastic leukemia (n = 17), and (3) newly diagnosed CML-CP treated with tablets or powder for oral suspension. Major cytogenetic response > 30% for imatinib-resistant/intolerant patients and complete cytogenetic response (CCyR) > 55% for newly diagnosed patients were of clinical interest. Results Of 113 patients with CML-CP, 14 (48%) who were imatinib-resistant/intolerant and 61 (73%) who were newly diagnosed remained on treatment at time of analysis. Major cytogenetic response > 30% was reached by 3 months in the imatinib-resistant/intolerant group and CCyR > 55% was reached by 6 months in the newly diagnosed CML-CP group. CCyR and major molecular response by 12 months, respectively, were 76% and 41% in the imatinib-resistant/intolerant group and 92% and 52% in newly diagnosed CML-CP group. Progression-free survival by 48 months was 78% and 93% in the imatinib-resistant/intolerant and newly diagnosed CML-CP groups, respectively. No dasatinib-related pleural or pericardial effusion, pulmonary edema, or pulmonary arterial hypertension were reported. Bone growth and development events were reported in 4% of patients. Conclusion In the largest prospective trial to date in children with CML-CP, we demonstrate that dasatinib is a safe, effective treatment of pediatric CML-CP. Target responses to first- or second-line dasatinib were met early, and deep molecular responses were observed. Safety of dasatinib in pediatric patients was similar to that observed in adults; however, no cases of pleural or pericardial effusion or pulmonary arterial hypertension were reported. PMID- 29498930 TI - Kallikrein-related peptidase 7 overexpression in melanoma cells modulates cell adhesion leading to a malignant phenotype. AB - We recently reported that human melanoma cells, but not benign melanocytes, aberrantly express kallikrein-related peptidase 7 (KLK7). Here, we show a KLK7 overexpression-mediated decrease of cell adhesion to extracellular matrix binding proteins, associated with downregulation of alpha5/beta1/alphav/beta3 integrin expression. We also report an up-regulation of MCAM/CD146 and an increase in spheroid formation of these cells. Our results demonstrate that aberrant KLK7 expression leads to a switch to a more malignant phenotype suggesting a potential role of KLK7 in melanoma invasion. Thus, KLK7 may represent a biomarker for melanoma progression and may be a potential therapeutic target for melanoma. PMID- 29498924 TI - SIRveNIB: Selective Internal Radiation Therapy Versus Sorafenib in Asia-Pacific Patients With Hepatocellular Carcinoma. AB - Purpose Selective internal radiation therapy or radioembolization (RE) shows efficacy in unresectable hepatocellular carcinoma (HCC) limited to the liver. This study compared the safety and efficacy of RE and sorafenib in patients with locally advanced HCC. Patients and Methods SIRveNIB (selective internal radiation therapy v sorafenib), an open-label, investigator-initiated, phase III trial, compared yttrium-90 (90Y) resin microspheres RE with sorafenib 800 mg/d in patients with locally advanced HCC in a two-tailed study designed for superiority/detriment. Patients were randomly assigned 1:1 and stratified by center and presence of portal vein thrombosis. Primary end point was overall survival (OS). Efficacy analyses were performed in the intention-to-treat population and safety analyses in the treated population. Results A total of 360 patients were randomly assigned (RE, 182; sorafenib, 178) from 11 countries in the Asia-Pacific region. In the RE and sorafenib groups, 28.6% and 9.0%, respectively, failed to receive assigned therapy without significant cross-over to either group. Median OS was 8.8 and 10.0 months with RE and sorafenib, respectively (hazard ratio, 1.1; 95% CI, 0.9 to 1.4; P = .36). A total of 1,468 treatment-emergent adverse events (AEs) were reported (RE, 437; sorafenib, 1,031). Significantly fewer patients in the RE than sorafenib group had grade >= 3 AEs (36 of 130 [27.7%]) v 82 of 162 [50.6%]; P < .001). The most common grade >= 3 AEs were ascites (five of 130 [3.8%] v four of 162 [2.5%] patients), abdominal pain (three [2.3%] v two [1.2%] patients), anemia (zero v four [2.5%] patients), and radiation hepatitis (two [1.5%] v zero [0%] patients). Fewer patients in the RE group (27 of 130 [20.8%]) than in the sorafenib group (57 of 162 [35.2%]) had serious AEs. Conclusion In patients with locally advanced HCC, OS did not differ significantly between RE and sorafenib. The improved toxicity profile of RE may inform treatment choice in selected patients. PMID- 29498931 TI - Functional characterization of the mouse Serpina1 paralog DOM-7. AB - The generation of authentic mouse-models for human alpha1-antitrypsin (A1AT) deficiency is difficult due to the high complexity of the mouse Serpina1 gene locus. Depending on the exact mouse strain, three to five paralogs are expressed, with different proteinase inhibitory properties. Nowadays with CRISPR-technology, genome editing of complex genomic loci is feasible and could be employed for the generation of A1AT-deficiency mouse models. In preparation of a CRISPR/Cas9-based genome-engineering approach we identified cDNA clones with a functional CDS for the Serpina1-paralog DOM-7. Here, we show that DOM-7 functionally inhibits neutrophil elastase (ELANE) and chymotrypsin, and therefore needs to be considered when aiming at the generation of A1AT-deficient models. PMID- 29498934 TI - Leptin, neuropeptide Y (NPY), melatonin and zinc levels in experimental hypothyroidism and hyperthyroidism: relation with melatonin and the pineal gland. AB - Background Melatonin, an important neurohormone released from the pineal gland, is generally accepted to exercise an inhibitor effect on the thyroid gland. Zinc mediates the effects of many hormones and is found in the structure of numerous hormone receptors. Aim The present study aims to examine the effect of melatonin supplementation and pinealectomy on leptin, neuropeptide Y (NPY), melatonin and zinc levels in rats with hypothyroidism and hyperthyroidism. Methods This study was performed on the 70 male rats. Experimental animals in the study were grouped as follows: control (C); hypothyroidism (PTU); hypothyroidism + melatonin (PTU + M); hypothyroidism + pinealectomy (PTU + Pnx); hyperthyroidism (H); hyperthyroidism + melatonin (H + M) and hyperthyroidism + pinealectomy (H + Pnx). Blood samples collected at the end of 4-week procedures were analyzed to determine melatonin, leptin, NPY and zinc levels. Results It was found that thyroid parameters thyroid stimulating hormone (TSH), free triiodthyronine (FT3), free thyroxine (FT4), total T3 (TT3) and total T4 (TT4) decreased in hypothyroidism groups and increased in the groups with hyperthyroidism. The changes in these hormones remained unaffected by melatonin supplementation and pinealectomy. Melatonin levels rose in hyperthyroidism and fell in hypothyroidism. Leptin and NPY levels increased in both hypothyroidism and hyperthyroidism. Zinc levels, on the other hand, decreased in hypothyroidism and pinealectomy, but increased in hyperthyroidism. Conclusion The results of the study demonstrate that hypothyroidism and hyperthyroidism affect leptin, NPY, melatonin and zinc values in different ways in rats. However, melatonin supplementation and pinealectomy do not have any significant influence on the changes occurring in leptin, NPY and zinc levels in thyroid dysfunction. PMID- 29498927 TI - Plasma Concentrations of Perfluoroalkyl Substances and Risk of Type 2 Diabetes: A Prospective Investigation among U.S. Women. AB - BACKGROUND: Emerging evidence suggests that perfluoroalkyl substances (PFASs) are endocrine disruptors and may contribute to the etiology of type 2 diabetes (T2D), but this hypothesis needs to be clarified in prospective human studies. OBJECTIVES: Our objective was to examine the associations between PFAS exposures and subsequent incidence of T2D in the Nurses' Health Study II (NHSII). In addition, we aimed to evaluate potential demographic and lifestyle determinants of plasma PFAS concentrations. METHODS: A prospective nested case-control study of T2D was conducted among participants who were free of diabetes, cardiovascular disease, and cancer in 1995-2000 [(mean+/-SD): 45.3+/-4.4 y) of age]. We identified and ascertained 793 incident T2D cases through 2011 (mean+/-SD) years of follow-up: 6.7+/-3.7 y). Each case was individually matched to a control (on age, month and fasting status at sample collection, and menopausal status and hormone replacement therapy). Plasma concentrations of five major PFASs, including perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexanesulfonate, perfluorononanoic acid, and perfluorodecanoic acid were measured. Odds ratios (ORs) of T2D by PFAS tertiles were estimated by conditional logistic regression. RESULTS: Shorter breastfeeding duration and higher intake of certain foods, such as seafood and popcorn, were significantly associated with higher plasma concentrations of PFASs among controls. After multivariate adjustment for T2D risk factors, including body mass index, family history, physical activity, and other covariates, higher plasma concentrations of PFOS and PFOA were associated with an elevated risk of T2D. Comparing extreme tertiles of PFOS or PFOA, ORs were 1.62 (95% CI: 1.09, 2.41; ptrend=0.02) and 1.54 (95% CI: 1.04, 2.28; ptrend=0.03), respectively. Other PFASs were not clearly associated with T2D risk. CONCLUSIONS: Background exposures to PFASs in the late 1990s were associated with higher T2D risk during the following years in a prospective case control study of women from the NHSII. These findings support a potential diabetogenic effect of PFAS exposures. https://doi.org/10.1289/EHP2619. PMID- 29498933 TI - Management of women with PCOS using myo-inositol and folic acid. New clinical data and review of the literature. AB - Introduction The use of 2 * 2000 mg myo-inositol +2 * 200 MUg folic acid per day is a safe and promising tool in the effective improvement of symptoms and infertility for patients with polycystic ovary syndrome (PCOS). In addition, PCOS is one of the pathological factors involved in the failure of in vitro fertilization (IVF). Typically, PCOS patients suffer of poor quality oocytes. Patients and methods In an open, prospective, non-blinded, non-comparative observational study, 3602 infertile women used myo-inositol and folic acid between 2 and 3 months in a dosage of 2 * 2000 mg myo-inositol +2 * 200 MUg folic acid per day. In a subgroup of 32 patients, hormonal values for testosterone, free testosterone and progesterone were analyzed before and after 12 weeks of treatment. The mean time of use was 10.2 weeks. In the second part of this trial it was investigated if the combination of myo-inositol + folic acid was able to improve the oocyte quality, the ratio between follicles and retrieved oocytes, the fertilization rate and the embryo quality in PCOS patients undergoing IVF treatments. Twenty-nine patients with PCOS, underwent IVF protocols for infertility treatment and were randomized prospectively into two groups. Group A (placebo) with 15 patients and group B (4000 mg myo-inositol +400 MUg folic acid per day) with 14 patients were evaluated. The patients of group B used 2 months' myo-inositol + folic acid before starting the IVF protocol. For statistically analyses Student's t-test was performed. Results Seventy percent of the women had a restored ovulation, and 545 pregnancies were observed. This means a pregnancy rate of 15.1% of all the myo-inositol and folic acid users. In 19 cases a concomitant medication with clomiphene or dexamethasone was used. One twin pregnancy was documented. Testosterone levels changed from 96.6 ng/mL to 43.3 ng/mL and progesterone from 2.1 ng/mL to 12.3 ng/mL in the mean after 12 weeks of treatment (p < 0.05) Student's t-test. No relevant side effects were present among the patients. The women in the IVF treatment the group A showed a higher number of retrieved oocytes than group B. Nevertheless, the ratio follicle/retrieved oocyte was clearly better in the myo-inositol group (= group B). Out of the 233 oocytes collected in the myo-inositol group, 136 where fertilized whereas only 128 out of 300 oocytes were fertilized in the placebo group. With regards to the oocytes quality, better data were obtained in the myo inositol group. More metaphase II and I oocytes were retrieved in relation to the total number of oocytes, when compared with the placebo group. Also, more embryos of grade I quality were observed in the myo-inositol group than in the placebo group. The duration of stimulation was 9.7 days (+/-3.3) in the myo-inositol group and 11.2 (+/-1.8) days in the placebo group and the number of used follicle stimulating hormone (FSH) units was lower in the myo-inositol group in comparison to the placebo group: 1850 FSH units (mean) versus 1850 units (mean). Discussion Myo-inositol has proven to be a new treatment option for patients with PCOS and infertility. The achieved pregnancy rates are at least in an equivalent or even superior range than those reported using metformin as an insulin sensitizer. No moderate to severe side effects were observed when myo-inositol was used at a dosage of 4000 mg per day. In addition, our evidence suggests that a myo-inositol therapy in women with PCOS results in better fertilization rates and a clear trend to a better embryo quality. As by the same way the number of retrieved oocytes was smaller in the myo-inositol group, the risk of a hyperstimulation syndrome in these patients can be reduced. Therefore, myo-inositol also represents an improvement in IVF protocols for patients with PCOS. PMID- 29498935 TI - Structural stability of coplanar 1T-2H superlattice MoS2 under high energy electron beam. AB - Coplanar heterojunctions composed of van der Waals layered materials with different structural polymorphs have drawn immense interest recently due to low contact resistance and high carrier injection rate owing to low Schottky barrier height. Present research has largely focused on efficient exfoliation of these layered materials and their restacking to achieve better performances. We present here a microwave assisted easy, fast and efficient route to induce high concentration of metallic 1T phase in the original 2H matrix of exfoliated MoS2 layers and thus facilitating the formation of a 1T-2H coplanar superlattice phase. High resolution transmission electron microscopy (HRTEM) investigations reveal formation of highly crystalline 1T-2H hybridized structure with sharp interface and disclose the evidence of surface ripplocations within the same exfoliated layer of MoS2. In this work, the structural stability of 1T-2H superlattice phase during HRTEM measurements under an electron beam of energy 300 keV is reported. This structural stability could be either associated to the change in electronic configuration due to induction of the restacked hybridized phase with 1T- and 2H-regions or to the formation of the surface ripplocations. Surface ripplocations can act as an additional source of scattering centers to the electron beam and also it is possible that a pulse train of propagating ripplocations can sweep out the defects via interaction from specific areas of MoS2 sheets. PMID- 29498936 TI - Effect of low frequency magnetic fields on the growth of MNP-treated HT29 colon cancer cells. AB - Recent investigations have attempted to understand and exploit the impact of magnetic field-actuated internalized magnetic nanoparticles (MNPs) on the proliferation rate of cancer cells. Due to the complexity of the parameters governing magnetic field-exposure though, individual studies to date have raised contradictory results. In our approach we performed a comparative analysis of key parameters related to the cell exposure of cancer cells to magnetic field actuated MNPs, and to the magnetic field, in order to better understand the factors affecting cellular responses to magnetic field-stimulated MNPs. We used magnetite MNPs with a hydrodynamic diameter of 100 nm and studied the proliferation rate of MNPs-treated versus untreated HT29 human colon cancer cells, exposed to either static or alternating low frequency magnetic fields with varying intensity (40-200 mT), frequency (0-8 Hz) and field gradient. All three parameters, field intensity, frequency, and field gradient affected the growth rate of cells, with or without internalized MNPs, as compared to control MNPs untreated and magnetic field-untreated cells. We observed that the growth inhibitory effects induced by static and rotating magnetic fields were enhanced by pre-treating the cells with MNPs, while the growth promoting effects observed in alternating field-treated cells were weakened by MNPs. Compared to static, rotating magnetic fields of the same intensity induced a similar extend of cell growth inhibition, while alternating fields of varying intensity (70 or 100 mT) and frequency (0, 4 or 8 Hz) induced cell proliferation in a frequency-dependent manner. These results, highlighting the diverse effects of mode, intensity, and frequency of the magnetic field on cell growth, indicate that consistent and reproducible results can be achieved by controlling the complexity of the exposure of biological samples to MNPs and external magnetic fields, through monitoring crucial experimental parameters. We demonstrate that further research focusing on the accurate manipulation of the aforementioned magnetic field exposure parameters could lead to the development of successful non-invasive therapeutic anticancer approaches. PMID- 29498937 TI - Fabrication of high crystalline SnS and SnS2 thin films, and their switching device characteristics. AB - Representative tin sulfide compounds, tin monosulfide (SnS) and tin disulfide (SnS2) are strong candidates for future nanoelectronic devices, based on non toxicity, low cost, unique structures and optoelectronic properties. However, it is insufficient for synthesizing of tin sulfide thin films using vapor phase deposition method which is capable of fabricating reproducible device and securing high quality films, and their device characteristics. In this study, we obtained highly crystalline SnS thin films by atomic layer deposition and obtained highly crystalline SnS2 thin films by phase transition of the SnS thin films. The SnS thin film was transformed into SnS2 thin film by annealing at 450 degrees C for 1 h in H2S atmosphere. This phase transition was confirmed by x-ray diffractometer and x-ray photoelectron spectroscopy, and we studied the cause of the phase transition. We then compared the film characteristics of these two tin sulfide thin films and their switching device characteristics. SnS and SnS2 thin films had optical bandgaps of 1.35 and 2.70 eV, and absorption coefficients of about 105 and 104 cm-1 in the visible region, respectively. In addition, SnS and SnS2 thin films exhibited p-type and n-type semiconductor characteristics. In the images of high resolution-transmission electron microscopy, SnS and SnS2 directly showed a highly crystalline orthorhombic and hexagonal layered structure. The field effect transistors of SnS and SnS2 thin films exhibited on-off drain current ratios of 8.8 and 2.1 * 103 and mobilities of 0.21 and 0.014 cm2 V-1 s-1, respectively. This difference in switching device characteristics mainly depends on the carrier concentration because it contributes to off-state conductance and mobility. The major carrier concentrations of the SnS and SnS2 thin films were 6.0 * 1016 and 8.7 * 1013 cm-3, respectively, in this experiment. PMID- 29498939 TI - Noninvasive Ventilation in Patients With Do-Not-Intubate and Comfort-Measures Only Orders: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: To assess the effectiveness of noninvasive ventilation in patients with acute respiratory failure and do-not-intubate or comfort-measures-only orders. DATA SOURCES: MEDLINE, EMBASE, CINAHL, Scopus, and Web of Science from inception to January 1, 2017. STUDY SELECTION: Studies of all design types that enrolled patients in the ICU or hospital ward who received noninvasive ventilation and had preset do-not-intubate or comfort-measures-only orders. DATA EXTRACTION: Data abstraction followed Meta-analysis of Observational Studies in Epidemiology guidelines. Data quality was assessed using a modified Newcastle Ottawa Scale. DATA SYNTHESIS: Twenty-seven studies evaluating 2,020 patients with do-not-intubate orders and three studies evaluating 200 patients with comfort measures-only orders were included. In patients with do-not-intubate orders, the pooled survival was 56% (95% CI, 49-64%) at hospital discharge and 32% (95% CI, 21-45%) at 1 year. Hospital survival was 68% for chronic obstructive pulmonary disease, 68% for pulmonary edema, 41% for pneumonia, and 37% for patients with malignancy. Survival was comparable for patients treated in a hospital ward versus an ICU. Quality of life of survivors was not reduced compared with baseline, although few studies evaluated this. No studies evaluated quality of dying in nonsurvivors. In patients with comfort-measures-only orders, a single study showed that noninvasive ventilation was associated with mild reductions in dyspnea and opioid requirements. CONCLUSIONS: A large proportion of patients with do-not-intubate orders who received noninvasive ventilation survived to hospital discharge and at 1 year, with limited data showing no decrease in quality of life in survivors. Provision of noninvasive ventilation in a well-equipped hospital ward may be a viable alternative to the ICU for selected patients. Crucial questions regarding quality of life in survivors, quality of death in nonsurvivors, and the impact of noninvasive ventilation in patients with comfort measures-only orders remain largely unanswered. PMID- 29498941 TI - Ultrasound-Guided Laryngeal Air Column Width Difference as a New Predictor for Postextubation Stridor in Children. AB - OBJECTIVES: To assess the efficacy of ultrasound-guided laryngeal air column width difference in predicting postextubation stridor in children. DESIGN: Prospective observational study. SETTING: Single, tertiary care pediatric hospital. PATIENTS: This study was carried out at PICU and surgical ICU, Tanta University Hospital on 400 ventilated children between January 2015 and May 2017. Patients who received mechanical ventilation and met criteria for a weaning trial were included. INTERVENTION: Laryngeal ultrasound and cuff leak test. MEASUREMENTS AND MAIN RESULTS: Ultrasound-guided laryngeal air column width and cuff leak test were measured before extubation. Laryngeal air column width is the width of air between the vocal cords seen by laryngeal ultrasonography. Laryngeal air column width difference is the width difference of air column passed through vocal cords with the balloon cuff inflated and deflated. Three-hundred fifty six patients (89%) had no postextubation stridor, whereas 44 patients (11%) developed postextubation stridor. Postextubation stridor was associated with younger age, less weight, female gender, prolonged duration of intubation, and ICU stay (p < 0.05). Both laryngeal air column width difference and cuff leak test showed significant decrease (p < 0.05) in patients with postextubation stridor in comparison with no postextubation stridor patients. Receiver operating characteristics curve analysis showed that laryngeal air column width difference at cutoff point of less than 0.8 mm gave a sensitivity of 93%, specificity of 86%, and accuracy of 91%, whereas cuff leak test at less than 11% yielded a sensitivity of (61%), specificity of (53%), and accuracy of (59%) for predicting postextubation stridor. CONCLUSIONS: Laryngeal air column width difference measurement may serve as a simple reliable noninvasive method for predicting postextubation stridor in children. PMID- 29498940 TI - Short-Latency Positive Peak Following N20 Somatosensory Evoked Potential Is Superior to N20 in Predicting Neurologic Outcome After Out-of-Hospital Cardiac Arrest. AB - OBJECTIVES: The absence of N20 somatosensory evoked potential after cardiac arrest is related to poor outcome. However, discrimination between the low amplitude and the absence of N20 is challenging. P25 and P30 are short-latency positive peaks with latencies between 25 and 30 ms following N20 (P25/30). P25/30 is evident even with an ambiguous N20 in patients with good outcome. Therefore, we evaluated the predictive value of P25/30 after cardiac arrest. DESIGN: A retrospective observational study. SETTING: University-affiliated hospital. SUBJECTS: Comatose survivors after out-of-hospital cardiac arrest treated by hypothermic targeted temperature management. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The specificity and the positive predictive value of P25/30 and N20 in predicting poor outcome were the same, showing a rate of 100%. The sensitivity of P25/30 in predicting poor outcome (90.12% [95% CI, 81.5-95.6%]) was higher than that of N20 (70.37% [95% CI, 59.2-80%]). Also, the negative predictive value of P25/30 in predicting poor outcome (81.4% [95% CI, 69.4-89.4%]) was higher than that of N20 (59.3% [95% CI, 51-67.1%]). The P25/30-based adjusted model showed a larger area under the curve (0.98 [95% CI, 0.95-1]) compared with the N20-based adjusted model (0.95 [95% CI, 0.91-0.98]) (p = 0.02). CONCLUSIONS: The absence of P25/30 is related to poor outcome with a higher sensitivity, negative predictive value than the absence of N20. PMID- 29498942 TI - Activated Prothrombin Complex Concentrate Versus 4-Factor Prothrombin Complex Concentrate for Vitamin K-Antagonist Reversal. AB - OBJECTIVES: To compare the international normalized ratio normalization efficacy of activated prothrombin complex concentrates and 4-factor prothrombin complex concentrates and to evaluate the thrombotic complications in patients treated with these products for warfarin-associated hemorrhage. DESIGN: Retrospective, Multicenter Cohort. SETTING: Large, Community, Teaching Hospital. PATIENTS: Patients greater than 18 years old and received either activated prothrombin complex concentrate or 4-factor prothrombin complex concentrate for the treatment of warfarin-associated hemorrhage. We excluded those patients who received either agent for an indication other than warfarin-associated hemorrhage, pregnant, had a baseline international normalized ratio of less than 2, received a massive transfusion as defined by hospital protocol, received plasma for treatment of warfarin-associated hemorrhage, or were treated for an acute warfarin ingestion. INTERVENTIONS: Patients in the activated prothrombin complex concentrate group (enrolled from one hospital) with an international normalized ratio of less than 5 received 500 IU and those with an international normalized ratio greater than 5 received 1,000 IU. Patients in the 4-factor prothrombin complex concentrate (enrolled from a separate hospital) group received the Food and Drug Administration approved dosing algorithm. MEASUREMENTS AND MAIN RESULTS: A total of 158 patients were included in the final analysis (activated prothrombin complex concentrate = 118; 4-factor prothrombin complex concentrate = 40). Those in the 4-factor prothrombin complex concentrate group had a higher pretreatment international normalized ratio (2.7 +/- 1.8 vs 3.5 +/- 2.9; p = 0.0164). However, the posttreatment international normalized ratio was similar between the groups. In addition, even when controlling for differences in the pretreatment international normalized ratio, there was no difference in the ability to achieve a posttreatment international normalized ratio of less than 1.4 (odds ratio, 0.753 [95% CI, 0.637-0.890]; p = 0.0009). Those in the activated prothrombin complex concentrate group did have higher odds of achieving a posttreatment international normalized ratio of less than 1.2 (odds ratio, 3.23 [95% CI, 1.34 7.81]; p = 0.0088). There was only one posttreatment thrombotic complication reported. CONCLUSIONS: A low, fixed dose of activated prothrombin complex concentrate was as effective as standard dose 4-factor prothrombin complex concentrate for normalization of international normalized ratio. In addition, we did not see an increase in thrombotic events. PMID- 29498938 TI - Sedation Intensity in the First 48 Hours of Mechanical Ventilation and 180-Day Mortality: A Multinational Prospective Longitudinal Cohort Study. AB - OBJECTIVES: In the absence of a universal definition of light or deep sedation, the level of sedation that conveys favorable outcomes is unknown. We quantified the relationship between escalating intensity of sedation in the first 48 hours of mechanical ventilation and 180-day survival, time to extubation, and delirium. DESIGN: Harmonized data from prospective multicenter international longitudinal cohort studies SETTING:: Diverse mix of ICUs. PATIENTS: Critically ill patients expected to be ventilated for longer than 24 hours. INTERVENTIONS: Richmond Agitation Sedation Scale and pain were assessed every 4 hours. Delirium and mobilization were assessed daily using the Confusion Assessment Method of ICU and a standardized mobility assessment, respectively. MEASUREMENTS AND MAIN RESULTS: Sedation intensity was assessed using a Sedation Index, calculated as the sum of negative Richmond Agitation Sedation Scale measurements divided by the total number of assessments. We used multivariable Cox proportional hazard models to adjust for relevant covariates. We performed subgroup and sensitivity analysis accounting for immortal time bias using the same variables within 120 and 168 hours. The main outcome was 180-day survival. We assessed 703 patients in 42 ICUs with a mean (SD) Acute Physiology and Chronic Health Evaluation II score of 22.2 (8.5) with 180-day mortality of 32.3% (227). The median (interquartile range) ventilation time was 4.54 days (2.47-8.43 d). Delirium occurred in 273 (38.8%) of patients. Sedation intensity, in an escalating dose-dependent relationship, independently predicted increased risk of death (hazard ratio [95% CI], 1.29 [1.15-1.46]; p < 0.001, delirium hazard ratio [95% CI], 1.25 [1.10-1.43]), p value equals to 0.001 and reduced chance of early extubation hazard ratio (95% CI) 0.80 (0.73-0.87), p value of less than 0.001. Agitation level independently predicted subsequent delirium hazard ratio [95% CI], of 1.25 (1.04-1.49), p value equals to 0.02. Delirium or mobilization episodes within 168 hours, adjusted for sedation intensity, were not associated with survival. CONCLUSIONS: Sedation intensity independently, in an ascending relationship, predicted increased risk of death, delirium, and delayed time to extubation. These observations suggest that keeping sedation level equivalent to a Richmond Agitation Sedation Scale 0 is a clinically desirable goal. PMID- 29498943 TI - Increased Single-Fiber Jitter Level Is Associated With Reduction in Motor Function With Aging. AB - OBJECTIVE: Age-associated skeletal muscle weakness is a major contributing factor to an increased late life mortality and morbidity, but its neurobiology is poorly understood. Previously, we provided histological evidence of dying-back axonal degeneration of motor neurons and denervation of neuromuscular junctions in age associated muscle weakness. Given this, we aimed to evaluate the relation between impaired neuromuscular transmission and various aspects of age-associated muscle weakness. DESIGN: We compared two electrophysiological measures, single-fiber jitter and compound motor action potential in mice of different age groups, and correlated them with various physical performance measures, such as grip strength, standing and walking time, and treadmill performance. RESULTS: Consistent with our previous histological data, single-fiber jitter, a measure of neuromuscular junction transmission, was significantly increased in older animals, whereas compound motor action potential shows no difference between young and old age groups. Neither jitter nor compound motor action potential correlated with any of physical performance measures, except for jitter and standing activity. CONCLUSIONS: Impaired neuromuscular transmission-represented as increase in single-fiber electromyography jitter level-reflects decline in motor function with aging. PMID- 29498945 TI - Type 2 Perioperative Myocardial Infarction: Can We Close Pandora's Box? PMID- 29498944 TI - Comparison of Transcutaneous and Serum Bilirubin Measurements in Neonates 30 to 34 Weeks' Gestation Before, During, and After Phototherapy. AB - BACKGROUND: The use of noninvasive, transcutaneous bilirubin monitoring (TcB) as a jaundice screen in full-term infants is well established; however, there is a paucity of research evaluating the use of TcB in premature infants. PURPOSE: To compare agreement and consistency of transcutaneous and serum bilirubin measurements in a multiracial premature infant population ranging from 30 to 34(Equation is included in full-text article.)weeks' gestation before, during, and after phototherapy. METHODS: Forty-five neonates, 30 to 34(Equation is included in full-text article.)weeks' gestation, were enrolled in this prospective, correlational study over a 12-month period. One set of paired transcutaneous and serum bilirubin measurements, per neonate, was obtained before phototherapy, during therapy, and after phototherapy. Exclusion criteria included neonates with positive direct coombs test or evidence of hemolytic disease, major congenital anomalies, hydrops fetalis, and those not expected to survive. RESULTS: There was a strong, positive correlation between TcB and total serum monitoring (TSB) measurements obtained pretherapy (r = 0.797, P < .001). A moderate correlation was noted between TcB and TSB measurements obtained during therapy (r = 0.588, P < .001). A strong correlation was noted between TcB and TSB measurements obtained posttherapy (r = 0.869, P < .001). There were no significant differences between paired samples across time (F = 0.891, P = .41, partial eta = 0.01). The TSB measurements were consistently lower than TcB pretherapy, during, and posttherapy. IMPLICATIONS FOR PRACTICE: The TcB measurements provide a reliable estimation, generally within 2 to 3 mg/dL of TSB levels, in premature infants 30 to 34(Equation is included in full-text article.)weeks' gestation. IMPLICATIONS FOR RESEARCH: Investigation of consumption of time and nursing personnel required to perform TcB testing, compared with TSB testing, is indicated. Cost analyses comparing TcB-driven screening protocols and interval TSB measurements, among premature infants, are indicated. As newer generations of TcB devices are approved for use, additional studies using mixed-race populations of premature infants will be necessary to continue to evaluate the reliability and validity of this screening tool within the everyday neonatal intensive care unit. PMID- 29498946 TI - Anomalous Drainage of Inferior Vena Cava into the Left Atrium. PMID- 29498947 TI - Pharmacokinetic Properties of a Sufentanil Sublingual Tablet Intended to Treat Acute Pain. AB - BACKGROUND: Desirable product attributes for treatment of moderate-to-severe acute pain in many medically supervised settings are rapid onset and a route of administration not requiring intravenous access. The pharmacokinetic characteristics of sublingually administered tablets containing 15 or 30 ug of sufentanil are described. METHODS: Blood was sampled from healthy subjects (four studies, 122 subjects) and patients (seven studies, 944 patients). Studies in healthy subjects determined bioavailability, effect of inhibition of cytochrome P450 3A4, and the plasma concentration profile with single and hourly sublingual doses. Studies in patients evaluated effects of weight, age, sex, and organ impairment on apparent clearance. Noncompartmental and mixed-effect population methods were used. RESULTS: Bioavailability of a single sublingual tablet was 52%, decreasing to 35% with repeat dosing. Ketoconazole (CYP3A4 inhibitor) increased maximum plasma concentration 19% and increased the area under the curve 77%. After a single 30-ug dose, plasma concentrations reached the published sufentanil analgesic threshold (24 pg/ml) within 30 min, peaked at 1 h, and then decreased below therapeutic concentrations by ~3 h. With hourly administration, plasma concentrations plateaued by the fifth dose. Time for concentrations to decrease 50% from maximal values was similar after 1 dose (2.5 +/- 0.85 h) and 12 doses (2.5 +/- 0.72 h). Clearance increased with weight, decreased with age, and was not affected by renal or hepatic impairment. CONCLUSIONS: The time course of a single 30-ug dose was consistent with onset of analgesia and redosing frequency observed in clinical trials. Sublingual sufentanil tablets provide the opportunity to noninvasively and rapidly treat moderate-to-severe pain in a monitored setting. PMID- 29498948 TI - Inhalational versus Intravenous Induction of Anesthesia in Children with a High Risk of Perioperative Respiratory Adverse Events: A Randomized Controlled Trial. AB - BACKGROUND: Limited evidence suggests that children have a lower incidence of perioperative respiratory adverse events when intravenous propofol is used compared with inhalational sevoflurane for the anesthesia induction. Limiting these events can improve recovery time as well as decreasing surgery waitlists and healthcare costs. This single center open-label randomized controlled trial assessed the impact of the anesthesia induction technique on the occurrence of perioperative respiratory adverse events in children at high risk of those events. METHODS: Children (N = 300; 0 to 8 yr) with at least two clinically relevant risk factors for perioperative respiratory adverse events and deemed suitable for either technique of anesthesia induction were recruited and randomized to either intravenous propofol or inhalational sevoflurane. The primary outcome was the difference in the rate of occurrence of perioperative respiratory adverse events between children receiving intravenous induction and those receiving inhalation induction of anesthesia. RESULTS: Children receiving intravenous propofol were significantly less likely to experience perioperative respiratory adverse events compared with those who received inhalational sevoflurane after adjusting for age, sex, American Society of Anesthesiologists physical status and weight (perioperative respiratory adverse event: 39/149 [26%] vs. 64/149 [43%], relative risk [RR]: 1.7, 95% CI: 1.2 to 2.3, P = 0.002, respiratory adverse events at induction: 16/149 [11%] vs. 47/149 [32%], RR: 3.06, 95% CI: 1.8 to 5.2, P < 0.001). CONCLUSIONS: Where clinically appropriate, anesthesiologists should consider using an intravenous propofol induction technique in children who are at high risk of experiencing perioperative respiratory adverse events. VISUAL ABSTRACT: An online visual overview is available for this article at http://links.lww.com/ALN/B725. PMID- 29498949 TI - Neurologic Considerations and Complications Related to Liver Transplantation. PMID- 29498950 TI - Benefit versus Severe Side Effects of Opioid Analgesia: Novel Utility Functions of Probability of Analgesia and Respiratory Depression. AB - BACKGROUND: Previous studies integrated opioid benefit and harm into one single function-the utility function-to determine the drug toxicity (respiratory depression) in light of its wanted effect (analgesia). This study further refined the concept of the utility function using the respiratory and analgesic effects of the opioid analgesic alfentanil as example. METHODS: Data from three previous studies in 48 healthy volunteers were combined and reanalyzed using a population pharmacokinetic-pharmacodynamic analysis to create utility probability functions. Four specific conditions were defined: probability of adequate analgesia without severe respiratory depression, probability of adequate analgesia with severe respiratory depression, probability of inadequate analgesia without severe respiratory depression, and probability of inadequate analgesia with severe respiratory depression. RESULTS: The four conditions were successfully identified with probabilities varying depending on the opioid effect-site concentration. The optimum analgesia probability without serious respiratory depression is reached at an alfentanil effect-site concentration of 68 ng/ml, and exceeds the probability of the most unwanted effect, inadequate analgesia with severe respiratory depression (odds ratio, 4.0). At higher effect-site concentrations the probability of analgesia is reduced and exceeded by the probability of serious respiratory depression. CONCLUSIONS: The utility function was successfully further developed, allowing assessment of specific conditions in terms of wanted and unwanted effects. This approach can be used to compare the toxic effects of drugs relative to their intended effect and may be a useful tool in the development of new compounds to assess their advantage over existing drugs. PMID- 29498951 TI - Association of Multimodal Pain Management Strategies with Perioperative Outcomes and Resource Utilization: A Population-based Study. AB - BACKGROUND: Multimodal analgesia is increasingly considered routine practice in joint arthroplasties, but supportive large-scale data are scarce. The authors aimed to determine how the number and type of analgesic modes is associated with reduced opioid prescription, complications, and resource utilization. METHODS: Total hip/knee arthroplasties (N = 512,393 and N = 1,028,069, respectively) from the Premier Perspective database (2006 to 2016) were included. Analgesic modes considered were opioids, peripheral nerve blocks, acetaminophen, steroids, gabapentin/pregabalin, nonsteroidal antiinflammatory drugs, cyclooxygenase-2 inhibitors, or ketamine. Groups were categorized into "opioids only" and 1, 2, or more than 2 additional modes. Multilevel models measured associations between multimodal analgesia and opioid prescription, cost/length of hospitalization, and opioid-related adverse effects. Odds ratios or percent change and 95% CIs are reported. RESULTS: Overall, 85.6% (N = 1,318,165) of patients received multimodal analgesia. In multivariable models, additions of analgesic modes were associated with stepwise positive effects: total hip arthroplasty patients receiving more than 2 modes (compared to "opioids only") experienced 19% fewer respiratory (odds ratio, 0.81; 95% CI, 0.70 to 0.94; unadjusted 1.0% [N = 1,513] vs. 2.0% [N = 1,546]), 26% fewer gastrointestinal (odds ratio, 0.74; 95% CI, 0.65 to 0.84; unadjusted 1.5% [N = 2,234] vs. 2.5% [N = 1,984]) complications, up to a -18.5% decrease in opioid prescription (95% CI, -19.7% to -17.2%; 205 vs. 300 overall median oral morphine equivalents), and a -12.1% decrease (95% CI, -12.8% to 11.5%; 2 vs. 3 median days) in length of stay (all P < 0.05). Total knee arthroplasty analyses showed similar patterns. Nonsteroidal antiinflammatory drugs and cyclooxygenase-2 inhibitors seemed to be the most effective modalities used. CONCLUSIONS: While the optimal multimodal regimen is still not known, the authors' findings encourage the combined use of multiple modalities in perioperative analgesic protocols. PMID- 29498952 TI - Risk Factors Linking Esophageal Squamous Cell Carcinoma With Head and Neck Cancer or Gastric Cancer. AB - GOALS: To investigate retrospectively the risk factors for synchronous and metachronous cancers in the upper gastrointestinal tract in patients with superficial esophageal squamous cell carcinoma (ESCC). BACKGROUND: In patients who have received endoscopic resection (ER) for ESCC, synchronous and metachronous cancers are frequently detected not only in the esophagus but also in the head and neck area and the stomach. STUDY: A total of 285 patients who received ER for superficial ESCC were enrolled in this analysis. These patients were periodically followed-up endoscopically. Cumulative occurrence rates of the metachronous second primary cancers were determined by Kaplan-Meier method. Risk factors for synchronous and metachronous cancers in the head and neck area and the stomach were determined by logistic regression analyses. RESULTS: During a mean follow-up period of 76 months, the 5-year cumulative occurrence of metachronous esophageal, head and neck, and stomach cancer was 14.0%, 2.8%, and 4.1%, respectively. Although the presence of multiple lugol-voiding lesions in the esophagus was a significant risk factor for synchronous and metachronous head and neck cancers (odds ratio, 3.8; 95% confidence interval, 1.7-9.0), older age (>65 y) was a significant risk factor for synchronous and metachronous gastric cancer (odds ratio, 3.1; 95% confidence interval, 1.2-9.3). CONCLUSIONS: The risk factors for the cooccurrence of head and neck cancer and that of gastric cancer in patients with ESCC differ. This information will likely be useful for managing patients who have been treated with ER for ESCC and who possess carcinogenic potential throughout the upper gastrointestinal tract. PMID- 29498953 TI - A Prospective Study on Cognitive Impairment in Middle-aged Adults With Newly Diagnosed Celiac Disease. AB - AIMS: Our objectives were to: (1) determine whether celiac disease (CD) patients have cognitive impairment at diagnosis; and (2) compare their cognitive performance with nonceliac subjects who have similar chronic symptoms and healthy controls. MATERIALS AND METHODS: Fifty adults (age range: 18 to 50 y) with symptoms and signs compatible with CD were enrolled in a prospective cohort irrespective of the final diagnosis. At baseline, all individuals underwent cognitive functional and psychological evaluation. CD patients were compared with subjects in whom CD was ruled out and with healthy controls matched by sex, age, and years of schooling. RESULTS: Thirty-three subjects (66%) were diagnosed with CD. Compared with the healthy controls (n=26), CD cases and disease controls (n=17; mostly irritable bowel syndrome) had impaired cognitive performance (P=0.02 and P=0.04, respectively), functional impairment (P<0.01), and higher depression (P<0.01). CD patients had similar cognitive performance and anxiety, but nonsignificant lower depression scores compared with disease controls. CONCLUSIONS: Abnormal cognitive functions detected in newly diagnosed CD adult patients seem not to be disease specific. Our results suggest that cognitive dysfunction could be related to the presence of prolonged symptoms due to a chronic disease. PMID- 29498955 TI - The Future of Psychotherapy in Turkey: Predictions for the Next 10 Years. AB - Making realistic predictions about the future is important in clinical psychology as in many other disciplines. This opinion survey aimed to examine clinical psychologists' predictions for the next 10 years regarding the status of psychotherapy in Turkey in two stages, with 107 participants in one and 69 in the other. The results revealed that the techniques predicted to increase the most in the next decade were the use of eclectic therapy, mindfulness therapy, solution focused therapy, system/family approaches, and cognitive-behavioral therapy. Among the therapeutic interventions expected to increase in popularity were Internet-based programs, smartphone applications, and problem solving. In terms of type of psychotherapists, family counselors with certificate/graduate degrees and Internet-based treatment programs were expected to become more common, whereas it was considered that shorter treatment formats and crisis intervention approaches would be preferred. In sum, the present findings provide a current overview for Turkey and a comparison with other literature findings. PMID- 29498954 TI - A Retrospective Estimate of Ear Disease Detection Using the "Red Flags" in a Clinical Sample. AB - OBJECTIVES: The purpose of this study was to evaluate the specificity and sensitivity of two red flag protocols in detecting ear diseases associated with changes in hearing. DESIGN: The presence of red-flag symptoms was determined in a chart review of 307 adult patients from the Mayo Clinic Florida Departments of Otorhinolaryngology and Audiology. Participants formed a convenience sample recruited for a separate study. Neurotologist diagnosis was the criterion for comparisons. RESULTS: Of the 251 patient files retained for analysis, 191 had one or more targeted diseases and 60 had age- or noise-related hearing loss. Food and Drug Administration red flags sensitivity was 91% (confidence interval [CI], 86 to 95%) and specificity was 72% (CI, 59 to 83%). American Academy of Otolaryngology-Head and Neck Surgery red flags sensitivity was 98% (CI, 95 to 99%) and specificity was 20% (CI, 11 to 32%). CONCLUSIONS: Stakeholders must determine which diseases are meaningful contraindications for hearing aid use and whether these red-flag protocols have acceptable levels of sensitivity and specificity. As direct-to-consumer models of hearing devices increase, a disease detection method that does not require provider intercession would be useful. PMID- 29498956 TI - When a Child Unexpectedly Draws a Violent Scene. AB - CASE: Carter is a 12-year-old boy who has been seeing a developmental-behavioral pediatrician since the age of 7 years for problems with behavioral regulation. Around that time, he began to receive special education services after an educational assessment of autism. He has average intellectual abilities, with below-average semantic-pragmatic speech (e.g., conversations are one-sided). His medical diagnoses included attention-deficit hyperactivity disorder (ADHD), combined presentation, and generalized anxiety disorder. He has never met the DSM criteria for autistic spectrum disorder (ASD) because although he has atypical sensory behaviors (e.g., preoccupied with sniffing objects), he has otherwise lacked restricted, repetitive behaviors. Other medical problems include obesity.His functional impairments associated with impulsivity, inattention, and anxiety improved with combined pharmacotherapy (a long-acting stimulant and a selective serotonin reuptake inhibitor [SSRI], on which he remains) and cognitive behavioral therapy (CBT). After starting sixth grade, his Individualized Educational Plan (IEP) was modified to address his social impairments, with a self-contained classroom without windows. Soon thereafter, he began to talk about "hating myself" and developed mild-to-moderate depression, which improved after several weeks of a higher dose of SSRI and more frequent visits with his therapist.Several weeks after starting seventh grade, the teacher sent an email to Carter's parents, which they forwarded to his developmental-behavioral pediatrician: "Carter drew a picture of himself shooting and stabbing a student he was mad at today (). He was very upset when I told him I was going to tell you. We haven't processed it through yet but I think a conversation at home about appropriate drawings and using other ways to calm down would help this not happen again." PMID- 29498958 TI - Percutaneous Pedicle Screw Stabilization: Surgical Technique, Fracture Reduction, and Review of Current Spine Trauma Applications. AB - Percutaneous pedicle screw fixation has evolved as a useful tool in the management of spinal trauma. As a minimally invasive approach, it provides the stability of open instrumentation while limiting blood loss, avoiding excessive muscle/soft-tissue insult, and improving postoperative pain and mobilization. Muscle-dilating techniques also preserve greater paraspinal muscle volume and strength compared with open midline approaches. In patients with spinal trauma, the use of percutaneous instrumentation and indirect reduction can theoretically preserve the fracture hematoma and its osteogenic inflammatory factors. The evolution of spinal instrumentation and the refinement of indirect reduction techniques has improved the capacity for correction of traumatic deformity. Although perioperative and short-term results have been well described, few long term outcomes data exist. PMID- 29498957 TI - Public Health Opportunities to Improve Late-Adolescent Immunization. AB - Seven state/local immunization program managers were convened to discuss how public health immunization programs could enhance their efforts to promote adolescent vaccination, with an emphasis on late adolescence (ages 16-18 years). The Centers for Disease Control and Prevention's revised childhood immunization schedule for 2017 and a recently proposed preventive care platform at 16 years of age provide a unique opportunity to focus on increasing adolescent immunization rates in this population. Public health officials discussed challenges to immunizing this population and suggested key strategies for supporting late adolescent immunization, including partnerships between public health and immunization providers; nationally supported public information campaigns; and using immunization data specific to this population to track progress. PMID- 29498959 TI - Surgical Procedures for Chronic Lateral Ankle Instability. AB - Surgical procedures for managing chronic lateral ankle instability include anatomic direct repair, anatomic reconstruction with an autograft or allograft, and arthroscopic repair. Open direct repair is commonly used for patients with sufficient ligament quality. Reconstruction incorporating either an autograft or an allograft is another promising option in the short term, although the longevity of this procedure remains unclear. Use of an allograft avoids donor site morbidity, but it comes with inherent risks. Arthroscopic repair of chronic lateral ankle instability can provide good to excellent short- and long-term clinical outcomes, but the evidence supporting this technique is limited. Deterioration of the ankle joint after surgery is also a concern. Studies are needed on not only treating ligament insufficiency but also on reducing the risk of ankle joint deterioration. PMID- 29498960 TI - Linking the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT) to the International Classification of Function. AB - PURPOSE: The purpose of the current study was to examine how comprehensively the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT) addresses Activity and Participation components of the International Classification of Functioning, Disability, and Health (ICF). METHODS: Two raters individually linked the 276 items of the PEDI-CAT to the ICF using ICF linking rules, the PEDI-CAT manual, and the ICF browser. Agreement between reviewers was evaluated, and reliability of the linking process was assessed using Cohen's kappa. RESULTS: All 9 chapters of Activity and Participation were represented within the PEDI-CAT. The highest frequency of representation was in Mobility (43%) and Self-care (20%) chapters. Agreement between the 2 raters was strong (kappa = 0.84). Two items were not definable in the ICF, and 3 linked to Body Function codes. CONCLUSIONS: The PEDI-CAT was strongly representative of the Activities and Participation component of the ICF. The linking process had substantial reliability. PMID- 29498961 TI - Short-Term Recovery of Balance Control: Association With Chemotherapy-Induced Peripheral Neuropathy in Pediatric Oncology. AB - PURPOSE: To describe the incidence and short-term recovery of balance control in children and adolescents receiving neurotoxic treatment for noncentral nervous system cancers and to investigate the association of chemotherapy-induced peripheral neuropathy and balance control. METHODS: Sixty-five children and adolescents diagnosed with leukemia, lymphoma, or other solid tumors were tested 3 to 6 months into treatment and 3 and 6 months following treatment using the Bruininks-Oseretsky Balance Subscale and Pediatric Modified Total Neuropathy Scale scores of chemotherapy-induced peripheral neuropathy (CIPN). RESULTS: Seventy-eight percent of the participants scored 1 standard deviation or more below population means on the balance subscale while on treatment, and this improved to 53% by 6 months posttreatment, with the leukemia group performing worse at both time points. On-treatment balance scores were moderately associated with motor CIPN, while at 6 months posttreatment they were more closely associated with sensory CIPN. CONCLUSIONS: Mild to moderate balance impairments improve but can persist, even when CIPN has improved, 6 months after treatment for childhood cancer. PMID- 29498962 TI - PREVALENCE OF POTENTIAL HYBRID AND CONVENTIONAL COCHLEAR IMPLANT CANDIDATES BASED ON AUDIOMETRIC PROFILE. PMID- 29498963 TI - Metastatic Renal Cell Carcinoma Presenting as a Cerebellopontine Angle and Internal Auditory Canal Mass. PMID- 29498964 TI - Structural Analysis of Tensor Tympani Muscle, Tympanic Diaphragm, Epitympanum, and Protympanum in Meniere's Disease: a Human Temporal Bone Study. AB - HYPOTHESIS: We hypothesized that there would be significant anatomic differences of the tensor tympani muscle (TTM), tympanic diaphragm, epitympanum, and protympanum in patients with versus without Meniere's disease. BACKGROUND: The effects of tenotomy on Meniere's disease suggested it relieves the pressure on the inner ear of the contraction of the TTM and of negative middle ear pressure. METHODS: Using human temporal bones from patients with Meniere's disease, two studies were conducted. We examined the presence of otitis media, cholesteatoma, and endolymphatic hydrops, the length, diameter, configuration, the volume of the TTM and tendon, and the area of the tympanic isthmus (Study 1). We examined the presence of otitis media, cholesteatoma and endolymphatic hydrops, and the area and volume of the protympanum (Study 2). RESULTS: In study 1, we observed no significant differences between the two groups. In study 2, we did not observe a small and narrow protympanum in the Meniere's disease group. None of the ears in the Meniere's or control groups had otitis media or cholesteatoma in either study. We observed hydrops in all the temporal bones of the Meniere's disease group and none in the control groups. CONCLUSION: The position, configuration, and size of the tensor tympani muscle and tendon do not seem to play a role in the pathogenesis of Meniere's disease. Because the tympanic isthmus and protympanum in Meniere's disease are not smaller than controls and that none of the temporal bones had otitis media or cholesteatoma, it is unlikely that there was dysventilation in the middle ear. PMID- 29498965 TI - Electrocochleography Results in Patients With Bilateral Vestibular Paresis and Sound- or Pressure-Induced Horizontal Nystagmus. AB - OBJECTIVE: To describe the electrocochleography (ECochG) findings in patients with bilateral vestibular paresis and sound- and/or pressure-induced horizontal nystagmus. DESIGN: Retrospective case series. SETTING: Tertiary care center. PATIENTS: Three adult patients with bilateral vestibular paresis and sound- and/or pressure-induced horizontal nystagmus were evaluated from 2012 to 2016. MAIN OUTCOME MEASURE: All patients underwent ECochG, vestibular evoked myogenic potential (VEMP) testing, bithermal caloric testing, rotary chair testing, audiometric testing, and temporal bone computed tomography (CT). For ECochG, the summating potential (SP) to action potential (AP) ratio was determined. RESULTS: All patients had normal temporal bone CT, reduced caloric responses bilaterally, decreased gain on rotary chair, and abnormal ECochG. For two subjects, the SP/AP was elevated bilaterally. One subject had unilateral SP/AP elevation. Cervical VEMPs were present in all subjects, but at reduced thresholds in two subjects. CONCLUSION: SP/AP elevation was found in all three patients with the syndrome of bilateral vestibular paresis and/or sound- or pressure-induced horizontal nystagmus. As the etiology of this syndrome remains unclear, understanding the basis for abnormal ECochG may shed insight into the pathophysiology of this condition. PMID- 29498967 TI - Does Nonmetropolitan Residence Impact Timely Chlamydia Treatment in Massachusetts? AB - A mean of 4.5 days until treatment was documented in a subset of reported laboratory-confirmed Massachusetts chlamydia cases selected for active case report form completion. Treatment delay was associated with longer test result turnaround time, and absence of symptoms or contact to sexually transmitted disease. Nonmetropolitan versus metropolitan residence did not appear to impact treatment time. PMID- 29498966 TI - Early Detection of Pancreatic Cancer: The Role of Depression and Anxiety as a Precursor for Disease. PMID- 29498968 TI - Descemet Membrane Endothelial Keratoplasty Learning Curve for Graft Preparation in an Eye Bank Using 645 Donor Corneas. AB - PURPOSE: To investigate the learning curve of Descemet membrane endothelial keratoplasty (DMEK) graft preparation in an eye bank. METHODS: Four operators prepared 645 DMEK grafts using the stripping technique between 2014 and 2017 at the Veneto Eye Bank Foundation, Italy. Endothelial cell loss (ECL) and tissue wastage were recorded retrospectively after DMEK preparation and correlated with the number of tissues prepared each year by each operator. On average, our operators performed 1 donor preparation a week over the course of this study. Only donors older than 60 years were used in this study, and approximately 10% of donors had diabetes. The Wilcoxon test for paired data and 1-way ANOVA were used for checking statistical significance with the Tukey test as post hoc analysis. P < 0.05 was considered statistically significant. RESULTS: ECL did not change significantly over time from operator 1. Significant ECL drop was noted from operator 2 between years 2014-2016 (P = 0.0049) and 2017 (P = 0.0094); from operator 3 between years 2015-2016 (P = 0.0288) and 2017 (P = 0.0097); and from operator 4 between 2015-2016 (P = 0.0469) and 2017 (P = 0.0331). Operators 1 and 3 did not show a significant difference, considering every 50 grafts prepared by each operator. Operator 2 showed significant ECL drop between 1 to 50 and 51 to 100 (P = 0.0002) and 1 to 50 and 101 to 150 (P = 0.0001) grafts. Operator 4 showed significant ECL drop between 1 to 50 and 101 to 150 (P = 0.002) and 51 to 100 and 101 to 141 (P = 0.0207) grafts. No intraoperator difference was observed per 50 grafts (P > 0.05). CONCLUSIONS: There is a learning curve for DMEK graft preparation. ECL and tissue wastage can be reduced with practice and skills. However, each operator may be limited to his or her own learning capability. PMID- 29498969 TI - Surgical Management and Evaluation of the Craniofacial Growth and Morphology in Cleidocranial Dysplasia. AB - Cleidocranial dysplasia (CCD, MIM 119600) is a rare autosomal dominant disorder affecting bone, cartilage, craniofacial growth, and tooth formation leading to supernumerary teeth. Few reports delineate the genotype-phenotype correlations related to the variations in craniofacial morphology and patterning of the dentition and the complexity of treating patient's malocclusion. Successful management of the craniofacial deformities in patients with CCD requires a multidisciplinary team of healthcare specialists. Approximately 70% of patients are due to point mutations in RUNX2 and <20% due to copy number variations with the remainder unidentified. There is no literature to date, describing the orthognathic management of CCD patients with deletion in one of the RUNX2 alleles. The purpose of this study was to evaluate the craniofacial morphology and dental patterning in a 14-year-old Caucasian female with CCD resulting from a novel microdeletion of RUNX2 in 1 allele. The CCD patient with RUNX2 haploinsufficiency due to microdeletion had decreased craniofacial bone and ankyloses in the permanent dentition. An altered extraction protocol of supernumerary teeth was followed in this patient. Craniofacial growth and morphologic analysis demonstrated atypical skull shape, persistent metopic suture, and decreased mandibular size. PMID- 29498970 TI - Influence of Backscatter Radiation on Cranial Bone Fixation Devices. AB - Postoperative radiation can cause ulcer formation, leading to the denudation of skin over alloplastic materials. The influence of backscatter radiation from fixation devices has not been investigated. The aim of this study is to evaluate backscatter dose variations for different cranial bone fixation devices in an experimental model designed to simulate postoperative radiotherapy. The authors assessed the radiation backscatter doses associated with resorbable (PLLA-PGA) and titanium plates. The samples were irradiated with 6 and 10 MV photon beams from a linear accelerator. Measurements were obtained using an ionization chamber and radiochromic films cut from the same batch. As a result, the backscatter radiation of water and PLLA-PGA proportionally decreased as the depth increased. However, the backscatter radiation of the titanium plate increased just above the plate. This depth lies in the region of the scalp. Each material showed a dose of radioactivity that was higher at 10 MV than that at 6 MV. These devices showed a significant difference, which suggested that these materials amplified the dose compared with water at 6 MV. In conclusion, it is supposed that PLLA-PGA should be used to fix the cranium to decrease the potential for radiation ulcers. PMID- 29498971 TI - Perforating Brain Injury By a Rusty Steel Bar. AB - A perforating head injury is a type of an injury wherein the projectile passes entirely through the cranium leaving both entrance and exit wounds. It is considered less prevalent than other kinds of head trauma such as closed or penetrating head injuries carry a worse prognosis among other varieties of head injuries. Having unique mechanism and pathophysiology it is considered a significant challenge for the practicing neurosurgeon mandating high precaution and novel approach to minimize further damage. Here, we presented a case of a 5 year-old boy who suffered from perforating brain injury by a fallen rusty steel bar. PMID- 29498972 TI - Comparing the Efficacy of Peritonsillar Injection of Tramadol With Honey in Controlling Post-Tonsillectomy Pain in Adults. AB - INTRODUCTION: The authors investigated the effect of honey on post-tonsillectomy pain and compare its efficacy with tramadol. METHODS: This clinical trial was performed on 60 patients with American Society of Anesthesia I and II aged between 18 and 55 years and underwent tonsillectomy. Induction of anesthesia was carried out using 2 mg/kg propofol and 0.5 atracurium following 1.5 MUg/kg fentanyl administration. Group B was given tramadol at dose of 2 mg/kg and with volume of 4 mL and Group A was given normal saline with the same volume 2 mL of medications were injected using needle (25) into tonsil bed and anterior old of each tonsil by an anesthesiologist. Three minutes after injection, the surgery was performed by the same ENT residents for all patients. In the recovery room Group B received antibiotics and oral acetaminophen. Group A was given antibiotics, oral acetaminophen, and honey dissolved in 40 mL warm water every 6 hours from when the patient was fully awake. Patients in Group A were told to eat honey 3 times a day 7 days postoperatively. Pain was scored using Numeric Rating Scale at the time points of 2, 6, 12, and 24 hours as well as 3 and 7 days postoperatively. Moreover, the healing status and epithelialization degree of tonsillar bed were considered on 1 and 7 days after the surgery by ENT specialist. RESULTS: The mean of pain score was significantly higher in Group A within 24 hours postoperatively as compared with Group B (P < 0.01). The mean of pain score was lower in Group B after 3 and 7 days but this difference was not statistically significant (P > 0.05). Considering restoration status and epithelialization degree of tonsillar bed on the 1st and 7th days, there was no statistically significant difference between 2 groups; however, tonsillar bed healing process was better in Group B on the 7th day. CONCLUSION: The current investigation confirmed the positive impact of tramadol on post-tonsillectomy pain relief in adults. The authors also found that honey can be used as a complementary treatment along with acetaminophen and other analgesics for reducing post-tonsillectomy pain. Considering honey impact on wound healing and its anti-inflammatory effect, it is suggested for relieving complications after surgery. PMID- 29498973 TI - The Specific Morphological Features of Alveolar Bone. AB - OBJECTIVE: The aim of the study was to study the specific morphological features of alveolar bone and compare it to femoral bone in rats. METHODS: Twelve 3-month old nonpregnant female Sprague-Dawley rats were used in the present study. The left maxillae and femurs of 6 rats were used for micro-computed tomography (micro CT) scanning. The trabecular bone of the distal femur and the interradicular alveolar bone of the maxillary first molar were reconstructed and analyzed. Another 6 rats were used for histological analysis of trabecular bone and alveolar bone. RESULTS: Micro-CT analysis suggested that the femoral trabecular bone was porous with rod-like trabeculae with a scattered distribution in bone marrow, whereas alveolar bone showed a compact structure with plate-like trabeculae and limited bone marrow. Tissue mineral density, bone mineral density, bone volume fraction, and trabecular thickness were dramatically higher in the alveolar bone compared with that in the trabecular bone. Alveolar bone displayed lower trabecular number and trabecular separation. Histomorphometric analysis showed that alveolar bone was formed of compact bone with wide trabeculae, whereas femurs were composed of loose bone with finer trabeculae. CONCLUSIONS: In comparison to the spongiosa of the distal femur, alveolar bone displays specific morphological features with compact, wide, and highly mineralized trabeculae. PMID- 29498974 TI - Successful Strategies for Dealing With Infected, Custom-Made Hydroxyapatite Cranioplasty. AB - When a cranioplasty implant becomes infected, standard operating procedure dictates its removal and the initiation of a long course of antibiotic therapy. However, removing such a prosthesis can have a series of adverse consequences, including delayed cognitive and motor recovery, lack of brain tissue protection, unsightly deformity, and the need for two additional surgical procedures, not to mention the additional costs involved. To maintain the advantages of cranioplasty, we opted for a conservative approach (levofloxacin and rifampicin every 24 hours for 8 weeks) in a 68-year-old woman whose custom-made porous hydroxyapatite implant, fitted following aneurysm clipping, had become infected. The tissues overlying the implant were curettaged, and the patient's clinical condition, blood markers, and infection course were continuously monitored (local monitoring was performed by single-photon emission computed tomography [SPECT]/computed tomography [CT after intravenous administration of Tc-labeled antigranulocyte antibody). Blood tests and SPECT/CT evidenced a progressive reduction in phlogosis indices and infection locus, even 1 month after antibiotic therapy was commenced, and at 2 years from cranioplasty, the same tests and clinical examination were negative. At 6-year follow-up, clinical assessment revealed nothing out of the ordinary.Hence, specific cases (hydroxyapatite prosthesis, intact dura, cranial CT and magnetic resonance imaging negative for empyema, well-vascularized scalp, antibiotic-responsive bacteria) of infected cranial implant can be treated using a conservative approach consisting of appropriate antibiotic therapy, accompanied by local debridement where necessary, and assiduous monitoring of phlogosis indices and local verification via labeled leukocyte scintigraphy. Our report, which was compiled after a long-term follow up period, shows that this conservative procedure appears to be a viable option in cases of infected, custom-made hydroxyapatite cranioplasty, provided that some basic rules concerning clinical and instrumental standards are adhered to, as clearly stated in our report. PMID- 29498975 TI - The State of Technology in Craniosynostosis. AB - INTRODUCTION: Craniosynostosis, the premature fusion of >=1 cranial sutures, is the leading cause of pediatric skull deformities, affecting 1 of every 2000 to 2500 live births worldwide. Technologies used for the management of craniofacial conditions, specifically in craniosynostosis, have been advancing dramatically. This article highlights the most recent technological advances in craniosynostosis surgery through a systematic review of the literature. METHODS: A systematic electronic search was performed using the PubMed database. Search terms used were "craniosynostosis" AND "technology" OR "innovation" OR "novel.' Two independent reviewers subsequently reviewed the resultant articles based on strict inclusion and exclusion criteria. Selected manuscripts deemed novel by the senior authors were grouped by procedure categories. RESULTS: Following review of the PubMed database, 28 of 536 articles were retained. Of the 28 articles, 20 articles consisting of 21 technologies were deemed as being novel by the senior authors. The technologies were categorized as diagnostic imaging (n = 6), surgical planning (n = 4), cranial vault evaluation (n = 4), machine learning (n = 3), ultrasound pinning (n = 3), and near-infrared spectroscopy (n = 1). CONCLUSION: Multiple technological advances have impacted the treatment of craniosynostosis. These innovations include improvement in diagnosis and objective measurement of craniosynostosis, preoperative planning, intraoperative procedures, communication between both surgeons and patients, and surgical education. PMID- 29498976 TI - Ruptured Pseudoaneurysm of the Maxillary Artery and Its Branches Following Le Fort I Osteotomy: Evidence-Based Guidelines. AB - BACKGROUND: Although rare, pseudoaneurysms (PA) can develop following Le Fort I osteotomy and lead to life-threatening hemorrhage. However, the typical presentation of a PA following a Le Fort I osteotomy is not well characterized. Evidence-based guidelines are not currently available for evaluation of PA following Le Fort I osteotomy. METHODS: A case report is presented of a 27-year old man who underwent Le Fort I advancement and subsequently developed a bleeding PA. A comprehensive search of journal articles was performed using the MEDLINE/PubMed database between 1964 and April 2016. Keywords and phrases used were "(osteotomy OR craniofacial OR orthognathic) AND (pseudoaneurysm OR aneurysm OR epistaxis)." Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) guidelines were followed. RESULTS: The literature search yielded 13 reports of 18 patients. All 18 patients underwent Le Fort I osteotomy and subsequently developed a delayed postoperative bleeding PA. All studies were level IV or V evidence. Twenty-eight percent (N = 5) of the cases documented "excessive" intraoperative bleeding or more than 500 mL of estimated blood loss. The average time for the first bleeding episode and time until final bleed was 17.3 +/- 14.3 days (range: 3-62 days) and 27.8 +/- 21.2 days following surgery (range: 6-77 days), respectively. Sixty-seven percent (N = 12) had multiple episodes of bleeding. The duration between the bleeding events averaged 10.6 (+/- 7.9 days) with a range of 1 to 35 days. Bleeding PA's were treated with image guided embolization (15/18 patients; 83.3%) or ligation or clamping (3/18 patients; 16.7%). CONCLUSION: In the setting of recurrent and/or delayed postoperative epistaxis following Le Fort I osteotomy, surgeons should maintain a high clinical suspicion for PA. Ruptured PA's are often preceded by multiple episodes of progressively worsening epistaxis. Based on the presented case report and pooled data from the literature, angiography is recommended to evaluate for PA in the setting of recurrent epistaxis following Le Fort I osteotomy, especially within the first 4 weeks following surgery. PMID- 29498977 TI - Reconstruction of Thin and Pliable Oral Mucosa After Wide Excision of Oral Cancer Using a Trimmed Anterolateral Thigh Free Flap as an Adipofascial Flap. AB - A 21-year-old female patient underwent wide excision of the buccal mucosa and tongue as well as selective neck dissection due to squamous cell carcinoma on the left side of the tongue. She had a severe limitation in opening her mouth, owing to fibrosis of the mucosa and scar contracture after adjuvant radiation therapy. Reconstruction of the oral mucosa and tongue defect was performed after removal of the scar to improve mouth opening. An anterolateral thigh (ALT) flap was used, trimmed to an adipofascial flap for the reconstruction of the thin and pliable oral mucosa and tongue. The maximum mouth opening improved to 40 mm intraoperatively and was 30 mm after surgery. The adipofascial ALT flap had excellent viability and presented neomucosa after secondary healing. An adipofascial flap obtained by trimming an ALT flap could be a reliable option for the reconstruction of thin and pliable oral mucosa after wide excision of oral cancer. PMID- 29498978 TI - Removal of Maxillary Sinus Antrolith and Concomitant Intrasinus Augmentation. AB - Maxillary sinus antrolithisis is a rare finding. Conservative surgical removal recommended. In the patients that need to maxillary intrasinus augmentation and antrolith is observed in preoperative radiography, 2 options remain. First, doing Caldwell-luc surgery to remove antrolith and delayed open sinus lift. Second way is removing antrolith and concomitant intrasinus augmentation.The first way has 2 disadvantages: prolonged waiting period and difficulty of open sinus lift in sinuses with scar and fibrosis. Coupling these 2 surgeries and using corticocancellous bone block as grafting material are recommended by us. Buccal fat pad is a good option to isolate this graft from maxillary sinus. PMID- 29498979 TI - Review of "The Prevalence of Burnout Among US Neurosurgery Residents" by Shakir HJ, McPheeters MJ, Shallwani H, Pittari JE, Reynolds RM in Neurosurgery [published ahead of print October 27, 2017] doi: 10.1093/neuros/nyx494. PMID- 29498980 TI - Does Pediatric Obstructive Sleep Apnea Syndrome Cause Systemic Microvascular Dysfunction? AB - The aim of this study was to evaluate whether pediatric obstructive sleep apnea syndrome (OSAS) secondary to adenoid hypertrophy causes systemic microvascular dysfunction. This is a prospective single-blinded case-control study. As the patient group, 81 patients diagnosed to have OSAS secondary to adenoid hypertrophy at our hospital between January 2016 and May 2016; as the control group, 26 healthy pediatric volunteers who presented to the hospital for health screening were included in this study. Three groups of OSAS patients were defined as mild, moderate, and severe respectively, according to the lateral nasopharynx x-ray. Patients with comorbid diseases were excluded from the study. For microvascular dysfunction, videocapillaroscopic evaluation was performed at the nailfold and capillary density (CD) and postocclusive reactive hyperemia (PORH) values were measured and statistical analysis between the groups was performed. The duration of complaints in all patients with OSAS was at least 6 months and <1 year. CD measurement in the control group and mild, moderate, and severe OSAS group was 94.1 +/- 7.9, 96.9 +/- 11, 94.7 +/- 8.4, and 93.7 +/- 9.4, respectively, with no significant difference between the groups (P > 0.05). PORH measurement in the control group and mild, moderate, and severe OSAS group was 95.6 +/- 8.6, 97.9 +/- 10.1, 96 +/- 8.7, and 93.9 +/- 9.3, respectively, with no significant difference between the groups (P > 0.05). OSAS secondary to adenoid hypertrophy in pediatric patients was demonstrated to cause no dysfunction in microvascular circulation and carried no cardiovascular risk in the early period. PMID- 29498981 TI - Anatomic Considerations for Temporomandibular Joint Vascularized Composite Allotransplantation. AB - Concomitant temporomandibular joint (TMJ) transplantation is an obvious advancement in the reconstructive armamentarium for face transplantation in scenarios involving TMJ ankylosis. This study investigates the fidelity of mandibular morphology and explores the feasibility of bilateral mandibular condyle transfer in facial vascularized composite allotransplantation. Geometric analysis was performed on 100 skeletally mature maxillofacial computed tomography scans. Exclusion criteria included mandibular trauma and dentoalveolar disease. Parameters measured were posterior height, ramus tilt, anterior height, intercondylar widths, condyle height, coronoid height, interglenoid distances, symphyseal and gonial angles, condyle and glenoid volumes, and condyle shapes. Parameters were compared by gender and ethnicity using chi, independent sample t tests, and one-way ANOVA. Correlation with age was assessed using Pearson correlation coefficients. Bilateral measurements were compared using paired sample t tests. Mean intercondylar width was 102.5 mm (SD 7.0 mm), anterior height 21.5 mm (5.5), and posterior height 65.3 mm (7.7), Males demonstrate larger geometric parameters, for example, intercondylar width (4 mm mean difference, P = 0.005), anterior height (2.3 mm, P = 0.032), posterior height (5 mm, P = 0.001). Asians demonstrated statistically larger intercondylar width (8 mm difference to Caucasians, P < 0.001). Increased age was associated with greater anterior height, gonial angle, and symphyseal angle; decreased glenoid height; and change in condyle shape. Despite significant disparity of laterality measurements within individuals, posterior height, glenoid, and condyle volumes are equivalent. Mandibular morphology is highly variable. However, transplantation of a facial allograft including the mandible and bilateral condyles is technically and anatomically feasible in patients with concomitant TMJ pathology. PMID- 29498982 TI - The Safety and Effectiveness of Abdominal Radical Trachelectomy for Early-Stage Cervical Cancer During Pregnancy. AB - OBJECTIVES: Cervical cancer is one of the most frequently diagnosed cancers in pregnancy. Our aim was to evaluate the safety and efficacy of abdominal radical trachelectomy (ART) for pregnant women with early-stage cervical cancer who strongly desire to preserve their pregnancies. METHODS/MATERIALS: A retrospective observational study was performed for stage IB1 cervical cancer patients who underwent ART or radical hysterectomy (RH) at our hospital between February 2013 and June 2017. We compared differences in perioperative findings and oncologic outcomes among ART during pregnancy (ART-DP), ART, and RH groups. RESULTS: A total of 38 patients were included in this analysis. Six, 10, and 22 patients were assigned to the ART-DP, ART, and RH groups, respectively. There were no significant differences in the distribution of pathological TNM classifications, histology, tumor size, stromal invasion, and lymph-vascular space invasion among the 3 groups. The patients in the ART-DP group were younger than those in the RH group (P = 0.014). The ART-DP group was associated with more blood loss and prolonged surgery compared with the RH group (P = 0.017 and P = 0.014). The number of total lymph nodes in the ART-DP group was lower than that in the RH group (P = 0.036). However, there were no significant differences in age, surgical time, blood loss, or lymph node count between the ART-DP and ART groups. There were no significant differences in progression-free and overall survival times among the 3 groups, and no recurrence was observed in the ART-DP group. CONCLUSIONS: Abdominal radical trachelectomy may be a tolerable treatment option for pregnant women with early-stage cervical cancer who strongly desire a baby. PMID- 29498983 TI - Safety and Efficacy of Extended Bevacizumab Therapy in Elderly (>=70 Years) Versus Younger Patients Treated for Newly Diagnosed Ovarian Cancer in the International ROSiA Study. AB - OBJECTIVE: The single-arm ROSiA study explored an extended duration of frontline bevacizumab-containing therapy for ovarian cancer. Post hoc analyses explored safety and efficacy according to age. PATIENTS AND METHODS: After primary debulking surgery, patients with stage IIB-IV or grade 3 stage I-IIA ovarian cancer received 4-8 cycles of paclitaxel [weekly or every 3 weeks (q3w)], carboplatin AUC 5-6 q3w, and bevacizumab 15 (or 7.5) mg/kg q3w, followed by single-agent bevacizumab until progression or for up to 24 months. The primary end point was safety; progression-free survival (PFS) was a secondary end point. RESULTS: Of 1021 patients treated, 121 (12%) were aged 70 years or older and 44 (4%) were 75 years or older. Compared with younger patients, more patients aged 70 years or older had hypertension at baseline, stage IV disease, and Eastern Cooperative Oncology Group performance status 1 or above. Bevacizumab was continued for more than 15 months in 49% of older versus 53% of younger patients. Older patients experienced higher incidences of all-grade anemia (44% vs 32%), diarrhea (35% vs 25%), and asthenia (22% vs 12%), and grade >=3 hypertension (41% vs 22%) and thromboembolic events (7% vs 2%) compared with younger patients. Fatal bevacizumab-related adverse events occurred in 1 (0.8%) older versus 5 (0.6%) younger patients. Median PFS was 23.7 (95% confidence interval, 18.6-27.9) versus 25.6 (95% confidence interval, 23.7-28.4) months in patients aged 70 or older versus those younger than 70 years, respectively. CONCLUSION: Bevacizumab treated patients aged 70 years or older had higher incidences of anemia, low grade diarrhea, and asthenia, and grade >=3 hypertension and thromboembolic events than those younger than 70 years, but no other relevant increase in toxicity. Median PFS of approximately 2 years is similar to that in younger patients despite the worse prognosis. Older age should not preclude bevacizumab therapy for ovarian cancer in carefully selected patients aged 70 years or older. Given the higher background hypertension prevalence, elderly patients should be monitored more closely while receiving bevacizumab. PMID- 29498984 TI - Combination of Scoring Criteria and Whole Exome Sequencing Analysis of Synchronous Endometrial and Ovarian Carcinomas. AB - OBJECTIVES: The purpose of this study was to distinguish synchronous primary endometrial and ovarian carcinomas from single primary tumor with metastasis by clinical pathologic criteria and whole exome sequencing (WES). MATERIAL AND METHODS: Fifty-two patients with synchronous endometrial and ovarian carcinomas (SEOCs) between 2010 and 2017 were reviewed and subjected to WES. RESULTS: On the basis of the Scully criteria, 11 cases were supposed as synchronous primary endometrial and ovarian carcinomas, 38 cases as single primary tumor with metastasis, and the remaining 3 cases (S50-S52) cannot be defined. Through a quantization scoring analysis, 9 cases that were scored 0-1 point were defined as synchronous primary endometrial and ovarian carcinomas, and 42 cases that were scored 3-8 points were defined as single primary tumor with metastasis. Two of the undefined cases were classified into metastatic disease, and another one that scored 2 points (S52) was subjected to WES. S52 was deemed synchronous primary endometrial and ovarian carcinomas, with few shared somatic mutations and overlapping copy number varieties. The finding of a serous component examined from the uterine endometrium samples further illustrated that the case was synchronous primary endometrial and ovarian carcinomas. CONCLUSION: By scoring criterion, SEOCs were divided into 2 groups: synchronous primary endometrial and ovarian carcinoma group and single primary tumor with metastasis group. The analysis of clonality indicated that the case that scored 2 (S52) can be considered as synchronous primary endometrial and ovarian carcinomas. Scoring criteria of clinical pathology, along with the study of the WES, may further identify the classification of SEOCs. PMID- 29498985 TI - The Caregiver Advise, Record, Enable (CARE) Act. PMID- 29498987 TI - Dry Eye Disease: Prevalence, Assessment, and Management. AB - Dry eye disease is a chronic condition of the corneal surface marked by persistent symptoms of irritation or burning that can cause inflammatory damage to the cornea and conjunctiva if untreated. Common risk factors for this syndrome include advancing age, female sex, low humidity environments, systemic medications, and autoimmune disorders. Treatments to relieve symptoms include tear replacement, humidification, improved nutrition, and anti-inflammatory ocular agents. Home healthcare nurses can identify signs and symptoms of dry eye syndrome and initiate strategies that range from warm compresses to physician referrals for more aggressive treatment. Consistent management of this condition improves quality of life and minimizes damage to the ocular surface. PMID- 29498988 TI - Development of a Home Health-Based Palliative Care Program for Patients With Heart Failure. AB - Heart failure is a significant burden to the healthcare system. Approximately 5.7 million adults in the United States were diagnosed with heart failure between 2009 and 2012 (). The American Heart Association projects that direct costs for heart failure may be as high as $77.7 billion by 2030 (). Technological and pharmaceutical advancements have delayed the progression of the disease; however, it is predicted that close to half of individuals with heart failure will die within 5 years of the initial diagnosis (; ). Current research suggests that the utilization of palliative care and an interdisciplinary team approach to the care of patients with heart failure improves the quality of life and decreases utilization of healthcare resources at the end of life (). This performance improvement project examined the knowledge of a home healthcare interdisciplinary team's knowledge about palliative care in patients with heart failure, the 30-day readmission rate for patients enrolled in a home-based palliative care program, and documentation of advanced directives in a home healthcare organization. PMID- 29498989 TI - Establishing Relationships and Navigating Boundaries When Caring for Children With Medical Complexity at Home. AB - Children with medical complexity receive care from many healthcare providers including home healthcare nurses. The objective of our study, based on a conceptual framework, was to describe the relationships between parents/caregivers of children with medical complexity and home healthcare nurses caring for these children. We collected qualitative data in 20 semistructured in depth interviews (15 English, 5 Spanish) with 26 primary caregivers of children with medical complexity, and 4 focus groups of 18 home healthcare nurses inquiring about their experiences about home healthcare nursing services for children with medical complexity. During an iterative analysis process, we identified recurrent themes related to caregiver-nurse relationships. Our study showed that: (1) caregiver-nurse relationships evolved over time and were determined by multiple factors; (2) communication and trust were essential to the establishment of caregiver-nurse relationships; (3) both caregivers and nurses described difficulties of navigating physical, professional, personal, and emotional boundaries, and identified strategies to maintain these boundaries; and (4) good caregiver-nurse relationships helped in the care of children with medical complexity, reduced caregiver burden, resulted in less stress for nurses, and was a factor in nurse retention. We conclude that trusted relationships between caregivers and nurses are important to the home care of children with medical complexity. Interventions to develop and maintain good caregiver-nurse relationships are necessary. PMID- 29498990 TI - Musculoskeletal Pain and Interest in Meditation and Yoga in Home Health Aides: Evidence From the Home Health Occupations Musculoskeletal Examinations (HHOME) Study. AB - Home healthcare aides (HHAs) are a growing U.S. workforce highly susceptible to workplace stressors and musculoskeletal pain. In the present study we: 1) examine the association of musculoskeletal pain to life satisfaction and emotional exhaustion; and 2) characterize interest in meditation and yoga in a sample of HHAs. A nonprobabilistic sample of HHAs employed at home healthcare agencies in Florida, Massachusetts, and Oregon (n = 285 total) completed a self-administered questionnaire with standard survey measures on musculoskeletal pain location, duration, and severity; life satisfaction; emotional exhaustion; and interest in meditation techniques and yoga. Among HHAs responding, 48.4% reported pain in the last 7 days and 46.6% reported pain in the last 3 months. Home healthcare aides who reported current pain and chronic pain had a significant (P < .05) decrease in satisfaction with life score and a significant increase in emotional exhaustion score. The majority of HHAs reported an interest in learning about the benefits (65.6%) and practice (66.4%) of meditation and a willingness to participate in a yoga class (59.2%) or stress management meeting (59.1%). The HHAs reported both acute and chronic musculoskeletal pain that was correlated with lower life satisfaction and greater emotional exhaustion. More efforts are needed to reduce the sources of injury and emotional exhaustion. PMID- 29498991 TI - Online Resources to Support Clinical Practice. AB - Evidence-based practice requires access to practice guidelines, research articles, and other resources; however, home healthcare clinicians can face barriers when seeking health information. The purpose of this article is to provide home care clinicians with: a) free resources available on the internet, b) suggestions for searching and evaluating health information found on the internet, and c) opportunities for free continuing education for home healthcare clinicians. PMID- 29498992 TI - Improving Patient Outcomes. PMID- 29498993 TI - Reminiscence. PMID- 29498994 TI - Blood Pressure Considerations for Therapists in Home Healthcare. PMID- 29498995 TI - "Use as Directed" Can Cause Confusion for Both Patients and Practitioners. PMID- 29498997 TI - Trust (Your Employees), but Verify (What They Are Doing) and Keep the Verification. PMID- 29498996 TI - International Home Care Nurses Organization (IHCNO) Webinar. PMID- 29498998 TI - A Day in the Life of a Bereavement Camp Volunteer. PMID- 29498999 TI - Understanding the Needs of Transgender Patients. PMID- 29499000 TI - Embrace OASIS: The Tool That Brings Quality Care to Your Patient Programs. PMID- 29499001 TI - Dry Eye Disease: Prevalence, Assessment, and Management. PMID- 29499002 TI - Health for the Healer: Keeping Work-Life Balance in Rehabilitation Nursing. PMID- 29499003 TI - The Impact of Stroke Nurse Navigation on Patient Compliance Postdischarge. AB - PURPOSE: The purpose of this study was to describe the impact a stroke nurse navigation program has on concurrent chart reviews and patient compliance postdischarge. DESIGN: Phase I: Concurrent chart review of The Joint Commission Primary Stroke Center core measures for ischemic stroke patients. Phase II: Longitudinal study of 100 ischemic stroke patients discharged to home. METHODS: Telephone surveys were conducted at prescribed intervals posthospital discharge (Phase II). Surveys focused on medication compliance, follow-up medical appointment compliance, and neurovascular emergency department (ED) visits/readmissions. FINDINGS: Phase I trends included increased stroke performance measures compliance. Phase II favorable trends included increased medication compliance (>98%), increased follow-up appointments (100%), decreased rate of neurovascular ED visits/rehospitalizations (3%), and improvement in activities of daily living and quality of life measures through 12 months postdischarge. CONCLUSIONS: Stroke nurse navigation increased conformity of stroke performance measures and stroke patient discharge compliance through 12 months postdischarge. PMID- 29499004 TI - Trauma-Informed Care Is the Best Clinical Practice in Rehabilitation Nursing. AB - PURPOSE: This clinical article explores how trauma-informed care (TIC) can be used by rehabilitation nurses with patients who have experienced pervasive adverse childhood experiences (ACEs). METHOD (INTERVENTION STRATEGIES): This clinical article gives suggestions for using the five guiding principles of TIC: safety, trustworthiness, choice, collaboration, and empowerment, as the best clinical practice. CONCLUSION: Implementing TIC promotes successful rehabilitation, improves patient outcomes, and reduces costs. For every $1 spent on TIC, $5 is saved in lifetime costs. CLINICAL RELEVANCE: ACEs cause physiological changes in the brain, leading to antisocial and risky behaviors, which may result in head injuries, spinal cord injuries, amputations, and multiple traumas with subsequent rehabilitation admissions, as well as obesity, and chronic illnesses. TIC is a cultural shift: We as providers must ask ourselves "What happened to this person?" instead of "What is wrong with this person?" Nurses are beginning to develop our literature and practice of TIC. PMID- 29499005 TI - Inactivity and Its Associated Factors in Adults Scheduled for Noncardiac Surgery: The PAMP Phase I Study. AB - PURPOSE: The aim of this study was to determine the prevalence of physical inactivity and its associated factors in adult patients admitted to hospital for noncardiac surgery. DESIGN: Cross-sectional study. METHODS: Five hundred able bodied patients (age >=45 years) admitted to hospital, also participants in the VISION study, were recruited before noncardiac surgery. The physical activity level (PAL) was assessed with the International Physical of Activity Questionnaire. Logistic regression analysis was conducted to determine the associations between a number of predetermined factors and physical inactivity. FINDINGS: Overall, 59.8% were inactive. Factors associated with inactivity included age, assistance with activities of daily living, and insulin-dependent diabetes. CONCLUSION: A substantial number of patients scheduled for noncardiac surgery are inactive. Elderly patients, those needing assistance, and those with long-lasting diabetes may benefit from PAL assessment before surgery. CLINICAL RELEVANCE: Healthcare providers should identify PALs and monitor for known risk factors to prepare patients for surgical procedures. PMID- 29499006 TI - Evaluation of Functional Status Associated With Overweight in Adults With Cerebral Palsy. AB - PURPOSE: The aim of this study was to describe the motor disability level of ambulatory adults with overweight and cerebral palsy (CP) and to investigate the functional factors associated with weight gain in this population. DESIGN: Cross sectional study. METHODS: Thirty adults with CP were classified according to their body mass index (BMI). Mobility, physical disability, functional independence, gait and balance, gross motor function, and maximum walking speed were assessed to evaluate their physical status. The influence of demographic and functional factors on BMI was analyzed using bivariate and multivariate regression analyses. FINDINGS: Multiple regression analyses showed that age (p = .012) and lower cardiorespiratory function/lower walking distance (p = .048) were significantly associated with higher BMI. Other functional outcomes were not associated with BMI. CONCLUSIONS: Greater age and reduced walking distance related to cardiorespiratory function seem to be the main factors associated with BMI. CLINICAL RELEVANCE: Cardiorespiratory rehabilitation is recommended in conjunction with nutritional nursing interventions. PMID- 29499007 TI - The Effectiveness of Discharge Training for Patients After Cardiac Surgery. AB - PURPOSE: The aim of this study was to evaluate the effectiveness of written and verbal discharge training given to patients who underwent cardiac surgery. DESIGN AND METHODS: It was conducted on 180 patients between November 2011 and June 2012. The patients were divided into two groups. The first 90 patients were given verbal discharge training, whereas the others were provided with both written and verbal trainings. Using pretest and posttest questionnaires, knowledge levels of the patients were evaluated before training and 1 month after discharge. Patients given verbal discharge training had a success rate of 10.2% pretest, 48.1% posttest, whereas the success rate of patients who received both written and verbal discharge training was 6.35% pretest, 90.7% posttest. FINDINGS: The findings show that both written and verbal discharge training increased the knowledge levels. CONCLUSION AND CLINICAL RELEVANCE: The findings imply that written-verbal discharge training may help patients to solve the problems after discharge, which may reduce the number of patients presenting at hospital and, in turn, related healthcare costs. PMID- 29499008 TI - Evaluation of an Exercise Program for Older Adults in a Residential Environment. AB - PURPOSE: The aim of this study was to examine the effectiveness of an older adult exercise program in a senior-living complex campus. DESIGN: A longitudinal one group design was used. METHODS: To supply residents with tools to maintain or improve general quality of life, balance, endurance, depression, and functional mobility, the Wellness and Fitness Center at the research setting provided a wide assortment of user-friendly equipment with many options. One fitness director in the selected setting evaluated participants every 6 months with 33 participants using the Senior Fitness Test (SFT). FINDINGS: Repeated ANOVAs identified factors impacting the effects of the exercise program using PROC MIXED SAS 9.0. The improvement or deterioration rate of SFT scores was tested as a time effect in balance, upper body strength, and lower body flexibility. A statistically significant gender effect emerged on the 6-minute walk, which measured aerobic endurance and the chair sit-and-reach test, which measured lower body flexibility. CONCLUSIONS: The 8-foot up-and-go, arm curl, chair stand, and chair sit-and-reach tests showed statistically significant improvement over time, which means balance, upper body strength, lower body strength, and lower body flexibility improved. CLINICAL RELEVANCE: Developing customized exercise protocols and using standardized measurement tools should be encouraged to enhance effective research and consistent measurement of exercise programs. PMID- 29499009 TI - Improving Patient Safety Through Video Monitoring. AB - PURPOSE: Falls are a major safety issue in rehabilitation settings. Patients receive mixed messages-try to be as independent as possible, but don't do anything in your room without calling for assistance. Despite the use of multiple falls interventions at this facility, the fall rate remained high. To impact this rate, the facility implemented a video monitoring system. This system allows for patients at risk for falling to be monitored from a remote location. The monitor technician is able to speak to the patient directly and/or contact staff members to respond to the room, preventing a fall. DESIGN: Sequential cohort design. METHOD: Fifteen video monitoring units were installed on high-risk units in a 115 bed inpatient rehabilitation facility. Total falls and falls rates were tracked and reported pre- and postimplementation. FINDINGS: Over a 21-month period prior to implementing the video monitoring system, the average hospital-wide rate of falls was 6.34 per 1,000 patient-days (SD = 1.7488). After a year of usage, that average has decreased to 5.099 falls per 1,000 patient-days (SD = 1.524). The reduction in falls was statistically significant. In addition, there have been significant cost savings by reducing sitter usage. CONCLUSIONS: Video monitoring can improve patient safety by decreasing falls; decreasing sitter usage and cost; and improving patient, family, and staff satisfaction. CLINICAL RELEVANCE: Falls are a significant issue in rehabilitation settings, and current fall prevention strategies fall short of reducing fall rates. Implementation of new video monitoring technology can help reduce fall rates in inpatient rehabilitation settings. PMID- 29499010 TI - An Interactive System for Fine Motor Rehabilitation. AB - PURPOSE: One of the most important aspects in neuromotor rehabilitation is the need of feedback for patients. The rehabilitation system's efficiency relies on the therapist's judgment; the therapist tells the patient whether he/she is performing the exercises correctly. This process may be quite subjective, because it depends on the therapist's personal opinion. On the other hand, recent studies have shown that vibrotactile biofeedback can improve the effectiveness of interaction as it is a very helpful tool in the physiological process of neuromotor rehabilitation. DESIGN: We designed an interactive system focused on rehabilitation of the upper limbs using active markers and image processing, which consists of drawing activities in both augment and virtual reality. METHODS: The system gives the user a correction through multimodal stimuli feedback (vibrotactile, visual, and sound stimulus) and force measurement to let the patients know if they are not achieving the tasks' goals. FINDINGS: The developed system could be used by nursing assistants to better help patients. The purpose of this system was assisting patients with injuries in shoulders, elbows, or wrists, providing an audio-vibrotactile feedback as a factor of correction in the movements of the patient. To examine our system, 11 participants were asked to participate in an experiment where they performed activities focused to strengthen their fine motor movements. CONCLUSIONS AND CLINICAL RELEVANCE: Results showed show that patients' fine motor skills improved 10% on average by comparing their error rates throughout the sessions. PMID- 29499014 TI - Electrical Stimulation Mapping of the Brain. PMID- 29499016 TI - A Guide for Cortical Electrical Stimulation Mapping. AB - Electrical stimulation mapping (ESM) of the brain remains a major procedure for guiding epilepsy and tumor surgeries. This article collates available experiences and data in ESM to develop a guide for conducting the procedure. There are many factors that influence the yield of ESM. The stimulation parameters offered in this article need to be adjusted within safe limits to address the factors. Each ESM procedure should be tailored to the patient's age and baseline mental or psychological capacity. Stimulation-induced seizures and EEG afterdischarges disrupt ESM procedure and render the interpretation of the results difficult. There are specific measures that can lessen the risk of seizures and afterdischarges during ESM. Electrical stimulation mapping procedure requires several tasks on the part of those conducting the procedure, such as operating the stimulator and the EEG recording equipment, administering behavioral or language tests and observing both patient and EEG responses to the stimulation. A team of experienced staff is necessary for individual assumption of each task. Knowledge of the spatial relationship between electrode contacts and underlying normal or abnormal brain structures is essential for interpreting ESM results. When testing for motor or sensory response, be aware of the distinction between responses at the primary motor area and responses at the supplementary sensorimotor area. The anatomy of supplementary sensorimotor area is more variable and functional than it is fixed and structural, although its general confines and somatotopic organization are known. In addition, negative motor responses to stimulation must be recognized to avoid misinterpretation of ESM results, especially in language mapping. PMID- 29499017 TI - Cortical Electrical Stimulation Mapping: Special Considerations in Children. AB - Cortical electrical stimulation mapping is often required to accurately delineate eloquent function before resective surgery for tumors or epilepsy. Although the technique is well established in adults, mapping poses special challenges in children that are addressed in this article. The concept of what constitutes a critical cortex is more difficult to assess, given the implications of plasticity and impact of deficits. Developmental factors affect the underlying neurophysiologic bases of responses to electrical stimulation, and evolving maturation requires adaptation of methodology. Furthermore, malformative substrates are the commonest substrate and often lead to aberrant representations of eloquent function. PMID- 29499015 TI - Electrical Stimulation Mapping of the Brain: Basic Principles and Emerging Alternatives. AB - The application of electrical stimulation mapping (ESM) of the brain for clinical use is approximating a century. Despite this long-standing history, the value of ESM for guiding surgical resections and sparing eloquent cortex is documented largely by small retrospective studies, and ESM protocols are largely inherited and lack standardization. Although models are imperfect and mechanisms are complex, the probabilistic causality of ESM has guaranteed its perpetuation into the 21st century. At present, electrical stimulation of cortical tissue is being revisited for network connectivity. In addition, noninvasive and passive mapping techniques are rapidly evolving to complement and potentially replace ESM in specific clinical situations. Lesional and epilepsy neurosurgery cases now offer different opportunities for multimodal functional assessments. PMID- 29499018 TI - Electrical Stimulation Mapping With Stereo-EEG Electrodes. AB - The practice of stereo-EEG (SEEG) is expanding. Electrical stimulation mapping remains an important part of the surgical evaluation process in SEEG, as it is in subdural electrocorticography cases. Because the technique and electrodes used in SEEG and electrocorticography are distinct, the clinician needs to be aware of the important differences between these techniques when performing electrical stimulation mapping. In this review, the advantages, disadvantages, and potential safety concerns related to electrical stimulation mapping in SEEG are discussed. A case is presented illustrating the utility of SEEG cortical stimulation and safety concerns that need to be considered when performing these evaluations. PMID- 29499019 TI - Differences in the Transcranial Motor Evoked Potentials Between Proximal and Distal Lower Extremity Muscles. AB - PURPOSE: Transcranial motor evoked potentials (TcMEPs) are the preferred modality to monitor the integrity of motor pathways during surgery. Recently, it has also been used as a method to help with detection of nerve roots injuries. Adequate baseline muscle responses are vital to detect nerve injury. We have observed that TcMEP responses are not homogeneous across multiple myotomes, but this has not been studied systematically. Our objective is to determine whether there are any relative differences in amplitude or morphology of TcMEPs across various lower extremity muscles. METHODS: Clinical and neurophysiological monitoring data from patients who had lumbar spine surgery were obtained retrospectively. Transcranial motor evoked potential responses were evaluated for each limb in the quadriceps, tibialis anterior, and intrinsic foot muscles. We compared TcMEP responses between these muscle groups using paired t-test statistical analysis. Each limb was analyzed separately. Only limbs without deficit in the interested muscle groups were included for analysis. RESULTS: A total of 40 patients and 69 limbs were included for analysis. The mean TcMEP amplitude difference between the tibialis anterior and quadriceps muscles was 458 uV (P < 0.0001), and between intrinsic feet and quadriceps muscles was 541 uV (P < 0.0001). Proximal muscles also demonstrated a significantly smaller number of TcMEP phases than their distal counterparts. CONCLUSIONS: Transcranial motor evoked potential amplitudes are significantly smaller in proximal lower extremity muscles compared with distal lower extremity muscles. The observed difference might be due to cortical representation or higher subcutaneous tissue in thigh muscles. PMID- 29499020 TI - Severe Malaria in African Children: Unraveling Issues of the Heart. PMID- 29499021 TI - "Doctor, Is My Child Going to Survive?" Does a New Score to Predict Mortality Following Pediatric In-Hospital Cardiac Arrest "GO-FAR" Enough? PMID- 29499022 TI - Renal Replacement Therapy in the United Kingdom: The Devil Is in the Details. PMID- 29499023 TI - "What Is Measured Gets Improved" (or If You Cannot Measure It, You Cannot Improve It). PMID- 29499024 TI - Dopamine and the Risk for Hospital-Acquired Infections. PMID- 29499025 TI - How Much Extracorporeal Membrane Oxygenation Is Enough? Oxidative Stress and the Goldilocks Principle. PMID- 29499026 TI - Mortality After Pediatric Critical Illness: Made It Home, Still Vulnerable. PMID- 29499028 TI - Is All Suffering Equal or Is It Time to Address Existential Suffering? PMID- 29499027 TI - Cardiopulmonary Resuscitation International Liaison Committee on Resuscitation Recommendation, Do They Need Local Adaptation? PMID- 29499029 TI - Cognitive Impairment Following Pediatric Critical Illness: Time to Pay Attention. PMID- 29499030 TI - Need of Data Collection in the Pre-PICU Setting for Transport Research. PMID- 29499031 TI - The authors reply. PMID- 29499032 TI - Dielectric Properties for Differentiating Normal and Malignant Thyroid Tissues. AB - BACKGROUND The incidence rate of thyroid cancer has increased greatly during the last few decades, and highly sensitive and specific methods for early diagnosis and prognostic evaluation remain lacking. In this study, we investigated a novel approach based on microwave theory to detect thyroid cancer. MATERIAL AND METHODS Freshly excised thyroid tissues (n=236) from 48 patients were identified as normal or malignant using histology. Each sample was measured for effective dielectric permittivity and effective conductivity (0.5-8 GHz). The means of each of these parameters of the normal and malignant groups were compared. RESULTS The effective dielectric permittivities of normal and malignant thyroid tissues were 24.026+/-1.951 to 17.950+/-1.648 and 69.782+/-2.734 to 57.356+/-1.802, respectively. Also, as a function of frequency, the effective conductivities of normal and malignant thyroid cancer were 0.8395+/-0.2013 to 1.8730+/-0.0979 and 1.8960+/-0.5024 to 9.7461+/-0.9349 (S/m), respectively. The mean effective dielectric permittivities and effective conductivities of normal thyroid tissues were significantly lower than that of thyroid cancer tissues. CONCLUSIONS Measuring the effective dielectric permittivity and effective conductivity of excised thyroid tissues may be a new and viable method to determine malignancy in thyroid cancer. PMID- 29499033 TI - Is augmentation with folate effective for major depressive disorder? AB - INTRODUCTION: Antidepressant treatment does not lead to a satisfactory response in a significant proportion of patients with depression. It has been postulated that co-administration of pharmacologically standardized nutrients (nutraceuticals), such as folate, would potentiate the effect of antidepressants. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified four systematic reviews including nine studies overall, of which eight were randomized trials. We concluded augmentation with folate for the treatment of major depressive disorder probably results in little or no difference in depressive symptoms. It would be interesting to evaluate the effects of specific presentation forms of folate or in population with objective folate deficit. PMID- 29499034 TI - Food addiction in Latin America. AB - Food addiction is a disorder characterized by an uncontrollable desire to eat foods high in fats and sugars. These foods activate the brain reward system in a similar way to drugs generating the release of neurotransmitters such as dopamine and oxytocin which trigger a need to repeat the behavior. In developed countries in Europe, Asia, and North America, there are reports of food addiction in children, adolescents, university students, sexual minorities, women and the adult population that suffer from obesity or overweight. In Latin America, studies conducted in Chile report that 10% of university students suffer food addiction, while in Brazil 4% of adults have the same disorder. There are few studies on the prevalence of food addiction. Likewise, validations of diagnostic instruments and studies on the effectiveness of psychotherapy are required to modify behaviors in this disorder. PMID- 29499035 TI - Population-specific design of de-immunized protein biotherapeutics. AB - Immunogenicity is a major problem during the development of biotherapeutics since it can lead to rapid clearance of the drug and adverse reactions. The challenge for biotherapeutic design is therefore to identify mutants of the protein sequence that minimize immunogenicity in a target population whilst retaining pharmaceutical activity and protein function. Current approaches are moderately successful in designing sequences with reduced immunogenicity, but do not account for the varying frequencies of different human leucocyte antigen alleles in a specific population and in addition, since many designs are non-functional, require costly experimental post-screening. Here, we report a new method for de immunization design using multi-objective combinatorial optimization. The method simultaneously optimizes the likelihood of a functional protein sequence at the same time as minimizing its immunogenicity tailored to a target population. We bypass the need for three-dimensional protein structure or molecular simulations to identify functional designs by automatically generating sequences using probabilistic models that have been used previously for mutation effect prediction and structure prediction. As proof-of-principle we designed sequences of the C2 domain of Factor VIII and tested them experimentally, resulting in a good correlation with the predicted immunogenicity of our model. PMID- 29499036 TI - An entropic barriers diffusion theory of decision-making in multiple alternative tasks. AB - We present a theory of decision-making in the presence of multiple choices that departs from traditional approaches by explicitly incorporating entropic barriers in a stochastic search process. We analyze response time data from an on-line repository of 15 million blitz chess games, and show that our model fits not just the mean and variance, but the entire response time distribution (over several response-time orders of magnitude) at every stage of the game. We apply the model to show that (a) higher cognitive expertise corresponds to the exploration of more complex solution spaces, and (b) reaction times of users at an on-line buying website can be similarly explained. Our model can be seen as a synergy between diffusion models used to model simple two-choice decision-making and planning agents in complex problem solving. PMID- 29499037 TI - Immune responses to an early lytic cytomegalovirus antigen in systemic lupus erythematosus patients: T-cell responses, cytokine secretions and antibody status. AB - We investigated immune responses to a lytic cytomegalovirus antigen (CMVpp52), and to a lytic human herpes virus (HHV) 6 antigen (HHV6p41), in systemic lupus erythematosus (SLE) patients and healthy controls (HCs), in order to clarify if the previously established impaired responses to Epstein-Barr virus (EBV) in SLE patients is a general defect in their responses against (all) HHVs. Multiplex Luminex technology results showed a normal induction of five quantified cytokines (interferon gamma, interleukin(IL)12, IL17, IL10, and tumor necrosis factor alpha) in SLE patients compared to HCs upon stimulation with CMVpp52 and HHV6p41. However, flow cytometric results showed a reduced upregulation of the activation marker CD69 on T-cells from SLE patients (n = 17) compared to HCs (n = 17) upon stimulation with CMVpp52, indicating limited or defective CMVpp52-specific T cells and/or poor antigen-presentation in SLE patients, and thereby possibly decreased control of the CMV infection. In conclusion, the dysfunctional immune response against EBV previously established in SLE patients does not seem to apply to the same degree regarding the immune responses against CMV or HHV6. Results designate that the main contributing HHV agent in development or exacerbation of SLE (in genetically predisposed individuals) is the previously determined uncontrolled EBV infection, and to a lesser extent CMV infection, and probably with no involvement of HHV6 infection. PMID- 29499038 TI - Crystal structures of PCNA mutant proteins defective in gene silencing suggest a novel interaction site on the front face of the PCNA ring. AB - Proliferating cell nuclear antigen (PCNA), a homotrimeric protein, is the eukaryotic sliding clamp that functions as a processivity factor for polymerases during DNA replication. Chromatin association factor 1 (CAF-1) is a heterotrimeric histone chaperone protein that is required for coupling chromatin assembly with DNA replication in eukaryotes. CAF-1 association with replicating DNA, and the targeting of newly synthesized histones to sites of DNA replication and repair requires its interaction with PCNA. Genetic studies have identified three mutant forms of PCNA in yeast that cause defects in gene silencing and exhibit altered association of CAF-1 to chromatin in vivo, as well as inhibit binding to CAF-1 in vitro. Three of these mutant forms of PCNA, encoded by the pol30-6, pol30-8, and the pol30-79 alleles, direct the synthesis of PCNA proteins with the amino acid substitutions D41A/D42A, R61A/D63A, and L126A/I128A, respectively. Interestingly, these double alanine substitutions are located far away from each other within the PCNA protein. To understand the structural basis of the interaction between PCNA and CAF-1 and how disruption of this interaction leads to reduced gene silencing, we determined the X-ray crystal structures of each of these mutant PCNA proteins. All three of the substitutions caused disruptions of a surface cavity on the front face of the PCNA ring, which is formed in part by three loops comprised of residues 21-24, 41-44, and 118-134. We suggest that this cavity is a novel binding pocket required for the interaction between PCNA and CAF-1, and that this region in PCNA also represents a potential binding site for other PCNA-binding proteins. PMID- 29499039 TI - Performance of glomerular filtration rate estimation equations in Congolese healthy adults: The inopportunity of the ethnic correction. AB - CONTEXT AND OBJECTIVE: In the estimation of glomerular filtration rate (GFR), ethnicity is an important determinant. However, all existing equations have been built solely from Caucasian and Afro-American populations and they are potentially inaccurate for estimating GFR in African populations. We therefore evaluated the performance of different estimated GFR (eGFR) equations in predicting measured GFR (mGFR). METHODS: In a cross-sectional study, 93 healthy adults were randomly selected in the general population of Kinshasa, Democratic Republic of the Congo, between June 2015 and April 2016. We compared mGFR by plasma clearance of iohexol with eGFR obtained with the Modified Diet in Renal Disease (MDRD) equation with and without ethnic factor, the Chronic Kidney Disease Epidemiology (CKD-EPI) serum creatinine (SCr)-based equation, with and without ethnic factor, the cystatin C-based CKD-EPI equation (CKD-EPI SCys) and with the combined equation (CKD-EPI SCrCys) with and without ethnic factor. The performance of the equations was studied by calculating bias, precision and accuracy within 30% (P30) of mGFR. RESULTS: There were 48 women and 45 men. Their mean age was 45.0+/-15.7 years and the average body surface area was 1.68+/ 0.16m2. Mean mGFR was 92.0+/-17.2 mL/min/1.73m2 (range of 57 to 141 mL/min/1.73m2). Mean eGFRs with the different equations were 105.5+/-30.1 and 87.2+/-24.8 mL/min/1.73m2 for MDRD with and without ethnic factor, respectively; 108.8+/-24.1 and 94.3x20.9 mL/min/1.73m2 for CKD-EPI SCr with and without ethnic factor, respectively, 93.5+/-18.6 mL/min/1.73m2 for CKD-EPI SCys; 93.5+/-18.0 and 101+/-19.6 mL/min/ 1.73m2 for CKD-EPI SCrCys with and without ethnic factor, respectively. All equations slightly overestimated mGFR except MDRD without ethnic factor which underestimated by -3.8+/-23.0 mL/min /1.73m2. Both CKD-EPI SCr and MDRD with ethnic factors highly overestimated mGFR with a bias of 17.9+/ 19.2 and 14.5+/-27.1 mL/min/1.73m2, respectively. There was a trend for better P30 for MDRD and CKD-EPI SCr without than with the ethnic factor [86.0% versus 79.6% for MDRD (p = 0.21) and 81.7% versus 73.1% for the CKD-EPI SCr equations (p = 0.057)]. CKD-EPI SCrCys and CKD-EPI SCys were more effective than creatinine based equations. CONCLUSION: In the Congolese healthy population, MDRD and CKD EPI equations without ethnic factors had better performance than the same equations with ethnic factor. The equations using Cys C (alone or combined with SCr) performed better than the creatinine-based equations. PMID- 29499040 TI - Molecular identification of Leishmania infection in the most relevant sand fly species and in patient skin samples from a cutaneous leishmaniasis focus, in Morocco. AB - BACKGROUND: Cutaneous leishmaniasis (CL) is an infectious disease caused by various species of Leishmania and transmitted by several species of sand flies. CL is among the most neglected tropical diseases, and it has represented a major health threat over the past 20 years in Morocco. The main objectives of this study were to identify relevant sand fly species and detect Leishmania infection in the most prevalent species and patient skin samples in Taza, a focus of CL in North-eastern Morocco. METHODOLOGY AND FINDING: A total of 3672 sand flies were collected by CDC miniature light traps. Morphological identification permitted the identification of 13 species, namely 10 Phlebotomus species and 3 Sergentomyia species. P. longicuspis was the most abundant species, comprising 64.08% of the total collected sand flies, followed by P. sergenti (20.1%) and P. perniciosus (8.45%). Using nested-kDNA PCR, seven pools of P. sergenti were positive to Leishmania tropica DNA, whereas 23 pools of P. longicuspis and 4 pools of P. perniciosus tested positive for Leishmania infantum DNA. The rates of P. longicuspis and P. perniciosus Leishmania infection were 2.51% (23/915) and 7.27% (4/55), respectively, whereas the infection prevalence of P. sergenti was 3.24%. We also extracted DNA from lesion smears of 12 patients suspected of CL, among them nine patients were positive with enzymatic digestion of ITS1 by HaeIII revealing two profiles. The most abundant profile, present in eight patients, was identical to L. infantum, whereas L. tropica was found in one patient. The results of RFLP were confirmed by sequencing of the ITS1 DNA region. CONCLUSION: This is the first molecular detection of L. tropica and L. infantum in P. sergenti and P. longicuspis, respectively, in this CL focus. Infection of P. perniciosus by L. infantum was identified for the first time in Morocco. This study also underlined the predominance of L. infantum and its vector in this region, in which L. tropica has been considered the causative agent of CL for more than 20 years. PMID- 29499041 TI - Ag85-focused T-cell immune response controls Mycobacterium avium chronic infection. AB - CD4+ T cells are essential players for the control of mycobacterial infections. Several mycobacterial antigens have been identified for eliciting a relevant CD4+ T cell mediated-immune response, and numerous studies explored this issue in the context of Mycobacterium tuberculosis infection. Antigen 85 (Ag85), a highly conserved protein across Mycobacterium species, is secreted at the early phase of M. tuberculosis infection leading to the proliferation of Ag85-specific CD4+ T cells. However, in the context of Mycobacterium avium infection, little is known about the expression of this antigen and the elicited immune response. In the current work, we investigated if a T cell receptor (TCR) repertoire mostly, but not exclusively, directed at Ag85 is sufficient to mount a protective immune response against M. avium. We show that P25 mice, whose majority of T cells express a transgenic TCR specific for Ag85, control M. avium infection at the same level as wild type (WT) mice up to 20 weeks post-infection (wpi). During M. avium infection, Ag85 antigen is easily detected in the liver of 20 wpi mice by immunohistochemistry. In spite of the propensity of P25 CD4+ T cells to produce higher amounts of interferon-gamma (IFNgamma) upon ex vivo stimulation, no differences in serum IFNgamma levels are detected in P25 compared to WT mice, nor enhanced immunopathology is detected in P25 mice. These results indicate that a T cell response dominated by Ag85-specific T cells is appropriate to control M. avium infection with no signs of immunopathology. PMID- 29499042 TI - Multidisease testing for HIV and TB using the GeneXpert platform: A feasibility study in rural Zimbabwe. AB - BACKGROUND: HIV Viral Load and Early Infant Diagnosis technologies in many high burden settings are restricted to centralized laboratory testing, leading to long result turnaround times and patient attrition. GeneXpert (Cepheid, CA, USA) is a polyvalent near point-of-care platform and is widely implemented for Xpert MTB/RIF diagnosis. This study sought to evaluate the operational feasibility of integrated HIV VL, EID and MTB/RIF testing in new GeneXpert platforms. METHODS: Whole blood samples were collected from consenting patients due for routine HIV VL testing and DBS samples from infants due for EID testing, at three rural health facilities in Zimbabwe. Sputum samples were collected from all individuals suspected of TB. GeneXpert testing was reserved for all EID, all TB suspects and priority HIV VL at each site. Blood samples were further sent to centralized laboratories for confirmatory testing. GeneXpert polyvalent testing results and patient outcomes, including infrastructural and logistical requirements are reported. The study was conducted over a 10-month period. RESULTS: The fully automated GeneXpert testing device, required minimal training and biosafety considerations. A total of 1,302 HIV VL, 277 EID and 1,581 MTB/RIF samples were tested on a four module GeneXpert platform in each study site. Xpert HIV-1 VL testing was prioritized for patients who presented with advanced HIV disease, pregnant women, adolescents and suspected ART failures patients. On average, the study sites had a GeneXpert utilization rate of 50.4% (Gutu Mission Hospital), 63.5% (Murambinda Mission Hospital) and 17.5% (Chimombe Rural Health Centre) per month. GeneXpert polyvalent testing error rates remained lower than 4% in all sites. Decentralized EID and VL testing on Xpert had shorter overall median TAT (1 day [IQR: 0-4] and 1 day [IQR: 0-1] respectively) compared to centralized testing (17 days [IQR: 13-21] and 26 days [IQR: 23-32] respectively). Among patients with VL >1000 copies/ml (73/640; 11.4%) at GMH health facility, median time to enhanced adherence counselling was 8 days and majority of those with documented outcomes had re-suppressed VL (20/32; 62.5%). Median time to ART initiation among Xpert EID positive infants at GMH was 1 day [IQR: 0-1]. CONCLUSION: Implementation of near point-of-care GeneXpert platform for integrated multi-disease testing within district and sub-district healthcare settings is feasible and will increase access to VL, and EID testing to priority populations. Quality management systems including monitoring of performance indicators, together with regular on-site supervision are crucial, and near-POC test results must be promptly actioned-on by clinicians for patient management. PMID- 29499043 TI - Patient and public engagement in priority setting: A systematic rapid review of the literature. AB - BACKGROUND: Current research suggests that while patients are becoming more engaged across the health delivery spectrum, this involvement occurs most often at the pre-preparation stage to identify 'high-level' priorities in health ecosystem priority setting, and at the preparation phase for health research. OBJECTIVE: The purpose of this systematic rapid review of the literature is to describe the evidence that does exist in relation to patient and public engagement priority setting in both health ecosystem and health research. DATA SOURCES: HealthStar (via OVID); CINAHL; Proquest Databases; and Scholar's Portal. STUDY ELIGIBILITY CRITERIA: i) published in English; ii) published within the timeframe of 2007-Current (10 years) unless the report/article was formative in synthesizing key considerations of patient engagement in health ecosystem and health research priority setting; iii) conducted in Canada, the US, Europe, UK, Australia/New Zealand, or Scandinavian countries. STUDY APPRAISAL AND SYNTHESIS: i) Is the research valid, sound, and applicable?; ii) what outcomes can we potentially expect if we implement the findings from this research?; iii) will the target population (i.e., health researchers and practitioners) be able to use this research?. A summary of findings from each of the respective processes was synthesized to highlight key information that would support decision-making for researchers when determining the best priority setting process to apply for their specific patient-oriented research. RESULTS: Seventy articles from the UK, US, Canada, Netherlands and Australia were selected for review. Results were organized into two tiers of public and patient engagement in prioritization: Tier 1-Deliberative and Tier 2-Consultative. Highly structured patient and public engagement planning activities include the James Lind Alliance Priority Setting Partnerships (UK), Dialogue Method (Netherlands), Global Evidence Mapping (Australia), and the Deep Inclusion Method/CHoosing All Together (US). LIMITATIONS: The critical study limitations include challenges in comprehensively identifying the patient engagement literature for review, bias in article selection due to the identified scope, missed information due to a more limited use of exhaustive search strategies (e.g., in-depth hand searching), and the heterogeneity of reported study findings. CONCLUSION: The four public and patient engagement priority setting processes identified were successful in setting priorities that are inclusive and objectively based, specific to the priorities of stakeholders engaged in the process. The processes were robust, strategic and aimed to promote equity in patient voices. Key limitations identified a lack of evaluation data on the success and extent in which patients were engaged. Issues pertaining to feasibility of stakeholder engagement, coordination, communication and limited resources were also considered. PMID- 29499044 TI - Classifying dynamic transitions in high dimensional neural mass models: A random forest approach. AB - Neural mass models (NMMs) are increasingly used to uncover the large-scale mechanisms of brain rhythms in health and disease. The dynamics of these models is dependent upon the choice of parameters, and therefore it is crucial to be able to understand how dynamics change when parameters are varied. Despite being considered low dimensional in comparison to micro-scale, neuronal network models, with regards to understanding the relationship between parameters and dynamics, NMMs are still prohibitively high dimensional for classical approaches such as numerical continuation. Therefore, we need alternative methods to characterise dynamics of NMMs in high dimensional parameter spaces. Here, we introduce a statistical framework that enables the efficient exploration of the relationship between model parameters and selected features of the simulated, emergent model dynamics of NMMs. We combine the classical machine learning approaches of trees and random forests to enable studying the effect that varying multiple parameters has on the dynamics of a model. The method proceeds by using simulations to transform the mathematical model into a database. This database is then used to partition parameter space with respect to dynamic features of interest, using random forests. This allows us to rapidly explore dynamics in high dimensional parameter space, capture the approximate location of qualitative transitions in dynamics and assess the relative importance of all parameters in the model in all dimensions simultaneously. We apply this method to a commonly used NMM in the context of transitions to seizure dynamics. We find that the inhibitory sub system is most crucial for the generation of seizure dynamics, confirm and expand previous findings regarding the ratio of excitation and inhibition, and demonstrate that previously overlooked parameters can have a significant impact on model dynamics. We advocate the use of this method in future to constrain high dimensional parameter spaces enabling more efficient, person-specific, model calibration. PMID- 29499045 TI - Deafness alters the spatial mapping of touch. AB - Auditory input plays an important role in the development of body-related processes. The absence of auditory input in deafness is understood to have a significant, and even irreversible, impact on these processes. The ability to map touch on the body is an important element of body-related processing. In this research, the crossed-arm temporal order judgment (TOJ) task was used to evaluate the spatial mapping of touch. This task elicits a conflict between visual and somatosensory body-related information through a change in posture. We used the crossed-arm TOJ task to evaluate the spatial mapping of touch in deaf participants. Results suggested that a change in posture had a greater impact on congenitally deaf participant TOJ than for hearing participants. This provides the first evidence for the role of early auditory exposure on spatial mapping of touch. More importantly, most deaf participants had auditory prosthetics which provided auditory input. This suggests an important, and possibly irreversible, impact of early auditory deprivation on this body-related process. PMID- 29499046 TI - Complement C1q expression in Erythema nodosum leprosum. AB - Complement C1q is a soluble protein capable of initiating components of the classical pathway in host defence system. In earlier qualitative studies, C1q has been implicated in the pathogenesis of Erythema Nodosum Leprosum (ENL). However, little is known about the role of this complement in ENL reaction. In the present study we described the protein level of C1q production and its gene expression in the peripheral blood and skin biopsies in patients with ENL reaction and lepromatous leprosy (LL) patient controls before and after treatment. Thirty untreated patients with ENL reaction and 30 non-reactional LL patient controls were recruited at ALERT Hospital, Ethiopia. Peripheral blood and skin biopsies were obtained from each patient before and after treatment. The level of circulating C1q in the plasma was determined by enzyme-linked immunosorbent assay. The mRNA expression of the three C1q components, C1qA, C1qB, and C1qC in the peripheral blood and skin biopsies was determined by qPCR. Circulating C1q in the peripheral blood of untreated ENL patients was significantly decreased compared to LL patient controls. Untreated ENL patients had increased C1q gene expression in the peripheral blood compared to LL controls. Similarly, C1qA and C1qC gene expression were substantially increased in the skin biopsies of untreated ENL patients compared to LL controls. However, after treatment none of these genes show significant difference in both groups. In conclusion, while circulating C1q is inversely correlated with active ENL reactions, its gene expression is directly correlated with ENL. The decreased circulating C1q may suggest the utilization of C1q in immune-complex formation in these patients. Therefore, C1q could be a potential diagnostic marker for active ENL reactions as well as for monitoring ENL treatment. PMID- 29499047 TI - Characterizing the metabolic phenotype of intestinal villus blunting in Zambian children with severe acute malnutrition and persistent diarrhea. AB - BACKGROUND: Environmental enteric dysfunction (EED) is widespread throughout the tropics and in children is associated with stunting and other adverse health outcomes. One of the hallmarks of EED is villus damage. In children with severe acute malnutrition (SAM) the severity of enteropathy is greater and short term mortality is high, but the metabolic consequences of enteropathy are unknown. Here, we characterize the urinary metabolic alterations associated with villus health, classic enteropathy biomarkers and anthropometric measurements in severely malnourished children in Zambia. METHODS/PRINCIPAL FINDINGS: We analysed 20 hospitalised children with acute malnutrition aged 6 to 23 months in Zambia. Small intestinal biopsies were assessed histologically (n = 15), anthropometric and gut function measurements were collected and the metabolic phenotypes were characterized by 1H nuclear magnetic resonance (NMR) spectroscopy. Endoscopy could not be performed on community controls children. Growth parameters were inversely correlated with enteropathy biomarkers (p = 0.011) and parameters of villus health were inversely correlated with translocation and permeability biomarkers (p = 0.000 and p = 0.015). Shorter villus height was associated with reduced abundance of metabolites related to gut microbial metabolism, energy and muscle metabolism (p = 0.034). Villus blunting was also related to increased sucrose excretion (p = 0.013). CONCLUSIONS/SIGNIFICANCE: Intestinal villus blunting is associated with several metabolic perturbations in hospitalized children with severe undernutrition. Such alterations include altered muscle metabolism, reinforcing the link between EED and growth faltering, and a disruption in the biochemical exchange between the gut microbiota and host. These findings extend our understanding on the downstream consequences of villus blunting and provide novel non-invasive biomarkers of enteropathy dysfunction. The major limitations of this study are the lack of comparative control group and gut microbiota characterization. PMID- 29499048 TI - In vitro immunotherapy potency assays using real-time cell analysis. AB - A growing understanding of the molecular interactions between immune effector cells and target tumor cells, coupled with refined gene therapy approaches, are giving rise to novel cancer immunotherapeutics with remarkable efficacy in the clinic against both solid and liquid tumors. While immunotherapy holds tremendous promise for treatment of certain cancers, significant challenges remain in the clinical translation to many other types of cancers and also in minimizing adverse effects. Therefore, there is an urgent need for functional potency assays, in vitro and in vivo, that could model the complex interaction of immune cells with tumor cells and can be used to rapidly test the efficacy of different immunotherapy approaches, whether it is small molecule, biologics, cell therapies or combinations thereof. Herein we report the development of an xCELLigence real time cytolytic in vitro potency assay that uses cellular impedance to continuously monitor the viability of target tumor cells while they are being subjected to different types of treatments. Specialized microtiter plates containing integrated gold microelectrodes enable the number, size, and surface attachment strength of adherent target tumor cells to be selectively monitored within a heterogeneous mixture that includes effector cells, antibodies, small molecules, etc. Through surface-tethering approach, the killing of liquid cancers can also be monitored. Using NK92 effector cells as example, results from RTCA potency assay are very well correlated with end point data from image-based assays as well as flow cytometry. Several effector cells, i.e., PBMC, NK, CAR-T were tested and validated as well as biological molecules such as Bi-specific T cell Engagers (BiTEs) targeting the EpCAM protein expressed on tumor cells and blocking antibodies against the immune checkpoint inhibitor PD-1. Using the specifically designed xCELLigence immunotherapy software, quantitative parameters such as KT50 (the amount of time it takes to kill 50% of the target tumor cells) and % cytolysis are calculated and used for comparing the relative efficacy of different reagents. In summary, our results demonstrate the xCELLigence platform to be well suited for potency assays, providing quantitative assessment with high reproducibility and a greatly simplified work flow. PMID- 29499049 TI - Calibrating emergent phenomena in stock markets with agent based models. AB - Since the 2008 financial crisis, agent-based models (ABMs), which account for out of-equilibrium dynamics, heterogeneous preferences, time horizons and strategies, have often been envisioned as the new frontier that could revolutionise and displace the more standard models and tools in economics. However, their adoption and generalisation is drastically hindered by the absence of general reliable operational calibration methods. Here, we start with a different calibration angle that qualifies an ABM for its ability to achieve abnormal trading performance with respect to the buy-and-hold strategy when fed with real financial data. Starting from the common definition of standard minority and majority agents with binary strategies, we prove their equivalence to optimal decision trees. This efficient representation allows us to exhaustively test all meaningful single agent models for their potential anomalous investment performance, which we apply to the NASDAQ Composite index over the last 20 years. We uncover large significant predictive power, with anomalous Sharpe ratio and directional accuracy, in particular during the dotcom bubble and crash and the 2008 financial crisis. A principal component analysis reveals transient convergence between the anomalous minority and majority models. A novel combination of the optimal single-agent models of both classes into a two-agents model leads to remarkable superior investment performance, especially during the periods of bubbles and crashes. Our design opens the field of ABMs to construct novel types of advanced warning systems of market crises, based on the emergent collective intelligence of ABMs built on carefully designed optimal decision trees that can be reversed engineered from real financial data. PMID- 29499050 TI - AFT survival model to capture the rate of aging and age-specific mortality trajectories among first-allogeneic hematopoietic stem cells transplant patients. AB - Accelerated failure time (AFT) model is commonly applied in engineering studies to address the failure rate of a machine. In humans, survival profile of transplant patients is among the rare scenarios whereby AFT is applicable. To date, it is uncertain whether reliable risk estimates and age-specific mortality trajectories have been published using conventional statistics approach. By investigating mortality trajectory, the rate of aging d(log(MU(x)))/dx of Hematopoietic Stem Cells Transplants (HSCTs) patients who had underwent first allogeneic transplants can be obtained, and to unveil the possibility of elasticity of human aging rate in HSCTs. A modified parametric frailty survival model was introduced to the survival profiles of 11,160 patients who had underwent first-allogeneic HSCTs in the United States between 1995 and 2006; data was shared by Center for International Bone and Marrow Transplant Research. In comparison to stratification, the modification permits two entities in relation to time to be presented; age and calendar time. To consider its application in empirical studies, the data contains arbitrary right-censoring, a statistical condition which is preferred by choice in many transplant studies. The finalized multivariate AFT model was adjusted for clinical and demographic covariates, and age-specific mortality trajectories were presented by donor source and post transplant time-lapse intervals. Two unexpected findings are presented: i) an inverse J-shaped hazard in unrelated donor-source t<=100-day; ii) convergence of unrelated-related hazard lines in 100-day365-day) must consider for periodic medical improvements, and transplant year as a standalone time-variable is not sufficient for statistical adjustment in the finalized multivariate model. In relevance to clinical studies, biennial event history analysis and age-specific mortality trajectories of long-term survivors provide a more relevant intervention audit report for transplant protocols than the popular statistical presentation; i.e. survival probabilities among donor source. PMID- 29499051 TI - Lower expression level of IL-33 is associated with poor prognosis of pulmonary adenocarcinoma. AB - OBJECTIVE: Lung cancer is one of the deadliest malignancies. The immune checkpoint-blockade (ICB) tumor therapy has led to striking improvement of long term survival for some lung cancer patients. However, the response rate of immunotherapy is still low for lung cancer. Studying the tumor microenvironment (TME) should shed light on improvement of immunotherapy of lung cancer. Interleukin-33 (IL-33), an "alarmin" cytokine, has been implicated in tumor associated immune responses and inflammatory diseases of the lung. The role of IL 33 in lung cancer progression, however, remains elusive. This study is designed to characterize IL-33 expression in lung tumor tissues and establish the clinical significance of IL-33 in non-small cell lung cancer lung cancer (NSCLC). MATERIALS AND METHODS: Tumor tissue specimens from patients suffering from NSCLC were analyzed for expression of IL-33 protein by immunohistochemistry and expression of IL-33 and ST2 mRNA by RT-quantitative PCR (RT-QPCR). The expression data were analyzed for their association with clinical and pathological parameters of NSCLC. In addition, the association between expression levels of IL 33 mRNA and patient survival was determined using 5 independent expression profiling datasets of human lung cancer. RESULTS AND CONCLUSION: The expression levels of IL-33 and ST2 were significantly down-regulated in both adenocarcinoma and squamous cell carcinoma of the lung when compared to adjacent normal lung tissues. In addition, the level of IL-33 protein was inversely correlated with tumor grade and size. Moreover, analysis of TCGA and GEO lung cancer expression datasets revealed that higher expression levels of IL-33 mRNA were correlated with longer overall survival of patients suffering from adenocarcinoma of the lung. These data indicate that the expression levels of IL-33 are inversely associated with lung cancer progression, consistent with the hypothesis that IL 33 is involved in immune surveillance of NSCLC. PMID- 29499052 TI - Absence of a secondary glucocorticoid response in C57BL/6J mice treated with topical dexamethasone. AB - Glucocorticoids such as dexamethasone can cause an increase in intraocular pressure (IOP) in some of the population, but not all. In this paper we used a mouse model of glucocorticoid induced ocular hypertension to examine the changes in the anterior segment of the eye in mice that failed to respond to glucocorticoid treatment with a sustained increase in IOP. C57BL/6J mice were treated with either 0.1% dexamethasone sodium phosphate ophthalmic solution or sterile PBS 3 times daily for up to 5 weeks. IOP was measured weekly at approximately the same time of the day. After 3-5 weeks of treatment, eyes were enucleated and evaluated for changes associated with steroid induced glaucoma. These studies showed that IOP was significantly elevated in dexamethasone (DEX) treated mice compared to PBS treated mice after 3 weeks of treatment, but IOP in DEX treated mice returned to baseline levels after 5 weeks of treatment. All the mice demonstrated a response to the glucocorticoid treatments and showed an elevation in FKBP5 expression after both 3 and 5 weeks of DEX treatment (primary glucocorticoid response protein) and a weight loss. Western blot analysis of anterior segments from treated mice, however, did not show an increase in secondary glucocorticoid response proteins such as beta3 integrin or myocilin. Fibronectin levels were also not statistically different. The data suggest that in mice, which do not exhibit a prolonged increase in IOP in response to the DEX treatment, there is a compensatory mechanism that can prevent or turn off the secondary glucocorticoid response. PMID- 29499054 TI - Identification of long noncoding RNAs involved in muscle differentiation. AB - Long noncoding RNAs (lncRNAs) are a large class of regulatory RNAs with diverse roles in cellular processes. Thousands of lncRNAs have been discovered; however, their roles in the regulation of muscle differentiation are unclear because no comprehensive analysis of lncRNAs during this process has been performed. In the present study, by combining diverse RNA sequencing datasets obtained from public database, we discovered lncRNAs that could behave as regulators in the differentiation of smooth or skeletal muscle cells. These analyses confirmed the roles of previously reported lncRNAs in this process. Moreover, we discovered dozens of novel lncRNAs whose expression patterns suggested their possible involvement in the phenotypic switch of vascular smooth muscle cells. The comparison of lncRNA expression change suggested that many lncRNAs have common roles during the differentiation of smooth and skeletal muscles, while some lncRNAs may have opposite roles in this process. The expression change of lncRNAs was highly correlated with that of their neighboring genes, suggesting that they may function as cis-acting lncRNAs. Furthermore, within the lncRNA sequences, there were binding sites for miRNAs with expression levels inversely correlated with the expression of corresponding lncRNAs during differentiation, suggesting a possible role of these lncRNAs as competing endogenous RNAs. The lncRNAs identified in this study will be a useful resource for future studies of gene regulation during muscle differentiation. PMID- 29499053 TI - Resting heart rate is an independent predictor of advanced colorectal adenoma recurrence. AB - BACKGROUND AND AIM: High heart rate is an independent predictor of total cancer incidence and all-cause mortality in patients with cancer. We aimed to evaluate the impact of resting heart rate on the recurrence of colorectal polyp, using long-term surveillance follow-up data of colorectal cancer survivors. METHODS: Three hundred patients were selected from the colorectal cancer survivor cohort of Severance Hospital, Seoul, Korea. Resting heart rate, physical activity, and body composition analysis at the time of 5-year survival, and clinical data including colonoscopy surveillance results were collected for mean follow-up duration of 8 years. RESULTS: Patients with a high resting heart rate showed a significantly higher recurrence rate of advanced adenoma than those with a low resting heart rate (quartile 1, 45-66 beats per minute (b.p.m.); quartile 2, 67 73 b.p.m.; quartile 3, 74-80 b.p.m.; quartile 4, 81-120 b.p.m.; 3.8% vs. 7.9% vs. 10.0% vs. 14.7%, p for trend = 0.018). After adjustment for various risk factors, patients in the highest quartile of resting heart rate (>= 81 b.p.m.) had a significantly higher risk of advanced adenoma recurrence (hazard ratio [HR]: 6.183, 95% confidence interval [CI]: 1.181-32.373, p = 0.031), compared to those in the lowest quartile (<= 66 b.p.m.). In subgroup analysis, the association of resting heart rate with advanced adenoma recurrence appeared to be stronger among patients who had more than normal body fat mass or sedentary life style. CONCLUSIONS: Elevated resting heart rate was independently associated with a higher rate of advanced adenoma recurrence in colorectal cancer survivors. PMID- 29499055 TI - Current Helicobacter pylori infection is significantly associated with subclinical coronary atherosclerosis in healthy subjects: A cross-sectional study. AB - Helicobacter pylori is a gastrointestinal pathogen known to be associated with cardiovascular disease (CVD). However, most analyses about the effect of H. pylori infection have been done in patients with a history of CVD but not in healthy subjects. We evaluated the association between H. pylori infection and subclinical atherosclerosis by using cardiac multidetector computed tomography (MDCT) in healthy subjects without previous CVD. From December 2007 to February 2014, 463 subjects who underwent the rapid urease test (CLO test), pulse-wave velocity (PWV) measurement, and MDCT for a self-referred health check-up were enrolled to this study. Helicobacter pylori infection was defined on the basis of CLO test positivity on endoscopic gastric biopsy. Significant coronary artery stenosis was defined as >=50% stenosis in any of the major epicardial coronary vessel on MDCT. The CLO-positive subjects had a lower high-density lipoprotein cholesterol (HDL-cholesterol) level compared to the CLO-negative subjects. The incidence of significant coronary stenosis was higher in the CLO-positive group (7.6% vs. 2.9%, P = 0.01). Furthermore, the number of subjects with coronary artery calcium score >0 and log{(number of segments with plaque)+1} were also significantly higher in the CLO-positive group. However, there was no statistical difference in the number of subjects with coronary artery calcium score >100, the prevalence of any plaque nor the plaque characteristics (calcified, mixed, or soft). Pulse-wave velocity (PWV) was neither associated with CLO test positivity. The CLO-positive group was 3-fold more likely to have significant coronary artery stenosis even after adjusting for confounding factors (adjusted odds ratio 2.813, 95% confidence interval 1.051-7.528, P = 0.04). In a healthy population, current H. pylori infection was associated with subclinical but significant coronary artery stenosis. The causal relationship between H. pylori infection and subclinical atherosclerosis in a "healthy" population remains to be investigated in the future. PMID- 29499057 TI - Increased T cell trafficking as adjunct therapy for HIV-1. AB - Although antiretroviral drug therapy suppresses human immunodeficiency virus-type 1 (HIV-1) to undetectable levels in the blood of treated individuals, reservoirs of replication competent HIV-1 endure. Upon cessation of antiretroviral therapy, the reservoir usually allows outgrowth of virus and approaches to targeting the reservoir have had limited success. Ongoing cycles of viral replication in regions with low drug penetration contribute to this persistence. Here, we use a mathematical model to illustrate a new approach to eliminating the part of the reservoir attributable to persistent replication in drug sanctuaries. Reducing the residency time of CD4 T cells in drug sanctuaries renders ongoing replication unsustainable in those sanctuaries. We hypothesize that, in combination with antiretroviral drugs, a strategy to orchestrate CD4 T cell trafficking could contribute to a functional cure for HIV-1 infection. PMID- 29499056 TI - Nubbin isoform antagonism governs Drosophila intestinal immune homeostasis. AB - Gut immunity is regulated by intricate and dynamic mechanisms to ensure homeostasis despite a constantly changing microbial environment. Several regulatory factors have been described to participate in feedback responses to prevent aberrant immune activity. Little is, however, known about how transcriptional programs are directly tuned to efficiently adapt host gut tissues to the current microbiome. Here we show that the POU/Oct gene nubbin (nub) encodes two transcription factor isoforms, Nub-PB and Nub-PD, which antagonistically regulate immune gene expression in Drosophila. Global transcriptional profiling of adult flies overexpressing Nub-PB in immunocompetent tissues revealed that this form is a strong transcriptional activator of a large set of immune genes. Further genetic analyses showed that Nub-PB is sufficient to drive expression both independently and in conjunction with nuclear factor kappa B (NF-kappaB), JNK and JAK/STAT pathways. Similar overexpression of Nub-PD did, conversely, repress expression of the same targets. Strikingly, isoform co overexpression normalized immune gene transcription, suggesting antagonistic activities. RNAi-mediated knockdown of individual nub transcripts in enterocytes confirmed antagonistic regulation by the two isoforms and that both are necessary for normal immune gene transcription in the midgut. Furthermore, enterocyte specific Nub-PB expression levels had a strong impact on gut bacterial load as well as host lifespan. Overexpression of Nub-PB enhanced bacterial clearance of ingested Erwinia carotovora carotovora 15. Nevertheless, flies quickly succumbed to the infection, suggesting a deleterious immune response. In line with this, prolonged overexpression promoted a proinflammatory signature in the gut with induction of JNK and JAK/STAT pathways, increased apoptosis and stem cell proliferation. These findings highlight a novel regulatory mechanism of host microbe interactions mediated by antagonistic transcription factor isoforms. PMID- 29499058 TI - Short- and long-term prognostic value of hyponatremia in patients with acute coronary syndrome: A systematic review and meta-analysis. AB - Hyponatremia is relevant to heart failure, liver cirrhosis and stroke, but the prognostic value of serum sodium levels in patients with acute coronary syndrome are still unclear. So we did a systematic review and meta-analysis to assess the prognostic value of hyponatremia on adverse events in patients after ACS. We systematically searched PubMed, Embase and Cochrane Library to find literatures which studied the prognostic value of hyponatremia in patients with ACS. Our main endpoints were the all-cause mortality and heart failure in the short- and long term. Of 369 identified studies, 20 studies were included in our analysis. Compared with the normal natrium, hyponatremia was significantly associated with the increased risks of all-cause mortality within 30 days (RR: 2.18; 95%CI: 1.96 2.42) and during the follow-ups (HR: 1.74; 95%CI: 1.56-1.942). For the second endpoint of short- and long-term heart failure, the pooled effect sizes in hyponatremia patients were 1.72(95%CI: 1.38-2.14) and 1.69(95%CI: 1.12-2.55) respectively. In conclusion, hyponatremia has a significant prognostic value for short- and long-term adverse event in patients after ACS, the dynamic monitoring of serum sodium levels may could help physicians to identify high risk ACS patients and to stratify risk for optimal management. PMID- 29499059 TI - Progranulin serum levels in human kidney transplant recipients: A longitudinal study. AB - BACKGROUND: The adipokine progranulin has metabolic proprieties, playing a role in obesity and insulin resistance. Its levels seems to be dependent of renal function, since higher progranulin concentration is observed in patients with end stage kidney disease. However, the effect of kidney transplantation on progranulin remains unknown. OBJECTIVE: To assess the serum progranulin levels in kidney transplant recipients before and after kidney transplantation. METHODS: Forty-six prospective kidney transplant recipients were included in this longitudinal study. They were evaluated before transplantation and at three and twelve months after transplantation. Clinical, anthropometric and laboratorial measurements were assessed. Progranulin was determined with enzyme-linked immunosorbent assays. RESULTS: Serum progranulin significantly decreased in the early period after transplantation (from 72.78 +/- 2.86 ng/mL before transplantation to 40.65 +/- 1.49 ng/mL at three months; p<0.01) and increased at one year (53.15 +/- 2.55 ng/mL; p<0.01 vs. three months), remaining significantly lower than before transplantation (p<0.01) (pover time<0.01). At one year after transplantation, there was a significant increase in body mass index, trunk fat and waist circumference compared to immediate period after transplantation. Progranulin was associated with waist circumference and fasting plasma glucose after adjusted for age, gender, study period, glomerular filtration rate, interleukin-6, high sensitivity C reactive protein and adiponectin. CONCLUSION: Progranulin serum levels are increased before transplantation and a reduction is observed in the early period after transplantation, possibly attributed to an improvement in renal function. At one year after transplantation, an increment in progranulin is observed, seems to be independent of glomerular filtration, and remained significantly lower than before transplantation. PMID- 29499060 TI - Household point of care CD4 testing and isoniazid preventive therapy initiation in a household TB contact tracing programme in two districts of South Africa. AB - BACKGROUND: In South Africa, TB household contact tracing provides an opportunity for increased TB and HIV case finding. We aimed to determine the effect of two new potential interventions for TB contact tracing programmes: Point of Care CD4 (PoC CD4) on HIV linkage to care and household Isoniazid Preventive Therapy (IPT) provision on uptake and retention of IPT. METHODS: A pragmatic, three-arm, cluster-randomized trial was undertaken. TB Household contacts were randomised to 3 arms: 1) Standard of Care TB and HIV testing (SOC); 2) SOC with POC CD4 for those testing HIV positive; 3) SOC with POC CD4 and IPT for eligible household members. Linkage to care within 90 days was assessed either through patient visits (at 10 weeks and 6 months) or via telephonic contact. RESULTS: 2,243 index TB patients and 3,012 contacts (64,3% female, median age 30 years) were enrolled. On self-report, 26(1.2%) were currently receiving TB treatment and 1816 (60.3%) reported a prior HIV test. HIV testing uptake was 34.7% in the SoC arm, 40.2% in the PoC CD4 arm (RR1.16, CI 0.99-1.36, p-value = 0.060) and 39.9% in the PoC CD4 + HH-IPT arm (RR = 1.15, CI 0.99-1.35, p-value = 0.075). Linkage to care within 3 months was 30.8% in the SoC arm and 42.1% in the POC CD4 arms (RR 1.37; CI: 0.68 2.76, p-value = 0.382). 20/21 contacts (95.2%) initiated IPT in the PoC CD4 + HH IPT arm, compared to 3/20 (15.0%) in the PoC CD4 arm (p = 0.004; p-value from Fisher's exact test < 0.001). Among 3,008 contacts screened for tuberculosis, 15 (3.4%) had bacteriologically confirmed TB with an overall yield of TB of 0.5% (95% CI: 0.3%, 0.8%). CONCLUSIONS: Household PoC CD4 testing and IPT initiation is feasible. There was only weak evidence that PoCCD4 led to a small increase in HCT uptake and no evidence for an increase in linkage-to-care. IPT initiation and completion was increased by the household intervention. Although feasible, these interventions had low impact due to the low uptake of HIV testing in households. PMID- 29499061 TI - Assessment of image co-registration accuracy for frameless gamma knife surgery. AB - Image co-registration is used in frameless gamma knife radiosurgery (GKSRS) to assign a stereotactic coordinate system and verify patient setup before irradiation. The accuracy of co-registration with cone beam computed tomography (CBCT) images of a Gamma Knife IconTM (GK Icon) was assessed, and the effects of the region of co-registration (ROC) were studied. CBCT-to-CBCT co-registration is used for patient setup verification, and its accuracy was examined by co registering CBCT images taken at various configurations with a reference CBCT series. The accuracy of stereotactic coordinate assignment was investigated by co registering stereotactic CT images with CBCT images taken at various configurations. An anthropomorphic phantom was used, and the coordinates of fifteen landmarks inside the phantom were measured. The co-registration accuracy between stereotactic magnetic resonance (MR) and CBCT images was evaluated using images from forty-one patients. The positions of the anterior and posterior commissures were measured in both a fiducial marker-based system and a co registered system. To assess the effects of MR image distortions, co-registration was performed with four different ranges, and the accuracy of the results was compared. Co-registration between CBCT images gave a mean three-dimensional deviation of 0.2 +/- 0.1 mm. The co-registration of stereotactic CT images with CBCT images produced a mean deviation of 0.5 +/- 0.2 mm. The co-registration of MR images with CBCT images resulted in the smallest three-dimensional difference (0.8 +/- 0.3 mm) when a co-registration region covering the skull base area was applied. The image co-registration errors in frameless GKSRS were similar to the imaging errors of frame-based GKSRS. The lower portion of the patient's head, including the base of the skull, is recommended for the ROC. PMID- 29499062 TI - Clinical and inflammatory characteristics of Asthma-COPD overlap in workers with occupational asthma. AB - INTRODUCTION: Although Asthma-COPD Overlap (ACO) has been described among populations of subjects with COPD or asthma, ACO has never been described among a population of subjects with occupational asthma (OA). OBJECTIVES: The aims of this study were to: 1. identify ACO in a population of subjects with OA; and 2. compare the clinical characteristics between ACO and OA. METHODS: This retrospective study included all subjects diagnosed with OA between 2000 and 2017 in an OA referral center. Occupational Asthma-COPD Overlap (OACO) was defined as post-bronchodilator FEV1/FVC < 70% and smoking history >= 10 pack-years, along with a diagnosis of OA. RESULTS: Three hundred and four subjects were included, 262 (86.2%) were classified as OA and 42 (13.8%) as OACO. OA subjects presented higher sputum eosinophil counts after a specific-inhalation challenge than subjects with OACO (median [IQR]: 6.5 [17.0] vs 2.3 [3.5]). After adjusting for confounding factors, subjects with OACO were older (OR: 1.10 [1.05; 1.14]) and were taking higher doses of inhaled corticosteroids than OA subjects (OR, 5.20 [1.77; 16.48]). Subjects with OACO were less often atopic than OA subjects (OR, 0.19 [0.07; 0.62]). CONCLUSIONS: Subjects with OACO constitute a distinct clinical and inflammatory phenotype from subjects with OA. PMID- 29499063 TI - Transcriptome analysis of embryonic domains in Norway spruce reveals potential regulators of suspensor cell death. AB - The terminal differentiation and elimination of the embryo-suspensor is the earliest manifestation of programmed cell death (PCD) during plant ontogenesis. Molecular regulation of suspensor PCD remains poorly understood. Norway spruce (Picea abies) embryos provide a powerful model for studying embryo development because of their large size, sequenced genome, and the possibility to obtain a large number of embryos at a specific developmental stage through somatic embryogenesis. Here, we have carried out global gene expression analysis of the Norway spruce embryo-suspensor versus embryonal mass (a gymnosperm analogue of embryo proper) using RNA sequencing. We have identified that suspensors have enhanced expression of the NAC domain-containing transcription factors, XND1 and ANAC075, previously shown to be involved in the initiation of developmental PCD in Arabidiopsis. The analysis has also revealed enhanced expression of Norway spruce homologues of the known executioners of both developmental and stress induced cell deaths, such as metacaspase 9 (MC9), cysteine endopeptidase-1 (CEP1) and ribonuclease 3 (RNS3). Interestingly, a spruce homologue of bax inhibitor-1 (PaBI-1, for Picea abies BI-1), an evolutionarily conserved cell death suppressor, was likewise up-regulated in the embryo-suspensor. Since Arabidopsis BI-1 so far has been implicated only in the endoplasmic reticulum (ER)-stress induced cell death, we investigated its role in embryogenesis and suspensor PCD using RNA interference (RNAi). We have found that PaBI-1-deficient lines formed a large number of abnormal embryos with suppressed suspensor elongation and disturbed polarity. Cytochemical staining of suspensor cells has revealed that PaBI-1 deficiency suppresses vacuolar cell death and induces necrotic type of cell death previously shown to compromise embryo development. This study demonstrates that a large number of cell-death components are conserved between angiosperms and gymnosperms and establishes a new role for BI-1 in the progression of vacuolar cell death. PMID- 29499064 TI - Dimensions and predictors of disability-A baseline study of patients entering somatic rehabilitation in secondary care. AB - PURPOSE: The purpose of this study was to investigate disability among patients who were accepted for admission to a Norwegian rehabilitation center and to identify predictors of disability. MATERIALS AND METHODS: In a cross-sectional study including 967 adult participants, the World Health Organization Disability Assessment Schedule version 2.0 36-item version was used for assessing overall and domain-specific disability as outcome variables. Patients completed the Hospital Anxiety and Depression Scale (HADS), EuroQoL EQ-5D-5L and questions about multi-morbidity, smoking and perceived physical fitness. Additionally, the main health condition, sociodemographic and environmental variables obtained from referrals and public registers were used as predictor variables. Descriptive statistics and linear regression analyses were performed. RESULTS: The mean (standard error) overall disability score was 30.0 (0.5), domain scores ranged from 11.9 to 44.7. Neurological diseases, multi-morbidity, low education, impaired physical fitness, pain, and higher HADS depressive score increased the overall disability score. A low HADS depressive score predicted a lower disability score in all domains. CONCLUSIONS: A moderate overall disability score was found among patients accepted for admission to a rehabilitation center but "life activities" and "participation in society" had the highest domain scores. This should be taken into account when rehabilitation strategies are developed. PMID- 29499065 TI - High content screening of patient-derived cell lines highlights the potential of non-standard chemotherapeutic agents for the treatment of glioblastoma. AB - BACKGROUND: Glioblastoma (GBM) is the most common primary brain malignancy in adults, yet survival outcomes remain poor. First line treatment is well established, however disease invariably recurs and improving prognosis is challenging. With the aim of personalizing therapy at recurrence, we have established a high content screening (HCS) platform to analyze the sensitivity profile of seven patient-derived cancer stem cell lines to 83 FDA-approved chemotherapy drugs, with and without irradiation. METHODS: Seven cancer stem cell lines were derived from patients with GBM and, along with the established cell line U87-MG, each patient-derived line was cultured in tandem in serum-free conditions as adherent monolayers and three-dimensional neurospheres. Chemotherapeutics were screened at multiple concentrations and cells double stained to observe their effect on both cell death and proliferation. Sensitivity was classified using high-throughput algorithmic image analysis. RESULTS: Cell line specific drug responses were observed across the seven patient-derived cell lines. Few agents were seen to have radio-sensitizing effects, yet some drug classes showed a marked difference in efficacy between monolayers and neurospheres. In vivo validation of six drugs suggested that cell death readout in a three-dimensional culture scenario is a more physiologically relevant screening model and could be used effectively to assess the chemosensitivity of patient-derived GBM lines. CONCLUSION: The study puts forward a number of non standard chemotherapeutics that could be useful in the treatment of recurrent GBM, namely mitoxantrone, bortezomib and actinomycin D, whilst demonstrating the potential of HCS to be used for personalized treatment based on the chemosensitivity profile of patient tumor cells. PMID- 29499068 TI - Transcriptome-wide selection of a reliable set of reference genes for gene expression studies in potato cyst nematodes (Globodera spp.). AB - Relative gene expression analyses by qRT-PCR (quantitative reverse transcription PCR) require an internal control to normalize the expression data of genes of interest and eliminate the unwanted variation introduced by sample preparation. A perfect reference gene should have a constant expression level under all the experimental conditions. However, the same few housekeeping genes selected from the literature or successfully used in previous unrelated experiments are often routinely used in new conditions without proper validation of their stability across treatments. The advent of RNA-Seq and the availability of public datasets for numerous organisms are opening the way to finding better reference genes for expression studies. Globodera rostochiensis is a plant-parasitic nematode that is particularly yield-limiting for potato. The aim of our study was to identify a reliable set of reference genes to study G. rostochiensis gene expression. Gene expression levels from an RNA-Seq database were used to identify putative reference genes and were validated with qRT-PCR analysis. Three genes, GR, PMP-3, and aaRS, were found to be very stable within the experimental conditions of this study and are proposed as reference genes for future work. PMID- 29499067 TI - Increased risk of overactive bladder in patients with idiopathic Parkinson's disease: Insight from a nationwide population-based cohort study. AB - BACKGROUND: Idiopathic Parkinson's disease (IPD) is a progressive neurodegenerative disorder characterized by typical motor impairment. However, lower urinary tract symptoms, including urinary urgency or frequency, which are non-motor phenomena, occur frequently among patients with IPD. In this study, we assess the risk of overactive bladder (OAB) in patients with IPD. METHODS: The National Health Insurance Research Database of Taiwan was used to identify patients with IPD (IPD cohort) and four-fold controls (non-IPD cohort) from 2000 to 2010. The non-IPD cohort was matched according to age, sex, and baseline comorbidities, including benign prostate hyperplasia, stress incontinence, diabetes, and cerebrovascular diseases. The occurrence of OAB was monitored until the end of 2011. Hazard ratios of OAB were estimated using Cox proportional hazards regression models. RESULTS: In total, 4,571 and 18,255 patients were included in IPD and non-IPD cohorts, respectively. Results showed a significantly higher overall incidence rate of OAB in the IPD cohort compared with the non-IPD cohort (14.5 vs. 6.37 per 10,000 person-years), with a 2.3-fold increased risk of OAB (95% confidence interval [CI] = 1.51-3.51) after controlling for benign prostate hyperplasia and stress incontinence. The mean follow-up period for the IPD cohort was 5.0 years. This cohort study showed that the cumulative incidence of OAB was 0.65% at the fifth year and 1.54% at the tenth year after IPD diagnosis; this risk was highest in the age group 65-74 years. CONCLUSION: This study reveals that IPD is independently associated with an increased risk of OAB in patients with IPD. The probability of OAB was 1.54% over a 10-year period after IPD diagnosis; the risk of OAB is considered to be age-dependent and most substantial in patients aged 65-74 years. PMID- 29499066 TI - The interferon-stimulated gene product oligoadenylate synthetase-like protein enhances replication of Kaposi's sarcoma-associated herpesvirus (KSHV) and interacts with the KSHV ORF20 protein. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is one of the few oncogenic human viruses known to date. Its large genome encodes more than 85 proteins and includes both unique viral proteins as well as proteins conserved amongst herpesviruses. KSHV ORF20 is a member of the herpesviral core UL24 family, but the function of ORF20 and its role in the viral life cycle is not well understood. ORF20 encodes three largely uncharacterized isoforms, which we found were localized predominantly in the nuclei and nucleoli. Quantitative affinity purification coupled to mass spectrometry (q-AP-MS) identified numerous specific interacting partners of ORF20, including ribosomal proteins and the interferon stimulated gene product (ISG) oligoadenylate synthetase-like protein (OASL). Both endogenous and transiently transfected OASL co-immunoprecipitated with ORF20, and this interaction was conserved among all ORF20 isoforms and multiple ORF20 homologs of the UL24 family in other herpesviruses. Characterization of OASL interacting partners by q-AP-MS identified a very similar interactome to that of ORF20. Both ORF20 and OASL copurified with 40S and 60S ribosomal subunits, and when they were co-expressed, they associated with polysomes. Although ORF20 did not have a global effect on translation, ORF20 enhanced RIG-I induced expression of endogenous OASL in an IRF3-dependent but IFNAR-independent manner. OASL has been characterized as an ISG with antiviral activity against some viruses, but its role for gammaherpesviruses was unknown. We show that OASL and ORF20 mRNA expression were induced early after reactivation of latently infected HuARLT rKSHV.219 cells. Intriguingly, we found that OASL enhanced infection of KSHV. During infection with a KSHV ORF20stop mutant, however, OASL-dependent enhancement of infectivity was lost. Our data have characterized the interaction of ORF20 with OASL and suggest ORF20 usurps the function of OASL to benefit KSHV infection. PMID- 29499069 TI - Peptide Inhibitor of Complement C1 (PIC1) demonstrates antioxidant activity via single electron transport (SET) and hydrogen atom transfer (HAT). AB - Reactive oxygen species (ROS) are natural byproducts of oxidative respiration that are toxic to organs and tissues. To mitigate ROS damage, organisms have evolved a variety of antioxidant systems to counteract these harmful molecules, however in certain pathological conditions these protective mechanisms can be overwhelmed. We have recently demonstrated that Peptide Inhibitor of Complement C1 (PIC1) mitigates peroxidase activity of the heme bearing proteins myeloperoxidase, hemoglobin, and myoglobin through a reversible process. To determine if this property of PIC1 was antioxidant in nature, we tested PIC1 in a number of well-established antioxidant assays. PIC1 showed dose-dependent antioxidant activity in a total antioxidant (TAC) assay, hydroxyl radical antioxidant capacity (HORAC) assay, oxygen radical antioxidant capacity (ORAC) assay as well as the thiobarbituric acid reactive substances (TBARS) assay to screen for PIC1 antioxidant activity in human plasma. The antioxidant activity of PIC1 in the TAC assay, as well as the HORAC/ORAC assay demonstrated that this peptide acts via the single electron transport (SET) and hydrogen atom transfer (HAT) mechanisms, respectively. Consistent with this mechanism of action, PIC1 did not show activity in a metal chelating activity (MCA) assay. PIC1 contains two vicinal cysteine residues and displayed similar antioxidant activity to the well characterized cysteine-containing tripeptide antioxidant molecule glutathione (GSH). Consistent with the role of the cysteine residues in the antioxidant activity of PIC1, oxidation of these residues significantly abrogated antioxidant activity. These results demonstrate that in addition to its described complement inhibiting activity, PIC1 displays in vitro antioxidant activity. PMID- 29499070 TI - Screening for human papillomavirus-driven oropharyngeal cancer: Considerations for feasibility and strategies for research. PMID- 29499071 TI - Do 1 in 5 cancer patients develop post-traumatic stress disorder? PMID- 29499072 TI - Cancer pain management and the opioid crisis in America: How to preserve hard earned gains in improving the quality of cancer pain management. AB - Cancer pain remains a feared consequence of the disease and its treatment. Although prevalent, cancer pain can usually be managed through the skillful application of pharmacologic and nonpharmacologic interventions. Unfortunately, access to these therapies has been hampered by interventions designed to contain another serious public health problem: the opioid misuse epidemic. This epidemic and the unintended consequences of efforts to control this outbreak are leading to significant barriers to the provision of cancer pain relief. Oncologists and other professionals treating those with cancer pain will require new knowledge and tools to provide safe and effective pain control while preventing additional cases of substance use disorders (SUDs), helping patients in recovery to maintain sobriety, and guiding those not yet in recovery to seek treatment. How do these 2 serious epidemics intersect and affect oncology practice? First, oncology professionals will need to adopt practices to prevent SUDs by assessing risk and providing safe pain care. Second, oncology practices are likely to see an increased number of patients with a current or past SUD, including opioid misuse. Few guidelines exist for the direct management of pain when opioids may be indicated in these individuals. Third, modified prescribing practices along with the education of patients and families are warranted to prevent the exposure of these medications to unintended persons. Finally, advocacy on behalf of those with cancer pain is imperative to avoid losing access to essential therapies, including opioids, for those who might benefit. Cancer 2018;124:2491-7. (c) 2018 American Cancer Society. PMID- 29499073 TI - Dose-intensified hypofractionated stereotactic body radiation therapy for painful spinal metastases: Results of a phase 2 study. AB - BACKGROUND: The objective of this study was to prospectively evaluate dose intensified hypofractionated stereotactic body radiation therapy (SBRT) in patients with painful spinal metastases in a multicenter, single-arm, phase 2 study. METHODS: Patients with 2 or fewer distinct, noncontiguous, painful, mechanically stable, unirradiated spinal metastases from a solid tumor with a Karnofsky performance status >= 60 were eligible. Patients with a long (Mizumoto score <= 4) or intermediate overall survival expectancy (Mizumoto score = 5-9) received 48.5 Gy in 10 fractions or 35 Gy in 5 fractions, respectively, with SBRT. The primary outcome was the overall (complete and partial) pain response as measured with international consensus guidelines 3 months after SBRT. RESULTS: There were 57 patients enrolled between 2012 and 2015, and 54 of these patients with 60 painful vertebral metastases were analyzed. The 3-month pain response was evaluated in 42 patients (47 lesions). An overall pain response was observed in 41 lesions (87%), and the pain response remained stable for at least 12 months. The mean maximum pain scores on a visual analogue scale significantly improved from the baseline of 6.1 (standard deviation, 2.5) to 2.0 (standard deviation, 2.3) 3 months after treatment (P < .001). The 5-level EuroQol 5-Dimension Questionnaire quality-of-life (QOL) dimensions (self-reported mobility, usual activities, and pain/discomfort) significantly improved from the baseline to 3 months after treatment. The 12-month overall survival and local control rates were 61.4% (95% confidence interval [CI], 48%-74.8%) and 85.9% (95% CI, 76.7% 95%), respectively. Grade 3 toxicity was limited to acute pain in 1 patient (2%). No patient experienced radiation-induced myelopathy. Six patients (11%) developed progressive vertebral compression fractures (VCFs), and 8 patients (15%) developed new VCFs. CONCLUSIONS: Dose-intensified SBRT achieved durable local metastasis control and resulted in pronounced and long-term pain responses and improved QOL. Cancer 2018;124:2001-9. (c) 2018 American Cancer Society. PMID- 29499075 TI - Nine-year prostate cancer survival differences between aggressive versus conservative therapy in men with advanced and metastatic prostate cancer. AB - BACKGROUND: To the authors' knowledge, the survival benefit of local therapy in the setting of advanced prostate cancer remains unknown. The authors investigated whether prostate-directed treatment with either surgery or radiotherapy versus conservative treatment in the setting of locally advanced or metastatic disease was associated with improved survival within a cohort of men from the Centers for Disease Control and Prevention's (CDC) Breast and Prostate Cancer Data Quality and Patterns of Care Study (CDC POC-BP). METHODS: Men diagnosed with locally advanced (cT3-T4 or N+ and M0) or metastatic prostate cancer were identified. The authors compared survival by treatment type, categorized as conservative (androgen deprivation therapy only) versus aggressive (radical prostatectomy or any type of radiotherapy). Nine-year overall survival and prostate cancer specific survival were estimated using the Kaplan-Meier method. The Cox proportional hazards model was used to determine factors independently associated with 9-year prostate cancer-specific survival. RESULTS: For men with advanced, nonmetastatic prostate cancer, conservative treatment alone was associated with a 4 times higher likelihood of prostate cancer mortality compared with men treated with surgery (hazard ratio, 4.18; 95% confidence interval, 1.44-12.14). In contrast, no difference was found between conservative versus aggressive treatment after adjusting for covariates for men with metastatic disease. The 9 year prostate cancer-specific survival rate was 27% for those receiving aggressive treatment versus 24% for men undergoing conservative treatment. CONCLUSIONS: The authors did not observe a survival advantage with local therapy in addition to standard androgen deprivation therapy for men with metastatic prostate cancer. However, the results of the current study did affirm advantages in the setting of locally advanced disease. Aggressive local therapy in the setting of metastatic disease needs to be studied carefully before clinical adoption. Cancer 2018;124:1921-8. (c) 2018 American Cancer Society. PMID- 29499074 TI - Breast cancer-specific survival by age: Worse outcomes for the oldest patients. AB - BACKGROUND: Although breast cancer often is perceived to be indolent in older women, breast cancer outcomes in the oldest patients are variable. In the current study, the authors examined breast cancer-specific death by age, stage, and disease subtype in a large, population-based cohort. METHODS: Using Surveillance, Epidemiology, and End Results data, a total of 486,118 women diagnosed with American Joint Committee on Cancer stage I to IV breast cancer between 2000 and 2012 were identified. Using a series of Fine and Gray regression models to account for competing risk, the authors examined the risk of breast cancer specific death by age and stage (I-IV) for subcohorts with hormone receptor (HR) positive, HR-negative, human epidermal growth factor receptor 2-positive, and triple-negative disease, adjusting for demographic and clinical variables. RESULTS: Overall, 18% of women were aged 65 to 74 years, 13% were aged 75 to 84 years, and 4% were aged >=85 years. Regardless of stage of disease within the HR positive and HR-negative cohorts, patients aged >=75 years (vs those aged 55-64 years) experienced a higher adjusted hazard of breast cancer-specific death, which was particularly evident for those with early-stage, HR-positive disease (hazard ratio for those aged 75-84 years, 1.88 [95% confidence interval, 1.68 2.09] and hazard ratio for those aged >=85 years, 3.59 [95% confidence interval, 3.12-4.13] [both for stage I disease]). In the cohorts with human epidermal growth factor receptor 2-positive and triple-negative disease, women aged >=70 years had a consistently higher risk of breast cancer-specific death across disease stages (vs those aged 51-60 years), with the exception of stage IV triple negative disease. CONCLUSIONS: Older patients experience worse breast cancer outcomes, regardless of disease subtype and stage. With an increasing number of older patients anticipated to develop breast cancer in the future, addressing disparities for older patients must emerge as a clinical and research priority. Cancer 2018;124:2184-91. (c) 2018 American Cancer Society. PMID- 29499076 TI - Reply to Do 1 in 5 cancer patients develop post-traumatic stress disorder? PMID- 29499077 TI - Human leukocyte antigen compatibility and lymphocyte cross-matching play no significant role in the current adult-to-adult living donor liver transplantation. AB - BACKGROUND: The impact of human leukocyte antigen (HLA) compatibility and positive lymphocyte cross-match (LCM) on organ transplantation is well-recognized particularly in kidney and heart transplantation; however, it is still debatable in liver transplantation (LT). So, the aim of this study was to evaluate the impact of HLA mismatch and positive LCM on the outcome of LT. METHODS: We retrospectively analyzed the data of all adult recipients who underwent living donor LT at our institute between January 2010 and July 2016. We excluded all ABO blood group incompatible LDLT patients and patients with incomplete data regarding HLA genotyping (n = 134). The type and degree of HLA-A, HLA-B, HLA-C, HLA-DR, HLA-DQ mismatch and LCM were assessed in each donor-recipient pair and their relationship to the occurrence of rejection, CMV infection and graft survival was evaluated. RESULTS: A higher percentage (>50%) of donor-recipient pairs had 1 HLA mismatch at each locus in the host-vs-graft direction and seventeen recipients (13%) had positive LCM. Human leukocyte antigen mismatch and positive LCM were not correlated with increased incidence of acute rejection (P = .37, P = .6, respectively), CMV infection post-transplant (P = .52, P = .76, respectively), or graft failure (HR 1.22, P = .68 and HR 1.73, P = .34, respectively). CONCLUSION: Positive LCM and HLA mismatches did not affect the overall graft survival after adult-to-adult LDLT and should not be considered as contraindications for liver transplantation. PMID- 29499078 TI - Ethylene mediates dichromate-induced inhibition of primary root growth by altering AUX1 expression and auxin accumulation in Arabidopsis thaliana. AB - The hexavalent form of chromium [Cr(VI)] causes a major reduction in yield and quality of crops worldwide. The root is the first plant organ that interacts with Cr(VI) toxicity, which inhibits primary root elongation, but the underlying mechanisms of this inhibition remain elusive. In this study, we investigate the possibility that Cr(VI) reduces primary root growth of Arabidopsis by modulating the cell cycle-related genes and that ethylene signalling contributes to this process. We show that Cr(VI)-mediated inhibition of primary root elongation was alleviated by the ethylene perception and biosynthesis antagonists silver and cobalt, respectively. Furthermore, the ethylene signalling defective mutants (ein2-1 and etr1-3) were insensitive, whereas the overproducer mutant (eto1-1) was hypersensitive to Cr(VI). We also report that high levels of Cr(VI) significantly induce the distribution and accumulation of auxin in the primary root tips, but this increase was significantly suppressed in seedlings exposed to silver or cobalt. In addition, genetic and physiological investigations show that AUXIN-RESISTANT1 (AUX1) participates in Cr(VI)-induced inhibition of primary root growth. Taken together, our results indicate that ethylene mediates Cr(VI) induced inhibition of primary root elongation by increasing auxin accumulation and polar transport by stimulating the expression of AUX1. PMID- 29499079 TI - Optimization of sample preparation for intact cell mass spectrometry (matrix assisted laser desorption/ionization linear time-of-flight mass spectrometry) of endophytic Xylaria. AB - RATIONALE: Although the fruiting-body of the fungi of the genus Xylaria shows a great variety of morphological characteristics, their mycelial forms are always very similar, imposing difficulties for their identification. Intact cell mass spectrometry (ICMS) using matrix-assisted laser desorption/ionization time-of flight mass spectrometry (MALDI-TOFMS) can be a fast and reliable strategy to support the differentiation/identification of Xylaria species in those cases where fruit-bodies are not available. METHODS: Many experimental parameters such as sample preparation and culture media are crucial for filamentous fungi analysis by MALDI-TOFMS. For the purposes of this study, we used four matrices (CHCA, DHB, FA and SA) with five different concentrations (0.1, 0.3, 0.5, 1.0 and 2.5%) of TFA in the matrix, the influence of six different culture media (solid and liquid), and three mycelium peptide/protein extraction protocols (acid, basic and thymol-supported solution) to optimize the sample preparation of the endophytic fungus X. arbuscula. RESULTS: It was observed that sinapinic acid (30 mg/mL) dissolved in acetonitrile/0.1% TFA and PDA were the best matrix solution and culture medium, respectively, for the ICMS of X. arbuscula. The formic acid and ammonium bicarbonate (AB) protocols provided similar mass spectra; however, a higher number of peaks were observed using AB extraction. Mass spectra obtained from different thymol-containing solutions (EtOH/aqueous 0.1% TFA and ACN/aqueous 0.1% TFA) show increasing peak abundances at m/z 3000-6500. CONCLUSIONS: X. arbuscula could be analyzed by ICMS. However, an extraction step was required to provide suitable MALDI mass spectra. Formic acid-, AB- and thymol-containing solutions were demonstrated to be good cocktails for the extraction of peptide/protein biomarkers from these fungi. PMID- 29499080 TI - Poloxamer 407-chitosan grafted thermoresponsive hydrogels achieve synchronous and sustained release of antigen and adjuvant from single-shot vaccines. AB - Sustained-release vaccine delivery systems may enhance the immunogenicity of subunit vaccines and reduce the need for multiple vaccinations. The aim of this study was to develop a thermoresponsive hydrogel using poloxamer 407-chitosan (CP) grafted copolymer as a delivery system for single-shot sustained-release vaccines. The CP copolymer was synthesized using 1-ethyl-3-(3 dimethylaminopropyl)-carbodiimide and N-hydroxysuccinimide chemistry. The CP copolymer was a free flowing solution at ambient temperature and transformed rapidly into a gel at body temperature. The hydrogels were loaded with vaccine antigen and adjuvants or the vaccine components were encapsulated in poly (lactic co-glycolic acid) nanoparticles in order to ensure synchronous release. The CP hydrogels were stable for up to 18 days in vitro. Release of both nanoparticles and the individual components was complete, with release of the individual components being modulated by incorporation into nanoparticles. In vivo, a single dose of CP hydrogel vaccine induced strong, long lasting, cellular and humoral responses that could protect against the development of tumors in a murine melanoma model. PMID- 29499081 TI - Beta-blockers for prevention and treatment of retinopathy of prematurity in preterm infants. AB - BACKGROUND: Retinopathy of prematurity (ROP) is a vision-threatening disease of preterm neonates. The use of beta-adrenergic blocking agents (beta-blockers), which modulate the vasoproliferative retinal process, may reduce the progression of ROP or even reverse established ROP. OBJECTIVES: To determine the effect of beta-blockers on short-term structural outcomes, long-term functional outcomes, and the need for additional treatment, when used either as prophylaxis in preterm infants without ROP, stage 1 ROP (zone I), or stage 2 ROP (zone II) without plus disease or as treatment in preterm infants with at least prethreshold ROP. SEARCH METHODS: We searched the Cochrane Neonatal Review Group Specialized Register; CENTRAL (in the Cochrane Library Issue 7, 2017); Embase (January 1974 to 7 August 2017); PubMed (January 1966 to 7 August 2017); and CINAHL (January 1982 to 7 August 2017). We checked references and cross-references and handsearched abstracts from the proceedings of the Pediatric Academic Societies Meetings. SELECTION CRITERIA: We considered for inclusion randomised or quasi-randomised clinical trials that used beta-blockers for prevention or treatment of ROP in preterm neonates of less than 37 weeks' gestational age. DATA COLLECTION AND ANALYSIS: We used the standard methods of Cochrane and the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: We included three randomised trials (N = 366) in this review. Two of these studies were at high risk of bias. All studies reported on prevention of ROP and compared oral propranolol with placebo or no treatment. We found no trials assessing beta-blockers in infants with established stage 2 or higher ROP with plus disease.In one trial, study medication was started after one week of life, i.e. prior to the first ROP screening. The other two trials included preterm infants if they had stage 2 or lower ROP without plus disease. Based on the GRADE assessment, we considered evidence to be of low quality for the following outcomes: rescue treatment with anti-VEGF or laser therapy; and arterial hypotension or bradycardia requiring inotropic support. Evidence was of moderate quality for the following outcomes: progression to stage 2 with plus disease; progression to stage 3 ROP; and progression to stage 4 or 5 ROP.Meta analysis of three trials (N = 366) suggested beneficial effects of oral beta blockers on the risk of requiring anti-VEGF agents (typical risk ratio (RR) 0.32, 95% confidence interval (CI) 0.12 to 0.86; I2 = 0%; typical risk difference (RD) 0.06, 95% CI -0.10 to -0.01; I2 = 75%; number needed to treat for an additional beneficial outcome (NNTB) 18, 95% CI 14 to 84) and laser therapy (typical RR 0.54, 95% CI 0.32 to 0.89; typical RD -0.09, 95% CI -0.16 to -0.02; I2 = 31%; NNTB 12, 95% CI 8 to 47). Meta-analysis of two trials (N = 161) demonstrated a beneficial effect of oral beta-blockers on progression to stage 3 ROP (typical RR 0.60, 95% CI 0.37 to 0.96; I2 = 0%; typical RD -0.15, 95% CI -0.28 to -0.02; I2 = 73%; NNTB 7, 95% CI 5 to 67). There was no significant effect of oral beta blockers on progression to stage 2 ROP with plus disease or to stage 4 or 5 ROP. Although meta-analysis did not indicate a significant effect of beta-blockers on arterial hypotension or bradycardia, propranolol dosage in one study was reduced by 50% in infants of less than 26 weeks' gestational age due to severe hypotension, bradycardia, and apnoea in several participants. Analyses did not indicate significant effects of beta-blockers on complications of prematurity or mortality. None of the trials reported on long-term visual impairment. AUTHORS' CONCLUSIONS: Limited evidence of low-to-moderate quality suggests that prophylactic administration of oral beta-blockers might reduce progression towards stage 3 ROP and decrease the need for anti-VEGF agents or laser therapy. The clinical relevance of those findings is unclear as no data on long-term visual impairment were reported. Adverse events attributed to oral propranolol at a dose of 2 mg/kg/d raise concerns regarding systemic administration of this drug for prevention of ROP at the given dose. There is insufficient evidence to determine the efficacy and safety of beta-blockers for prevention of ROP due to high risk of bias in two included trials and the lack of long-term functional outcomes. We would encourage researchers to conduct large, well-designed trials to confirm or refute the role of beta-blockers for prevention and treatment of ROP in preterm infants. Trials should report on long-term visual impairment. Researchers should consider dose-finding studies of systemic beta-blockers and topical administration of beta-blockers, in order to optimise drug delivery and minimise adverse events. PMID- 29499082 TI - Traditional herbal medicine prevents postoperative recurrence of small hepatocellular carcinoma: A randomized controlled study. AB - BACKGROUND: To explore the clinical efficacy of traditional herbal medicine (THM) in the prevention of disease recurrence of small hepatocellular carcinoma after surgery, a prospective randomized controlled study was conducted between October 2006 and May 2010. The results indicated that THM prevented the recurrence of SHCC with an efficacy that was superior to that of transarterial chemoembolization (TACE) during a median follow-up of 26.61 months. METHODS: The patients were followed up every 6 months, and the clinical data before October 20, 2015 were analyzed. The primary outcome measure was recurrence-free survival (RFS), and the secondary outcome measure was overall survival (OS). RESULTS: The 364 patients included 180 in the THM group and 184 in the TACE group. At the time of the data cutoff of October 20, 2015, a total of 205 patients demonstrated disease recurrence, including 85 patients in the THM group and 120 patients in the TACE group. The median RFS of the THM and TACE groups demonstrated a statistically significant difference (P<.001). Until October 20, 2105, there were 91 deaths, including 34 in the THM group and 57 in the TACE group. The median OS demonstrated a significant difference between the 2 groups (P = .008). Multivariate analysis indicated that THM was an independent factor influencing RFS and OS. CONCLUSIONS: The efficacy of THM was found to be superior to that of TACE in preventing disease recurrence in patients with small hepatocellular carcinoma and prolonging OS. Cancer 2018;124:2161-8. (c) 2018 American Cancer Society. PMID- 29499083 TI - Overt gastrointestinal bleeding caused by hookworm infection, diagnosed by capsule endoscopy. PMID- 29499085 TI - Left hippocampal dosimetry correlates with visual and verbal memory outcomes in survivors of pediatric brain tumors. AB - BACKGROUND: Radiotherapy (RT) in the pediatric brain tumor population causes late neurocognitive effects. In the current study, the authors investigated associations between clinical and dosimetric risk factors and memory outcomes in a cohort of patients treated with proton radiotherapy (PRT). METHODS: A total of 70 patients (median age at PRT, 12.1 years [range, 5.0-22.5 years]) who were treated with PRT were identified with baseline and follow-up evaluations of visual and verbal memory (Children's Memory Scale and the third edition of the Wechsler Memory Scale). Whole-brain as well as bilateral hippocampal and temporal lobe contours were delineated for the calculation of dosimetric indices. Multivariate analyses were performed to assess associations of score changes over time with clinical factors and dosimetric indices. RESULTS: The median neurocognitive follow-up was 3.0 years (range, 1.1-11.4 years). For the entire cohort, delayed and immediate verbal memory scaled scores demonstrated small declines. The mean decline for delayed verbal memory scores was 0.6 (P = .01), and that for immediate verbal memory scores was 0.5 (P = .06). Immediate and delayed visual memory scores were not found to change significantly (+0.1 and 0.3, respectively; P>.30). A higher left hippocampal V20GyE (percentage of the volume of a particular anatomical region receiving at least a 20 gray equivalent) was correlated with a score decline in all 4 measures. Female sex was found to be predictive of lower delayed verbal memory follow-up scores (P = .035). CONCLUSIONS: Only delayed verbal memory scores were found to have declined statistically significantly at follow-up after PRT, reflecting some weakness in verbal memory retrieval. Given a correlation of left hippocampal dosimetry and memory outcomes after PRT, left hippocampal-sparing PRT plans may assist patients with pediatric brain tumors in preserving memory-retrieval abilities. Cancer 2018;124:2238-45. (c) 2018 American Cancer Society. PMID- 29499086 TI - Adaptive responses of mature giant chloroplasts in the deep-shade lycopod Selaginella erythropus to prolonged light and dark periods. AB - Deep-shade plants have adapted to low-light conditions by varying morphology and physiology of cells and chloroplasts, but it still remains unclear, if prolonged periods of high-light or darkness induce additional modifications in chloroplasts' anatomy and pigment patterns. We studied giant chloroplasts (bizonoplasts) of the deep-shade lycopod Selaginella erythropus in epidermal cells of mature fully developed microphylls and subjected them to prolonged darkness and high-light conditions. Chloroplast size and ultrastructure were investigated by light and electron microscopy. Physiological traits were studied by pigment analyses, photosynthetic performance of photosystem II, and formation of reactive oxygen species. Results show that (a) thylakoid patterns and shape of mature bizonoplasts vary in response to light and dark conditions. (b) Prolonged darkness induces transitory formation of prolamellar bodies, which so far have not been described in mature chloroplasts. (c) Photosynthetic activity is linked to structural responses of chloroplasts. (d) Photosystem II is less active in the upper zone of bizonoplasts and more efficient in the grana region. (e) Formation of reactive oxygen species reflects the stress level caused by high-light. We conclude that during prolonged darkness, chlorophyll persists and even increases; prolamellar bodies form de novo in mature chloroplasts; bizonoplasts have spatial heterogeneity of photosynthetic performance. PMID- 29499088 TI - Neural and behavioral effects of subordinate-level training of novel objects across manipulations of color and spatial frequency. AB - Perceptual expertise is marked by subordinate-level recognition of objects in the expert domain. In this study, participants learned one family of full-color, artificial objects at the subordinate (species) level and another family at the basic (family) level. Discrimination of trained and untrained exemplars was tested before and after training across several image manipulations [full-color, grayscale, low spatial frequency (LSF) and high spatial frequency (HSF)] while event-related potentials (ERPs) were recorded. Regardless of image manipulation, discrimination (indexed by d') of trained and of untrained exemplars was enhanced after subordinate-level training, but not after basic-level training. Enhanced discrimination after subordinate-level training generalized to untrained exemplars and to grayscale images and images in which LSF or HSF information was removed. After training, the N170 and N250, recorded over occipital and occipitotemporal brain regions, were both more enhanced after subordinate-level training than after basic-level training. However, the topographic distribution of enhanced responses differed across components. The N170 latency predicted reaction time after both basic-level training and subordinate-level training, highlighting an association between behavioral and neural responses. These findings further elucidate the role of the N170 and N250 as ERP indices of subordinate-level expert object processing and demonstrate how low-level manipulations of color and spatial frequency impact behavior and the N170 and N250 components independent of training or expertise. PMID- 29499087 TI - Health-related quality of life in patients with chronic myeloid leukemia receiving first-line therapy with nilotinib. AB - BACKGROUND: Although a wealth of efficacy and safety data is available for many tyrosine kinase inhibitors used in chronic myeloid leukemia (CML), there is a dearth of information on their impact on patients' health-related quality of life (HRQOL). The primary objective of this study was to evaluate HRQOL and fatigue outcomes in patients with CML receiving first-line therapy with nilotinib. METHODS: This was a multicenter, prospective study enrolling 130 patients with chronic-phase CML. HRQOL and fatigue were evaluated with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and its validated Fatigue module at the baseline and then at 3, 6, 12, 18, and 24 months. The primary prespecified HRQOL endpoints defined in the study protocol for longitudinal analysis were the Physical Functioning, Social Functioning, Role Functioning, and Fatigue scales. The remaining scales were investigated on an exploratory basis. RESULTS: The rate of baseline compliance with the HRQOL assessment was 95.4% (124 of 130), and the rate of overall compliance with HRQOL forms was 91%. Among the 4 prespecified primary HRQOL endpoints, statistically significant improvements over time were found for Physical Functioning (P = .013), Role Functioning (P = .004), and Fatigue (P < .001). Clinically meaningful improvements were found already 3 months after the treatment start. The baseline patient self-reported fatigue severity was an independent predictive factor for the achievement of a major molecular response with an odds ratio of 0.960 (95% confidence interval, 0.934-0.988; P = .005). CONCLUSIONS: For most patients, HRQOL improvements with nilotinib occur during the early phase of therapy and are maintained over time. Also, a more systematic HRQOL evaluation during the diagnostic workup of CML may help to predict clinical outcomes. Cancer 2018;124:2228-37. (c) 2018 American Cancer Society. PMID- 29499089 TI - Processing of performance-matched visual object categories: faces and places are related to lower processing load in the frontoparietal executive network than other objects. AB - This study aimed to explore the differential role of the frontoparietal network in processing different visual object categories, matched for difficulty level, during a 1-back paradigm. To achieve this goal, we first mapped the effort related frontoparietal saliency network, by contrasting activation elicited by face, object, place, body and verbal stimulus categories, which were matched for performance level, and speed of processing, with difficult scrambled stimuli. We then computed the weight of object predictors on that specific network, using an independent orthogonal analysis. Overall, our results demonstrated that face (and to some extent also places) stimuli were associated with lower processing load in regions of the frontoparietal network comparing to other visual categories, suggesting that face/place processing does require to a much smaller extent the recruitment of the frontoparietal control network than any other object categories. Thus, face detection and place detection seem to be routed in specific neuronal systems that readily encode the holistic nature of this type of objects. We conclude that the more limited recruitment of frontoparietal networks reflects the automaticity of face and place processing and their smaller dependence on general capacity limits. PMID- 29499084 TI - Physical activity, diet and other behavioural interventions for improving cognition and school achievement in children and adolescents with obesity or overweight. AB - BACKGROUND: The global prevalence of childhood and adolescent obesity is high. Lifestyle changes towards a healthy diet, increased physical activity and reduced sedentary activities are recommended to prevent and treat obesity. Evidence suggests that changing these health behaviours can benefit cognitive function and school achievement in children and adolescents in general. There are various theoretical mechanisms that suggest that children and adolescents with excessive body fat may benefit particularly from these interventions. OBJECTIVES: To assess whether lifestyle interventions (in the areas of diet, physical activity, sedentary behaviour and behavioural therapy) improve school achievement, cognitive function (e.g. executive functions) and/or future success in children and adolescents with obesity or overweight, compared with standard care, waiting list control, no treatment, or an attention placebo control group. SEARCH METHODS: In February 2017, we searched CENTRAL, MEDLINE and 15 other databases. We also searched two trials registries, reference lists, and handsearched one journal from inception. We also contacted researchers in the field to obtain unpublished data. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials (RCTs) of behavioural interventions for weight management in children and adolescents with obesity or overweight. We excluded studies in children and adolescents with medical conditions known to affect weight status, school achievement and cognitive function. We also excluded self- and parent reported outcomes. DATA COLLECTION AND ANALYSIS: Four review authors independently selected studies for inclusion. Two review authors extracted data, assessed quality and risks of bias, and evaluated the quality of the evidence using the GRADE approach. We contacted study authors to obtain additional information. We used standard methodological procedures expected by Cochrane. Where the same outcome was assessed across different intervention types, we reported standardised effect sizes for findings from single-study and multiple study analyses to allow comparison of intervention effects across intervention types. To ease interpretation of the effect size, we also reported the mean difference of effect sizes for single-study outcomes. MAIN RESULTS: We included 18 studies (59 records) of 2384 children and adolescents with obesity or overweight. Eight studies delivered physical activity interventions, seven studies combined physical activity programmes with healthy lifestyle education, and three studies delivered dietary interventions. We included five RCTs and 13 cluster-RCTs. The studies took place in 10 different countries. Two were carried out in children attending preschool, 11 were conducted in primary/elementary school-aged children, four studies were aimed at adolescents attending secondary/high school and one study included primary/elementary and secondary/high school-aged children. The number of studies included for each outcome was low, with up to only three studies per outcome. The quality of evidence ranged from high to very low and 17 studies had a high risk of bias for at least one item. None of the studies reported data on additional educational support needs and adverse events.Compared to standard practice, analyses of physical activity-only interventions suggested high-quality evidence for improved mean cognitive executive function scores. The mean difference (MD) was 5.00 scale points higher in an after-school exercise group compared to standard practice (95% confidence interval (CI) 0.68 to 9.32; scale mean 100, standard deviation 15; 116 children, 1 study). There was no statistically significant beneficial effect in favour of the intervention for mathematics, reading, or inhibition control. The standardised mean difference (SMD) for mathematics was 0.49 (95% CI 0.04 to 1.01; 2 studies, 255 children, moderate-quality evidence) and for reading was 0.10 (95% CI -0.30 to 0.49; 2 studies, 308 children, moderate-quality evidence). The MD for inhibition control was -1.55 scale points (95% CI -5.85 to 2.75; scale range 0 to 100; SMD -0.15, 95% CI -0.58 to 0.28; 1 study, 84 children, very low-quality evidence). No data were available for average achievement across subjects taught at school.There was no evidence of a beneficial effect of physical activity interventions combined with healthy lifestyle education on average achievement across subjects taught at school, mathematics achievement, reading achievement or inhibition control. The MD for average achievement across subjects taught at school was 6.37 points lower in the intervention group compared to standard practice (95% CI -36.83 to 24.09; scale mean 500, scale SD 70; SMD -0.18, 95% CI -0.93 to 0.58; 1 study, 31 children, low quality evidence). The effect estimate for mathematics achievement was SMD 0.02 (95% CI -0.19 to 0.22; 3 studies, 384 children, very low-quality evidence), for reading achievement SMD 0.00 (95% CI -0.24 to 0.24; 2 studies, 284 children, low quality evidence), and for inhibition control SMD -0.67 (95% CI -1.50 to 0.16; 2 studies, 110 children, very low-quality evidence). No data were available for the effect of combined physical activity and healthy lifestyle education on cognitive executive functions.There was a moderate difference in the average achievement across subjects taught at school favouring interventions targeting the improvement of the school food environment compared to standard practice in adolescents with obesity (SMD 0.46, 95% CI 0.25 to 0.66; 2 studies, 382 adolescents, low-quality evidence), but not with overweight. Replacing packed school lunch with a nutrient-rich diet in addition to nutrition education did not improve mathematics (MD -2.18, 95% CI -5.83 to 1.47; scale range 0 to 69; SMD 0.26, 95% CI -0.72 to 0.20; 1 study, 76 children, low-quality evidence) and reading achievement (MD 1.17, 95% CI -4.40 to 6.73; scale range 0 to 108; SMD 0.13, 95% CI -0.35 to 0.61; 1 study, 67 children, low-quality evidence). AUTHORS' CONCLUSIONS: Despite the large number of childhood and adolescent obesity treatment trials, we were only able to partially assess the impact of obesity treatment interventions on school achievement and cognitive abilities. School and community-based physical activity interventions as part of an obesity prevention or treatment programme can benefit executive functions of children with obesity or overweight specifically. Similarly, school-based dietary interventions may benefit general school achievement in children with obesity. These findings might assist health and education practitioners to make decisions related to promoting physical activity and healthy eating in schools. Future obesity treatment and prevention studies in clinical, school and community settings should consider assessing academic and cognitive as well as physical outcomes. PMID- 29499090 TI - Arabidopsis nonresponding to oxylipins locus NOXY7 encodes a yeast GCN1 homolog that mediates noncanonical translation regulation and stress adaptation. AB - Stress adaptation and translational regulation was studied using noxy7 (nonresponding to oxylipins7) from a series of Arabidopsis thaliana mutants. We identified the noxy7 mutation in At1g64790, which encodes a homolog of the yeast translational regulator General Control Nonderepressible1 (GCN1) that activates the GCN2 kinase; GCN2 in turn phosphorylates the alpha subunit of the translation initiation factor eIF2. This regulatory circuit is conserved in yeast and mammals, in which phosphorylated eIF2alpha (P-eIF2alpha) facilitates stress adaptation by inhibiting protein synthesis. In phenotypic and de novo protein synthesis studies with Arabidopsis mutants, we found that NOXY7/GCN1 and GCN2 mediate P-eIF2alpha formation and adaptation to amino acid deprivation; however, P-eIF2alpha formation is not linked to general protein synthesis arrest. Additional evidence suggested that NOXY7/GCN1 but not GCN2 regulates adaptation to mitochondrial dysfunction, high boron concentration, and activation of plant immunity to infection by Pseudomonas syringae pv tomato (Pst). In these responses, NOXY7/GCN1 acts with GCN20 to regulate translation in a noncanonical pathway independently of GCN2 and P-eIF2alpha. These results show the lesser functional relevance of GCN2 and P-eIF2alpha in plants relative to other eukaryotes and highlight the prominent role of NOXY7/GCN1 and GCN20 in regulation of translation and stress adaptation in plants. PMID- 29499091 TI - Molecular control of B-cell homeostasis in health and malignancy. AB - Altered B-cell homeostasis underlies a wide range of pathologies, from cancers to autoimmunity and immunodeficiency. The molecular safeguards against those disorders, which also allow effective immune responses, are therefore particularly critical. Here, we review recent findings detailing the fine control of B-cell homeostasis, during B-cell development, maturation in the periphery and during activation and differentiation into antibody-producing cells. PMID- 29499092 TI - Ultra-early occlusion of the normal bile duct after uncovered self-expandable metallic stent placement in unresectable perihilar bile duct cancer. PMID- 29499093 TI - Haematinic deficiencies and patient clinical profiles in Polish patients with recurrent aphthous stomatitis (RAS). AB - BACKGROUND: Recurrent aphthous stomatitis is a common ulcerative disorder of the oral mucosa, where the immune impairment may develop in genetically predisposed subjects exposed to certain environmental factors. The aim of the study was to investigate the frequency of anaemia, iron and vitamin B12 deficiency in recurrent aphthous stomatitis (RAS) and to explore its impact on the clinical presentation of RAS. METHODS: A total of 141 adults including the following: 71 subjects with RAS and 70 controls were enrolled in the study. A detailed dental and haematological assessment, including full blood count, serum iron and vitamin B12 evaluation, was performed in all study participants. The results were statistically analysed with Mann-Whitney, Kruskal-Wallis, chi2 and Fisher tests with P < .05 designated as a significance level. RESULTS: Recurrent aphthous stomatitis patients were found to suffer anaemia, iron and vitamin B12 deficiency more frequently than the controls. The mean serum iron levels were also significantly lower in RAS subjects than in controls, although still within the norm. The lowest mean serum iron levels were observed in patients with a mild course of RAS. No significant differences in mean serum iron and vitamin B12 levels were revealed as a function of stratification according to the number of lesions per single flare-up. CONCLUSIONS: The results of our study indicate an association between iron and vitamin B12 deficiency and RAS in a Polish population. However, as the haematinic deficiencies did not significantly modify the course and clinical phenotype of the disease, further studies to explore their role in RAS aetiology are required. PMID- 29499094 TI - The significance of an algorithm for human papillomavirus detection in head and neck squamous cell carcinoma. PMID- 29499095 TI - Retraction. AB - : 'Influence of genetic variants of IDH1, IDH2, TET2 and DNMT3A on cytarabine cytotoxicity in different populations' by Y. Wang & J. K. Lamba1 The above article from the Journal of Clinical Pharmacy and Therapeutics, published online on 21 November 2017 in Wiley Online Library (wileyonlinelibrary.com), has been retracted following discussions with the authors, the Journal Editors and John Wiley & Sons Ltd. The Retraction has been agreed as this paper was submitted under the joint names of Yan Wang, Jatinder K. Lamba and a third co-author. After acceptance of the paper, Dr Wang wrote to the EiC asking for the name of the third co-author to be dropped because of insufficient contribution. The EiC asked that the request be signed by all three authors. When this arrived, the paper was published online with only Dr Wang and Dr Lamba. However, Dr Lamba wrote to the EiC after publication indicating that she had not previously seen the manuscript and that there were co-authors missing. As it is clear that Dr Lamba's signature was forged, we cannot rely on the integrity of the report. The retraction is with the agreement of Dr Lamba but not of Dr Wang. REFERENCE: 1. Wang Y, Lamba JK. Influence of genetic variants of IDH1, IDH2, TET2 and DNMT3A on cytarabine cytotoxicity in different populations. J Clin Pharm Ther. 2017;00:1-9. https://doi.org/10.1111/jcpt.12653. PMID- 29499097 TI - EAA clinical guideline on management of bone health in the andrological outpatient clinic. AB - Male osteoporosis is now a well-recognized medical disorder with established clinical guidelines for both diagnosis and management. Prevention as well as management of osteoporosis in men consulting the andrological outpatient clinic because of low testosterone, however, is not well established. This gap of knowledge is-at least partly-explained by the controversy with respect to the threshold of testosterone needed for skeletal maintenance. However, testosterone deficiency may be clearly associated with bone loss as well as frailty in men. If anything, andrologists should therefore be aware of the potential silent presence of osteoporosis in men with confirmed hypogonadism. Therefore, the management of patients with potential hypogonadism should include a complete bone health assessment, besides clinical and biochemical evaluation of gonadal status. Such bone health assessment should include specific items in medical history and physical examination related to fracture risk. Furthermore, dual-energy absorptiometry is indicated to evaluate fracture risk in men with confirmed clinical hypogonadism. Regarding treatment, besides general measures to prevent or manage male osteoporosis testosterone replacement can be initiated (as described in guidelines for hypogonadism), but data on its efficacy in preventing fractures are lacking. Thus, additional anti-osteoporotic may be needed, especially in men with very low testosterone who are at high risk of bone loss and/or in men not able to receive testosterone replacement. PMID- 29499096 TI - Functional collagen conduits combined with human mesenchymal stem cells promote regeneration after sciatic nerve transection in dogs. AB - Numerous studies have focused on the development of novel and innovative approaches for the treatment of peripheral nerve injury using artificial nerve guide conduits. In this study, we attempted to bridge 3.5-cm defects of the sciatic nerve with a longitudinally oriented collagen conduit (LOCC) loaded with human umbilical cord mesenchymal stem cells (hUC-MSCs). The LOCC contains a bundle of longitudinally aligned collagenous fibres enclosed in a hollow collagen tube. Our previous studies showed that an LOCC combined with neurotrophic factors enhances peripheral nerve regeneration. However, it remained unknown whether an LOCC seeded with hUC-MSCs could also promote regeneration. In this study, using various histological and electrophysiological analyses, we found that an LOCC provides mechanical support to newly growing nerves and functions as a structural scaffold for cells, thereby stimulating sciatic nerve regeneration. The LOCC and hUC-MSCs synergistically promoted regeneration and improved the functional recovery in a dog model of sciatic nerve injury. Therefore, the combined use of an LOCC and hUC-MSCs might have therapeutic potential for the treatment of peripheral nerve injury. PMID- 29499098 TI - The impact of histones linked to sperm chromatin on embryo development and ART outcome. AB - The purpose of this study was to investigate the relationship between the proportion of sperm chromatin linked to remaining histone and assisted reproductive technology (ART) outcome. A prospective cohort study was performed on couples undergoing ART process at the Department of Reproduction Medicine (HFME, Bron, France). The histone-to-protamine ratio (HPR) was measured using the method described by Wykes & Krawetz (2003) J Biol Chem 278, 29471. The correlations with sperm DFI, blastocyst formation, pregnancy rate, and delivery rate were investigated. A total of 291 ART cycles were included (42 c-IVF and 249 ICSI procedures): 3870 oocytes were punctured and 2211 embryos were obtained, among which 507 were transferred and 336 frozen. The mean HPR was 18.9%. A significant negative correlation was found between HPR and DFI (r = -0.12, p < 0.05). Regarding the type of ART procedure (c-IVF or ICSI), the same kind of relationship between HPR and ART parameters was observed. Regardless of the type of ART procedure used, when the HPR was within the range [6%; 26%], the blastocyst formation rate was higher: 87.8% vs. 71.2% (HPR<6%; p < 0.01) and 74.6% (HPR >26%; p < 0.01). The highest delivery rate (DR; 24.5%) was obtained for HPR within the range [6%; 26%]; DR was 21.9% for HPR<6% and 18.3% for HPR>26%; however, the differences were not statistically significant. The procedure described in this study seems to be a reliable evaluation of the HPR. The HPR parameter seems to be correlated to embryonic development up to the blastocyst stage, but its involvement in clinical pregnancy/delivery could not be confirmed. HPR should be further investigated for confirming the relationship with blastocyst formation. After this, the next step will be to investigate the etiologies of HPR alterations for improving the sperm nucleus quality for increasing the chance of pregnancy. PMID- 29499099 TI - Decellularized pancreas as a native extracellular matrix scaffold for pancreatic islet seeding and culture. AB - Diabetes mellitus involves the loss of function and/or absolute numbers of insulin-producing beta cells in pancreatic islets. Islet transplantation is currently being investigated as a potential cure, and advances in tissue engineering methods can be used to improve pancreatic islets survival and functionality. Transplanted islets experience anoikis, hypoxia, and inflammation mediated immune response, leading to early damage and subsequent failure of the graft. Recent development in tissue engineering enables the use of decellularized organs as scaffolds for cell therapies. Decellularized pancreas could be a suitable scaffold as it can retain the native extracellular matrix and vasculature. In this study, mouse pancreata were decellularized by perfusion using 0.5% sodium dodecyl sulfate. Different characterizations revealed that the resulting matrix was free of cells and retained part of the pancreas extracellular matrix including the vasculature and its internal elastic basal lamina, the ducts with their basal membrane, and the glycosaminoglycan and collagen structures. Islets were infused into the ductal system of decellularized pancreata, and glucose-stimulated insulin secretion results confirmed their functionality after 48 hr. Also, recellularizing the decellularized pancreas with green fluorescent protein-tagged INS-1 cells and culturing the system over 120 days confirmed the biocompatibility and non-toxic nature of the scaffold. Green fluorescent protein-tagged INS-1 cells formed pseudoislets that were, over time, budding out of the decellularized pancreata. Decellularized pancreatic scaffolds seeded with endocrine pancreatic tissue could be a potential bioengineered organ for transplantation. PMID- 29499101 TI - Programmed death ligand 1 testing in non-small cell lung carcinoma cytology cell block and aspirate smear preparations. AB - BACKGROUND: Immune checkpoint inhibitors targeting the programmed cell death 1 (PD-1) receptor and its ligand, programmed death ligand 1 (PD-L1), have emerged as a therapeutic approach for patients with non-small cell lung carcinoma (NSCLC). PD-L1 expression, assessed by immunohistochemistry (IHC), is used to select patients for PD-1/PD-L1 inhibitor therapy. Most studies have been performed with histology specimens, with limited data available on the performance in cytology specimens. This study evaluated PD-L1 in cytology specimens and compared the results with those from paired core-needle biopsy for concordance. METHODS: Forty-one NSCLC fine-needle aspiration cases that had paired core-needle biopsy specimens with PD-L1 IHC were selected. A Papanicolaou stained direct smear and a cell block section from each case were stained with a Dako PD-L1 pharmDx antibody (clone 22C3). Only slides with 100 or more tumor cells (37 smears and 38 cell blocks) were evaluated. Tumor proportion scores (TPS) were assessed on the basis of the partial/complete membranous staining of tumor cells and were correlated with those of paired core-needle biopsy. RESULTS: All 9 smears that were negative for PD-L1 staining showed 100% concordance with the paired core-needle biopsy, whereas 28 smears with PD-L1 expression showed a similar TPS, except for 1 smear that was discordant. In contrast, 10 negative paired core-needle biopsy cases corresponded to 9 concordant negative cell blocks, whereas 1 cell block had a TPS of 1% to 5%. The remaining 28 cell blocks demonstrated PD-L1 expression, with 22 cases showing a TPS similar to that of the paired core-needle biopsy, whereas 6 cell blocks were discordant, likely because of intratumoral heterogeneity. CONCLUSIONS: The results show that NSCLC cytology samples evaluated for PD-L1 have high concordance with paired core-needle biopsy samples and can be used for assessing PD-L1 expression. Cancer Cytopathol 2018;126:342-52. (c) 2018 American Cancer Society. PMID- 29499100 TI - A CD8alpha- Subset of CD4+SLAMF7+ Cytotoxic T Cells Is Expanded in Patients With IgG4-Related Disease and Decreases Following Glucocorticoid Treatment. AB - OBJECTIVE: An unconventional population of CD4+ signaling lymphocytic activation molecule family member 7-positive (SLAMF7+) cytotoxic effector memory T (TEM ) cells (CD4+ cytotoxic T lymphocytes [CTLs]) has been linked causally to IgG4 related disease (IgG4-RD). Glucocorticoids represent the first-line therapeutic approach in patients with IgG4-RD, but their mechanism of action in this specific condition remains unknown. We undertook this study to determine the impact of glucocorticoids on CD4+ CTLs in IgG4-RD. METHODS: Expression of CD8alpha, granzyme A, perforin, and SLAMF7 within the effector memory compartment of CD45RO+ (TEM ) and CD45RA+ effector memory T (TEMRA ) CD4+ cells was quantified by flow cytometry in 18 patients with active IgG4-RD, both at baseline and after 6 months of glucocorticoid treatment. Eighteen healthy subjects were studied as controls. Next-generation sequencing of the T cell receptor alpha- and beta-chain gene was performed on circulating CD4+ CTLs from patients with IgG4-RD before and after treatment and in affected tissues. RESULTS: Circulating CD4+ TEM and TEMRA cells were not expanded in IgG4-RD patients compared to healthy controls. CD4+SLAMF7+ TEM cells (but not TEMRA cells) were significantly increased among IgG4-RD patients. Within CD4+SLAMF7+ TEM cells, CD8alpha- cells but not CD8alphalow cells were elevated in IgG4-RD patients. The same dominant clones of CD8alpha-CD4+SLAMF7+ TEM cells found in peripheral blood were also identified in affected tissue. CD8alpha- and CD8alphalow CD4+SLAMF7+ TEM cells both expressed cytolytic molecules. Clonally expanded CD8alpha- but not CD8alphalow CD4+SLAMF7+ TEM cells decreased following glucocorticoid-induced disease remission. CONCLUSION: A subset of CD8alpha-CD4+SLAMF7+ cytotoxic TEM cells is oligoclonally expanded in patients with active IgG4-RD. This TEM cell population contracts following glucocorticoid-induced remission. Further characterization of this cell population may provide prognostic information and targets for therapeutic intervention. PMID- 29499102 TI - Lupus Regulator Peptide P140 Represses B Cell Differentiation by Reducing HLA Class II Molecule Overexpression. AB - OBJECTIVE: Phosphopeptide P140 (Lupuzor) is an inhibitor of autophagy currently being evaluated in late-stage clinical trials for the treatment of lupus. This study was undertaken to investigate the effect of P140 ex vivo on human T and B cells. METHODS: Human B cells, T cells, and dendritic cells were analyzed by flow cytometry and cellular assays. The expression of autophagy markers was evaluated by immunoblotting and flow cytometry. The levels of B cell receptor (BCR) signaling markers and HLA molecules were assessed by flow cytometry. Toll-like receptor ligands were screened using an assay with transfected HEK 293 cells. P140 cell entry and trafficking were measured by immunofluorescence in the presence of various inhibitors of endosomal pathways. RESULTS: As was previously observed after intravenous injection of the peptide in a mouse model of lupus, P140 entered human B cells by a clathrin coat-dependent endocytosis process and homed into lysosomes. The peptide displayed no direct effect on BCR signaling of memory, naive mature, transitional, and B1 cells. However, it strongly reduced the overexpression of HLA class II molecules on lupus B cells that were acting as antigen-presenting cells, down-regulated the maturation and differentiation of B cells into plasma cells, and decreased IgG secretion. CONCLUSION: These findings show that P140 down-regulates HLA class II overexpression in human lupus B cells, and also that P140 hampers the differentiation of B cells into autoantibody secreting plasma cells, likely due to the resulting lack of T cell signaling and activation. This mechanism appears to switch off the downstream events leading to secretion of pathogenic autoantibodies, thus explaining the highly promising results obtained in clinical trials of P140 (Lupuzor) for the treatment of lupus. PMID- 29499104 TI - Correlated evolution of thermal niches and functional physiology in tropical freshwater fishes. AB - The role of ecology in phenotypic and species diversification is widely documented. Nonetheless, numerous nonadaptive processes can shape realized niches and phenotypic variation in natural populations, complicating inferences about adaptive evolution at macroevolutionary scales. We tested for evolved differences in thermal tolerances and their association with the realized thermal niche (including metrics describing diurnal and seasonal patterns of temperature extremes and variability) across a genus of tropical freshwater fishes reared in a standardized environment. There was limited evolution along the thermal niche axis associated with variation in maximum temperature and in upper thermal limits. In contrast, there was considerable diversification along the first major axis of the thermal niche associated with minimum temperatures and in lower thermal limits. Across our adaptive landscape analyses, 70% of species exhibited evidence of divergence in thermal niches. Most importantly, the first two major axes of thermal niche variation were significantly correlated with variation in lower thermal limits. Our results indicate adaptation to divergent thermal niches and adaptive evolution of related functional traits, and highlight the importance of divergence in lower thermal limits for the evolution of tropical biodiversity. PMID- 29499105 TI - Combining mutations at genes encoding key enzymes involved in starch synthesis affects the amylose content, carbohydrate allocation and hardness in the wheat grain. AB - Modifications to the composition of starch, the major component of wheat flour, can have a profound effect on the nutritional and technological characteristics of the flour's end products. The starch synthesized in the grain of conventional wheats (Triticum aestivum) is a 3:1 mixture of the two polysaccharides amylopectin and amylose. Altering the activity of certain key starch synthesis enzymes (GBSSI, SSIIa and SBEIIa) has succeeded in generating starches containing a different polysaccharide ratio. Here, mutagenesis, followed by a conventional marker-assisted breeding exercise, has been used to generate three mutant lines that produce starch with an amylose contents of 0%, 46% and 79%. The direct and pleiotropic effects of the multiple mutation lines were identified at both the biochemical and molecular levels. Both the structure and composition of the starch were materially altered, changes which affected the functionality of the starch. An analysis of sugar and nonstarch polysaccharide content in the endosperm suggested an impact of the mutations on the carbon allocation process, suggesting the existence of cross-talk between the starch and carbohydrate synthesis pathways. PMID- 29499106 TI - Phenotypic integration in an extended phenotype: among-individual variation in nest-building traits of the alfalfa leafcutting bee (Megachile rotundata). AB - Structures such as nests and burrows are an essential component of many organisms' life-cycle and require a complex sequence of behaviours. Because behaviours can vary consistently among individuals and be correlated with one another, we hypothesized that these structures would (1) show evidence of among individual variation, (2) be organized into distinct functional modules and (3) show evidence of trade-offs among functional modules due to limits on energy budgets. We tested these hypotheses using the alfalfa leafcutting bee, Megachile rotundata, a solitary bee and important crop pollinator. Megachile rotundata constructs complex nests by gathering leaf materials to form a linear series of cells in pre-existing cavities. In this study, we examined variation in the following nest construction traits: reproduction (number of cells per nest and nest length), nest protection (cap length and number of leaves per cap), cell construction (cell size and number of leaves per cell) and cell provisioning (cell mass) from 60 nests. We found a general decline in investment in cell construction and provisioning with each new cell built. In addition, we found evidence for both repeatability and plasticity in cell provisioning with little evidence for trade-offs among traits. Instead, most traits were positively, albeit weakly, correlated (r ~ 0.15), and traits were loosely organized into covarying modules. Our results show that individual differences in nest construction are detectable at a level similar to that of other behavioural traits and that these traits are only weakly integrated. This suggests that nest components are capable of independent evolutionary trajectories. PMID- 29499103 TI - Precision medicine in diabetes prevention, classification and management. AB - Diabetes has become a major burden of healthcare expenditure. Diabetes management following a uniform treatment algorithm is often associated with progressive treatment failure and development of diabetic complications. Recent advances in our understanding of the genomic architecture of diabetes and its complications have provided the framework for development of precision medicine to personalize diabetes prevention and management. In the present review, we summarized recent advances in the understanding of the genetic basis of diabetes and its complications. From a clinician's perspective, we attempted to provide a balanced perspective on the utility of genomic medicine in the field of diabetes. Using genetic information to guide management of monogenic forms of diabetes represents the best-known examples of genomic medicine for diabetes. Although major strides have been made in genetic research for diabetes, its complications and pharmacogenetics, ongoing efforts are required to translate these findings into practice by incorporating genetic information into a risk prediction model for prioritization of treatment strategies, as well as using multi-omic analyses to discover novel drug targets with companion diagnostics. Further research is also required to ensure the appropriate use of this information to empower individuals and healthcare professionals to make personalized decisions for achieving the optimal outcome. PMID- 29499107 TI - Differentiation of human-induced pluripotent stem cell under flow conditions to mature hepatocytes for liver tissue engineering. AB - Hepatic differentiation of human-induced pluripotent stem cells (hiPSCs) under flow conditions in a 3D scaffold is expected to be a major step forward for construction of bioartificial livers. The aims of this study were to induce hepatic differentiation of hiPSCs under perfusion conditions and to perform functional comparisons with fresh human precision-cut liver slices (hPCLS), an excellent benchmark for the human liver in vivo. The majority of the mRNA expression of CYP isoenzymes and transporters and the tested CYP activities, Phase II metabolism, and albumin, urea, and bile acid synthesis in the hiPSC derived cells reached values that overlap those of hPCLS, which indicates a higher degree of hepatic differentiation than observed until now. Differentiation under flow compared with static conditions had a strong inducing effect on Phase II metabolism and suppressed AFP expression but resulted in slightly lower activity of some of the Phase I metabolism enzymes. Gene expression data indicate that hiPSCs differentiated into both hepatic and biliary directions. In conclusion, the hiPSC differentiated under flow conditions towards hepatocytes express a wide spectrum of liver functions at levels comparable with hPCLS indicating excellent future perspectives for the development of a bioartificial liver system for toxicity testing or as liver support device for patients. PMID- 29499108 TI - Design, Synthesis, and Structure-Activity Relationship Study of 2-Oxo-3,4 dihydropyrimido[4,5- d]pyrimidines as New Colony Stimulating Factor 1 Receptor (CSF1R) Kinase Inhibitors. AB - Colony stimulating factor 1 receptor kinase (CSF1R) is a well validated molecular target for anticancer drug discovery. Herein, we report the design, synthesis, and structure-activity relationship study of 2-oxo-3,4-dihydropyrimido[4,5- d]pyrimidines as new orally bioavailable CSF1R inhibitors. One of the most promising compounds, 3bw, potently inhibits CSF1R kinase with an IC50 value of 3.0 nM, while it is less potent against structurally related epidermal growth factor receptor (EGFR) and other kinases. The kinase inhibition of 3bw was further validated by Western blotting analysis in RAW264.7 macrophages. The molecule also potently blocks macrophage infiltration, abrogates the protumorigenic influences of macrophages, and exhibits reasonable pharmacokinetic profile. Compound 3bw may serve as a new valuable lead compound for future anticancer drug discovery. PMID- 29499109 TI - Shear Thickening Electrolyte Built from Sterically Stabilized Colloidal Particles. AB - We present a method to prepare shear thickening electrolytes consisting of silica nanoparticles in conventional liquid electrolytes with limited flocculation. These electrolytes rapidly and reversibly stiffen to solidlike behaviors in the presence of external shear or high impact, which is promising for improved lithium ion battery safety, especially in electric vehicles. However, in initial chemistries the silica nanoparticles aggregate and/or sediment in solution over time. Here, we demonstrate steric stabilization of silica colloids in conventional liquid electrolyte via surface-tethered PMMA brushes, synthesized via surface-initiated atom transfer radical polymerization. The PMMA increases the magnitude of the shear thickening response, compared to the uncoated particles, from 0.311 to 2.25 Pa s. Ultrasmall-angle neutron scattering revealed a reduction in aggregation of PMMA-coated silica nanoparticles compared to bare silica nanoparticles in solution under shear and at rest, suggesting good stabilization. Conductivity tests of shear thickening electrolytes (30 wt % solids in electrolyte) at rest were performed with interdigitated electrodes positioned near the meniscus of electrolytes over the course of 24 h to track supernatant formation. Conductivity of electrolytes with bare silica increased from 10.1 to 11.6 mS cm-1 over 24 h due to flocculation. In contrast, conductivity of electrolytes with PMMA-coated silica remained stable at 6.1 mS cm 1 over the same time period, suggesting good colloid stability. PMID- 29499110 TI - Operative Binding of Class I Release Factors and YaeJ Stabilizes the Ribosome in the Nonrotated State. AB - During translation, the small subunit of the ribosome rotates with respect to the large subunit primarily between two states as mRNA is being translated into a protein. At the termination of bacterial translation, class I release factors (RFs) bind to a stop codon in the A-site and catalyze the release of the peptide chain from the ribosome. Periodically, mRNA is truncated prematurely, and the translating ribosome stalls at the end of the mRNA forming a nonstop complex requiring one of several ribosome rescue factors to intervene. One factor, YaeJ, is structurally homologous with the catalytic region of RFs but differs by binding to the ribosome directly through its C-terminal tail. Structures of the ribosome show that the ribosome adopts the nonrotated state conformation when these factors are bound. However, these studies do not elucidate the influence of binding to cognate or noncognate codons on the dynamics of intersubunit rotation. Here, we investigate the effects of wild-type and mutant forms of RF1, RF2, and YaeJ binding on ribosome intersubunit rotation using single-molecule Forster resonance energy transfer. We show that both RF1 binding and RF2 binding are sufficient to shift the population of posthydrolysis ribosome complexes from primarily the rotated to the nonrotated state only when a cognate stop codon is present in the A-site. Similarly, YaeJ binding stabilizes nonstop ribosomal complexes in the nonrotated state. Along with previous studies, these results are consistent with the idea that directed conformational changes and binding of subsequent factors to the ribosome are requisite for efficient termination and ribosome recycling. PMID- 29499111 TI - Modeling Retrograde Vitrification in the Polystyrene-Toluene System. AB - Atactic polystyrene, as reported in a recent contribution by our group, displays a marked change in glass transition when exposed to toluene vapor due to plasticization associated with vapor sorption within the polymer. The dependence of the glass transition temperature of the polymer-penetrant mixture on the pressure of toluene vapor is characterized by the so-called "retrograde vitrification" phenomenon, in that, at a constant pressure, a rubber to glass transition occurs by increasing the temperature. In this contribution, we have used a theoretical approach, based on the nonrandom lattice fluid thermodynamic model for the polymer-toluene mixture, to predict the state of this system, i.e., rubbery or glassy, as a function of fluid pressure and system temperature. The experimentally detectable glass transition is assumed to be a kinetically affected evidence of an underlying II order thermodynamic transition of the polymer mixture. On the basis of this hypothesis, the Gibbs-Di Marzio criterion, stating that equilibrium configurational entropy is zeroed at the glass transition, has been applied to locate the transition. The working set of equations consists of the expression of configurational entropy obtained from the adopted lattice fluid model equated to zero, coupled with the equation expressing the phase equilibrium between the polymer phase and the pure toluene vapor phase in contact and with the equations of state for the two phases. Theoretical predictions are in good qualitative and quantitative agreement with the experimental results previously obtained gravimetrically performing "dynamic" sorption experiments, which represent a neat example of the occurrence of so called "type IV" glass transition temperature vs pressure behavior. The peculiar retrograde vitrification phenomenon and the glass transition temperature vs pressure envelope determined experimentally are well described by the proposed theoretical approach. PMID- 29499112 TI - Identifying Ammonia Hotspots in China Using a National Observation Network. AB - The limited availability of ammonia (NH3) measurements is currently a barrier to understanding the vital role of NH3 in secondary aerosol formation during haze pollution events and prevents a full assessment of the atmospheric deposition of reactive nitrogen. The observational gaps motivated us to design this study to investigate the spatial distributions and seasonal variations in atmospheric NH3 on a national scale in China. On the basis of a 1-year observational campaign at 53 sites with uniform protocols, we confirm that abundant concentrations of NH3 [1 to 23.9 MUg m-3] were identified in typical agricultural regions, especially over the North China Plain (NCP). The spatial pattern of the NH3 surface concentration was generally similar to those of the satellite column concentrations as well as a bottom-up agriculture NH3 emission inventory. However, the observed NH3 concentrations at urban and desert sites were comparable with those from agricultural sites and 2-3 times those of mountainous/forest/grassland/waterbody sites. We also found that NH3 deposition fluxes at urban sites account for only half of the emissions in the NCP, suggesting the transport of urban NH3 emissions to downwind areas. This finding provides policy makers with insights into the potential mitigation of nonagricultural NH3 sources in developed regions. PMID- 29499114 TI - IsRNA: An Iterative Simulated Reference State Approach to Modeling Correlated Interactions in RNA Folding. AB - Coarse-grained RNA folding models promise great potential for RNA structure prediction. A key component in a coarse-grained folding model is the force field. One of the challenges in the coarse-grained force field calculation is how to treat the correlation between the different degrees of freedoms. Here, we describe a new approach (IsRNA) to extract the correlated energy functions from the known structures. Through iterative molecular dynamics simulations, we build the correlation effects into the reference states, from which we extract the energy functions. The validity of IsRNA is supported by the close agreement between the simulated Boltzmann-like probability distributions for all the structure parameters and those observed from the experimentally determined structures. The correlated energy functions derived here may provide a new tool for RNA 3D structure prediction. PMID- 29499113 TI - Class I HDAC Inhibitors Display Different Antitumor Mechanism in Leukemia and Prostatic Cancer Cells Depending on Their p53 Status. AB - Previously, we designed and synthesized a series of o-aminobenzamide-based histone deacetylase (HDAC) inhibitors, among which the representative compound 11a exhibited potent inhibitory activity against class I HDACs. In this study, we report the development of more potent hydrazide-based class I selective HDAC inhibitors using 11a as a lead. Representative compound 13b showed a mixed, slow, and tight binding inhibition mechanism for HDAC1, 2, and 3. The most potent compound 13e exhibited low nanomolar IC50s toward HDAC1, 2, and 3 and could down regulate HDAC6 in acute myeloid leukemia MV4-11 cells. The EC50 of 13e against MV4-11 cells was 34.7 nM, which is 26 times lower than its parent compound 11a. In vitro responses to 13e vary significantly and interestingly based on cell type: in p53 wild-type MV4-11 cells, 13e induced cell death via apoptosis and G1/S cell cycle arrest, which is likely mediated by a p53-dependent pathway, while in p53-null PC-3 cells, 13e caused G2/M arrest and inhibited cell proliferation without inducing caspase-3-dependent apoptosis. PMID- 29499115 TI - Molecular Dynamics Investigation of Halide-Containing Phospho-Silicate Bioactive Glasses. AB - Oxyhalide-containing silicate glasses have been receiving increasing attention in recent years due to their extensive medical and dental applications. This manuscript reports the first detailed structural investigation using MD simulations in the context of chloride- and mixed-fluoride/chloride-containing phospho-silicate bioactive glasses. It is shown that adding fluoride, chloride, and mixed fluoride and chloride has not altered the Q n silicate distribution and phosphorus speciation significantly in all of the glasses investigated. The Q2 silicon species is the predominant species with smaller and nearly equal proportions of Q1 and Q3 species, whereas phosphorus is largely present as orthophosphate Q0 units. No Si-F/Cl and P-F/Cl bonds have been observed at room temperature. Both F and Cl anions are present as F-Ca(n) and Cl-Ca(n). MD simulations also indicate opposite effects of fluoride and chloride on the crystallization ability of the glasses. The environment of Cl in chloride containing glass series is quite different from the chlorapatite and CaCl2 crystals, and a significant structural reorganization is required to observe the appearance of the crystal nuclei. Instead, the environment of fluoride ions in the glasses is quite similar to that present in the FAP and CaF2 crystals and thus F-containing glasses manifest a high crystallization tendency. Moreover, in the mixed-fluoride/chloride-containing glasses, fluorine tends to surround phosphate, whereas chloride moves toward the silicate network. Finally, it was observed that a good correlation exists between the glass transition temperature and the overall strength of the glass network quantified by the Fnet factor. PMID- 29499116 TI - Accuracy Assessment of GW Starting Points for Calculating Molecular Excitation Energies Using the Bethe-Salpeter Formalism. AB - The performance of the Bethe-Salpeter equation (BSE) approach for the first principles computation of singlet and triplet excitation energies of small organic, closed-shell molecules has been assessed with respect to the quasiparticle energies used on input, obtained at various levels of GW theory. In the corresponding GW computations, quasiparticle energies have been computed for all orbital levels by means of using full spectral functions. The assessment reveals that, for valence excited states, quasiparticle energies obtained at the levels of eigenvalue-only self-consistent (ev GW) or quasiparticle self consistent theory (qs GW) are required to obtain results of comparable accuracy as in time-dependent density-functional theory (TDDFT) using a hybrid functional such as PBE0. In contrast to TDDFT, however, the BSE approach performs well not only for valence excited states but also for excited states with Rydberg or charge-transfer character. To demonstrate the applicability of the BSE approach, computation times are reported for a set of aromatic hydrocarbons. Furthermore, examples of computations of ordinary photoabsorption and electronic circular dichroism spectra are presented for (C60)2 and C84, respectively. PMID- 29499117 TI - Native Mass Spectrometry Gives Insight into the Allosteric Binding Mechanism of M2 Pyruvate Kinase to Fructose-1,6-Bisphosphate. AB - The various oligomeric states of the M2 isoform of pyruvate kinase (PKM2) were distinguished using native mass spectrometry. The effect of PKM2 concentration on its dimer-tetramer equilibrium was monitored, and a value for the dissociation constant ( Kd) of the two species was estimated to be 0.95 MUM. Results of binding of fructose-1,6-bisphosphate (FBP) to PKM2 are shown and provide insight into the allosteric mechanism and changes in the oligomerization status of PKM2. The average Kd for binding of FBP to the PKM2 tetramer was estimated to be 7.5 MUM. It is concluded that four molecules of FBP bind to the active PKM2 tetramer whereas binding of FBP to the PKM2 dimer was not observed. It is suggested that either FBP potentiates rapid tetramer formation after binding to apo PKM2 dimers or FBP binds to PKM2 apo tetramers, thus driving the dimer-tetramer equilibrium in the direction of fully FBP-bound tetramer. The binding occurs in a highly positively cooperative manner with a Hill coefficient ( n) of 3. PMID- 29499118 TI - Structural Dynamics of Carbon Dots in Water and N, N-Dimethylformamide Probed by All-Atom Molecular Dynamics Simulations. AB - Carbon dots (CDs), one of the youngest members of the carbon nanostructure family, are now widely experimentally studied for their tunable fluorescence properties, bleaching resistance, and biocompatibility. Their interaction with biomolecular systems has also been explored experimentally. However, many atomistic details still remain unresolved. Molecular dynamics (MD) simulations enabling atomistic and femtosecond resolutions simultaneously are a well established tool of computational chemistry which can provide useful insights into investigated systems. Here we present a full procedure for performing MD simulations of CDs. We developed a builder for generating CDs of a desired size and with various oxygen-containing surface functional groups. Further, we analyzed the behavior of various CDs differing in size, surface functional groups, and degrees of functionalization by MD simulations. These simulations showed that surface functionalized CDs are stable in a water environment through the formation of an extensive hydrogen bonding network. We also analyzed the internal dynamics of individual layers of CDs and evaluated the role of surface functional groups on CD stability. We observed that carboxyl groups interconnected the neighboring layers and decreased the rate of internal rotations. Further, we monitored changes in the CD shape caused by an excess of charged carboxyl groups or carbonyl groups. In addition to simulations in water, we analyzed the behavior of CDs in the organic solvent DMF, which decreased the stability of pure CDs but increased the level of interlayer hydrogen bonding. We believe that the developed protocol, builder, and parameters will facilitate future studies addressing various aspects of structural features of CDs and nanocomposites containing CDs. PMID- 29499120 TI - Factors related to HIV infection among unmarried youth in rural areas of Southwest China. AB - We evaluated HIV prevalence among unmarried youth in rural areas of Liangshan Prefecture in southwest China over the period of 2011-2015, and the interactions between behaviors associated with HIV risk. We used HIV sentinel surveillance (HSS) data for our analysis. We used questionnaires to investigate information among unmarried youth aged 15 to 25 years and performed HIV testing. Multivariate logistic regression and path analysis were applied to explore associations between behavioral factors related with HIV infection. A total of 9536 unmarried youth were enrolled in this study, of whom 2.75% (262/9536) tested positive for HIV infection. Multivariate logistic regression showed that male gender, Yi ethnicity, illiteracy, out-migrating for work, needle sharing, and engaging in high-risk sexual behaviors were risk factors. Path analysis revealed that needle sharing had the greatest effect on HIV infection (0.267), followed by drug use (0.171), out-migrating for work (0.079), and high-risk sexual behavior (0.064). The epidemic of HIV infection among unmarried youth in rural areas of Liangshan Prefecture is severe, and prevention efforts should focus on high-risk groups such as youth who are male, Yi, illiterate, and out-migrating for work, and those who engage in high-risk sexual behaviors and needle sharing. PMID- 29499121 TI - Bladder Management in Children: Intermittent Catheterization Education. AB - Clean intermittent catheterization (IC) of the bladder is one example of advanced medical care required by students with special health care needs. The success of a child's intermittent catheterization program in a community setting such as a school is dependent on an educated team. This article discusses indications and problems that arise with IC bladder management in the pediatric population. The article also provides information about current best practice for IC management to assist school nurses in the optimization of bladder health. PMID- 29499122 TI - Short-term changes in daily movement behaviour influence salivary C-reactive protein in healthy women. AB - This study assessed the effect of changing daily movement behaviour on C-reactive protein (CRP) measured in saliva. Two groups of women either reduced daily movement or increased physical activity for 10 days. Salivary CRP increased by 31% in the sedentary group (0.378 +/- 0.596 to 0.487 +/- 0.793 MUg.L-1) and decreased by 22% in the active group (0.414 +/- 0.640 to 0.259 +/- 0.284 MUg.L 1). These results suggest short-term changes in daily movement behaviour can affect salivary CRP, a marker of systemic inflammation. PMID- 29499125 TI - RANKL Triggers Treg-Mediated Immunoregulation in Inflammatory Osteolysis. AB - The chronic inflammatory immune response triggered by the infection of the tooth root canal system results in the local upregulation of RANKL, resulting in periapical bone loss. While RANKL has a well-characterized role in the control of bone homeostasis/pathology, it can play important roles in the regulation of the immune system, although its possible immunoregulatory role in infectious inflammatory osteolytic conditions remains largely unknown. Here, we used a mouse model of infectious inflammatory periapical lesions subjected to continuous or transitory anti-RANKL inhibition, followed by the analysis of lesion outcome and multiple host response parameters. Anti-RANKL administration resulted in arrest of bone loss but interfered in the natural immunoregulation of the lesions observed in the untreated group. RANKL inhibition resulted in an unremitting proinflammatory response, persistent high proinflammatory and effector CD4 response, decreased regulatory T-cell (Treg) migration, and lower levels of Treg related cytokines IL-10 and TGFb. Anti-RANKL blockade impaired the immunoregulatory process only in early disease stages, while the late administration of anti-RANKL did not interfere with the stablished immunoregulation. The impaired immunoregulation due to RANKL inhibition is characterized by increased delayed-type hypersensitivity in vivo and T-cell proliferation in vitro to the infecting bacteria, which mimic the effects of Treg inhibition, reinforcing a possible influence of RANKL on Treg-mediated suppressive response. The adoptive transfer of CD4+FOXp3+ Tregs to mice receiving anti-RANKL therapy restored the immunoregulatory capacity, attenuating the inflammatory response in the lesions, reestablishing normal T-cell response in vivo and in vitro, and preventing lesion relapse upon anti-RANKL therapy cessation. Therefore, while RANKL inhibition efficiently limited the periapical bone loss, it promoted an unremitting host inflammatory response by interfering with Treg activity, suggesting that this classic osteoclastogenic mediator plays a role in immunoregulation. PMID- 29499126 TI - Contemporary Management of Mandibular Fracture Nonunion-A Retrospective Review and Treatment Algorithm. AB - PURPOSE: Nonunion is an uncommon complication after mandibular fractures. The purpose of this investigation was to compare outcomes of patients with mandibular fracture nonunion who were treated with a 1- versus 2-stage approach and propose a pragmatic treatment algorithm for surgical management based on preoperative characteristics. MATERIALS AND METHODS: The authors conducted a retrospective study consisting of patients who presented to 2 level 1 trauma centers for the management of mandibular fracture nonunion over a 10-year period. The primary predictor variable was 1- versus 2-stage treatment. Outcomes were examined to propose a treatment algorithm. RESULTS: Eighteen patients were included in the study. The sample's mean age was 44.0 +/- 19.3 years and most were men (88.9%). Mandibular angle and body accounted for 77.8% of cases. A single-stage approach was used in 13 patients (72.2%). Bone grafts or vascularized bone flaps were required in 13 patients (72.2%). Patients who required 2-stage treatments had intraoral soft tissue defects. Mean length of follow-up was 13.3 +/- 20.4 months. All patients achieved bony union, with complications occurring in 5 patients (27.8%). The authors' 10-year experience was used to formulate a treatment algorithm based on bony defect size and soft tissue status, which can be used to inform optimal surgical management. CONCLUSIONS: Nonunion of mandibular fractures is an infrequent and complex condition requiring careful and deliberate surgical management. A single-stage approach is appropriate in most cases and does not negatively affect outcomes. Bony defect size and soft tissue status are essential parameters for determining the approach and timing of reconstruction. PMID- 29499127 TI - Submucosal tunnel endoscopic resection for extraluminal tumors: a novel endoscopic method for en bloc resection of predominant extraluminal growing subepithelial tumors or extra-gastrointestinal tumors (with videos). AB - BACKGROUND AND AIMS: The management of subepithelial tumors with a predominant extraluminal growth pattern or extra-GI tumors can be challenging and traditionally requires a surgical resection that is not only invasive but may carry a significant risk of morbidity and mortality. We aimed to assess the feasibility, safety, and efficacy of a novel endoscopic technique termed submucosal tunnel endoscopic resection for extraluminal tumors (STER-ET). METHODS: We prospectively enrolled patients who underwent STER-ET for GI subepithelial tumors with a predominant extraluminal growth pattern or extra-GI tumors located at the level of cardia or the proximal part of the lesser curvature of the stomach seen on cross-sectional imaging between January 2016 and March 2017. RESULTS: Eight patients underwent STER-ET. The mean (+/- standard deviation) tumor size was 2.8 +/- 0.6 cm and 2.3 +/- 0.8 cm in longest and shortest dimension, respectively. The average procedure time was 67 +/- 4.4 minutes. The rates of curative en bloc resection and en bloc retrieval was 100% and 87.5%, respectively. On final histology, 6 tumors were GI stromal tumors, 1 was a schwannoma, and 1 was a foregut cyst. Five patients had capnoperitoneum during the procedure and required abdominal decompression. One patient had a small mucosotomy successfully treated with a hemostatic clip. There were no major adverse events or deaths. The median length of hospital stay was 3 days. There was no residual tumor on surveillance imaging after a mean follow-up period of 10.0 +/- 2.1 months. CONCLUSIONS: STER-ET is a novel technique that appears to be safe and effective in achieving a curative resection for GI subepithelial tumors with a predominantly extraluminal growth pattern or extraluminal tumors in a selected group of patients. However, larger studies are required to validate our finding. PMID- 29499128 TI - SCF E3 Ligase Substrates Switch from CAN-D to Can-ubiquitylate. AB - Liu et al. (2018) report a mathematical model predicting how the cellular repertoire of SCF E3 ligases is assembled by "adaptive exchange on demand," with the limited pool of CUL1 scanning the vast sea of F-box proteins for those with substrates demanding ubiquitylation. PMID- 29499129 TI - Uneven Braking Spins RNA Polymerase into a Pause. AB - In this issue of Molecular Cell, Guo et al. (2018) and Kang et al. (2018) report structures of paused transcription complexes in which asynchronous translocation inhibits nucleotide addition, allowing for global rearrangements in RNA polymerase stabilized by RNA hairpin and NusA. PMID- 29499130 TI - Missing the Mark: PRDM9-Dependent Methylation Is Required for Meiotic DSB Targeting. AB - PRDM9 determines the localization of meiotic recombination hotspots, which are associated with histone H3 methylation. It is not known whether PRDM9's methyltransferase activity is required or how some PRDM9 alleles can dominate the distribution of hotspots over other alleles. Diagouraga, Clement, and colleagues (2018) show that methyltransferase activity is required for hotspot localization and that this activity is additive in combination, suggesting that the dominance of particular alleles is simply proportional to the frequency of targeted sites. PMID- 29499131 TI - Dynamic Regulation of Long-Chain Fatty Acid Oxidation by a Noncanonical Interaction between the MCL-1 BH3 Helix and VLCAD. AB - MCL-1 is a BCL-2 family protein implicated in the development and chemoresistance of human cancer. Unlike its anti-apoptotic homologs, Mcl-1 deletion has profound physiologic consequences, indicative of a broader role in homeostasis. We report that the BCL-2 homology 3 (BH3) alpha helix of MCL-1 can directly engage very long-chain acyl-CoA dehydrogenase (VLCAD), a key enzyme of the mitochondrial fatty acid beta-oxidation (FAO) pathway. Proteomic analysis confirmed that the mitochondrial matrix isoform of MCL-1 (MCL-1Matrix) interacts with VLCAD. Mcl-1 deletion, or eliminating MCL-1Matrix alone, selectively deregulated long-chain FAO, causing increased flux through the pathway in response to nutrient deprivation. Transient elevation in MCL-1 upon serum withdrawal, a striking increase in MCL-1 BH3/VLCAD interaction upon palmitic acid titration, and direct modulation of enzymatic activity by the MCL-1 BH3 alpha helix are consistent with dynamic regulation. Thus, the MCL-1 BH3 interaction with VLCAD revealed a separable, gain-of-function role for MCL-1 in the regulation of lipid metabolism. PMID- 29499132 TI - Mitochondrial Retrograde Signaling in Mammals Is Mediated by the Transcriptional Cofactor GPS2 via Direct Mitochondria-to-Nucleus Translocation. AB - As most of the mitochondrial proteome is encoded in the nucleus, mitochondrial functions critically depend on nuclear gene expression and bidirectional mito nuclear communication. However, mitochondria-to-nucleus communication pathways in mammals are incompletely understood. Here, we identify G-Protein Pathway Suppressor 2 (GPS2) as a mediator of mitochondrial retrograde signaling and a transcriptional activator of nuclear-encoded mitochondrial genes. GPS2-regulated translocation from mitochondria to nucleus is essential for the transcriptional activation of a nuclear stress response to mitochondrial depolarization and for supporting basal mitochondrial biogenesis in differentiating adipocytes and brown adipose tissue (BAT) from mice. In the nucleus, GPS2 recruitment to target gene promoters regulates histone H3K9 demethylation and RNA POL2 activation through inhibition of Ubc13-mediated ubiquitination. These findings, together, reveal an additional layer of regulation of mitochondrial gene transcription, uncover a direct mitochondria-nuclear communication pathway, and indicate that GPS2 retrograde signaling is a key component of the mitochondrial stress response in mammals. PMID- 29499133 TI - Cand1-Mediated Adaptive Exchange Mechanism Enables Variation in F-Box Protein Expression. AB - Skp1?Cul1?F-box (SCF) ubiquitin ligase assembly is regulated by the interplay of substrate binding, reversible Nedd8 conjugation on Cul1, and the F-box protein (FBP) exchange factors Cand1 and Cand2. Detailed investigations into SCF assembly and function in reconstituted systems and Cand1/2 knockout cells informed the development of a mathematical model for how dynamical assembly of SCF complexes is controlled and how this cycle is coupled to degradation of an SCF substrate. Simulations predicted an unanticipated hypersensitivity of Cand1/2-deficient cells to FBP expression levels, which was experimentally validated. Together, these and prior observations lead us to propose the adaptive exchange hypothesis, which posits that regulation of the koff of an FBP from SCF by the actions of substrate, Nedd8, and Cand1 molds the cellular repertoire of SCF complexes and that the plasticity afforded by this exchange mechanism may enable large variations in FBP expression during development and in FBP gene number during evolution. PMID- 29499135 TI - RNA Polymerase Accommodates a Pause RNA Hairpin by Global Conformational Rearrangements that Prolong Pausing. AB - Sequence-specific pausing by RNA polymerase (RNAP) during transcription plays crucial and diverse roles in gene expression. In bacteria, RNA structures are thought to fold within the RNA exit channel of the RNAP and can increase pause lifetimes significantly. The biophysical mechanism of pausing is uncertain. We used single-particle cryo-EM to determine structures of paused complexes, including a 3.8-A structure of an RNA hairpin-stabilized, paused RNAP that coordinates RNA folding in the his operon attenuation control region of E. coli. The structures revealed a half-translocated pause state (RNA post-translocated, DNA pre-translocated) that can explain transcriptional pausing and a global conformational change of RNAP that allosterically inhibits trigger loop folding and can explain pause hairpin action. Pause hairpin interactions with the RNAP RNA exit channel suggest how RNAP guides the formation of nascent RNA structures. PMID- 29499134 TI - FUS Regulates Activity of MicroRNA-Mediated Gene Silencing. AB - MicroRNA-mediated gene silencing is a fundamental mechanism in the regulation of gene expression. It remains unclear how the efficiency of RNA silencing could be influenced by RNA-binding proteins associated with the microRNA-induced silencing complex (miRISC). Here we report that fused in sarcoma (FUS), an RNA-binding protein linked to neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), interacts with the core miRISC component AGO2 and is required for optimal microRNA-mediated gene silencing. FUS promotes gene silencing by binding to microRNA and mRNA targets, as illustrated by its action on miR-200c and its target ZEB1. A truncated mutant form of FUS that leads its carriers to an aggressive form of ALS, R495X, impairs microRNA-mediated gene silencing. The C. elegans homolog fust-1 also shares a conserved role in regulating the microRNA pathway. Collectively, our results suggest a role for FUS in regulating the activity of microRNA-mediated silencing. PMID- 29499136 TI - Structural Basis for NusA Stabilized Transcriptional Pausing. AB - Transcriptional pausing by RNA polymerases (RNAPs) is a key mechanism to regulate gene expression in all kingdoms of life and is a prerequisite for transcription termination. The essential bacterial transcription factor NusA stimulates both pausing and termination of transcription, thus playing a central role. Here, we report single-particle electron cryo-microscopy reconstructions of NusA bound to paused E. coli RNAP elongation complexes with and without a pause-enhancing hairpin in the RNA exit channel. The structures reveal four interactions between NusA and RNAP that suggest how NusA stimulates RNA folding, pausing, and termination. An asymmetric translocation intermediate of RNA and DNA converts the active site of the enzyme into an inactive state, providing a structural explanation for the inhibition of catalysis. Comparing RNAP at different stages of pausing provides insights on the dynamic nature of the process and the role of NusA as a regulatory factor. PMID- 29499137 TI - Unique Structural Platforms of Suz12 Dictate Distinct Classes of PRC2 for Chromatin Binding. AB - Developmentally regulated accessory subunits dictate PRC2 function. Here, we report the crystal structures of a 120 kDa heterotetrameric complex consisting of Suz12, Rbbp4, Jarid2, and Aebp2 fragments that is minimally active in nucleosome binding and of an inactive binary complex of Suz12 and Rbbp4. Suz12 contains two unique structural platforms that define distinct classes of PRC2 holo complexes for chromatin binding. Aebp2 and Phf19 compete for binding of a non-canonical C2 domain of Suz12; Jarid2 and EPOP occupy an overlapped Suz12 surface required for chromatin association of PRC2. Suz12 and Aebp2 progressively block histone H3K4 binding to Rbbp4, suggesting that Rbbp4 may not be directly involved in PRC2 inhibition by the active H3K4me3 histone mark. Nucleosome binding enabled by Jarid2 and Aebp2 is in part accounted for by the structures, which also reveal that disruption of the Jarid2-Suz12 interaction may underlie the disease mechanism of an oncogenic chromosomal translocation of Suz12. PMID- 29499140 TI - The Dfm1 Derlin Is Required for ERAD Retrotranslocation of Integral Membrane Proteins. PMID- 29499138 TI - The Ubiquitin E3/E4 Ligase UBE4A Adjusts Protein Ubiquitylation and Accumulation at Sites of DNA Damage, Facilitating Double-Strand Break Repair. AB - Double-strand breaks (DSBs) are critical DNA lesions that robustly activate the elaborate DNA damage response (DDR) network. We identified a critical player in DDR fine-tuning: the E3/E4 ubiquitin ligase UBE4A. UBE4A's recruitment to sites of DNA damage is dependent on primary E3 ligases in the DDR and promotes enhancement and sustainment of K48- and K63-linked ubiquitin chains at these sites. This step is required for timely recruitment of the RAP80 and BRCA1 proteins and proper organization of RAP80- and BRCA1-associated protein complexes at DSB sites. This pathway is essential for optimal end resection at DSBs, and its abrogation leads to upregulation of the highly mutagenic alternative end joining repair at the expense of error-free homologous recombination repair. Our data uncover a critical regulatory level in the DSB response and underscore the importance of fine-tuning the complex DDR network for accurate and balanced execution of DSB repair. PMID- 29499141 TI - Engineering a Strong Bond between Stem Cells and Biotechnology. PMID- 29499142 TI - Living Up to the Hype: Protein Synthesis Promotes Hypertranscription in Embryonic Stem Cells. AB - The rapid proliferation and unlimited self-renewal of embryonic stem cells depends upon a permissive chromatin landscape that enables hypertranscription. In this issue of Cell Stem Cell, Bulut-Karslioglu et al. report that euchromatin and transcriptional output are enhanced by protein synthesis in embryonic stem cells (Bulut-Karslioglu et al., 2018). PMID- 29499139 TI - CRISPR RNA-Dependent Binding and Cleavage of Endogenous RNAs by the Campylobacter jejuni Cas9. AB - Cas9 nucleases naturally utilize CRISPR RNAs (crRNAs) to silence foreign double stranded DNA. While recent work has shown that some Cas9 nucleases can also target RNA, RNA recognition has required nuclease modifications or accessory factors. Here, we show that the Campylobacter jejuni Cas9 (CjCas9) can bind and cleave complementary endogenous mRNAs in a crRNA-dependent manner. Approximately 100 transcripts co-immunoprecipitated with CjCas9 and generally can be subdivided through their base-pairing potential to the four crRNAs. A subset of these RNAs was cleaved around or within the predicted binding site. Mutational analyses revealed that RNA binding was crRNA and tracrRNA dependent and that target RNA cleavage required the CjCas9 HNH domain. We further observed that RNA cleavage was PAM independent, improved with greater complementarity between the crRNA and the RNA target, and was programmable in vitro. These findings suggest that C. jejuni Cas9 is a promiscuous nuclease that can coordinately target both DNA and RNA. PMID- 29499143 TI - Sensors of Succinate: Neural Stem Cell Grafts Fight Neuroinflammation. AB - In this issue of Cell Stem Cell, Peruzzotti-Jametti et al. (2018) demonstrate how neural stem cells, transplanted in a mouse model of multiple sclerosis, respond to extracellular succinate and modulate neuroinflammation by releasing anti inflammatory prostaglandin E2 and scavenging succinate. This mechanism reduces CNS damage and ameliorates motor impairment. PMID- 29499144 TI - Reversing Time: Ezh1 Deficiency Hastens Definitive Hematopoiesis. AB - The inability to derive multipotent hematopoietic stem cells in vitro stems in part from a limited understanding of how multipotency is acquired during development. Recently in Nature,Vo et al. (2018) reveal the epigenetic enzyme Ezh1 as a master regulator of multipotency during hematopoietic stem cell development. PMID- 29499145 TI - Who Defends the Stem Cell's Citadel? AB - Recently in Cell, Wu et al. (2018) demonstrated that intrinsic expression of a subset of interferon stimulated genes confers resistance to viral infections in stem cells both in vitro and in vivo, while differentiated cells lose this intrinsic gatekeeper expression pattern in favor of inducible interferon responses. PMID- 29499146 TI - Organoid Models of Cancer Explode with Possibilities. AB - Organoids have tremendous promise for modeling human cancers and revealing new biological insights. Sachs et al. (2018), Seino et al. (2018) (in this issue of Cell Stem Cell), and Broutier et al. (2017) derive cancer organoids from breast, pancreas, and liver, respectively, not only reporting new methodologies but also showing their utility for translational and clinical cancer research. PMID- 29499147 TI - Human Pluripotent Stem Cell-Derived Engineered Tissues: Clinical Considerations. AB - The combined power of human pluripotent stem cells and tissue engineering promises to revolutionize medicine by building tissue patches and artificial replacement organs for patients battling diverse diseases. Here, we articulate some big questions that need to be addressed before such engineered tissues become mainstream in the clinic. PMID- 29499148 TI - Engineering Human Bone Marrow Proxies. AB - Recent advances in engineering complex organs in vitro inspire the development of human bone marrow equivalents to foster scientific discovery and innovative therapeutics. Here, we discuss challenges in generating relevant human bone marrow proxies, potential design principles, and future directions. PMID- 29499149 TI - Understanding the Extracellular Matrix to Enhance Stem Cell-Based Tissue Regeneration. AB - The extracellular matrix is a biologically critical entity that has historically been poorly understood. Here we discuss how new tools for characterizing matrix composition and function enable us to design and deliver advanced matrices in vitro, to optimize regeneration, and in vivo, within a variety of tissues and organs. PMID- 29499150 TI - Regenerative Rehabilitation: Applied Biophysics Meets Stem Cell Therapeutics. AB - The emerging field of regenerative rehabilitation integrates biological and bioengineering advances in regenerative medicine with rehabilitative sciences. Here we highlight recent stem cell-based examples of the regenerative rehabilitation paradigm to promote tissue repair and regeneration, and we discuss remaining challenges and future directions for the field. PMID- 29499151 TI - Organs-on-a-Chip: A Fast Track for Engineered Human Tissues in Drug Development. AB - Organs-on-a-chip (OOCs) are miniature tissues and organs grown in vitro that enable modeling of human physiology and disease. The technology has emerged from converging advances in tissue engineering, semiconductor fabrication, and human cell sourcing. Encompassing innovations in human stem cell technology, OOCs offer a promising approach to emulate human patho/physiology in vitro, and address limitations of current cell and animal models. Here, we review the design considerations for single and multi-organ OOCs, discuss remaining challenges, and highlight the potential impact of OOCs as a fast-track opportunity for tissue engineering to advance drug development and precision medicine. PMID- 29499154 TI - Vangl2/RhoA Signaling Pathway Regulates Stem Cell Self-Renewal Programs and Growth in Rhabdomyosarcoma. AB - Tumor growth and relapse are driven by tumor propagating cells (TPCs). However, mechanisms regulating TPC fate choices, maintenance, and self-renewal are not fully understood. Here, we show that Van Gogh-like 2 (Vangl2), a core regulator of the non-canonical Wnt/planar cell polarity (Wnt/PCP) pathway, affects TPC self renewal in rhabdomyosarcoma (RMS)-a pediatric cancer of muscle. VANGL2 is expressed in a majority of human RMS and within early mononuclear progenitor cells. VANGL2 depletion inhibited cell proliferation, reduced TPC numbers, and induced differentiation of human RMS in vitro and in mouse xenografts. Using a zebrafish model of embryonal rhabdomyosarcoma (ERMS), we determined that Vangl2 expression enriches for TPCs and promotes their self-renewal. Expression of constitutively active and dominant-negative isoforms of RHOA revealed that it acts downstream of VANGL2 to regulate proliferation and maintenance of TPCs in human RMS. Our studies offer insights into pathways that control TPCs and identify new potential therapeutic targets. PMID- 29499153 TI - The Transcriptionally Permissive Chromatin State of Embryonic Stem Cells Is Acutely Tuned to Translational Output. AB - A permissive chromatin environment coupled to hypertranscription drives the rapid proliferation of embryonic stem cells (ESCs) and peri-implantation embryos. We carried out a genome-wide screen to systematically dissect the regulation of the euchromatic state of ESCs. The results revealed that cellular growth pathways, most prominently translation, perpetuate the euchromatic state and hypertranscription of ESCs. Acute inhibition of translation rapidly depletes euchromatic marks in mouse ESCs and blastocysts, concurrent with delocalization of RNA polymerase II and reduction in nascent transcription. Translation inhibition promotes rewiring of chromatin accessibility, which decreases at a subset of active developmental enhancers and increases at histone genes and transposable elements. Proteome-scale analyses revealed that several euchromatin regulators are unstable proteins and continuously depend on a high translational output. We propose that this mechanistic interdependence of euchromatin, transcription, and translation sets the pace of proliferation at peri implantation and may be employed by other stem/progenitor cells. PMID- 29499156 TI - 2017 ASHG Awards and Addresses. AB - Each year at the annual meeting of the American Society of Human Genetics (ASHG), addresses are given in honor of the society and a number of award winners. A summary of each of these is provided below. On the following pages, we have printed the presidential address and the addresses for the William Allan Award, Curt Stern Award, and Victor A. McKusick Leadership Award. Webcasts of these addresses, as well as those of many other presentations, can be found at http://www.ashg.org. PMID- 29499152 TI - Vascular Tissue Engineering: Progress, Challenges, and Clinical Promise. AB - Although the clinical demand for bioengineered blood vessels continues to rise, current options for vascular conduits remain limited. The synergistic combination of emerging advances in tissue fabrication and stem cell engineering promises new strategies for engineering autologous blood vessels that recapitulate not only the mechanical properties of native vessels but also their biological function. Here we explore recent bioengineering advances in creating functional blood macro and microvessels, particularly featuring stem cells as a seed source. We also highlight progress in integrating engineered vascular tissues with the host after implantation as well as the exciting pre-clinical and clinical applications of this technology. PMID- 29499155 TI - SETD7 Drives Cardiac Lineage Commitment through Stage-Specific Transcriptional Activation. AB - Cardiac development requires coordinated and large-scale rearrangements of the epigenome. The roles and precise mechanisms through which specific epigenetic modifying enzymes control cardiac lineage specification, however, remain unclear. Here we show that the H3K4 methyltransferase SETD7 controls cardiac differentiation by reading H3K36 marks independently of its enzymatic activity. Through chromatin immunoprecipitation sequencing (ChIP-seq), we found that SETD7 targets distinct sets of genes to drive their stage-specific expression during cardiomyocyte differentiation. SETD7 associates with different co-factors at these stages, including SWI/SNF chromatin-remodeling factors during mesodermal formation and the transcription factor NKX2.5 in cardiac progenitors to drive their differentiation. Further analyses revealed that SETD7 binds methylated H3K36 in the bodies of its target genes to facilitate RNA polymerase II (Pol II) dependent transcription. Moreover, abnormal SETD7 expression impairs functional attributes of terminally differentiated cardiomyocytes. Together, these results reveal how SETD7 acts at sequential steps in cardiac lineage commitment, and they provide insights into crosstalk between dynamic epigenetic marks and chromatin modifying enzymes. PMID- 29499158 TI - 2017 William Allan Award Introduction: Kari Stefansson. PMID- 29499157 TI - 2017 Presidential Address: Checking, Balancing, and Celebrating Diversity: Celebrating Some of the Women Who Paved the Way. PMID- 29499159 TI - 2017 William Allan Award. PMID- 29499160 TI - 2017 Curt Stern Award Introduction: Nico Katsanis. PMID- 29499161 TI - 2017 Curt Stern Award: The Complexity of Simple Genetics. PMID- 29499162 TI - 2017 Victor A. McKusick Leadership Award Introduction: Arthur L. Beaudet. PMID- 29499163 TI - 2017 Victor A. McKusick Leadership Award. PMID- 29499164 TI - Single-Cell RNA-Seq of Mouse Dopaminergic Neurons Informs Candidate Gene Selection for Sporadic Parkinson Disease. AB - Genetic variation modulating risk of sporadic Parkinson disease (PD) has been primarily explored through genome-wide association studies (GWASs). However, like many other common genetic diseases, the impacted genes remain largely unknown. Here, we used single-cell RNA-seq to characterize dopaminergic (DA) neuron populations in the mouse brain at embryonic and early postnatal time points. These data facilitated unbiased identification of DA neuron subpopulations through their unique transcriptional profiles, including a postnatal neuroblast population and substantia nigra (SN) DA neurons. We use these population-specific data to develop a scoring system to prioritize candidate genes in all 49 GWAS intervals implicated in PD risk, including genes with known PD associations and many with extensive supporting literature. As proof of principle, we confirm that the nigrostriatal pathway is compromised in Cplx1-null mice. Ultimately, this systematic approach establishes biologically pertinent candidates and testable hypotheses for sporadic PD, informing a new era of PD genetic research. PMID- 29499165 TI - Ectopic GRHL2 Expression Due to Non-coding Mutations Promotes Cell State Transition and Causes Posterior Polymorphous Corneal Dystrophy 4. AB - In a large family of Czech origin, we mapped a locus for an autosomal-dominant corneal endothelial dystrophy, posterior polymorphous corneal dystrophy 4 (PPCD4), to 8q22.3-q24.12. Whole-genome sequencing identified a unique variant (c.20+544G>T) in this locus, within an intronic regulatory region of GRHL2. Targeted sequencing identified the same variant in three additional previously unsolved PPCD-affected families, including a de novo occurrence that suggests this is a recurrent mutation. Two further unique variants were identified in intron 1 of GRHL2 (c.20+257delT and c.20+133delA) in unrelated PPCD-affected families. GRHL2 is a transcription factor that suppresses epithelial-to mesenchymal transition (EMT) and is a direct transcriptional repressor of ZEB1. ZEB1 mutations leading to haploinsufficiency cause PPCD3. We previously identified promoter mutations in OVOL2, a gene not normally expressed in the corneal endothelium, as the cause of PPCD1. OVOL2 drives mesenchymal-to epithelial transition (MET) by directly inhibiting EMT-inducing transcription factors, such as ZEB1. Here, we demonstrate that the GRHL2 regulatory variants identified in PPCD4-affected individuals induce increased transcriptional activity in vitro. Furthermore, although GRHL2 is not expressed in corneal endothelial cells in control tissue, we detected GRHL2 in the corneal "endothelium" in PPCD4 tissue. These cells were also positive for epithelial markers E-Cadherin and Cytokeratin 7, indicating they have transitioned to an epithelial-like cell type. We suggest that mutations inducing MET within the corneal endothelium are a convergent pathogenic mechanism leading to dysfunction of the endothelial barrier and disease. PMID- 29499168 TI - Diesel exhaust particles up-regulate interleukin-17A expression via ROS/NF-kappaB in airway epithelium. AB - IL-17A is implicated in many aspects of pathogenesis of severe asthma, including inducing neutrophilic inflammation, airway hyperresponsiveness, steroid insensitivity and airway remodeling. Diesel exhaust particles (DEP) emission from vehicles has been shown to expand Th17 cells to increase IL-17A release that contributes to DEP-mediated exacerbation of asthma severity. It is not known whether non-immune cells in airways may also release IL-17A in response to DEP exposure. In this study, We found IL-17A expression was upregulated in the epithelium of severe allergic asthma patients from high road traffic pollution areas compared to those in low. Furthermore, we found DEP concentration dependently increased IL-17A synthesis and release by 122.3 +/- 15.72% and 235.5 +/- 18.37%, respectively in primary bronchial epithelial cells (PBEC), accompanied with increased ROS production. Pretreatment of ROS scavenger (NAC) significantly inhibited DEP-induced IL-17A mRNA expression. DEP-induced IkappaBalpha degradation can be inhibited by NAC. We also found DEP increased p65 and RelB subunits expression, and pretreatment of NF-kappaB inhibitor (SN50) also inhibited DEP-induced IL-17A expression. We further found DEP increased NF-kappaB subunit RelB recruitment to IL-17A promoter in PBEC and airway tissue of severe allergic asthma patients from high road traffic pollution areas. These results indicate DEP stimulates IL-17A expression in airway epithelium through ROS/NF kappaB pathway, and provide a possible link between traffic pollution exposure and IL-17A-related responses in severe allergic asthma patients. PMID- 29499166 TI - Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2. AB - Although mutations in more than 90 genes are known to cause CMT, the underlying genetic cause of CMT remains unknown in more than 50% of affected individuals. The discovery of additional genes that harbor CMT2-causing mutations increasingly depends on sharing sequence data on a global level. In this way-by combining data from seven countries on four continents-we were able to define mutations in ATP1A1, which encodes the alpha1 subunit of the Na+,K+-ATPase, as a cause of autosomal-dominant CMT2. Seven missense changes were identified that segregated within individual pedigrees: c.143T>G (p.Leu48Arg), c.1775T>C (p.Ile592Thr), c.1789G>A (p.Ala597Thr), c.1801_1802delinsTT (p.Asp601Phe), c.1798C>G (p.Pro600Ala), c.1798C>A (p.Pro600Thr), and c.2432A>C (p.Asp811Ala). Immunostaining peripheral nerve axons localized ATP1A1 to the axolemma of myelinated sensory and motor axons and to Schmidt-Lanterman incisures of myelin sheaths. Two-electrode voltage clamp measurements on Xenopus oocytes demonstrated significant reduction in Na+ current activity in some, but not all, ouabain insensitive ATP1A1 mutants, suggesting a loss-of-function defect of the Na+,K+ pump. Five mutants fall into a remarkably narrow motif within the helical linker region that couples the nucleotide-binding and phosphorylation domains. These findings identify a CMT pathway and a potential target for therapy development in degenerative diseases of peripheral nerve axons. PMID- 29499167 TI - Salubrinal and robenacoxib treatment after global cerebral ischemia. Exploring the interactions between ER stress and inflammation. AB - BACKGROUND: Blood reperfusion of the ischemic tissue after stroke promotes increases in the inflammatory response as well as accumulation of unfolded/misfolded proteins in the cell, leading to endoplasmic reticulum (ER) stress. Both Inflammation and ER stress are critical processes in the delayed death of the cells damaged after ischemia. The aim of this study is to check the putative synergic neuroprotective effect by combining anti-inflammatory and anti ER stress agents after ischemia. METHODS: The study was performed on a two-vessel occlusion global cerebral ischemia model. Animals were treated with salubrinal one hour after ischemia and with robenacoxib at 8 h and 32 h after ischemia. Parameters related to the integrity of the blood-brain barrier (BBB), such as matrix metalloproteinase 9 and different cell adhesion molecules (CAMs), were analyzed by qPCR at 24 h and 48 h after ischemia. Microglia and cell components of the neurovascular unit, including neurons, endothelial cells and astrocytes, were analyzed by immunofluorescence after 48 h and seven days of reperfusion. RESULTS: Pharmacologic control of ER stress by salubrinal treatment after ischemia, revealed a neuroprotective effect over neurons that reduces the transcription of molecules involved in the impairment of the BBB. Robenacoxib treatment stepped neuronal demise forward, revealing a detrimental effect of this anti-inflammatory agent. Combined treatment with robenacoxib and salubrinal after ischemia prevented neuronal loss and changes in components of the neurovascular unit and microglia observed when animals were treated only with robenacoxib. CONCLUSION: Combined treatment with anti-ER stress and anti-inflammatory agents is able to provide enhanced neuroprotective effects reducing glial activation, which opens new avenues in therapies against stroke. PMID- 29499169 TI - In vitro basal T-cell proliferation among asymptomatic Human T cell Leukemia Virus type 1 patients co-infected with hepatitis C and/or Human Immunodeficiency Virus type 1. AB - BACKGROUND: Infection with Human T cell Leukemia Virus type 1 can be associated with myelopathy/tropical spastic paraparesis (HAM/TSP) and other inflammatory diseases. Lymphocytes from about half of Human T cell Leukemia Virus type 1 infected subjects spontaneously proliferate in vitro, and how this phenomenon relates to symptomatic disease and viral burden is poorly understood. OBJECTIVE: To evaluate T-cell proliferation in vitro among patients co-infected with Human T cell Leukemia Virus type 1/Hepatitis C Virus/Human Immunodeficiency Virus type 1. MATERIAL AND METHODS: From 610 Human T cell Leukemia Virus-infected patients of the Human T cell Leukemia Virus outpatient clinic from Institute of Infectious Diseases "Emilio Ribas" in Sao Paulo, 273 agreed to participate: 72 had HAM/TSP (excluded from this analysis) and 201 were asymptomatic, a classification performed during a regular neurological appointment. We selected the subgroup made up only by the 201 asymptomatic subjects to avoid bias by the clinical status as a confounder effect, who had laboratory results of Human T cell Leukemia Virus type 1 proviral load and T-cell proliferation assay in our database. They were further grouped according to their serological status in four categories: 121 Human T cell Leukemia Virus type 1 asymptomatic mono-infected carriers; 32 Human T cell Leukemia Virus type 1/Hepatitis C Virus, 29 Human T cell Leukemia Virus type 1/Human Immunodeficiency Virus type 1, and 19 Human T cell Leukemia Virus type 1/Human Immunodeficiency Virus type 1/Hepatitis C Virus co-infected patients. Clinical data were obtained from medical records and interviews. DNA Human T cell Leukemia Virus type 1 proviral load (PVL) and T-cell proliferation (LPA) assay were performed for all samples. RESULTS: From a total of 273 subjects with Human T cell Leukemia Virus type 1, 80 presented co infections: 29 had Human Immunodeficiency Virus type 1, 32 had Hepatitis C Virus, and 19 had Human Immunodeficiency Virus type 1 and Hepatitis C Virus. Comparing the groups based on their serological status, independently of being asymptomatic carriers, we observed a significant increase of PVL (p<0.001) and LPA (p=0.001). However, when groups were stratified according to their clinical and serological status, there was no significant increase in Human T cell Leukemia Virus type 1 PVL and LPA. CONCLUSION: No significant increase of basal T-cell proliferation among Human T cell Leukemia Virus type 1 co-infected was observed. This interaction may be implicated in liver damage, worsening the prognosis of co infected patients or, on the contrary, inducing a higher spontaneous clearance of Hepatitis C Virus infection in Human T cell Leukemia Virus type 1 co-infected patients. PMID- 29499170 TI - First report of Panstrongylus megistus (Hemiptera, Reduviidae, Triatominae) in the State of Acre and Rondonia, Amazon, Brazil. AB - INTRODUCTION: This article reports, for the first time, the occurrence of Panstrongylus megistus in the Brazilian Western Amazon. METHODS: Specimens of P. megistus were collected in the cities of Rio Branco, Acre and Extrema, Rondonia. RESULTS: The number of triatomine species in the State of Acre increased from eight to nine and in Rondonia from seven to eight. This was also the first report of P. megistus in the Brazilian Western Amazon. CONCLUSION: The occurrence of P. megistus in the Western Amazon evidences an epidemiological alert, since it is an important vector of T. cruzi. PMID- 29499172 TI - Management of Common Benign Anorectal Disease: What All Physicians Need to Know. AB - Benign anorectal conditions produce anal pain, rectal bleeding, or discharge from the perianal region, which are highly prevalent symptoms in the general population. Hemorrhoidal disease, anal fissure, perianal abscess, proctalgia syndromes, and pruritus anii are the most common clinical disorders. Well-trained physicians, irrespective of their specialty, can treat most of these disorders and refer them to a specialist in proctology only when necessary. The aim of this review is to provide a practical guide to the management of benign anorectal disorders in terms of their initial management and the criteria for specialist referral. PMID- 29499171 TI - CSF biomarkers of Alzheimer's disease concord with amyloid-beta PET and predict clinical progression: A study of fully automated immunoassays in BioFINDER and ADNI cohorts. AB - INTRODUCTION: We studied whether fully automated Elecsys cerebrospinal fluid (CSF) immunoassay results were concordant with positron emission tomography (PET) and predicted clinical progression, even with cutoffs established in an independent cohort. METHODS: Cutoffs for Elecsys amyloid-beta1-42 (Abeta), total tau/Abeta(1-42), and phosphorylated tau/Abeta(1-42) were defined against [18F]flutemetamol PET in Swedish BioFINDER (n = 277) and validated against [18F]florbetapir PET in Alzheimer's Disease Neuroimaging Initiative (n = 646). Clinical progression in patients with mild cognitive impairment (n = 619) was studied. RESULTS: CSF total tau/Abeta(1-42) and phosphorylated tau/Abeta(1-42) ratios were highly concordant with PET classification in BioFINDER (overall percent agreement: 90%; area under the curve: 94%). The CSF biomarker statuses established by predefined cutoffs were highly concordant with PET classification in Alzheimer's Disease Neuroimaging Initiative (overall percent agreement: 89% 90%; area under the curves: 96%) and predicted greater 2-year clinical decline in patients with mild cognitive impairment. Strikingly, tau/Abeta ratios were as accurate as semiquantitative PET image assessment in predicting visual read-based outcomes. DISCUSSION: Elecsys CSF biomarker assays may provide reliable alternatives to PET in Alzheimer's disease diagnosis. PMID- 29499173 TI - Ab Interno Gel Implant-associated Bleb-related Infection. AB - PURPOSE: To examine the presentation and management of 3 cases of bleb-related infection following ab interno gel implant surgery, so as to add to the growing understanding of complications associated with the emerging landscape of newer, minimally invasive glaucoma surgical procedures, and how they are best managed. DESIGN: Multicenter retrospective interventional case series. METHODS: Consecutive cases of bleb-related infection following ab interno gel implant surgery from 2 university-affiliated hospitals were included. Risk factors, visual outcomes, intraocular pressure, and subsequent management were analyzed. RESULTS: We report 3 cases of late bleb-related infection occurring after ab interno gelatin stent insertion (8, 7, and 24 months after surgery). One case had blebitis only; the other 2 had bleb-related endophthalmitis. All cases responded rapidly to management of their infections according to standard bleb-related infection protocol, recovering to within 2 lines of their previous visual acuity (6/9, 6/12, and 6/18). Explantation of the devices was not required. CONCLUSIONS: Bleb-related infections after ab interno gel implant insertion can occur. If infection is treated appropriately, good clinical outcomes are possible. PMID- 29499174 TI - Shortest Distance From Fovea to Subfoveal Hemorrhage Border Is Important in Patients With Neovascular Age-related Macular Degeneration. AB - PURPOSE: To identify factors influencing visual outcome in patients with neovascular age-related macular degeneration (NVAMD) and subfoveal hemorrhage (SFH) treated with anti-vascular endothelial growth factor (VEGF) agents. DESIGN: Retrospective case series. METHODS: Anti-VEGF-treated eyes with SFH > 1 disc area (DA) were identified (n = 16) and changes in visual acuity (VA) and central subfield thickness (CST) from baseline to last follow-up, along with SFH area, thickness, minimum distance from fovea to SFH border, and time to resolution, were determined. RESULTS: At baseline, mean (+/- standard error of the mean) size and thickness of SFH were 14.9 +/- 2.8 DA and 386.6 +/- 46.9 MUm, and mean Snellen VA and CST were 20/250 and 591.7 +/- 57.0 MUm. Median follow-up was 47.6 months. While more than 50% of patients had VA <= 20/200 at baseline and all time points through week 48, the percentage of patients with VA >= 20/50 increased to 30%-40% at months 6 and 12 and remained stable through month 48. Spearman rank correlation demonstrated 2 independent variables that correlated with good visual outcome, smaller area of SFH at baseline (r = -0.630; P = .009), and high frequency of anti-VEGF injections (r = 0.646; P = .007). In exceptional patients with good visual outcome despite large baseline SFH, shortest distance between the fovea and hemorrhage border significantly correlated with baseline VA (r = 0.503, P = .047) and final VA (r = -0.575, P = .02). CONCLUSIONS: Patients with NVAMD and thick SFH, but short distance between fovea and uninvolved retina, can have good visual outcomes when given frequent anti-VEGF injections. PMID- 29499175 TI - Developing a colorimetric assay for Fe(II)/2-oxoglutarate-dependent dioxygenase. AB - The Fe(II)/2-oxoglutarate-dependent dioxygenases (2-OGDs) catalyze the oxidation of substrates ranging from small molecules to large biomolecules with concomitant oxidation of co-substrate (2-oxoglutarate) into succinate. In the present study, we reported a coupled colorimetric assay that can be generally applied to measure the activities of all members of 2-OGDs family. Succinyl-CoA synthetase is employed as the coupling enzyme to transform succinate produced from 2-OGDs catalysis to form succinyl-CoA with concomitant hydrolysis of ATP to form ADP and orthophosphate. Orthophosphate can be quantitated by reacting it with molybdic acid forming a blue pigment. As a proof of concept, kinetic parameters of ectoine hydroxylase obtained using this method are compared to a traditional time- and labor-consuming HPLC based method. As 2-OGDs family enzymes are important drug targets due to their impressive versatility in catalyzing numerous oxidative reactions that are still very challenging using synthetic chemistry, colorimetric method detailed in the manuscript has the potential to enable the practice of high throughput drug screening for 2-OGDs. PMID- 29499176 TI - Dorsal hippocampal galanin modulates anxiety-like behaviours in rats. AB - Galanin, a peptide expressed in mammalian brain regions, has been implicated in anxiety and depression. Galanin signalling occurs through three G protein-linked receptors (GAL1, GAL2 and GAL3). Galanin regulates the release of neurotransmitters in some brain regions related to anxiety, including the hippocampus. GAL2 is the most abundant galanin receptor in the dorsal hippocampus. In this study, we evaluated whether galanin administered in the dorsal hippocampus affected anxiety-like behaviours of rats. We also investigated if GAL2 receptors are involved in the anxiogenic-like effect of galanin using a GAL2 antagonist, M871. To achieve these objectives, male adult Wistar rats received intra-dorsal hippocampal delivery of galanin (0.3 and 1.0 nmol/0.5 ul) or vehicle in experiment 1 and GAL2 antagonist M871 (1.0 and 3.0 nmol/0.5 ul) or vehicle in experiment 2. Twenty min after administration of drugs, the animals were tested in the elevated plus-maze (EPM). Galanin (1.0 nmol) induced anxiogenic-like behaviours, while the GAL2 receptor antagonist M871 (3.0 nmol) induced anxiolytic-like behaviours in rats exposed to the EPM, indicating a tonic effect of galanin. In experiment 3, we evaluated whether previous infusion of the GAL2 antagonist M871 (1 or 2 nmol) in the dorsal hippocampus would block the anxiogenic-like effect of galanin in rats tested in the EPM. We showed that M871 (2.0 nmol) counteracted the anxiogenic-like effect of galanin infused in the dorsal hippocampus of rats. Altogether, our results provide evidence that galanin promotes pharmacological and tonic anxiogenic-like effects in the dorsal hippocampus, possibly mediated by GAL2 receptors. PMID- 29499177 TI - The role of Pax6 in brain development and its impact on pathogenesis of autism spectrum disorder. AB - Pax6 transcription factor is a key player in several aspects of brain development and function. Autism spectrum disorder (ASD) is a neurodevelopmental disorder in which several loci and/or genes have been suggested as causative candidate factors. Based on data obtained from meta-analyses of the transcriptome and ChIP analyses, we hypothesized that the neurodevelopmental gene PAX6 regulates and/or binds to a large number of genes (including many ASD-related ones) that modulate the fate of neural stem/progenitor cells and functions of neuronal cells, subsequently affecting animal behavior. Network analyses of PAX6/ASD-related molecules revealed significant clusters of molecular interactions involving regulation of cell-cell adhesion, ion transport, and transcriptional regulation. We discuss a novel function of Pax6 as a chromatin modulator that alters the chromatin status of ASD genes, thereby inducing diverse phenotypes of ASD and related neurodevelopmental diseases. PMID- 29499178 TI - Development of an In Situ Thoracic Surgery Crisis Simulation Focused on Nontechnical Skill Training. AB - BACKGROUND: Our vision was to develop an inexpensive training simulation in a functional operating room (in situ) that included surgical trainees and nursing and anesthesia staff to focus on effective interprofessional communication and teamwork skills. METHODS: The simulation scenario revolved around an airway obstruction by residual tumor after pneumonectomy. This model included our thoracic operating room with patient status displayed by an open access vital sign simulator and a reversibly modified Laerdal airway mannequin (Shavanger, Norway). The simulation scenario was run seven times. Simulations were video recorded and scored with the use of Non-Technical Skills for Surgeons (NOTSS) and TeamSTEPPS2. Latent safety threats (LSTs) and feedback were obtained during the debriefing after the simulation. Feedback was captured with the Method Material Member Overall (MMMO) questionnaire. RESULTS: Several LSTs were identified, which included missing and redundant equipment and knowledge gaps in participants' roles. Consultant surgeons received a higher overall score than thoracic surgery fellows on both NOTSS (3.8 versus 3.3) and TeamSTEPPS2 (4.1 versus 3.2) evaluations, suggesting that the scenario effectively differentiated learners from experts with regards to nontechnical skills. The MMMO overall simulation experience score was 4.7 of 5, confirming a high-fidelity model and useful experiential learning model. At the Canadian Thoracic Bootcamp, the MMMO overall experience score was 4.8 of 5, further supporting this simulation as a robust model. CONCLUSIONS: An inexpensive in situ intraoperative crisis simulation model for thoracic surgical emergencies was created, implemented, and demonstrated to be effective as a proof of concept at identifying latent threats to patient safety and differentiating the nontechnical skills of trainees and consultant surgeons. PMID- 29499179 TI - Hydatidosis: Preparation and evaluation of radiolabeled antigens and antibodies. AB - The present preliminary study intends to evaluate the in vitro use of hydatid antigen and their antibodies once labeled with iodine 125(I125) and characterized from viewpoint of radiochemical purity and immunoreactivity. Radiolabelled molecules gave satisfactory purity of 94% and 96%-98%, for hydatid antigen and IgG respectively. As regards, the specific activity of these latter, varied between 4.79 and 5.97 MUCi/MUg. The specificity test of radiolabelled IgG against the hydatid membranes showed a significant recognition that increased proportionally according to the contact surface. Likewise this immunoreactivity test performed with a simple binding assay, using human hydatid fluid antigen (HHF-Ag), previously fixed on a solid phase, gave satisfactory fixation rate of the order of 356 +/- 48.08cpm, 2539 +/- 550.12cpm and 6558 +/- 712.76cpm for the concentrations of 0.1 MUg/ml, 2 MUg/ml and 25 MUg/ml respectively. Statistical study of 88 sera, carried out with radiolabelled antigen (125I-HHF-Ag) in competitive radioimmunoassay test (CRIA) showed highly significant difference (p < 0.0001) in the binding capacity of antigens from patients sera with hydatid disease (65.63 +/- 9.12) compared to the negative sera (19.25 +/- 14.84). No cross reaction was observed using sera from patients with toxoplasmosis (33, 07 +/- 13, 07) and the difference was highly significant (p < 0.0001) compared to E granulosus infected patient sera. Furthermore, this test seemed to be sensitive since among the 43 sera tested, only 37 (86%) were found to be positive by passive hemagglutination (HAP), while the totality (100%) responded positively by CRIA. Our findings are encouraging, suggesting that these radiolabeled molecules could be useful for advancing toward new diagnostic and therapeutic modalities. PMID- 29499180 TI - Modulation of cis- and trans- Golgi and the Rab9A-GTPase during infection by Besnoitia besnoiti, Toxoplasma gondii and Neospora caninum. AB - Like most intracellular pathogens, the apicomplexan parasites Besnoitia besnoiti, Toxoplasma gondii and Neospora caninum scavenge metabolites from their host cells. Recruitment of the Golgi complex to the vicinity of the parasitophorous vacuole (PV) is likely to aid in this process. In this work, we comparatively assessed B. besnoiti, T. gondii and N. caninum infected human retinal pigmented epithelial (hTERT-RPE-1) cells at 24 h post-infection and used antibodies to confirm Golgi ribbon compaction in B. besnoiti, and Golgi ribbon dispersion in T. gondii, while no alteration in Golgi morphology was seen in N. caninum infected cells. In either case, the Golgi stacks of infected cells contained both cis- (GM130) and trans- (TGN46) Golgi proteins. The localization of Rab9A, an important regulator of endosomal trafficking, was also studied. GFP-tagged Rab9A was recruited to the vicinity of the PV of all three parasites. Toxoplasma infected cells exhibited increased expression of Rab9A in comparison to non infected cells. However, Rab9A expression levels remained unaltered upon infection with N. caninum and B. besnoiti tachyzoites. In contrast to Rab9A, a GFP-tagged dominant negative mutant form of Rab9A (Rab9A DN), was not recruited to the PV, and the expression of Rab9A DN did not affect host cell invasion nor replication by all three parasites. Thus, B. besnoiti, T. gondii and N. caninum show similarities but also differences in how they affect constituents of the endosomal/secretory pathways. PMID- 29499181 TI - DPPC monolayer response to non-spanning cobalt-cage metallosurfactants: Electrostatic complex formation. AB - A novel series of amphiphilic cobalt-cage derivatives (ACCD), bearing a diaza crown bridge and varying alkyl chains, facilitate ion transport across biomembrane models via self-aggregation. In this study, compression isotherm analyses and atomic force microscopy (AFM) were used to assess the interactions of these amphiphiles with Langmuir monolayers of dipalmitoylphosphatidylcholine (DPPC) in order to elucidate electrostatic and steric contributions to ion transport. The stability and compressibility of DPPC monolayers are disrupted by ACCD molecules with short (C12) alkyl chains. These top-heavy amphiphiles (large cone angles) create voids at the interface of the hydrophobic/aqueous layer leading to monolayer expansion and packing efficiency of the aliphatic chains is disrupted. Long-tailed analogues (C16, C18) are cohesively integrated into DPPC monolayers due to their smaller cone angles at the interfacial region and increased hydrocarbon compatibility in the hydrophobic region. Thermodynamic data indicate the formation of electrostatic complexes between DPPC and longer-tailed amphiphiles consistent with AFM observations of aggregate structures at the corresponding concentrations. PMID- 29499183 TI - An early nonsense mutation facilitates the expression of a short isoform of CNGA3 by alternative translation initiation. AB - The cyclic nucleotide-gated (CNG) channel - composed of CNGA3 and CNGB3 subunits mediates the influx of cations in cone photoreceptors after light stimulation and thus is a key element in cone phototransduction. Mutations in CNGA3 and CNGB3 are associated with achromatopsia, a rare autosomal recessive retinal disorder. Here, we demonstrate that the presence of an early nonsense mutation in CNGA3 induces the usage of a downstream alternative translation initiation site giving rise to a short CNGA3 isoform. The expression of this short isoform was verified by Western blot analysis and DAB staining of HEK293 cells and cone photoreceptor like 661W cells expressing CNGA3-GST fusion constructs. Functionality of the short isoform was confirmed by a cellular calcium influx assay. Furthermore, patients carrying an early nonsense mutation were analyzed for residual cone photoreceptor function in order to identify a potential role of the short isoform to modify the clinical outcome in achromatopsia patients. Yet the results suggest that the short isoform is not able to compensate for the loss of the long isoform leaving the biological role of this variant unclear. PMID- 29499182 TI - Glucuronylated core 1 glycans are required for precise localization of neuromuscular junctions and normal formation of basement membranes on Drosophila muscles. AB - T antigen (Galbeta1-3GalNAcalpha1-Ser/Thr) is an evolutionary-conserved mucin type core 1 glycan structure in animals synthesized by core 1 beta1,3 galactosyltransferase 1 (C1GalT1). Previous studies showed that T antigen produced by Drosophila C1GalT1 (dC1GalT1) was expressed in various tissues and dC1GalT1 loss in larvae led to various defects, including decreased number of circulating hemocytes, hyper-differentiation of hematopoietic stem cells in lymph glands, malformation of the central nervous system, mislocalization of neuromuscular junction (NMJ) boutons, and ultrastructural abnormalities in NMJs and muscle cells. Although glucuronylated T antigen (GlcAbeta1-3Galbeta1 3GalNAcalpha1-Ser/Thr) has been identified in Drosophila, the physiological function of this structure has not yet been clarified. In this study, for the first time, we unraveled biological roles of glucuronylated T antigen. Our data show that in Drosophila, glucuronylation of T antigen is predominantly carried out by Drosophila beta1,3-glucuronyltransferase-P (dGlcAT-P). We created dGlcAT-P null mutants and found that mutant larvae showed lower expression of glucuronylated T antigen on the muscles and at NMJs. Furthermore, mislocalization of NMJ boutons and a partial loss of the basement membrane components collagen IV (Col IV) and nidogen (Ndg) at the muscle 6/7 boundary were observed. Those two phenotypes were correlated and identical to previously described phenotypes in dC1GalT1 mutant larvae. In addition, dGlcAT-P null mutants exhibited fewer NMJ branches on muscles 6/7. Moreover, ultrastructural analysis revealed that basement membranes that lacked Col IV and Ndg were significantly deformed. We also found that the loss of dGlcAT-P expression caused ultrastructural defects in NMJ boutons. Finally, we showed a genetic interaction between dGlcAT-P and dC1GalT1. Therefore, these results demonstrate that glucuronylated core 1 glycans synthesized by dGlcAT-P are key modulators of NMJ bouton localization, basement membrane formation, and NMJ arborization on larval muscles. PMID- 29499184 TI - Pseudomonas aeruginosa overexpression system of nitric oxide reductase for in vivo and in vitro mutational analyses. AB - Membrane-integrated nitric oxide reductase (NOR) reduces nitric oxide (NO) to nitrous oxide (N2O) with protons and electrons. This process is essential for the elimination of the cytotoxic NO that is produced from nitrite (NO2-) during microbial denitrification. A structure-guided mutagenesis of NOR is required to elucidate the mechanism for NOR-catalyzed NO reduction. We have already solved the crystal structure of cytochrome c-dependent NOR (cNOR) from Pseudomonas aeruginosa. In this study, we then constructed its expression system using cNOR gene deficient and wild-type strains for further functional study. Characterizing the variants of the five conserved Glu residues located around the heme/non-heme iron active center allowed us to establish how the anaerobic growth rate of cNOR deficient strains expressing cNOR variants correlates with the in vitro enzymatic activity of the variants. Since bacterial strains require active cNOR to eliminate cytotoxic NO and to survive under denitrification conditions, the anaerobic growth rate of a strain with a cNOR variant is a good indicator of NO decomposition capability of the variants and a marker for the screening of functionally important residues without protein purification. Using this in vivo screening system, we examined the residues lining the putative proton transfer pathways for NO reduction in cNOR, and found that the catalytic protons are likely transferred through the Glu57 located at the periplasmic protein surface. The homologous cNOR expression system developed here is an invaluable tool for facile identification of crucial residues in vivo, and for further in vitro functional and structural studies. PMID- 29499185 TI - Ultrafast multi-pulse transient absorption spectroscopy of fucoxanthin chlorophyll a protein from Phaeodactylum tricornutum. AB - We have applied femtosecond transient absorption spectroscopy in pump-probe and pump-dump-probe regimes to study energy transfer between fucoxanthin and Chl a in fucoxanthin-Chl a complex from the pennate diatom Phaeodactylum tricornutum. Experiments were carried out at room temperature and 77 K to reveal temperature dependence of energy transfer. At both temperatures, the ultrafast (<100 fs) energy transfer channel from the fucoxanthin S2 state is active and is complemented by the second pathway via the combined S1/ICT state. The S1/ICT-Chl a pathway has two channels, the fast one characterized by sub-picosecond energy transfer, and slow having time constants of 4.5 ps at room temperature and 6.6 ps at 77 K. The overall energy transfer via the S1/ICT is faster at 77 K, because the fast component gains amplitude upon lowering the temperature. The pump-dump probe regime, with the dump pulse centered in the spectral region of ICT stimulated emission at 950 nm and applied at 2 ps after excitation, proved that the S1 and ICT states of fucoxanthin in FCP are individual, yet coupled entities. Analysis of the pump-dump-probe data suggested that the main energy donor in the slow S1/ICT-Chl a route is the S1 part of the S1/ICT potential surface. PMID- 29499186 TI - Role of the mitochondrial ATP synthase central stalk subunits gamma and delta in the activity and assembly of the mammalian enzyme. AB - The central stalk of mitochondrial ATP synthase consists of subunits gamma, delta, and epsilon, and along with the membraneous subunit c oligomer constitutes the rotor domain of the enzyme. Our previous studies showed that mutation or deficiency of epsilon subunit markedly decreased the content of ATP synthase, which was otherwise functionaly and structuraly normal. Interestingly, it led to accumulation of subunit c aggregates, suggesting the role of the epsilon subunit in assembly of individual enzyme domains. In the present study we focused on the role of subunits gamma and delta. Using shRNA knockdown in human HEK293 cells, the protein levels of gamma and delta were decreased to 30% and 10% of control levels, respectively. The content of the assembled ATP synthase decreased in accordance with the levels of the silenced subunits, which was also the case for most structural subunits. In contrast, the hydrophobic c subunit was increased to 130% or 180%, respectively and most of it was detected as aggregates of 150-400 kDa by 2D PAGE. In addition the IF1 protein was upregulated to 195% and 300% of control levels. Both gamma and delta subunits silenced cells displayed decreased ATP synthase function - lowered rate of ADP-stimulated respiration, a two-fold increased sensitivity of respiration to inhibitor oligomycin, and impaired utilization of mitochondrial membrane potential for ADP phosphorylation. In summary, similar phenotype of gamma, delta and epsilon subunit deficiencies suggest uniform requirement for assembled central stalk as driver of the c oligomer attachment in the assembly process of mammalian ATP synthase. PMID- 29499187 TI - The low spin - high spin equilibrium in the S2-state of the water oxidizing enzyme. AB - In Photosystem II (PSII), the Mn4CaO5-cluster of the active site advances through five sequential oxidation states (S0 to S4) before water is oxidized and O2 is generated. Here, we have studied the transition between the low spin (LS) and high spin (HS) configurations of S2 using EPR spectroscopy, quantum chemical calculations using Density Functional Theory (DFT), and time-resolved UV-visible absorption spectroscopy. The EPR experiments show that the equilibrium between S2LS and S2HS is pH dependent, with a pKa ~ 8.3 (n ~ 4) for the native Mn4CaO5 and pKa ~ 7.5 (n ~ 1) for Mn4SrO5. The DFT results suggest that exchanging Ca with Sr modifies the electronic structure of several titratable groups within the active site, including groups that are not direct ligands to Ca/Sr, e.g., W1/W2, Asp61, His332 and His337. This is consistent with the complex modification of the pKa upon the Ca/Sr exchange. EPR also showed that NH3 addition reversed the effect of high pH, NH3-S2LS being present at all pH values studied. Absorption spectroscopy indicates that NH3 is no longer bound in the S3TyrZ state, consistent with EPR data showing minor or no NH3-induced modification of S3 and S0. In both Ca-PSII and Sr-PSII, S2HS was capable of advancing to S3 at low temperature (198 K). This is an experimental demonstration that the S2LS is formed first and advances to S3via the S2HS state without detectable intermediates. We discuss the nature of the changes occurring in the S2LS to S2HS transition which allow the S2HS to S3 transition to occur below 200 K. This work also provides a protocol for generating S3 in concentrated samples without the need for saturating flashes. PMID- 29499188 TI - Interactions of dipalmitoylphosphatidylcholine with ceramide-based mixtures. AB - The outermost layer of the skin, the stratum corneum (SC), acts as the natural physical barrier. The SC consists of corneocytes embedded in a crystalline lipid matrix consisting of ceramides, free fatty acids and cholesterol. Although phospholipids are frequently present in topical formulations, no detailed information is reported on the interactions between phospholipids and SC lipids. The aim of this study was to examine the interactions between a model phospholipid, dipalmitoylphosphatidylcholine (DPPC) and synthetic ceramide-based mixtures (referred to as SC lipids). (Perdeuterated) DPPC was mixed with SC lipids and the lipid organization and mixing properties were examined. The studies revealed that DPPC participates in the same lattice as SC lipids thereby enhancing a hexagonal packing. Even at a high DPPC level, no phase separated pure DPPC was observed. When a DPPC containing formulation is applied to the skin surface it must partition into the SC lipid matrix prior to any mixing with the SC lipids. To mimic this, DPPC was applied on top of a SC lipid membrane. DPPC applied in a liquid crystalline state was able to mix with the SC lipids and participated in the same lattice as the SC lipids. However, when DPPC was applied in a rippled gel-state very limited partitioning of DPPC into the SC lipid matrix occurred. Thus, when applied to the skin, liquid crystalline DPPC will have very different interactions with SC lipids than DPPC in a (rippled-)gel phase. PMID- 29499189 TI - Thermal structural evolutions of DMPC-water biomimetic systems investigated by Raman Spectroscopy. AB - Many cell membranes of living organisms can be represented as phospholipid bilayers immersed into a water environment. The physical-chemical interactions at the membranes/water interface are responsible for the stabilization of the membranes. In addition, the drug efficiency, the pharmaceutical mechanism and the improvement of the drug design can be addressed to the interactions between the membranes-water interface with the drug and to the membrane-drug interface. In this framework, it is important to find membranes models able to simulate and simultaneously simplify the biological systems to better understand both physical and chemical interactions at the interface level. Dimyristoylphosphatidylcholine (DMPC) is a synthetic phospholipid used in order to make Multilamellar Vesicle (MLV), Large Unilamellar Vesicle (LUV) and Giant Unilamellar Vesicle (GUV). In order to understand the mechanisms of vesicle formation, we have analyzed mixtures of DMPC and water by micro-Raman spectroscopy at different temperatures in the range between 10 and 35 degrees C. Particularly, we analyzed the temperature dependence of the CN vibrational frequency, which appears well correlated to the order degree of the various phases. These investigations, beyond the determination of phospholipid hydrocarbon chains order, provide information about the conformation of the lipid membranes. We have identified the mixture of DMPC/water that is best suited for Raman studies and can be used as an in-vitro model for biological systems. A peculiar frequency shift across the transition gel-ripple-liquid crystalline phases has been proposed as a useful diagnostic marker to detect the "order degree" and subsequently the phases of biomimetic membranes made by DMPC. PMID- 29499190 TI - A single mutation on the human amyloid polypeptide modulates fibril growth and affects the mechanism of amyloid-induced membrane damage. AB - Amyloid fibril formation has been implicated in a wide range of human diseases and the interactions of amyloidogenic proteins with cell membranes are considered to be important in the aetiology of these pathologies. In type 2 diabetes mellitus (T2DM), the human islet amyloid polypeptide (hIAPP) forms amyloid fibrils which impair the functionality and viability of pancreatic beta cells. The mechanisms of hIAPP cytotoxicity are linked to the ability of the peptide to self-aggregate and to interact with membranes. Previous studies have shown that the N-terminal part of hIAPP from residues 1 to 19 is the membrane binding domain. The non-amyloidogenic and nontoxic mouse IAPP differs from hIAPP by six residues out of 37, among which a single one, residue 18, lies in the membrane binding region. To gain more insight into hIAPP-membrane interactions we herein performed comprehensive biophysical studies on four analogues (H18R-IAPP, H18K IAPP, H18E-IAPP and H18A-IAPP). Our data reveal that all peptides are able to insert efficiently in the membrane, indicating that residue 18 is not essential for hIAPP membrane binding and insertion. However, only wild-type hIAPP and H18K IAPP are able to form fibrils at the membrane. Importantly, all peptides induce membrane damage; wild-type hIAPP and H18K-IAPP presumably cause membrane disruption mainly by fibril growth at the membrane, while for H18R-IAPP, H18E IAPP and H18A-IAPP, membrane leakage is most likely due to high molecular weight oligomeric species. These results highlight the importance of the residue at position 18 in IAPP for modulating fibril formation at the membrane and the mechanisms of membrane leakage. PMID- 29499191 TI - L-carnitine mitigates UVA-induced skin tissue injury in rats through downregulation of oxidative stress, p38/c-Fos signaling, and the proinflammatory cytokines. AB - UVA comprises more than 90% of the solar UV radiation reaching the Earth. Artificial lightening lamps have also been reported to emit significant amounts of UVA. Exposure to UVA has been associated with dermatological disorders including skin cancer. At the molecular level, UVA damages different cellular biomolecules and triggers inflammatory responses. The current study was devoted to investigate the potential protective effect of L-carnitine against UVA-induced skin tissue injury using rats as a mammalian model. Rats were distributed into normal control group (NC), L-carnitine control group (LC), UVA-Exposed group (UVA), and UVA-Exposed and L-carnitine-treated group (UVA-LC). L-carnitine significantly attenuated UVA-induced elevation of the DNA damage markers 8-oxo-2' deoxyguanosine (8-oxo-dG) and cyclobutane pyrimidine dimers (CPDs) as well as decreased DNA fragmentation and the activity of the apoptotic marker caspase-3. In addition, L-carnitine substantially reduced the levels of lipid peroxidation marker (TBARS) and protein oxidation marker (PCC) and significantly elevated the levels of the total antioxidant capacity (TAC) and the antioxidant reduced glutathione (GSH) in the skin tissues. Interestingly, L-carnitine upregulated the level of the DNA repair protein proliferating cell nuclear antigen (PCNA). Besides it mitigated the UVA-induced activation of the oxidative stress-sensitive signaling protein p38 and its downstream target c-Fos. Moreover, L-carnitine significantly downregulated the levels of the early response proinflammatory cytokines TNF-alpha, IL-6, and IL-1beta. Collectively, our results highlight, for the first time, the potential attenuating effects of L-carnitine on UVA-induced skin tissue injury in rats that is potentially mediated through suppression of UVA-induced oxidative stress and inflammatory responses. PMID- 29499192 TI - Evidence for the involvement of TNF-alpha, IL-1beta and IL-10 in the antinociceptive and anti-inflammatory effects of indole-3-guanylhydrazone hydrochloride, an aromatic aminoguanidine, in rodents. AB - BACKGROUND: Indole-3-guanylhydrazone hydrochloride (LQM01) is a new derivative of aminoguanidine hydrochloride, an aromatic aminoguanidine. METHODS: Mice were treated with LQM01 (5, 10, 25 or 50 mg/kg, i.p.), vehicle (0.9% saline i.p.) or a standard drug. The mice were subjected to carrageenan-induced pleurisy, abdominal writhing induced by acetic acid, the formalin test and the hot-plate test. The model of non-inflammatory chronic muscle pain induced by saline acid was also used. Mice from the chronic protocol were assessed for withdrawal threshold, muscle strength and motor coordination. LQM01 or vehicle treated mice were evaluated for Fos protein. RESULTS: LQM01 inhibits TNF-alpha and IL-1beta production, as well as leukocyte recruitment during inflammation process. The level of IL-10 in LQM01-treated mice increased in pleural fluid. In addition, LQM01 decreased the nociceptive behavior in the acetic acid induced writhing test, the formalin test (both phases) and increased latency time on the hot plate. LQM01 treatment also decreased mechanical hyperalgesia in mice with chronic muscle pain, with no changes in muscle strength and motor coordination. LQM01 reduced the number of Fos positive cells in the superficial dorsal horn. This compound exhibited antioxidant properties in in vitro assays. CONCLUSIONS: LQM01 has an outstanding anti-inflammatory and analgesic profile, probably mediated through a reduction in proinflammatory cytokines release, increase in IL 10 production and reduction in neuron activity in the dorsal horn of the spinal cord in mice. GENERAL SIGNIFICANCE: Beneficial effects of LQM01 suggest that it has some important clinical features and can play a role in the management of 'dysfunctional pain' and inflammatory diseases. PMID- 29499193 TI - Polyphyllin I inhibits gastric cancer cell proliferation by downregulating the expression of fibroblast activation protein alpha (FAP) and hepatocyte growth factor (HGF) in cancer-associated fibroblasts. AB - The aim of this study was to identify the anti-cancer mechanism of Polyphyllin I (PPI) on gastric cancer cells via its activity on cancer-associated fibroblasts (CAFs). We cultured purified gastric CAFs obtained from fresh human gastric cancer tissue and examined the effect of Polyphyllin I on CAF proliferation using a colorimetric viability assay. In addition, we established a nude mouse xenograft model to examine the effect of Polyphyllin I administration on tumorigenesis. Using Western analysis, we quantified protein expression of the CAF-derived cytokines fibroblast activation protein alpha (FAP), secreted protein acidic and cysteine rich (SPARC), stromal cell-derived factor 1 (SDF-1), hepatocyte growth factor tenascin-C (TNC), and hepatocyte growth factor (HGF) in both in vitro and in vivo models. We found that Polyphyllin I inhibits the proliferation of CAFs in a concentration-dependent manner. Following treatment with 2 MUg/ml PPI for 24 h in vitro, the expression of FAP, SDF-1 and HGF protein in CAFs was significantly lower than that in the control group, but there was no significant difference in SPARC and TNC protein expression between the two groups. In the nude mouse xenograft model, the tumor inhibition rate was 45.5% when PPI was administered early and 29.4% with administration in the third week. The expression of FAP and HGF in the xenografts was significantly decreased, while the expression of SPARC, SDF-1, and TNC was largely unaltered. Altogether, these data suggest that Polyphyllin I can inhibit the proliferation of gastric cancer cells by downregulating the expression of FAP and HGF in CAFs in vivo. PMID- 29499194 TI - HDAC8 regulates neural differentiation through embryoid body formation in P19 cells. AB - Histone acetylation and deacetylation correlate with diverse biological phenomena through gene transcription. Histone deacetylases (HDACs) regulate deacetylation of histones and other proteins. However, as a member of the HDAC family, HDAC8 function during neurodevelopment is currently unknown. Therefore, we investigated HDAC8 function during neurodevelopment by examining embryoid body (EB) formation in P19 cells. HDAC8-selective inhibitor (NCC-149) (HDAC8i)-treated cells showed smaller EBs than non-treated cells, as well as reduced expression levels of the neuronal marker, NeuN. Additionally, HDAC8i treatment led to inhibition of cellular proliferation by G2/M phase accumulation and downregulated cyclin A2 and cyclin B1 gene expression. Furthermore, two independent HDAC8 knockout cell lines were established by CRISPR-Cas9, which resulted in smaller EBs, similar to HDAC8i treated cells. These results suggest that HDAC8 regulates neural differentiation by exerting control of EB formation. PMID- 29499195 TI - Disruption of LRRK2 in Zebrafish leads to hyperactivity and weakened antibacterial response. AB - As a protein with complex domain structure and roles in kinase, GTPase and scaffolding, LRRK2 is believed to be an important orchestration node leading to several cascades of signal transduction rather than one specific pathway. LRRK2 variants were found to be associated with Parkinson's disease, Crohn's disease and leprosy. Here we disrupt LRRK2 in zebrafish and found hyperactivity rather than hypoactivity in adult zebrafish mutants. By RNA-seq we found genes involved in infectious disease and immunological disease were notably affected. Functional studies also revealed a weakened antibacterial response in LRRK2 mutant. This mutant can be further explored for revealing molecular mechanisms and modeling of LRRK2 related diseases. PMID- 29499196 TI - Structural basis of the cystein protease inhibitor Clonorchis sinensis Stefin-1. AB - Cystein protease plays a critical role as a virulence factor in the development and progression of various diseases. Cystatin is a superfamily of cysteine protease inhibitors that participates in various physiological and pathological processes. The cysteine protease inhibitor CsStein-1 isolated from Clonorchis sinensis belongs to the type 1 stefin of cystatins. This inhibitor regulates the activity and processing of CsCF (Cathepsin F of Clonorchis sienesis), which plays an important role in parasite nutrition and host-parasite interaction. CsStefin-1 has also been proposed as a host immune modulator and a participant in the mechanism associated with anti-inflammatory ability. Here, we report the first crystal structure of CsStefin-1 determined by the multi-wavelength anomalous diffraction (MAD) method to 2.3 A. There are six molecules of CsStefin-1 per asymmetric unit, with a solvent content of 36.5%. The structure of CsStefin-1 is composed of twisted four-stranded antiparallel beta-sheets, a central alpha helix, and a short alpha-helix. We also demonstrate that CsStefin-1 binds to CsCF 8 cysteine protease and inhibits its activity. In addition, a molecular docking model of CsStefin-1 and CsCF-8 was developed using homology modeling based on their structures. The structural information regarding CsStefin-1 and molecular insight into its interaction with CsCF-8 are important to understanding their biological function and to design of inhibitors that modulate cysteine protease activity. PMID- 29499197 TI - Neurological deficit is predicted by S100B in children after cardiac surgery. AB - INTRODUCTION: Children undergoing cardiac surgery may suffer from brain injuries after surgery and develop neurological deficit. Early diagnosis of brain injury after surgery would enable early therapeutic interventions. The aim of the study is to test whether S100B can serve as a biomarker for brain injury after cardiac surgery. METHODS: Seventy-five patients were enrolled in the study. Serum S100B was collected at the beginning of the surgery, and 6, 12, 24 h after surgery. S100B z-scores were calculated based on norms for age. Neurological evolutions were done before surgery and at discharge by the Pediatric Stroke Outcome Measure (PSOM). New neurological deficit (NND) was defined as a 1 point increase on the PSOM scale. RESULTS: Twenty patients had an NND after cardiac surgery. Medical background was similar between the groups with and without NND. S100B z-scores were significantly higher in the NND group at all time points after surgery. Using a cut-off of 3 z-score at 6 h after surgery, the positive predictive value was 79% and the negative predictive value was 90%. CONCLUSIONS: S100B is a potent early biomarker for brain injury after cardiac surgery. Hopefully, S100B could be used to prevent progression of brain injuries after cardiac surgery. PMID- 29499198 TI - Serum tenascin-C predicts severity and outcome of acute intracerebral hemorrhage. AB - BACKGROUND: Tenascin-C is a matricellular protein related to brain injury. We studied serum tenascin-C in acute intracerebral hemorrhage (ICH) and examined the associations with severity and outcome following the acute event. METHODS: Tenascin-C samples were obtained from 162 patients with acute hemorrhagic stroke and 162 healthy controls. Poor 90-day functional outcome was defined as modified Rankin Scale score > 2. Early neurological deterioration (END) and hematoma growth (HG) were recorded at 24 h. RESULTS: Patients had higher tenascin-C levels than controls. Tenascin-C levels were positively correlated with hematoma volume or National Institutes of Health Stroke Scale score at baseline. Elevated tenascin-C levels were independently associated with END, HG, 90-day mortality and poor functional outcome. Moreover, tenascin-C levels significantly predicted END, HG and 90-day outcomes under receiver operating characteristic curves. CONCLUSIONS: An increase in serum tenascin-C level is associated with an adverse outcome in ICH patients, supporting the potential role of serum tenascin-C as a prognostic biomarker for hemorrhagic stroke. PMID- 29499199 TI - Mutation spectrum of hyperphenylalaninemia candidate genes and the genotype phenotype correlation in the Chinese population. AB - BACKGROUND: Hyperphenylalaninemia (HPA) is an inherited metabolic disorder that is caused by a deficiency of phenylalanine hydroxylase (PAH) or tetrahydrobiopterin. The prevalence of HPA varies widely around the world. METHODS: A spectrum of HPA candidate genes in 1020 Chinese HPA patients was reported. Sanger sequencing, next generation sequencing (NGS), multiplex ligation dependent probe amplification (MLPA) and quantitative real-time PCR (qRT-PCR) were applied to precisely molecular diagnose HPA patients. The allelic phenotype values (APV) and genotypic phenotype values (GPV) were calculated in PAH deficient patients based on a recently developed formula. RESULTS: Apart from genetic diagnoses confirmed in 915 HPA patients (89.7%) by Sanger sequencing, pathogenic variants were discovered in another 57 patients (5.6%) through deep detections (NGS, MLPA and qRT-PCR). We identified 196, 42, 10 and 2 variants in PAH, PTS, QDPR and GCH1, respectively. And a total of 47 novel variants were found in these genes. Through the APV and GPV calculations, it was found that the new GPV system was well correlated with metabolic phenotypes in most PAH deficient patients. CONCLUSIONS: More HPA candidate variants were identified using new molecular diagnostic methods. The new APV and GPV system is likely to be highly beneficial for predicting clinical phenotypes for PAH-deficient patients. PMID- 29499201 TI - Prognostic value of flotillins (flotillin-1 and flotillin-2) in human cancers: A meta-analysis. AB - Increasing evidence indicates that flotillins which associate with cell infiltration and metastasis are overexpressed in multiple tumors. The prognostic role of flotillins remains controversial. We conducted a comprehensive meta analysis of published research to investigate the prognostic value of flotillins in patients with cancer. Pooled HRs (hazard ratio) with 95% CIs (confidence interval) were collected to estimate the prognostic value. Twenty-seven studies with 4803 cancer patients were finally identified. The results indicated that: (1) elevated flotillins predicted poorer OS (overall survival) (HR = 2.17, 95% CI 1.87 to 2.52; HR = 1.61, 95% CI 1.44 to 1.81) and DFS (disease-free survival) (HR = 2.41, 95% CI 1.83 to 3.18; HR = 3.01, 95% CI 2.12 to 4.27) in patients with cancer; (2) Subgroup analysis showed that the prognostic value of flotillin-1 on OS and DFS in the investigated tumors were not altered by tumor type (such as digestive system cancers, renal cell cancer, lung cancer, or others), country (China or Canada), cutoff value, detection method, analysis type or paper quality and flotillin-2 overexpression indicates poor OS in human cancers except for nasopharyngeal carcinoma. Flotillins are promising as new biomarkers to predict poor prognosis of patients with tumors. This conclusion needs more clinical studies with different types of cancer to be proven. PMID- 29499200 TI - Monitoring opioid and benzodiazepine use and abuse: Is oral fluid or urine the preferred specimen type? AB - BACKGROUND: Oral fluid (OF) has become an increasingly popular matrix to assess compliance in pain management and addiction settings as it reduces the likelihood of adulteration. However, drug concentrations and windows of detection are not as well studied in OF as in urine (UR). We compared the clinical utility and analytical performance of OF and UR as matrices for detecting common benzodiazepines and opioids. METHODS: OF and UR concentrations of 5 benzodiazepines and 7 opioids were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 263 paired OF and UR specimens. UR creatinine was measured and prescription medications were reviewed. RESULTS: The benzodiazepines 7-aminoclonazepam, lorazepam, and oxazepam exhibited statistically higher detection rates in UR. For opioids, 6-AM was statistically more likely to be detected in OF, while hydromorphone and oxymorphone were statistically more likely to be detected in UR. Chemical properties including glucuronidation explain preferential detection in each matrix, not UR creatinine nor prescription status. CONCLUSION: We found that OF is the preferred matrix for 6-AM, while UR is preferred for 7-aminoclonazepam, lorazepam, oxazepam, hydromorphone, and oxymorphone. However, OF should be considered if the risk of adulteration is high and use and/or misuse of benzodiazepines, hydromorphone, and oxymorphone is low. PMID- 29499202 TI - Prognostic value of DcR3 in solid tumors: A meta-analysis. AB - BACKGROUND: Decoy receptor 3 (DcR3) has been reported to be overexpressed in a wide range of solid tumors, suggesting that DcR3 plays a crucial role in the development and progression of cancer. The present meta-analysis assesses the association between DcR3 expression and prognosis in patients with solid tumors. METHODS: Eligible studies were identified by searching the PubMed, Web of Science, Cochrane Library, EMBASE, Chinese CNKI, and Wan Fang databases. The pooled hazard ratios (HRs) for overall survival (OS) and recurrence-free survival (RFS) were calculated using fixed effects models and random effects models, respectively. RESULTS: Data from the 16 included studies, with 2209 patients, were reviewed and analyzed. DcR3 overexpression was significantly associated with worse OS in patients with solid tumors, but its expression might not be related to RFS in malignancies. CONCLUSIONS: Current evidence demonstrates that increased DcR3 expression correlates with a poor prognosis in cancer patients, which suggests that the expression status of DcR3 is a useful biomarker for the prediction of prognosis in patients with solid tumors. PMID- 29499203 TI - Anti-tumor effect of AZD8055 against neuroblastoma cells in vitro and in vivo. AB - Neuroblastoma (NB) is one of the most common solid tumors in children. High-risk NB remains lethal in about 50% of patients despite comprehensive and intensive treatments. Activation of PI3K/Akt/mTOR signaling pathway correlates with oncogenesis, poor prognosis and chemotherapy resistance in NB. Due to its central role in growth and metabolism, mTOR seems to be an important factor in NB, making it a possible target for NB. In this study, we investigated the effect of AZD8055, a potent dual mTORC1-mTORC2 inhibitor, in NB cell lines. Our data showed that mTOR signaling was extensively activated in NB cells. The activity of mTOR and downstream molecules were down-regulated in AZD8055-treated NB cells. Significantly, AZD8055 effectively inhibited cell growth and induced cell cycle arrest, autophagy and apoptosis in NB cells. Moreover, AZD8055 significantly reduced tumor growth in mice xenograft model without apparent toxicity. Taken together, our results highlight the potential of mTOR as a promising target for NB treatment. Therefore, AZD8055 may be further investigated for treatment in clinical trials for high risk NB. PMID- 29499204 TI - Alteration in microRNA-25 expression regulate cardiac function via renin secretion. AB - Heart failure arises from diverse cardiovascular diseases, including hypertension, ischemic disease and atherosclerosis, valvular insufficiency, myocarditis, and contractile protein mutations. MicroRNAs are dysregulated in heart failure, but identification of the specific microRNAs involved remains incomplete. Here, we evaluate miR-25 expression in the peripheral blood from healthy, dilated cardiomyopathy (DCM), remote infarct (OMI), hypertensive heart disease (HHD), and HHD resulting in heart failure (HHDF) using q-PCR. Interestingly, we discovered miR-25 expression in humans is initially decreased at the onset of heart failure but is later increased in end-stage heart failure. We also show that overexpression of miR-25 in normal mice causes cardiomyocyte fibrosis and apoptosis. However, inhibition of miR-25 in normal mice led to activate renin-angiotensin system (RAS) and high blood pressure, mild heart dilation. Notably, the miR-25 cluster knock-out mice was also characterized high blood pressure and no obvious cardiac function alteration. RNA sequencing showed the alteration of miR-25 target genes in angomir-treated mice, including the renin secretion signal related gene. In vitro, cotransfection with the miR-25 antagomir repressed luciferase activity from a reporter construct containing the Pde3a and Cacnalc untranslated region. In summary, miR-25 expression during different stages of heart disease, offers a new perspective for the role of miR 25 function in heart failure. PMID- 29499205 TI - Lab-on-a-chip platforms for quantification of multicellular interactions in bone remodeling. AB - Researchers have been using lab-on-a-chip systems to isolate factors for study, simulate laboratory analysis and model cellular, tissue and organ level processes. The technology is increasing rapidly, but the bone field has been slow to keep pace. Novel models are needed that have the power and flexibility to investigate the elegant and synchronous multicellular interactions that occur in normal bone turnover and in disease states in which remodeling is implicated. By removing temporal and spatial limitations and enabling quantification of functional outcomes, the platforms should provide unique environments that are more biomimetic than single cell type systems while minimizing complex systemic effects of in vivo models. This manuscript details the development and characterization of lab-on-a-chip platforms for stimulating osteocytes and quantifying bone remodeling. Our platforms provide the foundation for a model that can be used to investigate remodeling interactions as a whole or as a standard mechanotransduction tool by which isolated activity can be quantified as a function of load. PMID- 29499206 TI - Deficiency of S100B confers resistance to experimental diabetes in mice. AB - The calcium binding protein S100B has been implicated in diabetic neuronal and vascular complications but has not been examined in the development of diabetes. S100B knock out (S100B KO) and wild-type (WT) mice were injected with 40 mg/kg body weight streptozotocin (STZ) for 5 days. Blood and pancreatic tissue samples were obtained to examine islet structure and function, the profile of glucose and insulin and expression of glucose transporter 2 (Glut2), S100B and its receptor, the receptor for advanced glycation end products (RAGE). Primary islet beta-cells cultures from WT mice were used to test the apoptotic potential of S100B. S100B KO mice were resistant to STZ induced-diabetes with lower urine volume, food and water intake compared to WT mice. S100B increased in the WT islet following diabetes but did not co-localize with beta or peri-islet Schwann cells but with CD3 + T lymphocytes. S100B KO mice exhibited enhanced glucose tolerance, insulin sensitivity, prevented beta-cell destruction and functional impairment in response to STZ treatment. S100B deficiency was associated with decreased Glut2 and RAGE. In primary beta-cell cultures from WT mice, S100B induced reactive oxygen species (ROS) and RAGE-dependent apoptosis. In the STZ diabetic animal model, abrogation of S100B enhances insulin sensitivity and reduces pancreatic islet, and beta-cell destruction. S100B may be a promising target for pharmacological interventions aimed at repressing diabetes. PMID- 29499207 TI - Is it Safe to Reduce Water Intake in the Overactive Bladder Population? A Systematic Review. AB - PURPOSE: Overactive bladder imposes a significant socioeconomic burden on the health care system. It is a commonly held belief that increased fluid intake (8 glasses of water per day) is beneficial for health. However, increased fluid intake exacerbates overactive bladder symptoms. Thus, it is imperative that clinicians appropriately educate patients for whom increased water intake may be detrimental (women with overactive bladder), in contrast to patients with comorbidities that necessitate increased water intake (nephrolithiasis). We systematically reviewed the literature to determine the potential health advantages of increased water intake and identify specific subpopulations that need increased hydration. MATERIALS AND METHODS: We systematically reviewed published articles from 1972 through 2017 on PubMed(r) and the Cochrane Library. The data were reviewed independently by 2 individuals. Studies were included if they explored water intake in relation to the risk of a particular disease. RESULTS: Level 1 evidence supported increased fluid intake in patients with nephrolithiasis. There was no available evidence to support increased fluid intake in patients with cardiovascular disease, constipation, venous thromboembolism, headaches, cognitive function or bladder cancer. Dehydration may exacerbate some conditions, specifically chronic constipation and headache intensity. Increased fluid intake may have a role in preventing stroke recurrence but not in preventing primary stroke. CONCLUSIONS: The available reviewed literature suggests no benefit to drinking 8 glasses of water per day in patients without nephrolithiasis. Also, excess fluid intake can exacerbate symptoms of overactive bladder. PMID- 29499208 TI - Three-Year Treatment Outcomes of Water Vapor Thermal Therapy Compared to Doxazosin, Finasteride and Combination Drug Therapy in Men with Benign Prostatic Hyperplasia: Cohort Data from the MTOPS Trial. AB - PURPOSE: We evaluated the long-term outcomes of treatment of lower urinary tract symptoms due to benign prostatic hyperplasia to compare a 1-time water vapor thermal therapy procedure with daily medical therapy in cohorts from the MTOPS (Medical Therapy of Prostatic Symptoms) study. MATERIALS AND METHODS: Results in the treatment arm of a randomized, controlled trial of thermal therapy using the Rezum(r) System were compared to MTOPS subjects treated with doxazosin and/or finasteride. Evaluations were restricted to medical therapy subjects, representing 1,140 of the original 3,047 (37.4%), with a prostate volume of 30 to 80 cc and an International Prostate Symptom Score of 13 or greater to include men who met key criteria of the Rezum and MTOPS trials. Outcomes were compared during 3 years for symptom changes and clinical progression rates. RESULTS: Thermal therapy improved symptom scores by approximately 50% throughout 36 months (p <0.0001). Symptom improvement was greater than with either drug alone but similar to that of combination drugs (p <=0.02 and 0.73, respectively). The peak flow rate improved 4 to 5 ml per second after thermal therapy and doxazosin while thermal therapy was superior to finasteride and combination drugs for 24 and 12 months (p <0.001 and <0.01, respectively). Observed rates of clinical progression during 3 years corroborate these outcomes with approximately 5 times greater progression for any medical therapy vs a single thermal therapy procedure. CONCLUSIONS: A single water vapor thermal therapy procedure provided effective and durable improvements in symptom scores with lower observed clinical progression rates compared to daily long-term use of pharmaceutical agents. PMID- 29499209 TI - Curcumin restrains hepatic glucose production by blocking cAMP/PKA signaling and reducing acetyl CoA accumulation in high-fat diet (HFD)-fed mice. AB - OBJECTIVE: This study is designed to investigate whether curcumin reduces excessive hepatic glucose production (HGP) via regulation of second messenger cAMP. METHODS: High-fat diet (HFD)-fed mice were orally administrated of metformin (200 mg/kg) or curcumin (50 mg/kg) daily for 10 weeks. Meanwhile, we stimulated mouse primary hepatocytes with palmitate (PA). RESULTS: Curcumin reduced hepatic cAMP accumulation by preserving PDE4B induction, thereby suppressing gluconeogenesis via blocking cAMP/PKA activation. Curcumin reduced lipid deposition by reducing free fatty acid uptake and prevented acetyl CoA accumulation by combating mitochondrial oxidation. As a result from inhibiting acetyl CoA accumulation, curcumin protected pyruvate dehydrogenase (PDH) activity and inhibited pyruvate carboxylase (PC), limiting the shift of mitochondrial pyruvate from oxidation to gluconeogenesis via the carboxylation. CONCLUSION: Curcumin reduced cAMP accumulation by preserving PDE4B activity and inhibited acetyl CoA production by reducing mitochondrial fatty acid oxidation, thereby restraining pyruvate-driven hepatic glucose production. PMID- 29499210 TI - Molecular and thyroid hormone binding properties of lamprey transthyretins: The role of an N-terminal histidine-rich segment in hormone binding with high affinity. AB - Transthyretin (TTR) is a plasma thyroid hormone (TH) binder that emerged from an ancient hydroxyisourate hydrolase by gene duplication. To know how an ancient TTR had high affinity for THs, molecular and TH binding properties of lamprey TTRs were investigated. In adult serum, the lipoprotein LAL was a major T3 binder with low affinity. Lamprey TTRs had an N-terminal histidine-rich segment, and had two classes of binding sites for 3,3',5-triiodo-L-thyronine (T3): a high-affinity and a low-affinity site. Mutant TTRDelta3-11, lacking the N-terminal histidine-rich segment, lost the high-affinity T3 binding site. [125I]T3 binding to wild type TTR and mutant TTRDelta3-11, was differentially modulated by Zn2+. Zn2+ contents of wild type TTR were 7-10/TTR (mol/mol). Our results demonstrate that lamprey TTR is a Zn2+-dependent T3 binder. The N-terminal histidine-rich segment may be essential for neo-functionalization (i.e., high-affinity T3 binding activity) of an ancient TTR after gene duplication. PMID- 29499211 TI - The field-size effect: Short motions look faster than long ones. AB - Reducing the amount of motion information can surprisingly make motion look faster (e.g., motion behind Venetian blinds). We found that a textured pattern moving to the right at speeds ranging from 0.34 to 5.5 degrees /s appeared to move 50% faster when viewed through a short (0.5 degrees ) compared with a long (4.5 degrees ) horizontal slot. Perceived speed varied inversely with the log of the slot length. We varied the length of rectangular apertures over a tenfold range and manipulated their size, shape, and orientation. We attribute the field size effect mostly to landmarks provided by the ends of the slots, but we also examined temporal and spatial frequency and lateral inhibition of motion. PMID- 29499212 TI - Stable individual differences predict eye movements to the left, but not handedness or line bisection. AB - When observers view an image, their initial eye movements are not equally distributed but instead are often biased to the left of the picture. This pattern has been linked to pseudoneglect, the spatial bias to the left that is observed in line bisection and a range of other perceptual and attentional tasks. Pseudoneglect is often explained according to the dominance of the right hemisphere in the neural control of attention, a view bolstered by differences between left- and right-handed participants in both line bisection and eye movements. We re-examined this observation in eighty participants (half of whom reported being left handed) who completed a computerised line bisection task and viewed a series of images. We failed to replicate the previously-reported effect of handedness on eye movements in image viewing, with both groups showing a large average bias to the left on the first saccade. While there was a modest effect of handedness on line bisection, there was no correlation between the two tasks. Stable individual differences, as well as a shorter latency on the initial saccade, were robust predictors of an initial saccade to the left. Therefore, while there seems to be a reflexive and idiosyncratic drive to look to the left, it is not well accounted for by handedness and may have different mechanisms from other forms of pseudoneglect. PMID- 29499213 TI - Wolbachia affects sleep behavior in Drosophila melanogaster. AB - Wolbachia are endosymbiotic bacteria present in a wide range of insects. Although their dramatic effects on host reproductive biology have been well studied, the effects of Wolbachia on sleep behavior of insect hosts are not well documented. In this study, we report that Wolbachia infection caused an increase of total sleep time in both male and female Drosophila melanogaster. The increase in sleep was associated with an increase in the number of nighttime sleep bouts or episodes, but not in sleep bout duration. Correspondingly, Wolbachia infection also reduced the arousal threshold of their fly hosts. However, neither circadian rhythm nor sleep rebound following deprivation was influenced by Wolbachia infection. Transcriptional analysis of the dopamine biosynthesis pathway revealed that two essential genes, Pale and Ddc, were significantly upregulated in Wolbachia-infected flies. Together, these results indicate that Wolbachia mediates the expression of dopamine related genes, and decreases the sleep quality of their insect hosts. Our findings help better understand the host endosymbiont interactions and in particular the Wolbachia's impact on behaviors, and thus on ecology and evolution in insect hosts. PMID- 29499214 TI - The forgotten parent: Fathers' representation in family interventions to prevent childhood obesity. AB - Despite recognition that parents are critical stakeholders in childhood obesity prevention, obesity research has overwhelmingly focused on mothers. In a recent review, fathers represented only 17% of parent participants in >600 observational studies on parenting and childhood obesity. The current study examined the representation of fathers in family interventions to prevent childhood obesity and characteristics of interventions that include fathers compared with those that only include mothers. Eligible studies included family-based interventions for childhood obesity prevention published between 2008 and 2015 identified in a recent systematic review. Data on intervention characteristics were extracted from the original review. Using a standardized coding scheme, these data were augmented with new data on the number of participating fathers/male caregivers and mothers/female caregivers. Out of 85 eligible interventions, 31 (37%) included mothers and fathers, 29 (34%) included only mothers, 1 (1%) included only fathers, and 24 (28%) did not provide information on parent gender. Of the interventions that included fathers, half included 10 or fewer fathers. Across all interventions, fathers represented a mere 6% of parent participants. Father inclusion was more common in interventions targeting families with elementary school-aged children (6-10 years) and those grounded in Ecological Systems Theory, and was less common in interventions focused on very young children (0-1 years) or the prenatal period and those targeting the sleep environment. This study emphasizes the lack of fathers in childhood obesity interventions and highlights a particular need to recruit and engage fathers of young children in prevention efforts. PMID- 29499215 TI - For richer, for poorer: the relationship between adolescent obesity and future household economic prosperity. AB - Adolescent obesity not only has serious long-term health implications, but also the potential to lead to a socioeconomic trajectory of lower earnings and household income. However, the magnitude and mechanisms of such outcomes across the life course are poorly understood. Using birth cohort data from the British National Child Development Study (1958 to 2008), we examined the relationship between adolescent obesity (at age 16) and future household income, employment, wages, marriage and spousal earnings when individuals were in their 30s, 40s and 50s. We additionally investigated the role of obesity persistence from childhood (age 11) through to adulthood (age 33). After adjusting for a rich set of childhood characteristics, compared to normal weight, obesity at age 16 was associated with significantly lower levels of future household income for women (by approximately 14%), but not men. This household income penalty was greater for women with obesity in both childhood and adulthood. The household income penalty for women appeared to be driven by a lower likelihood of marriage and lower spousal earnings for those who were married, and not by their own wage penalty in the labour market. The spousal earnings penalty occurred even when obesity did not persist into adulthood. PMID- 29499216 TI - Brain derived neurotrophic factor (BDNF), its tyrosine kinase receptor B (TrkB) and nicotine. AB - Nicotine is the major neurotoxicant in cigarettes that affects many transmitter systems within the brain as well as other factors, including the growth factors. Brain derived neurotrophic factor (BDNF), is the most abundant growth factor in the brain and plays a critical role in early new neuron differentiation, development and synapsis growth, and the survival of fully developed neurons and synaptic activity. Over the past 3 decades, data has emerged on the effects of nicotine and cigarette smoke exposure on the expression of BDNF and its primary specific receptor tyrosine kinase receptor B (TrkB). This review summarizes data regarding the changes in brain BDNF expression after nicotine or cigarette smoke exposure, and discusses their implications considering BDNF's functional roles. PMID- 29499217 TI - Myxobacterial natural products: An under-valued source of products for drug discovery for neurological disorders. AB - Age-related disorders impose noticeable financial and emotional burdens on society. This impact is becoming more prevalent with the increasing incidence of neurodegenerative diseases and is causing critical concerns for treatment of patients worldwide. Parkinson's disease, Alzheimer's disease, multiple sclerosis and motor neuron disease are the most prevalent and the most expensive to treat neurodegenerative diseases globally. Therefore, exploring effective therapies to overcome these disorders is a necessity. Natural products and their derivatives have increasingly attracted attention in drug discovery programs that have identified microorganisms which produce a large range of metabolites with bioactive properties. Myxobacteria, a group of Gram-negative bacteria with large genome size, produce a wide range of secondary metabolites with significant chemical structures and a variety of biological effects. They are potent natural product producers. In this review paper, we attempt to overview some secondary metabolites synthesized by myxobacteria with neuroprotective activity through known mechanisms including production of polyunsaturated fatty acids, reduction of apoptosis, immunomodulation, stress reduction of endoplasmic reticulum, stabilization of microtubules, enzyme inhibition and serotonin receptor modulation. PMID- 29499218 TI - Dual-stimuli-responsive albumin-polyplex nanoassembly for spatially controlled gene release in metastatic breast cancer. AB - Stimuli-responsive polymeric nanoparticles are useful for overcoming challenges such as transfection efficiency and the specific and safe delivery of genes to cancer cells. Transfection outcomes can be improved through spatially and temporally controlled gene release. We formulated a nanoassembly comprising a disulfide-crosslinked polyethylenimine (ssPEI) conjugated with a tumor-specific cell-penetrating peptide (DS 4-3) (SPD) polyplex and bovine serum albumin (BSA) loaded IR780 (BI) nanoparticle, thereby forming a dual-stimulus-triggered, tumor penetrating and gene-carrying nanoassembly (BI-SPD) via electrostatic complexing. BI-SPD nanoassembly were composed of highly stable nanosized complexes with an average size of 457 +/- 27.5 nm, exhibiting an up to two-fold enhanced transfection efficiency with no sign of potential cytotoxicity in breast cancer cells. Moreover, upon laser irradiation, a four-fold increase in transfection efficiency was achieved due to the rapid endosomal escape of polyplexes triggered by the local heat induced by the BI-SPD nanoassembly. Additionally, the high redox environment in tumor cells facilitated the disassembly of the SPD polyplex for efficient plasmid release in the cytosol. The BI-SPD nanoassembly also exhibited high penetration and enhanced photothermally triggered gene expression in the 4T1 spheroid model. This BI-SPD nanoassembly has the potential to enhance the expression of therapeutic genes in tumor models without causing significant toxicity to surrounding healthy tissues, since it has shown higher tumor targeting and accumulation in the 4T1 tumor in mice model. PMID- 29499219 TI - Bioreduction-ruptured nanogel for switch on/off release of Bcl2 siRNA in breast tumor therapy. AB - In present study, gene concentrated as well as bioreduction-ruptured nanogel with local enrichment positive charge while low cytotoxicity was developed for Bcl2 siRNA delivery featured in intracellular switch on/off controlled release. Dynamic covalent bond crosslinked nanogel was formed by thiolated PEI of 1.8 kDa(PEI-1.8 kDa)and biodegradable dextrin. Once nanogel was uptake by tumor cells, high concentration of glutathione (GSH) in cytosol could bioreducible degrade and rupture the crosslink of this dextrin nanogel (DSP) into hypotoxic PEI-1.8 kDa and dextrin, following by burst release of packed siRNA and minimizing the restriction of polymer material for siRNA transcription. This switch on/off siRNA release strategy for gene therapy exhibited equal level of the deregulation of Bcl2 protein expression determined by western blot analysis compared with cationic PEI with 25 kDa molecular weight (PEI-25 kDa) in vitro. Moreover, the gene concentrated DSP based on hypotoxic PEI-1.8 kDa and biodegradable dextrin could be administrated intravenously for systematic therapy on safely. Tumor suppression study of DSP also exhibited a superior antitumor activity in 4T1-luc tumor cell bearing BALB/C mice. Furthermore, it exhibited lower cytotoxicity, almost none hemotoxicity, moreover avoiding recognition and clearance by RES system in healthy mice. Overall, these findings suggest that this reduction-sensitive while bioreduction-ruptured polymer nanogel is an innovative strategy and holds great promise for gene and drug delivery. PMID- 29499220 TI - In memoriam: Ronald J. Barfield (July 25, 1936-September 29, 2015). PMID- 29499222 TI - Proximity to traffic and asthma among Mexican American children: Independent and interactive effects. PMID- 29499221 TI - Histone deacetylase inhibitor treatment induces postpartum-like maternal behavior and immediate early gene expression in the maternal neural pathway in virgin mice. AB - The peripartum period is associated with the onset of behaviors that shelter, feed and protect young offspring from harm. The neural pathway that regulates caregiving behaviors has been mapped in female rats and is conserved in mice. However, rats rely on late gestational hormones to shift their perception of infant cues from aversive to attractive, whereas laboratory mice are "spontaneously" maternal, but their level of responding depends on experience. For example, pup-naive virgin female mice readily care for pups in the home cage, but avoid pups in a novel environment. In contrast, pup-experienced virgin mice care for pups in both contexts. Thus, virgin mice rely on experience to shift their perception of infant cues from aversive to attractive in a novel context. We hypothesize that alterations in immediate early gene activation may underlie the experience-driven shift in which neural pathways (fear/avoidance versus maternal/approach) are activated by pups to modulate context-dependent changes in maternal responding. Here we report that the effects of sodium butyrate, a drug that allows for an amplification of experience-induced histone acetylation and gene expression in virgins, are comparable to the natural onset of caregiving behaviors in postpartum mice and induce postpartum-like patterns of immediate early gene expression across brain regions. These data suggest that pups can activate a fear/defensive circuit in mice and experience-driven improvements in caregiving behavior could be regulated in part through decreased activation of this pathway. PMID- 29499223 TI - CD40LG duplication-associated autoimmune disease is silenced by nonrandom X chromosome inactivation. PMID- 29499224 TI - A critical role for IL-18 in transformation and maturation of naive eosinophils to pathogenic eosinophils. PMID- 29499225 TI - Development of a one-step RT-PCR assay for detection of pancoronaviruses (alpha-, beta-, gamma-, and delta-coronaviruses) using newly designed degenerate primers for porcine and avian 'fecal samples. AB - Coronaviruses (CoVs) are critical human and animal pathogens because of their potential to cause severe epidemics of respiratory or enteric diseases. In pigs, the newly emerged porcine deltacoronavirus (PDCoV) and re-emerged porcine epidemic diarrhea virus (PEDV) reported in the US and Asia, as well as the discovery of novel CoVs in wild bats or birds, has necessitated development of improved detection and control measures for these CoVs. Because the previous pancoronavirus (panCoV) RT-PCR established in our laboratory in 2007-2011 did not detect deltacoronaviruses (delta-CoVs) in swine fecal and serum samples, our goal was to develop a new panCoV RT-PCR assay to detect known human and animal CoVs, including delta-CoVs. In this study, we designed a new primer set to amplify a 668 bp-region within the RNA-dependent RNA polymerase (RdRP) gene that encodes the most conserved protein domain of alpha-, beta-, gamma-, and delta-CoVs. We established a one-step panCoV RT-PCR assay and standardized the assay conditions. The newly established panCoV RT-PCR assay was demonstrated to have a high sensitivity and specificity. Using a panel of 60 swine biological samples (feces, intestinal contents, and sera) characterized by PEDV, PDCoV and transmissible gastroenteritis virus-specific RT-PCR assays, we demonstrated that sensitivity and specificity of the newly established panCoV RT-PCR assay were 100%. 400 avian fecal (RNA) samples were further tested simultaneously for CoV by the new panCoV RT-PCR and a one-step RT-PCR assay with the delta-CoV nucleocapsid-specific universal primers. Four of 400 avian samples were positive for CoV, three of which were positive for delta-CoV by the conventional RT-PCR. PanCoV RT-PCR fragments for 3 of the 4 CoVs were sequenced. Phylogenetic analysis revealed the presence of one gamma-CoV and two delta-CoV in the sequenced samples. The newly designed panCoV RT-PCR assay should be useful for the detection of currently known CoVs in animal biological samples. PMID- 29499227 TI - Low digit ratio (2D:4D) and late pubertal onset indicate prenatal hyperandrogenziation in alcohol binge drinking. AB - BACKGROUND: Alcohol binge drinking behavior is an important public health issue. Causal rodent and human associational studies show that reinforcement of prenatal androgen signaling increases alcohol consumption in adulthood. However, the effects of prenatal androgen exposure on adult binge drinking patterns have not been investigated yet. METHOD: We analyzed data from 2225 participants of an online survey (conducted 06-07/2016) to evaluate biomarkers for prenatal androgen exposure (second-to-fourth finger length ratio [2D:4D], age at spermarche or menarche as hallmark for pubertal onset) in binge drinking (>=1 episode of 15+, 10+, and/or 5+ standard drinks of ~13 g of alcohol within 2 h during the 24 month and 2 week-recall periods). RESULTS: Men reported binge drinking more often than women (ORs > 1.4, P < .001). For the 24 month-recall period, binge drinkers showed lower 2D:4D (P = .006) and reported later pubertal onset (P = .022) than non-binge drinkers. These findings consistently suggest excess prenatal androgen exposure in adult binge drinkers. Moreover, 2D:4D was negatively associated with severity (15+/10+/5+/non-binge drinking, P = .005) and frequency of binge drinking episodes (P = .044). All of these effects were stronger in men than in women. For the 2 week-recall period, the biomarkers were not significantly related to binge drinking behavior. CONCLUSION: Our results indicate that increased prenatal androgen exposure is involved in the development of alcohol binge drinking behavior in adults. PMID- 29499226 TI - Clinicopathologic significance of HLA-G and HLA-E molecules in Tunisian patients with ovarian carcinoma. AB - BACKGROUND: The human leukocyte antigen (HLA)-G and HLA-E, non classical HLA class I molecules, have been highly implicated in immune tolerance. HLA-G and HLA E molecules were proposed as putative markers of several advanced cancers. As a step towards a better understanding of ovarian carcinoma, we evaluated the expression of both HLA-G and HLA-E molecules and explored their prognostic implication. METHODS: HLA-G and HLA-E expression were studied by immunohistochemistry on ovarian carcinoma tissues. This expression was semi quantitatively scored into four expression groups and correlated to clinicopathological parameters and patients' survival. RESULTS: HLA-G and HLA-E have been found to be highly expressed in ovarian carcinoma tissues (Respectively, 72.4% and 96.8%). They are frequently co-expressed. Univariate and multivariate analysis revealed that a positive HLA-G expression status in tumor tissue is a promising candidate parameter to predict disease recurrence in addition to the disease status in Tunisian patients with ovarian carcinoma. Moreover, the elevated HLA-E expression was associated with serous ovarian carcinoma subtype as well as with advanced stages of ovarian carcinoma. CONCLUSION: HLA-G and HLA-E are highly represented in ovarian carcinoma suggesting a potential association with progressive disease mechanism. HLA-G and HLA-E molecules might be new candidates' markers for ovarian carcinoma progression. PMID- 29499228 TI - Nrf2-Keap1 signaling in oxidative and reductive stress. AB - Nrf2 and its endogenous inhibitor, Keap1, function as a ubiquitous, evolutionarily conserved intracellular defense mechanism to counteract oxidative stress. Sequestered by cytoplasmic Keap1 and targeted to proteasomal degradation in basal conditions, in case of oxidative stress Nrf2 detaches from Keap1 and translocates to the nucleus, where it heterodimerizes with one of the small Maf proteins. The heterodimers recognize the AREs, that are enhancer sequences present in the regulatory regions of Nrf2 target genes, essential for the recruitment of key factors for transcription. In the present review we briefly introduce the Nrf2-Keap1 system and describe Nrf2 functions, illustrate the Nrf2 NF-kappaB cross-talk, and highlight the effects of the Nrf2-Keap1 system in the physiology and pathophysiology of striated muscle tissue taking into account its role(s) in oxidative stress and reductive stress. PMID- 29499230 TI - Regional variation in the characteristics, incidence and outcomes of out-of hospital cardiac arrest in Australia and New Zealand: Results from the Aus-ROC Epistry. AB - INTRODUCTION: The aim of this study was to investigate regional variation in the characteristics, incidence and outcomes of out-of-hospital cardiac arrest (OHCA) in Australia and New Zealand. METHODS: This was a population-based cohort study of OHCA using data from the Aus-ROC Australian and New Zealand OHCA Epistry over the period of 01 January 2015-31 December 2015. Seven ambulance services contributed data to the Epistry with a capture population of 19.8 million people. All OHCA attended by ambulance, regardless of aetiology or patient age, were included. RESULTS: In 2015, there were 19,722 OHCA cases recorded in the Aus-ROC Epistry with an overall crude incidence of 102.5 cases per 100,000 population (range: 51.0-107.7 per 100,000 population). Of all OHCA cases attended by EMS (excluding EMS-witnessed cases), bystander CPR was performed in 41% of cases (range: 36%-50%). Resuscitation was attempted (by EMS) in 48% of cases (range: 40%-68%). The crude incidence for attempted resuscitation cases was 47.6 per 100,000 population (range: 34.7-54.1 per 100,000 population). Of cases with attempted resuscitation, 28% survived the event (range: 21%-36%) and 12% survived to hospital discharge or 30 days (range: 9%-17%; data provided by five ambulance services). CONCLUSION: In the first results of the Aus-ROC Australian and New Zealand OHCA Epistry, significant regional variation in the incidence, characteristics and outcomes was observed. Understanding the system-level and public health drivers of this variation will assist in optimisation of the chain of survival provided to OHCA patients with the aim of improving outcomes. PMID- 29499229 TI - gamma-Tubulin has a conserved intrinsic property of self-polymerization into double stranded filaments and fibrillar networks. AB - gamma-Tubulin is essential for microtubule nucleation and also plays less understood roles in nuclear and cell-cycle-related functions. High abundancy of gamma-tubulin in acentrosomal Arabidopsis cells facilitated purification and biochemical characterization of large molecular species of gamma-tubulin. TEM, fluorescence, and atomic force microscopy of purified high molecular gamma tubulin forms revealed the presence of linear filaments with a double protofilament substructure, filament bundles and aggregates. Filament formation from highly purified gamma-tubulin free of gamma-tubulin complex proteins (GCPs) was demonstrated for both plant and human gamma-tubulin. Moreover, gamma-tubulin associated with porcine brain microtubules formed oligomers. Experimental evidence on the intrinsic ability of gamma-tubulin to oligomerize/polymerize was supported by conservation of alpha- and beta-tubulin interfaces for longitudinal and lateral interactions for gamma-tubulins. STED (stimulated emission depletion) microscopy of Arabidopsis cells revealed fine, short gamma-tubulin fibrillar structures enriched on mitotic microtubular arrays that accumulated at polar regions of acentrosomal spindles and the outer nuclear envelope before mitosis, and were also present in nuclei. Fine fibrillar structures of gamma-tubulin representing assemblies of higher order were localized in cell-cycle-dependent manner at sites of dispersed gamma-tubulin location in acentrosomal plant cells as well as at sites of local gamma-tubulin enrichment after drug treatment. Our findings that gamma-tubulin preserves the capability of prokaryotic tubulins to self-organize into filaments assembling by lateral interaction into bundles/clusters help understanding of the relationship between structure and multiple cellular functions of this protein species and suggest that besides microtubule nucleation and organization, gamma-tubulin may also have scaffolding or sequestration functions. PMID- 29499231 TI - Elucidation of possible molecular mechanisms underlying the estrogen-induced disruption of cartilage development in zebrafish larvae. AB - Estrogen can affect the cartilage development of zebrafish; however, the mechanism underlying its effects is not completely understood. Four-day-old zebrafish larvae were treated with 0.8 MUM estrogen, the 5 days post fertilization (dpf) zebrafish larvae did not demonstrate obvious abnormalities during development; however, the 6 dpf and 7 dpf larvae exhibited abnormal craniofacial bone development along with craniofacial bone degradation. RNA deep sequencing was performed to elucidate the mechanism involved. Gene Ontology functional and KEGG pathway enrichment analysis of differentially expressed genes (DEGs) showed that the extracellular matrix (ECM), extracellular region, ECM interaction receptor, focal adhesion, cell cycle, apoptosis, and bone-related signaling pathways were disrupted. In these signaling pathways, the expressions of key genes, such as collagen encoded (col19a1a, col7a1, col7al, col18a1, and col9a3), MAPK signaling pathway (fgf19, fgf6a), TGF-beta signaling pathway (tgfbr1), and cell cycle (cdnk1a) genes were altered. The qRT-PCR results showed that after treatment with 0.8 MUM 17-beta estradiol (E2), col19a1a, col7a1, col7al, col18a1, col9a3, fgf6a, cdkn1a were downregulated, and fgf19, tgfr1 were upregulated, which were consistent with deep sequencing analysis. Therefore, the effect of estrogen on cartilage development might occur via multiple mechanisms. The study results demonstrate the mechanism underlying the effect of estrogen on cartilage development. PMID- 29499232 TI - Direct detection of carbapenemase-associated proteins of Acinetobacter baumannii using nanodiamonds coupled with matrix-assisted laser desorption/ionization time of-flight mass spectrometry. AB - The appearance and spread of carbapenem-resistant Acinetobacter baumannii (CRAB) pose a challenge for optimization of antibiotic therapies and outbreak preventions. The carbapenemase production can be detected through culture-based methods (e.g. Modified Hodge Test-MHT) and DNA based methods (e.g. Polymerase Chain Reaction-PCR). The culture-based methods are time-consuming, whereas those of PCR assays need only a few hours but due to its specificity, can only detect known genetic targets encoding carbapenem-resistance genes. Therefore, new approaches to detect carbapenemase-producing A. baumannii are of great importance. Here, we have developed a rapid and novel method using detonation nanodiamonds (DNDs) as a platform for concentration and extraction of A. baumannii carbapenemase-associated proteins prior to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI TOF-MS) analysis. To concentrate and extract the A. baumannii carbapenemase-associated proteins, we tested several protein precipitation conditions and found a 0.5% trifluoroacetic acid (TFA) solution within the bacterial suspension could result in strong ion signals with DNDs. A total of 66 A. baumannii clinical-isolates including 51 carbapenem-resistant strains and 15 carbapenem-susceptible strains were tested. Our result showed that among the 51 carbapenem-resistant strains 49 strains had a signal at m/z ~40,279 (+/-87); among the 15 carbapenem-susceptible strains, 4 strains showed a signal at m/z ~40,279. With on-diamond digestion, we confirmed that the captured protein at m/z ~40,279 was related to ADC family extended spectrum class C beta-lactamase, from A. baumannii. Using this ADC family protein as a biomarker (m/z ~ 40,279) for carbapenem susceptibility testing of A. baumannii, the sensitivity and the specificity could reach 96% and 73% as compared to traditional imipenem susceptibility testing (MIC results). However, the sensitivity and specificity of this method reached 100% as compared to polymerase chain reaction (PCR) result. Our approach could directly detect the carbapenemase-associated proteins of A. baumannii within 90 min and does not require addition of carbapenemase substrate which is required in the MHT or other mass spectrometric methods. For future applications, our method could be efficiently used in the detection of other carbapenemase-producing bacteria. PMID- 29499233 TI - A multiplex TaqMan real-time PCR for detection and differentiation of four antigenic types of canine parvovirus in China. AB - Canine parvovirus (CPV) is an important pathogen in domestic dogs, and the original antigenic types CPV-2 and its variants, CPV-2a, 2b and 2c, are prevalent worldwide. A multiplex TaqMan real-time PCR method was developed for the detection and differentiation of four antigenic types of CPV. A set of primers and probes, CPV-305F/CPV-305R and CPV-2-305P (for CPV-2)/CPV-2a-305P (for CPV-2a, 2b and 2c), was able to differentiate CPV-2 and its variants (CPV-2a, 2b and 2c). Another set of primers and probes, CPV-426F/CPV-426R and CPV-2-426P (for CPV-2 and 2a)/CPV-2b-426P (for CPV-2b)/CPV-2c-426P (for CPV-2c), was able to differentiate CPV-2a (2), CPV-2b, and CPV-2c. With these primers and probes, the multiplex TaqMan real-time PCR assay detected effectively and differentiated CPV 2, 2a, 2b and 2c by two separate real-time PCRs. No cross reactivity was observed with canine distemper virus, canine adenovirus, and canine coronavirus. The detection limit of the assay is 101 genome copies/MUL for CPV-2, CPV-2a, CPV-2b, and 102 copies/MUL for CPV-2c. The multiplex real-time PCR has 100% agreement with DNA sequencing. We provide a sensitive assay that simultaneously detects and differentiate four antigenic types of CPV and the method was also used for quantification of CPVs viral genome. PMID- 29499234 TI - Construct Validity of the Spanish Versions of the Memorial Symptom Assessment Scale Short Form and Condensed Form: Rasch Analysis of Responses in Oncology Outpatients. AB - CONTEXT: The Memorial Symptom Assessment Scale (MSAS) is a self-rating instrument for the assessment of symptom distress in cancer patients. The Spanish version of the MSAS has recently been validated. However, we lack evidence of the internal construct validity of the shorter versions (short form [MSAS-SF] and condensed form [CMSAS]). In addition, rigorous testing of these scales with modern psychometric methods is needed. OBJECTIVES: The aim of this study was to evaluate the internal construct validity and reliability of the Spanish versions of the MSAS-SF and CMSAS in oncology outpatients using Rasch analysis. METHODS: Data from a convenience sample of oncology outpatients receiving chemotherapy (n = 306; mean age 60 years; 63% women) at a university hospital were analyzed. The Rasch unidimensional measurement model was used to examine response category functioning, item hierarchy, targeting, unidimensionality, reliability, and differential item functioning by age, gender, and marital status. RESULTS: The response category structure of the symptom distress items was improved by collapsing two categories. The scales were adequately targeted to the study patients, showed overall Rasch model fit (mean Infit MnSq ranged from 0.98 to 1.05), met criteria for unidimensionality, and the reliability of scores was good (person reliability > 0.80), except for the CMSAS prevalence scale. Only four items showed differential item functioning. CONCLUSION: The present study demonstrated that the Spanish versions of the MSAS-SF and CMSAS have adequate psychometric properties to evaluate symptom distress in oncology outpatients. Additional studies of the CMSAS are recommended. PMID- 29499235 TI - Family Caregivers' Preparations for Death: A Qualitative Analysis. AB - CONTEXT: Many family caregivers are not prepared for the death of their family member or friend. Palliative care services tend to emphasize the patients' preparation for death rather than caregivers' preparation for, or living after, death. Caregivers' perspectives on anticipating and preparing for death are under researched, despite preparation being associated with better bereavement outcomes. OBJECTIVES: The objective was to explore family caregivers' preparations for death. METHODS: A total of 16 family caregivers of people in receipt of palliative care participated in semi-structured, face-to-face interviews. Transcripts were coded and analyzed using grounded theory techniques. RESULTS: Analysis yielded two overarching themes: Here and Now centered on the caregivers' focus on the multidimensional and all-consuming nature of caregiving for someone who is near death. Negotiating the Here/After described the tension the caregivers faced in vacillating between focusing on the care during the illness trajectory (Here) and worries and plans for the future (After). CONCLUSION: This exploratory study is the first to focus solely on family caregivers' experiences of preparing for a death. The caregivers described the complexities of trying to prepare while feeling overwhelmed with demands of caregiving throughout an unpredictable illness trajectory. The caregivers in the present study were cognitively prepared, some were behaviorally prepared, but emotional preparedness was challenging. Services should not assume that all family caregivers are well-prepared for the death. Caregivers would likely benefit from the assessment and promotion of their death preparedness. PMID- 29499236 TI - Reducing blood culture contamination using a departmental report card. PMID- 29499237 TI - Metabolomic elucidation of the effects of media and carbon sources on fatty acid production by Yarrowia lipolytica. AB - Lipid production by oleaginous Yarrowia lipolytica depends highly on culture environments, such as carbon sources, carbon/nitrogen (C/N) ratios, types of media, and cellular growth phases. In this study, the effects of media and carbon sources on lipid and metabolite production were investigated by profiling fatty acids and intracellular metabolites of Y. lipolytica grown in various media. The highest total fatty acid yield 114.04 +/- 6.23 mg/g dry cell weight was achieved by Y. lipolytica grown in minimal medium with glycerol (SCG) in the exponential phase. The high lipid production by Y. lipolytica in SCG was presumed to be due to the higher C/N ratio in SCG than in the complex media. Moreover, glycerol promoted lipid production better than glucose in both complex and minimal media because glycerol can easily incorporate into the core of triglycerides. Metabolite profiling revealed that levels of long-chain fatty acids, such as stearic acid, palmitic acid, and arachidic acid, increased in SCG medium. Meanwhile, in complex media supplemented with either glucose or glycerol, levels of amino acids, such as cysteine, methionine, and glycine, highly increased. This metabolomic approach could be applied to modulate the global metabolic network of Y. lipolytica for producing lipids and other valuable products. PMID- 29499238 TI - Diverse functions of miR-17-92 cluster microRNAs in T helper cells. AB - T helper (Th) cells are critically involved in adaptive immune responses against various pathogens. In contrast, dysregulated T helper cell responses are associated with a variety of diseases, including autoimmunity, allergies, and cancer. Differentiation of naive CD4+ T cells into effector T helper cell subsets, including Th1, Th2, Th17, Treg, and T follicular helper (Tfh), requires precise dosing of signaling molecules and transcription factors. MicroRNAs (miRNAs), which are small endogenously expressed RNAs that regulate gene expression, play important roles in these processes. The miR-17-92 cluster, a miRNA polycistron also known as oncomiR-1, has emerged as a central integrator of gene expression events that govern T helper cell differentiation pathways. The complexity of miR-17-92-mediated gene regulation lies in the nature of this miRNA cluster, which consists of six different miRNAs. Individual miR-17-92 miRNAs, albeit initially transcribed as one transcript, can have cooperative or opposing effects on biological processes. Therefore, a better understanding of the molecular regulation of miR-17-92 and its downstream networks will provide important insights into T helper cell differentiation and diversity that may be harnessed for the design of advanced T cell-targeting therapies. PMID- 29499239 TI - An Artemisia-derived natural product-based fluorescent probe for the bitter taste receptor hTAS2R38. AB - The discovery of taste receptors hTAS2Rs expression in extra oral tissue, especially in the gastrointestinal tract and in the respiratory system, has endowed bitter receptors of functionalities that exceed the simple perception of taste and flavour. In particular, stimulation of hTAS2Rs by bitter agents in the airway smooth muscle triggers bronchodilation of possible pharmacological relevance. To study the receptor localization in pulmonary smooth muscle cells and to investigate their biological response to hTAS2R38 activation, we have developed a fluorescent probe for hTAS2R38 starting from the sesquiterpene lactone costunolide, available in multigram amounts from Artemisia umbelliformis Lam. The N-methylanthranilate-containing probe demonstrated a very low cytotoxicity compared to the natural product toward human airway smooth muscle cells and epithelial bronchial cells, but fully retained its binding to hTAS2R38, making it possible the fluorescent detection of cells expressing this bitter receptor. PMID- 29499240 TI - Transient and sustained ERP activity related to feedback processing in the probabilistic selection task. AB - Feedback processing represents a fundamental component of adaptive decision making. Extensive research using event-related brain potentials (ERPs) has explored the medial frontal feedback negativity (FN), P3a, and P3b components in the context of feedback processing. Additionally, recent studies examining the neural correlates of feedback processing in a gambling task revealed transient and sustained ERP activity over the lateral frontal and posterior regions of the scalp. Consistent with the neuroimaging literature, source analysis has localized this ERP activity to the lateral and medial frontal cortex, as well as the temporal-occipital and medial occipital cortices. The current experiments examine whether the pattern of transient medial frontal and sustained lateral frontal and posterior ERP activity extend to a reinforcement learning task, and may thereby represent a general property of feedback processing. Consistent with a large literature, the ERP data revealed the FN-P3a and P3b. In addition, these data revealed sustained ERP activity over the lateral frontal and posterior regions. These findings contribute to our understanding of the temporal dynamics of feedback processing across broadly distributed cortical and subcortical networks that are sensitive to the valence and probability of positive and negative outcomes. PMID- 29499241 TI - Modulation of the frontal-parietal network by low intensity anti-phase 20 Hz transcranial electrical stimulation boosts performance in the attentional blink task. AB - Performance in the attentional blink task has been demonstrated to be directly influenced by alpha and beta neural oscillatory activity. In two experiments we stimulated the right parietal cortex and left frontal cortex with transcranial alternating current stimulation. For the first experiment we targeted only the right parietal cortex and found a non-significant increase in performance from 20 Hz stimulation. In the second experiment we applied two stimulators to the right parietal and left frontal cortex and found a significant increase in performance from 20 Hz tACS with a phase difference of 180 degrees . Since low intensity stimulation has been shown to inhibit cortical excitability, and anti-phasic stimulation has been hypothesized to decrease presynaptic activation in one region and drive postsynaptic spikes in the other, we suggest that low intensity anti-phasic 20 Hz stimulation inhibited the parietal cortex, thereby disinhibiting the frontal cortex. This visual attention mechanism supposedly reduces processing of distractor stimuli and enhances processing of target stimuli. This study reveals that the frontal-parietal visual attention network may be modulated with low intensity 20 Hz anti-phase tACS. PMID- 29499242 TI - Implant and root canal treatment: Survival rates and factors associated with treatment outcome. AB - OBJECTIVES: To assess and compare the survival rates of implant and root canal treatment as well as to investigate the effect of patient and tooth related variables on the treatment outcome in a large-scale population-based study. METHODS: Dental records of patients who received root canal treatment and implant therapy were retrieved from the electronic records of the University of Minnesota School of Dentistry. Demographic characteristics, dental insurance status, socioeconomic status as well as medical history and tobacco use were recorded. The treatment outcome was included as a binary variable (survival/failure). RESULTS: A total of 13,434 records of patients who had implant (33.6%) or root canal therapy (66.4%) were included. The survival rate analysis and Kaplan-Meier table revealed the majority of the implants were removed within the first year (58.8%), while only 35.2% of the root canal treatments failed in the same time period. The overall survival rate was significantly (p < 0.001) higher for implant therapy (98.3%) compared to root canal treatment (72.7%). A statistically significant association was found between treatment (p = Lc, L <= Lc or for any L. This generalizes the usual statement that Lc represents the minimum habitat size. In addition, nonlinearities introduce dependence on the initial conditions, affecting Lc. PMID- 29499252 TI - How spatial structure and neighbor uncertainty promote mutualists and weaken black queen effects. AB - The ubiquity of cooperative cross-feeding (a resource-exchange mutualism) raises two related questions: Why is cross-feeding favored over self-sufficiency, and how are cross-feeders protected from non-producing cheaters? The Black Queen Hypothesis suggests that if leaky resources are costly, then there should be selection for either gene loss or self-sufficiency, but selection against mutualistic inter-dependency. Localized interactions have been shown to protect mutualists against cheaters, though their effects in the presence of self sufficient organisms are not well understood. Here we develop a stochastic spatial model to examine how spatial effects alter the predictions of the Black Queen Hypothesis. Microbes need two essential resources to reproduce, which they can produce themselves (at a cost) or take up from neighbors. Additionally, microbes need empty sites to give birth into. Under well mixed mean-field conditions, the cross-feeders will always be displaced by a non-producer and a self-sufficient microbe. However, localized interactions have two effects that favor production. First, a microbe that interacts with a small number of neighbors will not always receive the essential resources it needs; this effect slightly harms cross-feeders but greatly harms non-producers. Second, microbes tend to displace other microbes that produce resources they need; this effect also slightly harms cross-feeders but greatly harms non-producers. Our work therefore suggests localized interactions produce an accelerating cost of non production. Thus, the right trade-off between the cost of producing resources and the cost of sometimes being resource-limited can favor mutualistic inter dependence over both self-sufficiency and non-production. PMID- 29499253 TI - Cooperation-based branching as a mechanism of evolutionary speciation. AB - When performing complex tasks, coexistence of organisms in a shared environment can be achieved by means of different strategies. For example, individuals can evolve to complete all parts of the complex task, choosing self-sufficiency over cooperation. On the other hand, they may choose to split parts of the task and share the products for mutual benefit, such that distinct groups of the organisms specialize on a subset of elementary tasks. In contrast to the existing theory of specialization and task sharing for cells in multicellular organisms (or colonies of social insects), here we describe a mechanism of evolutionary branching which is based on cooperation and division of labor, and where selection happens at the individual level. Using a class of mathematical models and the methodology of adaptive dynamics, we investigate the conditions for such branching into distinct cooperating subgroups to occur. We show that, as long as performing multiple tasks is associated with additional cost, branching occurs for a wide parameter range, and this scenario is stable against the invasion of cheaters. We hypothesize that over time, this can lead to evolutionary speciation. Examples from bacterial evolution and the connection with the Black Queen Hypothesis are discussed. It is our hope that the theory of diversification rooted in cooperation may inspire further ecological research to identify more evolutionary examples consistent with this speciation mechanism. PMID- 29499254 TI - Mapping the protein phosphorylation sites in human mitochondrial complex I (NADH: Ubiquinone oxidoreductase): A bioinformatics study with implications for brain aging and neurodegeneration. AB - In eukaryotes, mitochondrial complex I (NADH: ubiquinone oxidoreductase; CI) is central to oxidative phosphorylation (OXPHOS). Mammalian CI is a 45 subunit complex that forms supercomplexes with other OXPHOS complexes. Since CI defects are associated with aging and neurodegeneration, it is pertinent to understand its structure-function relationship. Although genetic mutations could lower CI activity causing mitochondrial dysfunction in several pathologies, post translational modifications (PTMs) have emerged as a key mechanism contributing to altered CI activity. Among non-oxidative PTMs, protein phosphorylation is the most intricate regulatory mechanism controlling CI structure and function during normal physiology, aging and neurodegeneration. To comprehend this, we carried out a comprehensive bioinformatics analysis of protein phosphorylation of human CI subunits using software-based prediction of phosphorylation (phospho) sites and associated kinases. Phosphorylation was higher among core subunits and active domains of the complex. Among the subunits, NDUFS1 displayed significantly higher number as well as percent phospho sites compared to others. Analysis of the subunits containing iron-sulfur (Fe-S) cluster, NADH and FMN binding sites and quinone binding sites indicated the presence of phospho sites in close proximity to the binding sites of these cofactors with potential functional implications. Phosphoproteomics experiment in rat and human muscle mitochondria identified specific phospho sites in CI subunits, thereby validating the bioinformatic analysis. Molecular modeling of CI subunits indicated structural implications following phosphorylation. We surmise that protein phosphorylation, a transient and regulatory event could influence the structure-function relationship of CI thereby impinging on bioenergetics and ultimately contributing to aging and neurodegeneration. PMID- 29499255 TI - Reply by the Authors. PMID- 29499256 TI - Resolution of Diabetes Insipidus After Pyeloplasty: A Case Report and Review of the Literature. AB - Nephrogenic diabetes insipidus (NDI), a rare cause of polyuria and polydipsia in children, is usually managed with medications and careful monitoring of water intake. We present a child who was incidentally found to have right hydronephrosis secondary to ureteropelvic junction obstruction, and was subsequently also diagnosed with NDI. After being medically managed, he underwent open right pyeloplasty. His polydipsia abated within 1 month of surgery, and he has done well off of medications since that time. NDI resolution after correction of obstructive uropathy in adults has been reported, but this represents a novel case in pediatrics. PMID- 29499257 TI - Reply by the Authors. PMID- 29499258 TI - The Adverse Survival Implications of Bland Thrombus in Renal Cell Carcinoma With Venous Tumor Thrombus. AB - OBJECTIVE: To characterize the presence of bland (nontumor) thrombus in advanced renal cell carcinoma and assess the impact of this finding on cancer-specific survival. METHODS: A multi-institutional database of patients treated with nephrectomy with caval thrombectomy for locally-advanced renal tumors was assembled from 5 tertiary care medical centers. Using clinicopathologic variables including patient age, body mass index, Eastern Cooperative Oncology Group performance status, tumor stage, grade, nodal status and histology, and nearest neighbor and multiple-matching propensity score matched cohorts of bland thrombus vs nonbland thrombus patients were assessed. Multivariable analysis for predictors of cancer-specific survival was performed. RESULTS: From an initial cohort of 579 patients, 446 met inclusion criteria (174 with bland thrombus, 272 without). At baseline, patients with bland thrombus had significantly worse performance status, higher tumor stage, higher prevalence of regional nodal metastases and higher nuclear grade (P < .01 for all). In both nearest-neighbor and multiple-matching propensity score matched cohorts, the presence of bland thrombus presence was associated with inferior median cancer-specific survival (28.1 months vs 156.8 months, and 28.1 months vs 76.7 months, P < .001 for both). The presence of bland thrombus remained independently associated with an increased risk of cancer-specific mortality on multivariable analysis (hazard ratio 4.33, 95% confidence interval 2.79-6.73, P < .001). CONCLUSION: Presence of bland thrombus is associated with adverse survival outcomes in patients treated surgically for renal tumors with venous tumor thrombus. These findings may have important implications in patient counseling, selection for surgery and inclusion in clinical trials. PMID- 29499260 TI - Re: Linder et al.: Autologous Transobturator Urethral Sling Placement for Female Stress Urinary Incontinence: Short-term Outcomes (Urology 2016;93:55-59). PMID- 29499259 TI - Validation of a Low Cost, Disposable, and Ultrasound-guided Suprapubic Catheter Insertion Trainer. AB - OBJECTIVES: To validate the newly designed ultrasound-guided suprapubic catheter insertion trainer (US-SCIT) model against the real life experience by enrolling participants with prior confidence in the technique of US-guided suprapubic catheter (SPC) insertion. METHODS: The US-SCIT was self-constructed from common disposables and equipment found in the emergency department. A validation questionnaire was completed by all participants after SPC insertion on the US SCIT model. RESULTS: Fifty participants enrolled in the study. Each participant had reported confidence in the SPC insertion technique, prior to participation in this study. There were 13 "super-users" (>65 previous successful real life SPC insertions) in the study. The total material cost per US-SCIT unit was 1.71 USD. The US-SCIT's value in understanding the principals of US-guided SPC insertion had a mean score of 8.86 (standard deviation [SD] 1.03), whereas its value in simulating contextual anatomy had a mean score of 8.26 (SD 1.48). The mean score of the model's ability to provide realistic sensory feedback was 8.12 (SD 1.78), whereas that of realism of initial urine outflow was 9.06 (SD 1.20). Simulation with the model compared well with real life SPC insertion, with a mean score of 8.30 (SD1.48). CONCLUSIONS: The US-SCIT model performed well in various spheres developed to assess its ability to simulate real life SPC insertion. We are confident that this low-cost, validated, US compatible SPC trainer, constructed from common material present in the ED, will be a valuable learning asset to trainees across the globe. PMID- 29499261 TI - Photorealistic 3-Dimensional Cinematic Rendering of Clear Cell Renal Cell Carcinoma From Volumetric Computed Tomography Data. AB - The ability to create 3-dimensional (3D) renderings from multidetector computed tomography data enables a global overview of complex anatomy and disease processes which can be difficult to appreciate on 2-dimensional images. As such, 3D computed tomography has become an invaluable adjunct for diagnosis and treatment planning of many urologic conditions. A newly available method of 3D visualization, known as cinematic rendering, uses a complex lighting model to create photorealistic images and holds promise for improved discrimination of tumors and cancer staging in genitourinary imaging. Here, we present the first published case of a clear cell renal cell carcinoma visualized with cinematic rendering. PMID- 29499262 TI - Reduced Risk of Sepsis after Prostate Biopsy Using a Cephalosporin Fluoroquinolone Antibiotic Regimen and Isopropyl Alcohol Needle Washing. AB - OBJECTIVE: To compare 3 prophylactic regimens to assess their impact on postbiopsy sepsis incidence. METHODS: Data were reviewed for 829 consecutive patients who underwent prostate biopsy in a community practice setting between January 2013 and October 2017. Group 1 patients received ciprofloxacin 500 mg two times a day orally for 4 days starting the day prior to biopsy and gentamicin 80 mg intramuscularly 20 minutes prior to biopsy. From April 2015 to October 2017, 2 groups of patients were followed in parallel in a randomized manner. Group 2 received ciprofloxacin 500 mg two times a day orally for 4 days starting the day prior to biopsy and ceftriaxone 1 g intramuscularly 20 minutes prior to biopsy. Group 3 received the same antibiotic regimen as group 2 and also underwent isopropyl alcohol needle washing. RESULTS: All study groups were demographically equivalent. Microscopic bacterial counts were substantially decreased after isopropyl alcohol needle washing. Incidence of postbiopsy sepsis in groups 1 (n = 313), 2 (n = 259), and 3 (n = 257) was 3.8%, 2%, and 0%, respectively (analysis of variance; P = .006). Risk factors for sepsis included elevated body mass index, Charlson Comorbidity Score, and presence of type 2 diabetes mellitus. CONCLUSION: There was a significant reduction in the incidence of sepsis after prostate biopsy using a combination of a ciprofloxacin-ceftriaxone antibiotic regimen and isopropyl alcohol needle washing. The technique for needle washing is inexpensive and quick, and can be easily adopted into current biopsy protocols. PMID- 29499263 TI - Implication of a novel vitamin K dependent protein, GRP/Ucma in the pathophysiological conditions associated with vascular and soft tissue calcification, osteoarthritis, inflammation, and carcinoma. AB - Gla-rich protein (GRP) or unique cartilage matrix-associated protein (Ucma), the newest member of vitamin K dependent proteins, carries exceptionally high number of gamma-carboxyglutamic acid (Gla) residues which contributes to its outstanding capacity of binding with calcium in the extracellular environment indicating its potential role as a global calcium modulator. Recent studies demonstrated a critical function of GRP in the regulation of different pathophysiological conditions associated with vascular and soft tissue calcification including cardiovascular diseases, osteoarthritis, inflammation, and skin and breast carcinomas. These findings established an important relationship between gamma carboxylation of GRP and calcification associated disease pathology suggesting a critical role of vitamin K in the pathophysiological features of various health disorders. This review for the first time summarizes all of the updated findings related to the functional activities of GRP in the pathogenesis of several diseases associated with vascular and soft tissue mineralization, osteoarthritis, inflammation, and carcinoma. The outcome of this review will improve the understanding about the role of GRP in the pathogenesis of tissue calcification and its associated health disorders, which should in turn lead to the design of clinical interventions to improve the condition of patients associated with these health disorders. PMID- 29499265 TI - Polysaccharides from Phormidium versicolor (NCC466) protecting HepG2 human hepatocellular carcinoma cells and rat liver tissues from cadmium toxicity: Evidence from in vitro and in vivo tests. AB - The in vitro antioxidant, cytotoxic and cytoprotective properties and in vivo hepatoprotective activities of crude polysaccharides extracted from cyanobacteria Phormidim versicolor NCC466 (CFv-PS) were investigated. The CFv-PS, identified as heteropolysaccharides with molecular weight of 63.79kDa, exhibited relatively strong antioxidant activity, in a concentration-depended manner, in vitro assays. Additionally, CFv-PS did not induce cytotoxic effect on HepG2 human hepatocellular carcinoma cells within the range of tested concentrations (25 150MUg.mL-1) while preventing them against Cd. Moreover, in rats subjected to Cd induced hepatotoxicity, CFv-PS pretreatment significantly (P<0.05) reduced the level of ALAT, ASAT, biliburin, MDA, protein carbonyl and DNA damage, and markedly increased enzyme activities in liver tissues. These findings suggest that the cyanobacteria Phormidium versicolor is a potential source of natural products possessing antioxidant, cytoprotective and hepatoprotective properties. PMID- 29499264 TI - Optimization of pectin extraction from Uba mango peel through surface response methodology. AB - A central composite design was used to determine effects of pH (1.16-2.84), extraction temperature (63-97 degrees C) and time (35-85min) on the yield, degree of degree of esterification (DE) and viscosity of pectins extracted. For pectin extraction, the previously sanitized mango shells were dried and crushed to obtain the flour that was treated with an ethanol solution obtaining the alcohol insoluble residue (AIR). Subsequently, the AIR was mixed in ethanol with the extraction solution of hydrochloric acid. Pectin yields ranged from 18.8 to 32.1g/100g of AIR, whereas the degree of esterification (DE) and viscosity values ranged from 62.2 to 86.2% and from 1.58 to 45.85mPa.s, respectively. An inverse correlation was found between extraction yield and viscosity. Relying upon the desirability function, two optimum conditions were determined: 35min30% from the AIR, DE>=70.0% and eta>=20.0mPa.s. PMID- 29499266 TI - Microwave based synthesis and spectral characterization of thermo-sensitive poly(N,N-diethylacrylamide) grafted pectin copolymer. AB - The functionalization of polysaccharides with synthetic polymers has attracted great attention owing to its application in many industrial fields. The aim of this work was to study the impact of pectin functionalization with N,N diethylacrylamide (DEAAm). Pectin was modified via microwave-induced graft copolymerization of DEAAm using ceric ammonium nitrate (CAN) and N,N,N',N' tetramethylethylenediamine (TEMED). FTIR, 13C NMR, DSC/TGA, XRD, and SEM techniques were used to verify the structure of graft copolymers. Various reaction conditions such as microwave irradiation time, temperature, microwave power, monomer, initiator, and TEMED concentrations were investigated to get a maximum grafting yield of 192%. Lower critical solution temperatures (LCST) of graft copolymers were determined by UV spectroscopy. Graft copolymers were found to be thermo-sensitive, with LCST of 31 degrees C and high thermal resistance. Biocompatibility test of copolymers showed that copolymers were not cytotoxic to L929 fibroblasts cells and can be used as a biomaterial. PMID- 29499267 TI - Nano-magnesium oxide reinforced polylactic acid biofilms for food packaging applications. AB - This study is aimed at producing biofilms by reinforcement of Magnesium Oxide (MgO) nanoparticles in polylactic acid (PLA) biopolymer using the solvent casting method. In this study MgO nanoparticles (up to 4wt%) were reinforced in PLA biopolymer and their key mechanical, barrier, thermal and antibacterial properties were investigated for food packaging applications. Among the prepared biocomposite films, the 2wt% reinforced PLA films showed the maximum improvement in tensile strength and oxygen barrier properties (up to 29% and 25% respectively) in comparison to pristine PLA films. However, the water vapor barrier properties decreased by nearly 25% due to interfacial behavior and presence of free volumes near MgO nanoparticles. PLA/MgO films also exhibited superior antibacterial efficacy. The 2wt% biofilms caused progressive damage and death of nearly 46% of E. coli bacterial culture after 12h treatment. The produced films are transparent, capable of screening UV radiations and exhibit superior antibacterial efficacy making them an excellent food packaging material. PMID- 29499268 TI - Analysis of Kunitz inhibitors from plants for comprehensive structural and functional insights. AB - Legume Kunitz type trypsin inhibitor (KTI) family is one of the most versatile families of proteins. A typical KTI features a single peptide folded in beta trefoil manner, with the molecular weight about 20-22kDa and two disulphide bonds. The members are known to inhibit a wide range of serpins proteases at the same time many of them possess unique features. Copaifera langsdorffii Trypsin inhibitor (CTI) has a beta-trefoil fold made up of two non-covalently bound polypeptide chains with only a single disulfide bridge. Delonix regia Trypsin inhibitor (DrTI) has one amino acid insertion between P1 and P2 of the reactive site distorting its conformation. Bauhinia bauhinioides Cruzipain inhibitor (BbCI) has a conservative beta-trefoil fold but lacks disulfide bonds. Such subtle differences in structures make Kunitz inhibitors different from other inhibitor families. Most of the studies on these inhibitors are focused towards their proposed role in defense from insect pests and wounding but their exact physiological role in nature is still uncharted. Thus, it would be very interesting to closely analyze the structural details of these inhibitors in order to ascertain their biological role and other fascinating applications. PMID- 29499269 TI - Oncogenic KRas mobility in the membrane and signaling response. AB - Ras signaling initiates at the plasma membrane. Thus, Ras behavior at the membrane and how it relates to its interactions with Raf and PI3Kalpha, are of immense interest. Here we review factors influencing Ras lateral diffusion. We then ask whether oncogenic Ras diffusion speed in the membrane is important for signaling response times and whether it affects ubiquitously all pathways. We suggest that if Ras expression is sufficiently high to dimerize (or form nanoclusters), signaling response of those pathways where dimers (or nanoclusters) are involved corresponds to the speed with which Ras molecules travel in the membrane. On average, the faster the rate at which Ras travels to dimerize, the shorter the time to MAPK signaling; but not PI3Kalpha. However, we argue that KRas speed may not play an important functional role because changes in mobility at this scale are unlikely to be significant. In line with this, despite the anchors' variability, lateral diffusion speeds of KRas and HRas are similar, as is that of Lck kinase; however, even though with similar anchor, Cdc42 mobility presents a different pattern, commensurate with its role in the positioning of the apical domain, suggesting that mobility evolved for function. PMID- 29499270 TI - Dosing ribavirin in hepatitis E-infected solid organ transplant recipients. AB - Hepatitis E virus (HEV) is the most common cause of viral hepatitis worldwide. Genotypes 1 and 2 (GT1 and GT2) are mainly present in developing countries, while GT3 and GT4 are prevalent in developed and high-income countries. In the majority of cases, HEV causes a self-limiting hepatitis. GT3 and GT4 can be responsible for a chronic hepatitis that can lead to cirrhosis in immunocompromized patients, i.e. solid-organ- and stem-cell-transplant-patients, human immunodeficiency virus infected patients, and patients receiving chemotherapy or immunotherapy. HEV has also been associated with extra-hepatic manifestations such as neurologic disorders (Guillain-Barre Syndrome and neuralgic amyotrophy) and kidney disease. In patients with chronic hepatitis, reduction of immunosuppression, when possible, is the first therapeutic option. In the remaining patients, ribavirin therapy has been shown to very efficient for treating HEV infection leading to a sustained virological response in nearly 80-85% of patients. However, the mechanism of action of ribavirin in this setting is still unknown, as is the impact of HEV RNA polymerase mutations. There are unmet needs with regard to the treatment of chronic HEV with ribavirin. These include the optimal dosing and duration of treatment, and the potential beneficial effects of therapeutic drug monitoring on the virological response and the incidence of side effects. In the present review, we will provide an overview of HEV epidemiology, its mode of transmission and clinical manifestations, as well as its treatment by ribavirin with a focus on the drug's pharmacokinetics and dosing. PMID- 29499271 TI - 5-HT2A-mGlu2/3 receptor complex in rat spinal cord glutamatergic nerve endings: A 5-HT2A to mGlu2/3 signalling to amplify presynaptic mechanism of auto-control of glutamate exocytosis. AB - Presynaptic mGlu2/3 autoreceptors exist in rat spinal cord nerve terminals as suggested by the finding that LY379268 inhibited the 15 mM KCl-evoked release of [3H]D-aspartate ([3H]D-Asp) in a LY341495-sensitive manner. Spinal cord glutamatergic nerve terminals also possess presynaptic release-regulating 5-HT2A heteroreceptors. Actually, the 15 mM KCl-evoked [3H]D-Asp exocytosis from spinal cord synaptosomes was reduced by the 5-HT2A agonist (+/-)DOI, an effect reversed by the 5-HT2A antagonists MDL11,939, MDL100907, ketanserin and trazodone (TZD). We investigated whether mGlu2/3 and 5-HT2A receptors colocalize and cross-talk in these terminals and if 5-HT2A ligands modulate the mGlu2/3-mediated control of glutamate exocytosis. Western blot analysis and confocal microscopy highlighted the presence of mGlu2/3 and 5-HT2A receptor proteins in spinal cord VGLUT1 positive synaptosomes, where mGlu2/3 and 5-HT2A receptor immunoreactivities largely colocalize. Furthermore, mGlu2/3 immunoprecipitates from spinal cord synaptosomes were also 5-HT2A immunopositive. Interestingly, the 100 pM LY379268 induced reduction of the 15 mM KCl-evoked [3H]D-Asp overflow as well as its inhibition by 100 nM (+/-)DOI became undetectable when the two agonists were concomitantly added. Conversely, 5-HT2A antagonists (MDL11,939, MDL100907, ketanserin and TZD) reinforced the release-regulating activity of mGlu2/3 autoreceptors. Increased expression of mGlu2/3 receptor proteins in synaptosomal plasmamembranes paralleled the gain of function of the mGlu2/3 autoreceptors elicited by 5-HT2A antagonists. Based on these results, we propose that in spinal cord glutamatergic terminals i) mGlu2/3 and 5-HT2A receptors colocalize and interact one each other in an antagonist-like manner, ii) 5-HT2A antagonists are indirect positive allosteric modulator of mGlu2/3 autoreceptors controlling glutamate exocytosis. PMID- 29499273 TI - Environmental enrichment, alone or in combination with various pharmacotherapies, confers marked benefits after traumatic brain injury. AB - Traumatic brain injury (TBI) is a significant health care issue that affects over ten million people worldwide. Treatment options are limited with numerous failures resulting from single therapies. Fortunately, several preclinical studies have shown that combination treatment strategies may afford greater improvement and perhaps can lead to successful clinical translation, particularly if one of the therapies is neurorehabilitation. The aim of this review is to highlight TBI studies that combined environmental enrichment (EE), a preclinical model of neurorehabilitation, with pharmacotherapies. A series of PubMed search strategies yielded only nine papers that fit the criteria. The consensus is that EE provides robust neurobehavioral, cognitive, and histological improvement after experimental TBI and that the combination of EE with some pharmacotherapies can lead to benefits beyond those revealed by single therapies. However, it is noted that EE can be challenged by drugs such as the acetylcholinesterase inhibitor, donepezil, and the antipsychotic drug, haloperidol, which attenuate its efficacy. These findings may help shape clinical neurorehabilitation strategies to more effectively improve patient outcome. Potential mechanisms for the EE and pharmacotherapy-induced effects are also discussed. PMID- 29499272 TI - Receptor binding profiles and behavioral pharmacology of ring-substituted N,N diallyltryptamine analogs. AB - Substantial effort has been devoted toward understanding the psychopharmacological effects of tryptamine hallucinogens, which are thought to be mediated by activation of 5-HT2A and 5-HT1A receptors. Recently, several psychoactive tryptamines based on the N,N-diallyltryptamine (DALT) scaffold have been encountered as recreational drugs. Despite the apparent widespread use of DALT derivatives in humans, little is known about their pharmacological properties. We compared the binding affinities of DALT and its 2-phenyl-, 4 acetoxy-, 4-hydroxy-, 5-methoxy-, 5-methoxy-2-methyl-, 5-fluoro-, 5-fluoro-2 methyl-, 5-bromo-, and 7-ethyl-derivatives at 45 receptor and transporter binding sites. Additionally, studies in C57BL/6 J mice examined whether these substances induce the head twitch response (HTR), a 5-HT2A receptor-mediated response that is widely used as a behavioral proxy for hallucinogen effects in humans. Most of the test drugs bound to serotonin receptors, sigma sites, alpha2-adrenoceptors, dopaminergic D3 receptors, histaminergic H1 receptors, and the serotonin transporter. DALT and several of the ring-substituted derivatives were active in the HTR assay with the following rank order of potency: 4-acetoxy-DALT > 5-fluoro DALT > 5-methoxy-DALT > 4-hydroxy-DALT > DALT > 5-bromo-DALT. 2-Phenyl-DALT, 5 methoxy-2-methyl-DALT, 5-fluoro-2-methyl-DALT, and 7-ethyl-DALT did not induce the HTR. HTR potency was not correlated with either 5-HT1A or 5-HT2A receptor binding affinity, but a multiple regression analysis indicated that 5-HT2A and 5 HT1A receptors make positive and negative contributions, respectively, to HTR potency (R2 = 0.8729). In addition to supporting the established role of 5-HT2A receptors in the HTR, these findings are consistent with evidence that 5-HT1A activation by tryptamine hallucinogens buffers their effects on HTR. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'. PMID- 29499274 TI - Role of dorsal hippocampus kappa opioid receptors in contextual aversive memory consolidation in rats. AB - The main kappa opioid receptors (kappaORs) subtypes already described (kappa1ORs and kappa2ORs) are expressed in brain regions involved in aversive memory consolidation, including the dorsal hippocampus (DH). However, the role of DH kappaORs in consolidation of aversive memories with varied intensity and specificity is still uncertain. The present study aimed to investigate this question using pharmacological agents in rats subjected to a weak, moderate or strong contextual aversive conditioning (CAC) protocol. Antagonizing DH kappaORs with nor-binaltorphimine (nor-BNI), immediately after, but not 6 h later, a moderate CAC leads to intensified freezing behavior in the re-exposure to the paired context. Thus, indicating that DH kappaORs have an inhibitory role in the consolidation of an aversive memory. Increased DH kappaORs expression 1 h and 3 h after the moderate CAC was also observed. This up-regulation was absent in animals only exposed to the shock or to the context, indicating that this phenomenon requires a shock-context pairing to occur. Intra-DH nor-BNI infusion induced no changes following a weak CAC, but it was able to potentiate the expression of freezing behavior in novel and unpaired context after a strong CAC, indicating that DH kappaORs also modulate the consolidation of a more intense and generalized memory. Moreover, infusing the kappa2ORs agonist GR 89696, but not the kappa1ORs agonist U-69593, into the DH reduced the conditioned freezing expression. Nor-BNI pretreatment in a sub-effective dose prevented the kappa2ORs agonist effects. Altogether, the present findings provide convergent evidence that kappaORs activation negatively modulates contextual aversive memory consolidation in rat dorsal hippocampus. PMID- 29499276 TI - Fluorescence-Based High-Throughput Salt Screening. AB - The present study reports a high-throughput screening method for the salt formation of amine-containing active pharmaceutical ingredients (APIs) based on fluorescence measurements. A free form amine API was alkynylated by a solid-vapor reaction using propargyl bromide, and a fluorescent compound was produced by a subsequent reaction using 9-azidomethylanthracene. In contrast, salts were inert to propargyl bromide; thus, no fluorescence was observed. Samples for salt screening were prepared by grinding haloperidol with various counter acids, and these mixtures were derivatized in a 96-well microplate to determine whether the salt formation had occurred between haloperidol and the counter acids. Samples that turned into fluorescent and nonfluorescent were confirmed to be free form and salt form, respectively, using powder X-ray diffraction and Raman spectroscopy. In conclusion, our method adequately functions as an indicator of the salt formation of amine APIs. Further, this method allows for the rapid evaluation of the salt formation of APIs using 96-well microplates without the need for special reagents or techniques; thus, it is valuable for the discovery of an optimal salt form of newly developed amine APIs in the pharmaceutical industry. PMID- 29499275 TI - Altered hippocampal synaptic function in transgenic mice with increased astrocyte expression of CCL2 after withdrawal from chronic alcohol. AB - CNS actions of the chemokine CCL2 are thought to play a role in a variety of conditions that can have detrimental consequences to CNS function, including alcohol use disorders. We used transgenic mice that express elevated levels of CCL2 in the CNS (CCL2-tg) and their non-transgenic (non-tg) littermate control mice to investigate long-term consequences of CCL2/alcohol/withdrawal interactions on hippocampal synaptic function, including excitatory synaptic transmission, somatic excitability, and synaptic plasticity. Two alcohol exposure paradigms were tested, a two-bottle choice alcohol (ethanol) drinking protocol (2BC drinking) and a chronic intermittent alcohol (ethanol) (CIE/2BC) protocol. Electrophysiological measurements of hippocampal function were made ex vivo, starting ~0.6 months after termination of alcohol exposure. Both alcohol exposure/withdrawal paradigms resulted in CCL2-dependent interactions that altered the effects of alcohol on synaptic function. The synaptic alterations differed for the two alcohol exposure paradigms. The 2BC drinking/withdrawal treatment had no apparent long-term consequences on synaptic responses and long term potentiation (LTP) in hippocampal slices from non-tg mice, whereas synaptic transmission was reduced but LTP was enhanced in hippocampal slices from CCL2-tg mice. In contrast, the CIE/2BC/withdrawal treatment enhanced synaptic transmission but reduced LTP in the non-tg hippocampus, whereas there were no apparent long-term consequences to synaptic transmission and LTP in hippocampus from CCL2-tg mice, although somatic excitability was enhanced. These results support the idea that alcohol-induced CCL2 production can modulate the effects of alcohol exposure/withdrawal on synaptic function and indicate that CCL2/alcohol interactions can vary depending on the alcohol exposure/withdrawal protocol used. PMID- 29499277 TI - A Biopredictive In Vitro Comparison of Oral Locally Acting Mesalazine Formulations by a Novel Dissolution Model for Assessing Intraluminal Drug Release in Individual Subjects. AB - Drug release and availability at the site of action are the major factors determining the clinical response for locally-acting gastrointestinal (GI) drug products. The present work focused on the prediction of site and extent of in vivo mesalazine release after oral administration to a variety of subjects using individualized in vitro drug release experiments. First, experiments mimicking GI passages in average adult subjects were performed. Then, results from a study screening fasted in vivo pH and transit profiles in individual subjects were translated into a novel in vitro dissolution model enabling to mimic individual GI pH-profiles and transit times with physiologically relevant dissolution media. A selection of monolithic and multiparticulate mesalazine formulations with pH dependent and pH-independent drug release was screened with the novel dissolution model. Results of the study indicate that dosage form performance can be significantly different in individual subjects and highlight the importance of addressing individual physiological parameters relevant to intraluminal drug release when the aim is to predict the in vivo performance of locally-acting mesalazine formulations in individual patients. The novel in vitro dissolution approach thus represents a valuable tool for both improving individual oral therapy with locally-acting GI drug products and assessing bioequivalence of these formulations. PMID- 29499278 TI - A Conformationally Gated Model of Methadone and Loperamide Transport by P Glycoprotein. AB - P-glycoprotein (Pgp) is a multidrug resistance transporter that limits the penetration of a wide range of neurotherapeutics into the brain including opioids. The diphenylpropylamine opioids methadone and loperamide are structurally similar, but loperamide has about a 4-fold higher Pgp-mediated transport rate. In addition to these differences, they showed significant differences in their effects on Pgp-mediated adenosine triphosphate (ATP) hydrolysis. The activation of Pgp-mediated ATP hydrolysis by methadone was monophasic, whereas loperamide activation of ATP hydrolysis was biphasic implying methadone has a single binding site and loperamide has 2 binding sites on Pgp. Quenching of tryptophan fluorescence with these drugs and digoxin showed competition between the opioids and that loperamide does not compete for the digoxin-binding site. Acrylamide quenching of tryptophan fluorescence to probe Pgp conformational changes revealed that methadone- and loperamide-induced conformational changes were distinct. These results were used to develop a model for Pgp-mediated transport of methadone and loperamide where opioid binding and conformational changes are used to explain the differences in the opioid transport rates between methadone and loperamide. PMID- 29499279 TI - A Newly Identified Impurity in Polysorbate 80, the Long-Chain Ketone 12 Tricosanone, Forms Visible Particles in a Biopharmaceutical Drug Product. AB - Visible particles linked to polysorbates (PSs) used in biopharmaceutical drug products (DPs) have been observed repeatedly in recent years as an industry-wide issue, with PS degradation and insoluble degradation products, especially fatty acids and fatty acid esters, being suspected as root cause. We have shown that the visible particles observed in a monoclonal antibody DP solution in vials after 18 months of long-term storage at 5 +/- 3 degrees C were neither linked to reduction in PS (PS80) concentration nor to any known PS degradation product, but consist of 12-tricosanone, an impurity present in the raw material PS80, not a degradation product. The occurrence of visible 12-tricosanone particles in DP correlated with the usage of specific PS80 raw material lots, where 12 tricosanone was found as impurity at elevated levels. The quantities detected in these PS80 lots directly translate into the amount found in the respective monoclonal antibody DP batches. This is the first time that a clear correlation between the occurrence of the impurity 12-tricosanone in PS80 and the occurrence of visible particles in DP batches is reported. The observation and techniques described enable the control of this ketone in PS raw materials, providing means to prevent respective visible particle formation in DP. PMID- 29499280 TI - Lipoxin A4 may attenuate the progression of obesity-related glomerulopathy by inhibiting NF-kappaB and ERK/p38 MAPK-dependent inflammation. AB - OBJECTIVES: To investigate the effects of lipoxin A4 (LXA4) on inflammatory responses in obesity-related glomerulopathy (ORG) mouse model and its potential mechanisms. METHODS: Male C57BL/6 mice were randomly divided into 4 groups: normal, model, LXA4, and LXA4/Boc-2 groups (n = 8). Mice in LXA4 group were intraperitoneally injected with LXA4 (40 ng/kg) once daily for 3 days following 12 weeks of high-fat diet (HFD) feeding. LXA4 receptor antagonist, Boc-2, was administered in LXA4/Boc-2 group prior to LXA4 treatment to block the effects of LXA4. Renal morphology and function impairment were determined. Inflammation was tested by measuring serum and mRNA levels of pro-inflammatory cytokines and chemokines. HFD-induced activation of nuclear factor-kappa B (NF-kappaB) and phosphorylation of mitogen-activated protein kinases (MAPKs) were investigated by immunohistochemistry and western blot. RESULTS: HFD-feeding caused significant renal injury, pathological changes and inflammation in model group mice. LXA4 injection significantly alleviated HFD-induced effects on renal morphology and functions, as demonstrated by lower kidney index, glomerular diameter, 24 h urine protein, urinary albumin creatinine ratio and renal histomorphology. Moreover, HFD-induced accumulation of pro-inflammatory cytokines and chemokines were obviously attenuated by LXA4 administration, so did the HFD-induced activation of NF-kappaB and ERK/p38 MAPK pathways. However, these effects were markedly abrogated by BOC-2 pretreatment. CONCLUSION: LXA4 significantly attenuated HFD induced renal inflammation and injury in ORG models, and these effects may be associated with the inhibition of activation of NF-kappaB and ERK/p38 MAPK pathways. The findings of our study may shed light on LXA4 showed a potential therapeutic application in ORG. PMID- 29499281 TI - Isoniazid induces apoptosis: Role of oxidative stress and inhibition of nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). AB - AIMS: Long-term treatment of Isoniazid (INH) in tuberculosis (TB) patients can lead to anti-tuberculosis drug-induced hepatotoxicity. To understand the mechanism of hepatotoxicity, an attempt has been made to elucidate the role of Nrf2, a transcription factor induced by oxidative stress, in INH induced apoptosis liver cancer cell lines. MATERIALS AND METHODS: Cytotoxicity was evaluated by MTT assay. Apoptosis and reactive oxygen species (ROS) generation was performed by flow cytometry. mRNA and protein expression of various genes involves in INH induced toxicity was evaluated via Real-time PCR and western blot analysis respectively. Differential protein expression was performed by two dimensional gel electrophoresis followed by identification using MALDI TOF/TOF. KEY FINDINGS: INH induced ROS and apoptosis in HepG2 as well as THLE-2 cells. Nuclear damage was also observed by INH treatment in HepG2 cells. Expression of apoptotic (Cytochrome C and Caspase 9) and antioxidative (Keap1 and Nrf2) genes were observed to increase. INH induced PKCdelta phosphorylation and released Nrf2 from its inhibitor Keap1 in the cytoplasm of HepG2 cells. However, over expression of Nrf2 did not affect nuclear Nrf2 protein level as well as its downstream target NQO1. Nrf2 importer, Karyopherin beta1 level was observed to decrease in HepG2 as well as THLE-2 cells following INH treatment. SIGNIFICANCE: These findings suggest that INH prevented Nrf2 translocation into the nucleus by inhibiting its importer Karyopherin beta1. Therefore Nrf2 might not able to bind ARE sequences from inducing antioxidative response for protecting the cells undergoing apoptosis. PMID- 29499282 TI - Mitochondrial fission contributes to heat-induced oxidative stress in skeletal muscle but not hyperthermia in mice. AB - AIMS: We have previously demonstrated in vitro that heat-induced skeletal muscle damage is associated with an increase in dynamin-related protein 1 (Drp1) mediated mitochondrial fission and no change in mitochondrial fusion. In this study, we investigated the in vivo effects of mitochondrial fission inhibition on heat-induced oxidative skeletal muscle injury and hyperthermic response in mice. MAIN METHODS: Core body temperatures of mice pre-treated with vehicle or Mdivi-1 were recorded by radio telemetry during heat exposure. Tissue samples were obtained immediately following heat exposure. KEY FINDINGS: We found that heat exposure caused increased mitochondrial fragmentation and mitochondrial fission protein Drp1 expression, whereas had no effect on the mitochondrial fusion related proteins mitofusin 1, mitofusin 2 and OPA1 in mouse gastrocnemius muscles. Two groups of mice with a similar high level of heat-induced hyperthermia were allowed to recover for at least one week and subsequently treated with Mdivi-1 and vehicle, respectively. Neither Mdivi-1 nor vehicle altered the hyperthermic responses of mice during heat exposure. However, Mdivi-1 significantly reduced mitochondrial fragmentation and Drp1, reactive oxygen species levels and apoptotic responses in mouse gastrocnemius muscles following heat exposure compared with vehicle. SIGNIFICANCE: These results suggest that Drp1-mediated mitochondrial fission plays a role in heat-induced oxidative stress in skeletal muscle, but not in hyperthermic response in mice. PMID- 29499283 TI - Pharmacological benefits of neferine - A comprehensive review. AB - This article recapitulates the existing in vitro and in vivo studies focusing on the effects of neferine-an alkaloid derivative of lotus plant, in various disease models and its effects on key signaling molecules. The review also compiles a large number of research studies that demonstrate methods for isolation and extraction, biosynthetic pathway, pharmacological activity and mode of action of neferine and their underlying mechanisms at cellular level. Neferine is a unique bis-benzylisoquinoline alkaloid that possesses a number of therapeutic effects such as anti-cancer, anti-diabetic, anti-aging, anti-microbial, anti-thrombotic, anti-arrhythmic, anti-inflammatory and even anti-HIV. It also enhances the anti cancer properties of other anti-cancer drugs like cisplatin, adriamycin, taxol, etc. It is also reported to reverse chemo-resistance and enhance sensitivity of the cancer cells towards anti-cancer drugs. The underlying mechanisms for its activities mainly include apoptosis, autophagy and G1 arrest. Neferine protects them against the effect of drugs like cisplatin. The therapeutic properties of neferine is widely diverse, while it shows toxicity to cancer it also shows cyto protective effects against cardio-vascular diseases, pulmonary disease, and is also effective against Alzheimer's disease and elicits anti-oxidative effect in many cellular systems. This article thus is the first ever attempt to review the therapeutic activities of neferine established in in vitro and in vivo models and to compile all the fragmented data available on the omnipotent activities of neferine. PMID- 29499284 TI - Single mild traumatic brain injury results in transiently impaired spatial long term memory and altered search strategies. AB - Mild traumatic brain injury (mTBI) can lead to diffuse neurophysical damage as well as cognitive and affective alterations. The nature and extent of behavioral changes after mTBI are still poorly understood and how strong an impact force has to be to cause long-term behavioral changes is not yet known. Here, we examined spatial learning acquisition, retention and reversal in a Morris water maze, and assessed search strategies during task performance after a single, mild, closed skull traumatic impact referred to as "minimal" TBI. Additionally, we investigated changes in conditioned learning in a contextual fear-conditioning paradigm. Results show transient deficits in spatial memory retention, which, although limited, are indicative of deficits in long-term memory reconsolidation. Interestingly, minimal TBI causes animals to relapse to less effective search strategies, affecting performance after a retention pause. Apart from cognitive deficits, results yielded a sub-acute, transient increase in freezing response after fear conditioning, with no increase in baseline behavior, an indication of a stronger affective reaction to aversive stimuli after minimal TBI or greater susceptibility to stress. Furthermore, western blot analysis showed a short-term increase in hippocampal GFAP expression, most likely indicating astrogliosis, which is typically related to injuries of the central nervous system. Our findings provide evidence that even a very mild impact to the skull can have detectable consequences on the molecular, cognitive and affective-like level. However, these effects seemed to be very transient and reversible. PMID- 29499285 TI - NMDA or 5-HT receptor antagonists impair memory reconsolidation and induce various types of amnesia. AB - Elucidation of amnesia mechanisms is one of the central problems in neuroscience with immense practical application. Previously, we found that conditioned food presentation combined with injection of a neurotransmitter receptor antagonist or protein synthesis inhibitor led to amnesia induction. In the present study, we investigated the time course and features of two amnesias: induced by impairment of memory reconsolidation using an NMDA glutamate receptor antagonist (MK-801) and a serotonin receptor antagonist (methiothepin, MET) on snails trained with food aversion conditioning. During the early period of amnesia (<10th day), the unpaired presentation of conditioned stimuli (CS) or unconditioned stimuli (US) in the same training context did not have an effect on both types of amnesia. Retraining an on 1st or 3rd day of amnesia induction facilitated memory formation, i.e. the number of CS + US pairings was lower than at initial training. On the 10th or 30th day after the MET/reminder, the number of CS + US pairings did not change between initial training and retraining. Retraining on the 10th or 30th day following the MK-801/reminder in the same or a new context of learning resulted in short, but not long-term, memory, and the number of CS + US pairings was higher than at the initial training. This type of amnesia was specific to the CS we used at initial training, since long-term memory for another kind of CS could be formed in the same snails. The attained results suggest that disruption of memory reconsolidation using antagonists of serotonin or NMDA glutamate receptors induced amnesias with different abilities to form long-term memory during the late period of development. PMID- 29499286 TI - Baclofen blocks the acquisition and expression of mitragynine-induced conditioned place preference in rats. AB - Mitragynine is the major alkaloid found in the leaves of M. speciosa Korth (Rubiaceae), a plant that is native to Southeast Asia. This compound has been used, either traditionally or recreationally, due to its psychostimulant and opioid-like effects. Recently, mitragynine has been shown to exert conditioned place preference (CPP), indicating the rewarding and motivational properties of M. speciosa. Here, the involvement of GABAB receptors in mediating mitragynine reward is studied using a CPP paradigm in rats. First, we examined the effects of GABAB receptor agonist baclofen (1.25, 2.5 and 5 mg/kg) on the acquisition of mitragynine (10 mg/kg)-induced CPP. Second, the involvement of GABAB receptors in the expression of mitragynine-induced CPP was tested. We found that the acquisition of mitragynine-induced CPP could be blocked by higher doses (2.5 and 5 mg/kg) of baclofen. Baclofen at a high dose inhibited locomotor activity and caused a CPP. Furthermore, we found that baclofen (2.5 and 5 mg/kg) also blocked the expression of mitragynine-induced CPP. These findings suggest that both, the acquisition and expression of mitragynine's reinforcing properties is controlled by the GABAB receptor. PMID- 29499287 TI - A randomised double-blind placebo-controlled crossover trial of HUMira (adalimumab) for erosive hand OsteoaRthritis - the HUMOR trial. AB - OBJECTIVE: To assess the efficacy of adalimumab in patients with erosive hand osteoarthritis (OA). METHOD: Patients >50 years old, meeting the American College of Rheumatology (ACR) criteria for hand OA, with pain >50 on 100 mm visual analogue scale (VAS), morning stiffness >30 min and >=1 erosive joint on X-ray with synovitis present on magnetic resonance imaging (MRI) were included in a randomised double-blind placebo-controlled crossover trial. Patients were randomised to adalimumab (40 mg subcutaneous injections every other week) or identical placebo injections for 12 weeks followed by an 8-week washout and then crossed over treatment groups for another 12 weeks. The primary outcome was change in VAS hand pain over 12 weeks. Secondary outcomes included change in Australian/Canadian Hand OA Index (AUSCAN) pain, function and stiffness subscales from baseline to 4, 8 and 12 weeks, change in MRI-detected synovitis and bone marrow lesions (BMLs) from baseline to 12 weeks and change in VAS from baseline to 4 and 8 weeks. RESULTS: We recruited 51 patients and 43 were randomised to either Group 1 (N = 18, active then placebo) or Group 2 (N = 25, placebo then active). At 12 weeks there was no difference between the groups on the primary outcome measure (mean decrease in VAS pain of 3.2 mm standard deviation (SD 16.7) for adalimumab vs 0.8 mm (SD 29.6) for placebo). The adjusted treatment effect was -0.7 mm (95% confidence interval (CI) -9.3 to 8.0), P = 0.87. No statistically significant differences were found for any secondary outcomes. CONCLUSION: Adalimumab did not show any effect on pain, synovitis or BMLs in patients with erosive hand OA with MRI-detected synovitis as compared to placebo after 12 weeks. CLINICAL TRIAL REGISTRATION NUMBER: ACTRN12612000791831. PMID- 29499288 TI - NLRP3 as a potentially novel biomarker for the management of osteoarthritis. AB - Osteoarthritis (OA) was previously thought of as 'wear and tear' as humans age, however there is increasing evidence to support an inflammatory theory. The nucleotide-binding and oligomerization domain-like receptor containing protein 3 (NLRP3) inflammasome has been implicated in the pathogenesis of a number of arthritic disorders, producing proinflammatory cytokines and degradative enzymes such as Interleukin-1 beta (IL-1beta), Tumour necrosis factor alpha (TNF-alpha) and Matrix metalloproteinase-3 (MMP-3) which drive cartilage degeneration and synovial inflammation. This review aims to summarise the evidence of NLRP3 involvement in OA. Currently, treatment options focus on management of the disease and to date there is no cure. The development of novel biomarkers for OA could improve diagnosis, treatment and management. Importantly, this review provides detail on the involvement of the NLRP3 inflammasome in OA pathology and how its members could act as potential biomarkers to assist clinical decisions. PMID- 29499289 TI - The effect of intra-articular glucocorticosteroids and exercise on symptoms and bone marrow lesions in knee osteoarthritis: a secondary analysis of results from a randomized controlled trial. AB - OBJECTIVE: To evaluate if the relative volume of bone marrow lesions (BMLs) changed in patients with knee osteoarthritis (OA) during a therapeutic study. DESIGN: This study is a sub-study to a larger clinical trial which compared the clinical effects of intra-articular corticosteroid injection in knee OA to placebo injection, both given prior to exercise therapy. Clinical assessment using the Knee injury and Osteoarthritis Outcome Score (KOOS) and magnetic resonance imaging (MRI) examinations with BML assessments were performed at baseline and follow-up after 14 weeks and 26 weeks, respectively. The BML volume was determined using a computer assisted method focusing on participants with valid baseline and follow-up MRI examinations. Any changes in BML and KOOS were analyzed and investigated for associations. RESULTS: Fifty participants received steroid and placebo injection, respectively, of which 41 and 45 had complete MRI examinations at week 14, and 36 and 33 at week 26, respectively. All participants received 12 weeks of exercise. A significant change in relative BML volume was observed between the corticosteroid group and the placebo group after 14 weeks [ 1.1% vs 2.7%; between-group difference, 3.8% (95% CI 0.5-7.0)] but not after 26 weeks [0.8% vs 1.6%; between-group difference, 0.8% (95% CI -2.8 to 4.4)]. No significant association was found between changes in relative BML volume and KOOS. CONCLUSIONS: Despite the statistically significant difference in BML volume at 14 weeks after corticosteroid injection and 12 weeks exercise therapy compared to placebo injection and exercise, there is very little evidence on a relationship between corticosteroids and BML volume. EU CLINICAL TRIALS REGISTER: EudraCT number: 2012-002607-18. PMID- 29499290 TI - Dermatologists are the primary treating physicians of skin cancer in the United States Medicare population. PMID- 29499291 TI - Dermatology, climate change, and the perils of attacks on expertise. PMID- 29499292 TI - The risk of cardiovascular events in psoriasis patients treated with tumor necrosis factor-alpha inhibitors versus phototherapy: An observational cohort study. AB - BACKGROUND: Psoriasis is a risk factor for cardiovascular events. OBJECTIVE: To assess the risk of major cardiovascular events and the effect of cumulative treatment exposure on cardiovascular event risk in patients with psoriasis treated with tumor necrosis factor-alpha inhibitors (TNFis) versus phototherapy. METHODS: Adult patients with psoriasis were selected from a large US administrative claims database (from the first quarter of 2000 through the third quarter of 2014) and classified in 2 mutually exclusive cohorts based on whether they were treated with TNFis or phototherapy. Cardiovascular event risk was compared between cohorts using multivariate Cox proportional hazards models. Cumulative exposure was defined based on treatment persistence. RESULTS: A total of 11,410 TNFi and 12,433 phototherapy patients (psoralen plus ultraviolet A light phototherapy, n = 1117; ultraviolet B light phototherapy, n = 11,316) were included in this study. TNFi patients had a lower risk of cardiovascular events compared to phototherapy patients (adjusted hazard ratio 0.77, P < .05). The risk reduction associated with 6 months of cumulative exposure was 11.2% larger for patients treated with TNFis compared to phototherapy (P < .05). LIMITATIONS: Information on psoriasis severity and mortality was limited/not available. CONCLUSIONS: Patients with psoriasis who were treated with TNFis exhibited a lower cardiovascular event risk than patients treated with phototherapy. Cumulative exposure to TNFis was associated with an incremental cardiovascular risk reduction compared to phototherapy. PMID- 29499293 TI - Opioid, alcohol, and cannabis misuse among patients with hidradenitis suppurativa: A population-based analysis in the United States. AB - BACKGROUND: Patients with hidradenitis suppurativa (HS) experience chronic pain and have significant physical, emotional, and psychological disease impact. These patients may be at risk for substance abuse. OBJECTIVE: To evaluate substance use disorder (SUD) among patients with HS in the United States. METHODS: This cross sectional analysis of adult HS patients (n = 32,625) identified using electronic health records data was pulled from a population-based sample of >50 million patients. RESULTS: The prevalence of SUD among patients with HS was 4.0% (1315/32,625) compared to 2.0% (195,260/9,581,640) for patients without HS (P < .001). The most common forms of substance misuse among HS patients were alcohol (630/1315, 47.9% of SUD cases), followed by opioids (430/1315, 32.7% of SUD cases) and cannabis (430/1315, 29.7% of SUD cases). Patients with HS had 1.50 (95% confidence interval 1.42-1.59) times the adjusted odds of SUD compared to patients without HS. Patients with HS had significantly greater odds of SUD across demographic subgroups. The association between HS and SUD was generally stronger for patients 45 to 64 years of age, nonwhites, privately insured, and those without depressive or anxiety disorder. LIMITATIONS: SUD may not be accurately diagnosed. CONCLUSION: Patients with HS have higher odds of SUD and may benefit from periodic screening for substance abuse. PMID- 29499294 TI - Melanoma risk prediction using a multilocus genetic risk score in the Women's Health Initiative cohort. AB - BACKGROUND: Single-nucleotide polymorphisms (SNPs) associated with melanoma have been identified though genome-wide association studies. However, the combined impact of these SNPs on melanoma development remains unclear, particularly in postmenopausal women who carry a lower melanoma risk. OBJECTIVE: We examine the contribution of a combined polygenic risk score on melanoma development in postmenopausal women. METHODS: Genetic risk scores were calculated using 21 genome-wide association study-significant SNPs. Their combined effect on melanoma development was evaluated in 19,102 postmenopausal white women in the clinical trial and observational study arms of the Women's Health Initiative dataset. RESULTS: Compared to the tertile of weighted genetic risk score with the lowest genetic risk, the women in the tertile with the highest genetic risk were 1.9 times more likely to develop melanoma (95% confidence interval 1.50-2.42). The incremental change in c-index from adding genetic risk scores to age were 0.075 (95% confidence interval 0.041-0.109) for incident melanoma. LIMITATIONS: Limitations include a lack of information on nevi count, Fitzpatrick skin type, family history of melanoma, and potential reporting and selection bias in the Women's Health Initiative cohort. CONCLUSION: Higher genetic risk is associated with increased melanoma prevalence and incidence in postmenopausal women, but current genetic information may have a limited role in risk prediction when phenotypic information is available. PMID- 29499295 TI - Similar survival of patients with multiple versus single primary melanomas based on Utah Surveillance, Epidemiology, and End Results data (1973-2011). AB - BACKGROUND: Survival data are mixed comparing patients with multiple primary melanomas (MPM) to those with single primary melanomas (SPM). OBJECTIVES: We compared MPM versus SPM patient survival using a matching method that avoids potential biases associated with other analytic approaches. METHODS: Records of 14,138 individuals obtained from the Surveillance, Epidemiology, and End Results registry of all melanomas diagnosed or treated in Utah between 1973 and 2011 were reviewed. A single matched control patient was selected randomly from the SPM cohort for each MPM patient, with the restriction that they survived at least as long as the interval between the first and second diagnoses for the matched MPM patient. RESULTS: Survival curves (n = 887 for both MPM and SPM groups) without covariates showed a significant survival disadvantage for MPM patients (chi squared 39.29, P < .001). However, a multivariate Cox proportional hazards model showed no significant survival difference (hazard ratio 1.07, P = .55). Restricting the multivariate analysis to invasive melanomas also showed no significant survival difference (hazard ratio 0.99, P = .96). LIMITATIONS: Breslow depth, ulceration status, and specific cause of death were not available for all patients. CONCLUSIONS: Patients with MPM had similar survival times as patients with SPM. PMID- 29499296 TI - Video chat to prevent wrong site surgery. PMID- 29499297 TI - A synergistic effect of phosphate, pH and Phe159 substitution on the formycin A association to the E. coli purine nucleoside phosphorylase. AB - A steady-state absorption and emission spectroscopy was used to create a comprehensive work and to study the interaction of the wild type Escherichia coli purine nucleoside phosphorylase and its mutants, PNPF159Y and PNPF159A, with a potent E. coli PNP inhibitor - formycin A. The absorption and emission spectra were recorded in the presence and absence of the phosphate at the 50 mM concentration. From the collected sets of data dissociation constants (Kd), apparent dissociation constants (Kapp) and Hill's coefficients (h) were calculated. Additionally, the temperature dependence of the enzymes emission quenching at two temperatures, 10 degrees C and 25 degrees C, was examined. To verify the calculations, total difference absorption spectra were computed for all types of the complexes. A prominent quenching of the PNPF159Y emission indicates a complex formation, with the strongest association in the phosphate buffer, pH 7, relative to the wild type enzyme. On the other hand, results testify to a deterioration of the interactions in the E. coli PNP/PNPF159Y and formycin A complexes in the presence of the phosphate, pH 8.3. Moreover, data obtained for the PNPF159A-FA complexes confirm a weak association of the FA to the mutant's active center. PMID- 29499298 TI - Exercise training impacts exercise tolerance and bioenergetics in gastrocnemius muscle of non-obese type-2 diabetic Goto-Kakizaki rat in vivo. AB - The functional and bioenergetics impact of regular physical activity upon type-2 diabetic skeletal muscle independently of confounding factors of overweight remains undocumented. Here, gastrocnemius muscle energy fluxes, mitochondrial capacity and mechanical performance were assessed noninvasively and longitudinally in non-obese diabetic Goto-Kakizaki rats using magnetic resonance (MR) imaging and dynamic 31-phosphorus MR spectroscopy (31P-MRS) throughout a 6 min fatiguing bout of exercise performed before, in the middle (4-week) and at the end of an 8-week training protocol consisting in 60-min daily run on a treadmill. The training protocol reduced plasmatic insulin level (-61%) whereas blood glucose and non-esterified fatty acids levels remained unaffected, thereby indicating an improvement of insulin sensitivity. It also increased muscle mitochondrial citrate synthase activity (+45%) but this increase did not enhance oxidative ATP synthesis capacity in working muscle in vivo while glycolytic ATP production was increased (+33%). On the other hand, the training protocol impaired maximal force-generating capacity (-9%), total amount of force produced (-12%) and increased ATP cost of contraction (+32%) during the fatiguing exercise. Importantly, these deleterious effects were transiently worsened in the middle of the 8-week period, in association with reduced oxidative capacity and increased basal [Pi]/[PCr] ratio (an in vivo biomarker of muscle damage). These data demonstrate that the beneficial effect of regular training on insulin sensitivity in non-obese diabetic rat occurs separately from any improvement in muscle mitochondrial function and might be linked to an increased capacity for metabolizing glucose through anaerobic process in exercising muscle. PMID- 29499299 TI - Formulating monoclonal antibodies as powders for reconstitution at high concentration using spray drying: Models and pitfalls. AB - In anticipation of non-invasive routes capable of delivering adequately high, systemic monoclonal antibody (mAb) concentrations, subcutaneous (SC) injection is arguably the most patient friendly alternative administration route available for this drug class. However, due to the limited volume that can be administered through this route and mAbs' relatively low therapeutic activity, solutions for subcutaneous injection often need to be highly concentrated, making them inherently more prone to potentially detrimental protein (self-) interaction, which is why mAb formulations for SC injection and other highly concentrated mAb solutions are often dried to increase their stability. In this work we investigated spray drying (SD) as a drying technique for formulating mAbs as powders for reconstitution, assessing the influence of SD process parameters, as well as excipients present in the feed solution on both mAb stability and relevant powder characteristics for reconstitution using a model mAb. By employing a design of experiments approach, we were able to provide statistically substantiated evidence for the reconstitution time reducing and stability improving properties of l-arginineHCl, l-histidineHCl, l-lysineHCl and polysorbate 20 when combined with a disaccharide in SD mAb powders for reconstitution. Additionally, the study yielded several statistical models describing process parameter influences on relevant powder and mAb stability characteristics. PMID- 29499300 TI - Preparation of gellan-cholesterol nanohydrogels embedding baicalin and evaluation of their wound healing activity. AB - In the present work, the preparation, characterization and therapeutic potential of baicalin-loaded nanohydrogels are reported. The nanohydrogels were prepared by sonicating (S nanohydrogel) or autoclaving (A nanohydrogel) a dispersion of cholesterol-derivatized gellan in phosphate buffer. The nanohydrogel obtained by autoclave treatment showed the most promising results: smaller particles (~362 nm vs. ~530 nm), higher homogeneity (polydispersity index = ~0.24 vs. ~0.47), and lower viscosity than those obtained by sonication. In vitro studies demonstrated the ability of the nanohydrogels to favour the deposition of baicalin in the epidermis. A high biocompatibility was found for baicalin-loaded nanohydrogels, along with a great ability to counteract the toxic effect induced by hydrogen peroxide in cells, as the nanohydrogels re-established the normal conditions (~100% viability). Further, the potential of baicalin-loaded nanohydrogels in skin wound healing was demonstrated in vivo in mice by complete skin restoration and inhibition of specific inflammatory markers (i.e., myeloperoxidase, tumor necrosis factor-alpha, and oedema). PMID- 29499301 TI - Co-administration of a charge-conversional dendrimer enhances antitumor efficacy of conventional chemotherapy. AB - Despite extensive investigations, the clinical translation of nanocarrier-based drug delivery systems (NDDS) for cancer therapy is hindered by inefficient delivery and poor tumor penetration. Conventional chemotherapy by administration of free small molecule anticancer drugs remains the standard of care for many cancers. Herein, other than for carrying and releasing drugs, small nanoparticles were used as a potentiator of conventional chemotherapy by co-administration with free chemotherapeutic agents. This strategy avoided the problems associated with drug loading and controlled release encountered in NDDS, and was also much simpler than NDDS. Negatively charged poly(amido amine)-2,3-dimethylmaleic monoamide (PAMAM-DMA) dendrimers were prepared, which possessed low toxicity and can be converted to positively charged PAMAM dendrimers responsive to tumor acidic pH. The in situ formed PAMAM in tumor tissue promoted cellular uptake of co-administered doxorubicin by increasing the cell membrane permeability, and subsequently enhanced the cytotoxicity of doxorubicin. The small size of the dendrimers was favorable for deep penetration in tumor. Co-injection of PAMAM-DMA with doxorubicin into nude mice bearing human tumors almost completely inhibited tumor growth, with a mean tumor weight reducing by 55.9% after the treatment compared with the treatment with doxorubicin alone. PMID- 29499302 TI - Rethinking IL-6 and CRP: Why they are more than inflammatory biomarkers, and why it matters. AB - Behavioral researchers have increasingly become interested in the idea that chronic, low-grade inflammation is a pathway through which social and behavioral variables exert long-term effects on health. Much research in the area employs putative inflammatory biomarkers to infer an underlying state of inflammation. Interleukin 6 (IL-6) and C-reactive protein (CRP, whose production is stimulated by IL-6) are arguably the two most commonly assayed biomarkers. Yet, in contrast with near-universal assumptions in the field, discoveries in immunology over the past two decades show that neither IL-6 nor CRP are unambiguous inflammatory markers. IL-6 operates through two distinct signaling pathways, only one of which is specifically upregulated during inflammation; both pathways have a complex range of effects and influence multiple physiological processes even in absence of inflammation. Similarly, CRP has two isoforms, one of which is produced locally in inflamed or damaged tissues. The other isoform is routinely produced in absence of inflammation and may have net anti-inflammatory effects. We propose a functional framework to account for the multiple actions of IL-6 and CRP. Specifically, we argue that both molecules participate in somatic maintenance efforts; hence elevated levels indicate that an organism is investing in protection, preservation, and/or repair of somatic tissue. Depending on the state of the organism, maintenance may be channeled into resistance against pathogens (including inflammation), pathogen tolerance and harm reduction, or tissue repair. The findings and framework we present have a range of potential implications for the interpretation of empirical findings in this area-a point we illustrate with alternative interpretations of research on socioeconomic status, stress, and depression. PMID- 29499304 TI - Targeting metabotropic adenosine receptors for neuropathic pain: Focus on A2A. PMID- 29499303 TI - Chemerin suppresses neuroinflammation and improves neurological recovery via CaMKK2/AMPK/Nrf2 pathway after germinal matrix hemorrhage in neonatal rats. AB - Chemerin, an adipokine, has been reported to reduce the production of pro inflammatory cytokines and neutrophil infiltration. This study investigated the role of Chemerin and its natural receptor, ChemR23, as well as its downstream mediator calmodulin-dependent protein kinase kinase 2 (CAMKK2)/adenosine monophosphate-activated protein kinase (AMPK) /Nuclear factor erythroid 2-related factor 2 (Nrf2) following germinal matrix hemorrhage (GMH) in neonatal rats, with a specific focus on inflammation. GMH was induced by intraparenchymal injection of bacterial collagenase (0.3U) in P7 rat pups. The results demonstrated that human recombinant Chemerin (rh-Chemerin) improved neurological and morphological outcomes after GMH. Rh-Chemerin promoted accumulation and proliferation of M2 microglia in periventricular regions at 72 h. Rh-Chemerin increased phosphorylation of CAMKK2, AMPK and expression of Nrf2, and decreased IL-1beta, IL-6 and TNF-alpha levels. Selective inhibition of ChemR23/CAMKK2/AMPK signaling in microglia via intracerebroventricular delivery of liposome-encapsulated specific ChemR23 (Lipo-alpha-NETA), CAMKK2 (Lipo-STO-609) and AMPK (Lipo Dorsomorphin) inhibitor increased the expression levels of IL-1beta, IL-6 and TNF alpha, demonstrating that ChemR23/CAMKK2/AMPK signaling in microglia suppressed inflammatory response after GMH. Cumulatively, these data showed that rh-Chemerin ameliorated GMH-induced inflammatory response by promoting ChemR23/CAMKK2/AMPK/Nrf2 pathway, and M2 microglia may be a major mediator of this effect. Thus, rh-Chemerin can serve as a potential agent to reduce the inflammatory response following GMH. PMID- 29499305 TI - Understanding the mechanism of bias signaling of the insulin-like growth factor 1 receptor: Effects of LL37 and HASF. AB - The development of biased agonist drugs is widely recognized to be important for the treatment of many diseases, including cardiovascular disease. While GPCR biased agonism has been heavily characterized there is a distinct lack of information with respect to RTK biased agonism both in the identification of biased agonists as well as their attendant mechanisms. One such RTK, the Insulin like Growth Factor 1 Receptor (IGF1R) plays an important role in a range of biological and disease processes. The micropeptide LL37 has been described as a biased agonist of the IGF1R. We were interested to further understand the mechanism by which LL37 promotes biased signaling through the IGF1R. We found that LL37 biased agonism is dependent on beta-arrestin 2. Moreover, BRET assays indicated that LL37 biased agonism is explained by the inability of LL37 to promote the recruitment of IRS1 to the IGF1R compared to IGF1. LL37 promotes an altered association of IGF1R with GRK6, which could also serve as an explanation for bias. We also demonstrated a functional consequence of this bias by showing that while LL37 can promote cell proliferation, it does not induce protein synthesis, unlike IGF1, which does both. We have recently identified HASF, a natural protein released by mesenchymal stem cells, as a novel ligand of the IGF1R. HASF is a paracrine factor with potent cardioprotective and cardio regenerative properties which also acts via IGF1R biased signaling, preferentially activated ERK over Akt. PMID- 29499306 TI - ARF GTPases control phenotypic switching of vascular smooth muscle cells through the regulation of actin function and actin dependent gene expression. AB - Vascular smooth muscle cells (VSMC) can exhibit a contractile or a synthetic phenotype depending on the extracellular stimuli present and the composition of the extracellular matrix. Uncontrolled activation of the synthetic VSMC phenotype is however associated with the development of cardiovascular diseases. Here, we aimed to elucidate the role of the ARF GTPases in the regulation of VSMC dedifferentiation. First, we observed that the inhibition of the activation of ARF proteins with SecinH3, a blocker of the cytohesin ARF GEF family, reduced the ability of the cells to migrate and proliferate. In addition, this inhibitor also blocked expression of sm22alpha and alphaSMA, two contractile markers, at the transcription level impairing cell contractility. Specific knockdown of ARF1 and ARF6 showed that both isoforms were required for migration and proliferation, but ARF1 only regulated contractility through sm22alpha and alphaSMA expression. Expression of these VSMC markers was correlated with the degree of actin polymerization. VSMC treatment with SecinH3 as well as ARF1 depletion was both able to block the formation of stress fibres and focal adhesions, demonstrating the role of this GTPase in actin filament formation. Consequently, we observed that both treatments increased the ratio of G-actin to F-actin in these cells. The elevated amounts of cytoplasmic G-actin, acting as a signaling intermediate, blocked the recruitment of the Mkl1 (MRTF-A) transcription factor in the nucleus, demonstrating its involvement in the regulation of contractile protein expression. Altogether, these findings show for the first time that ARF GTPases are actively involved in VSMC phenotypic switching through the regulation of actin function in migration and proliferation, and the control of actin dependent gene regulation. PMID- 29499307 TI - Metabolomics assisted fingerprint of Hypericum perforatum chemotypes and assessment of their cytotoxic activity. AB - Hypericum perforatum is known as an important medicinal plant, used for the treatment of several diseases, while its pharmacological properties are attributed to the presence of a wide range of secondary metabolites. Due to the great chemotypic variability of Hypericum species in the nature, and the demand for standardized herbal products, a detailed phytochemical investigation was carried out on different parts (herba, leaf, flowers) from wild collected and cultivated populations, using advanced chromatographic tools. Liquid Chromatographic analysis (LC-MS/MS MRM) revealed significant variability in the secondary metabolites content of the examined methanolic extracts. The most common derivatives belong to 9 groups i.e. benzoic acids, phenylpropanoids, coumarins, flavones, flavonols, flavan-3-ols, anthocyanins, phloroglucinols and naphtodianthrones. The main polyphenolic compounds were catechin, epicatechin, quercetin, quercetin 3-O-rhamnoside, quercetin 3-O-glucoside, neochlorogenic acid, proanthocyanidins (A and B series) and cyanidin-3-O-glucoside. In addition, the content of the characteristic compounds hypericin and hyperforin in herba crude extracts ranged between 0.5 and 1.7 mg/g and 0.6-3.3 mg/g respectively. The cytotoxic activity of the crude extracts was assessed at concentrations ranged between 0.01 and 100 MUg/mL, on Caco-2 intestinal cancer cell cultures, and a cytotoxic behavior was shown only at the highest concentration of 100 MUg/mL. PMID- 29499308 TI - Pharmacological disruption of the MID1/alpha4 interaction reduces mutant Huntingtin levels in primary neuronal cultures. AB - Expression of mutant Huntingtin (HTT) protein is central to the pathophysiology of Huntington's Disease (HD). The E3 ubiquitin ligase MID1 appears to have a key role in facilitating translation of the mutant HTT mRNA suggesting that interference with the function of this complex could be an attractive therapeutic approach. Here we describe a peptide that is able to disrupt the interaction between MID1 and the alpha4 protein, a regulatory subunit of protein phosphatase 2A (PP2A). By fusing this peptide to a sequence from the HIV-TAT protein we demonstrate that the peptide can disrupt the interaction within cells and show that this results in a decrease in levels of ribosomal S6 phosphorylation and HTT expression in cultures of cerebellar granule neurones derived from HdhQ111/Q7 mice. This data serves to validate this pathway and paves the way for the discovery of small molecule inhibitors of this interaction as potential therapies for HD. PMID- 29499309 TI - Relationship between the hippocampal expression of selected cytochrome P450 isoforms and the animal performance in the hippocampus-dependent learning task. AB - Despite very extensive studies on the molecular mechanisms of memory formation, relatively little is known about the molecular correlates of individual variation in the learning skills within a random population of young normal subjects. The role of cytochrome P450 (CYP) enzymes in the brain also remains poorly understood. On the other hand, these enzymes are known to be related to the metabolism of substances important for neural functions including steroids, fatty acids, and retinoic acid. In the present study, we examined the potential correlation between the animals' performance in a place learning task and the levels of selected CYP isoforms (CYP2E1, CYP2D1 and CYP7A1) in the rat hippocampus. According to their performance, rats were classified as "good" learners (percent error/number of trials to criterion <= group mean - 3SEM) or "poor" learners (percent error/number of trials to criterion >= group mean + 3SEM). The CYP enzyme levels were determined by Western Blot at the early, intermediary and advanced stages of the task acquisition (day 4, day 8 and after reaching a performance criterion of 83% correct responses). In this study, as expected, CYP2E1 and CYP2D1 isoforms have been found in the rat hippocampus. However, a putative CYP7A1 isoform was also visualized. Hippocampal expression of these enzymes was shown to be dependent on the stage of learning and animals' cognitive status. In "good" learners compared to "poor" learners, significantly higher levels of CYP2E1 were found at the early stage of training, significantly higher levels of CYP2D1 were found at the intermediate stage of training, and significantly higher levels of CYP7A1-like protein were found after reaching the acquisition criterion. These findings suggest that the differential expression of some CYP isoforms in the hippocampus may have impact on individual learning skills and that different CYP isoforms may play different roles during the learning process. PMID- 29499310 TI - Spirulina maxima extract prevents cell death through BDNF activation against amyloid beta 1-42 (Abeta1-42) induced neurotoxicity in PC12 cells. AB - Spirulina maxima is a blue-green micro alga that contains abundant amounts of proteins (60-70%), vitamins, chlorophyll a, and C-phycocyanin (C-PC). It has been shown to reduce oxidative stress, and prevent diabetes and non-alcoholic fatty liver disease. However, it is unclear whether Spirulina maxima 70% ethanol extract (SM70EE), chlorophyll a, and C-PC prevent Abeta1-42-induced neurotoxicity in PC12 cells. The aim of this study was to investigate whether SM70EE, chlorophyll a, and C-PC prevent Abeta1-42-induced cell death. SM70EE, chlorophyll a, and C-PC suppressed the Abeta1-42-induced increase in poly-ADP ribose polymerase-1 (PARP-1) cleavage and reduced Abeta1-42-induced decreases in glutathione and its associated factors. The level of brain-derived neurotrophic factor (BDNF), which plays a critical role in neuronal survival and neuroprotection, was increased by SM70EE, chlorophyll a, and C-PC in Abeta1-42 treated cells. SM70EE treatment decreased oxidative stress and cell death in response to Abeta1-42 treatment, while simultaneously suppressing PARP cleavage and increasing the levels of glutathione (GSH) and its associated factors. Moreover, SM70EE lowered the levels of APP and BACE1, two major factors involved in APP processing, and increased BDNF expression during Abeta1-42-induced neurotoxicity in PC12 cells. We suggest that SM70EE prevents cell death caused by Abeta1-42 -induced neurotoxicity via the activation of BDNF signaling. PMID- 29499311 TI - Auditory stimulation by exposure to melodic music increases dopamine and serotonin activities in rat forebrain areas linked to reward and motor control. AB - Listening to melodic music is regarded as a non-pharmacological intervention that ameliorates various disease symptoms, likely by changing the activity of brain monoaminergic systems. Here, we investigated the effects of exposure to melodic music on the concentrations of dopamine (DA), serotonin (5-HT) and their respective metabolites in the caudate-putamen (CPu) and nucleus accumbens (NAcc), areas linked to reward and motor control. Male adult Wistar rats were randomly assigned to a control group or a group exposed to music. The music group was submitted to 8 music sessions [Mozart's sonata for two pianos (K. 488) at an average sound pressure of 65 dB]. The control rats were handled in the same way but were not exposed to music. Immediately after the last exposure or control session, the rats were euthanized, and their brains were quickly removed to analyze the concentrations of 5-HT, DA, 5-hydroxyindoleacetic acid (5-HIAA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the CPu and NAcc. Auditory stimuli affected the monoaminergic system in these two brain structures. In the CPu, auditory stimuli increased the concentrations of DA and 5-HIAA but did not change the DOPAC or 5-HT levels. In the NAcc, music markedly increased the DOPAC/DA ratio, suggesting an increase in DA turnover. Our data indicate that auditory stimuli, such as exposure to melodic music, increase DA levels and the release of 5-HT in the CPu as well as DA turnover in the NAcc, suggesting that the music had a direct impact on monoamine activity in these brain areas. PMID- 29499312 TI - Aversive aftertaste changes visual food cue reactivity: An fMRI study on cross modal perception. AB - In western cultures, we are surrounded by appealing visual food cues that stimulate our desire to eat, overeating and subsequent weight gain. Cognitive control of appetite (reappraisal) requires substantial attentional resources and effort in order to work. Therefore, we tested an alternative approach for appetite regulation via functional magnetic resonance imaging. Healthy, normal weight women were presented with images depicting food (high-/low-caloric), once in combination with a bitter aftertaste (a gustatory stop signal) and once with a neutral taste (water), in a retest design. The aversive aftertaste elicited increased activation in the orbitofrontal/dorsolateral prefrontal cortex (OFC, DLPFC), striatum and frontal operculum during the viewing of high-caloric food (vs. low-caloric food). In addition, the increase in DLPFC activity to high caloric food in the bitter condition was correlated with reported appetite reduction. The findings indicate that this aftertaste procedure was able to reduce the appetitive value of visual food cues. PMID- 29499313 TI - Multivariate pattern analysis for MEG: A comparison of dissimilarity measures. AB - Multivariate pattern analysis (MVPA) methods such as decoding and representational similarity analysis (RSA) are growing rapidly in popularity for the analysis of magnetoencephalography (MEG) data. However, little is known about the relative performance and characteristics of the specific dissimilarity measures used to describe differences between evoked activation patterns. Here we used a multisession MEG data set to qualitatively characterize a range of dissimilarity measures and to quantitatively compare them with respect to decoding accuracy (for decoding) and between-session reliability of representational dissimilarity matrices (for RSA). We tested dissimilarity measures from a range of classifiers (Linear Discriminant Analysis - LDA, Support Vector Machine - SVM, Weighted Robust Distance - WeiRD, Gaussian Naive Bayes - GNB) and distances (Euclidean distance, Pearson correlation). In addition, we evaluated three key processing choices: 1) preprocessing (noise normalisation, removal of the pattern mean), 2) weighting decoding accuracies by decision values, and 3) computing distances in three different partitioning schemes (non cross-validated, cross-validated, within-class-corrected). Four main conclusions emerged from our results. First, appropriate multivariate noise normalization substantially improved decoding accuracies and the reliability of dissimilarity measures. Second, LDA, SVM and WeiRD yielded high peak decoding accuracies and nearly identical time courses. Third, while using decoding accuracies for RSA was markedly less reliable than continuous distances, this disadvantage was ameliorated by decision-value-weighting of decoding accuracies. Fourth, the cross validated Euclidean distance provided unbiased distance estimates and highly replicable representational dissimilarity matrices. Overall, we strongly advise the use of multivariate noise normalisation as a general preprocessing step, recommend LDA, SVM and WeiRD as classifiers for decoding and highlight the cross validated Euclidean distance as a reliable and unbiased default choice for RSA. PMID- 29499314 TI - Feasibility of imaging epileptic seizure onset with EIT and depth electrodes. AB - Imaging ictal and interictal activity with Electrical Impedance Tomography (EIT) using intracranial electrode mats has been demonstrated in animal models of epilepsy. In human epilepsy subjects undergoing presurgical evaluation, depth electrodes are often preferred. The purpose of this work was to evaluate the feasibility of using EIT to localise epileptogenic areas with intracranial electrodes in humans. The accuracy of localisation of the ictal onset zone was evaluated in computer simulations using 9M element FEM models derived from three subjects. 5 mm radius perturbations imitating a single seizure onset event were placed in several locations forming two groups: under depth electrode coverage and in the contralateral hemisphere. Simulations were made for impedance changes of 1% expected for neuronal depolarisation over milliseconds and 10% for cell swelling over seconds. Reconstructions were compared with EEG source modelling for a radially orientated dipole with respect to the closest EEG recording contact. The best accuracy of EIT was obtained using all depth and 32 scalp electrodes, greater than the equivalent accuracy with EEG inverse source modelling. The localisation error was 5.2 +/- 1.8, 4.3 +/- 0 and 46.2 +/- 25.8 mm for perturbations within the volume enclosed by depth electrodes and 29.6 +/- 38.7, 26.1 +/- 36.2, 54.0 +/- 26.2 mm for those without (EIT 1%, 10% change, EEG source modelling, n = 15 in 3 subjects, p < 0.01). As EIT was insensitive to source dipole orientation, all 15 perturbations within the volume enclosed by depth electrodes were localised, whereas the standard clinical method of visual inspection of EEG voltages, only localised 8 out of 15 cases. This suggests that adding EIT to SEEG measurements could be beneficial in localising the onset of seizures. PMID- 29499315 TI - Comparison of two heuristic evaluation methods for evaluating the usability of health information systems. AB - OBJECTIVES: In addition to following the usual Heuristic Evaluation (HE) method, the usability of health information systems can also be evaluated using a checklist. The objective of this study is to compare the performance of these two methods in identifying usability problems of health information systems. METHODS: Eight evaluators independently evaluated different parts of a Medical Records Information System using two methods of HE (usual and with a checklist). The two methods were compared in terms of the number of problems identified, problem type, and the severity of identified problems. RESULTS: In all, 192 usability problems were identified by two methods in the Medical Records Information System. This was significantly higher than the number of usability problems identified by the checklist and usual method (148 and 92, respectively) (p < 0.0001). After removing the duplicates, the difference between the number of unique usability problems identified by the checklist method (n = 100) and usual method (n = 44) was significant (p < 0.0001). Differences between the mean severity of the real usability problems (1.83) and those identified by only one of the methods (usual = 2.05, checklist = 1.74) were significant (p = 0.001). CONCLUSIONS: This study revealed the potential of the two HE methods for identifying usability problems of health information systems. The results demonstrated that the checklist method had significantly better performance in terms of the number of identified usability problems; however, the performance of the usual method for identifying problems of higher severity was significantly better. Although the checklist method can be more efficient for less experienced evaluators, wherever usability is critical, the checklist should be used with caution in usability evaluations. PMID- 29499316 TI - Ceftazidime/avibactam susceptibility by three different susceptibility testing methods in carbapenemase-producing Gram-negative bacteria from Australia. AB - Avibactam (AVI) is a novel beta-lactamase inhibitor active against class A, class C and some class D beta-lactamases. In combination with ceftazidime, AVI may be useful for the treatment of infections due to Gram-negative bacteria producing carbapenemases from these classes; however, susceptibility data for some of the less common carbapenemases are limited. To assess the in vitro activity of ceftazidime/avibactam (CZA), a panel of 50 diverse carbapenemase-producing Gram negative bacteria collected from clinical samples in Victoria, Australia, containing KPC, GES, SME, OXA-23 and OXA-48-like carbapenemases were tested for susceptibility to CZA using the broth microdilution (BMD), Etest and disk diffusion methods. All isolates were susceptible to CZA. Etest correlated well with BMD, although Etest minimum inhibitory concentrations (MICs) were generally lower than BMD. Disk diffusion correlated moderately well with BMD, with two interpretive errors. This study confirms phenotypic CZA susceptibility in the carbapenemase groups tested, including the less common OXA-23-producing Escherichia coli, SME-producing Serratia marcescens and GES-5-producing Pseudomonas aeruginosa. PMID- 29499318 TI - Prediction Is Very Difficult, Especially About the Future. PMID- 29499317 TI - A large retrospective cohort study of cefazolin compared with flucloxacillin for methicillin-susceptible Staphylococcus aureus bacteraemia. AB - BACKGROUND AND OBJECTIVES: Antistaphylococcal penicillins (ASPs) are recommended as first-line treatment for invasive infections caused by methicillin-susceptible Staphylococcus aureus (MSSA). Cefazolin is an alternative option, but there is theoretical concern about its use as some MSSA strains produce beta-lactamases active against cefazolin. The study compared the outcomes in patients with MSSA infections treated with flucloxacillin and cefazolin. METHODS: We analysed data from The Australia and New Zealand Co-operative Outcomes of Staphylococcal Sepsis (ANZCOSS) observational study, which included all consecutive unique episodes of Staphylococcus aureus bacteraemia from 27 hospital-based or independent microbiology laboratories from January 2007 to September 2013. In this retrospective analysis of prospectively collected data, we compared 30-day all cause mortality in patients with MSSA bacteraemia treated with flucloxacillin to that in patients treated with cefazolin. RESULTS: We included data from 7312 episodes of MSSA bacteremia and found no difference in 30-day mortality in those treated with flucloxacillin (731/6520 [11.2%, 95% CI 10.9-12.5%]) compared to cefazolin (83/792 [10.7%, 95% CI 8.4-12.8%]), OR 0.93 (95% CI 0.72-1.17). In a propensity-adjusted analysis, mortality remained non-significantly lower in the cefazolin group (aOR 0.86 [95% CI 0.65-1.14]). CONCLUSIONS: This study supports the results from previous observational studies from other regions, while extending them to Australasia and to a much larger number of patients. Although this observational study indicates cefazolin is likely to have equivalent or superior outcomes to ASPs for MSSA bacteraemia, this can only be convincingly proven by a properly designed randomised controlled trial. PMID- 29499319 TI - Discussions in Cardiothoracic Treatment and Care: Mechanical Circulatory Support Left Ventricular Assist Device Therapy for Patients With Advanced Heart Failure. PMID- 29499320 TI - Long-Term Mechanical Circulatory Support vs Heart Transplant: A Half-Century of Progress, but When Will the Tin Man Arrive? PMID- 29499321 TI - Echocardiographic Evaluation of Diastolic Function Is of Limited Value in the Diagnosis and Management of HFpEF. PMID- 29499323 TI - Respiratory Muscle Weakness in Patients with Heart Failure: Time to Make It a Standard Clinical Marker and a Need for Novel Therapeutic Interventions? PMID- 29499324 TI - First paleoparasitological study of micromammal coprolites from the holocene of the Somuncura Plateau Protected Natural Area (Patagonia Argentina). AB - The Somuncura Plateau is a Protected Natural Area located in the middle of the northern extra-Andean arid Patagonia. Inhabited by at least 20 small mammal species, is the place with the uppermost species richness in Patagonia. The aim of this study was to examine the parasite remains from micromammal coprolites collected in association with a bone sequence recovered at the east of the Somuncura Plateau (site "Alero Las Lechuzas"). Coprolites came from the four temporal units previously defined: unit I (4790 +/- 100 yrs. 14C B.P.), unit II, unit III (7840 +/- 120 yrs. 14C B.P.) and unit IV. Each coprolite was processed, rehydrated, homogenized, processed by spontaneous sedimentation and examined using a light microscope. Coprolites and eggs were described, measured and photographed. Samples were positive for two nematode species: Helminthoxys caudatus Freitas, Lent & Almeida, 1937 (Oxyurida, Oxyuridae) and Trichuris spp. (Trichinellida: Trichuridae). This is the first paleoparasitological study developed for the Somuncura Plateau Protected Area. Moreover, this is the first time that the genus Helminthoxys is reported from ancient times worldwide. Coprolites were attributed to the mountain cavy Microcavia australis (Rodentia, Caviidae).The presence of H. caudatus for the Middle Holocene of northern Patagonia contributes to the study of the history of the histricomorphs and pinworms relationships. PMID- 29499322 TI - Pulmonary Congestion by Lung Ultrasound in Ambulatory Patients With Heart Failure With Reduced or Preserved Ejection Fraction and Hypertension. AB - BACKGROUND: Although pulmonary congestion can be quantified in heart failure (HF) by means of lung ultrasonography (LUS), little is known about LUS findings (B lines) in different HF phenotypes. This prospective cohort study investigated the prevalence and clinical and echocardiographic correlates of B-lines in ambulatory HF patients with preserved (HFpEF) or reduced (HFrEF) ejection fraction compared with hypertensive patients. We related LUS findings to 12-month HF hospitalizations and all-cause mortality. METHODS AND RESULTS: We used LUS to examine hypertensive (n = 111), HFpEF (n = 46), and HFrEF (n = 73) patients (median age 66 y, 56% male, 79% white, and median EF 55%) undergoing clinically indicated outpatient echocardiography. B-line number was quantified offline, across 8 chest zones, blinded to clinical and echocardiographic characteristics. The proportion of patients with >=3 B-lines was lower in hypertensive patients (13.5%) compared with both HFrEF (45.2%, P < .001) and HFpEF (34.8%; P = .05). HF patients with >=3 B-lines had a higher risk of the composite outcome (age- and sex-adjusted hazard ratio 2.62, 95% confidence interval 1.15-5.96; P = .022). CONCLUSIONS: When performed at the time of outpatient echocardiography, LUS findings of pulmonary congestion differ between patients with known HF and those with hypertension, and may be associated with adverse outcomes. PMID- 29499325 TI - YAP promotes breast cancer metastasis by repressing growth differentiation factor 15. AB - The transcriptional co-activator Yes-associated protein (YAP) has been implicated as an oncogene and is found to promote breast cancer metastasis. However, the pro metastatic mechanism of YAP remains unclear. Here, we demonstrated that YAP functions as a transcriptional repressor of growth differentiation factor-15 (GDF15), a divergent member of the transforming growth factor superfamily, in several breast cancer cell lines. Functionally, knockdown of YAP decreased, whereas knockdown of GDF15 increased, the metastatic potential of breast cancer cells. More than that, the reduced metastasis in YAP-depleted cells could be reversed by simultaneous knockdown of GDF15. Mechanistically, the repressive effect of YAP on GDF15 requires its transcriptional factor TEAD (TEA domain family). In addition, YAP recruits polycomb repressive complex 2 (PRC2) to tri methylate histone H3 lysine 27 in the promoter region of GDF15. Co immunoprecipitation experiments demonstrated that YAP and enhancer of zeste 2 PRC2 subunit (EZH2) physically interact with each other. In conclusion, our data reveal that YAP promotes metastasis of breast cancer cells by repressing GDF15 transcription and present a novel molecular mechanism underlying the pro metastasis function of YAP oncoprotein, with the implication of a therapeutic avenue for breast cancer treatment. PMID- 29499327 TI - Building a CAR Garage: Preparing for the Delivery of Commercial CAR T Cell Products at Memorial Sloan Kettering Cancer Center. AB - Two commercial chimeric antigen receptor (CAR) T cell therapies for CD19 expressing B cell malignancies, Kymriah and Yescarta, have recently been approved by the Food and Drug Administration. The administration of CAR T cells is a complex endeavor involving cell manufacture, tracking and shipping of apheresis products, and management of novel and severe toxicities. At Memorial Sloan Kettering Cancer Center, we have identified 8 essential tasks that define the CAR T cell workflow. In this review, we discuss practical aspects of CAR T cell program development, including clinical, administrative, and regulatory challenges for successful implementation. PMID- 29499326 TI - ERK1/2 activated PHLPP1 induces skeletal muscle ER stress through the inhibition of a novel substrate AMPK. AB - Nutritional abundance associated with chronic inflammation and dyslipidemia impairs the functioning of endoplasmic reticulum (ER) thereby hampering cellular responses to insulin. PHLPP1 was identified as a phosphatase which inactivates Akt, the master regulator of insulin mediated glucose homeostasis. Given the suggestive role of PHLPP1 phosphatase in terminating insulin signalling pathways, deeper insights into its functional role in inducing insulin resistance are warranted. Here, we show that PHLPP1 expression is enhanced in skeletal muscle of insulin resistant rodents which also displayed ER stress, an important mediator of insulin resistance. Using cultured cells and PHLPP1 knockdown mice, we demonstrate that PHLPP1 facilitates the development of ER stress. Importantly, shRNA mediated ablation of PHLPP1 significantly improved glucose clearance from systemic circulation with enhanced expression of glucose transporter 4 (GLUT-4) in skeletal muscle. Mechanistically, we show that endogenous PHLPP1 but not PP2Calpha interacts with and directly dephosphorylates AMPK Thr172 in myoblasts without influencing its upstream kinase, LKB1. While the association between endogenous PHLPP1 and AMPK was enhanced in ER stressed cultured cells and soleus muscle of high fat diet fed mice, the basal interaction between PP2Ac and AMPK was minimally altered. Further, we show that PHLPP1alpha is phosphorylated by ERK1/2 at Ser932 under ER stress which is required for its ability to interact with and dephosphorylate AMPK and thereby induce ER stress. Taken together, our data position PHLPP1 as a key regulator of ER stress. PMID- 29499328 TI - Symptoms of Fibromyalgia According to the 2016 Revised Fibromyalgia Criteria in Chronic Pain Patients Referred to Multidisciplinary Pain Rehabilitation: Influence on Clinical and Experimental Pain Sensitivity. AB - : Fibromyalgia (FM) is a condition with chronic widespread pain and signs of generalized pain hypersensitivity. FM has previously been classified according to the American College of Rheumatology-1990 criteria, where the presence of hypersensitivity is estimated by a tender point examination. Because of the limitations of these classification criteria, new diagnostic criteria have been proposed, abandoning this examination. This cross-sectional study investigated the prevalence of FM according to the revised 2016 FM criteria in a large cohort of chronic pain patients. Pain drawings, the FM Symptom Severity Scale, and questionnaires assessing manifestations of pain, pain-related disability, and psychological distress were collected from 1,343 patients with chronic nonmalignant pain referred to a multidisciplinary pain clinic. In addition, assessments of mechanical and thermal pain sensitivity were performed in 496 of the patients. Patients fulfilling the FM criteria (n = 498, 37%) reported significantly higher levels of pain, pain-related disability, psychological distress, and sensitivity to mechanical and heat stimuli (P < .05). Moreover, the proportion using opioids were significantly higher compared with patients not fulfilling the criteria (P = .015). Significant associations were found between heat and mechanical pain sensitivity (P < .001) indicating that patients who showed higher pain sensitivity to mechanical stimulation also showed higher pain sensitivity to thermal stimulation. PERSPECTIVE: More than one-third of patients were classified as FM, and patients classified showed increased clinical and experimental pain profiles. Because no data were collected on whether the included patients had a clinical FM diagnosis, future studies validating the American College of Rheumatology-2016 criteria in a cohort of patients with chronic nonmalignant pain are warranted. PMID- 29499329 TI - Advances in enzyme substrate analysis with capillary electrophoresis. AB - Capillary electrophoresis provides a rapid, cost-effective platform for enzyme and substrate characterization. The high resolution achievable by capillary electrophoresis enables the analysis of substrates and products that are indistinguishable by spectroscopic techniques alone, while the small volume requirement enables analysis of enzymes or substrates in limited supply. Furthermore, the compatibility of capillary electrophoresis with various detectors makes it suitable for KM determinations ranging from nanomolar to millimolar concentrations. Capillary electrophoresis fundamentals are discussed with an emphasis on the separation mechanisms relevant to evaluate sets of substrate and product that are charged, neutral, and even chiral. The basic principles of Michaelis-Menten determinations are reviewed and the process of translating capillary electrophoresis electropherograms into a Michaelis-Menten curve is outlined. The conditions that must be optimized in order to couple off line and on-line enzyme reactions with capillary electrophoresis separations, such as incubation time, buffer pH and ionic strength, and temperature, are examined to provide insight into how the techniques can be best utilized. The application of capillary electrophoresis to quantify enzyme inhibition, in the form of KI or IC50 is detailed. The concept and implementation of the immobilized enzyme reactor is described as a means to increase enzyme stability and reusability, as well as a powerful tool for screening enzyme substrates and inhibitors. Emerging techniques focused on applying capillary electrophoresis as a rapid assay to obtain structural identification or sequence information about a substrate and in-line digestions of peptides and proteins coupled to mass spectrometry analyses are highlighted. PMID- 29499330 TI - Molecular classification as prognostic factor and guide for treatment decision of pancreatic cancer. AB - Clinico-pathological factors fail to consistently predict the outcome after pancreatic resection for pancreatic ductal adenocarcinoma (PDAC). PDACs show a high level of inter- and intra- tumor genetic heterogeneity. A molecular classification should help sort patients into less heterogeneous and more appropriate groups regarding the metastatic risk and the therapeutic response, with the consequences of better predicting evolution and better orienting the treatment. PDAC can be classified based on mutational subtypes and 18gene alterations. Whole-genome sequencing identified mutational signatures, mutational burden and hyper-mutated tumors with specific DNA repair defects. Their overlap/similarities allow the definition of molecular subtypes. DNA and RNA classifications can be used in prognosis assessment. They are useful in therapeutic choice for they allow the design of approaches that can predict the respective drug sensitivity of each molecular subtype. This review provides a comprehensive analysis of available molecular classifications in PDAC and how this can help guide clinical decisions. PMID- 29499331 TI - Systemic administration of scAAV9-IGF1 extends survival in SOD1G93A ALS mice via inhibiting p38 MAPK and the JNK-mediated apoptosis pathway. AB - Amyotrophic lateral sclerosis (ALS) is closely associated with a reduction of neurotrophic factors in the central nervous system (CNS). Insulin-like growth factor 1 (IGF1)-encoding vectors delivered via intramuscular and intraparenchymal spinal cord injections have conferred therapeutic benefits in ALS model mice, although the development of a noninvasive delivery route is still needed. Intravenous administration of adeno-associated virus (AAV) vectors has been used to induce expression of neurotrophic genes in the lumbar spinal cords of adult mice. Therefore, the aim of this study was to investigate the effect of intravenous delivery of human IGF1 by self-complementary adeno-associated virus (scAAV) vectors in 90-day-old SOD1-G93A ALS mice. We found that IGF1 treatment decreased motor neuron death, mitigated myelin pathology in the ventral root, and prolonged the lifespan in SOD1-G93A mice. We also discovered that IGF1 inhibited phosphorylated p38 mitogen-activated protein kinase (p38 MAPK) and the c-Jun-N terminal kinase (JNK) pathway in the lumbar spinal cord, as evidenced by downregulated phosphorylated p38 and phosphorylated JNK. Furthermore, we detected the levels of proteins involved in the apoptosis pathway and found that the apoptotic inhibitor Bcl2 increased and the apoptotic promoter Bax, caspase 3, and caspase 9 decreased. In addition, the pro-inflammatory factor TNF-alpha was reduced after IGF1 treatment. In conclusion, we report a convenient and noninvasive ALS treatment method. Our results revealed a previously unrecognized role of IGF1 in p38 MAPK and the JNK-mediated pathway and its potential role as a therapeutic target for ALS. PMID- 29499332 TI - C-RAF function at the genome-wide transcriptome level: A systematic view. AB - C-RAF was the first member of the RAF kinase family to be discovered. Since its discovery, C-RAF has been found to regulate many fundamental cell processes, such as cell proliferation, cell death, and metabolism. However, the majority of these functions are achieved through interactions with different proteins; the genes regulated by C-RAF in its active or inactive state remain unclear. In the work, we used RNA-seq analysis to study the global transcriptomes of C-RAF bearing or C RAF knockout cells in quiescent or EGF activated states. We identified 3353 genes that are promoted or suppressed by C-RAF. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that these genes are involved in drug addiction, cardiomyopathy, autoimmunity, and regulation of cell metabolism. Our results provide a panoramic view of C-RAF function, including known and novel functions, and have revealed potential targets for elucidating the role of C-RAF. PMID- 29499333 TI - A survey of caregiver perspectives on emergency epinephrine autoinjector sharing. PMID- 29499334 TI - Erratum to: "How to manage a pregnant woman for emergency care, anesthesia or intensive care? Take home messages from the French Society of Anesthesiology and Intensive Care (SFAR) monothematic one-day meeting" [Anaesth. Crit. Care. Pain. Med. 35 (Suppl 1) (2016) S1-S3]. PMID- 29499335 TI - Metformin treatment prevents SREBP2-mediated cholesterol uptake and improves lipid homeostasis during oxidative stress-induced atherosclerosis. AB - Lipids are responsible for the atheromatous plaque formation during atherosclerosis by their deposition in the subendothelial intima of the aorta, leading to infarction. Sterol regulatory element-binding protein 2 (SREBP2), regulating cholesterol homeostasis, is suggested to play a pivotal role during the early incidence of atherosclerosis through dysregulation of lipid homeostasis. Here we demonstrate that oxidative stress stimulates SREBP2-mediated cholesterol uptake via low density lipoprotein receptor (LDLR), rather than cholesterol synthesis, in mouse vascular aortic smooth muscle cells (MOVAS) and THP-1 monocytes. The enhancement of mature form of SREBP2 (SREBP2-M) during oxidative stress was associated with the inhibition of AMP-activated protein kinase (AMPK) activation. In contrast, inhibition of either SREBP2 by fatostatin or LDLR by siLDLR resulted in decreased cholesterol levels during oxidative stress. Thereby confirming the role of SREBP2 in cholesterol regulation via LDLR. Metformin-mediated activation of AMPK was able to significantly abrogate cholesterol uptake by inhibiting SREBP2-M. Interestingly, although metformin administration attenuated angiotensin (Ang)-II-impaired lipid homeostasis in both aorta and liver tissues of ApoE-/- mice, the results indicate that SREBP2 through LDLR regulates lipid homeostasis in aorta but not in liver tissue. Taken together, AMPK activation inhibits oxidative stress-mediated SREBP2-dependent cholesterol uptake, and moreover, metformin-induced prevention of atheromatic events are in part due to its ability to regulate the SREBP2-LDLR axis. PMID- 29499336 TI - Ag+-promoted zinc oxide [Zn(O):Ag]: A novel structure for safe protection of human skin against UVA radiation. AB - Different sunscreens are employed to prevent photo damage (cancer, inflammation, etc.), including ZnO. ZnO is safe when applied as micro-size particle. To overcome some visual problems of ZnO micro-size particles, this sunscreen has been introduced as nano-size particles. Unfortunately, ZnO nanoparticles have raised some health concerns, due to Zn+2 release. On the other hand, it has been shown that ZnO metallic lattice change by metal doping decreases its solubility and toxicity. Therefore, we have decided here to develop new ZnO metallic lattice to reduce its cytotoxicity. In this study, Ag+1-promoted Zn-based nanocompounds [Zn(O):Ag] were synthesized as a novel compound and were characterized. XRD analysis showed that Ag+1 ion percolates into ZnO crystalline lattice and changes its lattice properties (strength bond, vacancies, and etc.). Cell culture studies and MTT assay on human skin (HFF-1) cells exposed to UVA radiation showed that [Zn(O):Ag] was increased cells viability in the presence of UVA radiation compared to ZnO. Actually, Ag+1 ion has catalyzed photoactivity of ZnO compound. UV-blocking tests showed that UVA-absorbance of [Zn(O):Ag] has increased compared to ZnO. Dichlorofluoroscein diacetate-ROS assay and Zn+2 release experiments in the presence of cells showed that [Zn(O):Ag] has reduced Zn+2 ions release into culture medium and its toxicity. Our study shows that doped ZnO nanostructure has the potential to be applied as a safe and effective nanoparticulate sunscreen. PMID- 29499337 TI - A strategy for systemic toxicity assessment based on non-animal approaches: The Cosmetics Europe Long Range Science Strategy programme. AB - When performing safety assessment of chemicals, the evaluation of their systemic toxicity based only on non-animal approaches is a challenging objective. The Safety Evaluation Ultimately Replacing Animal Test programme (SEURAT-1) addressed this question from 2011 to 2015 and showed that further research and development of adequate tools in toxicokinetic and toxicodynamic are required for performing non-animal safety assessments. It also showed how to implement tools like thresholds of toxicological concern (TTCs) and read-across in this context. This paper shows a tiered scientific workflow and how each tier addresses the four steps of the risk assessment paradigm. Cosmetics Europe established its Long Range Science Strategy (LRSS) programme, running from 2016 to 2020, based on the outcomes of SEURAT-1 to implement this workflow. Dedicated specific projects address each step of this workflow, which is introduced here. It tackles the question of evaluating the internal dose when systemic exposure happens. The applicability of the workflow will be shown through a series of case studies, which will be published separately. Even if the LRSS puts the emphasis on safety assessment of cosmetic relevant chemicals, it remains applicable to any type of chemical. PMID- 29499338 TI - Serum immune responses in common carp (Cyprinus carpio L.) to paraquat exposure: The traditional parameters and circulating microRNAs. AB - Paraquat (PQ) is a herbicide used worldwide, and it was shown to be a high-risk compound to aquatic organisms. This study was conducted to investigate the effects of PQ on traditional serum parameters and circulating microRNAs (miRNAs) in common carp to further elucidate the mechanism of PQ toxicity in fish. In the current study, a subacute toxicity test of common carp exposed to PQ at 1.596 and 3.192 mg/L for 7 d was conducted under laboratory conditions. The results showed that PQ exposure generally reduced the levels of T-AOC, SOD, CAT, and GST, but significantly increased MDA levels in the serum, indicating that PQ exposure induces oxidative stress and lipid peroxidation in the fish. The results of biochemical assays showed that PQ exposure not only significantly altered the activities of LDH, AST, ALT, ACP, AKP, and lysozyme and the contents of IgM and complement 3 but also promoted the expression of pro-inflammatory cytokines, including IFN-gamma, IL-1beta, IL-6, IL-8, and TNF-alpha. Additionally, PQ inhibited the levels of the anti-inflammatory cytokines IL-10 and TGF-beta, suggesting that PQ exposure may cause fish tissue injury and promote immune inflammatory responses. Furthermore, we found that serum circulating miRNAs, such as ccr-mir-122, ccr-mir-125b, ccr-mir-146a, and ccr-mir-155, were generally promoted in fish following PQ exposure. Based on our results and reports on miRNA based diagnosis of tissue damage and inflammatory responses in mammals, we suggest that serum ccr-mir-122, ccr-mir-125b, ccr-mir-146a, and ccr-mir-155 could be new biomarkers of PQ toxicity in fish. PMID- 29499339 TI - Cost-utility analysis of cervical deformity surgeries using 1-year outcome. AB - BACKGROUND CONTEXT: Cost-utility analysis, a special case of cost-effectiveness analysis, estimates the ratio between the cost of an intervention to the benefit it produces in number of quality-adjusted life years. Cervical deformity correction has not been evaluated in terms of cost-utility and in the context of value-based health care. Our objective, therefore, was to determine the cost utility ratio of cervical deformity correction. STUDY DESIGN: This is a retrospective review of a prospective, multicenter cervical deformity database. Patients with 1-year follow-up after surgical correction for cervical deformity were included. Cervical deformity was defined as the presence of at least one of the following: kyphosis (C2-C7 Cobb angle >10 degrees ), cervical scoliosis (coronal Cobb angle >10 degrees ), positive cervical sagittal malalignment (C2-C7 sagittal vertical axis >4 cm or T1-C6 >10 degrees ), or horizontal gaze impairment (chin-brow vertical angle >25 degrees ). Quality-adjusted life years were calculated by both EuroQol 5D (EQ5D) quality of life and Neck Disability Index (NDI) mapped to short form six dimensions (SF6D) index. Costs were assigned using Medicare 1-year average reimbursement for: 9+ level posterior fusions (PF), 4-8 level PF, 4-8 level PF with anterior fusion (AF), 2-3 level PF with AF, 4-8 level AF, and 4-8 level posterior refusion. Reoperations and deaths were added to cost and subtracted from utility, respectively. Quality-adjusted life year per dollar spent was calculated using standardized methodology at 1-year time point and subsequent time points relying on maintenance of 1-year utility. RESULTS: Eighty-four patients (average age: 61.2 years, 60% female, body mass index [BMI]: 30.1) were analyzed after cervical deformity correction (average levels fused: 7.2, osteotomy used: 50%). Costs associated with index procedures were 9+ level PF ($76,617), 4-8 level PF ($40,596), 4-8 level PF with AF ($67,098), 4-8 level AF ($31,392), and 4-8 level posterior refusion ($35,371). Average 1-year reimbursement of surgery was $55,097 at 1 year with eight revisions and three deaths accounted for. Cost per quality-adjusted life year (QALY) gained to 1-year follow-up was $646,958 by EQ5D and $477,316 by NDI SF6D. If 1-year benefit is sustained, upper threshold of cost-effectiveness is reached 3-4.5 years after intervention. CONCLUSIONS: Medicare 1-year average reimbursement compared with 1 year QALYdescribed $646,958 by EQ5D and $477,316 by NDI SF6D. Cervical deformity surgeries reach accepted cost-effectiveness thresholds when benefit is sustained 3-4.5 years. Longer follow-up is needed for a more definitive cost-analysis, but these data are an important first step in justifying cost-utility ratio for cervical deformity correction. PMID- 29499342 TI - Molecular aspects of sucrose transport and its metabolism to starch during seed development in wheat: A comprehensive review. AB - Wheat is one of the most important crops globally, and its grain is mainly used for human food, accounting for 20% of the total dietary calories. It is also used as animal feed and as a raw material for a variety of non-food and non-feed industrial products such as a feedstock for the production of bioethanol. Starch is the major constituent of a wheat grain, as a result, it is considered as a critical determinant of wheat yield and quality. The amount and composition of starch deposited in wheat grains is controlled primarily by sucrose transport from source tissues to the grain and its conversion to starch. Therefore, elucidation of the molecular mechanisms regulating these physiological processes provides important opportunities to improve wheat starch yield and quality through biotechnological approaches. This review comprehensively discusses the current understanding of the molecular aspects of sucrose transport and sucrose to-starch metabolism in wheat grains. It also highlights the advances and prospects of starch biotechnology in wheat. PMID- 29499343 TI - Development and quantification of measures for risky and delayed food and monetary outcome choices. AB - Probability discounting (PD) measures risky choice patterns between smaller, more certain vs. larger, less certain outcomes. PD is associated with obesity as well as higher intake of foods high in fat and sugar. We developed and validated a brief PD task specifically for food-related choices-the Probabilistic Food Choice Questionnaire (PFCQ). We also validated a brief, existing PD monetary measure, the Probabilistic Monetary Choice Questionnaire (PMCQ) by comparing it to a titrating PD task. Participants (N = 110) were randomly assigned to either a food or money condition. Those assigned to the food condition completed the PFCQ and a more established, adjusting-amount PD task for hypothetical food outcomes. Those assigned to the money condition completed the PMCQ and a more established, adjusting-amount PD task. Participants also completed delay discounting (DD) tasks for the same outcome commodity. The PFCQ and adjusting-amount PD tasks strongly correlated across three magnitudes suggesting that the PFCQ may be a satisfactory and briefer measure for risky food choice. The PMCQ also showed significant correlations with the adjusting-amount monetary PD task, supporting its use for a brief measure of monetary discounting. For DD, the choice questionnaires demonstrated significant correlations with the adjusting-amount DD procedures, replicating previous research. PMID- 29499344 TI - The effects of changeover delays on local choice. AB - In concurrent schedules with a changeover delay (COD), choice often strongly favours the just-reinforced alternative immediately after a reinforcer delivery. These 'preference pulses' may be caused by a change in reinforcer availability created by the COD, and/or because the COD decreases the overall probability of switching. We investigated which explanation better accounts for preference pulses by arranging concurrent schedules that allowed us to separate the COD's effects on reinforcer availability from its effects on the probability of switching. When the reinforcer ratio was 1:1, pulses were inconsistently accompanied by changes in reinforcer availability, but consistently accompanied by longer visits. These pulses appeared to be related only to the decreased probability of switching caused by the COD, providing the first evidence of pulses after reinforcers caused by the probability of switching alone. When the reinforcer ratio was 1:5 or 5:1; preference pulses were accompanied by changes in reinforcer availability and by longer visits. These pulses appeared to be related to the COD's effects on reinforcer availability, although a small portion appeared to be related to low probability of switching. These findings suggest that the COD affects preference pulses by both decreasing the probability of switching and creating a change in reinforcer availability. PMID- 29499345 TI - Effects of extinction of a nontarget CS on performance to a target CS. AB - When a target conditioned stimulus (CS A) is paired with an unconditioned stimulus in the presence of a second, conditioned stimulus (CS B) during compound conditioning trials, the associative strength of CS B can influence the magnitude of the conditioned response (CR) to CS A. For example, extinction of the competing, nontarget CS B can influence the CR to CS A. An enhancement of the CR to the target CS A due to extinction of the nontarget CS B after compound conditioning is sometimes referred to as "recovery from overshadowing" - a type of retrospective revaluation. The present experiments examined retrospective revaluation effects using a conditioned taste aversion procedure. The experiments obtained an effect on the CR to CS A following extinction of CS B. The results are discussed with respect to the comparator hypothesis, within-compound associations, and retrieval as well as other relationships between the target CS and nontarget CS. PMID- 29499340 TI - Paradigm shift - Metabolic transformation of docosahexaenoic and eicosapentaenoic acids to bioactives exemplify the promise of fatty acid drug discovery. AB - Fatty acid drug discovery (FADD) is defined as the identification of novel, specialized bioactive mediators that are derived from fatty acids and have precise pharmacological/therapeutic potential. A number of reports indicate that dietary intake of omega-3 fatty acids and limited intake of omega-6 promotes overall health benefits. In 1929, Burr and Burr indicated the significant role of essential fatty acids for survival and functional health of many organs. In reference to specific dietary benefits of differential omega-3 fatty acids, docosahexaenoic and eicosapentaenoic acids (DHA and EPA) are transformed to monohydroxy, dihydroxy, trihydroxy, and other complex mediators during infection, injury, and exercise to resolve inflammation. The presented FADD approach describes the metabolic transformation of DHA and EPA in response to injury, infection, and exercise to govern uncontrolled inflammation. Metabolic transformation of DHA and EPA into a number of pro-resolving molecules exemplifies a novel, inexpensive approach compared to traditional, expensive drug discovery. DHA and EPA have been recommended for prevention of cardiovascular disease since 1970. Therefore, the FADD approach is relevant to cardiovascular disease and resolution of inflammation in many injury models. Future research demands identification of novel action targets, receptors for biomolecules, mechanism(s), and drug-interactions with resolvins in order to maintain homeostasis. PMID- 29499341 TI - Bacterial components as naturally inspired nano-carriers for drug/gene delivery and immunization: Set the bugs to work? AB - Drug delivery is a rapidly growing area of research motivated by the nanotechnology revolution, the ideal of personalized medicine, and the desire to reduce the side effects of toxic anti-cancer drugs. Amongst a bewildering array of different nanostructures and nanocarriers, those examples that are fundamentally bio-inspired and derived from natural sources are particularly preferred. Delivery of vaccines is also an active area of research in this field. Bacterial cells and their components that have been used for drug delivery, include the crystalline cell-surface layer known as "S-layer", bacterial ghosts, bacterial outer membrane vesicles, and bacterial products or derivatives (e.g. spores, polymers, and magnetic nanoparticles). Considering the origin of these components from potentially pathogenic microorganisms, it is not surprising that they have been applied for vaccines and immunization. The present review critically summarizes their applications focusing on their advantages for delivery of drugs, genes, and vaccines. PMID- 29499346 TI - A nematode that can manipulate the behaviour of slugs. AB - The ability of parasites to manipulate the behaviour of their hosts has evolved multiple times, and has a clear fitness benefit to the parasite in terms of facilitating growth, reproduction and transfer to suitable hosts. The mechanisms by which these behavioural changes are induced are poorly understood, but in many cases parasite manipulation of serotonergic signalling in the host brain is implicated. Here we report that Phasmarhabditis hermaphrodita, a parasite of terrestrial gastropod molluscs, can alter the behaviour of slugs. Uninfected slugs (Deroceras panormitanum, Arion subfuscus and Arion hortensis) avoid areas where P. hermaphrodita is present, but slugs infected with P. hermaphrodita are more likely to be found where the nematodes are present. This ability is specific to P. hermaphrodita and other nematodes (Steinernema carpocapsae and Heterorhabditis bacteriophora) do not induce this behavioural change. To investigate how P. hermaphrodita changes slug behaviour we exposed slugs to fluoxetine (a selective serotonin reuptake inhibitor) and cyproheptadine (a serotonin receptor antagonist). Uninfected slugs fed fluoxetine no longer avoided areas where P. hermaphrodita was present; and conversely, infected slugs fed cyproheptadine showed no increased attraction to areas with nematodes. These findings suggest that a possible mechanism by which P. hermaphrodita is able to manipulate parasite avoidance behaviour in host slugs is by manipulating serotonergic signalling in the brain, and that increased serotonin levels are potentially associated with a reduction in parasite avoidance. PMID- 29499347 TI - Is oval window transport a royal gate for nanoparticle delivery to vestibule in the inner ear? AB - Drug delivery to the inner ear by nanomedicine strategies has emerged as an effective therapeutic approach for the management of inner ear diseases including hearing and balance disorders. It is well accepted that substance enters the perilymph from the middle ear through the round window membrane (RWM), but the passage through the oval window (OW) has long been neglected. Up to now, researchers still know little about the pathway via which nanoparticles (NPs) enter the inner ear or how they reach the inner ear following local applications. Herein, we engineered fluorescence traceable chitosan (CS) NPs, investigated the NP distribution within cochlear and vestibular organs, and assessed the availability of RWM and OW pathways to NP transport. Intriguingly, there were high levels of CS NPs in vestibular hair cells, dark cells and supporting cells, but negligible ones in cochlear hair cells and epithelial cells after intratympanic administration. However, the NPs were visualized in two cell models, L929 and HEI-OC1 cell lines, and in the hair cells of cochlear explants after co-incubation in vitro. These combined studies implied that CS NPs might enter the vestibule directly through the OW and then preferentially accumulated in the cells of vestibular organs. Thus, in vivo studies were carried out and clearly revealed that CS NPs entered the inner ear through both the RWM and OW, but the latter played a governing role in delivering NPs to the vestibule with vivid fluorescence signals in the thin bone of the stapes footplate. Overall, these findings firstly suggested that the OW, as a royal gate, afforded a convenient access to facilitate CS NPs transport into inner ear, casting a new light on future clinical applications of NPs in the effective treatment of vestibular disorders by minimizing the risk of hearing loss associated with cochlear hair cell pathology. PMID- 29499348 TI - Continuous manufacturing and analytical characterization of fixed-dose, multilayer orodispersible films. AB - Various drug therapies require more than one active pharmaceutical ingredient (API) for an effective treatment. There are many advantages, e.g. to improve the compliance or pharmacodynamic response in comparison to a monotherapy or to increase the therapy safety. Until now, there are only a few products available for the paediatric population due to the lack of age appropriate dosage forms or studies proving the efficacy and safety of these products. This study aims to develop orodispersible films (ODFs) in a continuous solvent casting process as child appropriate dosage form containing both enalapril maleate (EM) and hydrochlorothiazide (HCT) separated in different film layers. Furthermore, they should be characterised and the API migration analysed by confocal Raman microscopy (CRM). ODFs were successfully produced in a continuous manufacturing process in form of double- and triple-layer formulations based on hydroxypropylcellulose (HPC) or a combination of HPC and polyvinyl alcohol (PVA). CRM revealed that both APIs migrate within the film layers shortly after manufacturing. PVA inhibits the migration inside the double-layer film, but is not able to prevent the API migration as an interlayer inside a triple-layer ODF. With increasing film layers, the content of residual solvents and the disintegration time increases (mono-layer films: <10 s, triple-layer films: 37 s). In conclusion, it was feasible to produce fixed-dose combinations in therapeutic doses up to 9 mg HCT and 3.5 mg EM for the double-layer film with adequate mechanical properties, which enable coiling up onto jumbo rolls directly after production. The best separation of the two APIs was achieved by casting a double-layer ODF consisting of different film forming polymers, which can be beneficial when processing two incompatible APIs. PMID- 29499349 TI - Recent advances in aptamer-armed multimodal theranostic nanosystems for imaging and targeted therapy of cancer. AB - The side effects of chemotherapeutics during the course of cancer treatment limit their clinical outcomes. The most important mission of the modern cancer therapy modalities is the delivery of anticancer drugs specifically to the target cells/tissue in order to avoid/reduce any inadvertent non-specific impacts on the healthy normal cells. Nanocarriers decorated with a designated targeting ligand such as aptamers (Aps) and antibodies (Abs) are able to deliver cargo molecules to the target cells/tissue without affecting other neighboring cells, resulting in an improved treatment of cancer. For targeted therapy of cancer, different ligands (e.g., protein, peptide, Abs, Aps and small molecules) have widely been used in the development of different targeting drug delivery systems (DDSs). Of these homing agents, nucleic acid Aps show unique targeting potential with high binding affinity to a variety of biological targets (e.g., genes, peptides, proteins, and even cells and organs). Aps have widely been used as the targeting agent, in large part due to their unique 3D structure, simplicity in synthesis and functionalization, high chemical flexibility, low immunogenicity and toxicity, and cell/tissue penetration capability in some cases. Here, in this review, we provide important insights on Ap-decorated multimodal nanosystems (NSs) and discuss their applications in targeted therapy and imaging of cancer. PMID- 29499350 TI - Zero-order release of poorly water-soluble drug from polymeric films made via aqueous slurry casting. AB - In spite of significant recent interest in polymeric films containing poorly water-soluble drugs, dissolution mechanism of thicker films has not been investigated. Consequently, release mechanisms of poorly water-soluble drugs from thicker hydroxypropyl methylcellulose (HPMC) films are investigated, including assessing thickness above which they exhibit zero-order drug release. Micronized, surface modified particles of griseofulvin, a model drug of BSC class II, were incorporated into aqueous slurry-cast films of different thicknesses (100, 500, 1000, 1500 and 2000 MUm). Films 1000 MUm and thicker were formed by either stacking two or more layers of ~500 MUm, or forming a monolithic thick film. Compared to monolithic thick films, stacked films required simpler manufacturing process (easier casting, short drying time) and resulted in better critical quality attributes (appearance, uniformity of thickness and drug per unit area). Both the film forming approaches exhibited similar release profiles and followed the semi-empirical power law. As thickness increased from 100 MUm to 2000 MUm, the release mechanism changed from Fickian diffusion to zero-order release for films >=1000 MUm. The diffusional power law exponent, n, achieved value of 1, confirming zero-order release, whereas the percentage drug release varied linearly with sample surface area, and sample thickness due to fixed sample diameter. Thus, multi-layer hydrophilic polymer aqueous slurry-cast thick films containing poorly water-soluble drug particles provide a convenient dosage form capable of zero-order drug release with release time modulated through number of layers. PMID- 29499351 TI - Carotid Bifurcation Geometry as Assessed by Ultrasound is Associated with Early Carotid Atherosclerosis. AB - BACKGROUND: Atherosclerosis usually develops at geometrically susceptible areas, despite the impact of systemic risk factors on the entire vascular system. The aim of our study was to investigate whether carotid bifurcation geometry as assessed by ultrasound is associated with early carotid atherosclerosis, regardless of the presence of known atherosclerotic risk factors. MATERIAL AND METHODS: A nonrandomized prospective study was undertaken, including subjects of both genders, aged 50-60 years, without known cardiovascular family history, and symptoms and/or signs of cardiovascular disease. Clinical assessment and ultrasound of the carotid bifurcation evaluating geometrical characteristics, ultrasonic biopsy score (UBS), intima-media thickness (IMT), and the presence of plaque were recorded. RESULTS: Two hundred one subjects (95 men/106 women; mean age: 55 years) provided 286 carotid bifurcations associated with atherosclerotic risk factors and 114 without (one poor imaging). While UBS in the right common carotid artery (CCA) was higher in subjects with atherosclerotic risk factors but free of plaque (P = 0.035), larger diameter of the bulb (dBULB) (P < 0.001), lower ratios of internal carotid artery diameter + external carotid artery diameter/diameter of CCA ([dICA + dECA]/dCCA) (P = 0.004), and (dICA2 + dECA2)/dCCA2 (P = 0.025) were independently associated with higher CCA IMT. The presence of plaque among the total 400 carotid bifurcations was associated in the left and right CCA with lower values of bulb diameter/dCCA (dBULB/dCCA) (P = 0.014) and (dICA + dECA)/dCCA (P = 0.001), respectively. Among subjects without atherosclerotic risk factors (n = 114), the presence of plaque in the right CCA was associated with lower values of (dBULB + dECA)/dCCA (P = 0.001) and that in the left with lower values of dBULB/dCCA (P = 0.001). CONCLUSIONS: Different dimensional ratios of the carotid bifurcation assessed by ultrasound are associated with the development of early carotid atherosclerosis independently from the presence of atherosclerotic risk factors. Carotid atherosclerotic process may be side dependent. PMID- 29499352 TI - Remote Endarterectomy and Lamina Vastoadductoria Dissection Improves Superficial Femoral Artery Biomechanical Behavior during Limb Flexion. AB - BACKGROUND: Superficial femoral artery (SFA) remote endarterectomy offers the advantage of preserving anatomy and geometry of the native artery, but the risk of restenosis still exists. The particular role of the adductor canal (AC) in mechanical constraints has been highlighted. The aim of this study was to assess if a surgical protocol associating remote SFA endarterectomy and AC freeing would modify the SFA geometrical changes during physiological limb flexion. METHODS: From January 2015 to March 2015, 10 patients (Rutherford 3-5) with unilateral SFA occlusion were included. Functional postoperative assessments were performed through duplex ultrasound (DUS) examinations with flow velocity measurements in both straight and flexed positions and anatomical measurements through 3 dimensional computed tomography angiography (CTA) reconstructions with arterial angulations examination. Functional results were compared with similar findings in healthy volunteers, and anatomical results were compared with contralateral limb findings. RESULTS: Mean occlusion length was 243.0 +/- 17.7 mm. Technical success was achieved in all cases. No difference of peak flow velocities was noticed between operated patients and volunteers. CTA results showed that limb flexion induced SFA shortening in all segments, with a maximal value for the popliteal artery (PA) (10.4 +/- 4.4%). Comparisons between the operated and contralateral limbs showed that angles were less sharp during bending in the operated limb. CONCLUSIONS: This preliminary study demonstrates that freeing the AC modifies the biomechanical properties of the SFA. These results could potentially help in proposing future hybrid techniques that could improve technical performances for SFA occlusive disease treatment. PMID- 29499353 TI - Underutilization of Thrombolytic Therapy for Patients Diagnosed with Acute Deep Venous Thrombosis in the Outpatient Setting. AB - BACKGROUND: Catheter-directed thrombolysis (CDT) has been shown to be a safe and effective treatment for the management of acute iliofemoral deep venous thrombosis (DVT). The potential benefits of this therapy include more rapid resolution of symptoms and possible reduction in the long-term sequelae. Many patients diagnosed with DVT in the inpatient setting have contraindications to lytic therapy, but less is known regarding the suitability of thrombolysis for outpatients diagnosed with acute DVT. We sought to determine the proportion of patients who were candidates for thrombolytic therapy and referred to a vascular specialist for evaluation. METHODS: A manual search of an outpatient vascular laboratory associated with a tertiary medical center was performed to identify all patients referred for the purpose of ruling out DVT between January 2013 and December 2014. Vascular laboratory studies conducted for evaluation of venous insufficiency were excluded. The electronic medical records were reviewed to evaluate for contraindications for thrombolysis. RESULTS: Over a 2-year period, there were 689 referrals to the outpatient vascular laboratory for the evaluation of patients with suspected DVT. Of the 689 referrals, 47 (6.8%) were found to have acute DVT, and 66 (9%) were found to have chronic DVT. Of the 47 patients with acute DVT, 41 involved the lower extremities. Fifteen of the 41 patients (37%) with extensive acute iliofemoral DVT had no absolute or major contraindications for CDT. Of these 15 patients, only 33% were referred to a vascular specialist (4 to vascular surgery and 1 to IR). Two patients (13%) agreed to and underwent successful CDT. CONCLUSIONS: Although the majority of patients with acute lower extremity DVT diagnosed in the outpatient vascular laboratory were not candidates for thrombolysis, one-third of those who may have benefited from CDT were referred to a vascular specialist to discuss lytic therapy. Given the potential benefits of CDT, it is imperative that patients with acute iliofemoral or extensive femoral DVT be offered an evaluation by a vascular specialist to optimize outcomes after this diagnosis. PMID- 29499354 TI - Anatomical Suitability of the GORE EXCLUDER Iliac Branch Endoprosthesis in Japanese Patients with Common Iliac Aneurysms Treated by Standard EXCLUDER Endografts. AB - BACKGROUND: The EXCLUDER iliac branch endoprosthesis (IBE) is designed to exclude a common iliac artery (CIA) aneurysm (CIAA), preserving the internal iliac artery (IIA) during endovascular aneurysm repair (EVAR). We assessed the anatomical suitability of the IBE in patients whose aortoiliac aneurysms (AIAs) had already been treated with a standard EXCLUDER endograft, compromising their IIAs. METHODS: From June 2007 to January 2017, 202 patients underwent elective EVAR for AIAs with the EXCLUDER endograft at our institute. Among them, patients whose IIAs were embolized for the external iliac artery (EIA) landing were included in this study. Patients with solitary or small CIAAs of <25 mm in diameter were excluded. Preoperative computed tomography scans were analyzed using a 3D workstation to evaluate the suitability of the IBE when following its instructions for use. RESULTS: Twelve patients with bilateral CIAAs and 24 patients with unilateral CIAAs were enrolled in this study. Among the 48 iliac segments, 15 (31.3%) were eligible for unilateral IBE implantation. A total of 40% of the CIAAs did not have a large enough luminal diameter, which was the most common barrier to the use of the unilateral IBE in our patients. Among the iliac segments of the 12 patients with bilateral CIAAs, 2 (16.7%) were suitable for bilateral implantation. An insufficient length between the renal artery (RA) and the IIA was the major barrier to the use of bilateral IBE. CONCLUSIONS: A total of 31.3% of the compromised IIAs could have been preserved if the IBE was used. Bilateral implantation seemed possible in a limited number of cases. In addition to a small CIA lumen, an insufficient length between the RA and the IIA was also a predominant anatomical limitation, especially when bilateral implantation was planned. PMID- 29499355 TI - Therapeutic approaches to control tissue repair and fibrosis: Extracellular matrix as a game changer. AB - Organ fibrosis is characterized by the accumulation of disorganized and stiff extracellular matrix (ECM) and represents the final stage of several life threatening diseases. The progressive replacement of normal tissue by fibrotic ECM impedes organ functionality to the point of failure. Fibrosis affects millions of people worldwide with no effective cure for various reasons: (a) Due to the lack of clinical biomarkers and non-invasive detection methods fibrosis is often diagnosed too late, when organs are already destroyed beyond repair. (b) Fibrosis can be understood as dysregulated tissue repair that evolved robust programs to be able to respond to various injury scenarios. The redundant nature of these programs often evades linear therapeutic strategies. (c) Fibrosis perpetuates itself by establishing conditions that activate normal into fibrogenic cells which, in turn, create a pro-fibrotic environment. ECM takes center stage in the process of fibrosis as a defining feature and thus potential diagnostic biomarker. The ECM is also a main promoter of the disease process by providing lasting physicochemical pro-fibrotic cues to residing and recruiting cells. Effective anti-fibrotic therapies will need to take the lasting (mis-) instructive character of scar ECM into account. To restore organ functionality, it will be important to (re)turn fibrotic scar into functional ECM, for instance by dissolving fibrotic ECM and delivering cells with regenerative potential. PMID- 29499357 TI - Extracellular matrix functions in lung cancer. PMID- 29499358 TI - The pro-apoptotic protein Bmf co-operates with Bim and Puma in neuron death induced by beta-amyloid or NGF deprivation. AB - The pro-apoptotic Bcl-2 homology 3 domain only (BH3-only) proteins are central regulators of cell death in various physiological and pathological conditions, including Alzheimer's disease (AD). Bcl-2 modifying factor (Bmf) is one such BH3 only protein that is implicated in various death paradigms such as anoikis, seizures, cancer and autoimmunity. It also co-operates with other BH3-only proteins such as Bim in various death paradigms. However, its role in neurodegeneration is under-investigated. Here, we report for the first time the essential role of Bmf and its co-operativity with direct activator BH3-only proteins Bim and Puma in neuron death induced by beta-amyloid (Abeta) toxicity or NGF deprivation. Oligomeric Abeta is main pathologic species in AD and NGF deprivation is relevant for both developmental as well as pathologic neuron death. We find that Bmf over-expression causes cell death and Bmf knockdown protects neurons against death evoked by Abeta or NGF deprivation. We also find that Bmf co-operates with other important BH3-only proteins such as Bim and Puma in neuron death induced by Abeta or NGF deprivation. Simultaneous knocking down of these molecules by their respective shRNAs provide enhanced protection against Abeta. Taken together, our results elucidate the essential role of Bmf and its co operative effects with already known neuron death inducers, Bim and Puma, in neuron death evoked by Abeta treatment or NGF deprivation. PMID- 29499359 TI - Statin utilization and lipid goal attainment in high or very-high cardiovascular risk patients: Insights from Italian general practice. AB - BACKGROUND AND AIMS: Statin utilization and lipid goal achievement were estimated in a large sample of Italian patients at high/very-high cardiovascular (CV) risk. METHODS: Patients aged >=18 years with a valid low-density lipoprotein cholesterol (LDL-C) measurement in 2015 were selected from the IMS Health Real World Data database; non-high-density lipoprotein cholesterol (non-HDL-C) was assessed in those with available total cholesterol measurements. Index dates were defined as the last valid lipid measurement in 2015. Patients were hierarchically classified into mutually exclusive risk categories: heterozygous familial hypercholesterolemia (primary and secondary prevention), atherosclerotic CV disease (including recent acute coronary syndrome [ACS], chronic coronary heart disease, stroke, and peripheral arterial disease), and diabetes mellitus (DM) alone. Statin and non-statin lipid-modifying therapy (LMT) use, and European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guideline recommended goal attainment, were assessed. RESULTS: Among 66,158 patients meeting selection criteria, the overall rate of LMT prescriptions was 53.3%, including 7.7% on high-intensity statin therapy. Statin use was highest for recent ACS and lowest for DM alone. LDL-C goal attainment was 16.0% for <1.8 mmol/l and 45.0% for <2.5 mmol/l; 24.3% reached non-HDL-C <2.6 mmol/l and 52.2% were at <3.3 mmol/l. Goal achievement was greatest with high-intensity statin use. CONCLUSIONS: Statin use in this cohort was consistent with previous reports in Italian patients at high/very-high CV risk, and low relative to statin use in other European countries. The low rate of ESC/EAS lipid goal attainment observed was consistent with outcomes of other European studies. PMID- 29499360 TI - Ursolic acid prevents angiotensin II-induced abdominal aortic aneurysm in apolipoprotein E-knockout mice. AB - BACKGROUND AND AIMS: Abdominal aortic aneurysms (AAA) is a chronic inflammatory disease in which signal transducer and activator of transcription 3 (STAT3), and disintegrin and metalloproteinase 17 (ADAM17) play important roles. However, it remains unclear whether ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid, can have an impact on STAT3 and ADAM17 and hence influence the formation of AAA. The objective of this study was to characterize the potential effect of UA on the pathogenesis of AAA and on STAT3 and ADAM17. METHODS: Male ApoE-/- mice were infused with angiotensin II (AngII) (1000 ng/kg/min) for 4 weeks to induce AAAs. Daily intragastric gavage with 100 mg/kg UA or tap water containing Tween 80 as controls was provided. Immunohistochemistry, cell viability assay, colony formation, wound healing assay, and Western blot were used to explore the potential effect of UA on AAA. RESULTS: UA decreased the incidence of AngII-induced AAA in mice. UA alleviated the degradation of elastin fibers and inflammation and decreased the expression of MMP2, MMP9, ADAM17 and phospho-STAT3 (pSTAT3) in aorta of mice induced with AngII. UA inhibited the constitutive and stimuli-induced (AngII and tumor necrosis factor-alpha) expression of MMP2, MMP9, ADAM17 and pSTAT3 in vascular smooth muscle cells (VSMCs). Furthermore, UA decreased cell viability, and suppressed colony formation and wound healing in vitro. CONCLUSIONS: We demonstrated that UA ameliorated the severity of AAA and exhibited an inhibitory effect on the expression of pSTAT3 and ADAM17. UA might emerge as a promising agent contributing to the prevention or treatment of AAA. PMID- 29499361 TI - Post-Discharge Opioid Prescribing and Use after Common Surgical Procedure. AB - BACKGROUND: The number of deaths from prescription opioids in the US continues to increase and remains a major public health concern. Opioid-related deaths parallel prescribing trends, and postoperative opioids are a significant source of opioids in the community. Our objective was to identify opioid prescribing and use patterns after surgery to inform evidence-based practices. STUDY DESIGN: Data from a 340-bed academic medical institution and its affiliated outpatient surgical facility included retrospective medical record data and prospective telephone questionnaire and medical record data. Retrospective data included patients discharged after 1 of 19 procedure types, from July 2015 to June 2016 (n = 10,112). Prospective data included a consecutive sample of general and orthopaedic surgery and urology patients undergoing 1 of 13 procedures, from July 2016 to February 2017 (n = 539). Primary outcomes were the quantity of opioid prescribed and used in morphine milligram equivalents (MME), and the proportion of patients receiving instructions on disposal and nonopioid strategies. RESULTS: In the retrospective dataset, 76% of patients received an opioid after surgery, and 87% of prescriptions were prescribed by residents or advanced practice providers. Median prescription size ranged from 0 to 503 MME, with wide interquartile ranges (IQR) for most procedures. In the prospective dataset, there were 359 participants (67% participation rate). Of these, 92% of patients received an opioid and the median proportion used was 27%, or 24 MME (IQR 0 to 96). Only 18% of patients received disposal instructions, while 84% of all patients received instructions on nonopioid strategies. CONCLUSIONS: Median opioid use after surgery was 27% of the total prescribed, and only 18% of patients reported receiving disposal instructions. Significant variability in opioid prescribing and use after surgery warrants investigation into contributing factors. PMID- 29499356 TI - A role for proteoglycans in vascular disease. AB - The content of proteoglycans (PGs) is low in the extracellular matrix (ECM) of vascular tissue, but increases dramatically in all phases of vascular disease. Early studies demonstrated that glycosaminoglycans (GAGs) including chondroitin sulfate (CS), dermatan sulfate (DS), keratan sulfate (KS) and heparan sulfate (HS) accumulate in vascular lesions in both humans and in animal models in areas of the vasculature that are susceptible to disease initiation (such as at branch points) and are frequently coincident with lipid deposits. Later studies showed the GAGs were covalently attached to specific types of core proteins that accumulate in vascular lesions. These molecules include versican (CSPG), biglycan and decorin (DS/CSPGs), lumican and fibromodulin (KSPGs) and perlecan (HSPG), although other types of PGs are present, but in lesser quantities. While the overall molecular design of these macromolecules is similar, there is tremendous structural diversity among the different PG families creating multiple forms that have selective roles in critical events that form the basis of vascular disease. PGs interact with a variety of different molecules involved in disease pathogenesis. For example, PGs bind and trap serum components that accumulate in vascular lesions such as lipoproteins, amyloid, calcium, and clotting factors. PGs interact with other ECM components and regulate, in part, ECM assembly and turnover. PGs interact with cells within the lesion and alter the phenotypes of both resident cells and cells that invade the lesion from the circulation. A number of therapeutic strategies have been developed to target specific PGs involved in key pathways that promote vascular disease. This review will provide a historical perspective of this field of research and then highlight some of the evidence that defines the involvement of PGs and their roles in the pathogenesis of vascular disease. PMID- 29499362 TI - Anaemia in patients with chronic liver disease and its association with morbidity and mortality following liver transplantation. AB - : Pre-operative anaemia and the need for intra-operative transfusion have been associated with increased morbidity and mortality following cardiac and major non cardiac surgery. Anaemia is highly prevalent in patients with severe chronic liver disease. Whether this correlates with an altered morbidity and mortality following liver transplant has not been established. METHODS: Prospectively collected data was analysed for the period 1998-2012. Donor and recipient characteristics, blood profiles and complications were recorded. Graft and patient survival was calculated. All patients were followed up for 1 year or until death. Pre-operative haemoglobin levels were correlated with patient demographics and outcome using a binary logistic regression analysis. RESULTS: Pre-operative anaemia, according to WHO criteria, occurred in 73% of patients. Anaemia was more common with advanced liver disease (higher MELD score). As MELD score increased, Haemoglobin levels dropped. Anaemic patients were more commonly transfused (p < 0.001), spent longer ventilated (7 day vs 5 days, p = 0.005) and required longer ITU stays (8 days vs 6 days, p = 0.015). Pre-operative anaemia did not correlate with patient morbidity or mortality. CONCLUSIONS: Reduced haemoglobin levels reflect the severity of chronic liver disease but are not an independent risk factor for a poor outcome following liver transplantation. PMID- 29499363 TI - Maintenance versus non-maintenance intravesical Bacillus Calmette-Guerin instillation for non-muscle invasive bladder cancer: A systematic review and meta analysis of randomized clinical trials. AB - BACKGROUND: It is not clear whether maintenance Bacillus Calmette-Guerin (BCG) is necessary for intermediate- or high-risk non-muscle-invasive bladder cancer (NMIBC). This systematic review and meta-analysis aimed to illustrate the effects of maintenance BCG for intermediate- or high-risk NMIBC. METHODS: A comprehensive literature search of PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov databases and International Clinical Trials Register (ICTRP) Search was conducted to identify relevant randomized controlled trials (RCTs) that have assessed the efficacy of maintenance or non-maintenance BCG therapy for patients with NMIBC. The maintenance group first received induction BCG instillations, and subsequently received BCG intravesical instillations regularly for at least 1 year, while the control group only received induction BCG instillations. Systematic review and meta-analysis were performed according to Preferred Reporting Items for Systematic Reviews and Meta-analysis Criteria. RESULTS: Ten RCTs were eligible in this systematic review. The meta-analysis showed that induction BCG followed by maintenance BCG instillation after transurethral resection (TUR) could reduce the risk ratios of tumor recurrence by 21% (RR = 0.79; 95% CI 0.70-0.89; P < 0.0001) and prolong recurrence-free survival (RFS) by 33% (HR: 0.67; 95% CI, 0.54-0.82; P < 0.001), compared with non-maintenance BCG. It could also reduce the risk ratios of tumor progression (RR = 0.81; 95% CI 0.68 0.97; P = 0.02). However, these pooled results should be considered with caution since the quality of evidences for outcomes ranged low. Subgroup analysis implied that different durations of maintenance BCG instillations might be one of the sources of potential clinical heterogeneity of included studies. Begg's funnel plot and Egger's test did not reveal any evidence of publication bias in this meta-analysis. CONCLUSIONS: Induction BCG followed by maintenance BCG instillation after TUR, compared with induction BCG along, can reduce the risk ratios of tumor recurrence and tumor progression, and prolong RFS. However, these results with a lower level of evidence should be treated with caution. The optimal maintenance schedule has yet to be determined and a large multi institutional study in intermediate- and high-risk patients is also needed to determine the optimal maintenance schedule. PMID- 29499364 TI - Study of medical education in 3D surgical modeling by surgeons with free open source software: Example of mandibular reconstruction with fibula free flap and creation of its surgical guides. AB - INTRODUCTION: Benefits of 3D printing techniques, biomodeling and surgical guides are well known in surgery, especially when the same surgeon who performed the surgery participated in the virtual surgical planning. Our objective was to evaluate the transfer of know how of a neutral 3D surgical modeling free open source software protocol to surgeons with different surgical specialities. METHODS: A one-day training session was organised in 3D surgical modeling applied to one mandibular reconstruction case with fibula free flap and creation of its surgical guides. Surgeon satisfaction was analysed before and after the training. RESULTS: Of 22 surgeons, 59% assessed the training as excellent or very good and 68% considered changing their daily surgical routine and would try to apply our open-source software protocol in their department after a single training day. The mean capacity in using the software improved from 4.13 on 10 before to 6.59 on 10 after training for OsiriX(r) software, from 1.14 before to 5.05 after training for Meshlab(r), from 0.45 before to 4.91 after training for Netfabb(r) and from 1.05 before and 4.41 after training for Blender(r). According to surgeons, using the software Blender(r) became harder as the day went on. DISCUSSION: Despite improvement in the capacity in using software for all participants, more than a single training day is needed for the transfer of know how on 3D modeling with open-source software. Although the know-how transfer, overall satisfaction, actual learning outcomes and relevance of this training were appropriated, a longer training including different topics will be needed to improve training quality. PMID- 29499365 TI - Frontalis suspension using autogenous temporal fascia by Fox technique. AB - INTRODUCTION: Severe ptosis of more than 4mm with poor levator function of less than 4mm is treated via the frontalis muscle suspension technique using autogenous temporal fascia. TECHNICAL NOTE: The surgery was performed under general anaesthesia. The eyelid crease was incised and the tarsus exposed. An incision centered on the mid-pupillary level was then made just above the eyebrow with exposure of the frontalis muscle. The temporal fascia strip was sutured to the tarsus at three points. Every free end of the strip was then slid through the adjacent forehead subcutaneous tunnel to emerge together through the medial forehead incision. The eyelid crease was re-formed by suturing the skin with the graft. DISCUSSION: Frontalis suspension using autologous material is a harmless procedure, which does not alter the upper eyelid structures. It is an effective procedure in the long-term. PMID- 29499367 TI - Uses of biologics in allergic diseases: What to choose and when. PMID- 29499366 TI - Development and Cross-Validation of the Short Form of the Cultural Competence Scale for Nurses. AB - PURPOSE: To develop and validate the short form of the Korean adaptation of the Cultural Competence Scale for Nurses. METHODS: To shorten the 33-item Cultural Competence Scale for Nurses, an expert panel (N = 6) evaluated its content validity. The revised items were pilot tested using a sample of nine nurses, and clarity was assessed through cognitive interviews with respondents. The original instrument was shortened and validated through item analysis, exploratory factor analysis, convergent validity, and reliability using data from 277 hospital nurses. The 14-item final version was cross-validated through confirmatory factor analysis, convergent validity, discriminant validity, known-group comparisons, and reliability using data from 365 nurses belonging to 19 hospitals. RESULTS: A 4-factor, 14-item model demonstrated satisfactory fit with significant factor loadings. The convergent validity between the developed tool and transcultural self-efficacy was significant (r = .55, p < .001). The convergent validity evaluated using the Average Variance Extracted and discriminant validity were acceptable. Known-group comparisons revealed significant differences in the mean scores of the groups who spent more than one month abroad (p = .002) were able to communicate in a foreign language (p < .001) and had education to care for foreign patients (p = .039). Cronbach's alpha was .89, and the reliability of the subscales ranged from .74 to .91. CONCLUSION: The Cultural Competence Scale for Nurses-Short Form demonstrated good reliability and validity. It is a short and appropriate instrument for use in clinical and research settings to assess nurses' cultural competence. PMID- 29499368 TI - Human factors study in untrained adolescents comparing a recently approved single dose epinephrine prefilled syringe with an approved autoinjector. PMID- 29499370 TI - Epinephrine auto-injector needle lengths: Can both subcutaneous and periosteal/intraosseous injection be avoided? AB - BACKGROUND: Epinephrine should be administered intramuscularly in the anterolateral aspect of the thigh. The length of the epinephrine auto-injector (EAI) needle should ensure intramuscular injection. OBJECTIVE: To discuss suitable EAI needle lengths based on ultrasound measurements related to weight. METHODS: The skin-to-muscle distance (STMD) and skin-to-bone distance (STBD) were measured by ultrasound in the mid-third of the anterolateral area of the right thigh when applying high pressure (8 lb; high-pressure EAI [HPEAI]) or low pressure (low-pressure EAI [LPEAI]) on the ultrasound probe. The study included 302 children and adolescents and 99 adults. The maximum and minimum STMD and the maximum and minimum STBD were estimated. RESULTS: Using HPEAIs, the risk of periosteal or intraosseous penetration was 32% in children weighing less than 15 kg. The risk of subcutaneous injection was 12% in adolescents and 33% in adults. With LPEAIs, there was no risk of periosteal or intraosseous injection and the risk of subcutaneous injections in adolescents and adults was lower at 2% and 10%, respectively. A new EAI for injection in small children would have no risk of periosteal or intraosseous injection but would have 71% chance of subcutaneous deposit of epinephrine. CONCLUSION: Common HPEAIs have a high risk of periosteal or intraosseous penetration in children and subcutaneous injections in overweight and obese adults. LPEAIs have some risk of subcutaneous injection in adults. HPEAIs with 0.1 mg of epinephrine and shorter needles have no risk of periosteal or intraosseous injection but have a high risk of subcutaneous deposit. For adult or overweight or obese patients, HPEAIs and LPEAIs should have longer needles. Future studies should focus on triggering pressures and variations in needle length. PMID- 29499369 TI - The eosinophil: For better or worse, in sickness and in health. PMID- 29499371 TI - Association between involuntary weight loss with low muscle mass and health related quality of life in community-dwelling older adults: Nationwide surveys (KNHANES 2008-2011). AB - OBJECTIVES: To investigate the relationship between involuntary weight loss with low muscle mass and health-related quality of life in a large representative sample of older adults. METHODS: A nationwide cross-sectional study based on data from the Korea National Health and Nutritional Examination Survey, 2008 to 2011. Study participants included 2249 individuals aged >=70 years. The participants reported an unintentional weight loss >3 kg in the past year. Appendicular lean mass was measured using dual-energy X-ray absorptiometry and calculated with the appendicular lean mass index. Health-related quality of life was measured using the EuroQol-5 dimension (EQ-5D) instrument. Univariate and multivariate survey logistic regression models were used to calculate odds ratios (OR) with 95% confidence intervals (95% CI) for the lowest quintile of the EQ-5D index. RESULTS: In total, 39.1% of participants were male and 60.9% were female. The weighted mean age was 75.6 years (95% CI; 75.3-75.9). Clinically significant weight loss is typically 5% of one's body weight; average, 2.8 kg (3.1 kg for men; 2.7 kg, women) for our participants. Compared with the normal reference group and after adjusting for potential confounders, the ORs for the lowest quintile of the EQ-5D indices were 1.39 (95% CI, 0.92-2.10), 2.56 (95% CI, 1.56 4.18), and 3.40 (95% CI, 2.05 to 5.63) for the low muscle mass, involuntary weight loss, involuntary weight loss with low muscle mass groups, respectively. CONCLUSION: Involuntary weight loss combined with low muscle mass was more closely associated with poor quality of life than involuntary weight loss alone in community-dwelling older adults. PMID- 29499372 TI - Frailty and health status of older individuals in three European countries: The COURAGE cross-sectional study. AB - BACKGROUND AND AIM: Frailty is characterized by several deficits in multiple health related domains. Although cognition is among the important components of frailty, there is lack of evidence on the role of specific neuro-cognitive dimensions. The primary aim of the present work was to evaluate the multidimensional definition of frailty, and to assess whether neuro-cognitive function is a constituent of the frailty syndrome among adults aged >=50 years living in three European countries. As a secondary aim, the construct validity of the created frailty index was tested (with inpatient and outpatient hospitalization), as well as its determinants. METHODS: Data were obtained from a cross-sectional, community-based, nationally-representative survey conducted in Finland, Poland and Spain (n = 7987 individuals aged >=50 years). Socio demographic, clinical, lifestyle and social factors were assessed using validated procedures. Cognitive function was assessed with the following tests: learning and short-term memory, working memory and verbal fluency. A frailty index was constructed based on 31 frailty attributes. Principal component analysis was used to identify the components of the frailty index. Logistic and Poisson regression analysis was also conducted. RESULTS: The factor analysis on the components of the index extracted three main dimensions for frailty (disability and daily functioning, cognitive function, chronic health conditions), confirming the multiple dimensions of frailty. Various socio-demographic (e.g., financial status, education level) and lifestyle habits (alcohol consumption) were related with frailty. The presence of frailty was associated with 3.1 times higher odds for inpatient hospitalization (95%CI 2.75 to 3.51). Frailty was also related with higher frequency of outpatient visits. CONCLUSIONS: These findings suggest that frailty is a multidimensional concept with three major dimensions. Neuro congitive function seems to be a separate dimension of the frailty syndrome. Smoking habits and alcohol intake were positively related with frailty while inpatient and outpatient hospitalization were found to be associated to the level of frailty. PMID- 29499373 TI - The associations between liver enzymes and the risk of metabolic syndrome in the elderly. AB - BACKGROUND: Studies have demonstrated that liver enzymes are associated with metabolic syndrome (MetS). However, little information is available regarding these relationships in elderly populations. Our present study aimed to explore the associations between liver enzymes and the risk of MetS in elderly populations. METHODS: This cross-sectional study included 1444 elder participants (970 men and 474 women) who attended annual physical examinations. Univariate and multivariate logistic regressions were performed to estimate the associations between liver enzymes and the risk of MetS and its components according to quartiles of the concentration of each liver enzyme. RESULTS: The prevalence of MetS and its components increased remarkably with increasing quartiles of alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT) and alkaline phosphatase (ALP) but not with aspartate aminotransferase (AST) in the elderly. Compared with subjects in the bottom quartile, the adjusted odds ratio for MetS in the highest ALT, GGT and ALP quartiles were 1.78 (95% CI 1.21-2.61), 2.58 (95% CI 1.77-3.78) and 1.85 (95%CI 1.27-2.70) respectively. No statistically significant increases in the odds ratio for MetS according to increased quartiles of AST were found in either the univariate or multivariate logistic regression analyses. CONCLUSIONS: Elevated liver enzymes levels (mainly ALT, GGT and ALP but not AST) are positively associated with the prevalence of MetS in elderly populations. PMID- 29499374 TI - Borago officinalis L. attenuates UVB-induced skin photodamage via regulation of AP-1 and Nrf2/ARE pathway in normal human dermal fibroblasts and promotion of collagen synthesis in hairless mice. AB - Ultraviolet B (UVB) irradiation is regarded as the main cause of skin photodamage. After exposure to UVB irradiation, collagen degradation is accelerated by upregulation of matrix metalloproteinases (MMPs), and collagen synthesis is decreased via downregulation of transforming growth factor (TGF) beta1 signaling. Borago officinalis L. (BO) is an annual herb with medicinal and culinary applications. Although BO has been demonstrated to have antioxidant and anti-inflammatory activities, its potential anti-photoaging effects have not been examined. In this study, we examined the protective effects of BO against skin photodamage in UVB-exposed normal human dermal fibroblasts (NHDFs) in vitro and hairless mice in vivo. BO downregulated the expression of MMP-1, MMP-3, and IL-6, and enhanced TGF-beta1 by modulating activator protein (AP-1) and nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling in UVB-irradiated NHDFs. We also found that dietary BO reduced wrinkle formation, epidermal thickness, and erythema in UVB-exposed skin. Moreover, skin hydration and collagen synthesis were improved by dietary BO treatment. Our results demonstrate that BO can be used in functional foods, cosmetic products, and medicines for prevention and treatment of UVB-induced skin photodamage. PMID- 29499375 TI - Metabolic engineering of mevalonate-producing Escherichia coli strains based on thermodynamic analysis. AB - Thermodynamic states of the central metabolism in a metabolically engineered Escherichia coli strain producing mevalonate (MVA) were studied to identify metabolic reactions with regulatory function for improvement of the specific rate of MVA production. Intracellular concentrations of metabolites were determined for E. coli strains expressing Enterococcus faecalis genes mvaE and mvaS (strain MV) by gas chromatography (GC)- and liquid chromatography (LC)-mass spectrometry (MS). Mixtures of 13C-labeled metabolites served as internal standards were prepared from E. coli cultured in a completely 13C-labeled medium. Based on the concentration data, the change in Gibbs energy (DeltaG) and substrate saturation ([S]/KM) were calculated for each metabolic reaction and then compared between the control and MVA-producing strains. The thermodynamic and kinetic analyses showed that further activation of thermodynamically feasible reactions in the upper part of glycolysis and the pentose phosphate pathway seems difficult and that metabolic bypassing to the Entner-Doudoroff pathway was a promising strategy to improve the acetyl coenzyme A (AcCoA) and NADPH supply required for MVA biosynthesis. Strain MV-DeltaGndDeltaGntR was constructed by deletion of the gnd and gntR genes, which respectively encode 6-phosphogluconate dehydrogenase and a negative regulator of the expression of two enzyme genes responsible for the Entner-Doudoroff pathway. Cultivation in the nongrowth phase revealed that the yield and specific production rate of MVA increased to 0.49 +/- 0.01 Cmol (Cmol glucose)-1 and 2.61 +/- 0.10 mmol (g dry cell weight)-1 h-1, which were 113% and 158% that of the MV strain, respectively. PMID- 29499376 TI - Improving Resident Knowledge in Pediatric and Adolescent Gynecology: An Evaluation of the North American Society for Pediatric and Adolescent Gynecology Short Curriculum. AB - STUDY OBJECTIVE: Resident education in pediatric and adolescent gynecology (PAG) is challenging. It encompasses patients from neonates to young adults with different disorders involving multiple subspecialties. Residents have inadequate exposure to PAG topics and report lack of knowledge in this area. The objective of this study was to determine if the North American Society for Pediatric and Adolescent Gynecology (NASPAG) Short Curriculum improves self-reported knowledge in PAG among obstetrics and gynecology (ObGyn), family medicine, and pediatric residents. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: Participants were 47 US ObGyn, family medicine, and pediatric residency training programs across a 4-month study window, from September to December 2016. The NASPAG Short Curriculum was distributed to them with a request to complete a retrospective pre- and post-test survey. Primary outcome measure was improvement in self-perceived knowledge after exposure to the curriculum. RESULTS: Forty eight programs responded to the study comprising a total of 1130 residents. One program was excluded because of logistical barriers to the distribution of study incentive. In total, 1080 residents were invited and 103 chose to participate (10% response rate); 68 residents completed all survey questions to be included in the final analysis. After completing the curriculum, self-reported knowledge improved in all 10 learning objectives, across all 3 specialties (47% [32/68] to 82% [56/68]; P < .01). Pre-test knowledge correlated with previous clinical exposure to PAG patients, but did not correlate with year of residency training, type of residency, or previous PAG lectures. CONCLUSION: Significant deficiencies exist regarding self-reported knowledge of core PAG topics among ObGyn, family medicine, and pediatric residents. Use of the NASPAG Short Curriculum improves self-reported knowledge in PAG trainees across all 3 specialties. PMID- 29499377 TI - Recent advances in brain tumor therapy: application of electrospun nanofibers. AB - Despite much effort to treat glioblastoma multiforme (GBM), the median survival of patients has not significantly improved. The high rate of tumor recurrence after tumor resection and the blood-brain barrier (BBB) decrease the treatment efficacy. Local drug delivery at the surgical resection site via implantable electrospun nanofibers not only circumvents the BBB, but can also reduce the rate of tumor recurrence. Nanofibers can provide a sustained release and a high concentration of chemotherapeutics at the tumor vicinity, while decreasing their systemic exposure and toxicity. In another scenario, aligned nanofibers can mimic the topographical features of the brain extracellular matrix (ECM), which can be utilized for in vitro studies on GBM cell migration. This strategy is beneficial to investigate the interactions of tumor cells with the microenvironment which has a dominant role in regulating tumor formation, progression, and metastasis. PMID- 29499378 TI - The integrated stress response system in cardiovascular disease. AB - The integrated stress response system represents an ancillary, extremely conserved signalling pathway present in virtually all eukaryotic cells, which plays an important part in the pathophysiology of several disorders such as cancer and neurodegeneration. However, its role in the cardiovascular system remains largely elusive. Hence, this review aims to acknowledge recent findings regarding the action of the eIF2alpha kinases in the cardiovascular system and their role in the pathophysiology of related disorders. PMID- 29499379 TI - Pediatric Program Leadership's Contribution Toward Resident Wellness. AB - BACKGROUND: Residency program leaders are required to support resident well being, but often they do not receive training in how to do so. OBJECTIVE: To determine frequency in which program leadership provides support for resident well-being, comfort in supporting resident well-being, and factors associated with need for additional training in supporting resident well-being. METHODS: National cross-sectional web-based survey in June 2015 of pediatric program directors, associate program directors, and coordinators about their experiences supporting resident well-being. Univariate and bivariate descriptive statistics compared responses between groups. Generalized linear modeling, adjusting for program region, size, program leadership role, and number of years in role determined factors associated with need for additional training. RESULTS: The response rate was 39.3% (322/820). Most respondents strongly agreed that supporting resident well-being is an important part of their role, but few reported supporting resident well-being as part of their job description. Most reported supporting residents' clinical, personal, and health issues at least annually, and in some cases weekly, with 72% spending >10%of their time on resident well-being. Most program leaders desired more training. After adjusting for level of comfort in dealing with resident well-being issues, program leaders more frequently exposed to resident well-being issues were more likely to desire additional training (P < .02). CONCLUSIONS: Program leaders spend a significant amount of time supporting resident well-being. Although they think that supporting resident well-being is an important part of their job, opportunities exist for developing program leaders through including resident wellness on job descriptions and training program leaders how to support resident well-being. PMID- 29499380 TI - Teaching Pediatric Otoscopy Skills to Pediatric and Emergency Medicine Residents: A Cross-Institutional Study. AB - OBJECTIVE: To evaluate a pediatric otoscopy curriculum with the use of outcome measures that included assessment of skills with real patients. METHODS: Thirty three residents in an intervention group from 2 institutions received the curriculum. In the previous year, 21 residents in a nonintervention group did not receive the curriculum. Both groups were evaluated at the beginning and end of their internship years with the use of the same outcome assessments: 1) a written test, 2) an objective standardized clinical examination (OSCE), and 3) direct observation of skills in real patients with the use of a checklist with established validity. RESULTS: The intervention group had a significant increase in percentage reaching minimum passing levels between the beginning and end of the internship year for the written test (12% vs 97%; P < .001), OSCE (0% vs 78%; P < .001), and direct observation (0% vs 75%; P < .001); significant mean percentage gains for the written test (21%; P < .001), OSCE (28%; P < .001), and direct observation (52%; P = .008); and significantly higher (P < .001) mean percentage gains than the nonintervention group on the written test, OSCE, and direct observation. The nonintervention group did not have a significant increase (P = .99) in percentage reaching minimum passing levels, no significant mean percentage gains in the written test (2.7%; P = .30) and direct observation (6.7%; P = .61), and significant regression in OSCE (-5.2%; P = .03). CONCLUSIONS: A pediatric otoscopy curriculum with multimodal outcome assessments was successfully implemented across different specialties at multiple institutions and found to yield gains, including in skills with real patients. PMID- 29499382 TI - Chronic exertional compartment syndrome in hands successfully treated with botulinum toxin-A: A case. PMID- 29499381 TI - Mixed qualitative and quantitative approach for validating an information booklet before total hip arthroplasty. AB - OBJECTIVE: Providing patients with validated information before total hip arthroplasty may help lessen discrepancies between patients' expectations and the surgical result. This study sought to validate an information booklet for candidates for hip arthroplasty by using a mixed qualitative and quantitative approach based on a panel of patients and a sample of healthcare professionals. METHODS: We developed a booklet in accordance with the standard methods and then conducted focus groups to collect the opinions of a sample of multidisciplinary experts involved in the care of patients with hip osteoarthritis. The number of focus groups and experts was determined according to the data saturation principle. A panel of patients awaiting hip arthroplasty or those in the immediate post-operative period assessed the booklet with self-reporting questionnaires (knowledge, beliefs, and expectations) and semi-structured interviews. RESULTS: All experts and both patient groups validated the booklet in terms of content and presentation. Semi-structured interviews were uninformative, especially for post-operative patients. Reading the booklet significantly (P<0.001) improved the knowledge scores in both groups, with no intergroup differences, but did not affect beliefs in either patient group. Only pre operative patients significantly changed their expectations. CONCLUSION: Our mixed qualitative and quantitative approach allowed us to validate a booklet for patients awaiting hip arthroplasty, taking into account the opinions of both patients and healthcare professionals. PMID- 29499383 TI - Home-based cycling program tailored to older people with lumbar spinal stenosis: Barriers and facilitators. AB - BACKGROUND: Lumbar-flexion-based endurance training, namely cycling, could be effective in reducing pain and improving function and health-related quality of life in older people with chronic low back pain. OBJECTIVES: To assess barriers and facilitators to home-based cycling in older patients with lumbar spinal stenosis (LSS). METHODS: We conducted a retrospective mixed-method study. Patients>=50 years old followed up for LSS from November 2015 to June 2016 in a French tertiary care center were screened. The intervention consisted of a single supervised session followed by home-based sessions of cycling, with dose (number of sessions and duration, distance and power per session) self-determined by patient preference. The primary outcome was assessed by a qualitative approach using semi-structured interviews at baseline and 3 months and was the identification of barriers and facilitators to the intervention. Secondary outcomes were assessed by a quantitative approach and were adherence monitored by a USB stick connected to the bicycle, burden of treatment assessed by the Exercise Therapy Burden Questionnaire (ETBQ) and clinical efficacy assessed by change in lumbar pain, radicular pain, disability, spine-specific activity limitation and maximum walking distance at 3 months. RESULTS: Overall, 15 patients were included and data for 12 were analyzed at 3 months. At baseline, the mean age was 70.9 years (95% CI: 64.9-76.8) and 9/15 patients (60.0%) were women. Barriers to cycling were fear of pain and fatigue, a too large bicycle, burden of hospital follow-up and lack of time and motivation. Facilitators were clinical improvement, surveillance and ease-of-use of the bicycle. Adherence remained stable overtime. The burden of treatment was low [mean ETBQ score: 21.0 (95% confidence interval: 11.5-30.5)]. At 3 months, 7/12 patients (58.3%) self reported clinical improvement, with reduced radicular pain and disability [mean absolute differences: -27.5 (-43.3 to -11.7), P<0.01 and -17.5 (-32.1 to -2.9), P=0.01, respectively]. CONCLUSIONS: For people with LSS, home-based cycling is a feasible intervention. PMID- 29499385 TI - The cell surface phenotype of human dendritic cells. AB - Dendritic cells (DC) are bone marrow derived leucocytes that are part of the mononuclear phagocytic system. These are surveillance cells found in all tissues and, as specialised antigen presenting cells, direct immune responses. Membrane molecules on the DC surface form a landscape that defines them as leucocytes and part of the mononuclear phagocytic system, interacts with their environment and directs interactions with other cells. This review describes the DC surface landscape, reflects on the different molecules confirmed to be on their surface and how they provide the basis for manipulation and translation of the potent functions of these cells into new diagnostics and immune therapies for the clinic. PMID- 29499384 TI - Exposure to a Brazilian pulp mill effluent impacts the testis and liver in the zebrafish. AB - While many studies have shown that pulp mill effluents can affect ovarian physiology in fish, far fewer studies have considered the effects in males. We conducted a lab study to examine the effects of effluent from a Brazilian pulp and paper mill on hepatic and testicular morphology and various aspects of testicular physiology in the zebrafish Danio rerio. Males were exposed to lab water (control) or 4% effluent for 14 days. Effluent exposure did not affect testis size as measured by the gonadosomatic index, but contributed to morphological changes in the seminiferous tubules. The number of cysts with histopathological changes was elevated in effluent-exposed fish and the number of cysts containing spermatids was significantly reduced. The testis of effluent exposed fish had reduced levels of lactate, elevated lactate dehydrogenase activity, increased levels of reactive oxygen species and reduced levels of phosphorylated P38 mitogen-activated protein kinase (pP38 MAPK). Separate studies showed that the addition of lactate to testicular tissue incubated in vitro increased the activation of P38 MAPK. Effluent exposure also increased vacuolization, necrosis, apoptosis, hyperemia, and fat infiltration of the hepatocytes. Collectively, we provide evidence of short term effects of pulp mill effluent on testicular and hepatic physiology and biochemistry in the zebrafish. PMID- 29499386 TI - Oocyte-to-zygote transition. PMID- 29499387 TI - Complement in leucocyte development and function. PMID- 29499388 TI - Muscle activation and sound during voluntary single coughs and cough peals in healthy volunteers: Insights into cough intensity. AB - Very few studies have addressed how coughing varies in intensity. We assessed the influence of cough effort and operating volume on the mechanics of coughing using respiratory muscle surface electromyography (EMG), oesophageal/gastric pressures and cough sounds recorded from 15 healthy subjects [8 female, median age 30 (IQR 30-50)years] performing 120 voluntary coughs from controlled operating volume/effort and three cough peals. For single coughs, low operating volumes and high efforts were associated with the highest EMG activity (p < 0.001); the resultant pressures increased with effort but volume had little influence. In contrast, cough sounds increased with both volume and effort. During cough peals, EMG fell initially, increasing towards the end of peals, pressures remained stable and sound parameters fell steadily to the end of the peal. In conclusion, effort and operating volume have important influences on cough mechanics but modulate muscle activation, pressure and cough sound amplitude and energy differently. Consequently, these cough sound parameters poorly represent voluntary cough mechanics and have limited potential as a surrogate intensity measure. PMID- 29499389 TI - IPVS statement moving towards elimination of cervical cancer as a public health problem. PMID- 29499390 TI - Activation of neutrophils by Chlamydia trachomatis-infected epithelial cells is modulated by the chlamydial plasmid. AB - The obligate intracellular bacterium Chlamydia trachomatis is the most common bacterial agent of sexually transmitted disease world-wide. Chlamydia trachomatis primarily infects epithelial cells of the genital tract but the infection may be associated with ascending infection. Infection-associated inflammation can cause tissue damage resulting in female infertility and ectopic pregnancy. The precise mechanism of inflammatory tissue damage is unclear but earlier studies implicate the chlamydial cryptic plasmid as well as responding neutrophils. We here rebuilt the interaction of Chlamydia trachomatis-infected epithelial cells and neutrophils in-vitro. During infection of human (HeLa) or mouse (oviduct) epithelial cells with Chlamydia trachomatis, a soluble factor was produced that attracted neutrophils and prolonged neutrophil survival, independently of Toll like receptor signaling but dependent on the chlamydial plasmid. A number of cytokines, but most strongly GM-CSF, were secreted at higher amounts from cells infected with plasmid-bearing, compared to plasmid-deficient, bacteria. Blocking GM-CSF removed the secreted pro-survival activity towards neutrophils. A second, neutrophil TNF-stimulatory activity was detected in supernatants, requiring MyD88 or TRIF independently of the plasmid. The results identify two pro-inflammatory activities generated during chlamydial infection of epithelial cells and suggest that the epithelial cell, partly through the chlamydial plasmid, can initiate a myeloid immune response and inflammation. PMID- 29499391 TI - Effects of PACT using phenothiazine-derived drugs and red light on the macrophage x S. aureus interface. AB - The aim of this study was to evaluate the lethal potential of macrophages infected with Staphylococcus aureus after PACT (Photochemical Antimicrobial Chemotherapy) using phenothiazine derivatives (a solution containing 1:1 methylene blue and O toluidine blue) and laser (660 nm, 40 mW, 60 s, 12 J/cm2) or LED (632 +/- 2 nm, 145 mW, 40 s, 12 J/cm2). Six experimental groups were evaluated: Control Group (untreated); Photosensitizer group (phenothiazines - 12.5 MUg/mL); Laser Group; LED Group; Laser PACT Group; and LED PACT Group. The pre-irradiation time used in this study was 5 min. Macrophages and bacteria were cultured in specific culture media and/or allowed interaction between the cell types. Subsequently, tests were carried out to evaluate microbial proliferation, ROS production by macrophages and survival capacity of S. aureus after phagocytosis. Fluorescence microscopy assays were performed with the H2DCFDA probe, after PACT, at the initial time (0 h), 4-h and 12-h. The tests were performed in triplicate and the statistical test used was ANOVA with Tukey post test. After PACT, a statistically significant difference (p > 0.0001) was observed between the microbial growth of the control group and the PACTs groups. Laser PACT and LED PACT groups presented, respectively, reductions of 84.2% and 81.5% when compared to control and 53.3% and 46% when compared to the photosensitizer group. It is concluded that the therapeutic protocols presented in this study increased the phagocytic capacity, the response rate of the phagocytes and the consequent reduction of the numbers of S. aureus for both PACT protocols, however the increase in ROS production was only observed in the group irradiated with Laser light. PMID- 29499392 TI - The response surface methodology speeds up the search for optimal parameters in the photoinactivation of E. coli by photodynamic therapy. AB - Antimicrobial Photodynamic Inactivation (a-PDI) is based on the oxidative destruction of biological molecules by reactive oxygen species generated by the photo-excitation of a photosensitive molecule. When a-PDT is performed with the use of mathematical models, the optimal conditions for maximum inactivation are found. Experimental designs allow a multivariate analysis of the experimental parameters. This is usually made using a univariate approach, which demands a large number of experiments, being time and money consuming. This paper presents the use of the response surface methodology for improving the search for the best conditions to reduce E. coli survival levels by a-PDT using methylene blue (MB) and toluidine blue (TB) as photosensitizers and white light. The goal was achieved by analyzing the effects and interactions of the three main parameters involved in the process: incubation time (IT), photosensitizer concentration (CPS), and light dose (LD). The optimization procedure began with a full 23 factorial design, followed by a central composite one, in which the optimal conditions were estimated. For MB, CPS was the most important parameter followed by LD and IT whereas, for TB, the main parameter was LD followed by CPS and IT. Using the estimated optimal conditions for inactivation, MB was able to inactivate 99.999999% CFU mL-1 of E. coli with IT of 28 min, LD of 31 J cm-2, and CPS of 32 MUmol L-1, while TB required 18 min, 39 J cm-2, and 37 MUmol L-1. The feasibility of using the response surface methodology with a-PDT was demonstrated, enabling enhanced photoinactivation efficiency and fast results with a minimal number of experiments. PMID- 29499393 TI - Using ecological momentary assessments to predict relapse after adult substance use treatment. AB - BACKGROUND: A key component of relapse prevention is to self-monitor the internal (feelings or cravings) and external (people, places, activities) factors associated with relapse. Smartphones can deliver ecological momentary assessments (EMA) to help individuals self-monitor. The purpose of this exploratory study was to develop a model for predicting an individual's risk of future substance use after each EMA and validate it using a multi-level model controlling for repeated measures on persons. METHODS: Data are from 21,897 observations from 43 adults following their initial episode of substance use treatment in Chicago from 2015 to 2016. Participants were provided smartphones for six months and asked to complete two to three minute EMAs at five random times per day (81% completion). In any given EMA, 2.7% reported substance use and 8% reported any use in the next five completed EMA. Chi-square Automatic Interaction Detector (CHAID) was used to classify EMAs into six levels of risk and then validated with a hierarchical linear model (HLM). RESULTS: The major predictors of substance use in the next five completed EMAs were substance use pattern over the current and prior five EMAs (no recent/current use, either recent or current use [but not both], continued use [both recent and current]), negative affect (feelings), and craving (rating). Negative affect was important for EMAs with no current or recent use reported; craving was important for EMAs with either recent or current use; and neither mattered for EMAs with continued use. The CHAID gradated EMA risk from 0.7% to 36.6% of the next five completed EMAs with substance use reported. It also gradated risk of "any" use in the next five completed EMAs from 3% to 82%. CONCLUSIONS: This study demonstrated the potential of using smartphone-based EMAs to monitor and provide feedback for relapse prevention in future studies. PMID- 29499394 TI - Effects of white matter lesions on brain perfusion in patients with mild cognitive impairment. AB - OBJECTIVE: To evaluate the effects of white matter lesions on regional cerebral blood flow in subjects with amnestic mild cognitive impairment. PATIENTS AND METHODS: Seventy-five subjects with mild cognitive impairment (36 men and 39 women; mean age, 78.1 years) were included in the study. We used the Mini-Mental State Examination to assess cognitive function. All subjects underwent brain magnetic resonance imaging and 99mTc ethylcysteinate dimer single photon emission computed tomography. Subjects were stratified based on the presence or absence of white matter lesions on magnetic resonance imaging. Statistical parametric mapping of differences in regional cerebral blood flow between the two groups were assessed by voxel-by-voxel group analysis using SPM8. RESULTS: Of all 75 subjects with mild cognitive impairment, 46 (61.3%) had mild to moderate white matter lesions. The prevalence of hypertension tended to be higher in subjects with white matter lesions than in those without white matter lesions. Mini-Mental State Examination scores were significantly lower in subjects with white matter lesions than in those without white matter lesions. Subjects with white matter lesions had decreased regional cerebral blood flow mainly in the frontal, parietal, and medial temporal lobes, as well as the putamen, compared to those without white matter lesions. CONCLUSION: In subjects with mild cognitive impairment, white matter lesions were associated with cognitive impairment and mainly frontal lobe brain function. PMID- 29499395 TI - Influence of the workplace on physical activity and cardiometabolic health: Results of the multi-centre cross-sectional Champlain Nurses' study. AB - BACKGROUND: Nurses are the largest professional group within the health care workforce, and their work is perceived as being physically demanding. Regular physical activity helps to prevent or ameliorate cardiometabolic conditions (e.g. cardiovascular disease, diabetes). It is not known whether Canadian nurses are meeting current physical activity guidelines. OBJECTIVE: To assess the influence of the workplace on the physical activity and cardiometabolic health of nurses from hospitals in the Champlain region of Ontario, Canada. DESIGN: A multi centre, cross-sectional study. SETTING: Hospitals in the Champlain Local Health Integration Network of Ontario. METHODS: Nurses wore an ActiGraph accelerometer to objectively assess levels of moderate-to-vigorous intensity physical activity measured in minutes/day in bouts >=10 min. All completed the Perceived Workplace Environment (PWE) scale and International Physical Activity Questionnaire (IPAQ). Height, body mass, waist circumference, blood pressure and heart rate were measured, and body mass index (BMI) was determined. Each nurse's 5-year cardiovascular risk was calculated using the Harvard Score. FINDINGS: A total of 410 nurses (94% female; mean +/- SD: age = 43 +/- 12 years) from 14 hospitals participated. Nurses spent an average of 96 +/- 100 min/week in bouts >=10 min of moderate-to-vigorous intensity physical activity; 23% of nurses met recommended physical activity guidelines. Nurses working 8- vs. 12-h shifts (16 +/- 16 vs. 10 +/- 11 min/day, p = 0.026), fixed vs. rotating shifts (15 +/- 15 vs. 12 +/- 13 min/day, p = 0.012) and casual vs. full-time (29 +/- 17 vs. 13 +/- 15 min/day, p < 0.001) or vs. part-time (29 +/- 17 vs. 13 +/- 12 min/day, p = 0.001) accumulated more moderate-to-vigorous intensity physical activity in bouts >=10 min. The average PWE score was 2.4 +/- 0.9, with no association between PWE scores and moderate-to-vigorous intensity physical activity in bouts >=10 min (p > 0.05). Nurses working 8-h shifts, fixed shifts and in urban hospitals reported better PWE scores (p < 0.05). Nurses working fixed vs. rotating shifts had higher systolic blood pressure (median: 114 vs. 112 mmHg, p = 0.043), and nurses working in rural vs. urban hospitals had higher BMI (median: 27.8 vs. 25.6 kg/m2, p = 0.007) and waist circumference (median: 82.3 vs. 78.6 cm, p = 0.015). CONCLUSIONS: Nurses are not meeting current physical activity guidelines (150 min of moderate-to-vigorous intensity physical activity per week in 10-min bouts), yet exceeded these recommendations when examining their continuous (i.e. non bouts) physical activity levels. No association between the PWE and moderate-to vigorous intensity physical activity was observed. Rotating vs. fixed shifts, 12- vs. 8-h shifts, and/or full-time or part-time vs. casual hours may impede nurses' ability to meet recommended physical activity levels. The low physical activity levels and poor cardiometabolic health of Canadian nurses warrant attention. PMID- 29499396 TI - Differences in dynamic behavior of single diatom cells caused by changing wavelengths. AB - We investigate a motion of diatom cells stimulated by a halogen lamp irradiation. Diatom cells are single-celled organisms which have chloroplast. Chloroplast contains photosynthetic pigment which absorbs blue light (wave length of the light is 400 nm-450 nm) and red one (650 nm-700 nm). Light intensity of the halogen lamp is fixed about 500 Lx during the experiment. We used colored films to cut the blue or red light and observed motion of diatom cells by using the optical microscope. We found that the speed of diatom cells decreases when the colored film is inserted, and it increases after ejecting the film. It is noted that the light intensity is constant during the experiment, which means that we change wave length of the irradiated light. Our results show that the average speed of diatom cells is influenced by not the light intensity but the wave length of the light. PMID- 29499397 TI - siRNA-mediated inhibition of skNAC and Smyd1 expression disrupts myofibril organization: Immunofluorescence and electron microscopy study in C2C12 cells. AB - skNAC (skeletal and heart muscle-specific variant of nascent polypeptide associated complex) and Smyd1 (SET and MYND domain-containing 1) form a protein dimer which is specific for striated muscle cells. Its function is largely unknown. On the one hand, skNAC-Smyd1 appears to control transcriptional processes in the nucleus, on the other hand, specifically at later stages of myogenic differentiation, both proteins translocate to the sarcoplasm and at least Smyd1 specifically associates with sarcomeric structures and might control myofibrillogenesis and/or sarcomere architecture. Here, using immunofluorescence and electron microscopy, we analyzed sarcomere formation and myofibril organization after siRNA-mediated knockdown of skNAC or Smyd1 expression in murine C2C12 skeletal muscle cells. We found that inhibition of skNAC or Smyd1 expression indeed prevents myofibrillogenesis and sarcomere formation, leading to a disorganized array of myofilaments predominantly within the region immediately beneath the plasma membrane. PMID- 29499398 TI - Epigenetic alteration of mismatch repair genes in the population chronically exposed to arsenic in West Bengal, India. AB - INTRODUCTION: Arsenic exposure and its adverse health outcome, including the association with cancer risk are well established from several studies across the globe. The present study aims to analyze the epigenetic regulation of key mismatch repair (MMR) genes in the arsenic-exposed population. METHOD: A case control study was conducted involving two hundred twenty four (N=224) arsenic exposed [with skin lesion (WSL=110) and without skin lesion (WOSL=114)] and one hundred and two (N=102) unexposed individuals. The methylation status of key MMR genes i.e. MLH1, MSH2, and PMS2 were analyzed using methylation-specific PCR (MSP). The gene expression was studied by qRTPCR. The expression of H3K36me3, which was earlier reported to be an important regulator of MMR pathway, was assessed using ELISA. RESULTS: Arsenic-exposed individuals showed significant promoter hypermethylation (p < 0.0001) of MLH1 and MSH2 compared to those unexposed with consequent down-regulation in their gene expression [MLH1 (p=0.001) and MSH2 (p<0.05)]. However, no significant association was found in expression and methylation of PMS2 with arsenic exposure. We found significant down-regulation of H3K36me3 in the arsenic-exposed group, most significantly in the WSL group (p<0.0001). The expression of SETD2, the methyltransferase of an H3K36me3 moiety was found to be unaltered in arsenic exposure, suggesting the involvement of other regulatory factors yet to be identified. DISCUSSION: In summary, the epigenetic repression of DNA damage repair genes due to promoter hypermethylation of MLH1 and MSH2 and inefficient recruitment of MMR complex at the site of DNA damage owing to the reduced level of H3K36me3 impairs the mismatch repair pathway that might render the arsenic-exposed individuals more susceptible towards DNA damage and associated cancer risk. PMID- 29499399 TI - Cancer cells biomineralize ionic gold into nanoparticles-microplates via secreting defense proteins with specific gold-binding peptides. AB - : Cancer cells have the capacity to synthesize nanoparticles (NPs). The detailed mechanism of this process is not very well documented. We report the mechanism of biomineralization of aqueous gold chloride into NPs and microplates in the breast cancer cell line MCF7. Spherical gold NPs are synthesized in these cells in the presence of serum in the culture media by the reduction of HAuCl4. In the absence of serum, the cells exhibit gold microplate formation through seed-mediate growth albeit slower reduction. The structural characteristics of the two types of NPs under different media conditions were confirmed using scanning electron microscopy (SEM); crystallinity and metallic properties were assessed with transmission electron microscopy (TEM) and x-ray photoelectron spectroscopy (XPS). Gold-reducing proteins, related to cell stress initiate the biomineralization of HAuCl4 in cells (under serum free conditions) as confirmed by infrared (IR) spectroscopy. MCF7 cells undergo irreversible replicative senescence when exposed to a high concentration of ionic gold and conversely remain in a dormant reversible quiescent state when exposed to a low gold concentration. The latter cellular state was achievable in the presence of the rho/ROCK inhibitor Y-27632. Proteomic analysis revealed consistent expression of specific proteins under serum and serum-free conditions. A high-throughput proteomic approach to screen gold-reducing proteins and peptide sequences was utilized and validated by quartz crystal microbalance with dissipation (QCM-D). STATEMENT OF SIGNIFICANCE: Cancer cells are known to synthesize gold nanoparticles and microstructures, which are promising for bioimaging and other therapeutic applications. However, the detailed mechanism of such biomineralization process is not well understood yet. Herein, we demonstrate that cancer cells exposed to gold ions (grown in serum/serum-free conditions) secrete shock and stress-related proteins with specific gold-binding/reducing polypeptides. Cells undergo reversible senescence and can recover normal physiology when treated with the senescence inhibitor depending on culture condition. The use of mammalian cells as microincubators for synthesis of such particles could have potential influence on their uptake and biocompatibility. This study has important implications for in-situ reduction of ionic gold to anisotropic micro-nanostructures that could be used in-vivo clinical applications and tumor photothermal therapy. PMID- 29499400 TI - The '6W' multidimensional model of care trajectories for patients with chronic ambulatory care sensitive conditions and hospital readmissions. AB - OBJECTIVES: To synthesize concepts and approaches related to the analysis of patterns or processes of care and patient's outcomes into a comprehensive model of care trajectories, focusing on hospital readmissions for patients with chronic ambulatory care sensitive conditions (ACSCs). STUDY DESIGN: Narrative literature review. METHODS: Published studies between January 2000 and November 2017, using the concepts of 'continuity', 'pathway', 'episode', and 'trajectory', and focused on readmissions and chronic ACSCs, were collected in electronic databases. Qualitative content analysis was performed with emphasis on key constituents to build a comprehensive model. RESULTS: Specific common constituents are shared by the concepts reviewed: they focus on the patient, aim to measure and improve outcomes, follow specific periods of time and consider other factors related to care providers, care units, care settings, and treatments. Using these common denominators, the comprehensive '6W' multidimensional model of care trajectories was created. Considering patients' attributes and their chronic ACSCs illness course ('who' and 'why' dimensions), this model reflects their patterns of health care use across care providers ('which'), care units ('where'), and treatments ('what'), at specific periods of time ('when'). CONCLUSIONS: The '6W' model of care trajectories could provide valuable information on 'missed opportunities' to reduce readmission rates and improve quality of both ambulatory and inpatient care. PMID- 29499401 TI - Serine peptidase inhibitor Kunitz type 2 (SPINT2) in cancer development and progression. AB - Understanding the molecular basis and mechanisms involved in neoplastic transformation and progression is important for the development of novel selective target therapeutic strategies. Hepatocyte growth factor (HGF)/c-MET signaling plays an important role in cell proliferation, survival, migration and motility of cancer cells. Serine peptidase inhibitor Kunitz type 2 (SPINT2) binds to and inactivates the HGF activator (HGFA), behaving as an HGFA inhibitor (HAI) and impairing the conversion of pro-HGF into bioactive HGF. The scope of the present review is to recapitulate and review the evidence of SPINT2 participation in cancer development and progression, exploring the clinical, biological and functional descriptions of the involvement of this protein in diverse neoplasias. Most studies are in agreement as to the belief that, in a large range of human cancers, the SPINT2 gene promoter is frequently methylated, resulting in the epigenetic silence of this gene. Functional assays indicate that SPINT2 reactivation ameliorates the malignant phenotype, specifically reducing cell viability, migration and invasion in diverse cancer cell lines. In sum, the SPINT2 gene is epigenetically silenced or downregulated in human cancers, altering the balance of HGF activation/inhibition ratio, which contributes to cancer development and progression. PMID- 29499402 TI - The potential pathogenic role of IL-17/Th17 cells in both type 1 and type 2 diabetes mellitus. AB - Diabetes mellitus (DM) is a serious medical problem affecting millions of peoples worldwide, and has a great socio-economic impacts. Cytokines possess a pivotal role in modulation of immune reactions and disease pathogenesis. T-helper type 17 (Th17) cells, an important proinflammatory CD4+ T cell subset secreting interleukin 17 (IL-17), has been embroiled in development of DM. There are recent evidences supporting a definitive role of Th17 cells in the etiology of type 1 diabetes (T1D). In addition, IL-17 has been shown to play a crucial role in inflammation, insulin resistance, and type 2 diabetes (T2D). Recently, small molecules which have been specified to block Th17 cells differentiation are considered as potential therapeutics for the disease. Anti-IL-17 neutralizing antibodies and/or antibodies targeting Th17 cells have been investigated to protect individuals at risk from disease development. In this review we aimed to shed light on the potential role of IL-17 and Th17 cells in both T1D and T2D pathogenesis and future therapeutic strategies. PMID- 29499403 TI - Effects of ozone repeated short exposures on the airway/lung inflammation, airway hyperresponsiveness and mucus production in a mouse model of ovalbumin-induced asthma. AB - OBJECTIVE: The purpose of this study is to explore the influence of ozone repeated short exposures on airway/lung inflammation, airway hyperresponsiveness (AHR) and airway hypersecretion in ovalbumin (OVA) sensitized/challenged asthmatic mouse model. METHODS: OVA sensitization was performing by intraperitoneal injection. Ozone exposures (3ppm for 3hours) were given one hour after aerosolized OVA challenges (once every other day, 4 times totally). Methacholine (MCH) bronchial provocation tests, Liu's staining of BALF cell smears, hematoxylin-eosin (HE) staining and Periodic Acid-Schiff (PAS) staining of lung tissue were performed. Interleukins (ILs; IL-4, IL-13, IL-1beta, and IL 18) protein (ELISA) and mRNA expression levels (RT-qPCR) in murine lung, 8 hydroxy-2'-deoxyguanosine (8-OHdG, ELISA), malondialdehyde (MDA, thiobarbituric acid assay), reduced glutathione (GSH, spectrophotometric method) in bronchoalveolar lavage fluid (BALF), and GSH1 mRNA relative expression levels (RT qPCR) in lung tissue were analyzed. RESULT: Repeated ozone exposures down regulated the AHR to MCH in mice undergoing OVA sensitization and challenge, however not all parameters associated with asthma were decreased since obvious mucus hypersecretion was induced and airway inflammation increased slightly, especially around small airways. Following ozone co-exposure, the increase of IL 4 and IL-13 levels in murine lung caused by OVA sensitization/challenge were reversed. Instead, levels of IL-1beta in BALF remained, higher than negative control group. Ozone repeated short exposures also induced significant increase of 8-OHdG in BALF in OVA sensitized and challenged mice. CONCLUSION: For asthmatic mice undergoing ozone exposures, AHR is not an accurate indicator of the severity of asthma. Repeated short ozone exposures increase mucus hypersecretion, possibly via an increase in oxidative stress and immune dysregulation. PMID- 29499404 TI - Protective effects of essential oils from Rimulus cinnamon on endotoxin poisoning mice. AB - The essential oils from Rimulus cinnamon (EORC) have anti-inflammation activities, but the effects of EORC on endotoxin poisoning mice remain to be explored, the mechanism is still unclear. This study was designed to investigate the protective effects and mechanism of EORC on lipopolysaccharide (LPS)-induced endotoxin poisoning mice. Pre-treatment with EORC decreased the production of pro inflammatory cytokines (Interleukin-1beta, Interleukin-18, Interleukin-5, and Interferon-gamma) and chemokines (Monocyte chemotactic protein-1, Macrophage colony-stimulating factor, and Macrophage inflammatory protein-1beta) in serum of endotoxin poisoning mice. The histopathological study showed that the lung injury was improved and EORC decreased the numbers of neutrophils and Nitric oxide (NO) levels in lung. EORC could reduce the mRNA expression of NLR family, pyrin domain containing 3 (NLRP3), Interleukin (IL)-1beta, and nitric oxide synthase (iNOS). In addition, EORC decreased the protein expression of NLRP3, Caspase-1 (p20), Pro IL-1beta, and purinergic P2 * 7 receptor (P2 * 7R) in the lung tissues. The results above indicated that the EORC may have protective effects on LPS-induced endotoxin poisoning mice via inhibiting the activation of P2 * 7R/NLRP3 inflammasome. PMID- 29499405 TI - Huaier Granule extract inhibit the proliferation and metastasis of lung cancer cells through down-regulation of MTDH, JAK2/STAT3 and MAPK signaling pathways. AB - Although the effect of Huaier has been widely studied, its role and its molecular mechanism in lung cancer are not clear. In this study, we explored the inhibitory effect of Huaier on lung cancer cells and its molecular mechanism. The cell viability, migration and invasion were analyzed by CCK-8 and BrdU cell proliferation assay kits, Transwell and colony forming assay. The cell cycle and apoptosis were analyzed by flow cytometry. The experimental results showed that the viability, migration and invasion of A549 and NCI-H1650 cells were inhibited by Huaier in a dose and time-dependent manner. Huaier induced cell apoptosis and the cells were blocked in the S phase to inhibit cell proliferation. Western blotting results showed that Huaier inhibited the expression of MTDH and increased the proportion of Bax/Bcl-2, it could also promote the expression of Cleaved Caspase-3 and increase the activity of Caspase-3, promote cell apoptosis and inhibit cell proliferation. Huaier inhibited the metastasis and invasion of lung cancer cells by inhibiting the expression levels of EMT related proteins, it also inhibited the expression of JAK2/STAT3 and MAPK signaling pathways. Therefore, our results showed that Huaier may inhibit the proliferation and metastasis of lung cancer cells through multiple targets, it had the potential for treatment of lung cancer. PMID- 29499406 TI - Long non-coding RNA as potential biomarkers in non-small-cell lung cancer: What do we know so far? AB - Non-small-cell lung cancer (NSCLC) remains one of the most frequent types of lung cancer characterized by its local advancement at diagnosis. Therefore, identification of new prognostic biomarkers has become one of the most important issue in NSCLC therapy. It is now well understood that genetic and epigenetic alterations are responsible for NSCLC development. Moreover, it has been recently revealed that the non-protein coding regions of the genome may serve as a template for transcription of various type of RNAs, collectively referred to as non-coding RNAs. Non-coding RNAs, including long non-coding RNAs (lncRNAs) are involved in multiple cellular processes and it has been suggested that aberrant expression of lncRNAs may lead to tumour development, including NSCLC. Furthermore, some of the established risk factors for NSCLC may have an impact on expression level of several types of lncRNAs, and thus, affect the lung carcinogenesis through lncRNAs regulation. In this review, we would like to summarise the to-date knowledge about lncRNAs as potential biomarkers in NSCLC and the role of various environmental factors, such as smoking and air pollution, in development and progression of this tumour and their effect on lncRNAs expression. PMID- 29499407 TI - Physalin B induces cell cycle arrest and triggers apoptosis in breast cancer cells through modulating p53-dependent apoptotic pathway. AB - Physalin B (PB), one of the major active steroidal constituents of Cape gooseberry (Physalis alkekengi L.), possesses a wide spectrum of biological activities. Although the anticancer activity of PB was reported in previous studies, the underlying mechanisms are still not well stated. In this study, the anticancer effect and the underlying mechanisms of PB were investigated in breast cancer cells. PB significantly reduced the viability of three human breast cancer cell lines, MCF-7, MDA-MB-231 and T-47D, in a concentration- and time-dependent manner. PB induced cell cycle arrest at G2/M phase and promoted cleavage of PARP (poly (ADP-ribose) polymerase), caspases 3, caspase 7 and caspase 9 to stimulate cell apoptosis. Further studies showed that PB induced breast cancer cells apoptosis in a p53-dependent manner in MCF-7 cells. PB also suppressed the phosphorylation of Akt (protein kinase B) and PI3K (phosphoinositide 3-kinase), and increased the phosphorylation of GSK-3beta (glycogen synthase kinase 3beta). Taken together, our results indicated that PB might serve as a potential therapeutic agent for breast cancer. PMID- 29499408 TI - Overexpression of secretagogin promotes cell apoptosis and inhibits migration and invasion of human SW480 human colorectal cancer cells. AB - OBJECTIVE: In order to investigate the effect of secretagogin (SCGN) on colorectal cancer (CRC) cells apoptosis, invasion and migration in vitro. METHODS: Expression of SCGN in CRC tissues and the paired adjacent non-tumorous tissues (n = 36) and four human CRC cell lines (HT29, HCT116, SW480 and SW620) were detected. SW480 cells were transfected with the SCGN overexpression plasmid (eGFP-SCGN), si-SCGN-773, and the corresponding negative controls (NCs). Then, cell-cycle distribution, cell apoptosis, migration, invasion and expression of apoptosis- and metastasis-related proteins were detected. RESULTS: SCGN was significantly downregulated in CRC tissues as compared with the adjacent non tumorous tissues. The expression of SCGN in HT29 and SW480 cells were lower than those in HT116 and SW620 cells. We transfected SW480 cells with SCGN overexpression plasmid eGFP-SCGN and found the increased cell apoptosis, with cell arresting at G0/G1 phase. SW480 cells with SCGN overexpression showed wider wound width and fewer invaded cells than control and blank cells, with upregulated Bax, cleaved Caspase 3 and E-cadherin, and downregulated Bcl-2 and Vimentin. We also transfected SW480 cells with si-SCGN-773 and found si-SCGN increased cell migration and invasion, but did not affect cell apoptosis and expression of related proteins. CONCLUSION: We concluded that the overexpression of SCGN in SW480 cells promoted cell apoptosis and inhibited cell migration and invasion. PMID- 29499409 TI - Liquiritigenin prevents palmitate-induced beta-cell apoptosis via estrogen receptor-mediated AKT activation. AB - Liquiritigenin (LQ) is a major active component of licorice root, which is a flavone used for treating many diseases, including diabetes. LQ has been shown to exhibit a glucose-lowering effect in diabetic mice. Therefore, we investigated the potential of LQ to protect against lipotoxicity-induced beta-cell apoptosis and the underlying molecular mechanisms. Exposure of INS-1 rat insulinoma cells to LQ significantly increased cell viability and blocked palmitate (PA)-induced apoptosis, as evidenced by the reduction of Annexin-V-stained cells, cleaved caspase-3 levels, and poly (ADP-ribose) polymerase (PARP) activity, as well as upregulation of Bcl-2 expression. Moreover, LQ treatment significantly reduced the endoplasmic reticulum (ER) stress response by reducing phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (PERK), phosphorylated eIF-2a, and CHOP expression in PA-treated INS-1 cells. The anti-apoptotic effect of LQ treatment was reversed through co-treatment with fulvestrant, a specific inhibitor of the estrogen receptor. LQ also increased AKT phosphorylation, and inactivation of this molecular event failed to decrease PERK phosphorylation with LQ treatment in PA-treated INS-1 cells. This effect was further accompanied by an inability to recover cell viability. These results suggest that LQ protects INS-1 cells from lipotoxicity-induced apoptosis by suppressing ER stress. We conclude that estrogen receptor-mediated AKT phosphorylation is one of the mechanisms contributing to the anti-apoptotic effect of LQ. PMID- 29499410 TI - Sauchinone prevents TGF-beta-induced EMT and metastasis in gastric cancer cells. AB - Sauchinone, one of the active lignan isolated from the roots of Saururus chinensis, was reported to possess diverse pharmacological properties, such as hepatoprotective, anti-inflammatory and anti-tumor effects. However, the possible role of sauchinone in the epithelial-mesenchymal transition (EMT) remains unclear. Thus, the aim of this study was to investigate the effect of sauchinone on the EMT in gastric cancer cells. Our results demonstrated that sauchinone significantly inhibited transforming growth factor-beta1 (TGF-beta1)-induced migration and invasion in gastric cancer cells. In addition, sauchinone efficiently suppressed TGF-beta1-induced EMT process in gastric cancer cells. Furthermore, pretreatment with sauchinone dramatically inhibited the activation of PI3K/Akt and Smad2/3 signaling pathways in TGF-beta1-stimulated gastric cancer cells. In conclusion, our findings revealed that sauchinone inhibits the TGF beta1-induced EMT in gastric cancer cells via down-regulation of PI3K/Akt and Smad2/3 signaling pathways. Thus, sauchinone may be a therapeutic agent for treatment of gastric cancer. PMID- 29499411 TI - GIRK1-mediated inwardly rectifying potassium current suppresses the epileptiform burst activities and the potential antiepileptic effect of ML297. AB - G protein-gated inwardly rectifying potassium (GIRK) channels are important inhibitory regulators of neuronal excitability in central nervous system, and the impairment of GIRK channel function has been reported to be associated with the susceptibility of epilepsy. However, the dynamics of GIRK channels in the pathogenesis of epilepsy are still unclear. In this study, our results showed that cyclothiazide, a potent convulsant, dose dependently increased the epileptiform bursting activities and suppressed the baclofen induced GIRK currents. In addition, TPQ, a selective GIRK antagonist, significantly decreased the total inwardly rectifying potassium (Kir) current, and increased the neuronal epileptiform activities. In contrast, ML297, a potent and selective GIRK channel agonist, reversed the cyclothiazide induced decrease of GIRK currents and the increase of neuronal excitability in cultured hippocampal neurons. Further investigation revealed that GIRK1, but not GIRK2, played a key role in suppressing epileptic activities. Finally, in pilocarpine mice seizure model, we demonstrated that ML297 significantly suppressed the seizure behavior. In summary, our current results indicate that GIRK channels, especially GIRK1 containing channels, are involved in epileptic activities and ML297 has a potential antiepileptic effect. PMID- 29499412 TI - STVNa attenuates right ventricle hypertrophy and pulmonary artery remodeling in rats induced by transverse aortic constriction. AB - Right heart failure and pulmonary artery remodeling resulting from increased left heart pressure are prevalent in a clinical setting, and the specific pathological feature exhibits cancer-like cell proliferation in lung. STVNa has been previously demonstrated its anti-proliferation property. In this study, we want to verify the therapeutic effect of STVNa against right ventricle hypertrophy and pulmonary artery remodeling in rats induced by transverse aortic constriction (TAC). The results show that TAC surgery increased mean right ventricle pressure (mRVP) less in the STVNa group than that in the vehicle group (11.81 vs 22.71 mmHg/ml, p < 0.01). STVNa treatment reduced the right ventricle cardiomyocyte area (p < 0.05) and the proliferation of pathological smooth muscle cells proving by PCNA immunohistochemical staining. Gene expression of brain natriuretic peptide (BNP), smooth muscle actin (SMA) and CD31 assessed by real-time polymerase chain reaction were confirmed the above results. Also, STVNa treatment decreased the lung fibrosis content and alleviated the inflammation infiltration. The expression of ET-1 and the phosphorylation of signal-regulated kinase (ERK) were lower in STVNa group compared to vehicle group (p < 0.05). In summary, STVNa could relieve right ventricle hypertrophy and pulmonary artery remodeling formation in rats after 9 weeks of TAC surgery by reducing ET-1 expression and suppressing ERK phosphorylation signal and subsequently inhibiting cell proliferation. PMID- 29499413 TI - Relationship between social-cognitive and social-perceptual aspects of theory of mind and neurocognitive deficits, insight level and schizotypal traits in obsessive-compulsive disorder. AB - OBJECTIVE: The primary aim of the current study was to investigate different aspects of theory of mind (ToM), including social-cognitive (ToM-reasoning) and social-perceptual (ToM-decoding) in obsessive-compulsive disorder (OCD). We also aimed to investigate the relationship between ToM, neurocognition and a number of clinical variables including overvalued ideas, schizotypal personality traits, level of insight, and disease severity. METHOD: Thirty-four patients who have been diagnosed with OCD according to DSM-IV and 30 healthy controls were included in the study. All participants were given a neuropsychological battery including tasks measuring ToM-reasoning, ToM-decoding and other neurocognitive functions. Schizotypal Personality Questionnaire (SPQ), Yale Brown Obsession and Compulsion Scale (YBOC-S) and Overvalued Ideas Scale (OVIS) were also administered to the participants. RESULTS: Patients with OCD showed significant deficits in both aspects of ToM. ToM performances of patients showed a significant positive correlation with neurocognitive functions. When controlled for general cognition factor, patient-control difference for ToM-reasoning (F = 3,917; p = 0,05), but not ToM-decoding, remained statistically significant. ToM-reasoning impairment of patients was significantly related to the severity of OCD symptoms and poor insight (p = 0,026 and p = 0,045, respectively). On the other hand, general cognitive factor (beta = 0,778; t = 3,146; p = 0,04) was found to be the only significant predictor of ToM-reasoning in OCD patients in the multiple linear regression model. CONCLUSION: OCD is associated with ToM impairment, which is related to schizotypal traits, disease severity and poor insight, yet neurocognitive deficits also significantly contribute to this finding. However, ToM-reasoning impairment could be considered as a relatively distinct feature of OCD, which is partly separate from general cognitive deficits. PMID- 29499414 TI - Joint study of two genome-wide association meta-analyses identified 20p12.1 and 20q13.33 for bone mineral density. AB - In the present study, aiming to identify loci associated with osteoporosis, we conducted a joint association study of 2 independent genome-wide association meta analyses of femoral neck and lumbar spine bone mineral densities (BMDs): 1) an in house study of 6 samples involving 7484 subjects, and 2) the GEFOS-seq study of 7 samples involving 32,965 subjects. The in-house samples were imputed by the 1000 genomes project phase 3 reference panel. SNP-based association test was applied to 7,998,108 autosomal SNPs in each meta-analysis, and for each SNP the 2 association signals were then combined for joint analysis and for mutual replication. Combining the evidence from both studies, we identified 2 novel loci associated with BMDs at the genome-wide significance level (alpha=5.0*10-8): 20p12.1 (rs73100693 p=2.65*10-8, closest gene MACROD2) and 20q13.33 (rs2380128 p=3.44*10-8, OSBPL2). We also replicated 7 loci that were reported by two recent studies on heel and total body BMD. Our findings provide useful insights that enhance our understanding of bone development, osteoporosis and fracture pathogenesis. PMID- 29499415 TI - Antibody-based inhibition of circulating DLK1 protects from estrogen deficiency induced bone loss in mice. AB - Soluble delta-like 1 homolog (DLK1) is a circulating protein that belongs to the Notch/Serrate/delta family, which regulates many differentiation processes including osteogenesis and adipogenesis. We have previously demonstrated an inhibitory effect of DLK1 on bone mass via stimulation of bone resorption and inhibition of bone formation. Further, serum DLK1 levels are elevated and positively correlated to bone turnover markers in estrogen (E)-deficient rodents and women. In this report, we examined whether inhibition of serum DLK1 activity using a neutralizing monoclonal antibody protects from E deficiency-associated bone loss in mice. Thus, we generated mouse monoclonal anti-mouse DLK1 antibodies (MAb DLK1) that enabled us to reduce and also quantitate the levels of bioavailable serum DLK1 in vivo. Ovariectomized (ovx) mice were injected intraperitoneally twice weekly with MAb DLK1 over a period of one month. DEXA-, microCT scanning, and bone histomorphometric analyses were performed. Compared to controls, MAb DLK1 treated ovx mice were protected against ovx-induced bone loss, as revealed by significantly increased total bone mass (BMD) due to increased trabecular bone volume fraction (BV/TV) and inhibition of bone resorption. No significant changes were observed in total fat mass or in the number of bone marrow adipocytes. These results support the potential use of anti-DLK1 antibody therapy as a novel intervention to protect from E deficiency associated bone loss. PMID- 29499417 TI - Biochemical transformation of calciprotein particles in uraemia. AB - Calciprotein particles (CPP) have emerged as nanoscale mediators of phosphate induced toxicity in Chronic Kidney Disease (CKD). Uraemia favors ripening of the particle mineral content from the amorphous (CPP-I) to the crystalline state (CPP II) but the pathophysiological significance of this transformation is uncertain. Clinical studies suggest an association between CPP ripening and inflammation, vascular dysfunction and mortality. Although ripening has been modelled in vitro, it is unknown whether particles synthesised in serum resemble their in vivo counterparts. Here we show that in vitro formation and ripening of CPP in uraemic serum is characterised by extensive physiochemical rearrangements involving the accretion of mineral, loss of surface charge and transformation of the mineral phase from a spherical arrangement of diffuse domains of amorphous calcium phosphate to densely-packed lamellar aggregates of crystalline hydroxyapatite. These physiochemical changes were paralleled by enrichment with small soluble apolipoproteins, complement factors and the binding of fatty acids. In comparison, endogenous CPP represent a highly heterogeneous mixture of particles with characteristics mostly intermediate to synthetic CPP-I and CPP-II, but are also uniquely enriched for carbonate-substituted apatite, DNA fragments, small RNA and microbe-derived components. Pathway analysis of protein enrichment predicted the activation of cell death and pro-inflammatory processes by endogenous CPP and synthetic CPP-II alike. This comprehensive characterisation validates the use of CPP-II generated in uraemic serum as in vitro equivalents of their endogenous counterparts and provides insight into the nature and pathological significance of CPP in CKD, which may act as vehicles for various bioactive ligands. PMID- 29499416 TI - Amino acids as signaling molecules modulating bone turnover. AB - Except for the essential amino acids (AAs), much of the focus on adequate dietary protein intake has been on total nitrogen and caloric intake rather than AA composition. Recent data, however, demonstrate that "amino-acid sensing" can occur through either intracellular or extracellular nutrient-sensing mechanisms. In particular, members of the class 3 G-protein coupled receptor family, like the calcium-sensing receptor are known to preferentially bind specific AAs, which then modulate receptor activation by calcium ions and thus potentially impact bone turnover. In pursuing the possibility of direct nutrient effects on bone cells, we examined individual AA effects on osteoprogenitor/bone marrow stromal cells (BMSCs), a key target for bone anabolism. We demonstrate that BMSCs express both intracellular and extracellular nutrient sensing pathways and that AAs are required for BMSC survival. In addition, certain AA types, like members of the aromatic AAs, can potently stimulate increases in intracellular calcium and ERK phosphorylation/activation. Further, based on the in vitro data, we examined the effect of specific AAs on bone mass. To better evaluate the impact of specific AAs, we added these to a low-protein diet. Our data demonstrate that a low protein diet itself is associated with a significant drop in bone mineral density (BMD) in the older mice, related, at least in part, to an increase in osteoclastic activity. This drop in BMD in mice on the low-protein diet is prevented by addition of AAs from the aromatic group. Taken together our data show that AAs function as specific and selective signaling molecules in bone cells. PMID- 29499418 TI - Diagnostic strategies and genotype-phenotype correlation in a large Indian cohort of osteogenesis imperfecta. AB - Osteogenesis Imperfecta (OI) is a clinically and genetically heterogeneous disorder. Although differential diagnosis is greatly facilitated by next generation sequencing, its availability can vary considerably. In this study, we compared targeted gene panel or exome sequencing with clinical scoring and grouping in a cohort of 50 OI index patients recruited by a single Indian clinical center in an unselected fashion. In 48 patients we observed a total of 24 novel mutations and 24 known OI mutations, of which several were recurrent. In one patient neither gene panel nor exome sequencing revealed any significant mutation and another patient harbored a class III COL1A1 intronic variant. The percentage of autosomal recessive forms due to mutations in BMP1, FKBP10, LEPRE1, SERPINF1, and WNT1 was unusually high (48%). Grouping according to phenotypic and radiographic features revealed four individuals with Bruck syndrome due to FKBP10 mutations, three patients with hypertrophic callus caused by IFITM5 mutations, and twenty with pronounced bone bowing, of which eight carried WNT1 mutations. There was a clear correlation between genotype and phenotype severity: IFITM5=LEPRE1>WNT1>SERPINF1>COL1A1 (qualitative)>BMP1>FKBP10>COL1A2 (qualitative)>COL1A1 (quantitative)>COL1A2 (quantitative). In one patient we found heterozygous variants in COL1A1 and COL1A2 inherited from parents without an obvious bone phenotype indicating that both variants might contribute to the phenotype. Our findings demonstrate the clinical utility of gene panel testing for OI, but in cases with contractures, hypertrophic callus formation, or - to some extent - extensive bowing single gene analysis might still be more cost effective. PMID- 29499419 TI - A soluble activin type IIA receptor mitigates the loss of femoral neck bone strength and cancellous bone mass in a mouse model of disuse osteopenia. AB - Disuse causes a rapid and substantial bone loss distinct in its pathophysiology from the bone loss associated with cancers, age, and menopause. While inhibitors of the activin-receptor signaling pathway (IASPs) have been shown to prevent ovariectomy- and cancer-induced bone loss, their application in a model of disuse osteopenia remains to be tested. Here, we show that a soluble activin type IIA receptor (ActRIIA-mFc) increases diaphyseal bone strength and cancellous bone mass, and mitigates the loss of femoral neck bone strength in the Botulinum Toxin A (BTX)-model of disuse osteopenia in female C57BL/6J mice. We show that ActRIIA mFc treatment preferentially stimulates a dual-effect (anabolic-antiresorptive) on the periosteal envelope of diaphyseal bone, demonstrating in detail the effects of ActRIIA-mFc on cortical bone. These observations constitute a previously undescribed feature of IASPs that mediates at least part of their ability to mitigate detrimental effects of unloading on bone tissue. The study findings support the application of IASPs as a strategy to combat bone loss during disuse. PMID- 29499420 TI - Novel pyridine-containing azacrownethers for the chelation of therapeutic bismuth radioisotopes: Complexation study, radiolabeling, serum stability and biodistribution. PMID- 29499421 TI - Increased risk of hematologic malignancies in primary immunodeficiency disorders: opportunities for immunotherapy. AB - Primary immunodeficiency disorders (PIDs) convey increased susceptibility to infections and sometimes to malignancies, particularly lymphomas. Such cancer development can be contributed by immune impairments resulting in weakened immunological surveillance against (pre)malignant cells and oncogenic viruses. Molecular defects in PID-patients are therefore being clarified, identifying new targets for innovative immunotherapy. Particularly pediatric cancers are being scrutinized, where over one-third of cancer-related deaths are accounted for by leukemia and lymphomas. Here we review how immunopathogenic mechanisms of several PIDs might associate with lymphoma development. We furthermore delineate existing immunotherapy strategies in adults for potential therapeutic application in childhood leukemia and lymphomas. PMID- 29499422 TI - Percutaneous Transforaminal Endoscopic Discectomy for the Treatment of Lumbar Disc Herniation in Obese Patients: Health-Related Quality of Life Assessment in a 2-Year Follow-Up. AB - BACKGROUND: Percutaneous transforaminal endoscopic discectomy (PTED) is a minimally invasive surgical technique used principally for the treatment of lumbar disc herniation (LDH). LDH is a frequent spinal ailment in obese individuals. The aim of this prospectively designed study was to assess for the first time in the literature the impact of PTED in postoperative parameters of health-related quality of life (HRQoL) in obese patients with LDH within a 2-year follow-up period, to further evaluate the effectiveness of PTED. METHODS: Patients with surgically treatable LDH were divided into 2 groups. Group A constituted 20 obese patients, and group B was composed of 10 patients with normal body mass index (BMI). A visual analog scale was used for pain evaluation, and the Short Form SF-36 Medical Survey Questionnaire contributed to HRQoL assessment. Follow-up was conducted preoperatively and at 6 weeks and 3, 6, 12, and 24 months postoperatively. RESULTS: Two of the 20 patients (10%) presented with severe postoperative pain, necessitating conventional microdiscectomy. All studied parameters exhibited maximal improvement at 6 months in group A and at 6 weeks in group B, with subsequent stabilization. Obese patients scored lower in all parameters compared with their healthy counterparts with normal BMI, acquiring a less favorable clinical benefit. CONCLUSIONS: PTED appears to be a generally safe and effective method for treating obese patients with LDH. However, major technical challenges that lead to a higher frequency of complications, as well as the lesser acquired clinical benefit, in obese patients may contribute to the further consideration for PTED in specific obese patients, especially on the grounds of low surgical experience. PMID- 29499423 TI - Praying Sitting Position for Pineal Region Surgery: An Efficient Variant of a Classic Position in Neurosurgery. AB - BACKGROUND: The sitting position has lost favor among neurosurgeons partly owing to assumptions of increased complications, such as venous air embolisms and hemodynamic disturbances. Moreover, the surgeon must assume a tiring posture. We describe our protocol for the "praying position" for pineal region surgery; this variant may reduce some of the risks of the sitting position, while providing a more ergonomic surgical position. METHODS: A retrospective review of 56 pineal lesions operated on using the praying position between January 2008 and October 2015 was performed. The praying position is a steeper sitting position with the upper torso and the head bent forward and downward. The patient's head is tilted about 30 degrees making the tentorium almost horizontal, thus providing a good viewing angle. G-suit trousers or elastic bandages around the lower extremities are always used. RESULTS: Complete lesion removal was achieved in 52 cases; subtotal removal was achieved in 4. Venous air embolism associated with persistent hemodynamic changes was nonexistent in this series. When venous air embolism was suspected, an immediate reaction based on good teamwork was imperative. No cervical spine cord injury or peripheral nerve damage was reported. The microsurgical time was <45 minutes in most of the cases. Postoperative pneumocephalus was detected in all patients, but no case required surgical treatment. CONCLUSIONS: A protocolized praying position that includes proper teamwork management may provide a simple, fast, and safe approach for proper placement of the patient for pineal region surgery. PMID- 29499424 TI - Transnasal Endoscopic and Lateral Approaches to the Clivus: A Quantitative Anatomic Study. AB - BACKGROUND: Transnasal endoscopic approaches to the clivus have been established recently. Comparative analyses with classic lateral approaches are limited. In this study, we compared transnasal endoscopic and lateral approaches to the clivus, quantifying the exposure and working volume of each approach in the anatomy laboratory. METHODS: High-resolution computed tomography scans were performed on 5 injected specimens (10 sides). In each specimen, transnasal endoscopic approaches (i.e., paraseptal, transrostral, extended transrostral, transethmoidal, and extended transclival without and with intradural hypophysiopexy) and lateral approaches (i.e., retrosigmoid, far-lateral, presigmoid retrolabyrinthine and translabyrinthine) to the clivus were performed. An optic neuronavigation system and dedicated software (ApproachViewer; Guided Therapeutics Program, University Health Network, Toronto, Ontario, Canada) were used to quantify the working volume and exposed clival area of each approach. Statistical evaluation was performed with the Kruskal-Wallis test and Steel-Dwass Critchlow-Fligner post hoc test. RESULTS: Endoscopic transnasal transclival approaches showed higher working volume and larger clival exposure compared with lateral approaches. Incremental volumetric values were evident for transnasal approaches; presigmoid approaches provided less working volume than retrosigmoid approaches. A transnasal transclival approach with hypophysiopexy provided significant exposure of the upper clivus (84.4%). The transrostral approach was the first transnasal approach providing satisfactory access to the midclivus (66%); retrosigmoid and far-lateral approaches provided exposure of approximately one half of the midclivus. The lower clivus was optimally exposed with endoscopic transclival approaches (83%), whereas access to this region was limited with lateral approaches. CONCLUSIONS: This quantitative anatomic study shows that endoscopic transnasal approaches to the clivus provide a larger working volume and wider exposure of the clivus compared with lateral approaches. PMID- 29499425 TI - Rate of Adjacent Segment Degeneration of Cervical Disc Arthroplasty Versus Fusion Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: The concern of adjacent segment disease (ASD) has led to the development of motion-preserving technologies, such as cervical disc arthroplasty (CDA). However, there is still controversy whether CDA is superior to anterior cervical decompression and fusion (ACDF) as to the incidence of ASD. The purpose of this study is to evaluate the rate of ASD between CDA and ACDF. METHODS: Systematic searches of all relevant studies through November 2017 were identified from the Cochrane Library, PubMed, Embase, and CNKI. Randomized controlled trials comparing the clinical effectiveness of CDA and ACDF for cervical degenerative disc disease (DDD) were included. Two independent reviewers searched and assessed all literature according to the standard of Cochrane systematic review. Data extraction and quality assessment were conducted, and RevMan 5.2 was used for data analysis. The random effects model was used if there was heterogeneity between studies; otherwise, the fixed effects model was used. RESULTS: Twenty-one studies were included in our meta-analysis. The pooled data revealed that the CDA group had significantly lower adjacent segment diseases than the ACDF group did. Furthermore, there were fewer adjacent segment reoperations in the CDA group compared with the ACDF group. CONCLUSIONS: In this meta-analysis, we conclude that CDA was better than the ACDF in terms of ASD and adjacent segment reoperations. This conclusion suggests that CDA is a superior alternative invention for the treatment of cervical DDD to preserve cervical range of motion and reduce the risk of ASD; however, this requires further validation and investigation in larger sample-size prospective and randomized studies with long term follow-up. PMID- 29499426 TI - Coil and Single-Stent Placement for Ruptured Dissecting Aneurysm of Middle Cerebral Artery: A Case Report. AB - BACKGROUND: Ruptured dissecting aneurysms located at the middle cerebral artery (MCA) are rare, and their standard treatment has not been defined. Furthermore, lenticulostriate artery involvement in the dissecting segment makes treatment extremely difficult, and no previous reports have described successful treatment for such conditions. CASE DESCRIPTION: We herein report the case of a 74-year-old woman who presented with sudden severe headache from subarachnoid hemorrhage due to dissection in the proximal M1 segment of left MCA involving lenticulostriate arteries. Digital subtraction angiography on day 6 showed that the dissecting aneurysm had enlarged despite strict blood pressure control. On day 8, the patient was treated successfully with a self-expanding closed cell stent and coil embolization, preserving blood flow in the lenticulostriate arteries as well as the MCA. CONCLUSIONS: Follow-up digital subtraction angiography performed 5 weeks after endovascular therapy showed healing of the dissecting lesion, and the patient was discharged neurologically intact. PMID- 29499427 TI - Intraoperative Resuturing of Occluded Superficial Temporal Artery-Middle Cerebral Artery Anastomoses: Single-Center Retrospective Study. AB - BACKGROUND: In superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis, there is a certain risk of intraoperative acute occlusion of the bypass that can cause operative complications. OBJECTIVE: We sought to assess the efficacy of resuturing at the same site after intraoperative acute occlusion of the bypass. METHODS: In total, 129 STA-MCA anastomosis operations were performed on 125 patients at our institution. The electronic medical records of each patient were reviewed to gather information regarding intraoperative occlusion events, and the operative videos and postoperative radiologic images were also reviewed. RESULTS: Twelve intraoperative acute occlusions were identified. In each case, resuturing was performed after cutting all knots, flushing the thrombus, and trimming the edges of the STAs. In 11 cases, indocyanine green videoangiography and/or Doppler sonography revealed patency during the operation, which was confirmed by postoperative magnetic resonance angiography. None of the 12 cases exhibited high-signal intensities in the MCA area on diffusion-weighted images. CONCLUSION: If intraoperative acute occlusion of STA-MCA anastomosis occurs, reanastomosis at the site should be the first option. PMID- 29499428 TI - Performances of metal concentrations from three permeable pavement infiltrates. AB - The U.S. Environmental Protection Agency constructed a 4000-m2 parking lot in Edison, New Jersey in 2009. The parking lot is surfaced with three permeable pavements [permeable interlocking concrete pavers (PICP), pervious concrete (PC), and porous asphalt (PA)]. Samples of each permeable pavement infiltrate, surface runoff from traditional asphalt, and rainwater were analyzed in duplicate for 22 metals (total and dissolved) for 6 years. In more than 99% of the samples, the concentration of barium, chromium, copper, manganese, nickel and zinc, and in 60% 90% of the samples, the concentration of arsenic, cadmium, lead, and antimony in infiltrates from all three permeable pavements met both the groundwater effluent limitations (GEL) and maximum contaminant levels (MCL). The concentration of aluminum (50%) and iron (93%) in PICP infiltrates samples exceed the GELs; however, the concentration in more than 90% samples PA and PC infiltrates met the GELs. No measurable difference in metal concentrations was found from the five sources for arsenic, cadmium, lead, antimony, and tin. Large concentrations of eleven metals, including manganese, copper, aluminum, iron, calcium, magnesium, sodium, potassium, silica, strontium and vanadium, were detected in surface runoff than the rainwater. Chromium, copper, manganese, nickel, aluminum, zinc, iron and magnesium concentrations in PICP infiltrates; calcium, barium, and strontium concentrations in PA infiltrates; sodium, potassium and vanadium concentrations in PC infiltrates were statistically larger than the other two permeable pavement infiltrates. PMID- 29499429 TI - Time does matter! Acute copper exposure abolishes rhythmicity of clock gene in Danio rerio. AB - The circadian clock is a key cellular timing system that coordinates physiology and behavior. Light is a key regulator of the clock mechanism via its activation of Per and Cry clock gene expression. Evidence points to a key role of reactive oxygen species (ROS) in resetting this process. In this context, the aim of the present study was to explore copper as a ROS generator, using an innovative approach investigating its effects on circadian timing. Liver and brain from Danio rerio specimens exposed to 0, 5, 25 and 45 MUg/L copper concentrations were obtained. Daily oscillations of superoxide dismutase (SOD) and catalase (CAT) enzymatic activity and their correlations both with clock genes (per1, per2, and cry1a) and with organism energy cost were determined. CAT expression correlates with per2 and cry1a and, thus, provides data to support the hypothesis of hydrogen peroxide production by a phototransducing flavin-containing oxidase. Higher SOD activity is correlated with higher intracellular ATP levels. Copper disturbed the daily oscillation of antioxidant enzymes and clock genes, with disturbed per1 rhythmicity in both the brain and liver, while cry1a rhythmicity was abolished in the liver at 25 MUg/L copper. Coordination between the SOD and the CAT enzymes was lost when copper concentrations exceeded the limits established by international laws. These results indicate that organism synchronization with the environment may be impaired due to acute copper exposure. PMID- 29499430 TI - Two facets of patience in young children: Waiting with and without an explicit reward. AB - Patience, or the ability to tolerate delay, is typically studied using delay of gratification (DoG) tasks. However, among other factors (e.g., type of reward), the use of a reward to test patience is affected by an individual's motivation to obtain the reward (e.g., degree of preference for the small vs. large reward). In addition, DoG tasks do not assess the extent to which an individual can wait in the absence of an explicit reward-or what we term "patience as a virtue." Accordingly, the current study used a new measure of patience-the "pure waiting paradigm"-in which 3- to 5-year-old children waited 3 min with nothing to do and with no explicit reward. We then examined the relation between performance on this task (as assessed by children's spontaneous patient behaviors) and performance on two DoG tasks (candy and video rewards). Significant correlations were found between DoG performance and patient behaviors in the pure waiting paradigm, especially when controlling for motivation. These results and methodology show for the first time a direct link between patience as a virtue and DoG performance and also provide new insights about the study of patience in children. PMID- 29499431 TI - Reaching the goal: Active experience facilitates 8-month-old infants' prospective analysis of goal-based actions. AB - From early in development, infants view others' actions as structured by intentions, and this action knowledge may be supported by shared action production/perception systems. Because the motor system is inherently prospective, infants' understanding of goal-directed actions should support predictions of others' future actions, yet little is known about the nature and developmental origins of this ability, specifically whether young infants use the goal-directed nature of an action to rapidly predict future social behaviors and whether their action experience influences this ability. Across three conditions, we varied the level of action experience infants engaged in to determine whether motor priming influenced infants' ability to generate rapid social predictions. Results revealed that young infants accurately generated goal-based visual predictions when they had previously been reaching for objects; however, infants who passively observed a demonstration were less successful. Further analyses showed that engaging the cognitively based prediction system to generate goal based predictions following motor engagement resulted in slower latencies to predict, suggesting that these smart predictions take more time to deploy. Thus, 8-month-old infants may have motor representations of goal-directed actions, yet this is not sufficient for them to predict others' actions; rather, their own action experience supports the ability to rapidly implement knowledge to predict future behavior. PMID- 29499432 TI - Verbal task demands are key in explaining the relationship between paired associate learning and reading ability. AB - Paired-associate learning (PAL) tasks measure the ability to form a novel association between a stimulus and a response. Performance on such tasks is strongly associated with reading ability, and there is increasing evidence that verbal task demands may be critical in explaining this relationship. The current study investigated the relationships between different forms of PAL and reading ability. A total of 97 children aged 8-10 years completed a battery of reading assessments and six different PAL tasks (phoneme-phoneme, visual-phoneme, nonverbal-nonverbal, visual-nonverbal, nonword-nonword, and visual-nonword) involving both familiar phonemes and unfamiliar nonwords. A latent variable path model showed that PAL ability is captured by two correlated latent variables: auditory-articulatory and visual-articulatory. The auditory-articulatory latent variable was the stronger predictor of reading ability, providing support for a verbal account of the PAL-reading relationship. PMID- 29499433 TI - Exogenous gibberellic acid application induces the overexpression of key genes for pedicel lignification and an increase in berry drop in table grape. AB - Most table grape (Vitis vinifera L.) varieties require gibberellic acid (GA3) applications to obtain an adequate berry size in order to satisfy market requirements. However, GA3 treatments also produce severe berry drop in some cultivars, which occurs mainly after a cold storage period during post-harvest. Berry drop in bunches treated with GA3 has been related to the hardening and thickening of the pedicel produced by the over-accumulation of cellulose and its lignification. The main goal of this study was to compare the morphology and gene expression in pedicel samples of genotypes contrasting for berry drop susceptibility. These genotypes are Thompson Seedless, which exhibits a low incidence of berry drop, and a genetic line (Line #23) of INIA's breeding program that is very susceptible to berry drop at harvest and after storage in bunches sprayed with GA3. The parameters measured to study this phenomenon during fruit growth and post-harvest storage included fruit detachment force (FDF), hardness and thickness of the pedicel and berry drop frequency. Histological analyses of pedicel structures at harvest showed an increase in cell size and deposition of lignin in the cortex zone in both contrasting genotypes treated with GA3. The expression profile in both genotypes of the key lignin biosynthesis genes Vv4CL4, VvCCR1L and VvCAD1 analyzed by quantitative real time PCR (qPCR) revealed evident changes in response to GA3 treatments. In particular, gene VvCAD1 is overexpressed (100X) in pedicels of line #23 treated with GA3 after 30 and 45 days in cold storage compared to control. Moreover, the frequency of berry drop was higher for Line #23 treated with GA3 than for the control (23% vs. 1%). Our results suggest that gibberellic acid regulates the expression of the biosynthesis of lignin genes, generating changes in cell wall composition and pedicel structure that result in an increase in berry drop. PMID- 29499434 TI - Systems-level feedback regulation of cell cycle transitions in Ostreococcus tauri. AB - Ostreococcus tauri is the smallest free-living unicellular organism with one copy of each core cell cycle genes in its genome. There is a growing interest in this green algae due to its evolutionary origin. Since O. tauri is diverged early in the green lineage, relatively close to the ancestral eukaryotic cell, it might hold a key phylogenetic position in the eukaryotic tree of life. In this study, we focus on the regulatory network of its cell division cycle. We propose a mathematical modelling framework to integrate the existing knowledge of cell cycle network of O. tauri. We observe that feedback loop regulation of both G1/S and G2/M transitions in O. tauri is conserved, which can make the transition bistable. This is essential to make the transition irreversible as shown in other eukaryotic organisms. By performing sequence analysis, we also predict the presence of the Greatwall/PP2A pathway in the cell cycle of O. tauri. Since O. tauri cell cycle machinery is conserved, the exploration of the dynamical characteristic of the cell division cycle will help in further understanding the regulation of cell cycle in higher eukaryotes. PMID- 29499435 TI - Desi chickpea genotypes tolerate drought stress better than kabuli types by modulating germination metabolism, trehalose accumulation, and carbon assimilation. AB - Chickpea is mostly grown in rainfed environments and, consequently, its growth is affected by drought stress. This study comprised two independent experiments to investigate the physiological basis of drought tolerance in desi and kabuli chickpea genotypes. In Experiment 1, six genotypes each of desi and kabuli types were planted in soil-filled pots under natural conditions. Ten days after planting, soil moisture was maintained at 75% water holding capacity (well watered) or 50% water holding capacity (drought stress). Drought stress significantly reduced seedling dry weight, specific leaf area (SLA), and transpiration efficiency (TE) in both chickpea types, relative to the well watered controls, but their responses varied, with relatively fewer reductions in desi genotypes, Bakhar-2011 and Bitall-2016, and kabuli genotypes, K-70005 and Noor-2013. These four genotypes were used in experiment 2, which was similar to the first but conducted in a climate chamber and the drought was imposed at planting. Drought stress reduced stand establishment, growth, photosynthesis, water relations, alpha-amylase activity, sugar metabolism, proline, phenolic accumulation, nitrogen and potassium to varying degrees in the four tested genotypes. The reductions were greater in kabuli genotypes than desi genotypes. Under drought stress, desi genotypes germinated better, and had higher trehalose, total and reducing sugars, sucrose, alpha-amylase activity, photosynthesis, growth, and mineral concentrations than kabuli genotypes. The desi genotype Bakhar-2011 performed better under drought than the desi genotype Bitall-2016 due to better germination metabolism and accumulation of free proline, total phenolics, and trehalose, which maintained carbon assimilation and prevented oxidative damage. In conclusion, desi chickpea types tolerate drought stress better than kabuli types due to better germination metabolism and trehalose accumulation, which prevented oxidative damage, helped with efficient water use, and sustained plant growth. PMID- 29499436 TI - Fully-automated alignment of 3D fetal brain ultrasound to a canonical reference space using multi-task learning. AB - Methods for aligning 3D fetal neurosonography images must be robust to (i) intensity variations, (ii) anatomical and age-specific differences within the fetal population, and (iii) the variations in fetal position. To this end, we propose a multi-task fully convolutional neural network (FCN) architecture to address the problem of 3D fetal brain localization, structural segmentation, and alignment to a referential coordinate system. Instead of treating these tasks as independent problems, we optimize the network by simultaneously learning features shared within the input data pertaining to the correlated tasks, and later branching out into task-specific output streams. Brain alignment is achieved by defining a parametric coordinate system based on skull boundaries, location of the eye sockets, and head pose, as predicted from intracranial structures. This information is used to estimate an affine transformation to align a volumetric image to the skull-based coordinate system. Co-alignment of 140 fetal ultrasound volumes (age range: 26.0 +/- 4.4 weeks) was achieved with high brain overlap and low eye localization error, regardless of gestational age or head size. The automatically co-aligned volumes show good structural correspondence between fetal anatomies. PMID- 29499437 TI - Engineering functional and histological regeneration of vascularized skeletal muscle. AB - Tissue engineering strategies to treat patients with volumetric muscle loss (VML) aim to recover the structure and contractile function of lost muscle tissue. Here, we assessed the capacity of novel electrospun fibrin hydrogel scaffolds seeded with murine myoblasts to regenerate the structure and function of damaged muscle within VML defects to the mouse tibialis anterior muscle. The electrospun fibrin scaffolds provide pro-myogenic alignment and stiffness cues, myomimetic hierarchical structure, suturability, and scale-up capabilities. Myoblast-seeded scaffolds enabled remarkable muscle regeneration with high myofiber and vascular densities after 2 and 4 weeks, mimicking that of native skeletal muscle, while acellular scaffolds lacked muscle regeneration. Both myoblast-seeded and acellular scaffolds fully recovered muscle contractile function to uninjured values after 2 and 4 weeks. Electrospun scaffolds pre-vascularized with co cultured human endothelial cells and human adipose-derived stem cells implanted into VML defects for 2 weeks anastomosed with host vasculature and were perfused with host red blood cells. These data demonstrate the significant potential of electrospun fibrin scaffolds seeded with myoblasts to fully regenerate the structure and function of volumetric muscle defects and these scaffolds offer a promising treatment option for patients with VML. PMID- 29499438 TI - Necroptotic cancer cells-mimicry nanovaccine boosts anti-tumor immunity with tailored immune-stimulatory modality. AB - Recent breakthroughs in cancer immunotherapy offer new paradigm-shifting therapeutic options for combating cancer. Personalized therapeutic anti-cancer vaccines training T cells to directly fight against tumor cells endogenously offer tremendous benefits in working synergistically with immune checkpoint inhibitors. Biomimetic nanotechnology offers a versatile platform to boost anticancer immunity by efficiently co-delivering optimized immunogenic antigen materials and adjuvants to antigen presenting cells (APC). Necroptotic tumor cells can release danger associated molecule patterns (DAMPs) like heat shock proteins, being more immunogenic than naive tumor cells. Here, nano-size "artificial necroptotic cancer cell" (alphaHSP70p-CM-CaP) composing of phospholipid bilayer and a phosphate calcium core was designed as a flexible vaccine platform for co-delivering cancer membrane proteins (CM), DAMPs signal augmenting element alpha-helix HSP70 functional peptide (alphaHSP70p) and CpG to both natural killer (NK) cells and APC. Mechanically, immunogenic B16OVA tumor cells membrane-associated antigens and alphaHSP70p were reconstituted in artificial outer phospholipid bilayer membrane via one-step hydration and CpG encapsulated in the phosphate calcium core. The resulted alphaHSP70p-CM-CaP exhibited 30 nm in diameter with the immunogenic membrane proteins reserved in the particles to produce synergistic effect on bone marrow derived dendritic cells maturation and antigen-presentation. Following alphaHSP70p-CM-CaP vaccination, efficient lymph node trafficking and multi-epitope-T cells response was observed in mice. Vitally, alphaHSP70p-CM-CaP was also able to induce expansion of IFN-gamma-expressing CD8+ T cells and NKG2D+ NK cells subsets. Most promisingly, alphaHSP70p-CM-CaP vaccination led to the killing of target cells and tumor regression in vivo when combined with anti-PD-1 antibody treatment on mice B16OVA melanoma models. Altogether, we demonstrated proof-of-concept evidence for the feasibility, capability and safety of a nanovaccine platform towards efficient personalized anticancer application. PMID- 29499439 TI - Outcomes during anticoagulation in patients with symptomatic vs. incidental splanchnic vein thrombosis. AB - INTRODUCTION: Current guidelines recommend the use of anticoagulant therapy in patients with symptomatic splanchnic vein thrombosis (SVT) and suggest no routine anticoagulation in those with incidental SVT. METHODS: We used the RIETE (Registro Informatizado Enfermedad Trombo Embolica) registry to assess the rate and severity of symptomatic venous thromboembolism (VTE) recurrences and major bleeding events appearing during the course of anticoagulation in patients with symptomatic or incidental SVT. RESULTS: In March 2017, 521 patients with SVT were recruited. Of them, 212 (41%) presented with symptomatic SVT and 309 had incidental SVT. Most (93%) patients received anticoagulant therapy (median, 147 days). During the course of anticoagulation, 20 patients developed symptomatic VTE recurrences (none died) and 26 had major bleeding (fatal bleeding, 5). On multivariable analysis, patients with incidental SVT had a non-significantly higher risk for symptomatic VTE recurrences (adjusted hazard ratio [HR]: 2.04; 95%CI: 0.71-5.88) and a similar risk for major bleeding (HR: 1.12; 95%CI: 0.47 2.63) than those with symptomatic SVT. Active cancer was associated with at increased risk for VTE recurrences (HR: 3.06; 95%CI: 1.14-8.17) and anaemia (HR: 4.11; 95%CI: 1.45-11.6) or abnormal prothrombin time (HR: 4.10; 95%CI: 1.68-10.1) were associated with at increased risk for major bleeding. CONCLUSIONS: The rates of recurrent SVT and major bleeding were similar between patients with incidental or symptomatic SVT. Because the severity of bleeding complications during anticoagulation may outweigh the severity of VTE recurrences in both groups, further studies should identify those SVT patients who benefit from anticoagulant therapy. PMID- 29499440 TI - 7Be concentration in the near-surface layer of the air in Bialystok (north eastern Poland) in the years 1992-2010. AB - Weekly measurements of air 7Be concentrations (n = 769) were performed in the years 1992-2010 in Bialystok (north-eastern Poland) using gamma spectrometry. The arithmetic mean (AM) concentration of 7Be was 2.51 mBq m-3, and the median (M) was 2.24 mBq m-3 (range 0.47-7.81 mBq m-3). The observed 7Be concentrations were within the range of levels recorded in Europe. Typical seasonal variability was observed. Concentrations of 7Be in the warm season (May, June, July) were almost twice as high as those in the cold season (November, December, January). A correlation was found between weekly 7Be concentrations and mean weekly values of relative humidity, temperature, and wind speed throughout the observation period. Pearson's correlation coefficients were -0.63, p < 0.001; 0.477, p < 0.001; 0.288, p < 0.001, respectively. The correlation coefficient between sunspot number and mean annual 7Be concentrations in the air in the years 1992-2010 was 0.609. PMID- 29499441 TI - Short transverse myelitis in Chinese patients with neuromyelitis optica spectrum disorders. AB - BACKGROUND: Short transverse myelitis (STM) is considered uncommon in neuromyelitis optica spectrum disorders (NMOSD). Poor recognition of STM occurring in NMOSD may lead to increased delay in diagnosis and appropriate treatment. OBJECTIVES: The aim of this study was to assess the frequency and characteristics of STM in Chinese patients with NMOSD. METHODS: We enrolled 91 patients with NMOSD based on the 2015 International Consensus Diagnostic Criteria for NMOSD. The patients were divided into STM group and longitudinally extensive transverse myelitis (LETM) group according to the length of initial spinal cord lesions at the initial myelitis manifestation of NMOSD. RESULTS: Initial STM was observed in 18 patients (18/91, 19.8%). The STM episode was the first manifestation of NMOSD in 9 patients (50%) and preceded by optic neuritis in 3 patients (16.7%), area postrema syndrome in 5(27.8%) and brainstem syndrome in 1(5.6%). Compared to the NMOSD patients with an initial LETM, patients with STM suffered less motor and bowel or bladder disability, had minor EDSS at clinical onset, but suffered earlier relapse (P<.05). Thirteen patients had single short spinal lesion (13/18, 72.2%) and 5 patients had two short lesions. Of the 23 STM lesions, 4 lesions spanned 2.5 vertebral segments, 12 showed a length of continuous 2 vertebral segments, 7 were confined to single vertebral segment. The lesions on axial imaging involved the central grey matter in 61.1% (11/18) patients with STM and in 95.9%(70/73)patients with LETM (P<.05). Both the patients with STM(50%)and LETM (34.2%) had brain lesions. CONCLUSIONS: Initial STM does not exclude consideration of NMOSD diagnosis. PMID- 29499442 TI - Autoimmune GFAP astrocytopathy after viral encephalitis: A case report. AB - Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a novel autoimmune disease. This is the first report of a case of autoimmune GFAP astrocytopathy after herpes simplex viral encephalitis (HSVE). A 35-year-old female patient presented with a combination of headache, fever, seizure and psychiatric/behavioral abnormalities. She had GFAP-IgG in both serum and cerebrospinal fluid (CSF). Magnetic resonance imaging (MRI) with gadolinium enhancement revealed linear enhancement oriented radially to the ventricles. After treatment with corticosteroids, her symptoms were alleviated, the lesions enhancement reduced, and the immunoreactive intensity of GFAP-IgG decreased. This case shows an observational link between HSVE and autoimmune GFAP astrocytopathy, suggesting that autoimmune GFAP astrocytopathy may provide a new differential diagnosis for relapsing HSVE. PMID- 29499443 TI - Creatinine as a normalization factor to estimate the representativeness of urine sample - Intra-subject and inter-subject variability studies. AB - In-vitro bioassay monitoring generally involves analysis of overnight urine samples (~12 h) collected from radiation workers to estimate the excretion rate of radionuclides from the body. The unknown duration of sample collection (10-16 h) adds to the overall uncertainty in computation of internal dose. In order to minimize this, IAEA recommends measurement of specific gravity or creatinine excretion rate in urine. Creatinine is excreted at a steady rate with normally functioning kidneys therefore, can be used as a normalization factor to infer the duration of collection and/or dilution of the sample, if any. The present study reports the chemical procedure standardized and its application for the estimation of creatinine as well as creatinine co-efficient in normal healthy individuals. Observations indicate higher inter-subject variability and lower constancy in daily excretion of creatinine for the same subject. Thus creatinine excretion rate may not be a useful indicator for extrapolating to 24 h sample collection. PMID- 29499444 TI - N values estimation based on photon flux simulation with Geant4 toolkit. AB - N values are routinely introduced in photon activation analysis (PAA) as the ratio of special activities of product nuclides to compare the relative intensities of different reaction channels. They determine the individual activities of each radioisotope and the total activity of the sample, which are the primary concerns of radiation safety. Traditionally, N values are calculated from the gamma spectroscopy in real measurements by normalizing the activities of individual nuclides to the reference reaction [58Ni(gamma, n)57Ni] of the nickel monitor simultaneously irradiated in photon activation. Is it possible to use photon flux simulated by Monte Carlo software to calculate N values even before the actual irradiation starts? This study has applied Geant4 toolkit, a popular platform of simulating the passage of particles through matter, to generate photon flux in the samples. Assisted with photonuclear cross section from IAEA database, it is feasible to predict N values in different experimental setups for simulated target material. We have validated of this method and its consistency with Geant4. Results also show that N values are highly correlated with the beam parameters of incoming electrons and the setup of the electron-photon converter. PMID- 29499445 TI - Measurement of activation cross sections of alpha particle induced reactions on iridium up to an energy of 50 MeV. AB - Cross sections of alpha particle induced nuclear reactions on iridium were investigated using a 51.2-MeV alpha particle beam. The standard stacked-foil target technique and the activation method were applied. The activity of the reaction products was assessed without chemical separation using high resolution gamma-ray spectrometry. Excitation functions for production of gold, platinum and iridium isotopes (196m2Au, 196m,gAu, 195m,gAu, 194Au, 193 m,gAu, 192Au, 191m,gAu, 191Pt, 195mPt, 194gIr, 194mIr, 192gIr, 190gIr and 189Ir) were determined and compared with available earlier measured experimental data and results of theoretical calculations using TALYS code system. Cross section data were reported for the first time for the natIr(alpha,x)196m2Au, natIr(alpha,x)196m,gAu, natIr(alpha,x)191Pt, natIr(alpha,x)195mPt, natIr(alpha,x)194gIr, natIr(alpha,x)194mIr, natIr(alpha,x)190gIr and natIr(alpha,x)189Ir processes. A possible production route for 195mPt, the potentially important radionuclide in nuclear medicine, is discussed. PMID- 29499446 TI - Ehlers-Danlos syndromes and epilepsy: An updated review. AB - The Ehlers-Danlos syndromes (EDS) comprise a clinically and genetically heterogeneous group of heritable connective tissue disorders (HCTDs), characterised by joint hypermobility, hyperextensibility of the skin and tissue fragility that can induce symptoms from multiple organ systems. The latest EDS nosology distinguished thirteen subtypes with an overlap of phenotypic features, making the clinical diagnosis rather difficult and highlighting the importance of molecular diagnostic confirmation. Although the nervous system is not considered a primary target of the underlying molecular defect, recently, increasing attention has been focused on neurological manifestations of EDS. Among them, epilepsy represents a frequent cause of morbidity in these syndromes and can influence the long-term evolution of these patients, but the mechanisms are needed to be clarified. The aim of this review is to give a comprehensive overview and to analyze a possible association between EDS and epilepsy, focusing on the various brain anomalies and the types of epilepsy reported in patients affected by EDS. PMID- 29499447 TI - Neurocognitive functioning and quality of life in patients with and without deficit syndrome of schizophrenia. AB - Deficit syndrome of schizophrenia is a subtype of schizophrenia characterized by primary and enduring negative symptoms. This study examined the differences in neurocognitive functioning and quality of life (QOL) between deficit and non deficit patients, and specific predictors of both clinical measures. Overall, 344 subjects (175 patients with non-deficit schizophrenia (NDSZ), 58 patients with deficit schizophrenia (DSZ) and 111 healthy controls) were evaluated on severity of psychopathology, QOL and a smaller subset of 198 subjects (104 NDSZ, 27 DSZ, 67 healthy controls) underwent neurocognitive assessments. Multivariate analyses were used to determine differences in outcomes between subject groups and predictors of clinical measures. Both DSZ and NDSZ had significantly worse QOL compared with healthy controls. DSZ had more extensive cognitive deficits compared with healthy controls and performed worse on semantic fluency task compared to NDSZ. Multiple linear regression analysis found that DSZ, shorter duration of illness were associated with poorer QOL whereas fewer years of education, lower premorbid intelligence were associated with poorer overall neurocognitive functioning. The poorer QOL, greater extent of neurocognitive deficits especially semantic fluency associated with DSZ behoves the need for greater attention during clinical evaluation and treatment planning of this subgroup of individuals with schizophrenia. PMID- 29499448 TI - Ensemble of shape functions and support vector machines for the estimation of discrete arm muscle activation from external biceps 3D point clouds. AB - BACKGROUND: Muscle activation level is currently being captured using impractical and expensive devices which make their use in telemedicine settings extremely difficult. To address this issue, a prototype is presented of a non-invasive, easy-to-install system for the estimation of a discrete level of muscle activation of the biceps muscle from 3D point clouds captured with RGB-D cameras. METHODS: A methodology is proposed that uses the ensemble of shape functions point cloud descriptor for the geometric characterization of 3D point clouds, together with support vector machines to learn a classifier that, based on this geometric characterization for some points of view of the biceps, provides a model for the estimation of muscle activation for all neighboring points of view. This results in a classifier that is robust to small perturbations in the point of view of the capturing device, greatly simplifying the installation process for end-users. RESULTS: In the discrimination of five levels of effort with values up to the maximum voluntary contraction (MVC) of the biceps muscle (3800 g), the best variant of the proposed methodology achieved mean absolute errors of about 9.21% MVC - an acceptable performance for telemedicine settings where the electric measurement of muscle activation is impractical. CONCLUSIONS: The results prove that the correlations between the external geometry of the arm and biceps muscle activation are strong enough to consider computer vision and supervised learning an alternative with great potential for practical applications in tele-physiotherapy. PMID- 29499449 TI - Radiocesium contamination in house dust within evacuation areas close to the Fukushima Daiichi nuclear power plant. AB - Outdoor decontamination efforts have been ongoing since the Fukushima Daiichi nuclear power plant (FDNPP) accident; however, little is known about indoor contamination. Therefore, house dust was sampled based on particle size in 21 wooden buildings (19 residential houses and 2 community centers) within the evacuation area close to the FDNPP, Fukushima Prefecture, Japan. Activities of radiocesium (137Cs) per gram of house dust increased with decreasing particle size (mean: 6.1 * 103, 2.6 * 103, 1.6 * 103, 7.5 * 102, 5.0 * 102, and 4.6 * 102 Bq/g for <4-20, 20-63, 63-180, 180-500, 500-1000, and 1000-2000 MUm, respectively). The 137Cs concentrations in house dust were inversely related to the square of distance from the FDNPP for <4-1000 MUm particles. From the results of the multiple linear regression analysis, distance from the FDNPP and direction from the FDNPP (northwest) were significantly related to the radioactivity of house dust. It was found that 19%, 33%, and 48% of 137Cs in house dust were extracted in water, 1 M HCl, and not extracted, respectively. Considering the bioaccessibility and assuming a 20 mg/day daily intake of house dust, the daily doses would be 7.2 Bq/day (mean) and 18 Bq/day (95th percent quantile). These results provide valuable insight into indoor radioactive Cs contamination in the area around the FDNPP and possible oral exposure to indoor radioactive Cs after returning home. PMID- 29499451 TI - High-throughput profiling of seasonal variations of antibiotic resistance gene transport in a peri-urban river. AB - The rapid expansion of human activity in a region can exacerbate human health risks induced by antibiotic resistance genes (ARGs). Peri-urban ecosystems serve at the symbiotic interface between urban and rural ecosystems, and investigations into the dissemination of ARGs in peri-urban areas provide a basic framework for tracking the spread of ARGs and potential mitigations. In this study, through the use of high-throughput quantitative PCR and 16S rRNA gene high-throughput sequencing, seasonal and geographical distributions of ARGs and their host bacterial communities were characterized in a peri-urban river. The abundance of ARGs in downstream was 5.2-33.9 times higher than upstream, which indicated distinct antibiotic resistance pollution in the areas where human lives. With the comparison classified based on land use nearby, the abundance of ARGs in samples near farmland and villages was higher than in the background (3.47-5.58 times), pointing to the high load in the river caused by farming and other human activities in the peri-urban areas. With the co-occurrence pattern revealed by network analysis, blaVEB and tetM were proposed to be indicators of ARGs which get together in the same module. Furthermore, seasonal variations in ARGs and the transport of bacterial communities were observed. The effects of seasonal temperature on the dissemination of ARGs along the watershed was also evaluated. The highest absolute abundance of ARGs occurred in summer (2.81 * 109 copies/L on average), the trends of ARG abundances in four seasons were similar with local air temperature. The Linear discriminant analysis effect size (LEfSe) suggested that nine bacterial genera were implicated as biomarkers for the corresponding season. Mobile genetic elements (MGEs) showed significant positive correlation with ARGs (P < 0.01) and MGEs were also identified as the key-contributing factor driving ARG alteration. This study provides an overview of seasonal and geographical variations in ARGs distribution in a peri-urban river and draws attention to controlling pollutants in peri-urban ecosystems. PMID- 29499452 TI - Mixture effects in samples of multiple contaminants - An inter-laboratory study with manifold bioassays. AB - Chemicals in the environment occur in mixtures rather than as individual entities. Environmental quality monitoring thus faces the challenge to comprehensively assess a multitude of contaminants and potential adverse effects. Effect-based methods have been suggested as complements to chemical analytical characterisation of complex pollution patterns. The regularly observed discrepancy between chemical and biological assessments of adverse effects due to contaminants in the field may be either due to unidentified contaminants or result from interactions of compounds in mixtures. Here, we present an interlaboratory study where individual compounds and their mixtures were investigated by extensive concentration-effect analysis using 19 different bioassays. The assay panel consisted of 5 whole organism assays measuring apical effects and 14 cell- and organism-based bioassays with more specific effect observations. Twelve organic water pollutants of diverse structure and unique known modes of action were studied individually and as mixtures mirroring exposure scenarios in freshwaters. We compared the observed mixture effects against component-based mixture effect predictions derived from additivity expectations (assumption of non-interaction). Most of the assays detected the mixture response of the active components as predicted even against a background of other inactive contaminants. When none of the mixture components showed any activity by themselves then the mixture also was without effects. The mixture effects observed using apical endpoints fell in the middle of a prediction window defined by the additivity predictions for concentration addition and independent action, reflecting well the diversity of the anticipated modes of action. In one case, an unexpectedly reduced solubility of one of the mixture components led to mixture responses that fell short of the predictions of both additivity mixture models. The majority of the specific cell- and organism-based endpoints produced mixture responses in agreement with the additivity expectation of concentration addition. Exceptionally, expected (additive) mixture response did not occur due to masking effects such as general toxicity from other compounds. Generally, deviations from an additivity expectation could be explained due to experimental factors, specific limitations of the effect endpoint or masking side effects such as cytotoxicity in in vitro assays. The majority of bioassays were able to quantitatively detect the predicted non-interactive, additive combined effect of the specifically bioactive compounds against a background of complex mixture of other chemicals in the sample. This supports the use of a combination of chemical and bioanalytical monitoring tools for the identification of chemicals that drive a specific mixture effect. Furthermore, we demonstrated that a panel of bioassays can provide a diverse profile of effect responses to a complex contaminated sample. This could be extended towards representing mixture adverse outcome pathways. Our findings support the ongoing development of bioanalytical tools for (i) compiling comprehensive effect-based batteries for water quality assessment, (ii) designing tailored surveillance methods to safeguard specific water uses, and (iii) devising strategies for effect-based diagnosis of complex contamination. PMID- 29499450 TI - Epigenetics as a mechanism linking developmental exposures to long-term toxicity. AB - A variety of experimental and epidemiological studies lend support to the Developmental Origin of Health and Disease (DOHaD) concept. Yet, the actual mechanisms accounting for mid- and long-term effects of early-life exposures remain unclear. Epigenetic alterations such as changes in DNA methylation, histone modifications and the expression of certain RNAs have been suggested as possible mediators of long-term health effects of environmental stressors. This report captures discussions and conclusions debated during the last Prenatal Programming and Toxicity meeting held in Japan. Its first aim is to propose a number of criteria that are critical to support the primary contribution of epigenetics in DOHaD and intergenerational transmission of environmental stressors effects. The main criteria are the full characterization of the stressors, the actual window of exposure, the target tissue and function, the specificity of the epigenetic changes and the biological plausibility of the linkage between those changes and health outcomes. The second aim is to discuss long-term effects of a number of stressors such as smoking, air pollution and endocrine disruptors in order to identify the arguments supporting the involvement of an epigenetic mechanism. Based on the developed criteria, missing evidence and suggestions for future research will be identified. The third aim is to critically analyze the evidence supporting the involvement of epigenetic mechanisms in intergenerational and transgenerational effects of environmental exposure and to particularly discuss the role of placenta and sperm. While the article is not a systematic review and is not meant to be exhaustive, it critically assesses the contribution of epigenetics in the long-term effects of environmental exposures as well as provides insight for future research. PMID- 29499453 TI - Gold-manganese oxide nanocomposite suppresses hypoxia and augments pro inflammatory cytokines in tumor associated macrophages. AB - The tumor microenvironment, essentially hypoxic, is sustained by the hypoxia inducing factor (HIF), released from the pro-tumorigenic tumor associated macrophages (TAMs), functionally identical to the M2 phenotype macrophages. Stability of HIF mainly depends on molecular oxygen and an iron-dependent enzyme prolyl hydroxylase, while its activity may be inhibited by high levels of reactive oxygen species and nitric oxide. The present work showcases a novel approach utilizing the anti-tumorigenic potential of a gold-manganese oxide nanocomposite material in the tumor microenvironment that affects tumor hypoxia, exploring the possibility of restoring the immunoregulatory nature of TAMs from their pro-tumorigenic state. Along with the biochemical markers, ELISA and FACS analyses have also confirmed the potential of these nanoparticles in reverting back the M2 phenotype of TAMs to their classically activated M1 phenotype. PMID- 29499454 TI - Lack of tocopherols influences the PSII antenna and the functioning of photosystems under low light. AB - As tocopherols are expected to protect PSII against toxic singlet oxygen it is surprising that the null tocopherol mutant vte1 has been reported to show only a weak enhancement of photosystem II photoinhibition under high irradiance. Based on the view that singlet oxygen is formed also in unstressed conditions, such as low light (LL), we hypothesized that some defense strategies are activated in vte1 in these light conditions. In support for that we noted several symptoms of stress at PSII in the mutant under LL, by means of parameters of fast and slow kinetics of chlorophyll fluorescence and of changes in the relative contribution of PSII antenna in comparison to those of PSI. This was associated with a lower extent of phosphorylation of PSII core proteins (D1 and CP43). PSII RCs do not totally recover from stress in vte1 even after the nocturnal phase. As a clear compensation for the impeded performance of PSII in the vte1 we noted an increased quantum efficiency of PSI. A pronounced changes between WT and the vte1 mutant were also related to conformation of LHCII at the beginning of photoperiod, suggesting the absence of LHCII trimers in the mutant. The thylakoids thickness was similar in WT and vte1 under LL, but a pronounced unstacking of thylakoids was evoked by HL only in vte1. In conclusion, we postulate that action of 1O2 on PSII in vte1 leads to some permanent damage at PSII core and at LHCII already under LL. PMID- 29499455 TI - The effect of chitin nanoparticles on surface behavior of DPPC/DPPG Langmuir monolayers. AB - The effect of chitin nanoparticles on surface behavior of lipid systems containing dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylglycerol (DPPG) is studied by surface pressure (pi)-area (A) isotherms, polarization-modulation infrared reflection absorption spectroscopy (PM-IRRAS), Brewster angle microscopy (BAM). The variation of surface behavior of DPPC/DPPG monolayers is induced mainly by electrostatic interactions between nanoparticles and head groups of phospholipids. At lower surface pressure, nanoparticles can penetrate into the monolayers and the positive charges carried by nanoparticles benefits the enrichment of phospholipid molecules at surface, which not only increases the mean molecular area but also hinders the formation of phospholipid liquid-condensed (LC) phase. However, when surface pressure is higher, the nanoparticles flee away from the surface and some of the phospholipid molecules are pulled out of the monolayers together to the subphase and decrease the order degree of the monolayers. Moreover, nanoparticles can destroy the hydrogen-bond between water molecules and phosphate head groups and thus lead to the dehydration of phosphate groups. This work confirms that chitin nanoparticles can affect the surface behavior of DPPC/DPPG monolayers. Furthermore, the results obtained using mixed monolayer containing two major lung surfactants DPPC/DPPG and nanoparticles will be helpful for deep understanding the harm of PM2.5 to lung health. PMID- 29499456 TI - Designing a stable feedback control system for blind image deconvolution. AB - Blind image deconvolution is one of the main low-level vision problems with wide applications. Many previous works manually design regularization to simultaneously estimate the latent sharp image and the blur kernel under maximum a posterior framework. However, it has been demonstrated that such joint estimation strategies may lead to the undesired trivial solution. In this paper, we present a novel perspective, using a stable feedback control system, to simulate the latent sharp image propagation. The controller of our system consists of regularization and guidance, which decide the sparsity and sharp features of latent image, respectively. Furthermore, the formational model of blind image is introduced into the feedback process to avoid the image restoration deviating from the stable point. The stability analysis of the system indicates the latent image propagation in blind deconvolution task can be efficiently estimated and controlled by cues and priors. Thus the kernel estimation used for image restoration becomes more precision. Experimental results show that our system is effective on image propagation, and can perform favorably against the state-of-the-art blind image deconvolution methods on different benchmark image sets and special blurred images. PMID- 29499457 TI - Thermal expansion coefficient measurement from electron diffraction of amorphous films in a TEM. AB - We measured the linear thermal expansion coefficients of amorphous 5-30 nm thick SiN and 17 nm thick Formvar/Carbon (F/C) films using electron diffraction in a transmission electron microscope. Positive thermal expansion coefficient (TEC) was observed in SiN but negative coefficients in the F/C films. In case of amorphous carbon (aC) films, we could not measure TEC because the diffraction radii required several hours to stabilize at a fixed temperature. PMID- 29499458 TI - Synthesis, structural and antimicrobial studies of type II topoisomerase-targeted copper(II) complexes of 1,3-disubstituted thiourea ligands. AB - A series of Cu(II) complexes of 3-(trifluoromethyl)phenylthiourea derivatives was synthesized. Their structural properties were investigated by spectroscopic techniques (infrared and electron paramagnetic resonance), as well as molecular modeling. All studied coordination compounds are mononuclear complexes containing two chelating ligands bonded to the metal cation via S and deprotonated N atoms. The new chelates were evaluated for their antimicrobial potency. The complex of 1 (3,4-dichlorophenyl)-3-[3-(trifluoromethyl)phenyl]thiourea (3) presented the highest activity against Gram-positive pathogens, even stronger than the activity of its non-complexed counterpart and the reference drug. The compound also prevented the biofilm formation of methicillin-resistant and standard strains of staphylococcal cocci. The title derivatives were found to be effective inhibitors of DNA gyrase and topoisomerase IV isolated from Staphylococcus aureus. The binding modes of the ligand L3 with DNA gyrase and topoisomerase IV were presented. PMID- 29499459 TI - Computational design of the helical hairpin structure of membrane-active antibacterial peptides based on RSV glycoprotein epitope scaffold. AB - Peptides with helical hairpin conformation have been found to possess potent membrane activity and can be exploited as the structural scaffold of antibacterial peptides (ABPs). Here, we attempted to computationally design membrane-active ABPs based on the helical hairpin motif of respiratory syncytial virus (RSV) glycoprotein epitope. Dynamics simulations revealed that the epitope peptide Rfe (net charge = -1) cannot effectively interact with and permeabilize bacterial membrane due to the electrostatic repulsion between the negatively charged peptide and anionic membrane surface. The native Rfe can be modified to a cationic peptide Rfe-KKK (net charge = +6) by triple mutation of its positively charged residues Glu256, Asp263 and Asp269 to a basic lysine as well as by C terminal amidation. As might be expected, the modified peptide was able to target membrane surface with a moderate antibacterial potency (MIC = 50-100 MUg/ml). Next, a cyclized version of the linear Rfe-KKK was generated, termed as cycRfe KKK, which was observed to have improved membrane activity and increased antibacterial potency (MIC < 50 MUg/ml) by pre-stabilizing amphipathic hairpin conformation of the peptide. PMID- 29499460 TI - Rapid, reliable, and sensitive detection of adenosine deaminase activity by UHPLC Q-Orbitrap HRMS and its application to inhibitory activity evaluation of traditional Chinese medicines. AB - Adenosine deaminase (ADA), which is a key enzyme in the metabolism of purine nucleosides, plays important roles in diverse disorders, such as tuberculosis, diabetes, liver disorders, and cancer. Determination of the activities of ADA and its isoenzymes in body fluids has received considerable attention in the diagnosis and treatment of relative diseases. Ultraviolet spectroscopy with adenosine (AD) as a substrate is a classical approach for screening potential ADA inhibitors by measuring the decrease in substrate (AD) at 265 nm or increase in the product (inosine) at 248 nm. However, AD and inosine share a very close maximum absorption wavelength, and the reaction is uncertain and is frequently interfered by the background color of matrix compounds or plant extracts. Thus, the method usually yields false positive or negative results. In this study, a novel, rapid, sensitive, and accurate ultra-high-performance liquid chromatography-Q exactive hybrid quadrupole orbitrap high-resolution accurate mass spectrometric (UHPLC-Q-Orbitrap HRMS) method was developed for determining and screening ADA inhibitors by directly determining the deamination product of AD, inosine. A proper separation was achieved for inosine and chlormequat (internal standard) within 2 min via isocratic elution (0.1% formic acid:methanol = 85:15, v/v) at a flow rate of 0.3 mL min-1 on a Waters ACQUITY HSS T3 column (2.1 mm * 100 mm, 1.8 MUm) following a simple precipitation of proteins. The intra- and inter-day precisions of the developed method were below 7.17% and 8.99%, respectively. The method exhibited advantages of small total reaction volume (60 MUL), short running time (2 min), high sensitivity (lowest limit of quantification of 0.02 MUM for inosine), and low cost (small enzyme consumption of 0.007 unit mL-1 for ADA and substrate of 3.74 MUM for AD in individual inhibition), and no matrix effects (101.64%-107.12%). Stability results showed that all analytes were stable under the investigated conditions. The developed method was successfully applied to the detection of the inhibitory activity of ADA from traditional Chinese medicines. PMID- 29499461 TI - Glycosimilarity assessment of biotherapeutics 1: Quantitative comparison of the N glycosylation of the innovator and a biosimilar version of etanercept. AB - The carbohydrate moieties on the polypeptide chains in most glycoprotein based biotherapeutics and their biosimilars play essential roles in such major mechanisms of actions as antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, anti-inflammatory functions and serum clearance. In addition, alteration in glycosylation may influence the safety and efficacy of the product. Glycosylation, therefore, is considered as one of the important critical quality attributes of glycoprotein biotherapeutics, and consequently for their biosimilar counterparts. Thus, the carbohydrate moieties of such biopharmaceuticals (both innovator and biosimilar products) should be closely scrutinized during all stages of the manufacturing process. In this paper we introduce a rapid, capillary gel electrophoresis based process to quantitatively assess the glycosylation aspect of biosimilarity (referred to as glycosimilarity) between the innovator and a biosimilar version of etanercept (Enbrel(r) and Benepali(r), respectively), based on their N-linked carbohydrate profiles. Differences in sialylated, core fucosylated, galactosylated and high mannose glycans were all quantified. Since the mechanism of action of etanercept is TNFalpha binding, only mannosylation was deemed as critical quality attribute for glycosimilarity assessment due to its influence on serum half-life. PMID- 29499462 TI - Identification, characterization and HPLC quantification of formulation-related impurities of honokiol, an antitumor natural drug candidate in clinical trials. AB - Natural products and their derivatives have historically been invaluable as a source of therapeutic agents. Honokiol, as a well-known natural product in Chinese herbal medicine Houpu, is finally being studied in a Phase I clinical trial (CTR20170822) in patients with Advanced Non-Small Cell Lung Cancer (NSCLS) in China this year. During the honokiol liposome formulation process, five major impurities were present in the range of 0.05-0.1% based on the HPLC analysis. These five major impurities were obtained from the forced degradation product of honokiol through countercurrent chromatography and prep-HPLC. The structure were elucidated with 1H NMR, 13C NMR, 2D NMR and MS spectral data. The proposed HPLC method was validated for specificity, linearity (concentration range 0.01-1.62, 0.003-0.96, 0.05-7.98, 0.04-6.52, 0.03-5.18 MUg/ml for impurities I-V respectively, R2 > 0.9988), accuracy (99.11-100.67%), precision (CV < 1.6%), and sensitivity (LOD 3.3, 0.1, 16.7, 13.3, 10.0 ng/ml for impurities I-V respectively). The validated method was employed in the further study of the honokiol drug substance. PMID- 29499463 TI - Catalytic potential of bio-synthesized silver nanoparticles using Convolvulus arvensis extract for the degradation of environmental pollutants. AB - Herein, we reported a facile, green and environmental friendlier biosynthesis of silver nanoparticles using the Convolvulus arvensis extract. The influences of various physicochemical factors such as the concentration of the plant extract, reaction time, and different pH levels were investigated by UV-Vis spectroscopy. The UV-Visible absorption spectrum of biogenic silver nanoparticles at lambdamax around ~400 nm suggested the biosynthesis of silver nanoparticles. Fourier transform infrared spectroscopy was employed to confirm the chemical transformation and role of various phyto-reductants in the conversion of Ag+ to Ag0. The surface morphology, topography, and elemental composition were analyzed by scanning electron microscopy, transmission electron microscopy, and energy dispersive X-ray spectroscopy, respectively. X-ray diffraction corroborated the face-centered cubic crystalline structure. The dynamic light scattering and zeta potential demonstrate the size distribution (90.9 nm) and surface charge (-18.5). Finally, the newly developed C. arvensis based silver nanoparticles were exploited as a catalyst for the catalytic reduction of azo dyes in the presence of NaBH4 as a reducing agent, and reducing the activity of C. arvensis based silver nanoparticles was evaluated by a decrease in optical density using UV-Vis spectrophotometer. The nanoparticles developed herein displayed potential efficiency for the degradation of all the tested dye pollutants. Conclusively, plant-based synthesis of nanoparticles provides an environmentally-responsive option for the reduction of highly environmental-polluted organic compounds including toxic azo dyes as compared to chemical and physical methods. PMID- 29499464 TI - Simultaneous quantification of three alkylated-purine adducts in human urine using sulfonic acid poly(glycidyl methacrylate-divinylbenzene)-based microspheres as sorbent combined with LC-MS/MS. AB - Three alkylated DNA adducts, N3-methyladenine, N3-ethyladenine and N7 ethylguanine, have been proved to be potential biomarkers for DNA injury caused by exposure to cigarette smoke. In this study, a highly specific and sensitive method using a new mixed-mode sulfonate-functionalized poly(glycidyl methacrylate divinylbenzene) as a solid-phase extraction sorbent was developed for the analysis of these three alkylated-purine adducts in human urine. Under optimized conditions, the prepared sorbent interacts strongly with these urinary adducts, demonstrating high clean-up efficiency and extraction recovery. The method detection limits (S/N >= 3) of N3-MeA, N3-EtA and N7-EtG were 1.75, 0.20, and 0.15 pg mL-1, respectively, while the method quantitation limits were found to be 5.78, 0.66, and 0.49 pg mL-1 for N3-MeA, N3-EtA and N7-EtG, respectively. The intra-day and inter-day precisions were investigated, of which were in the range of 1.6-3.8% and 3.2-5.6%, respectively. The recovery values of the alkylated DNA adducts in spiked urine sample were ranged 89.7-104.5%. Their concentrations were statistically significantly higher in smokers than in nonsmokers. These results show that the proposed method is suitable for the analysis of alkylated DNA adducts. PMID- 29499465 TI - Supercritical fluid chromatographic-tandem mass spectrometry method for monitoring dissipation of thiacloprid in greenhouse vegetables and soil under different application modes. AB - A rapid, sensitive and effective supercritical fluid chromatographic-tandem mass spectrometry (SFC-MS/MS) method was developed to analyze thiacloprid for the first time. The SFC-MS/MS conditions were optimized with the ultra-performance convergence chromatography (UPC2) BEH column (100 mm * 3.0 mm, 1.7 MUm particle size) and thiacloprid was eluted at 1.22 min in gradient mode with CO2/methanol as mobile phase. The 0.1% formic acid in methanol (v/v) was used as postcolumn compensation solution to improve sensitivity. The ABPR pressure, flow rate of mobile phase and flow rate of compensation pump were set at 1800 psi, 1.8 mL/min, and 0.1 mL/min, respectively. The average recoveries of thiacloprid in soil at four spiking levels (5, 10, 100, 1000 MUg/kg) ranged between 78.8% and 107.1% with relative standard deviations (RSDs) lower than 12.2% and the limit of quantitation (LOQ) was 5 MUg/kg. The proposed method can distinctly improve the analysis efficiency by 2-12 times and reduce the solvent consumption by 5%-95% compared with reported methods. It was applied to investigate the dissipation rates of thiacloprid in greenhouse vegetables and soil under different application modes. The half-lives of thiacloprid in cucumber and soil were 9.55 20.44 days and 3.74-9.14 days separately under different application modes, 10.60 days in tomato under foliar spraying. The residues in vegetables under root irrigation were all less than that under foliar spraying. The results could offer useful data for risk assessment of thiacloprid in agricultural production. PMID- 29499467 TI - Adverse physiological and psychological effects of screen time on children and adolescents: Literature review and case study. AB - : A growing body of literature is associating excessive and addictive use of digital media with physical, psychological, social and neurological adverse consequences. Research is focusing more on mobile devices use, and studies suggest that duration, content, after-dark-use, media type and the number of devices are key components determining screen time effects. Physical health effects: excessive screen time is associated with poor sleep and risk factors for cardiovascular diseases such as high blood pressure, obesity, low HDL cholesterol, poor stress regulation (high sympathetic arousal and cortisol dysregulation), and Insulin Resistance. Other physical health consequences include impaired vision and reduced bone density. Psychological effects: internalizing and externalizing behavior is related to poor sleep. Depressive symptoms and suicidal are associated to screen time induced poor sleep, digital device night use, and mobile phone dependency. ADHD-related behavior was linked to sleep problems, overall screen time, and violent and fast-paced content which activates dopamine and the reward pathways. Early and prolonged exposure to violent content is also linked to risk for antisocial behavior and decreased prosocial behavior. Psychoneurological effects: addictive screen time use decreases social coping and involves craving behavior which resembles substance dependence behavior. Brain structural changes related to cognitive control and emotional regulation are associated with digital media addictive behavior. A case study of a treatment of an ADHD diagnosed 9-year-old boy suggests screen time induced ADHD-related behavior could be inaccurately diagnosed as ADHD. Screen time reduction is effective in decreasing ADHD-related behavior. CONCLUSIONS: Components crucial for psychophysiological resilience are none-wandering mind (typical of ADHD-related behavior), good social coping and attachment, and good physical health. Excessive digital media use by children and adolescents appears as a major factor which may hamper the formation of sound psychophysiological resilience. PMID- 29499466 TI - Alkaloids with neuroprotective effects from the leaves of Isatis indigotica collected in the Anhui Province, China. AB - Six undescribed alkaloids, indiforine A-F, together with four known ones, were isolated from the leaves of Isatis indigotica Fortune. Their structures were elucidated on the basis of extensive spectroscopic analyses. The absolute configurations of indiforine A and B were determined by comparison of the experimental and calculated electronic circular dichroism spectra, as well as experimental and calculated optical rotations. The isolated alkaloids were evaluated for their neuroprotective activities against H2O2-induced cell injury in human neuroblastoma SH-SY5Y cells. The results showed that in H2O2-induced SH SY5Y cell injury models, indiforine A and B exhibited potent neuroprotective activities. Further investigation of the most potent indiforine A by Hoechst 33258 staining and Annexin V/PI analysis demonstrated that it could protect SH SY5Y cells from oxidative damage through inhibiting cell apoptosis. PMID- 29499468 TI - Persistent organic pollutants and organophosphate esters in feathers and blood plasma of adult kittiwakes (Rissa tridactyla) from Svalbard - associations with body condition and thyroid hormones. AB - Polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), organochlorine pesticides (OCPs) and organophosphate esters (OPEs) were assessed in blood plasma and feathers of 19 adult black-legged kittiwakes (Rissa tridactyla) breeding in two colonies (Blomstrandhalvoya and Krykkjefjellet) at the Arctic archipelago, Svalbard. Potential associations with body condition index (BCI) and thyroid hormones were investigated. All compound classes were detected in both blood plasma and feathers, but due to low sample size and volumes, OPEs could only be quantified in four individuals, warranting larger follow-up studies. Kittiwakes breeding at Blomstrandhalvoya had significantly higher concentrations of organic pollutants in blood plasma than kittiwakes breeding at Krykkjefjellet (p < 0.001). Concentrations in blood plasma and feathers did not significantly correlate for any of the investigated compounds, and feather concentrations did not differ significantly between the colonies. This suggests that pollutant levels in adult kittiwake feathers do not reflect local contamination at breeding sites and are as such not useful to monitor local contamination at Svalbard. Significant negative associations between BCI and most pollutants were found in both populations, whereas significant correlations between the BCI, the ratio of total triiodothyronine to free triiodothyronine (TT3:fT3), and several pollutants were only found for kittiwakes from Blomstrandhalvoya (all r >= -0.60 and p <= 0.05). This indicates that higher levels of circulating pollutants during the breeding period covary with the TT3: fT3 ratio, and may act as an additional stressor during this period. PMID- 29499469 TI - Polycyclic aromatic hydrocarbons bioaccessibility in seafood: Culinary practices effects on dietary exposure. AB - This work aimed to determine the effect of culinary practices on the contamination level and bioaccessibility of polycyclic aromatic hydrocarbons (PAHs) in seafood. The selected farmed seafood species (marine shrimp, clams and seaweed) were commercially available in Portugal. The mean concentrations of PAHs varied between 0.23 and 51.8 ug kg-1, with the lowest value being observed in raw shrimp and the highest in dried seaweed. The number of compounds detected in seaweed and clams (naphthalene, acenaphthene, fluorene, phenanthrene, benzo(b)fluoranthene and benzo(j)fluoranthene) were higher than in shrimp (fluorene and pyrene). Among the PAHs measured, fluorene was the predominant one. There was a significant interaction effect between species and culinary treatment (p < 0.05), thus boiled and dried seaweed samples presented the lowest and the highest levels of fluorene (0.13 and 1.8 ug kg-1), respectively. The daily intake of PAHs decreased with bioaccessibility, varying from 22% for benzo(k)fluoranthene (in raw clam) to 84% for phenanthrene (in steamed clam). According to the potency equivalent concentrations, screening values and bioaccessibility of PAHs, the consumption of marine shrimp, clam and seaweed is considered as safe for consumers. PMID- 29499470 TI - A counterfactual impact evaluation of a bilingual program on students' grade point average at a spanish university. AB - This observational study intends to estimate the causal effects of an English as a Medium of Instruction (EMI) program (as predictor) on students Grade Point Average (GPA) (as outcome) at a particular University in Spain by using a Counterfactual Impact Evaluation (CIE). The need to address the crucial question of causal inferences in EMI programs to produce credible evidences of successful interventions contrasts, however, with the absence of experimental or quasi experimental research and evaluation designs in the field. CIE approach is emerging as a methodologically viable solution to bridge that gap. The program evaluated here consisted in delivering an EMI program in a Primary Education Teacher Training Degree group. After achieving balance on the observed covariates and recreating a situation that would have been expected in a randomized experiment, three matching approaches such as genetic matching, nearest neighbor matching and Coarsened Exact Matching were used to analyze observational data from a total of 1288 undergraduate students, including both treatment and control group. Results show unfavorable effects of the bilingual group treatment condition. Potential interpretations and recommendations are provided in order to strengthen future causal evidences of bilingual education programs' effectiveness in Higher Education. PMID- 29499471 TI - Effect of wobble board training on movement strategies to maintain equilibrium on unstable surfaces. AB - Standing on unstable surfaces requires more complex motor control mechanisms to sustain balance when compared to firm surfaces. Surface instability enhances the demand to maintain equilibrium and is often used to challenge balance, but little is known about how balance training affects movement strategies to control posture while standing on unstable surfaces. This study aimed at assessing the effects of isolated wobble board (WB) training on movement strategies to maintain balance during single-leg standing on a WB. Twenty healthy men were randomly assigned to either a control or a training group. The training group took part in four weeks of WB training and both groups were tested pre and post the intervention. Electromyography from the supporting lower limb muscles, full-body kinematics and ground reaction forces were recorded during firm surface (FS) and WB single-leg standing. WB training did not affect FS performance (p = 0.865), but tripled WB standing time (p < 0.002). Moreover, training decreased lower leg muscle activation (29-59%), leg and trunk velocities (30% and 34%, respectively), and supporting limb angular velocity (24-47% across all planes for the ankle, knee and hip joints). Post intervention standing time was significantly correlated with angular velocities at the hip (r = 0.79) and knee (r = -0.83) for controls, while it correlated significantly with contra-lateral leg (r ~ 0.70) and trunk velocity (r = -0.74) for trained participants. These results support the assumption that WB training enhances the ability to control counter-rotation mechanisms for balance maintenance on unstable surfaces, which may be a crucial protective factor against sports injuries. PMID- 29499472 TI - Concordance of mitochondrial DNA sequencing methods on bloodstains using Ion PGMTM. AB - In this study, the complete mitochondrial genome (mtGenome) of six samples from three forensic cases was sequenced using the Ion Torrent Personal Genome Machine (PGM). The analyzed samples from forensic cases included bloodstains from several materials, such as gauze, Flinder's Technology Associates (FTA) cards and swabs. The age of the samples ranged from two months to twelve years. The complete mtGenomes were amplified using the tiling sequencing strategy which divided the whole mtGenome into 162 amplicons. All amplicons were successfully recovered. A phylogenetic analysis was performed to determine the accuracy of the PGM data, and which were compared to partial Sanger-based sequencing data. The average coverage of the PGM data were above 4000* in all case samples, and 99.86% concordance was observed using both sequencing methods. In conclusion, we demonstrate the ability to recover the complete mtGenome from bloodstains with relatively poor DNA quality by PGM. Moreover, the results are concordant with Sanger sequencing data. This new method has potential use in forensic practice. PMID- 29499473 TI - Effects of adjunctive eslicarbazepine acetate on serum lipids in patients with partial-onset seizures: Impact of concomitant statins and enzyme-inducing antiepileptic drugs. AB - PURPOSE: To evaluate the effects of eslicarbazepine acetate (ESL) on lipid metabolism and to determine whether reduced statin exposure during ESL therapy has clinical consequences. SUBJECTS AND METHODS: We conducted a post-hoc analysis of pooled data for serum lipids (laboratory values) from three phase III, multicenter, randomized, double-blind, placebo-controlled trials of adjunctive ESL therapy (400, 800, or 1200 mg once daily) in patients with treatment refractory partial-onset seizures. Changes from baseline in serum lipid levels were analyzed according to use of statins and/or enzyme-inducing antiepileptic drugs (EIAEDs) during the baseline period. KEY FINDINGS: In total, 426 and 1021 placebo- and ESL-treated patients, respectively, were included in the analysis. With regard to the changes from baseline in serum concentrations, there were statistically significant differences between the placebo and ESL 1200 mg QD groups, for both total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C), but the effect sizes were small (+4.1 mg/dL and +1.8 mg/dL, respectively). A small but significant difference in low-density lipoprotein cholesterol (LDL-C; -5.0 mg/dL) was observed between the ESL 400 mg QD group and the placebo group. In patients not taking a concomitant EIAED, there were no changes with ESL 400 mg QD, but modest and statistically significant increases in cholesterol fractions (TC, LDL-C and HDL-C) with ESL 800 mg QD (<6 mg/dL) and ESL 1200 mg QD (<10 mg/dL). ESL had no consistent effect on lipids in patients taking a concomitant EIAED. In patients taking statins during baseline, there were no clinically relevant changes in serum lipids during use of ESL, although the subgroups were small. SIGNIFICANCE: These results suggest that ESL does not appear to have clinically significant effects on serum lipids, nor does the pharmacokinetic interaction between ESL and statins have an impact on serum lipid concentrations. PMID- 29499474 TI - DNA methylation of ANKK1 and response to aripiprazole in patients with acute schizophrenia: A preliminary study. AB - Epigenetic modification including DNA methylation may affect pathophysiology and the response to antipsychotic drugs in patients with schizophrenia. The objective of the present study was to investigate the effect of the DNA methylation of ANKK1 (ankyrin repeat and kinase domain containing 1) on the response to aripiprazole and plasma levels of monoamine metabolites in antipsychotic-free acute schizophrenia patients. The subjects were 34 Japanese patients with schizophrenia who had been treated with aripiprazole for 6 weeks. Comprehensive DNA methylation of ANKK1 was determined using a next-generation sequencer. DNA methylation levels at CpG site 387 of ANKK1 were higher in responders to treatment with aripiprazole and correlated with the changes in Positive and Negative Syndrome Scale scores, although the associations did not remain significant after Bonferroni correction. In responders, methylation at all CpG sites was significantly correlated with plasma levels of homovanillic acid (r = 0.587, p = 0.035) and 3-methoxy-4hydroxyphenylglycol (r = 0.684, p = 0.010) at baseline. Despite our non-significant results after multiple correction, our preliminary findings suggest that methylation levels at CpG site 387 of ANKK1 may be associated with treatment response to aripiprazole. Furthermore, methylation of ANKK1 may affect dopaminergic neural transmission in the treatment of schizophrenia, and may influence treatment response. Caution is needed in interpreting these findings because of the small sample size, and further studies are needed to confirm and expand our preliminary results. PMID- 29499475 TI - Cocaine + nicotine mixture enhances induction and expression of behavioral sensitization in rats. AB - BACKGROUND: Psychoactive substance abuse is a health problem worldwide. Has been reported a high prevalence of use of tobacco and cocaine, either separately or in combination. Clinical and animal studies have suggested that the concurrent use of cocaine and nicotine reinforces the potency of one or both drugs and that nicotine may enhance the reinforcing effects of cocaine. Our study evaluated the combined effects of cocaine and nicotine on locomotor activity during the induction and expression phases of locomotor sensitization-a physiological mechanism that plays an important role in establishing some of the defining characteristics of drug abuse. METHODS: We used Wistar rats which were dosed with cocaine, nicotine or cocaine and nicotine combination and recorded their locomotor activity in different phases of the experiment. RESULTS: We found that a daily dose of cocaine combined with nicotine enhanced cocaine- and nicotine induced locomotor activity, as well as induction and expression of locomotor sensitization. Moreover, we found that pretreatment with nicotine enhanced the locomotor sensitization expression. CONCLUSION: These results suggest that concurrent use of cocaine and nicotine may result in co-abuse of these drugs. PMID- 29499477 TI - Proteomics of cyanobacteria: current horizons. AB - Application of proteomics has made a profound impact on the cyanobacterial research. It has not only provided a global identification of expressed proteins in cyanobacterial cells, but has also brought valuable insights into dynamics of cell responses to environmental challenges, regulation mechanisms, structure of protein complexes, compartmentalization, and other important biological questions. In this review, we highlight current trends in proteomics of cyanobacteria and bring to focus rising techniques which have a huge potential in expanding our knowledge about cyanobacterial proteins and in developing cyanobacteria-based biotechnological applications. PMID- 29499476 TI - Pharmacognosy in the digital era: shifting to contextualized metabolomics. AB - Humans have co-evolved alongside numerous other organisms, some having a profound effect on health and nutrition. As the earliest pharmaceutical subject, pharmacognosy has evolved into a meta-discipline devoted to natural biomedical agents and their functional properties. While the acquisition of expanding data volumes is ongoing, contextualization is lagging. Thus, we assert that the establishment of an integrated and open databases ecosystem will nurture the discipline. After proposing an epistemological framework of knowledge acquisition in pharmacognosy, this study focuses on recent computational and analytical approaches. It then elaborates on the flux of research data, where good practices could foster the implementation of more integrated systems, which will in turn help shaping the future of pharmacognosy and determine its constitutional societal relevance. PMID- 29499478 TI - Is the Ebbinghaus illusion a size contrast illusion? AB - The Ebbinghaus illusion, in which a central target surrounded by larger context figures looks smaller than when surrounded by smaller context figures, is usually classified as a size contrast illusion. Thus "size contrast" is the dominant account of this effect. However, according to an alternative "contour interaction" account this phenomenon has little to do with size contrast but is rather caused by distance-dependent attractive and repulsive interactions between neural representation of contours. Here evidence is presented against the size contrast account and consistent with the contour interaction account. Experiment 1 was a control study confirming that the illusion can be obtained using displays consisting only of squares, which are more convenient to manipulate than the standardly used circles. In Experiment 2, the standard configuration involving small context figures surrounding the target was compared to a novel configuration, which involved many "spread" small context figures. The illusory effect of the standard context was stronger than the illusory effect of the spread context, in accord with the prediction of the contour interaction account, and contrary to the prediction of the size contrast account. In Experiment 3 two novel configurations were used, based on standard and spread contexts. The results were in accord with the prediction of the contour interaction account, whereas the size contrast account had no prediction because the stimuli did not involve conventional size contrast. Additional aspects of the stimuli and an account of the illusion based on a perspective interpretation are also discussed. PMID- 29499479 TI - Meaningful participation for children in the Dutch child protection system: A critical analysis of relevant provisions in policy documents. AB - Policymakers are increasingly focusing on the participation of children in the child protection system (CPS). However, research shows that actual practice still needs to be improved. Embedding children's participation in legislation and policy documents is one important prerequisite for achieving meaningful participation in child protection practice. In this study, the participation of children in the Dutch CPS under the new Youth Act 2015 is critically analyzed. National legislation and policy documents were studied using a model of "meaningful participation" based on article 12 of the UNCRC. Results show that the idea of children's participation is deeply embedded in the current Dutch CPS. However, Dutch policy documents do not fully cover the three dimensions of what is considered to be meaningful participation for children: informing, hearing, and involving. Furthermore, children's participation differs among the organizations included in the child protection chain. A clear overall policy concerning the participation of children in the Dutch CPS is lacking. The conclusions of this critical analysis of policy documents and the framework of meaningful participation presented may provide a basis for the embedding of meaningful participation for children in child protection systems of other countries. PMID- 29499480 TI - Numerical investigation of the relationship between pin deviations and joint coordinates of a unilateral external fixator. AB - BACKGROUND: Fracture correction is an important orthopedic operation, which can be performed using a unilateral external fixator. Regulating the rotational and translational joints of the fixator is usually necessary to correct complex deformities. However, pin deviations inevitably occur during surgery, and the fixator has its own limitations. Therefore, the relationship between fixator joint adjustment and pin deviations must be identified and discussed. METHODS: The influence of pin deviation on the fixator joint adjustment was analyzed using the inverse kinematics method based on a 6-DOF unilateral external fixator. The effect of multiple pin deviations on fixator joint was also discussed. FINDINGS: This study reveals that the single pin deviations in different axes affect different fixator joints. When multiple deviations occur simultaneously, the regulated quantity is equal to the sum of that of each deviation. INTERPRETATION: Reasonable pin placement can reduce the joint adjustment values and prevent reaching limit values of fixator joint, which aids in expanding the application scope of the fixator. This research can also help reduce the duration of orthopedic surgeries, if the relationship between pin deviation and joint adjustment is known in advance. PMID- 29499481 TI - Shoulder mechanical demands of slow underwater exercises in the scapular plane. AB - BACKGROUND: The mechanical demands of underwater shoulder exercises have only been assessed indirectly via electromyographical measurements. Yet, this is insufficient to understand all the clinical implications. The purpose of this study was to evaluate musculoskeletal system loading during slow (30 degrees /s) scapular plane arm elevation and lowering performed in two media (air vs water) and body positions (sitting vs supine). METHODS: Eighteen participants' upper bodies were scanned and virtually animated within unsteady numerical fluid flow simulations to compute hydrodynamic forces. Together with weight, buoyancy and segment inertial parameters, these were fed into an inverse dynamics model to obtain net shoulder moments, power and work. FINDINGS: Positive mechanical work done at the shoulder was 32.4% (95% CI [29.2, 35.6]) and 25.0% [22.8, 27.2] that when performing the same movement on land, supine and sitting respectively. Arm elevation was ~2.5* less demanding sitting than supine (mean 0.012 (SD 0.018) vs mean 0.027 (SD 0.012) J.kg-1, P = 0.034). Instantaneous power was consistently positive when sitting albeit very low during elevation (0.003 W.kg-1) whereas, when supine, it was alternately negative for short period (~1.2 s) and positive (~4.8 s), peaking at levels 3* higher (0.01 W.kg-1). INTERPRETATION: Performing sitting elicited concentric muscle contractions at very low effort, which is advantageous during early rehabilitation to restore joint mobility. Exercising supine, by contrast, required rapid pre-stretch followed by concentric force production at an overall higher mechanical cost, and is therefore better suited to more advanced rehabilitation stages. PMID- 29499482 TI - The functional 3'-end of immunoglobulin heavy chain variable (IGHV) genes. AB - Inference of antibody gene repertoires using transcriptome data has emerged as an alternative approach to the complex process of sequencing of adaptive immune receptor germline gene loci. The diversity introduced during rearrangement of immunoglobulin heavy chain variable (IGHV), diversity, and joining genes has however been identified as potentially affecting inference specificity. In this study, we have addressed this issue by analysing the nucleotide composition of unmutated human immunoglobulin heavy chains-encoding transcripts, focusing on the 3o most bases of 47 IGHV germline genes. Although transcripts derived from some of the germline genes predominately incorporated the germline encoded base even at position 320, the last base of most IGHV genes, transcripts originating in other genes presented other nucleotides to the same extent at this position. In transcripts derived from two of the germline genes, IGHV3-13*01 and IGHV4-30 2*01, the predominating nucleotide (G) was in fact not that of the gene (A). Hence, we suggest that inference of IGHV genes should be limited to bases preceding nucleotide 320, as inference beyond this would jeopardize the specificity of the inference process. The different degree of incorporation of the final base of the IGHV gene directly influences the distribution of amino acids of the ascending strand of the third complementarity determining region of the heavy chain. Thereby it influences the nature of this specificity-determining part of the antibody population. In addition, we also present data that indicate the existence of a common so far un-recognized allelic variant of IGHV3-7 that carries an A318G difference in relation to IGHV3-7*02. PMID- 29499483 TI - Discovery and characterization of a potent Wnt and hedgehog signaling pathways dual inhibitor. AB - Embryonic stem cell pathways such as hedgehog and Wnt pathways are central to the tumorigenic properties of cancer stem cells (CSC). Since CSCs are characterized by their ability to self-renew, form differentiated progeny, and develop resistance to anticancer therapies, targeting the Wnt and hedgehog signaling pathways has been an important strategy for cancer treatment. Although molecules targeting either Wnt or hedgehog are common, to the best of our knowledge, those targeting both pathways have not been documented. Here we report a small molecule (compound 1) that inhibits both Wnt (IC50 = 0.5 nM) and hedgehog (IC50 = 71 nM) pathways based on reporter gene assays. We further identified that the molecular target of 1 for Wnt pathway inhibition was porcupine (a member of the membrane bound O-acyltransferase family of proteins), a post-translational modification node in Wnt signaling; while the target of 1 mitigating hedgehog pathway was Smoothened, a key G protein coupled receptor (GPCR) mediating hedgehog signal transduction. Preliminary analysis of structure-activity-relationship identified key functional elements for hedgehog/Wnt inhibition. In in vivo studies, compound 1 demonstrated good oral exposure and bioavailability while eliciting no overt toxicity in mice. An important consideration in cancer treatment is the potential therapeutic escape through compensatory activation of an interconnected pathway when only one signaling pathway is inhibited. Toward this end, compound 1 may not only lead to the development of new therapeutics for Wnt and hedgehog related cancers, but may also help to develop potential cancer treatment which needs to target Wnt and hedgehog signaling simultaneously. PMID- 29499484 TI - beta,gamma-diamino acids as building blocks for new analogues of Gramicidin S: Synthesis and biological activity. AB - We describe here the synthesis and biological activity study of a pair of diastereomeric analogues of Gramicidin S using beta,gamma-diamino acids as beta turn mimic. The synthesis of the orthogonally protected beta,gamma-diamino acids was achieved in 6 steps starting from d-alanine. The analogues were then synthesized in solution phase and on solid phase. Biological activity tests showed that, compared with Gramicidin S, both analogues exerted diminished hemolytic activity while they retained interesting antibacterial activity. PMID- 29499485 TI - Design, synthesis, and biological evaluation of compounds with a new scaffold as anti-neuroinflammatory agents for the treatment of Alzheimer's disease. AB - Twenty-eight compounds with a new scaffold were designed and synthesized by assembling fragments derived from known agents such as stilbenes and piperazinyl pyrimidines. Many strategies have been explored to improve the druggability of these series of compounds, such as increasing the distance between two benzene rings in the scaffold and introducing functional groups at designated positions. These compounds were validated for their anti-neuroinflammatory activity in BV2 cells. Experimental results reveal that the most active compound 8b can inhibit nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta) production with IC50 values of 1.0, 2.6, and 0.5 MUM, respectively. The compound can also significantly modulate the MAPK pathways through inhibiting the phosphorylation of JNK, ERK1/2, and p38 MAPK without disturbing NF-kappaB pathway. Parallel artificial membrane permeation assay demonstrated that the most active compound can overcome the blood-brain barrier (BBB). Therefore, this compound can be a promising lead for the treatment of Alzheimer's disease. PMID- 29499486 TI - Pyrazole-pyrazoline as promising novel antimalarial agents: A mechanistic study. AB - A series of pyrazole-pyrazoline substituted with benzenesulfonamide were synthesized and evaluated for their antimalarial activity in vitro and in vivo. The compounds were active against both chloroquine (CQ) sensitive (3D7) and CQ resistant (RKL-9) strains of Plasmodium falciparum. Seven compounds (7e, 7i, 7j, 7l, 7m, 7o and 7p) exhibiting EC50 less than 2 MUM. A mechanistic study of compound 7o revealed that these compound act through the inhibition of beta hematin. The study indicated that these compounds can serve as lead compounds for further development of potent antimalarial drugs. PMID- 29499487 TI - Rational modifications on a benzylidene-acrylohydrazide antiviral scaffold, synthesis and evaluation of bioactivity against Chikungunya virus. AB - Chikungunya virus is a re-emerging arbovirus transmitted to humans by Aedes mosquitoes, responsible for an acute febrile illness associated with painful and debilitating arthralgia, which can persist for several months or become chronic. Over the past few years, infection with this virus has spread worldwide with a previously unknown virulence. No specific antiviral treatments nor vaccines are currently available against this important pathogen. Starting from the structure of a class of selective anti-CHIKV agents previously identified in our research group, different modifications to this scaffold were rationally designed, and 69 novel small-molecule derivatives were synthesised and evaluated for their inhibition of Chikungunya virus replication in Vero cells. Further structure activity relationships associated with this class of antiviral agents were elucidated for the original scaffolds, and novel antiviral compounds with EC50 values in the low micromolar range were identified. This work provides the foundation for further investigation of these new structures as antivirals against Chikungunya virus. PMID- 29499488 TI - Endoperoxide-8-aminoquinoline hybrids as dual-stage antimalarial agents with enhanced metabolic stability. AB - Hybrid compounds may play a critical role in the context of the malaria eradication agenda, which will benefit from therapeutic tools active against the symptomatic erythrocytic stage of Plasmodium infection, and also capable of eliminating liver stage parasites. To address the need for efficient multistage antiplasmodial compounds, a small library of 1,2,4,5-tetraoxane-8- aminoquinoline hybrids, with the metabolically labile C-5 position of the 8-aminoquinoline moiety blocked with aryl groups, was synthesized and screened for antiplasmodial activity and metabolic stability. The hybrid compounds inhibited development of intra-erythrocytic forms of the multidrug-resistant Plasmodium falciparum W2 strain, with EC50 values in the nM range, and with low cytotoxicity against mammalian cells. The compounds also inhibited the development of P. berghei liver stage parasites, with the most potent compounds displaying EC50 values in the low MUM range. SAR analysis revealed that unbranched linkers between the endoperoxide and 8-aminoquinoline pharmacophores are most beneficial for dual antiplasmodial activity. Importantly, hybrids were significantly more potent than a 1:1 mixture of 8-aminoquinoline-tetraoxane, highlighting the superiority of the hybrid approach over the combination therapy. Furthermore, aryl substituents at C-5 of the 8-aminoquinoline moiety improve the compounds' metabolic stability when compared with their primaquine (i.e. C-5 unsubstituted) counterparts. Overall, this study reveals that blocking the quinoline C-5 position does not result in loss of dual-stage antimalarial activity, and that tetraoxane-8- aminoquinoline hybrids are an attractive approach to achieve elimination of exo- and intraerythrocytic parasites, thus with the potential to be used in malaria eradication campaigns. PMID- 29499489 TI - Facile synthesis of 1,2-dione-containing abietane analogues for the generation of human carboxylesterase inhibitors. AB - Recently, a series of selective human carboxylesterase inhibitors have been identified based upon the tanshinones, with biologically active molecules containing a 1,2-dione group as part of a naphthoquinone core. Unfortunately, the synthesis of such compounds is complex. Here we describe a novel method for the generation of 1,2-dione containing diterpenoids using a unified approach, by which boronic acids are joined to vinyl bromo-cyclohexene derivatives via Suzuki coupling, followed by electrocyclization and oxidation to the o phenanthroquinones. This has allowed the construction of a panel of miltirone analogues containing an array of substituents (methyl, isopropyl, fluorine, methoxy) which have been used to develop preliminary SAR with the two human carboxylesterase isoforms. As a consequence, we have synthesized highly potent inhibitors of these enzymes (Ki < 15 nM), that maintain the core tanshinone scaffold. Hence, we have developed a facile and reproducible method for the synthesis of abietane analogues that have resulted in a panel of miltirone derivatives that will be useful tool compounds to assess carboxylesterase biology. PMID- 29499490 TI - Synthesis and biological evaluation of alpha-santonin derivatives as anti hepatoma agents. AB - A series of alpha-santonin-derived compounds as potentially anti-hepatoma agents were designed and synthesized in an effort to find novel therapeutic agents. Among them, derivative 5h was more potent than the positive control 5 fluorouracil (5-Fu) on HepG-2, QGY-7703 and SMMC-7721 with IC50 values of 7.51, 3.06 and 4.08 MUM, respectively. The structure-activity relationships (SARs) of these derivatives were discussed. In addition, flow cytometry and western blot assay revealed that the derivatives induced hepatoma cells apoptosis by facilitating apoptosis-related proteins expressions. Our findings suggested that these alpha-santonin-derived analogues hold promise as chemotherapeutic agents for the treatment of human hepatocellular cancer. PMID- 29499492 TI - The impact of inverted text on visual word processing: An fMRI study. AB - Visual word recognition has been studied for decades. One question that has received limited attention is how different text presentation orientations disrupt word recognition. By examining how word recognition processes may be disrupted by different text orientations it is hoped that new insights can be gained concerning the process. Here, we examined the impact of rotating and inverting text on the neural network responsible for visual word recognition focusing primarily on a region of the occipto-temporal cortex referred to as the visual word form area (VWFA). A lexical decision task was employed in which words and pseudowords were presented in one of three orientations (upright, rotated or inverted). The results demonstrate that inversion caused the greatest disruption of visual word recognition processes. Both rotated and inverted text elicited increased activation in spatial attention regions within the right parietal cortex. However, inverted text recruited phonological and articulatory processing regions within the left inferior frontal and left inferior parietal cortices. Finally, the VWFA was found to not behave similarly to the fusiform face area in that unusual text orientations resulted in increased activation and not decreased activation. It is hypothesized here that the VWFA activation is modulated by feedback from linguistic processes. PMID- 29499491 TI - Zirconium catalyzed synthesis of 2-arylidene Indan-1,3-diones and evaluation of their inhibitory activity against NS2B-NS3 WNV protease. AB - A simple and efficient Knoevenagel procedure for the synthesis of 2-arylidene indan-1,3-diones is herein reported. These compounds were prepared via ZrOCl2.8H2O catalyzed reactions of indan-1,3-dione with several aromatic aldehydes and using water as the solvent. The 2-arylidene indan-1,3-diones were obtained with 53%-95% yield within 10-45 min. The synthesized compounds were evaluated as inhibitors of the NS2B-NS3 protease of West Nile Virus (WNV). It was found that hydroxylated derivatives impaired enzyme activity with varying degrees of effectiveness. The most active hydroxylated derivatives, namely 2-(4 hydroxybenzylidene)-1H-indene-1,3(2H)-dione (14) and 2-(3,4-dihydroxybenzylidene) 1H-indene-1,3(2H)-dione (17), were characterized as noncompetitive enzymes inhibitors, with IC50 values of 11 MUmol L-1 and 3 MUmol L-1, respectively. Docking and electrostatic potential surfaces investigations provided insight on the possible binding mode of the most active compounds within an allosteric site. PMID- 29499493 TI - Non-invasive brain stimulation to investigate language production in healthy speakers: A meta-analysis. AB - Non-invasive brain stimulation (NIBS) has become a common method to study the interrelations between the brain and language functioning. This meta-analysis examined the efficacy of transcranial magnetic stimulation (TMS) and direct current stimulation (tDCS) in the study of language production in healthy volunteers. Forty-five effect sizes from 30 studies which investigated the effects of NIBS on picture naming or verbal fluency in healthy participants were meta-analysed. Further sub-analyses investigated potential influences of stimulation type, control, target site, task, online vs. offline application, and current density of the target electrode. Random effects modelling showed a small, but reliable effect of NIBS on language production. Subsequent analyses indicated larger weighted mean effect sizes for TMS as compared to tDCS studies. No statistical differences for the other sub-analyses were observed. We conclude that NIBS is a useful method for neuroscientific studies on language production in healthy volunteers. PMID- 29499494 TI - Associations between nutritional quality of meals and snacks assessed by the Food Standards Agency nutrient profiling system and overall diet quality and adiposity measures in British children and adolescents. AB - OBJECTIVE: This cross-sectional study examined how the nutritional quality of meals and snacks was associated with overall diet quality and adiposity measures. METHODS: Based on 7-d weighed dietary record data, all eating occasions were divided into meals or snacks based on time (meals: 06:00-09:00 h, 12:00-14:00 h, and 17:00-20:00 h; snacks: others) or contribution to energy intake (meals: >=15%; snacks: <15%) in British children aged 4-10 (n = 808) and adolescents aged 11-18 (n = 809). The nutritional quality of meals and snacks was assessed as the arithmetical energy intake-weighted means of the Food Standards Agency (FSA) nutrient profiling system score of each food and beverage consumed, based on the contents of energy, saturated fatty acid, total sugar, sodium, fruits/vegetables/nuts, dietary fiber, and protein. RESULTS: Regardless of the definition of meals and snacks, higher FSA score (lower nutritional quality) of meals was inversely associated with overall diet quality assessed by the Mediterranean diet score in both children and adolescents (P <0.0001), whereas the inverse associations for the FSA score of snacks did not reach statistical significance. The FSA score of meals based on time was inversely associated with body mass index z-score only in children, whereas that of snacks based on time showed a positive association. CONCLUSION: Lower nutritional quality of meals, but not snacks, assessed by the FSA score was associated with lower overall diet quality, whereas no consistent associations were observed with regard to adiposity measures. PMID- 29499495 TI - Pathway governing nitrogen removal in artificially aerated constructed wetlands: Impact of aeration mode and influent chemical oxygen demand to nitrogen ratios. AB - This study aimed at assessing the influence of aeration mode and influent COD/N ratio on nitrogen removal in constructed wetlands (CWs). The results showed that a simultaneous partial nitrification, anammox and denitrification (SNAD) process was established in the intermittent aerated V1. While nitrogen removal pathway gradually changed from partial nitrification-denitrification to complete nitrification-denitrification along with reducing COD/N ratio in the continuous limited aerated V2. Effective inhibition of NOBs under intermittent aeration conditions, good retention of anammox bacteria biomass and much faster depletion of COD prior to substantial NH4+-N conversion jointly led to the successful achievement of stable SNDA process with elevated influent COD/N ratios in V1. Furthermore, the presence of SNAD ensured a robust ammonium (84-92%) and TN (80 91%) removal efficiency in V1 under varying COD loading rates. In contrast, the TN removal efficiency decreased rapidly along with the reducing influent COD/N ratios in V2. PMID- 29499496 TI - New insights into enhanced anaerobic degradation of Fischer-Tropsch wastewater with the assistance of magnetite. AB - In this study, magnetite (Fe3O4), as the typical conductive material, was supplemented in anaerobic sequential batch reactor (ASBR) with the attempt to enhance pollutants removal and methane production during Fischer-Tropsch wastewater treatment. The results showed that COD removal efficiency and cumulative methane production with the addition of optimum magnetite dosage (0.4 g) were as high as 84.3 +/- 2.0% and 7.46 +/- 0.24 L, which were higher than other test groups (0, 0.2 and 0.6 g). Furthermore, the combination of high throughput 16S rRNA gene pyrosequencing and metagenomic analysis in this study further confirmed that the Geobacter and Methanosaeta species were specially enriched in bacterial and archaeal community at the optimum magnetite dosage, suggesting that magnetite-mediated direct interspecies electron transfer (DIET) between Geobacter and Methanosaeta species was likely a crucial reason to promote syntrophic metabolism of propionic acid and butyric acid, and further enhance final methanogenesis. PMID- 29499497 TI - Enhancing cadmium bioremediation by a complex of water-hyacinth derived pellets immobilized with Chlorella sp. AB - A complex of water-hyacinth derived pellets immobilized with Chlorella sp. was applied, for the first time, in the bioremediation of Cadmium (Cd). The Cd(II) removal efficiency of the complex was optimized by investigating several parameters, including the pellet materials, algal culture age, and light intensity. Results showed that the Cd(II) removal efficiency was positively related to the algal immobilization efficiency and the algal bioaccumulation capacity. Since higher surface hydrophilicity leads to higher immobilization efficiency, the water-hyacinth leaf biochar pellet (WLBp) was selected as the optimal carrier. A maximum Cd(II) removal efficiency of 92.45% was obtained by the complex of WLBp immobilized with algal cells in stationary growth phase and illuminated with a light intensity of 119 MUmol m-2 s-1. Recovery tests on both microalgal cells and the WLBp demonstrated that the algal cells and the biochar pellet can be economically recycled and reused. PMID- 29499498 TI - Generation of a human iPSC line by mRNA reprogramming. AB - The human iPSC cell line, derived from foreskin fibroblasts was generated by non integrative, non-viral reprogramming technology using OCT4, SOX2, KLF4, LIN28, c MYC mRNAs. PMID- 29499499 TI - Generation of RAB39B knockout isogenic human embryonic stem cell lines to model RAB39B-mediated Parkinson's disease. AB - Mutations in RAB39B are a known cause of X-linked early onset Parkinson's disease. Isogenic human embryonic stem cell lines carrying two independent deletions of RAB39B were generated using CRISPR/Cas9 genome editing tool. The deletions were confirmed by PCR and direct sequence analysis in two edited stem cell lines. Both cell lines showed pluripotency and displayed a normal karyotype. Further, they were able to form embryoid bodies in vitro, and express markers indicative of differentiation to the three germ layers. PMID- 29499500 TI - Optimized procedures for generating an enhanced, near physiological 2D culture system from porcine intestinal organoids. AB - An important practical limitation of the three-dimensional geometry of stem-cell derived intestinal organoids is that it prevents easy access to the apical epithelium for testing food components, microorganisms, bioactive and toxic compounds. To this end, we here report on a new robust method for generating confluent intestinal cell monolayers from single-cell suspensions of enzymatically-dissociated porcine organoids using modified culture conditions. With this method, cell seeding densities can be standardised, overcoming problems with methods based on mechanical dissociation of organoids. Confluent monolayers formed tight junctions with high transepithelial electrical resistance in three days and could be used in experiments for up to two weeks. Multilineage differentiation of ileal stem cells was demonstrated by immunohistochemistry and RT-qPCR of cell-specific transcripts, also unequivocally confirming the controversial existence of Paneth-like cells in the porcine small intestine. The method described here is useful to standardize primary epithelial monolayer formation from intestinal organoids and allows rapid and robust studies of intestinal physiology. PMID- 29499501 TI - Basal forebrain septal nuclei are enlarged in healthy subjects prior to the development of Alzheimer's disease. AB - Alzheimer's disease (AD) is known to be associated with loss of cholinergic neurons in the nucleus basalis of Meynert, located in the posterior basal forebrain. Structural changes of septal nuclei, located in the anterior basal forebrain, have not been well studied in AD. Using a validated algorithm, we manually traced septal nuclei on high-resolution coronal magnetic resonance imaging (MRI) in 40 subjects with mild cognitive impairment (MCI) or AD, 89 healthy controls, and 18 subjects who were cognitively normal at the time of MRI but went on to develop AD an average of 2.8 years later. We found that cognitively normal subjects destined to develop AD in the future had enlarged septal nuclei as compared to both healthy controls and patients with current MCI or AD. To our knowledge, this is the first time a brain structure has been found to be enlarged in association with risk of AD. Further research is needed to determine if septal enlargement reflects neuroplastic compensation, amyloid deposition, inflammation, or another process and to determine whether it can serve as an early MRI biomarker of AD. PMID- 29499502 TI - 12-month prevalence and concomitants of DSM-IV depression and anxiety disorders in two violence-prone cities in Brazil. AB - BACKGROUND: Estimating 12-month prevalence of depression, anxiety, and comorbid anxiety/depression in noninstitutionalized adults (age 15-75) in two violence prone cities. METHODS: The Composite International Diagnostic Interview v2.1 (Portuguese), administered in population-representative surveys (age 15-75) in Sao Paulo (N = 2536) and Rio de Janeiro (N = 1208), yielded 12-month prevalence of violent events experienced, and DSM-IV diagnoses of depression and anxiety, which were classified into mutually exclusive groups: 1) no anxiety/depression; 2) anxiety only; 3) depression only; 4) comorbid anxiety/depression. Weighted analyses estimated 12-month prevalence, multinomial logistic regression compared the demographic characteristics of the diagnosis groups, and association with experienced violence. RESULTS: Twelve-month prevalence of anxiety alone, depression alone, and comorbid anxiety/depression was 12.7% (of whom 24.9% were also depressed), 4.9% (of whom 46.2% had anxiety), and 4.2% respectively for Sao Paulo; and 12.1% (18.2% of whom were depressed), 4.6% (37.0% with anxiety), and 2.7% respectively for Rio de Janeiro. All conditions were approximately twice as prevalent in women than in men in both cities. In Sao Paulo, comorbidity was associated with age under 60, depression alone was more prevalent among 30-59 year olds, but in 23-29 year-olds in Rio de Janeiro. Exposure to violence increased the odds of anxiety, depression, and their comorbidity. With rare exception, marital status, education, and race/ethnicity were not associated with anxiety, depression, or their comorbidity. LIMITATIONS: Cross-sectional design. CONCLUSIONS: Prevalence rates for all conditions were high, and particularly associated with exposure to violence. Means to ameliorate violence, and its mental health effects, particularly for women, are needed. PMID- 29499503 TI - Increased sensitivity to positive social stimuli in monozygotic twins at risk of bipolar vs. unipolar disorder. AB - BACKGROUND: Abnormalities in affective cognition are putative endophenotypes for bipolar and unipolar disorders but it is unclear whether some abnormalities are disorder-specific. We therefore investigated affective cognition in monozygotic twins at familial risk of bipolar disorder relative to those at risk of unipolar disorder and to low-risk twins. METHODS: Seventy monozygotic twins with a co-twin history of bipolar disorder (n = 11), of unipolar disorder (n = 38) or without co twin history of affective disorder (n = 21) were included. Variables of interest were recognition of and vigilance to emotional faces, emotional reactivity and regulation in social scenarios and non-affective cognition. RESULTS: Twins at familial risk of bipolar disorder showed increased recognition of low to moderate intensity of happy facial expressions relative to both unipolar disorder high risk twins and low-risk twins. Bipolar disorder high-risk twins also displayed supraliminal attentional avoidance of happy faces compared with unipolar disorder high-risk twins and greater emotional reactivity in positive and neutral social scenarios and less reactivity in negative social scenarios than low-risk twins. In contrast with our hypothesis, there was no negative bias in unipolar disorder high-risk twins. There were no differences between the groups in demographic characteristics or non-affective cognition. LIMITATIONS: The modest sample size limited the statistical power of the study. CONCLUSIONS: Increased sensitivity and reactivity to positive social stimuli may be a neurocognitive endophenotype that is specific for bipolar disorder. If replicated in larger samples, this 'positive endophenotype' could potentially aid future diagnostic differentiation between unipolar and bipolar disorder. PMID- 29499504 TI - A randomized controlled trial of an Internet delivered dialectical behavior therapy skills training for suicidal and heavy episodic drinkers. AB - BACKGROUND: Given that alcohol misuse elevates risk of suicide death among ideators, the paucity of treatment outcome research for individuals presenting with both suicide ideation and problem drinking is particularly troubling. Dialectical behavior therapy (DBT) skills training, which effectively targets behaviors associated with emotion dysregulation including addictive and suicidal behaviors, provides a fitting model amenable to computerization. As stigma and scarcity stand as potential barriers to treatment, online dissemination platforms provide means for efficient treatment delivery that can augment the utility of suitable interventions. This pilot RCT sought to evaluate the feasibility, acceptability, and preliminary efficacy of an Internet-delivered DBT skills training intervention (iDBT-ST) for suicidal individuals who engage in heavy episodic drinking METHODS: Participants (N = 59) were randomized to receive iDBT ST immediately or after an 8-week waiting period. Clinical outcomes were suicide ideation, alcohol use, and emotion dysregulation. RESULTS: Participants on average saw a significant reduction in all outcomes over the four-month study period. Compared to waitlist controls, individuals who received iDBT-ST immediately showed faster reductions in alcohol consumption. CONCLUSIONS: Preliminary results suggest that iDBT-ST may be a viable resource for the high risk and underserved group represented in this study, and pathways for future development are suggested. LIMITATIONS: There was difficulty retaining and engaging participants due to technological barriers. PMID- 29499505 TI - Association between genetic variation in the myo-inositol monophosphatase 2 (IMPA2) gene and age at onset of bipolar disorder. AB - INTRODUCTION: The age at onset of bipolar disorder (BD) has significant implications for severity, duration of affective episodes, response to treatment, and psychiatric comorbidities. It has been suggested that early-onset BD (EO-BD) could represent a clinically distinct subtype with probable genetic risk factors different from those of late-onset BD (LO-BD). To date, several genes have been associated with BD risk but few studies have investigated the genetic differences between EO-BD and LO-BD. The aim of this study was to evaluate if variants of the gene coding for myo-inositol monophosphatase (IMPA2) are linked to age at onset of BD. METHOD: 235 bipolar patients were recruited and assessed. The final sample consisting of 192 euthymic individuals, was compared according to the age at onset. Polymorphisms were genotyped in the IMPA2 gene (rs669838, rs1020294, rs1250171, and rs630110). Early-onset was defined by the appearance of a first affective episode before the age of 18. RESULTS: The analyses showed that in the genotype distribution rs1020294 (p = .01) and rs1250171 (p = .01) were associated with the age at onset. The significant effect remained only in the rs1020294 SNP in which G carriers were more likely to debut later compared to patients presenting the AA genotype (p = .002; OR = 9.57, CI95%[2.37-38.64]). The results also showed that EO-BD tended to experience more alcohol misuse (p = .003; OR = .197, CI95%[.07-.58]) compared to LO-BD. CONCLUSIONS: Our results provide evidence for genetic differences between EO-BD and LO-BD at the IMPA2 gene as well as clinical differences between subgroups with therapeutic implications. PMID- 29499506 TI - Cognitive complaints and predictors of perceived cognitive dysfunction in adults with major depressive disorder: Findings from the Cognitive Dysfunction in Asians with Depression (CogDAD) study. AB - BACKGROUND: Several studies have described the presence of perceived cognitive dysfunction amongst Asian patients with major depressive disorder (MDD). To date, no study has been conducted investigating the predictors of perceived cognitive dysfunction amongst Asian MDD patients. METHODS: This was a post-hoc analysis of the Cognitive Dysfunction in Asian patients with Depression (CogDAD) study. Descriptive statistics were used to describe the most common cognitive complaints by patients. Univariate and multivariate analyses were performed to determine variables associated with perceived cognitive dysfunction (Perceived Deficit Questionnaire-Depression, PDQ-D). RESULTS: The CogDAD study population is comprised of MDD patients with mild-to-moderate depression (Patient Health Questionnaire 9-item [PHQ-9]: 11.3 +/- 6.9) who reported perceived cognitive dysfunction (PDQ-D = 22.6 +/- 16.2). The most common cognitive complaints were: mind drifting (42.3%), trouble making decision (39.6%) and trouble concentrating (38.0%). Predictors of perceived cognitive dysfunction were: being Southeast Asians (vs. Taiwanese) (p < 0.001), current episode longer than 8 weeks (vs. 1-8 weeks) (p < 0.05), the presence of disability (vs. no disability) (p < 0.05), younger age (p < 0.01), and higher PHQ-9 total scores (p < 0.001). LIMITATIONS: The causal relationship between predictive variables and PDQ-D could not be tested due to the cross-sectional nature of the study. Furthermore, a neuropsychological test was not included in the CogDAD study and use of concomitant medications, including anti-depressants, could have impacted patient's perceived cognitive ability. CONCLUSIONS: The present study results suggest a potential role for subjective cognitive assessment in patients with MDD who are young, with long durations of depression or severe depression. PMID- 29499507 TI - Depressive symptoms, alcohol use and coping drinking motives: Examining various pathways to suicide attempts among young men. AB - BACKGROUND: Research has identified several correlates of suicidal behaviors including depressive symptoms, alcohol use and coping drinking motives. However, their associations and their role as possible causal mechanisms in the prediction of suicide attempt are not well understood. This study examined, both cross sectionally and longitudinally, the potential pathways from alcohol use, drinking coping motives, and depression to suicide attempts. METHODS: Participants (N = 4617) were young Swiss men (mean age = 19.95) participating in the Cohort Study on Substance Use Risk Factors. Measures of depressive symptoms, alcohol use (total drinks per week, heavy episode drinking) and coping drinking motives were used from the baseline and/or 15-month follow-up assessments to predict follow-up suicide attempt. RESULTS: Main findings showed indirect associations through depressive symptoms, such that coping drinking motives were positively associated with depressive symptoms, which were in turn positively related to suicide attempts over time (for total drinks per week models, cross-sectional model: B = 0.130, SE = 0.035, 95% CI = 0.072, 0.207; longitudinal model: B = 0.039, SE = 0.013, 95% CI = 0.019, 0.069). Alcohol use was not significantly related to suicide attempt. LIMITATIONS: Main limitation includes a low prevalence rate for suicide attempt potentially reducing power effects in the analyses and our focus on distal-yet not proximal, role of alcohol use on suicide attempt. CONCLUSIONS: Findings of this study suggest that young men with depressive symptoms and/or those who use alcohol to cope with negative affect may benefit from programs targeting suicidal behaviors. PMID- 29499508 TI - Patterns and predictors of posttraumatic stress disorder in refugees: A latent class analysis. AB - BACKGROUND: Although elevated rates of posttraumatic stress disorder (PTSD) have been well-documented in refugees, no study has investigated the heterogeneity of DSM-5 PTSD symptomatology in such populations. This study aimed to determine whether there are unique patterns of DSM-5 defined PTSD symptomatology in refugees, and investigate whether factors characteristic of the refugee experience, including trauma exposure and post-migration stress, predict symptom profiles. METHODS: Participants were 246 refugees and asylum-seekers from an Arabic-, English-, Farsi-, or Tamil-speaking background who had been resettled in Australia. Participants completed measures of post-migration living difficulties, trauma exposure, PTSD symptoms and functional disability. Latent class analysis was used to identify PTSD symptom profiles, and predictors of class membership were elucidated via multinomial logistic regression. RESULTS: Four classes were identified: a high-PTSD class (21.3%), a high-re-experiencing/avoidance class (15.3%), a moderate-PTSD class (23%), and a no PTSD class (40.3%). Trauma exposure and post-migration stress significantly predicted class membership and classes differed in degree of functional disability. LIMITATIONS: The current study employed a cross-sectional design, which precluded inferences regarding the stability of classes of PTSD symptomatology. CONCLUSIONS: This study provides evidence for distinct patterns of PTSD symptomatology in refugees. We identified a novel class, characterized by high-re-experiencing and avoidance symptoms, as well as classes characterized by pervasive, moderate, and no symptomatology. Trauma exposure and post-migration stress differentially contributed to the emergence of these profiles. Individuals with high and moderate probability of PTSD symptoms evidenced substantial disability. These results support conceptualizations of PTSD as a heterogeneous construct, and highlight the importance of considering sub-clinical symptom presentations, as well as the post migration environment, in clinical contexts. PMID- 29499509 TI - Exploring the sortilin related receptor, SorLA, in depression. AB - BACKGROUND: Studies of individual biomarkers for depression have shown insufficient sensitivity and specificity for clinical use, and most likely combinations of biomarkers may provide a better signature. The sorting-related receptor with A-type repeats (SorLA) is a well-studied pathogenic factor for Alzheimer's. SorLA belongs to the Vps10p domain receptor family, which also encompasses sortilin and SorCS1-3. All family members have been implicated in neurological and mental disorders. Notably, the SORCS3 gene is genome-wide significantly associated with depression and serum protein levels of sortilin are reduced in depressed individuals. SorLA regulates the activity of neurotrophic factors and cytokines and we hence speculated that SorLA might be implicated in depression. METHODS: Serum SorLA levels were measured in two well-defined clinical samples using ELISA. Generalized linear models were used in the statistical analyses. RESULTS: We identified a multivariate model to discriminate depressed individuals from healthy controls. Interestingly, the model consisted of serum SorLA levels and additional four predictors: previous depressive episode, stressful life events, serum levels of sortilin and VEGF. However, as an isolated factor, we observed no significant difference in SorLA levels between 140 depressed individuals and 140 healthy controls. Nevertheless, we observed a significant increase in SorLA levels following 12 weeks of treatment with nortriptyline, but not escitalopram. LIMITATIONS: The number of biomarkers included in the multivariate model for depression and lack of replication limit our study. CONCLUSIONS: Our results suggest SorLA as one of five factors that in combination may support the depression diagnosis, but not as an individual biomarker for depression or treatment response. PMID- 29499510 TI - Assessment of depression before and after inpatient rehabilitation in COPD patients: Psychometric properties of the German version of the Patient Health Questionnaire (PHQ-9/PHQ-2). AB - BACKGROUND: Depression is a frequent comorbidity of COPD and leads to worse clinical COPD-outcomes. PHQ-9 and PHQ-2 are two widely used brief instruments to assess depression. However, psychometric properties in COPD patients are unknown. This study examines factorial validity, measurement invariance and composite reliability (CR) of PHQ-9/PHQ-2, respectively, and concordance between both tools. METHODS: This is a secondary analysis of N = 561 COPD patients who filled out the PHQ-9 at the begin (T0), the end (T1) and 3/6/9/12 (T2/T3/T4/T5) months after pulmonary inpatient rehabilitation. Structural equation modeling was used to examine factorial validity and measurement invariance between gender, GOLD disease severity groups and over time. Concordance was assessed using Cohen's Kappa, Yules Y, positive and negative agreement. RESULTS: A one-factor model (with one freed residual covariance) showed best model fit. At least partial scalar invariance could be established. Concordance between both instruments was substantial. 31.7% (26.2%) COPD patients showed clinically relevant depression according to PHQ-9 (PHQ-2) at T0. At T0-T2, PHQ-9 classified more patients as depressed than did PHQ-2. According to both measures, depression rates declined after rehabilitation. Reliability was high for both PHQ-9 (CR = 0.94) and PHQ-2 (CR = 0.89). LIMITATIONS: No gold-standard (clinical interview) to assess depression was used. Therefore, diagnostic accuracy for PHQ-9/PHQ-2 remains unclear. CONCLUSIONS: PHQ-9 and PHQ-2 fulfill important psychometric criteria (factorial validity, invariance, reliability) for measuring depression in COPD. The results support their use in clinical practice to assess severity of depression. Diagnostic accuracy to identify major/minor depression of both instruments should be examined in future studies. PMID- 29499511 TI - A unique case of accessory/double nail of middle finger. AB - INTRODUCTION: A rudimentary, accessory or double nail of the middle finger of hand is extremely rare. Although rudimentary, accessory or double nail of the toes only described four times before, in the literature. Most cases are incidentally detected and only few patients seek help because they have discomfort and pain or cosmetic reasons. Some have a positive family history, but most patients cannot give any information concerning heredity or any previous trauma. PRESENTATION: A 28 year old male presented with an abnormal growth of the nail of middle finger of left hand,which was hard and pointed. It was causing pain and discomfort to patient when touched. This growth was made of keratinized material and inseparable from nail bed, which showed a longitudinal depression corresponding to a slight protuberance of the cuticle of primary nail. DISCUSSION: Being an extremely rare entity, this situation can lead to difficulty in diagnosis, so its symptoms and pattern of occurrence should be thoroughly noted. Surgical excision is the treatment of choice for patient's symptomatic relief and cosmetic concern. Nail unit resection procedure can easily be performed under local anesthesia. CONCLUSION: Accessory nail of finger should be removed surgically due to pain and discomfort or cosmetic reasons and histopathology should be done afterwards. PMID- 29499512 TI - Jejunogastric intussusception after distal gastrectomy with Roux-en-Y reconstruction: A case report. AB - INTRODUCTION: Jejunogastric intussusception is a rare complication after gastric operation. Intussusception after gastric operation occurs mostly at the gastrojejunal anastomosis site and Braun anastomosis site of Billroth II reconstruction, and at the Y anastomosis site of Roux-en-Y reconstruction. However, jejunogastric intussusception after distal gastrectomy with Roux-en-Y reconstruction is very rare. We report a surgical case of jejunogastric intussusception after distal gastrectomy for gastric cancer treatment. PRESENTATION OF CASE: An 82-year-old woman underwent laparoscopic distal gastrectomy for early gastric cancer treatment. Reconstruction was performed using Roux-en-Y anastomosis. Oral intake was started on postoperative day 4, however vomiting and high-grade fever occurred on postoperative day 12, after which oral intake became difficult. DISCUSSION: Anastomotic stenosis of the gastrojejunostomy was suspected, and various examinations were performed. Gastroendoscopy and computed tomography revealed an elevated lesion with ring like folds protruding through the anastomosis site into the remnant stomach. Reoperation was performed on postoperative day 28 after a diagnosis of jejunogastric intussusception was made. It failed to reduce the intussusception, so partial resection of the gastrojejunal anastomosis was performed and Roux-en-Y reconstruction was repeated. Reconstruction was conducted after taking into consideration the recurrence of intussusception. CONCLUSION: Jejunogastric intussusceptions after distal gastrectomy is a rare complication; however, when it occurs, early diagnosis and appropriate management are necessary. PMID- 29499513 TI - A siphon-like retrogastric transverse colon: A case report. AB - INTRODUCTION: Intestinal interposition is a term that describes rare anatomic variations where parts of the colon deviate from their normal intraabdominal position, attaching between two organs. Most patients with colonic interpositions are asymptomatic and diagnosed incidentally by computed tomography or ultrasound. Here we present a case of a symptomatic restrogastric colon, interposing kinked between stomach and pancreas. PRESENTATION OF CASE: A 66-year old female patient presented with an eight-year history of intermittent spastic bowel movements, epigastralgia and nausea. Consecutively, the patient lost 12 kg. Physical examination was unremarkable and routine blood tests were within normal limits. Subsequently performed colonoscopy and cross-sectional imaging diagnosed a retrogastric colon. Finally, the patient underwent surgical treatment. The intraoperative findings were consistent with the computed tomography images and showed a kinked retrogastric protrusion of the transverse colon into the lesser sac, adhering to both, the posterior wall of the stomach, and the anterior surface of the pancreas. After adhesiolysis and mobilization, the transverse colon slipped back to the normal position within the abdominal cavity. The patient recovered well after surgery and was discharged on the sixth postoperative day. Six-month follow-up revealed cured bowel function, weight regain and no signs of recurrence. DISCUSSION & CONCLUSION: These rare cases of intestinal interpositions are very often difficult to diagnose, as symptoms are misleading. In case of diagnosis adequate surgical treatment strategies should be considered. PMID- 29499514 TI - Bilateral split hand foot malformation in siblings: Case series. AB - INTRODUCTION: Split Hand-Foot malformation (SHFM) is a congenital limb defect that affects the central rays of the hands and/or feet. It is a rare condition that has genetic and environmental etiologies. It ranges in severity depending on the extent of the malformation. We report on two siblings with severe SHFM affecting all limbs. METHODS: We described two cases of siblings with SHFM and discuss the possible causes of the condition. This research did not require ethical approval due to the institute not requiring it for this type of study. RESULTS: Case 1 is a 7-year-old boy, and case 2 is his 4-year-old brother. They are both medically and surgically free. They had normal growth and development and were products of a consanguineous marriage. They both presented with bilateral deformities of the hands and feet, and had no previous family history of congenital anomalies. CONCLUSION: SHFM may occur as a result of consanguineous marriage, genetic mutation, and chemical exposure. Genetic counseling and thorough assessment of associated anomalies is mandatory. PMID- 29499515 TI - A black adrenal adenoma with high FDG uptake on PET/CT scan in a patient with esophageal carcinoma: A case report. AB - INTRODUCTION: Black adrenal adenoma (BAA) is a rare, benign adrenal lesion with a black or brown appearance. This is the first report of this lesion in a patient with a synchronous esophageal cancer and highlights the importance of considering a false positive finding on a Positron Emission Tomography (PET) scan, which might otherwise preclude resection. PRESENTATION OF CASE: A 73-year-old male was diagnosed with mid-esophagus carcinoma. Computed tomography scan revealed an enlarged left adrenal gland. Plasma adrenocorticotropic hormones levels were normal. To characterize the adrenal lesion, a PET scan was obtained which showed high uptake of 18F-fluoro-2-deoxy-d-glucose (FDG), consistent with a metastasis, suggesting T3N2M1, clinical stage IV esophageal cancer. After two courses of neo adjuvant therapy, sub-total esophagectomy and left adrenalectomy were performed. The adrenal tumor was soft, and black in color, diagnosed as a BAA on histology. The pathologic stage of the esophageal cancer was T3N0M0, Stage II. Six months after surgery, he is alive without recurrence. DISCUSSION: High FDG uptake by an adrenal lesion on PET scan, as in this patient, usually suggests a metastatic lesion. Although rare, patients with esophageal cancer and adrenal metastases have been reported to have long-term survival, so it is important to characterize an adrenal lesion when found. CONCLUSION: Most adrenal lesions with high FDG uptake are malignant, but BAA is also positive on PET scan. Although rare, BAA should be considered in patients with solitary adrenal lesions with high uptake on PET scan, even in the presence of a malignancy. PMID- 29499516 TI - Redo surgery for extensive chronic type A dissecting aneurysm following a Bentall operation. AB - INTRODUCTION: Despite the technical improvements, redo surgery on the aortic root and arch is still associated with high morbidity and mortality due to the trauma of repeat open-heart surgery and technical complexity. We present the case of extended chronic type A dissecting aneurysm that developed after a Bentall operation, which was successfully treated by applying a modified long elephant trunk technique and surgical aortic fenestration. CASE PRESENTATION: A 77-year old man, who had previously undergone a Bentall procedure and an abdominal surgery, developed a type A aortic dissection. At presentation, the aortic dissection extended from the proximal arch to the terminal aorta, which were treated with an axillobifemoral bypass. After 8 months follow-up, the dissecting aneurysm had extended and the visceral arteries were perfused from the false lumen, without re-entry. We successfully repaired a complicated and extended chronic type A dissecting aneurysm by applying a modified long elephant trunk technique and surgical aortic fenestration. Postoperatively, the thoracic aorta false lumen was thromboexcluded, and the visceral perfusion was preserved through the fenestration. CONCLUSION: In the treatment of complicated aortic arch diseases especially in redo cases, appropriate strategies are mandatory to achieve optimal outcomes. In the extended aortic dissection without the reentry for visceral perfusion, a primary entry closure may lead to visceral ischemia. Modified long elephant trunk technique combined with fenestration technique may be one of the useful techniques to treat the complicated aortic dissection extending to the terminal aorta. PMID- 29499517 TI - Insights into the mechanism of persulfate activated by rice straw biochar for the degradation of aniline. AB - This study investigated the degradation of aniline by persulfate (PS) activated with rice straw biochar (RSBC). The results demonstrate that aniline could be rapidly decomposed by a combination of PS and RSBC. The degradation efficiency of aniline was up to 94.1% within 80 min, and meanwhile 52% of the total organic carbon was removed. In the initial pH range of 3-9, aniline could be efficiently removed. Reactive species resulting in the rapid degradation of aniline were investigated via radical and hole quenching experiments with various scavengers (e.g., methanol, tert-butyl alcohol and EDTA) and electron paramagnetic resonance technique. Based on the analysis and observation made here, it is speculated that the predominant reactive species responsible for the degradation of aniline may be holes instead of SO4- and OH radicals. It is concluded that RSBC could be used as an effective catalyst to activate PS for the degradation of aniline. PMID- 29499518 TI - Preparation, performances and mechanisms of magnetic Saccharomyces cerevisiae bionanocomposites for atrazine removal. AB - Saccharomyces cerevisiae and nanoparticles of iron oxide (Fe3O4) which were linked with chitosan (CS) through epichlorohydrin (ECH) were encapsulated in calcium alginate to prepare a novel type of bionanocomposites. Characterization results showed that the Fe3O4-ECH-CS nanoparticles were quasi-spherical with an average diameter of 30 nm to which chitosan was successfully attached through epichlorohydrin. The saturation magnetization value of the nanoparticles was 21.88 emu/g, and ferrous and ferric irons were simultaneously observed in the magnetic nanoparticles. Data of atrazine removal by yeasts showed that both inactivated and live yeasts could decrease the concentration of atrazine effectively. The inactivated yeasts achieved 20% removal rate, which indicated that adsorption by the yeasts also played a role in the removal. Removal efficiency of atrazine was maximized at 88% under 25 degrees C, pH of 7 and an initial atrazine concentration of 2 mg/L. When the magnetic bionanocomposite was recycled and reused twice, only 12% and 20% drop in removal efficiency was observed at the first time and the second time severally. So, atrazine could be used by the yeasts as the sole carbon source for growth and multiplication, and both adsorption and biodegradation by the bionanocomposite contributed to atrazine removal. PMID- 29499519 TI - The challenging use and interpretation of circulating biomarkers of exposure to persistent organic pollutants in environmental health: Comparison of lipid adjustment approaches in a case study related to endometriosis. AB - The gold-standard matrix for measuring the internal levels of persistent organic pollutants (POPs) is the adipose tissue, however in epidemiological studies the use of serum is preferred due to the low cost and higher accessibility. The interpretation of serum biomarkers is tightly related to the understanding of the underlying causal structure relating the POPs, serum lipids and the disease. Considering the extended benefits of using serum biomarkers we aimed to further examine if through statistical modelling we would be able to improve the use and interpretation of serum biomarkers in the study of endometriosis. Hence, we have conducted a systematic comparison of statistical approaches commonly used to lipid-adjust the circulating biomarkers of POPs based on existing methods, using data from a pilot case-control study focused on severe deep infiltrating endometriosis. The odds ratios (ORs) obtained from unconditional regression for those models with serum biomarkers were further compared to those obtained from adipose tissue. The results of this exploratory study did not support the use of blood biomarkers as proxy estimates of POPs in adipose tissue to implement in risk models for endometriosis with the available statistical approaches to correct for lipids. The current statistical approaches commonly used to lipid adjust circulating POPs, do not fully represent the underlying biological complexity between POPs, lipids and disease (especially those directly or indirectly affecting or affected by lipid metabolism). Hence, further investigations are warranted to improve the use and interpretation of blood biomarkers under complex scenarios of lipid dynamics. PMID- 29499520 TI - A non-targeted high-resolution mass spectrometry data analysis of dissolved organic matter in wastewater treatment. AB - The dissolved organic matter (DOM) in wastewater is typically described by a limited number of concentration measurements of select DOM fractions or micro contaminants, which determine the removal efficiency in a wastewater treatment. Current methods do not necessarily reflect the true performance of the treatment with regard to environmental and public health risk. Herein we describe the development and application of a non-targeted liquid chromatography-high resolution mass spectrometry (LC-HRMS) data analysis for the evaluation of wastewater treatment processes. Our data analysis approach was applied to a real wastewater system with secondary biological treatment and tertiary treatment consisting of sand filtration, UV-treatment, and chlorination. We identified significant changes in DOM during wastewater treatment. The secondary treatment removed 1617 of 2409 (67%) detected molecular features (grouped isotopologues belonging to the same molecule) from the influent while 255 of 1047 (24%) new molecular features appeared in the secondary effluent. A reduction in the number of large molecules (>450 Da) and an increase in unsaturated molecular features of the effluent organic matter was observed. Van Krevelen plots revealed the distribution of unsaturation and heteroatoms and Kendrick mass defect plots uncovered CH2 homologous series implying a removal of heavy constituents in that fraction. The demonstrated approach is a step towards a more comprehensive monitoring of DOM in wastewater and contributes to the understanding of current treatment technologies. PMID- 29499521 TI - Fe-Ti/Fe (II)-loading on ceramic filter materials for residual chlorine removal from drinking water. AB - Ceramic filter material was prepared with silicon dioxide (SiO2), which was recovered from red mud and then modified with Fe (II) and Fe-Ti bimetal oxide. Ceramic filter material can be used to reduce the content of residual chlorine from drinking water. The results showed that after a two-step leaching process with 3 M hydrochloric acid (HCl) and 90% sulfuric acid (H2SO4), the recovery of SiO2 exceeded 80%. Fe (II)/Fe-Ti bimetal oxide, with a high adsorption capacity of residual chlorine, was prepared using a 3:1 M ratio of Fe/Ti and a concentration of 0.4 mol/L Fe2+. According to the zeta-potential, scanning electron microscopy (SEM) and Brunauer-Emmett-Teller (BET) analysis, Fe (II) and Fe-Ti bimetal oxide altered the zeta potential and structural properties of the ceramic filter material. There was a synergistic interaction between Fe and Ti in which FeOTi bonds on the material surface and hydroxyl groups provided the active sites for adsorption. Through a redox reaction, Fe (II) transfers hypochlorite to chloride, and FeOTiCl bonds were formed after adsorption. PMID- 29499522 TI - The social role of C-reactive protein point-of-care testing to guide antibiotic prescription in Northern Thailand. AB - New and affordable point-of-care testing (POCT) solutions are hoped to guide antibiotic prescription and to help limit antimicrobial resistance (AMR) especially in low- and middle-income countries where resource constraints often prevent extensive diagnostic testing. Anthropological and sociological research has illuminated the role and impact of rapid point-of-care malaria testing. This paper expands our knowledge about the social implications of non-malarial POCT, using the case study of a C-reactive-protein point-of-care testing (CRP POCT) clinical trial with febrile patients at primary-care-level health centres in Chiang Rai province, northern Thailand. We investigate the social role of CRP POCT through its interactions with (a) the healthcare workers who use it, (b) the patients whose routine care is affected by the test, and (c) the existing patient health system linkages that might resonate or interfere with CRP POCT. We conduct a thematic analysis of data from 58 purposively sampled pre- and post intervention patients and healthcare workers in August 2016 and May 2017. We find widespread positive attitudes towards the test among patients and healthcare workers. Patients' views are influenced by an understanding of CRP POCT as a comprehensive blood test that provides specific diagnosis and that corresponds to notions of good care. Healthcare workers use the test to support their negotiations with patients but also to legitimise ethical decisions in an increasingly restrictive antibiotic policy environment. We hypothesise that CRP POCT could entail greater patient adherence to recommended antibiotic treatment, but it could also encourage riskier health behaviour and entail potentially adverse equity implications for patients across generations and socioeconomic strata. Our empirical findings inform the clinical literature on increasingly propagated point-of-care biomarker tests to guide antibiotic prescriptions, and we contribute to the anthropological and sociological literature through a novel conceptualisation of the patient-health system interface as an activity space into which biomarker testing is introduced. PMID- 29499523 TI - Application and validation of isotope dilution method (IDM) for predicting bioavailability of hydrophobic organic contaminants in soil. AB - Risk assessment of hydrophobic organic contaminants (HOCs) using the total chemical concentration following exhaustive extraction may overestimate the actual availability of HOCs to non-target organisms. Existing methods for estimating HOC bioavailability in soil have various operational limitations. In this study, we explored the application of isotope dilution method (IDM) to quantify the accessible fraction (E) of DDTs and PCBs in both historically contaminated and freshly-spiked soils. After addition of 13C or deuterated analogues to a soil sample, the phase distribution of isotope-labeled and native chemicals reached an apparent equilibrium within 48 h of mixing. The derived E values in the three soils ranged from 0.19 to 0.82, depending on the soil properties and also the contact time of HOCs (i.e., aging). The isotope dilution method consistently predicted greater accumulation into earthworm (Eisenia fetida) than that by polyethylene (PE) or solid phase microextraction (SPME) sampler, likely because desorption in the gut enhanced bioavailability of soil borne HOCs. A highly significant linear regression (R2 = 0.91) was found between IDM and 24-h Tenax desorption, with a slope statistically identical to 1. The IDM derived accessible concentration (Ce) was further shown to accurately predict tissue residues in earthworm exposed in the same soils. Given the relatively short duration and simple steps, IDM has the potential to be readily adopted for measuring HOC bioaccessibility in soil and for improving risk assessment and evaluation of remediation efficiency. PMID- 29499524 TI - Correction of scan line shift artifacts in scanning electron microscopy: An extended digital image correlation framework. AB - High resolution scanning electron microscopy (HR-SEM) is nowadays very popular for different applications in different fields. However, SEM images may exhibit a considerable amount of imaging artifacts, which induce significant errors if the images are used to measure geometrical or kinematical fields. This error is most pronounced in case of full field deformation measurements, for instance by digital image correlation (DIC). One family of SEM artifacts result from positioning errors of the scanning electron beam, creating artifactual shifts in the images perpendicular to the scan lines (scan line shifts). This leads to localized distortions in the displacement fields obtained from such images, by DIC. This type of artifacts is corrected here using global DIC (GDIC). A novel GDIC framework, considering the nonlinear influence of artifacts in the imaging system, is introduced for this purpose. Using an enriched regularization in the global DIC scheme, based on an error function, the scan line shift artifacts are captured and eliminated. The proposed methodology is demonstrated in virtually generated and deformed images as well as real SEM micrographs. The results confirm the proper detection and elimination of this type of SEM artifacts. PMID- 29499525 TI - Hereditary association between testicular cancer and familial ovarian cancer: A Familial Ovarian Cancer Registry study. AB - BACKGROUND: Although family history of testicular cancer is well-established as a risk factor for testicular cancer, it is unknown whether family history of ovarian cancer is associated with risk of testicular cancer. MATERIALS AND METHODS: Using data from the Familial Ovarian Cancer Registry on 2636 families with multiple cases of ovarian cancer, we systematically compared relative frequencies of ovarian cancer among relatives of men with testicular and non testicular cancers. RESULTS: Thirty-one families with cases of both ovarian and testicular cancer were identified. We observed that, among men with cancer, those with testicular cancer were more likely to have a mother with ovarian cancer than those with non-testicular cancers (OR = 3.32, p = 0.004). Zero paternal grandmothers of men with testicular cancer had ovarian cancer. CONCLUSION: These observations provide compelling preliminary evidence for a familial association between ovarian and testicular cancers Future studies should be designed to further investigate this association and evaluate X-linkage. PMID- 29499526 TI - Uterine massage for preventing postpartum hemorrhage at cesarean delivery: Which evidence? AB - BACKGROUND: Cesarean delivery could be complicated by postpartum hemorrhage (PPH), the first cause of maternal death. OBJECTIVES: To evaluate the efficacy of uterine massage in preventing postpartum hemorrhage at cesarean delivery. DATA SOURCES: Electronic databases from their inception until October 2017. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS: We included all RCTs comparing uterine massage alone or as part of the active management of labor before or after delivery of the placenta, or both, with non-massage in the setting of cesarean delivery. DATA COLLECTION AND ANALYSIS: The primary outcome was PPH, defined as blood loss >1000 mL. Meta-analysis was performed using the random effects model of DerSimonian and Laird, to produce summary treatment effects in terms of mean difference (MD) or relative risk (RR) with 95% confidence interval (CI). RESULTS: Only 3 RCTs comparing uterine massage vs no uterine massage were found. The quality of these 3 trials in general was very low with high or unclear risk of bias. All of them included only women in the setting of spontaneous vaginal delivery and none of them included cesarean delivery, and therefore the meta-analysis was not feasible. CONCLUSIONS: There is not enough evidence to determine if uterine massage prevents postpartum hemorrhage at cesarean delivery. PMID- 29499527 TI - Covalent immobilization of lipase onto chitosan-mesoporous silica hybrid nanomaterials by carboxyl functionalized ionic liquids as the coupling agent. AB - Chitosan-mesoporous silica SBA-15 hybrid nanomaterials (CTS-SBA-15) were synthesized by means of carboxyl functionalized ionic liquids as the coupling agent. The as-prepared CTS-SBA-15 support was characterized by TEM, FTIR, TG and nitrogen adsorption-desorption techniques. Porcine pancreas lipase (PPL) was then bound to the hybrid nanomaterials by using the cross-linking reagent glutaraldehyde (GA). Further, the parameters like cross-linking concentration, time and ratio of supports to enzyme were optimized. The property of immobilized lipase were tested in detail by enzyme activity assays. The results indicated that the hybrid nanomaterials could form three-dimensional (3D) structure with homogeneous mesoporous structures and immobilized PPL revealed excellent enzymatic performance. PMID- 29499528 TI - Diet and self-rated health among oldest-old Chinese. AB - INTRODUCTION: Dietary behavior is a central modifiable risk factor for human health. This study examined the longitudinal relationship between dietary habits and self-rated health among the oldest-old Chinese. METHODS: Participants aged 80 years and above (N = 7273) were first interviewed in 1998 and followed in subsequent waves 2-3 years apart till 2011-2012 in the Chinese Longitudinal Healthy Longevity Survey. Cox proportional hazards regressions were performed to estimate the effects of dietary habits on poor self-rated health, adjusting for various individual characteristics. RESULTS: Compared to those who rarely/never consumed fruit, vegetable, meat, egg, and soybean-derived product, participants consuming such products almost every day were 28%, 20%, 32%, 16%, and 16% less likely to report poor self-rated health during follow-up, respectively. Compared to those who rarely/never consumed fruit, meat, fish, soybean-derived product, and tea, participants consuming such products occasionally were 12%, 24%, 11%, 15%, and 14% less likely to report poor self-rated health during follow-up, respectively. Compared to those who rarely/never consumed sugar, participants consuming sugar almost every day were 14% more likely to report poor self-rated health during follow-up. The effects of dietary habits on self-rated health to some extent differed by sex. CONCLUSIONS: Oldest-old Chinese could gain health benefit from regular consumption of fruit, vegetable, meat, fish, egg, soybean derived product, and tea; whereas their sugar consumption may need to be reduced. Future research is warranted to establish the recommended daily nutrient allowances for the oldest-old adults and better address the nutritional needs of this vulnerable population. PMID- 29499529 TI - VALIDATION OF EDMONTON FRAIL SCALE INTO ELDERLY TURKISH POPULATION. AB - PURPOSE: The purpose of this methodological study was to assess the validity and reliability of Turkish version of the "Edmonton Frail Scale" (EFS). METHOD: 130 individuals aged 65 and over residing at the Izmir Narlidere Nursing Home between September 2011 - April 2012 who agreed to participate in the study constituted the sample for the research. Individuals with communication problems (deafness, blindness or language barriers) and problems with manual dexterity were not included in the study. The EFS is composed of 11 items, with a minimum score of zero and a maximum score of 17. Initially, the scale was translated into Turkish and then back translated in order to ensure language equivalence. Six experts were consulted with regard to content validity and agreement among the experts was assessed using Kendall's W. When testing the reliability of the EFS, the scale was re-administered to 30 participants two-three weeks after the initial administration in order to determine its consistency over time and agreement between the first and second administration was analysed using the kappa statistic. Pearson's Moment Correlation Coefficient and Cronbach's Alpha were also used to establish reliability. FINDINGS: The overall Cronbach's alpha value for the scale was 0.75. An "item analysis" calculated item-total correlation coefficients of between 0.12-0.65 for scale items, and the item-total correlation for item six was found to be less than 0.20. This item solicits the number of medications used by the subject, and since the number of medications used is significant in the determination of frailty it was not removed from the scale. The scale was found to be highly consistent over time (Kappa (kappa) = Min: 0.95, Max: 1.00) CONCLUSION: EFS indicators were found to be sufficiently reliable and valid for the Turkish population. Accordingly, it is recommended that this scale be used in determining the frailty of older individuals. PMID- 29499530 TI - Enhancement of chronic bee paralysis virus levels in honeybees acute exposed to imidacloprid: A Chinese case study. AB - Though honeybee populations have not yet been reported to be largely lost in China, many stressors that affect the health of honeybees have been confirmed. Honeybees inevitably come into contact with environmental stressors that are not intended to target honeybees, such as pesticides. Although large-scale losses of honeybee colonies are thought to be associated with viruses, these viruses usually lead to covert infections and to not cause acute damage if the bees do not encounter outside stressors. To reveal the potential relationship between acute pesticides and viruses, we applied different doses of imidacloprid to adult bees that were primarily infected with low levels (4.3*105 genome copies) of chronic bee paralysis virus (CBPV) to observe whether the acute oral toxicity of imidacloprid was able to elevate the level of CBPV. Here, we found that the titer of CBPV was significantly elevated in adult bees after 96h of acute treatment with imidacloprid at the highest dose 66.9ng/bee compared with other treatments and controls. Our study provides clear evidence that exposure to acute high doses of imidacloprid in honeybees persistently infected by CBPV can exert a remarkably negative effect on honeybee survival. These results imply that acute environmental stressors might be one of the major accelerators causing rapid viral replication, which may progress to cause mass proliferation and dissemination and lead to colony decline. The present study will be useful for better understanding the harm caused by this pesticide, especially regarding how honeybee tolerance to the viral infection might be altered by acute pesticide exposure. PMID- 29499531 TI - Rainfall variability and drought characteristics in two agro-climatic zones: An assessment of climate change challenges in Africa. AB - This paper examines drought characteristics as an evidence of climate change in two agro-climatic zones of Nigeria and farmers' climate change perceptions of impacts and adaptation strategies. The results show high spatial and temporal rainfall variability for the stations. Consequently, there are several anomalies in rainfall in recent years but much more in the locations around the Guinea savanna. The inter-station and seasonality statistics reveal less variable and wetter early growing seasons and late growing seasons in the Rainforest zone, and more variable and drier growing seasons in other stations. The probability (p) of dry spells exceeding 3, 5 and 10 consecutive days is very high with 0.62<=p>=0.8 in all the stations, though, the p-values for 10day spells drop below 0.6 in Ibadan and Osogbo. The results further show that rainfall is much more reliable from the month of May until July with the coefficient of variance for rainy days <0.30, but less reliable in the months of March, August and October (CV-RD>0.30), though CV-RD appears higher in the month of August for all the stations. It is apparent that farmers' perceptions of drought fundamentally mirror climatic patterns from historical weather data. The study concludes that the adaptation facilities and equipment, hybrids of crops and animals are to be provided to farmers, at a subsidized price by the government, for them to cope with the current condition of climate change. PMID- 29499532 TI - The concentration-discharge slope as a tool for water quality management. AB - Recent technological breakthroughs of optical sensors and analysers have enabled matching the water quality measurement interval to the time scales of stream flow changes and led to an improved understanding of spatially and temporally heterogeneous sources and delivery pathways for many solutes and particulates. This new ability to match the chemograph with the hydrograph has promoted renewed interest in the concentration-discharge (c-q) relationship and its value in characterizing catchment storage, time lags and legacy effects for both weathering products and anthropogenic pollutants. In this paper we evaluated the stream c-q relationships for a number of water quality determinands (phosphorus, suspended sediments, nitrogen) in intensively managed agricultural catchments based on both high-frequency (sub-hourly) and long-term low-frequency (fortnightly-monthly) routine monitoring data. We used resampled high-frequency data to test the uncertainty in water quality parameters (e.g. mean, 95th percentile and load) derived from low-frequency sub-datasets. We showed that the uncertainty in water quality parameters increases with reduced sampling frequency as a function of the c-q slope. We also showed that different sources and delivery pathways control c-q relationship for different solutes and particulates. Secondly, we evaluated the variation in c-q slopes derived from the long-term low-frequency data for different determinands and catchments and showed strong chemostatic behaviour for phosphorus and nitrogen due to saturation and agricultural legacy effects. The c-q slope analysis can provide an effective tool to evaluate the current monitoring networks and the effectiveness of water management interventions. This research highlights how improved understanding of solute and particulate dynamics obtained with optical sensors and analysers can be used to understand patterns in long-term water quality time series, reduce the uncertainty in the monitoring data and to manage eutrophication in agricultural catchments. PMID- 29499533 TI - Impacts of fullerene C60 and virgin olive oil on cadmium-induced genotoxicity in rats. AB - Currently, cadmium is considered to be one of the major environmental pollutants. Environmentally, cadmium is released in various forms e.g. oxide, chloride and sulphide. The aim of the present study was to examine the genotoxic impact of fullerene nanoparticles C60 (C60) and virgin olive oil (VOO) on cadmium chloride (CdCl2)-induced genotoxicity in rats. To evaluate these effects on DNA damage and chromosomal frequency, 25 albino rats were randomly assigned to 5 groups (n=5 per group): Group 1 served as a control; Group 2 received a single intraperitoneal dose of CdCl2 (3.5mg/kg); Group 3 animals were treated with C60 (4mg/kg, orally) every other day for 20days; Group 4 received a single intraperitoneal dose of CdCl2 (3.5mg/kg) and an oral dose of C60 (4mg/kg); and Group 5 received a single intraperitoneal dose of CdCl2 (3.5mg/kg) and oral doses of VOO every other day for 20 consecutive days. Genotoxic and anti-genotoxic effects of C60 and VOO were evaluated in the liver, kidney and bone marrow using molecular and cytogenetic assays. As expected, CdCl2 and C60 administration was associated with band number alterations in both liver and kidney; however, C60 pretreatment recovered to approximately basal number. Surprisingly, C60 and VOO significantly attenuated the genotoxic effects caused by CdCl2 in livers and kidneys. In bone marrow, in addition to a reduction in the chromosomal number, several chromosomal aberrations were caused by CdCl2. These chromosomal alterations were also reversed by C60 and VOO. In conclusion, molecular and cytogenetic studies showed that C60 and VOO exhibit anti-genotoxic agents against CdCl2-induced genotoxicity in rats. Further studies are needed to investigate the optimal conditions for potential biomedical applications of these anti-genotoxic agents. PMID- 29499534 TI - Effects of intake interruptions on dune infiltration systems in the Netherlands, their quantification and mitigation. AB - In the coastal dunes of the Western Netherlands, managed aquifer recharge (MAR) is applied for drinking water supply since 1957. The MAR systems belong to the Aquifer Transfer Recovery (ATR) type, because recharge and recovery are operated without interruption. This makes these systems very vulnerable to intake interruptions, which are expected to increase in frequency and duration due to climate change. Such interruptions are problematic, because: (i) groundwater recovery from dunes needs to continue to supply fresh drinking water to the Western Netherlands; (ii) risks of salt water intrusion are high, and (iii) MAR bordering wet dune slacks with an EU Natura 2000 status cannot survive for long without MAR. In this paper, effects of intake stops are discussed and quantified. The hydrological effects consist of the decline of water tables, disappearance of flow-through dune lakes, reservoir depletion, salt water intrusion, disruption of rainwater lenses, and entrapped air hampering a rapid refill of the groundwater reservoir. Water quality effects include changes in (i) redox environment of the flushed aquifer, impacting the behavior of nutrients, calcium, sulfate and organic micro-pollutants, and (ii) the mixing ratio of water types. The main ecological impacts comprise the dying of organisms in recharge ponds and dune lakes, and a decline of biodiversity. Effects of very long intake interruptions (years) are predicted via historical observations during the long overexploitation period (1900-1957) prior to MAR. A closed form analytical solution for safe yield of a semiconfined aquifer is proposed, together with a related upconing risk index. Both also apply to the pumping from any fresh water lens without MAR. Some mitigation strategies are discussed, such as a dual intake, raising the storage capacity, earlier mud removal, and accelerated refilling of the reservoir. A magnitude scale for intake stops (MIS) is proposed. PMID- 29499535 TI - Epidemiological investigation of tattoo-like skin lesions among bottlenose dolphins in Shark Bay, Australia. AB - Bottlenose dolphins are excellent bioindicators of ocean ecosystem health for three reasons: (a) as long-lived apex predators they accumulate biotoxins and contaminants; (b) they are visible, routinely appearing at the water's surface in coastal areas, often coming into close contact with humans; and, (c) they exhibit a range of pathogenic lesions attributable to environmental degradation. In this study, we analyzed tattoo-like skin lesions in a population of Tursiops aduncus studied for 30+years in Shark Bay, Australia, a UNESCO World Heritage Site. We provide important baseline data by documenting epidemiological patterns of tattoo like skin lesions in a healthy, free-ranging population that builds on the previous data of tattoo skin disease (TSD) derived from free ranging, stranded, and dead dolphins. Individual dolphins were classified as symptomatic with tattoo like skin disease if at least one photograph showed a lesion similar to TSD. The average age of infection was 26.6months (+/-34.8months) with the symptomatic period lasting 137+/-29.8days. Overall prevalence of tattoo-like skin disease in the population was 19.4%. Age, but not sex, was significant, with yearlings (1 2years) exhibiting tattoo-like lesions more than younger and older calves. Tattoo like lesions were rare among juvenile and adult dolphins (N=68 calves, 4 juveniles, and 3 adults). We hypothesize that the lower prevalence in youngest calves (<1year) is due to maternal immunity, while older individuals (>2years) have infection-acquired immunity, as reported for other small cetaceans. The low prevalence of tattoo-like lesions in Shark Bay compared to other populations with poxvirus is consistent with reproductive and demographic viability analyses. Furthermore, by documenting the demography of the disease, we can monitor changes in the prevalence of tattoo-like lesions as a sentinel indicator of ecosystem health. PMID- 29499536 TI - Simultaneous ammonium and phosphate recovery and stabilization from urban sewage sludge anaerobic digestates using reactive sorbents. AB - The use of low-cost inorganic sorbents as a new sustainable strategy to enhance the valorization of nutrients (N-P-K), from the urban water cycle (e.g., side streams from sewage sludge anaerobic digestion), in agriculture applications is presented. The simultaneous recovery and stabilization of ammonium and phosphate by using a mixture of two reactive sorbents (Na and K zeolites and magnesium oxide) was evaluated. The nutrients stabilization process, favoured at alkaline pH values, is carried out by a) the precipitation of phosphate ions with magnesium and/or ammonium ions and b) the sorption of ammonium by Na- and K zeolites. MgO(s) promoted the stabilization of phosphate as bobierrite (Mg3(PO4)2(s)) or struvite (MgNH4PO4(s)) depending on the applied dose. Doses with the stoichiometric molar ratio of Mg/P promote the formation of bobierrite, while molar ratios higher than 3 favour the formation of struvite. Na zeolites (NaP1-NA, NaP1-IQE) demonstrated efficiency on ammonium stabilization between 60+/-2 (for 15gZ/L) to 90+/-3% (for 50gZ/L). The ammonium recovery efficiency is limited by the zeolite sorption capacity. If the target of the fertilizing criteria should include K, then the use of a K-zeolite (e.g., 5AH-IQE) provides a good solution. The optimum pH for the precipitation of struvite and bobierrite is 9.5 and the optimum pH for ammonium removal is between 4 and 8.5. N is present in higher concentrations (up 0.7-1gNH4+/L) when pH is ranged between 8.2 and 8.6. The ammonium recovery ratios were better than those previously reported using only magnesium oxide or even a more expensive reagent as newberrite (MgHPO4(s)). The recovery mechanisms described generate low-solubility stabilized nutrients forms that potentially can be applied as slow-release fertilizers in agriculture. Thus, the use in agriculture of blends of digested sludge with low-solubility stabilized nutrients forms will improve soils quality properties in terms of organic matter and nutrients availability. PMID- 29499537 TI - Effects of relative humidity on childhood hand, foot, and mouth disease reinfection in Hefei, China. AB - BACKGROUND: In recent years, hand, foot, and mouth disease (HFMD) has become a major public health issue in China, and its reinfection rate has been high. Numerous studies have examined the effects of meteorological factors involved in HFMD infection. However, no study has investigated the effects on HFMD reinfection. The present study analyzed the relationship between relative humidity and HFMD reinfection. METHODS: We employed a distributed lag nonlinear model to evaluate the relationship between relative humidity and childhood HFMD reinfection in Hefei, China during 2011-2016. This model controlled confounding factors, including seasonality, long-term trend, day of the week, precipitation, and mean temperature. RESULTS: Childhood HFMD reinfection cases occurred mainly from April to July, and the second peak occurred from October to December. A statistically significant association was observed between relative humidity and HFMD reinfection with delayed effects. The adverse effect of high relative humidity (>75%) appeared later than those of low relative humidity (<75%). Moreover, the highest relative risk (RR 1.08, 95% CI 1.04-1.13) occurred when the relative humidity was 100% and had an 8-day lag. Given the differences between gender and age groups, the effects of extremely high relative humidity on females and those aged >=4years were higher than those of other groups and caused the highest cumulative relative risks at lag 0-9 or 0-10days (Female: RR 2.00, 95% CI 1.23-3.26; Male: RR 1.55, 95% CI 1.04-2.30; Aged >=4years: RR 2.31, 95% CI 1.27 4.18; Aged <4years: RR 1.51, 95% CI 1.04-2.20). CONCLUSION: High and low relative humidity were found to cause the elevated risks of HFMD reinfection, and the highest risk was observed at extremely high relative humidity. Early warning systems should be built for the protection of susceptible populations, particularly females and children aged >=4years. PMID- 29499538 TI - Mapping environmental land use conflict potentials and ecosystem services in agricultural watersheds. AB - In mountainous watersheds, agricultural land use cause changes in ecosystem services, with trade-offs between crop production and erosion regulation. Management of these watersheds can generate environmental land use conflicts among regional stakeholders with different interests. Although several researches have made a start in mapping land use conflicts between human activities and conservation, spatial assessment of land use conflicts on environmental issues and ecosystem service trade-offs within agricultural areas has not been fully considered. In this study, we went further to map land use conflicts between agricultural preferences for crop production and environmental emphasis on erosion regulation. We applied an agricultural land suitability index, based on multi-criteria analysis, to estimate the spatial preference of agricultural activities, while applying the Revised Universal Soil Loss Equation (RUSLE) to reflect the environmental importance of soil erosion. Then, we classified the agricultural catchment into four levels of land use conflicts (lowest, low, high and highest) according to preference and importance of farmland areas, and we compared the classes by crop type. Soil loss in agricultural areas was estimated as 45.1thayr, and agricultural suitability as 0.873; this indicated that land use conflicts in the catchment could arise between severe soil erosion (environmental importance) and agricultural suitability (land preferences). Dry-field farms are mainly located in areas of low land use conflict level, where land preference outweighs environmental importance. When we applied farmland management scenarios with consideration of services, conversion to highest-conflict areas (Scenario 1) as 7.5% of the total area could reduce soil loss by 24.6%, while fallow land management (Scenario 2) could decrease soil loss 19.4% more than the current scenario (Business as usual). The result could maximize land management plans by extracting issues of spatial priority and use-versus-conservation conflicts as ecosystem service trade-offs from arguments over land use policy. PMID- 29499539 TI - Antioxidant enzyme responses to the oxidative stress due to chlorpyrifos, dimethoate and dieldrin stress in palak (Spinacia oleracea L.) and their toxicity alleviation by soil amendments in tropical croplands. AB - A field experiment was conducted to assess the impact of pesticides viz., chlorpyrifos, dimethoate and dieldrin alone and in combination with different soil amendments like chemical fertilizer, farmyard manure and combination of 50% chemical fertilizer and 50% farmyard manure on the growth, photosynthetic pigments, oxidative stress markers: superoxide radical (SOR) and hydrogen peroxide (H2O2) and their consequent damage on lipids in terms of malondialdehyde equivalents and electrolyte leakage, and different antioxidant enzymes activity like superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), glutathione-s transferase (GST), ascorbate peroxidase (APX) and glutathione reductase (GR) in palak (Spinacia oleracea L.) grown widely in tropical croplands. The pesticides effect was analyzed at its recommended dose in agriculture for growing plants when applied two times after germination. Our results showed distinct increase in SOR and H2O2 which further manifested in marked oxidative damages in case of pesticides treatment individually that lead to decline in growth characteristics and yield. Further the application of different types of soil amendments led to consistent increase in levels of antioxidant system along with the amelioration in oxidative damage indices which was comparable across the combined treatments. The photosynthetic pigments, yield, antioxidants were maximum in case of pesticides applied in combination with 50% chemical fertilizer and 50% farmyard manure (pesticides+NF). It was apparent from the results that the application of pesticides+NF might be recommended in tropics as it ameliorates oxidative damages and maintains high quality of plant along yield which in turn will lead to no negative consequences on the global population. PMID- 29499540 TI - One-time phosphate fertilizer application to grassland columns modifies the soil microbiota and limits its role in ecosystem services. AB - This study evaluated the effect of one-time phosphate fertilization on the soil microbiota, its cycling of phosphorus (P) and grass growth. Soil columns were established in a greenhouse using a P-limited Irish soil (index 1), planted with Lolium perenne and fertilized with 0 (control), 5 (quarter), 10 (half) and 20 (full)kgPha-1 as inorganic phosphate. Only traces of phosphate in soil solution were detected over the 14week experiment, even after phosphate fertilization. Grass dry matter yield between treatments was not significantly different. Full phosphate fertilization significantly reduced the arbuscular mycorrhization (AM) rate, bacterial- and fungal-feeding nematode population, bacterial phoD gene abundance, but increased alkaline and acid phosphatase activities at the time of harvest. Full and half P treatments significantly shifted the bacterial, fungal and AM community structures compared to the control. Furthermore, the control had a significantly higher relative abundance of bacterial genera including Bacillus, Bradyrhizobium, Paenibacillus, Nocardioides and Balneimonas, that have been associated with P mobilization in the past, when compared to the full phosphate treatment. These results suggest that a positive effect of a single phosphate application on plant growth in a soil can be cancelled out by its negative effect on the soil microbiota and their ecosystem services. PMID- 29499541 TI - Water quality impacts of irrigation return flow on stream and groundwater in an intensive agricultural watershed. AB - Irrigation return flow can include contaminants derived from agricultural practices, and then deteriorate the quality of surface and subsurface water within the watershed. Thus, it is important to estimate the effect of irrigation return flow on water chemistry/quality. To do that water samples were collected between November 2004 and December 2005 from stream and groundwater in a small watershed that contains extensive rice paddy fields. The water isotopic compositions represented seasonal variation, particularly in downstream of main channel and the tributary. In April and May, water samples in the downstream and tributary could not be explained by three-component (soil water, groundwater and rainfall) hydrograph separation models (THSM). These results indicated that the stream water was affected by high evaporation and that another water body (e.g. quick return flow) impacted on THSM. Plot of Cl/NO3 and NO3/HCO3 showed that the water chemistry of all water samples was mainly regulated by soil water and groundwater. In addition, the water chemistry was related to water derived from rice paddy fields (WR) and manure. Manure impacted the water chemistry in tributary, one of the shallow groundwaters and the deep groundwaters, whereas that water in downstream was affected by WR. On a plot of delta15NNO3 and delta18ONO3 values, many samples were in a cluster indicative of manure and on a denitrification line. These imply that irrigation return flow characterized by denitrification processes was involved in determining the water chemistry. We suggest that chemical and multi-isotopes approach combined with the THSM is useful to elucidate the sources and processes controlling water chemistry in stream associated with rice paddy fields. PMID- 29499542 TI - Minimal climate change impacts on natural organic matter forecasted for a potable water supply in Ireland. AB - Natural organic matter poses an increasing challenge to water managers because of its potential adverse impacts on water treatment and distribution, and subsequently human health. Projections were made of impacts of climate change on dissolved organic carbon (DOC) in the primarily agricultural Boyne catchment which is used as a potable water supply in Ireland. The results indicated that excluding a potential rise in extreme precipitation, future projected loads are not dissimilar to those observed under current conditions. This is because projected increases in DOC concentrations are offset by corresponding decreases in precipitation and hence river flow. However, the results presented assume no changes in land use and highlight the predicted increase in DOC loads from abstracted waters at water treatment plants. PMID- 29499543 TI - Organic matter geochemical signatures (TOC, TN, C/N ratio, delta13C and delta15N) of surface sediment from lakes distributed along a climatological gradient on the western side of the southern Andes. AB - Paleolimnological studies in western South America, where meteorological stations are scarce, are critical to obtain more realistic and reliable regional reconstructions of past climate and environmental changes, including vegetation and water budget variability. However, climate and environmental geochemical indicators must be tested before they can be applied with confidence. Here we present a survey of lacustrine surface sediment (core top, 0 to ~1cm) biogeochemical proxies (total organic carbon [TOC], total nitrogen [TN], carbon/nitrogen ratio [C/N ratio] and bulk organic delta13C and total delta15N) from a suite of 72 lakes spanning the transition from a Mediterranean climate with a patchwork of cultivated vegetation, pastureland, and conifers in central Chile to a rainy temperate climate dominated by broadleaf deciduous and evergreen forest further south. Sedimentary data are compared to the latitudinal and orographic climatic trends of the region based on the climatology (precipitation and temperature) produced with Climate Forecast System Reanalysis (CFSR) data and the modern Southern Hemisphere Westerly Winds (SWW) location. The geochemical data show inflection points at ~42 degrees S latitude and ~1500m elevation that are likely related to the northern limit of influence of the SWW and elevation of the snow line, respectively. Overall the organic proxies were able to mimic climatic trends (Mean Annual Precipitation [MAP] and temperature [MAT]), indicating that they are a useful tool to be included in paleoclimatological reconstruction of the region. PMID- 29499544 TI - A Tier-I leaching risk assessment of three anticoagulant compounds in the forested areas of Hawai'i. AB - The anticoagulant rodenticides brodifacoum, chlorophacinone, and diphacinone have been proposed for broadcast application in some forested areas in Hawai'i to protect rare and endangered native bird species from introduced mice and rats. Groundwater resources in Hawai'i are prone to contamination due to the intrinsic aquifer vulnerability to leaching from the land surface. Because of the hydrogeologic complexity, Hawai'i uses a Tier-I leaching assessment tool, CLERS, to make registration decisions for new or existing chemicals. The CLERS tool uses soil and pesticide properties as well as water recharge through the soil profile in a GIS framework to estimate mass attenuation of the chemicals at a given depth and compares against this attenuation factor against those of a known leacher and a non-leacher. Disturbed soil samples were collected across the state of Hawai'i, including the islands of Hawai'i, Kaho'olawe, Kaua'i, Lana'i, Maui, Moloka'i, and O'ahu, with two sampling locations per island, except for Kaua'i which had three. As only limited information on chemical properties of these anticoagulants in soils is available, laboratory experiments were performed to determine the sorption capacity (Kd) and the degradation rate (T1/2) of brodifacoum, chlorophacinone, and diphacinone to construct a proper chemical database. Depending on the soil type, T1/2 values ranged between 37 and 248days for diphacinone, between 39 and 1000days for chlorophacinone, and between 72 and 462days for brodifacoum. These data were used in the CLERS tool to estimate leaching risks for these chemicals primarily in forested areas of the state where the chemicals are likely to be applied. The results from the CLERS tool indicate low risks of leaching of these three compounds into aquifers in five out of six major Hawaiian Islands. Diphacinone showed medium risk of leaching in a few remote areas in Maui. PMID- 29499545 TI - Vulnerability assessment including tangible and intangible components in the index composition: An Amazon case study of flooding and flash flooding. AB - The vulnerability of cities and communities in the Amazon to flooding and flash flooding is increasing. The effects of extreme events on populations vary across landscapes, causing vulnerability to differ spatially. Traditional vulnerability studies in Brazil and across the world have used the vulnerability index for the country and, more recently, municipality scales. The vulnerability dimensions are exposure, sensitivity, and adaptive capacity. For each of these dimensions, there is a group of indicators that constitutes a vulnerability index using quantitative data. Several vulnerability assessments have used sensitivity and exposure analyses and, recently, adaptive capacity has been considered. The Geographical Information Systems (GIS) analysis allows spatial regional modeling using quantitative vulnerability indicators. This paper presents a local-scale vulnerability assessment in an urban Amazonian area, Santarem City, using interdisciplinary methods. Data for exposure and sensitivity were gathered by remote sensing and census data, respectively. However, adaptive capacity refers to local capacities, whether infrastructural or not, and the latter were gathered by qualitative participatory methods. For the mixed data used to study adaptive capacity, we consider tangible components for countable infrastructure that can cope with hazards, and intangible components that reflect social activities based on risk perceptions and collective action. The results indicate that over 80% of the area is highly or moderately vulnerable to flooding and flash flooding. Exposure and adaptive capacity were determinants of the results. Lower values of adaptive capacity play a significant role in vulnerability enhancement. PMID- 29499546 TI - Assessing the environmental impacts of soil compaction in Life Cycle Assessment. AB - Maintaining biotic capacity is of key importance with regard to global food and biomass provision. One reason for productivity loss is soil compaction. In this paper, we use a statistical empirical model to assess long-term yield losses through soil compaction in a regionalized manner, with global coverage and for different agricultural production systems. To facilitate the application of the model, we provide an extensive dataset including crop production data (with 81 crops and corresponding production systems), related machinery application, as well as regionalized soil texture and soil moisture data. Yield loss is modeled for different levels of soil depth (0-25cm, 25-40cm and >40cm depth). This is of particular relevance since compaction in topsoil is classified as reversible in the short term (approximately four years), while recovery of subsoil layers takes much longer. We derive characterization factors quantifying the future average annual yield loss as a fraction of the current yield for 100years and applicable in Life Cycle Assessment studies of agricultural production. The results show that crops requiring enhanced machinery inputs, such as potatoes, have a major influence on soil compaction and yield losses, while differences between mechanized production systems (organic and integrated production) are small. The spatial variations of soil moisture and clay content are reflected in the results showing global hotspot regions especially susceptible to soil compaction, e.g. the South of Brazil, the Caribbean Islands, Central Africa, and the Maharashtra district of India. The impacts of soil compaction can be substantial, with highest annual yield losses in the range of 0.5% (95% percentile) due to one year of potato production (cumulated over 100y this corresponds to a one-time loss of 50% of the present yield). These modeling results demonstrate the necessity for including soil compaction effects in Life Cycle Impact Assessment. PMID- 29499547 TI - ICP-MS based methods to characterize nanoparticles of TiO2 and ZnO in sunscreens with focus on regulatory and safety issues. AB - This study sought to develop analytical methods to characterize titanium dioxide (TiO2) and zinc oxide (ZnO) nanoparticles (NPs), including the particle size distribution and concentration, in cream and spray sunscreens with different sun protection factor (SPF). The Single Particle Inductively Coupled Plasma-Mass Spectrometry (SP ICP-MS) was used as screening and fast method to determine particles size and number. The Asymmetric Flow-Field Flow Fractionation (AF4-FFF) as a pre-separation technique was on-line coupled to the Multi-Angle Light Scattering (MALS) and ICP-MS to determine particle size distributions and size dependent multi-elemental concentration. Both methods were optimized in sunscreens in terms of recovery, repeatability, limit of detection and linear dynamic range. Results showed that sunscreens contained TiO2 particles with an average size of <=107 nm and also a minor number of ZnO particles sized <=98 nm. The higher fraction of particles <100 nm was observed in sunscreens with SPF 50+ (ca. 80%); the lower percentage (12-35%) in sunscreens with lower SPF values. Also the higher TiO2 (up to 24% weight) and ZnO (ca. 0.25% weight) concentrations were found in formulations of SPF 50+. Creamy sunscreens could be considered safe containing TiO2 and ZnO NPs less than the maximum allowable concentration of 25% weight as set by the European legislation. On the contrary, spray products required additional considerations with regard to the potential inhalation of NPs. The developed methods can contribute to the actual demand for regulatory control and safety assessment of metallic NPs in consumers' products. PMID- 29499548 TI - The long-term impacts of anthropogenic and natural processes on groundwater deterioration in a multilayered aquifer. AB - In many regions around the world, there are issues associated with groundwater resources due to human and natural factors. However, the relation between these factors is difficult to determine due to the large number of parameters and complex processes required. In order to understand the relation between land use allocations, the intrinsic factors of the aquifer, climate change data and groundwater chemistry in the multilayered aquifer system in Malaysia's Northern Kelantan Basin, twenty-two years hydrogeochemical data set was used in this research. The groundwater salinisation in the intermediate aquifer, which mainly extends along the coastal line, was revealed through the hydrogeochemical investigation. Even so, there had been no significant trend detected on groundwater salinity from 1989 to 2011. In contrast to salinity, as seen from the nitrate contaminations there had been significantly increasing trends in the shallow aquifer, particularly in the central part of the study area. Additionally, a strong association between high nitrate values and the areas covered with palm oil cultivations and mixed agricultural have been detected by a multiple correspondence analysis (MCA), which implies that the increasing nitrate concentrations are associated with nitrate loading from the application of N fertilisers. From the process of groundwater salinisation in the intermediate aquifer, could be seen that it has a strong correlation the aquifer lithology, specifically marine sediments which are influenced by the ancient seawater trapped within the sediments. PMID- 29499549 TI - Future temperature-related years of life lost projections for cardiovascular disease in Tianjin, China. AB - It is widely accepted that temperatures is associated with cardiovascular mortality, however, few studies have explored the effects of temperature on years of life lost (YLL) from cardiovascular mortality in China under future global warming scenarios. Therefore, there is an urgent need to obtain projections of YLL from cardiovascular diseases. Here we applied nineteen global-scale climate models (GCMs) and three Representative Concentration Pathway emission scenarios (RCPs) in the 2050s and 2070s for temperature-related YLL projection in Tianjin, China. We found the relationships between daily maximum temperatures with YLL from cardiovascular mortality were basically U-shaped. We observed increasing net annual YLL across a range of multiple models under different climate scenarios, suggesting that increasing heat-related YLL from cardiovascular mortality could offset decreasing cold-related YLL from cardiovascular mortality. The largest temperature-related YLL from cardiovascular mortality were observed under the RCP8.5 scenario and increased more rapidly in the 2070s versus the 2050s. Monthly analyses of percent changes in YLL from cardiovascular mortality showed that the largest percent increases occurred from May to September. If warm adaptation occurs, only the adverse effects under RCP2.6 could be fully offset in both 2050 and 2070. Our exploration provided further evidence for the potential health impacts of global warming and highlighted that government should develop environmental policies for future health risks. PMID- 29499550 TI - Impact of water chemistry on surface charge and aggregation of polystyrene microspheres suspensions. AB - The discharge of microplastics into aquatic environment poses the potential threat to the hydrocoles and human health. The fate and transport of microplastics in aqueous solutions are significantly influenced by water chemistry. In this study, the effect of water chemistry (i.e., pH, foreign salts and humic acid) on the surface charge and aggregation of polystyrene microsphere in aqueous solutions was conducted by batch, zeta potentials, hydrodynamic diameters, FT-IR and XPS analysis. Compared to Na+ and K+, the lower negative zeta potentials and larger hydrodynamic diameters of polystyrene microspheres after introduction of Mg2+ were observed within a wide range of pH (2.0-11.0) and ionic strength (IS, 0.01-500mmol/L). No effect of Cl-, HCO3- and SO42- on the zeta potentials and hydrodynamic diameters of polystyrene microspheres was observed at low IS concentrations (<5mmol/L), whereas the zeta potentials and hydrodynamic diameters of polystyrene microspheres after addition of SO42- were higher than that of Cl- and HCO3- at high IS concentrations (>10mmol/L). The zeta potentials of polystyrene microspheres after HA addition were decreased at pH2.0 11.0, whereas the lower hydrodynamic diameters were observed at pH<4.0. According to FT-IR and XPS analysis, the change in surface properties of polystyrene microspheres after addition of hydrated Mg2+ and HA was attributed to surface electrostatic and/or steric repulsions. These investigations are crucial for understanding the effect of water chemistry on colloidal stability of microplastics in aquatic environment. PMID- 29499551 TI - Task activation and functional connectivity show concordant memory laterality in temporal lobe epilepsy. AB - OBJECTIVE: In epilepsy, asymmetries in the organization of mesial temporal lobe (MTL) functions help determine the cognitive risk associated with procedures such as anterior temporal lobectomy. Past studies have investigated the change/shift in a visual episodic memory laterality index (LI) in mesial temporal lobe structures through functional magnetic resonance imaging (fMRI) task activations. Here, we examine whether underlying task-related functional connectivity (FC) is concordant with such standard fMRI laterality measures. METHODS: A total of 56 patients with temporal lobe epilepsy (TLE) (Left TLE [LTLE]: 31; Right TLE [RTLE]: 25) and 34 matched healthy controls (HC) underwent fMRI scanning during performance of a scene encoding task (SET). We assessed an activation-based LI of the hippocampal gyrus (HG) and parahippocampal gyrus (PHG) during the SET and its correspondence with task-related FC measures. RESULTS: Analyses involving the HG and PHG showed that the patients with LTLE had a consistently higher LI (right lateralized) than that of the HC and group with RTLE, indicating functional reorganization. The patients with RTLE did not display a reliable contralateral shift away from the pathology, with the mesial structures showing quite distinct laterality patterns (HG, no laterality bias; PHG, no evidence of LI shift). The FC data for the group with LTLE provided confirmation of reorganization effects, revealing that a rightward task LI may be based on underlying connections between several left-sided regions (middle/superior occipital and left medial frontal gyri) and the right PHG. The FCs between the right HG and left anterior cingulate/medial frontal gyri were also observed in LTLE. Importantly, the data demonstrate that the areas involved in the LTLE task activation shift to the right hemisphere showed a corresponding increase in task-related FCs between the hemispheres. SIGNIFICANCE: Altered laterality patterns based on mesial temporal lobe epilepsy (MTLE) pathology manifest as several different phenotypes, varying according to side of seizure onset and the specific mesial structures involved. There is good correspondence between task LI activation and FC patterns in the setting of LTLE, suggesting that reliable visual episodic memory reorganization may require both a shift in nodal activation and a change in nodal connectivity with mesial temporal structures involved in memory. PMID- 29499552 TI - Corrigendum to: "Does outcome measurement of treatment for substance use disorder reflect the personal concerns of patients? A scoping review of measures recommended in Europe" [Drug Alcohol Dependence 179 (2017) 299-308]. PMID- 29499553 TI - Maternal and partner prenatal alcohol use and infant cognitive development. AB - BACKGROUND: Teratogenicity of heavy prenatal alcohol exposure is established, but uncertainty remains regarding the impact of moderate alcohol exposure on cognitive deficits in infants. Separating in utero effects from environmental confounding is a challenge for observational studies; consideration of alcohol use by partners as well as mothers may help clarify this. This study examined associations between prenatal alcohol use by both mothers and their partners and infant cognitive developmental outcomes at 12-months. METHODS: Pregnant women (n = 1331) and their partners (n = 699) were recruited from antenatal clinics of three metropolitan public hospitals in Australia, and completed detailed interviews about alcohol consumptions throughout pregnancy. Infants were assessed with the Bayley Scales of Infant Development - Third edition (Bayley) at 12 months of age. RESULTS: Alcohol use during pregnancy was reported by 65.7% of mothers and 84.1% of partners. Using multiple methods to adjust for confounding factors, no evidence for impaired cognitive ability associated with alcohol use by mothers or their partners was observed. Children born to women who drank low levels of alcohol had slightly higher Bayley cognitive scores than those born to abstaining women. There was some evidence for an interaction between sociodemographic factors and prenatal alcohol exposure on infant cognitive outcomes. CONCLUSION: This finding corroborates existing evidence to suggest there are no detrimental effects to infant cognitive development at 12-months of age following low-level prenatal alcohol exposure. Future prospective studies involving families of a broad range of backgrounds would be informative to clarify interaction between alcohol exposure and environmental factors on developmental outcomes. PMID- 29499554 TI - Opioid use and stigma: The role of gender, language and precipitating events. AB - The stigma of drug addiction is associated with negative perceptions and can be a barrier to treatment. With the rise in opioid overdose deaths, understanding stigmatizing attitudes towards individuals who use opioids is a crucial matter. There is a lack of opioid use research on stigma and, therefore, we aimed to discern stigmatizing attitudes towards people with opioid addiction. A randomized, between-subjects case vignette study (n = 2605) was conducted with a nation-wide online survey. Participants rated a hypothetical individual addicted to opioids on different dimensions of stigma after seeing one version of a vignette that varied by three conditions: 1) a male versus a female, 2) an individual labeled as being a "drug addict" versus having an "opioid use disorder" and 3) an individual whose use started by taking prescription opioids from a friend versus receiving a prescription from a doctor. Our results indicated that there were higher stigmatizing attitudes overall towards a male, an individual labeled as a "drug addict" and an individual who took prescription opioids from a friend. Interaction effects also showed that a female labeled with an "opioid use disorder" and male labeled as a "drug addict" were rated with higher stigma. The findings from our study are the first to show that information about gender, precipitating events and language matter when assessing stigma and opioid use and may affect the delivery of patient care. PMID- 29499555 TI - Photocatalytic degradation of bisphenol A in aqueous media: A review. AB - Bisphenol A (BPA) is known to be an emerging pollutant in various environmental compartments. Human exposure to BPA occurs widely because it is commonly used as the raw material in a variety of industrial processes (e.g., the preparation of epoxy and polycarbonate resins). In this review, a brief survey was carried out to cover a range of photocatalytic materials (e.g., titania, zinc, silver, carbon, and bismuth) and their modified forms as an effective means to treat water systems contaminated with BPA. The overall efficiency and limitations of these catalysts are described for the photocatalytic treatment of BPA. PMID- 29499556 TI - Prospective association between major depressive disorder and leukocyte telomere length over two years. AB - BACKGROUND: Reduced leukocyte telomere length (LTL) has been found to be associated with multiple common age-related diseases, including heart disease, diabetes, and cancer. A link has also been suggested between shortened LTL and major depressive disorder (MDD), suggesting that MDD may be a disease of accelerated aging. This prospective, longitudinal study examined the association between depression diagnosis at baseline and change in LTL over two years in a well-characterized sample of N = 117 adults with or without MDD at baseline, using rigorous entry criteria. METHODS: Participants aged 18-70 were assessed with validated instruments by trained, doctoral-level clinician raters at baseline and at two-year follow-up, and blood samples were obtained at both visits. LTL was assayed under identical methods using quantitative polymerase chain reaction (qPCR). The effect of an MDD diagnosis at baseline on change in LTL over two years was examined via hierarchical mixed models, which included potential confounders. RESULTS: Individuals with MDD at baseline had greater LTL shortening over two years than individuals without MDD (p = 0.03), even after controlling for differences in age, sex, and body mass index (BMI). In the sub sample of individuals with MDD diagnoses at baseline, no significant associations between LTL change and symptom severity or duration were found. CONCLUSION: A baseline diagnosis of MDD prospectively predicted LTL shortening over two years. Our results provide further support for MDD as a disease associated with accelerated aging in a well-characterized sample using validated, clinician-rated measures. PMID- 29499557 TI - A new composite of graphene and molecularly imprinted polymer based on ionic liquids as functional monomer and cross-linker for electrochemical sensing 6 benzylaminopurine. AB - Molecularly imprinted polymers prepared using traditional functional monomers and cross-linkers exhibit slow binding kinetics, low electrocatalytic activity and adsorption capacity. Herein, we report a new composite of ionic liquid-based graphene and molecularly imprinted polymer (IL-GR-MIP) with high electrocatalytic activity and adsorption capacity to construct an effective electrochemical sensor for 6-benzylaminopurine (6-BAP). Our objective was to enhance the efficiency of the sensor by incorporating more IL in the MIP framework. We synthesized IL-GR MIP using ionic liquid 1-vinyl-3-butylimidazolium tetrafluoroborate (IL1) as functional monomer, ionic liquid 1,4-butanediyl-3,3'-bis-l-vinylimidazolium dibromide (IL2) as cross-linker, 6-BAP as template, and GR as supporter. IL-GR MIP was characterized by Fourier transform infrared spectroscopy, thermal gravimetric analysis, Raman spectroscopy, X-ray photoelectron spectroscopy, and scanning electron microscope. Compared with GR-MIP composites based on methacrylic acid or IL1 as functional monomer, N, N'-methylenebisacrylamide and ethylene glycol dimethacrylate as cross-linker, the IL-GR-MIP (prepared with ionic liquids as functional monomer and cross-linker) sensor exhibited highest peak current for 6-BAP. The results indicate the ability of IL2 as cross-linker to enhance electrocatalytic activity and adsorption capacity for 6-BAP of IL-GR MIP. Under the optimized conditions, the peak current of IL-GR-MIP sensor was linear to 6-BAP concentration in the range of 0.5-50 MUM with a detection limit of 0.2 MUM (S/N = 3). The IL-GR-MIP sensor exhibited good selectivity with the anti-interference ability of 1000-fold ascorbic acid in 6-BAP determination. Furthermore, we demonstrated practical applicability of IL-GR-MIP sensor in detecting 6-BAP in real samples with satisfactory results. PMID- 29499558 TI - Dual-reaction triggered sensitivity amplification for ultrasensitive peptide cleavage based electrochemical detection of matrix metalloproteinase-7. AB - In this work, a new strategy of dual-reaction triggered sensitivity amplification for ultrasensitive electrochemical detection of matrix metalloproteinase-7 (MMP 7) was developed. The sensitivity of amperometric biosensor relies on the current signal differences (DeltaI) caused by per unit concentration target. Benefited from dual-reaction catalytic activities of Pd nanoparticles, dual catalytic reactions were implemented in the biosensor to amplify the DeltaI: (1) Fenton like reaction was triggered by the probes to degrade redox species methylene blue; (2) catalytic precipitation reaction was followed subsequently to generate insoluble precipitation by 4-chloro-1-naphthol oxidation. Dual-enhancement of DeltaI triggered by Pd nanoparticle-based catalytic probes significantly improved the detection performance of the biosensor. The peptide-cleavage based biosensor integrated Pd nanoparticle-based catalytic probes with reduced graphene oxide Au/methylene blue-sodium alginate hydrogel (Au-rGO/MB-SA) nanocomposites substrate for ultrasensitive detection of MMP-7. Under optimal conditions, the proposed biosensor exhibited a wide linear range from 10 fg mL-1 to 10 ng mL-1 with an ultralow detection limit of 3.1 fg mL-1. This strategy successfully combines the multiple catalytic reactions triggered by nanomaterials with peptide cleavage pattern in electrochemical biosensor, providing a promising method for detection of other proteases. PMID- 29499559 TI - Electron beam-irradiated polypyrrole decorated with Bovine serum albumin pores: Simultaneous determination of epinephrine and L-tyrosine. AB - In current work highly sensitive and stable electrochemical sensor for simultaneous non-enzymatic detection of epinephrine (EP), L-tyrosine (L-Tyr) is constructed based on Electron beam irradiated Polypyrrole (EB-Ppy) nanospheres (Zeta potential 33.69 mV at pH 7) embedded over bovine serum albumin (BSA) (Zeta potential - 11.54 mV at pH 7) porous structure, fabricated by simple chemical routes. The BSA structure has the advantages of large surface area, excellent structure stability, rich pore channels and redox mediator role. The constructed sensor exhibited excellent sensor performances by the combination of protein with NH group and recorded the linear response of EP, L-Tyr individual in the concentration range of 100 nM-1 mM, 100 nM-800 MUM, with detection limit 7.1 nM, 8.8 nM (S/N = 3sigma/b). The EB-Ppy-BSA/GCE electrochemical sensor manifests intriguing application with good sensitivity, selectivity and reproducibility towards the EP, L-Tyr detection. The practical analytical utility provides great promise by selective measurements in tea, and chicken extract which has a promising future for biological and healthcare applications. PMID- 29499560 TI - Octapartite negative-sense RNA genome of High Plains wheat mosaic virus encodes two suppressors of RNA silencing. AB - High Plains wheat mosaic virus (HPWMoV, genus Emaravirus; family Fimoviridae), transmitted by the wheat curl mite (Aceria tosichella Keifer), harbors a monocistronic octapartite single-stranded negative-sense RNA genome. In this study, putative proteins encoded by HPWMoV genomic RNAs 2-8 were screened for potential RNA silencing suppression activity by using a green fluorescent protein based reporter agroinfiltration assay. We found that proteins encoded by RNAs 7 (P7) and 8 (P8) suppressed silencing induced by single- or double-stranded RNAs and efficiently suppressed the transitive pathway of RNA silencing. Additionally, a Wheat streak mosaic virus (WSMV, genus Tritimovirus; family Potyviridae) mutant lacking the suppressor of RNA silencing (DeltaP1) but having either P7 or P8 from HPWMoV restored cell-to-cell and long-distance movement in wheat, thus indicating that P7 or P8 rescued silencing suppressor-deficient WSMV. Furthermore, HPWMoV P7 and P8 substantially enhanced the pathogenicity of Potato virus X in Nicotiana benthamiana. Collectively, these data demonstrate that the octapartite genome of HPWMoV encodes two suppressors of RNA silencing. PMID- 29499561 TI - Transient receptor potential vanilloid 4 (TRPV4) expression on the nerve fibers of human dental pulp is upregulated under inflammatory condition. AB - OBJECTIVE: Transient receptor potential vanilloid 4 (TRPV4) has been considered as a mechano-, thermo- and osmo-receptor. Under inflammatory conditions in dental pulp, teeth can become sensitive upon exposure to a variety of innocuous stimuli. The objective of the present study was to investigate the expression of the TRPV4 channel on nerve fibers in human dental pulp of non-symptomatic and symptomatic teeth associated with inflammatory conditions. DESIGN: Dental pulp from extracted human permanent teeth was processed for fluorescence immunohistochemistry. Ten asymptomatic (normal) and 10 symptomatic (symptoms associated with pulpitis) teeth were used in this study. Nerve fibers were identified by immunostaining for a marker, protein gene product 9.5, and the cells were counterstained with 4',6 diamidino-2-phenylindole. An anti-TRPV4 antibody was used to trace TRPV4 expression. RESULTS: TRPV4 expression was co-localized with the nerve fiber marker. Immunoreactivity for TRPV4 was more intense (p < 0.05) in the nerves of symptomatic teeth than those of normal teeth. The number of co-localization spots was increased significantly (p < 0.05) in the dental pulp of symptomatic teeth compared with that of asymptomatic (normal) teeth. CONCLUSIONS: There is expression of TRPV4 channels on the nerve fibers of human dental pulp. Our findings suggest upregulation of TRPV4 expression under inflammatory conditions in the pulp. The upregulation of TRPV4 channels may be associated with the exaggerated response of dental pulp to innocuous mechanical, thermal and osmotic stimuli under inflammatory conditions. PMID- 29499562 TI - In vitro investigation on probiotic, anti-Candida, and antibiofilm properties of Lactobacillus pentosus strain LAP1. AB - OBJECTIVE: To investigate the probiotic characteristics, anti-Candida activity, and antibiofilm attributes of Hentak derived Lactobacillus pentosus strain LAP1. DESIGN: The probiotic properties of strain LAP1 were depicted by adapting standard protocols. The anti-Candida and antibiofilm properties of isolate were determined using agar well diffusion assay and ELISA reader test, respectively. The time-kill assay was performed using viable colony count assay. Further, the co-aggregation property of strain LAP1 was determined based on standard methodology. RESULTS: Strain LAP1 exhibited not only tolerance to acidic pH but also showed resistivity (P <= 0.05) to simulated gastric juice exposure. Similarly, the strain was able to tolerate bile salt, showed hyperproteolytic activity, and also depicted susceptibility to most of the antibiotics tested. Auto-aggregation phenomenon (37.5-60%), hydrophobicity nature (42.85%), and survival potentiality of strain LAP1 under freeze-dried condition (9.0 +/- 0.01 log CFU/ml) made the isolate a promising probiotic candidate. Cell-free neutralized supernatant (CFNS) of strain LAP1 exhibited potent antifungal activities against C. albicans, C. tropicalis, and C. krusei with arbitrary unit of 150 +/- 4.34, 200 +/- 5.21, and 130 +/- 5.13 AU/ml, respectively and depicted remarkable reduction in the biofilm formation of respective Candida sp. in a concentration dependent manner. Moreover, time-kill assay data provided the growth inhibition of all Candida sp. in a time dependent manner. Additionally, strain LAP1 revealed significant co-aggregate percentage with C. albicans, C. tropicalis, and C. krusei. CONCLUSIONS: L. pentosus strain LAP1 exhibited a good probiotic characteristics, potent anti-Candida activity, and significant antibiofilm property that could be undoubtedly recommended for its vast applications not only in food industries but also as biotherapeutic agent against Candida infections in pharmaceutical industries. PMID- 29499563 TI - Astrocytic CCAAT/Enhancer-binding protein delta contributes to reactive oxygen species formation in neuroinflammation. AB - Excessive reactive oxygen species (ROS) can form an oxidative stress and an associated neuroinflammation. However, the contribution of astrocytes to ROS formation, the cause of the resistance of astrocytes to oxidative stress, and the consequences on neurons remain largely uninvestigated. The transcription factor CCAAT/enhancer-binding protein delta (CEBPD) is highly expressed in astrocytes and has been suggested to contribute to the progress of Alzheimer's disease (AD). In this study, we found that ROS formation and expression of p47phox and p67phox, subunits of NADPH oxidase, were increased in AppTg mice but attenuated in AppTg/Cebpd-/- mice. Cebpd can up-regulate p47phox and p67phox transcription via a direct binding on their promoters, which results in an increase in intracellular oxidative stress. In addition, Cebpd also up-regulated Cu/Zn superoxide dismutase (Sod1) in astrocytes. Inactivation of Sod1 increased the sensitization to oxidative stress, which provides a reason for the resistance of astrocytes in an oxidative stress environment. Taken together, the study first revealed and dissected the involvement of astrocytic Cebpd in the promotion of oxidative stress and the contribution of CEBPD to the resistance of astrocytes in an oxidative stress environment. PMID- 29499564 TI - Impact of carbonylation on glutathione peroxidase-1 activity in human hyperglycemic endothelial cells. AB - AIMS: High levels of glucose and reactive carbonyl intermediates of its degradation pathway such as methylglyoxal (MG) may contribute to diabetic complications partly via increased generation of reactive oxygen species (ROS). This study focused on glutathione peroxidase-1 (GPx1) expression and the impact of carbonylation as an oxidative protein modification on GPx1 abundance and activity in human umbilical vein endothelial cells (HUVEC) under conditions of mild to moderate oxidative stress. RESULTS: High extracellular glucose and MG enhanced intracellular ROS formation in HUVECs. Protein carbonylation was only transiently augmented pointing to an effective antioxidant defense in these cells. Nitric oxide synthase expression was decreased under hyperglycemic conditions but increased upon exposure to MG, whereas superoxide dismutase expression was not significantly affected. Increased glutathione peroxidase (GPx) activity seemed to compensate for a decrease in GPx1 protein due to enhanced degradation via the proteasome. Mass spectrometry analysis identified Lys-114 as a possible carbonylation target which provides a vestibule for the substrate H2O2 and thus enhances the enzymatic reaction. INNOVATION: Oxidative protein carbonylation has so far been associated with functional inactivation of modified target proteins mainly contributing to aging and age-related diseases. Here, we demonstrate that mild oxidative stress and subsequent carbonylation seem to activate protective cellular redox signaling pathways whereas severe oxidative stress overwhelms the cellular antioxidant defense leading to cell damage. CONCLUSIONS: This study may contribute to a better understanding of redox homeostasis and its role in the development of diabetes and related vascular complications. PMID- 29499565 TI - Early cysteine-dependent inactivation of 26S proteasomes does not involve particle disassembly. AB - Under oxidative stress 26S proteasomes suffer reversible disassembly into its 20S and 19S subunits, a process mediated by HSP70. This inhibits the degradation of polyubiquitinated proteins by the 26S proteasome and allows the degradation of oxidized proteins by a free 20S proteasome. Low fluxes of antimycin A-stimulated ROS production caused dimerization of mitochondrial peroxiredoxin 3 and cytosolic peroxiredoxin 2, but not peroxiredoxin overoxidation and overall oxidation of cellular protein thiols. This moderate redox imbalance was sufficient to inhibit the ATP stimulation of 26S proteasome activity. This process was dependent on reversible cysteine oxidation. Moreover, our results show that this early inhibition of ATP stimulation occurs previous to particle disassembly, indicating an intermediate step during the redox regulation of the 26S proteasome with special relevance under redox signaling rather than oxidative stress conditions. PMID- 29499567 TI - Peer mentoring: Enhancing the transition from student to professional. AB - OBJECTIVE: to share the experience of a model of peer mentoring in a pre qualification midwifery programme DESIGN: description of the framework and benefits of the model SETTING: University and practice PARTICIPANTS: third year midwifery students INTERVENTIONS: practical activities meeting regulatory body requirements in a pre-qualification mentorship module MEASUREMENTS AND FINDINGS: informal evaluations by students of key activities undertaken during peer mentoring demonstrated a range of positive outcomes. These included enhanced confidence, self-awareness, interpersonal and teaching skills, team-working and leadership - factors also associated with emotional intelligence. Students developed an appreciation of the accountability of the mentor including making practice assessment decisions. They stated that the learning achieved had aided their professional development and enhanced employability. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: this module equips students with skills for their future role in facilitating learners and contributes to development of a 'professional persona', enhancing their transition to qualified midwives. The Peer Mentoring Model would be easily adapted to other programmes and professional contexts. PMID- 29499566 TI - The immunoproteasome subunit LMP10 mediates angiotensin II-induced retinopathy in mice. AB - Inflammation has been implicated in a variety of retinal diseases. The immunoproteasome plays a critical role in controlling inflammatory responses, but whether activation of immunoproteasome contributes to angiotensin II (Ang II) induced retinopathy remains unclear. Hypertensive retinopathy (HR) was induced by infusion of Ang II (3000 ng/kg/min) in wild-type (WT) and immunoproteasome subunit LMP10 knockout (KO) mice for 3 weeks. Changes in retinal morphology, vascular permeability, superoxide production and inflammation were examined by pathological staining. Our results showed that immunoproteasome subunit LMP10 expression and its trypsin-like activity were significantly upregulated in the retinas and serum of Ang II-infused mice and in the serum from patients with hypertensive retinopathy. Moreover, Ang II-infused WT mice showed an increase in the central retinal thickness, vascular permeability, reactive oxygen species (ROS) production and inflammation compared with saline controls, and these effects were significantly attenuated in LMP10 KO mice, but were aggravated in mice intravitreally injected with rAAV2-LMP10. Interestingly, administration of IKKbeta specific inhibitor IMD-0354 remarkably blocked an Ang II-induced increase in vascular permeability, oxidative stress and inflammation during retinopathy. Mechanistically, Ang II-induced upregulation of LMP10 promoted PTEN degradation and activation of AKT/IKK signaling, which induced IkBalpha phosphorylation and subsequent degradation ultimately leading to activation of NF-kB target genes in retinopathy. Therefore, this study provided novel evidence demonstrating that LMP10 is a positive regulator of NF-kB signaling, which contributes to Ang II induced retinopathy. Strategies for inhibiting LMP10 or IKKbeta activity in the eye could serve as a novel therapeutic target for treating hypertensive retinopathy. PMID- 29499568 TI - 17-DMAG inhibits the multiplication of several Babesia species and Theileria equi on in vitro cultures, and Babesia microti in mice. AB - Heat shock protein 90 (Hsp90) is a chaperone protein that stabilizes cells during stress or non-stress responses. Previous reports have shown that Hsp90 is a potential drug target to suppress the multiplication of several protozoan parasites. In this study, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17 DMAG), an Hsp90 inhibitor, was evaluated for its inhibitory effect on five in vitro cultures of Babesia and Theileria species, including B. bovis, B. bigemina, B. divergens, B. caballi, and T. equi, and on the multiplication of a B. microti infected mouse model. 17-DMAG showed the inhibitory effect in all of the species tested. The half maximum inhibition concentration (IC50) of 17-DMAG on B. bovis, B. bigemina, B. divergens, B. caballi, and T. equi was 77.6 +/- 2.9, 62.4 +/- 1.9, 183.8 +/- 3.2, 88.5 +/- 9.6, and 307.7 +/- 7.2 nM, respectively. The toxicity assay on MDBK and NIH/3T3 cell lines showed that 17-DMAG affected the viability of cells with an IC50 of 15.5 +/- 4 and 8.8 +/- 2 MUM, respectively. Since the IC50s were much lower on the parasites than on the host cell lines, the selectivity index were high for all tested species. Furthermore, the two-drug combination of 17-DMAG with diminazene aceturate (DA) and atovaquone (AV) showed synergism or addition on in vitro cultures of Babesia and Theileria parasites. In the mouse model, 17-DMAG at a concentration of 30 mg/kg BW effectively inhibited the multiplication of B. microti. Moreover, if combined with DA or AV, 17-DMAG showed a comparable inhibition at the half dose. Taken together, these results indicate that 17-DMAG is a potent drug for treating piroplamosis. The data warrant further evaluation of 17-DMAG as an antibabesial drug and as an option in combination with atovaquone for the treatment of human babesiosis. PMID- 29499569 TI - Raman spectroscopic and theoretical study of liquid and solid water within the spectral region 1600-2300cm-1. AB - Raman spectra of liquid water and ice were measured at different temperatures. The intensity of the band assigned to bending vibrations of water molecules was observed to decrease at the liquid-to-solid transition, while the Raman line near 2200cm-1 showed an anomalously high intensity in the solid phase. A tetrahedral model was used for computer analysis of the observed spectral changes. Quantum chemical calculations of the structure, normal vibrations and Raman spectra in the harmonic approximation, as well as frequencies and intensities of some vibrations using 1D and 2D potential energy surfaces, were carried out using B3LYP with the cc-pVTZ basis set. The influence of the number of hydrogen bonds on the frequency and Raman activity of the bending vibrations was analyzed. The possibility of hydrogen bond weakening upon excitation of the combined bending rocking vibration due to the large amplitude of this vibration is considered. PMID- 29499570 TI - Determination of nutritional parameters of yoghurts by FT Raman spectroscopy. AB - FT-Raman quantitative analysis of nutritional parameters of yoghurts was performed with the help of partial least squares models. The relative standard errors of prediction for fat, lactose and protein determination in the quantified commercial samples equalled to 3.9, 3.2 and 3.6%, respectively. Models based on attenuated total reflectance spectra of the liquid yoghurt samples and of dried yoghurt films collected with the single reflection diamond accessory showed relative standard errors of prediction values of 1.6-5.0% and 2.7-5.2%, respectively, for the analysed components. Despite a relatively low signal-to noise ratio in the obtained spectra, Raman spectroscopy, combined with chemometrics, constitutes a fast and powerful tool for macronutrients quantification in yoghurts. Errors received for attenuated total reflectance method were found to be relatively higher than those for Raman spectroscopy due to inhomogeneity of the analysed samples. PMID- 29499571 TI - Mid-infrared spectroscopy for characterization of Baltic amber (succinite). AB - Natural Baltic amber (succinite) is the most appreciated fossil resin of the rich cultural traditions dating back to prehistoric times. Its unequivocal identification is extremely important in many branches of science and trades including archeology, paleontology, chemistry and finally mineralogical and gemological societies. Current methods of modification of natural succinite are more and more sophisticated making the identification of natural Baltic amber often challenging. In article the systematic analytical approach for identification of natural and modified under different conditions succinite, using mid-infrared spectroscopy (transmission, Drifts and ATR techniques) is presented. The correlation between spectral characteristics and properties of succinite is discussed pointing that the understanding of the nature of changes is the key of identification of this precious material. PMID- 29499572 TI - Cross-sectional and temporal associations between cyber dating abuse victimization and mental health and substance use outcomes. AB - The purpose of this study was to investigate the cross-sectional and temporal associations between cyber dating abuse victimization (CDAV) and mental health (i.e., anxiety, PTSD, and depression), and substance use (i.e., alcohol, cigarettes, marijuana and hard drugs). We used data from the 5th and 6th waves of an ongoing longitudinal study of ethnically diverse adolescents from seven public high schools in Texas, U.S. Participants were 641 adolescents (63.3% female) with a mean age of 19.1 years (SD = .79) at Wave 5. Analyses suggested that while CDAV was associated with mental health and substance use cross-sectionally, when examining over time, it was only associated with past year hard drug and past month marijuana use. Although long-term mental health effects of CDAV did not emerge in the current study, we identified a temporal link to marijuana and hard drugs, highlighting the need for prevention efforts to incorporate messages about substance use. PMID- 29499573 TI - Validation of the first peoples cultural capability measurement tool with undergraduate health students: A descriptive cohort study. AB - BACKGROUND: Health professional graduates require the capacity to work safely, both clinically and culturally, when delivering care to Indigenous peoples worldwide. In the Australian context, the Aboriginal and Torres Strait Islander Health Curriculum Framework (The Framework) provides guidance for health professional programs to integrate, teach and assess Aboriginal and Torres Strait Islander peoples' (First Peoples) health content. There is, however, a lack of validated tools that measure the development of students' cultural capabilities. OBJECTIVES: To validate the Cultural Capability Measurement Tool with a cohort of health professional students. DESIGN: A descriptive cohort design was used. SETTING AND PARTICIPANTS: All students (N = 753) enrolled in a discrete First Peoples Health course at an Australian university were invited to complete the Cultural Capability Measurement Tool. METHODS: The tool was tested for reliability, content and construct validity using confirmatory factor analysis; and concurrent validity using and the Cultural Understanding Self-Assessment Tool. RESULTS: A sample of 418 (73% response rate) was recruited. Most participants were enrolled in the Bachelor of Nursing program (n = 369, 82%). The Cultural Capability Measurement Tool had a Cronbach's alpha coefficient of 0.86. A five-factor solution was confirmed which reflected the cultural capability domains and accounted for 51% of the variance. Scores correlated with students' cultural understanding (r = 0.28, p < 0.001). CONCLUSIONS: Successful implementation of The Framework requires instruments to measure changes in students' cultural capabilities. Measuring nursing students' cultural capabilities can inform their development, identify areas of strengths and deficits for educators, and will ultimately contribute to the development of a culturally safe nursing workforce. PMID- 29499574 TI - Metabolomic analysis of two rice (Oryza sativa) varieties exposed to 2, 2', 4, 4' tetrabromodiphenyl ether. AB - Polybrominated diphenyl ethers (PBDEs) are toxic chemicals widely distributed in the environment, but few studies are available on their potential toxicity to rice at metabolic level. Therefore we exposed ten rice (Oryza sativa) varieties to 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), a predominant congener of PBDEs, in hydroponic solutions with different concentrations. Two varieties that showed different biological effects to BDE-47, YY-9 and LJ-7, were screened as sensitive and tolerant varieties according to changes of morphological and physiological indicators. Metabolic research was then conducted using gas chromatography-mass spectrometry combined with diverse analyses. Results showed that LJ-7 was more active in metabolite profiles and adopted more effective antioxidant defense machinery to protect itself against oxidative damages induced by BDE-47 than YY 9. For LJ-7, the contents of 13 amino acids and 24 organic acids, especially l glutamic acid, beta-alanine, glycolic acid and glyceric acid were up-regulated significantly which contributed to scavenging reactive oxygen species. In the treatment of 500 MUg/L BDE-47, the contents of these four metabolites increased by 33.6-, 19.3-, 10.6- and 10.2-fold, respectively. The levels of most saccharides (such as d-glucose, lactulose, maltose, sucrose and d-cellobiose) also increased by 1.7-12.4 fold which promoted saccharide-related biosynthesis metabolism. Elevation of tricarboxylic acid cycle and glyoxylate and dicarboxylate metabolism enhanced energy-producing processes. Besides, the contents of secondary metabolites, chiefly polyols and glycosides increased significantly to act on defending oxidative stress induced by BDE-47. In contrast, the levels of most metabolites decreased significantly for YY-9, especially those of 13 amino acids (by 0.9%-67.1%) and 19 organic acids (by 7.8% 70.0%). The positive metabolic responses implied LJ-7 was tolerant to BDE-47, while the down-regulation of most metabolites indicated the susceptible nature of YY-9. Since metabolic change might affect the yield and quality of rice, this study can provide useful reference for rice cultivation in PBDEs-polluted areas. PMID- 29499575 TI - Brain morphometric profiles and their seasonal modulation in fish (Liza aurata) inhabiting a mercury contaminated estuary. AB - Mercury (Hg) is a potent neurotoxicant known to induce important adverse effects on fish, but a deeper understanding is lacking regarding how environmental exposure affects the brain morphology and neural plasticity of specific brain regions in wild specimens. In this work, it was evaluated the relative volume and cell density of the lateral pallium, hypothalamus, optic tectum and molecular layer of the cerebellum on wild Liza aurata captured in Hg-contaminated (LAR) and non-contaminated (SJ) sites of a coastal system (Ria de Aveiro, Portugal). Given the season-related variations in the environment that fish are naturally exposed, this assessment was performed in the winter and summer. Hg triggered a deficit in cell density of hypothalamus during the winter that could lead to hormonal dysfunctions, while in the summer Hg promoted larger volumes of the optic tectum and cerebellum, indicating the warm period as the most critical for the manifestation of putative changes in visual acuity and motor-dependent tasks. Moreover, in fish from the SJ site, the lateral pallium relative volume and the cell density of the hypothalamus and optic tectum were higher in the winter than in summer. Thus, season-related stimuli strongly influence the size and/or cell density of specific brain regions in the non-contaminated area, pointing out the ability of fish to adapt to environmental and physiological demands. Conversely, fish from the Hg-contaminated site showed a distinct seasonal profile of brain morphology, presenting a larger optic tectum in the summer, as well as a larger molecular layer of the cerebellum with higher cell density. Moreover, Hg exposure impaired the winter-summer variation of the lateral pallium relative size (as observed at SJ). Altogether, seasonal variations in fish neural morphology and physiology should be considered when performing ecotoxicological studies in order to better discriminate the Hg neurotoxicity. PMID- 29499576 TI - Development of a hierarchical model for predicting microbiological contamination of private groundwater supplies in a geologically heterogeneous region. AB - Private groundwater sources in the Republic of Ireland provide drinking water to an estimated 750,000 people or 16% of the national population. Consumers of untreated groundwater are at increased risk of infection from pathogenic microorganisms. However, given the volume of private wells in operation, remediation or even quantification of public risk is both costly and time consuming. In this study, a hierarchical logistic regression model was developed to 'predict' contamination with E. coli based on the results of groundwater quality analyses of private wells (n = 132) during the period of September 2011 to November 2012. Assessment of potential microbial contamination risk factors were categorised into three groups: Intrinsic (environmental factors), Specific (local features) and Infrastructural (groundwater source characteristics) which included a total of 15 variables. Overall, 51.4% of wells tested positive for E. coli during the study period with univariate analysis indicating that 11 of the 15 assessed risk factors, including local bedrock type, local subsoil type, septic tank reliance, 5 day antecedent precipitation and temperature, along with well type and depth, were all significantly associated with E. coli presence (p < 0.05). Hierarchical logistic regression was used to develop a private well susceptibility model with the final model containing 8 of the 11 associated variables. The model was shown to be highly efficient; correctly classifying the presence of E. coli in 94.2% of cases, and the absence of E. coli in 84.7% of cases. Model validation was performed using an external data set (n = 32) and it was shown that the model has promising accuracy with 90% of positive E. coli cases correctly predicted. The developed model represents a risk assessment and management tool that may be used to develop effective water-quality management strategies to minimize public health risks both in Ireland and abroad. PMID- 29499577 TI - Endoscopic ultrasound-guided entero-enterostomy for the treatment of afferent loop syndrome: a multicenter experience. AB - BACKGROUND: Afferent loop syndrome (ALS) is traditionally managed surgically and, more recently, endoscopically. The role of endoscopic ultrasound-guided entero-enterostomy (EUS-EE) has not been well described. The aim of this study was to assess the technical and clinical success and safety of EUS-EE. METHODS: This was a multicenter, retrospective series at six centers in patients with ALS treated by EUS-EE. Data on patients treated with enteroscopy-assisted luminal stenting (EALS) at a single center were also collected. RESULTS: 18 patients (mean age 64.2 years, 72 % post-pancreaticoduodenectomy, 10 female) underwent EUS EE. The most common symptoms were vomiting (27.8 %) and jaundice (33.3 %). Clinical success included resolution of symptoms in 88.9 % and improvement to allow hospital discharge in 11.1 %. Technical success was achieved in 100 % of cases, with a mean procedure time of 29.7 minutes. The most common procedure was a gastro-jejunostomy (72.2 %). Three adverse events (16.7 %) occurred (two mild, one moderate). When compared with data on EALS, patients treated with EUS-EE needed fewer re-interventions (16.6 % vs. 76.5 %; P < 0.001). CONCLUSION: EUS-EE seems to be safe and effective in the treatment of ALS. Indirect comparison with EALS suggested that EUS-EE is associated with a reduced need for re-intervention. PMID- 29499578 TI - Efficacy of an over-the-scope clip for preventing adverse events after duodenal endoscopic submucosal dissection: a prospective interventional study. AB - BACKGROUND: Duodenal endoscopic submucosal dissection (ESD) remains technically challenging, with a high risk of severe adverse events. Because exposure of the duodenal post-ESD mucosal defect to pancreatic juice and bile acid reportedly induces delayed perforation and bleeding, we examined whether defect closure using an over-the-scope clip (OTSC) system was useful for preventing postoperative adverse events. METHODS: From April 2016 to February 2017, a total of 50 consecutive patients with superficial non-ampullary duodenal epithelial tumors (SNADETs) larger than 10 mm, with no more than semi-circumferential spread, were prospectively enrolled in this study. All of the lesions were treated by experienced ESD operators and the post-ESD mucosal defect was closed using OTSCs. RESULTS: All of the SNADETs were completely removed by ESD, with an R0 resection rate of 88.0 %. The mean procedure and closure times were 67.3 +/- 58.8 minutes and 9.8 +/- 7.2 minutes, respectively. Although complete defect closure was achieved in 94.0 % of the patients (47/50), two patients required surgical conversion. Delayed perforation occurred in only one patient (2.1 %), who did not have successful closure of the defect, as misplacement of the OTSC exposed the muscle layer. Meanwhile, delayed bleeding occurred in three patients (6.3 %); however, the bleeding was easily controlled using endoscopic coagulation. The mean duration of postoperative hospitalization was 5.5 +/- 7.2 days. CONCLUSIONS: Prophylactic defect closure using OTSCs may be effective in reducing severe adverse events after duodenal ESD. PMID- 29499579 TI - [Sleep disorders and impaired sleep as adverse drug reactions of psychotropic drugs: an evaluation of data of summaries of product characteristics]. AB - OBJECTIVE: Psychopharmacotherapy is essential in the treatment of many mental disorders. Adverse drug reactions (ADR) have impact on compliance and tolerability. Sleep disorders or impaired sleep may occur as ADRs of psychopharmacotherapy. Sleep disorders are associated with an increased risk for physical and mental illness and may impair cognition, impulse control, emotion regulation and mood. Objective of the following study was the systematic presentation of type and risk of sleep disorders/impairments of sleep of frequently prescribed psychotropic drugs. METHODS: Psychotropic agents that are most frequently prescribed in Germany were identified by using the Arzneiverordnungs-Report 2016. Summaries of product characteristics (SmPC) of corresponding original products were analyzed regarding presence and frequency of sleep disorders/impairments of sleep according to the International Classification of Sleep Disorders 3 (ICSD-3). RESULTS: N = 64 SmPCs were analyzed. In most of the analyzed SmPCs, at least one sleep disorder (50/64; 78 %) was listed. At least one SmPC with a corresponding ADR was found in the categories insomnia (52 %), parasomnias (33 %), and sleep-related movement disorders (20 %); sleep-related breathing disorders (6 %) and central disorders of hypersomnolence (5 %) were rarely listed; circadian rhythm sleep-wake disorder was not found. The SmPCs of the four most frequently prescribed agents (citalopram > venlafaxine > mirtazapine > sertraline) listed insomnia as an ADR. Nearly all analysed hypnotics (except chloral hydrate) were associated with nightmares. CONCLUSION(S): Most of the psychotropic agents frequently prescribed in Germany may induce sleep disorders/impairments of sleep. The four most frequently prescribed agents were antidepressants and all of the corresponding SmPCs listed insomnia as a possible ADR. Sleep disorders should be taken seriously as possible ADRs of psychopharmacotherapy. PMID- 29499580 TI - [Body schema, multisensory integration and developmental disorders]. AB - Our body is both, the object experiencing the world and the subject of our self- experience. As an object, the body provides sensory information via the bodily surface, which is processed and integrated into a coherent representation of the body, the body schema. This representation is considered to form a crucial structure underlying bodily self-identification. The process of integrating multimodal information into a coherent body representation has received extensive research interest with the aim to further clarify its neuronal correlates and functioning in health and disease. However, little is known about the ontogenetic functioning of body schema or multisensory integration processing and their role in the development of socio-emotional in children. This narrative overview discusses implication of a dysfunctional body schematic functioning for socio emotional competencies. A general introduction on body schematic processes is followed by a narrative review of current findings on the maturation of the body schema and multisensory integration. We finally outline implications for the self and socio-emotional development in children and discuss possible implications for a role of disrupted body schema functions in developmental disorders. PMID- 29499581 TI - ? PMID- 29499582 TI - [A Structured and Photographic Documentation of the Vacuum-Assisted Vaginal Delivery]. AB - The correct placement of the vacuum cup is essential to reduce both maternal and neonatal morbidity after a vacuum-assisted vaginal delivery. Therefore, a checklist based report with all relevant clinical findings and a photo of the infant's head with the location of vacuum tag was introduced to make the exact application of the cup reproducible for. training/instruction purpose. PMID- 29499583 TI - [Single Deepest Vertical Pocket or Amniotic Fluid Index as Evaluation Test for Predicting Adverse Pregnancy Outcome (SAFE trial): A Multicenter, Open-Label, Randomized Controlled Trial]. AB - Objective of this randomized-controlled multicenter-trial was to determine whether the amniotic fluid index (AFI) or the single deepest vertical pocket (SDP) technique for estimating amniotic fluid volume is superior for predicting adverse perinatal outcome. Pregnant women at term were randomized in AFI or SDP group for assessing amniotic fluid at four unversitary hospitals. These two groups were not different with regards to primary outcome parameter (rate of postpartum admission to NICU), but concerning secondary outcome parameters: there were significantly more cases with the diagnosis oligohydramnios (9,8 vs. 2.2%), more induction of labour for oligohydrmanios (12.7 vs. 3.6%) and more abnormal CTG (32.3 vs. 26.2%) in the AFI group. None of the methods were superior to predict adverse perinatal outcome. However, the probability to diagnose oligohydramnios and to induce labour for oligohydramnios was higher when AFI technique was used. PMID- 29499584 TI - [Can Pravastatin influence Pregnancies at High-risk for Preeclampsia?] AB - Statins seem to positively influence the inflammatory, anti-angiogenic milieu of pregnancies with underlying placental ischemia by their pleiotropic effects. This might prevent, ameliorate and delay preeclampsia. To confirm the benefits of pravastatin on gestational age at birth as well as clinic and angiogenic markers in pregnancies at high-risk for preeclampsia, the Department of Obstetrics at the University Hospital Leipzig plans a randomized, double-blinded, placebo controlled feasibility study. PMID- 29499585 TI - ? PMID- 29499586 TI - Hyperforin and Miquelianin from St. John's Wort Attenuate Gene Expression in Neuronal Cells After Dexamethasone-Induced Stress. AB - Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis plays an important part in the development of depressive symptoms. In this study, the effects of a commercial St. John's wort extract (STW3-VI), hyperforin, miquelianin, and the selective serotonin reuptake inhibitor citalopram on the expression of genes relevant to HPA axis function were investigated in human neuronal cells. SH-SY5Y cells were treated with STW3-VI (20 ug/mL), hyperforin (1 uM), miquelianin (10 uM), or citalopram (10 uM) in the presence of the glucocorticoid receptor agonist dexamethasone (DEX,10 uM) for 6 h and 48 h, respectively. Quantitative real-time polymerase chain reaction was used to determine the expression of FKBP5 (FK506 binding protein 51), CREB (cAMP responsive element binding protein), GRIK4 (glutamate ionotropic receptor kainate type subunit 4), VEGF (vascular endothelial growth factor), NET (norepinephrine transporter), and ARRB (beta arrestins), promising biomarkers of antidepressant therapy. Using DEX to mimic stress conditions, it was shown that the gene expression pattern of FKBP5, CREB, GRIK4, VEGF, NET, and ARRB2 in SH-SY5Y cells is time- and treatment-dependent. Most pronounced effects were observed for FKBP5: after 6 h of co-incubation, only STW3-VI could reverse the DEX-induced increase in FKBP5 expression, and after 48 h, citalopram, miquelianin, and hyperforin also reversed the glucocorticoid induced increase in FKBP5 mRNA expression. The effects observed on FKBP5, CREB, GRIK4, VEGF, NET, and ARRB2 are in good correlation with published data, suggesting that this in vitro model could be used to screen the responsiveness of antidepressants under stress conditions. PMID- 29499587 TI - Ergot Alkaloids and their Hallucinogenic Potential in Morning Glories. AB - Naturally occurring and semisynthetic ergot alkaloids play a role in health care or as recreational drugs in Western and indigenous Mexican societies. Evidence is summarized that ergot alkaloids present in Central American Convolvulaceae like Turbina corymbosa, Ipomoea violacea, and Ipomoea asarifolia are colonized by different species of a newly described clavicipitaceous fungal genus named Periglandula. The fungi are associated with peltate glandular trichomes on the adaxial leaf surface of its host plants. The Periglandula fungi are not yet culturable in vitro but were demonstrated to have the capacity to synthesize ergot alkaloids. The alkaloids do not remain in the fungal mycelium but are translocated via the glandular trichomes into their plant host. Both fungi and host benefit from a symbiotic lifestyle. In evolutionary terms the alkaloid biosynthetic gene cluster in the Periglandula/Ipomoea symbiosis is likely to have a conserved (basic) structure while biosynthetic ergot gene clusters within the genera Claviceps and Epichloe were under ecological selection for alkaloid diversification. PMID- 29499588 TI - A validated, sensitive electrophoretic method for the detection of activin receptor type II-Fc fusion proteins in human blood. AB - New therapeutic proteins that trap circulating members of the transforming growth factor (TGF) beta superfamily (activins and growth differentiation factors) show promising effects on erythropoiesis and muscular growth. They are dimeric recombinant fusion proteins composed of the extracellular domain of a human activin receptor (ActRIIA or IIB) linked to the Fc part of human IgG1. Sotatercept (ActRIIA-Fc) and Luspatercept (a modified ActRIIB-Fc) in particular are now in phase 2/3 of clinical trials against anemia and included in the prohibited list established by the World Anti-Doping Agency. To prevent a potential misuse by athletes in the near future, a robust and sensitive method of detection is needed. We validated an approach adapted from an electrophoretic method used for the detection of recombinant erythropoietins that allowed detection of various ActRIIA-Fc and ActRIIB-Fc proteins, including variants produced in different cell types, after a single immuno-extraction step. After separation by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS PAGE), an initial testing procedure performed by single-blotting can indicate the presence of an ActRII-Fc (indifferently type IIA or IIB). A confirmation performed by double-blotting using different antibodies for detection allows a more precise identification of the type of ActRII-Fc (IIA, IIB). Starting from a few hundred microliters of serum or plasma, this method is specific, sensitive, and easy to perform. It could easily be adopted by anti-doping laboratories. PMID- 29499589 TI - Letter to the Editor Regarding "Long-Term Outcomes of Surgical Treatment in 181 Patients with Supratentorial Cerebral Cavernous Malformation-Associated Epilepsy". PMID- 29499590 TI - Letter to the Editor Regarding "Direct C2 Pedicle Screw Fixation for Axis Body Fracture". PMID- 29499591 TI - Letter to the Editor Regarding "Endoscopic Submandibular Retropharyngeal Approach to the Craniocervical Junction and Clivus: An Anatomic Study". PMID- 29499592 TI - Neurosurgical Management of Spontaneous Intrauterine Depressed Skull Fracture. PMID- 29499593 TI - Management of Cerebral Venous and Sinus Thrombosis Following Transsphenoidal Surgery for Cushing Disease During Early Postoperative Period: Uncommon Neurosurgical Complication. PMID- 29499594 TI - Antithrombotic Therapy in Chronic Subdural Hematoma: Solving the Dilemma. PMID- 29499595 TI - In Reply to "Antithrombotic Therapy in Chronic Subdural Hematoma: Solving the Dilemma". PMID- 29499596 TI - Letter to the Editor Regarding "Risk Factors for the Rupture of Intracranial Aneurysms Using Computed Tomography Angiography". PMID- 29499597 TI - In Reply to the Letter to the Editor Regarding "Risk Factors for the Rupture of Intracranial Aneurysms Using Computed Tomography Angiography". PMID- 29499598 TI - Is Neurosurgery Ready for Cisternostomy in Traumatic Brain Injuries? PMID- 29499599 TI - In Reply to "Is Neurosurgery Ready for Cisternostomy in Traumatic Brain Injuries?" PMID- 29499600 TI - Selective Amygdalohippocampectomy for Mesial Temporal Sclerosis: Special Considerations in Geniuses. PMID- 29499601 TI - In Reply to "Selective Amygdalohippocampectomy for Mesial Temporal Sclerosis: Special Considerations in Geniuses". PMID- 29499602 TI - Letter to the Editor Regarding "Clinical Features, Treatment, and Long-Term Outcomes of Central Neurocytoma: 20-Year Experience at a Single Center". PMID- 29499603 TI - In Reply to Letter to the Editor Regarding "Clinical Features, Treatment, and Long-Term Outcomes of Central Neurocytoma: 20-Year Experience at a Single Center". PMID- 29499604 TI - Letter to the Editor Regarding "Optic Nerve Meningioma Mimicking Cavernous Hemangioma". PMID- 29499605 TI - A Reply to Commentaries on "Surgical and Teaching Mission to Mongolia: Experience and Lessons". PMID- 29499606 TI - Strategic Planning of Surgical Missions. PMID- 29499607 TI - Twitter - @WorldNeurosurg. PMID- 29499609 TI - Costs, Substitution, and Material Use: The Case of Rare Earth Magnets. AB - Environmental technologies depend on raw materials, some of which are subject to volatile costs and availability concerns. One way to address these concerns is through substitution, of which there are many types. An important form of substitution in the short term is adopting an alternative production process, yielding a material with the same functional properties with less material input. In effect, technology substitutes for material. This study elucidates the role increased and uncertain material costs play in inducing different substitution types in the short to medium term. Specifically, this paper uses an expert survey to determine the relative importance of eight specific industry responses taken by magnet and wind turbine manufacturers in response to the 2010/2011 rare-earth price spike through 2016. Statistical tests show adopting an existing production process for magnets was the most important response, followed by cost passthrough, using an alternate magnet grade in a redesigned generator system, and using alternate systems altogether. The paper also provides specific findings for the magnet and wind turbine industries with respect to each substitution type. PMID- 29499608 TI - The Maillard Reaction Reduced the Sensitization of Tropomyosin and Arginine Kinase from Scylla paramamosain, Simultaneously. AB - The Maillard reaction was established to reduce the sensitization of tropomyosin (TM) and arginine kinase (AK) from Scylla paramamosain, and the mechanism of the attenuated sensitization was investigated. In the present study, the Maillard reaction conditions were optimized for heating at 100 degrees C for 60 min (pH 8.5) with arabinose. A low level of allergenicity in mice was shown by the levels of allergen-specific antibodies, and more Th1 and less Th2 cells cytokines produced and associated transcription factors with the Maillard reacted allergen (mAllergen). The tolerance potency in mice was demonstrated by the increased ratio of Th1/Th2 cytokines. Moreover, mass spectrometry analysis showed that some key amino acids of IgE-binding epitopes (K112, R125, R133 of TM; K33, K118, R202 of AK) were modified by the Maillard reaction. The Maillard reaction with arabinose reduced the sensitization of TM and AK, which may be due to the masked epitopes. PMID- 29499610 TI - Metabolomics Reveal Optimal Grain Preprocessing (Milling) toward Rice Koji Fermentation. AB - A time-correlated mass spectrometry (MS)-based metabolic profiling was performed for rice koji made using the substrates with varying degrees of milling (DOM). Overall, 67 primary and secondary metabolites were observed as significantly discriminant among different samples. Notably, a higher abundance of carbohydrate (sugars, sugar alcohols, organic acids, and phenolic acids) and lipid (fatty acids and lysophospholipids) derived metabolites with enhanced hydrolytic enzyme activities were observed for koji made with DOM of 5-7 substrates at 36 h. The antioxidant secondary metabolites (flavonoids and phenolic acid) were relatively higher in koji with DOM of 0 substrates, followed by DOM of 5 > DOM of 7 > DOM of 9 and 11 at 96 h. Hence, we conjecture that the rice substrate preprocessing between DOM of 5 and 7 was potentially optimal toward koji fermentation, with the end product being rich in distinctive organoleptic, nutritional, and functional metabolites. The study rationalizes the substrate preprocessing steps vital for commercial koji making. PMID- 29499611 TI - Laser postionization of neutral molecules sputtered using bismuth and argon cluster primary ions. AB - In this study, the influence of two different cluster primary ions in laser secondary neutral mass spectrometry (Laser-SNMS) has been investigated. Despite the many advantages of Laser-SNMS, fragmentation of neutral organic molecules during both sputtering and photoionization has limited its efficiency for the study of large organic and biological molecules. Cluster ion sputtering, and in particular large argon gas cluster sputtering, has been proposed as a means of reducing this fragmentation. Molecules of 9-fluorenylmethoxycarbonyl-pentafluoro l-phenylalanine were sputtered using Bi3+ and Ar2000+ cluster primary ions, and the desorbed neutral species ("secondary neutrals") were postionized using a 7.87 eV vacuum ultraviolet laser light fluorine excimer laser. By varying timing parameters and laser power density, time-of-flight and laser power density distributions were obtained to investigate the fragmentation and energy distributions of the sputtered neutral species. Changing from 30 keV Bi3+ sputtering to 10 keV Ar2000+ resulted in a significant reduction in fragmentation of the molecule as well as a suppression of the high background that results from metastable decay of highly excited ions, yielding significantly improved detection of the intact molecule and characteristic fragments. Analysis of the influence of laser power density and laser pulse delay time indicates a reduction of fragmentation in both the sputtering phase and the photoionization phase. This study demonstrates the importance of soft desorption for efficient laser postionization of large organic molecules and shows the potential for improving the efficiency of laser postionization by using large gas cluster ion sputtering. PMID- 29499612 TI - Overall severities of gastrointestinal symptoms in pediatric outpatients with and without autism spectrum disorder. AB - In order to determine the effectiveness of a Gastrointestinal Severity Index to screen for gastrointestinal disorders, the Gastrointestinal Severity Index was administered to 135 children with autism spectrum disorders and 146 comparisons with and without gastrointestinal disorders. The mean Gastrointestinal Severity Index scores of the groups were 3.53 +/- 1.78, 3.15 +/- 1.99, 0.81 +/- 1.25, and 0.29 +/- 0.76 (comparative pediatric patients with gastrointestinal disorder = autism spectrum disorder + gastrointestinal disorder > autism spectrum disorder gastrointestinal disorder > comparative pediatric patients without gastrointestinal disorder, respectively), Ps < 0.05. Receiver operating characteristic curves and areas under the receiver operating characteristic curves were calculated to ascertain which Gastrointestinal Severity Index cutoff scores yielded the highest sensitivity and specificity rates for the diagnosis of gastrointestinal disorders. The area under the receiver operating characteristic curve (0.97) for the comparison group was higher (P < 0.001) than the area under the receiver operating characteristic curve (0.85) for autism spectrum disorder children indicating that the Gastrointestinal Severity Index was more effective in screening for gastrointestinal disorders in comparisons. However, the same Gastrointestinal Severity Index cutoff score of 2 and above yielded, respectively, sensitivity and specificity rates of 92% and 93% for comparisons and 80% and 79% for autism spectrum disorder children. The negative and positive predictive values based on these sensitivity and specificity rates were calculated for a range of prevalences of gastrointestinal disorders and indicated that the Gastrointestinal Severity Index may be useful for screening children with and without autism spectrum disorder for gastrointestinal symptoms. PMID- 29499613 TI - How belief in a just world might shape responses to discrimination: A case study of left-behind children in China. AB - BACKGROUND: Previous study has indicated that perceived discrimination affected the children's behaviors, but whether belief in a just world moderates the relationship between perceived discrimination and problem behaviors among left behind children and whether there are differences between boys and girls are still unknown. AIMS: This study aims at exploring whether perceived discrimination influences the left-behind children's behaviors and the moderating role of belief in a just world among both boys and girls. METHODS: Using cross sectional data on rural left-behind children in Henan Province of China, this study examined the relationships among perceived discrimination (personal and group), belief in a just world and problem behaviors for both boys and girls. The participants included 336 boys and 310 girls. Self-report questionnaires captured perceived discrimination, belief in a just world and problem behaviors. RESULTS: The results demonstrated that Chinese left-behind boys who perceived a high amount of personal discrimination were prone to exhibit problem behaviors. Yet, neither perceived personal nor group discrimination was associated with problem behaviors among the left-behind girls. Moreover, the children's belief in a just world moderated the association between perceived discrimination and problem behaviors among the boys; in those who reported higher levels of belief in a just world, the negative effect of perceived personal discrimination on problem behaviors appeared weaker, comparing to those who reported lower levels of belief in a just world. In addition, the negative effect of perceived group discrimination on problem behaviors appeared stronger among the left-behind boys who reported higher levels of belief in a just world. CONCLUSION: Belief in a just world provided a protect function for the left-behind children when facing perceived personal discrimination. More attention should be paid on belief in a just world, perceived discrimination and problem behaviors among left-behind children. PMID- 29499614 TI - Use of functional respiratory imaging to characterize the effect of inhalation profile and particle size on lung deposition of inhaled corticosteroid/long acting beta2-agonists delivered via a pressurized metered-dose inhaler. AB - BACKGROUND: Functional respiratory imaging (FRI) uses three-dimensional models of human lungs and computational fluid dynamics to simulate functional changes within airways and predict the deposition of inhaled drugs. This study used FRI to model the effects of different patient inhalation and drug formulation factors on lung deposition of an inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA) combination, administered by a pressurized metered-dose inhaler. METHODS: Three-dimensional models of the lungs of six patients with asthma (mean forced expiratory volume in 1 s, 83%), treated with an ICS/LABA, were included. FRI modelling was used to simulate (1) the effects on lung deposition of inhalation duration and particle size [fine particle fraction (FPF), proportion of particles <5 um; and mass median aerodynamic diameter (MMAD), average size of inhalable particles]; (2) deposition of fluticasone propionate/formoterol (FP/FORM) 125/5 ug; and (3) how inhalation profiles and flow rates affected FP/FORM deposition. RESULTS: Total lung depositions (TLDs) following 1-, 3- and 5 s inhalations were 22.8%, 36.1% and 41.6% (metered dose), respectively, and central-to-peripheral deposition (C:P) ratios were 1.81, 0.86 and 0.61, respectively. TLD increased with increasing FPF, from ~8% at 10% FPF to ~36% at 40% FPF (metered dose); by contrast, MMAD had little effect on TLD, which was similar across MMADs (1.5-4.5 um) at each FPF. FP/FORM deposited throughout central and peripheral airways with gradual (sinusoidal) and sharp (rapid) inhalations. TLD ranged from 35.8 to 44.0% (metered dose) for gradual and sharp inhalations at 30 and 60 L/min mean flow rates. CONCLUSIONS: These data provide important insights into the potential effects of inhalation characteristics (inhalation profile and duration) and aerosol formulation (FPF) on lung deposition of inhaled therapies. FRI thus represents a useful alternative to scintigraphy techniques. Future FRI studies will further our understanding of the deposition of inhaled drugs and help improve the management of asthma. PMID- 29499615 TI - Health literacy in a complex digital media landscape: Pediatric obesity patients' experiences with online weight, food, and health information. AB - This study aimed to explore experiences with online information regarding food, weight management, and health in a group of adolescents in treatment for obesity. Individual semi-structured interviews with 20 adolescents were conducted. Participants used a screen-recorded laptop to demonstrate their search procedures and online information sources. The transcribed interviews were categorized using qualitative content analysis. The adolescents described both encouraging and discouraging experiences. On one hand, they said that online forums could provide nutritious meal ideas and inspiration as well as social support for behavior change. On the other hand, they mentioned that there was a confusing amount of misleading commercial content online and also experiences of peer-facilitated food marketing in online networks. An overarching theme was generated: social media might be a resource for health inspiration, health information, and social support, but requires awareness and competencies. Implications for clinical practice are discussed in light of these findings. PMID- 29499616 TI - Investigation of the tableting behavior of Ibuprofen DC 85 W. AB - The aim of the present study was to investigate the tableting behavior of Ibuprofen DC 85 W with special focus on the tablet disintegration time, the tablet crushing strength, and the sticking tendency to punch surfaces. To simulate production conditions, tableting was conducted on a rotary press, equipped with three compaction stations. An I-optimal design of experiments was used to analyze the influence of the pre-compaction, the intermediate compaction, and the main compaction force on the two responses: tablet disintegration time and crushing strength. It was shown that Ibuprofen DC 85 W showed a good tableting behavior with regard to both responses. The tablet disintegration was considerably affected by the maximum compaction force applied, but was also slightly affected by preceding compaction events. The tablet crushing strength was mainly affected by the maximum applied compaction force independent of the order of these forces. The sticking tendency of Ibuprofen DC 85 W was compared with that two other ibuprofen powder formulations in long-term tableting runs. Compared to the other two formulations, sticking was considerably lower with Ibuprofen DC 85 W. The sticking tendency was not influenced by the addition of an intermediate compaction force, but was remarkably reduced by the choice of the punch tip coating. PMID- 29499620 TI - Influence of the balance of the intertropical front on seasonal variations of the isotopic composition in rainfall at Kisiba Masoko (Rungwe Volcanic Province, SW, Tanzania). AB - Tropical rainfall isotopic composition results from complex processes. The climatological and environmental variability in East Africa increases this complexity. Long rainfall isotope datasets are needed to fill the lack of observations in this region. At Kisiba Masoko, Tanzania, rainfall and rain isotopic composition have been monitored during 6 years. Mean year profiles allow to analyse the seasonal variations. The mean annual rainfall is 2099 mm with a rain-weighted mean composition of -3.2 0/00 for delta18O and -11.7 0/00 for delta2H. The results are consistent with available data although they present their own specificity. Thus, if the local meteoric water line is delta2H = 8.6 delta18O + 14.8, two seasonal lines are observed. The seasonality of the isotopic composition in rain and deuterium excess has been compared with precipitating air masses backtracking trajectories to characterize a simple scheme of vapour histories. The three major oceanic sources have two moisture signatures with their own trajectory histories: one originated from the tropical Indian Ocean at the beginning of the rainy season and one from the Austral Ocean at its end. The presented isotopic seasonality depends on the balance of the intertropical front and provides a useful dataset to improve the knowledge about local processes. PMID- 29499621 TI - A Bayesian basket trial design using a calibrated Bayesian hierarchical model. AB - BACKGROUND: The basket trial evaluates the treatment effect of a targeted therapy in patients with the same genetic or molecular aberration, regardless of their cancer types. Bayesian hierarchical modeling has been proposed to adaptively borrow information across cancer types to improve the statistical power of basket trials. Although conceptually attractive, research has shown that Bayesian hierarchical models cannot appropriately determine the degree of information borrowing and may lead to substantially inflated type I error rates. METHODS: We propose a novel calibrated Bayesian hierarchical model approach to evaluate the treatment effect in basket trials. In our approach, the shrinkage parameter that controls information borrowing is not regarded as an unknown parameter. Instead, it is defined as a function of a similarity measure of the treatment effect across tumor subgroups. The key is that the function is calibrated using simulation such that information is strongly borrowed across subgroups if their treatment effects are similar and barely borrowed if the treatment effects are heterogeneous. RESULTS: The simulation study shows that our method has substantially better controlled type I error rates than the Bayesian hierarchical model. In some scenarios, for example, when the true response rate is between the null and alternative, the type I error rate of the proposed method can be inflated from 10% up to 20%, but is still better than that of the Bayesian hierarchical model. LIMITATION: The proposed design assumes a binary endpoint. Extension of the proposed design to ordinal and time-to-event endpoints is worthy of further investigation. CONCLUSION: The calibrated Bayesian hierarchical model provides a practical approach to design basket trials with more flexibility and better controlled type I error rates than the Bayesian hierarchical model. The software for implementing the proposed design is available at http://odin.mdacc.tmc.edu/~yyuan/index_code.html. PMID- 29499622 TI - Stress-related upper gastrointestinal bleeding in adult neurocritical care patients: a Chinese multicenter, retrospective study. AB - OBJECTIVE: China has limited data on stress-related gastrointestinal ulcers in patients admitted for neurosurgical care. This study evaluated the incidence of upper gastrointestinal bleeding (UGIB) and use of stress ulcer prophylaxis (SUP) in Chinese neurocritical care patients (Glasgow Coma Scale [GCS] score <=10). METHODS: This multicenter, retrospective study was performed from January 2015 to July 2015. Medical records of 1468 patients hospitalized during 2014 were reviewed. An estimated UGIB incidence rate of 4.4% was considered for precision of 1.3% for estimation of UGIB. The primary endpoint was evaluation of overall incidence of any overt UGIB in <=14 days after cerebral lesion. Secondary endpoints included incidence of UGIB with or and without clinically significant complications, time to UGIB, associated risk factors and SUP used. RESULTS: We analyzed 1416 patients (mean age: 53.7 +/- 14.00 years; males: 62.4%) with cerebral lesions. Overall incidence rate of UGIB <=14 days was 12.9% (95% CI: 11.2%-14.7%), 0.76% with and 12.1% without significant clinical complications. Average time and duration of bleeding were 2.9 +/- 3.37 days and 4.2 +/- 8.4 days, respectively. The most significant risk factors for UGIB were mechanical ventilation for >48 hours (p < .0001), UGIB history (p = .0026) and use of anticoagulants (p < .0001). Acid-suppression drugs were administered for SUP in 79.0% of the patients, whereas 40.5% received hemostatic drugs. CONCLUSIONS: The rate of UGIB incidence was higher than the estimated rate in neurocritical care patients in China, suggesting the need for better management and treatment for stress-related mucosal disease in China. History of UGIB, mechanical ventilation and/or anticoagulants significantly affected UGIB. ClinicalTrials registry number: NCT02316990. PMID- 29499623 TI - Evaluation of chemical composition, antioxidant and anti-hyperglycemic activities of the essential oil based nanoemulsions of Cinnamomum litseifolium. AB - In the present study, antioxidant and anti-hyperglycemic activities of nanoemulsions of the leaf essential oils of Cinnamomum litseifolium Thwaites collected from two different locations in the Western Ghats namely, Kannikatty, Kalakad Mundandurai Tiger Reserve, Tamil Nadu (Cl1) and Karamanayar, Agasthyamalai hills, Kerala (Cl2), India were studied. Essential oils were extracted from the leaves and characterized by GC-FID and GC-MS. Slight variation in the composition of leaf essential oils was observed. Essential oil based nanoemulsions were prepared using a surfactant (Tween-80), co-surfactant (propylene glycol) and an emulsifier (lecithin) by homogenization followed by ultra-sonication. Upon characterization, the nanoemulsion of Cl1 showed better stability than Cl2. Both nanoemulsions inhibited alpha-amylase and alpha glucosidase enzymes with IC50 values of 1.998 and 0.780 mg/mL for Cl1 and 3.587 and 1.455 mg/mL for Cl2 respectively. PMID- 29499624 TI - Acute Cardiovascular Care 2018. PMID- 29499626 TI - Resilience as a moderator between syndemics and depression in mothers living with HIV. AB - Physical and emotional adversities in mothers have rippling effects across the family system. While an association between individual maternal adversities and problematic mental health outcomes has been established, less is known about co existing adversities in mothers. Consistent with the syndemic conceptual framework, we examined the co-occurrence of Substance Abuse, Violence, and AIDS/HIV (i.e., SAVA), which are three adversities that uniquely affect racial/ethnic minorities, individuals living in poverty, and people in urban communities. We assessed the relationship between SAVA adversities and depressive symptoms among mothers living with HIV, as well as the moderating effect of resilience on this relationship. Participants included 55 mothers (Mage = 41.24, SD = 9.01; 81% Black) living with HIV in the U.S. MidSouth. Mothers were recruited from community agencies serving individuals living with HIV and completed hour-long interviews about SAVA, depression, resilience, life stressors, and their child's mental health. Analyses were conducted in PROCESS for SPSS to test the relationship between SAVA and depression, as moderated by resilience. Analyses controlled for the influence of child maladaptive functioning (given known associations with maternal mental health) and maternal life stressors (given established associations with depressive symptoms). Findings indicated that experiencing more than one SAVA variable was associated with greater depressive symptoms (p < .05). Higher resilience was associated with lower depressive symptoms (r = -.45; p < .01). Moderation was supported (beta = .80; p < .01) as the relationship between more SAVA epidemics and higher depressive symptoms was stronger when resilience was low and weaker when resilience was high. Results not only highlight how co-occurring adversities exacerbate depressive symptoms, but also underscore the role of resilience as a key protective factor among mothers living with HIV. Resilience could therefore be a target of strengths-based treatment to reduce the negative effects of SAVA on depressive symptoms among mothers. PMID- 29499627 TI - Editorial to special section 'Application of isotopes in river water research'. PMID- 29499629 TI - Intracellular localization of sirtuin and cell length analysis of Lactobacillus paracasei suggest possible role of sirtuin in cell division and cell shape regulation. AB - Sirtuin has been associated in prolonging lifespan of different model organisms. It has been shown to have an enzymatic activity of NAD+-dependent protein deacetylation targeting acetylated proteins. To determine targets and possible roles of sirtuin (LpSirA) in the Lactobacillus paracasei BL23, deletion (DeltasirA), sirtuin overexpressor (highsirA) and GFP fusion (highsirA-Venus) strains were generated, and microscopic localization and cell length analysis were done. Microscopic analysis revealed localization of LpSirA at cell division plates, at cell poles and all throughout the cell length in a spiral manner. Cell length analysis revealed that 46.9% of the DeltasirA cells were observed to be shorter (<2 MUm), whereas 12.6% of the highsirA cells were observed to be longer (>4 MUm) in comparison with the wild-type with only 17.1% short cells and 5.3% long cells. Our results suggest that sirtuin may have an essential role in cell division and cell shape regulation. PMID- 29499630 TI - Serum starvation induces abnormal spindle location, RhoA delocalization, and extension of intercellular bridge with the midbody. AB - Serum starvation induces binucleation in HeLa cells, but the effects of serum starvation on mitosis and the significance of binucleation remain unknown. We investigated the effect of serum starvation on mitosis and analyzed the growth of binucleated cells. The frequency of binucleation caused by cytokinesis failure in DMEM without FBS (0% medium) was higher than that in DMEM with FBS (10% medium). In 0% medium, the metaphase spindle location was off-center, and RhoA localization significantly lacked symmetry. The frequency of the extension of intercellular bridge with the midbody in 0% medium was significantly higher than that in 10% medium. Moreover, all mononucleated mitotic cells caused bipolar mitosis and produced only mononucleated daughter cells, but binucleated cells produced various nucleated cells by multipolar mitosis in 0% medium. These results suggest that serum starvation may have various effects on mitosis, and binucleated cells may be related to formation of aneuploidy. PMID- 29499628 TI - In vivo inhibition of nuclear factor of activated T-cells leads to atherosclerotic plaque regression in IGF-II/LDLR-/-ApoB100/100 mice. AB - AIMS: Despite vast clinical experience linking diabetes and atherosclerosis, the molecular mechanisms leading to accelerated vascular damage are still unclear. Here, we investigated the effects of nuclear factor of activated T-cells inhibition on plaque burden in a novel mouse model of type 2 diabetes that better replicates human disease. METHODS & RESULTS: IGF-II/LDLR-/-ApoB100/100 mice were generated by crossbreeding low-density lipoprotein receptor-deficient mice that synthesize only apolipoprotein B100 (LDLR-/-ApoB100/100) with transgenic mice overexpressing insulin-like growth factor-II in pancreatic beta cells. Mice have mild hyperglycaemia and hyperinsulinaemia and develop complex atherosclerotic lesions. In vivo treatment with the nuclear factor of activated T-cells blocker A 285222 for 4 weeks reduced atherosclerotic plaque area and degree of stenosis in the brachiocephalic artery of IGF-II/LDLR-/-ApoB100/100 mice, as assessed non invasively using ultrasound biomicroscopy prior and after treatment, and histologically after termination. Treatment had no impact on plaque composition (i.e. muscle, collagen, macrophages). The reduced plaque area could not be explained by effects of A-285222 on plasma glucose, insulin or lipids. Inhibition of nuclear factor of activated T-cells was associated with increased expression of atheroprotective NOX4 and of the anti-oxidant enzyme catalase in aortic vascular smooth muscle cells. CONCLUSION: Targeting the nuclear factor of activated T-cells signalling pathway may be an attractive approach for the treatment of diabetic macrovascular complications. PMID- 29499631 TI - Analysis of the structure and activity of the promoter regions of the metallothionein genes of the freshwater pearl mussel Hyriopsis schlegelii. AB - To investigate the regulation of metallothionein genes (HsMTs) of Hyriopsis schlegelii, 1,121-bp and 1,270-bp regions of the HsMT1 and HsMT2 promoters were cloned and analyzed, respectively. The two promoters shared partially conserved features and possessed distinct characteristics such as the number or position of metal response elements (MREs). Further analysis of the HsMT1 and HsMT2 promoters was performed by the reporter assay using the luciferase gene. Both promoters were activated by various metals, and presented different levels of metal ions inducibility in human hepatoblastoma cells. Deletion mutant assays demonstrated that both the longest promoter regions achieved the maximum inducibility, and the metal inducibility was dependent on the presence of the MRE in HsMT1 and the distal MRE in HsMT2. In addition, we cloned a putative metal responsive transcription factor (hereby designated as HsMTF-like) and studied its effect on HsMTs expression in human hepatoblastoma cells. An in vivo assay demonstrated that HsMTF-like activates basal HsMTs transcription level, and the MRE in the HsMTs promoter mediates this activation process. Moreover, this basal transcription level can be further boosted by zinc treatment. In conclusion, the regulation mechanism for MT activation in H. schlegelii should be evolutionarily conserved. PMID- 29499632 TI - Cha-Koji, comprising green tea leaves fermented with Aspergillus luchuensis var kawachii kitahara, increases regulatory T cell production in mice and humans. AB - Green tea leaves fermented with Aspergillus luchuensis var kawachii kitahara (Cha Koji) are a health food containing live A. luchuensis. In this study, we examined the effects of Cha-Koji on the immune system and the enteric environment. First, we designed a clinical trial; after ingesting Cha-Koji daily for 28 days, blood parameters and the fecal composition of the participants were analyzed. Similarly, mice were administered (oral administration) with Cha-Koji suspension or its vehicle for 14 days. Thereafter, both humans and mice were examined by analyzing their immune cell phenotypes and intestinal microbiota. Regulatory T cell (Treg) numbers were significantly increased after administering Cha-Koji. An increase of Clostridium subcluster XIVa, that were known to be rich in butyrate producing bacterium, was observed in human feces, but not in mice. These results suggest that Cha-Koji has the ability to increase Treg production in both humans and mice, irrespective of the presence of enteric butyrate. PMID- 29499634 TI - Editorial: New Strategies for the Prevention and Treatment of Bone Loss. PMID- 29499633 TI - Preliminary investigation about the expression of tubulin in platelets from patients with iron deficiency anemia and thrombocytosis. AB - OBJECTIVE: In order to inquire into the pathogenesis of increased platelet counts in peripheral blood of patients with iron deficiency anemia (IDA), the phenomenon of thrombocytosis was confirmed, and then the expression of tubulin within platelets from IDA patients was investigated. METHODS: Peripheral blood samples were collected from 79 patients with IDA and were divided into 2 groups, group of IDA with normal platelet counts (34 cases), and group of IDA with increased platelet counts (thrombocytosis) (45 cases). Additionally, 45 peripheral blood samples from healthy volunteers were enrolled as a group of healthy controls. Count of platelets in peripheral blood was detected by means of LH-780 hematology analyzer and hemocytometer under a microscope respectively, and analyzed statistically. RESULTS: There was no statistical difference between platelet counts detected by LH-780 hematology analyzer and hemocytometer under a microscope (P > .05). The mean fluorescence intensity (MFI) of both alpha-tubulin and beta-tubulin within platelets from IDA patients with thrombocytosis was significantly less than that from healthy volunteers and IDA patients with normal platelet counts (P < .01), and there was no statistical difference between the latter two groups (P > .05). CONCLUSION: Some patients with IDA are accompanied by thrombocytosis, from which the expression of alpha-tubulin and beta-tubulin within platelets reduced obviously compared with those with normal platelet counts and healthy controls respectively. It is implied that downregulation of tubulin probably is a part of the pathogenesis leading to increased platelet counts in IDA. PMID- 29499635 TI - Editorial: Antiepileptic Drugs in Neurosurgical Practic. PMID- 29499636 TI - Editorial: Novel Pharmacotherapeutic Targets and Emerging Approaches to Prevent Preterm Birth. PMID- 29499637 TI - Chronic kidney disease and poor outcomes in ischemic stroke: is impaired cerebral autoregulation the missing link? AB - BACKGROUND: Chronic kidney disease increases stroke incidence and severity but the mechanisms behind this cerebro-renal interaction are mostly unexplored. Since both vascular beds share similar features, microvascular dysfunction could be the possible missing link. Therefore, we examined the relationship between renal function and cerebral autoregulation in the early hours post ischemia and its impact on outcome. METHODS: We enrolled 46 ischemic strokes (middle cerebral artery). Dynamic cerebral autoregulation was assessed by transfer function (coherence, phase and gain) of spontaneous blood pressure oscillations to blood flow velocity within 6 h from symptom-onset. Estimated glomerular filtration rate (eGFR) was calculated. Hemorrhagic transformation (HT) and white matter lesions (WML) were collected from computed tomography performed at presentation and 24 h. Outcome was evaluated with modified Rankin Scale at 3 months. RESULTS: High gain (less effective autoregulation) was correlated with lower eGFR irrespective of infarct side (p < 0.05). Both lower eGFR and higher gain correlated with WML grade (p < 0.05). Lower eGFR and increased gain, alone and in combination, progressively reduced the odds of a good functional outcome [ipsilateral OR = 4.39 (CI95% 3.15-25.6), p = 0.019; contralateral OR = 8.15 (CI95% 4.15-15.6), p = 0.002] and increased risk of HT [ipsilateral OR = 3.48 (CI95% 0.60-24.0), p = 0.132; contralateral OR = 6.43 (CI95% 1.40-32.1), p = 0.034]. CONCLUSIONS: Lower renal function correlates with less effective dynamic cerebral autoregulation in acute ischemic stroke, both predicting a bad outcome. The evaluation of serum biomarkers of renal dysfunction could have interest in the future for assessing cerebral microvascular risk and relationship with stroke complications. PMID- 29499638 TI - Compound heterozygous variants in the multiple PDZ domain protein (MPDZ) cause a case of mild non-progressive communicating hydrocephalus. AB - BACKGROUND: Congenital hydrocephalus (CH) results from the accumulation of excessive amounts of cerebrospinal fluid (CSF) in the brain, often leading to severe neurological impairments. However, the adverse effects of CH can be reduced if the condition is detected and treated early. Earlier reports demonstrated that some CH cases are caused by mutations in L1CAM gene encoding the neural cell adhesion molecule L1. On the other hand, recent studies have implicated the multiple PDZ domain (MPDZ) gene in some severe forms of CH, inherited in an autosomal recessive pattern. METHODS: In this study, whole-exome and Sanger sequencing were performed on a 9 months old Emirati child clinically diagnosed by CH. In addition, in silico, cellular, and molecular assays have been conducted to confirm pathogenicity of the identified variants and to establish disease mechanism. RESULTS: Whole exome sequencing revealed two compound heterozygous novel variants (c.394G > A and c.1744C > G) in the affected child within the MPDZ gene. Segregation analysis revealed that each of the parents is heterozygous for one of the two variants and therefore passed that variant to their child. The outcome of the in silico and bioinformatics analyses came in line with the experimental data, suggesting that the two variants are most likely disease causing. CONCLUSIONS: The compound heterozygous variants identified in this study are the most likely cause of CH in the affected child. The study further confirms MPDZ as a gene underlying some CH cases. PMID- 29499639 TI - Polypharmacy in the oldest old (>=80 years of age) patients in China: a cross sectional study. AB - BACKGROUND: The oldest old generally have worse health and more comorbidities than the general population of older adults, and they are more likely to be exposed to polypharmacy. Reliable investigation of polypharmacy among the oldest old (>=80 years of age) in China are lacking. So this study aims to describe the polypharmacy status of oldest old patients >=80 years of age and to assess the factors influencing medication compliance. METHODS: This was a cross-sectional study of 258 oldest old patients >= 80 years of age and hospitalized at a tertiary hospital in Beijing between December 1, 2014 and June 30, 2015. They completed three validated questionnaires to assess their pre-admission status (general demographics, medication knowledge, and medication adherence). Potentially inappropriate medications (PIM) use was evaluated by physicians. RESULTS: The majority of the patients (55.4%) took < 10 types of drugs. The numbers of drugs taken ranged from 8 to 60 drugs (median of 22.9). Patients taking 11-20 drugs accounted for 46.1% of the patients. Subjects with a history of adverse drug reactions accounted for 40.3%. The proportion of PIMs was 27.1%. Compliance was only 32.6% among the oldest old patients with polypharmacy. Age and medication classes were independently negatively associated with compliance, and medication knowledge was independently positively associated with compliance. CONCLUSION: Oldest old patients (>= 80 years of age) had a poor medication knowledge. Age, medication classes, and medication knowledge were independently associated with medication compliance. PMID- 29499640 TI - Grade III bone cement implantation syndrome in malignant lung cancer patient: a case report. AB - BACKGROUND: Bone cement implantation syndrome is a known complication causing mortality during perioperative period particularly in patients with malignancy. With rise in aging population with malignancy in low income country, the syndrome is more likely to be encountered. CASE PRESENTATION: We present a case of 66 years old male patient with metastatic bronchogenic carcinoma of lung with pathological proximal femur fracture of left hip that underwent a cemented endoprosthesis under combined spinal epidural anesthesia who succumbed to intraoperative mortality due to grade III bone cement implantation syndrome even after aggressive fluid resuscitation, vasopressor use, and mechanical ventilation. CONCLUSIONS: Careful identification of risk factors with aggressive vigilance and intervention in part of surgeons and anesthesia both during intraoperative and postoperative period can mitigate the risk of bone cement implantation syndrome. PMID- 29499641 TI - Percutaneous closure versus medical therapy for stroke with patent foramen Ovale: a systematic review and meta-analysis. AB - BACKGROUND: Patent foramen ovale (PFO) closure has emerged as a secondary prevention option in patients with PFO and cryptogenic stroke. However, the comparative efficacy and safety of percutaneous closure and medical therapy in patients with cryptogenic stroke and PFO remain unclear. METHODS: Randomized controlled trials (RCTs) and comparative observational studies that compared PFO closure against medical therapy, each with a minimal of 20 patients in the closure arm and 1-year follow-up were included. RESULTS: We analyzed 6961 patients from 20 studies (5 RCTs and 15 observational studies) with a median follow-up of 3.1 years. Moderate-quality evidence showed that PFO closure was associated with a significantly lower incidence of the composite outcome of ischemic stroke, transient ischemic attack (TIA), or all-cause death (odds ratio [OR]: 0.57; 95% confidence interval [CI]: 0.38 to 0.85; P = 0.006), mainly driven by lower incidence of stroke (OR: 0.39; 95% CI: 0.24 to 0.63; P < 0.001). The numbers needed to treat were 43 and 39 for the composite outcome and recurrent ischemic stroke respectively. PFO closure increased the risks for atrial fibrillation or atrial flutter (OR: 5.74; 95% CI: 3.08 to 10.70; P < 0.001; high quality evidence) and pulmonary embolism (OR: 3.03; 95% CI: 1.06 to 8.63; P = 0.038; moderate-quality evidence), with the numbers needed to harm being 30 and 143 respectively. The risks for TIA, all-cause death, and major bleeding were not statistically different. Analyses limited to RCTs showed similar findings, as did a series of other subgroup analyses. CONCLUSION: In conclusion, PFO closure reduced the incidences of stroke and the composite outcome of ischemic stroke, TIA, or all-cause death, but increased risks for atrial fibrillation or atrial flutter and pulmonary embolism compared with medical therapy. PMID- 29499642 TI - Expansion of a urethritis-associated Neisseria meningitidis clade in the United States with concurrent acquisition of N. gonorrhoeae alleles. AB - BACKGROUND: Increased reports of Neisseria meningitidis urethritis in multiple U.S. cities during 2015 have been attributed to the emergence of a novel clade of nongroupable N. meningitidis within the ST-11 clonal complex, the "U.S. NmNG urethritis clade". Genetic recombination with N. gonorrhoeae has been proposed to enable efficient sexual transmission by this clade. To understand the evolutionary origin and diversification of the U.S. NmNG urethritis clade, whole genome phylogenetic analysis was performed to identify its members among the N. meningitidis strain collection from the Centers for Disease Control and Prevention, including 209 urogenital and rectal N. meningitidis isolates submitted by U.S. public health departments in eleven states starting in 2015. RESULTS: The earliest representatives of the U.S. NmNG urethritis clade were identified from cases of invasive disease that occurred in 2013. Among 209 urogenital and rectal isolates submitted from January 2015 to September 2016, the clade accounted for 189/198 male urogenital isolates, 3/4 female urogenital isolates, and 1/7 rectal isolates. In total, members of the clade were isolated in thirteen states between 2013 and 2016, which evolved from a common ancestor that likely existed during 2011. The ancestor contained N. gonorrhoeae-like alleles in three regions of its genome, two of which may facilitate nitrite dependent anaerobic growth during colonization of urogenital sites. Additional gonococcal-like alleles were acquired as the clade diversified. Notably, one isolate contained a sequence associated with azithromycin resistance in N. gonorrhoeae, but no other gonococcal antimicrobial resistance determinants were detected. CONCLUSIONS: Interspecies genetic recombination contributed to the early evolution and subsequent diversification of the U.S. NmNG urethritis clade. Ongoing acquisition of N. gonorrhoeae alleles by the U.S. NmNG urethritis clade may facilitate the expansion of its ecological niche while also increasing the frequency with which it causes urethritis. PMID- 29499644 TI - Combined value of left ventricular ejection fraction and the Model for End-Stage Liver Disease (MELD) score for predicting mortality in patients with acute coronary syndrome who were undergoing percutaneous coronary intervention. AB - BACKGROUND: The purpose of the study was to investigate whether the addition of left ventricular ejection fraction (LVEF) to the MELD score enhances the prediction of mortality in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). METHODS: This retrospective study analyzed 846 consecutive patients with ACS undergoing PCI who were not receiving previous anticoagulant therapy. The patients were grouped as survivors or non survivors. The MELD score and LVEF were calculated in all patients. The primary end point was all-cause death during the median follow-up of 28 months. RESULTS: During the follow-up, there were 183 deaths (21.6%). MELD score was significantly higher in non-survivors than survivors (10.1 +/- 4.4 vs 7.8 +/- 2.4, p < 0.001). LVEF was lower in non-survivors compared with survivors (41.3 +/- 11.8% vs. 47.5 +/- 10.0%, p < 0.001). In multivariate analysis, both MELD score and LVEF were independent predictors of total mortality. (HR: 1.116, 95%CI: 1.069-1.164, p < 0.001; HR: 0.972, 95%CI: 0.958-0.986, p < 0.001, respectively). The addition of LVEF to MELD score was associated with significant improvement in predicting mortality compared with the MELD score alone (AUC:0.733 vs 0.690, p < 0.05). Also, the combining LVEF with MELD score improved the reclassification (NRI:24.6%, p < 0.001) and integrated discrimination (IDI:0.045, p < 0.001) of patients compared with MELD score alone. CONCLUSIONS: Our study demonstrated that the combining LVEF with MELD score may be useful to predict long-term survival in patients with ACS who were undergoing PCI. PMID- 29499643 TI - Identification of placental nutrient transporters associated with intrauterine growth restriction and pre-eclampsia. AB - BACKGROUND: Gestational disorders such as intrauterine growth restriction (IUGR) and pre-eclampsia (PE) are main causes of poor perinatal outcomes worldwide. Both diseases are related with impaired materno-fetal nutrient transfer, but the crucial transport mechanisms underlying IUGR and PE are not fully elucidated. In this study, we aimed to identify membrane transporters highly associated with transplacental nutrient deficiencies in IUGR/PE. RESULTS: In silico analyses on the identification of differentially expressed nutrient transporters were conducted using seven eligible microarray datasets (from Gene Expression Omnibus), encompassing control and IUGR/PE placental samples. Thereby 46 out of 434 genes were identified as potentially interesting targets. They are involved in the fetal provision with amino acids, carbohydrates, lipids, vitamins and microelements. Targets of interest were clustered into a substrate-specific interaction network by using Search Tool for the Retrieval of Interacting Genes. The subsequent wet-lab validation was performed using quantitative RT-PCR on placentas from clinically well-characterized IUGR/PE patients (IUGR, n = 8; PE, n = 5; PE+IUGR, n = 10) and controls (term, n = 13; preterm, n = 7), followed by 2D hierarchical heatmap generation. Statistical evaluation using Kruskal-Wallis tests was then applied to detect significantly different expression patterns, while scatter plot analysis indicated which transporters were predominantly influenced by IUGR or PE, or equally affected by both diseases. Identified by both methods, three overlapping targets, SLC7A7, SLC38A5 (amino acid transporters), and ABCA1 (cholesterol transporter), were further investigated at the protein level by western blotting. Protein analyses in total placental tissue lysates and membrane fractions isolated from disease and control placentas indicated an altered functional activity of those three nutrient transporters in IUGR/PE. CONCLUSIONS: Combining bioinformatic analysis, molecular biological experiments and mathematical diagramming, this study has demonstrated systematic alterations of nutrient transporter expressions in IUGR/PE. Among 46 initially targeted transporters, three significantly regulated genes were further investigated based on the severity and the disease specificity for IUGR and PE. Confirmed by mRNA and protein expression, the amino acid transporters SLC7A7 and SLC38A5 showed marked differences between controls and IUGR/PE and were regulated by both diseases. In contrast, ABCA1 may play an exclusive role in the development of PE. PMID- 29499645 TI - Cost analysis of rapid diagnostics for drug-resistant tuberculosis. AB - BACKGROUND: Growth-based drug susceptibility testing (DST) is the reference standard for diagnosing drug-resistant tuberculosis (TB), but standard time to result (TTR) is typically >= 3 weeks. Rapid tests can reduce that TTR to days or hours, but accuracy may be lowered. In addition to the TTR and test accuracy, the cost of a diagnostic test may affect whether it is adopted in clinical settings. We examine the cost-effectiveness of rapid diagnostics for extremely drug resistant TB (XDR-TB) in three different high-prevalence settings. METHODS: 1128 patients with confirmed TB were enrolled at clinics in Mumbai, India; Chisinau, Moldova; and Port Elizabeth, South Africa. Patient sputum samples underwent DST for first and second line TB drugs using 2 growth-based (MGIT, MODS) and 2 molecular (Pyrosequencing [PSQ], line-probe assays [LPA]) assays. TTR was the primary measure of effectiveness. Sensitivity and specificity were also evaluated. The cost to perform each test at each site was recorded and included test-specific materials, personnel, and equipment costs. Incremental cost effectiveness ratios were calculated in terms of $/day saved. Sensitivity analyses examine the impact of batch size, equipment, and personnel costs. RESULTS: Our prior results indicated that the LPA and PSQ returned results in a little over 1 day. Mean cost per sample without equipment or overhead was $23, $28, $33, and $41 for the MODS, MGIT, PSQ, and LPA, respectively. For diagnosing XDR-TB, MODS was the most accurate, followed by PSQ, and LPA. MODS was quicker and less costly than MGIT. PSQ and LPA were considerably faster but cost more than MODS. Batch size and personnel costs were the main drivers of cost variation. CONCLUSIONS: Multiple factors must be weighed when selecting a test for diagnosis of XDR-TB. Rapid tests can greatly improve the time required to diagnose drug-resistant TB, potentially improving treatment success, and preventing the spread of XDR-TB. Faster time to result must be weighed against the potential for reduced accuracy, and increased costs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02170441 . PMID- 29499647 TI - Control procedures and estimators of the false discovery rate and their application in low-dimensional settings: an empirical investigation. AB - BACKGROUND: When many (up to millions) of statistical tests are conducted in discovery set analyses such as genome-wide association studies (GWAS), approaches controlling family-wise error rate (FWER) or false discovery rate (FDR) are required to reduce the number of false positive decisions. Some methods were specifically developed in the context of high-dimensional settings and partially rely on the estimation of the proportion of true null hypotheses. However, these approaches are also applied in low-dimensional settings such as replication set analyses that might be restricted to a small number of specific hypotheses. The aim of this study was to compare different approaches in low-dimensional settings using (a) real data from the CKDGen Consortium and (b) a simulation study. RESULTS: In both application and simulation FWER approaches were less powerful compared to FDR control methods, whether a larger number of hypotheses were tested or not. Most powerful was the q-value method. However, the specificity of this method to maintain true null hypotheses was especially decreased when the number of tested hypotheses was small. In this low-dimensional situation, estimation of the proportion of true null hypotheses was biased. CONCLUSIONS: The results highlight the importance of a sizeable data set for a reliable estimation of the proportion of true null hypotheses. Consequently, methods relying on this estimation should only be applied in high-dimensional settings. Furthermore, if the focus lies on testing of a small number of hypotheses such as in replication settings, FWER methods rather than FDR methods should be preferred to maintain high specificity. PMID- 29499646 TI - What to consider when pseudohypoparathyroidism is ruled out: iPPSD and differential diagnosis. AB - BACKGROUND: Pseudohypoparathyroidism (PHP) is a rare disease whose phenotypic features are rather difficult to identify in some cases. Thus, although these patients may present with the Albright's hereditary osteodystrophy (AHO) phenotype, which is characterized by small stature, obesity with a rounded face, subcutaneous ossifications, mental retardation and brachydactyly, its manifestations are somewhat variable. Indeed, some of them present with a complete phenotype, whereas others show only subtle manifestations. In addition, the features of the AHO phenotype are not specific to it and a similar phenotype is also commonly observed in other syndromes. Brachydactyly type E (BDE) is the most specific and objective feature of the AHO phenotype, and several genes have been associated with syndromic BDE in the past few years. Moreover, these syndromes have a skeletal and endocrinological phenotype that overlaps with AHO/PHP. In light of the above, we have developed an algorithm to aid in genetic testing of patients with clinical features of AHO but with no causative molecular defect at the GNAS locus. Starting with the feature of brachydactyly, this algorithm allows the differential diagnosis to be broadened and, with the addition of other clinical features, can guide genetic testing. METHODS: We reviewed our series of patients (n = 23) with a clinical diagnosis of AHO and with brachydactyly type E or similar pattern, who were negative for GNAS anomalies, and classify them according to the diagnosis algorithm to finally propose and analyse the most probable gene(s) in each case. RESULTS: A review of the clinical data for our series of patients, and subsequent analysis of the candidate gene(s), allowed detection of the underlying molecular defect in 12 out of 23 patients: five patients harboured a mutation in PRKAR1A, one in PDE4D, four in TRPS1 and two in PTHLH. CONCLUSIONS: This study confirmed that the screening of other genes implicated in syndromes with BDE and AHO or a similar phenotype is very helpful for establishing a correct genetic diagnosis for those patients who have been misdiagnosed with "AHO-like phenotype" with an unknown genetic cause, and also for better describing the characteristic and differential features of these less common syndromes. PMID- 29499648 TI - Genome-wide identification, phylogeny, evolution, and expression patterns of MtN3/saliva/SWEET genes and functional analysis of BcNS in Brassica rapa. AB - BACKGROUND: Members of the MtN3/saliva/SWEET gene family are present in various organisms and are highly conserved. Their precise biochemical functions remain unclear, especially in Chinese cabbage. Based on the whole genome sequence, this study aims to identify the MtN3/saliva/SWEETs family members in Chinese cabbage and to analyze their classification, gene structure, chromosome distribution, phylogenetic relationship, expression pattern, and biological functions. RESULTS: We identified 34 SWEET genes in Chinese cabbage and analyzed their localization on chromosomes and transmembrane regions of their corresponding proteins. Analysis of a phylogenetic tree indicated that there were at least 17 supposed ancestor genes before the separation in Brassica rapa and Arabidopsis. The expression patterns of these genes in different tissues and flower developmental stages of Chinese cabbage showed that they are mainly involved in reproductive development. The Ka/Ks ratio between paralogous SWEET gene pairs of B. rapa were far less than 1. In our previous study, At2g39060 homologous gene Bra000116 (BraSWEET9, also named BcNS, Brassica Nectary and Stamen) played an important role during flower development in Chinese cabbage. Instantaneous expression experiments in onion epidermal cells showed that the gene encoding this protein is localized to the plasma membrane. A basal nectary split is the phenotype of transgenic plants transformed with the antisense expression vector. CONCLUSION: This study is the first to perform a sequence analysis, structures analysis, physiological and biochemical characteristics analysis of the MtN3/saliva/SWEETs gene in Chinese cabbage and to verify the function of BcNS. A total of 34 SWEET genes were identified and they are distributed among ten chromosomes and one scaffold. The Ka/Ks ratio implies that the duplication genes suffered strong purifying selection for retention. These genes were differentially expressed in different floral organs. The phenotypes of the transgenic plants indicated that BcNs participates in the development of the floral nectary. This study provides a basis for further functional analysis of the MtN3/saliva/SWEETs gene family. PMID- 29499649 TI - BpWrapper: BioPerl-based sequence and tree utilities for rapid prototyping of bioinformatics pipelines. AB - BACKGROUND: Automated bioinformatics workflows are more robust, easier to maintain, and results more reproducible when built with command-line utilities than with custom-coded scripts. Command-line utilities further benefit by relieving bioinformatics developers to learn the use of, or to interact directly with, biological software libraries. There is however a lack of command-line utilities that leverage popular Open Source biological software toolkits such as BioPerl ( http://bioperl.org ) to make many of the well-designed, robust, and routinely used biological classes available for a wider base of end users. RESULTS: Designed as standard utilities for UNIX-family operating systems, BpWrapper makes functionality of some of the most popular BioPerl modules readily accessible on the command line to novice as well as to experienced bioinformatics practitioners. The initial release of BpWrapper includes four utilities with concise command-line user interfaces, bioseq, bioaln, biotree, and biopop, specialized for manipulation of molecular sequences, sequence alignments, phylogenetic trees, and DNA polymorphisms, respectively. Over a hundred methods are currently available as command-line options and new methods are easily incorporated. Performance of BpWrapper utilities lags that of precompiled utilities while equivalent to that of other utilities based on BioPerl. BpWrapper has been tested on BioPerl Release 1.6, Perl versions 5.10.1 to 5.25.10, and operating systems including Apple macOS, Microsoft Windows, and GNU/Linux. Release code is available from the Comprehensive Perl Archive Network (CPAN) at https://metacpan.org/pod/Bio::BPWrapper . Source code is available on GitHub at https://github.com/bioperl/p5-bpwrapper . CONCLUSIONS: BpWrapper improves on existing sequence utilities by following the design principles of Unix text utilities such including a concise user interface, extensive command-line options, and standard input/output for serialized operations. Further, dozens of novel methods for manipulation of sequences, alignments, and phylogenetic trees, unavailable in existing utilities (e.g., EMBOSS, Newick Utilities, and FAST), are provided. Bioinformaticians should find BpWrapper useful for rapid prototyping of workflows on the command-line without creating custom scripts for comparative genomics and other bioinformatics applications. PMID- 29499650 TI - P_RNA_scaffolder: a fast and accurate genome scaffolder using paired-end RNA sequencing reads. AB - BACKGROUND: Obtaining complete gene structures is one major goal of genome assembly. Some gene regions are fragmented in low quality and high-quality assemblies. Therefore, new approaches are needed to recover gene regions. Genomes are widely transcribed, generating messenger and non-coding RNAs. These widespread transcripts can be used to scaffold genomes and complete transcribed regions. RESULTS: We present P_RNA_scaffolder, a fast and accurate tool using paired-end RNA-sequencing reads to scaffold genomes. This tool aims to improve the completeness of both protein-coding and non-coding genes. After this tool was applied to scaffolding human contigs, the structures of both protein-coding genes and circular RNAs were almost completely recovered and equivalent to those in a complete genome, especially for long proteins and long circular RNAs. Tested in various species, P_RNA_scaffolder exhibited higher speed and efficiency than the existing state-of-the-art scaffolders. This tool also improved the contiguity of genome assemblies generated by current mate-pair scaffolding and third-generation single-molecule sequencing assembly. CONCLUSIONS: The P_RNA_scaffolder can improve the contiguity of genome assembly and benefit gene prediction. This tool is available at http://www.fishbrowser.org/software/P_RNA_scaffolder . PMID- 29499651 TI - Comparison of drug-eluting balloon versus drug-eluting stent for treatment of coronary artery disease: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Drug-eluting balloons (DEB) have significant value for treating coronary artery disease (CAD). However, the merits of using DEB versus drug eluting stents (DES) to treat CAD remain controversial. Herein, we conducted a meta-analysis to compare the safety and efficacy of DEB and DES for treatment of CAD. METHODS: We searched MEDLINE, EMBASE, and CENTRAL databases for eligible trials comparing DEB with DES for treatment of CAD. The primary endpoint was major adverse cardiac events (MACE); the secondary endpoints included in-lesion late lumen loss (LLL), binary restenosis (BR), myocardial infarction (MI), target lesion revascularization (TLR) and mortality. RESULTS: Twenty-three trials with a total of 2712 patients were included. There were no significant differences in the primary endpoint of MACE between the DEB and DES groups (Risk Ratio (RR) 1.19; 95% confidence interval (CI) (0.87, 1.63); P = 0.27), or in the clinical outcomes of each of MACE's components, including TLR, MI and mortality. However, efficacy was significantly different between the DEB and DES groups, especially when we compared DEB to second-generation DES: in-lesion LLL (Mean Difference (MD) 0.11; (0.01, 0.22); P = 0.03); binary restenosis (RR 1.46; (1.00, 2.13); P = 0.05). CONCLUSIONS: DEB is equivalent to DES in terms of safety for managing CAD, and DEB may be considered as an alternative choice for treatment of CAD. PMID- 29499652 TI - Systematic reviews and cancer research: a suggested stepwise approach. AB - Systematic reviews, with or without meta-analysis, play an important role today in synthesizing cancer research and are frequently used to guide decision-making. However, there is now an increase in the number of systematic reviews on the same topic, thereby necessitating a systematic review of previous systematic reviews. With a focus on cancer, the purpose of this article is to provide a practical, stepwise approach for systematically reviewing the literature and publishing the results. This starts with the registration of a protocol for a systematic review of previous systematic reviews and ends with the publication of an original or updated systematic review, with or without meta-analysis, in a peer-reviewed journal. Future directions as well as potential limitations of the approach are also discussed. It is hoped that the stepwise approach presented in this article will be helpful to both producers and consumers of cancer-related systematic reviews and will contribute to the ultimate goal of preventing and treating cancer. PMID- 29499653 TI - Phase II study of bevacizumab, cisplatin, and docetaxel plus maintenance bevacizumab as first-line treatment for patients with advanced non-squamous non small-cell lung cancer combined with exploratory analysis of circulating endothelial cells: Thoracic Oncology Research Group (TORG)1016. AB - BACKGROUND: Preclinical studies have demonstrated that docetaxel and bevacizumab may act synergistically by decreasing endothelial cell proliferation and preventing circulating endothelial progenitor mobilization. The objective of this study was to assess the efficacy and safety of a combination therapy of bevacizumab, cisplatin, and docetaxel in chemotherapy-naive Japanese patients with advanced non-squamous non-small-cell lung cancer (NSCLC). METHODS: Eligible patients were chemotherapy-naive and had advanced/recurrent non-squamous NSCLC. The patients received 4 cycles of docetaxel (60 mg/m2), cisplatin (80 mg/m2), and bevacizumab (15 mg/kg) once every 3 weeks, followed by bevacizumab as maintenance therapy, every 3 weeks until disease progression or attainment of unacceptable toxicity level. The primary endpoint was objective response rate (ORR). The numbers of circulating endothelial cells (CEC) were also estimated on days 1 and 8 of the first cycle for the exploratory analysis of efficacy prediction. RESULTS: A total of 47 patients were enrolled from October 2010 to April 2012. Bevacizumab as maintenance therapy was administered to 41 patients (87.2%), and the median number of total treatment cycles was 9 (range: 1-36). ORR, median progression-free survival (PFS), and median overall survival of the patients were 74.5%, 9.0 months, and 27.5 months, respectively. The most common grade 3/4 adverse event was neutropenia (95.7%), followed by leukopenia (59.6%) and hypertension (46.8%). PFS was longer in patients with >=10 count increase in CECs than that in patients with < 10 count increase in CECs (respective median PFS of 11.0 months versus 6.90 months) although the difference was not statistically significant (p = 0.074). CONCLUSIONS: A combination therapy of bevacizumab, cisplatin, and docetaxel, followed by bevacizumab as maintenance was highly effective in patients with non-squamous NSCLC despite the high incidence of grade 3/4 neutropenia. The increase in CEC count between days 1 and 8 may predict the efficacy of our bevacizumab-contained treatment regimen. TRIAL REGISTRATION: UMIN Clinical Trial Registry; UMIN000004368 . Registered date; October 11, 2010 (Retrospectively registered). PMID- 29499654 TI - Patients' experiences of diagnosis and management of papillary thyroid microcarcinoma: a qualitative study. AB - BACKGROUND: In recent years management practices in relation to low-risk papillary microcarcinoma (PMC) have been evolving with increased awareness of the potential overdiagnosis and overtreatment of PMCs, and guidelines recommendations for non-surgical management options such as active surveillance. This study aimed to develop an in-depth understanding of patients' experiences of the communication of their PMC diagnosis, their treatment preferences and decision making. METHODS: Semi-structured qualitative interviews with 25 patients diagnosed pre-operatively with PMC < 1 year since their diagnosis and treatment. Interviews were conducted between September 2015 and July 2016 and were audio recorded and transcribed verbatim. Framework analysis method was used to analyse the data. RESULTS: The diagnosis and treatment experience of PMC patients varied widely. The majority of patients were asymptomatic, and their PMC was initially detected via an imaging test requested for a reason unrelated to a thyroid disorder or symptom. Clinicians generally described PMC to patients as being a "small" or "slow-growing" cancer, and there was little evidence that clinicians had discussions about the possibility of overdiagnosis or overtreatment. Overall, surgery was the only option discussed and offered to patients. Patients preference for treatment was largely based on eliminating the possibility of the cancer spreading (thyroidectomy) or not wanting to be on thyroid replacement medication for the rest of their life (hemi-thyroidectomy). Many patients reported emotional and physical side-effects associated with their diagnosis and treatment, however patients generally indicated that active surveillance is not something they would have been interested in if it was offered to them. CONCLUSIONS: Evidence continues to emerge that many patients with PMCs may be overdiagnosed, and management guidelines are recommending more conservative management options for these patients. As a result, shared decision making around treatment options is vital so that patients are fully aware of the meaning of their diagnosis and their management options including active surveillance. Importantly, interventions to reduce unnecessary diagnoses of PMC are critically needed. PMID- 29499655 TI - Identification of novel enriched recurrent chimeric COL7A1-UCN2 in human laryngeal cancer samples using deep sequencing. AB - BACKGROUND: As hybrid RNAs, transcription-induced chimeras (TICs) may have tumor promoting properties, and some specific chimeras have become important diagnostic markers and therapeutic targets for cancer. METHODS: We examined 23 paired laryngeal cancer (LC) tissues and adjacent normal mucous membrane tissue samples (ANMMTs). Three of these pairs were used for comparative transcriptomic analysis using high-throughput sequencing. Furthermore, we used real-time polymerase chain reaction (RT-PCR) for further validation in 20 samples. The Kaplan-Meier method and Cox regression model were used for the survival analysis. RESULTS: We identified 87 tumor-related TICs and found that COL7A1-UCN2 had the highest frequency in LC tissues (13/23; 56.5%), whereas none of the ANMMTs were positive (0/23; p < 0.0001). COL7A1-UCN2, generated via alternative splicing in LC tissue cancer cells, had disrupted coding regions, but it down-regulated the mRNA expression of COL7A1 and UCN2. Both COL7A1 and UCN2 were down-expressed in LC tissues as compared to their paired ANMMTs. The COL7A1:beta-actin ratio in COL7A1 UCN2-positive LC samples was significantly lower than that in COL7A1-UCN2 negative samples (p = 0.019). Likewise, the UCN2:beta-actin ratio was also decreased (p = 0.21). Furthermore, COL7A1-UCN2 positivity was significantly associated with the overall survival of LC patients (p = 0.032; HR, 13.2 [95%CI, 1.2-149.5]). CONCLUSION: LC cells were enriched in the recurrent chimera COL7A1 UCN2, which potentially affected cancer stem cell transition, promoted epithelial mesenchymal transition in LC, and resulted in poorer prognoses. PMID- 29499657 TI - New paste for severe stomatitis in patients undergoing head-and-neck cancer radiotherapy and/or chemotherapy with oral appliance. AB - BACKGROUND: The aim of the present study was to evaluate the physical properties of "admixture paste", which is a commercially available gel containing hinokitiol for use against severe stomatitis, and its characteristics as a moisturizing gel and denture adhesive. METHODS: The admixture paste, which contained dexamethasone (Dexaltin(r)), gel for oral care (Refrecare H(r)) and petrolatum, and its 3 components, either alone or in different combinations, were subjected to viscosity, adhesiveness and elution testing to compare their physical properties. Viscosity was measured with a stress-controlled rheometer. Adhesive force was measured by tension test. Elution under a simulated oral environment was evaluated by monitoring with a fixed-point camera and absorbance. Both adhesiveness and elution were evaluated every hour for 6 h. A linear mixed effects model was used to assess differences in the time course of elution between samples. In 3 og-rank test was used to compare time to elution into saliva among samples. RESULTS: The results of viscosity testing demonstrated that the admixture paste had similar viscosity to cream-type denture adhesives and this was temperature independent. In the adhesiveness tests, the admixture paste showed stronger adhesiveness than that of cream-type denture adhesives. In the elution test, the admixture paste demonstrated gradual dissolution and apparent temporal changes for 6 h in a simulated oral environment. CONCLUSIONS: The results of the present study demonstrated that the admixture paste has adhesive force similar to those of denture adhesives and good local retention in saliva, and that it might be suitable for therapeutic use in patients with severe stomatitis derived from radiotherapy and/or chemotherapy for cancer. PMID- 29499656 TI - High CD8+ and absence of Foxp3+ T lymphocytes infiltration in gallbladder tumors correlate with prolonged patients survival. AB - BACKGROUND: Gallbladder cancer (GBC), although infrequent in industrialized countries, has high incidence rates in certain world regions, being a leading cause of death among elderly Chilean women. Surgery is the only effective treatment, and a five-year survival rate of advanced-stage patients is less than 10%. Hence, exploring immunotherapy is relevant, although GBC immunogenicity is poorly understood. This study examined the relationship between the host immune response and GBC patient survival based on the presence of tumor-infiltrating lymphocytes at different disease stages. METHODS: Tumor tissues from 80 GBC patients were analyzed by immunohistochemistry for the presence of CD3+, CD4+, CD8+, and Foxp3+ T cell populations, and the results were associated with clinical stage and patient survival. RESULTS: The majority of tumor samples showed CD3+ T cell infiltration, which correlated with better prognosis, particularly in advanced disease stages. CD8+, but not CD4+, T cell infiltration correlated with improved survival, particularly in advanced disease stages. Interestingly, a < 1 CD4+/CD8+ T cell ratio was related with increased survival. Additionally, the presence of Foxp3+ T cells correlated with decreased patient survival, whereas a <= 1 Foxp3+/CD8+ T cell ratio was associated with improved patient survival. CONCLUSIONS: Depending on the disease stage, the presence of CD8+ and absence of Foxp3+ T cell populations in tumor tissues correlated with improved GBC patient survival, and thus represent potential markers for prognosis and management of advanced disease, and supports testing of immunotherapy. PMID- 29499658 TI - Disentangling the effect of illness perceptions on health status in people with type 2 diabetes after an acute coronary event. AB - BACKGROUND: Chronically ill patients such as people with type 2 diabetes develop perceptions of their illness, which will influence their coping behaviour. Perceptions are formed once a health threat has been recognised. Many people with type 2 diabetes suffer from multimorbidity, for example the combination with cardiovascular disease. Perceptions of one illness may influence perceptions of the other condition. The aim of the current study was to evaluate the effect of an intervention in type 2 diabetes patients with a first acute coronary event on change in illness perceptions and whether this mediates the intervention effect on health status. The current study is a secondary data analysis of a RCT. METHODS: Two hundred one participants were randomised (1:1 ratio) to the intervention (n = 101, three home visits) or control group (n = 100). Outcome variables were diabetes and acute coronary event perceptions, assessed with the two separate Brief Illness Perceptions Questionnaires (BIPQs); and health status (Euroqol Visual Analog Scale (EQ-VAS)). The intervention effect was analysed using ANCOVA. Linear regression analyses were used to assess whether illness perceptions mediated the intervention effect on health status. RESULTS: A positive intervention effect was found on the BIPQ diabetes items coherence and treatment control (F = 8.19, p = 0.005; F = 14.01, p < 0.001). No intervention effect was found on the other BIPQ diabetes items consequence, personal control, identity, illness concern and emotional representation. Regarding the acute coronary event, a positive intervention effect on treatment control was found (F = 7.81, p = 0.006). No intervention effect was found on the other items of the acute coronary event BIPQ. Better diabetes coherence was associated with improved health status, whereas perceiving more treatment control was not. The mediating effect of the diabetes perception 'coherence' on health status was not significant. CONCLUSION: Targeting illness perceptions of people with diabetes after an acute coronary event has no effect on most domains, but can improve the perceived understanding of their diabetes. Discussing perceptions prevents people with type 2 diabetes who recently experienced an acute coronary event from the perception that they will lose control of both their diabetes and the acute coronary event. Illness perceptions of diabetes patients should therefore be discussed in the dynamic period after an acute coronary event. TRIAL REGISTRATION: Nederlands trial register; NTR3076 , Registered September 20 2011. PMID- 29499659 TI - Video-calls to reduce loneliness and social isolation within care environments for older people: an implementation study using collaborative action research. AB - BACKGROUND: Older people in care may be lonely with insufficient contact if families are unable to visit. Face-to-face contact through video-calls may help reduce loneliness, but little is known about the processes of engaging people in care environments in using video-calls. We aimed to identify the barriers to and facilitators of implementing video-calls for older people in care environments. METHODS: A collaborative action research (CAR) approach was taken to implement a video-call intervention in care environments. We undertook five steps of recruitment, planning, implementation, reflection and re-evaluation, in seven care homes and one hospital in the UK. The video-call intervention 'Skype on Wheels' (SoW) comprised a wheeled device that could hold an iPad and handset, and used Skype to provide a free video-call service. Care staff were collaborators who implemented the intervention within the care-setting by agreeing the intervention, recruiting older people and their family, and setting up video calls. Field notes and reflective diaries on observations and conversations with staff, older people and family were maintained over 15 months, and analysed using thematic analysis. RESULTS: Four care homes implemented the intervention. Eight older people with their respective social contacts made use of video-calls. Older people were able to use SoW with assistance from staff, and enjoyed the use of video-calls to stay better connected with family. However five barriers towards implementation included staff turnover, risk averseness, the SoW design, lack of family commitment and staff attitudes regarding technology. CONCLUSIONS: The SoW intervention, or something similar, could aid older people to stay better connected with their families in care environments, but if implemented as part of a rigorous evaluation, then co-production of the intervention at each recruitment site may be needed to overcome barriers and maximise engagement. PMID- 29499660 TI - Involvement of polymorphisms of the nerve growth factor and its receptor encoding genes in the etiopathogenesis of ischemic stroke. AB - BACKGROUND: Despite the important role of the nerve growth factor in the survival and maintenance of neurons in ischemic stroke, data regarding the relationships between variations in the encoding gene and stroke are lacking. In the present study, we evaluated the association of the functional polymorphisms in NGF (rs6330) and NGFR (rs2072446 and rs734194) genes with ischemic stroke in an Armenian population. METHODS: In total, 370 unrelated individuals of Armenian nationality were enrolled in this study. Genomic DNA samples of patients and healthy controls were genotyped using polymerase chain reaction with sequence specific primers. RESULTS: The results obtained indicate that the minor allele of rs6330 (P corr = 2.4E-10) and rs2072446 (P corr = 0.02) are significantly overrepresented in stroke group, while the minor allele of rs734194 (P corr = 8.5E-10) was underrepresented in diseased subjects. Single nucleotide polymorphisms in NGF gene (rs6330) and NGFR gene (rs2072446 and rs734194) are associated with the disease. Furthermore, it was shown that the carriage of the NGF rs6330*T minor allele is associated with increased infarct volume and higher risk of recurrent stroke. CONCLUSIONS: In conclusion, our findings suggest that the NGF rs6330*T and NGFR rs2072446*T minor alleles might be nominated as a risk factor for developing ischemic stroke and NGFR rs734194*G minor allele as a protective against this disease at least in Armenian population. PMID- 29499661 TI - Are physiotherapists employing person-centred care for people with dementia? An exploratory qualitative study examining the experiences of people with dementia and their carers. AB - BACKGROUND: People with dementia may receive physiotherapy for a variety of reasons. This may be for musculoskeletal conditions or as a result of falls, fractures or mobility difficulties. While previous studies have sought to determine the effectiveness of physiotherapy interventions for people with dementia, little research has focused on the experiences of people receiving such treatment. The aim of this study was to gain an in-depth understanding of people's experiences of receiving physiotherapy and to explore these experiences in the context of principles of person-centred care. METHODS: Semi-structured interviews were undertaken with people with dementia or their carers between September 2016 and January 2017. A purposive sampling strategy recruited participants with dementia from the South West of England who had recently received physiotherapy. We also recruited carers to explore their involvement in the intervention. Thematic analysis was used to analyse the data. RESULTS: A total of eleven participants were recruited to the study. Six people with dementia were interviewed and five interviews undertaken separately with carers of people with dementia. Three themes were identified. The first explores the factors that enable exercises to be undertaken successfully, the second deals with perceived resource pressures, and the final theme "the physiotherapy just vanished" explores the feeling of abandonment felt when goals and expectations of physiotherapy were not discussed. When mapped against the principles of person centred care, our participants did not describe physiotherapy adopting such an approach. CONCLUSION: Lack of a person-centred care approach was evident by ineffective communication, thus failing to develop a shared understanding of the role and aims of physiotherapy. The incorporation of person-centred care may help reduce the frustration and feelings of dissatisfaction that some of our participants reported. PMID- 29499662 TI - Safety assessment of sorafenib in Chinese patients with unresectable hepatocellular carcinoma: subgroup analysis of the GIDEON study. AB - BACKGROUND: This study aimed to investigate the safety of sorafenib for the treatment of unresectable hepatocellular carcinoma in Chinese patients. METHODS: A subgroup of 345 Chinese patients from the international database of the Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib (GIDEON) study was included in this analysis. Safety assessment measures were adverse events (AEs) and serious adverse events (SAEs) graded using the National Cancer Institute Common Terminology Criteria version 3.0. RESULTS: Of 331 evaluable patients, 98% started sorafenib at 800 mg/day. The median treatment duration was 22 weeks (range, 0.1-116 weeks), and median overall survival (OS) was 322 days (10.7 months). Approximately 50% of patients had at least one adverse event, and 6% had grade 3-4 adverse events. Drug-related adverse events were experienced by 29% of patients, and 3.6% had grade 3-4 drug related adverse events. Overall, 23% of patients (n = 77) experienced serious adverse events, among which only 1 event was drug-related (0.3%). No differences in overall adverse events, serious adverse events, and deaths were observed between Child-Pugh A and Child-Pugh B patients. The most frequent drug-related adverse events were dermatological/skin (24%), hand-foot skin reaction (20%), gastrointestinal (11%), and diarrhea (11%). The majority of adverse events occurred within 30 days of beginning sorafenib. CONCLUSION: Sorafenib has satisfactory efficacy and safety in Chinese Child-Pugh A and B patients with unresectable HCC using the recommended dosage of 800 mg/day, and the safety of sorafenib is not affected by liver function. Prophylaxis for gastrointestinal adverse events may help to decrease dose interruptions or discontinuation. TRIAL REGISTRATION: ClinicalTrials.gov ; Identifier: NCT00812175. Date of registration: December 19, 2008. PMID- 29499663 TI - Feasibility, useability and acceptability of technology-based interventions for informal cancer carers: a systematic review. AB - BACKGROUND: Carers looking after someone with cancer often experience negative impacts on their own health. M-health interventions have been designed to provide information and support to patients and their carers. However, the effectiveness of technology-based interventions for carers is less well understood. The objectives were to assess the feasibility, useability and acceptability of technology-based interventions among carers of people living with cancer. METHODS: A systematic search of the CINAHL, MEDLINE and PSYCINFO databases was performed using terms related to web-based interventions and smartphone applications, carers and cancer. Studies were included if a randomised controlled trial or pilot study was conducted, focused on adult carers looking after another adult with cancer and were published between January 2007-June 2017. Articles were excluded if they reported qualitative results only or were evaluating existing websites and applications. Feasibility was measured by attrition, recruitment rates and frequency of intervention use; useability was measured by the ease of intervention use and the role of features to minimise errors in use. Acceptability was measured by carers' perception of the appropriateness of the content and their ability to incorporate the intervention into their daily routines. RESULTS: Of the 729 articles, six articles met the inclusion criteria. Attrition ranged from 14% - 77%, recruitment rates from 20% - 66% and intervention useability varied across studies. Half of the studies implemented measures to improve useability. Overall, carers rated the content of the interventions as appropriate and reported improved knowledge and communication. Acceptability was further demonstrated as carers preferred the flexibility available with web-based interventions. CONCLUSIONS: Technology-based interventions are suitable for use among carers of people with cancer. Further research is required to fully assess the impact of technology as an information and support mechanism for carers. PMID- 29499664 TI - The fast exodrift after the first surgical treatment of exotropia and its correlation with surgical outcome of second surgery. AB - BACKGROUND: To compare the rate of exodrift after a second surgery for recurrent exotropia, in patients grouped to fast versus slow exodrift after their first surgery. To determine whether there is a correlation with surgical outcome, and to evaluate the factors associated with fast exodrift. METHODS: Patients with recurrent intermittent exotropia, who underwent contralateral lateral rectus recession and medial rectus resection as the second surgery and were followed up for 24 months postoperatively between January 1991 and January 2013, were reviewed retrospectively. The patients were divided into two groups according to the rate of exodrift after the first surgery: Group F, patients exhibiting fast exodrift after the first surgery (> 10 prism diopters [PD] before postoperative month 6); and Group S, patients exhibiting slow exodrift after the first surgery (<=10 PD before postoperative month 6). The difference in the clinical course over the 24 months after the second surgery between the two groups and factors associated with fast exodrift were analyzed. RESULTS: In total, 106 patients with recurrent exotropia were enrolled in this study. Of these, 68 (64.2%) and 38 (35.8%) patients were included in group F and S, respectively. Group F showed more exodrift compared with groups S over the 24-month postoperative period; however, there was no significant difference in the clinical course between the two groups during that time (p = 0.54, repeated-measure ANOVA). In logistic analysis, immediate postoperative deviation after the first surgery was associated with fast exodrift (p < 0.001). CONCLUSION: Although patients with recurrent exotropia had shown fast exodrift after the first surgery, no significant difference in the surgical outcome was observed after the second surgery according to the rate of exodrift after the first surgery. PMID- 29499665 TI - Antimicrobial efficacy of corneal cross-linking in vitro and in vivo for Fusarium solani: a potential new treatment for fungal keratitis. AB - BACKGROUND: Fungal keratitis is one of the major causes of visual impairment worldwide. However, the effectiveness of corneal collagen cross-linking (CXL) for fungal keratitis remains controversial. In this study, we developed an in vitro and an in vivo models to assess the efficacy of CXL for Fusarium keratitis. METHODS: The effect of in vitro CXL fungicidal was evaluated on the cultures of Fusarium solani which were exposed to irradiation for different durations. Viability of fungal was appraised under four conditions: no treatment (control); CXL: UVA (365 nm)/riboflavin; riboflavin and UVA (365 nm). Each batch of sterile plate culture was irradiated for different CXL durations. The in vivo Therapeutic effect was studied on a mouse keratitis model. The animals were divided randomly into three groups: group A with no treatment (control); Group B with CXL treatment for two minutes and group C with CXL treatment for three minutes. The CXL procedure was performed 24 h post inoculation in each group. All mice with corneal involvement were scored daily for 7 days and 10 days after infection. Corneals were extracted at various time points for quantitative fungal recovery. Histological evaluations were conducted to calculate the number of polymorphonuclear cells. RESULTS: Viability of fungal decreased significantly in CXL group with 30-min irradiation compared with that in control, riboflavin and UVA groups (P < 0.01). The colony-forming units (CFUs) of fungal solutions in culture significantly decreased with CXL treatment (P < 0.05). Clinical scores, corneal lesion, corneal opacity, neovascularization and the depth of ulceration scores in group B and group C were remarkably lower than that in group A (P < 0.05, P = 0.001, P = 0.001, P = 0.034 and P = 0.025 respectively). Scores of group C were much lower than that in group B. Histological revealed that destruction of corneal collagen fibers and infiltration of inflammatory cells into corneal tissue in group B and group C were much lower than that in group A. CONCLUSIONS: We believe that CXL treatment may be applied to fungal keratitis, therapeutic efficacy will improve with longer treatment duration. PMID- 29499667 TI - What factors impact on the implementation of clubfoot treatment services in low and middle-income countries?: a narrative synthesis of existing qualitative studies. AB - BACKGROUND: Around 100,000 children are born annually with clubfoot worldwide and 80% live in low and middle-income counties (LMICs). Clubfoot is a condition in which children are born with one or both feet twisted inwards and if untreated it can limit participation in everyday life. Clubfoot can be corrected through staged manipulation of the limbs using the Ponseti method. Despite its efficacy and apparent availability, previous research has identified a number of challenges to service implementation. The aim of this study was to synthesise these findings to explore factors that impact on the implementation of clubfoot services in LMICs and strategies to address them. Understanding these may help practitioners in other settings develop more effective services. METHODS: Five databases were searched and articles screened using six criteria. Articles were appraised using the Critical Appraisal Skills Programme (CASP) checklist. 11 studies were identified for inclusion. A thematic analysis was conducted. RESULTS: Thematic analysis of the included studies showed that a lack of access to resources was a challenge including a lack of casting materials and abduction braces. Difficulties within the working environment included limited space and a need to share treatment space with other clinics. A shortage of healthcare professionals was a concern and participants thought that there was a lack of time to deliver treatment. This was exacerbated by the competing demands on clinicians. Lack of training was seen to impact on standards, including the nurses and midwives attending to the child at birth that were failing to diagnose the condition. Financial constraints were seen to underlie many of these problems. Some participants identified failures in communication and cooperation within the healthcare system such as a lack of awareness of clinics. Strategies to address these issues included means of increasing resource availability and the delivery of targeted training. The use of non-governmental organisations to provide financial support and methods to disseminate best practice were discussed. CONCLUSIONS: This study identified factors that impact on the implementation of clubfoot services in LMIC settings.Findings may be used to improve service delivery. PMID- 29499666 TI - Nanotechnology in orthopedics: a clinically oriented review. AB - The utility of nanotechnology in medicine, specifically within the field of orthopedics, is a topic of extensive research. Our review provides a unique comprehensive overview of the current and potential future uses of nanotechnology with respect to orthopedic sub-specialties. Nanotechnology offers an immense assortment of novel applications, most notably the use of nanomaterials as scaffolds to induce a more favorable interaction between orthopedic implants and native bone. Nanotechnology has the capability to revolutionize the diagnostics and treatment of orthopedic surgery, however the long-term health effects of nanomaterials are poorly understood and extensive research is needed regarding clinical safety. PMID- 29499668 TI - Progress towards the UNAIDS 90-90-90 goals by age and gender in a rural area of KwaZulu-Natal, South Africa: a household-based community cross-sectional survey. AB - BACKGROUND: The Joint United Nations Programme on HIV/AIDS (UNAIDS) has developed an ambitious strategy to end the AIDS epidemic. After eight years of antiretroviral therapy (ART) program we assessed progress towards the UNAIDS 90 90-90 targets in Mbongolwane and Eshowe, KwaZulu-Natal, South Africa. METHODS: We conducted a cross-sectional household-based community survey using a two-stage stratified cluster probability sampling strategy. Persons aged 15-59 years were eligible. We used face-to-face interviewer-administered questionnaires to collect information on history of HIV testing and care. Rapid HIV testing was performed on site and venous blood specimens collected from HIV-positive participants for antiretroviral drug presence test, CD4 count and viral load. At the time of the survey the CD4 threshold for ART initiation was 350 cells/MUL. We calculated progression towards the 90-90-90 UNAIDS targets by estimating three proportions: HIV positive individuals who knew their status (first 90), those diagnosed who were on ART (second 90), and those on ART who were virally suppressed (third 90). RESULTS: We included 5649/6688 (84.5%) individuals. Median age was 26 years (IQR: 19-40), 62.3% were women. HIV prevalence was 25.2% (95% CI: 23.6-26.9): 30.9% (95% CI: 29.0-32.9) in women; 15.9% (95% CI: 14.0-18.0) in men. Overall progress towards the 90-90-90 targets was as follows: 76.4% (95% CI: 74.1-78.6) knew their status, 69.9% (95% CI: 67.0-72.7) of those who knew their status were on ART and 93.1% (95% CI: 91.0-94.8) of those on ART were virally suppressed. By sex, progress towards the 90-90-90 targets was: 79%-71%-93% among women; and 68%-68% 92% among men (p-values of women and men comparisons were < 0.001, 0.443 and 0.584 respectively). By age, progress was: 83%-75%-95% among individuals aged 30 59 years and 64%-58%-89% among those aged 15-29 years (p-values of age groups comparisons were < 0.001, < 0.001 and 0.011 respectively). CONCLUSIONS: In this context of high HIV prevalence, significant progress has been achieved with regards to reaching the UNAIDS 90-90-90 targets. The third 90, viral suppression in people on ART, was achieved among women and men. However, gaps persist in HIV diagnosis and ART coverage particularly in men and individuals younger than 30 years. Achieving 90-90-90 is feasible but requires additional investment to reach youth and men. PMID- 29499669 TI - Generational differences in patterns of physical activities over time in the Canadian population: an age-period-cohort analysis. AB - BACKGROUND: Using longitudinal panel data, the aim of this study was to examine the contribution of age, period, and cohort effects on changes in physical activity over time in a population-based sample of Canadians. We focused on three domains of physical activities: leisure time, commuting (i.e. walking and cycling), and daily activities (i.e. sedentary behavior). We also examined whether changes in sedentary behavior related to changes in participation in leisure time and commuting activities. METHODS: We used data from the Longitudinal National Population Health Survey (1994-2011): 10050 participants born between 1935 and 1984 grouped in five 10-years birth cohorts. We examined three outcomes: moderate-to-vigorous leisure time physical activity, active commuting, and sedentary behavior. We also included education, income, and body mass index as covariates. We used hierarchical age-period-cohort analysis to examine the contribution of age, period, and cohort effects to changes over time for each outcome. RESULTS: We found that recent cohorts were more likely to report sedentary behavior and greater participation in leisure time physical activities and active commuting. We also found a significant trend of increasing participation in active leisure time physical activity and active commuting among Canadians from 1994/95 to 2010/11 and, at the same time, an increase in sedentary behavior. The greater participation in leisure time physical activities and active commuting in each succeeding recent cohort was partially related to the secular trend of increasing participation in physical activities over time in the population. Furthermore, those with sedentary behavior were less likely to report participation in physical activities. Overall, obese individuals were less likely to be physically active and more likely to be sedentary, while the effect of socio-economic status varied by outcome. CONCLUSIONS: The greater participation in physical activities (leisure time and commuting) in recent cohorts is encouraging and was substantially explained by period effects, which reflect broad social and environmental factors affecting the whole population. The large cohort effect of increasing sedentary behavior and the inverse relationship between sedentary behavior and physical activity is concerning, and identifies a target group for future interventions. PMID- 29499670 TI - Exclusive breastfeeding practice during first six months of an infant's life in Bangladesh: a country based cross-sectional study. AB - BACKGROUND: Breastfeeding offers incredible health benefits to both child and mother. It is suggested by World Health Organization that an able mother should practice and maintain exclusive breastfeeding for first six months of her infant's life. The objective of this study was to determine the prevalence and factors associated with exclusive breastfeeding for first six months of an infant's life in Bangladesh. METHODS: Data was extracted from Bangladesh Demographic and Health Survey (BDHS-2014). BDHS-2014 collected data from 17,863 Bangladeshi married women in reproductive age from the entire country using two stages stratified cluster sampling. We included only mothers having at least one child currently aged not less than 6 months. Mothers who did not have child to breastfeed, some incomplete information and missing samples were excluded from the data set and consequently 3541 mothers were considered in the present study. Chi-square test, binary logistic regression models were used in this study. RESULTS: The prevalence of exclusive breastfeeding (EBF) for first six months of an infant's life in Bangladesh was 35.90%. Binary multivariable logistic regression model demonstrated that relatively less educated mothers were more likely to exclusively breastfeed their children than higher educated mothers. (AOR = 2.28, 95% CI: 1.05-4.93; p < 0.05). Housewife mothers were more likely to be EBF than their counterparts (AOR = 1.20, 95% CI: 1.02-1.42; p < 0.05). Higher rate of EBF was especially found among mothers who were living in Sylhet division, within 35-49 years old, and had access to mass media, had more than 4 children, had delivered at home and non-caesarean delivery, took breastfeeding counseling, antenatal and postnatal cares. CONCLUSIONS: Stepwise regression model exhibited that most of the important predictors were modifiable factors for exclusive breastfeeding. Authorities should provide basic education on EBF to educated mothers, and organize more general campaign on EBF. PMID- 29499671 TI - Posttraumatic venous gas in the liver - a case report and review of the current literature. AB - BACKGROUND: There are numerous causes of hepatic gas formation that range from serious pathologies to incidental findings, including mesenteric infarction, liver abscess, inflammatory bowel disease or minimally invasive hepatic interventions. CASE PRESENTATION: We report a case of a 50-year-old man who was admitted to the emergency room after a car accident. The clinical examination and further diagnostics revealed a craniocerebral injury with a fracture of the skull, concomitant soft tissue lesions and subarachnoidal bleeding. Furthermore, a blunt thoracic trauma with hemopneumothorax due to rib fractures was treated with a chest tube. No obvious abdominal pathology was seen. While in the operating theatre for the surgical revision of the cranial soft tissue lesions, a femoral venous catheter was inserted without any complications. A routine ultrasound of the abdomen six hours after the trauma revealed unclear hepatic gas formation. A contrast-enhanced computer tomography (CT) scan of the abdomen was performed, and the gas formation was found to be localized within the left hepatic vein. Afterwards, there was no specific treatment of the hepatic venous gas formation, as no alterations of liver function or liver enzymes were seen. The further course of the patient was uneventful regarding the gas formation in the liver, and another ultrasound two days later revealed no further gas in the liver. CONCLUSIONS: The placement of a femoral venous catheter is a risk factor for gas formation in liver veins. No further treatment is needed in cases with stable liver function. To rule out serious pathologies, diagnostic findings (e.g., ultrasound, CT), clinical history and underlying diseases need to be analyzed carefully after the detection of intrahepatic gas formation. With contrast-enhanced CT, the localization of the gas and its potential causes might be detectable. PMID- 29499672 TI - Prevalence of metabolic syndrome in Bangladesh: a systematic review and meta analysis of the studies. AB - BACKGROUND: Metabolic syndrome (MS) is a cluster of health problems that set the stage for serious health conditions and places individuals at higher risk of cardiovascular disease, diabetes and stroke. The worldwide prevalence of MS in the adult population is on the rise and Bangladesh is no exception. According to some epidemiological study, MS is highly prevalent in Bangladesh and has increased dramatically in last few decades. To provide a clear picture of the current situation, we conducted a systematic review and meta-analysis with an objective to assess the prevalence of metabolic syndrome among the Bangladeshi population using data already published in the scientific literature. METHODS: We searched MEDLINE, EMBASE and PubMed and manually checked references of all identified relevant publications that described the prevalence of MS in Bangladesh. Random effects meta-analysis was used to pool the prevalence. Heterogeneity was explored using formal tests and subgroup analyses. Study quality and publication bias was also explored. RESULTS: Electronic and grey literature search retrieved 491 potentially relevant papers. After removing duplicates, reviewing titles and abstracts and screening full texts, 10 studies were finally selected. Most of the studies were conducted in rural populations and study participants were mostly females. The weighted pooled prevalence of metabolic syndrome regardless of gender and criteria used to define metabolic syndrome, was 30.0% with high heterogeneity observed. Weighted pooled prevalence of metabolic syndrome is higher in females (32%) compared to males (25%) though not statistically significant (p = 0.434). Prevalence was highest (37%) when Modified NCEP ATP III criteria was used to define MS, while it was lowest (20%) when WHO criteria was used. In most cases, geographical area (urban/rural) was identified as a source of heterogeneity between the studies. Most of the studies met study quality assessment criteria's except adequate sample size criteria and evidence of small study effect was also detected. CONCLUSIONS: The prevalence of metabolic syndrome is high and rising in Bangladesh. Strategies aimed at primary prevention are required to mitigate a further increase in the prevalence and for the reduction of the morbidity and mortality associated with metabolic syndrome. PMID- 29499673 TI - Incidence of distal radius fracture surgery in Finns aged 50 years or more between 1998 and 2016 - too many patients are yet operated on? AB - BACKGROUND: Although optimal treatment of distal radius fractures is controversial, surgery has gained popularity. The purpose of this study was to evaluate recent trends in the surgical treatment of distal radius fractures in Finns aged 50 years or more. METHODS: A nationwide hospital discharge register based study was conducted among all patients 50 years of age or older who had a surgically treated distal radius fracture in Finland between 1998 and 2016. The number and rate of different surgical procedures were calculated per 100,000 person-years. RESULTS: Altogether 21,965 surgically treated distal radius fractures were identified. During the study period the rate of percutaneous pinning and external fixation diminished while the rate of plate fixation significantly increased. The rate of operative treatment increased continually from 1998 to 2008 whereupon the peak of the incidence was achieved. After 2008, the rate of operative treatment of distal radius fracture remained quite constant, ranging between 61.1 and 67.8 per 100,000 person-years. CONCLUSIONS: Plate fixation has almost completely replaced both external fixation and percutaneous pinning in the surgical treatment of distal radius fractures in Finland. Despite growing evidence for less invasive treatment options in elderly patients, operative treatment of distal radius fracture is still rather popular today. PMID- 29499674 TI - Visual field defects and retinal nerve fiber imaging in patients with obstructive sleep apnea syndrome and in healthy controls. AB - BACKGROUND: To assess the retinal sensitivity in obstructive sleep apnea hypopnea syndrome (OSAHS) patients evaluated with standard automated perimetry (SAP). And to correlate the functional SAP results with structural parameters obtained with optical coherence tomography (OCT). METHODS: This prospective, observational, case-control study consisted of 63 eyes of 63 OSAHS patients (mean age 51.7 +/- 12.7 years, best corrected visual acuity >=20/25, refractive error less than three spherical or two cylindrical diopters, and intraocular pressure < 21 mmHg) who were enrolled and compared with 38 eyes of 38 age-matched controls. Peripapillary retinal nerve fiber layer (RNFL) thickness was measured by Stratus OCT and SAP sensitivities and indices were explored with Humphrey Field Analyzer perimeter. Correlations between functional and structural parameters were calculated, as well as the relationship between ophthalmologic and systemic indices in OSAHS patients. RESULTS: OSAHS patients showed a significant reduction of the sensitivity for superior visual field division (p = 0.034, t-student test). When dividing the OSAHS group in accordance with the severity of the disease, nasal peripapillary RNFL thickness was significantly lower in severe OSAHS than that in controls and mild-moderate cases (p = 0.031 and p = 0.016 respectively, Mann-Whitney U test). There were no differences between groups for SAP parameters. We found no correlation between structural and functional variables. The central visual field sensitivity of the SAP revealed a poor Pearson correlation with the apnea-hipopnea index (0.284, p = 0.024). CONCLUSIONS: Retinal sensitivity show minor differences between healthy subjects and OSAHS. Functional deterioration in OSAHS patients is not easy to demonstrate with visual field examination. PMID- 29499675 TI - Digital IAPT: the effectiveness & cost-effectiveness of internet-delivered interventions for depression and anxiety disorders in the Improving Access to Psychological Therapies programme: study protocol for a randomised control trial. AB - BACKGROUND: Depression and anxiety are common mental health disorders worldwide. The UK's Improving Access to Psychological Therapies (IAPT) programme is part of the National Health Service (NHS) designed to provide a stepped care approach to treating people with anxiety and depressive disorders. Cognitive Behavioural Therapy (CBT) is widely used, with computerised and internet-delivered cognitive behavioural therapy (cCBT and iCBT, respectively) being a suitable IAPT approved treatment alternative for step 2, low- intensity treatment. iCBT has accumulated a large empirical base for treating depression and anxiety disorders. However, the cost-effectiveness and impact of these interventions in the longer-term is not routinely assessed by IAPT services. The current study aims to evaluate the clinical and cost-effectiveness of internet-delivered interventions for symptoms of depression and anxiety disorders in IAPT. METHODS: The study is a parallel groups, randomised controlled trial examining the effectiveness and cost effectiveness of iCBT interventions for depression and anxiety disorders, against a waitlist control group. The iCBT treatments are of 8 weeks duration and will be supported by regular post-session feedback by Psychological Wellbeing Practitioners. Assessments will be conducted at baseline, during, and at the end of the 8-week treatment and at 3, 6, 9, and 12-month follow-up. A diagnostic interview will be employed at baseline and 3-month follow-up. Participants in the waitlist control group will complete measures at baseline and week 8, at which point they will receive access to the treatment. All adult users of the Berkshire NHS Trust IAPT Talking Therapies Step 2 services will be approached to participate and measured against set eligibility criteria. Primary outcome measures will assess anxiety and depressive symptoms using the GAD-7 and PHQ-9, respectively. Secondary outcome measures will allow for the evaluation of long term outcomes, mediators and moderators of outcome, and cost-effectiveness of treatment. Analysis will be conducted on a per protocol and intention-to-treat basis. DISCUSSION: This study seeks to evaluate the immediate and longer-term impact, as well as the cost effectiveness of internet-delivered interventions for depression and anxiety. This study will contribute to the already established literature on internet-delivered interventions worldwide. The study has the potential to show how iCBT can enhance service provision, and the findings will likely be generalisable to other health services. TRIAL REGISTRATION: Current Controlled Trials ISRCTN ISRCTN91967124. DOI: https://doi.org/10.1186/ISRCTN91967124 . Web: http://www.isrctn.com/ISRCTN91967124 . Clinicaltrials.gov : NCT03188575. Trial registration date: June 8, 2017 (prospectively registered). PMID- 29499676 TI - Health-related quality of life of children and adolescents with osteogenesis imperfecta: a cross-sectional study using PedsQLTM. AB - BACKGROUND: Osteogenesis imperfecta (OI) is a disorder of bone formation leading to low mineral density and fractures. Children and adolescents with OI require periodic medical follow up, corrective surgery, drug therapy and physical therapy, as well as specific daily care practices. In addition, they have an increased incidence of fractures, which require immobilization and cause severe discomfort and short-term disability. This study evaluated the health-related quality of life of children and adolescents with OI in two reference centers for OI treatment in southern Brazil. METHODS: In this prospective cross-sectional study, the Pediatric Quality of Life Inventory (PedsQLTM) was applied in two university-affiliated reference centers for OI treatment in southern Brazil. Children and adolescents aged >= 5 years with clinical diagnoses of OI were included. Clinical data and socioeconomic status was evaluated. RESULTS: The sample consisted of 52 children and adolescents with OI (aged 5-17 years); 26 (50%) participants with type I OI, 13 (25%) type IV, 12 (23.1 %) type III, and 1 (1.9%) type V OI. Physical and social functioning domains differed significantly according to clinical presentation of OI with lowest scores in the severe type (OI type III). Pain seems to be the variable that is most associated with impact on the PedsQL domains. CONCLUSIONS: Overall, this study revealed differences in physical functioning and social functioning in relation to OI clinical presentation. These results reinforcing the importance of the clinical management of these patients with the aim of functional improvement and importance of pain control. PMID- 29499677 TI - Reasons for reported suspicion of child maltreatment and responses from the child welfare - a cross-sectional study of Norwegian public dental health personnel. AB - BACKGROUND: To prevent child maltreatment, the identification of vulnerable children is essential. In Norway, public dental health personnel (PDHP) report suspicion of child maltreatment to child welfare services (CWS) at a relatively high rate. However, their reasons for reporting and the response from CWS have not been investigated. The objectives of this study were to (1) explore the reasons that PDHP send reports of concern, (2) examine how CWS responds to PDHP reports, and (3) assess whether different reasons for concern are associated with a given response from CWS. METHODS: A national cross-sectional study was conducted by an electronic survey distributed to public dental hygienists and dentists in Norway. Descriptive statistics were calculated in terms of mean (SD) distributions and frequency, expressed as % (n). To account for clustering of responses among respondents, binomial generalized estimating equation analysis was used to estimate odds ratios (ORs) and confidence intervals (CIs) of CWS responses across number of reports with different reasons for concern. RESULTS: Of a total of 1542 questionnaire recipients, 1200 (77.8%) responded to the survey. From 2012 to 2014, 42.5% of the respondents sent 1214 reports to CWS, with a mean number of 2.7 (SD = 2.0) reports per respondent. The PDHP sent the reports due to suspicion of neglect or physical, sexual and/or psychological abuse. Non-attendance at dental appointments and grave caries were reported most frequently. Among the reports, 24.5% resulted in measures being taken by CWS, 20.7% were dropped, and 29.4% lacked information from CWS on the outcome. Reports due to suspicion of sexual abuse, (OR 1.979, 95% CI (1.047-3.742), P = 0.036), grave caries (OR 1.628, 95% CI (1.148-2.309), P = 0.006), and suspicion of neglect (OR 1.649, 95% CI (1.190-2.285), P = 0.003) had the highest association with the implementation of measures. CONCLUSIONS: PDHP report on several forms of child maltreatment and contributes in detection of victimized children. However, the relatively low number of measures being taken by CWS and the number of reports that lack a response to reporters reveal a need for a closer cooperation between the services, as this would benefit both the children at risk and the services. PMID- 29499678 TI - Social capital and frequent attenders in general practice: a register-based cohort study. AB - BACKGROUND: Frequent attendance to primary care constitutes a large use of resources for the health care system. The association between frequent attendance and illness-related factors has been examined in several studies, but little is known about the association between frequent attendance and individual social capital. The aim of this study is to explore this association. METHODS: The analysis is conducted on responders to the North Denmark Region Health Profile 2010 (n = 23,384), individually linked with information from administrative registers. Social capital is operationalized at the individual level, and includes cognitive (interpersonal trust and norms of reciprocity) as well as structural (social network and civic engagement) dimensions. Frequent attendance is defined as the upper-quartile of the total number of measured consultations with a general practitioner over a period of 148 weeks. RESULTS: Using multiple logistic regression, we found that frequent attendance was associated with a lower score in interpersonal trust [OR 0.86 (0.79-0.94)] and social network [OR 0.88 (0.79-0.98)] for women, when adjusted for age, education, income and SF12 health scores. Norms of reciprocity and civic engagement were not significantly associated with frequent attendance for women [OR 1.05 (0.99-1.11) and OR 1.01 (0.92-1.11) respectively]. None of the associations were statistically significant for men. CONCLUSION: This study suggests that for women, some aspects of social capital are associated with frequent attendance in general practice, and the statistically significant dimensions belonged to both cognitive and structural aspects of social capital. This association was not seen for men. This indicates a multifaceted and heterogeneous relationship between social capital and frequent attendance among genders. PMID- 29499679 TI - Phytochemical profiling and in vitro screening for anticholinesterase, antioxidant, antiglucosidase and neuroprotective effect of three traditional medicinal plants for Alzheimer's Disease and Diabetes Mellitus dual therapy. AB - BACKGROUND: Extensive epidemiological and clinical studies revealed that Alzheimer's Disease (AD) and Type 2 Diabetes Mellitus (T2D) are most likely to appear simultaneously in aged people as T2D is a major risk factor for AD. Therefore, development of potential multifunctional agents for dual therapy of AD and T2D has received much attention. Buchanania axillaris, Hemidesmus indicus and Rhus mysorensis have been used extensively in popular medicine. The present study was aimed at phytochemical profiling and evaluating multifunctional ability of titled plants in the AD and T2D dual therapy. METHODS: Methanolic extracts and their derived fractions were evaluated for their inhibitory capacities against acetylcholinesterase (AChE) & butyrylcholinesterase (BuChE), and alpha- & beta glucosidase besides kinetic analysis of inhibition using methods of Elmann and Shibano, respectively. Antioxidant potency of active fractions was assessed by their DPPH and ABTS radical scavenging activities. Active fractions were tested by the MTT assay to verify cytotoxicity and neuroprotective ability in human nueroblastoma cell lines. Phytochemical screening was done with the aid of spectrophotometric methods. RESULTS: All the methanolic extracts of test plants (BAM, HIM, RMM) showed concentration dependent inhibitory activities against AChE, BuChE, alpha- and beta-glucosidase enzymes. Subsequent fractionation and evaluation revealed that chloroform fractions BAC, HIC and RMC with IC50 values of 12.29+/-2.14, 9.94+/-2.14, 16.65+/-1.99 and 27.38+/-1.24; 28.14+/-0.9, 5.16+/ 0.22, 11.03+/-0.5 and 87.64+/-15.41; 41.35+/-1.6, 15.86+/-7.3, 26.04+/-0.37 and 25.33+/-0.3 were most prominent with regard to inhibition potential against AChE, BuChE, alpha- and beta-glucosidase, respectively. Kinetic analysis of these active fractions proved that they disclosed mixed-type inhibition against AChE, BuChE, alpha- and beta-glucosidase enzymes. In the MTT assay, active fractions BAC, HIC, RMC showed significant cell viability at high concentrations (400 MUg). Moreover, in MTT assay, the active fractions displayed excellent neuroprotective effects against oxidative stress induced cell death and significant cell viability in SK N SH cells at all concentrations. CONCLUSION: The strong anticholinesterase, antiglucosidase, antioxidant and neuroprotective activities of methanolic extracts and their derived chloroform fractions indicate the potential of Buchanania axillaris, Hemidesmus indicus and Rhus mysorensis as multifunctional therapeutic remedies for the dual therapy of T2D and AD. PMID- 29499680 TI - Hand grip strength and maximum peak expiratory flow: determinants of bone mineral density of adolescent students. AB - BACKGROUND: Maintaining and building healthy bones during the lifetime requires a complicated interaction between a number of physiological and lifestyle factors. Our goal of this study was to analyze the association between hand grip strength and the maximum peak expiratory flow with bone mineral density and content in adolescent students. METHODS: The research team studied 1427 adolescent students of both sexes (750 males and 677 females) between the ages of 11.0 and 18.9 years in the Maule Region of Talca (Chile). Weight, standing height, sitting height, hand grip strength (HGS), and maximum peak expiratory flow (PEF) were measured. Furthermore, bone mineral density (BMD) and total body bone mineral content (BMC) were determined by using the Dual-Energy X-Ray Absorptiometry (DXA). Hand grip strength and PEF were categorized in tertiles (lowest, middle, and highest). Linear regression was performed in steps to analyze the relationship between the variables. Differences between categories were determined through ANOVA. RESULTS: In males, the hand grip strength explained 18-19% of the BMD and 20-23% of the BMC. For the females, the percentage of variation occurred between 12 and 13% of the BMD and 17-18% of the BMC. The variation of PEF for the males was observed as 33% of the BMD and 36% of the BMC. For the females, both the BMD and BMC showed a variation of 19%. The HGS and PEF were divided into three categories (lowest, middle, and highest). In both cases, significant differences occurred in bone density health between the three categories. CONCLUSIONS: In conclusion, the HGS and the PEF related positively to the bone density health of both sexes of adolescent students. The adolescents with poor values for hand grip strength and expiratory flow showed reduced values of BMD and BMC for the total body. Furthermore, the PEF had a greater influence on bone density health with respect to the HGS of the adolescents of both sexes. PMID- 29499681 TI - A case of bilateral revision total knee arthroplasty using distal femoral allograft-prosthesis composite and femoral head allografting at the tibial site with a varus-valgus constrained prosthesis: ten-year follow up. AB - BACKGROUND: We report the successful use of allograft-prosthesis composite (APC) and structural femoral head allografting in the bilateral reconstruction of large femoral and tibial uncontained defects during revision total knee arthroplasty (RTKA). CASE PRESENTATION: A 67-year-old female with degenerative arthritis underwent bilateral total knee arthroplasty (TKA) using the Press Fit Condylar (PFC) modular knee system at our clinic in March, 1996. At 8 years postoperatively, the patient presented with painful, bilateral varus knees, with swelling, limited passive range of motion (ROM), and severe instability. We treated to reconstruct both knee using a femoral head allograft at the tibial site, a structural distal femoral allograft at the femoral site, and a varus valgus constrained (VVC) prosthesis with cement. At the 10-year follow up, we found no infection, graft failure, loosening of implants, in spite of using massive bilateral structural femoral head allografts in RTKA. CONCLUSION: The use of APC enabled a stable and durable reconstruction in this uncommon presentation with large femoral bone deficiencies encountered during a RTKA. PMID- 29499682 TI - What do medical students know about e-cigarettes? A cross-sectional survey from one U.S. medical school. AB - BACKGROUND: Although electronic cigarette (e-cigarette) use has rapidly increased, there is little data about what United States medical students know or are taught about them. This study examined medical students' experiences, knowledge, and attitudes regarding e-cigarettes, as well as their evaluation of their education on e-cigarettes. METHODS: A cross-sectional online survey of medical students currently enrolled at the University of Minnesota Medical School (n = 984) was conducted over a three-week period in August and September 2015. Primary outcomes included students' personal experiences with e-cigarettes, knowledge and attitudes about e-cigarettes, and students' assessment of their education on e-cigarettes. RESULTS: 66.9% medical students completed the survey. 58% (n = 382) of participants identified as female. 35.8% (n = 235) were "not sure" whether e-cigarettes were approved by the FDA for smoking cessation, while 4.1% (n = 27) falsely believed they were. While 82.9% (n = 543) agreed or strongly agreed that they felt confident in their ability to discuss traditional cigarette use with patients, only 12.4% (n = 81) agreed or strongly agreed that they felt confident in their ability to discuss e-cigarettes with patients. 94.8% (n = 619) of participants believed that they had not received adequate education about e-cigarettes in medical school. A higher proportion of males reported ever using an e-cigarette. CONCLUSIONS: The gaps in medical student knowledge and wide variances in attitudes about e-cigarettes at one medical school together with their report of inadequate education in an environment of increasing use of e cigarette use in the U.S. speaks to a need for the development of medical school curriculum on e-cigarettes. PMID- 29499683 TI - What women say about their dysmenorrhea: a qualitative thematic analysis. AB - BACKGROUND: Dysmenorrhea is highly prevalent and is the leading cause of absence from school and work among women of reproductive age. Evidence suggests that dysmenorrhea may also be a risk factor for other chronic pain conditions. Limited research has examined women's experience with dysmenorrhea using qualitative data. Research is warranted to address issues and needs that are important from women's own perspectives. Therefore, the purpose of this study was to describe women's salient thoughts about their experiences of dysmenorrhea. METHODS: We analyzed data collected from an open-ended question within a cross-sectional survey study conducted in the United States. Using qualitative thematic analysis, free text responses to a question asking women to share their experience with dysmenorrhea were analyzed. RESULTS: The sample consisted of 225 women who provided valid responses to the open-ended question. Six themes were identified: (1) The dysmenorrhea symptom experience varied among women; (2) The dysmenorrhea symptom experience varied across time, (3) A variety of factors influenced the dysmenorrhea symptom experience, (4) Dysmenorrhea symptoms could have a negative impact on the women's daily lives, (5) Dysmenorrhea was not seen as a legitimate health issue by the women, health care providers, or society, and (6) Treatment for women with dysmenorrhea varied in acceptability and effectiveness. CONCLUSIONS: The findings of this study have important implications for dysmenorrhea symptom assessment and the development of personalized interventions to support dysmenorrhea management. PMID- 29499684 TI - A searchable database of medical education objectives - creating a comparable gold standard. AB - BACKGROUND: Medical school curricula strives to teach as much material as can be retained in a limited amount of time. A common "gold standard" resource used building curricula are medical objectives suggested by national societies. Unfortunately these objectives suffer from several functional limitations such as limited accessibility to society members, non-searchable formats (such as nested tables or pdf images), and inability to compare and search across societal objectives for redundancy or gaps. The shift towards integrated curriculums in medical school also highlights the need to access suggested content across classical discipline categories. MAIN BODY: We have codified recommendations from national societies in the United States for medical school objectives in a common tabular format and developed an open access database which can be searched across disciplines and societies. A front end website that allows for searching objectives by keyword while filtering on society or discipline was created. The objectives returned from the initial search can be subsearched by a second term. There is a large range in the format, age, breadth, quantity, and quality of objectives from different societies. Some unique disciplines have overlapping suggested content though most of the content does seem "binnable" by discipline. The choice of metadata for objectives from each given society was also very inconsistent. CONCLUSION: A free and searchable database of medical content to deliver during medical school has been developed with over 13,000 objectives from 18 societies and 22 disciplines at http://data.medobjectives.marian.edu/ . The normalization of the different disciplines' objectives into a common database allows a platform to standardize objectives moving forward. Future work could include adding user accounts to access the database, submission of new objectives, voting up and down suggested objectives, and adding "answers" mapped to objectives. Keyword tagging could allow import of content (e.g. PowerPoints) and outputting of suggested objectives, which would also allow comparison of curriculum across medical schools. PMID- 29499685 TI - Kangaroo mother care: using formative research to design an acceptable community intervention. AB - BACKGROUND: Low and middle income countries (LMICs), including India, contribute to a major proportion of low birth weight (LBW) infants globally. These infants require special care. Kangaroo Mother Care (KMC) in hospitals is a cost effective and efficacious intervention. In institutional deliveries, the duration of facility stay is often short. In LMICs, a substantial proportion of deliveries still occur at home and access to health care services is limited. In these circumstances, a pragmatic choice may be to initiate KMC at home for LBW babies. However, evidence is lacking on benefits of community-initiated KMC (cKMC). Promoting KMC at home without an understanding of its acceptability may lead to limited success. METHODS: We conducted formative research to assess the feasibility, acceptability and adoption of cKMC with the aim of designing an intervention package for a randomised controlled trial in LBW infants in Haryana, India. Qualitative methods included 40 in-depth interviews with recently delivered women and 6 focus group discussions, two each with fathers and grandfathers, grandmothers, and community health workers. A prototype intervention package to promote cKMC was developed and tested in 28 mother-infant pairs (of them, one mother had twins), using Household (HH) trials. RESULTS: We found that most mothers in the community recognized that babies born small required special care. In spite of not being aware of the practice of KMC, respondents felt that creating awareness of KMC benefits will promote practice. They expressed concerns about doing KMC for long periods because mothers needed rest after delivery. However, the cultural practice of recently delivered women not expected to be doing household chores and availability of other family members were identified as enablers. HH trials provided an opportunity to test the intervention package and showed high acceptability for KMC. Most mothers perceived benefits such as weight gain and increased activity in the infant. CONCLUSIONS: Community-initiated KMC is acceptable by mothers and adoption rates are high. Formative research is essential for developing a strategy for delivery of an intervention. TRIAL REGISTRATION: Trial registration number CTRI/2015/10/006267 . Name of Registry: Clinical Trials Registry - India. URL of Registry: http://ctri.nic.in/Clinicaltrials/login.php Date of Registration: 15/10/2015. Date of enrolment of the first participant to the trial: 18/04/2015. PMID- 29499686 TI - Variations in the rancid-flavor compounds of human breastmilk under general frozen-storage conditions. AB - BACKGROUND: Human breastmilk provides the best nutrition for infants. When women or infants have difficulties in breastfeeding directly, breastmilk is usually pumped and frozen for later use. However, while frozen, breastmilk may develop a rancid flavor, which induces infant feeding stress and raises the mothers' concerns about the quality of frozen breastmilk. Nevertheless, few studies have investigated the variations in the compounds that cause the rancid flavor of breastmilk during frozen storage. METHODS: A repeated-measures design was adopted to quantify the variations in rancid-flavor compounds, namely acid value (AV), total free fatty acids (FFAs), and short-and intermediate-chain FFAs of breastmilk during frozen storage. Breastmilk was obtained from ten healthy mothers of full-term infants and each milk sample was divided into three aliquots: fresh, 7-day frozen and 30-day frozen samples. The fresh samples were immediately analyzed, while the others were frozen in a domestic fridge within a temperature range of -15 to -18 degrees C and analyzed 7 and 30 days later. RESULTS: The rancid-flavor compounds of the breastmilk, namely AV, total FFAs and intermediate-chain FFAs, significantly increased with storage time, all of which reached the sensory threshold for detecting the rancid flavor of milk. In addition, the FFAs of the breastmilk samples frozen for 7 days far exceeded the detection threshold for unpleased rancid flavor, while the 30-day samples were higher than the intolerable level for most people. CONCLUSIONS: This study revealed that the human breastmilk develops a rancid flavor during frozen storage. Therefore, we recommend that when infants refuse thawed milk, mothers can try to provide freshly expressed milk whenever possible or provide breastmilk frozen for less than 7 days. Future studies could explore the methods for slowing breastmilk lipolysis to maintain its fresh flavor. PMID- 29499687 TI - Prevalence of excessive body fat among adolescents of a south Brazilian metropolitan region and State capital, associated risk factors, and consequences. AB - BACKGROUND: The prevalence of overweight/obesity has become a major concern for public health in developing countries. Risk factors need to be well documented so that these countries develop public policies to fight the problem. Thus, the objective of this study is to determine the prevalence of excess fat among adolescents of a South Brazilian State Capital associated with risk factors and their consequences. METHODS: This study was conducted between 2014 and 2016 with adolescents aged 11-18 years. The following body composition measurements were collected: body mass, height, waist circumference, fat mass and bone mineral density (this latter through dual energy X-ray absorptiometry). Biochemical data as glucose, total cholesterol, and triglycerides were also collected. Finally, socioeconomic questionnaires were applied, as well as questionnaires regarding: the education level of guardians, active transportation, time spent with sedentary activities and physical activities. Odds ratios and chi-square test were applied in statistical analysis. RESULTS: Data from 675 adolescents, from which 70% were males, were analyzed. The mean age was 14.7 +/- 1.8 years. The prevalence of excess fat was 18.2% in boys and 92.1% in girls. As for sedentary lifestyle and physical inactivity, having one of these factors increased the risk of being overweight by 7.9 times for boys and 3.0 times for girls. In boys, there was a significant association between excess fat and waist circumference (p = 0.000; OR = 13.5; CI = 7.0-25.9), physical activity level (p = 0.000; OR = 4.0; CI = 2.5-6.5), triglycerides (p = 0.019; OR = 2.2; CI = 1.1-4.2) and total cholesterol (p = 0.000; OR = 2.6; CI = 1.6-4.5). In girls, there was an association between having excess fat and an increase in total cholesterol (p = 0.000; OR = 8.0; CI = 2.6-24.4). CONCLUSIONS: The high prevalence of excess fat was greater than what was described by some studies conducted in developed countries. This reality demonstrates the need to implement public policies that can directly promote the reduction of sedentary habits and reinforce the importance of adopting an active lifestyle. PMID- 29499688 TI - Psychosocial factors affecting resilience in Nepalese individuals with earthquake related spinal cord injury: a cross-sectional study. AB - BACKGROUND: One of many types of injuries following an earthquake is spinal cord injury (SCI) which is a life-long medically complex injury and high-cost health problem. Despite several negative consequences, some persons with SCI are resilient enough to achieve positive adjustment, greater acceptance, and better quality of life. Since resilience is influenced by several factors and can vary by context, it is beneficial to explore factors that affect the resilience of people who sustained spinal cord injury from the 2015 earthquake in Nepal. METHODS: A descriptive cross-sectional study included 82 participants from the Spinal Injury Rehabilitation Center and communities in Nepal. Participants completed the Demographic and Injury-related Questionnaire, Connor-Davidson Resilience Scale, Multidimensional Scale of Perceived Social Support, Moorong Self-efficacy Scale, Intrinsic Spirituality Scale, and Patient Health Questionnaire-9. Pearson's correlation and point biserial correlation analyses were performed to examine associations between resilience and independent variables. A hierarchical regression analysis was used to identify the influence of certain factors. RESULTS: Findings indicated significant associations between resilience and social support (r = 0.42, p < 0.001), self-efficacy (r = 0.53, p < 0.001), depressive mood (r = - 0.50, p < 0.001) and demographic variables which included sex (r = 0.47, p < 0.001), employment (r = 0.27, p = 0.016), and current living location (r = 0.24, p = 0.029). There was a non-significant association between resilience and spirituality (r = - 0.12, p > 0.05). In hierarchical regression analysis, an overall regression model explained 46% of the variance in resilience. Self-efficacy (beta = 0.28, p = 0.007) and depressive mood (beta = - 0.24, p = 0.016) significantly determined resilience after controlling the effect of demographic variables. Among the demographic factors, being male significantly explained the variance in resilience (beta = 0.31, p = 0.001). CONCLUSIONS: Multiple psychosocial and demographic factors were associated with resilience in people who sustained an earthquake-related SCI. Mental health professionals should demonstrate concern and consider such factors in allocating care in this group. Development of intervention research concerning resilience is recommended to strengthen resilience in order to improve rehabilitation outcomes and enhance reintegration of individuals with SCI into their communities. PMID- 29499689 TI - Adiposity and the isotemporal substitution of physical activity, sedentary time and sleep among school-aged children: a compositional data analysis approach. AB - BACKGROUND: Daily activity data are by nature compositional data. Accordingly, they occupy a specific geometry with unique properties that is different to standard Euclidean geometry. This study aimed to estimate the difference in adiposity associated with isotemporal reallocation between daily activity behaviours, and to compare the findings from compositional isotemporal subsitution to those obtained from traditional isotemporal substitution. METHODS: We estimated the differences in adiposity (body fat%) associated with reallocating fixed durations of time (isotemporal substitution) between accelerometer-measured daily activity behaviours (sleep, sedentary time and light and moderate-to-vigorous physical activity (MVPA)) among 1728 children aged 9-11 years from Australia, Canada, Finland and the UK (International Study of Childhood Obesity, Lifestyle and the Environment, 2011-2013). We generated estimates from compositional isotemporal substitution models and traditional non compositional isotemporal substitution models. RESULTS: Both compositional and traditional models estimated a positive (unfavourable) difference in body fat% when time was reallocated from MVPA to any other behaviour. Unlike traditional models, compositional models found the differences in estimated adiposity (1) were not necessarily symmetrical when an activity was being displaced, or displacing another (2) were not linearly related to the durations of time reallocated, and (3) varied depending on the starting composition. CONCLUSION: The compositional isotemporal model caters for the constrained and therefore relative nature of activity behaviour data and enables all daily behaviours to be included in a single statistical model. The traditional model treats data as real variables, thus the constrained nature of time is not accounted for, nor reflected in the findings. Findings from compositional isotemporal substitution support the importance of MVPA to children's health, and suggest that while interventions to increase MVPA may be of benefit, attention should be directed towards strategies to avoid decline in MVPA levels, particularly among already inactive children. Future applications of the compositional model can extend from pair-wise reallocations to other configurations of time-reallocation, for example, increasing MVPA at the expense of multiple other behaviours. PMID- 29499690 TI - Development of the Japanese Core Outcome Measures Index (COMI): cross-cultural adaptation and psychometric validation. AB - BACKGROUND: The patient-rated Core Outcome Measures Index (COMI) assesses the multidimensional impact of back problems on the sufferer. The brevity and comprehensibility of the tool make it practical for use in clinical and research settings. Although the COMI has been cross-culturally adapted in various languages worldwide, there is currently no Japanese version. The aim of this study was to develop a Japanese version of the COMI by: (1) performing a cross cultural adaptation of the English version and (2) evaluating the psychometric properties of the Japanese version of the COMI in Japanese volunteers with chronic back problems. METHODS: The English version of the COMI was cross culturally adapted for the Japanese language using established guidelines. The pre-final version was pilot-tested in five Japanese-speaking patients with low back pain (LBP) and a history of spine surgery. The psychometric properties of the Japanese COMI were tested in a group of 1052 individuals with chronic LBP (LBP >=3 months), aged 20-69 years, who were recruited through a web-based survey. The psychometric properties that were evaluated included convergent and known-group validity, using the following reference questionnaires: EuroQol 5 Dimension, Roland Morris Disability Questionnaire, Short Form 8TM Health Survey, and the Keele STarT Back Screening Tool. RESULTS: The pre-final version of the cross-culturally adapted Japanese COMI was completed without any major problems of understanding or acceptability. For the evaluation of its psychometric properties, tests for convergent validity showed moderate correlations between COMI items and the respective reference questionnaires for symptom-specific well being [- 0.33--0.48] and disability domains [0.48] and strong correlations (> 0.5) for the other domains and the COMI summary score. The analysis of known group validity showed a linear trend for the COMI score in relation to prognostic risk (P < 0.001). CONCLUSIONS: The Japanese COMI retained conceptual equivalence to the original using comprehensible and acceptable Japanese expressions. We developed a Japanese version of the COMI that displayed qualities that support its convergent and known-group validity. The availability of a Japanese version of the COMI should allow for improved documentation of the care provided to patients with back problems. PMID- 29499691 TI - Eplerenone attenuates pathological pulmonary vascular rather than right ventricular remodeling in pulmonary arterial hypertension. AB - BACKGROUND: Aldosterone is a mineralocorticoid hormone critically involved in arterial blood pressure regulation. Although pharmacological aldosterone antagonism reduces mortality and morbidity among patients with severe left-sided heart failure, the contribution of aldosterone to the pathobiology of pulmonary arterial hypertension (PAH) and right ventricular (RV) heart failure is not fully understood. METHODS: The effects of Eplerenone (0.1% Inspra(r) mixed in chow) on pulmonary vascular and RV remodeling were evaluated in mice with pulmonary hypertension (PH) caused by Sugen5416 injection with concomitant chronic hypoxia (SuHx) and in a second animal model with established RV dysfunction independent from lung remodeling through surgical pulmonary artery banding. RESULTS: Preventive Eplerenone administration attenuated the development of PH and pathological remodeling of pulmonary arterioles. Therapeutic aldosterone antagonism - starting when RV dysfunction was established - normalized mineralocorticoid receptor gene expression in the right ventricle without direct effects on either RV structure (Cardiomyocyte hypertrophy, Fibrosis) or function (assessed by non-invasive echocardiography along with intra-cardiac pressure volume measurements), but significantly lowered systemic blood pressure. CONCLUSIONS: Our data indicate that aldosterone antagonism with Eplerenone attenuates pulmonary vascular rather than RV remodeling in PAH. PMID- 29499692 TI - The influence of preoperative determinants on quality of life, functioning and pain after total knee and hip replacement: a pooled analysis of Dutch cohorts. AB - BACKGROUND: Previous research has identified preoperative determinants that predict health related quality of life (HRQoL), functioning and pain after total knee or hip arthroplasty (TKA/THA), but these differed between studies and had opposite directions. This may be due to lack of power and not adjusting for confounders. The present study aims to identify the preoperative determinants that influence health related quality of life (HRQoL), functioning and pain after total knee or hip arthroplasty (TKA/THA). METHODS: We pooled individual patient from 20 cohorts with OA patients data (n = 1783 TKA and n = 2400 THA) in the Netherlands. We examined the influence of age, gender, BMI and preoperative values of HRQoL, functioning and pain on postoperative status and total improvement. Linear mixed models were used to estimate the effect of each preoperative variable on a particular outcome for each cohort separately. These effects were pooled across cohorts using a random effects model. RESULTS: For each increase in preoperative point in HRQoL, the postoperative HRQoL increased by 0.51 points in TKA and 0.37 points in THA (SF-36 scale). Similarly, each point increase in preoperative functioning, resulted in a higher postoperative functioning of 0.31 (TKA) and 0.21 (THA) points (KOOS/HOOS-ADL scale). For pain this was 0.18 (TKA) and 0.15 (THA) points higher (KOOS/HOOS-pain scale) (higher means less pain). Even though patients with better preoperative values achieved better postoperative outcomes, their improvement was smaller. Women and patients with a higher BMI had more pain after a TKA and THA. Higher age and higher BMI was associated with lower postoperative HRQoL and functioning and more pain after a THA. CONCLUSIONS: Patients with a better preoperative health status have better outcomes, but less improvement. Even though the independent effects may seem small, combined results of preoperative variables may result in larger effects on postoperative outcomes. PMID- 29499693 TI - Screening for infectious diseases of asylum seekers upon arrival: the necessity of the moral principle of reciprocity. AB - BACKGROUND: With a large number of forcibly displaced people seeking safety, the EU is facing a challenge in maintaining solidarity. Europe has seen millions of asylum seekers crossing European borders, the largest number of asylum seekers since the second world war. Endemic diseases and often failing health systems in their countries of origin, and arduous conditions during transit, raise questions around how to meet the health needs of this vulnerable population on arrival in terms of screening, vaccination, and access to timely and appropriate statutory health services. This paper explores the potential role of the principle of reciprocity, defined as the disposition 'to return good in proportion to the good we receive, and to make reparations for the harm we have done', as a mid-level principle in infectious disease screening policies. MAIN TEXT: More than half of the European countries implemented screening programmes for newly arrived asylum seekers. Screening may serve to avoid potential infectious disease risks in the receiving countries as well as help identify health needs of asylum seekers. But screening may infringe upon basic rights of those screened, thus creating an ethical dilemma. The use of the principle of reciprocity can contribute to the identification of potential improvements for current screening programmes and emphasizes the importance of certain rights into guidelines for screening. It may create a two way moral obligation, upon asylum seekers to actively participate in the programme, and upon authorities to reciprocate the asylum seekers' participation and the benefits for the control of public health. CONCLUSION: The authors argue that the reciprocity principle leads to a stronger ethical justification of screening programmes and help achieve a balance between justifiable rights claims of the host population and the asylum seekers. The principle deserves a further and more thorough exploration of its potential use in the field of screening, migration and infectious diseases. PMID- 29499694 TI - Developing a workbook to support the contextualisation of global health systems guidance: a case study identifying steps and critical factors for success in this process at WHO. AB - BACKGROUND: Global guidance can help countries strengthen their health systems to deliver effective interventions to their populations. However, to have an impact, guidance needs to be contextualised or adapted to local settings; this process includes consideration of health system arrangements and political system factors. To date, methods to support contextualisation do not exist. In response, a workbook was designed to provide specific methods and strategies to enable the contextualisation of WHO's 'Optimizing health worker roles to improve maternal and newborn health' (OptimizeMNH) guidance at the national or subnational level. The objective of this study was to describe the process of developing the workbook and identify key steps of the development process, barriers that arose and facilitators that helped overcome some of these barriers. METHODS: A qualitative single case study design was carried out. Interviews, documents and a reflexive journal were used. Constant comparison and an edit-style of organisation were used during data analysis to develop concepts, themes, subthemes and relationships among them. RESULTS: Thirteen interviews were conducted and 52 documents were reviewed. Three main steps were identified in the process of developing the workbook for health systems guidance contextualisation, namely (1) determining the need for and gaining approval to develop the workbook, (2) developing the workbook (taking on the task, creating the structure of the workbook, operationalising its components, undergoing approval processes and editing it), and (3) implementing the workbook both at the WHO level and at the national/subnational level. Five barriers and/or facilitators emerged relevant to each step, namely (1) having well-placed and credible champions, (2) creating and capitalising on opportunities, (3) finding the right language to engage various actors and obtain buy-in, (4) obtaining and maintaining meaningful buy-in, and (5) ensuring access to resources. CONCLUSIONS: Understanding the key steps and the critical factors involved in the process of developing the workbook could help in the planning of similar and other tools aimed to support the implementation of WHO guidance. A plan for dissemination and implementation needs to be addressed during the preparation of these tools. PMID- 29499696 TI - Objectivity applied to embodied subjects in health care and social security medicine: definition of a comprehensive concept of cognitive objectivity and criteria for its application. AB - BACKGROUND: The article defines a comprehensive concept of cognitive objectivity (CCCO) applied to embodied subjects in health care. The aims of this study were: (1) to specify some necessary conditions for the definition of a CCCO that will allow objective descriptions and assessments in health care, (2) to formulate criteria for application of such a CCCO, and (3) to investigate the usefulness of the criteria in work disability assessments in medical certificates from health care provided for social security purposes. METHODS: The study design was based on a philosophical conceptual analysis of objectivity and subjectivity, the phenomenological notions 'embodied subject', 'life-world', 'phenomenological object' and 'empathy', and an interpretation of certificates as texts. The study material consisted of 18 disability assessments from a total collection of 86 medical certificates provided for social security purposes, written in a Norwegian hospital-based mental health clinic. RESULTS: Four necessary conditions identified for defining a CCCO were: (A) acknowledging the patient's social context and life-world, (B) perceiving patients as cognitive objects providing a variety of meaningful data (clinical, psychometric, and behavioural data - i.e. activities and actions, meaningful expressions and self-reflection), (C) interpreting data in context, and (D) using general epistemological principles. The criteria corresponding to these conditions were: (a) describing the patient's social context and recognizing the patient's perspective, (b) taking into consideration a variety of quantitative and qualitative data drawn from the clinician's perceptions of the patient as embodied subject, (c) being aware of the need to interpret the data in context, and (d) applying epistemological principles (professional expertise, dialogical intersubjectivity, impartiality, accuracy and correctness). Genuine communication is presupposed. These criteria were tested in the work disability assessments of medical certificates. The criteria were useful for understanding both how objectivity fails during work disability assessments and how it can be improved in the writing of certificates. CONCLUSION: The article specifies four necessary conditions for the definition of a CCCO in health care and social security medicine and the corresponding criteria for its application. Analysis of the objectivity of work disability assessments in medical certificates for social security confirmed the usefulness of the criteria. PMID- 29499695 TI - MEKK1, JNK, and SMAD3 mediate CXCL12-stimulated connective tissue growth factor expression in human lung fibroblasts. AB - BACKGROUND: In idiopathic pulmonary fibrosis, the interaction of CXCL12 and CXC receptor 4 (CXCR4) plays a critical role in lung fibrosis. Connective tissue growth factor (CTGF) overexpression underlies the development of pulmonary fibrosis. Our previous report showed that the Rac1-dependent extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and activator protein (AP) 1 pathways are involved in CXCL12-generated CTGF expression in human lung fibroblasts (WI-38). In present study, we additionally inspected the involvement of mitogen-activated protein kinase kinase kinase 1 (MEKK1)/JNK-dependent SMAD3 in CXCL12-triggered CTGF expression in WI-38 cells. METHODS: WI-38 cells were stimulated with CXCL12 in the absence or presence of specific inhibitors or small interfering RNAs (siRNAs). CTGF expression and signaling transduction molecules were assessed by Western blot, luciferase activity assay, or ChIP assay. RESULTS: CXCL-12-induced CTGF expression was attenuated by SIS3 (a SMAD3 inhibitor) and SMAD3 siRNA, but not by SB431542 (an activin receptor-like kinase 5, ALK5, inhibitor). CXCL12-stimulated CTGF expression was also attenuated by MEKK1 siRNA. Treatment of cells with CXCL12 caused an increase in SMAD3 phosphorylation at Ser208, translocation to nuclei, SMAD3-luciferase activity, and recruitment of SMAD3 to the CTGF promoter. Stimulation of cells with CXCL12 resulted in increase in JNK phosphorylation at Thr183/Tyr185 and MEKK1 phosphorylation at Thr261. Moreover, CXCL12-mediated SMAD3 phosphorylation or SMAD3-luciferase activity was inhibited by MEKK1 siRNA or SP600125. Finally, CXCL12-mediated JNK phosphorylation was attenuated by MEKK1 siRNA. CONCLUSION: In conclusion, results of this study suggest that CXCL12 activates the MEKK1/JNK signaling pathway, which in turn initiates SMAD3 phosphorylation, its translocation to nuclei, and recruitment of SMAD3 to the CTGF promoter, which ultimately induces CTGF expression in human lung fibroblasts. PMID- 29499697 TI - Virulence gene profiles: alpha-hemolysin and clonal diversity in Staphylococcus aureus isolates from bovine clinical mastitis in China. AB - BACKGROUND: Staphylococcus aureus, a common cause of bovine mastitis, is known for its ability to acquire to antimicrobial resistance and to secrete numerous virulence factors that can exacerbate inflammation. In addition, alpha-hemolysin has an important role in S. aureus infections, diversity of the hla gene (that produces alpha-hmolysin) in S. aureus isolated from bovine mastitis has not been well characterized. The objective was, therefore, to determine diversity of virulence genes, hla gene sequences, and clonal profiles of S. aureus from bovine mastitis in Chinese dairy herds, and to evaluate inter-relationships. RESULTS: The antimicrobials resistance varies from as low as 1.9% (2/103) for CTX to as high as 76.7% (79/103) for penicilin in the 103 isolates and 46 (44.7%) S. aureus were determined as multi-resistant isolates with diverse resistance patterns. Thirty-eight virulence gene patterns (with variable frequencies) were identified in the 103 isolates and correlated with MLST types, indicating a great diversity. Although the hla gene also had great diversity (14 genotypes), Hla peptides were relatively more conserved. With 7 clonal complexes identified from 24 spa types and 7 MLST types. Regarding the letter, ST 97 was the dominant type in S. aureus from bovine mastitis in China. Furthermore, based on phylogenetic analysis, there was a distinct evolutionary relationship between the hla gene and MLST. CONCLUSION: Multi-resistant S. aureus occurred in bovine mastitis with diverse resistance patterns. The diversity of virulence gene profiles, especially the hla gene and, their relationship with molecular types were reported for the first time in S. aureus from bovine mastitis, which will be useful for future studies on immunogenicity and vaccine development. In addition, based on the distinct evolutionary relationship between the hla gene and MLST types, we inferred that the hla gene has potential role for molecular typing of S. aureus. PMID- 29499698 TI - Identification of priority health conditions for field-based screening in urban slums in Bangalore, India. AB - BACKGROUND: Urban slums are characterised by unique challenging living conditions, which increase their inhabitants' vulnerability to specific health conditions. The identification and prioritization of the key health issues occurring in these settings is essential for the development of programmes that aim to enhance the health of local slum communities effectively. As such, the present study sought to identify and prioritise the key health issues occurring in urban slums, with a focus on the perceptions of health professionals and community workers, in the rapidly growing city of Bangalore, India. METHODS: The study followed a two-phased mixed methods design. During Phase I of the study, a total of 60 health conditions belonging to four major categories: - 1) non communicable diseases; 2) infectious diseases; 3) maternal and women's reproductive health; and 4) child health - were identified through a systematic literature review and semi-structured interviews conducted with health professionals and other relevant stakeholders with experience working with urban slum communities in Bangalore. In Phase II, the health issues were prioritised based on four criteria through a consensus workshop conducted in Bangalore. RESULTS: The top health issues prioritized during the workshop were: diabetes and hypertension (non-communicable diseases category), dengue fever (infectious diseases category), malnutrition and anaemia (child health, and maternal and women's reproductive health categories). Diarrhoea was also selected as a top priority in children. These health issues were in line with national and international reports that listed them as top causes of mortality and major contributors to the burden of diseases in India. CONCLUSIONS: The results of this study will be used to inform the development of technologies and the design of interventions to improve the health outcomes of local communities. Identification of priority health issues in the slums of other regions of India, and in other low and lower middle-income countries, is recommended. PMID- 29499699 TI - LZTS2 promoter hypermethylation: a potential biomarker for the diagnosis and prognosis of laryngeal squamous cell carcinoma. AB - BACKGROUND: LZTS2 (leucine zipper tumor suppressor 2), a candidate tumor suppressor gene, suppresses cell growth and plays a vital role in the carcinogenesis and development of tumors. No studies to date have described methylation of the LZTS2 promoter in human cancers, including LSCC (laryngeal squamous cell carcinoma). Therefore, the aim of this study was to explore the relationship between LZTS2 promoter methylation and risk of LSCC. METHODS: In our study, LZTS2 promoter methylation levels in LSCC tumor and adjacent normal tissues from 96 patients were measured using quantitative methylation-specific polymerase chain reaction (qMSP) assays. RESULTS: The qMSP analyses revealed that LZTS2 promoter methylation levels in the LSCC tumor samples were significantly higher than those in paired adjacent healthy tissue samples. Furthermore, LZTS2 methylation levels were elevated in smokers, advanced T classified, and clinically staged patients, as well as in patients with lymph node metastases. In addition, Kaplan-Meier survival curves results showed that overall survival of LSCC patients with hypomethylated LZTS2 promoters was significantly higher than that in patients with hyper-methylated LZTS2 promoters (log-rank test P = 0.028). Meanwhile, the area under the receiver operating characteristic curve was 0.920. The diagnostic threshold value for LZTS2 methylation was 11.63% (94.7% sensitivity and 80.4% specificity). CONCLUSIONS: LZTS2 promoter hypermethylation is associated with risk, progression, and prognosis of LSCC in a cohort of 96 human subjects; LZTS2 promoter hypermethylation is a candidate diagnostic and prognostic biomarker for LSCC. PMID- 29499700 TI - Access to primary care and computed tomography use in the emergency department. AB - BACKGROUND: The decision to obtain a computed tomography CT scan in the emergency department (ED) is complex, including a consideration of the risk posed by the test itself weighed against the importance of obtaining the result. In patients with limited access to primary care follow up the consequences of not making a diagnosis may be greater than for patients with ready access to primary care, impacting diagnostic reasoning. We set out to determine if there is an association between CT utilization in the ED and patient access to primary care. METHODS: We performed a cross-sectional study of all ED visits in which a CT scan was obtained between 2003 and 2012 at an academic, tertiary-care center. Data were abstracted from the electronic medical record and administrative databases and included type of CT obtained, demographics, comorbidities, and access to a local primary care provider (PCP). CT utilization rates were determined per 1000 patients. RESULTS: A total of 595,895 ED visits, including 98,001 visits in which a CT was obtained (16.4%) were included. Patients with an assigned PCP accounted for 55% of all visits. Overall, CT use per 1000 ED visits increased from 142.0 in 2003 to 169.2 in 2012 (p < 0.001), while the number of annual ED visits remained stable. CT use per 1000 ED visits increased from 169.4 to 205.8 over the 10-year period for patients without a PCP and from 118.9 to 142.0 for patients with a PCP. Patients without a PCP were more likely to have a CT performed compared to those with a PCP (OR 1.57, 95%CI 1.54 to 1.58; p < 0.001). After adjusting for age, gender, year of visit and number of comorbidities, patients without a PCP were more likely to have a CT performed (OR 1.20, 95% CI 1.18 to 1.21, p < 0.001). CONCLUSIONS: The overall rate of CT utilization in the ED increased over the past 10 years. CT utilization was significantly higher among patients without a PCP. Increased availability of primary care, particularly for follow-up from the ED, could reduce CT utilization and therefore decrease costs, ED lengths of stay, and radiation exposure. PMID- 29499701 TI - Case report about a successful full robotic radical gastric cancer surgery with intracorporeal robot-sewn anastomosis in a patient with situs inversus totalis and a two-and-a-half-year follow-up study. AB - BACKGROUND: During the last decade, total laparoscopic and laparoscopic-assisted distal gastrectomy for gastric cancer patients has been developed as alternatives to open resection. In recent years, this minimally invasive surgery has been extended using robotic-assisted surgery. CASE PRESENTATION: Here, we report a surgical intervention using a Da Vinci surgical robot in which a lower two-third stomach resection with subsequent Billroth II gastrojejunostomy was performed. The patient was a 53-year-old male with complete situs inversus gastric cancer who had received 2 cycles of neo-adjuvant oxaliplatin combined with S-1 medication. The operation took 3 h in total without complications. The amount of bleeding was about 50 mL, and on day 5 after the operation, the patient was discharged. CONCLUSIONS: This is the first report of a successful robot-assisted gastric cancer resection of advanced gastric cancer in a patient with the anatomical abnormality of situs inversus totalis. PMID- 29499702 TI - Sustainability in Health care by Allocating Resources Effectively (SHARE) 8: developing, implementing and evaluating an evidence dissemination service in a local healthcare setting. AB - BACKGROUND: This is the eighth in a series of papers reporting Sustainability in Health care by Allocating Resources Effectively (SHARE) in a local healthcare setting. The SHARE Program was a systematic, integrated, evidence-based program for disinvestment within a large Australian health service. One of the aims was to explore methods to deliver existing high quality synthesised evidence directly to decision-makers to drive decision-making proactively. An Evidence Dissemination Service (EDS) was proposed. While this was conceived as a method to identify disinvestment opportunities, it became clear that it could also be a way to review all practices for consistency with current evidence. This paper reports the development, implementation and evaluation of two models of an in-house EDS. METHODS: Frameworks for development of complex interventions, implementation of evidence-based change, and evaluation and explication of processes and outcomes were adapted and/or applied. Mixed methods including a literature review, surveys, interviews, workshops, audits, document analysis and action research were used to capture barriers, enablers and local needs; identify effective strategies; develop and refine proposals; ascertain feedback and measure outcomes. RESULTS: Methods to identify, capture, classify, store, repackage, disseminate and facilitate use of synthesised research evidence were investigated. In Model 1, emails containing links to multiple publications were sent to all self-selected participants who were asked to determine whether they were the relevant decision-maker for any of the topics presented, whether change was required, and to take the relevant action. This voluntary framework did not achieve the aim of ensuring practice was consistent with current evidence. In Model 2, the need for change was established prior to dissemination, then a summary of the evidence was sent to the decision-maker responsible for practice in the relevant area who was required to take appropriate action and report the outcome. This mandatory governance framework was successful. The factors influencing decisions, processes and outcomes were identified. CONCLUSION: An in house EDS holds promise as a method of identifying disinvestment opportunities and/or reviewing local practice for consistency with current evidence. The resource-intensive nature of delivery of the EDS is a potential barrier. The findings from this study will inform further exploration. PMID- 29499703 TI - Community mobilization and maternal Care of Women Living with HIV in poor settings: the case of Mfuwe, Zambia. AB - BACKGROUND: Research has shown that community mobilization is a useful strategy in promoting maternal care of HIV negative women in resource poor settings; however, similar evidence for women living with HIV is missing. Therefore, in this study we provide this evidence by exploring the relevance of community mobilization in the promotion of maternal health care among women living with HIV in resource-poor settings by using Mfuwe, a rural district in Zambia as a case study. METHODS: By relying on Focus Group Discussions (FGDs), qualitative data were collected from Mfuwe, Zambia. The data were digitally recorded, transcribed and later translated from CheChewa (local language) to English. We relied on Thematic analysis to analyze the data. RESULTS: By focusing on community mobilization, our results showed that within their social fabrics, resource-poor communities often contain unrecognized and sometimes ignored strategies which are contextually-feasible and have been used for generations to promote maternal care for HIV positive women. Further, it was evident that although the three forms of community mobilization were largely and uniquely useful in promoting maternal health care of women living with HIV, they also presented unique and various shortcomings. CONCLUSION: We demonstrated that community mobilization was largely and often characterized as a force for good (e.g. providing support, improving access to maternal care etc.) and sometimes for bad (e.g. reinforced harmful misconceptions, superstition and stigma). Thus we recommend that community mobilization needs to be factored into maternal health care policies for HIV positive women in resource poor settings either to optimize their potential benefits or to minimize their potential harm. PMID- 29499704 TI - HIV status disclosure to male partners among rural Nigerian women along the prevention of mother-to-child transmission of HIV cascade: a mixed methods study. AB - BACKGROUND: HIV status disclosure to male partners is important for optimal outcomes in the prevention of mother-to-child transmission of HIV (PMTCT). Depending on timing of HIV diagnosis or pregnancy status, readiness to disclose and disclosure rates may differ among HIV-positive women. We sought to determine rates, patterns, and experiences of disclosure among Nigerian women along the PMTCT cascade. METHODS: HIV-positive women in rural North-Central Nigeria were purposively recruited according to their PMTCT cascade status: pregnant-newly HIV diagnosed, pregnant-in care, postpartum, and lost-to-follow-up (LTFU). Participants were surveyed to determine rates of disclosure to male partners and others; in-depth interviews evaluated disclosure patterns and experiences. Tests of association were applied to quantitative data. Qualitative data were manually analysed by theme and content using the constant comparative method in a Grounded Theory approach. RESULTS: We interviewed 100 women; 69% were 21-30 years old, and 86% were married. There were 25, 26, 28 and 21 women in the newly-diagnosed, in care, postpartum, and LTFU groups, respectively. Approximately 81% of all participants reported disclosing to anyone; however, family members were typically disclosed to first. Ultimately, more women had disclosed to male partners (85%) than to family members (55%). Rates of disclosure to anyone varied between groups: newly-diagnosed and LTFU women had the lowest (56%) and highest (100%) rates, respectively (p = 0.001). However, family (p = 0.402) and male partner (p = 0.218) disclosure rates were similar between cascade groups. Across all cascade groups, fear of divorce and intimate partner violence deterred women from disclosing to male partners. However, participants reported that with assistance from healthcare workers, disclosure and post-disclosure experiences were mostly positive. CONCLUSION: In our study cohort, although disclosure to male partners was overall higher, family members appeared more approachable for initial disclosure. Across cascade groups, male partners were ultimately disclosed to at rates > 75%, with no significant inter-group differences. Fear appears to be a major reason for non-disclosure or delayed disclosure by women to male partners. Augmentation of healthcare workers' skills and involvement can mediate gender power differentials, minimize fear and shorten time to male partner disclosure among women living with HIV, regardless of their PMTCT cascade status. TRIAL REGISTRATION: Clinicaltrials.gov registration number NCT 01936753 , September 3, 2013 (retrospectively registered). PMID- 29499705 TI - PM2.5 promotes human bronchial smooth muscle cell migration via the sonic hedgehog signaling pathway. AB - BACKGROUND: The contribution of airway remodeling in chronic obstructive pulmonary disease (COPD) has been well documented, with airway smooth muscle cell proliferation and migration playing a role in the remodeling process. Here, we aimed to verify the effects of fine particulate matter (PM2.5) on human bronchial smooth muscle cell (HBSMC) migration and to explore the underlying signaling pathways. METHODS: HBSMC apoptosis, proliferation and migration were measured using flow cytometry, cell counting and transwell migration assays, respectively. The role of the hedgehog pathway in cell migration was assessed by western blotting to measure the expression of Sonic hedgehog (Shh), Gli1 and Snail. Furthermore, siRNA was used to knock down Gli1 or Snail expression. RESULTS: PM2.5 induced HBSMC apoptosis in a dose-dependent manner, although certain concentrations of PM2.5 did not induce HBSMC proliferation or apoptosis. Interestingly, cell migration was stimulated by PM2.5 doses far below those that induced apoptosis. Additional experiments revealed that these PM2.5 doses enhanced the expression of Shh, Gli1 and Snail in HBSMCs. Furthermore, PM2.5 induced cell migration and protein expression were enhanced by recombinant Shh and attenuated by cyclopamine. Similar results were obtained by knocking down Gli1 or Snail. CONCLUSIONS: These findings suggest that PM2.5, which may exert its effects through the Shh signaling pathway, is necessary for the migration of HBSMCs. These data define a novel role for PM2.5 in airway remodeling in COPD. PMID- 29499706 TI - Test-retest variability of left ventricular 4D flow cardiovascular magnetic resonance measurements in healthy subjects. AB - BACKGROUND: Quantification and visualisation of left ventricular (LV) blood flow is afforded by three-dimensional, time resolved phase contrast cardiovascular magnetic resonance (CMR 4D flow). However, few data exist upon the repeatability and variability of these parameters in a healthy population. We aimed to assess the repeatability and variability over time of LV 4D CMR flow measurements. METHODS: Forty five controls underwent CMR 4D flow data acquisition. Of these, 10 underwent a second scan within the same visit (scan-rescan), 25 returned for a second visit (interval scan; median interval 52 days, IQR 28-57 days). The LV-end diastolic volume (EDV) was divided into four flow components: 1) Direct flow: inflow that passes directly to ejection; 2) Retained inflow: inflow that enters and resides within the LV; 3) Delayed ejection flow: starts within the LV and is ejected and 4) Residual volume: blood that resides within the LV for > 2 cardiac cycles. Each flow components' volume was related to the EDV (volume-ratio). The kinetic energy at end-diastole (ED) was measured and divided by the components' volume. RESULTS: The dominant flow component in all 45 controls was the direct flow (volume ratio 38 +/- 4%) followed by the residual volume (30 +/- 4%), then delayed ejection flow (16 +/- 3%) and retained inflow (16 +/- 4%). The kinetic energy at ED for each component was direct flow (7.8 +/- 3.0 microJ/ml), retained inflow (4.1 +/- 2.0 microJ/ml), delayed ejection flow (6.3 +/- 2.3 microJ/ml) and the residual volume (1.2 +/- 0.5 microJ/ml). The coefficients of variation for the scan-rescan ranged from 2.5%-9.2% for the flow components' volume ratio and between 13.5%-17.7% for the kinetic energy. The interval scan results showed higher coefficients of variation with values from 6.2-16.1% for the flow components' volume ratio and 16.9-29.0% for the kinetic energy of the flow components. CONCLUSION: LV flow components' volume and their associated kinetic energy values are repeatable and stable within a population over time. However, the variability of these measurements in individuals over time is greater than can be attributed to sources of error in the data acquisition and analysis, suggesting that additional physiological factors may influence LV flow measurements. PMID- 29499707 TI - Translation efficiency of heterologous proteins is significantly affected by the genetic context of RBS sequences in engineered cyanobacterium Synechocystis sp. PCC 6803. AB - BACKGROUND: Photosynthetic cyanobacteria have been studied as potential host organisms for direct solar-driven production of different carbon-based chemicals from CO2 and water, as part of the development of sustainable future biotechnological applications. The engineering approaches, however, are still limited by the lack of comprehensive information on most optimal expression strategies and validated species-specific genetic elements which are essential for increasing the intricacy, predictability and efficiency of the systems. This study focused on the systematic evaluation of the key translational control elements, ribosome binding sites (RBS), in the cyanobacterial host Synechocystis sp. PCC 6803, with the objective of expanding the palette of tools for more rigorous engineering approaches. RESULTS: An expression system was established for the comparison of 13 selected RBS sequences in Synechocystis, using several alternative reporter proteins (sYFP2, codon-optimized GFPmut3 and ethylene forming enzyme) as quantitative indicators of the relative translation efficiencies. The set-up was shown to yield highly reproducible expression patterns in independent analytical series with low variation between biological replicates, thus allowing statistical comparison of the activities of the different RBSs in vivo. While the RBSs covered a relatively broad overall expression level range, the downstream gene sequence was demonstrated in a rigorous manner to have a clear impact on the resulting translational profiles. This was expected to reflect interfering sequence-specific mRNA-level interaction between the RBS and the coding region, yet correlation between potential secondary structure formation and observed translation levels could not be resolved with existing in silico prediction tools. CONCLUSIONS: The study expands our current understanding on the potential and limitations associated with the regulation of protein expression at translational level in engineered cyanobacteria. The acquired information can be used for selecting appropriate RBSs for optimizing over-expression constructs or multicistronic pathways in Synechocystis, while underlining the complications in predicting the activity due to gene-specific interactions which may reduce the translational efficiency for a given RBS-gene combination. Ultimately, the findings emphasize the need for additional characterized insulator sequence elements to decouple the interaction between the RBS and the coding region for future engineering approaches. PMID- 29499708 TI - Scoping literature review on the basic health benefit package and its determinant criteria. AB - BACKGROUND: There are various criteria and methods to develop Basic Health Benefit Package (BHBP) in world health systems. The present study aimed to extract criteria used in health systems in different countries around the world using scoping review method. METHODS: A systematic search was carried out in Cochrane Library, PubMed, Scopus, Science Direct, Web of Science, ProQuest, World Bank, World Health Organization, and Google databases between January and April 2016. Papers and reports were gathered according to selected keywords and were examined by two authors. Finally, the criteria were extracted from the selected papers. RESULTS: The primary search included 8876 papers. After studying the articles' titles, abstracts, and full texts, 9 articles and 14 reports were selected for final analysis. After the final analysis, 19 criteria were extracted. Due to diversity of criteria in terms of number and nature, they were divided into three categories. The categories included intervention-related criteria, disease-related criteria, and community-related criteria. The largest number of criteria belonged to the first category. Indeed, the most widely applied criteria included cost-effectiveness (20), effectiveness (19), budget impact (12), equity (12), and burden of disease (10). CONCLUSION: According to the results, different criteria were identified in terms of number and nature in developing BHBP in world health systems. It seems that certain criteria, such as cost-effectiveness, effectiveness, budget impact, burden of disease, equity, and necessity, that were most widely utilized in countries under study could be for designing BHBP with regard to social, cultural, and economic considerations. PMID- 29499709 TI - Selling my sheep to pay for medicines - household priorities and coping strategies in a setting without universal health coverage. AB - BACKGROUND: The first month of life is the period with the highest risk of dying. Despite knowledge of effective interventions, newborn mortality is high and utilization of health care services remains low in Ethiopia. In settings without universal health coverage, the economy of a household is vulnerable to illness, and out-of-pocket payments may limit families' opportunities to seek health care for newborns. In this paper we explore intra-household resource allocation, focusing on how families prioritize newborn health versus other household needs and their coping strategies for managing these priorities. METHODS: A qualitative study was conducted in 2015 in Butajira, Ethiopia, comprising observation, semi structured interviews, and focus group discussions with household members, health workers, and community members. Household members with hospitalized newborns or who had experienced neonatal death were primary informants. RESULTS: In this predominantly rural and poor district, households struggled to pay out-of-pocket for services such as admission, diagnostics, drugs, and transportation. When newborns fell ill, families made hard choices balancing concerns for newborn health and other household needs. The ability to seek care, obtain services, and follow medical advice depended on the social and economic assets of the household. It was common to borrow money from friends and family, or even to sell a sheep or the harvest, if necessary. In managing household priorities and high costs, families waited before seeking health care, or used cheaper traditional medicines. For poor families with no money or opportunity to borrow, it became impossible to follow medical advice or even seek care in the first place. This had fatal health consequences for the sick newborns. CONCLUSIONS: While improving neonatal health is prioritized at policy level in Ethiopia, poor households with sick neonates may prioritize differently. With limited money at hand and high direct health care costs, families balanced conflicting concerns to newborn health and family welfare. We argue that families should not be left in situations where they have to choose between survival of the newborn and economic ruin. Protection against out-of-pocket spending is key as Ethiopia moves towards universal health coverage. A necessary step is to provide prioritized newborn health care services free of charge. PMID- 29499710 TI - The Strengthening Exercises in Shoulder Impingement trial (The SExSI-trial) investigating the effectiveness of a simple add-on shoulder strengthening exercise programme in patients with long-lasting subacromial impingement syndrome: Study protocol for a pragmatic, assessor blinded, parallel-group, randomised, controlled trial. AB - BACKGROUND: Subacromial impingement syndrome (SIS) is a painful, and often long lasting, shoulder condition affecting patient function and quality of life. In a recent study, we observed major strength impairments in shoulder external rotation and abduction (~30%) in a population of patients with pronounced and long-lasting SIS. However, the current rehabilitation of such strength impairments may be inadequate, with novel rehabilitation programmes including exercise therapy only improving external rotation strength by 4-13%. As these previous studies are the basis of current practice, this suggests that the strengthening component could be inadequate in the rehabilitation of these patients, and it seems likely that more emphasis should be placed on intensifying this part of the rehabilitation. The purpose of this study is to investigate the effectiveness of a programme consisting of progressive home-based resistance training using an elastic band, aimed at improving shoulder external rotation and abduction strength, added to usual care and initiated shortly after diagnosis has been established. METHODS: A pragmatic randomised controlled superiority trial will be conducted, including 200 patients with pronounced and long-lasting SIS, diagnosed using predefined criteria. Participants will be randomised to receive either an add-on intervention of progressive home-based resistance training using an elastic band in addition to usual care or usual care alone in a 1:1 allocation ratio. The randomisation sequence is computer generated, with permuted blocks of random sizes. The primary outcome will be change in Shoulder Pain And Disability Index (SPADI) score from baseline to 16 weeks follow-up. Outcome assessors are blinded to group allocation. Intervention receivers will be kept blind to treatment allocation through minimal information about the content of the add-on intervention and control condition until group allocation is final. Analyses are performed by blinded data analysts. DISCUSSION: If effective, the simple shoulder strengthening exercise programme investigated in this trial could easily be added to usual care. The usefulness of the trial is further supported by the magnitude of the problem, the information gained from the study and the pragmatism, patient centeredness and transparency of the trial. TRIAL REGISTRATION: The trial is pre registered at ClinicalTrials.gov with the ID NCT02747251 on April 19, 2016. PMID- 29499711 TI - Estimation of French cattle herd immunity against bluetongue serotype 8 at the time of its re-emergence in 2015. AB - BACKGROUND: From 2006 to 2010, France experienced two bluetongue epidemics caused by serotype 1 (BTV-1) and 8 (BTV-8) which were controlled by mass vaccination campaigns. After five years without any detected cases, a sick ram was confirmed in August 2015 to be infected by a BTV-8 strain almost identical to that circulating during the previous outbreak. By then, part of the French cattle population was expected to be still protected, since bluetongue antibodies are known to last for many years after natural infection or vaccination. The objective of this study was to estimate the proportion of cattle in France still immune to BTV-8 at the time of its re-emergence in 2015. RESULTS: We used BTV group-specific cELISA results from 8525 cattle born before the vaccination ban in 2013 and 15,799 cattle born after the ban. Samples were collected from January to April 2016 to estimate seroprevalence per birth cohort. The overall seroprevalence in cattle at national and local levels was extrapolated from seroprevalence results per birth cohort and their respective proportion at each level. To indirectly assess pre-immune status of birth cohorts, we computed prevalence per birth cohort on infected farms in autumn 2015 using 1377 RT-PCR results. These revealed limited BTV circulation in 2015. Seroprevalence per birth cohort was likely to be connected to past exposure to natural infection and/or vaccination with higher seroprevalence levels in older animals. A seroprevalence of 95% was observed for animals born before 2008, of which > 90% were exposed to two compulsory vaccination campaigns in 2008-2010. None of the animals born before 2008 were found to be infected, unlike 19% of the young cattle which had never been vaccinated. This suggests that most ELISA-positive animals were pre immune to BTV-8. We estimated that 18% (from 12% to 32% per departement) of the French cattle population was probably pre-immune in 2015. CONCLUSIONS: These results strongly suggest a persistence of antibodies for at least 5-6 years after natural infection or vaccination. The herd immunity of the French cattle population probably limited BTV circulation up to 2015, by which time more than 80% of cattle were naive. PMID- 29499712 TI - Pilot testing of the spring operated wearable enhancer for arm rehabilitation (SpringWear). AB - BACKGROUND: Robotic devices for neurorehabilitation of movement impairments in persons with stroke have been studied extensively. However, the vast majority of these devices only allow practice of stereotyped components of simulated functional tasks in the clinic. Previously we developed SpringWear, a wearable, spring operated, upper extremity exoskeleton capable of assisting movements during real-life functional activities, potentially in the home. SpringWear assists shoulder flexion, elbow extension and forearm supination/pronation. The assistance profiles were designed to approximate the torque required to move the joint passively through its range. These three assisted DOF are combined with two passive shoulder DOF, allowing complex multi-joint movement patterns. METHODS: We performed a cross-sectional study to assess changes in movement patterns when assisted by SpringWear. Thirteen persons with chronic stroke performed range of motion (ROM) and functional tasks, including pick and place tasks with various objects. Sensors on the device measured rotation at all 5 DOF and a kinematic model calculated position of the wrist relative to the shoulder. Within subject t tests were used to determine changes with assistance from SpringWear. RESULTS: Maximum shoulder flexion, elbow extension and forearm pronation/supination angles increased significantly during both ROM and functional tasks (p < 0.002). Elbow flexion/extension ROM also increased significantly (p < 0.001). When the subjects volitionally held up the arm against gravity, extension at the index finger proximal interphalangeal joint increased significantly (p = 0.033) when assisted by SpringWear. The forward reach workspace increased 19% (p = 0.002). Nine subjects could not complete the functional tasks unassisted and only one showed improvement on task completion with SpringWear. CONCLUSIONS: SpringWear increased the usable workspace during reaching movements, but there was no consistent improvement in the ability to complete functional tasks. Assistance levels at the shoulder were increased only until the shoulder could be voluntarily held at 90 degrees of flexion. A higher level of assistance may have yielded better results. Also combining SpringWear with HandSOME, an exoskeleton for assisting hand opening, may yield the most dramatic improvements in functional task performance. These low-cost devices can potentially reduce effort and improve performance during task practice, increasing adherence to home training programs for rehabilitation. PMID- 29499713 TI - Efficient targeted tumor imaging and secreted endostatin gene delivery by anti CD105 immunoliposomes. AB - BACKGROUND: Anti-CD105 mAb-conjugated immunoliposomes, loaded with secreted mouse endostatin gene, were developed for targeted tumor imaging and antiangiogenic gene therapy. METHODS: The liposomes were investigated for size, zeta-potential, lipid content, antibody binding ability, and pcDNA loading capacity. The ability of immunoliposomes to target tumor-derived endothelial cells and perform gene transfer in vitro was measured and their basic biocompatibility was evaluated. A nude mouse/breast cancer xenograft model was used to examine the tumor internalization of fluorescent-labeled liposomes and the clinical potential of immnuoliposomes loaded with pcDNA3.1-CSF1-endostatin. RESULTS: Loaded immunoliposomes were homogenously distributed with a well-defined spherical shape and bilayer, diameter of 122 +/- 11 nm, and zeta potential + 1.40 mV. No significant differences were observed in body weight, liver index, oxidative stress, or liver and kidney function in mice after liposomes exposure. The addition of CD105 mAb to liposomes conferred the ability to target tumor-derived endothelial cells in vitro and in vivo. Systemic intravenous administration of fluorescent immunoliposomes in the xenograft model resulted in selective and efficient internalization in tumor vasculature. Treatment of mice with pcDNA3.1 CSF1-endostatin-loaded immunoliposomes suppressed tumor growth by 71%. CONCLUSIONS: These data demonstrate the advantages of using anti-CD105 mAb conjugated immunoliposomes to enhance tumor targeting, imaging, and gene transfer applications. PMID- 29499714 TI - Updated and standardized genome-scale reconstruction of Mycobacterium tuberculosis H37Rv, iEK1011, simulates flux states indicative of physiological conditions. AB - BACKGROUND: The efficacy of antibiotics against M. tuberculosis has been shown to be influenced by experimental media conditions. Investigations of M. tuberculosis growth in physiological conditions have described an environment that is different from common in vitro media. Thus, elucidating the interplay between available nutrient sources and antibiotic efficacy has clear medical relevance. While genome-scale reconstructions of M. tuberculosis have enabled the ability to interrogate media differences for the past 10 years, recent reconstructions have diverged from each other without standardization. A unified reconstruction of M. tuberculosis H37Rv would elucidate the impact of different nutrient conditions on antibiotic efficacy and provide new insights for therapeutic intervention. RESULTS: We present a new genome-scale model of M. tuberculosis H37Rv, named iEK1011, that unifies and updates previous M. tuberculosis H37Rv genome-scale reconstructions. We functionally assess iEK1011 against previous models and show that the model increases correct gene essentiality predictions on two different experimental datasets by 6% (53% to 60%) and 18% (60% to 71%), respectively. We compared simulations between in vitro and approximated in vivo media conditions to examine the predictive capabilities of iEK1011. The simulated differences recapitulated literature defined characteristics in the rewiring of TCA metabolism including succinate secretion, gluconeogenesis, and activation of both the glyoxylate shunt and the methylcitrate cycle. To assist efforts to elucidate mechanisms of antibiotic resistance development, we curated 16 metabolic genes related to antimicrobial resistance and approximated evolutionary drivers of resistance. Comparing simulations of these antibiotic resistance features between in vivo and in vitro media highlighted condition-dependent differences that may influence the efficacy of antibiotics. CONCLUSIONS: iEK1011 provides a computational knowledge base for exploring the impact of different environmental conditions on the metabolic state of M. tuberculosis H37Rv. As more experimental data and knowledge of M. tuberculosis H37Rv become available, a unified and standardized M. tuberculosis model will prove to be a valuable resource to the research community studying the systems biology of M. tuberculosis. PMID- 29499715 TI - Comparison of a twin interlocking derotation and compression screw cephalomedullary nail (InterTAN) with a single screw derotation cephalomedullary nail (proximal femoral nail antirotation): a systematic review and meta-analysis for intertrochanteric fractures. AB - BACKGROUND: Intertrochanteric hip fractures are common and devastating injuries especially for the elderly. Surgical treatment is the optimal strategy for managing intertrochanteric fractures as it allows early rehabilitation and functional recovery. The relative effects of internal fixation strategies for intertrochanteric fracture after operation remain limited to relatively small studies which create uncertainty in attempts to establish evidence-based best practice. METHODS: We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) and observational studies to assess the clinical effectiveness of two commonly used intramedullary devices: a twin screw integrated cephalomedullary nail (InterTAN) versus a single screw cephalomedullary nail (proximal femoral nail antirotation) in patients with intertrochanteric fractures. The following outcomes were considered: revisions, implant-related failures, non-unions, pain, Harris Hip Score and intraoperative outcomes. Odds ratios or mean differences with 95% confidence intervals in brackets are reported. RESULTS: Six studies met the inclusion criteria, two randomised controlled trials and four observational studies enrolling 970 patients with mean age of 77 years, and 64% of patients were female. There was a statistically significant difference (p value < 0.05) for revisions OR 0.27 (0.13 to 0.56), implant-related failures OR 0.16 (0.09 to 0.27) and proportion of patients complaining of pain OR 0.50 (0.34 to 0.74). There was no difference in non-unions and Harris Hip Score (p value > 0.05). There was a significant difference in blood loss and fluoroscopy usage in favour of PFNA, whilst no difference in operating times were observed between the two devices. CONCLUSIONS: Our meta-analysis suggests that a twin screw integrated cephalomedullary nail InterTAN is clinically more effective when compared to a single screw cephalomedullary nail proximal femoral nail antirotation resulting in fewer complications, fewer revisions and fewer patients complaining of pain. No difference has been established regarding non-unions and Harris Hip Score. Intraoperative outcomes favour PFNA with less blood loss and fluoroscopy usage. Further studies are warranted to explore the cost-effectiveness of these and other implants in managing patients with intertrochanteric fractures. PMID- 29499716 TI - Improving usability and pregnancy rates of a fertility monitor by an additional mobile application: results of a retrospective efficacy study of Daysy and DaysyView app. AB - BACKGROUND: Daysy is a fertility monitor that uses the fertility awareness method by tracking and analyzing the individual menstrual cycle. In addition, Daysy can be connected to the application DaysyView to transfer stored personal data from Daysy to a smartphone or tablet (IOS, Android). This combination is interesting because as it is shown in various studies, the use of apps is increasing patients' focus on their disease or their health behavior. The aim of this study was to investigate if by the additional use of an App and thereby improved usability of the medical device, it is possible to enhance the typical-use related as well as the method-related pregnancy rates. RESULT: In the resultant group of 125 women (2076 cycles in total), 2 women indicated that they had been unintentionally pregnant during the use of the device, giving a typical-use related Pearl-Index of 1.3. Counting only the pregnancies which occurred as a result of unprotected intercourse during the infertile (green) phase, we found 1 pregnancy, giving a method-related Pearl-Index of 0.6. Calculating the pregnancy rate resulting from continuous use and unprotected intercourse exclusively on green days, gives a perfect-use Pearl-Index of 0.8. CONCLUSION: It seems that combining a specific biosensor-embedded device (Daysy), which gives the method a very high repeatable accuracy, and a mobile application (DaysyView) which leads to higher user engagement, results in higher overall usability of the method. PMID- 29499717 TI - Factors driving metabolic diversity in the budding yeast subphylum. AB - BACKGROUND: Associations between traits are prevalent in nature, occurring across a diverse range of taxa and traits. Individual traits may co-evolve with one other, and these correlations can be driven by factors intrinsic or extrinsic to an organism. However, few studies, especially in microbes, have simultaneously investigated both across a broad taxonomic range. Here we quantify pairwise associations among 48 traits across 784 diverse yeast species of the ancient budding yeast subphylum Saccharomycotina, assessing the effects of phylogenetic history, genetics, and ecology. RESULTS: We find extensive negative (traits that tend to not occur together) and positive (traits that tend to co-occur) pairwise associations among traits, as well as between traits and environments. These associations can largely be explained by the biological properties of the traits, such as overlapping biochemical pathways. The isolation environments of the yeasts explain a minor but significant component of the variance, while phylogeny (the retention of ancestral traits in descendant species) plays an even more limited role. Positive correlations are pervasive among carbon utilization traits and track with chemical structures (e.g., glucosides and sugar alcohols) and metabolic pathways, suggesting a molecular basis for the presence of suites of traits. In several cases, characterized genes from model organisms suggest that enzyme promiscuity and overlapping biochemical pathways are likely mechanisms to explain these macroevolutionary trends. Interestingly, fermentation traits are negatively correlated with the utilization of pentose sugars, which are major components of the plant biomass degraded by fungi and present major bottlenecks to the production of cellulosic biofuels. Finally, we show that mammalian pathogenic and commensal yeasts have a suite of traits that includes growth at high temperature and, surprisingly, the utilization of a narrowed panel of carbon sources. CONCLUSIONS: These results demonstrate how both intrinsic physiological factors and extrinsic ecological factors drive the distribution of traits present in diverse organisms across macroevolutionary timescales. PMID- 29499718 TI - Evaluation of the expression and clinical value of lncRNA AC010761.9 in human gastric adenocarcinoma. AB - BACKGROUND: The current study determined the expression and clinical value of lncRNA AC010761.9 in human gastric adenocarcinoma (GA). METHODS: Real-time quantitative reverse transcription (qRT)-PCR was used to detect the level of lncRNA expression in 145 GA tissues and three GA cell lines, and the correlation between its level and clinicopathologic characteristics and potential corresponding mRNA of TNF receptor-associated factor 4 gene (TRAF4) was then evaluated. RESULTS: Elevated lncRNA AC010761.9 was detected in all 6 GA tissues by previous lncRNA expression profile microarray assay. LncRNA AC010761.9 was over-expressed in 99 of 145 GA tissues (68.3%) with an elevated fold change of up to 35.14 compared to matched paracancerous tissues (p < 0.05), and was also over expressed in the 3 GA cell lines (MGC803, BGC823, and SGC7901) compared to the normal gastric mucosal epithelial cell line (GES-1 cells; p < 0.05) by qRT-PCR. The elevated expression of this lncRNA was related to tumor size (p = 0.028), degree of differentiation (p = 0.047), and serum carbohydrate antigen (CA19-9) and carcinoembryonic antigen (CEA) concentrations (p = 0.026 and p = 0.037, respectively). Multivariate analysis further confirmed that the expression of lncRNA AC010761.9 was related to the degree of tumor differentiation (p = 0.015). Additionally, the expression of lncRNA AC010761.9 had a positive correlation with the mRNA expression of the potentially associated gene (TRAF4) in GA tissues (r = 0.385, p < 0.01). CONCLUSIONS: LncRNA AC010761.9 may be linked to GA progression and is a potential new biomarker for GA. PMID- 29499719 TI - The effects of continuity of care on hospital utilization in patients with knee osteoarthritis: analysis of Nationwide insurance data. AB - BACKGROUND: Korea's rapidly aging population has led to a rise in the prevalence of knee osteoarthritis (which reached upwards of 21.3% in 2017) in elderly people aged 65 years and over. Most patients with knee osteoarthritis require ongoing management in the community or through primary care. Continuity of care is a desirable attribute of primary care. However, previous studies on the association between continuity of care and health outcomes have focused on specific disease populations, particularly diabetes mellitus and hypertension. The objectives of this study were to determine whether there is an association between continuity of care for outpatients with knee osteoarthritis and health outcomes. METHODS: We conducted a cohort study using claims data from 2014. The study population included 131,566 patients. We measured hospital admission and medical costs during the final 3 months and the continuity of care by Most Frequent Provider Continuity (MFPC), Modified Modified Continuity Index (MMCI), and Continuity of Care (COC) index in the 9 preceding months, using multiple logistic regression analyses to determine which index best explains continuity. We evaluated the relationship between COC and hospital admissions, using negative binomial regression analysis due to over-dispersion. Finally, multiple regressions were used to examine the relationship between the COC and medical costs. RESULTS: We selected the COC index to determine the association between hospital admission and cost; the area under the receiver operating characteristic curve (AUC) of the COC was the largest (0.904), while those for the MFPC (0.894) and MMCI (0.893) were similar. The negative binomial regression analysis showed that continuity of care was significantly related to hospitalization, with the relative risk (RR) of hospital admission being low for patients with high continuity of care [RR = 27.17 for those with the reference group COC (0.76-1.00); 95% CI, 3.09-3.51]. Continuity of care was significantly related to medical costs after considering other covariates. A higher COC index was associated with a lower cost. CONCLUSIONS: Higher continuity of care for knee osteoarthritis patients might decrease hospital admission and medical costs. PMID- 29499720 TI - The current insecticide resistance status of Anopheles gambiae (s.l.) (Culicidae) in rural and urban areas of Bouake, Cote d'Ivoire. AB - BACKGROUND: Several studies were carried out in experimental hut station in areas surrounding the city of Bouake, after the crisis in Cote d'Ivoire. They reported increasing resistance levels to insecticide for malaria transmiting mosquitoes. The present work aims to evaluate the current resistance level of An. gambiae (s.l.) in rural and urban areas in the city of Bouake. METHODS: Larvae of Anopheles gambiae (s.l.) were collected from five different study sites and reared to adult stages. The resistance status was assessed using the WHO bioassay test kits for adult mosquitoes, with eight insecticides belonging to pyrethroids, organochlorines, carbamates and organophosphates classes. Molecular assays were performed to identify the molecular forms of An. gambiae (s.l.), the L1014F kdr and the ace-1R alleles in individual mosquitoes. The synergist PBO was used to investigate the role of enzymes in resistance. Biochemical assays were performed to detect potential increased activities in mixed function oxidase (MFO) levels, non-specific esterases (NSE) and glutathione S-transferases (GST). RESULTS: High resistance levels to pyrethroids, organochlorines, and carbamates were observed in Anopheles gambiae (s.l.) from Bouake. Mortalities ranged between 0 and 73% for the eight tested insecticides. The pre-exposure to PBO restored full or partial susceptibility to pyrethroids in the different sites. The same trend was observed with the carbamates in five sites, but to a lesser extent. With DDT, pre-exposure to PBO did not increase the mortality rate of An. gambiae (s.l.) from the same sites. Tolerance to organophosphates was observed. An increased activity of NSE and higher level of MFO were found compared to the Kisumu susceptible reference strain. Two molecular forms, S form [(An. gambiae (s.s)] and M form (An. coluzzi) were identified. The kdr allele frequencies vary from 85.9 to 99.8% for An. gambiae (s.s.) and from 81.7 to 99.6% for An. coluzzii. The ace-1R frequencies vary between 25.6 and 38.8% for An. gambiae (s.s.) and from 28.6 to 36.7% for An. coluzzii. CONCLUSION: Resistance to insecticides is widespread within both An. gambiae (s.s.) and An. coluzzii. Two mechanisms of resistance, i.e. metabolic and target-site mutation seemed to largely explain the high resistance level of mosquitoes in Bouake. Pyrethroid resistance was found exclusively due to the metabolic mechanism. PMID- 29499721 TI - Novel t(1;2)(p36.1;q23) and t(7;19)(q32;q13.3) chromosomal translocations in ischemic fasciitis: expanding the spectrum of pseudosarcomatous lesions with clonal pathogenetic link. AB - BACKGROUND: Ischemic fasciitis is a distinctive pseudosarcomatous entity with a marked predilection for elderly and physically debilitated or immobilized patients. The etiology of these lesions is unknown but felt to be related to ischemic vascular events. CASE PRESENTATION: Herein, we report for the first time, two cytogenetic translocations, t(1;2)(p36.1;q23) and t(7;19)(q32;q13.3) in a 75 year-old ambulating female with a history of left total hip arthroplasty 20 years ago. CONCLUSION: These translocations suggest a possible clonal pathogenetic link though their significance remains to be established. PMID- 29499722 TI - CONTRACT Study - CONservative TReatment of Appendicitis in Children (feasibility): study protocol for a randomised controlled Trial. AB - BACKGROUND: Currently, the routine treatment for acute appendicitis in the United Kingdom is an appendicectomy. However, there is increasing scientific interest and research into non-operative treatment of appendicitis in adults and children. While a number of studies have investigated non-operative treatment of appendicitis in adults, this research cannot be applied to the paediatric population. Ultimately, we aim to perform a UK-based multicentre randomised controlled trial (RCT) to test the clinical and cost effectiveness of non operative treatment of acute uncomplicated appendicitis in children, as compared with appendicectomy. First, we will undertake a feasibility study to assess the feasibility of performing such a trial. METHODS/DESIGN: The study involves a feasibility RCT with a nested qualitative research to optimise recruitment as well as a health economic substudy. Children (aged 4-15 years inclusive) diagnosed with acute uncomplicated appendicitis that would normally be treated with an appendicectomy are eligible for the RCT. Exclusion criteria include clinical/radiological suspicion of perforated appendicitis, appendix mass or previous non-operative treatment of appendicitis. Participants will be randomised into one of two arms. Participants in the intervention arm are treated with antibiotics and regular clinical assessment to ensure clinical improvement. Participants in the control arm will receive appendicectomy. Randomisation will be minimised by age, sex, duration of symptoms and centre. Children and families who are approached for the RCT will be invited to participate in the embedded qualitative substudy, which includes recording of recruitment consultants and subsequent interviews with participants and non-participants and their families and recruiters. Analyses of these will inform interventions to optimise recruitment. The main study outcomes include recruitment rate (primary outcome), identification of strategies to optimise recruitment, performance of trial treatment pathways, clinical outcomes and safety of non-operative treatment. We have involved children, young people and parents in study design and delivery. DISCUSSION: In this study we will explore the feasibility of performing a full efficacy RCT comparing non-operative treatment with appendicectomy in children with acute uncomplicated appendicitis. Factors determining success of the present study include recruitment rate, safety of non-operative treatment and adequate interest in the future RCT. Ultimately this feasibility study will form the foundation of the main RCT and reinforce its design. TRIAL REGISTRATION: ISRCTN15830435 . Registered on 8 February 2017. PMID- 29499723 TI - Increases in inflammatory and CD14dim/CD16pos/CD45pos patrolling monocytes in sepsis: correlation with final outcome. AB - BACKGROUND: Evidence on the changes in the absolute counts of monocyte subpopulations in sepsis is missing. METHODS: Firstly, absolute counts of circulating CD14pos/HLA-DRpos/CD45pos monocytes were measured by flow cytometry in 70 patients with Gram-negative sepsis and in 10 healthy volunteers. In the second phase, immunophenotyping was performed and the absolute count of circulating inflammatory monocytes and of circulating CD14dim/CD16pos/CD45pos patrolling monocytes were measured in another 55 patients and 10 healthy volunteers. Measurements were repeated on days 3, 7, and 10. Results were correlated with survival after 28 days. RESULTS: Greater numbers of CD14pos/HLA DRpos/CD45pos monocytes were found on day 1 in survivors compared to nonsurvivors (p = 0.030). Receiver operating characteristic (ROC) analysis showed that a cutoff higher than 337 cells/mm3 on day 1 could discriminate between survivors and nonsurvivors with a positive predictive value (PPV) of 91.1%. Logistic regression including Sequential Organ Failure Assessment (SOFA) score and Acute Physiology and Chronic Health Evaluation (APACHE) II score showed that an absolute count greater than 337 cells/mm3 was independently associated with unfavorable outcome (odds ratio (OR) 0.19, p = 0.050). The absolute counts of inflammatory and of CD14dim/CD16pos/CD45pos monocytes were greater in patients than healthy controls during the entire 10 days of follow-up. The absolute counts on day 3 of CD14dim/CD16pos/CD45pos monocytes were greater in survivors than nonsurvivors (p = 0.027). ROC analysis revealed that the cutoff at 27 cells/mm3 could discriminate between survivors and nonsurvivors with PPV of 94.1%. Logistic regression including age, SOFA score, and APACHE II score showed that an absolute count greater than 27 cells/mm3 was independently associated with unfavorable outcome (OR 0.06, p = 0.033). Logistic regression analysis showed that intra abdominal infection on day 1 was predictive of low CD14dim/ CD16pos/CD45pos count on day 3. CONCLUSION: Circulating counts of inflammatory and patrolling monocytes are greatly increased in Gram-negative sepsis. Absolute counts of CD14pos/HLA DRpos/CD45pos monocytes on day 1 and CD14dim/CD16pos/CD45pos monocytes on day 3 are independently associated with final outcome. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01223690 . Registered retrospectively on 18 October 2010. PMID- 29499724 TI - IL28B gene polymorphism rs12979860, but not rs8099917, contributes to the occurrence of chronic HCV infection in Uruguayan patients. AB - BACKGROUND: Host single-nucleotide polymorphisms (SNPs) near the interleukin 28B (IL28B) locus are associated with sustained virological response to antiviral therapy and with spontaneous Hepatitis C Virus (HCV) clearance. Prevalence of these SNPs varies depending on ethnicity. The impact of IL28B SNPs in HCV infected patients is currently unknown in Uruguay. Therefore, the aim of this study was to evaluate and compare the distribution of polymorphisms in the IL28B gene (rs12979860 and rs8099917) among HCV-infected patients and healthy individuals in Uruguay and thus assess their possible association with the establishment of HCV infection. METHODS: DNA was recovered from 92 non-infected individuals and 78 HCV-infected patients and SNPs were determined by RFLP and allelic discrimination by real-time PCR. RESULTS: The distribution of rs12979860 genotypes for the infected population was 29.5%-CC, 47.4%-CT and 23.1%-TT and for the control group 45.7%, 42.4% and 11.9%, respectively. Prevalence in both infected and uninfected individuals is similar to that reported in other countries with admixed populations. The distribution of rs8099917 genotypes for the infected population was 57.7%-TT, 27.2%-TG and 14.1%-GG and for the control group 60.9%, 33.7% and 5.4%, respectively. The comparison of rs12979860 genotype distribution between the two populations evidenced a higher prevalence of the favourable genotype (CC) in the uninfected control group (p < 0.05). Additionally, results generated using logistic regression analysis show that individuals carrying rs12979860-TT or CT genotypes have a higher likelihood of developing chronic hepatitis upon infection with HCV, when compared to CC carriers, considering rs8099917 genotype as constant. CONCLUSION: Patients with HCV infection have a statistically significant lower prevalence of the favourable rs12979860 genotype when compared to uninfected individuals; therefore we can establish that only IL28B rs12979860-CT and TT genotypes seem to contribute to the occurrence of chronic HCV infection in the cohort of Uruguayan population studied. Considering that a trend towards a higher frequency of "good" response genotypes was observed in responder patients, we believe that IL28B rs12979860 genotyping could be a useful tool for predicting different therapies outcome, including in the DAA era. PMID- 29499725 TI - Laboratory investigation into the role of largemouth bass virus (Ranavirus, Iridoviridae) in smallmouth bass mortality events in Pennsylvania rivers. AB - BACKGROUND: Mortality episodes have affected young-of-year smallmouth bass (Micropterus dolomieu) in several river systems in Pennsylvania since 2005. A series of laboratory experiments were performed to determine the potential role of largemouth bass virus (Ranavirus, Iridoviridae) in causing these events. RESULTS: Juvenile smallmouth bass experimentally infected with the largemouth bass virus exhibited internal and external clinical signs and mortality consistent with those observed during die-offs. Microscopically, infected fish developed multifocal necrosis in the mesenteric fat, liver, spleen and kidneys. Fish challenged by immersion also developed severe ulcerative dermatitis and necrotizing myositis and rarely panuveitis and keratitis. Largemouth bass virus challenged smallmouth bass experienced greater mortality at 28 degrees C than at 23 or 11 degrees C. Co-infection with Flavobacterium columnare at 28 degrees C resulted in significant increase in mortality of smallmouth bass previously infected with largemouth bass virus. Aeromonas salmonicida seems to be very pathogenic to fish at water temperatures < 23 degrees C. While co-infection of smallmouth bass by both A. salmonicida and largemouth bass virus can be devastating to juvenile smallmouth bass, the optimal temperatures of each pathogen are 7-10 degrees C apart, making their synergistic effects highly unlikely under field conditions. CONCLUSIONS: The sum of our data generated in this study suggests that largemouth bass virus can be the causative agent of young-of-year smallmouth bass mortality episodes observed at relatively high water temperature. PMID- 29499726 TI - Varicella-zoster-virus vaccination in immunosuppressed children with rheumatic diseases using a pre-vaccination check list. AB - BACKGROUND: The goal of this study was to apply the varicella zoster virus (VZV) vaccine to patients with pediatric rheumatic diseases (PRD) at risk for severe chickenpox, without interrupting their current immunosuppression, including biological agents, using an immunological-based pre-vaccination checklist to assure safety. A pre-vaccination checklist was implemented to ensure adequate immune competence prior to immunization. METHODS: This prospective study included seronegative patients (VZV-IgG <=200 mIU/ml) and patients who had previously received only a single dose of VZV vaccine. All vaccinees demonstrated clinically inactive PRD. Patients were categorized according to their actual treatment in low-intensity IS (LIIS) and high-intensity IS (HIIS) including biological therapy. The pre-vaccination checklist defined thresholds for the following basic laboratory tests: white blood cell count >=3000/mm3, lymphocytes >=1200/mm3, serum IgG >=500 mg/dl, IgM >=20 mg/dl, tetanus toxoid antibody >=0.1 IU/ml. In case of HIIS additional specifications included a CD4+ lymphocyte count >=200/mm3 and a positive T-cell function (via analyzable positive control of a standard tuberculosis interferon-gamma-release-assay (TB-IGRA) indicating mitogen-induced T cell proliferation). Patients who met the criteria of the pre-vaccination checklist received the first and/or second VZV vaccination. Immunologic response and side effects were monitored. RESULTS: Twenty-three patients were recruited of whom nine had already received one VZV immunization before initiating IS. All patients met the pre-vaccination checklist criteria despite ongoing IS. There was no overall difference in VZV-IgG levels when comparing the LIIS (n=9) and HIIS (n=14) groups. In total, 21 patients (91%) showed a positive vaccination response, after the first immunization the median VZV-IgG across all patients was 224 (59-1219) mIU/ml (median (range)), after booster immunization it increased to 882 (30-4685) mIU/ml. Two patients in the HIIS group failed to raise positive VZV IgG, despite booster immunization. All nine patients receiving only the second immunization on IS reached high titers of VZV-IgG >500 mIU/ml (1117 (513-4685) mIU/ml). There were no cases of rash or other vaccine-induced varicella disease symptoms and no evidence of PRD flare. CONCLUSIONS: VZV vaccination is safe and largely immunogenic in children with ongoing IS fulfilling an immunological based pre-vaccination checklist. This new approach is based on immunologic function rather than on type of medications. TRIAL REGISTRATION NUMBER: ISRCRTN trial registration number 21654693 , date of registration February 12, 2018, retrospectively registered. PMID- 29499727 TI - Distinct alterations of CD68+CD163+ M2-like macrophages and myeloid-derived suppressor cells in newly diagnosed primary immune thrombocytopenia with or without CR after high-dose dexamethasone treatment. AB - BACKGROUND: Although impaired myeloid-derived suppressor cells (MDSCs) recently have been studied in immune thrombocytopenia (ITP), another myeloid-derived cell population signified as M2 macrophages has not been investigated properly in ITP patients. In the present study, we intended to determine the features of circulating M2-like macrophages, to examine its relationship with MDSCs, and to explore their prognostic values in ITP. METHODS: Peripheral blood mononuclear cells from healthy controls and primary ITP patients were isolated to test the circulating M2-like macrophages and MDSCs. The circulating M2-like macrophage population defined as CD68+CD163+ and circulating MDSC population as CD11b+CD33+HLA-DR- were determined by flow cytometry. Plasma inflammatory cytokines were measured by multiplex ELISA. RESULTS: The percentages of MDSCs were found to be expanded in newly diagnosed patients of ITP, especially among those of the complete response (CR) group (p < 0.0001). Positive linear correlation was verified between percentages of M2-like macrophages and MDSCs. The same correlation was also determined in the CR group. After treatment, the percentages of M2-like macrophages and MDSCs were both increased significantly in CR group, while those patients among the PR + NR group manifested a significant numeric decrease of MDSCs but only a moderate decrease in M2-like macrophages. MIP-1alpha/CCL3 was negatively correlated with M2-like macrophages while MCP-1 possessed a positive correlation with M2-like macrophages, eotaxin-1/CCL11 was negatively correlated with MDSCs and interleukin-1beta (IL-1beta) was found to be negatively correlated with both M2-like macrophages and MDSCs. CONCLUSIONS: The present findings indicated critical roles of both circulating M2-like macrophages and MDSCs in ITP. The positive correlation between them might be related to inflammatory factors-mediated bidirectional interactions or partially due to their similar background patterns during differentiation. MIP-1alpha/CCL3, MCP-1, eotaxin-1/CCL11 and IL-1beta might play a critical role in the expansion of both M2 macrophages and MDSCs population in ITP patients, which deserves further investigation. PMID- 29499728 TI - The effect of a six-week osteopathic visceral manipulation in patients with non specific chronic low back pain and functional constipation: study protocol for a randomized controlled trial. AB - BACKGROUND: The aim of the proposed study is to analyze the effect of a six-week osteopathic visceral manipulation (OVM) program on the flexion-relaxation phenomenon in individuals with non-specific chronic low back pain (LBP) and functional constipation. METHODS/DESIGN: An assessor-blinded, two-arm, randomized, placebo-controlled trial will be conducted. The sample will comprise 76 individuals with non-specific chronic LBP who have functional intestinal constipation, aged 18-65 years. The participants will be randomly allocated to two groups: (1) OVM and (2) sham OVM (SOVM). Evaluations will involve an interview, the Oswestry Disability Index, Fear-Avoidance Beliefs Questionnaire, functional constipation according to Rome III criteria, Biering-Sorensen test to normalize electromyographic (EMG) data, T12-L1 paraspinal level of the EMG signal during the flexion-relaxation phenomenon, 11-point numeric pain rating scale and fingertip-to-floor test. OVM and SOVM will be performed once per week for six weeks. Group 1 will receive OVM for 15 min and Group 2 will receive a sham visceral technique. Evaluations will be performed before and after the first session, after six weeks of treatment, and three months after randomization (follow-up). The findings will be analyzed statistically considering a 5% significance level (p <= 0.05). The limitation of the study is that the therapist will not be blinded. DISCUSSION: This will be the first trial to analyze the clinical response and electromyographic signals during the flexion-relaxation phenomenon after OVM. TRIAL REGISTRATION: Brazilian Clinical Trial Registry, RBR 7sx8j3 . Registered on 26 October 2017. PMID- 29499729 TI - Feasibility, safety, and utility of bronchoscopy in patients with ARDS while in the prone position. PMID- 29499731 TI - Correction to: Achilles tenodesis for calcaneal insufficiency avulsion fractures associated with diabetes mellitus. AB - The original publication of this article [1] contained the wrong versions of tables 1, 2 and 3. In this correction the updated tables are published. The original publication has been updated. PMID- 29499730 TI - Outcome after PSMA PET/CT based radiotherapy in patients with biochemical persistence or recurrence after radical prostatectomy. AB - BACKGROUND: PSMA PET/CT visualises prostate cancer residual disease or recurrence at lower PSA levels compared to conventional imaging and results in a change of treatment in a remarkable high number of patients. Radiotherapy with dose escalation to the former prostate bed has been associated with improved biochemical recurrence-free survival. Thus, it can be hypothesised that PSMA PET/CT-based radiotherapy might improve the prognosis of these patients. METHODS: One hundred twenty-nine patients underwent PSMA PET/CT due to biochemical persistence (52%) or recurrence (48%) after radical prostatectomy without evidence of distant metastases (February 2014-May 2017) and received PSMA PET/CT based radiotherapy. Biochemical recurrence free survival (PSA <= 0.2 ng/ml) was defined as the study endpoint. RESULTS: Patients with biochemical persistence were significantly more often high-risk patients with significantly shorter time interval before PSMA PET/CT than patients with biochemical recurrence. Patients with biochemical recurrence had significantly more often no evidence of disease or local recurrence only in PSMA PET/CT, whereas patients with biochemical persistence had significantly more often lymph node involvement. Seventy-three patients were started on antiandrogen therapy prior to radiotherapy due to macroscopic disease in PSMA PET/CT. Cumulatively, 70 (66-70.6) Gy was delivered to local macroscopic tumor, 66 (63-66) Gy to the prostate fossa, 61.6 (53.2-66) Gy to PET-positive lymph nodes and 50.4 (45-52.3) Gy to lymphatic pathways. Median PSA after radiotherapy was 0.07 ng/ml with 74% of patients having a PSA <= 0.1 ng/ml. After a median follow-up of 20 months, median PSA was 0.07 ng/ml with ongoing antiandrogen therapy in 30 patients. PET-positive patients without antiandrogen therapy at last follow-up (45 patients) had a median PSA of 0.05 ng/ml with 89% of all patients, 94% of patients with biochemical recurrence and 82% of patients with biochemical persistence having a PSA <= 0.2 ng/ml. Post radiotherapy PSA <= 0.1 ng/ml and biochemical recurrence vs. persistence were significantly associated with a PSA <= 0.2 ng/ml at last follow-up. CONCLUSIONS: PSMA PET/CT-based radiotherapy is an effective local salvage treatment option with significant PSA response in patients with biochemical recurrence or persistence after radical prostatectomy leading to deferral of long-term ADT or systemic therapy. PMID- 29499732 TI - Evaluation of the anti-feeding and insecticidal effects of a topically administered combination of imidacloprid and permethrin (Advantix(r)) against Phlebotomus (Larroussius) perniciosus (Newstead, 1911) in dogs following monthly administration. AB - BACKGROUND: Two laboratory experiments (Studies 1 and 2) were conducted to confirm the efficacy of an imidacloprid and permethrin combination (Advantix(r) Spot-on, Bayer) to repel and kill Phlebotomus (Larroussius) perniciosus sand flies when applied once a month topically to dogs. METHODS: Both studies compared dogs treated with a combination containing 100 mg/ml imidacloprid + 500 mg/ml permethrin (Advantix(r) Spot-on, Bayer) to placebo treated dogs. The treatments were applied topically on Day -28 (Study 2) and Day 0 (Studies 1 and 2). Sand fly exposures with 80 unfed females were performed before the first treatment for allocation purposes and post-treatment on study days (SDs) 1, 7, 14, 21 and 28 (following first or second monthly treatment for Studies 1 and 2, respectively). After 60 min, sand flies were assessed for mortality and engorgement status. RESULTS: Repellent evaluation (anti-feeding effect) on all days post-infestation showed efficacies that ranged between 88.1-99.3% during the first month and 92.2 98.9% during the second. Analyses of the comparison of fed sand fly counts for each treatment group resulted in a highly significant reduction (P < 0.0001) at all post-infestation time points for those dogs treated with Advantix(r). A significant (P < 0.0001 for all time points) insecticidal effect was equally demonstrated. No treatment related adverse events were observed during the study. CONCLUSIONS: In the present studies Advantix(r) Spot-on demonstrated to be safe and to provide excellent four-week sand fly (P. perniciosus) repellency of >=88.1% and >=92.2% after a first and second monthly treatment, respectively. A significant insecticidal effect was also observed. PMID- 29499733 TI - Primaquine-induced haemolysis in females heterozygous for G6PD deficiency. AB - Oxidative agents can cause acute haemolytic anaemia in persons with G6PD deficiency. Understanding the relationship between G6PD genotype and the phenotypic expression of the enzyme deficiency is necessary so that severe haemolysis can be avoided. The patterns of oxidative haemolysis have been well described in G6PD deficient hemizygous males and homozygous females; and haemolysis in the proportionally more numerous heterozygous females has been documented mainly following consumption of fava beans and more recently dapsone. It has long been known that 8-aminoquinolines, notably primaquine and tafenoquine, cause acute haemolysis in G6PD deficiency. To support wider use of primaquine in Plasmodium vivax elimination, more data are needed on the haemolytic consequences of 8-aminoquinolines in G6PD heterozygous females. Two recent studies (in 2017) have provided precisely such data; and the need has emerged for the development of point of care quantitative testing of G6PD activity. Another priority is exploring alternative 8-aminoquinoline dosing regimens that are practical and improve safety in G6PD deficient individuals. PMID- 29499734 TI - Comparison of two FDA-approved interspinous spacers for treatment of lumbar spinal stenosis: Superion versus X-STOP-a meta-analysis from five randomized controlled trial studies. AB - BACKGROUND: Decompressive laminectomy (DI) is a standard operation for lumbar spinal stenosis (LSS) patient with severe claudication symptoms for many years. However, patients whose symptom severity does not meet undergoing invasive surgery make therapeutic options into dilemma. Interspinous spacers (ISP) bridge the gap between surgical interventions and CC in management of LSS. In our study, we aim to systematically assess the two FDA-approved interspinous spacers for treatment of lumbar spinal stenosis: Superion versus X-STOP. METHODS: Electronic databases, including PubMed, Embase, MEDLINE, Cochrane Library were searched to retrieve clinical trials concerning the comparison between Superion and X-STOP in treatment for lumbar spinal stenosis before April 2017. The following outcome measures were extracted: (1) Zurich Claudication Questionnaire (ZCQ) patient satisfaction score, (2) axial pain severity, (3) extremity pain severity, (4) back-specific functional impairment, (5) reoperation, and (6) complication. The data analysis was conducted with Review Manager 5.3. RESULTS: Five randomized controlled trials (RCTs) with 1118 patients were included in this meta-analysis. The pooled analysis indicated that the Superion group is superior to X-STOP in axial pain severity (SMD: 0.03; 95% CI 0.15, 0.45; p < 0.0001, I2 = 41%, p = 0.16), ZCQ patient satisfaction score (SMD: 0.23; 95% CI 0.08, 0.38; p = 0.002, I2 = 0%, p = 0.61). However, Superion group showed similarity outcome in extremity pain severity (SMD: 0.18; 95% CI - 0.06, 0.43; p = 0.14, I2 = 62%, p = 0.05), back-specific functional impairment (SMD: 0.04; 95% CI - 0.10, 0.19; p = 0.56, I2 = 0%, p = 0.77), reoperation rate (RR: 1.10; 95% CI 0.82, 1.48; p = 0.51, I2 = 19%, p = 0.30), and complication (RR: 0.98; 95% CI 0.63, 1.53; p = 0.92, I2 = 0%, p = 0.83). CONCLUSION: Both the Superion and X-STOP interspinous spacers can relieve symptoms of LSS. In addition, the Superion spacer may represent a promising spacer for patient with LSS. As we know, the effectiveness and safety of ISP is still considered investigational and unfavor clinical results in the medical literature may continue to limit the appeal of IPS to many surgeons in the future. However, because of the advantage of IPS technique, it will win a wide place in the future degenerative lumbar microsurgery. PMID- 29499736 TI - Magnitude of institutional delivery service utilization and associated factors among women in pastoral community of Awash Fentale district Afar Regional State, Ethiopia. AB - OBJECTIVE: Reduction of maternal mortality is a global priority particularly in developing countries like Ethiopia where maternal mortality ratio is one of the highest in the world. Most deliveries in developing countries occur at home without skilled birth attendants. Therefore, the objective of this study was to assess institutional delivery service utilization and associated factors among women in pastoral community of Awash Fentale district, Ethiopia. RESULTS: Overall, 35.2% of women delivered at health facilities. Women who had good knowledge AOR = 2.1, 95% CI 1.32, 4.87), Ante Natal Care (ANC) follow up (AOR = 3.2, 95% CI 1.55, 6.63), resided in a place where distance to reach at the nearby health facilities takes < 30 min (AOR = 3.1; 95% CI 2.57, 66.33) and women whose husband involved in decision regarding delivery place (AOR = 1.9; 95% CI 1.49, 5.07) were more likely to deliver at health facility. Therefore, strengthening ANC services, improving maternal knowledge, involving husbands in decision of delivery place and expanding health facilities in the community would enhance institutional delivery. PMID- 29499735 TI - Bacterial microbiota of Aedes aegypti mosquito larvae is altered by intoxication with Bacillus thuringiensis israelensis. AB - BACKGROUND: Insect microbiota is a dynamic microbial community that can actively participate in defense against pathogens. Bacillus thuringiensis (Bt) is a natural entomopathogen widely used as a bioinsecticide for pest control. Although Bt's mode of action has been extensively studied, whether the presence of microbiota is mandatory for Bt to effectively kill the insect is still under debate. An association between a higher tolerance and a modified microbiota was already evidenced but a critical point remained to be solved: is the modified microbiota a cause or a consequence of a higher tolerance to Bt? METHODS: In this study we focused on the mosquito species Aedes aegypti, as no work has been performed on Diptera on this topic to date, and on B. thuringiensis israelensis (Bti), which is used worldwide for mosquito control. To avoid using antibiotics to cure bacterial microbiota, mosquito larvae were exposed to an hourly increasing dose of Bti during 25 hours to separate the most susceptible larvae dying quickly from more tolerant individuals, with longer survival. RESULTS: Denaturing gradient gel electrophoresis (DGGE) fingerprinting revealed that mosquito larval bacterial microbiota was strongly affected by Bti infection after only a few hours of exposure. Bacterial microbiota from the most tolerant larvae showed the lowest diversity but the highest inter-individual differences. The proportion of Bti in the host tissue was reduced in the most tolerant larvae as compared to the most susceptible ones, suggesting an active control of Bti infection by the host. CONCLUSIONS: Here we show that a modified microbiota is associated with a higher tolerance of mosquitoes to Bti, but that it is rather a consequence of Bti infection than the cause of the higher tolerance. This study paves the way to future investigations aiming at unraveling the role of host immunity, inter-species bacterial competition and kinetics of host colonization by Bti that could be at the basis of the phenotype observed in this study. PMID- 29499737 TI - Comparison of benign peritoneal fluid- and ovarian cancer ascites-derived extracellular vesicle RNA biomarkers. AB - BACKGROUND: Extracellular vesicles (EVs) are considered as a new class of resources for potential biomarkers. We analyzed expression of specific mRNA and miRNA in EVs derived from ovarian cancer ascites and the ideal controls, peritoneal fluids from benign patients for potential early detection and prognostic biomarkers. METHODS: Fluids were collected from subjects with benign cysts or endometrioma (n = 10), or low/high grade serous ovarian carcinoma (n = 8). EV particles were captured using primarily ExoComplete filterplate or ultracentrifugation and analyzed by nanoparticle tracking analysis, ELISA, and scanning electron microscopy. EV RNAs extracted from two ascites and three peritoneal fluids were submitted for next-generation sequencing. The expression of 34 mRNA and 18 miRNAs in the EVs isolated from patient fluids and cell line media was determined using qPCR. RESULTS: EVs isolated from patient samples had concentrations greater than 1010 EV particles/mL and 30% were EpCAM-positive based on ELISA. EV particle sizes averaged 113 +/- 11.5 nm. The qPCR studies identified five mRNA (CA11, MEDAG, LAMA4, SPINT2, NANOG) and six miRNA (let-7b, miR23b, miR29a, miR30d, miR205, miR720) that were significantly differentially expressed between cancer ascites and peritoneal fluids. In addition, CA11 mRNA was decreased to 0.5-fold and SPINT2 and NANOG mRNA were significantly increased up to 100-fold in conditioned media of cancer cells compared to immortalized ovarian surface and fallopian tube epithelial cell lines, the hypothesized cells of origin for ovarian cancer development. CONCLUSIONS: This study indicates that EV mRNA profiles can reflect the disease stage and may provide a potentially novel source for discovery of biomarkers in ovarian cancer. PMID- 29499738 TI - Personal wellbeing in posttraumatic stress disorder (PTSD): association with PTSD symptoms during and following treatment. AB - BACKGROUND: It remains unclear to what extent treatment-related gains in posttraumatic stress disorder (PTSD) symptoms translate to improvements in broader domains of personal wellbeing, such as community connectedness, life achievement and security. We sought to determine whether: 1. personal wellbeing improves during the course of a treatment program and 2. changes in core symptom domains (PTSD, anxiety and depression) were associated with improvements in overall personal wellbeing. METHODS: Participants (N = 124) completed the PTSD Checklist, the Depression and Anxiety Stress Scales and the Personal Wellbeing Index at the start and end of a 4-week Trauma Focused CBT residential program, as well as 3- and 9-months post-treatment. RESULTS: Personal wellbeing improved significantly across the 9-months of the study. Generalised estimating equations analyses indicated that (older) age and improvements in PTSD and depressive symptoms were independent predictors of personal wellbeing across time. CONCLUSIONS: Although personal wellbeing improved in tandem with PTSD symptoms, the magnitude of improvement was small. These findings highlight a need to better understand how improvements in personal wellbeing can be optimised following PTSD treatment. PMID- 29499739 TI - Isolated choanal and gut atresias: pathogenetic role of serine protease inhibitor type 2 (SPINT2) gene mutations unlikely. AB - BACKGROUND: Choanal (CA) and gastrointestinal atresias (GA) are an important feature of syndromic congenital sodium diarrhea (sCSD), a disorder recently associated with mutations in the gene for serine protease inhibitor type 2 (SPINT2). It is, however, not known whether isolated non-syndromic CA and GA themselves might result from SPINT2 mutations. METHODS: We performed a prospective cohort study to investigate 19 CA and/or GA patients without diarrhea ("non-sCSD") for potential sCSD characteristic clinical features and SPINT2 mutations. RESULTS: We found a heterozygous SPINT2 splice mutation (c.593-1G>A), previously demonstrated in sCSD in homozygous form, in only 1 of the 19 patients of the "non-sCSD" cohort. This patient presented with isolated anal atresia and borderline low laboratory parameters of sodium balance. In the remaining 18 non sCSD CA/GA patients investigated, SPINT2 sequence analysis and clinical markers of sodium homeostasis were normal. None of the 188 healthy controls tested in a regional Tyrolean population harbored the c.593-1G>A mutation, which is also not listed in the ExAc and gnomAD databases. CONCLUSIONS: The finding of only one heterozygous SPINT2 mutation in 19 patients with isolated CA/GA was not statistically significant. Therefore, SPINT2 mutations are an unlikely cause of non-sCSD atresia. Trial registration ISRCTN73824458. Retrospectively registered 28 September 2014. PMID- 29499740 TI - Mesenchymal stem cells in the treatment of Cesarean section skin scars: study protocol for a randomized, controlled trial. AB - BACKGROUND: Cesarean delivery has already become a very common method of delivery around the world, especially in low-income countries. Hypertrophic scars and wound infections have affected younger mothers and frustrated obstetricians for a long time. Mesenchymal stem cells (MSCs) have strong potential for self-renewal and differentiation to multilineage cells. Previous studies have demonstrated that MSCs are involved in enhancing diabetic wound healing. Therefore, this study is designed to investigate the safety and efficacy of using MSCs in the treatment of Cesarean section skin scars. METHODS: This trial is a prospective, randomized, double-blind, placebo-controlled, single-center trial with three parallel groups. Ninety eligible participants will be randomly allocated to placebo, low-dose (transdermal hydrogel MSCs; 3 * 106 cells) or high-dose (transdermal hydrogel MSCs; 6 * 106 cells) groups at a 1:1:1 allocation ratio according to a randomization list, once a day for six consecutive days. Study duration will last for 6 months, comprising a 1 week run-in period and 24 weeks of follow-up. The primary aim of this trial is to compare the difference in Vancouver Scar Scale rating among the three groups at the 6th month. Adverse events, including severe and slight signs or symptoms, will be documented in case report forms. The study will be conducted at the Department of Obstetric of Southern Medical University Affiliated Maternal & Child Health Hospital of Foshan. DISCUSSION: This trial is the first investigation of the potential for therapeutic use of MSCs for the management of women's skin scar after Cesarean delivery. The results will give us an effective therapeutic strategy to combat Cesarean section skin scars, even with uterine scarring. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02772289 . Registered on 10 May 2016. PMID- 29499741 TI - Does elasticity of Achilles tendon change after suture applications? Evaluation of repair area by acoustic radiation force impulse elastography. AB - BACKGROUND: Achilles tendon injuries are one of the most common tendon injuries. Surgical treatment is preferred in young and active patients. Although there are studies which evaluate the repair area with magnetic resonance imaging and ultrasonography after surgical treatment, there are very few studies which analyzes the elasticity of the tendon by quantitative methods. ARFI (acoustic radiation force impulse) elastography is a simple and non-invasive method that can quantitatively measure the elasticity of the soft tissues. Our study aims to evaluate the elasticity in the repair area of the surgically treated Achilles tendons, compare them to the non-injured side, and evaluate the effect of the suture method to the elasticity of the repaired tendons by using ARFI elastography. METHODS: In our retrospectively designed study, 19 patients who underwent surgical treatment with Krackow and modified Kessler suture methods after the Achilles tendon rupture between 2006 and 2014 were included. Shear wave velocity (SWV) of the repaired and non-injured Achilles tendons were measured by ARFI elastography in four different positions of the ankle. RESULTS: It was determined that SWV in the surgically repaired tendons were significantly higher in each four different position of the ankle, compared to the non-injured side (p < 0.01), indicating less elasticity in the repaired tendons. There was no statistically significant difference between the SWV of Krackow and modified Kessler suture method groups at four different positions of the ankle (p > 0.05). AOFAS Ankle-Hindfoot, VISA-A, VAS, and FAOS scores were not also statistically different between these two suture methods (p > 0.05). CONCLUSIONS: In the repaired Achilles tendon, there is a decrease in the elasticity compared to the non-injured side. The functional and elastographic results of Krackow and modified Kessler suture methods are similar in long-term follow-ups of the patients. PMID- 29499742 TI - Comparison of Wiltse's paraspinal approach and open book laminectomy for thoracolumbar burst fractures with greenstick lamina fractures: a randomized controlled trial. AB - BACKGROUND: Posterior short-segment pedicle screw fixation is used to treat thoracolumbar burst fractures. However, no randomized controlled studies have compared the efficacy of the two approaches--the Wiltse's paraspinal approach and open book laminectomy in the treatment of thoracolumbar burst fractures with greenstick lamina fractures. MATERIALS AND METHODS: Patients with burst fractures of the thoracolumbar spine without neurological deficit were randomized to receive either the Wiltse's paraspinal approach (group A, 24 patients) or open book laminectomy (group B, 23 patients). Patients were followed postoperatively for average of 27.4 months. Clinical and radiographic data of the two approaches were collected and compared. RESULTS: Our results showed the anterior segmental height, kyphotic angle, visual analog scale (VAS) score, and Smiley-Webster Scale (SWS) score significantly improved postoperatively in both groups, indicating that both the Wiltse's paraspinal approach and open book laminectomy can effectively treat thoracolumbar burst fractures with greenstick lamina fractures. The Wiltse's paraspinal approach was found to have significantly shorter operating time, less blood loss, and shorter length of hospital stay compared to open book laminectomy. However, there were two (2/24) patients in group A that had neurological deficits postoperatively and required a second exploratory operation. Dural tears and/or cauda equina entrapment were subsequently found in four patients in group B and all two patients of neurological deficits in group A during operation. No screw loosening, plate breakage, or other internal fixation failures were found at final follow-up. CONCLUSIONS: The results demonstrated that either of the two surgical approaches can achieve satisfactory results in treating thoracolumbar burst fractures in patients with greenstick lamina fractures. However, if there is any clinical or radiographic suspicion of a dural tear and/or cauda equina entrapment pre-operation, patients should receive an open book laminectomy to avoid a second exploratory operation. More research is still needed to optimize clinical decision-making regarding surgical approach. PMID- 29499743 TI - Rhipicephalus appendiculatus ticks transmit Theileria parva from persistently infected cattle in the absence of detectable parasitemia: implications for East Coast fever epidemiology. AB - BACKGROUND: East Coast fever (ECF) is a devastating disease of cattle and a significant constraint to improvement of livestock production in sub-Saharan Africa. The protozoan parasite causing ECF, Theileria parva, undergoes obligate sexual stage development in its tick vector Rhipicephalus appendiculatus. Tick borne acquisition and transmission occurs transstadially; larval and nymphal ticks acquire infection while feeding and transmit to cattle when they feed after molting to the next stage. Much of the current knowledge relating to tick-borne acquisition and transmission of T. parva has been derived from studies performed during acute infections where parasitemia is high. In contrast, tick-borne transmission during the low-level persistent infections characteristic of endemic transmission cycles is rarely studied. METHODS: Cattle were infected with one of two stocks of T. parva (Muguga or Marikebuni). Four months post-infection when parasites were no longer detectable in peripheral blood by PCR, 500 R. appendiculatus nymphs were fed to repletion on each of the cattle. After they molted to the adult stage, 20 or 200 ticks, respectively, were fed on two naive cattle for each of the parasite stocks. After adult ticks fed to repletion, cattle were tested for T. parva infection by nested PCR and dot blot hybridization. RESULTS: Once they had molted to adults the ticks that had fed as nymphs on Muguga and Marikebuni infected cattle successfully transmitted Theileria parva to all naive cattle, even though T. parva infection was not detectable by nested PCR on salivary gland genomic DNA of a sample of individual ticks. However, a salivary gland homogenate from a single Marikebuni infected tick was able to infect primary bovine lymphocytes. Infection was detected by nested p104 PCR in 3 of 4 calves and detected in all 4 calves by T. parva 18S nested PCR/dot blot hybridization. CONCLUSION: We show that R. appendiculatus ticks are able to acquire T. parva parasites from infected cattle even in the absence of detectable parasitemia. Although infection was undetectable in a sample of individual ticks, cumulatively as few as 20 ticks were able to transmit T. parva to naive cattle. These results have important implications for our understanding of T. parva transmission by R. appendiculatus in ECF endemic regions. PMID- 29499745 TI - Efficacy and safety of electroacupuncture for post stroke depression: study protocol for a randomized controlled trial. AB - BACKGROUND: Poststroke depression is closely related to increased mortality in stroke patients. Compared with antidepressants, electroacupuncture (EA) treatment for poststroke depression (PSD) has relatively more stable effectiveness and can reduce side effects. This trial is designed to provide solid evidence for the efficacy and safety of EA treatment for patients with PSD. METHODS/DESIGN: This ongoing study is a single-blind, single-center, parallel group, randomized controlled trial. Sixty-two participants will be recruited from Shanghai Shuguang Hospital and randomized into either the EA group or the sham EA group. Baihui, Sishencong, Ganshu, Sanyinjiao, and Taichong are selected as the treatment acupoints in both groups. The EA group will receive the traditional EA treatment with de-qi sensation, and the sham EA group will receive sham EA treatment without needle penetration and electrostimulation. Participants will receive treatment 3 times per week for a total of 12 sessions over 4 weeks. The primary outcome is Hamilton Rating Scale for Depression score, and the secondary outcomes are scores on the Zung Self-Rating Depression Scale, National Institutes of Health Stroke Scale, Barthel Index of Activities of Daily Living, and Depression Scale of traditional Chinese medicine. All of the outcome measures will be assessed at baseline, 2 weeks after EA treatment onset, 4 weeks after treatment onset, and at 8-week follow-up. Safety assessments will be done at each visit. DISCUSSION: The results of this trial will demonstrate the efficacy and safety of EA treatment for PSD with credible and important clinical evidence, thus supporting EA treatment as an ideal choice for PSD treatment. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-IOR-17012610. Registered on 7 September 2017. http://www.chictr.org.cn/edit.aspx?pid=21494&htm=4. PMID- 29499744 TI - Keeping track of mosquitoes: a review of tools to track, record and analyse mosquito flight. AB - The health impact of mosquito-borne diseases causes a huge burden on human societies. Recent vector control campaigns have resulted in promising declines in incidence and prevalence of these diseases, notably malaria, but resistance to insecticides and drugs are on the rise, threatening to overturn these gains. Moreover, several vector-borne diseases have re-emerged, requiring prompt and effective response measures. To improve and properly implement vector control interventions, the behaviour of the vectors must be well understood with detailed examination of mosquito flight being an essential component. Current knowledge on mosquito behaviour across its life history is briefly presented, followed by an overview of recent developments in automated tracking techniques for detailed interpretation of mosquito behaviour. These techniques allow highly accurate recording and observation of mating, feeding and oviposition behaviour. Software programmes built with specific algorithms enable quantification of these behaviours. For example, the crucial role of heat on host landing and the multimodal integration of carbon dioxide (CO2) with other host cues, has been unravelled based on three-dimensional tracking of mosquito flight behaviour. Furthermore, the behavioural processes underlying house entry and subsequent host searching and finding can be better understood by analysis of detailed flight recordings. Further potential of these technologies to solve knowledge gaps is discussed. The use of tracking techniques can support or replace existing monitoring tools and provide insights on mosquito behaviour that can lead to innovative and more effective vector-control measures. PMID- 29499746 TI - Descriptions of Mikrocytos veneroides n. sp. and Mikrocytos donaxi n. sp. (Ascetosporea: Mikrocytida: Mikrocytiidae), detected during important mortality events of the wedge clam Donax trunculus Linnaeus (Veneroida: Donacidae), in France between 2008 and 2011. AB - BACKGROUND: Microcell parasites are small intracellular protozoans mostly detected in molluscs and can be associated with mortalities. In 2010 and 2011, strong increases in mortality events were reported in different wild beds of the wedge clam Donax trunculus Linnaeus, along the Atlantic coast of France and the presence of potential pathogens, including microcells, was investigated. METHODS: Clams collected in different beds showing mortality were examined by histology. Based on histological observations, confirmatory analyses were carried out, including transmission electron microscopy (TEM) and molecular characterization. RESULTS: Histological analyses revealed the presence of small protozoans similar to microcell parasites in different tissues of Donax trunculus, particularly in muscular and connective tissues. TEM examination confirmed the intracellular localization of the protozoans. Moreover, the lack of haplosporosomes and mitochondria suggested that the observed parasites belong to the genus Mikrocytos Farley, Wolf & Elston, 1988. Mikrocytos genus-specific PCR and in situ hybridization results supported the microscopic observations. Sequence fragments of the 18S rRNA gene shared 75-83% identity with the different Mikrocytos spp. described previously, including Mikrocytos mackini Farley, Wolf & Elston, 1988 and M. boweri Abbott, Meyer, Lowe, Kim & Johnson, 2014. Phylogenetic analyses confirmed that the microcell parasites observed in Donax trunculus in France belong to the genus Mikrocytos and suggest the existence of two distinct species. CONCLUSIONS: Based on morphological, ultrastructural, molecular data and host information, the two microcell parasites detected in Donax trunculus belong to the genus Mikrocytos and are distinct from previously described members of this genus. This is the first report of Mikrocytos spp. found in France and infecting the clam Donax trunculus. Mikrocytos veneroides n. sp. was detected in different wild beds and Mikrocytos donaxi n. sp. was detected only in Audierne Bay. PMID- 29499747 TI - Prevalence and genetic diversity of Trichomonas vaginalis clinical isolates in a targeted population in Xinxiang City, Henan Province, China. AB - BACKGROUND: Trichomonas vaginalis (TV) is a protozoan parasite that causes trichomoniasis, a sexually transmitted disease, worldwide. In this study, we investigated the prevalence and genetic characterization of T. vaginalis and contrasted the most prevalent strains of T. vaginalis isolated from Xinxiang City, Henan Province, China. RESULTS: In Xinxiang from September 2015 to September 2017, a total of 267 (1.64%, 95% confidence interval, CI: 1.45-1.85) clinical T. vaginalis-positive samples from vaginal secretions were observed by wet mount microscopy from 16,294 women with some clinical symptoms of trichomoniasis. We found that trichomoniasis frequently occurred in the 21- to 40 year-old age group and in winter. After the 267 clinical T. vaginalis positive samples were cultured, 68 isolates of T. vaginalis were harvested and identified as genotype E (58.82%), H (17.65%), mixed 1 (17.65%) and mixed 2 (5.88%) using a sensitive and reliable polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) typing method on the actin gene. The phylogenetic diversity analysis showed that the genotype E samples fell within a separate clade compared to the other T. vaginalis isolates, while the samples of the genotype H separated into two clades. CONCLUSIONS: Our results demonstrate a notable gene polymorphism of clinical isolates from the targeted population and provide insight into the performance of these genetic markers in the molecular epidemiology of trichomoniasis. However, further studies are needed to clarify the association between a certain genotype and the pathogenicity of T. vaginalis. PMID- 29499748 TI - Development and validation of a duplex real-time PCR assay for the diagnosis of equine piroplasmosis. AB - BACKGROUND: Equine piroplasmosis (EP) is an economically significant infection of horses and other equine species caused by the tick-borne protozoa Theileria equi and Babesia caballi. The long-term carrier state in infected animals makes importation of such subclinical cases a major risk factor for the introduction of EP into non-enzootic areas. Regulatory testing for EP relies on screening of equines by serological methods. The definitive diagnosis of EP infection in individual animals will benefit from the availability of sensitive direct detection methods, for example, when used as confirmatory assays for non-negative serological test results. The objectives of this study were to develop a real time quantitative polymerase chain reaction (qPCR) assay for simultaneous detection of both agents of EP, perform comprehensive evaluation of its performance and assess the assay's utility for regulatory testing. RESULTS: We developed a duplex qPCR targeting the ema-1 gene of T. equi and the 18S rRNA gene of B. caballi and demonstrated that the assay has high analytical sensitivities for both piroplasm species. Validation of the duplex qPCR on samples from 362 competitive enzyme-linked immunosorbent assay (cELISA)-negative horses from Canada and the United States yielded no false-positive reactions. The assay's performance was further evaluated using samples collected from 430 horses of unknown EP status from a highly endemic area in Brazil. This set of samples was also tested by a single-target 18S rRNA qPCR for T. equi developed at the OIE reference laboratory for EP in Japan, and a previously published single-target 18S rRNA qPCR for B. caballi whose oligonucleotides we adopted for use in the duplex qPCR. Matching serum samples were tested for antibodies to these parasites using cELISA. By the duplex qPCR, T. equi-specific 18S rRNA qPCR and cELISA, infections with T. equi were detected in 87.9% (95% confidence interval, CI: 84.5 90.7%), 90.5% (95% CI: 87.3-92.3%) and 87.4% (95% CI: 84.0-90.2%) of the horses, respectively. The B. caballi prevalence estimates were 9.3% (95% CI: 6.9-12.4%) by the duplex qPCR and 7.9% (95% CI: 5.7-10.9%) by the respective single-target qPCR assay. These values were markedly lower compared to the seroprevalence of 58.6% (95% CI: 53.9-63.2%) obtained by B. caballi-specific cELISA. The relative diagnostic sensitivity of the duplex qPCR for T. equi was 95.5%, as 359 of the 376 horses with exposure to T. equi confirmed by cELISA had parasitemia levels above the detection limit of the molecular assay. In contrast, only 39 (15.5%) of the 252 horses with detectable B. caballi-specific antibodies were positive for this piroplasm species by the duplex qPCR. CONCLUSIONS: The duplex qPCR described here performed comparably to the existing single-target qPCR assays for T. equi and B. caballi and will be more cost-effective in terms of results turnaround time and reagent costs when both pathogens are being targeted for disease control and epidemiological investigations. These validation data also support the reliability of the ema-1 gene-specific oligonucleotides developed in this study for confirmatory testing of non-negative serological test results for T. equi by qPCR. However, the B. caballi-specific qPCR cannot be similarly recommended as a confirmatory assay for routine regulatory testing due to the low level of agreement with serological test results demonstrated in this study. Further studies are needed to determine the transmission risk posed by PCR-negative equines with detectable antibodies to B. caballi. PMID- 29499750 TI - Grading of cytokine release syndrome associated with the CAR T cell therapy tisagenlecleucel. AB - BACKGROUND: Anti-CD19 CAR T cell therapy has demonstrated high response rates in patients with relapsed or refractory (r/r) B cell malignancies but is associated with significant toxicity. Cytokine release syndrome (CRS) is the most significant complication associated with CAR T cell therapy, and it is critical to have a reproducible and easy method to grade CRS after CAR T cell infusions. DISCUSSION: The Common Terminology Criteria for Adverse Events scale is inadequate for grading CRS associated with cellular therapy. Clinical experience with the anti-CD19 CAR T cell therapy tisagenlecleucel at the University of Pennsylvania (Penn) was used to develop the Penn grading scale for CRS. The Penn grading scale depends on easily accessible clinical features; does not rely on location of care or quantitation of supportive care; assigns grades to guide CRS management; distinguishes between mild, moderate, severe, and life-threatening CRS; and applies to both early-onset and delayed-onset CRS associated with T cell therapies. Clinical data from 55 pediatric patients with r/r B cell acute lymphoblastic leukemia and 42 patients with r/r chronic lymphocytic lymphoma treated with tisagenlecleucel were used to demonstrate the current application of the Penn grading scale. CONCLUSION: We show that the Penn grading scale provides reproducible CRS grading that can be useful to guide therapy and that can be applied across clinical trials and treatment platforms. PMID- 29499749 TI - Barriers, supports, and effective interventions for uptake of human papillomavirus- and other vaccines within global and Canadian Indigenous peoples: a systematic review protocol. AB - BACKGROUND: Despite the existence of human papilloma virus (HPV) vaccines with demonstrated safety and effectiveness and funded HPV vaccination programs, coverage rates are persistently lower and cervical cancer burden higher among Canadian Indigenous peoples. Barriers and supports to HPV vaccination in Indigenous peoples have not been systematically documented, nor have interventions to increase uptake in this population. This protocol aims to appraise the literature in Canadian and global Indigenous peoples, relating to documented barriers and supports to vaccination and interventions to increase acceptability/uptake or reduce hesitancy of vaccination. Although HPV vaccination is the primary focus, we anticipate only a small number of relevant studies to emerge from the search and will, therefore, employ a broad search strategy to capture literature related to both HPV vaccination and vaccination in general in global Indigenous peoples. METHODS: Eligible studies will include global Indigenous peoples and discuss barriers or supports and/or interventions to improve uptake or to reduce hesitancy, for the HPV vaccine and/or other vaccines. Primary outcomes are documented barriers or supports or interventions. All study designs meeting inclusion criteria will be considered, without restricting by language, location, or data type. We will use an a priori search strategy, comprised of key words and controlled vocabulary terms, developed in consultation with an academic librarian, and reviewed by a second academic librarian using the PRESS checklist. We will search several electronic databases from date of inception, without restrictions. A pre-defined group of global Indigenous websites will be reviewed for relevant gray literature. Bibliographic searches will be conducted for all included studies to identify relevant reviews. Data analysis will include an inductive, qualitative, thematic synthesis and a quantitative analysis of measured barriers and supports, as well as a descriptive synthesis and quantitative summary of measures for interventions. DISCUSSION: To our knowledge, this study will contribute the first systematic review of documented barriers, supports, and interventions for vaccination in general and for HPV vaccination. The results of this study are expected to inform future research, policies, programs, and community-driven initiatives to enhance acceptability and uptake of HPV vaccination among Indigenous peoples. SYSTEMATIC REVIEW REGISTRATION: PROSPERO Registration Number: CRD42017048844. PMID- 29499751 TI - Temporal and spatial trends in insecticide resistance in Anopheles arabiensis in Sudan: outcomes from an evaluation of implications of insecticide resistance for malaria vector control. AB - BACKGROUND: Long-lasting insecticidal nets (LLINs) (with pyrethroids) and indoor residual spraying (IRS) are the cornerstones of the Sudanese malaria control program. Insecticide resistance to the principal insecticides in LLINs and IRS is a major concern. This study was designed to monitor insecticide resistance in Anopheles arabiensis from 140 clusters in four malaria-endemic areas of Sudan from 2011 to 2014. All clusters received LLINs, while half (n = 70), distributed across the four regions, had additional IRS campaigns. METHODS: Anopheles gambiae (s.l.) mosquitoes were identified to species level using PCR techniques. Standard WHO insecticide susceptibility bioassays were carried out to detect resistance to deltamethrin (0.05%), DDT (4%) and bendiocarb (0.1%). TaqMan assays were performed on random samples of deltamethrin-resistant phenotyped and pyrethrum spray collected individuals to determine Vgsc-1014 knockdown resistance mutations. RESULTS: Anopheles arabiensis accounted for 99.9% of any anopheline species collected across all sites. Bioassay screening indicated that mosquitoes remained susceptible to bendiocarb but were resistance to deltamethrin and DDT in all areas. There were significant increases in deltamethrin resistance over the four years, with overall mean percent mortality to deltamethrin declining from 81.0% (95% CI: 77.6-84.3%) in 2011 to 47.7% (95% CI: 43.5-51.8%) in 2014. The rate of increase in phenotypic deltamethrin-resistance was significantly slower in the LLIN + IRS arm than in the LLIN-only arm (Odds ratio 1.34; 95% CI: 1.02 1.77). The frequency of Vgsc-1014F mutation varied spatiotemporally with highest frequencies in Galabat (range 0.375-0.616) and New Halfa (range 0.241-0.447). Deltamethrin phenotypic-resistance correlated with Vgsc-1014F frequency. CONCLUSION: Combining LLIN and IRS, with different classes of insecticide, may delay pyrethroid resistance development, but the speed at which resistance develops may be area-specific. Continued monitoring is vital to ensure optimal management and control. PMID- 29499752 TI - Sex tourism among Chinese men who have sex with men: a cross-sectional observational study. AB - BACKGROUND: Sex tourism among men who have sex with men (MSM) may exacerbate transmission of HIV and other sexually transmitted infections (STIs). Sex tourism is defined as purchasing sex with gifts or money outside of one's hometown. Our objective was to characterize the frequency, socio-demographic characteristics, and sexual risk behaviors among Chinese MSM sex tourists. METHODS: An online, cross-sectional survey for high-risk MSM throughout China was conducted in November 2015 covering sociodemographic characteristics, sexual risk behaviors, and sex tourism. Univariate and multivariable logistic regressions were performed to identify correlates of sex tourism. The mean MSM HIV prevalence of sex tourism journey origins and destinations were compared. RESULTS: Of 1189 MSM who completed the survey, 62 (5%) men identified as sex tourists; among these sex tourists, twenty (32%) traveled primarily to purchase sex and the remainder purchased sex while traveling for another purpose. There was minimal socio demographic and behavioral difference between the two groups. In multivariable analyses, adjusting for age and income, sex tourism was correlated with high-risk sexual behaviors, higher income (aOR 4.44, 95%CI 1.77-11.18) and living with HIV (aOR 2.79, 95%CI 1.03-7.55). Sex tourism was more often from locations with lower to higher MSM HIV prevalence (mean = 4.47, SD = 2.01 versus mean = 6.86, SD = 5.24). CONCLUSION: MSM sex tourists were more likely to have risky sexual behaviors and travel to locations with a higher HIV prevalence. MSM sex tourists may be part of core groups that are disproportionately responsible for MSM HIV transmission. Enhanced surveillance and interventions tailored to MSM sex tourists should be considered. PMID- 29499753 TI - Validation of the Orebro musculoskeletal pain screening questionnaire in patients with chronic neck pain. AB - OBJECTIVES: To validate the German version of OMPSQ (OMPSQ-G) for patients with chronic neck pain. RESULTS: After translating OMPSQ to German, we assessed the discriminant validity between patients and healthy adults. Convergent validity was assessed using Pearson's correlation coefficients between domains of OMPSQ-G and the German version of neck disability index (NDI-G) and visual analogue scale (VAS) of neck pain intensity. Floor and ceiling effects, internal consistency, test-retest and relative reliability were assessed. Fifty patients with chronic neck pain (mean age, 43.6 years; 34 females) and 24 healthy adults (mean age, 50.4 years; 18 females) participated. Mann-Whitney U tests showed significant differences in OMPSQ scores between both groups at the baseline (z = - 4.6; p < 0.001) and second time point (z = - 4.8; p < 0.001). OMPSQ-G scores highly and moderately correlated with NDI-G (rho = 0.70) and VAS (rho = 0.41) scores, respectively. There were no floor or ceiling effects. Cronbach's alpha was 0.94. OMPSQ-G showed high reliability (intraclass correlation 2.1: 0.93; standard error of measurement, 6.9; smallest detectable change, 20 points). The Bland-Altman plot indicated no systematic error. OMPSQ-G showed good validity and reliability in patients with neck pain. Trial registration NCT02540343. PMID- 29499754 TI - Foodborne intestinal protozoan infection and associated factors among patients with watery diarrhea in Northern Ethiopia; a cross-sectional study. AB - BACKGROUND: Intestinal protozoa are parasites transmitted by consumption of contaminated water and food and mainly affect children and elder people and cause considerable health problems. They are the leading causes of outpatient morbidity due to diarrhea in the developing countries. So, assessing water and food source of diarrheal patients and identifying the main associated factors for transmission of protozoan parasitic infections help for effective control measures of protozoan infections. Hence, the current study was aimed at determining the prevalence of foodborne intestinal protozoa infections and associated factors among diarrheic patients in North Ethiopia. METHODS: A health facility based cross-sectional study was conducted among 223 patients with watery diarrhea in four selected government health facilities in North Ethiopia from November 2016-June 2017. A structured questionnaire was used to collect data on socio-demography of study participants and factors associated with foodborne protozoa infections. The diarrheic stool samples were collected, transported, and processed using direct wet mount, formal-ether concentration and modified ZiehlNeelson staining methods. The data were analyzed using SPSS version 21 and descriptive statistics, bi-variate, and multivariate logistic regressions were computed. P-value < 0.05 at 95% confidence interval was considered statistically significant. RESULTS: The overall prevalence of foodborne protozoa infection was 101 (45.3%). The predominant protozoa species identified was Entamoeba histolytica/dispar 55 (24.7%), followed by Giardia intestinalis 25 (11.2%) and Cryptosporidium species 5 (2.2%). The highest proportion of protozoa infection was observed among males (23.3%) and the age group 15-24 years (13.5%). Statistically significant associations were observed between foodborne protozoan infection and not using any type of recipe to decontaminate salads and fruits (AOR = 2.64, 95 CI: 1.34-5.19, P = 0.005) and using vinegar as a decontaminant (AOR = 2.83, 95 CI: 1.24-6.48, P = 0.014). Eating out (meals at a restaurant) on the other hand was found to be protective for foodborne protozoan infection (AOR = 0.43, 95 CI: 0.23-0.78, P = 0.006). CONCLUSION: Our study revealed that foodborne protozoa infections are of public health significance in the study area. Vinegar, which is frequently used as a recipe for decontaminating salads and fruits, is inversely related to foodborne protozoa parasite infection . PMID- 29499755 TI - Three-dimensional analysis of synapses in the transentorhinal cortex of Alzheimer's disease patients. AB - Synaptic dysfunction or loss in early stages of Alzheimer's disease (AD) is thought to be a major structural correlate of cognitive dysfunction. Early loss of episodic memory, which occurs at the early stage of AD, is closely associated with the progressive degeneration of medial temporal lobe (MTL) structures of which the transentorhinal cortex (TEC) is the first affected area. However, no ultrastructural studies have been performed in this region in human brain samples from AD patients. In the present study, we have performed a detailed three dimensional (3D) ultrastructural analysis using focused ion beam/scanning electron microscopy (FIB/SEM) to investigate possible synaptic alterations in the TEC of patients with AD. Surprisingly, the analysis of the density, morphological features and spatial distribution of synapses in the neuropil showed no significant differences between AD and control samples. However, light microscopy studies showed that cortical thickness of the TEC was severely reduced in AD samples, but there were no changes in the volume occupied by neuronal and glial cell bodies, blood vessels, and neuropil. Thus, the present results indicate that there is a dramatic loss of absolute number of synapses, while the morphology of synaptic junctions and synaptic spatial distribution are maintained. How these changes affect cognitive impairment in AD remains to be elucidated. PMID- 29499756 TI - Rapid detection of 2-hydroxyglutarate in frozen sections of IDH mutant tumors by MALDI-TOF mass spectrometry. AB - All isocitrate dehydrogenase (IDH) mutant solid neoplasms exhibit highly elevated levels of D-2-hydroxyglutarate (D-2HG). Detection of 2HG in tumor tissues currently is performed by gas or liquid chromatography-mass spectrometry (GC- or LC-MS) or biochemical detection. While these methods are highly accurate, a considerable amount of time for tissue preparation and a relatively high amount of tissue is required for testing. We here present a rapid approach to detect 2HG in brain tumor tissue based on matrix-assisted laser desorption ionization - time of flight mass spectrometry (MALDI-TOF). We analyzed 26 brain tumor samples with known IDH1 or IDH2 mutation and compared readouts to those from 28 brain tumor samples of wildtype IDH status. IDH mutant samples exhibited a clear positive signal for 2HG which was not observed in any of the IDH wildtype tumors. Our analytical pipeline allowed for 2HG detection in less than 5 min. Data were validated by determining 2HG levels in all tissues with a biochemical assay. In conclusion, we developed a protocol for rapid detection of 2HG levels and illustrate the possibility to use MALDI-TOF for the detection of metabolites on frozen tissue sections in a diagnostic setting. PMID- 29499757 TI - Septic shock from descending necrotizing mediastinitis - combined treatment with IgM-enriched immunoglobulin preparation and direct polymyxin B hemoperfusion: a case report. AB - BACKGROUND: Descending necrotizing mediastinitis is a common and progressive polymicrobial infection involving the neck and chest with a high death rate (10 to 40%). From a microbiological point of view, descending necrotizing mediastinitis is sustained by Gram-positive bacteria (43-62%), anaerobes (46 78%), and, rarely, Gram-negative bacteria. Data collected during the Antibiotic Resistance-Istituto Superiore di Sanita project confirmed that Italy is positioned among the countries with the highest levels of resistance in most pathogenic species under surveillance. In particular, 32.9% of Klebsiella pneumoniae isolates were resistant to carbapenem, 33.6% of Staphylococcus aureus to methicillin, and 28.7% and 43.9% of Escherichia coli isolates to third generation cephalosporins and fluoroquinolones, respectively. CASE PRESENTATION: We describe the case of a 38-year-old white man with septic shock due to descending necrotizing mediastinitis sustained by multidrug-resistant Gram negative and Gram-positive bacteria treated after surgery with an IgM-enriched immunoglobulin preparation and polymyxin B hemoperfusion therapy. CONCLUSION: Despite the contrasting data on the use of immunoglobulins and polymyxin B hemoperfusion in septic shock and the lack of literature in cases of acute mediastinitis caused by both Gram-negative and Gram-positive multidrug-resistant bacteria, we obtained an improvement in clinical conditions and the survival of our patient, against all odds. PMID- 29499758 TI - Favorable longitudinal change of lung function in patients with asthma-COPD overlap from a COPD cohort. AB - BACKGROUND: The recognition of asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) as a distinct phenotype of COPD or asthma has increased. Although ACO has worse clinical features than non-ACO COPD, limited information is available on long-term outcomes of lung function decline for ACO and non-ACO COPD. METHODS: COPD patients with at least 3 years of follow-up were selected from the Korean Obstructive Lung Disease cohort. ACO was defined based on 3 major criteria: 1) airflow limitation in individuals 40 years of age and older, 2) >=10 pack-years of smoking history, and 3) a history of asthma or bronchodilator response of > 400 mL in forced expiratory volume in 1 s (FEV1) at baseline; and at least 1 minor criterion: 1) history of atopy or allergic rhinitis, 2) two separated bronchodilator responses of >=12% and 200 mL in FEV1, or 3) peripheral blood eosinophils >=300 cells/MUL. Lung function decline was compared using a linear mixed effects model for longitudinal data with random intercept and random slope. RESULTS: Among 239 patients, 47 were diagnosed with ACO (19.7%). During the follow-up period, change in smoking status, use of inhaled corticosteroids (ICS) and long-acting beta2-agonists or ICS and at least 2 exacerbations per year were similar between patients with non-ACO COPD and ACO. Over a median follow-up duration of 5.8 years, patients with non-ACO COPD experienced a faster annual decline in pre-bronchodilator FEV1 than patients with ACO (- 29.3 ml/year vs. 13.9 ml/year, P = 0.042), which was persistent after adjustment for confounders affecting lung function decline. CONCLUSION: Patients with ACO showed favorable longitudinal changes in lung function compared to COPD patients over a median follow-up of 5.8 years. PMID- 29499759 TI - Taxa-function robustness in microbial communities. AB - BACKGROUND: The species composition of a microbial community is rarely fixed and often experiences fluctuations of varying degrees and at varying frequencies. These perturbations to a community's taxonomic profile naturally also alter the community's functional profile-the aggregate set of genes encoded by community members-ultimately altering the community's overall functional capacities. The magnitude of such functional changes and the specific shift that will occur in each function, however, are strongly dependent on how genes are distributed across community members' genomes. This gene distribution, in turn, is determined by the taxonomic composition of the community and would markedly differ, for example, between communities composed of species with similar genomic content vs. communities composed of species whose genomes encode relatively distinct gene sets. Combined, these observations suggest that community functional robustness to taxonomic perturbations could vary widely across communities with different compositions, yet, to date, a systematic study of the inherent link between community composition and robustness is lacking. RESULTS: In this study, we examined how a community's taxonomic composition influences the robustness of that community's functional profile to taxonomic perturbation (here termed taxa function robustness) across a wide array of environments. Using a novel simulation-based computational model to quantify this taxa-function robustness in host-associated and non-host-associated communities, we find notable differences in robustness between communities inhabiting different body sites, including significantly higher robustness in gut communities compared to vaginal communities that cannot be attributed solely to differences in species richness. We additionally find between-site differences in the robustness of specific functions, some of which are potentially related to site-specific environmental conditions. These taxa-function robustness differences are most strongly associated with differences in overall functional redundancy, though other aspects of gene distribution also influence taxa-function robustness in certain body environments, and are sufficient to cluster communities by environment. Further analysis revealed a correspondence between our robustness estimates and taxonomic and functional shifts observed across human-associated communities. CONCLUSIONS: Our analysis approach revealed intriguing taxa-function robustness variation across environments and identified features of community and gene distribution that impact robustness. This approach could be further applied for estimating taxa-function robustness in novel communities and for informing the design of synthetic communities with specific robustness requirements. PMID- 29499760 TI - Influence of vascular geometry on local hemodynamic parameters: phantom and small rodent study. AB - BACKGROUND: Many studies have demonstrated that the geometry of the carotid bifurcation enables prediction of blood flow variation associated with atherosclerotic plaque formation. The phase angle between the arterial wall circumferential strain and its instantaneous wall shear stress is known as stress phase angle (SPA). This parameter is used to evaluate hemodynamic factors of atherogenesis. Note that SPA can be numerically computed for the purpose of locating atherosclerosis in different artery geometries. However, there is no experimental data to verify its role in the location of atherosclerosis in different artery geometries. In this study, we use an ultrasonic biomechanical method to experimentally evaluate the role of SPA for locating atherosclerosis in carotid bifurcation. RESULTS: For carotid anthropomorphic vascular phantom experiments, the SPAs of common carotid arteries (CCAs), external carotid arteries (ECAs) and internal carotid arteries (ICAs) are - 148.53 +/- 6.92 degrees , - 153.95 +/- 5.11 degrees , and - 238.69 +/- 1.72 degrees , respectively. The corresponding SPAs are - 173.47 +/- 0.065 degrees , - 115.57 +/ 4.83 degrees and - 233.9 +/- 8.12 degrees for the polyvinyl alcohol (PVA-c) phantoms. In vivo mouse experiments indicated that the wall shear stress and circumferential strain were out of phase in the ICAs (- 280.08 +/- 13.12 degrees ) to a greater extent as compared to CCAs (- 141.97 +/- 8.03 degrees ) and ECAs ( 170.07 +/- 9.24 degrees ). CONCLUSIONS: The results suggested that SPA may be a useful indicator to locate the atherosclerosis position in carotid bifurcation. PMID- 29499761 TI - High-frequency percussive ventilation in acute respiratory distress syndrome: knocking at the door but can it be let in? PMID- 29499762 TI - Systematic review of antiepileptic drugs' safety and effectiveness in feline epilepsy. AB - BACKGROUND: Understanding the efficacy and safety profile of antiepileptic drugs (AEDs) in feline epilepsy is a crucial consideration for managing this important brain disease. However, there is a lack of information about the treatment of feline epilepsy and therefore a systematic review was constructed to assess current evidence for the AEDs' efficacy and tolerability in cats. The methods and materials of our former systematic reviews in canine epilepsy were mostly mirrored for the current systematic review in cats. Databases of PubMed, CAB Direct and Google scholar were searched to detect peer-reviewed studies reporting efficacy and/or adverse effects of AEDs in cats. The studies were assessed with regards to their quality of evidence, i.e. study design, study population, diagnostic criteria and overall risk of bias and the outcome measures reported, i.e. prevalence and 95% confidence interval of the successful and affected population in each study and in total. RESULTS: Forty studies describing clinical outcomes of AEDs' efficacy and safety were included. Only two studies were classified as "blinded randomised controlled trials". The majority of the studies offered high overall risk of bias and described low feline populations with unclear diagnostic criteria and short treatment or follow-up periods. Individual AED assessments of efficacy and safety profile showed that phenobarbital might currently be considered as the first choice AED followed by levetiracetam and imepitoin. Only imepitoin's safety profile was supported by strong level of evidence. Imepitoin's efficacy as well as remaining AEDs' efficacy and safety profile were supported by weak level of evidence. CONCLUSIONS: This systematic review reflects an evidence-based assessment of the published data on the AEDs' efficacy and safety for feline epilepsy. Currently, phenobarbital is likely to be the first-line for feline epileptic patients followed by levetiracetam and imepitoin. It is essential that clinicians evaluate both AEDs' effectiveness and tolerability before tailoring AED to the individual patient. Further studies in feline epilepsy treatment are by far crucial in order to establish definite guidelines for AEDs' efficacy and safety. PMID- 29499764 TI - Prevalence of loss-of-function alleles does not correlate with lifetime fecundity and other life-history traits in metazoans. AB - BACKGROUND: Natural selection is possible only because all species produce more offsprings than what is needed to maintain the population. Still, the lifetime number of offspring varies widely across species. One may expect natural selection to be stronger in high-fecundity species. Alternatively, natural selection could be stronger in species where a female invests more into an individual offspring. This issue needed to be addressed empirically. RESULTS: We analyzed the prevalence of loss-of-function alleles in 35 metazoan species and have found that the strength of negative selection does not correlate with lifetime fecundity or other life-history traits. CONCLUSIONS: Higher random mortality in high-fecundity species may negate the effect of increased opportunity for selection. Perhaps, invariance of the strength of negative selection across a wide variety of species emerges because natural selection optimized the life history in each of them, leading to the strongest possible competition. REVIEWERS: This article was reviewed by Nicolas Galtier and I. King Jordan. PMID- 29499763 TI - Modulatory effects of trophoblast-secreted CXCL12 on the migration and invasion of human first-trimester decidual epithelial cells are mediated by CXCR4 rather than CXCR7. AB - BACKGROUND: Maternal-fetal crosstalk during embryo implantation is complex and regulated by local signaling molecules. Chemokines and their receptors are critical signaling components required for implantation and the process of pregnancy. This study aimed to explore whether human first-trimester trophoblast cells (TCs) were capable of modulating the migration and invasion of human first trimester decidual epithelial cells (DECs) via CXCL12/CXCR4/CXCR7 signaling. METHOD: The expression of CXCR4 and CXCR7 in DECs was examined by immunohistochemistry, immunocytochemistry, immunofluorescence, flow cytometry, real-time polymerase chain reactions and western blotting. The effects of recombinant human CXCL12 (rhCXCL12) and TC-conditioned medium (TC-CM) on DEC viability in vitro were explored using a viability assay. The modulatory effects of rhCXCL12 and TC/DEC co-cultures on DEC migration and invasion were examined with migration/invasion assays. RESULT: CXCR4 and CXCR7 were co-expressed in human first-trimester DECs. Human rhCXCL12 and TC-CM had no effects on DEC viability in vitro (P > 0.05). Both exogenous CXCL12 and co-culture with TCs significantly increased the migration and invasion of DECs (P < 0.05). Neutralizing antibodies against CXCR4 (P < 0.05) or CXCL12 (P < 0.05), but not CXCR7 (P > 0.05), significantly blocked the enhanced migration and invasion of DECs induced by exogenous CXCL12 or TC co-culture. CONCLUSIONS: CXCR4 and CXCR7 were co-expressed in human first-trimester DECs. TC-derived CXCL12 promoted the migration and invasion of DECs via CXCR4, but not CXCR7, in a paracrine manner during early pregnancy. PMID- 29499765 TI - Osteoglycin (OGN) reverses epithelial to mesenchymal transition and invasiveness in colorectal cancer via EGFR/Akt pathway. AB - BACKGROUND: Many types of cancers are devoid of the small leucine-rich proteoglycans: osteoglycin (OGN), but its role in tumorigenesis is poorly studied especially in colorectal cancers (CRC). Here we aim to evaluate the relationship between OGN expression patterns and the clinical course of CRC, and the role of OGN in cancer progression. METHODS: The tissue microarray staining was performed and the relevance between OGN expression and oncologic outcomes was performed using Cox regression analysis. The effect of OGN on cell proliferation and tumorigenesis was examined in vitro and in vivo. Immunoprecipitation assay, immunofluorescence analysis and internalization assay were used for mechanistic study. RESULTS: Patients with high expression of OGN were associated with a profound longer survival in CRC and the high serum OGN level was also indicative of fewer recurrences consistently. In colon cancer cells, OGN increased dimerization of EGFR, then triggered EGFR endocytosis and induced the recruitment of downstream components of the EGFR internalization machinery (Eps15 and epsin1). Above all, OGN reduced Zeb-1 expression via EGFR/Akt leading to inhibition of epithelial-mesenchymal transition. As results, in vitro and in vivo, the OGN expression was demonstrated to reduce cell proliferation, inhibit invasion of colon cancer cells then impede cancer progression. CONCLUSIONS: There is a positive association between OGN level and prolonged survival in CRC. OGN plays a restrictive role in colorectal cancer progression by reduced activation of EGFR/AKT/Zeb-1. PMID- 29499766 TI - Effects of combined high-intensity aerobic interval training program and Mediterranean diet recommendations after myocardial infarction (INTERFARCT Project): study protocol for a randomized controlled trial. AB - BACKGROUND: Exercise therapy has long been used for rehabilitation purposes after myocardial infarction (MI) and the benefit of regular physical exercise is also well-established. High-intensity interval training (HIIT) has been proposed to be more effective than continuous exercise for improving exercise capacity and health-related adaptations to low-volume (LV) and HIIT are also known. Furthermore, the Mediterranean diet (Mediet) has been widely reported to be a model of healthy eating for its contribution to a favorable health status and a better quality of life, reducing overall mortality. This study will investigate the effects of different HIIT programs (high-volume [HV] vs LV) and Mediet recommendations in clinical condition, cardiorespiratory fitness, biomarkers, ventricular function, and perception of quality of life after MI, and compared to an attention control group that is recommended to Mediet and physical activity without supervision sessions. METHODS/DESIGN: In this randomized controlled trial, cardiorespiratory fitness, anthropometry, central and peripheral cardiovascular variables, biochemical and nutritional condition, and quality of life will be assessed before and after 16 weeks of intervention in 177 participants diagnosed with MI type 1. All participants will be randomly (1:1:1) assigned to the attention control group or two exercise groups (Mediet recommendations plus supervised aerobic exercise two days/week: (1) HV (40 min) HIIT group and (2) LV (20 min) HIIT group. DISCUSSION: This study will be the first clinical trial comparing the effects of two different volumes of HIIT programs with Mediet recommendations for people after MI. The results of this study will provide good evidence for physical rehabilitation in this population. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02876952 . Registered on 24 August 2016. PMID- 29499768 TI - Editorial overview: Viral immunology: Generating immunity to diverse viral pathogens. PMID- 29499769 TI - CAR T-cell design: a long road ahead. PMID- 29499770 TI - How the Barn Owl Computes Auditory Space. AB - In a series of seminal behavioral and electrophysiological experiments, Knudsen and Konishi studied the mechanisms of hearing. Their 1979 article showed how the barn owl utilizes unique anatomical features for creating a systematic internal representation of auditory space. This established the barn owl as a prime model for studying sensory systems. PMID- 29499767 TI - White matter changes in Alzheimer's disease: a focus on myelin and oligodendrocytes. AB - Alzheimer's disease (AD) is conceptualized as a progressive consequence of two hallmark pathological changes in grey matter: extracellular amyloid plaques and neurofibrillary tangles. However, over the past several years, neuroimaging studies have implicated micro- and macrostructural abnormalities in white matter in the risk and progression of AD, suggesting that in addition to the neuronal pathology characteristic of the disease, white matter degeneration and demyelination may be also important pathophysiological features. Here we review the evidence for white matter abnormalities in AD with a focus on myelin and oligodendrocytes, the only source of myelination in the central nervous system, and discuss the relationship between white matter changes and the hallmarks of Alzheimer's disease. We review several mechanisms such as ischemia, oxidative stress, excitotoxicity, iron overload, Abeta toxicity and tauopathy, which could affect oligodendrocytes. We conclude that white matter abnormalities, and in particular myelin and oligodendrocytes, could be mechanistically important in AD pathology and could be potential treatment targets. PMID- 29499771 TI - The Memory Map of Visual Space. AB - A 1989 paper by Patricia Goldman-Rakic and colleagues reported that the prefrontal cortex coded the visual space during working memory. This landmark work not only offered a biological explanation for this cognitive function, but also opened up a wide field of research aimed at understanding the biological bases of various cognitive functions. PMID- 29499772 TI - Building on a Solid Baseline: Anticipatory Biases in Attention. AB - A brain-imaging paper by Kastner and colleagues in 1999 was the first to demonstrate that merely focusing attention at a spatial location changed the baseline activity level in various regions of human visual cortex even before any stimuli appeared. The study provided a touchstone for investigating cognitive sensory interactions and understanding the proactive endogenous signals that shape perception. PMID- 29499773 TI - Cell Type-Specific Optogenetic Dissection of Brain Rhythms. AB - A pair of 2009 papers by Cardin et al. and Sohal et al. marked a watershed moment as optogenetics exploded onto the scene of systems neuroscience. This pair of back-to-back papers in the June issue of Nature leveraged a powerful combination of the Cre/lox system, adeno-associated viral gene vectors, and optogenetics to re-examine the circuit basis of neuronal synchronization. PMID- 29499774 TI - Production of myo-inositol from glucose by a novel trienzymatic cascade of polyphosphate glucokinase, inositol 1-phosphate synthase and inositol monophosphatase. AB - Myo-inositol (inositol) is important in the cosmetics, pharmaceutical and functional food industries. Here, we report a novel pathway to produce inositol from glucose by a trienzymatic cascade system involving polyphosphate glucokinase (PPGK), inositol 1-phosphate synthase (IPS) and inositol monophosphatase (IMP). The system contained three highly active enzymes, AspPPGK from Arthrobacter sp. OY3WO11, TbIPS from Trypanosoma brucei TREU927, and EcIMP from Escherichia coli. A trienzymatic cascade reaction was implemented, and the conversion ratio from glucose to inositol reached 90%, which is promising for the enzymatic synthesis of inositol without ATP supplementation. PMID- 29499775 TI - d-Xylose and l-arabinose laurate esters: Enzymatic synthesis, characterization and physico-chemical properties. AB - Efficient enzymatic synthesis of d-xylose and l-arabinose lauryl mono- and diesters has been achieved by transesterification reactions catalysed by immobilized Candida antarctica lipase B as biocatalyst, in organic medium in the presence of d-xylose or l-arabinose and vinyllaurate at 50 degrees C. In case of l-arabinose, one monoester and one diester were obtained in a 57% overall yield. A more complex mixture was produced for d-xylose as two monoesters and two diesters were synthesized in a 74.9% global yield. The structures of all these pentose laurate esters was solved. Results demonstrated that the esterification first occurred regioselectively onto the primary hydroxyl groups. Pentose laurate esters exhibited interesting features such as low critical aggregation concentrations values all inferior to 25 MUM. Our study demonstrates that the enzymatic production of l-arabinose and d-xylose-based esters represents an interesting approach for the production of green surfactants from lignocellulosic biomass-derived pentoses. PMID- 29499776 TI - Identification and characterization of GH62 bacterial alpha-l-arabinofuranosidase from thermotolerant Streptomyces sp. SWU10 that preferentially degrades branched l-arabinofuranoses in wheat arabinoxylan. AB - We previously described thermotolerant Streptomyces sp. SWU10, which produced four endo-xylanases and one xylosidase able to digest xylan backbones. To achieve arabinoxylan degradation, the swu62A gene was cloned and overexpressed in Escherichia coli, and the recombinant enzyme, termed SWUAbf62A, was characterized. The 438 amino acids of SWUAbf62A revealed Glyco_hydro_62 and closely related with putative alpha-l-arabinofuranosidases belonging to glycoside hydrolase family 62. SWUAbf62A was purified in two steps, Ni-affinity and size exclusion column chromatographies, and its molecular mass without signal peptide was determined to be 49 kDa. SWUAbf62A showed optimum activity at pH 5.0 and 50 degrees C, and more than 70% of its initial enzymatic activity remained after incubation at pH 4.1-10.5, while SWUAbf62A lost all activity after 1 h at 60 degrees C. SWUAbf62A activity was stimulated by Ba2+, Ca2+, and Mn2+ and decreased by Ag+, Cu2+, Fe2+, and EDTA. SWUAbf62A had no activity towards p nitrophenyl-alpha-l-arabinofuranoside or p-nitrophenyl-beta-d-xylopyranoside synthetic substrates. On the other hand, SWUAbf62A had the highest activity against wheat arabinoxylan, with a specific activity of 1.29 U/mg, and was also active against sugar beet arabinan, with a specific activity of 0.14 U/mg; these results indicated that SWUAbf62A is an arabinoxylan arabinofuranohydrolase. Using 1H-NMR analysis, SWUAbf62A was found to release l-arabinofuranoses singly linked to O-3 of wheat arabinoxylan. In addition, SWUAbf62A acted synergistically with endo-xylanase (XynSW3) and alpha-l-arabinofuranosidase, which releases arabinose linked to O-3 of double-substituted xylose residues on arabinoxylan, to digest the wheat arabinoxylan. SWUAbf62A is an important debranching enzyme for hydrolysis of hemicelluloses to monosaccharides and can be applied in various industrial biotechnologies. PMID- 29499777 TI - Characterization of two styrene monooxygenases from marine microbes. AB - Styrene monooxygenases (SMOs) are highly stereoselective enzymes that catalyze the formation of chiral epoxides as versatile building blocks. To expand the enzyme toolbox, two bacterial SMOs were identified from the genome of marine microbes Paraglaciecola agarilytica NO2 and Marinobacterium litorale DSM 23545, and heterologously expressed in Escherichia coli in soluble form. Both of the resulting whole-cell biocatalysts exhibited maximal activity at 30 degrees C and pH 8.0. They catalyzed the sulfoxidation reactions, and the epoxidation of both conjugated and unconjugated styrene derivatives with up to >99%ee. MlSMO displayed higher activity toward most substrates tested. Compared to an established SMO from Pseudomonas species (PsSMO), MlSMO achieved 3.0-, 3.4- and 2.6-fold conversions for substrates styrene, cinnamyl alcohol and 4-vinyl-2, 3 dihydrobenzofuran, respectively. PMID- 29499778 TI - Biocontrol activity of recombinant aspartic protease from Trichoderma harzianum against pathogenic fungi. AB - The use of cell wall degrading enzymes of Trichoderma is a promising alternative for improving food storage. The aspartic protease P6281 secreted by the fungus Trichoderma harzianum plays an important role in mycoparasitism on phytopathogenic fungi. In this study, recombinant P6281 (rP6281) expressed in Pichia pastoris showed high activity of 321.8 U/mL. Maximum activity was observed at pH 2.5 and 40 degrees C, and the enzyme was stable in the pH range of 2.5 6.0. rP6281 significantly inhibited spore germination and growth of plant and animal pathogenic fungi such as Botrytis cinerea, Mucor circinelloides, Aspergillus fumigatus, Aspergillus flavus, Rhizoctonia solani, and Candida albicans. Transmission electron microscopy revealed that rP6281 efficiently damages the cell wall of Botrytis cinerea. In addition, the protease significantly inhibited the development of grey mold that causes rotting of apple, orange, and cucumber, indicating that rP6281 may be developed as an effective anti-mold agent for fruit storage. PMID- 29499779 TI - Development of an electrochemical immunosensor based on gold nanoparticles incorporated chitosan biopolymer nanocomposite film for the detection of prostate cancer using PSA as biomarker. AB - In this study, we have developed an electrochemical immunosensor for the detection of prostate-specific antigen (PSA) based on gold nanoparticles (AuNPs) and a chitosan (CHI) nanocomposite film coated on a screen printed electrode (SPE). The modified SPE was characterized using scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). The immunosensor was fabricated by sequential immobilization of anti-PSA primary antibody, PSA antigen and HRP tagged secondary antibody on the surface of AuNPs/CHI/SPE. When this immunosensor was placed in 2.5mM H2O2, as HRP substrate, and 1mM methylene blue (MB), as redox mediator, greatly amplified immunosensing signals were observed. Immunosensing signals for the reduction of H2O2 were monitored in phosphate buffer (pH 7.0) by CV and square wave voltammetry (SWV). Under optimized conditions steady state current increased linearly with PSA concentration over the range 1-18ng/ml with a detection limit of 0.001ng/ml. The fabricated immunosensor demonstrated excellent sensitivity, stability and reproducibility and therefore was successfully applied to analyse PSA in biological samples. Finally, the results indicate that the proposed immunosensor has potential in clinical screening of cancer biomarkers. PMID- 29499780 TI - Cloning and characterization of a novel phenylalanine ammonia-lyase gene from Inonotus baumii. AB - Phenylalanine ammonia-lyase (PAL) gene plays an important role in the synthesis of flavones, lignin, and other bioactive compounds in living organisms. Inonotus baumii, the only known flavone-producing filamentous fungus, is of great importance in the investigation of flavone metabolic pathways. To study the function of PAL enzyme in I. baumii flavone synthesis, a full-length cDNA of pal gene was cloned from I. baumii using DOP-PCR and RACE-PCR. The 2502-bp PAL coding region encodes an 833 amino acid protein with an approximate MW of 88.2kDa. Three introns and four exons are present in the DNA sequence of IbPAL. Amino acid sequence alignment showed that IbPAL shares 76% similarity with PALs of Inonotus fungi. The three-dimensional structure of IbPAL showed that it is composed of an MIO domain, a core domain and an inserted shielding domain. On this basis, the IbPAL was expressed and purified using the prokaryotic expression vector pSMART-V with a 6xHis-tag in Escherichia coli, and its enzymatic activity was subsequently detected. Our results will aid in understanding the enzymatic properties of PAL and further confirm the mechanism of flavone synthesis in I. baumii. PMID- 29499781 TI - FCS and ECH dependent production of phenolic aldehyde and melanin pigment from l tyrosine in Escherichia coli. AB - In this study, we engineered E. coli cells to express l-tyrosine converting enzymes, including tyrosine ammonia-lyase (TAL), p-coumarate 3-hydroxylase (C3H), feruloyl-CoA synthetase (FCS), and enoyl-CoA hydratase/aldolase (ECH). A catabolic circuit, which consisted of the protocatechualdehyde and p hydroxybenzaldehyde production pathways, was reconstituted through combinatorial production of discrete enzymes. First, cells expressing FCS and ECH could convert each 5mM of caffeic acid and ferulic acid into protocatechualdehyde (70.5%) and vanillin (96.5%), respectively. Second, TAL and C3H were co-expressed with FCS and ECH. This strain converted l-tyrosine into caffeic acid, which was then converted into protocatechualdehyde. Ascorbic acid was used as an inhibitor of catechol aldehyde-based melanin formation, and the production yields of protocatechualdehyde and p-hydroxybenzaldehyde were 31.0+/-5.6 and 24.0+/ 4.2mg/L, respectively. Finally, caffeic acid-based melanin formation was observed with higher production rate of 40.9+/-6.2mg/L/h by co-expressing FCS and ECH in the presence of caffeic acid. PMID- 29499782 TI - Chemoenzymatic lignin valorization: Production of epoxidized pre-polymers using Candida antarctica lipase B. AB - An innovative chemoenzymatic catalytic system for functionalizing lignin from Organosolv and Kraft pulping processes to obtain oxirane rings was investigated. Novozym435 (immobilized C. antarctica lipase B: CalB) was used to catalyze the peroxidation of caprylic acid to peroxycaprylic acid, which in turn reacted with unsaturated CC bonds to form the oxirane ring. The conversion of OH groups to oxirane rings (epoxides) reached 90% and 55% after 12 h for the two processes, respectively. The residual enzyme activity over the time course of the reactions indicated transient denaturing due to association with the lignin substrate (10 50%) as well as irreversible denaturation due to exposure to hydrogen peroxide. Functionalized lignin has potential applications in the production of epoxy adhesive resins, and chemoenzymatic synthesis represents a "greener" pathway to this synthesis. PMID- 29499783 TI - An OPAA enzyme mutant with increased catalytic efficiency on the nerve agents sarin, soman, and GP. AB - The wild-type OPAA enzyme has relatively high levels of catalytic activity against several organophosphate G-type nerve agents. A series of mutants containing replacement amino acids at the OPAA Y212, V342, and I215 sites showed several fold enhanced catalytic efficiency on sarin, soman, and GP. One mutant, Y212F/V342L, showed enhanced stereospecificity on sarin and that enzyme along with a phosphotriesterase mutant, GWT, which had the opposite stereospecificity, were used to generate enriched preparations of each sarin enantiomer. Inhibition of acetylcholinesterase by the respective enantioenriched sarin solutions subsequently provided identification of the sarin enantiomers as separated by normal phase enantioselective liquid chromatography coupled with atmospheric pressure chemical ionization-mass spectrometry. PMID- 29499784 TI - Identification and characterization of the first beta-1,3-d-xylosidase from a gram-positive bacterium, Streptomyces sp. SWU10. AB - In previous reports, we characterized four endo-xylanases produced by Streptomyces sp. strain SWU10 that degrade xylans to several xylooligosaccharides. To obtain a set of enzymes to achieve complete xylan degradation, a beta-d-xylosidase gene was cloned and expressed in Escherichia coli, and the recombinant protein, named rSWU43A, was characterized. SWU43A is composed of 522 amino acids and does not contain a signal peptide, indicating that the enzyme is an intracellular protein. SWU43A was revealed to contain a Glyco_hydro_43 domain and possess the three conserved amino acid residues of the glycoside hydrolase family 43 proteins. The molecular mass of rSWU43A purified by Ni-affinity column chromatography was estimated to be 60kDa. The optimum reaction conditions of rSWU43A were pH 6.5 and 40 degrees C. The enzyme was stable up to 40 degrees C over a wide pH range (3.1-8.9). rSWU43A activity was enhanced by Fe2+ and Mn2+ and inhibited by various metals (Ag+, Cd2+, Co2+, Cu2+, Hg2+, Ni2+, and Zn2+), d-xylose, and l-arabinose. rSWU43A showed activity on p-nitrophenyl beta-d-xylopyranoside and p-nitrophenyl-alpha-l-arabinofuranoside substrates, with specific activities of 0.09 and 0.06U/mg, respectively, but not on any xylosidic or arabinosidic polymers. rSWU43A efficiently degraded beta-1,3 xylooligosaccharides to produce xylose but showed little activity towards beta 1,4-xylobiose, with specific activities of 1.33 and 0.003U/mg, respectively. These results demonstrate that SWU43A is a beta-1,3-d-xylosidase (EC 3.2.1.72), which to date has only been described in the marine bacterium Vibrio sp. Therefore, rSWU43A of Streptomyces sp. is the first beta-1,3-xylosidase found in gram-positive bacteria. SWU43A could be useful as a specific tool for the structural elucidation and production of xylose from beta-1,3-xylan in seaweed cell walls. PMID- 29499785 TI - Rational selection of biphasic reaction systems for geranyl glucoside production by Escherichia coli whole-cell biocatalysts. AB - Geranyl glucoside, the glucosylated, high-value derivative of the monoterpenoid geraniol, has various applications in the flavor and fragrance industry and can be produced through whole-cell biotransformation of geraniol with Escherichia coli whole-cell biocatalysts expressing the glucosyltransferase VvGT14a. However, the low water solubility and high cytotoxicity of geraniol require the design of a proper biphasic system where the second, non-aqueous phase functions as an in situ substrate reservoir. In this work, a rational selection strategy was applied for choosing suitable sequestering phases for geranyl glucoside production by whole-cell biotransformation of geraniol. Hansen solubility parameters and octanol/water distribution coefficients were used as first principle methods in combination with extensive database research to preselect 12 liquid and 6 solid sequestering phases. Subsequently, experimental approaches were applied to determine physicochemical characteristics and the distribution of geraniol and geranyl glucoside between the phases. Moreover, the effects of the sequestering phases on the whole-cell biocatalysts and on the produced geranyl glucoside concentration were measured during parallel biotransformations in milliliter scale stirred-tank bioreactors. The fatty acid ester isopropyl myristate emerged as the best choice due to its low viscosity, very poor water solubility, low price and compatibility with the whole-cell biocatalyst. The biphasic system containing 20% (v/v) of this solvent boosted geranyl glucoside production (4.2 fold increase of geranyl glucoside concentration in comparison to aqueous system) and exhibits advantageous partitioning of geraniol into the organic phase (logD of 2.42+/-0.03) and of geranyl glucoside into the water phase (logD of -2.08+/ 0.05). The systematic selection of a suitable biphasic system constitutes basic groundwork for the development of new bioprocesses involving geraniol. Moreover, this study can serve as a guideline for selecting sequestering phases for other whole-cell biotransformation processes. PMID- 29499787 TI - You have questions...APIC Text Online has the answers! PMID- 29499786 TI - Biochemical characterization of a novel tyrosine phenol-lyase from Fusobacterium nucleatum for highly efficient biosynthesis of l-DOPA. AB - Tyrosine phenol-lyase (TPL) catalyzes the reversible cleavage of l-tyrosine to phenol, pyruvate and ammonia. When pyrocatechol is substituted for phenol, l dihydroxyphenylalanine (l-DOPA) is produced. The TPL-catalyzed route was regarded as the most economic process for l-DOPA production. In this study, a novel TPL from Fusobacterium nucleatum (Fn-TPL) was successfully overexpressed in Escherichia coli and screened for l-DOPA synthesis with a specific activity of 2.69Umg-1. Fn-TPL was found to be a tetramer, and the optimal temperature and pH for alpha, beta-elimination of l-tyrosine was 60 degrees C and pH 8.5, respectively. The enzyme showed broad substrate specificity toward natural and synthetic l-amino acids. Kinetic analysis suggested that the kcat/Km value for l tyrosine decomposition was much higher than that for l-DOPA decomposition, while Fn-TPL exhibited similar catalytic efficiency for synthesis of l-tyrosine and l DOPA. With whole cells of recombinant E. coli as biocatalyst, l-DOPA yield reached 110gL-1 with a pyrocatechol conversion of 95%, which was comparable to the reported highest level. The results demonstrated the great potential of Fn TPL for industrial production of l-DOPA. PMID- 29499788 TI - Determining training and education needs pertaining to highly infectious disease preparedness and response: A gap analysis survey of US emergency medical services practitioners. AB - BACKGROUND: The Ebola virus disease outbreak highlighted the lack of consistent guidelines and training for workers outside of hospital settings. Specifically, emergency medical services (EMS) workers, who are frequently the first professionals to evaluate patients, often do not have advanced notice of patient diagnosis, and have limited time in their national curricula devoted to highly infectious disease (HID) identification and containment. All of these can place them at increased risk. To explore the depth of US EMS practitioners' HID training and education, a pilot gap analysis survey was distributed to determine where the aforementioned can be bolstered to increase occupational safety. METHODS: Electronic surveys were distributed to EMS organization members. The survey collected respondent willingness to encounter HID scenarios; current policies and procedures; and levels of knowledge, training, and available resources to address HIDs. RESULTS: A total of 2,165 surveys were initiated and collected. Eighty percent of frontline personnel were aware that their agency had an HID standard operating guideline. Almost 85% of respondents correctly marked routes of exposure for select HIDs. More than half of respondents indicated no maximum shift times in personal protective equipment. DISCUSSION: This research suggests EMS practitioners could benefit from enhanced industry-specific education, training, and planning on HID mitigation and management. CONCLUSION: Strengthening EMS preparedness in response to suspected or confirmed HID cases may not only improve patient outcomes, but also worker and community safety. PMID- 29499789 TI - Journal club: A pilot gap analysis survey of US emergency medical services practitioners to determine training and education needs pertaining to highly infectious disease preparedness and response. PMID- 29499790 TI - The Duty to Lead by Example. PMID- 29499791 TI - Hysteroscopic Endometrial Polypectomy: Clinical and Economic Data in Decision Making. AB - STUDY OBJECTIVE: To compare the costs of hysteroscopic polypectomy using mechanical and electrosurgical systems in the hospital operating room and an office-based setting. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: Tertiary referral hospital and center for gynecologic care. PATIENTS: Seven hundred and fifty-four women who underwent endometrial polypectomy between January 20, 2015, and April 27, 2016. INTERVENTIONS: Hysteroscopic endometrial polypectomy performed in the same-day hospital setting or office setting using one of the following: bipolar electrode, loop electrode, mechanical device, or hysteroscopic tissue removal system. MEASUREMENTS AND MAIN RESULTS: The various costs associated with the 2 clinical settings at Palagi Hospital, Florence, Italy were compiled, and a direct cost comparison was made using an activity-based cost-management system. The costs for using reusable loop electrode resection-16 or loop electrode resection-26 were significantly less expensive than using disposable loop electrode resection-27, the tissue removal system, or bipolar electrode resection (p = .0002). Total hospital costs for polypectomy with all systems were significantly less expensive in an office setting compared with same-day surgery in the hospital setting (p = .0001). Office-based hysteroscopic tissue removal was associated with shorter operative time compared with the other procedures (p = .0002) CONCLUSION: The total cost of hysteroscopic polypectomy is markedly higher when using disposable equipment compared with reusable equipment, both in the hospital operating room and the office setting. Same-day hospital or office-based surgery with reusable loop electrode resection is the most cost-effective approach in each settings, but requires experienced surgeons. Finally, the shorter surgical time should be taken into consideration for patients undergoing vaginal polypectomy in the office setting, owing more to patient comfort than to cost savings. PMID- 29499792 TI - Using assessment to individualize early mathematics instruction. AB - Accumulating evidence suggests that assessment-informed personalized instruction, tailored to students' individual skills and abilities, is more effective than more one-size-fits-all approaches. In this study, we evaluate the efficacy of Individualizing Student Instruction in Mathematics (ISI-Math) compared to Reading (ISI-Reading) where classrooms were randomly assigned to ISI-Math or ISI-Reading. The literature on child characteristics X instruction or skill X treatment interaction effects point to the complexities of tailoring instruction for individual students who present with constellations of skills. Second graders received mathematics instruction in small flexible learning groups based on their assessed learning needs. Results of the study (n=32 teachers, 370 students) revealed significant treatment effects on standardized mathematics assessments. With effect sizes (d) of 0.41-0.60, we show that we can significantly improve 2nd graders' mathematics achievement, including for children living in poverty, by using assessment data to individualize the mathematics instruction they receive. The instructional regime, ISI-Math, was implemented by regular classroom teachers and it led to about a 4-month achievement advantage on standardized mathematics tests when compared to students in control classrooms. These results were realized within one school year. Moreover, treatment effects were the same regardless of school-level poverty and students' gender, initial mathematics or vocabulary scores. PMID- 29499793 TI - Psychosocial Burden and Other Impacts of Rosacea on Patients' Quality of Life. AB - Rosacea is a common and chronic skin disorder with substantial impact on a patients' quality of life. Its varying phenotypic features and facial localization can adversely affect the mental health and socialization of those affected. Although there are no curative interventions, certain therapies have greater effect in improving patient quality of life. This article summarizes the associated psychosocial implications of rosacea. Several skin disease and rosacea specific quality-of-life measures and their application in clinical care and research studies are also summarized. The recognition and management of the psychosocial impact of rosacea is critical to improving patient outcomes. PMID- 29499794 TI - Rosacea Comorbidities. AB - Rosacea is a chronic inflammatory cutaneous disorder with an unclear pathogenesis. It has been associated with multiple comorbidities, including cardiovascular diseases, malignancies, depression, migraines, dementia, Parkinson disease, gastrointestinal disorders, and autoimmune conditions. The extent, clinical significance, and implications of these associations remain a topic of discussion. Further evaluation of these comorbidities may offer valuable insight for future screening practices and treatment recommendations. PMID- 29499795 TI - Rosacea Triggers: Alcohol and Smoking. AB - A variety of triggers are thought to exacerbate rosacea. A validated self assessment tool and survey was used to study the relationship between rosacea severity and triggers. Subjects were adult patients with a clinical diagnosis of rosacea. Increased severity of disease was significantly associated with consumption of many alcoholic beverages in 1 day and employment at a job requiring extensive sun exposure. The authors' findings may inform physician counseling practices; patients may be provided with practical measures for managing their rosacea, such as limiting alcohol consumption over short periods of time and increasing sun protection, especially in the summer. PMID- 29499796 TI - Evaluating and Optimizing the Diagnosis of Erythematotelangiectatic Rosacea. AB - Erythematotelangiectatic rosacea is the most prevalent rosacea subtype. Multiple dermatologic conditions may mimic erythematotelangiectatic rosacea. The authors review a comprehensive approach to evaluating subjects with a suspected diagnosis of erythematotelangiectatic rosacea and discuss findings that may warrant further investigation. Differential diagnoses can be narrowed based on the presence of characteristics such as transient erythema, nontransient erythema, and telangiectasias. A thorough history and physical examination are critical in ruling out conditions such as dermatomyositis, lupus erythematosus, atopic dermatitis, and seborrheic dermatitis. PMID- 29499797 TI - A Review of the Current Modalities for the Treatment of Papulopustular Rosacea. AB - Papulopustular rosacea is characterized by papules and pustules in the central facial region. We review the literature surrounding the treatment of papulopustular rosacea. PubMed, EMBASE, and Cochrane (Central) databases searches of articles published from 1980 to 2015 were performed using the MeSH terms or keywords "rosacea" and "clinical trial." Additional searches were performed to include rosacea and each treatment modality used. Topical metronidazole, azelaic acid, ivermectin, and oral doxycycline have the most robust data to support their use. Variation in assessment tools and a lack of clinical trial standardization makes comparison of therapeutic options difficult. PMID- 29499798 TI - Medical Management of Facial Redness in Rosacea. AB - Persistent centrofacial erythema is a predominant component of rosacea. The authors review the topical and systemic treatments for rosacea-related erythema and flushing to aid in treatment decision making in clinical practice. Databases were searched for literature pertaining to treatment options for erythema related to rosacea. The paucity of large-scale clinical trials in patients with the erythematotelangiectatic rosacea subtype makes it difficult to draw firm conclusions regarding treatment. Although certain topical and oral treatments appear to have modest benefit in reducing erythema, there is a need for high quality, well-designed, and rigorously reported studies for the treatments for rosacea. PMID- 29499799 TI - Revisiting Rosacea Criteria: Where Have We Been, Where Are We Going, and How Will We Get There? AB - Rosacea is one of the most common and misunderstood dermatologic conditions. Currently, rosacea criteria are based on expert opinion; the definition of rosacea is primarily a reflection of opinion that is prone to bias. It has been more than a decade since the initial criteria were created by the National Rosacea Society. Revisiting the criteria and incorporating evidence-based techniques used by rheumatology and psychiatry can improve the validity and reliability of rosacea criteria. Literature from other specialties is reviewed and a method proposed for developing valid criteria. Examples are provided to motivate and highlight the importance of implementing such techniques. PMID- 29499800 TI - Patient Costs Associated with Rosacea. AB - The recalcitrance of rosacea to many treatment options may prompt patients to spend exorbitant amounts of money on unsubstantiated treatment regimens in an effort to achieve relief. The authors examine the relationship between disease severity and treatment cost across several demographic and socioeconomic strata. Familiarization of evidence-based clinical recommendations and consensus guidelines may equip physicians to educate patients about the most efficacious and cost-effective treatment options to assist patients in making cost-conscious decisions in the management of their rosacea. PMID- 29499801 TI - Coping Mechanisms and Resources for Patients Suffering from Rosacea. AB - Rosacea has significant quality of life impact. The authors review the literature and Internet sources pertaining to rosacea to identify coping mechanisms and resources available to rosacea patients. MEDLINE and PsycINFO databases were searched to identify pertinent articles. The term "rosacea" was searched in combination with "patient resources," "coping," "dealing with," "blog," "forum," "support," "nonpharmacologic," and "psychological." There are several social and educational coping resources available to rosacea patients. These may optimize quality of life and psychosocial outcomes in patients with rosacea. PMID- 29499802 TI - Rosacea Pathogenesis. AB - Rosacea is a chronic inflammatory skin disorder that is not fully understood but involves the complex interplay of genetic factors, immune dysregulation, neurovascular dysregulation, presence of microorganisms, and environmental factors. Increased activation of the immune system occurs through multiple stimuli, including increased levels of cathelicidin and kallikrein 5, Toll-like receptor 2, matrix metalloproteinases, and mast cells within the skin. Their effects are enhanced by the presence of microorganisms and external triggers, such as UV radiation. PMID- 29499803 TI - Genetic Predisposition to Rosacea. AB - Rosacea is a common inflammatory skin disease with a multifaceted pathophysiology, including environmental stressors and neurovascular and immune dysfunction affected by the presence of pathogens. The genetic component of this disorder is not well understood. However, a possible genetic origin in Northern European descendants, family inheritance, twin concordance, and genetic associations with autoimmune disorders attest the genetic predisposition to rosacea. Currently, one single-nucleotide polymorphism has been identified in association with rosacea and is intergenic between HLA-DRA and BTNL2. Additional associations with HLA alleles and immune-mediated disorders support the role of immune-regulating genes and innate and adaptive immunity in rosacea. PMID- 29499804 TI - Validity and Reliability of a Rosacea Self-Assessment Tool. AB - The lack of validated rosacea assessment tools is a hurdle in assessing rosacea severity. This article discusses a valid and reliable rosacea severity self assessment tool (RSAT) to measure rosacea severity. To determine test-retest validity, participants completed the self-assessment twice. A blinded physician graded the participant's disease severity with the Investigator Global Severity (IGS) score. Pearson correlations were used to assess the relationship between the self-assessment measure and the IGS. Test-retest RSAT measurements were correlated. The RSAT represents a valid and reliable tool. This tool may facilitate determination of rosacea severity in survey research studies. PMID- 29499805 TI - Measurement of Disease Severity in a Population of Rosacea Patients. AB - Severity of rosacea in populations is not well characterized. A validated self assessment tool was used to study the relationship between rosacea severity and demographic factors. Subjects were adult patients with a clinical diagnosis of rosacea. Self-assessment severity scores were significantly higher in participants less than 60 years old (mean 3.43 +/- 1.07) compared with those greater than or equal to 60 years old (mean 3.09 +/- 1.13; P = .04). Self assessment severity scores were significantly higher in men (3.6 +/- 1.3) than women (3.2 +/- 1.0; P = .04). The authors conclude that rosacea is more severe in men and younger patients. PMID- 29499806 TI - Complexities of Rosacea. PMID- 29499807 TI - Applying Population Health Approaches to Undiagnosed Hypertension. PMID- 29499808 TI - Improving Identification and Diagnosis of Hypertensive Patients Hiding in Plain Sight (HIPS) in Health Centers. AB - BACKGROUND: Hypertension is the most prevalent chronic condition diagnosed among patients served in the safety net in the United States; however, many safety-net patients with hypertension are not formally diagnosed and may remain untreated and at increased risk for cardiovascular events. Identifying undiagnosed hypertension using algorithmic logic programmed into clinical decision support (CDS) approaches is a promising practice but has not been broadly tested in the safety-net setting. METHODS: The project used a quality improvement approach wherein information flows and actions related to blood pressure measurement were modified to include algorithm criteria to identify patients who might have undiagnosed hypertension. Identified patients were recalled for evaluation and hypertension diagnosis, if appropriate. Ten health centers in Arkansas, California, Kentucky, and Missouri were selected to participate in the project on the basis of high hypertension prevalence (compared to national average), demographic and geographic diversity, mature information systems infrastructure, and executive support. The project targeted patients from 18 to 85 years of age. RESULTS: After implementation of algorithm-based interventions, diagnosed hypertension prevalence increased significantly from 34.5% to 36.7% (p <0.05). A cohort of patients was tracked from 8 of the 10 health centers to assess follow up evaluation and diagnosis rates; 65.2% completed a follow-up evaluation, of which 31.9% received a hypertension diagnosis. CONCLUSION: Using algorithmic logic and other CDS-enabled care process improvements appears to be an effective way health centers can identify and engage patients at risk for undiagnosed hypertension. Appropriately diagnosing all hypertensive patients ensures that hypertension control efforts yield maximal improvements in population health. PMID- 29499809 TI - Empowering Informal Caregivers with Health Information: OpenNotes as a Safety Strategy. AB - BACKGROUND: Enabling family/friend caregivers with access to visit notes may help avoid errors, delayed diagnoses, or other ambulatory safety risks. Patient, parent, and caregiver perceptions of how shared notes affect safety behaviors and attitudes were studied in an exploratory study. METHODS: To assess the impact of OpenNotes on safety, 24,722 patients with active portal accounts and >= 1 available visit notes during the prior year at an urban hospital were surveyed between June and September 2016. Surveys were sent to patient portal accounts, and respondents designated themselves as patients or caregivers. Although the hospital does not have formal proxy portal registration, some patients share access with their caregivers. RESULTS: Of 24,722 portal accounts accessed during the study, 7,058 (28.5%) surveys were returned, with 150 (2.1%) participants identified as caregivers. Among patients who had tests and referrals, reading notes helped caregivers understand the reason for the test (96/120 [80.0%]) or referral (48/52 [92.3%]), remember to get patient tests done (66/120 [55.0%]), check (98/120 [81.7%]) and understand (98/120 [81.7%]) results, and remember patient appointments (36/52 [69.2%]). As a result of reading notes, 54.1% (59/109) of caregivers helping patients on prescription medications reported better assisting patients to take them correctly. Among note-reading caregivers, 53.7% (n = 72/134) trusted the clinician more (44.8% no change), and 58.2% (n = 78/134) reported better teamwork (41.0% no change) as a result of open notes. In total, 30.3% (n = 40/132) reported at least one mistake or possible mistake in the patient's notes. Finding a possible mistake did not negatively affect trust or teamwork. CONCLUSION: OpenNotes may enable caregivers with patient health information, answering the call to better support this critical group in the health care system and to engage patients and families in safety efforts. PMID- 29499810 TI - When Clinicians Drop Out and Start Over after Adverse Events. AB - BACKGROUND: The impact of adverse clinical events on health care workers has become a growing topic of research. Previous research has confirmed that after adverse clinical events, clinical staff often feel as though they failed not only their patient but also themselves, resulting in second-guessing of their clinical skills, competencies, and even career choices. This exploratory study reports on the experiences of health care providers who changed career paths as a consequence of an adverse clinical event. METHODS: The authors designed a 39 question survey capturing personal and professional demographics, participant recall of the clinical event, insights into their lived experiences, health care institutions' response(s) to the event, decision-making influences relating to future employment, and insights into interventional strategies. RESULTS: Consistent with prior research, clinicians reported a pattern of inadequate social support after the event. Results further show the salience of emotional labor as a driving force among those who changed roles. In clinicians' own assessments about the lasting impact of the event, many felt less joy and meaning in their new clinical roles, but others thrived by rededicating their careers toward implementing patient safety initiatives and enhancing peer-support networks. Clinicians reported a desire for more transparency and support to help them recover. CONCLUSION: Clinicians aligned their emotional displays to be consistent with organizational expectations, resulting in suppressed feelings of guilt and shame that may have contributed to burnout, changed roles, or even premature retirement. Study findings highlight the need to develop better support systems for clinicians who are party to an adverse clinical event. PMID- 29499811 TI - Meeting Quality Measures for Adolescent Preventive Care: Assessing the Perspectives of Key Stakeholders. AB - BACKGROUND: Health plans are increasingly implementing quality improvement strategies aimed at meeting adolescent clinical quality measures, yet clinics often struggle to meet these measures. This qualitative study was conducted to explore how efforts to meet the National Committee for Quality Assurance (NCQA) Healthcare Effectiveness Data and Information Set (HEDIS) performance measure for adolescent well-care visits were perceived by a multidisciplinary group of stakeholders. METHODS: The research team conducted 26 in-depth, semistructured interviews with participants from three stakeholder groups: clinic staff with direct patient contact, health care institutional leaders, and representatives of a payer organization. Interviews were about 45 minutes in duration, audio recorded, and professionally transcribed. Framework analysis was used to identify and organize emergent themes, and Atlas.ti was used to facilitate data management and analysis. RESULTS: Stakeholder groups diverged in their opinions regarding strategies for achieving adolescent quality measures. Stakeholders with no direct patient interaction touted transactional quality improvement strategies that directly incentivized patients and families. In contrast, clinic staff with direct patient contact believed that incentive-based efforts undermined patient provider relationships and the clinics' focus on wellness. CONCLUSION: A considerable disconnect exists between stakeholders with and without patient contact with regard to approaches to the delivery of well care and quality improvement strategies for meeting the adolescent well-care visit performance measure. Efforts to reconcile discordant perspectives and promote a mutual understanding between payers, institutional leaders, and clinic staff could inform the development of creative initiatives that are sustainable and effective at achieving adolescent and family engagement, as well as clinical performance benchmarks. PMID- 29499812 TI - Highly Adoptable Improvement: A Practical Model and Toolkit to Address Adoptability and Sustainability of Quality Improvement Initiatives. AB - BACKGROUND: Failure to consider the impact of change on health care providers is a barrier to success. Initiatives that increase workload and have low perceived value are less likely to be adopted. A practical model and supporting tools were developed on the basis of existing theories to help quality improvement (QI) programs design more adoptable approaches. METHODS: Models and theories from the diffusion of innovation and work stress literature were reviewed, and key informant interviews and site visits were conducted to develop a draft Highly Adoptable Improvement (HAI) Model. A list of candidate factors considered for inclusion in the draft model was presented to an expert panel. A modified Delphi process was used to narrow the list of factors into main themes and refine the model. The resulting model and supporting tools were pilot tested by 16 improvement advisors for face validity and usability. RESULTS: The HAI Model depicts how workload and perceived value influence adoptability of QI initiatives. The supporting tools include an assessment guide and suggested actions that QI programs can use to help design interventions that are likely to be adopted. Improvement advisors reported good face validity and usability and found that the model and the supporting tools helped address key issues related to adoption and reported that they would continue to use them. CONCLUSION: The HAI Model addresses important issues regarding workload and perceived value of improvement initiatives. Pilot testing suggests that the model and supporting tools are helpful and practical in guiding design and implementation of adoptable and sustainable QI interventions. PMID- 29499813 TI - Improving Quality of Care in Hospitals for Victims of Elder Mistreatment: Development of the Vulnerable Elder Protection Team. AB - PROBLEM DEFINITION: Hospitals have an opportunity to improve the quality of care provided to a particularly vulnerable population: victims of elder mistreatment. Despite this, no programs to prevent or stop elder abuse in the acute care hospital have been reported. An innovative, multidisciplinary emergency department (ED)-based intervention for elder abuse victims, the Vulnerable Elder Protection Team (VEPT), was developed at NewYork-Presbyterian / Weill Cornell Medical Center (New York City). APPROACH: The VEPT is a consultation service available 24 hours a day/7 days a week to improve identification, comprehensive assessment, and treatment for potential victims of elder abuse or neglect. All ED providers have been trained on how to recognize signs of elder mistreatment. Any provider can activate the VEPT via a single page/telephone call, which triggers the VEPT's often time-consuming, complex assessment of the potential mistreatment victim. First, the ED social worker on duty performs the initial bedside assessment and separately interviews the potential perpetrator and/or caregiver. He or she then contacts the on-call VEPT medical provider to discuss next steps and other team members' potential involvement. For patients admitted to the hospital, the VEPT connects with the inpatient social workers and medical team to ensure appropriate follow-up and care planning. NEXT STEPS/PLANNED EVALUATION: The VEPT program was launched in April 2017 after comprehensive training. Its impact will be measured by tracking the short-term and long-term mistreatment related outcomes, as well as medical, mental health, functional, psychosocial, and legal outcomes of the vulnerable ED patients for whom the team provides care. PMID- 29499814 TI - Respiratory Synchronized Versus Intermittent Pneumatic Compression in Prevention of Venous Thromboembolism After Total Joint Arthroplasty: A Systematic Review and Meta-Analysis. AB - The objective of this study was to evaluate the efficacy of respiratory synchronized compression devices (RSCDs) versus nonsynchronized intermittent pneumatic compression devices (NSIPCDs) in preventing venous thromboembolism (VTE) after total joint arthroplasty. A systematic literature review was conducted. Data regarding surgical procedure, deep vein thrombosis, pulmonary embolism, mortality, and adverse events were abstracted. Compared with control groups, the risk ratio of deep vein thrombosis development was 0.51 with NSIPCDs and 0.47 with RSCDs. This review demonstrates that RSCDs may be marginally more effective at preventing VTE events than NSIPCDs. Furthermore, the addition of mechanical prophylaxis to any chemoprophylactic regimen increases VTE prevention. PMID- 29499815 TI - Bundle Payment for Musculoskeletal Care: Current Evidence (Part 1). AB - In the face of escalating costs and variations in quality of care, bundled payment models for total joint arthroplasty procedures are becoming increasingly common, both through the Centers for Medicare & Medicaid Services and private payer organizations. The effective implementation of these payment models requires cooperation between multiple service providers to ensure economic viability without deterioration in care quality. This article introduces a stepwise model for the financial analysis of bundled contracts for use in negotiations between hospitals and private payer organizations. PMID- 29499816 TI - Bundle Payment for Musculoskeletal Care: Current Evidence (Part 2). AB - In an effort to rein in expenditures and improve quality of care, the Centers for Medicare and Medicaid Services (CMS) has initiated bundled reimbursement programs for total joint arthroplasty (TJA) procedures. The success of CMS's bundled payment models has prompted some private insurers to collaborate with provider organizations to institute similar bundled contracts for TJA. The authors review the experiences of orthopedic groups in the implementation of bundled payments for primary and revision TJA through both public and private payers. The authors also discuss the potential benefits, risks, and barriers groups may encounter under this novel payment model. PMID- 29499817 TI - Use of Tourniquets in Limb Trauma Surgery. AB - Although tourniquets are commonly used in patients with limb trauma patients, both in the acute and elective settings, no set protocols exist for their indications, contraindications, or proper use. This article addresses the current literature on optimal pressure, timing, cuff design, and complications of tourniquets in trauma patients. General issues are discussed, followed by those specific to upper and lower extremities. Lastly, serious complications, such as pulmonary embolism, are described. PMID- 29499818 TI - Articular Incongruity in the Lower Extremity: How Much Is Too Much? AB - Intraarticular fractures carry a significant risk for posttraumatic osteoarthritis, and this risk varies across different joint surfaces of the lower extremity. These differences are likely due to the anatomic and biomechanical specifics of each joint surface. High-quality human studies are lacking to delineate the threshold articular incongruity that significantly increases risk for posttraumatic osteoarthritis and diminished clinical outcomes for many joint surfaces. Even with anatomic reduction of the articular surface, close attention must be paid to mechanical axis and joint stability to optimize outcomes. PMID- 29499819 TI - Hip Surveillance in Children with Cerebral Palsy. AB - The hip is the second most common involved joint in cerebral palsy. Hip displacement occurs in more than 33% of children with cerebral palsy, with a higher prevalence in nonambulatory children. Hip displacement in this population is typically progressive. Hip dislocation can result in pain and difficulty with sitting and perineal care. Since early stage of hip displacement can be silent, and hip surveillance programs are recommended. Most programs use the degree of hip dysplasia and Growth Motor Function Classification System level for screening recommendations. Treatment depends on the degree of dysplasia, functional status of the patient, and patient's age. PMID- 29499820 TI - Current Use of Evidence-Based Medicine in Pediatric Spine Surgery. AB - Evidence-based medicine (EBM) is a process of decision-making aimed at making the best clinical decisions as they relate to patients' health. The current use of EBM in pediatric spine surgery is varied, based mainly on the availability of high-quality data. The use of EBM is limited in idiopathic scoliosis, whereas EBM has been used to investigate the treatment of pediatric spondylolysis. Studies on early onset scoliosis are of low quality, making EBM difficult in this condition. Future focus and commitment to study quality in pediatric spinal surgery will likely increase the role of EBM in these conditions. PMID- 29499821 TI - Pediatric Orthopedic Trauma: An Evidence-Based Approach. AB - The management of pediatric fractures has evolved over the past several decades, and many injuries that were previously being managed nonoperatively are now being treated surgically. The American Academy of Orthopaedic Surgeons has developed clinical guidelines to help guide decision making and streamline patient care for certain injuries, but many topics remain controversial. This article analyzes the evidence regarding management of 5 of the most common and controversial injuries in pediatric orthopedics today. PMID- 29499822 TI - Evidence-Based Review of Distal Radius Fractures. AB - Distal radius fractures are one of the most commonly treated fractures in the United States. The highest rates are seen among the elderly, second only to hip fractures. With the increasing aging population these numbers are projected to continue to increase. Distal radius fractures include a spectrum of injury patterns encountered by general practitioners and orthopedists alike. This evidence-based review of distal radius fractures incorporates current and available literature on the diagnosis, management, and treatment of fractures of the distal radius. PMID- 29499823 TI - Carpal Tunnel Syndrome: Making Evidence-Based Treatment Decisions. AB - Carpal tunnel syndrome (CTS) is one of the most common musculoskeletal disorders of the upper extremity. Comorbidities associated with the development of CTS include diabetes and obesity. Although a high rate of repetitive hand/wrist motions is a risk factor, there is insufficient evidence to implicate computer use in the development of CTS. Initial treatment generally is nonoperative, with the strongest evidence supporting bracing/splinting. Strong evidence supports operative treatment, regardless of technique, as superior to nonoperative treatment. Complications are infrequent and most are minor and transient. PMID- 29499824 TI - Injection Therapies for Rotator Cuff Disease. AB - Rotator cuff disease affects a large proportion of the overall population and encompasses a wide spectrum of pathologies, including subacromial impingement, rotator cuff tendinopathy or tear, and calcific tendinitis. Various injection therapies have been used for the treatment of rotator cuff disease, including corticosteroid, prolotherapy, platelet-rich plasma, stem cells, and ultrasound guided barbotage for calcific tendinitis. However, the existing evidence for these therapies remains controversial or sparse. Ultimately, improved understanding of the underlying structural and compositional deficiencies of the injured rotator cuff tissue is needed to identify the biological needs that can potentially be targeted with injection therapies. PMID- 29499825 TI - Antibiotic Prophylaxis and Prevention of Surgical Site Infection in Shoulder and Elbow Surgery. AB - Infection after orthopedic procedures is a devastating and serious complication associated with significant clinical and financial challenges to the health care system and unfortunate patient. The time and resource-intensive nature of treating infection after orthopedic procedures has turned attention toward enhancing prevention and establishing quality improvement measures. Prevention strategies throughout the perioperative period include host optimization, risk mitigation, reducing bacterial burden and proper wound management. Understanding the most common offending organisms of the shoulder, Propionibacterium acnes and coagulase negative Staphylococcus species, and their hypothesized mechanism of infection is crucial to selecting appropriate preventative measures. PMID- 29499826 TI - Venous Thromboembolism Prophylaxis in Shoulder Surgery. AB - The incidence of venous thromboembolic events (VTEs) complicating shoulder surgery is difficult to estimate. Case reports, retrospective studies, prospective studies, and systematic reviews vary in terms of separating symptomatic versus asymptomatic VTEs, those occurring in the upper versus lower extremities, and those leading to pulmonary embolism. Reported rates vary between 0.02% and 13%. Arthroplasty is associated with a higher incidence than arthroscopy. Surgery for fracture presents increased risk. Mechanical prophylaxis using compression devices could be considered given its favorable risk-benefit profile. Chemical prophylaxis should be considered for high-risk patients. Evidence-based criteria cannot be obtained from current literature on VTEs after shoulder surgery. PMID- 29499827 TI - Venous Thromboembolism Disease Prophylaxis in Foot and Ankle Surgery. AB - There are limited data to guide the use of venous thromboembolism disease (VTED) prophylaxis after foot and ankle surgery. Although there is general consensus that the overall risk is lower than after hip or knee replacement, subpopulations of patients may be at relatively heightened risk. Furthermore, existing data are often conflicting regarding the efficacy of prophylaxis, with little acknowledgment of the tradeoffs between VTED prophylaxis and potential complications associated with the use of such medications. This article provides an overview of currently available evidence to guide decision making regarding VTED prophylaxis in patients who undergo foot and ankle surgery. PMID- 29499829 TI - Evidence-Based Medicine. PMID- 29499828 TI - Patient-Reported Outcomes in Foot and Ankle Surgery. AB - Patient-reported outcomes (PROs) are a measure of health care quality that empower patients to share their health care perceptions with their providers. In orthopedic foot and ankle surgery, these measures can range from global assessments of pain or satisfaction to complex questionnaires designed to assess the function of specific anatomic regions or the recovery from specific procedures. This article seeks to characterize the use of PROs in foot and ankle surgery, describe some of the most commonly used measures, discuss implementation in everyday clinical practice, and explore the future of PROs in foot and ankle orthopedics. PMID- 29499830 TI - Learning and teaching electrocardiography in the 21st century: A neglected art. PMID- 29499831 TI - Clinical Predictors of Regression of Choroidal Melanomas after Brachytherapy: A Growth Curve Model. AB - PURPOSE: To build multivariate models to assess correctly and efficiently the contribution of tumor characteristics on the rate of regression of choroidal melanomas after brachytherapy in a way that adjusts for confounding and takes into account variation in tumor regression patterns. DESIGN: Modeling of longitudinal observational data. PARTICIPANTS: Ultrasound images from 330 of 388 consecutive choroidal melanomas (87%) irradiated from 2000 through 2008 at the Helsinki University Hospital, Helsinki, Finland, a national referral center. METHODS: Images were obtained with a 10-MHz B-scan during 3 years of follow-up. Change in tumor thickness and cross-sectional area were modeled using a polynomial growth-curve function in a nested mixed linear regression model considering regression pattern and tumor levels. Initial tumor dimensions, tumor node-metastasis (TNM) stage, shape, ciliary body involvement, pigmentation, isotope, plaque size, detached muscles, and radiation parameters were considered as covariates. MAIN OUTCOME MEASURES: Covariates that independently predict tumor regression. RESULTS: Initial tumor thickness, largest basal diameter, ciliary body involvement, TNM stage, tumor shape group, break in Bruch's membrane, having muscles detached, and radiation dose to tumor base predicted faster regression, whether considering all tumors or those that regressed in a pattern compatible with exponential decay. Dark brown pigmentation was associated with slower regression. In multivariate modeling, initial tumor thickness remained the predominant and robust predictor of tumor regression (P < 0.0001). In addition, use of ruthenium isotope as opposed to iodine isotope (P = 0.018) independently contributed to faster regression of tumor thickness. For both isotopes considered alone, initial tumor thickness was the sole clinical predictor of regression (P < 0.0001). CONCLUSIONS: Regression of choroidal melanoma after brachytherapy was associated with several clinical tumor and treatment parameters, most of which were shown to reflect initial tumor size. An independent predictor of regression of tumor thickness was the isotope used. These 2 covariates need to be adjusted for when exploring the associations with the rate of regression of histopathologic or genetic features of the tumor. Our model allows such future analyses efficiently without matching. PMID- 29499832 TI - Trunk and lower limb coordination during lifting in people with and without chronic low back pain. AB - Differences in synchronous movement between the trunk and lower limb during lifting have been reported in chronic low back pain (CLBP) patients compared to healthy people. However, the relationship between movement coordination and disability in CLBP patients has not been investigated. A cross-sectional study was conducted to compare regional lumbar and lower limb coordination between CLBP (n = 43) and control (n = 29) groups. The CLBP group was divided into high- and low-disability groups based on their Oswestry Disability Index (ODI) score. The mean absolute relative phase (MARP) angles and mean deviation phase (DP) between the (1) lumbar spine and hip, and (2) hip and knee were measured. The relationship between MARP angle and DP and ODI were investigated using linear regression. The higher-disability CLBP group demonstrated significantly greater lumbar-hip MARP angles than the lower-disability CLBP group (mean difference = 12.97, % difference = 36, p = 0.041, 95% CI [2.97, 22.98]). The higher-disability CLBP group demonstrated significantly smaller hip-knee DP than controls (mean difference = 0.11, % difference = 76, p = 0.011, 95% CI [0.03, 0.19]). There were no significant differences in lumbar-hip and hip-knee MARP and DP between the lower-disability CLBP and control groups. Lumbar-hip MARP was positively associated with ODI (R2 = 0.092, beta = 0.30, p = 0.048). High-disability CLBP patients demonstrated decreased lumbar-hip movement coordination and stiffer hip knee movement during lifting than low-disability CLBP patients and healthy controls. PMID- 29499833 TI - Successful Suppression of Recurrent Zosteriform Mycosis Fungoides With Maintenance Valacyclovir. PMID- 29499834 TI - Targeting bacterial energetics to produce new antimicrobials. AB - From the war on drug resistance, through cancer biology, even to agricultural and environmental protection: there is a huge demand for rapid and effective solutions to control infections and diseases. The development of small molecule inhibitors was once an accepted "one-size fits all" approach to these varied problems, but persistence and resistance threaten to return society to a pre antibiotic era. Only five essential cellular targets in bacteria have been developed for the majority of our clinically-relevant antibiotics. These include: cell wall synthesis, cell membrane function, protein and nucleic acid biosynthesis, and antimetabolites. Many of these targets are now compromised through rapidly spreading antimicrobial resistance and the need to target non replicating cells (persisters). Recently, an unprecedented medical breakthrough was achieved by the FDA approval of the drug bedaquiline (BDQ, trade name Sirturo) for the treatment of multidrug-resistant tuberculosis disease. BDQ targets the membrane-bound F1Fo-ATP synthase, validating cellular energy generating machinery as a new target space for drug discovery. Recently, BDQ and several other FDA-approved drugs have been demonstrated to be respiratory "uncouplers" disrupting transmembrane electrochemical gradients, in addition to binding to enzyme targets. In this review, we summarize the role of bioenergetic systems in mycobacterial persistence and discuss the multi-targeting nature of uncouplers and the place these molecules may have in future drug development. PMID- 29499835 TI - An update on beta-lactamase inhibitor discovery and development. AB - Antibiotic resistance, and the emergence of pan-resistant clinical isolates, seriously threatens our capability to treat bacterial diseases, including potentially deadly hospital-acquired infections. This growing issue certainly requires multiple adequate responses, including the improvement of both diagnosis methods and use of antibacterial agents, and obviously the development of novel antibacterial drugs, especially active against Gram-negative pathogens, which represent an urgent medical need. Considering the clinical relevance of both beta lactam antibiotics and beta-lactamase-mediated resistance, the discovery and development of combinations including a beta-lactamase inhibitor seems to be particularly attractive, despite being extremely challenging due to the enormous diversity, both structurally and mechanistically, of the potential beta-lactamase targets. This review will cover the evolution of currently available beta lactamase inhibitors along with the most recent research leading to new beta lactamase inhibitors of potential clinical interest or already in the stage of clinical development. PMID- 29499837 TI - Redundant angiogenic signaling and tumor drug resistance. AB - Angiogenesis research in the past two decades has contributed significantly towards understanding the molecular pathophysiology of cancer progression and inspired target-oriented research and pharma industry for the development of novel anti-angiogenic agents. Currently, over eleven drugs targeting angiogenesis have been approved by the FDA for the treatment of various malignancies. Of the registered anti-angiogenic clinical trials until the end of 2017 (ClinicalTrials.gov), over 47% were completed, 10% were terminated, 3% withdrawn, over 0.5% were suspended and only 4 trials have culminated in FDA approval for marketing. On the one hand, the clinical benefits of anti-angiogenic drugs prompted the development of novel anti-angiogenic agents. On the other hand, however, a plethora of recent studies demonstrated the emergence of tumor drug resistance towards currently used anti-angiogenic therapeutics. Series of preclinical and clinical studies have highlighted the enigma of drug resistance with functional bypass pathways, and identified compensatory or alternative angiogenic mechanisms assuring tumor growth in the midst of an anti-angiogenic stress environment. In the present review the classical literature of such redundant angiogenic pathways in concert with the key angiogenic factors and specialized cells involved in anti-angiogenic escape mechanisms is described. A strategic discourse regarding increasing tumor drug resistance and future modalities for anti-angiogenic therapy is also discussed in view of recent advances. PMID- 29499838 TI - Thyroid Fine Needle Aspiration: Successful Prospective Implementation of Strategies to Eliminate Unnecessary Biopsy in the Veteran Population. AB - OBJECTIVE: Thyroid nodules are prevalent in over half the general population. Several multidisciplinary societies have management recommendations. However, the majority of data to support these guidelines are derived from studies of predominantly younger and female populations. This study's aim was to evaluate characteristics of thyroid nodules in a largely older and male Veteran population and apply these findings prospectively to reduce unnecessary thyroid fine needle aspiration (FNA). MATERIALS AND METHODS: Over a 4-year period, all ultrasound guided FNA of thyroid nodules performed in our department were reviewed. Sonographic features, patterns, and histopathology were evaluated. A prospective strategy of avoiding FNA in all lesions matching imaging patterns of benignity was implemented and positive predictive value (PPV) of malignancy was calculated and compared to the retrospective data. RESULTS: Retrospectively, FNA was performed on 351 successive thyroid nodules, 9 of which were malignant. Statistically significant malignant features include presence of microcalcifications, irregular or amorphous morphology, taller-than-wide shape, spiculated margins, vascularity, and lymphadenopathy. PPV of thyroid FNA was 2.6% in this period. Four sonographic patterns were 100% specific for benignity, including: "spongiform," "cyst with a colloid clot," "giraffe," and "white knight" patterns. Over 23 months, prospective avoidance of FNA of lesions characterized as a benign pattern (159 nodules) was implemented and PPV was calculated as 7.2% resulting in a cost savings of $477,000. CONCLUSION: Four sonographic patterns were 100% specific for benignity in the older and predominantly male Veteran population. Strict prospective application of avoiding biopsy in these benign patterns resulted in a decrease of unnecessary biopsies, decrease in patient morbidity, and improved allocation of health care resources. PMID- 29499839 TI - Mixed method evaluation of the Virtual Traveller physically active lesson intervention: An analysis using the RE-AIM framework. AB - BACKGROUND: Physically active lessons integrating movement into academic content are a way to increase children's physical activity levels. Virtual Traveller was a physically active lesson intervention set in Year 4 (aged 8-9) primary school classes in Greater London, UK. Implemented by classroom teachers, it was a six week intervention providing 10-min physically active Virtual Field Trips three times a week. The aim of this paper is to report the process evaluation of the Virtual Traveller randomized controlled trial according to RE-AIM framework criteria (Reach, Effectiveness, Adoption, Implementation and Maintenance). METHODS: A mixed methods approach to evaluation was conducted with five intervention group classes. Six sources of data were collected via informed consent logs, teacher session logs, teacher and pupil questionnaires, teacher interviews and pupil focus groups. RESULTS: High participation and low attrition rates were identified (Reach) alongside positive evaluations of Virtual Traveller sessions from pupil and teachers (Effectiveness). Participants were from more deprived and ethnic backgrounds than local and national averages, with Virtual Traveller having the potential to be a free intervention (Adoption). 70% of sessions were delivered overall (Implementation) but no maintenance of the programme was evident at three month follow-up (Maintenance). CONCLUSIONS: Mixed method evaluation of Virtual Traveller showed potential for it to be implemented as a low-cost physically active lesson intervention in UK primary schools. PMID- 29499836 TI - New tools for old drugs: Functional genetic screens to optimize current chemotherapy. AB - Despite substantial advances in the treatment of various cancers, many patients still receive anti-cancer therapies that hardly eradicate tumor cells but inflict considerable side effects. To provide the best treatment regimen for an individual patient, a major goal in molecular oncology is to identify predictive markers for a personalized therapeutic strategy. Regarding novel targeted anti cancer therapies, there are usually good markers available. Unfortunately, however, targeted therapies alone often result in rather short remissions and little cytotoxic effect on the cancer cells. Therefore, classical chemotherapy with frequent long remissions, cures, and a clear effect on cancer cell eradication remains a corner stone in current anti-cancer therapy. Reliable biomarkers which predict the response of tumors to classical chemotherapy are rare, in contrast to the situation for targeted therapy. For the bulk of cytotoxic therapeutic agents, including DNA-damaging drugs, drugs targeting microtubules or antimetabolites, there are still no reliable biomarkers used in the clinic to predict tumor response. To make progress in this direction, meticulous studies of classical chemotherapeutic drug action and resistance mechanisms are required. For this purpose, novel functional screening technologies have emerged as successful technologies to study chemotherapeutic drug response in a variety of models. They allow a systematic analysis of genetic contributions to a drug-responsive or -sensitive phenotype and facilitate a better understanding of the mode of action of these drugs. These functional genomic approaches are not only useful for the development of novel targeted anti cancer drugs but may also guide the use of classical chemotherapeutic drugs by deciphering novel mechanisms influencing a tumor's drug response. Moreover, due to the advances of 3D organoid cultures from patient tumors and in vivo screens in mice, these genetic screens can be applied using conditions that are more representative of the clinical setting. Patient-derived 3D organoid lines furthermore allow the characterization of the "essentialome", the specific set of genes required for survival of these cells, of an individual tumor, which could be monitored over the course of treatment and help understanding how drug resistance evolves in clinical tumors. Thus, we expect that these functional screens will enable the discovery of novel cancer-specific vulnerabilities, and through clinical validation, move the field of predictive biomarkers forward. This review focuses on novel advanced techniques to decipher the interplay between genetic alterations and drug response. PMID- 29499840 TI - Discovered acetylcholinesterase inhibition and antibacterial activity of polyacetylenes in tansy root extract via effect-directed chromatographic fingerprints. AB - The knowledge about the activity of polyacetylenes was extended by their new acetylcholinesterase inhibition and antibacterial activity against plant pathogenic bacteria. For this discovery, an utmost streamlined workflow, which we consider to be of high potential in the field of natural product or superfood search was developed. It demonstrates the combined power of biological, biochemical and chemical fingerprints. Bioactive components of tansy (Tanacetum vulgare L.) root extract were profiled and identified by high-performance thin layer chromatography hyphenated with in situ effect-directed analysis, chemical derivatizations and high-resolution mass spectrometry (HPTLC-UV/Vis/FLD-EDA HRMS). The effect-directed profiling was performed using four bacterial bioassays including two plant pathogens, an antioxidant assay and acetyl- and butyrylcholinesterase inhibitory assays. The chromatographic, spectral and powerful mass spectrometric study of zones that exerted substantial antibacterial and/or antioxidant and/or acetylcholinesterase inhibitory effects allowed these multi-potent zones to be identified as polyacetylenes. Five polyacetylene compounds were assigned to be 2-non-1-ene-3,5,7-triynyl-3-vinyl-oxirane, 2-(2,4 hexadiynylidene)-3,4-epoxy-1,6-dioxaspiro[4.5]decane, trans- and cis-2-(2,4 hexadiynylidene)-1,6-dioxaspiro[4.5]dec-3-ene and tetradeca-2,4,6-triine-8-en-12 one. This study clearly showed the advantage of the combined use of different ionization sources, i.e. electrospray ionization via an elution-head based interface and also the Direct Analysis in Real Time interface, for HRMS analysis of compounds from the same class with very similar chromatographic behavior and polarity. PMID- 29499841 TI - Synthesis of boronate-decorated polyethyleneimine-grafted porous layer open tubular capillaries for enrichment of polyphenols in fruit juices. AB - A combination between modification with porous layer and grafting of polyethyleneimine (PEI) on the inner face of capillary was for the first time developed for boronate affinity in-tube solid-phase microextraction (SPME) material to enhance the extraction capacity for cis-diol-containing polyphenols. The successful synthesis of boronate-decorated polyethyleneimine-grafted porous layer open tubular (BPPLOT) capillary was confirmed by scanning electron micrograph, Fourier transform-infrared spectra and absorption experiments. The porous layer, PEI and boronate affinity provided high specific surface area, more binding sites for boronate groups and specific selectivity of BPPLOT capillary, respectively. The maximum binding quantity of BPPLOT capillary greatly improved, and ranged from 143 to 170 MUg m-1 for cis-diol-containing polyphenols (catechin, chlorogenic acid, caffeic acid and epicatechin). A green method based on boronate affinity in-tube SPME was developed for separation and enrichment polyphenols, and some parameters of in-tube SPME were optimized. After in-tube SPME, HPLC with UV detection was used for quantitative determination of polyphenols. Recoveries of standard spiked cis-diol-containing polyphenols from fruit juice were between 80.9% and 102%, with intra-day and inter-day coefficient of variation ranging from 4.8% to 7.3% and 5.0% to 8.6%, respectively. Conversely, recovery of non-cis diol-containing ferulic acid was no greater than 3.0%. These results suggested that the BPPLOT capillary could effectively separate and enrich cis-diol containing polyphenols from real samples. PMID- 29499842 TI - A two-step purification strategy using calmodulin as an affinity tag. AB - Calmodulin (CaM) is a Ca2+-binding protein that plays an important role in cellular Ca2+-signaling. CaM interacts with diverse downstream target proteins and regulates their functions in a Ca2+-dependent manner. CaM changes its conformation and hydrophobicity upon [Ca2+] change and consequently changes its interaction with CaM-binding domains from the targets. Based on these special properties of CaM, it was used as an affinity tag to develop a novel purification strategy by using it for two sequential orthogonal purification steps: 1) an affinity purification step, in which CaM-tag interacts with an immobilized CaM binding domain; and 2) a hydrophobic interaction chromatography step, during which CaM binds to a phenyl sepharose column. In both steps, the CaM-tagged protein binds in the presence of Ca2+ and unbinds in the presence of ethylenediaminetetraacetic acid (EDTA). An optional third step can be added to remove the CaM-tag if necessary. We used green fluorescent protein (GFP) as a test protein to demonstrate the effectiveness of the method. High yield and high purity of GFP with proper function was obtained using this novel strategy. We believe that this method can be applied to a wide range of protein targets for structural and functional studies. PMID- 29499843 TI - Impact of Multidisciplinary Standardization of Care for Gastroschisis: Treatment, Outcomes, and Cost. AB - BACKGROUND/PURPOSE: Elimination of unnecessary practice variation through standardization creates opportunities for improved outcomes and cost effectiveness. A quality improvement (QI) initiative at our institution used evidence and consensus to standardize management of gastroschisis (GS) from birth to discharge. METHODS: An interdisciplinary team utilized best practice evidence and expert opinion to standardize GS care. Following stakeholder engagement and education, care standardization was implemented in September 2014. A comparative cohort study was conducted on consecutive patients treated before (n=33) and after (n=24) standardization. Demographic, treatment, and outcome measures were collected from a prospective GS registry. Direct costs were estimated, and protocol compliance was audited. RESULTS: BW, GA, and bowel injury severity were comparable between groups. Key practice changes were: closure technique (pre-88% primary fascial, post-83% umbilical cord flap; p<0.001), closure location (pre 97% OR, post-67% NICU; p<0.001), and GA avoidance (pre-0%, post-48%; p<0.001). Median post-closure ventilation days were shorter (pre-4, post-1; p<0.001), and SSI rates trended lower (pre-21%, post-8%; p=0.3) in the post-implementation group with no differences in TPN days or LOS. No significant difference was seen in average per-patient costs: pre-$85,725 ($29,974-221,061), post-$76,329 ($14,205-176,856). CONCLUSION: Care standardization for GS enables practice transformation, cost-effective outcome improvement, and supports an organizational culture dedicated to continuous improvement. LEVEL OF EVIDENCE: III. PMID- 29499844 TI - The relationship between preoperative nutritional state and adverse outcome following abdominal and thoracic surgery in children: Results from the NSQIP database. AB - INTRODUCTION: Anthropometric measurements can be used to define pediatric malnutrition. Our study aims to: (1) characterize the preoperative nutritional status of children undergoing abdominal or thoracic surgery, and (2) describe the associations between WHO-defined acute (stunting) and chronic (wasting) undernutrition (Z-scores <-2) and obesity (BMI Z-scores >+2) with 30-day postoperative outcomes. METHODS: We queried the Pediatric NSQIP Participant Use File and extracted data on patients' age 29days to 18years who underwent abdominal or thoracic procedures. Normalized anthropometric measures were calculated, including weight-for-height for <2years, BMI for ages >=2years, and height for age. Logistic regression models were developed to assess nutritional outlier status as an independent predictor of postoperative outcome. RESULTS: 23,714 children (88% >=2y) were evaluated. 4272 (18%) were obese, while 2640 (11.1%) and 904 (3.8%) were stunted and wasted, respectively, after controlling for gender, ASA/procedure/wound classification, preoperative steroid use, need for preoperative nutritional support, and obese children had higher odds of SSIs (OR 1.29, 95% CI 1.1-1.5, p=0.001), while stunted children were at increased risk of any 30-day postoperative complication (OR 1.16, 95% CI 1.0-1.3, p=0.036). CONCLUSION: Children who are stunted or obese are at increased risk of adverse outcome after abdominal or thoracic surgery. LEVEL OF EVIDENCE: III. PMID- 29499846 TI - Letter to the Editor. PMID- 29499845 TI - Anticoagulation results in increased line salvage for children with intestinal failure and central venous thrombosis. AB - PURPOSE: The purpose of this study was to investigate whether anticoagulation (AC) results in thrombus resolution and increased line longevity in children with intestinal failure (IF) and catheter-associated central venous thrombosis (CVT). METHODS: A retrospective, single institution review was performed of children with IF who were dependent on parenteral nutrition with known CVT between 2006 and 2017. Frequency of catheter-related complications including infection, occlusion, and breakage were compared 18months prior to and after starting AC. Thrombus resolution during anticoagulation was also determined. Data were analyzed using Poisson regression. p-Values <0.05 were considered significant. RESULTS: Eighteen children had >=1 CVT, with the subclavian vein most commonly thrombosed (44%). All children were treated with low molecular weight heparin, and 6 patients (33%) had clot resolution on re-imaging while receiving AC. Bloodstream infections decreased from 7.9 to 4.4 per 1000 catheter days during AC (p=0.01), and the number of infections requiring catheter replacement decreased from 3.0 to 1.0 per 1000 catheter days (p=0.01). There were no significant differences in line occlusions or breakages. CONCLUSION: Anticoagulation for children with intestinal failure and central venous thrombosis may prevent thrombus propagation, and decrease blood stream infections and line replacements. Further research is needed to determine optimal dosing and duration of therapy. LEVEL OF EVIDENCE: III; Retrospective Comparative Study. PMID- 29499847 TI - Reply to Letter to the Editor. PMID- 29499848 TI - [Impact of duration of untreated psychosis on quality of life and cognitive functions]. AB - OBJECTIVES: The duration of untreated psychosis is defined as the interval between the first psychotic symptoms and the first starting treatment. The duration of untreated psychosis is highly variable but often prolonged and may be influenced by several factors. Some studies suggested that duration of untreated psychosis is associated with poor outcome. The objectives of this study were to assess the duration of untreated psychosis in a Tunisian cohort and its impact on the quality of life and the cognitive functions of schizophrenic patients at 2 years. METHODS: We conducted a cross sectional study at Razi Hospital between January 2014 and June 2014 that included patients with Schizophrenia diagnosis as defined in the DSMIV-TR with regular monitoring for at least 2 years. Eligible participants are those who had been hospitalized for the first time, between January 2011 and December 2012 for a first psychotic episode. Data were collected from medical records and by interviewing the patients and their family. Duration of untreated psychosis was determined using the Symptom Onset in Schizophrenia Inventory. The quality of life was assessed by the 'Short Form-36 Health Survey' scale in its Arabic version. All patients were evaluated with 'The Tunisian Cognitive Battery' composed of 7 tests. Patient scores are expressed as 'Z scores', which represents the position of the scores in a term of standard deviation from the mean of healthy subjects established by the authors of the battery. We divided the population into two groups based on the duration of untreated psychosis median. A short duration of untreated psychosis was lower than the median, and a long duration of untreated psychosis was equal to or greater than the median. RESULTS: Our sample involved 42 patients with a mean age of 31.38 years. The average duration of untreated psychosis was 75.38 weeks with a range from 2 to 364 weeks and a median duration of 47.5 weeks. Patients with a short duration of untreated psychosis had a better quality of life with better scores for the majority of the dimensions and a significant difference in the limitations score due to the mental state (P=0.01). For cognitive function, the short duration of untreated psychosis was significantly correlated with a free recall of 'Hopkins Verbal Learning Test'. CONCLUSION: Our study suggest that the average duration of untreated psychosis in Tunisia is comparable to the one reported in the literature and that a short duration of untreated psychosis is correlated with better outcomes in terms of quality of life and verbal learning. PMID- 29499849 TI - Stress and Senescence: A Special Issue dedicated to Olivier Toussaint. PMID- 29499850 TI - One-carbon metabolism markers are associated with cardiometabolic risk factors. AB - BACKGROUND AND AIMS: Alterations to one-carbon metabolism, especially elevated plasma homocysteine (Hcy), have been suggested to be both a cause and a consequence of the metabolic syndrome (MS). A deeper understanding of the role of other one-carbon metabolites in MS, including s-adenosylmethionine (SAM), s adenosylhomocysteine (SAH), and the methylation capacity index (SAM:SAH ratio) is required. METHODS AND RESULTS: 118 men and women with MS-risk factors were included in this cross-sectional study and cardiometabolic outcomes along with markers of one-carbon metabolism, including fasting plasma SAM, SAH, Hcy and vitamin B12 concentrations, were analysed. Multiple linear regression models were also used to examine the association between plasma one-carbon metabolites and cardiometabolic health features. We found that fasting plasma concentrations of Hcy, SAM and SAH were all positively correlated with markers of adiposity, including BMI (increase in BMI per 1-SD increase in one-carbon metabolite: 0.92 kg/m2 95% CI (0.28; 1.56), p = 0.005; 0.81 (0.15; 1.47), p = 0.02; 0.67 (-0.01; 1.36), p = 0.05, respectively). Hcy, but not SAM, SAH or SAM:SAH ratio was associated with BMI and body fat percentage after mutual adjustments. SAM concentrations were associated with higher fasting insulin (9.5% 95% CI (0.3; 19.5) per SD increase in SAM, p = 0.04), HOMA-IR (10.8% (0.8; 21.9), p = 0.03) and TNF-alpha (11.8% (5.0; 19.0), p < 0.001). CONCLUSION: We found little evidence for associations between SAM:SAH ratio and cardiometabolic variables, but higher plasma concentrations of SAM, SAH and Hcy are related to an overall higher risk of metabolic dysfunctions. The studies were registered at www.clinicaltrials.gov (NCT01719913 &NCT01731366). PMID- 29499851 TI - Effect of nutrient deprivation on the expression and the epigenetic signature of sirtuin genes. AB - BACKGROUND AND AIM: Over the last decades advances in understanding the molecular bases of the close relationship between nutrition, metabolism, and diseases have been impressive. However, there are always novel frontiers coming up and epigenetics is one of these. Sirtuins, are pivotal factors in the control of metabolic pathways according to nutrient availability. In the present study we evaluated the effect of nutrient deprivation on expression, DNA methylation and chromatin status of the sirtuin genes. METHODS AND RESULTS: We performed these studies in mouse hepatoma cells, that were grown in standard medium, or in media containing low glucose concentration, or no glucose, or no amino acids. We applied quantitative real-time PCR to cDNA, methylation-enriched DNA and nuclease treated DNA in order to evaluate gene expression, DNA methylation, and chromatin condensation, respectively. This study shows that the expression of sirtuin genes varies following nutrient deprivation. Moreover, we observed that changes of DNA methylation and chromatin condensation occur at the transcription start site of sirtuin genes following nutrient deprivation. CONCLUSIONS: Epigenetic mechanisms may have a role in the sirtuin response to nutrient deprivations in cultured hepatoma cells. Replicating these results in vivo to achieve a comprehensive understanding of the epigenetic control of sirtuin expression following nutrient deprivations might open up novel therapeutic possibilities to cure metabolic diseases and promote human health. PMID- 29499852 TI - Short and long-term prognosis following acute myocardial infarction according to the country of origin. Soroka acute myocardial infarction II (SAMI II) project. AB - BACKGROUND: Reports from many countries have shown birthplace-associated disparities in the incidence and mortality following acute myocardial infarction (AMI). The aims of the study were to identify and compare short- and long-term post-AMI mortality according to birthplace. METHODS: A retrospective analysis of Israeli AMI patients from a tertiary medical center in Southern Israel throughout 2002-2012. DATA SOURCE: the hospital's computerized systems. Patients were classified according to the country of birth (Israel, Southern Europe/Balkans, Northern Africa, Eastern/Central Europe, India/Pakistan, Middle-East, Yemen, and Ethiopia). STUDY OUTCOMES: in-hospital and up to 10-years post-discharge all cause mortality. RESULTS: The study included 11,143 patients, age 67.4 +/- 13.9 and 67.5% men. Israeli-born patients were significantly younger, with lower rate of diabetes mellitus and hypertension but significantly higher rate of obesity, smoking, history of coronary artery disease and male sex compared with immigrants. The rate of STEMI and administration of percutaneous coronary revascularization was higher, yet extent of coronary findings and severe left ventricular dysfunction was lower in Israeli-born patients. In-hospital as well as post-discharge 1-and 10-year mortality rates were approximately 65% lower in Israeli-born patients compared with immigrants. Following adjustment for potential confounders the inequalities in post-discharge mortality attenuated (Yemen OR = 2.3 [95%CI: 1.4-3.6], Southern Europe/Balkans 1.75 [1.2-2.5], Northern Africa 1.5 [1.3-1.8], Eastern/Central Europe 1.4 [1.2-1.7] and India/Pakistan 1.4 [1.1-1.9], for 10-years mortality, p < 0.05 for each) and those for in-hospital mortality disappeared. CONCLUSIONS: Immigrants are at increased risk for post-discharge, yet not in-hospital mortality following AMI. Appropriate targeted preventive programs are required for these groups of patients. PMID- 29499853 TI - Corrigendum to "A case of false positive cardiac troponin I in CANOMAD syndrome" [Int. J. Cardiol. 222 (2016) 359-360]. PMID- 29499854 TI - Clinical value of survivin and its underlying mechanism in ovarian cancer: A bioinformatics study based on GEO and TCGA data mining. AB - OBJECTIVE: An increasing number of studies have confirmed that survivin (BIRC5) plays essential roles in ovarian cancer. Nevertheless, inconsistent or controversial results exist in some studies. In the present study, we sought to determine the clinical significance of survivin and its potential molecular pathways. METHODS: The correlation between survivin (BIRC5) expression and diagnostic value, prognostic value and clinicopathological features was assessed by meta-analysis with more than 4000 patients from literature, GEO and TCGA. In addition, the potential molecular mechanism of survivin in ovarian cancer was also determined. RESULTS: The pooled sensitivity and specificity were 0.71 (95%CI: 0.68-0.74) and 0.97 (95%CI: 0.94-0.98), respectively. The AUC of sROC was 0.8765. The results showed that there was also a significant relationship between survivin expression and poor overall survival (HR: 1.24, 95%CI: 1.14-1.35, p < 0.001), disease-free survival (HR: 1.53, 95%CI: 0.57-4.09, p < 0.001), as well as higher recurrence rate (HR: 1.11, 95%CI: 0.97-1.27). Moreover, survivin expression was also associated with tumor progression (cancerous vs. benign, OR: 11.29, 95%CI: 8.96-14.24, p < 0.001), TNM stage (III + IV vs. I + II, OR: 5.38, 95%CI: 4.16-6.97, p < 0.001), histological grades (G3 vs. G1 ~ G2, OR: 4.36, 95%CI: 3.29-5.77, p < 0.001), and lymphatic metastasis (metastasis vs. non metastasis, 3.35, 95%CI 2.36-4.75, p < 0.001). Bioinformatics analysis revealed the 50 most frequently altered neighboring genes of survivin in OC, and then Gene Oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were conducted. GO analysis showed that these genes were related to signal conduction, cell cycle, apoptosis, and metabolism. KEGG pathways analysis indicated that these genes were primarily enriched in mitotic prometaphase, PLK1 signaling events and the regulation of glucokinase by the glucokinase regulatory protein. CONCLUSION: Survivin (BIRC5) expression might become a specific but low sensitivity biomarker in ovarian cancer patients, and its presence indicated poor prognosis and worse TNM stages. This protein might function as an oncoprotein by influencing specific pathways involving the 50 genes identified herein. Additional studies are needed to confirm these results. PMID- 29499856 TI - The Presence of Distolingual Root in Mandibular First Molars Is Correlated with Complicated Root Canal Morphology of Mandibular Central Incisors: A Cone-beam Computed Tomographic Study in a Taiwanese Population. AB - INTRODUCTION: The aim of this study was to assess the prevalence of complicated root canals in permanent mandibular central incisors (PMCIs) and its correlation with the presence of a distolingual root (DLR) in permanent mandibular first molars (PMFMs) using cone-beam computed tomographic imaging in a Taiwanese population. METHODS: A total of 400 patients (800 pairs of PMCIs and PMFMs) were qualified for further analysis. The prevalence of DLRs in PMFMs along with root canal configurations of PMCIs were assessed at subject and tooth levels. Multivariable logistic regression analysis was used to evaluate the correlation between the root canal configurations of PMCIs with the existence of DLRs in PMFMs. RESULTS: The prevalence of PMFMs with DLRs and complicated root canal configurations in PMCIs was 23.0% and 15.6%, respectively. A significant difference in age (<50 years vs >=50 years) was found for complicated root canal configurations in PMCIs. The most prevalent root canal system in PMCIs was Vertucci type I (84.4%) followed by type III (13.5%). A positive correlation between the presence of DLRs in PMFMs and complicated root canal configurations in PMCIs was noted. After adjusting for categoric variables including sex, age, and side, the odds ratios for the occurrence of complicated root canal configurations of PMCIs in the unilateral DLR group and the bilateral DLR group compared with the non-DLR group were 2.13 and 2.53, respectively. CONCLUSIONS: The concurrent appearance of DLRs in PMFMs and complicated root canal morphology in PMCIs is prominent in Taiwanese individuals. PMID- 29499855 TI - Dose-Related Target Occupancy and Effects on Circuitry, Behavior, and Neuroplasticity of the Glycine Transporter-1 Inhibitor PF-03463275 in Healthy and Schizophrenia Subjects. AB - BACKGROUND: Glycine transporter-1 (GlyT1) inhibitors may ameliorate cognitive impairments associated with schizophrenia. The dose-related occupancy and target engagement of the GlyT1 inhibitor PF-03463275 were studied to inform optimal dose selection for a clinical trial for cognitive impairments associated with schizophrenia. METHODS: In substudy 1, the effects of PF-03463275 (10, 20, and 40 mg twice a day) on occupancy of GlyT1 were tested using positron emission tomography and 18F-MK-6577, and visual long-term potentiation (LTP) in schizophrenia patients (SZs) and healthy control subjects. Furthermore, the capacity of PF-03463275 to attenuate ketamine-induced disruption of working memory-related activation of a "working memory" circuit was tested only in healthy control subjects using functional magnetic resonance imaging. Subsequently, the effects of PF-03463275 (60 mg twice a day) on occupancy of GlyT1 and long-term potentiation were examined only in SZs (substudy 2). RESULTS: PF-03463275 at 10, 20, 40, and 60 mg twice a day produced ~44%, 61%, 76%, and 83% GlyT1 occupancy, respectively, in SZs with higher ligand binding to GlyT1 in subcortical versus cortical regions. PF-03463275 did not attenuate any ketamine induced effects but did improve working memory accuracy in healthy control subjects. PF-03463275 increased long-term potentiation only in SZs with peak effects at 40 mg twice a day (~75% GlyT1 occupancy) and with a profile suggestive of an inverted U dose response. PF-03463275 was well-tolerated. CONCLUSIONS: The dose-related GlyT1 occupancy of PF-03463275 is linear. While PF-03463275 did not show evidence of facilitating N-methyl-D-aspartate receptor function in the ketamine assay, it enhanced neuroplasticity in SZs. These findings provide support for a clinical trial to test the ability of PF-03463275 to enhance cognitive remediation toward addressing cognitive impairments associated with schizophrenia. PMID- 29499858 TI - Discussion of "Instant replay: Evaluation of instant video feedback in surgical novices for a laparoscopic gallbladder dissection". PMID- 29499857 TI - Characteristics of melanocyte spheroids formed through different biomaterial induced processes. AB - BACKGROUND/PURPOSE: Cell behaviors in three-dimensional spheroids are known to be different from those in monolayer cultures; however, very few studies have compared the characteristics of cell spheroids formed through different biomaterial-induced processes. This study investigated the mechanism of melanocyte spheroid formation by using membranes composed of two hydrophilic polymer-based biomaterials, namely chitosan and polyvinyl alcohol (PVA). Our findings revealed that different spheroid-forming processes occurred on the two biomaterials. METHODS: Human melanocytes were provided by the cell bank of the Department of Dermatology, National Taiwan University Hospital. The cell viability was determined through the MTT (3-(4,5-dimethylthiazol-2-yl)-diphenyl tetrazolium bromide; Sigma) colorimetric assay. The cell living rate was determined using the trypan blue exclusion test. The amount of fibronectin adsorbed was quantified through Western blot analysis. Statistical significance was calculated using one-way analysis of variance (ANOVA) followed by Duncan's test, and p values <0.05 or <0.01 was considered significant. RESULTS: In the study, the melanocytes attached to, migrated on, and aggregated on the chitosan surface and then formed spheroids. By contrast, on the PVA surface, the melanocytes directly aggregated to form three-dimensional spheres in suspension. The proliferative ability and survival rate of the melanocytes were considerably higher on the chitosan membranes than on the PVA membranes. CONCLUSION: We concluded that only cell-cell interactions dominated in melanocytes seeded on the PVA membrane, whereas cell-cell and cell-substrate interactions occurred on the chitosan membranes and further enhanced cellular functions. The chitosan-induced spheroids could probably overcome the diffusion and assimilation of trophic factors. PMID- 29499859 TI - The evolution of transanal surgery for obstructed defecation syndrome: Mid-term results from a randomized study comparing double TST 36 HV and Contour TRANSTAR staplers. AB - A randomized study was carried out to compare the mid-term outcome of transanal rectal resection with the CCS-30 TRANSTAR and two TST36 staplers in patients with obstructed defecation syndrome. After selection, patients were randomly assigned to 2 groups:104 underwent a TRANSTAR operation and 104 a transanal rectal resection with two TST36 staplers. Patients were followed up with clinical examination, and defecography. Cumulative complication rate was significantly higher in TRANSTAR operation (P = 0.019). All symptoms and defecographic parameters significantly improved (P < 0.001), without differences. Costs were significantly lower with double TST (P = 0.035). Recurrence rates were 6.2% in TRANSTAR group and 11.4% with double TST (P = 0.206). Two circular TST 36 staplers consent to obtain the same clinical and functional results than the CCS 30, with significantly lower complication rate and costs. PMID- 29499860 TI - Parastomal hernia repair using the "top hat" technique - An initial experience in 30 patients at Memorial Sloan Kettering Cancer Center. AB - Parastomal hernia repair remains a significant surgical challenge. Recurrence after standard "keyhole" or primary suture repair is common. We adopted and modified a new technique using a construct shaped like an inverted top hat. We review our experience over the last six years in the first 30 patients (31 consecutive procedures). Of these 31 procedures, six (19%) resulted in a parastomal hernia recurrence with a median follow-up of 31 months (range 0.5-80). Four of the recurrences occurred in our initial experience, when we constructed the top hat of xenograft alone. When the technique was modified, using a synthetic composite mesh for the underlay portion of the hat, there were only two subsequent recurrences in 16 patients (13%) with a median follow-up of 22 months. One of these "recurrences" was secondary to infection of the top hat construct, which had to be removed. This initial success in preventing recurrence of parastomal hernia is probably due to the design of the construct, for it occludes the vulnerable stoma/fascial angle, through which most parastomal hernia recurrences occur. PMID- 29499861 TI - Risk management decisions in women with BRCA1 and BRCA2 mutations. AB - INTRODUCTION: Pathogenic mutations and variants of uncertain significance (VUS) occur in BRCA1/2 genes. METHODS: Records of women with a pathogenic mutation or VUS in BRCA1/2 treated between 2008 and 2017 were reviewed. RESULTS: One hundred and ten women were included. Mean age was 47. A pathogenic mutation or a VUS in BRCA1/2 was detected in 85 (77%) and 25 (23%) patients, respectively. The rate of risk reducing mastectomy (RRM) was 50% in women with a pathogenic mutation and 30% in women with a VUS (P = 0.232). Among women with breast cancer, 65% with a pathogenic mutation and 40% with a VUS underwent RRM. Over 50% of women with a pathogenic mutation in BRCA1/2 chose surveillance over operation. DISCUSSION: There was no statistical difference in the rate of RRM among women with a pathogenic mutation or a VUS in BRCA1/2 in our population. The majority of high risk women in our study chose to forgo RRM for breast cancer screening. PMID- 29499862 TI - Frailty is to predictive as Jello is to wall. PMID- 29499863 TI - Sutureless aortic valve replacement in combined procedures: Check whether there is room for the new guy before inviting them. PMID- 29499864 TI - Epidemiology and management of thoracic aortic dissections and thoracic aortic aneurysms in Ontario, Canada: A population-based study. AB - OBJECTIVES: To determine hospital incidence, mortality, and management for thoracic aortic dissections and aneurysms. METHODS: A population-based retrospective cohort study of anonymously linked data for residents of Ontario, Canada, was carried out. Incident cases of thoracic aortic dissections and aneurysms were identified between 2002 and 2014. Treatment and mortality trends were assessed. RESULTS: There were 5966 aortic dissections (Type A n = 2289 [38%] and Type B n = 3632 [61%]). Overall incidence proportion for aortic dissections was 4.6 per 100,000. There were 9392 thoracic aortic aneurysms with an overall incidence proportion of 7.6 per 100,000. The incidence for both dissections and aneurysms significantly increased over the 12-year study. Only 53% (1204 out of 2289) of Type A dissections underwent surgery. Type B dissection treatment was 83% (3000 out of 3632) medical, 10% (370 out of 3632) surgery, and 7% (262 out of 3632) endovascular. Thoracic aortic aneurysm treatment was 53% (4940 out of 9392) surgery, 44% (4129 out of 9392) medical, and 3% (323 out of 9392) endovascular. Thirty-five percent of known descending thoracic aortic aneurysms (323 out of 924) received a stent graft. Cardiac surgeons performed 87% of the open surgical repairs. Vascular surgeons performed 91% of the endovascular procedures. All cause 3-year mortality significantly decreased for both aortic dissections (44% to 40%) and aneurysms (30% to 22%). All-cause hospital mortality also decreased. Women had worse outcomes than men. CONCLUSIONS: The incidence of thoracic aortic dissections and aneurysms increased over time but all-cause hospital and late outcomes improved. Gender differences exist. Men incur more disease but women have higher hospital mortality. Surgery was primarily referred to cardiac surgeons. Endovascular therapy was primarily referred to vascular surgeons. PMID- 29499865 TI - Ten-year clinical experience of humanitarian cardiothoracic surgery in Rwanda: Building a platform for ultimate sustainability in a resource-limited setting. AB - OBJECTIVE: Despite its near complete eradication in resource-rich countries, rheumatic heart disease remains the most common acquired cardiovascular disease in sub-Saharan Africa. With a ratio of physicians/population of 1 per 10,500, including only 4 cardiologists for a population of 11.4 million, Rwanda represents a resource-limited setting lacking the local capacity to detect and treat early cases of strep throat and perform lifesaving operations for advanced rheumatic heart disease. Humanitarian surgical outreach in this region can improve the delivery of cardiovascular care by providing sustainability through mentorship, medical expertise, training, and knowledge transfer, and ultimately the creation of a cardiac center. METHODS: We describe the experience of consecutive annual visits to Rwanda since 2008 and report the outcomes of a collaborative approach to enable sustainable cardiac surgery in the region. The Ferrans and Powers Quality of Life Index tool's Cardiac Version (http://www.uic.edu/orgs/qli/) was administered to assess the postoperative quality of life. RESULTS: Ten visits have been completed, performing 149 open procedures, including 200 valve implantations, New York Heart Association class III or IV, with 4.7% 30-day mortality. All procedures were performed with the participation of local Rwandan personnel, expatriate physicians, nurses, residents, and support staff. Early complications included cerebrovascular accident (n = 4), hemorrhage requiring reoperation (n = 6), and death (n = 7). Quality of life was assessed to further understand challenges encountered after cardiac surgery in this resource-limited setting. Four major domains were considered: health and functioning, social and economic, psychologic/spiritual, and family. The mean total quality of life index was 20.79 +/- 4.07 on a scale from 0 to 30, for which higher scores indicated higher quality of life. Women had significantly lower "social and economic" subscores (16.81 +/- 4.17) than men (18.64 +/- 4.10) (P < .05). Patients who reported receiving their follow-up care in rural health centers also had significantly lower "social and economic" subscores (15.67 +/- 3.81) when compared with those receiving follow-up care in urban health facilities (18.28 +/- 4.16) (P < .005). Value afforded to family and psychologic factors remained high among all groups. Major postsurgical challenges faced included barriers to follow-up and systemic anticoagulation. CONCLUSIONS: This report represents the first account of a long-term humanitarian effort to develop sustainability in cardiac surgery in a resource-limited setting, Rwanda. With the use of volunteer teams to deliver care, transfer knowledge, and mentor local personnel, the results demonstrate superior outcomes and favorable indices of quality of life. The credibility gained over a decade of effort has created the opportunity for a partnership with Rwanda to establish a dedicated center of cardiac care to assist in mitigating the burden of cardiovascular disease throughout sub-Saharan Africa. PMID- 29499866 TI - Donor tissue-specific exosome profiling enables noninvasive monitoring of acute rejection in mouse allogeneic heart transplantation. AB - OBJECTIVE: In heart transplantation, there is a critical need for development of biomarkers to noninvasively monitor cardiac allografts for immunologic rejection or injury. Exosomes are tissue-specific nanovesicles released into circulation by many cell types. Their profiles are dynamic, reflecting conditional changes imposed on their tissue counterparts. We proposed that a transplanted heart releases donor-specific exosomes into the recipient's circulation that are conditionally altered during immunologic rejection. We investigated this novel concept in a rodent heterotopic heart transplantation model. MATERIALS AND METHODS: Full major histocompatibility mismatch (BALB/c [H2-Kd] into C57BL/6 [H2 Kb]) heterotopic heart transplantation was performed in 2 study arms: Rejection (n = 64) and Maintenance (n = 28). In the Rejection arm, immunocompetent recipients fully rejected the donor heart, whereas in the Maintenance arm, immunodeficient recipients (C57BL/6 PrkdcSCID) accepted the allograft. Recipient plasma exosomes were isolated and a donor heart-specific exosome signal was characterized on the nanoparticle detector for time-specific profile changes using anti-H2-Kd antibody quantum dot. RESULTS: In the Maintenance arm, allografts were viable throughout follow-up of 30 days, with histology confirming absence of rejection or injury. Time course analysis (days 1, 2, 3, 4, 5, 7, 9, 11, 15, and 30) showed that total plasma exosome concentration (P = .157) and donor heart exosome signal (P = .538) was similar between time points. In the Rejection arm, allografts were universally rejected (median, day 11). Total plasma exosome quantity and size distribution were similar between follow-up time points (P = .278). Donor heart exosome signals peaked on day 1, but significantly decreased by day 2 (P = 2 * 10-4) and day 3 (P = 3.3 * 10-6), when histology showed grade 0R rejection. The receiver operating characteristic curve for a binary separation of the 2 study arms (Maintenance vs Rejection) demonstrated that a donor heart exosome signal threshold < 0.3146 was 91.4% sensitive and 95.8% specific for diagnosis of early acute rejection. CONCLUSIONS: Transplant heart exosome profiling enables noninvasive monitoring of early acute rejection with high accuracy. Translation of this concept to clinical settings might enable development of a novel biomarker platform for allograft monitoring in transplantation diagnostics. PMID- 29499867 TI - Discussion. PMID- 29499868 TI - Discussion. PMID- 29499869 TI - Cardiac lipoma arising from left ventricular papillary muscle: Resect or not? PMID- 29499870 TI - Discussion. PMID- 29499871 TI - Combined ovarian serous cystadenoma and thecoma. PMID- 29499872 TI - Antifungal susceptibility testing in Australasian clinical laboratories: we must improve our performance. PMID- 29499874 TI - Hypertension: time for doctors to switch the driver's seat? PMID- 29499875 TI - A young female with cyanosis and clubbing. PMID- 29499876 TI - Progress in the treatment of Friedreich ataxia. AB - Friedreich ataxia (FRDA) is a progressive neurological disorder affecting approximately 1 in 29,000 individuals of European descent. At present, there is no approved pharmacological treatment for this condition however research into treatment of FRDA has advanced considerably over the last two decades since the genetic cause was identified. Current proposed treatment strategies include decreasing oxidative stress, increasing cellular frataxin, improving mitochondrial function as well as modulating frataxin controlled metabolic pathways. Genetic and cell based therapies also hold great promise. Finally, physical therapies are being explored as a means of maximising function in those affected by FRDA. PMID- 29499877 TI - Novel mutations in mitochondrial carrier family gene SLC25A38, causing congenital sideroblastic anemia in Iranian families, identified by whole exome sequencing. AB - Sideroblastic anemias are heterogeneous rare hematological disorders, representing diverse phenotypes. In this study, the genetic cause of congenital, transfusion dependent anemia in four unrelated families consisting of eighteen individuals, with one affected member was investigated. Probands were suspected to rare anemias, including sideroblastic anemia. Whole exome sequencing in probands followed by segregation analysis in families was performed. Two novel frame shift mutations and one previously reported missense mutation in SLC25A38 gene was identified in these families. Mutations and their recessive mood of inheritance in each family were confirmed by PCR and Sanger sequencing. These findings suggest that sideroblastic anemia must be considered a possible etiology in cases with unexplained hemolytic anemia. Furthermore, mutations in SLC25A38 gene could be a prevalent cause of congenital sideroblastic anemia (CSA) in the Iranian population. Considering that parents of all affected individuals had consanguineous marriage and belong to sub populations, where consanguineous marriage is prevalent, it is important to perform carrier screening and genetic counseling in these families and their close relatives as prevention strategy in populations at risk. PMID- 29499878 TI - Applying the QUARTZ Trial Results in Clinical Practice: Development of a Prognostic Model Predicting Poor Outcomes for Non-small Cell Lung Cancers with Brain Metastases. AB - AIMS: The role of whole brain radiotherapy (WBRT) in patients with brain metastases from non-small cell lung cancers (NSCLC) has been questioned. However, no reliable criteria exist to identify patients who do not benefit from WBRT. The objective of the current study was to develop a prognostic model to identify such patients whose survival matches that of the Quality of Life after Treatment for Brain Metastases (QUARTZ) study. MATERIALS AND METHODS: Outcome data of patients with NSCLC with brain metastases undergoing WBRT enrolled in a prospective observational study in a tertiary cancer centre were used to develop a prognostic model. Baseline clinico-radiological factors were used for development of the model. The model was internally validated and calibration accuracy was checked for prediction of 70 day mortality. The generated prognostic model was presented as a nomogram. RESULTS: The median overall survival of 140 patients enrolled in the study was 166 days (95% confidence interval 108-242 days). The prognostic model identified gender, Karnofsky performance status and epidermal growth factor receptor activating mutation status as significant factors influencing overall survival. The model showed a modest discriminative ability with an optimism corrected C-index of 0.64. However, model calibration error did reveal a moderate degree of calibration error. The high-risk subgroup identified by the model had a median overall survival of 67 days (95% confidence interval 56-101 days), which was similar to that observed in the QUARTZ trial. CONCLUSION: This prognostic model derived from traditional clinico-radiological features had a modest ability to identify patients with poor prognosis who may not benefit from WBRT. However, the high-risk subgroup identified using this prognostic model had a survival similar to that observed for patients in the QUARTZ trial. PMID- 29499879 TI - Efficacy of Prophylactic Radiotherapy in the Treatment of Heterotopic Ossification. PMID- 29499880 TI - Measurement of Glomerular Filtration Rate as a Diagnostic Test: Old Limitations and New Directions and Challenges Worthy of an Olympic Gold Medal. PMID- 29499881 TI - Kinetic Glomerular Filtration Rate in Routine Clinical Practice-Applications and Possibilities. AB - When the [creatinine] is changing, the kidney function can still be tracked with a quantitative technique called kinetic glomerular filtration rate (GFR). The equation yields useful information on the severity of acute kidney injury, the clinical course of kidney and dialysis clearances, and the timing of kidney recovery. It has been validated in at least 3 independent studies, where it performed sufficiently well in intensive care unit and kidney transplant settings, and in head-to-head comparisons with biomarkers. Because it is based on a mathematical model, the kinetic GFR faces limitations depending on the accuracy of its assumptions. As the assumptions more accurately reflect the complexities of biology, some of these limitations can be overcome in a more sophisticated model. Kinetic GFR is an easy-to-use, low-cost tool that should be more widely incorporated into medical practice. PMID- 29499873 TI - Efficacy of self-monitored blood pressure, with or without telemonitoring, for titration of antihypertensive medication (TASMINH4): an unmasked randomised controlled trial. AB - BACKGROUND: Studies evaluating titration of antihypertensive medication using self-monitoring give contradictory findings and the precise place of telemonitoring over self-monitoring alone is unclear. The TASMINH4 trial aimed to assess the efficacy of self-monitored blood pressure, with or without telemonitoring, for antihypertensive titration in primary care, compared with usual care. METHODS: This study was a parallel randomised controlled trial done in 142 general practices in the UK, and included hypertensive patients older than 35 years, with blood pressure higher than 140/90 mm Hg, who were willing to self monitor their blood pressure. Patients were randomly assigned (1:1:1) to self monitoring blood pressure (self-montoring group), to self-monitoring blood pressure with telemonitoring (telemonitoring group), or to usual care (clinic blood pressure; usual care group). Randomisation was by a secure web-based system. Neither participants nor investigators were masked to group assignment. The primary outcome was clinic measured systolic blood pressure at 12 months from randomisation. Primary analysis was of available cases. The trial is registered with ISRCTN, number ISRCTN 83571366. FINDINGS: 1182 participants were randomly assigned to the self-monitoring group (n=395), the telemonitoring group (n=393), or the usual care group (n=394), of whom 1003 (85%) were included in the primary analysis. After 12 months, systolic blood pressure was lower in both intervention groups compared with usual care (self-monitoring, 137.0 [SD 16.7] mm Hg and telemonitoring, 136.0 [16.1] mm Hg vs usual care, 140.4 [16.5]; adjusted mean differences vs usual care: self-monitoring alone, -3.5 mm Hg [95% CI -5.8 to 1.2]; telemonitoring, -4.7 mm Hg [-7.0 to -2.4]). No difference between the self monitoring and telemonitoring groups was recorded (adjusted mean difference -1.2 mm Hg [95% CI -3.5 to 1.2]). Results were similar in sensitivity analyses including multiple imputation. Adverse events were similar between all three groups. INTERPRETATION: Self-monitoring, with or without telemonitoring, when used by general practitioners to titrate antihypertensive medication in individuals with poorly controlled blood pressure, leads to significantly lower blood pressure than titration guided by clinic readings. With most general practitioners and many patients using self-monitoring, it could become the cornerstone of hypertension management in primary care. FUNDING: National Institute for Health Research via Programme Grant for Applied Health Research (RP PG-1209-10051), Professorship to RJM (NIHR-RP-R2-12-015), Oxford Collaboration for Leadership in Applied Health Research and Care, and Omron Healthcare UK. PMID- 29499882 TI - Pragmatic Use of Kidney Function Estimates for Drug Dosing: The Tide Is Turning. AB - Creatinine clearance has been the most common method of estimating kidney function for the purpose of drug dosing for decades. The availability and extensive clinical use of estimated glomerular filtration rate (eGFR) now provides clinicians a potential alternative. Currently, data demonstrating the validity of eGFR-based drug dosing is limited, but proof of principle has been established and the tide related to use of eGFR for drug dosing appears to be turning. Use of the same kidney function estimate for management of kidney disease, drug development and dosing, and harmonization in all clinical arenas would be ideal. Use of multiple equations can lead to differences in kidney function estimates and corresponding drug dosing regimens, which necessitates clinical judgment and a pragmatic approach when rendering drug dosing decisions. Careful consideration of the risk-benefit ratio of individual drugs and dosing regimens within each patient is warranted. Going forward, FDA guidance will likely incentivize pharmaceutical manufacturers to generate eGFR-based dosing recommendations in addition to creatinine clearance for inclusion in the label of newly approved drugs. However, dosing information for currently approved drugs will continue to be based on creatinine clearance alone, so clinicians must be vigilant in the assessment of kidney function in order to provide optimal pharmacotherapy. PMID- 29499883 TI - Assessment of Glomerular Filtration Rate and End-Stage Kidney Disease Risk in Living Kidney Donor Candidates: A Paradigm for Evaluation, Selection, and Counseling. AB - Living donor kidney transplantation is the preferred treatment option for ESRD. However, recent data suggest a small increase in the long-term risk of kidney failure in living kidney donors when compared to healthy nondonors. These data have led to a need for reconsideration of how donor candidates are evaluated and selected for donation. A Kidney Disease: Improving Global Outcomes (KDIGO) work group completed a comprehensive clinical practice guideline for evaluation of living kidney donor candidates in 2017, based on systematic evidence review, de novo evidence generation, and expert opinion. Central to the evaluation framework is assessment of glomerular filtration rate (GFR), which is used to screen for kidney disease and aid the prediction of long-term kidney failure risk after donation. Accurate estimation of the level of GFR and risk of kidney failure, and communication of estimated risks, can support evidence-based donor selection and shared decision-making. In this review, we discuss approaches to optimal GFR estimation in the donor evaluation process, long-term risk projection, and risk communication to donor candidates, integrating recommendations from the new KDIGO guideline, other recent literature, and experience from our own research and practice. We conclude by highlighting topics for further research in this important area of transplant medicine. PMID- 29499885 TI - A Roadmap for Estimated Glomerular Filtration Rate: Where Have We Been, Where Are We Now, and Where Do We Need to Go? PMID- 29499884 TI - Kidney Function in Obesity-Challenges in Indexing and Estimation. AB - As the prevalence of obesity continues to increase worldwide, an increasing number of people are at risk for kidney disease. Thus, there is a critical need to understand how best to assess kidney function in this population, and several challenges exist. The convention of indexing glomerular filtration rate (GFR) to body surface area (BSA) attempts to normalize exposure to metabolic wastes across populations of differing body size. In obese individuals, this convention results in a significantly lower indexed GFR than unindexed GFR, which has practical implications for drug dosing. Recent data suggest that "unindexing" estimated GFR (multiplying by BSA/1.73 m2) for drug dosing may be acceptable, but pharmocokinetic data to support this practice are lacking. Beyond indexing, biomarkers commonly used for estimating GFR may induce bias. Creatinine is influenced by muscle mass, whereas cystatin C correlates with fat mass, both independent of kidney function. Further research is needed to evaluate the performance of estimating equations and other filtration markers in obesity, and determine whether unindexed GFR might better predict optimal drug dosing and clinical outcomes in patients whose BSA is very different than the conventional normalized value of 1.73 m2. PMID- 29499886 TI - Glomerular Filtration Rates in Asians. AB - The National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines recommended the Modification of Diet in Renal Disease study equation for estimating glomerular filtration rate (GFR) for the classification of CKD, but its accuracy was limited to North American patients with estimated GFR <60 mL/min per 1.73 m2 body surface area of European (White) or African (Black) descent. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) developed another equation for estimating GFR, derived from a population that included both participants without kidney disease and with CKD. But many ethnicities were inadequately represented. The International Society of Nephrology, Kidney Disease Improving Global Outcomes committee promulgated clinical practice guidelines, which recommended the CKD-EPI equation. Investigators in Asia subsequently assessed the performance of these GFR estimating equations-the Modification of Diet in Renal Disease study equation, the CKD-EPI equation (creatinine only), and the CKD-EPI equations (creatinine and cystatin C). In this review, we summarize the studies performed in Asia on validating or establishing new Asian ethnicity GFR estimating equations. We included both prospective and retrospective studies which used serum markers traceable to reference materials and focused the review of the performance of GFR estimation by comparisons with the GFR estimations obtained from the CKD-EPI equations. PMID- 29499887 TI - Assessment of Kidney Function in Patients With Cancer. AB - Cancer patients are living longer. The sequelae of cancer treatment and the role of comorbid conditions present before the diagnosis, such as CKD, have been increasingly recognized. The interface between CKD and cancer is multifaceted. CKD is frequently observed in patients with cancer, and cancer treatment contributes to CKD development and progression. In addition, CKD has been recognized as an important risk factor for cancer development and reduced specific cancer survival. In this context, an accurate evaluation of the glomerular filtration rate (GFR) during oncologic treatment is pivotal and is used to define surgery strategies, program prophylactic management of contrasted examinations, make decisions on cisplatin eligibility, and adjust drug prescriptions, particularly chemotherapy agents. Although the most commonly used equations to estimate GFR based on serum creatinine levels in clinical practice (Cockcroft-Gault, Modification of Diet in Renal Disease Study, and CKD Epidemiology Collaboration equations) have not been validated in patients with cancer in large prospective studies, there is increasingly evidence supporting the use of CKD Epidemiology Collaboration equation to assess the GFR in patients with cancer, including for the use of chemotherapy prescriptions. Many patients with cancer may have changes in nutrition status and clearance measurements such as exogenous filtration markers might be extremely useful when clinical decisions differ depending on the GFR level. Future perspectives include the advent of new serum GFR biomarkers such as cystatin C, beta-trace protein, and beta-2 microglobulin as well as the GFR assessment by measuring total kidney parenchymal volume through image examinations. PMID- 29499888 TI - Alternatives for the Bedside Schwartz Equation to Estimate Glomerular Filtration Rate in Children. AB - The bedside Schwartz equation has long been and still is the recommended equation to estimate glomerular filtration rate (GFR) in children. However, this equation is probably best suited to estimate GFR in children with chronic kidney disease (reduced GFR) but is not optimal for children with GFR >75 mL/min/1.73 m2. Moreover, the Schwartz equation requires the height of the child, information that is usually not available in the clinical laboratory. This makes automatic reporting of estimated glomerular filtration rate (eGFR) along with serum creatinine impossible. As the majority of children (even children referred to nephrology clinics) have GFR >75 mL/min/1.73 m2, it might be interesting to evaluate possible alternatives to the bedside Schwartz equation. The pediatric form of the Full Age Spectrum (FAS) equation offers an alternative to Schwartz, allowing automatic reporting of eGFR since height is not necessary. However, when height is involved in the FAS equation, the equation is essentially equal to the Schwartz equation for children, but there are large differences for adolescents. Combining standardized biomarkers increases the prediction performance of eGFR equations for children, reaching P10 ~ 45% and P30 ~ 90%. There are currently good and simple alternatives to the bedside Schwartz equation, but the more complex equations combining serum creatinine, serum cystatin C, and height show the highest accuracy and precision. PMID- 29499889 TI - Estimated Glomerular Filtration Rate From a Panel of Filtration Markers-Hope for Increased Accuracy Beyond Measured Glomerular Filtration Rate? AB - The recent Kidney Disease Improving Global Outcomes 2012 CKD guidelines recommend estimating GFR from serum creatinine (eGFRcr) as a first-line test to assess kidney function and using cystatin C or measured glomerular filtration rate (GFR) as confirmatory tests. eGFRcr may be inaccurate in people with variation in muscle mass or diet, and eGFRcys is not more accurate than eGFRcr. eGFRcrcys is more accurate than either, but it is not independent of eGFRcr. Measured GFR is not practical and is susceptible to error due to variation in clearance methods and in the behavior of exogenous filtration markers. Over the past few years, we have hypothesized, and begun to test the hypothesis, that a panel of filtration markers (panel eGFR) from a single blood draw would require fewer demographic or clinical variables and could estimate GFR as accurately as measured GFR. In this article, we describe the conceptual background and rationale for this hypothesis and summarize our work thus far including evaluation of novel low-molecular weight proteins and metabolites and then outline how we envision that such a panel could be used in clinical practice, research, and public health. PMID- 29499890 TI - Estimated Glomerular Filtration Rate; Laboratory Implementation and Current Global Status. AB - In 2002, the Kidney Disease Outcomes Quality Initiative guidelines for identifying and treating CKD recommended that clinical laboratories report estimated glomerular filtration rate (eGFR) with every creatinine result to assist clinical practitioners to identify people with early-stage CKD. At that time, the original Modification of Diet in Renal Disease (MDRD) Study equation based on serum creatinine measurements was recommended for calculating eGFR. Because the MDRD Study equation was developed using a nonstandardized creatinine method, a Laboratory Working Group of the National Kidney Disease Education program was formed and implemented standardized calibration traceability for all creatinine methods from global manufacturers by approximately 2010. A modified MDRD Study equation for use with standardized creatinine was developed. The Chronic Kidney Disease Epidemiology Collaboration developed a new equation in 2009 that was more accurate than the MDRD Study equation at values above 60 mL/min/1.73 m2. As of 2017, reporting eGFR with creatinine is almost universal in many countries. A reference system for cystatin C became available in 2010, and manufacturers are in the process to standardize cystatin C assays. Equations for eGFR based on standardized cystatin C alone and with creatinine are now available from the Chronic Kidney Disease Epidemiology Collaboration and other groups. PMID- 29499892 TI - Challenges in Measuring Glomerular Filtration Rate: A Clinical Laboratory Perspective. AB - The assessment of kidney function is a cornerstone in the clinical management and health of the patient. Although the kidneys perform many physiologic functions and are essential for maintaining homeostasis, kidney function is typically evaluated, quantitated, and understood using the glomerular filtration rate (GFR). Although GFR can be directly measured using a variety of externally administered glomerular filtration markers, in general practice, the GFR is usually estimated (eGFR) using endogenous markers that are cleared primarily by kidney filtration. Common situations exist where the GFR needs to be measured (mGFR) in order to proceed with care. This manuscript will review laboratory challenges in the assessment of GFR. Key points to consider when implementing a mGFR testing protocol are the following: marker selection, clearance methodology (urinary vs solely plasma measurements of filtration marker), sample collection, number of samples to collect, staff required, and analytical measurement technology for the filtration marker selected. We suggest those wanting to implement mGFR testing examine site-specific institutional resources along with patient population and proceed with the approaches best suited for their clinical needs and laboratory resources available. PMID- 29499891 TI - Measured GFR in Routine Clinical Practice-The Promise of Dried Blood Spots. AB - Accurate determination of glomerular filtration rate (GFR) is crucial for the diagnosis of kidney disease. Estimated GFR (eGFR) calculated by serum creatinine and/or cystatin C is a mainstay in clinical practice and epidemiologic research but lacks precision and accuracy until GFR <60 mL/min/1.73 m2. Furthermore, eGFR may not precisely and accurately represent changes in GFR longitudinally. The lack of precision and accuracy is of concern in populations at high risk for kidney disease, as the dissociation between changes in eGFR and GFR may lead to missed diagnoses of early kidney disease. Therefore, improved methods to quantify GFR are needed. Whereas direct measures of GFR have been too cumbersome for screening and ambulatory care, a practical method of measuring GFR by iohexol clearance using dried capillary blood spots exists. In this review, we examine the current literature and data addressing GFR measurements by dried capillary blood spots and its potential application in high-risk groups. PMID- 29499894 TI - Transcarotid transcatheter aortic valve implantation: A systematic review. AB - BACKGROUND: The carotid artery is a novel access route for transcatheter aortic valve implantation (TAVI), especially useful in patients unsuitable for traditional access routes including transfemoral (TF), subclavian, transapical (TAp), and aortic (TAo). This systematic review summarizes the evidence on TAVI via the carotid artery for its efficacy and safety. METHODS: A systematic review was conducted as per the Preferred Reporting Instructions for Systematic Reviews and Meta-analysis (PRISMA) guidelines on three online databases: Medline (via Pubmed), SCOPUS, and Cochrane Database. RESULTS: There were 8 non-randomized controlled trials identified comprising 650 patients in four TAVI vascular access sites: transcarotid (TC) (N=364), TF (N=100), TAp (N=151), TAo (N=35). The 30-day rates of mortality and neurological complications for TC TAVI were 6.5% and 3.8%, respectively, with 1 incidence of myocardial infarction. Other complications included vascular complications (7.7%), insertion of new pacemaker (17.4%), atrial fibrillation (5.2%), and acute kidney injury (6.9%), bleeding episodes (14.3%), of which 13 (3.6%) cases were life-threatening; 5 (1.4%) were major; and 35 (9.3%) were minor cases. Follow-up to 1 year showed 19 further deaths. There were no significant differences in terms of mortality rates [risk ratio (RR)=0.31, 95%CI 0.05-1.79; p=0.19] and onset of dialysis treatment (RR=2.53, 95%CI 0.31-19.78; p=0.38) between the TC and TAp groups. CONCLUSION: The available data on TC TAVI show comparable technical feasibility with other traditional access routes, representing a viable alternative. However, the paucity of data warrants the need for larger randomized controlled trials to establish a firm conclusion. PMID- 29499893 TI - Measurement and Estimation of Residual Kidney Function in Patients on Dialysis. AB - Residual kidney function (RKF) in patients on dialysis is strongly associated with survival and better quality of life. Assessment of kidney function underlies the management of patients with chronic kidney disease before dialysis initiation. However, methods to assess RKF after dialysis initiation are just now being refined. In this review, we discuss the definition of RKF and methods for measurement and estimation of RKF, highlighting the unique aspects of dialysis that impact these assessments. PMID- 29499895 TI - [Characteristics present in secondary school students who do not smoke and who have no intention to smoke]. AB - OBJECTIVE: To know the variables present in primary and secondary school students who do not smoke or intend to smoke from a positive health model. METHODS: Cross sectional study with 482 students from Andalusia and Catalonia using a validated questionnaire (ESFA and PASE project). Binary logistic regression analysis was performed. RESULTS: Those who did not intend to smoke viewed smoking unfavourably and had high self-efficacy (p <0.001). In non-consumers, the most associated variables were attitude, social model (p <0.001), and self-efficacy (p =0.005). CONCLUSIONS: The results show motivational factors present in students who do not smoke and do not intend to do so. Attitude and self-efficacy are strongly associated with intention and behaviour. This information might be useful for developing positive health promotion strategies from a salutogenesis approach. PMID- 29499896 TI - [Biosafety devices and training to prevent accidental biological exposures in hospitals]. PMID- 29499897 TI - In utero gene delivery to spinal cord motor neurons. PMID- 29499898 TI - Ceftriaxone combination therapy versus respiratory fluoroquinolone monotherapy for community-acquired pneumonia: A meta-analysis. AB - BACKGROUND: The goal of this study was to investigate whether ceftriaxone combination therapy is associated with better clinical outcomes than respiratory fluoroquinolone monotherapy for adults with community-acquired pneumonia (CAP). We conducted a meta-analysis of published studies. METHODS: Using the PubMed, EMBASE, and Cochrane Library databases, we performed a literature search of available randomized controlled trials (RCTs) published as original articles before September 2017. RESULTS: Nine RCTs, involving 1520 patients, were included in the meta-analysis. The pooled relative risks (RRs) for the efficacy of ceftriaxone combination therapy versus respiratory fluoroquinolones monotherapy were 0.96 (95% CI: 0.92-1.01), based on clinically evaluable populations, and 0.93 (95% CI: 0.88-0.99) based on intention-to-treat (ITT) populations. No statistically significant differences were observed in microbiological treatment success (pooled RR=0.99, 95% CI: 0.90-1.09), although drug-related adverse events were significantly lower with ceftriaxone combination therapy than with respiratory fluoroquinolones monotherapy (pooled RR=1.27, 95% CI: 1.04-1.55). CONCLUSIONS: Current evidence showed that the efficacy of ceftriaxone combination therapy was similar to respiratory fluoroquinolone monotherapy for hospitalized CAP patients, and was associated with lower drug-related adverse events. PMID- 29499899 TI - Determinants of turnover among low wage earners in long term care: the role of manager-employee relationships. AB - The demand for Long-Term Care (LTC) is steadily increasing as Baby Boomers age and enter retirement. High turnover rates among employees in LTC creates challenges for supervisors and administrators, and can negatively impact quality of care. This study examines manager-subordinate relationship quality using Leader-Member Exchange Theory (LMX) as an antecedent to turnover among low-wage earners in the LTC environment. Survey data measuring LMX, job satisfaction, and demographic information was collected at time 1, and turnover data was collected 18 months later at time 2. The results reveal that all four LMX dimensions were rated significantly different among subordinates who left versus those who stayed, however, only the LMX dimension of supervisor loyalty was a significant predictor of turnover among low wage earners. Our study adds a more nuanced view of the reasons low-wage employees turnover, and presents implications for clinical managers and LTC organizations more broadly. PMID- 29499900 TI - Does preserved sphincter of Oddi function prevent common bile duct stones recurrence in patients after endoscopic papillary balloon dilation? AB - BACKGROUND: Whether preserving sphincter of Oddi (SO) function by endoscopic papillary balloon dilation (EPBD) is beneficial for preventing recurrent common bile duct stone disease (CBDS) is controversial. The aim of this study was to measure sphincter of Oddi (SO) function by using SO manometry, and to evaluate the association with recurrent CBDS. METHODS: Patients with suspected CBDS who underwent successful EPBD were included. These patients underwent SO manometry at two months after EPBD with bile duct clearance. They were regularly followed for recurrent CBDS. RESULTS: From January 2000 to December 2009, 185 patients received EPBD and SO manometry was included. There were 64% male with mean age of 65 +/- 15.6 years. Mean ballooning inflation size was 1.1 +/- 0.19 cm and mean ballooning time was 4.5 +/- 0.85 min 55.7% had a sphincter of Oddi basal pressure (SOBP) of 0 mmHg, 16.2% < 10 mmHg, 26.5% 10-40 mmHg, and 1.6% > 40 mmHg. In multivariate analysis, EPBD with balloon >=1.2 cm was the only factor for loss of SO function. Moreover, patients with preserved SO function had higher stone recurrence rate (15% vs. 5%, p = 0.034). CONCLUSION: EPBD using balloon >=1.2 cm is a major factor for loss of SO function, which seems to reduce the risk of recurrent CBD stones. PMID- 29499901 TI - Pd-catalyzed coupling reactions of anhydro-aldose tosylhydrazones with aryl bromides to produce substituted exo-glycals. AB - Palladium-catalyzed cross-couplings of O-peracylated and O-permethylated 2,6 anhydro-aldose tosylhydrazones with aryl halides were studied under thermic conditions in the presence of LiOtBu and phosphine ligands. The reactions gave the corresponding aryl substituted exo-glycals as mixtures of diastereomers in 11 75% yields. The transformations represent a new access to these types of glycomimetic compounds. The double bond of some aryl substituted exo-glycals was saturated to give good yields of benzylic C-glycosyl derivatives. PMID- 29499902 TI - Effect of UGT, SLCO, ABCB and ABCC polymorphisms on irinotecan toxicity. AB - BACKGROUND AND OBJECTIVES: Evaluate the relationship between the presence of polymorphisms in genes involved in the pharmacodynamics of irinotecan (UGT1A, SLCO1B1, ABCB1 and ABCC2) and the safety of irinotecan in the treatment of metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Prospective observational, single-centre study of 30 months duration, which included patients diagnosed with mCRC treated with FOLFIRI was carried out. Toxicity was evaluated in each treatment cycle according to the Common Terminology Criteria for Adverse Events (CTCAE) v.4.0 NCI. Genomic DNA was obtained with a peripheral blood sample from an extraction method based on alkaline lysis. Genetic characterisation was performed using the LigthCycler(r)480 platform and allele-specific HybProbe(r) fluorescent probes. Analysed polymorphisms were: UGT1A1*28, UGT1A1*60, UGT1A7*1,*2,*3,*4, UGT1A7*12, UGT1A9*22, SLCO1B1 (rs11045879), ABCC2 (rs717620) and ABCB1 (rs1045642). RESULTS: Thirty-four patients were included (73.5% were male, mean age 59.9 years [27-81]) in the study. Polymorphisms rs8175347, rs17868323, rs3832043, rs11692021 and rs7577677 were associated with a higher incidence of adverse effects. Furthermore, it was observed that those patients with wild-type in UGT family genes analysed have lower rates of toxicity associated with irinotecan treatment than those with certain mutated allele (P=.010). CONCLUSIONS: These results suggest that the presence of certain polymorphisms in the UGT1A family of genes is related to the development of toxicity during treatment with irinotecan. PMID- 29499904 TI - The Hungarian initiative for Ayurveda: European Institute of Ayurvedic Sciences. PMID- 29499903 TI - 12 weeks ombitasvir/paritaprevir-ritonavir + ribavirin achieve high SVR rates in HCV-4 patients with advanced fibrosis. AB - BACKGROUND: Ombitasvir/paritaprevir-ritonavir (OBT/PTV-r) plus ribavirin (RBV) for 12 weeks in hepatitis C virus (HCV) genotype 4 patients with advanced fibrosis has been only investigated in clinical trials. AIMS: To assess safety and efficacy of OBT/PTV-r + RBV for 12 weeks in real-life HCV-4 patients with advanced fibrosis. METHODS: HCV-4 patients with advanced fibrosis consecutively receiving OBT/PTV-r + RBV for 12 weeks in a single center were enrolled. Fibrosis was staged by transient elastography (TE) (F3: >=10 kPa; F4 >=11.9 kPa) or histologically. Sustained virological response (SVR) was defined as undetectable HCV-RNA 12 weeks post-treatment. RESULTS: Between January 2016 and February 2017, 49 HCV-4 patients were included: median age 54 (39-72) years, 84% males, 59% Egyptians, 35% fibrosis F3 and 65% F4, all Child Pugh class A. Median RBV dose was 1200 (200-1200) mg/day. At ITT analysis, 47 (96%) patients achieved an SVR (100% at PP analysis). SVR was not affected by ancestry (Egyptian vs. Italian 97% vs. 95%, p = 1.0), fibrosis stage (F3 vs. F4 100% vs. 94%, p = .53), presence of baseline resistance associated substitutions (RASs) or RBV reduction. CONCLUSIONS: We report 100% SVR with 12-weeks of OBT/PTV-r + RBV in HCV-4 patients with advanced liver disease, including compensated cirrhotics. PMID- 29499905 TI - Pediatric Fall Risk Assessment Tool Comparison and Validation Study. AB - PURPOSE: Compare two pediatric fall risk assessment tools (I'M SAFE and Humpty Dumpty) used at the same organization to determine if one is better able to predict which patients fall. DESIGN AND METHODS: Retrospective data was obtained from patients admitted in 2014. Each patient who experienced a fall during hospitalization was matched with two non-fallers based on age and diagnosis. Logistic regression was performed to identify which tool more accurately determines fall risk and reliability testing was completed for the I'M SAFE tool. RESULTS: Over 22,000 patient files were extracted for this study. One hundred seventy-seven falls were identified, seventy-one of them were intrinsic. Of those patients who fell, the majority were assessed to be at high risk for falls. There were too few falls during the study period using the Humpty Dumpty tool to assess and make formal conclusions. The results for the I'M SAFE tool were opposite of what was expected and showed an increased risk for falls for patients who scored low risk using this tool. CONCLUSIONS: At completion of this study the data reflected that the I'M SAFE tool was not adequately predicting patients at greatest risk for intrinsic falls for this particular population. PRACTICE IMPLICATIONS: Further research on these tools is needed in other populations or across multiple sites. Additional work to adapt the tools may be necessary to better predict fall risk without over identifying high risk patients. PMID- 29499906 TI - ? PMID- 29499908 TI - CD21-independent Epstein-Barr virus entry into NK cells. AB - Extranodal natural killer (NK)/T-cell lymphoma is an aggressive malignant disease that is associated with Epstein-Barr viral (EBV) infection. To date, the mechanism of viral entry into NK cells remains uncertain. Here, we investigated this mechanism using human NK cells in vitro. CD21 mRNA expression, an EBV-entry receptor, was transiently detected in NK cells after exosome treatment, and levels decreased after further culture. CD21 protein expression was also transiently transferred to NK cells after co-culture with an EBV-positive Burkitt lymphoma cell line (Raji) via trogocytosis. However, EBV did not infect NK cells through CD21-mediated trogocytosis. Unexpectedly, when NK cell leukemia cells, as well as primary NK cells, were treated with viral supernatant, EBV genes, but not RNA, were detected in the NK cells, at latency stage 0. Therefore, these results suggest that EBV-NK cell infection results from the direct transfer of viral episomes, independent of EBV-positive B cells. PMID- 29499907 TI - Genetic Villains: Killer Meiotic Drivers. AB - Unbiased allele transmission into progeny is a fundamental genetic concept canonized as Mendel's Law of Segregation. Not all alleles, however, abide by the law. Killer meiotic drivers are ultra-selfish DNA sequences that are transmitted into more than half (sometimes all) of the meiotic products generated by a heterozygote. As their name implies, these loci gain a transmission advantage in heterozygotes by destroying otherwise viable meiotic products that do not inherit the driver. We review and classify killer meiotic drive genes across a wide spectrum of eukaryotes. We discuss how analyses of these ultra-selfish genes can lead to greater insight into the mechanisms of gametogenesis and the causes of infertility. PMID- 29499909 TI - Increased mTOR cancels out the effect of reduced Xbp-1 on antibody secretion in IL-1alpha-deficient B cells. AB - IL-1alpha in vitro promotes immunoglobulin secretion by inducing proliferation of mature B cells, whereas IL-1alpha deficiency has no effect on in vivo antibody production. However, the reason IL-1alpha deficiency does not reduce in vivo antibody production is still unclear. In this study, we found that similar as in vivo data, IL-1alpha deficiency did not affect antibody production in in vitro LPS-stimulated B cells. Surprisingly, LPS-stimulated IL-1alpha-/- B cells reduced a key antibody production-related transcription factor X-box binding protein 1 (Xbp-1) expression. Furthermore, we found that IL-1alpha deficiency up-regulated mTOR expression, which bypassed Xbp-1 for immunoglobulin secretion. Finally, we showed that Xbp-1 suppressed mTOR expression, whereas mTOR suppressed the activation of Xbp-1 promoter via JunB. Together, these data suggest that IL-1a deficiency reduced Xbp-1 and up-regulated mTOR. This may explain why IL-1alpha deficiency has no effect on antibody production. PMID- 29499910 TI - A Special Issue on "Stem Cell Immunology". PMID- 29499911 TI - MRA of the skin: mapping for advanced breast reconstructive surgery. AB - Autologous breast reconstruction using muscle-sparing free flaps are becoming increasingly popular, although microvascular free flap reconstruction has been utilised for autologous breast reconstructions for >20 years. This innovative microsurgical technique involves meticulous dissection of artery-vein bundle (perforators) responsible for perfusion of the subcutaneous fat and skin of the flap; however, due to unpredictable anatomical variations, preoperative imaging of the donor site to select appropriate perforators has become routine. Preoperative imaging also reduces operating time and enhances the surgeon's confidence in choosing the appropriate donor site for harvesting flaps. Although computed tomography angiography has been widely used for preoperative imaging, concerns over excessive exposure to ionising radiation and poor iodinated contrast agent enhancement of the intramuscular perforator course has made magnetic resonance angiography, the first choice imaging modality in our centre. Magnetic resonance angiography with specific post-processing of the images has established itself as a reliable method for mapping tiny perforator vessels. Multiple donor sites can be imaged in a single setting without concern for ionising radiation exposure. This provides anatomical information of more reconstruction donor site options, so that a surgeon can design a flap of tissue centralised around the best perforator, as well as a back-up perforator, and even a back-up flap option located on a different region of the body. This information is especially helpful in patients with a history of scar tissue from previous surgeries, where the primary choice perforator is found to be damaged or unsuitable intraoperatively. In addition, chest magnetic resonance angiography evaluates recipient site blood vessel suitability including vessel diameters, course, and branching patterns. In this article we provide a broad overview of various skin flaps, clinical indications, advantages and disadvantages of each of these flaps, basic imaging technique, along with advanced sequences for visualising tiny arteries in the groin and in the chest. Post-processing techniques, structure of the report and how automation of the reporting system improves workflow is described. We also describe applications of magnetic resonance angiography in postoperative imaging. PMID- 29499912 TI - Quantitative bowel apparent diffusion coefficient measurements in children with inflammatory bowel disease are not reproducible. AB - AIM: To investigate the intra-observer and interobserver variability of quantitative apparent diffusion coefficient (ADC) measurements in children with inflammatory bowel disease. MATERIALS AND METHODS: Nine readers were recruited. Six magnetic resonance imaging (MRI) enterography cases with known active disease in the jejunum, terminal ileum, or colon were analysed. Readers measured repeat ADC values from the known diseased site and an unaffected site, at two sittings. RESULTS: Seven readers completed the study. The Lin concordance coefficient for intra-observer agreement was poor (0.844, 95% confidence interval [CI]: 0.77, 0.896). Bland-Altman limits of agreement for intra-observer agreement were 0.66*10-3 mm2/s (95% CI: 0.46, 0.86), and -0.56*10-3 mm2/s (95% CI: -0.36, 0.76). Therefore, a single measured value would be compatible with no disease, superficial ulceration, or deep ulceration according to published thresholds. Interobserver variability was poor to moderate across all observers (intraclass correlation coefficient [ICC]: 0.51, 95% CI: 0.27, 0.77). Between the two best agreeing observers, agreement was good using the ICC (ICC 0.85, 95% CI: 0.43, 1.0), but poor using the Lin correlation coefficient (Lin 0.83, 95% CI: 0.65, 0.93), and Bland-Altman. CONCLUSION: The intra-observer and interobserver agreement is inadequate to allow accurate characterisation of disease activity using previously published thresholds. Qualitative ADC assessment may be preferable. PMID- 29499914 TI - Radiological evaluation of C1 pedicle screw anatomic feasibility. AB - C1 pedicle screw instrumentation is a recently documented technique, which may have benefits over other more popularised procedures, however it may not be possible in all patients. This study aims to investigate the applicability of the C1 pedicle screw technique to a cohort of patients through assessment of radiological parameters. A retrospective review of 150 consecutive patients undergoing computer tomography (CT) of the cervical spine was performed. Based on defined parameters images were assessed for feasibility of placement of pedicle screws. C1 pedicle height (PH), pedicle width (PW), screw trajectory length (LML) and width (LMW) were recorded with PH >= 4 mm defined as the primary outcome measure. A total of 115 patients and 230 C1 pedicles were examined. The mean PH was found to be 5.1 mm. 207 pedicles were deemed suitable for placement of pedicle screw instrumentation. Overall C1 pedicle screw instrumentation was deemed possible in 94.6% of male pedicles and 84% of female pedicles. C1 pedicle screw instrumentation is feasible to be performed in more than 90% of the patients. PMID- 29499913 TI - Determinants of organophosphate pesticide exposure in pregnant women: A population-based cohort study in the Netherlands. AB - BACKGROUND: In the Netherlands organophosphate (OP) pesticides are frequently used for pest control in agricultural settings. Despite concerns about the potential health impacts of low-level OP pesticides exposure, particularly in vulnerable populations, the primary sources of exposure remain unclear. The present study was designed to investigate the levels of DAP metabolites concentrations across pregnancy and to examine various determinants of DAP metabolite concentrations among an urban population of women in the Netherlands. METHOD: Urinary concentrations of six dialkyl phosphate (DAP) metabolites, the main urinary metabolites of OP pesticides, were determined at <18, 18-25, and >25 weeks of pregnancy in 784 pregnant women participating in the Generation R Study (between 2004 and 2006), a large population-based birth cohort in Rotterdam, the Netherlands. Questionnaires administered prenatally assessed demographic and lifestyle characteristics and maternal diet. Linear mixed models, with adjustment for relevant covariates, were used to estimate associations between the potential exposure determinants and DAP metabolite concentrations expressed as molar concentrations divided by creatinine levels. RESULTS: The median DAP metabolite concentration was 311 nmol/g creatinine for the first trimester, 317 nmol/g creatinine for the second trimester, and 310 nmol/g creatinine for the third trimester. Higher maternal age, married/living with a partner, underweight or normal weight (BMI of <18.5 and 18.5-<25), high education, high income, and non smoking were associated with higher DAP metabolite concentrations, and DAP metabolite concentrations tended to be higher during the summer. Furthermore, fruit intake was associated with increased DAP metabolite concentrations. Each 100 g/d difference in fruit consumption was associated with a 7% higher total DAP metabolite concentration across pregnancy. Other food groups were not associated with higher DAP metabolite concentrations. CONCLUSIONS: The DAP metabolite concentrations measured in the urine of pregnant women in the Netherlands were higher than those in most other studies previously conducted. Fruit intake was the main dietary source of exposure to OP pesticides in young urban women in the Netherlands. The extent to which DAP metabolite concentrations reflect exposure to the active parent pesticide rather than to less toxic metabolites remains unclear. Further research will be undertaken to investigate the possible effects of this relatively high level OP pesticides exposure on offspring health. PMID- 29499916 TI - DCTN1 F52L mutation case of Perry syndrome with progressive supranuclear palsy like tauopathy. AB - INTRODUCTION: Perry syndrome is a rapidly progressive, autosomal dominant parkinsonism characterized by central hypoventilation, depression and severe weight loss. To date, eight DCTN1 mutations have been identified associated with Perry syndrome. A novel F52L DCTN1 mutation case of Perry syndrome is characterized by late-onset parkinsonism and frontotemporal atrophy. METHODS: A Japanese woman suffered from slowly progressing parkinsonism since age 48. At age 59, she developed central hypoventilation, and required breathing assistance. Gene analysis identified a p.F52L mutation in DCTN1 and she was diagnosed with Perry syndrome. She died of aspiration pneumonia at age 74. RESULTS: Postmortem examination revealed severe neuronal loss in the substantia nigra and the putamen. Immunohistochemistry for DCTN1 revealed many abnormal aggregates, mainly in neurons in the brainstem and basal ganglia. Additionally, numerous abnormal phosphorylated tau deposits including neurofibrillary tangles, tuft-shaped astrocytes and coiled bodies were observed mainly in the basal ganglia, brainstem and cerebellum. These correspond with the neuropathologic criteria for progressive supranuclear palsy. Colocalization of DCTN1 and tau were occasionally seen. Colocalization of phosphorylated alpha-synuclein and DCTN1 were also observed in Lewy body-like structures in oculomotor nuclei. Phosphorylated TARDBP positive neuronal cytoplasmic inclusions were few. CONCLUSION: In conjunction with long disease duration and aging, our findings suggest that the F52L DCTN1 mutation may evoke severe tauopathy and moderate alpha-synucleinopathy. PMID- 29499915 TI - Self-report depressive symptoms are dissociated from tremor severity in essential tremor. AB - BACKGROUND: Depressive symptoms are associated with essential tremor (ET). However, the relationship between cognitive, functional, and motor measures with depressive symptoms in ET is not yet understood. METHODS: The following measures were cross-sectionally assessed in a group of 223 subjects with ET: the Montreal Cognitive Assessment (MoCA) Scale, the Lawton Independent Activities of Daily Living (IADL) Scale, a neurologist assessment of tremor severity, and the Geriatric Depression Scale (GDS). RESULTS: 20% (44) of the subjects met GDS criteria for depression (GDS >= 10). 43% (94) of the subjects showed at least some cognitive impairment (<=24 on the MoCA), and 15.3% (34) reported significant functional impairment (IADL score < 7). There was no significant association between GDS score and tremor scale score. The total GDS was negatively associated with the total MoCA score (Spearman's r = -0.15, p = 0.03). The total GDS was also negatively associated with the IADL score (Spearman's r = -0.19, p = 0.02), (logistic model odds ratio, OR = 4.91, p < 0.01). Over 60% of subjects who were depressed, per GDS cut-off score (>=10), were not receiving medical treatment for depression. CONCLUSIONS: There was a high point prevalence of depressive symptoms in subjects with ET. Self-report depressive symptoms are dissociated from tremor severity. Hence, these data do not support the hypothesis that depression in ET represents a psychological reaction to the tremor. There appears to be a clustering of cognitive, functional, and depressive symptoms in ET. Screening of depression in ET can improve our understanding and treatment of this disorder. PMID- 29499917 TI - In Vivo Imaging of Microvasculature during Anesthesia with High-Resolution Photoacoustic Microscopy. AB - Anesthesia monitoring is extremely important in improving the quality of anesthesia and ensuring the safety of patients in operation. Photoacoustic microscopy (PAM) is proposed to in vivo image the skin microvasculature of 10 nude mice undergoing general anesthesia by using the isoflurane gas with a concentration of 3%. Benefiting from strong optical absorption of hemoglobin, PAM has good contrast and high resolution in mapping of microvasculature. A series of high quality images can clearly reveal the subtle changes of capillaries in morphology over time. Two indices, vessel intensity and vessel density, are extracted from these images to measure the microvasculature quantitatively. The imaging results show that the vessel intensity and density are increased over time. After 65 min, the vessel intensity increased 42.7 +/- 8.6% and the density increased 28.6 +/- 12.2%. These indices extracted from photoacoustic images accurately reflect the greater blood perfusion undergoing general anesthesia. Additionally, abnormal reductions of vessel intensity and density are also observed as overtime anesthesia. This preclinical study suggests that PAM holds potential to monitor anesthesia by imaging the skin microvasculature. PMID- 29499918 TI - Generation of Reactive Oxygen Species in Heterogeneously Sonoporated Cells by Microbubbles with Single-Pulse Ultrasound. AB - To develop and realize sonoporation-based macromolecule delivery, it is important to understand the underlying cellular bioeffects involved. It is known that an appropriate level of reactive oxygen species (ROS) is necessary to maintain normal physiologic function, but excessive ROS triggers adverse downstream bioeffects. However, it is still unclear whether a relationship exists between intracellular ROS levels and sonoporation. Using a customized platform for 1.5 MHz ultrasound exposure (13.33 us duration and 0.70 MPa peak negative pressure) and imaging the dynamics of sonoporation and intracellular ROS at the single-cell level, we quantified the exogenous molecular uptake and the concentration of intracellular ROS indicator to evaluate the extent of sonoporation and ROS change, respectively. Our results revealed that the intracellular ROS level was correlated with the degree of the sonoporation. (i) Within ~120 s of the onset of ultrasound, during which membrane perforation and complete membrane resealing occurred, intracellular ROS rapidly decreased because of extracellular diffusion of dichlorofluorescein through the perforated membrane and positively correlated with the degree of the sonoporation. (ii) In the following 270 s (120-390 s post exposure), ROS generation in reversibly sonoporated cells gradually increased and was positively correlated with the degree of the sonoporation. (iii) The ROS level in irreversibly sonoporated cells reduced to depletion during this time interval. It is possible that ROS generation in reversibly sonoporated cells can impact their long-term fate. These results thus provide new insight into the biological response to sonoporation. PMID- 29499919 TI - Ultrasound Irradiation Combined with Hepatocyte Growth Factor Accelerate the Hepatic Differentiation of Human Bone Marrow Mesenchymal Stem Cells. AB - This study investigated the impact of ultrasound (US) irradiation on the hepatic differentiation of human bone marrow mesenchymal stem cells (hBMSCs) induced by hepatocyte growth factor (HGF) and the possible mechanisms. We treated hBMSCs, using HGF with and without US irradiation. Cell viability and stem cell surface markers were analyzed. Hepatocyte-like cell markers and functional markers including alpha-fetoprotein (alphaFP/AFP), cytokeratin 18 (CK18), albumin (ALB) and glycogen content were analyzed at the time point of day 1, 3 and 5 after treatment. The involvement of Wnt/beta-catenin signaling pathway was evaluated as well. The results showed that the US treatment at 1.0 W/cm2 or 1.5 W/cm2 for 30 s or 60 s conditions yielded favorable cell viability and engendered stem cell differentiation. At day 5, the expressions of AFP, CK18, ALB and the glycogen content were significantly elevated in the US-treated group at both messenger ribonucleic acid and protein levels (all p <0.05), in comparison with HGF and control groups. Among all the US treated groups, the expression levels of specific hepatic markers in the (1.5 W/cm2 for 60 s) group were the highest. Furthermore, Wnt1, beta-Catenin, c-Myc and Cyclin D1 were significantly increased after US irradiation (all p <0.05), and the enhancements of c-Myc and Cyclin D1 could be obviously impaired by the inhibitor ICG-001 (p <0.05, p <0.05), in accordance with decreased ALB and CK18 expression and glycogen content (all p <0.05). In conclusion, US irradiation was able to promote the hBMSCs' differentiation mediated by HGF in vitro safely, easily and controllably. The activation of Wnt/beta-catenin signaling pathway was involved in this process. US irradiation could serve as a potentially beneficial tool for the research and application of stem cell differentiation. PMID- 29499920 TI - Oleoresin urushiol: Can its immunogenicity be exploited for healthcare? PMID- 29499921 TI - Pharmacological treatment of gestational diabetes mellitus: point/counterpoint. AB - Controversies persist over the most efficacious pharmacologic treatment for gestational diabetes mellitus. For purposes of accuracy in this article, the individual American College of Obstetricians and Gynecologists Practice Bulletin and American Diabetes Association Standards of Medical Care positions on each issue are quoted and then deliberated with evidence of counter claims presented in point/counterpoint. This is a review of all the relevant evidence for the most holistic picture possible. The main issues are (1) which diabetic drugs cross the placenta, (2) the quality of evidence and data source validity, (3) the rationale for the designation of glucose control as the primary outcome in gestational diabetes mellitus, and (4) which drugs (metformin, glyburide, or insulin) are most effective in improving secondary outcomes. The concept that 1 drug fits all, whether it be insulin, glyburide, or metformin, is a fallacy. Different drugs provide certain benefits but not all the benefits and not to all patients. In addition, the steps in the gestational diabetes mellitus management decision path and the current cost of the use of insulin, glyburide, or metformin are addressed. In the future, we must consider studying the potential of diabetic drugs that currently are used in nonpregnancy and incorporating the concept of precision medicine in the decision tree to maximize pregnancy outcomes. PMID- 29499922 TI - Erratum to "Perception, culture, and science: A framework to identify in-home heating options to improve indoor air quality in the Navajo Nation" [Sci. Total Environ. 580(2017) 297-306]. PMID- 29499923 TI - Prognostic Significance and Clinical Utility of Intraventricular Conduction Delays on the Preoperative Electrocardiogram. AB - The prognostic significance of the preoperative electrocardiogram (ECG), particularly intraventricular conduction delays (IVCDs), on postoperative outcomes among patients undergoing noncardiac surgery is uncertain. In a retrospective cohort, we evaluated the risk associated with preoperative IVCDs on in-hospital death and postoperative myocardial infarction (POMI). The 152,479 patients who underwent noncardiac surgery were categorized by preoperative electrocardiographic findings: normal (36.1%), left bundle branch block (LBBB, 1.2%), right bundle branch block (2.9%), nonspecific IVCD (3.3%), and any other ECG abnormality (56.5%). The primary and secondary outcomes were postoperative in hospital mortality and POMI, respectively. In multivariable-adjusted models, compared with normal ECGs, each electrocardiographic abnormality category was associated with increased risk of postoperative death: LBBB odds ratio (OR) 1.89 (95% confidence interval [CI] 1.35 to 2.65), right bundle branch block OR 1.73 (95% CI 1.33 to 2.24), nonspecific IVCD OR 1.95 (95% CI 1.53 to 2.48), and other abnormal ECG OR 1.94 (95% CI 1.68 to 2.25). ECGs with conduction delays did not confer increased risk of postoperative death compared with other ECG abnormalities. Moreover, receiver operating characteristic analysis of models incorporating demographic and co-morbidity data demonstrated marginal additive benefit of any electrocardiographic data. Risk of POMI was not significantly increased among ECGs with conduction delays compared with both normal and other abnormal ECGs. In conclusion, patients with intraventricular conduction disease, including LBBB, on preoperative ECG are not at greater risk of postoperative in hospital death or POMI compared with patients with other ECG abnormalities. Furthermore, any preoperative electrocardiographic abnormalities, including intraventricular delays, provide marginal clinical utility beyond demographic and clinical history for predicting postoperative in-hospital death or POMI. PMID- 29499924 TI - Usefulness of Carotid Plaques as Predictors of Obstructive Coronary Artery Disease and Cardiovascular Events in Asymptomatic Individuals With Diabetes Mellitus. AB - Carotid intima-media thickness (CIMT) measurement and carotid plaque detection by B-mode ultrasound are frequently used as surrogates to predict coronary artery disease (CAD). However, their systematic use in routine clinical management of asymptomatic patients with diabetes mellitus (DM) has not been studied. The aim of the study was to identify carotid parameters that predict cardiovascular events in patients with asymptomatic type 2 DM by evaluating the relation between carotid disease and CAD. This multicenter, observational, prospective study included 259 asymptomatic patients with type 2 DM followed-up for 34 months after measurement of CIMT and carotid plaque with carotid ultrasound, and CAD assessment with computed tomography coronary angiography. Statistically significant differences between patients with and without carotid plaque were found for coronary plaque >50% stenosis (59 vs 36, p = 0.02). Greater maximal CIMT was associated with an increased risk of coronary plaque >50% (odds ratio 1.21 [1.02, 1.44], p = 0.03) and >70% stenosis (odds ratio 1.23 [1.01, 1.50], p = 0.04) after adjusting for traditional risk factors. At 34-month follow-up, the occurrence of total major adverse cardiovascular event was estimated to be 7.1% (mean age 68 years, 6% male and 1.1% female) in the whole study population. The subgroup of patients with carotid plaque showed increased incidence of major adverse cardiovascular event compared with patients with no carotid plaque (p = 0.005). In conclusion, carotid plaque was a strong predictor of future cardiovascular events and may be a prognostic marker in asymptomatic patients with type 2 DM. Carotid plaque and maximal intima-media thickness were independently associated with obstructive CAD. PMID- 29499925 TI - High Efficiency Gene Correction in Hematopoietic Cells by Donor-Template-Free CRISPR/Cas9 Genome Editing. AB - The CRISPR/Cas9 prokaryotic adaptive immune system and its swift repurposing for genome editing enables modification of any prespecified genomic sequence with unprecedented accuracy and efficiency, including targeted gene repair. We used the CRISPR/Cas9 system for targeted repair of patient-specific point mutations in the Cytochrome b-245 heavy chain gene (CYBB), whose inactivation causes chronic granulomatous disease (XCGD)-a life-threatening immunodeficiency disorder characterized by the inability of neutrophils and macrophages to produce microbicidal reactive oxygen species (ROS). We show that frameshift mutations can be effectively repaired in hematopoietic cells by non-integrating lentiviral vectors carrying RNA-guided Cas9 endonucleases (RGNs). Because about 25% of most inherited blood disorders are caused by frameshift mutations, our results suggest that up to a quarter of all patients suffering from monogenic blood disorders could benefit from gene therapy employing personalized, donor template-free RGNs. PMID- 29499927 TI - Transplantation of Gene-Edited Hepatocyte-like Cells Modestly Improves Survival of Arginase-1-Deficient Mice. AB - Progress in gene editing research has been accelerated by utilizing engineered nucleases in combination with induced pluripotent stem cell (iPSC) technology. Here, we report transcription activator-like effector nuclease (TALEN)-mediated reincorporation of Arg1 exons 7 and 8 in iPSCs derived from arginase-1-deficient mice possessing Arg1Delta alleles lacking these terminal exons. The edited cells could be induced to differentiate into hepatocyte-like cells (iHLCs) in vitro and were subsequently used for transplantation into our previously described (Sin et al., PLoS ONE 2013) tamoxifen-inducible Arg1-Cre arginase-1-deficient mouse model. While successful gene-targeted repair was achieved in iPSCs containing Arg1Delta alleles, only minimal restoration of urea cycle function could be observed in the iHLC-transplanted mice compared to control mice, and survival in this lethal model was extended by up to a week in some mice. The partially rescued phenotype may be due to inadequate regenerative capacity of arginase-1 expressing cells in the correct metabolic zones. Technical hurdles exist and will need to be overcome for gene-edited iPSC to iHLC rescue of arginase-1 deficiency, a rare urea cycle disorder. PMID- 29499926 TI - RNA Nanotherapeutics for the Amelioration of Astroglial Reactivity. AB - In response to injuries to the CNS, astrocytes enter a reactive state known as astrogliosis, which is believed to be deleterious in some contexts. Activated astrocytes overexpress intermediate filaments including glial fibrillary acidic protein (GFAP) and vimentin (Vim), resulting in entangled cells that inhibit neurite growth and functional recovery. Reactive astrocytes also secrete inflammatory molecules such as Lipocalin 2 (Lcn2), which perpetuate reactivity and adversely affect other cells of the CNS. Herein, we report proof-of-concept use of the packaging RNA (pRNA)-derived three-way junction (3WJ) motif as a platform for the delivery of siRNAs to downregulate such reactivity-associated genes. In vitro, siRNA-3WJs induced a significant knockdown of Gfap, Vim, and Lcn2 in a model of astroglial activation, with a concomitant reduction in protein expression. Knockdown of Lcn2 also led to reduced protein secretion from reactive astroglial cells, significantly impeding the perpetuation of inflammation in otherwise quiescent astrocytes. Intralesional injection of anti-Lcn2-3WJs in mice with contusion spinal cord injury led to knockdown of Lcn2 at mRNA and protein levels in vivo. Our results provide evidence for siRNA-3WJs as a promising platform for ameliorating astroglial reactivity, with significant potential for further functionalization and adaptation for therapeutic applications in the CNS. PMID- 29499928 TI - Exosomes in Cancer Liquid Biopsy: A Focus on Breast Cancer. AB - The important challenge about cancer is diagnosis in primary stages and proper treatment. Although classical clinico-pathological features of the tumor have major prognostic value, the advances in diagnosis and treatment are indebted to discovery of molecular biomarkers and control of cancer in the pre-invasive state. Moreover, the efficiency of available therapeutic options is highly diminished, and chemotherapy is still the main treatment due to lack of enough specific targets. Accordingly, finding the new noninvasive biomarkers for cancer is still an important clinical challenge that is not achieved yet. There are current technologies to screen, diagnose, prognose, and treat cancer, but the limitations of these implements and procedures are undeniable. Liquid biopsy as a noninvasive method has a promising future in the field of cancer, and exosomes as one of the recent areas have drawn much attention. In this review, the potential capability of exosomes is summarized in cancer with the special focus on breast cancer as the second cause of cancer mortality in women all around the world. It discusses reasons to choose exosomes for liquid biopsy and the studies related to different potential biomarkers found in the exosomes. Moreover, exosome studies on milk as a specific biofluid are also discussed. At last, because choosing the method for exosome studies is very challenging, a summary of different techniques is provided. PMID- 29499929 TI - Inhibition of TDP43-Mediated SNHG12-miR-195-SOX5 Feedback Loop Impeded Malignant Biological Behaviors of Glioma Cells. AB - Long non-coding RNA (lncRNA) dysregulation is involved in tumorigenesis and regulation of diverse cellular processes in gliomas. lncRNA SNHG12 is upregulated and promotes cell growth in human osteosarcoma cells. TAR-DNA binding protein 43 (TDP43) functions as an oncogene in various tumors by modulating RNA expression. Downregulation of TDP43 or SNHG12 significantly inhibited malignant biological behaviors of glioma cells. miR-195, downregulated in glioma tissues and cells, significantly impaired the malignant progression of glioma cells. TDP43 upregulated miR-195 in an SNHG12-dependent manner. We further revealed that SNHG12 and miR-195 were in an RNA-induced silencing complex (RISC). Inhibition of SNHG12 combined with restoration of miR-195 robustly reduced tumor growth in vivo. SOX5 was overexpressed in glioma tissues and cells. miR-195 targeted SOX5 3' UTR in a sequence-specific manner. Gelsolin was activated by SOX5. More importantly, SOX5 activated SNHG12 promoter and upregulated its expression, forming a feedback loop. Dysregulation of SNHG12, miR-195, and SOX5 predicted poor prognosis of glioma patients. The present study demonstrated that SNHG12-miR 195-SOX5 feedback loop exerted a crucial role in the regulation of glioma cells' malignant progression. PMID- 29499930 TI - Prevention of Asthma Exacerbation in a Mouse Model by Simultaneous Inhibition of NF-kappaB and STAT6 Activation Using a Chimeric Decoy Strategy. AB - Transactivation of inflammatory and immune mediators in asthma is tightly regulated by nuclear factor kappaB (NF-kappaB) and signal transducer and activator of transcription 6 (STAT6). Therefore, we investigated the efficacy of simultaneous inhibition of NF-kappaB and STAT6 using a chimeric decoy strategy to prevent asthma exacerbation. The effects of decoy oligodeoxynucleotides were evaluated using an ovalbumin-induced mouse asthma model. Ovalbumin-sensitized mice received intratracheal administration of decoy oligodeoxynucleotides 3 days before ovalbumin challenge. Fluorescent-dye-labeled decoy oligodeoxynucleotides could be detected in lymphocytes and macrophages in the lung, and activation of NF-kappaB and STAT6 was inhibited by chimeric decoy oligodeoxynucleotide transfer. Consequently, treatment with chimeric or NF-kappaB decoy oligodeoxynucleotides protected against methacholine-induced airway hyperresponsiveness, whereas the effect of chimeric decoy oligodeoxynucleotides was significantly greater than that of NF-kappaB decoy oligodeoxynucleotides. Treatment with chimeric decoy oligodeoxynucleotides suppressed airway inflammation through inhibition of overexpression of interleukin-4 (IL-4), IL-5, and IL-13 and inflammatory infiltrates. Histamine levels in the lung were reduced via suppression of mast cell accumulation. A significant reduction in mucin secretion was observed due to suppression of MUC5AC gene expression. Interestingly, the inhibitory effects on IL-5, IL-13, and histamine secretion were achieved by transfer of chimeric decoy oligodeoxynucleotides only. This novel therapeutic approach could be useful to treat patients with various types of asthma. PMID- 29499931 TI - Long Non-coding RNA LINC00339 Stimulates Glioma Vasculogenic Mimicry Formation by Regulating the miR-539-5p/TWIST1/MMPs Axis. AB - Glioma is recognized as a highly angiogenic malignant brain tumor. Vasculogenic mimicry (VM) greatly restricts the therapeutic effect of anti-angiogenic tumor therapy for glioma patients. However, the molecular mechanisms of VM formation in glioma remain unclear. Here, we demonstrated that LINC00339 was upregulated in glioma tissue as well as in glioma cell lines. The expression of LINC00339 in glioma tissues was positively correlated with glioma VM formation. Knockdown of LINC00339 inhibited glioma cell proliferation, migration, invasion, and tube formation, meanwhile downregulating the expression of VM-related molecular MMP-2 and MMP-14. Furthermore, knockdown of LINC00339 significantly increased the expression of miR-539-5p. Both bioinformatics and luciferase reporter assay revealed that LINC00339 regulated the above effects via binding to miR-539-5p. Besides, overexpression of miR-539-5p resulted in decreased expression of TWIST1, a transcription factor known to play an oncogenic role in glioma and identified as a direct target of miR-539-5p. TWIST1 upregulated the promoter activities of MMP-2 and MMP-14. The in vivo study showed that nude mice carrying tumors with knockdown of LINC00339 and overexpression of miR-539-5p exhibited the smallest tumor volume through inhibiting VM formation. In conclusion, LINC00339 may be used as a novel therapeutic target for VM formation in glioma. PMID- 29499932 TI - In Vivo SELEX of an Inhibitory NSCLC-Specific RNA Aptamer from PEGylated RNA Library. AB - Aptamers are widely used in numerous biochemical, bioanalytical, and biological studies. Most aptamers are developed through an in vitro selection process called SELEX against either purified targets or living cells expressing targets of interest. We report here an in vivo SELEX in mice using a PEGylated RNA library for the identification of a 2'-F RNA aptamer (RA16) that specifically binds to NCI-H460 non-small-cell lung cancer cells with an affinity (KD) of 9 +/- 2 nM. Interestingly, RA16 potently inhibited cancer cell proliferation in a dose dependent manner with an IC50 of 116.7 nM. When tested in vivo in xenografted mice, RA16 showed gradual migration toward tumor and accumulation at tumor site over time. An in vivo anti-cancer study showed that the average inhibition rate for mouse tumors in the RA16-treated group was 54.26% +/- 5.87% on day 16 versus the control group. The aptamer RA16 adducted with epirubicin (RA16-epirubicin) showed significantly higher toxicity against targeted NCI-H460 cells and low toxicity against non-targeted tumor cells. Furthermore, RA16-epirubicin adduct exhibited in vivo anti-cancer efficacy, with an inhibition rate of 64.38% +/- 7.92% when administrated in H460 xenograft mouse model. In summary, a specific bi functional RNA aptamer RA16 was selected targeting and inhibiting toward NCI-H460 in vitro and in vivo. PMID- 29499933 TI - Selection and Identification of Skeletal-Muscle-Targeted RNA Aptamers. AB - Oligonucleotide gene therapy has shown great promise for the treatment of muscular dystrophies. Nevertheless, the selective delivery to affected muscles has shown to be challenging because of their high representation in the body and the high complexity of their cell membranes. Current trials show loss of therapeutic molecules to non-target tissues leading to lower target efficacy. Therefore, strategies that increase uptake efficiency would be particularly compelling. To address this need, we applied a cell-internalization SELEX (Systematic Evolution of Ligands by Exponential Enrichment) approach and identified a skeletal muscle-specific RNA aptamer. A01B RNA aptamer preferentially internalizes in skeletal muscle cells and exhibits decreased affinity for off-target cells. Moreover, this in vitro selected aptamer retained its functionality in vivo, suggesting a potential new approach for targeting skeletal muscles. Ultimately, this will aid in the development of targeted oligonucleotide therapies against muscular dystrophies. PMID- 29499934 TI - Downregulation of MicroRNA-455-3p Links to Proliferation and Drug Resistance of Pancreatic Cancer Cells via Targeting TAZ. AB - Drug resistance is a major cause of treatment failure in pancreatic cancer. The limited evidence indicates the involvement of miR-455-3p in chemotherapy resistance of cancer. Here we observed by qPCR that miR-455-3p was significantly decreased in pancreatic cancer tissues and cell lines. We then confirmed that the inhibition of miR-455-3p increased cell proliferation and gemcitabine resistance of pancreatic cancer, whereas forced overexpression of miR-455-3p had the opposite effect. Furthermore, we demonstrated that TAZ, which is associated with drug resistance of pancreatic cancer, is a new direct downstream target of miR 455-3p. Our present study suggests that miR-455-3p contributes to cell proliferation and drug resistance in pancreatic cancer cells via targeting TAZ. PMID- 29499935 TI - Targeted Delivery of Auristatin-Modified Toxins to Pancreatic Cancer Using Aptamers. AB - Pancreatic cancer is one of the most lethal malignancies. Treatment with the first-line agent, gemcitabine, is often unsuccessful because it, like other traditional chemotherapeutic agents, is non-specific, resulting in off-target effects that necessitate administration of subcurative doses. Alternatively, monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF) are highly toxic small molecules that require ligand-targeted delivery. MMAE has already received FDA approval as a component of an anti-CD30 antibody-drug conjugate, brentuximab vedotin. However, in contrast to antibodies, aptamers have distinct advantages. They are chemicals, which allows them to be produced synthetically and facilitates the rapid development of diagnostics and therapeutics with clinical applicability. In addition, their small size allows for enhanced tissue distribution and rapid systemic clearance. Here, we assayed the toxicity of MMAE and MMAF conjugated to an anti-transferrin receptor aptamer, Waz, and an anti epidermal growth factor receptor aptamer, E07, on the pancreatic cancer cell lines Panc-1, MIA PaCa-2, and BxPC3. In vitro, our results indicate that these aptamers are a viable option for the targeted delivery of toxic payloads to pancreatic cancer cells. PMID- 29499936 TI - Circular siRNAs for Reducing Off-Target Effects and Enhancing Long-Term Gene Silencing in Cells and Mice. AB - Circular non-coding RNAs are found to play important roles in biology but are still relatively unexplored as a structural motif for chemically regulating gene function. Here, we investigated whether small interfering RNA (siRNA) with a circular structure can circumvent off-target gene silencing, a problem often observed with standard linear duplex siRNA. In the present work, we, for the first time, synthesized a series of circular siRNAs by cyclizing two ends of a single-stranded RNA (sense or antisense strand) to construct circular siRNAs that were more resistant to enzymatic degradation. Gene silencing of GFP and luciferase was successfully achieved using these circular siRNAs with circular sense strand RNAs and their complementary linear antisense strand RNAs. The off target effect of sense strand RNAs was evaluated and no cross off-target effects were observed. In addition, we successfully achieved longer gene-silencing efficiency in mice with circular siRNAs than with linear siRNAs. These results indicate the promise of circular siRNAs for overcoming off-target effects of siRNAs and enhancing the possible long-term effect of siRNA gene silencing in basic research and drug development. PMID- 29499937 TI - circHLA-C Plays an Important Role in Lupus Nephritis by Sponging miR-150. AB - Circular RNAs (circRNAs) participate in the pathogenesis of various diseases by sponging microRNAs (miRs). However, the roles of circRNAs remain unreported in glomerular diseases. We previously reported that miR-150 positively correlated with renal chronicity index in patients with lupus nephritis (LN). We aimed to investigate renal circRNA profiling and the interaction between circRNAs and miR 150 in LN patients. Six renal biopsies from untreated female patients with LN class IV and five normal kidney tissues from urology patients were used for circRNA sequencing. 171 circRNAs with 2-fold differential expression were identified in LN compared with normal control. Ten selected circRNAs were validated by real-time qPCR, and seven circRNAs showed the same significant increases as the sequencing results. circHLA-C positively correlated with proteinuria (R = 0.92, p < 0.01), serum creatinine (R = 0.76, p = 0.08), renal activity index (R = 0.88, p < 0.05), and crescentic glomeruli (R = 0.93, p < 0.01). Renal circHLA-C increased 2.72-fold, and miR-150 decreased 66% in LN compared with normal control (p < 0.05). Bio-informatic analysis predicted miR 150 was regulated by circHLA-C and displayed one perfect match seed between circHLA-C and miR-150. The renal miR-150 showed a tendency of negative correlation with circHLA-C in LN patients. In conclusion, circHLA-C may play an important role in the pathogenesis of lupus nephritis by sponging miR-150. PMID- 29499938 TI - MicroRNA-300 Regulates the Ubiquitination of PTEN through the CRL4BDCAF13 E3 Ligase in Osteosarcoma Cells. AB - Cullins, critical members of the cullin-RING ubiquitin ligases (CRLs), are often aberrantly expressed in different cancers. However, the underlying mechanisms regarding aberrant expression of these cullins and the specific substrates of CRLs in different cancers are mostly unknown. Here, we demonstrate that overexpressed CUL4B in human osteosarcoma cells forms an E3 complex with DNA damage binding protein 1 (DDB1) and DDB1- and CUL4-associated factor 13 (DCAF13). In vitro and in vivo analyses indicated that the CRL4BDCAF13 E3 ligase specifically recognized the tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) for degradation, and disruption of this E3 ligase resulted in PTEN accumulation. Further analyses indicated that miR-300 directly targeted the 3' UTR of CUL4B, and DNA hypermethylation of a CpG island in the miR 300 promoter region contributed to the downregulation of miR-300. Interestingly, ectopic expression of miR-300 or treatment with 5-AZA-2'-deoxycytidine, a DNA methylation inhibitor, decreased the stability of CRL4BDCAF13 E3 ligase and reduced PTEN ubiquitination. By applying in vitro screening to identify small molecules that specifically inhibit CUL4B-DDB1 interaction, we found that TSC01131 could greatly inhibit osteosarcoma cell growth and could disrupt the stability of the CRL4BDCAF13 E3 ligase. Collectively, our findings shed new light on the molecular mechanism of CUL4B function and might also provide a new avenue for osteosarcoma therapy. PMID- 29499939 TI - Long Non-coding RNAs, Novel Culprits, or Bodyguards in Neurodegenerative Diseases. AB - Long non-coding RNA (lncRNA) is a kind of non-coding RNA (ncRNA), with a length of 200 nt to 100 kb, that lacks a significant open reading frame (ORF) encoding a protein. lncRNAs are widely implicated in various physiological and pathological processes, such as epigenetic regulation, cell cycle regulation, cell differentiation regulation, cancer, and neurodegenerative diseases, through their interactions with chromatin, protein, and other RNAs. Numerous studies have suggested that lncRNAs are closely linked with the occurrence and development of a variety of diseases, especially neurodegenerative diseases, of which the etiologies are complicated and the underlying mechanisms remain elusive. Determining the roles of lncRNA in the pathogenesis of neurodegenerative diseases will not only deepen understanding of the physiological and pathological processes that occur in those diseases but also provide new ideas and solutions for their diagnosis and prevention. This review aims to highlight the progress of lncRNA research in the pathological and behavioral changes of neurodegenerative diseases. Specifically, we focus on how lncRNA dysfunctions are involved in the pathogenesis of Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. PMID- 29499940 TI - RNA-Seq Analysis of an Antisense Sequence Optimized for Exon Skipping in Duchenne Patients Reveals No Off-Target Effect. AB - Non-coding uridine-rich small nuclear RNAs (UsnRNAs) have emerged in recent years as effective tools for exon skipping for the treatment of Duchenne muscular dystrophy (DMD), a degenerative muscular genetic disorder. We recently showed the high capacity of a recombinant adeno-associated virus (rAAV)-U7snRNA vector to restore the reading frame of the DMD mRNA in the muscles of DMD dogs. We are now moving toward a phase I/II clinical trial with an rAAV-U7snRNA-E53, carrying an antisense sequence designed to hybridize exon 53 of the human DMD messenger. As observed for genome-editing tools, antisense sequences present a risk of off target effects, reflecting partial hybridization onto unintended transcripts. To characterize the clinical antisense sequence, we studied its expression and explored the occurrence of its off-target effects in human in vitro models of skeletal muscle and liver. We presented a comprehensive methodology combining RNA sequencing and in silico filtering to analyze off-targets. We showed that U7snRNA E53 induced the effective exon skipping of the DMD transcript without inducing the notable deregulation of transcripts in human cells, neither at gene expression nor at the mRNA splicing level. Altogether, these results suggest that the use of the rAAV-U7snRNA-E53 vector for exon skipping could be safe in eligible DMD patients. PMID- 29499941 TI - Formulation of Stable and Homogeneous Cell-Penetrating Peptide NF55 Nanoparticles for Efficient Gene Delivery In Vivo. AB - Although advances in genomics and experimental gene therapy have opened new possibilities for treating otherwise incurable diseases, the transduction of nucleic acids into the cells and delivery in vivo remain challenging. The high molecular weight and anionic nature of nucleic acids require their packing into nanoparticles for the delivery. The efficacy of nanoparticle drugs necessitates the high bioactivity of constituents, but their distribution in organisms is mostly governed by the physical properties of nanoparticles, and therefore, generation of stable particles with strictly defined characteristics is highly essential. Using previously designed efficient cell-penetrating peptide NF55, we searched for strategies enabling control over the nanoparticle formation and properties to further improve transfection efficacy. The size of the NF55/pDNA nanoparticles correlates with the concentration of its constituents at the beginning of assembly, but characteristics of nanoparticles measured by DLS do not reliably predict the applicability of particles in in vivo studies. We introduce a new formulation approach called cryo-concentration, where we acquired stable and homogeneous nanoparticles for administration in vivo. The cryo concentrated NF55/pDNA nanoparticles exhibit several advantages over standard formulation: They have long shelf-life and do not aggregate after reconstitution, have excellent stability against enzymatic degradation, and show significantly higher bioactivity in vivo. PMID- 29499942 TI - GLP2 Promotes Directed Differentiation from Osteosarcoma Cells to Osteoblasts and Inhibits Growth of Osteosarcoma Cells. AB - Glucagon-like peptide 2 (GLP2) is a proglucagon-derived peptide that is involved in the regulation of energy absorption and exerts beneficial effects on glucose metabolism. However, the exact mechanisms underlying the GLP2 during osteogenic differentiation has not been illustrated. Herein, we indicated that GLP2 was demonstrated to result in positive action during the osteogenic differentiation of human osteosarcoma cells. Our findings demonstrate that GLP2 inhibis the growth of osteosarcoma cells in vivo and in vitro. Mechanistic investigations reveal GLP2 inhibits the expression and activity of nuclear factor kappaB (NF kappaB), triggering the decrease of c-Myc, PKM2, and CyclinD1 in osteosarcoma cells. In particular, rescued NF-kappaB abrogates the functions of GLP2 in osteosarcoma cells. Strikingly, GLP2 overexpression significantly increased the expression of osteogenesis-associated genes (e.g., Ocn and PICP) dependent on c Fos-BMP signaling, which promotes directed differentiation from osteosarcoma cells to osteoblasts with higher alkaline phosphatase activity. Taken together, our results suggested that GLP2 could be a valuable drug to promote directed differentiation from osteosarcoma cells to osteoblasts, which may provide potential therapeutic targets for the treatment of osteosarcoma. PMID- 29499943 TI - Thermodynamic, Anticoagulant, and Antiproliferative Properties of Thrombin Binding Aptamer Containing Novel UNA Derivative. AB - Thrombin is a serine protease that plays a crucial role in hemostasis, fibrinolysis, cell proliferation, and migration. Thrombin binding aptamer (TBA) is able to inhibit the activity of thrombin molecule via binding to its exosite I. This 15-nt DNA oligonucleotide forms an intramolecular, antiparallel G quadruplex structure with a chair-like conformation. In this paper, we report on our investigations on the influence of certain modified nucleotide residues on thermodynamic stability, folding topology, and biological properties of TBA variants. In particular, the effect of single incorporation of a novel 4 thiouracil derivative of unlocked nucleic acid (UNA), as well as single incorporation of 4-thiouridine and all four canonical UNAs, was evaluated. The studies presented herein have shown that 4-thiouridine in RNA and UNA series, as well as all four canonical UNAs, can efficiently modulate G-quadruplex thermodynamic and biological stability, and that the effect is strongly position dependent. Interestingly, TBA variants containing the modified nucleotide residues are characterized by unchanged folding topology. Thrombin time assay revealed that incorporation of certain UNA residues may improve G-quadruplex anticoagulant properties. Noteworthy, some TBA variants, characterized by decreased ability to inhibit thrombin activity, possess significant antiproliferative properties reducing the viability of the HeLa cell line even by 95% at 10 MUM concentration. PMID- 29499944 TI - Targeting EGFR/HER2/HER3 with a Three-in-One Aptamer-siRNA Chimera Confers Superior Activity against HER2+ Breast Cancer. AB - HER family members are interdependent and functionally compensatory. Simultaneously targeting EGFR/HER2/HER3 by antibody combinations has demonstrated superior treatment efficacy over targeting one HER receptor. However, antibody combinations have their limitations, with high immunogenicity and high cost. In this study, we have developed a three-in-one nucleic acid aptamer-small interfering RNA (siRNA) chimera, which targets EGFR/HER2/HER3 in one molecule. This inhibitory molecule was constructed such that a single EGFR siRNA is positioned between the HER2 and HER3 aptamers to create a HER2 aptamer-EGFR siRNA HER3 aptamer chimera (H2EH3). EGFR siRNA was delivered into HER2-expressing cells by HER2/HER3 aptamer-induced internalization. HER2/HER3 aptamers act as antagonist molecules for blocking HER2 and HER3 signaling pathways and also as tumor-targeting agents for siRNA delivery. H2EH3 enables down-modulation of the expression of all three receptors, thereby triggering cell apoptosis. In breast cancer xenograft models, H2EH3 is able to bind to breast tumors with high specificity and significantly inhibits tumor growth via either systemic or intratumoral administration. Owing to low immunogenicity, ease of production, and high thermostability, H2EH3 is a promising therapeutic to supplement current single HER inhibitors and may act as a treatment for HER2+ breast cancer with intrinsic or acquired resistance to current drugs. PMID- 29499945 TI - circ-SHKBP1 Regulates the Angiogenesis of U87 Glioma-Exposed Endothelial Cells through miR-544a/FOXP1 and miR-379/FOXP2 Pathways. AB - Circular RNAs (circRNAs) are a type of endogenous non-coding RNAs, which have been considered to mediate diverse tumorigenesis including angiogenesis. The present study aims to elucidate the potential role and molecular mechanism of circ-SHKBP1 in regulating the angiogenesis of U87 glioma-exposed endothelial cells (GECs). The expression of circ-SHKBP1, but not linear SHKBP1, was significantly upregulated in GECs compared with astrocyte-exposed endothelial cells (AECs). circ-SHKBP1 knockdown inhibited the viability, migration, and tube formation of GECs dramatically. The expressions of miR-379/miR-544a were downregulated in GECs, and circ-SHKBP1 functionally targeted miR-544a/miR-379 in an RNA-induced silencing complex (RISC) manner. Dual-luciferase reporter assay demonstrated that forkhead box P1/P2 (FOXP1/FOXP2) were targets of miR-544a/miR 379. The expressions of FOXP1/FOXP2 were upregulated in GECs, and silencing of FOXP1/FOXP2 inhibited the viability, migration, and tube formation of GECs. Meanwhile, FOXP1/FOXP2 promoted angiogenic factor with G patch and FHA domains 1 (AGGF1) expression at the transcriptional level. Furthermore, knockdown of AGGF1 suppressed the viability, migration, and tube formation of GECs via phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK)1/2 pathways. Taken together, the present study demonstrated that circ-SHKBP1 regulated the angiogenesis of GECs through miR-544a/FOXP1 and miR 379/FOXP2 pathways, and these findings might provide a potential target and effective strategy for combined therapy of gliomas. PMID- 29499946 TI - Transcriptome Profiling of Neovascularized Corneas Reveals miR-204 as a Multi target Biotherapy Deliverable by rAAVs. AB - Corneal neovascularization (NV) is the major sight-threatening pathology caused by angiogenic stimuli. Current drugs that directly target pro-angiogenic factors to inhibit or reverse the disease require multiple rounds of administration and have limited efficacies. Here, we identify potential anti-angiogenic corneal microRNAs (miRNAs) and demonstrate a framework that employs discovered miRNAs as biotherapies deliverable by recombinant adeno-associated viruses (rAAVs). By querying differentially expressed miRNAs in neovascularized mouse corneas induced by alkali burn, we have revealed 39 miRNAs that are predicted to target more than 5,500 differentially expressed corneal mRNAs. Among these, we selected miR-204 and assessed its efficacy and therapeutic benefit for treating injured corneas. Our results show that delivery of miR-204 by rAAV normalizes multiple novel target genes and biological pathways to attenuate vascularization of injured mouse cornea. Importantly, this gene therapy treatment alternative is efficacious and safe for mitigating corneal NV. Overall, our work demonstrates the discovery of potential therapeutic miRNAs in corneal disorders and their translation into viable treatment alternatives. PMID- 29499947 TI - Delineation of the Exact Transcription Termination Signal for Type 3 Polymerase III. AB - Type 3 Pol III promoters such as U6 are widely used for expression of small RNAs, including short hairpin RNA for RNAi applications and guide RNA in CRISPR genome editing platforms. RNA polymerase III uses a T-stretch as termination signal, but the exact properties have not been thoroughly investigated. Here, we systematically measured the in vivo termination efficiency and the actual site of termination for different T-stretch signals in three commonly used human Pol III promoters (U6, 7SK, and H1). Both the termination efficiency and the actual termination site depend on the T-stretch signal. The T4 signal acts as minimal terminator, but full termination efficiency is reached only with a T-stretch of >=6. The termination site within the T-stretch is quite heterogeneous, and consequently small RNAs have a variable U-tail of 1-6 nucleotides. We further report that such variable U-tails can have a significant negative effect on the functionality of the crRNA effector of the CRISPR-AsCpf1 system. We next improved these crRNAs by insertion of the HDV ribozyme to avoid U-tails. This study provides detailed design guidelines for small RNA expression cassettes based on Pol III. PMID- 29499948 TI - Endogenous Cellular MicroRNAs Mediate Antiviral Defense against Influenza A Virus. AB - The reciprocal interaction between influenza virus and host microRNAs (miRNAs) has been implicated in the regulation of viral replication and host tropism. However, the global roles of the cellular miRNA repertoire and the mechanisms of miRNA-mediated antiviral defense await further elucidation. In this study, we systematically screened 297 cellular miRNAs from human and mouse epithelial cells and identified five inhibitory miRNAs that efficiently inhibited influenza virus replication in vitro and in vivo. Among these miRNAs, hsa-mir-127-3p, hsa-mir-486 5p, hsa-mir-593-5p, and mmu-mir-487b-5p were found to target at least one viral gene segment of both the human seasonal influenza H3N2 and the attenuated PR8 (H1N1) virus, whereas hsa-miR-1-3p inhibited viral replication by targeting the supportive host factor ATP6V1A. Moreover, the number of miRNA binding sites in viral RNA segments was positively associated with the activity of host miRNA induced antiviral defense. Treatment with a combination of the five miRNAs through agomir delivery pronouncedly suppressed viral replication and effectively improved protection against lethal challenge with PR8 in mice. These data suggest that the highly expressed miRNAs in respiratory epithelial cells elicit effective antiviral defenses against influenza A viruses and will be useful for designing miRNA-based therapies against viral infection. PMID- 29499949 TI - Gene Therapy via Trans-Splicing for LMNA-Related Congenital Muscular Dystrophy. AB - We assessed the potential of Lmna-mRNA repair by spliceosome-mediated RNA trans splicing as a therapeutic approach for LMNA-related congenital muscular dystrophy. This gene therapy strategy leads to reduction of mutated transcript expression for the benefit of corresponding wild-type (WT) transcripts. We developed 5'-RNA pre-trans-splicing molecules containing the first five exons of Lmna and targeting intron 5 of Lmna pre-mRNA. Among nine pre-trans-splicing molecules, differing in the targeted sequence in intron 5 and tested in C2C12 myoblasts, three induced trans-splicing events on endogenous Lmna mRNA and confirmed at protein level. Further analyses performed in primary myotubes derived from an LMNA-related congenital muscular dystrophy (L-CMD) mouse model led to a partial rescue of the mutant phenotype. Finally, we tested this approach in vivo using adeno-associated virus (AAV) delivery in newborn mice and showed that trans-splicing events occurred in WT mice 50 days after AAV delivery, although at a low rate. Altogether, while these results provide the first evidence for reprogramming LMNA mRNA in vitro, strategies to improve the rate of trans-splicing events still need to be developed for efficient application of this therapeutic approach in vivo. PMID- 29499950 TI - The lncRNA Plscr4 Controls Cardiac Hypertrophy by Regulating miR-214. AB - Cardiac hypertrophy accompanied by maladaptive cardiac remodeling is the uppermost risk factor for the development of heart failure. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have various biological functions, and their vital role in the regulation of cardiac hypertrophy still needs to be explored. In this study, we demonstrated that lncRNA Plscr4 was upregulated in hypertrophic mice hearts and in angiotensin II (Ang II)-treated cardiomyocytes. Next, we observed that overexpression of Plscr4 attenuated Ang II-induced cardiomyocyte hypertrophy. Conversely, the inhibition of Plscr4 gave rise to cardiomyocyte hypertrophy. Furthermore, overexpression of Plscr4 attenuated TAC (transverse aortic constriction)-induced cardiac hypertrophy. Finally, we demonstrated that Plscr4 acted as an endogenous sponge of miR-214 and forced expression of Plscr4 downregulated miR-214 expression to promote Mfn2 and attenuate hypertrophy. In contrast, knockdown of Plscr4 upregulated miR-214 to induce cardiomyocyte hypertrophy. Additionally, luciferase assay showed that miR-214 was the direct target of Plscr4, and overexpression of miR-214 counteracted the anti-hypertrophy effect of Plscr4. Collectively, these findings identify Plscr4 as a negative regulator of cardiac hypertrophy in vivo and in vitro due to its regulation of the miR-214-Mfn2 axis, suggesting that Plscr4 might act as a therapeutic target for the treatment of cardiac hypertrophy and heart failure. PMID- 29499951 TI - STAT3 Gene Silencing by Aptamer-siRNA Chimera as Selective Therapeutic for Glioblastoma. AB - Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor in adults, and despite advances in neuro-oncology, the prognosis for patients remains dismal. The signal transducer and activator of transcription-3 (STAT3) has been reported as a key regulator of the highly aggressive mesenchymal GBM subtype, and its direct silencing (by RNAi oligonucleotides) has revealed a great potential as an anti-cancer therapy. However, clinical use of oligonucleotide based therapies is dependent on safer ways for tissue-specific targeting and increased membrane penetration. The objective of this study is to explore the use of nucleic acid aptamers as carriers to specifically drive a STAT3 siRNA to GBM cells in a receptor-dependent manner. Using an aptamer that binds to and antagonizes the oncogenic receptor tyrosine kinase PDGFRbeta (Gint4.T), here we describe the design of a novel aptamer-siRNA chimera (Gint4.T-STAT3) to target STAT3. We demonstrate the efficient delivery and silencing of STAT3 in PDGFRbeta+ GBM cells. Importantly, the conjugate reduces cell viability and migration in vitro and inhibits tumor growth and angiogenesis in vivo in a subcutaneous xenograft mouse model. Our data reveals Gint4.T-STAT3 conjugate as a novel molecule with great translational potential for GBM therapy. PMID- 29499952 TI - PIWIL1/piRNA-DQ593109 Regulates the Permeability of the Blood-Tumor Barrier via the MEG3/miR-330-5p/RUNX3 Axis. AB - The blood-tumor barrier (BTB) restricts the efficient delivery of anti-glioma drugs to cranial glioma tissues. Increased BTB permeability may allow greater delivery of the therapeutic agents. Increasing evidence has revealed that PIWI proteins and PIWI-interacting RNAs (piRNAs) play an important role in tumor progression. However, whether PIWI proteins and piRNAs regulate BTB permeability remains unclear. In the present study, we demonstrated that the PIWIL1/piRNA DQ593109 (piR-DQ593109) complex was the predominant regulator of BTB permeability. Briefly, PIWIL1 was upregulated in glioma endothelial cells (GECs). Furthermore, piR-DQ593109 was also overexpressed in GECs, as revealed via a piRNA microarray. Downregulation of PIWIL1 or piR-DQ593109 increased the permeability of the BTB. Moreover, PIWIL1 and piR-DQ593109, which formed a piRNA-induced silencing complex, degraded the long non-coding RNA maternally expressed 3 (MEG3) in a sequenced-dependent manner. Furthermore, restoring MEG3 released post transcriptional inhibition of Runt related transcription factor 3 (RUNX3) by sponging miR-330-5p. In addition, RUNX3 bounded to the promoter regions and reduced the promoter activities of ZO-1, occludin, and claudin-5, which significantly impaired the expression levels of ZO-1, occludin, and claudin-5. In conclusion, downregulating PIWIL1 and piR-DQ593109 increased BTB permeability through the MEG3/miR-330-5p/RUNX3 axis. These data may provide insight into glioma treatment. PMID- 29499953 TI - MicroRNA-140 Inhibits the Epithelial-Mesenchymal Transition and Metastasis in Colorectal Cancer. AB - MicroRNA-140, a cartilage-specific microRNA, has recently been implicated in the cancer progression. However, the comprehensive role of miR-140 in the invasion and metastasis of colorectal cancer (CRC) is still not fully understood. In this study, we confirmed that miR-140 downregulates SMAD family member 3 (Smad3), which is a key downstream effector of the TGF-beta signaling pathway, at the translational level in the CRC cell lines. Ectopic expression of miR-140 inhibits the process of epithelial-mesenchymal transition (EMT), at least partially through targeting Smad3, and induces the suppression of migratory and invasive capacities of CRC cells in vitro. miR-140 also attenuates CRC cell proliferation possibly via downregulating Samd3. Furthermore, overexpression of miR-140 inhibits the tumor formation and metastasis of CRC in vivo, and silenced Smad3 has the similar effect. Additionally, miR-140 expression is decreased in the clinical primary CRC specimens and appears as a progressive reduction in the metastatic specimens, whereas Smad3 is overexpressed in the CRC samples. Taken together, our findings suggest that miR-140 might be a key suppressor of CRC progression and metastasis through inhibiting EMT process by targeting Smad3. miR 140 may represent a novel candidate for CRC treatment. PMID- 29499954 TI - Effects of Aptamer to U87-EGFRvIII Cells on the Proliferation, Radiosensitivity, and Radiotherapy of Glioblastoma Cells. AB - Glioblastoma multiforme (GBM) is the most prevalent and lethal malignant intracranial tumor in the brain, with very poor prognosis and survival. The epidermal growth factor receptor variant III (EGFRvIII) contributes to increased oncogenicity that does not occur through binding EGFR ligands and instead occurs through constitutive activation, which enhances glioma tumorigenicity and resistance to targeted therapy. Aptamers are nucleic acids with high affinity and specificity to targets selected by systematic evolution of ligands by exponential enrichment (SELEX), and are usually developed as antagonists of disease associated factors. Herein, we generated a DNA aptamer U2, targeting U87-EGFRvIII cells, and demonstrated that U2 alters the U87-EGFRvIII cell growth, radiosensitivity, and radiotherapy of glioblastoma cells. We detected U2 and U87 EGFRvIII cells by flow cytometry and confocal microscopy to explore the binding ability of U2 to U87-EGFRvIII cells. Then, we found that aptamer U2 inhibits the proliferation, migration, invasion, and downstream signaling of U87-EGFRvIII cells. Moreover, the U2 aptamer can increase the radiosensitivity of U87-EGFRvIII in vitro and has a better antitumor effect on 188Re-U2 in vivo. Therefore, the results revealed the promising potential of the U2 aptamer to be a new type of drug candidate and aptamer-targeted drug delivery system for glioblastoma therapy. PMID- 29499955 TI - A Sensitive In Vitro Approach to Assess the Hybridization-Dependent Toxic Potential of High Affinity Gapmer Oligonucleotides. AB - The successful development of high-affinity gapmer antisense oligonucleotide (ASO) therapeutics containing locked nucleic acid (LNA) or constrained ethyl (cEt) substitutions has been hampered by the risk of hepatotoxicity. Here, we present an in vitro approach using transfected mouse fibroblasts to predict the potential hepatic liabilities of LNA-modified ASOs (LNA-ASOs), validated by assessing 236 different LNA-ASOs with known hepatotoxic potential. This in vitro assay accurately reflects in vivo findings and relates hepatotoxicity to RNase H1 activity, off-target RNA downregulation, and LNA-ASO-binding affinity. We further demonstrate that the hybridization-dependent toxic potential of LNA-ASOs is also evident in different cell types from different species, which indicates probable translatability of the in vitro results to humans. Additionally, we show that the melting temperature (Tm) of LNA-ASOs maintained below a threshold level of about 55 degrees C greatly diminished the hepatotoxic potential. In summary, we have established a sensitive in vitro screening approach for assessing the hybridization-dependent toxic potential of LNA-ASOs, enabling prioritization of candidate molecules in drug discovery and early development. PMID- 29499956 TI - Rapid, Single-Cell Analysis and Discovery of Vectored mRNA Transfection In Vivo with a loxP-Flanked tdTomato Reporter Mouse. AB - mRNA therapeutics hold promise for the treatment of diseases requiring intracellular protein expression and for use in genome editing systems, but mRNA must transfect the desired tissue and cell type to be efficacious. Nanoparticle vectors that deliver the mRNA are often evaluated using mRNA encoding for reporter genes such as firefly luciferase (FLuc); however, single-cell resolution of mRNA expression cannot generally be achieved with FLuc, and, thus, the transfected cell populations cannot be determined without additional steps or experiments. To more rapidly identify which types of cells an mRNA formulation transfects in vivo, we describe a Cre recombinase (Cre)-based system that permanently expresses fluorescent tdTomato protein in transfected cells of genetically modified mice. Following in vivo application of vectored Cre mRNA, it is possible to visualize successfully transfected cells via Cre-mediated tdTomato expression in bulk tissues and with single-cell resolution. Using this system, we identify previously unknown transfected cell types of an existing mRNA delivery vehicle in vivo and also develop a new mRNA formulation capable of transfecting lung endothelial cells. Importantly, the same formulations with mRNA encoding for fluorescent protein delivered to wild-type mice did not produce sufficient signal for any visualization in vivo, demonstrating the significantly improved sensitivity of our Cre-based system. We believe that the system described here may facilitate the identification and characterization of mRNA delivery vectors to new tissues and cell types. PMID- 29499957 TI - Function Control of Anti-microRNA Oligonucleotides Using Interstrand Cross-Linked Duplexes. AB - MicroRNA (miRNA)-guided argonaute (Ago) controls gene expression upon binding to the 3' UTR of mRNA. The miRNA function can be competitively inhibited by single stranded anti-miRNA oligonucleotides (AMOs). In this study, we constructed a novel type of AMO flanked by interstrand cross-linked 2'-O-methylated RNA duplexes (CLs) that confer a stable helical conformation. Compared with other structured AMOs, AMO flanked by CLs at the 5' and 3' termini exhibited much higher inhibitory activity in cells. Anti-miRNA activity, nuclease resistance, and miRNA modification pattern distinctly differed according to the CL-connected positions in AMOs. Moreover, we found that the 3'-side CL improves nuclease resistance, whereas the 5'-side CL contributes to stable binding with miRNA in Ago upon interaction with the 3' part of miRNA. These structure-function relationship analyses of AMOs provide important insights into the function control of Ago-miRNA complexes, which will be useful for basic miRNA research as well as for determining therapeutic applications of AMO. PMID- 29499958 TI - Delivery Pathway Regulation of 3',3"-Bis-Peptide-siRNA Conjugate via Nanocarrier Architecture Engineering. AB - Small interfering RNA (siRNA) has been continuously explored for clinical applications. However, neither nanocarriers nor conjugates have been able to remove the obstacles. In this study, we employed a combined nanochemistry strategy to optimize its delivery dilemma, where different interactions and assembly modes were cooperatively introduced into the forming process of siRNA/lipids nanoplexes. In the nanoplexes, the 3',3"-bis-peptide-siRNA conjugate (pp-siRNA) and gemini-like cationic lipids (CLDs) were employed as dual regulators to improve their bio-behavior. We demonstrated that the "cicada pupa" shaped nanoplexes of MT-pp-siRNA/CLDs (MT represented the mixed two-phase method) exhibited more compact multi-sandwich structure (~25 layers), controllable size (~150 nm), and lower zeta potential (~22 mV) than other comparable nanoplexes and presented an increased siRNA protection and stability. Significantly, the nanoplex was internalized into melanoma cells by almost caveolae-mediated endocytosis and macropinocytosis (~99.46%), and later reduced/avoided lysosomal degradation. Finally, the nanoplex facilitated the silencing of mRNA of the mutant B-Raf protein (down by ~60%). In addition, pp-siRNA had a high intracellular sustainability, a significantly prolonged circulating time, and accumulation in tumor tissues in vivo. Our results have demonstrated that the combined approach can improve the intracellular fate of siRNA, which opens up novel avenues for efficient siRNA delivery. PMID- 29499961 TI - Paleo-oncology in the Dakhleh Oasis, Egypt: Case studies and a paleoepidemiological perspective. AB - This article describes six cases of cancer from the Dakhleh Oasis, Egypt. A mummy had a confirmed 'primary' diagnosis of adenocarcinoma of the rectum. The remaining diagnoses were based on the distribution and types of skeletal lesions in conjunction with age, sex, and/or the molecular phylogeny of the Human Papillomavirus (HPV). HPV is a confirmed cause of cancer of the uterine cervix (UC) and testes (TC) and it evolved in Africa long before Homo sapiens emerged. Today these cancers are common in young adult females and males, a fact which was pivotal in respectively including them in the differential diagnosis of UC and TC. The remaining diagnoses were acute lymphocytic leukemia in a 3-5 year old child and an older female with metastatic carcinoma. Due to problems of determining specific diagnoses and their prevalence in 'paleo' populations, we opted for a lifetime cancer risk statistic (LTCR). The LTCR in ancient Dakhleh was ~5/1000 (6/1087). In modern Western societies the LTCR cancer approaches 50% (500/1000). Thus the LTCR in today's western societies is 100 times greater than in ancient Dakhleh. These cases demonstrate that oncogenes and their environmental cofactors were present in antiquity, but were significantly less pervasive than today. PMID- 29499959 TI - A Novel Therapeutic Strategy for Cancer Using Phosphatidylserine Targeting Stearylamine-Bearing Cationic Liposomes. AB - There is a pressing need for a ubiquitously expressed antigen or receptor on the tumor surface for successful mitigation of the deleterious side effects of chemotherapy. Phosphatidylserine (PS), normally constrained to the intracellular surface, is exposed on the external surface of tumors and most tumorigenic cell lines. Here we report that a novel PS-targeting liposome, phosphatidylcholine stearylamine (PC-SA), induced apoptosis and showed potent anticancer effects as a single agent against a majority of cancer cell lines. We experimentally proved that this was due to a strong affinity for and direct interaction of these liposomes with PS. Complexation of the chemotherapeutic drugs doxorubicin and camptothecin in these vesicles demonstrated a manyfold enhancement in the efficacies of the drugs both in vitro and across three advanced tumor models without any signs of toxicity. Both free and drug-loaded liposomes were maximally confined to the tumor site with low tissue concentration. These data indicate that PC-SA is a unique and promising liposome that, alone and as a combination therapy, has anticancer potential across a wide range of cancer types. PMID- 29499960 TI - miR-185 Inhibits Fibrogenic Activation of Hepatic Stellate Cells and Prevents Liver Fibrosis. AB - Recent studies have shown the effect of microRNAs on HSC activation and transformation, which is essential for the pathogenesis of liver fibrosis. In our study, we explored the role of miR-185 in liver fibrosis. Plasma miR-185 was detected in hepatitis B virus-related liver fibrosis patients (S2/3, n = 10) by Illumina HiSeq sequencing, and healthy volunteers were selected (n = 8) as the control group. We found that the plasma miR-185 level in fibrosis patients was significantly downregulated. CCl4-induced fibrosis tissues in mouse livers and TGF-beta1-activated HSCs also presented downregulated miR-185 concomitant with an increased expression of RHEB and RICTOR. To explore the correlations, LX-2 cells were transiently transfected with miR-185 mimics. The expression levels of alpha SMA, collagen I, and collagen III were decreased as well as RHEB and RICTOR. Inhibition of endogenous miR-185 increased fibrogenic activity. Furthermore, dual luciferase reporter assays indicated that miR-185 inhibited the expression of RHEB and RICTOR by directly targeting their 3' UTRs. Moreover, silencing RHEB and RICTOR suppressed alpha-SMA and collagen expression levels. In conclusion, miR 185 prevents liver fibrogenesis by inhibiting HSC activation via inhibition of RHEB and RICTOR. These results provide new insights into the mechanisms behind the anti-fibrotic effect of miR-185. PMID- 29499962 TI - Proverb comprehension deficits in patients with schizophrenia-Neurocognitive and social cognitive correlates. PMID- 29499963 TI - Damage to the left uncinate fasciculus is associated with heightened schizotypal traits: A multimodal lesion-mapping study. AB - A growing body of evidence suggests that individuals with pronounced schizotypal traits also display particular neurophysiological and morphological features - notably with regard to left frontotemporal connectivity. However, the studies published to date have focused on subclinical subjects and psychiatric patients, rather than brain-damaged patients. Here, we used the French version of the Schizotypal Personality Questionnaire to assess schizotypal traits in a sample of 97 patients having undergone surgical resection of a diffuse low-grade glioma. Patients having received other neurooncological treatments (including chemotherapy and radiotherapy) were not included. A combination of ROI-based based voxel-wise and tract-wise lesion-symptom mapping and a disconnectome analysis were performed, in order to identify the putative neural network associated with schizotypy. The ROI-based lesion-symptom mapping revealed a significant relationship between the cognitive-perceptual (positive) dimension of schizotypy and the left inferior gyrus (including the pars opercularis and the pars orbitalis). Importantly, we found that disconnection of the left uncinate fasciculus (UF) was a powerful predictor of the positive dimension of schizotypy. Lastly, the disconnection analysis indicated that the positive dimension of schizotypy was significantly associated with the white matter fibres deep in the left orbital and inferior frontal gyri and the left superior temporal pole, which mainly correspond to the spatial topography of the left UF. Taken as a whole, our results suggest that dysconnectivity of the neural network supplied by the left UF is associated with heightened positive schizotypal traits. Our new findings may be of value in interpreting current research in the field of biological psychiatry. PMID- 29499964 TI - Validation of the importance of continua in representing delusional ideation in the general population. AB - BACKGROUND: Previous studies have examined the distribution of psychotic like experiences (PLE) with the aim of informing the debate concerning the categorical versus continuous nature of psychosis. We extend this research by subjecting a number of competing models of delusional ideation to validation analysis to further examine previous findings. METHODS: We constructed latent variable models representing the factor structure of delusional ideation reported previously, using self-reported delusional ideation (Peter's Delusional Inventory; PDI) at age 21 in a general population prospective birth cohort study. After firstly eliminating models which exhibited poor fit we performed a longitudinal validation analyses among the competing models to investigate whether increasing levels of ideation were associated with developmental antecedents, correlates and distal indicators of psychotic disorder. RESULTS: Four latent variable models were found to adequately represent the delusional ideation data, two comprised exclusively of continua (a multidimensional 5 factor model and a bifactor model with 1 general and 4 specific factors), and two which included both categories and continua (two factor mixture models, each with 3 classes and 1 factor per class, but with varying levels of parameter restrictions). Exclusively categorical latent models obtained poor fit and the categorical components of hybrid models failed to discriminate on psychotic illness, while among the models incorporating continuous latent factors validation analyses did not clearly identify any model as better than the others. CONCLUSION: We provide novel evidence of the importance of continua in adequately and validly representing delusional ideation in the general population. Beyond this, our data suggests it is not possible to further refine the structure of delusional ideation in the general population. PMID- 29499965 TI - Shorter telomere length in people with schizophrenia who live alone? PMID- 29499966 TI - Anhedonia reflects impairment in making relative value judgments between positive and neutral stimuli in schizophrenia. AB - Anhedonia (i.e., diminished capacity to experience pleasure) has traditionally been viewed as a core symptom of schizophrenia (SZ). However, modern laboratory based studies suggest that this definition may be incorrect, as hedonic capacity may be intact. Alternative conceptualizations have proposed that anhedonia may reflect an impairment in generating mental representations of affective value that are needed to guide decision-making and initiate motivated behavior. The current study evaluated this hypothesis in 42 outpatients with SZ and 19 healthy controls (CN) who completed two tasks: (a) an emotional experience task that required them to indicate how positive, negative, and calm/excited they felt in response to a single emotional or neutral photograph; (b) a relative value judgment task where they selected which of 2 photographs they preferred. Results indicated that SZ and CN reported similar levels of positive emotion and arousal in response to emotional and neutral stimuli; however, SZ reported higher negative affect for neutral and pleasant stimuli than CN. In the relative value judgment task, CN displayed clear preference for stimuli differing in valence; however, SZ showed less distinct preferences for positive over neutral stimuli. Findings suggest that although in-the-moment experiences of positive emotion to singular stimuli may be intact in SZ, the ability to make relative value judgments that are needed to guide decision-making is impaired. Original conceptualizations of anhedonia as a diminished capacity for pleasure in SZ may be inaccurate; anhedonia may more accurately reflect a deficit in relative value judgment that results from impaired value representation. PMID- 29499967 TI - TNF-alpha and IL-6 are associated with the deficit syndrome and negative symptoms in patients with chronic schizophrenia. AB - INTRODUCTION: Increased inflammatory markers have been found in patients with chronic schizophrenia, and have been associated with negative symptoms. The deficit syndrome is a distinct subtype of schizophrenia, characterized by primary and enduring negative symptoms. METHOD: We measured inflammatory markers in patients with and without deficit schizophrenia and controls. RESULTS: Using multivariate analyses, tumor necrosis factor (TNF)-alpha and interleukin-6 were associated with the deficit syndrome, and TNF-alpha predicted blunted affect, alogia, and total negative symptoms. CONCLUSIONS: Findings suggest that deficit schizophrenia subtype is associated with increased inflammation and immunotherapies may be a novel target for negative symptoms. PMID- 29499968 TI - Temporal lobe thickness and verbal memory in first-degree relatives of individuals with schizophrenia. AB - Cortical thinning in frontal and temporal regions has been reported in individuals diagnosed with schizophrenia and, less consistently, among their unaffected first-degree relatives. Likewise, first-degree relatives demonstrate attenuated differences in neurocognitive performance relative to healthy controls, indicating that neurocognitive performance may be an important endophenotype of the disorder. Less is known about how cortical thickness relates to neurocognitive performance in these individuals. Given the robust nature of temporal structural abnormalities in schizophrenia, this study aimed to identify how temporal lobe cortical thickness might relate to verbal memory in first degree relatives. Unaffected parents and siblings of individuals with adult-onset schizophrenia (N=62) and individuals in healthy control families (N=70) participating in the UCLA Family Study received a structural MRI and completed a battery of neurocognitive tests. Cortical thickness was estimated across the cortex and thickness measures of all regions in the temporal lobe were summed, averaged, and residualized for age and sex to produce a variable. A verbal learning factor was derived from two common tests of verbal learning and memory, the CVLT-II and Logical Memory of the WMS-III. Results demonstrated a significant interaction between group and verbal learning in relationship to temporal lobe thickness. Post-hoc analyses revealed significant correlations between verbal learning and cortical thickness in the relatives of schizophrenia patients which were driven by immediate recall scores on the CVLT-II and Logical Memory. These findings indicate that cortical thickness in the temporal cortex may represent a structural correlate for encoding verbal information in unaffected relatives of individuals with schizophrenia. PMID- 29499969 TI - Schizophrenia-associated rs4702 G allele-specific downregulation of FURIN expression by miR-338-3p reduces BDNF production. AB - Genome-wide association studies (GWAS) reveal numerous schizophrenia (SCZ) associated single-nucleotide polymorphisms (SNPs); however, functional characterizations of the risk variants remain to be established. Using data from 108 SCZ GWAS loci, we performed systematic miRNA binding site screening of 128 SCZ-associated SNPs and found that 2 out of 3 SNPs located in the 3'UTR were predicted to alter 3 miRNAs' binding sites in 2 target genes. Of the identified SNPs, the most genome-wide significant SNP rs4702 (A/G) in the FURIN 3'UTR, previously identified as an SCZ-associated cis-expression quantitative trait loci (downregulated by the risk G allele), is located in the binding site of miR-338 3p in the presence of the risk G allele. Allele-specific downregulation of FURIN by miR-338-3p was validated with a luciferase reporter assay. Furthermore, we demonstrated that miR-338-3p-mediated FURIN inhibition reduced brain-derived neurotrophic factor (BDNF) maturation and secretion in human embryonic kidney 293T cells. Our data reveal that schizophrenia-associated rs4702 G allele specific downregulation of FURIN by miR-338-3p reduces mature BDNF production. These data help elucidate the mechanism of genetic predisposition toward schizophrenia or other neurodevelopmental diseases. PMID- 29499970 TI - Erratum to "Retraction notice to acetate-triggered granular sludge floatation in methanogenic bioreactors" [Water Res. 107 (2016) 93-101]. PMID- 29499971 TI - The Incremental Burden of Acute Respiratory Distress Syndrome: Long-term Follow up of a Population-Based Nested Case-Control Study. AB - OBJECTIVE: To evaluate the long-term survival of patients at similar risk for hospital-acquired acute respiratory distress syndrome (ARDS) who did and did not develop ARDS. METHODS: We conducted long-term follow-up of a population-based nested case-control study in a consecutive cohort of adult Olmsted County, Minnesota, patients admitted from January 1, 2001, through December 31, 2010. Patients in whom ARDS developed during their hospital stay (cases) were matched to similar-risk patients without ARDS (controls) by 6 characteristics: age, sex, sepsis, high-risk surgery, ratio of oxygen saturation to fraction of inspired oxygen, and ARDS risk according to the Lung Injury Prediction Score. Hospital mortality, discharge disposition, and long-term survival were compared. RESULTS: Patients who developed hospital-acquired ARDS (n=400) had higher hospital mortality than at-risk controls (n=400) (35% vs 5%; P<.001). Among hospital survivors (252 matched pairs), ARDS cases were more likely to be discharged to rehabilitation (13% vs 4%) and long-term care (30% vs 15%) facilities, whereas more controls were discharged home (71% vs 41%). After discharge, differences in survival persisted beyond 90 days (adjusted hazard ratio [HR], 1.76; 95% CI, 1.2 2.5; P=.002) and 6 months (adjusted HR, 1.73; 95% CI, 1.2-2.6; P<.001). CONCLUSION: These results suggest that in a population-based matched case-control study of patients with similar characteristics at the time of hospital admission, those who developed hospital-acquired ARDS had worse long-term survival. PMID- 29499972 TI - No effect of saturated fatty acid chain length on meal-induced thermogenesis in overweight men. AB - Monounsaturated (MUFA) fatty acids have been shown to induce greater meal-induced thermogenesis (MIT) than saturated fatty acids (SFA) in some studies, however, the effect of SFA chain length has not been examined. We hypothesized that a meal rich in short- to medium-chain SFA would elicit a greater MIT than one rich in long-chain SFA, and that MIT responses would be comparable between the short- to medium-chain SFA and the MUFA rich meal. A 3-arm crossover study was conducted with healthy overweight men, aged 18 to 40 years. Participants consumed either an iso-energetic (3780 +/- 4.3 kJ), high fat (45%) meal rich in short-/medium-chain SFA (SMCSFA) (2-12 carbons); long-chain SFA (LCSFA) (14-24 carbons), and MUFA. MIT, fat oxidation, triglyceride and subjective appetite were measured for 6 hours post-prandial. Data were analyzed as total area under the curve and compared using a one-way repeated-measures ANOVA. The mean BMI of participants (n =13) was 29.3 +/- 0.6 kg/m2 and mean age 23.8+/-1.4 years. MIT was not different between the meals: MUFA (204.2 +/- 20.5 kJ/6 h), SMCSFA (192.6 +/- 21.8 kJ/6 h), LCSFA (198.1 +/- 21.5 kJ/6 h) (P = .888). Fat oxidation, plasma triglyceride, and hunger and fullness were similar after each meal (P > .05 all values). This study demonstrated that in healthy overweight men, SFA chain length, and fatty acid saturation have no acute differential effect on MIT, fat oxidation, triglyceride, or subjective appetite responses. PMID- 29499973 TI - Radionuclide transfer to wildlife at a 'Reference site' in the Chernobyl Exclusion Zone and resultant radiation exposures. AB - This study addresses a significant data deficiency in the developing environmental protection framework of the International Commission on Radiological Protection, namely a lack of radionuclide transfer data for some of the Reference Animals and Plants (RAPs). It is also the first study that has sampled such a wide range of species (invertebrates, plants, amphibians and small mammals) from a single terrestrial site in the Chernobyl Exclusion Zone (CEZ). Samples were collected in 2014 from the 0.4 km2 sampling site, located 5 km west of the Chernobyl Nuclear Power complex. We report radionuclide (137Cs, 90Sr, 241Am and Pu-isotopes) and stable element concentrations in wildlife and soil samples and use these to determine whole organism-soil concentration ratios and absorbed dose rates. Increasingly, stable element analyses are used to provide transfer parameters for radiological models. The study described here found that for both Cs and Sr the transfer of the stable element tended to be lower than that of the radionuclide; this is the first time that this has been demonstrated for Sr, though it is in agreement with limited evidence previously reported for Cs. Studies reporting radiation effects on wildlife in the CEZ generally relate observations to ambient dose rates determined using handheld dose meters. For the first time, we demonstrate that ambient dose rates may underestimate the actual dose rate for some organisms by more than an order of magnitude. When reporting effects studies from the CEZ, it has previously been suggested that the area has comparatively low natural background dose rates. However, on the basis of data reported here, dose rates to wildlife from natural background radionuclides within the CEZ are similar to those in many areas of Europe. PMID- 29499974 TI - Specialized Proresolving Mediators: Enhancing Nonalcoholic Steatohepatitis and Fibrosis Resolution. AB - The resolution of necroinflammation and fibrosis remains a primary clinical target in nonalcoholic steatohepatitis (NASH), the most common chronic liver disease and a major cause of end-stage liver disease. Our understanding of the basic molecular mechanisms driving inflammation and fibrosis and their resolution in obesity-related conditions, including NASH, have led to the proposal of a novel, tractable therapeutic paradigm involving specialized proresolving mediators (SPMs), namely lipoxins (LXs), resolvins (Rvs), protectins (PDs), and maresins (MaRs). Growing evidence from cellular and in vivo animal models, as well as observational human data, suggests that the therapeutic potential of SPMs and their synthetic mimetics expands to the regression of hepatic necroinflammatory and fibrotic changes in NASH. Here, we review preclinical and clinical evidence linking SPMs to the pathogenesis of inflammation and fibrosis in NASH, as well as potential therapeutic use of these new molecules for the resolution of steatohepatitis and of fibrosis in NASH. PMID- 29499975 TI - The Double Dutch technique: A new way of creating an ileocystoplasty with a lengthy catheterizable ileal tube. AB - INTRODUCTION: A tubularized conduit from an open 2-cm vascularized ileal segment is a frequently used technique to create a continent catheterizable channel in cases of an inappropriate or absent appendix. In the long term, many patients experience catheterization problems with the classic ileal segment tube, and even more with spiral or double-segment tubes. OBJECTIVE: The objective of this paper was to introduce an ileocystoplasty modification combined with a long ileal segment tube that has better support by surrounding tissue than other lengthy ileal segment tubes. Briefly summarized, this newly introduced method begins with isolating approximately 30 cm of ileum and dividing it into two parts. Two strips are then created and closed as a double-length tube. The ileal segments are opened antimesenterically and closed over the tube in the middle. The lower part of the tube is implanted with a submucosal tunnel in the bladder wall, and the ileal patch is then anastomosed with the bladder. The tube is anastomosed to the umbilicus in an ordinary way without any traction (see Summary Fig.). STUDY DESIGN: Between May 2005 and November 2012 the new technique was used at the current institution in nine children who needed an ileocystoplasty (mean age: 9 years and 3 months). Underlying etiology was neurogenic bladder in seven cases and epispadias in two. RESULTS: All patients ultimately had stomas without leakage or strictures. During follow-up, three of nine tubes developed stenoses that were corrected; four stomas in total had some sort of surgical revision. Median follow-up was 93 months. Intermittent catheterization was uncomplicated in all at this time. DISCUSSION: With this modification of the standard technique it seemed to be possible to create a more stable channel. The blood supply of the tube was secured by completely embedding the mesentery of the tube. Limitations included the small number of patients treated so far. CONCLUSION: The lengthy tubes appeared to be straight and well supported by the surrounding tissues, which prevented kinking and sacculation. It is hoped that this technique will have better results and fewer complications at long-term follow-up. PMID- 29499976 TI - Effect of two different sublingual dosages of vitamin B12 on cobalamin nutritional status in vegans and vegetarians with a marginal deficiency: A randomized controlled trial. AB - BACKGROUND & AIMS: Vegetarians and vegans are more vulnerable to vitamin B12 deficiency with severe risks of megaloblastic anemia, cognitive decline, neuropathy, and depression. An easy and simple method of supplementation consists of taking one weekly dosage of 2000 MUg. However, single large oral doses of vitamin B12 are poorly absorbed. The present research evaluates the ability of two different sublingual dosages of vitamin B12 (350 MUg/week vs 2000 MUg/week) in improving cyanocobalamin (vitamin B12) nutritional status in vegans and vegetarians with a marginal deficiency. METHODS: A 12-week randomized, double blind, controlled, parallel intervention trial was performed. Forty subjects with marginal vitamin B12 deficiency were enrolled and randomly divided into two groups: test group Ld (low dose, 350 MUg/week) and control group Hd (high dose, 2000 MUg/week) vitamin B12 supplementation. Blood samples were collected at baseline and after 15, 30, 60, and 90 days from the intervention for the determination of vitamin B12, related metabolic markers, and blood cell counts. RESULTS: Two-way analysis of variance showed a significant effect of time (P < 0.0001) and of time * treatment interaction (P = 0.012) on serum concentration of vitamin B12 that increased after 90-day supplementation (Ld and Hd) compared to baseline. Both the supplements increased (P < 0.0001, time effect) the levels of holotranscobalamin, succinic acid, methionine and wellness parameter, while decreased (P < 0.0001, time effect) the levels of methylmalonic acid, homocysteine and folate compared to baseline. No difference was observed between groups (LdvsHd). No effect was detected for vitamin B6 and blood cell count. CONCLUSIONS: In our experimental conditions, both supplements were able to restore adequate serum concentrations of vitamin B12 and to improve the levels of related metabolic blood markers in subjects with a marginal deficiency. The results support the use of a sublingual dosage of 50 MUg/day (350 MUg/week) of cobalamin, instead of 2000 MUg/week (provided as a single dose), to reach a state of nutritional adequacy of vitamin B12 in this target population. This study was registered at www.isrctn.org as ISRCTN75099618. PMID- 29499977 TI - Sarcopenic obesity and overall mortality: Results from the application of novel models of body composition phenotypes to the National Health and Nutrition Examination Survey 1999-2004. AB - BACKGROUND/OBJECTIVES: There is no consensus on the definition of sarcopenic obesity (SO), resulting in inconsistent associations of SO with mortality risk. We aim to evaluate association of dual energy x-ray absorptiometry (DXA) SO models with mortality risk in a US adult population (>=50 years). SUBJECTS/METHODS: The study population consisted of 3577 participants aged 50 years and older from the 1999-2004 National Health and Nutrition and Examination Survey with mortality follow-up data through December 31, 2011. Difference in survival time in people with and without SO defined by three body composition DXA models (Model 1: body composition phenotype model; Model 2: Truncal Fat Mass (TrFM)/Appendicular Skeletal Muscle Mass (ASM) ratio model; Model 3: Fat Mass (FM)/Fat Free Mass (FFM) ratio). The differences between the models were assessed by the acceleration failure time model, and expressed as time ratios (TR). RESULTS: Participants age 50-70 years with SO had a significantly decreased survival time, according to the body composition phenotype model (TR: 0.92; 95% CI: 0.87-0.97), and TrFM/ASM ratio model (TR: 0.88; 95% CI: 0.81-0.95). The FM/FFM ratio model did not detect significant differences in survival time. Participants with SO aged 70 years and older did not have a significantly decreased survival time, according to all three models. CONCLUSIONS: A SO phenotype increases mortality risk in people of age 50-70 years, but not in people aged 70 years and older. The application of the body composition phenotype and the TrFM/ASM ratio models may represent useful diagnostic approaches to improve the prediction of disease and mortality risk. PMID- 29499978 TI - Evaluation of implementation of fasting guidelines for enterally fed critical care patients. AB - BACKGROUND & AIMS: Critically ill adults have increased nutrition risk. Prior to procedures patients are often fasted, leading to nutritional deficits. The use of fasting guidelines may therefore help reduce deficits from accumulating. The aim of this work was to determine the impact on nutrition support delivery following the implementation of fasting guidelines in addition to characterizing staff knowledge of the guidelines. DESIGN: Retrospective data were collected on n = 74 patients at two different time points; prior to launch of fasting guidelines and post launch, with regards to estimated nutritional requirements, nutritional targets, volume of enteral nutrition (EN) delivered and periods of fasting. Clinical variables of interest were collected for up to 14 days. Questionnaires assessing staff knowledge/barriers to usage of the fasting guidelines were administered to ICU staff. SETTING: 3 ICUs (General, Cardiac and Neurosciences) within University Hospital Southampton NHS Foundation Trust. PATIENTS: Mechanically ventilated adults in an ICU and receiving exclusive EN. MEASUREMENTS AND MAIN RESULTS: Comparison was made between pre- and post-guideline implementation with statistically significant improvements in the % EN delivered (76.4 +/- 11.8 vs. 84.1 +/- 10.8 (p = 0.0009)) and duration of feeds withheld (41.5 +/- 26.6 vs. 27.6 +/- 20.8 h (p = 0.02)). There were non-significant improvements pre- and post-implementation in the % of energy and protein delivered (80.7 +/- 16.4 vs. 86.5 +/- 17.3 (p = 0.15 (NS)); 74 +/- 18.3 vs. 79 +/ 18.5 (p = 0.15 (NS))). 77% of staff were familiar with the guidelines, whilst 42% requested further education. The main barriers to guideline compliance were delays and unpredictable timing of procedures, and differing guidance from senior staff and non-ICU teams. CONCLUSIONS: Implementation of fasting guidelines led to significant improvements in EN delivery and reduced duration of feed breaks. The use of fasting guidelines is a positive step towards increasing nutrition delivery in the ICU. Further staff education and better planning around procedures is required to promote further adherence to the fasting guidelines. PMID- 29499979 TI - Serious limitations in a systematic review about the effects of placing posts in endodontically treated teeth result in evidence that is not useful in making decisions. PMID- 29499980 TI - Toothbrushing once per day or more is associated with fewer periodontal pockets, but increasing the frequency may not result in important differences. PMID- 29499981 TI - Caries removal with an erbium laser may result in a small increase in cavity preparation time but also in a reduction in required extra local anesthetic compared with traditional drilling. PMID- 29499982 TI - Very low certainty in evidence suggesting that internal implant-abutment connections result in negligible bone loss and similar survival and complication rates compared with external implant-abutment connections. PMID- 29499983 TI - The Association Between Smoking and Electronic Cigarette Use in a Cohort of Young People. AB - PURPOSE: Electronic cigarette (e-cigarette) use is associated with smoking initiation among young people; however, it is also possible that smoking is associated with e-cigarette initiation. This study explores these associations among young people in Great Britain. METHODS: A longitudinal survey of 1,152 11- to 18-year-olds was conducted with baseline in April 2016 and follow-up between August and October 2016. Logistic regression models and causal mediation analyses assessed whether (1) ever e-cigarette use and escalation were associated with smoking initiation (ever smoking at follow-up) among baseline never smokers (n = 923), and (2) ever smoking and escalation were associated with e-cigarette initiation (ever e-cigarette use at follow-up) among baseline never e-cigarette users (n = 1,020). RESULTS: At baseline, 19.8% were ever smokers and 11.4% were ever e-cigarette users. Respondents who were ever e-cigarette users (vs. never users, 53% vs. 8%, odds ratio [OR] = 11.89, 95% confidence interval [CI] = 3.56 39.72) and escalated their e-cigarette use (vs. did not, 41% vs. 8%, OR = 7.89, 95% CI = 3.06-20.38) were more likely to initiate smoking. Respondents who were ever smokers (vs. never smokers, 32% vs. 4%, OR = 3.54, 95% CI = 1.68-7.45) and escalated their smoking (vs. did not, 34% vs. 6%, OR = 5.79, 95% CI = 2.55-13.15) were more likely to initiate e-cigarette use. There was a direct effect of ever e cigarette use on smoking initiation (OR = 1.34, 95% CI = 1.05-1.72), and ever smoking on e-cigarette initiation (OR = 1.08, 95% CI = 1.01-1.17); e-cigarette and smoking escalation, respectively, did not mediate these effects. CONCLUSIONS: Among young people in Great Britain, ever e-cigarette use is associated with smoking initiation, and ever smoking is associated with e-cigarette initiation. PMID- 29499984 TI - Multidimensional intervention to improve the short-term prognosis of frail elderly patients discharged from a short-stay unit: A quasiexperimental study. AB - OBJECTIVE: To study the effect of a multidimensional intervention on the prognosis at 30 days for frail elderly patients discharged from a short-stay unit. MATERIAL AND METHOD: A quasiexperimental study was conducted with a historical control cohort. We included frail patients (Identification of Seniors at Risk score>=2) 75 years of age or older, discharged from an short-stay unit over 2 months in 2013 (control group) and in 2016 (intervention group). An intervention was conducted based on the activation of resources, based on the deficiencies detected after an abbreviated geriatric assessment, in conjunction with Primary Care. The main endpoint was the presence of an adverse result (death or readmission for any cause or severe functional impairment) at 30 days of discharge. RESULTS: We included 137 (62.8%) patients in the intervention group and 81 (37.2%) in the control group. Eighteen (13.1%) patients in the intervention group and 29 (35.8%) in the control group presented an adverse event at 30 days. A multivariate analysis showed that the implementation of a multidimensional intervention was a protective factor for presenting an adverse event at 30 days of discharge (adjusted RR 0.40; 95% CI 0.23-0.68; P=.001). CONCLUSIONS: The implementation of an individual care plan for frail elderly patients, based on the activation of resources according to the deficiencies detected after an abbreviated geriatric assessment and in conjunction with Primary Care, could improve the results at 30 days of discharge from an short stay unit. PMID- 29499985 TI - Patient and public involvement in hospital policy-making: Identifying key elements for effective participation. AB - The involvement of patients and the public in healthcare decisions becomes increasingly important. Although patient involvement on the level of the individual patient-healthcare worker relationship is well studied, insight in the process of patient and public involvement on a more strategic level is limited. This study examines the involvement of patient and public (PPI) in decision making concerning policy in six Flemish hospitals. The hospitals organized a stakeholder committee which advised the hospital on strategic policy planning. A three-phased mixed- methods study design with individual questionnaires (n = 69), observations (n = 10) and focus groups (n = 4) was used to analyze, summarize and integrate the findings. The results of this study indicate that: (1) PPI on hospital level should include the possibility to choose topics, like operational issues; (2) PPI-stakeholders should be able to have proper preparation; (3) PPI stakeholders should be externally supported by a patient organization; (4) more autonomy should be provided for the stakeholder committee. Additionally, the study indicates that the influence of national legislation on stakeholder initiatives in different countries is limited. In combination with the growing importance of PPI and the fact that the recommendations presented are not claimed to be exhaustive, more transnational and conceptual research is needed in the future. PMID- 29499986 TI - WASP: Is open access publishing the way forward? A review of the different ways in which research papers can be published. AB - Academics have a duty towards peers and scholars alike to engage in research work and to publish their findings. This also assists in establishing personal academic success as well as the attainment of research grants. In the past, authors used to publish their research articles for free but access to these articles was restricted to subscription users only. Recently, open access publishing has gained momentum, whereby such articles are made freely accessible online. However open access publishing comes with a price tag for the author through article processing charges. Open access may also question a journal's credibility within the academic world if improperly implemented. This is particularly so following the unsolicited bombardment of researchers' email accounts with invitations for submissions to predatory open access journals. For these reasons, authors needs to rigorously weigh the pros and cons of whether to choose a subscription based or an open access journal for publication. PMID- 29499987 TI - WASP (Write a Scientific Paper): An existential metamotivational influence as to why teach and publish. AB - Carrying out research beyond that which is required by one's work/academic obligations, and teaching and training others so that one can be replaced or even surpassed, are both metamotivational. The Write a Scientific Paper (WASP) course provides a metamotivational outlet for senior academics to impart their collective experiences to WASP delegates in this crucial aspect of career progress. PMID- 29499988 TI - Consensus Based Definition of Growth Restriction in the Newborn. AB - OBJECTIVE: To develop a consensus definition of growth restriction in the newborn that can be used clinically to identify newborn infants at risk and in research to harmonize reporting and definition in the current absence of a gold standard. STUDY DESIGN: An international panel of pediatric leaders in the field of neonatal growth were invited to participate in an electronic Delphi procedure using standardized methods and predefined consensus rules. Responses were fed back at group-level and the list of participants was provided. Nonresponders were excluded from subsequent rounds. In the first round, variables were scored on a 5 point Likert scale; in subsequent rounds, inclusion of variables and cut-offs were determined with a 70% level of agreement. In the final round participants selected the ultimate algorithm. RESULTS: In total, 57 experts participated in the first round; 79% completed the procedure. Consensus was reached on the following definition: birth weight less than the third percentile, or 3 out of the following: birth weight <10th percentile; head circumference <10th percentile; length <10th percentile; prenatal diagnosis of fetal growth restriction; and maternal pregnancy information. CONCLUSIONS: Consensus was reached on a definition for growth restriction in the newborn. This definition recognizes that infants with birth weights <10th percentile may not be growth restricted and that infants with birth weights >10th percentile can be growth restricted. This definition can be adopted in clinical practice and in clinical trials to better focus on newborns at risk, and is complementary to the previously determined definition of fetal growth restriction. PMID- 29499989 TI - Clinical, Pathologic, and Genetic Features of Neonatal Dubin-Johnson Syndrome: A Multicenter Study in Japan. AB - OBJECTIVE: To clarify the clinical, pathologic, and genetic features of neonatal Dubin-Johnson syndrome. STUDY DESIGN: Ten patients with neonatal Dubin-Johnson syndrome were recruited from 6 pediatric centers in Japan between September 2013 and October 2016. Clinical and laboratory course, macroscopic and microscopic liver findings, and molecular genetic findings concerning ATP-binding cassette subfamily C member 2 (ABCC2) were retrospectively and prospectively examined. RESULTS: All neonates exhibited cholestasis, evident as prolonged jaundice with or without acholic stools and elevations of serum direct bilirubin as well as gamma-glutamyltransferase or total bile acids. Only 38% (3 of 8) of patients who underwent liver biopsy showed a grossly black liver or melanin-like pigment deposits in hepatocytes; their biopsies were performed in early infancy. Immunohistochemically, all liver specimens showed no expression of multidrug resistance-associated protein 2 but increased expression of the bile salt export pump protein. Homozygous or compound heterozygous pathogenic variants of ABCC2 were identified in all patients, representing 11 distinct pathogenic variants including 2 not previously reported. CONCLUSIONS: Immunohistochemical staining of the liver for multidrug resistance-associated protein 2 and molecular genetic analysis of ABCC2 are crucial for accurate diagnosis of neonatal Dubin-Johnson syndrome. PMID- 29499990 TI - Prospective Study of Live Attenuated Vaccines for Patients with Nephrotic Syndrome Receiving Immunosuppressive Agents. AB - OBJECTIVE: To conduct a prospective study to evaluate the immunogenicity and safety of live attenuated vaccines in patients with nephrotic syndrome receiving immunosuppressive agents. STUDY DESIGN: Patients with nephrotic syndrome receiving immunosuppressive agents with negative or borderline antibody titers (virus-specific IgG levels <4.0) against measles, rubella, varicella, and/or mumps fulfilling the criteria of cellular and humoral immunity were enrolled. Virus-specific IgG levels were measured using an enzyme immunoassay. The primary endpoint was the seroconversion rate (ie, achievement of virus-specific IgG levels >=4.0) at 2 months after vaccination. Virus-specific IgG levels at 1 year, breakthrough infections (wild-type infections), and adverse events were also evaluated. RESULTS: A total of 116 vaccinations were administered to 60 patients. Seroconversion rates were 95.7% for measles, 100% for rubella, 61.9% for varicella, and 40.0% for mumps. More patients with a borderline antibody titer before vaccination achieved seroconversion than those with negative antibody titer, with statistical significance after varicella and mumps vaccination. The rate of patients who maintained seropositivity at 1 year after vaccination was 83.3% for measles, 94.1% for rubella, 76.7% for varicella, and 20.0% for mumps. No patient experienced breakthrough infection. No serious adverse events, including vaccine-associated infection, were observed. CONCLUSION: Immunization with live attenuated vaccines may be immunogenic and is apparently safe in our cohort of patients with nephrotic syndrome receiving immunosuppressive agents if their cellular and humoral immunologic measures are within clinically acceptable levels. TRIAL REGISTRATION: UMIN-CTR UMIN 000007710. PMID- 29499991 TI - The Effects of Gestational Alloimmune Liver Disease on Fetal and Infant Morbidity and Mortality. AB - OBJECTIVES: To evaluate pregnancy outcomes in pedigrees of neonatal hemochromatosis to determine the spectrum of gestational alloimmune liver disease (GALD) in a large cohort. STUDY DESIGN: We prospectively collected data from women with a prior offspring with proven neonatal hemochromatosis between 1997 and 2015 and analyzed pregnancy outcomes. RESULTS: The pedigrees from 150 women included 350 gestations with outcomes potentially related to GALD. There were 105 live-born infants without liver disease, 157 live-born infants with liver failure, and 88 fetal losses. Fetal loss occurred in 25% of total gestations. Ninety-seven pedigrees contained a single affected offspring, whereas 53 contained multiple affected offspring. Analysis of these 53 pedigrees yielded a per-pregnancy repeat occurrence rate of 95%. Notably, the first poor outcome occurred in the first pregnancy in 60% of pedigrees. Outcomes of the 157 live born infants with liver failure were poor: 18% survived, 82% died. Of the 134 live-born infants with treatment data, 20 received intravenous immunoglobulin with or without double-volume exchange transfusion of which 9 (45%) survived; 14 infants (10%) received a liver transplant of which 6 (43%) survived. CONCLUSIONS: GALD is a significant cause of both fetal loss and neonatal mortality with a high rate of disease recurrence in untreated pregnancies at risk. Poor outcomes related to GALD commonly occur in the first gestation, necessitating a high index of suspicion to diagnose this disorder at first presentation. PMID- 29499992 TI - Point-of-Care Ultrasound for the Diagnosis of Skull Fractures in Children Younger Than Two Years of Age. AB - OBJECTIVES: To determine the accuracy of skull point-of-care ultrasound (POCUS) for identifying fractures in children younger than 2 years of age with signs of head trauma, and the ability of POCUS to identify the type and depth of fracture depression. STUDY DESIGN: This was a multicenter, prospective, observational study of children younger than 2 years of age with nontrivial mechanisms of injury and signs of scalp/skull trauma. Patients were enrolled if they underwent computed tomography (CT). Patients underwent clinical evaluation, in addition to a cranial POCUS in the emergency department (ED). From the POCUS examinations, we documented whether fractures were present or absent, their location, characteristics, and depth. POCUS and CT findings were compared to calculate the diagnostic accuracy. RESULTS: We enrolled a convenience sample of 115 of 151 (76.1%) eligible patients. Of the 115 enrolled, 88 (76.5%) had skull fractures. POCUS had a sensitivity of 80 of 88 (90.9%; 95% CI 82.9-96.0) and a specificity of 23 of 27 (85.2%; 95% CI 66.3-95.8) for identifying skull fractures. Agreement between POCUS and CT to identify the type of fracture as linear, depressed, or complex was 84.4% (97 of 115) with a kappa of 0.75 (95% CI 0.70-0.84). CONCLUSIONS: POCUS performed by emergency physicians may identify the type and depth of fractures in infants with local physical signs of head trauma with substantial accuracy. Emergency physicians should consider POCUS as an adjunct to clinical evaluation and prediction rules for traumatic brain injuries in children younger than 2 years of age. PMID- 29499993 TI - Development of an analytical method for polycyclic aromatic hydrocarbons in coffee beverages and dark beer using novel high-sensitivity technique of supercritical fluid chromatography/mass spectrometry. AB - Polycyclic aromatic hydrocarbons (PAHs) are carcinogenic substances that are mainly generated during heating in food; therefore, the European Union (EU) has regulated the amount of benzo[a]pyrene and PAH4 in various types of food. In addition, the Scientific Committee on Food of the EU and the Joint Food and Agriculture Organization/World Health Organization Expert Committee on Food Additives have recommended that 16 PAHs should be monitored. Since coffee beverages and dark beer are roasted during manufacture, monitoring these 16 PAHs is of great importance. On the other hand, supercritical fluid chromatography (SFC) is a separation method that has garnered attention in recent years as a complement for liquid and gas chromatography. Therefore, we developed a rapid high-sensitivity analytical method for the above-mentioned 16 PAHs in coffee beverages and dark beer involving supercritical fluid chromatography/atmospheric pressure chemical ionization-mass spectrometry (SFC/APCI-MS) and simple sample preparation. In this study, we developed a novel analytical technique that increased the sensitivity of MS detection by varying the back-pressure in SFC depending on the elution of PAHs. In addition, analysis of commercially available coffee and dark beer samples in Japan showed that the risk of containing the 16 PAHs may be low. PMID- 29499994 TI - Sensitive typing of reverse ABO blood groups with a waveguide-mode sensor. AB - Portable, on-site blood typing methods will help provide life-saving blood transfusions to patients during an emergency or natural calamity, such as significant earthquakes. We have previously developed waveguide-mode (WM) sensors for forward ABO and Rh(D) blood typing and detection of antibodies against hepatitis B virus and hepatitis C virus. In this study, we evaluated a WM-sensor for reverse ABO blood typing. Since reverse ABO blood typing is a method for detection of antibodies against type A and type B oligosaccharide antigens on the surface of red blood cells (RBCs), we fixed a synthetic type A or type B trisaccharide antigen on the sensor chip of the WM sensor. We obtained significant changes in the reflectance spectra from a WM sensor on type A antigen with type B plasma and type O plasma and on type B antigen with type A plasma and type O plasma, and no spectrum changes on type A antigen or type B antigen with type AB plasma. Signal enhancement with the addition of a peroxidase reaction failed to increase the sensitivity for detection on oligosaccharide chips. By utilizing hemagglutination detection using regent type A and type B RBCs, we successfully determined reverse ABO blood groups with higher sensitivity compared to a method using oligosaccharide antigens. Thus, functionality of a portable device utilizing a WM sensor can be expanded to include reverse ABO blood typing and, in combination with forward ABO typing and antivirus antibody detection, may be useful for on-site blood testing in emergency settings. PMID- 29499995 TI - Metabolic flux of the oxidative pentose phosphate pathway under low light conditions in Synechocystis sp. PCC 6803. AB - The role of the oxidative pentose phosphate pathway (oxPPP) in Synechocystis sp. PCC 6803 under mixotrophic conditions was investigated by 13C metabolic flux analysis. Cells were cultured under low (10 MUmol m-2 s-1) and high light intensities (100 MUmol m-2 s-1) in the presence of glucose. The flux of CO2 fixation by ribulose bisphosphate carboxylase/oxygenase under the high light condition was approximately 3-fold higher than that under the low light condition. Although no flux of the oxPPP was observed under the high light condition, flux of 0.08-0.19 mmol gDCW-1 h-1 in the oxPPP was observed under the low light condition. The balance between the consumption and production of NADPH suggested that approximately 10% of the total NADPH production was generated by the oxPPP under the low light condition. The growth phenotype of a mutant with deleted zwf, which encodes glucose-6-phosphate dehydrogenase in the oxPPP, was compared to that of the parental strain under low and high light conditions. Growth of the Deltazwf mutant nearly stopped during the late growth phase under the low light condition, whereas the growth rates of the two strains were identical under the high light condition. These results indicate that NADPH production in the oxPPP is essential for anabolism under low light conditions. The oxPPP appears to play an important role in producing NADPH from glucose and ATP to compensate for NADPH shortage under low light conditions. PMID- 29499996 TI - [Optimizing medical treatment of abdominal aortic aneurysm: Interest of vascular centers]. AB - Diagnosis of abdominal aortic aneurysm (AAA) at preoperative stage is increasingly frequent. It carries both a local risk of rupture and an increased global cardiovascular risk. Patients with AAA have indeed a 20 times higher risk of dying from myocardial infarction or stroke than from a ruptured aneurysm. Cardiovascular risk factors control is therefore essential, particularly smoking cessation. Treatment in cardiovascular prevention is also warranted. Seeking for atheromatous sites is needed as they determine prognosis. Evidence of the benefit of medical treatment to slow AAA growth is still lacking. In practice, it is recommended to prescribe statins and angiotensin converting enzyme inhibitor to prevent cardiovascular events. These preventive measures are as well necessary to improve postoperative prognosis and must be continued after surgical repair. A vascular medical and surgical cooperation is primordial to enhance comprehensive management of patients with AAA. PMID- 29499997 TI - Effects of using WeChat-assisted perioperative care instructions for parents of pediatric patients undergoing day surgery for herniorrhaphy. AB - OBJECTIVE: This study examined the effects of WeChat-assisted perioperative instructions for parents whose children were to undergo herniorrhaphy. METHOD: A randomized controlled trial was conducted in a day surgery center in China. Participants were randomly assigned to the intervention (WeChat) group (n = 209) and the control (Leaflet) group (n = 209). The primary outcomes of this study were parents' knowledge regarding hernia and rate of cancellation of children's surgery. The secondary outcomes were the rate of lost-to-follow-up and the rate of complications and adverse events during the seventh postoperative follow-up day. RESULTS: There was a significant difference in the rate of cancelling the surgery and the mean knowledge score between the WeChat group and leaflet groups. The lost-to-follow-up rate was significantly lower in the WeChat group (0.54%) than in the leaflet group (3.66%). The incidence of postoperative complications were higher in the control group. CONCLUSIONS: WeChat-assisted perioperative care instructions enhanced parents' knowledge on perioperative instructions and promoted the preparation of their children for day surgery resulting in lower rate of cancelling the surgery. PRACTICE IMPLICATIONS: WeChat has the ability to expand health services outside the hospital confines and could be used as an important low-cost health educational medium in China. PMID- 29499998 TI - [Implementation of a remote oncology-monitoring program for cancer patients in outpatient care unit: A major challenge for the different actors]. AB - INTRODUCTION: The development of outpatient departments requires health professionals to reorganize practices for a better patient monitoring and a better patient care pathway. OBJECTIVE: To evaluate, using indicators, the impact of an oncology-monitoring program on activity and organizational fluidity in a Cytotoxic Preparation Unit and clinical departments. Method the clinical and biological data are collected between two injections by calling the patient two days prior chemotherapy is performed by a specialist nurse of an outsourced medical call center. After medical and pharmaceutical validation, early preparations (D-1) for expensive and non-expensive molecules are performed. RESULTS: The program is started in February 2016. After 3 months, 382 patients were included into the program. Twenty-three patients on average are called per day related to 1162 completed clinical questionnaires (87%). Among the files, 47% are complete at D-2 (biological and clinical data). The early preparation rate of expensive drugs, zero before the program for financial reasons, has reached 40% at 3 months. The destroyed preparation rate because of non-administration decreased from 5 to 2%. DISCUSSION: Preliminary results show a significant patient compliance, feasibility of early preparation of expensive and non expensive chemotherapy. These are preliminary results of a one-year study. They will be completed by an evaluation of patients' and health professionals' satisfaction, evaluation of length of stay, optimization of operations for clinical departments and CPU. The D-2 biological data collection must be improved. A strong doctor/pharmacist collaboration is essential for better patient care pathway. PMID- 29499999 TI - Randomized Clinical Trial Evaluating Complications and Complication-Related Removal of Arm-Situated Power-Injectable and Non-Power-Injectable Totally Implanted Venous Access Devices among Cancer Patients. AB - PURPOSE: To evaluate the hypothesis that power-injectable (PI) totally implanted venous access devices (TIVADs) situated in the arm are associated with more frequent complications and complication-related removal than non-power-injectable (NPI) arm TIVADs among adult cancer patients. MATERIALS AND METHODS: In this single-center trial, 211 adult chemotherapy patients were randomized to receive either a PI or a NPI arm TIVAD. Follow-up involved a standardized telephone interview 1 week after insertion, followed by a chest X-ray, arm X-ray, and Doppler ultrasound at 3 months and 12 months. Online complication reporting was also provided by patients and care providers for a minimum of 1 year. The primary end point was removal for port-related complications; the secondary end point was the occurrence of any port-related complication. RESULTS: Forty-two complications occurred (19.9% of patients), precipitating the removal of 6 PI ports and 7 standard ports. Time-to-removal did not differ between TIVAD types (hazard ratio 0.75, 95% confidence interval [CI] 0.25-2.24; P = .61). Complications were related to thrombosis, infection, or mechanical issues, with no statistical difference between groups for overall occurrence (23.1% vs 17.0%, odds ratio 1.47, 95% CI 0.74-2.92; P = .27); however, by type of complication, thrombosis occurred more frequently among PI TIVAD patients (15.2% vs 6.1%, odds ratio 2.79, 95% CI 1.04-7.44; P = .03). CONCLUSIONS: There was no difference in port-related complication occurrence or complication-related removal when using the arm PI port compared with the NPI port among cancer patients. PMID- 29500000 TI - Distribution and Detection of Radiopaque Beads after Hepatic Transarterial Embolization in Swine: Cone-Beam CT versus MicroCT. AB - PURPOSE: To determine the true distribution of radiopaque beads (ROBs) after hepatic embolization in swine as imaged by micro-computed tomography (microCT) compared with in vivo cone-beam computerized tomography (CT) imaged at different kVp settings. MATERIALS AND METHODS: Swine (n = 3) underwent hepatic transarterial embolization (n = 6) with the use of 70-150-MUm ROBs under fluoroscopic guidance. After stasis, in vivo cone-beam CT was performed at 120, 100, and 80 kVp. The animal was euthanized, the liver resected, and microCT with 17 MUm resolution performed on embolized tissue samples. The resulting cone-beam CT and microCT data were segmented and registered. Total vessel length, minimum volume-enclosing ellipsoid (MVEE), and number of independent volumes were measured. Maximum-intensity projections (MIPs) were generated for each cone-beam CT. RESULTS: Metrics for all cone-beam CT segmentations differed significantly from microCT segmentations. Segmentations at 80 kVp presented significantly greater vessel length, MVEE, and number of independent volumes compared with 100 kVp and 120 kVp. In addition, 100 kVp segmentations presented significantly greater vessel length than 120 kVp. MIPs presented greater visualization than cone-beam CT segmentations and improved as kVp decreased. CONCLUSIONS: The full ROB distribution was more extensive than was apparent on cone-beam CT. Quantitative measures of embolic distribution demonstrated significantly better correlation with microCT with decreasing kVp. Similarly, qualitative analysis of MIPs showed improved visualization of beads with decreasing kVp. These findings demonstrate the clinical value of 80 kVp and 100 kVp protocols in the imaging of radiopaque embolizations compared with 120 kVp. However, considerations on X-ray penetration and dose may favor use of 100 kVp imaging over 80 kVp. PMID- 29500001 TI - Flexible flatfoot of 6-13-year-old children: A cross-sectional study. AB - BACKGROUND: This cross-sectional study aims to investigate the flexible flatfoot (FFF) prevalence and related factors in school-aged children. METHODS: A total of 1059 children aged 6-13 years were included. Dynamic footprints according to the FootScan system were collected from both feet. The relationship of FFF with age, gender, side, and body mass index (BMI) was investigated. RESULTS: FFF percentage decreased from 39.5% at 6 years to 11.8% at 12 years and reached a plateau at 12 13 years. Overweight (OR 1.35, 95%CI 1.03-1.77, P = 0.03) and obese (OR 2.43, 95%CI 1.81-3.26, P<0.01) showed a positive correlation with percentage of FFF children. No correlation was found between FFF prevalence and gender or side. CONCLUSIONS: FFF prevalence decreases with age and reaches a plateau at 12-13 years. Moreover, FFF prevalence is positively correlated with increased BMI and body height. PMID- 29500002 TI - Improved retransplant outcomes: early evidence of the share35 impact. AB - BACKGROUND: Share 35 prioritizes offers of deceased donor livers to regional candidates with Model for End-Stage Liver Disease (MELD) >=35 over local candidates with lower MELD scores. Analysis of Share35 has shown that overall 1- or 2-year post-transplant (LTx) outcomes have been unchanged while waitlist mortality has been reduced. However, these studies exclude retransplant (reLTx) recipients. This study aims to investigate the outcomes of liver retransplants in evaluating the impact of the Share35 policy. METHODS: A retrospective analysis of data from the United Network for Organ Sharing database over the period June 2011 June 2015 was performed. RESULTS: A total of 19,748 LTx and 312 reLTx recipients were identified. Of the LTx recipients, 9626 (48.7%) underwent transplant pre Share 35 and 10,122 (51.3%) post-Share 35. 123 (39.4%) reLTx recipients underwent retransplantation pre-Share 35 and 189 (60.6%) post-Share 35. ReLTx recipients experienced improved 2-year graft survival post-Share 35 compared to pre-Share 35 (67% vs. 21.1%). Patient survival also improved at 2-years for reLTx recipients post-Share 35 compared to pre-Share 35 (69.2% vs. 33.1%). Transplant post-Share 35 was protective for both 2-year graft (HR = 0.669, CI = 0.454-0.985, p = 0.04) and patient (HR = 0.659, CI = 0.44-0.987, p = 0.003) survival. CONCLUSION: Share35 is associated with improved outcomes after retransplantation. PMID- 29500003 TI - Emerging In Vitro 3D Tumour Models in Nanoparticle-Based Gene and Drug Therapy. AB - 3D models are emerging as valuable tools for personalised nanoparticle-based cancer treatments. 3D models represent in vivo cancers more realistically than 2D patterns that are grown in Petri dishes. However, creating a 3D cancer model that mimics the complexity and heterogeneity of cancers in vivo remains difficult. PMID- 29500004 TI - Microbial Production of l-Serine from Renewable Feedstocks. AB - l-Serine is a non-essential amino acid that has wide and expanding applications in industry with a fast-growing market demand. Currently, extraction and enzymatic catalysis are the main processes for l-serine production. However, such approaches limit the industrial-scale applications of this important amino acid. Therefore, shifting to the direct fermentative production of l-serine from renewable feedstocks has attracted increasing attention. This review details the current status of microbial production of l-serine from renewable feedstocks. We also summarize the current trends in metabolic engineering strategies and techniques for the typical industrial organisms Corynebacterium glutamicum and Escherichia coli that have been developed to address and overcome major challenges in the l-serine production process. PMID- 29500005 TI - Simultaneous Removal of Multicomponent VOCs in Biofilters. AB - Volatile organic compounds (VOCs) are significant atmospheric pollutants that cause environmental and health risks. Waste gases polluted with multiple VOCs often need to be purified simultaneously in biofilters, which may lead to antagonistic, neutral, or synergistic effects on removal performance. Antagonism limits the application of biofilters to simultaneous treatment of multiple VOCs, while synergism has not yet been fully exploited. We review the interactions among multiple target pollutants and the changes in the bioavailability and biodegradability of substrates that are responsible for substrate interactions. Potential strategies for enhancing biofilter performance are then discussed. Finally, we propose further efforts to alleviate antagonism by enhancing bioavailability and biodegradability, and discuss possible challenges to take advantage of synergism. PMID- 29500006 TI - Hacking Hackathons: Preparing the next generation for the multidisciplinary world of healthcare technology. AB - OBJECTIVE: Machine learning in healthcare, and innovative healthcare technology in general, require complex interactions within multidisciplinary teams. Healthcare hackathons are being increasingly used as a model for cross disciplinary collaboration and learning. The aim of this study is to explore high school student learning experiences during a healthcare hackathon. By optimizing their learning experiences, we hope to prepare a future workforce that can bridge technical and health fields and work seamlessly across disciplines. METHODS: A qualitative exploratory study utilizing focus group interviews was conducted. Eight high school students from the hackathon were invited to participate in this study through convenience sampling Participating students (n = 8) were allocated into three focus groups. Semi structured interviews were completed, and transcripts evaluated using inductive thematic analysis. FINDINGS: Through the structured analysis of focus group transcripts three major themes emerged from the data: (1) Collaboration, (2) Transferable knowledge and skills, and (3) Expectations about hackathons. These themes highlight strengths and potential barriers when bringing this multidisciplinary approach to high school students and the healthcare community. CONCLUSION: This study found that students were empowered by the interdisciplinary experience during a hackathon and felt that the knowledge and skills gained could be applied in real world settings. However, addressing student expectations of hackathons prior to the event is an area for improvement. These findings have implications for future hackathons and can spur further research into using the hackathon model as an educational experience for learners of all ages. PMID- 29500007 TI - eHealth, ICT and its relationship with self-reported health outcomes in the EU countries. AB - This work contributes to the discussion on the relationship between ICT and ehealth solutions in primary care, and self-reported health and health status in the European Union. The method used is an ordinary least squares linear model. The results show that there is no significant relation between self-reported health outcomes and ICT and ehealth indexes, except for self-reported chronic health problems. The more advanced that countries are in ICT, the larger is the share of people reporting a chronic health problem. This provides evidence on the existence of a link between chronic patients and ICT development. PMID- 29500008 TI - Experiences of building a medical data acquisition system based on two-level modeling. AB - BACKGROUND AND PURPOSE: Compared to traditional software development strategies, the two-level modeling approach is more flexible and applicable to build an information system in the medical domain. However, the standards of two-level modeling such as openEHR appear complex to medical professionals. This study aims to investigate, implement, and improve the two-level modeling approach, and discusses the experience of building a unified data acquisition system for four affiliated university hospitals based on this approach. METHOD: After the investigation, we simplified the approach of archetype modeling and developed a medical data acquisition system where medical experts can define the metadata for their own specialties by using a visual easy-to-use tool. RESULT: The medical data acquisition system for multiple centers, clinical specialties, and diseases has been developed, and integrates the functions of metadata modeling, form design, and data acquisition. To date, 93,353 data items and 6,017 categories for 285 specific diseases have been created by medical experts, and over 25,000 patients' information has been collected. DISCUSSION AND CONCLUSION: OpenEHR is an advanced two-level modeling method for medical data, but its idea to separate domain knowledge and technical concern is not easy to realize. Moreover, it is difficult to reach an agreement on archetype definition. Therefore, we adopted simpler metadata modeling, and employed What-You-See-Is-What-You-Get (WYSIWYG) tools to further improve the usability of the system. Compared with the archetype definition, our approach lowers the difficulty. Nevertheless, to build such a system, every participant should have some knowledge in both medicine and information technology domains, as these interdisciplinary talents are necessary. PMID- 29500009 TI - A framework for m-health service development and success evaluation. AB - The emergence of mobile technology has influenced many service industries including health care. Mobile health (m-Health) applications have been used widely, and many services have been developed that have changed delivery systems and have improved effectiveness of health care services. Stakeholders of m-Health services have various resources and rights that lends to a complexity in service delivery. In addition, abundance of different m-Health services makes it difficult to choose an appropriate service for these stakeholders that include customers, patients, users or even providers. Moreover, a comprehensive framework is not yet provided in the literature that would help manage and evaluate m health services, considering various stakeholder's benefits. In this paper, a comprehensive literature review has been done on famous frameworks and models in the field of Information Technology and electronic health with the aim of finding different aspects of developing and managing m-health services. Using the results of literature review and conducting a stakeholder analysis, we have proposed an m health evaluation framework which evaluates the success of a given m-health service through a three-stage life cycle: (1) Service Requirement Analysis, (2) Service Development, and (3) Service Delivery. Key factors of m-health evaluation in each step are introduced in the proposed framework considering m-health key stakeholder's benefits. The proposed framework is validated via expert interviews, and key factors in each evaluation step is validated using PLS model. Results show that path coefficients are higher than their threshold which supports the validity of proposed framework. PMID- 29500010 TI - Physician satisfaction with a critical care clinical information system using a multimethod evaluation of usability. AB - INTRODUCTION: Physician satisfaction with electronic medical records has often been poor. Usability has frequently been identified as a source for decreased satisfaction. While surveys can identify many issues, and are logistically easier to administer, they may miss issues identified using other methods This study sought to understand the level of physician satisfaction and usability issues associated with a critical care clinical information system (eCritical Alberta) implemented throughout the province of Alberta, Canada. METHOD: All critical care attending physicians using the system were invited to participate in an online survey. Questions included components of the User Acceptance of Information Technology and Usability Questionnaire as well as free text feedback on system components. Physicians were also invited to participate in a think aloud test using simulated scenarios. The transcribed think aloud text and questionnaire were subjected to textual analysis. RESULTS: 82% of all eligible physicians completed the on-line survey (n = 61). Eight physicians were invited and seven completed the think aloud test. Overall satisfaction with the system was moderate. Usability was identified as a significant factor contributing to satisfaction. The major usability factors identified were system response time and layout. The think aloud component identified additional factors beyond those identified in the on-line survey. CONCLUSION: This study found a modestly high level of physician satisfaction with a province-wide clinical critical care information system. Usability continues to be a significant factor in physician satisfaction. Using multiple methods of evaluation can capture the benefits of a large sample size and deeper understanding of the issues. PMID- 29500011 TI - Individual dose-response models for levodopa infusion dose optimization. AB - BACKGROUND AND OBJECTIVE: To achieve optimal effect with continuous infusion treatment in Parkinson's disease (PD), the individual doses (morning dose and continuous infusion rate) are titrated by trained medical personnel. This study describes an algorithmic method to derive optimized dosing suggestions for infusion treatment of PD, by fitting individual dose-response models. The feasibility of the proposed method was investigated using patient chart data. METHODS: Patient records were collected at Uppsala University hospital which provided dosing information and dose-response evaluations. Mathematical optimization was used to fit individual patient models using the records' information, by minimizing an objective function. The individual models were passed to a dose optimization algorithm, which derived an optimized dosing suggestion for each patient model. RESULTS: Using data from a single day's admission the algorithm showed great ability to fit appropriate individual patient models and derive optimized doses. The infusion rate dosing suggestions had 0.88 correlation and 10% absolute mean relative error compared to the optimal doses as determined by the hospital's treating team. The morning dose suggestions were consistency lower that the optimal morning doses, which could be attributed to different dosing strategies and/or lack of on-off evaluations in the morning. CONCLUSION: The proposed method showed promise and could be applied in clinical practice, to provide the hospital personnel with additional information when making dose adjustment decisions. PMID- 29500012 TI - Interface design dividing physical findings into medical and trauma findings facilitates clinical document entry in the emergency department: A prospective observational study. AB - PURPOSE: The interface design and its effect on workflow are key determinants of the usability of electronic medical records (EMRs) in the emergency department (ED). However, whether the overall clinical care can be improved by dividing the interface design of physical findings into medical and trauma findings is unknown. We previously developed an EMR system in which the checkpoints were separated into different sections according to the body part. Herein, we modified this EMR system by remaking the interface design specifically for trauma patients, and evaluated its performance. METHODS: This study was undertaken in a single-center ED between October 2014 and September 2015. In the modified EMR system, all trauma findings are displayed together on the screen, according to the Japan Advanced Trauma Evaluation and Care. We compared the time to final documentation entry and the length of ED stay between the previous (used in the first 6 months) and current systems (used in the latter 6 months). Furthermore, we stratified the patients by triage levels. RESULTS: The study involved 2141 patients (934 and 1207 assessed using the previous and modified EMR systems, respectively). The modified EMR in trauma patients significantly decreased the time to final documentation entry from 131.5 [interquartile range, 86.8-207.3] to 115 [78.8-161] min (p = 0.049). When stratifying trauma patients by triage level, significantly shorter clinical documentation times were observed with the modified EMR system in levels 2 (emergency) and 3 (urgent). CONCLUSIONS: Using different interfaces for trauma findings shortened the time for clinical documentation for trauma patients. PMID- 29500013 TI - Applying natural language processing techniques to develop a task-specific EMR interface for timely stroke thrombolysis: A feasibility study. AB - OBJECTIVE: To reduce errors in determining eligibility for intravenous thrombolytic therapy (IVT) in stroke patients through use of an enhanced task specific electronic medical record (EMR) interface powered by natural language processing (NLP) techniques. MATERIALS AND METHODS: The information processing algorithm utilized MetaMap to extract medical concepts from IVT eligibility criteria and expanded the concepts using the Unified Medical Language System Metathesaurus. Concepts identified from clinical notes by MetaMap were compared to those from IVT eligibility criteria. The task-specific EMR interface displays IVT-relevant information by highlighting phrases that contain matched concepts. Clinical usability was assessed with clinicians staffing the acute stroke team by comparing user performance while using the task-specific and the current EMR interfaces. RESULTS: The algorithm identified IVT-relevant concepts with micro averaged precisions, recalls, and F1 measures of 0.998, 0.812, and 0.895 at the phrase level and of 1, 0.972, and 0.986 at the document level. Users using the task-specific interface achieved a higher accuracy score than those using the current interface (91% versus 80%, p = 0.016) in assessing the IVT eligibility criteria. The completion time between the interfaces was statistically similar (2.46 min versus 1.70 min, p = 0.754). DISCUSSION: Although the information processing algorithm had room for improvement, the task-specific EMR interface significantly reduced errors in assessing IVT eligibility criteria. CONCLUSION: The study findings provide evidence to support an NLP enhanced EMR system to facilitate IVT decision-making by presenting meaningful and timely information to clinicians, thereby offering a new avenue for improvements in acute stroke care. PMID- 29500014 TI - An ensemble boosting model for predicting transfer to the pediatric intensive care unit. AB - BACKGROUND: Early deterioration indicators have the potential to alert hospital care staff in advance of adverse events, such as patients requiring an increased level of care, or the need for rapid response teams to be called. Our work focuses on the problem of predicting the transfer of pediatric patients from the general ward of a hospital to the pediatric intensive care unit. OBJECTIVES: The development of a data-driven pediatric early deterioration indicator for use by clinicians with the purpose of predicting encounters where transfer from the general ward to the PICU is likely. METHODS: Using data collected over 5.5 years from the electronic health records of two medical facilities, we develop machine learning classifiers based on adaptive boosting and gradient tree boosting. We further combine these learned classifiers into an ensemble model and compare its performance to a modified pediatric early warning score (PEWS) baseline that relies on expert defined guidelines. To gauge model generalizability, we perform an inter-facility evaluation where we train our algorithm on data from one facility and perform evaluation on a hidden test dataset from a separate facility. RESULTS: We show that improvements are witnessed over the modified PEWS baseline in accuracy (0.77 vs. 0.69), sensitivity (0.80 vs. 0.68), specificity (0.74 vs. 0.70) and AUROC (0.85 vs. 0.73). CONCLUSIONS: Data-driven, machine learning algorithms can improve PICU transfer prediction accuracy compared to expertly defined systems, such as a modified PEWS, but care must be taken in the training of such approaches to avoid inadvertently introducing bias into the outcomes of these systems. PMID- 29500015 TI - Agent-based computational models to explore diffusion of medical innovations among cardiologists. AB - BACKGROUND: Diffusion of medical innovations among physicians rests on a set of theoretical assumptions, including learning and decision-making under uncertainty, social-normative pressures, medical expert knowledge, competitive concerns, network performance effects, professional autonomy or individualism and scientific evidence. OBJECTIVES: The aim of this study was to develop and test four real data-based, agent-based computational models (ABM) to qualitatively and quantitatively explore the factors associated with diffusion and application of innovations among cardiologists. METHODS: Four ABM were developed to study diffusion and application of medical innovations among cardiologists, considering physicians' network connections, leaders' opinions, "adopters' categories", physicians' autonomy, scientific evidence, patients' pressure, affordability for the end-user population, and promotion from companies. RESULTS: Simulations demonstrated that social imitation among local cardiologists was sufficient for innovation diffusion, as long as opinion leaders did not act as detractors of the innovation. Even in the absence of full scientific evidence to support innovation, up to one-fifth of cardiologists could accept it when local leaders acted as promoters. Patients' pressure showed a large effect size (Cohen's d > 1.2) on the proportion of cardiologists applying an innovation. Two qualitative patterns (speckled and granular) appeared associated to traditional Gompertz and sigmoid cumulative distributions. CONCLUSIONS: These computational models provided a semiquantitative insight on the emergent collective behavior of a physician population facing the acceptance or refusal of medical innovations. Inclusion in the models of factors related to patients' pressure and accesibility to medical coverage revealed the contrast between accepting and effectively adopting a new product or technology for population health care. PMID- 29500016 TI - Validation of the ICU-DaMa tool for automatically extracting variables for minimum dataset and quality indicators: The importance of data quality assessment. AB - BACKGROUND: Big data analytics promise insights into healthcare processes and management, improving outcomes while reducing costs. However, data quality is a major challenge for reliable results. Business process discovery techniques and an associated data model were used to develop data management tool, ICU-DaMa, for extracting variables essential for overseeing the quality of care in the intensive care unit (ICU). OBJECTIVE: To determine the feasibility of using ICU DaMa to automatically extract variables for the minimum dataset and ICU quality indicators from the clinical information system (CIS). METHODS: The Wilcoxon signed-rank test and Fisher's exact test were used to compare the values extracted from the CIS with ICU-DaMa for 25 variables from all patients attended in a polyvalent ICU during a two-month period against the gold standard of values manually extracted by two trained physicians. Discrepancies with the gold standard were classified into plausibility, conformance, and completeness errors. RESULTS: Data from 149 patients were included. Although there were no significant differences between the automatic method and the manual method, we detected differences in values for five variables, including one plausibility error and two conformance and completeness errors. Plausibility: 1) Sex, ICU-DaMa incorrectly classified one male patient as female (error generated by the Hospital's Admissions Department). Conformance: 2) Reason for isolation, ICU-DaMa failed to detect a human error in which a professional misclassified a patient's isolation. 3) Brain death, ICU-DaMa failed to detect another human error in which a professional likely entered two mutually exclusive values related to the death of the patient (brain death and controlled donation after circulatory death). Completeness: 4) Destination at ICU discharge, ICU-DaMa incorrectly classified two patients due to a professional failing to fill out the patient discharge form when thepatients died. 5) Length of continuous renal replacement therapy, data were missing for one patient because the CRRT device was not connected to the CIS. CONCLUSIONS: Automatic generation of minimum dataset and ICU quality indicators using ICU-DaMa is feasible. The discrepancies were identified and can be corrected by improving CIS ergonomics, training healthcare professionals in the culture of the quality of information, and using tools for detecting and correcting data errors. PMID- 29500017 TI - A fuzzy logic control in adjustable autonomy of a multi-agent system for an automated elderly movement monitoring application. AB - Autonomous agents are being widely used in many systems, such as ambient assisted living systems, to perform tasks on behalf of humans. However, these systems usually operate in complex environments that entail uncertain, highly dynamic, or irregular workload. In such environments, autonomous agents tend to make decisions that lead to undesirable outcomes. In this paper, we propose a fuzzy logic-based adjustable autonomy (FLAA) model to manage the autonomy of multi agent systems that are operating in complex environments. This model aims to facilitate the autonomy management of agents and help them make competent autonomous decisions. The FLAA model employs fuzzy logic to quantitatively measure and distribute autonomy among several agents based on their performance. We implement and test this model in the Automated Elderly Movements Monitoring (AEMM-Care) system, which uses agents to monitor the daily movement activities of elderly users and perform fall detection and prevention tasks in a complex environment. The test results show that the FLAA model improves the accuracy and performance of these agents in detecting and preventing falls. PMID- 29500018 TI - Perceptions of the use of intelligent information access systems in university level active learning activities among teachers of biomedical subjects. AB - BACKGROUND: Student participation and the use of active methodologies in classroom learning are being increasingly emphasized. The use of intelligent systems can be of great help when designing and developing these types of activities. Recently, emerging disciplines such as 'educational data mining' and 'learning analytics and knowledge' have provided clear examples of the importance of the use of artificial intelligence techniques in education. OBJECTIVE: The main objective of this study was to gather expert opinions regarding the benefits of using complementary methods that are supported by intelligent systems, specifically, by intelligent information access systems, when processing texts written in natural language and the benefits of using these methods as companion tools to the learning activities that are employed by biomedical and health sciences teachers. METHODS: Eleven teachers of degree courses who belonged to the Faculties of Biomedical Sciences (BS) and Health Sciences (HS) of a Spanish university in Madrid were individually interviewed. These interviews were conducted using a mixed methods questionnaire that included 66 predefined close ended and open-ended questions. In our study, three intelligent information access systems (i.e., BioAnnote, CLEiM and MedCMap) were successfully used to evaluate the teacher's perceptions regarding the utility of these systems and their different methods in learning activities. RESULTS: All teachers reported using active learning methods in the classroom, most of which were computer programs that were used for initially designing and later executing learning activities. All teachers used case-based learning methods in the classroom, with a specific emphasis on case reports written in Spanish and/or English. In general, few or none of the teachers were familiar with the technical terms related to the technologies used for these activities such as "intelligent systems" or "concept/mental maps". However, they clearly realized the potential applicability of such approaches in both the preparation and the effective use of these activities in the classroom. Specifically, the themes highlighted by a greater number of teachers after analyzing the responses to the open-ended questions were the usefulness of BioAnnote system to provide reliable sources of medical information and the usefulness of the bilingual nature of CLEiM system for learning medical terminology in English. CONCLUSIONS: Three intelligent information access systems were successfully used to evaluate the teacher's perceptions regarding the utility of these systems in learning activities. The results of this study showed that integration of reliable sources of information, bilingualism and selective annotation of concepts were the most valued features by the teachers, who also considered the incorporation of these systems into learning activities to be potentially very useful. In addition, in the context of our experimental conditions, our work provides useful insights into the way to appropriately integrate this type of intelligent information access systems into learning activities, revealing key themes to consider when developing such approaches. PMID- 29500019 TI - Patients' intention to use online postings of ED wait times: A modified UTAUT model. AB - BACKGROUND: As health care becomes more reliant on technology, a better understanding of the factors that contribute to acceptance and use of technology is now critical. The Unified Theory of Acceptance and Use of Technology (UTAUT) has been applied to study a variety of technologies in different settings, and it is one of the most cited theories in Information Systems (IS) research. However, there has been limited application of UTAUT to health IT and, in particular, to patients' IT use. OBJECTIVES: The aim of this study is to adapt UTAUT to the context of patient acceptance and use of an Emergency Department (ED) wait-times website, and to empirically test the modified model and compare the results to those of the original UTAUT model. Specifically, it is proposed that there will be a significant relationship between facilitating conditions and behavioral intention. METHODS: A survey of patients in the ED of a Canadian hospital was conducted, yielding 118 completed surveys, and subsequently analyzed using Partial least squares (PLS). RESULTS: This study found that the modified UTAUT produced a substantial improvement in variance explained in behavioral intention compared to the original UTAUT (66% versus 46%). The modified-UTAUT model showed significant effects in performance expectancy (r = 0.302, p < 0.01) and facilitating conditions (r = 0.539, p < 0.001) on behavioral intention to use the website, while the effort expectancy impact was not significant. CONCLUSIONS: This study provides empirical support for the modified-UTAUT in the context of patients' intention to use an ED wait times website. Some results of this study support prior research, while some differ, such as the non-significant relationship between effort expectancy and behavioral intention and the finding that performance expectancy is not the main driver of intention to use. As proposed, facilitating conditions - having the resources necessary to view the website and having the ability to find the website - were the most important factors influencing behavioral intention. UTAUT is a key theoretical advance in IS research and by modifying it to the context of patient use, we contribute to both IS and health research. PMID- 29500020 TI - Assessing team effectiveness and affective learning in a datathon. AB - BACKGROUND: Datathons are increasingly organized in the healthcare field. The goal is to assemble people with different backgrounds to work together as a team and engage in clinically relevant research or develop algorithms using health related datasets. Criteria to assess the return of investment on such events have traditionally included publications produced, patents for prediction, classification, image recognition and other types of software, and start-up companies around the application of machine learning in healthcare. Previous studies have not evaluated whether a datathon can promote affective learning and effective teamwork. METHODS: Fifty participants of a health datathon event in Sao Paulo, Brazil at Hospital Israelita Albert Einstein (HIAE) were divided into 8 groups. A survey with 25 questions, using the Affective Learning Scale and Team Review Questionnaire, was administered to assess team effectiveness and affective learning during the event. Multivariate regression models and Pearson's correlation tests were performed to evaluate the effect of affective learning on teamwork. RESULTS: Majority of the participants were male 76% (37/49); 32% (16/49) were physicians. The mean score for learning (scale from 1 to 10) was 8.38, while that for relevance of the perceived teamwork was 1.20 (scale from 1 to 5; "1" means most relevant). Pearson's correlation between the learning score and perception of teamwork showed moderate association (r = 0.36, p = 0.009). Five learning and 10 teamwork variables were on average positively graded in the event. The final regression model includes all learning and teamwork variables. Effective leadership was strongly correlated with affective learning (beta = 0.27, p < 0.01, R2 = 75%). Effective leadership, team accomplishment, criticism, individual development and creativity were the variables significantly associated with higher levels of affective learning. CONCLUSION: It is feasible to enhance affective knowledge and the skill to work in a team during a datathon. We found that teamwork is associated with higher affective learning from participants' perspectives. Effective leadership is essential for teamwork and is a significant predictor of learning. PMID- 29500021 TI - The impact of media type on shared decision processes in third-age populations. AB - PURPOSE: To examine the relationship between the media, through which medical information was made available (e.g. digital versus printed), and the patients' desire to play an active part in a medical decision in an SDM or an ISDM-based process. The goal of this research was to expand knowledge concerning social and personal factors that affect and explain patients' willingness to participate in the process. METHODS: A questionnaire was distributed in this empirical study of 103 third-age participants. A theoretical model formed the basis for the study and utilized a variety of factors from technology acceptance, as well as personal and environmental influences to investigate the likelihood of subjects preferring a certain decision-making approach. The research population included men and women aged 65 or older who resided in five assisted living facilities in Israel. The sample was split randomly into 2 groups. One group used digital information and the other print. A path analysis was conducted, using Structural Equation Modelling (SEM) in AMOS SPSS, to determine the influence of the information mode of presentation on the patient's choice of the SDM or ISDM model. RESULTS: When digital media was accessible, the information's perceived usefulness (PU) led participants to choose an ISDM-based process; this was not true with printed information. When information was available online, higher self-efficacy (SE) led participants to prefer an SDM-based process. When the information was available in print, a direct positive influence was found on the participant's choice of SDM, while a direct negative influence was found on their choice of an ISDM-based process. PU was found to be affected by external peer influences, particularly when resources were made available in print. This meant that digital resources tended to be accepted at face value more readily. Cognitive absorption had a positive effect on the research variables only when the information was available digitally. The findings suggest the use of digital information may be related to cognitive functions of older adults, since the use of digital technology and information requires more cognitive effort. CONCLUSIONS: The study illustrates factors that make patients choose SDM or ISDM-based processes in third-age populations. In general, the results suggest that, even though a physician may attempt to place the patient in the center of the decision process, printed information does not empower the patient in the same way that digital resources do. This may have wider ramifications if the patient does not buy into the treatment plan is and becomes less motivated to be compliant with the treatment. Another key contribution of this research is to identify processes that reflect information assessment and adoptions, and the behaviors related to medical decision making, both as a model and as a process. This study suggests what health care professionals should expect to see as the transition to more digital information sources becomes the norm among the elderly population. Future research is needed to examine this model under different conditions, and to check for other variables and mechanisms perceived as mediators in the choice of SDM or ISDM processes. PMID- 29500022 TI - Federated learning of predictive models from federated Electronic Health Records. AB - BACKGROUND: In an era of "big data," computationally efficient and privacy-aware solutions for large-scale machine learning problems become crucial, especially in the healthcare domain, where large amounts of data are stored in different locations and owned by different entities. Past research has been focused on centralized algorithms, which assume the existence of a central data repository (database) which stores and can process the data from all participants. Such an architecture, however, can be impractical when data are not centrally located, it does not scale well to very large datasets, and introduces single-point of failure risks which could compromise the integrity and privacy of the data. Given scores of data widely spread across hospitals/individuals, a decentralized computationally scalable methodology is very much in need. OBJECTIVE: We aim at solving a binary supervised classification problem to predict hospitalizations for cardiac events using a distributed algorithm. We seek to develop a general decentralized optimization framework enabling multiple data holders to collaborate and converge to a common predictive model, without explicitly exchanging raw data. METHODS: We focus on the soft-margin l1-regularized sparse Support Vector Machine (sSVM) classifier. We develop an iterative cluster Primal Dual Splitting (cPDS) algorithm for solving the large-scale sSVM problem in a decentralized fashion. Such a distributed learning scheme is relevant for multi institutional collaborations or peer-to-peer applications, allowing the data holders to collaborate, while keeping every participant's data private. RESULTS: We test cPDS on the problem of predicting hospitalizations due to heart diseases within a calendar year based on information in the patients Electronic Health Records prior to that year. cPDS converges faster than centralized methods at the cost of some communication between agents. It also converges faster and with less communication overhead compared to an alternative distributed algorithm. In both cases, it achieves similar prediction accuracy measured by the Area Under the Receiver Operating Characteristic Curve (AUC) of the classifier. We extract important features discovered by the algorithm that are predictive of future hospitalizations, thus providing a way to interpret the classification results and inform prevention efforts. PMID- 29500023 TI - Bayesian averaging over decision tree models: An application for estimating uncertainty in trauma severity scoring. AB - INTRODUCTION: For making reliable decisions, practitioners need to estimate uncertainties that exist in data and decision models. In this paper we analyse uncertainties of predicting survival probability for patients in trauma care. The existing prediction methodology employs logistic regression modelling of Trauma and Injury Severity Score (TRISS), which is based on theoretical assumptions. These assumptions limit the capability of TRISS methodology to provide accurate and reliable predictions. METHODS: We adopt the methodology of Bayesian model averaging and show how this methodology can be applied to decision trees in order to provide practitioners with new insights into the uncertainty. The proposed method has been validated on a large set of 447,176 cases registered in the US National Trauma Data Bank in terms of discrimination ability evaluated with receiver operating characteristic (ROC) and precision-recall (PRC) curves. RESULTS: Areas under curves were improved for ROC from 0.951 to 0.956 (p = 3.89 * 10-18) and for PRC from 0.564 to 0.605 (p = 3.89 * 10-18). The new model has significantly better calibration in terms of the Hosmer-Lemeshow H^ statistic, showing an improvement from 223.14 (the standard method) to 11.59 (p = 2.31 * 10 18). CONCLUSION: The proposed Bayesian method is capable of improving the accuracy and reliability of survival prediction. The new method has been made available for evaluation purposes as a web application. PMID- 29500024 TI - Behind the scenes: A medical natural language processing project. AB - Advancement of Artificial Intelligence (AI) capabilities in medicine can help address many pressing problems in healthcare. However, AI research endeavors in healthcare may not be clinically relevant, may have unrealistic expectations, or may not be explicit enough about their limitations. A diverse and well functioning multidisciplinary team (MDT) can help identify appropriate and achievable AI research agendas in healthcare, and advance medical AI technologies by developing AI algorithms as well as addressing the shortage of appropriately labeled datasets for machine learning. In this paper, our team of engineers, clinicians and machine learning experts share their experience and lessons learned from their two-year-long collaboration on a natural language processing (NLP) research project. We highlight specific challenges encountered in cross disciplinary teamwork, dataset creation for NLP research, and expectation setting for current medical AI technologies. PMID- 29500025 TI - A six-year repeated evaluation of computerized clinical decision support system user acceptability. AB - OBJECTIVE: Long-term acceptability among computerized clinical decision support system (CDSS) users in pediatrics is unknown. We examine user acceptance patterns over six years of our continuous computerized CDSS integration and updates. MATERIALS AND METHODS: Users of Child Health Improvement through Computer Automation (CHICA), a CDSS integrated into clinical workflows and used in several urban pediatric community clinics, completed annual surveys including 11 questions covering user acceptability. We compared responses across years within a single healthcare system and between two healthcare systems. We used logistic regression to assess the odds of a favorable response to each question by survey year, clinic role, part-time status, and frequency of CHICA use. RESULTS: Data came from 380 completed surveys between 2011 and 2016. Responses were significantly more favorable for all but one measure by 2016 (OR range 2.90 12.17, all p < 0.01). Increasing system maturity was associated with improved perceived function of CHICA (OR range 4.24-7.58, p < 0.03). User familiarity was positively associated with perceived CDSS function (OR range 3.44-8.17, p < 0.05) and usability (OR range 9.71-15.89, p < 0.01) opinions. CONCLUSION: We present a long-term, repeated follow-up of user acceptability of a CDSS. Favorable opinions of the CDSS were more likely in frequent users, physicians and advanced practitioners, and full-time workers. CHICA acceptability increased as it matured and users become more familiar with it. System quality improvement, user support, and patience are important in achieving wide-ranging, sustainable acceptance of CDSS. PMID- 29500027 TI - Trusting telemedicine: A discussion on risks, safety, legal implications and liability of involved stakeholders. AB - OBJECTIVES: The main purpose of the article is to raise awareness among all the involved stakeholders about the risks and legal implications connected to the development and use of modern telemedicine systems. Particular focus is given to the class of "active" telemedicine systems, that imply a real-world, non mediated, interaction with the final user. A secondary objective is to give an overview of the European legal framework that applies to these systems, in the effort to avoid defensive medicine practices and fears, which might be a barrier to their broader adoption. METHODS: We leverage on the experience gained during two international telemedicine projects, namely MobiGuide (pilot studies conducted in Spain and Italy) and AP@home (clinical trials enrolled patients in Italy, France, the Netherlands, United Kingdom, Austria and Germany), whose development our group has significantly contributed to in the last 4 years, to create a map of the potential criticalities of active telemedicine systems and comment upon the legal framework that applies to them. Two workshops have been organized in December 2015 and March 2016 where the topic has been discussed in round tables with system developers, researchers, physicians, nurses, legal experts, healthcare economists and administrators. RESULTS: We identified 8 features that generate relevant risks from our example use cases. These features generalize to a broad set of telemedicine applications, and suggest insights on possible risk mitigation strategies. We also discuss the relevant European legal framework that regulate this class of systems, providing pointers to specific norms and highlighting possible liability profiles for involved stakeholders. CONCLUSIONS: Patients are more and more willing to adopt telemedicine systems to improve home care and day-by-day self-management. An essential step towards a broader adoption of these systems consists in increasing their compliance with existing regulations and better defining responsibilities for all the involved stakeholders. PMID- 29500026 TI - Critical Care Health Informatics Collaborative (CCHIC): Data, tools and methods for reproducible research: A multi-centre UK intensive care database. AB - OBJECTIVE: To build and curate a linkable multi-centre database of high resolution longitudinal electronic health records (EHR) from adult Intensive Care Units (ICU). To develop a set of open-source tools to make these data 'research ready' while protecting patient's privacy with a particular focus on anonymisation. MATERIALS AND METHODS: We developed a scalable EHR processing pipeline for extracting, linking, normalising and curating and anonymising EHR data. Patient and public involvement was sought from the outset, and approval to hold these data was granted by the NHS Health Research Authority's Confidentiality Advisory Group (CAG). The data are held in a certified Data Safe Haven. We followed sustainable software development principles throughout, and defined and populated a common data model that links to other clinical areas. RESULTS: Longitudinal EHR data were loaded into the CCHIC database from eleven adult ICUs at 5 UK teaching hospitals. From January 2014 to January 2017, this amounted to 21,930 and admissions (18,074 unique patients). Typical admissions have 70 data-items pertaining to admission and discharge, and a median of 1030 (IQR 481-2335) time-varying measures. Training datasets were made available through virtual machine images emulating the data processing environment. An open source R package, cleanEHR, was developed and released that transforms the data into a square table readily analysable by most statistical packages. A simple language agnostic configuration file will allow the user to select and clean variables, and impute missing data. An audit trail makes clear the provenance of the data at all times. DISCUSSION: Making health care data available for research is problematic. CCHIC is a unique multi-centre longitudinal and linkable resource that prioritises patient privacy through the highest standards of data security, but also provides tools to clean, organise, and anonymise the data. We believe the development of such tools are essential if we are to meet the twin requirements of respecting patient privacy and working for patient benefit. CONCLUSION: The CCHIC database is now in use by health care researchers from academia and industry. The 'research ready' suite of data preparation tools have facilitated access, and linkage to national databases of secondary care is underway. PMID- 29500028 TI - Presenting an evaluation model of the trauma registry software. AB - OBJECTIVE: Trauma is a major cause of 10% death in the worldwide and is considered as a global concern. This problem has made healthcare policy makers and managers to adopt a basic strategy in this context. Trauma registry has an important and basic role in decreasing the mortality and the disabilities due to injuries resulted from trauma. Today, different software are designed for trauma registry. Evaluation of this software improves management, increases efficiency and effectiveness of these systems. Therefore, the aim of this study is to present an evaluation model for trauma registry software. METHODS: The present study is an applied research. In this study, general and specific criteria of trauma registry software were identified by reviewing literature including books, articles, scientific documents, valid websites and related software in this domain. According to general and specific criteria and related software, a model for evaluating trauma registry software was proposed. Based on the proposed model, a checklist designed and its validity and reliability evaluated. Mentioned model by using of the Delphi technique presented to 12 experts and specialists. To analyze the results, an agreed coefficient of %75 was determined in order to apply changes. Finally, when the model was approved by the experts and professionals, the final version of the evaluation model for the trauma registry software was presented. RESULTS: For evaluating of criteria of trauma registry software, two groups were presented: 1- General criteria, 2- Specific criteria. General criteria of trauma registry software were classified into four main categories including: 1- usability, 2- security, 3- maintainability, and 4 interoperability. Specific criteria were divided into four main categories including: 1- data submission and entry, 2- reporting, 3- quality control, 4- decision and research support. CONCLUSION: The presented model in this research has introduced important general and specific criteria of trauma registry software and sub criteria related to each main criteria separately. This model was validated by experts in this field. Therefore, this model can be used as a comprehensive model and a standard evaluation tool for measuring efficiency and effectiveness and performance improvement of trauma registry software. PMID- 29500029 TI - To wheeze or not to wheeze: the question of RSV prevention. PMID- 29500031 TI - Immunomodulation as Rescue for Chronic Atonic Skin Wounds. AB - Chronic skin wounds, caused by arterial or venous insufficiency or by physical pressure, constitute an increasing medical problem as populations age. Whereas typical wounds are characterized by local inflammation that participates in the healing process, atonic wounds lack inflammatory markers, such as neutrophil infiltration, and generally do not heal. Recently, prominent roles in the immunopathology of chronic wounds were attributed to dysregulations in specific cytokines, chemokines, matrix metalloproteinases (MMPs), and their substrates. Together with the complement system, these molecular players provide necessary defense against infections, initiate angiogenesis, and prepare tissue reconstitution. Here, we review the current state of the field and include the concept that, aside from surgery and stem cell therapy, healing may be enhanced by immunomodulating agents. PMID- 29500030 TI - Respiratory syncytial virus prevention and asthma in healthy preterm infants: a randomised controlled trial. AB - BACKGROUND: Respiratory syncytial virus (RSV) infection is associated with subsequent wheeze and asthma. We previously reported on the causal relationship between prevention of RSV infection during infancy and reduced frequency of subsequent wheeze using a double-blind, randomised, placebo-controlled trial (MAKI). We continued follow-up and analysed the effect of RSV prevention during infancy on asthma and lung function at age 6 years. METHODS: We studied 429 infants born at 32-35 weeks of gestation between 2008-10 who had randomly received either palivizumab for RSV immunoprophylaxis or placebo during the RSV season of their first year of life. After the first year of follow-up, single, assessor-blind follow-up of children continued until they were aged 6 years. Primary outcomes were parent-reported current asthma and forced expiratory volume in 0.5 s (FEV0.5). The trial is registered in the ISRCTN registry, number ISRCTN73641710. FINDINGS: 395 (92%) of 429 participants completed this 6-year follow-up study. Parent-reported current asthma was reported in 28 (14.1%) of 199 children in the RSV prevention group and 47 (24.0%) of 196 children in the placebo group (absolute risk reduction [ARR] 9.9%, 95% CI 2.2 to 17.6). The difference in current asthma, which was a composite endpoint, was due to a difference in infrequent wheeze (one to three episodes in the past year; 12 [6.0%] of 199 vs 26 [13.4%] of 194, ARR 7.4%, 95% CI 1.5 to 13.2). FEV0.5 percentage predicted values were similar between the RSV prevention group (89.1% [SD 10.6]) and placebo group (90.1% [11.1]), with a mean difference of 1.0 (95% CI -1.3 to 3.3). The proportion of children with current physician-diagnosed asthma was similar between the RSV prevention group (19 [10.3%] of 185) and placebo group (18 [9.9%] of 182), with an ARR of -0.4 (95% CI -6.5 to 5.8). INTERPRETATION: In otherwise healthy preterm infants, this single-blind, randomised, placebo-controlled trial showed that RSV prevention did not have a major effect on current asthma or lung function at age 6 years. Future research will inform on the effect of RSV prevention on asthma at school age in the general population. FUNDING: AbbVie. PMID- 29500032 TI - Chronic mucocutaneous candidiasis, a case study and literature review. AB - Chronic mucocutaneous candidiasis (CMC) is a clinically heterogeneous disease. Some immunologic and hormonal abnormalities have been associated with CMC. The factors that predispose host to CMC infection could be autosomal or acquisitive. The disease usually occurs in childhood. Here, we reviewed the published literature on chronic mucocutaneous candidiasis and a four years old girl is presented with CMC. She had a history of recurrent thrush and otomycosis since the age of one. Candida albicans was detected in skin scraping and biopsy samples. Serum iron was low. TSH hormone level was high and T4 level was low. Giardia cysts were found in stool sample. Mucocutaneous and nail manifestations of the disease were disappeared after a period of Itraconazole therapy. PMID- 29500033 TI - Neglected Tropical Disease Control - The Case for Adaptive, Location-specific Solutions. AB - The world is experiencing environmental and social change at an unprecedented rate, with the effects being felt at local, regional, and international scales. This phenomenon may disrupt interventions against neglected tropical diseases (NTDs) that operate on the basis of linear scaling and 'one-size-fits-all'. Here we argue that investment in field-based data collection and building modelling capacity is required; that it is important to consider unintended consequences of interventions; that inferences can be drawn from wildlife ecology; and that interventions should become more location-specific. Collectively, these ideas underpin the development of adaptive decision-support tools that are sufficiently flexible to address emerging issues within the Anthropocene. PMID- 29500035 TI - "The times they are a'changin'" - Positioning the European Association for the Study of the Liver in the changing landscape of hepatology. PMID- 29500034 TI - Revamping Mosquito-borne Disease Control to Tackle Future Threats. AB - The global approach to mosquito-borne diseases (MBDs) is in need of critical re evaluation. Although there have been dramatic reductions in malaria incidence since 2000, malaria elimination from high-transmission settings remains problematic. At the same time, arbovirus outbreaks have increased in their frequency and impact. The 2015-2016 Zika virus epidemic exposed the dire state of MBD control in many countries, calling for united global action. Despite international resolve to prevent future epidemics, current practices in MBD control are mostly reactive and of limited efficacy. In this Opinion article, we summarize the views of 25 international mosquito experts about the current state of MBD control and highlight the issues that must be addressed in order to tackle emerging threats on the horizon. PMID- 29500036 TI - How Has Microbiology Changed over the Past 25 Years? PMID- 29500037 TI - Hepatitis B Virus. AB - This infographic about hepatitis B virus explores its replication cycle, natural history of infection and pathogenesis, and how this can be controlled and treated. Hepatitis B virus (HBV) is a common worldwide blood-borne pathogen. Chronic hepatitis B can progress to an inactive carrier state, and then, in some patients, give rise to cirrhosis and cancer of the liver, leading to death. An HBV surface-antigen vaccine is effective, but treatments are currently not curative. HBV replicates via reverse transcription. Its covalently closed circular (ccc) DNA in the nucleus encodes a pregenomic RNA (pgRNA), which can be encapsidated by HBV polymerase. Reverse transcription occurs in the capsids by using the pgRNA as a template for the synthesis of single-stranded linear and then partially double-stranded relaxed circular (rc) DNA. Capsids containing a mature rc DNA genome target to the nucleus for ccc DNA synthesis. Persistent HBV infection is caused mainly by ccc DNA and immune tolerance to HBV antigens in the liver. Unlike acute infection, chronic carriers contain only a low level of HBV core-antigen-specific T cell activity, contributing to the lack of viral clearance. PMID- 29500038 TI - Impact of the time-to-treatment concept on the outcome of acute heart failure: A pilot study. AB - BACKGROUND: An optimal maximum time of 60minutes has been recommended in recent guidelines for the first evaluation and treatment of patients with acute heart failure (AHF); however, this has not been tested prospectively. AIM: To analyze the impact of a time-to-treatment (TTT) strategy of <60minutes on the in-hospital outcome of patients with AHF. METHODS: During a single 1-month period, we consecutively enrolled all patients hospitalized with AHF in a prospective cohort. In this pilot study, TTT was defined as the time between the first medical contact to the onset of the first medical intervention. The primary outcome was a composite including in-hospital death or worsening AHF. RESULTS: Of the 74 patients included, 23 (31%) had a TTT of <60minutes. Although these patients were more likely to have a more severe episode of AHF, the primary outcome occurred only in patients with a TTT of >=60minutes. The primary outcome was significantly associated with a TTT of >=60minutes (P=0.036), low systolic blood pressure (P<0.01), rales more than halfway up the lung fields (P=0.02), infectious precipitating factor (P=0.04) and high serum concentrations of B-type natriuretic peptide (P<0.01) and urea (P=0.03). No significant differences were observed in the rate of treatment-induced acute renal insufficiency or in the long-term rates of death or rehospitalization for heart failure according to TTT. CONCLUSIONS: This study suggests that the recently recommended TTT strategy of <60minutes in the setting of AHF might be associated with a better prognosis during hospitalization. Further large prospective works are needed to confirm these preliminary results, and to define more precisely which types of AHF could benefit from this strategy. PMID- 29500039 TI - Simultaneous bilateral percutaneous nephrolithotomy: Effectiveness and safety. AB - OBJECTIVES: To evaluate the effectiveness and safety of simultaneous bilateral percutaneous nephrolithotomy performed in patients affected with bilateral renal calculi. MATERIALS AND METHODS: This is a prospective study from September 2012 to November 2016. Patients diagnosed of bilateral kidney stones with abdominal CT scan were included. Surgical technique prone position, renal puncture guided by fluoroscopy and tract dilation up to 24Ch. We reviewed demographic and stone characteristics, stone free rate, clinical success, complications and follow-up. RESULTS: During the study period, 732 percutaneous nephrolithotomies were performed. Eighteen patients were included (36 renal units, 2.5%), 13 men and 5 women, with a median age of 58 years and an interquartile range (IQR) of 40-66. Median stone burden was 228mm2 (IQR 134-389); median operative time, 150minutes (IQR 97-180); and median hospital stay, 5 days (IQR 5-15). Stone free rate was 80%. Residual calculi were encountered in 8 renal units (22.2%) and required other complementary techniques for their complete tesolution 4 external shockwave lithotripsies, one open ureterolithotomy, 2 ureteroscopies and one second look. Major complications included 4 cases of severe hemorrhage managed with angiographic embolization. The median follow-up was 36 months (range 26-46). CONCLUSIONS: Simultaneous bilateral percutaneous nephrolithotomy is an effective and safe procedure in patients affected with bilateral renal calculi. It is a surgical challenge that should be performed in selected patients and in centers with experience. PMID- 29500040 TI - Innate immunity gene expression by epithelial cells of upper respiratory tract in children with adenoid hypertrophy. AB - BACKGROUND: A major role of the innate immunity in the defence of mucosal tissue is well established. However, a balance between the main components of the immunity such as toll-like receptors (TLRs) and defensins in the pathology of upper respiratory tract in children has not been addressed yet. Our aim was to investigate the gene expression of some TLRs as well as alpha and beta-defensins in children suffered from adenoid hyperthrophy in comparison with healthy children. METHODS: Samples (nasal epithelium and adenoids) from patients with hypertrophic adenoids (n = 77) and control group (n = 33) were investigated. Quantification of HBD-1 and 2 mRNA, alpha-defensin-HNP1 and toll-like receptors (TLR) 2, 4 and 9 mRNA expression was performed by real-time polymerase chain reaction (PCR). The detection of TLR4 and TLR9 was performed by immunohistochemistry. RESULTS: The main finding of the study is a dramatic up regulation of TLR2 and TLR4 expression (but down-regulation of TLR9) along with a significant reduction in the expression of the defensins in children with adenoid hyperthrophy. CONCLUSION: The data suggest that one of the mechanisms of mucosal involvement in the pathogenesis of upper respiratory tract infection might by a disbalance between TLRs and defensins revealed in our study. PMID- 29500041 TI - Diagnostic Value of Tryptase in Food Allergic Reactions: A Prospective Study of 160 Adult Peanut Challenges. AB - BACKGROUND: Serum tryptase is useful in diagnosing drug and venom anaphylaxis. Its utility in food anaphylaxis is unknown. OBJECTIVE: The objective of this study was to determine whether tryptase rises in food allergic reactions, optimal sampling time points, and a diagnostic cutoff for confirming a clinical reaction. METHODS: Characterized peanut allergic patients were recruited and underwent up to 4 peanut challenges and 1 placebo challenge each. Tryptase was measured serially on challenge days both before (baseline) and during the challenge. The peak percentage tryptase rise (peak/baseline) was related to reaction severity. Receiver operating characteristic (ROC) curves were generated establishing an optimal diagnostic cutoff. RESULTS: Tryptase was analyzed in 160 reactive (9% anaphylaxis) and 45 nonreactive (placebo) challenges in 50 adults aged 18 to 39 years. Tryptase rose above the normal range (11.4 ng/mL) in 4 of 160 reactions. When compared with baseline levels, a rise was observed in 100 of 160 (62.5%) reactions and 0 of 45 placebo challenges. The median rise (95% confidence interval [CI]) for all reactions was 25% (13.3% to 33.3%) and 70.8% (33.3% to 300%) during anaphylaxis. Peak levels occurred at 2 hours and correlated with severity (P < .05). Moderate-to-severe respiratory symptoms, generalized erythema, dizziness, and hypotension were correlated with a higher peak/baseline tryptase (P < .05). ROC curve analysis demonstrated the optimal cutoff to identify a reaction as a 30% rise (sensitivity 0.53; specificity 0.85), area under the curve 0.72 (95% CI, 0.67-0.78). CONCLUSIONS: Serum tryptase measurement is valuable in food allergic reactions, and correlates with symptom severity. Comparing peak reaction levels at 2 hours with baseline is essential. A rise in tryptase of 30% is associated with food allergic reactions. PMID- 29500042 TI - Low Frequency repetitive Transcranial Magnetic Stimulation: Potential role in treatment of patients with hemispheric cerebellar strokes. PMID- 29500043 TI - Long-lasting effects of transcranial static magnetic field stimulation on motor cortex excitability. AB - BACKGROUND: Transcranial static magnetic field stimulation (tSMS) was recently added to the family of inhibitory non-invasive brain stimulation techniques. However, the application of tSMS for 10-20 min over the motor cortex (M1) induces only short-lasting effects that revert within few minutes. OBJECTIVE: We examined whether increasing the duration of tSMS to 30 min leads to long-lasting changes in cortical excitability, which is critical for translating tSMS toward clinical applications. METHODS: The study comprised 5 experiments in 45 healthy subjects. We assessed the impact of 30-min-tSMS over M1 on corticospinal excitability, as measured by the amplitude of motor evoked potentials (MEPs) and resting motor thresholds (RMTs) to single-pulse transcranial magnetic stimulation (TMS) (experiments 1-2). We then assessed the impact of 30-min-tSMS on intracortical excitability, as measured by short-interval intracortical facilitation (SICF) and short-interval intracortical inhibition (SICI) using paired-pulse TMS protocols (experiments 2-4). We finally assessed the impact of 10-min-tSMS on SICF and SICI (experiment 5). RESULTS: 30-min-tSMS decreased MEP amplitude compared to sham for at least 30 min after the end of the stimulation. This long-lasting effect was associated with increased SICF and reduced SICI. 10-min-tSMS -previously reported to induce a short-lasting decrease in MEP amplitude- produced the opposite changes in intracortical excitability, decreasing SICF while increasing SICI. CONCLUSIONS: These results suggest a dissociation of intracortical changes in the consolidation from short-lasting to long-lasting decrease of corticospinal excitability induced by tSMS. The long-lasting effects of 30-min-tSMS open the way to the translation of this simple, portable and low-cost technique toward clinical trials. PMID- 29500044 TI - Immunodominance of LipL3293-272 peptides revealed by leptospirosis sera and therapeutic monoclonal antibodies. AB - BACKGROUND/PURPOSE: Leptospirosis is a neglected zoonosis, imposing significant human and veterinary public health burdens. In this study, recombinant LipL3293 147 and LipL32148-184 middle domain of LipL3293-184, and LipL32171-214, and LipL32215-272 of c-terminal LipL32171-272 truncations were defined for immunodominance of the molecule during Leptospira infections revealed by leptospirosis sera. RESULTS: IgM-dominant was directed to highly surface accessible LipL32148-184 and Lipl32171-214. IgG dominance of LipL32148-184 revealed by rabbit anti-Leptospira sera and convalescent leptospirosis paired sera were mapped to highly accessible surface of middle LipL32148-184 truncation whereas two LipL32148-184 and LipL32215-272 truncations were IgG-dominant when revealed by single leptospirosis sera. The IgM-dominant of LipL32148-214 and IgG dominant LipL32148-184 peptides have highly conserved amino acids of 70% identity among pathogenic and intermediate Leptospira species and were mapped to the highly surface accessible area of LipL32 molecule that mediated interaction of host components. IgG dominance of two therapeutic epitopes located at LipL32243 253 and LipL32122-130 of mAbLPF1 and mAbLPF2, respectively has been shown less IgG-dominant (<30%), located outside IgG-dominant regions characterized by leptospirosis paired sera. CONCLUSION: The IgM- and IgG-dominant LipL32 could be further perspectives for immunodominant LipL32-based serodiagnosis and LipL32 epitope-based vaccine. PMID- 29500045 TI - Human papillomavirus infection is not associated with laryngeal squamous cell carcinoma in Taiwan. AB - BACKGROUND/PURPOSE: To examine whether the prevalence rate of human papillomavirus (HPV) infection in Taiwanese patients with primary laryngeal squamous cell carcinoma (LSCC) is different from that in those with a vocal polyp (VP) or vocal fold leukoplakia (VFL). METHODS: This prospective cohort study recruited 41 consecutive patients with primary LSCC and 27 and 20 patients with VP and VFL, respectively. The HPV L1 gene in surgical specimens was detected using polymerase chain reaction. High-risk HPV DNA in tissue microarray specimens was detected using in situ hybridization. Expression of p16INK4a in tissue microarray specimens was determined through immunohistochemistry. RESULTS: The prevalence of HPV L1 DNA in the LSCC group was equivalent to that in the VP and VFL groups (7.3% vs. 7.4% vs. 10.0%; P = 0.929; effect size = 0.20). High-risk HPV DNA detected using in situ hybridization was relatively rare in all groups (2.6% vs. 5.3% vs. 0.0%; P = 0.636; effect size = 0.81). The prevalence of p16INK4a positivity was significantly lower in the LSCC group than in the VP and VFL groups (5.1% vs. 58.8% vs. 14.3%; P < 0.001). Multivariate analysis results revealed that age >=65 years (adjusted odds ratio, 4.09; 95% confidence interval, 1.21-13.91; P = 0.024) and p16INK4a positivity (adjusted odds ratio, 0.10; 95% confidence interval, 0.02-0.53; P = 0.006) were LSCC risk factors. CONCLUSION: HPV infection is uncommon in Taiwanese patients with LSCC and seems not to be associated with an increased LSCC risk. Larger sample size is warranted for further study. PMID- 29500046 TI - To warn or not to warn: A reappraisal of brainstem auditory evoked potential warning criteria during surgery. PMID- 29500047 TI - Intracompartmental Versus Extracompartmental Transposition of the Extensor Pollicis Longus for Treating Thumb-in-Palm Deformity: A Biomechanical Comparison. AB - PURPOSE: Transecting the extensor pollicis longus (EPL) tendon and rerouting it through the first extensor compartment is an established technique for treating thumb-in-palm deformity (TIPD). An alternative technique that approximates the trajectory of the first extensor compartment without violating the compartment or transecting the EPL tendon can be accomplished by creating an artificial sheath from the extensor retinaculum to radialize the tendon glide path. This study compares this extracompartmental (EC) EPL transposition to the established, intracompartmental (IC) transposition by evaluating, in a cadaver model, the extent of thumb extension in both techniques. METHODS: Eighteen fresh-frozen cadaveric hands were each tested under 3 different conditions: EPL in situ (baseline); EPL rerouted above the first extensor compartment (EC); and EPL rerouted through the first extensor compartment (IC). A controlled traction of 10 N was applied to the EPL under each condition. The range of thumb extension with respect to the fixed index finger was recorded utilizing infrared reflective markers and digital video capture. RESULTS: The mean extension of the thumb with the EPL tendon in situ was 16.7 degrees . The mean extension of the thumb was 22.0 degrees with the EC transposition versus 25.0 degrees with the IC technique. The measured thumb extension in both the EC and the IC techniques were found to be similar because both EPL transpositions yielded a significant difference in thumb extension when compared with baseline. CONCLUSIONS: This biomechanical model demonstrates that radial transposition of the EPL tendon enhances extension of the thumb regardless of whether the tendon is routed through, or superficial to, the first extensor compartment. CLINICAL RELEVANCE: A novel technique, the EC EPL transposition, offers a similar enhancement in measured thumb extension as the already-described IC EPL transposition. PMID- 29500048 TI - Does the U Stand for Useless? The Urine Drug Screen and Emergency Department Psychiatric Patients. AB - BACKGROUND: Behavioral emergencies account for a significant portion of emergency department (ED) visits in the United States. Substance abuse is common in this population and may precipitate or exacerbate preexisting psychiatric illness. Contrary to ED policy guidelines, many behavior health centers (BH) require a urine drug screen (UDS) in stable patients prior to transfer. OBJECTIVE: We sought to determine the role of the UDS in ED length of stay (LOS), cost, and charges to patients and inpatient psychiatric care. METHODS: We performed a retrospective chart review of all patients transferred to an in-network BH from September 1-30, 2014. Clinical data were extracted and analyzed from our electronic medical record, including records from both the ED visit and the BH stay. RESULTS: There were 205 patient encounters identified; 89 patients had a UDS performed in the ED and 89% were obtained after the ED medical clearance. LOS were similar between the two groups, however, time to ED departure from time of medical clearance was delayed in the UDS group. BH providers mentioned UDS results < 25% of the time and no confirmatory tests were performed. There was no difference in BH LOS or discharge diagnosis of substance-abuse disorder. Patient charges for UDS over the month totaled $21,093. CONCLUSION: The UDS did not seem to have any significant effect on inpatient psychiatric care; whereas ED LOS and cost were both negatively affected. Based on these results, the UDS seems to be of little-to-no benefit in the setting of acute psychiatric illness. PMID- 29500049 TI - Mobile epibenthic fauna consume organic waste from coastal fin-fish aquaculture. AB - Organic waste released from fin-fish aquaculture is being dispersed further as industry growth has led to the expansion of open net cages in dynamic coastal locations. Here we investigate the response of three mobile epibenthic invertebrates (brittle stars, urchins and brown crabs), whose natural habitats overlap with large scale coastal salmon farming. Using fatty acids and stable isotopes, we found these organisms displayed decreases in delta13C and delta15N and elevated levels of C18 fatty acids reflective of terrestrial components of fin-fish feeds. Furthermore, we found these three species consume aquaculture organic waste not only directly adjacent to the farm vicinity (0-20 m from cage edge) but up to 1 km away in the case of brittle stars and brown crabs. As aquaculture feeds shift to contain more terrestrial ingredients, the biochemistry of fauna feeding on organic waste is also being shifted, the result of these changes is currently unclear. PMID- 29500050 TI - Spiculosiphon oceana (Foraminifera) a new bio-indicator of acidic environments related to fluid emissions of the Zannone Hydrothermal Field (central Tyrrhenian Sea). AB - The new record of a shallow-water submarine hydrothermal field (<150 m w.d.) in the western Mediterranean Sea (Tyrrhenian Sea, Italy) allows us to study CO2 fluid impact on benthic foraminifers. Benthic foraminifers calcification process is sensitive to ocean acidification and to local chemical and physical parameters of seawater and pore water. Thus, foraminifers can record specific environmental conditions related to hydrothermal fluids, but at present their response to such activity is poorly defined. The major outcome of this study is the finding of a very uncommon taxon for the Mediterranean Sea, i.e., the Spiculosiphon oceana, a giant foraminifer agglutinating spicules of sponges. This evidence, along with the strong decrease of calcareous tests in the foraminiferal assemblages associated to hydrothermal activity, provides new insights on the meiofauna living in natural stressed environment. In particular, observations obtained from this study allow us to consider S. oceana a potential tolerant species of high CO2 concentrations (about 2-4 times higher than the normal marine values) and a proxy of acidic environments as well as of recent ocean acidification processes. PMID- 29500051 TI - Reproductive trade-offs in a temperate reef fish under high pCO2 levels. AB - Fishes are currently facing novel types of anthropogenic stressors that have never experienced in their evolutionary history, such as ocean acidification. Under these stressful conditions, energetically costly processes, such as reproduction, may be sacrificed for increased chances of survival. This trade-off does not only affect the organism itself but may result in reduced offspring fitness. In the present study, the effects of exposure to high pCO2 levels were tested on the reproductive performance of a temperate species, the two-spotted goby, Gobiusculus flavescens. Breeding pairs were kept under control (~600 MUatm, pH~ 8.05) and high pCO2 levels (~2300 MUatm, pH~ 7.60) conditions for a 4-month period. Additionally, oxidative stress and energy metabolism-related biomarkers were measured. Results suggest that reproductive activity is stimulated under high pCO2 levels. Parental pairs in the simulated ocean acidification conditions exhibited increased reproductive output, with 50% more clutches and 44% more eggs per clutch than pairs under control conditions. However, there was an apparent trade-off between offspring number and size, as larvae of parental pairs under high pCO2 levels hatched significantly smaller, suggesting differences in parental provisioning, which could be related to the fact that these females produce more eggs. Moreover, results support the hypothesis of different energy allocation strategies used by females under high pCO2 conditions. These changes might, ultimately, affect individual fitness and population replenishment. PMID- 29500052 TI - Seminal plasma affects the survival rate and motility pattern of raw llama spermatozoa. AB - : The objectives of this study were to evaluate the effect over time of different percentages of seminal plasma (SP) on llama sperm characteristics in raw semen and correlate the techniques routinely used to evaluate sperm viability and acrosome status with the Fluorescein Isothiocyanate -Arachis hypogea agglutinin/Propidium Iodide (FITC-PNA/PI). Eighteen ejaculates, obtained from 6 male llamas using electroejaculation, were incubated in 0.1% collagenase in HEPES TALP (HT), centrifuged and resuspended with SP and HT: 0, 10, 50 and 100% SP. Samples were incubated (37 degrees C) until evaluation at 0; 1.5 and 3 h. Split plot and factorial designs were used to analyze sperm motility, viability, membrane function and acrosome status and Spearman's test was used for correlation. At 0 h, samples with 100% SP showed oscillatory motility; whereas in samples with 0 and 10% SP, progressive motility was predominant. Viability, membrane function and total motility decreased significantly at 3 h of incubation in samples with 100% SP. Sperm with intact acrosomes were fewer in 0% SP media at all times. FITC-PNA/PI correlated with 6-Carboxyfluorescein Diacetate and Propidium Iodide (CFDA/PI) and with Coomassie Blue (CB) stains (r = 0.8; p = 0.0 and r = 0.5; p = 0.0 respectively). CONCLUSIONS: the motility pattern of llama sperm is influenced by the concentration of SP. The use of SP as the only medium is not able to maintain sperm motility, viability and membrane function for 3 h. A certain percentage of SP is necessary in the medium to avoid spontaneous acrosome reactions. The correlations observed could help to shorten evaluation times and reduce costs in sperm laboratories. PMID- 29500053 TI - Reproductive parameters of donkey jacks undergoing puberty. AB - In male donkeys, puberty and the related events have been poorly characterized. The aim of this study was to evaluate the age at which male donkeys reach puberty, and characterize age associated changes in testicular size, testicular blood flow, serum testosterone concentration and semen quality. Every two months, starting at 6 months and finishing at 24 months of age, five male donkeys born in May to July were subjected to B-mode ultrasound examination to assess testicular size and scrotum content and blood serum sampling for testosterone concentration. From the age of 8 months, pulsed Doppler was employed to evaluate blood flow in the testicular artery. Testosterone serum concentration was evaluated via RIA. From the age of 12 months, monthly semen collections were attempted and semen was evaluated for sperm number, motility and morphology. Onset of puberty was defined as the first ejaculate containing >=50 * 106 spermatozoa with >=10% total motility. One of the donkeys was excluded from the statistical analyses due to a hydrocele presented during the study. Testes width was affected by age (P < 0.0001) and after an initial plateau increased linearly from 10 months of age. Pulsatility and resistivity indexes were also affected by age (P < 0.01), being significantly higher at 14 months than at 24 months. Testosterone serum concentration was affected by age (P < 0.0001) and was significantly lower at 6 months (0.1 ng/ml) compared to 22-24 months (>=0.8 ng/ml). Spermatozoa appeared in the ejaculate at a mean age of 18.7 months and puberty was attained between 19 and 20 months of age (mean: 19.5 months), between January and February. In conclusion, late spring born Amiata donkey colts reached puberty at 19-20 months of age. Puberty was accompanied by changes in testicular size, testicular blood flow and serum testosterone concentration. PMID- 29500054 TI - Elevated frequency of IL-37- and IL-18Ralpha-positive T cells in the peripheral blood of rheumatoid arthritis patients. AB - OBJECTIVE: To detect the expression of IL-37 and its receptors IL-18Ralpha and IL 1R8 in CD4+ T cells and total lymphocytes in rheumatoid arthritis (RA) patients and the relationship between autoantibodies and disease activity. To investigate the mechanism of IL-37 and its receptors involved in the pathogenesis of RA. To evaluate the effects of different concentrations of rhIL-37 on peripheral blood mononuclear cells (PBMCs) in RA patients with TNF-alpha, and IL-6. METHODS: The expression of IL-37 and its receptor IL-18Ralpha and IL-1R8 in peripheral blood CD4+ T cells and total lymphocytes in RA patients and healthy controls were measured by flow cytometry. The levels of TNF-alpha and IL-6 in the supernatant were measured by ELISA after rhIL-37 stimulation with PBMCs. RESULTS: The expression of IL-37 and IL-18Ralpha in the total lymphocytes, especially in CD4+ T cells in RA patients, was significantly higher than in the healthy control group. There was a positive correlation between the frequency of IL-37- or IL 18Ralpha-positive CD4+ T cells and ESR, CRP, and DAS28 values. Additionally, rhIL 37 significantly down-regulated TNF-alpha and IL-6 production in RA patients' PBMCs. CONCLUSIONS: IL-37 plays an important role in the regulation of inflammation in RA. IL-37 and its receptors may play an immunoregulatory role in the activation of lymphocytes, especially CD4+ T cells, in RA patients. IL-37 may represent a therapeutic target for rheumatoid arthritis. PMID- 29500055 TI - Does talking the talk matter? Effects of supervisor safety communication and safety climate on long-haul truckers' safety performance. AB - This study examines the distinct contribution of supervisory safety communication and its interaction with safety climate in the prediction of safety performance and objective safety outcomes. Supervisory safety communication is defined as subordinates' perceptions of the extent to which their supervisor provides them with relevant safety information about their job (i.e., top-down communication) and the extent to which they feel comfortable discussing safety issues with their supervisor (i.e., bottom-up communication). Survey data were collected from 5162 truck drivers from a U.S. trucking company with a 62.1% response rate. Individual employees' survey responses were matched to their safety outcomes (i.e., lost time injuries) six months after the survey data collection. Results showed that the quality of supervisor communication about safety uniquely contributes to safety outcomes, above and beyond measures of both group-level and organization level safety climate. The construct validity of a newly-adapted safety communication scale was demonstrated, particularly focusing on its distinctiveness from safety climate and testing a model showing that communication had both main and moderating effects on safety behavior that ultimately predicted truck drivers' injury rates. Our findings support the need for continued attention to supervisory safety communication as an important factor by itself, as well as a contingency factor influencing how safety climate relates to safety outcomes. PMID- 29500056 TI - Surgical Care and Otolaryngology in Global Health. AB - Surgical access is inadequate for most people. The Lancet Commission on Global Surgery established 6 indicators to measure surgical access: geographic accessibility, density of surgical providers, number of procedures performed, perioperative mortality, impoverishing expenditure, and catastrophic expenditure. Otolaryngology surgical, training, and research efforts use these 6 indicators to maximize impact and coordination of worldwide efforts in surgery. Research must be rigorous and consider the counterfactual. For otolaryngologists who want to contribute, focusing on 1 of the 6 indicators may be most impactful. PMID- 29500057 TI - Nondiabetic ketoacidosis in a pregnant woman due to acute starvation with concomitant influenza A (H1N1) and respiratory failure. AB - Threatening refractory metabolic acidosis due to short-term starvation nondiabetic ketoacidosis is rarely reported. Severe ketoacidosis due to starvation itself is a rare occurrence, and more so in pregnancy with a concomitant stressful clinical situation. This case report presents a nondiabetic woman admitted in intensive care for respiratory failure type 1 during the third trimester of pregnancy with a severe metabolic acidosis refractory to medical treatment. We diagnosed the patient with acute starvation ketoacidosis based on her history and the absence of other causes of high anion gap metabolic acidosis after doing a rigorous analysis of her acid-base disorder. PMID- 29500058 TI - Is a blood sample for hemoglobins in the transfusional range reliable? AB - OBJECTIVE: To evaluate the correlation and agreement in our unit and population of hemoglobin in gasometry versus hematology analyzer, to evaluate errors in transfusion or lack thereof. RESULTS: strong association between Point-of-care (POC) and hematimetry, with P<.001, with a coefficient of determination r2 of 0.56, an intraclass correlation coefficient of 0.63 and a Lin's concordance correlation coefficient of 0.65. For hemoglobins less than 7g/dL, a success rate of 29.41% was obtained. CONCLUSIONS: Low-moderate agreement of POC hemoglobin with standard haemothymetry. High probability of errors in the indication of transfusion based on gasometer hemoglobins, especially in low hemoglobins. PMID- 29500059 TI - Morphological and histological characters of penile organization in eleven species of molossid bats. AB - The penis is the reproductive organ that ensures efficient copulation and success of internal fertilization in all species of mammals, with special challenges for bats, where copulation can occur during flight. Comparative anatomical analyses of different species of bats can contribute to a better understanding of morphological diversity of this organ, concerning organization and function. In this study, we describe the external morphology and histomorphology of the penis and baculum in eleven species of molossid bats. The present study showed that penile organization in these species displayed the basic vascular mammalian pattern and had a similar pattern concerning the presence of the tissues constituting the penis, exhibiting three types of erectile tissue (the corpus cavernosum, accessory cavernous tissue, and corpus spongiosum) around the urethra. However, certain features varied among the species, demonstrating that most species are distinguishable by glans and baculum morphology and glans histological organization. Major variations in glans morphology were genus specific, and the greatest similarities were shared by Eumops species and N. laticaudatus. The greatest interspecific similarities occurred between M. molossus and M. rufus and between Eumops species. Save for M. molossus and M. rufus, morphology of the baculum was species-specific; and in E. perotis, it did not occur in all specimens, indicating that it is probably under selection. In the histological organization, the most evident differences were number of septa and localization of the corpora cavernosa. In species with a baculum (Molossus, Eumops and Nyctinomops species), the corpora cavernosa predominantly occupied the dorsal region of the penile glans and is associated with the proximal (basal) portion of the baculum. In species that do not have a baculum (Cynomops, Molossops and Neoplatymops species), the corpora cavernosa predominantly occupied the ventro-lateral region of the glans. PMID- 29500060 TI - Thermoregulation of a temperate reptile in a forested habitat. AB - A major focus in zoology is to understand the phenotypic responses of animals to environmental variation. This is particularly important when dealing with ectotherms in a thermally heterogenous environment. We measured body temperatures of a free-ranging, medium sized temperate reptile, the tuatara, Sphenodon punctatus, to investigate its thermal opportunities and the degree to which the animal actively regulates its body temperature. We found high variation in body temperature between individuals, but this variation could not be attributed to sex or body size. However, variation among individuals in timing of burrow use did affect body temperature and in one of the years studied tuatara were found to be more effective in their thermoregulation when sharing a burrow with a seabird (Pachyptila turtur). The strength of this study is that it includes both biotic and behavioural components of the thermal environment of a temperate reptile, areas which are often missing from thermal studies that focus on the abiotic aspects. PMID- 29500061 TI - Selected mosquito borne illnesses - Zika. PMID- 29500062 TI - Thermostable xylanase-aided two-stage hydrolysis approach enhances sugar release of pretreated lignocellulosic biomass. AB - One of the challenges in biorefinery is the still too much enzyme involved in the saccharification of the cellulosic component. High-temperature hydrolysis with thermostable enzyme showed promise. In this study, a temperature-elevated two stage hydrolysis, including xylan "coat" removal at high-temperature by thermostable xylanase (Xyn10A) from Thermotoga thermarum DSM 5069 followed with saccharification step by commercial cellulase, was introduced to improve biomass deconstruction. Results showed that high-temperature xylanase treatment considerably increased cellulose accessibility/hydrolyzability towards cellulases, with smoothed fiber surface morphology. Comparing with commercial xylanase (HTec) treatment at 50 degrees C, thermostable Xyn10A pre-hydrolysis at 85 degrees C was able to achieve a slightly better improvement of cellulose hydrolysis with much lower xylanase loading (about 5 times lower than HTec). It appeared that the increased temperature during thermostable xylanase treatment facilitated biomass slurry viscosity reduction, which exhibited more benefits during hydrolysis of various steam pretreated substrates at increased solid content (up to 10% w/w). PMID- 29500063 TI - Salinity build-up in osmotic membrane bioreactors: Causes, impacts, and potential cures. AB - Osmotic membrane bioreactor (OMBR), which integrates forward osmosis (FO) with biological treatment, has been developed to advance wastewater treatment and reuse. OMBR is superior to conventional MBR, particularly in terms of higher effluent quality, lower membrane fouling propensity, and higher membrane fouling reversibility. Nevertheless, advancement and future deployment of OMBR are hindered by salinity build-up in the bioreactor (e.g., up to 50 mS/cm indicated by the mixed liquor conductivity), due to high salt rejection of the FO membrane and reverse diffusion of the draw solution. This review comprehensively elucidates the relative significance of these two mechanisms towards salinity build-up and its associated effects in OMBR operation. Recently proposed strategies to mitigate salinity build-up in OMBR are evaluated and compared to highlight their potential in practical applications. In addition, the complementarity of system optimization and modification to effectively manage salinity build-up are recommended for sustainable OMBR development. PMID- 29500064 TI - Landiolol hydrochloride to successfully treat refractory ventricular arrhythmia during weaning from cardiopulmonary bypass. PMID- 29500066 TI - A kinetically controlled, isothermal method for the detection of single nucleotide mismatches. AB - We describe an isothermal, enzyme-free method to detect single nucleotide differences between oligonucleotides of close homology. The approach exploits kinetic differences in toe-hold-mediated, nucleic acid strand-displacement reactions to detect single nucleotide polymorphisms (SNPs) with essentially "digital" precision. The theoretical underpinning, experimental analyses, predictability, and accuracy of this new method are reported. We demonstrate detection of biologically relevant SNPs and single nucleotide differences in the let-7 family of microRNAs. The method is adaptable to microarray formats, as demonstrated with on-chip detection of SNP variants involved in susceptibility to the therapeutic agents abacavir, Herceptin, and simvastatin. PMID- 29500065 TI - Plasma Cell-free DNA Concentration and Outcomes from Taxane Therapy in Metastatic Castration-resistant Prostate Cancer from Two Phase III Trials (FIRSTANA and PROSELICA). AB - BACKGROUND: Noninvasive biomarkers are needed to guide metastatic castration resistant prostate cancer (mCRPC) treatment. OBJECTIVE: To clinically qualify baseline and on-treatment cell-free DNA (cfDNA) concentrations as biomarkers of patient outcome following taxane chemotherapy. DESIGN, SETTING, AND PARTICIPANTS: Blood for cfDNA analyses was prospectively collected from 571 mCRPC patients participating in two phase III clinical trials, FIRSTANA (NCT01308567) and PROSELICA (NCT01308580). Patients received docetaxel (75mg/m2) or cabazitaxel (20 or 25mg/m2) as first-line chemotherapy (FIRSTANA), and cabazitaxel (20 or 25mg/m2) as second-line chemotherapy (PROSELICA). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Associations between cfDNA concentration and prostate specific antigen (PSA) response were tested using logistic regression models. Survival was estimated using Kaplan-Meier methods for cfDNA concentration grouped by quartile. Cox proportional hazard models, within each study, tested for associations with radiological progression-free survival (rPFS) and overall survival (OS), with multivariable analyses adjusting for baseline prognostic variables. Two-stage individual patient meta-analysis combined results for cfDNA concentrations for both studies. RESULTS AND LIMITATIONS: In 2502 samples, baseline log10 cfDNA concentration correlated with known prognostic factors, shorter rPFS (hazard ratio [HR]=1.54; 95% confidence interval [CI]: 1.15-2.08; p=0.004), and shorter OS on taxane therapy (HR=1.53; 95% CI: 1.18-1.97; p=0.001). In multivariable analyses, baseline cfDNA concentration was an independent prognostic variable for rPFS and OS in both first- and second-line chemotherapy settings. Patients with a PSA response experienced a decline in log10 cfDNA concentrations during the first four cycles of treatment (per cycle -0.03; 95% CI: -0.044 to -0.009; p=0.003). Study limitations included the fact that blood sample collection was not mandated for all patients and the inability to specifically quantitate tumour-derived cfDNA fraction in cfDNA. CONCLUSIONS: We report that changes in cfDNA concentrations correlate with both rPFS and OS in patients receiving first- and second-line taxane therapy, and may serve as independent prognostic biomarkers of response to taxanes. PATIENT SUMMARY: In the past decade, several new therapies have been introduced for men diagnosed with metastatic prostate cancer. Although metastatic prostate cancer remains incurable, these novel agents have extended patient survival and improved their quality of life in comparison with the last decade. To further optimise treatment allocation and individualise patient care, better tests (biomarkers) are needed to guide the delivery of improved and more precise care. In this report, we assessed cfDNA in over 2500 blood samples from men with prostate cancer who were recruited to two separate international studies and received taxane chemotherapy. We quantified the concentration of cfDNA fragments in blood plasma, which partly originates from tumour. We identified that higher concentrations of circulating cfDNA fragments, prior to starting taxane chemotherapy, can be used to identify patients with aggressive prostate cancer. A decline in cfDNA concentration during the first 3-9 wk after initiation of taxane therapy was seen in patients deriving benefit from taxane chemotherapy. These results identified circulating cfDNA as a new biomarker of aggressive disease in metastatic prostate cancer and imply that the study of cfDNA has clinical utility, supporting further efforts to develop blood-based tests on this circulating tumour-derived DNA. PMID- 29500067 TI - Irritable Bowel Syndrome with predominant diarrhea and giardiasis: is it one or the other? PMID- 29500068 TI - Endoscopic balloon dilation of oesophageal stenosis in a patient with recessive dystrophic epidermolysis bullosa. PMID- 29500069 TI - Generation of alloreactivity-reduced donor lymphocyte products retaining memory function by fully automatic depletion of CD45RA-positive cells. AB - BACKGROUND AIMS: For patients needing allogeneic stem cell transplantation but lacking a major histocompatibility complex (MHC)-matched donor, haplo-identical (family) donors may be an alternative. Stringent T-cell depletion required in these cases to avoid lethal graft-versus-host disease (GVHD) can delay immune reconstitution, thus impairing defense against virus reactivation and attenuating graft-versus-leukemia (GVL) activity. Several groups reported that GVHD is caused by cells residing within the naive (CD45RA+) T-cell compartment and proposed use of CD45RA-depleted donor lymphocyte infusion (DLI) to accelerate immune reconstitution. We developed and tested the performance of a CD45RA depletion module for the automatic cell-processing device CliniMACS Prodigy and investigated quality attributes of the generated products. METHODS: Unstimulated apheresis products from random volunteer donors were depleted of CD45RA+ cells on CliniMACS Prodigy, using Good Manufacturing Practice (GMP)-compliant reagents and methods throughout. Using phenotypic and functional in vitro assays, we assessed the cellular constitution of CD45RA-depleted products, including T-cell subset analyses, immunological memory function and allo-reactivity. RESULTS: Selections were technically uneventful and proceeded automatically with minimal hands-on time beyond tubing set installation. Products were near-qualitatively CD45RA+ depleted, that is, largely devoid of CD45RA+ T cells but also of almost all B and natural killer cells. Naive and effector as well as gamma/delta T cells were greatly reduced. The CD4:CD8 ratio was fivefold increased. Mixed lymphocyte reaction assays of the product against third-party leukocytes revealed reduced allo-reactivity compared to starting material. Anti-pathogen responses were retained. DISCUSSION: The novel, closed, fully GMP-compatible process on Prodigy generates highly CD45RA-depleted cellular products predicted to be clinically meaningfully depleted of GvH reactivity. PMID- 29500070 TI - Screening for TSC1 and TSC2 mutations using NGS in Greek children with tuberous sclerosis syndrome. AB - Tuberous Sclerosis Complex (TSC) is a rare neurocutaneous syndrome inherited by an autosomal dominant manner. The disorder is commonly manifested by the presence of multiple benign tumors located in numerous tissues, including the brain, heart, skin and kidneys. Seizures, autism, developmental and behavioral delay, as well as non-neurological phenotypic findings, are suggestive of TSC. The identification of one pathogenic mutation in either the TSC1 or TSC2 genes is considered to be an independent diagnostic criterion. In our study, seventeen Greek patients, 2yo on average, were analyzed for the presence of pathogenic germline mutations in the aforementioned loci by Next-Generation Sequencing. A TSC1/2 gene panel was designed for the molecular diagnosis of the disease. Patients underwent initial diagnosis based on their clinical symptoms, most frequently involving the presence of skin lesions and/or epilepsy. Only one case was familial. Sixteen different genetic alterations were identified in TSC1 and TSC2 genes in fifteen patients, giving a 88% detection rate by employing NGS technology. Overall, most pathogenic mutations (11/15) identified were located in the TSC2 gene with exon 41 being the most frequent. With respect to genotype phenotype association, no patient TSC1 (+) developed SEGA or renal cysts. No significant differences were observed between different types of TSC2 mutations and any clinical feature. Sequencing also revealed 18 different SNPs across the TSC1 and 20 across the TSC2 genes. This is the first registry of the genetic profile of TSC patients in Greece using a custom-made gene panel as molecular diagnostic tool. PMID- 29500071 TI - Transient regional cerebral hypoperfusion during a paroxysmal hemiplegic event in GLUT1 deficiency syndrome. AB - GLUT1 deficiency syndrome (GLUT1DS) is a well described neurometabolic disorder that results from impaired glucose transport into the central nervous system. GLUT1DS classically presents with infantile-onset epilepsy, progressive microcephaly, developmental delay, ataxia, dystonia, and spasticity, but a minority of patients may manifest with paroxysmal non-epileptic phenomena including hemiparesis (Wang et al., 2002). We report for the first time cerebral perfusion changes during an acute episode of hemiparesis in a 9 year old child with GLUT1DS. The patient presented as a code stroke with her second episode of acute-onset left hemiparesis and altered mental status. Emergency MRI of brain demonstrated normal diffusion-weighted imaging, but arterial spin label perfusion weighted imaging (ASL-PWI) showed regional hypoperfusion of the right cerebral hemisphere and magnetic resonance angiography (MRA) revealed distally restricted flow related enhancement in the right MCA. The patient's deficits resolved entirely within several hours from onset. Repeat MRI one month later was normal. Our report suggests that GLUT1DS-related hemiplegic events are associated with transient lateralized cerebrovascular hypoperfusion similar to that described in hemiplegic migraine and other pediatric stroke mimics. The underlying pathophysiology for this phenomenon in GLUT1DS is not known, but may relate to cortical energy failure or abnormal cerebral microvasculature. PMID- 29500072 TI - Anatomic landmarks for arthroscopic suprapectoral biceps tenodesis: a cadaveric study. AB - BACKGROUND: Biceps tenodesis reduces the incidence of Popeye deformity occurring with tenotomy, but pain may occur with tenodesis superior to or within the bicipital groove. Arthroscopic suprapectoral tenodesis is an attractive alternative. The purpose of this study was to establish landmarks for arthroscopic suprapectoral tenodesis and determine the appropriate fixation point to optimize muscle tension. METHODS: Twelve fresh cadaveric shoulders were dissected. Urethane polymer was injected into the axillary artery. The position of the anterior branch of the axillary nerve was marked. The transverse humeral ligament was split, exposing the biceps (long head of the biceps [LHB]) from its origin to the pectoralis major tendon (PMT). The intra-articular portion was released. Measurements were taken from the proximal tendon to described landmarks. RESULTS: The mean length of the intra-articular LHB was 2.53 cm (range, 1.72-3.55 cm). The mean distance from the LHB origin to the inferior lesser tuberosity (LT) was 5.58 cm (range, 4.02-6.87 cm), and that to the superior border of the PMT was 8.46 cm (range, 6.46-10.78 cm). The suprapectoral tenodesis zone (inferior LT to superior PMT) was 2.96 cm (range, 1.54-4.40 cm). In all specimens, a branch of the anterior humeral circumflex arose medial to the LHB and distal to the LT and crossed the suprapectoral zone from medial to lateral at 1.49 +/- 0.42 cm proximal to the PMT, approximately at the level of the axillary nerve. The musculocutaneous nerve was on average 3.06 cm (range, 1.86-3.76 cm) from the tenodesis zone. CONCLUSION: A branch of the anterior humeral circumflex is a reliable landmark for identifying the mid-suprapectoral zone. The distance from the proximal LHB tendon to this crossing vessel averaged 6.32 cm in female specimens and 8.28 cm in male specimens. These findings allow appropriate tensioning of the LHB during arthroscopic suprapectoral tenodesis. PMID- 29500073 TI - The Root Transition Zone: A Hot Spot for Signal Crosstalk. AB - The root transition zone (TZ), located between the apical meristem and basal elongation region, has a unique role in root growth and development. The root TZ is not only the active site for hormone crosstalk, but also the perception site for various environmental cues, such as aluminum (Al) stress and low phosphate (Pi) stress. We propose that the root TZ is a hot spot for the integration of diverse inputs from endogenous (hormonal) and exogenous (sensorial) stimuli to control root growth. PMID- 29500075 TI - [Immunosuppressive therapy and fertility preservation: Indications and methods]. AB - Fertility preservation is routinely performed in cancerology but less systematically used in the field of immune diseases, even though the use of gonadotoxic treatments in young patients may be required and even though the disease itself can alter fertility. This review aimed to clarify the indications and methods of fertility preservation in this context. Cyclophosphamide is the only immunosuppressive drug requiring fertility preservation in women. In men, fertility preservation should be proposed before treatment with cyclophosphamide, methotrexate, mycophenolate mofetil or mTOR inhibitors. Other factors inherent to the disease or the patient may alter fertility. Thus, screening for infertility and fertility preservation have to be implemented as much as possible to increase the chances of successful procreation in patients with immune disease. For women, the choice between the different preservation methods depends on the patient's age, disease activity, the time available before the start of treatment, the possibility of future pregnancy and the woman's and even couple's wishes. Before puberty, the only accepted method is cryopreservation of ovarian tissue. After puberty, the first-line method is the cryopreservation of mature oocytes. If the treatment has to be started in an emergency, if ovarian hyperstimulation/oocyte retrieval is contraindicated or if the patient refuses this option, cryopreservation of ovarian tissue or GnRH agonists could be proposed. For men, the accepted method is sperm cryopreservation. For prepubertal boys, the cryopreservation of spermatogonia after testicular biopsy is still experimental. PMID- 29500074 TI - Executive function in high-functioning autism: Decision-making consistency as a characteristic gambling behaviour. AB - Restricted and repetitive patterns of behaviours, interests, or activities are a critical diagnostic criterion for autism spectrum disorder (ASD). Previous studies using gambling paradigms with ASD populations have identified that, unlike typically developed control participants, people with a diagnosis of ASD tend to maintain particular response patterns regardless of the magnitude of potential outcomes to uncertain gains or losses. Here we designed a gambling test that permitted calculation of the response consistency in gambling choices in situations that presented varying expected outcomes in terms of gains or losses. The task was administered to 33 adults with a diagnosis of ASDs and compared to a group of 47 typically-developed (TD) control participants who were matched for age and IQ. When presented with choices where participants could either make a risky gamble or a safe choice in terms of gains or losses (e.g., 20% chance of winning L5 vs. 100% chance of winning L1), the ASD participants did not differ from the TDs in their overall risk-taking behaviour. However, they were more consistent in their individual choices from trial to trial. Furthermore, the proportion of participants who either implemented an invariate response strategy (e.g., either always choosing the most risky or most "safe" option) was significantly higher in the ASD group compared with the controls. Additionally, while the ASD group were slower to make their responses in the win frame and the first half of the lose frame, by the end of the task their decision times were the same as the TD controls. These findings suggest that the ASD tendency towards repetitive behaviour may demonstrate itself even in high-level decision-making tasks, which needs to be understood if we are to be sure what such tasks are measuring. PMID- 29500076 TI - Immunotherapy for cervical cancer: Can it do another lung cancer? AB - Cervical cancer, although preventable, is still the second most common cancer among women worldwide. In developing countries like India, where screening for cervical cancer is virtually absent, most women seek treatment only at advanced stages of the disease. Although standard treatment is curative in more than 90% of women during the early stages, for stage IIIb and above this rate drops to 50% or less. Hence, novel therapeutic adjuvants are required to improve survival at advanced stages. Lung cancer has shown the way forward with the use of Immunotherapeutic interventions as standard line of treatment in advanced stages. In this review, we provide an overview of mechanisms of immune evasion, strategies that can be employed to boost the immune system in order to improve the overall survival of the patients and summarize briefly the clinical trials that have been completed or that are underway to bring therapeutic vaccines for cervical cancer to the clinics. PMID- 29500077 TI - Protective role of 6-formylindolo[3,2-b]carbazole (FICZ), an endogenous ligand for arylhydrocarbon receptor, in chronic mite-induced dermatitis. AB - BACKGROUND: Chronic eczema such as atopic dermatitis imposes significant socio econo-psychologic burdens on the affected individuals. In addition to conventional topical treatments, phototherapy is recommended for patients with extensive lesions. Although immunosuppression is believed to explain its primary effectiveness, the underlying mechanisms of phototherapy remain unsolved. Ultraviolet irradiation generates various tryptophan photoproducts including 6 formylindolo[3,2-b]-carbazole (FICZ). FICZ is known to be a potent endogenous agonist for aryl hydrocarbon receptor (AHR); however, the biological role of FICZ in chronic eczema is unknown. OBJECTIVE: To investigate the effect of FICZ on chronic eczema such as atopic dermatitis. METHODS: We stimulated HaCaT cells and normal human epidermal keratinocytes (NHEKs) with or without FICZ and then performed quantitative reverse transcriptase polymerase chain reaction, immunofluorescence, and siRNA treatment. We used the atopic dermatitis-like NC/Nga murine model and treated the mice for 2 weeks with either Vaseline(r) as a control, FICZ ointment, or betamethasone 17-valerate ointment. The dermatitis score, transepidermal water loss, histology, and expression of skin barrier genes and proteins were evaluated. RESULTS: FICZ significantly upregulated the gene expression of filaggrin in both HaCaT cells and NHEKs in an AHR-dependent manner, but did not affect the gene expression of other barrier-related proteins. In addition, FICZ improved the atopic dermatitis-like skin inflammation, clinical scores, and transepidermal water loss in NC/Nga mice compared with those of control mice. On histology, FICZ significantly reduced the epidermal and dermal thickness as well as the number of mast cells. Topical FICZ also significantly reduced the gene expression of Il22. CONCLUSION: These findings highlight the beneficial role of FICZ-AHR and provide a new strategic basis for developing new drugs for chronic eczema. PMID- 29500078 TI - Cognitive Computational Neuroscience: A New Conference for an Emerging Discipline. AB - Understanding the computational principles that underlie complex behavior is a central goal in cognitive science, artificial intelligence, and neuroscience. In an attempt to unify these disconnected communities, we created a new conference called Cognitive Computational Neuroscience (CCN). The inaugural meeting revealed considerable enthusiasm but significant obstacles remain. PMID- 29500079 TI - Explicit instructions facilitate performance of OCD participants but impair performance of non-OCD participants on a serial reaction time task. AB - Previous studies have shown that individuals diagnosed with OCD tend to rely on explicit processing while performing implicit learning tasks. We sought to investigate whether individuals with OCD are capable of implicit learning, but would demonstrate improved performance when explicit processing strategies are enhanced. Twenty-four participants with OCD and 24 non-psychiatric control (NPC) participants performed an implicit learning task in which they responded to a single target stimulus that successively appears at one of four locations according to an underlying sequence. We manipulated the learning strategy by informing half of the participants that the target stimulus location was determined by an underlying sequence, which they should identify (intentional learning). The other half of the participants was not informed of the existence of the underlying sequence, and was expected to learn the sequence implicitly (standard learning). We predicted that OCD participants will exhibit inferior performance compared to NPC participants in the standard learning condition, and that intentional learning instructions would impair the performance of NPC participants, but enhance the performance of OCD participants. The results supported these predictions and suggest that individuals with OCD prefer controlled to automatic processing. We discuss the implications of this conclusion to our understanding of OCD. PMID- 29500080 TI - [Nephrotoxicity of antiretrovirals other than tenofovir]. AB - The remarkable improvement of the outcome of HIV infection came with the price of substantial toxicity of some antiretrovirals. The first molecules used to treat HIV included an important nephrotoxicity. Zalcitabine, stavudine and didanosine can induce severe lactic acidosis. Lactate production is enhanced and the renal capacity to regulate pH is overwhelmed. However, this side effect is not due to a direct dysfunction of the kidneys. Zalcitabine was withdrawn from the market because of this risk. Indinavir, a protease inhibitor, is soluble only in very acidic solutions. Consequently, the small fraction that is excreted in the urine precipitates and can be responsible for uro-nephrolithiasis, leukocyturia, cristalluria, obstructive acute kidney failure, and acute or chronic interstitial nephritis. This is the reason why indinavir is almost not prescribed nowadays, even if it is still marketed. In addition to the direct nephrotoxicity of some antiretrovirals, anti-HIV treatment also includes a toxicity which pathophysiology is not completely elucidated. This nephrotoxicity is the consequence of organ accelerated ageing and of an increased vascular risk. Kidney vascularization (from renal arteries to capillaries) is essential to kidney function and all cardiovascular risks are also renal risks. It is now clearly established that combined antiretroviral treatment increases the vascular risk. A better comprehension of the links between HIV infection, its treatment and very long-term kidney risk is needed to improve the complex management of patients who have now cumulated several decades of HIV infection and treatment with various toxicities. PMID- 29500081 TI - Laboratory studies on effect of fiber content on dynamic characteristics of municipal solid waste. AB - The dynamic characterization of municipal solid waste (MSW), especially in regions with high seismicity, is of considerable importance in the stability assessment of landfills. Additionally, findings indicated that the response of MSW under dynamic loadings is significantly affected by fibrous material. Therefore, a comprehensive strain-controlled cyclic triaxial testing program was performed on MSW samples retrieved from a landfill in the Kahrizak area, Tehran province. The tests were conducted on fresh MSW specimens (with a diameter of 100 mm) with different percentage of fibers in the consolidated undrained condition. The potential reinforcing capability of fibers and their impacts on changes in the MSW composition were investigated under variations of different factors including confining pressure, loading frequency, Poisson's ratio, and loading cycles. From the results of the study, increasing fiber content in specimens resulted in improved elastic behavior of MSW under dynamic loadings, irrespective of the test conditions, such that the normalized shear modulus reduction curves shifted to the right, while the damping ratio curves exhibited no specific trend. However, it is necessary to simultaneously consider the impact of fiber contents, confining stress and shear strain on the variation rates of normalized shear modulus reduction values. This trend is attributed to the greater values of stiffness from changing the composition when compared with the one generated by obtained reinforcement within the studied strain range. Given the lack of systematic evaluations on the effect of the fibrous waste materials on the dynamic response of MSW, the results of this study provide additional insight into the seismic analysis of landfills. PMID- 29500082 TI - Mesophilic anaerobic co-digestion of the organic fraction of municipal solid waste with the liquid fraction from hydrothermal carbonization of sewage sludge. AB - In the present study, the influence of substrate pre-treatment (grinding and sieving) on batch anaerobic digestion of the organic fraction of municipal solid waste (OFMSW) was first assessed, then followed by co-digestion experiments with the liquid fraction from hydrothermal carbonization (LFHTC) of dewatered sewage sludge (DSS). The methane yield of batch anaerobic digestion after grinding and sieving (20 mm diameter) the OFMSW was considerably higher (453 mL CH4 STP g-1 VSadded) than that of untreated OFMSW (285 mL CH4 STP g-1 VSadded). The modified Gompertz model adequately predicted process performance. The maximum methane production rate, Rm, for ground and sieved OFMSW was 2.4 times higher than that of untreated OFMSW. The anaerobic co-digestion of different mixtures of OFMSW and LFHTC of DSS did not increase the methane yield above that of the anaerobic digestion of OFMSW alone, and no synergistic effects were observed. However, the co-digestion of both wastes at a ratio of 75% OFMSW-25% LFHTC provides a practical waste management option. The experimental results were adequately fitted to a first-order kinetic model showing a kinetic constant virtually independent of the percentage of LFHTC (0.52-0.56 d-1) and decreasing slightly for 100% LFHTC (0.44 d-1). PMID- 29500083 TI - Influence of pork and bone on product characteristics during the fast pyrolysis of pig carcasses. AB - The characteristics of the products of pig carcass pyrolysis depend on initial feedstock composition, specifically tissue and bone, as well as the interaction between these components. In this work, the raw pork (RP), pig bone (PB), and a mixture of RP and PB to simulate pig carcasses with a mass ratio of 2:1 (RB21) were pyrolyzed at 650 degrees C and compared to investigate pig carcass pyrolytic product characteristics. The presence of minerals in PB was found to increase the gaseous product yields of RB21 by 16%, especially the CO2, C2H4 and C2H6 yields through steam gasification and steam reforming reactions. These minerals also affect tar product distribution, promoting the cracking of long chain hydrocarbons and the cyclization reaction of hydrocarbons, esters, amides/nitriles to produce more aromatic, O-heterocyclic and N-heterocyclic compounds, respectively. The Brunauer-Emmett-Teller (BET) surface area of pyrolytic RB21 char is 134.025 m2/g and it is a porous material rich in minerals like Ca, P, and K. The addition of RP causes more wrinkles on the surface and reduces its mesopore diameter from 6.263 nm to 5.412 nm. The Ca and P in char are derived from hydroxyapatite occurring in PB, and K presents in RP participates in the crystallization of RB21 char, forming a new crystal compound Ca8H2(PO4)6.KHCO3. PMID- 29500085 TI - Current strategies for the treatment of inborn errors of metabolism. AB - Inborn errors of metabolism (IEMs) are a large group of inherited disorders characterized by disruption of metabolic pathways due to deficient enzymes, cofactors, or transporters. The rapid advances in the understanding of the molecular pathophysiology of many IEMs, have led to significant progress in the development of many new treatments. The institution and continued expansion of newborn screening provide the opportunity for early treatment, leading to reduced morbidity and mortality. This review provides an overview of the diverse therapeutic approaches and recent advances in the treatment of IEMs that focus on the basic principles of reducing substrate accumulation, replacing or enhancing absent or reduced enzyme or cofactor, and supplementing product deficiency. In addition, the challenges and obstacles of current treatment modalities and future treatment perspectives are reviewed and discussed. PMID- 29500084 TI - Imaging biomarkers of outcome after radiotherapy for pediatric ependymoma. AB - BACKGROUND AND PURPOSE: Ependymoma is the third most common brain tumor in children. Radiation therapy (RT) is systematically administered after maximum surgical resection, utilizing recent advances in radiation delivery. Imaging can make a significant contribution to improving treatment outcome. This prompted us to look for significant preoperative and postoperative imaging markers for survival. MATERIAL AND METHODS: We undertook a national retrospective review of 121 patients who had undergone resection followed by RT. Preoperative tumor volumes on T1 and FLAIR images were delineated, together with postoperative hyperintense volumes on FLAIR images. Overall survival (OS) and disease-free survival (DFS) analyses included clinical data and volumes extracted from images. RESULTS: After a median follow-up of 38.5 months, 80.2% of patients were alive, but 39.7% had experienced at least one event. Statistically significant differences between patients with and without postoperative FLAIR abnormalities were found for both DFS (71.9% vs. 40.3%; p = 0.006) and OS (93.7% vs. 72.4%; p = 0.023) in the univariate analyses, and for OS (p = 0.049) in the multivariate analyses. CONCLUSIONS: Postoperative FLAIR hyperintensities are a negative prognostic factor for intracranial ependymoma and may be a surrogate for residual disease. They could therefore prove helpful in patients' surgical and radiotherapeutic management. PMID- 29500086 TI - Precision medicine in hearing loss. AB - Precision medicine (PM) proposes customized medical care based on a patient's unique genome, biomarkers, environment and behaviors. Hearing loss (HL) is the most common sensorineural disorder worldwide and is frequently caused by a single genetic mutation. With recent advances in PM tools such as genetic sequencing and data analysis, the field of HL is ideally positioned to adopt the strategies of PM. Here, we review current and future applications of PM in HL as they relate to the four core qualities of PM (P4): predictive, personalized, patient-centered, and participatory. We then introduce a strategy for effective incorporation of HL PM into the design of future research studies, electronic medical records, and clinical practice to improve diagnostics, prognostics, and, ultimately, individualized patient treatment. Finally, specific anticipated ethical and economic concerns in this growing era of genomics-based HL treatment are discussed. By integrating PM principles into translational HL research and clinical practice, hearing specialists are uniquely positioned to effectively treat the heterogeneous causes and manifestations of HL on an individualized basis. PMID- 29500087 TI - The Use of Fluoroscopy During Direct Anterior Hip Arthroplasty: Powerful or Misleading? AB - BACKGROUND: Direct anterior approach total hip arthroplasty (THA) with fluoroscopic assistance is growing in popularity. Variables such as pelvic tilt, c-arm technique, and patient positioning can affect the perceived fluoroscopic view. This study evaluates the effect of these variables on the position of the acetabular component. METHODS: Forty-one hips in 40 patients undergoing direct anterior arthroplasty THA with fluoroscopic assistance underwent routine postoperative radiographs and postoperative pelvic computed tomography scan. The acetabular component position as defined by a 3-dimensional reconstruction was compared to the surgeon's intraoperative perception of the component's position and compared to routine postoperative plain radiograph measurements. RESULTS: Although fluoroscopy was used to create an anteroposterior pelvic radiograph utilizing the coccyx to pubis symphysis distance, a 3D reconstruction created in the same pelvic orientation as the fluoroscopic images confirmed that 39/41 hips were placed with unrecognized excess of anteversion and inclination secondary to imaging the pelvis in extension. CONCLUSION: Intraoperative imaging during supine direct anterior arthroplasty THA confirms appropriate component placement. Pelvic tilt can greatly affect the perceived position of the acetabular component and cannot be accurately compensated for by assessing the relationship between the coccyx and pubic symphysis due to morphologic variation and orientation. We recommend positioning the c-arm so that the size and shape of the obturator foramen matches the standing preoperative anteroposterior pelvis image. This technique allows for the native standing pelvic tilt to be accounted for intraoperatively and will result in the least variation in intraoperative and postoperative standing acetabular component orientation. PMID- 29500088 TI - Dual-Mobility Constructs in Revision Total Hip Arthroplasties. AB - Dislocation after revision total hip arthroplasty (THA) continues to be one of the most common and concerning complications after the procedure. As with every hip arthroplasty, it is essential to optimize component positioning, minimize impingement, and maintain the integrity of the abductor complex during the revision THAs. However, in several revision circumstances, additional strategies are required to mitigate the risk of dislocation, particularly those being revised for instability or those with cognitive or neuromuscular disorders. In such revision THAs, dual-mobility constructs offer lower rates of dislocations and re-revisions for dislocations in the midterm. However, it is important to note that dual-mobility constructs should not be considered as compensation for poor surgical technique or technical errors such as poor cup orientation or inappropriate restoration of soft-tissue tension. While intraprosthetic dislocations are a unique complication to dual-mobility constructs, they are exceedingly rare. Furthermore, additional follow-up is required with modular dual mobility constructs utilized with increasing frequency during revision THAs in North America. PMID- 29500089 TI - Venous Thromboembolism Following Total Knee Arthroplasty: Does Race Matter? AB - BACKGROUND: Venous thromboembolism (VTE) (deep venous thrombosis and pulmonary embolism) is a known complication following total knee arthroplasty (TKA). Recent literature has identified differences in VTE risk based on race with African Americans having higher risk of VTE. This study evaluated the impact of race on VTE following TKA using a large multicenter database. METHODS: We queried the American College of Surgeons National Surgical Quality Improvement Program to identify patients who underwent primary TKA in 2010-2014. Patients were stratified based on race: Asian, Black/African American, White, and Other. Demographics were compared to determine the impact on 30-day postoperative complications. Multivariate logistic regression analysis was performed to control for confounding demographics and comorbidities between races. Primary outcomes included overall complications and VTE. RESULTS: In total, 96,230 patients were included. Univariate analysis demonstrated that Blacks had a significantly higher rate of any complication (5.5%), deep venous thrombosis (1.3%), and pulmonary embolism (1.1%) than other races (P = .007, P < .001, and P < .001, respectively). Overall mortality rate did not differ between races (P = .26). Multivariate regression analysis identified that Blacks were significantly more likely to have a VTE than Whites (odds ratio 1.7, 95% confidence interval 1.4 2.0). Overall complications were significantly higher for Blacks than Whites (odds ratio 1.1, 95% confidence interval 1.02-1.3). There were no differences in the rates of VTE or overall complications between Asians/Other races and Whites. CONCLUSION: Blacks have a significantly higher risk of VTE following primary TKA than other races. Future studies should investigate causes for this disparity. PMID- 29500090 TI - Kaiser Permanente: Joint Arthroplasty in an Integrated Capitated Care Delivery Model. AB - BACKGROUND: Total joint arthroplasty is a successful operation with increasing prevalence in the United States. Kaiser Permanente has been using multiple tools to optimize patient outcomes while keeping health-care expenditures in check. METHODS: We describe the patient, surgeon, and hospital perspective toward the delivery of sustainable arthroplasty care for a growing elderly population. Quality metrics for each stakeholder are presented. RESULTS: Kaiser Permanente optimizes value for the patient, surgeon, and hospital with the use of evidence based integrated care pathways and a national joint arthroplasty registry. CONCLUSION: A continued focus on value-driven care will provide continued efficiency in a time of growth with maintenance of excellent outcomes. PMID- 29500091 TI - Cementless Total Hip Arthroplasty in Crowe III and IV Dysplasia: High Hip Center and Modular Necks. AB - BACKGROUND: Total hip arthroplasty (THA) in severe developmental dysplasia of the hip (DDH) is a challenging procedure. The most used techniques involve anatomic cup positioning, augmentation femoral osteotomy. However, anatomic cup positioning is not always feasible in severe DDH and osteotomy nonunion may ensue. The purpose of the study was to assess the survivorship, the hip score results, the radiological parameters (fixation, loosening, component position) of a large cohort of patients with Crowe III and IV DDH, treated with high hip center and modular necks THAs. METHODS: Eighty-four THAs in Crowe III and IV DDH were evaluated, achieving a final follow-up of 15.1 years. All the patients were treated with the same cementless implant (modular necks and ceramic-on-ceramic coupling) and the same approach (high cup placement with slight medialization). The patients were clinically evaluated (Harris Hip score and Merle d'Aubigne and Postel score). A radiographic evaluation was performed, analyzing the orientation of the cup. RESULTS: Eighty patients were available at the last follow-up. The clinical scores were good at the final follow-up. Two sciatic lesions occurred: one patient fully recovered. The overall survivorship was 90.5% at 15 years: only 2 cases of aseptic loosening were reported. The mean center of rotation height was 33 +/- 8 mm and the medialization was 30 +/- 5 mm. CONCLUSION: A high cup placement with slight medialization is a valid technique in DDH patients. A good restoration of the offset, ceramic-on-ceramic coupling and a porous socket may provide durable results, overcoming the effects of increasing joint reaction forces related to high cup placement. PMID- 29500092 TI - Gym-based exoskeleton walking: A preliminary exploration of non-ambulatory end user perspectives. AB - BACKGROUND: Robotic walking devices (RWD) have shown many physical benefits in Spinal Cord Injury (SCI) rehabilitation. No study to date has explored end-user perceptions of these devices or gained insight into the use of these devices in a gym-based setting. OBJECTIVE: This preliminary study explores the perspectives of four non-ambulatory individuals with SCI on using an exoskeleton walking device in a gym-based community setting. METHODS: In-depth, semi-structured interviews were conducted with four SCI individuals living in the community. Interviews were audio-recorded and transcribed verbatim. Inductive thematic analysis established common overarching themes and subthemes. RESULTS: Four primary themes emerged addressing "The Psychological Adjustments Around Using RWDs with Respect to Disability", "Perceived Physical, Social and Psychological Benefits of Using an Exoskeleton", "The Role of External Influences", and "A Wellness Model to Health". A fully integrated gym setting was found to provide a positive and encouraging space to utilise the device. In addition, both the ability to set training goals and the positive attitude of robotic trainers were deemed to be important factors. CONCLUSIONS: This preliminary study provides detailed perspectives of four non-ambulatory individuals with SCI on utilising an exoskeleton walking device in a community setting. It suggests that gym-based RWDs impact positively on the users' lives and enhance their perceived wellbeing and sense of community integration. Enabling access to similar, community-based facilities should be prioritised for those with longstanding SCI disability. PMID- 29500094 TI - Ketogenic diet and avoidance of mitochondrion-toxic AEDs may improve the outcome of mitochondrial epilepsy. PMID- 29500093 TI - Breast cancer screening in women with cerebral palsy: Could care delivery be improved? AB - BACKGROUND: Women with disabilities (WWD) have reported lower mammography rates than the general population, however rates for women with cerebral palsy (CP) have not been specifically studied. OBJECTIVE: To evaluate mammography rates in women with CP and to identify strengths and barriers with their screening experience. METHODS: Women with CP 40 years or older (n = 118) participating in a prospective cross-sectional survey were queried regarding screening status, imaging modality, and accommodation needs and availability. Categorical variables were summarized and Chi-square testing used to assess factors contributing to screening compliance. The effect of functional factors on screening was evaluated using logistic regression. RESULTS: 77 women (65.3%) had mammograms within the past two years; 56 (47.5%) were screening mammograms. Severity of fine motor deficits was associated with lack of screening (OR 0.559, p = 0.019). 85 (72.0%) experienced positive staff attitudes. Facilities most often met needs for ramps, elevators, and/or wide doorways (92.9%), exam explanations (84.4%), and accessible parking (82.5%). Needs least often met included accommodations for standing (59.3%) or for difficulties with arm/shoulder positioning (57.1%), and wheelchair-accessible mammogram machines (59.1%). CONCLUSIONS: The screening compliance rate for women with CP is low, although the 2-year mammography rate is comparable to that reported for WWD and the general female U.S. POPULATION: Women were usually offered respectful care. Adequate physical accommodations during the procedure were reported less often than overall facility environmental accommodations. These findings demonstrate the need for improved screening rates in women with CP, and highlight areas for improving their screening experience. PMID- 29500096 TI - HIV-Related Stigma, Quality of Care, and Coping Skills: Exploring Factors Affecting Treatment Adherence Among PLWH in Haiti. AB - Stigma is a primary barrier to care and support for people living with HIV (PLWH). We explored relationships between HIV-related stigma and treatment adherence and the effects of psychological and structural factors on these relationships. HIV treatment adherence, stigma, and coping strategies were measured with questionnaires. Participants included 285 PLWH in Haiti. Multivariable linear regression was used to estimate predictors of treatment adherence. Structural equation modeling was used to determine whether relationships between stigma and treatment adherence variables were mediated by coping variables. Mean adherence was 93.1%; 72.3% of participants reported >= 95% adherence. Perceived stigma and quality-of-care satisfaction scores significantly predicted treatment adherence. Maladaptive coping did not act as a mediator between perceived stigma and treatment adherence, which could be due to stronger effects of perceived stigma on treatment adherence. Our study may help to improve treatment adherence and the care and quality of life for PLWH. PMID- 29500095 TI - Pulmonary vein orientation is independently associated with outcomes following cryoballoon-based atrial fibrillation ablation. AB - AIMS: Several studies have investigated the influence of pulmonary vein (PV) anatomy on outcomes of atrial fibrillation (AF) ablation. We aimed to evaluate the relationship between PV orientation and AF-free survival following cryoablation. METHODS: 160 patients scheduled for cryoablation between September 2012-March 2014 were included. Patients underwent a pre-procedural cardiac CT scan with retrospective ECG gating. PV orientation was assessed according to the position of the PV orifice relative to the sagittal plane with reference to coronal and horizontal planes. RESULTS: 160 patients (57 +/- 9 years, 54% male, 33% persistent AF) were included and followed for a median of 17 (12-36) months. Excluding a blanking period of 3 months, freedom from AF after a single ablation procedure was 76%. Ventral-caudal left upper PV (p = 0.044) and ventral-caudal left lower PV orientation (p = 0.001) were more common in patients with AF recurrence. In multivariate Cox regression analysis, only left lower PV orientation [particularly dorsal-caudal (HR: 3.447, 95% CI: 1.180-10.070, p = 0.024) and ventral-caudal (HR: 3.391, 95% CI: 1.088-10.571, p = 0.035) orientations compared to dorsal-cranial orientation] as well as LA diameter (HR: 3.420, 95% CI: 1.809-6.465, p < 0.001) were significantly associated with AF recurrence. CONCLUSION: This is the first study to demonstrate the impact of PV orientation on prediction of AF recurrence following cryoablation. Preprocedural assessment of PV orientation may modify operator preferences on treatment strategies in AF. PMID- 29500097 TI - "I Am a Good Example": Suggestions From HIV-Infected Cambodians for Preventing HIV Infection in Marital Relationships. AB - Developing effective and influential messages for HIV prevention in marriage has been difficult. We explored couple-based HIV prevention measures that would be socially and culturally suitable for Cambodia. Thirty in-depth qualitative interviews were conducted with people living with HIV in the local Khmer language. Using thematic analysis, codes and themes were generated to get to the meanings of participant data. Male and female suggestions were analyzed together, and four themes emerged: (a) Safer practices, (b) Trustworthy relationships, (c) Sexual variety, and (d) Exemplar. Premarital HIV testing, grooming oneself, sexual variety within a married relationship, monogamy, and sex education for teenagers were significant suggestions derived from participant input about protecting spouses from HIV infection. The explained strategies illustrated the importance of gender-based prevention programs in Cambodia and provided insight about needed and possible interventions to prevent HIV transmission within marriage. PMID- 29500100 TI - Theta burst stimulation on social cognition and N-Acetyl aspartate in two patients with schizophrenia. PMID- 29500099 TI - Reply to the letter to the editor by Josef Finsterer and Sinda Zarrouk-Mahjoub. PMID- 29500101 TI - Short communication: Sex-linked differences in gamma-aminobutyric acid (GABA) are related to social functioning in autism spectrum disorder. AB - Magnetic resonance spectroscopy (MRS) was utilized to investigate sex differences in gamma-aminobutyric acid (GABA) between adults with autism spectrum disorder (ASD) and neurotypical (NT) controls. GABA at the right superior temporal sulcus (STS) is reported for 12 ASD and 14 NT participants. The results show no group differences in GABA. There was, however, a significant positive association between GABA at the STS and autism-related social impairments in females with ASD. These findings provide preliminary support for sex differences in GABAergic distribution and processes that contribute to social functioning in ASD. PMID- 29500098 TI - SREBPs in Lipid Metabolism, Insulin Signaling, and Beyond. AB - Sterol regulatory element-binding proteins (SREBPs) are a family of membrane bound transcription factors that activate genes encoding enzymes required for synthesis of cholesterol and unsaturated fatty acids. SREBPs are controlled by multiple mechanisms at the level of mRNA synthesis, proteolytic activation, and transcriptional activity. In this review, we summarize the recent findings that contribute to the current understanding of the regulation of SREBPs and their physiologic roles in maintenance of lipid homeostasis, insulin signaling, innate immunity, and cancer development. PMID- 29500102 TI - Prevalence of methicillin-resistant Staphylococcus aureus among veterinary staff in small animal hospitals in Sapporo, Japan, between 2008 and 2016: A follow up study. AB - The aim of the present study was to determine and compare the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) and their molecular characteristics among veterinary staff in Sapporo in 2008 and 2016. We isolated MRSA from veterinarians (Vet; n = 91), veterinary technicians (VT; n = 113), and other staff members (n = 24) from 45 small animal hospitals (animal hospitals), as well as from surface swabs (n = 123) obtained from 37 animal hospitals, in 2016. MRSA was observed in 14 Vets (15%), 7 VTs (6%), 2 other staff members (8%), and 6 environmental samples (5%). The prevalence of MRSA among veterinary staff tended to decrease, in comparison to 2008. All the MRSA isolates were classified as CC5/SCCmecII, which is commonly observed in medical settings in Japan. Upon performing pulse-field gel electrophoresis, with SmaI and EagI, and clfB sequence typing, it was observed that 16 of the MRSA isolates from 2016 were highly similar to those obtained in 2008. This suggests that some MRSA isolates persisted throughout 8 years, although their origins remain unclear. The continuation of education and monitoring of MRSA is necessary for the prevention and control of infection in these settings. PMID- 29500103 TI - Preclinical randomized controlled trial of bilateral discectomy versus bilateral discopexy in Black Merino sheep temporomandibular joint: TEMPOJIMS - Phase 1- histologic, imaging and body weight results. AB - INTRODUCTION: The role of temporomandibular joint (TMJ) surgery is not well defined due to a lack of quality randomized controlled clinical trials, comparing different TMJ surgical treatments with medical and placebo interventions. The temporomandibular joint interposal study (TEMPOJIMS) is a rigorous preclinical trial divided in 2 phases. In phase 1 the authors investigated the role of the TMJ disc and in phase 2 the authors evaluated 3 different interposal materials. The present work of TEMPOJIMS - phase 1, aims to evaluate histopathologic and imaging changes of bilateral discectomy and discopexy in Black Merino sheep TMJ, using a high-quality trial following the ARRIVE guidelines. MATERIAL AND METHODS: This randomized, blinded and controlled preclinical trial was conducted in 9 Black Merino sheep to investigate histopathologic (primary outcome), imaging and body weight (secondary outcomes) changes after bilateral discectomy, discopexy and sham surgery. RESULTS: Significant changes were noticed in discectomy group, both in imaging and histopathologic analyses. Body weight changes were most pronounced in the discectomy group in the first 4 months after surgery with recovery to baseline weight 6 months after surgery. Discopexy induced nonsignificant changes in histopathologic, imaging and body weight analyses. CONCLUSIONS: This study reinforces the importance of developing an effective interposal material to substitute the TMJ disc and the need to explore the molecular mechanisms that underlie TMJ cartilage degeneration. The study design proposed in TEMPOJIMS represents an important progress towards future rigorous TMJ investigations. PMID- 29500104 TI - Increased neutrophil to lymphocyte ratio predicts myocardial injury in patients undergoing non-cardiac surgery. AB - BACKGROUND: The neutrophil to lymphocyte ratio (NLR), has been proposed as potential indicator of cardiovascular events. Our aim was to determine the relationship between NLR and development of myocardial injury after non-cardiac surgery (MINS). METHODS: This observational cohort study included 255 consecutive noncardiac surgery patients aged >=45 years. Electrocardiography recordings and high sensitivity cardiac troponin T (hscTnT) levels of the patients were obtained for a period of 3 days postoperatively. RESULTS: MINS was detected in 30 (11.8%) patients using the cut-off level of >=14 ng/L for hscTnT. In the MINS group NLR (3.79 +/- 0.7 vs. 2.69 +/- 0.6, p < 0.000) values were higher than non-NLR group. The NLR to be independently associated with the development of MINS (OR: 11.690; CI: 4.619-29.585, p < 0.000). CONCLUSIONS: NLR seems to be a simple, easy and cheap tool to predict the development of MINS in patient undergoing non-cardiac surgery. PMID- 29500105 TI - Reliability of a Market Basket Assessment Tool (MBAT) for Use in SNAP-Ed Healthy Retail Initiatives. AB - OBJECTIVE: To evaluate the reliability of the Market Basket Assessment Tool (MBAT) for assessing the availability of fruits and vegetables, low-fat or nonfat dairy and eggs, lean meats, whole-grain products, and seeds, beans, and nuts in Supplemental Nutrition Assistance Program-authorized retail environments. METHODS: Different trained raters used the MBAT simultaneously at 14 retail environments to measure interrater reliability. Raters returned to 12 retail environments (85.7%) 1 week later to measure test-retest reliability. Data were analyzed using paired-sample t tests and correlations. RESULTS: No significant differences were found for interrater reliability or test-retest reliability for individual categories (mean differences, 0.0 to 0.3 +/- 0.2 points) or total score (mean difference, 0.5 +/- 0.4 points and (mean differences, 0.0 to 0.3 +/- 0.3 points) or total score (mean difference, 0.8 +/- 0.4 points), respectively. CONCLUSIONS AND IMPLICATIONS: Future steps include validation of the MBAT. A low burden tool can facilitate evaluation of efforts to promote healthful foods in retail environments. PMID- 29500106 TI - Teacher Perceptions and Preferences for 5 School Breakfast Program Models. AB - OBJECTIVE: Identify differences in teacher perceptions of benefits, challenges, and preferences to different School Breakfast Program (SBP) service models. DESIGN: A cross-sectional study design was used and an electronic survey was distributed to teachers throughout the state of Utah. SETTING: Kindergarten through 12th-grade schools throughout Utah. PARTICIPANTS: A convenience sample of 369 kindergarten through 12th-grade teachers in Utah. VARIABLES MEASURED: Demographics, benefits and challenges, and teacher preference for SBP models in Utah. ANALYSIS: Frequencies and multiple comparison analysis tests were performed. A level of significance of <.001 was chosen to protect for multiple comparisons. RESULTS: Traditional breakfast was the most preferred model, with a mean score of 2.8; Breakfast in the Classroom was the least preferred model by teachers, with a mean of -1.3 (scale used = -5 to 0 to 5). Children not going hungry was the greatest benefit (95.4%; n = 352) to SBP and food waste was the greatest challenge (45.8%; n = 168). CONCLUSIONS AND IMPLICATIONS: Teachers prefer traditional SBP model over BIC and other nontraditional models. Increased awareness and education regarding benefits and challenges of SBP models may increase teacher preference for nontraditional SBP models, especially BIC. PMID- 29500108 TI - Integrated skin flash planning technique for intensity-modulated radiation therapy for vulvar cancer prevents marginal misses and improves superficial dose coverage. AB - INTRODUCTION: Radiation therapy (RT) plays a definitive role in locally advanced vulvar cancer, and in the adjuvant setting with high risk postoperative features after wide local excision. There is significant morbidity associated with traditional, large RT fields using 2D or 3D techniques, and the use of intensity modulated radiation therapy (IMRT) in vulvar cancer is increasing. However, there remains a paucity of technical information regarding the prevention of a marginal miss during the treatment planning process. The use of an integrated skin flash (ISF) during RT planning can be used to account for anatomic variation, and intra and interfraction motion seen during treatment. CASE DESCRIPTION: Herein we present the case of a patient with a T1aN0M0, Stage IA vulva cancer to illustrate the progressive vulvar swelling and lymph edema seen during treatment and retrospectively evaluate the dosimetric effects of using an ISF RT plan vs standard RT planning techniques. CONCLUSIONS: Standard planning techniques to treat vulvar cancer patients with IMRT do not sufficiently account for the change in patient anatomy and can lead to a marginal miss. ISF is an RT planning technique that can decrease the risk of a marginal miss and the technique is easily implemented during the planning stages of RT treatment. Furthermore, use of an ISF technique can improve vulvar clinical target volume coverage and plan homogeneity. Based on our experience, and this study, a 2-cm ISF is suggested to account for variations in daily clinical setup and changes in patient anatomy during treatment. PMID- 29500109 TI - Analysis of ion beam teletherapy patient-specific quality assurance. AB - The objective of this study was to evaluate the procedures for patient-specific quality assurance measurements using modulated scanned and energy stacked beams for proton and carbon ion teletherapy. Delivery records from 1734 portal measurements were analyzed using a 3-point pass criteria: more than 22 of 24 chambers in a water phantom (WP) had to have a measured dose difference from the planned portal doses less than or equal to 3%, or the distance from the measurement point location to a point location in the plan having the same dose had to be less than or equal to 3 mm (distance to agreement [DTA]), and the mean dose deviation of all chambers had to be less than 3%. Stratification of results showed some associations between measurement parameters and pass rates. For proton portals, pass rates were high at all measurement depths, but for carbon ion portals, pass rates decreased as a function of increasing measurement depth. Pass rates of both proton and carbon ion portals with 1 WP were slightly lower than those with a second WP. The total pass rates were 97.7% and 91.9% for proton and carbon ion patient portals, respectively. In general, the measured doses exhibited good agreement with the treatment planning system (TPS) calculated doses. When the chamber position was deeper than 150 mm in carbon ion beams, a lower pass rate was observed, which may have been caused by ion chamber array setup uncertainty (lateral and depth) in highly modulated portals or incorrect modeling of scatter by the TPS. These deviations need further investigation. PMID- 29500107 TI - Circulating cytokine levels are associated with symptoms of depression and anxiety among people with alcohol and drug use disorders. AB - BACKGROUND: Psychological distress is common among people with a substance abuse disorder in treatment. Identifying correlates of psychological distress may serve as points of intervention to improve substance abuse treatment outcomes. Immune function measured as cytokine levels have been associated with psychological distress, but this association remains unexplored among people with a substance abuse disorder in treatment. This study aimed to examine whether cytokine levels in patients treated for a substance use disorder were related to depression, anxiety, and overall psychological distress, and to observe these associations separately among people with a past year alcohol use disorder and those with a past year drug use disorder. METHODS: We collected cross-sectional data from 80 inpatients at five alcohol and substance abuse treatment centers in Norway. We determined alcohol and drug diagnoses, and assessed symptoms of depression, anxiety, and overall psychological distress. We tested blood samples for IL-1, IL 6, TNF-alpha, INF-gamma, and IL-10. We used multivariate linear regressions to examine the associations between cytokine levels and psychological distress measures. RESULTS: All cytokines were significantly and positively associated with depression score. INF-gamma was significantly and negatively associated with anxiety, and IL-6 was significantly and positively associated psychological distress. Among people with only an alcohol use disorder, IL-6 was positively associated with depression and psychological distress scores, and IL-10 was negatively associated with anxiety score. Among people with only a drug use disorder, TNF-alpha was positively associated with depression score. CONCLUSION: The relationship between immune function and psychological distress is robust in the context of substance abuse, and further research is warranted. PMID- 29500110 TI - A critical review of melanoma self-screening tools on YouTube - A missed opportunity? PMID- 29500111 TI - Aesthetic and functional outcomes of radial forearm flap donor site reconstruction with biosynthetic skin substitutes. PMID- 29500112 TI - Efficacy of a novel strategy for poststernotomy deep sternal infection after thoracic aorta replacement using a prosthetic graft. AB - BACKGROUND: Poststernotomy deep sternal wound infections are persistent and occasionally fatal, especially in cases involving prosthetic grafts, because of their complicated structure and virtual impossibility of removal. We aimed to verify the influence of cooperation with plastic surgeons and our novel strategy for treating deep sternal wound infection after aortic replacement on cardiovascular surgery outcomes. PATIENTS AND METHODS: Nine hundred eighty-three consecutive patients were divided into two groups: an early group (2012-2013) and a late group (2014-2015). The late group had received cooperatively improved perioperative wound management: our novel strategy of deep sternal infection based on radical debridement and immediate reconstruction decided by reference to severities of the patient's general condition and widespread infection by early intervention of plastic surgeons. The groups were analysed retrospectively. Binary variables were analysed statistically with the Fisher exact test and continuous variables with the Mann-Whitney U test. Inter-group differences were assessed with the chi-square test. RESULTS: Twenty of 390 cases in the early group and 13 of 593 cases in the late group were associated with deep sternal infection. Morbidity rates of deep sternal wound infection and associated mortality rates 1 year after reconstruction surgery were significantly less (p <0.05 for both) in the late group. CONCLUSIONS: Intervention by plastic surgeons improved perioperative wound management outcomes. Our treatment strategy for deep sternal wound infection also reduced associated mortality rates. Facilities should consider the early inclusion of plastic surgeons in the treatment of patients undergoing aortic replacement to facilitate better outcomes. PMID- 29500113 TI - Lymphaticovenular anastomosis for breast cancer treatment-related lymphedema: Three-line strategy for an optimal outcome. PMID- 29500115 TI - Advanced Modeled Iterative Reconstruction (ADMIRE) Facilitates Radiation Dose Reduction in Abdominal CT. AB - RATIONALE AND OBJECTIVES: This study aimed to determine the potential degree of radiation dose reduction achievable using Advanced Modeled Iterative Reconstruction (ADMIRE) in abdominal computed tomography (CT) while maintaining image quality. Moreover, this study compared differences in image noise reduction of this iterative algorithm with radiation dose reduction. METHODS: Eleven consecutive patients scheduled for abdominal CT were scanned according to our institute's standard protocol (100 kV, 289 reference mAs). Using a proprietary reconstruction software, CT images of these patients were reconstructed as either full-dose weighted filtered back projections or with simulated radiation dose reductions down to 10% of the full-dose level and ADMIRE at either strength 3 or strength 5. Images were marked with arrows pointing on anatomic structures of the abdomen, differing in their contrast to the surrounding tissue. Structures were grouped into high-, medium-, and low-contrast subgroups. In addition, the intrinsic noise of these structures was measured. That followed, image pairs were presented to observers, with five readers assessing image quality using two alternative-forced-choice comparisons. In total, 3000 comparisons were performed that way. RESULTS: Both ADMIRE 3 and 5 decreased noise of the anatomic structures significantly compared to the filtered back projection, with an additional significant difference between ADMIRE 3 and 5. Radiation dose reduction potential for ADMIRE ranged from 29.0% to 53.5%, with no significant differences between ADMIRE 3 and 5 within the contrast subgroups.The potential levels of radiation dose reduction for ADMIRE 3 differed significantly between high-, medium-, and low-contrast structures, whereas for ADMIRE 5, there was only a significant difference between the high- and the medium-contrast subgroups. CONCLUSION: Although ADMIRE 5 permits significantly higher noise reduction potential than ADMIRE 3, it does not facilitate higher levels of radiation dose reduction. ADMIRE nonetheless holds remarkable potential for radiation dose reduction, which features a certain dependency on the contrast of the structure of interest. Applying ADMIRE with a strength of 3 in abdominal CT may permit radiation dose reduction of about 30%. PMID- 29500114 TI - Quality of life comparison between smokers and non-smokers with chronic pancreatitis. AB - OBJECTIVES: The aim of this study was to evaluate the impact of smoking on quality of life in patients with chronic pancreatitis. METHODS: This is a cross sectional study of chronic pancreatitis patients followed at a single institution comparing smokers with non-smokers. The primary outcome was quality of life and secondary outcomes included demographics, drug and alcohol use, anxiety and depression, pain level, nutritional status, and metabolic factors. RESULTS: 48 smokers and 45 non-smokers participated in this study. Smokers had a worse overall quality of life and higher rates of opioid addiction and depression than non-smokers. Smokers also had less racial diversity, lower education levels, and higher amounts of narcotic use than non-smokers. Furthermore, smokers had a lower BMI and a higher proportional use of pancreatic enzyme replacement therapy. Smoking was found to be independently associated with worse quality of life on multivariable regression. CONCLUSIONS: The worse overall quality of life and higher rates of depression and anxiety create cause for concern in chronic pancreatitis patients who smoke. Smoking cessation should be an important target in chronic pancreatitis patients. Multicenter, multiethnic studies are needed to further elucidate this relationship. PMID- 29500116 TI - Multilevel linear modelling of the response-contingent learning of young children with significant developmental delays. AB - AIM: The purpose of the study was to isolate the sources of variations in the rates of response-contingent learning among young children with multiple disabilities and significant developmental delays randomly assigned to contrasting types of early childhood intervention. METHOD: Multilevel, hierarchical linear growth curve modelling was used to analyze four different measures of child response-contingent learning where repeated child learning measures were nested within individual children (Level-1), children were nested within practitioners (Level-2), and practitioners were nested within the contrasting types of intervention (Level-3). RESULTS: Findings showed that sources of variations in rates of child response-contingent learning were associated almost entirely with type of intervention after the variance associated with differences in practitioners nested within groups were accounted for. Rates of child learning were greater among children whose existing behaviour were used as the building blocks for promoting child competence (asset-based practices) compared to children for whom the focus of intervention was promoting child acquisition of missing skills (needs-based practices). IMPLICATIONS: The methods of analysis illustrate a practical approach to clustered data analysis and the presentation of results in ways that highlight sources of variations in the rates of response-contingent learning among young children with multiple developmental disabilities and significant developmental delays. PMID- 29500117 TI - Extracorporeal membrane oxygenation in severe respiratory failure resulting from burns and smoke inhalation injury. AB - Extracorporeal membrane oxygenation (ECMO) is one of the most frequent forms of extracorporeal life support (ECLS) and can be used as rescue therapy in patients with severe respiratory failure resulting from burns and/or smoke inhalation injury. Experience and literature on this treatment option is still very limited, consequently results are varied. We report a retrospective analysis of our experience with veno-venous (VV) ECMO in burn patients. All five patients, three male and two female (age: 28-37 years) had flame type burns and smoke inhalation injury. Their Murray scores ranged between 3.25 and 3.75, and their revised Baux scores between 62 and 102. The mean pre-ECMO conventional ventilation time was 7.4days (3-13). The mean ECMO duration was 18days (8-35). Three patients were cannulated with dual lumen, two with separate cannulae. One oxygenator had to be changed due to technical issues and two patients needed two parallel oxygenators. Four patients had renal replacement therapy. All patients needed vasoconstrictor support, antibiotics and packed red blood cells (5-62 units). Three had steroid treatment. All five patients were successfully weaned from ECMO. One patient died later from multi-organ failure in the ICU, the other four patients survived. VV ECMO is a useful rescue intervention in patients with burns related severe respiratory failure. Patients in our institution benefit from having both burns and ECMO centres with major expertise in the field under one roof. The results from this small cohort are encouraging, although more cases are needed to draw more robust conclusions. PMID- 29500118 TI - Clinical Utility of Serum Concentrations of Adalimumab as Predictor of Treatment Adherence. AB - OBJECTIVE: to evaluate the usefulness of serum concentrations (Sc) of adalimumab (ADA) as a predictor of medication adherence using the medication possession ratio (MPR) and Morisky Green test (MGT) in patients with chronic inflammatory diseases. MATERIAL AND METHOD: Design a prospective descriptive cohort study. INCLUSION CRITERIA: adult patients diagnosed with inflammatory arthropathy (IA) or inflammatory bowel disease (IBD) treated with ADA. EXCLUSION CRITERIA: positive anti-adalimumab antibody. VARIABLES: sex, age, diagnosis, dosage regimen, Sc (mg/mL), MPR (MPR >= 80% adherent) and MGT (non-adherent or adherent). Statistical analysis was performed using STATA v13.0. RESULTS: Forty five patients (23 women) with an age of 52.22 (14.39) years, 17 IBD (37.78%), 26 IA (57.78%) and 2 with both conditions (4.44%) treated with 40mg ADA every 14 days (42/45; 93.33%) or every 7 days (3/45; 6.67%). We detected subtherapeutic Sc in 22.22% of patients (10/45); 10% (1/10) were classified as non-adherent and 90% (9/10) as adherent according to MGT and MPR. The quantification of Sc shows weak agreement with MPR, as was the case with the indirect methods of each (MPR and MGT). The association was slightly greater when the indirect methods were compared to each other (0.244 vs. 0.378). CONCLUSION: the determination of Sc of ADA alone has limited utility in the detection of non-adherent patients. PMID- 29500119 TI - Single versus multi-item self-assessment of sedentary behaviour: A comparison with objectively measured sedentary time in nurses. AB - OBJECTIVES: To compare sedentary time (ST) measured by self-report using a single question from the short-form International Physical Activity Questionnaire (SF IPAQ), 18-items from the Sedentary Behaviour Questionnaire (SBQ) and objectively using an accelerometer among a large sample of nurses. DESIGN: Cross-sectional. METHODS: Participants wore an ActiGraph GT3X accelerometer (>=4 days, >=10h/day) and self-reported usual day sitting using the IPAQ and sitting in different modes using the SBQ. Measures were compared using correlations, a Friedman test with Wilcoxon signed-ranks tests for pairwise comparisons, linear regression and Bland Altman plots. RESULTS: A total of 313 nurses (95% female; mean+/-SD: age=43+/-12 years) from 14 hospitals participated. Participants self-reported sitting for a median of 240min/day using the SF-IPAQ and 328min/day using the SBQ. Median ST measured by the ActiGraph was 434min/day. All measures were weakly correlated with each other (rho=0.31-40, ps<0.001). Limits of agreement were wide between all measures. Significant proportional bias between the ActiGraph and the SF-IPAQ and SBQ existed, suggesting that with greater amounts of ST, there is greater disagreement between the self-report and objective measures. CONCLUSIONS: In a sample of nurses, self-reported ST using the SF-IPAQ and SBQ was significantly lower than that measured by accelerometer. A single-item tool performed more poorly than a multi-item questionnaire. Future studies should consider including both objective and self-report measures of ST, and where possible use a tool that quantifies ST across multiple domains, define a 'usual day' and are meaningful for those with daily schedule variations such as among shift-worker populations. PMID- 29500120 TI - Does addressing prediabetes help to improve population health? PMID- 29500121 TI - Cardiovascular and renal burdens of prediabetes in the USA: analysis of data from serial cross-sectional surveys, 1988-2014. AB - BACKGROUND: There is controversy over the usefulness of prediabetes as a diagnostic label. Using data from US National Health and Nutrition Examination Surveys (NHANES) between 1988 and 2014, we examined the cardiovascular and renal burdens in adults with prediabetes over time and compared patterns with other glycaemic status groups. METHODS: We analysed cross-sectional survey data from non-pregnant adults aged 20 years and older from the NHANES survey periods 1988 94, 1999-2004, 2005-10, and 2011-14. We defined diagnosed diabetes as patients' self-report that they had been previously diagnosed by a physician or health professional; among those with no self-reported diabetes, prediabetes was defined as a fasting plasma glucose (FPG) concentration of 100-125 mg/dL (5.6-6.9 mmol/L) or an HbA1c of 5.7-6.4% (39-47 mmol/mol); undiagnosed diabetes as an FPG of 126 mg/dL (7.0 mmol/L) or higher or an HbA1c of 6.5% (48 mmol/mol) or higher; and normal glycaemic status as an FPG of less than 100 mg/dL (5.6 mmol/L) and an HbA1c of less than 5.7% (39 mmol/mol). We repeated the analyses using varying definitions of prediabetes (FPG 110-125 mg/dL [6.1-6.9 mmol/L] or HbA1c 5.7-6.4% [39-47 mmol/mol], FPG 110-125 mg/dL [6.1-6.9 mmol/L] or HbA1c 6.0-6.4% [42-47 mmol/mol], and FPG 100-125 mg/dL [5.6-6.9 mmol/L] and HbA1c 5.7-6.4% [39-47 mmol/mol]). For each group over time, we estimated the prevalences of hypertension and dyslipidaemia; and among individuals with those conditions, we estimated the proportions who had been treated and who were achieving care goals. By glycaemic group, we estimated those who were current, former, and never smokers; mean 10-year risk of cardiovascular disease (using estimators from the Framingham Heart Study, the United Kingdom Prospective Diabetes Study (UKPDS), and the ACC/AHA ASCVD guidelines); albuminuria (median and albumin-to-creatinine ratio >=30 mg/g), estimated glomerular filtration rate (eGFR; mean and <60 mL/min per 1.73m2); and prevalence of myocardial infarction and stroke. For all estimates, we calculated predicted changes between 1988-94 and 2011-14 using logistic regression models adjusted for age, sex, and race or ethnic group. FINDINGS: We obtained data for 27 971 eligible individuals. In 2011-14, in the population of adults with prediabetes, 36.6% (95% CI 32.8-40.5) had hypertension, 51.2% (47.0-55.3) had dyslipidaemia, 24.3% (21.7-27.3) smoked; 7.7% (6.8-8.8) had albuminuria; 4.6% (3.7-5.9) had reduced eGFR; and 10-year cardiovascular event risk ranged from 5% to 7%. From 1988-94 to 2011-14, adults with prediabetes showed significant increases in hypertension (+9.7 percentage points [95% CI 5.4 14.0]); no change in dyslipidaemia; decreases in smoking (-6.4 percentage points [-10.7 to -2.1]); increased use of treatment to lower blood pressure (54.2% [49.0 59.3] to 81.4% [76.7-85.3], +27.2 percentage points [20.5-33.8] p<0.0001) and to reduce lipids (6.6% to 40.2%, +33.6 percentage points [30.2-37.0], p<0.0001); and increased goal achievements for blood pressure (25.8% to 62.0%, +36.2 percentage points [30.7-41.8], p<0.0001) and lipids (1.0% to 32.8%, +31.8 percentage points [29.1-34.4, p<0.0001]). People with prediabetes also showed decreases in cardiovascular risk (ASCVD -1.9 percentage points [-2.5 to -1.3] to UKPDS -2.7 [ 3.5 to -1.9], p<0.0001); but no change in prevalence of albuminuria, reduced eGFR, myocardial infarction, or stroke. Prevalence and patterns were consistent across all prediabetes definitions examined. Compared with adults with prediabetes, adults with diagnosed diabetes showed much larger improvements in cardiovascular and renal risk treatments, apart from smoking, which did not decline. INTERPRETATION: Over 25 years, cardiovascular and renal risks and disease have become highly prevalent in adults with prediabetes, irrespective of the definitions used. Identification of people with prediabetes might increase the opportunity for cardiovascular and renal risk reduction. FUNDING: None. PMID- 29500122 TI - Factors influencing taper failure of modular revision hip stems. AB - Stem modularity of revision hip implant systems offers the advantage of the restoration of individual patient geometry but introduces additional interfaces, which are subjected to repetitive bending loading and have a propensity for fretting corrosion. The male stem taper is the weakest part of the modular junction due to its reduced cross section compared to the outside diameter of the stem. Taper fractures can be the consequence of overloading in combination with corrosion. The purpose of this study was to assess the influence of implant design factors, patient factors, and surgical factors on the risk of taper failure of the modular junction of revision stems. An analytical bending model was used to estimate the strength of the taper connection for pristine, fatigued and corroded conditions. Additionally, a finite element contact model of the taper connection was developed to assess the relative motion and potential for surface damage at the taper interface under physiological loading for varyied assembly and design parameters. Increasing the male taper diameter was shown to be the most effective means for increasing taper strength but would require a concurrent increase in the outer implant diameter to limit a greater risk of total surface damage for a thinner female taper wall. Increasing the assembly force decreases the total surface damage but not local magnitudes, which are probably responsible for crack initiation. It is suggested that in unfavourable loading conditions a monobloc implant system will reduce the risk of failure. PMID- 29500123 TI - Considerations on the negative electroretinogram. PMID- 29500124 TI - Management of the Critically Ill Adult With Congenital Heart Disease. AB - Survival of adults with congenital heart disease (CHD) has improved significantly over the last 2 decades, leading to an increase in hospital and intensive care unit (ICU) admissions of these patients. Whereas most of the ICU admissions in the past were related to perioperative management, the incidence of medical emergencies from long-term sequelae of palliative or corrective surgical treatment of these patients is rising. Intensivists now are confronted with patients who not only have complex anatomy after congenital cardiac surgery, but also complex pathophysiology due to decades of living with abnormal cardiac anatomy and diseases of advanced age. Comorbidities affect all organ systems, including cognitive function, pulmonary and cardiovascular systems, liver, and kidneys. Critical care management requires an in-depth understanding of underlying anatomy and pathophysiology in order to apply contemporary concepts of adult ICU care to this population and optimize patient outcomes. In this review, the main CHD lesions and their common surgical management approaches are described, and the sequelae of CHD physiology are discussed. In addition, the effects of chronic comorbidities on the management of critically ill adults are explored, and the adjustments of current ICU management modalities and pharmacology to optimize care are discussed. PMID- 29500125 TI - Non-traumatic splenic rupture in a patient with human granulocytic anaplasmosis and focused review of the literature. AB - We report a rare case of a 53-year-old man with no significant past medical history who reported multiple tick bites within a 2-month period. The patient reported not "feeling well" for the 2 1/2 weeks. He complained of generalized body aches, pains, and chills. He did not report nausea, vomiting, or yellowish discoloration of the eyes or skin. He presented to the emergency room with syncope preceded by severe abdominal pain. Upon presentation, he was pale and hypotensive. He had not experienced any trauma. Computed tomography revealed a splenic rupture, hemoperitoneum, and active extravasation of contrast material. The estimated amount of hemoperitoneum was 1.5 liters of blood. Subsequently, an infectious disease work-up revealed a positive Anaplasma phagocytophilum polymerase reaction in blood. The patient was aggressively resuscitated, and a splenectomy was performed followed by doxycycline therapy. He successfully recovered. PMID- 29500126 TI - Extracardiac intrapericardial myxosarcoma causing right ventricular outflow tract obstruction in a dog. AB - A 13-year-old male castrated pomeranian cross was referred for evaluation of episodes of collapse and a suspected cardiac mass. The presence of a mass at the base of the heart within the pericardial space was confirmed by echocardiography. Additional diagnostics included computed tomography, ultrasound-guided fine needle aspirate, and thoracic radiographs. The mass was surgically debulked and diagnosed as myxosarcoma via histopathology. This case report describes the diagnostic imaging, laboratory findings, and short-term positive clinical outcome of a dog with a myxosarcoma in a previously undescribed location. PMID- 29500127 TI - Pelvic Chlamydial Infection Predisposes to Ectopic Pregnancy by Upregulating Integrin beta1 to Promote Embryo-tubal Attachment. AB - Tubal ectopic pregnancies are a leading cause of global maternal morbidity and mortality. Previous infection with Chlamydia trachomatis is a major risk factor for tubal embryo implantation but the biological mechanism behind this association is unclear. Successful intra-uterine embryo implantation is associated with increased expression of endometrial "receptivity" integrins (cell adhesion molecules). We examined integrin expression in Fallopian tubes of women with previous C. trachomatis infection, in mice experimentally infected with C. trachomatis, in immortalised human oviductal epithelial cells (OE-E6/E7) and in an in vitro model of human embryo attachment (trophoblast spheroid-OE-E6/7 cell co-culture). Previous exposure with C. trachomatis increased Fallopian tube/oviduct integrin-subunit beta-1 (ITGB1) in women and mice compared to controls. C. trachomatis increased OE-E6/E7 cell ITGB1 expression and promoted trophoblast attachment to OE-E6/E7 cells which was negated by anti-ITGB1 antibody. We demonstrate that infection with C. trachomatis increases tubal ITGB1 expression, predisposing to tubal embryo attachment and ectopic pregnancy. PMID- 29500128 TI - Therapeutic Genome Editing With CRISPR/Cas9 in a Humanized Mouse Model Ameliorates alpha1-antitrypsin Deficiency Phenotype. AB - alpha1-antitrypsin (AAT) is a circulating serine protease inhibitor secreted from the liver and important in preventing proteolytic neutrophil elastase associated tissue damage, primarily in lungs. In humans, AAT is encoded by the SERPINA1 (hSERPINA1) gene in which a point mutation (commonly referred to as PiZ) causes aggregation of the miss-folded protein in hepatocytes resulting in subsequent liver damage. In an attempt to rescue the pathologic liver phenotype of a mouse model of human AAT deficiency (AATD), we used adenovirus to deliver Cas9 and a guide-RNA (gRNA) molecule targeting hSERPINA1. Our single dose therapeutic gene editing approach completely reverted the phenotype associated with the PiZ mutation, including circulating transaminase and human AAT (hAAT) protein levels, liver fibrosis and protein aggregation. Furthermore, liver histology was significantly improved regarding inflammation and overall morphology in hSERPINA1 gene edited PiZ mice. Genomic analysis confirmed significant disruption to the hSERPINA1 transgene resulting in a reduction of hAAT protein levels and quantitative mRNA analysis showed a reduction in fibrosis and hepatocyte proliferation as a result of editing. Our findings indicate that therapeutic gene editing in hepatocytes is possible in an AATD mouse model. PMID- 29500129 TI - Synthesis and evaluation of a novel 'off-on' chemical sensor based on rhodamine B and the 2,5-pyrrolidinedione moiety for selective discrimination of glutathione and its bioimaging in living cells. AB - A new "turn-on" fluorescent probe, RDMBM, based on the rhodamine B dye and the 2,5-pyrrolidinedione moiety was synthesized and characterized. Its sensing behavior toward various amino acids was evaluated via UV-vis and fluorescence spectroscopic techniques. The observed spectral changes showed that RDMBM displays high selectivity and sensitivity toward GSH in MeOH/H2O (1:2, v/v, pH 7.40, Tris-HCl buffer, 1 mM) solution and that it undergoes 1:1 covalent binding with GSH. More importantly, the hydrogenation and ring-opening of the nitrogen atom in the spirane structure of rhodamine B derivatives were tightly bound to the induction effects of different groups. Furthermore, fluorescence imaging applications demonstrated that RDMBM can be successfully used for the detection of GSH in human breast cancer cells MCF-7. PMID- 29500130 TI - Design, synthesis and biological evaluation of novel hydroxamic acid based histone deacetylase 6 selective inhibitors bearing phenylpyrazol scaffold as surface recognition motif. AB - In recent years, inhibition of HDAC6 became a promising therapeutic strategy for the treatment of cancer and HDAC6 inhibitors were considered to be potent anti cancer agents. In this work, celecoxib showed moderate degree of HDAC6 inhibition activity and selectivity in preliminary enzyme inhibition activity assay. A series of hydroxamic acid derivatives bearing phenylpyrazol moiety were designed and synthesized as HDAC6 inhibitors. Most compounds showed potent HDAC6 inhibition activity. 11i was the most selective compound against HDAC6 with IC50 values of 0.020uM and selective factor of 101.1. Structure-activity relationship analysis indicated that locating the linker group at 1' of pyrazol gave the most selectivity. The most compounds 11i (GI50=3.63MUM) exhibited 6-fold more potent than vorinostat in HepG2 cells. Considering of the high selectivity against HDAC6 and anti-proliferation activity, such compounds have potential to be developed as anti-cancer agents. PMID- 29500131 TI - Structure optimization and preliminary bioactivity evaluation of N hydroxybenzamide-based HDAC inhibitors with Y-shaped cap. AB - Histone deacetylase inhibitors (HDACIs) are effective small molecules in the treatment of human cancers. In our continuing efforts to develop novel N hydroxyterephthalamide-based HDACIs, herein we report the design and development of a new class of N-hydroxybenzamide-based HDACIs. In this new class of analogs, we inserted an ethylene moiety in the linker and used indole as a part of the Y shaped cap group. Biological characterization identified compounds 4o, 4p, 4q and 4t to show improved HDAC inhibition, while no isoform selectivity for HDACs was observed. These compounds also exhibited improved anti-proliferative activity against multiple cancer cell lines when compared to their parent compound and positive control SAHA. PMID- 29500132 TI - Multifunctional 5,6-dimethoxybenzo[d]isothiazol-3(2H)-one-N-alkylbenzylamine derivatives with acetylcholinesterase, monoamine oxidases and beta-amyloid aggregation inhibitory activities as potential agents against Alzheimer's disease. AB - A series of 5,6-dimethoxybenzo[d]isothiazol-3(2H)-one-N-alkylbenzylamine derivatives were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease (AD). The in vitro assays indicated that most of these derivatives were selective AChE inhibitors with good multifunctional properties. Among them, compounds 11b and 11d displayed comprehensive advantages, with good AChE (IC50 = 0.29 +/- 0.01 MUM and 0.46 +/- 0.02 MUM, respectively), MAO-A (IC50 = 8.2 +/- 0.08 MUM and 7.9 +/- 0.07 MUM, respectively) and MAO-B (IC50 = 20.1 +/- 0.16 MUM and 43.8 +/- 2.0% at 10 MUM, respectively) inhibitory activities, moderate self-induced Abeta1-42 aggregation inhibitory potency (35.4 +/- 0.42% and 48.0 +/- 1.53% at 25 MUM, respectively) and potential antioxidant activity. In addition, the two representative compounds displayed high BBB permeability in vitro. Taken together, these multifunctional properties make 11b and 11d as a promising candidate for the development of efficient drugs against AD. PMID- 29500133 TI - Current status of clinical transfusion practice in Sichuan, China: A cross sectional survey. AB - OBJECTIVE: The safety and effectiveness of clinical transfusion are highly associated with clinical blood transfusion level. A survey was conducted with the aim of providing references to improve the level of clinical blood transfusion. STUDY DESIGN AND METHODS: A survey was undertaken by means of a questionnaire which consisted of hospitals' basic conditions, utilization of blood products and application of autologous blood transfusion in hospitals with scale, geographic and religious diversity in Sichuan, China. Data analysis was conducted in 3 groups according to the official classification of hospital. RESULTS: 76.8% (384/500) hospitals answered the questions completely. From 2011 to 2015, the usage of whole blood showed significant decreasing trend (P = 0.047); in level 2 and level 3 hospitals, the used units of plasma and RBC were closely associated with the number of inpatient and operation (all r >= 0.442; P < 0.01). The plasma used per operation per year by level 3 hospitals and RBC used per inpatient per year by level 2 hospitals both showed a decreasing trend (P = 0.047 and P < 0.001); the plasma: RBC transfused by level 3 hospitals was higher than 1:1.8; the ABT rate was lower than 42.16% in all hospitals. CONCLUSIONS: The clinical blood transfusion level of hospitals in Sichuan, China has improved a lot in the past 5 years, but problems still existed, such as whole blood still being used, overuse of plasma and low ABT rate, and further work and improvements are needed to strengthen the management of clinical blood transfusion. PMID- 29500134 TI - Cost and cost-effectiveness studies in urologic oncology using large administrative databases. AB - OBJECTIVE: Urologic cancers are not only among the most common types of cancers, but also among the most expensive cancers to treat in the United States. This study aimed to review the use of CEAs and other cost analyses in urologic oncology using large databases to better understand the value of management strategies of these cancers. METHODS: A literature review on CEAs and other cost analyses in urologic oncology using large databases. RESULTS: The options for and costs of diagnosing, treating, and following patients with urologic cancers can be expected to rise in the coming years. There are numerous opportunities in each urologic cancer to use CEAs to both lower costs and provide high-quality services. Improved cancer care must balance the integration of novelty with ensuring reasonable costs to patients and the health care system. CONCLUSION: With the increasing focus cost containment, appreciating the value of competing strategies in caring for our patients is pivotal. Leveraging methods such as CEAs and harnessing large databases may help evaluate the merit of established or emerging strategies. PMID- 29500135 TI - Pharmacokinetics and pharmacodynamics of intravesical and intravenous TMX-101 and TMX-202 in a F344 rat model. AB - OBJECTIVES: To evaluate and compare the pharmacokinetic and pharmacodynamic properties of 2 investigational Toll-like receptor 7 agonists, TMX-101, and TMX 202 after intravenous and intravesical administration in a rat model. TLR-7 agonists are successfully used as topical treatment for various (pre)malignant skin lesions and are now under investigation as intravesical therapy for non muscle-invasive bladder cancer. METHODS: Rats received an intravesical instillation with TMX-101, TMX-202, or vehicle. Additionally 2 groups of rats received an intravenous injection with TMX-101 or TMX-202. Blood sampling was performed at different time points, including pre-exposure and postexposure to determine the plasma concentrations of study drugs for pharmacokinetic and pharmacodynamic analyses and to determine the plasma concentrations of cytokines (IL-2, IL-6, and TNF-alpha). RESULTS: We observed no signs of toxicity after intravesical or intravenous administration. There was a limited dose dependent systemic uptake of TMX-101 and TMX-202 after intravesical administration. The systemic uptake of TMX-202 after intravesical instillation was 25 times lower compared to TMX-101. CONCLUSIONS: This in vivo study confirms the safety of intravesical TMX-101 and TMX-202 administration, with TMX-202 showing lower systemic uptake. TMX-202 has a larger molecule-mass compared to TMX-101, and it may therefore have a favorable safety profile when treating patients with non muscle-invasive bladder cancer intravesically. PMID- 29500136 TI - Treatment of Castration-naive Metastatic Prostate Cancer. AB - Both docetaxel+androgen deprivation therapy (ADT) and abiraterone acetate 1000mg/d+prednisone/prednisolone 5mg/d+ADT improved survival in patients with metastatic castration-naive prostate cancer. Their use should be offered and guided by patient's own characteristics. PMID- 29500137 TI - Haematuria in Sport: A Review. AB - CONTEXT: Haematuria is a common urological presentation associated with patient anxiety and clinically relevant underlying pathology. However, the prevalence and pathophysiology of haematuria following sporting exercise is less well documented. OBJECTIVES: This review paper seeks to clarify the prevalence of microscopic and macroscopic haematuria in association with sporting exercise reported in the literature, and the pathophysiology behind it. We review the relation of haematuria to injury to the urinary tract in sport, as well as the incidence of underlying disease, urological and incidental, following investigation for exercise-induced haematuria. EVIDENCE ACQUISITION: A non systematic literature review was conducted of articles and studies using the Pubmed database. Articles were selected with preference for the highest level of evidence available, with relevant data extracted, analysed, and summarised. Supplementary information was collected by cross-referencing the reference lists. EVIDENCE SYNTHESIS: Multiple studies have shown that clinically significant haematuria is common after exercise. Physiological changes occurring during exercise result in increased glomerular permeability and microscopic haematuria in up to 95% of cases. The degree of haematuria is related to the intensity of the exercise. However, participating in contact sports increases the risk of macroscopic haematuria. Red cell haemolysis and rhabdomyolysis also play a role in urine discolouration following exercise and can be present in 30%. Haematuria following exercise-related trauma is regarded an important indication for further urological investigation. Haematuria may be absent in 44% of cases of urological injury. Renal trauma accounts for 80% of urological trauma, with 30% of these being due to sporting activity. Incidental findings on computed tomography for haematuria are common, with 50% showing positive extraurinary findings. Incidental malignancy, however, is rare. CONCLUSIONS: Haematuria is common following exercise and results from physiological changes and contact-related trauma to the urinary tract. All cases of haematuria should be investigated as underlying trauma and extraurinary disease are common incidental findings on investigation. PATIENT SUMMARY: Blood in the urine following exercise is a common phenomenon and occurs due to vascular responses to sports and trauma as well as blood and muscle cell breakdown. Although it may not be present in all cases of trauma, blood in the urine should be investigated due to the risk of discovering underlying injury to the urinary tract and other incidental findings. PMID- 29500138 TI - Late manifestation of alloantibody-associated injury and clinical pulmonary antibody-mediated rejection: Evidence from cell-free DNA analysis. AB - BACKGROUND: Antibody-mediated rejection (AMR) often progresses to poor health outcomes in lung transplant recipients (LTRs). This, combined with the relatively insensitive clinical tools used for its diagnosis (spirometry, histopathology) led us to determine whether clinical AMR is diagnosed significantly later than its pathologic onset. In this study, we leveraged the high sensitivity of donor derived cell-free DNA (ddcfDNA), a novel genomic tool, to detect early graft injury after lung transplantation. METHODS: We adjudicated AMR and acute cellular rejection (ACR) in 157 LTRs using the consensus criteria of the International Society for Heart and Lung Transplantation (ISHLT). We assessed the kinetics of allograft injury in relation to ACR or AMR using both clinical criteria (decline in spirometry from baseline) and molecular criteria (ddcfDNA); percent ddcfDNA was quantitated via shotgun sequencing. We used a mixed-linear model to assess the relationship between and ddcfDNA levels and donor-specific antibodies (DSA) in AMR+ LTRs. RESULTS: Compared with ACR, AMR episodes (n = 42) were associated with significantly greater allograft injury when assessed by both spirometric (0.1 liter vs -0.6 liter, p < 0.01) and molecular (ddcfDNA) analysis (1.1% vs 5.4%, p < 0.001). Allograft injury detected by ddcfDNA preceded clinical AMR diagnosis by a median of 2.8 months. Within the same interval, spirometry or histopathology did not reveal findings of allograft injury or dysfunction. Elevated levels of ddcfDNA before clinical diagnosis of AMR were associated with a concurrent rise in DSA levels. CONCLUSION: Diagnosis of clinical AMR in LTRs lags behind DSA-associated molecular allograft injury as assessed by ddcfDNA. PMID- 29500139 TI - Assessing the Risk for Peripheral Neuropathy in Patients Treated With Dronedarone Compared With That in Other Antiarrhythmics. AB - PURPOSE: There are few data on the risk for peripheral neuropathy associated with dronedarone, a newer antiarrhythmic medicine. The objective of this study was to assess whether dronedarone is potentially associated with an increased risk for peripheral neuropathy compared with other antiarrhythmics, including amiodarone, sotalol, flecainide, and propafenone. METHODS: The MarketScan database was used for identifying patients who were at least 18 years of age, had atrial fibrillation or flutter, and had not been diagnosed with peripheral neuropathy in the 180-day period prior to or on the date of the first prescription of an antiarrhythmic between July 20, 2009, and December 31, 2011. Peripheral neuropathy that occurred during the treatment period for a study drug was ascertained using ICD-9-CM diagnostic codes. For each antiarrhythmic, the incidence rate of peripheral neuropathy was calculated. The adjusted hazard ratio (aHR) for peripheral neuropathy for dronedarone compared with another antiarrhythmic was obtained, with control for age, sex, diabetes mellitus status, and the presence of other comorbidities. FINDINGS: The study population included 106,933 patients treated with dronedarone (n = 12,989), amiodarone (n = 45,173), sotalol (n = 22,036), flecainide (n = 14,244), or propafenone (n = 12,491). The incidence rates (per 1000 person-years) of peripheral neuropathy were 1.33 for dronedarone, 2.38 for amiodarone, 1.20 for sotalol, 1.08 for flecainide, and 1.97 for propafenone. The aHRs for peripheral neuropathy for dronedarone relative to other drugs ranged from 0.53 (95% CI, 0.21-1.34) compared with propafenone, to 0.94 (95% CI, 0.38-2.30) compared with sotalol. A new-user analysis showed similar results. IMPLICATIONS: The risks for peripheral neuropathy were not significantly different between dronedarone and other antiarrhythmics. PMID- 29500140 TI - Comparative Efficacy of Treatments for Previously Treated Multiple Myeloma: A Systematic Literature Review and Network Meta-analysis. AB - PURPOSE: New therapies, including daratumumab plus lenalidomide plus dexamethasone (DRd) and daratumumab plus bortezomib plus dexamethasone (DVd), have recently been approved in the United States for patients with multiple myeloma (MM) who have received at least 1 prior line of therapy. However, few treatments have been compared in head-to-head clinical trials to determine the most efficacious therapy. In an update of the POLLUX (Phase 3 Study Comparing DRd Versus Rd in Subjects with Relapsed or Refractory Multiple Myeloma [RRMM]) trial, median progression-free survival (PFS) for DRd was not reached; the hazard ratio compared with Rd was 0.41. In an update of the CASTOR (Phase 3 Study Comparing DVd Versus Vd in Subjects with RRMM) trial, median PFS for DVd was 16.7 months, compared with 7.1 months for Vd with a PFS hazard ratio of 0.31. A systematic literature review and network meta-analysis (NMA) was performed to estimate the relative efficacy of treatments for previously treated patients with MM. METHODS: A systematic search of MEDLINE, EMBASE, BioSciences Information Service, and the Cochrane Library databases was conducted from initiation to September 2016. Abstracts published by international congresses (2014-2016) and bibliographies of pertinent systematic reviews and meta-analyses were also searched. Eligible studies consisted of randomized controlled trials (RCTs) or long-term follow-up studies with >1 treatment arm assessing the efficacy or safety of MM therapies. An NMA was conducted by using Bayesian fixed effect mixed-treatment comparisons. Outcomes considered were hazard ratios for PFS and odds ratios for overall response rate (ORR). FINDINGS: In total, 108 articles reporting 27 RCTs were included in the NMA. Data formed 2 evidence networks: RCTs with DRd and RCTs with DVd. Primary analysis of PFS found that DRd and DVd had a higher probability of being the best treatments (probability, 0.997 and 0.999, respectively) and had the lowest risk of progression or death than other treatments approved by the US Food and Drug Administration for the treatment of MM. Results from sensitivity analyses using time to progression as a proxy for missing PFS data were consistent. DRd and DVd also showed improved ORR compared with other treatments. Subgroup analyses of PFS in patients treated with only 1 prior therapy were like the results of the primary analyses. IMPLICATIONS: This NMA provides comparative efficacy for MM treatments not studied in head-to-head RCTs. The NMA suggests that, compared with other approved MM treatments in the United States, DRd and DVd have a higher probability of providing the longest PFS in patients who have received at least 1 prior therapy and in patients who have received only 1 prior therapy. PMID- 29500141 TI - Polymorphisms in CYP450 Genes and the Therapeutic Effect of Atorvastatin on Ischemic Stroke: A Retrospective Cohort Study in Chinese Population. AB - PURPOSE: Ischemic stroke (IS) is one of the most common neurologic diseases and is the main cause of death and disability in the Chinese population. This retrospective cohort study was performed to elucidate the relationship between single nucleotide polymorphisms (SNPs) in cytochrome P450 genes and the therapeutic effect of atorvastatin. METHODS: A total of 192 cases of IS were enrolled in the study. All patients were treated with atorvastatin, and their lipid levels and proportions were measured. Six SNPs in 4 cytochrome P450 genes (CYP2C19, CYP2D6, CYP3A4, and CYP4F2) related to drug metabolism were selected to be genotyped and analyzed. FINDINGS: Data were analyzed for 192 patients (sex, male/female, 122/70; mean age, 69.81 [9.35] years; Hypertension, 163[84.90%]; Cigarette smoking, 34[17.71%]). Among the 192 patients with IS treated with atorvastatin, it was found that the G allele of rs1065852 (CYP2D6) had a better effect on lowering of DeltaLDL (P < 0.001), DeltaLDL/LDL (P < 0.001), Delta(LDL/HDL) (P < 0.001), and Delta(LDL/HDL)/(LDL/HDL) (P < 0.001). We also found that rs2242480 (CYP3A4) showed marginal association with DeltaLDL (P = 0.049) under the dominant model. In addition, rs2242480 and rs1065852 exhibited cumulative effects on the lipid-lowering (DeltaLDL, DeltaLDL/LDL, and Delta[LDL/HDL]) efficacy of atorvastatin (P < 0.001). IMPLICATIONS: The results suggest that CYP2D6 and CYP3A4 affect treatment with atorvastatin in patients with IS. PMID- 29500142 TI - [Anal incontinence and obstetrical anal sphincter injuries, epidemiology and prevention]. AB - Our main objectives were to identify risk factors, methods for early diagnosis, and prevention of obstetric anal sphincter injuries (OASIs), using a literature review. The main risk factors for OASIs are nulliparity, instrumental delivery, posterior presentation, median episiotomy, prolonged second phase of labor and fetal macrosomia. Asian origin, short ano-vulvar distance, ligamentous hyperlaxity, lack of expulsion control, non-visualization of the perineum or maneuvers for shoulder dystocia also appear to be risk factors. There is a risk of under-diagnosis of OASIs in the labor ward. Experience of the accoucheur is a protective factor. Secondary prevention is based on the training of birth professionals in recognition and repair of OASIs. Primary prevention of OASIs is based on training in the maneuvers of the second phase of labor; if possible, instrumental extractions should be avoided. Mediolateral episiotomy may have a preventive role in high-risk OASIs deliveries. A robust predictive model is still lacking to allow a selective use of episiotomy. PMID- 29500143 TI - Resident Wellness and Social Support: Development and Cognitive Validation of a Resident Social Capital Assessment Tool. AB - OBJECTIVE: The purpose of this study is to develop and generate validity evidence for an instrument to measure social capital in residents. DESIGN: Mixed-methods, phased approach utilizing a modified Delphi technique, focus groups, and cognitive interviews. SETTING: Four residency training institutions in Washington state between February 2016 and March 2017. PARTICIPANTS: General surgery, anesthesia, and internal medicine residents ranging from PGY-1 to PGY-6. RESULTS: The initial resident-focused instrument underwent revision via Delphi process with 6 experts; 100% expert consensus was achieved after 4 cycles. Three focus groups were conducted with 19 total residents. Focus groups identified 6 of 11 instrument items with mean quality ratings <=4.0 on a 1-5 scale. The composite instrument rating of the draft version was 4.1 +/- 0.5. After refining the instrument, cognitive interviews with the final version were completed with 22 residents. All items in the final version had quality ratings >4.0; the composite instrument rating was 4.8 +/- 0.1. CONCLUSIONS: Social capital may be an important factor in resident wellness as residents rely upon each other and external social support to withstand fatigue, burnout, and other negative sequelae of rigorous training. This instrument for assessment of social capital in residents may provide an avenue for data collection and potentially, identification of residents at-risk for wellness degradation. PMID- 29500144 TI - Impact of Teaching on Surgical Site Infection after Colonic Surgery. AB - OBJECTIVE: The present study aimed to evaluate whether teaching had an influence on surgical site infections (SSI) after colonic surgery. DESIGN: Colonic surgeries between January 2014 and December 2016 were retrospectively reviewed. Demographics, surgical details, and SSI rates were compared between teaching procedures vs. experts. Risk factors for SSI were identified by multinominal logistic regression. SETTING: SSI were prospectively assessed by an independent National Surveillance Program (www.swissnoso.ch) at Lausanne University Hospital CHUV, a tertiary academic institution. PARTICIPANTS: Included in the present analysis were patients documented in a prospective institutional enhanced recovery after surgery (ERAS) database and who were prospectively monitored by the independent National Infection Surveillance Committee between January 1, 2014 and December 31, 2016. RESULTS: In all, 315 patients constituted the study cohort. Demographic and surgical items were comparable between teaching (n = 161) vs. expert operations (n = 135) except for higher occurrence of wound contamination class III-IV (13 vs. 19%, p = 0.046) in patients operated by experts. Overall, 61 patients (19%) developed SSI, namely 25 patients (16%) in the teaching group and 32 patients (24%) in the expert group (p = 0.077). Contamination class III-IV (OR = 3.2; 95% CI: 1.4-7.5, p = 0.005) and open surgery (OR = 3.4; 95% CI: 1.8-6.7, p < 0.001) were independent risk factors for SSI, while teaching had no significant impact (OR = 0.6; 95% CI: 0.3-1.2, p = 0.153). CONCLUSIONS: Surgical teaching was feasible and safe after colonic surgery in the present cohort and had no impact on SSI rate. PMID- 29500145 TI - Meta-Analysis of Surgeon Burnout Syndrome and Specialty Differences. AB - OBJECTIVE: Surgeon burnout compromises the quality of life of physicians and the delivery of care to patients. Burnout rates and interpretation of the Maslach Burnout Inventory (MBI) complicates the interpretation of surgeon burnout. The purpose of this study is to apply a standardized interpretation of severe surgeon burnout termed, "burnout syndrome" to analyze inherent variation within surgical specialties. DESIGN: A systematic literature search was performed using MEDLINE, PsycINFO, and EMBASE to identify studies reporting MBI data by surgical specialty. Data extraction was performed to isolate surgeon specific data. SETTING: A meta-analysis was performed. RESULTS: A total of 16 cross-sectional studies were included in this meta-analysis, totaling 3581 subjects. A random effects model approximated burnout syndrome at 3.0% (95% CI: 2.0%-5.0%; I2 = 78.1%). Subscale analysis of emotional exhaustion, depersonalization, and personal accomplishment indicated subscale burnout in 30.0% (CI: 25.0%-36.0%; I2 = 93.2%), 34.0% (CI: 25.0%-43.0%; I2 = 96.9%), and 25.0% (CI: 18.0%-32.0%; I2 = 96.5%) of surgeons, respectively. Significant differences (p < 0.001) in MBI subscale scoring existed among surgical specialties. CONCLUSIONS: Approximately 3% of surgeons suffer from extreme forms of burnout termed "burnout syndrome," although surgeon burnout may occur in up to 34% of surgeons, characterized by high burnout in 1 of 3 subscales. Surgical specialties have significantly different rates of burnout subscales. Future burnout studies should target the specialty-specific level to understand inherent differences in an effort to better understand methods of improving surgeon burnout. PMID- 29500146 TI - N-Acetylcysteine supplementation decreased brain lipid and protein oxidations produced by experimental homocysteine thiolactone exposure: Relevance to neurodegeneration. AB - High levels of homocysteine (Hcy) have neurotoxic effects. Homocysteine thiolactone (HcyT), a thioester of Hcy, plays a role in Hcy-induced toxicity. In this study, effects of HcyT treatment (500 mg/kg body weight/day in drinking water) for 6 weeks on serum Hcy levels and brain prooxidant-antioxidant balance were investigated in rats. The effect of N-acetylcysteine (NAC) treatment (1 g/kg body weight/day in chow) for 6 weeks on HcyT-induced neurotoxicity was evaluated. Reactive oxygen species (ROS), thiobarbituric acid reactive substances (TBARS), diene conjugate (DC), protein carbonyl (PC) and advanced oxidation protein products (AOPP) were determined in the brain tissue. Ferric reducing antioxidant power (FRAP) and non-protein sulfydryl groups (NPSH) levels as well as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities were also measured to evaluate the antioxidant potential of brain the tissue. HcyT elevated serum Hcy levels and brain ROS, TBARS, DC, PC and AOPP levels. However, HcyT did not affect FRAP levels and SOD, and GSH-Px activities. NAC treatment decreased serum Hcy and brain ROS, TBARS, DC, PC and AOPP levels in HCyT-treated rats. Our results indicate that NAC supplementation may be effective in decreasing serum Hcy levels and HcyT-induced oxidative stress in brain of rats. PMID- 29500147 TI - A Retrospective Study of Double-hit Lymphomas in Elderly Patients (Aged > 70 Years): Overall Outcomes. AB - BACKGROUND: Double-hit lymphomas (DHLs) are high-grade diffuse large B-cell lymphomas with concurrent translocations involving myc and bcl-2 and/or bcl-6. A patient with DHL often has advanced disease at presentation and typically responds poorly to standard therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). More intensive treatment regimens have been studied; however, few data are available on the outcomes in elderly patients (aged > 70 years) treated with these therapies. We retrospectively studied the efficacy and tolerability of chemotherapy regimens in elderly patients within the Advocate Healthcare System. MATERIALS AND METHODS: A system-wide search of patients treated from 2012 to 2017 was completed to identify patients with c-myc with bcl-2 and/or bcl-6 translocations using fluorescence in situ hybridization. The patients were reviewed for the following: age at diagnosis, stage, lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, chemotherapy details, grade 3/4 toxicities, and response to therapy. Overall survival (OS) and event-free survival (EFS) were calculated. RESULTS: We identified 17 patients (9 men and 8 women) with a median age of 73 years (range, 70-89 years). Six patients received R-EPOCH (rituximab, etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin), 5 received R-CHOP, 1 received bendamustine and rituximab, 1 received the MaGrath regimen, and 1 received cyclophosphamide and rituximab. Three patients were not treated and were referred to hospice care. For all patients, the median follow-up period was 25 months, the EFS and OS were 28% at 36 months, and the median survival was 7.5 months. For patients treated with R-EPOCH, the EFS was 33% at 24 months. For the R-CHOP group, the EFS was 40% at 24 months. Most common grade 3/4 toxicities were neutropenia, anemia, thrombocytopenia, and infections and were more common in the R-EPOCH group. Three patients each died in the R-EPOCH and R-CHOP groups. CONCLUSION: Although the numbers are small, elderly patients with DHL can achieve durable EFS and OS. Using the comprehensive geriatric assessment can aid in decision making in the treatment options for elderly patients. Our retrospective analysis, given a small sample size, suggests that intensive treatment regimens can be offered to elderly patients with DHL. PMID- 29500148 TI - Thiotepa, Etoposide, Cyclophosphamide, Cytarabine, and Melphalan (TECAM) Conditioning Regimen for Autologous Stem Cell Transplantation in Lymphoma. AB - BACKGROUND: High-dose chemotherapy and autologous stem cell transplantation (ASCT) is the current standard of care for relapsed non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). Conditioning regimens with high-dose carmustine have been associated with idiopathic pneumonitis syndrome. We, therefore, created a modified alternative TECAM conditioning regimen, consisting of etoposide, thiotepa, cytarabine, cyclophosphamide, and melphalan. PATIENTS AND METHODS: We retrospectively analyzed our cohort of 212 NHL and HL patients, who had undergone ASCT with the TECAM conditioning regimen from 2000 to 2013. Although toxicity and engraftment were analyzed for all 212 patients, the survival analysis was performed for the 2 largest groups of patients, those with diffuse large B-cell lymphoma (DLBCL) and those with HL (n = 127) to minimize heterogeneity. RESULTS: The 3-year overall survival among the DLBCL and HL patients was 0.618 (95% confidence interval [CI], 0.490-0.722) and 0.828 (95% CI, 0.701-0.904), respectively. Stage IV disease at transplantation was a statistically significant poor prognostic factor. Higher Eastern Cooperative Oncology Group performance status and progressive disease at transplantation were found to be borderline significant. No idiopathic pneumonitis syndrome cases were reported in our cohort. Six patients died of treatment-related toxicity during the first 100 days. The 3-year progression-free survival was 0.5 (95% CI, 0.37-0.61) for HL patients and 0.49 (95% CI, 0.36-0.60) for DLBCL patients. CONCLUSION: Our results are encouraging and justify evaluation of TECAM versus BEAM (carmustine, etoposide, cytarabine, melphalan) in a prospective multicenter study in a large homogenous patient population. PMID- 29500149 TI - Clinical Features and Treatment Outcomes of Primary Cutaneous B-cell Lymphomas: A Thirty-year Experience. PMID- 29500150 TI - Response to the Commentary on "Post-Carotid Hypertension Part 2: Association with Peri-operative Clinical, Anaesthetic, and Transcranial Doppler Derived Parameters". PMID- 29500151 TI - Small Renal Masses in Close Proximity to the Collecting System and Renal Sinus Are Enriched for Malignancy and High Fuhrman Grade and Should Be Considered for Early Intervention. AB - INTRODUCTION: Recent reports show a correlation between renal tumor radiographic characteristics and pathologic features. We hypothesize that a more central location within the relatively hypoxic renal medulla might confer a more aggressive tumor phenotype. To test this, radiographic tumor characteristics were compared with tumor grade and histology. MATERIALS AND METHODS: We retrospectively reviewed renal masses <4 cm in diameter that underwent resection between 2008 and 2013. Tumor location was recorded using standard R.E.N.A.L. Nephrometry Score. Multivariate logistic regression was performed to compare independent anatomic features with incidence of malignancy and high nuclear grade. RESULTS: A total of 334 renal tumors had information available for analysis. Univariate analysis showed that increasing endophycity and proximity to the collecting system (<4 mm) were predictors of malignancy and high-grade features. In multivariate analysis, proximity to the collecting system <4 mm remained the as the only anatomical variable predictive of malignancy (odds ratio [OR], 3.58; 95% confidence interval [CI], 1.06-12.05; P = .04) and high nuclear grade (OR, 2.81; 95% CI, 1.44-5.51; P = .003). CONCLUSION: Malignancy and high tumor grade occur with much greater frequency when tumors are located deep in the kidney, in close proximity to the collecting system and renal sinus. Ninety-six percent of small renal masses in this region were cancers and nearly half were Fuhrman Grade 3 or 4, suggesting that these small centrally located tumors should be targeted for early intervention. PMID- 29500153 TI - White matter is what matters after cardiac arrest. PMID- 29500152 TI - Cognitive and neuroimaging features and brain beta-amyloidosis in individuals at risk of Alzheimer's disease (INSIGHT-preAD): a longitudinal observational study. AB - BACKGROUND: Improved understanding is needed of risk factors and markers of disease progression in preclinical Alzheimer's disease. We assessed associations between brain beta-amyloidosis and various cognitive and neuroimaging parameters with progression of cognitive decline in individuals with preclinical Alzheimer's disease. METHODS: The INSIGHT-preAD is an ongoing single-centre observational study at the Salpetriere Hospital, Paris, France. Eligible participants were age 70-85 years with subjective memory complaints but unimpaired cognition and memory (Mini-Mental State Examination [MMSE] score >=27, Clinical Dementia Rating score 0, and Free and Cued Selective Reminding Test [FCSRT] total recall score >=41). We stratified participants by brain amyloid beta deposition on 18F-florbetapir PET (positive or negative) at baseline. All patients underwent baseline assessments of demographic, cognitive, and psychobehavioural, characteristics, APOE epsilon4 allele carrier status, brain structure and function on MRI, brain glucose-metabolism on 18F-fluorodeoxyglucose (18F-FDG) PET, and event-related potentials on electroencephalograms (EEGs). Actigraphy and CSF investigations were optional. Participants were followed up with clinical, cognitive, and psychobehavioural assessments every 6 months, neuropsychological assessments, EEG, and actigraphy every 12 months, and MRI, and 18F-FDG and 18F-florbetapir PET every 24 months. We assessed associations of amyloid beta deposition status with test outcomes at baseline and 24 months, and with clinical status at 30 months. Progression to prodromal Alzheimer's disease was defined as an amnestic syndrome of the hippocampal type. FINDINGS: From May 25, 2013, to Jan 20, 2015, we enrolled 318 participants with a mean age of 76.0 years (SD 3.5). The mean baseline MMSE score was 28.67 (SD 0.96), and the mean level of education was high (score >6 [SD 2] on a scale of 1-8, where 1=infant school and 8=higher education). 88 (28%) of 318 participants showed amyloid beta deposition and the remainder did not. The amyloid beta subgroups did not differ for any psychobehavioural, cognitive, actigraphy, and structural and functional neuroimaging results after adjustment for age, sex, and level of education More participants positive for amyloid beta deposition had the APOE epsilon4 allele (33 [38%] vs 29 [13%], p<0.0001). Amyloid beta1-42 concentration in CSF significantly correlated with mean 18F-florbetapir uptake at baseline (r=-0.62, p<0.0001) and the ratio of amyloid beta1-42 to amyloid beta1-40 (r=-0.61, p<0.0001), and identified amyloid beta deposition status with high accuracy (mean area under the curve values 0.89, 95% CI 0.80-0.98 and 0.84, 0.72-0.96, respectively). No difference was seen in MMSE (28.3 [SD 2.0] vs 28.9 [1.2], p=0.16) and Clinical Dementia Rating scores (0.06 [0.2] vs 0.05 [0.3]; p=0.79) at 30 months (n=274) between participants positive or negative for amyloid beta. Four participants (all positive for amyloid beta deposition at baseline) progressed to prodromal Alzheimer's disease. They were older than other participants positive for amyloid beta deposition at baseline (mean 80.2 years [SD 4.1] vs 76.8 years [SD 3.4]) and had greater 18F-florbetapir uptake at baseline (mean standard uptake value ratio 1.46 [SD 0.16] vs 1.02 [SD 0.20]), and more were carriers of the APOE epsilon4 allele (three [75%] of four vs 33 [39%] of 83). They also had mild executive dysfunction at baseline (mean FCSRT free recall score 21.25 [SD 2.75] vs 29.08 [5.44] and Frontal Assessment Battery total score 13.25 [1.50] vs 16.05 [1.68]). INTERPRETATION: Brain beta-amyloidosis alone did not predict progression to prodromal Alzheimer's disease within 30 months. Longer follow-up is needed to establish whether this finding remains consistent. FUNDING: Institut Hospitalo-Universitaire and Institut du Cerveau et de la Moelle Epiniere (IHU-A-ICM), Ministry of Research, Fondation Plan Alzheimer, Pfizer, and Avid. PMID- 29500155 TI - One step towards dementia prevention. PMID- 29500154 TI - Use of brain diffusion tensor imaging for the prediction of long-term neurological outcomes in patients after cardiac arrest: a multicentre, international, prospective, observational, cohort study. AB - BACKGROUND: Prediction of neurological outcome after cardiac arrest is a major challenge. The aim of this study was to assess whether quantitative whole-brain white matter fractional anisotropy (WWM-FA) measured by diffusion tensor imaging between day 7 and day 28 after cardiac arrest can predict long-term neurological outcome. METHODS: This prospective, observational, cohort study (part of the MRI COMA study) was done in 14 centres in France, Italy, and Belgium. We enrolled patients aged 18 years or older who had been unconscious for at least 7 days after cardiac arrest into the derivation cohort. The following year, we recruited the validation cohort on the same basis. We also recruited a minimum of five healthy volunteers at each centre for the normalisation procedure. WWM-FA values were compared with standard criteria for unfavourable outcome, conventional MRI sequences (fluid-attenuated inversion recovery and diffusion-weighted imaging), and proton magnetic resonance spectroscopy. The primary outcome was the best achieved Glasgow-Pittsburgh Cerebral Performance Categories (CPC) at 6 months, dichotomised as favourable (CPC 1-2) and unfavourable outcome (CPC 3-5). Prognostication performance was assessed by the area under the receiver operating characteristic (ROC) curves and compared between groups. This study was registered with ClinicalTrials.gov, number NCT00577954. FINDINGS: Between Oct 1, 2006, and June 30, 2014, 185 patients were enrolled in the derivation cohort, of whom 150 had an interpretable multimodal MRI and were included in the analysis. 33 (22%) patients had a favourable neurological outcome at 6 months. Prognostic accuracy, as quantified by the area under the ROC curve, was significantly higher with the normalised WWM-FA value (area under the ROC curve 0.95, 95% CI 0.91 0.98) than with the standard criteria for unfavourable outcome or other MRI sequences. In a subsequent validation cohort of 50 patients (enrolled between April 1, 2015, and March 31, 2016), a normalised WWM-FA value lower than 0.91, set from the derivation cohort, had a negative predictive value of 71.4% (95% CI 41.9-91.6) and a positive predictive value of 100% (90.0-100), with 89.7% sensitivity (75.8-97.1) and 100% specificity (69.1-100) for the prediction of unfavourable outcome. INTERPRETATION: In patients who are unconscious 7 days after cardiac arrest, the normalised WWM-FA value, measured by diffusion tensor imaging, could be used to accurately predict neurological outcome at 6 months. This evidence requires confirmation from future large-scale trials with a strict protocol of withdrawal or limitation-of-care decisions and time window for MRI. FUNDING: French Ministry of Health, French National Agency for Research, Italian Ministry of Health, and Regione Lombardia. PMID- 29500156 TI - Rethinking isolated cleft lip and palate as a syndrome. AB - OBJECTIVE: The goal of the present work was to use dental conditions that have been independently associated with cleft lip and palate (CL/P) as a tool to identify a broader collection of individuals to be used for gene identification that lead to clefts. STUDY DESIGN: We studied 1573 DNA samples combining individuals that were born with CL/P or had tooth agenesis, supernumerary teeth, molar incisor hypomineralization, or dental caries with the goal to identify genetic associations. We tested 2 single-nucleotide polymorphisms that were located in the vicinity of regions suggested to contribute to supernumerary teeth. Overrepresentation of alleles were determined for combinations of individuals as well as for each individual phenotypic group with an alpha of .05. RESULTS: We determined that the allele C of rs622260 was overrepresented in all individuals studied compared with a group of unrelated individuals who did not present any of the conditions described earlier. When subgroups were tested, associations were found for individuals with hypomineralization. CONCLUSIONS: Although we did not test this hypothesis directly in the present study, based on associations reported previously, we believe that CL/P is actually a syndrome of alterations of the dentition, and considering it that way may allow for the identification of genotype-phenotype correlations that may be useful for clinical care. PMID- 29500157 TI - Crush the Crave: Development and Formative Evaluation of a Smartphone App for Smoking Cessation. AB - BACKGROUND: Emerging evidence supports the use of smartphone apps for smoking cessation, especially in young adults given their high smoking rates and high smartphone ownership rates. Although evaluative evidence is encouraging for supporting smoking cessation, there remains a paucity of research describing the design and development processes of mobile health (mHealth) interventions. OBJECTIVE: The aim of this paper was to describe the process of developing Crush the Crave (CTC), an evidence-informed app to support smoking cessation in young adults, and the results of a formative evaluation of app usage behavior, as part of a broader program of research that seeks to establish the effectiveness of the CTC app. METHODS: The Spiral Technology Action Research (STAR) 5-cycle model (listen, plan, do, act, and study) was employed to guide the development, implementation, and dissemination of CTC. The approach to development and formative evaluation included focus groups with young adult smokers (n=78) across 2 phases, analysis of the content of existing apps, 2 sessions with content experts, and Google Analytics to assess user behavior during a 12-month pilot. RESULTS: LISTEN-focus groups revealed young adult smoker preferences of (1) positive reinforcement, (2) personalization, (3) social support, (4) quit support, (5) tracking the behavior, and (6) tracking quit benefits. PLAN-informed by evidence for smoking cessation, young adult preferences and an assessment of popular cessation apps, content experts produced a mind map and a storyboard describing app content and structure. DO-focus groups with young adult smokers provided feedback on the first version of the app with opinions on content and suggestions for improvement such as providing alerts and distractions from craving. ACT-refinements were made, and app content was organized using the 4 key design components informed by principles of persuasive technology for behavior change: credibility, task support, dialogue support, and social support. CTC was launched in April 2013 and piloted from the period July 2013 to June 2014 where 1987 Android users had 18,567 sessions, resulting in 59,384 page views and 89.58% (1780/1987) of users returning within the same day to use CTC. STUDY-a pragmatic randomized controlled trial of CTC was launched in August 2014 to demonstrate that including mHealth technology as a population-based intervention can help young adult smokers to quit. The results of this phase will be presented in a subsequent publication. CONCLUSIONS: CTC is one of the first smoking cessation apps designed to meet the needs of young adult smokers. The development was informed by the inclusion of young adults in the design and the systematic application of multiple stakeholder input, scientific evidence, and theory. The STAR model approach was followed from the beginning of intervention development, which should facilitate optimization of mHealth interventions in the future. TRIAL REGISTRATION: ClinicalTrials.gov NCT01983150; http://clinicaltrials.gov/ct2/show/NCT01983150 (Archived by WebCite at http://www.webcitation.org/6VGyc0W0i). PMID- 29500158 TI - Usage, Acceptability, and Effectiveness of an Activity Tracker in a Randomized Trial of a Workplace Sitting Intervention: Mixed-Methods Evaluation. AB - BACKGROUND: Wearable activity trackers are now a common feature of workplace wellness programs; however, their ability to impact sitting time (the behavior in which most of the desk-based workday is spent) is relatively unknown. This study evaluated the LUMOback, an activity tracker that targets sitting time, as part of a cluster-randomized workplace sitting intervention in desk-based office workers. OBJECTIVE: Study objectives were to explore: (1) office workers' self-directed LUMOback use, (2) individual-level characteristics associated with LUMOback use, (3) the impact of LUMOback use on activity and sitting behaviors, and (4) office workers' perceived LUMOback acceptability. METHODS: Exploratory analyses were conducted within the activity tracker intervention group (n=66) of a 2-arm cluster-randomized trial (n=153) with follow-up at 3 and 12 months. The intervention, delivered from within the workplace, consisted of organizational support strategies (eg, manager support, emails) to stand up, sit less, and move more, plus the provision of a LUMOback activity tracker. The LUMOback, worn belted around the waist, provides real-time sitting feedback through a mobile app. LUMOback usage data (n=62), Web-based questionnaires (n=33), activPAL assessed sitting, prolonged (>=30 min bouts) and nonprolonged (<30 min bouts) sitting, standing and stepping time (7-day, 24 h/day protocol; n=40), and telephone interviews (n=27) were used to evaluate study aims. LUMOback usage data were downloaded and described. Associations between user characteristics and LUMOback usage (in the first 3 months) were analyzed using zero-inflated negative binomial models. Associations between LUMOback usage and 3-month activity outcomes were analyzed using mixed models, correcting for cluster. LUMOback acceptability was explored using 3-month questionnaire data and thematic analysis of telephone interviews (conducted 6 to 10 months post intervention commencement). RESULTS: Tracker uptake was modest (43/61, 70%), and among users, usage over the first 3 months was low (1-48 days, median 8). Usage was greatest among team leaders and those with low self-perceived scores for job control and supervisor relationships. Greater tracker use (>=5 days vs <5 days) was significantly associated only with changes in prolonged unbroken sitting (-50.7 min/16 h; 95% CI -94.0 to -7.3; P=.02) during all waking hours, and changes in nonprolonged sitting (+32.5 min/10 h; 95% CI 5.0 to 59.9; P=.02) during work hours. Participants found the LUMOback easy to use but only somewhat comfortable. Qualitatively, participants valued the real-time app feedback. Nonuptake was attributed to being busy and setup issues. Low usage was attributed to discomfort wearing the LUMOback. CONCLUSIONS: The LUMOback-although able to reduce prolonged sitting time-was only used to a limited extent, and its low usage may provide a partial explanation for the limited behavior changes that occurred. Discomfort limited the feasibility of the LUMOback for ongoing use. Such findings yield insight into how to improve upon implementing activity trackers in workplace settings. PMID- 29500159 TI - More Stamina, a Gamified mHealth Solution for Persons with Multiple Sclerosis: Research Through Design. AB - BACKGROUND: Multiple sclerosis (MS) is one of the world's most common neurologic disorders. Fatigue is one of most common symptoms that persons with MS experience, having significant impact on their quality of life and limiting their activity levels. Self-management strategies are used to support them in the care of their health. Mobile health (mHealth) solutions are a way to offer persons with chronic conditions tools to successfully manage their symptoms and problems. Gamification is a current trend among mHealth apps used to create engaging user experiences and is suggested to be effective for behavioral change. To be effective, mHealth solutions need to be designed to specifically meet the intended audience needs. User-centered design (UCD) is a design philosophy that proposes placing end users' needs and characteristics in the center of design and development, involving users early in the different phases of the software life cycle. There is a current gap in mHealth apps for persons with MS, which presents an interesting area to explore. OBJECTIVE: The purpose of this study was to describe the design and evaluation process of a gamified mHealth solution for behavioral change in persons with MS using UCD. METHODS: Building on previous work of our team where we identified needs, barriers, and facilitators for mHealth apps for persons with MS, we followed UCD to design and evaluate a mobile app prototype aimed to help persons with MS self-manage their fatigue. Design decisions were evidence-driven and guided by behavioral change models (BCM). Usability was assessed through inspection methods using Nielsen's heuristic evaluation. RESULTS: The mHealth solution More Stamina was designed. It is a task organization tool designed to help persons with MS manage their energy to minimize the impact of fatigue in their day-to-day life. The tool acts as a to-do list where users can input tasks in a simple manner and assign Stamina Credits, a representation of perceived effort, to the task to help energy management and energy profiling. The app also features personalization and positive feedback. The design process gave way to relevant lessons to the design of a gamified behavioral change mHealth app such as the importance of metaphors in concept design, negotiate requirements with the BCM constructs, and tailoring of gamified experiences among others. Several usability problems were discovered during heuristic evaluation and guided the iterative design of our solution. CONCLUSIONS: In this paper, we designed an app targeted for helping persons with MS in their fatigue management needs. We illustrate how UCD can help in designing mHealth apps and the benefits and challenges that designers might face when using this approach. This paper provides insight into the design process of gamified behavioral change mHealth apps and the negotiation process implied in it. PMID- 29500160 TI - Therapist-Assisted Progressive Resistance Training, Protein Supplements, and Testosterone Injections in Frail Older Men with Testosterone Deficiency: Protocol for a Randomized Placebo-Controlled Trial. AB - BACKGROUND: Fall accidents are a major cause of mortality among the elderly and the leading cause of traumatic brain injury. After a fall, many elderly people never completely recover and need help in coping with everyday life. Due to the increasing older population in the world, injuries, disabilities, and deaths caused by falls are a growing worldwide problem. Muscle weakness leads to greatly increased risk of falling, decreased quality of life, and decline in functional capacity. Muscle mass and muscle power decrease about 40% from age 20 to 80 years, and the level of testosterone decreases with age and leads to impaired muscle mass. In addition, 20% of men older than 60 years-and 50% older than 80 years-have low levels of testosterone. Treatments after a fall are significant financial burdens on health and social care, and it is important to find treatments that can enhance function in the elderly people. OBJECTIVE: The purpose of this study is to investigate whether testosterone and progressive resistance training alone or combined can improve muscle strength and reduce the risk of falls in older men. Additionally, we will examine whether such treatments can improve quality of life, functional capacity, including sexual function, and counteract depression. METHODS: This is a randomized placebo-controlled, double blind trial in which frail older men with testosterone deficiency are treated with testosterone supplemental therapy and therapist-assisted progressive resistance training for 20 weeks, with the possibility to continue treatment for 1 year. Four study arms of 48 participants each are provided based on factorial assignment to testosterone supplemental therapy and progressive resistance training. The 4 groups are as follows: controls given placebo injections without physical exercise for 20 weeks, testosterone-alone group given testosterone injections without physical exercise for 20 weeks, training-alone group given placebo injections for 20 weeks combined with 16 weeks of progressive strength training, and combination group given testosterone injections for 20 weeks combined with 16 weeks of progressive strength training. Performance in the 30 second chair stand test to measure improvement of general strength, balance, and power in lower extremities is the primary endpoint. Secondary endpoints comprising tests of cognition, muscle strength, and quality of life are applied before and after the training. RESULTS: Funding was provided in October 2016. Results are expected to be available in 2020. Sample size was calculated to 152 participants divided into 4 equal-sized groups. Due to age, difficulty in transport, and the time-consuming intervention, up to 25% dropouts are expected; thus, we aim to include at least 192 participants. CONCLUSIONS: This investigation will evaluate the efficacy of testosterone supplemental therapy alone or combined with progressive resistance training. Additionally, improvements in quality of life and cognition are explored. TRIAL REGISTRATION: Clinicaltrials.gov NCT02873559; https://clinicaltrials.gov/ct2/show/NCT02873559 (Archived by WebCite at http://www.webcitation.org/6x0BhU2p3). PMID- 29500161 TI - Improving Transplant Medication Safety Through a Pharmacist-Empowered, Patient Centered, mHealth-Based Intervention: TRANSAFE Rx Study Protocol. AB - BACKGROUND: Medication errors, adverse drug events, and nonadherence are the predominant causes of graft loss in kidney transplant recipients and lead to increased healthcare utilization. Research has demonstrated that clinical pharmacists have the unique education and training to identify these events early and develop strategies to mitigate or prevent downstream sequelae. In addition, studies utilizing mHealth interventions have demonstrated success in improving the control of chronic conditions that lead to kidney transplant deterioration. OBJECTIVE: The goal of the prospective, randomized TRANSAFE Rx study is to measure the clinical and economic effectiveness of a pharmacist-led, mHealth based intervention, as compared to usual care, in kidney transplant recipients. METHODS: TRANSAFE Rx is a 12-month, parallel, two-arm, 1:1 randomized controlled clinical trial involving 136 participants (68 in each arm) and measuring the clinical and economic effectiveness of a pharmacist-led intervention which utilizes an innovative mobile health application to improve medication safety and health outcomes, as compared to usual posttransplant care. RESULTS: The primary outcome measure of this study will be the incidence and severity of MEs and ADRs, which will be identified, categorized, and compared between the intervention and control cohorts. The exploratory outcome measures of this study are to compare the incidence and severity of acute rejections, infections, graft function, graft loss, and death between research cohorts and measure the association between medication safety issues and these events. Additional data that will be gathered includes sociodemographics, health literacy, depression, and support. CONCLUSIONS: With this report we describe the study design, methods, and outcome measures that will be utilized in the ongoing TRANSAFE Rx clinical trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT03247322: https://clinicaltrials.gov/ct2/show/NCT03247322 (Archived by WebCite at http://www.webcitation.org/6xcSUnuzW). PMID- 29500162 TI - Safety, Quality, and Acceptability of Contraceptive Subdermal Implant Provision by Community Health Extension Workers Versus Nurses and Midwives in Nigeria: Protocol for a Quasi-Experimental, Noninferiority Study. AB - BACKGROUND: As part of its Family Planning 2020 commitment, the Nigerian government is aiming for a contraceptive prevalence rate of 36% by 2018, and in 2014, approved a policy to allow community health extension workers (CHEWs), in addition to doctors, nurses, and midwives, to provide contraceptive subdermal implants. There is a lack of rigorous evidence on the safety of long-acting reversible contraceptive provision, such as implants, among lower cadres of health providers. OBJECTIVE: This study aimed to compare implant provision by CHEWs versus nurses and midwives up to 14 days post insertion. METHODS: The quasi experimental, noninferiority study will take place in public sector facilities in Kaduna and Ondo States. In each state, we will select 60 facilities, and from these, we will select a total of 30 nurses and midwives and 30 CHEWs to participate. Selected providers will be trained to provide implant services. Once trained, providers will recruit a minimum of 8125 women aged between 18 and 49 years who request and are eligible for an implant, following comprehensive family planning counseling. During implant insertion, providers will record data about the process and any adverse events, and 14 days post insertion, providers will ask 4410 clients about adverse events arising from the implant. Supervisors will observe 792 implant insertions to assess service provision quality and ask clients about their satisfaction with the procedure. We will conclude noninferiority if the CI for the difference in the proportion of adverse events between CHEWs and nurses and midwives on the day of insertion or 14 days post insertion lies to the right of -2%. RESULTS: In September and October 2015, we trained 60 CHEWs and a total of 60 nurses and midwives from 12 local government areas (LGAs) in Kaduna and 23 LGAs in Ondo. Recruitment took place between November 2015 and December 2016. Data analysis is being finalized, and results are expected in March 2018. CONCLUSIONS: The strength of this study is having a standard care (nurse and midwife provision) group with which CHEW provision can be compared. The intervention builds on existing training and supervision procedures, which increases the sustainability and scalability of CHEW implant provision. Important limitations include the lack of randomization due to nurses and midwives in Nigeria working in separate types of health care facilities compared with CHEWs, and that providers self-assess their own practices. It is unfeasible to observe all procedures independently, and observation may change practice. Although providers will be trained to conduct implant removals, the study time will be too short to reach the sample size required to make noninferiority comparisons for removals. TRIAL REGISTRATION: ClinicalTrials.gov NCT03088722; https://clinicaltrials.gov/ct2/show/NCT03088722 (Archived by WebCite at http://www.webcitation.org/6xIHImWvu). PMID- 29500163 TI - Deprescribing in nursing homes is safe and should be pursued. PMID- 29500164 TI - How the gut inflames the joints. PMID- 29500165 TI - The role of temporal artery biopsy in patients with giant-cell arteritis is debated. PMID- 29500167 TI - Are you ready for General Data Protection Regulation? PMID- 29500166 TI - Prevalence of Major Behavioral Risk Factors for Type 2 Diabetes. AB - OBJECTIVE: We examined the proportion of American adults without type 2 diabetes that engages in lifestyle behaviors known to reduce type 2 diabetes risk. RESEARCH DESIGN AND METHODS: We conducted a cross-sectional analysis of 3,679 nonpregnant, nonlactating individuals aged >=20 years without diabetes (self reported diagnosis or glycated hemoglobin >=6.5% [8 mmol/mol] or fasting plasma glucose >=126 mg/dL) and who provided 2 days of reliable dietary data in the 2007 2012 National Health and Nutrition Examination Surveys (NHANES). We used the average of 2 days of dietary recall and self-reported leisure-time physical activity to assess whether participants met type 2 diabetes risk reduction goals (meeting four or more MyPlate recommendations [adequate consumption of fruits, vegetables, dairy, grains, meat, beans, and eggs]; not exceeding three maximum allowances for alcoholic beverages, added sugars, fat, and cholesterol; and meeting physical activity recommendations [>=150 min/week]). RESULTS: Approximately 21%, 29%, and 13% of individuals met fruit, vegetable, and dairy goals, respectively. Half (51.6%) met the goal for total grains, compared with 18% for whole grains, and 54.2% met the meat/beans goal and 40.6% met the oils goal. About one-third (37.8%) met the physical activity goal, and 58.6% met the weight loss/maintenance goal. Overall, 3.1% (95% CI 2.4-4.0) of individuals met the majority of type 2 diabetes risk reduction goals. Younger age and lower educational attainment were associated with lower probability of meeting goals. CONCLUSIONS: A small proportion of U.S. adults engages in risk reduction behaviors. Research and interventions targeted at young and less-educated segments of the population may help close gaps in risk reduction behaviors. PMID- 29500168 TI - Medical model of care needs updating, say experts. PMID- 29500171 TI - Management of relapsed/refractory classical Hodgkin lymphoma in transplant ineligible patients. AB - Addition of brentuximab vedotin, a CD30-targeted antibody-drug conjugate, and the programmed death 1 (PD-1) inhibitors nivolumab and pembrolizumab to the armamentarium for transplant-ineligible relapsed/refractory classical Hodgkin lymphoma has resulted in improved outcomes, including the potential for cure in a small minority of patients. For patients who have failed prior transplant or are unsuitable for dose-intense approaches based on age or comorbidities, an individualized approach with sequential use of single agents such as brentuximab vedotin, PD-1 inhibitors, everolimus, lenalidomide, or conventional agents such as gemcitabine or vinorelbine may result in prolonged survival with a minimal or modest effect on quality of life. Participation in clinical trials evaluating new approaches such as combination immune checkpoint inhibition, novel antibody-drug conjugates, or cellular therapies such as Epstein-Barr virus-directed cytotoxic T lymphocytes and chimeric antigen receptor T cells offer additional options for eligible patients. PMID- 29500170 TI - Transplant strategies in relapsed/refractory Hodgkin lymphoma. AB - The majority of patients with Hodgkin lymphoma (HL) are cured with initial therapy. However, high-dose therapy with autologous hematopoietic cell transplant (AHCT) allows for the cure of an additional portion of patients with relapsed or primary refractory disease. Positron emission tomography-negative complete remission before AHCT is critical for long-term disease control. Several salvage options are available with comparable response rates, and the choice can be dependent of comorbidities and logistics. Radiation therapy can also improve the remission rate and is an important therapeutic option for selected patients. Brentuximab vedotin (BV) maintenance after AHCT is beneficial in patients at high risk for relapse, especially those with more than 1 risk factor, but can have the possibility of significant side effects, primarily neuropathy. Newer agents with novel mechanisms of action are under investigation to improve response rates for patients with subsequent relapse, although are not curative alone. BV and the checkpoint inhibitors nivolumab and pembrolizumab are very effective with limited side effects and can bridge patients to curative allogeneic transplants (allo HCT). Consideration for immune-mediated toxicities, timing of allogeneic hematopoietic cell transplant based on response, and the potential for increased graft-versus-host disease remain important. Overall, prospective investigations continue to improve outcomes and minimize toxicity for relapsed or primary refractory HL patients. PMID- 29500169 TI - Antiphospholipid antibodies induce thrombosis by PP2A activation via apoER2-Dab2 SHC1 complex formation in endothelium. AB - In the antiphospholipid syndrome (APS), antiphospholipid antibody (aPL) recognition of beta2 glycoprotein I promotes thrombosis, and preclinical studies indicate that this is due to endothelial nitric oxide synthase (eNOS) antagonism via apolipoprotein E receptor 2 (apoER2)-dependent processes. How apoER2 molecularly links these events is unknown. Here, we show that, in endothelial cells, the apoER2 cytoplasmic tail serves as a scaffold for aPL-induced assembly and activation of the heterotrimeric protein phosphatase 2A (PP2A). Disabled-2 (Dab2) recruitment to the apoER2 NPXY motif promotes the activating L309 methylation of the PP2A catalytic subunit by leucine methyl transferase-1. Concurrently, Src homology domain-containing transforming protein 1 (SHC1) recruits the PP2A scaffolding subunit to the proline-rich apoER2 C terminus along with 2 distinct regulatory PP2A subunits that mediate inhibitory dephosphorylation of Akt and eNOS. In mice, the coupling of these processes in endothelium is demonstrated to underlie aPL-invoked thrombosis. By elucidating these intricacies in the pathogenesis of APS-related thrombosis, numerous potential new therapeutic targets have been identified. PMID- 29500172 TI - Introduction to a review series on Hodgkin lymphoma: change is here. PMID- 29500173 TI - Optimizing therapy in advanced-stage Hodgkin lymphoma. AB - The treatment of Hodgkin lymphoma has evolved continuously since the introduction of extended-field radiotherapy in the 1960s to involved-field and then involved node radiotherapy, multiagent chemotherapy, combined chemoradiotherapy, risk adapted and response-adapted modulation, and, most recently, introduction of antibody-drug conjugates and immune checkpoint-blocking antibodies. These changes have translated into progressively increasing cure rates, so that 10-year survival figures now exceed 80%, compared with <50% 40 years ago. The challenge now is how to improve upon success while maintaining, or if possible improving, the quality of life for survivors. Steering between undertreatment, with the risk of avoidable recurrences, and overtreatment, with the risk of unnecessary toxicity, remains complex because control of the lymphoma and the probability of survival are no longer closely linked. This requires trials with long follow-up and continuous reappraisal of the interaction between the illness; the method used to define risk, and the type of treatment involved. One important factor in this is age: outcomes in older patients have not improved at the same rate as those in the population under 60 years of age, reflecting the need for different approaches. Recently, treatment has moved from being primarily risk-based, using baseline characteristics such as anatomical stage and severity of the illness, to a more dynamic approach that takes account of the response to therapy, using functional imaging to make an early appraisal, with the option to modulate subsequent treatment. The results of several trials indicate that this has advantages, but a combination of risk- and response-adaptation is probably ideal. PMID- 29500174 TI - Balancing risk and benefit in early-stage classical Hodgkin lymphoma. AB - With defined chemotherapy and radiotherapy (RT) and risk-adapted treatment, early stage classical Hodgkin lymphoma (HL) has become curable in a majority of patients. Hence, a major current goal is to reduce treatment-related toxicity while maintaining long-term disease control. Patients with early-stage favorable disease (ie, limited stage without risk factors [RFs]) are frequently treated with 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (2*ABVD) followed by 20-Gy involved-field or involved-site RT (IF/ISRT). In patients with early-stage unfavorable disease (ie, limited stage with RFs), 4 cycles of chemotherapy are usually consolidated with 30-Gy IF/ISRT. Compared with 4*ABVD, 2 cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (2*BEACOPPescalated) followed by 2*ABVD improved 5 year progression-free survival (PFS), with similar 5-year overall survival. Recently, treatment strategies based on [18F]fluorodeoxyglucose positron emission tomography (PET) response were evaluated. In early-stage unfavorable HL, a majority of patients achieved a negative interim PET after 2*ABVD and an excellent outcome after 4*ABVD, whereas in those with a positive interim PET, 2*BEACOPPescalated improved 5-year PFS. Furthermore, a PET-guided RT approach was evaluated to decrease long-term toxicity. Although both the RAPID and H10 trials reported poorer disease control without RT, PET-guided omission of RT can constitute a valid therapeutic option in patients with an increased risk of RT associated toxicity (eg, because of sex, age, or disease localization). Implementation of drugs such as the anti-CD30 antibody-drug conjugate brentuximab vedotin or the anti-programmed death 1 antibodies nivolumab or pembrolizumab might allow further reduction of overall mortality and improve quality of life in affected patients. PMID- 29500175 TI - Biology of classical Hodgkin lymphoma: implications for prognosis and novel therapies. AB - Hodgkin lymphoma is considered a prime example of treatment success, with cure rates exceeding 80% using modern combined modality therapies. However, especially in adolescents and young adults, treatment-related toxicity and long-term morbidity still represent persistent challenges. Moreover, outcomes in patients with relapsed or refractory disease remain unfavorable in the era of high-dose chemotherapy and stem-cell transplantation. Hence, there is a high demand for novel and innovative alternative treatment approaches. In recent years, many new therapeutic agents have emerged from preclinical and clinical studies that target molecular hallmarks of Hodgkin lymphoma, including the aberrant phenotype of the tumor cells, deregulated oncogenic pathways, and immune escape. The antibody-drug conjugate brentuximab vedotin and immune checkpoint inhibitors have already shown great success in patients with relapsed/refractory disease, leading to US Food and Drug Administration approval and new trials testing these agents in various clinical settings. The expanding knowledge and understanding of Hodgkin lymphoma biology and disease progression, as well as the development of robust tools for biomarker-driven risk stratification and therapeutic decision making, continue to be fundamentally important for the success of these and other novel agents. We anticipate that the availability and clinical implementation of novel molecular assays will be instrumental in an era of rapid shifts in the treatment landscape of this disease. Here, we review the current knowledge of Hodgkin lymphoma pathobiology, highlighting the related development of novel treatment strategies and prognostic models that hold the promise to continually challenge and change the current standard of care in classical Hodgkin lymphoma. PMID- 29500176 TI - The NCX1/TRPC6 Complex Mediates TGFbeta-Driven Migration and Invasion of Human Hepatocellular Carcinoma Cells. AB - TGFbeta plays an important role in the progression and metastasis of hepatocellular carcinoma (HCC), yet the cellular and molecular mechanisms underlying this role are not completely understood. In this study, we investigated the roles of Na+/Ca2+ exchanger 1 (NCX1) and canonical transient receptor potential channel 6 (TRPC6) in regulating TGFbeta in human HCC. In HepG2 and Huh7 cells, TGFbeta-stimulated intracellular Ca2+ increases through NCX1 and TRPC6 and induced the formation of a TRPC6/NCX1 molecular complex. This complex mediated Ca2+ signaling regulated the effect of TGFbeta on the migration, invasion, and intrahepatic metastasis of human HCC cells in nude mice. TGFbeta upregulated TRPC6 and NCX1 expression, and there was a positive feedback between TRPC6/NCX1 signaling and Smad signaling. Expression of both TRPC6 and NCX1 were markedly increased in native human HCC tissues, and their expression levels positively correlated with advancement of HCC in patients. These data reveal the role of the TRPC6/NCX1 molecular complex in HCC and in regulating TGFbeta signaling, and they implicate TRPC6 and NCX1 as potential targets for therapy in HCC.Significance: TGFbeta induces the formation and activation of a TRPC6/NCX1 molecular complex, which mediates the effects of TGFbeta on the migration, invasion, and intrahepatic metastasis of HCC. Cancer Res; 78(10); 2564-76. (c)2018 AACR. PMID- 29500178 TI - TAK1 restricts spontaneous NLRP3 activation and cell death to control myeloid proliferation. AB - The NOD-like receptor (NLR)-P3 inflammasome is a global sensor of infection and stress. Elevated NLRP3 activation levels are associated with human diseases, but the mechanisms controlling NLRP3 inflammasome activation are largely unknown. Here, we show that TGF-beta activated kinase-1 (TAK1) is a central regulator of NLRP3 inflammasome activation and spontaneous cell death. Absence of TAK1 in macrophages induced spontaneous activation of the NLRP3 inflammasome without requiring toll-like receptor (TLR) priming and subsequent activating signals, suggesting a distinctive role for TAK1 in maintaining NLRP3 inflammasome homeostasis. Autocrine tumor necrosis factor (TNF) signaling in the absence of TAK1 induced spontaneous RIPK1-dependent NLRP3 inflammasome activation and cell death. We further showed that TAK1 suppressed homeostatic NF-kappaB and extracellular signal-related kinase (ERK) activation to limit spontaneous TNF production. Moreover, the spontaneous inflammation resulting from TAK1-deficient macrophages drives myeloid proliferation in mice, and was rescued by RIPK1 deficiency. Overall, these studies identify a critical role for TAK1 in maintaining NLRP3 inflammasome quiescence and preserving cellular homeostasis and survival. PMID- 29500180 TI - Pseudomembranous colitis in acute lymphoblastic leukaemia. PMID- 29500179 TI - Growth of Mycobacterium tuberculosis in vivo segregates with host macrophage metabolism and ontogeny. AB - To understand how infection by Mycobacterium tuberculosis (Mtb) is modulated by host cell phenotype, we characterized those host phagocytes that controlled or supported bacterial growth during early infection, focusing on the ontologically distinct alveolar macrophage (AM) and interstitial macrophage (IM) lineages. Using fluorescent Mtb reporter strains, we found that bacilli in AM exhibited lower stress and higher bacterial replication than those in IM. Interestingly, depletion of AM reduced bacterial burden, whereas depletion of IM increased bacterial burden. Transcriptomic analysis revealed that IMs were glycolytically active, whereas AMs were committed to fatty acid oxidation. Intoxication of infected mice with the glycolytic inhibitor, 2-deoxyglucose, decreased the number of IMs yet increased the bacterial burden in the lung. Furthermore, in in vitro macrophage infections, 2-deoxyglucose treatment increased bacterial growth, whereas the fatty acid oxidation inhibitor etomoxir constrained bacterial growth. We hypothesize that different macrophage lineages respond divergently to Mtb infection, with IMs exhibiting nutritional restriction and controlling bacterial growth and AMs representing a more nutritionally permissive environment. PMID- 29500181 TI - SELF-PRUNING Acts Synergistically with DIAGEOTROPICA to Guide Auxin Responses and Proper Growth Form. AB - The SELF PRUNING (SP) gene is a key regulator of growth habit in tomato (Solanum lycopersicum). It is an ortholog of TERMINAL FLOWER1, a phosphatidylethanolamine binding protein with antiflorigenic activity in Arabidopsis (Arabidopsis thaliana). A spontaneous loss-of-function mutation (sp) has been bred into several industrial tomato cultivars, as it produces a suite of pleiotropic effects that are favorable for mechanical harvesting, including determinate growth habit, short plant stature, and simultaneous fruit ripening. However, the physiological basis for these phenotypic differences has not been thoroughly explained. Here, we show that the sp mutation alters polar auxin transport as well as auxin responses, such as gravitropic curvature and elongation of excised hypocotyl segments. We also demonstrate that free auxin levels and auxin regulated gene expression patterns are altered in sp mutants. Furthermore, diageotropica, a mutation in a gene encoding a cyclophilin A protein, appears to confer epistatic effects with sp Our results indicate that SP affects the tomato growth habit at least in part by influencing auxin transport and responsiveness. These findings suggest potential novel targets that could be manipulated for controlling plant growth habit and improving productivity. PMID- 29500182 TI - Ku DNA End-Binding Activity Promotes Repair Fidelity and Influences End Processing During Nonhomologous End-Joining in Saccharomyces cerevisiae. AB - The Ku heterodimer acts centrally in nonhomologous end-joining (NHEJ) of DNA double-strand breaks (DSB). Saccharomyces cerevisiae Ku, like mammalian Ku, binds and recruits NHEJ factors to DSB ends. Consequently, NHEJ is virtually absent in yeast Ku null (yku70? or yku80?) strains. Previously, we unexpectedly observed imprecise NHEJ proficiency in a yeast Ku mutant with impaired DNA end-binding (DEB). However, how DEB impairment supported imprecise NHEJ was unknown. Here, we found imprecise NHEJ proficiency to be a feature of a panel of DEB-impaired Ku mutants and that DEB impairment resulted in a deficiency in precise NHEJ. These results suggest that DEB-impaired Ku specifically promotes error-prone NHEJ. Epistasis analysis showed that classical NHEJ factors, as well as novel and previously characterized NHEJ-specific residues of Ku, are required for the distinct error-prone repair in a Ku DEB mutant. However, sequencing of repair junctions revealed that imprecise repair in Ku DEB mutants was almost exclusively characterized by small deletions, in contrast to the majority of insertions that define imprecise repair in wild-type strains. Notably, while sequencing indicated a lack of Pol4-dependent insertions at the site of repair, Pol2 exonuclease activity, which mediates small deletions in NHEJ, contributed to imprecise NHEJ in a Ku DEB mutant. The deletions were smaller than in Ku-independent microhomology-mediated end-joining (MMEJ) and were neither promoted by Mre11 nuclease activity nor Sae2 Thus, the quality of Ku's engagement at the DNA end influences end-processing during NHEJ and DEB impairment unmasks a Ku-dependent error-prone pathway of end-joining distinct from MMEJ. PMID- 29500183 TI - Inferring Fitness Effects from Time-Resolved Sequence Data with a Delay Deterministic Model. AB - A common challenge arising from the observation of an evolutionary system over time is to infer the magnitude of selection acting upon a specific genetic variant, or variants, within the population. The inference of selection may be confounded by the effects of genetic drift in a system, leading to the development of inference procedures to account for these effects. However, recent work has suggested that deterministic models of evolution may be effective in capturing the effects of selection even under complex models of demography, suggesting the more general application of deterministic approaches to inference. Responding to this literature, we here note a case in which a deterministic model of evolution may give highly misleading inferences, resulting from the nondeterministic properties of mutation in a finite population. We propose an alternative approach that acts to correct for this error, and which we denote the delay-deterministic model. Applying our model to a simple evolutionary system, we demonstrate its performance in quantifying the extent of selection acting within that system. We further consider the application of our model to sequence data from an evolutionary experiment. We outline scenarios in which our model may produce improved results for the inference of selection, noting that such situations can be easily identified via the use of a regular deterministic model. PMID- 29500184 TI - IPMNs with co-occurring invasive cancers: neighbours but not always relatives. AB - OBJECTIVE: Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions that can give rise to invasive pancreatic carcinoma. Although approximately 8% of patients with resected pancreatic ductal adenocarcinoma have a co-occurring IPMN, the precise genetic relationship between these two lesions has not been systematically investigated. DESIGN: We analysed all available patients with co occurring IPMN and invasive intrapancreatic carcinoma over a 10-year period at a single institution. For each patient, we separately isolated DNA from the carcinoma, adjacent IPMN and distant IPMN and performed targeted next generation sequencing of a panel of pancreatic cancer driver genes. We then used the identified mutations to infer the relatedness of the IPMN and co-occurring invasive carcinoma in each patient. RESULTS: We analysed co-occurring IPMN and invasive carcinoma from 61 patients with IPMN/ductal adenocarcinoma as well as 13 patients with IPMN/colloid carcinoma and 7 patients with IPMN/carcinoma of the ampullary region. Of the patients with co-occurring IPMN and ductal adenocarcinoma, 51% were likely related. Surprisingly, 18% of co-occurring IPMN and ductal adenocarcinomas were likely independent, suggesting that the carcinoma arose from an independent precursor. By contrast, all colloid carcinomas were likely related to their associated IPMNs. In addition, these analyses showed striking genetic heterogeneity in IPMNs, even with respect to well-characterised driver genes. CONCLUSION: This study demonstrates a higher prevalence of likely independent co-occurring IPMN and ductal adenocarcinoma than previously appreciated. These findings have important implications for molecular risk stratification of patients with IPMN. PMID- 29500187 TI - Adiposity at Age 10 and Mammographic Density among Premenopausal Women. AB - Although childhood adiposity is inversely associated with breast cancer risk, the association of childhood adiposity with mammographic density in premenopausal women has not been adequately studied. We analyzed data from 365 premenopausal women who came in for screening mammography at Washington University (St. Louis, MO) from 2015 to 2016. Body size at age 10 was self-reported using somatotype pictogram. Body mass index (BMI) at age 10 was imputed using data from Growing Up Today Study. Volpara software was used to evaluate volumetric percent density (VPD), dense volume (DV), and nondense volume (NDV). Adjusted multivariable linear regression models were used to evaluate the associations between adiposity at age 10 and mammographic density measures. Adiposity at age 10 was inversely associated with VPD and positively associated with NDV. A 1 kg/m2 increase in BMI at age 10 was associated with a 6.4% decrease in VPD, and a 6.9% increase in NDV (P < 0.001). Compared with women whose age 10 body size was 1 or 2, women with body size 3 or 4 had a 16.8% decrease in VPD and a 26.6% increase in NDV, women with body size 5 had a 32.2% decrease in VPD and a 58.5% increase in NDV, and women with body sizes >=6 had a 47.8% decrease in VPD and a 80.9% increase in NDV (P < 0.05). The associations were attenuated, but still significant after adjusting for current BMI. Mechanistic studies to understand how childhood adiposity influences breast development, mammographic density, and breast cancer in premenopausal women are needed. Cancer Prev Res; 11(5); 287-94. (c)2018 AACR. PMID- 29500185 TI - Toward engineering E. coli with an autoregulatory system for lignin valorization. AB - Efficient lignin valorization could add more than 10-fold the value gained from burning it for energy and is critical for economic viability of future biorefineries. However, lignin-derived aromatics from biomass pretreatment are known to be potent fermentation inhibitors in microbial production of fuels and other value-added chemicals. In addition, isopropyl-beta-d-1 thiogalactopyranoside and other inducers are routinely added into fermentation broth to induce the expression of pathway enzymes, which further adds to the overall process cost. An autoregulatory system that can diminish the aromatics' toxicity as well as be substrate-inducible can be the key for successful integration of lignin valorization into future lignocellulosic biorefineries. Toward that goal, in this study an autoregulatory system is demonstrated that alleviates the toxicity issue and eliminates the cost of an external inducer. Specifically, this system is composed of a catechol biosynthesis pathway coexpressed with an active aromatic transporter CouP under induction by a vanillin self-inducible promoter, ADH7, to effectively convert the lignin-derived aromatics into value-added chemicals using Escherichia coli as a host. The constructed autoregulatory system can efficiently transport vanillin across the cell membrane and convert it to catechol. Compared with the system without CouP expression, the expression of catechol biosynthesis pathway with transporter CouP significantly improved the catechol yields about 30% and 40% under promoter pTrc and ADH7, respectively. This study demonstrated an aromatic-induced autoregulatory system that enabled conversion of lignin-derived aromatics into catechol without the addition of any costly, external inducers, providing a promising and economically viable route for lignin valorization. PMID- 29500186 TI - Monitoring uterine contractility in mice using a transcervical intrauterine pressure catheter. AB - In mouse models used to study parturition or pre-clinical therapeutic testing, measurement of uterine contractions is limited to either ex vivo isometric tension or operative intrauterine pressure (IUP). The goal of this study was to: (1) develop a method for transcervical insertion of a pressure catheter to measure in vivo intrauterine contractile pressure during mouse pregnancy, (2) determine whether this method can be utilized numerous times in a single mouse pregnancy without affecting the timing of delivery or fetal outcome and (3) compare the in vivo contractile activity between mouse models of term and preterm labor (PTL). Visualization of the cervix allowed intrauterine pressure catheter (IUPC) placement into anesthetized pregnant mice (plug = day 1, delivery = day 19.5). The amplitude, frequency, duration and area under the curve (AUC) of IUP was lowest on days 16-18, increased significantly (P < 0.05) on the morning of day 19 and reached maximal levels during by the afternoon of day 19 and into the intrapartum period. An AUC threshold of 2.77 mmHg discriminated between inactive labor (day 19 am) and active labor (day 19 pm and intrapartum period). Mice examined on a single vs every experimental timepoint did not have significantly different IUP, timing of delivery, offspring number or fetal/neonatal weight. The IUP was significantly greater in LPS-treated and RU486-treated mouse models of PTL compared to time-matched vehicle control mice. Intrapartum IUP was not significantly different between term and preterm mice. We conclude that utilization of a transcervical IUPC allows sensitive assessment of in vivo uterine contractile activity and labor progression in mouse models without the need for operative approaches. PMID- 29500188 TI - Metabolomics Profiles of Hepatocellular Carcinoma in a Korean Prospective Cohort: The Korean Cancer Prevention Study-II. AB - In the prospective Korean Cancer Prevention Study-II (KCPS-II), we investigated the application of metabolomics to differentiate subjects with incident hepatocellular carcinoma (HCC group) from subjects who remained free of cancer (control group) during a mean follow-up period of 7 years with the aim of identifying valuable metabolic biomarkers for HCC. We used baseline serum samples from 75 subjects with incident HCC and 134 age- and gender-matched cancer-free subjects. Serum metabolic profiles associated with HCC incidence were investigated via metabolomics analysis. Compared with the control group, the HCC group showed significantly higher serum levels of aspartate aminotransferase (AST), alanine aminotransferase, and gamma-glutamyl transpeptidase. At baseline, compared with the control group, the HCC group showed significantly higher levels of 9 metabolites, including leucine, 5-hydroxyhexanoic acid, phenylalanine, tyrosine, arachidonic acid, and tauroursodeoxycholic acid (TUDCA), but lower levels of 28 metabolites, including oleamide, androsterone sulfate, L palmitoylcarnitine, lysophosphatidic acid (LPA) 16:0, LPA 18:1, and lysophosphatidylcholines (lysoPC). Multiple linear regression revealed that the incidence of HCC was associated with the levels of tyrosine, AST, lysoPCs (16:1, 20:3), oleamide, 5-hydroxyhexanoic acid, androsterone sulfate, and TUDCA (adjusted R2 = 0.514, P = 0.036). This study showed the clinical relevance of the dysregulation of not only branched amino acids, aromatic amino acids, and lysoPCs but also bile acid biosynthesis and linoleic acid, arachidonic acid, and fatty acid metabolism. In addition, tyrosine, AST, lysoPCs (16:1, 20:3), oleamide, 5 hydroxyhexanoic acid, androsterone sulfate, and TUDCA were identified as independent variables associated with the incidence of HCC. Cancer Prev Res; 11(5); 303-12. (c)2018 AACR. PMID- 29500189 TI - Basal mitophagy is widespread in Drosophila but minimally affected by loss of Pink1 or parkin. AB - The Parkinson's disease factors PINK1 and parkin are strongly implicated in stress-induced mitophagy in vitro, but little is known about their impact on basal mitophagy in vivo. We generated transgenic Drosophila melanogaster expressing fluorescent mitophagy reporters to evaluate the impact of Pink1/parkin mutations on basal mitophagy under physiological conditions. We find that mitophagy is readily detectable and abundant in many tissues, including Parkinson's disease-relevant dopaminergic neurons. However, we did not detect mitolysosomes in flight muscle. Surprisingly, in Pink1 or parkin null flies, we did not observe any substantial impact on basal mitophagy. Because these flies exhibit locomotor defects and dopaminergic neuron loss, our findings raise questions about current assumptions of the pathogenic mechanism associated with the PINK1/parkin pathway. Our findings provide evidence that Pink1 and parkin are not essential for bulk basal mitophagy in Drosophila They also emphasize that mechanisms underpinning basal mitophagy remain largely obscure. PMID- 29500190 TI - A homeostatic clock sets daughter centriole size in flies. AB - Centrioles are highly structured organelles whose size is remarkably consistent within any given cell type. New centrioles are born when Polo-like kinase 4 (Plk4) recruits Ana2/STIL and Sas-6 to the side of an existing "mother" centriole. These two proteins then assemble into a cartwheel, which grows outwards to form the structural core of a new daughter. Here, we show that in early Drosophila melanogaster embryos, daughter centrioles grow at a linear rate during early S-phase and abruptly stop growing when they reach their correct size in mid- to late S-phase. Unexpectedly, the cartwheel grows from its proximal end, and Plk4 determines both the rate and period of centriole growth: the more active the centriolar Plk4, the faster centrioles grow, but the faster centriolar Plk4 is inactivated and growth ceases. Thus, Plk4 functions as a homeostatic clock, establishing an inverse relationship between growth rate and period to ensure that daughter centrioles grow to the correct size. PMID- 29500192 TI - Substituted decision making and the dispositional choice account. AB - There are two main ways of understanding the function of surrogate decision making in a legal context: the Best Interests Standard and the Substituted Judgment Standard. First, we will argue that the Best Interests Standard is difficult to apply to unconscious patients. Application is difficult regardless of whether they have ever been conscious. Second, we will argue that if we accept the least problematic explanation of how unconscious patients can have interests, we are also obliged to accept that the Substituted Judgment Standard can be coherently applied to patients who have never been conscious at the same extent as the Best Interests Standard. We then argue that acknowledging this result is important in order to show patients respect. PMID- 29500191 TI - Primary cilia sensitize endothelial cells to BMP and prevent excessive vascular regression. AB - Blood flow shapes vascular networks by orchestrating endothelial cell behavior and function. How endothelial cells read and interpret flow-derived signals is poorly understood. Here, we show that endothelial cells in the developing mouse retina form and use luminal primary cilia to stabilize vessel connections selectively in parts of the remodeling vascular plexus experiencing low and intermediate shear stress. Inducible genetic deletion of the essential cilia component intraflagellar transport protein 88 (IFT88) in endothelial cells caused premature and random vessel regression without affecting proliferation, cell cycle progression, or apoptosis. IFT88 mutant cells lacking primary cilia displayed reduced polarization against blood flow, selectively at low and intermediate flow levels, and have a stronger migratory behavior. Molecularly, we identify that primary cilia endow endothelial cells with strongly enhanced sensitivity to bone morphogenic protein 9 (BMP9), selectively under low flow. We propose that BMP9 signaling cooperates with the primary cilia at low flow to keep immature vessels open before high shear stress-mediated remodeling. PMID- 29500194 TI - An efficient platform for generating somatic point mutations with germline transmission in the zebrafish by CRISPR/Cas9-mediated gene editing. AB - Homology-directed recombination (HDR)-mediated genome editing is a powerful approach for both basic functional study and disease modeling. Although some studies have reported HDR-mediated precise editing in nonrodent models, the efficiency of establishing pure mutant animal lines that carry specific amino acid substitutions remains low. Furthermore, because the efficiency of nonhomologous end joining (NHEJ)-induced insertion and deletion (indel) mutations is normally much higher than that of HDR-induced point mutations, it is often difficult to identify the latter in the background of indel mutations. Using zebrafish as the model organism and Y box-binding protein 1 (Ybx1/ybx1) as the model molecule, we have established an efficient platform for precise CRISPR/Cas9 mediated gene editing in somatic cells, yielding an efficiency of up to 74% embryos. Moreover, we established a procedure for screening germline transmission of point mutations out of indel mutations even when germline transmission efficiency was low (<2%). To further improve germline transmission of HDR-induced point mutations, we optimized several key factors that may affect HDR efficiency, including the type of DNA donor, suppression of NHEJ, stimulation of HDR pathways, and use of Cas9 protein instead of mRNA. The optimized combination of these factors significantly increased the efficiency of germline transmission of point mutation up to 25%. In summary, we have developed an efficient procedure for creating point mutations and differentiating mutant individuals from those carrying knockouts of entire genes. PMID- 29500195 TI - Design and evaluation of bi- and trispecific antibodies targeting multiple filovirus glycoproteins. AB - Filoviruses (family Filoviridae) include five ebolaviruses and Marburg virus. These pathogens cause a rapidly progressing and severe viral disease with high mortality rates (generally 30-90%). Outbreaks of filovirus disease are sporadic and, until recently, were limited to less than 500 cases. However, the 2013-2016 epidemic in western Africa, caused by Ebola virus (EBOV), illustrated the potential of filovirus outbreaks to escalate to a much larger scale (over 28,000 suspected cases). mAbs against the envelope glycoprotein represent a promising therapeutic platform for managing filovirus infections. However, mAbs that exhibit neutralization or protective properties against multiple filoviruses are rare. Here we examined a panel of engineered bi- and trispecific antibodies, in which variable domains of mAbs that target epitopes from multiple filoviruses were combined, for their capacity to neutralize viral infection across filovirus species. We found that bispecific combinations targeting EBOV and Sudan virus (another ebolavirus), provide potent cross-neutralization and protection in mice. Furthermore, trispecific combinations, targeting EBOV, Sudan virus, and Marburg virus, exhibited strong neutralization potential against all three viruses. These results provide important insights into multispecific antibody engineering against filoviruses and will inform future immunotherapeutic discoveries. PMID- 29500196 TI - A nuclease specific to lepidopteran insects suppresses RNAi. AB - More than 70% of all agricultural pests are insects in the order Lepidoptera, which, unlike other related insect orders, are not very sensitive to RNAi, limiting genetic studies of this insect group. However, the reason for this distinct lepidopteran characteristic is unknown. Previously, using transcriptome analysis of the Asian corn borer Ostrinia furnacalis, we identified a gene, termed up56, that is up-regulated in response to dsRNA. Here we report that this Lepidoptera-specific gene encodes a nuclease that contributes to RNAi insensitivity in this insect order. Its identity was experimentally validated, and sequence analysis indicated that up56 encodes a previously uncharacterized protein with homologous sequences in seven other lepidopteran species. Its computationally predicted three-dimensional structure revealed a high structural similarity to human exonuclease I. Exposure to dsRNA in O. furnacalis strongly up regulated this gene's expression, and the protein could digest single-stranded RNA (ssRNA), dsRNA, and dsDNA both in vitro and in vivo Of note, we found that this up-regulation of up56 expression is faster than that of the gene encoding the key RNAi-associated nuclease Dicer. up56 knockdown in O. furnacalis significantly enhanced RNAi efficiency. Moreover, up56 overexpression in Drosophila melanogaster suppressed RNAi efficiency. Finally, up56 knockdown significantly increased the amount and diversity of small RNAs. Therefore, we renamed this protein RNAi efficiency-related nuclease (REase). In conclusion, we propose that REase may explain why lepidopterans are refractory to RNAi and that it represents a target for further research of RNAi efficiency in this insect order. PMID- 29500197 TI - Drug industry broke promises on medical research, say experts. PMID- 29500198 TI - Combination therapy of anabolic agents and bisphosphonates on bone mineral density in patients with osteoporosis: a meta-analysis of randomised controlled trials. AB - OBJECTIVE: We aimed to determine whether the concomitant combination therapy of anabolic agents and bisphosphonates produces more effects on bone mineral density (BMD) than anabolic agents alone in patients with osteoporosis. METHODS: We searched MEDLINE, EMBASE and the Cochrane Library for publications from 1 January 1980 to 1 August 2016 to identify all the randomised controlled trials (RCTs) and quasi-RCTs. The primary outcome was the mean per cent changes in BMD at the lumbar spine, the total hip and the femoral neck with an optimal period of treatment (6 to 12 months). The secondary outcome was the mean per cent changes in BMD at the same sites with the full period of recommendation (18 to 24 months). A random-effects model was used to estimate the standardised mean differences (SMDs) and the 95% CIs. RESULTS: Seven studies, with 747 patients, were included. With the optimal period, the concomitant combination therapy demonstrated a significant advantage over a monotherapy in BMD improvement at the total hip (SMD 0.42; 95% CI 0.26 to 0.58) and the femoral neck (SMD 0.30; 95% CI 0.14 to 0.46), but not for the spine BMD (SMD 0.13; 95% CI -0.17 to 0.43). With the full period, the concomitant combination therapy did not improve the BMD at the lumbar spine (SMD -0.06; 95% CI -0.71 to 0.59), the total hip (SMD 0.05; 95% CI -0.71 to 0.82) and the femoral neck (SMD -0.32; 95% CI -1.15 to 0.50). CONCLUSIONS: Compared with anabolic monotherapy, the concomitant combination therapy of anabolic agents and bisphosphonates significantly improved the BMD at the total hip and femoral neck with a shorter term (6 to 12 months) and produced similar benefits on BMD for the longer term (18 to 24 months). Also, the effect of concomitant combination therapy might be affected by the dose of anabolic agents. PROSPERO REGISTRATION NUMBER: CRD42016041335. PMID- 29500199 TI - Realist evaluation of a complex integrated care programme: protocol for a mixed methods study. AB - INTRODUCTION: The lack of understanding of how complex integrated care programmes achieve their outcomes due to the lack of acceptable methods leads to difficulties in the development, implementation, adaptation and scaling up of similar interventions. In this study, we evaluate an integrated care network, the National University Health System (NUHS) Regional Health System (RHS), consisting of acute hospitals, step down care, primary care providers, social services and community partners using a theory-driven realist evaluation approach. This study aims to examine how and for whom the NUHS-RHS works to improve healthcare utilisations, outcomes, care experiences and reduce healthcare costs. By using a realist approach that balances the needs of context-specific evaluation with international comparability, this study carries the potential to address current research gaps. METHODS AND ANALYSIS: This evaluation will be conducted in three research phases: (1) development of initial programme theory (IPT) underlying the NUHS-RHS; (2) testing of programme theory using empirical data; and (3) refinement of IPT. IPT was elicited and developed through reviews of programme documents, informal discussions and in-depth interviews with relevant stakeholders. Then, a convergent parallel mixed method study will be conducted to assess context (C), mechanisms (M) and outcomes (O) to test the IPT. Findings will then be analysed according to the realist evaluation formula of CMO in which findings on the context, mechanisms will be used to explain the outcomes. Finally, based on findings gathered, IPT will be refined to highlight how to improve the NUHS-RHS by detailing what works (outcome), as well as how (mechanisms) and under what conditions (context). ETHICS AND DISSEMINATION: The National Healthcare Group, Singapore, Domain Specific Review Board reviewed and approved this study protocol. Study results will be published in international peer-reviewed journals and presented at conferences and internally to NUHS-RHS and Ministry of Health, Singapore. PMID- 29500200 TI - Linkage of Maternity Hospital Episode Statistics data to birth registration and notification records for births in England 2005-2014: Quality assurance of linkage of routine data for singleton and multiple births. AB - OBJECTIVES: To quality assure a Trusted Third Party linked data set to prepare it for analysis. SETTING: Birth registration and notification records from the Office for National Statistics for all births in England 2005-2014 linked to Maternity Hospital Episode Statistics (HES) delivery records by NHS Digital using mothers' identifiers. PARTICIPANTS: All 6 676 912 births that occurred in England from 1 January 2005 to 31 December 2014. PRIMARY AND SECONDARY OUTCOME MEASURES: Every link between a registered birth and an HES delivery record for the study period was categorised as either the same baby or a different baby to the same mother, or as a wrong link, by comparing common baby data items and valid values in key fields with stepwise deterministic rules. Rates of preserved and discarded links were calculated and which features were more common in each group were assessed. RESULTS: Ninety-eight per cent of births originally linked to HES were left with one preserved link. The majority of discarded links were due to duplicate HES delivery records. Of the 4854 discarded links categorised as wrong links, clerical checks found 85% were false-positives links, 13% were quality assurance false negatives and 2% were undeterminable. Births linked using a less reliable stage of the linkage algorithm, births at home and in the London region, and with birth weight or gestational age values missing in HES were more likely to have all links discarded. CONCLUSIONS: Linkage error, data quality issues, and false negatives in the quality assurance procedure were uncovered. The procedure could be improved by allowing for transposition in date fields, and more discrimination between missing and differing values. The availability of identifiers in the datasets supported clerical checking. Other research using Trusted Third Party linkage should not assume the linked dataset is error-free or optimised for their analysis, and allow sufficient resources for this. PMID- 29500201 TI - Risk of pneumococcal diseases in adults with underlying medical conditions: a retrospective, cohort study using two Japanese healthcare databases. AB - OBJECTIVES: To quantify the risk of pneumococcal pneumonia (PP) and invasive pneumococcal disease (IPD) in adults aged >=19 years with underlying medical conditions compared with healthy adults of the same age in Japan. DESIGN: An observational, retrospective, cohort study using two healthcare claims databases in Japan: Japan Medical Data Center (JMDC) and Medical Data Vision (MDV) databases. PARTICIPANTS: A total of 10.4 million individuals, representing 9.3 million person-years of follow-up, were included in the analysis. Eleven medical conditions as well as PP and IPD were identified by the International Statistical Classification of Diseases and Related Health Problems version 10 diagnostic codes and/or local disease codes used in Japan. PRIMARY OUTCOME MEASURES: Adjusted rate ratios (RRs) for PP and IPD in adults with a medical condition versus adults without any medical condition were calculated using multivariate Poisson regression models with age and/or sex as covariates. RESULTS: In the JMDC and MDV databases, respectively, adults >=19 years with a medical condition (RRs for PP: 3.3 to 13.4, 1.7 to 5.2; RRs for IPD: 12.6 to 43.3, 4.4 to 7.1), adults with two or more medical conditions (PP: 11.6, 2.8; IPD: 18.7, 5.8) and high-risk adults (PP: 12.9, 1.8; IPD: 29.7, 4.0) were at greater risk of PP and IPD compared with their healthy counterparts. Adults aged 50-64 years with an underlying medical condition (PP rate: 38.6 to 212.1 per 100 000 person-years) had a higher rate of PP than those aged >=65 years without any condition (PP rate: 13.2 to 93.0 per 100 000 person-years). CONCLUSIONS: Adults of all ages with an underlying medical condition are at greater risk of PP and IPD compared with adults without any medical condition. This risk increases with the number of underlying medical conditions. Our results support extending pneumococcal vaccination to younger adults with an underlying medical condition, especially those aged 50-64 years. PMID- 29500202 TI - Dental caries and preterm birth: a systematic review and meta-analysis. AB - OBJECTIVES: The primary objective of this systematic review was to evaluate the association between dental caries and preterm birth (PTB). The secondary objective was ascertaining the difference between women with dental caries who experienced PTB and those who did not with regard to decayed, missing and filled teeth (DMFT), and decayed, missing and filled surfaces (DMFS) indices. METHODS: MEDLINE, Embase, CINAHL and Cochrane databases were searched initially in November 2015 and repeated in December 2016. We included observational cohort and case-control studies. Only studies reporting the risk of PTB in women affected compared with those not affected by dental caries in pregnancy were included. Random-effect meta-analyses were used to compute the summary OR of PTB among women with caries versus women without caries, and the mean difference in either DMFT or DMFS indices between women experiencing PTB and those without PTB. RESULTS: Nine observational studies (4826 pregnancies) were included. Women affected by dental caries during pregnancy did not show a significantly higher risk of PTB (OR: 1.16, 95% CI 0.90 to 1.49, P=0.25, I2=35%). Also, the women with PTB did not show significantly higher DMFT or DMFS indices (summary mean differences: 1.56, P=0.10; I2=92% and -0.15, P=0.9, I2=89%, respectively). CONCLUSION: Dental caries does not appear to be a substantial risk factor for PTB. TRIAL REGISTRATION NUMBER: NCT01675180; Pre-results. PMID- 29500204 TI - Development of an English-language version of a Japanese iPad application to facilitate collaborative goal setting in rehabilitation: a Delphi study and field test. AB - OBJECTIVE: This study aimed to investigate the content of an English-language version of a Japanese iPad application designed to facilitate shared decision making around goal setting in rehabilitation: Aid for Decision-making in Occupational Choice-English (ADOC-E). DESIGN: Phase 1: Delphi methods to reach consensus with an international group of expert occupational therapists on the text and images in ADOC-E. Phase 2: Testing correct recognition (unprompted and prompted) of images in ADOC-E by health service users in inpatient rehabilitation and residential care. SETTING: Phase 1: International, online. Phase 2: Three healthcare services in New Zealand-(1) a residential rehabilitation service for traumatic brain injury, (2) a nursing home for frail older adults and (3) an inpatient rehabilitation ward in a public hospital. PARTICIPANTS: Phase 1: Fourteen experienced occupational therapists from New Zealand (4), Australia (4), UK (2) and USA (4). Phase 2: Twenty-four rehabilitation and residential care service users (10 men, 14 women; 20-95 years; Mini-Mental State Exam scores 13 30). RESULTS: Four Delphi rounds were required to reach consensus with the experienced occupational therapists on the content of ADOC-E, ending with 100 items covering daily activities that people do and social roles they participate in. Ninety-five per cent (95/100) of ADOC-E items could each be correctly identified by over 80% of service user participants with either unprompted or prompted recognition. CONCLUSION: While a few of the more abstract concepts in ADOC-E (related to complex social roles) were less likely to be correctly recognised by all participants, the text and images ADOC-E were deemed to be fit for purpose overall and ready for future clinical testing. PMID- 29500203 TI - Model-based recursive partitioning to identify risk clusters for metabolic syndrome and its components: findings from the International Mobility in Aging Study. AB - OBJECTIVE: Conceptual models underpinning much epidemiological research on ageing acknowledge that environmental, social and biological systems interact to influence health outcomes. Recursive partitioning is a data-driven approach that allows for concurrent exploration of distinct mixtures, or clusters, of individuals that have a particular outcome. Our aim is to use recursive partitioning to examine risk clusters for metabolic syndrome (MetS) and its components, in order to identify vulnerable populations. STUDY DESIGN: Cross sectional analysis of baseline data from a prospective longitudinal cohort called the International Mobility in Aging Study (IMIAS). SETTING: IMIAS includes sites from three middle-income countries-Tirana (Albania), Natal (Brazil) and Manizales (Colombia)-and two from Canada-Kingston (Ontario) and Saint-Hyacinthe (Quebec). PARTICIPANTS: Community-dwelling male and female adults, aged 64-75 years (n=2002). PRIMARY AND SECONDARY OUTCOME MEASURES: We apply recursive partitioning to investigate social and behavioural risk factors for MetS and its components. Model-based recursive partitioning (MOB) was used to cluster participants into age-adjusted risk groups based on variabilities in: study site, sex, education, living arrangements, childhood adversities, adult occupation, current employment status, income, perceived income sufficiency, smoking status and weekly minutes of physical activity. RESULTS: 43% of participants had MetS. Using MOB, the primary partitioning variable was participant sex. Among women from middle incomes sites, the predicted proportion with MetS ranged from 58% to 68%. Canadian women with limited physical activity had elevated predicted proportions of MetS (49%, 95% CI 39% to 58%). Among men, MetS ranged from 26% to 41% depending on childhood social adversity and education. Clustering for MetS components differed from the syndrome and across components. Study site was a primary partitioning variable for all components except HDL cholesterol. Sex was important for most components. CONCLUSION: MOB is a promising technique for identifying disease risk clusters (eg, vulnerable populations) in modestly sized samples. PMID- 29500205 TI - Interventions to encourage smoke-free homes in remote indigenous Australian communities: a study protocol to evaluate the effects of a community-inspired awareness-raising and motivational enhancement strategy. AB - INTRODUCTION: Rates of secondhand smoke exposure are currently significantly higher among remote indigenous communities in the top end of Australia. By implementing a 'smoke-free home' rule, secondhand smoke exposure can be reduced. Smoke-free homes encourage quit attempts and improve the health of children. The prevalence of indigenous smoking rates in remote, discrete communities in Australia is elevated compared with their non-indigenous counterparts. The primary aim of this project is to examine the feasibility of conducting a health driven intervention to encourage community members to make their homes a smoke free zone. METHODS AND ANALYSIS: This study uses mixed-methods exploratory evaluation design to obtain data from key informants and community householders to assess their willingness to implement a 'smoke-free' rule in their homes. Initial focus groups will provide guidance on intervention content and deliver evaluation procedures and community requirements. A rapid survey will be conducted to ascertain interest from community members in having the project team visit to discuss study objectives further and to have a particle meter (with consent) placed in the house. Focus groups recordings will be transcribed and analysed thematically. Rapid surveys will be analysed using frequency distributions and tabulations of responses. ETHICS AND DISSEMINATION: The National Health and Medical Research Council guidelines on ethical research approaches to indigenous studies will be adhered to. The James Cook University Human Research Ethics Committee has provided ethics approval. PMID- 29500206 TI - Developing a UK registry to investigate the role of cardiovascular magnetic resonance (CMR) in patients who activate the primary percutaneous coronary intervention (PPCI) pathway: a multicentre, feasibility study linking routinely collected electronic patient data. AB - OBJECTIVES: To determine whether it is feasible to set up a national registry, linking routinely collected data from hospital information systems (HIS), to investigate the role of cardiovascular magnetic resonance (CMR) in patients who activate the primary percutaneous coronary intervention (PPCI) pathway. DESIGN: Feasibility prospective cohort study, to establish whether: (1) consent can be implemented; (2) data linkage and extraction from multiple HIS can be achieved for >90% of consented patients; (3) local data can be successfully linked with hospital episode data (Hospital Episode Statistics, HES; Patient Episode Database for Wales, PEDW) for >90% of consented patients and (4) the proportion of patients activating the PPCI pathway who get a CMR scan is >=10% in hospitals with dedicated CMR facilities. PARTICIPANTS: Patients from four 24/7 PPCI hospitals in England and Wales (two with and two without a dedicated CMR facility) who activated the PPCI pathway and underwent an emergency coronary angiogram. RESULTS: Consent was successfully implemented at all hospitals (consent rates ranged from 59% to 74%) and 1670 participants were recruited. Data submission was variable: all hospitals submitted clinical data (for >=82% of patients); only three hospitals submitted biochemistry data (for >=98% of patients) and echocardiography data (for 34%-87% of patients); only one hospital submitted medications data (for 97% of patients). At the two CMR centres, 14% and 20% of patients received a CMR scan. Data submitted by hospitals were linked with HES and PEDW for 99% of all consented patients. CONCLUSION: We successfully consented patients but obtaining individual, opt-in consent would not be feasible for a national registry. Linkage of data from HIS with hospital episode data was feasible. However, data from HIS are not uniformly available/exportable and, in centres with a dedicated CMR facility, some referrals for CMR were for research rather than clinical purposes. PMID- 29500207 TI - Does physiological distribution of blood parameters in children depend on socioeconomic status? Results of a German cross-sectional study. AB - OBJECTIVES: In the present study, we examined the relation between socioeconomic status (SES) and the physiological distribution of iron-related blood parameters. DESIGN: This is a cross-sectional analysis of longitudinal population-based cohort study. SETTING: Based on a sample of healthy participants from a German research centre, various blood parameters and values of clinical examinations and questionnaires were collected. PARTICIPANTS: A total of 1206 healthy volunteers aged 2.5 to 19 years, one child per family randomly selected, were included. PRIMARY AND SECONDARY OUTCOME MEASURES: Associations between the SES of children by Winkler-Stolzenberg Index (WSI) and its dimensions (income, education, occupation) and iron-related blood parameters (haemoglobin, ferritin and transferrin) were analysed by linear regression analyses. Gender and pubertal stage were included as covariables. Additionally, associations between SES of children by WSI and physical activity (side-to-side jumps, push-ups) as well as body mass index (BMI) were analysed by linear regression analyses. RESULTS: Children with high WSI or family income showed significantly increased z-scores for haemoglobin (P=0.046; P<0.001). Children with increased WSI or family income showed significantly lower z-scores for transferrin (P<0.001). There was a significant correlation between haemoglobin and gender (P<0.001) and between transferrin and pubertal stage (P=0.024). Furthermore, physical activity was positively correlated and BMI was negatively correlated with WSI (P<0.001). DISCUSSION: Our data show an association between SES and the distribution of iron dependent parameters. Lower SES is correlated with lower values for haemoglobin and higher values for transferrin. Furthermore, we demonstrate that physical activity and BMI are associated with SES. Whereas higher SES is correlated with higher values for physical activity and lower BMI. Our parameters are standardised as z-scores with the advantages that the results are comparable across different age groups and present physiological courses. TRIAL REGISTRATION NUMBER: NCT02550236; Results. PMID- 29500208 TI - Foundation Year 2 doctors' reasons for leaving UK medicine: an in-depth analysis of decision-making using semistructured interviews. AB - OBJECTIVES: To explore the reasons that doctors choose to leave UK medicine after their foundation year two posts. SETTING: All four regions of Scotland. PARTICIPANTS: Foundation year two doctors (F2s) working throughout Scotland who were considering leaving UK medicine after foundation training were recruited on a volunteer basis. Maximum variation between participants was sought. PRIMARY AND SECONDARY OUTCOME MEASURES: Semistructured interviews were coded using template analysis. Six perspectives, described by Feldman and Ng, were used as the initial coding template. The codes were then configured to form a framework that explores the interplay of factors influencing Foundation Year 2 (F2) doctors' decisions to leave UK medicine. RESULTS: Seventeen participants were interviewed. Six perspectives were explored. Structural influences (countrywide and worldwide issues) included visas, economic and political considerations, structure of healthcare systems and availability of junior doctor jobs worldwide. Organisational influences (the National Health Service (NHS) and other healthcare providers) included staffing and compensation policies, the working environment and the learning environment. Occupational influences (specific to being a junior doctor) comprised the junior doctor contract, role and workload, pursuit of career interests and the structure of training. Work group influences (relationships with colleagues) included support at work, task interdependence and use of locums. Personal life influences consisted of work-life balance, and support in resolving work-life conflict. The underlying theme of 'taking a break' recurred through multiple narratives. CONCLUSIONS: F2s give reasons similar to those given by any professional considering a change in their job. However, working within the NHS as an F2 doctor brought specific challenges, such as a need to make a choice of specialty within the F2 year, exposure to workplace bullying and difficulties in raising concerns. Despite these challenges, most F2s did not view their decision to leave as a permanent job change, but as a temporary break from their current working lives. PMID- 29500209 TI - 7-day compared with 10-day antibiotic treatment for febrile urinary tract infections in children: protocol of a randomised controlled trial. AB - INTRODUCTION: The optimal duration of antibiotic therapy in children with febrile urinary tract infections (UTIs) is still a matter of debate. Current guidelines recommend treating children with febrile UTIs with antimicrobials for 7 to 14 days. We aim to compare the efficacy and safety of 7-day versus 10-day course of oral or sequence therapy (intravenous with a switch to oral) with cefuroxime/cefuroxime axetil for febrile UTIs in children. METHODS AND ANALYSIS: A non-inferiority, double-blind, randomised, controlled trial will be conducted. Two hundred twenty-one patients aged 3 months to 7 years with febrile UTIs (defined as a combination of fever and leucocyturia in urine sediment) will be randomly assigned to a 7-day treatment arm (7 days of cefuroxime/cefuroxime axetil followed by 3 days of blinded placebo) or a 10-day treatment arm (7 days of cefuroxime/cefuroxime axetil followed by 3 days of blinded cefuroxime axetil). The primary outcome measure will be frequencies of recurrence and reinfection of UTI during the 6 months after the intervention. ETHICS AND DISSEMINATION: The Bioethics Committee approved the study protocol. The findings of this trial will be submitted to a peer-reviewed paediatric journal. Abstracts will be submitted to relevant national and international conferences. DATE AND PROTOCOL VERSION IDENTIFIER: 04/09/2017 TRIAL REGISTRATION NUMBER: NCT03221504. PMID- 29500210 TI - Do non-inferiority trials of reduced intensity therapies show reduced effects? A descriptive analysis. AB - OBJECTIVES: To identify non-inferiority trials within a cohort where the experimental therapy is the same as the active control comparator but at a reduced intensity and determine if these non-inferiority trials of reduced intensity therapies have less favourable results than other non-inferiority trials in the cohort. Such a finding would provide suggestive evidence of biocreep in these trials. DESIGN: This metaresearch study used a cohort of non inferiority trials published in the five highest impact general medical journals during a 5-year period. Data relating to the characteristics and results of the trials were abstracted. PRIMARY OUTCOME MEASURES: Proportions of trials with a declaration of superiority, non-inferiority and point estimates favouring the experimental therapy and mean absolute risk differences for trials with outcomes expressed as a proportion. RESULTS: Our search yielded 163 trials reporting 182 non-inferiority comparisons; 36 comparisons from 31 trials were between the same therapy at reduced and full intensity. Compared with trials not evaluating reduced intensity therapies, fewer comparisons of reduced intensity therapies demonstrated a favourable result (non-inferiority or superiority) (58.3%vs82.2%; P=0.002) and fewer demonstrated superiority (2.8%vs18.5%; P=0.019). Likewise, point estimates for reduced intensity therapies more often favoured active control than those for other trials (77.8%vs39.7%; P<0.001) as did mean absolute risk differences (+2.5% vs -0.7%; P=0.018). CONCLUSIONS: Non-inferiority trials comparing a therapy at reduced intensity to the same therapy at full intensity showed reduced effects compared with other non-inferiority trials. This suggests these trials may have a high rate of type 1 errors and biocreep, with significant implications for the design and interpretation of future non-inferiority trials. PMID- 29500211 TI - Differences in rates and odds for emergency caesarean section in six Palestinian hospitals: a population-based birth cohort study. AB - OBJECTIVE: To assess the differences in rates and odds for emergency caesarean section among singleton pregnancies in six governmental Palestinian hospitals. DESIGN: A prospective population-based birth cohort study. SETTING: Obstetric departments in six governmental Palestinian hospitals. PARTICIPANTS: 32 321 women scheduled to deliver vaginally from 1 March 2015 until 29 February 2016. METHODS: To assess differences in sociodemographic and antenatal obstetric characteristics by hospital, chi2 test, analysis of variance and Kruskal-Wallis test were applied. Logistic regression was used to estimate differences in odds for emergency caesarean section, and ORs with 95% CIs were assessed. MAIN OUTCOME MEASURES: The primary outcome was the adjusted ORs of emergency caesarean section among singleton pregnancies for five Palestinian hospitals as compared with the reference (Hospital 1). RESULTS: The prevalence of emergency caesarean section varied across hospitals, ranging from 5.8% to 22.6% among primiparous women and between 4.8% and 13.1% among parous women. Compared with the reference hospital, the ORs for emergency caesarean section were increased in all other hospitals, crude ORs ranging from 1.95 (95% CI 1.42 to 2.67) to 4.75 (95% CI 3.49 to 6.46) among primiparous women. For parous women, these differences were less pronounced, crude ORs ranging from 1.37 (95% CI 1.13 to 1.67) to 2.99 (95% CI 2.44 to 3.65). After adjustment for potential confounders, the ORs were reduced but still statistically significant, except for one hospital among parous women. CONCLUSION: Substantial differences in odds for emergency caesarean section between the six Palestinian governmental hospitals were observed. These could not be explained by the studied sociodemographic or antenatal obstetric characteristics. PMID- 29500212 TI - Cross-sectional and prospective associations of neighbourhood environmental attributes with screen time in Japanese middle-aged and older adults. AB - OBJECTIVES: This study examined cross-sectional and 2-year prospective associations of perceived and objectively measured environmental attributes with screen time among middle-aged Japanese adults. DESIGN: Prospective cohort study. SETTING: Nerima and Kanuma cities of Japan. PARTICIPANTS: Data were collected from adults aged 40-69 years living in two cities of Japan in 2011 (baseline: n=1011; 55.3+/-8.4 years) and again in 2013 (follow-up: n=533; 52.7% of baseline sample). MEASURES: The exposure variables were five geographic information system based and perceived attributes of neighbourhood environments (residential density, access to shops and public transport, footpaths, street connectivity), respectively. The outcome variables were baseline screen time (television viewing time and leisure-time internet use) and its change over 2 years. Multilevel generalised linear modelling was used. RESULTS: On average, participants' screen time was not statistically different over 2 years (2.3 hours/day at baseline and 2.2 hours/day at follow-up; P=0.24). There were cross-sectional associations of objective (exp(beta): 1.11; 95% CI 1.01 to 1.22) and perceived (1.12; 1.02 to 1.23) good access to public transport, perceived good access to shop (1.18; 1.04 to 1.36) and perceived good street connectivity (1.11; 1.01 to 1.23) with higher time spent in screen time at baseline. No objective and perceived environmental attributes were significantly associated with change in screen time. CONCLUSIONS: Activity-supportive neighbourhood environmental attributes appear to be related to higher levels of screen time cross-sectionally. Pattern of screen time might be maintained rather than changed over time under the same neighbourhood environments. Environmental interventions that promote physical activity may need to consider the potential negative health impact of screen time in Japan. PMID- 29500213 TI - Comorbid psychiatric disorders in a clinical sample of adults with ADHD, and associations with education, work and social characteristics: a cross-sectional study. AB - OBJECTIVES: Adults with attention-deficit hyperactive disorder (ADHD) report high rates of comorbid disorders, educational and occupational failure, and family instability. The aim of this study was to examine the prevalence of comorbid psychiatric disorders in a clinical population of adults with ADHD and to examine associations between educational level, work participation, social characteristics and the rates of psychiatric comorbidity. METHODS: Out of 796 patients diagnosed with ADHD in a specialised outpatient clinic in Oslo, Norway, 548 (68%) agreed to participate in this cross-sectional study: 277 women and 271 men. ADHD was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria. Comorbid disorders were diagnosed using the Mini-International Neuropsychiatric Interview. RESULTS: In this clinical sample, 53.5% had at least one current comorbid psychiatric disorder. The most prevalent disorders were major depression, substance use disorders and social phobia. Women had more eating disorders than men, whereas men had more alcohol and substance use disorders. Education above high school level (>12 years) and work participation were associated with lower rates of comorbid disorders (adjusted ORs 0.52 and 0.63, respectively). Gender, age, marital status, living with children or living in a city were not associated with comorbidity. CONCLUSIONS: Adult ADHD is associated with high rates of comorbid psychiatric disorders, irrespective of gender and age. It appears that higher education and work participation are related to lower probability of comorbidity. PMID- 29500214 TI - Use of the nominal group technique to identify stakeholder priorities and inform survey development: an example with informal caregivers of people with scleroderma. AB - OBJECTIVES: The nominal group technique (NGT) allows stakeholders to directly generate items for needs assessment surveys. The objective was to demonstrate the use of NGT discussions to develop survey items on (1) challenges experienced by informal caregivers of people living with systemic sclerosis (SSc) and (2) preferences for support services. DESIGN: Three NGT groups were conducted. In each group, participants generated lists of challenges and preferred formats for support services. Participants shared items, and a master list was compiled, then reviewed by participants to remove or merge overlapping items. Once a final list of items was generated, participants independently rated challenges on a scale from 1 (not at all important) to 10 (extremely important) and support services on a scale from 1 (not at all likely to use) to 10 (very likely to use). Lists generated in the NGT discussions were subsequently reviewed and integrated into a single list by research team members. SETTING: SSc patient conferences held in the USA and Canada. PARTICIPANTS: Informal caregivers who previously or currently were providing care for a family member or friend with SSc. RESULTS: A total of six men and seven women participated in the NGT discussions. Mean age was 59.8 years (SD=12.6). Participants provided care for a partner (n=8), parent (n=1), child (n=2) or friend (n=2). A list of 61 unique challenges was generated with challenges related to gaps in information, resources and support needs identified most frequently. A list of 18 unique support services was generated; most involved online or in-person delivery of emotional support and educational material about SSc. CONCLUSIONS: The NGT was an efficient method for obtaining survey items directly from SSc caregivers on important challenges and preferences for support services. PMID- 29500215 TI - Temporal trends in severe maternal and neonatal trauma during childbirth: a population-based observational study. AB - OBJECTIVE: Instrumental vaginal delivery is associated with birth trauma to infant and obstetric trauma to mother. As caesarean delivery rates increased during the past decades, the rate of instrumental vaginal delivery declined. We examined concomitant temporal changes in the rates of severe birth trauma and maternal obstetric trauma. DESIGN: A retrospective observational study. SETTINGS AND PARTICIPANTS: All hospital singleton live births in Washington State, USA, 2004-2013, excluding breech delivery. Severe birth trauma (brain, nerve injury, fractures and other severe birth trauma) and obstetric trauma (third/fourth degree perineal lacerations, cervical/high vaginal lacerations) were identified from hospitalisation data. Pregnancy and delivery characteristics were obtained from birth certificates. Temporal trends were assessed by the Cochran-Armitage test. Logistic regression was used to obtain adjusted ORs (AORs) and 95% CI. RESULTS: Overall, 732 818 live births were included. The rate of severe birth trauma declined from 5.3 in 2004 to 4.5 per 1000 live births in 2013 (P<0.001). The decline was observed only in spontaneous vaginal delivery, the rates of fractures and other severe birth trauma declined by 5% and 4% per year, respectively (AOR: 0.95, 95% CI 0.94 to 0.97 and AOR: 0.96, 95% CI 0.93 to 0.99; respectively). The rate of third/fourth degree lacerations declined in spontaneous vaginal delivery from 3.5% to 2.3% (AOR: 0.95; 95% CI 0.94 to 0.95) and in vacuum delivery from 17.3% to 14.5% (AOR: 0.97, 95% CI 0.96 to 0.98). Among women with forceps delivery, these rates declined from 29.8% to 23.4% (AOR: 0.98, 95% CI 0.96 to 1.00). CONCLUSION: While the rates of fractures and other birth trauma declined among infants delivered by spontaneous vaginal delivery, the rate of birth trauma remained unchanged in instrumental vaginal delivery and caesarean delivery. Among mothers, the rates of severe perineal lacerations declined, except for women with forceps delivery. PMID- 29500216 TI - Negotiating acceptable termination of pregnancy for non-lethal fetal anomaly: a qualitative study of professional perspectives. AB - OBJECTIVE: This study aims to explore the perspectives of professionals around the issue of termination of pregnancy for non-lethal fetal anomaly (TOPFA). METHODS: Semi-structured interviews were undertaken with medical professionals (14 consultants in fetal medicine, obstetrics, neonatology and paediatrics) and social care professionals (nine individuals with roles supporting people living with impairment) from the Northeast of England. Analysis adopted an inductive thematic approach facilitated by NVivo. RESULTS: The overarching theme to emerge from the interview data was of professionals, medical and social care, wanting to present an acceptable self-image of their views on TOPFA. Professionals' values on 'fixing', pain and 'normality' influenced what aspects of moral acceptability they gave priority to in terms of their standpoint and, in turn, their conceptualisations of acceptable TOPFA. Thus, if a termination could be defended morally, including negotiation of several key issues (including 'fixing', perceptions of pain and normality), then participants conceptualised TOPFA as an acceptable pregnancy outcome. CONCLUSION: Despite different professional experiences, these professional groups were able to negotiate their way through difficult terrain to conceptualise TOPFA as a morally acceptable principle. While professionals have different moral thresholds, no one argued for a restriction of the current legislation. The data suggest that social care professionals also look at the wider social context of a person with an impairment when discussing their views regarding TOPFA. Medical professionals focus more on the individual impairment when discussing their views on TOPFA. PMID- 29500218 TI - Complete correction of hemophilia B phenotype by FIX-Padua skeletal muscle gene therapy in an inhibitor-prone dog model. PMID- 29500217 TI - CoMET: a protocol for a randomised controlled trial of co-commencement of METformin as an adjunctive treatment to attenuate weight gain and metabolic syndrome in patients with schizophrenia newly commenced on clozapine. AB - INTRODUCTION: Clozapine, while effective in treatment refractory schizophrenia, is associated with significant weight gain, heart disease and increased risk of type 2 diabetes mellitus (T2DM). Although there is evidence for weight loss with metformin for people with obesity who are already taking clozapine, there have been no published trials that have investigated the effect of metformin in attenuating weight gain at the time of clozapine initiation. METHODS AND ANALYSIS: A 24-week double-blind placebo-controlled trial of concomitant prescription of metformin at clozapine commencement. Eighty-six people being commenced on clozapine will be randomised to placebo or metformin (variable dose, up to 2 g/day). The primary outcome is comparative end point body weight, between the placebo and metformin groups. Secondary outcomes are comparative rates of conversion to T2DM, alteration of metabolic syndrome parameters, proportion gaining >5% body weight and changes in diet and appetite. We will additionally examine biomarkers associated with change in weight among trial participants. ETHICS AND DISSEMINATION: Ethics approval was granted by the Metro South Human Research Ethics Committee HREC/17/QPAH/538-SSA/17/QPAH/565. We plan to submit a manuscript of the results to a peer-reviewed journal, and present results at conferences, consumer forums and hospital grand rounds. TRIAL REGISTRATION NUMBER: ACTRN12617001547336; Pre-results. PMID- 29500220 TI - Emergency admissions rise 24% in past decade, costing almost L14bn a year. PMID- 29500219 TI - RUNX transcription factors potentially control E-selectin expression in the bone marrow vascular niche in mice. AB - Although the function of Runt-related (RUNX) transcription factors has been well characterized in leukemogenesis and regarded as an ideal target in antileukemia strategies, the effect of RUNX-inhibition therapy on bone marrow niche cells andr its impact on the engraftment of acute myeloid leukemia (AML) cells have largely been unknown. Here, we provide evidence suggesting the possible involvement of RUNX transcription factors in the transactivation of E-selectin, a member of selectin family of cell adhesion molecules, on the vascular endothelial cells of the mice bone marrow niche. In our experiments, gene switch-mediated silencing of RUNX downregulated E-selectin expression in the vascular niche and negatively controlled the engraftment of AML cells in the bone marrow, extending the overall survival of leukemic mice. Our work identified the novel role of RUNX family genes in the vascular niche and showed that the vascular niche, a home for AML cells, could be strategically targeted with RUNX-silencing antileukemia therapies. Considering the excellent efficacy of RUNX-inhibition therapy on AML cells themselves as we have previously reported, this strategy potentially targets AML cells both directly and indirectly, thus providing a better chance of cure for poor-prognostic AML patients. PMID- 29500221 TI - Response to letter regarding: 'A source of tension'. PMID- 29500222 TI - NHS can lead in reducing pollution to improve public health, says chief medical officer. PMID- 29500223 TI - Protective effects of the angiotensin II AT2 receptor agonist compound 21 in ischemic stroke: a nose-to-brain delivery approach. AB - Significant neuroprotective effects of angiotensin II type 2 (AT2) receptor (AT2 receptor) agonists in ischemic stroke have been previously demonstrated in multiple studies. However, the routes of agonist application used in these pre clinical studies, direct intracerebroventricular (ICV) and systemic administration, are unsuitable for translation into humans; in the latter case because AT2 receptor agonists are blood-brain barrier (BBB) impermeable. To circumvent this problem, in the current study we utilized the nose-to-brain (N2B) route of administration to bypass the BBB and deliver the selective AT2 receptor agonist Compound 21 (C21) to naive rats or rats that had undergone endothelin 1 (ET-1)-induced ischemic stroke. The results obtained from the present study indicated that C21 applied N2B entered the cerebral cortex and striatum within 30 min in amounts that are therapeutically relevant (8.4-9 nM), regardless of whether BBB was intact or disintegrated. C21 was first applied N2B at 1.5 h after stroke indeed provided neuroprotection, as evidenced by a highly significant, 57% reduction in cerebral infarct size and significant improvements in Bederson and Garcia neurological scores. N2B-administered C21 did not affect blood pressure or heart rate. Thus, these data provide proof-of-principle for the idea that N2B application of an AT2 receptor agonist can exert neuroprotective actions when administered following ischemic stroke. Since N2B delivery of other agents has been shown to be effective in certain human central nervous system diseases, the N2B application of AT2 receptor agonists may become a viable mode of delivering these neuroprotective agents for human ischemic stroke patients. PMID- 29500224 TI - TLR2 and TLR4 play opposite role in autophagy associated with cisplatin-induced acute kidney injury. AB - Acute kidney injury (AKI) is considered an inflammatory disease in which toll like receptors (TLRs) signaling pathways play an important role. The activation of TLRs results in production of several inflammatory cytokines leading to further renal damage. In contrast, TLRs are key players on autophagy induction, which is associated with a protective function on cisplatin-induced AKI. Hence, the present study aimed to evaluate the specific participation of TLR2 and TLR4 molecules on the development of cisplatin-induced AKI. Complementarily, we also investigated the link between TLRs and heme oxygenase-1 (HO-1), a promisor cytoprotective molecule. First, we observed that only the absence of TLR2 but not TLR4 in mice exacerbated the renal dysfunction, tissue injury and mortality rate, even under an immunologically privileged microenvironment. Second, we demonstrated that TLR2 knockout (KO) mice presented lower expression of autophagy associated markers when compared with TLR4 KO animals. Similar parameter was confirmed in vitro, using tubular epithelial cells derived from both KO mice. To test the cross-talking between HO-1 and TLRs, hemin (an HO-1 internal inducer) was administrated in cisplatin-treated TLR2 and TLR4 KO mice and it was detected an improvement in the global renal tissue parameters. However, this protection was less evident at TLR2 KO mice. In summary, we documented that TLR2 plays a protective role in cisplatin-induced AKI progression, in part, by a mechanism associated with autophagy up-regulation, considering that its interplay with HO-1 can promote renal tissue recover. PMID- 29500226 TI - Mapping regulatory circuits in allergic skin inflammation. AB - RORalpha+ skin-resident regulatory T cells restrain innate lymphoid cell driven allergic skin inflammation. PMID- 29500225 TI - RORalpha-expressing T regulatory cells restrain allergic skin inflammation. AB - Atopic dermatitis is an allergic inflammatory skin disease characterized by the production of the type 2 cytokines in the skin by type 2 innate lymphoid cells (ILC2s) and T helper 2 (TH2) cells, and tissue eosinophilia. Using two distinct mouse models of atopic dermatitis, we show that expression of retinoid-related orphan receptor alpha (RORalpha) in skin-resident T regulatory cells (Tregs) is important for restraining allergic skin inflammation. In both models, targeted deletion of RORalpha in mouse Tregs led to exaggerated eosinophilia driven by interleukin-5 (IL-5) production by ILC2s and TH2 cells. Expression of RORalpha in skin-resident Tregs suppressed IL-4 expression and enhanced expression of death receptor 3 (DR3), which is the receptor for tumor necrosis factor (TNF) family cytokine, TNF ligand-related molecule 1 (TL1A), which promotes Treg functions. DR3 is expressed on both ILC2s and skin-resident Tregs Upon deletion of RORalpha in skin-resident Tregs, we found that Tregs were no longer able to sequester TL1A, resulting in enhanced ILC2 activation. We also documented higher expression of RORalpha in skin-resident Tregs than in peripheral blood circulating Tregs in humans, suggesting that RORalpha and the TL1A-DR3 circuit could be therapeutically targeted in atopic dermatitis. PMID- 29500227 TI - The kidney gets caught in a macrophage trap. AB - Myoglobulin released from dead muscle is shown to induce acute kidney injury through a mechanism dependent on platelets and macrophage extracellular traps. PMID- 29500228 TI - Stemming the tide of viral infection. AB - A subset of canonical "interferon-stimulated" antiviral genes are intrinsically expressed in and protect mammalian stem cells. PMID- 29500229 TI - Investigation and management of adult hypertension. PMID- 29500230 TI - EPT1 (selenoprotein I) is critical for the neural development and maintenance of plasmalogen in humans. AB - Ethanolamine phosphotransferase (EPT)1, also known as selenoprotein 1 (SELENOI), is an enzyme that transfers phosphoethanolamine from cytidine diphosphate ethanolamine to lipid acceptors to produce ethanolamine glycerophospholipids, such as diacyl-linked phosphatidylethanolamine (PE) and ether-linked plasmalogen [1-alkenyl-2-acyl-glycerophosphoethanolamine (plasmenyl-PE)]. However, to date there has been no analysis of the metabolomic consequences of the mutation of EPT1 on the concentration of ethanolamine glycerophospholipids in mammalian cells. We studied a patient with severe complicated hereditary spastic paraplegia, sensorineural-deafness, blindness, and seizures. Neuroimaging revealed hypomyelination, followed by brain atrophy mainly in the cerebellum and brainstem. Using whole exome sequencing, we identified a novel EPT1 mutation (exon skipping). In vitro EPT activity, as well as the rate of biosynthesis of ethanolamine glycerophospholipids, was markedly reduced in cultures of the patient's skin fibroblasts. Quantification of phospholipids by LC-MS/MS demonstrated reduced levels of several PE species with polyunsaturated fatty acids, such as 38:6, 38:4, 40:6, 40:5, and 40:4. Notably, most plasmenyl-PE species were significantly decreased in the patient's cells, whereas most plasmanylcholine [1-alkyl-2-acyl-glycerophosphocholine (plasmanyl-PC)] species were increased. Similar findings regarding decreased plasmenyl-PE and increased plasmanyl-PC were obtained using EPT1-KO HeLa cells. Our data demonstrate for the first time the indispensable role of EPT1 in the myelination process and neurodevelopment, and in the maintenance of normal homeostasis of ether-linked phospholipids in humans. PMID- 29500231 TI - Caspase-9 CARD : core domain interactions require a properly formed active site. AB - Caspase-9 is a critical factor in the initiation of apoptosis and as a result is tightly regulated by many mechanisms. Caspase-9 contains a Caspase Activation and Recruitment Domain (CARD), which enables caspase-9 to form a tight interaction with the apoptosome, a heptameric activating platform. The caspase-9 CARD has been thought to be principally involved in recruitment to the apoptosome, but its roles outside this interaction have yet to be uncovered. In this work, we show that the CARD is involved in physical interactions with the catalytic core of caspase-9 in the absence of the apoptosome; this interaction requires a properly formed caspase-9 active site. The active sites of caspases are composed of four extremely mobile loops. When the active-site loops are not properly ordered, the CARD and core domains of caspase-9 do not interact and behave independently, like loosely tethered beads. When the active-site loop bundle is properly ordered, the CARD domain interacts with the catalytic core, forming a single folding unit. Taken together, these findings provide mechanistic insights into a new level of caspase-9 regulation, prompting speculation that the CARD may also play a role in the recruitment or recognition of substrate. PMID- 29500232 TI - Heme degradation enzyme biliverdin IXbeta reductase is required for stem cell glutamine metabolism. AB - Bioenergetic requirements of hematopoietic stem cells and pluripotent stem cells (PSCs) vary with lineage fate, and cellular adaptations rely largely on substrate (glucose/glutamine) availability and mitochondrial function to balance tricarboxylic acid (TCA)-derived anabolic and redox-regulated antioxidant functions. Heme synthesis and degradation converge in a linear pathway that utilizes TCA cycle-derived carbon in cataplerotic reactions of tetrapyrrole biosynthesis, terminated by NAD(P)H-dependent biliverdin reductases (IXalpha, BLVRA and IXbeta, BLVRB) that lead to bilirubin generation and cellular antioxidant functions. We now demonstrate that PSCs with targeted deletion of BLVRB display physiologically defective antioxidant activity and cellular viability, associated with a glutamine-restricted defect in TCA entry that was computationally predicted using gene/metabolite topological network analysis and subsequently validated by bioenergetic and isotopomeric studies. Defective BLVRB regulated glutamine utilization was accompanied by exaggerated glycolytic accumulation of the rate-limiting hexokinase reaction product glucose-6 phosphate. BLVRB-deficient embryoid body formation (a critical size parameter of early lineage fate potential) demonstrated enhanced sensitivity to the pentose phosphate pathway (PPP) inhibitor 6-aminonicotinamide with no differences in the glycolytic pathway inhibitor 2-deoxyglucose. These collective data place heme catabolism in a crucial pathway of glutamine-regulated bioenergetic metabolism and suggest that early stages of lineage fate potential require glutamine anaplerotic functions and an intact PPP, which are, in part, regulated by BLVRB activity. In principle, BLVRB inhibition represents an alternative strategy for modulating cellular glutamine utilization with consequences for cancer and hematopoietic metabolism. PMID- 29500233 TI - Reliability of capillary blood potassium measurements in children with acute gastroenteritis. PMID- 29500234 TI - Global Health Watch: Challenging entrenched ideas in global health. PMID- 29500235 TI - Intrinsic DNA binding properties demonstrated for lineage-specifying basic helix loop-helix transcription factors. AB - During development, transcription factors select distinct gene programs, providing the necessary regulatory complexity for temporal and tissue-specific gene expression. How related factors retain specificity, especially when they recognize the same DNA motifs, is not understood. We address this paradox using basic helix-loop-helix (bHLH) transcription factors ASCL1, ASCL2, and MYOD1, crucial mediators of lineage specification. In vivo, these factors recognize the same DNA motifs, yet bind largely different genomic sites and regulate distinct transcriptional programs. This suggests that their ability to identify regulatory targets is defined either by the cellular environment of the partially defined lineages in which they are endogenously expressed, or by intrinsic properties of the factors themselves. To distinguish between these mechanisms, we directly compared the chromatin binding properties of this subset of bHLH factors when ectopically expressed in embryonic stem cells, presenting them with a common chromatin landscape and cellular components. We find that these factors retain distinct binding sites; thus, specificity of binding is an intrinsic property not requiring a restricted landscape or lineage-specific cofactors. Although the ASCL factors and MYOD1 have some distinct DNA motif preference, it is not sufficient to explain the extent of the differential binding. All three factors can bind inaccessible chromatin and induce changes in chromatin accessibility and H3K27ac. A reiterated pattern of DNA binding motifs is uniquely enriched in inaccessible chromatin at sites bound by these bHLH factors. These combined properties define a subclass of lineage-specific bHLH factors and provide context for their central roles in development and disease. PMID- 29500237 TI - Antibiotics in palliative care: less can be more. Recognising overuse is easy. The real challenge is judicious prescribing. PMID- 29500236 TI - Complete avian malaria parasite genomes reveal features associated with lineage specific evolution in birds and mammals. AB - Avian malaria parasites are prevalent around the world and infect a wide diversity of bird species. Here, we report the sequencing and analysis of high quality draft genome sequences for two avian malaria species, Plasmodium relictum and Plasmodium gallinaceum We identify 50 genes that are specific to avian malaria, located in an otherwise conserved core of the genome that shares gene synteny with all other sequenced malaria genomes. Phylogenetic analysis suggests that the avian malaria species form an outgroup to the mammalian Plasmodium species, and using amino acid divergence between species, we estimate the avian- and mammalian-infective lineages diverged in the order of 10 million years ago. Consistent with their phylogenetic position, we identify orthologs of genes that had previously appeared to be restricted to the clades of parasites containing Plasmodium falciparum and Plasmodium vivax, the species with the greatest impact on human health. From these orthologs, we explore differential diversifying selection across the genus and show that the avian lineage is remarkable in the extent to which invasion-related genes are evolving. The subtelomeres of the P. relictum and P. gallinaceum genomes contain several novel gene families, including an expanded surf multigene family. We also identify an expansion of reticulocyte binding protein homologs in P. relictum, and within these proteins, we detect distinct regions that are specific to nonhuman primate, humans, rodent, and avian hosts. For the first time in the Plasmodium lineage, we find evidence of transposable elements, including several hundred fragments of LTR retrotransposons in both species and an apparently complete LTR-retrotransposon in the genome of P. gallinaceum. PMID- 29500238 TI - 'Song of Life': music therapy in terminally ill patients with cancer. AB - OBJECTIVES: Music therapy (MT) holds a promising potential to meet emotional and existential needs in palliative care patients. The aim of the present pilot study was to assess the feasibility, acceptance and potential effectiveness of a novel MT intervention to improve life closure and spiritual well-being of terminally ill patients with cancer receiving palliative care. METHODS: The 'Song of Life' (SOL) intervention was provided on two consecutive sessions containing a biographical interview and a live performance of a song with high biographical relevance to the patient in a lullaby style. Pre-to-post intervention assessments comprised brief self-report measures on life closure, well-being, stress, worry and pain. RESULTS: 13 out of 15 patients were able to complete the protocol as intended. The chosen songs were associated with a close person, an important place or event or with a religious belief. The results showed medium-sized improvements with regard to life closure, well-being, relaxation, worry and pain. CONCLUSION: 'SOL' proved to be a feasible and highly accepted intervention for patients approaching the end of their lives. Further consideration with regard to the procedures and outcomes is necessary before implementation of a randomised trial. PMID- 29500239 TI - Risk of 12-month mortality among hospital inpatients using the surprise question and SPICT criteria: a prospective study. AB - OBJECTIVES: People with serious life-limiting disease benefit from advance care planning, but require active identification. This study applied the Gold Standards Framework Proactive Identification Guidance (GSF-PIG) to a general hospital population to describe high-risk patients and explore prognostic performance for 12-month mortality. METHODS: Prospective cohort study conducted in a metropolitan teaching hospital in Australia. Hospital inpatients on a single day aged 18 years and older were eligible, excluding maternity and neonatal, mental health and day treatment patients. Data sources included medical record and structured questions for medical and nursing staff. High-risk was predefined as positive response to the surprise question (SQ) plus two or more SPICT indicators of general deterioration. Descriptive variables included demographics, frailty and functional measures, treating team, advance care planning documentation and hospital utilisation. Primary outcome for prognostic performance was 12-month mortality. RESULTS: We identified 540 eligible inpatients on the study day and 513 had complete data (mean age 60, 54% male, 30% living alone, 19% elective admissions). Of these, 191 (37%) were high-risk; they were older, frailer, more dependent and had been in hospital longer than low-risk participants. Within 12 months, 92 participants (18%) died (72/191(38%) high-risk versus 20/322(6%) low-risk, P<0.001), providing sensitivity 78%, specificity 72%, positive predictive value 38% and negative predictive value 94%. SQ alone provided higher sensitivity, adding advanced disease indicators improved specificity. CONCLUSIONS: The GSF-PIG approach identified a large minority of hospital inpatients who might benefit from advance care planning. Future studies are needed to investigate the feasibility, cost and impact of screening in hospitals. PMID- 29500240 TI - Murine gamma-Herpesvirus 68 Induces Severe Lung Inflammation in IL-27-Deficient Mice with Liver Dysfunction Preventable by Oral Neomycin. AB - IL-27 is an immunoregulatory cytokine consisting of p28 and EBI3. Its receptor also has two subunits, WSX1 and gp130. Although IL-27 promotes Th1 differentiation in naive T cells, it also induces IL-10 expression in effector Th1 cells to curtail excessive immune responses. By using p28-deficient mice and WSX1-deficient mice (collectively called IL-27-deficient mice), we examined the role of IL-27 in primary infection by murine gamma-herpesvirus 68 (MHV68), a murine model of EBV. Upon airway infection with MHV68, IL-27-deficient mice had more aggravated lung inflammation than wild-type mice, although MHV68 infection per se was better controlled in IL-27-deficient mice. Although epithelial cells and alveolar macrophages were primarily infected by MHV68, interstitial macrophages and dendritic cells were the major producers of IL-27. The lung inflammation of IL-27-deficient mice was characterized by more IFN-gamma producing CD8+ T cells and fewer IL-10-producing CD8+ T cells than that of wild type mice. An infectious mononucleosis-like disease was also aggravated in IL-27 deficient mice, with prominent splenomegaly and severe hepatitis. Infiltration of IFN-gamma-producing effector cells and upregulation of the CXCR3 ligand chemokines CXCL9, CXCL10, and CXCL11 were noted in the liver of MHV68-infected mice. Oral neomycin effectively ameliorated hepatitis, with decreased production of these chemokines in the liver, suggesting that the intestinal microbiota plays a role in liver inflammation through upregulation of these chemokines. Collectively, IL-27 is essential for the generation of IL-10-producing effector cells in primary infection by MHV68. Our findings may also provide new insight into the mechanism of hepatitis associated with infectious mononucleosis. PMID- 29500241 TI - Statistical Validation of Rare Complement Variants Provides Insights into the Molecular Basis of Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy. AB - Atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) are associated with dysregulation and overactivation of the complement alternative pathway. Typically, gene analysis for aHUS and C3G is undertaken in small patient numbers, yet it is unclear which genes most frequently predispose to aHUS or C3G. Accordingly, we performed a six-center analysis of 610 rare genetic variants in 13 mostly complement genes (CFH, CFI, CD46, C3, CFB, CFHR1, CFHR3, CFHR4, CFHR5, CFP, PLG, DGKE, and THBD) from >3500 patients with aHUS and C3G. We report 371 novel rare variants (RVs) for aHUS and 82 for C3G. Our new interactive Database of Complement Gene Variants was used to extract allele frequency data for these 13 genes using the Exome Aggregation Consortium server as the reference genome. For aHUS, significantly more protein-altering rare variation was found in five genes CFH, CFI, CD46, C3, and DGKE than in the Exome Aggregation Consortium (allele frequency < 0.01%), thus correlating these with aHUS. For C3G, an association was only found for RVs in C3 and the N-terminal C3b-binding or C terminal nonsurface-associated regions of CFH In conclusion, the RV analyses showed nonrandom distributions over the affected proteins, and different distributions were observed between aHUS and C3G that clarify their phenotypes. PMID- 29500242 TI - PARP14 Controls the Nuclear Accumulation of a Subset of Type I IFN-Inducible Proteins. AB - The enzymes of the poly-ADP-ribose polymerase (PARP) superfamily control many relevant cellular processes, but a precise understanding of their activities in different physiological or disease contexts is largely incomplete. We found that transcription of several Parp genes was dynamically regulated upon murine macrophage activation by endotoxin. PARP14 was strongly induced by several inflammatory stimuli and translocated into the nucleus of stimulated cells. Quantitative mass spectrometry analysis showed that PARP14 bound to a group of IFN-stimulated gene (ISG)-encoded proteins, most with an unknown function, and it was required for their nuclear accumulation. Moreover, PARP14 depletion attenuated transcription of primary antiviral response genes regulated by the IFN regulatory transcription factor 3, including Ifnb1, thus reducing IFN-beta production and activation of ISGs involved in the secondary antiviral response. In agreement with the above-mentioned data, PARP14 hindered Salmonella typhimurium proliferation in murine macrophages. Overall, these data hint at a role of PARP14 in the control of antimicrobial responses and specifically in nuclear activities of a subgroup of ISG-encoded proteins. PMID- 29500243 TI - All-Trans Retinoic Acid Enhances Antibody Production by Inducing the Expression of Thymic Stromal Lymphopoietin Protein. AB - Many classical vaccines contain whole pathogens and, thus, may occasionally induce adverse effects, such as inflammation. Vaccines containing purified rAgs resolved this problem, but, owing to their low antigenicity, they require adjuvants. Recently, the use of several cytokines, including thymic stromal lymphopoietin (TSLP), has been proposed for this purpose. However, it is difficult to use cytokines as vaccine adjuvants in clinical practice. In this study, we examined the effects of all-trans retinoic acid (atRA) on TSLP production and Ag-induced Ab production. Application of atRA onto the ear lobes of mice selectively induced TSLP production without inducing apparent inflammation. The effects appeared to be regulated via retinoic acid receptors gamma and alpha. Treatment with atRA was observed to enhance OVA-induced specific Ab production; however, this effect was completely absent in TSLP receptor knockout mice. An enhancement in Ab production was also observed when recombinant hemagglutinin was used as the Ag. In conclusion, atRA was an effective adjuvant through induction of TSLP production. Therefore, we propose that TSLP-inducing low m.w. compounds, such as atRA, may serve as effective adjuvants for next generation vaccines. PMID- 29500244 TI - Anticancer Mechanisms in Two Murine Bone Marrow-Derived Dendritic Cell Subsets Activated with TLR4 Agonists. AB - Dendritic cells (DCs) are well-known for their functions in orchestrating the innate and adaptive arms of immune defense. However, under certain conditions, DCs can exert tumoricidal activity. We have elucidated the mechanism of tumor suppression by TLR4-activated bone marrow-derived DCs (BMDCs) isolated from BALB/c mice. We identified that two distinct subsets of BMDCs (CD11b+CD11c+I A/Eint and CD11b+CD11c+I-A/Ehigh) have different cytotoxic mechanisms of action. The cytotoxicity of the former subset is mediated through NO and reactive oxygen species and type I IFN (IFN-beta), whereas the latter subset acts only through IFN-beta. TLR4 agonists, LPS or pharmaceutical-grade ImmunoMax, activate CD11c+ BMDCs, which, in turn, directly kill 4T1 mouse breast cancer cells or inhibit their proliferation in an MHC-independent manner. These data define two populations of BMDCs with different mechanisms of direct cytotoxicity, as well as suggest that the I-A/Eint subset could be less susceptible to counteracting mechanisms in the tumor microenvironment and support investigation of similar subsets in human DCs. PMID- 29500245 TI - Functional Anti-TIGIT Antibodies Regulate Development of Autoimmunity and Antitumor Immunity. AB - Coinhibitory receptors, such as CTLA-4 and PD-1, play a critical role in maintaining immune homeostasis by dampening T cell responses. Recently, they have gained attention as therapeutic targets in chronic disease settings where their dysregulated expression contributes to suppressed immune responses. The novel coinhibitory receptor TIGIT (T cell Ig and ITIM domain) has been shown to play an important role in modulating immune responses in the context of autoimmunity and cancer. However, the molecular mechanisms by which TIGIT modulates immune responses are still insufficiently understood. We have generated a panel of monoclonal anti-mouse TIGIT Abs that show functional properties in mice in vivo and can serve as important tools to study the underlying mechanisms of TIGIT function. We have identified agonistic as well as blocking anti-TIGIT Ab clones that are capable of modulating T cell responses in vivo. Administration of either agonist or blocking anti-TIGIT Abs modulated autoimmune disease severity whereas administration of blocking anti-TIGIT Abs synergized with anti-PD-1 Abs to affect partial or even complete tumor regression. The Abs presented in this study can thus serve as important tools for detailed analysis of TIGIT function in different disease settings and the knowledge gained will provide valuable insight for the development of novel therapeutic approaches targeting TIGIT. PMID- 29500246 TI - Visceral Adipose Tissue Drives Cardiac Aging Through Modulation of Fibroblast Senescence by Osteopontin Production. AB - BACKGROUND: Aging induces cardiac structural and functional changes linked to the increased deposition of extracellular matrix proteins, including OPN (osteopontin), conducing to progressive interstitial fibrosis. Although OPN is involved in various pathological conditions, its role in myocardial aging remains unknown. METHODS: OPN deficient mice (OPN-/-) with their wild-type (WT) littermates were evaluated at 2 and 14 months of age in terms of cardiac structure, function, histology and key molecular markers. OPN expression was determined by reverse-transcription polymerase chain reaction, immunoblot and immunofluorescence. Luminex assays were performed to screen plasma samples for various cytokines/adipokines in addition to OPN. Similar explorations were conducted in aged WT mice after surgical removal of visceral adipose tissue (VAT) or treatment with a small-molecule OPN inhibitor agelastatin A. Primary WT fibroblasts were incubated with plasma from aged WT and OPN-/- mice, and evaluated for senescence (senescence-associated beta-galactosidase and p16), as well as fibroblast activation markers (Acta2 and Fn1). RESULTS: Plasma OPN levels increased in WT mice during aging, with VAT showing the strongest OPN induction contrasting with myocardium that did not express OPN. VAT removal in aged WT mice restored cardiac function and decreased myocardial fibrosis in addition to a substantial reduction of circulating OPN and transforming growth factor beta levels. OPN deficiency provided a comparable protection against age-related cardiac fibrosis and dysfunction. Intriguingly, a strong induction of senescence in cardiac fibroblasts was observed in both VAT removal and OPN-/- mice. The addition of plasma from aged OPN-/- mice to cultures of primary cardiac fibroblasts induced senescence and reduced their activation (compared to aged WT plasma). Finally, Agelastatin A treatment of aged WT mice fully reversed age related myocardial fibrosis and dysfunction. CONCLUSIONS: During aging, VAT represents the main source of OPN and alters heart structure and function via its profibrotic secretome. As a proof-of-concept, interventions targeting OPN, such as VAT removal and OPN deficiency, rescued the heart and induced a selective modulation of fibroblast senescence. Our work uncovers OPN's role in the context of myocardial aging and proposes OPN as a potential new therapeutic target for a healthy cardiac aging. PMID- 29500247 TI - Whole exome sequencing identifies mutations in 10% of patients with familial non syndromic cleft lip and/or palate in genes mutated in well-known syndromes. AB - BACKGROUND: Oral clefts, that is, clefts of the lip and/or cleft palate (CL/P), are the most common craniofacial birth defects with an approximate incidence of ~1/700. To date, physicians stratify patients with oral clefts into either syndromic CL/P (syCL/P) or non-syndromic CL/P (nsCL/P) depending on whether the CL/P is associated with another anomaly or not. In general, patients with syCL/P follow Mendelian inheritance, while those with nsCL/P have a complex aetiology and, as such, do not adhere to Mendelian inheritance. Genome-wide association studies have identified approximately 30 risk loci for nsCL/P, which could explain a small fraction of heritability. METHODS: To identify variants causing nsCL/P, we conducted whole exome sequencing on 84 individuals with nsCL/P, drawn from multiplex families (n=46). RESULTS: We identified rare damaging variants in four genes known to be mutated in syCL/P: TP63 (one family), TBX1 (one family), LRP6 (one family) and GRHL3 (two families), and clinical reassessment confirmed the isolated nature of their CL/P. CONCLUSION: These data demonstrate that patients with CL/P without cardinal signs of a syndrome may still carry a mutation in a gene linked to syCL/P. Rare coding and non-coding variants in syCL/P genes could in part explain the controversial question of 'missing heritability' for nsCL/P. Therefore, gene panels designed for diagnostic testing of syCL/P should be used for patients with nsCL/P, especially when there is at least third-degree family history. This would allow a more precise management, follow-up and genetic counselling. Moreover, stratified cohorts would allow hunting for genetic modifiers. PMID- 29500248 TI - Correction for Delay and Dispersion Results in More Accurate Cerebral Blood Flow Ischemic Core Measurement in Acute Stroke. AB - BACKGROUND AND PURPOSE: This study aimed to assess how the ischemic core measured by perfusion computed tomography (CTP) was affected by the delay and dispersion effect. METHODS: Ischemic stroke patients having CTP performed within 6 hours of onset were included. The CTP data were processed twice, generating standard cerebral blood flow (sCBF) and delay- and dispersion-corrected CBF (ddCBF), respectively. Ischemic core measured by the sCBF and ddCBF was then compared at the relative threshold <30% of normal tissue. Two references for ischemic core were used: acute diffusion-weighted imaging or 24-hour diffusion-weighted imaging in patients with complete recanalization. Difference of core volume between CTP and diffusion-weighted imaging was estimated by Mann-Whitney U test and limits of agreement. Patients were also classified into favorable and unfavorable CTP patterns. The imaging pattern classification by sCBF and ddCBF was compared by the chi2 test; their respective ability to predict good clinical outcome (3-month modified Rankin Scale score) was tested in logistic regression. RESULTS: Fifty five patients were included in this study. Median sCBF ischemic core volume was 38.5 mL (12.4-61.9 mL), much larger than the median core volume of 17.2 mL measured by ddCBF (interquartile range, 5.5-38.8; P<0.001). Moreover, compared with sCBF <30%, ddCBF <30% measured the ischemic core much closer to diffusion weighted imaging core references, with the mean volume difference of -0.1 mL (95% limits of agreement, -25.4 to 25.2; P=0.97) and 16.7 mL (95% limits of agreement, -21.7 to 55.2; P<0.001), respectively. Imaging patterns defined by sCBF showed a difference to that defined by ddCBF (P<0.001), with 12 patients classified as favorable imaging patterns by ddCBF but as unfavorable by sCBF. The favorable imaging pattern classified by ddCBF, compared with sCBF classification, had higher predictive power for good clinical outcome (odds ratio, 7.8 [2-30.5] and 3.1 [0.9-11], respectively). CONCLUSIONS: Delay and dispersion correction increases the accuracy of ischemic core measurement on CTP. PMID- 29500250 TI - Multilevel Small-Area Estimation of Colorectal Cancer Screening in the United States. AB - Background: The U.S. Preventive Services Task Force recommends routine screening for colorectal cancer for adults ages 50 to 75 years. We generated small-area estimates for being current with colorectal cancer screening to examine sociogeographic differences among states and counties. To our knowledge, nationwide county-level estimates for colorectal cancer screening are rarely presented.Methods: We used county data from the 2014 Behavioral Risk Factor Surveillance System (BRFSS; n = 251,360 adults), linked it to the American Community Survey poverty data, and fitted multilevel logistic regression models. We post-stratified the data with the U.S. Census population data to run Monte Carlo simulations. We generated county-level screening prevalence estimates nationally and by race/ethnicity, mapped the estimates, and aggregated them into state and national estimates. We evaluated internal consistency of our modeled state-specific estimates with BRFSS direct state estimates using Spearman correlation coefficients.Results: Correlation coefficients were >=0.95, indicating high internal consistency. We observed substantial variations in current colorectal cancer screening estimates among the states and counties within states. State mean estimates ranged from 58.92% in Wyoming to 75.03% in Massachusetts. County mean estimates ranged from 40.11% in Alaska to 79.76% in Florida. Larger county variations were observed in various race/ethnicity groups.Conclusions: State estimates mask county variations. However, both state and county estimates indicate that the country is far behind the "80% by 2018" target.Impact: County-modeled estimates help identify variation in colorectal cancer screening prevalence in the United States and guide education and enhanced screening efforts in areas of need, including areas without BRFSS direct estimates. Cancer Epidemiol Biomarkers Prev; 27(3); 245-53. (c)2018 AACR. PMID- 29500251 TI - What factors must be considered in 'return to school' following concussion and what strategies or accommodations should be followed? A systematic review. AB - OBJECTIVE: To evaluate the evidence regarding (1) factors affecting return to school (RTS) and (2) strategies/accommodations for RTS following a sport-related concussion (SRC) in children and adolescents. DESIGN: A systematic review of original studies specifically addressing RTS following concussion in the paediatric and sporting context. DATA SOURCES: MEDLINE (Ovid), Embase (Ovid), PsycInfo (Ovid) electronic databases and the grey literature OpenGrey, ClinicalTrials.gov and Google Advanced. ELIGIBILITY CRITERIA: Studies were included if they were original research on RTS following SRC in children aged 5 18 years published in English between 1985 and 2017. RESULTS: A total of 180 articles were identified; 17 articles met inclusion criteria. Several factors should be considered for RTS after concussion, including: symptomatology; rest following injury; age/grade; and course load. On RTS after concussion, 17%-73% of students were provided academic accommodations or experienced difficulty with RTS. Students were more likely to obtain academic accommodations in schools with a concussion policy if they had a medical RTS letter and had regular medical follow-up after concussion. CONCLUSIONS: Schools should have a concussion policy and offer individualised academic accommodations to students recovering from SRC on RTS; a medical letter should be provided to facilitate provision/receipt of academic accommodations; students should have early, regular medical follow-up following SRC to help with RTS and monitor recovery; students may require temporary absence from school after SRC; clinicians should assess risk factors/modifiers that may prolong recovery and require more intensive academic accommodations. PROSPERO REGISTRATION NUMBER: CRD42016039184. PMID- 29500252 TI - Implementation of the 2017 Berlin Concussion in Sport Group Consensus Statement in contact and collision sports: a joint position statement from 11 national and international sports organisations. AB - The 2017 Berlin Concussion in Sport Group Consensus Statement provides a global summary of best practice in concussion prevention, diagnosis and management, underpinned by systematic reviews and expert consensus. Due to their different settings and rules, individual sports need to adapt concussion guidelines according to their specific regulatory environment. At the same time, consistent application of the Berlin Consensus Statement's themes across sporting codes is likely to facilitate superior and uniform diagnosis and management, improve concussion education and highlight collaborative research opportunities. This document summarises the approaches discussed by medical representatives from the governing bodies of 10 different contact and collision sports in Dublin, Ireland in July 2017. Those sports are: American football, Australian football, basketball, cricket, equestrian sports, football/soccer, ice hockey, rugby league, rugby union and skiing. This document had been endorsed by 11 sport governing bodies/national federations at the time of being published. PMID- 29500253 TI - Geolocalisation of athletes for out-of-competition drug testing: ethical considerations. Position statement by the WADA Ethics Panel. AB - Through the widespread availability of location-identifying devices, geolocalisation could potentially be used to place athletes during out-of competition testing. In light of this debate, the WADA Ethics Panel formulated the following questions: (1) should WADA and/or other sponsors consider funding such geolocalisation research projects?, (2) if successful, could they be proposed to athletes as a complementary device to Anti-Doping Administration and Management System to help geolocalisation and reduce the risk of missed tests? and (3) should such devices be offered on a voluntary basis, or is it conceivable that they would be made mandatory for all athletes in registered testing pools? In this position paper, the WADA Ethics Panel concludes that the use of geolocalisation could be useful in a research setting with the goal of understanding associations between genotype, phenotype and environment; however, it recognises that the use of geolocalisation as part of or as replacement of whereabouts rules is replete with ethical concerns. While benefits remain largely hypothetical and minimal, the potential invasion of privacy and the data security threats are real. Considering the impact on privacy, data security issues, the societal ramifications of offering such services and various pragmatic considerations, the WADA Ethics Panel concludes that at this time, the use of geolocalisation should neither be mandated as a tool for disclosing whereabouts nor implemented on a voluntary basis. PMID- 29500254 TI - Transferable Plasmid-Borne mcr-1 in a Colistin-Resistant Shigella flexneri Isolate. AB - Since the initial discovery of mcr-1 in an Escherichia coli isolate from China, the gene has also been detected in Klebsiella pneumoniae and Salmonella enterica but is rarely reported in other Enterobacteriaceae Here, we report the isolation and identification of a Shigella flexneri strain harboring mcr-1 from stool samples in a pig farm in China from 2009. The MIC of colistin for the isolate is 4 MUg/ml. Conjugation assays showed that the donor S. flexneri strain has functional and transferable colistin resistance. Sequencing revealed that mcr-1 was present on a putative composite transposon flanked by inverted repeats of ISApl1IMPORTANCE There are four species of Shigella, and Shigella flexneri is the most frequently isolated species in low- and middle-income countries (LMICs). In this study, we report a functional, transferable, plasmid-mediated mcr-1 gene in S. flexneri We have shown that mcr-1 is located on a novel composite transposon which is flanked by inverted repeats of ISApl1 The host strain is multidrug resistant, and this multidrug resistance is also transferable. The finding of a functional mcr-1 gene in S. flexneri, a human-associated Enterobacteriaceae family member, is a cause for concern as infections due to S. flexneri are the main Shigella infections in most low- and middle-income countries. PMID- 29500255 TI - Long-Term Exposure of Agricultural Soil to Veterinary Antibiotics Changes the Population Structure of Symbiotic Nitrogen-Fixing Rhizobacteria Occupying Nodules of Soybeans (Glycine max). AB - Antibiotics are entrained in agricultural soil through the application of manures from medicated animals. In the present study, a series of small field plots was established in 1999 that receive annual spring applications of a mixture of tylosin, sulfamethazine, and chlortetracycline at concentrations ranging from 0.1 to 10 mg . kg-1 soil. These antibiotics are commonly used in commercial swine production. The field plots were cropped continuously for soybeans, and in 2012, after 14 annual antibiotic applications, the nodules from soybean roots were sampled and the occupying bradyrhizobia were characterized. Nodules and isolates were serotyped, and isolates were distinguished using 16S rRNA gene and 16S to 23S rRNA gene intergenic spacer region sequencing, multilocus sequence typing, and RSalpha fingerprinting. Treatment with the antibiotic mixture skewed the population of bradyrhizobia dominating the nodule occupancy, with a significantly larger proportion of Bradyrhizobium liaoningense organisms even at the lowest dose of 0.1 mg . kg-1 soil. Likewise, all doses of antibiotics altered the distribution of RSalpha fingerprint types. Bradyrhizobia were phenotypically evaluated for their sensitivity to the antibiotics, and there was no association between in situ treatment and a decreased sensitivity to the drugs. Overall, long term exposure to the antibiotic mixture altered the composition of bradyrhizobial populations occupying nitrogen-fixing nodules, apparently through an indirect effect not associated with the sensitivity to the drugs. Further work evaluating agronomic impacts is warranted.IMPORTANCE Antibiotics are entrained in agricultural soil through the application of animal or human waste or by irrigation with reused wastewater. Soybeans obtain nitrogen through symbiotic nitrogen fixation. Here, we evaluated the impact of 14 annual exposures to antibiotics commonly used in swine production on the distribution of bradyrhizobia occupying nitrogen-fixing nodules on soybean roots in a long-term field experiment. By means of various sequencing and genomic fingerprinting techniques, the repeated exposure to a mixture of tylosin, sulfamethazine, and chlortetracycline each at a nominal soil concentration of 0.1 mg . kg-1 soil was found to modify the diversity and identity of bradyrhizobia occupying the nodules. Nodule occupancy was not associated with the level of sensitivity to the antibiotics, indicating that the observed effects were not due to the direct toxicity of the antibiotics on bradyrhizobia. Altogether, these results indicate the potential for long-term impacts of antibiotics on this agronomically important symbiosis. PMID- 29500256 TI - Butenolides from Streptomyces albus J1074 Act as External Signals To Stimulate Avermectin Production in Streptomyces avermitilis. AB - In streptomycetes, autoregulators are important signaling compounds that trigger secondary metabolism, and they are regarded as Streptomyces hormones based on their extremely low effective concentrations (nM) and the involvement of specific receptor proteins. Our previous distribution study revealed that butenolide-type Streptomyces hormones, including avenolide, are a general class of signaling molecules in streptomycetes and that Streptomyces albus strain J1074 may produce butenolide-type Streptomyces hormones. Here, we describe metabolite profiling of a disruptant of the S. albusaco gene, which encodes a key biosynthetic enzyme for butenolide-type Streptomyces hormones, and identify four butenolide compounds from S. albus J1074 that show avenolide activity. The compounds structurally resemble avenolide and show different levels of avenolide activity. A dual culture assay with imaging mass spectrometry (IMS) analysis for in vivo metabolic profiling demonstrated that the butenolide compounds of S. albus J1074 stimulate avermectin production in another Streptomyces species, Streptomyces avermitilis, illustrating the complex chemical interactions through interspecies signals in streptomycetes.IMPORTANCE Microorganisms produce external and internal signaling molecules to control their complex physiological traits. In actinomycetes, Streptomyces hormones are low-molecular-weight signals that are key to our understanding of the regulatory mechanisms of Streptomyces secondary metabolism. This study reveals that acyl coenzyme A (acyl-CoA) oxidase is a common and essential biosynthetic enzyme for butenolide-type Streptomyces hormones. Moreover, the diffusible butenolide compounds from a donor Streptomyces strain were recognized by the recipient Streptomyces strain of a different species, resulting in the initiation of secondary metabolism in the recipient. This is an interesting report on the chemical interaction between two different streptomycetes via Streptomyces hormones. Information on the metabolite network may provide useful hints not only to clarification of the regulatory mechanism of secondary metabolism, but also to understanding of the chemical communication among streptomycetes to control their physiological traits. PMID- 29500257 TI - Growth and Population Dynamics of the Anaerobic Fe(II)-Oxidizing and Nitrate Reducing Enrichment Culture KS. AB - Most isolated nitrate-reducing Fe(II)-oxidizing microorganisms are mixotrophic, meaning that Fe(II) is chemically oxidized by nitrite that forms during heterotrophic denitrification, and it is debated to which extent Fe(II) is enzymatically oxidized. One exception is the chemolithoautotrophic enrichment culture KS, a consortium consisting of a dominant Fe(II) oxidizer, Gallionellaceae sp., and less abundant heterotrophic strains (e.g., Bradyrhizobium sp., Nocardioides sp.). Currently, this is the only nitrate reducing Fe(II)-oxidizing culture for which autotrophic growth has been demonstrated convincingly for many transfers over more than 2 decades. We used 16S rRNA gene amplicon sequencing and physiological growth experiments to analyze the community composition and dynamics of culture KS with various electron donors and acceptors. Under autotrophic conditions, an operational taxonomic unit (OTU) related to known microaerophilic Fe(II) oxidizers within the family Gallionellaceae dominated culture KS. With acetate as an electron donor, most 16S rRNA gene sequences were affiliated with Bradyrhizobium sp. Gallionellaceae sp. not only was able to oxidize Fe(II) under autotrophic and mixotrophic conditions but also survived over several transfers of the culture on only acetate, although it then lost the ability to oxidize Fe(II). Bradyrhizobium spp. became and remained dominant when culture KS was cultivated for only one transfer under heterotrophic conditions, even when conditions were reverted back to autotrophic in the next transfer. This study showed a dynamic microbial community in culture KS that responded to changing substrate conditions, opening up questions regarding carbon cross-feeding, metabolic flexibility of the individual strains in KS, and the mechanism of Fe(II) oxidation by a microaerophile in the absence of O2IMPORTANCE Nitrate-reducing Fe(II)-oxidizing microorganisms are present in aquifers, soils, and marine and freshwater sediments. Most nitrate-reducing Fe(II) oxidizers known are mixotrophic, meaning that they need organic carbon to continuously oxidize Fe(II) and grow. In these microbes, Fe(II) was suggested to be chemically oxidized by nitrite that forms during heterotrophic denitrification, and it remains unclear whether or to what extent Fe(II) is enzymatically oxidized. In contrast, the enrichment culture KS was shown to oxidize Fe(II) autotrophically coupled to nitrate reduction. This culture contains the designated Fe(II) oxidizer Gallionellaceae sp. and several heterotrophic strains (e.g., Bradyrhizobium sp.). We showed that culture KS is able to metabolize Fe(II) and a variety of organic substrates and is able to adapt to dynamic environmental conditions. When the community composition changed and Bradyrhizobium became the dominant community member, Fe(II) was still oxidized by Gallionellaceae sp., even when culture KS was cultivated with acetate/nitrate [Fe(II) free] before being switched back to Fe(II)/nitrate. PMID- 29500258 TI - FISH-SIMS imaging of an autotrophic, nitrate-reducing, Fe(II)-oxidizing enrichment culture provides insights into carbon metabolism. AB - The enrichment culture KS is one of the few existing autotrophic, nitrate reducing Fe(II)-oxidizing cultures that can be continuously transferred without an organic carbon source. We used a combination of Catalyzed Amplification Reporter Deposition Fluorescence In-Situ Hybridization (CARD-FISH) and Nanoscale Secondary Ion Mass Spectrometry (NanoSIMS) to analyze community dynamics, single cell activities and interactions among the two most abundant microbial community members (i.e, Gallionellaceae sp. and Bradyrhizobium spp.) under autotrophic and heterotrophic growth conditions. CARD-FISH cell counts showed the dominance of the Fe(II)-oxidizer Gallionellaceae sp. under autotrophic conditions as well as of Bradyrhizobium spp. under heterotrophic conditions. We used NanoSIMS to follow the fate of 13C-labeled bicarbonate and acetate as well as 15N-labeled ammonium at the single-cell level for both taxa. Under autotrophic conditions only the Gallionellaceae sp. was actively incorporating 13C-labeled bicarbonate and 15N labeled ammonium. Interestingly, both Bradyrhizobium spp. and Gallionellaceae sp. became enriched in 13C-acetate and 15N-ammonium under heterotrophic conditions. Our experiments demonstrated that Gallionellaceae sp. was capable of assimilating 13C-acetate while Bradyrhizobium spp. were not able to fix CO2, although a metagenomics survey of culture KS recently revealed that Gallionellaceae sp. lacks genes for acetate uptake and that the Bradyrhizobium sp. carries the genetic potential to fix CO2 The study furthermore extends our understanding of the microbial reactions that interlink the nitrogen and Fe cycles in the environment.Importance Microbial mechanisms by which ferrous iron is oxidized with nitrate as the terminal electron acceptor are generally referred to as "nitrate-dependent Fe(II) oxidation" (NDFO). NDFO has been demonstrated in laboratory cultures (such as the one studied in this work) and in a variety of marine and freshwater sediments. Recently, the importance of NDFO for the transport of sediment-derived Fe in aquatic ecosystems has been emphasized in a series of studies discussing the impact of NDFO for sedimentary nutrient cycling and redox dynamics in marine and freshwater environments. In this manuscript we report results from an isotope labeling study performed with the autotrophic, nitrate-reducing, Fe(II)-oxidizing enrichment culture KS, which was first described by Straub et al. (1) about 20 years ago. Our current study builds on the recently published metagenome of culture KS (2). PMID- 29500259 TI - Discovery and Biosynthesis of the Antibiotic Bicyclomycin in Distantly Related Bacterial Classes. AB - Bicyclomycin (BCM) is a clinically promising antibiotic that is biosynthesized by Streptomyces cinnamoneus DSM 41675. BCM is structurally characterized by a core cyclo(l-Ile-l-Leu) 2,5-diketopiperazine (DKP) that is extensively oxidized. Here, we identify the BCM biosynthetic gene cluster, which shows that the core of BCM is biosynthesized by a cyclodipeptide synthase, and the oxidative modifications are introduced by five 2-oxoglutarate-dependent dioxygenases and one cytochrome P450 monooxygenase. The discovery of the gene cluster enabled the identification of BCM pathways encoded by the genomes of hundreds of Pseudomonas aeruginosa isolates distributed globally, and heterologous expression of the pathway from P. aeruginosa SCV20265 demonstrated that the product is chemically identical to BCM produced by S. cinnamoneus Overall, putative BCM gene clusters have been found in at least seven genera spanning Actinobacteria and Proteobacteria (Alphaproteobacteria, Betaproteobacteria, and Gammaproteobacteria). This represents a rare example of horizontal gene transfer of an intact biosynthetic gene cluster across such distantly related bacteria, and we show that these gene clusters are almost always associated with mobile genetic elements.IMPORTANCE Bicyclomycin is the only natural product antibiotic that selectively inhibits the transcription termination factor Rho. This mechanism of action, combined with its proven biological safety and its activity against clinically relevant Gram negative bacterial pathogens, makes it a very promising antibiotic candidate. Here, we report the identification of the bicyclomycin biosynthetic gene cluster in the known bicyclomycin-producing organism Streptomyces cinnamoneus, which will enable the engineered production of new bicyclomycin derivatives. The identification of this gene cluster also led to the discovery of hundreds of bicyclomycin pathways encoded in highly diverse bacteria, including in the opportunistic pathogen Pseudomonas aeruginosa This wide distribution of a complex biosynthetic pathway is very unusual and provides an insight into how a pathway for an antibiotic can be transferred between diverse bacteria. PMID- 29500260 TI - Dynamic Dispersal of Surface Layer Biofilm Induced by Nanosized TiO2 Based on Surface Plasmon Resonance and Waveguide. AB - Pollutant degradation is present mainly in the surface layer of biofilms, and the surface layer is the most vulnerable to impairment by toxic pollutants. In this work, the effects of nanosized TiO2 (n-TiO2) on the average thicknesses of Bacillus subtilis biofilm and on bacterial attachment on different surfaces were investigated. The binding mechanism of n-TiO2 to the cell surface was also probed. The results revealed that n-TiO2 caused biofilm dispersal and the thicknesses decreased by 2.0 to 2.6 MUm after several hours of exposure. The attachment abilities of bacteria with extracellular polymeric substances (EPS) on hydrophilic surfaces were significantly reduced by 31% and 81% under 10 and 100 mg/liter of n-TiO2, respectively, whereas those of bacteria without EPS were significantly reduced by 43% and 87%, respectively. The attachment abilities of bacteria with and without EPS on hydrophobic surfaces were significantly reduced by 50% and 56%, respectively, under 100 mg/liter of n-TiO2 The results demonstrated that biofilm dispersal can be attributed to the changes in the cell surface structure and the reduction of microbial attachment ability.IMPORTANCE Nanoparticles can penetrate into the outer layer of biofilm in a relatively short period and can bind onto EPS and bacterial surfaces. The current work probed the effects of nanosized TiO2 (n-TiO2) on biofilm thickness, bacterial migration, and surface properties of the cell in the early stage using the surface plasmon resonance waveguide mode. The results demonstrated that n-TiO2 decreased the adhesive ability of both cell and EPS and induced bacterial migration and biofilm detachment in several hours. The decreased adhesive ability of microbes and EPS worked against microbial aggregation, reducing the effluent quality in the biological wastewater treatment process. PMID- 29500261 TI - Plant Homeodomain Genes Play Important Roles in Cryptococcal Yeast-Hypha Transition. AB - Cryptococcus neoformans is a major opportunistic fungal pathogen. Like many dimorphic fungal pathogens, C. neoformans can undergo morphological transition from the yeast form to the hypha form, and its morphotype is tightly linked to its virulence. Although some genetic factors controlling morphogenesis have been identified, little is known about the epigenetic regulation in this process. Proteins with the plant homeodomain (PHD) finger, a structurally conserved domain in eukaryotes, were first identified in plants and are known to be involved in reading and effecting chromatin modification. Here, we investigated the role of the PHD finger family genes in Cryptococcus mating and yeast-hypha transition. We found 16 PHD finger domains distributed among 15 genes in the Cryptococcus genome, with two genes, ZNF1alpha and RUM1alpha, located in the mating type locus. We deleted these 15 PHD genes and examined the impact of their disruption on cryptococcal morphogenesis. The deletion of five PHD finger genes dramatically affected filamentation. The rum1alphaDelta and znf1alphaDelta mutants showed enhanced ability to initiate filamentation but impaired ability to maintain filamentous growth. The bye1Delta and the phd11Delta mutants exhibited enhanced filamentation, while the set302Delta mutants displayed reduced filamentation. Ectopic overexpression of these five genes in the corresponding null mutants partially or completely restored the defect in filamentation. Furthermore, we demonstrated that Phd11, a suppressor of filamentation, regulates the yeast-hypha transition through the known master regulator Znf2. The findings indicate the importance of epigenetic regulation in controlling dimorphic transition in C. neoformansIMPORTANCE Morphotype is known to have a profound impact on cryptococcal interaction with various hosts, including mammalian hosts. The yeast form of Cryptococcus neoformans is considered the virulent form, while its hyphal form is attenuated in mammalian models of cryptococcosis. Although some genetic regulators critical for cryptococcal morphogenesis have been identified, little is known about epigenetic regulation in this process. Given that plant homeodomain (PHD) finger proteins are involved in reading and effecting chromatin modification and their functions are unexplored in C. neoformans, we investigated the roles of the 15 PHD finger genes in Cryptococcus mating and yeast-hypha transition. Five of them profoundly affect filamentation as either a suppressor or an activator. Phd11, a suppressor of filamentation, regulates this process via Znf2, a known master regulator of morphogenesis. Thus, epigenetic regulation, coupled with genetic regulation, controls this yeast-hypha transition event. PMID- 29500262 TI - A Gene Homologous to rRNA Methylase Genes Confers Erythromycin and Clindamycin Resistance in Bifidobacterium breve. AB - Bifidobacteria are mutualistic intestinal bacteria, and their presence in the human gut has been associated with health-promoting activities. The presence of antibiotic resistance genes in this genus is controversial, since, although bifidobacteria are nonpathogenic microorganisms, they could serve as reservoirs of resistance determinants for intestinal pathogens. However, until now, few antibiotic resistance determinants have been functionally characterized in this genus. In this work, we show that Bifidobacterium breve CECT7263 displays atypical resistance to erythromycin and clindamycin. In order to delimit the genomic region responsible for the observed resistance phenotype, a library of genomic DNA was constructed and a fragment of 5.8 kb containing a gene homologous to rRNA methylase genes was able to confer erythromycin resistance in Escherichia coli This genomic region seems to be very uncommon, and homologs of the gene have been detected in only one strain of Bifidobacterium longum and two other strains of B. breve In this context, analysis of shotgun metagenomics data sets revealed that the gene is also uncommon in the microbiomes of adults and infants. The structural gene and its upstream region were cloned into a B. breve-sensitive strain, which became resistant after acquiring the genetic material. In vitro conjugation experiments did not allow us to detect gene transfer to other recipients. Nevertheless, prediction of genes potentially acquired through horizontal gene transfer events revealed that the gene is located in a putative genomic island.IMPORTANCEBifidobacterium breve is a very common human intestinal bacterium. Often described as a pioneer microorganism in the establishment of early-life intestinal microbiota, its presence has been associated with several beneficial effects for the host, including immune stimulation and protection against infections. Therefore, some strains of this species are considered probiotics. In relation to this, because probiotic bacteria are used for human and animal consumption, one of the safety concerns over these bacteria is the presence of antibiotic resistance genes, since the human gut is a densely populated habitat that could favor the transfer of genetic material to potential pathogens. In this study, we analyzed the genetic basis responsible for the erythromycin and clindamycin resistance phenotype of B. breve CECT7263. We were able to identify and characterize a novel gene homologous to rRNA methylase genes which confers erythromycin and clindamycin resistance. This gene seems to be very uncommon in other bifidobacteria and in the gut microbiomes of both adults and infants. Even though conjugation experiments showed the absence of transferability under in vitro conditions, it has been predicted to be located in a putative genomic island recently acquired by specific bifidobacterial strains. PMID- 29500263 TI - Identification and characterization of bacterial enzymes catalyzing the synthesis of 1,8-dihydroxynaphthalene, a key precursor of dihydroxynaphthalene melanin, from Sorangium cellulosum. AB - 1,8-Dihydroxynaphthalene (1,8-DHN) is a key intermediate in the biosynthesis of DHN melanin, which is specific to fungi. In this study, we characterized the enzymatic properties of the gene products of an operon consisting of soceCHS1, bdsA, and bdsB from the gram-negative bacterium, Sorangium cellulosum Heterologous expression of soceCHS1, bdsA, and bdsB in Streptomyces coelicolor caused secretion of a dark-brown pigment into the broth. High-performance liquid chromatography analysis of the broth revealed that the recombinant strain produced 1,8-DHN, indicating that the operon encoded a novel enzymatic system for the synthesis of 1,8-DHN. Simultaneous incubation of the recombinant SoceCHS1, BdsA, and BdsB with malonyl-CoA and NADPH resulted in the synthesis of 1,8-DHN. SoceCHS1, a type III polyketide synthase (PKS), catalyzed the synthesis of 1,3,6,8-tetrahydroxynaphthalene (T4HN) in vitro T4HN was in turn converted to 1,8 DHN by successive steps of reduction and dehydration, which were catalyzed by BdsA and BdsB. BdsA, which is a member of the aldo-keto reductase (AKR) superfamily, catalyzed the reduction of T4HN and 1,3,8-tetrahydroxynaphthalene (T3HN) to scytalone and vermelone, respectively. The stereoselectivity of T4HN reduction by BdsA occurred on the si-face to give (R)-scytalone with more than 99% optical purity. BdsB, a SnoaL2-like protein, catalyzed the dehydration of scytalone and vermelone to T3HN and 1,8-DHN, respectively. The fungal pathway for the synthesis of 1,8-DHN is comprised of a type I PKS, naphthol reductases of the short-chain dehydrogenase/reductase (SDR) superfamily, and scytalone dehydratase (SD). These findings demonstrated 1,8-DHN synthesis by novel enzymes of bacterial origin.IMPORTANCE Although the DHN biosynthetic pathway was thought to be specific to fungi, we discovered novel DHN synthesis enzymes of bacterial origin. The biosynthesis of bacterial DHN utilized a type III PKS for polyketide synthesis, an AKR superfamily for reduction, and a SnoaL2-like NTF2 superfamily for dehydration, whereas the biosynthesis of fungal DHN utilized a type I PKS, SDR superfamily enzyme, and SD-like NTF2 superfamily. Surprisingly, the enzyme systems comprising the pathway were significantly different from each other, suggesting independent, parallel evolution leading to the same biosynthesis. DHN melanin plays roles in host invasion and adaptation to stress in pathogenic fungi and is therefore important to study. However, it is unclear whether DHN biosynthesis occurs in bacteria. Importantly, we did find that bacterial DHN biosynthetic enzymes were conserved among pathogenic bacteria. PMID- 29500264 TI - Efficacy of a Sonicating Swab for Removal and Capture of Microorganisms from Experimental and Natural Contaminated Surfaces. AB - Enhancements in swabbing technology to increase sample collection efficacy would benefit the food industry. Specifically, these enhancements would assist the food industry in implementing the FDA Food Safety Modernization Act (FSMA) requirements by improving environmental monitoring effectiveness. A sonicating swab device, an example of an enhanced swabbing technology, was demonstrated previously to remove biofilm from stainless steel more efficiently than a standard cotton swab. Within this study, the performance of the sonicating swab was compared to that of the standard cotton swab for the recovery of Listeria monocytogenes from inoculated surfaces (plastic cutting board, wood cutting board, vinyl floor tile, and quarry clay floor tile). Additionally, we demonstrate the sonicating swab performance for collection of a microbiological sample from used commercial plastic cutting boards (noninoculated) in comparison to cotton swabs, foam swabs, and sponges. The sonicating swab captured significantly (P <= 0.05) more L. monocytogenes than the cotton swab for both the quarry tile and wood cutting board, while no significant differences were observed for the plastic cutting board or the vinyl floor tile. The sonicating swab consistently recovered significantly (P <= 0.05) more bacteria from the used cutting boards than did the standard cotton swab or the 3M Enviro swab, and it recovered significantly (P <= 0.05) more bacteria than the sponge swab for a majority of the time (4 of 6 trials). The results of this study indicate that swab technology can still be improved and that the sonicating swab is a viable technological enhancement which aids microbiological sample collection.IMPORTANCE Swabbing of surface areas for microbial contamination has been the standard for the detection and enumeration of microorganisms for many years. Inadequate surface sampling can result in foodborne illness outbreaks due to biotransfer of harmful microorganisms from food contact surfaces to foods. Swab material type, surface characteristics, and swabbing method used are a few of the factors associated with swabbing that can result in the variability of bacterial cell recovery for detection and enumeration. A previous study highlighted a sonicating swab prototype and its ability to recover cells from a stainless steel surface more efficiently and reliably than a standard swab method (T. A. Branck, M. J. Hurley, G. N. Prata, C. A. Crivello, and P. J. Marek, Appl Environ Microbiol 83:e00109-17, 2017, https://doi.org/10.1128/AEM.00109-17). This study expands upon the capabilities of the sonicating swab technology to recover cells from multiple surface types with increased performance over traditional swabbing methods as a tool to further assist in the prevention of foodborne illness outbreaks. PMID- 29500265 TI - Complementary Mechanisms for Degradation of Inulin-Type Fructans and Arabinoxylan Oligosaccharides among Bifidobacterial Strains Suggest Bacterial Cooperation. AB - Inulin-type fructans (ITF) and arabinoxylan oligosaccharides (AXOS) are broken down to different extents by various bifidobacterial strains present in the human colon. To date, phenotypic heterogeneity in the consumption of these complex oligosaccharides at the strain level remains poorly studied. To examine mechanistic variations in ITF and AXOS constituent preferences present in one individual, ITF and AXOS consumption by bifidobacterial strains isolated from the simulator of the human intestinal microbial ecosystem (SHIME) after inoculation with feces from one healthy individual was investigated. Among the 18 strains identified, four species-independent clusters displaying different ITF and AXOS degradation mechanisms and preferences were found. Bifidobacterium bifidum B46 showed limited growth on all substrates, whereas B. longum B24 and B. longum B18 could grow better on short-chain-length fractions of fructooligosaccharides (FOS) than on fructose. B. longum B24 could cleave arabinose substituents of AXOS extracellularly, without using the AXOS-derived xylose backbones, whereas B. longum B18 was able to consume oligosaccharides (up to xylotetraose) preferentially and consumed AXOS to a limited extent. B. adolescentis B72 degraded all fractions of FOS simultaneously, partially degraded inulin, and could use xylose backbones longer than xylotetraose extracellularly. The strain specific degradation mechanisms were suggested to be complementary and indicated resource partitioning. Specialization in the degradation of complex carbohydrates by bifidobacteria present on the individual level could have in vivo implications for the successful implementation of ITF and AXOS, aiming at bifidogenic and/or butyrogenic effects. Finally, this work shows the importance of taking microbial strain-level differences into account in gut microbiota research.IMPORTANCE It is well known that bifidobacteria degrade undigestible complex polysaccharides, such as ITF and AXOS, in the human colon. However, this process has never been studied for strains coexisting in the same individual. To examine strain-dependent mechanistic variations in ITF and AXOS constituent preferences present in one individual, ITF and AXOS consumption by bifidobacterial strains isolated from the SHIME after inoculation with feces from one healthy individual was investigated. Among the 18 bifidobacterial strains identified, four species-independent clusters displaying different ITF and AXOS degradation mechanisms and preferences were found, indicating that such strains can coexist in the human colon. Such specialization in the degradation of complex carbohydrates by bifidobacteria present on the individual level could have in vivo implications for the successful implementation of ITF and AXOS, aiming at bifidogenic and/or butyrogenic effects. PMID- 29500266 TI - Redundancy of anaerobic digestion microbiomes during disturbances by the antibiotic monensin. AB - The antibiotic monensin is fed to dairy cows to increase milk production efficiency. A fraction of this monensin is excreted into the cow manure. Previous studies have found that cow manure containing monensin can negatively impact the performance of anaerobic digesters, especially upon first introduction. Few studies have examined whether the anaerobic digester microbiome can adapt to monensin during the operating time. Here, we conducted a long-term, time-series study of four lab-scale anaerobic digesters fed with cow manure. We examined changes in both the microbiome composition and function of the anaerobic digesters when subjected to the dairy antibiotic monensin. In our digesters, monensin was not rapidly degraded at anaerobic conditions. The two anaerobic digesters that were subjected to manure from monensin feed-dosed cows exhibited relatively small changes in microbiome composition and function due to relatively low monensin concentrations. At higher concentrations of monensin, which we dosed directly to control manure (from dairy cows without monensin), we observed major changes in the microbiome composition and function of two anaerobic digesters. Rapid introduction of monensin to one of these anaerobic digesters led to the impairment of methane production. Conversely, more gradual addition of the same concentrations of monensin to the other anaerobic digester led to the adaptation of the anaerobic digester microbiome to the relatively high monensin concentration. A member of the candidate OP11 (Microgenomates) phylum arose in this anaerobic digester and appeared to be redundant with certain Bacteroidetes phylum members, which had previously been dominating.IMPORTANCE Monensin is a common antibiotic given to dairy cows in the United States and is partly excreted with dairy manure. An improved understanding of how monensin affects the anaerobic digester microbiome composition and function is important to prevent process failure for farm-based anaerobic digesters. This time-series study demonstrates how anaerobic digester microbiomes are inert to low monensin concentrations and can adapt to relatively high monensin concentrations by redundancy of an already existing population. Therefore, our work provides further insight into the importance of microbiome redundancy in maintaining the stability of anaerobic digesters. PMID- 29500267 TI - Promoter Engineering Reveals the Importance of Heptameric Direct Repeats for DNA Binding by Streptomyces Antibiotic Regulatory Protein-Large ATP-Binding Regulator of the LuxR Family (SARP-LAL) Regulators in Streptomyces natalensis. AB - The biosynthesis of small-size polyene macrolides is ultimately controlled by a couple of transcriptional regulators that act in a hierarchical way. A Streptomyces antibiotic regulatory protein-large ATP-binding regulator of the LuxR family (SARP-LAL) regulator binds the promoter of a PAS-LuxR regulator encoding gene and activates its transcription, and in turn, the gene product of the latter activates transcription from various promoters of the polyene gene cluster directly. The primary operator of PimR, the archetype of SARP-LAL regulators, contains three heptameric direct repeats separated by four-nucleotide spacers, but the regulator can also bind a secondary operator with only two direct repeats separated by a 3-nucleotide spacer, both located in the promoter region of its unique target gene, pimM A similar arrangement of operators has been identified for PimR counterparts encoded by gene clusters for different antifungal secondary metabolites, including not only polyene macrolides but peptidyl nucleosides, phoslactomycins, or cycloheximide. Here, we used promoter engineering and quantitative transcriptional analyses to determine the contributions of the different heptameric repeats to transcriptional activation and final polyene production. Optimized promoters have thus been developed. Deletion studies and electrophoretic mobility assays were used for the definition of DNA-binding boxes formed by 22-nucleotide sequences comprising two conserved heptameric direct repeats separated by four-nucleotide less conserved spacers. The cooperative binding of PimRSARP appears to be the mechanism involved in the binding of regulator monomers to operators, and at least two protein monomers are required for efficient binding.IMPORTANCE Here, we have shown that a modulation of the production of the antifungal pimaricin in Streptomyces natalensis can be accomplished via promoter engineering of the PAS-LuxR transcriptional activator pimM The expression of this gene is controlled by the Streptomyces antibiotic regulatory protein-large ATP-binding regulator of the LuxR family (SARP-LAL) regulator PimR, which binds a series of heptameric direct repeats in its promoter region. The structure and importance of such repeats in protein binding, transcriptional activation, and polyene production have been investigated. These findings should provide important clues to understand the regulatory machinery that modulates antibiotic biosynthesis in Streptomyces and open new possibilities for the manipulation of metabolite production. The presence of PimR orthologues encoded by gene clusters for different secondary metabolites and the conservation of their operators suggest that the improvements observed in the activation of pimaricin biosynthesis by Streptomyces natalensis could be extrapolated to the production of different compounds by other species. PMID- 29500269 TI - Extreme resistance: The GLK-Rx1 alliance. AB - Plants immune surveillance systems depend on nucleotide-binding leucine-rich repeat receptors (NLRs). A subset of NLRs are nuclear-localized, including Rx1, which confers an extreme immunity against potato virus X (PVX). As with many NLRs, the downstream signaling partners of Rx1 are unknown. Townsend et al. identify a Golden-like transcription factor that interacts with Rx1 and mediates antiviral immunity, providing the first insights into the specificity factors that enable the nonspecific DNA-binding Rx1 to confer extreme resistance to PVX. PMID- 29500268 TI - Bifidobacterium breve UCC2003 employs multiple transcriptional regulators to control metabolism of particular human milk oligosaccharides. AB - Bifidobacterial carbohydrate metabolism has been studied in considerable detail for a variety of both plant and human-derived glycans, particularly involving the bifidobacterial prototype Bifidobacterium breve UCC2003. We recently elucidated the metabolic pathways by which the human milk oligosaccharide (HMO) constituents lacto-N-tetraose (LNT), lacto-N-neotetraose (LNnT) and lacto-N-biose (LNB) are utilized by B. breve UCC2003. However, to date no work has been carried out on the regulatory mechanisms that control expression of the genetic loci involved in these HMO metabolic pathways. In the current study, we describe the characterization of three transcriptional regulators and corresponding operator and associated (inducible) promoter sequences, the latter governing transcription of the genetic elements involved in LN(n)T/LNB metabolism. The activity of these regulators is dependent on the release of specific monosaccharides, which are believed to act as allosteric effectors, and which are derived from the corresponding HMOs targeted by the particular locus.Importance Human milk oligosaccharides (HMOs) are a key factor in the development of the breastfed infant microbiota. They function as prebiotics, selecting for a specific range of microbes, including a number of infant-associated species of bifidobacteria, which are thought to provide a range of health benefits to the infant host. While much research has been carried out on elucidating the mechanisms of HMO metabolism in infant-associated bifidobacteria, there is to date very little understanding of the transcriptional regulation of these pathways. The current study reveals a multi-component transcriptional regulation system that controls the recently-identified pathways of HMO metabolism in the infant-associated Bifidobacterium breve prototype strain UCC2003. This not only provides insight into the regulatory mechanisms present in other infant-associated bifidobacteria, but also provides an example of a network of sequential steps regulating microbial carbohydrate metabolism. PMID- 29500270 TI - How MHC molecules grab citrullinated peptides to foster rheumatoid arthritis. AB - The molecular immunologist's dream is to elucidate a fundamental biochemical process that explains the basis of an affliction that affects millions of people, and that, precisely understood, might yield a rational approach to diagnosis, prevention, or therapy. In this issue of JBC, Ting et al. report proteomic, biochemical, and structural analyses that better explain how the antigen presenting HLA-DR4 molecules bind citrullinated peptides to provoke rheumatoid arthritis (RA), a chronic autoimmune disease that affects 0.5-1% of the population. PMID- 29500271 TI - The Herbert Tabor Young Investigator Awards: Meet the awardees! PMID- 29500272 TI - Correlation of Somatic Genomic Alterations Between Tissue Genomics and ctDNA Employing Next-Generation Sequencing: Analysis of Lung and Gastrointestinal Cancers. AB - Next-generation Sequencing (NGS) of cancer tissues is increasingly being carried out to identify somatic genomic alterations that may guide physicians to make therapeutic decisions. However, a single tissue biopsy may not reflect complete genomic architecture due to the heterogeneous nature of tumors. Circulating tumor DNA (ctDNA) analysis is a robust noninvasive method to detect and monitor genomic alterations in blood in real time. We analyzed 28 matched tissue NGS and ctDNA from gastrointestinal and lung cancers for concordance of somatic genomic alterations, driver, and actionable alterations. Six patients (21%) had at least one concordant mutation between tissue and ctDNA sequencing. At the gene level, among all the mutations (n = 104) detected by tissue and blood sequencing, 7.7% (n = 8) of mutations were concordant. Tissue and ctDNA sequencing identified driver mutations in 60% and 64% of the tested samples, respectively. We found high discordance between tissue and ctDNA testing, especially with respect to the driver and actionable alterations. Both tissue and ctDNA NGS detected actionable alterations in 25% of patients. When somatic alterations identified by each test were combined, the total number of patients with actionable mutations increased to 32%. Our data show significant discordance between tissue NGS and ctDNA analysis. These results suggest tissue NGS and ctDNA NGS are complementary approaches rather than exclusive of each other. When performed in isolation, tissue and ctDNA NGS can each potentially miss driver and targetable alterations, suggesting that both approaches should be incorporated to enhance mutation detection rates. Larger prospective studies are needed to better clarify this emerging precision oncology landscape. Mol Cancer Ther; 17(5); 1123-32. (c)2018 AACR. PMID- 29500273 TI - Role model: Anita Thapar. PMID- 29500274 TI - Retinoid isomerase inhibitors impair but do not block mammalian cone photoreceptor function. AB - Visual function in vertebrates critically depends on the continuous regeneration of visual pigments in rod and cone photoreceptors. RPE65 is a well-established retinoid isomerase in the pigment epithelium that regenerates rhodopsin during the rod visual cycle; however, its contribution to the regeneration of cone pigments remains obscure. In this study, we use potent and selective RPE65 inhibitors in rod- and cone-dominant animal models to discern the role of this enzyme in cone-mediated vision. We confirm that retinylamine and emixustat-family compounds selectively inhibit RPE65 over DES1, the putative retinoid isomerase of the intraretinal visual cycle. In vivo and ex vivo electroretinography experiments in Gnat1-/- mice demonstrate that acute administration of RPE65 inhibitors after a bleach suppresses the late, slow phase of cone dark adaptation without affecting the initial rapid portion, which reflects intraretinal visual cycle function. Acute administration of these compounds does not affect the light sensitivity of cone photoreceptors in mice during extended exposure to background light, but does slow all phases of subsequent dark recovery. We also show that cone function is only partially suppressed in cone-dominant ground squirrels and wild-type mice by multiday administration of an RPE65 inhibitor despite profound blockade of RPE65 activity. Complementary experiments in these animal models using the DES1 inhibitor fenretinide show more modest effects on cone recovery. Collectively, these studies demonstrate a role for continuous RPE65 activity in mammalian cone pigment regeneration and provide further evidence for RPE65 independent regeneration mechanisms. PMID- 29500275 TI - IDO1 Inhibition Synergizes with Radiation and PD-1 Blockade to Durably Increase Survival Against Advanced Glioblastoma. AB - Purpose: Glioblastoma is the most aggressive primary brain tumor in adults with a median survival of 15-20 months. Numerous approaches and novel therapeutics for treating glioblastoma have been investigated in the setting of phase III clinical trials, including a recent analysis of the immune checkpoint inhibitor, nivolumab (anti-PD-1), which failed to improve recurrent glioblastoma patient survival. However, rather than abandoning immune checkpoint inhibitor treatment for glioblastoma, which has shown promise in other types of cancer, ongoing studies are currently evaluating this therapeutic class when combined with other agents.Experimental Design: Here, we investigated immunocompetent orthotopic mouse models of glioblastoma treated with the potent CNS-penetrating IDO1 enzyme inhibitor, BGB-5777, combined with anti-PD1 mAb, as well as radiotherapy, based on our recent observation that tumor-infiltrating T cells directly increase immunosuppressive IDO1 levels in human glioblastoma, the previously described reinvigoration of immune cell functions after PD-1 blockade, as well as the proinflammatory effects of radiation.Results: Our results demonstrate a durable survival benefit from this novel three-agent treatment, but not for any single- or dual-agent combination. Unexpectedly, treatment efficacy required IDO1 enzyme inhibition in non-glioblastoma cells, rather than tumor cells. Timing of effector T-cell infiltration, animal subject age, and usage of systemic chemotherapy, all directly impacted therapy-mediated survival benefit.Conclusions: These data highlight a novel and clinically relevant immunotherapeutic approach with associated mechanistic considerations that have formed the basis of a newly initiated phase I/II trial for glioblastoma patients. Clin Cancer Res; 24(11); 2559-73. (c)2018 AACR. PMID- 29500276 TI - A Phase I Clinical Trial of Guadecitabine and Carboplatin in Platinum-Resistant, Recurrent Ovarian Cancer: Clinical, Pharmacokinetic, and Pharmacodynamic Analyses. AB - Purpose: Epigenetic changes are implicated in acquired resistance to platinum. Guadecitabine is a next-generation hypomethylating agent (HMA). Here, we report the clinical results, along with pharmacokinetic (PK) and pharmacodynamic analyses of the phase I study of guadecitabine and carboplatin in patients with recurrent, platinum-resistant high-grade serous ovarian cancer, primary peritoneal carcinoma (PPC), or fallopian tube cancer (FTC).Experimental Design: Guadecitabine was administered once daily on days 1 to 5 followed by carboplatin i.v. on day 8 of a 28-day cycle. Patients had either measurable or detectable disease. Safety assessments used CTCAE v4.Results: Twenty patients were enrolled and treated. Median age was 56 years (38-72 years). The median number of prior regimens was 7 (1-14). In the first cohort (N = 6), the starting doses were guadecitabine 45 mg/m2 and carboplatin AUC5. Four patients experienced dose limiting toxicity (DLT; neutropenia and thrombocytopenia), leading to dose deescalation of guadecitabine to 30 mg/m2 and of carboplatin to AUC4. No DLTs were observed in the subsequent 14 patients. Grade >=3 adverse events >=10% were neutropenia, leukopenia, anemia, nausea, vomiting, ascites, constipation, hypokalemia, pulmonary embolism, small-intestinal obstruction, and thrombocytopenia. Three patients had a partial response (PR), and 6 patients had stable disease (SD) >3 months, for an overall response rate (ORR) and clinical benefit rate of 15% and 45%, respectively. LINE-1 demethylation in PBMCs and promoter demethylation/gene reexpression in paired tumor biopsies/ascites were recorded.Conclusions: Guadecitabine and carboplatin were tolerated and induced clinical responses in a heavily pretreated platinum-resistant ovarian cancer population, supporting a subsequent randomized phase II trial. Clin Cancer Res; 24(10); 2285-93. (c)2018 AACR. PMID- 29500277 TI - Sequencing Pancreatic Juice: Squeezing the Most Out of Surveillance. AB - Next-generation sequencing of pancreatic juice can detect and quantify tumor promoting mutations, supporting imaging and cytology findings to predict the degree of dysplasia in patients at high risk for pancreatic cancer. Future studies are needed to optimize this approach and determine how it best fits into clinical practice. Clin Cancer Res; 24(12); 2713-5. (c)2018 AACRSee related article by Suenaga et al., p. 2963. PMID- 29500279 TI - What does research tell us about the future of dental hygiene? PMID- 29500280 TI - A Study of Visible Tattoos in Entry-Level Dental Hygiene Education Programs. AB - Purpose: The purpose of this study was to survey entry-level dental hygiene program directors in the United States (U.S.) to assess their perceptions of dental hygienists with visible tattoos as well as to determine current policies related to dress codes in U.S. dental hygiene programs.Methods: Data was collected with an online survey emailed to 340 dental hygiene program directors yielding a 43% (n=141) response rate. Participants indicated their opinions of visible tattoos on the basis of professionalism and school policy satisfaction.Results: Eighty percent of respondents reported their program as having dress code policies on visible tattoos, with the majority (97%) requiring visible tattoos to be covered. Results revealed both students (M=5.57, p<.0005) and faculty (M=5.76, p<.0005) with visible tattoos were perceived as significantly less professional. Most participants agreed that dental hygiene faculty should discuss the impact of visible tattoos on future employment opportunities, and that the community would view the school as less professional if students had visible tattoos (p<0.0005). Personal tolerance toward tattoos (p< 0.001), but not age, (p = 0.50), was significantly associated with satisfaction concerning program tattoo policies. A lower tolerance towards visible tattoos (p < 0.001) was associated with an increased likelihood that the dental hygiene program dress code included policy on visible tattoos.Conclusion: Study results showed that visible tattoos were not perceived favorably and that personal perceptions of dental hygiene program directors may have influenced school dress code polices regarding visible tattoos. These findings provide evidence based information for dental hygienists, students, faculty, administrators and hiring managers for formulating policies relating to body art. PMID- 29500278 TI - Chemotherapy Induces Breast Cancer Stemness in Association with Dysregulated Monocytosis. AB - Purpose: Preoperative or neoadjuvant therapy (NT) is increasingly used in patients with locally advanced or inflammatory breast cancer to allow optimal surgery and aim for pathologic response. However, many breast cancers are resistant or relapse after treatment. Here, we investigated conjunctive chemotherapy-triggered events occurring systemically and locally, potentially promoting a cancer stem-like cell (CSC) phenotype and contributing to tumor relapse.Experimental Design: We started by comparing the effect of paired pre- and post-NT patient sera on the CSC properties of breast cancer cells. Using cell lines, patient-derived xenograft models, and primary tumors, we investigated the regulation of CSCs and tumor progression by chemotherapy-induced factors.Results: In human patients and mice, we detected a therapy-induced CSC-stimulatory activity in serum, which was attributed to therapy-associated monocytosis leading to systemic elevation of monocyte chemoattractant proteins (MCP). The post-NT hematopoietic regeneration in the bone marrow highlighted both altered monocyte macrophage differentiation and biased commitment of stimulated hematopoietic stem cells toward monocytosis. Chemotherapeutic agents also induce monocyte expression of MCPs through a JNK-dependent mechanism. Genetic and pharmacologic inhibitions of the MCP-CCR2 pathway blocked chemotherapy's adverse effect on CSCs. Levels of nuclear Notch and ALDH1 were significantly elevated in primary breast cancers following NT, whereas higher levels of CCR2 in pre-NT tumors were associated with a poor response to NT.Conclusions: Our data establish a mechanism of chemotherapy induced cancer stemness by linking the cellular events in the bone marrow and tumors, and suggest pharmacologic inhibition of CCR2 as a potential cotreatment during conventional chemotherapy in neoadjuvant and adjuvant settings. Clin Cancer Res; 24(10); 2370-82. (c)2018 AACR. PMID- 29500281 TI - Engaging Stakeholders in Patient-Centered Outcomes Research Regarding School Based Sealant Programs. AB - Purpose: The purpose of this study was to use qualitative methods to describe the key lessons learned during the stakeholder engagement stage of planning a randomized clinical trial comparing outcomes of silver diamine fluoride (SDF) as an alternative to pit-and-fissure sealants in a school-based delivery system.Methods: Eighteen caregivers and community-based stakeholders with involvement in the school-based sealant program Sealants for Smiles from the state of Montana, were recruited for this qualitative study. United States (U.S.) Patient-Centered Outcomes Research Institute (PCORI) methodology standards were used to develop two semi-structured interview guides consisting of 6 questions. One interview guide was used for telephone interviews with caregivers and the second was used for a stakeholder focus group. Content analytic methods were used to analyze the data.Results: All participants believed that a study comparing SDF and sealants was clinically relevant. Non-caregiver stakeholders agreed with the proposed primary outcome of the study (caries prevention) whereas caregivers also emphasized the importance of child-centered outcomes such as minimizing dental anxiety associated with dental care. Stakeholders described potential concerns associated with SDF such as staining and perceptions of safety and discussed ways to address these concerns through community engagement, appropriate framing of the study, proper consent procedures, and ongoing safety monitoring during the trial. Finally, stakeholders suggested dissemination strategies such as direct communication of findings through professional organizations and encouraging insurance plans to incentivize SDF use by reimbursing dental providers.Conclusions: Involving key stakeholders in early planning is essential in developing patient-centered research questions, outcomes measures, study protocols, and dissemination plans for oral health research involving a school based delivery system. PMID- 29500282 TI - Dental Fluorosis over Time: A comparison of National Health and Nutrition Examination Survey data from 2001-2002 and 2011-2012. AB - Purpose: Excessive fluoride ingestion has been associated with dental fluorosis. The purpose of this study was to determine if there was a difference in dental fluorosis prevalence comparing National Health and Nutrition Examination Survey (NHANES) trend data for adolescents, aged 16 and 17 years, when compared to data collected in 2001-2002 to data from 2011-2012.Methods: The sample included 875 participants. Data analyses included Chi square tests and logistic regressions. The data were from a nationally representative survey by calibrated dental examiners using the modified Dean's fluorosis classification system. The data analysis of the prevalence of fluorosis severity level was dichotomized to very mild/above vs. normal/questionable.Results: In 2001-2002, the weighted percentage prevalence of the denoted dental fluorosis categories were: 49.8% normal (i.e., unaffected), 20.5% questionable, and 29.7% very mild and above. In 2011-2012, the weighted percentage prevalence categories were: 31.2% normal, 7.5% questionable, and 61.3% very mild and above. When comparing years 2001-2002 with the years 2011 2012, the prevalence of very mild and above fluorosis increased by 31.6% (P <.0001) for the 2011-2012 group. In adjusted logistic regression, participants from the years 2011-2012 were more likely to have very mild and above dental fluorosis than participants in 2001-2002 as compared with normal/questionable fluorosis (Adjusted odds ratio= 3.85; 95% confidence interval= 2.20, 6.72; P <.0001).Conclusion: There was a difference of 31.6% in dental fluorosis prevalence between 2012-2011 when compared to data from 2002-2001 in adolescents aged 16 and 17 years. The continued increase in fluorosis rates in the U.S. indicates that additional measures need to be implemented to reduce its prevalence. PMID- 29500283 TI - General Dentists' Perceptions of Dental Hygienists' Professional Role: A Survey. AB - Purpose: Changes in dental hygienists' scope of practice in the United States (U.S.) are not independent of general dentists' attitudes and behavior related to dental hygienists' professional roles. The purpose of this study was to assess perceptions and knowledge of general dentists concerning the legally allowable duties of dental hygienists in their state versus the services they provide in their individual practices; the importance of dental hygienists' contributions to the practice; and how well dental hygienists interact with dentists and patients. The relationships between dentists' attitudes, and dental hygienists' actual behavior, the age of the dentist and the number of dental hygienists and dental assistants employed in the practice were also explored.Methods: Survey data were collected from 292 general dentists in the state of Michigan concerning their attitudes and behavior related to dental hygienists' scope of practice.Results: The average number of services dental hygienists provided in the practices surveyed were lower than the average number of services that dental hygienists are legally permitted to provide in the state of Michigan. The higher the importance dentists placed on dental hygienists' clinical and overall contributions to their practice and their patient management skills, the more diagnostic services and therapies the dental hygienists performed. The older the dentists were, the higher they rated the importance of dental hygienists' clinical contributions, their contributions for the provision of patient care, and the more often dental hygienists performed diagnostic and additional procedures.Conclusions: While dentists did not indicate delegating all of the legally allowable dental hygiene duties in their practices, they did indicate having a very high appreciation of the contributions of dental hygienists to their practice. The perceived value of dental hygienists' contributions correlated positively with the number of diagnostic and adjunctive services dentists delegated dental hygienists to perform in their practices. PMID- 29500284 TI - Factors Influencing Dental Hygienists' Decisions to Pursue Doctoral Degrees. AB - Purpose: To identify the factors that have influenced dental hygienists to pursue post-graduate education opportunities, specifically dental (DDS, DMD) as compared to academic doctoral degrees, such as doctor of philosophy (PhD) or doctor of education (EdD).Methods: A convenience sample of dental hygienists with doctoral degrees were identified from multiple sources (n=140) and sent a 27-item web based survey. Univariate logistic regression analysis was used to explore the influence of independent variables (respondents' demographic and personal characteristics, influential persons and experiences, encouraging and motivating factors) on the respondents' decision to pursue either a dental or an academic doctoral degree.Results: Of the 140 potential participants, 69 (n=69) responded (49% response rate): 17 dental degree respondents, 46 academic degree respondents. In contrast to academic degree respondents, those with dental degrees graduated from dental hygiene programs more recently (p=0.03), spent less time working as a dental hygienist (p=0.01), considered themselves mechanically inclined (p=0.03), and preferred to learn a new skill rather than read about a current research study (p=0.002). Both groups agreed that working one-on-one with people was important to career satisfaction. Dental degree respondents were more likely to have been influenced or encouraged to pursue dentistry by dentists (p=0.01) and family (p=0.004). Academic degree respondents were more likely to have had experiences with a researcher/scientist (p=0.004) or had been influenced by an educator (p=0.01). Only 40% of all respondents reported that dental hygiene instructors were instrumental in encouraging their advanced education.Conclusion: Dental hygienists possessing characteristics similar to the academic degree respondents in this study should be encouraged to pursue academic doctoral education, providing the necessary skills to advance the dental hygiene profession. PMID- 29500285 TI - Effectiveness of an Antigen-Specific Streptococcus mutans Chairside Test as Compared to a Culture-Based S. mutans Test. AB - Purpose: To compare the effectiveness of an antigen-specific Streptococcus mutans (S. mutans) chairside test to a culture based S. mutans test.Methods: Fifty-three patients receiving dental hygiene care at the University of Missouri-Kansas City, School of Dentistry were enrolled in the study. Stimulated saliva was collected from the patients and utilized for both bacteria tests. The antigen-specific test was compared to the culture-based bacteria test and to a caries risk assessment measuring sensitivity and specificity.Results: The majority of participants were male (53%) with high caries risk (60%). The culture based test results were primarily negative (62%); while the antigen-specific test had more positives (76%). The sensitivity and specificity comparing the antigen-specific test to the culture based test was high (88%, 95% CI = (78%, 97%) and low (25%, 95% CI = (13%, 37%), respectively. The sensitivity and specificity comparing the antigen specific test to caries risk was high (83%, 95% CI = (72%, 93%) and low (38%, 95% CI = (24%, 51%) respectively.Conclusions: While the sensitivity of the antigen specific test was high for both the culture-based test and caries risk, the specificity was low for both. These results suggest that the antigen-specific test tends to give a higher proportion of false positive results. PMID- 29500286 TI - Reduced Depth Technique with the Posterior Superior Alveolar Block. AB - Purpose: The posterior superior alveolar (PSA) block is one of many techniques used to provide profound anesthesia for invasive dental procedures. This technique has a long history, with a high success rate, but is not without complication risks. The purpose of this study was to determine if pulpal anesthesia of the maxillary second molar could be achieved using a posterior superior alveolar block with a reduced depth of penetration of 10 mm compared to the current suggested depth of 16 mm.Methods: Using a cold refrigerant, a thermal test was conducted using the buccal surface of a maxillary second molar of 43 participants. Positive neural responses were obtained from 100% of the participants (n=43) during the pretest. Each participant received a posterior superior alveolar block using a short (20mm), 27-gauge needle with the penetration depth reduced to 10mm. Post-test neural responses of these molars were evaluated using same cold thermal test technique.Results: Study results demonstrated that the reduced depth technique for the PSA block was successful in 88% (n=38) of the participants; pulpal anesthesia of the maxillary second molar had been achieved. Furthermore, there were zero positive aspirations and zero hematomas observed in the participants.Conclusion: The reduced needle depth technique showed promise in achieving desired results of pulpal anesthesia coupled with decreasing risk and complications associated with the PSA block. Additional blinded, randomized clinical studies are recommended to achieve evidence-based support for this reduced depth PSA block technique. PMID- 29500288 TI - Remodel mitochondria and get energized. PMID- 29500287 TI - Regional oxygen extraction predicts border zone vulnerability to stroke in sickle cell disease. AB - OBJECTIVE: To determine mechanisms underlying regional vulnerability to infarction in sickle cell disease (SCD) by measuring voxel-wise cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen utilization (CMRO2) in children with SCD. METHODS: Participants underwent brain MRIs to measure voxel-based CBF, OEF, and CMRO2. An infarct heat map was created from an independent pediatric SCD cohort with silent infarcts and compared to prospectively obtained OEF maps. RESULTS: Fifty-six participants, 36 children with SCD and 20 controls, completed the study evaluation. Whole-brain CBF (99.2 vs 66.3 mL/100 g/min, p < 0.001), OEF (42.7% vs 28.8%, p < 0.001), and CMRO2 (3.7 vs 2.5 mL/100 g/min, p < 0.001) were higher in the SCD cohort compared to controls. A region of peak OEF was identified in the deep white matter in the SCD cohort, delineated by a ratio map of average SCD to control OEF voxels. CMRO2 in this region, which encompassed the CBF nadir, was low relative to all white matter (p < 0.001). Furthermore, this peak OEF region colocalized with regions of greatest infarct density derived from an independent SCD cohort. CONCLUSIONS: Elevated OEF in the deep white matter identifies a signature of metabolically stressed brain tissue at increased stroke risk in pediatric patients with SCD. We propose that border zone physiology, exacerbated by chronic anemic hypoxia, explains the high risk in this region. PMID- 29500289 TI - The promise of noninvasive cerebral hemodynamic assessment in sickle cell anemia. PMID- 29500290 TI - Quality improvement in neurology: Neuro-oncology quality measurement set. PMID- 29500291 TI - Epileptogenic role of occult temporal encephalomeningocele: Case-control study. AB - OBJECTIVE: The purpose of this case-control study is to evaluate the prevalence of occult temporal encephalomeningocele (OTE) in patients with temporal lobe epilepsy (TLE) of unknown etiology presenting to an epilepsy center, independently from drug sensitivity. METHODS: We studied 95 patients with TLE (51 female, mean age 49.4 +/- 17.1 years) and 151 controls (88 female, mean age 54.1 +/- 21.0 years) using a 1.5T brain MRI, including balanced steady-state gradient echo sequences, targeted to the temporal lobes. RESULTS: OTE was found in 5.2% of the TLE population (9.5% of drug-resistant TLE) and in none of the controls (p = 0.008). Two patients with OTE and drug-resistant TLE became seizure-free after lesionectomy (follow-up 18-24 months). CONCLUSION: OTE is not a rare finding in unselected patients with TLE of unknown origin, provided that it is carefully searched. The absence of OTE in a large group of nonepileptic controls adds evidence to its epileptogenic role. PMID- 29500292 TI - Randomized dose-escalation trial of elamipretide in adults with primary mitochondrial myopathy. AB - OBJECTIVE: To assess the safety and efficacy of elamipretide, an aromatic cationic tetrapeptide that readily penetrates cell membranes and transiently localizes to the inner mitochondrial membrane where it associates with cardiolipin, in adults with primary mitochondrial myopathy (PMM). METHODS: A Study Investigating the Safety, Tolerability, and Efficacy of MTP-131 for the Treatment of Mitochondrial Myopathy (MMPOWER) was a phase I/II multicenter, randomized, double-blind, placebo-controlled trial of elamipretide in 36 participants with genetically confirmed PMM. Participants were randomized to intravenous elamipretide (0.01, 0.1, and 0.25 mg/kg/h or placebo for 2 hours in a dose-escalating sequence). The primary efficacy measure was the change in distance walked in the 6-minute walk test (6MWT) after 5 days of treatment. Other efficacy measures included changes in cardiopulmonary exercise testing parameters, in participant-reported symptoms, and in serum and urinary biomarkers. Safety, tolerability, and pharmacokinetics were also measured. RESULTS: Participants who received the highest dose of elamipretide walked a mean of 64.5 m farther at day 5 compared to a change of 20.4 m in the placebo group (p = 0.053). In addition, there was a dose-dependent increase in distance walked on the 6MWT with elamipretide treatment (p = 0.014). In a model that adjusted for additional covariates possibly affecting response, the adjusted change for the highest dose of elamipretide was 51.2 vs 3.0 m in the placebo group (p = 0.0297). No significant differences were observed in other efficacy and safety endpoints. CONCLUSIONS: Elamipretide increased exercise performance after 5 days of treatment in patients with PMM without increased safety concerns. These findings, as well as additional functional and patient-reported measures, remain to be tested in larger trials with longer treatment periods to detect other potential therapeutic benefits in individuals affected by this condition. CLASSIFICATION OF EVIDENCE: This trial provides Class I evidence that for patients with PMM, elamipretide improved the distance walked on the 6MWT. PMID- 29500293 TI - Stimulation Interventions and Parenting in Low- and Middle-Income Countries: A Meta-analysis. AB - CONTEXT: Early childhood stimulation interventions positively impact early child development (ECD) outcomes in low- and middle-income countries. However, trials have less comprehensively evaluated the effects of such parenting programs on caregivers' skills and capacities. OBJECTIVE: We conducted a systematic review and meta-analysis to assess the effectiveness of stimulation interventions on improving parenting outcomes. DATA SOURCES: Six electronic bibliographic databases. STUDY SELECTION: Inclusion criteria included randomized controlled trials of stimulation interventions designed to improve ECD outcomes during the first 2 years of life that measured any maternal or parenting-related outcome after the start of the intervention. DATA EXTRACTION: Two independent reviewers extracted data by using a structured form. RESULTS: Fifteen studies representing 13 unique randomized controlled trials met the inclusion criteria. Pooled standardized mean differences (SMDs) based on random-effects models revealed medium-to-large benefits of stimulation interventions for improving the home caregiving environment (n = 10; SMD = 0.57; 95% confidence interval [CI], 0.37 to 0.77), mother-child interactions (n = 3; SMD = 0.44; 95% CI, 0.14 to 0.74), and maternal knowledge of ECD (n = 6; SMD = 0.91; 95% CI, 0.51 to 1.31). No significant difference was seen for maternal depressive symptoms (n = 9; SMD = 0.10; 95% CI, -0.23 to -0.03). LIMITATIONS: Limitations include heterogeneity across interventions, lack of standardized measures, and different time points of assessments across studies. CONCLUSIONS: Early childhood stimulation interventions improve several distinct aspects of maternal parenting. Improvements in parenting capacities may serve as key mechanisms by which these programs benefit ECD outcomes. PMID- 29500294 TI - Concerns Regarding the Single Operator Model of Sedation in Young Children. PMID- 29500296 TI - Medulloblastoma Circulating Tumor Cells Form Leptomeningeal Metastases. AB - NCAM+CD45+ medulloblastoma cells were shown to be medulloblastoma circulating tumor cells (CTC). PMID- 29500295 TI - Colorectal Tumors Require NUAK1 for Protection from Oxidative Stress. AB - Exploiting oxidative stress has recently emerged as a plausible strategy for treatment of human cancer, and antioxidant defenses are implicated in resistance to chemotherapy and radiotherapy. Targeted suppression of antioxidant defenses could thus broadly improve therapeutic outcomes. Here, we identify the AMPK related kinase NUAK1 as a key component of the antioxidant stress response pathway and reveal a specific requirement for this role of NUAK1 in colorectal cancer. We show that NUAK1 is activated by oxidative stress and that this activation is required to facilitate nuclear import of the antioxidant master regulator NRF2: Activation of NUAK1 coordinates PP1beta inhibition with AKT activation in order to suppress GSK3beta-dependent inhibition of NRF2 nuclear import. Deletion of NUAK1 suppresses formation of colorectal tumors, whereas acute depletion of NUAK1 induces regression of preexisting autochthonous tumors. Importantly, elevated expression of NUAK1 in human colorectal cancer is associated with more aggressive disease and reduced overall survival.Significance: This work identifies NUAK1 as a key facilitator of the adaptive antioxidant response that is associated with aggressive disease and worse outcome in human colorectal cancer. Our data suggest that transient NUAK1 inhibition may provide a safe and effective means for treatment of human colorectal cancer via disruption of intrinsic antioxidant defenses. Cancer Discov; 8(5); 632-47. (c)2018 AACR.This article is highlighted in the In This Issue feature, p. 517. PMID- 29500297 TI - A Small-Molecule Splicing Modulator Targets Spliceosome-Mutant Cells. AB - The small molecule H3B-8800 binds to and modulates the SF3b complex to kill spliceosome-mutant cells. PMID- 29500298 TI - SETD1A Interacts with Cyclin K to Promote Leukemia Cell Survival. AB - SETD1A enhances leukemic cell growth and survival independent of its methyltransferase activity. PMID- 29500299 TI - Umbralisib Inhibits PI3Kdelta with Less Toxicity Than Previous Inhibitors. AB - Umbralisib is well tolerated and has activity against relapsed or refractory hematologic cancers. PMID- 29500300 TI - Oncogenes Induce Replication Stress via Intragenic Replication Origins. AB - Oncogenes induce premature S phase, resulting in replication-transcription conflicts and replication stress. PMID- 29500301 TI - Can accountable care organisations really improve the English NHS? Lessons from the United States. PMID- 29500302 TI - Oral Therapies for Multiple Sclerosis. AB - Multiple sclerosis treatment faces tremendous changes owing to the approval of new medications, some of which are available as oral formulations. Until now, the four orally available medications, fingolimod, dimethylfumarate (BG-12), teriflunomide, and cladribine have received market authorization, whereas laquinimod is still under development. Fingolimod is a sphingosine-1-phosphate inhibitor, which is typically used as escalation therapy and leads to up to 60% reduction of the annualized relapse rate, but might also have neuroprotective properties. In addition, there are three more specific S1P agonists in late stages of development: siponimod, ponesimod, and ozanimod. Dimethylfumarate has immunomodulatory and cytoprotective functions and is used as baseline therapy. Teriflunomide, the active metabolite of the rheumatoid arthritis medication leflunomide, targets the dihydroorotate dehydrogenase, thus inhibiting the proliferation of lymphocytes by depletion of pyrimidines. Here we will review the mechanisms of action, clinical trial data, as well as data about safety and tolerability of the compounds. PMID- 29500303 TI - Biomarkers in Multiple Sclerosis. AB - Multiple sclerosis (MS) is a chronic neurodegenerative autoimmune disease with a complex clinical course characterized by inflammation, demyelination, and axonal degeneration. Diagnosis of MS most commonly includes finding lesions in at least two separate areas of the central nervous system (CNS), including the brain, spinal cord, and optic nerves. In recent years, there has been a remarkable increase in the number of available treatments for MS. An optimal treatment is usually based on a personalized approach determined by an individual patient's prognosis and treatment risks. Biomarkers that can predict disability progression, monitor ongoing disease activity, and assess treatment response are integral in making important decisions regarding MS treatment. This review describes MS biomarkers that are currently being used in clinical practice; it also reviews and consolidates published findings from clinically relevant potential MS biomarkers in recent years. The work also discusses the challenges of validating and application of biomarkers in MS clinical practice. PMID- 29500304 TI - Natalizumab: Perspectives from the Bench to Bedside. AB - Probably no other disease-modifying drug for multiple sclerosis has a more fascinating story than natalizumab from both the bench to bedside perspective and the postmarketing experience standpoint. Natalizumab is a monoclonal antibody that inhibits the trafficking of lymphocytes from the blood into the central nervous system by blocking the adhesion molecule alpha4-integrin. Natalizumab was approved as a disease-modifying drug for relapsing remitting multiple sclerosis only 12 years after the discovery of its target molecule-a time line that is rather fast for drug development. However, a few months after its U.S. Food and Drug Administration approval, natalizumab was withdrawn from the market because of an unanticipated complication-progressive multifocal leukoencephalopathy. It was later reinstated with required adherence to a strict monitoring program and incorporation of mitigation strategies. PMID- 29500305 TI - Globalization and the Changing Epidemiology of Hepatitis A Virus. AB - Increased economic interdependence, social integration, and other aspects of globalization are contributing to significant changes in hepatitis A epidemiology. Globally, the incidence of hepatitis A virus (HAV) infection is decreasing, the age at midpoint of population immunity (AMPI) is increasing, and the proportion of symptomatic cases is increasing as the average age at infection increases. In low-income countries, HAV remains endemic but improved water and sanitation systems are reducing transmission rates among young children. In high income countries, most adults remain susceptible to HAV and foodborne outbreaks are becoming more frequent. Middle-income countries have diverse epidemiological profiles, and they play important roles in the global spread of HAV through international trade and travel. Future changes in the epidemiology of hepatitis A will be heavily influenced by globalization processes. PMID- 29500306 TI - Alemtuzumab as Treatment for Multiple Sclerosis. AB - Alemtuzumab, the first monoclonal antibody to be used as a therapy and the first to be humanized, was introduced into the treatment of multiple sclerosis in 1991 after its successful use in hematology, oncology, and transplantation medicine. One phase 2 and two phase 3 trials of this lymphocyte-depleting agent have established alemtuzumab's superior efficacy to interferon beta-1a over the short term (2-3 years) with greater relapse rate reduction, reduced accumulation of disability, and more frequent sustained improvement in disability. Longer-term extension studies show durable effects on slowing cerebral atrophy over 6 years and maintained low relapse rates over 10 years, despite roughly half of patients not needing further dosing. Homeostatic proliferation of residual T cells after alemtuzumab-induced lymphopenia is probably responsible for its most common side effects: secondary autoimmunity 1 or 2 years after the last infusion of alemtuzumab affecting the thyroid gland (30% of patients), platelets (1%), or renal glomeruli (0.1%). With the prerequisite of patient and physician adherence to a prolonged safety-monitoring protocol, alemtuzumab offers durable high efficacy from infrequent dosing. PMID- 29500308 TI - Developmental milestones at one year for the offspring of mothers with congenital hypothyroidism: a population-based study AB - OBJECTIVE: Maternal thyroid dysfunction during pregnancy is associated with neurodevelopmental impairment in the offspring. No data are currently available for the offspring of patients treated early for congenital hypothyroidism (CH). The aim of this study was to investigate motor and language milestones at one year of age in a population-based registry of children born to young women with CH. DESIGN AND METHODS: We assessed 110 children born to mothers with CH, and 1367 children from the EDEN French population-based birth cohort study prospectively, at the age of one year, with identical questionnaires. Outcomes were assessed in terms of scores for childhood developmental milestones relating to mobility, motor coordination, communication, motricity and language skills. RESULTS: After adjustment for confounding factors, children born to mothers with CH were found to have a higher risk of poor motor coordination than those of the EDEN cohort (OR: 4.18, 95% CI: 2.52-6.93). No differences were identified for the other four domains investigated. Children born to mothers with gestational diabetes have a higher risk of low motor coordination score than their peers (OR: 2.10, 95% CI: 1.21-3.66). Children born to mothers with TSH >= 10 IU/L during the first six months of pregnancy were more likely to have low motricity or communication skills scores than those born to mothers with lower TSH concentrations (56% vs 21% for each score, P < 0.04). CONCLUSIONS: Maternal CH may have slight adverse effects on some developmental milestones in the child at one year of age, particularly for children born to mothers with uncontrolled hypothyroidism. However, it remains unclear whether these adverse effects modify subsequent neurodevelopment. PMID- 29500307 TI - Neural Regulation of Bone and Bone Marrow. AB - Bones provide both skeletal scaffolding and space for hematopoiesis in its marrow. Previous work has shown that these functions were tightly regulated by the nervous system. The central and peripheral nervous systems tightly regulate compact bone remodeling, its metabolism, and hematopoietic homeostasis in the bone marrow (BM). Accumulating evidence indicates that the nervous system, which fine-tunes inflammatory responses and alterations in neural functions, may regulate autoimmune diseases. Neural signals also influence the progression of hematological malignancies such as acute and chronic myeloid leukemias. Here, we review the interplay of the nervous system with bone, BM, and immunity, and discuss future challenges to target hematological diseases through modulation of activity of the nervous system. PMID- 29500309 TI - Phenotypic spectrum and responses to recombinant human IGF1 (rhIGF1) therapy in patients with homozygous intronic pseudoexon growth hormone receptor mutation. AB - BACKGROUND: Patients with homozygous intronic pseudoexon GH receptor (GHR) mutations (6Psi) have growth hormone insensitivity (GHI) (growth failure, IGF1 deficiency and normal/elevated serum GH). We report 9 patients in addition to previously described 11 GHR 6Psi patients and their responses to rhIGF1 therapy. METHODS: 20 patients (12 males, 11 families, mean age 4.0 +/- 2.2 years) were diagnosed genetically in our centre. Phenotypic data and responses to rhIGF1 treatment were provided by referring clinicians. Continuous parametric variables were compared using Student t-test or ANOVA. RESULTS: 10/20 (50%) had typical facial features of GHI, 19/20 (95%) from consanguineous families and 18/20 (90%) of Pakistani origin. At diagnosis, mean height SDS: -4.1 +/- 0.95, IGF1 SDS: -2.8 +/- 1.4; IGFBP3 SDS: -3.0 +/- 2.1 and mean basal and peak GH levels: 11.9 ug/L and 32.9 ug/L, respectively. 1/12 who had IGF1 generation test, responded (IGF1: 132-255 ng/mL). 15/20 (75%; 11M) received rhIGF1 (mean dose: 114 ug/kg twice daily, mean duration: 5.3 +/- 2.5 years). Mean baseline height velocity of 4.7 +/ 1.1 cm/year increased to 7.4 +/- 1.8 cm/year (P = 0.001) during year 1 of therapy. Year 3 mean height SDS (-3.2 +/- 1.0) was higher than pre-treatment height SDS (-4.3 +/- 0.8) (P = 0.03). Mean cumulative increase in height SDS after year 5 was 1.4 +/- 0.9. Difference between target height (TH) SDS and adult or latest height SDS was less than that of TH SDS and pre-treatment height SDS (2.1 +/- 1.2 vs 3.0 +/- 0.8; P = 0.02). CONCLUSION: In addition to phenotypic heterogeneity in the cohort, there was mismatch between clinical and biochemical features in individual patients with 6Psi GHR mutations. rhIGF1 treatment improved height outcomes. PMID- 29500311 TI - Social causes of the slowdown in health improvement. PMID- 29500312 TI - Etiology and Pharmacology of Neuropathic Pain. AB - Injury to or disease of the nervous system can invoke chronic and sometimes intractable neuropathic pain. Many parallel, interdependent, and time-dependent processes, including neuroimmune interactions at the peripheral, supraspinal, and spinal levels, contribute to the etiology of this "disease of pain." Recent work emphasizes the roles of colony-stimulating factor 1, ATP, and brain-derived neurotrophic factor. Excitatory processes are enhanced, and inhibitory processes are attenuated in the spinal dorsal horn and throughout the somatosensory system. This leads to central sensitization and aberrant processing such that tactile and innocuous thermal information is perceived as pain (allodynia). Processes involved in the onset of neuropathic pain differ from those involved in its long term maintenance. Opioids display limited effectiveness, and less than 35% of patients derive meaningful benefit from other therapeutic approaches. We thus review promising therapeutic targets that have emerged over the last 20 years, including Na+, K+, Ca2+, hyperpolarization-activated cyclic nucleotide-gated channels, transient receptor potential channel type V1 channels, and adenosine A3 receptors. Despite this progress, the gabapentinoids retain their status as first line treatments, yet their mechanism of action is poorly understood. We outline recent progress in understanding the etiology of neuropathic pain and show how this has provided insights into the cellular actions of pregabalin and gabapentin. Interactions of gabapentinoids with the alpha2delta-1 subunit of voltage-gated Ca2+ channels produce multiple and neuron type-specific actions in spinal cord and higher centers. We suggest that drugs that affect multiple processes, rather than a single specific target, show the greatest promise for future therapeutic development. PMID- 29500310 TI - Safety and convenience of once-weekly somapacitan in adult GH deficiency: a 26 week randomized, controlled trial. AB - OBJECTIVE: Somapacitan is a reversible albumin-binding growth hormone (GH) derivative, developed for once-weekly administration. This study aimed to evaluate the safety of once-weekly somapacitan vs once-daily Norditropin(r). Local tolerability and treatment satisfaction were also assessed. DESIGN: 26-week randomized, controlled phase 3 safety and tolerability trial in six countries (Nbib2382939). METHODS: Male or female patients aged 18-79 years with adult GH deficiency (AGHD), treated with once-daily GH for >=6 months, were randomized to once-weekly somapacitan (n = 61) or once-daily Norditropin (n = 31) administered subcutaneously by pen. Both treatments were dose titrated for 8 weeks to achieve insulin-like growth factor I (IGF-I) standard deviation score (SDS) levels within the normal range, and then administered at a fixed dose. Outcome measures were adverse events (AEs), including injection site reactions; occurrence of anti somapacitan/anti-GH antibodies and change in treatment satisfaction, assessed using the Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9). RESULTS: Mean IGF-I SDS remained between 0 and 2 SDS throughout the trial in both groups. AEs were mostly mild or moderate and transient in nature. The most common AEs were nasopharyngitis, headache and fatigue in both groups. More than 1500 somapacitan injections were administered and no clinically significant injection site reactions were reported. No anti-somapacitan or anti-GH antibodies were detected. The TSQM-9 score for convenience increased significantly more with somapacitan vs Norditropin (P = 0.0171). CONCLUSIONS: In this 26-week trial in patients with AGHD, somapacitan was well tolerated and no safety issues were identified. Once-weekly somapacitan was reported to be more convenient than once daily Norditropin. PMID- 29500313 TI - Altered Odor-Induced Brain Activity as an Early Manifestation of Cognitive Decline in Patients With Type 2 Diabetes. AB - Type 2 diabetes is reported to be associated with olfactory dysfunction and cognitive decline. However, whether and how olfactory neural circuit abnormalities involve cognitive impairment in diabetes remains uncovered. This study thus aimed to investigate olfactory network alterations and the associations of odor-induced brain activity with cognitive and metabolic parameters in type 2 diabetes. Participants with normal cognition, including 51 patients with type 2 diabetes and 41 control subjects without diabetes, underwent detailed cognitive assessment, olfactory behavior tests, and odor-induced functional MRI measurements. Olfactory brain regions showing significantly different activation between the two groups were selected for functional connectivity analysis. Compared with the control subjects, patients with diabetes demonstrated significantly lower olfactory threshold score, decreased brain activation, and disrupted functional connectivity in the olfactory network. Positive associations of the disrupted functional connectivity with decreased neuropsychology test scores and reduced pancreatic function were observed in patients with diabetes. Notably, the association between pancreatic function and executive function was mediated by olfactory behavior and olfactory functional connectivity. Our results suggested the alteration of olfactory network is present before clinically measurable cognitive decrements in type 2 diabetes, bridging the gap between the central olfactory system and cognitive decline in diabetes. PMID- 29500315 TI - Delivery of positive end-expiratory pressure to preterm lambs using common resuscitation devices. AB - BACKGROUND: In neonatal resuscitation, a ventilation device providing positive end-expiratory pressure (PEEP) is recommended. There is limited information about PEEP delivery in vivo, using different models of self-inflating bag (SIB) at different inflation rates and PEEP settings. METHODS: We compared PEEP delivery to intubated preterm lambs using four commonly available models of paired SIBs and PEEP valves, with a T-piece, with gas flow of 8 L/min. Peak inspiratory pressure inflations of 30 cmH2O, combined with set PEEP of 5, 7 and 10 cmH2O, were delivered at rates of 20, 40 and 60/min. These combinations were repeated without gas flow. We measured mean PEEP, maximum and minimum PEEP, and its difference (PEEP reduction). RESULTS: A total of 3288 inflations were analysed. The mean PEEP delivered by all SIBs was lower than set PEEP (P<0.001), although some differences were <0.5 cmH2O. In 55% of combinations, the presence of gas flow resulted in increased PEEP delivery (range difference 0.3-2 cmH2O). The mean PEEP was closer to set PEEP with faster inflation rates and higher set PEEPs. The mean (SD) PEEP reduction was 3.9 (1.6), 8.2 (1.8), 2 (0.6) and 1.1 (0.6) cmH2O with the four SIBs, whereas it was 0.5 (0.2) cmH2O with the T-piece. CONCLUSIONS: PEEP delivery with SIBs depends on the set PEEP, inflation rate, device model and gas flow. At recommended inflation rates of 60/min, some devices can deliver PEEP close to the set level, although the reduction in PEEP makes some SIBs potentially less effective for lung recruitment than a T-piece. PMID- 29500314 TI - Postnatal Ontogenesis of the Islet Circadian Clock Plays a Contributory Role in beta-Cell Maturation Process. AB - Development of cell replacement therapies in diabetes requires understanding of the molecular underpinnings of beta-cell maturation. The circadian clock regulates diverse cellular functions important for regulation of beta-cell function and turnover. However, postnatal ontogenesis of the islet circadian clock and its potential role in beta-cell maturation remain unknown. To address this, we studied wild-type Sprague-Dawley as well as Period1 luciferase transgenic (Per1:LUC) rats to determine circadian clock function, clock protein expression, and diurnal insulin secretion during islet development and maturation process. We additionally studied beta-cell-specific Bmal1-deficient mice to elucidate a potential role of this key circadian transcription factor in beta cell functional and transcriptional maturation. We report that emergence of the islet circadian clock 1) occurs during the early postnatal period, 2) depends on the establishment of global behavioral circadian rhythms, and 3) leads to the induction of diurnal insulin secretion and gene expression. Islet cell maturation was also characterized by induction in the expression of circadian transcription factor BMAL1, deletion of which altered postnatal development of glucose stimulated insulin secretion and the associated transcriptional network. Postnatal development of the islet circadian clock contributes to early-life beta cell maturation and should be considered for optimal design of future beta-cell replacement strategies in diabetes. PMID- 29500316 TI - Cognitive outcome in childhood of birth weight discordant monochorionic twins: the long-term effects of fetal growth restriction. AB - AIM: Intrauterine growth restriction (IUGR) is associated with poorer outcomes in later life. We used a monochorionic twin model with IUGR in one twin to determine its impact on growth and neurocognitive outcomes. METHODS: Monochorionic twins with >=20% birth weight discordance born in the north of England were eligible. Cognitive function was assessed using the British Ability Scales. The Strength and Difficulties Questionnaire was used to identify behavioural problems. Auxological measurements were collected. Generalised estimating equations were used to determine the effects of birth weight on cognition. RESULTS: Fifty-one monochorionic twin pairs were assessed at a mean age of 6.3 years. Mean birth weight difference was 664 g at a mean gestation of 34.7 weeks. The lighter twin had a General Conceptual Ability (GCA) score that was three points lower (TwinL 105.4 vs TwinH -108.4, 95% CI -0.9 to -5.0), and there was a significant positive association (B 0.59) of within-pair birth weight differences and GCA scores. Mathematics and memory skills showed the largest differences. The lighter twin at school age was shorter (mean difference 2.1 cm+/-0.7) and lighter (mean difference 1.9 kg+/-0.6). Equal numbers of lighter and heavier twins were reported to have behavioural issues. CONCLUSIONS: In a monochorionic twin cohort, fetal growth restriction results in lower neurocognitive scores in early childhood, and there remain significant differences in size. Longer term follow up will be required to determine whether growth or cognitive differences persist in later child or adulthood, and whether there are any associated longer term metabolic sequelae. PMID- 29500317 TI - New in the mechanism of one-substrate transketolase reaction. AB - Transketolase catalyzes the transfer of a glycolaldehyde residue from ketose (the donor substrate) to aldose (the acceptor substrate). In the absence of aldose, transketolase catalyses the one-substrate reaction that involves only ketose. The mechanism of this reaction was unknown. Here we show that hydroxypyruvate serves as a substrate for one-substrate reaction and the reaction product is erythrulose rather than glycol aldehyde, as was shown earlier for xylulose 5 phosphate. The amount of erythrulose released into the medium is equimolar to a double amount of the transformed substrate. This could only be the case if the glycol aldehyde formed from the first ketose molecule (the product of the first half reaction) remains bound to the enzyme and is not released into the medium, waiting for condensation with the second molecule of glycol aldehyde, the product of the half reaction with the second molecule of the substrate. Using mass spectrometry of catalytic intermediates and their subsequent fragmentation, we show here that interaction of the holotransketolase with hydroxypyruvate results in the remainder of the active glycol aldehyde being equiprobably bound to the thiazole ring of thiamine diphosphate and to the amino group of its aminopyrimidine ring. We show also, that after the first formed molecule of glycolaldehyde passes from the thiazole ring of thiamine diphosphate to its aminopyrimidine ring, binding and splitting of the second ketosubstrate molecule occurs on the thiazole ring. The condensation of two molecules of glycolaldehyde occurs on the thiazole ring of thiamine diphosphate. PMID- 29500321 TI - Mitotic regulation of ARHGAP19 and RhoA. PMID- 29500319 TI - A practical approach to the diagnosis of spinal cord lesions. AB - Every neurologist will be familiar with the patient with atypical spinal cord disease and the challenges of taking the diagnosis forward. This is predominantly because of the limited range of possible clinical and investigation findings making most individual features non-specific. The difficulty in obtaining a tissue diagnosis further contributes and patients are often treated empirically based on local prevalence and potential for reversibility. This article focuses on improving the diagnosis of adult non-traumatic, non-compressive spinal cord disorders. It is structured to start with the clinical presentation in order to be of practical use to the clinician. We aim, by combining the onset phenotype with the subsequent course, along with imaging and laboratory features, to improve the diagnostic process. PMID- 29500318 TI - Bacteria Exploit Autophagy for Proteasome Degradation and Enhanced Virulence in Plants. AB - Autophagy and the ubiquitin-proteasome system (UPS) are two major protein degradation pathways implicated in the response to microbial infections in eukaryotes. In animals, the contribution of autophagy and the UPS to antibacterial immunity is well documented and several bacteria have evolved measures to target and exploit these systems to the benefit of infection. In plants, the UPS has been established as a hub for immune responses and is targeted by bacteria to enhance virulence. However, the role of autophagy during plant-bacterial interactions is less understood. Here, we have identified both pro- and antibacterial functions of autophagy mechanisms upon infection of Arabidopsis thaliana with virulent Pseudomonas syringae pv tomato DC3000 (Pst). We show that Pst activates autophagy in a type III effector (T3E)-dependent manner and stimulates the autophagic removal of proteasomes (proteaphagy) to support bacterial proliferation. We further identify the T3E Hrp outer protein M1 (HopM1) as a principle mediator of autophagy-inducing activities during infection. In contrast to the probacterial effects of Pst-induced proteaphagy, NEIGHBOR OF BRCA1-dependent selective autophagy counteracts disease progression and limits the formation of HopM1-mediated water-soaked lesions. Together, we demonstrate that distinct autophagy pathways contribute to host immunity and bacterial pathogenesis during Pst infection and provide evidence for an intimate crosstalk between proteasome and autophagy in plant-bacterial interactions. PMID- 29500322 TI - Regulatory motifs in connexin32. PMID- 29500323 TI - Molecular basis for tension-dependent Hippo signalling. PMID- 29500327 TI - Autophagy in the Tumor or in the Host: Which Plays a Greater Supportive Role? AB - Autophagy has been identified as a potential therapeutic target in pancreatic ductal adenocarcinoma, one of the most lethal cancers, with few therapeutic options. Yang and colleagues successfully created a genetically engineered mouse model focused on the autophagy gene Atg4b that allows the study of therapeutic autophagy inhibition in fully formed tumors. Using this tool, they demonstrated that selective autophagy inhibition in either the tumor cells, normal host cells, or both suppresses tumor growth. Cancer Discov; 8(3); 266-8. (c)2018 AACRSee related article by Yang et al., p. 276. PMID- 29500328 TI - Digital Circulating Tumor Cell Analyses for Prostate Cancer Precision Oncology. AB - In this issue of Cancer Discovery, Miyamoto and colleagues adapted their microfluidic CTC-iChip isolation platform with a digital RNA-PCR readout for eight prostate-specific transcripts and two assays for the androgen receptor mRNA splice variant ARV7 and the TMPRSS2-ERG translocation transcript. In patients with metastatic castrate-resistant prostate cancer at initiating abiraterone therapy in a first-line setting, the resulting RNA-based digital circulating tumor cell signatures identified patients with a shorter overall survival, and in patients with clinically localized disease, the signatures identified those with seminal vesicle invasion and pelvic lymph node involvement. Cancer Discov; 8(3); 269-71. (c)2018 AACR.See related article by Miyamoto et al., p. 288. PMID- 29500329 TI - Driver Oncogenes but Not as We Know Them: Targetable Fusion Genes in Breast Cancer. AB - Two reports in this issue of Cancer Discovery outline how the genomic composition of tumors, including the presence of intragenic gene fusions, could inform the selection of treatment approaches in aggressive forms of the disease. Cancer Discov; 8(3); 272-5. (c)2018 AACRSee related article by Matissek et al., p. 336See related article by Liu et al., p. 354. PMID- 29500330 TI - Do senescence markers correlate in vitro and in situ within individual human donors? AB - Little is known on how well senescence markers in vitro and in situ correlate within individual donors. We studied correlations between the same and different in vitro markers. Furthermore, we tested correlations between in vitro markers with in situ p16INK4a positivity.From 100 donors (20-91 years), cultured dermal fibroblasts were assessed for reactive oxygen species (ROS), telomere-associated foci (TAF), p16INK4a and senescence-associated beta-gal (SAbeta-gal), with/ without 0.6 uM rotenone for 3 days (short-term). In fibroblasts from 40 donors, telomere shortening, ROS and SAbeta-gal were additionally assessed, with/ without 20 nM rotenone for 7 weeks (long-term). In skin from 52 donors, the number of p16INK4a positive dermal cells was assessed in situ.More than half of the correlations of the same senescence markers in vitro between duplicate experiments and between short-term versus long-term experiments were significant. Half of the different senescence marker correlations were significant within the short-term and within the long-term experiments. The different senescence markers in vitro were not significantly correlated intra-individually with in situ p16INK4a positivity.?In conclusion, the same and different senescence markers are frequently correlated significantly within and between in vitro experiments, but in vitro senescence markers are not correlated with p16INK4a positivity in situ. PMID- 29500331 TI - Taking a HIF pill for old age diseases? PMID- 29500333 TI - Intestinal immunity in hypopituitary dwarf mice: effects of age. AB - Hypopituitary dwarf mice demonstrate advantages of longevity, but little is known of their colon development and intestinal immunity. Herein we found that Ames dwarf mice have shorter colon and colonic crypts, but larger ratio of mesenteric lymph nodes (MLNs) over body weight than age-matched wild type (WT) mice. In the colonic lamina propria (cLP) of juvenile Ames mice, more inflammatory neutrophils (A: 0.15% vs. 0.03% in WT mice) and monocytes (A: 7.97% vs. 5.15%) infiltrated, and antigen presenting cells CD11c+ dendritic cells (A: 1.39% vs. 0.87%), CD11b+ macrophages (A: 3.22% vs. 0.81%) and gamma delta T (gammadelta T) cells (A: 5.56% vs. 1.35%) were increased. In adult Ames dwarf mice, adaptive immune cells, such as IL-17 producing CD4+ T helper (Th17) cells (A: 8.3% vs. 4.7%) were augmented. In the MLNs of Ames dwarf mice, the antigen presenting and adaptive immune cells also altered when compared to WT mice, such as a decrease of T-regulatory (Treg) cells in juvenile Ames mice (A: 7.7% vs.10.5%), but an increase of Th17 cells (A: 0.627% vs.0.093%). Taken together, these data suggest that somatotropic signaling deficiency influences colon development and intestinal immunity. PMID- 29500332 TI - The role of FSH and TGF-beta superfamily in follicle atresia. AB - Most of the mammalian follicles undergo a degenerative process called "follicle atresia". Apoptosis of granulosa cells is the main characteristic of follicle atresia. Follicle stimulating hormone (FSH) and the transforming growth factor beta (TGF-beta) superfamily have important regulatory functions in this process. FSH activates protein kinase A and cooperating with insulin receptor substrates, it promotes the PI3K/Akt pathway which weakens apoptosis. Both Smad or non-Smad signaling of the transforming growth factor beta superfamily seem to be related to follicle atresia, and the effect of several important family members on follicle atresia is concluded in this article. FSH and TGF-beta are likely to mutually influence each other and what we have already known about the possible underlying molecular mechanism is also discussed below. PMID- 29500335 TI - Child/Adolescent development and autonomous vehicle operation: "operator's licenses" instead of driver's licenses. PMID- 29500334 TI - The prevalence of sexual violence during pregnancy in Iran and the world: a systematic review and meta-analysis. AB - BACKGROUND: Domestic violence during pregnancy is a public health crisis, because it affects both mother and fetus simultaneously, resulting in irreversible consequences for mothers and their newborns. This study was performed to determine the prevalence of sexual violence during pregnancy in the world and Iran as meta-analysis. METHODS: This study is a meta-analysis on the prevalence of sexual violence during pregnancy in the world and Iran that was conductedon Persian and English published articles up to 2015. To this end, through searching the information by key words and their compounds at SID, Medlib, Irandoc, Google scholar, Pubmid, ISI, Iranmedex, Scopus and Magiran, all related articles were extracted independently by two trained researchers. The results of studies analyzed using the STATA and Spss 16 software. RESULTS: In the initial searching of 167 articles, 33 articles related to Iran, 40 articles related to other parts of the world and totally 73 articles met inclusion criteria for study. The prevalence of sexual violence during pregnancy were estimated in the world 17% (CI 95%: 15% -18%) and in Iran 28% (CI 95%: 23%-32%). The prevalence of sexual violence during pregnancy in Iran is 11 percent more than the world. CONCLUSIONS: According to the present meta-analysis results, the prevalence of sexual violence during pregnancy in Iran is high. Given that sexual violence during pregnancy causes damage to the mother and infant, it is recommended that the relevant authorities with the implementation of intervention and educational programs reduce the prevalence of sexual violence during pregnancy. PMID- 29500336 TI - Bleeding from a Small-Intestinal Ulcer Associated with Chronic Hepatitis C. AB - BACKGROUND Hepatitis C virus infection is probably the most common chronic viral infection and affects an estimated 180 million people worldwide. Extrahepatic manifestations are well recognized among patients with chronic HCV infection. CASE REPORT We report a case of melena occurring in a 69-year-old Japanese man who had been diagnosed with CHC and who was treated with antiviral therapy. CONCLUSIONS Finally, he was diagnosed with multiple small intestine ulcers in a short time. We herein report the case of HCV with rapidly developing small intestine ulcers. PMID- 29500337 TI - Src Promotes Metastasis of Human Non-Small Cell Lung Cancer Cells through Fn14 Mediated NF-kappaB Signaling. AB - BACKGROUND Src and Fn14 are implicated in the aggressiveness of non-small cell lung cancer (NSCLC) cells, yet the molecular mechanism is not fully understood. MATERIAL AND METHODS The proliferation, migration, and invasion of HCC827 cells with Src knockdown were examined in vitro. The expression of Fn14 and the activation of NF-kappaB signaling pathway in Src-silenced HCC827 cells were detected by western blot. The role of Fn14 in Src-regulated cell migration/invasion and activation of NF-kappaB signaling was investigated by overexpressing Fn14 in Src knockdown NSCLC cells. Furthermore, the pro-metastatic role of Src was validated in a NSCLC metastasis mouse model. RESULTS Knockdown of Src inhibited the proliferation, migration, and invasion of HCC827 cells, which was associated with reduced levels of Fn14, p-IkappaBalpha, p-IKKbeta, and nuclear NF-kappaB p65. Overexpression of Fn14 restored the potential of migration and invasion as well as the activation of NF-kappaB signaling in Src-silenced NSCLC cells. In addition, silencing of Src suppressed lung metastasis of HCC827 cells in mice, and inhibited the expression of Fn14 and nuclear translocation of NF-kappaB p65 in vivo. CONCLUSIONS The data demonstrated that the Src/Fn14/NF kappaB axis plays a critical role in NSCLC metastasis. PMID- 29500338 TI - Visible light reduces C. elegans longevity. AB - The transparent nematode Caenorhabditis elegans can sense UV and blue-violet light to alter behavior. Because high-dose UV and blue-violet light are not a common feature outside of the laboratory setting, we asked what role, if any, could low-intensity visible light play in C. elegans physiology and longevity. Here, we show that C. elegans lifespan is inversely correlated to the time worms were exposed to visible light. While circadian control, lite-1 and tax-2 do not contribute to the lifespan reduction, we demonstrate that visible light creates photooxidative stress along with a general unfolded-protein response that decreases the lifespan. Finally, we find that long-lived mutants are more resistant to light stress, as well as wild-type worms supplemented pharmacologically with antioxidants. This study reveals that transparent nematodes are sensitive to visible light radiation and highlights the need to standardize methods for controlling the unrecognized biased effect of light during lifespan studies in laboratory conditions. PMID- 29500339 TI - Hydroxychloroquine attenuates renal ischemia/reperfusion injury by inhibiting cathepsin mediated NLRP3 inflammasome activation. AB - Inflammation is a major contributor to the pathogenesis of ischemic acute kidney injury (AKI), which complicates the post-operative outcomes of large numbers of hospitalized surgical patients. Hydroxychloroquine (HCQ), a well-known anti malarial drug, is commonly used in clinical practice for its anti-inflammatory actions. However, little is known about its role in renal ischemia/reperfusion (I/R) injury. In the current study, mice were subjected to I/R injury and HCQ was administered for seven days by gavage prior to surgery. In parallel, HK-2 human renal proximal tubule cells were prophylactically treated with HCQ and then were exposed to hypoxia/reoxygenation (H/R). The results showed that HCQ significantly attenuated renal dysfunction evidenced by blunted decreases in serum creatinine and kidney injury molecular-1 expression and the improvement of HK-2 cell viability. Additionally, HCQ markedly reduced macrophage and neutrophil infiltration, pro-inflammatory cytokine production, and NLRP3 inflammasome activation. Mechanistic studies showed that HCQ could inhibit the priming of the NLRP3 inflammasome by down-regulating I/R or H/R-induced NF-kappaB signaling. Moreover, HCQ reduced cathepsin (CTS) B, CTSD and CTSL activity, and their redistribution from lysosomes to cytoplasm. CTSB and CTSL (not CTSD) were implicated in I/R triggered NLRP3 inflammasome activation. Notably, we found that HCQ attenuated renal injury through downregulation of CTSB and CTSL-mediated NLRP3 inflammasome activation. This study provides new insights into the anti inflammatory effect of HCQ in the treatment of AKI. PMID- 29500340 TI - Spin-orbit interaction of light induced by transverse spin angular momentum engineering. AB - The investigations on optical angular momenta and their interactions have broadened our knowledge of light's behavior at sub-wavelength scales. Recent studies further unveil the extraordinary characteristics of transverse spin angular momentum in confined light fields and orbital angular momentum in optical vortices. Here we demonstrate a direct interaction between these two intrinsic quantities of light. By engineering the transverse spin in the evanescent wave of a whispering-gallery-mode-based optical vortex emitter, a spin-orbit interaction is observed in generated vortex beams. Inversely, this unconventional spin-orbit interplay further gives rise to an enhanced spin-direction locking effect in which waveguide modes are unidirectionally excited, with the directionality jointly controlled by the spin and orbital angular momenta states of light. The identification of this previously unknown pathway between the polarization and spatial degrees of freedom of light enriches the spin-orbit interaction phenomena, and can enable various functionalities in applications such as communications and quantum information processing. PMID- 29500341 TI - Impairments in action-outcome learning in schizophrenia. AB - Learning the causal relation between actions and their outcomes (AO learning) is critical for goal-directed behavior when actions are guided by desire for the outcome. This can be contrasted with habits that are acquired by reinforcement and primed by prevailing stimuli, in which causal learning plays no part. Recently, we demonstrated that goal-directed actions are impaired in schizophrenia; however, whether this deficit exists alongside impairments in habit or reinforcement learning is unknown. The present study distinguished deficits in causal learning from reinforcement learning in schizophrenia. We tested people with schizophrenia (SZ, n = 25) and healthy adults (HA, n = 25) in a vending machine task. Participants learned two action-outcome contingencies (e.g., push left to get a chocolate M&M, push right to get a cracker), and they also learned one contingency was degraded by delivery of noncontingent outcomes (e.g., free M&Ms), as well as changes in value by outcome devaluation. Both groups learned the best action to obtain rewards; however, SZ did not distinguish the more causal action when one AO contingency was degraded. Moreover, action selection in SZ was insensitive to changes in outcome value unless feedback was provided, and this was related to the deficit in AO learning. The failure to encode the causal relation between action and outcome in schizophrenia occurred without any apparent deficit in reinforcement learning. This implies that poor goal-directed behavior in schizophrenia cannot be explained by a more primary deficit in reward learning such as insensitivity to reward value or reward prediction errors. PMID- 29500343 TI - 5th International Multithematic Scientific Bio-Medical Congress (IMBMC), Nicosia, Cyprus, 2-4 November 2017. PMID- 29500342 TI - The harsh microenvironment in infarcted heart accelerates transplanted bone marrow mesenchymal stem cells injury: the role of injured cardiomyocytes-derived exosomes. AB - Stem cell therapy can be used to repair and regenerate damaged hearts tissue; nevertheless, the low survival rate of transplanted cells limits their therapeutic efficacy. Recently, it has been proposed that exosomes regulate multiple cellular processes by mediating cell survival and communication among cells. The following study investigates whether injured cardiomyocytes-derived exosomes (cardiac exosomes) affect the survival of transplanted bone marrow mesenchymal stem cells (BMSCs) in infarcted heart. To mimic the harsh microenvironment in infarcted heart that the cardiomyocytes or transplanted BMSCs encounter in vivo, cardiomyocytes conditioned medium and cardiac exosomes collected from H2O2-treated cardiomyocytes culture medium were cultured with BMSCs under oxidative stress in vitro. Cardiomyocytes conditioned medium and cardiac exosomes significantly accelerated the injury of BMSCs induced by H2O2; increased cleaved caspase-3/caspase-3 and apoptotic percentage, and decreased the ratio of Bcl-2/Bax and cell viability in those cells. Next, we explored the role of cardiac exosomes in the survival of transplanted BMSCs in vivo by constructing a Rab27a knockout (KO) mice model by a transcription activator-like effector nuclease (TALEN) genome-editing technique; Rab27a is a family of GTPases, which has critical role in secretion of exosomes. Male mouse GFP-modified BMSCs were implanted into the viable myocardium bordering the infarction in Rab27a KO and wild-type female mice. The obtained results showed that the transplanted BMSCs survival in infarcted heart was increased in Rab27a KO mice by the higher level of Y-chromosome Sry DNA, GFP mRNA, and the GFP fluorescence signal intensity. To sum up, these findings revealed that the injured cardiomyocytes-derived exosomes accelerate transplanted BMSCs injury in infarcted heart, thus highlighting a new mechanism underlying the survival of transplanted cells after myocardial infarction. PMID- 29500344 TI - Three-dimensional localization of nanoscale battery reactions using soft X-ray tomography. AB - Battery function is determined by the efficiency and reversibility of the electrochemical phase transformations at solid electrodes. The microscopic tools available to study the chemical states of matter with the required spatial resolution and chemical specificity are intrinsically limited when studying complex architectures by their reliance on two-dimensional projections of thick material. Here, we report the development of soft X-ray ptychographic tomography, which resolves chemical states in three dimensions at 11 nm spatial resolution. We study an ensemble of nano-plates of lithium iron phosphate extracted from a battery electrode at 50% state of charge. Using a set of nanoscale tomograms, we quantify the electrochemical state and resolve phase boundaries throughout the volume of individual nanoparticles. These observations reveal multiple reaction points, intra-particle heterogeneity, and size effects that highlight the importance of multi-dimensional analytical tools in providing novel insight to the design of the next generation of high-performance devices. PMID- 29500345 TI - Studying light-harvesting models with superconducting circuits. AB - The process of photosynthesis, the main source of energy in the living world, converts sunlight into chemical energy. The high efficiency of this process is believed to be enabled by an interplay between the quantum nature of molecular structures in photosynthetic complexes and their interaction with the environment. Investigating these effects in biological samples is challenging due to their complex and disordered structure. Here we experimentally demonstrate a technique for studying photosynthetic models based on superconducting quantum circuits, which complements existing experimental, theoretical, and computational approaches. We demonstrate a high degree of freedom in design and experimental control of our approach based on a simplified three-site model of a pigment protein complex with realistic parameters scaled down in energy by a factor of 105. We show that the excitation transport between quantum-coherent sites disordered in energy can be enabled through the interaction with environmental noise. We also show that the efficiency of the process is maximized for structured noise resembling intramolecular phononic environments found in photosynthetic complexes. PMID- 29500346 TI - A peptide tag-specific nanobody enables high-quality labeling for dSTORM imaging. AB - Dense fluorophore labeling without compromising the biological target is crucial for genuine super-resolution microscopy. Here we introduce a broadly applicable labeling strategy for fixed and living cells utilizing a short peptide tag specific nanobody (BC2-tag/bivBC2-Nb). BC2-tagging of ectopically introduced or endogenous proteins does not interfere with the examined structures and bivBC2-Nb staining results in a close-grained fluorophore labeling with minimal linkage errors. This allowed us to perform high-quality dSTORM imaging of various targets in mammalian and yeast cells. We expect that this versatile strategy will render many more demanding cellular targets amenable to dSTORM imaging. PMID- 29500347 TI - Resource acquisition and reproductive strategies of tropical forest in response to the El Nino-Southern Oscillation. AB - The El Nino-Southern Oscillation (ENSO) is the largest source of interannual climate variability in much of the tropics. We hypothesize that tropical plants exhibit interannual variation in reproduction and resource acquisition strategies driven by ENSO that mirrors their seasonal responses. We analyze the relationship of leaf and seed fall to climate variation over 30 years in a seasonally dry tropical forest in Panama where El Nino brings warm, dry, and sunny conditions. Elevated leaf fall precedes the onset of El Nino, and elevated seed production follows, paralleling associations with dry seasons. Our results provide evidence of a shift in allocation from leafing to fruiting in response to a warming phase of ENSO. This shift may enable plants to take advantage of higher light availability, while coping with higher atmospheric water demand and lower water supply. These findings might be an indicator of adaptive strategies to optimize reproduction and resource acquisition. PMID- 29500348 TI - Germinal center entry not selection of B cells is controlled by peptide-MHCII complex density. AB - B cells expressing high affinity antigen receptors are advantaged in germinal centers (GC), perhaps by increased acquisition of antigen for presentation to follicular helper T cells and improved T-cell help. In this model for affinity dependent selection, the density of peptide/MHCII (pMHCII) complexes on GC B cells is the primary determinant of selection. Here we show in chimeric mice populated by B cells differing only in their capacity to express MHCII (MHCII+/+ and MHCII+/-) that GC selection is insensitive to halving pMHCII density. Alone, both B cell types generate identical humoral responses; in competition, MHCII+/+ B cells are preferentially recruited to early GCs but this advantage does not persist once GCs are established. During GC responses, competing MHCII+/+ and MHCII+/- GC B cells comparably accumulate mutations and have indistinguishable rates of affinity maturation. We conclude that B-cell selection by pMHCII density is stringent in the establishment of GCs, but relaxed during GC responses. PMID- 29500349 TI - Measurement of the Berry curvature of solids using high-harmonic spectroscopy. AB - Berry phase and Berry curvature have become ubiquitous concepts in physics, relevant to a variety of phenomena, such as polarization, various Hall effects, etc. Studies of these phenomena call for characterization of Berry phase or curvature which is largely limited to theory, and a few measurements in optical lattices. In this work, we report polarimetry of high-harmonic emission from solids and exploit this novel capability to directly retrieve the Berry curvature of alpha-quartz. We show that the two manifestations of broken inversion symmetry in solids lead to perpendicular or parallel polarization of even harmonics with respect to the driving field. Using semiclassical transport theory, we retrieve the Berry curvature from spectra measured in perpendicular polarization, the results being supported by ab initio calculation. Our work demonstrates an approach for the direct measurement of Berry curvature in solids, which could serve as a benchmark for theoretical studies. PMID- 29500350 TI - Strong selection during the last millennium for African ancestry in the admixed population of Madagascar. AB - While admixed populations offer a unique opportunity to detect selection, the admixture in most of the studied populations occurred too recently to produce conclusive signals. By contrast, Malagasy populations originate from admixture between Asian and African populations that occurred ~27 generations ago, providing power to detect selection. We analyze local ancestry across the genomes of 700 Malagasy and identify a strong signal of recent positive selection, with an estimated selection coefficient >0.2. The selection is for African ancestry and affects 25% of chromosome 1, including the Duffy blood group gene. The null allele at this gene provides resistance to Plasmodium vivax malaria, and previous studies have suggested positive selection for this allele in the Malagasy population. This selection event also influences numerous other genes implicated in immunity, cardiovascular diseases, and asthma and decreases the Asian ancestry genome-wide by 10%, illustrating the role played by selection in recent human history. PMID- 29500352 TI - Concurrent miR-21 suppression and FXR activation as a mechanism of improvement in nonalcoholic fatty liver disease. PMID- 29500351 TI - Nfat/calcineurin signaling promotes oligodendrocyte differentiation and myelination by transcription factor network tuning. AB - Oligodendrocytes produce myelin for rapid transmission and saltatory conduction of action potentials in the vertebrate central nervous system. Activation of the myelination program requires several transcription factors including Sox10, Olig2, and Nkx2.2. Functional interactions among them are poorly understood and important components of the regulatory network are still unknown. Here, we identify Nfat proteins as Sox10 targets and regulators of oligodendroglial differentiation in rodents and humans. Overall levels and nuclear fraction increase during differentiation. Inhibition of Nfat activity impedes oligodendrocyte differentiation in vitro and in vivo. On a molecular level, Nfat proteins cooperate with Sox10 to relieve reciprocal repression of Olig2 and Nkx2.2 as precondition for oligodendroglial differentiation and myelination. As Nfat activity depends on calcium-dependent activation of calcineurin signaling, regulatory network and oligodendroglial differentiation become sensitive to calcium signals. NFAT proteins are also detected in human oligodendrocytes, downregulated in active multiple sclerosis lesions and thus likely relevant in demyelinating disease. PMID- 29500353 TI - A mechanism for CO regulation of ion channels. AB - Despite being highly toxic, carbon monoxide (CO) is also an essential intracellular signalling molecule. The mechanisms of CO-dependent cell signalling are poorly defined, but are likely to involve interactions with heme proteins. One such role for CO is in ion channel regulation. Here, we examine the interaction of CO with KATP channels. We find that CO activates KATP channels and that heme binding to a CXXHX16H motif on the SUR2A receptor is required for the CO-dependent increase in channel activity. Spectroscopic and kinetic data were used to quantify the interaction of CO with the ferrous heme-SUR2A complex. The results are significant because they directly connect CO-dependent regulation to a heme-binding event on the channel. We use this information to present molecular level insight into the dynamic processes that control the interactions of CO with a heme-regulated channel protein, and we present a structural framework for understanding the complex interplay between heme and CO in ion channel regulation. PMID- 29500355 TI - A light carbon isotope composition for the Sun. AB - Measurements by the Genesis mission have shown that solar wind oxygen is depleted in the rare isotopes, 17O and 18O, by approximately 80 and 1000/00, respectively, relative to Earth's oceans, with inferred photospheric values of about -600/00 for both isotopes. Direct astronomical measurements of CO absorption lines in the solar photosphere have previously yielded a wide range of O isotope ratios. Here, we reanalyze the line strengths for high-temperature rovibrational transitions in photospheric CO from ATMOS FTS data, and obtain an 18O depletion of delta18O = 50 +/- 110/00 (1sigma). From the same analysis we find a carbon isotope ratio of delta13C = -48 +/- 70/00 (1sigma) for the photosphere. This implies that the primary reservoirs of carbon on the terrestrial planets are enriched in 13C relative to the bulk material from which the solar system formed, possibly as a result of CO self-shielding or inheritance from the parent cloud. PMID- 29500354 TI - CryoEM structure of the human SLC4A4 sodium-coupled acid-base transporter NBCe1. AB - Na+-coupled acid-base transporters play essential roles in human biology. Their dysfunction has been linked to cancer, heart, and brain disease. High-resolution structures of mammalian Na+-coupled acid-base transporters are not available. The sodium-bicarbonate cotransporter NBCe1 functions in multiple organs and its mutations cause blindness, abnormal growth and blood chemistry, migraines, and impaired cognitive function. Here, we have determined the structure of the membrane domain dimer of human NBCe1 at 3.9 A resolution by cryo electron microscopy. Our atomic model and functional mutagenesis revealed the ion accessibility pathway and the ion coordination site, the latter containing residues involved in human disease-causing mutations. We identified a small number of residues within the ion coordination site whose modification transformed NBCe1 into an anion exchanger. Our data suggest that symporters and exchangers utilize comparable transport machinery and that subtle differences in their substrate-binding regions have very significant effects on their transport mode. PMID- 29500356 TI - Spontaneous imbibition in fractal tortuous micro-nano pores considering dynamic contact angle and slip effect: phase portrait analysis and analytical solutions. AB - Shales have abundant micro-nano pores. Meanwhile, a considerable amount of fracturing liquid is imbibed spontaneously in the hydraulic fracturing process. The spontaneous imbibition in tortuous micro-nano pores is special to shale, and dynamic contact angle and slippage are two important characteristics. In this work, we mainly investigate spontaneous imbibition considering dynamic contact angle and slip effect in fractal tortuous capillaries. We introduce phase portrait analysis to analyse the dynamic state and stability of imbibition. Moreover, analytical solutions to the imbibition equation are derived under special situations, and the solutions are verified by published data. Finally, we discuss the influences of slip length, dynamic contact angle and gravity on spontaneous imbibition. The analysis shows that phase portrait is an ideal tool for analysing spontaneous imbibition because it can evaluate the process without solving the complex governing ordinary differential equations. Moreover, dynamic contact angle and slip effect play an important role in fluid imbibition in fractal tortuous capillaries. Neglecting slip effect in micro-nano pores apparently underestimates imbibition capability, and ignoring variations in contact angle causes inaccuracy in predicting imbibition speed at the initial stage of the process. Finally, gravity is one of the factors that control the stabilisation of the imbibition process. PMID- 29500357 TI - The Stress-Dependent Activation Parameters for Dislocation Nucleation in Molybdenum Nanoparticles. AB - Many specimens at the nanoscale are pristine of dislocations, line defects which are the main carriers of plasticity. As a result, they exhibit extremely high strengths which are dislocation-nucleation controlled. Since nucleation is a thermally activated process, it is essential to quantify the stress-dependent activation parameters for dislocation nucleation in order to study the strength of specimens at the nanoscale and its distribution. In this work, we calculate the strength of Mo nanoparticles in molecular dynamics simulations and we propose a method to extract the activation free-energy barrier for dislocation nucleation from the distribution of the results. We show that by deforming the nanoparticles at a constant strain rate, their strength distribution can be approximated by a normal distribution, from which the activation volumes at different stresses and temperatures are calculated directly. We found that the activation energy dependency on the stress near spontaneous nucleation conditions obeys a power-law with a critical exponent of approximately 3/2, which is in accordance with critical exponents found in other thermally activated processes but never for dislocation nucleation. Additionally, significant activation entropies were calculated. Finally, we generalize the approach to calculate the activation parameters for other driving-force dependent thermally activated processes. PMID- 29500358 TI - The effects of currents and potentials on the selectivities of copper toward carbon dioxide electroreduction. AB - Copper electrodes have been shown to be selective toward the electroreduction of carbon dioxide to ethylene, carbon monoxide, or formate. However, the underlying causes of their activities, which have been attributed to a rise in local pH near the surface of the electrode, presence of atomic-scale defects, and/or residual oxygen atoms in the catalysts, etc., have not been generally agreed on. Here, we perform a study of carbon dioxide reduction on four copper catalysts from -0.45 to -1.30 V vs. reversible hydrogen electrode. The selectivities exhibited by 20 previously reported copper catalysts are also analyzed. We demonstrate that the selectivity of carbon dioxide reduction is greatly affected by the applied potentials and currents, regardless of the starting condition of copper catalysts. This study shows that optimization of the current densities at the appropriate potential windows is critical for designing highly selective copper catalysts. PMID- 29500359 TI - Atomic visualization of a non-equilibrium sodiation pathway in copper sulfide. AB - Sodium ion batteries have been considered a promising alternative to lithium ion batteries for large-scale energy storage owing to their low cost and high natural abundance. However, the commercialization of this device is hindered by the lack of suitable anodes with an optimized morphology that ensure high capacity and cycling stability of a battery. Here, we not only demonstrate that copper sulfide nanoplates exhibit close-to-theoretical capacity (~560 mAh g-1) and long-term cyclability, but also reveal that their sodiation follows a non-equilibrium reaction route, which involves successive crystallographic tuning. By employing in situ transmission electron microscopy, we examine the atomic structures of four distinct sodiation phases of copper sulfide nanoplates including a metastable phase and discover that the discharge profile of copper sulfide directly reflects the observed phase evolutions. Our work provides detailed insight into the sodiation process of the high-performance intercalation conversion anode material. PMID- 29500360 TI - Protecting tropical forests from the rapid expansion of rubber using carbon payments. AB - Expansion of Hevea brasiliensis rubber plantations is a resurgent driver of deforestation, carbon emissions, and biodiversity loss in Southeast Asia. Southeast Asian rubber extent is massive, equivalent to 67% of oil palm, with rapid further expansion predicted. Results-based carbon finance could dis incentivise forest conversion to rubber, but efficacy will be limited unless payments match, or at least approach, the costs of avoided deforestation. These include opportunity costs (timber and rubber profits), plus carbon finance scheme setup (transaction) and implementation costs. Using comprehensive Cambodian forest data, exploring scenarios of selective logging and conversion, and assuming land-use choice is based on net present value, we find that carbon prices of $30-$51 per tCO2 are needed to break even against costs, higher than those currently paid on carbon markets or through carbon funds. To defend forests from rubber, either carbon prices must be increased, or other strategies are needed, such as corporate zero-deforestation pledges, and governmental regulation and enforcement of forest protection. PMID- 29500361 TI - Nitrogen-doped tungsten carbide nanoarray as an efficient bifunctional electrocatalyst for water splitting in acid. AB - Tungsten carbide is one of the most promising electrocatalysts for the hydrogen evolution reaction, although it exhibits sluggish kinetics due to a strong tungsten-hydrogen bond. In addition, tungsten carbide's catalytic activity toward the oxygen evolution reaction has yet to be reported. Here, we introduce a superaerophobic nitrogen-doped tungsten carbide nanoarray electrode exhibiting high stability and activity toward hydrogen evolution reaction as well as driving oxygen evolution efficiently in acid. Nitrogen-doping and nanoarray structure accelerate hydrogen gas release from the electrode, realizing a current density of -200 mA cm-2 at the potential of -190 mV vs. reversible hydrogen electrode, which manifest one of the best non-noble metal catalysts for hydrogen evolution reaction. Under acidic conditions (0.5 M sulfuric acid), water splitting catalyzed by nitrogen-doped tungsten carbide nanoarray starts from about 1.4 V, and outperforms most other water splitting catalysts. PMID- 29500362 TI - Computationally-Guided Development of a Stromal Inflammation Histologic Biomarker in Lung Squamous Cell Carcinoma. AB - The goal of this study is to use computational pathology to help guide the development of human-based prognostic H&E biomarker(s) suitable for research and potential clinical use in lung squamous cell carcinoma (SCC). We started with high-throughput computational image analysis with tissue microarrays (TMAs) to screen for histologic features associated with patient overall survival, and found that features related to stromal inflammation were the most strongly prognostic. Based on this, we developed an H&E stromal inflammation (SI) score. The prognostic value of the SI score was validated by two blinded human observers on two large cohorts from a single institution. The SI score was found to be reproducible on TMAs (Spearman rho = 0.88 between the two observers), and highly prognostic (e.g. hazard ratio = 0.32; 95% confidence interval: 0.19-0.54; p-value = 2.5 * 10-5 in multivariate analyses), particularly in comparison to established histologic biomarkers. Guided by downstream molecular/biomarker correlation studies starting with TCGA cases, we investigated the hypothesis that epithelial PD-L1 expression modified the prognostic value of SI. Our research demonstrates that computational pathology can be an efficient hypothesis generator for human pathology research, and support the histologic evaluation of SI as a prognostic biomarker in lung SCCs. PMID- 29500363 TI - Enhanced insulin receptor, but not PI3K, signalling protects podocytes from ER stress. AB - Disruption of the insulin-PI3K-Akt signalling pathway in kidney podocytes causes endoplasmic reticulum (ER) stress, leading to podocyte apoptosis and proteinuria in diabetic nephropathy. We hypothesised that by improving insulin sensitivity we could protect podocytes from ER stress. Here we use established activating transcription factor 6 (ATF6)- and ER stress element (ERSE)-luciferase assays alongside a novel high throughput imaging-based C/EBP homologous protein (CHOP) assay to examine three models of improved insulin sensitivity. We find that by improving insulin sensitivity at the level of the insulin receptor (IR), either by IR over-expression or by knocking down the negative regulator of IR activity, protein tyrosine-phosphatase 1B (PTP1B), podocytes are protected from ER stress caused by fatty acids or diabetic media containing high glucose, high insulin and inflammatory cytokines TNFalpha and IL-6. However, contrary to this, knockdown of the negative regulator of PI3K-Akt signalling, phosphatase and tensin homolog deleted from chromosome 10 (PTEN), sensitizes podocytes to ER stress and apoptosis, despite increasing Akt phosphorylation. This indicates that protection from ER stress is conferred through not just the PI3K-Akt pathway, and indeed we find that inhibiting the MEK/ERK signalling pathway rescues PTEN knockdown podocytes from ER stress. PMID- 29500364 TI - Simultaneous induction and blockade of autophagy by a single agent. AB - Besides cell death, autophagy and cell senescence are the main outcomes of anticancer treatment. We demonstrate that tacrine-melatonin heterodimer C10, a potent anti-Alzheimer's disease drug, has an antiproliferative effect on MCF-7 breast cancer cells. The main cell response to a 24 h-treatment with C10 was autophagy enhancement accompanied by inhibition of mTOR and AKT pathways. Significantly increased autophagy markers, such as LC3B- and ATG16L-positive vesicles, confirmed autophagy induction by C10. However, analysis of autophagic flux using mCherry-GFP-LC3B construct revealed inhibition of autophagy by C10 at the late-stage. Moreover, electron microscopy and analysis of colocalization of LC3B and LAMP-1 proteins provided evidence of autophagosome-lysosome fusion with concomitant inhibition of autolysosomal degradation function. After transient treatment with IC50 dose of C10 followed by cell culture without the drug, 20% of MCF-7 cells displayed markers of senescence. On the other hand, permanent cell treatment with C10 resulted in massive cell death on the 5th or 6th day. Recently, an approach whereby autophagy is induced by one compound and simultaneously blocked by the use of another one has been proposed as a novel anticancer strategy. We demonstrate that the same effect may be achieved using a single agent, C10. Our findings offer a new, promising strategy for anticancer treatment. PMID- 29500365 TI - Green synthesis of gold nanoparticles by thermophilic filamentous fungi. AB - Alternative methods, including green synthetic approaches for the preparation of various types of nanoparticles are important to maintain sustainable development. Extracellular or intracellular extracts of fungi are perfect candidates for the synthesis of metal nanoparticles due to the scalability and cost efficiency of fungal growth even on industrial scale. There are several methods and techniques that use fungi-originated fractions for synthesis of gold nanoparticles. However, there is less knowledge about the drawbacks and limitations of these techniques. Additionally, identification of components that play key roles in the synthesis is challenging. Here we show and compare the results of three different approaches for the synthesis of gold nanoparticles using either the extracellular fraction, the autolysate of the fungi or the intracellular fraction of 29 thermophilic fungi. We observed the formation of nanoparticles with different sizes (ranging between 6 nm and 40 nm) and size distributions (with standard deviations ranging between 30% and 70%) depending on the fungi strain and experimental conditions. We found by using ultracentrifugal filtration technique that the size of reducing agents is less than 3 kDa and the size of molecules that can efficiently stabilize nanoparticles is greater than 3 kDa. PMID- 29500366 TI - Deletion of the Syncytin A receptor Ly6e impairs syncytiotrophoblast fusion and placental morphogenesis causing embryonic lethality in mice. AB - Fetal growth and survival is dependent on the elaboration and propinquity of the fetal and maternal circulations within the placenta. Central to this is the formation of the interhaemal membrane, a multi-cellular lamina facilitating exchange of oxygen, nutrients and metabolic waste products between the mother and fetus. In rodents, this cellular barrier contains two transporting layers of syncytiotrophoblast, which are multinucleated cells that form by cell-cell fusion. Previously, we reported the expression of the GPI-linked cell surface protein LY6E by the syncytial layer closest to the maternal sinusoids of the mouse placenta (syncytiotrophoblast layer I). LY6E has since been shown to be a putative receptor for the fusogenic protein responsible for fusion of syncytiotrophoblast layer I, Syncytin A. In this report, we demonstrate that LY6E is essential for the normal fusion of syncytiotrophoblast layer I, and for the proper morphogenesis of both fetal and maternal vasculatures within the placenta. Furthermore, specific inactivation of Ly6e in the epiblast, but not in placenta, is compatible with embryonic development, indicating the embryonic lethality reported for Ly6e-/- embryos is most likely placental in origin. PMID- 29500367 TI - SESN2 negatively regulates cell proliferation and casein synthesis by inhibition the amino acid-mediated mTORC1 pathway in cow mammary epithelial cells. AB - Amino acids (AA) are one of the key nutrients that regulate cell proliferation and casein synthesis in cow mammary epithelial cells (CMEC), but the mechanism of this regulation is not yet clear. In this study, the effect of SESN2 on AA mediated cell proliferation and casein synthesis in CMEC was assessed. After 12 h of AA starvation, CMECs were cultured in the absence of all AA (AA-), in the presences of only essential AA (EAA+), or of all AA (AA+). Cell proliferation, casein expression, and activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway were increased; but SESN2 expression was decreased in response to increased EAA or AA supply. Overexpressing or inhibiting SESN2 demonstrated that cell proliferation, casein expression, and activation of the mTORC1 pathway were all controlled by SESN2 expression. Furthermore, the increase in cell proliferation, casein expression, and activation of the mTORC1 pathway in response to AA supply was inhibited by overexpressing SESN2, and those effects were reversed by inhibiting SESN2. These results indicate that SESN2 is an important inhibitor of mTORC1 in CMEC blocking AA-mediated cell proliferation and casein synthesis. PMID- 29500368 TI - Observation of microwave absorption and emission from incoherent electron tunneling through a normal-metal-insulator-superconductor junction. AB - We experimentally study nanoscale normal-metal-insulator-superconductor junctions coupled to a superconducting microwave resonator. We observe that bias-voltage controllable single-electron tunneling through the junctions gives rise to a direct conversion between the electrostatic energy and that of microwave photons. The measured power spectral density of the microwave radiation emitted by the resonator exceeds at high bias voltages that of an equivalent single-mode radiation source at 2.5 K although the phonon and electron reservoirs are at subkelvin temperatures. Measurements of the generated power quantitatively agree with a theoretical model in a wide range of bias voltages. Thus, we have developed a microwave source which is compatible with low-temperature electronics and offers convenient in-situ electrical control of the incoherent photon emission rate with a predetermined frequency, without relying on intrinsic voltage fluctuations of heated normal-metal components or suffering from unwanted losses in room temperature cables. Importantly, our observation of negative generated power at relatively low bias voltages provides a novel type of verification of the working principles of the recently discovered quantum-circuit refrigerator. PMID- 29500369 TI - Mahanine drives pancreatic adenocarcinoma cells into endoplasmic reticular stress mediated apoptosis through modulating sialylation process and Ca2+-signaling. AB - Endoplasmic reticulum (ER) stress results from protein unfolding/misfolding during cellular maturation, which requires a coordinated action of several chaperones and enzymes and Ca2+ signalling. ER-stress possibly has a positive effect on survival of pancreatic cancer cell. Therefore, detailed insights into this complex signaling network are urgently needed. Here, we systematically analyzed the impact of ER stress-mediated unfolded protein response (UPR) and Ca2+-signaling cross-talk for the survival of pancreatic adenocarcinoma (PDAC) cells. We observed enhanced ER activity and initiation of UPR signaling induced by a carbazole alkaloid (mahanine). This event triggers a time-dependent increase of intracellular Ca2+ leakage from ER and subsequently Ca2+ signaling induced by enhanced reactive oxygen species (ROS) produced by this pro-oxidant agent. In addition, we observed an altered glycosylation, in particular with regard to reduced linkage-specific sialic acids possibly due to decreased sialyltransferase activity. Changes in sialylation entailed enhanced expression of the ganglioside GD3 in the treated cells. GD3, an inducer of apoptosis, inhibited pancreatic xenograft tumor. Taken together, our study describes a molecular scenario how PDAC cells are driven into apoptosis by mahanine by UPR-driven ER stress associated and ROS-mediated calcium signaling and possibly defective sialylation. PMID- 29500370 TI - Common variants of ARID1A and KAT2B are associated with obesity in Indian adolescents. AB - Obesity involves alterations in transcriptional programs that can change in response to genetic and environmental signals through chromatin modifications. Since chromatin modifications involve different biochemical, neurological and molecular signaling pathways related to energy homeostasis, we hypothesize that genetic variations in chromatin modifier genes can predispose to obesity. Here, we assessed the associations between 179 variants in 35 chromatin modifier genes and overweight/obesity in 1283 adolescents (830 normal weight and 453 overweight/obese). This was followed up by the replication analysis of associated signals (18 variants in 8 genes) in 2247 adolescents (1709 normal weight and 538 overweight/obese). Our study revealed significant associations of two variants rs6598860 (OR = 1.27, P = 1.58 * 10-4) and rs4589135 (OR = 1.22, P = 3.72 * 10-4) in ARID1A with overweight/obesity. We also identified association of rs3804562 (beta = 0.11, P = 1.35 * 10-4) in KAT2B gene with BMI. In conclusion, our study suggests a potential role of ARID1A and KAT2B genes in the development of obesity in adolescents and provides leads for further investigations. PMID- 29500371 TI - Assessing the Heterogeneity of the Fc-Glycan of a Therapeutic Antibody Using an engineered FcgammaReceptor IIIa-Immobilized Column. AB - The N-glycan moiety of IgG-Fc has a significant impact on multifaceted properties of antibodies such as in their effector function, structure, and stability. Numerous studies have been devoted to understanding its biological effect since the exact composition of the Fc N-glycan modulates the magnitude of effector functions such as the antibody-dependent cell mediated cytotoxicity (ADCC), and the complement-dependent cytotoxicity (CDC). To date, systematic analyses of the properties and influence of glycan variants have been of great interest. Understanding the principles on how N-glycosylation modulates those properties is important for the molecular design, manufacturing, process optimization, and quality control of therapeutic antibodies. In this study, we have separated a model therapeutic antibody into three fractions according to the composition of the N-glycan by using a novel FcgammaRIIIa chromatography column. Notably, Fc galactosylation was a major factor influencing the affinity of IgG-Fc to the FcgammaRIIIa immobilized on the column. Each antibody fraction was employed for structural, biological, and physicochemical analysis, illustrating the mechanism by which galactose modulates the affinity to FcgammaRIIIa. In addition, we discuss the benefits of the FcgammaRIIIa chromatography column to assess the heterogeneity of the N-glycan. PMID- 29500372 TI - Antimycobacterial drug discovery using Mycobacteria-infected amoebae identifies anti-infectives and new molecular targets. AB - Tuberculosis remains a serious threat to human health world-wide, and improved efficiency of medical treatment requires a better understanding of the pathogenesis and the discovery of new drugs. In the present study, we performed a whole-cell based screen in order to complete the characterization of 168 compounds from the GlaxoSmithKline TB-set. We have established and utilized novel previously unexplored host-model systems to characterize the GSK compounds, i.e. the amoeboid organisms D. discoideum and A. castellanii, as well as a microglial phagocytic cell line, BV2. We infected these host cells with Mycobacterium marinum to monitor and characterize the anti-infective activity of the compounds with quantitative fluorescence measurements and high-content microscopy. In summary, 88.1% of the compounds were confirmed as antibiotics against M. marinum, 11.3% and 4.8% displayed strong anti-infective activity in, respectively, the mammalian and protozoan infection models. Additionally, in the two systems, 13 14% of the compounds displayed pro-infective activity. Our studies underline the relevance of using evolutionarily distant pathogen and host models in order to reveal conserved mechanisms of virulence and defence, respectively, which are potential "universal" targets for intervention. Subsequent mechanism of action studies based on generation of over-expresser M. bovis BCG strains, generation of spontaneous resistant mutants and whole genome sequencing revealed four new molecular targets, including FbpA, MurC, MmpL3 and GlpK. PMID- 29500373 TI - Structure based function-annotation of hypothetical protein MGG_01005 from Magnaporthe oryzae reveals it is the dynein light chain orthologue of dynlt1/3. AB - Magnaporthe oryzae is a model fungal plant pathogen employed for studying plant fungi interactions. Whole genome sequencing and bioinformatics analyses revealed that this fungal pathogen has more than 12,000 protein-coding genes with 65% of the genes remaining functionally un-annotated. Here, we determine the structure of the hypothetical protein, MGG_01005 and show that it is the Magnaporthe oryzae Dynein light chain Tctex-type 1 (dynlt1/3), demonstrated by its structural similarity to other orthologous dynlt1 proteins and its conserved interaction with the N-terminus of the Magnaporthe oryzae dynein intermediate chain, MoDyn1I2. In addition, we present the structure of the MGG_01005-MoDyn1I2 complex together with mutagenesis studies that reveals a di-histidine motif interaction with a glutamate residue in the dynein intermediate chain within a conserved molecular interface. These results demonstrate the utility of structure-based annotation and validate it as a viable approach for the molecular assignment of hypothetic proteins from phyto-pathogenic fungi. PMID- 29500374 TI - Replica molding-based nanopatterning of tribocharge on elastomer with application to electrohydrodynamic nanolithography. AB - Replica molding often induces tribocharge on elastomers. To date, this phenomenon has been studied only on untextured elastomer surfaces even though replica molding is an effective method for their nanotexturing. Here we show that on elastomer surfaces nanotextured through replica molding the induced tribocharge also becomes patterned at nanoscale in close correlation with the nanotexture. By applying Kelvin probe microscopy, electrohydrodynamic lithography, and electrostatic analysis to our model nanostructure, poly(dimethylsiloxane) nanocup arrays replicated from a polycarbonate nanocone array, we reveal that the induced tribocharge is highly localized within the nanocup, especially around its rim. Through finite element analysis, we also find that the rim sustains the strongest friction during the demolding process. From these findings, we identify the demolding-induced friction as the main factor governing the tribocharge's nanoscale distribution pattern. By incorporating the resulting annular tribocharge into electrohydrodynamic lithography, we also accomplish facile realization of nanovolcanos with 10 nm-scale craters. PMID- 29500375 TI - A machine learning approach for automated assessment of retinal vasculature in the oxygen induced retinopathy model. AB - Preclinical studies of vascular retinal diseases rely on the assessment of developmental dystrophies in the oxygen induced retinopathy rodent model. The quantification of vessel tufts and avascular regions is typically computed manually from flat mounted retinas imaged using fluorescent probes that highlight the vascular network. Such manual measurements are time-consuming and hampered by user variability and bias, thus a rapid and objective method is needed. Here, we introduce a machine learning approach to segment and characterize vascular tufts, delineate the whole vasculature network, and identify and analyze avascular regions. Our quantitative retinal vascular assessment (QuRVA) technique uses a simple machine learning method and morphological analysis to provide reliable computations of vascular density and pathological vascular tuft regions, devoid of user intervention within seconds. We demonstrate the high degree of error and variability of manual segmentations, and designed, coded, and implemented a set of algorithms to perform this task in a fully automated manner. We benchmark and validate the results of our analysis pipeline using the consensus of several manually curated segmentations using commonly used computer tools. The source code of our implementation is released under version 3 of the GNU General Public License ( https://www.mathworks.com/matlabcentral/fileexchange/65699-javimazzaf qurva ). PMID- 29500376 TI - Mass spectrometry and multivariate analysis to classify cervical intraepithelial neoplasia from blood plasma: an untargeted lipidomic study. AB - Cervical cancer is still an important issue of public health since it is the fourth most frequent type of cancer in women worldwide. Much effort has been dedicated to combating this cancer, in particular by the early detection of cervical pre-cancerous lesions. For this purpose, this paper reports the use of mass spectrometry coupled with multivariate analysis as an untargeted lipidomic approach to classifying 76 blood plasma samples into negative for intraepithelial lesion or malignancy (NILM, n = 42) and squamous intraepithelial lesion (SIL, n = 34). The crude lipid extract was directly analyzed with mass spectrometry for untargeted lipidomics, followed by multivariate analysis based on the principal component analysis (PCA) and genetic algorithm (GA) with support vector machines (SVM), linear (LDA) and quadratic (QDA) discriminant analysis. PCA-SVM models outperformed LDA and QDA results, achieving sensitivity and specificity values of 80.0% and 83.3%, respectively. Five types of lipids contributing to the distinction between NILM and SIL classes were identified, including prostaglandins, phospholipids, and sphingolipids for the former condition and Tetranor-PGFM and hydroperoxide lipid for the latter. These findings highlight the potentiality of using mass spectrometry associated with chemometrics to discriminate between healthy women and those suffering from cervical pre cancerous lesions. PMID- 29500377 TI - Acceleration of phenological advance and warming with latitude over the past century. AB - In the Northern Hemisphere, springtime events are frequently reported as advancing more rapidly at higher latitudes, presumably due to an acceleration of warming with latitude. However, this assumption has not been investigated in an analytical framework that simultaneously examines acceleration of warming with latitude while accounting for variation in phenological time series characteristics that might also co-vary with latitude. We analyzed 743 phenological trend estimates spanning 86 years and 42.6 degrees of latitude in the Northern Hemisphere, as well as rates of Northern Hemisphere warming over the same period and latitudinal range. We detected significant patterns of co variation in phenological time series characteristics that may confound estimates of the magnitude of variation in trends with latitude. Notably, shorter and more recent time series tended to produce the strongest phenological trends, and these also tended to be from higher latitude studies. However, accounting for such variation only slightly modified the relationship between rates of phenological advance and latitude, which was highly significant. Furthermore, warming has increased non-linearly with latitude over the past several decades, most strongly since 1998 and northward of 59 degrees N latitude. The acceleration of warming with latitude has likely contributed to an acceleration of phenological advance along the same gradient. PMID- 29500379 TI - Author Correction: Immune system deregulation in hypertensive patients chronically RAS suppressed developing albuminuria. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29500378 TI - Next generation sequencing reveals changes of the gammadelta T cell receptor repertoires in patients with pulmonary tuberculosis. AB - Tuberculosis (TB) is a severe global threat to human health. The immune protection initiated by gammadelta T cells play an important role in mycobacterial infection. Vaccines for Mycobacterium tuberculosis (Mtb) based on gammadelta T cells provide a novel approach for TB control. In our previous studies, we found a preponderant complementarity-determining region 3 (CDR3) sequence of the gammadelta T cell receptor (TCR) in TB patients, and successfully identified a tuberculosis antigen that can effectively activate gammadelta T cells with a reverse genetic strategy. However, due to the throughput limitation of the method we used, the information we obtained about the gammadelta TCR repertoire and preponderant CDR3 sequences was limited. In this study, we introduced next generation sequencing (NGS) to study the gammadelta TCR CDR3 repertoires in TB patients. We found that the CDR3delta tended to be more polyclonal and CDR3gamma tended to be longer in TB patients; the gammadelta T cells expressing CDR3 sequences using a Vgamma9-JgammaP rearrangement expanded significantly during Mtb infection. We also identified new preponderant CDR3 sequences during Mtb infection. This study comprehensively characterized the gammadelta T cell receptor repertoire changes, and provides useful information for the development of new vaccines and adjuvants against TB. PMID- 29500380 TI - Comparison of the diagnostic accuracy of cone beam computed tomography and radiography for scaphoid fractures. AB - The aim of this study was to evaluate and compare the diagnostic accuracy, the inter-rater agreement and raters' certainty of cone beam computed tomography (CBCT) and radiography for the detection of scaphoid fractures. Our hypothesis is that the CBCT has a higher diagnostic accuracy for scaphoid fractures than radiography. We retrospectively analysed patients who underwent both radiography and CBCT examinations within 4 days to rule out a scaphoid fracture over a 2-year period in our institution. 4 blinded radiologists and orthopaedic surgeons independently rated the images regarding the presence of a scaphoid fracture. The reference standard was evaluated by two radiologists in a consensus reading. Inter-rater correlation was evaluated, pooled sensitivity, specificity, positive and negative predictive values were calculated and compared. 102 patients met the inclusion criteria. 52% of them had a scaphoid fracture. The inter-rater correlation was higher in the CBCT compared to radiography (P < 0.001). Sensitivity, specificity, positive and negative predictive values were higher for CBCT than for radiography (P < 0.019). Observers' fracture classifications showed a higher correlation with the reference standard in the CBCT. Observers' certainty for fracture detection and classification were higher in the CBCT. CBCT shows a higher diagnostic accuracy for scaphoid fractures than radiography. PMID- 29500381 TI - gDNA qPCR is statistically more reliable than mRNA analysis in detecting leukemic cells to monitor CML. AB - Chronic Myeloid Leukemia (CML) is a stem cell cancer that arises when t(9;22) translocation occurs in a hematopoietic stem cells. This event results in the expression of the BCR-ABL1 fusion gene, which codes for a constitutively active tyrosine kinase that is responsible for the transformation of a HSC into a CML stem cell, which then gives rise to a clonal myeloproliferative disease. The introduction of Tyrosine Kinase Inhibitors (TKIs) has revolutionized the management of the disease. However, these drugs do not seem to be able to eradicate the malignancy. Indeed, discontinuation trials (STIM; TWISER; DADI) for those patients who achieved a profound molecular response showed 50% relapsing within 12 months. We performed a comparative analysis on 15 CML patients and one B-ALL patient, between the standard quantitative reverse-transcriptase PCR (qRT PCR) and our genomic DNA patient-specific quantitative PCR assay (gDNA qPCR). Here we demonstrate that gDNA qPCR is better than standard qRT-PCR in disease monitoring after an average follow-up period of 200 days. Specifically, we statistically demonstrated that DNA negativity is more reliable than RNA negativity in indicating when TKIs therapy can be safely stopped. PMID- 29500382 TI - Item-level analyses reveal genetic heterogeneity in neuroticism. AB - Genome-wide association studies (GWAS) of psychological traits are generally conducted on (dichotomized) sums of items or symptoms (e.g., case-control status), and not on the individual items or symptoms themselves. We conduct large scale GWAS on 12 neuroticism items and observe notable and replicable variation in genetic signal between items. Within samples, genetic correlations among the items range between 0.38 and 0.91 (mean rg = .63), indicating genetic heterogeneity in the full item set. Meta-analyzing the two samples, we identify 255 genome-wide significant independent genomic regions, of which 138 are item specific. Genetic analyses and genetic correlations with 33 external traits support genetic differences between the items. Hierarchical clustering analysis identifies two genetically homogeneous item clusters denoted depressed affect and worry. We conclude that the items used to measure neuroticism are genetically heterogeneous, and that biological understanding can be gained by studying them in genetically more homogeneous clusters. PMID- 29500383 TI - A CREB2-targeting microRNA is required for long-term memory after single-trial learning. AB - Although single-trial induced long-term memories (LTM) have been of major interest in neuroscience, how LTM can form after a single episode of learning remains largely unknown. We hypothesized that the removal of molecular inhibitory constraints by microRNAs (miRNAs) plays an important role in this process. To test this hypothesis, first we constructed small non-coding RNA (sncRNA) cDNA libraries from the CNS of Lymnaea stagnalis subjected to a single conditioning trial. Then, by next generation sequencing of these libraries, we identified a specific pool of miRNAs regulated by training. Of these miRNAs, we focussed on Lym-miR-137 whose seed region shows perfect complementarity to a target sequence in the 3' UTR of the mRNA for CREB2, a well-known memory repressor. We found that Lym-miR-137 was transiently up-regulated 1 h after single-trial conditioning, preceding a down-regulation of Lym-CREB2 mRNA. Furthermore, we discovered that Lym-miR-137 is co-expressed with Lym-CREB2 mRNA in an identified neuron with an established role in LTM. Finally, using an in vivo loss-of-function approach we demonstrated that Lym-miR-137 is required for single-trial induced LTM. PMID- 29500384 TI - High Sensitivity of T-Ray for Thrombus Sensing. AB - Atherosclerotic plaque rupture or erosion and subsequent development of platelet containing thrombus formation is the fundamental cause of cardiovascular disease, which is the most common cause of death and disability worldwide. Here we show the high sensitivity of 200-270 GHz T-ray to distinguish thrombus formation at its early stage from uncoagulated blood. A clinical observational study was conducted to longitudinally monitor the T-ray absorption constant of ex-vivo human blood during the thrombus formation from 29 subjects. Compared with the control group (28 subjects) with uncoagulated blood samples, our analysis indicates the high sensitivity of 200-270 GHz T-Ray to detect thrombus with a low p-value < 10-5. Further analysis supports the significant role of platelet activated thrombotic cascade, which modified the solvation dynamics of blood and occurred during the early coagulation stage, on the measured T-Ray absorption change. The ability to sense the thrombus formation at its early stage would hold promise for timely identification of patients at risk of various atherothrombotic disorders and save billions of lives. PMID- 29500385 TI - Author Correction: Human Sexual Cycles are Driven by Culture and Match Collective Moods. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29500386 TI - Ductile and brittle transition behavior of titanium alloys in ultra-precision machining. AB - Titanium alloys are extensively applied in biomedical industries due to their excellent material properties. However, they are recognized as difficult to cut materials due to their low thermal conductivity, which induces a complexity to their deformation mechanisms and restricts precise productions. This paper presents a new observation about the removal regime of titanium alloys. The experimental results, including the chip formation, thrust force signal and surface profile, showed that there was a critical cutting distance to achieve better surface integrity of machined surface. The machined areas with better surface roughness were located before the clear transition point, defining as the ductile to brittle transition. The machined area at the brittle region displayed the fracture deformation which showed cracks on the surface edge. The relationship between depth of cut and the ductile to brittle transaction behavior of titanium alloys in ultra-precision machining(UPM) was also revealed in this study, it showed that the ductile to brittle transaction behavior of titanium alloys occurred mainly at relatively small depth of cut. The study firstly defines the ductile to brittle transition behavior of titanium alloys in UPM, contributing the information of ductile machining as an optimal machining condition for precise productions of titanium alloys. PMID- 29500388 TI - Ferromagnetic domain walls as spin wave filters and the interplay between domain walls and spin waves. AB - Spin waves (SW) are low energy excitations of magnetization in magnetic materials. In the promising field of magnonics, fundamental SW modes, magnons, are accessible in magnetic nanostructure waveguides and carry information. The SW propagates in both metals and insulators via magnetization dynamics. Energy dissipation through damping can be low compared to the Joule heating in conventional circuits. We performed simulations in a quasi-one-dimensional ferromagnetic strip and found that the transmission of the propagating SW across the domain wall (DW) depends strongly on the tilt angle of the magnetization at low frequencies. When the SW amplitude is large, the magnetization tilt angle inside the DW changes due to the effective fields. The SW transmission, the DW motion, and the magnetization tilt angle couple to each other, which results in complex DW motion and SW transmission. Both SW filtering and DW motions are key ingredients in magnonics. PMID- 29500387 TI - Global phenotypic characterisation of human platelet lysate expanded MSCs by high throughput flow cytometry. AB - Mesenchymal stromal cells (MSCs) are a promising cell source to develop cell therapy for many diseases. Human platelet lysate (PLT) is increasingly used as an alternative to foetal calf serum (FCS) for clinical-scale MSC production. To date, the global surface protein expression of PLT-expended MSCs (MSC-PLT) is not known. To investigate this, paired MSC-PLT and MSC-FCS were analysed in parallel using high-throughput flow cytometry for the expression of 356 cell surface proteins. MSC-PLT showed differential surface protein expression compared to their MSC-FCS counterpart. Higher percentage of positive cells was observed in MSC-PLT for 48 surface proteins, of which 13 were significantly enriched on MSC PLT. This finding was validated using multiparameter flow cytometry and further confirmed by quantitative staining intensity analysis. The enriched surface proteins are relevant to increased proliferation and migration capacity, as well as enhanced chondrogenic and osteogenic differentiation properties. In silico network analysis revealed that these enriched surface proteins are involved in three distinct networks that are associated with inflammatory responses, carbohydrate metabolism and cellular motility. This is the first study reporting differential cell surface protein expression between MSC-PLT and MSC-FSC. Further studies are required to uncover the impact of those enriched proteins on biological functions of MSC-PLT. PMID- 29500389 TI - Multi-modal survey of Adelie penguin mega-colonies reveals the Danger Islands as a seabird hotspot. AB - Despite concerted international effort to track and interpret shifts in the abundance and distribution of Adelie penguins, large populations continue to be identified. Here we report on a major hotspot of Adelie penguin abundance identified in the Danger Islands off the northern tip of the Antarctic Peninsula (AP). We present the first complete census of Pygoscelis spp. penguins in the Danger Islands, estimated from a multi-modal survey consisting of direct ground counts and computer-automated counts of unmanned aerial vehicle (UAV) imagery. Our survey reveals that the Danger Islands host 751,527 pairs of Adelie penguins, more than the rest of AP region combined, and include the third and fourth largest Adelie penguin colonies in the world. Our results validate the use of Landsat medium-resolution satellite imagery for the detection of new or unknown penguin colonies and highlight the utility of combining satellite imagery with ground and UAV surveys. The Danger Islands appear to have avoided recent declines documented on the Western AP and, because they are large and likely to remain an important hotspot for avian abundance under projected climate change, deserve special consideration in the negotiation and design of Marine Protected Areas in the region. PMID- 29500391 TI - Temperature- and field-driven spin reorientations in triple-layer ruthenate Sr4Ru3O10. AB - Sr4Ru3O10, the n = 3 member of the Ruddlesden-Popper type ruthenate Srn+1Ru n O3n+1, is known to exhibit a peculiar metamagnetic transition in an in-plane magnetic field. However, the nature of both the temperature- and field-dependent phase transitions remains as a topic of debate. Here, we have investigated the magnetic transitions of Sr4Ru3O10 via single-crystal neutron diffraction measurements. At zero field, we find that the system undergoes a ferromagnetic transition with both in-plane and out-of-plane magnetic components at Tc ~ 100 K. Below T * = 50 K, the magnetic moments incline continuously toward the out-of plane direction. At T = 1.5 K, where the spins are nearly aligned along the c axis, a spin reorientation occurs above a critical field Bc, giving rise to a spin component perpendicular to the plane defined by the field direction and the c axis. We suggest that both the temperature- and field-driven spin reorientations are associated with a change in the magnetocrystalline anisotropy, which is strongly coupled to the lattice degrees of freedom. This study elucidates the long-standing puzzles on the zero-field magnetic orders of Sr4Ru3O10 and provides new insights into the nature of the field-induced metamagnetic transition. PMID- 29500390 TI - Development of an Injectable Slow-Release Metformin Formulation and Evaluation of Its Potential Antitumor Effects. AB - Metformin is an antidiabetic drug which possesses antiproliferative activity in cancer cells when administered at high doses, due to its unfavorable pharmacokinetics. The aim of this work was to develop a pharmacological tool for the release of metformin in proximity of the tumor, allowing high local concentrations, and to demonstrate the in vivo antitumor efficacy after a prolonged metformin exposition. A 1.2% w/w metformin thermoresponsive parenteral formulation based on poloxamers P407 and P124, injectable at room temperature and undergoing a sol-gel transition at body temperature, has been developed and optimized for rheological, thermal and release control properties; the formulation is easily scalable, and proved to be stable during a 1-month storage at 5 degrees C. Using NOD/SCID mice pseudo-orthotopically grafted with MDA-MB 231/luc+ human breast cancer cells, we report that multiple administrations of 100 mg of the optimized metformin formulation close to the tumor site cause tissue accumulation of the drug at levels significantly higher than those observed in plasma, and enough to exert antiproliferative and pro-apoptotic activities. Our results demonstrate that this formulation is endowed with good stability, tolerability, thermal and rheological properties, representing a novel tool to be pursued in further investigations for adjuvant cancer treatment. PMID- 29500392 TI - Early relapsed disease of multiple myeloma following up-front HDM-ASCT: a study based on the Danish Multiple Myeloma Registry in the period 2005 to 2014. PMID- 29500393 TI - Essential oils and their components are a class of antifungals with potent vapour phase-mediated anti-Candida activity. AB - Multi-resistant microorganisms continue to challenge medicine and fuel the search for new antimicrobials. Here we show that essential oils and their components are a promising class of antifungals that can have specific anti-Candida activity via their vapour-phase. We quantify the vapour-phase-mediated antimicrobial activity (VMAA) of 175 essential oils and 37 essential oil components, representing more than a 1,000 unique molecules, against C. albicans and C. glabrata in a novel vapour-phase-mediated susceptibility assay. Approximately half of the tested essential oils and their components show growth-inhibitory VMAA. Moreover, an average greater activity was observed against the intrinsically more resistant C. glabrata, with essential oil component citronellal having a highly significant differential VMAA. In contrast, representatives of each class of antifungals currently used in clinical practice showed no VMAA. The vapour-phase-mediated susceptibility assay presented here thus allows for the simple detection of VMAA and can advance the search for novel (applications of existing) antimicrobials. This study represents the first comprehensive characterisation of essential oils and their components as a unique class of antifungals with antimicrobial properties that differentiate them from existing antifungal classes. PMID- 29500394 TI - miR-27b regulates myogenic proliferation and differentiation by targeting Pax3 in goat. AB - This study found that miR-27 is expressed in muscle and regulates muscle proliferation and differentiation. We explored the function and regulatory mechanism of miR-27b in goat muscle proliferation and differentiation. Compared with the Boer goat, higher expression of miR-27b was observed in all of the collected muscle tissues of Anhuai goat, excluding the kidney, whereas the opposite expression pattern was observed for Pax3, which showed lower expression in Anhuai goat. Expression of miR-27b decreased gradually during the proliferation of skeletal muscle satellite cells in Anhuai goat and increased during differentiation; however, the expression pattern of Pax3 was opposite. The regulatory activity of miR-27b demonstrated that miR-27b inhibited the proliferation of skeletal muscle satellite cells, but promoted their differentiation. Moreover, function research demonstrated that Pax3 negatively regulated myogenic differentiation of goat skeletal muscle satellite cells, but accelerated their proliferation. The results of a dual-luciferase reporter analysis showed that miR-27b directly targeted the 3'-untranslated regions of Pax3 mRNA, and western blot and immunofluorescence staining analyses showed that miR-27b inhibited expression of the Pax3 protein. In goats, miR-27b can regulate myogenic proliferation and differentiation by targeting Pax3. PMID- 29500395 TI - Origin, Maintenance and Variability of the Asian Tropopause Aerosol Layer (ATAL): The Roles of Monsoon Dynamics. AB - Using NASA MERRA2 daily data, we investigated the origin, maintenance and variability of the Asian Tropopause Aerosol Layer (ATAL) in relation to variations of the Asia Monsoon Anticyclone (AMA) during the summer of 2008. During May-June, abundant quantities of carbon monoxide (CO), carbonaceous aerosols (CA) and dusts are found in the mid- and upper troposphere over India and China, arising from enhanced biomass burning emissions, as well as westerly transport from the Middle East deserts. During July-August, large quantities of dusts transported from the deserts are trapped and accumulate over the southern and eastern foothills of the Tibetan Plateau. Despite strong precipitation washout, ambient CO, CA and dust are lofted by orographically forced deep convection to great elevations, 12-16 km above sea level, via two key pathways over heavily polluted regions: a) the Himalayas-Gangetic Plain, and b) the Sichuan Basin. Upon entering the upper-troposphere-lower-stratosphere, the pollutants are capped by a stable layer near the tropopause, advected and dispersed by the anticyclonic circulation of AMA, forming the ATAL resembling a planetary-scale "double-stem chimney cloud". The development and variability of the ATAL are strongly linked to the seasonal march and intraseasonal (20-30 days and higher frequency) oscillations of the Asian monsoon. PMID- 29500396 TI - Retinal microvascular parameters are not associated with reduced renal function in a study of individuals with type 2 diabetes. AB - The eye provides an opportunistic "window" to view the microcirculation. There is published evidence of an association between retinal microvascular calibre and renal function measured by estimated glomerular filtration rate (eGFR) in individuals with diabetes mellitus. Beyond vascular calibre, few studies have considered other microvascular geometrical features. Here we report novel null findings for measures of vascular spread (vessel fractal dimension), tortuosity, and branching patterns and their relationship with renal function in type 2 diabetes over a mean of 3 years. We performed a nested case-control comparison of multiple retinal vascular parameters between individuals with type 2 diabetes and stable (non-progressors) versus declining (progressors) eGFR across two time points within a subset of 1072 participants from the GoDARTS study cohort. Retinal microvascular were measured using VAMPIRE 3.1 software. In unadjusted analyses and following adjustment for age, gender, systolic blood pressure, HbA1C, and diabetic retinopathy, no associations between baseline retinal vascular parameters and risk of eGFR progression were observed. Cross-sectional analysis of follow-up data showed a significant association between retinal arteriolar diameter and eGFR, but this was not maintained following adjustment. These findings are consistent with a lack of predictive capacity for progressive loss of renal function in type 2 diabetes. PMID- 29500397 TI - Publisher Correction: Controllable molecular motors engineered from myosin and RNA. AB - An incorrect Supplementary Information file was originally published. The file has been replaced with the correct one. PMID- 29500398 TI - A Printed Organic Amplification System for Wearable Potentiometric Electrochemical Sensors. AB - Electrochemical sensor systems with integrated amplifier circuits play an important role in measuring physiological signals via in situ human perspiration analysis. Signal processing circuitry based on organic thin-film transistors (OTFTs) have significant potential in realizing wearable sensor devices due to their superior mechanical flexibility and biocompatibility. Here, we demonstrate a novel potentiometric electrochemical sensing system comprised of a potassium ion (K+) sensor and amplifier circuits employing OTFT-based pseudo-CMOS inverters, which have a highly controllable switching voltage and closed-loop gain. The ion concentration sensitivity of the fabricated K+ sensor was 34 mV/dec, which was amplified to 160 mV/dec (by a factor of 4.6) with high linearity. The developed system is expected to help further the realization of ultra-thin and flexible wearable sensor devices for healthcare applications. PMID- 29500399 TI - Formation of size-dependent and conductive phase on lithium iron phosphate during carbon coating. AB - Carbon coating is a commonly employed technique for improving the conductivity of active materials in lithium ion batteries. The carbon coating process involves pyrolysis of organic substance on lithium iron phosphate particles at elevated temperature to create a highly reducing atmosphere. This may trigger the formation of secondary phases in the active materials. Here, we observe a conductive phase during the carbon coating process of lithium iron phosphate and the phase content is size, temperature, and annealing atmosphere dependent. The formation of this phase is related to the reducing capability of the carbon coating process. This finding can guide us to control the phase composition of carbon-coated lithium iron phosphate and to tune its quality during the manufacturing process. PMID- 29500400 TI - Loss of PTEN-assisted G2/M checkpoint impedes homologous recombination repair and enhances radio-curability and PARP inhibitor treatment response in prostate cancer. AB - Here we report that PTEN contributes to DNA double-strand break (DSB) repair via homologous recombination (HR), as evidenced by (i) inhibition of HR in a reporter plasmid assay, (ii) enhanced sensitivity to mitomycin-C or olaparib and (iii) reduced RAD51 loading at IR-induced DSBs upon PTEN knockdown. No association was observed between PTEN-status and RAD51 expression either in-vitro or in-vivo in a tissue microarray of 1500 PTEN-deficient prostate cancer (PC) samples. PTEN depletion and sustained activation of AKT sequestered CHK1 in the cytoplasm, thus impairing the G2/M-checkpoint after irradiation. Consistently, AKT inhibition recovered the G2/M-checkpoint and restored HR efficiency in PTEN-depleted cells. We show that, although PTEN loss correlates with a worse prognosis, it may predict for improved response of PC patients to radiotherapy. Further, we provide evidence for the use of PTEN as a biomarker for predicting the response to PARP inhibitors as radiosensitizing agents in prostate cancer. Collectively, these data implicate PTEN in maintaining genomic stability by delaying G2/M-phase progression of damaged cells, thus allowing time for DSB repair by HR. Furthermore, we identify PTEN-status in PC as a putative predictor of (i) radiotherapy response and (ii) response to treatment with PARP inhibitor alone or combined with radiotherapy. PMID- 29500401 TI - Transcription factor YY1 is essential for iNKT cell development. AB - Invariant natural killer T (iNKT) cells develop from CD4+CD8+ double-positive (DP) thymocytes and express an invariant Valpha14-Jalpha18 T-cell receptor (TCR) alpha-chain. Generation of these cells requires the prolonged survival of DP thymocytes to allow for Valpha14-Jalpha18 gene rearrangements and strong TCR signaling to induce the expression of the iNKT lineage-specific transcription factor PLZF. Here, we report that the transcription factor Yin Yang 1 (YY1) is essential for iNKT cell formation. Thymocytes lacking YY1 displayed a block in iNKT cell development at the earliest progenitor stage. YY1-deficient thymocytes underwent normal Valpha14-Jalpha18 gene rearrangements, but exhibited impaired cell survival. Deletion of the apoptotic protein BIM failed to rescue the defect in iNKT cell generation. Chromatin immunoprecipitation and deep-sequencing experiments demonstrated that YY1 directly binds and activates the promoter of the Plzf gene. Thus, YY1 plays essential roles in iNKT cell development by coordinately regulating cell survival and PLZF expression. PMID- 29500402 TI - Phenytoin inhibits necroptosis. AB - Receptor-interacting protein kinases 1 and 3 (RIPK1/3) have best been described for their role in mediating a regulated form of necrosis, referred to as necroptosis. During this process, RIPK3 phosphorylates mixed lineage kinase domain-like (MLKL) to cause plasma membrane rupture. RIPK3-deficient mice have recently been demonstrated to be protected in a series of disease models, but direct evidence for activation of necroptosis in vivo is still limited. Here, we sought to further examine the activation of necroptosis in kidney ischemia reperfusion injury (IRI) and from TNFalpha-induced severe inflammatory response syndrome (SIRS), two models of RIPK3-dependent injury. In both models, MLKL-ko mice were significantly protected from injury to a degree that was slightly, but statistically significantly exceeding that of RIPK3-deficient mice. We also demonstrated, for the first time, accumulation of pMLKL in the necrotic tubules of human patients with acute kidney injury. However, our data also uncovered unexpected elevation of blood flow in MLKL-ko animals, which may be relevant to IRI and should be considered in the future. To further understand the mode of regulation of cell death by MLKL, we screened a panel of clinical plasma membrane channel blockers and we found phenytoin to inhibit necroptosis. However, we further found that phenytoin attenuated RIPK1 kinase activity in vitro, likely due to the hydantoin scaffold also present in necrostatin-1, and blocked upstream necrosome formation steps in the cells undergoing necroptosis. We further report that this clinically used anti-convulsant drug displayed protection from kidney IRI and TNFalpha-induces SIRS in vivo. Overall, our data reveal the relevance of RIPK3-pMLKL regulation for acute kidney injury and identifies an FDA-approved drug that may be useful for immediate clinical evaluation of inhibition of pro death RIPK1/RIPK3 activities in human diseases. PMID- 29500403 TI - Author Correction: Human eyes with dilated pupils induce pupillary contagion in infants. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29500405 TI - Reconstructing vapor pressure deficit from leaf wax lipid molecular distributions. AB - Estimates of atmospheric moisture are critical for understanding the links and feedbacks between atmospheric CO2 and global climate. At present, there are few quantitative moisture proxies that are applicable to deep time. We present a new proxy for atmospheric moisture derived from modern climate and leaf biomarker data from North and Central America. Plants have a direct genetic pathway to regulate the production of lipids in response to osmotic stress, which is manifested in a change in the distribution of simple aliphatic lipids such as n alkanes. The Average Chain Length (ACL) of these lipids is therefore statistically related to mean annual vapor pressure deficit (VPDav), enabling quantitative reconstruction of VPD from sedimentary n-alkanes. We apply this transfer function to the Armantes section of the Calatayud-Daroca Basin in Central Spain, that spans the Middle Miocene Climatic Optimum (MMCO) and the Middle Miocene Climate Transition (MMCT). Reconstructed VPDav rises from 0.13 to 0.92 kPa between 16.5 and 12.4 Ma, indicating a substantial drying through the MMCT. These data are consistent with fossil assemblages and mammalian stable isotope data, highlighting the utility of this new organic molecular tool for quantifying hydrologic variability over geologic timescales. PMID- 29500404 TI - Comparison of diurnal blood pressure and urine production between people with and without chronic spinal cord injury. AB - STUDY DESIGN: Observational study. OBJECTIVES: To quantify diurnal blood pressure (BP) patterns and nocturnal hypertension and to measure diurnal urine production in people with chronic spinal cord injury (SCI), compared with controls without SCI. SETTING: Chronic SCI population in the community in Victoria, Australia. METHODS: Participants were recruited by advertisement, and sustained SCI at least a year prior or were healthy able-bodied volunteers. Participants underwent ambulatory BP monitoring (ABPM), measurement of urine production, and completed questionnaires regarding orthostatic symptoms. Comparisons were made between participants with tetraplegia or paraplegia and able-bodied controls. Participants with night:day systolic BP < 90% were classified as dippers, 90-100% as nondippers, and >100% as reverse dippers. RESULTS: Groups with tetraplegia (n = 51) and paraplegia (n = 33) were older (42.1 +/- 15 and 41.1 +/- 15 vs. 32.4 +/ 13 years, mean +/- s.d.) and had a higher prevalence of males (88 and 85% vs. 60%) than controls (n = 52). The average BP was 110.8 +/- 1.5/64.4 +/- 1.2 mmHg, 119.4 +/- 2.1/69.8 +/- 1.5 mmHg, and 118.1 +/- 1.4/69.8 +/- 1.0 mmHg in tetraplegia, paraplegia, and controls, respectively. Of participants with tetraplegia, paraplegia and controls, reverse dipping was observed in 45, 13, and 2% (p < 0.001), while nocturnal hypertension was observed in 13, 23, and 18%, respectively (p = 0.48). A reduction in nocturnal urine flow rate compared with the day was observed in paraplegia and controls, but not tetraplegia. CONCLUSIONS: Similar to the effects of acute SCI, chronic SCI, specifically tetraplegia, also causes isolated nocturnal hypertension, reverse dipping, orthostatic intolerance, and nocturnal polyuria. Cardiovascular risk management and assessment of orthostatic symptoms should include ABPM. PMID- 29500406 TI - DNMTi/HDACi combined epigenetic targeted treatment induces reprogramming of myeloma cells in the direction of normal plasma cells. AB - BACKGROUND: Multiple myeloma (MM) is the second most common hematologic malignancy. Aberrant epigenetic modifications have been reported in MM and could be promising therapeutic targets. As response rates are overall limited but deep responses occur, it is important to identify those patients who could indeed benefit from epigenetic-targeted therapy. METHODS: Since HDACi and DNMTi combination have potential therapeutic value in MM, we aimed to build a GEP-based score that could be useful to design future epigenetic-targeted combination trials. In addition, we investigated the changes in GEP upon HDACi/DNMTi treatment. RESULTS: We report a new gene expression-based score to predict MM cell sensitivity to the combination of DNMTi/HDACi. A high Combo score in MM patients identified a group with a worse overall survival but a higher sensitivity of their MM cells to DNMTi/HDACi therapy compared to a low Combo score. In addition, treatment with DNMTi/HDACi downregulated IRF4 and MYC expression and appeared to induce a mature BMPC plasma cell gene expression profile in myeloma cell lines. CONCLUSION: In conclusion, we developed a score for the prediction of primary MM cell sensitivity to DNMTi/HDACi and found that this combination could be beneficial in high-risk patients by targeting proliferation and inducing maturation. PMID- 29500408 TI - Low Threshold Room Temperature Amplified Spontaneous Emission in 0D, 1D and 2D Quantum Confined Systems. AB - We address optical amplification properties of quantum nanoparticles of the cadmium selenide/cadmium sulfide (CdSe/CdS) material system with different dimensionality of spatial confinement. CdSe/CdS core/shell quantum dots (QDs), core/shell quantum rods (QRs) and 5 monolayer thick core/crown nanoplatelets (NPLs) at ambient temperature are considered, exhibiting 0D, 1D and 2D spatial confinement dimensionality of the electronic system, respectively. Continuous films of all these nanoparticles are synthesised, and amplified spontaneous emission (ASE) spectra are measured under femtosecond pumping at wavelengths of 400 nm and 800 nm, respectively. The lowest threshold is found for NPLs and the highest for QDs, demonstrating the influence of the rod-like and plate-like CdS structures. To emphasize this effect, ASE is demonstrated also in CdSe/CdS QRs and NPLs under nanosecond pumping at 355 nm in the same material films. The amplification has been achieved without use of any feedback structure, emphazising the efficiency of the antenna effect. The pumping threshold fluences for NPLs and QRs are observed to be similar, but no ASE is observed in QDs up to the damage threshold of the nanoparticle layers. The length variation investigation with nanosecond pumping resulted in the gain coefficients of 29 cm 1 and 37 cm-1 for QRs and NPLs, respectively. PMID- 29500407 TI - MT4-MMP deficiency increases patrolling monocyte recruitment to early lesions and accelerates atherosclerosis. AB - Matrix metalloproteinases are involved in vascular remodeling. Little is known about their immune regulatory role in atherosclerosis. Here we show that mice deficient for MT4-MMP have increased adherence of macrophages to inflamed peritonea, and larger lipid deposits and macrophage burden in atherosclerotic plaques. We also demonstrate that MT4-MMP deficiency results in higher numbers of patrolling monocytes crawling and adhered to inflamed endothelia, and the accumulation of Mafb+ apoptosis inhibitor of macrophage (AIM)+ macrophages at incipient atherosclerotic lesions in mice. Functionally, MT4-MMP-null Mafb+AIM+ peritoneal macrophages express higher AIM and scavenger receptor CD36, are more resistant to apoptosis, and bind acLDL avidly, all of which contribute to atherosclerosis. CCR5 inhibition alleviates these effects by hindering the enhanced recruitment of MT4-MMP-null patrolling monocytes to early atherosclerotic lesions, thus blocking Mafb+AIM+ macrophage accumulation and atherosclerosis acceleration. Our results suggest that MT4-MMP targeting may constitute a novel strategy to boost patrolling monocyte activity in early inflammation. PMID- 29500409 TI - Genomic evidence of speciation reversal in ravens. AB - Many species, including humans, have emerged via complex reticulate processes involving hybridisation. Under certain circumstances, hybridisation can cause distinct lineages to collapse into a single lineage with an admixed mosaic genome. Most known cases of such 'speciation reversal' or 'lineage fusion' involve recently diverged lineages and anthropogenic perturbation. Here, we show that in western North America, Common Ravens (Corvus corax) have admixed mosaic genomes formed by the fusion of non-sister lineages ('California' and 'Holarctic') that diverged ~1.5 million years ago. Phylogenomic analyses and concordant patterns of geographic structuring in mtDNA, genome-wide SNPs and nuclear introns demonstrate long-term admixture and random interbreeding between the non-sister lineages. In contrast, our genomic data support reproductive isolation between Common Ravens and Chihuahuan Ravens (C. cryptoleucus) despite extensive geographic overlap and a sister relationship between Chihuahuan Ravens and the California lineage. These data suggest that the Common Raven genome was formed by secondary lineage fusion and most likely represents a case of ancient speciation reversal that occurred without anthropogenic causes. PMID- 29500410 TI - Central s-resistin deficiency ameliorates hypothalamic inflammation and increases whole body insulin sensitivity. AB - S-resistin, a non-secretable resistin isoform, acts as an intracrine factor that regulates adipocyte maduration, inflammatory and insulin response in 3T3-L1 cells. However, its intracellular function in vivo is still unknown. In this study, we analyze the central role of s-resistin, decreasing its hypothalamic expression using an intracerebroventricular injection of lentiviral RNAi. The data present herein support an improvement in the hypothalamic leptin and insulin signaling pathway upon s-resistin downregulation. Furthermore, hypothalamic levels of pro-inflammatory markers decrease, meanwhile those of the anti inflammatory cytokine IL-10 increases. Interestingly, peripheral NEFA decreases alike circulating leptin and resistin levels. These data demonstrate that hypothalamic s-resistin controls fuel mobilization and adipokines secretion. Importantly, central s-resistin downregulation improves systemic insulin sensitivity, as demonstrated after an IPGTT. Interestingly, our data also indicate that s-resistin downregulation could improve hypothalamic inflammation in aged Wistar rats. Altogether, our findings suggest that hypothalamic s resistin seems to be a key regulator of the brain-fat axis which links inflammation with metabolic homeostasis. PMID- 29500411 TI - Astrocytic JWA deletion exacerbates dopaminergic neurodegeneration by decreasing glutamate transporters in mice. AB - Astrocytic JWA exerts neuroprotective roles by alleviating oxidative stress and inhibiting inflammation. However, the molecular mechanisms of how astrocytic JWA is involved in dopaminergic neurodegeneration in Parkinson's disease (PD) remain largely unknown. In this study, we found that astrocyte-specific JWA knockout mice (JWA CKO) exacerbated dopamine (DA) neuronal loss and motor dysfunction, and reduced the levels of DA and its metabolites in a 1-methyl-4-phenyl-1, 2, 3, 6 tetrahydropyridine/probenecid (MPTP/p)-induced PD model. Astrocytic JWA deficiency repressed expression of excitatory amino-acid transporter 2 (GLT-1) and glutamate uptake both in vivo and in vitro. Further, the regulation of GLT-1 expression was involved in JWA-triggered activation of the MAPK and PI3K signaling pathways. JWA-increased GLT-1 expression was abolished by inhibitors of MEK and PI3K. Silencing CREB also abrogated JWA-increased GLT-1 expression and glutamate uptake. Additionally, JWA deficiency activated glial fibrillary acidic protein (GFAP), and increased the expression of STAT3. Similarly to the MPTP model, paraquat (PQ) exposure produced PD-like phenotypes in JWA CKO mice. Taken together, our findings provide novel insights into astrocytic JWA function in the pathogenesis of neurotoxin mouse models of PD. PMID- 29500412 TI - Author Correction: Isothermal Amplification of Long, Discrete DNA Fragments Facilitated by Single-Stranded Binding Protein. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29500413 TI - Author Correction: Distinct arsenic metabolites following seaweed consumption in humans. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29500414 TI - Epigenetic modifiers promote mitochondrial biogenesis and oxidative metabolism leading to enhanced differentiation of neuroprogenitor cells. AB - During neural development, epigenetic modulation of chromatin acetylation is part of a dynamic, sequential and critical process to steer the fate of multipotent neural progenitors toward a specific lineage. Pan-HDAC inhibitors (HDCis) trigger neuronal differentiation by generating an "acetylation" signature and promoting the expression of neurogenic bHLH transcription factors. Our studies and others have revealed a link between neuronal differentiation and increase of mitochondrial mass. However, the neuronal regulation of mitochondrial biogenesis has remained largely unexplored. Here, we show that the HDACi, sodium butyrate (NaBt), promotes mitochondrial biogenesis via the NRF-1/Tfam axis in embryonic hippocampal progenitor cells and neuroprogenitor-like PC12-NeuroD6 cells, thereby enhancing their neuronal differentiation competency. Increased mitochondrial DNA replication by several pan-HDACis indicates a common mechanism by which they regulate mitochondrial biogenesis. NaBt also induces coordinates mitochondrial ultrastructural changes and enhanced OXPHOS metabolism, thereby increasing key mitochondrial bioenergetics parameters in neural progenitor cells. NaBt also endows the neuronal cells with increased mitochondrial spare capacity to confer resistance to oxidative stress associated with neuronal differentiation. We demonstrate that mitochondrial biogenesis is under HDAC-mediated epigenetic regulation, the timing of which is consistent with its integrative role during neuronal differentiation. Thus, our findings add a new facet to our mechanistic understanding of how pan-HDACis induce differentiation of neuronal progenitor cells. Our results reveal the concept that epigenetic modulation of the mitochondrial pool prior to neurotrophic signaling dictates the efficiency of initiation of neuronal differentiation during the transition from progenitor to differentiating neuronal cells. The histone acetyltransferase CREB-binding protein plays a key role in regulating the mitochondrial biomass. By ChIP-seq analysis, we show that NaBt confers an H3K27ac epigenetic signature in several interconnected nodes of nuclear genes vital for neuronal differentiation and mitochondrial reprogramming. Collectively, our study reports a novel developmental epigenetic layer that couples mitochondrial biogenesis to neuronal differentiation. PMID- 29500415 TI - DNA origami scaffold for studying intrinsically disordered proteins of the nuclear pore complex. AB - The nuclear pore complex (NPC) is the gatekeeper for nuclear transport in eukaryotic cells. A key component of the NPC is the central shaft lined with intrinsically disordered proteins (IDPs) known as FG-Nups, which control the selective molecular traffic. Here, we present an approach to realize artificial NPC mimics that allows controlling the type and copy number of FG-Nups. We constructed 34 nm-wide 3D DNA origami rings and attached different numbers of NSP1, a model yeast FG-Nup, or NSP1-S, a hydrophilic mutant. Using (cryo) electron microscopy, we find that NSP1 forms denser cohesive networks inside the ring compared to NSP1-S. Consistent with this, the measured ionic conductance is lower for NSP1 than for NSP1-S. Molecular dynamics simulations reveal spatially varying protein densities and conductances in good agreement with the experiments. Our technique provides an experimental platform for deciphering the collective behavior of IDPs with full control of their type and position. PMID- 29500416 TI - Sipa1 deficiency unleashes a host-immune mechanism eradicating chronic myelogenous leukemia-initiating cells. AB - Chronic myelogenous leukemia (CML) caused by hematopoietic stem cells expressing the Bcr-Abl fusion gene may be controlled by Bcr-Abl tyrosine kinase inhibitors (TKIs). However, CML-initiating cells are resistant to TKIs and may persist as minimal residual disease. We demonstrate that mice deficient in Sipa1, which encodes Rap1 GTPase-activating protein, rarely develop CML upon transfer of primary hematopoietic progenitor cells (HPCs) expressing Bcr-Abl, which cause lethal CML disease in wild-type mice. Resistance requires both T cells and nonhematopoietic cells. Sipa1-/- mesenchymal stroma cells (MSCs) show enhanced activation and directed migration to Bcr-Abl+ cells in tumor tissue and preferentially produce Cxcl9, which in turn recruits Sipa1-/- memory T cells that have markedly augmented chemotactic activity. Thus, Sipa1 deficiency uncovers a host immune mechanism potentially capable of eradicating Bcr-Abl+ HPCs via coordinated interplay between MSCs and immune T cells, which may provide a clue for radical control of human CML. PMID- 29500417 TI - 2-Aminoethoxydiphenylborane sensitizes anti-tumor effect of bortezomib via suppression of calcium-mediated autophagy. AB - Non-small-cell lung cancer (NSCLC) accounts for most lung cancer cases. Therapeutic interventions integrating the use of different agents that focus on different targets are needed to overcome this set of diseases. The proteasome system has been demonstrated clinically as a potent therapeutic target for haematological cancers. However, promising preclinical data in solid tumors are yet to be confirmed in clinics. Herein, the combinational use of Bortezomib (BZM) and 2-aminoethoxydiphenylborane (2-APB) toward NSCLC cells was studied. We confirmed that BZM-triggered cytoprotective autophagy that may counteract with the cytotoxic effects of the drug per se. 2-APB was selected from screening of a commercial natural compounds library, which potentiated BZM-induced cytotoxicity. Such an enhancement effect was associated with 2-APB-mediated autophagy inhibition. In addition, we revealed that 2-APB suppressed calcium-induced autophagy in H1975 and A549 NSCLC cells. Interestingly, BZM [0.3 mg/kg/3 days] combined with 2-APB [2 mg/kg/day] significantly inhibited both primary (around 47% tumor growth) and metastatic Lewis lung carcinoma after a 20-day treatment. Our results suggested that BZM and 2-APB combination therapy can potentially be developed as a novel formulation for lung cancer treatment. PMID- 29500418 TI - Lamprey Prohibitin2 Arrest G2/M Phase Transition of HeLa Cells through Down regulating Expression and Phosphorylation Level of Cell Cycle Proteins. AB - Prohibitin 2(PHB2) is a member of the SFPH trans-membrane family proteins. It is a highly conserved and functionally diverse protein that plays an important role in preserving the structure and function of the mitochondria. In this study, the lamprey PHB2 gene was expressed in HeLa cells to investigate its effect on cell proliferation. The effect of Lm-PHB2 on the proliferation of HeLa cells was determined by treating the cells with pure Lm-PHB2 protein followed by MTT assay. Using the synchronization method with APC-BrdU and PI double staining revealed rLm-PHB2 treatment induced the decrease of both S phase and G0/G1 phase and then increase of G2/M phase. Similarly, cells transfected with pEGFP-N1-Lm-PHB2 also exhibited remarkable reduction in proliferation. Western blot and quantitative real-time PCR(qRT-PCR) assays suggested that Lm-PHB2 caused cell cycle arrest in HeLa cells through inhibition of CDC25C and CCNB1 expression. According to our western blot analysis, Lm-PHB2 was also found to reduce the expression level of Wee1 and PLK1 and the phosphorylation level of CCNB1, CDC25C and CDK1 in HeLa cells. Lamprey prohibitin 2 could arrest G2/M phase transition of HeLa cells through down-regulating expression and phosphorylation level of cell cycle proteins. PMID- 29500419 TI - Identification of genomic differences among peripheral arterial beds in atherosclerotic and healthy arteries. AB - Calcification is independently associated with cardiovascular events and morbidity. The calcification burden in atherosclerotic lesions quantitatively and qualitatively differs between arterial beds. Cardiovascular risk factors (CVRF) differentially affect plaque development between arterial beds. The aim of this study was to evaluate the impact of CVRF on atherosclerotic plaque calcification and to further study the molecular arterial heterogeneity that could account for these differences. Histological analysis was performed on atherosclerotic plaques from 153 carotid, 97 femoral and 28 infrapopliteal arteries. CVRF showed minor associations with plaque calcification: age and hypertension affected only the overall presence of calcification but not the type of the calcification, which significantly differed between arterial beds. Transcriptome analysis revealed distinct gene expression profiles associated with each territory in atherosclerotic and healthy arteries. Canonical pathway analysis showed the preferential involvement of immune system-related processes in both atherosclerotic and healthy carotid arteries. Bone development-related genes were among those mostly enriched in atherosclerotic and healthy femoral arteries, which are more prone to developing endochondral calcification. This study highlights the heterogeneous nature of arteries from different peripheral vascular beds and contributes to a better understanding of atherosclerosis formation and evolution. PMID- 29500420 TI - Identifying inhibitors of the Leishmania inositol phosphorylceramide synthase with antiprotozoal activity using a yeast-based assay and ultra-high throughput screening platform. AB - Leishmaniasis is a Neglected Tropical Disease caused by the insect-vector borne protozoan parasite, Leishmania species. Infection affects millions of the world's poorest, however vaccines are absent and drug therapy limited. Recently, public private partnerships have developed to identify new modes of controlling leishmaniasis. Drug discovery is a significant part of these efforts and here we describe the development and utilization of a novel assay to identify antiprotozoal inhibitors of the Leishmania enzyme, inositol phosphorylceramide (IPC) synthase. IPC synthase is a membrane-bound protein with multiple transmembrane domains, meaning that a conventional in vitro assay using purified protein in solution is highly challenging. Therefore, we utilized Saccharomyces cerevisiae as a vehicle to facilitate ultra-high throughput screening of 1.8 million compounds. Antileishmanial benzazepanes were identified and shown to inhibit the enzyme at nanomolar concentrations. Further chemistry produced a benzazepane that demonstrated potent and specific inhibition of IPC synthase in the Leishmania cell. PMID- 29500421 TI - Carboxylic acid-modified metal oxide catalyst for selectivity-tunable aerobic ammoxidation. AB - Controlling the reaction selectivity of a heterobifunctional molecule is a fundamental challenge in many catalytic processes. Recent efforts to design chemoselective catalysts have focused on modifying the surface of metal nanoparticle materials having tunable properties. However, precise control over the surface properties of base-metal oxide catalysts remains a challenge. Here, we show that green modification of the surface with carboxylates can be used to tune the ammoxidation selectivity toward the desired products during the reaction of hydroxyaldehyde on manganese oxide catalysts. These modifications improve the selectivity for hydroxynitrile from 0 to 92% under identical reaction conditions. The product distribution of dinitrile and hydroxynitrile can be continuously tuned by adjusting the amount of carboxylate modifier. This property was attributed to the selective decrease in the hydroxyl adsorption affinity of the manganese oxides by the adsorbed carboxylate groups. The selectivity enhancement is not affected by the tail structure of the carboxylic acid. PMID- 29500422 TI - Ambient nitrate switches the ammonium consumption pathway in the euphotic ocean. AB - Phytoplankton assimilation and microbial oxidation of ammonium are two critical conversion pathways in the marine nitrogen cycle. The underlying regulatory mechanisms of these two competing processes remain unclear. Here we show that ambient nitrate acts as a key variable to bifurcate ammonium flow through assimilation or oxidation, and the depth of the nitracline represents a robust spatial boundary between ammonium assimilators and oxidizers in the stratified ocean. Profiles of ammonium utilization show that phytoplankton assemblages in nitrate-depleted regimes have higher ammonium affinity than nitrifiers. In nitrate replete conditions, by contrast, phytoplankton reduce their ammonium reliance and thus enhance the success of nitrifiers. This finding helps to explain existing discrepancies in the understanding of light inhibition of surface nitrification in the global ocean, and provides further insights into the spatial linkages between oceanic nitrification and new production. PMID- 29500423 TI - Metabolic Reprogramming in Amyotrophic Lateral Sclerosis. AB - Mitochondrial dysfunction in the spinal cord is a hallmark of amyotrophic lateral sclerosis (ALS), but the neurometabolic alterations during early stages of the disease remain unknown. Here, we investigated the bioenergetic and proteomic changes in ALS mouse motor neurons and patients' skin fibroblasts. We first observed that SODG93A mice presymptomatic motor neurons display alterations in the coupling efficiency of oxidative phosphorylation, along with fragmentation of the mitochondrial network. The proteome of presymptomatic ALS mice motor neurons also revealed a peculiar metabolic signature with upregulation of most energy transducing enzymes, including the fatty acid oxidation (FAO) and the ketogenic components HADHA and ACAT2, respectively. Accordingly, FAO inhibition altered cell viability specifically in ALS mice motor neurons, while uncoupling protein 2 (UCP2) inhibition recovered cellular ATP levels and mitochondrial network morphology. These findings suggest a novel hypothesis of ALS bioenergetics linking FAO and UCP2. Lastly, we provide a unique set of data comparing the molecular alterations found in human ALS patients' skin fibroblasts and SODG93A mouse motor neurons, revealing conserved changes in protein translation, folding and assembly, tRNA aminoacylation and cell adhesion processes. PMID- 29500425 TI - Exposure of Insects to Radio-Frequency Electromagnetic Fields from 2 to 120 GHz. AB - Insects are continually exposed to Radio-Frequency (RF) electromagnetic fields at different frequencies. The range of frequencies used for wireless telecommunication systems will increase in the near future from below 6 GHz (2 G, 3 G, 4 G, and WiFi) to frequencies up to 120 GHz (5 G). This paper is the first to report the absorbed RF electromagnetic power in four different types of insects as a function of frequency from 2 GHz to 120 GHz. A set of insect models was obtained using novel Micro-CT (computer tomography) imaging. These models were used for the first time in finite-difference time-domain electromagnetic simulations. All insects showed a dependence of the absorbed power on the frequency. All insects showed a general increase in absorbed RF power at and above 6 GHz, in comparison to the absorbed RF power below 6 GHz. Our simulations showed that a shift of 10% of the incident power density to frequencies above 6 GHz would lead to an increase in absorbed power between 3-370%. PMID- 29500424 TI - Systemic inflammation induced by lipopolysaccharide aggravates inherited retinal dystrophy. AB - Retinal neurodegenerative diseases involve a scenario of inflammation and cell death that leads to morphological alterations and visual impairment. Non-ocular inflammatory processes could affect neurodegenerative retinal disorders and their progression, at least in part by activating microglial cells and releasing pro inflammatory cytokines. Our purpose was to study the consequences of a systemic inflammatory process in the progression of retinal degeneration in P23H rats, a retinitis pigmentosa (RP) model. In order to induce a mild chronic systemic inflammation, we administered low doses of lipopolysaccharide (LPS) from age P20 to P60 to dystrophic P23H rats and healthy SD rats. Visual responsiveness was assessed by electroretinography (ERG). The morphological state of the retinas was analyzed by fluorescent immunohistochemistry (IHC), evaluating the number, morphology, and connectivity of different neuronal populations by means of cell type-specific markers. Microglia density, distribution, and degree of activation were evaluated by IHC and flow cytometry. The expression levels of inflammation- and apoptosis-related genes were analyzed by qRT-PCR arrays. Low-dose LPS administration did not induce significant functional or morphological changes in the retina of SD rats, although at the molecular level, we detected expression changes in genes related to apoptosis. Otherwise, systemic injection of LPS into P23H rats induced a further deterioration in the ERG response, with greater loss of photoreceptors and worsening of synaptic connectivity, accompanied by increasing numbers of microglial cells, which also showed a more intense activation state. Several inflammation- and apoptosis-related genes were upregulated. Our results indicate that chronic exacerbation of the inflammatory response in response to LPS accelerates neurodegeneration in dystrophic P23H rats, suggesting that in patients with ocular neurodegenerative diseases, peripheral damage, as a systemic infection or chronic inflammatory process, could accelerate disease progression, and should be taken into account in order to select an appropriate therapy to revert, block or slow-down the degenerative process. PMID- 29500426 TI - Historical domestication-driven population expansion of the dung beetle Gymnopleurus mopsus (Coleoptera: Scarabaeidae) from its last refuge in Mongolia. AB - Populations of Gymnopleurus mopsus (family Scarabaeidae), a dung beetle that displays dung-rolling behavior (i.e., a telecoprid), have recently experienced sharp declines, and many populations are now at high risk of local extinction. However, Mongolia, which constitutes a major portion of the species' distribution, still sustains a relatively large population. Here, we used mitochondrial COI sequences to investigate the within-population genetic diversity and both the genetic and phylogeographic structures of 24 G. mopsus populations across the species' main distribution in Mongolia. Several lines of evidence indicated that the phylogeographic structure of G. mopsus had been influenced by a recent and sudden demographic expansion. Interestingly, the expansion of Mongolia's G. mopsus population corresponded to the advent of livestock domestication in the region, and the species' genetic structure coincided with road networks, which presumably serve as migration routes for livestock that might mediate the beetle's dispersal. In addition, we also found that G. mopsus possesses high levels of haplotype diversity, which is generally indicative of large effective population sizes (Ne). Overall, the present study contributes to the current understanding of G. mopsus' demographic history and dispersal patterns and also provides valuable information for the species' conservation and management. PMID- 29500427 TI - Inhibiting PSMalpha-induced neutrophil necroptosis protects mice with MRSA pneumonia by blocking the agr system. AB - Given its high resistance, enhanced virulence, and high transmissibility, community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) pneumonia is highly associated with high morbidity and mortality. Anti-virulence therapy is a promising strategy that bypasses the evolutionary pressure on the bacterium to develop resistance. RNAIII-inhibiting peptide (RIP), as an accessory gene regulator (agr)-specific inhibitor, significantly restricts the virulence of S. aureus and protects infected mice from death by blocking the agr quorum sensing system. The protective effects of RIP on the neutropenic mice completely disappeared in a neutrophil-deleted mouse infection model, but not in the macrophage-deleted mice. This result confirmed that the in vivo antibacterial activity of RIP is highly associated with neutrophil function. Phenol-soluble modulins (PSMs), as major leukocyte lysis toxins of CA-MRSA, are directly regulated by the agr system. In this experiment, PSMalpha1, 2, and 3 significantly induced neutrophil necroptosis by activating mixed lineage kinase like protein (MLKL) phosphorylation and increasing lactate dehydrogenase release. The S. aureus supernatants harvested from the agr or psmalpha mutant strains both decreased the phosphorylation level of MLKL and cell lysis. PSMalpha1-mediated neutrophil lysis was significantly inhibited by necrosulfonamide, necrostatin-1, TNFalpha antibody, and WRW4. These results showed PSMalpha1 induced necroptosis depends on formylpeptide receptor 2 (FPR2)-mediated autocrine TNFalpha. Moreover, the neutrophil necroptosis induced by S. aureus was significantly suppressed and pneumonia was effectively prevented by the blockage of agrA and psmalpha expression levels. These findings indicate that PSMalpha-induced necroptosis is a major cause of lung pathology in S. aureus pneumonia and suggest that interfering with the agr quorum sensing signaling pathway is a potential therapeutic strategy. PMID- 29500428 TI - Long-lasting ergot lipids as new biomarkers for assessing the presence of cereals and cereal products in archaeological vessels. AB - Cereals were very important in ancient diets, however evidence from archaeological sites of the vessels used for processing or storing cereals is comparatively rare. Micro-organisms, as well as chemical-physical effects can easily degrade cereals during the burial period. This can lead to a complete cereal decay and to serious difficulties in estimating the intensity of use of the cereals by ancient populations. Here, we present a novel biomarker approach entailing the detection of secondary lipid metabolites produced by ergot fungi (genus Claviceps), which are common cereal pests. The aim was to identify the original presence of Gramineae and to indirectly establish if vessels were used for cereal storage/processing. The fatty acid and TAG-estolide profiles of the remains from more than 30 archaeological vessels were investigated by gas chromatography/mass spectrometry (GC/MS) and high performance liquid chromatography/high resolution mass spectrometry (HPLC/ESI-Q-ToF). The detection of lipids derived from ergot in archaeological and historic contexts rests on its complex chemistry, providing a unique and relatively recalcitrant chemical signature for cereals. This research demonstrated that the combination of our innovative biomarker approach along with environmental and archaeological evidence can provide unprecedented insights into the incidence of cereals and related processing activities in ancient societies. PMID- 29500429 TI - Rotating robots move collectively and self-organize. AB - Biological organisms and artificial active particles self-organize into swarms and patterns. Open questions concern the design of emergent phenomena by choosing appropriate forms of activity and particle interactions. A particularly simple and versatile system are 3D-printed robots on a vibrating table that can perform self-propelled and self-spinning motion. Here we study a mixture of minimalistic clockwise and counter-clockwise rotating robots, called rotors. Our experiments show that rotors move collectively and exhibit super-diffusive interfacial motion and phase separate via spinodal decomposition. On long time scales, confinement favors symmetric demixing patterns. By mapping rotor motion on a Langevin equation with a constant driving torque and by comparison with computer simulations, we demonstrate that our macroscopic system is a form of active soft matter. PMID- 29500430 TI - Discovery of coding regions in the human genome by integrated proteogenomics analysis workflow. AB - Proteogenomics enable the discovery of novel peptides (from unannotated genomic protein-coding loci) and single amino acid variant peptides (derived from single nucleotide polymorphisms and mutations). Increasing the reliability of these identifications is crucial to ensure their usefulness for genome annotation and potential application as neoantigens in cancer immunotherapy. We here present integrated proteogenomics analysis workflow (IPAW), which combines peptide discovery, curation, and validation. IPAW includes the SpectrumAI tool for automated inspection of MS/MS spectra, eliminating false identifications of single-residue substitution peptides. We employ IPAW to analyze two proteomics data sets acquired from A431 cells and five normal human tissues using extended (pH range, 3-10) high-resolution isoelectric focusing (HiRIEF) pre-fractionation and TMT-based peptide quantitation. The IPAW results provide evidence for the translation of pseudogenes, lncRNAs, short ORFs, alternative ORFs, N-terminal extensions, and intronic sequences. Moreover, our quantitative analysis indicates that protein production from certain pseudogenes and lncRNAs is tissue specific. PMID- 29500432 TI - Graphene Electrode Enabling Electrochromic Approaches for Daylight-Dimming Applications. AB - For environmental reason, buildings increasingly install smart windows, which can dim incoming daylight based on active electrochromic devices (ECDs). In this work, multi-layered graphene (MLG) was investigated as an ECD window electrode, to minimize carbon dioxide (CO2) emissions by decreasing the electricity consumption for building space cooling and heating and as an alternative to the transparent conductor tin-doped indium oxide (ITO) in order to decrease dependence on it. Various MLG electrodes with different numbers of graphene layers were prepared with environmentally friendly poly(3,4 ethylenedioxythiophene):poly(styrene-sulfonate) (PEDOT:PSS) to produce ECD cells. Tests demonstrated the reproducibility and uniformity in optical performance, as well as the flexibility of the ECD fabrication. With the optimized MLG electrode, the ECD cells exhibited a very fast switching response for optical changes from transparent to dark states of a few hundred msec. PMID- 29500431 TI - Integrative analysis of omics summary data reveals putative mechanisms underlying complex traits. AB - The identification of genes and regulatory elements underlying the associations discovered by GWAS is essential to understanding the aetiology of complex traits (including diseases). Here, we demonstrate an analytical paradigm of prioritizing genes and regulatory elements at GWAS loci for follow-up functional studies. We perform an integrative analysis that uses summary-level SNP data from multi-omics studies to detect DNA methylation (DNAm) sites associated with gene expression and phenotype through shared genetic effects (i.e., pleiotropy). We identify pleiotropic associations between 7858 DNAm sites and 2733 genes. These DNAm sites are enriched in enhancers and promoters, and >40% of them are mapped to distal genes. Further pleiotropic association analyses, which link both the methylome and transcriptome to 12 complex traits, identify 149 DNAm sites and 66 genes, indicating a plausible mechanism whereby the effect of a genetic variant on phenotype is mediated by genetic regulation of transcription through DNAm. PMID- 29500433 TI - Simulating and predicting cellular and in vivo responses of colon cancer to combined treatment with chemotherapy and IAP antagonist Birinapant/TL32711. AB - Apoptosis resistance contributes to treatment failure in colorectal cancer (CRC). New treatments that reinstate apoptosis competency have potential to improve patient outcome but require predictive biomarkers to target them to responsive patient populations. Inhibitor of apoptosis proteins (IAPs) suppress apoptosis, contributing to drug resistance; IAP antagonists such as TL32711 have therefore been developed. We developed a systems biology approach for predicting response of CRC cells to chemotherapy and TL32711 combinations in vitro and in vivo. CRC cells responded poorly to TL32711 monotherapy in vitro; however, co-treatment with 5-fluorouracil (5-FU) and oxaliplatin enhanced TL32711-induced apoptosis. Notably, cells from genetically identical populations responded highly heterogeneously, with caspases being activated both upstream and downstream of mitochondrial outer membrane permeabilisation (MOMP). These data, combined with quantities of key apoptosis regulators were sufficient to replicate in vitro cell death profiles by mathematical modelling. In vivo, apoptosis protein expression was significantly altered, and mathematical modelling for these conditions predicted higher apoptosis resistance that could nevertheless be overcome by combination of chemotherapy and TL32711. Subsequent experimental observations agreed with these predictions, and the observed effects on tumour growth inhibition correlated robustly with apoptosis competency. We therefore obtained insights into intracellular signal transduction kinetics and their population based heterogeneities for chemotherapy/TL32711 combinations and provide proof-of concept that mathematical modelling of apoptosis competency can simulate and predict responsiveness in vivo. Being able to predict response to IAP antagonist based treatments on the background of cell-to-cell heterogeneities in the future might assist in improving treatment stratification approaches for these emerging apoptosis-targeting agents. PMID- 29500434 TI - Thickness-modulated metal-to-semiconductor transformation in a transition metal dichalcogenide. AB - The possibility of tailoring physical properties by changing the number of layers in van der Waals crystals is one of the driving forces behind the emergence of two-dimensional materials. One example is bulk MoS2, which changes from an indirect gap semiconductor to a direct bandgap semiconductor in the monolayer form. Here, we show a much bigger tuning range with a complete switching from a metal to a semiconductor in atomically thin PtSe2 as its thickness is reduced. Crystals with a thickness of ~13 nm show metallic behavior with a contact resistance as low as 70 Omega.um. As they are thinned down to 2.5 nm and below, we observe semiconducting behavior. In such thin crystals, we demonstrate ambipolar transport with a bandgap smaller than 2.2 eV and an on/off ratio of ~105. Our results demonstrate that PtSe2 possesses an unusual behavior among 2D materials, enabling novel applications in nano and optoelectronics. PMID- 29500436 TI - Detailed Visualization of Phase Evolution during Rapid Formation of Cu(InGa)Se2 Photovoltaic Absorber from Mo/CuGa/In/Se Precursors. AB - Amongst several processes which have been developed for the production of reliable chalcopyrite Cu(InGa)Se2 photovoltaic absorbers, the 2-step metallization-selenization process is widely accepted as being suitable for industrial-scale application. Here we visualize the detailed thermal behavior and reaction pathways of constituent elements during commercially attractive rapid thermal processing of glass/Mo/CuGa/In/Se precursors on the basis of the results of systematic characterization of samples obtained from a series of quenching experiments with set-temperatures between 25 and 550 degrees C. It was confirmed that the Se layer crystallized and then melted between 250 and 350 degrees C, completely disappearing at 500 degrees C. The formation of CuInSe2 and Cu(InGa)Se2 was initiated at around 450 degrees C and 550 degrees C, respectively. It is suggested that pre-heat treatment to control crystallization of Se layer should be designed at 250-350 degrees C and Cu(InGa)Se2 formation from CuGa/In/Se precursors can be completed within a timeframe of 6 min. PMID- 29500435 TI - On the design of a MEMS piezoelectric accelerometer coupled to the middle ear as an implantable sensor for hearing devices. AB - The presence of external elements is a major limitation of current hearing aids and cochlear implants, as they lead to discomfort and inconvenience. Totally implantable hearing devices have been proposed as a solution to mitigate these constraints, which has led to challenges in designing implantable sensors. This work presents a feasibility analysis of a MEMS piezoelectric accelerometer coupled to the ossicular chain as an alternative sensor. The main requirements of the sensor include small size, low internal noise, low power consumption, and large bandwidth. Different designs of MEMS piezoelectric accelerometers were modeled using Finite Element (FE) method, as well as optimized for high net charge sensitivity. The best design, a 2 * 2 mm2 annular configuration with a 500 nm thick Aluminum Nitride (AlN) layer was selected for fabrication. The prototype was characterized, and its charge sensitivity and spectral acceleration noise were found to be with good agreement to the FE model predictions. Weak coupling between a middle ear FE model and the prototype was considered, resulting in equivalent input noise (EIN) lower than 60 dB sound pressure level between 600 Hz and 10 kHz. These results are an encouraging proof of concept for the development of MEMS piezoelectric accelerometers as implantable sensors for hearing devices. PMID- 29500437 TI - Decomposing the Bragg glass and the peak effect in a Type-II superconductor. AB - Adding impurities or defects destroys crystalline order. Occasionally, however, extraordinary behaviour emerges that cannot be explained by perturbing the ordered state. One example is the Kondo effect, where magnetic impurities in metals drastically alter the temperature dependence of resistivity. In Type-II superconductors, disorder generally works to pin vortices, giving zero resistivity below a critical current jc. However, peaks have been observed in the temperature and field dependences of jc. This peak effect is difficult to explain in terms of an ordered Abrikosov vortex lattice. Here we test the widespread paradigm that an order-disorder transition of the vortex ensemble drives the peak effect. Using neutron scattering to probe the vortex order in superconducting vanadium, we uncover an order-disorder transition from a quasi-long-range-ordered phase to a vortex glass. The peak effect, however, is found to lie at higher fields and temperatures, in a region where thermal fluctuations of individual vortices become significant. PMID- 29500438 TI - Ultraslow isomerization in photoexcited gas-phase carbon cluster [Formula: see text]. AB - Isomerization and carbon chemistry in the gas phase are key processes in many scientific studies. Here we report on the isomerization process from linear [Formula: see text] to its monocyclic isomer. [Formula: see text] ions were trapped in an electrostatic ion beam trap and then excited with a laser pulse of precise energy. The neutral products formed upon photoexcitation were measured as a function of time after the laser pulse. It was found using a statistical model that, although the system is excited above its isomerization barrier energy, the actual isomerization from linear to monocyclic conformation takes place on a very long time scale of up to hundreds of microseconds. This finding may indicate a general phenomenon that can affect the interstellar medium chemistry of large molecule formation as well as other gas phase processes. PMID- 29500439 TI - Indoleamine 2,3-dioxygenase expression regulates the survival and proliferation of Fusobacterium nucleatum in THP-1-derived macrophages. AB - Fusobacterium nucleatum (Fn) is a tumor-associated obligate anaerobic bacterium, which has a role in the progression of colorectal cancer (CRC). Fn can invade and promote colon epithelial cells proliferation. However, how Fn survives and proliferates in its host cells remains largely unknown. In this study, we aimed to determine the molecular mechanisms underlying the morphology, survival, and proliferation of Fn in THP-1-derived macrophages (dTHP1). For the first time, we found that Fn is a facultative intracellular bacterium that can survive and limited proliferate in dTHP1 cells up to 72 h, and a live Fn infection can inhibit apoptosis of dTHP1 cells by activating the PI3K and ERK pathways. Both Fn bacteria and dTHP1 cells exhibit obvious morphological changes during infection. In addition, Infection of Fn-induced indoleamine 2,3-dioxygenase (IDO) expression by TNF-alpha-dependent and LPS-dependent pathway in a time-dependent and dose dependent manner, and the IDO-induced low tryptophan and high kynurenine environment inhibited the intracellular multiplication of Fn in dTHP1 cells. IDO expression further impaired the function of peripheral blood lymphocytes, permitting the escape of Fn-infected macrophages from cell death. IDO inhibition abrogated this effect caused by Fn and relieved immune suppression. In conclusion, we identified IDO as an important player mediating intracellular Fn proliferation in macrophages, and inhibition of IDO may aggravate infection in Fn associated tumor immunotherapy. PMID- 29500440 TI - Assembly, growth and conductive properties of tellurium nanorods produced by Rhodococcus aetherivorans BCP1. AB - Tellurite (TeO32-) is a hazardous and toxic oxyanion for living organisms. However, several microorganisms can bioconvert TeO32- into the less toxic form of elemental tellurium (Te0). Here, Rhodococcus aetherivorans BCP1 resting (non growing) cells showed the proficiency to produce tellurium-based nanoparticles (NPs) and nanorods (NRs) through the bioconversion of TeO32-, depending on the oxyanion initial concentration and time of cellular incubation. Te-nanostructures initially appeared in the cytoplasm of BCP1 cells as spherical NPs, which, as the exposure time increased, were converted into NRs. This observation suggested the existence of an intracellular mechanism of TeNRs assembly and growth that resembled the chemical surfactant-assisted process for NRs synthesis. The TeNRs produced by the BCP1 strain showed an average length (>700 nm) almost doubled compared to those observed in other studies. Further, the biogenic TeNRs displayed a regular single-crystalline structure typically obtained for those chemically synthesized. The chemical-physical characterization of the biogenic TeNRs reflected their thermodynamic stability that is likely derived from amphiphilic biomolecules present in the organic layer surrounding the NRs. Finally, the biogenic TeNRs extract showed good electrical conductivity. Thus, these findings support the suitability of this strain as eco-friendly biocatalyst to produce high quality tellurium-based nanomaterials exploitable for technological purposes. PMID- 29500441 TI - Transcriptome analysis provides insights into xylogenesis formation in Moso bamboo (Phyllostachys edulis) shoot. AB - Maturation-related changes in cell wall composition and the molecular mechanisms underlying cell wall changes were investigated from the apical, middle and basal segments in moso bamboo shoot (MBS). With maturation extent from apical to basal regions in MBS, lignin and cellulose content increased, whereas heteroxylan exhibited a decreasing trend. Activities of phenylalanine amonnialyase (PAL), cinnamyl alcohol dehydrogenase (CAD) and cinnamate-4-hydroxylase (C4H), which are involved in lignin biosynthesis, increased rapidly from the apex to the base sections. The comparative transcriptomic analysis was carried out to identify some key genes involved in secondary cell walls (SCW) formation underlying the cell wall compositions changes including 63, 8, 18, and 31 functional unigenes encoding biosynthesis of lignin, cellulose, xylan and NAC-MYB-based transcription factors, respectively. Genes related to secondary cell wall formation and lignin biosynthesis had higher expression levels in the middle and basal segments compared to those in the apical segments. Furthermore, the expression profile of PePAL gene showed positive relationships with cellulose-related gene PeCESA4, xylan-related genes PeIRX9 and PeIRX10. Our results indicated that lignification occurred in the more mature middle and basal segments in MBS at harvest while lignification of MBS were correlated with higher expression levels of PeCESA4, PeIRX9 and PeIRX10 genes. PMID- 29500442 TI - Radiomics Features Differentiate Between Normal and Tumoral High-Fdg Uptake. AB - Identification of FDGavid- neoplasms may be obscured by high-uptake normal tissues, thus limiting inferences about the natural history of disease. We introduce a FDG-PET radiomics tissue classifier for differentiating FDGavid- normal tissues from tumor. Thirty-three scans from 15 patients with Hodgkin lymphoma and 68 scans from 23 patients with Ewing sarcoma treated on two prospective clinical trials were retrospectively analyzed. Disease volumes were manually segmented on FDG-PET and CT scans. Brain, heart, kidneys and bladder and tumor volumes were automatically segmented on PET images. Standard-uptake-value (SUV) derived shape and first order radiomics features were computed to build a random forest classifier. Manually segmented volumes were compared to automatically segmented tumor volumes. Classifier accuracy for normal tissues was 90%. Classifier performance was varied across normal tissue types (brain, left kidney and bladder, hear and right kidney were 100%, 96%, 97%, 83% and 87% respectively). Automatically segmented tumor volumes showed high concordance with the manually segmented tumor volumes (R2 = 0.97). Inclusion of texture-based radiomics features minimally contributed to classifier performance. Accurate normal tissue segmentation and classification facilitates accurate identification of FDGavid tissues and classification of those tissues as either tumor or normal tissue. PMID- 29500443 TI - Improved isolation strategies to increase the yield and purity of human urinary exosomes for biomarker discovery. AB - Circulating miRNAs are detected in extracellular space and body fluids such as urine. Circulating RNAs can be packaged in secreted urinary extracellular vesicles (uEVs) and thus protected from degradation. Urinary exosome preparations might contain specific miRNAs, relevant as biomarkers in renal and bladder diseases. Major difficulties in application of uEVs into the clinical environment are the high variability and low reproducibility of uEV isolation methods. Here we used five different methods to isolate uEVs and compared the size distribution, morphology, yield, presence of exosomal protein markers and RNA content of uEVs. We present an optimized ultracentrifugation and size exclusion chromatography approach for highly reproducible isolation for 50-150 nm uEVs, corresponding to the exosomes, from 50 ml urine. We profiled the miRNA content of uEVs and total urine from the same samples with the NanoString platform and validated the data using qPCR. Our results indicate that 18 miRNAs, robustly detected in uEVs were always present in the total urine. However, 15 miRNAs could be detected only in the total urine preparations and might represent naked circulating miRNA species. This is a novel unbiased and reproducible strategy for uEVs isolation, content normalization and miRNA cargo analysis, suitable for biomarker discovery studies. PMID- 29500444 TI - Metformin-induced caveolin-1 expression promotes T-DM1 drug efficacy in breast cancer cells. AB - Trastuzumab emtansine (T-DM1) is an antibody drug conjugate (ADC) that was recently approved for the treatment of HER-2-positive metastatic breast cancer. The drug sensitivity of ADCs depends mainly on the internalization efficiency of the drug. Caveolin-1 was shown to promote T-DM1 internalization and enhance drug sensitivity. Whether caveolin-1 can be overexpressed to improve T-DM1 efficacy is interesting and has the potential for clinical application. In this study, diabetes drug metformin was investigated in terms of induction of caveolin-1 expression for increased efficacy of subsequent T-DM1 application. BT-474 cells were pretreated with metformin, followed by combined therapy with metformin and T DM1. The T-DM1 internalization and drug efficacy were determined, and the protein expressions for signal transduction were also monitored. Caveolin-1 shRNA was applied to suppress endogenous caveolin-1 expression, and the ability of metformin to promote T-DM1 efficacy was investigated. Result showed that in BT 474 cells pretreated with metformin, cellular caveolin-1 overexpression was induced, which then promoted drug efficacy by enhancing T-DM1 internalization. As cellular caveolin-1 was suppressed by shRNA, the effect of metformin-enhanced T DM1 cytotoxicity was decreased. This study demonstrated that metformin can be applied prior to T-DM1 treatment to improve the clinical efficacy of T-DM1 by enhancing caveolin-1-mediated endocytosis. PMID- 29500446 TI - Significance of risk polymorphisms for depression depends on stress exposure. AB - Depression is a polygenic and multifactorial disorder where environmental effects exert a significant impact, yet most genetic studies do not consider the effect of stressors which may be one reason for the lack of replicable results in candidate gene studies, GWAS and between human studies and animal models. Relevance of functional polymorphisms in seven candidate genes previously implicated in animal and human studies on a depression-related phenotype given various recent stress exposure levels was assessed with Bayesian relevance analysis in 1682 subjects. This Bayesian analysis indicated a gene-environment interaction whose significance was also tested with a traditional multivariate analysis using general linear models. The investigated genetic factors were only relevant in the moderate and/or high stress exposure groups. Rank order of genes was GALR2 > BDNF > P2RX7 > HTR1A > SLC6A4 > CB1 > HTR2A, with strong relevance for the first four. Robust gene-gene-environment interaction was found between BDNF and HTR1A. Gene-environment interaction effect was confirmed, namely no main effect of genes, but a significant modulatory effect on environment-induced development of depression were found. Our data support the strong causative role of the environment modified by genetic factors, similar to animal models. Gene environment interactions point to epigenetic factors associated with risk SNPs. Galanin-2 receptor, BDNF and X-type purin-7 receptor could be drug targets for new antidepressants. PMID- 29500445 TI - A macromolecular approach to eradicate multidrug resistant bacterial infections while mitigating drug resistance onset. AB - Polymyxins remain the last line treatment for multidrug-resistant (MDR) infections. As polymyxins resistance emerges, there is an urgent need to develop effective antimicrobial agents capable of mitigating MDR. Here, we report biodegradable guanidinium-functionalized polycarbonates with a distinctive mechanism that does not induce drug resistance. Unlike conventional antibiotics, repeated use of the polymers does not lead to drug resistance. Transcriptomic analysis of bacteria further supports development of resistance to antibiotics but not to the macromolecules after 30 treatments. Importantly, high in vivo treatment efficacy of the macromolecules is achieved in MDR A. baumannii-, E. coli-, K. pneumoniae-, methicillin-resistant S. aureus-, cecal ligation and puncture-induced polymicrobial peritonitis, and P. aeruginosa lung infection mouse models while remaining non-toxic (e.g., therapeutic index-ED50/LD50: 1473 for A. baumannii infection). These biodegradable synthetic macromolecules have been demonstrated to have broad spectrum in vivo antimicrobial activity, and have excellent potential as systemic antimicrobials against MDR infections. PMID- 29500447 TI - Biological and mechanical interplay at the Macro- and Microscales Modulates the Cell-Niche Fate. AB - Tissue development, regeneration, or de-novo tissue engineering in-vitro, are based on reciprocal cell-niche interactions. Early tissue formation mechanisms, however, remain largely unknown given complex in-vivo multifactoriality, and limited tools to effectively characterize and correlate specific micro-scaled bio mechanical interplay. We developed a unique model system, based on decellularized porcine cardiac extracellular matrices (pcECMs)-as representative natural soft tissue biomaterial-to study a spectrum of common cell-niche interactions. Model monocultures and 1:1 co-cultures on the pcECM of human umbilical vein endothelial cells (HUVECs) and human mesenchymal stem cells (hMSCs) were mechano-biologically characterized using macro- (Instron), and micro- (AFM) mechanical testing, histology, SEM and molecular biology aspects using RT-PCR arrays. The obtained data was analyzed using developed statistics, principal component and gene-set analyses tools. Our results indicated biomechanical cell-type dependency, bi modal elasticity distributions at the micron cell-ECM interaction level, and corresponding differing gene expression profiles. We further show that hMSCs remodel the ECM, HUVECs enable ECM tissue-specific recognition, and their co cultures synergistically contribute to tissue integration-mimicking conserved developmental pathways. We also suggest novel quantifiable measures as indicators of tissue assembly and integration. This work may benefit basic and translational research in materials science, developmental biology, tissue engineering, regenerative medicine and cancer biomechanics. PMID- 29500448 TI - Genome-wide identification and expression analysis of GRAS family transcription factors in tea plant (Camellia sinensis). AB - GRAS proteins are important transcription factors that play multifarious roles in regulating the growth and development as well as stress responses of plants. Tea plant is an economically important leaf -type beverage crop. Information concerning GRAS family transcription factors in tea plant is insufficient. In this study, 52 CsGRAS genes encoding GRAS proteins were identified from tea plant genome database. Phylogenetic analysis of the identified GRAS proteins from tea plant, Arabidopsis, and rice divided these proteins into at least 13 subgroups. Conserved motif analysis revealed that the gene structure and motif compositions of the proteins were considerably conserved among the same subgroup. Functional divergence analysis indicated that the shifted evolutionary rate might act as a major evolutionary force driving subfamily-specific functional diversification. Transcriptome analysis showed that the transcriptional levels of CsGRAS genes under non-stress conditions varied among different tea plant cultivars. qRT-PCR analysis revealed tissue and development stage-specific expression patterns of CsGRAS genes in tea plant. The expression patterns of CsGRAS genes in response to abiotic stresses and gibberellin treatment suggested the possible multiple functions of these genes. This study provides insights into the potential functions of GRAS genes. PMID- 29500449 TI - Culture-free Antibiotic-susceptibility Determination From Single-bacterium Raman Spectra. AB - Raman spectrometry appears to be an opportunity to perform rapid tests in microbiological diagnostics as it provides phenotype-related information from single bacterial cells thus holding the promise of direct analysis of clinical specimens without any time-consuming growth phase. Here, we demonstrate the feasibility of a rapid antibiotic-susceptibility determination based on the use of Raman spectra acquired on single bacterial cells. After a two-hour preculture step, one susceptible and two resistant E. coli strains were incubated, for only two hours, in the presence of different bactericidal antibiotics (gentamicin, ciprofloxacin, amoxicillin) in a range of concentrations that included the clinical breakpoints used as references in microbial diagnostic. Spectra were acquired and processed to isolate spectral modifications associated with the antibiotic effect. We evidenced an "antibiotic effect signature" which is expressed with specific Raman peaks and the coexistence of three spectral populations in the presence of antibiotic. We devised an algorithm and a test procedure that overcome single-cell heterogeneities to estimate the MIC and determinate the susceptibility phenotype of the tested bacteria using only a few single-cell spectra in four hours only if including the preculture step. PMID- 29500450 TI - In vivo virulence of Mycobacterium tuberculosis depends on a single homologue of the LytR-CpsA-Psr proteins. AB - LytR-cpsA-Psr (LCP) domain containing proteins fulfil important functions in bacterial cell wall synthesis. In Mycobacterium tuberculosis complex (Mtbc) strains, the causative agents of tuberculosis (TB), the genes Rv3484 and Rv3267 encode for LCP proteins which are putatively involved in arabinogalactan transfer to peptidoglycan. To evaluate the significance of Rv3484 for Mtbc virulence, we generated a deletion mutant in the Mtbc strain H37Rv and studied its survival in mice upon aerosol infection. The deletion mutant failed to establish infection demonstrating that Rv3484 is essential for growth in mice. Following an initial phase of marginal replication in the lungs until day 21, the Rv3484 deletion mutant was almost eliminated by day 180 post-infectionem. Interestingly, the mutant also showed higher levels of resistance to meropenem/clavulanate and lysozyme, both targeting peptidoglycan structure. We conclude that Rv3484 is essential for Mtbc virulence in vivo where its loss of function cannot be compensated by Rv3267. PMID- 29500451 TI - Increased Spatial Variability and Intensification of Extreme Monsoon Rainfall due to Urbanization. AB - While satellite data provides a strong robust signature of urban feedback on extreme precipitation; urbanization signal is often not so prominent with station level data. To investigate this, we select the case study of Mumbai, India and perform a high resolution (1 km) numerical study with Weather Research and Forecasting (WRF) model for eight extreme rainfall days during 2014-2015. The WRF model is coupled with two different urban schemes, the Single Layer Urban Canopy Model (WRF-SUCM), Multi-Layer Urban Canopy Model (WRF-MUCM). The differences between the WRF-MUCM and WRF-SUCM indicate the importance of the structure and characteristics of urban canopy on modifications in precipitation. The WRF-MUCM simulations resemble the observed distributed rainfall. WRF-MUCM also produces intensified rainfall as compared to the WRF-SUCM and WRF-NoUCM (without UCM). The intensification in rainfall is however prominent at few pockets of urban regions, that is seen in increased spatial variability. We find that the correlation of precipitation across stations within the city falls below statistical significance at a distance greater than 10 km. Urban signature on extreme precipitation will be reflected on station rainfall only when the stations are located inside the urban pockets having intensified precipitation, which needs to be considered in future analysis. PMID- 29500452 TI - Noise Source and Individual Physiology Mediate Effectiveness of Bird Songs Adjusted to Anthropogenic Noise. AB - Anthropogenic noise is a pervasive pollutant altering behaviour of wildlife that communicates acoustically. Some species adjust vocalisations to compensate for noise. However, we know little about whether signal adjustments improve communication in noise, the extent to which effectiveness of adjustments varies with noise source, or how individual variation in physiology varies with response capacity. We played noise-adjusted and unadjusted songs to wild Passerculus sandwichensis (Savannah Sparrows) after measurements of adrenocortical responsiveness of individuals. Playbacks using songs adjusted to noisy environments were effective in restoring appropriate conspecific territorial aggression behaviours in some altered acoustic environments. Surprisingly, however, levels of adrenocortical responsiveness that reduced communication errors at some types of infrastructure were correlated with increased errors at others. Song adjustments that were effective in communicating for individuals with lower adrenocortical responsiveness at pumpjacks were not effective at screwpumps and vice versa. Our results demonstrate that vocal adjustments can sometimes allow birds to compensate for disruptions in communication caused by anthropogenic noise, but that physiological variation among receivers may alter effectiveness of these adjustments. Thus mitigation strategies to minimize anthropogenic noise must account for both acoustic and physiological impacts of infrastructure. PMID- 29500453 TI - Sophora flavescens protects against mycobacterial Trehalose Dimycolate-induced lung granuloma by inhibiting inflammation and infiltration of macrophages. AB - The immune system responds to Mycobacterium tuberculosis (MTB) infection by forming granulomas to quarantine the bacteria from spreading. Granuloma-mediated inflammation is a cause of lung destruction and disease transmission. Sophora flavescens (SF) has been demonstrated to exhibit bactericidal activities against MTB. However, its immune modulatory activities on MTB-mediated granulomatous inflammation have not been reported. In the present study, we found that flavonoids from Sophora flavescens (FSF) significantly suppressed the pro inflammatory mediators released from mouse lung alveolar macrophages (MH-S) upon stimulation by trehalose dimycolate (TDM), the most abundant lipoglycan on MTB surface. Moreover, FSF reduced adhesion molecule (LFA-1) expression on MH-S cells after TDM stimulation. Furthermore, FSF treatment on TDM-activated lung epithelial (MLE-12) cells significantly downregulated macrophage chemoattractant protein (MCP-1/CCL2) expression, which in turn reduced the in vitro migration of MH-S to MLE-12 cells. In addition, FSF increased the clearance of mycobacterium bacteria (Mycobacterium aurum) in macrophages. FSF mainly affected the Mincle-Syk Erk signaling pathway in TDM-activated MH-S cells. In TDM-induced mouse granulomas model, oral administration with FSF significantly suppressed lung granulomas formation and inflammation. These findings collectively implicated an anti-inflammatory role of FSF on MTB-mediated granulomatous inflammation, thereby providing evidence of FSF as an efficacious adjunct treatment during mycobacterial infection. PMID- 29500454 TI - The effects of angiotensin receptor neprilysin inhibition by sacubitril/valsartan on adipose tissue transcriptome and protein expression in obese hypertensive patients. AB - Increased activation of the renin-angiotensin system is involved in the onset and progression of cardiometabolic diseases, while natriuretic peptides (NP) may exert protective effects. We have recently demonstrated that sacubitril/valsartan (LCZ696), a first-in-class angiotensin receptor neprilysin inhibitor, which blocks the angiotensin II type-1 receptor and augments natriuretic peptide levels, improved peripheral insulin sensitivity in obese hypertensive patients. Here, we investigated the effects of sacubitril/valsartan (400 mg QD) treatment for 8 weeks on the abdominal subcutaneous adipose tissue (AT) phenotype compared to the metabolically neutral comparator amlodipine (10 mg QD) in 70 obese hypertensive patients. Abdominal subcutaneous AT biopsies were collected before and after intervention to determine the AT transcriptome and expression of proteins involved in lipolysis, NP signaling and mitochondrial oxidative metabolism. Both sacubitril/valsartan and amlodipine treatment did not significantly induce AT transcriptional changes in pathways related to lipolysis, NP signaling and oxidative metabolism. Furthermore, protein expression of adipose triglyceride lipase (ATGL) (Ptime*group = 0.195), hormone-sensitive lipase (HSL) (Ptime*group = 0.458), HSL-ser660 phosphorylation (Ptime*group = 0.340), NP receptor-A (NPRA) (Ptime*group = 0.829) and OXPHOS complexes (Ptime*group = 0.964) remained unchanged. In conclusion, sacubitril/valsartan treatment for 8 weeks did not alter the abdominal subcutaneous AT transcriptome and expression of proteins involved in lipolysis, NP signaling and oxidative metabolism in obese hypertensive patients. PMID- 29500455 TI - Trichostatin A reverses the chemoresistance of lung cancer with high IGFBP2 expression through enhancing autophagy. AB - Insulin-like growth factor (IGF) signaling plays an important role in tumorigenesis and metastasis. Here, we analyzed insulin-like growth factor (IGF) binding protein-2 (IGFBP2) expression in 81 lung cancer patients and 36 controls consisting of healthy and benign pulmonary lesion participants for comparison, then validated the IGFBP2 expression in additional 84 lung cancer patients, and evaluated the prognostic and chemoresistant significance of IGFBP2 in two cohorts respectively. Next we detected the reversal effect of trichostatin A (TSA) on chemoresistance in cell lines with high IGFBP2 expression. As a result, the mean expression of IGFBP2 in lung cancer patients was significantly higher than that in controls and increased with lung cancer progressed to advanced stage. In addition, high IGFBP2 expression was independently predictive for chemoresistance; over-expressed IGFBP2 enhances cell activity and TSA can reverse the chemoresistance induced by high IGFBP2 expression through enhancing autophagy. Furthermore, multivariate analysis showed that lung cancer patients whose blood IGFBP2 was higher had a poor survival outcome, with a hazard ratio of 8.22 (95%CI 1.78-37.92, P = 0.007) after adjustment for stage, histopathology, EGFR mutation, age, smoking and surgery. PMID- 29500456 TI - Author Correction: ERV1 Overexpression in Myeloid Cells Protects against High Fat Diet Induced Obesity and Glucose Intolerance. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29500458 TI - Interaction of smoking and dietary habits modifying the risk of coronary heart disease in women: results from a case-control study. AB - BACKGROUND/OBJECTIVES: Smoking is a strong risk factor for coronary heart disease particularly in women. The risk may be aggravated by dietary habits, though. SUBJECTS/METHODS: The Coronary Risk for Atherosclerosis Study (CORA) compares dietary, lifestyle, biochemical, and clinical factors in 200 consecutive pre- and postmenopausal women with incident coronary heart disease to those of 255 age matched population-based controls. A mixed logistic regression model was used to assess the possible interactions between smoking habits and dietary patterns. RESULTS: Each increase of 100 kcal energy intake per day was positively associated with coronary risk (OR 1.10, 95% CI 1.03-1.17; p = 0.006). Doubling the intake of alcohol and vegetables was negatively related with coronary risk (alcohol: OR 0.61, 95% CI 0.50-0.73; p < 0.001; vegetables: OR 0.50, 95% CI 0.032 0.080; p = 0.003). In contrast, doubling the intake of meat was associated with an increase of coronary risk, but only in smoking women (OR 2.61, 95%CI 1.58 4.29; p < 0.001). In smoking women a high meat-over-vegetable-ratio indicated an even higher risk (ratio of 2.0: OR 5.77, 95% CI 2.13-15.67; p < 0.001), while a low meat-over-vegetable-ratio did not have a significant impact on coronary risk (ratio of 0.5: OR 1.28, 95% CI 0,78-2.09). CONCLUSIONS: This explorative analysis of the CORA-study indicates that a high intake of meat is significantly associated with an increase in coronary risk particularly in smoking women, and may account for part of the unadjusted risk of smoking. PMID- 29500459 TI - Different risk scores consider different types of risks: the deficiencies of the 2015 ESPEN consensus on diagnostic criteria for malnutrition. AB - In 2015, an European Society for the Parenteral and Enteral Nutrition malnutrition diagnosis consensus was published to unify the definition and simplify the diagnostic procedure of malnutrition, in which 'nutritional risk', 'malnutrition risk' and 'at risk of malnutrition' were referred to several times, and 'at risk of malnutrition' was encouraged to be coded and reimbursed in the International Classification of Diseases and diagnosis-related group system systems. However, there may be some mistakes when using the concepts of different 'risk' mentioned above. In this study, we aimed to explain different 'risks' using the original concept by different screening tools to clarify the definition and provide a recommendation for nutritional screening. PMID- 29500457 TI - Structural and functional studies on Pseudomonas aeruginosa DspI: implications for its role in DSF biosynthesis. AB - DspI, a putative enoyl-coenzyme A (CoA) hydratase/isomerase, was proposed to be involved in the synthesis of cis-2-decenoic acid (CDA), a quorum sensing (QS) signal molecule in the pathogen Pseudomonas aeruginosa (P. aeruginosa). The present study provided a structural basis for the dehydration reaction mechanism of DspI during CDA synthesis. Structural analysis reveals that Glu126, Glu146, Cys127, Cys131 and Cys154 are important for its enzymatic function. Moreover, we show that the deletion of dspI results in a remarkable decreased in the pyoverdine production, flagella-dependent swarming motility, and biofilm dispersion as well as attenuated virulence in P. aeruginosa PA14. This study thus unravels the mechanism of DspI in diffusible signal factor (DSF) CDA biosynthesis, providing vital information for developing inhibitors that interfere with DSF associated pathogenicity in P. aeruginosa. PMID- 29500460 TI - Dietary phosphorus intake estimated by 4-day dietary records and two 24-hour urine collections and their associated factors in Japanese adults. AB - BACKGROUND/OBJECTIVES: Both self-reported dietary information and urinary excretion have limitations in the assessment of phosphorus intake. We conducted a cross-sectional study to estimate dietary phosphorus intake by dietary records (DR) and 24-h urine collections (UC) and examined associated factors. SUBJECTS/METHODS: A total of 161 men and 161 women aged 20-69 years completed a 4 day DR and two 24-h UC. Phosphorus intake by UC was estimated using the mean phosphorus absorption rate of 14 papers. Associations between phosphorus intake and urinary excretion and age, body mass index (BMI), physical activity, education, and smoking status were examined using multiple linear regression. RESULTS: Phosphorus intake estimated by UC was higher than that estimated by DR (mean: 1393 vs. 1176 mg/day, P < 0.0001 in men; 1082 vs. 1021 mg/day, P = 0.008 in women). Values were significantly correlated (r = 0.29, P = 0.0002 in men; r = 0.30, P = 0.0001 in women). Phosphorus intake estimated by DR was positively associated with age in women. Male current smokers consumed less phosphorus than never smokers. Higher urinary phosphorus excretion was associated with higher BMI in both sexes and higher physical activity in women. CONCLUSIONS: This study showed dietary phosphorus intakes estimated by 4-day DR and by 2-day UC in adults. Although dietary phosphorus intake estimated by DR showed moderate correlation with that by UC, they differed in their association with age, BMI, physical activity, and smoking status. PMID- 29500461 TI - Non-alcoholic beverage consumption and risk of depression: epidemiological evidence from observational studies. AB - BACKGROUND/OBJECTIVES: Recent epidemiological studies have examined associations between various types of non-alcoholic beverage consumption and risk of depression, but the associations were inconsistent. To provide a quantitative assessment of this association, we performed a systematic review and meta analysis of observational studies. SUBJECTS/METHODS: We searched PubMed and Web of Science databases through February 2017 for eligible studies and examined the reference lists of the retrieved articles. A random-effects model was used to calculate pooled relative risks (RR) with 95% CIs after adjusting for important confounders. RESULTS: We identified fifteen observational studies (9 cross sectional studies; 6 prospective studies) of beverage consumption and depression, including 20,572 cases of depression among 347,691 participants. For coffee and tea consumption, the pooled RRs of depression for the high vs. low categories of consumption were 0.73 (95% CI 0.59-0.90) and 0.71 (95% CI 0.55-0.91), respectively. For soft drinks, however, the pooled RR for the high vs. low category of consumption was 1.36 (95% CI 1.24-1.50). The inverse association with coffee or tea consumption and the positive association with soft drink consumption for risk of depression did not vary by gender, country, high consumption category, and adjustment factors such as alcohol, smoking and physical activity. CONCLUSIONS: Our findings suggest that high consumption of coffee and tea may reduce the risk of depression, while high consumption of soft drinks may increase the risk of depression. Further well-designed large prospective studies are needed to provide definitive evidence to address the effects of various types of beverages on risk of depression. PMID- 29500462 TI - Poor dietary habits in Greek schoolchildren are strongly associated with screen time: results from the EYZHN (National Action for Children's Health) Program. AB - BACKGROUND/OBJECTIVES: To investigate adherence to the Mediterranean diet (MD) and the relationship between MD and lifestyle factors in a representative sample of Greek school children. SUBJECTS/METHODS: The data derived from 232,401 (51% boys) children aged 8 to 17 years old who participated in a health survey (2015). Physical fitness (PF) and anthropometric estimations were obtained by trained investigators. Physical activity (PA) status, sedentary activities and sleeping hours were assessed through self-completed questionnaires. Mediterranean diet was evaluated via KIDMED test. RESULTS: Forty percent of participants presented an optimal adherence to MD (>=8), while one to ten incorporated a low adherence to MD (<=3), in both genders. Participants with optimal adherence to MD presented a more favourable status in anthropometric and lifestyle characteristics. Adjusting for several potential confounders, increased screen time (<2 h/d) augmented odds of low adherence by 135% (95% CI: 2.216-2.491) and 150% (95% CI: 2.346-2.687), in boys and girls, respectively. For each 1-year enlarge in the age of children the odds of low adherence to MD enlarged by almost 11% (95%CI: 1.101-1.138) in both genders, while, boys had almost 6% increased probabilities to the low adherence (95%CI: 1.039, 1.102) than girls. Furthermore, insufficient sleeping hours (>2 h/d) and inadequate PA status were connected to higher odds of low adherence to MD. CONCLUSIONS: Support a modest adherence to the MD and an enhancement considered necessary to adjust dietary intake to current guidelines. However, screen time presented a strong association with low adherence to MD. PMID- 29500463 TI - Association between plasma trans fatty acids concentrations and leucocyte telomere length in US adults. AB - BACKGROUND/OBJECTIVES: To assess the relationship between plasma trans-fatty acids (TFAs) levels and leucocyte telomere length (TL) in a US adult population sample. SUBJECTS/METHODS: National Health and Nutrition Examination Survey (NHANES) database was used for this study. Gas chromatography was used to separate derivatised fatty acids (Four major TFAs [palmitelaidic acid (C16:1n 7t), trans vaccenic acid (C18:1n-7t), elaidic acid (C18:1n-9t), and linoelaidic acid (C18:2n-6t,9t)]) which were then quatified using negative chemical ionization mass spectrometry. Data analyses used multivariable linear regressions, while accounting for the survey design. RESULTS: A total of 5446 eligible participants, with 46.8% (n = 2550) being men, were included. Their average age was 47.1 years for the total sample, and 47.8 and 46.5 years in men and women respectively (p = 0.085 for men vs. women difference). Concentrations of palmitelaidic acid and linolelaidic acid decreased with increasing length of the telomere (p < 0.05). Univariable linear regressions revealed a significant negative association between levels of the palmitelaidic acid, elaidic acid, vaccenic acid, and linolelaidic acid with TL. However when models were adjusted for age, sex, ethnicity, education, marital status, sub-clinical inflammation, body mass index, and smoking, only palmitelaidic acid and linolelaidic acid remained significant (p < 0.05). CONCLUSIONS: TFAs levels and particularly palmitelaidic and linolelaidic acids, are likely negatively associated with telomere lenght. Future studies should explore the potential implications of these associations. PMID- 29500464 TI - Spin-controlled atom-ion chemistry. AB - Quantum control of chemical reactions is an important goal in chemistry and physics. Ultracold chemical reactions are often controlled by preparing the reactants in specific quantum states. Here we demonstrate spin-controlled atom ion inelastic (spin-exchange) processes and chemical (charge-exchange) reactions in an ultracold Rb-Sr+ mixture. The ion's spin state is controlled by the atomic hyperfine spin state via spin-exchange collisions, which polarize the ion's spin parallel to the atomic spin. We achieve ~ 90% spin polarization due to the absence of strong spin-relaxation channel. Charge-exchange collisions involving electron transfer are only allowed for (RbSr)+ colliding in the singlet manifold. Initializing the atoms in various spin states affects the overlap of the collision wave function with the singlet molecular manifold and therefore also the reaction rate. Our observations agree with theoretical predictions. PMID- 29500466 TI - Far-field probing of leaky topological states in all-dielectric metasurfaces. AB - Topological phase transitions in condensed matter systems give rise to exotic states of matter such as topological insulators, superconductors, and superfluids. Photonic topological systems open a whole new realm of research and technological opportunities, exhibiting a number of important distinctions from their condensed matter counterparts. Photonic modes can leak into free space, which makes it possible to probe topological photonic phases by spectroscopic means via Fano resonances. Based on this idea, we develop a technique to retrieve the topological properties of all-dielectric metasurfaces from the measured far field scattering characteristics. Collected angle-resolved spectra provide the momentum-dependent frequencies and lifetimes of the photonic modes that enable the retrieval of the effective Hamiltonian and extraction of the topological invariant. Our results demonstrate how the topological states of open non Hermitian systems can be explored via far-field measurements, thus paving a way to the design of metasurfaces with unique scattering characteristics controlled via topological effects. PMID- 29500468 TI - RNF213-related susceptibility of Japanese CADASIL patients to intracranial arterial stenosis. AB - Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), caused by NOTCH3, primarily affects small cerebral arteries; however, stenosis of major intracranial arteries has occasionally been reported. Recent studies identified a close association between the c.14576G>A (p.R4859K, rs112735431) variant of the ring finger protein 213 (RNF213) gene and sporadic intracranial arterial stenosis (ICAS). To determine whether RNF213 is associated with ICAS in CADASIL, we genotyped rs112735431 for 124 patients with CADASIL. The c.14576G>A carrier rate in CADASIL patients with ICAS (4/17; 23.5%) was significantly higher compared with those without ICAS (2/107; 1.9%) (P = 0.0032). Among patients with ICAS, frequency of territorial infarction was significantly higher in c.14576G>A carriers (75.0%) than in non-carriers (20.0%) (P = 0.0410). In addition, rate of >=50% stenosis or occlusion tended to be higher in c.14576G>A carriers (4/4; 100%) than in non-carriers (6/13; 46.2%) (P = 0.1029). We conclude that RNF213 is a gene associated with susceptibility to ICAS in CADASIL patients. MRA follow-up and close observation are necessary for CADASIL patients with the RNF213 variant, as they may be predisposed to ICAS. PMID- 29500467 TI - A Mathematical Model of the Phosphoinositide Pathway. AB - Phosphoinositides are signalling lipids that constitute a complex network regulating many cellular processes. We propose a computational model that accounts for all species of phosphoinositides in the plasma membrane of mammalian cells. The model replicates the steady-state of the pathway and most known dynamic phenomena. Sensitivity analysis demonstrates model robustness to alterations in the parameters. Model analysis suggest that the greatest contributor to phosphatidylinositol 4,5-biphosphate (PI(4,5)P2) production is a flux representing the direct transformation of PI into PI(4,5)P2, also responsible for the maintenance of this pool when phosphatidylinositol 4 phosphate (PI(4)P) is decreased. PI(5)P is also shown to be a significant source for PI(4,5)P2 production. The model was validated with siRNA screens that knocked down the expression of enzymes in the pathway. The screen monitored the activity of the epithelium sodium channel (ENaC), which is activated by PI(4,5)P2. While the model may deepen our understanding of other physiological processes involving phosphoinositides, we highlight therapeutic effects of ENaC modulation in Cystic Fibrosis (CF). The model suggests control strategies where the activities of the enzyme phosphoinositide 4-phosphate 5-kinase I (PIP5KI) or the PI4K + PIP5KI + DVL protein complex are decreased and cause an efficacious reduction in PI(4,5)P2 levels while avoiding undesirable alterations in other phosphoinositide pools. PMID- 29500465 TI - The role of osteopontin in the progression of solid organ tumour. AB - Osteopontin (OPN) is a bone sialoprotein involved in osteoclast attachment to mineralised bone matrix, as well as being a bone matrix protein, OPN is also a versatile protein that acts on various receptors which are associated with different signalling pathways implicated in cancer. OPN mediates various biological events involving the immune system and the vascular system; the protein plays a role in processes such as immune response, cell adhesion and migration, and tumorigenesis. This review discusses the potential role of OPN in tumour cell proliferation, angiogenesis and metastasis, as well as the molecular mechanisms involved in these processes in different cancers, including brain, lung, kidney, liver, bladder, breast, oesophageal, gastric, colon, pancreatic, prostate and ovarian cancers. The understanding of OPN's role in tumour development and progression could potentially influence cancer therapy and contribute to the development of novel anti-tumour treatments. PMID- 29500470 TI - Production and Characterization of Superhydrophobic and Antibacterial Coated Fabrics Utilizing ZnO Nanocatalyst. AB - Dirt and microorganisms are the major problems in textiles which can generate unpleasant odor during their growth. Here, zinc oxide (ZnO) nanoparticles prepared by sol-gel method were loaded on the cotton fabrics using spin coating technique to enhance their antimicrobial properties and water repellency. The effects of ZnO precursor concentration, precursor solution pH, number of coating runs, and Mg doping percent on the structures, morphologies, and water contact angles (WCA) of the ZnO-coated fabrics were addressed. At 0.5 M concentration and pH7, more homogeneous and smaller ZnO nanoparticles were grown along the preferred (0 0 2) direction and uniformly distributed on the fabric with a crystallite size 17.98 nm and dislocation density 3.09 * 10-3 dislocation/nm2. The substitution of Zn 2+ with Mg 2+ ions slightly shifted the (002) peak position to a higher angle. Also, the zeta potential and particle size distribution were measured for ZnO nanoparticle suspension. A superhydrophobic WCA = 154 degrees was measured for the fabric that coated at 0.5 M precursor solution, pH 7, 20 runs and 0% Mg doping. Moreover, the antibacterial activities of the ZnO-coated fabric were investigated against some gram-positive and gram negative bacteria such as Salmonella typhimurium, Klebsiella pneumonia, Escherichia coli, and Bacillus subtilis. PMID- 29500469 TI - Clinically diverse phenotypes and genotypes of patients with branchio-oto-renal syndrome. AB - Branchio-oto-renal (BOR) syndrome is a rare autosomal dominant disorder characterized by branchiogenic anomalies, hearing loss, and renal anomalies. The aim of this study was to reveal the clinical phenotypes and their causative genes in Japanese BOR patients. Patients clinically diagnosed with BOR syndrome were analyzed by direct sequencing, multiplex ligation-dependent probe amplification (MLPA), array-based comparative genomic hybridization (aCGH), and next-generation sequencing (NGS). We identified the causative genes in 38/51 patients from 26/36 families; EYA1 aberrations were identified in 22 families, SALL1 mutations were identified in two families, and SIX1 mutations and a 22q partial tetrasomy were identified in one family each. All patients identified with causative genes suffered from hearing loss. Second branchial arch anomalies, including a cervical fistula or cyst, preauricular pits, and renal anomalies, were frequently identified (>60%) in patients with EYA1 aberrations. Renal hypodysplasia or unknown-cause renal insufficiency was identified in more than half of patients with EYA1 aberrations. Even within the same family, renal phenotypes often varied substantially. In addition to direct sequencing, MLPA and NGS were useful for the genetic analysis of BOR patients. PMID- 29500472 TI - Geotechnology in the analysis of forest fragments in northern Mato Grosso, Brazil. AB - Pasture implantation fragments and reduces the Amazonian forest area. The objective was to quantify landscape changes in 1985, 2000 and 2015 in northern Mato Grosso, Brazil. The study was carried out in three scenes obtained by the LANDSAT satellite of a microbasin (2742.33 ha) in the municipality of Alta Floresta. Forest, water bodies, pasture and exposed soil were the thematic classes determined to e mapping the land use evolution. The edge, density and shape indexes of the fragments were measured. Normalized vegetation difference (NDVI) values were high in 1985. Land use and occupation over 15 years (1985 2000) reduced forest cover by 69.8%, but it increased by 1.7% over the next 15 years (2000-2015). The number of exposed soil patches increased between the periods, but the total area and number of the patches of the forest fragments decreased. The high values of NDVI in 1985 showed vegetated areas with high density. Reducing forest cover decreases the size of the fragments, increases the isolation and the number of soil patches exposed. The mapping of land use showed a reduction of the Amazon forest in the microbasin in the north of Mato Grosso, in the years 2000 and 2015 compared to 1985. PMID- 29500471 TI - A cascading nonlinear magneto-optical effect in topological insulators. AB - Topological insulators (TIs) are characterized by possessing metallic (gapless) surface states and a finite band-gap state in the bulk. As the thickness of a TI layer decreases down to a few nanometers, hybridization between the top and bottom surfaces takes place due to quantum tunneling, consequently at a critical thickness a crossover from a 3D-TI to a 2D insulator occurs. Although such a crossover is generally accessible by scanning tunneling microscopy, or by angle resolved photoemission spectroscopy, such measurements require clean surfaces. Here, we demonstrate that a cascading nonlinear magneto-optical effect induced via strong spin-orbit coupling can examine such crossovers. The helicity dependence of the time-resolved Kerr rotation exhibits a robust change in periodicity at a critical thickness, from which it is possible to predict the formation of a Dirac cone in a film several quintuple layers thick. This method enables prediction of a Dirac cone using a fundamental nonlinear optical effect that can be applied to a wide range of TIs and related 2D materials. PMID- 29500473 TI - Marketing techniques in television advertisements of food and drinks directed at children in Spain, 2012. AB - OBJECTIVES: To analyse marketing techniques used in television advertisements of food and drinks (AFDs) directed to children, and their nutritional quality. METHODS: This is a cross-sectional study of television AFDs directed to children in Spain over 7 days in 2012. Primary appeal, persuasive and nutritional marketing techniques, and links to Internet were registered. The foods were classified according to their nutritional quality using an international codification system and the UK nutrient profile model. Frequency of AFDs using marketing techniques and percentages for unhealthy products were calculated. RESULTS: Taste and fun were the main primary appeals used. Persuasive and nutritional marketing techniques and links to Internet were used in 61%, 68.5% and 65.2% of AFDs, respectively. These techniques were more common during weekdays, enhanced protection time slots and on channels with particular appeal to children. More than two-thirds of AFDs using these techniques were for unhealthy products, reaching 96.2% of AFDs with premium offers and gifts. CONCLUSIONS: There is an extensive use of marketing techniques in television AFDs directed to children in Spain. Most products advertised were unhealthy, so stronger governmental regulations are required. PMID- 29500474 TI - [Development and treatment of localized/systemic BCGitis : Retrospective studies in direct comparison to mitomycin C]. AB - Adjuvant therapy with different bacillus Calmette-Guerin (BCG) preparations is a well-established guideline-endorsed treatment for nonmuscle invasive bladder cancer (NMIBC). Our observational study demonstrates equality between BCG and mitomycin C (MMC) treatment based on the oncological outcome. However, there were significant toxicity differences with higher rates in the BCG treatment group. The potential adverse effects of BCG in terms of a BCGitis are controversially discussed regarding their occurrence. As such, we sought to retrospectively evaluate the incidence in 106 consecutive patients. The BCG group demonstrated minor adverse effects in 78.4% and major adverse effects in 43.3%-partially coincident. Moreover, the parallel MMC group showed in 34.7% respectively 1.4% adverse events-as expected distinctly lower. In the context of this clinical discussion, we refer to alternative treatment concepts. Our data show a high clinical relevance of the patient's primary comorbidity. PMID- 29500475 TI - [Anticorruption Act : A criminal proceedings prophylaxis for urologists]. AB - Since the introduction of the German Act to Combat Corruption in the Healthcare Sector concerns of fear and uncertainty are present. An elementary protection against criminal investigations can be achieved by complying with the physician professional law. Service contracts with the industry can be concluded if the interest in the service is reasonable and the payment is appropriate. There is a restrictive scale for clinical trials with already authorized products regarding any compensation granted which should correspond to the amount determined by the applicable elements of the German scale of medical fees (GOA). Invitations to academic training events can be accepted within an appropriate framework. PMID- 29500476 TI - [Physical and chemical emergencies in dermatology]. AB - Physical and chemical emergencies are often caused by household or work accidents. Regardless of the medical field and outside specialized clinics, the physician may be confronted with the situation for first or secondary care. The identification of the causing agent and a rapid assessment of the extent and severity of the tissue damage are essential to initiate early transfer to a specialized burn clinic. Grade 2b tissue damage is usually surgically treated. Smaller and superficial injuries can often be conservatively treated. Even supposedly safe and over-the-counter medicines can also lead to serious tissue damage. PMID- 29500477 TI - The TRPM7 kinase limits receptor-induced calcium release by regulating heterotrimeric G-proteins. AB - The melastatin-related transient receptor potential member 7 (TRPM7) is a unique fusion protein with both ion channel function and enzymatic alpha-kinase activity. TRPM7 is essential for cellular systemic magnesium homeostasis and early embryogenesis; it promotes calcium transport during global brain ischemia and emerges as a key player in cancer growth. TRPM7 channels are negatively regulated through G-protein-coupled receptor-stimulation, either by reducing cellular cyclic adenosine monophosphate (cAMP) or depleting phosphatidylinositol bisphosphate (PIP2) levels in the plasma membrane. We here identify that heterologous overexpression of human TRPM7-K1648R mutant will lead to disruption of protease or purinergic receptor-induced calcium release. The disruption occurs at the level of Gq, which requires intact TRPM7 kinase phosphorylation activity for orderly downstream signal transduction to activate phospholipase (PLC)beta and cause calcium release. We propose that this mechanism may support limiting GPCR-mediated calcium signaling in times of insufficient cellular ATP supply. PMID- 29500479 TI - Regeneration of lateral discoid meniscus after arthroscopic partial meniscectomy in an adult patient. AB - Arthroscopic partial resection is indicated for patients who have symptomatic discoid meniscus with overall satisfactory clinical outcomes. Reports regarding regeneration of discoid meniscus after arthroscopic surgery are limited. There are only two reports for children in the literature. To the authors' knowledge, the present study is the first report in the literature to report regeneration of discoid lateral meniscus after arthroscopic partial meniscectomy in an adult patient. The diagnosis was confirmed by both magnetic resonance imaging and arthroscopy. Surgeons should be aware that regeneration of discoid meniscus can occur in adult as well as pediatric patients.Level of evidence V. PMID- 29500478 TI - Transcriptional and post-transcriptional regulation of the genes encoding the small GTPases RhoA, RhoB, and RhoC: implications for the pathogenesis of human diseases. AB - Rho GTPases are highly conserved proteins that play critical roles in many cellular processes including actin dynamics, vesicular trafficking, gene transcription, cell-cycle progression, and cell adhesion. The main mode of regulation of Rho GTPases is through guanine nucleotide binding (cycling between an active GTP-bound form and an inactive GDP-bound form), but transcriptional, post-transcriptional, and post-translational modes of Rho regulation have also been described. In the present review, we summarize recent progress on the mechanisms that control the expression of the three members of the Rho-like subfamily (RhoA, RhoB, and RhoC) at the level of gene transcription as well as their post-transcriptional regulation by microRNAs. We also discuss the progress made in deciphering the mechanisms of cross-talk between Rho proteins and the transforming growth factor beta signaling pathway and their implications for the pathogenesis of human diseases such as cancer metastasis and fibrosis. PMID- 29500480 TI - Feasibility of state of the art PET/CT systems performance harmonisation. AB - PURPOSE: The objective of this study was to explore the feasibility of harmonising performance for PET/CT systems equipped with time-of-flight (ToF) and resolution modelling/point spread function (PSF) technologies. A second aim was producing a working prototype of new harmonising criteria with higher contrast recoveries than current EARL standards using various SUV metrics. METHODS: Four PET/CT systems with both ToF and PSF capabilities from three major vendors were used to acquire and reconstruct images of the NEMA NU2-2007 body phantom filled conforming EANM EARL guidelines. A total of 15 reconstruction parameter sets of varying pixel size, post filtering and reconstruction type, with three different acquisition durations were used to compare the quantitative performance of the systems. A target range for recovery curves was established such that it would accommodate the highest matching recoveries from all investigated systems. These updated criteria were validated on 18 additional scanners from 16 sites in order to demonstrate the scanners' ability to meet the new target range. RESULTS: Each of the four systems was found to be capable of producing harmonising reconstructions with similar recovery curves. The five reconstruction parameter sets producing harmonising results significantly increased SUVmean (25%) and SUVmax (26%) contrast recoveries compared with current EARL specifications. Additional prospective validation performed on 18 scanners from 16 EARL accredited sites demonstrated the feasibility of updated harmonising specifications. SUVpeak was found to significantly reduce the variability in quantitative results while producing lower recoveries in smaller (<=17 mm diameter) sphere sizes. CONCLUSIONS: Harmonising PET/CT systems with ToF and PSF technologies from different vendors was found to be feasible. The harmonisation of such systems would require an update to the current multicentre accreditation program EARL in order to accommodate higher recoveries. SUVpeak should be further investigated as a noise resistant alternative quantitative metric to SUVmax. PMID- 29500481 TI - Addition of bevacizumab to gemcitabine for platinum-resistant recurrent ovarian cancer: a retrospective analysis. AB - PURPOSE: To compare a cohort of patients with platinum-resistant recurrent ovarian cancer (PROC) treated with bevacizumab and gemcitabine (Bev-Gem) to that of patients treated only with gemcitabine (Gem). METHODS: Between 2011 and 2017, we identified the Bev-Gem and Gem PROC groups. The regimen included 1000 mg/m2 of Gem on days 1, 8, and 15, and 15 mg/m2 of Bev on day 1, every 4 weeks. Progression-free survival (PFS) and overall survival (OS) were calculated from the date of the administration of Bev-Gem or Gem until disease progression or death. RESULTS: The Bev-Gem and Gem groups included 18 and 29 patients, respectively. More patients had advanced stage disease in the Bev-Gem group (p = 0.048); no other characteristics differed between the groups. The response rates [ratio of complete remission (CR) to partial remission (PR)] of Bev-Gem and Gem were 38.9 and 3.4%, respectively (p < 0.01). The clinical benefit rates [combined percentages of CR, PR, and stable disease] of the Bev-Gem and Gem groups were 88.9 and 41.4%, respectively (p = 0.04). PFS and OS of the Bev-Gem group were superior (p < 0.01, p = 0.03, respectively). Bev-Gem was the better prognostic factor of both PFS [hazard ratio (HR) 0.17, p < 0.01] and OS (HR 0.31, p = 0.01). The frequency of hematologic and non-hematologic adverse effects was similar in each group. CONCLUSION: Bev-Gem regimens improved PFS and OS for PROC. Furthermore, the adverse effects of Bev-Gem were tolerable. Thus, Bev-Gem could be a candidate treatment strategy for PROC. PMID- 29500482 TI - Correction to: Reducing task-based fMRI scanning time using simultaneous multislice echo planar imaging. AB - The original version of this article contained a mistake. The correct Affiliation 2 is Semmelweis University, Janos Szentagothai PhD School, MR Research Centre, Balassa Street 6, Budapest 1083, Hungary. PMID- 29500483 TI - Novel electrochemical aptasensor for ultrasensitive detection of sulfadimidine based on covalently linked multi-walled carbon nanotubes and in situ synthesized gold nanoparticle composites. AB - In the current study, a sensitive electrochemical sensing strategy based on aptamer (APT) for detection of sulfadimidine (SM2) was developed. A bare gold electrode (AuE) was first modified with 2-aminoethanethiol (2-AET) through self assembly, used as linker for the subsequent immobilization of multi-walled carbon nanotubes and gold nanoparticle composites (MWCNTs/AuNPs). Then, the thiolated APT was assembled onto the electrode via sulfur-gold affinity. When SM2 existed, the APT combined with SM2 and formed a complex structure. The specific binding of SM2 and APT increased the impedance, leading to hard electron transfer between the electrode surface and the redox probe [Fe(CN)6]3-/4- and producing a significant reduction of the signal. The SM2 concentration could be reflected by the current difference of the peak currents before and after target binding. Under optimized conditions, the linear dynamic range is from 0.1 to 50 ng mL-1, with a detection limit of 0.055 ng mL-1. The sensor exhibited desirable selectivity against other sulfonamides and performs successfully when analyzing SM2 in pork samples. Graphical abstract A new electrochemical biosensor for ultrasensitive detection of sulfadimidine (SM2) by using a gold electrode modified with MWCNTs/AuNPs for signal amplification and aptamer (APT) for selectivity improvement. PMID- 29500484 TI - Synchronous bilateral lipoma arborescens of bicipitoradial bursa-a rare entity. AB - Lipoma arborescens is a rare non-neoplastic condition that affects the synovial lining of joints and bursae accounting for less than 1% of all lipomatous lesions. Characterized by villous proliferation of the synovium, it is an uncommon cause of intra/periarticular mass presenting as a painless, slowly progressive longstanding swelling, and is sometimes accompanied by intermittent monoarticular effusions. We describe a rare case of bilateral lipoma arborescens in the bicipitoradial bursae in a young male referred for MRI evaluation of spontaneous bilateral elbow swelling. We chose to bring this case to light because of the rare simultaneous involvement of the bicipitoradial bursae bilaterally and the role of MR in providing a definite diagnosis, hence obviating the need for biopsy and avoiding consideration of other complex intra/periarticular masses. PMID- 29500485 TI - MRI findings associated with medial patellofemoral capsuloligamentous plication. AB - OBJECTIVE: To review the MRI appearance of medial patellofemoral capsuloligamentous plication (also known as reefing or imbrication) for proximal patellar realignment in patients with patellofemoral instability. MATERIALS AND METHODS: Retrospective analysis of our surgical and PACS databases identified cases of medial plication performed between June 2011 and July 2016. Pre- and postoperative MRI characteristics were reviewed. Correlation was made with operative reports and clinical records to define postoperative appearances on MRI. RESULTS: Forty-one patients underwent medial plication during the study period; 29 were excluded owing to a lack of postoperative imaging. Ultimately, 12 knees were included in 11 patients who had postoperative MRI studies available (8 women and 3 men, mean age 27.3 +/- 10.2 years). Ten (83%) of the surgeries were performed open and 2 (17%) arthroscopically. There were differences in the post surgical MRI appearance of medial plications carried out after surgery using the open and arthroscopic techniques. The open technique produces a "heaped up" distal vastus medialis obliquus (VMO) with centralized patellar insertion (100%), which was absent in the case of arthroscopic plication, where subtle medial retinaculum thickening was demonstrated without alteration of its patellar insertion. The mean postoperative lateral patellar and patellofemoral congruence angles measured 2.5 degrees +/- 5.6 degrees and 12.4 degrees +/- 19.9 degrees respectively. A significant association was found regarding change in patellofemoral alignment (p = 0.018 and p = 0.004 respectively). CONCLUSION: The MRI appearance of medial plication is not well described in the radiology literature; radiologists should be familiar with anticipated post-plication findings to avoid potential confusion for pathology and allow more accurate interpretation of postoperative imaging findings from this common surgery. PMID- 29500486 TI - A pooled analysis of en bloc right hemicolectomy with pancreaticoduodenectomy for locally advanced right-sided colon cancer. AB - PURPOSE: The aim of this study was to evaluate the safety and efficacy of en bloc right hemicolectomy with pancreaticoduodenectomy (RHCPD) for locally advanced right-sided colon cancer (LARCC). METHOD: A pooled data analysis was performed on individual patients identified from the literature and the authors' institutions. The short- and long-term outcomes were assessed. RESULTS: Recruited in this study were 81 LARCC patients undergoing RHCPD, including 75 patients reported in the literature and 6 patients from our own institutions. R0 resection was achieved in 97.5% cases. Morbidity and the 30-day mortality rate were 53.8 and 3.7%, respectively. The median survival duration was 70.4 months, and the 1-, 3- and 5 year overall survival rates were 77.8, 64.6, and 55.2%, respectively. Multivariable analysis identified only lymph node metastasis (hazard ratio 3.474, 95% confidence interval 1.323-9.120; P = 0.011) as independent predictors of poor survival. CONCLUSION: En bloc RHCPD for LARCC can be performed safely with a high proportion of R0 resection and a good postoperative survival outcome. PMID- 29500487 TI - Long-term functional outcomes of perineal gangrene: worse than expected?-an observational retrospective study. AB - PURPOSE: For survivors of perineal gangrene (PG), quality of life and functional prognosis of pelvic functions are probably overestimated. The aim of this study was to report long-term anal and urinary sphincter dysfunctions, sexual sequelae, and patients' quality of life after treatment of perineal gangrene. METHODS: This retrospective observational study was conducted in one university hospital over 16 years. Seventy-three patients experienced PG; 22 were subject to long-term follow-up. Three questionnaires were sent to patients to assess pelvic dysfunction and quality of life: the GIQLI, the Cleveland Incontinence Score, and the USP score for urinary dysfunction. Sexual sequelae were considered if orchiectomy or penile resection for male patients and vulvar resection for female patients were performed. RESULTS: Of the 72 patients included, seven died before discharge (9.7%) and at least 14 died during follow-up (19.4%), despite a mean age of 62 years (+/- 13). Among the surviving patients, seven experienced an alteration of their quality of life (44%) (GIQLI < 96). Six patients still had a colostomy, and among the remaining patients, 11 experienced minimal to mild incontinence (68.7%), while one experienced constipation (6.2%). One patient suffered from urinary incontinence (4.5%), and six suffered from dysuria (27.3%). Three male patients (14%) underwent an orchiectomy, and one female patient (100%) underwent a vulvar resection. CONCLUSION: PG leads to a high rate of anal and urinary dysfunctions. Urinary dysfunctions are taken into account and treated; however, anal incontinence is not investigated even though it could lead to decreased quality of life. PMID- 29500488 TI - Demographic consequences of invasion by a native, controphic competitor to an insular bird population. AB - Species invasions and range shifts can lead to novel competitive interactions between historically resident and colonizing species, but the demographic consequences of such interactions remain controversial. We present results from field experiments and 45 years of demographic monitoring to test the hypothesis that the colonization of Mandarte Is., BC, Canada, by fox sparrows (Passerella iliaca) caused the long-term decline of the resident population of song sparrows (Melospiza melodia). Several lines of evidence indicate that competition with fox sparrows for winter food reduced over-winter survival in juvenile song sparrows by 48% from 1960 to 2015, enforcing population decline despite an increase in annual reproductive rate in song sparrows over the same period. Preference for locally abundant seeds presented at experimental arenas suggested complete overlap in diet in song and fox sparrows, and observations at arenas baited with commercial seed showed that fox sparrows displaced song sparrows in 91-100% of interactions in two periods during winter. In contrast, we found no evidence of interspecific competition for resources during the breeding season. Our results indicate that in the absence of marked shifts in niche dimension, range expansions by dominant competitors have the potential to cause the extirpation of historically resident species when competitive interactions between them are strong and resources not equitably partitioned. PMID- 29500490 TI - Investigating grounded conceptualization: motor system state-dependence facilitates familiarity judgments of novel tools. AB - Theories of embodied cognition propose that we recognize tools in part by reactivating sensorimotor representations of tool use in a process of simulation. If motor simulations play a causal role in tool recognition then performing a concurrent motor task should differentially modulate recognition of experienced vs. non-experienced tools. We sought to test the hypothesis that an incompatible concurrent motor task modulates conceptual processing of learned vs. non-learned objects by directly manipulating the embodied experience of participants. We trained one group to use a set of novel, 3-D printed tools under the pretense that they were preparing for an archeological expedition to Mars (manipulation group); we trained a second group to report declarative information about how the tools are stored (storage group). With this design, familiarity and visual attention to different object parts was similar for both groups, though their qualitative interactions differed. After learning, participants made familiarity judgments of auditorily presented tool names while performing a concurrent motor task or simply sitting at rest. We showed that familiarity judgments were facilitated by motor state-dependence; specifically, in the manipulation group, familiarity was facilitated by a concurrent motor task, whereas in the spatial group familiarity was facilitated while sitting at rest. These results are the first to directly show that manipulation experience differentially modulates conceptual processing of familiar vs. unfamiliar objects, suggesting that embodied representations contribute to recognizing tools. PMID- 29500489 TI - Potent viral suppression and improvements in alpha-fetoprotein and measures of fibrosis in Japanese patients receiving a daclatasvir/asunaprevir/beclabuvir fixed-dose combination for the treatment of HCV genotype-1 infection. AB - BACKGROUND: In the UNITY-3 study, 96% sustained virologic response (SVR12) rate was observed in Japanese patients with hepatitis C virus (HCV) genotype (GT)-1 infection treated for 12 weeks with fixed-dose daclatasvir, asunaprevir, and beclabuvir (DCV-TRIO). As HCV clearance may improve liver outcomes, we assessed hepatic fibrosis and alpha-fetoprotein (AFP), a hepatocellular carcinoma risk marker, pre- and post-treatment in UNITY-3. METHODS: Treatment-naive or interferon-experienced UNITY-3 patients with HCV GT-1 who received twice-daily DCV-TRIO were assessed for fibrosis [FibroTest; FibroScan; fibrosis-4 index (FIB 4), aspartate-aminotransferase-to-platelet-ratio index] and AFP at baseline and Weeks 4 (FIB-4 only), 12 or 24 post-treatment. RESULTS: Of 217 patients, 99% had GT-1b infection, 46% were aged > 65 years, 21% had compensated cirrhosis, and 26% baseline HCV-RNA > 107 IU/mL. All GT-1b patients treated >= 4 weeks achieved SVR12 with (n = 54) or without (n = 144) baseline NS5A polymorphisms associated with DCV resistance (positions 28/30/31/93). Statistically significant post treatment reductions from baseline were observed for all fibrosis measures and AFP, with numerically greater reductions in cirrhotic patients. FibroTest category improved in 44%, remained stable in 50%, and worsened in 6% of patients; 98% with baseline AFP < 6 MUg/L remained < 6 MUg/L and 51% with baseline AFP >= 6 MUg/L were < 6 MUg/L post-treatment. CONCLUSIONS: DCV-TRIO administered for 12 weeks to Japanese patients with primarily GT-1b infection achieved a high SVR12 rate and resulted in improved measures of hepatic fibrosis and serum AFP that may reduce the risk of future liver disease progression and hepatocellular carcinoma, particularly in those with compensated cirrhosis. PMID- 29500491 TI - Overexpression of FOXQ1 enhances anti-senescence and migration effects of human umbilical cord mesenchymal stem cells in vitro and in vivo. AB - Mesenchymal stem cells (MSCs) are unique precursor cells characterized by active self-renewal and differentiation potential. These cells offer the advantages of ease of isolation and limited ethical issues as a resource and represent a promising cell therapy for neurodegenerative diseases. However, replicative senescence during cell culture as well as low efficiency of cell migration and differentiation after transplantation are major obstacles. In our previous study, we found that FOXQ1 binds directly to the SIRT1 promoter to regulate cellular senescence and also promotes cell proliferation and migration in many tumor cell lines. Currently, little is known about the effects of FOXQ1 on normal somatic cells. Therefore, we examine the effects of FOXQ1 on senescence and migration of MSCs. Lentiviral vector-mediated overexpression of FOXQ1 in human umbilical cord mesenchymal stem cells (hUC-MSCs) resulted in enhanced cell proliferation and viability. Furthermore, the expression of proteins and markers positively associated with senescence (p16, p21, p53) was reduced, whereas expression of proteins negatively associated with senescence (SIRT1, PCNA) was promoted. Following transplantation of hUC-MSCs overexpressing FOXQ1 in an animal model of Alzheimer's disease (APPV717I transgenic mice) resulted in amelioration of the effects of Alzheimer's disease (AD) on cognitive function and pathological senescence accompanied the increased numbers of hUC-MSCs in the AD brain. In conclusion, FOXQ1 overexpression promotes anti-senescence and migration of hUC MSCs in vitro and in vivo. These findings also suggest that this strategy may contribute to optimization of the efficiency of stem cell therapy. PMID- 29500492 TI - Potential for Methanosarcina to Contribute to Uranium Reduction during Acetate Promoted Groundwater Bioremediation. AB - Previous studies of acetate-promoted bioremediation of uranium-contaminated aquifers focused on Geobacter because no other microorganisms that can couple the oxidation of acetate with U(VI) reduction had been detected in situ. Monitoring the levels of methyl CoM reductase subunit A (mcrA) transcripts during an acetate injection field experiment demonstrated that acetoclastic methanogens from the genus Methanosarcina were enriched after 40 days of acetate amendment. The increased abundance of Methanosarcina corresponded with an accumulation of methane in the groundwater. In order to determine whether Methanosarcina species could be participating in U(VI) reduction in the subsurface, cell suspensions of Methanosarcina barkeri were incubated in the presence of U(VI) with acetate provided as the electron donor. U(VI) was reduced by metabolically active M. barkeri cells; however, no U(VI) reduction was observed in inactive controls. These results demonstrate that Methanosarcina species could play an important role in the long-term bioremediation of uranium-contaminated aquifers after depletion of Fe(III) oxides limits the growth of Geobacter species. The results also suggest that Methanosarcina have the potential to influence uranium geochemistry in a diversity of anaerobic sedimentary environments. PMID- 29500493 TI - Endophytic and Epiphytic Phyllosphere Fungal Communities Are Shaped by Different Environmental Factors in a Mediterranean Ecosystem. AB - The diversity and factors influencing fungal assemblages in phyllosphere of Mediterranean tree species have been barely studied, especially when endophytic and epiphytic communities are simultaneously considered. In this work, the endophytic and epiphytic fungal communities from olive tree phyllosphere were studied. This tree species is natural from the Mediterranean region and adapted to grow under adverse climatic conditions. The main objectives were to determine whether there are differences between both fungal communities and to examine whether different abiotic (climate-related) and biotic (plant organs) factors play a pivotal role in structuring these communities. Both communities differed in size and composition, with epiphytic community being richer and more abundant, displaying also a dominance of melanized fungi. Season was the major driver of community composition, especially of epiphytes. Other drivers shaping epiphytes were wind speed and temperature, while plant organ, rainfall, and temperature were the major drivers for endophytic composition. In contrast, canopy orientation caused slight variations in community composition of fungi, but with distinct effects in spring and autumn seasons. In conclusion, epiphytic and endophytic communities are not driven by the same factors. Several sources of variation undergo complex interactions to form and maintain phyllosphere fungal community in Mediterranean climates. Climatic parameters have influence on these fungal communities, suggesting that they are likely to be affected by climate changes in a near future. PMID- 29500494 TI - The effect of Stone-Wales defects and roughness degree on the lubricity of graphene on gold surfaces. AB - In this study, the lubricity of perfect and defective graphene on the gold substrate (Au (111)) has been investigated by using molecular dynamics simulations. The influence of surface morphology as well as the Stone-Wales (SW) defects concentration on the friction of graphene on the gold surface is explored. The SW defects in the range of 0-2.55% are randomly distributed into the graphene. Furthermore, the self-affine fractal method is employed to generate realistic rough surfaces. The effect of the external force, F E , in the range of 0.25-1.0 nN, on the drag coefficients is also investigated. It is shown that the friction force slightly depends on the sliding velocity for all systems. We show that by increasing the defect concentration, the lubricity of graphene nano-sheet slightly decreases. Moreover, it is shown that the friction is almost insensitive to the roughness degree, within the range studied. Both of these effects can be rationalized through variations in the real atomic contact area. Graphical abstract By increasing the SW defect concentration of the graphene, the shape of the deformation is different from a sine wave profile, the real contact area, and the friction increases. PMID- 29500495 TI - Impact of Metal Toxicity on Oxidative Balance and Mitochondrial Enzyme Function in Muscle of Tilapia. AB - Present study investigates the effect of metal accumulation on antioxidant level and mitochondrial enzymes function in muscle of Oreochromis mossambicus. Metal accumulation in muscle upregulated stress marker malondialdehyde and the activity of different antioxidant enzymes with no significant alteration in glutathione system. Metal exposure to fish muscle decreased the activity of mitochondrial enzymes. AMP deaminase, aldolase, cytochrome C oxidase and lipoamide reductase showed positive correlation with acetylcholinesterase, glutathione reductase, reduced glutathione and glutathione peroxidase, but negative correlation with superoxide dismutase, catalase, glutathione S-transferase and thiobarbituric acid reactive substance. Analysis of these biomarkers clearly indicates the change in oxidative load in muscle tissues and provides insight to muscle response to the metal exposure. Therefore, the study outlines the potential use of biomarkers in context of muscle mitochondrial enzymes relating to oxidative processes that take place in the fish muscle following metal exposure and toxicity. PMID- 29500496 TI - Heavy Rare Earth Elements Affect Sphaerechinus granularis Sea Urchin Early Life Stages by Multiple Toxicity Endpoints. AB - Heavy rare earth elements (HREEs) were tested for adverse effects to early life stages of the sea urchin Sphaerechinus granularis. Embryos were exposed to analytically measured HREE concentrations ranging from 10-7 to 10-5 M. No significant developmental defect (DD) increases were observed in embryos exposed to 10-7 M HREEs, whereas 10-5 M HREEs resulted in significant DD increase up to 96% for HoCl3 versus 14% in controls. Embryos exposed to 10-6 M HREEs showed the highest DD frequency in embryos exposed to 10-6 M DyCl3 and HoCl3. Cytogenetic analysis of HREE-exposed embryos revealed a significant decrease in mitotic activity, with increased mitotic aberrations. When S. granularis sperm were exposed to HREEs, the offspring of sperm exposed to 10-5 M GdCl3 and LuCl3 showed significant DD increases. The results warrant investigations on HREEs in other test systems, and on REE-containing complex mixtures. PMID- 29500497 TI - On the classification of hydropic ear disease (Meniere's disease). AB - More than 150 years after its initial description by Prosper Meniere, the disease named after him is still at the center of scientific debates. Two recent developments have specifically created a breeding ground for controversy: (1) Since its first description 10 years ago, magnetic resonance imaging diagnosis of endolymphatic hydrops in living patients has seen an increasing and worldwide application. (2) The Barany Society Classification Committee published diagnostic criteria for Meniere's disease in 2015 and proposed a concept of the disease that has elicited widespread criticism. In order to promote the understanding of the underlying controversies and arguments, this article gives an overview of and discusses relevant classification proposals for Meniere's disease, including the new classification system of hydropic ear disease. PMID- 29500498 TI - [Rare differential diagnosis of conductive hearing loss in childhood]. PMID- 29500499 TI - [Medical examination: preparation for ENT specialisation : Part 35]. PMID- 29500500 TI - [B cells in head and neck oncology]. AB - As immunotherapy is becoming increasingly important in the treatment of head and neck cancer, a fundamental understanding of the immunological relationships in the tumor microenvironment is required. The importance of tumor-infiltrating B cells (TIL-B) has been largely neglected so far. In the current literature, however, a significant influence of B cells on tumor growth is described, so that this cell population is now also perceived as a therapeutic target structure. Regulatory B cells (Breg) represent a subset of B cells with immunosuppressive properties. In addition to the secretion of IL-10, Breg can be defined by their ability to produce adenosine. Adenosine is known as an immunosuppressive messenger in the tumor microenvironment whose effect can be prevented by immunotherapeutic approaches. Understanding the tumor immunological relationships, including the different B-cell functions, can help to effectively combine standard approaches including surgery or radiochemotherapy with immunotherapy. In the present article, recent findings on B cells and adenosine in head and neck cancer are described. PMID- 29500501 TI - Tinnitus-New challenge and therapeutic approaches. PMID- 29500502 TI - [Diagnostics and management of choanal atresia]. AB - Choanal atresia is a rare malformation that represents a special challenge. While bilateral choanal atresia usually needs to be surgically treated within a few days of birth, the intervention for one-sided choanal atresia can be postponed for years. Treatment planning requires adequate imaging (CT or MRI), which also serves to exclude other skull base malformities. Surgical treatment currently focuses on transnasal endoscopic techniques. Simultaneous resection of the parts of the vomer involved in the atresia seems to be important surgical success. Postoperative stenting is still controversially discussed. Postoperative application of corticosteroid nasal sprays and saline nasal rinsing for several weeks is of great importance. Due to the rarity of the diagnosis, the absence of prospective randomized controlled trials does not allow definitive statements regarding the optimal surgical technique or stenting. PMID- 29500504 TI - Development and Implementation of a Standardized Heparin Protocol for Left-Sided Pediatric Electrophysiology Procedures. AB - Heparin is used to decrease the risk of thromboembolic complications during electrophysiology studies (EPS); however, there is wide practice variation and minimal evidence to guide heparin dosing, particularly in pediatric patients. This study retrospectively analyzed heparin dosing and response, measured via activated clotting time (ACT), in patients undergoing EPS and used these data (pre-protocol cohort, n = 40), as well as guidance from available literature to implement a standardized heparin protocol (phase 1, n = 43). We utilized quality improvement methodology to refine this protocol (phase 2, n = 40) to improve therapeutic heparin response. Prior to the protocol, patients achieved therapeutic ACT levels (250-350 s) only 35% of the time which improved to 60% during phase 1 (p < 0.05) and to 73% during phase 2 (p < 0.001 compared to pre protocol). There were no thromboses or significant adverse events in any group. These results demonstrate the effectiveness of a standardized heparin protocol in achieving effective antithrombotic therapy during left-sided pediatric EPS. PMID- 29500505 TI - Restoring Fetal Circulation as a Means of Bridging Treatment Prior to Surgical Repair of Anomalous Origin of the Right Pulmonary Artery from the Ascending Aorta with Persistent Pulmonary Hypertension of the Newborn. AB - Anomalous origin of one pulmonary artery from the ascending aorta is a rare congenital anomaly. Even more rarely reported is its presence in conjunction with persistent pulmonary hypertension of the newborn (PPHN). We present a case of a full-term infant, initially thought to have PPHN and later found to have anomalous origin of the right pulmonary artery from the ascending aorta. We discuss our management concept which included use of PgE1 infusion to restore fetal circulation prior to surgical treatment in this unique clinical scenario. PMID- 29500503 TI - [Management of acute vertigo and dizziness : Patients in emergency departments in Germany]. AB - BACKGROUND: Dizziness and vertigo are some of the most common reasons for seeking medical help. Acute dizziness and vertigo require interdisciplinary cooperation. New diagnostic methods (the video head impulse test) and modern algorithms (HINTS: head impulse test/nystagmus [direction changing]/test-of-skew) are increasingly used in case of the acute vestibular syndrome in emergency care. METHODS: In a survey on the management and participation of the ENT specialist area, the authors interviewed 168 German ENT clinics during the spring of 2017 using an online survey. RESULTS: Of the 168 departments, 100 departments participated in the survey. The specialties with first medical contact in cases with acute vertigo were ENT (48%), neurology (32%), and internal medicine (17%). Most of the patients were hospitalized. Patients with acute dizziness were referred most commonly to the ENT (62%) and neurology (16%) departments for further therapy, rarely, to internal medicine wards. For emergency diagnostic workup, the video head impulse test is frequently used in ENT (72%). CONCLUSIONS: In acute vertigo syndromes, the ENT physician has a special role and responsibility in the interdisciplinary workup, since ontological disorders are the most common cause. In any case, an ENT consultation is recommended. In German emergency departments, otorhinolaryngologists use modern diagnostic tools and algorithms such as the video head pulse test and HINTS to objectify peripheral vestibulopathy or identify central causes. Thus, this is a contribution to improving medical care. PMID- 29500506 TI - [3D augmented reality visualization for navigated osteosynthesis of pelvic fractures]. AB - BACKGROUND: Despite great advances in the development of hardware and software components, surgical navigation systems have only seen limited use in current clinical settings due to their reported complexity, difficulty of integration into clinical workflows and questionable advantages over traditional imaging modalities. OBJECTIVES: Development of augmented reality (AR) visualization for surgical navigation without the need for infrared (IR) tracking markers and comparison of the navigation system to conventional imaging. MATERIAL AND METHODS: Novel navigation system combining a cone beam computed tomography (CBCT) capable C-arm with a red-green-blue depth (RGBD) camera. Testing of the device by Kirschner wire (K-wire) placement in phantoms and evaluation of the necessary operating time, number of fluoroscopic images and overall radiation dose were compared to conventional x-ray imaging. RESULTS: We found a significant reduction of the required time, number of fluoroscopic images and overall radiation dose in 3D AR navigation in comparison to x-ray imaging. CONCLUSION: Our AR navigation using RGBD cameras offers a flexible and intuitive visualization of the operating field for the navigated osteosynthesis without IR tracking markers, enabling surgeons to complete operations quicker and with a lower radiation exposure to the patient and surgical staff. PMID- 29500507 TI - [Paresis of the brachial plexus after anterior shoulder luxation : Traumatic damage or compression due to hematoma?] AB - After traumatic anterior shoulder dislocation and self-reduction, the patient initially showed an inconspicuous clinical course. At the time of presentation in the emergency room the upper limb neurological status was reported to be normal. After discharge, paresis of the brachial plexus of the left arm occurred within 8 h. A subsequently performed computed tomography (CT) scan revealed a hematoma close to the brachial plexus, which was treated by surgical decompression and resulted in symptom relief. This case report describes a rare but significant complication after anterior shoulder dislocation, which should not be underestimated in the setting of a surgical emergency admission. PMID- 29500509 TI - [Impact of medical TV series on surgical hospital patient's perception of reality]. AB - BACKGROUND: Medical TV series are very popular. Media research emphasizes that watching TV has an influence on patient's expectations and estimations concerning upcoming surgery. We analyzed these associations in our own patients. We suspected that reality as presented in the media and the actual reality of hospitals are not always conceived as two different worlds. METHODS: Over a 15 month period a standardized questionnaire was used to interview 162 in-house patients who had been admitted for an elective standard operation. They were interviewed 1-2 days prior to surgery and shortly before discharge from hospital. The questions aimed at their social situation and their TV viewing habits with special consideration of medical TV series. RESULTS: The knowledge of medical TV series is highly associated with a realistic assessment of these programs (p < 0.05). Furthermore, the knowledge of these programs is correlated with patient's unrealistic estimations of upcoming surgery. CONCLUSION: Medical TV series have a significant influence on surgical in-house patients. Patients with knowledge of many medical TV series believe that the medical setting in these shows is realistic. This can result in false estimations concerning real surgery. PMID- 29500510 TI - ? PMID- 29500508 TI - [Single-port VATS-assisted internal fixation of serial rib fractures]. AB - This article describes the operative stabilization of a flail chest due to traumatic serial rib fractures with extensive chest wall deformation and respiratory insufficiency. Initial conservative treatment including systemic and regional pain management and non-invasive positive pressure ventilation did not improve the pain or ventilation. Therefore, a single-port video-assisted thoracoscopic surgery (VATS) assisted internal fixation of the ribs was performed. The thoracoscopy enabled easy repositioning of the ribs and additionally an estimation of intrathoracic injuries. PMID- 29500511 TI - Robot-sewn ileoileal anastomosis during robot-assisted cystectomy. AB - PURPOSE: To analyze the feasibility and perioperative results of patients undergoing robot-assisted cystectomy with intracorporeal urinary diversion and robot-sewn ileoileal anastomosis. METHODS: This is a mono-centric analysis of perioperative data from 48 consecutive patients undergoing robot-assisted cystectomy with intracorporeal urinary diversion and robot-sewn ileoileal anastomosis. Data include the preoperative variables, operative and postoperative course and complication rates related to bowel anastomosis. End points were time spent for anastomosis and intra- and postoperative complication rates. RESULTS: Median operating time was 23.0 (13-60) min for the ileoileal anastomosis. Median overall operating time was 295 (200-780) min, with a median of 282 (200-418) min and 414.0 (225-780) min for the ileum conduit (N = 35) and ileal neobladder (N = 13). Two patients developed paralytic ileus; in another patient acute peritonitis occurred, but was caused by urinary leakage and therefore unrelated to the bowel anastomosis. No anastomotic leakage was noticed. Costs for the robot-sewn anastomosis was 8? compared to 1250? for a stapled anastomosis which was performed in previous cases. Limitations are the non-comparative nature of the analysis and the limited number of patients. CONCLUSIONS: Robot-sewn ileoileal anastomosis is feasible with low complication rates. Compared to the stapled anastomosis, a robot-sewn ileoileal anastomosis may serve as an alternative and cost-saving approach. PMID- 29500512 TI - Mesenchymal stem cells inhibit hypoxia-induced inflammatory and fibrotic pathways in bladder smooth muscle cells. AB - PURPOSE: Partial bladder outlet obstruction is a multifactorial urological condition in which hypoxia plays a significant role. We recently investigated hypoxia's role as a single stressor and found that hypoxia induced an intense inflammatory and profibrotic switch in bladder smooth muscle cells (bSMCs). With the immunomodulatory capacity of mesenchymal stem cells (MSCs), we aimed to investigate if the hypoxia-signaling pathways can be mitigated using MSCs. METHODS: Bladder smooth muscle cells were cultured in 3% oxygen tension for 72 h with either the direct or indirect co-culture with bone marrow derived MSCs. High pore density transwells were used for indirect co-cultures. Total RNA was extracted for gene expression analysis and the Mesoscale multiplex assay was used for secreted cytokines and growth factor measurements. Total collagen contents were determined using the Sirius Red collagen assay. RESULTS: Hypoxia induced increase of HIF3alpha, VEGF, TGFbeta1, TNFalpha, IL-1beta, IL-6, alphaSMA, and total collagen expression and decreased IL-10 levels in bSMCs. Both direct and indirect MSCs co-cultures inhibited > 50% of hypoxia-induced TGFbeta1 and IL-6 expression (p < 0.005) in a HIF-independent manner. Also, both MSCs co-culture techniques induced > 200% increase in IL-10 protein (p < 0.005) and inhibited hypoxia-induced alphaSMA, collagen I and III transcripts as well as total collagen proteins (p < 0.0001). Contrastingly, the hypoxia-induced IL-1beta and TNFalpha were inhibited by only the direct co-cultures (p < 0.05). CONCLUSIONS: MSCs co-culture with bSMCs potently mitigates hypoxia-induced inflammatory and profibrotic pathways. This work has elucidated the role of cell-cell contact and paracrine immunomodulatory mechanisms of MSCs action and opened avenues for therapeutic intervention. PMID- 29500514 TI - Updates on Gallbladder Cancer Management. AB - PURPOSE OF REVIEW: We will review the current standard of care management for metastatic gallbladder cancer (GBC), recommendations for resection of incidentally or non-incidentally diagnosed GBC, and developments in preoperative risk stratification and adjuvant chemotherapy. RECENT FINDINGS: Gemcitabine cisplatin is the standard of care therapy for advanced-stage disease. Patients with incidentally diagnosed GBC should undergo re-resection for T1b, T2, or T3 disease. The presence of residual disease is associated with decreased survival. Diagnostic laparoscopy should be used in select patients to avoid unnecessary laparotomy. Major hepatectomy and common bile duct excision should only be performed in select cases. Current standard of care for adjuvant therapy includes 6 months of oral capecitabine. Gallbladder cancer continues to carry high mortality rates due to its aggressive course and early spread. Recent developments in preoperative risk stratification, surgical resection, and chemotherapy have greatly shaped management of this malignancy in the current era. PMID- 29500513 TI - Existence and stability of periodic solutions of an impulsive differential equation and application to CD8 T-cell differentiation. AB - Unequal partitioning of the molecular content at cell division has been shown to be a source of heterogeneity in a cell population. We propose to model this phenomenon with the help of a scalar, nonlinear impulsive differential equation (IDE). To study the effect of molecular partitioning at cell division on the effector/memory cell-fate decision in a CD8 T-cell lineage, we study an IDE describing the concentration of the protein Tbet in a CD8 T-cell, where impulses are associated to cell division. We discuss how the degree of asymmetry of molecular partitioning can affect the process of cell differentiation and the phenotypical heterogeneity of a cell population. We show that a moderate degree of asymmetry is necessary and sufficient to observe irreversible differentiation. We consider, in a second part, a general autonomous IDE with fixed times of impulse and a specific form of impulse function. We establish properties of the solutions of that equation, most of them obtained under the hypothesis that impulses occur periodically. In particular, we show how to investigate the existence of periodic solutions and their stability by studying the flow of an autonomous differential equation. Then we apply those properties to prove the results presented in the first part. PMID- 29500515 TI - Prevalence and predictors of double incontinence 1 year after first delivery. AB - INTRODUCTION AND HYPOTHESIS: Urinary (UI) and anal incontinence (AI) are common pelvic floor disorders (PFD), and postpartum women experiencing double incontinence (DI), the combination of UI and AI, tend to have more severe symptoms and a greater impact on quality of life. Our objective was to investigate the prevalence and predictors of postpartum DI and UI alone 1 year after first delivery. METHODS: In this prospective cohort study, 976 women reported the prevalence of DI and UI alone 1 year after their first delivery in one of two hospitals in Norway using the St Marks score and the ICI-Q UI SF. RESULTS: DI was significantly reduced from 13% in late pregnancy to 8% 1 year later, whereas 30% reported UI at both time points. Incontinence in late pregnancy predicted incontinence 1 year after delivery. Higher age was associated with UI alone. Compared with caesarean delivery, normal vaginal or instrumental delivery increased the risk of UI alone more than three and four times respectively. Obstetric anal sphincter injuries showed a four-fold increase in the risk of DI. CONCLUSIONS: Nearly 50% reported incontinence symptoms 1 year after first delivery. Continence status during pregnancy was one of the main predictors of postpartum continence status. Mode of delivery increased the risk of postpartum UI, whereas obstetric anal sphincter injuries increased the risk of postpartum DI. PMID- 29500517 TI - Laparoscopic high uterosacral ligament suspension: an alternative route for a traditional technique. AB - INTRODUCTION AND HYPOTHESIS: Uterovaginal prolapse treatment is a challenge for the urogynecologist. Surgical management for apical prolapse can be successful with native tissue and uterosacral ligament (USL) fixation. However, some complications have been described, especially with use of the vaginal approach. The aim of this video is to describe an alternative laparoscopic approach to a traditional vaginal procedure to reduce nerve injury and ureteral complications. METHODS: A 75-year-old woman was referred to our unit for symptomatic stage III apical prolapse and underwent laparoscopic USL fixation, according to the technique described herein. RESULTS: This surgical technique was successful in correcting apical prolapse. CONCLUSIONS: This video tutorial may be useful to urogynecologists for improving surgical technique, thus leading to a reduction in the risk of nerve and ureteral complications. The technique offers the possibility of a correct under-vision suture positioning. Laparoscopic USL fixation can be safely performed to treat apical prolapse. PMID- 29500516 TI - Modified laparoscopic pectopexy: short-term follow-up and its effects on sexual function and quality of life. AB - INTRODUCTION AND HYPOTHESIS: This study examined the early outcomes of laparoscopic (LS) pectopexy and evaluated its effects on female sexual function and quality of life (QoL). METHODS: Twenty-two patients with apical prolapse who underwent LS pectopexy were included. Outcomes of the procedure were noted; the Female Sexual Function (FSFI) and Prolapse Quality of Life (P-QOL) questionnaires were completed preoperatively and 6 months postoperatively. RESULTS: There was no evidence of recurrent prolapse or constipation; the percentages of exacerbation of cystocele, rectocele, de novo stress urinary incontinence (SUI), and de novo urgency (UUI) were 4.5%, 9.0%, 4.5%, and 4.5%, respectively (mean follow-up 10.41 months). FSFI and P-QOL scores improved significantly (p < 0.05) postoperatively. CONCLUSIONS: LS pectopexy shows promising results for pelvic organ prolapse (POP) surgery with comparable outcomes. It also improved the FSFI and P-QOL scores in POP patients. PMID- 29500520 TI - Effect of Annealing on Microstructures and Hardening of Helium-Hydrogen-Implanted Sequentially Vanadium Alloys. AB - The effect of post-irradiation annealing on the microstructures and mechanical properties of V-4Cr-4Ti alloys was studied. Helium-hydrogen-irradiated sequentially V-4Cr-4Ti alloys at room temperature (RT) were undergone post irradiation annealing at 450 degrees C over periods of up to 30 h. These samples were carried out by high-resolution transmission electron microscopy (HRTEM) observation and nanoindentation test. With the holding time, large amounts of point defects produced during irradiation at RT accumulated into large dislocation loops and then dislocation nets which promoted the irradiation hardening. Meanwhile, bubbles appeared. As annealing time extended, these bubbles grew up and merged, and finally broke up. In the process, the size of bubbles increased and the number density decreased. Microstructural changes due to post irradiation annealing corresponded to the change of hardening. Dislocations and bubbles are co-contributed to irradiation hardening. With the holding time up to 30 h, the recovery of hardening is not obvious. The phenomenon was discussed by dispersed barrier hardening model and Friedel-Kroupa-Hirsch relationship. PMID- 29500519 TI - The metaplastic mosaic of Barrett's oesophagus. AB - Barrett's oesophagus surveillance biopsies represent a significant share of the daily workload for a busy histopathology department. Given the emphasis on endoscopic detection and dysplasia grading, it is easy to forget that the benefits of these screening programs remain unproven. The majority of patients are at low risk of progression to oesophageal adenocarcinoma, and periodic surveillance of these patients is burdensome and costly. Here, we investigate the parallels in the development of Barrett's oesophagus and other scenarios of wound healing in the intestine. There is now increased recognition of the full range of glandular phenotypes that can be found in patients' surveillance biopsies, and emerging evidence suggests parallel pathways to oesophageal adenocarcinoma. Greater understanding of the conditions that favour progression to cancer in the distal oesophagus will allow us to focus resources on patients at increased risk. PMID- 29500523 TI - [Quality assurance in molecular pathology]. PMID- 29500522 TI - Multigene sequencing reveals heterogeneity of NLRP12-related autoinflammatory disorders. AB - NLRP12-related autoinflammatory disease (NLRP12-AID) is an exceptionally rare autosomal dominant disorder caused by germline mutations in NLRP12 gene. Very few patients with NLRP12-AD have been identified worldwide; therefore, there is a scarcity of data on phenotypic presentation of this syndrome. Here we provide evidence that NLRP12-AID may have clinical manifestations characteristic for primary immune deficiencies (PID). 246 children with periodic fever (PF) of unknown origin were subjects to the next generation sequencing (NGS) analysis; 213 of these patients had signs of primary immunodeficiency (PID) manifested by recurrent infections, while 33 kids had isolated PF. The NGS panel was composed of 302 genes implicated in PID and/or AID. 15 patients (9 girls and 6 boys) with NLRP12-AID were identified. Median age of first AID-related fever episode was 12 months, ranging from 2 months to 13 years. Main clinical features of NLRP12 related AID were periodic fever (100%), abdominal pain and diarrhea (47%), arthralgia (20%), headache (20%) and failure to thrive (33%). Nine patients demonstrated increased susceptibility to infection and two children suffered from Crohn's disease. Administration of short courses of NSAID or corticosteroids resulted in resolution of the disease flare. In one severe case, canakinumab (anti-interleukin-1beta antibody) was successfully used. Significant number of patients with genetically assigned diagnosis of NLPR12-AID has clinical features which close resemble primary immune deficiency. This phenotypic overlap may result in underdiagnosis of NLPR12-AID among patients with PID. PMID- 29500521 TI - Endoscopic Management of Ureteral Strictures: an Update. AB - PURPOSE OF REVIEW: This review focuses on the role of endoscopic treatment of ureteral stricture disease (USD) in the era of minimally invasive surgery. RECENT FINDINGS: There is a relative paucity of recent literature regarding the endoscopic treatment of USD. Laser endopyelotomy and balloon dilation are associated with good outcomes in treatment-naive patients with short (< 2 cm), non-ischemic, benign ureteral strictures with a functional renal unit. If stricture recurs, repetitive dilation and laser endopyleotomy is not recommended, as success rates are low in this scenario. Patients with low-complexity ureteroenteric strictures and transplant strictures may benefit from endoscopic treatment options, although formal reconstruction offers higher rates of success. Formal ureteral reconstruction remains the gold-standard treatment for ureteral stricture disease as it is associated with higher rates of complete resolution. However, in carefully selected patients, endoscopic treatment modalities provide a low-cost, low-morbidity alternative. PMID- 29500526 TI - Changes in bone mineral density after kidney transplantation: 2-year assessment of a French cohort. AB - INTRODUCTION: In renal transplant patients, bone loss may be related to the drugs patients are taking but also to their past history of chronic kidney disease. The purpose of this study was to assess changes in BMD 2 years after an initial assessment (performed 9 months post transplantation) and the factors associated with these changes. METHODS: This longitudinal study included patients who had undergone a renal transplantation between 2005 and 2011, and who were followed up at the Lille Regional University Hospital. Patients were included if they had a first bone evaluation (including bone densitometry, spine X-rays and biological assessment) and at least another BMD assessment. The first assessment was performed on average 9 months post transplantation. A second assessment was performed at 2 years. RESULTS: Two hundred fifty-nine out of 366 patients satisfied the inclusion criteria. The population included 96 women. Mean age at transplantation was 49.7 +/- 12.1 years. Mean duration of dialysis was 3.2 +/- 3.3 years. For 75 patients (29.0%), corticosteroid treatment was discontinued 7 days after transplantation without subsequent resumption during follow-up. Vertebral fractures assessed by X-rays at baseline were found in 28 patients (10.8%). According to the WHO classification, 106 patients (40.9%) patients had osteoporosis and 111 patients (42.8%) had osteopenia at the first assessment. Oral bisphosphonates were prescribed for 95 patients. The decision to prescribe bisphosphonates was taken jointly by rheumatologists and nephrologists based on BMD assessment, past history of fracture and corticosteroid management. In all patients, BMD gains at the second evaluation (2.2 +/- 0.79 years) compared with baseline were significant (3.9 +/- 6.6, 2.6% +/- 7.6, 3.0 +/- 7.2% at the lumbar spine, femoral neck and total hip respectively; p < 0.0001). The difference in gain between bisphosphonate-treated and untreated patients was significant (+ 5.0 +/- 0.8% (p < 0.0001), + 2.5 +/- 1.0% (p = 0.01) and + 2.7 +/- 0.9% (p < 0.01) at the lumbar spine, femoral neck and total hip respectively. The patients who benefited early corticosteroid discontinuation had higher gains in BMD at the lumbar spine (+ 2.1 +/- 0.9%; p = 0.02) and total hip (+ 2.0 +/- 1.0%; p = 0.04) compared to those for whom corticosteroid therapy was maintained. Stepwise regression analysis (patients without bisphosphonates) showed associations between change in BMD (femoral neck) and duration of corticosteroid therapy, bone alkaline phosphatase level at baseline, and absence of vertebral fracture. No correlation was found between change in BMD and duration of dialysis or renal function. CONCLUSION: Kidney transplant recipients have an increased risk of bone fragility in the year following transplantation. Bisphosphonates and early corticosteroid discontinuation can improve BMD. PMID- 29500527 TI - Association of sarcopenia and fractures in community-dwelling older adults: a systematic review and meta-analysis of cohort studies. AB - To our knowledge, no comprehensive meta-analysis has examined the association between sarcopenia and the risk of fractures. This systematic review and meta analysis of prospective cohort studies aims to summarize whether sarcopenia is a risk factor for fractures among community-dwelling older adults. We searched four electronic literature databases (Ovid MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, PubMed) for relevant publications from inception to December 2017, using relevant keywords. We conducted a pooled analysis of the association between sarcopenia and the risk of fractures by employing a random effects model. Subgroup analyses were conducted based on definitions of sarcopenia and gender. In total, nine studies were included in our systematic review and meta-analysis. The prevalence of sarcopenia ranged from 4.3 to 33.1%. The pooled RR of fractures for the sarcopenic versus the nonsarcopenic was 1.34 (95% CI = 1.13-1.58, P = 0.001, I2 = 5.5%, P-heterogeneity = 0.391). Subgroup analyses showed that associations between sarcopenia and fractures were significant when using the AWGS definition (combined effect size = 1.78, 95% CI = 1.25-2.54, P = 0.001), and studies in males (combined effect size = 1.39, 95% CI = 1.13-1.71, P = 0.002). In conclusion, we found that compared to nonsarcopenic, the association between sarcopenia and fractures among community-dwelling older people was significant when using the AWGS definition, and only for males. Future studies are needed to establish a possible association between sarcopenia definitions and risk of fractures of different sites. PMID- 29500528 TI - Comments on Feskanich et al.: Milk and other dairy foods and risk of hip fracture in men and women. PMID- 29500531 TI - Outcomes of poor responders following growth hormone co-treatment with IVF/ICSI mild stimulation protocol: a retrospective cohort study. AB - PURPOSE: No research has studied the effect of GH co-treatment in mild stimulation protocol for poor responders. We therefore conducted this retrospective analysis to assess the outcome of IVF/ICSI cycles after the adjunct GH use to the mild stimulation protocol in poor responders. METHODS: 132 poor responders who received mild stimulation protocol at Reproductive Medicine Center of Changzheng Hospital from January 2014 to December 2016 were included in this study. Good-quality embryo rate, clinical pregnancy rate, and live birth rate were compared between the GH group (n = 61) and control group (n = 71). RESULTS: IVF good-quality embryo rate (68.1 versus 51.5%; P = 0.008*) and ICSI good quality embryo rate (53.9 versus 36.7%; P = 0.045*) was significantly higher in the GH group. Though the clinical outcomes did not reach a statistically significant difference between the two groups due to the limited sample size, there was a trend of higher rate in GH group in the aspect of clinical pregnancy rate (52.4 versus 47.1%; P = 0.609) and live birth rate (35.7 versus 27.5%; P = 0.392). CONCLUSION: The results suggested that the adjuvant GH treatment in mild stimulation protocol for poor responders could significantly improve good-quality embryo rate, and might therefore improve the clinical outcomes. PMID- 29500530 TI - Molecular evolution between chemistry and biology : The interplay of competition, cooperation, and mutation. AB - Biological evolution is reduced to three fundamental processes in the spirit of a minimal model: (i) Competition caused by differential fitness, (ii) cooperation of competitors in the sense of symbiosis, and (iii) variation introduced by mutation understood as error-prone reproduction. The three combinations of two fundamental processes each, ([Formula: see text]) competition and mutation, ([Formula: see text]) cooperation and competition, and ([Formula: see text]) cooperation and mutation, are analyzed. Changes in population dynamics that are induced by bifurcations and threshold phenomena are discussed. PMID- 29500529 TI - From quasispecies to quasispaces: coding and cooperation in chemical and electronic systems. AB - This contribution addresses the physical roles of spatial structures, either externally imposed or generated through self-assembly, either passive or active, on the physical chemistry of evolution. Starting with simple diffusion in closed capillaries, a one-dimensional space, it covers eight aspects of experimental and theoretical research into the interaction of evolution with spatial structures: in various dimensions, including hitherto unexplored ones, spanning from externally defined physical spaces to actively tailored spaces, assembled by the evolving components themselves. As such, it contains some original research by the author as well as tracing how other insights grew over three decades out of the mentorship of Manfred Eigen in the 1980s. Much of the early interest in spatial structures centres on its role in stabilizing higher order cooperative structures involving the coevolution of different molecules, as the genetic coding system exemplifies. Modern nanotechnology enables the design and construction of genetically encoded variants of smart components that can actively control both the proliferation of molecules and the structuring of space. A key role for this article is to show the continuity in this line of enquiry, beginning with quasispecies and projecting to autonomous microparticles with electronic genomes able to form programmable quasispaces. PMID- 29500532 TI - Evolutionary Divergence of TNL Disease-Resistant Proteins in Soybean (Glycine max) and Common Bean (Phaseolus vulgaris). AB - Disease-resistant genes (R genes) encode proteins that are involved in protecting plants from their pathogens and pests. Availability of complete genome sequences from soybean and common bean allowed us to perform a genome-wide identification and analysis of the Toll interleukin-1 receptor-like nucleotide-binding site leucine-rich repeat (TNL) proteins. Hidden Markov model (HMM) profiling of all protein sequences resulted in the identification of 117 and 77 regular TNL genes in soybean and common bean, respectively. We also identified TNL gene homologs with unique domains, and signal peptides as well as nuclear localization signals. The TNL genes in soybean formed 28 clusters located on 10 of the 20 chromosomes, with the majority found on chromosome 3, 6 and 16. Similarly, the TNL genes in common bean formed 14 clusters located on five of the 11 chromosomes, with the majority found on chromosome 10. Phylogenetic analyses of the TNL genes from Arabidopsis, soybean and common bean revealed less divergence within legumes relative to the divergence between legumes and Arabidopsis. Syntenic blocks were found between chromosomes Pv10 and Gm03, Pv07 and Gm10, as well as Pv01 and Gm14. The gene expression data revealed basal level expression and tissue specificity, while analysis of available microRNA data showed 37 predicted microRNA families involved in targeting the identified TNL genes in soybean and common bean. PMID- 29500533 TI - DFT study of the mechanisms of nonenzymatic DNA repair by phytophenolic antioxidants. AB - Reactive oxygen species (ROS) can oxidize and thus damage DNA. Exposure to high levels of ROS is therefore linked with the development of severe illnesses such as cancer, diabetes, and coronary heart disease. Effective treatments for these diseases are yet to be found, despite intensive research. However, it is known that the natural nonenzymatic repair of DNA damage using phytophenols occurs more rapidly than the corresponding enzymatic repair process. Carvacrol, thymol, thymohydroquinone, and p-cymene-2,3-diol are strong natural antioxidant phytophenols that are found in medicinal plants. Their antioxidant activities, which involve reacting with and eliminating ROS before they reach and damage DNA, were studied in this work. Homolytic and heterolytic antioxidant mechanisms that allow these phytophenol antioxidants to eliminate the ROS .OH and .O2- in both vacuum and water (physiological environment) were investigated using density functional theory (DFT). The results showed that the homolytic mechanism is preferred in vacuum, whereas the heterolytic mechanisms are more probable in polar environments. In addition, the electronic properties of these phytophenols were studied and correlated with their antioxidant activities. It appears that these phytophenols can be used as antioxidants in vitro and in vivo to protect living systems from dangerous ROS. Graphical abstract Antioxidant reaction of carvacrol with OH. and .O-2 radicals. PMID- 29500534 TI - Satisfaction rate of patients undergoing sleeve gastrectomy as day-case surgery compared to conventional hospitalization: a prospective non-randomized study. AB - PURPOSE: Day-case surgery (DCS) has boomed over recent years. However, day-case bariatric surgery remains controversial due to a lack of evaluation. The objective of this study was to compare the experiences and satisfaction with general anesthesia of patients undergoing sleeve gastrectomy (SG) as DCS compared to conventional hospitalization. METHODS: Between January 2015 and June 2016, all patients undergoing primary SG as day-case surgery or with conventional hospitalization were prospectively included in this non-randomized, non inferiority study comparing the level of satisfaction of patients undergoing SG with conventional hospitalization (CH group, gold standard) versus SG as DCS (DCS group). The primary efficacy endpoint was comparison of the overall satisfaction rate using the EVAN-G questionnaire. The secondary endpoints were evaluation of the 6 dimensions of the EVAN-G questionnaire, discharge from hospital, adhesion with SG management and overall satisfaction with SG. RESULTS: One-hundred and twenty-four patients met the inclusion criteria (62 in both groups). The DCS group was younger with fewer comorbidities (p <= 0.01) and had a lower BMI (p <= 0.01). Overall, the mean EVAN-G questionnaire score was 66.4 (63.9-68.9) for the DCS group and 68.9 (65.9-71.8) for the CH group (non-inferiority of DCS group). In the DCS group, 19% of patients would have preferred to spend the night in hospital, while 82% of patients in the CH group would have preferred DCS and a total of 75% of patients reported a high level of satisfaction. CONCLUSION: Overall satisfaction of patients undergoing SG as day-case surgery was not inferior to that of patients managed by conventional hospitalization. PMID- 29500535 TI - Astigmatism in Chinese primary school children: prevalence, change, and effect on myopic shift. AB - PURPOSE: To study the prevalence, type, and progression of astigmatism in primary school children, and its effect on myopic shift. STUDY DESIGN: A prospective study carried out in a primary school in southern Taiwan. METHODS: The study was performed on a subset of children, one year after initial examination. Refractive error measured by cycloplegic autorefraction was the main study outcome. Astigmatism was recorded as negative cylinder form, and we defined clinical significant astigmatism (CSA) as cylinder refraction -1.0 D or greater. Myopia was defined as a spherical equivalent refraction (SER) of -0.50 D or greater. RESULTS: Three hundred sixty-two children, mean age was 8.97 y/o (SD 1.41; range 7 to 11 y/o) participated in the study. One hundred nineteen (32.9 %) subjects had CSA at the initial screening. The mean cylinder refraction was -0.80 + 0.84 diopters (D) (-5.25 D to 0.00 D), with predominant with rule astigmatism (69.7%). In the 183 children studied longitudinally, the mean cylinder refraction was reduced from -0.74 D to -0.58 D (p< 0.05). The cylinder refraction in the initial CSA group was not associated with SER change (p=0.99) or axial length change (p=0.55). Compared to the initial non-CSA group, the initial CSA group had no significant difference in axial length elongation (p=0.20). CONCLUSION: The prevalence of astigmatism was not low in the Chinese primary school children and with-the-rule astigmatism was predominant. The astigmatism decreased during the 1 year follow-up. The CSA was not associated with myopia progression (p=0.99). PMID- 29500536 TI - The TrkB agonist 7,8-dihydroxyflavone changes the structural dynamics of neocortical pyramidal neurons and improves object recognition in mice. AB - BDNF and its receptor TrkB have important roles in neurodevelopment, neural plasticity, learning, and memory. Alterations in TrkB expression have been described in different CNS disorders. Therefore, drugs interacting with TrkB, specially agonists, are promising therapeutic tools. Among them, the recently described 7,8-dihydroxyflavone (DHF), an orally bioactive compound, has been successfully tested in animal models of these diseases. Recent studies have shown the influence of this drug on the structure of pyramidal neurons, specifically on dendritic spine density. However, there is no information yet on how DHF may alter the structural dynamics of these neurons (i.e., real-time study of the addition/elimination of dendritic spines and axonal boutons). To gain knowledge on these effects of DHF, we have performed a real-time analysis of spine and axonal dynamics in pyramidal neurons of barrel cortex, using cranial windows and 2-photon microscopy during a chronic oral treatment with this drug. After confirming TrkB expression in these neurons, we found that DHF increased the gain rates of spines and axonal boutons, as well as improved object recognition memory. These results help to understand how the activation of the BDNF-TrkB system can improve basic behavioral tasks through changes in the structural dynamics of pyramidal neurons. Moreover, they highlight DHF as a promising therapeutic vector for certain brain disorders in which this system is altered. PMID- 29500538 TI - Letter to the Editor concerning pain catastrophizing as a predictor for postoperative pain and opiate consumption in total joint arthroplasty patients. Arch Orthop Trauma Surg. 2017 ;137:1623-1629. PMID- 29500537 TI - Spatio-temporal specialization of GABAergic septo-hippocampal neurons for rhythmic network activity. AB - Medial septal GABAergic neurons of the basal forebrain innervate the hippocampus and related cortical areas, contributing to the coordination of network activity, such as theta oscillations and sharp wave-ripple events, via a preferential innervation of GABAergic interneurons. Individual medial septal neurons display diverse activity patterns, which may be related to their termination in different cortical areas and/or to the different types of innervated interneurons. To test these hypotheses, we extracellularly recorded and juxtacellularly labeled single medial septal neurons in anesthetized rats in vivo during hippocampal theta and ripple oscillations, traced their axons to distant cortical target areas, and analyzed their postsynaptic interneurons. Medial septal GABAergic neurons exhibiting different hippocampal theta phase preferences and/or sharp wave-ripple related activity terminated in restricted hippocampal regions, and selectively targeted a limited number of interneuron types, as established on the basis of molecular markers. We demonstrate the preferential innervation of bistratified cells in CA1 and of basket cells in CA3 by individual axons. One group of septal neurons was suppressed during sharp wave-ripples, maintained their firing rate across theta and non-theta network states and mainly fired along the descending phase of CA1 theta oscillations. In contrast, neurons that were active during sharp wave-ripples increased their firing significantly during "theta" compared to "non-theta" states, with most firing during the ascending phase of theta oscillations. These results demonstrate that specialized septal GABAergic neurons contribute to the coordination of network activity through parallel, target area- and cell type-selective projections to the hippocampus. PMID- 29500539 TI - Palaeotoxicity: reconstructing the risk of multiple sedimentary pollutants to freshwater organisms. AB - 'Real-world' contaminant exposure of sediment-dwelling biota is typically long term, low-level and to multiple pollutants. However, sediment quality guidelines, designed to protect these organisms, relate only to single contaminants. This study uses radiometrically dated sediment cores from 7 English lakes with varying contamination histories to reconstruct temporal changes in likely risk to biota (herein termed 'palaeotoxicity'). The Probable Effects Concentration Quotient (PEC-Q) approach was used to combine sediment concentrations from multiple contaminants (trace metals; PCBs; PBDEs) to determine risk allocated to metals and persistent organic pollutants (POPs) separately as well as combined (PEC-Q Mean-All). Urban-influenced lakes were considerably more contaminated, exceeding PEC-Q thresholds of 0.5 and 2.0 over long durations (some since the nineteenth century). This has been mainly due to metals (principally lead) and by factors of up to 10 for individual metals and by > 2 for PEC-Q Mean-Metals. In 6 out of 7 lakes, considerable reductions in risk associated with trace metals are observed since emissions reductions in the 1970s. However, at all lakes, PEC-Q Mean-POPs has increased sharply since the 1950s and at 5 out of 7 lakes now exceeds PEC-Q Mean-Metals. These organic pollutants are therefore now the dominant driver behind elevated contaminant risk to sediment-dwelling biota and recent temporal trends in PEC-Q Mean-All remain above threshold values as a result. Finally, PEC Q Mean-All values were compared to standard biological toxicity tests for surface sediments at each site. While chironomid growth and daphniid reproduction were significantly reduced compared to controls at 5 out of 7, and all lakes, respectively, the scale of these reductions showed only limited quantitative agreement with predicted risk. PMID- 29500540 TI - Evaluation of the chemopreventive effects of Ankaferd Bloodstopper in 7,12 dimethylbenz[a]anthracene-induced oral epithelial dysplasia. AB - OBJECTIVES: Ankaferd BloodStopper(r) (ABS) is an herbal extract which has been used historically as a hemostatic agent in traditional Turkish medicine. ABS comprises of standardized mixture of herbs Thymus vulgaris, Glycyrrhiza glabra, Vitis vinifera, Alpinia officinarum, and Urtica dioica. In addition to its hemostatic effects, the herb ABS contains some other biological effects including antioxidant and antitumoral properties. The aim of this study is to investigate the chemopreventive effects of ABS in 7,12-dimethylbenz[a]anthracene (DMBA) induced oral epithelial dysplasia. MATERIALS AND METHODS: A total of 40 Sprague Dawley rats were randomly divided into four groups. Group 1 animals received DMBA alone, and group 2 animals received both DMBA and Ankaferd. Group 3 animals received ABS alone while group 4 animals served as control group and received only liquid paraffine. All animals were sacrificed, and tissue samples were analyzed histologically at the end of the experimental period (14 weeks). RESULTS: Histological studies have shown that the buccal pouches of animals treated with DMBA alone revealed severe dysplasia while only mild or no dysplasia were noticed in DMBA + ABS group. Ankaferd were administered to animals and control group showed no dysplasia or other oral lesions. CONCLUSION: The results suggest that Ankaferd Bloodstopper(r) has chemopreventive effect against DMBA induced oral epithelial dysplasia. CLINICAL RELEVANCE: Ankaferd Bloodstopper(r) could be used as a supportive treatment option of cancer in oral and maxillofacial surgery since it possesses chemopreventive effect. PMID- 29500541 TI - Impact of different concentrations of an octenidine dihydrochloride mouthwash on salivary bacterial counts: a randomized, placebo-controlled cross-over trial. AB - OBJECTIVES: This bi-centric, placebo-controlled, randomized, evaluator-blinded, incomplete cross-over clinical phase II trial was initialized to identify the most appropriate concentration of octenidine dihydrochloride (OCT) in mouth rinses. MATERIALS AND METHODS: Rinses of 0.10, 0.15, and 0.20% OCT were compared to a saline placebo rinse regarding the reduction of salivary bacterial counts (SBCs) in 90 gingivitis patients over 4 days. Changes in plaque (PI) and gingival index (GI), taste perception, and safety issues were evaluated. RESULTS: At baseline, the first OCT (0.10, 0.15, 0.20%) rinse resulted in a decrease of SBC (reduction by 3.63-5.44 log10 colony forming units [CFU]) compared to placebo (p < 0.001). Differences between OCT concentrations were not verified. After 4 days, the last OCT rinse again resulted in a significant SBC decrease (3.69-4.22 log10 CFU) compared to placebo (p < 0.001). Overall, SBC reduction between baseline and day 4 was significantly higher in OCT 0.15 and 0.20% groups compared to OCT 0.10% and placebo. Mean GI/PIs were significantly lower in OCT groups than in the placebo group (p < 0.001). Differences in GI/PI between OCT groups were not verified. Adverse effects increased with increasing OCT concentrations. CONCLUSIONS: Considering antibacterial efficacy, frequency of adverse events, and user acceptance, 0.10% OCT was identified as the preferred concentration to be used in future clinical trials. CLINICAL RELEVANCE: Due to its low toxicity and pronounced antibacterial properties, octenidine dihydrochloride (OCT) is a promising candidate for the use in antiseptic mouth rinses. OCT concentrations of 0.10% are recommended for future clinical trials evaluating the plaque-reducing properties of OCT mouth rinses. ( www.clinicaltrials.gov , NCT022138552). PMID- 29500542 TI - Cardiac autonomic function in children with type 1 diabetes. AB - : Cardiovascular autonomic neuropathy (CAN) is a major complication of type 1 diabetes (T1D). This study aimed to evaluate cardiac autonomic nervous system (ANS) function in children with T1D and its relation to different demographic, clinical and laboratory variable. This cross-sectional study included 60 children with T1D (mean age = 15.1 +/- 3.3 years; duration of diabetes = 7.95 +/- 3.83 years). The following 8 non-invasive autonomic testing were used for evaluation: heart rate at rest and in response to active standing (30:15 ratio), deep breathing and Valsalva maneuver (indicating parasympathetic function); blood pressure response to standing (orthostatic hypotension or OH), sustained handgrip and cold; and heart rate response to standing or positional orthostatic tachycardia syndrome or POTs (indicating sympathetic function). None had clinically manifest CAN. Compared to healthy children (5%), 36.67% of children with T1D had >= 2 abnormal tests (i.e., CAN) (P = 0.0001) which included significantly abnormal heart rate response to standing (POTs) (P = 0.052), active standing (30:15 ratio) (P = 0.0001) and Valsalva maneuver (P = 0.0001), indicating parasympathetic autonomic dysfunction, and blood pressure response to cold (P = 0.01), indicating sympathetic autonomic dysfunction. 54.55, 27.27 and 18.18% had early, definite and severe dysfunction of ANS. All patients had sensorimotor peripheral neuropathy. The longer duration of diabetes (> 5 years), presence of diabetic complications and worse glycemic control were significantly associated with CAN. CONCLUSIONS: The study concluded that both parasympathetic and sympathetic autonomic dysfunctions are common in children with T1D particularly with longer duration of diabetes and presence of microvascular complications. What is Known: * Cardiovascular autonomic neuropathy (CAN) is a major complication of type 1 diabetes (T1D). * Limited studies evaluated CAN in children with T1D. What is New: * CAN is common in children with T1D. * Cardiac autonomic functions should be assessed in children with T1D particularly in presence of microvascular complications. PMID- 29500543 TI - Recurrent esophageal perforation after anterior cervical spine surgery: case report. AB - PURPOSE: Delayed esophageal perforation after anterior cervical discectomy and fusion (ACDF) is an extremely rare cause of infection such as spondylodiscitis. We present a rare case in which a patient had two delayed esophageal perforations occurring 20 and 25 years after ACDF. By sharing our experience of this rare case, we hope to provide new information related to delayed esophageal perforation. METHODS: We present the case of a 72-year-old patient who underwent ACDF due to cervical spondylosis 25 years ago. Delayed esophageal perforation occurred 20 years postoperatively and healed spontaneously with conservative treatment. RESULTS: Five years later, a second esophageal perforation occurred, which required surgical intervention and involved recurrent infection. CONCLUSIONS: We suggest that it is important to consider follow-up in patients with spontaneously healed esophageal perforations. Furthermore, any patient with symptoms subsequent to a spontaneously healed esophageal perforation, even after an interval of several years, should receive a thorough evaluation for possible recurrent esophageal perforation. PMID- 29500544 TI - Effects of environmental parameters on the chestnut gall wasp and its complex of indigenous parasitoids. AB - The chestnut gall wasp (CGW), Dryocosmus kuriphilus, an invasive pest native to China, has caused severe yield and economic losses to chestnut production in Europe since its arrival in 2002. In Southern Italy, the complex of indigenous parasitoids colonizing CGW was monitored between 2013 and 2015, with the aim of estimating the composition of the indigenous parasitoid complex, its ability to control CGW populations, and the interactions of both factors with several measured environmental parameters. We compared results among three differently managed field types. Results showed an increase in the rate of parasitism both when the host population density was lower and in unmanaged chestnut stands with more natural conditions. The percentage of parasitism in galls was related to morphological traits of the galls and to higher seasonal temperatures, which reduced the parasitism intensity because CGW develops earlier under such conditions. The host-parasitoid mortality inside galls varied among sites and was associated mostly with rot fungi during wet spring and summer months. Parasitoid species richness was similar among the study sites, but the proportion of parasitoid species differed between orchards and unmanaged coppice stands. The timing of attack by parasitoids followed a species-specific successional sequence throughout the larva-to-adult life cycle of the CGW. These interactions should be considered in future research on trophic relationships and when modeling invasive scenarios for new pest species. PMID- 29500545 TI - Effect of Qinghuang Powder () combined with Bupi Yishen Decoction () in treating patients with refractory cytopenia with multilineage dysplasia through regulating DNA methylation. AB - OBJECTIVE: To explore the effect of Qinghuang Powder (QHP, ) combined with Bupi Yishen Decoction (BPYS, ) on myelodysplastic syndromes (MDS) patients with refractory cytopenia with multilineage dysplasia (RCMD) and determine the change of DNA methylation in MDS-RCMD patients after the treatment of Chinese medicine formula. METHODS: All 308 MDS-RCMD patients were treated with QHP combined with BPYS for 2 months at least, absolute neutrophil count (ANC), hemoglobin (Hb), platelets (PLT), primitive bone marrow cells and chromosome karyotype were chosen as the main evaluation indexes to analyze the treatment effect according to criteria from the MDS International Working Group. Then 43 bone marrow samples from 15 MDS-RCMD patients and 28 healthy donors were obtained for the examination of DNA methylation. Gene Ontology (GO) and Pathway analysis were applied to analyze the methylation data. RESULTS: The overall MDS response rate to QHP was 61.68% (190/360) including hematologic improvement-neutrophil (HI-N) or hematologic improvement-erythroid (HI-E) or hematologic improvement-platelet (HI P). Patients with anemia had a better response rate than patients with neutropenia or thrombocypenia (55.88% vs 31.54% or 55.88% vs. 36.9%). The DNA methylation microarray analysis disclosed that 4,257 hypermethylated genes were demethylated upon the treatment with QHP and BPYS. GO analysis and Pathway analysis showed that these demethylated genes were involved in a lot of tumor related pathways and functions. CONCLUSIONS: QHP combined with BPYS could effectively treat MDS-RCMD patients through hematologic improvement (HI-N, HI-P or HI-E) and PLT and RBC transfusion independence due to the demethylation, thereby providing another choice for the treatment of patients with MDS-RCMD. PMID- 29500546 TI - A gender dimorphism in up-regulation of BACE1 gene expression in schizophrenia. AB - Schizophrenia has long been considered as a devastating brain disorder in which both genetic and environmental factors are involved. The BACE1 gene is one of the most important susceptibility genes for this disorder. However, the changes in BACE1 expression in schizophrenic patients compared with healthy subjects have not been evaluated yet. In this case-control study, we examined BACE1 expression in a group of 50 patients with schizophrenia and 50 healthy controls. The level of BACE1 gene expression was measured using Real-Time PCR. Substantial increase in gene expression was detected in the patients compared with normal individuals (P = 0.001). Furthermore, a gender dimorphism was observed in BACE1 gene expression in the patients in a way that the male patients manifested a statistically significant higher levels of BACE1 expression (P = 0.002). BACE1 might be implicated in the pathogenesis of schizophrenia. Besides, BACE1 physiology may be gender -based at some levels. Our findings warrant an investigation of BACE1 gene in a larger number of cases and controls. PMID- 29500547 TI - A new large-scale index (AcED) for assessing traffic noise disturbance on wildlife: stress response in a roe deer (Capreolus capreolus) population. AB - Anthropogenic noise is a growing ubiquitous and pervasive pollutant as well as a recognised stressor that spreads throughout natural ecosystems. However, there is still an urgent need for the assessment of noise impact on natural ecosystems. This article presents a multidisciplinary study which made it possible to isolate noise due to road traffic to evaluate it as a major driver of detrimental effects on wildlife populations. A new indicator has been defined: AcED (the acoustic escape distance) and faecal cortisol metabolites (FCM) were extracted from roe deer faecal samples as a validated indicator of physiological stress in animals moving around in two low-traffic roads that cross a National Park in Spain. Two key findings turned out to be relevant in this study: (i) road identity (i.e. road type defined by traffic volume and average speed) and AcED were the variables that best explained the FCM values observed in roe deer, and (ii) FCM concentration was positively related to increasing traffic volume (road type) and AcED values. Our results suggest that FCM analysis and noise mapping have shown themselves to be useful tools in multidisciplinary approaches and environmental monitoring. Furthermore, our findings aroused the suspicion that low-traffic roads (< 1000 vehicles per day) could be capable of causing higher habitat degradation than has been deemed until now. PMID- 29500548 TI - CpG-PEG Conjugates and their Immune Modulating Effects after Systemic Administration. AB - PURPOSE: Synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs were found to be able to target cells that express Toll-like receptor 9 to modulate innate and adaptive immune reactions. But their in vivo application in immunotherapy against cancer has not been successful. We attempted in this study to examine polyethylene-glycol (PEG) conjugated CpG ODNs and investigated their mechanism of immune modulation in anti-cancer therapy. METHODS: CpG-PEG conjugates with different PEG lengths were synthesized. In vitro activity as well as in vivo pharmacokinetics and pharmacodynamics properties were evaluated. RESULTS: CpG-PEG20Ks were found to be able to persist longer in circulation and activate various downstream effector cells. After intravenous injection, they resulted in higher levels of IL-12p70 in the circulation and lower M-MDSC infiltrates in the tumor microenvironment. Such activities were different from those of CpG ODNs without PEGylation, suggesting different PK-PD profiles systemically and locally. CONCLUSIONS: Our data support the development of CpG PEGs as a new therapeutic agent that can be systemically administered to modulate immune responses and the microenvironment in tumor tissues. PMID- 29500549 TI - Study on the Mechanisms of Active Compounds in Traditional Chinese Medicine for the Treatment of Influenza Virus by Virtual Screening. AB - In recent years, new strains of influenza virus such as H7N9, H10N8, H5N6 and H5N8 had continued to emerge. There was an urgent need for discovery of new anti influenza virus drugs as well as accurate and efficient large-scale inhibitor screening methods. In this study, we focused on six influenza virus proteins that could be anti-influenza drug targets, including neuraminidase (NA), hemagglutinin (HA), matrix protein 1 (M1), M2 proton channel (M2), nucleoprotein (NP) and non structural protein 1 (NS1). Structure-based molecular docking was utilized to identify potential inhibitors for these drug targets from 13144 compounds in the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. The results showed that 56 compounds could inhibit more than two drug targets simultaneously. Further, we utilized reverse docking to study the interaction of these compounds with host targets. Finally, the 22 compound inhibitors could stably bind to host targets with high binding free energy. The results showed that the Chinese herbal medicines had a multi-target effect, which could directly inhibit influenza virus by the target viral protein and indirectly inhibit virus by the human target protein. This method was of great value for large-scale virtual screening of new anti-influenza virus compounds. PMID- 29500550 TI - [Case series on SBRT in ventricular tachycardia reveals an impressive therapeutic effect]. PMID- 29500552 TI - [Arthroscopic decompression of extra-articular subspinal hip impingement]. AB - OBJECTIVE: Complete arthroscopic decompression of the impinging subspinal soft tissues and resection of the hypertrophic bone formation between the anterior hip capsule and the anterior inferior iliac spine (AIIS) or decompression of a hypertrophic AIIS. INDICATIONS: Painful anterior hip impingement and decreased hip flexion following a hypertrophic osseous subspinal deformation. CONTRAINDICATIONS: No clinical symptoms or decreased anterior hip function despite radiological osseous subspinal hip impingement. SURGICAL TECHNIQUE: Hip arthroscopy in supine position on an extension table. Treatment of possible intraarticular hip pathologies in the central or peripheral compartment. Arthroscopic visualization of the hypertrophic impinging soft tissues below the AIIS and decompression using a shaver or radiofrequency device. Complete arthroscopic resection of the hypertrophic AIIS parts and the osseous subspinal deformation using a high speed burr under fluoroscopic control. POSTOPERATIVE MANAGEMENT: Early functional rehabilitation with full weight-bearing and unlimited hip motion; 3 weeks ossification prophylaxis and 8 weeks of limitation for jumping and running sports activities. RESULTS: There are no comparative studies or medium- and long-term study results in the literature for arthroscopic AIIS decompression. However, currently published case series show an improvement of the determined scores. PMID- 29500553 TI - A hybrid computational model for collective cell durotaxis. AB - Collective cell migration is regulated by a complex set of mechanical interactions and cellular mechanisms. Collective migration emerges from mechanisms occurring at single cell level, involving processes like contraction, polymerization and depolymerization, of cell-cell interactions and of cell substrate adhesion. Here, we present a computational framework which simulates the dynamics of this emergent behavior conditioned by substrates with stiffness gradients. The computational model reproduces the cell's ability to move toward the stiffer part of the substrate, process known as durotaxis. It combines the continuous formulation of truss elements and a particle-based approach to simulate the dynamics of cell-matrix adhesions and cell-cell interactions. Using this hybrid approach, researchers can quickly create a quantitative model to understand the regulatory role of different mechanical conditions on the dynamics of collective cell migration. Our model shows that durotaxis occurs due to the ability of cells to deform the substrate more in the part of lower stiffness than in the stiffer part. This effect explains why cell collective movement is more effective than single cell movement in stiffness gradient conditions. In addition, we numerically evaluate how gradient stiffness properties, cell monolayer size and force transmission between cells and extracellular matrix are crucial in regulating durotaxis. PMID- 29500551 TI - Immune modulatory effects of radiotherapy as basis for well-reasoned radioimmunotherapies. AB - BACKGROUND: Radiotherapy (RT) has been known for decades as a local treatment modality for malign and benign disease. In order to efficiently exploit the therapeutic potential of RT, an understanding of the immune modulatory properties of ionizing radiation is mandatory. These should be used for improvement of radioimmunotherapies for cancer in particular. METHODS: We here summarize the latest research and review articles about immune modulatory properties of RT, with focus on radiation dose and on combination of RT with selected immunotherapies. Based on the knowledge of the manifold immune mechanisms that are triggered by RT, thought-provoking impulse for multimodal radioimmunotherapies is provided. RESULTS: It has become obvious that ionizing radiation induces various forms of cell death and associated processes via DNA damage initiation and triggering of cellular stress responses. Immunogenic cell death (ICD) is of special interest since it activates the immune system via release of danger signals and via direct activation of immune cells. While RT with higher single doses in particular induces ICD, RT with a lower dose is mainly responsible for immune cell recruitment and for attenuation of an existing inflammation. The counteracting immunosuppression emanating from tumor cells can be overcome by combining RT with selected immunotherapies such as immune checkpoint inhibition, TGF-beta inhibitors, and boosting of immunity with vaccination. CONCLUSION: In order to exploit the full power of RT and thereby develop efficient radioimmunotherapies, the dose per fraction used in RT protocols, the fractionation, the quality, and the quantity of certain immunotherapies need to be qualitatively and chronologically well-matched to the individual immune status of the patient. PMID- 29500554 TI - Titanium mini locking plate with trans-osseous sutures for the treatment of humeral greater tuberosity fracture osteosynthesis versus PHILOS: a retrospective view. AB - PURPOSE: Greater tuberosity fractures (GTFs) account for 17 to 21% of proximal humerus fractures, most of these fractures are treated conservatively, but treatment for displaced fractures is still controversial. The aim of this study is to compare intra-operative clinical conditions and post-operative outcomes when displaced GTFs are treated with either proximal humeral internal locking system (PHILOS) or mini locking plate with trans-osseous sutures. METHODS: This is a retrospective study conducted in Shanghai Tenth People's Hospital. A total of 60 patients (22 males and 38 females) with displaced humeral GTF between May 2013 and March 2017 were included, of whom 43 underwent PHILOS implant treatment and 17 underwent titanium mini plate implant with trans-osseous suture treatment. Intra-operative (incision size, intra-operative blood loss, operative duration) and postoperative (Constant-Murley score (CMS) and implant cost) variables were recorded for the comparison. RESULTS: Mini locking plate with trans-osseous sutures shows better results. Operative duration (PHILOS mean 77.0 minutes vs mean 63.7 minutes, p value < 0.05), blood loss during surgery (PHILOS mean 111.5 vs 66.5 ml, p value < 0.05), incision size (PHILOS mean 7.2 vs 4.6 cm, p value < 0.05), CMS (PHILOS mean 81.0 vs 87.3, p value < 0.05), and implant costs (PHILOS mean 26,192.6 renminbi (RMB) vs mean 21,358.8 RMB, p value < 0.05). On the other hand, 9.30% of impingement in the PHILOS group was observed to have no complications compared to the mini locking plate group. CONCLUSIONS: Mini locking plate with trans-osseous sutures shows better efficacy in reducing the incision size, operative duration, intraoperative blood loss, and implant cost and in improving CMS. No complication was found with its use. Our data can provide rationale and inform sample- size calculations for such studies. Larger, control studies are needed for better understanding. PMID- 29500555 TI - Switching Reference Medicines to Biosimilars: A Systematic Literature Review of Clinical Outcomes. AB - INTRODUCTION: To evaluate the possibility that switching from reference biologic medicines to biosimilars could lead to altered clinical outcomes, including enhanced immunogenicity, compromised safety, or diminished efficacy for patients, a systematic literature review was conducted of all switching studies between related biologics (including biosimilars). METHODS: A systematic search was conducted using the Medline(r) and Embase(r) databases up to 30 June 2017 employing specific medical subject heading terms. Additionally, the snowball method and a hand search were also applied. Publications were considered if they contained efficacy or safety information related to a switch from a reference medicine to a biosimilar. Non-English, non-human studies, editorials, notes, and short surveys were excluded. RESULTS: Primary data were available from 90 studies that enrolled 14,225 unique individuals. They included protein medicines used in supportive care as well as those used as therapeutic agents. The medicines contained seven different molecular entities that were used to treat 14 diseases. The great majority of the publications did not report differences in immunogenicity, safety, or efficacy. The nature and intensity of safety signals reported after switching from reference medicines to biosimilars were the same as those already known from continued use of the reference medicines alone. Three large multiple switch studies with different biosimilars did not show differences in efficacy or safety after multiple switches between reference medicine and biosimilar. Two publications reported a loss of efficacy or increased dropout rates. CONCLUSIONS: While use of each biologic must be assessed individually, these results provide reassurance to healthcare professionals and the public that the risk of immunogenicity-related safety concerns or diminished efficacy is unchanged after switching from a reference biologic to a biosimilar medicine. PMID- 29500556 TI - Correction to: Lonoctocog Alfa: A Review in Haemophilia A. AB - The article Lonoctocog Alfa: A Review in Haemophilia A, written by Zaina T. Al Salama and Lesley J. Scott, was originally published Online First without open access. After publication in volume 77, issue 15, pages 1677-1686 CSL Behring GmbH requested that the article be Open Choice to make the article an open access publication. Post-publication open access was funded by CSL Behring GmbH. Further details may be found at http://www.medengine.com/Redeem/CBD8F060224F2E65 . The article is forthwith distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License ( http://creativecommons.org/licenses/by-nc/4.0/ ), which permits any noncommercial use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. PMID- 29500557 TI - Assessing information needs and use of online resources for disease self management in patients with rheumatoid arthritis: a qualitative study. AB - To explore the information needs of patients with rheumatoid arthritis (RA) and their acceptance of online resources and Facebook in particular, as a source of information, interaction, and support among peers. Participants were adults with RA of <= 10 years duration, had ongoing or prior treatment with disease-modifying anti-rheumatic drugs or biologic agents, and internet access. We conducted 20 in depth interviews using semi-structured interview guide to explore: (1) RA information needs, (2) use of self-management health behaviors, (3) use of internet resources for disease management, (4) role of peer support in health self-management, and (5) use of social networking sites (SNS) such as Facebook in disease management. Data were analyzed using content analysis and constant comparative methods. Participants were mainly female (85%), White (70%), and over 50 years old (70%). Specific information needs included knowledge regarding medications, disease course, pain control, diet, and exercise. Most participants had a narrow perception of SNS as a tool for disease management. However, they found SNS acceptable and were open to participating in a support group on Facebook with reasonable assurance of privacy. Although the overarching theme was RA information needs, the other themes contribute in supporting the robust emergence of Internet media in informing patients about their health and support systems. Our findings can inform the choice and format of materials to be considered for online education on self-management and social networking for RA patients. PMID- 29500558 TI - Emergency physician-performed ultrasound-guided nerve blocks in proximal femoral fractures provide safe and effective pain relief: a prospective observational study in The Netherlands. AB - BACKGROUND: The treatment of acute pain in the emergency department is not always optimal. Peripheral nerve blocks using "blind" or nerve stimulator techniques have substantial disadvantages. Ultrasound-guided regional anesthesia may provide quick, safe, and effective pain relief in patients with proximal femoral fractures with severe pain. However, no evidence exists on emergency physician performed ultrasound-guided regional anesthesia in these patients in Dutch emergency departments. We hypothesized that emergency physicians can be effectively trained to safely perform and implement ultrasound-guided femoral nerve blocks, resulting in effective pain relief in patients with proximal femoral fractures. METHODS: In this prospective observational study, emergency physicians were trained by expert anesthesiologists to perform ultrasound-guided femoral nerve blocks during a single-day course. Femoral nerve blocks were performed on patients with proximal femoral fractures. A system of direct supervision by skilled anesthesiologists and residents was put in place. RESULTS: A total of 64 femoral nerve blocks were performed. After 30 min, blocks were effective in 69% of patients, and after 60 min, in 83.3%. The mean reduction in pain scores after 30 and 60 min was 3.84 and 4.77, respectively (both p < 0.001). Patients reported a mean satisfaction of 8.42 (1 to 10 scale). No adverse events occurred. CONCLUSIONS: Ultrasound-guided femoral nerve block is an effective, safe, and easy to learn (single-day course) procedure for emergency physicians to implement and perform in the emergency department. Patient satisfaction was high. PMID- 29500560 TI - Agrobacterium-Mediated Transformation in the Evolution of Plants. AB - In most cases, the genetic engineering of plants uses Agrobacterium-mediated transformation to introduce novel genes. In nature, insertion of T-DNA into the plant genome and its subsequent transfer via sexual reproduction have been shown for several species in the genera Nicotiana, Ipomoea , and Linaria . A sequence homologous to T-DNA of the Ri plasmid of Agrobacterium rhizogenes was found in the genome of wild-type Nicotiana glauca (section Noctiflorae) more than 30 years ago and was named "cellular T-DNA" (cT-DNA). It comprises an imperfect inverted repeat and contains homologs of several T-DNA oncogenes (NgrolB, NgrolC, Ngorf13, Ngorf14) and an opine synthesis gene (Ngmis). Multiple cT-DNAs have also been found in species of the sections Tomentosae and Nicotiana of the genus Nicotiana. These ancient cT-DNA genes are still expressed, indicating that they may play a role in the evolution of these plants. In 2012-2013, cT-DNA was detected and characterized in Linaria vulgaris and L. genistifolia ssp. dalmatica. Their cT DNA is present in two copies and organized as an imperfect direct tandem repeat, containing LvORF2, LvORF3, LvORF8, LvrolA, LvrolB, LvrolC, LvORF13, LvORF14, and the Lvmis genes. In 2015, cT-DNA was found in Ipomoea. Two types of T-DNA-like sequences were described within this genera, and their distribution varied among cultured hexaploid, tetraploid, and wild diploid forms. Thus, several independent T-DNA integration events occurred in the genomes of these three plant genera. We propose that the events of T-DNA insertion in the plant genome might have affected their evolution, resulting in the creation of new plant species. In this chapter, we focus on the structure and functions of cT-DNA in Linaria, Nicotiana, and Ipomoea and discuss their possible evolutionary role. PMID- 29500559 TI - The prognostic value of bispectral index and suppression ratio monitoring after out-of-hospital cardiac arrest: a prospective observational study. AB - BACKGROUND: We investigated the ability of bispectral index (BIS) monitoring to predict poor neurological outcome in out-of-hospital cardiac arrest (OHCA) patients fully treated according to guidelines. RESULTS: In this prospective, observational study, 77 successfully resuscitated OHCA patients were enrolled in whom BIS, suppression ratio (SR) and electromyographic (EMG) values were continuously monitored during the first 36 h after the initiation of targeted temperature management at 33 degrees C. The Cerebral Performance Category (CPC) scale was used to define patients' outcome at 180 days after OHCA (CPC 1-2: good CPC 3-5: poor neurological outcome). Using mean BIS and SR values calculated per hour, receiver operator characteristics curves were constructed to determine the optimal time point and threshold to predict poor neurological outcome. At 180 days post-cardiac arrest, 39 patients (51%) had a poor neurological outcome. A mean BIS value <= 25 at hour 12 predicted poor neurological outcome with a sensitivity of 49% (95% CI 30-65%), a specificity of 97% (95% CI 85-100%) and false positive rate (FPR) of 6% (95% CI 0-29%) [AUC: 0.722 (0.570-0.875); p = 0.006]. A mean SR value >= 3 at hour 23 predicted poor neurological with a sensitivity of 74% (95% CI 56-87%), a specificity of 92% (95% CI 78-98%) and FPR of 11% (95% CI 3-29%) [AUC: 0.836 (0.717-0.955); p < 0.001]. No relationship was found between mean EMG and BIS < 25 (R2 = 0.004; p = 0.209). CONCLUSION: This study found that mean BIS <= 25 at hour 12 and mean SR >= 3 at hour 23 might be used to predict poor neurological outcome in an OHCA population with a presumed cardiac cause. Since no correlation was observed between EMG and BIS < 25, our calculated BIS threshold might assist with poor outcome prognostication following OHCA. PMID- 29500561 TI - Beyond Agrobacterium-Mediated Transformation: Horizontal Gene Transfer from Bacteria to Eukaryotes. AB - Besides the massive gene transfer from organelles to the nuclear genomes, which occurred during the early evolution of eukaryote lineages, the importance of horizontal gene transfer (HGT) in eukaryotes remains controversial. Yet, increasing amounts of genomic data reveal many cases of bacterium-to-eukaryote HGT that likely represent a significant force in adaptive evolution of eukaryotic species. However, DNA transfer involved in genetic transformation of plants by Agrobacterium species has traditionally been considered as the unique example of natural DNA transfer and integration into eukaryotic genomes. Recent discoveries indicate that the repertoire of donor bacterial species and of recipient eukaryotic hosts potentially are much wider than previously thought, including donor bacterial species, such as plant symbiotic nitrogen-fixing bacteria (e.g., Rhizobium etli) and animal bacterial pathogens (e.g., Bartonella henselae, Helicobacter pylori), and recipient species from virtually all eukaryotic clades. Here, we review the molecular pathways and potential mechanisms of these trans kingdom HGT events and discuss their utilization in biotechnology and research. PMID- 29500562 TI - One More Decade of Agrobacterium Taxonomy. AB - This chapter presents a historical overview of the development and changes in scientific approaches to classifying members of the Agrobacterium genus. We also describe the changes in the inference of evolutionary relationships among Agrobacterium biovars and Agrobacterium strains from using the 16S rRNA marker to recA genes and to the use of multilocus sequence analysis (MLSA). Further, the impacts of the genomic era enabling low cost and rapid whole genome sequencing on Agrobacterium phylogeny are reviewed with a focus on the use of new and sophisticated bioinformatics approaches to refine phylogenetic inferences. An updated genome-based phylogeny of ninety-seven Agrobacterium tumefaciens complex isolates representing ten known genomic species is presented, providing additional support to the monophyly of the Agrobacterium clade. Additional taxon sampling within Agrobacterium genomovar G3 indicates potential exceptions to interpretation of the concept of bacterial genomics species as ecological species because the genomovar G3 genomic cluster, which initially includes clinical strains, now also includes plant-associated and cave isolates. PMID- 29500563 TI - ? PMID- 29500564 TI - ? PMID- 29500565 TI - Spheroid Culture System Confers Differentiated Transcriptome Profile and Functional Advantage to 3T3-L1 Adipocytes. AB - This study highlights functional differences between 2-D monolayer and 3-D spheroid 3T3-L1 adipocyte culture models and explores the underlying genomic mechanisms responsible for the different phenotypes present. The spheroids showed higher triglyceride accumulation than the monolayer culture and further increase with larger spheroid size. Whole transcriptome analysis indicated significant differential expression of genes related to adipogenesis, including adipocytokine signaling, fatty acid metabolism, and PPAR-gamma signaling. Spheroids also showed downregulation of matrix metalloproteinases (MMPs), integrin, actin-cytoskeleton associated genes, and Rho/GTPase3 expression relative to 2-D monolayer, indicating suppression of the Rho-ROCK pathway and thereby promoting adipogenic differentiation. When exposed to linoleic acid (500 MUM) and TNF-alpha (125 ng/mL) to promote chronic adiposity, linoleic acid treatment resulted in increased intracellular triglycerides and subsequent TNF-alpha treatment resulted in significantly altered adipocytokine signaling, fatty acid metabolism, and PPAR signaling, in addition to upregulation of multiple MMPs in spheroids vs. monolayer. Overall, 3-D spheroids showed enhanced adipogenic phenotype as indicated by triglyceride synthesis and transcriptome changes while retaining sensitivity to a pro-inflammatory stimulus. The 3-D spheroid culture thus may provide a simple, convenient, and sensitive in vitro model to study adipocyte response to metabolic stresses relevant to clinical pathologies. PMID- 29500566 TI - Development of an In Vitro 3D Brain Tissue Model Mimicking In Vivo-Like Pro inflammatory and Pro-oxidative Responses. AB - To analyze complex inflammatory responses in an in vitro system, we constructed a new 3D in vitro brain tissue model that exhibits in vivo-like tissue responses (e.g. immune cell phenotypes, and molecular response) to inflammatory stimuli. Finite element modeling of oxygen diffusion and cellular oxygen consumption predicted the oxygen profile within 3D structures, consisting of Type I collagen hydrogel embedded with murine microglia. Viability and cytotoxicity analyses supported the mathematical analysis, determining optimal cell growth conditions for 3D construct development. Real-time RT-PCR and ELISA demonstrated significant up-regulation of pro-inflammatory mediators, such as TNF-alpha, MCP-1, IL-6 and IL-1beta, in lipopolysaccharide (LPS)-stimulated in vitro cell culture (2D and 3D) and in vivo mouse model systems. Interestingly, levels of inflammatory responses from the in vitro 3D model system were more similar to in vivo than in vitro 2D. Additionally, in situ dihydroethidium (DHE) assay and immunofluorescence staining revealed that levels of LPS-stimulated reactive oxygen species (ROS) generation and microglial activation from in vitro 3D model system were closer to in vivo than in vitro 2D. These results demonstrated that an in vitro 3D model provides more physiologically relevant pro-oxidative and pro inflammatory environments in brain than an in vitro 2D model. PMID- 29500567 TI - Contact force facilitates the achievement of an unexcitable ablation line during pulmonary vein isolation. AB - AIMS: Contact force (CF) catheters provide catheter-tissue contact information to improve outcome of pulmonary vein isolation (PVI) in paroxysmal atrial fibrillation (PAF). We evaluated different target-CF values for achievement of the additional endpoint of an unexcitable ablation line. METHODS: A total of 106 patients undergoing PVI were randomized into three groups (G) (G1: target-CF 15 g, G2: target-CF 10 g, G3: CF concealed from operator). The PVI encircling line was divided into predefined sections. Excitable tissue along the PVI-line identified by high output pacing (10 V, 2 ms) was targeted for further ablation. RESULTS: Mean average CF was 17.4 +/- 4.7 g (G1) vs. 12.3 +/- 6.0 g (G2) vs. 11.1 +/- 6.5 g (G 3) (p < 0.001). Primary unexcitable ablation lines were found in 38.6, 19.4 and 5.7% (G1, G2, G3 respectively; G1 vs. G2 p < 0.05, G1 vs. G3 p < 0.001, G2 vs. G3 ns). Additional radiofrequency (RF)-energy to achieve unexcitability was lowest in G1 (3.6 +/- 3.1 kJ vs. 8.6 +/- 7.2 kJ (G2) and 10.4 +/- 6.7 (G3), p <= 0.001, G2 vs. G3 ns) with accordingly lowest additional RF applications in G1 (3.0 +/- 2.6 vs. 7.0 +/- 5.4 in G2 and 8.4 +/- 4.0 in G3; G1 vs. G2 and G3, p < 0.001, G 2 vs. G 3 ns). Sections along ablation lines with low initial CF were most likely to reveal excitability. Single procedure success was 81.9 vs. 73.5 vs. 71.4% (G 1, 2 and 3, p = 0.6) during 437 +/- 254 day follow-up. CONCLUSION: Higher tip-to-tissue CF during PVI facilitates the achievement of an unexcitable ablation line, requiring less additional RF-energy. PMID- 29500568 TI - Patent foramen ovale closure or medical therapy for cryptogenic ischemic stroke: an updated meta-analysis of randomized controlled trials. AB - BACKGROUND: Previous randomized controlled trials (RCT) failed to demonstrate benefits of patent foramen ovale (PFO) closure (PFO-C) over medical therapy (MT) for secondary prevention of cryptogenic ischemic stroke. Three recently published RCTs, however, turned out positive for PFO-C and warrant an updated meta analysis. METHODS: Data from all available RCTs on PFO-C vs. MT for secondary prevention of cryptogenic ischemic stroke up until October 2017 were abstracted and analyzed in a comprehensive meta-analysis. Clinical efficacy outcomes were recurrent stroke, recurrent TIA, and their combination; safety outcomes were mortality, major bleeding, venous thromboembolism (VTE), and new-onset atrial fibrillation/flutter (NOAF). RESULTS: Five trials including a total of 3440 patients were included in the meta-analysis. PFO-C significantly reduced recurrent stroke [odds ratio (OR) 0.41, 95% confidence interval (CI) 0.19-0.90; p = 0.03] and the combination of recurrent stroke + TIA (OR 0.53, CI 0.36-0.80; p = 0.002) compared to MT; recurrent TIA alone showed no differences (OR 0.77; CI 0.51-1.14; p = 0.19). NOAF was significantly more frequent after PFO-C (OR 5.75, CI 3.09-10.70; p < 0.00001). Mortality (OR 0.80, CI 0.39-1.67), major bleeding (OR 0.96, CI 0.48-1.92), and VTE (OR 2.45, CI 0.75-7.99) remained neutral. Trials with superior patient selection for PFO-C showed advantageous results compared to MT. CONCLUSIONS: PFO-C after cryptogenic ischemic stroke is safe and effective to reduce the risk of recurrent stroke and recurrent stroke + TIA, albeit with an increased risk for NOAF. PMID- 29500569 TI - A pathological study of the tongues of rabid dogs in the Philippines. AB - During rabies virus infections, the minor salivary glands are one of the important organs for virus replication and excretion into the oral cavity. However, details of pathological findings and viral antigen distribution in the minor salivary glands remain poorly understood. In this study, we conducted pathological tests on the tongues of 71 rabid dogs in the Philippines; the minor salivary glands (von Ebner's glands, lingual glands), circumvallate papilla, autonomic ganglia, and skeletal muscles were evaluated. Inflammatory changes were observed in the von Ebner's glands of 20/71 dogs, in the circumvallate papilla of 10/71, and in the tongue muscle of 1/71. Conversely, no morphological changes were observed in the lingual glands and autonomic ganglia. Viral antigens were detected via immunohistochemistry-based methods in the cytoplasm of the acinar epithelium in the von Ebner's glands of all 71 dogs. Virus particles were confirmed in the intercellular canaliculi and acinar lumen via electron microscopy. In the autonomic ganglia, viral antigens were detected in 67/71 rabid dogs. Viral antigens were detected in the taste buds of all 71 dogs, and were distributed mainly in type II and III taste bud cells. In tongue muscle fibers, viral antigens were detected in 11/71 dogs. No virus antigens were detected in lingual glands. These findings suggest that rabies virus descends in the tongue along the glossopharyngeal nerve after proliferation in the brain, and von Ebner's glands and taste buds are one of the portals of virus excretion into the saliva in rabid dogs. PMID- 29500570 TI - Discovery of a novel geminivirus associated with camellia chlorotic dwarf disease. AB - Next-generation sequencing of small RNAs and PCR amplification with two pairs of back-to-back primers, followed by cloning and sequencing, allowed identification of a novel geminivirus isolate provisionally named camellia chlorotic dwarf associated virus (CaCDaV). The complete genome sequence of CaCDaV comprises 3,687 nucleotides (nts) and six open reading frames (ORFs). The genome and putative proteins of CaCDaV were most closely related to those of two unclassified geminiviruses: citrus chlorotic dwarf-associated virus (CCDaV, 3,640 nt) and mulberry mosaic dwarf-associated virus (MMDaV, 2,952 nt). Phylogenetic analysis revealed a distinct clade for CaCDaV, CCDaV and MMDaV, supporting their inclusion in a new genus within the family Geminiviridae. Because CaCDaV and CCDaV shared a high genome nucleotide sequence identity (54.8%), we propose that the CaCDaV should be included as a member in this new genus. PMID- 29500571 TI - A genetic analysis of an important hydrophobic interaction at the P22 tailspike protein N-terminal domain. AB - P22 bacteriophage has been studied extensively and has served as a model for many important processes such as in vivo protein folding, protein aggregation and protein-protein interactions. The trimeric tailspike protein (TSP) serves as the receptor-binding protein for the P22 bacteriophage to the bacterial host. The homotrimeric P22 tail consists of three chains of 666aa in which the first 108aa form a trimeric dome-like structure which is called the N-terminal domain (NTD) and is responsible for attachment of the tailspike protein to the rest of the phage particle structure in the phage assembly pathway. Knowledge of this interaction requires information on what amino acids are interacting in the interface and how the NTD structure is maintained. The first 23aa form the "stem peptide" which originates at the dome top and terminates at the dome bottom. It contains a hydrophobic valine patch (V8-V9-V10) located within the dome structure. It is hypothesized that the interaction between the hydrophobic valine patch located on stem peptide and the adjacent polypeptide is critical for the interchain interaction which should be important for the stability of the P22 TSP NTD itself. To test this hypothesis, each amino acid in the valine residues is substituted by an acid, a basic, and a hydrophobic amino acid. The results of such substitutions are presented as well as associated studies. The data strongly suggest that the valine patch is of critical importance in the hydrophobic interaction between stem peptide valine patch and an adjacent chain. PMID- 29500573 TI - [The 20-year results of 5-year hormone therapy in breast cancer : Early Breast Cancer Trialists' Collaborative Group (EBCTCG)]. PMID- 29500572 TI - Rectal E. coli above ciprofloxacin ECOFF associate with infectious complications following prostate biopsy. AB - : Transrectal prostate biopsies carry the risk of infection. By using non selective culture plates, instead of commonly used ciprofloxacin (CIP)-containing plates, we analyzed the association between Escherichia coli CIP minimal inhibitory concentration (MIC) and post-biopsy infectious complications. A pre biopsy rectal swab was taken from 207 consecutive men, scheduled for transrectal 12-core prostate biopsy with CIP 750 mg as the mostly used prophylaxis. CIP MIC of rectal Gram-negative bacilli was determined from a chromogenic agar. Rectal E. coli were categorized to resistant (R) and intermediate (I) isolates together (R + I, MIC > 0.25 mg/l) and to sensitive (S, MIC <= 0.25 mg/l) using EUCAST clinical breakpoints. In addition, epidemiological cutoff (ECOFF R, MIC > 0.064 mg/l) was used for categorization. Eighteen (8.7%) men showed CIP R + I E. coli by the EUCAST breakpoints and 41 (19.8%) using the ECOFF R criteria. During follow-up, 15 (7.2%) men had infectious symptoms, of which 9 (4.3%) were culture confirmed infections. Only 4 (26.7%) of these 15 patients showed R + I E. coli in the rectal swab according to EUCAST, but 10 (66.7%) using the ECOFF cutoff. Rectal E. coli CIP R + I by the EUCAST clinical breakpoints associated with infectious complications with OR 5.7 (95% CI 1.5-21.8, P = 0.005) and ECOFF R E. coli by OR 10.7 (95% CI 3.0-37.6, P < 0.001). Men carrying rectal E. coli with moderately lowered CIP susceptibility (MIC > ECOFF 0.064 mg/l) were identified and, interestingly, they showed a high risk of developing infectious symptoms after the biopsy. This explains why some men develop infectious complications despite appropriate antibiotics before prostatic biopsies. TRIAL REGISTRATION: NCT02140502. PMID- 29500574 TI - [Refeeding syndrome : Pathophysiology, risk factors, prevention, and treatment]. AB - Refeeding syndrome is a life-threatening complication that may occur after initiation of nutritional therapy in malnourished patients, as well as after periods of fasting and hunger. Refeeding syndrome can be effectively prevented and treated if its risk factors and pathophysiology are known. The initial measurement of thiamine level and serum electrolytes, including phosphate and magnesium, their supplementation if necessary, and a slow increase in nutritional intake along with close monitoring of serum electrolytes play an important role. Since refeeding syndrome is not well known and the symptoms can be extremely heterogeneous, this complication is poorly recognized, especially against the background of severe disease and multimorbidity. This overview aims to summarize the current knowledge and increase awareness about refeeding syndrome. PMID- 29500575 TI - The non-cell autonomy of human gametes. PMID- 29500576 TI - Adolescent Sleep Barriers: Profiles within a Diverse Sample of Urban Youth. AB - Most adolescents face numerous obstacles to good sleep, which may undermine healthy development. In this study, we used latent class analysis and identified four categories of sleep barriers in a diverse sample of 553 urban youth (57% female). The majority profile, School/Screens Barriers, reported the most homework and extracurricular barriers, along with high screen time. The Home/Screens Barriers class (i.e., high environmental noise, light, screen use) and the High/Social Barriers class (i.e., high barriers across domains, particularly social) reported the poorest sleep quality and highest depressive/anxiety symptoms. The Minimal Barriers class-predominately male, with low depressive/anxiety symptoms-reported more sleep per night. We discuss implications of our findings for targeting interventions to address poor adolescent sleep among specific clusters of students. PMID- 29500578 TI - [Simulator model for ultrasound-guided pericardiocentesis : Construction manual and practical evaluation]. AB - An important challenge in learning ultrasound-assisted interventions, such as pericardiocentesis, is the navigation of the needle in a three-dimensional space on the basis of a two-dimensional image. In order to learn this in vitro realistic simulators are required. We manufactured a model which allows simulation of pericardiocentesis on the basis of ballistic gelatin (12.6%, 250 Bloom). Furthermore, the pericardiocentesis model was subjectively evaluated by 37 anesthetists in a pre-post design. The models used proved to be technically simple to manufacture, hard wearing and realistic. They are therefore regularly used in our hospitals to learn ultrasound-assisted interventions. PMID- 29500577 TI - Longitudinal Examination of the Bullying-Sexual Violence Pathway across Early to Late Adolescence: Implicating Homophobic Name-Calling. AB - The Bully-Sexual Violence Pathway theory has indicated that bullying perpetration predicts sexual violence perpetration among males and females over time in middle school, and that homophobic name-calling perpetration moderates that association among males. In this study, the Bully-Sexual Violence Pathway theory was tested across early to late adolescence. Participants included 3549 students from four Midwestern middle schools and six high schools. Surveys were administered across six time points from Spring 2008 to Spring 2013. At baseline, the sample was 32.2% White, 46.2% African American, 5.4% Hispanic, and 10.2% other. The sample was 50.2% female. The findings reveal that late middle school homophobic name calling perpetration increased the odds of perpetrating sexual violence in high school among early middle school bullying male and female perpetrators, while homophobic name-calling victimization decreased the odds of high school sexual violence perpetration among females. The prevention of bullying and homophobic name-calling in middle school may prevent later sexual violence perpetration. PMID- 29500579 TI - [The most important publications of the year 2017 from the Working Group Neuroanesthesia]. PMID- 29500580 TI - [Entrustable professional activities : Promising concept in postgraduate medical education]. AB - Entrustable professional activities (EPAs) are characterized as self-contained units of work in a given typical clinical context, which may be entrusted to a trainee for independent execution at a certain point of training. An example could be the intraoperative anesthesia management of an ASA 1 patient for an uncomplicated surgical intervention as an EPA in early postgraduate anesthesia training. The EPAs can be described as an evolution of a competency-based medical educational concept, applying the concept of the competencies of a person to specific workplace contexts. In this way the expected level of skills and supervision at a certain stage of training have a more practical meaning and the danger of fragmentation of individual competencies in the competence-based model is avoided. It is a more holistic view of a trainee. Experience with this new concept is so far limited, therefore, further studies are urgently needed to determine whether and how EPAs can contribute to improvements in further training. PMID- 29500582 TI - Examining the preliminary efficacy of an intervention for fear of cancer recurrence in female cancer survivors: a randomized controlled clinical trial pilot study. AB - PURPOSE: Among cancer survivors, fear of cancer recurrence (FCR) is the most frequently reported unmet need. Despite this, research on psychosocial interventions that target FCR is limited. To address this gap, an individual cognitive-existential psychotherapy intervention for FCR was pilot tested via small-scale RCT. METHODS: Participants were recruited via study posters, healthcare professionals' referrals, and an electronic hospital database. Twenty five female cancer survivors were randomized to experimental or wait-list control groups. Sessions included cognitive restructuring techniques, behavioral experiments, discussion of existential concerns, and relaxation exercises. Nineteen women completed the 6-week intervention and completed questionnaire packages at various time points. All participants completed self-administered questionnaires at pre-intervention (T1), post-intervention (T2), and at 3-month follow-up (T3). Participants in the control group also completed the same questionnaires, including at baseline (T0). RESULTS: Statistically significant results of between-within ANOVAs included time by condition interactions in the primary outcome measure of FCR and, for the experimental group participants, time by condition interactions in the secondary outcome measures of cancer-specific distress and uncertainty in illness. Statistically significant results of repeated measures ANOVAs included reductions in FCR, cancer-specific distress, uncertainty in illness, reassurance seeking, cognitive avoidance, and intolerance of uncertainty, as well as improvements in positive reinterpretation and growth, emotional coping, and quality of life (improved mental health), when compared to the control group. Most changes were maintained at 3-month follow-up. CONCLUSIONS: This intervention responds to a need for evidence-based individual modality interventions targeting quality of life in cancer survivors. Our results demonstrate preliminary promising results in addressing FCR in female cancer survivors. Future research could seek to replicate results with a larger sample. Further research is needed to test this intervention with patients of mixed cancer sites. PMID- 29500581 TI - Attitudes and experiences of childhood cancer survivors transitioning from pediatric care to adult care. AB - PURPOSE: Survivors of pediatric cancer are prone to late effects which require ongoing medical care. Young adult survivors often transition from specialist pediatric care to adult-oriented or community-based healthcare. This study aims to describe the attitudes and experiences of survivors and their parents towards transition barriers and enablers. METHODS: Long-term survivors and parents (of survivors < 16 years) were recruited from 11 hospitals in Australia and New Zealand to participate in a semi-structured telephone interview regarding their transition experiences. Transcribed interviews were coded and content analysis was used to number participants within themes. RESULTS: Thirty-three participants were interviewed, of which 18 were survivors (mean age 26 years, SD = 6.3; mean time since treatment completion 13.3 years, SD = 6.1) and 15 were parents (mean survivor age 15 years, SD = 1.9; mean time since treatment completion 8.4 years, SD = 2.8). Participants described their transition attitudes as positive (55%), neutral (15%), or negative (30%). Key barriers to transition included dependence on pediatric healthcare providers, less confidence in primary care physicians (PCPs), inadequate communication, and cognitive difficulty. Enablers included confidence in and proximity to physicians, good communication, information, independence, and age. CONCLUSIONS: Many survivors face barriers to their transition out of pediatric care. Early introduction to transition, greater collaboration between healthcare professionals, and better information provision to survivors may improve the transition process. Future research of survivors' experience of barriers/enablers to transition is needed. Development of interventions, such as those that address self-management skills, is required to facilitate transition and encourage long-term engagement. PMID- 29500583 TI - Meagre's melatonin profiles under captivity: circadian rhythmicity and light sensitiveness. AB - The present study reveals the first characterization of the plasma melatonin rhythms of the meagre (Argyrosomus regius) under aquaculture conditions. Melatonin levels were monitored during a 24 h cycle under a photoperiod of 16 L:8D and under constant darkness (DD), respectively to characterize the daily rhythm of this indoleamine and to test its endogenous origin. Besides, to identify which light intensities are perceived as night or day by this species, the degree of inhibition of nocturnal melatonin production caused by increasing intensities of light was tested (3.3, 5.3, 10.5, and 120 MUW/cm2), applying 1 h light pulses at Mid-Dark. The result for melatonin daily rhythm in plasma showed a typical profile: concentration remained low during all daytime points, increasing greatly during dark points, with maximum values at 16:00 and 22:00 h, zeitgeber time. Under DD conditions, the plasma melatonin profile persisted, with a similar acrophase but with a lower amplitude between subjective day and night periods, indicating this rhythm as being endogenously driven. Moreover, meagre seemed to be very sensitive to dim levels of illumination during the night, since an intensity of just 3.3 MUW/cm2 inhibited melatonin production. However, only the pulse of 5.3 MUW/cm2 caused a melatonin drop till daytime concentrations. Thus, the threshold of light detection by the pineal organ was suggested as being located between 3.3 and 5.3 MUW/cm2. Such results are an added value for this species biology knowledge, and in consequence to its adaptation to aquaculture conditions, allowing the improvement of culture husbandry protocols. PMID- 29500585 TI - Comparing the effects of oxazepam and diazepam in actual highway driving and neurocognitive test performance: a validation study. AB - OBJECTIVE: Screening of drug-induced performance impairment is needed to provide meaningful information for users and prescribers regarding the impact of drugs on driving. The main objective was to assess the effects of oxazepam 10 mg (OXA10), oxazepam 30 mg (OXA30), and diazepam 10 mg (DIA10) on standard deviation of lateral position (SDLP) in a highway driving test in actual traffic and to determine the ability of eight neurocognitive tests to detect comparable effects. METHODS: Twenty-three healthy volunteers participated in a four-way double-blind, placebo-controlled, crossover study. The highway driving test was conducted between 4 and 5 h after drug intake. A range of neurocognitive tests was conducted before and after driving, 2 and 6 h post-treatment, respectively. RESULTS: Mean SDLP increased by 1.83, 3.03, and 7.57 cm after OXA10, DIA10, and OXA30, respectively. At 2 h post-treatment, all neurocognitive tests, except the useful field of view, showed performance impairment in all active treatments. Effect sizes (ES) were moderate for OXA10, large ES for DIA10, and largest ES for OXA30. Modest correlations were found between changes in SDLP and performance in the attention network test (ANT), the divided attention test (DAT), and the psychomotor vigilance test (PVT). CONCLUSION: OXA10 caused minor, DIA10 moderate, and OXA30 severe driving impairment. No neurocognitive test was both dose dependently sensitive and able to be associated with driving impairment. No neurocognitive test can replace the on-the-road highway driving test. PMID- 29500586 TI - Different angioregulatory activity of monovalent galectin-9 isoforms. AB - Galectin-9 consists of two peptide-linked carbohydrate recognition domains (CRDs), but alternative splicing and proteolytic processing can give rise to multiple galectin-9 isoforms. Some of these consist of a single CRD and can exert different functions in cell biology. Here, we explored the role of these galectin 9 isoforms in endothelial cell function and angiogenesis. For this, we compared the effects of the two separate CRDs (Gal-9N and Gal-9C) with the tandem repeat galectin-9M on endothelial cell proliferation, migration, sprouting and tube formation in vitro as well as on angiogenesis in vivo using the chicken chorioallantoic membrane (CAM) assay. Galectin-9 isoforms significantly affected proliferation in quiescent endothelial cells and migration in activated endothelial cells. Interestingly, both monovalent gal-9 CRDs displayed opposite effects compared to gal-9M on proliferation and migration. Sprouting was significantly inhibited by gal-9C, while all isoforms appeared to stimulate tube formation. Angiogenesis in vivo was hampered by all three isoforms with predominant effects on vessel length. In general, the isoforms induced only subtle concentration-dependent effects in vitro as well as in vivo. Collectively, the effects of different galectin-9 isoforms in endothelial cell biology depend on the cellular activation status. While opposing effects can be observed on a cellular level in vitro, all galectin-9 isoforms hamper angiogenesis in vivo. This warrants further investigation of the regulatory mechanisms that underlie the diverging roles of galectin-9 isoforms in endothelial cell biology since this could provide therapeutic opportunities. PMID- 29500584 TI - Preclinical evaluation of avermectins as novel therapeutic agents for alcohol use disorders. AB - The deleterious effects of alcohol use disorders (AUDs) on human health have been documented worldwide. The enormous socioeconomic burden coupled with lack of efficacious pharmacotherapies underlies the need for improved treatment strategies. At present, there is a growing body of preclinical evidence that demonstrates the potential of avermectins [ivermectin (IVM), selamectin (SEL), abamectin (ABM), and moxidectin (MOX)] in treatment of AUDs. Avermectins are derived by fermentation of soil micro-organism, Streptomyces avermitilis, and have been extensively used for treatment of parasitic infections. From the mechanistic standpoint, avermectins are positive modulators of purinergic P2X4 receptors (P2X4Rs). P2X4Rs belong to P2X superfamily of cation-permeable ion channels gated by adenosine 5'-triphosphate (ATP). Building evidence has implicated a role for P2X4Rs in regulation of ethanol intake and that ethanol can inhibit ATP-gated currents in P2X4Rs. Investigations using recombinant cell models and animal models of alcohol drinking have reported that IVM, ABM, and MOX, but not SEL, were able to antagonize the inhibitory effects of ethanol on P2X4Rs in vitro and reduce ethanol intake in vivo. Furthermore, IVM was shown to reduce ethanol consumption via P2X4R potentiation in vivo, supporting the involvement of P2X4Rs in IVM's anti-alcohol effects and that P2X4Rs can be used as a platform for developing novel anti-alcohol compounds. Taken together, these findings support the utility of avermectins as a novel class of drug candidates for treatment of AUDs. PMID- 29500587 TI - Metal accumulation in populations of Calamagrostis epigejos (L.) Roth from diverse anthropogenically degraded sites (SE Europe, Serbia). AB - Heavy metal accumulation is recognized as a very important global pollution problem in the last decades. Plant species have been recognized as natural bioindicators of environmental pollution, especially the amount of heavy metals in soils. Moreover, only a limited number of plant species can survive in highly contaminated soils. It is also known that metal accumulation can vary greatly among different populations of the same species. This study examines the chemical composition and accumulation potential of the expansive clonal grass Calamagrostis epigejos at five localities exposed to different levels of anthropogenic pressure. Considerable differences were observed between uptake, translocation, and accumulation of total and available heavy metals, such differences corresponding to soil physico-chemical characteristics and the level of site pollution. The results indicate that Calamagrostis epigejos uptakes a significant portion of the available fraction of heavy metals in the soil and stores it in the roots, thereby exhibiting a certain potential for metal phytostabilization. PMID- 29500588 TI - Urban wastewater treatment by using Ag/ZnO and Pt/TiO2 photocatalysts. AB - In this study, the treatment of wastewater coming from a river highly polluted with domestic and industrial effluents was evaluated. For this purpose, series of photocatalysts obtained by ZnO and TiO2 modification were evaluated. The effect of metal addition and Ti precursor (in the case of the titania series) over the physicochemical and photocatalytic properties of the materials obtained was also analyzed. The evaluation of the photocatalytic activity showed that semiconductor modification and precursor used in the materials synthesis are important factors influencing the physicochemical and therefore the photocatalytic properties of the materials obtained. The water samples analyzed in the present work were taken from a highly polluted river, and it was found that the effectiveness of the photocatalytic treatment increases when the reaction time increases and for both, wastewater samples and isolated Escherichia coli strain follow the next order Pt/TiO2 << ZnO. It was also observed that biochemical and chemical demand oxygen and turbidity significantly decrease after treatment, thus indicating that photocatalysis is a non-selective technology, which can lead to recover wastewater containing different pollutants. PMID- 29500589 TI - Enhanced electro-reduction of NO to NH3 on Pt cathode at electro-scrubber. AB - Besides cheaper electrodes used in NH3 product formation during NO degradation by mediated electrochemical reduction (MER), a specific electrode that can perform direct electrochemical reduction (DER) and MER of NO is an added advantage. In the present study, a Pt electrode was used to examine NO degradation through NH3 formation during the electro-scrubbing process. Initially, the DER of NO was tested on a Pt electrode to determine if the DER of NO is possible. The NO degradation by only absorption, DER on Pt, and MER using electrogenerated [Ni(I)(CN)4]3- showed that a combination of DER and MER increased the NO degradation efficiency. In addition, the online FTIR spectra obtained under different conditions showed that the product formed was NH3, either from the DER or MER during electro-scrubbing. The feed gas flow rate and feed concentration results of NH3 formation revealed an additional chemical reaction that was influenced by the Pt electrode in addition to the DER and MER processes. Furthermore, the degradation efficiency of NO when using the Pt electrode increased to 90% compared to that of the Cu electrode (65%), which showed that Pt follows a combination of DER and MER processes. Based on the gas-phase FTIR results of NH3 formation during NO degradation, higher NH3 production (0.32 mg/h) was obtained when using a Pt electrode than that using a Cu electrode (0.21 mg/h), highlighting the specificity of the Pt electrode in NH3 formation during the degradation of NO gas. PMID- 29500590 TI - Comparison of gold nanoparticles biosynthesized by cell-free extracts of Labrys, Trichosporon montevideense, and Aspergillus. AB - Biosynthesis of gold nanoparticles (AuNPs) by microbes has received much attention as an efficient and eco-friendly process. However, the characteristics of AuNPs biosynthesized by different microbial cell-free extracts are rarely comparatively studied. In this study, three locally isolated strains, i.e., bacteria Labrys sp. WJW, yeast Trichosporon montevideense WIN, and filamentous fungus Aspergillus sp. WL-Au, were selected for AuNPs biosynthesis. UV-Vis absorption bands at 538, 539, and 543 nm confirmed the formation of AuNPs by these strains. Transmission electron microscopy and selected area electron diffraction analyses revealed that the as-synthesized AuNPs were crystalline with spherical or pseudo-spherical shapes. However, the average sizes of these AuNPs were diverse, which were 18.8, 22.2 and 9.5 nm, respectively. The biomolecules involved in nanoparticles stabilization were demonstrated by Fourier transform infrared spectroscopy analysis. Four common functional groups such as -N-H, -C=C, -N=O, and -S=O groups were detected in these AuNPs, while a distinct -C=O group was involved in WL-Au-AuNPs. The catalytic rate of WL-Au-AuNPs toward 4 nitrophenol reduction (0.37 min-1) was much higher than those of others (WJW AuNPs 0.27 min-1 and WIN-AuNPs 0.23 min-1). This research would provide useful information for exploring efficient microbial candidates to synthesize AuNPs with excellent performances. PMID- 29500591 TI - Spatiotemporal variations in vegetation cover on the Loess Plateau, China, between 1982 and 2013: possible causes and potential impacts. AB - Vegetation is a key component of the ecosystem and plays an important role in water retention and resistance to soil erosion. In this study, we used a multiyear normalized difference vegetation index (NDVI) dataset (1982-2013) and corresponding datasets for observed climatic variables to analyze changes in the NDVI at both temporal and spatial scales. The relationships between NDVI, climate change, and human activities were also investigated. The annual average NDVI showed an upward trend over the 32-year study period, especially in the center of the Loess Plateau. NDVI variations lagged behind monthly temperature changes by approximately 1 month. The contribution of human activities to variations in NDVI has become increasingly significant in recent years, with human activities responsible for 30.4% of the change in NDVI during the period 2001-2013. The increased vegetation coverage has reduced soil erosion on the Loess Plateau in recent years. It is suggested that natural restoration of vegetation is the most effective measure for control of erosion; engineering measures that promote this should feature in the future governance of the Loess Plateau. PMID- 29500592 TI - A novel method to prepare a magnetic carbon-based adsorbent with sugar-containing water as the carbon source and DETA as the modifying reagent. AB - A novel magnetic heavy metal adsorbent was prepared via diethylenetriamine (DETA) modification on magnetic hydrothermal carbon, with glucose and sugar-containing waste water as the carbon source. The prepared materials were characterized by FT IR, SEM, TEM, EDXRF, TGA, elemental analysis, XPS, and magnetic moment determination. In this paper, the adsorption mechanism of the modified and unmodified adsorbents was well discussed. Four kinds of waste water (watermelon juice, expired sprite, sugar-pressing waste water, and confectionary waste water) were employed to produce heavy metal ion adsorbents; the chemical properties of hydrothermal carbon derived from the proposed sources were analyzed as well. The maximum uptake capacity for Cu2+, Pb2+, and Cd2+ of the adsorbent produced from glucose was 26.88, 103.09, and 25.38 mg g-1, respectively. After 5 cycles, the adsorption ability was still well preserved. This work represents an efficient new direction for the treatment of heavy metal ions in water and the reuse of sugar-containing waste water. Graphical abstract The schemetic of DETA-modified magnetic carbon preparing from sugar-containing wastewater. PMID- 29500593 TI - Correction to: Multi-sensor temporal assessment of tropospheric nitrogen dioxide column densities over Pakistan. AB - The present address of Rabbia Murtaza is shown in this paper. (please tag the affiliation below, this is only for Rabbia Murtaza). PMID- 29500594 TI - Effect of lablab and pigeon pea leaf meal supplementation on performance of goats fed a basal diet of haricot bean haulms. AB - An experiment was conducted to evaluate the effect of lablab and pigeon pea leaf supplementation on feed intake, digestibility, weight gain, and carcass characteristics of goats fed a basal diet of haricot bean haulms. Thirty-two yearling intact male goats with an average initial body weight of 14.4 +/- 1.04 kg (Means +/- SD) were assigned to one of the four treatments in a randomized complete block design. The dietary treatments were 17.5% lablab + 17.5% pigeon pea leaf + 63% wheat bran (T1), 35% pigeon leaf + 63% wheat bran (T2), 35% lablab leaf + 63% wheat bran (T3), and 88% wheat bran + 10% noug seed cake (T4). In addition, all treatment diets contained 1 and 1% limestone. The feeding trial lasted for 90 days followed by 7 days of digestibility trial. Carcass evaluation was conducted at the end of the feeding trial. Final body weight ranged from 16.3 kg for T4 to 21.1 kg for T3. The total dry matter (DM) intake for T3 was higher (P < 0.05) than T2 and T4. The total crude protein (CP) intake for T2 was greater (P < 0.05) than T3 and T4. Goats supplemented with T3 diets had the highest (P > 0.05) digestibility of DM, organic matter, and CP and attained the highest (P < 0.05) average daily gain, the heaviest (P < 0.05) hot carcass weight, and the highest (P < 0.05) rib-eye muscle area than those supplemented with T1, T2, and T4 diets. In conclusion, 35% lablab leaf meal and 63% what bran (T3) were found to be a very promising supplement in sheep fed low-quality crop residues under the condition of the current experiment. PMID- 29500595 TI - Antecedents of Emotional Distress and Sexual Dissatisfaction in Circumcised Men: Previous Findings and Future Directions-Comment on Bossio and Pukall (2017). PMID- 29500596 TI - #TimesUp in Native Communities. PMID- 29500598 TI - Linguistic Reflections on Psychotherapy: Change in Usage of The First Person Pronoun in Information Structure Positions. AB - Aim of present study was to understand changes in speech of clients with regard to certain linguistic features from 5th to 15th session of psychotherapy. First person pronoun use in information structure positions were analyzed in speech of clients. Participants of this study were 11 psychotherapists (clinical psychology master and doctorate students) and 16 clients (applicants to AYNA Psychotherapy Unit). In present study word count results of clinets' speeches were analyzed by ANOVA method. According to results, use of first person pronoun changed significantly in preverbal position from 5th to 15th sessions of psychotherapy. Findings of this study suggest that, psychotherapy leads to certain linguistic changes, and these changes discussed to be means of understand change of clients during psychotherapy. PMID- 29500597 TI - Fidelity of DNA replication-a matter of proofreading. AB - DNA that is transmitted to daughter cells must be accurately duplicated to maintain genetic integrity and to promote genetic continuity. A major function of replicative DNA polymerases is to replicate DNA with the very high accuracy. The fidelity of DNA replication relies on nucleotide selectivity of replicative DNA polymerase, exonucleolytic proofreading, and postreplicative DNA mismatch repair (MMR). Proofreading activity that assists most of the replicative polymerases is responsible for removal of incorrectly incorporated nucleotides from the primer terminus before further primer extension. It is estimated that proofreading improves the fidelity by a 2-3 orders of magnitude. The primer with the incorrect terminal nucleotide has to be moved to exonuclease active site, and after removal of the wrong nucleotide must be transferred back to polymerase active site. The mechanism that allows the transfer of the primer between pol and exo site is not well understood. While defects in MMR are well known to be linked with increased cancer incidence only recently, the replicative polymerases that have alterations in the exonuclease domain have been associated with some sporadic and hereditary human cancers. In this review, we would like to emphasize the importance of proofreading (3'-5' exonuclease activity) in the fidelity of DNA replication and to highlight what is known about switching from polymerase to exonuclease active site. PMID- 29500600 TI - ? PMID- 29500599 TI - Converting cyclosporine A from intravenous to oral administration in hematopoietic stem cell transplant recipients and the role of azole antifungals. AB - PURPOSE: Cyclosporine A (CsA) is the most widely used immunosuppressive agent after a hematopoietic stem cell transplantation (HSCT). Although recommendations for CsA dose conversion from intravenous to oral administration differ from 1:1 to 1:3, most studies did not consider the role of azole antifungals as an important confounder. Therefore, we assess the optimal conversion rate of CsA from intravenous to oral administration in HSCT recipients, taking into account the concomitant use of azole antifungals. METHODS: We retrospectively included patients from a large database of 483 patients who underwent a HSCT and received intravenous CsA as part of the conditioning regimen and peritransplant immunosuppression. All patients were converted from intravenous to oral administration in a 1:1 conversion rate. We collected for each patient three CsA trough concentrations during intravenous and oral administration, directly before and after conversion to oral administration. RESULTS: We included 71 patients; 50 patients co-treated with fluconazole, 10 with voriconazole, and 11 without azole co-medication. In patients with voriconazole, the dose-corrected CsA concentration (CsA concentration divided by CsA dosage) was not different between intravenous and oral administration (2.6% difference, p = 0.754), suggesting a CsA oral bioavailability of nearly 100%. In patients with fluconazole and without azole co-medication, the dose-corrected CsA concentration was respectively 21.5% (p < 0.001) and 25.2% (p = 0.069) lower during oral administration. CONCLUSIONS: In patients with voriconazole, CsA should be converted 1:1 from intravenous to oral administration. In patients with fluconazole and without azole co medication, a 1:1.3 substitution is advised to prevent subtherapeutic CsA concentrations. PMID- 29500601 TI - Clinical study of pregnancy-associated fulminant type 1 diabetes. AB - BACKGROUND: Studies reported that fulminant type 1 diabetes (fT1DM) can occurred during pregnancy or within 2 weeks after delivery, and was defined as pregnancy associated fulminant type 1 diabetes (PF). In PF patients, plasma glucose (PG) levels have an abrupt rise while glycated hemoglobin (HbA1C) levels are not markedly elevated, resulting in a sharply increased PG/HbA1C ratio. METHODS: We studied 30 PF patients, 21 non-pregnant fulminant type 1 diabetes (NPF) patients, and 26 female patients of child-bearing age (13-49 years) with diabetic ketoacidosis (DKA), all from China. We analyzed the PG/HbA1C ratio among these groups, with the goal of finding a method for predicting PF. The clinical and biochemical characteristics of the PF and NPF patients were analyzed and compared with the characteristics of the DKA patients. In order to detect PF in DKA patients, receiver-operating characteristic curves analysis was used to identify the cut-off points of the PG/HbA1C ratio. RESULTS: When we compared the clinical characteristics of these three groups, we found that the onset of hyperglycemic symptoms, arterial PH value, serum potassium, PG, HbA1C, fasting and postprandial serum C-peptide concentration, glutamic acid decarboxylase (GAD) antibodies positivity were all significantly different (P < 0.001). The PG/HbA1C ratio was significantly higher in PF and NPF patients (5.29 +/- 1.39 and 6.38 +/- 2.62) than in DKA patients (1.93 +/- 0.55; P < 0.001). Receiver-operating characteristic (ROC) curves analyses showed that PG/HbA1C ratio at a cut-off value of 3.3 resulted in the highest Youden index, with corresponding sensitivity of 93 and 100% specificity for identifying PF from DKA. CONCLUSIONS: PF patients showed a more severe acidosis, with maternal and fetal mortality rates being high. PG/HbA1C ratio with a threshold of >=3.3 can be used as a cut-off point in predicting PF from DKA in China. Elevated PG/HbA1C ratio at the time of diagnosis is predictive for more severe insulin secretion dysfunction and poor prognosis. PMID- 29500603 TI - Effects of Ketoconazole and Rifampicin on the Pharmacokinetics of Nintedanib in Healthy Subjects. AB - BACKGROUND: Nintedanib is a substrate for p-glycoprotein which can impact bioavailability. We investigated the effects of ketoconazole, a p-glycoprotein inhibitor, and rifampicin, a p-glycoprotein inducer, on the pharmacokinetics of nintedanib. METHODS: In the ketoconazole study, 34 healthy subjects received nintedanib 50 mg orally alone and 1 h after the last dose of ketoconazole given orally at a dose of 400 mg once daily for 3 days in 1 of 2 randomized sequences. In the rifampicin study, 26 subjects received nintedanib 150 mg orally alone and the morning after the last dose of rifampicin given orally at a dose of 600 mg once daily for 7 days. The primary objective was to determine the relative bioavailability of nintedanib administered following multiple doses of ketoconazole or rifampicin versus alone, based on AUC from time 0 extrapolated to infinity (AUC0-infinity) and maximum concentration (Cmax) calculated using an analysis of variance. Geometric mean ratios and 2-sided 90% CIs were calculated. RESULTS: Exposure to nintedanib increased when it was administered following ketoconazole versus alone (AUC0-infinity: geometric mean ratio, 160.5% [90% CI, 148.2-173.7]; Cmax: geometric mean ratio, 179.6% [90% CI, 157.6-204.8]) and decreased when it was administered following rifampicin versus alone (AUC0 infinity: geometric mean ratio, 50.1% [90% CI, 47.2-53.3]; Cmax: geometric mean ratio, 59.8% [90% CI, 53.8-66.4]). The time to reach Cmax (tmax) and half-life (t1/2) of nintedanib were unaffected by co-administration of ketoconazole or rifampicin. CONCLUSIONS: Exposure to nintedanib is increased by co-administration of ketoconazole and decreased by co-administration of rifampicin, likely due to effects on bioavailability of the absorbed fraction. ClinicalTrials.govidentifiers:NCT01679613, NCT01770392. PMID- 29500605 TI - Comment to: "Laser-Assisted Liposuction (LAL) Versus Traditional Liposuction: Systematic Review". PMID- 29500604 TI - Asymmetries, heterosis, and phenotypic profiles of red junglefowl, White Plymouth Rocks, and F1 and F2 reciprocal crosses. AB - During the domestication of farm animals, humans have manipulated genetic variation for growth and reproduction through artificial selection. Here, data are presented for growth, reproductive, and behavior traits for the red junglefowl, a line of White Plymouth Rock chickens, and their F1 and F2 reciprocal crosses. Intra- and intergenerational comparisons for growth related traits reflected considerable additive genetic variation. In contrast, those traits associated with reproduction exhibited heterosis. The role of sexual selection was seen in the evolution of prominent secondary sexual ornaments that lend to female choice and male-male competition. The large differences between parental lines in fearfulness to humans were only mitigated slightly in the intercross generations. Whereas, overall F1 generation heterosis was not transferred to the F2, there was developmental stability in the F2, as measured by relative asymmetry of bilateral traits. Through multigenerational analyses between the red junglefowl and the domestic White Plymouth Rocks, we observed plasticity and considerable residual genetic variation. These factors likely facilitated the adaptability of the chicken to a broad range of husbandry practices throughout the world. PMID- 29500602 TI - Imaging technologies for cardiac fiber and heart failure: a review. AB - There has been an increasing interest in studying cardiac fibers in order to improve the current knowledge regarding the mechanical and physiological properties of the heart during heart failure (HF), particularly early HF. Having a thorough understanding of the changes in cardiac fiber orientation may provide new insight into the mechanisms behind the progression of left ventricular (LV) remodeling and HF. We conducted a systematic review on various technologies for imaging cardiac fibers and its link to HF. This review covers literature reports from 1900 to 2017. PubMed and Google Scholar databases were searched using the keywords "cardiac fiber" and "heart failure" or "myofiber" and "heart failure." This review highlights imaging methodologies, including magnetic resonance diffusion tensor imaging (MR-DTI), ultrasound, and other imaging technologies as well as their potential applications in basic and translational research on the development and progression of HF. MR-DTI and ultrasound have been most useful and significant in evaluating cardiac fibers and HF. New imaging technologies that have the ability to measure cardiac fiber orientations and identify structural and functional information of the heart will advance basic research and clinical diagnoses of HF. PMID- 29500606 TI - The Visual Analog Scale as a Comprehensible Patient-Reported Outcome Measure (PROM) in Septorhinoplasty. AB - The patient's satisfaction with the esthetic result is a major criterion of success in septorhinoplasty. However, the idea of esthetic perfection varies greatly and primarily depends on subjective perception. Hence, patient-reported instruments are important and necessary to assess the outcome in septorhinoplasty. To analyze the potential of the visual analog scale (VAS) as a patient-reported outcome measure in septorhinoplasty, the perception of the nasal appearance was assessed by a VAS pre- and postoperatively in 213 patients undergoing septorhinoplasty. Furthermore, in this prospective study, the patients' satisfaction concerning the procedure's result was analyzed using a five-point Likert scale. Females had lower preoperative VAS scores but a higher increase compared to males. Patients with lower initial VAS scores showed a higher improvement in the VAS score postoperatively compared to patients with higher initial VAS scores. Satisfaction with the result depends on the increase in the VAS score value. The VAS scale is a short and comprehensible tool to assess patients' perception of nasal appearance preoperatively and represents an appropriate instrument to assess the esthetic patient-reported outcome in septorhinoplasty.Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29500607 TI - Clinical features of brain metastases from hepatocellular carcinoma using gamma knife surgery. AB - BACKGROUND: Brain metastases from hepatocellular carcinoma (HCC) are rare, but their incidence is increasing because of developments in recent therapeutic advances. The purpose of this study was to investigate the characteristics of brain metastases from HCC, to evaluate the predictive factors, and to assess the efficacy of gamma knife surgery (GKS). METHOD: A retrospective study was performed on patients with brain metastases from HCC who were treated at Tokyo Gamma Unit Center from 2005 to 2014. RESULTS: Nineteen patients were identified. The median age at diagnosis of brain metastases was 67.0 years. Fifteen patients were male and four patients were female. Six patients were infected with hepatitis B virus (HBV). Two patients were infected with hepatitis C virus (HCV). Eleven patients were not infected with HBV or HCV. The median interval from the diagnosis of HCC to brain metastases was 32.0 months. The median number of brain metastases was two. The median Karnofsky performance score at first GKS was 70. The median survival time following brain metastases was 21.0 weeks. Six-month and 1-year survival rates were 41.2 and 0%, respectively. One month after GKS, no tumor showed progressive disease. The HBV infection (positive vs. negative) was significantly associated with survival according to univariate analysis (p = 0.002). CONCLUSIONS: The patients having brain metastases from HCC had poor prognosis and low performance state. Therefore, GKS is an acceptable option for controlling brain metastases from HCC because GKS is noninvasive remedy and local control is reasonable. PMID- 29500608 TI - Conversion surgery after S-1 plus oxaliplatin combination chemotherapy for advanced gastric cancer with multiple liver metastases. AB - Conversion therapy for gastric cancer is a new therapeutic concept. We report a case of a patient with advanced gastric cancer who underwent conversion surgery due to a remarkable regression of multiple liver metastases following chemotherapy. A 71-year-old man was referred to our hospital with gastric cancer. Esophagogastroduodenoscopy (EGD) revealed an irregular, nodular, ulcerated lesion in the lower third of the stomach. Analysis of biopsy specimens revealed a poorly differentiated adenocarcinoma. Abdominal contrast-enhanced computed tomography (CT) showed multiple liver mass lesions. The patient was clinically diagnosed with advanced gastric cancer with liver metastases and received S-1 plus oxaliplatin chemotherapy. After 6 cycles of chemotherapy, CT and magnetic resonance imaging showed complete resolution of the liver metastases, and EGD detected mucosal irregularities only. Since there was no evidence of further metastatic lesions in other organs, the patient underwent distal gastrectomy with D2 lymphadenectomy. The gross appearance of the surgically resected specimen showed a slightly elevated tumor measuring 4.5 * 3.5 cm. Pathological examination confirmed the diagnosis of a moderately differentiated gastric adenocarcinoma invading the muscularis propria with no lymph node metastases. The postoperative course was uneventful. The patient has continued to receive S-1 and oxaliplatin chemotherapy, and there has been no evidence of recurrence for 3 months following the operation. We propose that conversion therapy might be an effective treatment for patients with advanced gastric cancer; however, further studies and assessments are needed to confirm and establish this treatment strategy. PMID- 29500609 TI - Leiomyosarcoma of the stomach treated by endoscopic submucosal dissection. AB - There have been no reports of primary leiomyosarcoma of the stomach treated by endoscopic submucosal dissection (ESD). We report an extremely rare case of gastric leiomyosarcoma that was successfully treated by ESD. An asymptomatic 74 year-old female underwent esophagogastroduodenoscopy for screening in December 2013. A centrally depressed submucosal tumor 10 mm in diameter was detected at the posterior wall of the upper gastric body. Follow-up esophagogastroduodenoscopy conducted 5 months later showed that the tumor diameter had increased to 15 mm. Endoscopic ultrasound revealed a hypoechoic mass located in the second to the middle of the third layer. Endoscopic ultrasound guided fine-needle aspiration demonstrated a myogenic tumor. The tumor was completely resected by ESD without complications. Immunohistopathological diagnosis of the resected specimen was gastric leiomyosarcoma derived from the muscularis mucosae, with negative lateral and vertical margins. No local recurrence or metastasis has been detected at 36 months after ESD. This is the first report of gastric leiomyosarcoma treated by ESD in the English language literature. PMID- 29500610 TI - Population data and phylogenetic structure of Han population from Jiangsu province of China on GlobalFiler STR loci. AB - Forensic statistical parameters based on allelic frequencies of commonly used short tandem repeats were estimated for the Han population of Jiangsu province from P.R. China. The 6-dye GlobalFilerTM PCR amplification kit incorporates 21 autosomal STRs, providing reliable DNA typing results with enhanced the power of discrimination. Here, we analyzed the GlobalFilerTM STR loci in 516 unrelated individuals from Jiangsu Han population. A total of 256 alleles were observed ranging between 5 and 35.2 repeat units, and SE33 showed the greatest power of discrimination (34 alleles) in Jiangsu Han population. Most of the loci were found to be in the Hardy-Weinberg equilibrium after the Bonferroni correction with the exception of D3S1358. The combined power of exclusion (CPE) was 0.999999996353609, and the combined match probability (CMP) was 3.64 * 10-25. Phylogenetic parameters including pairwise genetic distances showed that Han population living in Jiangsu had closest genetic relationship with other East Asian populations. The present study provides precise reference database for forensic applications and population genetic studies. PMID- 29500611 TI - Does altered protein metabolism interfere with postmortem degradation analysis for PMI estimation? AB - An accurate estimation of the postmortem interval (PMI) is a central aspect in forensic routine. Recently, a novel approach based on the analysis of postmortem muscle protein degradation has been proposed. However, a number of questions remain to be answered until sensible application of this method to a broad variety of forensic cases is possible. To evaluate whether altered in vivo protein metabolism interferes with postmortem degradation patterns, we conducted a comparative study. We developed a standardized animal degradation model in rats, and collected additional muscle samples from animals recovering from muscle injury and from rats with developed disuse muscle atrophy after induced spinal cord injury. All samples were analyzed by SDS-PAGE and Western blot, labeling well-characterized muscle proteins. Tropomyosin was found to be stable throughout the investigated PMI and no alterations were detected in regenerating and atrophic muscles. In contrast, significant predictable postmortem changes occurred in desmin and vinculin protein band patterns. While no significant deviations from native patterns were detected in at-death samples of disuse muscle atrophy, interestingly, samples of rats recovering from muscle injury revealed additional desmin and vinculin degradation bands that did not occur in this form in any of the examined postmortem samples regardless of PMI. It remains to be investigated whether in vivo-altered metabolism influences postmortem degradation kinetics or if such muscle samples undergo postmortem degradation in a regular fashion. PMID- 29500612 TI - [Diverticular disease : Complications and differential diagnosis]. AB - BACKGROUND: Diverticular disease is becoming increasingly more common in the western world. It is clinically subdivided into uncomplicated diverticular disease and diverticular disease with a complicated course. In approximately 20% of cases the diverticula will become symptomatic during the lifetime of patients. RESULTS: In contrast to previous medical opinions, the occurrence of diverticula cannot be prevented by a diet rich in fiber; however, the development into complicated diverticulitis can be reduced by dietary measures. Complications include perforations, abscess and fistula formation or mechanical ileus. In addition, hemorrhage can occur as a complication, which can, however, occur in diverticulosis and also diverticulitis and especially in the chronic form. For the differential diagnostics a broad spectrum of inflammatory and noninflammatory diseases of the abdomen and pelvis must be taken into consideration. CONCLUSION: According to the new S2K guidelines the subdivision of diverticulitis should be implemented using the so-called classification of diverticular diseases (CDD). This enables a stratification of patients for outpatient or inhospital treatment. PMID- 29500613 TI - [Radiological characterization of chronic inflammatory bowel disease]. AB - BACKGROUND: During the course of the disease, chronic inflammatory bowel diseases (CIBD) show different activities, which-in addition to morphological changes significantly influence the choice of therapy. OBJECTIVE: The value of imaging in characterization of the activity of inflammatory changes is evaluated. MATERIALS AND METHODS: In the present review of the current literature, indications, performance, and findings of imaging of inflammatory bowel disease and on the assessment of disease activity are assessed. RESULTS: Magnetic resonance (MR) enterography allows the assessment of inflammatory bowel disease activity and subtyping. CONCLUSION: In addition to clinical, laboratory, and endoscopic information, MR enterography provides essential information for the assessment of CIBD activity. PMID- 29500614 TI - Expression and characterization of glutamate decarboxylase from Lactobacillus brevis HYE1 isolated from kimchi. AB - A putative gene (gadlbhye1) encoding glutamate decarboxylase (GAD) was cloned from Lactobacillus brevis HYE1 isolated from kimchi, a traditional Korean fermented vegetable. The amino acid sequences of GADLbHYE1 showed 48% homology with the GadA family and 99% identity with the GadB family from L. brevis. The cloned GADLbHYE1 was functionally expressed in Escherichia coli using inducible expression vectors. The expressed recombinant GADLbHYE1 was successfully purified by Ni-NTA affinity chromatography, and had a molecular mass of 54 kDa with optimal hydrolysis activity at 55 degrees C and pH 4.0. Its thermal stability was determined to be higher than that of other GADs from L. brevis, based on its melting temperature (75.18 degrees C). Kinetic parameters including Km and Vmax values for GADLbHYE1 were 4.99 mmol/L and 0.224 mmol/L/min, respectively. In addition, the production of gamma-aminobutyric acid in E. coli BL21 harboring gadlbhye1/pET28a was increased by adding pyridoxine as a cheaper coenzyme. PMID- 29500615 TI - A Comparison of Variable- and Person-Oriented Approaches in Evaluating a Universal Preventive Intervention. AB - Evaluations of prevention programs, such as the PAX Good Behavior Game (PAX), often have multiple outcome variables (e.g., emotional, behavioral, and relationship problems). These are often reported for multiple time points (e.g., pre- and post-intervention) where data are multilevel (e.g., students nested in schools). In this paper, we present both variable-oriented and person-oriented statistical approaches, to evaluate an intervention program with multilevel, longitudinal multivariate outcomes. Using data from the Manitoba PAX Study, we show how these two approaches provide us with different information that can be complementary. Data analyses with the variable-oriented approach (multilevel linear regression model) provided us with overall PAX program effects for each outcome variable; the person-oriented approach (latent transition analysis) allowed us to explore the transition of multiple outcomes across multiple time points and how the intervention program affects this transition differently for students with different risk profiles. We also used both approaches to examine how gender and socio-economic status related to the program effects. The implications of these results and the use of both types of approaches for program evaluation are discussed. PMID- 29500617 TI - Epoetin Biosimilars in the Treatment of Renal Anemia: What Have We Learned from a Decade of European Experience? AB - Biosimilars are biological medicines that are approved via stringently defined regulatory pathways on the basis that comparable safety, efficacy, and quality have been demonstrated to their reference medicine. The advantage of biosimilar drugs is that they may be less expensive than the reference medicine, allowing for greater patient access and cost savings in already stretched healthcare budgets. Biosimilar epoetins have been available in Europe for a decade. Complementing in vitro and preclinical characterization, and pharmacokinetic/pharmacodynamic studies, clinical trials provided the additional data needed to reassure European authorities that biosimilar epoetins were sufficiently similar to the reference epoetin to warrant approval. Post-approval, real-world studies have provided further evidence that biosimilar epoetins are an effective and well-tolerated option for the treatment of renal anemia, with ongoing pharmacovigilance and observational studies monitoring for any unexpected long-term signals that have not been identified in clinical development studies. As the evidence and experience with these products increase, many of the initial concerns are being alleviated. Nephrologists can be increasingly confident that European Medicines Agency-approved biosimilars offer high-quality, affordable, effective alternatives to existing reference medicines used to treat renal anemia, and may help yield cost savings and improve patient access. PMID- 29500618 TI - Direct oral anticoagulants: what can we learn? AB - Direct oral anticoagulants (DOACs) represent an innovation because they avoid periodic laboratory monitoring, and also reduce cerebral bleeding. An examination of the performance of DOACs versus warfarin in randomized clinical trials dedicated to atrial fibrillation would reveal the poor performance of warfarin because the percentage of major bleeding is always above 3%; however, the percentage of major bleeding is less than half of that when the management is done in anticoagulation clinics (ACs). Several years ago, a common opinion was that ACs would disappear as soon as DOACs enter the market. We proposed then that ACs could be transformed into thrombosis centres (TCs) because we envisaged many new activities in terms of diagnostic tools and therapeutic choices. After the introduction of DOACs, the role of the ACs has been re-evaluated because their role may be crucial in selecting both the most appropriate diagnostic approach and the best therapeutic option (including anti-vitamin K drugs) for the single patient. TCs can organize a regular follow-up to improve patient adherence to DOACs. Marketing might have a role in the decision making of the single doctor. Efforts should be made for limiting the relationships between doctors and pharmaceutical companies. It seems reasonable to better prepare doctors, during their university courses, for them to develop a greater scientific culture that would enable them to critically read clinical studies and acquire an independent opinion. Ideally, an expert in haemostasis and thrombosis should handle new and old anticoagulants. PMID- 29500619 TI - Reliability of the CARE rule and the HEART score to rule out an acute coronary syndrome in non-traumatic chest pain patients. AB - In patients consulting in the Emergency Department for chest pain, a HEART score <= 3 has been shown to rule out an acute coronary syndrome (ACS) with a low risk of major adverse cardiac event (MACE) occurrence. A negative CARE rule (<= 1) that stands for the first four elements of the HEART score may have similar rule out reliability without troponin assay requirement. We aim to prospectively assess the performance of the CARE rule and of the HEART score to predict MACE in a chest pain population. Prospective two-center non-interventional study. Patients admitted to the ED for non-traumatic chest pain were included, and followed-up at 6 weeks. The main study endpoint was the 6-week rate of MACE (myocardial infarction, coronary angioplasty, coronary bypass, and sudden unexplained death). 641 patients were included, of whom 9.5% presented a MACE at 6 weeks. The CARE rule was negative for 31.2% of patients, and none presented a MACE during follow-up [0, 95% confidence interval: (0.0-1.9)]. The HEART score was <= 3 for 63.0% of patients, and none presented a MACE during follow-up [0% (0.0-0.9)]. With an incidence below 2% in the negative group, the CARE rule seemed able to safely rule out a MACE without any biological test for one-third of patients with chest pain and the HEART score for another third with a single troponin assay. PMID- 29500620 TI - Three-dimensional evaluation of perirenal fat volume in patients with nephrolithiasis. AB - The concept of adipose tissue as an organ unto itself represents a new medical construct; already differences in the volume of perirenal fat around a tumor bearing kidney have been described. We hypothesized that renal calculi may have similar impact on perirenal fat or alternatively abnormalities in urinary metabolites may be the result of perirenal fat affecting renal metabolism and subsequent stone formation. Accordingly, we conducted a study utilizing three dimensional imaging software to evaluate perirenal fat volume (PFV) in patients with nephrolithiasis. Among 40 patients with a history of unilateral nephrolithiasis who underwent percutaneous nephrolithotomy between 2010 and 2016, the following data were acquired: body mass index, past medical history, stone characteristics and composition (i.e., calcium oxalate, calcium phosphate, uric acid, and struvite calculi). In addition, patients were stratified by dominant stone composition (>= 50% fraction). Bilateral PFV measurements were obtained using the preoperative computed tomography scan and specialized three-dimensional imaging software. The PFV of stone-bearing kidneys was significantly greater than non-stone-bearing kidneys (397.3 and 323 cc, respectively; p = 0.004), with the PFV difference in patients with CO-dominant stone-bearing kidneys reaching statistical significance (p = 0.003). Subgroup analysis showed greater PFV surrounding the stone-bearing kidney irrespective of gender (p = 0.03), with male patients possessing significantly greater stone-bearing (p = 0.01) and bilateral PFV (p = 0.01) compared to females. No significant correlations were found between PFV and stone volume or stone density. The PFV of calcium oxalate stone bearing kidneys is significantly greater than non-stone-bearing kidneys for both male and female patients with nephrolithiasis. PMID- 29500621 TI - Predictors of new-onset atrial fibrillation in elderly patients with acute coronary syndrome undergoing percutaneous coronary intervention. AB - BACKGROUND: The development of atrial fibrillation (AF) during the course of acute coronary syndrome (ACS) is related to poor prognosis. Possible predictors of new-onset AF (NOAF) have not been adequately investigated in elderly patients with ACS undergoing percutaneous coronary intervention (PCI). We aimed to identify the factors associated with NOAF in such patients. METHODS: A total of 308 elderly patients with ACS undergoing PCI were enrolled in the study. Patients were divided into two groups: without NOAF [254 patients, 64.6% men, age: 73.5 (69.0-79.0) years] and with NOAF [54 patients, 70.4% men, age: 75.0 (68.7-81.2) years]. Clinical, angiographic, and laboratory features including neutrophil-to lymphocyte ratio (NLR) and monocyte-to-high-density lipoprotein ratio (MHR) were compared between the groups. RESULTS: The percentages of prior myocardial infarction (MI) (20.4 vs. 5.9%) and Killip III/ IV (24.1 vs. 7.1%), NLR [4.5 (2.6 7.2) vs. 3.2 (2.0-6.0)], and MHR [19.4 (15.7-26.5) vs. 12.9 (9.9-18.5)] were higher in patients with NOAF compared to the others (p = 0.020, < 0.001, 0.030, and < 0.001, respectively). In multivariate regression analysis, prior MI (OR 4.509, 95% CI 1.679-12.106, p = 0.003) and MHR (OR 1.102, 95% CI 1.054-1.152, p < 0.001) independently predicted NOAF. In addition, Killip III/IV was found to be an independent predictor of 6-month overall mortality (HR 2.949, 95% CI 1.218 7.136, p = 0.016). CONCLUSIONS: Prior MI and MHR are independent predictors of NOAF in elderly patients with ACS undergoing PCI. Killip III/IV predicts 6-month overall mortality in such patients. PMID- 29500622 TI - Age-related differences in recovery from inhalational anesthesia: a retrospective study. AB - INTRODUCTION: It is important to understand the anesthetic requirements of elderly patients. However, little is known about age-related recovery from inhalational anesthetics. In this retrospective study, we compared age-related differences in recovery from three inhalational anesthetics in elderly subjects. METHODS: Patients were investigated as three age groups which can be defined as age ranges pediatric (< 15 years), adult (15-64 years), and elderly patients ( > 65 years) under general anesthesia using inhalational anesthetics. Anesthesia and surgery times, drug end-tidal concentrations, the time to first movement, time to eye opening, body movement, extubation, and discharge were recorded. The data were analyzed using a Kruskal-Wallis test and Steel-Dwass multiple comparisons. RESULTS: A total of 594 patients were included in the study. In inhalational anesthetics such as sevoflurane, isoflurane, or desflurane, recovery from general anesthesia was not significantly different among age groups (P > 0.05). In inhalational group, recovery was significantly 5-40% faster in desflurane group than in other inhalational anesthetics groups (P < 0.05). There were 20% faster recovery in pediatric and adult groups with desflurane than in elderly with desflurane group. Drug end-tidal inhalational concentrations in pediatric group were significantly higher than that in adult and elderly groups of all inhalational anesthetics, respectively (P < 0.05). CONCLUSION: In the current study, we have found that recovery from desflurane was faster in younger patients than in other inhalational anesthetics and aged patients. PMID- 29500623 TI - Irradiation-Induced Compositional Effects on Human Bone After Extracorporeal Therapy for Bone Sarcoma. AB - The present study investigates Raman scattering of human bone irradiated with 50 Gy single dose during therapeutic treatment of Ewing and Osteosarcoma. Bone quality was evaluated via mineral-to-matrix ratio, degree of crystallinity, change in amount of calcium, and carbonate substitution. Alteration in collagen and its cross-links was quantified through second-derivative deconvolution of Amide I peak. A dose of 50 Gy radiation leads to almost 50% loss of mineral content, while maintaining mineral crystallinity, and small changes in carbonate substitution. Deconvolution of Amide I suggested modifications in collagen structure via increase in amount of enzymatic trivalent cross-linking (p < 0.05). Overall irradiation led to detrimental effect on bone quality via changes in its composition, consequently reducing its elastic modulus with increased plasticity. The study thus quantifies effect of single-dose 50 Gy radiation on human bone, which in turn is necessary for designing improved radiation dosage during ECRT and for better understanding post-operative care. PMID- 29500624 TI - An Internet support group for parents of children with neurofibromatosis type 1: a qualitative analysis. AB - Parents of children with neurofibromatosis type 1 (NF1), a rare genetic condition, are at risk for emotional distress. While they may benefit from support groups, they may find it difficult to access support. We conducted an 8 week Internet support group (ISG) with 33 parents (29 mothers, 4 fathers) of children with NF1. Transcripts were evaluated using inductive thematic analysis to determine parental needs and concerns; a process and content theme were identified, with each containing codes and subcodes. In terms of process, parents utilized the ISG to seek out information, share information and experiences, and provide and receive emotional support. Common content codes included medical concerns, psychosocial/cognitive development, and accessing NF1 community resources. These concerns highlight the importance of providing parents with reliable information about their child's condition, providing multidisciplinary support to the children with NF1 and their families, and encouraging involvement in the NF1 community. PMID- 29500625 TI - Theoretical study of an anti-Markovnikov addition reaction catalyzed by beta cyclodextrin. AB - beta-Cyclodextrin (beta-CD) has a hydrophilic exterior and a hydrophobic internal cavity, which allows it to form host-guest complexes with a wide range of guests, such as organics, inorganics, and biomolecules. The aforementioned features lead to an extensive range of applications of beta-CD, as the properties of beta-CD mean that it is environmentally friendly and can be recovered and reused without mass loss. Here, the beta-CD-catalyzed anti-Markovnikov addition of styrene to thiophenol in the presence of aerial oxygen and in aqueous solution to give 1 phenyl-2-(phenylsulfanyl)-1-ethanol was studied using density functional theory (DFT) and the Hartree-Fock (HF) method. The optimal configuration of the inclusion complex of styrene and thiophenol within beta-CD was obtained, which indicated that styrene and thiophenol enter from the secondary and primary hydroxyl ends of beta-CD, respectively. Moreover, hydrogen bonding of beta-CD with styrene and thiophenol contributes to the stability of the inclusion complex. An investigation of the charges from electrostatic potentials using a grid-based method (CHELPG) highlighted the distribution of atomic charges upon complexation. The reaction sites of styrene and thiophenol were determined based on electrostatic potentials (ESPs) and condensed dual descriptors. The calculated 1H nuclear magnetic resonance (1H NMR) spectrum of beta-CD implied that the chemical shifts of its protons change and H3 and H5 move to higher fields upon complexation, while the calculated 13C nuclear magnetic resonance (13C NMR) spectrum of styrene suggested that this molecule is electrophilic. Graphical abstract ?. PMID- 29500626 TI - A Clinical Decision Support Tool to Predict Cancer Risk for Commonly Tested Cancer-Related Germline Mutations. AB - The rapid drop in the cost of DNA sequencing led to the availability of multi gene panels, which test 25 or more cancer susceptibility genes for a low cost. Clinicians and genetic counselors need a tool to interpret results, understand risk of various cancers, and advise on a management strategy. This is challenging as there are multiple studies regarding each gene, and it is not possible for clinicians and genetic counselors to be aware of all publications, nor to appreciate the relative accuracy and importance of each. Through an extensive literature review, we have identified reliable studies and derived estimates of absolute risk. We have also developed a systematic mechanism and informatics tools for (1) data curation, (2) the evaluation of quality of studies, and (3) the statistical analysis necessary to obtain risk. We produced the risk prediction clinical decision support tool ASK2ME (All Syndromes Known to Man Evaluator). It provides absolute cancer risk predictions for various hereditary cancer susceptibility genes. These predictions are specific to patients' gene carrier status, age, and history of relevant prophylactic surgery. By allowing clinicians to enter patient information and receive patient-specific cancer risks, this tool aims to have a significant impact on the quality of precision cancer prevention and disease management activities relying on panel testing. It is important to note that this tool is dynamic and constantly being updated, and currently, some of its limitations include (1) for many gene-cancer associations risk estimates are based on one study rather than meta-analysis, (2) strong assumptions on prior cancers, (3) lack of uncertainty measures, and (4) risk estimates for a growing set of gene-cancer associations which are not always variant specific. All of these concerns are being addressed on an ongoing basis, aiming to make the tool even more accurate. PMID- 29500627 TI - Parkinson's Disease: Patients' Knowledge, Attitudes, and Interest in Genetic Counseling. AB - The objective of this study was to assess the genetics knowledge of patients with Parkinson's disease (PD), and to explore their attitudes on genetic testing and interest in genetic counseling. We surveyed 158 patients from the University of Maryland Parkinson's Disease and Movement Disorders Center. Patients averaged a score of 63% on general genetics knowledge and 73% on PD genetics knowledge. Participants had an overall positive attitude toward genetic testing: 80% believed that the use of genetic tests among people should be promoted, and 83% would undertake genetic test for PD if it was available. Patients reported a high interest to discuss the benefits, risks, and impacts of genetic testing for PD (mean sum score = 26, range = 9-35), and 43% patients expressed interest in meeting with a genetic counselor. Multivariate regression analysis showed that patients who had more positive attitudes toward genetic testing for PD were more interested in meeting with a genetic counselor (beta = 0.6, p < 0.001). This study is the first to demonstrate an interest in genetic counseling among patients with PD. Our findings demonstrate a new niche for genetic counselors to support patients in clarifying gaps or misconceptions in knowledge about PD genetics as well as the possible risks, benefits, and limitations of genetic testing. PMID- 29500628 TI - [Nummular headache : Subcutaneous peripheral nerve field stimulation as an individual therapeutic attempt]. AB - BACKGROUND: Subcutaneous peripheral nerve field stimulation (sPNFS) is an established procedure for the treatment of chronic localized neuropathic pain of peripheral origin. The treatment of nummular headache primarily focuses on conservative methods with limited prospects of success. The role of sPNFS in the treatment of nummular headache has not been investigated as yet. QUESTION: Is the sPNFS an option in the management of nummular headache? MATERIALS AND METHODS: In addition to a summary of established methods in the treatment of nummular headache, sPNFS as a possible form of therapy is discussed. RESULTS: A positive effect of sPNFS in terms of the treatment of nummular headache is shown. DISCUSSION: sPNFS stimulates free subcutaneous nerves and transmits a pleasant form of paraesthesia in the area of pain. If regular conservative therapy has already been exhausted, then sPNFS might be an effective new option in the treatment of nummular headache. sPNFS is a minimally invasive and low-risk procedure. However, the high treatment cost and restrictions regarding fitness to undergo MRI are points of criticism. Further studies are needed to define its potential and role in the treatment of nummular headache. PMID- 29500629 TI - A plea for more uremic toxin research in children with chronic kidney disease. PMID- 29500630 TI - Extra uterine development of preterm kidneys. AB - OBJECTIVE: We carried out a study to determine the impact of prematurity on renal development. The primary outcomes measured were nephrinuria and albuminuria; renal volume and glomerular filtration rate were the secondary outcomes. METHODS: Preterm neonates born at less than 28 weeks of gestation, with birth weight between 10th and 90th centile (appropriate for gestational age), were recruited and underwent assessments at 28, 32 and 37 weeks postmenstrual age (PMA). RESULTS: Fifty-three premature neonates and 31 term neonates (control) were recruited. The median gestational age of the premature neonates was 26.4 [24.7 27.4] weeks, with a mean birth weight of 886 (179) g. The mean gestational age of term neonates was 39.1 (1.2) weeks and the mean birth weight was 3406 (406) g. The median age of the term neonates was 6.5 [3.0-12.5] days. The total kidney volume (TKV) almost doubled from 10.3 (2.9) cm3 at 28 weeks PMA to 19.2 (3.7) cm3 at 37 weeks PMA (P = 0.0001). TKV at 37 weeks PMA was significantly smaller compared to term neonates (19.2 (3.7) vs 26.3 (7.0) cm3; P = 0.0001). However, there was no significant difference in estimated glomerular filtration rate (eGFR) between premature neonates (at 37 weeks PMA) and term neonates (control) (43.5 [39.7-48.9] vs. 42.0 [38.2-50.0] mL/min/1.73 m2; P = 0.75). There was a statistically significant decline in nephrin-creatinine ratio and albumin creatinine ratio from 32 to 37 weeks PMA. CONCLUSIONS: Despite having a smaller renal volume (and fewer nephrons), extremely premature neonates achieve similar eGFRs at corrected term as term-born neonates, likely through single nephron hyperfiltration. Extremely premature neonates also show evidence of glomerular injury. PMID- 29500632 TI - Correction to: Effects of obesity and metabolic syndrome on cardiovascular outcomes in pediatric kidney transplant recipients: a longitudinal study. AB - As originally published, this article contained errors owing to oversights in typesetting. The article has now been amended accordingly. PMID- 29500631 TI - Prevalence, morbidity, and therapy of hepatitis E virus infection in pediatric renal allograft recipients. AB - BACKGROUND: Hepatitis E virus (HEV) infection in immunocompromised patients such as solid organ transplant recipients may bear a high risk of becoming a chronic infection with progression to liver cirrhosis. So far, data on HEV infection in pediatric renal transplant recipients are limited. METHODS: This single-center cohort study investigated period prevalence, morbidity, and treatment of HEV infection in 90 pediatric renal allograft recipients aged 9.9 +/- 5.6 years at transplantation (58.9% males). HEV serology was determined by enzyme-linked immunosorbent assay and immunoblot, HEV replication by quantitative nucleic acid testing. RESULTS: Twelve of 90 (13.3%) patients were HEV seropositive, and 4/90 (4.4%) recipients showed active HEV replication (103-108 copies/mL, corresponding to 0.5 * 103 and 0.5 * 108 WHO IU/mL) in serum and stool. In all patients with HEV replication, genotype 3 was identified by partial sequencing of HEV ORF1 and ORF2 and phylogenetic analysis. All patients with HEV replication developed chronic infection associated with moderately elevated liver enzymes. HEV replication was unresponsive to reduction of immunosuppression, whereas ribavirin monotherapy (mean dosage 9.7 +/- 3.6 mg/kg per day over 85 +/- 11 days) was associated with sustained viral clearance and normalization of liver enzymes in all patients. Ribavirin therapy was associated with reversible, hyporegenerative anemia. CONCLUSIONS: Given an HEV seroprevalence of 13.3% in pediatric renal transplant recipients and an HEV viremia of 4.4%, HEV infection should be considered in patients with otherwise unexplained elevation of liver enzymes. HEV infection does not necessarily respond to reduction of immunosuppressive therapy, but can be effectively and safely treated with ribavirin. PMID- 29500633 TI - Impaired lymphocyte function in patients with hepatic malignancies after selective internal radiotherapy. AB - The purpose of our study was to assess the immune function of patients with inoperable hepatic malignancies after treatment with selective internal radiotherapy (SIRT) and to identify possible correlations with clinical parameters. In 25 patients receiving SIRT lymphocyte proliferation and the production of pro- and anti-inflammatory cytokines (interferon-gamma and interleukin-10) after stimulation with mitogens and microbial antigens were tested prior to therapy, directly after therapy (day 1) and at day 2, 7 and 28 post therapy using the lymphocyte transformation test and enzyme-linked immunospot assays. Absolute counts and percentages of leukocyte and lymphocyte subsets were determined by flow cytometry. The most prominent finding was an immediate and significant (p < 0.05) decrease of lymphocyte proliferation and interferon-gamma production directly after therapy which lasted until day 28 and was stronger upon stimulation with microbial antigens than with mitogens. Moreover, lymphopenia was revealed, affecting all lymphocyte subsets (CD3+, CD4+, CD8+ T cells, CD4+ CD8+ T cells, B cells and NK cells). SIRT led to a reduction in the percentage of activated HLA-DR+ monocytes and of CD45R0+ memory T cells. Higher radiation activity, the presence of liver cirrhosis, chronic kidney disease, diabetes mellitus and metastases were unfavorable factors for immunocompetence, while a better Eastern Cooperative Oncology Group performance status was associated with stronger immunological reactions. In conclusion, SIRT leads to severe impairment of cellular in vitro immune responses. Further studies are needed to assess a potential clinical impact. PMID- 29500634 TI - The Third Institute for Cancer Vaccines and Immunotherapy (ICVI) symposium on immunotherapy: May 12-13, 2017, Royal Society, London, UK. PMID- 29500635 TI - Daratumumab augments alloreactive natural killer cell cytotoxicity towards CD38+ multiple myeloma cell lines in a biochemical context mimicking tumour microenvironment conditions. AB - Natural killer (NK) cell-based immunotherapy is a promising novel approach to treat cancer. However, NK cell function has been shown to be potentially diminished by factors common in the tumor microenvironment (TME). In this study, we assessed the synergistic potential of antibody-dependent cell-mediated cytotoxicity (ADCC) and killer immunoglobin-like receptor (KIR)-ligand mismatched NK cells to potentiate NK cell antitumor reactivity in multiple myeloma (MM). Hypoxia, lactate, prostaglandin E2 (PGE2) or combinations were selected to mimic the TME. To investigate this, NK cells from healthy donors were isolated and NK cell ADCC capacity in response to MM cells was assessed in flow cytometry-based cytotoxicity and degranulation (CD107a) assays in the presence of TME factors. Hypoxia, lactate and PGE2 reduced cytotoxicity of NK cells against myeloma target cells. The addition of daratumumab (anti-CD38 antibody) augmented NK-cell cytotoxicity against target cells expressing high CD38, but not against CD38 low or negative target cells also in the presence of TME. Co-staining for inhibitory KIRs and NKG2A demonstrated that daratumumab enhanced degranulation of all NK cell subsets. Nevertheless, KIR-ligand mismatched NK cells were slightly better effector cells than KIR-ligand matched NK cells. In summary, our study shows that combination therapy using strategies to maximize activating NK cell signaling by triggering ADCC in combination with an approach to minimize inhibitory signaling through a selection of KIR-ligand mismatched donors, can help to overcome the NK suppressive TME. This can serve as a platform to improve the clinical efficacy of NK cells. PMID- 29500636 TI - Laboratory Diagnosis and Characterization of Fungal Disease in Patients with Cystic Fibrosis (CF): A Survey of Current UK Practice in a Cohort of Clinical Microbiology Laboratories. AB - There is much uncertainty as to how fungal disease is diagnosed and characterized in patients with cystic fibrosis (CF). A 19-question anonymous electronic questionnaire was developed and distributed to ascertain current practice in clinical microbiology laboratories providing a fungal laboratory service to CF centres in the UK. Analyses of responses identified the following: (1) current UK laboratory practice, in general, follows the current guidelines, but the scope and diversity of what is currently being delivered by laboratories far exceeds what is detailed in the guidelines; (2) there is a lack of standardization of fungal tests amongst laboratories, outside of the current guidelines; (3) both the UK CF Trust Laboratory Standards for Processing Microbiological Samples from People with Cystic Fibrosis and the US Cumulative Techniques and Procedures in Clinical Microbiology (Cumitech) Guidelines 43 Cystic Fibrosis Microbiology need to be updated to reflect both new methodological innovations, as well as better knowledge of fungal disease pathophysiology in CF; (4) there is a need for clinical medicine to decide upon a stratification strategy for the provision of new fungal assays that will add value to the physician in the optimal management of CF patients; (5) there is also a need to rationale what assays should be performed at local laboratory level and those which are best served at National Mycology Reference Laboratory level; and (6) further research is required in developing laboratory assays, which will help ascertain the clinical importance of 'old' fungal pathogens, as well as 'emerging' fungal pathogens. PMID- 29500639 TI - Raise Concerns Without Fear and Protect Confidentiality: Why the Two Orders? PMID- 29500638 TI - Diagnosing internal herniation after laparoscopic Roux-en-Y gastric bypass: usefulness of systematically reviewing CT scans using ten signs. AB - OBJECTIVES: To evaluate if systematically reviewing CT scans using ten signs leads to a better accuracy in diagnosing internal herniation (IH), compared to the original report. Also, the difference in accuracy was analysed between experience levels. METHODS: Patients were retrospectively included if they had undergone laparoscopic gastric bypass surgery between 2011 and 2014, and if additional radiological examination was performed for suspected IH between 2011 and 2016. Out of 1475 patients who had undergone laparoscopic gastric bypass surgery, 183 patients had one or more additional radiological examinations. A total of 245 CT scans were performed. All were reassessed by an abdominal radiologist, a radiology resident and intern. Assessment was done using ten signs from previous literature. Overall suspicion of IH was graded using a 5-point Likert scale. Accuracy was calculated using two-way contingency tables. Interobserver agreement was calculated using Fleiss' kappa. RESULTS: After 70 reoperations an IH was diagnosed in 48.6% (34/70). There was an increase in specificity for diagnosing IH with reoperation as reference from 52.8% (19/36; 95% CI 35.7-69.2%) in the original report to 86.1% (31/36; 95% CI 74.8-97.4%) for the radiologist (p = 0.002), 77.8% (28/36; 95% CI 64.2-91.4%) for the resident (p = 0.026) and 77.8% (28/36; 95% CI 64.2-91.4%) for the intern (p = 0.026). Interobserver agreement was good. CONCLUSIONS: Systematically reviewing CT scans using a list of ten CT signs can improve specificity and thereby reduce unnecessary reoperations, especially in a high pre-test probability population. The tool can be easily taught to less experienced readers. KEY POINTS: * Computed tomography is useful to diagnose internal herniation(IH) after gastric bypass surgery * Ten signs are described to improve CT diagnosis of IH * Systematically reviewing CT scans improves specificity * There is no difference in experience levels when using these ten signs. PMID- 29500637 TI - RNA-Seq Profile Reveals Th-1 and Th-17-Type of Immune Responses in Mice Infected Systemically with Aspergillus fumigatus. AB - With the increasing numbers of immunocompromised hosts, Aspergillus fumigatus emerges as a lethal opportunistic fungal pathogen. Understanding innate and acquired immunity responses of the host is important for a better therapeutic strategy to deal with aspergillosis patients. To determine the transcriptome in the kidneys in aspergillosis, we employed RNA-Seq to obtain single 76-base reads of whole-genome transcripts of murine kidneys on a temporal basis (days 0; uninfected, 1, 2, 3 and 8) during invasive aspergillosis. A total of 6284 transcripts were downregulated, and 5602 were upregulated compared to baseline expression. Gene ontology enrichment analysis identified genes involved in innate and adaptive immune response, as well as iron binding and homeostasis, among others. Our results showed activation of pathogen recognition receptors, e.g., beta-defensins, C-type lectins (e.g., dectin-1), Toll-like receptors (TLR-2, TLR 3, TLR-8, TLR-9 and TLR-13), as well as Ptx-3 and C-reactive protein among the soluble receptors. Upregulated transcripts encoding various differentiating cytokines and effector proinflammatory cytokines, as well as those encoding for chemokines and chemokine receptors, revealed Th-1 and Th-17-type immune responses. These studies form a basic dataset for experimental prioritization, including other target organs, to determine the global response of the host against Aspergillus infection. PMID- 29500640 TI - Systematic review of qualitative evaluations of reentry programs addressing problematic drug use and mental health disorders amongst people transitioning from prison to communities. AB - BACKGROUND: The paper presents a systematic review and metasynthesis of findings from qualitative evaluations of community reentry programs. The programs sought to engage recently released adult prison inmates with either problematic drug use or a mental health disorder. METHODS: Seven biomedical and social science databases, Cinahl, Pubmed, Scopus, Proquest, Medline, Sociological abstracts and Web of Science and publisher database Taylor and Francis were searched in 2016 resulting in 2373 potential papers. Abstract reviews left 140 papers of which 8 were included after detailed review. Major themes and subthemes were identified through grounded theory inductive analysis of results from the eight papers. Of the final eight papers the majority (6) were from the United States. In total, the papers covered 405 interviews and included 121 (30%) females and 284 (70%) males. RESULTS: Findings suggest that the interpersonal skills of case workers; access to social support and housing; and continuity of case worker relationships throughout the pre-release and post-release period are key social and structural factors in program success. CONCLUSION: Evaluation of community reentry programs requires qualitative data to contextualize statistical findings and identify social and structural factors that impact on reducing incarceration and improving participant health. These aspects of program efficacy have implications for reentry program development and staff training and broader social and health policy and services. PMID- 29500641 TI - The 'lottery' of cardiovascular risk estimation with Internet-based risk calculators. AB - The cardiovascular disease (CVD) is the leading cause of disability and premature death around the world. The ongoing publication of systematic and critical literature reviews has contributed to generate a kaleidoscope of guidelines by different scientific organizations. We investigated the accordance among the most popular web-based CVD risk calculators on the Internet. We carried out a simple study, by estimating the risk of CVD using the most popular Internet-based calculators available on the Internet. A Google search was performed, using the keyword "cardiovascular risk calculator", to identify the first 10 websites providing free on-line CVD risk calculators. We arbitrarily selected the cardiovascular profile of two subjects of a typical Western family: a 55-year man at a likely intermediate cardiovascular risk and a 45-year woman at a probable low risk. The score calculated according to the two arbitrary CVD risk profiles, one of whom was supposed to be at intermediate risk and the other at lower risk, was extremely variable. More specifically, the 10-year CVD risk of the 55-year old man varied from 3% to over 25% (median value, 12.9%, interquartile range [IQR], 10.7-19.0%), whereas that of the 45-year women varied between 0% and 4% (median value, 1.2%; IQR, 0.4-2.2%), thus displaying a nearly 10-fold variation in both cases. We concluded from our analysis of 11 different Internet-based CVD risk calculators that the final 10-year risk score can be extremely different, especially for the 55-year old man at predictably intermediate risk. PMID- 29500642 TI - Ultrasound: novel techniques. PMID- 29500643 TI - Spherical liver in primary sclerosing cholangitis. PMID- 29500644 TI - Combined chemoembolization and thermal ablation for the treatment of metastases to the liver. AB - PURPOSE: The purpose of the study was to evaluate safety, time to recurrence, and overall survival (OS) in patients with liver metastases (LM), treated with transarterial chemoembolization (TACE) followed by ablation. MATERIALS AND METHODS: This retrospective study included all patients with LM treated with combined TACE and ablation from August 1998 to September 2015. Forty-two patients (12 women, 30 men; age 62.9 +/- 11.9 years) were treated for 44 LMs. Tumor characteristics, imaging response to treatment, recurrence, and OS data were reviewed. Statistical analysis included Kaplan-Meier estimation, Cox regression and Fisher's exact, Wilcoxon rank sum, or log rank tests. RESULTS: Median follow up was 10.3 months. Eighteen patients had 1 hepatic lesion, 16 had 2-5, and 8 had > 5. Median index lesion size was 4.7 cm (range 1.5-8 .0 cm). Tumor response (mRECIST) was available for 41/44 treated lesions, with CR in 32 (78.0%), PR in 8 (19.5%), and PD in 1 (2.4%). Long-term imaging follow-up was available for 38 patients. Freedom from local recurrence was 61% at 1 year and 50% at 2 years. OS was 55% at 1 year and 30% at 2 years (median OS, 14.5 months). Tumor size and histology were not predictors of time to progression or OS. Complications occurred in 19 patients (45%). Major complications occurred in 19% of patients and included hospitalization for fever (n = 2), hepatic abscess (n = 3) and fall requiring transfusion, portal vein thrombus causing lobar infarct, biliary fistula, and retroperitoneal hematoma (n = 1 each). CONCLUSIONS: Combined TACE and ablation is effective for local tumor control of liver metastases up to 8 cm when part of a multidisciplinary treatment strategy. Major complications occurred in 19% of patients. PMID- 29500645 TI - Fractal analysis of contrast-enhanced CT images for preoperative prediction of malignant potential of gastrointestinal stromal tumor. AB - PURPOSE: The purpose of this study is to assess the heterogeneity of tumor enhancement using fractal analysis on contrast-enhanced computed tomography (CE CT) for predicting malignant potential of gastrointestinal stromal tumor (GIST). METHODS: We retrospectively identified 64 patients (36 M/28 W; median age: 65) with GISTs who received CE-CT and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) followed by curative surgery. Fractal analysis was applied to CE-CT image, and fractal dimension (FD) was measured. Diagnostic value of FD for malignant potential of GIST was compared with that of FDG-PET using the risk classification and Ki67 index. RESULTS: 14 patients were categorized as the high risk, and 50 patients were as the very low, low or intermediate risk. FD of high risk group was significantly higher than that of the other-risk group (p < 0.05). The areas under the ROC curves of FD and SUVmax for prediction of high-risk group were 0.82 and 0.93 (accuracy: 84.4% and 98.5%). FD showed a significant positive correlation with Ki67 index (p = 0.01). CONCLUSION: Diagnostic value of CT fractal analysis for prediction of high-risk GIST is comparable with FDG-PET. In terms of cost and availability, fractal analysis has a potential to be an optimal preoperative biomarker. PMID- 29500647 TI - Kissing ovaries sign on MRI. PMID- 29500646 TI - Vascular complications in kidney transplant recipients. AB - Vascular complications are a significant source of morbidity and mortality among renal transplant recipients. Imaging using ultrasound, CT, and MRI plays a key role in diagnosing such complications. This review focuses on the major vascular complications of renal grafts, which include transplant renal arterial and venous stenoses, arterial and venous thromboses, arteriovenous fistulas, and pseudoaneurysms. Etiology, diagnostic modalities useful for diagnosis, and imaging appearance will be presented. PMID- 29500648 TI - Diffusion-weighted MRI as a screening tool for hepatocellular carcinoma in cirrhotic livers: correlation with explant data-a pilot study. AB - OBJECTIVE: The purpose of this study was to compare the sensitivity and specificity of diffusion-weighted liver MRI alone with complete, multiphasic gadoteridol-enhanced MRI for the detection of hepatocellular carcinoma in cirrhotic patients before liver transplant. MATERIALS AND METHODS: This single institution retrospective study was performed after IRB approval and was HIPAA compliant. MRI scans of 37 patients who underwent liver transplant were evaluated and findings correlated with liver explant (36) or biopsy (1). All MRI scans were obtained within six months of explant. MRI from 17 patients with liver lesions by report at imaging subsequently proven to be HCC at pathology and 20 controls without liver lesions by imaging and pathology were reviewed in random order on the radiology PACS by three independent readers blinded to the MRI reports and pathology reports in two separate sittings. First, only the diffusion-weighted images (DWI) were interpreted. Second, the complete multiphasic MRI exam with DWI was reviewed. A consensus read was obtained by two separate radiologists who had access to the patients' explant data in order to map lesions. Reader-specific and pooled classification was assessed using sensitivity, specificity, positive predictive value, and negative predictive values and corresponding 95% confidence intervals (CI) for both DWI and complete MRI examination readings compared to pathology. McNemar's test and Kappa coefficient were used to assess differences (agreement) in DWI and complete examination readings. RESULTS: A total of 37 patients have been studied (25M 12F age range 21-70). Averaged results of the three independent readers demonstrated a sensitivity of 78% (95% CI 65-89%) and specificity of 88% (95% CI 77-95%) for DWI alone for detection of liver lesions, with a positive predictive value of 85% (95% CI 72-94%) and a negative predictive value of 83% (95% CI 71-91%). Review of the complete MRI exam showed a sensitivity of 90% (95% CI 76-97%) and a specificity of 82% (95% CI 66-92%) with a positive predictive value of 83% (95% CI 69-93%) and a negative predictive value of 89% (95% CI 74-97%). McNemar's agreement test revealed no significant difference between the DWI and complete multiphasic interpretations (p = 0.3458), with simple Kappa coefficient of 0.6716 (95% CI 0.5332-0.8110). Lesions identified on DWI ranged in size from 1.5 to 5 cm. Detection of lesions was decreased in the presence of artifact from motion, large ascites, and technical issues. CONCLUSION: Diffusion-weighted MRI has NPV and PPV comparable to complete multiphasic MRI examination for liver lesion detection in cirrhotic patients and may have a role in screening. PMID- 29500649 TI - Using T1 mapping in cardiovascular magnetic resonance to assess congestive hepatopathy. AB - The goal of this study was to assess the ability of quantitative T1 cardiovascular magnetic resonance (CMR) imaging to calculate liver extracellular volume (ECV) in patients with varying degrees of congestive hepatopathy (CH). T1 measurements and ECV calculations were performed retrospectively in three cohorts of patients: normal cardiac function, tetralogy of fallot (TOF) repair and Fontan palliation. All CMR studies included modified look-locker inversion recovery (MOLLI) T1 mapping scans performed pre- and post-injection of a gadolinium-based contrast agent (GBCA). Pixel intensity data were manually collected from images of the liver and cardiac blood pool to determine contrast-induced changes in T1 for liver and blood. These data were then used to compute liver ECV. 172 subjects were included in the study. Of these, 140 subjects were normal cardiac function patients, 16 were TOF repair patients and 16 patients were with Fontan palliation. A statistically significant difference in both the liver native T1 and ECV measurements was found between patients with normal cardiac function vs. Fontan palliation patients (p < 0.01). Our data indicate that measuring T1 maps both pre- and post-GBCA injection within CMR scan session can be used to follow progression of liver fibrosis. This technique has the potential to improve diagnosis and treatment of patients with chronic liver disease and liver fibrosis. PMID- 29500650 TI - Mimics of malrotation on pediatric upper gastrointestinal series: a pictorial review. AB - Intestinal malrotation is a continuum of congenital anomalies due to lack of rotation or incomplete rotation of the fetal intestine around the superior mesenteric artery axis. The abnormal bowel fixation (by mesenteric bands) or absence of fixation of portions of the bowel increases the risk of bowel obstruction, acute or chronic volvulus, and bowel necrosis. The clinical presentation of patients with malrotation without, with intermittent, or with chronic volvulus can be problematic, with an important minority presenting late or having atypical or chronic symptoms, such as intermittent vomiting, abdominal pain, duodenal obstruction, or failure to thrive. The diagnosis is heavily reliant on imaging. Upper GI series remain the gold standard with the normal position of the duodenojejunal junction lateral to the left-sided pedicles of the vertebral body, at the level of the duodenal bulb on frontal views and posterior (retroperitoneal) on lateral views. However, a variety of conditions might influence the position of the duodenojejunal junction, potentially leading to a misdiagnosis of malrotation. Such conditions include improper technique, gastric over distension, splenomegaly, renal or retroperitoneal tumors, liver transplant, small bowel obstruction, the presence of properly or malpositioned enteric tubes, and scoliosis. All of these may cause the duodenojejunal junction to be displaced. We present a series of cases highlighting conditions that mimic malrotation without volvulus to increase the practicing radiologist awareness and help minimize interpretation errors. PMID- 29500651 TI - Differentiation between pancreatic metastases from clear cell renal cell carcinoma and pancreatic neuroendocrine tumor using double-echo chemical shift imaging. AB - PURPOSE: The purpose of the study was to retrospectively analyze whether double echo gradient-echo (GRE) chemical shift imaging (CSI) can differentiate between pancreatic metastases from clear cell renal cell carcinoma (PM-ccRCC) and pancreatic neuroendocrine tumor (pNET). METHODS: Institutional review board approval and informed consent were waived. CSI, T2WI, DWI, and DCE magnetic resonance imaging (MRI) were performed in patients with PM-ccRCC and pNET. Eleven patients with PM-ccRCC and 24 patients with pNET were enrolled into this retrospective study. The signal intensity was measured in the pancreatic tumor and spleen on in-phase and opposed-phase images. The signal intensity index (SII) and tumor-to-spleen ratio (TSR) in PM-ccRCC and pNET were calculated and compared. Receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic accuracy of SII and TSR in the differentiation between PM ccRCC and pNET. RESULTS: The SII between PM-ccRCC and pNET (20.3% +/- 16.8% vs. - 3.2% +/- 11.4%) was significantly different (P < 0.001), as was the TSR (- 19.2% +/- 16.6% vs. 6.0% +/- 13.8%) (P < 0.001). The area under the ROC curve was 0.917 for the SII and 0.902 for the TSR. Additionally, an SII threshold value of 8.1% permitted the differentiation of PM-ccRCC from pNET with a sensitivity of 90.9%, a specificity of 91.7%, a positive predictive value of 90.1%, a negative predictive value of 91.7%, and an accuracy of 91.4%. A TSR cut-off value of - 4.7% enabled the differentiation of the two groups with a sensitivity of 79.2%, a specificity of 90.9%, a positive predictive value of 90.9%, a negative predictive value of 79.2% and an accuracy of 82.9%. CONCLUSION: Double-echo GRE chemical shift MR imaging can accurately differentiate between PM-ccRCC and pNET. PMID- 29500652 TI - 18F-FDG PET/CT in splenic marginal zone lymphoma. AB - PURPOSE: The detection rate and the metabolic behavior of 18F-FDG-PET/CT in splenic marginal zone lymphoma (SMZL) are not yet clear. Our aim was to investigate the metabolic behavior of SMZL and whether the tumor stage (acc. Ann Arbor) epidemiological (age, gender), histological (Ki-67 index, plasmacytic differentiation), and morphological (splenic diameter maximum) features might be related to 18F-FDG PET/CT results. METHODS: Fifty-one patients (34 male, 17 female; average age 70 years) with histologically confirmed SMZL who underwent a 18F-FDG PET/CT for initial staging were included: PET/CT images were analyzed visually and semi-quantitatively (SUVmax, lesion-to-liver SUVmax ratio, and lesion-to-blood pool SUVmax ratio). Splenic uptake was divided as diffuse or focal. RESULTS: Thirty-nine patients (76%) had FDG-avid SMZL (7 with focal splenic lesions and 32 with diffuse splenic uptake), while the remaining 12 had no increased splenic uptake. Among patients with FDG-avid lesions, average SUVmax was 4.3, lesion-to-liver SUVmax ratio 2.3, and lesion-to-blood pool SUVmax ratio 3. 18F-FDG avidity was significantly associated with Ki-67 index and not correlated with other features. Semiquantitative PET/CT parameters (SUVmax, lesion-to-liver SUVmax ratio, and lesion-to-blood pool SUVmax ratio) did not correlate significantly with any variable. Progression-free survival time was not influenced by FDG avidity of SMZL. CONCLUSIONS: 18F-FDG avidity was noted in 76% of SMZL with diffuse splenic uptake as main pattern of presentation and is correlated with Ki-67 score only. PMID- 29500653 TI - Transjugular intrahepatic portosystemic shunt (TIPS) dysfunction: quantitative assessment of flow and perfusion changes using 2D-perfusion angiography following shunt revision. AB - PURPOSE: To analyze the feasibility of 2D-perfusion angiography (2D-PA) to quantify flow and perfusion changes pre- and post-transjugular intrahepatic portosystemic shunt (TIPS) revision. MATERIALS AND METHODS: Fifteen consecutive patients (54 +/- 14 years, seven men and eight women) scheduled for TIPS revision were included in this study. To quantify flow and perfusion changes caused by TIPS revision, digital subtraction angiography (DSA) series acquired during the revision were post-processed using a dedicated software. Reference region-of interest (ROI) in the main portal vein (input function) and target ROIs in the TIPS lumen, the liver parenchyma and in the right atrium were placed in corresponding areas on DSA pre- and post-TIPS revision. 2D-PA evaluation included time to peak (TTP), peak density (PD), and the area under the curve (AUC) assessment. The ratios of reference ROI to target ROIs pre- and post-TIPS revision were calculated (TTPparenchyma/TTPinflow, PDparenchyma/PDinflow, AUCparenchyma/AUCinflow, TTPTIPS/TTPinflow, PDTIPS/PDinflow, AUCTIPS/AUCinflow, TTPatrium/TTPinflow, PDatrium/PDinflow, and AUCatrium/AUCinflow). Pressure measurements pre- and post-TIPS revision were performed and correlated to the 2D PA parameters. Reproducibility of 2D-PA was assessed by the intra-class correlation coefficient (ICC). RESULTS: The portosystemic pressure gradient was significantly reduced following TIPS revision (17.1 +/- 6.3 vs. 8.9 +/- 4.3 mmHg; p < 0.0001). PDTIPS/PDinflow (0.22 vs. 0.35; p = 0.0014) and AUCTIPS/AUCinflow (0.24 vs. 0.39; p = 0.0012) increased significantly. Likewise, PDatrium/PDinflow (0.32 vs. 0.78; p = 0.0004) and AUCatrium/AUCinflow (0.3 vs. 0.79; p < 0.0001) increased, whereas PDparenchyma/PDinflow decreased significantly (0.14 vs. 0.1; p = 0.0084). Pressure gradient changes correlated significantly with the increase in PDatrium/PDinflow (r = - 0.77, p = 0.0012) and AUCatrium/AUCinflow (r = - 0.76, p = 0.0018). ICC of the 2D-PA parameters was in the range of 0.88-0.99. CONCLUSION: 2D-PA offers a feasible approach to quantify flow and perfusion changes during TIPS revision. Therefore, 2D-PA may be a valuable amendment to mere pressure measurements. PMID- 29500654 TI - Antibacterial Activity of In Situ Prepared Chitosan/Silver Nanoparticles Solution Against Methicillin-Resistant Strains of Staphylococcus aureus. AB - BACKGROUND: Investigation of new effective drugs against the methicillin resistant strains of Staphylococcus aureus (MRSA) is an urgent issue of modern medicine. Antiseptics as an alternative of antibiotics are strong, sustained, and active preparations against resistant strains and do not violate microbiocenosis. MATERIALS AND METHODS: The activity of in situ prepared chitosan-Ag nanoparticles (Ag NPs) solution with different component ratio was tested against MRSA isolated from patients. Ag NPs were synthesized via chemical reduction method using green chemistry approach. In order to improve antimicrobial activity and dispersibility of Ag NPs, surface modification of Ag NPs by cetrimonium bromide (CTAB) was performed. Ag NPs and chitosan-Ag NPs solution were characterized using X-ray diffraction, transmission electron microscopy, infrared spectroscopy, and spectrophotometric measurements. RESULTS AND CONCLUSIONS: The results of XRD, FTIR, UV-Vis, and TEM measurements confirmed the chemical composition of chitosan and Ag NPs and their high purity. Chitosan-AgNPs solutions have shown their superior antimicrobial efficacy compared to its pure forms. At the same time, in situ preparation of chitosan-Ag NPs solution (chitosan powder 6.0 MUg/ml, Ag/CTAB NPs) was not possible due to the precipitation of the components. This result is very promising and may be considered as an effective solution in fighting against drug-resistant bacteria. PMID- 29500655 TI - Cutaneous neural activity and endothelial involvement in cold-induced vasodilatation. AB - Whether sympathetic withdrawal or endothelial dilators such as nitric oxide (NO) contributes to cold-induced vasodilation (CIVD) events is unclear. We measured blood flow and finger skin temperature (Tfinger) of the index finger in nine participants during hand immersion in a water bath at 35 degrees C for 30 min, then at 8 degrees C for 30 min. Data were binned into 10 s averages for the entire 60 min protocol for laser-Doppler flux (LDF) and Tfinger. At baseline, Tfinger was 35.3 +/- 0.2 degrees C and LDF was 227 +/- 28 PU. During hand cooling, minimum Tfinger was 10.9 +/- 0.4 degrees C and LDF was 15 +/- 4 PU. All participants exhibited at least one CIVD event (Tfinger increase >= 1 degrees C), with a mean peak Tfinger 13.2 +/- 0.8 degrees C and a corresponding peak LDF of 116 +/- 34 PU. A Morlet mother wavelet was then used to perform wavelet analysis on the LDF signal, with frequency ranges of 0.005-0.01 Hz (endothelial NO-independent), 0.01-0.02 Hz (endothelial NO-dependent), and 0.02-0.05 Hz (neurogenic). The synchronicity of wavelet fluctuations with rising LDF coincident with CIVD events was then quantified using Auto-regressive Integrated Moving Average time-series analysis. Fluctuations in neural activity were strongly synchronized in real time with increasing LDF (stationary-r2 = 0.73 and Ljung-box statistic > 0.05), while endothelial activities were only moderately synchronized (NO-independent r2 = 0.15, > 0.05; NO dependent r2 = 0.16, > 0.05). We conclude that there is a direct, real-time correlation of LDF responses with neural activity but not endothelial-mediated mechanisms. Importantly, it seems that neural activity is consistently reduced prior to CIVD, suggesting that sympathetic withdrawal directly contributes to CIVD onset. PMID- 29500656 TI - Clinicopathological features and endoscopic findings of HER2-positive gastric cancer. AB - BACKGROUND: Human epidermal growth factor receptor 2 (HER2) expression in gastric cancer is highly heterogeneous. Therefore, it is important to take endoscopic samples from appropriate tumor sites. METHODS: Between January 2008 and April 2015, patients with gastric or gastroesophageal junction cancer with histologically confirmed adenocarcinoma were included. Surgical samples or endoscopic biopsy samples were examined for HER2 using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Tissues were considered to be HER2 positive when either assessment revealed either an IHC score of 3+ or an IHC score of 2+ accompanied by a positive FISH result. Endoscopic findings were retrieved in all cases where available, and we examined the portion from which a biopsy was obtained. RESULTS: Out of the 612 patients included in the study, 104 (17%) were HER2 positive. The proportion of HER2-positive gastric tumors with differentiated (vs. undifferentiated) histology was significantly higher (29 vs. 6%, respectively; p < 0.001). The HER2-positive rate of papillary adenocarcinomas (vs. tubular) was particularly high (62%, 8/13; p = 0.023). The proportion of HER2-positive gastric tumors of Borrmann classification 0 or 1 was significantly higher than that of tumors of classified as 2, 3, or 4 (45 vs. 16%, respectively; p < 0.001). The HER2-positive rates per biopsy specimen from the superficial spreading portion, ulcer mound, ulcer bed, and mass portion were 100, 91, 45, and 100%, respectively. CONCLUSIONS: HER2-positive gastric cancer tends to be associated with a differentiated histology, particularly papillary adenocarcinoma, and a Borrmann classification of 0 or 1 tumors. Based on these endoscopic findings, it is important to recognize the superficial spreading portion and the mass portion of gastric malignancies. PMID- 29500657 TI - Primary Care for the Elderly Bereaved: Recommendations for Medical Education. AB - The aim of this study was to explore the current practices of primary care physicians (PCPs) in providing bereavement care to elderly patients, with implications for medical education. A total of 63 PCPs answered a brief online survey about their typical practices, barriers, comfort level with bereavement, and confidence in their ability to diagnose prolonged grief disorder (PGD). They were recruited through an online newsletter and contacts of one of the authors. The results found that two-thirds of the PCPs do not routinely screen their elderly patients for recent losses, nor do they refer to mental health clinicians when loss is identified. Barriers included not learning of the deaths in patients' lives and lack of time during clinic visits. Those PCPs who had experienced their own losses were significantly more comfortable in speaking to patients about recent losses and more confident in their ability to diagnose PGD. We recommend bereavement education be incorporated into the medical school curriculum from the outset, utilizing the psychological principle of graded exposure to bereaved individuals. PMID- 29500658 TI - Maternal filicide in a cohort of English Serious Case Reviews. AB - A national mixed-methods study of English Serious Case Reviews (SCRs) was carried out to better understand the characteristics and circumstances of maternally perpetrated filicides, to compare these with paternally perpetrated cases, and to identify learning points for mental health professionals. Published reports for all SCRs of children in England dying as a result of abuse or neglect from 2011 to 2014 were subject to qualitative analysis using a system of layered reading and inductive thematic analysis, along with descriptive and comparative quantitative analysis. There were 86 deaths directly attributable to child maltreatment within the immediate family. The mother was the suspected perpetrator in 20. Twelve of the mother perpetrators were victims of domestic violence, while 15 of the father perpetrators were known to be perpetrators of domestic violence. Those deaths resulting from impulsive violence or severe, persistent cruelty are almost exclusively perpetrated by males, while those with an apparent intent to kill the child are slightly more likely to be perpetrated by mothers. Four key themes were identified through the qualitative analysis: domestic violence, maternal mental illness, separation and maternal isolation, and the invisibility of the child. These findings highlight the important role of domestic violence and its interaction with maternal mental health. Professionals working with mothers with mental health problems need to adopt a supportive but professionally curious stance, to be alert to signs of escalating stress or worsening mental ill-health, and to provide supportive and accessible structures for at-risk families. PMID- 29500659 TI - Clinical significance of understanding lateral and medial circumflex femoral artery origin variability. AB - The common femoral artery (CFA) divides into the superficial femoral artery (SFA) and deep femoral artery (DFA). The lateral circumflex femoral artery (LCFA) and medial circumflex femoral artery (MCFA) are most often branches of the DFA, although a large number of different variations in their origin has been described. We performed microdissection on both lower limbs of 30 fetuses, gestational age from 7 to 10 lunar months. Our results show that the LCFA and MCFA usually arise from the DFA. In 78.3% of cases, the MCFA originated from the DFA. In 11.7% of cases, the MCFA originated from the CFA, and in 5% of cases from the SFA. One case showed a common trunk with the DFA. Also, the MCFA was missing in one case, and it had a common trunk with the LCFA in one case. In 83.3% of cases, the LCFA arose from the DFA and in 6.7% of cases from the CFA. In one case, it had a common trunk with the DFA, and in one case with the MCFA. In 3.3% of cases, the LCFA was missing. In 66.7% of cases, both arteries originated from the DFA, in 15% of cases one originated from the DFA and the other from the CFA or SFA. Our results are in accordance with some published studies but also differ from the outcomes of other studies. Comprehensive knowledge of different variation types is imperative in order to prevent complications during surgical and orthopedic interventions. PMID- 29500660 TI - Enhanced production of exopolysaccharides using industrial grade starch as sole carbon source. AB - Industrial grade soluble corn starch was used directly and effectively as the fermentation substrate for microbial exopolysaccharides production. Bacillus subtilis mutant strain NJ308 grew with untreated starch raw material as the sole carbon source. The real-time PCR results demonstrated that up-regulated genes encoding N-acetylglucosaminyltransferase, mannosyltransferase, and N acetylglucosamine-1-phosphate uridyltransferase were the key elements of B. subtilis mutant strain NJ308 for exopolysaccharides production from industrial grade starch. Subsequently, the culture conditions for B. subtilis NJ308 were optimized using Plackett-Burman design and central composite design methods, and the related key genes in the synthesis pathway of exopolysaccharides from the starch raw material were analyzed by real-time PCR. The maximum exopolysaccharides titration (3.41 g/L) was obtained when the initial starch concentration was 45 g/L. This corresponds to volumetric productivity values of 71.04 mg/L h. PMID- 29500661 TI - Growth medium sterilization using decomposition of peracetic acid for more cost efficient production of omega-3 fatty acids by Aurantiochytrium. AB - Aurantiochytrium can produce significant amounts of omega-3 fatty acids, specifically docosahexaenoic acid and docosapentaenoic acid. Use of a glucose based medium for heterotrophic growth is needed to achieve a high growth rate and production of abundant lipids. However, heat sterilization for reliable cultivation is not appropriate to heat-sensitive materials and causes a conversion of glucose via browning (Maillard) reactions. Thus, the present study investigated the use of a direct degradation of Peracetic acid (PAA) for omega-3 production by Aurantiochytrium. Polymer-based bioreactor and glucose-containing media were chemically co-sterilized by 0.04% PAA and neutralized through a reaction with ferric ion (III) in HEPES buffer. Mono-cultivation was achieved without the need for washing steps and filtration, thereby avoiding the heat induced degradation and dehydration of glucose. Use of chemically sterilized and neutralized medium, rather than heat-sterilized medium, led to a twofold faster growth rate and greater productivity of omega-3 fatty acids. PMID- 29500662 TI - Risk of post-operative venous thromboembolism in patients with meningioma. AB - The surgical resection of meningiomas can be complicated by venous thromboembolism (VTE) in the post-operative period, but the exact incidence of this event is not known. Aim of this study was to assess the occurrence of VTE in patients operated for meningioma who underwent a post-operative clinical and objective screening for VTE. Patients undergoing meningioma resection between 2000 and 2010 who accepted to be investigated for VTE in the post-operative period were included in the study. The screening included daily clinical assessment, pulmonary perfusion scintigraphy (Q-SCAN) on day 2 and venous compression ultrasonography (CUS) of the lower limbs within day 7. The univariate and multivariate statistical analysis of risk factors for VTE included sex, age, presence of comorbidities, pre- and post-operative Karnofsky Performance scale (KPS), post-operative neurological worsening and post-operative walking ability. Two-hundred and seventy-five patients were included in the study. VTE was diagnosed in 82 patients (29.8%). Univariate analysis revealed that age >= 65 years, cardiovascular comorbidities, pre- and post-operative KPS < 80/100, post operative neurological worsening and impaired post-operative walking ability were significantly associated with VTE. Multivariate analysis confirmed only age >= 65 years (p = 0.011) and post-operative KPS < 80/100 (p = 0.002) as independent risk factors for VTE. Patients operated for meningioma have a 30% risk of VTE. Age >= 65 years and post-operative KPS < 80 were independent risk factors for VTE. PMID- 29500663 TI - Allergic conditions and risk of glioma and meningioma in the CERENAT case-control study. AB - Inverse association between allergic conditions and glioma risk has been consistently reported in epidemiological studies with little attention paid to potential environmental confounders; the association with meningioma risk is less consistent. We examined the association between allergy history and risk of glioma and meningioma in adults using data from the CERENAT (CEREbral tumors: a NATional study) multicenter case-control study carried out in 4 areas in France in 2004-2010. Participants' histories of doctor-diagnosed allergic asthma, eczema, rhinitis/hay fever and other allergic conditions were collected at onset through a detailed questionnaire delivered in a face-to-face interview. Conditional logistic regression for matched sets was adjusted for participants' educational level and mobile phone use. A total of 273 glioma cases, 218 meningioma cases and 982 matched controls selected from the local electoral rolls were analyzed. A significant inverse association was found between glioma and a history of any allergy (OR 0.52, 95% CI 0.36-0.75), with a dose-effect relationship with the number of allergic conditions reported (p-trend = 0.001) and a particularly strong association with hay fever/allergic rhinitis (OR 0.46, 95% CI 0.30-0.72). Interestingly, associations with glioma risk were more pronounced in women. For meningioma, no association was observed with overall or specific allergic conditions. Our findings confirmed the inverse association between allergic conditions and glioma risk but questioned the role of allergy in meningioma risk. Future research is needed to clarify the biological mechanism of overall allergy and allergic rhinitis on glioma and to confirm the different effect by gender. PMID- 29500664 TI - Repeat stereotactic radiosurgery for Cushing's disease: outcomes of an international, multicenter study. AB - Stereotactic radiosurgery (SRS) is frequently used for Cushing's disease (CD) after failed pituitary surgery. Management of patients with persistent CD after failed SRS is complex, as the alternative therapeutic options harbor significant risks. The outcomes of repeat pituitary radiosurgery, however, have not been described. We sought to determine the outcomes of repeat SRS in patients with CD. We pooled data from five institutions participating in the International Gamma Knife Research Foundation for patients with recurrent or persistent CD >= 12 months after initial SRS. Patients were included in the study if they had >= 6 months endocrine follow-up after repeat SRS. Twenty patients were included in the study. Repeat single-session SRS was performed 1.3-9.7 years after initial SRS. Median endocrine follow-up was 6.6 years (1.4-19.1 years). Median margin dose was 20 Gy (range 10.8-35 Gy). Endocrine remission after second SRS was noted in 12 patients (60%), with a median time to remission of 6 months (range 2-64 months). Biochemical recurrence occurred in two patients (17%) after initial remission. Overall, the cumulative rates of durable endocrine remission at 5 and 10 years were 47 and 53%, respectively. Two patients (10%) experienced adverse radiation effects, including transient visual loss and permanent diplopia. Repeat SRS achieves lasting biochemical remission in approximately half of patients with CD refractory to both prior microsurgery and SRS. Because of the morbidity of refractory or recurrent CD, repeat SRS should be considered for carefully selected patients with hypercortisolism confirmed one or more years after initial SRS. PMID- 29500665 TI - Computational redesign of human respiratory syncytial virus epitope as therapeutic peptide vaccines against pediatric pneumonia. AB - Human respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants and young children. Here, the RSV fusion (F) glycoprotein epitope FFL was redesigned based on its complex crystal structure with motavizumab, an mAb drug in development for the prevention of RSV infections, aiming to obtain therapeutic peptide vaccines with high affinity to induce RSV-specific neutralizing antibodies. Computational modeling and analysis found that only a small region covering the helix-turn-helix (HTH) motif of FFL can directly interact with motavizumab and confer stability and specificity to the complex system, while the rest of the epitope primarily serves as a structural scaffold that stabilizes the HTH conformation of motavizumab-binding site. Molecular dynamics simulations revealed a large flexibility and intrinsic disorder for the isolated linear HTH peptide, which would incur a considerable entropy penalty upon binding to motavizumab. In this respect, the FFL epitope was redesigned by truncation, mutation, and cyclization to derive a number of small cyclic peptide immunogens. We also employed in vitro fluorescence-based assays to demonstrate that the linear epitope peptide has no observable affinity to motavizumab, whereas redesigned versions of the peptide can bind with a moderate or high potency. Graphical abstract Computationally modeled complex structure of RSV F glycoprotein with motavizumab and zoom up of the complex binding site. PMID- 29500666 TI - Is there synergistic interaction between fungicides inhibiting different enzymes in the ergosterol biosynthesis pathway in toxicity tests with the green alga Raphidocelis subcapitata? AB - Products used for plant protection or as biocides often contain more than one active substance together with numerous formulation additives. The environmental risk assessment for such commercial mixtures applies as default the concept of concentration addition. There is remaining regulatory concern, however, that underestimation of risks can occur if components in the mixture interact synergistically, i.e., elicit effects greater than those predicted by concentration addition. While cases of true synergism appear to be rare, the combination of substances targeting different steps in the same biosynthesis pathway was pointed out as one potential case of synergistic interaction although mechanistic explanations are lacking. The present study aimed to verify this hypothesis using the green alga Raphidocelis subcapitata as the regulatory standard test organism for which such synergism had been indicated earlier. Algal growth inhibition tests were conducted with mixtures of ergosterol biosynthesis inhibitors (tebuconazole, fenpropidin, and fenpropimorph). The fungicides were first tested individually to derive reliable data for a mixture toxicity prediction. The here determined toxicity estimates for two of the fungicides were considerably lower than the endpoints in the regulatory dossiers, which had been used for earlier mixture toxicity predictions. Experimentally observed toxicity estimates for the mixtures deviated <2.6-fold from the predicted values. Hence, the hypothesis of synergistic interaction between fungicides targeting different enzymes in the ergosterol biosynthesis was clearly not confirmed for the green alga R. subcapitata. Overall, the present study demonstrates the importance of reliable and correct input data for mixture toxicity predictions in order to avoid erroneous conclusions on non-additive (synergistic) interactions. PMID- 29500667 TI - Evidence of citation bias in the pesticide ecotoxicology literature. AB - As scientists, we are tasked with letting evidence guide our conclusions. In the world of pesticides this takes on added importance as the data can influence ecological and human health outcomes and regulations, and even the manner in which we grow food. Yet, there seems to be a reticence to engage with the totality of the pesticide ecotoxicology literature, especially papers that report few or no effects or low risk to non-target organisms. We suspected that these studies would have fewer citations than studies that report significant effects or risk for the same compound, and this would be unrelated to the strength of the study, e.g., high quality studies with few or no effects would be cited less frequently than weaker studies that reported effects. To investigate this, we examined a subset of literature around the herbicide atrazine. We found that papers reporting an effect had significantly more citations per year than those that did not (p < 0.05). There was no significant relationship between the strength of the study and number of citations, but a general trend for weaker studies to have greater number of citations. The impact factor of journals was not positively correlated with the strength of the study methods, but studies that reported effects were published in journals with a greater mean impact factor than those that reported no effects (p < 0.05). This analysis reveals evidence of citation bias within the pesticide ecotoxicology literature, as well as bias by journals to publish studies that report effects, regardless of study quality. PMID- 29500668 TI - Assessing the role of hypothalamic microglia and blood vessel disruption in the development of angiotensin II-dependent hypertension in Cyp1a1-Ren2 rats. AB - Elevated plasma levels of the hormone vasopressin have been implicated in the pathogenesis of some forms of hypertension. Hypothalamic paraventricular and supraoptic nuclei neurons regulate vasopressin secretion into the circulation. Vasopressin neuron activity is elevated by day 7 in the development of angiotensin II-dependent hypertension in Cyp1a1-Ren2 rats. While microglial activation and blood-brain barrier (BBB) breakdown contribute to the maintenance of well-established hypertension, it is not known whether these mechanisms contribute to the early onset of hypertension. Hence, we aimed to determine whether microglia are activated and/or the BBB is compromised during the onset of hypertension. Here, we used the Cyp1a1-Ren2 rat model of hypertension and showed that ionised calcium-binding adapter molecule 1 staining of microglia does not change in the paraventricular and supraoptic nuclei on day 7 (early onset) and day 28 (well established) of hypertension, compared to the normotensive control. Endothelial transferrin receptor staining, which stains endothelia and reflects blood vessel density, was also unchanged at day 7, but was reduced at day 28, suggesting that breakdown of the BBB begins between day 7 and day 28 in the development of hypertension. Hence, this study does not support the idea that microglial activation or BBB disruption contribute to the onset of angiotensin II dependent hypertension in Cyp1a1-Ren2 rats, although BBB disruption might contribute to the progression from the early onset to well-established hypertension. PMID- 29500669 TI - The role of RyR2 oxidation in the blunted frequency-dependent facilitation of Ca2+ transient amplitude in rabbit failing myocytes. AB - Defective Ca2+ regulation plays a key role in the blunted force-frequency response in heart failure (HF). Since HF is commonly associated with oxidative stress, we studied whether oxidation of ryanodine receptor (RyR2) contributes to this defect. In control ventricular myocytes, oxidative stress induced formation of disulfide bonds between RyR2 subunits: intersubunit cross-linking (XL). Western blot analysis and Ca2+ imaging revealed a strong positive correlation between RyR2 XL and sarcoplasmic reticulum (SR) Ca2+ leak. These results illustrate that RyR2 XL can be used as a sensitive indicator of RyR2 dysfunction during oxidative stress. HF myocytes were in a state of oxidative stress since they exhibited an increase in reactive oxygen species (ROS) level, a decrease in ROS defense and an overall protein oxidation. These myocytes were also characterized by RyR2 XL and increased SR Ca2+ leak. Moreover, the frequency dependent increase of Ca2+ transient amplitude was suppressed due to the inability of the SR to maintain Ca2+ load at high pacing rates. Because SR Ca2+ load is determined by the balance between SR Ca2+ uptake and leak, the blunted frequency-dependent inotropy in HF can be mediated by ROS-induced SR Ca2+ leak. Preventing RyR2 XL in HF myocytes decreased SR Ca2+ leak and increased Ca2+ transients at high pacing rate. We also studied whether RyR2 oxidation alone can cause the blunted frequency-dependent facilitation of Ca2+ transient amplitude in control myocytes. When RyR2 XL was induced in control myocytes to a similar level seen in HF, an increase of Ca2+ transient amplitude at high pacing rate was significantly suppressed. These results suggest that SR Ca2+ leak induced by RyR2 oxidation can play an important role in the blunted frequency-dependent inotropy of HF. PMID- 29500670 TI - Role of G protein-regulated inducer of neurite outgrowth 3 (GRIN3) in beta arrestin 2-Akt signaling and dopaminergic behaviors. AB - The G protein-regulated inducer of neurite growth (GRIN) family has three isoforms (GRIN1-3), which bind to the Galphai/o subfamily of G protein that mediate signal processing via G protein-coupled receptors (GPCRs). Here, we show that GRIN3 is involved in regulation of dopamine-dependent behaviors and is essential for activation of the dopamine receptors (DAR)-beta-arrestin signaling cascade. Analysis of functional regions of GRIN3 showed that a di-cysteine motif (Cys751/752) is required for plasma membrane localization. GRIN3 was co immunoprecipitated with GPCR kinases 2/6 and beta-arrestins 1/2. Among GRINs, only GRIN3, which is highly expressed in striatum, strongly interacted with beta arrestin 2. We also generated GRIN3-knockout mice (GRIN3KO). GRIN3KO exhibited reduced locomotor activity and increased anxiety-like behavior in the elevated maze test, as well as a reduced locomoter response to dopamine stimulation. We also examined the phosphorylation of Akt at threonine 308 (phospho308-Akt), which is dephosphorylated via a beta-arrestin 2-mediated pathway. Dephosphorylation of phospho308-Akt via the D2R-beta-arrestin 2 signaling pathway was completely abolished in striatum of GRIN3KO. Our results suggest that GRIN3 has a role in recruitment and assembly of proteins involved in beta-arrestin-dependent, G protein-independent signaling. PMID- 29500671 TI - Sleeve Gastrectomy Recovering Disordered Brain Function in Subjects with Obesity: a Longitudinal fMRI Study. AB - OBJECTIVE: Bariatric surgery could recover regional dysfunction of cerebral cortex. However, it is unknown whether bariatric surgery could recover the global level dysfunction in subjects with obesity. The aim of this study was to investigate the effect of bariatric surgery on global-level dysfunction in subjects with obesity by resting-state functional magnetic resonance imaging (fMRI). METHODS: Resting-state fMRI was used to investigate dysfunction of whole brain in 34 subjects with obesity and 34 age-and gender-matched normal-weight subjects, in which 17 subjects with obesity received sleeve gastrectomy. Fractional amplitude of low-frequency fluctuation (fALFF) and functional connectivity (FC) among the whole brain were used to estimate the brain functional differences among the preoperative subjects, postoperative subjects, and the controls. RESULTS: The preoperative subjects compared to controls had decreased resting-state activities in reward processing and cognitive control regions such as orbitofrontal cortex, middle frontal gyrus, superior frontal gyrus, and gyrus rectus. It was important that increased FC was also found in these regions. Correlation analysis showed that body mass index (BMI) was associated with these decreased activity and increased FC. More importantly, the dysfunction in these regions was recovered by the bariatric surgery. CONCLUSIONS: These results suggest that bariatric surgery-induced weight loss could reverse the global-level dysfunction in subjects with obesity. The dysfunction in these regions might play a key role in the development of obesity, which might serve as a biomarker in the treatment of obesity. PMID- 29500672 TI - Preoperative Detection of Sarcopenic Obesity Helps to Predict the Occurrence of Gastric Leak After Sleeve Gastrectomy. AB - BACKGROUND: Sleeve gastrectomy (SG) has become the primary procedure for many bariatric teams and staple-line leak represents its most feared complication. Sarcopenic obesity combines the risks of obesity and depleted lean mass leading possibly to an inferior surgical outcome after abdominal surgery. OBJECTIVES: The aim of this study was to evaluate the existence of a potential link between radiologically determined sarcopenic obesity and staple-line leak risk after SG. METHODS: A retrospective analysis of a prospective database was performed in consecutive patients undergoing SG as primary procedure. Total psoas muscles (TPA) and total visible muscles (TMA) areas were measured on a preoperative computed tomography (CT). Sarcopenia was defined as lowest tertile of skeletal muscular mass indexes (muscular areas over square of height) in each gender (using TPA or TMA). Multivariate analysis was performed to determine preoperative risk factors for staple-line leak. RESULTS: During the study period, 205 patients were included in the analysis. Median BMI was 40.8 kg/m2 (34.2-49.6), and 9 patients (4.4%) presented a gastric leak. The sex-specific cut-offs for skeletal muscular mass index according to TPA were 8.2 cm2/m2 for men and 6.08 cm2/m2 for women. After multivariate analysis, preoperative weight (OR = 1043) and sarcopenia (TPA) (OR = 5204) were independent predictive factors for gastric leak. CONCLUSIONS: The present series suggests that CT scan-determined sarcopenic obesity is associated with increased risk of gastric leak after SG. This preoperatively radiological examination would be a useful clinical tool to tailor patient management according to gastric leak risk. PMID- 29500673 TI - EUS-Guided Endoscopic Gastrointestinal Anastomosis with Lumen-Apposing Metal Stent: Feasibility, Safety, and Efficacy. AB - Traditionally, restoration of normal bowel continuity after resection and bypass of a diseased or obstructed gastrointestinal tract can only be achieved through surgery, which can be technically challenging and comes with a risk of adverse events. Here, we describe our institutions' experience with endoscopic-guided gastroenterostomy or enteroenterostomy with lumen-apposing metal stent (LAMS) from March 2015 to August 2016. Ten patients had gastrogastrostomy (gastric pouch to gastric remnant) and three patients had jejunogastrostomy (Roux limb to gastric remnant) for the reversal of Roux-en-Y bariatric surgery. One patient had gastroduodenostomy (stomach to duodenal bulb) post antrectomy and one patient had jejunojejunostomy for distal obstruction following Roux-en-Y reconstruction. Technical and clinical success were achieved in all patients, save for delayed anastomotic stenosis following stent removal in one patient, with a mean follow up of 126 days (3-318 days) with minimal complications in two patients. Endoscopic gastrointestinal anastomosis therefore may be a safe and feasible technique to re-establish continuity of the digestive system following bypass in the short-term. PMID- 29500674 TI - Can Helicobacter pylori Eradication Treatment Modify the Metabolic Response to Bariatric Surgery? AB - BACKGROUND: Helicobacter pylori (HP) colonization is common in severely obese patients undergoing bariatric surgery. HP eradication treatment could influence the evolution of weight loss and metabolic markers after bariatric surgery. OBJECTIVE: To assess the influence of HP eradication in the clinical course of morbid obesity patients treated with bariatric surgery (gastric bypass (LRYGB) and sleeve gastrectomy (LSG)) METHODS: Retrospective analysis of a prospective cohort of 229 patients that underwent bariatric surgery between 2010 and 2013 in Hospital del Mar. HP infection was tested preoperatively by gastric biopsy and, if positive, treated with omeprazole, clarithromycin, and amoxicillin for 14 days. Patients were followed at 3, 6, 12, 18, and 24 months after bariatric surgery. Short-term weight loss and metabolic outcomes were evaluated. RESULTS: HP treated (HPt) patients had a greater reduction in BMI at 3 months after LSG (DeltaBMI (kg/cm2) 8.5 +/- 4.1 vs 11.3 +/- 3.05 kg/m2; p = 0.004) and a reduction in the evolution of triglyceride levels from baseline to 12 months (p = 0.014) compared to HP-negative (HP-) subjects. Also, non-diabetic HPt patients had a greater reduction in glucose levels at all time points that was maintained up to 24 months after LRYGB (p = 0.003). No differences were observed in total and LDL cholesterol levels, HOMA-IR, or HbA1C. CONCLUSIONS: Preoperative HP eradication has a short-term influence on some metabolic parameters after bariatric surgery. PMID- 29500675 TI - A Randomized Trial of a Novel Chewable Multivitamin and Mineral Supplement Following Roux-en-Y Gastric Bypass. AB - BACKGROUND: Vitamin and mineral deficiencies are common following Roux-en-Y gastric bypass (RYGB) and can lead to significant morbidity, but little research on the efficacy of vitamin supplementation regimens exists. We compared the efficacy and tolerability of an investigational versus a standard multivitamin regimen in patients undergoing RYGB. METHODS: Fifty-six patients, aged 18 to 65, were randomized to an investigational versus a standard multivitamin. Plasma levels of vitamins A, B-12, D, E-alpha, E-beta/gamma, thiamine, folate, iron, iron-binding capacity, iron saturation, prealbumin, and parathyroid hormone (PTH) were measured at 3 and 6 months postoperatively. Proteins induced by vitamin K absence (PIVKA), beta-carotene, coenzyme Q10, and mixed tocopherols were measured at 3 months postoperatively. Primary outcomes were differences in plasma levels at 3 and 6 months. Secondary outcomes were palatability, ease of use, and adherence. RESULTS: Twenty-one patients were randomized to the standard regimen and 26 to the investigational multivitamin. Nine were lost to follow-up. At 3 months, plasma levels of PTH were lower (p = 0.042), and levels of vitamin D (p = 0.033), thiamine (p = 0.009), and beta-carotene (p = 0.033) were higher in the investigational multivitamin arm compared to those in the standard regimen arm. Patients receiving the investigational multivitamin reported higher taste satisfaction than those receiving the standard regimen (p = 0.035). CONCLUSION: The investigational multivitamin appears to be more effective than a standard multivitamin in maintaining therapeutic levels of clinically relevant vitamins and minerals, and was more palatable. Additional studies should be conducted to confirm these findings and refine the optimal dosing regimen. TRIAL REGISTRATION: www.clinicaltrials.gov under identifier NCT01475617. PMID- 29500676 TI - Pandora's Box: Unpredictable Evolution of a 20-Year History of a Bariatric Patient-Report of Small Bowel Migrated Gastric Band after Redo Banded Gastric Bypass. PMID- 29500677 TI - Alcohol Consumption in Obese Patients Before and After Gastric Bypass as Assessed with the Alcohol Marker Phosphatidylethanol (PEth). AB - INTRODUCTION: Roux-en-Y gastric bypass (RYGB) causes more rapid and enhanced absorption of alcohol. RYGB patients have also been reported to use more inpatient care for alcohol-related disease than do patients after other bariatric procedures. The present study was designed to evaluate alcohol consumption level before and after gastric bypass using a sensitive and specific alcohol biomarker. MATERIALS AND METHODS: Two separate consecutive groups of patients and a group of healthy blood donors, as reference group, were included in the study. Alcohol intake was assessed using the alcohol marker phosphatidylethanol (PEth) at preoperative baseline and at 1 and 2 years postoperatively. In the first patient group (n = 133), neither surgeon nor patient was informed about the results of PEth testing. In the second group (n = 214), PEth results above 0.30 MUmol/L were considered to indicate excessive alcohol consumption and led to preoperative alcohol counseling. The groups were followed for 2 and 1 year, respectively. RESULTS: PEth results were significantly lower in both patient groups at baseline as well as postoperatively compared with the reference group. In both patient groups, there was a significant increase in PEth values at postoperative follow up compared to baseline. CONCLUSIONS: Several physiological changes postoperatively have to be considered when interpreting PEth results in obese patients with dramatic weight reductions. According to results for PEth, obese patients treated with bariatric surgery would seem to have lower alcohol consumption compared with the reference group. Although slightly increasing their PEth values postoperatively, the RYGB patients did not reach the PEth values of the reference group. PMID- 29500678 TI - A Randomised Trial of Text Message Support for Reducing Weight Regain Following Sleeve Gastrectomy. AB - INTRODUCTION: Sleeve gastrectomy (SG) is a common bariatric procedure with high rates of weight regain (WR). Clinicians and patients have identified a lack of follow-up support and maladaptive lifestyle behaviours as potential causes for WR. While text message support has been shown to be effective for weight loss in non-surgical patients, it has not been investigated for reducing WR in bariatric patients. PURPOSE: To determine the effectiveness of text message support in reducing weight regain following sleeve gastrectomy. METHODS: A text message intervention was designed. The effectiveness of the intervention was investigated by a randomised trial powered to detect a 15% difference in the primary outcome of percent excess weight loss (84 participants required). Secondary outcomes were the Bariatric Analysis and Reporting System (BAROS) score and patient satisfaction. Outcomes were assessed at 6 and 12 months. RESULTS: Ninety-five participants were randomised to either standard care or text message support (daily text message for 1 year). While there was no significant difference in the primary outcome at 6 or 12 months, patients who received the intervention tended to have less WR and a significantly better BAROS score at 12 months. Participants who received text message support found it beneficial, would have liked the messages to continue, and felt WR was reduced by having the text message support. CONCLUSION: Text message support following SG is feasible, may reduce weight regain, improves the BAROS score and is valued by patients. TRIAL REGISTRATION: NCT02341001. PMID- 29500679 TI - Bariatric Surgery Improves Hyperandrogenism, Menstrual Irregularities, and Metabolic Dysfunction Among Women with Polycystic Ovary Syndrome (PCOS). AB - OBJECTIVE: To characterize the impact of bariatric surgery on reproductive and metabolic features common to polycystic ovary syndrome (PCOS) and to assess the relevance of preoperative evaluations in predicting likelihood of benefit from surgery. METHODS: A retrospective chart review of records from 930 women who had undergone bariatric surgery at the Cleveland Clinic Foundation from 2009 to 2014 was completed. Cases of PCOS were identified from ICD coding and healthy women with pelvic ultrasound evaluations were identified using Healthcare Common Procedure Coding System coding. Pre- and postoperative anthropometric evaluations, menstrual cyclicity, ovarian volume (OV) as well as markers of hyperandrogenism, dyslipidemia, and dysglycemia were evaluated. RESULTS: Forty four women with PCOS and 65 controls were evaluated. Both PCOS and non-PCOS had significant reductions in body mass index (BMI) and markers of dyslipidemia postoperatively (p < 0.05). PCOS had significant reductions in androgen levels (p < 0.05) and percent meeting criteria for hyperandrogenism and irregular menses (p < 0.05). OV did not significantly decline in either group postoperatively. Among PCOS, independent of preoperative BMI and age, preoperative OV associated with change in hemoglobin A1c (beta 95% (confidence interval) 0.202 (0.011-0.393), p = 0.04) and change in triglycerides (6.681 (1.028-12.334), p = 0.03), and preoperative free testosterone associated with change in total cholesterol (3.744 (0.906-6.583), p = 0.02) and change in non-HDL-C (3.125 (0.453-5.796), p = 0.03). CONCLUSIONS: Bariatric surgery improves key diagnostic features seen in women with PCOS and ovarian volume, and free testosterone may have utility in predicting likelihood of metabolic benefit from surgery. PMID- 29500680 TI - Environmental risk factors in neuromyelitis optica spectrum disorder: a case control study. AB - Neuromyelitis optica spectrum disorder (NMOSD) has unknown risk factors. The aim of this study was to identify the environmental risk factors for NMOSD. A case control study was conducted in Tehran from 2015 to 2016 among 100 patients with NMOSD. Sex-matched healthy controls (n = 400) were selected through random digit dialing (RDD). Logistic regression was used to estimate unadjusted and adjusted ORs (odds ratio) at 95% confidence intervals (CI) via SPSS. Compared with the control population, in NMOSD patients, the adjusted OR for low dairy consumption per week was (OR = 18.09; 95% CI 6.91, 47.37), following low sea food intake (OR = 13.91; 95% CI 6.13, 31.57) and low fruit and vegetable consumption (OR = 6.23; 95% CI 3.07, 12.62). The lower heavy physical activity (OR: 16.11, 95% CI 7.03, 36.91) among patients had risen the risk of NMOSD. A past history of head trauma was considered a risk for NMOSD (OR: 8.39, 95% CI 4.97, 14.16). The association between NMOSD and intentional abortion only among females (OR: 7.42, 95% CI 2.81, 19.55) was detected. This study indicates significant associations between dietary habits, life style, history of head trauma and intentional abortion in female and the later diagnosis of NMOSD. PMID- 29500681 TI - Correction to: Management of immune thrombocytopenia in multiple sclerosis patients treated with alemtuzumab: a Belgian consensus. AB - The article Management of immune thrombocytopenia in multiple sclerosis patients treated with alemtuzumab: a Belgian consensus, written by Lambert et al., was originally published electronically on the publisher's internet portal on 27 January 2018 without open access. PMID- 29500682 TI - Integral nutritional approach to the care of cancer patients: results from a Delphi panel. AB - INTRODUCTION: Malnutrition is a common complication in cancer patients and can negatively affect the outcome of treatments. This study aimed to reach a consensus on nutritional needs and optimize nutritional care in the management of cancer patients at a national level. METHODS: A qualitative, multicenter, two round Delphi study involving 52 specialists with experience in nutritional support in cancer patients was conducted. RESULTS: Regarding the presence of malnutrition, 57.7% of the participants stated that < 30% of the patients had malnutrition at the time of diagnosis, 40.4% considered that 31-50% had malnutrition during cancer treatment, and 26.9% that > 50% at the end of the treatment. Forty percent of participants believed that the main objective of nutritional treatment was to improve quality of life and 34.6% to improve tolerability and adherence to chemotherapy. The quality nutritional care provided at their centers was rated as medium-low by 67.3%. Enteral and parenteral nutrition was administered to less than 10% and less than 5% of patients in 40.4 and 76.9% of cases, respectively. In relation to nutritional screening at the time of diagnosis, 62.9% of participants considered than screening to assess the risk of malnutrition was performed in < 30% of patients. CONCLUSIONS: There is an important variability in the management of cancer patient nutrition, which is associated with the absence of a national consensus on nutritional support in this field. Given the incidence of nutritional disorders in cancer patients, a specialist in clinical nutrition (regardless of his/her specialty) should be integrated into the strategic cancer plan. PMID- 29500683 TI - Based on Real Time Remote Health Monitoring Systems: A New Approach for Prioritization "Large Scales Data" Patients with Chronic Heart Diseases Using Body Sensors and Communication Technology. AB - This paper presents a new approach to prioritize "Large-scale Data" of patients with chronic heart diseases by using body sensors and communication technology during disasters and peak seasons. An evaluation matrix is used for emergency evaluation and large-scale data scoring of patients with chronic heart diseases in telemedicine environment. However, one major problem in the emergency evaluation of these patients is establishing a reasonable threshold for patients with the most and least critical conditions. This threshold can be used to detect the highest and lowest priority levels when all the scores of patients are identical during disasters and peak seasons. A practical study was performed on 500 patients with chronic heart diseases and different symptoms, and their emergency levels were evaluated based on four main measurements: electrocardiogram, oxygen saturation sensor, blood pressure monitoring, and non sensory measurement tool, namely, text frame. Data alignment was conducted for the raw data and decision-making matrix by converting each extracted feature into an integer. This integer represents their state in the triage level based on medical guidelines to determine the features from different sources in a platform. The patients were then scored based on a decision matrix by using multi criteria decision-making techniques, namely, integrated multi-layer for analytic hierarchy process (MLAHP) and technique for order performance by similarity to ideal solution (TOPSIS). For subjective validation, cardiologists were consulted to confirm the ranking results. For objective validation, mean +/- standard deviation was computed to check the accuracy of the systematic ranking. This study provides scenarios and checklist benchmarking to evaluate the proposed and existing prioritization methods. Experimental results revealed the following. (1) The integration of TOPSIS and MLAHP effectively and systematically solved the patient settings on triage and prioritization problems. (2) In subjective validation, the first five patients assigned to the doctors were the most urgent cases that required the highest priority, whereas the last five patients were the least urgent cases and were given the lowest priority. In objective validation, scores significantly differed between the groups, indicating that the ranking results were identical. (3) For the first, second, and third scenarios, the proposed method exhibited an advantage over the benchmark method with percentages of 40%, 60%, and 100%, respectively. In conclusion, patients with the most and least urgent cases received the highest and lowest priority levels, respectively. PMID- 29500684 TI - The Association between Anticholinergic Drug Use and Rehabilitation Outcome in Post-Acute Hip Fractured Patients: A Retrospective Cohort Study. AB - BACKGROUND: Anticholinergic (AC) drugs are associated with significant impairment in cognitive and physical function which may affect rehabilitation in older people. We aimed to evaluate whether AC burden is associated with rehabilitation achievement in post-acute hip-fractured patients. METHODS: A retrospective cohort study carried out in a post-acute geriatric rehabilitation center on 1019 hip fractured patients admitted from January 2011 to October 2015. The Anticholinergic Cognitive Burden Scale (ACB) was used to quantify the AC burden. Main outcome measures included the Functional Independence Measure (FIM) instrument, motor FIM (mFIM), Montebello Rehabilitation Factor Score (MRFS) on the mFIM, and length of stay (LOS). The study population was divided into two groups: individuals with low admission AC burden (ACB <= 1) and those with high admission AC burden (ACB >= 2). The relationship between the admission AC burden and clinical, demographic and comorbidity variables was assessed using the Mann Whitney and Chi square tests. A multiple linear regression model was used to estimate the association between admission AC burden and discharge FIM score after controlling for sociodemographic characteristics and chronic diseases. RESULTS: Patients with a high admission AC burden had a significantly higher rate of high education, a significantly lower rate reside at home, they waited a longer period of time from surgery to rehabilitation, were less independent pre fracture, and presented with a higher rate of vascular disorders and depression compared with patients with a lower admission AC burden. These patients also exhibited a significantly lower FIM score on admission and at discharge, a lower FIM score change, and a lower achievement on the MRFS compared with patients with a lower admission AC burden. A multiple linear regression analysis showed that admission AC burden was significantly associated with the discharge FIM score after adjustment for confounding variables. CONCLUSION: High admission AC drug burden is significantly associated with less favorable discharge functional status in post-acute hip-fractured patients, independent of relevant risk factors. PMID- 29500685 TI - Neoadjuvant Radiation Is Associated with Fistula Formation Following Pancreaticoduodenectomy. AB - BACKGROUND: Post-operative pancreatic fistulas remain a significant source of morbidity following pancreatic surgery. Few studies have evaluated the effect of neoadjuvant chemotherapy and radiation on this adverse outcome. This study aims to evaluate the effects of neoadjuvant therapy on 30-day morbidity and mortality following pancreaticoduodenectomy. STUDY DESIGN: A retrospective analysis was performed utilizing the targeted pancreas module of the National Surgical Quality Improvement Project (NSQIP) from 2014 to 2015 for patients undergoing pancreaticoduodenectomy with pancreaticojejunal reconstruction. A fistula was defined according to the NSQIP definition. Patient demographics, operative variables, and 30-day outcomes were compared between those who received no neoadjuvant therapy, chemoradiation, chemotherapy alone, and radiation alone. Univariate analysis was completed using chi-square, Fisher exact test, Student's t test, and Mann-Whitney U test where appropriate. Independent predictors of fistula formation were established using multivariable regression. A P value < 0.05 was considered significant. RESULTS: Three thousand one hundred fourteen patients were included of which 559 patients (18%) developed a pancreatic fistula. Two thousand six hundred thirty-five (85%) patients did not undergo neoadjuvant therapy, 207 (6.6%) had chemoradiation, 256 (8.2%) had chemotherapy alone, and 16 (0.5%) had radiation alone. Patients who developed a fistula had increased 30-day mortality (4.9 vs. 1.7%, P < .001) and major morbidities. Following multivariable analysis, neoadjuvant radiation (OR 2.1, 95% CI 1.0-4.5) was associated with increased fistula formation while neoadjuvant chemotherapy (OR 0.5, 95% CI 0.3-0.9) was protective. CONCLUSION: Neoadjuvant chemotherapy provides protection against the development of pancreatic fistulas while neoadjuvant radiation potentiates formation likely due to their effects on the texture of the pancreatic gland. Given the morbidity of pancreatic fistula formation, these factors should be considered in neoadjuvant regimens. PMID- 29500686 TI - Variable epilepsy phenotypes associated with heterozygous mutation in the SCN9A gene: report of two cases. AB - Up to now, SCN9A mutations encoding Nav1.7 have been limited to inherited pain syndromes. A few of pathogenic SCN9A mutations with or without SCN1A mutations have been identified in epileptic patients. Here, we report two heterozygous SCN9A mutations with no SCN1A mutations, which are associated with variable epilepsy phenotypes and explored the possibility of SCN9A contributing to a multifactorial etiology for epilepsy. Our findings suggest that the two SCN9A mutations (c.980G>A chr2:167149868 p.G327E; c.5702_5706del chr2:167055410 p.I1901fs) should be regarded as pathogenic mutations. Two heterozygous mutations of SCN9A are associated with a wide clinical spectrum of seizure phenotypes including simple febrile seizures, afebrile seizures, generalized tonic-clonic seizure, myoclonic or tonic seizures, and focal clonic seizures. Patients with deletion mutations tend to be associated with more severe seizure type than missense mutations. PMID- 29500687 TI - The use of Goal Attainment Scaling (GAS) in the rehabilitation of ataxic patients. AB - The aim of this study was to formulate an exercise program according to GAS, an approach that reflects the patients' point of view and expectations and investigate the effects of this program in ataxia rehabilitation. This study was designed as an assessor-blinded, single-group trial, and 24 patients with cerebellar ataxia were included. Treatment goals, postural control, disease severity, and daily living activities were assessed pre- and post-treatment using the Goal Attainment Scaling (GAS), the Sensory Organization Test (SOT), the International Cooperative Ataxia Rating Scale (ICARS), and the Barthel Index (BI), respectively. An exercise program was applied by taking patients' individual expectations and treatment goals into account. The participants enrolled in the physiotherapy program for 8 weeks, 3 days a week for 1 hour per day. The mean age of the patients was 34.00 +/- 9.15 years. While the GAS, kinetic functions ICARS subscores, ICARS total scores, SOT-composite, and BI scores improved significantly after treatment (p < 0.05), other ICARS subscores did not change after treatment (p > 0.05). The results showed that putting the patient at the center of the evaluation and treatment process while formulating a treatment plan had a positive effect on treatment outcome. If the functions that patients consider important are known and the treatment process concentrates on these functions, a patient's participation in his/her individual treatment is supported by increasing his/her motivation and contribution to more successful rehabilitation practices. PMID- 29500689 TI - Comparative Metagenomic Profiling of Viromes Associated with Four Common Mosquito Species in China. AB - Vast viruses are thought to be associated with mosquitoes. Anopheles sinensis, Armigeres subalbatus, Culex quinquefasciatus, and Culex tritaeniorhynchus are very common mosquito species in China, and whether the virome structure in each species is species-specific has not been evaluated. In this study, a total of 2222 mosquitoes were collected from the same geographic location, and RNAs were sequenced using the Illumina Miseq platform. After querying to the Refseq database, a total of 3,435,781, 2,223,509, 5,727,523, and 6,387,867 paired-end reads were classified under viral sequences from An. sinensis, Ar. subalbatus, Cx. quinquefasciatus, and Cx. tritaeniorhynchus, respectively, with the highest prevalence of virus-associated reads being observed in Cx. quinquefasciatus. The metagenomic comparison analysis showed that the virus-related reads were distributed across 26 virus families, together with an unclassified group of viruses. Anelloviridae, Circoviridae, Genomoviridae, Iridoviridae, Mesoniviridae, Microviridae, Myoviridae, Parvoviridae, Phenuiviridae, and Podoviridae were the top ten significantly different viral families among the four species. Further analysis reveals that the virome is species-specific in four mosquito samples, and several viral sequences which maybe belong to novel viruses are discovered for the first time in those mosquitoes. This investigation provides a basis for a comprehensive knowledge on the mosquito virome status in China. PMID- 29500688 TI - Protective effects of PACAP in ischemia. AB - Pituitary adenylate cyclase activating polypeptide (PACAP) is an ubiquitous peptide involved, among others, in neurodevelopment, neuromodulation, neuroprotection, neurogenic inflammation and nociception. Presence of PACAP and its specific receptor, PAC1, in the trigeminocervical complex, changes of PACAP levels in migraine patients and the migraine-inducing effect of PACAP injection strongly support the involvement of PACAP/PAC1 receptor in migraine pathogenesis. While antagonizing PAC1 receptor is a promising therapeutic target in migraine, the diverse array of PACAP's functions, including protection in ischemic events, requires that the cost-benefit of such an intervention is well investigated by taking all the beneficial effects of PACAP into account. In the present review we summarize the protective effects of PACAP in ischemia, especially in neuronal ischemic injuries, and discuss possible points to consider when developing strategies in migraine therapy interfering with the PACAP/PAC1 receptor system. PMID- 29500691 TI - Serological Evidence of Bat SARS-Related Coronavirus Infection in Humans, China. PMID- 29500690 TI - Chevrier's Field Mouse (Apodemus chevrieri) and Pere David's Vole (Eothenomys melanogaster) in China Carry Orthohepeviruses that form Two Putative Novel Genotypes Within the Species Orthohepevirus C. AB - Hepatitis E virus (HEV) is the prototype of the family Hepeviridae and the causative agent of common acute viral hepatitis. Genetically diverse HEV-related viruses have been detected in a variety of mammals and some of them may have zoonotic potential. In this study, we tested 278 specimens collected from seven wild small mammal species in Yunnan province, China, for the presence and prevalence of orthohepevirus by broad-spectrum reverse transcription (RT)-PCR. HEV-related sequences were detected in two rodent species, including Chevrier's field mouse (Apodemus chevrieri, family Muridae) and Pere David's vole (Eothenomys melanogaster, family Cricetidae), with the infection rates of 29.20% (59/202) and 7.27% (4/55), respectively. Further four representative full-length genomes were generated: two each from Chevrier's field mouse (named RdHEVAc14 and RdHEVAc86) and Pere David's vole (RdHEVEm40 and RdHEVEm67). Phylogenetic analyses and pairwise distance comparisons of whole genome sequences and amino acid sequences of the gene coding regions showed that orthohepeviruses identified in Chinese Chevrier's field mouse and Pere David's vole belonged to the species Orthohepevirus C but were highly divergent from the two assigned genotypes: HEV C1 derived from rat and shrew, and HEV-C2 derived from ferret and possibly mink. Quantitative real-time RT-PCR demonstrated that these newly discovered orthohepeviruses had hepatic tropism. In summary, our work discovered two putative novel genotypes orthohepeviruses preliminarily named HEV-C3 and HEV-C4 within the species Orthohepevirus C, which expands our understanding of orthohepevirus infection in the order Rodentia and gives new insights into the origin, evolution, and host range of orthohepevirus. PMID- 29500692 TI - Longitudinal Surveillance of Betacoronaviruses in Fruit Bats in Yunnan Province, China During 2009-2016. AB - Previous studies indicated that fruit bats carry two betacoronaviruses, BatCoV HKU9 and BatCoV GCCDC1. To investigate the epidemiology and genetic diversity of these coronaviruses, we conducted a longitudinal surveillance in fruit bats in Yunnan province, China during 2009-2016. A total of 59 (10.63%) bat samples were positive for the two betacorona-viruses, 46 (8.29%) for HKU9 and 13 (2.34%) for GCCDC1, or closely related viruses. We identified a novel HKU9 strain, tentatively designated as BatCoV HKU9-2202, by sequencing the full-length genome. The BatCoV HKU9-2202 shared 83% nucleotide identity with other BatCoV HKU9 stains based on whole genome sequences. The most divergent region is in the spike protein, which only shares 68% amino acid identity with BatCoV HKU9. Quantitative PCR revealed that the intestine was the primary infection organ of BatCoV HKU9 and GCCDC1, but some HKU9 was also detected in the heart, kidney, and lung tissues of bats. This study highlights the importance of virus surveillance in natural reservoirs and emphasizes the need for preparedness against the potential spill-over of these viruses to local residents living near bat caves. PMID- 29500693 TI - Development of Multi-analyte Suspension Assay for Simultaneously Efficient Detection of Avian Influenza Virus A Subtypes. PMID- 29500694 TI - [Referral behavior of general physicians for patients with obesity]. AB - The prevalence of obesity and overweight is constantly rising. Thus, obesity is increasingly considered as one of the most important healthcare problems in Germany. Surgical interventions have been proven to be the only treatment option to achieve sustained weight loss along with a reduction of obesity-related comorbidities in the vast majority of morbidly obese patients. With respect to the small numbers of weight loss surgeries conducted in Germany, several reasons are currently discussed. General practitioners play a very important role in gatekeeping when it comes to decisions about treatment. Research has shown that knowledge and stigma play a role when treatment pathways for patients with obesity are defined. Interventions are required to make treatment decisions by physicians or patients independent of social pressure due to stigma or gaps in expertise. PMID- 29500695 TI - Diversity and motif conservation in protein 3D structural landscape: exploration by a new multivariate simulation method. AB - In this paper, diversity and conservation in the 'landscape' of random variation of protein tertiary structures are explored for quantitative feature-vector models of major types of functionally important 3D structural motifs. For this, I have deployed a recently developed nonparametric regression (NPR)-based multidimensional copula method of simulation. Apart from improved accuracy of multidimensional random sample generation, the simulation provides additional insight into diversity in the protein structural landscape in terms of random variation in the feature-vector. It shows the relative importance of several features, with biological implications, in conservation of motifs. Mapping of this landscape in distance-preserving 2D eigenspace also shows consistency in demarcation of different motif classes and preservation of their characteristic patterns in this 2D space. PMID- 29500696 TI - Longitudinal quantitative assessment of macula during therapy with fingolimod in relapsing-remitting multiple sclerosis. AB - PURPOSE: Fingolimod is the first oral drug approved for treatment of relapsing remitting multiple sclerosis (RR-MS), and it has potential macular side effects. Despite the qualitative evidence of macular oedema under treatment, longitudinal quantitative assessment is lacking. To address this issue, we measured macular volume and central foveal thickness in a cohort of MS patients on fingolimod over 12 months of treatment. METHODS: Central foveal thickness (CFT) and total macular volume (TMV) were longitudinally recorded with spectral-domain optical coherence tomography in a cohort of 23 RR-MS patients treated with fingolimod at baseline, 3, 6 and 12 months. OCT parameters were analysed considering previous history of optic neuritis (ON). Comparison of means was performed with variance analysis (ANOVA). RESULTS: Macular oedema occurred in none of the patients. Comparing both groups of patients (with and without previous ON), no statistically significant difference was found during the follow-up both for CFT and TMV (p = 0.99 and p = 0.96, respectively) although a slight early but not significant TMV reduction was detected. CONCLUSIONS: In our cohort, therapy with fingolimod did not cause any change in CFT and TMV in MS patients during a 12-month follow-up independent of previous ON. PMID- 29500697 TI - Contrast sensitivity of patients with congenital color vision deficiency. AB - PURPOSE: To investigate the static and dynamic contrast sensitivity (CS) of patients with congenital red-green color vision deficiency (CVD) and to compare these values with those of healthy control subjects. METHODS: The study included 25 subjects with congenital CVD (10 with strong protan defect and 15 with strong deutan defect) and 20 age- and gender-matched healthy subjects. Following detailed ophthalmological examination, monocular static and dynamic CS measurements were taken with the Monpack3 device (Metrovision, Perenchies, France) on all subjects. The data from the right eyes of all the subjects were used for statistical analysis. RESULTS: The mean age of the groups was similar (deutan group: 25.3 +/- 11.3 years, protan group: 27.1 +/- 12.2 years, control group: 26.7 +/- 8.8 years, p = 0.98). The mean static and dynamic CS values in the protan and deutan groups were higher compared to those of the healthy control subjects, but not at a statistically significant level (all p > 0.017). CONCLUSION: The static and dynamic CS values of patients with congenital red green CVD were similar to those of healthy control subjects. PMID- 29500698 TI - Emulsified silicone oil droplets in the canal of Schlemm. AB - PURPOSE: To demonstrate the presence of emulsified silicone oil (SO) droplets in the canal of Schlemm with anterior segment optical coherence tomography (AS-OCT). METHODS: AS-OCT images from an eye that had undergone retinal detachment (RD) surgery three years ago were reviewed. At the time of surgery, SO had been used as the tamponading agent. RESULTS: The AS-OCT images demonstrated that minute emulsified SO droplets were present in the canal of Schlemm. CONCLUSION: Retention of SO in the eye for an extended period of time after RD surgery leads to secondary glaucoma. Presence of minute emulsified SO droplets in the canal of Schlemm may contribute to this process. PMID- 29500699 TI - Prediction of pupil size under binocular open-view settings using the new CASIA2 device. AB - PURPOSE: Pupillometry should be performed under conditions as close to natural viewing as possible. The present study aimed to determine whether pupil size in binocular open-view settings can be predicted based on pupil size measured using the CASIA2 device. METHODS: The present study included 61 participants (25 men and 36 women; mean age, 49 +/- 15 years; age range, 22-69 years) with no history of ophthalmic disease other than refractive errors and cataract. We measured pupil size using the new CASIA2 device and a binocular open-view digital pupillometer (FP-10000II, TMI Co., Ltd., Saitama). Intra-class and inter-class reliabilities were evaluated by measuring pupil times three times with each device (two independent examiners) in 21 of the 61 participants. Reproducibility was analyzed using intra-class and inter-class correlation coefficients (ICCs). Regression formulae for calculating FP10000II pupil size based on CASIA2 pupil size were developed via simple linear regression analyses. RESULTS: Both devices exhibited high ICC values (> 0.80). The regression formulae for calculating the FP10000II pupil size for the distant and near views based on CASIA2 pupil size were y = 0.5702x + 0.4611 (determination coefficient, 0.67) and y = 0.502x + 0.445 (determination coefficient, 0.64), respectively. CONCLUSIONS: Pupil size under binocular open-view settings can be predicted based on simultaneous measurement of pupil size during evaluation of the anterior segment using the CASIA2 device. The calculated pupil size may represent a useful index for determining the most appropriate treatment strategy in candidates for cataract and refractive surgery. PMID- 29500700 TI - The 2018 World Health Organization SAVE LIVES: Clean Your Hands Campaign targets sepsis in health care. PMID- 29500702 TI - Accidental placement of a dialysis catheter into the accessory hemiazygos vein. PMID- 29500703 TI - Driving airway and transpulmonary pressure are correlated to VILI determinants during controlled ventilation. PMID- 29500701 TI - Fluid therapy in neurointensive care patients: ESICM consensus and clinical practice recommendations. AB - OBJECTIVE: To report the ESICM consensus and clinical practice recommendations on fluid therapy in neurointensive care patients. DESIGN: A consensus committee comprising 22 international experts met in October 2016 during ESICM LIVES2016. Teleconferences and electronic-based discussions between the members of the committee subsequently served to discuss and develop the consensus process. METHODS: Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles generated. The consensus focused on three main topics: (1) general fluid resuscitation and maintenance in neurointensive care patients, (2) hyperosmolar fluids for intracranial pressure control, (3) fluid management in delayed cerebral ischemia after subarachnoid haemorrhage. After an extensive literature search, the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system were applied to assess the quality of evidence (from high to very low), to formulate treatment recommendations as strong or weak, and to issue best practice statements when applicable. A modified Delphi process based on the integration of evidence provided by the literature and expert opinions-using a sequential approach to avoid biases and misinterpretations-was used to generate the final consensus statement. RESULTS: The final consensus comprises a total of 32 statements, including 13 strong recommendations and 17 weak recommendations. No recommendations were provided for two statements. CONCLUSIONS: We present a consensus statement and clinical practice recommendations on fluid therapy for neurointensive care patients. PMID- 29500704 TI - Management of elderly women with cervical cancer. AB - BACKGROUND: Elderly women with cervical cancer receive less therapy in comparison with their younger counterparts. The exact reason(s) for this treatment strategy remains unclear. PATIENTS AND METHODS: We performed a multicenter, retrospective registry-based study of 1559 patients with cervical cancer. The primary outcome was the reason for not performing the indicated treatment. RESULTS: Median follow up was 67.8 months. A total of 956 women were eligible for analysis: 693 (64.2%) were younger than 60 years and 387 (35.8%) were aged 61 years old and older. Elderly women were more likely to have undifferentiated cervical cancer at an advanced stage. For early stage (stage IA1-IIA), tumors patients 61 years old and older were less likely to receive surgery [odds ratio (OR) 0.39; 95% CI 0.20 0.77] and radiochemotherapy (OR 0.37; 95% CI 0.21-0.66) compared with the group of patients aged < 60 years. The rate of lymphadenectomy was similar in both age groups. Patients 61 years old and older with advanced stage (IIB-IV) cervical cancer were also less likely to receive surgery [odds ratio (OR) 0.42; 95% CI 0.27-0.66], lymphadenectomy (OR 0.30; 95% CI 0.12-0.51) and radiochemotherapy (OR 0.31; 95% CI 0.20-0.48) compared with patients aged < 60 years. Notably, the rate of indicated but not performed therapies proportionally increased with an increase in patient age and the most important reason for this phenomenon was the failing of recommendation. CONCLUSIONS: Elderly women with cervical cancer are undertreated and this is more likely because the therapy was not recommended. PMID- 29500705 TI - Primary management of atypical meningioma: treatment patterns and survival outcomes by patient age. AB - PURPOSE: The initial management of atypical meningiomas poses a distinct clinical challenge in that treatment protocols have not been fully established, and outcomes, especially differences by patient age, have not been broadly measured. The National Cancer Database (NCDB) allows for analysis of a large, diverse patient population to determine clinical parameters and survival outcomes based on the initial treatment of patients with atypical meningiomas. METHODS: Analysis of the NCDB yielded 3611 atypical meningioma patients treated between 2008 and 2012. Principal treatment paradigms included surgery with or without radiation. Survival estimates were calculated using Kaplan-Meier curves stratified by age at diagnosis for each treatment paradigm. Subset analysis was performed for socio economic factors. RESULTS: Overall 5-year survival rate was 77.6% and declined with increasing patient age (p < 0.0001). Five-year survival for patients <= 45 years undergoing surgery alone was 89.3 vs. 44.4% for those > 75 years (p < 0.0001). For patients undergoing surgery with adjuvant radiation, 5-year survival was 93.7% in those <= 45 years and 54.1% in those > 75 years (p < 0.0001). Use of adjuvant radiation was stable over time. Private-insured patients were more likely to receive adjuvant radiation (p = 0.0001). CONCLUSIONS: Patients treated for atypical meningioma have high rates of 5-year survival. A marginal survival benefit of adjuvant radiation was observed for patients < 55 and > 75 years, while patients between 55 and 75 years tended to have slightly improved survival with surgery alone. Though surgery remains the standard of care in the primary treatment of atypical meningioma, the decision to administer radiation post operatively has remained controversial. PMID- 29500706 TI - Incorporating Quantitative Patient Preference Data into Healthcare Decision Making Processes: Is HTA Falling Behind? PMID- 29500709 TI - How do organ-specific metastases affect prognosis and surgical treatment for patients with metastatic upper tract urothelial carcinoma: first evidence from population based data. AB - To evaluate the prognostic roles of organ-specific metastases and analyze the impact of organ-specific metastases on surgical resection of the primary tumor for metastatic upper tract urothelial carcinoma (UTUC) patients. A population based study using Surveillance, Epidemiology, and End Results database was carried out. Kaplan-Meier analysis were used for survival comparisons. Multivariate Cox regression model was employed to analyze the effect of distant metastatic organs on overall survival (OS) and cancer specific survival (CSS). 337 patients from 2010 to 2014 were included. Patients with brain metastasis had significantly worse OS (p = 0.012) and CSS (p = 0.004). Liver metastasis could only independently predict unfavorable OS rather than CSS. Multivariate analysis showed that patients with bone, lung or distant lymph node metastasis was not independent prognostic factor for patients' survival. Surgical resection of the primary tumor was an independent favorable predictor for both OS (p = 0.004) and CSS advantages (p = 0.006). In subgroup analysis, patients with multiple organs of metastasis or distant lymph node involvement could benefit from surgical resection of the primary tumor. However, the presence of liver or lung metastasis could make such surgery become meaningless from the point of survival benefits. Our study showed that brain metastasis independently predicted both unfavorable OS and CSS for metastatic UTUC patients while liver metastasis was only associated with worse OS. More importantly, surgical resection of the primary tumor might still lead to survival benefits for highly selected patients. PMID- 29500710 TI - Genome-wide genotype-based risk model for survival in core binding factor acute myeloid leukemia patients. AB - The present study attempted to build a single nucleotide polymorphism (SNP)-based risk model for predicting overall survival (OS) and event-free survival (EFS) in patients with core binding factor acute myeloid leukemia (CBF-AML). Adopting genome-wide SNP array using Affymetrix SNP array 6.0, we analyzed 868,157 SNPs with respect to OS and EFS in 104 patients with CBF-AML. Significant SNPs were identified from single SNP analysis. The risk model was constructed with incorporation of six SNPs and three clinical factors (age, c-kit exon 17 mutation, and LDH) for OS and six SNPs and three clinical factors (age, WBC, and LDH) for EFS. The model was further defined into low- and high-risk groups based on risk scores. The median age was 39 years, and the subgroup of t(8;21) and inv(16) or t(16;16) was assessed in 68 (65.4%) and 36 patients (34.6%). Finally, six SNPs per each OS (rs4353685, rs4908185, rs7709207, rs12034, rs1554844, and rs17241868) and EFS (rs13385610, rs11210617, rs11169282, rs7709207, rs4438401, and rs16894846) were incorporated into the risk model. OS was significantly different in favor of the low risk group (80.4 +/- 8.4%) compared to the high risk group (22.0 +/- 7.3% at 3 years; p = 8.75 * 10- 13; HR 8.67). For EFS, there was also a significant difference between the low- (75.0 +/- 5.8%) versus high risk group (17.1 +/- 6.3% at 3 years; p = 5.95 * 10- 13; HR 7.67). A genome-wide SNP-based risk model can stratify CBF-AML patients according to their OS and EFS in 104 patients. PMID- 29500711 TI - Immunomodulatory drugs and the risk of serious infection in multiple myeloma: systematic review and meta-analysis of randomized and observational studies. AB - The effect of immunomodulatory drugs (IMiDs) on serious infection remains uncertain. We therefore conducted a systematic review and meta-analysis to assess the possible impact of IMiDs on serious infection in patients with multiple myeloma (MM). We searched randomized controlled trials (RCTs) and observational studies from databases that addressed the effect of IMiDs on serious infection in patients with MM. We pooled data from RCTs and observational studies separately and used the GRADE approach to rate the quality of evidence. Rates in patients with individual IMiDs at different treatment status ranged from 7.00 to 23.00%. The use of thalidomide- or lenalidomide-based regimen induction therapy for autologous stem cell transplantation (ASCT)-ineligible patients suggests increase in serious infection (RR = 1.59, 95% CI 1.31-1.93, p < 0.01). Compared to conventional therapy, IMiDs' induction in ASCT-eligible patients significantly decreases the risk of serious infection (RR = 0.82, 95% CI 0.72-0.94, p < 0.01). Lenalidomide-based therapy was associated with a significant increase in risk of serious infection in patients treated compared with conventional therapy (RR = 2.45, 95% CI 1.57-3.83, p < 0.01). The current evidence suggests that patients with MM treated with IMiDs are at a high risk of serious infection. PMID- 29500712 TI - Quarter Century of Anti-HIV CAR T Cells. AB - PURPOSE OF REVIEW: A therapy that might cure HIV is a very important goal for the 30-40 million people living with HIV. Chimeric antigen receptor T cells have recently had remarkable success against certain leukemias, and there are reasons to believe they could be successful for HIV. This manuscript summarizes the published research on HIV CAR T cells and reviews the current anti-HIV chimeric antigen receptor strategies. RECENT FINDINGS: Research on anti-HIV chimeric antigen receptor T cells has been going on for at least the last 25 years. First- and second-generation anti-HIV chimeric antigen receptors have been developed. First-generation anti-HIV chimeric antigen receptors were studied in clinical trials more than 15 years ago, but did not have meaningful clinical efficacy. There are some reasons to be optimistic about second-generation anti-HIV chimeric antigen receptor T cells, but they have not yet been tested in vivo. PMID- 29500713 TI - 'Who's a good boy?!' Dogs prefer naturalistic dog-directed speech. AB - Infant-directed speech (IDS) is a special speech register thought to aid language acquisition and improve affiliation in human infants. Although IDS shares some of its properties with dog-directed speech (DDS), it is unclear whether the production of DDS is functional, or simply an overgeneralisation of IDS within Western cultures. One recent study found that, while puppies attended more to a script read with DDS compared with adult-directed speech (ADS), adult dogs displayed no preference. In contrast, using naturalistic speech and a more ecologically valid set-up, we found that adult dogs attended to and showed more affiliative behaviour towards a speaker of DDS than of ADS. To explore whether this preference for DDS was modulated by the dog-specific words typically used in DDS, the acoustic features (prosody) of DDS or a combination of the two, we conducted a second experiment. Here the stimuli from experiment 1 were produced with reversed prosody, meaning the prosody and content of ADS and DDS were mismatched. The results revealed no significant effect of speech type, or content, suggesting that it is maybe the combination of the acoustic properties and the dog-related content of DDS that modulates the preference shown for naturalistic DDS. Overall, the results of this study suggest that naturalistic DDS, comprising of both dog-directed prosody and dog-relevant content words, improves dogs' attention and may strengthen the affiliative bond between humans and their pets. PMID- 29500714 TI - [Subconjunctival minimally invasive glaucoma surgery : Methods and clinical results]. AB - Minimally invasive glaucoma surgery (MIGS) has been developed for all drainage pathways in glaucoma treatment. Besides implants overriding the resistance in the trabecular meshwork (iStent(r), iStent Inject(r) [both Glaukos Germany GmbH, Wiesbaden, Germany], Hydrus Microstent(r) [Ivantis, Irvine, CA, USA]) and draining to the suprachoroidal space (Cypass Micro Stent(r) [Alcon Laboratories, Inc., Fort Worth, TX, USA], iStent Supra(r) [Glaukos Germany GmbH]), surgeons can further drain aqueous humor into the subconjunctival space with a transscleral MIGS implant (XEN45(r) [Allergan Plc., Dublin, Irland]). The XEN45(r) is a gelatine tube 6 mm in length, which is implanted ab interno via a small corneal incision through the sclera. Additional aqueous humor is drained from the anterior chamber via the tube and filtered in a filter cushion in order to sink the total drainage resistance. The internal diameter of the lumen of the implant is 45 um, therefore a passive resistance is present for prevention of postoperative hypotension. The by-passed aqueous humor forms a conjunctival bleb. Although the first study results are promising in terms of efficacy and safety, further studies are necessary before a clear picture of the effectiveness, safety, advantages and disadvantages of the gelatine tube can be drawn. PMID- 29500715 TI - [Screening for retinopathy of prematurity: Trends over the past 5 years in two German university hospitals]. AB - BACKGROUND: The number of preterm births in Germany has been increasing continuously over the past decades. Retinopathy of prematurity (ROP) is a major complication of preterm birth and one of the leading causes of blindness in children. OBJECTIVES: This study analyzes the development of the incidence of ROP over the past 5 years at two German university hospitals, utilizing data from ROP screening examinations. MATERIAL AND METHODS: We assessed all children born in the years 2012-2016 who were included in the ROP screening program at two German university hospitals according to the criteria of the German ROP screening guidelines. Parameters such as gestational age, birth weight, ROP stage and zone, and need for therapeutic intervention were assessed. RESULTS: We analyzed the data of 863 children who had undergone a total of 4117 screening examinations. The number of children included in the screening program per study year increased continuously over the study period by a total of 43.1% (137 in 2012, 196 in 2016). Likewise, the number of screening examinations per year increased by 58.4% (608 in 2012, 963 in 2016). Overall, 27.5% of screened infants were diagnosed with ROP of any stage and 2.5% required treatment for ROP. The number of children diagnosed with ROP of any stage per year increased by 100.0% (32 in 2012, 64 in 2016). Mean gestational age (29.0 +/- 3.0 weeks) and mean birth weight (1192 +/- 513 g) remained stable over the study period. CONCLUSION: Screening data for ROP from two German university hospitals demonstrates a significant increase in both the number of screened infants and the number of infants affected by ROP over the past 5 years. PMID- 29500716 TI - Awake mapping is not an additional surgical technique but an alternative philosophy in the management of low-grade glioma patients. PMID- 29500717 TI - Imaging Abeta and tau in early stage Alzheimer's disease with [18F]AV45 and [18F]AV1451. AB - BACKGROUND: AD is a progressive neurodegenerative disorder that is associated with the accumulation of two different insoluble protein aggregates, Abeta plaques and hyperphosphorylated tau. This study aimed to investigate the optimal acquisition and quantification of [18F]AV45 and [18F]AV1451 to image Abeta and tau, respectively, in subjects with AD. Fifteen subjects with early stage AD underwent a T1-weighted structural MRI and two dynamic PET scans to image Abeta (60 min, [18F]AV45) and tau (120 min, [18F]AV1451). Both dynamic BPND and static SUVR outcome measures were calculated and compared for 12 out of 15 subjects who completed 60 min of the Abeta PET scan and at least 110 min of the tau PET scan. The SRTM and reference Logan graphical analysis were applied to the dynamic data to estimate regional BPND values and SUVR ratios from the static data. Optimal acquisition windows were explored for both the dynamic and static acquisitions. In addition, the spatial correlation between regional Abeta and tau signals was explored. RESULTS: Both the SRTM and graphical analysis methods showed a good fit to the dynamic data for both Abeta and tau dynamic PET scans. Mean regional BPND estimates became stable 30 min p.i. for [18F]AV45 and 80 min p.i. for [18F]AV1451. Time stability analysis of static SUVR data showed that the outcome measure starts to become stable for scan windows of 30-50 min p.i. for [18F]AV45 and 80-100 min p.i. for [18F]AV1451. The results from these time windows correlated well with the results from the full dynamic analysis for both tracers (R2 = 0.74 for [18F]AV45 and R2 = 0.88 for [18F]AV1451). There was a high correlation between amyloid uptake estimate using both dynamic analysis methods in thalamus and tau uptake in thalamus, hippocampus and amygdala. CONCLUSIONS: Short static PET scans at appropriate time windows provided SUVR values which were in reasonable agreement with BPND values calculated from dynamic scans using SRTM and reference Logan. These simplified methods may be appropriate for classification and intervention studies, although caution should be employed when considering interventional studies where blood flow and extraction could change. PMID- 29500718 TI - Interaction Between a Gelsolin from Dendrorhynchus zhejiangensis with Three Gelsolin-Like Domains and Actin In Vitro. AB - The gelsolin family proteins are best known for involvement in cytoskeletal rearrangement by controlling actin organization during a variety of cellular processes. Previously, a 1962 bp cDNA encoding a 41.7 kDa protein with three gelsolin-like domains (G domains) from Dendrorhynchus zhejiangensis was identified and named as DzGSN. In this study, the sequence and function of a novel member of the gelsolin family proteins from D. zhejiangensis have been analyzed. Sequence alignment indicates that DzGSN is highly homologous to human gelsolin (35% identity) and human CapG (36% identity). The important functional motifs and critical amino acids were identified. The nucleating- and severing actin activities of recombinant DzGSN (rDzGSN) were then investigated by using atomic force microscopy in vitro. After incubation with rDzGSN in the presence of Ca2+, global actin (G-actin) was observed to aggregate into a ring structure, while filament actin (F-actin) was observed to be shortened. Additionally, the yeast two-hybrid system also verified that DzGSN can interact with actin. The results provide new insight into functional diversity and evolution of gelsolin family proteins. PMID- 29500719 TI - Computational Approaches and Analysis for a Spatio-Structural-Temporal Invasive Carcinoma Model. AB - Spatio-temporal models have long been used to describe biological systems of cancer, but it has not been until very recently that increased attention has been paid to structural dynamics of the interaction between cancer populations and the molecular mechanisms associated with local invasion. One system that is of particular interest is that of the urokinase plasminogen activator (uPA) wherein uPA binds uPA receptors on the cancer cell surface, allowing plasminogen to be cleaved into plasmin, which degrades the extracellular matrix and this way leads to enhanced cancer cell migration. In this paper, we develop a novel numerical approach and associated analysis for spatio-structuro-temporal modelling of the uPA system for up to two-spatial and two-structural dimensions. This is accompanied by analytical exploration of the numerical techniques used in simulating this system, with special consideration being given to the proof of stability within numerical regimes encapsulating a central differences approach to approximating numerical gradients. The stability analysis performed here reveals instabilities induced by the coupling of the structural binding and proliferative processes. The numerical results expound how the uPA system aids the tumour in invading the local stroma, whilst the inhibitor to this system may impede this behaviour and encourage a more sporadic pattern of invasion. PMID- 29500720 TI - Voltage-Sensitive Calcium Channels in the Brain: Relevance to Alcohol Intoxication and Withdrawal. AB - Voltage-sensitive Ca2+ (CaV) channels are the primary route of depolarization induced Ca2+ entry in neurons and other excitable cells, leading to an increase in intracellular Ca2+ concentration ([Ca2+]i). The resulting increase in [Ca2+]i activates a wide range of Ca2+-dependent processes in neurons, including neurotransmitter release, gene transcription, activation of Ca2+-dependent enzymes, and activation of certain K+ channels and chloride channels. In addition to their key roles under physiological conditions, CaV channels are also an important target of alcohol, and alcohol-induced changes in Ca2+ signaling can disturb neuronal homeostasis, Ca2+-mediated gene transcription, and the function of neuronal circuits, leading to various neurological and/or neuropsychiatric symptoms and disorders, including alcohol withdrawal induced-seizures and alcoholism. PMID- 29500722 TI - Vitamin K2 in multiple sclerosis patients. AB - BACKGROUND: Vitamin K2 (VK2) belongs to the vitamin K family and comprises a number of subtypes differing in length of side chains consisting of isoprenoid groups (menaquinone-n, MK-n). It is essential for a number of physiological functions although the full spectrum of activity has not yet been elucidated. Due to its role in protection of mitochondrial damage, VK2 could be relevant in preventing disease progress in multiple sclerosis (MS). METHODS: We measured VK2 serum levels by the double antibody sandwich Enzyme-linked Immunosorbent Assay (ELISA) technique in MS patients and age and sex matched controls, both under vitamin D supplementation, and related it to disease characteristics and treatment. RESULTS: Overall, 45 MS patients (31 females and 39 of the relapsing remitting type) and 29 healthy controls (19 females) were included in the analysis. The MS patients had vastly lower VK2 blood levels than controls (235 +/ 100 ng/ml vs. 812 +/- 154 ng/ml, respectively). Female patients had significantly lower VK2 levels than males and a decrease with age by approximately 10% per decade was found. The VK2 levels were lower with increasing numbers of attacks per year and were higher in patients with optic nerve lesions. No consistent relationship with medications was detected. CONCLUSION: The substantially lower levels of VK2 in MS patients could be due to depletion, lower production in the gut, diminished absorption or, less likely, reduced intake of precursor vitamin K1. The role of VK2 in MS development and progress deserves further study. PMID- 29500721 TI - Innate Immune Signaling and Alcohol Use Disorders. AB - Innate immune signaling is an important feature in the pathology of alcohol use disorders. Alcohol abuse causes persistent innate immune activation in the brain. This is seen in postmortem human alcoholic brain specimens, as well as in primate and rodent models of alcohol consumption. Further, in vitro models of alcohol exposure in neurons and glia also demonstrate innate immune activation. The activation of the innate immune system seems to be important in the development of alcohol use pathology, as anti-immune therapies reduce pathology and ethanol self-administration in rodent models. Further, innate immune activation has been identified in each of the stages of addiction: binge/intoxication, withdrawal/negative affect, and preoccupation/craving. This suggests that innate immune activation may play a role both in the development and maintenance of alcoholic pathology. In this chapter, we discuss the known contributions of innate immune signaling in the pathology of alcohol use disorders, and present potential therapeutic interventions that may be beneficial for alcohol use disorders. PMID- 29500723 TI - Crystalloid fluid choice in the critically ill : Current knowledge and critical appraisal. AB - Intravenous infusion of crystalloid solutions is one of the most frequently administered medications worldwide. Available crystalloid infusion solutions have a variety of compositions and have a major impact on body systems; however, administration of crystalloid fluids currently follows a "one fluid for all" approach than a patient-centered fluid prescription. Normal saline is associated with hyperchloremic metabolic acidosis, increased rates of acute kidney injury, increased hemodynamic instability and potentially mortality. Regarding balanced infusates, evidence remains less clear since most studies compared normal saline to buffered infusion solutes.; however, buffered solutes are not homogeneous. The term "buffered solutes" only refers to the concept of acid-buffering in infusion fluids but this does not necessarily imply that the solutes have similar physiological impacts. The currently available data indicate that balanced infusates might have some advantages; however, evidence still is inconclusive. Taking the available evidence together, there is no single fluid that is superior for all patients and settings, because all currently available infusates have distinct differences, advantages and disadvantages; therefore, it seems inevitable to abandon the "one fluid for all" strategy towards a more differentiated and patient-centered approach to fluid therapy in the critically ill. PMID- 29500724 TI - The Effect of Boric Acid and Borax on Oxidative Stress, Inflammation, ER Stress and Apoptosis in Cisplatin Toxication and Nephrotoxicity Developing as a Result of Toxication. AB - The development of treatment protocols that can reduce side effects in chemotherapy applications is extremely important in terms of cancer treatment. In this context, it was aimed to investigate the effects of boric acid and borax on cisplatin toxicity (nephrotoxicity) in rats. In the experimental phase, eight groups were formed from rats. Boric acid and borax were given to the treatment groups with three different doses using gavage. On the fifth day of the study, cisplatin (10 mg/kg) was administered to all rats except the control group. At the end of the study, oxidative stress-related (GSH, MDA, PCO, GPx, 8-OHdG), inflammation-related (TNF-alpha, IL-1beta, IL-18, MCP-1, ICAM, TGF-beta), apoptosis-related (p53, caspase 1, 3, 8, 12, bcl-2, bcl-xL, NFkB), and ER stress related (GRP78, ATF-6, PERK) basic parameters were analyzed in serum, erythrocyte, and kidney tissues. Kidney tissues were also examined by histopathological and immunohistochemical methods. Borax and boric acid at different doses decreased inflammation and oxidative stress caused by cisplatin toxicity and increased ER stress. As a result of the treatments applied to experimental animals, it was determined that boric acid and borax reduced apoptotic damage in kidney tissue, but the decrease was statistically significant only in 200 mg/kg boric acid-administered group. In the study, low anti-apoptotic effects of borate doses with the anti-inflammatory and antioxidant effect may be due to increased ER stress at the relevant doses. Further studies on the effects of boron compounds on ER stress and apoptotic mechanisms may clarify this issue. Thus, possible side effects or if there are new usage areas of borone compounds which have many usage areas in clinics can be detected. PMID- 29500725 TI - Lessons Learned in Promoting Evidence-Based Public Health: Perspectives from Managers in State Public Health Departments. AB - Evidence-based public health (EBPH) practice, also called evidence-informed public health, can improve population health and reduce disease burden in populations. Organizational structures and processes can facilitate capacity building for EBPH in public health agencies. This study involved 51 structured interviews with leaders and program managers in 12 state health department chronic disease prevention units to identify factors that facilitate the implementation of EBPH. Verbatim transcripts of the de-identified interviews were consensus coded in NVIVO qualitative software. Content analyses of coded texts were used to identify themes and illustrative quotes. Facilitator themes included leadership support within the chronic disease prevention unit and division, unit processes to enhance information sharing across program areas and recruitment and retention of qualified personnel, training and technical assistance to build skills, and the ability to provide support to external partners. Chronic disease prevention leaders' role modeling of EBPH processes and expectations for staff to justify proposed plans and approaches were key aspects of leadership support. Leaders protected staff time in order to identify and digest evidence to address the common barrier of lack of time for EBPH. Funding uncertainties or budget cuts, lack of political will for EBPH, and staff turnover remained challenges. In conclusion, leadership support is a key facilitator of EBPH capacity building and practice. Section and division leaders in public health agencies with authority and skills can institute management practices to help staff learn and apply EBPH processes and spread EBPH with partners. PMID- 29500727 TI - An Investigation of Islamic Well-Being and Mental Health. AB - The overall aim of this study was to develop the Islamic Well-Being Scale and examine the relationship between mental health and Islamic well-being. In this study, four sub-studies were performed to create the one-factor Islamic Well Being Scale, perform a confirmatory factor analysis and validate the Islamic Well Being Scale, differentially predict ill-being and well-being outcomes using the Islamic Well-Being Scale, and compare individuals with different Islamic belief levels using the Islamic Well-Being Scale. In total, 170 adults, 209 adults, 216 theological faculty students and 152 undergraduate educational faculty students participated in each sub-study. Several scales related to well-being and ill being were used in this study. The Islamic Well-Being Scale was found to be valid and reliable. Islamic well-being was related to certain indicators of well-being and ill-being. PMID- 29500726 TI - Biological conversion of aromatic monolignol compounds by a Pseudomonas isolate from sediments of the Baltic Sea. AB - Bacterial strains were isolated from the sediments of the Baltic Sea using ferulic acid, guaiacol or a lignin-rich softwood waste stream as substrate. In total nine isolates were obtained, five on ferulic acid, two on guaiacol and two on a lignin-rich softwood stream as a carbon source. Three of the isolates were found to be Pseudomonas sp. based on 16S rRNA sequencing. Among them, isolate 9.1, which showed the fastest growth in defined M9 medium, was tentatively identified as a Pseudomonas deceptionensis strain based on the gyrB sequencing. The growth of isolate 9.1 was further examined on six selected lignin model compounds (ferulate, p-coumarate, benzoate, syringate, vanillin and guaiacol) from different upper funneling aromatic pathways and was found able to grow on four out of these six compounds. No growth was detected on syringate and guaiacol. The highest specific growth and uptake rates were observed for benzoate (0.3 h-1 and 4.2 mmol g CDW-1 h-1) whereas the lowest were for the compounds from the coniferyl branch. Interestingly, several pathway intermediates were excreted during batch growth. Vanillyl alcohol was found to be excreted during growth on vanillin. Several other intermediates like cis,cis-muconate, catechol, vanillate and 4-hydroxybenzoate from the known bacterial catabolic pathways were excreted during growth on the model compounds. PMID- 29500728 TI - Action-Related Speech Modulates Beta Oscillations During Observation of Tool-Use Gestures. AB - Language and action have been thought of as closely related. Comprehending words or phrases that are related to actions commonly activates motor and premotor areas, and this comprehension process interacts with action preparation and/or execution. However, it remains unclear whether comprehending action-related language interacts with action observation. In the current study, we examined whether the observation of tool-use gesture subjects to interaction with language. In an electroencephalography (EEG) study (n = 20), participants were presented with video clips of an actor performing tool-use (TU, e.g., hammering with a fist) and emblematic (EM, e.g., the thumb up sign for 'good job') gestures accompanied by either comprehensible German (G) or incomprehensible Russian sentences (R). Participants performed a semantic judging task, evaluating whether the co-speech gestures were object- or socially-related. Behavioral results from the semantic task showed faster response for the TU versus EM gestures only in the German condition. For EEG, we found that TU elicited beta power decrease (~ 20 Hz) when compared to EM gestures, however this effect was reduced when gestures were accompanied by German instead of Russian sentences. We concluded that the processing of action-related sentences might facilitate gesture observation, in the sense that motor simulation required for TU gestures, as indexed by reduced beta power, was modulated when accompanied by comprehensible German speech. Our results corroborate the functional role of the beta oscillations during perception of hand gestures, and provide novel evidence concerning language-motor interaction. PMID- 29500730 TI - Advanced Rotator Cuff Tear Score (ARoCuS): a multi-scaled tool for the classification and description of rotator cuff tears. AB - BACKGROUND: To introduce a (semi-)quantitative surgical score for the classification of rotator cuff tears. MATERIAL AND METHODS: A total of 146 consecutive patients underwent rotator cuff repair and were assessed using the previously defined Advanced Rotator Cuff Tear Score (ARoCuS) criteria: muscle tendon, size, tissue quality, pattern as well as mobilization of the tear. The data set was split into a training (125 patients) and a testing set (21 patients). The training data set fitted a nonlinear predictive model of the tear score based on the ARoCuS criteria, while the testing data served as control. Based on the scoring results, rotator cuff tears were assigned to one of four categories (DeltaV I-IV) and received a stage-adapted treatment. For statistical analysis, mean values +/- standard deviation, interclass correlation coefficients (ICC) and kappa values were calculated. RESULTS: Overall, 32 patients were classified as DeltaV I, 68 as DeltaV II and 37 as DeltaV III. Nine patients showed DeltaV IV tears. Patients of all DeltaV groups improved significantly their Constant scores (p < 0.001) and profited from significant pain reduction after surgery (p < 0.001). To date, ten patients have undergone revision surgery with five of them primarily classified as DeltaV IV. Kappa values for the interobserver reliability ranged between 0.69 and 0.95. ICC scores for the DeltaV category were 0.95 for interobserver reliability. CONCLUSIONS: The ARoCuS facilitates intra-operative decision-making and enables surgeons and researches to document rotator cuff tears in a standardized and reproducible manner. PMID- 29500731 TI - Reproductive ageing-turning back the clock? AB - BACKGROUND: Unintended childlessness is a distressing, and often unintended, consequence of delayed childbearing and reproductive ageing. The average maternal age at first birth has risen steadily in many industrialised countries since the 1980s. There are many societal factors involved in the decision to postpone motherhood. As a result, many women are postponing having children until it is too late. In this review, we aim to summarise the reasons behind delayed childbearing, the impact of delayed childbearing and the scientific advances that seek to reverse reproductive ageing and ensure reproductive autonomy for women. METHODS: An extensive literature search of PubMed was conducted to include all published articles on delayed childbearing and the consequences of reproductive ageing. Secondary articles were identified from key paper reference listings. CONCLUSION: If the current reproductive trends continue, many women will find themselves in the harrowing position of being unintentionally childless. In addition, many will inevitably turn to assisted reproductive technologies in an effort to protect and preserve their reproductive autonomy. However, it is not always possible to reverse the effects of reproductive ageing. PMID- 29500729 TI - Clinical applications of multiparametric CMR in left ventricular hypertrophy. AB - There are a number of diseases which can increase left ventricular myocardial wall thickness through a number of different mechanisms. Multi-parametric mapping techniques are a new addition to the cardiovascular magnetic resonance (CMR) armoury with a number of potential clinical roles. In this review article, we will explore the role of imaging in left ventricular hypertrophy, and particularly developments in CMR. We focus on ability of CMR to characterize myocardial tissue using multiparametric mapping (native T1, T2 and extracellular volume mapping), to bridge from the microscopic histological domain and into the clinical domain of non-invasive imaging. PMID- 29500732 TI - Exploration of spatial patterns of congenital anomalies in Los Angeles County using the vital statistics birth master file. AB - Research has shown linkages between environmental exposures and population health metrics such as low birth weight and incidence of congenital anomalies. While the exact causal relationship between specific environmental teratogens and suspected corresponding congenital anomalies has largely not been established, spatial analysis of anomaly incidence can identify potential locations of increased risk. This study uses the Vital Statistics Birth Master File to map and analyze the rates of congenital anomalies of births from non-smoking mothers 15-35 years old within Los Angeles County. Hot spot analysis shows that the distribution of congenital anomalies is not randomly distributed throughout the county and identified the Antelope Valley and San Gabriel Foothills as two areas with elevated incidence rates. These results are not explained by potential confounders such as maternal age, race, smoking status, or socioeconomic status and seem to correlate well with the concentration of atmospheric ozone. This approach demonstrates the value of using spatial techniques to inform future research efforts and the need to establish and maintain a comprehensive reproductive health surveillance system. PMID- 29500733 TI - Profiling of Germline Mutations in Major Hotspot Codons of TP53 Using PCR-RFLP. AB - Tumor suppressor protein, TP53 also known as the "guardian of the genome" plays a key role in preventing malignant transformation. Almost 50% of human tumors carry mutations in this gene; in the remaining tumors, the TP53 network is functionally inoperative. The majority of TP53 mutations are missense mutations and more than 90% of the missense mutations affect specific codons in the DNA-binding domain, called "hotspot codons." The present study was aimed at analyzing the germline mutation status of four hotspot codons in TP53 namely, codon 175, codon 245, codon 248 (within the DNA binding domain) and codon 72 (outside the DNA binding domain) in cancer cases encountered in a tertiary care hospital in South India by PCR-RFLP. The case-control study included 85-10 subjects respectively. The results of the study indicated that majority of the cancer cases did not harbor germline mutations in the four hot spot codons of TP53. The study further highlights the usefulness of PCR-RFLP as a simple and cost effective tool for checking gene mutations. PMID- 29500734 TI - What is this image? 2018: Image 6. PMID- 29500735 TI - The Impact of Urban US Policing Practices on Black Men Who Have Sex with Men's HIV Vulnerability: Ethnographic Findings and a Conceptual Model for Future Research. AB - This paper advances research on racism and health by presenting a conceptual model that delineates pathways linking policing practices to HIV vulnerability among Black men who have sex with men in the urban USA. Pathways include perceived discrimination based on race, sexuality and gender performance, mental health, and condom-carrying behaviors. The model, intended to stimulate future empirical work, is based on a review of the literature and on ethnographic data collected in 2014 in New York City. This paper contributes to a growing body of work that examines policing practices as drivers of racial health disparities extending far beyond violence-related deaths. PMID- 29500736 TI - Traveling by Bus Instead of Car on Urban Major Roads: Safety Benefits for Vehicle Occupants, Pedestrians, and Cyclists. AB - Some studies have estimated fatality and injury rates for bus occupants, but data was aggregated at the country level and made no distinction between bus types. Also, injured pedestrians and cyclists, as a result of bus travel, were overlooked. We compared injury rates for car and city bus occupants on specific urban major roads, as well as the cyclist and pedestrian injuries associated with car and bus travel. We selected ten bus routes along major urban arterials (in Montreal, Canada). Passenger-kilometers traveled were estimated from vehicle counts at intersections (2002-2010) and from bus passenger counts (2008). Police accident reports (2001-2010) provided injury data for all modes. Injury rates associated with car and bus travel were calculated for vehicle occupants, pedestrians, and cyclists. Injury rate ratios were also computed. The safety benefits of bus travel, defined as the number of vehicle occupant, cyclist, and pedestrian injuries saved, were estimated for each route. Overall, for all ten routes, the ratio between car and bus occupant injury rates is 3.7 (95% CI [3.4, 4.0]). The rates of pedestrian and cyclist injuries per hundred million passenger kilometers are also significantly greater for car travel than that for bus travel: 4.1 (95% CI [3.5, 4.9]) times greater for pedestrian injuries; 5.3 (95% CI [3.8, 7.6]) times greater for cyclist injuries. Similar results were observed for fatally and severely injured vehicle occupants, cyclists, and pedestrians. At the route level, the safety benefits of bus travel increase with the difference in injury rate associated with car and bus travel but also with the amount of passenger-kilometers by bus. Results show that city bus is a safer mode than car, for vehicle occupants but also for cyclists and pedestrians traveling along these bus routes. The safety benefits of bus travel greatly vary across urban routes; this spatial variation is most likely linked to environmental factors. Understanding the safety benefits of public transit for specific transport routes is likely to provide valuable information for mobilizing city and transportation planners. PMID- 29500738 TI - Autonomic dysfunction: a novel neurological phenotype associated with Zika virus infection? PMID- 29500737 TI - A Lagrangian cylindrical coordinate system for characterizing dynamic surface geometry of tubular anatomic structures. AB - Vascular morphology characterization is useful for disease diagnosis, risk stratification, treatment planning, and prediction of treatment durability. To quantify the dynamic surface geometry of tubular-shaped anatomic structures, we propose a simple, rigorous Lagrangian cylindrical coordinate system to monitor well-defined surface points. Specifically, the proposed system enables quantification of surface curvature and cross-sectional eccentricity. Using idealized software phantom examples, we validate the method's ability to accurately quantify longitudinal and circumferential surface curvature, as well as eccentricity and orientation of eccentricity. We then apply the method to several medical imaging data sets of human vascular structures to exemplify the utility of this coordinate system for analyzing morphology and dynamic geometric changes in blood vessels throughout the body. Graphical abstract Pointwise longitudinal curvature of a thoracic aortic endograft surface for systole and diastole, with their absolute difference. PMID- 29500739 TI - The Experience of Partners of Adults with Type 1 Diabetes: an Integrative Review. AB - PURPOSE OF REVIEW: The purpose of this review was to synthesize the research on the experience of partners living with adults with type 1 diabetes (T1D). RECENT FINDINGS: Eleven studies were included in the review. Three themes on the experience of living with a person with T1D were identified: the undercurrent of hypoglycemia, partners' involvement in diabetes care, and the impact on partners' lives. Due to considerable fear of hypoglycemia, partners had pervasive and deliberate ways in which they made attempts to minimize hypoglycemia in the person with diabetes and its cascade to a health emergency. As a result, partners of adults with T1D experienced considerable distress and disrupted lives. Partners also expressed a need for more support from family, friends, and health professionals. Research is needed on the partner experience across the lifespan and the specific supportive services they need in order to optimize their health outcomes. PMID- 29500740 TI - Determination of Backbone Amide Hydrogen Exchange Rates of Cytochrome c Using Partially Scrambled Electron Transfer Dissociation Data. AB - The technological goal of hydrogen/deuterium exchange-mass spectrometry (HDX-MS) is to determine backbone amide hydrogen exchange rates. The most critical challenge to achieve this goal is obtaining the deuterium incorporation in single amide resolution, and gas-phase fragmentation may provide a universal solution. The gas-phase fragmentation may generate the daughter ions which differ by a single amino acid and the difference in deuterium incorporations in the two analogous ions can yield the deuterium incorporation at the sub-localized site. Following the pioneering works by Jorgensen and Rand, several papers utilized the electron transfer dissociation (ETD) to determine the location of deuterium in single-amide resolution. This paper demonstrates further advancement of the strategy by determining backbone amide hydrogen exchange rates, instead of just determining deuterium incorporation at a single time point, in combination with a wide time window monitoring. A method to evaluate the effects of scrambling and to determine the exchange rates from partially scrambled HDX-ETD-MS data is described. All parent ions for ETD fragmentation were regio-selectively scrambled: The deuterium in some regions of a peptide ion was scrambled while that in the other regions was not scrambled. The method determined 31 backbone amide hydrogen exchange rates of cytochrome c in the non-scrambled regions. Good fragmentation of a parent ion, a low degree of scrambling, and a low number of exchangeable hydrogens in the preceding side chain are the important factors to determine the exchange rate. The exchange rates determined by the HDX-MS are in good agreement with those determined by NMR. Graphical Abstract ?. PMID- 29500741 TI - Anti-aging Properties of Conditioned Media of Epidermal Progenitor Cells Derived from Mesenchymal Stem Cells. AB - INTRODUCTION: Reduced number and activities of epidermal stem cells are related to the features of photoaged skin. It was reported that conditioned media from various stem cell cultures are capable of improving the signs of cutaneous aging. This work was performed to establish epidermal progenitor cells derived from mesenchymal stem cells, and to evaluate the anti-aging efficacy of its conditioned media. METHODS: Epidermal progenitor cell culture was established by differentiation from mesenchymal stem cells, and its conditioned medium (EPC-CM) was prepared. Normal human dermal fibroblasts were exposed to hydrogen peroxide and the protective effects of EPC-CM were investigated, monitoring intracellular reactive oxygen species (ROS), cellular defense enzymes, collagen biosynthesis, and mitogen-associated protein kinase (MAPK) signaling. Anti-aging efficacy of cosmetic essence (5% EPC-CM) was evaluated by a clinical test with 25 Korean women aged between 29 and 69. RESULTS: Hydrogen peroxide hindered proliferation of fibroblasts and increased the levels of intracellular ROS. Pretreatment of EPC CM protected fibroblasts from oxidative stress as shown by accelerated proliferation and reduced ROS generation. EPC-CM effectively prevented hydrogen peroxide-induced alterations of the activities, as well as mRNA and protein levels, of antioxidative enzymes, such as superoxide dismutase, catalase, and glutathione peroxidase. Reduced type I collagen biosynthesis and stimulated phosphorylation of MAPK signaling proteins, induced by oxidative damage, were also prevented by EPC-CM. In clinical study, wrinkle, depression, and skin texture were improved by the topical application of a formulation containing 5% EPC-CM within 4 weeks. CONCLUSION: Epidermal progenitor cell culture was established, and its conditioned medium was developed for anti-aging therapy. EPC CM improved signs of skin aging in clinical study, possibly via activation of cellular the defense system, as supported by in vitro results. PMID- 29500743 TI - Erratum to: Dynamic range of mass accuracy in LTQ orbitrap hybrid mass spectrometer. AB - In the July issue, in the article, "Dynamic Range of Mass Accuracy in LTQ Orbitrap Hybrid Mass Spectrometer" by Alexander Makarov, Eduard Denisov, Oliver Lange, and Stevan Horning (Vol. 17, no. 7, pages 977-982), Figure 4 was printed in black and white, when it should have been published in color. The correct rendering of the figure, with its accompanying legend, is provided below. PMID- 29500744 TI - Erratum to: Reactivity of aromatic sigma,sigma-biradicals toward riboses. AB - After publication of the paper, the authors realized that the affiliation of the fourth author (Tiberiu Esanu) was given incorrectly. Its correct version appears above. Moreover, a second funding grant was missed in the acknowledgements. We give their complete correct version below. PMID- 29500745 TI - 25-Hydroxyvitamin D levels and bone mineral density evaluation in patients with cholecystectomy: a case-control study. AB - : This study compared the 25-hyrdoxyvitamin (OH) D and bone mineral density (BMD) values of patients with and without cholecystectomy. Although 25(OH) D levels were significantly lower in the cholecystectomy group (12.1 +/- 6.2 vs. 15.6 +/- 6.6 ng/mL), no significant difference was observed between the groups in terms of BMD measurements. INTRODUCTION: Although 25 (OH) D levels were studied and found to be lower in patients with cholecystectomy, the data is scarce as regards the BMD. Therefore, the aim of this study was to compare the 25(OH) D and BMD values of patients with cholecystectomy and without cholecystectomy. METHODS: This study was a single-center and case-control trial. The cholecystectomy group comprised the patients with a history of cholecystectomy. In addition, a healthy control group without history of cholecystectomy was defined. All patients were selected consecutively from the patients who admitted to the outpatient clinics of physical and rehabilitation medicine or internal medicine between the June 2016 and August 2016. The patients were ambulatory and did not receive any osteoporosis treatment before. Chemiluminescence microparticle immunoassay method was used for 25(OH) D measurements. Dual-energy X-ray absorptiometry was used for the BMD evaluations. RESULTS: There were 46 patients in the cholecystectomy group with a mean age of 58.6 +/- 14.1 years and 64 patients in the control group with a mean age of 59.2 +/- 13.3 years. Although 25(OH) D levels were significantly lower in the cholecystectomy group (12.1 +/- 6.2 vs. 15.6 +/- 6.6 ng/mL) (p = 0.010), no significant difference was observed between the groups in terms of BMD measurements (p > 0.05). While there was a weak positive correlation between the BMI and BMD measurements (all p < 0.05), linear regression analyses showed that the models were not valid (femoral neck R = 0.092; femur total R = 0.170; and lumbar total R = 0.199). No significant difference was observed between the BMD measurements and time after cholecystectomy in the cholecystectomy group (p > 0.05). CONCLUSION: In the light of our results, cholecystectomy patients seem to have lower level of 25(OH) D levels in comparison with healthy subjects, but both groups have similar BMD values. Further studies in cohort designs taking into account the bone formation and resorption markers are awaited. PMID- 29500746 TI - Writing an effective literature review : Part II: Citation technique. PMID- 29500747 TI - Welcoming the new WHO classification of pituitary tumors 2017: revolution in TTF 1-positive posterior pituitary tumors. AB - The fourth edition of the World Health Organization classification of endocrine tumors (EN-WHO2017) was released in 2017. In this new edition, changes in the classification of non-neuroendocrine tumors are proposed particularly in tumors arising in the posterior pituitary. These tumors are a distinct group of low grade neoplasms of the sellar region that express thyroid transcription factor-1, and include pituicytoma, granular cell tumor of the sellar region, spindle cell oncocytoma, and sellar ependymoma. This short review focuses on the classification of posterior pituitary tumors newly proposed in EN-WHO2017, and controversies in their pathological differential diagnosis are discussed based on recent cases. PMID- 29500748 TI - Reproductive biology of the threatened Lilium pomponium (Liliaceae), a species endemic to Maritime and Ligurian Alps. AB - Pollination ecology and breeding system of Lilium pomponium L. were studied, and their effect on the reproductive outcome was assessed. This species has high conservation interest in Europe, because it is included in Annex V of the EU Habitat Directive and it is one out of the five Lilium species listed in IUCN Global Red List. To achieve our aim, the pollen vectors as well as the effect of bagging, emasculation and artificial pollination on reproductive output were studied. The most frequent visitor was the Lepidopteran Gonepteryx rhamnii. In general, reproductive outputs were close to zero for all the self-pollination treatments; however, geitonogamy and facilitated selfing seem slightly more efficient than autogamy, as also confirmed by self-compatibility and autofertility indices. Altogether, our results suggest a self-incompatible outcrossing breeding system, with a poor capacity for selfing. Nevertheless, climate change and anthropic threats might promote a shift toward self fertilization, even maladaptive, favouring the few individuals able to produce selfed seeds. PMID- 29500749 TI - Lamelloplasts and minichloroplasts in Begoniaceae: iridescence and photosynthetic functioning. AB - Iridoplasts (modified plastids in adaxial epidermal cells) reported from Begonia were originally hypothesized to cause iridescence, which was broadly accepted for decades. However, several species of Begonia with iridoplasts are not iridescent causing confusion. Here chloroplast ultrastructure was observed in 40 taxa of Begoniaceae to explore the phenomenon of iridescence. However, 22 Begonias and Hillebrandia were found to have iridoplasts, but only nine display visually iridescent blue to blue-green leaves. Unexpectedly, a new type of plastid, a 'minichloroplast,' was found in the abaxial epidermal cells of all taxa, but was present in adaxial epidermal cells only if iridoplasts were absent. Comparative ultrastructural study of iridoplasts and a shading experiment of selected taxa show that a taxon with iridoplasts does not inevitably have visual iridescence, but iridescence is greatly affected by the spacing between thylakoid lamellae (stoma spacing). Thus, we propose instead the name 'lamelloplast' for plastids filled entirely with regular lamellae to avoid prejudging their function. To evaluate photosynthetic performance, chlorophyll fluorescence (F v /F m ) was measured separately from the chloroplasts in the adaxial epidermis and lower leaf tissues by using leaf dermal peels. Lamelloplasts and minichloroplasts have much lower photosynthetic efficiency than mesophyll chloroplasts. Nevertheless, photosynthetic proteins (psbA protein of PSII, RuBisCo and ATPase) were detected in both plastids as well as mesophyll chloroplasts in an immunogold labeling. Spectrometry revealed additional blue to blue-green peaks in visually iridescent leaves. Micro-spectrometry detected a blue peak from single blue spots in adaxial epidermal cells confirming that the color is derived from lamelloplasts. Presence of lamelloplasts or minichloroplasts is species specific and exclusive. High prevalence of lamelloplasts in Begoniaceae, including the basal clade Hillebrandia, highlights a unique evolutionary development. These new findings clarify the association between iridescence and lamelloplasts, and with implications for new directions in the study of plastid morphogenesis. PMID- 29500750 TI - Facile One-Step Sonochemical Synthesis and Photocatalytic Properties of Graphene/Ag3PO4 Quantum Dots Composites. AB - In this study, a novel graphene/Ag3PO4 quantum dot (rGO/Ag3PO4 QD) composite was successfully synthesized via a facile one-step photo-ultrasonic-assisted reduction method for the first time. The composites were analyzed by various techniques. According to the obtained results, Ag3PO4 QDs with a size of 1-4 nm were uniformly dispersed on rGO nanosheets to form rGO/Ag3PO4 QD composites. The photocatalytic activity of rGO/Ag3PO4 QD composites was evaluated by the decomposition of methylene blue (MB). Meanwhile, effects of the surfactant dosage and the amount of rGO on the photocatalytic activity were also investigated. It was found that rGO/Ag3PO4 QDs (WrGO:Wcomposite = 2.3%) composite exhibited better photocatalytic activity and stability with degrading 97.5% of MB within 5 min. The improved photocatalytic activities and stabilities were majorly related to the synergistic effect between Ag3PO4 QDs and rGO with high specific surface area, which gave rise to efficient interfacial transfer of photogenerated electrons and holes on both materials. Moreover, possible formation and photocatalytic mechanisms of rGO/Ag3PO4 QDs were proposed. The obtained rGO/Ag3PO4 QDs photocatalysts would have great potentials in sewage treatment and water splitting. PMID- 29500751 TI - Inhibitory effect of Japanese black vinegar on IgE-mediated degranulation of RBL 2H3 cells and a murine model of Japanese cedar pollinosis. AB - Japanese black vinegar (JBV) is a traditional vinegar manufactured with steamed unpolished rice. After screening, beneficial effects of JBV on IgE-mediated allergic responses were found. In this study, acetic acid-free JBV was used to evaluate its antiallergic effects. JBV suppressed degranulation of rat basophilic leukemia RBL-2H3 cells in a dose-dependent manner without cytotoxicity. The inhibitory effect of JBV on the degranulation seemed to be caused by the bioactive ingredients other than proteins, because the activity was not affected by heat treatment or protease digestion. JBV inhibited the elevation in the intracellular Ca2+ concentration induced by antigen. Immunoblot analysis revealed that JBV suppresses degranulation of RBL-2H3 cells by downregulated phosphorylation of PI3K, Akt, and PLCgamma1. In addition, oral administration of JBV significantly suppressed passive cutaneous anaphylaxis reaction in mice and an allergic symptom in Cry j1-induced pollinosis model mice. Thus, JBV has a potential as a health-promoting food with the antiallergy effect. PMID- 29500752 TI - Attractiveness of Host Plant Volatile Extracts to the Asian Citrus Psyllid, Diaphorina citri, is Reduced by Terpenoids from the Non-Host Cashew. AB - Diaphorina citri is a vector of the bacterial causative agent of Huanglongbing (HLB = Citrus greening), a severe disease affecting citrus crops. As there is no known control for HLB, manipulating insect behaviour through deployment of semiochemicals offers a promising opportunity for protecting citrus crops. The behavioural responses of D. citri to plant volatiles, and the identity of these plant volatiles were investigated. Volatiles were collected from host plants Murraya paniculata, Citrus sinensis, C. reshni, C. limettioides, Poncirus trifoliata, and from non-host plants Psidium guajava, Mangifera indica, Anacardium occidentale. In behavioural assays, female D. citri spent more time in the arms containing volatiles from either M. paniculata or C. sinensis compared to the control arms. When D. citri was exposed to volatiles collected from A. occidentale, they preferred the control arm. Volatiles emitted from the other studied plants did not influence the foraging behaviour of D. citri. Chemical analyses of volatile extracts from C. sinensis, M. paniculata, and A. occidentale revealed the presence of the terpenoids (E)-4,8-dimethylnona-1,3,7-triene (DMNT) and (E,E)-4,8,12-trimethyltrideca-1,3,7,11-tetraene (TMTT) in higher amounts in A. occidentale. In further behavioural bioassays, female D. citri spent less time in arms containing a synthetic blend of DMNT and TMTT compared to the control arms. Female D. citri also spent less time in arms containing the synthetic blend in combination with volatile extracts from either M. paniculata or C. sinensis compared to the control arms. Results suggest that higher release of the two terpenoids by A. occidentale make this species unattractive to D. citri, and that the terpenoids could be used in reducing colonisation of citrus plants and therefore HLB infection. PMID- 29500753 TI - Engineering improved thermostability of the GH11 xylanase from Neocallimastix patriciarum via computational library design. AB - Xylanases, which cleave the beta-1,4-glycosidic bond between xylose residues to release xylooligosaccharides (XOS), are widely used as food additives, animal feeds, and pulp bleaching agents. However, the thermally unstable nature of xylanases would hamper their industrial application. In this study, we used in silico design in a glycoside hydrolase family (GH) 11 xylanase to stabilize the enzyme. A combination of the best mutations increased the apparent melting temperature by 14 degrees C and significantly enhanced thermostability and thermoactivation. The variant also showed an upward-shifted optimal temperature for catalysis without compromising its activity at low temperatures. Moreover, a 10-fold higher XOS production yield was obtained at 70 degrees C, which compensated the low yield obtained with the wild-type enzyme. Collectively, the variant constructed by the computational strategy can be used as an efficient biocatalyst for XOS production at industrially viable conditions. PMID- 29500754 TI - Genomic and phenotypic diversity of Listeria monocytogenes clonal complexes associated with human listeriosis. AB - Listeria monocytogenes is a pathogen of significant concern in many ready to eat foods due to its ability to survive and multiply even under significant environmental stresses. Listeriosis in humans is a concern, especially to high risk populations such as those who are immunocompromised or pregnant, due to the high rates of morbidity and mortality. Whole genome sequencing has become a routine part of assessing L. monocytogenes isolated from patients, and the frequency of different genetic subtypes associated with listeriosis is now being reported. The recent abundance of genome sequences for L. monocytogenes has provided a wealth of information regarding the variation in core and accessory genomic elements. Newly described accessory genomic regions have been linked to greater virulence capabilities as well as greater resistance to environmental stressors such as sanitizers commonly used in food processing facilities. This review will provide a summary of our current understanding of stress response and virulence phenotypes of L. monocytogenes, within the context of the genetic diversity of the pathogen. PMID- 29500755 TI - The molecular basis for lipase stereoselectivity. AB - Lipases are among the most applied biocatalysts in organic synthesis to catalyze the kinetic resolution of a wide range of racemic substrates to yield optically pure compounds. Due to the rapidly increased demands for optically pure compounds, deep understanding of the molecular basis for lipase stereoselectivity and how to obtain lipases with excellent asymmetric selectivity have become one of primary research goals in this field. This review is focused on the molecular factors that have impacts on the stereoselectivity of lipases including the steric complementarity between the lipase topological structure and its substrate, the regional structural flexibility, the hydrogen bonds between the residues around the catalytic site and the tetrahedral intermediates, and the electrostatic interactions between surface residues. Moreover, the synergistic effects of these structural factors on the catalytic properties including stereoselectivity, activity, and stability are also discussed. PMID- 29500756 TI - Processing Speed is Impaired in Adults with Autism Spectrum Disorder, and Relates to Social Communication Abilities. AB - Autism spectrum disorder (ASD) is characterized by a variety of social and non social behavioral deficits. One potential mechanism that could unify this diverse profile of behaviors is slower processing speed. Seventy-six high-functioning adults with ASD were compared to 64 matched controls on standardized measures of processing speed. Participants with ASD were significantly slower on all measures, and on the composite score from the three tests (d's > .65). ASD participants with slower processing speeds scored higher on the ADOS Communication and Reciprocal Social Interaction scale (r = .34). These findings provide evidence of slower processing speeds in adults with ASD, and that this may be contributing to impairments in social communication skills. Interventions that improve processing speed might improve social communication abilities in ASD. PMID- 29500758 TI - Modification of the Children's Sleep Habits Questionnaire for Children with Autism Spectrum Disorder. AB - Sleep problems are common in children with autism spectrum disorder (ASD) and adversely impact daytime functioning. Although no questionnaires have been developed to assess sleep in children with ASD, the 33-item Children's Sleep Habits Questionnaire (CSHQ) is widely used in this population. We examined the factor structure of the CSHQ in 2872 children (age 4-10 years) enrolled in the Autism Treatment Network. A four-factor solution (Sleep Initiation and Duration, Sleep Anxiety/Co-Sleeping, Night Waking/Parasomnias, and Daytime Alertness) with 5-6 items per factor explained 75% of the total variation. Ten items failed to load on any factor. This abbreviated 23-item four-factor version of this measure may be useful when assessing sleep in children with ASD. PMID- 29500757 TI - Caregiver Mental Health, Parenting Practices, and Perceptions of Child Attachment in Children with Autism Spectrum Disorder. AB - This paper investigates the role of caregiver mental health and parenting practices as predictors of attachment in children with intellectual disability/developmental delay, comparing between children with ASD (n = 29) and children with other developmental disabilities (n = 20). Parents reported that children with ASD had high levels of anxiety and stress, and attachment insecurity in children (less closeness and more conflict in attachment relationships, and more inhibited attachment behaviours) compared with children with other developmental disabilities. Children's attachment quality was associated with parenting practices and the presence of an ASD diagnosis. These results highlight the bidirectional nature of the quality of caregiving environments and attachment in children with ASD, and also provide a strong rationale for targeting children's attachment quality in early interventions. PMID- 29500759 TI - In vitro assessment of the accuracy of digital impressions prepared using a single system for full-arch restorations on implants. AB - PURPOSE: This study describes a method for measuring the accuracy of the virtual impression. METHODS: In vitro measurements according to a metrological approach were based on (1) use of an opto-mechanical coordinate measuring machine to acquire 3D points from a master model, (2) the mathematical reconstruction of regular geometric features (planes, cylinders, points) from 3D points or an STL file, and (3) consistent definition and evaluation of position and distance errors describing scanning inaccuracies. Two expert and two inexpert operators each made five impressions. The 3D position error, with its relevant X, Y, and Z components, the mean 3D position error of each scanbody, and the intra-scanbody distance error were measured using the analysis of variance and the Sheffe's test for multiple comparison. RESULTS: Statistically significant differences in the accuracy of the impression were observed among the operators for each scanbody, despite the good reliability (Cronbach's [Formula: see text] = 0.897). The mean 3D position error of the digital impression was between 0.041 +/- 0.023 mm and 0.082 +/- 0.030 mm. CONCLUSIONS: Within the limitations of this in vitro study, which was performed using a single commercial system for preparing digital impressions and one test configuration, the data showed that the digital impressions had a level of accuracy comparable to that reported in other studies, and which was acceptable for clinical and technological applications. The distance between the individual positions (#36 to #46) of the scanbody influenced the magnitude of the error. The position error generated by the intraoral scanner was dependent on the length of the arch scanned. Operator skill and experience may influence the accuracy of the impression. PMID- 29500760 TI - Use the force: deformation correction in robotic 3D ultrasound. AB - PURPOSE: Ultrasound acquisitions are typically affected by deformations due to the pressure applied onto the contact surface. While a certain amount of pressure is necessary to ensure good acoustic coupling and visibility of the anatomy under examination, the caused deformations hinder accurate localization and geometric analysis of anatomical structures. These complications have even greater impact in case of 3D ultrasound scans as they limit the correct reconstruction of acquired volumes. METHODS: In this work, we propose a method to estimate and correct the induced deformation based solely on the tracked ultrasound images and information about the applied force. This is achieved by modeling estimated displacement fields of individual image sequences using the measured force information. By representing the computed displacement fields using a graph-based approach, we are able to recover a deformation-less 3D volume. RESULTS: Validation is performed on 30 in vivo human datasets acquired using a robotic ultrasound framework. Compared to ground truth, the presented deformation correction shows errors of [Formula: see text] for an applied force of 5 N at a penetration depth of 55 mm. CONCLUSION: The proposed technique allows for the correction of deformations induced by the transducer pressure in entire 3D ultrasound volumes. Our technique does not require biomechanical models, patient specific assumptions or information about the tissue properties; it can be employed based on the information from readily available robotic ultrasound platforms. PMID- 29500761 TI - Application of Ultra-Centrifugation and Bench-Top 19F NMR for Measuring Drug Phase Partitioning for the Ophthalmic Oil-in-Water Emulsion Products. AB - Generic drug products are expected to have the same active pharmaceutical ingredient (API) (Q1) with the same content (Q2) and microstructure arrangement (Q3) as the innovator product. In complex oil-in-water emulsion drugs, the hydrophobic API is mainly formulated in oil droplets stabilized by surfactant and micelles composed of extra surfactant molecules. The API phase partition in oil and water (mainly micelle) is a critical quality attribute (CQA) of emulsion product in demonstrating physicochemical equivalence using difluprednate (DFPN) emulsion product Durezol(r) as a model, we developed a novel low-field benchtop NMR method to demonstrate its applicability in measuring DFPN phase partition for ophthalmic oil-in-water emulsion products. Low-field 19F spectra were collected for DFPN in formulation, in water phase and oil phase after separation from ultra centrifugation. The NMR data showed the mass balance of DFPN before and after phase separation. The average water phase content of different Durezol(r) lots was 32 +/- 3% with 1% variation from method reproducibility test. The partition results were 52 +/- 2% for the in-house control products prepared in Q1/Q2 equivalence to Durezol(r) but by a different process. The significant difference in DFPN-phase partition between Durezol(r) and the in-house formulation demonstrated manufacture difference readily changed the API partition. The newly developed ultra-centrifugation and 19F NMR by benchtop instrument is a simple, robust, and sensitive analytical method for ophthalmic emulsion drug product development and control. PMID- 29500762 TI - Mucoadhesive Properties of Eudragit(r)RS100, Eudragit(r)S100, and Poly(epsilon caprolactone) Nanocapsules: Influence of the Vehicle and the Mucosal Surface. AB - The use of polymers as mucoadhesive materials has been explored in several drug delivery systems. It is well known that the resulting mucoadhesiveness not only depends on the polymers by themselves, but also on the way they are delivered and on the application target. However, little attention has been given to the combined effect of such characteristics. Therefore, the objective of this study is to analyze the mucoadhesion resulting from combined effects of nanocapsules produced with polymers of different ionic properties, Eudragit(r)RS100, Eudragit(r)S100, or poly(epsilon-caprolactone), when they are incorporated into different vehicles (suspension, hydrogel, and powder) and applied on different mucosal surfaces (mucin, porcine vaginal, and buccal mucosa). Mucoadhesion was measured by a tensile stress tester. Our findings show that polymeric self assembling as nanocapsules improved the mucoadhesion of the polymers. Eudragit(r)RS100 nanocapsules have the best performance, independently of the vehicle and surface used. Regarding the vehicle, hydrogels showed higher adhesion when compared to suspensions and powders. When considering different types of surfaces, mucin presented a similar pattern like the animal mucosa, but it overestimated the mucoadhesiveness of all formulations. In conclusion, this study demonstrated that the best strategy to achieve high mucoadhesive formulations is by incorporating Eudragit(r)RS100 nanocapsules in hydrogels. Moreover, mucin is a suitable substrate to compare and screen different formulations but not as a conclusive estimation of the mucoadhesion values that can be achieved. These results are summarized in a decision tree that can help to understand different strategies of combination of these factors and the expected outcomes. PMID- 29500763 TI - The C-Reactive Protein/Albumin Ratio is a Novel Significant Prognostic Factor in Patients with Malignant Pleural Mesothelioma: A Retrospective Multi-institutional Study. AB - BACKGROUND: Malignant pleural mesothelioma (MPM), a devastating neoplasm, is traditionally considered to be resistant to antitumor therapy. Identification of clinical prognostic indicators is therefore needed. Although the C-reactive protein/albumin ratio (CAR) has been used to predict the prognosis of many types of malignancy, its utility in patients with MPM is unknown. METHODS: The data of 100 patients diagnosed as having MPM from 1995 to 2015 at the National Kyushu Cancer Center and Kyushu University were analyzed. The CAR was calculated as serum C-reactive protein concentration divided by albumin concentration. A cutoff for CAR was set at 0.58 according to a receiver operating characteristics curve for 1-year survival. RESULTS: Thirty-five of the 100 (35.0%) patients were classified as having a high CAR. A high CAR was significantly associated with advanced clinical stage (p < 0.001) and chemotherapy alone (p = 0.002). Patients with a high CAR had significantly shorter overall survival (OS) (p < 0.001) and disease- or progression-free survival (DFS/PFS) (p < 0.001). These associations between CAR and prognosis remained significant after propensity score-matching. In multivariate analysis, a high CAR was an independent predictor of shorter OS and DFS/PFS (p = 0.003 and p = 0.008, respectively). Multivariate analyses of the subgroups of patients who had received chemotherapy and of patients who had undergone surgery also showed that a high CAR was an independent predictor of shorter OS and DFS/PFS. CONCLUSIONS: CAR is an independent predictor of prognosis in MPM patients. This prognostic index contributes to clinicians' ability to predict benefit from treatment. Further larger, prospective studies are necessary to validate these findings. PMID- 29500765 TI - Impact of Micro- and Macroscopically Positive Surgical Margins on Survival after Resection of Adrenocortical Carcinoma. AB - PURPOSE: Adrenocortical carcinoma (ACC) is a rare, aggressive cancer; complete surgical resection offers the best chance for long-term survival. The impact of surgical margin status on survival is poorly understood. Our objective was to determine the association of margin status with survival. METHODS: Patients with ACC were identified from the National Cancer Data Base, 1998-2012, and stratified based on surgical margin status (negative vs. microscopically positive [+] vs. macroscopically [+]). Univariate/multivariate regression/survival analyses were utilized to determine factors associated with margin status and overall survival (OS). RESULTS: A total of 1553 patients underwent surgery at 589 institutions: 86% had negative, 12% microscopically (+), and 2% macroscopically (+) margins. Those with microscopically (+) and macroscopically (+) margins more often received adjuvant chemotherapy (39.4% macroscopically (+) vs. 38.5% microscopically (+) vs. 25.2% negative margins, p < 0.001). For unadjusted analysis, there was a significant difference in OS between the groups (log-rank p < 0.001), with median survival times of 58 months (95% confidence interval [CI] 49-66) for those with negative margins, 22 months (95% CI 18-34) microscopically (+), and 14 months (95% CI 6-27) macroscopically (+) margins. After adjustment, both microscopically (+) (HR 1.76, p < 0.001) and macroscopically (+) (HR 2.10, p = 0.0019) margin status were associated with compromised survival. CONCLUSIONS: Having micro- or macroscopically (+) margin status after ACC resection is associated with dose-dependent compromised survival. These results underscore the importance of achieving negative surgical margins for optimizing long-term patient outcomes. PMID- 29500764 TI - The Rationale and Emerging Use of Neoadjuvant Immune Checkpoint Blockade for Solid Malignancies. AB - Unprecedented advances in the treatment of cancer have occurred through the use of immunotherapy, with several agents currently approved by the Food and Drug Administration (FDA) for the treatment of widespread metastatic disease across cancer types. Immune checkpoint blockade represents a particularly promising class of agents that block inhibitory molecules on the surface of T cells, resulting in their activation and propagation of an immune response. Treatment with these agents may re-invigorate anti-tumor immunity, resulting in therapeutic responses, and use of these agents currently is being studied in the adjuvant setting. Additionally, a strong rationale exists for their use in the neoadjuvant setting for high-risk resectable disease (e.g., regional nodal disease in the case of melanoma). This rationale is based on the relatively high risk of relapse for these patients, as well as on scientific evidence suggesting that long-term immunologic memory and tumor control may be superior in the setting of treatment for an intact tumor (i.e., neoadjuvant therapy) as opposed to treatment in the setting of micrometastatic disease (e.g., adjuvant treatment). The potential advantages of this approach and the current landscape for neoadjuvant immune checkpoint blockade is discussed in this report, as well as caveats that should be considered by clinicians contemplating this strategy. PMID- 29500766 TI - Clinical and Genetic Implications of Mutation Burden in Squamous Cell Carcinoma of the Lung. AB - BACKGROUND: Lung squamous cell carcinoma (LSCC) is a major histological subtype of lung cancer. In this study, we investigated genomic alterations in LSCC and evaluated the clinical implications of mutation burden (MB) in LSCC. METHODS: Genomic alterations were determined in Japanese patients with LSCC (N = 67) using next-generation sequencing of 415 known cancer genes. MB was defined as the number of non-synonymous mutations per 1 Mbp. Programmed death-ligand 1 (PD-L1) protein expression in cancer cells was evaluated by immunohistochemical analysis. RESULTS: TP53 gene mutations were the most common alteration (n = 51/67, 76.1%), followed by gene alterations in cyclin-dependent kinase inhibitor 2B (CDKN2B; 35.8%), CDKN2A (31.3%), phosphatase and tensin homolog (30.0%), and sex determining region Y-box 2 (SOX2, 28.3%). Histological differentiation was significantly poorer in tumors with high MB (greater than or equal to the median MB) compared with that in tumors with low MB (less than the median MB; p = 0.0446). The high MB group had more tumors located in the upper or middle lobe than tumors located in the lower lobe (p = 0.0019). Moreover, cancers in the upper or middle lobes had significantly higher MB than cancers in the lower lobes (p = 0.0005), and tended to show higher PD-L1 protein expression (p = 0.0573). SOX2 and tyrosine kinase non-receptor 2 amplifications were associated with high MB (p = 0.0065 and p = 0.0010, respectively). CONCLUSIONS: The MB level differed according to the tumor location in LSCC, suggesting that the location of cancer development may influence the genomic background of the tumor. PMID- 29500782 TI - Risk Factors During Pregnancy and Early Childhood in Rural West Bengal, India: A Feasibility Study Implemented via Trained Community Health Workers Using Mobile Data Collection Devices. AB - Objectives This study measures the prevalence of risk factors among pregnant women and young children aged 12-24 months in a rural community in West Bengal, India. Methods Community health workers (CHWs) enrolled women and children into this 2015 cross-sectional study. Pregnant women were evaluated for underweight, anemia, and abnormal blood pressure. Children were evaluated for underweight, abnormal head and upper arm circumferences, and low scores from the Ages and Stages Questionnaire (ASQ). Data were collected on smartphones and tablets or by paper. Results More than half of the 279 women (59.9%) had a risk factor during pregnancy: 48.7% were anemic, 35.1% had low blood pressure, and 7.5% were underweight. Among the 366 children, 59.3% had a risk factor, including 24.0% with low ASQ scores and 49.7% who had abnormal anthropometric measures. Conclusions for Practice Vulnerable populations, such as pregnant women and young children, needed a greater connection to doctors in this rural community. This study demonstrated the feasibility of CHWs to listen to health concerns and connect underserved populations with health care services. PMID- 29500767 TI - Seroepidemiological and biomolecular survey on Toxoplasma gondii infection on organic pig farms. AB - Pigs are an important reservoir of Toxoplasma gondii, and pork meat is considered one of the main sources of human infection. The present survey assesses the prevalence of T. gondii in organically reared pigs in Sardinia found on the island using various diagnostic methods. Firstly, a seroepidemiological survey was carried out on 63 farms, examining individual blood samples from 414 adult pigs. Secondly, a biomolecular investigation carried out on another 62 farms, examining the brain samples from 107 adult pigs. The seroprevalence detected for T. gondii at the farm level was 85.7% (54 out of the 63 pig farms examined). However, the prevalence rate in the investigated pigs was 51.7% (214 positives out of 414 examined). A total of 54.8% (34/62) of the monitored pig farms were found to be positive by PCR. The presence of T. gondii DNA in individual brain samples was detected in 47.7% (51/107) of the examined animals. The high prevalence of T. gondii found is alarming and suggests that pigs reared on organic farms should be considered as a significant source of infection for humans in the areas investigated. PMID- 29500783 TI - Examination of Child and Adolescent Hospital Admission Rates in Queensland, Australia, 1995-2011: A Comparison of Coal Seam Gas, Coal Mining, and Rural Areas. AB - Objectives At present, coal seam gas (CSG) is the most common form of unconventional natural gas development occurring in Australia. Few studies have been conducted to explore the potential health impacts of CSG development on children and adolescents. This analysis presents age-specific hospitalisation rates for a child and adolescent cohort in three study areas in Queensland. Methods Three geographic areas were selected: a CSG area, a coal mining area, and a rural area with no mining activity. Changes in area-specific hospital admissions were investigated over the period 1995-2011 in a series of negative binomial regression analyses for 19 International Classification of Diseases (ICD) chapters, adjusting for sociodemographic factors. Results The strongest associations were found for respiratory diseases in 0-4 year olds (7% increase [95% CI 4%, 11%] and 6% increase [95% CI 2%, 10%] in the CSG area relative to the coal mining and rural areas, respectively) and 10-14 year olds (9% increase [95% CI 1%, 18%] and 11% increase [95% CI 1%, 21%] in the CSG area compared to the coal mining and rural areas, respectively). The largest effect size was for blood/immune diseases in 5-9 year olds in the CSG area (467% increase [95% CI 139%, 1244%]) compared to the rural area with no mining activity. Conclusions for Practice Higher rates of hospitalisation existed in the CSG area for certain ICD chapters and paediatric age groups, suggesting potential age-specific health impacts. This study provides insights on associations that should be explored further in terms of child and adolescent health. PMID- 29500784 TI - Hepatitis C Virus Knowledge Among Pregnant Women with Opioid Use Disorder. AB - Objectives To evaluate Hepatitis C virus (HCV) knowledge and awareness among pregnant women with opioid use disorder (OUD). Methods From May through November 2015, a one-time survey was distributed to a convenience sample of pregnant women with OUD to assess their knowledge and awareness of (a) risk factors for HCV infection, (b) HCV transmission prevention strategies, (c) hepatotoxic risk reduction and (d) perinatal transmission and neonatal implications of HCV infection. Chi square and Fisher's exact tests were used to compare demographic characteristics and HCV knowledge between participants who were HCV positive and negative. Results Of 179 pregnant women with OUD approached, 169 (94%) completed the survey. Of these, 153 (90.5%) reported at least one risk factor for HCV infection, 85 (50.3%) were HCV positive and 38 (44.7%) of HCV positive women were diagnosed with HCV for the first time during pregnancy. When HCV knowledge was evaluated, 114 (66.7%) responded that sharing eating utensils could transmit HCV, 69 (55.0%) responded that there is a vaccine to prevent HCV and 56 (32.7%) did not identify intranasal drug use as a risk factor for HCV transmission. Among HCV positive women, 61 (71.8%) associated breastfeeding with an increased risk for HCV transmission, 33 (38.1%) failed to identify the importance of pediatric follow-up for HCV-exposed children and 16 (18.8%) perceived the risk of HCV vertical transmission as "likely" or "very likely." Conclusions for Practice Gaps in HCV knowledge exist among a rapidly growing population of pregnant women with OUD. Healthcare providers have a unique opportunity to provide HCV education and counseling during pregnancy. PMID- 29500785 TI - Low-Income, African American and American Indian Children's Viewpoints on Body Image Assessment Tools and Body Satisfaction: A Mixed Methods Study. AB - Objectives Pediatric obesity is complicated by many factors including psychological issues, such as body dissatisfaction. Body image assessment tools are used with children to measure their acceptance of their body shape or image. Limited research has been conducted with African American and American Indian children to understand their opinions on assessment tools created. This study investigated: (a) children's perception about body image and (b) differences between two body image instruments among low-income, multi-ethnic children. Methods This study uses mixed methodology including focus groups (qualitative) and body image assessment instruments (quantitative). Fifty-one children participated (25 girls, 26 boys); 53% of children identified as African American and 47% as American Indian. The average age was 10.4 years. Open coding methods were used by identify themes from focus group data. SPSS was used for quantitative analysis. Results Children preferred the Figure Rating Scale (FRS/silhouette) instrument over the Children's Body Image Scale (CBIS/photo) because their body parts and facial features were more detailed. Children formed their body image perception with influence from their parents and the media. Children verbalized that they have experienced negative consequences related to poor body image including disordered eating habits, depression, and bullying. Healthy weight children are also aware of weight-related bullying that obese and overweight children face. Conclusions for Practice Children prefer that the images on a body image assessment tool have detailed facial features and are clothed. Further research into body image assessment tools for use with African American and American Indian children is needed. PMID- 29500786 TI - Confronting Adversity: MCH Responds to ACEs. PMID- 29500787 TI - Melanoma Immunotherapy in the Elderly. AB - The incidence of cutaneous melanoma in the elderly continues to rise. Immunotherapies such as the immune checkpoint inhibitors ipilimumab, nivolumab, and pembrolizumab have shown great promise in the management of this disease. There are growing data, mostly out of clinical trial experience, that shows the efficacy and tolerability of these agents across all ages, including those older than 75 years. Though at first glance immunotherapy for melanoma may appear to be a one-size fits all when it comes to age, a rationale is evolving for why this approach may warrant additional personalization in the older patient. This paper aims to summarize the clinical experience with these agents for elderly melanoma patients, as well as to introduce the concept of a personalized approach for elderly patients with consideration of incidence and management of side effects, and strategies for optimizing efficacy in the context of an aging immune system. PMID- 29500788 TI - Pigeon chest: comparative analysis of surgical techniques in minimal access repair of pectus carinatum (MARPC). AB - BACKGROUND: After minimally invasive repair for pectus excavatum (MIRPE), similar procedures for pectus carinatum were developed. This study aimed to analyse the various published techniques of minimal access repair for pectus carinatum (MARPC) and compare the outcomes. DATA SOURCES: Literature was reviewed on PubMed with the terms "pectus carinatum", "minimal access repair", "thoracoscopy" and "children". RESULTS: Twelve MARPC techniques that included 13 articles and 140 patients with mean age 15.46 years met the inclusion criteria. Success rate of corrections was n = 125, about 89% in cumulative reports, with seven articles reporting 100%. The complication rate was 39.28%. Since the pectus bar is placed over the sternum and has a large contact area, skin irritation was the most frequent morbidity (n = 20, 14.28%). However, within the complication group (n = 55), wire breakage (n = 21, 38.18%) and bar displacement (n = 10, 18.18%) were the most frequent complications. Twenty-two (15.71%) patients required a second procedure. Recurrences have been reported in four of twelve techniques. There were no lethal outcomes. CONCLUSIONS: MARPC techniques are not standardized, as MIRPE are, so comparative analysis is difficult as the only common denominator is minimal access. Surgical morbidity is high in MARPC and affects > 2/3rd patients with about 15% requiring surgery for complication management. PMID- 29500789 TI - Recovery Services and Outcomes in a State Psychiatric Hospital. AB - Recovery has emerged as a focus of mental health rehabilitation in the past decade. Many have suggested that various domains of recovery-orientated services are integrated to an efficacious mental health care system. In this study we examined the association of domains of recovery-oriented services with recovery outcomes among inpatients in a state psychiatric hospital. A convenience sample of 36 hospital patients participated in a survey that included two standardized scales, with one measuring 6 domains of recovery-orientation of hospital-based services and one measuring 5 aspects of patients' recovery outcomes. We used regression analysis to estimate the association between recovery-oriented services and recovery outcomes adjusting for gender, race, and education. Nearly 90% of patients had lengths of stay of more than 3 months. On average, patients reported receiving moderate levels of recovery-oriented services. Nevertheless those who reported receiving higher levels of recovery-oriented services also reported better recovery outcomes. Specifically three domains of recovery oriented services, i.e., life goal vs. symptom management, individual tailored, and diversity of treatment options, are associated with better overall recovery and 3 specific aspects of recovery, namely willingness to ask for help, goal and success orientation, and reliance on others. The data from a small sample of patients at a state psychiatric hospital suggest that self-reported recovery oriented services received are associated with better recovery outcomes. Future larger studies are warranted to confirm the study findings, and to examine whether a contemporary recovery-focused care model can facilitate even greater recovery outcomes. PMID- 29500790 TI - Predictors of severe stenosis at invasive coronary angiography in patients with normal myocardial perfusion imaging. AB - PURPOSE: Normal myocardial perfusion imaging (MPI) is associated with excellent prognosis. However, in patients with persisting symptoms, it may be difficult to determine the patients in whom invasive angiography is justified to rule out false negative MPI. We evaluated predictors for severe stenosis at invasive angiography in patients with persisting symptoms after normal MPI. METHODS: 229 consecutive patients with normal MPI, without previous bypass surgery, underwent invasive angiography within 6 months. Older age was defined as >65 years. Multivariable analyses were performed to adjust for differences in baseline variables. RESULTS: Mean age was 62 +/- 11 years, 48% were women. Severe stenosis was observed in 34%, and of these patients 60% had single-vessel disease (not left main coronary artery disease). After adjusting for several variables, including diabetes, smoking status, hypertension and hypercholesterolaemia, predictors of severe stenosis were male gender, odds ratio (OR) 2.7 (95% confidence interval (CI) 1.5-4.9), older age, OR 1.9 (95% CI 1.02-3.54) previous PCI, OR 2.0 (95% CI 1.0-4.3) and typical angina, OR 2.5 (95% CI 1.4-4.6). CONCLUSIONS: Increasing age, male gender, previous PCI and typical symptoms are predictors of severe stenosis at invasive coronary angiography in patients with normal MPI. The majority of these patients have single-vessel disease. PMID- 29500792 TI - Safety and Efficacy of Epigenetically Converted Human Fibroblasts Into Insulin Secreting Cells: A Preclinical Study. AB - Type 1 Diabetes Mellitus (T1DM) is a chronic disease that leads to loss of insulin secreting beta-cells, causing high levels of blood glucose. Exogenous insulin administration is not sufficient to mimic the normal function of beta cells and, consequently, diabetes mellitus often progresses and can lead to major chronic complications and morbidity. The physiological control of glucose levels can only be restored by replacing the beta-cell mass.We recently developed a new strategy that allows for epigenetic conversion of dermal fibroblasts into insulin secreting cells (EpiCC), using a brief exposure to the demethylating agent 5-aza cytidine (5-aza-CR), followed by a pancreatic induction protocol. This method has notable advantages compared to the alternative available procedures and may represent a promising tool for clinical translation as a therapy for T1DM. However, a thought evaluation of its therapeutic safety and efficacy is mandatory to support preclinical studies based on EpiCC treatment.We here report the data obtained using human fibroblasts isolated from diabetic and healthy individuals, belonging the two genders. EpiCC were injected into 650 diabetic severe combined immunodeficiency (SCID) mice and demonstrated to be able to restore and maintain glycemic levels within the physiological range. Cells had the ability to self regulate and not to cause hypoglycemia, when transplanted in healthy animals. Efficacy tests showed that EpiCC successfully re-established normoglycemia in diabetic mice, using a dose range that appeared clinically relevant to the concentration 0.6 * 106 EpiCC. Necropsy and histopathological investigations demonstrated the absence of malignant transformation and cell migration to organs and lymph nodes.The present preclinical study demonstrates safety and efficacy of human EpiCC in diabetic mice and supports the use of epigenetic converted cells for regenerative medicine of diabetes mellitus. PMID- 29500791 TI - Safety, Effectiveness, and Treatment Persistence of Golimumab in Elderly Patients with Rheumatoid Arthritis in Real-World Clinical Practice in Japan. AB - INTRODUCTION: Golimumab has been proven as an effective treatment for rheumatoid arthritis in clinical trials. However, there is a scarcity of data regarding its use in elderly patients in a real-world setting. This study aims to evaluate the safety, effectiveness, and treatment persistence of golimumab in elderly Japanese patients (>= 75 years) with rheumatoid arthritis. METHODS: This study was a post hoc analysis of post-marketing surveillance data on 5137 Japanese patients with active rheumatoid arthritis who received golimumab for 24 weeks. The study population was divided into two age groups (younger: < 75 years and elderly: >= 75 years), and the safety, effectiveness, and treatment persistence of golimumab were assessed. Also, the reasons for discontinuing golimumab treatment were analyzed by multi-logistic regression. RESULTS: During golimumab treatment over 24 weeks, younger and elderly groups exhibited comparable improvement of disease activity as measured by EULAR response criteria with similar overall rates of adverse events. However, the survival curve of golimumab for elderly patients was significantly different from that for younger patients due largely to the discontinuation at 4 weeks. The most common reason for discontinuation in elderly patients was patient choice, while it was disease progression in younger patients. Analysis of elderly patients who discontinued treatment by their own decision identified EULAR good response as a factor associated with continuation of golimumab treatment whereas no predictive factor associated with discontinuation was identified. CONCLUSIONS: The safety and effectiveness of golimumab treatment in elderly Japanese patients aged 75 years or older were comparable to those in younger patients in real-world clinical practice. Analysis of the survival curves suggested that continuous use of golimumab might further improve clinical benefit of golimumab in elderly patients, underpinning the importance of effective communication between physicians and elderly patients based on the treat-to-target strategy. FUNDING: Janssen Pharmaceutical K.K. and Mitsubishi Tanabe Pharma Corporation. PMID- 29500793 TI - Heart Failure: From Research to Clinical Practice. AB - "Heart failure: from research to clinical practice", a collection of selected reviews, which comes out also as a book, covers essentially all important aspects of heart failure, including the pathogenesis, clinical features, biomarkers, imaging techniques, medical treatment and surgical treatments, use of pacemakers and implantable cardioverter defibrillators, and palliative care. The reviews include essential background information, state of the art, critical and in-depth analysis, and directions for future researches for elucidation of the unresolved issues. Everyone interested in heart failure is expected to find this compilation helpful for a deeper understanding of some of the complex issues. PMID- 29500794 TI - The Art and Science of Using Diuretics in the Treatment of Heart Failure in Diverse Clinical Settings. AB - It is important to understand the rationale for appropriate use of different diuretics, alone or in combination, in different heart failure patients, under diverse clinical settings. Clinicians and nurses engaged in heart failure care, must be familiar with different diuretics, their appropriate doses, methods of administration, monitoring of the responses, and the side-effects. Inappropriate use of diuretics, both under-treatment and overtreatment, and poor follow-up can lead to failures, and adverse outcomes. Adequate treatment of congestion, with rather aggressive use of diuretics, is necessary, even if that may worsen renal function temporarily in some patients. Diuretic treatment should later be titrated down, by early recognition of the euvolemic sate, which can be assessed by clinical examination, measurement of the natriuretic peptides, and when possible, echocardiographic estimation of the left ventricular filling pressure. You need to treat patients, who are truly resistant to the loop diuretics, by administering the diuretics as intravenous bolus injection followed by continuous infusion, and/or by sequential nephron blockade by adding the thiazide diuretics. You need to use the diuretics based on a sound understanding of the pathophysiology of the disease process, the pharmacokinetics and pharmacodynamics of the diuretics, even when strong evidences for your choices might be lacking. Some patients may benefit from injection of loop diuretics together with hypertonic saline, and others from injection of loop diuretics with albumin. Patient education, and regular follow up of the treatment of heart failure patients, in out-patient settings are important for reducing the rates of complications, and for reducing the needs for urgent hospitalizations. PMID- 29500795 TI - The impact of log odds of positive lymph nodes (LODDS) in colon and rectal cancer patient stratification: a single-center analysis of 323 patients. AB - Log odds of positive nodes (LODDS), defined as the log of the ratio between the number of positive nodes and the number of negative nodes, has been recently introduced as a tool in predicting prognosis. This study aims to establish the effective and prognostic value of LODDS in predicting the survival outcome of CRC patients undergoing surgical resection. The study population is represented by 323 consecutive patients with primary colon or rectal adenocarcinoma thatunderwent curative resection. LODDS values were calculated by empirical logistic formula, log(pnod + 0.5)/(tnod - pnod + 0.5). It was defined as the log of the ratio between the number of positive nodes and the number of negative nodes. The patients were divided into three groups: LODDS0 (<= - 1.36), LODDS1 (> - 1.36 <= - 0.53) and LODDS2 (> - 0.53). Kaplan-Meier curve analyses showed 3 year OS rates of the patients staged by LODDS classification. These values were 88.3, 74.8 and 61.8% for LODDS0, LODDS1 and LODDS2, respectively (P <= 0.001). In a multivariate analysis, LODDS is an independent prognostic factor of 3-year OS. This is in contrast to pN stage and lymph node ratio, which shows no statistical significance. ROC analyses showed that LODDS predicted OS better than lymph node ratio. LODDS classification has a better prognostic effect than pN stage and lymph node ratio. LODDS offers a finer stratification and accurately predicts survival of CRC patients. PMID- 29500797 TI - An Updated Subsequent Injury Categorisation Model (SIC-2.0): Data-Driven Categorisation of Subsequent Injuries in Sport. AB - BACKGROUND: Accounting for subsequent injuries is critical for sports injury epidemiology. The subsequent injury categorisation (SIC-1.0) model was developed to create a framework for accurate categorisation of subsequent injuries but its operationalisation has been challenging. OBJECTIVES: The objective of this study was to update the subsequent injury categorisation (SIC-1.0 to SIC-2.0) model to improve its utility and application to sports injury datasets, and to test its applicability to a sports injury dataset. METHODS: The SIC-1.0 model was expanded to include two levels of categorisation describing how previous injuries relate to subsequent events. A data-driven classification level was established containing eight discrete injury categories identifiable without clinical input. A sequential classification level that sub-categorised the data-driven categories according to their level of clinical relatedness has 16 distinct subsequent injury types. Manual and automated SIC-2.0 model categorisation were applied to a prospective injury dataset collected for elite rugby sevens players over a 2-year period. Absolute agreement between the two coding methods was assessed. RESULTS: An automated script for automatic data-driven categorisation and a flowchart for manual coding were developed for the SIC-2.0 model. The SIC-2.0 model was applied to 246 injuries sustained by 55 players (median four injuries, range 1-12), 46 (83.6%) of whom experienced more than one injury. The majority of subsequent injuries (78.7%) were sustained to a different site and were of a different nature. Absolute agreement between the manual coding and automated statistical script category allocation was 100%. CONCLUSIONS: The updated SIC-2.0 model provides a simple flowchart and automated electronic script to allow both an accurate and efficient method of categorising subsequent injury data in sport. PMID- 29500798 TI - Safety Communication Tools and Healthcare Professionals' Awareness of Specific Drug Safety Issues in Europe: A Survey Study. AB - INTRODUCTION: National competent authorities (NCAs) use Direct Healthcare Professional Communications (DHPCs) to communicate new drug safety issues to healthcare professionals (HCPs). More knowledge is needed about the effectiveness of DHPCs and the extent to which they raise awareness of new safety issues among HCPs. OBJECTIVE: The objective was to assess and compare general practitioners' (GPs'), cardiologists', and pharmacists' familiarity with DHPCs as communication tools, their awareness of specific drug safety issues, and the sources through which they had become aware of the specific issues. METHODS: GPs, cardiologists, and pharmacists from nine European countries (Croatia, Denmark, Ireland, Italy, the Netherlands, Norway, Spain, Sweden, and the UK) completed a web-based survey. The survey was conducted in the context of the Strengthening Collaboration for Operating Pharmacovigilance in Europe (SCOPE) Joint Action. Respondents were asked about their familiarity with DHPCs in general and their awareness of safety issues that had recently been communicated and involved the following drugs: combined hormonal contraceptives, diclofenac, valproate, and ivabradine. Those HCPs who were aware of the specific safety issues were subsequently asked to indicate the source through which they had become aware of them. Differences between professions in familiarity with DHPCs and awareness were tested using a Pearson chi2 test per country and post hoc Pearson chi2 tests in the case of statistically significant differences. RESULTS: Of the 3288 included respondents, 54% were GPs, 40% were pharmacists, and 7% were cardiologists. The number of respondents ranged from 67 in Denmark to 916 in Spain. Most respondents (92%) were familiar with DHPCs, with one significant difference between the professions: pharmacists were more familiar than GPs in Italy (99 vs 90%, P = 0.004). GPs' awareness ranged from 96% for the diclofenac issue to 70% for the ivabradine issue. A similar pattern was shown for pharmacists (91% aware of the diclofenac issue to 66% of the ivabradine issue). Cardiologists' awareness ranged from 91% for the ivabradine issue to 34% for the valproate issue. Overall, DHPCs were a common source through which GPs (range: 45% of those aware of the contraceptives issue to 60% of those aware of the valproate issue), cardiologists (range: 33% for the contraceptives issue to 61% for the valproate issue), and pharmacists (range: 41% for the contraceptives issue to 51% for the ivabradine issue) had become aware of the specific safety issues, followed by information on websites or in newsletters. CONCLUSIONS: GPs, cardiologists, and pharmacists were to a similar extent (highly) familiar with DHPCs, but they differed in awareness levels of specific safety issues. Cardiologists were less aware of safety issues associated with non-cardiology drugs even if these had cardiovascular safety concerns. This implies that additional strategies may be needed to reach specialists when communicating safety issues regarding drugs outside their therapeutic area but with risks related to their field of specialisation. DHPCs were an important source for the different professions to become aware of specific safety issues, but other sources were also often used. NCAs should consider the use of a range of sources when communicating important safety issues to HCPs. PMID- 29500796 TI - Foreword to 'Multiscale structural biology: biophysical principles and mechanisms underlying the action of bio-nanomachines', a special issue in Honour of Fumio Arisaka's 70th birthday. AB - This issue of Biophysical Reviews, titled 'Multiscale structural biology: biophysical principles and mechanisms underlying the action of bio-nanomachines', is a collection of articles dedicated in honour of Professor Fumio Arisaka's 70th birthday. Initially, working in the fields of haemocyanin and actin filament assembly, Fumio went on to publish important work on the elucidation of structural and functional aspects of T4 phage biology. As his career has transitioned levels of complexity from proteins (hemocyanin) to large protein complexes (actin) to even more massive bio-nanomachinery (phage), it is fitting that the subject of this special issue is similarly reflective of his multiscale approach to structural biology. This festschrift contains articles spanning biophysical structure and function from the bio-molecular through to the bio nanomachine level. PMID- 29500799 TI - Thromboembolism with Janus Kinase (JAK) Inhibitors for Rheumatoid Arthritis: How Real is the Risk? AB - Two different Janus kinase (JAK) inhibitors-baricitinib and tofacitinib-are effective and licensed in active rheumatoid arthritis (RA). There have been recent concerns about potential thromboembolic risks with these drugs. Concerns about baricitinib focus on clinical trial findings. Using all publically available data, we estimate thromboembolic risks are approximately five events per 1000 patient years with 4 mg baricitinib daily. Concerns about tofacitinib have been raised by analyses of the Federal Drug Administration Adverse Event Reporting System (FAERs). These show some evidence of increased risks of pulmonary thrombosis, though not pulmonary embolism or venous thrombosis. Observational studies suggest in the general population and non-RA controls there are one to four thromboembolic events per 1000 patient years. In RA, thromboembolic risks increase to three to seven per 1000 patient years. The impact of biologics and disease-modifying anti-rheumatic drugs (DMARDs) on disease risk appears minimal, and the number of thromboembolic events is between four and eight per 1000 patient years. In the short term, full details of thromboembolic events in trials of JAK inhibitors need to be published. As the numbers of thromboembolic events will be small and patients enrolled in trials are not representative of all RA patients who may receive JAK inhibitors, this information is unlikely to provide definitive answers. Consequently, in the longer term, large observational studies are needed to accurately quantify thromboembolic risks attributable to JAK inhibitors and other drugs used to treat RA, and differentiate these from risks attributable to RA itself and its comorbidities. PMID- 29500800 TI - Interest in a Mobile App for Two-Way Risk Communication: A Survey Study Among European Healthcare Professionals and Patients. AB - INTRODUCTION: Previously, an app has been developed for healthcare professionals (HCPs) and patients to report adverse drug reactions (ADRs) to national medicines agencies and to receive drug safety information. OBJECTIVE: This study aimed to assess (1) European HCPs' and patients' interest in an app for this two-way risk communication; (2) their preferences and perceptions towards specific app characteristics; and (3) which HCPs and patients are particularly interested in the app. In addition, these aspects were studied specifically for the countries where such an app was already available, i.e. Croatia, The Netherlands, and The UK. METHODS: European HCPs and patients were asked to complete a web-based survey developed in the context of the Web-Recognizing Adverse Drug Reactions (Web-RADR) project. Data on app interest and preferences and perceptions towards app characteristics were analysed descriptively. Logistic regression analyses were conducted to assess the association of HCP characteristics and patient characteristics on the level of interest in the app (i.e. very interested vs. not/somewhat interested). RESULTS: In total, 399 HCPs and 656 patients completed the survey. About half of the patients (48%; ranging from 38% from The Netherlands to 54% from The UK), and 61% of the HCPs (ranging from 42% from The Netherlands to 54% from The UK) were very interested in the app. A faster means of reporting ADRs and easier access to the reporting form were the main perceived benefits. HCPs and patients who already use a health app were particularly interested in the app (HCPs: odds ratio [OR] 3.52; 95% confidence interval [CI] 1.96-6.30, patients: OR 1.64; 95% CI 1.19-2.27). CONCLUSIONS: An app is positively perceived by HCPs and patients for reporting ADRs quickly and for receiving drug safety information from national medicines agencies. In particular, HCPs and patients who already use other health apps were interested in the app. PMID- 29500801 TI - Experimental Simulation of the Effects of Essential and Toxic Trace Elements on Thyroid Function. AB - The effects of essential (I, Se, and Zn) and toxic (Pb and Cd) trace elements on the thyroid function were studied experimentally. The protective effects of iodine, zinc, and selenium on thyroid tissue and antithyroid effects of toxic trace elements promoting a decrease in the levels of thyroid hormones (T3, T4) and imbalance of pituitary hormones (TSH) were detected. Addition of toxic trace elements to the ration of experimental rats led to their accumulation in the thyroid (0.051 MUg/g Pb and 0.190 MUg/g Cd). Negative correlations between the levels of toxic and essential trace element accumulation in the organ were detected. Essential trace elements zinc and selenium involved in thyroid hormone metabolism promoted normalization of the thyroid function. A complex of essential trace elements (I, Se, and Zn) was recommended for correction of mineral metabolism under conditions of iodine deficiency and thyroid hypofunction and in exposure to toxic trace elements. PMID- 29500802 TI - Sex Differences in the Production of SLC5A5, Thyroid Peroxidase, and Thyroid Hormones in Pubertal Rats Exposed to Endocrine Disruptor Dichlorodiphenyltrichloroethane (DDT) during Postnatal Ontogeny. AB - Sex differences in the expression of iodide transporter SLC5A5 and thyroid peroxidase in thyroid follicular epithelium and thyroid serum profile were assessed in pubertal rats exposed to endocrine disruptor DDT starting from the first postnatal day. It was found that exposure to DDT reduced expression of SLC5A5 in peripheral regions of thyroid lobes in males and in central regions in females. The most pronounced sex differences were observed in thyroid peroxidase expression that remained sensitive to thyroid stimulating hormone regulation in males and lost sensitivity to pituitary stimulation in females after exposure to disruptor, which determines more pronounced hypothyroidism in females. PMID- 29500803 TI - Cellular Composition of the B- and T-Cell-Dependent Areas in the Small Intestine during the Post-Stress Period (Experimental Study). AB - A quantitative study of lymphoid cells in the B- and T-cell-dependent areas of intestinal lymphoid nodules and mesenteric lymph nodes in behaviorally passive and active rats was performed at various periods after acute stress on the model of 1-h immobilization with simultaneous electrocutaneous stimulation. Stress exposure is accompanied by a decrease in the number of lymphoid cells in immunogenic structures of the gastrointestinal tract. Post-stress changes in the cytoarchitectonics of B- and T-cell-dependent areas in mesenteric lymph nodes of animals are less pronounced than in lymphoid nodules. Quantitative changes in lymphoid cells of B-cell-dependent areas in the small intestine of rats are greater than in T-cell-dependent areas. Changes in the cellular composition of immunogenic structures in the digestive system are most significant at the early stages of the post-stress period (1st week). Passive rats are characterized by significant changes in the cytoarchitectonics of B- and Tcell-dependent areas in the small intestine after extreme exposure, which illustrates functional exhaustion of the lymphoid tissue in stress-predisposed specimens. PMID- 29500804 TI - Nootropic Activity of a Novel (-)-Cytisine Derivative (3aR,4S,8S,12R, 12aS,12bR) 10-Methyl-2-Phenyloctahydro-1H-4,12a-Etheno-8,12 Methanopyrrolo[3',4':3,4]Pyrido[1,2-a] [1,5]Diazocine-1,3,5(4H)-Trione. AB - We performed screening of nootropic properties of 10 new derivatives of quinolizidine alkaloid (-)-cytisine. Compounds with beta-endo stereochemistry were more active than alpha-endo-isomers. Under stress conditions (3aR,4S,8S,12R,12aS,12bR)-10-methyl-2-phenyloctahydro-1H-4,12a-etheno-8,12 methanopyrrolo[3',4':3,4]pyrido[1,2-a] [1,5]diazocine-1,3,5(4H)-trione enhanced memory and had a positive effect on cognitive functions of rats. According to molecular docking data, the nootropic activity of the compound can be associated with its affinity for the glutamate-binding subunits GluK1 and GluR2 of the kainate and AMPA receptor, respectively. PMID- 29500805 TI - alpha-Tocopherol Reduces Morphological Changes and Oxidative Stress during Gentamicin-Induced Acute Renal Failure. AB - We studied the effect of alpha-tocopherol on gentamicin-induced morphological and functional changes in the kidneys of Wistar rats. Special attention was paid to the ability of alpha-tocopherol administered in combination with gentamicin to correct ultrastructural changes in the glomerular basal membrane and tubules. Combined treatment with alpha-tocopherol (100 mg/kg) and gentamicin (100 mg/kg) led to correction of histopathological and biochemical changes and oxidative injury to the kidneys induced by this antibiotic. PMID- 29500806 TI - Pumping Function of Heart Ventricles in Different Mammalian Species under Conditions of Electrical Cardiostimulation. AB - Pumping function of the heart ventricles under conditions of electrical stimulation was examined in adult dogs and rabbits. Pacing induced different changes in intracardiac hemodynamics manifested in impairment of pumping function of the right ventricle, which is largely determined by the functional state of the left ventricle. Initially high HR in rabbits more deeply limited functional reserve of the myocardium in response to electrical stimulus and was accompanied by more pronounced disturbances of pumping function of both ventricles. PMID- 29500807 TI - Effect of Physical Rehabilitation on Echocardiographic Parameters in Patients with Acute Coronary Syndrome. AB - Echocardiographic parameters were assessed in patients with non-ST segment elevation acute coronary syndrome, who underwent emergency percutaneous coronary intervention followed by various outpatient physical cardiac rehabilitation programs. The patients underwent physical rehabilitation for 3 months under conditions of diagnostic centre in the rehabilitation unit according to the standard program including in treadmill or bicycle exercise in the exercise therapy room or with Nordic walking in the main training block. After rehabilitation course, the left ventricular mass index significantly decreased and systolic volume and left ventricular ejection fraction significantly increased in both groups. Nordic walking training for 3 months non-ST segment elevation acute coronary syndrome induced similar positive shifts in the parameters of intracardiac hemodynamics, as standard treadmill or bicycle training program, which allows considering it as an alternative cardiac rehabilitation method. PMID- 29500808 TI - Changes in Activity of Cysteine Cathepsins B and L in Brain Structures of Mice with Aggressive and Depressive-Like Behavior Formed under Conditions of Social Stress. AB - We studied activity of lysosomal cysteine proteases, cathepsins B and L, in brain structures (frontal cortex, caudate nucleus, hippocampus, and hypothalamus) of C57Bl/6J mice with aggressive and depressive-like behavior formed under conditions of chronic social stress (repeated experience of victories and defeats within 20 days). Mice with depressive-like behavior showed increased activity of cathepsin V in the hypothalamus and nucleus caudatus and increased activity of cathepsin L in the hippocampus compared to control animals not subjected to agonistic confrontations. In mice with aggressive behavior, protease activity in the studied brain structures was not changed. In 4 h after immune system activation with LPS (250 MUg/kg), cathepsin L activity in the hippocampus of control mice increased in comparison with mice receiving saline. In contrast to control animals, LPS caused a decrease in activity of the enzyme in the caudate nucleus and frontal cortex of aggressive mice and in the hippocampus of mice with depressive-like behavior. PMID- 29500809 TI - Studies on ternary metallo-beta lactamase-inhibitor complexes using electrospray ionization mass spectrometry. AB - Metallo-beta-lactamases (MBLs) are targets for medicinal chemistry as they mediate bacterial resistance to beta-lactam antibiotics. Electrospray-ionization mass spectrometry (ESI-MS) was used to study the inhibition by a set of mercaptocarboxylates of two representative MBLs with different optimal metal stoichiometries for catalysis. BcII is a dizinc MBL (Class B1), whilst the CphA MBL (Class B2) exhibits highest activity with a single zinc ion in the active site. Experimental parameters for the detection of the metallo-enzyme and the metallo-enzyme-inhibitor complexes were evaluated and optimized. Following investigations on the stoichiometry of metal binding, the affinity of the inhibitors was investigated by measuring the relative abundance of the complex compared to the metalloprotein. The results for the BcII enzyme were in general agreement with solution assays and demonstrated that the inhibitors bind to the dizinc form of the BcII enzyme. The results for the CphA(ZnII) complex unexpectedly revealed an increased affinity for the binding of a second metal ion in the presence of thiomandelic acid. The results demonstrate that direct ESI-MS analysis of enzyme:inhibitor complexes is a viable method for screening inhibitors and for the rapid assay of the enzyme:metal:inhibitor ratios. PMID- 29500810 TI - Nutritional Value of Commercial Protein-Rich Plant Products. AB - The goal of this work was to analyze nutritional value of various minimally processed commercial products of plant protein sources such as faba bean (Vicia faba), lupin (Lupinus angustifolius), rapeseed press cake (Brassica rapa/napus subsp. Oleifera), flaxseed (Linum usitatissimum), oil hemp seed (Cannabis sativa), buckwheat (Fagopyrum esculentum), and quinoa (Chenopodium quinoa). Basic composition and various nutritional components like amino acids, sugars, minerals, and dietary fiber were determined. Nearly all the samples studied could be considered as good sources of essential amino acids, minerals and dietary fiber. The highest content of crude protein (over 30 g/100 g DW) was found in faba bean, blue lupin and rapeseed press cake. The total amount of essential amino acids (EAA) ranged from 25.8 g/16 g N in oil hemp hulls to 41.5 g/16 g N in pearled quinoa. All the samples studied have a nutritionally favorable composition with significant health benefit potential. Processing (dehulling or pearling) affected greatly to the contents of analyzed nutrients. PMID- 29500811 TI - Efficacy of Propranolol, Bisoprolol, and Pyridostigmine for Postural Tachycardia Syndrome: a Randomized Clinical Trial. AB - : Postural tachycardia syndrome (POTS) is a form of dysautonomia which presents with complex symptoms including orthostatic intolerance. Several medications are prescribed for POTS; however, the efficacy of sustained medical treatment has not been well-investigated. Here, we conducted a 2 * 2 factorial design, randomized, clinical trial of a 3-month medical treatment regimen in POTS patients. Patients were randomly allocated to 4 treatment groups (Group 1: propranolol; Group 2: bisoprolol; Group 3: propranolol + pyridostigmine; Group 4: bisoprolol + pyridostigmine). The orthostatic intolerance questionnaire (OIQ), Beck depression inventory-II (BDI-II), and short-form health survey (SF-36) were conducted at baseline, 1 and 3 months after treatment. Seventy-seven patients who completed the 3-month follow-up were analyzed. In total, every clinical score improved significantly after medical treatment. The OIQ score was significantly lower than that at baseline (18.5 +/- 6.7) after 1 month (12.5 +/- 4.5, P < 0.01), which decreased further after 3 months (7.8 +/- 5.7, P < 0.01). The OIQ score improvements were consistent across every treatment group. In the subgroup analysis of 59 patients who did not receive antidepressants, the BDI-II score significantly decreased after treatment, regardless of the regimen. Physical components of the SF-36 improved after 3 months in every group, while mental components improved only in Group 3. The amount of changes in each score was similar among groups throughout the comparisons. Sustained medical treatment is beneficial to POTS patients, not only for orthostatic intolerance symptoms but also for depression and diminished quality of life, even without prescriptions for antidepressants. The efficacy of each regimen in POTS patients was comparable. TRIAL REGISTRATION: NCT02171988. PMID- 29500812 TI - Acute ocular pain during magnetic resonance imaging due to retained intraocular metallic foreign body: the role of ultrasonography and ultrasound biomicroscopy in diagnosis and management of this condition. AB - PURPOSE: To report the case of a 65-year-old metalworker with no known history of ocular trauma, who suffered from intense ocular pain during magnetic resonance imaging (MRI) of the brain, due to a retained intraocular metallic foreign body (IOFB). CASE REPORT: Meticulous ophthalmological examination was inconclusive. An IOFB was confirmed with X-ray scan, whereas its exact localization was enabled by means of ultrasonography and ultrasound biomicroscopy (UBM). CONCLUSIONS: Despite appropriate screening protocols, MRI-related ocular complications might occur in the presence of a hidden metallic IOFB. Clinical detection of ocular foreign bodies can sometimes be challenging. Ultrasonography and UBM are valuable adjuncts for the accurate localization, especially of small or hidden particles. PMID- 29500813 TI - Measurements of auto-antibodies to alpha-synuclein in the serum and cerebral spinal fluids of patients with Parkinson's disease. AB - Biomarkers for alpha-synuclein are needed for diagnosis and prognosis in Parkinson's disease (PD). Endogenous auto-antibodies to alpha-synuclein could serve as biomarkers for underlying synucleinopathy, but previous assessments of auto-antibodies have shown variability and inconsistent clinical correlations. We hypothesized that auto-antibodies to alpha-synuclein could be diagnostic for PD and explain its clinical heterogeneity. To test this hypothesis, we developed an enzyme-linked immunosorbent assay for measuring alpha-synuclein auto-antibodies in human samples. We evaluated 69 serum samples (16 healthy controls (HC) and 53 PD patients) and 145 CSF samples (52 HC and 93 PD patients) from our Institution. Both serum and CSF were available for 24 participants. Males had higher auto antibody levels than females in both fluids. CSF auto-antibody levels were significantly higher in PD patients as compared with HC, whereas serum levels were not significantly different. CSF auto-antibody levels did not associate with amyloid-beta1-42 , total tau, or phosphorylated tau. CSF auto-antibody levels correlated with performance on the Montreal Cognitive Assessment, even when controlled for CSF amyloidbeta1-42 . CSF hemoglobin levels, as a proxy for contamination of CSF by blood during lumbar puncture, did not influence these observations. Using recombinant alpha-synuclein with N- and C-terminal truncations, we found that CSF auto-antibodies target amino acids 100 through 120 of alpha-synuclein. We conclude that endogenous CSF auto-antibodies are significantly higher in PD patients as compared with HC, suggesting that they could indicate the presence of underlying synucleinopathy. These auto-antibodies associate with poor cognition, independently of CSF amyloidbeta1-42 , and target a select C-terminal region of alpha-synuclein. Read the Editorial Highlight for this article on page 433. PMID- 29500814 TI - Predicting Potential Adverse Events During a Skilled Nursing Facility Stay: A Skilled Nursing Facility Prognosis Score. AB - OBJECTIVES: To derive a risk prediction score for potential adverse outcomes in older adults transitioning to a skilled nursing facility (SNF) from the hospital. DESIGN: Retrospective analysis. SETTING: Medicare Current Beneficiary Survey (2003-11). PARTICIPANTS: Previously community-dwelling Medicare beneficiaries who were hospitalized and discharged to SNF for postacute care (N=2,043). MEASUREMENTS: Risk factors included demographic characteristics, comorbidities, health status, hospital length of stay, prior SNF stays, SNF size and ownership, treatments received, physical function, and active signs or symptoms at time of SNF admission. The primary outcome was a composite of undesirable outcomes from the patient perspective, including hospital readmission during the SNF stay, long SNF stay (>=100 days), and death during the SNF stay. RESULTS: Of the 2,043 previously community-dwelling beneficiaries hospitalized and discharged to a SNF for post-acute care, 589 (28.8%) experienced one of the three outcomes, with readmission (19.4%) most common, followed by mortality (10.5%) and long SNF stay (3.5%). A risk score including 5 factors (Barthel Index, Charlson-Deyo comorbidity score, hospital length of stay, heart failure diagnosis, presence of an indwelling catheter) demonstrated very good discrimination (C-statistic=0.75), accuracy (Brier score=0.17), and calibration for observed and expected events. CONCLUSION: Older adults frequently experience potentially adverse outcomes in transitions to a SNF from the hospital; this novel score could be used to better match resources with patient risk. PMID- 29500815 TI - Role of G protein-coupled receptor kinase 2 in oxidative and nitrosative stress related neurohistopathological changes in a mouse model of sepsis-associated encephalopathy. AB - Sepsis-associated encephalopathy (SAE), characterized as diffuse brain dysfunction and neurological manifestations secondary to sepsis, is a common complication in critically ill patients and can give rise to poor outcome, but understanding the molecular basis of this disorder remains a major challenge. Given the emerging role of G protein-coupled receptor 2 (GRK2), first identified as a G protein-coupled receptor (GPCR) regulator, in the regulation of non-G protein-coupled receptor-related molecules contributing to diverse cellular functions and pathology, including inflammation, we tested the hypothesis that GRK2 may be linked to the neuropathogenesis of SAE. When mouse MG6 microglial cells were challenged with lipopolysaccharide (LPS), GRK2 cytosolic expression was highly up-regulated. The ablation of GRK2 by small interfering RNAs (siRNAs) prevented an increase in intracellular reactive oxygen species generation in LPS stimulated MG6 cells. Furthermore, the LPS-induced up-regulation of inducible nitric-oxide synthase expression and increase in nitric oxide production were negated by GRK2 inhibitor or siRNAs. However, GRK2 inhibition was without effect on overproduction of tumor necrosis factor-alpha, interleukin (IL)-6, and IL 1beta in LPS-stimulated MG cells. In mice with cecal ligation and puncture induced sepsis, treatment with GRK2 inhibitor reduced high levels of oxidative and nitrosative stress in the mice brains, where GRK2 expression was up regulated, alleviated neurohistological damage observed in cerebral cortex sections, and conferred a significant survival advantage to CLP mice. Altogether, these results uncover the novel role for GRK2 in regulating cellular oxidative and nitrosative stress during inflammation and suggest that GRK2 may have a potential as an intriguing therapeutic target to prevent or treat SAE. PMID- 29500816 TI - A deep 3D residual CNN for false-positive reduction in pulmonary nodule detection. AB - PURPOSE: The automatic detection of pulmonary nodules using CT scans improves the efficiency of lung cancer diagnosis, and false-positive reduction plays a significant role in the detection. In this paper, we focus on the false-positive reduction task and propose an effective method for this task. METHODS: We construct a deep 3D residual CNN (convolution neural network) to reduce false positive nodules from candidate nodules. The proposed network is much deeper than the traditional 3D CNNs used in medical image processing. Specifically, in the network, we design a spatial pooling and cropping (SPC) layer to extract multilevel contextual information of CT data. Moreover, we employ an online hard sample selection strategy in the training process to make the network better fit hard samples (e.g., nodules with irregular shapes). RESULTS: Our method is evaluated on 888 CT scans from the dataset of the LUNA16 Challenge. The free response receiver operating characteristic (FROC) curve shows that the proposed method achieves a high detection performance. CONCLUSIONS: Our experiments confirm that our method is robust and that the SPC layer helps increase the prediction accuracy. Additionally, the proposed method can easily be extended to other 3D object detection tasks in medical image processing. PMID- 29500817 TI - Effect of noise on MTF calculations using different phantoms. AB - PURPOSE: In this work, the effect of noise on the precision in the modulation transfer function (MTF) calculation using different phantoms is investigated. Three different techniques are studied, based on three different phantoms: edge, bar, and star bar. For each technique, theoretical expressions for the standard deviation and the signal to noise ratio (SNR) of the MTF are derived. In addition, Monte Carlo simulations are carried out to study the accuracy and precision of all the three techniques. METHODS: Using the analytic expressions for the MTF calculation, statistical fluctuations of noise in the phantom images are propagated to MTF values. Then, for each frequency the standard deviation and the SNR of the MTF are calculated. Monte Carlo simulations are carried out for each phantom image and for different noise level. Images are artificially generated following a procedure that simulates sampling, blurring, and noise present in a real phantom image and takes into account the attenuation of each phantom. Then, oversampling procedures are applied to these images to obtain presampled MTFs. RESULTS: In all three techniques the standard deviation of the MTF is proportional to that of the noise in the image. For the edge image, the standard deviation is proportional to the frequency f, whereas for the bar and star bar techniques it is proportional to the square root of f. Regarding the precision, theoretical expressions and simulations results agree that the bar technique shows the best precision for all the frequencies and all the noise levels analyzed in this study. In addition, simulation results show how, for large levels of noise, the edge technique gives rise to large bias errors at high and medium frequencies. Finally, the precision of the star bar technique is similar to that of the bar technique for isotropic systems, but worse for nonisotropic ones. CONCLUSION: The uncertainties in the MTF calculation with the edge technique are larger than with the bar technique, and the differences increase with the frequency. On the one hand, the stronger dependency on the frequency shown by the standard deviation of the MTF makes the precision gets worse faster in the edge technique. On the other hand, in the case of the edge and for high levels of noise, differentiation produces line spread functions (LSF) with a poor SNR, increasing erroneously the MTF and worsening accuracy. PMID- 29500818 TI - A machine learning approach to the accurate prediction of monitor units for a compact proton machine. AB - PURPOSE: Clinical treatment planning systems for proton therapy currently do not calculate monitor units (MUs) in passive scatter proton therapy due to the complexity of the beam delivery systems. Physical phantom measurements are commonly employed to determine the field-specific output factors (OFs) but are often subject to limited machine time, measurement uncertainties and intensive labor. In this study, a machine learning-based approach was developed to predict output (cGy/MU) and derive MUs, incorporating the dependencies on gantry angle and field size for a single-room proton therapy system. The goal of this study was to develop a secondary check tool for OF measurements and eventually eliminate patient-specific OF measurements. METHOD: The OFs of 1754 fields previously measured in a water phantom with calibrated ionization chambers and electrometers for patient-specific fields with various range and modulation width combinations for 23 options were included in this study. The training data sets for machine learning models in three different methods (Random Forest, XGBoost and Cubist) included 1431 (~81%) OFs. Ten-fold cross-validation was used to prevent "overfitting" and to validate each model. The remaining 323 (~19%) OFs were used to test the trained models. The difference between the measured and predicted values from machine learning models was analyzed. Model prediction accuracy was also compared with that of the semi-empirical model developed by Kooy (Phys. Med. Biol. 50, 2005). Additionally, gantry angle dependence of OFs was measured for three groups of options categorized on the selection of the second scatters. Field size dependence of OFs was investigated for the measurements with and without patient-specific apertures. RESULTS: All three machine learning methods showed higher accuracy than the semi-empirical model which shows considerably large discrepancy of up to 7.7% for the treatment fields with full range and full modulation width. The Cubist-based solution outperformed all other models (P < 0.001) with the mean absolute discrepancy of 0.62% and maximum discrepancy of 3.17% between the measured and predicted OFs. The OFs showed a small dependence on gantry angle for small and deep options while they were constant for large options. The OF decreased by 3%-4% as the field radius was reduced to 2.5 cm. CONCLUSION: Machine learning methods can be used to predict OF for double-scatter proton machines with greater prediction accuracy than the most popular semi-empirical prediction model. By incorporating the gantry angle dependence and field size dependence, the machine learning-based methods can be used for a sanity check of OF measurements and bears the potential to eliminate the time-consuming patient-specific OF measurements. PMID- 29500819 TI - Cyclic AMP-producing chemogenetic activation of indirect pathway striatal projection neurons and the downstream effects on the globus pallidus and subthalamic nucleus in freely moving mice. AB - The indirect pathway striatal medium spiny projection neurons (iMSNs) are critical to motor and cognitive brain functions. These neurons express a high level of cAMP-increasing adenosine A2a receptors. However, the potential effects of cAMP production on iMSN spiking activity have not been established, and recording identified iMSNs in freely moving animals is challenging. Here, we show that in the transgenic mice expressing cAMP-producing G protein Gs -coupled designer receptor exclusively activated by designer drug (Gs-DREADD) in iMSNs, the baseline spike firing in MSNs is normal, indicating DREADD expression does not affect the normal physiology of these neurons. Intraperitoneal injection of the DREADD agonist clozapine-N-oxide (CNO; 2.5 mg/kg) increased the spike firing in 50% of the recorded MSNs. However, CNO did not affect MSN firing in Gs-DREADD negative mice. We also found that CNO injection inhibited the spike firing of globus pallidus external segment (GPe) neurons in Gs-DREADD-positive mice, further indicating CNO excitation of iMSNs. Temporally coincident with these effects on spiking firing in the indirect pathway, CNO injection selectively inhibited locomotion in D2 Gs-DREADD mice. Taken together, our results strongly suggest that cAMP production in iMSNs can increase iMSN spiking activity and cause motor inhibition, thus addressing a long-standing question about the cellular functions of the cAMP-producing adenosine A2a receptors in iMSNs. Cover Image for this issue: doi: 10.1111/jnc.14181. PMID- 29500820 TI - Activity of novel lipid glycine transporter inhibitors on synaptic signalling in the dorsal horn of the spinal cord. AB - BACKGROUND AND PURPOSE: Inhibitory neurotransmission plays an important role in controlling excitability within nociceptive circuits of the spinal cord dorsal horn. Loss of inhibitory signalling is thought to contribute to the development of pathological pain. Preclinical studies suggest that increasing inhibitory glycinergic signalling is a good therapeutic strategy for treating pain. One approach to increase synaptic glycine is to inhibit the activity of the glycine transporter 2 (GlyT2) on inhibitory nerve terminals. These transporters are involved in regulating glycine concentrations and recycling glycine into presynaptic terminals. Inhibiting activity of GlyT2 increases synaptic glycine, which decreases excitability in nociceptive circuits and provides analgesia in neuropathic and inflammatory pain models. EXPERIMENTAL APPROACH: We investigated the effects of reversible and irreversible GlyT2 inhibitors on inhibitory glycinergic and NMDA receptor-mediated excitatory neurotransmission in the rat dorsal horn. The effect of these drugs on synaptic signalling was determined using patch-clamp electrophysiology techniques to measure glycine- and NMDA mediated postsynaptic currents in spinal cord slices in vitro. KEY RESULTS: We compared activity of four compounds that increase glycinergic tone with a corresponding increase in evoked glycinergic postsynaptic currents. These compounds did not deplete synaptic glycine release over time. Interestingly, none of these compounds increased glycine-mediated excitatory signalling through NMDA receptors. The results suggest that these compounds preferentially inhibit GlyT2 over G1yT1 with no potentiation of the glycine receptor and without inducing spillover from inhibitory to excitatory synapses. CONCLUSIONS AND IMPLICATIONS: GlyT2 inhibitors increase inhibitory neurotransmission in the dorsal horn and have potential as pain therapeutics. LINKED ARTICLES: This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc. PMID- 29500822 TI - Minimum Data Set Changes in Health, End-Stage Disease and Symptoms and Signs Scale: A Revised Measure to Predict Mortality in Nursing Home Residents. AB - OBJECTIVES: To revise the Minimum Data Set (MDS) Changes in Health, End-stage disease and Symptoms and Signs (CHESS) scale, an MDS 2.0-based measure widely used to predict mortality in institutional settings, in response to the release of MDS 3.0. DESIGN: Development of a predictive scale using observational data from the MDS and Medicare Master Beneficiary Summary File. SETTING: All Centers for Medicare and Medicaid Services (CMS)-certified nursing homes in the United States. PARTICIPANTS: Development cohort of 1.3 million Medicare beneficiaries newly admitted to a CMS-certified nursing home during 2012. Primary validation cohort of 1.2 million Medicare recipients who were newly admitted to a CMS certified nursing home during 2013. MEASUREMENTS: Items from the MDS 3.0 assessments identified as likely to predict mortality. Death information was obtained from the Medicare Master Beneficiary Summary File. RESULTS: MDS-CHESS 3.0 scores ranges from 0 (most stable) to 5 (least stable). Ninety-two percent of the primary validation sample with a CHESS scale score of 5 and 15% with a CHESS scale of 0 died within 1 year. The risk of dying was 1.63 times as great (95% CI=1.628-1.638) for each unit increase in CHESS scale score. The MDS-CHESS 3.0 is also strongly related to hospitalization within 30 days and successful discharge to the community. The scale predicted death in long-stay residents at 30 days (C=0.759, 95% confidence interval (CI)=0.756-0.761), 60 days (C=0.716, 95% CI=0.714-0.718) and 1 year (C=0.655, 95% CI=0.654-0.657). CONCLUSION: The MDS CHESS 3.0 predicts mortality in newly admitted and long-stay nursing home populations. The additional relationship to hospitalizations and successful discharges to community increases the utility of this scale as a potential risk adjustment tool. PMID- 29500824 TI - Rational Suicide in Elderly Adults: A Clinician's Perspective. AB - Geriatricians are increasingly encountering older adults expressing suicidal wishes in the absence of overt mental illness. This is expected to grow as life expectancy increases. This article describes the case of an older adult who expressed the wish to end his life in the absence of a diagnosable mental illness. Although he had chronic medical illnesses, he was not terminally ill. The complex subject of rational suicide in elderly adults is approached from a clinician's perspective. Issues of ageism, gerontophobia, and changing perspectives on death are highlighted. The experience of being a Baby Boomer and its influence on rational suicide is reviewed. Finally, clinical topics such as aging, frailty, dependence on younger and healthier individuals, and the older adult's need for a sense of control are explored. PMID- 29500823 TI - Brain-resident memory CD8+ T cells induced by congenital CMV infection prevent brain pathology and virus reactivation. AB - Congenital HCMV infection is a leading infectious cause of long-term neurodevelopmental sequelae. Infection of newborn mice with mouse cytomegalovirus (MCMV) intraperitoneally is a well-established model of congenital human cytomegalovirus infection, which best recapitulates the hematogenous route of virus spread to brain and subsequent pathology. Here, we used this model to investigate the role, dynamics, and phenotype of CD8+ T cells in the brain following infection of newborn mice. We show that CD8+ T cells infiltrate the brain and form a pool of tissue-resident memory T cells (TRM cells) that persist for lifetime. Adoptively transferred virus-specific CD8+ T cells provide protection against primary MCMV infection in newborn mice, reduce brain pathology, and remain in the brain as TRM cells. Brain CD8+ TRM cells were long lived, slowly proliferating cells able to respond to local challenge infection. Importantly, brain CD8+ TRM cells controlled latent MCMV and their depletion resulted in virus reactivation and enhanced inflammation in brain. PMID- 29500821 TI - Hemopexin increases the neurotoxicity of hemoglobin when haptoglobin is absent. AB - Hemopexin (Hpx) binds heme with extraordinary affinity, and after haptoglobin may provide a second line of defense against the toxicity of extracellular hemoglobin (Hb). In this series of experiments, the hypothesis that Hpx protects neurons from Hb neurotoxicity was evaluated in murine primary cultures containing neurons and glial cells. Contrary to hypothesis, Hpx increased neuronal loss due to micromolar concentrations of Hb by 4- to 12-fold, as measured by LDH release assay; conversely, the neurotoxicity of hemin was completely prevented. The endogenous fluorescence of Hpx was quenched by Hb, consistent with transfer of Hb bound heme to Hpx. This was associated with precipitation of globin chains, as detected by immunostaining and fluorescent Hb labeling. A portion of this precipitate attached firmly to cells and could not be removed by multiple washes. Concomitant treatment with haptoglobin (Hp) prevented globin precipitation and most of the increase in neuronal loss. Hpx weakly attenuated the increase in culture non-heme iron produced by Hb treatment, quantified by ferrozine assay. However, Hb-Hpx toxicity was iron-dependent, and was blocked by deferoxamine and ferrostatin-1. Up-regulation of cell ferritin expression, a primary cell defense against Hb toxicity, was not observed on western blots of culture lysates that had been concomitantly treated with Hpx. These results suggest that Hpx destabilizes Hb in the absence of haptoglobin, leading to globin precipitation and exacerbation of iron-dependent oxidative cell injury. Combined therapy with hemopexin plus haptoglobin may be preferable to hemopexin alone after CNS hemorrhage. PMID- 29500825 TI - Case of punctate palmoplantar keratoderma type I treated with combination of low dose oral acitretin and topical salicylic acid and steroid. AB - Palmoplantar keratodermas (PPK) are heterogeneous disorders characterized by abnormal keratinization. Especially, punctate PPK (PPPK), one of the subtypes of hereditary PPK, is a rare punctate keratoderma characterized by tiny "raindrop" keratoses having a tendency to coalesce on the edge of soles, which are exposed to sustained pressure. If typical punctate lesions are confined to the palms and soles and the patient has a family history and late onset, it can be considered as PPPK type I (PPKP1), also called Buschke-Fisher-Brauer disease. The exact etiology of PPPK has not been fully understood. Furthermore, no standardized treatment for PPPK has been established and treatment options are limited. Above all, traditional systemic retinoids have been used in several cases, but dose related adverse effects are common. Therefore, combination of low-dose systemic retinoids and adjuvant topical therapy can be an alternative treatment option for PPPK. Herein, we report a case of PPKP1 treated with combination of low-dose oral acitretin (10 mg/day) and topical salicylic acid and steroid. Despite low capacity, low-dose acitretin showed excellent regression of the lesions by combined use of topical ointments. The supplementary topical therapy may be useful in reducing the dose of systemic retinoids and preventing potential toxicity. PMID- 29500826 TI - Social Causes of Rational Suicide in Older Adults. PMID- 29500827 TI - Concordance between point-of-care blood gas analysis and laboratory autoanalyzer in measurement of hemoglobin and electrolytes in critically ill patients. AB - BACKGROUND: We tested the hypothesis that the results of the same test performed on point-of-care blood gas analysis (BGA) machine and automatic analyzer (AA) machine in central laboratory have high degree of concordance in critical care patients and that the two test methods could be used interchangeably. METHODS: We analyzed 9398 matched pairs of BGA and AA results, obtained from 1765 patients. Concentration pairs of the following analytes were assessed: hemoglobin, glucose, sodium, potassium, chloride, and bicarbonate. We determined the agreement using concordance correlation coefficient (CCC) and Bland-Altman analysis. The difference in results was also assessed against the United States Clinical Laboratory Improvement Amendments (US-CLIA) 88 rules. The test results were considered to be interchangeable if they were within the US-CLIA variability criteria and would not alter the clinical management when compared to each other. RESULTS: The median time interval between sampling for BGA and AA in each result pair was 5 minutes. The CCC values ranged from 0.89(95% CI 0.89-0.90) for chloride to 0.98(95% CI 0.98-0.99) for hemoglobin. The largest bias was for hemoglobin. The limits of agreement relative to bias were largest for sodium, with 3.4% of readings outside the US-CLIA variation rule. The number of readings outside the US-CLIA acceptable variation was highest for glucose (7.1%) followed by hemoglobin (5.9%) and chloride (5.2%). CONCLUSION: We conclude that there is moderate to substantial concordance between AA and BGA machines on tests performed in critically ill patients. However, the two tests methods cannot be used interchangeably, except for potassium. PMID- 29500828 TI - Imagery rescripting and cognitive dissonance: A randomized controlled trial of two brief online interventions for women at risk of developing an eating disorder. AB - OBJECTIVE: This pilot study compared two brief online interventions, imagery rescripting and cognitive dissonance, to an assessment-only control condition in a sample of body-dissatisfied young women at risk of developing an eating disorder. We examined the degree to which each intervention reduced disordered eating and modified risk and protective factors for eating disorders. METHOD: Female university students (N = 107, 17-28 years of age) completed a screening questionnaire, followed by random allocation to one of the three conditions, followed by a baseline assessment, body dissatisfaction induction, and brief online intervention. Participants in the active conditions then completed online daily home practice and a postintervention questionnaire. RESULTS: Findings provide qualified support for the imagery rescripting intervention, with participants reporting higher body image acceptance (Cohen's d = 0.49) than the cognitive dissonance condition, and higher self-compassion (d = 0.59) and lower levels of disordered eating (d = 0.59) than the control condition, at postintervention. There was no significant impact of cognitive dissonance on any factors. Change in body image acceptance and self-compassion mediated the relationship between allocated condition and change in disordered eating at postintervention. DISCUSSION: These findings provide preliminary support for the use of online-adapted imagery-based techniques (e.g., imagery rescripting) to reduce risk for the development of an eating disorder by strengthening protective factors (i.e., body image acceptance and self-compassion) and reducing disordered eating. Further exploration of the use of imagery strategies in the prevention of disordered eating is required, including prospective tests of the mechanisms of action. PMID- 29500829 TI - Preparation, characterization, and pharmacokinetics in swine of a florfenicol enteric formulation prepared using hot-melt extrusion technology. AB - The objective of this work was to manufacture an enteric formulation of florfenicol (FF) using hot-melt extrusion (HME) technology and to evaluate its in vitro dissolution and in vivo pharmacokinetics. For the HME process, hypromellose acetate succinate LG (HPMCAS-LG) was the enteric polymer mixed with FF, and the two components were extruded with a standard screw configuration at a speed of 50 rpm. Differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), powder X-ray diffraction (PXRD), and Fourier transform infrared spectroscopy (FT IR) were performed to characterize the HME extrudate. The release percentage of the enteric formulation in the acidic stage was <10% of the loaded FF, whereas that in the phosphate buffer stage was >80%. Pharmacokinetic evaluations in swine revealed that the enteric formulation had a longer t1/2lambda and MRT than commercially available FF powder (FULAIKA(r) ), indicating that the novel formulation exhibited enteric and sustained release properties. Compared with the commercial product, the relative bioavailability of the enteric formulation reached up to 117.2%. This study suggests that this formulation may have potential for future commercialization. PMID- 29500830 TI - Changes in salivary chromogranin A levels in adults with atopic dermatitis are correlated with changes in their condition. AB - Stress-induced scratching is an issue in patients with adult atopic dermatitis (AD). Symptoms of stress-induced AD are common in clinical practise. Salivary chromogranin A (CgA) level has research value as a possible index related to a patient's psychological stress. Using saliva, which is easily collectable, we compared two assessments of the severities of AD and stress with the levels of stress proteins in the saliva of 30 patients with AD in the Department of Dermatology of Shimane University between April 2015 and May 2017. The severities of AD and stress were assessed using the Scoring Atopic Dermatitis (SCORAD) score and State-Trait Anxiety Inventory score, respectively. Additionally, the assessments included those of personality using the Tokyo University Egogram (TEG)-II score and quality of life using the Dermatology Life Quality Index score. Simultaneously, we measured their salivary CgA levels. The change in salivary CgA per protein in patients with AD was correlated with their changes in SCORAD score (correlation coefficient, r = 0.596, P = 0.001) and objective SCORAD (r = 0.608, P < 0.001). The changes in CgA per protein correlated with those in TEG-II A (r = 0.370, P = 0.022), while the changes in SCORAD score correlated with those in DLQI (r = 0.309, P = 0.048). Our results suggest that changes in a patient's condition are reflective of the changes in the patient's stress. The changes in salivary CgA level in patients with AD correlated with the changes in their condition. PMID- 29500831 TI - Mediation analysis of systemic inflammation on the association between periodontitis and glycaemic status. AB - AIM: This cross-sectional study investigated the associations between periodontitis, systemic inflammation and glycaemic status. MATERIALS AND METHODS: The participants were divided into three groups: normoglycaemia, impaired fasting glucose (IFG) and diabetes. Multinomial logistic regression was used to examine the associations between periodontitis severity and glycaemic status, adjusting for potential confounders. Mediation analysis of four systemic inflammatory biomarkers, C-reactive protein (CRP), white blood cell count (WBC), neutrophil lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR), was performed. RESULTS: This study comprised 2,036 participants, aged 39-66 years. Severe periodontitis was associated with IFG and diabetes with odds ratios of 1.6 (95% confidence interval [CI]: 1.1-2.4, p = .023) and 2.4 (95% CI: 1.3-4.5, p = .006), respectively. The CRP, WBC and PLR were associated with both periodontitis severity and glycaemic status (p < .05). In contrast, the NLR was associated with periodontitis severity (p < .05) but not glycaemic status (p > .05). The CRP, WBC and PLR mediated 8%, 13% and 6%, respectively, of the association between severe periodontitis and diabetes. Similar proportions mediated were observed for the periodontitis-IFG association. CONCLUSIONS: Our findings support the role of systemic inflammation as mediators of the associations between periodontitis and IFG or diabetes. PMID- 29500832 TI - Improved diagnosis in nonimmune hydrops fetalis using a standardized algorithm. PMID- 29500833 TI - Splice site mutation in COL7A1 resulting in aberrant in-frame transcripts identified in a case of recessive dystrophic epidermolysis bullosa, pretibial. AB - Dystrophic epidermolysis bullosa (DEB), pretibial, a rare subtype of epidermolysis bullosa (EB), is characterized by recurrent blisters and erosions predominantly on the pretibial region. We report the case of a 60-year-old Japanese woman with persistent blistering eruptions and scar formation on the pretibial region and elbows. Mutational analysis revealed a previously reported c.5797C>T mutation in exon 70 (p.R1933X) and a novel c.6348+1G>A mutation in intron 76 of COL7A1. Reverse transcription polymerase chain reaction revealed that the c.6348+1G>A mutation resulted in the skipping of exon 76 (69 bp) and the retention of intron 76 (75 bp), and both transcripts were in-frame. From these results, we diagnosed the patient as having recessive DEB, pretibial. A review of previously reported mutations in DEB, pretibial, revealed that one-third of DEB, pretibial, cases showed a recessive inheritance pattern, and no case had a combination of premature termination codon (PTC)/PTC mutations. The DEB, pretibial, case described herein is the first reported case of a compound heterozygote with PTC/in-frame mutations. Although no special characteristic features of the mutations were identified, a high diversity of COL7A1 mutations was shown even in DEB, pretibial. PMID- 29500834 TI - Dual-opposite multi-walled carbon nanotube modified carbon fiber microelectrode for microfluidic chip-capillary electrophoresis determination of methyl parathion metabolites in human urine. AB - Methyl parathion (MP) is a highly toxic organophosphate and its exposure may lead to substantial adverse effects to human health. The existence of 4-nitrophenol (4 NP) in the form of free phenol, glucuronide (4-NP-G) or as a sulfate ester (4-NP S) can be used as biomarkers to assess the duration and extent of MP exposure. In this work, a MC-CE device incorporating post-CE amperometric detection using multi-walled carbon nanotubes (MWNTs) modified carbon fiber microelectrode (CFME) was fabricated and assessed for simultaneous determination of 4-NP, 4-NP-G, and 4 NP-S in human urine. The detection sensitivity and stability was greatly enhanced by the modification of MWNTs. The capability of the MC-CE device with dual MWNTs modified CFME for detecting impurity was assessed and reliability established by high recoveries from 95 to 97% for spiked MP biomarkers. The method developed is shown to provide a simple, sensitive, and reliable means for monitoring 4-NP, 4 NP-G, and 4-NP-S in human urine. PMID- 29500835 TI - Childhood adverse life events, disordered eating, and body mass index in US Military service members. AB - OBJECTIVE: US service members appear to be at high-risk for disordered eating. Further, the military is experiencing unprecedented prevalence of overweight and obesity. US service members also report a high prevalence of childhood adverse life event (ALE) exposure. Despite consistent links between early adversity with eating disorders and obesity, there is a dearth of research examining the association between ALE exposure and disordered eating and weight in military personnel. METHOD: An online survey study was conducted in active duty personnel to examine childhood ALE history using the Life Stressor Checklist - Revised, disordered eating using the Eating Disorder Examination - Questionnaire total score, and self-reported body mass index (BMI, kg/m2 ). RESULTS: Among 179 respondents, multiple indices of childhood ALE were positively associated with disordered eating. Traumatic childhood ALE and subjective impact of childhood ALE were associated with higher BMI and these associations were mediated by disordered eating. DISCUSSION: Findings support evaluating childhood ALE exposure among service members with disordered eating and weight concerns. Moreover, findings support the need for prospective research to elucidate these relationships. PMID- 29500836 TI - The effect of decellularized tissue engineered constructs on periodontal regeneration. AB - AIM: To evaluate the effect of decellularized tissue engineered constructs on cell differentiation in vitro and periodontal regeneration in vivo. MATERIALS AND METHODS: Periodontal ligament cell (PDLC) sheets were loaded on polycaprolactone (PCL) scaffolds and then decellularized. Constructs were assessed for their effect on allogenic PDLC and mesenchymal stem cell (MSC) differentiation in vitro, as evaluated by gene expression of bone and periodontal ligament tissue markers post-seeding. Expression of MSC marker STRO-1 was assessed by immunostaining. Decellularized constructs were evaluated in a rat periodontal defect model to assess their biocompatibility and tissue integration. Microcomputed topography (MUCT) and histological assessment were performed to assess the regenerative potential of the constructs at 2 and 4 weeks postoperatively. RESULTS: There was upregulation of bone marker gene expression by PDLCs especially on the 14th day. MSCs lacked bone markers expression, but showed increased collagen I marker expression on day 14. STRO-1 expression by the MSCs decreased over the three timepoints when seeded on decellularized sheets. Histological assessment demonstrated the biocompatibility of the decellularized constructs in vivo. More new attachment formation was observed on the decellularized constructs compared to scaffold only controls. CONCLUSION: Decellularized tissue engineered constructs are capable of inducing cell differentiation in vitro and have the potential to facilitate periodontal regeneration in vivo. PMID- 29500837 TI - Investigation of factors that influence pain experienced and the use of pain medication following periodontal surgery. AB - AIMS: To determine the relationship between anticipated pain and actual pain experienced following soft tissue grafting or implant surgery; to identify the factors that predict actual pain experienced and the use of pain medication following soft tissue grafting or implant surgery. MATERIALS AND METHODS: Prior to dental implant placement (n = 98) or soft tissue grafting (n = 115) and for seven days following the procedure, patients completed a visual analog scale indicating anticipated or experienced pain, respectively. The use of pain medication and alcohol, and smoking were measured. RESULTS: Actual pain experienced on day 1 was lower (p < .01) than anticipated pain and continued to decrease (p <= .01) for each of the 7 consecutive days. Anticipated and actual pain were positively correlated. Increasing age (p < .05), having sedation during the surgery (p < .05), and lower use of pain pills (p < .01) predicted lower pain experienced. Actual pain experienced was a predictor of pain pill use (p < .01). Greater nervousness (p < .01) prior to surgery was a predictor of greater anticipated pain. CONCLUSIONS: Patients anticipated more pain than they actually experienced. Sedation, age and number of pain pills used predicted pain experienced. This trial was registered with clinicaltrials.gov as NCT03064178. PMID- 29500838 TI - Stability of dobutamine in continuous ambulatory delivery devices. AB - WHAT IS KNOWN AND OBJECTIVE: Continuous infusion of dobutamine plays an important role in the management of patients with end-stage heart failure. Home infusion of dobutamine using a continuous ambulatory delivery device (CADD) facilitates the management of patients in their home, avoiding complications associated with long term hospitalization. However, the stability of dobutamine in CADD is currently unknown. Therefore, this study investigated the physicochemical stability of dobutamine in CADDs at three different temperatures over various time points. METHODS: Six CADDs (three containing dobutamine 10 mg/mL in 0.9% sodium chloride and three containing dobutamine 10 mg/mL in 5% glucose) were prepared and stored at 4 degrees C for 7 days, followed by 12 hours at 35 degrees C and then for another 12 hours at 25 degrees C. An aliquot (n = 3) was withdrawn aseptically at 0, 24, 48, 72, 96, 120, 144 and 168 hours when stored at 4 degrees C, and at 0, 6 and 12 hours when stored at the other two temperatures. Each sample was analysed for dobutamine concentration using a stability-indicating high-performance liquid chromatography. All the samples were also evaluated for change in pH, colour and for particle content. RESULTS AND DISCUSSION: No evidence of particle formation, colour or pH change was observed throughout the study period. Dobutamine, when admixed with 0.9% sodium chloride or 5% glucose, was found to be chemically stable for at least 168 hours at 4 degrees C and for another 12 hours at 35 degrees C and for another 12 hours at 25 degrees C. WHAT IS NEW AND CONCLUSIONS: Our findings will allow health professionals to provide a weekly supply of dobutamine-containing CADDs to patients for home infusions. Continuous infusion over a 24-hour period using one CADD per day will also decrease the number of exchanges required and thus reduce the risk of catheter-related bloodstream infections. PMID- 29500839 TI - Green tea prevents vascular disturbs and attenuates periodontal breakdown in long term hyperglycaemia in T1D rats. AB - AIM: The effects of green tea on the modulation of vascularization during the progression of spontaneous periodontitis in long-term hyperglycaemia in streptozotocin-induced type 1 diabetic (T1D) rats were evaluated. MATERIALS AND METHODS: Wistar rats normoglycaemic (NG) and T1D were divided into two control groups, which received water (NG-W and T1D-W) and two experimental groups that received green tea (NG-GT and T1D-GT). Periodontal structures were evaluated by microtomographic and histological analyses. Number of immunostained cells for VEGF (NcVEGF+/mm2 ) and CD31 (NcCD31+/mm2 ), as well microvessel density (MVD) in the periodontal ligament (PDL) were evaluated. RESULTS: Long-term hyperglycaemia in T1D-W rats induced vascular alterations in PDL with a reduction of 36% in MVD, a decrease of 33% in NcCD31+/mm2 and an increase of 53% in NcVEGF+/mm2 . Concomitantly, a severe degree of periodontitis with higher reduction in bone volume and periodontal bone level was observed. In T1D-GT, green tea maintained the MVD, NcCD31+/mm2 and NcVEGF+/mm2 in the PDL similar to normoglycaemic groups. Clinically, in T1D-GT rats, green tea reduced dental plaque accumulation and the degree of periodontitis when compared to T1D-W. CONCLUSION: Daily green tea consumption has a therapeutic effect on the diabetic vascular disorder in PDL and the progression of periodontitis in long-term hyperglycaemia in T1D rats. PMID- 29500841 TI - European health inequality through the 'Great Recession': social policy matters. AB - This paper investigates the association between the Great Recession and educational inequalities in self-rated general health in 25 European countries. We investigate four different indicators related to economic recession: GDP; unemployment; austerity and a 'crisis' indicator signifying severe simultaneous drops in GDP and welfare generosity. We also assess the extent to which health inequality changes can be attributed to changes in the economic conditions and social capital in the European populations. The paper uses data from the European Social Survey (2002-2014). The analyses include both cross-sectional and lagged associations using multilevel linear regression models with country fixed effects. This approach allows us to identify health inequality changes net of all time-invariant differences between countries. GDP drops and increasing unemployment were associated with decreasing health inequalities. Austerity, however, was related to increasing health inequalities, an association that grew stronger with time. The strongest increase in health inequality was found for the more robust 'crisis' indicator. Changes in trust, social relationships and in the experience of economic hardship of the populations accounted for much of the increase in health inequality. The paper concludes that social policy has an important role in the development of health inequalities, particularly during times of economic crisis. PMID- 29500840 TI - Virulence profile of Escherichia coli O157 strains isolated from surface water in cattle breeding areas. AB - : Shiga toxin-producing Escherichia coli (STEC) O157:H7 is a worldwide concern. Cattle are their main reservoir and may contaminate watercourses through manure. We characterized a collection of 38 STEC O157:H7 strains isolated from surface water in feedlots areas (puddles inside pens formed after the rainfall or by spill around drinking troughs, and small water courses and lagoons, formed by runoff). Nineteen (50.0%) strains harboured stx2a /stx2c genes, 18 (47.4%) stx2c and one stx1a /stx2c . All strains harboured eae, ehxA, rfbO157 and fliCH7 genes, and the putative virulence determinants ECSP_0242, ECSP_2687 and ECSP_3620. All isolates tested as Lineage I/II by lineage-specific polymorphism assay-6. Nineteen (50%) belonged to the high virulent clade 8. The q21 allele was found in all strains and q933 /q21 alleles in 17 (44.7%). By XbaI-pulsed-field gel electrophoresis, 29 strains were grouped into seven clusters. Four clusters grouped isolates from distant places separated by 150-250 km. This may be related to vectors, like birds, involved in their spread. Otherwise, three clusters contained isolates recovered at same places with intervals of 1-9 months. This could be explained by the high environmental persistence of STEC O157:H7. These strains recovered from surface water showed similar genotypes to those found in the bovine reservoir and in human diseases, and could be linked to the high incidence of haemolytic uremic syndrome in Argentina. SIGNIFICANCE AND IMPACT OF THE STUDY: The challenge for the growing global demand for food is to find sustained production strategies without collateral effects. Intensive livestock operations generate large volumes of manure that can contaminate a finite resource, the water. This study shows how water contaminated by confined feeding operations can transport dangerous pathogens and warns to pay more attention to control and sanitation systems to prevent this type of pollution. PMID- 29500842 TI - A meta-analysis of the efficacy of cognitive behavior therapy on quality of life and psychological health of breast cancer survivors and patients. AB - OBJECTIVE: The aim of this study was to examine the effect of cognitive behavior therapy (CBT) on quality of life (QOL) and psychological health of breast cancer survivors and patients. METHODS: A total of 1289 references were examined from an overall literature search in PubMed, Embase, CINAHL, and the Cochrane Database of Systematic Reviews. Randomized controlled trials assessing the efficacy of CBT compared with a range of comparators in cancer survivors. We assessed the effect of CBT by using the standardized mean difference as effect size. RESULTS: Among 1289 abstracts and 292 full-text articles reviewed, 10 studies were included. At the posttreatment period, the pooled effect size for CBT on QOL was 0.57 (95% CI, 0.44 to 0.69; P < .001), on depression was -1.11 (95% CI, -1.28 to -0.94; P < .001), on stress was -0.40 (95% CI, -0.53 to -0.26; P < .001), on anxiety was 1.10 (95% CI, -1.27 to -0.93; P < .001), and on hyperarousal cluster of symptoms was -0.18 (95% CI, -0.30 to -0.05; P < .001). The QOL was considered statistically medium effect sizes. The depression and anxiety were considered statistically large effect sizes. CONCLUSIONS: Cognitive behavior therapy is an effective therapy for psychological symptoms of cancer survivors and patients, with meaningfully clinical effect sizes. These findings suggested that CBT should be used as the intervention for breast cancer survivors and patients when possible. PMID- 29500844 TI - IL-33/ST2 axis affects the polarization and efferocytosis of decidual macrophages in early pregnancy. AB - PROBLEM: To explore whether IL-33/ST2 axis modulates the polarization and efferocytosis of decidual macrophages (dMphis). METHOD OF STUDY: The phenotype characteristics of dMphis from both normal pregnant women and recurrent spontaneous abortion (RSA) patients were determined by real-time polymerase chain reaction (RT-PCR) and flow cytometry (FCM). Then, the efferocytosis and expression of IL-33 and its receptor (ST2) in dMphis were analyzed by FCM. Finally, the effects of sST2, a decoy receptor for IL-33 that inhibits the IL 33/ST2 signaling pathway, on the polarization and efferocytosis of dMphis and human macrophage cell line U937 were investigated. RESULTS: Compared with normal pregnancy, dMphis from RSA patients presented a M1 phenotype with high secretion of IL-33, whereas the expression of ST2 decreased. However, dMphis from RSA patients possessed a more powerful efferocytosis ability to clear the apoptotic decidual stromal cells (DSCs) compared with dMphis from normal pregnancy patients. Treatment with recombinant human sST2 led to the up-regulation of M1 bias and efferocytosis ability of both normal dMphis and U937. CONCLUSION: This study indicates that IL-33 secreted by dMphis promotes M2 bias at the feto maternal interface, and as a result, RSA might attribute to the disturbance of IL 33/ST2 axis and the enhancement of efferocytosis of dMphis subsequently. PMID- 29500845 TI - Sarcopenia in lung transplant candidates: A novel biomarker to estimate skeletal muscle mass. PMID- 29500843 TI - Phase I study of taselisib in Japanese patients with advanced solid tumors or hormone receptor-positive advanced breast cancer. AB - Taselisib is a potent and selective phosphatidylinositide 3-kinase (PI3K) inhibitor. The present article reports the first study of taselisib administration in Japanese patients. The aim of this 2-stage, phase I, multicenter, open-label, dose-escalation study was to evaluate the safety, pharmacokinetics, and preliminary efficacy of taselisib as monotherapy in Japanese patients with advanced solid tumors (stage 1), and as part of combination therapy in Japanese patients with hormone receptor (HR)-positive locally advanced or recurrent breast cancer (stage 2). In stage 1, oral taselisib tablets 2, 4, and 6 mg/d were given in 28-day cycles. In stage 2, successive cohorts of patients received oral taselisib tablets (2 or 4 mg/d) with i.m. fulvestrant 500 mg. Nine and 6 patients were enrolled in stage 1 and stage 2, respectively. Taselisib was well tolerated. No dose-limiting toxicities were experienced in any cohort of patients and no deaths were observed. The most common treatment-related adverse events in stage 1 and stage 2, respectively, were rash (55.6%, 66.7%), diarrhea (44.4%, 66.7%), and stomatitis (44.4%, 66.7%). Taselisib was rapidly absorbed after dosage; its half-life was 12.9-32.0 hours in stage 1 and 16.1-26.5 hours in stage 2. Two patients achieved partial response (PR), 5 patients had stable disease (SD) and 2 patients had progressive disease (PD) in stage 1, and 1 patient had PR and 3 patients had SD in stage 2. All patients with PR were positive for PIK3CA gene mutations. These preliminary data suggest that taselisib may be effective in patients with PIK3CA-mutated solid tumors or HR-positive advanced breast cancer. PMID- 29500846 TI - Illustrated instructions for mechanical quality assurance of a medical linear accelerator. AB - PURPOSE: The purpose of this study was to develop and test a set of illustrated instructions for effective training for mechanical quality assurance (QA) of medical linear accelerators (linac). METHODS: Illustrated instructions were created for mechanical QA and underwent several steps of review, testing, and refinement. Eleven testers with no recent QA experience were then recruited from our radiotherapy department (one student, two computational scientists, and eight dosimetrists). This group was selected because they have experience of radiation therapy but no preconceived ideas about how to do QA. The following parameters were progressively decalibrated on a Varian C-series linac: Group A = gantry angle, ceiling laser position, X1 jaw position, couch longitudinal position, physical graticule position (five testers); Group B = Group A + wall laser position, couch lateral and vertical position, collimator angle (three testers); Group C = Group B + couch angle, wall laser angle, and optical distance indicator (three testers). Testers were taught how to use the linac and then used the instructions to try to identify these errors. An experienced physicist observed each session, giving support on machine operation as necessary. RESULTS: Testers were able to follow the instructions. They determined gantry, collimator, and couch angle errors within 0.4 degrees , 0.3 degrees , and 0.9 degrees of the actual changed values, respectively. Laser positions were determined within 1 mm and jaw positions within 2 mm. Couch position errors were determined within 2 mm and 3 mm for lateral/longitudinal and vertical errors, respectively. Accessory positioning errors were determined within 1 mm. Optical distance indicator errors were determined within 2 mm when comparing with distance sticks and 6 mm when using blocks, indicating that distance sticks should be the preferred approach for inexperienced staff. CONCLUSIONS: Inexperienced users were able to follow these instructions and catch errors within the criteria suggested by AAPM TG-142 for linacs used for intensity-modulated radiation therapy. These instructions are, therefore, suitable for QA training. PMID- 29500847 TI - Cultural adaptation and psychometric testing of The Scenario Test UK for people with aphasia. AB - BACKGROUND: This study explores the psychometric properties of The Scenario Test UK, a culturally adapted version of the Dutch original (The Scenario Test) developed by van der Meulen et al. in 2010, which evaluates functional, daily life communication in aphasia. The Scenario Test assesses communication in an interactive context with a supportive communication partner. AIMS: To evaluate the reliability (internal consistency, interrater and test-retest reliability) and construct validity (convergent, discriminant and known-groups validity) of The Scenario Test UK. METHODS & PROCEDURES: The Scenario Test UK and other language, cognition and praxis assessments were administered to persons with aphasia after stroke (3+ months post-stroke) and to non-aphasic controls. Participants were recruited primarily through community stroke groups. Measures were completed in an interview format. Standard psychometric criteria were used to evaluate reliability and construct validity. OUTCOMES & RESULTS: A total of 74 participants with aphasia and 20 participants without aphasia took part in The Scenario Test UK. The test showed high levels of reliability. Internal consistency (Cronbach's alpha = 0.92), interrater reliability (ICC = 0.95) and test-retest reliability (ICC = 0.96) were excellent. Interrater agreement in scores on the individual items ranged from good to excellent (kappa = 0.41-1.00) for all but two items (item 4c kappa = 0.38, item 6c kappa = 0.36). The test demonstrated good levels of convergent (rho = 0.37-0.75) and discriminant validity (rho = -0.04 to 0.23). There was strong evidence for known groups validity (U = 132.50, p < .001), with those with aphasia scoring significantly lower [median (interquartile range-IQR) = 47 (39.8-51.0)] than those without aphasia [53 (52-54)]. CONCLUSIONS & IMPLICATIONS: The data support the reliability and validity of the Scenario Test UK as an assessment of functional, daily-life communication for persons with aphasia. Further testing is needed in independent samples on the measure's psychometric properties, including its sensitivity to change. Pending this testing, The test can be used as an assessment tool to evaluate communication skills with people with aphasia, to guide goal setting for therapy and to measure outcomes in response to therapy. PMID- 29500848 TI - Acute health effects of desktop 3D printing (fused deposition modeling) using acrylonitrile butadiene styrene and polylactic acid materials: An experimental exposure study in human volunteers. AB - 3D printers are increasingly run at home. Nanoparticle emissions from those printers have been reported, which raises the question whether adverse health effects from ultrafine particles (UFP) can be elicited by 3D printers. We exposed 26 healthy adults in a single-blinded, randomized, cross-over design to emissions of a desktop 3D printer using fused deposition modeling (FDM) for 1 hour (high UFP-emitting acrylonitrile butadiene styrene [ABS] vs low-emitting polylactic acid [PLA]). Before and after exposures, cytokines (IL-1beta, IL-6, TNF-alpha, INF-gamma) and ECP in nasal secretions, exhaled nitric oxide (FeNO), urinary 8 isoprostaglandin F2alpha (8-iso PGF2alpha ), and self-reported symptoms were assessed. The exposures had no significant differential effect on 8-iso PGF2alpha and nasal biomarkers. However, there was a difference (P < .05) in the time course of FeNO, with higher levels after ABS exposure. Moreover, indisposition and odor nuisance were increased for ABS exposure. These data suggest that 1 hour of exposure to 3D printer emissions had no acute effect on inflammatory markers in nasal secretions and urine. The slight relative increase in FeNO after ABS printing compared to PLA might be due to eosinophilic inflammation from inhaled UFP particles. This possibility should be investigated in further studies using additional biomarkers and longer observation periods. PMID- 29500849 TI - Gene expression of indoor fungal communities under damp building conditions: Implications for human health. AB - Dampness and visible mold growth in homes are associated with negative human health outcomes, but causal relationships between fungal exposure and health are not well established. The purpose of this study was to determine whether dampness in buildings impacts fungal community gene expression and how, in turn, gene expression may modulate human health impacts. A metatranscriptomic study was performed on house dust fungal communities to investigate the expression of genes and metabolic processes in chamber experiments at water activity levels of 0.5, 0.85, and 1.0. Fungi at water activities as low as 0.5 were metabolically active, focusing their transcriptional resources on primary processes essential for cell maintenance. Metabolic complexity increased with water activity where communities at 1.0 displayed more diverse secondary metabolic processes. Greater gene expression at increasing water activity has important implications for human health: Fungal communities at 1.0 aw upregulated a greater number of allergen-, mycotoxin-, and pathogenicity-encoding genes versus communities at 0.85 and 0.5 aw . In damp buildings, fungi may display increases in secondary metabolic processes with the potential for greater per-cell production of allergens, toxins, and pathogenicity. Assessments in wet versus dry buildings that do not account for this elevated health impact may not accurately reflect exposure. PMID- 29500851 TI - Detection of some new Trichosporon species from the dystrophied nails of three female members of a family from North Indian State of Jammu and Kashmir. AB - Dermatophytes are considered as the main pathogens responsible for onychomycosis, but recently successive isolations of yeast-like fungi from the infected nails has led to consider these also as primary agents of nail infections. Trichosporon species which are non-candidal, basidiomycetous, yeast-like, anamorphic fungi are commonly isolated from soil but they are also emerging as important etiological agents of onychomycosis. Three species of Trichosporon viz., T. asahii, T. asteroides and T. faecale were isolated from the infected nails of three female members of a family from district Doda of Jammu and Kashmir State. Among the isolated species of Trichosporon, T. asahii was recovered from the nail samples of all the three members, thus confirming its recognition as a main pathogenic species of onychomycosis. So far, there is no report of T. asteroides and T. faecale causing onychomycosis and hence they constitute new additions to the list of onychomycotic fungi. Some of the predisposing factors like low socio-economic condition, poor hygiene, frequent exposure of finger nails to water and dirt, climatic conditions and nail trauma were observed to be the main causes of nail infection in these patients. However, a link between the pathogenic genus and the genetic makeup of the patients is also probable. PMID- 29500853 TI - Molecular identification and susceptibility profile of Sporothrix schenckii sensu lato isolated in Argentina. AB - We studied 23 clinical and environmental strains of Sporothrix schenckii sensu lato collected from 1984 to 2017 in Argentina. The molecular identification (partial sequencing of a fragment of the calmodulin gene) of the strains was performed. For the yeast and mycelial phases, the in vitro susceptibility testing by a microdilution reference method was determined against eight antifungal drugs. Strains studied were identified as S. schenckii sensu stricto 13 (56.5%), S. brasiliensis 8 (34.7%) and S. globosa 2 (8.7%). The most active antifungal drugs tested for the yeast and mycelial phases expressed as geometric mean (GM) value of the minimal inhibitory concentration (MIC) (MUg mL-1 ) were terbinafine (0.07 and 0.24), posaconazole (0.13 and 0.58), itraconazole (0.38 and 1.10) and ketoconazole (0.22 and 0.89), while fluconazole (110.10 and 131.92) and flucytosine (2.96 and 79.03) were the less active. For voriconazole and amphotericin B the GM-MIC values were acceptably low for the yeast phase (0.39 and 0.72 MUg mL-1 ), while the mycelial phase showed values >=2-fold higher (8.76 and 1.88 MUg mL-1 ), P < .05. Here, we described S. schenckii sensu stricto, S. brasiliensis and S. globosa, these species were isolated from humans, animals and soil and are circulating in Argentina since at least 1984. PMID- 29500852 TI - Associations between personality disorders and cannabis use and cannabis use disorder: a population-based twin study. AB - BACKGROUND AND AIMS: Individual differences in DSM-IV personality disorders (PDs) are associated with increased prevalence of substance use disorders. Our aims were to determine which combination of PDs trait scores best predict cannabis use (CU) and cannabis use disorder (CUD), and to estimate the size and significance of genetic and environmental risks in PD traits shared with CU and CUD. DESIGN: Linear mixed-effects models were used to identify PD traits for inclusion in twin analyses to explore the genetic and environmental associations between the traits and cannabis use. SETTING: Cross-sectional data were obtained from Norwegian adult twins in a face-to-face interview in 1999-2004 as part of a population based study of mental health. PARTICIPANTS: Subjects were 1419 twins (MUage = 28.2 years, range = 19-36) from the Norwegian Institute of Public Health Twin Panel with complete PD and cannabis data. MEASUREMENTS: PD traits were assessed using DSM-IV criteria. Life-time CU and CUD were based on DSM-IV abuse and dependence criteria, including withdrawal and craving. FINDINGS: After adjusting for age and sex, antisocial [beta = 0.23, 95% confidence interval (CI) = 0.19 0.28] and borderline PDs (beta = 0.20, 95% CI = 0.14-0.26) were associated strongly with CU. Antisocial (beta = 0.26, 95% CI = 0.21-0.31) and borderline PDs (beta = 0.12, 95% CI = 0.06-0.18) were also linked strongly to CUD. Genetic risks in antisocial and borderline PD traits explained 32-60% of the total variance in CU and CUD. Dependent and avoidant PDs explained 11 and 16% of the total variance in CU and CUD, respectively. CONCLUSIONS: Individual differences in the liability to cannabis use and cannabis use disorder appear to be linked to genetic risks correlated with antisocial and borderline personality disorder traits. PMID- 29500854 TI - Characterization of microbiota in male infertility cases uncovers differences in seminal hyperviscosity and oligoasthenoteratozoospermia possibly correlated with increased prevalence of infectious bacteria. AB - PROBLEM: Sexually transmitted diseases and other infections of male genitourinary tract are thought to negatively impact reproductive health, affecting semen quality. Despite a possible link between bacteria and infertility, few studies attempted to characterize seminal microbiota in healthy and diseased subjects. METHODS OF THE STUDY: A high-throughput sequencing of 16S ribosomal RNA gene was performed in a cohort of infertility-related cases (N = 89) and controls (N = 29) using a pooled sample approach. RESULTS: A global characterization of microbiota was obtained at low cost, without compromising the identification of bacterial taxa. This strategy allowed us to detect changes in the microbiota of infertility related phenotypes, such as an increment of Proteobacteria in seminal hyperviscosity, and to separate this later group from oligoasthenoteratozoospermia based in bacterial (family/genus) abundances. CONCLUSION: We provide data for a likely contribution of bacteria into seminal hyperviscosity and oligoasthenoteratozoospermia, partially correlated with an increment of Neisseria, Klebsiella, and Pseudomonas pathogens and a reduction in Lactobacillus probiotic agent. PMID- 29500850 TI - The immunophenotype of amniotic fluid leukocytes in normal and complicated pregnancies. AB - PROBLEM: The immune cellular composition of amniotic fluid is poorly understood. Herein, we determined: 1) the immunophenotype of amniotic fluid immune cells during the second and third trimester in the absence of intra-amniotic infection/inflammation; 2) whether amniotic fluid T cells and ILCs display different phenotypical characteristics to that of peripheral cells; and 3) whether the amniotic fluid immune cells are altered in women with intra-amniotic infection/inflammation. METHOD OF STUDY: Amniotic fluid samples (n = 57) were collected from 15 to 40 weeks of gestation in women without intra-amniotic infection/inflammation. Samples from women with intra-amniotic infection/inflammation were also included (n = 9). Peripheral blood mononuclear cells from healthy adults were used as controls (n = 3). Immunophenotyping was performed using flow cytometry. RESULTS: In the absence of intra-amniotic infection/inflammation, the amniotic fluid contained several immune cell populations between 15 and 40 weeks. Among these immune cells: (i) T cells and ILCs were greater than B cells and natural killer (NK) cells between 15 and 30 weeks; (ii) T cells were most abundant between 15 and 30 weeks; (iii) ILCs were most abundant between 15 and 20 weeks; (iv) B cells were scarce between 15 and 20 weeks; yet, they increased and were constant after 20 weeks; (v) NK cells were greater between 15 and 30 weeks than at term; (vi) ILCs expressed high levels of RORgammat, CD161, and CD103 (ie, group 3 ILCs); (vii) T cells expressed high levels of RORgammat; (viii) neutrophils increased as gestation progressed; and (ix) monocytes/macrophages emerged after 20 weeks and remained constant until term. All of the amniotic fluid immune cells, except ILCs, were increased in the presence of intra-amniotic infection/inflammation. CONCLUSION: The amniotic fluid harbors a diverse immune cellular composition during normal and complicated pregnancies. PMID- 29500855 TI - Development of a chest digital tomosynthesis R/F system and implementation of low dose GPU-accelerated compressed sensing (CS) image reconstruction. AB - PURPOSE: This work describes the hardware and software developments of a prototype chest digital tomosynthesis (CDT) R/F system. The purpose of this study was to validate the developed system for its possible clinical application on low dose chest tomosynthesis imaging. METHODS: The prototype CDT R/F system was operated by carefully controlling the electromechanical subsystems through a synchronized interface. Once a command signal was delivered by the user, a tomosynthesis sweep started to acquire 81 projection views (PVs) in a limited angular range of +/-20 degrees . Among the full projection dataset of 81 images, several sets of 21 (quarter view) and 41 (half view) images with equally spaced angle steps were selected to represent a sparse view condition. GPU-accelerated and total-variation (TV) regularization strategy-based compressed sensing (CS) image reconstruction was implemented. The imaged objects were a flat-field using a copper filter to measure the noise power spectrum (NPS), a Catphan(r) CTP682 quality assurance (QA) phantom to measure a task-based modulation transfer function (MTFTask ) of three different cylinders' edge, and an anthropomorphic chest phantom with inserted lung nodules. The authors also verified the accelerated computing power over CPU programming by checking the elapsed time required for the CS method. The resultant absorbed and effective doses that were delivered to the chest phantom from two-view digital radiographic projections, helical computed tomography (CT), and the prototype CDT system were compared. RESULTS: The prototype CDT system was successfully operated, showing little geometric error with fast rise and fall times of R/F x-ray pulse less than 2 and 10 ms, respectively. The in-plane NPS presented essential symmetric patterns as predicted by the central slice theorem. The NPS images from 21 PVs were provided quite different pattern against 41 and 81 PVs due to aliased noise. The voxel variance values which summed all NPS intensities were inversely proportional to the number of PVs, and the CS method gave much lower voxel variance by the factors of 3.97-6.43 and 2.28-3.36 compared to filtered backprojection (FBP) and 20 iterations of simultaneous algebraic reconstruction technique (SART). The spatial frequencies of the f50 at which the MTFTask reduced to 50% were 1.50, 1.55, and 1.67 cycles/mm for FBP, SART, and CS methods, respectively, in the case of Bone 20% cylinder using 41 views. A variety of ranges of TV reconstruction parameters were implemented during the CS method and we could observe that the NPS and MTFTask preserved best when the regularization and TV smoothing parameters alpha and tau were in a range of 0.001-0.1. For the chest phantom data, the signal difference to noise ratios (SDNRs) were higher in the proposed CS scheme images than in the FBP and SART, showing the enhanced rate of 1.05-1.43 for half view imaging. The total averaged reconstruction time during 20 iterations of the CS scheme was 124.68 s, which could match-up a clinically feasible time (<3 min). This computing time represented an enhanced speed 386 times greater than CPU programming. The total amounts of estimated effective doses were 0.12, 0.53 (half view), and 2.56 mSv for two-view radiographs, the prototype CDT system, and helical CT, respectively, showing 4.49 times higher than conventional radiography and 4.83 times lower than a CT exam, respectively. CONCLUSIONS: The current work describes the development and performance assessment of both hardware and software for tomosynthesis applications. The authors observed reasonable outcomes by showing a potential for low-dose application in CDT imaging using GPU acceleration. PMID- 29500856 TI - Normal tissue doses from MV image-guided radiation therapy (IGRT) using orthogonal MV and MV-CBCT. AB - PURPOSE: The aim of this study was to measure and compare the mega-voltage imaging dose from the Halcyon medical linear accelerator (Varian Medical Systems) with measured imaging doses with the dose calculated by Eclipse treatment planning system. METHODS: An anthropomorphic thorax phantom was imaged using all imaging techniques available with the Halcyon linac - MV cone-beam computed tomography (MV-CBCT) and orthogonal anterior-posterior/lateral pairs (MV-MV), both with high-quality and low-dose modes. In total, 54 imaging technique, isocenter position, and field size combinations were evaluated. The imaging doses delivered to 11 points in the phantom (in-target and extra-target) were measured using an ion chamber, and compared with the imaging doses calculated using Eclipse. RESULTS: For high-quality MV-MV mode, the mean extra-target doses delivered to the heart, left lung, right lung and spine were 1.18, 1.64, 0.80, and 1.11 cGy per fraction, respectively. The corresponding mean in-target doses were 3.36, 3.72, 2.61, and 2.69 cGy per fraction, respectively. For MV-MV technique, the extra-target imaging dose had greater variation and dependency on imaging field size than did the in-target dose. Compared to MV-MV technique, the imaging dose from MV-CBCT was less sensitive to the location of the organ relative to the treatment field. For high-quality MV-CBCT mode, the mean imaging doses to the heart, left lung, right lung, and spine were 8.45, 7.16, 7.19, and 6.51 cGy per fraction, respectively. For both MV-MV and MV-CBCT techniques, the low-dose mode resulted in an imaging dose about half of that in high-quality mode. CONCLUSION: The in-target doses due to MV imaging using the Halcyon ranged from 0.59 to 9.75 cGy, depending on the choice of imaging technique. Extra-target doses from MV-MV technique ranged from 0 to 2.54 cGy. The MV imaging dose was accurately calculated by Eclipse, with maximum differences less than 0.5% of a typical treatment dose (assuming a 60 Gy prescription). Therefore, the cumulative imaging and treatment plan dose distribution can be expected to accurately reflect the actual dose. PMID- 29500858 TI - A regulated multiscale closed-loop cardiovascular model, with applications to hemorrhage and hypertension. AB - A computational tool is developed for simulating the dynamic response of the human cardiovascular system to various stressors and injuries. The tool couples 0 dimensional models of the heart, pulmonary vasculature, and peripheral vasculature to 1-dimensional models of the major systemic arteries. To simulate autonomic response, this multiscale circulatory model is integrated with a feedback model of the baroreflex, allowing control of heart rate, cardiac contractility, and peripheral impedance. The performance of the tool is demonstrated in 2 scenarios: neurogenic hypertension by sustained stimulation of the sympathetic nervous system and an acute 10% hemorrhage from the left femoral artery. PMID- 29500857 TI - Comparison of MLC error sensitivity of various commercial devices for VMAT pre treatment quality assurance. AB - The purpose of this study was to compare the MLC error sensitivity of various measurement devices for VMAT pre-treatment quality assurance (QA). This study used four QA devices (Scandidos Delta4, PTW 2D-array, iRT systems IQM, and PTW Farmer chamber). Nine retrospective VMAT plans were used and nine MLC error plans were generated for all nine original VMAT plans. The IQM and Farmer chamber were evaluated using the cumulative signal difference between the baseline and error induced measurements. In addition, to investigate the sensitivity of the Delta4 device and the 2D-array, global gamma analysis (1%/1, 2%/2, and 3%/3 mm), dose difference (1%, 2%, and 3%) were used between the baseline and error-induced measurements. Some deviations of the MLC error sensitivity for the evaluation metrics and MLC error ranges were observed. For the two ionization devices, the sensitivity of the IQM was significantly better than that of the Farmer chamber (P < 0.01) while both devices had good linearly correlation between the cumulative signal difference and the magnitude of MLC errors. The pass rates decreased as the magnitude of the MLC error increased for both Delta4 and 2D array. However, the small MLC error for small aperture sizes, such as for lung SBRT, could not be detected using the loosest gamma criteria (3%/3 mm). Our results indicate that DD could be more useful than gamma analysis for daily MLC QA, and that a large-area ionization chamber has a greater advantage for detecting systematic MLC error because of the large sensitive volume, while the other devices could not detect this error for some cases with a small range of MLC error. PMID- 29500859 TI - Aberrant KIF20A expression might independently predict poor overall survival and recurrence-free survival of hepatocellular carcinoma. AB - Kinesin family member 20A (KIF20A) is an essential regulator of cytokinesis. In this study, by performing a retrospective study based on data from the Cancer Genome Atlas (TCGA)-Liver and Hepatocellular Carcinoma (LIHC) cohort, we tried to assess the independent prognostic value of KIF20A in terms of overall survival (OS) and recurrence-free survival (RFS). Results showed that normal liver tissues had very low KIF20A expression compared with normal tissues in other cohorts in TCGA. However, the primary HCC tissues (N = 371) had significantly elevated KIF20A expression than normal liver tissues (N = 50). Immunohistochemistry (IHC) data showed that normal hepatocytes had weak KIF20A staining. In comparison, some HCC tissues had medium and strong KIF20A expression, with nuclear-enhanced staining. By grouping patients with primary HCC (N = 365) into high and low KIF20A expression groups, we found that the high expression group had a substantially higher proportion of high-grade tumors (G3/G4) (34/65, 52.3% vs. 96/295, 32.5%, P = 0.0027), advanced tumors (stage III/IV) (28/61, 45.9% vs. 59/280, 21.1%, P < 0.0001) and death (44/67, 65.7% vs. 86/298, 28.9%, P < 0.0001) compared with the low expression group. Kaplan-Meier curves of OS and RFS indicated that high KIF20A expression was associated with worse survival outcomes. Subgroup analysis confirmed the associations in G1/G2, G3/G4 tumors and in early and advanced stages. Following univariate and multivariate analysis revealed that KIF20A expression was an independent prognostic indicator for poor OS (HR: 1.304, 95%CI: 1.157-1.469, P < 0.001) and RFS (HR: 1.144, 95%CI: 1.028 1.272, P < 0.001). Based on these findings, we infer that KIF20A was aberrantly expressed in HCC tissues and its expression might independently predict poor OS and RFS. (c) 2018 IUBMB Life, 70(4):328-335, 2018. PMID- 29500861 TI - High-fluorescent cells: A marker of malignancy in the analysis of body fluid samples. PMID- 29500860 TI - Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome or Fowler syndrome: Report of a family and insight into the disease's mechanism. AB - BACKGROUND: Fowler syndrome is a rare autosomal recessive disorder characterized by hydranencephaly-hydrocephaly and multiple pterygium due to fetal akinesia. To date, around 45 cases from 27 families have been reported, and the pathogenic bi allelic mutations in FLVCR2 gene described in 15 families. The pathogenesis of this condition has not been fully elucidated so far. METHODS: We report on an additional family with two affected fetuses carrying a novel homozygous mutation in FLVCR2 gene, and describe the impact of known mutants on the protein structural and functional impairment. RESULTS: The present report confirms the genetic homogeneity of Fowler syndrome and describes a new FLVCR2 mutation affecting the protein function. The structural analysis of the present and previously published FLVCR2 mutations supports the hypothesis of a reduced heme import as the underlying disease's mechanism due to the stabilization of the occluded conformation or a protein misfolding. CONCLUSION: Our data suggest the hypothesis of heme deficiency as the major pathogenic mechanism of Fowler syndrome. PMID- 29500862 TI - Role of CD81 and CD58 in minimal residual disease detection in pediatric B lymphoblastic leukemia. AB - INTRODUCTION: Minimal residual disease (MRD) in B lymphoblastic leukemia has been demonstrated to be a powerful predictor of clinical outcome in numerous studies in both children and adults. In this study, we evaluated 86 pediatric patients with both diagnostic and remission flow cytometry studies and compared expression of CD81, CD58, CD19, CD34, CD20, and CD38 in the detection of MRD. METHODS: We evaluated 86 patients with B lymphoblastic leukemia who had both diagnostic studies and remission studies for the presence of MRD using multicolor flow cytometry. We established our detection limit for identifying abnormal lymphoblasts using serial dilutions. We also compared flow cytometry findings with molecular MRD detection in a subset of patients. RESULTS: We found that we can resolve differences between hematogones and lymphoblasts in 85 of 86 cases using a combination of CD45, CD19, CD34, CD10, CD20, CD38, CD58, and CD81. Our detection limit using flow cytometry is 0.002% for detecting a population of abnormal B lymphoblasts. Comparison with MRD assessment by molecular methods showed a high concordance rate with flow cytometry findings. CONCLUSIONS: Our study highlights importance of using multiple markers to detect MRD in B lymphoblastic leukemia. Our findings indicate that including both CD58 and CD81 markers in addition to CD19, CD34, CD20, CD38, and CD10 are helpful in MRD detection by flow cytometry. PMID- 29500863 TI - Identification of inhibitors of Tartrate-resistant acid phosphatase (TRAP/ACP5) activity by small-molecule screening. AB - Tartrate-resistant acid phosphatase (TRAP/ACP5) occurs as two isoforms-TRAP 5a with low enzymatic activity due to a loop interacting with the active site and the more active TRAP isoform 5b generated upon proteolytic cleavage of this loop. TRAP has been implicated in several diseases, including cancer. Thus, this study set out to identify small-molecule inhibitors of TRAP activity. A microplate based enzymatic assay for TRAP 5b was applied in a screen of 30,315 compounds, resulting in the identification of 90 primary hits. After removal of promiscuous compounds, unwanted groups, and false positives by orthogonal assays and three concentration validation, the properties of 52 compounds were further investigated to better understand their mechanism of action. Full-concentration response curves for these compounds were established under different enzyme concentrations and (pre)incubation times to remove compounds with inconsistent results and low potencies. Full-concentration-response curves were also performed for both isoforms, to examine isoform prevalence. Filtering led to six prioritized compounds, representing different clusters. One of these, CBK289001 or (6S)-6-[3-(2H-1,3-benzodioxol-5-yl)-1,2,4-oxadiazol-5-yl]-N-(propan-2-yl) 1H,4H,5H,6H,7H-imidazo[4,5-c]pyridine-5-carboxamide, demonstrated efficacy in a migration assay and IC50 values from 4 to 125 MUm. Molecular docking studies and analog testing were performed around CBK289001 to provide openings for further improvement toward more potent blockers of TRAP activity. PMID- 29500864 TI - Association between serum autotaxin or phosphatidylserine-specific phospholipase A1 levels and melanoma. AB - Autotaxin (ATX), a producing enzyme for lysophosphatidic acids, was first identified from the medium of a melanoma cell line and has been considered to be one of the candidate targets to treat melanoma; however, the association between serum ATX and melanoma in human subjects has not been elucidated. Along with ATX, phosphatidylserine-specific phospholipase A1 (PS-PLA1 ) is a producing enzyme for lysophosphatidylserine, a similar glycero-lysophospholipid mediator to lysophosphatidic acids. In the present study, we aimed to investigate the association between serum ATX or PS-PLA1 levels and melanoma. We measured the serum levels of ATX, ATX isoforms and PS-PLA1 in subjects with melanoma (n = 57) and healthy subjects (n = 58). We further investigated the existence of trends according to the clinical stages of melanoma. We observed that serum total ATX and classical ATX levels were significant higher and serum novel ATX levels tended to be higher in male subjects with melanoma, while no significant difference was observed between the two groups in female subjects. The trend test revealed that the serum total ATX and ATX isoforms were significantly associated with the clinical stages of female subjects with melanoma. Regarding PS-PLA1 , serum PS-PLA1 levels were significantly higher in the melanoma subjects and associated with the clinical stages. The present study is the first study which revealed the association between ATX or PS-PLA1 and melanoma, suggesting the possible involvement of ATX/lysophosphatidic acids or PS-PLA1 /lysophosphatidylserine axis in the pathogenesis of melanoma. PMID- 29500865 TI - Disparities in eating disorder diagnosis and treatment according to weight status, race/ethnicity, socioeconomic background, and sex among college students. AB - OBJECTIVE: Eating disorders (EDs) present a significant threat to the health of adolescents and young adults, yet remain under-diagnosed and under-treated at a population-level. EDs have historically been thought to afflict "skinny, white, affluent girls" (the SWAG stereotype). As such, higher-weight individuals, racial/ethnic minorities, those from socioeconomically disadvantaged backgrounds, and males may not recognize their need for treatment, may not be properly screened for EDs, and/or may not be referred to treatment. METHOD: Using large scale survey data from the healthy bodies study, we examined variations in prevalence of perceived need for ED treatment, ED diagnosis, past-year ED treatment, and treatment barriers according to weight status, race, socioeconomic background, and sex among undergraduate and graduate students with symptoms of an ED (N = 1,747). RESULTS: Among students with symptoms of an ED, 30.7% perceived a need for treatment, 10.5% had received a diagnosis, and 13.6% had received treatment in the past year. Individual characteristics were highly associated with perceived need, diagnosis, and past-year treatment. Females were more likely than males to perceive a need for treatment (OR = 1.97), to be diagnosed (OR = 4.66), and to be treated (OR = 1.64) for their ED symptoms. Socioeconomic background was associated with perceived need for treatment and past-year treatment, with students from affluent backgrounds having higher odds of perceiving need (OR = 1.52) and of receiving treatment (OR = 1.89) compared with their non-affluent peers. DISCUSSION: At a population-level, the unmet need for ED treatment disproportionately affects certain groups. Stereotypes about who develops EDs could contribute to disparities in ED treatment and outcomes. PMID- 29500866 TI - Lymph node segmentation by dynamic programming and active contours. AB - PURPOSE: Enlarged lymph nodes are indicators of cancer staging, and the change in their size is a reflection of treatment response. Automatic lymph node segmentation is challenging, as the boundary can be unclear and the surrounding structures complex. This work communicates a new three-dimensional algorithm for the segmentation of enlarged lymph nodes. METHODS: The algorithm requires a user to draw a region of interest (ROI) enclosing the lymph node. Rays are cast from the center of the ROI, and the intersections of the rays and the boundary of the lymph node form a triangle mesh. The intersection points are determined by dynamic programming. The triangle mesh initializes an active contour which evolves to low-energy boundary. Three radiologists independently delineated the contours of 54 lesions from 48 patients. Dice coefficient was used to evaluate the algorithm's performance. RESULTS: The mean Dice coefficient between computer and the majority vote results was 83.2%. The mean Dice coefficients between the three radiologists' manual segmentations were 84.6%, 86.2%, and 88.3%. CONCLUSIONS: The performance of this segmentation algorithm suggests its potential clinical value for quantifying enlarged lymph nodes. PMID- 29500867 TI - New methods for measuring atmospheric heavy noble gas isotope and elemental ratios in ice core samples. AB - RATIONALE: The global ocean constitutes the largest heat buffer in the global climate system, but little is known about its past changes. The isotopic and elemental ratios of heavy noble gases (krypton and xenon), together with argon and nitrogen in trapped air from ice cores, can be used to reconstruct past mean ocean temperatures (MOTs). Here we introduce two successively developed methods to measure these parameters with a sufficient precision to provide new constraints on past changes in MOT. METHODS: The air from an 800-g ice sample - containing roughly 80 mL STP air - is extracted and processed to be analyzed on two independent dual-inlet isotope ratio mass spectrometers. The primary isotope ratios (delta15 N, delta40 Ar and delta86 Kr values) are obtained with precisions in the range of 1 per meg (0.0010/00) per mass unit. The three elemental ratio values deltaKr/N2 , deltaXe/N2 and deltaXe/Kr are obtained using sequential (non simultaneous) peak-jumping, reaching precisions in the range of 0.1-0.30/00. RESULTS: The latest version of the method achieves a 30% to 50% better precision on the elemental ratios and a twofold better sample throughput than the previous one. The method development uncovered an unexpected source of artefactual gas fractionation in a closed system that is caused by adiabatic cooling and warming of gases (termed adiabatic fractionation) - a potential source of measurement artifacts in other methods. CONCLUSIONS: The precisions of the three elemental ratios deltaKr/N2 , deltaXe/N2 and deltaXe/Kr - which all contain the same MOT information - suggest smaller uncertainties for reconstructed MOTs (+/-0.3-0.1 degrees C) than previous studies have attained. Due to different sensitivities of the noble gases to changes in MOT, deltaXe/N2 provides the best constraints on the MOT under the given precisions followed by deltaXe/Kr, and deltaKr/N2 ; however, using all of them helps to detect methodological artifacts and issues with ice quality. PMID- 29500868 TI - Cutaneous sarcoidosis in a patient with rheumatoid arthritis receiving tocilizumab. PMID- 29500869 TI - Pediatric laparoscopic sleeve gastrectomy in Turkey: Short-term results. AB - BACKGROUND: Obesity is one of the most rapidly increasing health problems in children. Laparoscopic sleeve gastrectomy (LSG) is one of the best treatment options and is feasible and safe in children. The aim of this study was to present the short-term results of a laparoscopic sleeve gastrectomy series in children. METHODS: Children who underwent LSG in 2014-2017 were included in the study. Charts were investigated retrospectively and short-term weight loss was analyzed. RESULTS: Patients who had surgery in 2014-2017 were included in the study. There were six girls and two boys, and the median age was 15 years (range, 11-18 years). Mean weight was 159.25 +/- 19.78 kg, and mean body mass index was 61.05 +/- 8.5 kg/m2 . Mean operation time was 70 min (range, 65-90 min), mean hospital stay was 5.1 days (range, 3-7 days), and mean follow up was 19.2 months (range, 1-43 months). Of these patients, five had hypertension and were under medication and two of these five also had hyperinsulinemia. One of the five children had Bardet-Biedl syndrome and one had bronchial asthma. After operation, medication was stopped in four of the eight children. At the time of writing, six patients were doing well without postoperative complications, or the need for reoperation. CONCLUSION: Even though the follow-up period was short and the number of patients was small, LSG was a feasible and promising surgical method for morbidly obese children. A multidisciplinary approach and lifelong behavior therapy are key steps for success. PMID- 29500870 TI - LncRNA UCA1 impacts cell proliferation, invasion, and migration of pancreatic cancer through regulating miR-96/FOXO3. AB - This study was expected to reveal the regulatory effects of lncRNA UCA1 on pancreatic cancer cell progression through targeting miR-96/FOXO3. Microarray analysis was carried out on 36 cases of pancreatic cancer tissues and 16 cases of adjacent tissues among them. Expression levels of lncRNA UCA1, miR-96, and FOXO3 in pancreatic cancer tissues and cell lines were determined by qRT-PCR. Expression levels of FOXO3 protein were determined by western blot. Cell viability, cell cycle and apoptosis, cell invasion and migration were detected by CCK-8, flow cytometry, and transwell assay, respectively. The colocalization relationship between lncRNA UCA1 and miR-96 was detected by RNA FISH. Whether UCA1 could target miR-96 and whether miR-96 could target FOXO3 3'UTR were verified by dual-luciferase reporter gene assay. High expression of lncRNA UCA1 and FOXO3 and low expression of miR-96 were shown in pancreatic cancer. Inhibition of UCA1 suppressed pancreatic tumor cell proliferation, colony formation, and metastasis, while inhibition of miR-96 promoted pancreatic cancer cell progression. FOXO3 was the downstream target gene of miR-96 and showed the opposite effects. LncRNA UCA1 promoted cell proliferation, invasion, migration and inhibited cell apoptosis of pancreatic cancer through down-regulating miR-96 and up-regulating FOXO3. (c) 2018 IUBMB Life, 70(4):276-290, 2018. PMID- 29500871 TI - A mechanistic linkage between oral lichen planus and autoimmune thyroid disease. AB - OBJECTIVE: To determine the levels of antithyroid antibodies and thyroid hormones in the sera of patients with oral lichen planus (OLP), and to quantify the expression of thyroid proteins in OLP lesions. SUBJECTS AND METHODS: Venous blood samples were drawn from 110 patients with OLP who had no history of thyroid disease or levothyroxine supplementation (OLP+/LT4 -). A random population sample of 657 healthy subjects was used as the control group. Two additional groups were used as comparators. Immunohistochemical and qPCR analyses were performed on tissue specimens collected from the patients with OLP and thyroid disease and healthy subjects. RESULTS: No association was found between the presence of antithyroid antibodies and OLP. More patients in the OLP+/LT4 - group showed high levels of thyroid-stimulating hormone and low levels of free thyroxine than were seen in the control group. Thyroid-stimulating hormone receptor was more highly expressed in the OLP lesions of patients with thyroid disease than in the healthy oral mucosa. CONCLUSIONS: A significant number of patients with OLP who are not previously diagnosed with thyroid disease have thyroid parameters that are compatible with hypothyroidism. The expression of thyroid-stimulating hormone receptor in OLP lesions suggests that mechanisms related to autoimmune thyroid disease are involved in the aetiology of OLP. PMID- 29500872 TI - Evaluation of marginal gap of lithium disilicate glass ceramic crowns with optical coherence tomography. AB - Marginal gap (MG) was the most important factor to evaluate the success of crowns. The study was to assess the MG of lithium disilicate glass ceramic crowns with spectral domain optical coherence tomography (OCT) and stereomicroscopy in vitro, and to provide evidence to measure the MG with OCT. Consistency was observed between OCT and stereomicroscopy to measure the MG after cementation. There was no significant difference between the MG of lithium disilicate glass ceramic crowns using OCT and stereomicroscopy (OCT 59.55 +/- 7.22 MUm, stereomicroscope 59.48 +/- 6.53 MUm, P = 0.736) after cementation. OCT was a noninvasive diagnostic technique to measure the MG of lithium disilicate glass ceramic crowns. PMID- 29500873 TI - Long-term fluorescence lifetime imaging of a genetically encoded sensor for caspase-3 activity in mouse tumor xenografts. AB - Caspase-3 is known for its role in apoptosis and programmed cell death regulation. We detected caspase-3 activation in vivo in tumor xenografts via shift of mean fluorescence lifetimes of a caspase-3 sensor. We used the genetically encoded sensor TR23K based on the red fluorescent protein TagRFP and chromoprotein KFP linked by 23 amino acid residues (TagRFP-23-KFP) containing a specific caspase cleavage DEVD motif to monitor the activity of caspase-3 in tumor xenografts by means of fluorescence lifetime imaging-Forster resonance energy transfer. Apoptosis was induced by injection of paclitaxel for A549 lung adenocarcinoma and etoposide and cisplatin for HEp-2 pharynx adenocarcinoma. We observed a shift in lifetime distribution from 1.6 to 1.9 ns to 2.1 to 2.4 ns, which indicated the activation of caspase-3. Even within the same tumor, the lifetime varied presumably due to the tumor heterogeneity and the different depth of tumor invasion. Thus, processing time-resolved fluorescence images allows detection of both the cleaved and noncleaved states of the TR23K sensor in real time mode during the course of several weeks noninvasively. This approach can be used in drug screening, facilitating the development of new anticancer agents as well as improvement of chemotherapy efficiency and its adaptation for personal treatment. PMID- 29500874 TI - High-resolution, label-free two-photon imaging of diseased human corneas. AB - The diagnosis of corneal diseases may be improved by monitoring the metabolism of cells and the structural organization of the stroma using two-photon imaging (TPI). We used TPI to assess the differences between nonpathological (NP) human corneas and corneas diagnosed with either keratoconus, Acanthamoeba keratitis, or stromal corneal scars. Images were acquired using a custom-built five-dimensional laser-scanning microscope with a broadband sub-15 femtosecond near-infrared pulsed excitation laser and a 16-channel photomultiplier tube detector in combination with a time-correlated single photon counting module. Morphological alterations of epithelial cells were observed for all pathologies. Moreover, diseased corneas showed alterations to the cells' metabolism that were revealed using the NAD(P)H free to protein-bound ratios. The mean autofluorescence lifetime of the stroma and the organization of the collagen fibers were also significantly altered due to the pathologies. We demonstrate that TPI can be used to distinguish between NP and diseased human corneas, based not only on alterations of the cells' morphology, which can also be evaluated using current clinical devices, but on additional morphological and functional features such as the organization of the stroma and the cells' metabolism. Therefore, TPI could become an efficient tool for diagnosing corneal diseases and better understanding the biological processes of the diseases. PMID- 29500875 TI - Robust eye tracking based on multiple corneal reflections for clinical applications. AB - A set of methods in terms of both image processing and gaze estimation for accurate eye tracking is proposed. The eye-tracker used in this study relies on the dark-pupil method with up to 12 corneal reflections and offers an unprecedented high resolution imaging of the pupil and the cornea. The potential benefits of a higher number of glints and their optimum arrangement are analyzed considering distinct light sources configurations with 12, 8, 6, 4, and 2 corneal reflections. Moreover, a normalization factor of the pupil-glint vector is proposed for each configuration. There is a tendency for increasing accuracy with the number of glints, especially vertically (0.47 deg for 12 glints configuration versus 0.65 deg for 2 glints configuration). Besides the number of corneal reflections, their arrangement seems to have a stronger effect. A configuration that minimizes the interference of the eyelids with the corneal reflections is desired. Finally, the normalization of the pupil-glint vectors improves the vertical eye tracking accuracy up to 43.2%. In addition, the normalization also limits the need for a higher number of light sources to achieve better spatial accuracy. PMID- 29500876 TI - Laser-induced breakdown spectroscopy as a potential tool for autocarbonization detection in laserosteotomy. AB - In laserosteotomy, it is vital to avoid thermal damage of the surrounding tissue, such as carbonization, since carbonization does not only deteriorate the ablation efficiency but also prolongs the healing process. The state-of-the-art method to avoid carbonization is irrigation systems; however, it is difficult to determine the desired flow rate of the air and cooling water based on previous experiments without online monitoring of the bone surface. Lack of such feedback during the ablation process can cause carbonization in case of a possible error in the irrigation system or slow down the cutting process when irrigating with too much cooling water. The aim of this paper is to examine laser-induced breakdown spectroscopy as a potential tool for autocarbonization detection in laserosteotomy. By monitoring the laser-driven plasma generated during nanosecond pulse ablation of porcine bone samples, carbonization is hypothesized to be detectable. For this, the collected spectra were analyzed based on variation of a specific pair of emission line ratios in both groups of samples: normal and carbonized bone. The results confirmed a high accuracy of over 95% in classifying normal and carbonized bone. PMID- 29500877 TI - In vivo imaging in the oral cavity by endoscopic optical coherence tomography. AB - The common way to diagnose hard and soft tissue irregularities in the oral cavity is initially the visual inspection by an experienced dentist followed by further medical examinations, such as radiological imaging and/or histopathological investigation. For the diagnosis of oral hard and soft tissues, the detection of early transformations is mostly hampered by poor visual access, low specificity of the diagnosis techniques, and/or limited feasibility of frequent screenings. Therefore, optical noninvasive diagnosis of oral tissue is promising to improve the accuracy of oral screening. Considering this demand, a rigid handheld endoscopic scanner was developed for optical coherence tomography (OCT). The novelty is the usage of a commercially near-infrared endoscope with fitting optics in combination with an established spectral-domain OCT system of our workgroup. By reaching a high spatial resolution, in vivo images of anterior and especially posterior dental and mucosal tissues were obtained from the oral cavity of two volunteers. The convincing image quality of the endoscopic OCT device is particularly obvious for the imaging of different regions of the human soft palate with highly scattering fibrous layer and capillary network within the lamina propria. PMID- 29500878 TI - A new year, a new Journal. AB - Let us start this first editorial of 2018 with wishing you all a marvelous year where most of your dreams come true. In the last years, the editors of Rhinology felt often very unhappy when again we had to refuse papers send to us for Rhinology. Unfortunately, every year we can only accept around 15% of the papers we receive. With pain in our hearts, we often have to refuse papers of good quality but just not innovative enough or with slight methodological imperfections. The editorial board of Rhinology recognized this feeling and we decided to start a new journal: Rhinology Online to have space for all those papers that are good but just do not make the cut for Rhinology. Rhinology Online is a journal of the European Rhinologic Society, and will provide a platform for the dissemination of rhinologic research and reviews, as well as position papers, task force reports and guidelines, amongst an international scientific audience. PMID- 29500879 TI - A penalized likelihood method for multi-group structural equation modelling. AB - In the past two decades, statistical modelling with sparsity has become an active research topic in the fields of statistics and machine learning. Recently, Huang, Chen and Weng (2017, Psychometrika, 82, 329) and Jacobucci, Grimm, and McArdle (2016, Structural Equation Modeling: A Multidisciplinary Journal, 23, 555) both proposed sparse estimation methods for structural equation modelling (SEM). These methods, however, are restricted to performing single-group analysis. The aim of the present work is to establish a penalized likelihood (PL) method for multi group SEM. Our proposed method decomposes each group model parameter into a common reference component and a group-specific increment component. By penalizing the increment components, the heterogeneity of parameter values across the population can be explored since the null group-specific effects are expected to diminish. We developed an expectation-conditional maximization algorithm to optimize the PL criteria. A numerical experiment and a real data example are presented to demonstrate the potential utility of the proposed method. PMID- 29500880 TI - Triptolide sensitizes breast cancer cells to Doxorubicin through the DNA damage response inhibition. AB - Triptolide is an active component from a Chinese herb, Tripterygium wilfordii which has been applied for treating immune-related diseases over centuries. Recently, it was reported that a variety of cancer cell lines could be sensitized to DNA-damage based chemotherapy drugs in combination with Triptolide treatment. In the present study, we show that a short time exposure (3 h) to Triptolide, which did not trigger apoptosis, could specifically increase breast cancer cells sensitivity to Doxorubicin rather than other chemotherapy drugs including Paclitaxel, Fluorouracil, and Mitomycin C. Further studies revealed Triptolide downregulated ATM expression and inhibited DNA damage response to DNA double- strand breaks. Moreover, the chemosensitization effect to Doxorubicin from Triptolide was attenuated by overexpression of ATM in breast cancer cells. Our findings suggest that Triptolide specifically chemosensitizes breast cancer cells to Doxorubicin prior to apoptosis initiation through downregulating ATM expression and inhibiting DNA damage response. PMID- 29500881 TI - NDRG4 in gastric cancer determines tumor cell proliferation and clinical outcome. AB - As a novel candidate tumor suppressor, NDRG4 is largely unstudied in human malignancies. In this study, we investigated the protein expression level of NDRG4 in gastric cancer and its association with outcome of patients. In the present study, we recruited 286 patients with gastric cancer and investigated the protein and mRNA expression of NDRG4 in cancer and adjacent normal specimens by immunohistochemistry assay and real-time PCR. The association of NDRG4 level with clinicopathological characteristics was investigated by appropriate statistical analysis. NDRG4 overexpression and knockdown cell lines were established in order to detect its impact on proliferation and apoptosis. Significant decreased protein and mRNA expression of NDRG4 was found in gastric cancer, compared with adjacent normal specimens. Besides, it was found that NDRG4 protein expression in gastric cancer was significantly associated with tumor differentiation, invasion, metastasis, and stage. Patients with tumors of decreased NDRG4 level were more likely to have unfavorable disease-free and overall survival, in both univariate and multivariate analysis. In addition, overexpression of NDRG4 suppressed cell proliferation of gastric cancer cells in vitro; conversely, the proliferation of gastric cancer cells were enhanced by knockdown of NDRG4. These results proved for the first time that NDRG4 could be a potential tumor suppressor and prognostic marker of gastric cancer. PMID- 29500882 TI - Design of Fusion Proteins for Efficient and Soluble Production of Immunogenic Ebola Virus Glycoprotein in Escherichia coli. AB - The Ebola hemorrhagic fever caused by Ebola virus is an extremely dangerous disease, and effective therapeutic agents are still lacking. Platforms for the efficient production of vaccines are crucial to ensure quick response against an Ebola virus outbreak. Ebola virus glycoprotein (EbolaGP) on the virion surface is responsible for membrane binding and virus entry, thus becoming the key target for vaccine development. However, heterologous expression of this protein still faces engineering challenges such as low production levels and insoluble aggregation. Here, the authors design and compare various fusion strategies, attaching great importance to the solubility-enhancing effect, and tag removal process. It is found that a C-terminal intein-based tag greatly enhances the solubility of EbolaGP and allows one-step chromatographic purification of the untagged EbolaGP through thiol-catalyzed self-cleavage. The purified untagged EbolaGP alone or with Freund's adjuvant are highly immunogenic, as confirmed in a mouse model. Consequently, the present study puts forward a new strategy for the efficient and soluble expression of untagged immunogenic EbolaGP. The intein based protein fusion approach may be of importance for the large-scale production of Ebola virus subunit vaccine. PMID- 29500883 TI - Icariin attenuates titanium particle-induced inhibition of osteogenic differentiation and matrix mineralization via miR-21-5p. AB - Inhibition of bone regeneration by wear debris is the main cause of peri prosthetic osteolysis. Here, we investigated the effect of icariin on cell proliferation, apoptosis, osteogenic differentiation and matrix mineralization of osteoblasts in an in vitro model of titanium (Ti) particle-induced osteolysis. In the present study, MC3T3-E1 cells were pretreated with 10-8 M icariin for 4 h and then incubated with Ti particles (0.1 mg/mL). The results showed that Ti particles inhibited cell proliferation and promoted cell apoptosis of MC3T3-E1 cells, whereas icariin pretreatment blocked the effect of Ti particles. In addition, we found that icariin stimulation alone increased ALP activity, accelerated matrix mineralization and upregulated the levels of bone morphogenetic protein 2 (BMP2), Runt-related transcription factor 2 (Runx2), osteocalcin (OCN) and miR-21-5p; whereas, Ti particles alone exerted the opposite effects. Icariin partly reversed the effect of Ti particles on cell differentiation and mineralization. Twenty hours after transfection with antagomiR-21-5p or antagomiR-NC, the cells were pretreated with icariin for 4 h and then incubated with Ti particles. Further studies showed that partial knockdown of miR-21-5p abolished the promotion effect of icariin on osteoblast differentiation and matrix mineralization in Ti particle-stimulated MC3T3-E1 cells. In conclusion, miR-21-5p may be a potential pro-osteogenesis regulator and icariin may protect against Ti particle-induced inhibition of osteogenic differentiation and mineralization through upregulation of miR-21-5p. PMID- 29500884 TI - Yeast membrane lipid imbalance leads to trafficking defects toward the Golgi. AB - Protein recycling is an essential cellular process involving endocytosis, intracellular trafficking, and exocytosis. In mammalian systems membrane lipids, including cholesterol, sphingolipids, and phospholipids, play a pivotal role in protein recycling. To address this role in budding yeast, Saccharomyces cerevisiae, we utilized GFP-Snc1, a v-SNARE protein serving as a fluorescent marker for faithfully reporting the recycling pathway. Here we demonstrate results that display moderate to significant GFP-Snc1 recycling defects upon overexpression or inactivation of phospholipid, ergosterol, and sphingolipid biosynthesis enzymes, indicating that the homeostasis of membrane lipid levels is prerequisite for proper protein recycling. By using a truncated version of GFP Snc1 that cannot be recycled from the plasma membrane, we determined that abnormalities in Snc1 localization in membrane lipid overexpression or underexpression mutants are not due to defects in the synthetic/secretory pathway, but rather in the intracellular trafficking pathway. We found that membrane lipid imbalance resulted in an accumulation of the late endosome marker Vps10-GFP, indicating trafficking from the endosomes to the Golgi may be being hindered, preventing recycling to the plasma membrane. To elucidate the possible mechanism for this trafficking hindrance, we stained the actin cytoskeleton, then quantified the percentage of cells with visible actin cables. Compared to wild type cells, membrane lipid mutant cells exhibited lower levels of actin cables, indicating the actin cytoskeleton is disrupted upon membrane lipid imbalance. Taken together, our results show that impairment of proper recycling may be due to disruption of the actin cytoskeleton, which causes trafficking hindrance between the endosomes and Golgi. PMID- 29500885 TI - Germline control of somatic Kras mutations in mouse lung tumors. AB - Somatic KRAS mutations are common in human lung adenocarcinomas and are associated with worse prognosis. In mice, Kras is frequently mutated in both spontaneous and experimentally induced lung tumors, although the pattern of mutation varies among strains, suggesting that such mutations are not random events. We tested if the occurrence of Kras mutations is under genetic control in two mouse intercrosses. Codon 61 mutations were prevalent, but the patterns of nucleotide changes differed between the intercrosses. Whole genome analysis with SNPs in (A/J x C57BL/6)F4 mice revealed a significant linkage between a locus on chromosome 19 and 2 particular codon 61 variants (CTA and CGA). In (AIRmax * AIRmin) F2 mice, there was a significant linkage between SNPs located on distal chromosome 6 (around 135 Mbp) and the frequency of codon 61 mutation. These results reveal the presence of two loci, on chromosomes 6 and 19, that modulate Kras mutation frequency in different mouse intercrosses. These findings indicate that somatic mutation frequency and type are not simple random events, but are under genetic control. PMID- 29500886 TI - Biological effects of trans fatty acids and their possible roles in the lipid rafts in apoptosis regulation. AB - A large number of recent studies are focused on evaluating the mechanism of action of trans fatty acids (TFAs) on the progression of apoptosis. A strong positive association has been reported between TFA and coronary heart disease (CHD), obesity and nonalcoholic steatohepatitis and so on. The present study reviewed the biological effects of trans fatty acids (TFA) and their possible roles in lipid rafts in regulating apoptosis. The following aspects of TFA were included: the research about TFA and diseases affecting serum lipid levels, inducing system inflammation and immune response, and the correlation between TFA and apoptosis. The primary purpose of the review article was to comprehensively evaluate the potential correlation between lipid rafts and apoptosis induced by different structures of TFA and provide some new research progress and future directions about it. PMID- 29500888 TI - In this Issue: Volume 109, Issue 3, March 2018. PMID- 29500887 TI - TGFbeta-induced epithelial-to-mesenchymal transition in prostate cancer cells is mediated via TRPM7 expression. AB - Growth factors, such as the transforming growth factor beta (TGFbeta), play an important role in promoting metastasis of prostate cancer, thus understanding how TGFbeta could induce prostate cancer cell migration may enable us to develop targeted strategies for treatment of advanced metastatic prostate cancer. To more clearly define the mechanism(s) involved in prostate cancer cell migration, we undertook a series of studies utilizing non-malignant prostate epithelial cells RWPE1 and prostate cancer DU145 and PC3 cells. Our studies show that increased cell migration was observed in prostate cancer cells, which was mediated through epithelial-to-mesenchymal transition (EMT). Importantly, addition of Mg2+ , but not Ca2+ , increased cell migration. Furthermore, TRPM7 expression, which functions as an Mg2+ influx channel, was also increased in prostate cancer cells. Inhibition of TRPM7 currents by 2-APB, significantly blocked cell migration in both DU145 and PC3 cells. Addition of growth factor TGFbeta showed a further increase in cell migration, which was again blocked by the addition of 2-APB. Importantly, TGFbeta addition also significantly increased TRPM7 expression and function, and silencing of TRPM7 negated TGFbeta-induced cell migration along with a decrease in EMT markers showing loss of cell adhesion. Furthermore, resveratrol, which decreases prostate cancer cell migration, inhibited TRPM7 expression and function including TGFbeta-induced cell migration and activation of TRPM7 function. Together, these results suggest that Mg2+ influx via TRPM7 promotes cell migration by inducing EMT in prostate cancer cells and resveratrol negatively modulates TRPM7 function thereby inhibiting prostate cancer metastasis. PMID- 29500889 TI - Editorial: Chemistry of Linkers for Conjugated Biotherapeutics. PMID- 29500890 TI - Editorial: Multitarget Molecules for Alzheimer's Disease Therapy. PMID- 29500891 TI - Tensor fasciae latae muscle in human embryos and fetuses with special reference to its contribution to the development of the iliotibial tract. AB - The human fasciae latae muscle (TFL) is inserted into the iliotibial tract and plays a critical role in lateral stabilization of the hip joint. We previously described a candidate of the initial iliotibial tract that originated from the gluteus maximus muscle and extended distally. This study extended our observations by examining 30 human embryos and fetuses of gestational age (GA) 7 14 (crown-to-rump length [CR:] 24-108 mm). At GA 7 weeks, the TFL appeared as a small muscle mass floating in the subcutaneous tissue near the origins of the gluteus medius and rectus femoris muscles. Subsequently, the TFL obtained an iliac origin adjacent to the rectus femoris tendon, but the distal end remained a tiny fibrous mass on the vastus lateralis muscle. Until GA 10 weeks, the TFL muscle fibers were inserted into a vastus lateralis fascia that joined the quadriceps tendon distally. The next stage consisted of the TFL muscle belly "connecting" the vastus fascia and the gluteus fascia, including our previous candidate of the initial iliotibial tract. Until GA 14 weeks, the TFL was sandwiched by two laminae of the connecting fascia. These findings suggested that, when the vastus lateralis fascia separated from the quadriceps tendon to attach to the tibia, possibly after birth, the resulting iliotibial tract would consist of a continuous longitudinal band from the gluteus maximus fascia, via the vastus fascia, to the tibia. Although it is a small muscle, the fetal TFL plays a critical role in the development of the iliotibial tract. PMID- 29500892 TI - Anatomy of the feeding arteries of the cerebral arteriovenous malformations. AB - BACKGROUND: Identification and anatomic features of the feeding arteries of the arteriovenous malformations (AVMs) is very important due to neurologic, radiologic, and surgical reasons. MATERIALS AND METHODS: Seventy-seven patients with AVMs were examined by using a digital subtraction angiographic (DSA) and computerized tomographic (CT) examination, including 3D reconstruction of the brain vessels. In addition, the arteries of 4 human brain stems and 8 cerebral hemispheres were microdissected. RESULTS: The anatomic examination showed a sporadic hypoplasia, hyperplasia, early bifurcation and duplication of certain cerebral arteries. The perforating arteries varied from 1 to 8 in number. The features of the leptomeningeal and choroidal vessels were presented. The radiologic examination revealed singular (22.08%), double (32.48%) or multiple primary feeding arteries (45.45%), which were dilated and elongated in 58.44% of the patients. The feeders most often originated from the middle cerebral artery or MCA (23.38%), less frequently from the anterior cerebral artery or ACA (12.99%), and the posterior cerebral artery or PCA (10.39%). Multiple feeders commonly originated from the ACA and MCA (11.69%), the MCA and PCA (10.39%), the ACA and PCA (7.79%), and the ACA, MCA and PCA (5.19%). The infratentorial feeders were found in 9.1% of the AVMs. Contribution from the middle meningeal and occipital arteries was seen in 3.9% angiograms. Two cerebral arteries had a saccular aneurysm. The AVM hemorrhage appeared in 63.6% of patients. CONCLUSIONS: The knowledge of the origin and anatomic features of the AVMs feeders is important in the explanation of neurologic signs, and in a decision regarding the endovascular embolization, neurosurgical and radiosurgical treatments. PMID- 29500893 TI - Variations in carotid sinus anatomy and their relevance to carotid interventions. AB - BACKGROUND: The carotid sinus (CS) is a dilatation in the carotid bifurcation usually at the origin of proximal internal carotid artery (ICA). It contains baroreceptors which influence blood pressure. Variations in the location of the CS are of importance as atheromatous plaque commonly forms in this area and procedures such as carotid endarterectomy are performed to reduce the risk of stroke. Inadvertent stimulation of the CS baroreceptors during interventions can have profound effects on the patient's hemodynamic status both intra- and postoperatively, causing serious complications. The aim of this study is to determine the inter- and intra-individual variations in the location of the CS. MATERIALS AND METHODS: Eighty-two carotid arteries were dissected bilaterally from 41 cadavers. The locations of the CS were noted and divided into four potential sites. RESULTS: The commonest site is the origin of the ICA (74.3%), but the CS can also be found in the distal part of the common carotid artery (CCA) inferior to the bifurcation (17.1%); at the bifurcation involving the distal CCA and origins of both the external carotid (ECA) and internal carotid arteries (7.32%); and at the origin of the ECA (1.22%). In individual cadavers, the CS was located at the origin of the ICA in 97.6% on at least one side. The sites of the CS were asymmetrical in 34.1%. CONCLUSIONS: Clinicians performing carotid interventions should be aware of these anatomical variations to avoid inadvertent stimulation of the CS which can cause profound bradycardia and hypotension. PMID- 29500894 TI - Variations of the cephalic vein anterior to the clavicle in humans. AB - BACKGROUND: Clinicians should understand that jugulocephalic vein variants may be occasionally found. This study aims to classify jugulocephalic vein variants and obtain their frequency. MATERIALS AND METHODS: We investigated anatomical variants of the cephalic vein in 55 human cadavers during a gross anatomy course at our medical school. RESULTS: The percentage of jugulocephalic veins that pass through the anterior part of the clavicle and anastomose to the jugular vein as per previous studies and our study was approximately 2 to 5%. Five cases with anastomosis between the cephalic and external jugular veins that pass through the anterior part of the clavicle were found. The courses were classified into 1A, 1B, 2A, and 2B. Type 1 extends beyond the clavicle and anastomoses with the external jugular vein. Type 2 follows the same course as Type 1, but anastomoses with the subclavian vein. Subtype A does not have a branch that anastomoses with the axillary vein, whereas subtype B does. We encountered two cases of Type 1A and three of Type 1B. CONCLUSIONS: Four anatomical variants of the cephalic vein around the clavicle were identified. Clinicians' knowledge of these variants is expected to decrease possible complications if venous access via the cephalic vein is needed. PMID- 29500895 TI - Determination and classification of cutaneous innervation of dorsum of the foot in fetal cadavers. AB - BACKGROUND: The aim of this study is to determine of cutaneous innervation of dorsum of the foot on fetal cadavers. MATERIALS AND METHODS: In this study 200 limbs from 100 embalmed fetuses (54 males and 46 females) were studied in Anatomy Laboratory. Contributions of medial, lateral and intermediate dorsal cutaneous nerves (MDCN, LDCN and IDCN) of the foot were identified. FINDINGS: Cutaneous innervation of dorsum of the foot was classified into five Types. Type I (75%) where MDCN innervated medial border of the foot and second interdigital cleft; IDCN innervated third, fourth and fifth interdigital clefts; and LDCN innervated the lateral border of the foot. Type II (21%) where MDCN innervated medial border of the foot, second and third interdigital clefts; IDCN innervated fourth and fifth interdigital clefts; and LDCN innervated the lateral border of the foot. In Type III (1.5%) where saphenous nerve (SN) innervated medial border of the foot; MDCN innervated second and third interdigital clefts; IDCN innervated fourth and fifth interdigital clefts; and LDCN innervated the lateral border of the foot. Type IV (1.5%) was similar to Type I, with an extra connection between the MDCN and IDCN on the dorsum of the foot. Type V (1%) where superficial fibular nerve (SFN) innervated medial border of the foot, and second, third and fourth interdigital clefts; and sural nerve (SrN) innervated fifth interdigital cleft and lateral border of the foot. CONCLUSIONS: The present study provides a new classification for the cutaneous innervation of the dorsum of the foot. PMID- 29500896 TI - Common celiacomesenteric trunk: a computed tomography radiological study. AB - BACKGROUND: There is an increasing trend for administration of invasive radiological interventions, laparoscopic surgery, and transplantation procedures in recent years, and determining the vascular variations prior to these procedures is crucially important. Celiacomesenteric trunk (CMT) is among these variations. This study aimed to retrospectively evaluate this rare anomaly by computed tomography (CT). MATERIALS AND METHODS: A total of 1000 CT angiography images were analyzed retrospectively, and the patients with mesenteric and celiac arteries arising from the abdominal aorta with a single root were identified. The level that CMT arose, and its branching patterns were determined individually for all patients. RESULTS: Ten patients (6 males and 4 females) with a mean age of 50.2 years (17-87 years) had CMT in CT images. CONCLUSIONS: The knowledge of variations in the CMT prior to vascular or laparoscopic interventions will contribute to early intervention in case of a complication, or to avoid from a potential damage. PMID- 29500897 TI - Morphometric analysis of the sella turcica in Turkish individuals with different dentofacial skeletal patterns. AB - BACKGROUND: The aim of this study was to evaluate the morphometric analysis of sella turcica in a Turkish population according to gender, age, and dentofacial skeletal type and to investigate the prevalence of sella turcica shapes in different dentofacial skeletal types. MATERIALS AND METHODS: The lateral cephalometric radiographs of 362 patients (145 males, 217 females) were included and grouped by age, gender, and dentofacial skeletal patterns. Linear dimensions of sella turcica, which include the length, height, and diameter, were measured, and the shapes of sella turcica were evaluated. RESULTS: The anatomical variants of the sella turcica in this study were normal morphology (39.0%), followed by pyramidal shape (15.5%), double contour of floor (14.6%), oblique anterior wall (14.4%), irregular dorsum sella (8.6%), and sella turcica bridge (8.0%). Significant differences were found between sella turcica shapes and dentofacial skeletal types (p < 0.01). Females had greater diameter size of sella turcica than males (p < 0.01). In addition, the subjects in the 15-21 age group had larger sella turcica depths and diameters than the subjects in the 9-14 age group (p < 0.05 and p < 0.01, respectively). However, no significant differences were found between age groups in terms of sella turcica lengths (p > 0.05). CONCLUSIONS: Results from this study showed that the sample had a higher rate of morphological variation (39% normal, 61% other types) in comparison with other populations or ethnic groups. The class III patients had more irregularity (notching) types in the posterior part of the dorsum sella and fewer oblique anterior wall types than the others. Linear dimensions and morphological types of sella turcica in this study can be used as reference for additional investigators, such as radiologists, orthodontists, maxillofacial surgeons, and neurosurgeons, to interpret and plan surgical procedures involving the sellar region. PMID- 29500898 TI - Radiological study on mandibular ramus asymmetry in young population. AB - BACKGROUND: The aim of this study was to estimate the prevalence of ramus asymmetries related to age and gender in a young population and the influence of growth spurt on ramus asymmetry. MATERIALS AND METHODS: The study consisted of 776 panoramic radiographs of individuals aged 9 to 21 years (335 males and 441 females). Individuals were divided into two groups with respect of linear growth spurt as age 12 in females and age 14 in males. The first group consisted of females aged between 9-11 and males between 9-13. The second group consisted of females aged between 12-21 and males between 14-21. Bilateral ramus heights on each radiograph were measured. A panoramic software program was used to measure the ramus heights. Quantitative data was tested by Student's t test. Qualitative data was tested by chi-square test. The intraclass correlation coefficient (ICC) was calculated for the magnitude error of the measurement. RESULTS: The mean of ramus asymmetry was found to be 2.90+/-2.58%. Significant differences between the right and left ramus height ratios were observed (p<0.01). There was a high prevalence (10.8%) of ramus asymmetry, which did not correlate with the age, and gender of the patients. CONCLUSIONS: This study revealed a high prevalence of ramus asymmetry in 9-21 year old population. Within the limitations of this study, it can be concluded that ramus asymmetry should carefully be evaluated in all ages for the potential relation with temporomandibular dysfunctions and also for orthodontic anomalies. PMID- 29500899 TI - Novel variations in spatial relations between the facial nerve and superficial temporal and maxillary veins. AB - Variations in the relationship of the retromandibular vein to the facial nerve have been widely reported due to their relevance for surgical approaches in parotid, osteotomy and mandibular condyle surgery. In the context of the retromandibular retroparotid approach, remaining deep to the retromandibular vein is advised to decrease the likelihood of encountering the facial nerve during mandibular condyle surgery. In the present report, an unusual variant of the superficial temporal vein lying superficial to the facial nerve is described. This represents a variation of the venous branching pattern within the parotid gland, whereby the superficial temporal vein joins the maxillary vein inferior to its usual communication. These findings are discussed in the context of commonly used surgical approaches to the mandible for condylar trauma or osteotomy surgery. PMID- 29500900 TI - New biomarkers for drug-induced liver injury. PMID- 29500901 TI - Reply. PMID- 29500903 TI - Choice of reconstitution protocol modulates the aggregation state of full-length membrane-reconstituted synaptotagmin-1. AB - Synaptotagmin-1 (Syt1) functions as the Ca2+ sensor in neuronal exocytosis, and it is routinely incorporated into lipid bilayers along with other components of the fusion machinery in order to reconstruct the in vivo fusion process. Here, we demonstrate that the detergent used to reconstitute full-length Syt1 has a significant effect on the state of the protein in bilayers. When octyl-beta-d glucopyranoside is used to reconstitute the protein, Syt1 is present in an aggregated state that is mediated by the long juxta-membrane linker. EPR spectra from spin labels in the two C2 domains of Syt1 no longer resemble those obtained from a soluble construct containing these domains, and the C2B domain no longer exhibits a Ca2+ -dependent membrane insertion. In contrast, when reconstituted using 3-[(3-cholamidopropyl) dimethylammonio]-1-propanesulfonate, Syt1 is largely monomeric and the EPR spectra from C2A and C2B resemble those of the soluble construct. This result demonstrates that the choice of detergent used to reconstitute Syt1 can modulate the state of the neuronal Ca2+ -sensor. PMID- 29500904 TI - Is Sorafenib an Optimal Treatment for Hepatocellular Carcinoma With Macrovascular Invasion or Metastatic Disease? PMID- 29500902 TI - Distinct sites in tropomyosin specify shared and isoform-specific regulation of myosins II and V. AB - Muscle contraction, cytokinesis, cellular movement, and intracellular transport depend on regulated actin-myosin interaction. Most actin filaments bind one or more isoform of tropomyosin, a coiled-coil protein that stabilizes the filaments and regulates interactions with other actin-binding proteins, including myosin. Isoform-specific allosteric regulation of muscle myosin II by actin-tropomyosin is well-established while that of processive myosins, such as myosin V, which transport organelles and macromolecules in the cell periphery, is less certain. Is the regulation by tropomyosin a universal mechanism, the consequence of the conserved periodic structures of tropomyosin, or is it the result of specialized interactions between particular isoforms of myosin and tropomyosin? Here, we show that striated muscle tropomyosin, Tpm1.1, inhibits fast skeletal muscle myosin II but not myosin Va. The non-muscle tropomyosin, Tpm3.1, in contrast, activates both myosins. To decipher the molecular basis of these opposing regulatory effects, we introduced mutations at conserved surface residues within the six periodic repeats (periods) of Tpm3.1, in positions homologous or analogous to those important for regulation of skeletal muscle myosin by Tpm1.1. We identified conserved residues in the internal periods of both tropomyosin isoforms that are important for the function of myosin Va and striated myosin II. Conserved residues in the internal and C-terminal periods that correspond to Tpm3.1 specific exons inhibit myosin Va but not myosin II function. These results suggest that tropomyosins may directly impact myosin function through both general and isoform-specific mechanisms that identify actin tracks for the recruitment and function of particular myosins. PMID- 29500905 TI - A sensitive LC-MS/MS method for simultaneous determination of cabozantinib and its metabolite cabozantinib N-oxide in rat plasma and its application in a pharmacokinetic study. AB - Cabozantinib (CBZ) is used for the treatment of progressive, metastatic medullary thyroid cancer. Its major oxidative metabolite is cabozantinib N-oxide (CBN), which contains a structural alert associated with mutagenicity, yet the pharmacokinetics studies lack the simultaneous investigation of CBN and dose proportionality. In the current study a simple LC-MS/MS method was developed and validated for the simultaneous estimation and pharmacokinetic investigation of CBZ and CBN in rat plasma. The analytes were separated on a Waters Atlantics C18 column (2.1 * 150 mm, 3 MUm). The mass spectrometry analysis was conducted in positive ionization mode with multiple reaction monitoring. Good linearity was observed over the concentration ranges of 0.500-5000 ng/mL for CBZ and 0.525-2100 ng/mL for CBN. The extraction recoveries were constant and the intra- and inter batch precision and accuracy were acceptable for the analysis of biological samples. The method was successfully applied for the simultaneous estimation of CBZ and CBN in a pharmacokinetic study in Sprague-Dawley rats. After oral administration of CBZ (1, 5 and 12.6 mg/kg), although CBZ showed dose proportionality, the metabolite CBN showed obvious nonlinear elimination pharmacokinetics with greater than dose-proportional increases in exposure. PMID- 29500906 TI - A tale of two "half tongues". PMID- 29500908 TI - Efficacy of a new nail brace for the treatment of ingrown toenails. AB - BACKGROUND AND OBJECTIVES: Surgery is the mainstay of treatment for complicated ingrown toenails. However, alternative treatments using nail braces have been reported to show good efficacy. The objective of the present study was to investigate the efficacy of a new nail brace for the treatment of ingrown toenails. PATIENTS AND METHODS: We conducted a retrospective study on patients with ingrown toenails treated at Wan Fang Hospital between June 1, 2015 and May 30, 2016. Ingrown toenails were classified into acute inflamed/infected (AI) and chronic dystrophic (CD) types. Using physician global assessment scores, the efficacy of nail braces for the two types of ingrown toenails was compared 1, 2, 3, and 6 months after treatment initiation and during the final visit. RESULTS: Twenty-one patients (42 sites) had CD-type ingrown toenails; 25 patients (36 sites) had ingrown toenails of the AI type. Of the affected sites, 81 %, 94 %, and 100 % showed an excellent or fair outcome at 1, 3, and 6 months, respectively. Recurrence rates were 10.3 %; complication rates, 7.7 %. While, in the first three months, AI-type ingrown toenails tended to achieve excellent results more rapidly than CD-type nails, outcomes were similar at six months. CONCLUSIONS: Nail braces are an effective therapeutic option, particularly for CD type ingrown toenails. PMID- 29500907 TI - Alterations in gut microbial function following liver transplant. AB - Liver transplantation (LT) improves daily function and ameliorates gut microbial composition. However, the effect of LT on microbial functionality, which can be related to overall patient benefit, is unclear and could affect the post-LT course. The aims were to determine the effect of LT on gut microbial functionality focusing on endotoxemia, bile acid (BA), ammonia metabolism, and lipidomics. We enrolled outpatient patients with cirrhosis on the LT list and followed them until 6 months after LT. Microbiota composition (Shannon diversity and individual taxa) and function analysis (serum endotoxin, urinary metabolomics and serum lipidomics, and stool BA profile) and cognitive tests were performed at both visits. We enrolled 40 patients (age, 56 +/- 7 years; mean Model for End Stage Liver Disease score, 22.6). They received LT 6 +/- 3 months after enrollment and were re-evaluated 7 +/- 3 months after LT with a stable course. A significant improvement in cognition with increase in microbial diversity, increase in autochthonous and decrease in potentially pathogenic taxa, and reduced endotoxemia were seen after LT compared with baseline. Stool BAs increased significantly after LT, and there was evidence of greater bacterial action (higher secondary, oxo and iso-BAs) after LT although the levels of conjugated BAs remained similar. There was a reduced serum ammonia and corresponding rise in urinary phenylacetylglutamine after LT. There was an increase in urinary trimethylamine-N-oxide, which was correlated with specific changes in serum lipids related to cell membrane products. The ultimate post-LT lipidomic profile appeared beneficial compared with the profile before LT. In conclusion, LT improves gut microbiota diversity and dysbiosis, which is accompanied by favorable changes in gut microbial functionality corresponding to BAs, ammonia, endotoxemia, lipidomic, and metabolomic profiles. Liver Transplantation 24 752-761 2018 AASLD. PMID- 29500909 TI - Residual level of dimethachlon in rice-paddy field system and cooked rice determined by gas chromatography with electron capture detector. AB - In this study, a modified quick, easy, cheap, effective, rugged and safe method coupled with gas chromatography with electron capture detection was established to determine dimethachlon residues in paddy soil, rice husk, rice straw, brown rice and cooked rice. The limits of quantification of dimethachlon were 0.01 mg/kg for paddy soil, brown rice and cooked rice and 0.02 mg/kg for rice straw and rice husk. The mean recoveries were in the range 78.59-104.7% with relative standard deviation values of <10% for dimethachlon in the five matrices. For field experiments, the final residues of dimethachlon in paddy soil were < 0.05 mg/kg and were < 1.21 mg/kg in rice straw from six sites. The final residues of dimethachlon in the brown rice at 21, 28 and 35 days after spraying from six sites were 0.08-7.58 mg/kg, and 0.16-30.1 mg/kg in rice husk. Our six test sites covered the main rice-producing areas of China. The routine rice cooking process of a Chinese family could apparently increase the removal of dimethachlon in rice compared with brown rice, and the reduction ratios were > 96%. PMID- 29500911 TI - Macrophages come on tap for liver fibrosis therapy. PMID- 29500910 TI - Enantioseparation and determination of dufulin enantiomers in cucumber and soil by chiral liquid chromatography-tandem mass spectrometry. AB - A simple and rapid method for enantioselective determination of dufulin in cucumber and soil was developed by liquid chromatography with tandem mass spectrometry. The enantiomers were separated on a Superchiral S-OD chiral cellulose tris(3,5-dimethylphenylcarbamate) column at 20 degrees C, with a mixture of acetonitrile and water (0.1% formic acid; 52:48, v/v) as mobile phase at a flow rate of 0.65 mL/min. The pretreatment conditions were optimized using an orthogonal test, and the optimized method showed good linearity and sensitivity. The limits of detection and limits of quantification of two dufulin enantiomers were 0.006 and 0.02 mg/kg, respectively. The average recoveries of S enantiomer and R-enantiomer in cucumber and soil were 80.61-99.83% and 80.97 102.96%, respectively, with relative standard deviations of 1.30-9.72%. The method was successfully applied to determine dufulin in real cucumber and soil samples. The results demonstrate that the method could facilitate further research on the differences between individual dufulin enantiomers with respect to metabolites and environmental fate and finally help reveal the complex interactions that exist between dufulin, humans and the environment. PMID- 29500913 TI - Growth factor therapy for decompensated cirrhosis: Much ado about nothing? PMID- 29500912 TI - Low-dose valganciclovir for cytomegalovirus prophylaxis in intermediate-risk liver transplantation recipients. AB - Liver transplantation recipients (LTRs) who are seropositive for cytomegalovirus (CMV) (recipient seropositive [R+]) are at intermediate risk for CMV disease. A preventative strategy following transplant is considered standard of care. Current guidelines recommend high-dose valganciclovir (VGCV; 900 mg/day adjusted for renal function) for prophylaxis given limited data on the efficacy and safety of low-dose VGCV (450 mg/day adjusted for renal function). We describe our experience using low-dose VGCV prophylaxis for R+ LTRs at our institution. A single-center, retrospective study was conducted using a database of 364 LTRs over a 4-year period (2011-2014). Adult first-time R+ LTRs receiving low-dose VGCV prophylaxis were included. The primary endpoint was CMV disease at 1 year after transplant. Patients were compared with historical controls receiving high dose VGCV prophylaxis. Secondary endpoints were biopsy-proven rejection and leukopenia on VGCV. With respect to leukopenia, patients receiving low-dose VGCV were compared with a group of D+R- patients from the database receiving high-dose VGCV. Univariate analyses were performed using chi-squared, Fisher's exact, and Wilcoxon rank sum tests. A total of 200 R+ LTRs met inclusion criteria. Median age was 60 years (interquartile range [IQR], 54-66 years), and 129 (65%) LTRs were male. Median Model for End-Stage Liver Disease score was 22 (IQR, 14-31), and 178 (89%) patients received deceased donor transplants. CMV disease occurred in only 9 (5%) patients, similar to rates in previous studies of LTRs receiving high-dose VGCV. Biopsy-proven rejection occurred in 18 (9%) patients. Patients received VGCV prophylaxis for a median of 3.4 (IQR, 3.1-4.3) months; 151 (76%) R+ LTRs receiving low-dose VGCV developed leukopenia. Premature VGCV discontinuation and granulocyte-colony stimulating factor use were infrequent and not significantly different between the 2 groups. In conclusion, low-dose VGCV was safe and effective for prevention of CMV disease in our cohort of 200 R+ LTR and should be considered as an option in future guidelines. Liver Transplantation 24 616-622 2018 AASLD. PMID- 29500914 TI - Crosstalk between mesenchymal stem cells and T regulatory cells is crucially important for the attenuation of acute liver injury. AB - One of the therapeutic options for the treatment of fulminant hepatitis is repopulation of intrahepatic regulatory cells because their pool is significantly reduced during acute liver failure. Although it is known that mesenchymal stem cells (MSCs), which have beneficent effects in the therapy of fulminant hepatitis, may promote expansion of regulatory T cells (Tregs) and regulatory B cells (Bregs), the role of these regulatory cells in MSC-mediated attenuation of acute liver injury is unknown. Herewith, we described the molecular mechanisms involved in the crosstalk between MSCs and liver regulatory cells and analyzed the potential of MSC-based therapy for the expansion of intrahepatic regulatory cells in mouse model of acute liver failure. MSC-dependent attenuation of alpha galactosylceramide (alpha-GalCer)-induced acute liver injury in mice was accompanied with an increased presence of interleukin (IL) 10-producing CD4+ CD25+ forkhead box P3+ Tregs and IL10- and transforming growth factor beta producing marginal zone-like Bregs in the liver. Depletion of Bregs did not alter MSC-based alleviation of acute liver failure, whereas depletion of Tregs completely abrogated hepatoprotective effects of MSCs and inhibited their capacity to attenuate hepatotoxicity of liver natural killer T cells (NKTs), indicating that Tregs, and not Bregs, were critically involved in MSC-based modulation of acute liver inflammation. MSCs, in a paracrine, indoleamine 2,3 dioxygenase-dependent manner, significantly increased the capacity of Tregs to produce immunosuppressive IL10 and to suppress hepatotoxicity of liver NKTs. Accordingly, adoptive transfer of MSC-primed Tregs resulted in the complete attenuation of alpha-GalCer-induced acute liver failure. In conclusion, our findings highlighted the crucial importance of Tregs for MSC-based attenuation of acute liver failure and indicated the significance of MSC-mediated priming of Tregs as a new therapeutic approach in Treg-based therapy of acute liver injury. Liver Transplantation 24 687-702 2018 AASLD. PMID- 29500915 TI - A fusion-protein approach enabling mammalian cell production of tumor targeting protein domains for therapeutic development. AB - A single chain Fv fragment (scFv) is a fusion of the variable regions of heavy (VH ) and light (VL ) chains of immunoglobulins. They are important elements of chimeric antigen receptors for cancer therapy. We sought to produce a panel of 16 extracellular protein domains of tumor markers for use in scFv yeast library screenings. A series of vectors comprising various combinations of expression elements was made, but expression was unpredictable and more than half of the protein domains could not be produced using any of the constructs. Here we describe a novel fusion expression system based on mouse TEM7 (tumor endothelial marker 7), which could facilitate protein expression. With this approach we could produce all but one of the tumor marker domains that could not otherwise be expressed. In addition, we demonstrated that the tumor associated antigen hFZD10 produced as a fusion protein with mTEM7 could be used to enrich scFv antibodies from a yeast display library. Collectively our study demonstrates the potential of specific fusion proteins based on mTEM7 in enabling mammalian cell production of tumor targeting protein domains for therapeutic development. PMID- 29500916 TI - A social-contextual investigation of smoking among rural women: multi-level factors associated with smoking status and considerations for cessation. AB - INTRODUCTION: The social-contextual model of tobacco control and the potential mechanisms of the maintenance or cessation of smoking behavior among disadvantaged women, including rural residents, have yet to be comprehensively studied. The purpose of this study was to determine the association between selected individual, interpersonal, workplace, and neighborhood characteristics and smoking status among women in Appalachia, a US region whose residents experience a disproportionate prevalence of tobacco-related health disparities. These findings may assist in efforts to design and test scientifically valid tobacco control interventions for this and other disadvantaged populations. METHODS: Women, 18 years of age and older, residing in three rural Ohio Appalachian counties, were recruited using a two-phase address-based sampling methodology for a cross-sectional interview-administered survey between August 2012 and October 2013 (N=408). Multinomial logistic regression was employed to determine associations between select multilevel factors (independent variables) and smoking status (dependent variable). The sample included 82 (20.1%) current smokers, 92 (22.5%) former smokers, and 234 (57.4%) women reporting never smoking (mean age 51.7 years). RESULTS: In the final multivariable multinomial logistic regression model, controlling for all other significant associations, constructs at multiple social-contextual levels were associated with current versus either former or never smoking. At the individual level, for every additional year in age, the odds of being a former or never smoker increased by 7% and 6% (odds ratio (OR) (95% confidence interval(CI)): 1.07 (1.0-1.11) and 1.06 (1.02-1.09)), respectively, as compared to the odds of being a current smoker. With regard to depression, for each one unit increase in the Center for Epidemiologic Studies Depression Scale score, the odds of being a former or never smoker were 5% and 7% lower (OR(95%CI): 0.95(0.91-0.999) and 0.93(0.88-0.98)), respectively. Five interpersonal factors were associated with smoking status. As the social influence injunctive norm score increased by one unit, indicating perception of smoking to be more acceptable, the odds of being a former or never smoker decreased by 23% and 30%, respectively. For every one unit increase in the social participation score, indicating past-year engagement in one additional activity type, the odds of being a former or never smoker increased by 17% and 36%, respectively. For every 10% increase in the percentage of social ties in the participant's advice network who smoked, the odds of being a former or never smoker were 24% and 28% less, respectively. For every 0.1 unit increase in the E/I index, indicating increasing homophily on smoking in one's social network, the odds of being a former or never smoker were 20% and 24% less, respectively, in the time network, and 18% and 20% less, respectively, in the advice network. At the neighborhood level, for every one unit increase in neighborhood cohesion score, indicating increasing cohesion, the odds of being a former smoker or never smoker were 12% and 14% less, respectively. CONCLUSIONS: These findings indicate that a social-contextual approach to tobacco control may be useful for narrowing a widening trajectory of smoking disparity for rural women. Interpersonal context, in particular, must be considered in the development of culturally targeted cessation interventions for Ohio Appalachian women. PMID- 29500917 TI - Targeting autophagy for the treatment of cancer. AB - Macroautophagy (herein termed autophagy) is evolutionarily highly conserved across eukaryotic cells and represents an intracellular catabolic process that targets damaged macromolecules and organelles for degradation. Autophagy is dysregulated in various human diseases including cancer. In addition, many drugs currently used for the treatment of cancer can engage autophagy, which typically promotes cancer cell survival by mitigating cellular stress. However, under certain circumstances activation of autophagy upon anticancer drug treatment can also trigger a lethal type of autophagy termed autophagic cell death (ACD). This may pave new avenues for exploiting the autophagic circuitry in oncology. This review presents the concept and some examples of anticancer drug-induced ACD. PMID- 29500918 TI - Intracellular communication between lipid droplets and peroxisomes: the Janus face of PEX19. AB - In order to adapt to environmental changes, such as nutrient availability, cells have to orchestrate multiple metabolic pathways, which are catalyzed in distinct specialized organelles. Lipid droplets (LDs) and peroxisomes are both endoplasmic reticulum (ER)-derived organelles that fulfill complementary functions in lipid metabolism: Upon nutrient supply, LDs store metabolic energy in the form of neutral lipids and, when energy is needed, supply fatty acids for oxidation in peroxisomes and mitochondria. How these organelles communicate with each other for a concerted metabolic output remains a central question. Here, we summarize recent insights into the biogenesis and function of LDs and peroxisomes with emphasis on the role of PEX19 in these processes. PMID- 29500919 TI - Simulation of personalised haemodynamics by various mounting positions of a prosthetic valve using computational fluid dynamics. AB - Diseases of the cardiovascular system account for nearly 42% of all deaths in the European Union. In Germany, approximately 12,000 patients receive surgical replacement of the aortic valve due to heart valve disease alone each year. A three-dimensional (3D) numerical model based on patient-specific anatomy derived from four-dimensional (4D) magnetic resonance imaging (MRI) data was developed to investigate preoperatively the flow-induced impact of mounting positions of aortic prosthetic valves to select the best orientation for individual patients. Systematic steady-state analysis of blood flow for different rotational mounting positions of the valve is only possible using a virtual patient model. A maximum velocity of 1 m/s was used as an inlet boundary condition, because the opening angle of the valve is at its largest at this velocity. For a comparative serial examination, it is important to define the standardised general requirements to avoid impacts other than the rotated implantation of the prosthetic aortic valve. In this study, a uniform velocity profile at the inlet for the inflow of the aortic valve and the real aortic anatomy were chosen for all simulations. An iterative process, with the weighted parameters flow resistance (1), shear stress (2) and velocity (3), was necessary to determine the best rotated orientation. Blood flow was optimal at a 45 degrees rotation from the standard implantation orientation, which will offer a supply to the coronary arteries. PMID- 29500920 TI - Factors related to job burnout among nurses in the Razi Psychiatric Hospital, Iran. AB - Background One of the most prevalent problems in work places that is considered as an important risk factor for the health of the employee is job burnout (JB). JB could be harmful to employees, their families and society. Therefore, decreasing JB among individuals and determining factors associated with it is important to improve the working environment and prevent its negative outcomes. This study aims to elicit the conditions and factors that cause job burnout among nurses of the Razi Psychiatric Hospital, Iran. Methods This study was a descriptive correlational and cross-sectional survey which the demographic and occupational burnout variables of nurses were measured. The study was conducted from January to April 2016. Accordingly, with a type I error probability of 0.05 and a power of 0.80, the sample size was determined to be 100 nurses for each group (men and women). Then, 200 were selected in the Razi Psychiatric Hospital (of whom approx. 60% worked in a rotating shift schedule). The data were collected in two phases: the first step was created by the authors, including gathering demographic data with questionnaire such as gender, age, marital status, education level, years of professional experience, hours of overtime working per month, shift schedules, and their working hospitals and wards. The second step was the Maslach burnout inventory (MBI), human services survey (HSS) version, developed by Maslach and Jackson to assess the three dimensions of burnout. Descriptive statistics (frequency distribution) were used for integrating the demographic variables. Additionally, logistical regression was applied to realize the association between demographic characteristics with the job burnout in SPSS software V.19. Results Our findings indicated that age, hours of work per week, nursing skills, management experience and work experiences accounted for 30% of the variance of depersonalization. Formal employment was significantly associated with emotional exhaustion (p < 0.04). Also, sex was significantly associated with low personal accomplishment (p < 0.006). Conclusion The employment status and gender of nurses participating in the study has an effect on emotional exhaustion and personal achievement. Paying more attention to gender in the nursing profession and the change in their work status to a stable and formalized format can lead to a reduction in job burnout among nurses. PMID- 29500921 TI - Corrigendum to: Possible modulation of PPAR-gamma cascade against depression caused by neuropathic pain in rats. PMID- 29500922 TI - Electrodermal response to auditory stimuli in relation to menopausal transition period. AB - BACKGROUND: Menopause-associated estrogen deficiency results in climacteric symptoms like vasomotor, psychological and sleep disturbances that cause a decline in the quality of life. Electrodermal activity (EDA), a psychophysiological measure, reflects sympathetic activity, which provides information associated with individual's emotions, phobias, arousal, cognition and stress. The study compared electrodermal response to auditory stimuli between postmenopausal and perimenopausal women with and without symptoms and also correlated the association of scores of the menopausal transition symptoms with indices of EDA. METHODS: Seventy-five women volunteers in the age group of 45-60 years, 25 in each group who were postmenopausal, perimenopausal with symptoms and perimenopausal without symptoms, were recruited. Indices of EDA such as latency, amplitude, rise time and half recovery time for auditory stimuli were quantified using standard techniques. Symptoms of menopausal transition were assessed using Women Health Questionnaire. RESULTS: Analysis using one-way analysis of covariance after controlling for variables showed that mean skin conductance level of EDA was significantly higher among perimenopausal women with symptoms compared with perimenopausal women without symptoms and postmenopausal women. Perimenopausal women with symptoms had significantly lower latency of response when compared with other groups. Analysis using Pearson correlation test showed that latency of EDA had significant positive correlation and amplitude had significant negative correlation with menopausal transition symptom scores. CONCLUSIONS: Perimenopausal women with symptoms exhibited increased sympathetic sudomotor activity when compared with perimenopausal women without symptoms and postmenopausal women as measured by EDA. Further, select measures of EDA exhibited significant association with the symptoms of menopausal transition. PMID- 29500923 TI - Regulation of hypoxia inducible factor/prolyl hydroxylase binding domain proteins 1 by PPARalpha and high salt diet. AB - BACKGROUND: Hypoxia inducible factor (HIF)/prolyl hydroxylase domain (PHD) containing proteins are involved in renal adaptive response to high salt (HS). Peroxisome proliferator activated receptor alpha (PPARalpha), a transcription factor involved in fatty acid oxidation is implicated in the regulation of renal function. As both HIF-1alpha/PHD and PPARalpha contribute to the adaptive changes to altered oxygen tension, this study tested the hypothesis that PHD-induced renal adaptive response to HS is PPARalpha-dependent. METHODS: PPARalpha wild type (WT) and knock out (KO) mice were fed a low salt (LS) (0.03% NaCl) or a HS (8% NaCl) diet for 8 days and treated with hydralazine. PPARalpha and heme oxygenase (HO)-1 expression were evaluated in the kidney cortex and medulla. A 24 h urinary volume (UV), sodium excretion (UNaV), and nitrite excretion (UNOx V) were also determined. RESULTS: PHD1 expression was greater in the medulla as compared to the cortex of PPARalpha WT mice (p<0.05) fed with a LS (0.03% NaCl) diet. The HS diet (8% NaCl) downregulated PHD1 expression in the medulla (p<0.05) but not the cortex of WT mice whereas expression was downregulated in the cortex (p<0.05) and medulla (p<0.05) of KO mice. These changes were accompanied by HS induced diuresis (p<0.05) and natriuresis (p<0.05) that were greater in WT mice (p<0.05). Similarly, UNOx V, index of renal nitric oxide synthase (NOS) activity or availability and heme oxygenase (HO)-1 expression was greater in WT (p<0.05) but unchanged in KO mice on HS diet. Hydralazine, a PHD inhibitor, did not affect diuresis or natriuresis in LS diet-fed WT or KO mice but both were increased (p<0.05) in HS diet-fed WT mice. Hydralazine also increased UNOx V (p<0.05) with no change in diuresis, natriuresis, or HO-1 expression in KO mice on HS diet. CONCLUSIONS: These data suggest that HS-induced PPARalpha-mediated downregulation of PHD1 is a novel pathway for PHD/HIF-1alpha transcriptional regulation for adaptive responses to promote renal function via downstream signaling involving NOS and HO. PMID- 29500924 TI - The effects of fennel on menstrual bleeding: A systematic review and meta analysis. PMID- 29500925 TI - Siting childcare centres on busy roads: what are the dangers? PMID- 29500926 TI - Effects of climate change on the spread of zika virus: a public health threat. AB - Zika is a vector-borne viral disease transmitted to humans primarily by Aedes aegypti mosquitoes. The increased climate instability has contributed to the emergence of infections carried by mosquitoes like dengue, chikungunya and zika. While infection with the zika virus is not new, the recent epidemic of microcephaly in Brazil and other countries in South America resulting from the infection of pregnant women with the zika virus raise a number of serious public health concerns. These include the question of how climate change affects the range of zika vectors, what can we do to shorten the length of mosquito season, how and why the symptoms of zika infection have changed and what can be done to reduce the burden of human disease from this infection? Another important question that needs to be answered is what are the factors that caused the zika virus to leave the non-human primates and/or other mammals and invade the human population? PMID- 29500927 TI - Management of Severe Lower Cervical Facet Dislocation without Vertebral Body Fracture Using Skull Traction and an Anterior Approach. AB - BACKGROUND Cervical facet dislocation is the anterior displacement of one cervical vertebral body on another. The aim of this study was to evaluate the clinical efficacy of skull traction through an anterior cervical approach in the treatment of severe lower cervical facet dislocation without vertebral body fracture. MATERIAL AND METHODS Forty subjects with severe lower cervical facet dislocation, without vertebral body fracture, were treated between February 2010 and December 2013. Road traffic accident was the primary cause of injury. Patients presented with dislocated segments in C3-C4 (n=4), C4-C5 (n=4), C5-C6 (n=12), and C6-C7 (n=20). Twenty-six patients had unilateral facet dislocation, and 14 patients had bilateral facet dislocation. Spinal injuries were graded according to the American Spinal Injury Association (ASIA) impairment scale and included grade A (eight cases), grade B (six cases), grade C (six cases), grade D (12 cases), and grade E (eight cases). The mean follow-up time was 4.2 years. RESULTS All procedures were completed successfully, with no major complications. Postoperative X-rays showed satisfactory height for the cervical intervertebral space and recovery of the vertebral sequence. Bone fusion was completed within four to six months after surgery. Surgery significantly improved neurological function in all patients. CONCLUSIONS Skull traction and an anterior approach can be used to successfully treat severe lower cervical facet dislocation, obtaining complete decompression, good reduction, and maintenance of intervertebral height with retention of the physiological curvature of the cervical spine. PMID- 29500928 TI - Exchange factor directly activated by cAMP-PKCepsilon signalling mediates chronic morphine-induced expression of purine P2X3 receptor in rat dorsal root ganglia. AB - BACKGROUND AND PURPOSE: The P2X3 receptor is a major receptor in the processing of nociceptive information in dorsal root ganglia. We investigated the role of the P2X3 receptor and the detailed mechanisms underlying chronic morphine-induced analgesic tolerance in rats. EXPERIMENTAL APPROACH: Repeated i.t. morphine treatment was used to induce anti-nociceptive tolerance. The expression of spinal P2X3 receptor, phosphorylated PKCepsilon and exchange factor directly activated by cAMP (Epac) were evaluated. Effects of A-317491 (P2X3 antagonist), epsilon-V1 2 (PKCepsilon inhibitor) and ESI-09 (Epac inhibitor) on mechanical pain thresholds and tail-flick latency after chronic morphine treatment were determined. Co-localization of P2X3 receptor with NeuNs (marker of neuron), IB4 (marker of small DRG neurons), peripherin, PKCepsilon and Epac were performed by double immunofluorescence staining. KEY RESULTS: Chronic morphine time dependently increased the expression of P2X3 receptor, phosphorylated PKCepsilon and Epac in DRGs. epsilon-V1-2 prevented chronic morphine-induced expression of P2X3 receptor. ESI-09 decreased the phosphorylation of PKCepsilon and up regulated expression of Epac after chronic morphine exposure. Mechanical pain thresholds and tail-flick latency showed that A317491, epsilon-V1-2 and ESI-09 significantly attenuated the loss of morphine's analgesic potency. Morphine induced P2X3 receptor expression mainly occurred in neurons staining for IB4 and peripherin. Co-localization of P2X3 receptor with PKCepsilon and Epac was demonstrated in the same neurons. CONCLUSIONS AND IMPLICATIONS: Chronic morphine exposure increased the expression of P2X3 receptor, and i.t. P2X3 receptor antagonists attenuated the loss of morphine's analgesic effect. Inhibiting Epac/PKCepsilon signalling was shown to play a significant inhibitory role in chronic morphine-induced P2X3 receptor expression and attenuate morphine-induced tolerance. PMID- 29500930 TI - From known to unknown: moving to unvisited locations in a novel sensorimotor map. AB - Sensorimotor learning requires knowledge of the relationship between movements and sensory effects: a sensorimotor map. Generally, these mappings are not innate but have to be learned. During learning, the challenge is to build a continuous map from a set of discrete observations, that is, predict locations of novel targets. One hypothesis is that the learner linearly interpolates among discrete observations that are already in the map. Here, this hypothesis is tested by exposing human subjects to a novel mapping between arm movements and sounds. Participants were passively moved to the edges of the workspace receiving the corresponding sounds and then were presented intermediate sounds and asked to make movements to locations they thought corresponded to those sounds. It is observed that average movements roughly match linear interpolation of the space. However, the actual distribution of participants' movements is best described by a bimodal reaching strategy in which they move to one of two locations near the workspace edge where they had prior exposure to the sound-movement pairing. These results suggest that interpolation happens to a limited extent only and that the acquisition of sensorimotor maps may not be driven by interpolation but instead relies on a flexible recombination of instance-based learning. PMID- 29500929 TI - Mapping ligand binding pockets in chloride ClC-1 channels through an integrated in silico and experimental approach using anthracene-9-carboxylic acid and niflumic acid. AB - BACKGROUND AND PURPOSE: Although chloride channels are involved in several physiological processes and acquired diseases, the availability of compounds selectively targeting CLC proteins is limited. ClC-1 channels are responsible for sarcolemma repolarization after an action potential in skeletal muscle and have been associated with myotonia congenita and myotonic dystrophy as well as with other muscular physiopathological conditions. To date only a few ClC-1 blockers have been discovered, such as anthracene-9-carboxylic acid (9-AC) and niflumic acid (NFA), whereas no activator exists. The absence of a ClC-1 structure and the limited information regarding the binding pockets in CLC channels hamper the identification of improved modulators. EXPERIMENTAL APPROACH: Here we provide an in-depth characterization of drug binding pockets in ClC-1 through an integrated in silico and experimental approach. We first searched putative cavities in a homology model of ClC-1 built upon an eukaryotic CLC crystal structure, and then validated in silico data by measuring the blocking ability of 9-AC and NFA on mutant ClC-1 channels expressed in HEK 293 cells. KEY RESULTS: We identified four putative binding cavities in ClC-1. 9-AC appears to interact with residues K231, R421 and F484 within the channel pore. We also identified one preferential binding cavity for NFA and propose R421 and F484 as critical residues. CONCLUSIONS AND IMPLICATIONS: This study represents the first effort to delineate the binding sites of ClC-1. This information is fundamental to discover compounds useful in the treatment of ClC-1-associated dysfunctions and might represent a starting point for specifically targeting other CLC proteins. PMID- 29500931 TI - Abnormal resting-state functional connectivity in posterior cingulate cortex of Parkinson's disease with mild cognitive impairment and dementia. AB - OBJECTIVE: To investigate changes in the functional connectivity (FC) pattern in the posterior cingulate cortex (PCC) of Parkinson's disease (PD) patients with mild cognitive impairment and dementia by employing resting-state functional magnetic resonance imaging (RS-fMRI). METHODS: Twenty-seven PD patients with different cognitive status and 9 healthy control subjects (control group) were enrolled for RS-fMRI. The RS-fMRI data were analyzed with DPARSF and REST software. Regions with changed functional connectivity were determined by the seed-based voxelwise method and compared between groups. Correlation between the intensity of FC and the MoCA scores of PD group was analyzed. RESULTS: Parametric maps showed statistical increases in PCC functional connectivity in PD-MCI patients and decreases in PCC connectivity in PDD patients. The latter group of patients also showed evidence for increased connectivity between prefrontal cortices and posterior cerebellum. A significant positive correlation was found between the MoCA scores and the strength of PCC connectivity in the angular gyrus and posterior cerebellum and a negative correlation between MoCA scores and PCC connectivity in all other brain regions. CONCLUSION: When patients transition from PD-NCI to PD-MCI, there appears to be an increase in functional connectivity in the PCC, suggesting an expansion of the cortical network. Another new network (a compensatory prefrontal cortical-cerebellar loop) later develops during the transition from PD-MCI to PDD. PMID- 29500932 TI - Development and validation of an LC-ESI-MS/MS method for the quantification of D 84, reboxetine and citalopram for their use in MS Binding Assays addressing the monoamine transporters hDAT, hSERT and hNET. AB - MS Binding Assays represent a label-free alternative to radioligand binding assays. In this study, we present an LC-ESI-MS/MS method for the quantification of (R,R)-4-(2-benzhydryloxyethyl)-1-(4-fluorobenzyl)piperidin-3-ol [(R,R)-D-84, (R,R)-1], (S,S)-reboxetine [(S,S)-2], and (S)-citalopram [(S)-3] employed as highly selective nonlabeled reporter ligands in MS Binding Assays addressing the dopamine [DAT, (R,R)-D-84], norepinephrine [NET, (S,S)-reboxetine] and serotonin transporter [SERT, (S)-citalopram], respectively. The developed LC-ESI-MS/MS method uses a pentafluorphenyl stationary phase in combination with a mobile phase composed of acetonitrile and ammonium formate buffer for chromatography and a triple quadrupole mass spectrometer in the multiple reaction monitoring mode for mass spectrometric detection. Quantification is based on deuterated derivatives of all three analytes serving as internal standards. The established LC-ESI-MS/MS method enables fast, robust, selective and highly sensitive quantification of all three reporter ligands in a single chromatographic run. The method was validated according to the Center for Drug Evaluation and Research (CDER) guideline for bioanalytical method validation regarding selectivity, accuracy, precision, calibration curve and sensitivity. Finally, filtration-based MS Binding Assays were performed for all three monoamine transporters based on this LC-ESI-MS/MS quantification method as read out. The affinities determined in saturation experiments for (R,R)-D-84 toward hDAT, for (S,S)-reboxetine toward hNET, and for (S)-citalopram toward hSERT, respectively, were in good accordance with results from literature, clearly demonstrating that the established MS Binding Assays have the potential to be an efficient alternative to radioligand binding assays widely used for this purpose so far. PMID- 29500933 TI - Treatment with IL-19 improves locomotor functional recovery after contusion trauma to the spinal cord. AB - BACKGROUND AND PURPOSE: IL-19 skews the immune response towards a Th2 type and appears to stimulate angiogenesis. In the current study, we tested if IL-19 treatment could reduce secondary injury and improve functional recovery after contusion spinal cord injury (SCI). EXPERIMENTAL APPROACH: Firstly, mice were given a moderate-severe thoracic SCI at the T9-10 level and expression of IL-19 and its receptor was measured in the injured spinal cord. Then SCI mice were treated with mouse recombinant IL-19 and its blocking antibody to investigate the therapeutic effect of IL-19. KEY RESULTS: Protein expression of IL-19 and its receptor IL-20R1 and IL-20R2 was up-regulated in the injured spinal cord of mice. IL-19 treatment promoted the recovery of locomotor function dose-dependently and reduced loss of motor neurons and microglial and glial activation following SCI. Treatment of SCI mice with IL-19 attenuated macrophage accumulation, reduced protein levels of TNF-alpha and CCL2 and promoted Th2 response and M2 macrophage activation in the injured region. Treatment of SCI mice with IL-19 promoted angiogenesis through up-regulating VEGF in the injured region. Treatment of SCI mice with IL-19 up-regulated HO-1 expression and decreased oxidative stress in the injured region. The beneficial effect of IL-19 was abolished by coadministration of the blocking antibody. Additionally, IL-19 deficiency in mice delayed the recovery of locomotor function following SCI. CONCLUSIONS AND IMPLICATIONS: IL-19 treatment reduced secondary injuries and improved locomotor functional recovery after contusion SCI, through diverse mechanisms including immune cell polarization, angiogenesis and anti-oxidative responses. PMID- 29500934 TI - Genotype and allele frequencies of TYMS rs2790 A > G polymorphism in a Chinese paediatric population with acute lymphoblastic leukaemia. AB - WHAT IS KNOWN AND OBJECTIVE: Thymidylate synthase (TYMS) is an important target for methotrexate (MTX). Genetic variations in the TYMS gene contribute to the differences in treatment responses to MTX. The aim of this study was to investigate the distribution of a microRNA (miRNA) binding site polymorphism (rs2790 A > G) in the 3'-untranslated region (3'-UTR) of TYMS and its association with MTX concentration and haematological toxicity in Chinese paediatric patients with acute lymphoblastic leukaemia (ALL). METHODS: The Sequenom MassARRAY system was used for TYMS rs2790 A > G genotyping in 118 children with ALL. Serum MTX concentrations were measured by a fluorescence polarization immunoassay. Clinical data were extracted from the electronic medical records. RESULTS AND DISCUSSION: The minor allele frequency noted in this study (39.8%) was significantly higher than those in the CEU (Utah residents with northern and western Europe ancestry; 16.2%) and YRI (Yoruba in Ibadan, Nigeria; 25.0%) samples reported in the 1000 Genomes Project (P < .01). The frequency of MTX level >40 MUmol/L at 24 hours in patients with the AA genotype (36.6%) was significantly higher than that in GG genotype carriers (5.9%, P < .05). However, the incidence rates of haematological toxicity were similar in the three genotype groups. Whereas there was evidence of higher blood levels in the A homozygotes, the evidence for this translating to higher toxicity was lacking. A larger study would be required to answer this. WHAT IS NEW AND CONCLUSION: The results of this study confirmed the significant ethnic differences in the distributions of the TYMS rs2790 A > G polymorphism. Whereas there was evidence of differences in MTX blood levels according to genotype, our study was not powered to show whether this would lead to more haematological toxicity. PMID- 29500935 TI - Simultaneous determination of three flavonoids and one coumarin by LC-MS/MS: Application to a comparative pharmacokinetic study in normal and arthritic rats after oral administration of Daphne genkwa extract. AB - A selective and sensitive liquid chromatography-tandem mass spectrometry method was developed and validated for investigating the pharmacokinetics of umbelliferone, apigenin, genkwanin and hydroxygenkwanin after oral administration of Daphne genkwa extract. Plasma samples were treated by protein precipitation with acetonitrile. Analytes were detected by triple-quadrupole MS/MS with an ESI source in negative selection reaction monitoring mode. The transitions of m/z 161 -> 133 for umbelliferone, m/z 269 -> 117 for apigenin, m/z 283 -> 268 for genkwanin and m/z 299 -> 284 for hydroxygenkwanin were confirmed for quantification. Chromatographic separation was conducted using an Eclipse XDB-C18 column, and the applied isocratic elution program allowed for simultaneous determination of the four analytes for a total run time of 2.5 min. The linearity was validated over the plasma concentration ranges of 1.421-1421 ng/mL for umbelliferone, 0.845-845 ng/mL for apigenin, 1.025-1025 ng/mL for genkwanin and 0.845-845 ng/mL for hydroxygenkwanin. The extraction recovery rate was >82.7% for each analyte. No apparent matrix effect was observed during the bioanalysis. After full validation, the proposed method was successfully applied to compare the pharmacokinetics of these analytes between normal and arthritic rats. PMID- 29500937 TI - Inhibition of phosphodiesterases as a strategy to achieve neuroprotection in Huntington's disease. AB - Huntington's disease (HD) is a fatal neurodegenerative condition, due to a mutation in the IT15 gene encoding for huntingtin. Currently, disease-modifying therapy is not available for HD, and only symptomatic drugs are administered for the management of symptoms. In the last few years, preclinical and clinical studies have indicated that pharmacological strategies aimed at inhibiting cyclic nucleotide phosphodiesterase (PDEs) may develop into a novel therapeutic approach in neurodegenerative disorders. PDEs are a family of enzymes that hydrolyze cyclic nucleotides into monophosphate isoforms. Cyclic nucleotides are second messengers that transduce the signal of hormones and neurotransmitters in many physiological processes, such as protein kinase cascades and synaptic transmission. An alteration in their balance results in the dysregulation of different biological mechanisms (transcriptional dysregulation, immune cell activation, inflammatory mechanisms, and regeneration) that are involved in neurological diseases. In this review, we discuss the action of phosphodiesterase inhibitors and their role as therapeutic agents in HD. PMID- 29500936 TI - CTLA-4Ig (abatacept) balances bone anabolic effects of T cells and Wnt-10b with antianabolic effects of osteoblastic sclerostin. AB - Activated lymphocytes promote inflammation and bone destruction in rheumatoid arthritis (RA), making T cells and B cells therapeutic targets. Indeed, pharmacological blockade of CD28 costimulation using CTLA-4Ig (abatacept), approved for amelioration of RA, renders T cells dormant (anergic). CTLA-4Ig also promotes bone accretion in healthy mice; surprisingly, however, this effect is driven exclusively through upregulation of bone formation, rather than anti inflammatory effects on resorption. In the study presented here, we utilized T cell receptor beta gene and Wnt-10b gene knockout mice to investigate the roles of T cells and Wnt-10b in CTLA-4Ig-induced bone anabolism. Ablation of either T cells or Wnt-10b not only abolished CTLA-4Ig-induced bone anabolism but also, paradoxically, suppressed bone formation leading to bone loss. Stalled bone formation was accompanied by bone marrow stromal cell expression of the Wnt pathway inhibitor sclerostin. Our data suggest that an immunoskeletal pivot may promote or suppress bone formation, depending on the net outcome of CTLA-4Ig action directed independently on T cells and osteoblast-linage cells that counter Wnt-10b-induced bone anabolism, by secretion of sclerostin. While CTLA-4Ig action is tipped in favor of bone formation under physiological conditions, pathological immunodeficiency may lead to suppressed bone formation and skeletal damage. PMID- 29500938 TI - An influence of structural changes in ammonium cations on ecotoxicity of 2,2' thiodiacetate mono and bis-salts. AB - 2,2'-Thiodiacetates with their excellent complexing properties may be used as metal extraction agents, fluorescent and superparamagnetic materials, antibacterial and anticancer medical agents, however there are no data concerning the environmental impact of 2,2'-thiodiacetates derivatives and data definying the potential hazard connected with their use. This study describes the ecotoxicity assessment of seven 2,2'-thiodiacetates with non-metallic, alkyl and aryl ammonium cations, which were obtained in an environmentally friendly, solvent-free syntheses. The ecotoxicity of these water soluble compounds was tested in aquatic and benthic environments using luminescent marine bacteria Vibrio fischeri (Microtox(r) test) and the crustaceans Heterocypris incongruens (Ostracodtoxkit FTM), respectively. The antimicrobial and antifungal activity against Trichoderma viridis, Aspergillus niger, Rhizoctonia solani and Escherichia coli was also investigated. The results showed how structural changes within ammonium cations themselves influence ecotoxicity: the QASs with alkylammonium cations exhibited a similar, rather low toxicity both to Vibrio fischeri and Heterocypris incongruens, and they would not pose a risk to these organisms in case of leakage. Higher toxicity was observed in case of two isoquinolinium salts, however it was rather associated with the heteroaromatic cation, than with the 2,2'-thiodiacetate anion. PMID- 29500939 TI - Catabolic profiles dynamics during the bioremediation process of chlorimuron ethyl contaminated soil by Methanolivorans CHL1T. AB - Excessive application of the long-term herbicide chlorimuron-ethyl has resulted in series of environmental problems. Bioaugmentation usually a useful method in contaminated-environment remediation. In this study, the strain Methanolivorans CHL1T with highly chlorimuron-ethyl degrading efficiency was employed to assess its remediation effects on chlorimuron-ethyl-contaminated soil. The chlorimuron ethyl residues in the soils and the survival condition of strain CHL1T were detected. Meanwhile, the shifts of soil microbial catabolic profile were investigated by MicroRespTM analysis for the first time. The results indicated that strain CHL1T significantly shorten the half-life (6-17 days) of chlorimuron ethyl and removed 95-100% of chlorimuron-ethyl by the end of the experiment. Meanwhile, the strain CHL1 could inhabit in soil steadily (4.2-4.7 * 107 per g dry soil) for a long time. The inoculation with strain CHL1 significantly shorten and relieved the disturbance effects of chlorimuron-ethyl on soil CLPPs. After inoculation with strain CHL1 60 days, the basal respiration rates and Shannon Wiener indices of groups S10+ and S30+ had recovered to the control level. Even in the high chlorimuron-ethyl-treated groups (S100), the basal respiration rates and Shannon-Wiener indices were significantly higher in S100+ than that in S100-. These results show the outstanding remediation effects of strain CHL1 and provide new insights into the assessment of the remediation process of chlorimuron-ethyl contaminated soils. PMID- 29500940 TI - The chemical diversity and structure-based evolution of non-peptide CXCR4 antagonists with diverse therapeutic potential. AB - The CXC chemokine receptor 4 (CXCR4) is a highly reserved G-protein coupled 7 transmembrane (TM) chemokine receptor which consists of 352 amino acids. CXCR4 has only one endogenous chemokine ligand of CXCL12, besides several other natural nonchemokine ligands such as extracellular ubiquitin and noncognate ligand of MIF. CXCR4 strongly binds to CXCL12 and the resulting CXCLl2/CXCR4 axis is the molecular basis of their various biological functions, which include: (1) mediating immune and inflammatory response; (2) regulation of hematopoietic stem cell migration and homing; (3) an essential co-receptor for HIV entry into host cells; (4) participation in the process of embryonic development; (5) malignant tumor invasion and metastasis; (6) myocardial infarction, ischemic stroke and acute kidney injury. Correspondingly, CXCR4 antagonists find potential therapeutic applications in HIV infection, as well as hematopoietic stem cell migration, inflammation, immune-related diseases, tumor and ischemic diseases. Recently, great achievements have been made and a number of non-peptide CXCR4 antagonists with diversity scaffolds have been discovered. In this review, the discovery of small molecule CXCR4 antagonists focused on the structures, activities, evolution and development of representative CXCR4 antagonists is comprehensively described. The central role of CXCR4 in diverse cellular signaling pathways and its involvement in several diseases progressions are discussed as well. PMID- 29500941 TI - Gait assessment of the expectant mothers - Systematic review. AB - INTRODUCTION: Since pregnant women may have potentially greater difficulty maintaining balance, their stability has been investigated by some researchers. However, there is no consensus considering the results. The purpose of our investigation was to compare all the experimental studies focusing on the analysis of gait that have been conducted over the last years to assess their methodological issues and changes induced by pregnancy. METHODS: The PRISMA Guidelines incorporating a risk of bias and strength of recommendations were used as a methodological template for this review. Literature searches were conducted using the following databases: PubMed, Embase, SPORTDiscus, Scopus. After limiting the search to meet the inclusion criteria, 25 articles remained in the final analysis. RESULTS: Some authors emphasised that adaptations due to pregnancy are recognised to provide safety and stability. Thus, they consistently reported reduced walking velocity as a result of lower frequency and smaller length of the steps. Longer contact times were reflected by the shortened peak forces. Plantar loads were redistributed from the rearfoot (decrease) to the midfoot and forefoot (increase) throughout pregnancy. Another adjustment was an increase of base of support to improve lateral gait stability which allows to compensate increased medio-lateral ground reaction force. During the course of pregnancy the increase of anterior body mass and hormonal changes enhance some realignments of the pelvis and lumbar spine. Methodological approaches varied across the included studies. The critical appraisal identified some areas of weaknesses that should be considered for designing the future investigations. CONCLUSIONS: Since many gait parameters are interrelated, in order to understand the cause-and-effect relationships an integrative and complete analysis of multiple factors is required. PMID- 29500942 TI - Dielectric properties of 3D-printed materials for anatomy specific 3D-printed MRI coils. AB - Additive manufacturing provides a low-cost and rapid means to translate 3D designs into the construction of a prototype. For MRI, this type of manufacturing can be used to construct various components including the structure of RF coils. In this paper, we characterize the material properties (dielectric constant and loss tangent) of several common 3D-printed polymers in the MRI frequency range of 63-300 MHz (for MRI magnetic field strengths of 1.5-7 T), and utilize these material properties in full-wave electromagnetic simulations to design and construct a very low-cost subject/anatomy-specific 3D-printed receive-only RF coil that fits close to the body. We show that the anatomy-specific coil exhibits higher signal-to-noise ratio compared to a conventional flat surface coil. PMID- 29500943 TI - Seronegativity to polio viruses among previously immunized adult candidates to solid organ transplantation. AB - In the current effort to eliminate polio from the world, it is important to recognize and vaccinate susceptible groups, especially immunocompromised patients living in countries where attenuated polio vaccine is still used. In this report, we describe the frequency of protective antibodies in a small sample of adult SOT candidates in whom previous vaccination could be ascertained. Patients included in this report were selected among the participants of an ongoing prospective study carried out at the Reference Center for Special Immunobiologicals of the Evandro Chagas National Institute of Infectious Diseases in Rio de Janeiro, Brazil. Among the first 100 patients enrolled in this study, only seven adult SOT candidates had proven polio vaccination at childhood. Three of these seven patients (43%) had no protective antibody titers to one or more poliovirus subtype before solid organ transplant. Proven childhood vaccination against polio does not reliably provide lifelong protective antibody titers for adult SOT candidates and should not be used as a criterion to analyze the need for vaccination in this population. PMID- 29500944 TI - Rocky Mountain spotted fever: brain imaging findings. PMID- 29500945 TI - Examining the association between adverse childhood experiences and smoking exacerbated illnesses. AB - OBJECTIVES: Adults who smoke increase their likelihood of death from smoking exacerbated illnesses. The presence of illnesses exacerbated by smoking can be a powerful incentive to quit smoking. However, having a smoking-exacerbated illness does not stop all patients from smoking. Understanding that smoking may be a coping mechanism for stress, this study examined the association between the experiences of adverse events in childhood with continued smoking in adulthood among individuals and a smoking-exacerbated illness. STUDY DESIGN: This retrospective observational study used 2014-2015 data from the South Carolina Behavioral Risk Factor Surveillance System survey. METHODS: We used multivariable logistic regression to examine the impact of adverse childhood experience (ACE) exposure on current smoking status. RESULTS: A total of 6321 respondents reported having a smoking-exacerbated illness. The most frequently reported categories of smoking-exacerbated illnesses were current asthma (63.9%), previous asthma (13.0%), and diabetes (12.3%). Overall, 62.4% of respondents had at least one ACE, with 20.3% of respondents having four or more ACEs. Respondents with one to three ACEs (adjusted odds ratio [aOR] 1.38; 95% confidence interval [CI] 1.37 1.40) and four or more ACEs (aOR 2.89; CI 2.86-2.92) were both significantly more likely to smoke than respondents with no ACEs, even in the presence of illnesses exacerbated by smoking. CONCLUSIONS: Results suggest that ACE exposure may influence risky health behaviors in adulthood, such as continued smoking even in the presence of illnesses that are exacerbated by smoking. Given that smoking has been found to be a coping mechanism for adversity, anti-smoking efforts might benefit from designing interventions and treatment plans that address ACE exposure. PMID- 29500946 TI - Work-family conflict and self-rated health among dwellers in Minia, Egypt: Financial strain vs social support. AB - OBJECTIVES: Egypt's economic reform is accompanied by both financial and social strains. Due to lack of evidence, we examined the associations between work family conflict in its 2 directions, work-to-family conflicts (WFCs), and family to-work conflicts (FWCs) and self-rated health in Minia, Egypt, and whether the association will vary by being financially responsible for others and by the level of perceived social support. STUDY DESIGN: A cross-sectional study that included 1021 healthy participants aged 18-60 years from Minia district. METHODS: Data on participants' work-family conflict, social, and demographic data and individual self-rated health were collected by a questionnaire survey. Multivariable logistic regression analyses were used to calculate the odds ratios (ORs) with its 95% confidence intervals (CIs) for poor self-rated health according to categories of work-family conflict. RESULTS: There were significant positive associations between the poor self-rated health and both high WFC and FWC. Compared with participants with low WFC and low FWC, participants with high WFC low FWC, low WFC high FWC, and high WFC high FWC had multivariable-adjusted ORs (95% CIs) for poor self-rated health of 6.93 (3.02-13.13), 2.09 (1.06-4.12), and 10.05 (4.98-20.27), respectively. Giving financial support to others but not the level of perceived social support from others was an effect modifier of the association. CONCLUSIONS: Work-family conflict was positively associated with the self-report of poor health, especially in those who were financially responsible for other family members. PMID- 29500947 TI - Number of colony forming units in urine at 35-37 weeks' gestation as predictor of the vaginal load of Group B Streptococci at birth. AB - OBJECTIVE: To evaluate GBS colony numbers in the urine at 35-37 weeks' gestation to predict the load of GBS-colonization of the vagina at birth. STUDY DESIGN: In this prospective observational study, we included 902 unselected pregnant women. Exposure was GBS colony forming units (CFU) per mL urine at 35-37 weeks' gestation. Outcome was vaginal GBS colonization at birth as assessed by a semi quantitative culture of a vaginal swab sample (negative, +1, +2, +3). RESULTS: Bacteriuria with GBS at 35-37 weeks' gestation performed with a sensitivity of 30% concerning any degree of vaginal GBS colonization at birth (31 of 104 cases); 19% for light (+1), 17% for medium (+2), and 52% for high load (+3) vaginal GBS colonization. The colony count in case of GBS bacteriuria at 35-37 weeks' gestation performed with positive predictive values of 35% for <104 CFU/mL, 70% for 104 CFU/mL, and 67% for >104 CFU/mL. CONCLUSION: Even though the urinary GBS CFU at 35-37 weeks' gestation is strongly associated with a high load of vaginal GBS colonization intrapartum, it may not perform satisfactorily as a standalone screening marker for risk of early-onset GBS disease. PMID- 29500948 TI - The impact of a remote monitoring program on the prenatal follow-up of women with gestational hypertensive disorders. AB - OBJECTIVES: In 2015, we showed the value of a remote monitoring (RM) follow-up program for women diagnosed with gestational hypertensive disorders (GHDs) compared with women who received conventional care (CC). We want to confirm or refute the conclusions drawn in 2015, by including data from 2016. STUDY DESIGN: A two year retrospective study in which all women diagnosed with GHD, who underwent prenatal follow-up at the outpatients prenatal clinic of Ziekenhuis Oost-Limburg (Genk, Belgium) during 2015 and 2016, were included. Of the 320 women diagnosed with GHD, ninety (28.13%) were monitored with RM. The other 230 (71.88%) GHD pregnancies were monitored with CC. Differences in continuous and categorical variables in maternal demographics and characteristics were tested using Unpaired Student's two sampled t-test or Mann Whitney U test and the c2 test. Both a univariate and multivariate analysis were performed for analyzing prenatal follow up and gestational outcomes. All statistical analyses are done at nominal level a = 0.05. RESULTS: The RM group had more women diagnosed with gestational hypertension but less with pre-eclampsia when compared to the CC group (69.77% versus 42.79% and 19.77% versus 44.19% respectively). In both uni- and multivariate analyses, the RM group had, when compared to the CC group, less prenatal admission (51.62% versus 71.63%), less prenatal admissions until the moment of the delivery (31.40% versus 57.67%), less induced starts of the birth process (43.00% versus 32.09%), more spontaneous starts of the birth process (32.86% versus 46.51%), more births after 37 weeks of gestational age in pregnancies complicated with gestational hypertension (91.67% versus 53.33%) and pregnancies complicated with pre-eclampsia (58.82% versus 53.33%). In multivariate analysis, a reduction in total number of prenatal visits was visible in the RM group when compared to the CC group (b = -1.76; CI = -2.74-0.77). Only in the univariate analysis was the mean gestational age at delivery between 34 and 37 weeks of gestation in pregnancies complicated with gestational hypertension higher in the CC group versus the RM group (35 w 4/7 (+/-0.49) versus 34 w 6/7 (+/-0.00).These conclusions were almost the same as in the analyses of 2015, except (1) there wasn't a difference anymore in NICU admissions between the RM and CC group in the analyses of 2015-2016 and (2) a significant decrease in total number of visits is reported in the RM group in the dataset of 2015-2016, which wasn't visible in the dataset of 2015. CONCLUSIONS: This study demonstrates that RM provides opportunities to offer timely interventions to pregnant women who require them. PMID- 29500949 TI - Alcohol and substance use are associated with altered metabolome in the first trimester serum samples of pregnant mothers. AB - BACKGROUND: Although the effects of alcohol on metabolic processes in the body have been studied widely, there do not appear to be any previous reports clarifying how substance abuse changes metabolic profiles of pregnant women during the first trimester of pregnancy. OBJECTIVE: Our aim was to evaluate the effect of substance abuse, especially alcohol use, on the metabolic profile of pregnant women during the first trimester. STUDY DESIGN: We applied mass spectrometry based non-targeted metabolite profiling of serum collected during routine visit to the hospital between gestational weeks 9 + 0 to 11 + 6 from controls (n = 55), alcohol users (n = 19), drug users (n = 24) and tobacco smokers (n = 40). RESULTS: We observed statistically significantly differences among the study groups in serum levels of glutamate, glutamine, and serotonin (p values <= 0.0001). The serum levels of glutamate were increased in alcohol and drug using mothers when compared to the controls, whereas levels of glutamine were decreased in alcohol and drug using mothers. In addition, serum levels of serotonin were decreased in alcohol using mothers when compared to the controls. CONCLUSION: The present study shows that alcohol and drug use were associated with increased glutamate, and decreased glutamine levels, and alcohol use is associated with decreased serotonin levels. This study serves as a proof-of concept that the metabolite profile of human first trimester serum samples could be used to detect alcohol exposure during pregnancy. PMID- 29500950 TI - Methanogenic capacity and robustness of hydrogenotrophic cultures based on closed nutrient recycling via microbial catabolism: Impact of temperature and microbial attachment. AB - A biological methanation system based on nutrient recycling via mixed culture microbial catabolism was investigated at mesophilic (37 degrees C) and thermophilic (55 degrees C) temperatures. At mesophilic temperatures, the formation of biofilms on two different types of material was assessed. Results showed that with intense mixing the biofilm reactors presented methanogenic capacities (per working volume) 50% higher than the ones operated with suspended cultures. Gas feeding rates of 200 L/L/d were achieved at a H2/CO2 to CH4 conversion efficiency of above 90% by linking two reactors in series. Furthermore the robustness of the cultures was assessed under a series of inhibitory conditions that simulated possible process interferences at full scale operation. Full recovery after separate intense oxygenation and long starvation periods was observed within 2-5 days. PMID- 29500951 TI - Characterization of coffee (Coffea arabica) husk lignin and degradation products obtained after oxygen and alkali addition. AB - The full use of biomass in future biorefineries has stimulated studies on utilization of lignin from agricultural crops, such as coffee husk, a major residue from coffee processing. This study focuses on characterizing the lignin obtained from coffee husk and its further wet oxidation products as a function of alkali loading, temperature and residence time. The lignin fraction after diluted acid and alkali pretreatments is composed primarily of p-hydroxylphenyl units (>=49%), with fewer guaiacyl and syringyl units. Linkages appear to be mainly beta-O-4 ether linkages. Thermal degradation of pretreated lignin during wet oxidation occurred in two stages. Carboxylic acids were the main degradation product. Due to the condensed structure of this lignin, relatively low yields of aromatic aldehydes were achieved, except with temperatures over 210 degrees C, 5 min residence time and 11.7 wt% NaOH. Optimization of the pretreatment and oxidation parameters are important to maximizing yield of high-value bioproducts from lignin. PMID- 29500953 TI - Cigarillo sales in legalized marijuana markets in the U.S. AB - BACKGROUND: Nearly half of marijuana users in the United States also smoke cigarillos, with many using the products as marijuana "blunts." The relationship between marijuana legalization and tobacco retail has not yet been examined. This study uses tobacco sales data to compare the cigarillo marketplace in states with legalized recreational marijuana to the overall U.S. marketplace in 2016. METHODS: Cigarillo sales data from 2016 were obtained from the Nielsen Research Company in the following market regions: Denver, CO; Seattle, WA; Portland, OR; and the overall U.S. Descriptive statistics highlighted differences in the market share of various product features (e.g., flavors, brand, pack size) across regions. RESULTS: Characteristics such as fruit flavors, single sticks, and 2-3 packs were more popular in legal marijuana regions compared to the overall U.S. Black & Mild, a brand not traditionally used for blunts, was the top brand nationally (32.8% market share), but Swisher was the top brand in legal marijuana regions. In Seattle and Portland, for example, over half of cigarillo sales were for Swisher products (59.1% and 52.1%, respectively). Cigarillo wraps (i.e., no tobacco filler) were particularly popular in Denver, constituting 11.4% all cigarillo sales versus 2.8% nationally. CONCLUSIONS: Cigarillo product characteristics traditionally associated with blunt use may shape the tobacco market in legal marijuana regions. As more states continue to legalize recreational marijuana, state and local governments should anticipate the potential impact on the tobacco marketplace and implement tobacco control policies (e.g., flavor bans, minimum pack sizes) that discourage product use. PMID- 29500952 TI - Individual differences in developmental plasticity: A role for early androgens? AB - Developmental plasticity is a widespread property of living organisms, but different individuals in the same species can vary greatly in how susceptible they are to environmental influences. In humans, research has sought to link variation in plasticity to physiological traits such as stress reactivity, exposure to prenatal stress-related hormones such as cortisol, and specific genes involved in major neurobiological pathways. However, the determinants of individual differences in plasticity are still poorly understood. Here we present the novel hypothesis that, in both sexes, higher exposure to androgens during prenatal and early postnatal life should lead to increased plasticity in traits that display greater male variability (i.e., a majority of physical and behavioral traits). First, we review evidence of greater phenotypic variation and higher susceptibility to environmental factors in males; we then consider evolutionary models that explain greater male variability and plasticity as a result of sexual selection. These empirical and theoretical strands converge on the hypothesis that androgens may promote developmental plasticity, at least for traits that show greater male variability. We discuss a number of potential mechanisms that may mediate this effect (including upregulation of neural plasticity), and address the question of whether androgen-induced plasticity is likely to be adaptive or maladaptive. We conclude by offering suggestions for future studies in this area, and considering some research designs that could be used to empirically test our hypothesis. PMID- 29500954 TI - Alcohol metabolism in hangover sensitive versus hangover resistant social drinkers. AB - BACKGROUND: Previous research demonstrated that urinary ethanol concentrations were significantly lower in hangover resistant individuals compared to drinkers who reported having a hangover. This finding suggests that the rate of ethanol metabolism is faster in drinkers who do not experience an alcohol hangover. This study aimed to directly compare alcohol metabolism after administering a low dose of ethanol to hangover sensitive drinkers and hangover resistant drinkers. METHODS: Social drinkers who previously participated in hangover trials at Utrecht University were invited to participate. It was aimed to include 12 hangover resistant drinkers and 12 hangover sensitive drinkers. Participants consumed alcohol to reach a breath alcohol concentration (BrAC) of 0.05%. Every 5 min BrAC was determined, until BrAC reached zero. Every 15 min, the Karolinska Sleeping Scale (KSS) was administered to assess subjective sleepiness, and subjective intoxication was measured. RESULTS: Data of N = 23 participants with a mean age of 22.4 (+/-1.9) years was included in the analyses. No significant difference in BrAC over time was found between the hangover resistant group and the hangover sensitive group. In line, subjective sleepiness scores and subjective intoxication ratings did not significantly differ between the groups at any point in time after alcohol consumption. CONCLUSION: Hangover resistant individuals and hangover sensitive drinkers did not significantly differ on BrAC, subjective sleepiness, and subjective intoxication after consuming a moderate amount of alcohol. These findings suggest that drinkers who usually experience hangovers after a heavy drinking occasion do not experience alcohol intoxication differently than hangover resistant drinkers. PMID- 29500955 TI - The association between depression and coronary artery calcification: A meta analysis of observational studies. AB - BACKGROUND AND AIMS: Cardiovascular diseases and depression are responsible for a great global burden of disease; however, the association between depression and coronary artery calcification (CAC) remain controversial and no quantitative meta analysis exists. Thus, we performed a meta-analysis aimed to evaluate the association between depression and CAC. METHODS: We performed a systematic search strategy using PubMed, Web of science, Embase, China National Knowledge Infrastructure and Cochrane library for relevant observational studies investigating depression and CAC from inception until April 2017. The pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) and subgroup analyses were calculated using a random effects model. RESULTS: After screening 411 non duplicated articles, a total of 15 studies involving 32,884 were included. Our analyses demonstrated a positive association between diagnosed depression and CAC (OR = 1.15; 95% CI: 1.04-1.28; I2 = 80.6), and a non-significant association between depressive symptoms and CAC (OR = 1.02; 95% CI: 0.97-1.07; I2 = 73.5%). In subgroup analysis for cohort studies, the positive association between diagnosed depression and CAC was enhanced (OR = 2.20; 95% CI: 1.33-3.64; I2 = 0). CONCLUSIONS: Our study indicated that diagnosed depression was associated with higher odds of CAC. Systematic screening for CAC may be useful to identify clinically depressed patients at higher risk of future cardiovascular diseases. PMID- 29500957 TI - Light therapy for older patients with non-seasonal depression: A systematic review and meta-analysis. AB - BACKGROUND: Light therapy has become an increasingly common treatment for adults with depression, yet the role of light therapy for non-seasonal depression among older adults remains unclear. OBJECTIVE: This meta-analysis sought to evaluate the effectiveness of light therapy among older patients with non-seasonal depression. METHODS: We searched the Cochrane Central Register of Controlled Trials, PubMed, Embase, Web of Science, CNKI and CBM from the inception of each database to May 2017. Two researchers conducted the literature screening, data extraction, and methodological quality assessment independently. We used the Cochrane Collaboration's bias assessment tool to evaluate the risk of bias for included studies, and Review Manager 5.2.3 Software for the meta-analysis. RESULTS: Six trials with a total of 359 patients were included, and five studies were assessed as being of low risk for bias. We evaluated the effect of light therapy on depression by the reduction of depressive symptoms (SMD = 0.45; 95% CI= [0.14, 0.75]). The subgroup analysis did not find significant moderating effects of depression with intervention intensity, light type, measuring scale or intervention duration. LIMITATIONS: Most of the study samples were not representative of the larger population of adults and therefore caution should be used when interpreting the findings. CONCLUSIONS: Light therapy has a positive effect on geriatric non-seasonal depression. Studies with larger sample sizes are needed to confirm the curative effect of light therapy in the future. PMID- 29500956 TI - High levels of mitochondrial DNA are associated with adolescent brain structural hypoconnectivity and increased anxiety but not depression. AB - BACKGROUND: Adolescent anxiety and depression are highly prevalent psychiatric disorders that are associated with altered molecular and neurocircuit profiles. Recently, increased mitochondrial DNA copy number (mtDNA-cn) has been found to be associated with several psychopathologies in adults, especially anxiety and depression. The associations between mtDNA-cn and anxiety and depression have not, however, been investigated in adolescents. Moreover, to date there have been no studies examining associations between mtDNA-cn and brain network alterations in mood disorders in any age group. METHODS: The first aim of this study was to compare salivary mtDNA-cn between 49 depressed and/or anxious adolescents and 35 well-matched healthy controls. The second aim of this study was to identify neural correlates of mtDNA-cn derived from diffusion tensor imaging (DTI) and tractography, in the full sample of adolescents. RESULTS: There were no diagnosis specific alterations in mtDNA-cn. However, there was a positive correlation between mtDNA-cn and levels of anxiety, but not depression, in the full sample of adolescents. A subnetwork of connections largely corresponding to the left fronto occipital fasciculus had significantly lower fractional anisotropy (FA) values in adolescents with higher than median mtDNA-cn. LIMITATIONS: Undifferentiated analysis of free and intracellular mtDNA and use of DTI-based tractography represent this study's limitations. CONCLUSIONS: The results of this study help elucidate the relationships between clinical symptoms, molecular changes, and neurocircuitry alterations in adolescents with and without anxiety and depression, and they suggest that increased mtDNA-cn is associated both with increased anxiety symptoms and with decreased fronto-occipital structural connectivity in this population. PMID- 29500958 TI - Suicide attempts and emotion regulation in psychiatric outpatients. AB - BACKGROUND: Suicidal behavior has been associated with maladaptive strategies for emotion regulation; however, limited research has explored this association after controlling for diagnosis. This study aims to explore this connection across diagnoses. We hypothesized that patients who reported greater difficulty with emotion regulation would be more likely to have made suicide attempts. METHOD: Participants included 1046 psychiatric outpatients. Diagnoses and information about suicide history were determined using semi-structured interviews. Patients also completed the Difficulties in Emotion Regulation Scale (DERS). Analyses were conducted to determine the relationships between emotion regulation difficulties and lifetime suicide attempts. RESULTS: Emotion regulation difficulties did not independently predict suicidal behavior. After controlling for the contribution of emotion dysregulation on lifetime suicide attempts, diagnoses of borderline personality disorder and posttraumatic stress disorder were the only disorders independently associated with a history of suicidal behavior. LIMITATIONS: The generalizability of our findings may be limited based on the sample's demographic characteristics and low base rate of suicide attempts. This study was cross sectional in nature; therefore, the predictive capacity of either DERS scores or psychiatric diagnoses in terms of future suicidal behavior could not be determined. CONCLUSIONS: The independent effect of emotion dysregulation on suicidal behavior was negated after controlling for psychiatric diagnosis. Individuals with certain disorders tend to make suicide attempts for reasons that are distinct from emotion dysregulation, whereas emotion dysregulation may be at the core of suicidality for individuals with other clinical presentations. PMID- 29500959 TI - An aqueous extract of Nomura's jellyfish ameliorates inflammatory responses in lipopolysaccharide-stimulated RAW264.7 cells and a zebrafish model of inflammation. AB - The recent mass emergence of Nomura's jellyfish (Nemopilema nomurai) has caused much economic and environmental damage. However, there is no innovative strategy to dispose of or utilize these jellyfish. Some reports suggest that the jellyfish may be bioactive resources and a source of important compounds with antibacterial activity. Here, we examined the effect of an aqueous extract of Nomura's jellyfish (AENJ) on lipopolysaccharide (LPS)-stimulated Raw 264.7 macrophages and a zebrafish model of inflammation and analyzed the underlying molecular mechanisms. AENJ downregulated inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA levels in LPS-stimulated Raw 264.7 macrophages, with no apparent cytotoxic effects. However, AENJ had no effect on expression of other inflammation-related genes such as interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and MCP-1. Furthermore, AENJ reduced expression of nerve injury-induced protein 1 (Ninj1), which is an important adhesion molecule, thereby reducing cell adhesion to the extracellular matrix (ECM) in vitro. The inhibitory effect of AENJ on leukocytes was confirmed in LPS-microinjected zebrafish larvae; AENJ reduced the number of the infiltrate accumulating at the site of inflammation. In addition, AENJ suppressed the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9 in LPS-stimulated Raw 264.7 cells. Finally, AENJ blocked nuclear translocation of nuclear factor kappa B (NF-kappaB), a key transcription factor for inflammatory responses, in Raw 264.7 cells in a dose-dependent manner. Collectively, the data suggest that AENJ inhibits expression of COX and iNOS by blocking NF-kappaB signaling pathways and suppresses the activity of macrophages by downregulating Ninj1 and MMPs. Therefore, AENJ may be a useful preventive neutraceutical, or therapeutic agent against inflammatory disorders. PMID- 29500960 TI - How are social-emotional and behavioral competences and problems at age 1 year associated with infant motor development? A general population study. AB - Based on limitations in previous research evidence, we concluded that more research is needed for deeper understanding of how social-emotional and behavioral (SEB) outcomes among infant-toddler-aged children in the general population are associated with early motor development. In this study, we investigated associations between early competencies and problems, as measured by the Brief Infant-Toddler Social and Emotional Assessment (BITSEA), and the timing of achievement of the main gross and fine motor milestones usually attained during the first year of life in a general population context. The study sample consisted of 515 infants (mean age 12.9 [SD 0.9] months) and their parents (514 mothers, 434 fathers), who were recruited in child health centers in Northern Finland. The infants were divided into two groups, based on their BITSEA screen status, and motor milestone achievement ages were compared across BITSEA screen status No Concern and Of-Concern infants. An Of-Concern screen status on the maternal and paternal Competence scale and Autism spectrum disorder (ASD) item cluster was associated with later infant achievement ages for gross motor milestones. By contrast, infants who were screened to be in the Of-Concern range on the maternal Problem scale achieved gross motor milestones earlier than infants with the corresponding No Concern screen status. No significant associations were found between the paternal Problem scale screen status and infant motor development. In further analyses, the strongest associations were found between an Of-Concern screen status on the paternal Competence scale and ASD item cluster and infant motor development. The findings indicate that the inclusion of infant motor developmental information may assist early identification and the clinical interpretation of parental reports of early SEB problems. Clinical implications of the current findings are discussed in the paper. PMID- 29500961 TI - Heuristics as Bayesian inference under extreme priors. AB - Simple heuristics are often regarded as tractable decision strategies because they ignore a great deal of information in the input data. One puzzle is why heuristics can outperform full-information models, such as linear regression, which make full use of the available information. These "less-is-more" effects, in which a relatively simpler model outperforms a more complex model, are prevalent throughout cognitive science, and are frequently argued to demonstrate an inherent advantage of simplifying computation or ignoring information. In contrast, we show at the computational level (where algorithmic restrictions are set aside) that it is never optimal to discard information. Through a formal Bayesian analysis, we prove that popular heuristics, such as tallying and take the-best, are formally equivalent to Bayesian inference under the limit of infinitely strong priors. Varying the strength of the prior yields a continuum of Bayesian models with the heuristics at one end and ordinary regression at the other. Critically, intermediate models perform better across all our simulations, suggesting that down-weighting information with the appropriate prior is preferable to entirely ignoring it. Rather than because of their simplicity, our analyses suggest heuristics perform well because they implement strong priors that approximate the actual structure of the environment. We end by considering how new heuristics could be derived by infinitely strengthening the priors of other Bayesian models. These formal results have implications for work in psychology, machine learning and economics. PMID- 29500962 TI - Correlates of autistic traits among patients with borderline personality disorder. AB - BACKGROUND: Despite discrete autism-related dimensions, such as deficits in communication, empathy and mentalizing are likely to affect the development of personality and despite they actually frequently occur in borderline patients, no research has so far investigated the relationship between autistic traits and Borderline Personality Disorder (BPD). The objective of this study is to investigate the clinical significance of autistic traits in subjects with BPD. METHODS: The sample included 50 patients with a clinical diagnosis of BPD and 69 healthy controls. The Structured Clinical Interview for DSM-5 Clinician Version was used to establish the presence of comorbid mental disorders among BPD subjects and to confirm the absence of lifetime mental disorders in the control group. Participants were also asked to fill three self-report instruments: the Adult Autism Subthreshold Spectrum (AdAS Spectrum), the Autism Spectrum Quotient (AQ) and the Mood Spectrum Self-Report (MOODS-SR). RESULTS: Patients with BPD reported higher autistic traits than healthy individuals. Moreover, autistic traits were shown to exert a significant impact on some clinical features and associated manifestation of BPD, such as suicidality and lifetime exposure to physical and/or sexual abuse. CONCLUSIONS: Subthreshold autism spectrum may be relevant for subjects suffering from BPD and future research may further address clinical correlates of autistic traits among patients with this disorder. PMID- 29500963 TI - Deconstructing spatial-numerical associations. AB - Spatial-numerical associations (SNAs) have been studied extensively in the past two decades, always requiring either explicit magnitude processing or explicit spatial-directional processing. This means that the typical finding of an association of small numbers with left or bottom space and of larger numbers with right or top space could be due to these requirements and not the conceptual representation of numbers. The present study compares explicit and implicit magnitude processing in an implicit spatial-directional task and identifies SNAs as artefacts of either explicit magnitude processing or explicit spatial- directional processing; they do not reveal spatial-conceptual links. This finding requires revision of current accounts of the relationship between numbers and space. PMID- 29500964 TI - The use of model based recursive partitioning as an analytic tool in child welfare. AB - Child welfare agencies are tasked with investigating allegations of child maltreatment and intervening when necessary. Researchers are turning to the field of predictive analytics to optimize data analysis and data-driven decision making. To demonstrate the utility of statistical algorithms that preceded the current predictive analytics, we used Model Based (MOB) recursive partitioning, a variant of regression analysis known as decision trees, on a dataset of cases and controls with a binary outcome of serious maltreatment (defined as hospitalization or death). We ran two models, one which split a robust set of variables significantly correlated with the outcome on the partitioning of a proxy variable for environmental poverty, and one which ran the same variable set partitioned on a variable representing confirmed prior maltreatment. Both models found that what most differentiated children was spending greater than 2% of the timeframe of interest in foster care, and that for some children, lack of Medicaid eligibility almost doubled or tripled the odds of serious maltreatment. We find that decision trees such as MOB can augment risk assessment tools and other data analyses, informing data-driven program and policy decision making. We caution that decision trees, as with any other predictive tool, must be evaluated for inherent biases that may be contained in the proxy variables and the results interpreted carefully. Predictive analytics, as a class, should be used to augment, but not replace, critical thinking in child welfare decision making. PMID- 29500965 TI - Subventricular zone predicts high velocity of tumor expansion and poor clinical outcome in patients with low grade astrocytoma. AB - OBJECTIVE: The aim of this study is to clarify the association between subventricular zone (SVZ) involvement and velocity of diametric expansion(VDE) in patients with low-grade astrocytoma and also assessed the clinical outcome of those patients. MATERIALS AND METHODS: A total of 168 adult patients with newly diagnosed supratentorial low-grade astrocytoma were studied retrospectively. RESULTS: There were 73 patients had SVZ involvement. Patients with SVZ involvement(7.16 +/- 6.53 mm/y) had a higher VDE than patients without SVZ involvement(4.38 +/- 5.35 mm/y). VDE was modeled as a categorical variable(<4, >=4 and, <8, >=8 and, <12, >=12 mm/y). Logistic regression showed that SVZ involvement was associated with high VDE after adjusting by confounding variables. On the univariate analysis, the results showed that tumor involved with SVZ, VDE >= 4 mm/y, VDE >= 8 mm/y, and VDE >= 8 mm/y were significant predictors of a shorter OS, progression-free survival (PFS) and malignant progression-free survival (MFS)(all p <0.05). The categorical variables of VDE (<4 mm/y, >=4 mm/y and, <8 mm/y, >=8 mm/y and, <12 mm/y, >=12 mm/y) were adjusted by confounding variables in multivariate analysis, respectively. The results indicated that VDE >= 8 mm/y, VDE >= 12 mm/y were worse prognostic factors for OS, while VDE >= 4 mm/y, VDE >= 8 mm/y and VDE >= 12 mm/y were related to shorter PFS and MFS. In addition, SVZ involvement was prognostic factors in predicting OS and PFS except MFS. CONCLUSION: Our results demonstrated that SVZ involvement predicted high VDE and worse clinical outcome, and high VDE was associated with poor prognosis in patients with low-grade astrocytoma. PMID- 29500966 TI - The substitution effect of heterocyclic rings to tune the optical and nonlinear optical properties of hybrid chalcones: A comparative study. AB - The present study spotlights the hybrid chalcone derivatives consisting of coumarin moieties conjugated systematically with different heterocyclic rings. The heterocyclic rings including bifuran, bicyclopentane, bipyrrole and bithiophenes groups are used to design compounds 1, 2, 3 and 4, respectively. Different density functional theory (DFT) methods are used for optimization of designed compounds. The M06 functional shows reasonably good accuracy for calculations of geometrical and absorption spectra as compared with other methods and/or available experimental data. The calculated average third-order NLO polarizabilities (gamma) for compounds 1, 2, 3 and 4 are found to be 526.22 * 10 36, 675.40 * 10-36, 939.58 * 10-36 and 1109.30 * 10-36 esu., respectively, at M06/6-311G** level of theory. The gamma amplitudes of compounds 1, 2, 3 and 4 are reasonably enhanced, which are about 25, 27, 30 and 32 times larger to the gamma amplitude of para nitroaniline (a prototype NLO molecule) at same M06/6-311G** level of theory. Furthermore, we highlight the structure-property relationship using TD-DFT calculations for absorption and emission spectra, frontier molecular orbitals and molecular electrostatic potential maps. Thus, the present study will evoke the interest of scientific community to develop the above title materials for efficient NLO applications. PMID- 29500967 TI - A Slovenian version of the "clinical learning environment, supervision and nurse teacher scale (Cles+T)" and its comparison with the Croatian version. AB - Nursing clinical learning environments are particularly important for the achievement of good practice in clinical training of student nurses, and thus, for the nursing competence development. Hence, it is important to have an instrument consisting of reliable and valid criteria for assessing the clinical learning environment, applicable in different contexts, and translated in the respondents mother tongue. The goal of the present research was to test the reliability and validity of the Slovenian version of the "Clinical Learning Environment, Supervision and Nurse Teacher evaluation scale", and to compare it with the Croatian version. The data was collected between 10 March and 10 June 2015 at four Slovenian institutions, where nursing BSc study programmes are performed. The final sample consisted of 232 students (response rate 68.8%): 81.9% were females and 18.1% males, average age was 23. The translated instrument in Slovenian language resulted as reliable and valid, it reflects the expected five factors of the original version despite some minor problems in the factor structure and in test-retest. The most important difference between the Slovenian and Croatian version is in the factor structure regarding the implementation of roles in clinical learning environment. PMID- 29500968 TI - Effects of a hypoenergetic diet rich in alpha-linolenic acid on fatty acid composition of serum phospholipids in overweight and obese patients with metabolic syndrome. AB - OBJECTIVES: Plant-derived alpha-linolenic acid (ALA) may exert cardioprotective effects. Dietary ALA can undergo desaturation and elongation to form long-chain omega-3 polyunsaturated fatty acids, but the extent to which this occurs in humans is unclear. The aim of the study was to examine the effects of an energy restricted diet enriched with ALA on fatty acid composition of serum phospholipids in patients with metabolic syndrome. METHODS: The present analysis compared the effects of a hypoenergetic diet high in ALA (3.4 g/d) with a control diet low in ALA (0.9 g/d) on fatty acid composition of serum phospholipids in 81 overweight or obese patients with features of metabolic syndrome. RESULTS: After a 26-wk intervention, concentration of ALA in serum phospholipids remained constant in both diet groups. The control group had a significant decrease in serum phospholipid eicosapentaenoic acid concentration, although no significant intergroup difference was observed. Serum phospholipid docosahexaenoic acid concentration significantly decreased to a similar extent with both interventions. Additionally, both interventions significantly decreased serum phospholipid concentrations of palmitic acid, stearic acid, total saturated fatty acids, linoleic acid, total omega-6 and omega-3 polyunsaturated fatty acids, with no effect of diet group on these changes. Compared with the ALA diet, the control diet led to a significant increase in serum phospholipid oleic acid concentration. CONCLUSION: Daily intake of 3.4 g of ALA during a 26-wk energy restricted diet did not lead to an enrichment of serum phospholipids with ALA and did not increase eicosapentaenoic acid due to conversion. Additionally, dietary ALA was unable to compensate for a decrease in serum phospholipid docosahexaenoic acid. PMID- 29500969 TI - Folate treatment partially reverses gestational low-protein diet-induced glucose intolerance and the magnitude of reversal is age and sex dependent. AB - OBJECTIVES: Gestational low-protein (LP) programming causes glucose intolerance (GI) and insulin resistance (IR) in adult offspring. Folate supplementation has been shown to rescue the offspring from various programming effects. The aim of this study was to investigate whether folate supplementation during pregnancy reverses LP-induced GI and IR. METHODS: Pregnant rats were fed control (20% protein), isocaloric low-protein (LP, 6%) or LP with 5 mg/kg folate (LPF) diets from gestational day 4 to delivery. The control diet was given during lactation and to pups after weaning. Glucose tolerance test was done at 1, 2, and 3 mo of age followed by euglycemic-hyperinsulinemic clamp at 4 mo. Rats were sacrificed at 4 mo and their gonadal, renal, inguinal, brown fat, and pancreas were weighed and expressed relative to their body weight. RESULTS: LP- and LPF-fed dams showed similar weight loss during late pregnancy after decreased feed intake. Both LP and LPF pups were smaller at birth but their weights caught up like that of controls by 3 mo. In males, folate supplementation reduced LP-induced GI at 2 mo (glucose area under the curve [AUC]: 1940 mmol/L * 180 min in LP, 1629 mmol/L * 180 min in LPF, and 1653 mmol/L * 180 min in controls; P <0.05, LP versus control and P <0.01, LP versus LPF) but the effect diminished at 3 mo. In females, folate reduced GI at 1 mo (glucose AUC: 1406 mmol/L * 180 min in LP, 1264 mmol/L * 180 min in LPF, and 1281 mmol/L * 180 min in controls; P <0.05, LP versus control and LP versus LPF) but had no effect at 2 and 3 mo. Interestingly, the LPF group had higher pancreatic weights than other groups, suggesting that folate helps in pancreatic development enabling the LPF rats to produce/secrete more insulin to maintain euglycemia. Euglycemic-hyperinsulinemic clamp shows both LP and LPF are insulin resistant compared with controls by 4 mo with LPF more severe than LP in males. Interestingly, females were more insulin resistant than males. CONCLUSIONS: Folate treatment partially reverses LP-induced GI and the magnitude of reversal is age and sex dependent. Furthermore, folate treatment does not reverse IR in either sex but makes it worse in males at 4 mo. The present study demonstrated that folate treatment is not sufficient to rescue the LP programming effects. PMID- 29500970 TI - Prognostic value of respiratory quotients in severe polytrauma patients with nutritional support. AB - OBJECTIVE: The association between energy metabolism and prognosis in polytrauma patients has not yet been defined. The aim of this study was to describe energy metabolism and analyze the prognostic value of respiratory quotient (RQ) and nonprotein respiratory quotient (npRQ) in fasting polytrauma patients (fPP) and polytrauma patients with nutritional support (nsPP). METHODS: Twenty-two polytrauma patients (before and after parenteral nutrition administration) and 22 healthy controls (after overnight fasting) were examined on day 4 (median) after admission to the intensive care unit. To evaluate energy expenditure in nsPP and resting energy expenditure in fPP and controls with RQ and npRQ in all groups, we used indirect calorimetry. With regression analysis, the descriptive models of intensive care unit (ICU) length of stay (LOS) and mechanical ventilation time (VT) were derived. RESULTS: RQ and npRQ were significantly lower in fPP than in controls (P < 0.05 and P < 0.01, respectively) and in nsPP (P < 0.05). In nsPP, relationships between RQ or npRQ and the ICU LOS or mechanical VT were demonstrated (P < 0.0001, r = -0.78 for RQ and VT; P < 0.0001, r = -0.78 for npRQ and VT; P < 0.001, r = -0.69 for RQ and LOS; P < 0.001, r = -0.72 for npRQ and LOS). CONCLUSIONS: RQ and npRQ parameters measured by indirect calorimetry in polytrauma patients with parenteral nutrition on the fourth day of ICU stay related to clinical outcomes such as duration of mechanical ventilation and ICU LOS. PMID- 29500971 TI - Electrochemical reductive dehalogenation of iodine-containing contrast agent pharmaceuticals: Examination of reactions of diatrizoate and iopamidol using the method of rotating ring-disc electrode (RRDE). AB - This study examined the electrochemical (EC) reduction of iodinated contrast media (ICM) exemplified by iopamidol and diatrizoate. The method of rotating ring disc electrode (RRDE) was used to elucidate rates and mechanisms of the EC reactions of the selected ICMs. Experiments were carried at varying hydrodynamic conditions, concentrations of iopamidol, diatrizoate, natural organic matter (NOM) and model compounds (resorcinol, catechol, guaiacol) which were used to examine interactions between products of the EC reduction of ICMs and halogenation-active species. The data showed that iopamidol and diatrizoate were EC-reduced at potentials < -0.45 V vs. s.c.e. In the range of potentials -0.65 to -0.85 V their reduction was mass transfer-controlled. The presence of NOM and model compounds did not affect the EC reduction of iopamidol and diatrizoate but active iodine species formed as a result of the EC-induced transformations of these ICMs reacted readily with NOM and model compounds. These data provide more insight into the nature of generation of iodine-containing by-products in the case of reductive degradation of ICMs. PMID- 29500972 TI - Biorefinery of cellulosic primary sludge towards targeted Short Chain Fatty Acids, phosphorus and methane recovery. AB - Cellulose from used toilet paper is a major untapped resource embedded in municipal wastewater which recovery and valorization to valuable products can be optimized. Cellulosic primary sludge (CPS) can be separated by upstream dynamic sieving and anaerobically digested to recover methane as much as 4.02 m3/capita.year. On the other hand, optimal acidogenic fermenting conditions of CPS allows the production of targeted short-chain fatty acids (SCFAs) as much as 2.92 kg COD/capita.year. Here propionate content can be more than 30% and can optimize the enhanced biological phosphorus removal (EBPR) processes or the higher valuable co-polymer of polyhydroxyalkanoates (PHAs). In this work, first a full set of batch assays were used at three different temperatures (37, 55 and 70 degrees C) and three different initial pH (8, 9 and 10) to identify the best conditions for optimizing both the total SCFAs and propionate content from CPS fermentation. Then, the optimal conditions were applied in long term to a Sequencing Batch Fermentation Reactor where the highest propionate production (100-120 mg COD/g TVSfed.d) was obtained at 37 degrees C and adjusting the feeding pH at 8. This was attributed to the higher hydrolysis efficiency of the cellulosic materials (up to 44%), which increased the selective growth of Propionibacterium acidopropionici in the fermentation broth up to 34%. At the same time, around 88% of the phosphorus released during the acidogenic fermentation was recovered as much as 0.15 kg of struvite per capita.year. Finally, the potential market value was preliminary estimated for the recovered materials that can triple over the conventional scenario of biogas recovery in existing municipal wastewater treatment plants. PMID- 29500973 TI - Phosphorus removal by in situ generated Fe(II): Efficacy, kinetics and mechanism. AB - The application of in situ electrochemical generation of ferrous (Fe(II)) ions for phosphorus (P) removal in wastewater treatment was investigated with attention to the efficacy, kinetics and mechanism. At concentrations typical of municipal wastewater, P could be removed by in situ Fe(II) with removal efficiency higher than achieved on addition of FeSO4 and close to that of FeCl3 under both anoxic and oxic conditions. The generation of alkalinity due to water electrolysis at the cathode created much higher pH conditions compared to FeSO4 dosing thereby resulting in very different pathways of Fe solid phase formation and associated P removal mechanisms. The remarkably similar dependence of P removal on accumulated Fe for all investigated currents, initial P concentrations and DO conditions indicated that kinetic aspects did not play a role in P removal during in situ Fe(II) dosing. Thermodynamic modelling was undertaken to investigate possible solid phase formation pathways under anoxic conditions and these insights were extended to oxic conditions. The exclusive formation of ferrous hydroxide during anoxic in situ Fe(II) dosing implied that P removal occurred via coprecipitation and adsorption. Under oxic conditions, the high pH conditions would have resulted in rapid Fe(II) oxidation and formation of ferric oxyhydroxides with associated coprecipitation and adsorption effecting P removal in a similar pattern to that observed under anoxic conditions. In situ Fe(II) dosing represents a versatile option for chemical P removal with the precise control of Fe dosage to optimize FeP forms for possible P recovery. PMID- 29500974 TI - Roles of an easily biodegradable co-substrate in enhancing tetracycline treatment in an intimately coupled photocatalytic-biological reactor. AB - Intimately coupled photocatalysis and biodegradation (ICPB) was realized in a macroporous carrier in which a photocatalyst was present on the outer surface, while a biofilm accumulated inside the carrier. In ICPB, photocatalysis products are rapidly biodegraded by a protected biofilm, leading to mineralization of the refractory organics, such as antibiotics. However, mineralization in ICPB could be compromised if the photocatalysis products remain refractory or are inhibitory. To address this, we attempted to increase metabolic activity by providing a readily biodegradable co-substrate (acetate) that could act as a source of energy and electrons to improve biotransformation and mineralization of the refractory antibiotic tetracycline (TCH). When we added acetate during ICPB of TCH, TCH removal increased by ~5%, mineralization increased by ~20%, and almost all photocatalysis products disappeared. Acetate addition also led to an increase in active biomass, an increase in the biomass's respiratory activity, and evolution of the microbial community to having more members able to biodegrade photocatalysis and biotransformation intermediates. Thus, providing an easily biodegradable co-substrate was an effective means for enhancing TCH removal and mineralization with the ICPB technology. PMID- 29500975 TI - Neural networks for dimensionality reduction of fluorescence spectra and prediction of drinking water disinfection by-products. AB - The use of fluorescence data coupled with neural networks for improved predictability of drinking water disinfection by-products (DBPs) was investigated. Novel application of autoencoders to process high-dimensional fluorescence data was related to common dimensionality reduction techniques of parallel factors analysis (PARAFAC) and principal component analysis (PCA). The proposed method was assessed based on component interpretability as well as for prediction of organic matter reactivity to formation of DBPs. Optimal prediction accuracies on a validation dataset were observed with an autoencoder-neural network approach or by utilizing the full spectrum without pre-processing. Latent representation by an autoencoder appeared to mitigate overfitting when compared to other methods. Although DBP prediction error was minimized by other pre processing techniques, PARAFAC yielded interpretable components which resemble fluorescence expected from individual organic fluorophores. Through analysis of the network weights, fluorescence regions associated with DBP formation can be identified, representing a potential method to distinguish reactivity between fluorophore groupings. However, distinct results due to the applied dimensionality reduction approaches were observed, dictating a need for considering the role of data pre-processing in the interpretability of the results. In comparison to common organic measures currently used for DBP formation prediction, fluorescence was shown to improve prediction accuracies, with improvements to DBP prediction best realized when appropriate pre-processing and regression techniques were applied. The results of this study show promise for the potential application of neural networks to best utilize fluorescence EEM data for prediction of organic matter reactivity. PMID- 29500976 TI - Metagenomic approaches to understanding bacterial communication during the anammox reactor start-up. AB - Increasing attention has been paid to the anammox community for its significant function in high-efficiency wastewater treatment. However, bacterial interaction in terms of bacterial communication is still elusive. This study firstly explored the intra- and interspecific communication of bacteria in the anammox community using metagenomic sequence data obtained during bioreactor operation. We verified the existence of multiple bacterial communication gene (BCG) subtypes by alignment with the constructed BCG database containing 11 identified gene subtypes. Bacterial communication was more active at the initial start-up than in the high loading-rate phase, and was correlated with the gradually decreasing bacterial diversity. Hdts, one of the key genes that produced the intraspecific signaling molecule AHL, and RpfF, the key gene that produced the intra- and interspecific signaling molecule DSF, were the primary communication engines in the anammox community because of their high abundance. Anammox bacteria mainly used Hdts genes to communicate with others, while RpfF gene played a core role characterized by their multiple correlations with other BCG subtypes. Interestingly, bacteria with abundant BCGs were more inclined to interact with the bacteria with the same functional traits, indicating the potential communication-related interaction among these bacteria in addition to the frequently reported substrate co-utilization. This highlights the primary importance of AHL and DSF for the anammox community, and thereby hints at a potential strategy for the target regulation of the signals to improve anammox viability and competitive capacity in wastewater treatment. PMID- 29500977 TI - Familial study of attentional and behavioural problems in children with Dyslexia and their first-degree relatives in Indian setting. AB - BACKGROUND: Dyslexia is one of the common problems seen in children worldwide. There is high co-morbidity of dyslexia with attentional and behaviour problems which could have familial pattern. This study aims to compare the attentional and behavioural problems in children with dyslexia and their first-degree relatives with controls. METHODS: This is a cross-sectional comparative study with single interview method in an out-patient setting. Formally diagnosed (ICD-10) cases of 30 children with specific reading disorder and 30 healthy matched controls and their first-degree relatives were assessed using scales in a single setting after application of inclusion and exclusion criteria. RESULTS: The children with dyslexia had significantly more problems in the domains of selective attention and behavioural problems as compared to controls and the siblings of the cases had significant problems in selective attention but not in behavioural problems. Also, no difference was seen in ADHD symptoms of parents in cases and controls. CONCLUSION: The results from our study are keeping with most of the published literature. We expect that this study will help in laying a good foundation for further studies with stronger methodologies incorporating molecular genetics. PMID- 29500978 TI - Perfluorooctyl bromide & indocyanine green co-loaded nanoliposomes for enhanced multimodal imaging-guided phototherapy. AB - As a highly biocompatible NIR dye, indocyanine green (ICG) has been widely explored for cancer treatment due to its various energy level transition pathways upon NIR light excitation simultaneously, which leads to different theranostic effects (eg. Photoacoustic (PA) and fluorescence imaging (FL), photodynamic and photothermal therapy (PDT&PTT)). However, the theranostic efficiency of ICG is restricted intrinsically, owing to the competitive relationship of its co existing imaging and therapeutic effect. Moreover, the extrinsic hypoxia nature of tumor further limits its therapeutic effect, especially for the oxygen dependent PDT. Herein, perfluorooctyl bromide (PFOB), another biocompatible chemical, was integrated with ICG in a nanoliposome structure via a facile two step emulsion method. Such an ICG&PFOB co-loaded nanoliposomes (LIP-PFOB-ICG) realized computed tomography (CT) contrast imaging in vivo, providing better anatomical information of tumor in comparison to ICG enabled PA and FL imaging. More importantly, LIP-PFOB-ICG inhibited MDA-MB-231 tumor growth completely via intravenous injection through enhanced PDT&PTT synergistic therapy due to the excellent oxygen carrying ability of PFOB, which effectively attenuated tumor hypoxia, improved the efficiency of collisional energy transfer between ICG and oxygen and reduced the expression of heat shock protein (HSP). As expected, the introduction of PFOB within nanoliposomes with ICG has augmented the theranostic effect of ICG comprehensively, which makes this simple biocompatible liposome based nanoagent a potential candidate for clinical imaging guided phototherapy of cancer. PMID- 29500979 TI - Hydrotalcite monolayer toward high performance synergistic dual-modal imaging and cancer therapy. AB - Recently, theranostic has drawn tremendous attention by virtue of the nanotechnology development and new material exploration. Herein, we reported a novel theranostic system by loading Au nanoclusters (AuNCs) and Chlorin e6 (photosensitizer, Ce6) onto the monolayer nanosheet surface of Gd-doped layered double hydroxide (Gd-LDH). The as-prepared Ce6&AuNCs/Gd-LDH exhibits a largely enhanced fluorescence quantum yield (QY) of 18.5% relative to pristine AuNCs (QY = 3.1%) as well as superior T1 magnetic resonance imaging (MRI) performance (r1 = 17.57 mM-1s-1) compared with commercial MRI contrast agent (Gd(III)-1,4,7,10 tetraazacyclododecane-1,4,7,10-tetraacetic acid (Gd-DOTA): r1 ~ 3.4 mM-1s-1), resulting from a synergistic effect between AuNCs and Gd-LDH. In addition, both in vitro and in vivo therapeutic evaluations demonstrate an efficient dual modality imaging guided anticancer performance, especially the synergetic enhanced magnetic resonance/fluorescence (MR/FL) visualization of tumor site. Therefore, this work demonstrates a successful paradigm for the design and preparation of LDHs monolayer-based theranostic material, which holds great promises in practical applications. PMID- 29500980 TI - Simulating damage onset and evolution in fully bio-resorbable composite under three-point bending. AB - This paper presents a strain-based damage model to predict the stress-strain relationship and investigate the damage onset and evolution of the fibre and matrix of a fully bio-resorbable phosphate glass fibre reinforced composite under three-point bending. The flexural properties of the composite are crucial, particularly when it is employed as implant for long bone fracture. In the model, the 3D case of the strain and stress was used and the response of the undamaged material was assumed to be linearly elastic. The onset of damage was indicated by two damage variables for the fibre and matrix, respectively. The damage evolution law was based on the damage variable and the facture energy of the fibre and matrix, individually. A finite element (FE) model was created to implement the constitutive model and conduct numerical tests. An auto-adaptive algorithm is integrated in the FE model to improve the convergence. The FE model was capable of predicting the flexural modulus with around 3% relative error, and the flexural strength within 2% relative error in comparison with the experimental data. The numerical indices showed that the top surface of the sample was the most vulnerable under three-point bending. It was also found that the damage initiated in the fibre, was the primary driver for composite failure under three point bending. PMID- 29500981 TI - A new mechanical indentation framework for functional assessment of articular cartilage. AB - The conventional mechanical properties of articular cartilage, such as compressive stiffness, have been shown to have limited capacity to distinguish visually normal from degraded cartilage samples. In this study, a new mechanical indentation framework for assessing functional properties of articular cartilage during loading/unloading, i.e. deformation and recovery, was established. The capacity of a ring-shaped indenter integrated with an ultrasound transducer to distinguish mechanically intact from proteoglycan-depleted tissue was investigated. To achieve this, normal and enzymatically degraded bovine osteochondral samples were subjected to loading/unloading while the response of the tissue at the middle was captured by ultrasound at the same time. The enzymatic degradation model was characterized by amount of proteoglycan content, glycosaminoglycan release and proteomic analysis. The mechanical response of a wider continuum of articular cartilage in the loaded area and its surrounding region was captured in this framework leading to investigate two parameters, L and TS, related to the surrounding tissue of the loaded area for functional assessment of cartilage. L is the distance between the ultrasound transducer and articular cartilage surface and TS is the transient strain of articular cartilage during loading and unloading. Classification Analysis based on Principal Component Analysis was used to investigate the capacity of the new parameters to assess the functionality of the tissue. Multivariate statistics based on Partial Least Squares regression was employed to identify the correlation between the response of the tissue in the indented area and its surrounding cartilage. The results of this study indicate that L during loading (deformation) can differentiate normal and mildly proteoglycan-depleted samples from severely depleted samples and L during unloading (recovery) can distinguish between normal and proteoglycan-depleted tissue. However, TS during deformation and recovery is unable to discriminate normal cartilage samples from proteoglycan-depleted tissue. The results also demonstrate a strong correlation between mechanical properties of the loaded area with the response of its surrounding cartilage during recovery. It is therefore concluded that L in this newly established framework can discriminate between normal and proteoglycan-depleted cartilage samples. However, more samples will be needed to verify the demarcation between samples degraded for varying amount of time. PMID- 29500982 TI - Optimization simulated injection molding process for ultrahigh molecular weight polyethylene nanocomposite hip liner using response surface methodology and simulation of mechanical behavior. AB - In this study, injection molding process of ultrahigh molecular weight polyethylene (UHMWPE) reinforced with nano-hydroxyapatite (nHA) was simulated and optimized through minimizing the shrinkage and warpage of the hip liners as an essential part of a hip prosthesis. Fractional factorial design (FFD) was applied to the design of the experiment, modeling, and optimizing the shrinkage and warpage of UHMWPE/nHA composite liners. The Analysis of variance (ANOVA) was applied to find the importance of operative parameters and their effects. In this experiment, seven input parameters were surveyed, including mold temperature (A), melt temperature (B), injection time (C), packing time (D), packing pressure (E), coolant temperature (F), and type of liner (G). Two models were capable of predicting warpage and volumetric shrinkage (%) in different conditions with R2 of 0.9949 and 0.9989, respectively. According to the models, the optimized values of warpage and volumetric shrinkage are 0.287222 mm and 13.6613%, respectively. Meanwhile, a finite element analysis (FE analysis) was also carried out to examine the stress distribution in liners under the force values of demanding and daily activities. The Von-Mises stress distribution showed that both of the liners can be applied to all activities with no failure. However, UHMWPE/nHA liner is more resistant to the highest loads than UHMWPE liner due to the effect of nHA in the nanocomposite. Finally, according to the results of injection molding simulations, optimization, structural analysis as well as the tensile strength and wear resistance, UHMWPE/nHA liner is recommended for the production of a hip prosthesis. PMID- 29500983 TI - Alpha lipoic acid protects against chlorpyrifos-induced toxicity in Wistar rats via modulating the apoptotic pathway. AB - The chronic exposure to chlorpyrifos (CPF) pesticide induces several human disorders including hepatotoxicity. Alpha-lipoic acid (ALA) is a natural antioxidant compound found in plants and animals. The present study aimed to investigate the possible protective effect of ALA against CPF-induced hepatotoxicity and the possible underlying molecular mechanism. Thirty-two male Wistar rats were divided into: Normal rats received only vehicle; ALA group received ALA (10 mg/kg, i.p.); CPF group received CPF (18 mg/kg, s.c.) and CPF ALA group received CPF (18 mg/kg, s.c.) once daily for 14 days. The present results demonstrated that administration of ALA significantly improved liver functions (p < 0.05) and limited the histopathological lesions induced by CPF in liver tissues. Furthermore, ALA decreased hepatic malondialdehyde contents while increased the glutathione peroxidase, catalase, superoxide dismutase and acetylcholinesterase activities. Interestingly, ALA showed significant antiapoptotic effects through downregulation of Bax and Caspase-3 expression levels. In conclusion, ALA possess protective effects against CPF-induced liver injury through attenuation of apoptosis and oxidative stress. PMID- 29500984 TI - Wrist sensor-based tremor severity quantification in Parkinson's disease using convolutional neural network. AB - Tremor is a commonly observed symptom in patients of Parkinson's disease (PD), and accurate measurement of tremor severity is essential in prescribing appropriate treatment to relieve its symptoms. We propose a tremor assessment system based on the use of a convolutional neural network (CNN) to differentiate the severity of symptoms as measured in data collected from a wearable device. Tremor signals were recorded from 92 PD patients using a custom-developed device (SNUMAP) equipped with an accelerometer and gyroscope mounted on a wrist module. Neurologists assessed the tremor symptoms on the Unified Parkinson's Disease Rating Scale (UPDRS) from simultaneously recorded video footages. The measured data were transformed into the frequency domain and used to construct a two dimensional image for training the network, and the CNN model was trained by convolving tremor signal images with kernels. The proposed CNN architecture was compared to previously studied machine learning algorithms and found to outperform them (accuracy = 0.85, linear weighted kappa = 0.85). More precise monitoring of PD tremor symptoms in daily life could be possible using our proposed method. PMID- 29500985 TI - Studies in the extensively automatic construction of large odds-based inference networks from structured data. Examples from medical, bioinformatics, and health insurance claims data. AB - Theoretical and methodological principles are presented for the construction of very large inference nets for odds calculations, composed of hundreds or many thousands or more of elements, in this paper generated by structured data mining. It is argued that the usual small inference nets can sometimes represent rather simple, arbitrary estimates. Examples of applications in clinical and public health data analysis, medical claims data and detection of irregular entries, and bioinformatics data, are presented. Construction of large nets benefits from application of a theory of expected information for sparse data and the Dirac notation and algebra. The extent to which these are important here is briefly discussed. Purposes of the study include (a) exploration of the properties of large inference nets and a perturbation and tacit conditionality models, (b) using these to propose simpler models including one that a physician could use routinely, analogous to a "risk score", (c) examination of the merit of describing optimal performance in a single measure that combines accuracy, specificity, and sensitivity in place of a ROC curve, and (d) relationship to methods for detecting anomalous and potentially fraudulent data. PMID- 29500986 TI - Is there a "right time" for bad news? Kairos in familial communication on hereditary breast and ovarian cancer risk. AB - Time has long been considered as an important dimension of the process of disclosure of information about genetic risk to kin. The question of the "right time to tell" has been frequently noticed but seldom placed at the centre of the analyses of social scientists. Based on an ethnographical fieldwork in a French cancer genetics clinic, this article aims to show that many dimensions of the practical issues of disclosure to family can be fruitfully addressed through the temporal lens of kairos. Relying on the case of hereditary breast and ovarian cancer risk, it firstly highlights the existence of a mismatch between the "chronological" time of prevention proposed by professionals and the "kairological" time of disclosure lived by informants. Secondly, it emphasizes the problematic nature of the pragmatic approach of time associated with kairos. On the one hand one can draw some benefits from seeking the right time to inform relatives, but on the other hand waiting on uncertain opportunities to disclose such information can make communication even more difficult. PMID- 29500987 TI - Ambient concentrations of particulate matter and hospitalization for depression in 26 Chinese cities: A case-crossover study. AB - OBJECTIVE: Air pollution with high ambient concentrations of particulate matter (PM) has been frequently reported in China. However, no Chinese study has looked into the short-term effect of PM on hospitalization for depression. We used a time-stratified case-crossover design to identify possible links between ambient PM levels and hospital admissions for depression in 26 Chinese cities. METHODS: Electronic hospitalization summary reports (January 1, 2014-December 31, 2015) were used to identify hospital admissions related to depression. Conditional logistic regression was applied to determine the association between PM levels and hospitalizations for depression, with stratification by sex, age, and comorbidities. RESULTS: Both PM2.5 and PM10 levels were positively associated with the number of hospital admissions for depression. The strongest effect was observed on the day of exposure (lag day 0) for PM10, with an interquartile range increase in PM10 associated with a 3.55% (95% confidence interval: 1.69-5.45) increase in admissions for depression. For PM2.5, the risks of hospitalization peaked on lag day 0 (2.92; 1.37-4.50) and lag day 5 (3.65; 2.09-5.24). The elderly (>65) were more sensitive to PM2.5 exposure (9.23; 5.09-13.53) and PM10 exposure (6.35; 3.31-9.49) on lag day 0, and patients with cardiovascular disease were likely to be hospitalized for depression following exposure to high levels of PM10 (4.47; 2.13-6.85). CONCLUSIONS: Short-term elevations in PM may increase the risk of hospitalization for depression, particularly in the elderly and in patients with cardiovascular disease. PMID- 29500988 TI - Perfluoroalkyl substances in adolescents in northern Norway: Lifestyle and dietary predictors. The Tromso study, Fit Futures 1. AB - Perfluoroalkyl substances (PFASs) are environmentally persistent chemicals widely used in many consumer products due to water and oil proofing and fire-resistant properties. Several PFASs are recognized as environmental pollutants. This study investigated serum concentrations of 18 different PFASs and their associations with diet and lifestyle variables in 940 adolescents (age 15-19 years) who participated in the Fit Futures 1 study in the Troms arctic district of Norway. Serum concentrations of PFASs were analyzed by ultrahigh pressure liquid chromatography coupled to a triple quadrupole mass spectrometer (UHPLC-MS/MS). The most abundant PFASs in this population were perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorohexane sulfonate (PFHxS), perfluorononanoate (PFNA) and perfluorodecanoate (PFDA) that were found in 99% of the participants. Perfluoroheptane sulfonate (PFHpS) was found in 98% of the participants. Median concentrations were: PFOS 6.20 ng/mL, PFOA 1.92 ng/mL, PFHxS 0.71 ng/mL, PFNA 0.50 ng/mL, PFDA 0.21 ng/mL and PFHpS 0.15 ng/mL. Median of PFASs sum concentration (?PFAS) was 10.7 ng/mL, the concentration range was 2.6-200.8 ng/mL. Intake of fat fish, fish liver, seagull eggs, reindeer meat and drinks with sugar were the main dietary predictors of several PFASs. Intake of junk food (pizza, hamburger, sausages) was positively associated with PFNA, intake of canned food was positively associated with PFHxS. Intake of fruits and vegetables, milk products, snacks and candy was not associated with PFASs concentrations. Lean fish intake was positively associated with PFUnDA, but not with other PFASs. There was a positive association of ?PFAS, PFHxS, PFOA, PFNA and PFDA with chewed tobacco use. PMID- 29500989 TI - CRISPR-based methods for high-throughput annotation of regulatory DNA. AB - Developments in CRISPR/Cas9-based technologies provide a new paradigm in functional screening of the genome. Conventional screening methods have focused on high-throughput perturbations of the protein-coding genome with technologies such as RNAi. However, equivalent methods for perturbing the non-coding genome have not existed until recently. CRISPR-based screening of genomic DNA has enabled the study of both genes and non-coding gene regulatory elements. Here we review recent progress in assigning function to the non-coding genome using CRISPR-based genomic and epigenomic screens, and discuss the prospects of these technologies to transforming our understanding of genome structure and regulation. PMID- 29500990 TI - A synthetic stroma-free germinal center niche for efficient generation of humoral immunity ex vivo. AB - B cells play a major role in the adaptive immune response by producing antigen specific antibodies against pathogens and imparting immunological memory. Following infection or vaccination, antibody-secreting B cells and memory B cells are generated in specialized regions of lymph nodes and spleens, called germinal centers. Here, we report a fully synthetic ex-vivo system that recapitulates the generation of antigen-specific germinal-center (GC) like B cells using material surface driven polyvalent signaling. This synthetic germinal center (sGC) reaction was effectively induced using biomaterial-based artificial "follicular T helper cells (TFH)" that provided both natural CD40-CD40L ligation as well as crosslinking of CD40 and by mimicking artificial "follicular dendritic cells (FDC)" to provide efficient, polyvalent antigen presentation. The artificial sGC reaction resulted in efficient B cell expansion, immunoglobulin (Ig) class switching, and expression of germinal center phenotypes. Antigen presentation during sGC reaction selectively enhanced the antigen-specific B cell population and induced somatic hyper-mutations for potential affinity maturation. The resulting B cell population consisted primarily of GC-like B cells (centrocytes) as well as some plasma-like B cells expressing CD138. With concurrent cell sorting, we successfully created highly enriched populations of antigen-specific B cells. Adoptive transfer of these GC-like B cells into non-irradiated isogeneic or non-lethally irradiated congenic recipient mice showed successful engraftment and survival of the donor cells for the 4 week test period. We show that this material-surface driven sGC reaction can be successfully applied to not only splenic B cells but also B cells isolated from more therapeutically relevant sources such as peripheral blood mononuclear cells (PBMCs), thus making our current work an exciting prospect in the new era of personalized medicine and custom-immunotherapy. PMID- 29500991 TI - A ratiometric fluorescence probe for lysosomal polarity. AB - Lysosomal polarity affects the interaction activities between enzymes and substrates at the cellular level. Abnormal lysosomal polarity closely linked with disorders and diseases is worthy of attention. The first fluorescence probe, which can image polarity ratiometrically and detect lysosomal polarity quantitatively, is reported herein. The probe termed NOH can emit dual-peaks both in solvents (lambdaem = 474, 552 nm) and in micro-environment. NOH exhibits the Boltzmann function response of the fluorescence intensity ratio to the polarity in a wide range and localizes at lysosomes specifically (Rr = 0.97). In the method of ratiometric fluorescence imaging with NOH, the variation of lysosomal polarity (Deltaf) can be directly discerned by the color changes. In virtue of ratiometric fluorescence imaging and the Boltzmann function relationship between the fluorescence intensity ratio and the polarity, lysosomal polarity in MCF-7 cells was calculated to be 0.224 and the polarity in the condition of lysosomal storage disorders (or cell death) could also be obtained. This probe will be a promising tool for studying lysosome-related physiological or pathological processes. PMID- 29500992 TI - Deconvoluting the effects of surface chemistry and nanoscale topography: Pseudomonas aeruginosa biofilm nucleation on Si-based substrates. AB - HYPOTHESIS: The nucleation of biofilms is known to be affected by both the chemistry and topography of the underlying substrate, particularly when topography includes nanoscale (<100 nm) features. However, determining the role of topography vs. chemistry is complicated by concomitant variation in both as a result of typical surface modification techniques. Analyzing the behavior of biofilm-forming bacteria exposed to surfaces with systematic, independent variation of both topography and surface chemistry should allow differentiation of the two effects. EXPERIMENTS: Silicon surfaces with reproducible nanotopography were created by anisotropic etching in deoxygenated water. Surface chemistry was varied independently to create hydrophilic (OH-terminated) and hydrophobic (alkyl-terminated) surfaces. The attachment and proliferation of Psuedomonas aeruginosa to these surfaces was characterized over a period of 12 h using fluorescence and confocal microscopy. FINDINGS: The number of attached bacteria as well as the structural characteristics of the nucleating biofilm were influenced by both surface nanotopography and surface chemistry. In general terms, the presence of both nanoscale features and hydrophobic surface chemistry enhance bacterial attachment and colonization. However, the structural details of the resulting biofilms suggest that surface chemistry and topography interact differently on each of the four surface types we studied. PMID- 29500993 TI - Effects of vibration-induced fatigue on the H-reflex. AB - Vibration exercise (VE) has been suggested as an effective training for improving muscle strength and coordination. However, the underlying physiological adaptation processes are not yet fully understood, limiting the development of safe and effective exercise protocols. To better understand the neuromuscular responses elicited by VE, we aimed at investigating the acute effects of superimposed vibration on the Hoffmann reflex (H-reflex), measured after fatiguing exercise. Twenty-five volunteers performed four isometric contractions of the right Flexor Carpi Radialis (FCR) with baseline load at 80% of their maximal voluntary contraction (MVC), both with no vibration and with superimposed vibration at 15, 30, and 45 Hz. Fatigue was estimated by MVC test and estimation of electromyographic spectral compression. H-reflex suppression was estimated as the relative decrease after exercise. Our results show that fatiguing exercise determined a decrease in H-reflex amplitude compared to rest condition while vibration determined a lower H-reflex suppression as compared to no vibration. The superimposition of 30-Hz vibration determined the largest acute reduction in force generating capacity (36 N, p < 0.05) and the lowest H-reflex suppression (20%, p < 0.05). These results suggest VE to be particularly suitable in rehabilitation programs for rapid restoration of muscle form and function after immobilization periods. PMID- 29500994 TI - Long-term effects of alum-treated litter, untreated litter and NH4NO3 application on phosphorus speciation, distribution and reactivity in soils using K-edge XANES and chemical fractionation. AB - Whereas soil test information on the fertility and chemistry of soils has been important to elaborate safe and sound agricultural practices, micro-scale information can give a whole extra dimension to understand the chemical processes occurring in soils. The objective of this study was to evaluate the effects that the consecutive application of untreated poultry litter, alum-treated litter or ammonium nitrate (NH4NO3) had on P solubility in soils over 20 years. For this, we used soil test data, sequential chemical fractionation (SCF) of P, and P K edge XANES and MU-fluorescence spectroscopies. Water extractable P data indicated that application of alum to poultry litter was a very effective treatment for reducing P solubility. On the basis of our SCF of P data, P was primarily found within the 0.1 M NaOH pool across the applied rates and regardless of the treatment, where application of alum-treated litter accounted for as much as 59 +/- 2% of the total, followed by NH4NO3, 49 +/- 4%, and untreated litter, 40 +/- 2%. It was also shown that in soils where alum-treated litter was applied, the Resin pool accounted for 10 +/- 1% of the total, followed by NH4NO3, 13 +/- 4%, and untreated litter, 18 +/- 2%, indicating that P was less readily available in soils where alum-treated litter was applied. Phosphorus XANES indicated that P was predominantly associated to Fe > Al > Ca > organic molecules, regardless of the treatment or applied rates, though the formation of PoAl complexes was only found in soils that received application of alum-treated litter and was positively related to the applied rates. The combination of P-XANES with SCF or MU-fluorescence data was shown to provide valuable information about P reactivity and distribution in soils and should thus be used to address the fate of applied P amendments in soils. PMID- 29500995 TI - Simultaneous removal of Cd (II) and p-cresol from wastewater by micellar-enhanced ultrafiltration using rhamnolipid: Flux decline, adsorption kinetics and isotherm studies. AB - Flux decline due to membrane fouling by surfactant micelles is the major problem limiting the use of micellar enhanced ultrafiltration (MEUF) for the treatment of wastewater. Understanding of underlying mechanisms of membrane fouling, adsorption kinetics and adsorption isotherm are very important for the successful application of MEUF studies. In the present study, an unsteady state model considering sequential occurrence of complete pore blocking and gel layer formation was proposed for explaining flux decline behavior during rhamnolipid based MEUF for simultaneous removal of Cd+2 and p-cresol from aqueous solution under batch concentration mode. The model was developed based on the Hermia's complete pore blocking model and resistance-in-series model coupled with gel layer theory incorporating the effects of feed temperature, variation of viscosity and retentate concentration with time, and pressure dependent mass transfer coefficient. A good agreement between the experimental data and model predictions was demonstrated. The effects of operating conditions were found to have a significant effect on the flux decline behavior and onset of gel layer formation. The use of ultrafiltration membrane for the study of adsorption kinetics and adsorption isotherm was demonstrated. Kinetic studies disclosed that both Cd+2 and p-cresol adsorption was better described by the pseudo-second order model for both single and binary solution. The results of isotherm studies revealed that adsorption of both Cd+2 and p-cresol was spontaneous in nature and equilibrium data was best fitted by Langmuir model with the maximum adsorption capacity of RHL vesicles of 208.33 and 53.27 mg g-1 for Cd+2 and p-cresol, respectively at 299 K. The model parameters of membrane fouling, adsorption kinetics and adsorption isotherm evaluated in this study could be useful in designing and scale up of RHL based MEUF process. PMID- 29500996 TI - Applications of magnetic hybrid adsorbent derived from waste biomass for the removal of metal ions and reduction of 4-nitrophenol. AB - The use of industrial waste to synthesize materials of technological interest is a rational way to minimize or solve environmental pollution problems. This work investigates the adsorption of cadmium and lead ions by magnetic hybrid adsorbents synthesized using the in natura biomasses coconut mesocarp (CCFe), sawdust (SAFe), and termite nest (TEFe) for the organic phases and magnetic cobalt ferrite as the inorganic phase. The formation of a cobalt ferrite phase was confirmed by XRD. The use of XRD and FTIR analyses revealed the presence of organic matter in the structure of the material. Removal assays performed at different pH values (2.0-8.0) showed the effectiveness of the adsorbent for the removal of Pb2+ at pH 3.0 and Cd2+ at pH 4.0. The adsorption processes showed fast kinetics, with removal of 79-86% of Pb2+ and 49% of Cd2+ within only 5 min, and removal of 92-96% of the metal species at equilibrium. In the case of cadmium, the hybrid sorbents (CCFe, SAFe, and TEFe) showed high removal capacity after three reuse cycles, while the removal of lead decreased from 99% to 40%. The adsorbent matrices saturated with the recovered cadmium and lead ions showed excellent catalytic performance in the reduction of 4-nitrophenol, with 99.9% conversion within 43-56 s. The materials showed high capacities for reuse in three successive reduction cycles. The findings highlight the effectiveness of an industrial symbiosis approach to the development of new technologically important materials. PMID- 29500997 TI - Transformational leadership as a framework for nurse education about hypertension in Uganda. AB - AIMS: The aim of the study was to describe nurses' knowledge, skills, and confidence related to hypertension and to assess the impact of a hypertension education initiative based in transformational leadership. METHODS: The exploratory study was conducted using a pre and posttest model of 18 Ugandan nurses during June of 2016 to assess knowledge and attitude about hypertension. Biometric screening of study participants was completed. Follow up information was collected from participants via email. RESULTS: Paired sample t-test revealed the nurses had increased knowledge after completion of workshop. Follow up e-mail query revealed the participants had acted on content of workshop and implemented programs in their communities to screen for and provide education related to hypertension. Biometric screening of participants found significant risk factors for hypertension but less than expected prevalence of hypertension. CONCLUSION: Despite having more formal education related to hypertension and healthy behaviors, nurses are at risk for obesity and hypertension. Their knowledge and commitment can be improved by an educational workshop. Linking educational workshops to a transformational leadership model that incorporates leadership of self, others, and systems has the potential to enhance nurses' health and leadership skills and to encourage dissemination of critical information. PMID- 29500998 TI - Shaping a valued learning journey: Student satisfaction with learning in undergraduate nursing programs, a grounded theory study. AB - BACKGROUND: Student satisfaction is a quality measure of increasing importance in undergraduate programs, including nursing programs. To date theories of student satisfaction have focused primarily on students' perceptions of the educational environment rather than their perceptions of learning. Understanding how students determine satisfaction with learning is necessary to facilitate student learning across a range of educational contexts and meet the expectations of diverse stakeholders. OBJECTIVES: To understand undergraduate nursing students' satisfaction with learning. DESIGN: Constructivist grounded theory methodology was used to identify how nursing students determined satisfaction with learning. SETTINGS: Two large, multi-campus, nursing schools in Australia. PARTICIPANTS: Seventeen demographically diverse undergraduate nursing students studying different stages of a three year program participated in the study. METHODS: Twenty nine semi-structured interviews were conducted. Students were invited to describe situations where they had been satisfied or dissatisfied with their learning. A constructivist grounded theory approach was used to analyse the data. RESULTS: Students are satisfied with learning when they shape a valued learning journey that accommodates social contexts of self, university and nursing workplace. The theory has three phases. Phase 1 - orienting self to valued learning in the pedagogical landscape; phase 2 - engaging with valued learning experiences across diverse pedagogical terrain; and phase 3 - recognising valued achievement along the way. CONCLUSION: When students experience a valued learning journey they are satisfied with their learning. Student satisfaction with learning is unique to the individual, changes over time and maybe transient or sustained, mild or intense. Finding from the research indicate areas where nurse academics may facilitate satisfaction with learning in undergraduate nursing programs while mindful of the expectations of other stakeholders such as the university, nurse registering authorities, employers and the receivers of nursing care. PMID- 29500999 TI - The effectiveness of outcome based education on the competencies of nursing students: A systematic review. AB - BACKGROUND: Outcome Based Education (OBE) is a student-centered approach of curriculum design and teaching that emphasize on what learners should know, understand, demonstrate and how to adapt to life beyond formal education. However, no systematic review has been seen to explore the effectiveness of OBE in improving the competencies of nursing students. OBJECTIVE: To appraise and synthesize the best available evidence that examines the effectiveness of OBE approaches towards the competencies of nursing students. DESIGN: A systematic review of interventional experimental studies. DATA SOURCES: Eight online databases namely CINAHL, EBSCO, Science Direct, ProQuest, Web of Science, PubMed, EMBASE and SCOPUS were searched. REVIEW METHODS: Relevant studies were identified using combined approaches of electronic database search without geographical or language filters but were limited to articles published from 2006 to 2016, handsearching journals and visually scanning references from retrieved studies. Two reviewers independently conducted the quality appraisal of selected studies and data were extracted. RESULTS: Six interventional studies met the inclusion criteria. Two of the studies were rated as high methodological quality and four were rated as moderate. Studies were published between 2009 and 2016 and were mostly from Asian and Middle Eastern countries. Results showed that OBE approaches improves competency in knowledge acquisition in terms of higher final course grades and cognitive skills, improve clinical skills and nursing core competencies and higher behavioural skills score while performing clinical skills. Learners' satisfaction was also encouraging as reported in one of the studies. Only one study reported on the negative effect. CONCLUSIONS: Although OBE approaches does show encouraging effects towards improving competencies of nursing students, more robust experimental study design with larger sample sizes, evaluating other outcome measures such as other areas of competencies, students' satisfaction, and patient outcomes are needed. PMID- 29501000 TI - Promoting interprofessional learning and enhancing the pre-registration student experience through reciprocal cross professional peer tutoring. AB - BACKGROUND: To improve collaboration and the quality of care, healthcare programmes are increasingly promoting interprofessional education thereby enabling students to learn with, from and about each other. A reciprocal peer learning model has developed among pre-registration physiotherapy and adult nursing students at Plymouth University, England. Embedded within the curriculum, it provides voluntary opportunities for year two students to become cross professional peer tutors to year one students while enhancing interprofessional understanding and skills acquisition. AIM: To explore participant experiences of two cross professional peer tutored clinical skills workshops delivered to a cohort of nursing (n = 67) and physiotherapy (n = 53) students in 2015. DESIGN: A mixed methods approach generated qualitative and quantitative data. Qualitative data was gathered via focus groups and individual interviews of peer tutors and learners (n = 27). These were recorded, transcribed and thematically analysed. The Readiness for Interprofessional Learning Scale questionnaire (n = 84) was completed before and after the workshops to consider any influence on students' attitudes towards interprofessional learning. RESULTS: Four themes evolved from thematic analysis; benefits of cross professional peer tutoring, interprofessional teamwork, quality of care and factors influencing the delivery of the workshops. Data showed students felt they developed greater understanding of interprofessional roles and acquired new skills. Peer tutors developed confidence in representing their profession while appearing to inspire early stage students. The Readiness for Interprofessional Learning Scale questionnaire data identified very positive attitudes towards interprofessional learning among the majority of students in both cohorts before and after the workshop. CONCLUSION: This study endorses the utility of enhancing the Higher Education experience by offering voluntary peer tutoring opportunities. Participating students build confidence in representing their profession, while potentially inspiring early stage students and supplementing interprofessional learning across a cohort. PMID- 29501001 TI - Phosphorus doped graphitic carbon nitride nanosheets as fluorescence probe for the detection of baicalein. AB - Phosphorus doped graphitic carbon nitride (P-g-C3N4) nanosheets were synthesized by calcination. P-g-C3N4 nanosheets were characterized by XRD, XPS, TEM, fluorescence, ultraviolet-visible absorption and Fourier transform infrared spectroscopy. The fluorescence of the P-g-C3N4 nanosheets was gradually quenched with the increase in the concentration of baicalein at room temperature. The proposed probe was used for the determination of baicalein in the concentration 2.0-30MUM with a detection limit of 53nM. The quenching mechanism was discussed. The P-g-C3N4 nanosheets have been successfully applied for effective and selective detection of baicalein in human urine samples and blood samples. PMID- 29501002 TI - Charge-transfer excited state in pyrene-1-carboxylic acids adsorbed on titanium dioxide nanoparticles. AB - The electronic structure of excited photosensitizer adsorbed at the surface of a solid is the key factor in the electron transfer processes that underlie the efficiency of dye-sensitized solar cells and photocatalysts. In this work, Stark effect (electroabsorption) spectroscopy has been used to measure the polarizability and dipole moment changes in electronic transitions of pyrene-1 carboxylic (PCA), -acetic (PAA) and -butyric (PBA) acids in ethanol, both free and adsorbed on colloidal TiO2, in glassy ethanol at low temperature. The lack of appreciable increase of dipole moment in the excited state of free and adsorbed PAA and PBA points that two or more single bonds completely prevent the expansion of pi-electrons from the aromatic ring towards the carboxylic group, thus excluding the possibility of direct electron injection into TiO2. In free PCA, the pyrene's forbidden S0->S1 transition has increased intensity, exhibits a long progression in 1400cm-1 Ag mode and is associated with |?MU| of 2 D. Adsorption of PCA on TiO2 causes a broadening and red shift of the S0->S1 absorption band and an increase in dipole moment change on electronic excitation to |?MU|=6.5 D. This value increased further to about 15 D when the content of acetic acid in the colloid was changed from 0.2% to 2%, and this effect is ascribed to the surface electric field. The large increase of |?MU| points that the electric field effect can not only change the energetics of electron transfer from the excited sensitizer into the solid, but can also shift the molecular electronic density, thus directly influencing the electronic coupling factor relevant for electron transfer at the molecule-solid interface. PMID- 29501003 TI - Application of reflectance spectroscopies (FTIR-ATR & FT-NIR) coupled with multivariate methods for robust in vivo detection of begomovirus infection in papaya leaves. AB - Nucleic acid & serology based methods have revolutionized plant disease detection, however, they are not very reliable at asymptomatic stage, especially in case of pathogen with systemic infection, in addition, they need at least 1 2days for sample harvesting, processing, and analysis. In this study, two reflectance spectroscopies i.e. Near Infrared reflectance spectroscopy (NIR) and Fourier-Transform-Infrared spectroscopy with Attenuated Total Reflection (FT-IR, ATR) coupled with multivariate exploratory methods like Principle Component Analysis (PCA) and Partial least square discriminant analysis (PLS-DA) have been deployed to detect begomovirus infection in papaya leaves. The application of those techniques demonstrates that they are very useful for robust in vivo detection of plant begomovirus infection. These methods are simple, sensitive, reproducible, precise, and do not require any lengthy samples preparation procedures. PMID- 29501004 TI - Spatial associations between social groups and ozone air pollution exposure in the Beijing urban area. AB - Few studies have linked social factors to air pollution exposure in China. Unlike the race or minority concepts in western countries, the Hukou system (residential registration system) is a fundamental reason for the existence of social deprivation in China. To assess the differences in ozone (O3) exposure among social groups, especially groups divided by Hukou status, we assigned estimates of O3 exposure to the latest census data of the Beijing urban area using a kriging interpolation model. We developed simultaneous autoregressive (SAR) models that account for spatial autocorrelation to identify the associations between O3 exposure and social factors. Principal component regression was used to control the multicollinearity bias as well as explore the spatial structure of the social data. The census tracts (CTs) with higher proportions of persons living alone and migrants with non-local Hukou were characterized by greater exposure to ambient O3. The areas with greater proportions of seniors had lower O3 exposure. The spatial distribution patterns were similar among variables including migrants, agricultural population and household separation (population status with separation between Hukou and actual residences), which fit the demographic characteristics of the majority of migrants. Migrants bore a double burden of social deprivation and O3 pollution exposure due to city development planning and the Hukou system. PMID- 29501005 TI - Steps forward reduction of environmental impact on children's health. PMID- 29501006 TI - Fish energy budget under ocean warming and flame retardant exposure. AB - Climate change and chemical contamination are global environmental threats of growing concern for the scientific community and regulatory authorities. Yet, the impacts and interactions of both stressors (particularly ocean warming and emerging chemical contaminants) on physiological responses of marine organisms remain unclear and still require further understanding. Within this context, the main goal of this study was to assess, for the first time, the effects of warming (+ 5 degrees C) and accumulation of a polybrominated diphenyl ether congener (BDE-209, brominated flame retardant) through dietary exposure on energy budget of the juvenile white seabream (Diplodus sargus). Specifically, growth (G), routine metabolism (R), excretion (faecal, F and nitrogenous losses, U) and food consumption (C) were calculated to obtain the energy budget. The results demonstrated that the energy proportion spent for G dominated the mode of the energy allocation of juvenile white seabream (56.0-67.8%), especially under the combined effect of warming plus BDE-209 exposure. Under all treatments, the energy channelled for R varied around 26% and a much smaller percentage was channelled for excretion (F: 4.3-16.0% and U: 2.3-3.3%). An opposite trend to G was observed to F, where the highest percentage (16.0 +/- 0.9%) was found under control temperature and BDE-209 exposure via diet. In general, the parameters were significantly affected by increased temperature and flame retardant exposure, where higher levels occurred for: i) wet weight, relative growth rate, protein and ash contents under warming conditions, ii) only for O:N ratio under BDE-209 exposure via diet, and iii) for feed efficiency, ammonia excretion rate, routine metabolic rate and assimilation efficiency under the combination of both stressors. On the other hand, decreased viscerosomatic index was observed under warming and lower fat content was observed under the combined effect of both stressors. Overall, under future warming and chemical contamination conditions, fish energy budget was greatly affected, which may dictate negative cascading impacts at population and community levels. Further research combining other climate change stressors (e.g. acidification and hypoxia) and emerging chemical contaminants are needed to better understand and forecast such biological effects in a changing ocean. PMID- 29501007 TI - Impact of wastewater effluent containing aged nanoparticles and other components on biological activities of the soil microbiome, Arabidopsis plants, and earthworms. AB - The amount of engineered nanomaterials (ENMs) in the environment has been increasing due to their industrial and commercial applications. Different types of metallic nanoparticles (NPs) have been detected in effluents from wastewater treatment plants (WWTPs). The effluents have been reclaimed for crop irrigation in many arid and semi-arid areas. Here, a soil micro-ecosystem was established including a microbiome, 4 Arabidopsis thaliana plants, and 3 Eisenia fetida earthworms, for a duration of 95 days. The impact of wastewater effluent (WE) containing aged NPs was studied. WE was taken from a local WWTP and exhibited the presence of Ti, Ag, and Zn up to 97.0 +/- 9.4, 27.4 +/- 3.9, and 4.1 +/- 3.6 ug/L, respectively, as well as the presence of nanoscale particles (1-100 nm in diameter). The plants were irrigated with WE or deionized water (DIW). After 95 days, significantly higher concentrations of extractable Ti and Zn (439.2 +/- 24.4 and 9.0 +/- 0.5 mg/kg, respectively) were found in WE-irrigated soil than those in DIW-irrigated soil (161.2 +/- 2.1 and 4.0 +/- 0.1 mg/kg). The extractable Ag concentrations did not differ significantly between the WE- and DIW-irrigated soil. Although microbial biomass carbon and nitrogen were not significantly reduced, the population distribution of the microbial communities was shifted in WE-irrigated soil compared to the control. The abundance of cyanobacteria (Cyanophyta) was increased by 12.5% in the WE-irrigated soil as manifested mainly by an increase of Trichodesmium spp., and the abundance of unknown archaea was enhanced from 26.7% in the control to 40.5% in the WE irrigated soil. The biomasses of A. thaliana and E. fetida were not significantly changed by WE exposure. However, A. thaliana had a noticeable shortened life cycle, and corrected total cell fluorescence was much higher in the roots of WE irrigated plants compared to the control. These impacts on the soil micro ecosystem may have resulted from the aged NPs and/or the metal ions released from these NPs, as well as other components in the WE. Taken together, these results should help inform the reuse of WE containing aged NPs and other components in sustainable agriculture. PMID- 29501008 TI - Effects of nutrient restriction and arginine treatment on oxidative stress in the ovarian tissue of ewes during the luteal phase. AB - The aim of this study was to determine whether nutrient restriction and arginine treatment affect energy metabolism changes and oxidative stress through the mitochondrial pathway in the ovarian tissue of ewes during the luteal phase. On days 6-15 of the estrous cycle, 24 multiparous Hu sheep (BW = 43.56 +/- 1.53 kg) were randomly assigned to three groups: control group (CG; n = 6), restriction group (RG; n = 9), and l-arginine group (AG; n = 9) administered Arg treatment (or vehicle) three times per day. The ewes were slaughtered at the end of treatment, and blood samples and ovaries were collected for analysis. In this study, the expression levels of antioxidase enzymes (SOD2, CAT and GPX1) and mitochondrial biogenesis-related genes (ESRRA and TFAM), as well as antioxidase activity and mitochondrial function were examined in ovarian tissue. Nutrient restriction resulted in activation of ESRRA and TFAM and an increase in relative mtDNA copy number, whereas arginine treatment led to a pronounced recovery of ovarian tissue. In addition, we observed increased AMPK phosphorylation at Thr172 and SIRT3 levels in nutrient restricted ewes, and these effects decreased with arginine treatment. In conclusion, the present results indicated that short-term nutritional restriction led to changes in energy metabolism and oxidative stress. These changes disrupted the redox balance, thus leading to apoptosis through the mitochondria-dependent apoptosis pathway. Arginine treatment altered gene expression in ovarian tissue and increased the resistance to oxidative stress and the anti-apoptosis capacity. The results presented here suggest a potential method to increase agricultural productivity and economic benefits in the sheep industry by using dietary supplementation with arginine to decrease temporary undernutrition of ewes. PMID- 29501009 TI - In vitro maturation of monocyte-derived dendritic cells results in two populations of cells with different surface marker expression, independently of applied concentration of interleukin-4. AB - Dendritic cells (DCs) play a crucial role in the development of adaptive immune response. Monocyte-derived dendritic cells (MDDCs) are generated in vitro to study DC biology and for use in immunotherapy. However, procedures to generate MDDCs vary and an impact this may have on their final phenotype is insufficiently studied. Monocytes isolated from healthy blood donors were cultured for 7 days with granulocyte-macrophage colony stimulating factor (50 ng/mL) and low (500 IU/mL, L-IL4) or high (1000 IU/mL, H-IL4) interleukin 4 (IL4), to obtain immature DCs and for the following 2 days with addition of soluble CD40 ligand (500 ng/mL) and prostaglandin E2 (1 MUg/mL) to obtain mature DCs. We measured mean fluorescence activity and percentage of cells, positive for CD14, HLA-DR, CD80, CD83, CD86, CCR7, and CD1a or CD209 markers after 7 and 9 days of culture, in both IL4 concentrations. Percentage of positively staining mature MDDCs was higher than among immature cells, for all studied markers. Interestingly, varying IL4 concentrations had negligible impact on staining of mature MDDCs. However, immature L-IL4 cultured MDDCs were less intensely stained for HLA-DR and CD209 than H-IL4 immature DCs. Flow cytometry revealed presence of 2 populations of cells (dominant P1 and less prevalent P2), when either L-IL4 or H-IL4 was used. Among mature MDDCs, population P1 had higher percentage of positively staining cells than P2, for all studied markers except CCR7. In conclusion, both concentrations of IL4 produce in vitro heterogeneous populations of mature MDDCs with similar staining for cell surface markers. PMID- 29501010 TI - The effects of chronic acetaminophen exposure on the kidney, gill and liver in rainbow trout (Oncorhynchus mykiss). AB - In this study, we examined if rainbow trout chronically exposed to acetaminophen (10 and 30 MUgL-1) showed histological changes that coincided with functional changes in the kidney, gill and liver. Histological changes in the kidney included movement and loss of nuclei, non-uniform nuclei size, non-uniform cytoplasmic staining, and loss of tubule integrity. Histological effects were more severe at the higher concentration and coincided with concentration dependent increases in urine flow rate and increased urinary concentrations of sodium, chloride, potassium, calcium, urea, ammonia, glucose, and protein. Yet, glomerular filtration rate was not altered with acetaminophen exposure. In the gill, filament end swelling, whole filament swelling, and swelling of the lamellae were observed in exposed fish. Lamellar spacing decreased in both exposure groups, but lamellar area decreased only with 30 MUgL-1 exposure. At faster swimming speeds, oxygen consumption was limited in acetaminophen exposed fish, and critical swimming speed was also decreased in both exposure groups. The liver showed decreased perisinusoidal spaces at 10 and 30 MUgL-1 acetaminophen, and decreased cytoplasmic vacuolation with 30 MUgL-1 acetaminophen. A decrease in liver glycogen was also observed at 30 MUgL-1. There was no change in plasma concentrations of sodium, chloride, potassium, calcium, magnesium, and glucose with exposure, suggesting compensation for urinary loss. Indeed, an increase in Na+-K+-ATPase activity in the gills was found with 30 MUgL-1 acetaminophen exposure. Chronic exposure of rainbow trout to the environmentally relevant pharmaceutical acetaminophen, alters both histology and function of organs responsible for ion and nutrient homeostasis. PMID- 29501011 TI - Predictors of youth e-cigarette use susceptibility in a U.S. nationally representative sample. AB - OBJECTIVES: Given that nicotine is one of the most addictive substances and that adolescents who are exposed to nicotine via e-cigarettes can progress to conventional cigarette smoking, there is a need to identify youth who are susceptible to e-cigarette use and prevent them from initiating e-cigarette use. Susceptibility to e-cigarette use, defined as the absence of a firm decision not to use e-cigarettes, is a useful concept that can be used to predict e-cigarette initiation and identify youth who have high risk of initiating e-cigarettes. This study was conducted to investigate factors that affect youth susceptibility to e cigarette use. METHODS: Youth who have never smoked conventional cigarettes and who had seen or heard of e-cigarettes but never used them (N = 9853) were drawn from the Population Assessment of Tobacco and Health (PATH) Study Wave 1 youth dataset collected from 2013 to 2014. Data were analyzed using logistic regression to investigate intrapersonal and environmental determinants of youth susceptibility to e-cigarette use. RESULTS: Overall, 24.2% (n = 2410) of youth who have never used e-cigarettes were susceptible to e-cigarette use. Psychological problems and rebelliousness were associated with increased susceptibility. Ever use of alcohol, marijuana, and other substances and household secondhand smoke exposure were found to be risk factors. Perceptions of e-cigarettes as addictive and harmful worked as protective factors. CONCLUSIONS: The results revealed determinants of e-cigarette use susceptibility. Multi-level intervention approach is needed to prevent youth from being susceptible to e cigarette initiation. PMID- 29501012 TI - The role of social support on emotion dysregulation and Internet addiction among Chinese adolescents: A structural equation model. AB - INTRODUCTION: Internet addiction is prevalent among adolescents and is associated with various negative outcomes. Relatively few studies examined the role of emotion dysregulation and social support on Internet addiction in this population. The present examined the association between emotion dysregulation, social support, and Internet addiction among junior secondary school students in Hong Kong. The mediating role of emotion dysregulation and Internet use on the relationship between social support and Internet addiction and the gender difference in such association were also tested. METHOD: A total of 862 junior secondary school students (grade 7 to 8) from 4 schools completed a cross sectional survey. RESULTS: 10.9% scored above the cut-off for Internet addiction based on the Chen Internet Addiction Scale. Results from structural equation modeling revealed that social support was negatively related to emotion dysregulation and Internet usage, which in turn, were positively related to Internet addiction. Results from multi-group analysis by gender showed that the relationship between social support and emotion dysregulation, Internet usage, and Internet addiction, and those between emotion dysregulation and Internet addiction and between Internet usage and Internet addiction were stronger among female participants. CONCLUSION: Emotion dysregulation is a potential risk factor while social support is a potential protective factor for Internet addiction. The role of social support on emotion dysregulation and Internet addiction were stronger among female students. Gender-sensitive interventions on Internet Addiction for adolescents are warranted, such interventions should increase social support and improve emotion regulation. PMID- 29501013 TI - (P)/(M)-corinepalensin A, a pair of axially chiral prenylated bicoumarin enantiomers with a rare C-5C-5' linkage from the twigs of Coriaria nepalensis. AB - A pair of undescribed bicoumarin enantiomers, (P)/(M)-corinepalensin A, two undescribed prenylated coumarins, corinepalensins B and C, along with ten known coumarins were isolated from the twigs of Coriaria nepalensis. (P)/(M) corinepalensin A feature a rare C-5C-5' axially chiral linkage between two prenylated coumarin monomers. Their structures were determined by a combination of spectroscopic methods, single crystal X-ray diffraction, and ECD calculations. All isolates were evaluated for the inhibitory activity against phosphodiesterase 4 (PDE4), which is a drug target for the treatment of asthma and chronic obstructive pulmonary disease. Compounds (P)-corinepalensin A, (M)-corinepalensin A, corinepalensin B, norbraylin, braylin, and nepalin C exhibited significant inhibition with IC50 values ranging from 0.43 to 7.15 MUM. PMID- 29501014 TI - Multimedia fate modeling of perfluorooctanoic acid (PFOA) and perfluorooctane sulphonate (PFOS) in the shallow lake Chaohu, China. AB - Freshwater shallow lake ecosystems provide valuable ecological services to human beings. However, these systems are subject to severe contamination from anthropogenic sources. Per- and polyfluoroalkyl substances (PFASs), including perfluorooctanoic acid (PFOA) and perfluorooctane sulphonate (PFOS), are among the contaminants that have received substantial attention, primarily due to abundant applications, environment persistence, and potential threats to ecological and human health. Understanding the environmental behavior of these contaminants in shallow freshwater lake environments using a modeling approach is therefore critical. Here, we characterize the fate, transport and transformation of both PFOA and PFOS in the fifth largest freshwater lake in China (Chaohu) during a two-year period (2013-2015) using a fugacity-based multimedia fate model. A reasonable agreement between the measured and modeled concentrations in various compartments confirms the model's reliability. The model successfully quantifies the environmental processes and identifies the major sources and input pathways of PFOA and PFOS to the Chaohu water body. Sensitivity analysis reveals the critical role of nonlinear Freundlich sorption, which contributes to a variable fraction of the model true uncertainty in different compartments (8.1% 93.6%). Through additional model scenario analyses, we further elucidate the importance of nonlinear Freundlich sorption that is essential for the reliable model performance. We also reveal the distinct composition of emission sources for the two contaminants, as the major sources are indirect soil volatilization and direct release from human activities for PFOA and PFOS, respectively. The present study is expected to provide implications for local management of PFASs pollution in Lake Chaohu and to contribute to developing a general model framework for the evaluation of PFASs in shallow lakes. PMID- 29501015 TI - Investigation of in-cabin volatile organic compounds (VOCs) in taxis; influence of vehicle's age, model, fuel, and refueling. AB - The air pollutant species and concentrations in taxis' cabins can present significant health impacts on health. This study measured the concentrations of benzene, toluene, ethylbenzene, xylene (BTEX), formaldehyde, and acetaldehyde in the cabins of four different taxi models. The effects of taxi's age, fuel type, and refueling were investigated. Four taxi models in 3 age groups were fueled with 3 different fuels (gas, compressed natural gas (CNG), and liquefied petroleum gas (LPG)), and the concentrations of 6 air pollutants were measured in the taxi cabins before and after refueling. BTEX, formaldehyde, and acetaldehyde sampling were actively sampled using NIOSH methods 1501, 2541, and 2538, respectively. The average BTEX concentrations for all taxi models were below guideline values. The average concentrations (+/-SD) of formaldehyde in Model 1 to Model 4 taxis were 889 (+/-356), 806 (+/-323), 1144 (+/-240), and 934 (+/-167) ppbv, respectively. Acetaldehyde average concentrations (+/-SD) in Model 1 to Model 4 taxis were 410 (+/-223), 441 (+/-241), 443 (+/-210), and 482 (+/-91) ppbv, respectively. Refueling increased the in-vehicle concentrations of pollutants primarily the CNG and LPG fuels. BTEX concentrations in all taxi models were significantly higher for gasoline. Taxi age inversely affected formaldehyde and acetaldehyde. In conclusion, it seems that refueling process and substitution of gasoline with CNG and LPG can be considered as solutions to improve in-vehicle air concentrations for taxis. PMID- 29501016 TI - Management of extensive surgical emphysema with subcutaneous drain: A case report. AB - INTRODUCTION: Subcutaneous emphysema (SE) is a frequent and often self-limiting complication of tube thoracostomy or other cardiothoracic procedures. On rare occasions, severe and extensive surgical emphysema marked by palpable cutaneous tension, dysphagia, dysphonia, palpebral closure or associated with pneumoperitoneum, airway compromise, "tension phenomenon" and respiratory failure require treatment. PRESENTATION OF CASE: A 67 year old lady presented with a large spontaneous pneumothorax on the background of end-stage chronic obstructive pulmonary disease (COPD) and newly diagnosed lung cancer, developed extensive surgical emphysema following insertion of a chest drain. Immediate improvement was observed after insertion of a large-bore, 26 French (Fr.) intercostal catheter, subcutaneous drain which was maintained under low suction (-5 cm H2O) for a further 24 h. DISCUSSION: Several methods have been described in the literature for the treatment of extensive subcutaneous emphysema, including: emergency tracheostomy, multisite subcutaneous drainage, infraclavicular "blow holes" incisions and subcutaneous drains or simply increasing suction on an in situ chest drain. Here a large-bore, fenestrated, subcutaneous drain maintained on low negative pressure also provided the necessary decompression. CONCLUSION: In the absence of a comparative study to identify the most effective method to manage extensive subcutaneous emphysema, this case highlights an effective, simple and safe management option. PMID- 29501017 TI - A case report on the successful perioperative management of hepatectomy for hepatocellular carcinoma in a patient with von Willebrand disease. AB - INTRODUCTION: Although von Willebrand disease (VWD) is a common inherited bleeding disorder, very few cases of surgery in patients with VWD have been reported. PRESENTATION OF CASE: A 77-year-old man was referred to our hospital for treatment of hepatocellular carcinoma (HCC) based on type C chronic hepatitis. He had also been treated for VWD in the hematology department of another hospital. Partial hepatectomy was performed with the administration of factor VIII/von Willebrand factor concentrate just before and after the operation. The perioperative course was uneventful, and the patient was discharged 12 days after surgery. DISCUSSION: VWD causes dysfunction of the platelet and destabilization of the blood clotting factor VIII. The patient was successfully treated with measurement of activated partial thromboplastin time (APTT) as an index for the management of hemostasis. CONCLUSION: This report describes a rare case of a successful perioperative management of hepatectomy in a patient with VWD. PMID- 29501018 TI - Combined laparoscopic abdomino-endoscopic perineal total mesorectal excision for anorectal malignant melanoma: A case report. AB - INTRODUCTION: This report presents a case of anorectal malignant melanoma treated with combined laparoscopic abdomino-endoscopic perineal total mesorectal excision. PRESENTATION OF CASE: An 82-year-old female presented with hematochezia. Colonoscopy revealed a 5-cm tumor in the anorectal junction, and biopsy specimen showed malignant melanoma. Modified ransanal total mesorectal excision was performed to get the sufficient surgical resection margins. After lymph node dissection in usual manner, mobilizing the rectum to the level of levator ani muscle. Then a skin incision was made around the anus and the transperineal access platform was placed. The fat tissue of the ischioanal fossa was divided until the levator ani muscle was exposed. The oral side of the colon was transected and specimen was extracted through the perineal incision site. Then stoma was placed laparoscopically. DISCUSSION: This procedure provides not only better exposure of the extralevator surgical field, but also efficient resection margins compared with the conventional andominoperineal resection. CONCLUSION: To the best of our knowledge, this is the first report of combined laparoscopic abdomino-endoscopic perineal total mesorectal excision for anorectal malignant melanoma. Our experience showed safety and feasible option for anorectal malignant diseases. PMID- 29501019 TI - Two-stage resection of a bilateral pheochromocytoma and pancreatic neuroendocrine tumor in a patient with von Hippel-Lindau disease: A case report. AB - INTRODUCTION: von Hippel-Lindau disease (vHL disease) is a hereditary disease in which tumors and cysts develop in many organs, in association with central nervous system hemangioblastomas, pheochromocytomas, and pancreatic tumors. We herein report a case of vHL disease (type 2A) associated with bilateral pheochromocytomas, pancreatic neuroendocrine tumors (PNET), and cerebellar hemangioblastomas treated via pancreatectomy after adrenalectomy. CASE PRESENTATION: A 51-year-old woman presented with a cerebellar tumor, bilateral hypernephroma, and pancreatic tumor detected during a medical checkup. 18F fluorodeoxyglucose positron emission tomography-computed tomography revealed a bilateral adrenal gland tumor and a tumor in the head of the pancreas, while an abdominal computed tomography examination revealed a 30-mm tumor with strong enhancement in the head of the pancreas. Cranial magnetic resonance imaging showed a hemangioblastoma in the cerebellum. Therefore, a diagnosis of vHL disease (type 2A) was made. Her family medical history included renal cell carcinoma in her father and bilateral adrenal pheochromocytoma and spinal hemangioblastoma in her brother. A detailed examination of endocrine function showed that the adrenal mass was capable of producing catecholamine. Treatment of the pheochromocytoma was prioritized, and therefore, laparoscopic left adrenalectomy and subtotal resection of the right adrenal gland were performed. Once the postoperative steroid levels were replenished, subtotal stomach preserving pancreatoduodenectomy was performed for the PNET. After a good postoperative course, the patient was discharged in remission on the 11th day following surgery. Histopathological examination findings indicated NET G2 (MIB-1 index 10-15%) pT3N0M0 Stage II A and microcystic serous cystadenoma throughout the resected specimen. The patient is scheduled to undergo treatment for the cerebellar hemangioblastoma. CONCLUSION: A two-staged resection is a safe and effective treatment option for bilateral pheochromocytoma and PNET associated with vHL disease. PMID- 29501020 TI - A unique case of total metastatic lobular breast carcinoma, originating from diffused microcalcifications, presented in a postmenopausal woman, without clinical manifestations. AB - INTRODUCTION: Lobular breast carcinoma includes lobular carcinoma in situ (LCIS) and invasive lobular carcinoma (ILC). The association of LCIS with total metastatic lobular breast cancer is very rare. PRESENTATION OF CASE: We present a case of a totally metastatic lobular breast cancer in an asymptomatic 64-year-old postmenopausal woman, with no suspicious microcalcifications in mammography. A total hysterectomy with bilateral salpingo-oophorectomy, pelvic lymphadenectomy, infracolic omentectomy and appendectomy was performed along with a quadrantectomy of the upper outer quadrant of left breast, and systematic isolateral lymphadenectomy of the left axilla. DISCUSSION: LCIS is usually undetectable because it isn't associated with clinical abnormalities in clinical examination and is presented in mammography as microcalcifications or focal asymmetric densities. ILC histopathologic features are responsible for the high false negative rates on mammography, leading to moderate detection sensitivity. CONCLUSION: Our case is a very rare condition. No 'similar' case have been described in the literature so far. PMID- 29501021 TI - Three-dimensional (3D) plasma micro-nanotextured slides for high performance biomolecule microarrays: Comparison with epoxy-silane coated glass slides. AB - Glass slides coated with a poly(methyl methacrylate) layer and plasma micro nanotextured to acquire 3D topography (referred as 3D micro-nanotextured slides) were evaluated as substrates for biomolecule microarrays. Their performance is compared with that of epoxy-coated glass slides. We found that the proposed three dimensional (3D) slides offered significant improvements in terms of spot intensity, homogeneity, and reproducibility. In particular, they provided higher spot intensity, by a factor of at least 1.5, and significantly improved spot homogeneity when compared to the epoxy-silane coated ones (intra-spot and between spot coefficients of variation ranging between 5 and 15% for the 3D micro nanotextured slides and between 25 and 85% for the epoxy-silane coated ones). The latter was to a great extent the result of a strong "coffee-ring" effect observed for the spots created on the epoxy-coated slides; a phenomenon that was severely reduced in the 3D micro-nanotextured slides. The 3D micro-nanotextured slides offered in addition higher signal to noise ratio values over a wide range of protein probe concentrations and shelf-life over one year without requirement for specific storage conditions. Finally, the protocols employed for protein probe immobilization were extremely simple. PMID- 29501022 TI - Preparation of anticancer micro-medicine based on quinoline and chitosan with pH responsive release performance. AB - N-(2-(3-fluorobenzyl)-2H-indazol-5-yl)-2-phenyl-2H-pyrazolo[4,3-c]qui- nolin-4 amine (LZC-2b) with a quinoline structure was synthesized as an anticancer prodrug. The pH sensitive anticancer drugs obtained by a simple hydrothermal method. The interaction of chitosan (Cts) and LZC-2b is used to complete the encapsulation without any cross-linking. The obtained micromedicine (LZC-2b@Cts MSs) has an average size of ~980 nm. The drug loading efficiency (DLE) of LZC 2b@Cts-MSs was about 79%. In addition, drug release from LZC-2b@Cts-MSs was pH depended. At pH = 7.4, only 5.1% of loaded LZC-2b was released, while 90.3% of loaded LZC-2b was released at pH = 5.0. Cell culture results indicate that LZC 2b@Cts-MSs can be easily uptaken by KB cells. Cell viability results show that KB cells can be effectively killed by LZC-2b@Cts-MSs. Our strategy of synthesis and preparation of pH responsive LZC-2b@Cts-MSs has promising prospect in chemotherapy of oral cancer. PMID- 29501023 TI - Sensitive immunoassay of von Willebrand factor based on fluorescence resonance energy transfer between graphene quantum dots and Ag@Au nanoparticles. AB - Graphene quantum dots (GQDs) and core-shell Ag@Au nanoparticles (Ag@Au NPs) were synthetized and they were characterized by transmission electron microscope and X ray photoelectron spectra, respectively. Von Willebrand factor antibody (vWF Ab) was bound on Ag@Au NPs to construct Ag@Au-Ab nanocomposites (Ag@Au-Ab NCs). The fluorescence of GQDs could be effectively quenched by the prepared nanocomposites owing to fluorescence resonance energy transfer (FRET). The immunoreaction between vWF and Ag@Au-Ab NCs resulted in the declined FRET efficiency and a degree of fluorescence recovery of GQDs. The fluorescence intensity change was found to be proportional to the logarithm of the vWF concentration in the range of 0.1 pg mL-1-10 ng mL-1 with a detection limit of 30 fg mL-1. The proposed fluorescence sensor was employed to investigate the relationship between the release of vWF and the oxidation-injury degree of vascular endothelial cells. The experimental results indicate that the vWF content in the growth medium was enhanced and the cell injury was intensified when the contact time of the cells with H2O2 was increased. PMID- 29501024 TI - Improved virus inactivation using a hot bubble column evaporator (HBCE). AB - An improved hot bubble column evaporator (HBCE) was used to study virus inactivation rates using hot bubble-virus interactions in two different conditions: (1) using the bubble coalescence inhibition phenomenon of monovalent electrolytes and (2) with reducing the electrostatic repulsive forces between virus and bubble, by the addition of divalent electrolytes. It is shown that the continuous flow of (dry) air, even at 150-250 degrees C, only heats the aqueous solution in the bubble column to about 45 degrees -55 degrees C and it was also established that viruses are not significantly affected by even long term exposure to this solution temperature, as confirmed separately from water bath experiments. Hence, the effects observed appeared to be caused entirely by collisions between the hot air bubbles and the virus organisms. It was also established that the use of high air inlet temperatures, for short periods of time, can reduce the thermal energy requirement to only about 25% (about 114 kJ/L) of that required for boiling (about 450 kJ/L). PMID- 29501025 TI - Synthetic post-translational modification of histones. AB - Chromatin is the physiological template of genetic information in all eukaryotic cells, a highly organised complex of DNA and histone proteins central in regulating gene expression and genome organisation. A multitude of histone post translational modifications (PTMs) have been discovered, providing a glance into the complex interplay of these epigenetic marks in cellular processes. In the last decade, synthetic and chemical biology techniques have emerged to study these modifications, including genetic code expansion, histone semisynthesis and post-translational chemical mutagenesis. These methods allow for the creation of histones carrying synthetic modifications which can in turn be assembled into designer nucleosomes. Their application in vitro and in vivo is now beginning to have an important impact on chromatin biology. Efforts towards introducing multiple labile modifications in histones as well as expanding their use in cellular biology promise new powerful tools to study epigenetics. PMID- 29501026 TI - Subcellular scaling: does size matter for cell division? AB - Among different species or cell types, or during early embryonic cell divisions that occur in the absence of cell growth, the size of subcellular structures, including the nucleus, chromosomes, and mitotic spindle, scale with cell size. Maintaining correct subcellular scales is thought to be important for many cellular processes and, in particular, for mitosis. In this review, we provide an update on nuclear and chromosome scaling mechanisms and their significance in metazoans, with a focus on Caenorhabditis elegans, Xenopus and mammalian systems, for which a common role for the Ran (Ras-related nuclear protein)-dependent nuclear transport system has emerged. PMID- 29501027 TI - New stationary phase for hydrophilic interaction chromatography to separate chito oligosaccharides with degree of polymerization 2-6. AB - A new 3-aminophenylboronic acid-functionalized stationary phase based on silica for hydrophilic interaction liquid chromatography (HILIC) was developed and showed great HILIC characteristics on separation for chito-oligosaccharides. The material was synthesized by grafting 3-aminophenylboronic acid group to silica, and it was characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), elemental analysis and thermal gravimetric analysis (TGA). Nucleobases and nucleosides were used to evaluate the retention property and to investigate retention mechanism by the models designed for description of partitioning and surface adsorption through adjusting ratio of water in the mobile phase. Parameters affecting chromatography behavior such as ionic strength, buffer pH and column temperature were also investigated. Results have indicated that the retention mechanism was a combination of partitioning and surface adsorption, and the hydrogen bond seemed to be the main force for the retention behavior. Finally, the new 3-aminophenylboronic acid-functionalized based on silica stationary phase was applied to separate chito-oligosaccharide samples with optimized mobile phase conditions and showed acceptable chromatograms. PMID- 29501028 TI - Asymmetric synthesis, molecular modeling and biological evaluation of 5-methyl-3 aryloxazolidine-2,4-dione enantiomers as monoamine oxidase (MAO) inhibitors. AB - Single enantiomers of the new 5-methyl-3-aryloxazolidine-2,4-diones have been obtained either by an asymmetric synthesis using the chiral pool strategy or by a semipreparative resolution of the racemic compound by HPLC on an optically active stationary phase. The single enantiomers were assayed for their in vitro monoamine oxidase (hMAO) inhibitory activity and selectivity. The most potent inhibitor among the studied compounds has been found as (5R)-3-phenyl-5-methyl 2,4-oxazolidinedione (compound 1-R) which appeared to be a good antidepressant drug candidate since it inhibited hMAO-A selectively, competitively and reversibly with Ki values in the micromolar range (0.16 +/- 0.01 MUM). To better understand the enzyme-inhibitor interaction and to explain the efficiency and selectivity of the compounds toward hMAOs, molecular modeling studies were carried out on new, high resolution hMAO-A and hMAO-B crystallographic structures. According to binding energies and inhibition constants obtained from molecular docking calculations, compound 1-R has been found as the most selective MAO-A inhibitor and its weak binding affinities to MAO-B (large Ki values) led to the enhancement in MAO-A selectivity. It bounded in close proximity to FAD in the active site of MAO-A and situated near the aromatic cage by means of pi-alkyl interactions with Tyr407 and Phe352 whereas its position in MAO-B was 10 A far from FAD and it was situated outside the Ile199 gate of the active site. None of the studied compounds showed any cytototoxicity on HepG2 cells at 1 and 5 uM concentrations. PMID- 29501029 TI - 1,3-Diphenylpropanes from Daphne giraldii induced apoptosis in hepatocellular carcinoma cells through nuclear factor kappa-B inhibition. AB - One new 1,3-diphenylpropane (1) together with six known analogues (2-7) were firstly isolated from the stem and root bark of Daphne giraldii. Their structures were determined by comprehensive NMR and HRESIMS spectroscopic data analyses. All the isolates were evaluated for their cytotoxicity against two hepatocellular carcinoma cell lines (HepG2 and Hep3B). Among them, compound 5 showed the most significant cytotoxicity against Hep3B cells, with an IC50 value of 17.21 MUM. A further study demonstrated that 5 obviously induced apoptotic cell death as well as the inactivation of nuclear factor kappa B p65 (NF-kappaB p65) in Hep3B cells. In addition, BAY 11-7082 (BAY), a NF-kB inhibitor, was used to determine the role of NF-kB signaling in 5-treated Hep3B cells. The results suggested that BAY could enhance 5-induced apoptosis of Hep3B cells. In conclusion, the data provided that 5 might be a potential candidate for the treatment of hepatocellular carcinoma through NF-kappaB inhibition. PMID- 29501030 TI - Response of morphology and microbial community structure of granules to influent COD/SO42 - ratios in an upflow anaerobic sludge blanket (UASB) reactor treating starch wastewater. AB - Biochemical properties of granules are of vital importance to UASB performance. This study characterized the granules cultivated at different COD/SO42- ratios to elucidate the influence of sulfidogenesis on starch wastewater (1000 mg-COD L-1) biodegradation kinetics and process stability. Suitable sulfate addition enriched granular microecosystems and stimulated the secretion of extracellular substances, facilitating cells cohersion and sludge aggregation. The percentage of granules larger than 2.8 mm increased from <10.0% to 58.8-69.4% with decreasing COD/SO42- ratio from 10 to 2. Starch-fed granules tended to grow flagella-like filaments on the surface. The filaments overwhelmed by hydrophilic biopolymers had high affinity for biogas-bubbles and water-molecules aggravating granule floatation and washout. 16 s rRNA gene analysis revealed that decreasing COD/SO42- ratio shifted Syntrophobacterales to Desulfovibrio, which co-worked with Methanosaeta while suppressing Methanobacterium thereby altering starch bioconversion routes. Decrease in Syntrophobacterales caused propionate accumulation and slight process upset. PMID- 29501031 TI - Effect of Fe (II) in low-nitrogen sewage on the reactor performance and microbial community of an ANAMMOX biofilter. AB - In this study, the effect of Fe (II) on Anaerobic Ammonium Oxidation (ANAMMOX) process was investigated by step-wise increasing the Fe (II) in influent from 1 to 50 mg L-1. The nitrogen removal, biofilm property and the microbial community were analyzed in each phase. Results showed that, the anaerobic ammonia-oxidizing bacteria (AAOB) bioactivity and the nitrogen removal of ANAMMOX system were slightly improved to 0.58 from the initial 0.51 kg m-3 d-1 by Fe (II) in 1-5 mg L 1. The nitrogen removal was suppressed and could recover to the initial level during the same period under 10-20 mg L-1 Fe (II), while it did not recover to the initial level under 30 mg L-1 Fe (II) and showed no recovery performance under 50 mg L-1 Fe (II). The irreversible suppression threshold of Fe (II) was calculated as 50 mg L-1. The iron content in ANAMMOX biofilm presented linear correlation with the influent Fe (II) in 1-20 mg L-1, which then tended to be stable when Fe (II) was higher. Dehydrogenase activity (DHA) showed similar and faster response to Fe (II) than the microbial activity, and it was an effective pre-indicator for the nitrogen removal performance in the ANAMMOX system suffered Fe (II). The Fe (II) feeding firstly led to the relative abundance of AAOB decreased to 11.04% from the initial 35.46%, and finally picked up to 19.39% after the long-term acclimatization. PMID- 29501032 TI - The effect of zerovalent iron on the microbial degradation of hexabromocyclododecane. AB - Hexabromocyclododecane (HBCD), a commonly used brominated flame retardant (BFR), has been listed as a persistent organic pollutant (POP). In order to remediate HBCD in the environment, the influence of microscale zerovalent iron (MZVI) on the HBCD degrading microcosm was evaluated. In the acclimated microcosm collected from river sediment, 49% of HBCD was initially removed through adsorption and then 30% of HBCD was biodegraded through non-debromination processes. In contrast to MZVI only, over 60% of HBCD was gradually degraded by MZVI through a debromination reaction. In the microcosm-MZVI combined system, the biodegradation ability of the microcosm was inhibited. The aqueous chemistry was changed by the addition of MZVI, which led to the alteration of microbial composition and biodegradation ability. These better understandings can facilitate an evaluation of the impact of MZVI on HBCD biodegradation when ZVI was used to remediate this BFR. PMID- 29501033 TI - Pb sorption on montmorillonite-bacteria composites: A combination study by XAFS, ITC and SCM. AB - Though abundant studies have targeted the characterization of heavy metal adsorption by either clay minerals or bacteria, to date, minimal literature exists which specifically assesses bacteria-clay mineral interactions in the context of metal immobilization. The adsorption of Pb onto montmorillonite, Pseudomonas putida, and their 1:1, 2:1, 6:1 and 12:1 mass ratio composites were investigated by using a combination of atomic force microscope (AFM), X-ray diffraction (XRD), surface complexation modeling (SCM), Pb-LIII edge extended X ray absorption fine structure (EXAFS) spectroscopy and isothermal titration calorimetry (ITC). The SCM and EXAFS demonstrated that Pb ions coordinate with phosphoryl and carboxyl functional groups on bacteria at low and high concentrations, respectively. The ITC analysis found adverse enthalpy values for Pb adsorption to permanent (-2.91 kJ/mol) and variable charge sites (6.93 kJ/mol) on montmorillonite. The ternary bridging model, EXAFS and ITC provide molecular and thermodynamic evidences for the formation of enthalpy driven (-4.74 kJ/mol) ternary complex (>AlO-Pb-PO4) in the composites. The proportion for the bridging structures increased at pH > 5 and high bacterial mass ratios. The formation of ternary complex did not result in the enhanced adsorption of Pb on the composites, but promoted the allocation of Pb on the mineral fraction. The results obtained from SCM, EXAFS and ITC may provide an essential assumption for predicting the speciation and fate of Pb in soils and associated environments. PMID- 29501034 TI - Inhibitory effects of heavy metals and antibiotics on nitrifying bacterial activities in mature partial nitritation. AB - To facilitate the use of partial nitritation (PN) in nitrogen removal processes for livestock wastewater, this work investigated the inhibitory effects of heavy metals and antibiotics on the nitrifying bacterial activities of the PN processes. Biomass was collected from a continuous-flow internal-loop airlift reactor and cultured with fixed ammonium concentrations of 921 mg N L-1. Batch activity tests were conducted to determine the specific oxygen uptake rate. The individual and interactive inhibitory effects of Zn2+, Cu2+, oxytetracycline (OTC) and sulfamethazine (SMZ) were evaluated using an orthogonal test. The results showed that the half maximal inhibitory concentration (IC50) values of Zn2+, Cu2+, OTC and SMZ on PN sludge were 50.1, 35.4, 447 and 1890 mg L-1, respectively. The joint toxicities of heavy metals (Zn2+ and Cu2+) and antibiotics (OTC and SMZ) in the PN mixed culture were generally synergistic, except for between Zn2+ and Cu2+, which was antagonistic. In joint toxicity tests, the significance of the inhibitory effect of Zn2+ (15.3-164.3 mg L-1), Cu2+ (13.8-90.9 mg L-1), OTC (27.0-866.5 mg L-1) and SMZ (290-3490 mg L-1) on the nitrifying bacterial activity can be ranked in the following order: SMZ > Cu2+ > Zn2+ > OTC. Additionally, different exposure times (1 h, 3 h and 24 h) with or without aeration were also comparatively studied. These results show that a greater PN sludge activity loss than when exposure without aeration. PMID- 29501035 TI - Removal of rhodamine B dye from aqueous solution by electro-Fenton process using iron-doped mesoporous silica as a heterogeneous catalyst. AB - In the current study, Rhodamine B (RhB) dye was removed by electro-Fenton (EF) process using iron-doped SBA-15 (Fe-SBA-15; SBA: Santa Barbara Amorphous) mesoporous silica as a heterogeneous catalyst. This catalyst was prepared with the help of ferric nitrate nonahydrate as a forerunner by wet impregnation method. Various techniques of characterization such as XRD and N2 adsorption desorption isotherms were performed to confirm the presence of iron particles in the pores of the catalyst. These characterization methods were also used to examine the morphological properties and textural arrangement of the synthesized material. In the batch study of EF process, 750 mL working volume of RhB dye was taken. Anode and cathode used in the process were graphite electrodes respectively with effective area of 25 cm2 each. To maximise the process efficiency, the effect of initial pH, applied voltage, electrode spacing, the concentration of supporting electrolyte and Fe-SBA-15 dosage were investigated and optimized. The optimum conditions obtained were pH of 2, voltage of 8 V, an electrode spacing of 3 cm and Fe-SBA-15 dosage of 15 mg L-1. At the end of 3 h electrolysis, maximum RhB removal of 97.7% and TOC removal of 35.1% were achieved for 10 mg L-1 RhB concentration. In a batch study with real wastewater, 97% of color and 39% of TOC were removed at optimum conditions. Utilization of EF heterogeneous catalyst Fe-SBA-15 is an alternative technique for the elimination of dyes from solution. PMID- 29501036 TI - Maternal exposure to NO2 enhances airway sensitivity to allergens in BALB/c mice through the JAK-STAT6 pathway. AB - Previous studies have indicated that nitrogen dioxide (NO2) exposure could increase airway sensitivity to allergens for children. Recently, fetal stress was proposed as a crucial factor for allergic airway response occurring in offspring. Considering that there is inadequate evidence linking maternal NO2 exposure to offspring airway sensitivity to allergens, pregnant Balb/c mice were exposed daily to 2.5 ppm NO2 throughout the gestation period; then, the offspring were challenged to an allergen (ovalbumin, OVA) to evaluate airway sensitivity. For air + saline group and air + OVA group, offspring mice were maternally exposed to clean air followed by treatment with saline and OVA, respectively, in adulthood. For NO2 + saline group and NO2 + OVA group, offspring mice were maternally exposed to NO2 followed by treatment with saline and OVA, respectively, in adulthood. The results showed that maternal NO2 exposure increased the level of OVA-immunoglobulin (Ig) E in serum and caused airway hyper-responsiveness and pathological changes in offspring. Furthermore, maternal NO2 exposure altered the expression of pro-inflammatory factors and impaired the T helper (Th) 1/Th2 balance. In addition, janus kinase)-signal transducer and activator of transcription 6 pathway participated in OVA-induced airway sensitivity of offspring. Our study showed that the potential risk of airway sensitivity to allergens in offspring is enhanced by maternal NO2 exposure and proposed a possible mechanism for preventing, alleviating, and evaluating the outcomes in polluted environments. PMID- 29501037 TI - Atmospheric concentrations of hexabromocyclododecane (HBCDD) diastereomers in the Great Lakes region. AB - The concentrations of alpha-, beta-, and gamma-hexabromocyclododecane (HBCDD) diastereomers in atmospheric particle phase samples were determined at four United States Integrated Atmospheric Deposition Network (IADN) sites located in the North American Great Lakes basin collected between 1 January and 31 December 2014. The concentrations ranged from 0.37 to 8.9 pg/m3, 0.12-4.0 pg/m3, and 0.26 22 pg/m3 for alpha-, beta-, and gamma-HBCDD, respectively among the four sampling sites. The median SigmaHBCDD concentrations for the four sites were 2.0 pg/m3, 2.1 pg/m3, 1.7 pg/m3 and 5.2 pg/m3 for Chicago, Cleveland, Sturgeon Point and Sleeping Bear Dunes, respectively. Higher levels of ?HBCDD were observed at the remote site of Sleeping Bear Dunes with comparable levels at the remaining three sites. alpha-HBCDD and gamma-HBCDD were the dominant isomers with an average contribution of about 40% and 50% to SigmaHBCDD concentrations, respectively. These HBCDD concentrations were compared with the levels of other brominated flame retardants measured in these samples, including polybrominated diphenyl ethers (PBDEs), 2,3,4,5-tetrabromoethylhexyl benzoate (EHTBB), bis(2-ethylhexyl) tetrabromophthalate (BEHTBP), and decabromodiphenylethane (DBDPE). ?HBCDD concentrations were significantly lower than or indistinguishable from those of PBDEs, EHTBB, BEHTBP, and DBDPE at all sites except Sleeping Bear Dunes. No significant correlations were found between SigmaHBCDD and SigmaPBDE, EHTBB, BEHTBP, and DBDPE concentrations, suggesting a different source of HBCDD contamination. This is the first study reporting concentrations of HBCDD isomers in the Great Lakes ambient air, and our results indicate that HBCDD is ubiquitous in the Great Lakes basin, including at remote sites. PMID- 29501038 TI - Determination of residual dimethylsulphoxide in drug loaded gelatin using thermal desorber - gas chromatography. AB - Traditional headspace - gas chromatography (HS-GC) methods for the determination of residual solvents (RS) start from a homogenous sample solution. Subsequently, it is challenging to determine RS using HS-GC techniques from insoluble solid samples like gelatin which is practically impossible to dissolve or distribute uniformly in water and common organic solvents. In this study, a thermal desorber combined with capillary gas chromatography and flame ionization detection/mass spectrometry (TD-GC-FID/MS) was used for quantitative determination of residual dimethylsulfoxide (DMSO) in gelatin without sample pretreatment. A sample of gelatin was sandwiched between two quartz filter double layers in a polytetrafluoroethylene insert which was then placed in its entirety into a thermal desorption tube. Factors affecting the performance of TD-GC including desorption time, desorption temperature, desorption flow and type of adsorbent were studied by applying a standard solution of DMSO in methanol on a blank gelatin bed. Validation results of the proposed method showed good linearity with an R2-value higher than 0.999 for a wide concentration range and good sensitivity with a limit of detection and limit of quantification of 0.1 MUg and 0.2 MUg on tube, respectively. The proposed method shows recovery values close to 100%. In addition, a conventional HS-GC method following enzymatic degradation of gelatin was developed to verify the proposed TD-GC method. Both methods were applied for the determination of residual DMSO in gelatin that was loaded with an experimental drug. Results were comparable, but the enzyme assisted HS-GC method was more time consuming and expensive. PMID- 29501039 TI - Clinical bioanalysis of treosulfan and its epoxides: The importance of collected blood processing for valid pharmacokinetic results. AB - Currently, there is an urgent need to establish the optimal dosing of TREO in conditioning prior to hematopoietic stem cell transplantation, especially in children. For that purpose, pharmacokinetic analyses are ongoing within clinical phase II and III trials. In this paper, HPLC methods for determination of prodrug treosulfan and/or its biologically active epoxides in human plasma or serum are reviewed for the first time, including the spectrum of analytes being quantified, detection type, and derivatization methodology. The major focus is addressed to the stability of TREO and its monoepoxide related with different strategies of patients' blood processing, e.g. blood pH lowering to different values, no pH adjustment; centrifugation of blood immediately after collection or within a few hours later. This issue is crucially important for the robust bioanalysis because the epoxytransformation of TREO is a nonenzymatic, highly pH and temperature dependent reaction. In-depth analysis of the literature results demonstrates that some methodologies of blood treatment could produce the systematic underestimation of TREO concentrations. Consequently, the drug clearance and volume of distribution will be overestimated, which might false the association of the drug exposure with the regimen-related toxicity and clinical outcomes. The paper indicates the deficiencies of the blood processing strategies and offers hints for their refinement. The provided information ought to be important in the current investigations of the personalized TREO pharmacokinetics. PMID- 29501040 TI - Validated determination of losartan and valsartan in human plasma by stir bar sorptive extraction based on acrylate monolithic polymer, liquid chromatographic analysis and experimental design methodology. AB - In our previous work, a new monolithic coating based on vinylpyrrolidone-ethylene glycol dimethacrylate polymer was introduced for stir bar sorptive extraction. The formulation of the prepared vinylpyrrolidone-ethylene glycol dimethacrylate monolithic polymer was optimized and the satisfactory quality of prepared coated stir bar was demonstrated. In this work, the prepared stir bar was utilized in combination with ultrasound-assisted liquid desorption, followed by high performance liquid chromatography with ultraviolet detection for the simultaneous determination of losartan (LOS) and valsartan (VAS) in human plasma samples. In a comparison study, the extraction efficiency of the prepared stir bar was accompanied much higher extraction efficiency than the two commercial stir bars (polydimethylsiloxand and polyacrylate) for both target compounds. In order to improve the desorption efficiency of LOS and VAS, the best values for effective parameters on desorption step were selected systematically. Also, the effective parameters on extraction step were optimized using a Box-Behnken design. Under the optimum conditions, the analytical performance of the proposed method displayed excellent linear dynamic ranges for LOS (24-1000 ng mL-1) and VAS (91 1000 ng mL-1), with correlation coefficients of 0.9998 and 0.9971 and detection limits of 7 and 27 ng mL-1, respectively. The intra- and inter-day recovery ranged from 98 to 117%, and the relative standard deviations were less than 8%. Finally, the proposed technique was successfully applied to the analysis of LOS and VAS at their therapeutic levels in volunteer patient plasma sample. The obtained results were confirmed using liquid chromatography-mass spectrometry. The proposed technique was more rapid than previously reported stir bar sorptive extraction techniques based on monolithic coatings, and exhibited lower detection limits in comparison with similar methods for the determination of LOS and VLS in biological fluids. The obtained results were demonstrated that the lower selectivity of UV in comparison with MS detection was rectified by appropriate sample preparation through proposed extraction method to eliminate as many interfering compounds as possible. PMID- 29501041 TI - Plumbagin ameliorates memory dysfunction in streptozotocin induced Alzheimer's disease via activation of Nrf2/ARE pathway and inhibition of beta-secretase. AB - Although plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) protects against cerebral ischemia and spinal cord injury-induced oxidative stress and inflammation by activating the nuclear factor-erythroid 2-related factor-2 /antioxidant response element (Nrf2/ARE) pathway, its role in the amelioration of neurodegenerative diseases remains unexplored. In the present study, we investigated the effect of plumbagin on Alzheimer's disease (AD)-like condition in mice. The animals were treated intracerebroventricularly with streptozotocin (STZ; 3 mg/kg) twice, on day 1 and 3, to induce AD-like condition, and the symptoms were evaluated after 14 days. While the loss of learning and memory performance was evident in the mice subjected to Morris water maze (MWM), there was a striking increase in the population of astrocytes labelled with glial fibrillary acidic protein (GFAP) in the hippocampus. Daily intraperitoneal (i.p.) treatment with plumbagin (0.5 and 1 mg/kg), starting from 1 h prior to first dose of STZ, significantly prevented the cognitive deficits in MWM. On the other hand, administration of Nrf2/ARE pathway inhibitor, trigonelline (10 and 15 mg/kg, i.p.) enhanced the effects of STZ. Pre-treatment with subeffective dose of trigonelline (5 mg/kg) significantly attenuated the effects of plumbagin in MWM. While plumbagin prevented the STZ induced GFAP expression, this effect of plumbagin was attenuated by trigonelline. Moreover, the in silico docking study revealed potent inhibitory effect of plumbagin on beta-secretase enzyme. The results of the present study suggest that plumbagin improves cognitive function in STZ induced mouse model of AD possibly via Nrf2/ARE mediated suppression of astrogliosis and inhibition of beta-secretase enzyme. PMID- 29501042 TI - Clostridium difficile toxin B recombinant protein inhibits tumor growth and induces apoptosis through inhibiting Bcl-2 expression, triggering inflammatory responses and activating C-erbB-2 and Cox-2 expression in breast cancer mouse model. AB - Clostridium difficile toxin B (cdtB) is a critical virulence factor characterized with potential cytotoxicity and pro-inflammatory activity. This study aims to investigate anti-tumor effects of cdtB on breast cancer development. Clostridium difficile strain was cultured and cdtB recombinant protein (rcdtB) was synthesized. Breast cancer cell line, MDA-MB-231, was divided into Normal control, rcdtB 50, 100, 200 and 400 ng/ml group in vitro. Mice were divided into Normal control and rcdtB treatment group (400 ng/ml) in vivo. 3-(4,5-dimethyl-2 thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay was performed to evaluate inhibitive effects of rcdtB on cell growth. Flow cytometry and transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) were employed to examine apoptosis in vitro and in vivo, respectively. Cell cycle distribution was analyzed by utilizing commercial kit. B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax) were examined using western blot. Inflammatory response was detected using haematoxylin and eosin (HE). Erythroblastic leukemia viral oncogene homolog 2 (C-erbB-2) and cyclooxygenase-2 (Cox-2) were examined using immunohistochemical and immunofluorescence assay, respectively. The results indicated that rcdtB significantly induced MDA-MB-231 death, inhibited growth and decreased S-phase cells compared to Normal control group (P < 0.05). rcdtB significantly induced early and late apoptosis, and decreased Bcl-2 levels compared to Normal control group (P < 0.05). rcdtB significantly inhibited cell migration compared to Normal control group (P < 0.05). rcdtB significantly inhibited tumor growth and activated inflammation of breast cancer model compared to Normal control group (P < 0.01). rcdtB significantly reduced C-erbB-2 and Cox-2 in tumor tissues compared to Normal control group (P < 0.01). In conclusion, rcdtB treatment inhibited tumor growth and induced apoptosis through inhibiting Bcl-2 expression, inflammatory responses, and activating C-erbB-2 and Cox-2 expression in breast cancer mouse model. PMID- 29501043 TI - RBBP6 promotes human cervical carcinoma malignancy via JNK signaling pathway. AB - Previous studies have shown that retinoblastoma binding protein 6 (RBBP6) was overexpressed in malignant tumors and was correlated with poorer prognosis in various cancers. However, its role in cervical carcinoma has not been elucidated. This study was to investigate the relationship between RBBP6 and cervical carcinoma. Cervical carcinoma cell lines SiHa and C33a were used to assess the effect of RBBP6 on cell viability, migration, and proliferation. RBBP6 mRNA and protein levels in cervical cancer tissues increased at least three times as that in the adjacent non-cancerous tissues. Overexpression of RBBP6 in SiHa and C33a cell lines resulted in increased phosphorylated c-Jun NH2-terminal kinase (p-JNK) as well as increased cell viability, migration, and proliferation. Moreover, this effect was suppressed by specific JNK inhibitor SP600125. RBBP6 might potentiate cervical carcinoma cell viability, migration and proliferation through JNK signaling pathway. RBBP6 and JNK inhibitor may be beneficial as a novel preventive and therapeutic target for cervical cancer. PMID- 29501044 TI - Sphenoid meningioma enplaque with proptosis: Surgical excision, reconstruction and outcome. AB - OBJECTIVE: To evaluate surgical outcome and reconstruction of bone defects after excision of sphenoid meningioma enplaque. PATIENT AND METHODS: Between June 2012 and May 2016, a series of 15 patients presented by proptosis attended to neurosurgery departments, Assiut university hospital, Qena university hospital, South Valley University and, These patients were diagnosed with sphenoid meningioma enplaque by fulfilling its criteria by neuroimaging (sheet-like meningioma and hyperostosis). All patients received preoperative imaging investigations including Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) to evaluate the extension of both tumor components - soft tissue and bone involvement. Fifteen patients were operated by pterional approach under general anesthesia. RESULTS: Fifteen patients with meningioma enplaque were treated surgically. The mean age of patients at the time of admission was 46.5 years, age ranged between 35-56 years. 80% of patients were females (female to male ratio was 4:1). Ten (66.7%) patients have left sided lesion representing. Proptosis was the main presented manifestation in all patients. Complete tumor excision was done in 10 patients while incomplete excision was done in the rest of patients. Proptosis was improved post-operatively in patients presented by it: Ten (66.7%) patients had complete improvement while the other five (33.3%) patients improved significantly. No mortality occurred in our study. A mean follow-up period of 2.1 years (range: 4 months to 4 years), three (20%) patients have tumor recurrence. CONCLUSIONS: Total excision of Sphenoid meningioma enplaque carries difficulties and high rate of post-operative morbidity. Early detection with experienced neurosurgeons, microsurgical techniques and availability of high speed drill decrease the risk of post-operative morbidity. Reconstruction of dural and bone defect is very important regarding functional and cosmetic aspects. PMID- 29501045 TI - Effects of edaravone, the free radical scavenger, on outcomes in acute cerebral infarction patients treated with ultra-early thrombolysis of recombinant tissue plasminogen activator. AB - OBJECTIVES: Edaravone, a free radical scavenger, alleviates blood-brain barrier disruption in conjunction with suppression of the inflammatory reaction in acute cerebral infarction. Thrombolysis with recombinant tissue plasminogen activator (rtPA) is an established therapy for acute cerebral infarction patients. The purpose of this study was to assess the effects of edaravone on outcomes in acute cerebral infarction patients treated with ultra-early thrombolysis of iv-rt-PA. PATIENTS AND METHODS: We conducted a retrospective cohort study using the database of Ningbo First Hospital. We identified patients who were admitted with a primary diagnosis of acute cerebral infarction and treated with intravenous rtPA(iv-rtPA) within 3 h of symptom onset from March 1st in 2014 to October 31st in 2016.Thenceforth,the patients were divided into 2 groups by treatment with(edaravone group) or without edaravone(non-edaravone group). Glasgow Coma Scale (GCS) scores and mRS score at admission were used. Clinical background, risk factors for acute cerebral infarction hemorrhagic transformation, 7-day mortality, recanalization rate, bleeding complications and blood rheology indexes were collected. We also collected the following factors: National Institutes of Health Stroke Scale scores, barthel index. RESULTS: 136 patients treated without edaravone during hospitalization were selected in non-edaravone group while edaravone group included 132 patients treated with edaravone during hospitalization. The patient baseline distributions were well balanced between non-edaravone group and edaravone group. The rate of hemorrhagic transformation in non-edaravone group was higher than that in edaravone group (P < 0.05). The NIHSS scores 7 days and 14 days after symptom onset were higher in non-edaravone group than in edaravone group (both P < 0.05). Edaravone group showed a higher recanalization rate and a lower bleeding complications rate at discharge than the non-edaravone group (both P < 0.05). The differences of all the blood rheology indexes between the two groups were statistically significant (all P < 0.05). CONCLUSIONS: Edaravone may improve outcomes of acute cerebral infarction patients treated with ultra-early thrombolysis of iv-rt-PA. PMID- 29501046 TI - Clinical study on microsurgical treatment for craniopharyngioma in a single consecutive institutional series of 335 patients. AB - OBJECTIVES: The optimal management of craniopharyngioma is still controversial. The aim of this study is to explore microsurgical outcomes of craniopharyngioma in 335 cases. PATIENTS AND METHODS: Clinical data of 335 consecutive patients with craniopharyngioma between March 2011 and March 2017 were retrospectively analyzed. RESULTS: Gross total resection (GTR) was achieved in 265 cases (79.1%), subtotal resection (STR) was obtained in 70 cases (20.9%). The GTR rate was 81.93% in pediatric group and 78.17% in adult group respectively, no significant difference regarding the GTR rate was found in adult group compared with in pediatric group (p > 0.05). However, there was a noticeable difference in the elevated hypothalamic obesity in children group compared with in adult group after operation (p < 0.05). Multivariate analysis indicated that the tumor recurrence and surgical times played a negative role in the resection extent, the odds ratio and 95% confidence interval of the tumor recurrence and surgical times is [0.306 (0.155-0.603), (p < 0.01)] and [2.135 (1.101-4.142), (p < 0.05)] respectively. There was significant difference on panhypopituitarism between GTR and STR group (p < 0.05). However, No significant difference regarding the postoperative visual dysfunction and indepent quality of life respectively between GTR and STR group was found (p > 0.05). Additionally, there were no statistically significant differences for recurrence-free curves between GTR and STR plus adjuvant radiotherapy (p > 0.05). CONCLUSIONS: Present findings demonstrated that tumor recurrence and surgical times contribute to negative total resection for craniopharyngioma. Postoperative precise adjuvant radiotherapy was considered in selected cases if pursuit of GTR was rather dangerous under disadvantageous removal factors. PMID- 29501047 TI - Simvastatin reduces circulating oxysterol levels in men with hypercholesterolaemia. AB - Oxysterols (OHC) are biologically active cholesterol metabolites circulating in plasma that may be formed enzymatically (e.g. 24S-OHC, 25-OHC and 27-OHC) or by autoxidative mechanisms (e.g. 7-ketocholesterol, 7beta-OHC and 25-OHC). Oxysterols are more soluble than cholesterol and are reported to exert inflammatory, cytoprotective and apoptotic effects according to concentration and species. Esterified oxysterols have been analysed in people with dementia and cardiovascular diseases although there is no consistent relationship between oxysterol esters and disease. However, oxysterol esters are held in lipoprotein core and may not relate to the concentration and activity of plasma free oxysterols. Methodological limitations have challenged the analysis of free oxysterols to date. We have developed a fast, sensitive and specific quantitative LC-MS/MS, multiple reaction monitoring (MRM) method to target five oxysterols in human plasma with analyte recoveries between 72% and 82% and sensitivities between 5 and 135 pg/ml. A novel method was used to investigate the hypothesis that simvastatin may reduce the concentrations of specific plasma free oxysterols in hypercholesterolaemia. Twenty healthy male volunteers were recruited (aged 41 63 years); ten were asymptomatic with high plasma cholesterol > 6.5 mM and ten were healthy with normal plasma cholesterol (< 6.5 mM). Simvastatin (40 mg/day) was prescribed to those with hypercholesterolaemia. Plasma samples were taken from both groups at baseline and after three months. Simvastatin reduced plasma cholesterol by ~35% (p < 0.05) at the end of three months. Oxysterols generated by autoxidation (but not enzymatically) were elevated up to 45 fold in hypercholesterolaemic midlife men. Plasma oxysterols were restored to those of healthy controls after simvastatin intervention suggesting that autoxidation is either prevented by simvastatin directly or that autoxidation is less prevalent when plasma cholesterol concentrations are within the normal range. PMID- 29501048 TI - Biomolecular logic devices based on stimuli-responsive PNIPAM-DNA film electrodes and bioelectrocatalysis of natural DNA with Ru(bpy)32+ as mediator. AB - In the present work, PNIPAM-DNA films were fabricated on the surface of electrodes by GOD-induced radical polymerization, where PNIPAM is poly(N isopropylacrylamide), DNA represents natural DNA from salmon testes, and GOD is glucose oxidase. The prepared film electrodes demonstrated reversible temperature , SO42--, and pH-switched cyclic voltammetry (CV) and electrochemiluminescence (ECL) behaviors toward tris(2,2'-bipyridine)ruthenium(II) (Ru(bpy)32+) in solution. Particularly, both CV and ECL signals at 1.15 V belonging to Ru(bpy)32+ were significantly amplified by the electrocatalysis of DNA in the films. Moreover, the addition of ferrocenemethanol (FcMeOH) into the solution led to the substantial quenching of the ECL signal of the system and produced a new CV peak pair at 0.35 V. Based upon these experiments, a 4-input/7-output logic gate system was successfully built, which also lead to a 2-to-1 encoder and a 1-to-2 decoder. On the same platform, a more complicated logic device, a half-adder, was also constructed. The present system combined electrocatalysis of natural DNA mediated by Ru(bpy)32+ and multiple stimuli-responsive PNIPAM-DNA films together with simultaneously obtained CV and ECL signals as outputs, leading to the development of novel types of biocomputing systems. PMID- 29501049 TI - Fabrication of magnetically assembled aptasensing device for label-free determination of aflatoxin B1 based on EIS. AB - Aflatoxin B1 (AFB1), one of the most common mycotoxins in food matrixes, has been identified as the most toxic contaminant with mutagenic, teratogenic, immunosuppressive, and carcinogenic effects. In this work, a magnetically assembled aptasensing device has been designed for label-free determination of AFB1 by employing a disposable screen-printed carbon electrode (SPCE) covered with a designed polydimethylsiloxane (PDMS) film as the micro electrolytic cell. The magnetically controlled bio-probes were firstly prepared by immobilization of the thiolated aptamers on the Fe3O4@Au magnetic beads, which was rapidly assembled on the working electrode of SPCE within 10 s, by using a magnet placed at the opposite side. The PDMS film with a centered hole was covered on the SPCE surface to achieve a more practicable and flexible electrochemical measurement. In this effort, a label-free aptasensor for the sensitive and selective determination of AFB1 has been developed using electrochemical impedance spectroscopy upon the biorecognition between aptamers and the targets. The developed method had a wide linear range of 20 pg mL-1-50 ng mL-1 with a detection limit of 15 pg mL-1 (S/N = 3) and succeeded in spiked samples of peanuts. The developed aptasensing device shows fantastic application prospect with simple design, easy operation, low cost, and high sensitivity and selectivity characteristics. This sensing strategy represents a promising path toward routine quality control of food safety and creates the opportunity to develop facile aptasensing device for other targets. PMID- 29501050 TI - Electrochemical detection of tyramine with ITO/APTES/ErGO electrode and its application in real sample analysis. AB - This work reports the development of a simple and cost-effective electrochemical sensor based on electrochemically reduced graphene oxide (ErGO) bound to the surface of indium tin oxide (ITO) electrode through 3-aminopropyltriethoxysilane (APTES) monolayer (ITO/APTES/ErGO) for selective and sensitive detection of tyramine. The features of the modified electrode were studied by scanning electron microscopy (SEM), cyclic voltammetry (CV), and electrochemical impedance (EIS) methods. The analytical performance of the developed sensor was evaluated with respect to linear detection range, limit of detection, stability, coexistence interference and reproducibility. The modified device exhibited electrocatalytic activity toward tyramine oxidation within two linear concentration range of 1-100 nM, and 1-100 uM, with LOD of 0.1 nM. Finally, the sensor successfully detected tyramine in commercially available real samples with satisfactory recovery ranges. The proposed modified sensor offers distinct advantages including low cost, simple handling, good sensitivity and high selectivity. PMID- 29501051 TI - Problems analysis and new fabrication strategies of mediated electrochemical biosensors for wastewater toxicity assessment. AB - Conventional mediated electrochemical biosensors for toxicity assessment were almost based on 'one-pot' principle, i.e., mediators and the under-test chemicals were mixed together in the same vessel. In this process, the electron mediator is assumed to be merely an electron acceptor and cannot react with under-test toxicants. Actually,some under-test pollutants (such as metal ions) could react with the electron mediators, thus affecting the detection accuracy and sensitivity of the sensors. It was also found that at least two other interference factors have been ignored in present'one-pot' mediated electrochemical biosensor systems, i.e., (1) the electrochemical sensitivity of mediators to pH; and (2) the potential reactions between under-test chemicals and buffers and the consequent pH changes. In this study, the three ignored interference factors have been investigated systematically and demonstrated by significance tests. Moreover, a solving strategy, an isolation method, is proposed for fabrication of novel mediated electrochemical biosensor to avoid the interference factors existing at present mediated electrochemical biosensor. According to the testing results obtained from the isolation method, IC50 values of Cu2+, Cd2+, Zn2+, Fe3+, Ni2+ and Cr3+ were 21.3 mg/L, 3.7 mg/L, 26.7 mg/L, 4.4 mg/L and 10.7 mg/L, respectively. The detection results of four real water samples also suggested this method could be applied for the practical and complex samples. PMID- 29501052 TI - Erratum to "The development of a stabbing machine for forensic textile damage analysis" [FSI (2017) 132-139]>. PMID- 29501053 TI - Error measurement in craniometrics: The comparative performance of four popular assessment methods using 2000 simulated cranial length datasets (g-op). AB - For measurements to be accurate and precise, measurement errors should be small. In the anthropometry and craniofacial identification literature, four methods are commonly used for assessing measurement error: Pearson's product moment correlation coefficient (r), intra-class correlation coefficients (ICC), statistical significance tests (often reported by P-values) and the technical error of measurement (TEM; also known as Dalberg's error/ratio). In this paper, the performance of all four of these statistics were evaluated using maximum cranial lengths (g-op) from Howells (n=2524), by duplicating the dataset and mathematically adding known degrees of error to the second set. This was repeated under a broad array of trials (2000 total) each with slightly different amounts of error simulation to comprehensively assess the four error metrics in terms of descriptive power and utility, using the same data for each of the four error assessment methods. Data simulations included the addition of random and systematic errors of different sizes with absolute differences ranging from 1 to 50mm (or in relative terms, 28% of the original measurement). Two sample sizes (n=25 and 2524 individuals) were explored and all analyses were conducted in R. P values from Student's t-tests only showed significant differences (P<0.05) for the larger sample size when the error was systematic. Small samples, and/or any with random error, did not yield low or significant P-values (P<0.05). When raw differences were <4mm for 95% of the sample (n=2524), the ICC and r were high (>0.97) and remained so even after tripling the error, such that 95% of the sample possessed raw differences up to 12mm (r=0.8). In contrast, the TEM was low initially (<2mm or r-TEM<1%), and then increased (<4.5mm and 2.5%, TEM and r-TEM respectively). These data show that P-values, ICC and r values hold substantial limits for error description as they do not always flag error well. In contrast, TEM appears to covary with error more saliently and holds the advantage that changes are reported in the units of the original measurement. For these reasons, TEM is recommended in favour to P-values, ICC and r. PMID- 29501054 TI - [European Directive on Falsified Medicines: Lights and shadows for the Hospital Pharmacy]. PMID- 29501055 TI - Monitoring the quality of the hospital pharmacoterapeutic process by sentinel patient program. AB - OBJECTIVE: To analyze the results of sentinel patient program to monitoring the quality pharmacoterapeutic process in the hospitalized patient through medication errors. METHOD: Design: Observational, prospective and transversal study. Ambit: General hospital of 1,000 beds. PERIOD: From May 2011 to June 2016. Sample: Patients with treatment prescribe within 24 hours of being admitted with 4 or more medications. VARIABLES: Medication error, drugs prescribed, medications and doses dispensing, drugs administered. Safety indicators were defined based on medication errors at each stage of the pharmacotherapeutic process. RESULTS: Of the 746 patients studied, 334 had at least 1 medication error (44.8%; IC95%: 41.7-47.8). In the 746 treatments, 564 medication errors were detected (0.75 errors by patient; IC95%: 0.7-0.8). The safety indicators (medication error by stage) were: 5.1% (38/746 patients) for omission of allergy record; 2.3% (156/6 724 drugs) for prescription; 0.6% (38/6 724 drugs) for validation, 2.6% for dispensing (142/5 465 drugs) y 3.7% (190/5 111 administered drugs observed) for administration. The temporal evolution of the indicators, with graphs of statistical control showed stable processes, except for the administration. The proposed improvement actions were of a training, standardization and organizational type. CONCLUSIONS: The sentinel patient program provides an overview of the quality of the pharmacotherapeutic process and promotes the safety culture at the center. Statistical control charts have been a useful tool for monitoring medication errors. The analysis of medication errors has served to propose improvement actions in each stage of the pharmacotherapeutic process. PMID- 29501056 TI - Grading the potential safety risk of medications used in hospital care. AB - OBJECTIVE: The aim of this study was to stratify medications used in hospital care according to their potential risk. METHOD: The RAND/UCLA Appropriateness Method was used. Anatomical Therapeutic Chemical subgroups were classified according to their potential risk. A literature search, bulletins, and alerts issued by patient safety organizations were used to identify the potential safety risk of these subgroups. Nine experts in patient/medication safety were selected to score the subgroups for their appropriateness in the classification. Two evaluation rounds were conducted: the first by email and the second by a panel meeting. RESULTS: A total of 298 Anatomical Therapeutic Chemical subgroups were evaluated. They were classified into three scenarios (low, medium, and high risk). In the first round, 266 subgroups were classified as appropriate to the assigned scenario, 32 were classified as uncertain, and none were classified as inappropriate. In the second round, all subgroups were classified as appropriate. The most frequent subgroups in the low-risk scenario belonged to group A "Alimentary tract and metabolism" (44%); the most frequent in the medium-risk scenario belonged to group J "Antiinfectives for systemic use" (32%); and the most frequent in the high-risk scenario belonged to group L "Antineoplastic and immunomodulating agents" (29%) and group N "Nervous system" (26%). CONCLUSIONS: Based on the RAND/UCLA appropriateness method, Anatomical Therapeutic Chemical subgroups used in hospital care were classified according to their potential risk (low, medium, or high). These lists can be incorporated into a risk-scoring tool for future patient/medication safety studies. PMID- 29501057 TI - Impact of the implementation of vasoactive drug protocols on costs in the treatment of critically ill patients. AB - OBJECTIVE: To evaluate the efficiency of the protocolization and centralization of the preparation of intravenous vasoactive drug mixtures in the treatment of critically ill patients. METHOD: A prospective interventional study (July 2012 December 2014) was conducted to measure the impact of different vasoactive drug protocols on costs in the treatment of critically ill patients. The economic impact was measured by comparing the direct costs (fixed and variable) of the preparation of intravenous vasoactive drug mixtures in the Pharmacy Department with their traditional preparation in hospital care units. The variables time and cost of preparation of an intravenous mixture were measured. Costs included pharmaceutical product, diluent, medical supplies, cost of manpower, and use of laminar flow cabinets in the Pharmacy Department. Costs were measured in Euros. RESULTS: A statistically significant difference was found between processing times in the Pharmacy Department and those in the hospital care unit (2.10 vs 2.86 minutes). Centralized preparation in the Pharmacy Department was more efficient. The average cost of preparation was ?5.24+/-1.45 in the Pharmacy Department and ?5.62+/-1.55 in the hospital care unit, although this difference did not reach statistical significance. If the analysis had included the cost of intravenous mixtures that had expired prior to their use, the centralized preparation of the mixtures in the Pharmacy Department would have entailed a higher cost (?2 174/y). CONCLUSIONS: The centralized preparation of intravenous mixtures in the Pharmacy Department entails significant time savings compared with their preparation in the hospital care unit. PMID- 29501058 TI - Survey on the use of zinc sulfate in parenteral nutrition in spanish hospitals. AB - OBJECTIVE: In certain situations parenteral nutrition subsidiary patients may have an increase in zinc demand (Zn). The objective of the study was to know the scope of the use of Zn sulfate in patients with parenteral nutrition in Spanish hospitals. METHOD: A survey was designed focusing on the incorporation of Zn sulfate into parenteral nutrition, under real practice conditions, in the adult and pediatric population. We asked about the number of parenteral nutrition supplemented with zinc in the last year, by the doses used, and the situations in which it was added to parenteral nutrition formula. The survey was conducted by telephone interview to the pharmacists responsible for the parenteral nutrition units. RESULTS: A total of 53.9% (n = 69) of the contacted hospitals responded to the survey. 60.9% incorporated Zn sulfate into the parenteral nutrition of adults, and 76.2% used it in pediatric patients. In adults, 31.1% used Zn to complete the dose provided by the solution of trace elements, 46.7% supplemented Zn in patients with high intestinal losses, and 28.6% did it in critically ill patients with a high degree of metabolic stress. The majority supplementation regimen was 10 mg/day (55.6%). In the pediatric population Zn ampules were used mainly in preterm infants, with the most used doses being 200 mcg/kg/day and 400 mcg/kg/day (42.6% and 23.4%, respectively). CONCLUSIONS: The use of zinc sulfate in adult parenteral nutrition to complete the dosages suggests that solutions of trace elements could be deficient in Zn. Its use as a supplement in adult parenteral nutrition is not an extended practice in specialized nutritional support protocols in Spanish hospitals, highlighting its low employment in patients with significant catabolism. PMID- 29501059 TI - Review of oritavancin for the treatment of acute bacterial skin and skin structure infections. AB - OBJECTIVE: To assess critically oritavancin, a second-generation lipoglycopeptide, for the treatment of Acute Bacterial Skin and Skin Structure Infections caused by susceptible Gram-positive bacteria, including methicillin resistant Staphylococcus aureus. METHOD: An evaluation report of oritavancin in Acute Bacterial Skin and Skin Structure Infections was carried out according to the methodology of the Group for drug evaluation, standardization and research in drug selection of the Spanish Society of Hospital Pharmacy (SEFH)1, with the MADRE 4.0 program. A search was made in PubMed, in the web www.clinicaltrials. gov, Embase, PubMed and UptoDate. The European Medication Agency and Food and Drug Administration evaluation reports were also used. RESULTS: Single-dose oritavancin demonstrated its non-inferiority efficacy versus vancomycin in Acute Bacterial Skin and Skin Structure nfections, with a similar safety profile. Its potential advantage over other therapeutic alternatives lies in its administration in single dose and in its no need for plasma levels monitoring, which would allow its administration on an outpatient basis. Regarding to the other alternative possibilities of oral (linezolid, tedizolid) or IM (teicoplanin) treatment, oritavancin would improve the adherence to the treatment. Although oritavancin could be more efficient in certain scenarios (outpatient treatment versus inpatient treatment with alternatives), there are no convincing studies in this regard so far. On the other hand, alternative drugs above-mentioned, can also allow outpatient treatment, reducing advantages of oritavancin and further increasing cost differences. Therefore, given that the efficacy is similar to the alternatives, a cost minimization analysis could be considered. CONCLUSIONS: Oritavancin is comparable in terms of efficacy and safety to the existing alternatives in Acute Bacterial Skin and Skin Structure Infections, without improvements in the cost-effectiveness ratio, because of the proposed positioning is to consider it for the treatment of vancomycinresistant enterococcal infection in adult patients when the use of linezolid or tedizolid is contraindicated. PMID- 29501060 TI - Consensus SEO-SEFH of recommendations for use and compounding of ophthalmic preparations. AB - There are many medicinal products that, although having shown efficacy and safety in different ophthalmological indications, they are not authorized or commercially available for ophthalmic administration. This implies, on one hand, that they must be used according to legislation that regulates the availability of medicines in special situations and, on the other hand, that they must be prepared in the pharmacy services for ophthalmic administration, according to quality criteria to ensure its effectiveness, stability and sterility. This document gathers the consensus between the Spanish Society of Ophthalmology and the Spanish Society of Hospital Pharmacy about these selected preparations which have shown enough evidence in their efficacy and safety for their ophthalmic use (off label) and ophthalmic administration. This document includes recommendations about its use according to the current legislation. In addition, with the aim of harmonizing the preparation of intraocular injections in the hospital pharmacy services, general recommendations are set in this document to ensure the compliance with standards established in the Spanish Guideline for Good Preparation Practices of Medicinal Products in Hospital Pharmacies. These recommendations include sections such as the area of preparation, material, technique, packaging, stability, quality control, prescription and traceability of intraocular preparations. PMID- 29501061 TI - [Refractory pericarditis successfully treated with anakinra in a pediatric patient]. PMID- 29501062 TI - Enhanced phenolic compounds tolerance response of Clostridium beijerinckii NCIMB 8052 by inactivation of Cbei_3304. AB - BACKGROUND: Phenolic compounds generated in hydrolysis of lignocellulosic materials are major limiting factors for biological production of solvents by Clostridia, but it lacks the attention on the study of adaptation or resistance mechanisms in response to phenolic compounds. RESULTS: Gene Cbei_3304, encoding a hypothetical membrane transport protein, was analyzed by bioinformatic method. After insertional inactivation of the functionally uncertain gene Cbei_3304 in Clostridium beijerinckii NCIMB 8052, resulted in enhanced phenolic compounds tolerance. Compared to the parent strain C. beijerinckii NCIMB 8052, evaluation of toxicity showed the recombination stain C. beijerinckii 3304::int had a higher level of tolerance to four model phenolic compounds of lignocellulose-derived microbial inhibitory compounds. A comparative transcriptome analysis showed that the genes were involved in membrane transport proteins (ABC and MFS family) and were up-regulated expression after disrupting gene Cbei_3304. Additionally, the adaptation of C. beijerinckii NCIMB 8052 in response to non-detoxified hemicellulosic hydrolysate was improved by disrupting gene Cbei_3304. CONCLUSION: Toxicity evaluation of lignocellulose-derived phenolic compounds shows that Cbei_3304 plays a significant role in regulating toxicities tolerance for ABE fermentation by C. beijerinckii, and the adaptation of non-detoxified hemicellulosic hydrolysate is significantly improved after inactivation of Cbei_3304 in wild-type strain C. beijerinckii NCIMB 8052. It provided a potential strategy for generating high inhibitor tolerance strains for using lignocellulosic materials to produce solvents by clostridia in this study. PMID- 29501063 TI - Tight glycemic control in critically ill pediatric patients: a systematic review and meta-analysis. AB - BACKGROUND: Hyperglycemia is prevalent in patients in the pediatric intensive care unit. The purpose of this study was to describe the benefits and risks of tight glucose control (TGC) in critically ill children. METHODS: A systemic review and meta-analysis of the literature was carried out on randomized controlled trials of TGC in critically ill children admitted to the pediatric intensive care unit. The databases searched were Medline, Embase, and CENTRAL databases until May 1, 2017. Paired reviewers independently screened citations, assessed risk of bias of included studies, and extracted data. A random-effects model was used to report all outcomes. The Grading of Recommendations Assessment, Development and Evaluation system was used to quantify absolute effects and quality of evidence. The primary outcome was hospital mortality. The secondary outcomes were hypoglycemia (any, severe), sepsis, new need for dialysis, and seizures. RESULTS: A total of 4030 patients were included from six studies. All six studies were rated as at low risk of bias. Our meta-analysis showed that TGC did not result in a decrease in risk of hospital mortality (odds ratio (OR), 0.95; 95% confidence interval (CI), 0.62-1.45; I2 = 40%; moderate quality), sepsis (OR, 0.82; 95% CI, 0.63-1.08), or seizures (OR, 0.98; 95% CI, 0.59-1.63). TGC was associated with a decrease in new need for dialysis (OR, 0.63; 95% CI, 0.45-0.86). However, TGC was associated with a significant increase in any hypoglycemia (OR, 4.39; 95% CI, 2.39-8.06) and severe hypoglycemia (OR, 4.11; 95% CI, 2.67-6.32). CONCLUSIONS: Among critically ill children with hyperglycemia, TGC does not result in a decrease in hospital mortality, but appears to reduce a new need for dialysis. However, TGC is associated with higher incidence of hypoglycemia. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42017074039 . PMID- 29501066 TI - Polygenic risk for schizophrenia and season of birth within the UK Biobank cohort. AB - BACKGROUND: There is strong evidence that people born in winter and in spring have a small increased risk of schizophrenia. As this 'season of birth' effect underpins some of the most influential hypotheses concerning potentially modifiable risk exposures, it is important to exclude other possible explanations for the phenomenon. METHODS: Here we sought to determine whether the season of birth effect reflects gene-environment confounding rather than a pathogenic process indexing environmental exposure. We directly measured, in 136 538 participants from the UK Biobank (UKBB), the burdens of common schizophrenia risk alleles and of copy number variants known to increase the risk for the disorder, and tested whether these were correlated with a season of birth. RESULTS: Neither genetic measure was associated with season or month of birth within the UKBB sample. CONCLUSIONS: As our study was highly powered to detect small effects, we conclude that the season of birth effect in schizophrenia reflects a true pathogenic effect of environmental exposure. PMID- 29501065 TI - Near-infrared quantum dots labelled with a tumor selective tetrabranched peptide for in vivo imaging. AB - BACKGROUND: Near-infrared quantum dots (NIR QDs) are a new class of fluorescent labels with excellent bioimaging features, such as high fluorescence intensity, good fluorescence stability, sufficient electron density, and strong tissue penetrating ability. For all such features, NIR QDs have great potential for early cancer diagnosis, in vivo tumor imaging and high resolution electron microscopy studies on cancer cells. RESULTS: In the present study we constructed NIR QDs functionalized with the NT4 cancer-selective tetrabranched peptides (NT4 QDs). We observed specific uptake of NT4-QDs in human cancer cells in in vitro experiments and a much higher selective accumulation and retention of targeted QDs at the tumor site, compared to not targeted QDs, in a colon cancer mouse model. CONCLUSIONS: NIR QDs labelled with the tetrabranched NT4 peptide have very promising performance for selective addressing of tumor cells in vitro and in vivo, proving rising features of NT4-QDs as theranostics. PMID- 29501064 TI - Adenocarcinoma and polyposis of the colon in a 20-year-old patient with Trisomy 13: a case report. AB - BACKGROUND: Trisomy 13 is one of the most common autosomal trisomies, and although increasing in number, patients surviving past the neonatal period remain rare. The natural history and expected complications in these patients as they age remains unknown. Despite the rarity of this condition, unusual malignancies have been reported in the medical literature for decades. It is clear that providers should suspect unusual malignancies in these patients, particularly as they age. CASE PRESENTATION: We report a 20-year-old Caucasian woman with Trisomy 13 who presented with colonic volvulus, found to have colonic polyposis and adenocarcinoma of the colon. Genetics of pathology specimens revealed 47(XX) + 13 without other mutations. She underwent prophylactic completion colectomy due to presumed risk of colorectal cancers given underlying adenomatous polyposis. She has recovered well without evidence of recurrence. CONCLUSIONS: The presence of colonic polyposis and colorectal cancer without family history or known mutations for polyposis syndrome suggests an intrinsic predisposition toward colorectal cancer in this patient with Trisomy 13. Recent research into colorectal cancer oncogenes supports that aneuploidy or increased copy number of certain genes on chromosome 13 may increase the risk of malignant transformation. This is an important correlation for researchers studying these topics and clinicians caring for patients with Trisomy 13 as they age. PMID- 29501067 TI - Ectopic pregnancy outcomes in patients discharged from the emergency department. AB - CLINICIAN'S CAPSULE What is known about the topic? There is a paucity of data that is useful for emergency department (ED) physicians counseling women with symptomatic early pregnancies about the future risk of ectopic pregnancy. What did this study ask? What are the clinical outcomes of pregnant women discharged from the ED where ectopic pregnancy had not yet been excluded? What did this study find? Of the 230 ectopic pregnancies, 5.1% patients had a ruptured ectopic pregnancy after their index ED visit. Why does this study matter to clinicians? Given the risk of a final diagnosis of ectopic pregnancy and more importantly possible rupture, patient education of these risks is critical on discharge from the ED. PMID- 29501068 TI - Automated Translation of Clinical Parameters in Evaluating Acute Radiation Injury: Results From a Mass Casualty Exercise. AB - OBJECTIVE: A radiological disaster could result in a large number of patients potentially exposed to harmful levels of radiation. Currently, early triage of patients for radiation exposure relies heavily on a clinical evaluation of signs and symptoms. However, detailed clinical assessment takes significant time and requires specialized training to accurately interpret the results. METHODS: During planning of a recent exercise, SMEs estimated that it would take up to 15 minutes per patient. Patient load would quickly overwhelm the number of qualified clinicians providing treatment. In this exercise organized by the NATO RTG HFM 222, we examined using automated translation of clinical data to facilitate clinic evaluations. We used two triage evaluation approaches; REAC/TS and METREPOL. These approaches allowed us to translate tabulated clinical data, first into categorical data for grouping patients, and then into recommendations for follow-up diagnostics and care. RESULTS: The organizers provided clinical evaluations of 191 case studies that were estimated to require up to 50 total hours for completion. However, using our application, we were able to evaluate all cases in less than 2 minutes. CONCLUSION: This study clearly demonstrates the need for automated tools to help translate clinical data for effective patient triage after a nuclear or radiological incident. (Disaster Med Public Health Preparedness. 2018;12:569-573). PMID- 29501069 TI - Creation of a national emergency medicine enhanced competency directory for residency training. AB - Canadian emergency medicine Royal College residency training allows for pursuing extra training in enhanced competency areas. A wealth of enhanced competency training opportunities exist nationally. However, the search for the right fit is a challenging one because there is no centralized resource that catalogues all of these opportunities. A working group of the Canadian Association of Emergency Physicians (CAEP) Resident Section was assembled in 2016 to create a freely accessible and comprehensive directory of Canadian enhanced competency areas. The working group used stakeholder surveys (of residents, recent graduates, and faculty members), social media engagement, and program website searches. Information was collated into the first edition of a national enhanced competency directory, which is available at no cost at http://caep.ca/sites/caep.ca/files/enhancedcompdoc.pdf. Limitations include the scope defined by the working group and survey responses. A biannual update is also incorporated into the CAEP Resident Section portfolio to ensure it remains up-to-date. PMID- 29501070 TI - Risk of suicide attempts in adolescents and young adults with attention-deficit hyperactivity disorder: a nationwide longitudinal study. AB - BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) increases the risk of suicidal behaviours through psychiatric comorbidities; however, a significant direct association has not been observed between ADHD and suicide attempts. Aims To evaluate the risk of suicide attempt in adolescents and young adults with ADHD. METHOD: Using a nationwide, population-based insurance claims database, this longitudinal cohort study enrolled 20 574 adolescents and young adults with ADHD and 61 722 age- and gender-matched controls between 2001 and 2009. Any suicide attempt was identified from enrolment to 31 December 2011. The association between ADHD medications and the likelihood of suicide attempt was assessed. RESULTS: ADHD was an independent risk factor for any suicide attempt (hazard ratio = 3.84, 95% CI = 3.19-4.62) and repeated suicide attempts (hazard ratio = 6.52, 95% CI = 4.46-9.53). Subgroup analyses of men, women, adolescents and young adults demonstrated the same trend. Methylphenidate or atomoxetine treatment did not increase the risk of suicide attempt or repeated suicide attempts. Long-term methylphenidate treatment was associated with a significantly decreased risk of repeated suicide attempts in men (hazard ratio = 0.46, 95% CI = 0.22-0.97). CONCLUSION: ADHD was a risk factor for suicide attempt and a stronger predictor of repeated suicide attempts, independent of comorbidities. Further investigation is warranted to explore the mechanism underlying the association between ADHD and suicidal behaviours. Declaration of interest None. PMID- 29501071 TI - The association between obesity and race among Brazilian adults is dependent on sex and socio-economic status. AB - OBJECTIVE: To verify the association of race, independent of socio-economic status (SES), with obesity among Brazilian adults. DESIGN: We investigated data from the 2008-2009 Brazilian Household Budget Survey. Obesity was defined using the WHO classification. Self-declared race was classified as White, Black and 'Pardo' (Brown). Factor analysis with principal component extraction was used to derive the SES index. The association between race and obesity independent of SES, adjusted for demographic variables, was estimated using multiple logistic regression, accounting for the survey design. Interaction term between race and SES was tested. SETTING: Brazilian households (n 55 970). SUBJECTS: Adults aged 20-65 years (n 80 702). RESULTS: The prevalence of obesity was 14.9 %. The first factor explained 51 % of the variance and was used as a SES indicator. Odds of obesity increased with increasing SES level for men and for Black women, whereas Brown and White women showed a decrease of obesity. The association between race and obesity was modified by SES level in both sexes. At lower level of SES (-2 sd), Black and Brown in comparison to White men had 35 and 27 % decreased odds of obesity, respectively. For women, at lower SES level, only Black compared with White women had 30 % decreased odds of obesity. At the higher SES level (+2 sd), Black women compared with White presented a threefold increase of obesity. CONCLUSIONS: Racial disparities in obesity are SES level- and sex-dependent in Brazil. Strategies exclusively targeting reductions in SES disparities are likely ineffective for decreasing racial disparities in obesity among women. PMID- 29501072 TI - What accounts for poor functioning in people with schizophrenia: a re-evaluation of the contributions of neurocognitive v. attitudinal and motivational factors. AB - BACKGROUND: Neurocognitive deficits are often seen as core features of schizophrenia, and as primary determinants of poor functioning. Yet, our clinical observations suggest that individuals who score within the impaired range on standardized tests can reliably perform better in complex real-world situations, especially when performance is embedded within a positive socio-affective context. METHODS: We analyzed literature on the influence of non-neurocognitive factors on test performance in order to clarify their contributions. RESULTS: We identified seven non-neurocognitive factors that significantly contribute to neurocognitive test performance: avolition, dysfunctional attitudes, effort, stress, negative emotions, asociality, and disorganized symptoms. We then proposed an alternative model based on dysfunctional (e.g. defeatist) attitudes and their consequences for motivation and sustained task engagement. We demonstrated that these factors account for substantial variance in negative symptoms, neurocognitive test performance, and functional outcomes. We then demonstrated that recovery-oriented cognitive therapy - which is derived from this alternative model and primarily targets dysfunctional beliefs - has been successful in the treatment of low functioning individuals with schizophrenia. CONCLUSION: The contributions of neurocognitive impairments to poor real-world functioning in people with schizophrenia may be overstated in the literature, and may even be limited relative to non-neurocognitive factors. We offer suggestions for further research to more precisely quantify the contributions of attitudinal/motivation v. neurocognitive factors in schizophrenia. PMID- 29501073 TI - The development of an outcome measure for liaison mental health services. AB - : Aims and methodTo develop and pilot a clinician-rated outcome scale to evaluate symptomatic outcomes in liaison psychiatry services. Three hundred and sixty patient contacts with 207 separate individuals were rated using six subscales (mood, psychosis, cognition, substance misuse, mind-body problems and behavioural disturbance) plus two additional items (side-effects of medication and capacity to consent for medical treatment). Each item was rated on a five-point scale from 0 to 5 (nil, mild, moderate, severe and very severe). RESULTS: The liaison outcome measure was acceptable and easy to use. All subscales showed acceptable interrater reliability, with the exception of the mind-body subscale. Overall, the measure appears to show stability and sensitivity to change.Clinical implicationsThe measure provides a useful and robust way to determine symptomatic change in a liaison mental health setting, although the mind-body subscale requires modification.Declaration of interestNone. PMID- 29501074 TI - Placental mitochondrial biogenesis and function was slightly changed by gestational hypercholesterolemia in full-term pregnant women. AB - It was reported that high blood cholesterol levels increased the susceptibility to mitochondrial dysfunction. This study hypothesized that the gestational hypercholesterolemia (HC) could induce the mitochondrial dysfunction in term human placenta. The eligible pregnant women were recruited from Xuanwu Hospital in Beijing during their first prenatal visit (before their 10th week of pregnancy). In total, 19 pregnant women whose serum total cholesterol levels were higher than 7.25 mm at third trimester (measured at 36-38 weeks) were selected as gestational HC. Other 19 pregnant women with normal cholesterol level matched with age, pre-gestational body mass index, and the neonatal gender were included as the control group. Full-term placenta samples were collected. The mitochondrial DNA (mtDNA) copy number, messenger RNA (mRNA) expression of cytochrome c oxidase subunit I, adenosine triphosphate monophosphatase 6 (ATP6ase), citrate synthase, peroxisome proliferator-activated receptor-gamma (PPARgamma) co-activator 1alpha, PPARgamma co-activator 1beta and estrogen related receptor-alpha, and the activity of mitochondrial respiratory chain enzyme complex were measured. Pregnancy outcomes were obtained by extraction from medical records and the labor ward register. The results showed that only placental mtDNA copy number and mRNA expression of ATP6ase were significantly decreased in HC group. No significant differences were detected of other measurements between the two groups. These findings indicated that gestational HC might not induce the damage of placental function seriously. PMID- 29501075 TI - Clinical validation of the Psychotic Depression Assessment Scale (PDAS) against independent global severity ratings in older adults. AB - OBJECTIVES: According to a recent study, ratings on the Psychotic Depression Assessment Scale (PDAS) obtained via a dedicated semi-structured interview are valid measures of the severity of psychotic depression. This study aimed to further test the validity, scalability and responsiveness of the PDAS in older adults using independent ratings on the Clinical Global Impression Scale - Severity (CGI-S) and the Montgomery-Asberg Depression Rating Scale (MADRS) as references. METHODS: Ratings were performed at admission and discharge at two old age psychiatric wards in Flanders, Belgium. In total, 62 older adults (mean age: 74.3 years) with psychotic depression were included. The PDAS was rated by trained nurses using the semi-structured PDAS interview. Senior psychiatrists scored the participants on the CGI-S. Psychologists or experienced nurses rated participants on the MADRS. Clinical validity was assessed by correlating the PDAS total scores with CGI-S ratings and MADRS total scores. Mokken analysis was performed to assess the scalability of the PDAS. Responsiveness was assessed by comparing the proportion of participants in remission (PDAS total score <8 at study baseline and endpoint). RESULTS: The Spearman correlation coefficients were 0.76 and 0.79 for the PDAS versus CGI-S and PDAS versus MADRS, respectively. The Mokken analysis yielded a Loevinger coefficient of 0.46, which is indicative of scalability. At admission, no participants met the PDAS remission criterion. At discharge, 54% (95% confidence interval: 47%-60%) of the patients met this criterion. CONCLUSION: The PDAS appears to be a clinically valid, scalable and responsive measure of the severity of psychotic depression in older adults. PMID- 29501076 TI - Corrigendum to: "Socioeconomic influences at different life stages on health in Guangzhou, China." [Social Science & Medicine, 72 (2011), 1884-1892]. PMID- 29501077 TI - Corrigendum to: "Understanding factors influencing substance use in people with recent onset psychosis: A qualitative study" [Social Science & Medicine 70 (2010) 1141-1147]. PMID- 29501078 TI - Corrigendum to: "The design and validation of a spatial microsimulation model of obesogenic environments for children in Leeds, UK: SimObesity" [Social Science & Medicine, 69 (2009), 1127-1134]. PMID- 29501079 TI - Corrigendum to: "Who profits from visual aids: Overcoming challenges in people's understanding of risks" [Social Science & Medicine, 70 (2010), 1019-1025. PMID- 29501080 TI - Low-dosage of rituximab in Chinese patients with neuromyelitis optica spectrum disorder. AB - Rituximab has been effectively used for treating neuromyelitis optica spectrum disorder (NMOSD) for several years. However those regimens exert a heavy burden on Chinese patients. The aim of our study was to investigate an effectiveness, economic alternatives of RTX. The enrolled patients received different immunosuppressant drugs. Annual relapse rate (ARR), neurological disability (Expanded Disability Status Scale, EDSS), time to the next relapse were evaluated after treatments. Fourteen patients treated with RTX and 37 relapse events from 23 patients treated with traditional immunosuppressant drugs (ISDs) were analyzed in our study. Patients with NMOSD treated with RTX showed a reduction in ARR (2.0 +/- 1.8 to 0.2 +/- 0.3, p = 0.002) and improve disability (EDSS: 3.7 +/- 2.1 to 2.3 +/- 2.3, p < 0.001) at last follow-up. Kaplan-Meier analysis indicated that patients treated with RTX had a longer time to next relapse compared with those who were treated with traditional ISDs. Our regimens of RTX treatment were effective in NMOSD patients, and exerted a lower risk of adverse events might be lower than did the high-dose RTX regimens. Moreover, our regimen provides an economic and convenient alternative for NMOSD patients. PMID- 29501081 TI - Etoricoxib inhibits peripheral inflammation and alters immune responses in intracerebroventricular colchicine injected rats. AB - The present study was designed to investigate the effectiveness of etoricoxib induced inhibition of neuroinflammation by studying the peripheral inflammatory markers and select immune parameters in intracerebroventricular colchicine injected rats (ICIR). Results showed time dependent upregulation of the inflammatory markers in the serum along with alterations of peripheral immune parameters in ICIR and dose-dependent recovery was observed upon administration of etoricoxib to ICIR; most of these effects were greater with the longer duration of study. The present study indicates that colchicine induced neuroinflammation may cause systemic inflammation and alteration of immune responses which are mediated by increased cox- 2 activity. PMID- 29501082 TI - A shift to glycolysis accompanies the inflammatory changes in PBMCs from individuals with an IQ-discrepant memory. AB - Identification of a blood-based biomarker that can detect early cognitive decline presents a significant healthcare challenge. We prepared peripheral blood mononuclear cells (PBMCs) from individuals who had a poorer than predicted performance in their delayed recall performance on the Logical Memory II Subtest of the Wechsler Memory Scale (WMS) relative to their IQ estimated by the National Adult Reading Test (NART); we described these individuals as IQ-discrepant, compared with IQ-consistent, individuals. Stimulation with Abeta + LPS increased production of TNFalpha to a greater extent in cells from IQ-discrepant, compared with IQ-consistent, individuals. This was associated with a shift towards glycolysis and the evidence indicates that 6-phosphofructo-2-kinase/fructose-2,6 biphosphatase (PFKFB)3 plays a role in driving glycolysis. A similar shift towards glycolysis was observed in MDMs prepared from IQ-discrepant, compared with IQ-consistent, individuals. The important finding here is that we have established an increased sensitivity to Abeta + LPS stimulation in PBMCs from individuals that under-perform on a memory task, relative to their estimated premorbid IQ, which may be an indicator of early cognitive decline. This may be a useful tool in determining the presence of early cognitive dysfunction. PMID- 29501083 TI - The clinical features of combined central and peripheral demyelination in Chinese patients. AB - BACKGROUND: Combined central and peripheral demyelination (CCPD) is rare and has never been reported as a spectrum disease in Han Chinese population. OBJECTIVES: To study the clinical features of CCPD in Han Chinese patients. METHODS: Twenty two CCPD patients were selected from 788 demyelination cases. We reviewed and compared the clinical manifestation, laboratory data, electrophysiological examination, MRI and the prognosis. RESULTS: CCPD patients presented with sensory disturbance (86.4%), plegia (77.3%), cranial nerve involvement (77.3%), abnormal deep tendon reflexes (72.7%). CSF data showed increased CSF protein in 81% patients. Oligoclonal IgG bands (OB) were negative. Cortical or juxtacortical, periventricular, infratentorial lesions, thoracic and cervical spinal cord were mostly affected. Visual evoked potentials indicated optic nerves demyelinating in 50% cases. 21 CCPD patients were treated with intravenous immunoglobulin or steroids or both of them, and the efficacy was 33.3%, 54.5%, 71.4%, respectively. One case that showed no response to steroids plus intravenous immunoglobulin treatment was improved significantly after using cyclophosphamide. CONCLUSIONS: CCPD is a spectrum disease that can't be regarded as a simple combination of MS and CIDP. A suspected CCPD should receive brain and spinal MRI as well as electrophysiological examination to obtain a precise diagnosis. PMID- 29501084 TI - The inhibition of CB1 receptor accelerates the onset and development of EAE possibly by regulating microglia/macrophages polarization. AB - Cannabinoid 1 receptor (CB1R) regulates the neuro-inflammatory and neurodegenerative damages of experimental autoimmune encephalomyelitis (EAE) and of multiple sclerosis (MS). The mechanism by which CB1R inhibition exerts inflammatory effects is still unclear. Here, we explored the cellular and molecular mechanisms of CB1R in the treatment of EAE by using a specific and selective CB1R antagonist SR141716A. Our study demonstrated that SR141716A accelerated the clinical onset and development of EAE, accompanied by body weight loss. SR141716A significantly up-regulated the expression of toll like receptor-4 (TLR-4) and nuclear factor-kappaB/p65 (NF-kappaB/p65) on microglia/macrophages of EAE mice as well as levels of inflammatory factors (TNF-alpha, IL-1beta, IL-6) and chemokines (MCP-1, CX3CL1), accompanied by the shifts of cytokines from Th2 (IL-4, IL-10) to Th1 (IFN-gamma)/Th17 (IL-17) in the spinal cords of EAE mice. Similar changes happened on splenic mononuclear cells (MNCs) except chemokine CX3CL1. Consistently, SR141716A promoted BV-2 microglia to release inflammatory factors (TNF-alpha, IL-1beta, IL-6) while inhibited the production of IL-10 and chemokines (MCP-1, CX3CL1). Furthermore, when splenic CD4+ T cells co-cultured with SR141716A-administered BV-2 microglia, the levels of IL-4 and IL-10 were decreased while production of IL-17 and IFN-gamma increased significantly. Our research indicated that inhibition of CB1R induced M1 phenotype-Th17 axis changed of microglia/macrophages through TLR-4 and NF-kappaB/p65 which accelerated the onset and development of EAE. Therefore, CB1R may be a promising target for the treatment of MS/EAE, but its complexity remains to be carefully considered and studied in further clinical application. PMID- 29501085 TI - Vertical nystagmus associated with glutamic acid decarboxylase antibodies responding to cyclophosphamide. AB - Several neurological disorders have been described in patients with autoimmunity associated with GAD antibodies. Among these disorders, nystagmus and oculomotor dysfunction are increasingly recognized, although they have been rarely reported isolated or as the main manifestation of anti-GAD autoimmunity. Moreover, therapeutic approaches for such patients are unclear. Here we present a 44-year old man with disabling oscillopsia secondary to downbeat nystagmus, abnormal saccades, ocular pursuit and optokinetic nystagmus, as well as mild gait ataxia and cerebellar atrophy associated with high serum GAD antibodies with intrathecal secretion of such antibodies. The patient did not have clinical benefit with plasma exchange, but had a robust symptomatic improvement with cyclophosphamide. We discuss the possible pathogenic role of GAD antibodies in nystagmus and the role of immunotherapy in these patients. PMID- 29501086 TI - Psychiatric symptoms delay the diagnosis of anti-LGI1 encephalitis. AB - The aim of this study was to analyze the detailed characteristics of the psychiatric symptoms in patients with anti-LGI1 encephalitis. Of 16 patients, ten showed psychiatric symptoms as the initial manifestations. All 10 patients experienced mood-related symptoms. The time to immune therapy was longer in those with initial psychiatric symptoms compared to those without them. Initial manifestation of psychiatric symptoms in patients with anti-LGI1 encephalitis may be a poor prognostic factor, at least in the short term, in that it misleads both the patients and the clinicians to neglect the typically accompanied symptoms of the disease such as faciobrachial dystonic seizure, delaying the timing of immune therapy. PMID- 29501087 TI - Calibration model maintenance in melamine resin production: Integrating drift detection, smart sample selection and model adaptation. AB - The physico-chemical properties of Melamine Formaldehyde (MF) based thermosets are largely influenced by the degree of polymerization (DP) in the underlying resin. On-line supervision of the turbidity point by means of vibrational spectroscopy has recently emerged as a promising technique to monitor the DP of MF resins. However, spectroscopic determination of the DP relies on chemometric models, which are usually sensitive to drifts caused by instrumental and/or sample-associated changes occurring over time. In order to detect the time point when drifts start causing prediction bias, we here explore a universal drift detector based on a faded version of the Page-Hinkley (PH) statistic, which we test in three data streams from an industrial MF resin production process. We employ committee disagreement (CD), computed as the variance of model predictions from an ensemble of partial least squares (PLS) models, as a measure for sample wise prediction uncertainty and use the PH statistic to detect changes in this quantity. We further explore supervised and unsupervised strategies for (semi )automatic model adaptation upon detection of a drift. For the former, manual reference measurements are requested whenever statistical thresholds on Hotelling's T2 and/or Q-Residuals are violated. Models are subsequently re calibrated using weighted partial least squares in order to increase the influence of newer samples, which increases the flexibility when adapting to new (drifted) states. Unsupervised model adaptation is carried out exploiting the dual antecedent-consequent structure of a recently developed fuzzy systems variant of PLS termed FLEXFIS-PLS. In particular, antecedent parts are updated while maintaining the internal structure of the local linear predictors (i.e. the consequents). We found improved drift detection capability of the CD compared to Hotelling's T2 and Q-Residuals when used in combination with the proposed PH test. Furthermore, we found that active selection of samples by active learning (AL) used for subsequent model adaptation is advantageous compared to passive (random) selection in case that a drift leads to persistent prediction bias allowing more rapid adaptation at lower reference measurement rates. Fully unsupervised adaptation using FLEXFIS-PLS could improve predictive accuracy significantly for light drifts but was not able to fully compensate for prediction bias in case of significant lack of fit w.r.t. the latent variable space. PMID- 29501088 TI - Estimation of the limit of detection in semiconductor gas sensors through linearized calibration models. AB - The limit of detection (LOD) is a key figure of merit in chemical sensing. However, the estimation of this figure of merit is hindered by the non-linear calibration curve characteristic of semiconductor gas sensor technologies such as, metal oxide (MOX), gasFETs or thermoelectric sensors. Additionally, chemical sensors suffer from cross-sensitivities and temporal stability problems. The application of the International Union of Pure and Applied Chemistry (IUPAC) recommendations for univariate LOD estimation in non-linear semiconductor gas sensors is not straightforward due to the strong statistical requirements of the IUPAC methodology (linearity, homoscedasticity, normality). Here, we propose a methodological approach to LOD estimation through linearized calibration models. As an example, the methodology is applied to the detection of low concentrations of carbon monoxide using MOX gas sensors in a scenario where the main source of error is the presence of uncontrolled levels of humidity. PMID- 29501089 TI - Oxidative polymerization of 5-hydroxytryptamine to physically and chemically immobilize glucose oxidase for electrochemical biosensing. AB - Poly(5-hydroxytryptamine) (poly(5-HT)) is exploited as a new and efficient enzyme immobilization matrix for amperometric and biofuel cell (BFC)-based biosensing. A GOx-poly(5-HT)-Pd nanoparticles (PdNPs) bionanocomposite is prepared by Na2PdCl4 initiated oxidized polymerization of 5-hydroxytryptamine (5-HT) in a neutral aqueous solution containing glucose oxidase (GOx), and this bionanocomposite and then chitosan (CS) are cast-coated on a Pd-plated Au electrode to yield a CS/GOx poly(5-HT)-PdNPs/Pdplate/Au enzyme electrode. Scanning/transmission electron microscopy, UV-vis spectrophotometry and electrochemical quartz crystal microbalance are employed for material characterization and/or process monitoring. Under optimized conditions, the amperometric response of the enzyme electrode is linear with glucose concentration from 2.0 MUM to 6.66 mM with a sensitivity of 110 MUA mM-1 cm-2, a limit of detection of 0.2 MUM, and excellent operation/storage stability in the first-generation biosensing mode. The sensitivity is larger than those of some conventional electrodes under identical conditions. The enzyme electrode also works well in the second-generation biosensing mode. By using the enzyme electrode as the anode for glucose oxidation and a Pdplate/Au electrode as the cathode for KMnO4 reduction, a monopolar BFC is constructed as a self-powered biosensor, the current response of which is linear with glucose concentration from 50 MUM to 34.5 mM. Experiments also show that poly(5-HT) is a physical and chemical dual-immobilization matrix of enzyme, since the abundant amino groups in poly(5-HT) can be used for chemical bonding of GOx. PMID- 29501090 TI - On-line monitoring of photolysis reactions using electrospray ionization mass spectrometry coupled with pressurized photoreactor. AB - A simple method by coupling a spray capillary with pressurized photoreactor for on-line monitoring of photolysis reactions was reported. In this method, only an inert gas is used to transfer the reaction solution, which avoids potential sample loss and contamination. The photolysis reaction is online quenched, and therefore, it has advantages of on-line detection and characterization of photolysis reaction intermediates. The assembly is easy to achieve, low-cost, and robust. Different from off-line methods, the photolysis reaction solution is directly transferred to a capillary tip for ionization, avoiding the delay in the detection of reactive intermediates. With this setup, this technique has been applied for on-line monitoring of degradation of cyclophosphamide (CP) in H2O2/UV for which two new intermediates were intercepted and structurally characterized for the first time by tandem mass spectrometry. In H2O2/UV, the degradation of CP occurred via hydroxylation, dehydrogenation, chlorine substitution reaction, and cleavage of the chloroethyl group. These results indicate that the coupling of electrospray ionization mass spectrometry with pressurized photoreactor can detect and characterize the key photolysis reaction intermediates, which render it a potential tool for elucidating the mechanism of water remediation. PMID- 29501091 TI - The composition of liquid atmospheric pressure matrix-assisted laser desorption/ionization matrices and its effect on ionization in mass spectrometry. AB - New liquid atmospheric pressure (AP) matrix-assisted laser desorption/ionization (MALDI) matrices that produce predominantly multiply charged ions have been developed and evaluated with respect to their performance for peptide and protein analysis by mass spectrometry (MS). Both the chromophore and the viscous support liquid in these matrices were optimized for highest MS signal intensity, S/N values and maximum charge state. The best performance in both protein and peptide analysis was achieved employing light diols as matrix support liquids (e.g. ethylene glycol and propylene glycol). Investigating the influence of the chromophore, it was found that 2,5-dihydroxybenzoic acid resulted in a higher analyte ion signal intensity for the analysis of small peptides; however, larger molecules (>17 kDa) were undetectable. For larger molecules, a sample preparation based on alpha-cyano-4-hydroxycinnammic acid as the chromophore was developed and multiply protonated analytes with charge states of more than 50 were detected. Thus, for the first time it was possible to detect with MALDI MS proteins as large as ~80 kDa with a high number of charge states, i.e. m/z values below 2000. Systematic investigations of various matrix support liquids have revealed a linear dependency between laser threshold energy and surface tension of the liquid MALDI sample. PMID- 29501092 TI - In-line UV spectroscopy for the quantification of low-dose active ingredients during the manufacturing of pharmaceutical semi-solid and liquid formulations. AB - UltraViolet (UV) spectroscopy was evaluated as an innovative Process Analytical Technology (PAT) - tool for the in-line and real-time quantitative determination of low-dosed active pharmaceutical ingredients (APIs) in a semi-solid (gel) and a liquid (suspension) pharmaceutical formulation during their batch production process. The performance of this new PAT-tool (i.e., UV spectroscopy) was compared with an already more established PAT-method based on Raman spectroscopy. In-line UV measurements were carried out with an immersion probe while for the Raman measurements a non-contact PhAT probe was used. For both studied formulations, an in-line API quantification model was developed and validated per spectroscopic technique. The known API concentrations (Y) were correlated with the corresponding in-line collected preprocessed spectra (X) through a Partial Least Squares (PLS) regression. Each developed quantification method was validated by calculating the accuracy profile on the basis of the validation experiments. Furthermore, the measurement uncertainty was determined based on the data generated for the determination of the accuracy profiles. From the accuracy profile of the UV- and Raman-based quantification method for the gel, it was concluded that at the target API concentration of 2% (w/w), 95 out of 100 future routine measurements given by the Raman method will not deviate more than 10% (relative error) from the true API concentration, whereas for the UV method the acceptance limits of 10% were exceeded. For the liquid formulation, the Raman method was not able to quantify the API in the low-dosed suspension (0.09% (w/w) API). In contrast, the in-line UV method was able to adequately quantify the API in the suspension. This study demonstrated that UV spectroscopy can be adopted as a novel in-line PAT-technique for low-dose quantification purposes in pharmaceutical processes. Important is that none of the two spectroscopic techniques was superior to the other for both formulations: the Raman method was more accurate in quantifying the API in the gel (2% (w/w) API), while the UV method performed better for API quantification in the suspension (0.09% (w/w) API). PMID- 29501093 TI - Adenosine-derived doped carbon dots: From an insight into effect of N/P co-doping on emission to highly sensitive picric acid sensing. AB - The various synthetic routes of carbon dots (C-dots) feature a considerable step toward their potential use in chemical sensors and biotechnology. Herein, by coupling phosphorus and nitrogen element introduction, the adenosine-derived N/P co-doped C-dots with fluorescence enhancement were achieved. By separately employing adenosine, adenosine monophosphate, adenosine diphosphate, and adenosine-5'-triphosphate as precursors, the effect of N/P co-doping on the fluorescence emission is discussed in detail. The formed C-dots with adenosine monophosphate exhibited strong blue fluorescence with a high quantum yield of 33.81%. Then the C-dots were employed as a fluorescent probe and utilized to develop a fast, sensitive, and selective picric acid sensor. The fluorescence of C-dots can be quenched by picric acid immediately, giving rise to a picric acid determination down to 30 nM. The possible mechanism of fluorescence quenching was discussed, which was proved to be inner filter effect and static quenching. Moreover, this method has the potential to detect picric acid in environmental water samples. PMID- 29501094 TI - A label-free fluorescent biosensor for the detection of protein kinase activity based on gold nanoclusters/graphene oxide hybrid materials. AB - Protein kinase (PKA) can regulate many cellular biological processes by phosphorylation substrate peptide or protein. A new fluorescent biosensing method for the detection of PKA activity was developed by using 11-mercaptoundecanoic acid-capped gold nanoclusters (MUA-Au NCs) and graphene oxide (GO) with low background noise. In this strategy, the special designed peptide could be anchored on the surface of MUA-Au NCs by the Au-S bond and also adsorbed on the surface of GO owing to the electrostatic interaction. As a result, the fluorescence of MUA-Au NCs was quenched leading to low background fluorescence due to the forster resonance energy transfer (FRET) between MUA-Au NCs and GO via peptide as a bridge. However, when the substrate peptide was phosphorylated by PKA, the FRET between GO and MUA-Au NCs was disrupted because of the weakened interaction between the phosphorylated peptide and the GO, resulting in recovery of the fluorescence intensity. The developed label-free fluorescence "turn-off on" method can detect protein kinase activity in the range of 0.6-2.0 U mL-1 with a detection limit of 0.17 U mL-1 (3sigma). The feasibility of this present method for kinase inhibitor screening was also studied by assessment of H-89 kinase inhibition with an IC50 value of 0.049 MUmol L-1. PMID- 29501095 TI - An active fluorescent probe based on aggregation-induced emission for intracellular bioimaging of Zn2+ and tracking of interactions with single stranded DNA. AB - A novel dual-sensing fluorescence probe L was designed and synthesized for highly selective and sensitive detection of Zn2+ and DNA. The probe L achieved a detection limit of 3.8 nM for Zn2+, which is lower than the acceptable level of Zn2+ in living cells. The probe L displayed high selectivity toward Zn2+ over other interference metal ions and amino acids. Moreover, the probe L displayed low cytotoxicity and good cell permeability, indicating its potential for detecting and bio-imaging of Zn2+. In addition, the probe L-Zn2+ exhibited enhanced fluorescence signal for DNA detection through the metal-coordination interaction between Zn2+ and DNA. The enhanced signal is higher than that of the classical ethidium bromide probe. The experiments in aqueous media verified the feasibility of applying probe L in real samples. PMID- 29501096 TI - Enhancing detectability of anabolic-steroid residues in bovine urine by actively modulated online comprehensive two-dimensional liquid chromatography - high resolution mass spectrometry. AB - In this study we describe an approach to enhance the sensitivity of an online comprehensive two-dimensional liquid chromatography (LC * LC) high-resolution mass spectrometry method for the separation and detection of trace levels of anabolic-steroid residues in complex urine matrices. Compared to one-dimensional liquid chromatography (1D-LC), LC * LC methods offer higher separation power, thanks to the combined effect of two different selectivities and a higher peak capacity. However, when using state-of-the-art LC * LC instrumentation, the price paid for the increase in separation power is a decrease in sensitivity and detectability of trace-level analytes. This can be ascribed to the sample dilution that takes place during each of the two chromatographic steps. The way in which fractions are collected and transferred from the first to the second column is also of paramount importance, especially the volume and the solvent composition of the fractions injected in the second column. To overcome the detection limitation, we present an active-modulation strategy, based on concentrating the fractions of the first-dimension effluent using a modulation interface that employs trap columns. We obtained a signal enhancement for anabolic-steroid compounds in a bovine-urine sample by a factor of 2.4-7.6 and an increase in the signal-to-noise ratio up to a factor of 7 in comparison with a standard loop-based modulation interface. In addition, thanks to the increased sensitivity of our method, a substantially larger number of peaks were detected (76 vs. 36). Moreover, we could reduce the solvent consumption by a factor of three (160 mL vs. 500 mL per run). PMID- 29501097 TI - A novel HPLC-ESI-Q-ToF approach for the determination of fatty acids and acylglycerols in food samples. AB - We propose a new analytical method using reverse phase High performance liquid chromatography (HPLC) coupled through an electrospray source with a tandem quadrupole-time-of-flight (ESI-Q-ToF) mass spectrometric detector for the full characterization and quantitation of the different classes of fatty acids and acylglycerols in lipid samples in a single chromatographic run. In this work, we optimized the derivatization reaction for free fatty acids with 2 hydrazinoquinoline, which is a low-cost approach, using a full factorial design. This reaction does not involve transesterification, thus enabling the free fatty acids to be separated and successfully quantified in the presence of mono-, di- and triacylglycerols without altering the whole glyceride profile. This new analytical method provides a full profile of fatty acids, mono-, di- and triglycerides within a relatively short chromatographic run (less than 40 min), with low operating back-pressure (less than 110 bar). The derivatization of the free fatty acids allows their detection in positive mode, with limits of detection in the range of 0.2-1.9 ng/g, and a dynamic range of two orders of magnitude. The figures of merit of the procedure are competitive with respect to the literature. The method was validated by characterizing two different types of olive oils. Free fatty acid content was quantified, and the results are consistent with literature data. The method was applied to the characterization of cow milk and an infant formula, after the precipitation of proteins and phospholipids, and proved suitable for the detection of short chain fatty acids, free fatty acids and glycerides highlighting differences in the composition of the two milks. The proposed procedure improves the current methods for the analysis of acylglyceride based materials, such as olive oil, and proved promising for the characterization of lipids in complex matrices, such as milk. PMID- 29501098 TI - American Board of Orthodontics: Time for change. AB - The American Board of Orthodontics (ABO) works to certify orthodontists in a fair, reliable, and valid manner. The process must examine an orthodontist's knowledge, abilities, and critical thinking skills to ensure that each certified orthodontist has the expertise to provide the highest level of patient care. Many medical specialty boards and 4 American Dental Association specialty boards use scenario-based testing for board certification. Changing to a scenario-based clinical examination will allow the ABO to test more orthodontists. The new process will not result in an easier examination; standards will not be lowered. It will offer an improved testing method that will be fair, valid, and reliable for the specialty of orthodontics while increasing accessibility and complementing residency curricula. The ABO's written examination will remain as it is. PMID- 29501099 TI - Moving toward patient-centered orthodontics: Patient-reported outcome measures. PMID- 29501100 TI - Author's response. PMID- 29501101 TI - Fixed-functional appliance treatment and growth hormone therapy. PMID- 29501102 TI - Way to evidence-based decision aids in orthodontics. PMID- 29501103 TI - Author's response. PMID- 29501104 TI - Authors' response. PMID- 29501105 TI - Unacceptable acceptance. PMID- 29501106 TI - Did someone push Lucy out of the tree? PMID- 29501107 TI - A short discussion on the evidence and ethics of orthodontic research. PMID- 29501108 TI - Effect of supplemental vibration on orthodontic treatment with aligners: A randomized trial. AB - INTRODUCTION: Supplemental vibration has been reported to accelerate orthodontic tooth movement and reduce discomfort. Our purpose was to investigate the effects of AcceleDent on Invisalign treatment. This randomized clinical trial was carried out in 2 orthodontic private practices with a 1:1 allocation ratio. METHODS: Adult patients who were beginning their orthodontic treatment were randomly allocated to either an active (A) or a sham (B) AcceleDent Aura device (OrthoAccel Technologies, Inc. Houston, TX). All patients were placed on a 1-week aligner change regimen, and fit was evaluated every 3 weeks. The outcomes were the ability to complete the initial set of aligners and the incisor irregularity measurements for those who completed their regimen of aligners. In addition, aligner compliance, pain levels, and oral health-related quality of life data were gathered from questionnaires. The subjects, investigators, and assessors were all blinded to the treatment arms. RESULTS: Twenty-seven subjects were randomized into 2 groups (A and B), 1 subject discontinued treatment, and 13 subjects were analyzed in each group. The Fisher exact test showed no significant difference in completion rates between the 2 groups (group A, 77%; group B, 85%; P = 1). Independent-sample t tests showed no significant difference between the final irregularity index or change in irregularity index between the 2 groups. Compliance was similar in both groups. The Wilcoxon rank sum test showed minimal differences in pain levels. Quality of life responses were similar in both groups. No serious harm was observed. CONCLUSIONS: We found no evidence that the AcceleDent Aura device impacts the ability to complete a series of aligners with a 1-week change regimen or the final alignment achieved in adult patients. It also had no significant effect on the reduction of orthodontic pain or oral health-related quality of life parameters when used with Invisalign. PMID- 29501109 TI - Gastric emptying rate before and after orthodontic treatment examined with the [13C] breath test: A pilot study. AB - INTRODUCTION: Orthodontic patients with malocclusion have significantly lower masticatory and gastrointestinal digestive function than persons with normal occlusion. Although several studies have suggested that masticatory function is improved after orthodontic treatment, the relationship between such improvement and change in gastrointestinal symptoms has not been quantitatively evaluated. In this study, we aimed to investigate the change in masticatory function and the gastric emptying rate in patients with malocclusion, before and after orthodontic treatment. METHODS: Seven women with malocclusion, before (pretreatment group) and after orthodontic treatment (posttreatment group), and 7 healthy dentate female volunteers (control group) underwent a 13C-acetate breath test (13CO2) with a liquid meal and the color changeable gum test, along with completing the frequency scale for symptoms of gastroesophageal reflux and a questionnaire on food intake. Between-group differences were evaluated. RESULTS: The pretreatment group had significantly longer maximum 13CO2 exhalation time and lower masticatory function, quantified using a higher red-color value on the gum test and the questionnaire on food intake, than did the posttreatment and control groups. No significant differences were identified between the posttreatment and the control groups. CONCLUSIONS: We provide evidence of improvement of masticatory function after orthodontic treatment, which was associated with a faster rate of gastric emptying. PMID- 29501110 TI - Registration area and accuracy when integrating laser-scanned and maxillofacial cone-beam computed tomography images. AB - INTRODUCTION: The purpose of this study was to examine changes in registration accuracy after including occlusal surface and incisal edge areas in addition to the buccal surface when integrating laser-scanned and maxillofacial cone-beam computed tomography (CBCT) dental images. METHODS: CBCT scans and maxillary dental casts were obtained from 30 patients. Three methods were used to integrate the images: R1, only the buccal and labial surfaces were used; R2, the incisal edges of the anterior teeth and the buccal and distal marginal ridges of the second molars were used; and R3, labial surfaces, including incisal edges of anterior teeth, and buccal surfaces, including buccal and distal marginal ridges of the second molars, were used. Differences between the 2 images were evaluated by color-mapping methods and average surface distances by measuring the 3 dimensional Euclidean distances between the surface points on the 2 images. RESULTS: The R1 method showed more discrepancies between the laser-scanned and CBCT images than did the other methods. The R2 method did not show a significant difference in registration accuracy compared with the R3 method. CONCLUSIONS: The results of this study indicate that accuracy when integrating laser-scanned dental images into maxillofacial CBCT images can be increased by including occlusal surface and incisal edge areas as registration areas. PMID- 29501111 TI - Factors influencing satisfaction with the process of orthodontic treatment in adult patients. AB - INTRODUCTION: Despite the increases in adults undergoing orthodontic treatment in both the public and private sectors, satisfaction with the treatment process has not been widely explored. In this study, we investigated factors influencing satisfaction with the process of orthodontic treatment in adult patients. METHODS: This was a prospective cross-sectional qualitative study. Participants were adults who had completed orthodontic treatment with fixed appliances and were recruited from 2 sites (a National Health Service public sector teaching hospital and a private specialist practice). Data were collected using in-depth interviews, and a content thematic analysis with a framework approach was used to analyze the data. RESULTS: A total of 26 adults were recruited (13 at each site). Five main themes were identified relating to patient satisfaction with the process of treatment: communication, staff, physical environment, appointments, and impact of appliance treatment. Effective communication was a dominant theme, particularly relating to explanations during treatment and making patients feel involved in their own care. CONCLUSIONS: In general, adult orthodontic patients were satisfied with the process of treatment, and good communication played a major part in this. Despite the differences in working models in the public and private sectors, many similarities arose when comparing the factors between the 2 sites. PMID- 29501112 TI - Influence of canine vertical position on smile esthetic perceptions by orthodontists and laypersons. AB - INTRODUCTION: Our objectives were to verify the impact of alterations in the vertical position of the maxillary canines in smile esthetic perceptions and to determine whether exposure of the gingival margins directly affects laypersons' and orthodontists' perceptions. METHODS: A smile photograph of a male subject showing gingival zeniths was selected, and the canine vertical positions were symmetrically modified in increments of 0.5 mm, creating 4 new images varying from 1.0 mm of intrusion to 1.0 mm of extrusion, with and without gingival exposure. The total of 10 images were evaluated by 60 orthodontists and 60 laypersons, who determined the level of attractiveness of each smile on a visual analog scale. RESULTS: For both orthodontists and laypersons, the canine vertical position modifications had a statistically significant influence (P <0.0001), and the gingival exposure had no significant influence on the smile esthetic evaluations. CONCLUSIONS: For both groups of evaluators, the most attractive smiles were the standard smile and the smiles with 0.5 mm of intrusion. The less attractive smiles were those with 1.0 mm of extrusion and 1.0 mm of intrusion. Orthodontists were more critical in their assessments. There were no differences in the esthetic evaluations of smiles with and without gingival margin exposure for both groups of evaluators. PMID- 29501113 TI - Agreement in the determination of preformed wire shape templates on plaster models and customized digital arch form diagrams on digital models. AB - INTRODUCTION: The aim of this study was to verify the accuracy of preformed wire shape templates on plaster models and those of customized digital arch form diagrams on digital models. METHODS: Twenty pairs of dental plaster models were randomly selected from the archives of the Department of Orthodontics of Federal Fluminense University, Niteroi, Rio de Janeiro, Brazil. All plaster model samples were scanned in a plaster model scanner to create the respective digital models. Three examiners defined the arch form on the mandibular arch of these models by selecting the ideal preformed wire shape template on each plaster model or by making a customized digital arch form on the digital models using a digital arch form customization tool. These 2 arch forms were superimposed by the best-fit method. The greatest differences in the 6 regions on the superimposed arches were evaluated. Each examiner presented a descriptive analysis with the means, standard deviation, and minimum and maximum intervals of the differences on the superimpositions. Intraclass correlation coefficient and paired t tests were used to evaluate the accuracy of the superimpositions. RESULTS: Among the 6 regions analyzed in the superimpositions, the largest differences in the anterior and premolar regions were considered clinically insignificant, whereas the largest differences in the right molar region, especially the second molar area, were considered clinically significant by all 3 examiners. The intraclass correlation coefficients showed a weak correlation in the premolar region and moderate correlations in the anterior and molar regions. The paired t test showed statistically significant differences in the left anterior and premolar regions. CONCLUSIONS: The superimpositions between the arch forms on plaster and digital models were considered accurate, and the differences were not clinically significant, with the exception of the second molar area. Despite the favorable results, the requirement of correcting some software problems may hamper the transition from plaster to digital models. PMID- 29501114 TI - Palatally impacted canines: A new 3-dimensional assessment of severity based on treatment objective. AB - INTRODUCTION: The severity of a palatally impacted canine (PIC) is gauged radiographically on 2-dimensional and 3-dimensional positional components: eg, angulation and height. We hypothesized that the position of a PIC relative to its virtual alignment in the arch is a better indication of impaction severity and treatment requirements. The aims of this research were to evaluate variations in PIC location on 3-dimensional images and to determine positional components associated with impaction severity. METHODS: Linear and angular measurements of 38 PICs from 28 cone-beam computed tomography scans were made on the panoramic, coronal, sagittal, and axial sections. Measurements included angulation of the PIC to the virtually aligned canine, midline, and palatal plane; and distances between cusp tip and apex to various reference planes-eg, occlusal and midpalatal. Statistical assessments comprised t tests for group comparisons based on PIC and virtually aligned canine severity (cutoff at 30 degrees ) and Pearson product moment correlations for associations among variables. RESULTS: Angulations of the PIC to the virtually aligned canine were 32.5 degrees +/- 15.5 degrees (range, 9 degrees -59 degrees ) and 19.6 degrees +/- 6.9 degrees and 45.37 degrees +/- 9.6 degrees , respectively, in the less severe and more severe groups (P <0.001). Group differences were significant (0.023

20ngmL 1), with a detection limit of ~ 0.04ngmL-1. It also showed good reproducibility and repeatability for three different cTnI concentration (1, 10 and 25ngmL-1) with satisfactory relative standard deviations (RSD). Hence, the proposed nanostructured immunosensor shows potential for point-of-care testing. PMID- 29501139 TI - A membrane film sensor with encapsulated fluorescent dyes towards express freshness monitoring of packaged food. AB - A new Membrane Film Sensor (MFS) has been developed to measure pH of fluids. MFS comprises a polyelectrolyte multilayer film with uniformly distributed compartments (microchambers) where a fluorescent sensing dye is encapsulated. Fabricated film is sealed onto a polyethylene film for a future use. MFS was applied to report changes in golden pomfret fillet upon its storage at 5 degrees C. MFS pH readings were correlated to bacteriological analysis of fish samples. A hike in pH of fish juices happens after 10 days of storage signaling bacterial spoilage of fish. The design of developed MFS allows easy integration with transparent packaging materials for future development of "SMART" packaging sensing food freshness. PMID- 29501140 TI - Development and characterization of DNA aptamers against florfenicol: Fabrication of a sensitive fluorescent aptasensor for specific detection of florfenicol in milk. AB - Specific ssDNA aptamers for the antibiotic florfenicol (FF) were developed from an enriched nucleotide library using magnetic beads-based SELEX (Systematic Evolution of Ligands by EXponential enrichment) technique with high-binding affinity. After 12 rounds of selection, thirty-six sequences were obtained that were then divided into five major families, according to the primary sequence similarity. Binding affinity analyses of three fluorescently tagged aptamers belonging to different families demonstrated that the dissociation constants (Kd) were in the low nanomolar range (Kd = 52.78-211.4 nmol L-1). Furthermore, to verify the potential application of the aptamers, a fluorescent aptasensor was fabricated for detecting the FF residue in raw milk samples based on the energy transfer between graphene oxide as the acceptor and fluorescently tagged FF specific aptamer as the donor. Under optimal conditions, the aptasensor displayed a wide linear range from 5 to 1200 nmol L-1 and a detection limit of 5.75 nmol L 1 with excellent selectivity in milk. The recovery rate in the milk was between 101% +/- 0.14% and 110% +/- 2.8%, indicating high accuracy. This fluorescent aptasensor possessed considerable potential for rapid analysis of FF in raw milk because of its simplicity of detection. Moreover, the interaction between the aptamer and FF was studied using molecular modeling. PMID- 29501141 TI - Microfluidic liquid-air dual-gradient chip for synergic effect bio-evaluation of air pollutant. AB - In this paper, a novel prototype liquid-air dual gradient chip is introduced, which has paved the way for effective synergic effect bio-evaluation of air pollutant. The chip is composed of an array of the agarose liquid-air interfaces, top air gradient layer and bottom liquid gradient layer. The novel agarose liquid air interface allows for non-biased exposure of cells to all the substances in the air and diffusive interactions with the liquid phase; while the dual liquid air gradient provides powerful screening abilities, which well reduced errors, saved time and cost from repeated experiment. Coupling the two functions, the chip subsequently facilitates synergic effect evaluation of both liquid and air factors on cells. Here cigarette smoke was taken as the model air pollutant, and its strong synergic effects with inflammatory level of A549 lung cancer cells on their fate were successfully quantified for the first time. These results well testified that the proposed dual-gradient chip is powerful and indispensable for bio-evaluation of air pollutant. PMID- 29501142 TI - A simple and economical spectrofluorimetric alternative for Al routine analysis in seafood. AB - A simple and economical spectrofluorimetric alternative for aluminium determination in bivalve mollusks based on the fluorescent blue-green colour complex between Al(III) and salicylaldehyde picolinoylhydrazone (SAPH) has been studied. The factors that are most likely to affect were optimized with a Box Behnken design. Optimum conditions were: pH 6.6, 0.9 mol L-1 acetic acid/acetate buffer, 3.0 mmol L-1 SAPH, and 50% ethanol. Detection and quantitation limits were found to be 2.7 MUg L-1 and 9.1 MUg L-1, respectively. The upper limit of application was assessed through the limit of linearity which was set as 300 MUg L-1. Intra-day repeatability and inter-day repeatability were evaluated showing an excellent precision for the fluorescence method (both < 5%). The method was sensitive enough for the satisfactory determination of aluminium in several bivalve mollusk samples both fresh and canned seafood. The results showed that commercial fresh wild products presented the smallest Al concentration (6-27 mg per 100 g dry weight), while bivalves preserved in cans the concentration was considerably higher (75 mg per 100 g dry weight). Thus, differences between Al concentration related to processing were identified. The study shows a simple, cost-effective and reliable tool for routine aluminium determination in seafood for food quality control. PMID- 29501143 TI - Dilute-and-shoot coupled to nanoflow liquid chromatography high resolution mass spectrometry for the determination of drugs of abuse and sport drugs in human urine. AB - In this work, a sensitive nanoflow liquid chromatography high-resolution mass spectrometry screening method has been developed for the determination of multiclass drugs of abuse and sport drugs in human urine. 81 drugs belonging to different multiclass pharmaceuticals were targeted. The method is based on the use of a nanoLC column (75 um * 150 mm, 3 um particle size and 100 A pore) with the nanospray emitter tip integrated so that dead volumes are significantly minimized. Data acquisition method included both full-scan and all ion fragmentation experiments using an Orbitrap analyser (Q-Exactive) operated in the positive ionization mode. To increase laboratory throughput, a dilute-and-shoot methodology has been tested and proposed, based solely on direct urine dilution without further sample workup. Matrix effects were evaluated, showing a negligible effect for all studied compounds when a dilution 1:50 was implemented. Despite this high-dilution factor, limits of quantification were still satisfactory, with values below 5 ug L-1 in most cases, being lower than their minimum required performance limits correspond established by the World Anti Doping Agency. Therefore, the use of the dilute-and-shoot method with the enhanced sensitivity provided by nanoflow LC setup could be useful tool for the determination of studied compounds in drug testing, thus increasing laboratory performance, because a minimum sample treatment steps are required. PMID- 29501144 TI - Untargeted screening of phase I metabolism of combretastatin A4 by multi-tool analysis. AB - The aim of the current study was to apply different strategies for generation of metabolites of combretastatin A4 (CA4) and subsequent identification of the unknown products of phase I metabolism. CA4 is a potent anti-tubulin agent currently undergoing clinical trials. The multi-tool analytical approach was based on electrochemistry (EC), in silico predictions, and in vitro studies with the use of rat liver microsomes. With the latter, two different analytical sample preparation methods were applied: protein precipitation and solid phase microextraction, both hyphenated to the liquid chromatography-high-resolution mass spectrometry platform (LC-HRMS). The EC was coupled directly to HRMS. Conventional techniques using enzyme fractions pooled from human or animals remain a method of choice for determinations of phase I of drug metabolism, EC and in silico methods, which enable determinations of metabolism patterns, are in turn considered to have great potential as fast alternatives to in vitro assays. While individual findings attained via employment of these four methods showed high similarity in relation to generated metabolic pathways for CA4, each method was found to provide unique features not identified with other approaches. In this paper, these differences are reviewed in view of potential artifacts and true metabolite production via various metabolism patterns under different experimental conditions. In addition, the reliability, applicability, MS compatibility issues, and potential of each of these technologies are discussed. PMID- 29501145 TI - Two-dimensional liquid chromatography consisting of twelve second-dimension columns for comprehensive analysis of intact proteins. AB - A comprehensive two-dimensional liquid chromatography (LCxLC) system consisting of twelve columns in the second dimension was developed for comprehensive analysis of intact proteins in complex biological samples. The system consisted of an ion-exchange column in the first dimension and the twelve reverse-phase columns in the second dimension; all thirteen columns were monolithic and prepared inside 250 um i.d. capillaries. These columns were assembled together through the use of three valves and an innovative configuration. The effluent from the first dimension was continuously fractionated and sequentially transferred into the twelve second-dimension columns, while the second-dimension separations were carried out in a series of batches (six columns per batch). This LCxLC system was tested first using standard proteins followed by real-world samples from E. coli. Baseline separation was observed for eleven standard proteins and hundreds of peaks were observed for the real-world sample analysis. Two-dimensional liquid chromatography, often considered as an effective tool for mapping proteins, is seen as laborious and time-consuming when configured offline. Our online LCxLC system with increased second-dimension columns promises to provide a solution to overcome these hindrances. PMID- 29501146 TI - 3D flower-like ferrous(II) phosphate nanostructures as peroxidase mimetics for sensitive colorimetric detection of hydrogen peroxide and glucose at nanomolar level. AB - Ferrous(II) phosphate nanoflowers (Fe3(PO4)2.8H2O NFs) were synthesized by a facial co-precipitation method. The structure, composition and morphology were characterized by XRD, EDX, element mapping and FESEM. The as-prepared Fe3(PO4)2.8H2O NFs exhibited excellent intrinsic peroxidase-like activity. Steady state kinetic studies showed that Fe3(PO4)2.8H2O NFs exhibited stronger affinities with 3,3,5,5-tetramethylbenzidine (TMB) and H2O2 as the substrates compared with the natural horseradish peroxidase (HRP) and the catalytic constant (kcat) value was even higher than HRP and other reported nanomaterial based peroxidase mimics. The investigation of the catalytic mechanism by cyclic voltammetry, fluorescence spectroscopy and ESR displayed the catalytic activity of Fe3(PO4)2.8H2O NFs originated from the generation of *OH. The Fe3(PO4)2.8H2O NFs also exhibited higher robustness and better storage stability than HRP. Then, a Fe3(PO4)2.8H2O NFs-based colorimetric platform was developed to determine H2O2 and glucose. The linear range of H2O2 and glucose was as broad as 1 * 10-5-2.5 mM and 8 * 10-4-1.2 mM, and the detection limit (LOD) was as low as 5 nM and 35 nM, respectively. This simple assay offered a highly sensitive and specific strategy for H2O2 and glucose determination, which had been successfully utilized for real sample analysis with good reproducibility and accuracy. PMID- 29501147 TI - High-throughput quantification of sodium saccharin in foods by ambient flame ionization mass spectrometry. AB - Ambient flame ionization (AFI) coupled with triple quadrupole tandem mass spectrometry was developed for quantitative analysis of sodium saccharin (SAC) in various food samples. Typically, the micro-flame by the combustion of n-butane provided a heating zone for fast desorption and ionization of analytes in milliseconds. Then high ion abundance of analyte could be produced in a short time, which made AFI-MS possess a very high sensitivity for SAC detection and was particularly appropriate for the quantification in multiple reaction monitor (MRM) mode. Liquid samples were introduced into outer flame using dip-it tips in order to facilitate a rapid and high-throughput analysis. Saccharin-d4 was used as the internal standard to compensate for the variations of the ion intensities. With a minimal sample preparation, a linear range of 4-100 MUg/mL was developed with all linear relationships of different matrices (including coke, juice, liquors, sunflower seeds and sweetmeats) greater than 0.992. Recoveries for coke and apple matrices were ranged from 88.4% to 108.9% at the concentration of 5, 20, 80 MUg/mL and the limits of detection (LODs) were in the range of 0.12-0.21 MUg/mL. Furthermore, the feasibility of this method was exhibited by the quantification analysis of SAC in seventeen real samples. These results indicated that AFI-MS was a valuable strategy for rapid screening detection and precise quantification analysis of SAC in food. PMID- 29501148 TI - Electrokinetic stacking of electrically neutral analytes with paper-based analytical device. AB - Electrokinetic stacking (ES) is effective for improving sensitivity of paper based analytical device (PAD) for charged analytes. In this paper, we successfully demonstrated ES of electrically neutral analytes on PAD, and the performance was characterized by smartphone-based colorimetry and fluorescence. Firstly, SDS from cathode reservoir stacked as a micelle band on an open paper fluidic channel by ES, and the target analyte was swept by the micelle. Meanwhile, the probes at the other side were carried by electroosmotic flow (EOF). Eventually, neutral components preloaded on the channel were concentrated as the narrow stacking band. Taking the rhodamine B as a probe, the effects of EOF, background electrolyte concentration and anionic surfactant concentration were investigated. Fluorescence detection of rhodamine B and colorimetric analysis of Sudan III demonstrated the sensitivity enhanced and its potential for the semi-quantitative test. Under the optimized conditions, fluorescence detection limit of 50 nM of rhodamine B was achieved with a linear range of 1.0 10 MUM (R2 = 0.99). The colorimetric detection limit for Sudan III was 5.2 MUM and the linear range was 5-40 MUM (R2= 0.99). Compared with direct analysis without stacking, the signal levels of rhodamine B and Sudan III were increased by 30-fold and 6-fold, respectively. This study showed that with ES, sensitive and rapid PAD detection of electrically neutral analytes could be achieved. PMID- 29501149 TI - Nanoparticle-Enhanced Laser Induced Breakdown Spectroscopy for the noninvasive analysis of transparent samples and gemstones. AB - In this paper, Nanoparticle-Enhanced Laser Induced Breakdown Spectroscopy is applied to transparent samples and gemstones with the aim to overcome the laser induced damage on the sample. We propose to deposit a layer of AuNPs on the sample surface by drying a colloidal solution before ablating the sample with a 532 nm pulsed laser beam. This procedure ensures that the most significant fraction of the beam, being in resonance with the AuNP surface plasmon, is mainly absorbed by the NP layer, which in turn results the breakdown to be induced on NPs rather than on the sample itself. The fast explosion of the NPs and the plasma induction allow the ablation and the transfer in the plasma phase of the portion of sample surface where the NPs were placed. The employed AuNPs are prepared in milliQ water without the use of any chemical stabilizers by Pulsed Laser Ablation in Liquids (PLAL), in order to obtain a strict control of composition and impurities, and to limit possible spectral interferences (except from Au emission lines). Therefore with this technique it is possible to obtain, together with the emission signal of Au (coming from atomized NPs), the emission spectrum of the sample, by limiting or avoiding the direct interaction of the laser pulse with the sample itself. This approach is extremely useful for the elemental analysis by laser ablation of high refractive index samples, where the laser pulse on an untreated surface can otherwise penetrate inside the sample, generate breakdown events below the superficial layer, and consequently cause cracks and other damage. The results obtained with NELIBS on high refractive index samples like glasses, tourmaline, aquamarine and ruby are very promising, and demonstrate the potentiality of this approach for precious gemstones analysis. PMID- 29501150 TI - Spiky gold shells on magnetic particles for DNA biosensors. AB - Combined separation and detection of biomolecules has the potential to speed up and improve the sensitivity of disease detection, environmental testing, and biomolecular analysis. In this work, we synthesized magnetic particles coated with spiky nanostructured gold shells and used them to magnetically separate out and detect oligonucleotides using SERS. The distance dependence of the SERS signal was then harnessed to detect DNA hybridization using a Raman label bound to a hairpin probe. The distance of the Raman label from the surface increased upon complementary DNA hybridization, leading to a decrease in signal intensity. This work demonstrates the use of the particles for combined separation and detection of oligonucleotides without the use of an extrinsic tag or secondary hybridization step. PMID- 29501151 TI - Renewable chemiluminescence optosensors based on implementation of bead injection principle with multicommutation. AB - In this work, the implementation of Bead Injection with multicommutation-based flow systems is reported. A surface renewable chemiluminescence (CL) flow sensor is presented based on the use of CL reaction of luminol with H2O2. Dowex 1 * 8 beads with immobilized luminol onto them were injected in the flow system by means of a six-port rotary valve and were accommodated into a 1 mm optical glass flow cell placed just in front of the rectangular photosensor window with the same size than the cell wall. Automatic computer-controlled manipulation of both reagents and sample solutions was undertaken using a multicommutated flow system which comprises five three-way solenoid valves, a home-made electronic interface and a Java-written software. Once the chemiluminescence signal was registered, sensing beads were automatically discarded out with a six-port rotary valve without needing to reverse or stop the flow. As a proof of concept and example, the enhancement of the chemiluminescence signal produced by Co(II) on the luminol H2O2 reaction in alkaline medium was used for illustrating this implementation determining vitamin B12 in pharmaceutical preparations (after mineralization for releasing Co(II)). The analytical performance of the approach was satisfactory, showing a linear dynamic range from 1.7 to 50 ug L-1, a detection limit of 0.5 ug L-1, RSD (%) of 5.3%, with a sampling frequency of 11 h-1. The proposed approach was applied to different samples and the results were consistent with those obtained with a reference method based on ICP-MS. Based on the same reaction (or re-configuring the system to accommodate it to reaction requirements) the approach can also be applied to the determination of other metal ions such as Cr(III) and Fe(II) and appropriately extended to molecules of bioanalytical interest based e.g. in CL immunoassays, given its versatility. PMID- 29501152 TI - Wafer-level detection of organic contamination by ZnO-rGO hybrid-assisted laser desorption/ionization time-of-flight mass spectrometry. AB - A technique for wafer-level detection of organic contaminations via surface assisted laser desorption/ionization time-of-flight mass spectrometry was developed. To replace the organic matrix in matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, zinc oxide-reduced graphene oxide (ZnO-rGO) hybrid was prepared by a hydrothermal reaction and used as the matrix in the detection of benzo[a]pyrene (B[a]P). By varying the rGO content and the amount of hybrid, the optimal rGO content in the hybrid for the detection of B[a]P was determined to be 4 wt% and the optimal amount of hybrid was 20 ng. The limit of detection of this method was found to be 1.6 * 1014 C atoms cm-2, which is lower than the concentration of residual organic contamination at which serious failure occurs during semiconductor fabrication. This method was also successfully used to detect other aromatic and aliphatic species on a semiconductor wafer. This approach is fast, accurate, simple, and inexpensive compared to other conventional methods, and can be used to identify localized micro-contamination in the semiconductor industry. PMID- 29501153 TI - A compact and low-cost laser induced fluorescence detector with silicon based photodetector assembly for capillary flow systems. AB - A compact and low-cost laser induced fluorescence (LIF) detector based on confocal structure for capillary flow systems was developed and applied for analysis of Her2 protein on single Hela cells. A low-power and low-cost 450 nm laser diode (LD) instead of a high quality laser was used as excitation light source. A compact optical design together with shortened optical path length improved the optical efficiency and detection sensitivity. A superior silicon based photodetector assembly was used for fluorescence detection instead of a photomultiplier (PMT). The limit of detection (LOD) for fluorescein sodium was 3 * 10-12 M or 165 fluorescein molecules in detection volume measured on a homemade capillary electroosmotic driven (EOD)-LIF system, which was similar to commercial LIFs. Compared to commercial LIFs, the whole volume of our LIF was reduced to 1/2 1/3, and the cost was less than 1/3 of them. PMID- 29501154 TI - Zirconium dioxide-reduced graphene oxide nanocomposite-coated stir-bar sorptive extraction coupled with ion mobility spectrometry for determining ethion. AB - In this study, we developed zirconium dioxide-reduced graphene oxide nanocomposite (ZrO2-rGO), as a novel coating for stir bar sorptive extraction (SBSE), prior to analysis by negative corona discharge ion mobility spectrometry (NCD-IMS). Ethion was selected as a test compound to evaluate the method. A stir bar was coated with the ZrO2-rGO nanocomposite using the sol-gel technique. ZrO2 has a high tendency towards the phosphonate group, hence its ability in absorbing ethion with high efficiency. On the other hand, graphene is a good sorbent for polar and semi-polar chemical compounds. Parameters affecting SBSE including extraction temperature, salt effect, stirring rate, desorption temperature, and extraction time were evaluated. The detection limit of this method for ethion was calculated to be 1.5 MUg L-1, and the good linear range of 5.0-200 MUg L-1 was obtained. The inter-day and intra-day relative standard deviations were 9% and 6%, respectively. This method was used to determine ethion in spiked river water and agricultural wastewater samples, and the obtained spiking recoveries were in the range of 93-97%. PMID- 29501155 TI - A new electrochemical immunoassay for prion protein based on hybridization chain reaction with hemin/G-quadruplex DNAzyme. AB - In this work, a new electrochemical immunosensor was developed for prion protein assay based on hybridization chain reaction (HCR) with hemin/G-quadruplex DNAzyme for signal amplification. In this amplification system, the hemin/G-quadruplex DNAzyme simultaneously mimicked the biocatalytic functions for H2O2 reduction and L-cysteine oxidation. In the presence of L-cysteine, the hemin/G-quadruplex catalyzed the oxidation of L-cysteine to L-cystine. At the same time, H2O2 was produced under the oxygen condition. Then, the hemin/G-quadruplex could quickly catalyze the reduction of H2O2, mimicking the catalytic performance of horseradish peroxidase (HRP). Under the optimal conditions, the immunosensor showed a wide linear response range from 0.5 pg/mL to 100 ng/mL with the low detection limit of 0.38 pg/mL (3sigma). By changing the specific antibody, this strategy could be easily extended to detect the infectious isoform of prion (PrPSc) and other proteins. Based on its good analytical performance, the developed method shows great potential applications in diagnosis of prion diseases at presymptomatic stage and bioanalysis. PMID- 29501156 TI - Solvent-stir bar microextraction system using pure tris-(2-ethylhexyl) phosphate as supported liquid membrane: A new and efficient design for the extraction of malondialdehyde from biological fluids. AB - A novel and efficient device of solvent stir-bar microextraction (SSBME) system coupled with GC-FID detection was introduced for the pre-concentration and determination of malondialdehyde (MDA) in different biological matrices. In the proposed device, a piece of porous hollow fiber was located on a magnetic rotor by using a stainless steel-wire (as a mechanical support) and the whole device could stir with the magnetic rotor in sample solution cell. The device provided higher pre-concentration factor and better precision in comparison with conventional SBME due to the reproducible, stable and high contact area between the stirred sample and the hollow fiber. Organic solvent type, donor and acceptor phase pH, temperature, electrolyte concentration, agitation speed, extraction time, and sample volume as the effective factors on the SSBME efficiency, were examined and optimized. Pure tris-(2-ethylhexyl) phosphate (TEHP) was examined for the first time as supported liquid membrane (SLM) for the determination of MDA by SSBME method. In contrast to the conventional SLMs of SBME in the literature, the SLM of TEHP was highly stable in contact with biological fluids and provided the highest extraction efficiency. Under optimized extraction conditions, the method provided satisfactory linearity in the range 1-500 ng mL 1, low LODs (0.3-0.7 ng mL-1), good repeatability and reproducibility (RSD% (n = 5) < 4.5) with the pre-concentration factors higher than 130-fold. To verify the accuracy of the proposed method, the traditional spectrophotometric TBA (2 thiobarbituric acid) test was used as a reference method. Finally, the proposed method was successfully applied for the determination and quantification of MDA in biological fluids. PMID- 29501157 TI - Dual-target recognition sandwich assay based on core-shell magnetic mesoporous silica nanoparticles for sensitive detection of breast cancer cells. AB - A novel dual-target recognition sandwich strategy for selective capture and detection of MCF-7 breast cancer cells based on core-shell magnetic mesoporous silica (Fe3O4@nSiO2@mSiO2@apt) nanoparticles was developed. Fe3O4@nSiO2@mSiO2@apt nanoparticles, which were prepared by a layer-by-layer method and were used for the first time to capture cancer cells, have large surface areas, particularly accessible mesochannels, and good biocompatibility, enabling aptamers to be compactly anchored onto the surface of the core-shell magnetic nanoparticles. A mucin 1 protein (MUC1)-targeted Fe3O4@nSiO2@mSiO2@apt nanoparticle was used as an affinity magnetic isolate material to capture target MCF-7 cells selectively and to reduce interference through affinity interaction between the anti-MUC1 aptamer and the MUC1 protein over-expressed on the surface of the MCF-7 cells. Meanwhile, a folate receptor (FR)-targeted affinity fluorescent probe (FA-BSA-FITC) was developed by coupling folic acid and FITC to the surface of BSA, enabling high sensitivity, selective fluorescent labeling of FR over-expressed MCF-7 cells. A dual-target recognition sandwich assay was developed based on the MUC1-targeted magnetic nanoparticles and the FR-targeted fluorescent probes. Under optimum conditions, a quantitative assay of MCF-7 cells was achieved with a dynamic range of 102-105 cells/mL (R2 = 0.9991). This assay showed high specificity and sensitivity to the target MCF-7 cells. Finally, the proposed strategy could be extended to detect MCF-7 cells in human plasma and whole blood with a recovery range of 86.1-104.0% and a RSD range of 1.2-8.4%, respectively. This indicates that the dual-target recognition method developed in this research exhibits good selectivity, anti-interference capability, and reliability even in plasma and whole blood samples and is more suitable for complex samples than previous targeted assays. Therefore, the approach proposed here may have great potential for early breast cancer diagnosis. PMID- 29501158 TI - Glycosylated liposomes loading carbon dots for targeted recognition to HepG2 cells. AB - It is important to obtain the targeted nanocarriers during cancer treatment. Herein, mannosylated liposomes encapsulating carbon dots (CDs) are provided for targeted recognition of liver cancer HepG2 cells, which is based on the specific interaction between D-mannose and glycoprotein on the surface of HepG2 cells. CDs were prepared by hydrothermal method. Then, they were encapsulated into liposomes by hydrophobic force. The encapsulation of CDs into liposomes increases their stability and fluorescence intensity. Furthermore, D-mannose can also be inserted into liposomes by the aldehyde amine reaction between aldehyde groups of mannose molecules and amino groups of liposomes. The obtained D-mannose-CDs-liposomes (Man-CDs-liposomes) exhibit selectively tracking and efficiently labelling for cancer cells. The work highlights the potential application of CDs for bioimaging and diagnostic. PMID- 29501159 TI - A novel strategy for discriminating marine oils by using the positional distribution (sn-1, sn-2, sn-3) of omega-3 polyunsaturated fatty acids in triacylglycerols. AB - A novel strategy for discriminating genuine and adulterated marine oils is proposed. The strategy consists of i) determining the stereospecific distribution (sn-1, sn-2 and sn-3) of omega 3 polyunsaturated fatty acids (omega-3 PUFA) on the backbone of triacylglycerols by using liquid chromatography tandem mass spectrometry; ii) transforming the qualitative stereospecific information into quantitative data by means of a novel strategy; iii) analyzing the transformed data by principal component analysis. The proposed strategy was tested on pure oils (seal, salmon, cod liver, sandeel, blue whiting, herring), a mixture of blue whiting, herring, sandeel and Norway pout and some intentionally adulterated oils. In addition, some published krill oil data were analyzed to confirm the reliability of the new approach. PMID- 29501160 TI - Fabrication of Pd-decorated TiO2/MoS2 ternary nanocomposite for enhanced benzene gas sensing performance at room temperature. AB - A high-performance benzene gas sensor based on Pd-decorated TiO2/MoS2 ternary nanocomposite was demonstrated in this paper. The morphologies, microstructures and composition of the Pd-TiO2/MoS2 nanocomposite were sufficiently examined by X ray diffraction (XRD), energy dispersive spectrometer (EDS), scanning electron microscopy (SEM), transmission electron microscope (TEM) and X-ray photoelectron spectroscopy (XPS), confirming its successful preparation and reasonability. The benzene-sensing performances of the Pd-TiO2/MoS2 sensor were investigated upon exposure to various concentrations of benzene vapor from 100 ppb to 100 ppm at room temperature. The experimental results showed that the sensor has a high response, short response-recovery time, good repeatability and selectivity toward benzene gas, which is largely superior to that of the pure TiO2 and MoS2 sensors. In addition, the influence of Pd loading in the nanocomposite on the benzene sensing was investigated. The sensing mechanism of the Pd-TiO2/MoS2 sensor was attributed to the synergistic effect of the ternary nanostructures, combining the modulation of potential barrier with electron transfer. This work indicates that the synthesized Pd-TiO2/MoS2 ternary nanocomposite is an excellent candidate for constructing high-performance benzene sensor for various applications. PMID- 29501161 TI - Modulating the protein content of complex proteomes using acetonitrile. AB - In this work we present acetonitrile as a tool to modulate the dynamic range of the proteome of complex samples. Different concentrations of acetonitrile ranging from 15% v/v to 65% v/v were used to modulate the protein content of serum samples from healthy people and patients with lymphoma and myeloma. We show that the proteome above 70 kDa is pelleted as a function of the concentration of acetonitrile and that profiling with PCA or Clustering is only possible using the supernatants obtained for concentrations of acetonitrile higher than 45% v/v or the pellets for concentrations of acetonitrile of 35% and 45%. The differentiation and classification of the three groups of sera samples (healthy, lymphoma and myeloma) were possible using acetonitrile at 55% v/v concentration. This work opens new avenues for the application of acetonitrile as a cost effective tool in proteomics applications. PMID- 29501162 TI - Simple screening technique for determination of adsorbed and absorbed mercury in particulate matter in atmospheric and aquatic environment. AB - The threat connected to mercury results from its capacity to be transported over long distances and its ability to bioaccumulate and biomagnify in the trophic chain, making it a global problem. Humans are situated at the top of the trophic ladder, and excess mercury manifests itself mainly in the onset of neurological conditions. The toxicity of mercury, as well as its residence time, depends on the form in which it occurs. However, analysis of mercury speciation is time consuming and poses a high risk of additional or negative contamination. Hence, the mercury thermodesorption method, and particularly its use for fractionating Hg, offers many new possibilities. Here, the thermodesorption technique was applied to the determination of mercury fraction in particulate matter using a DMA-80 direct mercury analyser (Milestone, Italy). The presented method allows direct (without prior mineralisation) determination of labile and stabile mercury fractions within a relatively short time. Heating sample in subsequent temperatures enables determination the share of mercury adsorbed on the surface (mainly associated with halogenides (Hgads1) and HgSO4/HgO/HgF2 (Hgads2), as well as absorbed within the suspended particulate organic matter (Hgabs), in a relatively short time. This fractionation is of great importance in terms of estimating the transfer of mercury to and along the trophic chain. This method determines the contribution of two stable mercury fractions:: HgS and residual Hg, strongly bound to particulate matter matrix (Hgres). The novelty of this technique is also its joint ability to determine gaseous mercury bound to airboirne particulate matter, which will enable better understand Hg cycling in the atmosphere as well as mercury fraction in dry deposition flux. This method enables assessment of global mercury circulation in environment. PMID- 29501163 TI - Core-shell assay based aptasensor for sensitive and selective thrombin detection using dark-field microscopy. AB - In this work, we developed a robust and ultrasensitive bio-sensor based on the target-aptamer recognition strategy and microscopic enumeration of gold nanoparticles (AuNPs) using dark field microscopy (DFM). The aptasensor with a core-shell structure consisting of a magnetic bead (MB), aptamer and AuNPs was fabricated by complementary hybridization of the DNA probe on the AuNPs surface to the aptamer coupled to the MB. Upon addition of the target molecule, the strong interaction between the aptamer and the target molecule, thrombin, results in the release of the AuNPs from the MB. The quantities of thrombin is therefore linearly correlated to the number of the released AuNPs, which can be digitally counted using DFM. To demonstrate the feasible use of the aptasensor for target detection, thrombin was evaluated as the model target. The limit of detection was determined to be 2.54 fM with dynamic range of 6 fM-100 fM. When the concentration of thrombin exceeded 100 fM, the counted number of AuNPs didn't correlate linearly to molecules of thrombin anymore, as the nanoparticles aggregated partly due to high concentration. However, the color of the solution changes to purple and the concentration of free AuNPs can be conveniently quantified by UV-Vis spectroscopy for up to 100 nM. It is noteworthy that our aptasensor is very easy to operate and requires neither complex isolation and amplification processes nor expensive instruments and consumables. Furthermore, this strategy can be easily generalized to other targets by replacing the corresponding aptamers and show great potential for the detection of biomarkers in clinical samples. PMID- 29501164 TI - An electrochemical immunoassay for Escherichia coli O157:H7 using double functionalized Au@Pt/SiO2 nanocomposites and immune magnetic nanoparticles. AB - A sensitive Point-of-Care Testing (POCT) with Au-Pt bimetallic nanoparticles (Au@Pt) functionalized silica nanoparticle (SiO2 NPs) and Fe3O4 magnetic nanoparticles (Fe3O4 NPs) was designed for the quantitative detection of Escherichia coli O157:H7 (E. coli O157:H7). The poly-(4-styrenesulfonic acid-co maleic acid) (PSSMA) as a negatively charged polyelectrolyte can be easily coated on surface of the amino group modified SiO2 NPs via electrostatic force. PSSMA is also a good stabilizer for water-soluble bimetallic nanostructures. The PSSMA is first time used as a "bridge" to connect the negative charge Au@Pt NPs to the SiO2 NPs, forming Au@Pt/SiO2 NPs. Antibody and invertase conjugated Au@Pt/SiO2 NPs (denoted as Ab/invertase-Au@Pt/SiO2 NPs) were used as signal labels. Monoclonal antibody against E. coli O157:H7 (Ab) functionalized magnetic nanoparticles (denoted as Ab-Fe3O4@SiO2 NPs) were used to enrich and capture the E. coli O157:H7 in positive sample. The immunosensing platform also composed of a personal glucometer (PGM) using for signal readout. Based on this sandwich-type immunoassay, the invertase in the final formed sandwich immunocomplex catalyzed the hydrolysis of sucrose to produce a large amount of glucose for quantitative readout by the PGM. Under optimal conditions, a linear relationship between the glucose concentration and the logarithm of E. coli O157:H7 concentration was obtained in the concentration range from 3.5 * 102 to 3.5 * 108 CFU mL-1 with a detection limit of 1.83 * 102 CFU mL-1 (3sigma). This method was used to detect E. coli O157:H7 in spiked milk samples, indicating its potential practical application. This protocol can be applied in various fields of study. PMID- 29501165 TI - Fluorescence method for quickly detecting ochratoxin A in flour and beer using nitrogen doped carbon dots and silver nanoparticles. AB - In this paper, a FRET (Forster resonance energy transfer) based fluorescence method was developed for the quickly detection of ochratoxin A (OTA) in agricultural products (e.g., flour and beer). A highly fluorescent nitrogen doped carbon dots (CD) were served as energy donor, the DNA and MCH (6-mercapto-1 hexanol) modified Ag nanoparticles were served as energy acceptor in the FRET system. OTA can be detected in a concentration range between 10 and 5000 nM, the limit of detection is 8.7 nM. This method has three advantages: (1) an enhanced fluorescent intensity can be acquired by utilizing the nitrogen doped CD synthesized by one-step approach without sophisticated modification of nanoparticles; (2) OTA detection was accomplished quickly (less than 30 min) by using MCH as assistant molecule; (3) an extended OTA detection linear range was acquired, which may facilitate the OTA detection in real agricultural samples, and is helpful for solving food safety problems. PMID- 29501167 TI - Covalent functionalization of MoS2 nanosheets synthesized by liquid phase exfoliation to construct electrochemical sensors for Cd (II) detection. AB - Surface functionalization is an effective strategy in the precise control of electronic surface states of two-dimensional materials for promoting their applications. In this study, based on the strong coordination interaction between the transition-metal centers and N atoms, the surface functionalization of few layer MoS2 nanosheets was successfully prepared by liquid phase exfoliation method in N, N-dimethylformamide (DMF), 1-methyl-2-pyrrolidinone, and formamide. The cytotoxicity of surface-functionalized MoS2 nanosheets was for the first time evaluated by the methylthiazolyldiphenyl-tetrazoliumbromide assays. An electrochemical sensor was constructed based on glass carbon electrode (GCE) modified by MoS2 nanosheets obtained in DMF, which exhibits relatively higher sensitivity to Cd2+ detection and lower cytotoxicity against MCF-7 cells. The mechanisms of surface functionalization and selectively detecting Cd2+ were investigated by density functional theory calculations together with various spectroscopic measurements. It was found that surface-functionalized MoS2 nanosheets could be generated through Mo-N covalent bonds due to the orbital hybridization between the 5 s orbitals of Mo atoms and the 2p orbitals of N atoms of the solvent molecules. The high selectivity of the sensor is attributed to the coordination reaction between Cd2+ and O donor atoms of DMF adsorbed on MoS2 nanosheets. The robust anti-interference is ascribed to the strong binding energy of Cd2+ and O atoms of DMF. Under the optimum conditions, the electrochemical sensor exhibits highly sensitive and selective assaying of Cd2+ with a measured detection limit of 0.2 nM and a linear range from 2 nM to 20 MUM. PMID- 29501166 TI - A comparison of three liquid chromatography (LC) retention time prediction models. AB - High-resolution mass spectrometry (HRMS) data has revolutionized the identification of environmental contaminants through non-targeted analysis (NTA). However, chemical identification remains challenging due to the vast number of unknown molecular features typically observed in environmental samples. Advanced data processing techniques are required to improve chemical identification workflows. The ideal workflow brings together a variety of data and tools to increase the certainty of identification. One such tool is chromatographic retention time (RT) prediction, which can be used to reduce the number of possible suspect chemicals within an observed RT window. This paper compares the relative predictive ability and applicability to NTA workflows of three RT prediction models: (1) a logP (octanol-water partition coefficient)-based model using EPI SuiteTM logP predictions; (2) a commercially available ACD/ChromGenius model; and, (3) a newly developed Quantitative Structure Retention Relationship model called OPERA-RT. Models were developed using the same training set of 78 compounds with experimental RT data and evaluated for external predictivity on an identical test set of 19 compounds. Both the ACD/ChromGenius and OPERA-RT models outperformed the EPI SuiteTM logP-based RT model (R2 = 0.81-0.92, 0.86-0.83, 0.66 0.69 for training-test sets, respectively). Further, both OPERA-RT and ACD/ChromGenius predicted 95% of RTs within a +/- 15% chromatographic time window of experimental RTs. Based on these results, we simulated an NTA workflow with a ten-fold larger list of candidate structures generated for formulae of the known test set chemicals using the U.S. EPA's CompTox Chemistry Dashboard (https://comptox.epa.gov/dashboard), RTs for all candidates were predicted using both ACD/ChromGenius and OPERA-RT, and RT screening windows were assessed for their ability to filter out unlikely candidate chemicals and enhance potential identification. Compared to ACD/ChromGenius, OPERA-RT screened out a greater percentage of candidate structures within a 3-min RT window (60% vs. 40%) but retained fewer of the known chemicals (42% vs. 83%). By several metrics, the OPERA-RT model, generated as a proof-of-concept using a limited set of open source data, performed as well as the commercial tool ACD/ChromGenius when constrained to the same small training and test sets. As the availability of RT data increases, we expect the OPERA-RT model's predictive ability will increase. PMID- 29501168 TI - A review of nanoscale LC-ESI for metabolomics and its potential to enhance the metabolome coverage. AB - Liquid chromatography-electrospray ionisation-mass spectrometry (LC-ESI-MS) platforms are widely used to perform high throughput untargeted profiling of biological samples for metabolomics-based approaches. However, these LC-ESI platforms usually favour the detection of metabolites present at relatively high concentrations because of analytical limitations such as ion suppression, thus reducing overall sensitivity. To counter this issue of sensitivity, the latest in terms of analytical platforms can be adopted to enable a greater portion of the metabolome to be analysed in a single analytical run. Here, nanoflow liquid chromatography-nanoelectrospray ionisation (nLC-nESI), which has previously been utilised successfully in proteomics, is explored for use in metabolomic and exposomic research. As a discovery based field, the markedly increased sensitivity of these nLC-nESI platforms offer the potential to uncover the roles played by low abundant signalling metabolites (e.g. steroids, eicosanoids) in health and disease studies, and would also enable an improvement in the detection of xenobiotics present at trace levels in biological matrices to better characterise the chemical exposome. This review aims to give an insight into the advantages associated with nLC-nESI for metabolomics-based approaches. Initially we detail the source of improved sensitivity prior to reviewing the available approaches to achieving nanoflow rates and nanospray ionisation for metabolomics. The robustness of nLC-nESI platforms was then assessed using the literature available from a metabolomic viewpoint. We also discuss the challenging point of sample preparation which needs to be addressed to fully enjoy the benefits of these nLC-nESI platforms. Finally, we assess metabolomic analysis utilising nano scale platforms and look ahead to the future of metabolomics using these new highly sensitive platforms. PMID- 29501169 TI - Nanostructured hybrid monolith with integrated stirring for the extraction of UV filters from water and urine samples. AB - This article presents a monolithic extraction unit with integrated stirring using carbon nanohorns and methacrylate-based compounds as monomers. The hybrid monolithic material was prepared by thermal polymerization at 70 degrees C for 24 h, and was applied for the extraction of UV-filters from waters and human urine samples. To achieve the integrated stirring unit, the monolith was grown over an ironware. Variables dealing with the polymerization mixture composition and the microextraction procedure were studied in depth. The resulting hybrid monolithic polymer was also characterized by scanning electron microscopy (SEM) and nitrogen intrusion porosimetry. The target analytes were quantified by UPLC DAD, and the limits of detection were between 1 and 10 MUg/L. The precision of the method (inter extraction units) expressed as relative standard deviation ranged from 5.4% and 7.9%. Also, relative recoveries values of the analyte spiked to swimming pool water and urine samples varied in the interval 72-124 and 71 114%, respectively. PMID- 29501170 TI - A new water-soluble polythiophene derivative as a probe for real-time monitoring adenosine 5'-triphosphatase activity in lysosome of living cells. AB - Detection of the adenosine 5'-triphosphatase (ATPase) activity in lysosome of living cells is of great importance for clinical diagnosis of many related diseases, including cancer. In this work, a new water-soluble polythiophene derivative named ZnPT bearing both quaternary ammonium salt groups and dipicolylamine-Zn2+ (DPA-Zn2+) complexes in its side chain, was designed and synthesized for this propose. The probe mainly localized to lysosome with good biocompatibility and membrane penetration. The real-time, continuous, direct, and label-free assays were achieved through a fluorescence "turn-on" mode by taking advantages of the reaction specificity of ATPase with ATP and the high binding selectivity of ZnPT toward ATP substrate over its hydrolysis product (ADP). This well designed strategy should provide a facile and effective way for investigating ATPase-relevant biological processes. PMID- 29501171 TI - Preparation of carbon-functionalized magnetic graphene/mesoporous silica composites for selective extraction of miglitol and voglibose in rat plasma. AB - In this work, magnetic graphene/mesoporous silica composites with carbon functionalized pore-walls (denoted as MG@mSiO2-C composites) were synthesized and applied as restricted access matrix solid phase extraction (RAM-SPE) adsorbents for the determination of miglitol and voglibose in rat plasma by LC-MS/MS. The MG@mSiO2-C composites were synthesized by using the template (Cetyltrimethyl Ammonium Bromide, CTAB) as carbon source with sulfuric acid pretreated. The obtained nano-composites were proven to have many unique properties such as large specific surface area of 277.1 cm2 g-1, uniform mesopores with average pore size of 3.35 nm, and carbon-functionalized pore-walls. Taking advantage of the hydrophilic interaction between carbon and glycans, alpha-glucosidase inhibitors (miglitol and voglibose) could be directly extracted from rat plasma with no need of other pre-treatment procedures. The SPE conditions such as the adsorbent amount, elution solvent type, adsorption time and elution time were optimized. For both miglitol and voglibose, good linearities of 10-2000 ng mL-1 were obtained with determination coefficients (R2) > 0.99. The intra-day and inter-day RSDs were 3.3-6.9% (n = 6) and 6.0-8.0% (n = 6), respectively. The recoveries were in the range of 99.9-100.4% and the sensitivities were as low as 2-2.5 ng mL 1 (LOD). This MG@mSiO2-C composites-based RAM-SPE method offers high extraction efficiency for the determination of alpha-glucosidase inhibitor in plasma. PMID- 29501172 TI - A fully validated liquid chromatography-mass spectrometry method for the quantification of the soluble receptor of advanced glycation end-products (sRAGE) in serum using immunopurification in a 96-well plate format. AB - The study of proteins is central to unraveling (patho)physiological processes and has contributed greatly to our understanding of biological systems. Corresponding studies often employ procedures to enrich proteins from their biological matrix using antibodies or other affinity binders coupled to beads with a large surface area and a correspondingly high binding capacity. Striving for maximal binding capacity may, however, not always be required or desirable, for example for proteins of low abundance. Here we describe a simplified immunoprecipitation in 96-well ELISA format (IPE) approach for fast and easy enrichment of proteins. The applicability of this approach for enriching low-abundant proteins was demonstrated by an IPE-based quantitative workflow using liquid chromatography mass spectrometry (LC-MS) for the soluble Receptor of Advanced Glycation End products (sRAGE), a promising biomarker in chronic obstructive pulmonary disease (COPD). The method was validated according to U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines and enabled accurate quantitation of sRAGE between 0.1 and 10 ng/mL in 50 uL serum. The assay showed substantial correlation with the two most commonly-used sRAGE immunoassays (ELISAs) (R2-values between 0.7 and 0.8). However, the LC-MS method reported 2-4 times higher sRAGE levels compared to the ELISAs, which is largely due to a suboptimal amount of capturing antibody and/or calibration strategy used by the immunoassays. In conclusion, our simplified IPE approach proved to be an efficient strategy for enriching the low-abundant protein sRAGE from serum and may provide an easy to use platform for enriching other (low-abundant) proteins from complex, biological matrices. PMID- 29501173 TI - Peroxidase-like activity of 2',7'-difluorofluorescein and its application for galactose detection. AB - The peroxidase-like activity of 2',7'-difluorofluorescein (DFF), was investigated using 3,3',5,5'-tetramethylbenzidine (TMB) as a chromogenic substrate in the presence of H2O2. DFF could catalyze oxidization of TMB by H2O2 to produce a blue colored oxidation product. Effect of various reaction conditions, such as pH, temperature, H2O2 concentration and reaction time on the catalytic activity of DFF was studied. The peroxidase-like activity of DFF was found to follow Michaelis-Menten kinetics, and its catalysis accorded with ping-pong mechanism. The calculated kinetic parameters (Kcat) of DFF catalysis showed higher peroxidase-like activity than fluorescein and 2',7'-dichlorofluorescein (DCF). According to the radical capture and electron spin resonance (ESR) spectroscopy results, we confirmed that hydroxyl radical (*OH) is the active specie of catalytic process. It is known that the oxidation of galactose by galactose oxidase (GAOx) enzyme leads to the formation of H2O2, the H2O2 released in this reaction was consequently quantified using DFF as peroxides mimics and TMB as the chromogen. Thus, a combination of above two reactions was exploited to establish a method for galactose detection. Under the optimum conditions, the linear range of this method was from 10 MUM to 20 mM with the detection limit down to 3 MUM. Moreover, the developed method was applied to detect galactose in urine samples. Our work will facilitate the utilization of DFF intrinsic peroxidase-like activity in medical diagnostics and biotechnology. PMID- 29501174 TI - Synergistic electron transfer effect-based signal amplification strategy for the ultrasensitive detection of dopamine. AB - The selective and sensitive detection of dopamine (DA) is of great significance for the identification of schizophrenia, Huntington's disease, and Parkinson's disease from the perspective of molecular diagnostics. So far, most of DA fluorescence sensors are based on the electron transfer from the fluorescence nanomaterials to DA-quinone. However, the limited electron transfer ability of the DA-quinone affects the level of detection sensitivity of these sensors. In this work, based on the DA can reduce Ag+ into AgNPs followed by oxidized to DA quinone, we developed a novel silicon nanoparticles-based electron transfer fluorescent sensor for the detection of DA. As electron transfer acceptor, the AgNPs and DA-quinone can quench the fluorescence of silicon nanoparticles effectively through the synergistic electron transfer effect. Compared with traditional fluorescence DA sensors, the proposed synergistic electron transfer based sensor improves the detection sensitivity to a great extent (at least 10 fold improvement). The proposed sensor shows a low detection limit of DA, which is as low as 0.1 nM under the optimal conditions. This sensor has potential applicability for the detection of DA in practical sample. This work has been demonstrated to contribute to a substantial improvement in the sensitivity of the sensors. It also gives new insight into design electron transfer-based sensors. PMID- 29501175 TI - Laser-assisted in situ synthesis of graphene-based magnetic-responsive hybrids for multimodal imaging-guided chemo/photothermal synergistic therapy. AB - Magnetic graphene-based hybrids are being increasing recognized as an effective nanotheranostic agent in biomedicine. Conventional technologies for their synthesis have drawbacks not only from a synthetic standpoint, mainly requiring high temperatures and multi-step processes, but also from a biological perspective, chemical precursors or surfactants involved in the chemical process are toxic to cells. Herein, we report a novel approach for one-step fabricating magnetic graphene hybrid nanocomposites based on laser irradiation of an Fe target in GO-PEG aqueous solution at room temperature without using any other chemical reagent. TEM, XPS, FT-IR, XRD, Mossbauer spectrum and VSM observation reveal that gamma-Fe2O3 nanoparticles were directly grown on the surface of GO PEG with uniform morphology and superior dispersibility. These GO-PEG-gamma-Fe2O3 nanocomposites (labeled as GPF) showed low cytotoxicity in vitro compared to chemically synthesized nanoparticles since the pulsed-laser-ablation-in-liquid (PLAL) process is free of toxic agents. After tail vein injection of the nanotheranostics, the tumor was clearly mapped by T2-weighted magnetic resonance of gamma-Fe2O3, photothermal imaging of graphene and fluorescence imaging of loaded antitumor DOX. Meanwhile the tumor cells both in vitro and in vivo achieved highly superior inhibition by the synergistic chemo/photothermal therapeutic effect which provided an intense heating effect and enhanced DOX release upon 808 nm NIR light exposure. The results revealed that the magnetic graphene-based hybrids prepared by PLAL is competent for future multi-modal imaging assisted tumor targeted chemo/photothermal synergistic therapy of cancer. PMID- 29501176 TI - Determination of lead content in drilling fueled soil using laser induced spectral analysis and its cross validation using ICP/OES method. AB - A detection system based on Laser Induced Breakdown Spectroscopy (LIBS) was designed, optimized, and successfully employed for the estimation of lead (Pb) content in drilling fueled soil (DFS) collected from oil field drilling areas in Pakistan. The concentration of Pb was evaluated by the standard calibration curve method as well as by using an approach based on the integrated intensity of strongest emission of an element of interest. Remarkably, our investigation clearly demonstrated that the concentration of Pb in drilling fueled soil collected at the exact drilling site was greater than the safe permissible limits. Furthermore, the Pb concentration was observed to decline with increasing distance away from the specific drilling point. Analytical determinations were carried out under the assumptions that laser generated plasma was optically thin and in local thermodynamic equilibrium (LTE). In order to improve the sensitivity of our LIBS detection system, various parametric dependence studies were performed. To further validate the precision of our LIBS results, the concentration of Pb present in the acquired samples were also quantified via a standard analytical tool like inductively coupled plasma/optical emission spectroscopy (ICP/OES). Both results were in excellent agreement, implying remarkable reliability for the LIBS data. Furthermore, the Limit of detection (LOD) of our LIBS system for Pb was estimated to be 125.14 mg L-1. PMID- 29501177 TI - A green separation strategy for neodymium (III) from cobalt (II) and nickel (II) using an ionic liquid-based aqueous two-phase system. AB - It is significant to develop sustainable strategies for the selective separation of rare earth from transition metals from fundamental and practical viewpoint. In this work, an environmentally friendly solvent extraction approach has been developed to selectively separate neodymium (III) from cobalt (II) and nickel (II) by using an ionic liquid-based aqueous two phase system (IL-ATPS). For this purpose, a hydrophilic ionic liquid (IL) tetrabutylphosphonate nitrate ([P4444][NO3]) was prepared and used for the formation of an ATPS with NaNO3. Binodal curves of the ATPSs have been determined for the design of extraction process. The extraction parameters such as contact time, aqueous phase pH, content of phase-formation components of NaNO3 and the ionic liquid have been investigated systematically. It is shown that under optimal conditions, the extraction efficiency of neodymium (III) is as high as 99.7%, and neodymium (III) can be selectively separated from cobalt (II) and nickel (II) with a separation factor of 103. After extraction, neodymium (III) can be stripped from the IL-rich phase by using dilute aqueous sodium oxalate, and the ILs can be quantitatively recovered and reused in the next extraction process. Since [P4444][NO3] works as one of the components of the ATPS and the extractant for the neodymium, no organic diluent, extra etractant and fluorinated ILs are used in the separation process. Thus, the strategy described here shows potential in green separation of neodymium from cobalt and nickel by using simple IL-based aqueous two-phase system. PMID- 29501178 TI - Peptide identifications and false discovery rates using different mass spectrometry platforms. AB - Characterization of endogenous neuropeptides produced from post-translational proteolytic processing of precursor proteins is a demanding task. A variety of complex prohormone processing steps generate molecular diversity from neuropeptide prohormones, making in silico neuropeptide discovery difficult. In addition, the wide range of endogenous peptide concentrations as well as significant peptide complexity further challenge the structural characterization of neuropeptides. Liquid chromatography-mass spectrometry (MS), performed in conjunction with bioinformatics, allows for high-throughput characterization of peptides. Mass analyzers and molecular dissociation techniques render specific characteristics to the acquired data and thus, influence the analysis of the MS data using bioinformatic algorithms for follow-up peptide identification. Here we evaluated the efficacy of several distinct peptidomic workflows using two mass spectrometers, the Thermo Orbitrap Fusion Tribrid and Bruker Impact HD UHR-QqTOF, for confident peptide discovery and characterization. We compared the results in several categories, including the numbers of identified peptides, full-length mature neuropeptides among all identifications, and precursor proteins mapped by the identified peptides. We also characterized the peptide false discovery rate (FDR) based on the occurrence of amidation, a known post-translational modification (PTM) that has been shown to require the presence of a C-terminal glycine. Thus, amidation events without a preceding glycine were considered false positive amidation assignments. We compared the FDR calculated by the search engine used here to the minimum FDR estimated via false amidation assignments. The search engine severely underestimated the rate of false PTM assignments among the identified peptides, regardless of the specific MS platform used. PMID- 29501179 TI - A small molecular pH-dependent fluorescent probe for cancer cell imaging in living cell. AB - A novel pH-dependent two-photon fluorescent molecular probe ABMP has been prepared based on the fluorophore of 2, 4, 6-trisubstituted pyridine. The probe has an absorption wavelength at 354 nm and corresponding emission wavelength at 475 nm with the working pH range from 2.20 to 7.00, especially owning a good liner response from pH = 2.40 to pH = 4.00. ABMP also has excellent reversibility, photostability and selectivity which promotes its ability in analytical application. The probe can be excited with a two-photon fluorescence microscopy and the fluorescence cell imaging indicated that the probe can distinguish Hela cancer cells out of normal cells with a two-photon fluorescence microscopy which suggested its potential application in tumor cell detection. PMID- 29501180 TI - Electrochemically enhanced antibody immobilization on polydopamine thin film for sensitive surface plasmon resonance immunoassay. AB - For sensitive immunoassay, it is essentially important to immobilize antibody on a surface with high density and full retention of their recognition activity. Bio inspired polydopamine (PDA) thin film has been widely utilized as a reactive coating to immobilize antibody on various surfaces. We herein report that the antibody immobilization capacity of PDA thin film is electrochemically enhanced by applying an oxidative potential to convert the surface catechol group to reactive quinone group. Quantitative surface plasmon resonance (SPR) investigation unveils that upon proper electrochemical oxidization, the antibody loading capacity of PDA film is significantly improved (up to 27%) and is very close to the theoretically maximal capacity of a planar surface if concentrated antibody solution is used. Using prostate-specific antigen (PSA) as a model target, it is further demonstrated that the SPR immunoassay sensitivity is greatly enhanced due to the improved antibody immobilization. This work offers an efficient strategy to enhance the reactivity of PDA film towards nucleophiles, and may also facilitate its immunoassay application among others. PMID- 29501181 TI - High oxidase-mimic activity of Fe nanoparticles embedded in an N-rich porous carbon and their application for sensing of dopamine. AB - The N-doped porous carbon (NC) has been regarded as one of the promising support materials for nanoparticles (NPs) catalyst due to its inherent virtues such as porosity, large surface areas, and heteroatom incorporation. In this work, Fe/NC 800 hybrid was facilely prepared by uniform dispersion of in situ formed FeNPs onto NC-800 from carbonization of ZIF-8 at 800 degrees C for the first time. The optimized Fe/NC-800 catalyst was characterized by TEM, XPS and XRD. Compared with sole FeNPs and NC-800, the Fe/NC-800 catalyst exhibited an enhanced oxidase-like activity that could oxidize the colorless 3,3',5,5'-tetramethylbenzidine (TMB) to the heavy blue without extra oxidants such as H2O2. The possible reason for the enhanced oxidase-like activity of the Fe/NC-800 was discussed on the basis of the experiments of radical scavengers, indicating the importance of superoxide (O2*-) and singlet (1O2) in colorimetric reaction between TMB and Fe/NC-800 hybrid. Furthermore, the oxidase-like activity of Fe/NC-800 was significantly inhibited by dopamine (DA), leading to blue color fading. On this basis, a sensitive and selective colorimetric sensor was fabricated for the quantitative analysis of DA with a linear range of 0.01-40 MUM and a low detection limit of 10 nM. The proposed colorimetric method was successfully applied to determine DA in human serum and injection samples, suggesting a promising application in biological analysis. PMID- 29501182 TI - Preparation of ionic liquid modified magnetic metal-organic frameworks composites for the solid-phase extraction of alpha-chymotrypsin. AB - A novel magnetic solid-phase extraction (MSPE) method based on 1-hexyl-3-methyl imidazolium chloride ionic liquid (IL) modified magnetic Fe3O4 nanoparticles, hydroxylated multiwall carbon nanotubes (MWCNTs-OH) and zeolitic imidazolate frameworks (ZIFs) nanocomposites (Fe3O4-MWCNTs-OH@ZIF-67@IL) were proposed and applied to extract alpha-chymotrypsin. The magnetic materials were synthesized successfully and characterized by X-ray diffraction (XRD), transmission electron microscope (TEM), thermal gravimetric analysis (TGA), fourier transform infrared spectrometry (FT-IR), vibrating sample magnetometer (VSM) and zeta potentials. Subsequently, the UV-vis spectrophotometer at about 280 nm was utilized to quantitatively analyze the alpha-chymotrypsin concentration in the supernatant. Furthermore, single factor experiments revealed that the extraction capacity was influenced by initial alpha-chymotrypsin concentration, ionic strength, extraction time, extraction temperature and pH value. The extraction capacity could reach up to about 635 mg g-1 under the optimized conditions, absolutely higher than that of extraction for Ovalbumin (OVA), Bovine serum albumin (BSA) and Bovine hemoglobin (BHb). In addition, the regeneration studies showed Fe3O4 MWCNTs-OH@ZIF-67@IL particles could be reused several times and kept a high extraction capacity. Besides, the study of enzymatic activity also indicated that the activity of the extracted alpha-chymotrypsin was well maintained 93% of initial activity. What's more, the proposed method was successfully applied to extract alpha-chymotrypsin in porcine pancreas crude extract with satisfactory results. All of above conclusions highlight the great potential of the proposed Fe3O4-MWCNTs-OH@ZIF-67@IL-MSPE method in the analysis of biomolecules. PMID- 29501183 TI - A multifunctional molecularly imprinted polymer-based biosensor for direct detection of doxycycline in food samples. AB - In this study, we developed a new type of multifunctional molecularly imprinted polymer (MIP) composite as an all-in-one biosensor for the low-cost, rapid and sensitive detection of doxycycline in pig plasma. The MIP composite consisted of a magnetic core for ease of manipulation, and a shell of fluorescent MIPs for selective recognition of doxycycline. By simply incorporating a small amount of fluorescent monomer (fluorescein-O-acrylate), the fluorescent MIP layer was successfully grafted onto the magnetic core via a surface imprinting technique. The resultant MIP composites showed significant doxycycline-dependent fluorescence quenching in an aqueous environment. Good linearity ranging from 0.2 to 6 uM was achieved, and the limit of detection was determined to be 117 nM. The biosensor also showed good selectivity towards doxycycline when compared to other common antibiotic residues. The multifunctional MIP composites were used to directly extract doxycycline from spiked pig plasma samples and quantify the antibiotics based on the quenched fluorescence signals. Recoveries of doxycycline were found in the range of 88-107%. PMID- 29501184 TI - Simultaneous accurate quantification of HO-1, CD39, and CD73 in human calcified aortic valves using multiple enzyme digestion - filter aided sample pretreatment (MED-FASP) method and targeted proteomics. AB - Several proteins such as membrane-associated ectonucleotidases: ecto-5' nucleotidase (E5NT/CD73) and ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1/CD39), and intracellular heme oxygenase-1 (HO-1) may contribute to protection from inflammation-related diseases such as calcific aortic valve stenosis (CAS). Accurate quantification of these proteins could contribute to better understanding of the disease mechanisms and identification of biomarkers. This report presents development and validation of quantification method for E5NT/CD73, ENTPD1/CD39 and HO-1. The multiplexed targeted proteomic assay involved antibody-free, multiple-enzyme digestion, filter-assisted sample preparation (MED-FASP) strategy and a nanoflow liquid chromatography/mass spectrometry under multiple reaction monitoring mode (LC-MRM/MS). The method developed presented high sensitivity (LLOQ of 5 pg/mL for each of the analytes) and accuracy that ranged from 92.0% to 107.0%, and was successfully applied for the absolute quantification of HO-1, CD39 and CD73 proteins in homogenates of human calcified and non-calcified valves. The absolute CD39 and CD73 concentrations were lower in calcified aortic valves (as compared to non-stenotic ones) and were found to be: 1.16 +/- 0.39 vs. 3.15 +/- 0.37 pmol/mg protein and 1.94 +/- 0.21 vs. 2.39 +/- 0.39 pmol/mg protein, respectively, while the quantity of HO-1 was elevated in calcified valves (10.72 +/- 1.18 vs. 4.28 +/- 0.42 amol/mg protein). These results were consistent but more reproducible as compared to immunoassays. In conclusion, multiplexed quantification of HO-1, CD39 and CD73 proteins by LC-MRM/MS works well in challenging human tissues such as aortic valves. This analysis confirmed the relevance of these proteins in pathogenesis of CAS and could be extended to other biomedical investigations. PMID- 29501185 TI - Preparation of a low bleeding polar stationary phase for hydrophilic interaction liquid chromatography. AB - A common drawback of silica-based polar stationary phase is obvious bleeding, probably resulting from silica dissolution in water attracted onto silica gel. Recently we have reported a polyvinyl alcohol (PVA) encapsulated silica gel stationary phase for hydrophilic interaction liquid chromatography (HILIC), which demonstrated good chromatographic performance. Although PVA coating outside could shield SiO2 inside from erosion by aqueous solution to a certain degree, obvious bleeding of such phase was still observed. To eliminate or reduce the bleeding level of the phase, fabricating multi-layers of PVA coating crosslinked with glutaraldehyde onto silica gel is performed (PVA-GA-Sil). ~20-fold decrease of the bleeding for PVA-GA-Sil can be achieved relative to bare silica gel, which is much lower than (or comparable to) commercial HILIC phases. PVA-GA-Sil also showed chromatographic performance and demonstrated superiority to commercial columns operated at gradient mode. PMID- 29501186 TI - Effect of the cleaning procedure of Tenax on its reuse in the determination of plasticizers after migration by gas chromatography/mass spectrometry. AB - This paper presents the simultaneous determination of a UV stabilizer (benzophenone (BP)) together with four plasticizers (butylated hydroxytoluene (BHT), diisobutyl phthalate (DiBP), bis(2-ethylhexyl) adipate (DEHA) and diisononyl phthalate (DiNP)) in Tenax by gas chromatography/mass spectrometry and PARAFAC, using DiBP-d4 as internal standard. Regulation (EU) No. 10/2011 establishes Tenax as food simulant E for testing specific migration from plastics into dry foodstuffs. This simulant must be cleaned before its use to eliminate impurities. Tenax is expensive, so its reuse would save costs. A two-way ANOVA was used to study some parameters affecting the cleaning and the extraction of Tenax. The most adequate conditions were chosen taking the values of the coefficient of variation and the average recovery rates of spiked Tenax samples into account. A study to determine if some analytes remain in Tenax when it is reused and the effect that the cleaning procedure may have in the adsorption capability of Tenax was proposed. This study led to the conclusion that Tenax could not be reused in this multiresidue determination. All the analytes were unequivocally identified in all the stages of this work and trueness was verified at a 95% confidence level in all cases. A calibration based on PARAFAC provided the following values of capability of detection (CCbeta): 2.28 ug L-1 for BHT, 10.57 ug L-1 for BP, 7.87 ug L-1 for DiBP, 3.04 ug L-1 for DEHA and 124.8 ug L-1 for DiNP, with the probabilities of false positive and false negative fixed at 0.05. The migration of the analytes from a printed paper sample into Tenax was also studied. The presence of BHT in the food simulant was confirmed and the amount released of this analyte from the paper was 2.56 MUg L-1. PMID- 29501187 TI - Enhancement effect of p-iodophenol on gold nanoparticle-catalyzed chemiluminescence and its applications in detection of thiols and guanidine. AB - In the present study, the effects of nine compounds on the luminol-O2 chemiluminescence (CL) reaction catalyzed by gold nanoparticles (Au NPs) were investigated. p-Iodophenol (PIP), known as a traditional enhancer in horseradish peroxidase (HRP)-catalyzed luminol-H2O2 CL reaction, exhibited the highest enhancement effect on the luminol-O2-Au NPs CL reaction. The addition of PIP at a final concentration of 1.25 mM to luminol-O2-Au NPs CL system enhanced the CL signal almost 30-fold. Interestingly, the enhanced CL reaction exhibited a slow and intense CL signal which is different from the CL profile of luminol-H2O2-Au NPs CL system reported in previously. The experimental conditions of the PIP enhanced luminol-O2-Au NPs CL system were investigated systematically in the present study. And the mechanism studies showed that superoxide anion (O2*-) and singlet oxygen (1O2) generated from dissolved oxygen played an important role during the CL reaction. Furthermore, the effects of some organic compounds on the enhanced CL system were investigated. The results showed that compounds containing -SH and guanidine group can inhibit the signal of the enhanced CL reaction indicating the applicability of the proposed CL reaction for the detection of such compounds. PMID- 29501188 TI - CoS2-decorated ionic liquid-functionalized graphene as a novel hydrazine electrochemical sensor. AB - Cobalt disulfide-decorated ionic liquid-functionalized graphene nanocomposites were prepared herein and characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), and X-ray photoelectron spectroscopy (XPS). The as-prepared nanocomposites were subsequently used to build a modified glassy carbon electrode serving as a hydrazine (N2H4) electrochemical sensor. The electrocatalytic performance of the prepared sensor towards the N2H4 oxidation reaction was evaluated by cyclic voltammetry (CV) and amperometric methods. A linear dependence was found between the oxidation peak current and the concentration of N2H4. Thus, linear calibration plots were obtained over wide linear ranges of 5-100 MUM (R2 = 0.9898) and 100-400 MUM (R2 = 0.9852), with a relatively low detection limit of 0.39 MUM (S/N = 3). The prepared sensor exhibited good electrocatalytic performance (i.e., sensitivity, reproducibility, and selectivity) towards the detection of N2H4. The sensor was successfully used for the practical determination of N2H4 in lake water samples with satisfactory recoveries. PMID- 29501189 TI - Analysis of bacterial FAMEs using gas chromatography - vacuum ultraviolet spectroscopy for the identification and discrimination of bacteria. AB - The identification of microorganisms is very important in different fields and alternative methods are necessary for a rapid and simple identification. The use of fatty acids for bacterial identification is gaining attention as phenotypic characteristics are reflective of the genotype and are more easily analyzed. In this work, gas chromatography-vacuum ultraviolet spectroscopy (GC-VUV) was used to determine bacteria fatty acid methyl esters (FAMEs), to identify and discriminate different environmental bacteria based on their fatty acid profile. Microorganisms were grown in agar and their fatty acids extracted, saponified, and esterified before analysis. Unique FAME profiles were obtained for each microorganism mainly composed of branched, cyclopropane, hydroxy, saturated, and unsaturated fatty acid methyl esters. S. maltophilia showed a higher diversity of fatty acids while Bacillus species showed higher complexity in terms of branched chain FAMEs, with several iso and anteiso forms. 12 different bacteria genera and 15 species were successfully differentiated based on their fatty acid profiles after performing PCA and cluster analysis. Some difficult to differentiate species, such as Bacillus sp., which are genetically very similar, were differentiated with the developed method. PMID- 29501190 TI - Study on the photocatalytic reaction kinetics in a TiO2 nanoparticles coated microreactor integrated microfluidics device. AB - For study of the photocatalytic reaction kinetics in a confined microsystem, a photocatalysis microreactor integrated on a microfluidic device has been fabricated using an on-line UV/vis detector. The performance of the photocatalysis microreactor is evaluated by the photocatalytic degradation of Rhodamine B chosen as model target by using commercial titanium dioxide (Degussa P25, TiO2) nanoparticles as a photocatalyst. Results show that the photocatalytic reaction occurs via the Langmuir-Hinshelwood mechanism and the photocatalysis kinetics in the confined microsystem (r = 0.359 min-1) is about 10 times larger than that in macrosystem (r = 0.033 min-1). In addition, the photocatalysis activity of the immobilized TiO2 nanoparticles in the microreactor exhibits good stability under flowing conditions. The present microchip device offers an interesting platform for screening of photocatalysts and exploration of photocatalysis mechanisms and kinetics. PMID- 29501191 TI - Comparison of backing materials of screen printed electrochemical sensors for direct determination of the sub-nanomolar concentration of lead in seawater. AB - An anodic stripping voltammetric method is reported in this study for the determination of sub-nanomolar Pb concentration using disposable sensors, each consisting of three (counter, working and reference) screen-printed electrodes. Sensor performance was optimized for the determination of Pb through several surface modifications, by using single-walled carbon nanotubes, electro-reduced graphene oxide and gold nanoparticles. A scanning electron microscopy study of the deposition of electrogenerated gold nanoparticles of various sizes on the working electrode surface showed that spherical nanoparticles of around 100 nm provided the best results. The modification of working electrodes with graphene and gold nanoparticles permitted the determination of Pb2+ in seawater (Detection Limit: 3.21.10-10 M) without modifying the pH of the sample. The electrode systems were printed on both rigid and textile backing materials, to observe the influence of those materials on the final performance of the sensor. PMID- 29501192 TI - A novel cerium oxide nanoparticles-based colorimetric sensor using tetramethyl benzidine reagent for antioxidant activity assay. AB - Antioxidant activity (AOA) assays using nanotechnology are recently developed utilizing nanoparticles of transition metal oxides, especially nanoceria that can switch between trivalent and tetravalent oxidation states of cerium. Cerium oxide nanoparticles (CeO-NPs) may act as both an oxidant and an antioxidant, depending on the preparation method and particle size. A novel colorimetric sensor for AOA assay is proposed with the use of poly(acrylic acid) sodium salt (PAANa)-coated CeO-NPs. PAANa-coated CeO-NPs oxidized tetramethyl benzidine (TMB), a peroxidase substrate, in a slightly acidic solution at pH 4.0 to a blue charge-transfer complex. Antioxidants decreased the color intensity of the nanoceria suspension, and were indirectly determined by absorbance difference. Detection limits, linearity, additivity and precision were calculated, e.g., quercetin quantification with the proposed assay showed a detection limit of 8.25 * 10-9 mol L-1. The trolox equivalent antioxidant capacities of hydrophilic and lipophilic antioxidants were compatible with those of conventional antioxidant assays. Potential interferents such as glucose, citric acid, mannitol, sorbitol and benzoic acid did not adversely affect AOA determination. The developed sensor is more sensitive and selective than similar colorimetric sensors relying on the intrinsic color change of nanoceria. The measurement wavelength is sufficiently red-shifted, preventing possible interferences from plant pigments. PMID- 29501193 TI - A general strategy to prepare SERS active filter membranes for extraction and detection of pesticides in water. AB - An important feature in the fabrication of surface-enhanced Raman scattering (SERS) platforms is, together with the high efficiency, to allow the rapid collection and analysis of a vestigial analyte. Conventional substrates based on rigid solid materials or metal hydrosols are not suitable for sample extraction, limiting their application in areas such as water quality monitoring. Herein, we have developed a strategy to fabricate SERS active substrates (Ag/LCP) based on liquid-crystal polymer (LCP) textile fibers decorated with Ag nanoparticles (NPs). Two distinct methods for substrate preparation envisaging the SERS detection of the pesticide thiram have been explored in this research. In a first stage, we have investigated the usefulness of both approaches using ethanolic solutions of the pesticide thiram, and after real samples spiked with thiram were used to explore the analysis in real environment. The SERS analysis of thiram dissolved in Aveiro Estuary water and in fruit juices have provided enhancement factors of 1.67 * 107 and 3.86 * 105, respectively, using the Ag/LCP composites. Noteworthy, in the latter case, the detection limit (0.024 ppm) achieved is lower than the maximal residue limit (MRL) of 5 ppm in fruit, as prescribed by European regulations (EU) 2016/1. Moreover, the selectivity of the SERS substrates for different pesticides was also evaluated, analyzing distinct pesticides such as paraquat and sodium diethyldithiocarbamate. SERS active Ag/LCP/PA filter membranes were also prepared using Ag/LCP composites supported by a polyamide (PA) filter, which can be an easy alternative to prepare simple, highly efficient and low-cost SERS active filter membranes for water analysis. PMID- 29501194 TI - Environmentally friendly microwave-assisted sequential extraction method followed by ICP-OES and ion-chromatographic analysis for rapid determination of sulphur forms in coal samples. AB - A rapid three-step sequential extraction method was developed under microwave radiation followed by inductively coupled plasma-optical emission spectroscopic (ICP-OES) and ion-chromatographic (IC) analysis for the determination of sulphur forms in coal samples. The experimental conditions of the proposed microwave assisted sequential extraction (MW-ASE) procedure were optimized by using multivariate mathematical tools. Pareto charts generated from 23 full factorial design showed that, extraction time has insignificant effect on the extraction of sulphur species, therefore, all the sequential extraction steps were performed for 5 min. The optimum values according to the central composite designs and counter plots of the response surface methodology were 200 degrees C (microwave temperature) and 0.1 g (coal amount) for all the investigated extracting reagents (H2O, HCl and HNO3). When the optimum conditions of the proposed MW-ASE procedure were applied in coal CRMs, SARM 18 showed more organic sulphur (72%) and the other two coal CRMs (SARMs 19 and 20) were dominated by sulphide sulphur species (52-58%). The sum of the sulphur forms from the sequential extraction steps have shown consistent agreement (95-96%) with certified total sulphur values on the coal CRM certificates. This correlation, in addition to the good precision (1.7%) achieved by the proposed procedure, suggests that the sequential extraction method is reliable, accurate and reproducible. To safe-guard the destruction of pyritic and organic sulphur forms in extraction step 1, water was used instead of HCl. Additionally, the notorious acidic mixture (HCl/HNO3/HF) was replaced by greener reagent (H2O2) in the last extraction step. Therefore, the proposed MW ASE method can be applied in routine laboratories for the determination of sulphur forms in coal and coal related matrices. PMID- 29501195 TI - SUPRAS extraction approach for matrix-independent determination of amphetamine type stimulants by LC-MS/MS. AB - Monitoring of amphetamine-type stimulant (ATS) confronts clinical labs with a high number of samples involving a variety of biological matrices. Liquid chromatography-tandem mass spectrometry (LC-MS/MS), routinely used for confirmation of ATS abuse, requires of laborious and matrix-dependent sample treatment methods, this increasing analysis time and cost. In this work, a universal and single-step sample treatment, based on supramolecular solvents (SUPRAS), was proposed for simplifying ATS confirmation in seven biological matrices. The SUPRAS was synthesized in situ in the sample (900 uL of basified oral fluid, urine, serum, sweat or breast milk or 50 mg of digested hair or fingernails) by the addition of hexanol (200 uL) and tetrahydrofuran (900 uL). The mixture was vortex-shaken and centrifuged and the SUPRAS extract was subsequently analyzed by positive ion mode electrospray LC-MS/MS. The method was fully validated for amphetamine (AMP), methamphetamine (MA), 3,4 methylenedioxyamphetamine (MDA), N-ethyl-3,4-methylenedioxyamphetamine (MDEA) and N-methyl-3,4-methylenedioxyamphetamine (MDMA). Maximum ion suppression or enhancement was 9% and 7%, respectively, and extraction recoveries (87-111%) and within- (0.1-6.7%) and between-day (0.3-9.7%) CVs were all within required values. The lower limits of quantification (LLOQ) for biological fluids (5 ng/mL), and hair and fingernails (100 ng/g) were all well below the cut-offs established by worldwide organizations. Confirmation of MDA was carried out in five urine samples that tested positive for ATS by immunoassay. The SUPRAS-LC MS/MS methodology succeeded in developing a hitherto unexplored and universal tool for quantifying ATS in a comprehensive pool of biological matrices of interest in forensic and clinical samples. PMID- 29501196 TI - Mass spectrometry investigation of DNA adduct formation from bisphenol A quinone metabolite and MCF-7 cell DNA. AB - Bisphenol A (BPA) is a widely used additive in the plastic industry and has been reported to have genotoxicity. A hypothesis that BPA may enhance breast cancer risk through the formation of its metabolic intermediate or DNA adduct has been proposed. In this study, breast cancer cell MCF-7 was cultured and the cellular DNA was extracted from the cells. The adducts of bisphenol A 3,4-quinone (BPAQ) with 2'-deoxyguanosine (dG), calf thymus DNA and MCF-7 cell DNA were investigated. DNA adducts were characterized by using electrospray ionization Orbitrap high-resolution mass spectrometry and tandem mass spectrometry. The BPA DNA adducts of BPAQ with dG, calf thymus and MCF-7 cell DNA were identified as 3 hydroxy-bisphenol A-N7-guanine (3-OH-BPA-N7Gua). The MS/MS fragmentation pathway of 3-OH-BPA-N7Gua was proposed based on obtained accurate mass data. BPA quinone metabolites can react with MCF-7 cell DNA in vitro. The findings provide evidence that BPA might covalently bind to DNA in MCF-7 cells mediated by quinone metabolites, which may increase our understanding of health risk associated with BPA exposure. PMID- 29501197 TI - Ammonium hydroxide enhancing electrospray response and boosting sensitivity of bisphenol A and its analogs. AB - As one of the most important analytical techniques for accurate quantification of bisphenol compounds, liquid chromatography coupled to online electrospray ionization (ESI) tandem mass spectrometry exhibits relative weak ESI response in negative mode, which greatly reduces their sensitivity and limits their detection at trace levels, especially in complex samples such as blood. Based on the facilitated deprotonation of bisphenol molecule under alkaline condition, post column injection of ammonium hydroxide (NH3.H2O) to mass spectrometer was explored to enhance the ionization efficiency of BPA and its eight analogs and improve their analytical sensitivity. Parameters effecting response intensity and stability were investigated, including mass concentration and flow rate of NH3.H2O. Under the optimal conditions with the addition of 2% (w/w) of NH3.H2O at 4 MUL min-1, the instrument detection limits for bisphenol compounds were greatly lowered to 0.001-0.04 ng mL-1, which were 2-28.6 times lower than the result obtained without injecting NH3.H2O, except TBBPA (0.03 ng mL-1 in either case). The relative standard deviations (RSDs) for instrument repeatability of BPA and its analogs at three different concentration levels were in a range of 1.2-20%. Furthermore, a decreased matrix effects (90-111%) for bisphenols (except TBBPA) analysis in serum extracts were found compared with the result obtained without NH3.H2O injection (43-111%). The results demonstrated that the improved instrumental method coupled with suitable pretreatment techniques is more feasible to analyze bisphenol compounds in complex bio-samples. PMID- 29501198 TI - Copper nanoclusters as probes for turn-on fluorescence sensing of L-lysine. AB - Herein, a unique protocol based on copper nanoclusters (CuNCs) probe for turn-on fluorescence sensing of L-lysine was developed. The fluorescent CuNCs with ovalbumin as the stabilizer was prepared by a simple, one-step and green method. When 370 nm was used as the excitation wavelength, the resultant CuNCs exhibited a pale blue fluorescence with the maximum emission at 440 nm. Interestingly, existence of L-lysine evoked the obvious fluorescence intensity increase of CuNCs. The detection limit of the proposed method for L-lysine was 5.5 MUM, with a good linear range from 10.0 MUM to 1.0 mM (r2 = 0.999). Moreover, the possible mechanism for enhanced fluorescence intensity of CuNCs by addition of L-lysine was explored and discussed briefly. Further, the as-prepared fluorescent CuNCs was successfully applied in detection of L-lysine in urine. Our results demonstrated that L-lysine could be monitored by the probe, providing new path for construction of CuNCs as fluorescent probes and showing great potential in quantification of L-lysine in real samples. PMID- 29501199 TI - Development of alanine aminotransferase reactor based on polymer@Fe3O4 nanoparticles for enzyme inhibitors screening by chiral ligand exchange capillary electrophoresis. AB - Alanine aminotransferase (ALT) plays significant role in biological and clinical research. In this study, a unique ALT enzyme reactor based on multifunctional polymer@magnetic nanoparticles has been constructed for the first time and the enzymolysis efficiency has been evaluated by chiral ligand exchange capillary electrophoresis technique. Poly(N-acryloxysuccinimide) has been synthesized by reversible addition-fragmentation chain transfer polymerization method and immobilized on the magnetic nanoparticles via the succinimide group in the polymer. Interestingly, the enzyme also could easily react with the succinimide group, which enables of ALT covalent bonding onto the polymer. The enzyme amount immobilized and the immobilization time have been investigated. Comparing with free ALT in solution (Vmax of free enzyme = 0.6 mM min-1), the resultant enzyme reactor has exhibited good reusability and stability, and displayed about five times enhanced enzymolysis efficiency with L-alanine as the substrate (Vmax of enzyme reactor = 3.4 mM min-1). Furthermore, the prepared enzyme reactor has been applied in ALT inhibitors screening. The enzyme reactors based on the multifunctional polymer@magnetic nanoparticles have depicted great potential in anti-liver drugs development, liver diseases study and ALT related biological process inspect. PMID- 29501200 TI - Ultrasensitive hexavalent chromium determination at bismuth film electrode prepared with mediator. AB - A bismuth film electrode prepared in situ with a reversibly deposited mediator (Zn) applied for ultrasensitive determination of Cr(VI) using differential pulse catalytic adsorptive stripping voltammetry is presented. The optimization of experimental conditions such as composition of the supporting electrolyte, potential and time of bismuth film formation as well as analyte accumulation, and DP mode parameters is reported. For 180 s accumulation time, very low limits of detection and quantification of Cr(VI) were obtained, with 5.8 * 10-14 and 1.9 * 10-13 mol L-1, respectively. The relative standard deviation for 5.0 * 10-13 mol L-1 of Cr(VI) was 3.9% (n = 5). Finally, the proposed procedure was applied to determine Cr(VI) in the certified reference materials - NASS-6 (seawater), SLEW-3 (estuarine water) and TMRAIN-04 (rainwater) - as well as in river water samples. Furthermore, the obtained results show that the proposed voltammetric procedure employing the bismuth film electrode prepared with mediator appears to form a very promising tool for the speciation of chromium at ultratrace level. PMID- 29501201 TI - Ionic liquid ultrasound-assisted dispersive liquid-liquid microextraction based on solidification of the aqueous phase for preconcentration of heavy metals ions prior to determination by LC-UV. AB - Ionic liquid ultrasound-assisted dispersive liquid-liquid microextraction based on solidification of the aqueous phase was used for preconcentration of Ni2+, Co2+, Cd2+, Cu2+, Pb2+ in natural water samples prior to liquid chromatography with UV detection. In the proposed method, the ammonium pyrrolidinedithiocarbamate was used as a complexing agent and the phosphonium ionic liquid trihexyl(tetradecyl)phosphonium bis[(2,4,4 trimethyl)pentyl]phosphinate (Cyphos IL 104) was used as an extractant. Ultrasound energy was used to disperse the extractant in the aqueous phase. After microextraction, the ionic liquid and aqueous phases were separated by centrifugation. Then the aqueous phase was frozen and the lighter than water ionic liquid phase containing metal ions complexes with pyrrolidinedithiocarbamate was separated and dissolved in a small volume of methanol prior to injection into the liquid chromatograph. Several parameters including the volume of extractant, the pH of the sample, the concentration of complexing agent, the time of ultrasound energy treatment, the time and speed of centrifugation and the effect of ionic strength were optimized. Under the optimized conditions (10 uL of Cyphos IL 104, pH = 5, 0.3% w/v ammonium pyrrolidinedithiocarbamate, 60 s of ultrasound use, 5 min/5000 rpm (2516*g) of centrifugation, 2.0 mg of NaCl), preconcentration factors were 211, 210, 209, 207 and 211 for Ni2+, Co2+, Cd2+, Cu2+ and Pb2+ respectively. Linearity was observed in the ranges 0.2-75.0 ug L-1 for Pb2+, Cd2+, Co2+ and 0.5-100.0 ug L-1 for Cu2+, Ni2+. The limits of detection were 0.03 ug L-1 for Ni2+, 0.03 ug L-1 for Co2+, 0.03 ug L-1 for Cd2+, 0.02 ug L-1 for Cu2+, 0.02 ug L-1 for Pb2+, respectively. The accuracy of this method was evaluated by preconcentration and determination of Ni2+, Co2+, Cd2+, Cu2+, Pb2+ in certified reference materials (TMRAIN-04 and NIST 1643e) with the recovery values in the range of 97-102%. The presented method has been successfully applied for the determination of analytes in natural water samples (river and lake waters). PMID- 29501202 TI - Determination of UV filters in high ionic strength sample solutions using matrix compatible coatings for solid-phase microextraction. AB - A double-confined polymeric ionic liquid (PIL) sorbent coating was fabricated for the determination of nine ultraviolet (UV) filters in sample solutions containing high salt content by direct immersion solid-phase microextraction (DI-SPME) coupled to high-performance liquid chromatography (HPLC). The IL monomer and crosslinker cations and anions, namely, 1-vinyl-3-decylimidazolium styrenesulfonate ([VImC10][SS]) and 1,12-di(3-vinylbenzylimidazolium) dodecane distyrenesulfonate ([(VBIm)2C12] 2[SS]), were co-polymerized to create a highly stable sorbent coating which allowed for up to 120 direct-immersion extractions in 25% NaCl (w/v) solution without a decrease in its extraction capability. Extraction and desorption parameters such as desorption solvent, agitation rate, extraction time, desorption solvent volume, and desorption time were evaluated and optimized. The analytical performance of the styrenesulfonate anion-based PIL fiber, PIL fiber containing chloride anions, and a commercially available polydimethylsiloxane/divinylbenzene (PDMS/DVB) fiber were compared. Coefficients of determination (R2) for the styrenesulfonate anion-based PIL fiber ranged from 0.995 to 0.999 and the limits of detection (LODs) varied from 0.1 to 5 ug L-1. The developed method was successfully applied in real water samples including tap, pool, and lake water, and acceptable relative recovery values were obtained. The lifetime of the PIL fiber containing chloride anions as well as the PDMS/DVB fiber were considerably shorter than the PIL fiber containing the styrenesulfonate anion, with both fibers showing a notable decrease in reproducibility and significant damage to the sorbent coating surface after 40 and 70 extractions, respectively. The R2 values for the chloride anion containing PIL fiber were at or higher than 0.991 with LODs ranging from 0.5 to 5 ug L-1. For the PDMS/DVB fiber, R2 values ranged from 0.992 to 0.999 and LODs were found to be as low as 0.2 ug L-1 and as high as 5 ug L-1. PMID- 29501203 TI - Development of a capillary zone electrophoresis method to quantify E. colil asparaginase and its acidic variants. AB - A capillary zone electrophoresis (CZE) method with UV detection was developed for the quantification of the E.colil-asparaginase (l-ASNase) and its acidic variants. During the initial method development, a variety of experimental conditions were screened. Subsequently, a Design of Experiments (DoE) was used to optimize the pH and concentration of the selected background electrolyte (BGE) containing both TRIS and boric acid. Optimization was performed taking into account both the separation efficiency of l-ASNase and its acidic variants as well as overall method robustness. A repeatable separation between E.colil-ASNase and its acidic variants was achieved on a bare fused silica capillary in combination with a BGE consisting of both 400 mM TRIS and boric acid. The method was validated for linearity, accuracy, precision, LOD, LOQ and robustness. The recovery for l-ASNase was 97.9-104.4% with a precision RSD of 1.5-3.2%, while the recovery of impurities was 92.1-109.8% with a RSD of 1.7-4.6%. The quantification limit was 1.9% (m/m). Moreover, the CZE-UV method was applied to determine the degradation rate in the presence of ammonium bicarbonate, confirming the suitability of the method. The degraded, partially charged l-ASNase was evaluated for its in-vitro enzymatic activity showing an insignificant different enzyme activity compared to the unmodified sample. PMID- 29501204 TI - Metrological approach to quantitative analysis of clinical samples by LA-ICP-MS: A critical review of recent studies. AB - Analysis of clinical specimens by imaging techniques allows to determine the content and distribution of trace elements on the surface of the examined sample. In order to obtain reliable results, the developed procedure should be based not only on the properly prepared sample and performed calibration. It is also necessary to carry out all phases of the procedure in accordance with the principles of chemical metrology whose main pillars are the use of validated analytical methods, establishing the traceability of the measurement results and the estimation of the uncertainty. This review paper discusses aspects related to sampling, preparation and analysis of clinical samples by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) with emphasis on metrological aspects, i.e. selected validation parameters of the analytical method, the traceability of the measurement result and the uncertainty of the result. This work promotes the introduction of metrology principles for chemical measurement with emphasis to the LA-ICP-MS which is the comparative method that requires studious approach to the development of the analytical procedure in order to acquire reliable quantitative results. PMID- 29501205 TI - Overview of the Biography and Legacy of Professor Athina Markou. PMID- 29501206 TI - Relation of Obesity to New-Onset Atrial Fibrillation and Atrial Flutter in Adults. AB - Prospective cohort studies involving older adults report an association of obesity and new-onset atrial fibrillation and atrial flutter. To assess this relation, we performed a longitudinal cohort study from January 1, 2006 to December 31, 2013, using a national claims database that tracks all inpatient, outpatient, and pharmacy claims data. The primary end point of new-onset atrial fibrillation was compared between obese and nonobese cohorts. We used logistic regression to determine the strength of association between obesity and new-onset atrial fibrillation controlling for age, gender, hypertension, and diabetes. Overall, 67,278 subjects were included in the cohort, divided evenly between those with and without a diagnosis of obesity. Obese subjects were significantly more likely to have hypertension (29.5% vs 14.6%) and diabetes (12.7% vs 5.2%) at study onset. Over 8 years of follow-up, we recorded a new diagnosis of atrial fibrillation in 1,511 (2.2%) subjects. Obesity was strongly associated with a new diagnosis of atrial fibrillation after controlling for age, gender, hypertension, and diabetes (odds ratio 1.4, 95% confidence interval 1.3 to 1.6). In conclusion, this information contributes to the growing evidence supporting the causal relation between obesity and atrial fibrillation, and emphasizes the need of addressing obesity as part of our therapeutic strategy to prevent atrial fibrillation. PMID- 29501207 TI - [Chronic myeloid leukemia in Madagascar]. PMID- 29501208 TI - [Precision medicine: A major step forward in specific situations, a myth in refractory cancers?] AB - In recent years, high-throughput sequencing techniques have been developed for cancerology and many clinical trials are currently structured around biomarkers that can guide specific treatment choices. This approach is characteristic of precision medicine, which is actually a concept initiated several decades ago with, for example, retinoic acid in promyelocytic leukemia. This paper will review the different types of molecular alterations and " -omics " biological analyses, bioinformatics tools, coupled drug/biomarkers already validated, the ethical issues of whole genomic sequencing of an individual as part of an inclusion in a clinical trial and finally the first results of precision medicine trials. The AcSe crizotinib program, supported by the Inca (french Cancer National Institute), is emblematic of a success of this personalized medicine illustrated by 4 points: the discovery of a cohort of patients with lung cancer with a ROS1 rearrangement characteristic of a sensitivity to crizotinib, a rapid availability of this innovation through the implementation of a temporary recommendation for use (ANSM), the obtention of a conditional marketing authorization by the pharmaceutical industry and finally, financial assumption of responsibility by French social security (HAS), despite preliminary and non comparative data. In the case of cancers refractory to standard chemotherapy, and regarding our system of access to drugs illustrated by the PROFILER clinical trial, this approach allows the access to a therapeutic drug targeting specific biomarkers only in 7% of patients included. This does not bode well for efficient treatment and even less for survival. Allowing patients to be included in trials that identify molecular targets by molecular screening, and not being able to propose the drug of interest is a traumatic event for those patients who live in the hope of an immediate future. In refractory disease we must rethink precision medicine in a more humanistic vision for our patients and not only in a dimension of medico-industrial promotion. The implementation of a new multi-drug/multi molecular target program could address this issue. PMID- 29501209 TI - Optimal image guided radiation therapy strategy for organs at risk sparing in radiotherapy of the prostate including pelvic lymph nodes. AB - BACKGROUND AND PURPOSE: Purpose of this study was to quantify the OAR dose for different position correction strategies, and to determine which strategy is most optimal for treating patients on the prostate and pelvic lymph nodes. MATERIALS AND METHODS: For 30 patients, four different treatment plans were made reflecting different correction strategies: online correction on bony anatomy; offline correction on bony anatomy; online correction on the prostate fiducials; using 1 cm margins around both CTVs. The dose to the PTVs and OARs was quantified and a pairwise statistical analysis was performed. RESULTS: No statistically significant differences were observed in the dose to the PTVs, ensuring that any OAR sparing is not caused by differences in PTV coverage. Dose to the rectum and anal canal was lowest when applying an online correction on prostate fiducials, although the total PTV volume was higher. Dose to the small bowel bag and femoral heads was slightly higher compared to online correction on bony structures, but well within clinically acceptable limits. CONCLUSION: Although the total PTV volume is higher when applying an online correction on the prostate, this strategy leads to the most optimal sparing of relevant OARs, at the cost of a slightly higher dose to the femoral heads and small bowel bag. PMID- 29501210 TI - A Randomized Trial of a Short 34-Gauge Needle for Intravitreal Injections. PMID- 29501211 TI - Addressing the Opioid Crisis: The Importance of Choosing Translational Endpoints in Analgesic Drug Discovery. AB - The opioid crisis has stimulated renewed interest in analgesic drug development. This effort will involve preclinical-to-clinical translational research and will benefit from a focus on endpoints that are both clinically relevant and shared across laboratory animals and humans. Measures of pain-related functional impairment and behavioral depression could serve this purpose. PMID- 29501213 TI - [Pulmonary veno-occlusive disease]. AB - Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension (PH) characterized by preferential remodelling of pulmonary venules and angioproliferation. PVOD term includes idiopathic, heritable (biallelic mutations of EIF2AK4 gene), drugs and toxins induced (alkylating agents, organic solvents) and connectivite-associated forms (especially systemic-sclerosis associated form). PVOD and pulmonary arterial hypertension (PAH) share a similar clinical presentation. Lung biopsy is contraindicated in PVOD due to high risk of life threatening bleeding. A noninvasive diagnostic approach, including oxygen parameters, low diffusing capacity for carbon monoxide and characteristic signs on high-resolution computed tomography of the chest, is used to support a diagnosis of PVOD. PVOD prognosis is worse than other forms of PAH. There is no evidence-based medical therapy for PVOD and life-threatening pulmonary edema may occur following PAH targeted therapy in PVOD. Lung transplantation remains the preferred definitive therapy for eligible patients. PMID- 29501212 TI - Immunotherapy as a treatment for biliary tract cancers: A review of approaches with an eye to the future. AB - Biliary tract cancers (BTC) are aggressive malignancies associated with resistance to chemotherapy and poor prognostic rates. Therefore, novel treatment approaches are in need. Immunotherapy represents a promising breakthrough that uses a patient's immune system to target a tumor. This treatment approach has shown immense progress with positive results for selected cancers such as melanoma and nonsmall cell lung cancer. Initial preclinical data and preliminary clinical studies suggest encouraging mechanistic effects for immunotherapy in BTC offering the hope for an expanding therapeutic role for this disease. These approaches include targeted tumor antigen therapy via peptide and dendritic cell based vaccines, allogenic cell adoptive immunotherapy, and the use of inhibitory agents targeting the immune checkpoint receptor pathway and multiple components of the tumor microenvironment. At this time demonstrating efficacy in larger clinical trials remains imperative. A multitude of ongoing trials aim to successfully translate mechanistic effects into antitumor efficacy and ultimately aim to incorporate immunotherapy into the routine management of BTC. With further research efforts, the optimization of dosing and therapeutic regimens, the identification of novel tumor antigens and a better understanding of alternative checkpoint pathway receptor expression may provide additional targets for rational combinatorial therapies which enhance the effects of immunotherapy and may offer hope for further advancing treatment options. Ultimately, the challenge remains to prospectively identify the subsets of patients with BTC who may respond to immunotherapy, and devising alternative strategies to sensitize those that do not with the hopes of improving outcomes for all with this deadly disease. PMID- 29501214 TI - Clinical characteristics and one-year mortality according to admission renal function in patients with a first acute heart failure hospitalization. AB - INTRODUCTION AND OBJECTIVES: Chronic kidney disease is related to poor outcomes in patients with heart failure (HF). Few studies have assessed whether renal function influences one-year mortality risk in patients admitted for the first time for acute HF. METHODS: We reviewed the medical records of all patients aged >50 years admitted within a two-year period for a first episode of decompensated HF. The sample was divided according to the patients' estimated glomerular filtration rate (eGFR) on admission into three groups (eGFR >60, 30-60 and <30 ml/min/1.73 m2). Index admission and one-year all-cause mortality rates were compared between groups using Cox regression analysis. RESULTS: A total of 985 patients were included in the study, mean age 78.4+/-9 years, and with mean admission eGFR of 60.5+/-26 ml/min/1.73 m2. Of these, 516 (52.3%) patients had eGFR <60 ml/min/1.73 m2. One-year all-cause mortality was 25.4%, with a significant association between worse eGFR category and mortality (p<0.0001). Cox regression analysis assessing eGFR as a categorical variable confirmed this association (HR 1.378; p=0.030), together with older age (HR 1.066; p<0.001), previous diagnosis of hypertension (HR 0.527; p<0.001), and both lower systolic blood pressure (HR 0.993; p=0.009) and higher serum potassium on admission (HR 1.471; p <0.001). CONCLUSIONS: Renal impairment is common in HF patients, even at the time of first admission. In this group of HF patients the presence of renal impairment was associated with higher mid-term (one-year) mortality risk. PMID- 29501215 TI - The learning effects of different presentations of worked examples on medical students' breaking-bad-news skills: A randomized and blinded field trial. AB - OBJECTIVES: Effective instructional approaches are needed to enable undergraduates to optimally prepare for the limited training time they receive with simulated patients (SPs). This study examines the learning effects of different presentation formats of a worked example on student SP communication. METHODS: Sixty-seven fourth-year medical students attending a mandatory communication course participated in this randomized field trial. Prior to the course, they worked through an e-learning module that introduced the SPIKES protocol for delivering bad news to patients. In this module, a single worked example was presented to one group of students in a text version, to a second group in a video version, and to a third group in a video version enriched with text hints denoting the SPIKES steps. RESULTS: The video-with-hints group broke bad news to SPs significantly more appropriately than either of the other groups. Although no further condition-related effects were revealed, students who learned from the text version most frequently (although non-significantly) ignored unpleasant emotions (standardised emotional cues and concerns) expressed by the SPs. CONCLUSIONS: The learning effect was strongest when the video-based worked example was accompanied by hints. PRACTICE IMPLICATIONS: Video-related learning approaches that embed attention-guiding hints can effectively prepare undergraduates for SP encounters. PMID- 29501216 TI - Arthroscopic Management of SLAP Lesions With Concomitant Spinoglenoid Notch Ganglion Cysts: A Systematic Review Comparing Repair Alone to Repair With Decompression. AB - PURPOSE: To determine if cyst management is necessary in the setting of SLAP lesions with concomitant paralabral ganglion cysts. METHODS: We performed a systematic review according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, including all studies that met inclusion criteria from January 1975 to July 2015. We included patients with a SLAP II-VII lesion and a concomitant paralabral ganglion cyst who underwent arthroscopic labral repair with or without cyst decompression. Patients with follow-up of less than 3 months, a SLAP I lesion, or who underwent concomitant cuff repair were excluded. The Methodological Index for Non-randomized Studies (MINORS) scoring system was used to quantify the potential bias in each study. Outcome measures reported were provided in a table format and a subjective analysis was performed. RESULTS: Nineteen studies were included yielding a total of 160 patients: 66 patients treated with repair alone [R] and 94 patients with additional cyst decompression or excision [R+D]. The VAS, Rowe, and Constant scores were excellent and similar in both groups. The mean VAS was 0.6 in [R] and ranged between 0 and 2 in [R+D] (0.5, 0, 2, 0.2). The mean Rowe scores were 94 and 98 in [R] and 95 in [R+D]. The mean Constant scores were 97 in [R] and ranged between 87 and 98 in [R+D] (98, 87, 92, 94). In total, 5 of 90 patients were unable to return to work and 2 of 45 were unable to return to sport. All 15 patients who had follow-up electromyographies displayed resolution, and in the 115 patients with follow-up MRIs, 12 did not have complete resolution of the cyst. CONCLUSIONS: Despite the lack of high-quality evidence, the studies subjectively analyzed in this review suggest that both groups have excellent results. The results do not show any advantages from performing decompression. LEVEL OF EVIDENCE: Level IV, systematic review of Level II and Level IV studies. PMID- 29501217 TI - Response to Letter to the Editor on "Interobserver and Intraobserver Reliability of Computed Tomography-Based Three-Dimensional Preoperative Planning for Primary Total Knee Arthroplasty". PMID- 29501218 TI - Letter to the Editor on "Interobserver and Intraobserver Reliability of Computed Tomography-Based Three-Dimensional Preoperative Planning for Primary Total Knee Arthroplasty". PMID- 29501219 TI - The Association of Prehospital Intravenous Fluids and Mortality in Patients with Penetrating Trauma. AB - BACKGROUND: The optimal approach to prehospital care of trauma patients is controversial, and thought to require balancing advanced field interventions with rapid transport to definitive care. OBJECTIVE: We sought principally to examine any association between the amount of prehospital IV fluid (IVF) administered and mortality. METHODS: We conducted a retrospective cohort analysis of trauma registry data patients who sustained penetrating trauma between January 2008 and February 2011, as identified in the Pennsylvania Trauma Systems Foundation registry with corresponding prehospital records from the Philadelphia Fire Department. Analyses were conducted with logistic regression models and instrumental variable analysis, adjusted for injury severity using scene vital signs before the intervention was delivered. RESULTS: There were 1966 patients identified. Overall mortality was 22.60%. Approximately two-thirds received fluids and one-third did not. Both cohorts had similar Trauma and Injury Severity Score-predicted mortality. Mortality was similar in those who received IVF (23.43%) and those who did not (21.30%) (p = 0.212). Patients who received IVF had longer mean scene times (10.82 min) than those who did not (9.18 min) (p < 0.0001), although call times were similar in those who received IVF (24.14 min) and those who did not (23.83 min) (p = 0.637). Adjusted analysis of 1722 patients demonstrated no benefit or harm associated with prehospital fluid (odds ratio [OR] 0.905, 95% confidence interval [CI] 0.47-1.75). Instrumental variable analysis utilizing variations in use of IVF across different Emergency Medical Services (EMS) units also found no association between the unit's percentage of patients that were provided fluids and mortality (OR 1.02, 95% CI 0.96-1.08). CONCLUSIONS: We found no significant difference in mortality or EMS call time between patients who did or did not receive prehospital IVF after penetrating trauma. PMID- 29501221 TI - The effects of folate supplementation on glucose metabolism and risk of type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. AB - PURPOSE: Observationally, homocysteine is associated with higher risk of diabetes. Folate, which reduces homocysteine, is promising for the prevention and treatment of diabetes. Previous meta-analysis of three trials suggested folate might lower hemoglobin A1c (HbA1c). METHODS: An updated systematic review and meta-analysis of placebo-controlled randomized trials was conducted. We searched PubMed using ("folate" or "folic acid") and trial and ("glucose" or "diabetes" or "insulin" or "hemoglobin A1c" or "HbA1c") in any field until February 3, 2017. We also conducted a bibliographic search of selected studies and relevant reviews. Relative risk of diabetes and mean differences in indicators of glucose metabolism between folate and placebo were summarized in a meta-analysis using inverse variance weighting with random effects. Heterogeneity, publication bias, and risk of bias were also assessed. RESULTS: Eighteen trials of 21,081 people with/without diabetes were identified. Folate decreased fasting glucose (-0.15 mmol/L, 95% confidence interval [CI] -0.29 to -0.01), homeostatic model assessment-insulin resistance (-0.83, 95% CI -1.31 to -0.34), and insulin (-1.94 MUIU/mL, 95% CI -3.28 to -0.61) but had no clear effect on diabetes or HbA1c. CONCLUSIONS: Our study suggests a potential benefit of folate on insulin resistance and glycemic control; the latter requires examination in more high quality trials. PMID- 29501220 TI - The role of obesity in the risk of gestational diabetes among immigrant and U.S. born women in New York City. AB - PURPOSE: To examine if the role of obesity in the risk of gestational diabetes differs between immigrant and U.S.-born women. METHODS: We used New York City linked 2010-2014 birth certificate and hospital data. We created four racial/ethnic groups (non-Hispanic black, Hispanic, non-Hispanic white, and Asian) and three subgroups (Mexican, Indian, and Chinese). Gestational diabetes mellitus (GDM) was ascertained by the birth certificate checkbox and discharge ICD-9 codes. We calculated relative risks for immigrant status and body mass index with GDM using covariate-adjusted log-binomial regression. We calculated multivariable population attributable risk to estimate the proportion of GDM that could be eliminated if overweight/obesity were eliminated by immigrant status. RESULTS: Immigrant women had higher risk of GDM than U.S.-born women, with adjusted relative risks ranging from 1.2 among non-Hispanic black women (95% confidence interval, 1.2-1.3) to 1.6 among Hispanic women (95% confidence interval, 1.4-1.8). Increasing body mass index was associated with GDM risk in all groups, but relative risks were weaker among immigrants (P for interaction <.05). The population attributable risk for overweight/obesity was lower in immigrant women than in U.S.-born women in all racial/ethnic groups. CONCLUSIONS: The lower proportion of GDM attributable to overweight/obesity among immigrant women may point to early life and migration influences on risk of GDM. PMID- 29501222 TI - Predictive findings on magnetic resonance imaging in patients with symptomatic acromioclavicular osteoarthritis. AB - BACKGROUND: A magnetic resonance imaging (MRI) scan of the shoulder can have added value in diagnosing symptomatic osteoarthritis of the acromioclavicular (AC) joint. Specific MRI signs have been recognized but not analyzed extensively before. This study aims to identify predictive MRI signs in patients with symptomatic AC osteoarthritis. METHODS: The MRI scans of 70 patients with symptomatic AC osteoarthritis were compared with those of 70 patients with subacromial pain syndrome and no clinical signs of symptomatic AC osteoarthritis. Seven variables were evaluated on the MRI scans of the AC joint: joint space narrowing, inferior osteophytes, joint effusion, osteolysis, bone marrow edema, impression on the supraspinatus, and inferior joint distension. Logistic regression analysis of these variables was performed. RESULTS: The presence of inferior osteophytes, bone marrow edema, impression on the supraspinatus, and inferior joint distension was individually associated with symptomatic AC osteoarthritis. Bone marrow edema was observed only in patients with symptomatic AC osteoarthritis. Multivariate analysis showed a significant association between inferior joint distension, as well as impression on the supraspinatus muscle, and symptomatic AC osteoarthritis. The area under the receiver operating characteristic curve in the multivariate logistic model was 0.839 (95% confidence interval, 0.771 to 0.907). Interobserver and intraobserver variability showed good to excellent kappa values (range, 0.68 to 0.88). CONCLUSION: We identified predictive MRI signs in patients with symptomatic AC osteoarthritis. These findings, including bone marrow edema, inferior joint distension, and impression on the supraspinatus muscle, showed good discriminative ability. They are practical and easy to use and can assist the physician in diagnosing symptomatic AC osteoarthritis. PMID- 29501223 TI - Total shoulder arthroplasty in patients with a B2 glenoid addressed with corrective reaming. AB - BACKGROUND: This study describes the short-term functional and radiographic outcomes after total shoulder arthroplasty (TSA) in shoulders with a B2 glenoid deformity addressed with corrective reaming. METHODS: We conducted a retrospective series of consecutive patients who underwent TSA with a Walch B2 glenoid quantified by computed tomography scan. All glenoid deformities were addressed using partially corrective glenoid reaming. Radiographic and functional outcome measures, including scores on the visual analog scale for pain, American Shoulder and Elbow Standardized Shoulder Assessment, and Simple Shoulder Test were collected. RESULTS: Functional outcome scores were available for 59 of 92 eligible subjects (64%) at a mean of 50 months. The mean preoperative retroversion measured 18 degrees (range, -1 degrees to 36 degrees ), superior inclination was 8 degrees (range, -11 degrees to 27 degrees ), and posterior subluxation was 67% (range, 39%-91%). Mean visual analog scale improved from 7.4 to 1.4, the American Shoulder and Elbow Shoulder Standardized Assessment improved from 35.4 to 84.3, and the SST improved from 4.5 to 9.1. Radiographs were evaluated at a mean of 31 months: 38 had no glenoid radiolucent lines, 13 glenoids had grade 1, 2 had grade 2, and 5 had grade 3 lucencies. There was no difference in the rate of progression of glenoid radiolucencies between shoulders with a preoperative glenoid version of <=20 degrees (27.8%) compared with glenoids with >20 degrees of retroversion (22.7%, P = .670). No shoulders were revised due to glenoid loosening or instability. CONCLUSION: TSA with partial corrective glenoid reaming in selected shoulders with a B2 glenoid deformity resulted in excellent functional and radiographic outcomes at short-term follow up, with a low risk of revision surgery. PMID- 29501224 TI - The impact of the luminance, size and location of LED billboards on drivers' visual performance-Laboratory tests. AB - A proper visual performance by drivers can be ensured by, among else, a correct distribution of luminance in their field of view. At night, when the driver's sight is adapted to low luminance levels, high luminance level objects located near the road may be a source of glare, which is not only a nuisance, but it may also blind the driver. For many years, LED billboards (light-emitting diode billboards) have been installed near roads. Such billboards are usually large, have high luminance and show dynamically changing images. These parameters have a significant impact on the drivers' visual performance and, in turn, on road traffic safety. The study on the impact of the luminance, size and location of LED billboards on the drivers' visual performance was conducted on a volunteer group. Testing the impact of LED billboards on the visual performance of drivers in real-life conditions is very difficult. Therefore, the tests have been conducted in laboratory conditions, using a car driving simulator. The paper describes the testing procedure and tests results. The permissible luminance and areas of LED screens in two locations near the road, which significantly reduce the drivers' visual performance in municipal traffic at night, were determined by conducting an analysis of the results. Recommendations on the permissible luminance and areas of LED billboards were formulated. PMID- 29501225 TI - Quantification of disturbed coronary flow by disturbed vorticity index and relation with fractional flow reserve. AB - BACKGROUND AND AIMS: The relation between FFR and local coronary flow patterns is incompletely understood. We aimed at developing a novel hemodynamic index to quantify disturbed coronary flow, and to investigate its relationship with lesion associated pressure-drop, and fractional flow reserve (FFR). METHODS: Three dimensional angiographic reconstruction and computational fluid dynamics were applied to simulate pulsatile coronary flow. Disturbed vorticity index (DVI) was derived to quantify the stenosis-induced flow disturbance. The relation between DVI and pressure-drop was assessed in 9 virtual obstruction models. Furthermore, we evaluated the correlation between DVI, FFR, hyperemic flow velocity, and anatomic parameters in 84 intermediate lesions from 73 patients. RESULTS: In virtual models, DVI increased with increasing flow rate, stenosis severity, and lesion complexity. The correlation between DVI and pressure-drop across all models was excellent (determination coefficient R2 = 0.85, p < 0.001). In vivo, DVI showed a correlation with FFR (rho (rho) = -0.74, p < 0.001) that was stronger than the relations of FFR with hyperemic flow velocity (rho = -0.27, p=0.015), lesion length (rho = -0.36, p=0.001) and percent diameter stenosis (rho = -0.40, p < 0.001). CONCLUSIONS: DVI, a novel index to quantify disturbed flow, was related to pressure-drop in virtual obstruction models and showed a strong inverse relation with FFR in intermediate lesions in vivo. It supports the prognostic value of FFR and may provide additional information about sources of energy loss when measuring FFR. PMID- 29501226 TI - Confounding and Adjustment Factors in the Effect of Intravenous Parecoxib on Shoulder Pain after Thoracotomy? PMID- 29501227 TI - Toward Improved Neurodevelopmental Outcomes: The Role of Transfontanel Ultrasound Assessment of Cerebral Blood Flow in Infants Undergoing Cardiac Surgery. PMID- 29501228 TI - GR-regulating Serine/Threonine Kinases: New Physiologic and Pathologic Implications. AB - Glucocorticoid hormones, end products of the hypothalamic-pituitary-adrenal axis, virtually influence all human functions both in a basal homeostatic condition and under stress. The glucocorticoid receptor (GR), a nuclear hormone receptor superfamily protein, mediates these actions of glucocorticoids by acting as a ligand-dependent transcription factor. Because glucocorticoid actions are diverse and strong, many biological pathways adjust them in local tissues by targeting the GR signaling pathway as part of the regulatory loop coordinating complex human functions. Phosphorylation of GR protein by serine/threonine kinases is one of the major regulatory mechanisms for this communication. In this review, recent progress in research investigating GR phosphorylation by these kinases is discussed, along with the possible physiologic and pathophysiologic implications. PMID- 29501229 TI - Mitochondria and Hypoxia: Metabolic Crosstalk in Cell-Fate Decisions. AB - Alterations in mitochondrial metabolism influence cell differentiation and growth. This process is regulated by the activity of 2-oxoglutarate (2OG) dependent dioxygenases (2OGDDs) - a diverse superfamily of oxygen-consuming enzymes - through modulation of the epigenetic landscape and transcriptional responses. Recent reports have described the role of mitochondrial metabolites in directing 2OGDD-driven cell-fate switches in stem cells (SCs), immune cells, and cancer cells. An understanding of the metabolic mechanisms underlying 2OGDD autoregulation is required for therapeutic targeting of this system. We propose a model dependent on oxygen and metabolite availability and discuss how this integrates 2OGDD metabolic signalling, the hypoxic transcriptional response, and fate-determining epigenetic changes. PMID- 29501230 TI - Milestones in thoracic surgery. AB - OBJECTIVE: To highlight some of the legendary figures in the medical field who have paved the path of thoracic surgery today. METHODS: We reviewed historical articles and landmark studies published in anesthesiology, pulmonology, and thoracic surgery, and summarized them as they pertain to current practice. RESULTS: Throughout our article, we have attempted to chronologically depict how our field has evolved, starting from the development of the stethoscope to reconstructing the esophagus using an extracorporeal tube to minimally invasive complex surgeries that we practice today. CONCLUSIONS: We hope that our article can inspire the young minds to further grow the field and take it to higher levels. PMID- 29501231 TI - Volume-outcome relationships: Does practice really make perfect? PMID- 29501232 TI - The shea(e)r stress of it all. PMID- 29501233 TI - QED? Not yet! PMID- 29501234 TI - Transcatheter mitral valve replacement in patients with severe mitral annular calcification: Pushing the limits to the sky. PMID- 29501235 TI - Nursing Now campaign: raising the status of nurses. PMID- 29501236 TI - Enrollment and reporting practices in pediatric general surgical randomized clinical trials: A systematic review and observational analysis. AB - BACKGROUND: Pediatric surgical randomized clinical trials (RCTs) are labor intensive and costly. This systematic review investigated patient accrual and estimates of study duration in RCTs by interrogating enrollment and registration practices. METHODS: We performed a peer-review search of multiple databases from 2000 to 2016 evaluating RCTs salient to the field with inclusion mandated that a self-identified pediatric surgeon be listed as an author. Trial registries were also searched. RCTs were appraised, and predictors of success were evaluated using multivariate logistic regression, with success defined as achievement of recruitment objectives. RESULTS: After screening, 137 RCTs were analyzed. Mean Jadad score was 1.80 (median=2). CONSORT scores ranged between 17% and 97% (median=58%). Sixty-seven studies described sample-size determination, 49 reported projected enrollment, and 26 were successful. Among 26 registered RCTs, 15 disclosed their expected completion date, which was achieved by 8. On average, protocols underwent 3.42 iterations. 9% of trials were terminated before completion, most commonly owing to poor recruitment. Trial registration and urgent cases significantly predicted success on multivariable analysis (p<0.05). CONCLUSION: Overall quality of reporting in pediatric surgical trials is poor. Sample-size calculation and patient accrual are frequently poorly performed or underestimated, resulting in trial overrun and/or premature termination. These data may help inform subsequent study design and facilitate successful completion. LEVEL OF EVIDENCE: Level III-Systematic Review and Observational (Case-Control) Analysis. PMID- 29501237 TI - Experience with peritoneal thermal injury during subcutaneous endoscopically assisted ligation for pediatric inguinal hernia. AB - BACKGROUND: Subcutaneous endoscopically-assisted ligation (SEAL) for pediatric inguinal hernia repair has gained in popularity although variations in techniques exist. Peritoneal scarring by thermal injury has been described as an adjunct. We explored the hypothesized inverse-correlation between peritoneal scarring and recurrence after SEAL. METHODS: We conducted a single-center retrospective review of all patients <18years old undergoing SEAL between 2010 and 2016 (REB 20172727). Demographics and outcomes were investigated. Univariate and multivariable logistic regressions were performed to evaluate the association between peritoneal scarring and recurrence. RESULTS: We identified 272 patients. Median age was 3years, 35% were female, and 19% were born premature. Median follow-up was 30months, >=1 visit/patient. Bilaterality was noted in 35%. There were no reported cases of metachronous hernia, vas injury, testicular atrophy or chronic pain, and recurrence rate was 4.6%. Prematurity, unilateral repair, incarceration, and suture-type (Ti-Cron(r) vs. Ethibond(r)) had significant correlation with recurrence on univariate analysis (p<0.25). Surgeon experience did not. Peritoneal scarring, performed in 195 cases (72%), was not predictive of recurrence (adjusted OR=0.87, p=0.830) on multivariable analysis. CONCLUSION: The rate of complications with SEAL compares favorably to published data. Thermal injury was not associated with improved recurrence rates. The benefits of peritoneal scarring may not outweigh the risks. LEVEL OF EVIDENCE: III - Retrospective Case-Control Study. PMID- 29501238 TI - Development and results of a novel pancreas transplant program in Spain: the surgeon's point of view. AB - INTRODUCTION: Simultaneous kidney-pancreas transplantation for patients with type 1 diabetes and end-stage chronic renal disease is widely performed. However, the rate of surgical morbidity from pancreatic complications remains high. The aim of this study was to describe the development and results of a new program, from the point of view of the pancreatic surgeon. METHODS: We analyzed 53 simultaneous kidney-pancreas transplantations performed over a period of seven years (2009 2016), with a median follow up of 39 months (range: 1-86 months). RESULTS: Out of the total of this series, two patients died: one patient because of cardiac arrest immediately after surgery; and another patient due to traffic accident, complicated by pneumonia. Among the 51 living patients, two grafts were lost: one due to chronic rejection four years after transplantation; and the other due to arterial thrombosis 20 days after transplantation (the only case requiring transplantectomy). In ten patients, one or more re-operations were necessary due to the following: graft pancreatitis (n=4), small intestinal obstruction (n=4), arterial thrombosis (n=1), fistula (n=1) and hemoperitoneum (n=1). Overall patient and graft survival rates after 1, 3 and 5 years were 98, 95 and 95% and 96, 93 and 89%, respectively. CONCLUSIONS: This study has shown that the results of a new pancreas transplant program, which relies on the previous experience of other groups, do not demonstrate a learning curve. Adequate surgeon education and training, as well as the proper use of standardized techniques, should ensure optimal results. PMID- 29501239 TI - Reply. PMID- 29501240 TI - Increased red cell distribution width: A novel predictor of adverse outcome in patients hospitalized due to acute exacerbation of chronic obstructive pulmonary disease. AB - BACKGROUND: Acute exacerbation of COPD (AECOPD) is one of the leading causes for hospitalization and readmission in developed countries. No laboratory indices were consistently found to be associated with readmission risk. Recent evidence attests that red blood cell distribution width (RDW), conveys important information for short and long term prognosis in a variety of medical conditions. Prognostic usefulness of RDW in patients with AECOPD has not been investigated. OBJECTIVE: To evaluate the usefulness of RDW in predicting early adverse outcomes in patients hospitalized due to AECOPD. METHODS: Patients hospitalized for AECOPD between 2011 and 2013 were revised. Clinical and laboratory parameters were noted. Participants were followed to determine the incidence of readmission due to AECOPD, readmission from any cause and composite end point of readmission or death during 60 days after discharge. RESULTS: 539 patients were included in the study. The 60-day overall readmission rate was 26.35%, of that, 41.55% were due to AECOPD. The Presence of heart failure, pH below 7.35 at discharge and abnormal RDW were associated with the composite endpoint. The negative predictive value of normal RDW was 80.12%. CONCLUSION: Increased RDW is an independent negative prognostic factor associated with adverse outcomes after hospitalization due to AECOPD. PMID- 29501241 TI - Identification of Pseudomonas aeruginosa and airway bacterial colonization by an electronic nose in bronchiectasis. AB - RATIONALE: Airway colonization by Potentially Pathogenic Microorganisms (PPM) in bronchiectasis is associated with worse clinical outcomes. The electronic nose is a non-invasive technology capable of distinguishing volatile organic compounds (VOC) in exhaled breath. We aim to explore if an electronic nose can reliably discriminate airway bacterial colonization in patients with bronchiectasis. METHODS: Seventy-three clinically stable bronchiectasis patients were included. PPM presence was determined using sputum culture. Exhaled breath was collected in Tedlar bags and VOC breath-prints were detected by the electronic nose Cyranose 320(r). Raw data was reduced to three factors with principal component analysis. Univariate ANOVA followed by post-hoc least significant difference test was performed with these factors. Patients were then classified using linear canonical discriminant analysis. Cross-validation accuracy values were defined by the percentage of correctly classified patients. RESULTS: Forty-one (56%) patients were colonized with PPM. Pseudomonas aeruginosa (n = 27, 66%) and Haemophilus influenzae (n = 7, 17%) were the most common PPM. VOC breath-prints from colonized and non-colonized patients were significantly different (accuracy of 72%, AUROC 0.75, p < 0.001). VOC breath-prints from Pseudomonas aeruginosa colonized patients were significantly different from those of patients colonized with other PPM (accuracy of 89%, AUROC 0.97, p < 0.001) and non-colonized patients (accuracy 73%, AUROC 0.83, p = 0.007). CONCLUSIONS: An electronic nose can accurately identify VOC breath-prints of clinically stable bronchiectasis patients with airway bacterial colonization, especially in those with Pseudomonas aeruginosa. PMID- 29501242 TI - Comorbidity, disease burden and mortality across age groups in a Swedish primary care asthma population: An epidemiological register study (PACEHR). AB - BACKGROUND: Asthma is often associated with other diseases. To identify and manage comorbidities is important, as these conditions may increase the disease burden. OBJECTIVE: To describe the prevalence of comorbidities, disease burden and mortality across age groups in a large Swedish primary care real-life asthma population. METHODS: Observational cohort study of asthma patients, all ages, identified from electronic medical records by ICD-10-CM code, data from 36 primary care centers. Data were linked to national mandatory Swedish health registers. Comorbidities were identified by ICD-10-CM codes and collected from electronic medical records and the National Patient Registers, mortality data from the Cause of Death Register. Exacerbations were defined as hospitalizations due to asthma, and/or emergency visits at hospital and/or prescription claims of oral steroids. RESULTS: In total 33,468 patients (58% women) were included. The most prevalent comorbidities were acute upper respiratory tract infection (53%), rhinitis (25%), acute lower respiratory tract infection (25%), hypertension (21%), anxiety and depression (20%). The comorbidities associated with highest risk for an exacerbation were COPD OR 1.98 (95%CI: 1.80-2.19), nasal polyps OR 1.75 (95%CI: 1.49-2.05) and rhinitis OR 1.52 (95%CI: 1.41-1.63). All-cause mortality was similar to the Swedish population, 1011 deaths per 100,000 person/year compared with 1058 deaths (standardized risk = 0.99 [95%CI:0.95 1.04]). The pulmonary related death rate was greater in the study population versus the Swedish population (122 versus 72 per 100,000person/year). CONCLUSION: Comorbid disease was frequent in this large real-life asthma population with an impact on exacerbations. To identify and treat comorbidities with impact on asthma outcomes are essential to improve asthma care. PMID- 29501243 TI - Pleural manometry-historical background, rationale for use and methods of measurement. AB - Subatmospheric pleural pressure (Ppl), which is approximately -3 to -5 cmH2O at functional residual capacity (FRC) makes pleura a unique organ in the human body. The negative Ppl is critical for maintaining the lungs in a properly inflated state and for proper blood circulation within the thorax. Significant and sudden pleural pressure changes associated with major pleural pathologies, as well as therapeutic interventions may be associated with life-threatening complications. The pleural pressure may show two different values depending on the measurement method applied. These are called pleural liquid pressure and pleural surface pressure. It should also be realized that there are significant differences in pleural pressure distribution in pneumothorax and pleural effusion. In pneumothorax, the pressure is the same throughout the pleural space, while in pleural effusion there is a vertical gradient of approximately 1 cm H2O/cm in the pleural pressure associated with the hydrostatic pressure of the fluid column. Currently, two main methods of pleural pressure measurement are used: simple water manometers and electronic systems. The water manometers are conceptually simple, cheap and user-friendly but they only allow the estimation of the mean values of pleural pressure. The electronic systems for pleural pressure measurement are based on pressure transducers. Their major advantages include precise measurements of instantaneous pleural pressure and the ability to display and to store a large amount of data. The paper presents principles and details of pleural pressure measurement as well as the rationale for its use. PMID- 29501244 TI - Systemic vascular dysfunction is associated with emphysema burden in mild COPD. AB - BACKGROUND: Cardiovascular diseases play a major role in morbidity and mortality in the earlier stages of COPD. We hypothesized that systemic vascular dysfunction would be present even in patients who are currently considered at "low-risk" for negative cardiovascular outcomes, i.e., those with largely preserved FEV1, few exacerbations and only mild burden of respiratory symptoms (GOLD spirometric grade 1, clinical group A). METHODS: 16 patients (FEV1 = 86 +/- 13%) and 16 age- and gender-matched controls underwent measurements of: a) central arterial stiffness by pulse wave velocity, b) brachial flow-mediated dilation and c) forearm muscle oxygenation by near-infrared spectroscopy. Computed tomography quantified emphysema (% of low attenuation areas (LAA)) and airway disease. RESULTS: Patients and controls were well matched for key clinical variables including co-morbidities burden. Thirteen patients presented with more than 5% LAA: emphysema extension was negatively related to transfer factor for carbon monoxide (TLCO) (r = -0.63; p = .01). Compared to controls, patients had higher central arterial stiffness, lower normalized (to shear stress) flow-mediated dilation, delayed time to peak flow-mediated dilation and poorer muscle oxygenation (p < .05). TLCO and emphysema, but not airway disease, were significantly related to each of these functional abnormalities (r values ranging from 0.51 to 0.66; p < .05). CONCLUSION: Systemic vascular dysfunction is present in the earlier stages of COPD, particularly in patients with greater emphysema burden and low TLCO. Regardless FEV1, patients showing those structural and functional abnormalities might be at higher risk of negative events thereby deserving closer follow-up for early detection of cardiovascular disease. PMID- 29501245 TI - Forty years of reference values for respiratory system impedance in adults: 1977 2017. AB - OBJECTIVE: To provide an evidence-based review of published data regarding normal range reference values and prediction equations for measurements of respiratory impedance using forced oscillation technique (FOT) and impulse oscillometry (IOs) in adults. METHODS: A non-language-restricted search was performed using forced oscillation technique and impulse oscillometry as primary terms. Original research studies reporting respiratory system impedance reference values or prediction equations based on cohorts of >=100 healthy adults were included. Publications cited in identified studies were also considered for inclusion. RESULTS: Of 882 publications identified, 34 studies were included: 14 studies of FOT, 19 studies of IOs, and one study of both techniques. Nineteen studies provided prediction equations. Most reports were from Europe (n = 20) and Asia (n = 12) and included relatively small cohorts (median = 264 subjects). Across publications, there was marked variability in performance and technique of impedance measurements. Height and sex emerged as major contributors to available prediction equations. The contribution of weight was more pronounced at the obese end of the weight spectrum. The contribution of age was less clear, and elderly were largely under-represented. Ethnicity likely plays a role, but was under reported in currently available literature. Inclusion of current and former smokers in some studies further confound the results. CONCLUSIONS: Currently available literature providing reference values and prediction equations for respiratory impedance measurements in adults is limited. Until larger-scale standardized studies are available, the choice of prediction equations should be based on datasets that best represent the target patient population and modality in use within each pulmonary physiology laboratory. PMID- 29501246 TI - Favorable association of polyphenol-rich diets with lung function: Cross sectional findings from the Moli-sani study. AB - BACKGROUND: The association of the polyphenol content of human diet with pulmonary function is not yet fully understood. This study aims at evaluating the association of polyphenol consumption with lung function in a novel holistic approach. METHODS: A cross-sectional analysis of 4551 women and 5108 men (age >=35 years) from the Moli-sani study was performed. Participants were randomly recruited from the general population. The EPIC-FFQ was used for the dietary assessment. Polyphenol intakes were calculated using Eurofir-eBASIS, and a polyphenol antioxidant content (PAC) score was constructed to assess the total content of the diet in these nutrients. Pulmonary function maneuvers were performed, and the forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1) were measured; FVC% predicted and FEV1% predicted were computed using the European Community of Coal and Steel prediction equations that included height and age. RESULTS: In both genders, in age, height, and energy intake adjusted models, the majority of classes of polyphenols (mg/day) showed a positive association with FEV1, FVC, FEV1% predicted, and FVC% predicted (beta coef >0, P < .05). Associations remained significant after adjustment for confounding factors in most cases (beta-coef >0, P < .05). The PAC score was associated in both genders with an increase in pulmonary function parameters (beta-coef >0, P < .05). The inclusion of white blood cell (WBC) counts in the multivariate model reduced the association in men but not in women. . CONCLUSIONS: A higher overall polyphenol content of human diet was associated with better pulmonary function in a general population. The association might be partially mediated by WBC in men. PMID- 29501247 TI - The impact of aging on outpatients with asthma in a real-world setting. AB - BACKGROUND: Asthma is characterized by airway inflammation and bronchial hyperreactivity. It is conceived that aging may affect asthma characteristics, but this issue is still not completely clarified in clinical practice. OBJECTIVE: The present study investigated whether aging may affect some clinical and functional factors in outpatients with asthma visited in a real-world setting, such as clinical practice. METHODS: Globally, 391 outpatients (163 males, median age 47 years) with asthma were consecutively evaluated. The following parameters were assessed: history, including, smoking, comorbidity, and inhaled corticosteroids (ICS) use, physical examination, body mass index (BMI), lung function, level of asthma control, asthma control test (ACT), and fractional exhaled NO (FeNO). RESULTS: The elderly with asthma had: more frequently not controlled asthma, higher BMI, higher ICS dosages, more impaired lung function, including plethysmographic parameters, than adult asthmatics (p < 0.001 for all, but p = 0.002 for RV and p = 0.008 for FRC). Elderly asthmatics were also less frequently allergic (p < 0.001) and had less rhinitis comorbidity (p < 0.001) and less nasal symptoms (p < 0.05) than younger asthmatics. CONCLUSIONS: The present study conducted in a real-world setting shows that aging significantly affects asthma, mainly concerning asthma control, lung function, and steroid-sensitivity. PMID- 29501248 TI - Serum 25-hydroxyvitamin D, vitamin D supplement and asthma control: The HUNT study. AB - Few studies have investigated the association between serum 25-hydroxyvitamin D (25[OH]D), vitamin D supplement and asthma control among adults. We aimed to examine whether low levels of serum 25(OH)D or not taking vitamin D supplement were associated with an increased risk of poorly controlled asthma among Norwegian adults with asthma. We used a definition of asthma control adapted from the Global Initiative for Asthma. We first examined cross-sectional associations between serum 25(OH)D (n = 806) or vitamin D supplement (n = 1179) and poorly controlled asthma. Next, among those with well controlled asthma at baseline, we examined prospective associations between serum 25(OH)D (n = 147) or vitamin D supplement (n = 208) and poorly controlled asthma at follow-up, approximately 11 years later. We estimated risk ratios (RR) and 95% confidence intervals (CI) with Poisson regression. The adjusted RR for poorly controlled asthma was 1.00 (95% CI, 0.89-1.13) for adults with serum 25(OH)D < 50 nmol/L in cross-sectional and 1.50 (95% CI, 0.46-4.95) in prospective analyses. The adjusted RR for poorly controlled asthma was 1.17 (95% CI 1.00-1.37) for non-users of vitamin D supplement in cross-sectional and 1.66 (95% CI 0.49-5.67) in prospective analyses. Our study did not show strong evidence that among adults with asthma, having a low serum 25(OH)D or being a non-user of vitamin D supplement was associated with an increased risk of poorly controlled asthma. Some point estimates indicated an increased risk, however our estimates were generally imprecise and further evidence is needed. PMID- 29501249 TI - Laboratory animal allergy reduction from 2001 to 2016: An intervention study. AB - Exposure to laboratory animals (LA) can cause allergic sensitization and symptoms as rhinitis, conjunctivitis, asthma, anaphylaxis and dermatitis. In 2000, a program was instituted at Trieste Universities to decrease LA allergy among scientists and technicians working with animals. The aim of our study was to investigate LA allergy in workers exposed to LA from 2001 to 2016, and to verify the effects of a preventive program. Four hundred sixty seven people underwent pre-employment screening for a job with laboratory animals at Universities of Trieste consisting in a medical examination, a full respiratory and allergy anamnesis, using a standardized questionnaire, skin prick test with common and occupational allergens, and spirometry. Every year, each worker repeated the medical examination and underwent again tests and questionnaire. Each worker can ask for a medical examination and skin prick test, in case of unset of symptoms. Logistic multivariate analysis and generalized equation estimation were use, to verify factors associated to LA allergy. Sensitization to LA decreased in years, going from 25.6% in 2001-2004 to 8.2% in 2013-2016 (p < 0.001). Multivariate logistic regression analysis confirmed the role of atopy by prick test (OR = 6; IC95% 2.2-16.6), of common allergic symptoms (OR = 2.9; IC95% 1.4-6.39) and of calendar periods. No association was found between LA allergy, years, and hours of exposure. Our study demonstrated a significant reduction of LA allergy after the application of a preventive program. PMID- 29501250 TI - Interstitial lung abnormalities are associated with increased mortality in smokers. AB - OBJECTIVE: The aim of this study was to investigate whether smokers with incidental findings of interstitial lung abnormalities have an increased mortality during long-term follow-up, and review the contributing causes of death. METHODS: Baseline CT scans of 1990 participants from the Danish Lung Cancer Screening Trial were qualitatively assessed for predefined interstitial lung abnormalities of any severity. Inclusion criteria for this lung cancer screening trial included current or former smoking, > 20 pack-years, and age 50 70 years. Patients were followed up for up to 12 years. RESULTS: We found interstitial lung abnormalities in 332 participants (16.7%). Interstitial lung abnormalities were associated with increased all-cause mortality in the full cohort (HR: 2.0, 95% CI: 1.4-2.7, P < 0.001) and in lung cancer-free participants (HR: 1.6, 95% CI: 1.1-2.4, P = 0.007). The findings were associated with death from lung cancer (HR: 3.2, 95% CI: 1.7-6.2, P < 0.001) and non-pulmonary malignancies (HR: 2.1, 95% CI: 1.1-4.0, P = 0.02). Participants with fibrotic and non-fibrotic interstitial lung abnormalities had similar survival. CONCLUSION: Interstitial lung abnormalities were common in this lung cancer screening population of relatively healthy smokers and were associated with mortality regardless of the interstitial morphological phenotype. The increased mortality was partly due to an association with lung cancer and non-pulmonary malignancies. PMID- 29501251 TI - Evaluation of criteria for clinical control in a prospective, international, multicenter study of patients with COPD. AB - BACKGROUND: The concept of clinical control in COPD has been developed to help in treatment decisions, but it requires validation in prospective studies. METHOD: This international, multicenter, prospective study aimed to validate the concept of control in COPD [control = stability (no exacerbations or impairment in CAT scores) + low impact (low level of symptoms)]. Data from the screening visit was used to: investigate the level of control, compare characteristics of patients according to the control status, and perform a sensitivity analysis of the levels of control using either clinical criteria or questionnaires (COPD Assessment Test -CAT- or Clinical COPD Questionnaire -CCQ-). RESULTS: A total of 314 patients were analysed, mean age was 68.5 years and mean FEV1 was 52.6% of predicted. According to the prespecified criteria 21% of patients were classified as controlled, all of them with mild/moderate COPD (Body mass index, Obstruction, Dyspnea and Exacerbations, -BODEx-index <5). A high level of dyspnea, a high CAT score or an exacerbation in the previous 3 months were found, using univariate analysis, to be the main reasons for patients not being classified as controlled. Multivariate analysis showed that female sex, chronic bronchitis and having exacerbations in the previous year were associated with uncontrolled COPD. Changing the severity cut off of BODEx from 5 to 3 did not change significantly the percentage of patients fulfilling the criteria of control. CONCLUSIONS: The proposed criteria of control were only fulfilled by 21% of patients. The suggested cut offs and their predictive value for poor outcomes need to be refined in prospective studies. PMID- 29501252 TI - Pulmonary function in former very low birth weight preterm infants in the first year of life. AB - BACKGROUND: Pulmonary function in former preterm infants may be compromised during childhood. OBJECTIVES: To assess pulmonary function in very-low-birth weight preterm infants at 6-12 months of corrected age and analyze the factors associated with abnormal pulmonary function. METHODS: Cross-sectional study with preterm infants at 6-12 months of corrected age with birth weight <1500 g. Children with malformations or affected by neuromuscular and respiratory diseases were excluded. Forced expiratory flows were assessed using the chest compression technique, and volumes were measured by total body plethysmography. Pulmonary function parameters in preterm infants were compared to a control group of same aged children born at term. RESULTS: We studied 51 preterm and 37 infants born at term. Preterm infants had: gestational age at birth (30.0 +/- 2.5 weeks), birth weight (1179 +/- 247 g), 27.5% had bronchopulmonary dysplasia, and 45% received mechanical ventilation. Preterm infants had lower median z-scores in comparison to term infants for the following parameters (p < 0.05): FVC (-0.3 vs. 0.7), FEV0.5 (-0.5 vs. 0.9), FEV0.5/FVC (-0.6 vs. -0.5), FEF50 (-0.4 vs. 0.9), FEF75 ( 0.3 vs. 0.8), FEF85 (-0.1 vs. 0.6) and FEF25-75 (-0.5 vs. 1.1). No term child had abnormal lung function, compared to 39.2% of preterm infants (p = 0.001). Factors associated with abnormal pulmonary function were lower gestational age at birth, small for gestational age, need for mechanical ventilation and presence of recurrent wheezing. CONCLUSIONS: Preterms had a high prevalence of abnormal pulmonary function and lower pulmonary function in comparison to term infants. Prematurity, intrauterine growth restriction, respiratory support and recurrent wheezing were associated with abnormal pulmonary function. PMID- 29501253 TI - Clinical significance of respiratory virus detection in patients with acute exacerbation of interstitial lung diseases. AB - BACKGROUND: The impact of viral infections on acute exacerbations in idiopathic pulmonary fibrosis (IPF) and/or non-IPF interstitial lung disease (ILDs) has been scarcely described. OBJECTIVES: To elucidate the frequency of virus infections in patients with IPF or non-IPF ILDs including idiopathic interstitial pneumonia (IIP) or connective tissue disease (CTD)-associated pneumonia, and its influence on their short-term mortality. METHODS: We prospectively enrolled adult patients with acute exacerbation of IPF and non-IPF ILDs who were admitted to the hospital during the last 3 years, and examined the respiratory samples obtained from nasopharyngeal, sputum, and bronchoalveolar lavage fluid. RESULTS: A total of 78 patients were identified, consisting of 27 patients with acute exacerbation of IPF and 51 patients with non-IPF ILDs (IIP: n = 27, CTD-associated IP: n = 24). Of all patients, 15 (19.2%) had viruses detected in their respiratory samples including the human herpesvirus 7 (HHV7; n = 4) and cytomegalovirus (CMV) plus HHV7 (n = 3). The proportion of virus infections in the IPF and non-IPF ILDs groups was comparable. The Kaplan-Meier survival curves over 60 days revealed a lower survival probability in the virus positive group (n = 15, 60%) than in the virus negative group (n = 60, 83.3%, p < 0.05). However, the virus infection itself could not predict the 60-day survival probability using simple logistic regression analysis. CONCLUSIONS: Viral infections, mostly CMV or HHV7, were identified in both patients with acute exacerbation of IPF and non-IPF ILDs, but the clinical significance on short-term mortality or isolation itself from respiratory samples remains to be determined. PMID- 29501254 TI - COPD and lung cancer in patients with pemphigus- a population based study. AB - BACKGROUND: Recent evidence indicates that autoimmunity may contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD). COPD was observed at higher frequency in patients with several autoimmune diseases. The association between pemphigus and COPD has not been evaluated in the past. OBJECTIVES: To study the association between pemphigus and COPD using a large-scale real-life computerized database. METHODS: A cross-sectional study was conducted comparing pemphigus patients with age-, sex- and ethnicity-matched control subjects regarding the prevalence of COPD and lung cancer. Chi-square and t-tests were used for bivariate analysis, and logistic regression model was used for multivariate analysis. The study was performed utilizing the computerized database of Clalit Health Services ensuring 4.4 million subjects. RESULTS: A total of 1985 pemphigus patients and 9874 controls were included in the study. The prevalence of COPD was greater in patients with pemphigus as compared to the control group (13.4% vs. 10.1%, respectively; P < 0.001). In a multivariate analysis adjusting for smoking and other confounding factors, pemphigus was significantly associated with COPD (OR, 1.312-1. 5) but not with lung cancer. Study findings were robust to sensitivity analysis that included patients under pemphigus-specific treatments. CONCLUSIONS: A significant association was found between COPD and pemphigus. Physicians treating patients with pemphigus might be aware of this possible association. This observation may further support the hypothesis that COPD has an autoimmune component. PMID- 29501255 TI - Airway clearance techniques in neuromuscular disorders: A state of the art review. AB - This is a unique state of the art review written by a group of 21 international recognized experts in the field that gathered during a meeting organized by the European Neuromuscular Centre (ENMC) in Naarden, March 2017. It systematically reports the entire evidence base for airway clearance techniques (ACTs) in both adults and children with neuromuscular disorders (NMD). We not only report randomised controlled trials, which in other systematic reviews conclude that there is a lack of evidence base to give an opinion, but also include case series and retrospective reviews of practice. For this review, we have classified ACTs as either proximal (cough augmentation) or peripheral (secretion mobilization). The review presents descriptions; standard definitions; the supporting evidence for and limitations of proximal and peripheral ACTs that are used in patients with NMD; as well as providing recommendations for objective measurements of efficacy, specifically for proximal ACTs. This state of the art review also highlights how ACTs may be adapted or modified for specific contexts (e.g. in people with bulbar insufficiency; children and infants) and recommends when and how each technique should be applied. PMID- 29501256 TI - [Computer-assisted therapy and video games in psychosocial rehabilitation for schizophrenia patients]. AB - OBJECTIVES: Video games and virtual reality have recently become used by clinicians for training or information media or as therapeutic tools. The purpose is to review the use of these technologies for therapy destined for schizophrenia patients. METHODS: We conducted a review in October 2016 using Pubmed, Scopus and PsychInfo using the following Medical Subject Headings (MESH): "video games", "virtual reality" and "therapy, computer-assisted/methods", each associated with "schizophrenia". Papers were included in the review if: (a) they were published in an English, Spanish or French-language peer-reviewed journal, (b) the study enrolled patients with schizophrenia or schizo-affective disorder, (c) the patients used a therapeutic video game or therapeutic virtual reality device. RESULTS: Eighteen publications were included. The devices studied are mainly therapeutic software developed specifically for therapeutic care. They can be classified according to their therapeutic objectives. These targets corresponded to objectives of psychosocial rehabilitation: improvement of residual symptomatology, cognitive remediation, remediation of cognition and social skills, improvement of everyday life activities, support for occupational integration. Very different devices were proposed. Some researchers analysed programs developed specifically for patients with schizophrenia, while others were interested in the impact of commercial games. Most of the studies were recent, preliminary and European. The impact of these devices was globally positive, particularly concerning cognitive functions. CONCLUSIONS: Computer assisted therapy, video games and virtual reality cannot replace usual care but could be used as adjunctive therapy. However, recommending their use seems premature because of the recent and preliminary character of most studies. Moreover, a link is still lacking between this field of research in psychiatry and other fields of research, particularly game studies. Finally, it might be interesting to analyse more precisely the neuropsychological impact of existing commercial games which could potentially be useful for psychosocial rehabilitation. PMID- 29501257 TI - New insights on renal transplant rejection, using ECP; a new assay for monitoring global fibrinolytic capacity; a concise review of inappropriateness in saline usage as a volume expander and cell washing & update on the use of SPC in blood transfusion establishments. PMID- 29501259 TI - Therapeutic plasma exchange in non-hematooncological disorders in pediatrics: A single center experience. AB - The use of therapeutic plasma exchange in the pediatric age group is mostly based on retrospective, single-center experiences. The decision to implement apheresis in pediatric patients is usually adopted from the results of studies on adult patients. In order to expand the limited data on pediatric TPE in general and non hematooncological disorders in particular, we retrospectively evaluated TPE experience in pediatric patients who underwent the procedure for reasons other than hematooncological disorders. A total of 160 sessions in 34 patients (21 females and 13 males) with a median age of 7 (1-17) were analyzed. Most of the patients had sepsis and organ failure (12 patients, 35 procedures). In only one patient (2.9%) with methyl malonic aciduria (MMA) and sepsis, the procedure was terminated due to a grade 3 allergic reaction. Among the study cohort, 4 patients passed away. No patient died due to complications of TPE. The relatively low discontinuation rate and the lack of procedure-related mortality indicate that TPE is generally well tolerated in the pediatric age group similar to the adult population. However, since there are very limited evidence-based data on TPE use, especially in the pediatric age group, retrospective case series may also be helpful for clinicians in the decision-making process. PMID- 29501260 TI - Prevalence trends tell us what did not precipitate the US obesity epidemic. PMID- 29501261 TI - Neuronal Cilia: Another Player in the Melanocortin System. AB - Melanocortin receptors play crucial roles in multiple physiological processes. Melanocortin receptor 4 (MC4R) is expressed in key brain regions, and MC4R gene mutations can cause severe obesity. However, the cellular biology of MC4R is less well understood owing to the lack of reliable methods to visualize its location. Recently, Siljee and colleagues localized MC4R to the cilia of the neurons within the hypothalamus and showed that cilial expression of MC4R is crucial for the control of metabolic phenotype. PMID- 29501262 TI - cAMP, cGMP and Amyloid beta: Three Ideal Partners for Memory Formation. AB - cAMP and cGMP are well established second messengers required for long-term potentiation (LTP) and memory formation/consolidation. By contrast, amyloid beta (Abeta), mostly known as one of the main culprits for Alzheimer's disease (AD), has received relatively little attention in the context of plasticity and memory. Of note, however, low physiological concentrations of Abeta seem necessary for LTP induction and for memory formation. This should come as no surprise, since hormesis emerged as a central dogma in biology. Additionally, recent evidence indicates that Abeta is one of the downstream effectors for cAMP and cGMP to trigger synaptic plasticity and memory. We argue that these emerging findings depict a new scenario that should change the general view on the amyloidogenic pathway, and that could have significant implications for the understanding of AD and its pharmacological treatment in the future. PMID- 29501263 TI - The Relationship of Quantitative Retinal Capillary Network to Kidney Function in Type 2 Diabetes. PMID- 29501264 TI - Altered Prostaglandin Signaling as a Cause of Thiazide-Induced Hyponatremia. PMID- 29501265 TI - Radon survey in Montenegro - A base to set national radon reference and "urgent action" level. AB - The first nationwide indoor radon survey in Montenegro started in 2002 and year long radon measurements with CR-39 track-etch detectors, within the national grid of 5 km * 5 km and local grids in urban areas of 0.5 km * 0.5 km, were performed in homes in half of the country's territory. The survey continued in 2014 and measurements in the rest of the country were completed at the end of 2015. The 953 valid results, obtained in the national radon survey, give an average radon activity concentration in Montenegrin homes of 110 Bq/m3. Assuming a log-normal distribution of the experimental results, geometric mean GM = 58.3 Bq/m3 and geometric standard deviation GSD = 2.91 are calculated. However, normality tests show that the experimental data are not log-normal, and that they become closest to a log-normal distribution after subtracting from them radon concentration in the outdoor air of 7 Bq/m3, which is theoretically calculated. Such a transformed distribution has GMtr = 46.7 Bq/m3 and GSDtr = 3.54. The estimations derived from positing a priory that the experimental results conform to a log-normal distribution underestimate the percentage of homes with radon concentrations at the thresholds of 300 Bq/m3 and above, which is better estimated by using GMtr and GSDtr. Based on the results of radon survey, a new national radon reference level of 300 Bq/m3 and an "urgent action level" of 1000 Bq/m3 are suggested, with estimated fractions of the national dwelling stock above these levels of 7.4% and 0.8% respectively. Fractions of homes with radon concentrations above the suggested levels are also estimated for each of the 23 municipalities in Montenegro, using appropriate GMtr and GSDtr. The six municipalities which have more than 10% of homes with radon concentration above 300 Bq/m3 are recommended as radon priority areas. PMID- 29501267 TI - Paradoxical Cerebral Embolism after Gastrointestinal Endoscopy in a Patient with Crohn's Disease. AB - Development of paradoxical cerebral embolism requires both unstable venous thrombosis and right-to-left shunt (RLS). Gastrointestinal endoscopy (GE) has the potential to affect intrathoracic and abdominal venous thrombi and to enhance RLS because the procedure alters intrathoracic and abdominal pressure. We describe a patient with Crohn's disease who developed paradoxical cerebral embolism after GE. Both an unstable venous thrombus in the superior vena cava and RLS through patent foramen ovale were thought to be responsible for the stroke. Considering that patients with digestive system diseases undergo GE as a routine examination or therapy, screenings for hypercoagulable state and intrathoracic and abdominal thrombi are important to prevent thromboembolism related to GE. PMID- 29501266 TI - Crystal structure of Brugia malayi venom allergen-like protein-1 (BmVAL-1), a vaccine candidate for lymphatic filariasis. AB - Brugia malayi is a causative agent of lymphatic filariasis, a major tropical disease. The infective L3 parasite stage releases immunomodulatory proteins including the venom allergen-like proteins (VALs), which are members of the SCP/TAPS (Sperm-coating protein/Tpx/antigen 5/pathogenesis related-1/Sc7) superfamily. BmVAL-1 is a major target of host immunity with >90% of infected B. malayi microfilaraemic cases being seropositive for antibodies to BmVAL-1. This study is part of ongoing efforts to characterize the structures and functions of important B. malayi proteins. Recombinant BmVAL-1 was produced using a plant expression system, crystallized and the structure was solved by molecular replacement and refined to 2.1 A, revealing the characteristic alpha/beta/alpha sandwich topology of eukaryotic SCP/TAPS proteins. The protein has more than 45% loop regions and these flexible loops connect the helices and strands, which are longer than predicted based on other parasite SCP/TAPS protein structures. The large central cavity of BmVAL-1 is a prototypical CRISP cavity with two histidines required to bind divalent cations. The caveolin-binding motif (CBM) that mediates sterol binding in SCP/TAPS proteins is large and open in BmVAL-1 and is N-glycosylated. N-glycosylation of the CBM does not affect the ability of BmVAL-1 to bind sterol in vitro. BmVAL-1 complements the in vivo sterol export phenotype of yeast mutants lacking their endogenous SCP/TAPS proteins. The in vitro sterol-binding affinity of BmVAL-1 is comparable with Pry1, a yeast sterol transporting SCP/TAPS protein. Sterol binding of BmVAL-1 is dependent on divalent cations. BmVAL-1 also has a large open palmitate-binding cavity, which binds palmitate comparably to tablysin-15, a lipid-binding SCP/TAPS protein. The central cavity, CBM and palmitate-binding cavity of BmVAL-1 are interconnected within the monomer with channels that can serve as pathways for water molecules, cations and small molecules. PMID- 29501268 TI - Significant Association between OPG/TNFRSF11B Variant and Common Complex Ischemic Stroke. AB - BACKGROUND: The serum level of osteoprotegerin (encoded by OPG or TNFRSF11B) was previously shown to be increased in patients with ischemic stroke. A single nucleotide polymorphism rs3134069 in the TNFRSF11B gene was previously associated with ischemic stroke in a population of diabetic patients in Italy. It remains to be determined whether rs3134069 is associated with ischemic stroke in the general population or populations without diabetes. MATERIALS AND METHODS: We genotyped rs3134069 and performed a case-control association study to test whether rs3134069 is associated with ischemic stroke in 2 independent Chinese Han populations, including a China-Central population with 1629 cases and 1504 controls and a China-Northern population with 1206 cases and 720 controls. RESULTS: rs3134069 showed significant association with ischemic stroke in the China-Central population (P = 9.24 * 10-3, odds ratio [OR] = 1.50). The association was replicated in the independent China-Northern population (P = 2.45 * 10-4, OR = 1.53). The association became more significant in the combined population (P = 7.09 * 10-6, OR = 1.41). The associations remained significant in the male population, female population, and population without type 2 diabetes. Our expression quantitative trait loci analysis found that the minor allele C of rs3134069 was significantly associated with a decreasedexpression level of TNFRSF11B (P = .002). CONCLUSIONS: This study demonstrates that rs3134069 in TNFRSF11B increases risk of ischemic stroke by decreasing TNFRSF11B expression. PMID- 29501269 TI - A Simple Score That Predicts Paroxysmal Atrial Fibrillation on Outpatient Cardiac Monitoring after Embolic Stroke of Unknown Source. AB - BACKGROUND: Occult paroxysmal atrial fibrillation (AF) is detected in 16%-30% of patients with embolic stroke of unknown source (ESUS). The identification of AF predictors on outpatient cardiac monitoring can help guide clinicians decide on a duration or method of cardiac monitoring after ESUS. METHODS: We included all patients with ESUS who underwent an inpatient diagnostic evaluation and outpatient cardiac monitoring between January 1, 2013, and December 31, 2016. Patients were divided into 2 groups based on detection of AF or atrial flutter during monitoring. We compared demographic data, clinical risk factors, and cardiac biomarkers between the 2 groups. Multivariable logistic regression was used to determine predictors of AF. RESULTS: We identified 296 consecutive patients during the study period; 38 (12.8%) patients had AF detected on outpatient cardiac monitoring. In a multivariable regression analysis, advanced age (ages 65-74: odds ratio [OR] 2.36, 95% confidence interval [CI] .85-6.52; ages 75 or older: OR 4.08, 95% CI 1.58-10.52) and moderate-to-severe left atrial enlargement (OR 4.66, 95% CI 1.79-12.12) were predictors of AF on outpatient monitoring. We developed the Brown ESUS-AF score: age (65-74 years: 1 point, 75 years or older: 2 points) and left atrial enlargement (moderate or severe: 2 points) with good prediction of AF (area under the curve .725) and was internally validated using bootstrapping. The percentage of patients with AF detected in each score category were as follows: 0: 4.2%; 1: 14.8%; 2: 20.8%; 3: 22.2%; 4: 55.6%. CONCLUSIONS: The Brown ESUS-AF score predicts AF on prolonged outpatient monitoring after ESUS. More studies are needed to externally validate our findings. PMID- 29501270 TI - The Mystery and Enigma of Spontaneous Coronary Artery Dissection. PMID- 29501271 TI - Entropic, vernacular and vehicular. PMID- 29501272 TI - Enhancement of microalgal growth and biocomponent-based transformations for improved biofuel recovery: A review. AB - Microalgal biomass has received much attention as feedstock for biofuel production due to its capacity to accumulate a substantial amount of biocomponents (including lipid, carbohydrate, and protein), high growth rate, and environmental benefit. However, commercial realization of microalgal biofuel is a challenge due to its low biomass production and insufficient technology for complete utilization of biomass. Recently, advanced strategies have been explored to overcome the challenges of conventional approaches and to achieve maximum possible outcomes in terms of growth. These strategies include a combination of stress factors; co-culturing with other microorganisms; and addition of salts, flue gases, and phytohormones. This review summarizes the recent progress in the application of single and combined abiotic stress conditions to stimulate microalgal growth and its biocomponents. An innovative schematic model is presented of the biomass-energy conversion pathway that proposes the transformation of all potential biocomponents of microalgae into biofuels. PMID- 29501273 TI - Recent developments in biohythane production from household food wastes: A review. AB - Biohythane is a hydrogen-methane blend with hydrogen concentration between 10 and 30% v/v. It can be produced from different organic substrates by two sequential anaerobic stages: a dark fermentation step followed by a second an anaerobic digestion step, for hydrogen and methane production, respectively. The advantages of this blend compared to either hydrogen or methane, as separate biofuels, are first presented in this work. The two-stage anaerobic process and the main operative parameters are then discussed. Attention is focused on the production of biohythane from household food wastes, one of the most abundant organic substrate available for anaerobic digestion: the main milestones and the future trends are exposed. In particular, the possibility to co-digest food wastes and sewage sludge to improve the process yield is discussed. Finally, the paper illustrates the developments of biohythane application in the automotive sector as well as its reduced environmental burden. PMID- 29501274 TI - Do flavouring compounds contribute to aldehyde emissions in e-cigarettes? AB - INTRODUCTION: A recent study identified up to 10,000-fold higher aldehyde emissions from flavoured compared to unflavoured e-cigarette liquids. We set to replicate this study and also test similar flavourings with a new-generation e cigarette device. METHODS: Three liquids with the highest levels of aldehyde emissions in the previous study were tested (in standard and sweetened versions) using the same e-cigarette device and puffing patterns. Additionally, similar flavourings from a different manufacturer were tested using a new-generation e cigarette device. Unflavoured samples were also tested. RESULTS: Low levels of formaldehyde (8.3-62 MUg/g), acetaldehyde (12.1-26.0 MUg/g) and acrolein (5.4 19.4 MUg/g) were detected, lower by up to 589-fold compared to the previous report. Unflavoured liquid emitted 16.1 MUg/g formaldehyde, 5.6 MUg/g acetaldehyde and 2.4 MUg/g acrolein, significantly lower compared to 2 liquids for formaldehyde and 1 for acrolein. Emissions from the new-generation device were even lower. Aldehyde emissions from all flavoured liquids were 79-99.8% lower than smoking and lower than commonly measured indoor levels and occupational and indoor safety limits. CONCLUSIONS: The e-cigarettes tested herein emit very low levels of aldehydes. Some flavourings may contribute to aldehyde emissions, but the absolute levels were minimal. Validated methods should be used when analysing e-cigarette emissions. PMID- 29501275 TI - Effects of perinatal exposure to bisphenol A on the intraprostatic levels of aromatase and 5alpha-reductase isozymes in juvenile rats. AB - The impact of bisphenol A (BPA) on the prostate gland has taken center stage, with a special focus placed on understanding how BPA affects prostate physiopathology. In this study, we evaluated the ability of lower doses of BPA to induce alterations in 5alpha-R isozymes and aromatase, in the prostate of juvenile rats exposed during developmental stage. Gestating Wistar rats were treated s.c with either vehicle or BPA (2.4 and 10 MUg/kg b.w./day) from gestational day 12 to parturition. Then, male pups were s.c treated from postnatal day 1 through day 21, when they were euthanized and qRT-PCR, western blot and hormone levels determination were performed. We found that BPA at dose of 2.4 and 10 MUg/kg b.w./day significantly decreased the mRNA and protein levels of 5alpha-R2. However, neither 5alpha-R1 nor 5alpha-R3 was affected by this exposure. BPA at dose of 10 MUg/kg b.w./day significantly increased the mRNA and protein levels of aromatase. BPA also decreased plasma levels of both testosterone and dihydrotestosterone and increased estradiol. These data lend support that low-dose BPA during fetal and neonatal prostate development interfere with in situ estrogen and androgen production in the prostate gland of juvenile rats through the enzymes aromatase and 5alpha-Reductase. PMID- 29501276 TI - Surgical timing of anterior cruciate ligament reconstruction to prevent associated meniscal and cartilage lesions. AB - BACKGROUND: The purpose of this study was to analyze the association between the prevalence of meniscal and chondral lesions and the timing of surgery in patients undergoing primary anterior cruciate ligament (ACL) reconstruction to determine a safe time for surgery. METHODS: This retrospective study involved 226 patients (91 females and 135 males; median age, 29 years) undergoing primary ACL reconstruction. Time interval from ACL injury to surgery (median, 4 months; range, 1-420 months) and concomitant meniscal and cartilage lesions in ACL reconstruction were reviewed. Receiver operating characteristic (ROC) curve analysis was used to determine the precise threshold interval to surgery to prevent meniscal or cartilage lesions. The risk of lesion occurrence after each cutoff period was determined using odds ratio (OR). RESULTS: The incidences of medial meniscus (MM), lateral meniscus (LM), and cartilage lesions were 43.8%, 32.7%, and 27.4%, respectively. ROC analysis revealed that patients who waited for more than 6, 4, and 5 months for ACL reconstruction had a significantly greater risk of associated MM, LM, and chondral lesions, respectively. Patients who underwent ACL reconstruction >=7 months after injury had OR of 4.1 (p < 0.001) for the presence of MM lesion as compared with those who underwent reconstruction within 6 months. Similarly, patients who underwent ACL reconstruction >=5 months after injury had OR of 1.9 (p = 0.023) for the presence of LM lesion as compared with those who underwent reconstruction within 4 months, and patients who underwent ACL reconstruction >=6 months after injury had OR of 2.9 (p < 0.001) for chondral lesion as compared with those who underwent reconstruction within 6 months. CONCLUSION: ACL reconstruction should be performed within approximately 6 months after the injury to prevent associated meniscal or chondral lesions. PMID- 29501277 TI - Editorial Comment. PMID- 29501279 TI - Corrections. PMID- 29501278 TI - Author Reply. PMID- 29501280 TI - Patterns of Partner and Nonpartner Violence Among High-Risk Youth. AB - PURPOSE: Perpetration of violent behavior begins to increase in adolescence and peaks in young adulthood (e.g., age 18-29) before decreasing by the early 30s. Considerable variability in reported perpetration, targets, and severity of violence suggests youth may change their violent behavior patterns over time. METHODS: We use latent transition analysis to describe profiles of violent behavior against partners and nonpartners in an at-risk sample of young adults (N = 599; 59% male; 61% African-American) over a period of 2 years. RESULTS: A four class solution provided the best fit to the data, with classes corresponding to (1) nonviolent behavior (48.3% of the sample); (2) violent only toward nonpartners (22.3%); (3) violent only toward partners (16.0%); and (4) violent toward nonpartners and partners (13.4%). Participants' sex, race, age, previous violent injury, antisocial behavior, alcohol dependence, and possession of firearms were associated with baseline class membership. CONCLUSIONS: Implications for prevention are discussed. PMID- 29501281 TI - Harm Perceptions of Intermittent Tobacco Product Use Among U.S. Youth, 2016. AB - PURPOSE: We aimed to describe U.S. youth harm perceptions of intermittent tobacco use. METHODS: Using data from the 2016 National Youth Tobacco Survey of U.S. students (grades 6-12; N = 20,675), we examined prevalence and correlates of all respondents' perceived harm of using four different tobacco products on "some days but not every day." Associations between current (past 30-day) use and harm perceptions were assessed using multivariable regression. RESULTS: Perceiving that intermittent use causes "no" or "little" harm was 9.7% for cigarettes, 12.0% for smokeless tobacco, 18.7% for hookah, and 37.5% for e-cigarettes. Compared with those who reported "a lot" of harm, youth with lower harm perceptions were more likely to report current use. CONCLUSIONS: One in ten youth perceived intermittent cigarette smoking as causing "little" or "no" harm; this perception was higher among current users. Efforts to educate youth about the risks of even intermittent tobacco product use could reduce misperceptions of harm. PMID- 29501282 TI - Simplified Preparation of alphavbeta3 Integrin-Targeted Microbubbles Based on a Clinically Available Ultrasound Contrast Agent: Validation in a Tumor-Bearing Mouse Model. AB - The usefulness of ultrasound molecular imaging with alphavbeta3 integrin-targeted microbubbles for detecting tumor angiogenesis has been demonstrated. Recently, we developed alphavbeta3 integrin-targeted microbubbles by modifying clinically available microbubbles (Sonazoid, Daiichi-Sankyo Pharmaceuticals, Tokyo, Japan) with a secreted glycoprotein (lactadherin). The aims of our present study were to simplify the preparation of lactadherin-bearing Sonazoid and to examine the diagnostic utility of lactadherin-bearing Sonazoid for alphavbeta3 integrin expressing tumor vessels by using SK-OV-3-tumor-bearing mice. By incubating 1.2 * 107 Sonazoid microbubbles with 1.0 ug lactadherin, the complicated washing and centrifugation steps during the microbubble preparation could be omitted with no significant reduction in labeling ratio of lactadherin-bearing Sonazoid. In addition, the number of Sonazoid microbubbles accumulated in the SK-OV-3 tumor was significantly increased by modifying Sonazoid with lactadherin. Our data suggest that the lactadherin-bearing Sonazoid is an easily prepared and potentially clinically translatable targeted microbubble for alphavbeta3 integrin expressing vessels. PMID- 29501283 TI - Focused Ultrasound-Induced Suppression of Auditory Evoked Potentials in Vivo. AB - The goal of this study was to determine the feasibility of focused ultrasound based neuromodulation affecting auditory evoked potentials (AEPs) in animals. Focused ultrasound-induced suppression of AEPs was performed in 22 rats and 5 pigs: Repetitive sounds were produced, and the induced AEPs were recorded before and repeatedly after FUS treatment of the auditory pathway. All treated animals exhibited a decrease in AEP amplitude post-treatment in contrast to animals undergoing the sham treatment. Suppression was weaker for rats treated at 2.3 W/cm2 (amplitudes decreased to 59.8 +/- 3.3% of baseline) than rats treated at 4.6 W/cm2 (36.9 +/- 7.5%, p <0.001). Amplitudes of the treated pigs decreased to 27.7 +/- 5.9% of baseline. This effect lasted between 30 min and 1 mo in most treated animals. No evidence of heating during treatment or later brain damage/edema was observed. These results demonstrate the feasibility of inducing significant neuromodulation with non-thermal, non-invasive, reversible focused ultrasound. The long recovery times may have clinical implications. PMID- 29501284 TI - Analysis of causality from observational studies and its application in clinical research in Intensive Care Medicine. AB - Random allocation of treatment or intervention is the key feature of clinical trials and divides patients into treatment groups that are approximately balanced for baseline, and therefore comparable covariates except for the variable treatment of the study. However, in observational studies, where treatment allocation is not random, patients in the treatment and control groups often differ in covariates that are related to intervention variables. These imbalances in covariates can lead to biased estimates of the treatment effect. However, randomized clinical trials are sometimes not feasible for ethical, logistical, economic or other reasons. To resolve these situations, interest in the field of clinical research has grown in designing studies that are most similar to randomized experiments using observational (i.e. non-random) data. Observational studies using propensity score analysis methods have been increasing in the scientific papers of Intensive Care. Propensity score analyses attempt to control for confounding in non-experimental studies by adjusting for the likelihood that a given patient is exposed. However, studies with propensity indexes may be confusing, and intensivists are not familiar with this methodology and may not fully understand the importance of this technique. The objectives of this review are: to describe the fundamentals of propensity index methods; to present the techniques to adequately evaluate propensity index models; to discuss the advantages and disadvantages of these techniques. PMID- 29501285 TI - Impact and safety of open lung biopsy in patients with acute respiratory distress syndrome (ARDS). AB - INTRODUCTION: Acute respiratory distress syndrome (ARDS) is an inflammatory lung disorder, and its pathological hallmark is diffuse alveolar damage (DAD). Given that open lung biopsy (OLB) can sometimes result in severe side effects, it is rarely performed in patients with ARDS. AIM: The aims of this study were to describe: (a) the rate of treatment change associated with the histological result; and (b) the incidence of side effects induced by OLB. DESIGN AND PATIENTS: A retrospective, single-center, descriptive observational study was carried out in Hospital Santa Clara (Bogota, Colombia) from February 2007 to January 2014. INCLUSION CRITERIA: Critically ill patients over 18 years of age, undergoing invasive mechanical ventilation, diagnosed with ARDS of unknown etiology, and with OLB performed at the bedside. ARDS was diagnosed according to the Berlin definition. DAD was defined by the presence of a hyaline membrane plus at least one of the following: intra-alveolar edema, alveolar type I cell necrosis, alveolar type II cell (cuboidal cells) proliferation progressively covering the denuded alveolar-capillary membrane, interstitial proliferation of fibroblasts and myofibroblasts, or organizing interstitial fibrosis. The rate of treatment change (RTC) was established according to whether the OLB pathology report resulted in: a) the prescription or discontinuation of an antimicrobial; b) the indication of new procedures; c) medical interconsultation; or d) limitation of therapeutic effort. Patients were followed-up until death or hospital discharge. This study was approved by the Ethics Committee. RESULTS: A total of 32 OLBs were performed during the study period; 17 were ruled out as they did not involve ARDS, and 15 were considered for further analysis. A histological diagnosis was reached in 14 of the 15 patients (12 DAD, one case of bronchiolitis obliterans organizing pneumonia and one case of Wegener's granulomatosis with alveolar hemorrhage). The RTC rate was 0.73. The most frequent intervention was discontinuation of antimicrobial or corticosteroid treatment. No deaths but four side effects (3 airway leaks and one hemothorax) were associated with the OLB procedure. All were resolved before ICU discharge. CONCLUSION: The information provided by OLB performed at the bedside in ARDS patients of unknown etiology could be relevant, as it may optimize treatment. The risk associated with OLB seems to be acceptable. PMID- 29501286 TI - Otological burdens of Nigerian children with sickle cell disease. AB - INTRODUCTION/OBJECTIVE: Sickle cell disease (SCD) is associated with episodic illnesses, multi-systemic affectations and end-organs damages. Otolaryngological related complications are not unexpected. Studies on the overall Otolaryngological pathologies in children with SCD relative to their non-SCD counterparts are scanty in Nigeria. We hypothesized that children with SCD are likely to have more otological burdens than their non-SCD counterparts. Thus, we embarked on this study to describe and compare the overall ear diseases burdens seen in children with sickle cell disease relative to their non-SCD counterparts. METHODOLOGY: A cross-sectional study of otologic diseases among children with SCD and their non-SCD counterparts attending the paediatrics and otolaryngological clinics of a Nigerian tertiary institution was conducted. RESULTS: Overall, 80 (47.62%) of the 168 ears of SCD patients compared to 37 (22.02%) of the 168 ears of their non-SCD counterparts were affected by diseases (p < 0.0001). The diseases were Wax, Otitis Media with Effusion, Suppurative Otitis Media, Otosclerosis and Sensorineural Hearing Loss (SNHL). There was a significant difference in the prevalence of SNHL and solitary otosclerosis between the SCD patients and their non-SCD counterparts (P < 0.05) respectively. Both the Haemoglobin concentration and HbF did not discriminate between the SCD participants with or without SNHL (P > 0.05). CONCLUSION: This study showed that otological burdens are more prevalent in children with SCD than the non-SCD population. The microbiological peculiarity of suppurative otitis media (SOM) among participants stresses the need for concerted efforts at preventing SOM in SCD children. There is need for special Otolaryngological care for SCD children. PMID- 29501287 TI - Nationwide readmissions after tonsillectomy among pediatric patients - United States. AB - OBJECTIVES: 1) Investigate incidence and predictors of readmissions after tonsillectomy with or without adenoidectomy (T&A) in children. 2) Identify factors that may predict readmission. SETTINGS: Nationwide cross-sectional survey of US hospital admissions. SUBJECTS: and Methods: The 2013 Nationwide Readmission Database (NRD) was used to examine all-cause readmissions within 30 days of T&A in children (age <18 years). Logistic regression was used to analyze the associations of demographics, diagnosis, insurance status, length of index stay, and median household income with readmission. RESULTS: 9079 children undergoing T&A resulted in 327 (3.6%) patients requiring readmission. The average age of children readmitted were 5.0 years and they were 51% female. The most common readmission diagnoses were dehydration (47%), hemorrhage (26%), and pain (16%). The average time to readmission was 7.3 days. The average times to readmission for hemorrhage, pain and dehydration were 6.3, 4.5 and 4.1 days, respectively. Children who needed respiratory intubation (OR = 4.0), had a medical or surgical complication (OR = 3.3), or prolonged hospital stay (OR = 1.03) during the index admission were more likely to be readmitted. Age, gender, payer and socioeconomic status and diagnosis of obstructive sleep apnea (OSA) did not increase the odds of readmission. CONCLUSIONS: Readmissions in children after T&A were primarily due to dehydration, hemorrhage, and pain. Adequate symptom control in children has the greatest potential to reduce readmission rates following T&A. PMID- 29501288 TI - The effect of adenotonsillectomy on the position of head, cervical and thoracic spine and scapular girdle of mouth breathing children. AB - : The clinical decision for surgical treatment of children diagnosed with mouth breathing depends on the percentage of mechanical obstruction correlated with exacerbation of upper respiratory tract infections and systemic changes. The benefits of adenotonsillectomy include changes in the nasopharyngeal space, the mandibular plane and myofunctional alterations. Post-adenotonsilectomy postural benefits have not yet been described. OBJECTIVES: To investigate the kinematics of the shoulder girdle, cervical and thoracic spine in children with mouth breathing before and after adenotonsillectomy. METHODS: Forty-nine mouth breathing children (6.3 +/- 1.8 years) of both sexes participated in the study. The measures of thoracic kyphosis, forward head position, shoulders protrusion and abduction, elevation, anterior tilt and internal rotation of the scapula were evaluated before and after surgery. The kinematic data were obtained using the system Qualysis ProReflex(r). RESULTS: There was a significant decrease in forward head position, shoulders protrusion, elevation and anterior tilt of the scapula after surgery compared to the pre-operative. CONCLUSION: One of adenotonsillectomy results is the improvement of the posture of the head and the shoulder girdle of mouth breathing children. Clinically these findings are important and will contribute to improving the quality of life of mouth breathing children. PMID- 29501289 TI - Treatment of extensive post tonsillectomy oropharyngeal stenosis secondary to fibromatosis. AB - Aggressive fibromatosis is an uncommon, benign tumor of fibroblastic origin with high potential for local invasion. Less than a quarter of these lesions are located in the head and neck, and although extremely rare, associations have been demonstrated with physical trauma. We describe a unique case of oropharyngeal fibromatosis with traumaticetiology, managed successfully with surgical excision of the lesion with negative surgical margins. A 5-year old patient was found to have an aggressive fibromatosis causing oropharyngeal stenosis following tonsillectomy. We demonstrate that surgical resection with a clear margin allowed for alleviation of stenosis without recurrences reported since the procedure. PMID- 29501290 TI - Population-based cross-sectional study to assess newborn hearing screening program in central Germany. AB - OBJECTIVES: Airway management during adenoidectomy is traditionally performed through endotracheal intubation (ETT). Laryngeal mask airway (LMA) may be less stimulating to the airway and allow for shorter overall operating room time. Previous studies report LMA use during adenotonsillectomy with conversion rates to ETT of up to 17%. There has been no prior evaluation of LMA use during adenoidectomy alone. In this study, we attempt to identify the rate and contributing factors of LMA failure during adenoidectomy. METHODS: All pediatric patients undergoing adenoidectomy between January 1, 2016 and June 30, 2017 were reviewed. Demographic and clinical data were collected and analysed to determine the need for conversion to ETT and the occurrence of any complications. RESULTS: Our study revealed 139 pediatric patients who underwent adenoidectomy during the study period. 110 patients had adenoidectomy performed with LMA and 27 patients had ETT. Two patients (1.8%) required conversion to ETT because of difficulty with ventilation when the mouth gag was in place. There were no complications. Mean operating room time was 20 min less in the LMA group (P < 0.05). CONCLUSIONS: The use of an LMA in adenoidectomy may be a safe and effective alternative to ETT. More study is required to determine overall complication rates. PMID- 29501291 TI - GJB2 mutations causing autosomal recessive non-syndromic hearing loss (ARNSHL) in two Iranian populations: Report of two novel variants. AB - OBJECTIVE: Hereditary hearing loss (HL) is a noticeable concern in medicine all over the world. On average, 1 in 166 babies born are diagnosed with HL in Iran, which makes it a major public health issue. Autosomal recessive non-syndromic HL (ARNSHL) is the most prevalent form of HL. Although over 60 genes have been identified for ARNSHL, GJB2 mutations are the most prevalent causes of ARNSHL in many populations. Previous studies have estimated the average frequency of GJB2 mutations to be between 16 and 18% in Iran, but would vary among different ethnic groups. In the present study, we aimed to determine the frequency and mutation profile of 70 deaf patients from two different provinces (center and west) of Iran. METHODS: We enrolled 70 Iranian deaf patients with ARNSHL from Isfahan (40 family) and Hamedan (30 family) provinces. After extraction of genomic DNA, the entire coding region of GJB2 was directly sequenced in all patients. Multiplex PCR was used for detection of del(GJB6-D13S1830) and del(GJB6-D13S1854) in the GJB6 gene. In silico analyses were also performed by available software tools. RESULTS: A total of eleven different mutations were detected, nine of which were previously reported and the other two (c.130T > G and c.178T > G) were novel. Homozygous GJB2 mutations were observed in 22.5% and 20% of all the subjects from Isfahan and Hamedan provinces, respectively. c.35delG was the most frequent mutation. One compound heterozygous genotype (c.358_360delGAG/c.35delG) was observed for c.35delG. Screening for the two GJB6 deletions did not reveal any positive sample among heterozygous or GJB2 negative samples. CONCLUSIONS: The present study suggests that mutations in the GJB2 gene specially c.35delG are important causes of ARNSHL in the center and west of Iran. Totally, 15% of the patients were heterozygous carriers. Further investigation is needed to detect the genetic cause of HL in the patients with monoallelic GJB2 mutations. PMID- 29501292 TI - Volume relationships between cricoid and main stem bronchi in children using three-dimensional computed tomography imaging. AB - BACKGROUND: There are limited data to guide the selection of the appropriate sized endobronchial tube for main stem intubation to provide one-lung ventilation in children. The relationship between the cricoid and the main bronchi (right and left) has been previously evaluated using two-dimensional computed tomography (CT) imaging and video-bronchoscopic images. The present study defines the three dimensional, CT-derived volume-based relationships between the right main-stem bronchus (RMB), left main-stem bronchus (LMB), and the cricoid ring. METHODS: The three-dimensional CT images of 35 children, less than 8 years of age, undergoing radiological evaluation unrelated to airway or mediastinal symptomatology were examined. The images of the airway column were evaluated at the level of the cricoid and main stem bronchi (right and left). Volumes were calculated and comparisons made between these levels. RESULTS: There was no statistically significant difference based on gender for the cricoid and main stem bronchi volumes. A statistically significant difference was observed between the cricoid and left main stem bronchi volumes as well as between the right and left main stem bronchi. CONCLUSION: The relationship (ratio) between the volumes of the cricoid and main stem bronchi remains constant by age. The cricoid dimensions can be used to predict the main stem bronchi dimensions. PMID- 29501293 TI - Meta-analysis of the comorbidity rate of allergic rhinitis and asthma in Chinese children. AB - OBJECTIVES: Allergic rhinitis (AR) and asthma often occur concomitantly and are the two most common inflammatory conditions of the airways in children. Large scale studies investigating the comorbidity of asthma and AR in children are rare. So, we performed a meta-analysis to describe the comorbidity rate of asthma and AR in Chinese children. METHODS: We retrieved related studies from Pubmed, Science, Springer, Elsevier, Embase, BMJ, and four Chinese biomedical databases, including Wanfang Data, VIP, CBM, and CNKI. From these individual studies, the comorbidity rate of asthma and AR in Chinese children was extracted and pooled to generate summary effect estimates in R version 3.2.3. RESULTS: The meta-analysis included 25 cross-sectional studies. The results indicated that in China, the incidence of asthma in children with AR is 35.01% (95% CI: 32.32%-37.70%) and the incidence of AR in children with asthma is 54.93% (95% CI: 53.05%-56.80%). CONCLUSIONS: The comorbidity of AR and asthma is high in Chinese children. Statistically, the prevalence of AR was higher in children with asthma, as opposed to the prevalence of asthma in children with AR. The comorbidity rate of AR and asthma signifies the importance of improving the recognition and treatment under both conditions by respiratory physicians and otolaryngologists. PMID- 29501294 TI - Human beta defensin-1 is involved in the susceptibility to adeno-tonsillar hypertrophy. AB - INTRODUCTION: Innate immunity molecules are known to play a pivotal role in the homeostasis of the oral mucosa, permitting the presence of commensal microflora and, at the same time, providing a first line of defense against pathogens attempting to invade the oral cavity. Tonsils represent the local immune tissue in oral cavity, being able to provide a non-specific response to pathogens; however, in the presence of microbes or foreign materials present in the mouth tonsils could became infected and develop chronic inflammation, thus leading to hypertrophy. The etiology of the disease is multifactorial depending upon environmental and host factors, the latter including molecules of mucosal innate immunity. METHODS: Ninety-five children with adeno-tonsillar hypertrophy subjected to adeno-tonsillectomy were recruited at the pediatric otorhinolaryngology service of the Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste (Italy). The specimen discarded from the surgery were used for genomic DNA extraction and genotyping, for mRNA extraction and gene expression analysis, finally the samples were cut and used to prepare slides to perform immunohistochemistry. RESULTS: Functional polymorphisms within DEFB1 gene, encoding the human beta defensin-1 (hBD-1), were analyzed finding association between DEFB1 rare haplotypes and susceptibility to adeno-tonsillar hypertrophy. DEFB1 mRNA expression was detected in the tonsils and the hBD-1 protein was localized at the epithelia of tonsils mainly in the proximity of the basal lamina. CONCLUSION: Our findings lead us to hypothesize an involvement of hBD-1 mediated innate immunity in the modulation of the susceptibility towards adeno-tonsillar hypertrophy development. PMID- 29501296 TI - A randomized study of four different types of tympanostomy ventilation tubes - Full-term follow-up. AB - OBJECTIVE: To evaluate the impact of tympanostomy ventilation tube material (silicone vs fluoroplastic) and shape (short vs long) regarding time to extrusion, occurrence of otorrhea, occlusion, tube removal and occurrence of persistent perforation. METHODS AND MATERIAL: Four different types of ventilation tubes were used; Long Armstrong tubes, Donaldson tubes, Shepard tubes and straight tubes, representing four specific combinations of VT material (silicone or fluoroplastic) and shape (short, double flanged or long, single flanged). Four hundred children scheduled for bilateral tube insertion were included in a randomized trial. The patients received one type of tube in the right ear and another type in the left ear. The incidence of tube extrusion and complications were monitored postoperatively every third month by an otolaryngologist. RESULTS: Twenty-two children were excluded during surgery. Out of the studied 378 children the mean age was 35.3 months. 63.8% were boys. Short tubes extruded earlier than long tubes; hazard ratio (HR) 4.84 (95% CI 3.50-6.69, p < 0.001). Long Armstrong tubes were least prone to extrude. Silicone tubes resulted in significantly longer time to first infection in a VT ear, HR 1.68 (95% CI 1.03-2.76, p = 0.039). Donaldson tubes rendered the longest mean time to first infection (p = 0.025). Infections did not affect tube extrusion rates significantly (p = 0.879). No significant differences were found regarding tube occlusion, tube extraction or persistent perforation. CONCLUSIONS: Long tubes are less prone to extrude early. Long Armstrong tubes have the least propensity to extrude early. Silicone tubes render significantly longer time to first infection. Donaldson tubes result in least infections. Infection does not affect extrusion rates significantly. LEVEL OF EVIDENCE: 1b. PMID- 29501295 TI - Pediatricians' attitudes in management of acute otitis media and ear pain in Turkey. AB - OBJECTIVES: Acute otitis media (AOM) is predominantly a disease of childhood and one of the common reasons for prescribing antibiotics. Ear pain is the main symptom of AOM, with the result that parents frequently seek immediate medical assistance for their children. Antibiotic therapy for AOM does not provide symptomatic relief in the first 24 hours, and analgesics are commonly recommended for relieving the pain associated with AOM. The aims of the present study were to assess pediatricians' attitudes toward AOM and ear pain management in Turkey. METHODS: This multicenter descriptive questionnaire study was conducted in 20 centers from different geographic locations in Turkey, with 977 pediatricians, between June 2015 and December 2016. The questionnaire comprised 20 questions focusing on the pediatricians' sociodemographic variables, experiences, and treatment related to AOM and ear pain. RESULTS: Of the pediatricians, 58.2% were residents, 36.5% were specialists, and 4.3% were lecturers. Most participants were working in a university hospital (54.8%) or education and research hospital (32.2%). In general daily practice, the AOM diagnosis rates were between 6% and 20% in outpatient clinics, and 52.3% of the participants stated the patients complained about ear pain in pediatric clinics. The watchful waiting (WW) rate, as opposed to immediate antibiotic treatment, was 39.8% for all the pediatricians. The pediatric residents used the WW strategy less than the specialists and lecturers did (p = 0.004). The rates of the WW strategy were higher in outpatient clinics where AOM was commonly diagnosed (p < 0.001). The most common antibiotic prescribed for AOM was amoxicillin clavulanate (76.7%). The mean recommended treatment period for AOM was 9.3 +/- 2.2 days. The choices for systemic ear pain treatment were acetaminophen (26.8%), ibuprofen (29.4%), and alternating between ibuprofen and acetaminophen (43.9%). Moreover, 34.6% of the participants recommended topical agents for otalgia. Topical agents were more commonly recommended by the pediatric residents than specialists or lecturers (p < 0.001). Finally, 58.3% of pediatricians had experiences of the parents' usage of a variety of herbal and folk remedies, such as breast milk or olive oil, for their children's ear pain. CONCLUSION: Amoxicillin clavulanate was the most frequently prescribed antibiotic for AOM. WW was approved by the pediatricians, and having more AOM patients was a significant factor in the physicians' choice of WW; nevertheless, the WW rate was poor. Implementation of educational intervention strategies will help pediatricians in improving their compliance with evidence-based guidelines for AOM treatment. Otalgia is taken seriously by parents and pediatricians, and otalgia treatment seems to be well accepted in Turkey for providing symptomatic relief and enhancing the patients' quality of life. PMID- 29501297 TI - Tracheal paraganglioma presenting as stridor in a pediatric patient, case report and literature review. AB - OBJECTIVE: To review tracheal paragangliomas and describe the clinical presentation, radiologic findings, operative management, and histologic findings of a pediatric patient who presented with stridor refractory to traditional asthma therapy. METHODS: Chart review of an 8-year-old male who presented to a tertiary care pediatric hospital and literature review of tracheal paragangliomas. RESULTS: We present the case of an 8-year-old male who presented with new-onset of wheezing and dyspnea on exertion. He was given a new diagnosis of asthma and treated with bronchodilators that failed to improve his symptoms, which progressed over 3 months until he presented urgently with biphasic stridor. Bedside flexible laryngoscopy failed to reveal an etiology. Computed tomography (CT) imaging demonstrated 17 * 12 * 16 mm exophytic mass arising from the posterior membranous trachea with extension of the mass to the border of the thyroid gland and separate from the esophagus. Magnetic resonance imaging (MRI) angiography confirmed vascular supply from the right thyrocervical trunk and inferior thyroid artery. Rigid microlaryngoscopy revealed a friable vascular polypoid mass 2 cm distal to the vocal folds with 75% obstruction of the airway from which a small biopsy was taken. Pathology confirmed paraganglioma with neuroendocrine cells arranged in "zellballen" architecture and strong immunopositivity for chromogranin and synaptophysin in the neuroendocrine cells and S100 immunopositivity in the sustentacular cells. The patient underwent complete open resection of the tumor including three tracheal rings with primary anastomosis. Final pathology confirmed paraganglioma and negative margins. Genetic screening revealed a succinate dehydrogenase complex subunit C (SDHC) germline mutation, confirming hereditary paraganglioma/pheochromocytoma syndrome. He remains well at 3 month follow up without dyspnea or stridor. CONCLUSION: Tracheal paragangliomas are exceptionally rare, with 12 reported cases. This is the only pediatric case reported. In pediatric patients with persistent airway complaints, subglottic and tracheal masses and obstruction should be considered. Due to the vascularity and endotracheal component of tracheal paragangliomas, a detailed surgical plan should consider embolization, endotracheal laser photocoagulation and electrocautery, and open surgical resection. Additionally, pediatric patients benefit from a multidisciplinary approach including radiology, endocrinology, and genetic counseling. PMID- 29501298 TI - Noise level in neonatal incubators: A comparative study of three models. AB - BACKGROUND: Preterm infants usually have to spend a long time in an incubator, excessive noise in which can have adverse physiological and psychological effects on neonates. In fact, incubator noise levels typically range from 45 to 70 dB but differences in this respect depend largely on the noise measuring method used. The primary aim of this work was to assess the extent to which noise in an incubator comes from its own fan and how efficiently the incubator can isolate external noise. METHODS: Three different incubator models were characterized for acoustic performance by measuring their internal noise levels in an anechoic chamber, and also for noise isolation efficiency by using a pink noise source in combination with an internal and an external microphone that were connected to an SVAN958 noise analyzer. RESULTS: The incubators studied produced continuous equivalent noise levels of 53.5-58 dB and reduced external noise by 5.2-10.4 dB. CONCLUSIONS: A preterm infant in an incubator is exposed to noise levels clearly exceeding international recommendations even though such levels usually comply with the limit set in the standard IEC60601-2-19: 2009 (60 dBA) under normal conditions of use. PMID- 29501299 TI - Indirect management of full-thickness tracheal erosion in a complex pediatric patient. AB - Prolonged tracheostomy dependence in pediatric patients can be associated with significant complications, including damage to the tracheal wall requiring reconstruction. We present a case of an 8 year-old female with full-thickness tracheal erosion secondary to the presence of a tracheostomy tube combined with a narrow thoracic inlet. A direct tracheal reconstruction was considered but eliminated due to the poor tissue quality of the trachea. Instead, a multi disciplinary surgical team conceived of a novel indirect approach to manage the patient's tracheal defect. To our knowledge the use of indirect repair of a full thickness tracheal defect has not been reported in the literature. PMID- 29501300 TI - Granulomatosis with polyangiitis presenting as facial nerve palsy in a teenager. AB - Granulomatosis with polyangiitis (GPA, previously known as Wegener's granulomatosis) is an autoimmune systemic small-vessel vasculitis, associated with the presence of anti-neurophil cytoplasmic antibodies with a cytoplasmic staining pattern (c-ANCA). It is characterized by necrotizing granulomas, usually affecting the airways and kidneys. GPA should be considered when patients do not improve despite adequate treatment of otologic symptoms, when patients have unspecific symptoms suggesting systemic disease (e.g. fever, malaise), or when other organs are involved (kidney, lungs, etc.). We present an interesting case of a 14-year-old female with eight-weeks of bilateral otalgia, unilateral facial nerve palsy, decreased appetite, and fatigue refractory to steroid, anti-viral, and antibiotic treatment ultimately diagnosed with GPA. PMID- 29501301 TI - Healthcare and psychosocial experiences of individuals with craniofacial microsomia: Patient and caregivers perspectives. AB - OBJECTIVE: Craniofacial microsomia (CFM) is primarily characterized by underdevelopment of the ear and mandible, with several additional possible congenital anomalies. Despite the potential burden of care and impact of CFM on multiple domains of functioning, few studies have investigated patient and caregiver perspectives. The objective of this study was to explore the diagnostic, treatment-related, and early psychosocial experiences of families with CFM with the aim of optimizing future healthcare delivery. METHODS: Forty two caregivers and nine adults with CFM responded to an online mixed-methods survey. Descriptive statistics and qualitative methods were used for the analysis. RESULTS: Survey respondents reported high rates of subspecialty evaluations, surgeries, and participation in therapies. Some participants reported receiving inaccurate or incomplete information about CFM and experienced confusion about etiology. Communication about CFM among family members included mostly positive messages. Self-awareness of facial differences began at a mean age of three years and teasing at mean age six, with 43% of individuals four years or older reporting teasing. Teasing often involved name-calling and frequent reactions were ignoring and negative emotional responses. Participants ranked "understanding diagnosis and treatment" as a top priority for future research and had the most questions about etiology and treatment guidance. CONCLUSIONS: The survey results on the healthcare and psychosocial experiences from birth through adulthood of individuals with CFM reinforce the need for ongoing psychological assessment and intervention. Healthcare provision could be improved through establishing diagnostic criteria and standardized treatment guidelines, as well as continued investigation of CFM etiology. PMID- 29501302 TI - Comparing audiological outcomes between the Bonebridge and bone conduction hearing aid on a hard test band: Our experience in children with atresia and microtia. AB - INTRODUCTION: To compare the audiological results of Bone Conduction Hearing Aid (BCHA) on hard test band and Bonebridge (BB) implant among children with microtia and atresia. METHODS: This is a retrospective review of patients with microtia and atresia who underwent BB implant insertion from September 2014 to February 2017 in Starship Children's Hospital. Preoperative audiological testing using a powered BCHA (Oticon Medical Ponto Pro Power) on a hard test band was used to compare post-operative hearing assessments with the BB. RESULTS: Ten microtia and atresia patients were treated with a BB of whom three were treated bilaterally The children were aged between 5 and 15 and all had moderate to moderately severe conductive hearing loss. For each ear tested and subsequently implanted, BB aided speech scores were equivalent to that obtained by a BCHA. The mean improvement of speech reception threshold level between unaided and BB was statistically significant (p > 0.0001). Subjective questionnaire data indicated that BB implanted patients were performing within the norms of overall listening, both in quiet and in noise. Aided Speech In Noise (SIN) testing values were found to range from 0.8-6.5 for BCHA and 0.2-1.2 for BB and the difference was not statistically significant with a p value of 0.143. CONCLUSION: In audiologic assessments BB performs comparably to BCHA among children with microtia and atresia. PMID- 29501303 TI - Auditory and language development in Mandarin-speaking children after cochlear implantation. AB - OBJECTIVE: To evaluate early auditory performance, speech perception and language skills in Mandarin-speaking prelingual deaf children in the first two years after they received a cochlear implant (CI) and analyse the effects of possible associated factors. METHODS: The Infant-Toddler Meaningful Auditory Integration Scale (ITMAIS)/Meaningful Auditory Integration Scale (MAIS), Mandarin Early Speech Perception (MESP) test and Putonghua Communicative Development Inventory (PCDI) were used to assess auditory and language outcomes in 132 Mandarin speaking children pre- and post-implantation. RESULTS: Children with CIs exhibited an ITMAIS/MAIS and PCDI developmental trajectory similar to that of children with normal hearing. The increased number of participants who achieved MESP categories 1-6 at each test interval showed a significant improvement in speech perception by paediatric CI recipients. Age at implantation and socioeconomic status were consistently associated with both auditory and language outcomes in the first two years post-implantation. CONCLUSION: Mandarin-speaking children with CIs exhibit significant improvements in early auditory and language development. Though these improvements followed the normative developmental trajectories, they still exhibited a gap compared with normative values. Earlier implantation and higher socioeconomic status are consistent predictors of greater auditory and language skills in the early stage. PMID- 29501304 TI - Sleep endoscopy findings in children with persistent obstructive sleep apnea after adenotonsillectomy. AB - OBJECTIVES: Describe the patterns of obstruction in persistent pediatric OSA and their relationship with patient weight. STUDY DESIGN: Retrospective review. METHODS: All pediatric DISE procedures performed at a tertiary care hospital between October 2010 and October 2015 were reviewed. Patients had polysomnography after adenotonsillectomy that confirmed persistent obstructive sleep apnea (OSA). Variables included age, gender, co-morbidities, and AHI. DISE findings focused on inferior turbinates, adenoid, tongue base, epiglottis, aryepiglottic (AE) folds, arytenoids, lingual tonsil and their contributions to obstruction. RESULTS: 34 patients were included with mean age of 7.85 (2-16) years, mean BMI of 23.15 (13.6-44.8) and mean AHI of 6.34 (1.5-25.2) events per hour. Obstruction occurred at the level of the epiglottis in 97%, with retropositioning by tongue base (73.6%) or lingual tonsil enlargement (70.5%). Obstruction occurred at the inferior turbinates in 76.5%, the adenoid in 64.7% and the palate in 58.8%. Shortened AE folds were less often identified (15%). Multiple sites of partial or complete obstruction were found in 97% of patients. Overweight or obese patients had a mean of 3 sites of complete obstruction and 4.69 sites of partial or complete obstruction as compared to 2.33 and 4.52 in underweight or normal weight children. Overweight or obese children were more likely to have obstruction at the lingual tonsil or adenoid than normal/underweight children. CONCLUSION: Multiple sites of obstruction in persistent pediatric OSA were found. Children with higher BMIs had slightly different findings, suggesting that attention to adenoid regrowth and lingual tonsil hypertrophy is important. PMID- 29501305 TI - Superiorly-based turnover skin flap: Pediatric tracheocutaneous fistula closure. AB - OBJECTIVE: To present a novel superiorly-based turnover skin flap for the primary repair of pediatric tracheocutaneous fistula closure, and to determine the efficacy and safety of this tracheocutaneous fistula turnover flap primary closure technique. SUBJECT AND METHODS: This retrospective review analyzed one surgeon's (DJK) pediatric tracheostomy decannulation methods and results, specifically relating to the development of tracheocutaneous fistulas, over a fourteen-year period, from October 2002 through June 2016. The review furthermore examined a turnover flap technique for the primary closure of tracheocutaneous fistulas described herein. RESULTS: Over the period of study, 57 patients were decannulated, of whom 31 (54%) developed a tracheocutaneous fistula. Mean duration of tracheostomy in patients who developed a tracheocutaneous fistula following decannulation was forty-two months compared to thirteen months in patients who did not. Duration of decannulation was an independently significant variable (P < .001) in tracheocutaneous fistula development while gender, age at tracheostomy and age at decannulation were not (P > .05). Of the 31 patients who developed a tracheocutaneous fistula, 30 (97%) elected to pursue tracheocutaneous fistula closure using the turnover flap technique described in this study. Mean time from decannulation to tracheocutaneous fistula repair was 132 days. All tracheocutaneous fistulas were successfully closed. There were no perioperative or postoperative complications and no patient required subsequent hospitalization or surgical revision. CONCLUSIONS: The turnover technique presented is simple, straightforward, reliable, safe, and effective with excellent cosmetic results. PMID- 29501306 TI - Bilateral congenital cholesteatoma: A case report and review of the literature. AB - OBJECTIVES: Congenital cholesteatoma (CC) occurs less commonly than acquired cholesteatoma (AC), and bilateral CC (BCC) is even more rare with only 38 such cases having been reported in the past 42 years. Because of the rarity of this condition, providers confronted with cases of BCC may find it difficult to treat while balancing complete removal of disease, optimal hearing outcomes, and minimized surgical burden in the pediatric patient. This review alerts physicians that BCC occurs, highlights past presentations and management strategies, describes the considerations in treatment and offers an algorithm helpful in the management of BCC. METHODS: Review of a single case with extensive review of published reports from 1975 to 2017 pertaining to management of BCC. RESULTS: A five-year-old boy presented with bilateral congenital cholesteatoma. Tympanomastoidectomy was performed to remove cholesteatoma in the left ear then in the right ear months later. Ossicular chain reconstruction was deferred in both cases. Second look procedures revealed persistent cholesteatoma in both ears. In the descriptions of the 38 published BCC cases, the extent and location of the CC varied widely as did the approach to management. In the 18 cases that had descriptions of surgical management, four had second look procedures. In the 16 reports that described extent of cholesteatoma, 12 had the first of two or more operations on the ear with more extensive cholesteatoma. CONCLUSIONS: Risks are increased for recidivism/recurrence and hearing impairment in children with BCC compared to children with unilateral CC. We present a novel algorithm for management of BCC that recommends surgery for cholesteatoma removal first in the more severely affected ear and delayed OCR for both ears. Simultaneous surgery may be considered in certain cases. PMID- 29501307 TI - Respiratory events after adenotonsillectomy requiring escalated admission status in children with obstructive sleep apnea. AB - OBJECTIVES: To characterize postoperative respiratory complications following adenotonsillectomy (AT) in children with obstructive sleep apnea (OSA) and to identify variables associated with pediatric intensive care unit (PICU) admission. METHODS: Retrospective analysis of 133 pediatric OSA patients with prior AT. Assessment of the postoperative hospital course informed patient stratification based on respiratory event severity, PICU admission status, and unscheduled escalation of care. RESULTS: Thirty-six (26.8%) patients were admitted to the PICU. Compared to non-PICU admissions, these patients were significantly younger and with greater preoperative apnea-hypopnea indices, comorbidities, and percentage of post-anesthesia care unit (PACU) time requiring supplemental oxygen. Seventy-one respiratory events occurred in 59 patients, with 60.6% affecting PICU patients. Fifteen severe events occurred, affecting 31% of PICU patients. Of 14 unscheduled escalations of care, 7 were PICU admissions who, compared to planned PICU admissions, spent significantly more time in the PACU and exhibited a trend towards greater PACU time on supplemental oxygen. CONCLUSIONS: Pediatric patients requiring post-AT PICU care have more risk factors for respiratory compromise. Total PACU time and total PACU time requiring supplemental oxygen may indicate patient risk for postoperative respiratory complications and need for intensive care. Future work includes prospective determination of appropriate post-AT PICU admission. PMID- 29501308 TI - Prevalence of upper respiratory tract infections in habitually snoring and mouth breathing children. AB - OBJECTIVES: The aim of the study was to investigate the prevalence of upper respiratory tract infections (URI) - as indicated by rhinosinusitis (RS), ear infections (EI), and antibiotic consumption - in a general pediatric population and evaluate the relationship between these conditions and habitual snoring and mouth breathing during sleep. METHODS: A population-based cross-sectional study was performed in three medium-sized Polish cities from 2011 to 2015. RESULTS: 4837/6963 questionnaires (69.5%) were completed, returned and analyzed. Mean age of studied group was 7.07 +/- 0.72 and 7.14 +/- 0.73 in girls and boys, respectively. Habitual mouth breathing during sleep (MB) was reported in 907 (18.7%) children and habitual snoring (HS) in 290 (6.0%). 230/290 (79.3%) of children with HS were also MB. Both HS and MB were more prevalent in boys than in girls (p = 0.027 and p < 0.0001, respectively) and neither was associated with BMI (p = 0.11 and p = 0.07, respectively). Habitual snoring and habitual mouth breathing were highly associated with more frequent bouts of rhinosinusitis, ear infections, and antibiotic use (p < 0.0001 for each parameter). CONCLUSIONS: Higher rates of rhinosinusitis, ear infections, and antibiotic consumption were similarly associated with HS and MB. MB is over three times more prevalent in the pediatric population relative to HS, therefore it might be considered as a risk factor for URI and may be included in history of URI. PMID- 29501309 TI - The use of laryngeal mask airway for adenoidectomy. AB - OBJECTIVES: Airway management during adenoidectomy is traditionally performed through endotracheal intubation (ETT). Laryngeal mask airway (LMA) may be less stimulating to the airway and allow for shorter overall operating room time. Previous studies report LMA use during adenotonsillectomy. There has been no prior evaluation of LMA use during adenoidectomy alone. In this study, we attempt to identify the rate and contributing factors of LMA failure during adenoidectomy. METHODS: All pediatric patients undergoing adenoidectomy between January 1, 2016 and June 30, 2017 were reviewed. Demographic and clinical data were collected and analyzed to determine the need for conversion to ETT and the occurrence of any complications. RESULTS: Our study revealed 139 pediatric patients who underwent adenoidectomy during the study period. 110 patients had adenoidectomy performed with LMA and 27 patients had ETT. Two patients (1.8%) required conversion to ETT because of difficulty with ventilation when the mouth gag was in place. There were no complications. Mean operating room time was 20 min less in the LMA group (P < 0.05). CONCLUSIONS: The use of an LMA in adenoidectomy may be a safe and effective alternative to ETT. More study is required to determine overall complication rates. PMID- 29501310 TI - Risk factors for laryngeal trauma and granuloma formation in pediatric intubations. AB - OBJECTIVE: Intubation has been associated with laryngeal injury that often resolves spontaneously without complication. We present a case of a child intubated for less than 48 hours, who presented with dysphonia and intermittent dyspnea two months after intubation due to epiglottic and vocal process granulomas. This is unusual in that multiple granulomas were found in the posterior glottis and supraglottis after short-term intubation. Our objective was to determine if there are risk factors for developing persistent post-intubation sequelae, including the delayed presentation and unusual location of post intubation granulomas in our case. STUDY DESIGN: Case report and systematic literature review. METHODS: Pubmed database, which is inclusive of MEDLINE, was used to perform a literature review with the search terms ((pediatric OR children OR neonatal OR infant) AND (laryngeal OR supraglottic) AND intubation AND (granuloma OR injury OR complication)). Only English language results were reviewed. Titles and abstracts from 379 results were reviewed. Full text was reviewed from all original studies which included human pediatric subjects and endoscopic examinations after endotracheal intubation. RESULTS: In our case, laryngeal granuloma size reduced significantly after starting anti-reflux medications. The remainder was removed with laryngeal microdebrider with no recurrence at 3 weeks and 2.5 years post-operatively. Overall, 28 of the 379 studies reviewed identified evidence of laryngeal trauma due to intubation, however only 6 studies documented any type of supraglottic injury. Risk factors identified for developing post-intubation sequelae included intubation duration greater than 24 h; trauma to the larynx via various mechanisms including traumatic intubation, need for reintubation and tube changes, and increased movement while intubated; and presence of respiratory tract infection during intubation. CONCLUSION: Trauma to the larynx during intubation should be avoided to minimize post-intubation injury in pediatric patients, by using appropriate intubation protocols, endotracheal tube size, and adequate sedation. PMID- 29501311 TI - Anatomical variations of the thymus in relation to the left brachiocephalic vein, findings of necropsia. AB - Two cases of anatomical variations of the thymus are presented with respect to the anatomical relations with the left brachiocephalic vein and found during the necropsy process. Less than 2 days after birth with Noonan Syndrome, when the left brachiocephalic vein was scanning behind the upper thymus horns, there were other adjacent lesions consisting of three supernumerary spleens and three hepatic veins. The second case was an 8-year-old infant with child malpractice who died from urinary sepsis due to obstructive uropathy, in which case the upper lobes of the thymus were fused and formed a ring through which the left brachiocephalic vein passed. PMID- 29501312 TI - Immunomodulatory effect of Polypodium leucotomos (Anapsos) in child palatine tonsil model. AB - BACKGROUND: Recurrent tonsillitis might reduce the immunological capability of fighting against the infection of tonsil tissue. Polypodium leucotomos (Anapsos) immunomodulating effect has been subject of research in the last years. The aim of this research is to test the in vitro immunomodulating capacity of Anapsos in a child palatine tonsil explants model. METHODS: Palatine tonsils explants of children undergoing amigdalectomy were stimulated with mononuclear cells obtained from their own blood by density gradient centrifugation. Some were then treated with Anapsos while others rest untreated. Cytokines were measured by ELISA, immune cells activation was measured by flow cytometry and activation of immunoglobulins was appreciated by indirect immunofluorescence in tonsils tissue. RESULTS: Anapsos activates Natural Killers cells. It increases IL-2 and IFN-gamma levels by the activation of Th2 lymphocytes, and IL-10, by the Th1 lymphocytes. Anapsos also increases immunoglobulins IgM, IgD and IgG4 by B-lymphocyte activation in tonsils tissue. CONCLUSION: Anapsos has an immunomodulating effect, both in humoral and cellular responses, which might benefit children suffering of recurrent tonsillitis as it could enhance their immune system. This effect might reduce the number of episodes suffered and therefore the number of children undergoing surgery. PMID- 29501313 TI - Diagnosis and treatment of paradoxical vocal fold motion in infants. AB - IMPORTANCE: Paradoxical vocal fold motion (PVFM) is a disorder often misdiagnosed in children presenting with shortness of breath and stridor. In infants, little is known about the clinical course and best approach for treatment of PVFM. This retrospective study assesses the approach to treatment and outcomes for infants with PVFM. OBJECTIVE: To investigate the clinical course of paradoxical vocal fold motion (PVFM) in infants. DESIGN: Retrospective review. SETTING: Tertiary academic medical center. PARTICIPANTS: Patients less than 2 years of age diagnosed with PVFM were identified and included in the study. MAIN OUTCOMES AND MEASURES: History, physical exam findings, and clinical course of treatment for patients less than 2 years old with PVFM were reviewed. Findings including those on flexible fiberoptic laryngoscopy (FFL) and subjective assessment by parents and clinicians were compiled for review. RESULTS: Seven infants were diagnosed with PVFM. All patients were full term at birth, and average age at diagnosis was 7 months. All patients initially presented with inspiratory stridor, and two patients had stertor. Two of seven patients also had a history of reactive airway disease and one with laryngomalacia. Five had a history of reflux. Two of seven patients had weight percentiles at diagnosis lower than the 25th percentile, while the remainder were between 37th and 75th percentiles. Initial voice evaluation revealed stridor in all patients, as well as finding of PVFM on FFL. All patients were started on anti-reflux medication. Average time to resolution of PVFM was 5.9 months after treatment. CONCLUSIONS: PVFM can be challenging to diagnose in the infant population. PVFM resolves uneventfully with reflux treatment, however, it is unknown whether reflux treatment is essential or if PVFM would spontaneously resolve. The rarity of infantile PVFM mandates formal evaluation and monitoring by a pediatric otolaryngologist. PMID- 29501314 TI - Translation and validation of the Listen Inventory for Education Revised into Dutch. AB - INTRODUCTION: In Belgium the majority of children with CI's are being educated in mainstream schools. In mainstream schools difficult listening situations occur (e.g. due to background noise) which may result in educational risks for children with CI's. A tool that identifies potential listening difficulties, the English Listen inventory for Education Revised (LIFE-R), was translated and validated into Dutch for elementary and secondary schools (LIFE-NL, LIFE2-NL respectively). METHODS: Two forward-backward translations were performed followed by a linguistic evaluation and validation by a multidisciplinary committee. The LIFE NL was further validated on content by pre-testing the questionnaire in 5 students with hearing loss (8-13 years). After minor cross-cultural adaptations normative data were assembled from 187 normal-hearing (NH) students enrolled in mainstream secondary education (1st to 4th grade). The normative data were further analysed based on grade and school type. Additionally, the internal consistency was evaluated by calculating Cronbach's alpha for 3 different scales of the LIFE2-NL: the LIFE total (situation 1-15), LIFE class (situation 1-10: listening situations in classroom) and LIFE social (situation 11-15: social listening situations in school). RESULTS: NH students scored on average 72.0 (SD = 19.9%) on the LIFE2-NL, indicating they experience some difficulties in secondary mainstream schools. The most difficult listening situations were those where fellow students are noisy or when students have to listen in large classrooms. NH students scored significantly higher on the LIFE class compared to the LIFE social (84.1 +/- 14.7% vs. 68.1 +/- 19.0%, p < .000). Moreover the LIFE social tend to decrease from the 3rd grade on. The different subscales of the LIFE2-NL showed high internal consistency (Cronbach's alpha of 0.86, 0.89 and 0.75 for LIFE total, LIFE class and LIFE social respectively). CONCLUSION: The LIFE-NL and LIFE2-NL are valid Dutch translations of the original LIFE-R and are fully comprehensible for students with hearing loss. The normative data of the LIFE2-NL provide a representative framework for interpreting the results of mainstreamed students with hearing loss in secondary schools. PMID- 29501315 TI - Mainstream school readiness skills of a group of young cochlear implant users. AB - OBJECTIVES: The aims of the study were to compare the mainstream school readiness skills of young cochlear implant (CI) users to that of a group of normal hearing (NH) children and assessed the inter-rater agreement between parents and teachers on school readiness skills of the CI children. METHODS: A total of 11 parents and 8 teachers of the 6-year old CI children participated and rated the children using the School Readiness Scale to Year One. Data from 207 6-year old NH children from five states in Malaysia were also collected using the same scale which has nine domains. Results from the NH children were categorized into the 25th and 75th percentile scores to be the reference cut-offs for below average (below the 25th percentile), average (25th to 75th percentile) and above average (above 75th percentile). RESULTS: The school readiness skills of the CI children were lower than the NH group as rated by teachers especially in the civic and language and communication domains. Comparisons between parents' and teachers' ratings for 8 CI children indicated that teachers tended to rate the CI children's school readiness poorer than that of parents especially in the academic domain. Intra-class correlation analysis revealed poor inter-rater agreement. CONCLUSIONS: The results suggest that our CI children, generally, need an intervention 'bridging' program to improve their school readiness skills. Parents and teachers had different views on the readiness of the CI children at school entry level. PMID- 29501316 TI - Long term platinum-induced ototoxicity in pediatric patients. AB - OBJECTIVES: Platinum-based chemotherapy treatments are effective against a variety of pediatric malignancies. However, its use can lead to permanent hearing loss. The aim of this study was to evaluate the long-term effect of platinum chemotherapy on hearing and evaluate its progression. METHODS: Prospective cohort study. All records of pediatric patients receiving platinum-based chemotherapy between 2001 and 2006 were reviewed. Demographics and audiograms performed before, during, and following chemotherapy were analyzed. An updated audiogram and a video head impulse test were performed. A hearing ability questionnaire was also completed. RESULTS: Thirty-nine patients met the inclusion criteria. Of these, 12 patients were included in the study; 14 were deceased, 8 had incomplete data and 5 were excluded for other reasons. Median age at chemotherapy was 4.3 years (range 10 months-14.2 years). Seven patients had received cisplatin, two received carboplatin and three received both agents. Five had also received cranial irradiation. With a median follow-up time of 11.9 years, 58.3% had developed hearing loss and two patients wore bilateral hearing aids; 67% of the patients with hearing loss had worsening of their hearing in the long-term. All patients referred difficulties in various subscales measured by the questionnaire. Three patients had decreased vestibulo-ocular reflex gains. CONCLUSION: Platinum-induced hearing loss in pediatric patients can be progressive and debilitating. A long term audiometric follow-up of at least 10 years is suggested for these patients. PMID- 29501317 TI - Hyperacusis in children: A clinical profile. AB - OBJECTIVE: Hyperacusis is commonly seen in clinical paediatric practice and can be distressing for the children and their families. This paper looks at the clinical profile of children seen for hyperacusis in a paediatric audiology service and reviews the possible underlying mechanisms. METHODS: Retrospective study of case notes of 61 children with troublesome hyperacusis seen in the paediatric audiology service, looking at their clinical presentation and presence of other medical conditions. RESULTS: Hyperacusis was the main presenting complaint in more than half of the cases (n = 31, 51%). The commonest age at presentation with this problem was 3-4 years (n = 33, 54%). Hearing was normal in the majority of these children (n = 41, 67%). An active middle ear problem was observed in nearly half (n = 29, 48%) of all the children, of which glue ear (otitis media with effusion, OME) was the commonest. Presence of a neurodevelopmental condition was found in almost half (n = 28, 46%) of these patients of which autistic spectrum disorder was the commonest (8/61, 13%). In nearly one-fourth of the children (23%), presence of both middle ear problems and neurodevelopmental was noted. Tinnitus was an accompanying symptom reported in 11% of all the patients. CONCLUSION: Hyperacusis may commonly present at a very young age. Awareness of different clinical presentations, presence of other medical conditions and possible underlying pathomechanisms in children with hyperacusis can be helpful for clinicians in informing prognosis, counselling and in individualising management plan. PMID- 29501318 TI - Epidemiological trends among preterm infants with apnea. A twelve-year database review. AB - OBJECTIVES: This study sought to characterize trends in the diagnosis of apnea, associated comorbidities and complications, and 30-day readmission rates in preterm singleton infants. SUBJECTS AND METHODS: The study design was a retrospective, longitudinal, observational study. 2003-2014 New York State Statewide Planning and Research Cooperative System and New York City Vital Statistics databases were merged identifying preterm live singleton births. Hospitalizations of preterm newborns with and without apnea were compared; multivariable logistic regression and log-linear Poisson regression models applied. RESULTS: Of 1,384,013 singleton births, 7.5% were identified as preterm. While relative risk of preterm birth rates declined (RR = 0.987, 95% CI = 0.982 0.991), the diagnosis of apnea increased significantly (RR = 1.069, 95% CI = 1.049-1.089). Multivariable analysis identified two apnea predictors, gastric reflux (OR = 3.19, 95% CI = 2.80-3.63) and early gestational age (OR = 0.83 for 1 week GA increase, 95% CI = 0.82-0.84). Preterm newborns with apnea were more likely to be readmitted within the first 30 days and total charges were 5.4 times higher. CONCLUSIONS: While the preterm birth rate has declined the rate of diagnosis of apnea with associated comorbidities and complications has increased. Given the additional findings of higher 30-day readmission rates and charges, more multidisciplinary research appears warranted to identify ways to optimize the quality of high risk newborn care. PMID- 29501319 TI - Endonasal measurements by acoustic rhinometry in children: A preliminary study. AB - : The acoustic reflection method (ARM) is a non-invasive technique which uses the reflection of acoustic waves to measure the cross sectional area of nasal cavities in adults and patency of endotracheal tubes. Characteristics and volume of normal nasal cavities in pre-school children has so far not been studied. OBJECTIVE: The aim of this study was to determine the optimal ARM recording and the minimal cross-sectional area (MCA) and volume (NV) values in healthy children. DESIGN: Prospective monocentric study using the ARM in pre-school children (<6 years of age). RESULTS - DISCUSSION: Seventy children (age 2 to 5) were included in the study. Reliable measures were difficult to obtain in children younger than 2 years of age. The use of a standard nosepiece and a single-use surgical filter enabled reliable, serial recordings. Mean MCA values were 0.46, 0.53 and 0.58 cm2 in the 24-35, 36-47 and 48-60 months-old age groups, respectively. Mean NV values were 2.14, 2.59, and 2.86 cm3 in the same age groups. The MCA and NV values were significantly correlated with height, age and weight. In conclusion, the ARM is feasible in children over the age of 2 and seems to be a promising non-invasive tool to study the nasal cavity patency, anatomy, and volume. PMID- 29501320 TI - A novel mutation in the SLC26A4 gene in a Chinese family with non-syndromic hearing loss and enlarged vestibular aqueduct. AB - OBJECTIVES: To identity the genetic causes of hearing loss in a Han Chinese family with enlarged vestibular aqueduct syndrome. METHODS: Multiplex PCR technology combined with Ion TorrentTM next-generation sequencing technology was used to search for pathogenic mutations. A group of 1500 ethnically-matched normal hearing subjects screened for mutations in deafness-related genes using the same method in previously studied were included as a control. RESULTS: The proband and his little sister suffered from typical features of sensorineural hearing loss with enlarged vestibular aqueduct (EVA). Both subjects harbored two compound heterozygous mutations in the SLC26A4 gene. A novel mutation named c.2110 G > C (p.Glu704Gln) in exon 19 and another previously reported mutation c.1673 A > T (p.Asn558Ile) were identified. These mutations were carried in the heterozygous state by the parents and therefore co-segregated with the genetic disease. The c.2110 G > C (p.Glu704Gln) mutation was absent in 1500 healthy newborns. Protein alignment indicated high evolutionary conservation of the p.E704 residue, and this mutation was predicted by online tools to be damaging and deleterious. CONCLUSION: This study demonstrates that the novel mutation c.2110 G > C (p.Glu704Gln) in compound heterozygosity with c.1673 A > T (p.Asn558Ile) in the SLC26A4 gene corresponds to the EVA in this family. Our study will provide a foundation for elucidating the SLC26A4-related mechanisms of hearing loss. PMID- 29501321 TI - Effectiveness of maternal pertussis vaccination in preventing infection and disease in infants: The NSW Public Health Network case-control study. AB - BACKGROUND: Infants are at the highest risk of severe complications - including death - as a result of pertussis infection. Controlling pertussis in this group has been challenging, particularly in those too young to be vaccinated. Following revised national recommendations in March 2015, the state of New South Wales, Australia, introduced a funded maternal vaccination campaign at 28 - 32 weeks of gestation using a 3-component tetanus-diphtheria-acellular pertussis vaccine (dTpa; Boostrix, GSK). This study aimed to assess the effectiveness of maternal vaccination and add to the growing body of evidence for this strategy. METHODS: A 1:1 matched case-control study was conducted between 16 August 2015 and 17 August 2016. Cases were laboratory or doctor notified, laboratory confirmed (nucleic acid testing or culture) and aged <6 months at onset. Each control infant was randomly selected from public hospital births in the same geographical area in the period up to 3 days before and after the case's birthdate. Odds ratios (OR) were calculated using conditional logistic regression. Vaccine effectiveness (VE) was calculated as 1 - OR. FINDINGS: In total, 117 cases and 117 controls were recruited. The overall VE estimate was non-significantly protective for infants <6 months old (VE 39%, 95% CI -12 to 66%). Higher VE was observed for infants <3 months old (VE 69%, 95% CI 13-89%) and against hospitalisation (VE 94%, 95% CI 59 99%). INTERPRETATION: Maternal pertussis vaccination with a 3-component acellular vaccine was found to be highly effective at preventing severe disease in infants, but was less effective at preventing disease which did not require hospitalisation. The overall VE reported in this study was lower than in prior studies and suggests that maternal vaccination, while an effective strategy at preventing severe pertussis, is less effective at protecting against infection or mild disease. PMID- 29501322 TI - Do sulphonylureas still have a place in clinical practice? AB - Sulphonylureas have been commercially available since the 1950s, but their use continues to be associated with controversy. Although adverse cardiovascular outcomes in some observational studies have raised concerns about sulphonylureas, findings from relatively recent, robust, and high-quality systematic reviews have indicated no increased risk of all-cause mortality associated with sulphonylureas compared with other active treatments. Results from large, multicentre, randomised controlled trials such as the UK Prospective Diabetes Study and ADVANCE have confirmed the microvascular benefits of sulphonylureas, a reduction in the incidence or worsening of nephropathy and retinopathy, and no increase in all-cause mortality, although whether these benefits were due to sulphonylurea therapy and not an overall glucose-lowering effect could not be confirmed. A comparison of sulphonylureas and pioglitazone in the TOSCA.IT trial also confirmed the efficacy and cardiovascular safety of sulphonylureas. Investigators of randomised controlled trials have reported an increased risk of hypoglycaemia and weight gain with sulphonylureas, but data from observational studies suggest that the incidence of severe hypoglycaemia is lower in people taking sulphonylurea than in people taking insulin, and weight gain with sulphonylureas has been relatively modest in large cohort studies. 80% of people with diabetes live in low-to-middle income countries, so the effectiveness, affordability, and safety of sulphonylureas are particularly important considerations when prescribing glucose-lowering therapy. Results of ongoing head-to-head studies with new drugs, such as the comparison of glimepiride with linagliptin in the CAROLINA study and the comparison of various therapies (including sulphonylureas) for glycaemic control in the GRADE study, will determine the place of sulphonylureas in glucose-lowering therapy algorithms for patients with type 2 diabetes. PMID- 29501323 TI - Antithrombotic therapies in children on durable Ventricular Assist Devices: A literature review. AB - INTRODUCTION: Ventricular Assist Devices (VADs) are increasingly utilised in children with end-stage heart failure, and experience high bleeding and clotting rates. In particular, pediatric VAD patients are more challenging than adults to anticoagulate due to developmental hemostasis, lack of suitable drug preparations, and difficult anticoagulation monitoring often due to poor vascular access; in addition to difficulties of VAD design in smaller children. This review aims to summarize the current evidence related to antithrombotic therapy in pediatric VAD patients. MATERIALS AND METHODS: A search of 2 databases across a 17-year period of time was undertaken using key words selected a priori. Identified publications were then categorized according to VAD types utilised and the anticoagulation protocols described. RESULTS: 27 articles were identified consistent with the inclusion criteria developed for this review. Devices included in the cohort were Berlin Heart EXCOR, Thoratec, Medos, Novacor, HeartMate II and HeartWare HVAD. Most studies reported the use of unfractionated heparin post-operatively with a transition to low molecular weight heparin and warfarin. Antiplatelet regimens most commonly included aspirin and dipyridamole. Definition of bleeding and clotting events differed between cohorts. The incidence of bleeding overall was 37% (209/558; range of 0 to 89%) and 26% (143/554; range of 8.3 to 100%) for thromboembolism events. All studies reported had significant methodological limitations. CONCLUSIONS: The clinical use of antithrombotic therapies - including dosages, timing and monitoring - varies considerably. This review highlights the further research required to improve understanding of hemostasis in the pediatric VAD field. PMID- 29501324 TI - WASP (Write a Scientific Paper) using Excel - 8: t-Tests. AB - t-Testing is a common component of inferential statistics when comparing two means. This paper explains the central limit theorem and the concept of the null hypothesis as well as types of errors. On the practical side, this paper outlines how different t-tests may be performed in Microsoft Excel, for different purposes, both statically as well as dynamically, with Excel's functions. PMID- 29501325 TI - Protein Disaggregation in Multicellular Organisms. AB - Protein aggregates are formed in cells with profoundly perturbed proteostasis, where the generation of misfolded proteins exceeds the cellular refolding and degradative capacity. They are a hallmark of protein conformational disorders and aged and/or environmentally stressed cells. Protein aggregation is a reversible process in vivo, which counteracts proteotoxicities derived from aggregate persistence, but the chaperone machineries involved in protein disaggregation in Metazoa were uncovered only recently. Here we highlight recent advances in the mechanistic understanding of the major protein disaggregation machinery mediated by the Hsp70 chaperone system and discuss emerging alternative disaggregation activities in multicellular organisms. PMID- 29501326 TI - How to Characterize the Function of a Brain Region. AB - Many brain regions have been defined, but a comprehensive formalization of each region's function in relation to human behavior is still lacking. Current knowledge comes from various fields, which have diverse conceptions of 'functions'. We briefly review these fields and outline how the heterogeneity of associations could be harnessed to disclose the computational function of any region. Aggregating activation data from neuroimaging studies allows us to characterize the functional engagement of a region across a range of experimental conditions. Furthermore, large-sample data can disclose covariation between brain region features and ecological behavioral phenotyping. Combining these two approaches opens a new perspective to determine the behavioral associations of a brain region, and hence its function and broader role within large-scale functional networks. PMID- 29501327 TI - Outcome of Head and Neck Squamous Cell Cancers in Low-Resource Settings: Challenges and Opportunities. AB - Head and neck squamous cell carcinomas (HNSCCs) are amongst the most common cancers in certain parts of the world. Low-income and low middle- income countries make up 65% of newly diagnosed HNSCC cases annually and account for about 75% of HNSCC global mortality. These countries also suffer from a significant shortage of skilled labor, equipment, and health facilities. This article discusses the burden of HNSCCs in developing countries and the differences in outcomes compared with developed countries. PMID- 29501329 TI - Detecting Staphylococcus aureus in milk from dairy cows using sniffer dogs. AB - Fast and accurate identification of disease-causing pathogens is essential for specific antimicrobial therapy in human and veterinary medicine. In these experiments, dogs were trained to identify Staphylococcus aureus and differentiate it from other common mastitis-causing pathogens by smell. Headspaces from agar plates, inoculated raw milk samples, or field samples collected from cows with Staphylococcus aureus and other mastitis-causing pathogens were used for training and testing. The ability to learn the specific odor of Staphylococcus aureus in milk depended on the concentration of the pathogens in the training samples. Sensitivity and specificity for identifying Staphylococcus aureus were 91.3 and 97.9%, respectively, for pathogens grown on agar plates; 83.8 and 98.0% for pathogens inoculated in raw milk; and 59.0 and 93.2% for milk samples from mastitic cows. The results of these experiments underline the potential of odor detection as a diagnostic tool for pathogen diagnosis. PMID- 29501328 TI - Population Turnover in Remote Oceania Shortly after Initial Settlement. AB - Ancient DNA from Vanuatu and Tonga dating to about 2,900-2,600 years ago (before present, BP) has revealed that the "First Remote Oceanians" associated with the Lapita archaeological culture were directly descended from the population that, beginning around 5000 BP, spread Austronesian languages from Taiwan to the Philippines, western Melanesia, and eventually Remote Oceania. Thus, ancestors of the First Remote Oceanians must have passed by the Papuan-ancestry populations they encountered in New Guinea, the Bismarck Archipelago, and the Solomon Islands with minimal admixture [1]. However, all present-day populations in Near and Remote Oceania harbor >25% Papuan ancestry, implying that additional eastward migration must have occurred. We generated genome-wide data for 14 ancient individuals from Efate and Epi Islands in Vanuatu from 2900-150 BP, as well as 185 present-day individuals from 18 islands. We find that people of almost entirely Papuan ancestry arrived in Vanuatu by around 2300 BP, most likely reflecting migrations a few hundred years earlier at the end of the Lapita period, when there is also evidence of changes in skeletal morphology and cessation of long-distance trade between Near and Remote Oceania [2, 3]. Papuan ancestry was subsequently diluted through admixture but remains at least 80%-90% in most islands. Through a fine-grained analysis of ancestry profiles, we show that the Papuan ancestry in Vanuatu derives from the Bismarck Archipelago rather than the geographically closer Solomon Islands. However, the Papuan ancestry in Polynesia-the most remote Pacific islands-derives from different sources, documenting a third stream of migration from Near to Remote Oceania. PMID- 29501330 TI - Coagulation efficiency and its determinant factors: A case study for Manchega ewe milk in the region of Castilla-La Mancha, Spain. AB - Milk coagulation, especially in small ruminant species, is often hard to evaluate, as coagulation traits are normally considered individually and several factors related to udder health might distort yield calculation. Due to the lack of studies about these factors, our objective was to determine milk coagulation efficiency (CE) and its determinants using a deterministic technical efficiency approach, an ordinary least square regression model, and ANOVA. Milk from 300 Manchega ewes was collected and analyzed for composition, milk coagulation properties, and hygienic quality. The study results indicate that the estimated CE in Manchega ewes was 0.69, implying an important proportion of the animals produce poorly coagulating milk. The results of the ordinary least square regression model and ANOVA revealed that the main factor causing inefficiency was the initial pH of milk. Crude protein, casein and plasmin activity had moderate effects on CE, and, finally, other factors such as freezing point depression, somatic cell count, colony-forming units, and fat concentration had minor effects. PMID- 29501331 TI - The effect of spray drying on the difference in flavor and functional properties of liquid and dried whey proteins, milk proteins, and micellar casein concentrates. AB - Traditionally most protein ingredients are sold as a powder due to transport ease and longer shelf life. Many high-protein powder ingredients such as milk protein concentrate with 85% protein and micellar casein concentrate have poor rehydration properties (e.g., solubility) after storage, which might limit their use. An alternative to the production of dried protein ingredients is the option to use liquid protein ingredients, which saves the cost of spray drying, but may also improve flavor and offer different functional properties. The objective of this study was to determine the effect of spray drying on the flavor and functionality of high-protein ingredients. Liquid and dried protein ingredients (whey protein concentrate with 80% protein, whey protein isolate, milk protein concentrate with 85% protein, and micellar casein concentrate) were manufactured from the same lot of milk at the North Carolina State University pilot plant. Functional differences were evaluated by measurement of foam stability and heat stability. Heat stability was evaluated by heating at 90 degrees C for 0, 10, 20, and 30 min followed by micro-bicinchoninic acid and turbidity loss measurements. Sensory properties were evaluated by descriptive analysis, and volatile compounds were evaluated by gas chromatography-mass spectrometry. No differences were detected in protein heat stability between liquids and powders when spray dried under these conditions. Whey protein concentrate with 80% protein (liquid or spray dried) did not produce a foam. All powders had higher aroma intensity and cooked flavors compared with liquids. Powder proteins also had low but distinct cardboard flavor concurrent with higher relative abundance of volatile aldehydes compared with liquids. An understanding of how spray drying affects both flavor and functionality may help food processors better use the ingredients they have available to them. PMID- 29501332 TI - Dairy cow breed interacts with stocking rate in temperate pasture-based dairy production systems. AB - Economic optimum stocking rates for grazing dairy systems have been defined by accounting for the pasture production potential of the farm [t of dry matter (DM)/ha], the amount of feed imported from outside the farm (t of DM/ha), and the size of the cow (kg). These variables were combined into the comparative stocking rate [CSR; kg of body weight (BW)/t of feed DM available] measure. However, CSR assumes no effect of cow genetics beyond BW, and there is increasing evidence of within-breed differences in residual feed intake and between-breed differences in the gross efficiency with which cows use metabolizable energy for milk production. A multiyear production system experiment was established to determine whether Jersey (J) and Holstein-Friesian (HF) breeds performed similarly at the same CSR. Fifty-nine J cows and 51 HF cows were randomly allocated to 1 of 2 CSR in a 2 * 2 factorial arrangement; systems were designed to have a CSR of either 80 or 100 kg of BW/t of feed DM (J-CSR80, J-CSR100, HF-CSR80, and HF-CSR100 treatment groups). Data were analyzed for consistency of farmlet response over years using ANOVA procedures, with year and farmlet as fixed effects and the interaction of farmlet with year as a random effect. The collated biological data and financial data extracted from a national economic database were used to model the financial performance for the different breed and CSR treatments. On average, annual and individual season pasture DM production was greater for the J farmlets and was less in the CSR100 treatment; however, the effect of CSR was primarily driven by a large decline in pasture DM production in the HF-CSR100 treatment (breed * CSR interaction). This interaction in feed availability resulted in a breed * CSR interaction for the per-cow and per-hectare milk production variables, with HF cows producing more milk and milk components per cow in the CSR80 treatment but the same amount as the J cows in the CSR100 treatment. On a per-hectare basis, HF cows produced the same amount of 4% fat-corrected milk and lactose as J cows in the CSR80 treatment, but less fat; at CSR100, J cows produced more 4% fat-corrected milk, fat, and protein per hectare than HF cows. Our results support a greater gross efficiency for use of metabolizable energy by the J cow; 11% less total metabolizable energy was required to produce 1 kg of fat and protein at a system level. Economic modeling indicated that profitability of both breeds was less at CSR100, but the decline in profitability with increasing stocking rate was much greater in the HF breed. Holstein-Friesian cows were more profitable at CSR80 but were less profitable at CSR100. PMID- 29501333 TI - Effect of fermentation temperature on the properties of exopolysaccharides and the acid gelation behavior for milk fermented by Streptococcus thermophilus strains DGCC7785 and St-143. AB - We investigated the effect of fermenting milk with 2 strains (DGCC7785 and St 143) of Streptococcus thermophilus, which are known to produce different types of exopolysaccharide (EPS) structures. The yields and physical properties of these ropy EPS were monitored during the fermentation of milk at different temperatures. We wanted to understand how these types of EPS properties affected yogurt gelation. Reconstituted skim milk was fermented at 33, 39, or 45 degrees C until pH values reached 5.2, 4.9, 4.7, and 4.5. Molar mass of ropy EPS samples was determined using size exclusion chromatography coupled with multiangle laser light scattering. Rheological properties of fermented milk gels were analyzed using small-strain dynamic oscillatory measurements. In both strains, concentrations of ropy EPS increased during fermentation and at all temperatures. Fermentation times, by both strains, were shortest at 45 degrees C and longest at 33 degrees C. For both strains, molar mass of ropy EPS ranged from 2 to 4 * 106 g/mol during fermentation. A major proteinaceous contaminant that was co-isolated with the ropy EPS fraction by our isolation method was identified as a milk derived phosphoglycoprotein PP3. Increase in fermentation temperature from 33 to 45 degrees C significantly decreased the storage modulus values (from 170 to 41 Pa) for milk gelled by strain DGCC7785, whereas the gels made with St-143 had very low storage modulus values (11-17 Pa) regardless of fermentation temperatures. For both strains, the values of maximum loss tangent in the milk gels increased with fermentation temperature; the maximum loss tangent occurred at higher pH values when milk was fermented by strain DGCC7785. The specific type of EPS produced appeared to be responsible for the differences in yogurt texture rather than the concentration or molar mass of the EPS. PMID- 29501334 TI - Evaluation of a commercial vacuum fly trap for controlling flies on organic dairy farms. AB - The objective of this study was to evaluate the efficacy of a commercial vacuum fly trap (CowVac, Spalding Laboratories, Reno, NV) in on-farm organic dairy production systems to control horn flies, stable flies, and face flies. As cows walk through the trap, flies are brushed off the face, flank, and back with hanging flaps and blown off the belly, udder, and legs from one side, and then vacuumed from the air into a chamber from vacuum inlets opposite the blower and above the cow. The study included 8 organic dairy farms during the summer of 2015 in Minnesota, and herds ranged from 30 to 350 cows in size. The farms were divided into pairs by location; during the first period of the summer (June to July), the trap was set up on 1 farm, whereas during the second period of the summer (August to September) the trap was sent to its paired farm. Farms were visited once per week to collect and count flies from the trap as well as count and record flies on cows. Bulk tank milk, fat, and protein production and somatic cell count were collected on farms during the entire study period. Data were analyzed using the GLM procedure of SAS (version 9.3, SAS Institute Inc., Cary, NC). Independent variables for analyses were the fixed effects of farm, trap presence, housing scenario, and summer period. Horn fly numbers on cows were lower by 44% on farm in the presence of a trap (11.4 vs. 20.5 flies/cow-side) compared with the absence of a trap. Stable fly (5.4 vs. 7.1 flies/leg) and face fly (1.0 vs. 1.0 flies/cow) numbers were similar on farm whether the trap was present or absent on farms, respectively. Milk production was similar for farms with the trap (15.5 kg/d) compared to without (15.3 kg/d) the trap. Bulk tank milk, milk components, and somatic cell count were statistically similar in the presence and absence of the trap, so potential benefits of the trap for those measures were not evident at low fly populations observed during the study. The presence of a trap on farm reduced horn fly population growth rates (-1.01 vs. 1.00 flies/d) compared with the absence of a trap. Cows on farms with no housing (100% pasture) tended to have reduced horn fly numbers (11.7 vs. 28.3 flies/cow side) in the presence of a trap compared with the absence of a trap on farm. Cows on farms with housing had similar horn fly numbers (11.2 vs. 14.8 flies/cow-side) in the presence of a trap compared with the absence of a trap on farm. In summary, these results indicate the trap was effective in reducing horn fly numbers on cows and reduced horn fly growth rates during the pasture season in organic dairy production systems, but benefits in improved milk production were not evident likely because of relatively low fly populations. PMID- 29501335 TI - Effect of prophylactic oral calcium supplementation on postpartum mineral status and markers of energy balance of multiparous Jersey cows. AB - The effects of prophylactic oral Ca supplementation on blood mineral status and markers of energy balance were evaluated on 205 multiparous Jersey cows at a commercial dairy. Postpartum, cows were systematically assigned to control (n = 105) or oral Ca supplementation (CaOS; 50 to 60 g of Ca as boluses; n = 100) at 0 and 1 d in milk (DIM). Blood samples for analysis of serum minerals (Ca, P, Mg, K, Na, Fe, Zn, and Cu) were collected before and 1 h after treatment at 0 and 1 DIM, and at 2 DIM. Urine pH was measured immediately before and 1 h after treatment administration (n = 96). A subset of 74 cows was evaluated for plasma glucose and fatty acid concentrations at 0, 1, and 2 DIM. Cows were classified according to their initial calcemic status (Ca status) as normocalcemic (NC; serum Ca >2.12 mmol/L) or subclinically hypocalcemic (SCH; serum Ca <=2.12 mmol/L). Average serum Ca concentration was higher in CaOS than control cows (2.12 vs. 2.06 mmol/L); this treatment effect was higher for SCH [CaOS (2.03 mmol/L); control (1.89 mmol/L)] than NC cows [CaOS (2.22 mmol/L); control (2.22 mmol/L)]. The incidence of subclinical hypocalcemia was lower for CaOS than control cows (53 vs. 65%); however, at 2 DIM the prevalence of subclinical hypocalcemia tended to be higher for CaOS cows, mostly because it was higher for CaOS-NC than control-NC cows (70 vs. 25%). Urine pH was lower for CaOS than control cows (6.10 vs. 7.04). Lower serum Mg concentration was detected for CaOS SCH (1.06 mmol/L) than for control-SCH (1.10 mmol/L) cows. Cows in the CaOS group had higher serum K (4.68 vs. 4.53 mmol/L), lower plasma glucose (2.97 vs. 3.10 mmol/L), and at 2 DIM higher plasma fatty acid concentrations (0.43 vs. 0.35 mmol/L) than control cows. Our results showed that postpartum serum Ca concentration increases with oral Ca supplementation, but calcemic status influenced treatment response. Future studies should evaluate the long-term implications on production and reproduction of oral Ca supplementation in Jersey cows. PMID- 29501336 TI - Short communication: The effect of temperature-humidity index on milk yield and milking frequency of dairy cows in pasture-based automatic milking systems. AB - Hot weather is known to negatively affect cow performance primarily through reduced feed intake and milk yield. However, little information is available on how it affects cow milk yield and milking frequency in automatic milking systems (AMS). Milking data were collected from 6 pasture-based AMS farms in Australia to assess the effect of temperature-humidity index (THI) on milk yield and milking frequency. Daily measures of average milk yield per cow and average milking frequency per cow during December to February (Australian summer) were assessed for associations with maximum, minimum, and average THI from d 0, -1, -2, and -3 in relation to the milking data. Average daily milk yield per cow was negatively associated with an increasing maximum, minimum, and average THI (-0.11, -0.08, and -0.15 kg/THI unit increase, respectively) on the collection day and up to 3 d prior. The average daily milking frequency was negatively associated with maximum THI on 1 d (-0.003/THI unit increase) and 2 d (-0.003/THI unit increase) before collection. Our results show that high THI conditions were negatively associated with milking frequency and milk yield in a pasture-based AMS and that research into management and infrastructure (cow cooling) in these systems is warranted to reduce production losses. PMID- 29501337 TI - Effect of hot season on blood parameters, fecal fermentative parameters, and occurrence of Clostridium tyrobutyricum spores in feces of lactating dairy cows. AB - High temperature influences rumen and gut health, passage rate, and diet digestibility, with effects on fermentative processes. The main aim of the study was to investigate the effect of hot season on hindgut fermentation, the occurrence of Clostridium tyrobutyricum spores in bovine feces, and on their relationship with metabolic conditions in dairy cows producing milk used for Grana Padano cheese. The study was carried out on 7 dairy farms located in the Po Valley (Italy), involving 1,950 Italian Friesian dairy cows. The study was carried out from November 2013 till the end of July 2014. Temperature and relative humidity were recorded daily by weather stations. Constant management conditions were maintained during the experimental period. Feed and diet characteristics, metabolic conditions, and fecal characteristics were recorded in winter (from late November 2013 to the end of January 2014), spring (from April to May 2014), and summer (July 2014) season. In each season, blood samples were collected from 14 multiparous lactating dairy cows per herd to measure biochemical indices related to energy, protein, and mineral metabolism, as well as markers of inflammation and some enzyme activities. Fecal samples were also collected and measurements of moisture, pH and volatile fatty acids (VFA) were performed. The DNA extracted and purified from fecal samples was used to detect Clostridium tyrobutyricum spores in a quantitative real-time PCR assay. The daily mean temperature-humidity index was 40.7 +/- 4.6 (range 25 to 55), 61.2 +/- 3.7 (range 39 to 77), and 70.8 +/- 3.2 (range 54 to 83) in winter, spring, and summer, respectively. Total VFA concentration in feces progressively decreased from winter to summer. The seasonal changes of acetate and propionate followed the same trend of total VFA; conversely, butyrate did not show any difference between seasons, and its molar proportion was greater in summer compared with winter. A greater occurrence of Cl. tyrobutyricum spores in summer compared with the other seasons was observed. The plasma concentrations of glucose, urea, albumin, Ca, Mg, Cl, Zn, and alkaline phosphatase activity were lower in summer compared with winter, whereas the opposite occurred for bilirubin and Na. Our results show that summer season, through direct and indirect effect of heat stress, affected fecal fermentative parameters and hindgut buffering capacity, and was responsible for the increasing occurrence of Cl. tyrobutyricum spores in feces. PMID- 29501338 TI - Gold nanoparticle-based enhanced lateral flow immunoassay for detection of Cronobacter sakazakii in powdered infant formula. AB - Cronobacter sakazakii is an opportunistic foodborne pathogen that can infect newborns through powdered infant formula (PIF). In this study, we developed a novel enhanced lateral flow immunoassay (LFA) with enhanced sensitivity for detection of C. sakazakii in PIF by the naked eye. The proposed strategy for signal enhancement of the traditional LFA used concentrated gold nanoparticles (AuNP) as the enhancer to conjugate with capture antibodies, which could increase the immobilized capture antibodies concentration at the detection zone to improve capture efficiency. Besides, the detection signal was further amplified by accumulated AuNP as the C. sakazakii labeled with AuNP probes was captured by antibodies conjugated with enhancer at the test line. We also studied the effect of different concentrations of capture antibodies and concentrated AuNP on detection performance, and found that 2.2 mg/mL of capture antibodies and 0.06 nM concentrated AuNP were the optimal combination that could avoid a false-positive signal and maximally amplify the detection signal of the enhanced LFA. Using this strategy, the detection sensitivity of the enhanced LFA was 103 cfu/mL and improved 100-fold compared with traditional LFA. The strip was highly specific to C. sakazakii, and the time for detection of C. sakazakii in PIF was shortened by 3 h. In summary, the enhanced LFA developed by the addition of concentrated AuNP as the enhancer can be used as a sensitive, rapid, visual qualitative and point of-care test method for detecting target analytes. PMID- 29501339 TI - Characterization of the nongenetic causes of variation in the calcium content of bovine milk on French farms. AB - Milk is an important source of Ca in Western diets. Milk Ca is important for the cheesemaking process and could be a useful biomarker of Ca regulation in cows. The objective of this study was to identify and quantify nongenetic factors affecting the variation of Ca content in bovine milk. During the PhenoFinLait program, a survey was performed in 3 major areas of milk production in France. This survey consisted of collecting milk samples, together with information about herd management and cow nutrition, from 924 commercial farms. More than 200,000 individual milk samples were collected, and Ca content was measured by mid infrared spectroscopy. Each farm was surveyed several times during the year, and 3 to 6 milk samples were collected from each cow. An equation to predict milk Ca content from mid-infrared spectra was developed based on the Ca contents of 292 milk samples, and the milk Ca contents of the 200,000 samples were then predicted. Milk Ca content was lowest in Holstein cows, intermediate in Montbeliarde cows, and highest in Normande cows. For all 3 breeds, milk Ca decreased during the first month of lactation and increased after the fourth month of lactation, with the range between minimum and maximum values largest in Holsteins, intermediate in Montbeliardes, and smallest in Normandes. Milk Ca content also decreased with parity in all 3 breeds. By using multiple factorial analysis, 6 major feeding strategies employed on French dairy farms were characterized based on the data from the survey. Calendar month and cow feeding strategy affected milk Ca content, which dropped in the spring during grazing turnout and was lower when cows were fed fresh and conserved grass rather than corn silage. In conclusion, environmental factors induce variations in milk Ca content in addition to the genetics of the cows, which to date have been identified as a main factor of variation of milk Ca content in dairy cows. In several of the tested conditions, increases in milk production and in the amount of Ca daily secreted in milk were associated with a decrease in milk Ca content as though the mammary gland operated to limit the exportation of Ca when milk production rapidly increased. This result would suggest that milk Ca content could be a biomarker of Ca regulation in dairy cows. PMID- 29501340 TI - Invited review: Learning from the future-A vision for dairy farms and cows in 2067. AB - The world's population will reach 10.4 billion in 2067, with 81% residing in Africa or Asia. Arable land available for food production will decrease to 0.15 ha per person. Temperature will increase in tropical and temperate zones, especially in the Northern Hemisphere, and this will push growing seasons and dairy farming away from arid areas and into more northern latitudes. Dairy consumption will increase because it provides essential nutrients more efficiently than many other agricultural systems. Dairy farming will become modernized in developing countries and milk production per cow will increase, doubling in countries with advanced dairying systems. Profitability of dairy farms will be the key to their sustainability. Genetic improvements will include emphasis on the coding genome and associated noncoding epigenome of cattle, and on microbiomes of dairy cattle and farmsteads. Farm sizes will increase and there will be greater lateral integration of housing and management of dairy cattle of different ages and production stages. Integrated sensors, robotics, and automation will replace much of the manual labor on farms. Managing the epigenome and microbiome will become part of routine herd management. Innovations in dairy facilities will improve the health of cows and permit expression of natural behaviors. Herds will be viewed as superorganisms, and studies of herds as observational units will lead to improvements in productivity, health, and well being of dairy cattle, and improve the agroecology and sustainability of dairy farms. Dairy farmers in 2067 will meet the world's needs for essential nutrients by adopting technologies and practices that provide improved cow health and longevity, profitable dairy farms, and sustainable agriculture. PMID- 29501341 TI - Exploring the influence of culture conditions on kefir's anticancer properties. AB - Cancer is a major health problem in many parts of the world. Conventional anticancer treatments are painful, expensive, and unsafe. Therefore, demand is increasing for cancer treatments preferentially in the form of functional foods or nutritional supplements. Kefir, a traditional fermented milk dairy product, has significant antimutagenic and antitumor properties. This research addresses the hypothesis that kefir's anticancer properties are affected by fermentation conditions. Initially, kefir extracts prepared under standard conditions were screened against 7 cancer cell lines using the tetrazolium dye 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric assay. Colon cancer and chronic myelogenous leukemia cells were found to be most susceptible to kefir extracts. Subsequently, a factorial design was implemented to assess the effects of 3 fermentation times (24, 48, and 72 h), 3 kefir-to-milk ratios (2, 5, and 10% wt/vol), and 3 fermentation temperatures (4, 25, and 40 degrees C) on kefir's anticancer properties. Remarkably, exploration of the fermentation conditions allowed the anticancer properties of kefir to be enhanced by 5- to 8 fold against susceptible cell lines. Overall, these results demonstrate the possibility of optimizing the anticancer properties of kefir as a functional food in cancer therapy. PMID- 29501342 TI - Cooling cows with sprinklers: Spray duration affects physiological responses to heat load. AB - Sprayed water reduces heat load in cattle. Determining appropriate spraying strategies (i.e., time on and off) may improve cooling efficiency and reduce water use. Our objective was to evaluate the effects of a single spray on the surrounding air temperature (AT), time it takes the coat to dry, and physiological responses to heat load in dairy cows. In a crossover design, spray duration (0, 0.5, 1.5, 3, and 13 min; flow rate: 4.9 L/min) was tested in 15 Holstein cows (milk yield: 37.7 +/- 2.6 kg/d) restrained in shaded head gates at the feed bunk for up to 1.75 h. Each treatment was replicated on 3 d (15 d total/cow) when AT, humidity, and temperature-humidity index averaged 31 +/- 3 degrees C, 27 +/- 10%, and 76 +/- 2, respectively (mean +/- SD). Water temperature at the nozzle outlet and dripping from the cow was measured every 1 s and averaged (mean +/- SD) 29.7 +/- 1.4 and 30.3 +/- 0.8 degrees C, respectively. Respiration rate, skin temperature of the shoulder and upper leg, and the surrounding AT were measured before and after the spray application and every 3 min for 30 min. At the same intervals, using water-sensitive paper we measured the time the coat took to dry. In contrast to the control, immediately after the spray was turned off, all water treatments reduced skin temperature on the shoulder (range of mean +/- SE: -1.1 to -4.4 +/- 0.2 degrees C). Within the same period, treatments >=1.5 min reduced respiration rate (range: -7 to -24 +/- 2 breaths/min) and the surrounding AT (range: -0.3 to -1.7 +/- 0.0 degrees C). Only spraying cows for >=3 min reduced leg surface temperature during spray duration (range of reduction: -0.1 to -0.6 +/- 0.0 degrees C). Spray duration had little effect on the time it took the coat to dry. Cows sprayed for 13 min took 2 min longer to dry compared with the other treatments (15.9 vs. 13.8, 14.9, and 14.2 +/- 0.6 min, respectively, for 0.5, 1.5, and 3 min). No additional cooling was observed in this phase except on windier days, when leg temperature and respiration rate reductions tended to be more marked (slope estimates: -0.06 and 3.6, respectively). Cooling benefits, as well as changes in AT surrounding the leg, were more pronounced when water was sprayed for longer. In this study, cooling was observed primarily when water was turned on, not during the time it took the coat to dry. PMID- 29501343 TI - Polyethylene glycol as an indigestible marker to estimate fecal output in dairy cows. AB - The objective of this study was to evaluate the accuracy of fecal output measurements using polyethylene glycol (PEG) as an external marker determined by near-infrared reflectance spectroscopy. In addition, the accuracy of dry matter intake predictions based on fecal output and digestibility estimated using an internal marker [indigestible neutral detergent fiber (iNDF)] was assessed. The experiment was conducted using 6 lactating dairy cows fed 2 different diets. Polyethylene glycol was administered twice daily into the rumen and the diurnal pattern of fecal concentrations and recovery in feces were determined. To evaluate the effects of alternative marker administration and sampling schemes on fecal output estimates, the passage kinetics of PEG in the digestive tract of dairy cows was determined and used for simulation models. The results indicate that PEG was completely recovered in feces and, thus, fecal output was accurately estimated using PEG. Good agreement between measured and predicted dry matter intake (standard error of prediction = 0.86 kg/d, R2 = 0.81) indicates good potential to determine feed intake using PEG in combination with iNDF. The precision of cow-specific digestibility estimates based on iNDF was unsatisfactory, but for a group of cows iNDF provided an accurate estimate of dry matter digestibility. The current study indicated that, to overcome inherent day to-day variation in feed intake and fecal output, the minimum of 4 fecal spot samples should be collected over 4 d. Preferably, these samples should be distributed evenly over the 12-h marker administration interval to compensate for the circadian variation in fecal PEG concentrations. PMID- 29501344 TI - Short communication: Investigation of antibiotic alternatives to improve health and growth of veal calves. AB - The inherent disease susceptibility of veal calves results in frequent antimicrobial use. Improvements in antimicrobial stewardship necessitate alternative therapies to improve calf health and growth, while reducing the need for antimicrobials important to human health. This study investigated the effect of 2 alternative therapies, lactoferrin (an iron-binding protein found in colostrum) and cinnamaldehyde (an essential oil of the cinnamon plant) on growth, disease incidence, and mortality risk in special-fed veal calves. On the day of arrival to the growing facility (3 to 7 d of age), calves (n = 80 per treatment) were randomized to 1 of 3 treatments: (1) control (no supplement), (2) lactoferrin (1 g/d in milk replacer for 7 d), or (3) cinnamaldehyde (1 g/d in milk replacer for 21 d). Body weight was measured on the day of arrival (d 0), 21, and 42 d postarrival. Health assessments were performed twice weekly through 21 d, and mortality records were obtained through 6 wk postarrival. A repeated measures ANOVA was used to compare growth between treatment groups, and a Poisson regression model (PROC GENMOD, SAS v. 9.4, SAS Institute Inc., Cary, NC) was used to test differences between groups in the incidence of diarrhea (fecal score >=2 with and without depression and temperature) and disease through 3 wk postarrival. Body weight and average daily gain were similar between treatments. Neither lactoferrin nor cinnamaldehyde had an effect on diarrhea incidence. However, the risk of navel inflammation was significantly lower for calves that received cinnamaldehyde compared with calves in the control group. Mortality through 6 wk postarrival was low, with 4, 1, and 0 deaths from the control, lactoferrin, and cinnamaldehyde treatment groups, respectively. Additional research is needed to investigate various doses of these alternative therapies on calf health and growth, in addition to different routes of administration. PMID- 29501345 TI - Flavor and flavor chemistry differences among milks processed by high temperature, short-time pasteurization or ultra-pasteurization. AB - Typical high-temperature, short-time (HTST) pasteurization encompasses a lower heat treatment and shorter refrigerated shelf life compared with ultra pasteurization (UP) achieved by direct steam injection (DSI-UP) or indirect heat (IND-UP). A greater understanding of the effect of different heat treatments on flavor and flavor chemistry of milk is required to characterize, understand, and identify the sources of flavors. The objective of this study was to determine the differences in the flavor and volatile compound profiles of milk subjected to HTST, DSI-UP, or IND-UP using sensory and instrumental techniques. Raw skim and raw standardized 2% fat milks (50 L each) were processed in triplicate and pasteurized at 78 degrees C for 15 s (HTST) or 140 degrees C for 2.3 s by DSI-UP or IND-UP. Milks were cooled and stored at 4 degrees C, then analyzed at d 0, 3, 7, and 14. Sensory attributes were determined using a trained panel, and aroma active compounds were evaluated by solid-phase micro-extraction or stir bar sorptive extraction followed by gas chromatography-mass spectrometry, gas chromatography-olfactometry, and gas chromatography-triple quad mass spectrometry. The UP milks had distinct cooked and sulfur flavors compared with HTST milks. The HTST milks had less diversity in aroma active compounds compared with UP milks. Flavor intensity of all milks decreased by d 14 of storage. Aroma active compound profiles were affected by heat treatment and storage time in both skim and 2% milk. High-impact aroma active compounds were hydrogen sulfide, dimethyl trisulfide, and methional in DSI-UP and 2 and 3-methylbutanal, furfural, 2-heptanone, 2-acetyl-1-pyrroline, 2-aminoacetophenone, benzaldehyde, and dimethyl sulfide in IND-UP. These results provide a foundation knowledge of the effect of heat treatments on flavor development and differences in sensory quality of UP milks. PMID- 29501346 TI - The clinical characteristics and neurodevelopmental outcome of preterm infants with persistent periventricular echogenicity. AB - PURPOSE: Periventricular echogenicity (PVE) presents as diffuse echo dense lesions of the periventricular white matter on cranial ultrasonography. Beyond two weeks of life, it is considered as prolonged or persistent PVE. The aim of our study was to investigate the clinical characteristics of preterm infants with persistent PVE beyond 2 weeks after birth and to determine whether these infants had an adverse neurodevelopmental outcome. METHODS: The medical records of preterm infants who were born at < 34 weeks of gestation and admitted to Pusan National University Hospital between 2009 and 2014 were reviewed. A total of 28 preterm infants with persistent PVE were enrolled. Sixty compatible infants closely matched for gestational age and birth weight to infants with PVE were selected as the control group. Clinical data, including maternal, perinatal and neonatal characteristics, were analyzed. We compared the Bayley Scales of Infant Development-III at 12 months' corrected age. RESULTS: The mean gestational age and birth weight were 31 + 3 (range, 29 + 2-33 + 6) weeks and 1523 (range, 911 2210) g, respectively, in the persistent PVE group. In the control group, the mean gestational age was 31 + 4 (range, 29 + 2-33 + 6) weeks and the mean birth weight was 1537 (range, 840-2100) g. There was no significant difference between the persistent PVE group and the control group, except for a significantly higher incidence of late sepsis in the persistent PVE group (p = 0.001). The results of Bayley test at 12 months of corrected age were available for 24 infants in the persistent PVE group and for 26 infants in the control group. A motor score of 86 (range, 78-95) versus 88 (range, 79-100), a language composite score of 88 (range, 78-97) versus 89 (range, 80-105), and a cognitive score of 90 (range, 81 100) versus 92 (range, 85-105) were observed in the persistent PVE group and the control group, respectively. No difference was detected in any scores between the two groups. CONCLUSION: The clinical characteristics and neurodevelopmental outcomes of preterm infants with persistent PVE were not different from those of infants with normal findings. Our study supports the concept that persistent PVE without cystic change may be a benign finding. PMID- 29501347 TI - Warfarin embryopathy: Balancing maternal and fetal risks with anticoagulation therapy. PMID- 29501348 TI - A predictive scoring system for insufficient liver hypertrophy after preoperative portal vein embolization. AB - BACKGROUND: The factors which affect hypertrophy of the future liver remnant after portal vein embolization remain unclear. The aim of this study was to clarify the clinical factors affecting the hypertrophy rate after portal vein embolization and to develop a scoring system predicting insufficient liver hypertrophy. METHODS: The cases of a total of 152 patients who underwent portal vein embolization of the right portal branch between 2006 and 2016 were reviewed retrospectively. The score to predict insufficient (<25%) hypertrophy was established based on logistic regression analyses of the clinical parameters before portal vein embolization. RESULTS: After portal vein embolization, the future liver remnant volume, expressed as the median (range), significantly increased from 364 (151-801) mL, 33% (18%-54%), to 451 (242-866) mL, 42% (26% 65%). The median hypertrophy rate was 24% (-5% to 96%). A preoperative predictive scoring system for insufficient liver hypertrophy was constructed using the following 3 factors: an initial future liver remnant volume >=35% (2 points), alkaline phosphatase >=450 IU/dL (1 point), and cholinesterase <220 mg/dL (1 point). The constructed scoring system indicated the proportion of patients with insufficient liver hypertrophy (<25%) to be 6 out of 42 (14%) in the low-score group (0 points), 44 out of 77 (57%) in the medium-score group (1-2 points), and 30 out of 33 (91%) in the high-score group (3-4 points). The hypertrophy rate of future liver remnant was different among the 3 groups (low-score group, 38.9% [ 2.4% to 81.4%]; medium-score group, 22.7% [-5.1% to 95.5%]; high-score group, 18.2% [2.4%-30.7%]) (P < .001). CONCLUSION: The constructed scoring system was able to stratify patients before portal vein embolization according to the possibility of developing insufficient liver hypertrophy. PMID- 29501349 TI - Does transcranial direct current stimulation during writing alleviate upper limb freezing in people with Parkinson's disease? A pilot study. AB - Transcranial direct current stimulation (tDCS) over the primary motor cortex (M1) can boost motor performance in Parkinson's disease (PD) when it is applied at rest. However, the potential supplementary therapeutic effect of the concurrent application of tDCS during the training of motor tasks is largely unknown. The present study examined the effects of tDCS on upper limb motor blocks during a freezing-provoking writing task (the funnel task) requiring up- and down-stroke movements at alternating amplitudes. Ten PD patients and 10 age-matched controls underwent two sessions of writing combined with 20 min of anodal or sham tDCS on the left M1 in a randomized cross-over design. The primary outcome was the number of upper limb freezing episodes during five trials of the funnel task on a touch sensitive tablet. PD patients showed a significant reduction in freezing episodes during tDCS compared to sham. No effects of tDCS were found for the amplitude, variability and speed of the strokes outside the freezing episodes. However, patients who reported freezing episodes in daily life (N = 6) showed a beneficial effect of tDCS on stroke characteristics. These results indicate a subgroup dependent variability in response to non-invasive brain stimulation applied during the performance of motor tasks in PD. This warrants future studies to examine tDCS as an adjuvant tool for training programs aimed to reduce motor deficits related to freezing. PMID- 29501350 TI - Hidradenitis suppurativa as an autoinflammatory keratinization disease. PMID- 29501351 TI - Reply. PMID- 29501352 TI - Validation of the Brazilian version of the "pediatric obstructive sleep apnea screening tool" questionnaire. AB - OBJECTIVE: To validate the pediatric obstructive sleep apnea screening tool for use in Brazil. MATERIALS AND METHODS: The Brazilian version of this questionnaire, originally validated and tested in the United States, was developed as follows: (a) translation; (b) back-translation; (c) completion of the final version; (d) pre-testing. The questionnaire was applied prior to polysomnography to children aged 3-9 years from October 2015 to October 2016, and its psychometric properties (i.e., validity and reliability) were evaluated. The accuracy was assessed from comparisons between polysomnographic results and corresponding questionnaire scores. RESULTS: Sixty patients were enrolled, and based on polysomnographic findings, 48% patients had normal apnea-hypopnea index, while the remaining 52% met the criteria for obstructive sleep apnea. Minimum O2 saturation level was significantly lower among obstructive sleep apnea children (p=0.021). Satisfactory concordance was found between individual apnea-hypopnea index and questionnaire scores. Bland-Altman plot-derived bias was 0.1 for the difference between measures, with 5.34 (95% CI: 4.14-6.55) and -5.19 (95%CI: 6.39 to -3.98) for the upper and lower agreement range. Internal consistency derived from Cronbach's alpha was 0.84 (95%CI: 0.78-0.90). CONCLUSION: The questionnaire was translated to and validated into Brazilian-Portuguese version, and showed good reliability and concordance with apnea-hypopnea index. This questionnaire offers a reliable screening option for sleep-disordered breathing in children. PMID- 29501353 TI - Magnetic resonance imaging-a diagnostic tool for postoperative evaluation of dental implants: a case report. AB - OBJECTIVE: Compared with cone beam computed tomography (CBCT), magnetic resonance imaging (MRI) might be superior for the diagnosis of nerve lesions associated with implant placement. STUDY DESIGN: A patient presented with unilateral pain associated with dysesthesia in the region of the right lower lip and chin after implant placement. Conventional orthopantomography could not identify an association between the position of the inferior alveolar nerve and the implant. For 3-dimensional display of the implant in relation to the surrounding anatomy, CBCT was compared with MRI. RESULTS: MRI enabled the precise depiction of the implant position and its spatial relation to the inferior alveolar nerve, whereas the nerve position and its exact course within the mandible could not be directly displayed in CBCT. CONCLUSION: MRI may be a valuable, radiation-free diagnostic tool for the visualization of intraoral hard and soft tissues, offering an objective assessment of nerve injuries by a direct visualization of the inferior alveolar neurovascular bundle. PMID- 29501354 TI - Oral carcinoma cuniculatum presenting with moth-eaten destruction of the mandible. AB - OBJECTIVE: Carcinoma cuniculatum (CC) is a rare variant of squamous cell carcinoma. We describe the clinicopathologic findings in a new case. STUDY DESIGN: This is a literature review and retrospective study of a case with CC. RESULTS: The clinical and imaging findings of CC are diverse; some cases might be challenging to diagnose accurately by biopsy. This article reports a case of CC that occurred in the retromolar region with involvement of the mandible. The patient was a 39-year-old man. Clinically, the lesion manifested as an ulcerative mass in the mandibular molar region. Imaging results showed that the lesion in the jaw exhibited moth-eaten destruction without obvious expansion of the jaw bone. The postoperative pathologic examinations were consistent with CC; additionally, metastases were present in 1 level II lymph node and 1 submandibular lymph node. Left soft tissue metastasis and right cervical lymph node metastases were detected 10 and 27 months after surgery, respectively. CONCLUSIONS: CC is a rare epithelial malignant tumor and has variable clinical manifestations. The diagnosis of CC mainly depends on pathologic features. Most patients with CC have a good prognosis; only a small percentage of patients might experience lymph node metastasis. PMID- 29501355 TI - Expression of cell cycle proteins according to HPV status in oral squamous cell carcinoma affecting young patients: a pilot study. AB - OBJECTIVE: Tobacco and alcohol consumption are considered the main risk factors for oral squamous cell carcinoma (OSCC); however, the role of these factors in patients younger than 40 years is controversial, so it has been suggested that genomic instability and high-risk human papillomavirus (HR-HPV) infection may be contributing factors to oral carcinogenesis at a young age. Therefore, the aim of this study was to evaluate the immunoexpression of cell cycle proteins according HPV status in OSCC affecting young patients. METHODS: A tissue microarray construction based on 34 OSCC samples from young patients (<40 years old) was subjected to immunohistochemical reactions for Ki67, cyclin D1, C-ErbB2, p21, Myc, epidermal growth factor receptor, p53, and p16 antibodies. RESULTS: The clinicopathologic features and the immunoexpression of all tested proteins were similar in both groups. Patients with HPV-related OSSC tended to have better cancer-specific survival (CSS; 39% vs 60% 5-y CSS), and overall survival (OS; 29.2% vs 60% 5-year OS). However, this difference was not statistically significant. CONCLUSION: No significant difference exists in the expression of cell cycle proteins studied between HR-HPV DNA-positive and HR-HPV DNA-negative OSCC affecting young patients. PMID- 29501356 TI - Management of head and neck cancer in older patients. AB - OBJECTIVE: A progressive increase in the number of older patients with head and neck cancer has been observed in the last few years. The aim of this study was to assess our experience in the management of older patients with head and neck cancer (HNC) in comparison with younger patients. STUDY DESIGN: A retrospective review was conducted for all patients admitted and treated for newly diagnosed HNC between January 2008 and December 2012. The clinical characteristics, management approaches, and outcome data were recorded. RESULTS: In total, 316 patients with HNC (232 males, 84 females) were enrolled: 203 (64%) were in the young group, whereas 113 patients (36%) were in the older group. Comorbidities (P < .000005) and stage IV tumors (P < .0005) were more frequently observed in the older group. Treatment options were uniformly distributed within the 2 groups; only radiotherapy alone was more frequently administered in older patients (P < .0005). CONCLUSIONS: Chronologic age should not be a reason to deny appropriate treatments that could prevent death in older patients. A careful pretreatment assessment should always be performed. PMID- 29501357 TI - Descriptions of the Pain Experience in Adults and Adolescents with Cystic Fibrosis. AB - BACKGROUND: People living with cystic fibrosis experience pain that is associated with decreased quality of life, poorer health outcomes, and increased mortality. Though pain is highly prevalent as a symptom, it is currently unknown how persons with CF describe their pain experiences or the ways those experiences impact their lives. AIMS: To explore and describe ways adolescents and adults with CF experience pain. Design/Setting/Subjects/Methods: An exploratory descriptive design was implemented to perform interviews with 10 individuals with CF and self reported moderate to severe pain. The interviews explored their pain experiences within five domains: Pain Characteristics, Activities, Relationships, Work/School Life, and Health Care Team. Transcribed interviews underwent a content analysis with team-based constant comparisons. RESULTS: Individuals with CF identify the disease as being painful; express how pain negatively affects all aspects of their lives, including loss of functionality and productivity; and are able to disclose their pain to those with whom they have relationships. Adolescents feel an emotional toll from the loss of socialization as a result of pain and feel their health care team adequately supports their pain. Adults express a unique emotional pain component to CF and feel stigmatized and unsupported by their health care team when asking for pain management solutions. CONCLUSION: There are differences in how pain is perceived by adolescents and adults with CF that have otherwise not been reported in the current literature. Further explorations of pain across the lifespan and health care provider attitudes toward pain management are needed to guide the development of effective pain management interventions for those with CF. PMID- 29501358 TI - The Influence of Race and Gender on Nursing Care Decisions: A Pain Management Intervention. AB - BACKGROUND: Understanding whether a patient's race or gender and/or the nurse's race or gender influence how nurses form care decisions can contribute to exploration of methods that can positively affect disparate treatment. AIMS: This research examined how the variables of race and gender of both the nurse and the patient influence nurses' decision making about pain management. DESIGN: A randomized four-group post-test-only experimental design was used to examine the variables and variable interactions. SETTINGS: An investigator-developed case vignette tool hosted online was used to obtain data about nursing pain management decisions. The vignette intervention was developed to simulate four exact patient scenarios that differed only by patient race and gender. Participants/Subjects: A quota sample of 400 nurses was recruited using a self-selected face-to-face recruitment technique. METHODS: A four-way between-groups analysis of variance assessed whether the gender of the nurse, race of the nurse, gender of the patient, or race of the patient made any differences in the dose intensity of pain medications selected by the nurse sample. RESULTS: No significant interactions were noted between any combinations of the four independent variables. A significant main effect was noted in medication intensity for nurse gender (F [1,384] = 9.75, p = .002). CONCLUSIONS: Data trends suggested that gender stereotypes about how patients managed pain played a role in dose intensity decisions because female patients on average were given higher doses of pain medication than male patients were by all the nurses in the study. Further research is needed in this complex area of study. PMID- 29501360 TI - Depression and Coping Behaviors Are Key Factors in Understanding Pain in Interstitial Cystitis/Bladder Pain Syndrome. AB - BACKGROUND: Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a urologic chronic pelvic pain syndrome with suboptimal treatment outcomes. Catastrophizing is an empirically supported risk factor for greater IC/BPS pain. AIMS: In this study, a moderated multiple mediation model is tested in which several additional psychosocial risk factors (depression, illness and wellness-focused behavioral coping strategies) are proposed as mediators or moderators in the existing relationship between catastrophizing and IC/BPS pain. DESIGN: The present questionnaire study employed a cross-sectional design. SETTINGS AND PARTICIPANTS: Female patients with an IC/BPS diagnosis (n = 341) were recruited at tertiary care sites. METHODS: Participants completed questionnaires assessing pain, catastrophizing, behavioral coping strategies, and depressive symptoms. Aggregate factor scores were calculated following exploratory factor analyses. RESULTS: It was found that patients with a greater tendency to catastrophize were more likely to engage in illness-focused coping strategies, which contributed to the reporting of greater sensory and affective pain. Furthermore, this mediating effect of illness-focused coping on affective pain was more likely to occur in those patients reporting greater depressive symptoms. CONCLUSIONS: Illness focused behavioral coping is an important mechanism between maladaptive pain cognition and aspects of patient pain, with patients reporting greater depressive symptoms at increased risk for elevated pain. Patient management techniques, including screening for catastrophizing, coping, and depression, are recommended to enrich IC/BPS management. PMID- 29501359 TI - Differences in Sensory Pain, Expectation, and Satisfaction Reported by Outpatients with Cancer or Sickle Cell Disease. AB - BACKGROUND: Patients with sickle cell disease (SCD) report pain scores that appear greater than those reported in a meta-analysis for patients with cancer, but statistical comparisons of the pain scores from both populations have not been published. AIMS: The goal of the study described here was to compare pain outcomes reported by outpatients with cancer or SCD. DESIGN: Descriptive comparative study. SETTING: Outpatient oncology or sickle cell clinics. SUBJECTS: The participants were outpatients (N = 415) from three studies: (1) 106 patients with SCD, 93% African-American (referent group); (2) 140 patients with cancer, 90% Caucasian (race discordant); (3) 169 patients with cancer, 20% Caucasian, 65% African-American (race concordant). METHODS: Patients completed the PAINReportIt including pain location, quality, pattern, intensity, expectation, satisfaction, and demographic questions. Analyses included the chi2 test, analysis of variance, and regression. RESULTS: Outpatients with SCD reported more pain location sites than the race-discordant (p < .001) and race-concordant (p < .001) cancer groups; higher pain quality than the race-discordant (p < .001) and race-concordant (p < .001) groups; and greater pain pattern scores than the race-discordant (p < .001) and race-concordant (p < .001) groups. The race-concordant group reported higher worst pain intensity than the SCD (p < .001) and race-discordant (p = .002) groups. The three groups did not differ significantly on pain expectation (p = .06). Regarding satisfaction with pain level, there was a significant difference between the race-concordant and SCD (p = .006) groups, but not between the race discordant and SCD (p = .12) groups or between the race-discordant and race concordant (p = .49) groups. CONCLUSIONS: Outpatients with SCD reported three of four sensory pain parameters that were greater than those reported by outpatients with cancer. A better understanding of these differences is pertinent to improving pain outcomes. PMID- 29501361 TI - The Use of Comfort Kits to Optimize Adult Cancer Pain Management. AB - Pain is one of the most feared of all symptoms for the cancer patient. Some studies estimate that up to 90% of all cancer patients experience pain. Advances in pharmaceuticals and expert provider knowledge have improved pain management overall for the patient with cancer; however, complementary therapies can synergize medications to provide optimal pain relief while decreasing the side effect profile. Despite this, nurses may have limited access to such resources. Many therapies can be administered directly by the bedside/chairside nurse with minimal training and the nurse can then teach the patient and family how to use the selected complementary therapy after leaving the hospital or clinic. The oncology nurse will be able to identify several easy-to-implement complementary therapies that can supplement pharmacologic pain management for cancer patients. As a quality project, comfort kits, containing such items as handheld massagers, guided imagery audiotapes, and aromatherapy essential oils, were distributed for use with patients through unit-based pain resource nurses. More than 500 comfort kit items were tracked by the pain clinical nurse specialist during the comfort kit trial, both by medical record review and by follow-up phone calls to patients. During the comfort kit trial, average pain intensity decreased by 2.25 points on a 0-10 scale in the 24-hour period after use of the item from the comfort kit. Patients also had an overall decrease in the use of pharmacologic pain interventions and an increase in ambulation in the 24-hour period after implementation. Comfort kits allow nurses easy access to inexpensive tools to supplement pharmaceutical pain management. Optimizing nonpharmacologic pain management can increase patient and nurse satisfaction, improve overall pain management, and decrease untoward side effects. PMID- 29501362 TI - Editorial Comment. PMID- 29501364 TI - Nedaplatin in nasopharyngeal cancer: the rebirth of platinum salts? PMID- 29501365 TI - Addition of platinum salts to neoadjuvant chemotherapy in triple-negative breast cancer: a new standard of care? PMID- 29501363 TI - Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. AB - BACKGROUND: Although several randomised trials in patients with triple-negative breast cancer have shown that the addition of carboplatin, with or without poly(ADP-ribose) polymerase (PARP) inhibitors, to neoadjuvant chemotherapy increases the likelihood of achieving a pathological complete response, the use of these therapies in this setting has remained controversial. The BrighTNess trial was designed to assess the addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple negative breast cancer. METHODS: We did a phase 3, randomised, double-blind, placebo-controlled trial (BrighTNess) across 145 sites in 15 countries. Patients aged 18 years and older with previously untreated histologically or cytologically confirmed clinical stage II-III triple-negative breast cancer, who were candidates for potentially curative surgery and had an Eastern Cooperative Oncology Group performance status of 0 or 1, were randomly assigned (2:1:1) by an interactive response technology system via permuted blocks (block size of four) within strata to receive one of three segment 1 regimens: paclitaxel (80 mg/m2 intravenously weekly for 12 doses) plus carboplatin (area under the curve 6 mg/mL per min, intravenously every 3 weeks, for four cycles) plus veliparib (50 mg orally, twice a day); paclitaxel plus carboplatin plus veliparib placebo (twice a day); or paclitaxel plus carboplatin placebo (every 3 weeks for four cycles) plus veliparib placebo. Following segment 1, all patients were assigned to segment 2 in which they received doxorubicin and cyclophosphamide every 2-3 weeks for four cycles. Randomisation for segment 1 was stratified by germline BRCA mutation status, nodal stage, and planned schedule of doxorubicin and cyclophosphamide administration. The primary endpoint was pathological complete response in breast and lymph nodes as determined by site pathologists following completion of neoadjuvant therapy. Efficacy analyses were done by intention to treat and safety analyses included all patients who received at least one dose of study treatment. These are the first results of an ongoing clinical trial; the data cutoff for the analyses presented was Dec 8, 2016. This study is registered with ClinicalTrials.gov, number NCT02032277. FINDINGS: Between April 4, 2014, and March 18, 2016, 634 patients were randomly assigned: 316 to paclitaxel plus carboplatin plus veliparib, 160 to paclitaxel plus carboplatin, and 158 to paclitaxel alone. The proportion of patients who achieved a pathological complete response was higher in the paclitaxel, carboplatin, and veliparib group than in patients receiving paclitaxel alone (168 [53%] of 316 patients vs 49 [31%] of 158, p<0.0001), but not compared with patients receiving paclitaxel plus carboplatin (92 [58%] of 160 patients, p=0.36). Grade 3 or 4 toxicities, and serious adverse events were more common in patients receiving carboplatin, whereas veliparib did not substantially increase toxicity. The most common grade 3 or 4 events overall were neutropenia (352 [56%] of 628 patients), anaemia (180 [29%]), and thrombocytopenia (75 [12%]) through complete treatment, and febrile neutropenia (88 [15%] of 601 patients) during segment 2. The most common serious adverse events were febrile neutropenia (80 [13%] of 628 patients) and anaemia (20 [3%]). INTERPRETATION: Although the addition of veliparib and carboplatin to paclitaxel followed by doxorubicin and cyclophosphamide improved the proportion of patients with triple-negative breast cancer who achieved a pathological complete response, the addition of veliparib to carboplatin and paclitaxel did not. Increased toxicities with the addition of carboplatin (with or without veliparib) to paclitaxel were manageable and did not substantially affect treatment delivery of paclitaxel followed by doxorubicin and cyclophosphamide. Given the consistent results with previous studies, the addition of carboplatin appears to have a favourable risk to benefit profile and might be considered as a potential component of neoadjuvant chemotherapy for patients with high-risk, triple-negative breast cancer. FUNDING: AbbVie. PMID- 29501366 TI - Concurrent chemoradiotherapy with nedaplatin versus cisplatin in stage II-IVB nasopharyngeal carcinoma: an open-label, non-inferiority, randomised phase 3 trial. AB - BACKGROUND: Cisplatin-based concurrent chemoradiotherapy is currently considered to be the standard treatment regimen for patients with advanced nasopharyngeal carcinoma, but has well known side-effects such as gastrointestinal reactions, nephrotoxicity, and ototoxicity. Nedaplatin was developed to decrease the toxic effects induced by cisplatin, and in this trial we assessed whether a nedaplatin based concurrent chemoradiotherapy regimen was non-inferior to a cisplatin-based regimen in patients with locoregional, stage II-IVB nasopharyngeal carcinoma. METHODS: We did an open-label, non-inferiority, phase 3, randomised, controlled trial at two centres in China. Patients aged 18-65 years with non-keratinising stage II-IVB (T1-4N1-3 or T3-4N0) nasopharyngeal carcinoma, a Karnofsky score of at least 70, and adequate haematological, renal, and hepatic function were randomly assigned (1:1) to receive intravenously either nedaplatin 100 mg/m2 or cisplatin 100 mg/m2 on days 1, 22, and 43 for three cycles concurrently with intensity-modulated radiotherapy. Randomisation was done manually using a computer-generated random number code and patients were stratified by treatment centre and clinical stage. Patients and clinicians were not masked to treatment allocation. The primary endpoint was progression-free survival at 2 years; non inferiority was shown if the upper limit of the 95% CI for the difference in 2 year progression-free survival between the two groups did not exceed 10%. Analyses were by both intention to treat and per protocol, including all patients who received at least one complete cycle of chemotherapy. This trial is registered with ClinicalTrials.gov, number NCT01540136, and is currently in follow-up. FINDINGS: Between Jan 16, 2012, and July 16, 2014, we randomly assigned 402 patients to nedaplatin-based (n=201) or cisplatin-based (n=201) concurrent chemoradiotherapy. In the intention-to-treat population, 2-year progression-free survival was 89.9% (95% CI 85.8-94.0) in the cisplatin group and 88.0% (83.5-94.5) in the nedaplatin group, with a difference of 1.9% (95% CI -4.2 to 8.0; pnon-inferiority=0.0048). In the per-protocol analysis (cisplatin group, n=197; nedaplatin group, n=196), 2-year progression-free survival was 89.7% (95% CI 85.4-94.0) in the cisplatin group and 88.7% (84.2-94.5) in the nedaplatin group, with a difference of 1.0% (95% CI -5.2 to 7.0; pnon-inferiority=0.0020). A significantly higher frequency of grade 3 or 4 vomiting (35 [18%] of 198 in the cisplatin group vs 12 [6%] of 200 in the nedaplatin group, p<0.0001), nausea (18 [9%] vs four [2%], p=0.0021), and anorexia (53 [27%] vs 26 [13%], p=0.00070) was observed in the cisplatin group compared with the nedaplatin group. 11 (6%) patients in the nedaplatin group had grade 3 or 4 thrombocytopenia compared with four (2%) in the cisplatin group (p=0.065). Patients in the cisplatin group had a higher frequency of any grade or grade 3 or 4 late auditory or hearing toxicities than did patients in the nedaplatin group (grade 3 or 4: three [2%] in the nedaplatin group vs 11 [6%] in the cisplatin group, p=0.030). No patients died from treatment-related causes. INTERPRETATION: Our findings show that nedaplatin based concurrent chemoradiotherapy represents an alternative doublet treatment strategy to cisplatin-based concurrent chemoradiotherapy for patients with locoregional, advanced nasopharyngeal carcinoma. Further investigations are needed to explore the potential use of this treatment as induction or adjuvant chemotherapy or in combination with other agents. FUNDING: National Key R&D Program of China, National Natural Science Foundation of China, Sun Yat-sen University Clinical Research 5010 Program, Sci-Tech Project Foundation of Guangzhou City, National Key Basic Research Program of China, Special Support Plan of Guangdong Province, Sci-Tech Project Foundation of Guangdong Province, Health & Medical Collaborative Innovation Project of Guangzhou City, National Science & Technology Pillar Program during the Twelfth Five-year Plan Period, PhD Start-up Fund of Natural Science Foundation of Guangdong Province, Cultivation Foundation for the Junior Teachers in Sun Yat-sen University, and Fundamental Research Funds for the Central Universities. PMID- 29501367 TI - The fat mass index, not the fat-free mass index, is associated with impaired physical performance in older adult subjects: Evidence from a cross-sectional study. AB - BACKGROUND: Impaired physical performance (IPP) and physical disability (PD) are two serious public health problems in older adult populations worldwide. While studies show that changes in body composition are important risk factors for developing these conditions, there is little evidence that the fat-free mass (FFM) and fat mass (FM) indices (FFMI and FMI, respectively) are associated with IPP in older men and women. This study assessed the association among FFMI, FMI, and IPP using Short Physical Performance Battery (SPPB) in Mexican men and women aged over 60 years. METHODS: This cross-sectional study included 217 older people (men 34.6%, women 65.4%; 60-92 years). FFM and FM were assessed by dual X-ray absorptiometry, assuming a two-compartment model. FFM and FM were adjusted by height squared and the indices were obtained. After assessment of physical performance by SPPB, subjects with scores <=6 were classified as having IPP. Associations were tested by multiple logistic regression analysis in separated models. RESULTS: IPP prevalence was 14.3%. Women were affected more than men. Regression analysis showed no significant association between FFMI and IPP, but FMI was strongly-associated, as for each unit increase in FMI, the risk of IPP rose significantly (OR: 1.14), and this result remained significant after adjusting for age, comorbidity, polypharmacy, and the appendicular skeletal muscle mass index (OR: 1.23; p <= 0.001). These results emphasize the importance of preventing increases in FM and avoiding overweight and obesity in older men and women. PMID- 29501368 TI - [A novel agent in the treatment of heart failure with depressed systolic function]. AB - INTRODUCTION: A review is presented on the evolution of the pharmacological treatment of heart failure (HF) in the last 25 years, from the concept of treatment with vasodilators to the blocking or inhibition of the renin angiotensin aldosterone system. Beta-adrenergic inhibition and its important contribution in the reduction of morbidity and mortality due to HF will be discussed along with the role of the natriuretic peptides. One of the most important studies in the cardiology area, and specifically in the management of HF, is presented, in which an approach is demonstrated of the modulator of the neurohumoral systems that are activated in these patients. OBJECTIVES: HF is the final stage of most cardiovascular diseases, and has a high rate of hospital admission, as well as cardiovascular morbidity and mortality. Therefore, there is constant interest in the need to find an innovative therapeutic agent that significantly reduces these complications and that improves the quality of life of those who suffer from it. METHODS: A description will be presented of the PARADIGM-HF Clinical Trial using a sacubitril/valsartan compound for the management of HF with a modulating mechanism different from the concept of a deleterious system blocker that is activated when a patient has symptoms and signs of heart failure. CONCLUSIONS: Death due to cardiovascular causes, or hospital admission due to heart failure (the primary endpoint) occurred in 914 patients (21.8%) in the Sacubitril / valsartan group, and 1117 patients (26.5%) in the enalapril group (risk ratio in the sacubitril / valsartan group, 0.80, with a 95% confidence interval [CI]: 0.73 to 0.87, P<0.001 [exact P= 4.0 * 10 - 7]). Of the patients receiving sacubitril / valsartan, 537 (12.8%) were hospitalised due to heart failure, compared with 658 patients (15.6%) receiving enalapril (hazard ratio 0.79, 95% CI: 0.71 to 0.89, P<.001). A total of 711 patients (17.0%) in the sacubitril / valsartan group, and 835 patients (19.8%) in the enalapril group, died (all-cause death rate, 0.84, 95% CI: 0.76 to 0.93, P<.001). PMID- 29501369 TI - Acute Pancreatitis Guideline. PMID- 29501370 TI - Anharmonic calculations of frequencies and intensities of OH stretching vibrations of (R)-1,3-butanediol conformers in the fundamentals and first overtones by density functional theory. AB - The frequencies and absorption intensities of the five kinds of conformers of 1,3 butanediol with the same carbon skeleton (GG') were calculated by anharmonic calculation for the fundamentals and first overtones of OH stretching vibrations. The four kinds of conformers form intramolecular hydrogen bonds and one conformer did not. Intramolecular hydrogen bond formation shifted the frequency of fundamental and first overtone of H-bonding OH stretching vibration to the lower frequency. The absorption intensities of the fundamentals as well as the vibrational anharmonicities increased upon hydrogen bond formation, while the intensities of first overtones decreased. The differences of conformers were clearly seen in the frequencies of the first overtones of free OH. PMID- 29501371 TI - What We Have Learned From the Ocular Hypertension Treatment Study. AB - PURPOSE: To identify results from the Ocular Hypertension Study that can aid patients and clinicians to make evidence-based decisions about the management of ocular hypertension. DESIGN: Perspective. RESULTS: At 60 months, the cumulative frequency of developing primary open-angle glaucoma (POAG) was 4.4% in the medication group and 9.5% in the observation group (hazard ratio for medication, 0.40; 95% confidence interval [CI], 0.27-0.59; P < .0001). At 13 years the cumulative proportion of participants who developed POAG was 0.22 (95% CI 0.19 0.25) in the original observation group and 0.16 (95% CI 0.13-0.19) in the original medication group (complementary log-log x2P = .009). A 5-factor model (older age, higher IOP, thinner central corneal thickness, larger cup-to-disc ratio, and higher visual field pattern standard deviation) separated participants at high and low risk of developing POAG. CONCLUSIONS: Clinicians and patients can make evidence-based decisions about the management of ocular hypertension using the risk model and considering patient age, medical status, life expectancy, and personal preference. PMID- 29501372 TI - Low maternal melatonin level increases autism spectrum disorder risk in children. AB - BACKGROUND: It is assumed that autism spectrum disorder (ASD) is caused by a combination of de novo inherited variation and common variation as well as environmental factors. It often co-occurs with intellectual disability (ID). Almost eight hundred potential causative genetic variations have been found in ASD patients. However, not one of them is responsible for more than 1% of ASD cases. Low melatonin levels are a frequent finding in ASD patients. Melatonin levels are negatively correlated with severity of autistic impairments, it is important for normal neurodevelopment and is highly effective in protecting DNA from oxidative damage. Melatonin deficiency could be a major factor, and well a common heritable variation, that increases the susceptibility to environmental risk factors for ASD. ASD is already present at birth. As the fetus does not produce melatonin, low maternal melatonin levels may be involved. METHODS: We measured 6-sulfatoxymelatonin in urine of 60 mothers of a child with ASD and controls. RESULTS: 6-sulfatoxymelatonin levels were significantly lower in mothers with an ASD child than in controls (p = 0.012). CONCLUSIONS: Low parental melatonin levels could be one of the contributors to ASD and possibly ID etiology. Our findings need to be duplicated on a larger scale. If our hypothesis is correct, this could lead to policies to detect future parents who are at risk and to treatment strategies to ASD and intellectual disability risk. PMID- 29501373 TI - Multiple origins and strong phenotypic convergence in fish-cleaning palaemonid shrimp lineages. AB - Several species of palaemonid shrimps are known to act as fish-cleaning symbionts, with cleaning interactions ranging from dedicated (obligate) to facultative. We confirmed five evolutionarily independent origins of fish cleaning symbioses within the family Palaemonidae based on a phylogenetic analysis and the ancestral state reconstruction of 68 species, including 13 fish cleaners from the genera Ancylomenes, Brachycarpus, Palaemon, Periclimenes, and Urocaridella. We focus in particular on two distantly related lineages of fish cleaning shrimps with allopatric distributions, the Indo-West Pacific Ancylomenes and the western Atlantic monophyletic Ancylomenes/Periclimenes group, which exhibit striking similarities in morphology, colouration and complex behaviour. Specifically, representatives of both lineages are similar in: (1) the general body shape and colour pattern; (2) the utilization of sea anemones as conspicuous cleaning stations; and (3) the use of sideways body swaying to visually promote their bright colour spots in order to attract fish clients. Such morphological, ecological and ethological convergences are apparently due to adaptations to fish cleaning linked to the establishment of similar modes of communication with fish clients in these species. PMID- 29501374 TI - Caught in the act: Incipient speciation across a latitudinal gradient in a semifossorial mammal from Madagascar, the mole tenrec Oryzorictes hova (Tenrecidae). AB - Madagascar is one of the world's foremost biodiversity hotspots, yet a large portion of its flora and fauna remains undescribed and the driving forces of in situ diversification are not well understood. Recent studies have identified a widespread, latitudinally structured phylogeographic pattern in Madagascar's humid-forest mammals, amphibians, reptiles, and insects. Several factors may be driving this pattern, namely biogeographic barriers (i.e., rivers or valleys) or past episodes of forest contraction and expansion. In this study, we describe the phylogeographic structure of the small, semifossorial mammal Oryzorictes hova, one of Madagascar's two species of mole tenrec, found throughout Madagascar's eastern humid forest belt, from high-elevation montane forest to low-elevation forests, as well as disturbed habitat such as rice fields. Using one mitochondrial locus, four nuclear loci, and 31 craniomandibular measurements, we identified three distinct populations of O. hova associated with the northern, central, and southern regions of the island. We found little evidence of gene flow among these populations, so we treated each population as a potential species. We validated species limits using two Bayesian methods: BP&P, employing only DNA sequence data, and iBPP using both DNA and morphological data, and we assessed whether these methods are susceptible to producing false positive errors. Molecular and morphological data support the recognition of each of the three populations of O. hova as distinct species, but formal species descriptions will require additional data from type specimens. This study illustrates the importance of using integrative datasets, multiple methodological approaches, and extensive geographic sampling for species delimitation and adds evidence for a widespread phylogeographic pattern in Madagascar's humid forest taxa. PMID- 29501376 TI - Re. "A simple technique for small diameter urethrocutaneous fistula repair: Ligation". PMID- 29501375 TI - Complex taxonomy of the 'brush tail' peregrine earthworm Pontoscolex corethrurus. AB - Pontoscolex corethrurus is the most widespread earthworm species in tropical and sub-tropical zones and one of the most studied in soil science. Although, ecological interactions of P. corethrurus with its environment are well documented, the taxonomic status of the species remains unclear. In this study, we investigated phylogenetic relationships within the genus Pontoscolex, in particular focusing on morphologically indistinguishable (i.e., cryptic) lineages. A total of 792 specimens collected from 25 different countries and islands all over the world were analyzed using two mitochondrial (COI and 16S rDNA) and two nuclear (internal transcribed spacers 2 and 28S rDNA) markers, and a total of 11 morphological characters both internal and external were investigated in all genetically characterized lineages. A large-scale multilocus sequence data matrix was also obtained for Pontoscolex spp. specimens using the Anchored Hybrid Enrichment (AHE) method. Multilocus phylogenetic and phylogenomic analyses, combined with species delimitation methods; including single locus (mPTP, ABGD) and multilocus (BPP) approaches, revealed congruent results. Four cryptic species were supported within the P. corethrurus species complex, and four potentially new species within the genus Pontoscolex. One widespread lineage (L1), within P. corethrurus complex was observed in the current population of Fritz Muller's garden where P. corethrurus was first described in 1856. Cryptic lineages were observed in sympatry at several localities. This, in combination with observed heteroplasmy in COI gene in one population raises an important question of reproductive isolation between these species. PMID- 29501377 TI - Laparoscopic nephrectomy for Wilms' tumor: Can we expand on the current SIOP criteria? AB - INTRODUCTION: Wilms' tumor now has a good overall prognosis with open radical nephrectomy having been the mainstay of surgical treatment. Recently laparoscopic nephrectomy (LN) has been growing in popularity. The aim of our study was to review our indications and outcomes for laparoscopic resections for Wilms' tumor and compare indications with International Society of Paediatric Oncology (SIOP) criteria for LN. MATERIAL AND METHODS: Patient demographics, preoperative management, surgical data, respect of SIOP criteria, complications, disease outcome, and follow-up were recorded on consecutive children who underwent nephrectomy for Wilms' tumor. RESULTS AND DISCUSSION: Fifty-four consecutive children with Wilms' tumor underwent a nephrectomy; 20 had a LN (Table). Nine of 20 (45%) patients who had LN did not meet SIOP criteria for LN. No patients had an intraoperative tumor rupture and one patient had positive margins because of preoperative rupture. There were two conversions: one caused by difficulty accessing the renal hilum and the other caused by difficulty maintaining oxygen saturations. There was one local recurrence. CONCLUSION: SIOP criteria are conservative and safe. Indications can be extended for teams experienced in surgical oncology and laparoscopy after agreement at a multidisciplinary meeting (MDM). PMID- 29501378 TI - Is surgical antibiotic prophylaxis necessary for pediatric orchiopexy? AB - INTRODUCTION: Surgeons frequently use surgical antibiotic prophylaxis (SAP), despite limited evidence to support its efficacy. Potential adverse events associated with antibiotic use include allergic reaction (including anaphylaxis), Clostridium difficile infection, and selecting for resistant bacteria. Surgical site infections (SSI) are very rare in patients undergoing clean pediatric urologic procedures. Current guidelines are unclear about the efficacy of surgical antibiotic prophylaxis for prevention of SSI in the pediatric population. OBJECTIVE: It was hypothesized that children who received SAP prior to orchiopexy would have no reduction in surgical site infection (SSI) risk but an increased risk of antibiotic-associated adverse events. METHODS: A retrospective cohort study was conducted of all males aged between 30 days and 18 years who underwent an orchiopexy (ICD-9 CM 62.5) in an ambulatory or observation setting from 2004 to 2015 using the Pediatric Health Information System database. Inpatients and those with concomitant procedures were excluded. Chi-squared or Fisher's exact tests were used to determine the association between SAP and allergic reaction (defined as a charge for epinephrine or ICD-9 diagnosis code for allergic reaction on the date of surgery) and any of the following within 30 days: SSI, hospital readmission or any repeat hospital encounter. Mixed effects logistic regression was performed, controlling for age, race, and insurance, and clustering of similar practice patterns by hospital. RESULTS: A total of 71,767 patients were included: median age was 4.6 years, 61.4% were white, and 49.3% had public insurance; 33.5% received SAP. Of these participants, 996/71,767 (1.4%) had a perioperative allergic reaction and <0.1% were diagnosed with an SSI. On mixed effects logistic regression, those who received SAP had 1.2 times the odds of a perioperative allergic reaction compared with those who did not receive SAP (P = 0.005). Surgical antibiotic prophylaxis was not associated with decreased rates of SSI, lower hospital readmission, nor a lower chance of a repeat encounter within 30 days. CONCLUSIONS: In patients undergoing orchiopexy, it was found that SAP did not reduce the risk of postoperative SSI, readmissions, or hospital visits. Patients who received SAP had significantly increased odds of perioperative allergic reaction. This demonstrated that the risks of SAP outweigh the benefits in children undergoing orchiopexy. PMID- 29501379 TI - Re: Urinary tract infection in children: Diagnosis, treatment, imaging - Comparison of current guidelines. PMID- 29501380 TI - Risk factors for postobstructive diuresis in pediatric patients with ureteropelvic junction obstruction, following open pyeloplasty in three high complexity institutions. AB - INTRODUCTION: Postobstructive diuresis (POD) is a polyuric state in which large quantities of salt and water are eliminated after solving a urinary tract obstruction. These patients are at increased risk of severe dehydration, electrolytic disturbances, hypovolemic shock, and death. Ureteropelvic junction obstruction (UPJO) is the most common etiology of collecting system dilatation in the fetal kidney, and a significant number of patients require pyeloplasty. There are limited data regarding prognostic risk factors for POD in this scenario. OBJECTIVE: To describe possible clinical risk factors for POD in the pediatric population after open pyeloplasty. STUDY DESIGN: This was a retrospective case series study of consecutive patients diagnosed with UPJO at three high complexity centers, managed with open pyeloplasty from 2006 to 2016. Multiple qualitative and quantitative variables possibly associated with POD were included according to the literature review. They were statistically analyzed with STATA 14 software. RESULTS: A total of 88 patients with UPJO following open pyeloplasty were analyzed. Twenty-seven patients (30%) had POD. A tendency to present POD in younger patients was found, with a mean age of 20.2 months vs. 72.3 months. There was also an increased risk of POD in patients with previous diagnosis of tubular acidosis. CONCLUSIONS: There are no data about prognostic clinical risk factors for POD after open pyeloplasty in the pediatric population. Our study corresponds to one of the larger series reported so far. It suggests that younger patients and patients with a previous diagnosis of tubular acidosis could be at greater risk of POD. Consequently, prospective studies are required for validation of our results, and possible impact on patient follow-up. PMID- 29501381 TI - Cryptic Disorder Out of Disorder: Encounter between Conditionally Disordered CP12 and Glyceraldehyde-3-Phosphate Dehydrogenase. AB - Among intrinsically disordered proteins, conditionally disordered proteins undergo dramatic structural disorder rearrangements upon environmental changes and/or post-translational modifications that directly modulate their function. Quantifying the dynamics of these fluctuating proteins is extremely challenging but paramount to understanding the regulation of their function. The chloroplast protein CP12 is a model of such proteins and acts as a redox switch by formation/disruption of its two disulfide bridges. It regulates the Calvin cycle by forming, in oxidized conditions, a supramolecular complex with glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and then phosphoribulokinase. In this complex, both enzymes are inactive. The highly dynamic nature of CP12 has so far hindered structural characterization explaining its mode of action. Thanks to a synergistic combination of small-angle X-ray scattering, nuclear magnetic resonance and circular dichroism that drove the molecular modeling of structural ensembles, we deciphered the structural behavior of Chlamydomonas reinhardtii oxidized CP12 alone and in the presence of GAPDH. Contrary to sequence-based structural predictions, the N-terminal region is unstable, oscillates at the ms timescale between helical and random conformations, and is connected through a disordered linker to its C-terminus, which forms a stable helical turn. Upon binding to GAPDH, oxidized CP12 undergoes an induced unfolding of its N-terminus. This phenomenon called cryptic disorder contributes to decrease the entropy cost and explains CP12 unusual high affinity for its partners. PMID- 29501382 TI - Expression, regulation and function of miR-126 in the mouse choroid vasculature. AB - MicroRNA miR-126 has been shown to be required for proper angiogenesis in several models. However, its expression, regulation and function in the mouse choroid remain unclear. Our previous data has shown that miR-126 expression is enriched in the endothelial cells (ECs) of the mouse choroid. Here we report that a 5.5 kb Egfl7/miR-126 promoter drives the expression of miR-126 in the choroid ECs during choroidal vascular development. The expression of miR-126 in the ECs is regulated by flow stress likely through Kruppel-like transcriptional factors. miR-126-/- mice show mildly delayed choroidal vascular development, but adult knockout mice develop periphery choroidal vascular lesions. This study suggests that miR-126 is largely dispensable for mouse choroidal development but required for maintaining choroidal vasculature integrity. PMID- 29501383 TI - Is pathological complete response after a trimodality therapy, a predictive factor of long-term survival in locally-advanced esophageal cancer? Results of a retrospective monocentric study. AB - OBJECTIVE: To evaluate long-term (5- and 10-year) survival and recurrence rates on the basis of the pathological complete response (pCR) in the specimens of patients with esophageal carcinoma, treated with trimodality therapy. METHODS: Between 1993 and 2014, all consecutives patients with esophageal locally-advanced non-metastatic squamous cell carcinoma (SCC) or adenocarcinoma (ADC) who received trimodality therapy were reviewed. According to histopathological analysis, patients were divided in two groups with pCR and with pathological residual tumor (pRT). The primary endpoint was overall survival (OS). The secondary endpoints included the disease-free survival (DFS), the recurrence rate, and the predictive factors of overall survival and recurrence. RESULTS: One hundred and three patients were included: 49 patients with pCR and 54 patients with pRT. The median OS was significantly longer in pCR group than in pRT group (132+/-22.3 vs. 25.5+/ 4 months), with both 5- and 10-years OS rates of 75.2% vs. 29.1%, and 51.1% vs. 13.6%, respectively (P<0.001). Also, pRT, major postoperative complications (Dindo-Clavien grade>IIIb) and recurrence were the 3 independent predictive factors for worse OS. CONCLUSIONS: Patients with locally-advanced oesophageal carcinoma, who responded to trimodality therapy with a pCR, could be achieved a 10-year survival rate of 51%. PMID- 29501384 TI - Alteration of Extracellular Nucleotide Metabolism in Pseudoxanthoma Elasticum. AB - Pseudoxanthoma elasticum (PXE) is a rare genetic condition primarily caused by hepatic ABCC6 transporter dysfunction. Most clinical manifestations of PXE are due to premature calcification of elastic fibers. However, the vascular impact of PXE is pleiotropic and remains ill defined. ABCC6 expression has recently been associated with cellular nucleotide export. We studied the impact of ABCC6 deficiency on blood levels of adenosine triphosphate and related metabolites and on soluble nucleotidase activities in PXE patients and Abcc6-/- mice. In addition, we investigated the expression of genes encoding ectocellular purinergic signaling proteins in mouse liver and aorta. Plasma adenosine triphosphate and pyrophosphate levels were significantly reduced in PXE patients and in Abcc6-/- mice, whereas adenosine concentration was not modified. Moreover, 5'-nucleotidase/CD73 activity was increased in the serum of PXE patients and Abcc6-/- mice. Consistent with alterations of purinergic signaling, the expression of genes involved in purine and phosphate transport/metabolism was dramatically modified in Abcc6-/- mouse aorta, with much less impact on the liver. ABCC6 deficiency causes impaired vascular homeostasis and tissue perfusion. Our findings suggest that these alterations are linked to changes in extracellular nucleotide metabolism that are remote from the liver. This opens new perspectives for the understanding of PXE pathophysiology. PMID- 29501385 TI - Endocannabinoid Tone Regulates Human Sebocyte Biology. AB - We have previously shown that endocannabinoids (eCBs) (e.g., anandamide) are involved in the maintenance of homeostatic sebaceous lipid production in human sebaceous glands and that eCB treatment dramatically increases sebaceous lipid production. Here, we aimed to investigate the expression of the major eCB synthesizing and degrading enzymes and to study the effects of eCB uptake inhibitors on human SZ95 sebocytes, thus exploring the role of the putative eCB membrane transporter, which has been hypothesized to facilitate the cellular uptake and subsequent degradation of eCBs. We found that the major eCB synthesizing (N-acyl phosphatidylethanolamine-specific phospholipase D, and diacylglycerol lipase-alpha and -beta) and degrading (fatty acid amide hydrolase, monoacylglycerol lipase) enzymes are expressed in SZ95 sebocytes and also in sebaceous glands (except for diacylglycerol lipase-alpha, the staining of which was dubious in histological preparations). eCB uptake-inhibition with VDM11 induced a moderate increase in sebaceous lipid production and also elevated the levels of various eCBs and related acylethanolamides. Finally, we found that VDM11 was able to interfere with the proinflammatory action of the TLR4 activator lipopolysaccharide. Collectively, our data suggest that inhibition of eCB uptake exerts anti-inflammatory actions and elevates both sebaceous lipid production and eCB levels; thus, these inhibitors might be beneficial in cutaneous inflammatory conditions accompanied by dry skin. PMID- 29501386 TI - Associations between clinical and psychosocial factors and metabolic and cardiovascular risk factors in overweight patients with schizophrenia spectrum disorders - Baseline and two-years findings from the CHANGE trial. AB - OBJECTIVES: People with severe mental disorders die averagely 15years earlier than people in the Western background population, cardiovascular disease being the most frequent cause of death with unhealthy eating habits and lower levels of physical activity as major contributing risk factors. Understanding possible associations and predictors of the specific cardiovascular risk may permit more targeted and effective prevention. The aim of this study was to investigate the associations between clinical and psychosocial factors and several separate cardiovascular risk factors in a cohort of 428 persons with schizophrenia and abdominal obesity enrolled in the CHANGE trial. METHODS: We used data from baseline and two-year follow-up of 428 individuals with schizophrenia spectrum disorders and abdominal overweight enrolled in the CHANGE trial. By linear regressions we explored the relationships between clinical and psychosocial factors and established cardiovascular risk factors: Dependent variables were baseline and follow-up values of the following: VO2max, waist circumference, high density lipoprotein (HDL), systolic blood pressure and HbA1c. Independent variables were baseline values of the following: negative symptoms, positive symptoms, cognition, level of functioning, antipsychotic medication, duration of illness, employment situation and whether the participants had any friend. RESULTS: Negative symptoms were associated with most baseline- as well as two years-outcome; negatively with cardiorespiratory fitness and with dietary quality and with HDL, and with increasing values of the variables waist circumference, BMI and HbA1c. Negative symptoms were seen also to predict poorer cardiorespiratory fitness and larger waist circumference, higher HbA1c and lower HDL at two year follow-up. Level of functioning and Cognitive function correlated positively with cardiorespiratory fitness and HDL, and correlated negatively with waist circumference and HbA1c. Both parameters also predicted a better fitness, higher HDL and lower HbA1c at two year follow-up. Isolating the antipsychotic drugs known to give the worst metabolic adverse effects (olanzapine, clozapine, quetiapine), the dosage was positively associated with cholesterol, but not with any other outcome. Psychotic symptoms and duration of illness were not significantly associated with any outcome. Employment of any kind was significantly associated with cardiorespiratory fitness and negatively associated with waist circumference, BMI and systolic blood pressure. At two year follow-up associations were significant for the two year outcomes cardiorespiratory fitness and waist circumference. Friendship relations were negatively associated with waist circumference and positively with HDL cholesterol. None of the two year outcomes were predicted by friendship. CONCLUSIONS: We found various clinical and psychosocial factors to be associated with less healthy lifestyle factors and higher risk of cardiovascular disease, with negative symptoms building the strongest associations, although a possible bidirectional causality needs to be regarded. Reduction of negative symptoms should be investigated further in order to reduce the increased cardiovascular morbidity and mortality in people with schizophrenia spectrum disorders. PMID- 29501387 TI - Emotional context restores cortical prediction error responses in schizophrenia. AB - The mismatch negativity (MMN) deficit in schizophrenia is a consistently replicated finding and is considered a potential biomarker. From the cognitive neuroscience perspective, MMN represents a cortical correlate of the prediction error, a fundamental computational operator that may be at the core of various cognitive and clinical deficits observed in schizophrenia. The impact of emotion on cognitive processes in schizophrenia is insufficiently understood, and its impact on basic operators of cortical computation is largely unknown. In the visual domain, the facial expression mismatch negativity (EMMN) offers an opportunity to investigate basic computational operators in purely cognitive and in emotional contexts. In this study, we asked whether emotional context enhances cortical prediction error responses in patients with schizophrenia, as is the case in normal subjects. Therefore, seventeen patients with schizophrenia and eighteen controls completed a visual sequence oddball task, which allows for directly comparing MMN components evoked by deviants with high, intermediate and low emotional engagement. Interestingly, patients with schizophrenia showed pronounced deficits in response to neutral stimuli, but almost normal responses to emotional stimuli. The dissociation between impaired MMN and normal EMMN suggests that emotional context not only enhances, but restores cortical prediction error responses in patients with schizophrenia to near-normal levels. Our results show that emotional processing in schizophrenia is not necessarily defect; more likely, emotional processing heterogeneously impacts on cognition in schizophrenia. In fact, this study suggests that emotional context may even compensate for cognitive deficits in schizophrenia that are, in a different sensory domain, discussed as biomarkers. PMID- 29501388 TI - Regulatory characterisation of the schizophrenia-associated CACNA1C proximal promoter and the potential role for the transcription factor EZH2 in schizophrenia aetiology. AB - Genomic wide association studies identified the CACNA1C locus as genetically associated with both schizophrenia and bipolar affective disorder. CACNA1C encodes Cav1.2, one of four subunits of L-type voltage gated calcium channels. Variation resides in non-coding regions of CACNA1C which interact with the promoter and are validated expression quantitative trait loci. Using reporter gene constructs we demonstrate the CACNA1C promoter is a major mediator of inducible regulation of CACNA1C activity in the SH-SY5Y neuroblastoma cell line. Exposure of SH-SY5Y cells to lithium and cocaine modulated both the endogenous CACNA1C gene and the promoter in reporter gene constructs. Deletion analysis of the promoter demonstrated the actions of both lithium and cocaine were mediated by the proximal promoter. Initial interrogation of ENCODE ChIP-seq data over the CACNA1C promoter indicated binding of the transcription factor 'Enhancer of zeste homolog 2' (EZH2), which was consistent with our data that overexpression of EZH2 repressed CACNA1C promoter reporter gene expression. Array data from the Human Brain Transcriptome demonstrated that EZH2 was highly expressed across the developing brain, but subsequently maintained at low levels after birth and adulthood. RNA-seq data obtained from PD_NGSAtlas, a reference database for epigenomic and transcriptomic data for psychiatric disorders, demonstrated a 3 fold increase in EZH2 expression in the anterior cingulate cortex of individuals with schizophrenia compared to controls. We propose that EZH2 may contribute to schizophrenia risk at two distinct time points either through disruption in development leading to neurodevelopmental changes, or through anomalous reactivation of expression in the adult brain. PMID- 29501389 TI - HAMP promoter hypomethylation and increased hepcidin levels as biomarkers for Kawasaki disease. AB - Kawasaki disease (KD) is the most common coronary vasculitis to appear in children with anemia and has been associated with elevated plasma hepcidin levels. We recruited a total of 241 cases, including 18 KD patients, who were tested both prior to receiving intravenous immunoglobulin (IVIG) and at least 3 weeks after IVIG treatment, and 18 febrile controls, who were observed in the Illumina HumanMethylation450 BeadChip study for their CpG markers. The remaining cases consisted of another 92 KD patients and 113 controls that were used for validation by pyrosequencing. We performed a genetic functional study using Luciferase assays. A support vector machine (SVM) classification model was adopted to identify KD patients and control subjects. In this study, KD patients clearly demonstrated a significantly epigenetic hypomethylation of HAMP promoter compared to controls. After receiving IVIG treatment, the hypomethylation status in KD patients was restored, and we observed a significant opposite tendency between the DNA methylation of target CpG sites (cg23677000 and cg04085447) and the hepcidin level. Furthermore, reporter gene assays were used to detect target CpG sites, the methylation of which displayed decreased levels of HAMP gene expression. Of particular note, we developed a SVM classification model with a 90.9% sensitivity, a 91.9% specificity, and 0.94 auROC in the training set. An independent blind cohort also had good performance (96.1% sensitivity and 89.7% specificity). In this study, we demonstrate HAMP promoter hypomethylation, which upregulates hepcidin expression in KD patients. Furthermore, the reliability and robustness of our SVM classification model can accurately serve as KD biomarkers. PMID- 29501390 TI - The role of the patellar tendon angle and patellar flexion angle in the interpretation of sagittal plane kinematics of the knee after knee arthroplasty: A modelling analysis. AB - BACKGROUND: Many different measures have been used to describe knee kinematics. This study investigated the changes of two measures, the patellar tendon angle and the patellar flexion angle, in response to variations in the geometry of the knee due to surgical technique or implant design. METHODS: A mathematical model was developed to calculate the equilibrium position of the extensor mechanism for a particular tibiofemoral position. Calculating the position of the extensor mechanism allowed for the determination of the patellar tendon angle and patellar flexion angle relationships to the knee flexion angle. The model was used to investigate the effect of anterior-posterior position of the femur, change in joint line, patellar thickness (overstuffing, understuffing), and patellar tendon length; these parameters were varied to determine the effect on the patellar tendon angle/knee flexion angle and patellar flexion angle/knee flexion angle relationships. RESULTS: The patellar tendon angle was a good indicator of anterior-posterior femoral position and change in patellar thickness, and the patellar flexion angle a good indicator of change in joint line, and patellar tendon length. CONCLUSIONS: The patellar tendon angle/knee flexion angle relationship was found to be an effective means of identifying abnormal kinematics post-knee arthroplasty. However, the use of both the patellar tendon angle and patellar flexion angle together provided a more informative overview of the sagittal plane kinematics of the knee. PMID- 29501391 TI - Increased glomerular Bax/Bcl2 ratio is positively correlated with glomerular sclerosis in lupus nephritis. AB - INTRODUCTION: The role of intrinsic pathway of apoptosis in pathogenesis of lupus nephritis (LN) is still not clear. We investigated the relation between the expression of two major proteins of the intrinsic pathway of apoptosis; bcl2 as an antiapoptotic protein and bax as a proapoptotic one; in renal tissue of LN. METHODS: The study included fifty paraffin embedded renal tissue obtained from renal biopsy specimens of LN patients (8 cases class II, 10 cases class III, 21 cases class IV and 11 cases class V) and five paraffin embedded apparently normal renal tissue obtained from nephrectomy specimens due to renal neoplasms as a control group. Immunohistochemical staining for bcl2 and bax antibodies was done. Ki67 immunohistochemical staining was done for class III and IV to assess the degree of proliferation. The number of intraglomerular bcl2, bax and ki67 positive cells per glomerular cross section was evaluated for each case. The results were analysed in different LN classes and correlated to different glomerular lesions. RESULTS: The expression of bax and bcl2 proteins was higher in LN glomeruli compared to normal. The expression of bcl2 was significantly higher in class IV and was correlated to the degree of endocapillary hypercellularity. The bax to bcl2 ratio was significantly correlated to the percentage and degree of glomerular sclerosis. CONCLUSION: The intrinsic pathway of apoptosis interfere in the pathogenesis of lupus glomerulonephritis. The balance between bax and bcl2 proteins might have a role in regulating the progression of glomeruli from proliferative to sclerotic state. PMID- 29501392 TI - Cathepsin D contributes to the accumulation of advanced glycation end products during photoaging. AB - BACKGROUND: The deposition of advanced glycation end products (AGEs) is accelerated in photoaged skin, but the underlying mechanisms remain elusive. Intracellular degradation has been recently considered to play an important role in AGEs removal. Although lysosomal cathepsin D (CatD), B (CatB), L(CatL) and proteasomes are found to degrade internalized AGEs, it remains unknown which protease degrades internalized AGEs in human dermal fibroblasts (HDFs), and whether a decrease in intracellular degradation contributes to enhanced AGEs deposition in photoaged skin. OBJECTIVE: This study aims to investigate the specific proteases that contribute to intracellular AGEs degradation in HDFs and regulate AGEs accumulation in photoaged skin. METHODS: Repetitive UVA irradiation was used to induce primary HDF photoaging in vitro. Uptake and degradation of AGE BSA were verified and compared between photoaged and non-photoaged fibroblasts with flow cytometry, ELISA and confocal microscopy. Proteasomal and lysosomal activity, expression of CatD, CatB and CatL were also investigated between photoaged and non-photoaged fibroblasts. Further, the effect of protease inhibitors and CatD overexpression via lentiviral transduction on AGE-BSA degradation was analyzed. Finally, the correlation between CatD expression and AGEs accumulation in sun-exposed and sun-protected skin of people from different age was studied with immunohistochemistry. RESULTS: Fibroblasts underwent photoaging in vitro after repetitive UVA irradiation. AGE-BSA was taken up by both photoaged and non-photoaged fibroblasts, but its degradation was significantly decreased in photoaged cells than that of non-photoaged cells. Although the activity of proteasome, CatB, Cat L and Cat D was significantly reduced in photoaged fibroblasts compared to that of non-photoaged cells, and the expression of CatB, CatL and CatD was profoundly attenuated in photoaged fibroblasts, inhibiting proteasome, CatB and CatL did not affect AGE-BSA degradation in HDFs. In contrast, inhibiting CatD activity dose-dependently decreased AGE-BSA degradation; whereas CatD overexpression significantly increased AGE-BSA degradation. Importantly, AGEs accumulation in photo-damaged skin in vivo was inversely correlated with CatD expression. CONCLUSION: CatD plays a major role in intracellular AGEs degradation. Decreased CatD expression and activity impairs intracellular AGEs degradation in photoaged fibroblasts, which may contribute to accelerated AGEs deposition in photoaged skin. The present study provides a potentially novel molecular basis for antiphotoaging therapy. PMID- 29501393 TI - Effect of cholesterol lowering with statins or proprotein convertase subtilisin/kexin type 9 antibodies on cataracts: A meta-analysis. AB - BACKGROUND: It is not known whether statins or proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies are associated with cataract and whether very low achieved low-density lipoprotein cholesterol (LDL-C) lowering may cause cataract. OBJECTIVE: To examine two questions: whether statins and/or PCSK9 antibodies cause or prevent cataracts and whether very low LDL-C is associated with increased risk of cataract. METHODS: Systematic searches of PubMed, ClinicalTrials.gov, Web of Science, The Cochrane Library, and an Federal Drug Administration report were used to perform random effects meta-analyses on the relationship of statins and/or PCSK9 antibodies with cataract. These meta analyses were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. RESULTS: Prespecified analyses indicated no significant effect of statins or PCSK9 antibodies (odds ratio [OR] 0.99, 95% confidence interval [CI] 0.83-1.17, P = .8889) or differences between the effects of statins (OR 0.89, 95% CI 0.66-1.19, P = .4349) and PCSK9 antibodies (OR 1.04, 95% CI 0.85-1.28, P = .7042) on the development of cataract. Also, there was no significant effect of LDL-C lowering to different levels with respect to cataract (OR 1.06, 95% CI 0.92-1.22, P = .4317). Meta-regression of the log OR for cataract vs LDL-C during treatment did not show a statistically significant relationship (P for slope = .3972). CONCLUSION: There was no significant effect of cholesterol lowering with statins or PCSK9 antibodies or differences between these two medication classes in causing or preventing cataracts. However, it is difficult to make definitive statements regarding PCSK9 antibodies because there is no long-term experience with these agents. Very low LDL-C was not associated with higher risk of cataract. PMID- 29501394 TI - Arthroplasty knee registry of Catalonia: What scientific evidence supports the implantation of our prosthesis? AB - INTRODUCTION: In our environment, it is increasingly necessary to perform an activity based on scientific evidence and the field of prosthetic surgery should be governed by the same principles. The national arthroplasty registries allow us to obtain a large amount of data in order to evaluate this technique. The aim of our study is to analyse the scientific evidence that supports the primary total knee arthroplasties implanted in Catalonian public hospitals, based on the Arthoplasty Registry of Catalonia (RACat) MATERIAL AND METHODS: A review of the literature was carried out on knee prostheses (cruciate retaining, posterior stabilized, constricted and rotational) recorded in RACat between the period 2005 2013 in the following databases: Orthopedic Data Evaluation Panel, PubMed, TripDatabase and Google Scholar. The prostheses implanted in fewer than 10 units (1,358 prostheses corresponding to 62 models) were excluded. RESULTS: 41,947 prostheses (96.86%) were analysed out of 43,305 implanted, corresponding to 74 different models. In 13 models (n = 4,715) (11.24%) no clinical evidence to support their use was found. In the remaining 36 models (n = 13,609) (32.45%), level iv studies were the most predominant evidence. CONCLUSIONS: There was a significant number of implanted prostheses (11.24%) for which no clinical evidence was found. The number of models should be noted, 36 out of 110, with fewer than 10 units implanted. The use of arthroplasty registries has proved an extremely useful tool that allows us to analyse and draw conclusions in order to improve the efficiency of this surgical technique. PMID- 29501395 TI - Rational drug design and synthesis of new alpha-Santonin derivatives as potential COX-2 inhibitors. AB - Sesquiterpene compounds are widely known for their numerous pharmacological activities. Herein the focus of the authors was on alpha-Santonin, a sesquiterpene lactone from the Artemisia genus: the aim was to determine whether alpha-Santonin could be considered in the treatment of inflammation and pain. To this purpose, a small series of derivatives was designed and screened in silico against the enzyme COX-2 along with the parent compound. Drug-likeness parameters were also assessed. The compounds were eventually synthesized, and few were tested to determine their efficacy in the inhibition of COX-2 activity and expression. Overall, compound A2 was the only one with a detectable inhibitory potential of COX-2 activity whilst two of its ether derivatives demonstrated improved ability in the inhibition of COX-2 expression. PMID- 29501396 TI - Pyridazine and pyridazinone derivatives as potent and selective factor XIa inhibitors. AB - Pyridazine and pyridazinone derivatives were designed and synthesized as coagulation factor XIa inhibitors. Potent and selective inhibitors with single digit nanomolar affinity for factor XIa were discovered. Selected inhibitors demonstrated moderate oral bioavailability. PMID- 29501397 TI - Public access defibrillation is insufficiently available in rural regions - When layperson efforts meet a lack of device distribution. PMID- 29501398 TI - The peptide toxin delta-hexatoxin-MrIX inhibits fast inactivation of NaVs in mouse cerebellar granule cells. AB - Spider venom is rich in peptide toxins that could be used to explore the structure and function of voltage-gated sodium channels (NaVs). This study has characterized a 44-amino acid peptide toxin, delta-hexatoxin-MrIX (delta-HXTX MrIX), from the venom of the spider Macrothele raveni. delta-hexatoxin-MrIX potently inhibited the fast inactivation of NaVs in mouse cerebellar granule cells (CGCs) with an EC50 of 35.3 +/- 5.9 nM. The toxin shifted both the steady state activation and the steady-state inactivation curves of CGC NaVs to the hyperpolarized direction. delta-hexatoxin-MrIX also acted on NaV1.3 and NaV1.4 channels heterologously expressed in HEK293T cells, as well as on NaVs in acutely isolated cockroach DUM neurons. However, the NaV1.5, NaV1.7 and NaV1.8 channels were resistant to delta-hexatoxin-MrIX. The toxin inhibited the fast inactivation of NaV1.3 and NaV1.4 with high affinity (EC50 values of 82.0 +/- 3.0 nM and 24.0 +/- 4.7 nM, respectively), but the saturating dose of toxin showed distinct efficacy on these two types of channels. delta-hexatoxin-MrIX is a peptide toxin acting on CGC NaVs and could be used as a pharmacological tool to explore the role of NaVs in granule cell maturation during cerebellum development. PMID- 29501399 TI - Outcome measurement of hand function following mirror therapy for stroke rehabilitation: A systematic review. AB - STUDY DESIGN: Systematic review. INTRODUCTION: Mirror therapy is a treatment used to address hand function following a stroke. Measurement of outcomes using appropriate assessment tools is crucial; however, many assessment options exist. PURPOSE OF THE STUDY: The purpose of this study is to systematically review outcome measures that are used to assess hand function following mirror therapy after stroke and, in addition, to identify the psychometric and descriptive properties of the included measures and through the linking process determine if the outcome measures are representative of the International Classification of Functioning, Disability and Health (ICF). METHODS: Following a comprehensive literature search, outcome measures used in the included studies were linked to the ICF and analyzed based on descriptive information and psychometric properties. RESULTS: Eleven studies met inclusion criteria and included 24 different assessment tools to measure hand or upper limb function. Most outcome measures used in the selected studies (63%) were rated by the evaluating therapist. Thirteen outcome measures (54%) linked to the ICF body function category and 10 measures (42%) linked to activities and participation. One outcome measure was linked to not defined, and all other ICF categories were not represented. A majority of outcome measures have been assessed for validity, reliability, and responsiveness, but responsiveness was the least investigated psychometric property. DISCUSSION: Current studies on mirror therapy after stroke are not consistent in the assessment tools used to determine hand function. Understanding of study outcomes requires analysis of the assessment tools. The outcome measures used in the included studies are not representative of personal and environmental factors, but tools linking to body functions and activities and participations provide important information on functional outcome. CONCLUSIONS: Integrating a combination of measures that are psychometrically sound and reflective of the ICF should be considered for assessment of hand function after mirror therapy after stroke. PMID- 29501400 TI - Commentary on "Post-carotid Endarterectomy Hypertension. Part 2: Association with Peri-operative Clinical, Anaesthetic, and Transcranial Doppler Derived Parameters". PMID- 29501401 TI - One Year Outcomes of 101 BeGraft Stent Grafts used as Bridging Stents in Fenestrated Endovascular Repairs. AB - OBJECTIVES: To evaluate the outcomes of the second generation BeGraft balloon expandable covered stent Graft System (Bentley InnoMed, Hechingen, Germany) implanted as bridging stent grafts during fenestrated endovascular aortic repair (FEVAR) of complex aneurysms. DESIGN: This was a single centre prospective study including all consecutive patients treated by FEVAR performed with second generation BeGraft stent grafts as bridging stents. METHODS: Demographics of patients, diameter and length of the bridging stent grafts, technical success, re interventions, occlusions, post-operative events, and imaging (Cone Beam CT and/or CT scan, and contrast enhanced ultrasound) were prospectively collected in an electronic database. Duplex ultrasound was performed before discharge and at 6 month follow-up. At 1 year, patients were evaluated clinically and by imaging (CT and ultrasound). RESULTS: Between November 2015 and September 2016, 39 consecutive patients (one woman) were treated with custom made fenestrated endografts (2-5 fenestrations) for complex aneurysms or type 1 endoleak after EVAR, using a variety of bridging stents including the BeGraft. All 101 BeGraft stent grafts were successfully delivered and deployed. There was no in hospital mortality. Early fenestration patency rate was 99% (96/97); the sole target vessel post-operative occlusion was secondary to a dissection of the renal artery distal to the stent. Complementary stenting was unsuccessful in recovering renal artery patency; bilateral renal stent occlusion was observed in the same patient on a CT scan performed 2 months after the procedure. He required post-operative dialysis. No additional renal impairment was observed. During follow-up (median 13 months [11-15]), all fenestrations stented with BeGraft stent grafts remained patent (95/97, 98%). One type 1b endoleak was detected and treated (2.6%). CONCLUSIONS: BeGraft stent grafts used as bridging stents during FEVAR are associated with favourable outcomes at 1 year follow-up. Long-term follow-up is required to confirm these promising results. PMID- 29501403 TI - Extent large-vessel vasculitis diagnosed with 18F-FDG PET/CT. PMID- 29501402 TI - Distribution of Giardia duodenalis (Assemblages A and B) and Cryptosporidium parvum amongst migrant workers in Peninsular Malaysia. AB - The influx of low skilled workers from socioeconomically deprived neighbouring countries to Malaysia has raised concerns about the transmission of communicable gastrointestinal diseases such as giardiasis and cryptosporidiosis to the local population. Therefore, a cross sectional study was conducted to investigate the prevalence of both diseases and the genetic diversity of these pathogens in the migrant population. Microscopic examination of faecal samples from 388 migrant workers involved in five working sectors were screened and 10.8% (n = 42) were found to be positive with Giardia spp. and 3.1% (n = 12) with Cryptosporidium spp. infections. PCR amplicons at the triosephosphate isomerase (tpi) gene were successfully obtained for Giardia duodenalis from 30 (30/388; 7.73%) samples with assemblages AII and B in 13 (13/30; 43.3%) and 17 (17/30; 56.7%) positive samples, respectively. Nine samples (9/388; 2.3%) were identified as Cryptosporidium parvum using PCR-RFLP analysis. Country of origin, duration of residence in Malaysia and working sectors significantly influenced G. duodenalis assemblage AII infections amongst the targeted population. Meanwhile, C. parvum infection was significantly associated with those working in the food service sector. Despite the low presence of pathogenic G. duodenalis and C. parvum in the study population, the results highlight the risk of anthroponotic foodborne and waterborne transmission and therefore call for implementation of control strategies through improvements in personal hygiene and sanitation standards. PMID- 29501405 TI - Comments on "Laparoscopic management of solid pseudo papillary neoplasm of pancreas in tertiary care centre from south India". PMID- 29501404 TI - Identification and characterization two isoforms of NADH:ubiquinone oxidoreductase from the hyperthermophilic eubacterium Aquifex aeolicus. AB - The NADH:ubiquinone oxidoreductase (complex I) is the first enzyme of the respiratory chain and the entry point for most electrons. Generally, the bacterial complex I consists of 14 core subunits, homologues of which are also found in complex I of mitochondria. In complex I preparations from the hyperthermophilic bacterium Aquifex aeolicus we have identified 20 partially homologous subunits by combining MALDI-TOF and LILBID mass spectrometry methods. The subunits could be assigned to two different complex I isoforms, named NQOR1 and NQOR2. NQOR1 consists of subunits NuoA2, NuoB, NuoD2, NuoE, NuoF, NuoG, NuoI1, NuoH1, NuoJ1, NuoK1, NuoL1, NuoM1 and NuoN1, with an entire mass of 504.17 kDa. NQOR2 comprises subunits NuoA1, NuoB, NuoD1, NuoE, NuoF, NuoG, NuoH2, NuoI2, NuoJ1, NuoK1, NuoL2, NuoM2 and NuoN2, with a total mass of 523.99 kDa. Three Fe-S clusters could be identified by EPR spectroscopy in a preparation containing predominantly NQOR1. These were tentatively assigned to a binuclear center N1, and two tetranuclear centers, N2 and N4. The redox midpoint potentials of N1 and N2 are -273 mV and -184 mV, respectively. Specific activity assays indicated that NQOR1 from cells grown under low concentrations of oxygen was the more active form. Increasing the concentration of oxygen in the bacterial cultures induced formation of NQOR2 showing the lower specific activity. PMID- 29501406 TI - An infant case of diffuse cerebrospinal lesions and cardiomyopathy caused by a BOLA3 mutation. AB - INTRODUCTION: Mitochondrial dysfunction results in a wide range of organ disorders through diverse genetic abnormalities. We herein present the detailed clinical course of an infant admitted for extensive, rapidly progressing white matter lesions and hypertrophic cardiomyopathy due to a BOLA3 gene mutation. CASE: A 6-month-old girl with no remarkable family or past medical history until 1 month prior presented with developmental regression and feeding impairment. Ultrasound cardiography and brain magnetic resonance imaging (MRI) respectively disclosed the presence of hypertrophic cardiomyopathy and symmetrical deep white matter lesions. She was transferred to our hospital at age 6 months. High lactate levels in her cerebrospinal fluid suggested mitochondrial dysfunction. Despite vitamin supplementation therapy followed by a ketogenic diet, the patient began exhibiting clusters of myoclonic seizures and respiratory failure. Brain and spinal cord MRI revealed rapid progression of the white matter lesions. She died at 10 months of age. Fibroblasts obtained pre-mortem displayed low mitochondrial respiratory chain complex I and II activity. A homozygous H96R (c. 287 A > G) mutation was identified in the BOLA3 gene. DISCUSSION: No reported case of a homozygous BOLA3 gene mutation has survived past 1 year of life. BOLA3 appears to play a critical role in the electron transport system and production of iron sulfur clusters that are related to lipid metabolism and enzyme biosynthesis. PMID- 29501407 TI - A novel mutation in sphingosine-1-phosphate lyase causing congenital brain malformation. AB - INTRODUCTION: Recently recessive mutations in sphingosine-1-phosphate lyase (SGPL1) have been published as a cause of syndromic congenital nephrotic syndrome with adrenal insufficiency. We have identified a case with fetal hydrops and brain malformations due to a mutation in SGPL1. CASE REPORT: We report a patient presenting with severe fetal hydrops, congenital nephrotic syndrome and adrenal calcifications. MRI imaging showed generalized cortical atrophy with simplified gyral pattern and hypoplastic temporal lobes as well as cerebellar hypoplasia and hyperintensity in the pons. The boy deceased at 6 weeks of age. Via whole exome sequencing, we identified a novel homozygous frameshift mutation c.1233delC (p.Phe411Leufs*56) in SGPL1. CONCLUSION: In our patient, we describe a novel mutation in sphingosine-1-phosphate lyase (SGPL1) leading to severe brain malformation. Neurodevelopmental phenotypes have been reported earlier, but not described in detail. To this end, we present a review on all published SGPL1 mutations and genotype-phenotype correlations focusing on neurodevelopmental outcomes. We hypothesized on the severe neurological phenotypes, which might be due to disruption of neuronal autophagy. Mutations in SGPL1 shall be considered in the differential diagnosis of fetal hydrops as well as congenital brain malformations and neuropathies. PMID- 29501408 TI - Fazio-Londe syndrome in siblings from India with different phenotypes. AB - BACKGROUND: Fazio-Londe syndrome also called progressive bulbar palsy of childhood is a very rare motor neuron disease of pediatric age group characterized by progressive paralysis of lower cranial nerves. OBJECTIVE: To describe Fazio-Londe syndrome in sibling with different phenotype. METHODS: A 6 years old female child presented with inability to close eyes, difficulty in swallowing, respiratory muscle weakness and voice change since 5 yr of age. Examination showed lower motor neuron facial nerve palsy, absent gag reflex, tongue atrophy, fasciculation, limb wasting and exaggerated deep tendon reflexes. An 11 year old boy, elder sibling of the above child presented with similar complaints at 10 years of age, other than later onset and lack of respiratory problem. Genetic testing in both cases confirmed the diagnosis of Fazio-Londe Syndrome. CONCLUSION: In any child who presents with progressive bulbar palsy with lower motor neuron facial palsy a diagnosis of Fazio-Londe Syndrome should be considered and family members should also be screened. PMID- 29501409 TI - Genetic diagnosis in neonatal-onset epilepsies: Back to the future. AB - Seizures are more frequent in newborns than in any other period of life. In most cases they are due to acute dysfunction of the central nervous system; however some can be true epileptic disorders with an early onset. Although rare, diagnosis of neonatal-onset epilepsies is rising as genetic testing increases. The spectrum of clinical severity associated with specific genes can vary widely with difficulties in providing genotype-phenotype correlations. Therefore, clinicians should strive in order to clearly delineate the clinical features associated with pathogenic genetic variants with the aim to guide the increasing use of genetic testing and improve clinical management. PMID- 29501410 TI - Are oral mucosal nevi potential precursors for oral mucosal melanoma? PMID- 29501411 TI - Social Cognition Differentiates Behavioral Variant Frontotemporal Dementia From Other Neurodegenerative Diseases and Psychiatric Disorders. AB - OBJECTIVE: Although deficits in social cognition are established as core features in behavioral variant frontotemporal dementia (bvFTD), it remains unresolved if impaired social cognition distinguishes bvFTD from the broad differential diagnoses in clinical practice. Our aim was to study whether social cognition discriminates bvFTD from other neurodegenerative diseases and psychiatric disorders in patients presenting with late-onset frontal symptoms. Next, we studied the association of social cognition with frontal symptoms and cognitive functioning. METHODS: In this longitudinal multicenter study, besides clinical rating scales for frontal symptoms, social cognition was determined by Ekman 60 Faces test and Faux Pas in addition to neuropsychological tests for other cognitive domains in patients with probable and definite bvFTD (N = 22), other neurodegenerative diseases (N = 24), and psychiatric disorders (N = 33). Median symptom duration was 2.8 years, and patients were prospectively followed over 2 years. RESULTS: Total scores from Ekman 60 Faces test were significantly lower in bvFTD than in other neurodegenerative diseases and psychiatric disorders. Ekman 60 Faces test explained 91.2% of the variance of psychiatric disorders and other neurodegenerative diseases versus bvFTD (chi2 = 11.02, df = 1, p = 0.001) and was associated with all other cognitive domains. Faux Pas and the other cognitive domains did not differ between these diagnostic groups. CONCLUSION: In this clinical sample Ekman 60 Faces test distinguished bvFTD successfully from other neurodegenerative diseases and psychiatric disorders. Although associated with social cognition, other cognitive domains were not discriminative. This study provides arguments to add the Ekman 60 Faces test to the neuropsychological examination in the diagnostic procedure of bvFTD. PMID- 29501412 TI - Invited Perspective on "Assessing the Decision Making Capacity of Terminally Ill Patients with Cancer. PMID- 29501413 TI - Images on Aging: Picasso's "The Old Guitarist". PMID- 29501414 TI - Aralkyl selenoglycosides and related selenosugars in acetylated form activate protein phosphatase-1 and -2A. AB - Aralkyl and aryl selenoglycosides as well as glycosyl selenocarboxylate derivatives were assayed on the activity of protein phosphatase-1 (PP1) and -2A (PP2A) catalytic subunits (PP1c and PP2Ac) in search of compounds for PP1c and PP2Ac effectors. The majority of tested selenoglycosides activated both PP1c and PP2Ac by ~2-4-fold in a phosphatase assay with phosphorylated myosin light chain substrate when the hydroxyl groups of the glycosyl moiety were acetylated, but they were without any effects in the non-acetylated forms. A peptide from the myosin phosphatase target subunit-1 (MYPT123-38) that included an RVxF PP1c binding motif attenuated activation of PP1c by 2-Trifluoromethylbenzyl 2,3,4,6 tetra-O-acetyl-1-seleno-beta-d-glucopyranoside (TFM-BASG) and 4-Bromobenzyl 2,3,4,6-tetra-O-acetyl-1-seleno-beta-d-glucopyranoside (Br-BASG). MYPT123-38 stimulated PP2Ac and contributed to PP2Ac activation exerted by either Br-BASG or TFM-BASG. Br-BASG and TFM-BASG suppressed partially binding of PP1c to MYPT1 in surface plasmon resonance based binding experiments. Molecular docking predicted that the hydrophobic binding surfaces in PP1c for interaction with either the RVxF residues of PP1c-interactors or selenoglycosides are partially overlapped. Br-BASG and TFM-BASG caused a moderate increase in the phosphatase activity of HeLa cells in 1 h, and suppressed cell viability in 24 h incubations. In conclusion, our present study identified selenoglycosides as novel activators of PP1 and PP2A as well as provided insights into the structural background of their interactions establishing a molecular model for future design of more efficient phosphatase activator molecules. PMID- 29501415 TI - Synthesis and evaluation of 4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3 c]pyran] analogues against both active and dormant Mycobacterium tuberculosis. AB - Need for new drugs to fight against tuberculosis (TB) is increasing day by day. In the present work we have taken a spiro compound (GSK 2200150A) reported by GSK as a lead and we modified the structure of the lead to study the antitubercular activity. For structure activity profiling twenty-one molecules have been synthesized, characterized and evaluated for their antimycobacterial potency against both active and dormant TB. Compound 06, 1-((4-methoxyphenyl)sulfonyl) 4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran] was found to be the most potent compound (MIC: 8.23 uM) in active TB and was less effective than the lead but more potent than standard first line drug ethambutol. It was also found to be more efficacious than Isoniazid and Rifampicin and equipotent as Moxifloxacin against dormant Mycobacterium tuberculosis (MTB). Compound 06 also showed good inhibitory potential against over expressed latent MTB enzyme lysine epsilon amino transferase with an IC50 of 1.04 +/- 0.32 uM. This compound is a good candidate for drug development owing to potential against both active and dormant stages of MTB. PMID- 29501416 TI - Adenosine analogs bearing phosphate isosteres as human MDO1 ligands. AB - The human O-acetyl-ADP-ribose deacetylase MDO1 is a mono-ADP-ribosylhydrolase involved in the reversal of post-translational modifications. Until now MDO1 has been poorly characterized, partly since no ligand is known besides adenosine nucleotides. Here, we synthesized thirteen compounds retaining the adenosine moiety and bearing bioisosteric replacements of the phosphate at the ribose 5' oxygen. These compounds are composed of either a squaryldiamide or an amide group as the bioisosteric replacement and/or as a linker. To these groups a variety of substituents were attached such as phenyl, benzyl, pyridyl, carboxyl, hydroxy and tetrazolyl. Biochemical evaluation showed that two compounds, one from both series, inhibited ADP-ribosyl hydrolysis mediated by MDO1 in high concentrations. PMID- 29501417 TI - Establishment of reference values in a healthy population and interpretation of serum PTH concentrations in hemodialyzed patients according to the KDIGO Guidelines using the Lumipulse(r) G whole PTH (3rd generation) assay. AB - BACKGROUND: 3rd generation PTH assays only detect the bioactive 1-84 fragment. Since standardization is still lacking, each new PTH assay requires to establish reference values and to assess the impact in the medical care of the mineral and bone disorders in hemodialyzed patients. METHODS: Using Fujirebio Lumipulse G wPTH assay, serum PTH levels were measured in a population of 439 healthy subjects from France and Belgium PTH levels were also determined in 119 hemodialyzed patients. These patients were classified according to the KDIGO recommendation. RESULTS: Reference range was found to be 6.5 (90%CI: 6.0-7.0) - 41.8 (90% CI: 38.1-43.7). In hemodialysis patients, Passing-Bablock regression between 3rd generation PTH from Fujirebio and DiaSorin was DiaSorin = 1.01 xFujirebio-2.4 with a slope not different from 1.0(95%CI: 0.96-1.04) and a non significant intercept, ranging from -6.0 to 0.1. Hemodialysis patients with a PTH concentration below 2-fold the Upper Limit of Normality (ULN), within the KDIGO range and upper 9-fold upper limit were respectively 33.6%, 54.6%, 11.8% (Fujirebio Lumipulse) and 36.1%, 51.3% and 12.6% (Diasorin Liaison). CONCLUSION: We determined a reference range with the 3rd generation PTH assay from Fujirebio. In a hemodialysis population, 3rd generation assays from Fujirebio and DiaSorin provide similar results. To the best of our knowledge, this is the first time that we can show similar PTH results obtained by 2 different 3rd generation PTH assays in healthy subjects and hemodialyzed patients without mathematically processing them. PMID- 29501418 TI - Endoscopic fistulotomy in inflammatory bowel disease (with video). AB - BACKGROUND AND AIMS: Fistulas in patients with inflammatory bowel disease (IBD) pose a key challenge in the management of these patients. We aimed to describe a novel endoscopic method to treat patients with IBD who have fistulas. METHODS: A cohort of 29 consecutive patients with fistulas and IBD were identified in the registry of our interventional IBD unit. An endoscopic fistulotomy with needle knife was performed. The primary outcome was healing of the fistula without the need for surgical intervention. RESULTS: A total of 29 patients underwent endoscopic fistulotomy; and the mean (+/- standard deviation) age of patients undergoing the procedure was 44.2 +/- 14.6 years. Thirteen patients were male (44.8%), and 16 were female (55.2%). Twenty-six patients (89.6%) achieved complete resolution of the fistula as confirmed by endoscopy with a guidewire and/or cross-sectional abdominal imaging, with 10 patients (34.4%) requiring a single endoscopic treatment session. Three patients (10.3%) had a persistent fistula and required surgical intervention. One patient had postoperative bleeding requiring blood transfusion and hospitalization. CONCLUSION: Endoscopic fistulotomy with a needle-knife appears to be safe and effective in treating IBD related fistulas. PMID- 29501419 TI - Antimicrobial susceptibility testing of Bacteroides fragilis using the MALDI Biotyper antibiotic susceptibility test rapid assay (MBT-ASTRA). AB - This study evaluated the MBT-ASTRA for antimicrobial susceptibility testing of Bacteroides fragilis with different classes of antibiotics. MALDI-TOF MS peak AUCs from suspensions with B. fragilis with and without an antibiotic were used to calculate the relative growth (AUC "with antibiotic" divided by "without antibiotic"). Antimicrobial susceptibility testing of B. fragilis ATCC 25285 (susceptible) and B. fragilis O18 (resistant) was demonstrated with a clear difference of the relative growth between susceptible and resistant. The MBT ASTRA needs further development and assessment but could be a relatively easy and inexpensive method for rapid antimicrobial susceptibility testing in specific cases of infection with B. fragilis. PMID- 29501421 TI - A Case of Novel Inversion Mutation of EGFR Exon 19 Leading to Primary Resistance to EGFR TKIs in Lung Adenocarcinoma. PMID- 29501420 TI - C-type natriuretic peptide functions as an innate neuroprotectant in neonatal hypoxic-ischemic brain injury in mouse via natriuretic peptide receptor 2. AB - Neonatal hypoxia-ischemia (HI) is the most common cause of brain injury in neonates, which leads to high neonatal mortality and severe neurological morbidity in later life (Vannucci, 2000; Volpe, 2001). Yet the molecular mechanisms of neuronal death and brain damage induced by neonatal HI remain largely elusive. Herein, using both in vivo and in vitro models, we determine an endogenous neuroprotectant role of c-type natriuretic peptide (CNP) in preserving neuronal survival after HI brain injury in mouse pups. Postnatal day 7 (P7) mouse pups with CNP deficiency (Nppclbab/lbab) exhibit increased brain infarct size and worsened long-term locomotor function after neonatal HI compared with wildtype control (Nppc+/+). In isolated primary cortical neurons, recombinant CNP dose dependently protects primary neurons from oxygen-glucose deprivation (OGD) insult. This neuroprotective effect appears to be mediated through its cognate natriuretic peptide receptor 2 (NPR2), in that antagonization of NPR2, but not NPR3, exacerbates neuronal death and counteracts the protective effect of CNP on primary neurons exposed to OGD insult. Immunoblot and confocal microscopy demonstrate the abundant expression of NPR2 in neurons of the neonatal brain and in isolated primary cortical neurons as well. Moreover, similar to CNP deficiency, administration of NPR2 antagonist P19 via intracerebroventricular injection prior to HI results in exacerbated neuronal death and brain injury after HI. Altogether, the present study indicates that CNP and its cognate receptor NPR2 mainly expressed in neurons represent an innate neuroprotective mechanism in neonatal HI brain injury. PMID- 29501423 TI - 3D FISH to analyse gene domain-specific chromatin re-modeling in human cancer cell lines. AB - Fluorescence in situ hybridization (FISH) is a common technique used to label DNA and/or RNA for detection of a genomic region of interest. However, the technique can be challenging, in particular when applied to single genes in human cancer cells. Here, we provide a step-by-step protocol for analysis of short (35 kb-300 kb) genomic regions in three dimensions (3D). We discuss the experimental design and provide practical considerations for 3D imaging and data analysis to determine chromatin folding. We demonstrate that 3D FISH using BACs (Bacterial Artificial Chromosomes) or fosmids can provide detailed information of the architecture of gene domains. More specifically, we show that mapping of specific chromatin landscapes informs on changes associated with estrogen stimulated gene activity in human breast cancer cell lines. PMID- 29501422 TI - Immune repertoire in the transcriptome of Littorina littorea reveals new trends in lophotrochozoan proto-complement evolution. AB - The evolution of complement system in invertebrates is poorly investigated. While the repertoire of complement genes in several Ecdysozoa lineages is found substantially different from that of Deuterostomia, the composition and function of the complement in the second protostome lineage, Lophotrochozoa, remains unclear. Here we report the general description of new transcriptomic data on the common periwinkle, Littorina littorea, and trace the evolutionary trajectories of the ancestral proto-complement repertoire. The repertoire is defined as immune cascade providing the minimum set of C3-associated molecules required for C3b amplification, opsonization of the targets and their phagocytosis: thioester protein (TEP) C3, serine protease C2/factor B (Bf) and complement receptors (CR). The reference transcriptome of L. littorea was built from the dual-species RNA seq experiment with the periwinkle and its tissue digenean parasite Himasthla elongata. Five TEPs, including the ortholog of the C3, are found expressed in the in the mollusk's inflamed tissues. The homolog of the complement receptors CR1/CR2 is also expressed, however the ortholog of Bf is not. The extensive phylogenetic analysis showed that the C3 ortholog and the complement receptors are retained in all key lophotrochozoan taxa: Mollusca, Annelida and Brachiopoda. However, the Bf ortholog was lost at least three times independently in different lineages: i) Cephalopoda, ii) a common ancestor of all Gastropoda and iii) one of the Annelida lineage, Clitellata. Both C3 and Bf molecules were retained in bivalve species, brachiopods and annelid worms from the Polychaeta lineage. Hypothetically, the function of the lost Bf in these animals can be compensated by Factor L (Lf) - the serine protease first found in L. littorea and homologous to both, the Bf and the arthropod factor C (Cf). The contrast differences in proto-complement repertoire between the sister mollusk' taxa, Bivalvia and Gastropoda (the conserved and modified sets, respectively), can underlie differences in their susceptibility to digenean infection. PMID- 29501424 TI - Comparison between iMSD and 2D-pCF analysis for molecular motion studies on in vivo cells: The case of the epidermal growth factor receptor. AB - Image correlation analysis has evolved to become a valuable method of analysis of the diffusional motion of molecules in every points of a live cell. Here we compare the iMSD and the 2D-pCF approaches that provide complementary information. The iMSD method provides the law of diffusion and it requires spatial averaging over a small region of the cell. The 2D-pCF does not require spatial averaging and it gives information about obstacles for diffusion at pixel resolution. We show the analysis of the same set of data by the two methods to emphasize that both methods could be needed to have a comprehensive understanding of the molecular diffusional flow in a live cell. PMID- 29501425 TI - A New Technique for Coronaplasty in Penile Reconstruction. AB - BACKGROUND: The coronaplasty is an important step of the phalloplasty procedure as it creates a prominent coronal ridge and a constricted coronal sulcus, resulting in the transformation of a regular skin flap into a flap resembling a circumcised penis. AIM: The aim of this article is to describe our new coronaplasty technique that exploits opposing contracting forces of 2 different skin grafts to hold the shape of a thick, distally based skin flap, resulting in a natural looking neo-phallus. METHODS: A distally based flap is raised at the junction of the middle and distal thirds of the neo-phallus. The dissection continues until adequate mobilization is obtained, so the flap can stand almost perpendicular to the axis of the shaft. 2 separate full-thickness skin grafts are harvested and placed: the first at the raw undersurface of the flap, the second at the flap's donor site. To make the sulcus deeper and to define the ridge, the lower part of the graft placed on the undersurface of the distal flap is sutured with tacking sutures. Depending on the type of flap used this procedure can be done during the phalloplasty procedure itself (axial flaps) or at least 1 week later (perforator flaps). OUTCOMES: The new technique that we developed shows a more distinct coronal sulcus and coronal ridge, long-lasting results, and a more aesthetically pleasing and natural-appearing glans penis. RESULTS: The harvested distal flap is progressively thicker and not folded, resulting in a more naturally looking ridge. The donor site is deeper than other techniques, creating a well-defined sulcus. By using 2 skin grafts the opposing force vectors increase the projection of the ridge and the deepness of the sulcus. CLINICAL TRANSLATION: This technique results in a more prominent glans penis and is an important step in creating an almost naturally looking neo-phallus. CONCLUSIONS: This procedure can be applied to all different kind of flaps used for phalloplasty, both in an immediate or delayed fashion. As grafts are used, partial or complete graft lost can appear. Furthermore, attention must be paid not to incise the distal flap too deep so vascularity to the distal part of the flap will not be impaired. A continuous search to optimize the aesthetic outcome of the phalloplasty procedure is necessary and with this new coronaplasty technique we hope to raise attention and take another step toward creating "the real thing." Sommeling CE, De Wolf EJ, Salim A, et al. A New Technique for Coronaplasty in Penile Reconstruction. J Sex Med 2018;15:920-923. PMID- 29501426 TI - Sensory Dysfunction and Sexuality in the U.S. Population of Older Adults. AB - BACKGROUND: The sexual experience is shaped by sensory function; with aging, sensory dysfunction may interfere with sexuality and sexual behavior between partners. Specifically, older adults with age-related sensory dysfunction may have less sexual activity than those with better sensory function. In addition, since sexual desire and attraction rests in part upon sensory function, sensory dysfunction may also be associated with less sexual motivation. AIM: To test the association between sexual activity and motivation in older adults and their sensory dysfunction. METHODS: Sensory dysfunction was measured both by global sensory impairment (a validated measure of dysfunction shared among the 5 classic senses: olfaction, vision, taste, touch, hearing) and by total sensory burden (cumulative sensory loss). Sexual activity was quantified by frequency and type of sexual behavior. Sexual motivation was measured by the frequency of sexual ideation and the importance of sex to the respondent. We used cross-sectional data from a nationally representative sample of community-dwelling older adults (aged 57-85 years) in the United States (National Social Life, Health, and Aging Project, N = 3,005) in logistic regression analyses. OUTCOMES: Sexual activity, sexual motivation, and satisfaction with the sexual relationship were self reported. RESULTS: Older adults with sensory dysfunction were less likely to be sexually active-an association that persisted when accounting for other factors that also affected sexual activity (age, gender, partnered status, mental and physical health, and relationship satisfaction). Nonetheless, sensory dysfunction did not impair sexual motivation, nor affect the physical and emotional satisfaction with the sexual relationship. Among currently sexually active older adults, sensory dysfunction did not affect the frequency of sex or the type of sexual activity (foreplay, vaginal intercourse, or oral sex). These results were the same for 2 different measures of sensory dysfunction. CLINICAL TRANSLATION: This is the first nationally representative study of sexuality and multisensory dysfunction in community-dwelling older adults. 4 of the 5 classic senses were measured with objective tests, and hearing was rated by interviewers in the context of their conversation. Medical and health care interventions that can reduce the burden of sensory dysfunction may improve older adults' sexual experience. CONCLUSIONS: Sensory dysfunction is associated with sexual inactivity, but not with sexual motivation. Among those who are sexually active, sensory dysfunction did not interfere with sexual expression. Improving the sexual experience of older adults requires a focus on sensory dysfunction as an impediment to sexual activity given that older adults remain sexually motivated. Zhong S, Pinto JM, Wroblewski KE, et al. Sensory Dysfunction and Sexuality in the U.S. Population of Older Adults. J Sex Med 2018;15:502-509. PMID- 29501427 TI - A miniaturized sorbent phase-based extraction device in the form of syringe filter holder using molecularly imprinted polymer as sorbent and its application to extract benzophenones. AB - The molecularly imprinted polymer using 2,4-dihydroxybenzophenone as the template (DHBP-MIP) was synthesized via sacrificial support method. The DHBP-MIP was demonstrated to possess good adsorption capacity and selectivity towards benzophenones. Moreover, a miniaturized sorbent phase-based extraction device in the form of syringe filter holder using DHBP-MIP as the sorbent was proposed, and named as MU-SPE-SFH-MIP device. The MU-SPE-SFH-MIP device consisted of a reusable syringe filter holder, flexible amount of sorbent and a sub-microporous membrane, which could be conveniently connected to different driving forces, like syringe pump, solid-phase extraction device and peristaltic pump. It was successfully applied to extract five benzophenones from swimming pool water and human urine samples, combined with high performance liquid chromatograph-UV analysis, with detection limits of 0.12-0.68 MUg L-1 and 0.21-1.05 MUg L-1, respectively. The accuracy and precision of the analytes were in the range of 89.27%-113.35% for swimming pool water samples and 90.65%-108.00% for urine samples, with all the relative standard deviation values below 7.89%. The MU-SPE-SFH-MIP device was portable, cost-effective operational convenient and suitable for the small-size samples; moreover, with the MIP as the sorbent, it afforded additional high selectivity and sensitivity. PMID- 29501429 TI - Zeolitic imidazolate framework-8 for selective extraction of a highly active anti oxidant flavonoid from Caragana Jubata. AB - The medicinal compositions or active components in medicinal plants are the major sources to find new drugs or lead compounds. Exploring novel sorbents with good selectivity for extraction and separation of medicinal compositions or active components from complex medicinal plants are interesting and challenging. Metal organic frameworks (MOFs) show great potential in adsorption and extraction recently. Herein, we report our primary attempt of zeolitic imidazolate framework 8 (ZIF-8) as a model MOF for selective extraction of a flavonoid named 3,4 dihydroxy-8,9-methylenedioxypterocarpan (compound 1) from a traditional medicinal plant Caragana Jubata. The enrichment factor of ZIF-8 for compound 1 is 57.7. The recoveries of compound 1 at three spiked levels (50, 100, 150 mg L-1) in Caragana Jubata dichloromethane extract are 62.1%, 66.4%, and 75.4%, respectively, with the relative standard deviations of less than 2.9%. The compound 1 also gave good linearity (R2 of 0.999) in the concentration range of 5-1000 mg L-1. The obtained compound 1 gave highly antioxidant activity (DPPH radical scavenging rate of 79.03%, inhibitory rate on lipid peroxidation of 75.30%, which were higher than the positive controls Vitamin C and BHT) and low IC50 values (5.438 +/- 0.068, 20.970 +/- 0.083 MUg mL-1 for DPPH radical scavenging activities and inhibitory effects on lipid peroxidation, respectively). These results demonstrated the feasibility of MOFs in selective extraction of medicinal compositions or active components from complex medicinal plants. The current work may open a new way of MOFs in selective extraction of pharmacological active components from medicinal plants. PMID- 29501428 TI - Heparin/heparan sulfate analysis by covalently modified reverse polarity capillary zone electrophoresis-mass spectrometry. AB - Reverse polarity capillary zone electrophoresis coupled to negative ion mode mass spectrometry (CZE-MS) is shown to be an effective and sensitive tool for the analysis of glycosaminoglycan mixtures. Covalent modification of the inner wall of the separation capillary with neutral or cationic reagents produces a stable and durable surface that provides reproducible separations. By combining CZE-MS with a cation-coated capillary and a sheath flow interface, a rapid and reliable method has been developed for the analysis of sulfated oligosaccharides from dp4 to dp12. Several different mixtures have been separated and detected by mass spectrometry. The mixtures were selected to test the capability of this approach to resolve subtle differences in structure, such as sulfation position and epimeric variation of the uronic acid. The system was applied to a complex mixture of heparin/heparan sulfate oligosaccharides varying in chain length from dp3 to dp12 and more than 80 molecular compositions were identified by accurate mass measurement. PMID- 29501430 TI - Integration of electropreconcentration and electrospray ionization in a microchip. AB - A microfluidic glass chip for performing sensitive mass spectrometry (MS) is developed by integrating nanochannel-based electropreconcentration with electrospray ionization (ESI). Cation analytes in acidic buffer conditions (~pH 3) were preconcentrated at a micro-nano-microchannel junction where a positively charged polymer, polyE-323, is coated to reverse the electroosmotic flows (anodic EOF) and prevent sample adsorption. The preconcentrated cation analytes were delivered to a monolithic spray tip using an integrated field-free electrokinetic pump, enabling a stable positive ESI with negligible dead volume. The sample preconcentration-ESI-MS achieved one order of magnitude signal enhancement in MS signal with a peptide mixture. PMID- 29501431 TI - Community pharmacist perceptions of their role and the use of social media and mobile health applications as tools in public health. AB - BACKGROUND: A number of barriers prevent community pharmacists (CPs) from impacting public health (PH) outcomes. Social media (SM) and mobile health apps (MH apps) may offer ways to help the public make positive health decisions. OBJECTIVES: To evaluate CP perceptions of their role in PH and the use of SM and MH apps in this regard. METHODS: This was a mixed method study using a cross sectional survey and follow-up interviews. The survey covered: CPs role in PH; CP use of SM; CP use of MH apps; non-identifiable demographic information. Following ethical approval and piloting, responses were collected on paper and online. The study population was CPs in Greater London, UK (n = 2931). A minimum sample size of 340 was calculated (95% confidence interval/5% margin of error). To achieve this, 596 surveys were distributed. Responses (n = 257) were analysed using descriptive statistics. Twenty-five respondents were willing to take part in follow-up one-to-one interviews. Twenty interviews were completed as data saturation was achieved after the 14th. Interviews were transcribed and analysed using framework methodology as described by Ritchie and Spencer in 1994. RESULTS: Survey response rate was 43%. Respondents represented English CPs in terms of age but males and non-whites were over-represented. The majority of CPs accessed SM and MH apps for personal use but did not recommend these in a professional capacity due to lack of awareness and confidentiality/liability concerns. Most would promote an SM health page (78.6%) or MH app (83.7%) if maintained by healthcare professionals (HCPs). Under 35s were more positive about these tools in PH. Two interview themes emerged: The role of CPs in PH; Concerns and opportunities for the use of technology in PH. CONCLUSIONS: Most CPs, particularly those under 30, were positive about the use of SM and MH apps in PH. Training on the use of such tools among the pharmacy team, and an awareness of the availability of evidence-based apps will ensure their wider adoption. PMID- 29501432 TI - Impact of right atrial pressure on fractional flow reserve calculation in the presence of a chronic total occlusion. AB - BACKGROUND: The aim of this study was to assess the impact of right atrial pressure (Pra) on non-CTO vessels FFR measurements in patients with a chronic total occlusion. METHODS: Consecutive patients who underwent PCI for a CTO of the right coronary artery (RCA) were included. Prior to RCA recanalization, FFR and FFRmyo were measured in non-CTO vessels. FFR was calculated using the Pd/Pa equation during maximum hyperaemia and also accounting for right atrial pressure (Pd-Pra/Pa-Pra). Non-CTO vessels were characterised as major or minor donors based on angiographic assessment of provided collaterals. RESULTS: FFR and FFRmyo were measured in 68 arteries (34 LAD and 34 Cx) in 34 consecutive patients with successful RCA CTO PCI. Patients' mean age was 62 +/- 10 years old and 88% were male. Mean left ventricular ejection fraction was 51% +/- 20. During maximum hyperaemia, mean Pra, Pa, and Pd were 4.1 +/- 3.8 mm Hg, 82.6 +/- 12.2 mm Hg, and 63.8 +/- 14.3 mm Hg, respectively. In the major donor vessel, FFRmyo showed a difference of 0.007 to FFR (0.760 +/- 0.113 vs. 0.767 +/- 0.112, p = 0.004). In the minor donor vessel the difference was 0.004 (0.895 +/- 0.067 vs. 0.899 +/- 0.065, p < 0.001). There was a strong positive correlation between the FFR and FFRmyo in both the major and minor donor vessel groups (r = 0.993, p < 0.001 and r = 0.996, p < 0.001 respectively). CONCLUSION: In the presence of a CTO, RA pressure adjustment of FFR in the non-CTO vessels leads to trivial numerical changes, which are statistically significant but clinically negligible. PMID- 29501433 TI - A precision medicine approach to repetitive Transcranial Magnetic Stimulation (rTMS). PMID- 29501434 TI - Utility of a blood culture time to positivity-incorporated scoring model in predicting vascular infections in adults with nontyphoid Salmonella bacteremia. AB - BACKGROUND: Vascular infections (VI) are potentially catastrophic complications of nontyphoid Salmonella (NTS). We aimed to develop a scoring model incorporating information from blood culture time to positivity (TTP-NTSVI) and compared the prediction capability for VI among adults with NTS bacteremia between TTP-NTSVI and a previously published score (Chen-NTSVI). METHODS: This retrospective cohort study enrolled 217 adults with NTS bacteremia ? 50 years old. We developed a TTP NTSVI score by multiple logistic regression modeling to identify independent predictors for imaging-confirmed VI and assigned a point value weighting by the corresponding natural logarithm of the odds ratio for each model predictor. Chen NTSVI score includes hypertension, male sex, serogroup C1, coronary arterial disease (CAD) as positive predictors, and malignancy and immunosuppressive therapy as negative predictors. The prediction capability of the two scores was compared by area under the receiver operating characteristic curve (AUC). RESULTS: The mean age was 68.3 +/- 11.2 years-old. Serogroup D was the predominant isolate (155/217, 71.4%). Seventeen (7.8%) patients had VI. Four independent predictors for VI were identified: male sex (24.9 [2.59-239.60]; 6) (odds ratio [95% confidence interval]; assigned score point), peripheral arterial occlusive disease (9.41 [2.21-40.02]; 4), CAD (4.0 [1.16-13.86]; 3), and TTP <10 h (4.67 [1.42-15.39]; 3). Youden's index showed best cutoff value of ?7 with 70.6% sensitivity and 82.5% specificity. TTP-NTSVI score had higher AUC than Chen NTSVI (0.851 vs 0.741, P = 0.039). CONCLUSION: While the previously reported scoring model performed well, a TTP-incorporated scoring model was associated with improved capability in predicting NTSVI. PMID- 29501435 TI - Hypertrophic osteoarthropathy. PMID- 29501436 TI - Beneficial effect of nocturnal oximetric control on the clinical and gasometric situation and the prognosis of patients with home non-invasive mechanical ventilation. AB - INTRODUCTION AND OBJECTIVE: The effectiveness of home non-invasive mechanical ventilation (NIMV) is assessed by determining blood gas values in wakefulness, the evolution of their symptoms, and the monitoring of ventilation at night. The aim of our study is to evaluate whether defined values reached with outpatient monitoring by oximetry is related to the clinical, arterial gases and survival of a sample of patients with home NIMV. MATERIAL AND METHOD: Retrospective observational cohort study of a series of patients receiving home NIMV treatment for different causes. Patients with amyotrophic lateral sclerosis and less than 3 months of follow-up were excluded. The evolution of the patient's symptoms, their baseline arterial blood gases in wakefulness, and home nocturnal oximetry records, are evaluated at each outpatient visit. Good maintained oximetry control (MOC) was defined when mean O2 saturation values were reached and maintained until the last revision. Patient groups were considered, according to whether or not a good MOC was achieved during follow-up. RESULT: Four hundred patients were evaluated. Three hundred and sixty four (91%) were included in the study; their median age was 68 years, 51% were male. 37.6% had a good MOC during follow-up. Compared to patients with not good MOC, a better long-term mortality was obtained (16.8% vs 28.2%, P=.013), and an improvement in symptoms (33.8% vs 18.6%, P=.002) and a lower proportion of patients with persistently>50mmHg PaCO2 (14.2% vs. 33.9%, P<.001) was observed. CONCLUSION: In the follow-up of patients with home NIMV in our context, values defined in home nocturnal oximetry (good MOC) are positively associated with clinical, gasometric and longer-term survival. PMID- 29501437 TI - Rectal linitis: A very unusual cause of stenosis. PMID- 29501438 TI - Evaluation of non-genomic, clinical risk and survival results in endocrine sensitive, HER-2 negative, node negative breast cancer. AB - BACKGROUND AND OBJECTIVES: In endocrine-sensitive, HER-2 negative, node negative breast cancer, the presence of a low genomic risk allows treatment with adjuvant endocrine therapy alone, obtaining excellent survival rates. The justification for this study is to show that excellent survival rates are also obtained by treating with adjuvant hormone therapy alone, based on clinical risk assessment. PATIENTS AND METHODS: A descriptive, observational and retrospective study was performed between 2006 and 2016 with endocrine-sensitive, HER-2 negative, node negative breast cancer, greater than 1cm or between 0.6 and 1cm with unfavourable features. Retrospective review of health records. Mortality data of the National Registry of Deaths. RESULTS: A total of 203 patients were evaluable for survival. One hundred and twenty-three (60.50%) were treated with adjuvant endocrine therapy alone, 77 (37.90%) with chemotherapy and endocrine therapy, one (0.50%) with chemotherapy alone and 2 (1%) were not treated. The overall survival rate at 5 years was 97% (95% confidence interval [CI] 94-100). Distant recurrence-free interval was 94% (95% CI 90-98). In the subgroup of patients treated with endocrine therapy alone, overall survival and distant recurrence-free interval rates at 5 years were 98% (95% CI 95-100) and 97% (95% CI 93-100), respectively. CONCLUSIONS: Patients with endocrine-sensitive, HER-2-negative, node negative breast cancer treated with endocrine therapy alone according to their clinical risk have similar survival outcomes as those treated with endocrine therapy according to their genomic risk. PMID- 29501439 TI - Pyonephrosis by Lelliottia amnigena. PMID- 29501440 TI - Correlation between epicardial fat thickness and biochemical markers of metabolic risk. AB - INTRODUCTION AND OBJECTIVE: Epicardial fat has been associated with increased cardiovascular risk and the development of atherosclerosis. Transthoracic echocardiography provides a reliable measurement of epicardial fat thickness (EFT). The aim of this study is to evaluate the relationship between EFT and biochemical parameters of metabolic risk. MATERIAL AND METHOD: We assessed 211 patients who underwent echocardiography; EFT was measured by two cardiologists. In addition, patients' glycaemia, lipid profile and serum uric acid were measured. Statistical analysis was performed with the Pearson coefficient test and Odds ratio. RESULTS: A positive correlation between EFT with glycaemia (r=.064), total serum cholesterol (r=.0056), high density lipoproteins (r=-.038), or with triglycerides (r=.118) was not observed. However, we did find a significant positive correlation between EFT and serum uric acid (r=.415, P<.00001). The odds ratio for EFT>3mm in patients with hyperuricemia was 6.26 (IC 95 2.79-14, P<.0001). CONCLUSION: Hyperuricemia is strongly associated with EFT in Mexican patients; EFT is a useful tool for global cardiovascular risk calculation. PMID- 29501443 TI - Serum calcium levels independently predict in-hospital mortality in patients with acute myocardial infarction. AB - BACKGROUND AND AIM: Serum calcium levels (sCa) were reported to be associated with cardiovascular risk factors, incidence of coronary artery disease and acute myocardial infarction (AMI). The current study evaluated the association between sCa and in-hospital mortality among AMI patients. METHODS AND RESULTS: Patients admitted in a tertiary medical center for AMI throughout 2002-2012 were analyzed. For each patient, mean sCa, corrected to albumin, was calculated and categorized to seven equally-sized groups: <8.9, 8.9-9.12, 9.12-9.3, 9.3-9.44, 9.44-9.62, 9.62-9.86, >=9.86 mg/dL. The primary outcome was all-cause in-hospital mortality. Out of 12,121 AMI patients, 11,446 were included, mean age 67.1 +/- 14 years, 68% Males. Mean number of sCa values for patient was 4.2 +/- 7.3. Mean sCa was 9.4 +/ 0.53 mg/dL, range 5.6-13.2 mg/dL sCa was significantly associated with cardiovascular risk-factors, in-hospital complications, more frequent 3-vessel coronary artery disease and decreased rate of revascularization, often in a U shaped association. Overall 794 (6.9%) patients died in-hospital. Multivariate analysis showed a significant U-shaped association between sCa and in-hospital mortality with sCa below 9.12 mg/dL and above 9.86 mg/dL as independent predictors of significantly increased in-hospital mortality: OR = 2.4 (95% CI:1.7 3.3) and 1.7 (95%CI:1.2-2.4), for Ca<8.9 and Ca>=9.86 mg/dL respectively p < 0.01, as compared with middle rage sCa group (9.3-9.44 mg/dL). CONCLUSION: sCa is an independent predictor of in-hospital mortality in patients with AMI with a U shaped association. Both increased and decreased sCa levels are associated with increased risk of in-hospital mortality. PMID- 29501441 TI - Change in Populations of Macrophages Promotes Development of Delayed Gastric Emptying in Mice. AB - BACKGROUND & AIMS: Muscularis propria macrophages lie close to cells that regulate gastrointestinal motor function, including interstitial cells of Cajal (ICC) and myenteric neurons. In animal models of diabetic gastroparesis, development of delayed gastric emptying has been associated with loss of macrophages that express cytoprotective markers and reduced networks of ICC. Mice with long-term diabetes and normal gastric emptying have macrophages that express anti-inflammatory markers and have normal gastric ICC. Mice homozygous for the osteopetrosis spontaneous mutation in the colony-stimulating factor 1 gene (Csf1op/op) do not have macrophages; when they are given streptozotocin to induce diabetes, they do not develop delayed gastric emptying. We investigated whether population of the gastric muscularis propria of diabetic Csf1op/op mice with macrophages is necessary to change gastric emptying, ICC, and myenteric neurons and investigated the macrophage-derived factors that determine whether diabetic mice do or do not develop delayed gastric emptying. METHODS: Wild-type and Csf1op/op mice were given streptozotocin to induce diabetes. Some Csf1op/op mice were given daily intraperitoneal injections of CSF1 for 7 weeks; gastric tissues were collected and cellular distributions were analyzed by immunohistochemistry. CD45+, CD11b+, F4/80+ macrophages were dissociated from gastric muscularis propria, isolated by flow cytometry and analyzed by quantitative real-time polymerase chain reaction. Cultured gastric muscularis propria from Csf1op/op mice was exposed to medium that was conditioned by culture with bone marrow derived macrophages from wild-type mice. RESULTS: Gastric muscularis propria from Csf1op/op mice given CSF1 contained macrophages; 11 of 15 diabetic mice given CSF1 developed delayed gastric emptying and had damaged ICC. In non-diabetic Csf1op/op mice, administration of CSF1 reduced numbers of gastric myenteric neurons but did not affect the proportion of nitrergic neurons or ICC. In diabetic Csf1op/op mice given CSF1 that developed delayed gastric emptying, the proportion of nitrergic neurons was the same as in non-diabetic wild-type controls. Medium conditioned by macrophages previously exposed to oxidative injury caused damage to ICC in cultured gastric muscularis propria from Csf1op/op mice; neutralizing antibodies against IL6R or TNF prevented this damage to ICC. CD45+, CD11b+, and F4/80+ macrophages isolated from diabetic wild-type mice with delayed gastric emptying expressed higher levels of messenger RNAs encoding inflammatory markers (IL6 and inducible nitric oxide synthase) and lower levels of messenger RNAs encoding markers of anti-inflammatory cells (heme oxygenase 1, arginase 1, and FIZZ1) than macrophages isolated from diabetic mice with normal gastric emptying. CONCLUSIONS: In studies of Csf1op/op and wild-type mice with diabetes, we found delayed gastric emptying to be associated with increased production of inflammatory factors, and reduced production of anti-inflammatory factors, by macrophages, leading to loss of ICC. PMID- 29501444 TI - Association between habitual coffee consumption and metabolic syndrome in type 1 diabetes. AB - BACKGROUND AND AIMS: In the general population, habitual coffee consumption is inversely associated with the metabolic syndrome, a syndrome that is rather common also in patients with type 1 diabetes. However, whether coffee intake is beneficially related to the metabolic syndrome also in type 1 diabetes, is not known. We, therefore, studied the potential association between coffee consumption and the metabolic syndrome in a large population of individuals with type 1 diabetes. Furthermore, we investigated whether coffee consumption is associated with insulin resistance (estimated glucose disposal rate, eGDR), kidney function (estimated glomerular filtration rate, eGFR), and low-grade chronic inflammation (high-sensitivity C-reactive protein, hsCRP). METHODS AND RESULTS: Data from 1040 participants in the Finnish Diabetic Nephropathy Study were included in these cross-sectional analyses. Metabolic syndrome was assumed if at least 3 of the following cardiovascular risk factors were present: central obesity, high blood pressure, low HDL-cholesterol concentration, high triglyceride concentration, and hyperglycaemia. Subjects were categorized based on self-reported daily coffee intake: non-consumers (<1 cup/d), low (>=1 cups/d < 3), moderate (>=3 cups/d < 5), and high coffee consumption (>=5 cups/d). In multivariable logistic regression analysis, moderate and high coffee consumption was associated with increased odds of the metabolic syndrome. Moreover, any level of coffee consumption was associated with increased risk of the blood pressure component. An increasing trend was observed in the eGFR with increasing coffee consumption. CONCLUSIONS: In type 1 diabetes, high coffee intake is associated with the metabolic syndrome, and especially its blood pressure-component. PMID- 29501442 TI - Analysis of Genes Associated With Monogenic Primary Immunodeficiency Identifies Rare Variants in XIAP in Patients With Crohn's Disease. AB - BACKGROUND & AIMS: A few rare monogenic primary immunodeficiencies (PIDs) are characterized by chronic intestinal inflammation that resembles Crohn's disease (CD). We investigated whether 23 genes associated with 10 of these monogenic disorders contain common, low-frequency, or rare variants that increase risk for CD. METHODS: Common and low frequency variants in 1 Mb loci centered on the candidate genes were analyzed using meta-data corresponding to genotypes of approximately 17,000 patients with CD or without CD (controls) in Europe. The contribution of rare variants was assessed by high-throughput sequencing of 4750 individuals, including 660 early-onset and/or familial cases among the 2390 patients with CD. Variants were expressed from vectors in SW480 or HeLa cells and functions of their products were analyzed in immunofluorescence, luciferase, immunoprecipitation, and immunoblot assays. RESULTS: We reproduced the association of the interleukin 10 locus with CD (P = .007), although none of the significantly associated variants modified the coding sequence of interleukin 10. We found XIAP to be significantly enriched for rare coding mutations in patients with CD vs controls (P = .02). We identified 4 previously unreported missense variants associated with CD. Variants in XIAP cause the PID X-linked lymphoproliferative disease type 2, yet none of the carriers of these variants had all the clinical features of X-linked lymphoproliferative disease type 2. Identified XIAP variants S123N, R233Q, and P257A were associated with an impaired activation of NOD2 signaling after muramyl dipeptide stimulation. CONCLUSIONS: In a systematic analysis of variants in 23 PID-associated genes, we confirmed the association of variants in XIAP with CD. Further screenings for CD-associated variants and analyses of their functions could increase our understanding of the relationship between PID-associated genes and CD pathogenesis. PMID- 29501445 TI - Pre-clinical atherosclerosis is associated with low coffee consumption and low adherence to Mediterranean Diet in pre-menopausal women. PMID- 29501446 TI - Elevated serum uric acid concentration at discharge confers additive prognostic value in elderly patients with acute heart failure. AB - BACKGROUND AND AIMS: Elevated serum uric acid (sUA) concentrations have been associated with worse prognosis in heart failure (HF) but little is known about elderly patients. We aimed to assess long-term additive prognostic value of sUA in elderly patients hospitalized for HF. METHODS AND RESULTS: Clinical and echocardiographic characteristics of 310 consecutive elderly patients hospitalized for HF were collected. During index period, 206 had sUA concentrations available, which were obtained within 24 h prior to discharge; 10 patients were lost to follow-up, leaving 196 patients available. Patients had a median age of 77 (IQR 69-83) years, and were mostly male (64.5%). sUA ranges for tertiles I-III were: 1.5-6.1, 6.2-8.3, and 8.4-18.9 mg/dl, respectively. During a median follow-up of 27 months (IQR 10.5-39.5), 122 combined events occurred (87 deaths and 73 HF rehospitalizations). Four-year event-free survival for the combined endpoint was 46 +/- 7% for tertile I, 34 +/- 7% for tertile II, and 21 +/- 5% for tertile III (P = 0.001). By multivariable Cox backward analysis, sUA was retained as a significant predictor. Compared with the lowest sUA tertile, tertile III showed a strong association with outcome, also after adjustment for other predictors (HR 1.84, 95% CI 1.16-2.93; P = 0.01). Importantly, addition of sUA to the other significant predictors of outcome resulted in improved risk classification (net reclassification improvement 0.19, P = 0.017). CONCLUSIONS: High sUA at discharge is a strong predictor of adverse outcome in elderly hospitalized for HF, and it significantly improves risk classification. Measuring sUA can be a simple and useful tool to identify high-risk elderly hospitalized for HF. PMID- 29501447 TI - Possible trends in incidence of diabetes in Italy. PMID- 29501448 TI - Improving the food waste composting facilities site selection for sustainable development using a hybrid modified MADM model. AB - With the growth of population and the development of urbanization, waste management has always been a critical global issue. Recently, more and more countries have found that food waste constitutes the majority of municipal waste, if they are disposed of properly, will bring more benefits in sustainable development. Regarding the issue of selecting and improving the location to make the disposal facility towards achieving the aspiration level for sustainable development, since it involves multiple and complicated interaction factors about environment, society, and economy which have to be considered properly in the decision-making process of mutual influence relationship. It is basically a multiple attribute decision making (MADM) issue, a difficult problem which has been obsessing the governments of many countries is widely studied and discussed. This study uses the new hybrid modified MADM model, as follows, first to build an influential network relation map (INRM) via DEMATEL technique, next to confirm the influential weightings via DANP (DEMATEL-based ANP), and then to construct a decision-making model via a hybrid modified VIKOR method to improve and select the location for remaining the best disposal facilities. Finally, an empirical case study is illustrated to demonstrate that the proposed model can be effective and useful. In finding the process of decision making, environmental pollution is the main concern of many people in the area, but actually it is the resistance by the general public that has to be considered with first priority. PMID- 29501449 TI - Quantifying greenhouse gas emissions from municipal solid waste dumpsites in Cameroon. AB - Open dumpsites that receive municipal solid waste are potentially significant sources of greenhouse gas (GHG) emissions into the atmosphere. There is little data available on emissions from these sources, especially in the unique climate and management of central Africa. This research aimed at quantifying CH4, N2O and CO2 emissions from two open dumpsites in Cameroon, located in Mussaka-Buea, regional headquarters of the South West Region and in Mbellewa-Bamenda, regional headquarters of the North West Region. Emissions were measured during the wet season (May 2015 and August 2016) at the Mussaka and Mbellewa dumpsites respectively. Dumpsite surfaces were partitioned into several zones for emission measurements, based on the current activity and the age of the waste. Static flux chambers were used to quantify gas emission rates thrice a day (mornings, afternoons and evenings). Average emissions were 96.80 +/- 144 mg CH4 m-2 min-1, 0.20 +/- 0.43 mg N2O m-2 min-1 and 224.78 +/- 312 mg CO2 m-2 min-1 in the Mussaka dumpsite, and 213.44 +/- 419 mg CH4 m-2 min-1, 0.15 +/- 0.15 mg N2O m-2 min-1 and 1103.82 +/- 1194 mg CO2 m-2 min-1 at the Mbellewa dumpsite. Emissions as high as 1784 mg CH4 m-2 min-1, 2.3 mg N2O m-2 min-1 and 5448 mg CO2 m-2 min-1 were measured from both dumpsites. Huge variations observed in emissions between the different zones on the waste surface were likely a result of the heterogeneous nature of the waste, different stages in waste decomposition and different environmental conditions within the waste. Management activities that disturb waste, such as spreading and compressing potentially increase gas emissions, while covering waste with a layer of soil potentially mitigate gas emissions. Recommendations were for dumpsites to be upgraded to sanitary landfills, and biogas production from such landfills should be exploited to reduce CH4 emissions. PMID- 29501450 TI - Improving Standards of Care through the Publication of Surgeon Identifiable Outcome Data in Urology. AB - Consultant Outcomes Publication aims to drive up standards of care by greater transparency and peer comparison of surgical practice and outcomes. This is despite difficulties of data entry and bias, and potential for risk avoidance and diminished training. PMID- 29501452 TI - The role of the Oxytocin-Neurophysin I gene in contributing to human personality traits promoting sociality. AB - Oxytocin (OT) plays a salient role in contributing to the high levels of human sociality that characterize our species. Across the lifespan this nonapeptide promotes prosocial behaviors and modulates stress responses. Curiously, the OXT Neurophysin I gene has been little studied despite the fact this is the structural gene for the OT nonapeptide. In a large group of Han Chinese undergraduate students (n = 1593) we examined associations of two single nucleotide polymorphisms of the OXT- Neurophysin I gene with personality traits. Results indicated that the OXT-Neurophysin I rs2770378 was related to extraversion, agreeableness, and neuroticism. AA homozygous individuals reported more prosocial personality traits, compared to participants carrying the G allele. These results indicate that variants of the OXT-Neurophysin-I gene resonate with phenotypes that foster positive social interactions, which may in turn facilitate the social regulation of stress responses. PMID- 29501451 TI - Effect of Prostate Cancer Severity on Functional Outcomes After Localized Treatment: Comparative Effectiveness Analysis of Surgery and Radiation Study Results. AB - BACKGROUND: Whether prostate cancer severity modifies patient-reported functional outcomes after radical prostatectomy (RP) or external beam radiotherapy (EBRT) for localized cancer is unknown. OBJECTIVE: The purpose of this study was to determine whether differences in predicted function over time between RP and EBRT varied by risk group. DESIGN, SETTING, AND PARTICIPANTS: The Comparative Effectiveness Analysis of Surgery and Radiation (CEASAR) study is a prospective, population-based, observational study that enrolled men with localized prostate cancer in 2011-2012. Among 2117 CEASAR participants who underwent RP or EBRT, 817 had low-risk, 902 intermediate-risk, and 398 high-risk disease. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patient-reported, disease-specific function was measured using the 26-item Expanded Prostate Index Composite (at baseline and 6, 12, and 36 mo). Predicted function was estimated using regression models and compared by disease risk. RESULTS AND LIMITATIONS: Low-risk EBRT patients reported 3-yr sexual function scores 12 points higher than those of low risk RP patients (RP, 39 points [95% confidence interval {CI}, 37-42] vs EBRT, 52 points [95% CI, 47-56]; p<0.001). The difference in 3-yr scores for high-risk patients was not clinically significant (RP, 32 points [95% CI, 28-35] vs EBRT, 38 points [95% CI, 33-42]; p=0.03). However, when using a commonly used binary definition of sexual function (erections firm enough for intercourse), no major differences were noted between RP and EBRT at 3 yr across low-, intermediate-, and high-risk disease strata. No clinically significant interactive effects between treatment and cancer severity were observed for incontinence, bowel, irritative voiding, and hormone domains. The primary limitation is the lack of firmly established thresholds for clinically significant differences in Expanded Prostate Index Composite domain scores. CONCLUSIONS: For men with low-risk prostate cancer, EBRT was associated with higher sexual function scores at 3 yr than RP; however, for men with high-risk prostate cancer, no clinically significant difference was noted. Men with high-risk prostate cancer should be counseled that EBRT and RP carry similar sexual function outcomes at 3 yr. PATIENT SUMMARY: In this report, we studied the urinary, sexual, bowel, and hormonal functions of patients 3 yr after undergoing prostate cancer surgery or radiation. We found that for patients with high-risk disease, sexual function was similar between surgery and radiation. We conclude that high-risk patients undergoing radiation therapy should be counseled that sexual function may not be as good as low-risk patients undergoing radiation. PMID- 29501453 TI - Staphylococcus aureus in the airways of cystic fibrosis patients - A retrospective long-term study. AB - BACKGROUND: Cystic fibrosis (CF) is an autosomal recessive disease associated with chronic airway infections by Staphylococcus aureus as one of the earliest and most prevalent pathogens. We conducted a retrospective study to determine the S. aureus infection status of CF patients treated since 1994 at two certified CF centres in Munster, Germany, to get insights into the dynamics of S. aureus airway infection and the clinical impact on lung function on a long-term perspective. MATERIALS AND METHODS: We used data from our microbiological database collected between 1994 and 2016 for patients treated at two centres in Munster, Germany, respectively, to determine the infection status for S. aureus. Furthermore, the resistance to selected antibiotics was determined for all patients' isolates and for 15 patients on a longitudinal basis. In addition, the prevalence of adaptive phenotypes such as small colony variants (SCVs) and mucoid S. aureus was assessed. RESULTS: For this study, 2867 patient years with respiratory specimens (mean of 9.3 years for every patient, range 1-22 years) were evaluated for 283 CF patients (median age of 7 years at the beginning of the observation period, range 0-57 years, 51% male). 18% of patients were rarely infected by S. aureus (<=24% of observation years), 20% of patients intermittently (25-49%) and 61% persistently (>=50% of observation period). Susceptibility testing for 12969 S. aureus isolates resulted in resistance to methicillin in 9%, trimethoprim/sulfamethoxazole in 10%, levofloxacin in 14%, gentamicin in 20%, erythromycin and/or clindamycin in 30% and penicillin in 80% of all isolates. S. aureus isolates of 15 patients revealed dynamics of resistance with increase, decrease and loss of resistant isolates to the analysed antibiotics during the study period. SCVs were isolated at least once from 42% (n = 118) of patients and mucoid isolates from 2% (n = 7) of patients. In the last study year, 89 patients were infected by S. aureus only, 44 patients by S. aureus and Pseudomonas aeruginosa and 18 by P. aeruginosa only. Patients infected by S. aureus only were younger and had better lung function compared to the other two groups. CONCLUSIONS: We determined a high percentage of patients with persistent S. aureus infection. During persistence, mostly fluctuation of resistance against various antibiotics was observed in the isolates indicating acquisition and loss of resistance genes by S. aureus. The prevalence of adaptive phenotypes during long-term persistence was high for SCVs (42% of patients), but low for mucoid isolates (2% of patients), which might be underestimated for mucoid phenotypes due to the retrospective study design and the difficulty to detect mucoid isolates in primary cultures. While patients with S. aureus only had better lung function and were younger, no difference was found between the group of P. aeruginosa and S. aureus co-infection and P. aeruginosa only with previous S. aureus infection. PMID- 29501454 TI - Neuroprotective potential of spermidine against rotenone induced Parkinson's disease in rats. AB - Parkinson's disease is a leading hypokinetic disorder characterized by selective loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) region of mid-brain. Degeneration of dopaminergic neurons is considered to be due to oxidative stress, neuroinflammation, disturbed calcium homeostasis and glutamate excitotoxicity etc. Spermidine is a polyamine which counteracts age associated cell death by scavenging free radical formation, activates authophagic machinery by enhancing formation of autophagosome, and antagonizes NMDA receptor. In the current study we investigated the neuroprotective potential of spermidine against rotenone induced PD in rats. Rats were treated subcutaneously with rotenone 1.5 mg/kg daily for 28 days. Spermidine 5&10 mg/kg was administered orally 1 h prior to rotenone administration from 15 to 28. Rotenone caused significant reduction in motor functioning and elevated levels of oxidative stress markers and proinflammatory cytokines levels (IL-1beta, IL6 and TNF-alpha). The neurochemical analysis revealed a significant decrease in serotonin, norepinephrine, dopamine and their metabolites accompanied by a significant loss of dopaminergic neurons in the SNpc following ROT injection. However, treatment with spermidine rescued DAergic neurons in SNpc and nerve terminals in the striatum following ROT insult. Spermidine treatment also attenuated oxidative stress, neuroinflammation and restored striatal neurochemistry. Results of our study suggest that spermidine has promising neuroprotective effect against degenerative changes in experimental PD, and the protective effects are mediated through its antioxidant and anti inflammatory properties. PMID- 29501455 TI - Using a Biopsychosocial Model to Understand Long-Term Outcomes in Persons With Burn Injuries. AB - OBJECTIVE: To determine the importance of preburn adjustment, injury-related variables, and selection of coping style in various outcome measures using a biopsychosocial model. DESIGN: Longitudinal study. SETTING: Outpatient burn clinics. PARTICIPANTS: Burn survivors (N=231) who participated in this study as part of a larger burn model system study of 645 patients with major burn injuries. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The 36-Item Short Form Health Survey was used to assess preburn adjustment. Other outcome measures entered into the model included the Ways of Coping Checklist Revised, the Brief Symptom Inventory, the Beck Depression Inventory-II, and the Davidson Trauma Scale. RESULTS: Correlational and mediational analyses revealed that preburn emotional health predicted better adjustment at year 1 and more posttraumatic stress disorder symptoms at year 2. Better preburn emotional health was also related to less use of avoidance coping strategies, which was found to be a mediator of the effect of preburn emotional health and posttraumatic stress disorder symptoms. Burn injury characteristics were not significantly associated with psychological adjustment at either year 1 or year 2. CONCLUSIONS: The results indicate that there is a complex relation between premorbid mental health and the selection of coping strategies that affect long-term adjustment in persons recovering from a burn injury. This relation seems to have greater effect on long-term outcomes than does preburn emotional or physical health alone or the severity of the burn. PMID- 29501456 TI - Contemporary Management of Ischemic Mitral Regurgitation: A Review. AB - Ischemic mitral regurgitation occurs relatively frequently in patients with coronary artery disease and is associated with an increased long-term risk. The pathophysiology of ischemic mitral regurgitation is vexing and poses both diagnostic and therapeutic challenges, leading to the need for a comprehensive, multidisciplinary approach. The management is largely focused on medical therapy, and for those eligible, coronary revascularization or cardiac resynchronization therapy may be considered. In select patients, mitral valve surgery or catheter based therapy may be undertaken with careful consideration of the underlying pathophysiology, surgical risk, and expected long-term outcomes. The appropriate evaluation of patients with ischemic mitral regurgitation involves a careful multidisciplinary approach that carefully considers symptomatology, the etiology and severity of the mitral regurgitation, and the assessment of comorbidities and operative risk to individualize the care of these patients. PMID- 29501457 TI - Chick cranial neural crest cells use progressive polarity refinement, not contact inhibition of locomotion, to guide their migration. AB - To move directionally, cells can bias the generation of protrusions or select among randomly generated protrusions. Here we use 3D two-photon imaging of chick branchial arch 2 directed neural crest cells to probe how these mechanisms contribute to directed movement, whether a subset or the majority of cells polarize during movement, and how the different classes of protrusions relate to one another. We find that, in contrast to Xenopus, cells throughout the stream are morphologically polarized along the direction of overall stream movement and do not exhibit contact inhibition of locomotion. Instead chick neural crest cells display a progressive sharpening of the morphological polarity program. Neural crest cells have weak spatial biases in filopodia generation and lifetime. Local bursts of filopodial generation precede the generation of larger protrusions. These larger protrusions are more spatially biased than the filopodia, and the subset of protrusions that are productive for motility are the most polarized of all. Orientation rather than position is the best correlate of the protrusions that are selected for cell guidance. This progressive polarity refinement strategy may enable neural crest cells to efficiently explore their environment and migrate accurately in the face of noisy guidance cues. PMID- 29501458 TI - Comment on: impact of bariatric surgery on outcomes of patients with nonalcoholic fatty liver disease: a nationwide inpatient sample analysis, 2004-2012. PMID- 29501459 TI - Evaluation of the promoting effect of soluble cyclodextrins in drug nail penetration. AB - Soluble derivatives of beta-cyclodextrin (CD) have a high capacity to solubilise hydrophobic molecules and to interact with proteins and membrane component. As consequence CD derivatives shows a significant activity as drug absorption enhancers through different delivery routes, such as the oral, nasal, ocular or topical route. In this paper, the effect of two CD derivatives -methyl-beta cyclodextrin (MBCD) and hydroxypropyl-beta-cyclodextrin (HPB)- on the structure and permeability of the nail plate has been studied using the drug model ciclopirox olamine. Results shows that MBCD and HPB interacting with the nail plate components, modifying their microporous structure and swelling characteristics. The ability of the cyclodextrins to interact with aromatic amino acids and to stabilise and unfold protein structures could be the most likely mechanisms responsible of the nail microstructure modifications. Aditionally CD allows to increase the soluble dose of ciclopirox olamine in aqueous lacquers made with poloxamer and N-acetylcysteine via the formation of high solubility complexes with the drug. Finally the studies of diffusion and penetration obtained using bovine hoof model confirm the enhancing effect of the cyclodextrins on the penetration and accumulation of the drug in the nail structure. Results shows the great potential of the CD for the elaboration of aqueous based nail lacquers containing hidrofobic drugs. PMID- 29501460 TI - Subaortic ventricular pouch in repaired tetralogy of Fallot mimicking right coronary artery aneurysm. PMID- 29501461 TI - Suspicious liver nodule in chronic liver disease: Usefulness of a second biopsy. AB - PURPOSE: To assess the usefulness of a second biopsy when the first one was inconclusive in patients with a liver nodule found during the follow-up for chronic liver disease. MATERIALS AND METHODS: Among 381 patients (544 nodules) included in a prospective study designed to evaluate the accuracy of imaging for the diagnosis of small hepatocellular carcinoma (HCC) in chronic liver disease, 254 nodules were biopsied. The following histological results were considered as conclusive: HCC, dysplastic or regenerative nodule, and other identified tumors (benign or malignant). For nodules with inconclusive results (e.g. fibrosis or no definite focal lesion), a second biopsy was suggested, but was not mandatory. RESULTS: A total of 242 patients (194 men, 48 women; mean age, 61.9+/-9.5 [SD]; range: 40.2-89.0years) with 254 nodules underwent a first biopsy. Mean nodule diameter was 19.2+/-5.4mm (range: 10-33mm). The first biopsy was conclusive in 189/254 nodules (74.4%): 157 HCCs (83.1%), 11 regenerative nodules (5.8%), 10 dysplastic nodules (5.3%), 3 cholangiocarcinomas (1.6%), and 8 other tumors (4.2%). Among the 65 nodules for which the first biopsy was inconclusive, a second biopsy was performed for 17 nodules in 16 patients within 6 months of the first one. It was conclusive in 13/17 nodules (76.5%): 10 HCCs (76.9%), 2 dysplastic nodules (15.4%), and 1 other tumor (7.7%). In 4/17 nodules (23.5%), no definitive diagnosis could be provided. CONCLUSION: The diagnostic yield of a second biopsy of a suspicious lesion suggestive of HCC in chronic liver disease is not decreased compared to the first one. Repeated biopsy after a first negative one could be an alternative option to the follow-up of patients with chronic liver disease. PMID- 29501462 TI - Cerebrospinal fluid biomarkers measured by Elecsys assays compared to amyloid imaging. AB - INTRODUCTION: Levels of amyloid beta peptide 42 (Abeta42), total tau, and phosphorylated tau-181 are well-established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease, but variability in manual plate-based assays has limited their use. We examined the relationship between CSF biomarkers, as measured by a novel automated immunoassay platform, and amyloid positron emission tomography. METHODS: CSF samples from 200 individuals underwent separate analysis for Abeta42, total tau, and phosphorylated tau-181 with automated Roche Elecsys assays. Abeta40 was measured with a commercial plate-based assay. Positron emission tomography with Pittsburgh Compound B was performed less than 1 year from CSF collection. RESULTS: Ratios of CSF biomarkers (total tau/Abeta42, phosphorylated tau-181/Abeta42, and Abeta42/Abeta40) best discriminated Pittsburgh Compound B-positive from Pittsburgh Compound B-negative individuals. DISCUSSION: CSF biomarkers and amyloid positron emission tomography reflect different aspects of Alzheimer's disease brain pathology, and therefore, less than-perfect correspondence is expected. Automated assays are likely to increase the utility of CSF biomarkers. PMID- 29501464 TI - Analysis of the Learning Curve in Mitral Valve Replacement Through the Right Anterolateral Minithoracotomy Approach: A Surgeon's Experience with the First 100 Patients. AB - BACKGROUND: To apply the cumulative sum (CUSUM) failure analysis to assess the performance of a single surgeon during mitral valve replacement via the right anterolateral minithoracotomy (RAMT) approach and to analyse the learning curve for the procedure. METHODS: A total of 100 mitral valve replacements were performed using the RAMT approach from June 2011 to April 2013 by a single surgeon with no prior experience of this technique. Patients were divided into five blocks according to the operation date. The perioperative data were collected prospectively and analysed using descriptive statistics and CUSUM failure analysis. RESULTS: No significant differences in the background factors among the five periods were observed, except for a small increase in patient age from periods 1 to 5 (p=0.004). The surgeon's performance improved with time; a decrease in the cross-clamp time, operative time, and blood loss was observed (p<0.001). However, no significant difference in the number of failed cases was observed among the periods. All failure cases were evaluated by the CUSUM failure analysis and the CUSUM curve reflected a learning curve associated with this new procedure. The surgeon crossed the lower 80% boundary after about 33 operations, which indicates that better results can be obtained after this point. CONCLUSIONS: Minimally invasive mitral valve surgery using the RAMT approach can be performed by a new surgeon. Furthermore, CUSUM curve analysis is a simple statistical method to implement continuous individual performance monitoring. PMID- 29501463 TI - In vitro and in vivo safety studies of cinnamon extract (Cinnamomum cassia) on general and genetic toxicology. AB - Cinnamomum cassia has been widely used as a natural product to treat diseases in Asia due to its diverse pharmacological functions including anti-inflammatory, anti-oxidant, anti-microbial, anti-diabetic, and anti-tumor effects. Despite its ethnomedicinal benefits, little information regarding its toxicity is currently available. The aim of this study was to evaluate its potential long-term toxicity and genotoxicity in compliance with test guidelines of the Organization for Economic Cooperation and Development. A 13-week repeat-dose oral toxicity study revealed that body weights of rats were normal after receiving cinnamon extract at up to 2000 mg/kg. High-dose intake of cinnamon extract (2000 mg/kg) showed potential nephrotoxicity and hepatotoxicity to both males and females as evidenced by obvious increases of kidney/liver weight along with a small but statistically elevation of total cholesterol level. Overall findings from genetic toxicity testing battery including Ames test, in vitro mammalian cell micronucleus assay, and in vivo bone marrow micronucleus assay indicated that cinnamon extract was not mutagenic or clastogenic. In conclusion, cinnamon extract may possess potential nephrotoxicity and hepatotoxicity at dose higher than its recommended daily safe dose. Further study is needed to clarify the mechanism involved in its induction of liver and kidney injury. PMID- 29501465 TI - The Effect of Atrial Fibrillation Ablation Techniques on P Wave Duration and P Wave Dispersion. AB - BACKGROUND: A reduction in surface electrocardiogram (ECG) P wave duration and dispersion is associated with improved outcomes in atrial fibrillation ablation. We investigated the effects of different ablation strategies on P wave duration and dispersion, hypothesising that extensive left atrial (LA) ablation with left atrial posterior wall isolation would give a greater reduction in P wave duration than more limited ablation techniques. METHODS: A retrospective analysis of ECGs from patients who have undergone atrial fibrillation (AF) ablation was performed and pre-procedural sinus rhythm ECGs were compared with the post procedure ECGs. Maximal P wave duration was measured in leads I or II, minimum P wave duration in any lead and values were calculated for P wave duration and dispersion. Left atrial dimensions and medications at the time of ECG were documented. Ablation strategies compared were; pulmonary vein isolation (PVI) for paroxysmal atrial fibrillation (PAF) and the persistent AF (PsAF) ablation strategies of pulmonary vein isolation plus additional linear lesions (Lines), left atrial posterior wall isolation via catheter (PWI) and left atrial posterior wall isolation via staged surgical and catheter ablation (Hybrid). RESULTS: Sixty-nine patients' ECGs were analysed: 19 PVI, 21 Lines, 14 PWI, 15 Hybrid. Little correlation was seen between pre-procedure left atrial size and P wave duration (r=0.24) but LA size and P wave duration was larger in PsAF patients. A significant difference was seen in P wave reduction driven by Hybrid AF ablation (p<0.005) and Lines (<0.02). There was no difference amongst P wave dispersion between groups but the largest reduction was seen in the Hybrid ablation group. CONCLUSIONS: P wave duration increased with duration of continuous atrial fibrillation. Hybrid AF ablation significantly reduced P wave duration and dispersion compared to other ablation strategies including posterior wall isolation via catheter despite this being the same lesion set. PMID- 29501466 TI - New genetic tools for the in vivo study of hematopoietic stem cell function. AB - The production of blood cells is dependent on the activity of a rare stem cell population that normally resides in the bone marrow (BM) of the organism. These hematopoietic stem cells (HSCs) have the ability to both self-renew and differentiate, ensuring this lifelong hematopoiesis. Determining the regulation of HSC functions should thus provide critical insight to advancing regenerative medicine. Until quite recently, HSCs were primarily studied using in vitro studies and transplantations into immunodeficient hosts. Indeed, the definition of a bona fide HSC is its ability to reconstitute lymphopenic hosts. In this review, we discuss the development of novel, HSC-specific genetic reporter systems that enable the prospective identification of HSCs and the study of their functions in the absence of transplantation. Coupled with additional technological advances, these studies are now defining the fundamental properties of HSCs in vivo. Furthermore, complex cellular and molecular mechanisms that regulate HSC dormancy, self-renewal, and differentiation are being identified and further dissected. These novel reporter systems represent a major technological advance for the stem cell field and allow new questions to be addressed. PMID- 29501467 TI - Megakaryocyte ontogeny: Clinical and molecular significance. AB - Fetal megakaryocytes (Mks) differ from adult Mks in key parameters that affect their capacity for platelet production. However, despite being smaller, more proliferative, and less polyploid, fetal Mks generally mature in the same manner as adult Mks. The phenotypic features unique to fetal Mks predispose patients to several disease conditions, including infantile thrombocytopenia, infantile megakaryoblastic leukemias, and poor platelet recovery after umbilical cord blood stem cell transplantations. Ontogenic Mk differences also affect new strategies being developed to address global shortages of platelet transfusion units. These donor-independent, ex vivo production platforms are hampered by the limited proliferative capacity of adult-type Mks and the inferior platelet production by fetal-type Mks. Understanding the molecular programs that distinguish fetal versus adult megakaryopoiesis will help in improving approaches to these clinical problems. This review summarizes the phenotypic differences between fetal and adult Mks, the disease states associated with fetal megakaryopoiesis, and recent advances in the understanding of mechanisms that determine ontogenic Mk transitions. PMID- 29501468 TI - Association between vitamin D levels and inflammatory activity in brain death: A prospective study. AB - BACKGROUND: Vitamin D insufficiency is linked to several common inflammatory disorders. Brain death (BD) causes a massive catecholamine release, leading to intense inflammatory activity. We aimed to evaluate vitamin D serum levels in brain-dead individuals in comparison to critically ill patients without BD to assess the correlation between vitamin D and cytokine levels. METHODS: Sixteen brain-dead patients and 32 critically ill controls were prospectively enrolled. Blood samples from 25 brain-dead patients from a previous study were also used for vitamin D quantification. Plasma TNF, IL-1beta, IL-6, IL-8, IL-10, IFN-gamma and serum vitamin D levels were compared using Student's t-test or one-way ANOVA. Spearman's test was used to assess the correlation between vitamin D and cytokine levels. RESULTS: Mean vitamin D levels were 16.4 +/- 7.9 ng/mL, with 52 patients (71.2%) classified as vitamin D deficient (serum levels < 20 ng/mL). Vitamin D levels were similar in 41 brain-dead patients as compared to control subjects (15.6 +/- 6.9 ng/mL vs 17.4 +/- 9.0 ng/mL; p = 0.383). Moderate direct correlations were observed between vitamin D and IL-8, IL-10, and IFN-gamma in the prospective group of 16 brain-dead patients (IL-8: r = 0.5, p = 0.049; IL-10 r = 0.67, p = 0.005; IFN-gamma r = 0.6, p = 0.015). Vitamin D was inversely correlated with IL-6 (r = -0.36, p = 0.044) in critically ill controls. CONCLUSIONS: Vitamin D serum levels were similarly low in brain-dead and critically ill patients. In brain-dead patients, vitamin D serum levels correlated with plasma IL-8, IL-10 and IFN-gamma. PMID- 29501469 TI - Evaluation of a surface plasmon resonance imaging-based multiplex O-antigen serogrouping for Escherichia coli using eleven major serotypes of Shiga -toxin producing E. coli. AB - The early detection of Shiga toxin-producing Escherichia coli (STEC) is important for early diagnosis and preventing the spread of STEC. Although the confirmatory test for STEC should be based on the detection of Shiga toxin using molecular analysis, isolation permits additional characterization of STEC using a variety of methods, including O:H serotyping. The conventional slide agglutination O antigen serogrouping used in many clinical laboratories is laborious and time consuming. Surface plasmon resonance (SPR)-based immunosensors are commonly used to investigate a large variety of bio-interactions such as antibody/antigen, peptide/antibody, DNA/DNA, and antibody/bacteria interactions. SPR imaging (SPRi) is characterized by multiplexing capabilities for rapidly screening (approximately 100 to several hundred sensorgrams in parallel) molecules. SPRi based O-antigen serogrouping method for STEC was recently developed by detecting the interactions between O-antigen-specific antibodies and bacterial cells themselves. The aim of this study was to evaluate its performance for E. coli serogrouping using clinical STEC isolates by comparing the results of slide agglutination tests. We tested a total of 188 isolates, including O26, O45, O91, O103, O111, O115, O121, O128, O145, O157, and O159. The overall sensitivity of SPRi-based O-antigen serogrouping was 98.9%. Only two O157 isolates were misidentified as nontypeable and O121. The detection limits of all serotypes were distributed between 1.1 * 106 and 17.6 * 106 CFU/ml. Pulsed-field gel electrophoresis (PFGE) revealed the heterogeneity of the examined isolates. In conclusion, SPRi is a useful method for the O-antigen serogrouping of STEC isolates, but the further evaluation of non-O157 minor serogroups is needed. PMID- 29501470 TI - Changes in cognitive function after a 12-week exercise intervention in adults with Down syndrome. AB - BACKGROUND: Between 250,000 and 400,000 individuals in the United States are diagnosed with Down syndrome (DS). Nearly all adults with DS will develop Alzheimer's disease pathology starting in their thirties. Recent studies suggest that increased physical activity (PA) may be important for maintaining components of cognition, including memory. OBJECTIVE: The purpose of this study was to evaluate changes in cognitive function after completion of a 12-week exercise intervention in adults with DS. METHODS: Participants were randomized to attend 30-minute group exercise sessions 1 or 2 times a week for 12 weeks. The exercise sessions were delivered via video conferencing on a tablet computer to groups of 5-8 participants. Sessions consisted of aerobic based exercises such as walking and jogging to music, dancing, as well as strength based exercises such as vertical jumps, bicep curls, and squats. Cognitive function was measured at baseline and end of study using the Cantab Dementia Battery for iPads, which assessed the cognitive domains of memory, attention, and reaction time. RESULTS: Twenty-seven participants (27.9 +/- 7.1 years of age, 40.7% female) enrolled and completed the 12-week intervention. Participants randomized to 1 session/week averaged 26.6 +/- 3.0 min/week of PA from the group exercise session. Participants randomized to 2 sessions/week averaged 57.7 +/- 15.3 min/week of PA from the group exercise sessions. Participants improved their performance on the two memory variables (p = 0.048 and p = 0.069). CONCLUSION: Increased exercise may have positive changes on memory and other cognitive functions. PMID- 29501471 TI - Exploring the aglycone subsite of a GH11 xylanase for the synthesis of xylosides by transglycosylation reactions. AB - Xylanases Tx-xyn10 and Tx-xyn11 were compared for their transxylosylation abilities in the presence of various acceptors. Tx-xyn10 exhibited a broad specificity for various acceptors, whereas xylanase Tx-xyn11 catalysed transxylosylation reactions only in presence of polyphenolic acceptors. A modelling approach was developed to study the molecular bottlenecks into the active site of the enzyme that could be responsible for this restricted specificity. The glycosyl-enzyme intermediate of Tx-xyn11 was modelled, and a rotamer of the Y78 residue was integrated. In silico mutations of some residues from the (+1) and (+2) subsites were tested for the deglycosylation step in the presence of non-polyphenolic acceptors. The results indicated that the mutant W126A was able to use aliphatic alcohols and benzyl alcohol as acceptors for transxylosylation. Experimental validation was tested by mutating the xylanase Tx xyn11 at position W126 into alanine. The specific activity and catalytic efficiency of the W126A mutant during the hydrolysis of xylans decreased by 2 fold and 4-fold, respectively, compared to wild-type xylanase. Among tested acceptors, transxylosylation catalysed by mutant W126A was improved with benzyl alcohol leading to a 2-fold higher concentration of benzyl xylobioside, as predicted by in silico mutation. This improved transxylosylation in the presence of benzyl alcohol leading to higher synthesis of benzyl xylobioside could likely be explained by lowest steric hindrance in the aglycone subsite of the mutated xylanase. No secondary hydrolysis of benzyl xylobioside occurred for both wild type and mutant xylanases. Finally, our results demonstrated that the modelling approach was limited and that accounting for protein dynamics can lead to improved models. PMID- 29501472 TI - Interplay between membrane curvature and protein conformational equilibrium investigated by solid-state NMR. AB - Many membrane proteins sense and induce membrane curvature for function, but structural information about how proteins modulate their structures to cause membrane curvature is sparse. We review our recent solid-state NMR studies of two virus membrane proteins whose conformational equilibrium is tightly coupled to membrane curvature. The influenza M2 proton channel has a drug-binding site in the transmembrane (TM) pore. Previous chemical shift data indicated that this pore-binding site is lost in an M2 construct that contains the TM domain and a curvature-inducing amphipathic helix. We have now obtained chemical shift perturbation, protein-drug proximity, and drug orientation data that indicate that the pore-binding site is restored when the full cytoplasmic domain is present. This finding indicates that the curvature-inducing amphipathic helix distorts the TM structure to interfere with drug binding, while the cytoplasmic tail attenuates this effect. In the second example, we review our studies of a parainfluenza virus fusion protein that merges the cell membrane and the virus envelope during virus entry. Chemical shifts of two hydrophobic domains of the protein indicate that both domains have membrane-dependent backbone conformations, with the beta-strand structure dominating in negative-curvature phosphatidylethanolamine (PE) membranes. 31P NMR spectra and 1H-31P correlation spectra indicate that the beta-strand-rich conformation induces saddle-splay curvature to PE membranes and dehydrates them, thus stabilizing the hemifusion state. These results highlight the indispensable role of solid-state NMR to simultaneously determine membrane protein structures and characterize the membrane curvature in which these protein structures exist. PMID- 29501473 TI - Enhanced butyric acid production in Clostridium tyrobutyricum by overexpression of rate-limiting enzymes in the Embden-Meyerhof-Parnas pathway. PMID- 29501474 TI - Factors associated with non-participation in cervical cancer screening - A nationwide study of nearly half a million women in Denmark. AB - Cervical cancer occurs most often in under-screened women. In this nationwide register study, we described differences in sociodemographic characteristics between passive and active non-participants and examined socio-demographic characteristics, reproductive history, and mental and physical health as potential determinants for passive non-participation compared with participation in the Danish cervical cancer screening program. Screening history in women aged 23-49 years invited for cervical cancer screening in 2008-2009 was retrieved from the Danish Pathology Databank with information about dates of invitation and unsubscription. We identified participants (n = 402,984), active non-participants (n = 10,251) and passive non-participants (n = 63,435) within four years following baseline invitation and retrieved data about the study population from high-quality registries. We examined differences in socio-demographic characteristics of passive and active non-participants, and used multiple logistic regression analyses to identify potential determinants of passive non participation. We found that active and passive non-participants differed in relation to socio-demography. When compared with screening participants, the odds of passive non-participation was increased in women who originated from less developed countries; were unmarried; had basic education or low income; had four or more children; smoked during pregnancy; had multiple induced abortions; or had a history of obesity, intoxicant abuse or schizophrenia or other psychoses. In conclusion, in this nationwide, prospective, population-based study, differences in socio-demographic characteristics between passive and active non-participants were found. Furthermore, sociodemography, reproductive history, and mental and physical health were determinants for passive non-participation. Addressing inequalities in screening attendance may help to further decrease the incidence of and mortality from cervical cancer. PMID- 29501475 TI - The association of flavored milk consumption with milk and energy intake, and obesity: A systematic review. AB - Taxes on sugary drinks are being implemented to prevent chronic diseases. Sugar sweetened milk has been exempt from such policies because of its nutritional value. This systematic review sought to examine whether flavored milk consumption was associated with milk and energy intake, and obesity among children. A search of PubMed, EMBASE, Cochrane, CINAHL, Web of Science, Cochrane Central Register of Controlled Trials and the grey literature was conducted for peer-reviewed publications published before June 6, 2016 that met the following criteria: 1) English-language publications 2) studies of children ages 1 to 18 years, 3) controlled experimental, cohort, case-control, systematic reviews, or meta analysis studies 4) dependent variable: flavored milk consumption 5) independent variable: weight, weight gain, weight change, body mass index, metabolic syndrome, waist circumference, cholesterol, triglycerides, blood pressure, serum glucose, calories, sugar, or milk consumed. Of 3978 studies identified, 13 met inclusion criteria. Ten studies were experimental and three were longitudinal cohort studies. Eleven studies found that flavored milk increased overall milk intake, five of seven studies that examined energy intake showed that flavored milk increased energy intake, and one of three studies that assessed obesity outcomes demonstrated an increase in weight gain with flavored milk consumption. Only one study was a randomized controlled trial, most studies had high bias, and over half were industry-funded or did not disclose funding. Although flavoring milk may increase milk intake, added sugars may promote increased energy intake. More data regarding flavored milk's impact on health is needed to inform its role in sugary drink policies. PMID- 29501476 TI - Developing an index of dose of exposure to early childhood obesity community interventions. AB - The recognition of the role of the environment in contributing to the obesity epidemic has led to increasing efforts to address obesity through environmental or place-based approaches in the past decade. This has challenged the use of the quasi-experimental design for evaluating community interventions. The objective of this study is to describe the development of an index of dose of exposure to community interventions that impact early childhood obesity. The goal is to provide an alternative means for evaluating the impact of multiple intervention strategies that target the same community at the same time. Two workgroups developed domains, constructs and protocols for estimating a "community intervention dose index" (CIDI). Information used to develop the protocol came from multiple sources including databases and reports of major funding organizations on obesity-related interventions implemented in Los Angeles County from 2005 to 2015, key informant interviews, and published literature. The workgroups identified five domains relevant to the consideration of dose of exposure to interventions: physical resources, social resources, context, capacity development, and programs and policies; developed a system for classifying programs and policies into macro- and micro-level intervention strategies; and sought ratings of strategy effectiveness from a panel of 13 experts using the Delphi technique, to develop an algorithm for calculating CIDI that considers intervention strength, reach and fidelity. This CIDI can be estimated for each community and used to evaluate the impact of multiple programs that use a myriad of intervention strategies for addressing a defined health outcome. PMID- 29501477 TI - Distribution, characteristics, and level of community awareness and use of formal shared use sites in Los Angeles. AB - Shared use agreements (SUA) could increase opportunities for physical activity (PA) in under-resourced, urban areas. Despite recent investments in SUAs, the extent to which they reach communities in need and the level of community awareness and use of SUAs remains unclear. This cross-sectional study examined: 1) the distribution of SUAs in Los Angeles (LA) during the 2015-2016 academic year, 2) the characteristics of communities where SUAs were located, and 3) the extent to which community members were aware of and using available facilities. Assessment methods included: 1) abstraction of school administrative data reflecting the geographic distribution and scope of SUAs in LA, 2) collation of community-level Census and local planning data to describe demographic characteristics and per capita park acreage of communities where SUAs were located, and 3) collection of data via an Internet panel survey of LA adults (n = 371) examining awareness and use of SUA facilities. Under 3% of schools had a SUA in place during the study period. Compared to other areas of the city, areas within one mile of SUAs had more Hispanic/Latino, low-income, and lower educational status residents. Among survey respondents, 25.6% of those living within one mile of a SUA reported having access to school facilities; 48.6% of those reporting access reported using them. Although potentially targeted in high needs areas, community members may not be aware of or utilizing SUA facilities. Additional efforts are needed to both expand access to school-based PA resources and attract community users. PMID- 29501478 TI - 25 Years of Trends in Microbiology: Window to the Past and Future. PMID- 29501479 TI - Nitrospira. AB - In this infographic, the key metabolic functions of Nitrospira and the role that these bacteria play in nitrification and other processes in the environment is shown. Nitrospira plays pivotal roles in nitrification as an aerobic chemolithoautotrophic nitrite-oxidizing bacterium. These bacteria often occur in close association with ammonia-oxidizing bacteria or archaea that convert ammonia to nitrite, which is further oxidized to nitrate by Nitrospira. However, in 'reciprocal feeding' interactions, Nitrospira can also provide ammonia oxidizers with ammonia released from urea or cyanate, which is further nitrified as described above. Recently discovered Nitrospira members even catalyze both nitrification steps alone and are therefore called complete ammonia oxidizers or 'comammox' organisms. Some strains of Nitrospira utilize alternative substrates, such as H2 and formate, using oxygen or nitrate as terminal electron acceptor, and can exploit these energy sources concurrently with aerobic nitrite oxidation. This metabolic versatility enables Nitrospira to colonize a broad range of habitats and to sustain shifts in environmental conditions such as changing oxygen concentrations. PMID- 29501480 TI - Nasal and ocular challenges. AB - Nasal and ocular challenges facilitate the evaluation of subjective and objective responses to defined allergen or irritant exposure. Nasal and ocular allergen challenges are the gold standard to diagnose allergic rhinitis and conjunctivitis, respectively, and aid in the evaluation of novel therapies in clinical trials. Additionally, nasal and ocular allergen challenges might help identify medically relevant allergens in clinical practice. Nonspecific or irritant challenges evaluate mucosal hyperreactivity. Direct mucosal challenges, which can be performed in an office or research setting, expose the participant to higher allergen doses than common in the natural environment. Park studies and environmental chambers, which are most practical in clinical trials, more closely simulate natural allergen exposure. International consensus guidelines for nasal and ocular challenges do not exist. Therefore the positivity criteria, methodologies, and extract or allergen preparations used in challenges vary in the literature. Regardless of these limitations, nasal and ocular challenges are helpful clinical and research tools for nasal and ocular diseases. PMID- 29501481 TI - Cymbopogon citratus and Cymbopogon giganteus essential oils have cytotoxic effects on tumor cell cultures. Identification of citral as a new putative anti proliferative molecule. AB - Cymbopogon species are used as traditional remedies in Burkina Faso for treating several diseases. We aimed to study the effects of their essential oils on cancer cell lines. For that purpose, Cymbopogon citratus (DC.) Stapf. and Cymbopogon giganteus Chiov. were studied for their essential oils after various chemical extractions. Antioxidant, potential anti-inflammatory action (inhibition of lipoxygenase) and cytotoxic activities were also tested on various prostate cancer and glioblastoma cell lines. Thirty-three compounds were identified in the essential oil of C. giganteus: Limonene (19.33%), Mentha-1(7),8-dien-2-ol cis (17.34%), Mentha-1(7),8-dien-2-ol trans (13.95%), trans-Mentha-2,8-diene-para-ol 1 (13.91%) and Mentha-2,8-diene-1-ol, cis-para (8.10%) were the most abundant. C. citratus essential oil contained 15 compounds and the major ones were geranial/citral A (48.18%) and neral/citral B (34.37%). Essential oil of C. citratus showed the highest ability to scavenge DPPH+ radicals (approximately 68% at 8 mg/mL) while C. giganteus exhibited the highest capability to reduce ABTS+ (0.59MUmolET/g). The essential oil of C. citratus was the most effective on prostate cell lines LNCaP (IC50 = 6.36 MUg/ml) and PC-3 (IC50 = 32.1 MUg/ml), and on glioblastoma cell lines (SF-767 (IC50 = 45.13 MUg/ml) and SF-763 (IC50 = 172.05 MUg/ml). Interestingly, the activity of essential oil of C. citratus was statistically equal to that of its major component, citral. Combination of both oils showed antagonist, additive, indifferent and synergistic effects on LNCaP, PC-3, SF-767 and SF-763 cell lines, respectively. In conclusion, plants from the traditional medicine in Burkina Faso could be of interest for identifying new compounds, such as citral, for the treatment of prostate cancer and glioblastoma. PMID- 29501482 TI - An extracellular yellow laccase from white rot fungus Trametes sp. F1635 and its mediator systems for dye decolorization. AB - A novel extracellular laccase was purified from fermentation broth of the white rot fungus Trametes sp. F1635 by a three-step protocol including two consecutive ion-exchange chromatography steps on DEAE-Sepharose and SP-Sepharose, and a final gel-filtration on Superdex 75. The purified laccase (TsL) was a monomeric protein with the molecular mass of 64.8 kDa. It demonstrated high oxidation activity of 4.00 * 104 U/mg towards ABTS. Its N-terminal amino acid sequence was AIGPVADLTIINNAV which was unique and sharing high similarity of other fungal laccases. TsL was a yellow laccase based on absorption spectrum analysis. It demonstrated an acidic pH optimum of 2.6 and temperature optimum of 50 degrees C towards ABTS. The Km and Vmax values towards ABTS were estimated to 18.58 MUM and 1.35 MUmol/min, respectively. TsL manifested effective decolorization activity towards eriochrome black T (EBT), remazol brilliant blue R (RBBR), malachite green (MG), and eriochrome black T (EBT) (over 60%). Violuric acid (VA) and acetosyringone (AS) were the optimal mediators for the laccase in dye decolorization. Results suggest that TsL demonstrates great potential for dye decolorization and water treatment. PMID- 29501483 TI - Comparison of long-term results between osteo-odonto-keratoprosthesis and tibial bone keratoprosthesis. AB - PURPOSE: To compare the anatomical and the functional results between osteo odonto-keratoprosthesis (OOKP) and keratoprosthesis using tibial bone autograft (Tibial bone KPro). METHODS: We reviewed the charts of 258 patients; 145 had OOKP whereas 113 had Tibial bone KPro implanted. Functional success was defined as best corrected visual acuity >=0.05 on decimal scale and anatomical success as retention of the keratoprosthesis lamina. Kaplan-Meier survival curves were calculated for anatomical and functional survival as well as to estimate the probability of post-op complications. RESULTS: The anatomical survival for both KPro groups was not significantly different and was estimated as 67% for OOKP and 54% for Tibial bone KPro at 10 years after surgery. There was also no difference found after subdividing for primary diagnosis groups such as chemical injury, thermal burn, trachoma and all autoimmune cases combined. Estimated functional survival at 10 years post-surgery was 49% for OOKP and 25% for Tibial bone KPro, which was significantly different. The probability of patients with Tibial bone KPro developing one or more post-operative complications at 10 years after surgery (65%) was significantly higher than those with OOKP (40%). Mucous membrane necrosis and retroprosthetic membrane formation were more common in Tibial bone KPro than OOKP. CONCLUSION: Both types of autologous biological KPro, OOKP and Tibial bone KPro, had statistically similar rate of keratoprosthesis extrusion. Although functional success rate was significantly higher in OOKP, it may have been influenced by a better visual potential in the patients in this group. PMID- 29501484 TI - Shrimp hemocyte homeostasis-associated protein (PmHHAP) interacts with WSSV134 to control apoptosis in white spot syndrome virus infection. AB - Hemocyte homeostasis-associated protein (PmHHAP) was first identified as a viral responsive gene, due to a high upregulation in transcription following white spot syndrome virus (WSSV) infection. Functional studies using RNA interference have suggested that PmHHAP is involved in hemocyte homeostasis by controlling apoptosis during WSSV infection. In this study, the role of PmHHAP in host-viral interactions was further investigated. Yeast two-hybrid assay and co immunoprecipitation revealed that PmHHAP binds to an anti-apoptosis protein, WSSV134. The viral protein WSSV134 is a late protein of WSSV, expressed 24 h post infection (hpi). Gene silencing of WSSV134 in WSSV-infected shrimp resulted in a reduction of the expression level of the viral replication marker genes VP28, wsv477, and ie-1, which suggests that WSSV134 is likely involved in viral propagation. However, co-silencing of PmHHAP and WSSV134 counteracted the effects on WSSV infection, which implies the importance of the host-pathogen interaction between PmHHAP and WSSV134 in WSSV infection. In addition, caspase 3/7 activity was noticeably induced in the PmHHAP and WSSV134 co-silenced shrimp upon WSSV infection. Moreover, PmHHAP and WSSV134 inhibited caspase-induced activation of PmCasp in vitro in a non-competitive manner. Taken together, these results suggest that PmHHAP and WSSV134 play a role in the host-pathogen interaction and work concordantly to control apoptosis in WSSV infection. PMID- 29501485 TI - CPEO - Like mitochondrial myopathy associated with m.8340G>A mutation. AB - Two patients with an m.8340G>A mitochondrial DNA variant have been reported with one patient showing ptosis, ophthalmoparesis and myopathy at 53% heteroplasmy and another with pigmentary retinopathy, cataracts and sensory neural deafness and slightly higher heteroplasmy (65%). Here we report that higher muscle mutant heteroplasmy (93%) for m.8340G>A is associated with ptosis, ophthalmoparesis and mitochondrial myopathy, thus confirming the initial phenotypic association and showing that heteroplasmy per se does not explain the phenotypic spectrum of disease associated with the m.8340G>A mutation. PMID- 29501486 TI - Hypereosinophilic syndrome presenting acutely with neurologic signs. PMID- 29501487 TI - Bowman capsulitis predicts poor kidney allograft outcome in T cell-mediated rejection. AB - Acute T cell-mediated rejection (TCMR) is an important cause of renal allograft loss. The Banff classification for tubulointerstitial (type I) rejection is based on the extent of both interstitial inflammation and tubulitis. Lymphocytes may also be present between parietal epithelial cells and Bowman capsules in this setting, which we have termed "capsulitis." We conducted this study to determine the clinical significance of capsulitis. We identified 42 patients from the pathology archives at The University of Chicago with isolated Banff type I TCMR from 2010 to 2015. Patient demographic data, Banff classification, and graft outcome measurements were compared between capsulitis and noncapsulitis groups using Mann-Whitney U test. Capsulitis was present in 26 (62%) and was more frequently seen in Banff IB than in IA TCMR (88% versus 44%, P = .01). Patients with capsulitis had a higher serum creatinine at biopsy (4.6 versus 2.9 mg/dL, P = .04) and were more likely to progress to dialysis (42% versus 13%, P = .06), with fewer recovering their baseline serum creatinine (12% versus 38%, P = .08). Patients with both Banff IA TCMR and capsulitis have clinical outcomes similar to or possibly worse than Banff IB TCMR compared with those with Banff IA and an absence of capsulitis. Capsulitis is an important pathologic parameter in the evaluation of kidney transplant biopsies with potential diagnostic, prognostic, and therapeutic implications in the setting of TCMR. PMID- 29501488 TI - Overexpression of apoptosis-inducing factor mitochondrion-associated 1 (AIFM1) induces apoptosis by promoting the transcription of caspase3 and DRAM in hepatoma cells. AB - Full-length apoptosis-inducing factor mitochondrion-associated 1 (AIFM1) (~67 kDa) induces apoptosis in a caspase-independent manner when it is cleaved at its N-terminus to produce truncated AIFM1 (~57 kDa). Here, we produced recombinant adenovirus AIFM1 (rAd-AIFM1) encoding full-length AIFM1 to detect whether full length AIFM1 suppresses cell growth and induces apoptosis of hepatoma cell lines (HepG2 and Hep3B). Hepatocellular carcinoma (HCC) is one of the most difficult cancers to treat worldwide. The MTT assay demonstrated that full-length AIFM1 inhibited the growth of hepatoma cells because rAd-AIFM1 infection suppressed the proliferation of HepG2 and Hep3B cells. TUNEL assay demonstrated that full-length AIFM1 overexpression induced apoptosis in HepG2 and Hep3B cells infected with rAd AIFM1, suggesting an apoptosis-inducing ability of full-length AIFM1. Our data further showed that the expression of two pro-apoptotic genes, caspase3 and DRAM, were involved in full-length AIFM1 infection-induced apoptosis, and full-length AIFM1 could also positively regulate the transcription of caspase3 and DRAM. Thus, overexpression of full-length AIFM1 can induce caspase-dependent apoptosis and suppresses cell growth of hepatoma cells. Our data uncover a potential role of rAd-AIFM1 in HCC gene therapy. PMID- 29501489 TI - rApoptin induces apoptosis in human breast cancer cells via phosphorylation of Nur77 and Akt. AB - Breast cancer is the leading cause of cancer incidence and cancer-related mortality among women and is becoming a major public health problem around the world. The current study aims to investigate the possible role and mechanism of recombinant Apoptin (rApoptin), a potential anticancer candidate that minimally impacts normal cells, in the breast cancer cell proliferation and apoptosis in vitro and in vivo. We found that rApoptin could effectively inhibit the proliferation and apoptosis in MCF-7 and MDA-MB-231 cells in vitro, which was further confirmed by flow cytometry analysis. Apoptin partially inhibited MCF-7 cell xenograft tumor development in vivo. Furthermore, we found via western blot that rApoptin-induced apoptosis in MCF-7 and MDA-MB-231 cells was associated with the phosphorylation of Nur77 (p-Nur77) and Akt (p-Akt). In addition, compared with the control groups, rApoptin-treated tissues showed significantly higher expression of Bax and Cyt c while Bcl-2 expression was decreased by rApoptin treatment. Together, our results are the first to demonstrate that rApoptin was able to effectively induce breast cancer cell apoptosis both in vitro and in vivo and that this activity could be regulated by the phosphorylation of Nur77 and Akt and the mitochondrial pathway. Our findings highlight the potential application of rApoptin as a breast cancer treatment. PMID- 29501490 TI - Physiological validation of photochemical reflectance index (PRI) as a photosynthetic parameter using Arabidopsis thaliana mutants. AB - Non-photochemical quenching (NPQ) is the most important photoprotective system in higher plants. NPQ can be divided into several steps according to the timescale of relaxation of chlorophyll fluorescence after reaching a steady state (i.e., the fast phase, qE; middle phase, qZ or qT; and slow phase, qI). The dissipation of excess energy as heat during the xanthophyll cycle, a large component of NPQ, is detectable during the fast to middle phase (sec to min). Although thermal dissipation is primarily investigated using indirect methods such as chlorophyll a fluorescence measurements, such analyses require dark adaptation or the application of a saturating pulse during measurement, making it difficult to continuously monitor this process. Here, we designed an unconventional technique for real-time monitoring of changes in thylakoid lumen pH (as reflected by changes in xanthophyll pigment content) based on the photochemical reflectance index (PRI), which we estimated by measuring light-driven leaf reflectance at 531 nm. We analyzed two Arabidopsis thaliana mutants, npq1 (unable to convert violaxanthin to zeaxanthin due to inhibited violaxanthin de-epoxidase [VDE] activity) and npq4 (lacking PsbS protein), to uncover the regulator of the PRI. The PRI was variable in wild-type and npq4 plants, but not in npq1, indicating that the PRI is related to xanthophyll cycle-dependent thermal energy quenching (qZ) rather than the linear electron transport rate or NPQ. In situ lumen pH substitution using a pH-controlled buffer solution caused a shift in PRI. These results suggest that the PRI reflects only xanthophyll cycle conversion and is therefore a useful parameter for monitoring thylakoid lumen pH (reflecting VDE activity) in vivo. PMID- 29501491 TI - Blockage of AKAP12 accelerates angiotensin II (Ang II)-induced cardiac injury in mice by regulating the transforming growth factor beta1 (TGF-beta1) pathway. AB - Hypertension is a multifactorial chronic inflammatory disease that leads to cardiac remodeling. A-kinase anchor protein 12 (AKAP12) is a scaffolding protein that has multiple functions in various biological events, including the regulation of vessel integrity and differentiation of neural barriers in blood. However, the role of AKAP12 in angiotensin II (Ang II)-induced cardiac injury remains unclear. In the present study, Ang II infusion reduced AKAP12 expressions in the hearts of wild-type (WT) mice, and AKAP12 knockout (KO) enhanced the infiltration of inflammatory cells. In addition, AKAP12 deletion accelerated Ang II-induced cardiac histologic alterations and dysfunction. Further, AKAP12-/- aggravated heart failure by promoting the inflammation, oxidative stress, cellular apoptosis, and autophagy induced by Ang II. Furthermore, AKAP12 KO elevated Ang II-induced cardiac fibrosis, as indicated by the following: (1) Masson trichrome staining showed that Ang II infusion markedly increased fibrotic areas of the WT mouse heart, which was greatly accelerated in AKAP12-/- mice; (2) immunohistochemistry analysis showed increased expression of transforming growth factor beta1 (TGF-beta1) and alpha-smooth muscle actin (alpha-SMA) in the AKAP12 /- mouse heart; (3) reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR) analysis showed increased expression of fibrosis-related molecules in the AKAP12-deficient mouse heart; and (4) Western blot analysis indicated significantly higher upregulation of p-SMAD2/3 in the AKAP12-/- mouse heart. In vitro, AKAP12 knockdown in HL-1 cells was responsible for TGF-beta1 induced inflammation, the generation of reactive oxygen species (ROS), apoptosis, autophagy, and fibrosis. Furthermore, overexpression of AKAP12 reduced fibrosis triggered by TGF-beta1 in cells. Overall, our study suggests that fibrosis induced by Ang II may be alleviated by AKAP12 expression through inactivation of the TGF-beta1 pathway. PMID- 29501492 TI - Mucus reduction promotes acetyl salicylic acid-induced small intestinal mucosal injury in rats. AB - BACKGROUND: Acetyl salicylic acid (ASA) is a useful drug for the secondary prevention of cerebro-cardiovascular diseases, but it has adverse effects on the small intestinal mucosa. The pathogenesis and prophylaxis of ASA-induced small intestinal injury remain unclear. In this study, we focused on the intestinal mucus, as the gastrointestinal tract is covered by mucus, which exhibits protective effects against various gastrointestinal diseases. MATERIALS AND METHODS: ASA was injected into the duodenum of rats, and small intestinal mucosal injury was evaluated using Evans blue dye. To investigate the importance of mucus, Polysorbate 80 (P80), an emulsifier, was used before ASA injection. In addition, rebamipide, a mucus secretion inducer in the small intestine, was used to suppress mucus reduction in the small intestine of P80-administered rats. RESULTS: The addition of P80 reduced the mucus and exacerbated the ASA-induced small intestinal mucosal injury. Rebamipide significantly suppressed P80-reduced small intestinal mucus and P80-increased intestinal mucosal lesions in ASA injected rats, demonstrating that mucus is important for the protection against ASA-induced small intestinal mucosal injury. These results provide new insight into the mechanism of ASA-induced small intestinal mucosal injury. CONCLUSION: Mucus secretion-increasing therapy might be useful in preventing ASA-induced small intestinal mucosal injury. PMID- 29501493 TI - Harmines inhibit cancer cell growth through coordinated activation of apoptosis and inhibition of autophagy. AB - Harmine and its analogs have long been considered as anticancer agents. In vitro analyses suggested that intercalating DNA or inhibiting topoisomerase might contribute to the cytotoxic effect of this class of compound. However, this idea has not been rigorously tested in intact cells. By synthesizing novel derivatives, here we demonstrate that harmines did not activate the DNA damage response, a cellular signaling commonly induced by agents that intercalate DNA or inhibit topoisomerase. These findings suggest that mechanisms other than DNA intercalating or topoisomerase inhibiting contribute to the toxicity of harmines in vivo. Using a novel N2-benzyl and N9-arylated alkyl compound 10f that has good solubility and stability as the model, we show that harmines strongly inhibited the growth of cancer cells originated from breast, lung, bone and pancreas, but not that of normal fibroblasts. We further show that 10f induced apoptosis and inhibited autophagy in a dose and time-dependent manner. An apoptosis inhibitor suppressed 10f-induced cell death. Together, our results reveal previously unidentified insights into the anticancer mechanism of harmines, supporting future development of this compound class in the treatment of human cancers. PMID- 29501494 TI - Hypoxia stimulates microenvironment in human embryonic stem cell through inflammatory signalling: An integrative analysis. AB - Despite, several lines of evidence suggesting the possible role of hypoxia in stem cell development and differentiation its significance in conferring the stemness and pluripotency remains elusive. In the present study we sought to delineate the candidate genes and molecular pathways imposed during hypoxic microenvironment and its physiological relevance in tipping the balance between the niche and cellular differentiation. Integrated meta-analysis was performed between the hypoxia exposed and normal human embryonic stem cells, employing three transcriptomic cohorts (GSE35819, GSE9510 and GSE37761) retrieved from Gene expression omnibus (GEO) database. Results reveal that a total number of 12 genes were consistently differentially expressed (6up regulated and 6 down regulated) with FDR <0.05 and fold change >1.5. The Gene Ontology (GO) functions and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis was performed using DAVID. The GO analysis showed DEG significantly enriched in terms of Cellular process (GO:0009987), protein binding (GO:0005515) and cell part (GO:0044464). KEGG analysis indicated participation of genes associated with circadian rthyum regulation and PPAR signalling pathway. Further, gene-set signature (MsigDB) enrichment analysis showed positive regulation with inflammatory signals and negative association with PPAR and p53 pathway. Protein-protein network of gene modules suggests significant hub proteins viz. CTTNB1 (Degree = 18), IL8 (Degree = 15), NFKB1 (Degree = 15) and RELA (Degree = 15) in the PPI network. MCODE algorithm was used for subnetworks of the PPI network. Our integrative analysis documents the potential candidate genes which serves distinct roles influencing metabolic shift and induce inflammatory effectors contributing to hypoxic mediated stem cell niche. PMID- 29501495 TI - PINK1-Parkin alleviates metabolic stress induced by obesity in adipose tissue and in 3T3-L1 preadipocytes. AB - Mitochondria play an important role in cellular metabolism and are closely related with metabolic stress. Recently, several studies have shown that mitophagy mediated by PTEN-induced putative kinase 1 (PINK1) and Parkin may play a critical role in clearing the damaged mitochondria and maintaining the overall balance of intracellular mitochondria in quality and quantity. A previous study showed that PINK1 and Parkin were overexpressed in adipose tissue in obese subjects. However, it is still unclear whether a direct relationship exists between obesity and mitophagy. In this study, we created a high-fat-diet (HFD) induced obese mouse model and examined the expression of PINK1 and Parkin in adipose tissue using western blot and real-time quantitative PCR. After we confirmed that there is an interesting difference between regular-chow-fed mice and HFD-induced obese mice in the expression of PINK1 and Parkin in vivo, we further tested the expression of PINK1 and Parkin in 3T3-L1 preadipocytes in vitro by treating cells with palmitic acid (PA) to induce metabolic stress. To better understand the role of PINK1 and Parkin in metabolic stress, 3T3-L1 preadipocytes were transfected with small interfering RNA (siRNA) of PINK1 and Parkin followed by PA treatment. Our results showed that under lower concentrations of PA, PINK1 and Parkin can be activated and play a protective role in resisting the harmful effects of PA, including protecting the mitochondrial function and resisting cellular death, while under higher concentrations of PA, the expression of PINK1 and Parkin can be inhibited. These results suggest that PINK1-Parkin can protect mitochondrial function against metabolic stress induced by obesity or PA to a certain degree. PMID- 29501496 TI - Stereoselective effects of lactate enantiomers on the enhancement of 3T3-L1 adipocyte differentiation. AB - Lactate contains a chiral carbon and thus has two optical isomers-d-lactate and l lactate. l-Lactate is the predominant form that is produced by the body and can be delivered to the organs. On the other hand, gut microbiota produce both isomers, which can then flow into the body. Although both d-lactate and l-lactate can contribute to energy metabolism, their potential roles in adipocyte differentiation remain to be elucidated. Here, we investigated the effects of l lactate and d-lactate on the differentiation of 3T3-L1 preadipocytes. Both lactate enantiomers were demonstrated to enhance triglyceride accumulation by stimulating the early phase of adipocyte differentiation. Notably, d-lactate was more potent than l-lactate in inducing triglyceride accumulation. The degree of triglyceride accumulation induced by l-lactate was similar to that induced by pyruvate. d-Lactate was more potent than l-lactate in increasing the activity of glycerol-3-phosphate dehydrogenase. Both lactate enantiomers did not affect cell viability. Moreover, both enantiomers upregulated the expression of peroxisome proliferator-activated receptor gamma, CCAAT/enhancer-binding protein (C/EBP) alpha, sterol regulatory element-binding protein-1c, and fatty acid synthase, with d-lactate exerting stronger effects than l-lactate. By contrast, lactate did not influence the expression of C/EBPbeta and C/EBPdelta. d-Lactate significantly increased and l-lactate tended to increase p38 MAPK phosphorylation, and the p38 MAPK inhibitor SB203580 inhibited the stimulation of adipocyte differentiation by d-lactate and l-lactate. These findings showed that both lactate enantiomers stimulate preadipocyte differentiation, with d-lactate showing more potent effects than l-lactate. In addition, our study demonstrated that d-lactate and l lactate exert different effects on physiological events. PMID- 29501497 TI - Is Routine Chest X-Ray After Ultrasound-Guided Central Venous Catheter Insertion Choosing Wisely?: A Population-Based Retrospective Study of 6,875 Patients. AB - BACKGROUND: A routine chest radiograph (CXR) is recommended as a screening test after central venous catheter (CVC) insertion. The goal of this study was to assess the value of a routine postprocedural CXR in the era of ultrasound-guided CVC insertion. METHODS: This population-based retrospective cohort study was performed to review the records of all adult patients who had a CVC inserted in the operating room in a tertiary institution between July 1, 2008, and December 31, 2015. We determined the incidence of pneumothorax and catheter misplacement after ultrasound-guided CVC insertion. A logistic regression analysis was performed to examine the potential risk factors associated with these complications, and a cost analysis was conducted to evaluate the economic impact. RESULTS: Of 18,274 patients who had a CVC inserted, 6,875 patients were included. The overall incidence of pneumothorax and catheter misplacement was 0.33% (95% CI, 0.22-0.5) (23 patients) and 1.91% (95% CI, 1.61-2.26) (131 patients), respectively. The site of catheterization was the major determinant of pneumothorax and catheter misplacement; left subclavian vein catheterization was the site at a higher risk for pneumothorax (OR, 6.69 [95% CI, 2.45-18.28]; P < .001), and catheterization sites other than the right internal jugular vein were at a higher risk for catheter misplacement. Expenditures on routine postprocedural CXR were US $105,000 to $183,000 per year at our institution. CONCLUSIONS: This study found that pneumothorax and catheter misplacement after ultrasound-guided CVC insertion were rare, and the costs of a postprocedural CXR were exceedingly high. We concluded that a routine postprocedural CXR is unnecessary and not a wise choice in our setting. PMID- 29501498 TI - Bacterial and fungal infections induce bursts of dopamine in the haemolymph of the Colorado potato beetle Leptinotarsa decemlineata and greater wax moth Galleria mellonella. AB - Dopamine (DA) is known as a hormone neurotrasnmitter molecule involved in several stress reactions in both vertebrates and invertebrates. Following infections with the fungi Metarhizium robertsii or Beauveria bassiana and the bacterium Bacillus thuringiensis, dopamine the concentration was measured at different time points in the haemolymph of the Colorado potato beetle, Leptinotarsa decemlineata and the larvae of the greater wax moth Galleria mellonella. The infection with M. robertsii increased (4 to 12-fold) DA concentrations in the haemolymph of the potato beetle larvae and the oral infection by B. thuringiensis also lead to a 30 and 45-fold increase. During infection of the greater wax moth larvae with Beauveria bassiana and B. thuringiensis DA increased 4 to 20-fold and about 2 to 2,5-fold respectively, compared to non-infected insects. The relative DA concentrations varied between the two insects and depended on the pathogens and post infection time. PMID- 29501499 TI - Assessing the health status of farmed mussels (Mytilus galloprovincialis) through histological, microbiological and biomarker analyses. AB - The Gulf of La Spezia (northern Tyrrhenian Sea, Italy) is a commercially important area both as a shipping port and for mussel farming. Recently, there has been increased concern over environmental disturbances caused by anthropogenic activities such as ship traffic and dredging and the effects they have on the health of farmed mussels. This paper reports the results of microbiological and histological analyses, as well as of measurement of several biomarkers which were performed to assess the health status of mussels (Mytilus galloprovincialis) from four rearing sites in the Gulf of La Spezia. Mussels were collected between October 2015 and September 2016 and histological analyses (including gonadal maturation stage), as well as the presence of pathogenic bacteria (Vibrio splendidus clade, V. aestuarianus and V. harveyi), viruses (Herpes virus and ostreid Herpes virus 1) and protozoa (Marteilia spp., in the summer season only) were carried out on a monthly basis. Conversely, biomarker responses in haemocyte/haemolymph (total haemocyte count, haemocyte diameter and volume, lysozyme and lactate dehydrogenase activities in cell-free haemolymph, and micronuclei frequency) and in gills and digestive gland (cortisol-like steroids and lipid peroxidation levels), were evaluated bimonthly. Microbiological data indicated that mussels contain a reservoir of potentially pathogenic bacteria, viruses and protozoa that in certain environmental conditions may cause a weakening of the immune system of animals leading to mortality episodes. The percentage of parasites detected in the mussels was generally low (9.6% for Steinhausia mytilovum, that is 17 samples out of 177 examined females; 3.4% for Proctoeces maculatus; 0.9% for Mytilicola intestinalis and 2% for ciliated protozoa), while symbiont loads were higher (31% for Eugymnanthea inquilina and Urastoma cyprinae). Interestingly, a previously undescribed haplosporidian was detected in a single mussel sample (0.2%) and was confirmed by in situ hybridization. Cells morphologically similar to Perkinsus sp. trophozoites were observed in 0.7% of the mussels analysed; however, infection with Perkinsus spp. could neither be confirmed by ISH nor by PCR. Different pathological aspects, such as host defence responses and regressive/progressive changes were detected in the gills, digestive glands, gonads and mantle. Only one single case of disseminated neoplasia (0.2%) was observed. As for the biomarker evaluation, the MANOVA analysis revealed the statistically significant effect that the variable "sampling site" had on the biological parameter measured, thus suggesting that the multibiomarker approach was able to differentiate the rearing sites. PMID- 29501500 TI - Assessment of oxytetracycline baths as therapeutic treatment for the control of the agent of withering syndrome (WS) in red abalone (Haliotis rufescens). AB - Withering Syndrome (WS) is a lethal disease that affects abalone species in both wild and farmed populations. This infection, caused by the rickettsial-like intracellular organism (RLO) Candidatus Xenohaliotis californiensis, can severely impair the normal development of affected animals, and ultimately, their survival. The most common line of action against the WS has been the use of antibiotics, specifically oxytetracycline (OTC), administered via intramuscular injection and per os via medicated feed. In the present study, we have assessed the effectiveness of OTC baths as therapeutic treatment for the control of the WS agent in H. rufescens. Clinical signs of infection were monitored for 11 months in treated juveniles, in addition to feed consumption rate, growth patterns and gonad development. Abalones were asymptomatic until the end of the experiment, when a small number of non-treated animals exhibited clinical signs of infection. Gonad maturity was not observed. OTC treated animals grew significantly less than their non-treated counterparts, being 4.3% shorter and 13.6% lighter at the end of the experiment. They also displayed negative allometry, i.e. for the same shell length, they were lighter than non-treated groups. Furthermore, the weight of muscle and soft tissues in OTC treated animals was lighter than in the other groups, while no differences were found in shell weight. The feed consumption rate was the same for all groups, thus the observed growth patterns cannot be attributed to a decreased feed intake. One possible explanation is that antibiotic treatment may have impacted gut microflora, thus preventing efficient nutrient digestion and absorption and, indirectly, reducing growth. Prevalence of RLOs causing WS (WS-RLO) and the variant form (RLOv), infected with a bacteriophague and non virulent, were significantly lower in the OTC-treated group than in the other groups. Similar results were observed for the mean intensity of RLOv, while for WS-RLO, the intensity in the OTC-treated group was higher, although not statistically significant, than the rest of the groups. These observations may be the consequence of an increased bacterial sensitivity to OTC effects associated with the phage infection or faster reproduction of WS RLOs than RLOv after OTC treatment. Our results let us infer that the prophylactic use of OTC in abalone to avoid the negative effects of WS on abalone farms could have an undesired negative effect on the biological control exerted by the phage on the bacteria after OTC treatment. PMID- 29501501 TI - Artificial Intelligence in Health Care: Brave New World or Golden Opportunity? PMID- 29501502 TI - Discrepancies in Radiograph Interpretation Between Pediatric Radiologists and Pediatric Intensivists in the Pediatric or Neonatal Intensive Care Unit. AB - BACKGROUND: In pediatric intensive care units (PICUs) and neonatal intensive care units (NICUs), patient management decisions are sometimes based on preliminary interpretations of radiographs by pediatric intensivists (PIs) before a formal interpretation by a pediatric radiologist (PR). OBJECTIVE: To quantify and classify discrepancies in radiographic interpretation between PRs and PIs in the PICU and NICU. MATERIALS AND METHODS: This institutional review board-approved multi-institutional prospective study included three PRs and PIs at two PICUs and three NICUs. Interpretations of chest and abdominal radiographs by PIs and PRs were recorded on online forms and compared. Discrepancies in interpretations were classified as "miss," "misinterpretation," or "overcall." The discrepancies were also categorized as "actionable" or "nonactionable" based on extrapolation of the ACR actionable reporting work group's list of actionable findings. RESULTS: In 960 radiographic interpretations, the total, nonactionable, and actionable discrepancy rates between PRs and PIs were 34.7%, 26.8%, and 7.9%, respectively. The most common actionable discrepancies were line or tube positions and identification and interpretation of parenchymal opacities in the lungs. Identification of air leaks in the PICU and differentiation of normal from abnormal bowel gas patterns in the NICU followed in frequency. Air leaks accounted for 1% of total discrepancies and 11% of actionable discrepancies. Most discrepancies were nonactionable and included retrocardiac atelectasis and mischaracterization of neonatal lung disease in the PICU and NICU, respectively. CONCLUSION: Although the total discrepancy rate was high, most discrepancies were nonactionable. Actionable discrepancies were predominantly due to line and tube position, which should be an area of focused education. PMID- 29501503 TI - The Potential Cost of Patient Satisfaction: A Mammography Experience. PMID- 29501504 TI - Availability and Location of Cardiac CT and MR Services in Massachusetts. PMID- 29501505 TI - Disruption of adult olfactory neurogenesis induces deficits in maternal behavior in sheep. AB - Profound behavioral changes occur in the mother at parturition, a time when the maternal brain undergoes extensive remodeling of neural circuits, especially in olfactory structures. Adult neurogenesis, a form of brain plasticity, could constitute an adaptive response to motherhood. The present study hypothesized that chemical disruption of olfactory neurogenesis would impair the establishment of maternal behavior in sheep. In addition, because ewes are able to learn the olfactory signature of their offspring, we also examined whether disruption of olfactory neurogenesis altered recognition of the familiar lamb. At one month of gestation, ewes received either infusion of the antimitotic drug Ara-C or saline into the lateral ventricles via one-month-long osmotic minipumps. Ara-C infusion dramatically decreased olfactory neurogenesis but spared hippocampal neurogenesis. Mothers exhibiting more than a 70% reduction in olfactory neurogenesis emitted fewer maternal bleats during the first hours after parturition. Reduction of olfactory neurogenesis also negatively affected discrimination of the familiar lamb. Differences in ewes' aggressive behavior toward familiar and alien lambs were observed in sham mothers, but not in mothers with reduced olfactory neurogenesis. In addition, when ewes were given the choice between familiar and unfamiliar anesthetized lambs, so that only olfactory cues were available, mothers with a reduction in neurogenesis greater than 70% were not able to discriminate their own lamb from an alien lamb. These results indicate that adult-born olfactory neurons are to some extent involved in the establishment of maternal behavior in sheep by contributing to the processing of offspring odors. PMID- 29501506 TI - Do TRPC channels support working memory? Comparing modulations of TRPC channels and working memory through G-protein coupled receptors and neuromodulators. AB - Working memory is a crucial ability we use in daily life. However, the cellular mechanisms supporting working memory still remain largely unclear. A key component of working memory is persistent neural firing which is believed to serve short-term (hundreds of milliseconds up to tens of seconds) maintenance of necessary information. In this review, we will focus on the role of transient receptor potential canonical (TRPC) channels as a mechanism underlying persistent firing. Many years of in vitro work have been suggesting a crucial role of TRPC channels in working memory and temporal association tasks. If TRPC channels are indeed a central mechanism for working memory, manipulations which impair or facilitate working memory should have a similar effect on TRPC channel modulation. However, modulations of working memory and TRPC channels were never systematically compared, and it remains unanswered whether TRPC channels indeed contribute to working memory in vivo or not. In this article, we review the effects of G-protein coupled receptors (GPCR) and neuromodulators, including acetylcholine, noradrenalin, serotonin and dopamine, on working memory and TRPC channels. Based on comparisons, we argue that GPCR and downstream signaling pathways that activate TRPC, generally support working memory, while those that suppress TRPC channels impair it. However, depending on the channel types, areas, and systems tested, this is not the case in all studies. Further work to clarify involvement of specific TRPC channels in working memory tasks and how they are affected by neuromodulators is still necessary in the future. PMID- 29501507 TI - Early social experience alters transcriptomic responses to species-specific song stimuli in female songbirds. AB - Amongst an array of stimuli from countless species, animals must recognize salient signals, including those of their own species. In songbirds, behavioral tests have demonstrated that preferences for conspecific male songs are determined by both preexisting biases and social experience with a male 'tutor' during the sensitive period for learning. Although immediate early gene expression (e.g. ZENK) and electrophysiological experiments generally find greater neural responses for conspecific songs, it remains unclear whether distinct mechanisms, such as sensory gating, are engaged to filter out irrelevant heterospecific songs. Here we compare the transcriptomic profiles, via RNA-seq, of non-singing females of a songbird, the zebra finch (Taeniopygia guttata), by focusing on the auditory forebrain, a region known to be critical in the processing of conspecific vs. heterospecific songs. Gene expression profiles demonstrate that different neural mechanisms are involved in the processing of conspecific versus heterospecific Bengalese finch (Lonchura striata) songs. In particular, one gene known to mediate sensory gating, the alpha 3 subunit member of nicotinic cholinergic receptors (CHRNA3), was significantly downregulated in response to hearing Bengalese finch song, but not when young females were tutored by a Bengalese male during early development. Overall, our results confirm previous behavioral and physiological studies, such that heterospecific-tutored individuals processed both conspecific and tutor songs similarly. Using transcriptomic profiling of peripheral blood samples, we also demonstrate the methodological potential of non-terminal sampling to identify transcriptomic biomarkers for conspecific auditory recognition. These results show how experience and inherited preferences facilitate the neural processing of salient songs by female songbirds. PMID- 29501508 TI - Neuroprotective effect of monophosphoryl lipid A, a detoxified lipid A derivative, in photothrombotic model of unilateral selective hippocampal ischemia in rat. AB - Finding a neuroprotective strategy to rescue patients suffering from acute brain damage is of great interest. Monophosphoryl lipid A (MPL) is a derivative of lipopolysaccharide (LPS) that lacks many of the endotoxic properties of the parent molecule, and yet has similar protective effect. Here, we report the first evidence that MPL preconditioning, similar to LPS preconditioning, can induce neuroprotection against cerebral ischemia. MPL (0.5, 1, 5 MUg/rat) was injected unilaterally into the left cerebral ventricle of male rats, and 48 h later, rats were subjected to ipsilateral selective hippocampal ischemia using a modified version of the photothrombotic method. The neuroprotective effects of MPL and LPS were evaluated by measuring infarct size and assessing cognitive function. The expression level of some inflammatory and anti-inflammatory cytokines involving in TLR4 signaling pathway was also measured. Cognitive impairment and infarct size were obvious in control group receiving normal saline intracerebroventricularly and then selective hippocampal ischemia, compared to the sham group. Immunologic preconditioning with MPL or LPS significantly reduced infarct size and improved cognitive function. Additionally, immunologic preconditioning resulted in inflammatory mediators, NF-kappaB and TNF-alpha, down regulation but anti-inflammatory mediators, IRF3, IFN-beta, and TGF-beta, up regulation. Our data showed that both MPL and LPS preconditioning may reprogram the TLR4 signaling pathway to produce a cytokine profile which eventually leads to neuroprotection against ischemia injury. MPL, unlike LPS, is safe and well tolerated in clinic, thus it could be considered as a new approach in prevention or even treatment of cerebral ischemic insult consequences. PMID- 29501509 TI - Enhanced cholinergic-tone during the stress induce a depressive-like state in mice. AB - Major depressive disorder has a heterogeneous etiology, since it arises from the interaction of multiple factors and different pathophysiological mechanisms are involved in the symptomatology. This study aimed to investigate the role of the cholinergic system in the susceptibility to stress and, consequently, in the depression-like behavior. C57BL/6 mice were treated with Physostigmine (PHYS), an acetylcholinesterase (AChE) inhibitor, and were submitted to the social defeat stress. For the behavioral evaluation of the locomotor activity, anxiety-like and depression-like behaviors the open field, elevated plus maze, sucrose preference, social interaction and forced swim were used. Hippocampus and prefrontal cortex samples were collected for evaluation of AChE activity, as well as blood samples for analysis of serum cortisol levels. Our results showed that 15 min after the injection of PHYS there was a significant inhibition of AChE activity in the hippocampus and in the prefrontal cortex. On the other hand, in the end of the experimental design, day 12, there was no difference in AChE activity levels. Inhibition of AChE and exposure to the stress led to an increase in cortisol levels. Animals that received PHYS and were exposed to stress showed less social interaction and greater learned helplessness, anhedonia and anxious-like behavior. Taken together, our findings suggest that increasing the cholinergic tone shortly before stress induction impacts on the ability to cope with upcoming stressful situations, leading to a depressive-like state. PMID- 29501511 TI - [Intermittent thoracic pain]. PMID- 29501510 TI - Glycosaminoglycan synthesis in the nucleus pulposus: Dysregulation and the pathogenesis of disc degeneration. AB - Few human tissues have functions as closely linked to the composition of their extracellular matrices as the intervertebral disc. In fact, the hallmark of intervertebral disc degeneration, commonly accompanying low back and neck pain, is the progressive loss of extracellular matrix molecules - specifically the GAG substituted proteoglycans. While this loss is often associated with increased extracellular catabolism via metalloproteinases and pro-inflammatory cytokines, there is strong evidence that disc degeneration is related to dysregulation of the enzymes involved in GAG biosynthesis. In this review, we discuss those environmental factors, unique to the disc, that control expression and function of XT-1, GlcAT-I, and ChSy/ChPF in the healthy and degenerative state. Additionally, we address the pathophysiology of aberrant GAG biosynthesis and highlight therapeutic strategies designed to augment the loss of extracellular matrix molecules that afflict the degenerative state. PMID- 29501512 TI - [Clinical overview of auto-inflammatory diseases]. AB - Monogenic auto-inflammatory diseases are characterized by genetic abnormalities coding for proteins involved in innate immunity. They were initially described in mirror with auto-immune diseases because of the absence of circulating autoantibodies. Their main feature is the presence of peripheral blood inflammation in crisis without infection. The best-known auto-inflammatory diseases are mediated by interleukines that consisted in the 4 following diseases familial Mediterranean fever, cryopyrinopathies, TNFRSF1A-related intermittent fever, and mevalonate kinase deficiency. Since 10 years, many other diseases have been discovered, especially thanks to the progress in genetics. In this review, we propose the actual panorama of the main known auto-inflammatory diseases. Some of them are recurrent fevers with crisis and remission; some others evaluate more chronically; some are associated with immunodeficiency. From a physiopathological point of view, we can separate diseases mediated by interleukine-1 and diseases mediated by interferon. Then some polygenic inflammatory diseases will be shortly described: Still disease, Schnitzler syndrome, aseptic abscesses syndrome. The diagnosis of auto-inflammatory disease is largely based on anamnesis, the presence of peripheral inflammation during attacks and genetic analysis, which are more and more performant. PMID- 29501513 TI - [Rosai-Dorfman disease: Diagnosis and therapeutic challenges]. AB - Rosai-Dorfman disease (RDD) was first described by the French pathologist Paul Destombes in 1965. It frequently affects children or young adults and is characterized by the presence of large histiocytes with emperipolesis. More than 50 years after this first description, the pathogenesis of this rare disease is still poorly understood. The revised classification of histiocytoses published in 2016 identified various forms of RDD, from familial RDD to IgG4-associated RDD. Almost 90% of the patients with RDD have cervical lymph nodes involvement although all the organs may virtually be involved. Outcomes are typically favorable. Treatments may be necessary in case of compression or obstruction, and are not well codified. The main therapeutic strategies rely on surgery, radiotherapy, steroids, immunosuppressive drugs or interferon-alpha and cladribine. PMID- 29501514 TI - Anatomy of the Limbic White Matter Tracts as Revealed by Fiber Dissection and Tractography. AB - BACKGROUND: The limbic tracts are involved in crucial cerebral functions such as memory, emotion, and behavior. The complex architecture of the limbic circuit makes it harder to approach compared with other white matter networks. Our study aims to describe the 3-dimensional anatomy of the limbic white matter by the use of 2 complementary study methods, namely ex vivo fiber dissection and in vivo magnetic resonance imaging-based tractography. METHODS: Three fiber dissection protocols were performed using blunt wooden instruments and a surgical microscope on formalin-fixed brains prepared according to the Klingler method. Diffusion tensor imaging acquisitions were done with a 3-Tesla magnetic resonance scanner on patients with head and neck pathology that did not involve the brain. Fiber tracking was performed with manually selected regions of interest. RESULTS: Cingulum, fornix, the anterior thalamic peduncle, the accumbofrontal bundle, medial forebrain bundle, the uncinate fasciculus, the mammillothalamic tract, ansa peduncularis, and stria terminalis were dissected and fiber tracked. For each tract, location, configuration, segmentation, dimensions, dissection and tractography particularities, anatomical relations, and terminations are described. The limbic white matter tracts were systematized as 2 concentric rings around the thalamus. The inner ring is formed by fornix, mammillothalamic tract, ansa peduncularis, stria terminalis, accumbofrontal fasciculus, and medial forebrain bundle and anterior thalamic peduncle, and the outer ring is formed by the cingulum and uncinate fasciculus. CONCLUSIONS: This paper proposes a fiber tracking protocol for the limbic tracts inspired and validated by fiber dissection findings that can be used routinely in the clinical practice. PMID- 29501515 TI - Value of Ventricular Intracranial Pressure Monitoring for Traumatic Bifrontal Contusions. AB - OBJECTIVE: To investigate clinical efficacy of and optimal therapeutic strategy for ventricular intracranial pressure monitoring (V-ICPM) in patients with traumatic bifrontal contusions (TBCs). METHODS: From 8760 patients with traumatic brain injury treated between January 2010 and January 2016, a retrospective analysis was performed on 105 patients with TBCs who underwent V-ICPM and 282 patients with TBCs who did not. All patients underwent treatment at the 101st Hospital of PLA, Wuxi, China. Rates of successful conservative treatment, decompressive craniectomy, and bifrontal craniotomy; incidence of neurologic dysfunction; length of stay; and medical expenses were compared between groups. RESULTS: Glasgow Outcome Scale was used to assess all patients during follow-up (range, 6 months to 5.5 years). There were no significant differences in prognosis between the 2 groups (P = 0.100). Compared with the patients who did not undergo V-ICPM, the V-ICPM group had a significantly better successful conservative treatment rate (64.8% vs. 47.2%, P = 0.002), decompressive craniectomy rate (8.1% vs. 22.1%, P = 0.008), and bifrontal craniotomy rate (5.7% vs. 15.6%, P = 0.01); shorter length of stay (P = 0.000); and lower medical expenses (P = 0.004). CONCLUSIONS: Patients with TBCs should be strictly, closely, and dynamically observed by neurosurgery intensive care unit physicians and nurses. Patients should undergo ventricular intracranial pressure probe implantation in a timely manner. V-ICPM can help optimize treatment. Although V ICPM did not significantly improve the prognosis of patients, it had many other advantages. V-ICPM warrants further clinical research and may be beneficial for patients with TBCs. PMID- 29501516 TI - Plurihormonal ACTH-GH Pituitary Adenoma: Case Report and Systematic Literature Review. AB - BACKGROUND: Plurihormonal adenomas (PHAs) represent 10%-15% of all functioning pituitary adenomas. The most frequent hormonal associations are with prolactin and growth hormone (GH). Here we describe a rare case of functional adrenocorticotropic hormone (ACTH) and GH microadenoma and report our findings from a systematic literature review of PHA. METHODS: We searched PubMed using the terms "plurihormonal pituitary adenoma," "ACTH GH pituitary adenoma," and "acromegaly AND Cushing's disease". In the 17 articles that were selected for literature review, only 20% (4/20) of patients presented with clinical signs of both diseases. Histologically, 19 were pituitary adenomas composed of two distinct cell populations, while only in 1 case was there evidence of a single cell producing both ACTH and GH. In the case reported here, a 60-year-old woman was incidentally diagnosed with a pituitary microadenoma. Endocrine assessment documented increased levels of insulin-like growth factor 1 and GH; ACTH and cortisol values were within normal ranges. Echocardiography documented ventricular hypertrophy. Because of clinical and biochemical evidence of acromegaly, surgery was recommended. Postoperatively, hormonal replacement therapy was started because of adrenal insufficiency. Her antihypertensive therapy was discontinued due to evidence of normal blood pressure values. Histological examination revealed an ACTH-GH PHA with 2 distinct populations of secreting cells. At 3-year follow-up, the patient showed stable clinical remission and was no longer receiving hormonal replacement therapy. CONCLUSIONS: This is an additional case to the 20 previously reported cases of ACTH-GH PHA. Awareness of this relatively rare entity is clinically relevant. The cytogenesis of ACTH-GH PHA remains a matter of debate, and several hypotheses have been postulated. PMID- 29501517 TI - Intraoperative Hypoglossal Nerve Mapping During Carotid Endarterectomy: Technical Note. AB - BACKGROUND: Hypoglossal nerve deficit is a possible complication caused by carotid endarterectomy (CEA). The accidental injury of the hypoglossal nerve during surgery is one of the major reasons for permanent hypoglossal nerve palsy. In this study, we investigated the usefulness of intraoperative mapping of the hypoglossal nerve to identify this nerve during CEA. METHODS: Five consecutive patients who underwent CEA for the treatment of symptomatic or asymptomatic carotid artery stenosis were studied. A hand-held probe was used to detect the hypoglossal nerve in the operative field, and the tongue motor evoked potentials (MEPs) were recorded. RESULTS: The tongue MEPs were obtained in all the patients. The invisible hypoglossal nerve was successfully identified without any difficulty when the internal carotid artery was exposed. Intraoperative mapping was particularly useful for identifying the hypoglossal nerve when the hypoglossal nerve passed beneath the posterior belly of the digastric muscle. In 1 of 2 cases, MEP was also elicited when the ansa cervicalis was stimulated, although the resulting amplitude was much smaller than that obtained by direct stimulation of the hypoglossal nerve. Postoperatively, none of the patients presented with hypoglossal nerve palsy. CONCLUSIONS: Intraoperative hypoglossal nerve mapping enabled us to locate the invisible hypoglossal nerve during the exposure of the internal carotid artery accurately without retracting the posterior belly of the digastric muscle and other tissues in the vicinity of the internal carotid artery. PMID- 29501518 TI - Variability in Treatment for Patients with Cervical Spine Fracture and Dislocation: An Analysis of 107,152 Patients. AB - BACKGROUND: Cervical spine injuries are a common cause of morbidity and mortality; however, the optimal treatment of many of these injuries is debated, and previous studies have shown substantial variation in treatment. We sought to examined treatment variation in arthrodesis and halo/tong placement in cervical spine injury patients over a 12-year period. METHODS: Data from the Healthcare Cost and Utilization Project National Inpatient Sample, from 2000 to 2011, were used for this study. Patients were identified with a cervical vertebral facture or dislocation based on the International Classification of Diseases, 9th Revision codes. Using chi2 analysis, spinal arthrodesis rates and halo/tong placement rates were compared between hospitals based on teaching status for patients with and without spinal cord injury (SCI). RESULTS: The records of 107,152 patients with cervical fractures were examined. From 2000 to 2011, the overall arthrodesis rates fell from 25.2% to 20.6% (P < 0.001), and halo/tong placement rates fell from 13.2% to 3.6% (P < 0.001). In patients with cervical fracture without SCI, arthrodesis rates fell from 17.6% to 13.9% (P < 0.001), in cervical fracture patients with SCI, arthrodesis rates rose from 50.0% to 58.9% (P < 0.001), and in cervical dislocation patients, arthrodesis rates rose from 47.6% to 57.5% (P < 0.001). During the 12-year period, teaching hospitals had higher arthrodesis rates compared with nonteaching hospitals for patients with cervical fractures with SCI (57.3% vs. 53.4%, P = 0.001) and higher halo/tong placement rates for patients with cervical dislocations (2.7% vs. 1.7%, P = 0.004). Individual hospital variation showed a 3.5-fold variation in arthrodesis rates in 2000 to 2002, which fell to 3.0-fold by 2009 to 2011. CONCLUSIONS: Arthrodesis rates for cervical fracture patients significantly decreased, and arthrodesis rates for cervical dislocation and SCI patients increased from 2000 to 2011, with variability in treatment based on hospital teaching status. Rates of halo/tong placement rapidly decreased for cervical spine trauma at both teaching and nonteaching hospitals. Individual hospital treatment variation also decreased over the study period. Further clinical studies examining the optimal treatment for spine trauma may lead to continued decreases in treatment variability. PMID- 29501519 TI - A retrospective analysis of mepolizumab in subjects with aspirin-exacerbated respiratory disease. PMID- 29501521 TI - Corrigendum to "Transient postictal MRI changes in patients with brain tumors may mimic disease progression" [Surgical Neurology* 67 (2007) 246-250]. PMID- 29501520 TI - The Frequency and Clinical Features of Hypersensitivity Reactions to Antiepileptic Drugs in Children: A Prospective Study. AB - BACKGROUND: Antiepileptic drugs (AEDs) can cause hypersensitivity reactions during childhood. Studies report a wide clinical spectrum of reactions with AED use, ranging from a mild rash to severe cutaneous reactions. OBJECTIVE: To determine the prevalence and clinical features of AED hypersensitivity reactions during childhood. METHODS: Patients in our pediatric neurology clinic who were prescribed an AED for the first time between November 2015 and November 2016 were monitored and those who developed skin rash during this period were evaluated. RESULTS: A total of 570 patients were evaluated. The median age of the patients was 8.86 (interquartile range, 4.2-13.7) years, and 55.8% (318) of patients were male. The most frequently used AEDs were valproic acid (42%, n = 285) and carbamazepine (20.4%, n = 116). Hypersensitivity reactions to AEDs developed in 5.4% of patients. Of these patients, 71% (29) had cutaneous drug reactions and 29% (9) had severe cutaneous drug reactions; 61.3% (19) were using aromatic AEDs, and the leading suspected AED was carbamazepine (45.2%). Comparison of patients who did and did not develop AED hypersensitivity showed that hypersensitivity was more frequent among patients who were younger than 12 years, who used aromatic AEDs, or who used multiple AEDs. In addition, according to regression analysis results, aromatic AED use significantly increased the risk of AED hypersensitivity (P < .001). CONCLUSIONS: Although allergic reactions to AEDs are rare, they are of significance because they can cause life-threatening severe cutaneous drug reactions. Therefore, patients receiving AEDs, especially aromatic AEDs, must be monitored closely. PMID- 29501522 TI - Combined treatment with melatonin and insulin improves glycemic control, white adipose tissue metabolism and reproductive axis of diabetic male rats. AB - AIMS: Melatonin treatment has been reported to be capable of ameliorating metabolic diabetes-related abnormalities but also to cause hypogonadism in rats. We investigated whether the combined treatment with melatonin and insulin can improve insulin resistance and other metabolic disorders in rats with streptozotocin-induced diabetes during neonatal period and the repercussion of this treatment on the hypothalamic-pituitary-gonadal axis. MAIN METHODS: At the fourth week of age, diabetic animals started an 8-wk treatment with only melatonin (0.2 mg/kg body weight) added to drinking water at night or associated with insulin (NHP, 1.5 U/100 g/day) or only insulin. Animals were then euthanized, and the subcutaneous (SC), epididymal (EP), and retroperitoneal (RP) fat pads were excised, weighed and processed for adipocyte isolation for morphometric analysis as well as for measuring glucose uptake, oxidation, and incorporation of glucose into lipids. Hypothalamus was collected for gene expression and blood samples were collected for biochemical assays. KEY FINDINGS: The treatment with melatonin plus insulin (MI) was capable of maintaining glycemic control. In epididymal (EP) and subcutaneous (SC) adipocytes, the melatonin plus insulin (MI) treatment group recovered the insulin responsiveness. In the hypothalamus, melatonin treatment alone promoted a significant reduction in kisspeptin-1, neurokinin B and androgen receptor mRNA levels, in relation to control group. SIGNIFICANCE: Combined treatment with melatonin and insulin promoted a better glycemic control, improving insulin sensitivity in white adipose tissue (WAT). Indeed, melatonin treatment reduced hypothalamic genes related to reproductive function. PMID- 29501523 TI - The effect of intrathecal injection of irisin on pain threshold and expression rate of GABAB receptors in peripheral neuropathic pain model. AB - BACKGROUND: and aim: Irisin is a new myokine that is secreted by myocytes during exercise, and plays a role in creating the beneficial effects of exercise on metabolism. Considering the benefits of exercise in reducing pain, this study was carried out to determine the probable effect of irisin on neuropathic pain in the chronic constriction injury (CCI) model in male rats. METHODS: To induce neuropathic pain CCI model was used. Animals were divided into groups of control, CCI, sham, CCI + vehicle, and CCI + irisin. Animals that had undergone CCI were divided into 6 groups and each received a different intrathecal dose of irisin (30, 10, 3, 1, 0.3, and 0.1 MUg/kg) via intrathecal administration. To evaluate the chronic effect of irisin, its effective dose was injected for 14 days in another group of animals. At the end of the experiment, animals were ranscardially perfused and their spinal cord tissue was prepared for immunohistochemical and hematoxylin-eosin staining. RESULTS: The results showed that in acute intrathecal injection of irisin, 1 MUg/kg dose has the highest analgesic effect compared to other doses. Nevertheless, in chronic administration of irisin with 1 MUg/kg dose, no analgesic effect was detected. In addition, irisin administration could not increase the expression level of GABAB1 and B2 or prevent the decline in the number of neurons. CONCLUSION: The findings of the present study showed that acute administration of Irisin increases the pain threshold, but the chronic injection of resin does not have an effect on pain reduction and the expression of GABA receptors and it seems that this peptide is not a proper replacement for exercise in patients with neuropathic pain, who cannot exercise. PMID- 29501524 TI - Effect of intermittent opening of breathable culture plugs and aeration of headspace on the structure of microbial communities in shake-flask culture. AB - In this study, we found that opening breathable culture plugs for 30 s during periodic and aseptic sampling affects the community structure of cultured soil microbes. Similar effects were observed using an automatic aeration flask system that mimics aseptic opening of the breathable culture plug during sampling, but without interruption in shaking. Thus, the observed changes in the microbial consortia appear to be due exclusively to the intermittent ventilation of the flask headspace. To elucidate the mechanism driving this phenomenon, we monitored CO2 and O2 concentrations in both headspace and culture broth using the new system termed as circulation direct monitoring and sampling system. The data show that the CO2 concentration in the culture broth temporarily decreased with the CO2 concentration in the headspace, strongly suggesting that the effect of intermittent ventilation of the headspace on the microbial consortia depends on CO2. Importantly, the data also imply that environmental variables during shake flask culture, especially CO2 concentration, is important for screening aerobic microorganisms. PMID- 29501525 TI - Hippocampal plasticity mechanisms mediating experience-dependent learning change over time. AB - The requirement of NMDA receptor (NMDAR) activity for memory formation is well described. However, the plasticity mechanisms for memory can be modified by experience, such that a future similar learning becomes independent of NMDARs. This effect has often been reported in learning events conducted with a few days interval. In this work, we asked whether the NMDAR-independency is permanent or the brain regions and plasticity mechanisms of experience-dependent learning may change over time. Considering that contextual memories undergo a gradual reorganization over time, becoming progressively independent from the hippocampus and dependent upon cortical regions, we investigated the brain regions mediating a new related learning conducted at a remote time-point, when the first memory was already cortically established. First, we demonstrated that anterior cingulate cortex was not able to support a learning subsequent to a previous systems-level consolidated memory; it did require at least one functional subregion of the hippocampus (ventral or dorsal). Moreover, after replicating findings showing that a few days interval between trainings induces a NMDAR independent learning, we managed to show that a learning following a longer interval once again becomes dependent on NMDARs in the hippocampus. These findings suggest that while the previous memory grows independent from the hippocampus over time, an experience-dependent learning following a systems consolidated memory once again engages the hippocampus and a NMDAR-dependent plasticity mechanism. PMID- 29501526 TI - Corrigendum to "Convergence of hepcidin deficiency, systemic iron overloading, heme accumulation, and REV-ERBalpha/beta activation in aryl hydrocarbon receptor elicited hepatotoxicity" [Toxicol. Appl. Pharmacol. 321 (2017) 1-17]. PMID- 29501527 TI - Retigabine ameliorates acute stress-induced impairment of spatial memory retrieval through regulating USP2 signaling pathways in hippocampal CA1 area. AB - Acute stress could trigger maladaptive changes associated with stress-related cognitive and emotional deficits. Dysfunction of ion channel or receptor in the hippocampal area has been linked to the cognitive deficits induced by stress. It is known that Kv7 channel openers, including FDA-approved drug retigabine, show cognitive protective efficacy. However, the underlying molecular mechanisms remain elusive. Here we showed that exposing adult male rats to acute stress significantly impaired the spatial memory, a cognitive process controlled by the hippocampus. Concomitantly, significantly reduced AMPA receptor expression was found in hippocampal CA1 area from acute stressed rats. This effect relied on the down-regulation of deubiquitinating enzyme USP2 and its upstream regulators (PGC 1alpha and beta-catenin), and the subsequent enhancement of mTOR-related autophagy which is regulated by USP2. These findings suggested that acute stress dampened AMPA receptor expression by controlling USP2-related signaling, which caused the detrimental effect on hippocampus-dependent cognitive processes. We also found that retigabine alleviated acute stress-induced spatial memory retrieval impairment through adjusting the aberrance of USP2, its upstream regulators (PGC-1alpha, E4BP4 and beta-catenin) and its downstream targets (mTOR, autophagy and GluA1). Our results have identified USP2 as a key molecule that mediates stress-induced spatial memory retrieval impairment, which provides a framework for new druggable targets to conceptually treat stress-associated cognitive deficits. PMID- 29501529 TI - Prevalence, antimicrobial resistance and virulence genes of Escherichia coli isolated from retail meat in Tamaulipas, Mexico. AB - OBJECTIVES: The aim of this study was to determinate the prevalence of Escherichia coli and its resistance to antimicrobials and the presence of virulence genes in retail samples of beef and pork in several locations in Tamaulipas, Mexico. METHODS: A total of 106 samples (54 beef and 52 pork) collected from August 2013 to March 2014 were analysed to detect E. coli isolates. The E. coli isolates were then analysed for detection of virulence factors and antimicrobial resistance genes. Antimicrobial susceptibility to 16 antimicrobial agents was also determined. RESULTS: A total of 158 E. coli isolates were obtained, among which 3 (1.9%) harboured the virulence gene stx1, 28 (17.7%) harboured stx2 and 34 (21.5%) harboured hlyA. High phenotypic resistance was observed in almost all isolates, since 146 (92.4%) showed a multiresistant phenotype with resistance to cefalotin (92%), ampicillin (92%), cefotaxime (78%), nitrofurantoin (76%) and tetracycline (75%). The antimicrobial resistance genes tet(A) and tet(B) were detected in 56% of isolates, strA in 9.6%, aadA in 17% and aac(3)-IV in only 0.6% of strains. CONCLUSIONS: Based on these results, it can be concluded that retail beef and pork meat may play a role in the spread of antimicrobial-resistant E. coli strains in this region. PMID- 29501528 TI - Comparative neuropharmacology of N-(2-methoxybenzyl)-2,5-dimethoxyphenethylamine (NBOMe) hallucinogens and their 2C counterparts in male rats. AB - 2,5-Dimethoxyphenethylamines (2C compounds) are 5-HT2A/2C receptor agonists that induce hallucinogenic effects. N-methoxybenzylation of 2C compounds markedly increases their affinity for 5-HT2A receptors, and two such analogs, 2-(4-chloro 2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25C-NBOMe) and 2-(4 iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25I-NBOMe), have emerged in recreational drug markets. Here, we investigated the neuropharmacology of 25C-NBOMe and 25I-NBOMe in rats, as compared to their 2C analogs and the prototypical 5-HT2A/2C agonist 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine (DOI). Compounds were tested in vitro using 5-HT2A receptor binding and calcium mobilization assays. For in vivo experiments, 25C-NBOMe (0.01-0.3 mg/kg), 25I NBOMe (0.01-0.3 mg/kg), 2-(4-chloro-2,5-dimethoxyphenyl)ethanamine (2C-C) (0.1 3.0 mg/kg), 2-(4-iodo-2,5-dimethoxyphenyl)ethanamine (2C-I) (0.1-3.0 mg/kg) and DOI (0.03-1.0 mg/kg) were administered subcutaneously (sc) to male rats, and 5 HT2A-mediated behaviors were assessed. NBOMes displayed higher affinity for 5 HT2A receptors than their 2C counterparts but were substantially weaker in functional assays. 25C-NBOMe and 25I-NBOMe were much more potent at inducing wet dog shakes (WDS) and back muscle contractions (BMC) when compared to 2C-C and 2C I. Pretreatment with the selective 5-HT2A antagonist (R)-(2,3-dimethoxyphenyl){1 [2-(4-fluorophenyl)ethyl]-4-piperidinyl}methanol (M100907) reversed behaviors produced by all agonists. Interestingly, binding affinities at the 5-HT2A receptor were significantly correlated with potencies to induce BMC but not WDS. Our findings show that NBOMes are highly potent 5-HT2A agonists in rats, similar to effects in mice, and consistent with the reported hallucinogenic effects in human users. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'. PMID- 29501530 TI - Neuronal pentraxin 1: A synaptic-derived plasma biomarker in Alzheimer's disease. AB - Synaptic neurodegeneration is thought to be an early event initiated by soluble beta-amyloid (Abeta) aggregates that closely correlates with cognitive decline in Alzheimer disease (AD). Apolipoprotein epsilon4 (APOE4) is the most common genetic risk factor for both familial AD (FAD) and sporadic AD; it accelerates Abeta aggregation and selectively impairs glutamate receptor function and synaptic plasticity. However, its molecular mechanisms remain elusive and these synaptic deficits are difficult to monitor. AD- and APOE4-dependent plasma biomarkers have been proposed, but synapse-related plasma biomarkers are lacking. We evaluated neuronal pentraxin 1 (NP1), a potential CNS-derived plasma biomarker of excitatory synaptic pathology. NP1 is preferentially expressed in brain and involved in glutamate receptor internalization. NP1 is secreted presynaptically induced by Abeta oligomers, and implicated in excitatory synaptic and mitochondrial deficits. Levels of NP1 and its fragments were increased in a correlated fashion in both brain and plasma of 7-8 month-old E4FAD mice relative to E3FAD mice. NP1 was also found in exosome preparations and reduced by dietary DHA supplementation. Plasma NP1 was higher in E4FAD+ (APOE4+/+/FAD+/-) relative to E4FAD- (non-carrier; APOE4+/+/FAD-/-) mice, suggesting NP1 is modulated by Abeta expression. Finally, relative to normal elderly, plasma NP1 was also elevated in patients with mild cognitive impairment (MCI) and elevated further in the subset who progressed to early-stage AD. In those patients, there was a trend towards increased NP1 levels in APOE4 carriers relative to non-carriers. These findings indicate that NP1 may represent a potential synapse-derived plasma biomarker relevant to early alterations in excitatory synapses in MCI and early stage AD. PMID- 29501532 TI - Rapid and sensitive detection of mink circovirus by recombinase polymerase amplification. AB - To date, the pathogenic role of mink circovirus (MiCV) remains unclear, and its prevalence and economic importance are unknown. Therefore, a rapid and sensitive molecular diagnosis is necessary for disease management and epidemiological surveillance. However, only PCR methods can identify MiCV infection at present. In this study, we developed a nested PCR and established a novel recombinase polymerase amplification (RPA) assay for MiCV detection. Sensitivity analysis showed that the detection limit of nested PCR and RPA assay was 101 copies/reaction, and these methods were more sensitive than conventional PCR, which has a detection limit of 105 copies/reaction. The RPA assay had no cross reactivity with other related viral pathogens, and amplification was completed in less than 20 min with a simple device. Further assessment of clinical samples showed that the two assays were accurate in identifying positive and negative conventional PCR samples. The detection rate of MiCV by the RPA assay in clinical samples was 38.09%, which was 97% consistent with that by the nested PCR. The developed nested PCR is a highly sensitive tool for practical use, and the RPA assay is a simple, sensitive, and potential alternative method for rapid and accurate MiCV diagnosis. PMID- 29501533 TI - Glucosylated nanomicelles target glucose-avid pediatric patient-derived sarcomas. AB - We report for the first time on a nano-drug delivery system based on glucosylated polymeric nanomicelles to actively target the second-generation tyrosine kinase inhibitor dasatinib to glucose-avid pediatric sarcomas by the intravenous route. After a comprehensive physicochemical characterization that confirmed the substantially lower critical micellar concentration and the higher encapsulation capacity of the glucosylated amphiphilic nanocarrier with respect to the pristine counterpart, we showed a 9-fold decrease of the half maximal inhibitory concentration of dasatinib in a rhabdomyosarcoma cell line, Rh30, in vitro. In immunodeficient mice bearing the glucose-avid Rh30 xenograft, we revealed that the glucosylated polymeric nanomicelles increased the delivery of dasatinib in the tumor parenchyma. Conversely, the exposure of off-target tissues and organs to the drug was substantially reduced. Upon experimental confirmation that most patient-derived xenograft (PDX) models of pediatric sarcomas overexpress glucose transporter 1 (GLUT-1), we demonstrated the selective accumulation of dasatinib in a patient-derived rhabdomyosarcoma model in vivo. Conversely, the reference dose administered by the oral route was not tumor-selective. Finally, the improved nanocarrier pharmacokinetics led to prolonged median survival of mice bearing a clinically relevant PDX model of alveolar rhabdomyosarcoma from 19 days for the untreated controls to 27 days for the targeted therapy. PMID- 29501531 TI - High-content imaging assays on a miniaturized 3D cell culture platform. AB - The majority of high-content imaging (HCI) assays have been performed on two dimensional (2D) cell monolayers for its convenience and throughput. However, 2D cultured cell models often do not represent the in vivo characteristics accurately and therefore reduce the predictability of drug toxicity/efficacy in vivo. Recently, three-dimensional (3D) cell-based HCI assays have been demonstrated to improve predictability, but its use is limited due to difficulty in maneuverability and low throughput in cell imaging. To alleviate these issues, we have developed miniaturized 3D cell culture on a micropillar/microwell chip and demonstrated high-throughput HCI assays for mechanistic toxicity. Briefly, Hep3B human hepatoma cell line was encapsulated in a mixture of alginate and fibrin gel on the micropillar chip, cultured in 3D, and exposed to six model compounds in the microwell chip for rapidly assessing mechanistic hepatotoxicity. Several toxicity parameters, including DNA damage, mitochondrial impairment, intracellular glutathione level, and cell membrane integrity were measured on the chip, and the IC50 values of the compounds at different readouts were determined to investigate the mechanism of toxicity. Overall, the Z' factors were between 0.6 and 0.8 for the HCI assays, and the coefficient of variation (CV) were below 20%. These results indicate high robustness and reproducibility of the HCI assays established on the miniaturized 3D cell culture chip. In addition, it was possible to determine the predominant mechanism of toxicity using the 3D HCI assays. Therefore, our miniaturized 3D cell culture coupled with HCI assays has great potential for high-throughput screening (HTS) of compounds and mechanistic toxicity profiling. PMID- 29501534 TI - Functional evidence for the inflammatory reflex in teleosts: A novel alpha7 nicotinic acetylcholine receptor modulates the macrophage response to dsRNA. AB - The inflammatory reflex modulates the innate immune system, keeping in check the detrimental consequences of overstimulation. A key player controlling the inflammatory reflex is the alpha 7 acetylcholine receptor (alpha7nAChR). This receptor is one of the signalling molecules regulating cytokine expression in macrophages. In this study, we characterize a novel teleost alpha7nAChR. Protein sequence analysis shows a high degree of conservation with mammalian orthologs and trout alpha7nAChR has all the features and essential amino acids to form a fully functional receptor. We demonstrate that trout macrophages can bind alpha bungarotoxin (alpha-BTX), a competitive antagonist for alpha7nAChRs. Moreover, nicotine stimulation produces a decrease in pro-inflammatory cytokine expression after stimulation with poly(I:C). These results suggest the presence of a functional alpha7nAChR in the macrophage plasma membrane. Further, in vivo injection of poly(I:C) induced an increase in serum ACh levels in rainbow trout. Our results manifest for the first time the functional conservation of the inflammatory reflex in teleosts. PMID- 29501535 TI - Encoding and immediate retrieval tasks in patients with epilepsy: A functional MRI study of verbal and visual memory. AB - PURPOSE: Medial lobe temporal structures and more specifically the hippocampus play a decisive role in episodic memory. Most of the memory functional magnetic resonance imaging (fMRI) studies evaluate the encoding phase; the retrieval phase being performed outside the MRI. We aimed to determine the ability to reveal greater hippocampal fMRI activations during retrieval phase. MATERIALS AND METHODS: Thirty-five epileptic patients underwent a two-step memory fMRI. During encoding phase, subjects were requested to identify the feminine or masculine gender of faces and words presented, in order to encourage stimulus encoding. One hour after, during retrieval phase, subjects had to recognize the word and face. We used an event-related design to identify hippocampal activations. RESULTS: There was no significant difference between patients with left temporal lobe epilepsy, patients with right temporal lobe epilepsy and patients with extratemporal lobe epilepsy on verbal and visual learning task. For words, patients demonstrated significantly more bilateral hippocampal activation for retrieval task than encoding task and when the tasks were associated than during encoding alone. Significant difference was seen between face-encoding alone and face retrieval alone. CONCLUSIONS: This study demonstrates the essential contribution of the retrieval task during a fMRI memory task but the number of patients with hippocampal activations was greater when the two tasks were taken into account. PMID- 29501536 TI - Evaluation of microvascular endothelial function and capillary density in patients with infective endocarditis using laser speckle contrast imaging and video-capillaroscopy. AB - OBJECTIVE: To evaluate the systemic microcirculation of patients with infective endocarditis (IE). METHODS: This is a comparative study of patients with definite IE by the modified Duke criteria admitted to our center for treatment. A reference group of sex- and age-matched healthy volunteers was included. Microvascular flow was evaluated in the forearm using a laser speckle contrast imaging system, for noninvasive measurement of cutaneous microvascular perfusion, in combination with skin iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP) to test microvascular reactivity. Microvascular density was evaluated using skin video-capillaroscopy. RESULTS: We studied 22 patients with IE; 15 were male and seven female. The mean age and standard deviation (SD) were 45.5 +/- 17.3 years. Basal skin microvascular conductance was significantly increased in patients with IE, compared with healthy individuals (0.36 +/- 0.13 versus 0.21 +/- 0.08 APU/mmHg; P < 0.0001). The increase in microvascular conductance induced by ACh in patients was 0.21 +/- 0.17 and in the reference group, it was 0.37 +/- 0.14 APU/mmHg (P = 0.0012). The increase in microvascular conductance induced by SNP in patients was 0.18 +/- 0.14 and it was 0.29 +/- 0.15 APU/mmHg (P = 0.0140) in the reference group. The basal mean skin capillary density of patients (135 +/- 24 capillaries/mm2) was significantly higher, compared with controls (97 +/- 21 capillaries/mm2; P < 0.0001). CONCLUSIONS: The main findings in the microcirculation of patients with IE were greater basal vasodilation and a reduction of the endothelium-dependent and -independent microvascular reactivity, as well as greater functional skin capillary density compared to healthy individuals. PMID- 29501537 TI - A new role of mast cells in arteriogenesis. AB - Arteriogenesis is defined as the growth of functional collateral arteries from pre-existing arterio-arteriolar anastomoses. The role of mast cells in arteriogenesis is largely unexplored. Recent evidences suggest that mast cells together with other inflammatory cells, including monocytes-macrophages, lymphocytes, NK cells and endothelial precursor cells (EPCs) may be involved in this process. This review article analyzes the literature concerning this new aspect of biological activity of mast cells. PMID- 29501538 TI - Impact of epidural analgesia on cesarean and operative vaginal delivery rates classified by the Ten Groups Classification System. AB - BACKGROUND: The Ten Group Classification System (TGCS) allows critical analysis according to the obstetric characteristics of women in labor: singleton or multiple pregnancy, nulliparous, multiparous, or multiparous with a previous cesarean delivery, cephalic, breech presentation or other malpresentation, spontaneous or induced labor, and term or preterm births. Labor outcomes associated with epidural analgesia may be different among the different labor classification groups. The aim of this study was to explore associations between epidural analgesia and cesarean delivery, and epidural analgesia and assisted vaginal delivery, in women classified using the TGCS. METHODS: Slovenian National Perinatal Information System data for the period 2007-2014 were analyzed. All women after spontaneous onset or induction of labor were classified according to the TGCS, within which cesarean and vaginal assisted delivery rates were investigated (P <0.003 significant). RESULTS: Data on 207 525 deliveries (and 211 197 neonates) were analyzed. In most TGCS groups women with epidural analgesia had lower cesarean delivery rates. Women in group 1 (nulliparous term women with singleton fetuses in cephalic presentation in spontaneous labor) with epidural analgesia had a higher cesarean delivery rate. In most TGCS groups women with epidural analgesia had higher assisted vaginal delivery rates. CONCLUSION: Epidural analgesia is associated with different effects on cesarean delivery and assisted vaginal delivery rates in different TGCS groups. PMID- 29501539 TI - Contribution of MTHFR gene variants in lupus related subclinical atherosclerosis. AB - OBJECTIVE: Elevated concentrations of homocysteine have been previously identified as an independent risk factor for subclinical atherosclerosis in patients with systemic lupus erythematosus (SLE). Given that heightened homocysteine levels are known to be strongly influenced by genetic factors, in the current study we investigated the contribution of high homocysteine levels as well as of functional polymorphisms of the gene encoding for the enzyme 5, 10- methylenetetrahydrofolate reductase (MTHFR) to atherosclerotic disease characterizing SLE patients. METHODS: Peripheral DNA samples from 150 SLE patients, 214 rheumatoid arthritis (RA) patients and 561 age/sex matched apparently healthy volunteers (HC) were genotyped by PCR-based assays for the detection of the MTHFR gene polymorphisms (c. 677C > T and c. 1298A > C). All SLE patients and 30 age sex matched RA patients underwent assessment for subclinical atherosclerosis [ultrasound measurement of intima-media thickness scores (IMT) and detection of carotid and/or femoral (C/F) plaque] and complete clinical and laboratory evaluation including serum homocysteine levels. Data were analyzed using univariate and multivariate models (SPSS 21.0). RESULTS: Hyperhomocysteinemia was detected in 26.0% of SLE patients compared to 6.7% of age/sex matched RA controls (p = 0.02). Higher serum B12 levels and decreased frequency of the MTHFR 677TT variant in RA patients could potentially account for the observed differences between the groups. In SLE patients, both hyperhomocysteinemia and MTHFR 677TT genotype were identified as independent contributors for plaque formation, following adjustment for traditional cardiovascular risk factors and disease related features, including age, sex, BMI, cholesterol and triglyceride levels, presence of arterial hypertension, smoking (pack/years), disease duration and total steroid dose [OR 95% (CI): 5.8 (1.0-35.8) and 5.2 (1.1-24.0), respectively]. MTHFR 677TT genotype, but not hyperhomocysteinemia was also found to confer increased risk for arterial wall thickening, after the above confounders were taken into account [OR (95%) CI: 4.9 (1.2-20.6)]. CONCLUSIONS: Hyperhomocysteinemia and MTHFR 677TT genetic variant emerged as independent risk factors for subclinical atherosclerosis in SLE patients, implying genetic influences as potential contributors to the increased burden of atherosclerotic disease characterizing SLE. PMID- 29501540 TI - Epigenetic interplay between immune, stromal and cancer cells in the tumor microenvironment. AB - Compelling evidences highlight the critical role of the tumor microenvironment as mediator of tumor progression and immunosuppression in several types of cancer. The reciprocal interplay between neoplastic and non-tumoral host cells is mediated by direct cell-to-cell contact, soluble factors and exosomes that result in differential gene expression patterns that are driven by epigenetic mechanisms. In this regard, extensive literature has described the abnormalities in the DNA methylation status and histone modification profiles in tumor cells. However, little is known about the mechanisms of epigenetic dysregulation that participate as a consequence of the intricate crosstalk among the cells within the tumor niche. This review summarizes the current knowledge on epigenetic changes that result from the interactions between myeloid, stromal and cancer cells in the tumor microenvironment and its functional impact in both tumorigenesis and tumor progression. We also discuss potential niche-specific epigenetic biomarkers to improve the prognosis and clinical treatment of cancer patients. PMID- 29501541 TI - Deformation of Stabilization Arch Following Post-Dilatation of Symetis ACURATE Neo Aortic Bioprosthesis. PMID- 29501542 TI - Native Right Ventricular Outflow Tract Transcatheter Pulmonary Valve Replacement Without Pre-Stenting. PMID- 29501543 TI - Spontaneous Retrograde Embolization From an Infarct-Related Artery to a Bystander Nonculprit Artery: An Unclear Pathophysiological Mechanism? PMID- 29501544 TI - The Impact of Left Ventricular Diastolic Dysfunction on Clinical Outcomes After Transcatheter Aortic Valve Replacement. AB - OBJECTIVES: This study sought to determine the impact of left ventricular diastolic dysfunction (LVDD) on clinical outcomes in patients undergoing transcatheter aortic valve replacement (TAVR). BACKGROUND: Left ventricular (LV) hypertrophy in response to afterload increase promotes the development of LVDD and represents an early stage in the progression to valvular heart failure. METHODS: In a consecutive cohort of 777 aortic stenosis patients undergoing TAVR, LVDD was categorized according to the latest guidelines. The primary endpoint was 1-year all-cause mortality. RESULTS: There were 545 (70.1%) patients with LVDD. Ninety-eight (18.0%), 198 (36.3%), and 104 (19.1%) patients were classified as LVDD grades I, II, and III, respectively. In 145 (26.6%) patients, LVDD grade could not be determined because of only 1 or 2 discrepant variables. One-year all cause mortality was higher in patients with LVDD grades I (16.3%; adjusted hazard ratio [HR]adj: 2.32; 95% confidence interval [CI]: 1.15 to 4.66), II (17.9%; HRadj: 2.58; 95% CI: 1.43 to 4.67), and III (27.6%; HRadj: 4.21; 95% CI: 2.25 to 7.86) than in those with normal diastolic function (6.9%). The difference in clinical outcome emerged within 30 days, was driven by cardiovascular death, and maintained in a sensitivity analysis of patients with normal systolic LV function. Furthermore, LVDD grades I (HRadj: 2.36; 95% CI: 1.17 to 4.74), II (HRadj: 2.58; 95% CI: 1.42 to 4.66), and III (HRadj: 4.41; 95% CI: 2.37 to 8.20) were independent predictors of 1-year mortality. CONCLUSIONS: Advancing stages of LVDD are associated with an incremental risk of all-cause mortality after TAVR, driven by cardiovascular death and taking effect as early as 30 days after the intervention. PMID- 29501545 TI - Transcatheter Closure of Pulmonary Arteriovenous Malformation to Facilitate Treatment of Pulmonary Arterial Hypertension. PMID- 29501546 TI - Successful MitraClip for Severe Mitral Regurgitation Secondary to Papillary Muscle Rupture as a Complication of Transcatheter Aortic Valve Replacement. PMID- 29501547 TI - Diastolic Dysfunction Pre-Transcatheter Aortic Valve Replacement: Is it Too Late? PMID- 29501548 TI - Male preference for conspecific mates is stronger than females' in Betta splendens. AB - The higher energetic cost related to female gamete investment is classically considered the driving force behind sexual selection. This asymmetric cost of reproduction is thought to cause female preference for elaborate male ornamentation. Subsequent co-evolution of female preferences and male ornaments is thought then to lead to a greater preference for conspecific mates in females as compared to males. Thus, female choice is classically assumed to contribute more than male choice to behavioral isolation between sexually dimorphic species. However, this hypothesis fails to account for the cost of maintaining a territory, building a nest, courtship displays, ornament investment, and parental care, as seen in males of the Siamese fighting fish, Betta splendens. Here we show that male B. splendens have a greater preference for female conspecifics than females have for male conspecifics, when given a choice between conspecifics and the allopatric Betta imbellis. We hypothesize that in B. splendens, the cost of mating may be higher for males than females, and predict that male choice would contribute to behavioral isolation upon secondary contact of wild populations. PMID- 29501549 TI - Attracted by a magnet: Exploration behaviour of rodents in the presence of magnetic objects. AB - Magnetosensitivity is widespread among animals with rodents being the most intensively studied mammalian group. The available behavioural assays for magnetoreception are time-consuming, which impedes screens for treatment effects that could characterize the enigmatic magnetoreceptors. Here, we present a fast and simple approach to test if an animal responds to magnetic stimuli: the magnetic object assay (MOA). The MOA focuses on investigating an animal's spontaneous exploration behaviour in the presence of a bar magnet compared to a demagnetised control. We present consistently longer exploration of the magnet in three different rodent species: Ansell's mole-rat (Fukomys anselli), C57BL/6J laboratory mouse, and naked mole-rat (Heterocephalus glaber). For the naked mole rat this is the first report that this species reacts on magnetic stimuli. We conclude that the MOA holds the potential to screen if an animal responds to magnetic stimuli, indicating the possession of a magnetic sense. PMID- 29501550 TI - Reply to letter by Floris Groenendaal regarding article "The prognostic value of proton magnetic resonance spectroscopy in term newborns treated with therapeutic hypothermia following asphyxia". PMID- 29501551 TI - The relationship of depression with the level of blood pressure in population based Kangbuk Samsung Health Study. AB - There has been increasing evidence about psychosomatic relationship between mood disorder and blood pressure (BP). However, the degree to which BP categories are associated with depression has been less well described. Thus, this study was to investigate the association of depression with BP categories. A total of 90,643 men and 68,933 women were enrolled in this study. They were stratified into four groups (normal, prehypertension, newly diagnosed hypertension, and recognized hypertension) according to the BP levels and the history of hypertension. Center for Epidemiological Studies-Depression was used to evaluate the depressive symptom, and the degree of depression was evaluated by the cutoff of Center for Epidemiological Studies-Depression (mild: 16-20, moderate: 21-24, severe: >=25). The multivariate logistic regression was used in calculating odds ratios for depression according to the four BP categories, with adjustment for multiple confounding factors. Subgroup analysis was conducted by gender and age. The adjusted odds ratios for depression tended to decrease from normal to newly diagnosed hypertension, but significantly increased in recognized hypertension (normal: reference, prehypertension: 0.85 [0.80-0.91], newly diagnosed hypertension: 0.75 [0.65-0.86], recognized hypertension: 1.11 [1.03-1.20]). Subgroup analysis also indicated the similar pattern of relationship, which was more prominent in male and middle-aged subgroup than any other subgroups. Depression was inversely associated with elevated BP. However, recognized hypertension had the increased likelihood of depression in male and young age group. These findings suggest that the association between depression and BP may be moderated by the chronicity of hypertension in men and young individuals. PMID- 29501552 TI - Functional differentiation between convergence and non-convergence zones of the striatum in children. AB - Most cortical areas send projections to the striatum. In some parts of the striatum, the connections converge from several cortical areas. It is unknown whether the convergence and non-convergence zones of the striatum differ functionally. Here, we used diffusion-weighted magnetic resonance imaging and probabilistic fiber tracking to parcellate the striatum based on its connections to dorsolateral prefrontal, parietal and orbitofrontal cortices in two different datasets (children aged 6-7 years and adults). In both samples, quantitative susceptibility mapping (QSM) values were significantly correlated with working memory (WM) in convergence zones, but not in non-convergence zones. In children, this was also true for mean diffusivity, MD. The association of MD to WM specifically in the convergent zone was replicated in the Pediatric Imaging, Neurocognition, and Genetics (PING) dataset for 135 children aged 6-9 years. QSM data was not available in the PING dataset, and the association to QSM still needs to be replicated. These results suggest that connectivity-based segments of the striatum exhibit functionally different characteristics. The association between convergence zones and WM performance might relate to a role in integrating and coordinating activity in different cortical areas. PMID- 29501553 TI - BOLD signal in sensorimotor regions reveals differential encoding of passive forefinger velocity and displacement amplitude. AB - Peripheral encoding of movement kinematics has been well-characterized, but there is little understanding of the relationship between movement kinematics and associated brain activation. We hypothesized that kinematics of passive movement is differentially represented in the sensorimotor network, reflecting the well studied afferent responses to movement. A robotic forefinger manipulandum was used to induce passive kinematic stimuli and monitor interaction force in 41 healthy participants during whole-brain functional magnetic resonance imaging (fMRI). Levels of forefinger displacement amplitude and velocity were presented in flexion and extension. Increases in velocity were linearly associated with activation in contralateral primary somatosensory cortex (S1), bilateral secondary somatosensory cortex (S2), primary motor cortex, and supplementary motor area. No difference in activation was found for direction of the finger movement. Unexpectedly, S1 and S2 activation decreased nonlinearly with increasing displacement amplitude. We conclude that while straightforward relations were found with velocity, the complex neural representation of displacement amplitude suggests a more nuanced relationship between peripheral responses to kinematic stimuli and sensorimotor network activity. Here we present a novel, systematic characterization of the whole-brain response to passive movement kinematics. PMID- 29501555 TI - Shared Decision Making in Prostate Cancer Care-Encouraging Every Patient to be Actively Involved in Decision Making or Ensuring the Patient Preferred Level of Involvement? AB - PURPOSE: The aims of this study were to 1) describe preferred and experienced roles in treatment decision making among patients with localized prostate cancer, 2) identify how often the roles experienced by patients matched their preferred roles and 3) determine whether active involvement in decision making regardless of role preferences or concordance between preferred and experienced roles would be the strongest predictor of more favorable patient reported outcomes. MATERIALS AND METHODS: In this prospective, multicenter, observational study we obtained serial questionnaire data from 454 patients with newly diagnosed, localized prostate cancer (cT1-cT2, or Gleason 7 or less and prostate specific antigen 20 ng/ml or less). Questionnaires were completed prior to treatment and at the 3, 6 and 12-month posttreatment followups. Clinical data were obtained from the patient medical records. Active involvement and role concordance were operationalized using the CPS (Control Preferences Scale). ANOVA and effect sizes (small and medium Cohen d = 0.2 and 0.5, respectively) were used to compare patient knowledge of prostate cancer, decision conflict, decision regret and overall health related quality of life. RESULTS: Of the patients 393 (87%) reported having been actively involved in treatment decision making. However, 78 patients (17%) indicated having had less or more involvement than preferred. Active involvement was significantly associated with more prostate cancer knowledge (d = 0.30), less decision conflict (d = 0.52) and less decision regret (d = 0.34). Role concordance was also but less strongly associated with less decision conflict (d = 0.41). CONCLUSIONS: Our findings support a policy of encouraging all patients with localized prostate cancer regardless of their stated role preferences to be actively involved in the treatment decision. PMID- 29501554 TI - Characterization of the hemodynamic response function across the majority of human cerebral cortex. AB - A brief (<4 s) period of neural activation evokes a stereotypical sequence of vascular and metabolic events to create the hemodynamic response function (HRF) measured using functional magnetic resonance imaging (fMRI). Linear analysis of fMRI data requires that the HRF be treated as an impulse response, so the character and temporal stability of the HRF are critical issues. Here, a simple audiovisual stimulus combined with a fast-paced task was used to evoke a strong HRF across a majority, ~77%, of cortex during a single scanning session. High spatiotemporal resolution (2-mm voxels, 1.25-s acquisition time) was used to focus HRF measurements specifically on the gray matter for whole brain. The majority of activated cortex responds with positive HRFs, while ~27% responds with negative (inverted) HRFs. Spatial patterns of the HRF response amplitudes were found to be similar across subjects. Timing of the initial positive lobe of the HRF was relatively stable across the cortical surface with a mean of 6.1 +/- 0.6 s across subjects, yet small but significant timing variations were also evident in specific regions of cortex. The results provide guidance for linear analysis of fMRI data. More importantly, this method provides a means to quantify neurovascular function across most of the brain, with potential clinical utility for the diagnosis of brain pathologies such as traumatic brain injury. PMID- 29501556 TI - Assessing the aversive nature of pain with an operant approach/avoidance paradigm. AB - Preclinical pain assessments can be criticized for failing to adequately characterize the human clinical pain experience. Although recent assessments have improved upon this shortcoming, there are still significant limitations. One concern is that current procedures fail to examine underlying motivational drives related to pain. Therefore, we used a novel approach-avoidance paradigm that allowed a rat to either satisfy hunger or avoid noxious stimulation to reveal prioritizing of motivational drives. The operant paradigm utilized a single lever that the animal pressed for appetitive reward (approach). The lever press was associated with mechanical stimulation of an inflamed paw induced by subcutaneous injection of carrageenan (avoidance). The results revealed that carrageenan injected animals had a significant suppression of lever pressing and, in addition, had a longer latency to approach and press a lever for appetitive reward. The pattern of operant behavioral responses indicates that the motivation to avoid pain superseded the motivation to alleviate hunger. Utilization of approach-avoidance paradigms, such as this one, can allow researchers to unravel the complexities of the pain experience with the goal of enhancing translation to clinical efficacy. PMID- 29501558 TI - Integration of non-invasive biometrics with sensory analysis techniques to assess acceptability of beer by consumers. AB - Traditional sensory tests rely on conscious and self-reported responses from participants. The integration of non-invasive biometric techniques, such as heart rate, body temperature, brainwaves and facial expressions can gather more information from consumers while tasting a product. The main objectives of this study were i) to assess significant differences between beers for all conscious and unconscious responses, ii) to find significant correlations among the different variables from the conscious and unconscious responses and iii) to develop a model to classify beers according to liking using only the unconscious responses. For this study, an integrated camera system with video and infrared thermal imagery (IRTI), coupled with a novel computer application was used. Videos and IRTI were automatically obtained while tasting nine beers to extract biometrics (heart rate, temperature and facial expressions) using computer vision analysis. Additionally, an EEG mobile headset was used to obtain brainwave signals during beer consumption. Consumers assessed foam, color, aroma, mouthfeel, taste, flavor and overall acceptability of beers using a 9-point hedonic scale with results showing a higher acceptability for beers with higher foamability and lower bitterness. i) There were non-significant differences among beers for the emotional and physiological responses, however, significant differences were found for the cognitive and self-reported responses. ii) Results from principal component analysis explained 65% of total data variability and, along with the covariance matrix (p < 0.05), showed that there are correlations between the sensory responses of participants and the biometric data obtained. There was a negative correlation between body temperature and liking of foam height and stability, and a positive correlation between theta signals and bitterness. iii) Artificial neural networks were used to develop three models with high accuracy to classify beers according to level of liking (low and high) of three sensory descriptors: carbonation mouthfeel (82%), flavor (82%) and overall liking (81%). The integration of both sensory and biometric responses for consumer acceptance tests showed to be a reliable tool to be applied to beer tasting to obtain more information from consumers physiology, behavior and cognitive responses. PMID- 29501557 TI - The role of stress response in the association between autonomy and adjustment in adolescents. AB - Developing autonomy is an important developmental task that has implications for adolescent adjustment and may be impacted by adolescents' response to stress. This study examined whether stress reactivity (i.e., cortisol and heart rate reactivity) to a parent-adolescent conflict interaction moderates the effect of autonomy on adjustment assessed one year later in 100 adolescents (M age = 15.09; 68% girls). Multiple group models suggested that youth who evidenced higher stress reactivity when compared to those with lower stress reactivity were more likely to report decreased externalizing problems and internalizing problems when their parents granted more autonomy. In contrast, youth who evidenced higher stress reactivity who experienced undermining of autonomy were more likely to report increased externalizing and internalizing problems than youth who evidenced lower stress reactivity. Results support biological sensitivity to context theory and highlight the importance of considering individual differences in the effect of developmental milestones on adolescents' adjustment. PMID- 29501559 TI - Structural studies of glyceraldehyde-3-phosphate dehydrogenase from Naegleria gruberi, the first one from phylum Percolozoa. AB - Naegleria gruberi is a free life amoeba believed to have more than one billion years of existence; it is not pathogenic and had its genome sequenced, which revealed a high complexity in the metabolic pathways. This paper presents the experimental structure of GAPDH from N. gruberi, the first one belonging to the phylum Percolozoa, comparisons to structures from various species and molecular dynamics studies of some particular features. The final refined structure presents Rcryst = 15.54% and Rfree = 19.84%. The catalytic domain formed by residues 134 to 313 is highly conserved, as expected, with the exception of Asn145, present only in NgGAPDH, while the other GAPDHs present either Ser or Thr on the corresponding position. Molecular dynamics analysis revealed that Asn145 has correlated motions with residues Ala123, Thr125 and Pro126 that belong to what was called "bonded loop". NgGAPDH residue Met35 presents an extended side chain, closer to the cofactor adenine ring than corresponding (different) residues and conformations found in some parasitic protozoa and the human GAPDHs. The enzyme was previously reported to present positive cooperativity, which is hypothesized to be related to certain atom distances. PMID- 29501560 TI - Zika virus: lessons learned in Brazil. AB - Zika virus (ZIKV) greatly impacted the international scientific and public health communities in the last two years due to its association with microcephaly and other neonatal alterations. This review will discuss lessons learned from viral pathogenesis, epidemiology and clinical findings observed during the ZIKV outbreak occurred between 2014 and 2016 in Brazil. PMID- 29501561 TI - IR thermography-based monitoring of respiration phase without image segmentation. AB - BACKGROUND: Respiratory rate is an essential parameter in biomedical research and clinical applications. Most respiration measurement techniques in preclinical animal models require surgical implantation of sensors. Current clinical measurement modalities typically involve attachment of sensors to the patient, causing discomfort. We have previously developed a non-contact approach to measuring respiration phase in head-restrained rodents using infrared (IR) thermography. While the non-invasive nature of IR thermography offers many advantages, it also bears the complexity of extracting respiration signals from videos. Previously reported algorithms involve image segmentation to identify the nose in IR videos and extract breathing-relevant pixels which is particularly challenging if the videos have low contrast or suffer from suboptimal focusing. NEW METHOD: To address this challenge, we developed a novel algorithm, which extracts respiration signals based on pixel time series, removing the need for nose-tracking and image segmentation. RESULTS & COMPARISON WITH EXISTING METHODS: We validated the algorithm by performing respiration measurements in head restrained mice and in humans with IR thermography in parallel with established standard techniques. We find the algorithm reliably detects inhalation onsets with high temporal precision. CONCLUSIONS: The new algorithm facilitates the application of IR thermography for measuring respiration in biomedical research and in clinical settings. PMID- 29501562 TI - Don't Just Do Something, Stand There! PMID- 29501563 TI - Voluntary vaccinations and vaccine shortages: A theoretical analysis. AB - A simple dynamic model of vaccination is presented and analyzed to study how the amount of vaccines available affects people's vaccination decisions. In addition, the model is used to examine how the level of vaccination in equilibrium compares to the efficient or socially optimal level. It is shown that, when the stock of vaccines is large so that a shortage could never arise, an equilibrium is generically unique, and there is too little vaccination compared to the social optimum. When the stock of vaccines is small so that not everyone in a population could get vaccinated, a shortage could occur in equilibrium. Moreover, the occurrence of a shortage could be self-fulfilling: when agents expect a shortage to develop, they have a greater incentive to demand the vaccine right away, which increases the likelihood that a shortage will result; and when agents do not expect a shortage to arise, they are more willing to delay their vaccination decision, which reduces the likelihood of a shortage developing. This leads to the possible co-existence of multiple equilibria that differ in the level of vaccination. Multiple equilibria can arise, however, only if agents are uncertain about the cost of being infected - if agents are sufficiently certain about the cost of infection, then an equilibrium is unique. Furthermore, when the stock of vaccines is small, an equilibrium level of vaccination may be too high relative to the socially optimal level. Increasing the vaccine stock could have ambiguous effects on the level of vaccination in equilibrium but unambiguously increases social welfare. PMID- 29501564 TI - A novel and reliable method for tetrahydrobiopterin quantification: Benzoyl chloride derivatization coupled with liquid chromatography-tandem mass spectrometry analysis. AB - Tetrahydrobiopterin (BH4) is a crucial cofactor for nitric oxide synthase, acylglycerol mono-oxygenase and aromatic amino acids hydroxylases. Its significant function for redox pathways in vivo attracted much attention for long. However, because of the oxidizable and substoichiometric nature, analysis of BH4 has never been truly achieved with adequate sensitivity and applicability. In the present work, we pioneeringly stabilized BH4 by derivatizing the active secondary amine on five-position with benzoyl chloride (BC). Benefiting from the favorable chemical stability and excellent mass spectrometric sensitivity of the product (BH4-BC), ultra-sensitive and reliable quantification of endogenous BH4 in plasma was achieved using liquid chromatography-tandem mass spectrometry (LC MS/MS) analysis. In such methodology, BH4-BC-d5 was introduced as stable isotopic internal standard. And the limit of quantification (LOQ) could reach 0.02 ng mL 1. In the end, after investigation of plasma BH4 in healthy volunteers (n = 38), we found that the levels of BH4 were significantly and negatively correlated to age. Comparing with all the other existed strategies, the present method was obviously superior in sensitivity, specificity and practical applicability. It could be expected that this work could largely promote the future studies in BH4 related fields. PMID- 29501565 TI - Redox tuning of Ca2+ signaling in microglia drives glutamate release during hypoxia. AB - Hypoxia causes oxidative stress and excitotoxicity, culminating in neuronal damage during brain ischemia. Hypoxia also activates microglia, the myeloid resident cells of the brain parenchyma. Upon activation, microglia release high amounts of the neurotransmitter glutamate, contributing for neuronal excitotoxicity during brain insults. Here, we reveal a signaling pathway controlling glutamate release from human microglia during hypoxia. We show that hypoxia-mediated redox imbalance promotes the activation of endoplasmic reticulum inositol 1,4,5-trisphosphate (InsP3) receptors leading to Ca2+ mobilization into the cytosol. Increasing cytosolic Ca2+ signaling in microglia activates the non receptor protein tyrosine kinase Src at the plasma membrane. Src activation enhances the permeability of microglial gap junctions promoting the release of glutamate during hypoxia. Preventing the hypoxia-triggered redox imbalance, using the dietary antioxidants neochlorogenic acid or vitamin C, inhibits InsP3 dependent Ca2+ signaling and abrogates the release of glutamate. Overall, modulating microglial Ca2+ signaling in response to changes in the redox microenvironment might be critical for controlling glutamate excitotoxicity during hypoxia. PMID- 29501566 TI - The IRF9-SIRT1-P53 axis is involved in the growth of human acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is a highly heterogeneous disease, with biologically and prognostically different subtypes. Although a growing number of distinct AML subsets have been increasingly characterized, patient management has remained disappointingly uniform. The molecular mechanism underlying AML needs to be further investigated. Here we identify IRF9 as a negative regulator of human AML. We show that IRF9 mRNA and protein levels are down-regulated in human AML samples compared with samples from healthy donors. IRF9 knockdown promotes proliferation, colony formation and survival of OCI/AML-2 and OCI/AML-3 cells, whereas IRF9 overexpression obtains oppose results. Mechanism analysis shows that IRF9 binds SIRT1 promoter and represses SIRT1 expression in OCI/AML-2 and OCI/AML-3 cells. In AML samples, the expression of SIRT1 is up-regulated and negatively correlated with IRF9 level. IRF9 also increases the acetylation of p53, a deacetylation substrate of SIRT1, and promotes the expression of p53 target genes. Knockdown of p53 blocks the effects of IRF9 on cell survival and growth in vitro. These findings provide evidence that IRF9 serves as an important regulator in human AML by repressing SIRT1-p53 pathway and that IRF9 may be a potential target for AML treatment. PMID- 29501567 TI - Neuron-specific knockdown of Drosophila PDHB induces reduction of lifespan, deficient locomotive ability, abnormal morphology of motor neuron terminals and photoreceptor axon targeting. AB - Pyruvate dehydrogenase complex deficiency (PDCD) is a common primary cause of defects in mitochondrial function and also can lead to peripheral neuropathy. Pyruvate dehydrogenase E1 component subunit beta (PDHB) is a subunit of pyruvate dehydrogenase E1, which is a well-known component of PDC. In Drosophila melanogaster, the CG11876 (dPDHB) gene is a homolog of human PDHB. In this study, we established a Drosophila model with neuron-specific knockdown of dPDHB to investigate its role in neuropathy pathogenesis. Knockdown of dPDHB in pan neurons induced locomotor defects in both larval and adult stages, which were consistent with abnormal morphology of the motor neuron terminals at neuromuscular junctions and mitochondrial fragmentation in brains. Moreover, neuron-specific knockdown of dPDHB also shortened the lifespan of adult flies. In addition, flies with knockdown of dPDHB manifested a rough eye phenotype and aberrant photoreceptor axon targeting. These results with the Drosophila model suggest the involvement of PDHB in peripheral neuropathy. PMID- 29501568 TI - Circulating regulatory Tfh cells are enriched in patients with chronic hepatitis B infection and induce the differentiation of regulatory B cells. AB - Chronic hepatitis B virus (HBV) infection is a complex disease with dysregulations in the immune system. Follicular helper T (Tfh) cells are professional B helper cells that are crucial to the development of antibody responses and are involved in a variety of diseases. In this study, we examined the circulating Tfh cells in patients with chronic HBV infection. We observed that CD3+CD4+CXCR5+ circulating Tfh cells contained a CD25+Foxp3+ Treg-like subset that was significantly enriched in patients with chronic HBV infections. The CD25+ Tfh subset presented distinctive cytokine secretion profile, such as lower interferon (IFN)-gamma and interleukin (IL)-17, and higher transforming growth factor (TGF)-beta secretion, compared to the CD25- Tfh subset. When incubated with autologous naive CD10-CD27-CD19+ B cells, the CD25+ Tfh subset was less capable of mediating CD20-/loCD38+ plasmablast differentiation than the CD25 Tfh subset. In terms of Ig production, CD25+ Tfh cells were more potent at inducing IgM but less potent at inducing IgG and IgA than CD25- Tfh cells. Interestingly, B cells following incubation with CD25+ Tfh cells presented elevated regulatory function, with higher production of IL-10 and enhanced capacity of suppressing autologous CD8+ T cell inflammation. In the chronic HBV infected patients, the frequency of IL-10+ B cells and the HBV viral load were positively correlated with the frequency of CD25+Foxp3+ CD4+CXCR5+ Tfh cells. Together, this study presented that CD25+Foxp3+ Treg-like Tfh cells were enriched in chronic HBV-infected patients and could promote regulatory B cell functions. PMID- 29501569 TI - Bach2 regulates aberrant activation of B cell in systemic lupus erythematosus and can be negatively regulated by BCR-ABL/PI3K. AB - OBJECTIVE: This study was aimed to explore the effect of Bach2 on B cells in systemic lupus erythematosus (SLE), as well as the underlying mechanisms. METHODS: Expression of Bach2, phosphorylated-Bach2 (p-Bach2), Akt, p-Akt and BCR ABL (p210) in B cells isolated from SLE patients and the healthy persons were assessed by Western blot. Immunofluorescence staining was performed to assess the localization of Bach2 in B cells. Enzyme-linked immunosorbent assay (ELISA) was employed to detect IgG produced by B cells. Cell counting kit-8 (CCK-8) and Annexin-V FITC/PI double staining assay were adopted to evaluate cell proliferation and apoptosis in B cells, respectively. RESULTS: Compared to the healthy controls, Bach2, p-Akt and p210 were significantly decreased, while nuclear translocation of Bach2, IgG, CD40 and CD86 obviously up-regulated in B cells from SLE patients. Bach2 significantly inhibited the proliferation, promoted apoptosis of B cells from SLE patients, whereas BCR-ABL dramatically reversed cell changes induced by Bach2. Besides, BCR-ABL also inhibited nuclear translocation of Bach2 in B cells from SLE patients. Further, LY294002 treatment had no effect on decreased expression of Bach2 induced by BCR-ABL, but significantly eliminated BCR-ABL-induced phosphorylation of Bach2 and restored reduced nuclear translocation of Bach2 induced by BCR-ABL in B cells from SLE. CONCLUSIONS: Bach2 may play a suppressive role in B cells from SLE, and BCR-ABL may inhibit the nuclear translocation of Bach2 via serine phosphorylation through the PI3K pathway. PMID- 29501570 TI - Exposure to mephedrone during gestation increases the risk of stillbirth and induces hippocampal neurotoxicity in mice offspring. AB - In recent years, abuse of synthetic cathinones, in particular, mephedrone, has increased among young adults worldwide. The study aim is to investigate the effects of mephedrone exposure during the gestational period on mice offspring outcomes, focusing on hippocampal neurotoxicity. The pregnant mice received mephedrone (50 mg/kg, sc) on a regular schedule (once daily on all days, from day 5 to 18 of gestation) or repeated schedule (thrice daily on day 5, 6, 11, 12, 17, and 18 of gestation) to simulate regular or recreational use of mephedrone, respectively. Results showed that the percentage of weight gain in pregnant mice was significantly lower in both regular and repeated schedule mephedrone groups (p < 0.01). Also, mephedrone significantly reduced the number and weight of delivered pups and increased the rate of stillbirth (p < 0.05). Immunohistochemistry and TUNEL assay showed an inhibition of cell proliferation (p < 0.05) and an increase of apoptosis (p < 0.05) in the hippocampus of delivered pups of the repeated schedule mephedrone group. This apoptotic effect was associated with enhanced expression of the pro-apoptotic Bax gene (p < 0.05) and reduction of expression of the anti-apoptotic Bcl-2 gene (p < 0.05) as evaluated by real-time PCR. The Morris water maze showed an impairment of spatial learning (p < 0.05) and reference memory (p < 0.01) in offspring born from litters exposed to mephedrone (repeated schedule). In conclusion, the present study has shown that regular and repeated exposure to mephedrone during the gestational period increases the risk of low birth weight and stillbirth. Also, repeated use of mephedrone impairs learning and memory processes through hippocampal damage. PMID- 29501571 TI - Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. AB - We performed a multiple 'omics study by integrating data on epigenomic, transcriptomic, and proteomic perturbations associated with mitochondrial dysfunction in primary human hepatocytes caused by the liver toxicant valproic acid (VPA), to deeper understand downstream events following epigenetic alterations in the mitochondrial genome. Furthermore, we investigated persistence of cross-omics changes after terminating drug treatment. Upon transient methylation changes of mitochondrial genes during VPA-treatment, increasing complexities of gene-interaction networks across time were demonstrated, which normalized during washout. Furthermore, co-expression between genes and their corresponding proteins increased across time. Additionally, in relation to persistently decreased ATP production, we observed decreased expression of mitochondrial complex I and III-V genes. Persistent transcripts and proteins were related to citric acid cycle and beta-oxidation. In particular, we identified a potential novel mitochondrial-nuclear signaling axis, MT-CO2-FN1-MYC-CPT1. In summary, this cross-omics study revealed dynamic responses of the mitochondrial epigenome to an impulse toxicant challenge resulting in persistent mitochondrial dysfunctioning. Moreover, this approach allowed for discriminating between the toxic effect of VPA and adaptation. PMID- 29501573 TI - Biophysical Analysis of Bacterial CTP Synthase Filaments Formed in the Presence of the Chemotherapeutic Metabolite Gemcitabine-5'-triphosphate. AB - While enzyme activity is often regulated by a combination of substrate/effector availability and quaternary structure, many cytosolic enzymes may be further regulated through oligomerization into filaments. Cytidine-5'-triphosphate (CTP) synthase (CTPS) forms such filaments-a process that is promoted by the product CTP. The CTP analog and active chemotherapeutic metabolite gemcitabine-5' triphosphate (dF-dCTP) is a potent inhibitor of CTPS; however, its effect on the enzyme's ability to form filaments is unknown. Alongside electron microscopy studies, dynamic light scattering showed that dF-dCTP induces Escherichia coli CTPS (EcCTPS) to form filaments in solution with lengths >=30 nm in the presence of CTP or dF-dCTP. The substrate UTP blocks formation of filaments and effects their disassembly. EcCTPS variants were constructed to investigate the role of CTP-binding determinants in CTP- and dF-dCTP-dependent filament formation. Substitution of Glu 149 (i.e., E149D), which interacts with the ribose of CTP, caused reduced affinity for both CTP and dF-dCTP, and obviated filament formation. Phe 227 appears to interact with CTP through an edge-on interaction with the cytosine ring, yet the F227A and F227L variants bound CTP and dF-dCTP. F227A EcCTPS did not form filaments, while F227L EcCTPS formed shorter filaments in the presence of CTP or dF-dCTP. Hence, Phe 227 plays a role in filament formation, although replacement by a bulky hydrophobic amino acid is sufficient for limited filament formation. That dF-dCTP can induce filament formation highlights the fact that nucleotide analogs employed as chemotherapeutic agents may affect the filamentous states of enzymes and potentially alter their regulation in vivo. PMID- 29501572 TI - Involvement of HIF-1alpha-regulated miR-21, acting via the Akt/NF-kappaB pathway, in malignant transformation of HBE cells induced by cigarette smoke extract. AB - Although the relationship between cigarette smoke and lung cancer has been widely studied, the molecular mechanism for cigarette smoke-induced lung cancer remains largely unclear. The present study investigated the roles of hypoxia-inducible factor (HIF)-1alpha and miR-21 in the malignant transformation of human bronchial epithelial (HBE) cells induced by cigarette smoke extract (CSE). In case of acute and chronic treatment of HBE cells, CSE increased the levels of HIF-1alpha, p Akt, p-NF-kappaB, and miR-21 and decreased PTEN levels. The increased miR-21 levels induced by CSE were prevented by down-regulation of HIF-1alpha. Further, elevated miR-21 suppressed PTEN levels, which decreased the levels of p-Akt and p NF-kappaB. However, those changes were attenuated in cells co-transfected with HIF-1alpha siRNA and an miR-21 mimic. Silencing of HIF-1alpha or NF-kappaB decreased colony formation and the invasion and migration capacities of CSE transformed HBE cells; however, up-regulation of miR-21 reversed these effects. These results indicate that the oncogenic capacity of HIF-1alpha in regulation of miR-21-inhibited PTEN in a manner dependent on the Akt/NF-kappaB pathway, a process that is involved in the CSE-induced malignant transformation of HBE cells. Thus, the present research has established a new mechanism for cigarette smoke-induced lung carcinogenesis. PMID- 29501574 TI - Cigarette smoke-induced inflammation: NLRP10-mediated mechanisms. AB - Chronic obstructive pulmonary disease (COPD) is a progressive, life-threatening disease that causes irreversible lung damage. Cigarette smoking is the chief etiologic factor for the commencement of this condition. Despite constant efforts to develop therapeutic interventions and to ascertain the molecular mechanism leading to the pathophysiology of this disease, much remains unknown. However, pattern recognition receptors (PRRs), i.e., Toll-like-receptors (TLRs) and NOD like receptors (NLRs) are believed to play important roles in COPD and could serve as effective therapeutic targets. Although the role of TLRs in COPD has been well studied, the importance of NLRs has not yet been explored in detail. The NLR family member NLRP10 (aka NOD8, PAN5, PYNOD) is the only member of this family of proteins that lacks the leucine rich repeat (LRR) domain responsible for detection of pathogen and danger-associated molecular patterns (PAMPs/DAMPs). Therefore, instead of functioning as a PRR, NLRP10 may have a broader regulatory role. To elucidate the role of NLRP10 in secondhand smoke (SHS)-induced inflammation, we exposed C57Bl/6 (WT) and Nlrp10-deficient mice (Nlrp10-/-) on the C57Bl/6 background to filtered air- or SHS- for 6 weeks (acute exposure) and assessed the resulting molecular events. Leukocyte recruitment in SHS-exposed Nlrp10-/- mice was found to be significantly lower compared to SHS-exposed WT mice. In addition, we observed an important role for NLRP10 in SHS-mediated caspase-1 activation, cytokine/chemokine production (IL-1beta, IL-18, MCP-1 and IL-17A), and induction of NF-kappaB and MAPKs in the lungs of C57Bl/6 mice. The reduced influx of CD4+IL-17A+ and CD8+IL-17A+ cells into the lungs of SHS-exposed Nlrp10-/- mice and impaired differentiation of Nlrp10-/- Th0 cells into Th17 cells (ex vivo) provide insight into the mechanistic details underlying NLRP10 dependent IL-17 production. We further substantiated our in vivo findings by challenging human alveolar type II epithelial cells (A549) transfected with scrambled- or Nlrp10-siRNA with cigarette smoke extract (CSE). We observed an important role of NLRP10 in cytokine and chemokine production as well as expression of NF-kappaB and MAPKs in CSE-exposed A549 cells. Furthermore, replenishment of A549 cell culture with recombinant IL-17A (rIL-17A) during NLRP10 knockdown rescued CSE-induced inflammatory responses. To identify upstream mediators of NLRP10 regulation we investigated epigenetic markers within the Nlrp10 promoter following cigarette smoke exposure and observed significant changes in active as well as repressive gene markers on histone 3 and histone 4 using both in vivo and in vitro study models. Further, alterations in the respective histone acetyl- and methyltransferases (PCAF, SET1, ESET, SUV20H1) correlated well with the observed histone modifications. Overall, our findings suggest a novel role of epigenetically regulated NLRP10 in Th17/IL-17 signaling during CS exposure. PMID- 29501575 TI - Orally administered nicotine effects on rat urinary bladder proliferation and carcinogenesis. AB - Tobacco smoking is a major risk factor for human cancers including urinary bladder carcinoma. Cigarette smoke inhalation in mice and orally administered nicotine in rats and mice increased urothelial cell proliferation. Nicotine, a major component of smoke, induced cell proliferation in multiple cell types in vitro. In the present study, the enhancing effects of nicotine on F344 rat bladder carcinogenesis induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) were examined. Nicotine administered in drinking water for 32 weeks following 4 weeks of BBN treatment significantly increased the incidence and number of urothelial carcinomas dose-dependently. Ki67 and pSTAT3 labeling indices and expression of nicotinic acetylcholine receptor alpha 7 (nAChRalpha7) in non-tumor bladder urothelial lesions were significantly increased by nicotine, but the TUNEL assay for apoptosis showed no increase. In a 4 week study, inhibitors of nicotinic acetylcholine receptor decreased nicotine-induced urothelial simple hyperplasia and Ki67 labeling index in the bladder and kidney pelvis at a single cytotoxic dose of nicotine (40 ppm). Urothelial cytotoxicity with regenerative proliferation was observed by light and scanning electron microscopy. In vitro, nicotine was not cytotoxic to rat or human immortalized urothelial cells (do not express nicotine receptors) below millimolar concentrations, nor in human RT4, T24 or UMUC3 urothelial carcinoma cells (express nicotine receptors). However, nicotine slightly, but statistically significantly, increased cell proliferation at micromolar concentrations in human urothelial carcinoma cells. These data suggest that nicotine enhances urinary bladder carcinogenesis by inducing cytotoxicity with regenerative proliferation. The possible role of direct mitogenesis, involving nAChR and STAT3 signaling and of nicotine receptors requires further investigation at non-cytotoxic doses of nicotine. PMID- 29501576 TI - Blood pressure variability and cardiovascular prognosis. Many expectations but limited data. PMID- 29501577 TI - Correlations between CSF proteins and spontaneous neuronal activity in Parkinson's disease. AB - The relationship between cerebrospinal fluid (CSF) proteins and brain function in Parkinson's disease (PD) is not explained clearly. We investigated the correlations between CSF proteins and spontaneous neuronal activity in PD patients via fractional amplitude of low-frequency fluctuation (fALFF) using the Parkinson's Progression Markers Initiative database. Twenty-eight PD patients underwent resting-state functional magnetic resonance imaging in "off" status and lumbar puncture within a month. Correlation analyses between CSF proteins and fALFF value in whole brain as well as clinical assessment scores were performed. We found CSF total tau (t-tau) level was negatively correlated with fALFF in posterior cingulate gyrus. And fALFF in posterior cingulate gyrus was positively correlated with Hopkins Verbal Learning Test-Revised recognition discrimination index. Besides, alpha-synuclein (alpha-syn) level was correlated with fALFF in bilateral inferior frontal gyrus. This study provides evidence that CSF proteins may have a relationship with brain function related to cognitive status in PD patients. PMID- 29501578 TI - Label-free and simple detection of endotoxins using a sensitive LSPR biosensor based on silver nanocolumns. AB - This paper describes the construction of a silver-based LSPR biosensor for endotoxin detection. We used GLAD method to procure reproducible silver nanocolumns. In this work, the silver nanostructures were considerably stabilized by a SAM of MPA, and the limit of detection of biosensor was measured to be 340 pg/ml for endotoxin E. coli. Considering endotoxin B. abortus as the second type of endotoxin contamination in our target samples (HBs-ag produced in Institute Pasteur, Iran), we investigated selectivity of the biosensor in various experiments. We showed that this biosensor can selectively detect both types of endotoxins compared to other biological species. Overall, this study proposes that LSPR biosensing can be considered as a sensitive, simple, and label-free method for endotoxin detection in the quality control laboratories. PMID- 29501579 TI - Chondroitin sulfate protects vascular endothelial cells from toxicities of extracellular histones. AB - Extracellular histones induce lethal thrombosis by promoting platelet aggregation, neutrophil migration, and cell injuries. Heparin, which has negative charges, can bind to extracellular histones; however, heparin strongly inhibits the activation of coagulation. Since chondroitin sulfate (CS) shows less effect on the coagulation system than heparin does, CS has the potential to become an effective drug for lethal thrombosis with high risk of bleeding. To elucidate the therapeutic mechanisms of CS in lethal thrombosis, we investigated the interaction between CS and extracellular histones. Mouse vascular endothelial cells were incubated with histones in the presence of heparin or CS, and the expression of caspase-3/7 was measured. The interactions between histones and heparin or CS were measured by surface plasmon resonance analysis. Vascular permeability, platelet counts, liver and renal functions, and coagulation times were evaluated in an in vivo assay. The apoptosis induced by histones was inhibited by treatment with heparin or CS. Heparin and CS showed strong binding to histones and inhibited vascular hyperpermeability. The platelet counts as well as liver and renal functions were not decreased by the treatment with heparin or CS. Moreover, CS showed less effect on the coagulation system than heparin did. These results suggested that CS can be a novel agent for lethal thrombosis with the risk for hemorrhage. Since vascular endothelial cell injuries occur at an early stage of lethal thrombosis, administration of CS might be a useful approach. PMID- 29501580 TI - The systemic bone protective effects of Gushukang granules in ovariectomized mice by inhibiting osteoclastogenesis and stimulating osteoblastogenesis. AB - Primary osteoporosis (POP), which is caused by unbalanced bone remodeling, leads to significant economic and societal burdens globally. Gushukang (GSK) granule serves as one commonly used prescription for POP in Traditional Chinese Medicine (TCM). The present study aimed to clarify the exact roles of GSK in bone remodeling with in vivo and in vitro assays. Here we showed that GSK prevented bone loss and the alternations of osteoporotic bone parameters as well as the decreased density of osteoclast in ovariectomized (OVX) mice. GSK inhibited receptor activator for nuclear factor-kappa B Ligand (RANKL)-activated osteoclastogenesis in bone marrow macrophages (BMMs). At the molecular levels, GSK inhibited the expression of nuclear factor of activated T cells cytoplasm 1(NFATc1) and c-Fos, two master regulators of osteoclastogenesis. GSK also inhibited bone resorbed genetic expression of matrix metalloproteinase 9 (MMP9), cathepsin K (Ctsk), TRAP and carbonic anhydrase II (Car2). Meanwhile, GSK stimulated osteoblastogenesis from bone primary mesenchymal stem cells (MSCs) and enhanced the expression of Osteirx, and Runx2. GSK also stimulated the expression of Col-1, Osteocalcein and alkaline phosphatase (ALP). Our investigation established the systemic bone protective effects of GSK by suppressing osteoclastogenesis and stimulating osteoblastogenesis and laid bases for new drugs discovery in treating POP. PMID- 29501582 TI - FB1-induced programmed cell death in hemocytes of Ostrinia furnacalis. AB - Fumonisins are a type of mycotoxin produced by Fusarium spp., mainly F. proliferatum and F. vertieilliodes. Fumonisins represent a potential hazard to the health of animals and humans. Autophagic cell death is a method of programed cell death called type II PCD, which has complicated connections with apoptosis. Our results indicated that FB1 substantially inhibited cell viability and was cytotoxic to hemocytes of Ostrinia furnacalis in a time and concentration dependent manner. We verified the activation of FB1-induced autophagy according to MDC staining, Lyso-Tracker Red probe staining, TEM observation and atg8-PE expression levels. We discovered that FB1 induced apoptosis in only a few cells based on Annexin V-FITC and PI staining. These results suggested that FB1 induced survivin inhibition and triggered autophagic cell death in the cell line. These findings might provide a plausible explanation for the underlying mechanisms of FB1 toxicity in insect cellular immune system. In addition, we provided the atg8 gene sequence of Ostrinia furnacalis, and it would be very useful to researchers if they were to study corn borer. PMID- 29501581 TI - Oligo-peptide I-C-F-6 inhibits hepatic stellate cell activation and ameliorates CCl4-induced liver fibrosis by suppressing NF-kappaB signaling and Wnt/beta catenin signaling. AB - Oligo-peptide I-C-F-6 is a Carapax trionycis extract component that has an effect on hepatic fibrosis, however, its mechanism of action is still unclear. This study investigated whether oligo-peptide I-C-F-6 could inhibit liver fibrosis by suppressing NF-kappaB and Wnt/beta-catenin signaling, which are important in liver fibrosis. HSC-T6 cells were treated with oligo-peptide I-C-F-6, and rats were divided randomly into five groups: control (saline), CCl4, CCl4 plus oligo peptide I-C-F-6 (0.12 and 0.24 mg/kg), and CCl4 plus colchicine (0.11 mg/kg). Here, we demonstrated that oligo-peptide I-C-F-6 ameliorated liver injury, inflammation, and hepatic fibrogenesis induced by CCl4. Oligo-peptide I-C-F-6 also inhibited the activation of hepatic stellate cells (HSCs) in vivo and in vitro, as evaluated by the expression of transforming growth factor-beta1 (TGF beta1) and alpha-smooth muscle actin (alpha-SMA), which is a specific marker of HSC activation. Moreover, oligo-peptide I-C-F-6 significantly reduced the expression and distribution of beta-catenin, P-AKT, phospho (P)-GSK-3beta, nuclear factor kappaB (NF-kappaB) P65, phospho-P65, and IkappaB kinase alpha/beta (IKK-alpha/beta) levels; additionally, IkappaB-alpha level was elevated both in vivo and in vitro. Together, these results indicate that oligo-peptide I-C-F-6 has hepatoprotective and anti-fibrotic effects in animal models of liver fibrosis, the mechanism of which may be related to modulating NF-kappaB and Wnt/beta-catenin signaling. PMID- 29501583 TI - The role of hydrogen sulfide in health and disease. PMID- 29501584 TI - Involvement of nociceptive transient receptor potential channels in repellent action of pulegone. AB - Pulegone, one of avian repellents, is used to prevent the economic loss caused by birds. Chemical repellents often evoke unpleasant sensations and sensory irritation resulting in avoidance under some circumstances. It is recognized that some TRP channels expressing sensory neurons are related to nociception. Here we determined the molecular mechanisms of the repellent action of pulegone using isolated chicken sensory neurons and heterologous expression system. Pulegone increased the intracellular Ca2+ concentration ([Ca2+]i) in chicken sensory neurons. There were two types of neurons exhibiting different sensitivity to pulegone. One was responded to it at low concentrations and the other at high concentrations. Pharmacological analyses revealed that the former was predominantly mediated by TRP melastatin 8 (TRPM8), and the latter by both TRP ankyrin 1 (TRPA1) and TRPM8. An activation of both channels by pulegone was also determined using heterologously expression system. At high concentrations, pulegone suppressed chicken TRPM8 but not chicken TRPA1. The intraplantar injection of pulegone in chicks caused pain-related behaviors that were attenuated by TRPA1 antagonist. These results indicate that pulegone stimulates both TRPM8 and TRPA1 channel in chicken sensory neurons and suppresses the former but not the latter at high concentrations. Together, these data suggest that the molecular target for the repellent action of pulegone in avian species is nociceptive TRPA1. PMID- 29501585 TI - Cytochrome P4501-inhibiting chemicals amplify aryl hydrocarbon receptor activation and IL-22 production in T helper 17 cells. AB - The aryl hydrocarbon receptor (AHR) controls interleukin 22 production by T helper 17 cells (Th17). IL-22 contributes to intestinal homeostasis but has also been implicated in chronic inflammatory disorders and colorectal cancer, highlighting the need for appropriate regulation of IL-22 production. Upon activation, the AHR induces expression of cytochrome P4501 (CYP1) enzymes which in turn play an important feedback role that curtails the duration of AHR signaling by metabolizing AHR ligands. Recently we described how agents that inhibit CYP1 function potentiate AHR signaling by disrupting metabolic clearance of the endogenous ligand 6-formylindolo[3,2-b]carbazole (FICZ). In the present study, we investigated the immune-modulating effects of environmental pollutants such as polycyclic aromatic hydrocarbons on Th17 differentiation and IL-22 production. Using Th17 cells deficient in CYP1 enzymes (Cyp1a1/1a2/1b1-/-) we show that these chemicals potentiate AHR activation through inhibition of CYP1 enzymes which leads to increases in intracellular AHR agonists. Our findings demonstrate that IL-22 production by Th17 cells is profoundly enhanced by impaired CYP1-function and strongly suggest that chemicals able to modify CYP1 function or expression may disrupt AHR-mediated immune regulation by altering the levels of endogenous AHR agonist(s). PMID- 29501586 TI - PARP1 interacts with STAT3 and retains active phosphorylated-STAT3 in nucleus during pathological myocardial hypertrophy. AB - The activation of signal transducer and activator of transcription 3 (STAT3) positively regulates myocardial hypertrophy, and its transcriptional activity is finely conditioned by diverse extracellular growth factors and cytokines. Here, we introduce novel evidence that poly(ADP-ribose) polymerase 1 (PARP1) interacts with STAT3 and promotes its activation in cardiomyocytes and rat heart tissues. PARP1 activity and phosphorylated STAT3 were augmented by hypertrophic stimuli both in vitro and in vivo. Infection of PARP1 adenovirus induced cardiomyocyte hypertrophy, which could be prevented by STAT3 knockdown or inhibition. Additionally, PARP1 enhanced STAT3 phosphorylation level, nuclear accumulation and transcriptional activity. Mechanistically, PARP1 interacts with STAT3 and retains active phosphorylated-STAT3 in nucleus. In conclusion, our findings provide the first evidence that PARP1 exacerbates cardiac hypertrophy by stabilizing active phosphorylated-STAT3, which suggests that multi-target therapeutic strategies counteracting PARP1 activity and STAT3 activation would be potential for treating cardiovascular diseases. PMID- 29501587 TI - RNA interference therapy for autosomal dominant osteopetrosis type 2. Towards the preclinical development. AB - Autosomal Dominant Osteopetrosis type 2 (ADO2) is a rare bone disease characterized by dense and brittle bones due to impairment of osteoclast bone resorption. Dominant negative mutations of the CLCN7 gene affect about 70% of ADO2 patients. ADO2 has no cure and our recent work established that it is suitable for gene silencing by a specific small interfering RNA that does not affect the normal mRNA, thus inducing a condition of pseudo-haplosufficiency and rescuing the bone phenotype. We performed a systematic study to test the likelihood that the therapy could progress towards clinical trials, treating Clcn7G213R/WT ADO2 mice with Clcn7G213R-specific siRNA and investigating the bone phenotype by MUCT and histomorphometry, and safety, by histopathology and serology. We demonstrated that our Clcn7G213R siRNA is not only effective in pre pubertal ADO2 male mice as we showed in our previous study, but also in adult and ageing mice, in males and females, by intraperitoneal and subcutaneous administration. Furthermore, the study also showed safety following prolonged chronic administration and allowed us to identify specific end-points to be potentially used in clinical trials. These results may pave the way towards regulatory toxicity studies, through which the therapy, that is patent-protected, can obtain approval from public health authorities for the transition to the Phase I/II clinical trials. The study also suggests that similar strategies could be applied to other autosomal dominant bone diseases, opening an avenue for a wider use of the RNA interference therapy in rare genetic disorders. PMID- 29501588 TI - Migration of blood cells and phospholipid vesicles induced by concentration gradients in microcavities. AB - Microcavities provide a well-controlled flow-free microenvironment and play an important role in many microfluidic systems, for example as cell-culturing microchambers. Here we show that transient concentration gradients that emerge during diffusive exchange of solutes in microcavities induce passive migration (diffusiophoresis) of blood cells and synthetic phospholipid vesicles. The passive migration is observed in various concentration gradients comprising non electrolytes and electrolytes, i.e., glucose, sucrose, sodium chloride, potassium chloride, potassium benzoate, and potassium sulfate. The results add to prior reports, where gradients of non-electrolytes and monovalent salts, produced by micropipette injection, did not induce a noticeable migration of vesicles. The migration distances measured depended on the solution and the cell or vesicle type, and were in the range of several tens of micrometers. The results show that diffusiophoresis of cells and vesicles is a notable phenomenon in a flow-free environment and has to be taken into account when an accurate spatiotemporal control of cells or vesicles in microcavities is required. PMID- 29501590 TI - Modeling of pharmacokinetics, efficacy, and hemodynamic effects of macitentan in patients with pulmonary arterial hypertension. AB - BACKGROUND: Macitentan is the first endothelin receptor antagonist with demonstrated efficacy on morbidity and mortality in pulmonary arterial hypertension (PAH) in the pivotal study SERAPHIN. METHODS: The pharmacokinetics (PK) of macitentan and its active metabolite, ACT-132577, were characterized in a population model. Efficacy and hemodynamics (pharmacodynamics, PD) were related to PK based on PK/PD modeling. RESULTS: Sex, age, and body weight influenced the PK to a statistically significant extent. Model-based simulations showed that these variables are clinically not relevant. Concomitant use of PAH medication (PDE-5 inhibitors) did not influence macitentan trough concentration to a relevant extent. Efficacy and hemodynamics showed clear differences from placebo for macitentan concentrations on 3 and 10 mg with consistent superior effects for 10 mg. After 6 months, PAH patients showed model-predicted 6-min walk distance (6 MWD) improvements of 1.0 m on placebo compared to 29.8 and 34.1 m on 3 and 10 mg of macitentan, respectively. Higher macitentan concentrations were associated with reductions in pulmonary vascular resistance (PVR), mean right atrial and pulmonary arterial pressure, and total pulmonary resistance (TPR) and increases in cardiac index (CI) and mixed venous oxygen saturation. Statistical significance was determined for PVR, TPR, and CI but not for 6-MWD. In addition, PVR showed more pronounced differences between active treatment and placebo than 6-MWD. CONCLUSIONS: Modeling identified statistically significant inter-patient differences; simulations to assess the magnitude of the effects permitted clinical judgment. The same approach will allow for extrapolation to children. Hemodynamic markers might be better markers of treatment effects than 6-MWD. TRIAL REGISTRATION: The SERAPHIN study and its open-label extension are registered with ClinicalTrials.gov with identifiers NCT00660179 (https://www.clinicaltrials.gov/ct2/show/NCT00660179) and NCT00667823 (https://clinicaltrials.gov/ct2/show/NCT00667823) and with EudraCT with identifiers 2007-002440-14 (https://www.clinicaltrialsregister.eu/ctr search/search?query=2007-002440-14) and 2007-003694-27 (https://www.clinicaltrialsregister.eu/ctr-search/search?query=2007-003694-27). PMID- 29501589 TI - Epithelial-mesenchymal transition in breast epithelial cells treated with cadmium and the role of Snail. AB - Epidemiological and experimental studies have implicated cadmium (Cd) with breast cancer. In breast epithelial MCF10A and MDA-MB-231 cells, Cd has been shown to promote cell growth. The present study examined whether Cd also promotes epithelial-mesenchymal transition (EMT), a hallmark of cancer progression. Human breast epithelial cells consisting of non-cancerous MCF10A, non-metastatic HCC 1937 and HCC 38, and metastatic MDA-MB-231 were treated with 1 or 3 MUM Cd for 4 weeks. The MCF10A epithelial cells switched to a more mesenchymal-like morphology, which was accompanied by a decrease in the epithelial marker E cadherin and an increase in the mesenchymal markers N-cadherin and vimentin. In both non-metastatic HCC 1937 and HCC 38 cells, treatment with Cd decreased the epithelial marker claudin-1. In addition, E-cadherin also decreased in the HCC 1937 cells. Even the mesenchymal-like MDA-MB-231 cells exhibited an increase in the mesenchymal marker vimentin. These changes indicated that prolonged treatment with Cd resulted in EMT in both normal and cancer-derived breast epithelial cells. Furthermore, both the MCF10A and MDA-MB-231 cells labeled with Zcad, a dual sensor for tracking EMT, demonstrated a decrease in the epithelial marker E cadherin and an increase in the mesenchymal marker ZEB-1. Treatment of cells with Cd significantly increased the level of Snail, a transcription factor involved in the regulation of EMT. However, the Cd-induced Snail expression was completely abolished by actinomycin D. Luciferase reporter assay indicated that the expression of Snail was regulated by Cd at the promotor level. Snail was essential for Cd-induced promotion of EMT in the MDA-MB-231 cells, as knockdown of Snail expression blocked Cd-induced cell migration. Together, these results indicate that Cd promotes EMT in breast epithelial cells and does so by modulating the transcription of Snail. PMID- 29501591 TI - Comparison of Outcomes in Below-Knee Amputation between Vascular and General Surgeons. AB - BACKGROUND: There is evidence to suggest outcomes may be related to surgeon experience or skill level. Lower extremity amputations are performed by both general surgeons (GSs) and vascular surgeons (VSs); however, the effect of specialty on postoperative outcome in below-knee amputation is not known. This retrospective study compares outcomes in below-knee amputations (BKA) between VS and GS. METHODS: Patients who underwent below-knee amputations between 2005 and 2014 were identified from the American College of Surgeons National Surgical Quality Improvement Project database. Data collected included patient demographics, comorbid conditions, and indication for procedures. Univariate and multivariate unconditional logistic regression models and linear regression models were employed to evaluate the associations between various outcomes and indications for surgery, emergency and teaching status, and surgical specialty. RESULTS: Amputations performed by GSs experienced an increased risk of developing pneumonia (odds ratio [OR] = 1.49, 95% confidence interval [CI]: 1.19-1.86), pulmonary embolism (OR = 2.10, 95% CI: 1.10-4.01), and sepsis (OR = 1.29, 95% CI: 1.05-1.59). When stratified by indications for BKA, similar outcomes were noted between GS and VS if indication for surgery was diabetes or peripheral vascular disease; however, there was increased risk of pneumonia (OR = 1.86, 95% CI: 1.26 2.74), sepsis (OR = 1.96, 95% CI: 1.39-2.75), and death (OR = 1.47, 95% CI: 1.04 2.07, P = 0.027) when GS performed BKA for infectious indications. Overall complications were higher when GS performed BKA emergently (OR = 1.17, 95% CI: 1.01-1.36). CONCLUSION: There are less postoperative complications when VSs performed BKA for infectious indications, during emergencies, and at nonteaching hospitals. Clinicians should consider vascular consultation for these specific scenarios. PMID- 29501592 TI - Patient-Reported Outcome Measures in Carotid Artery Revascularization: Systematic Review and Psychometric Analysis. AB - BACKGROUND: Patient-reported outcome measures (PROMs) provide a way to measure the impact of a disease and its associated treatments on the quality of life (QoL) from the patients' perspective. The aim of this review was to identify PROMs that have been developed and/or validated in patients with carotid artery stenosis (CAS) undergoing revascularization and to assess their psychometric properties and examine suitability for research and clinical use. METHODS: Eight electronic databases including MEDLINE and CINAHL were searched using a 2-stage search approach to identify studies reporting the development and/or validation of relevant PROMs in patients with CAS undergoing revascularization. Supplementary citation searching and hand-searching reference lists of included studies were also undertaken. The COnsensus-based Standards for the selection of health Measurement INstruments and Oxford criteria were used to assess the methodological quality of the included studies, and the psychometric properties of the PROMs were evaluated using established assessment criteria. RESULTS: Five studies reporting on 6 PROMs were included: 36-Item Short Form Health Survey (SF 36), Euro-QoL-5-Dimension Scale (EQ-5D), Hospital Anxiety and Depression Scale, Dizziness Handicap Inventory, QoL for carotid artery disease scale, and a disease specific PROM for CAS. The rigor of the psychometric assessment of the PROMs was variable with most only attempting to assess a single psychometric criterion. No study reported evidence on construct validity and test-retest reliability. Evidence for acceptability for the use of SF-36, EQ-5D, and the disease-specific PROM was rated good in most studies. Only one study reported a Cronbach alpha score >0.70 as evidence of internal consistency. Overall, the psychometric evaluation of all included PROMs was rated as poor within the CAS population undergoing revascularization. CONCLUSIONS: This review highlighted a lack of evidence in validated PROMs used for patients undergoing carotid artery revascularization. As a result, the development and validation of a new PROM for this patient population is warranted to provide data which can supplement traditional clinical outcomes (stroke<30 days post-procedural, myocardial infarction, and death) and capture changes in health status and QoL to help inform treatment decisions. PMID- 29501593 TI - Directional Atherectomy Is Associated with Better Long-Term Efficiency Compared with Angioplasty for Common Femoral Artery Occlusive Disease in Rutherford 2-4 Patients. AB - BACKGROUND: Despite increased interest in treating common femoral artery (CFA) with endovascular technology, there are little data regarding the long-term outcomes of different endovascular treatment modalities. We report the results after endovascular therapy of symptomatic obstructions of the CFA in a single center. METHODS: We retrospectively reviewed the records of consecutive patients with eligible CFA lesions who were treated with endovascular methods between 2011 and 2013. The preoperative demographic operative details and postoperative outcomes were compared and statistically analyzed. RESULTS: Ninety patients with CFA lesions were treated, and 76 (84.4%) completed a follow-up. Claudication was present in 62 of 76 (81.6%) patients, and stenosis was present in 60 of 76 (78.9%) patients. Angioplasty was performed in 45 patients, and atherectomy was performed in 31 patients. There was no significant difference in the preoperative demographic data, procedure time, contrast administration, or length of hospital stay between the 2 groups. In-hospital treatment costs were significantly higher in the atherectomy group (69,822 RenMinBi Yuan vs. 49,078 RenMinBi Yuan; P = 0.043). During the 4-year primary patency, for whole group or bifurcated/claudicant subgroup, all patients within the atherectomy group were significantly better than those in the angioplasty group. CONCLUSIONS: Atherectomy may be a better alternative to angioplasty for CFA atherosclerotic obstructions lesions. Compared with angioplasty, atherectomy seems to have better results in bifurcated lesions or claudicant patients. In diabetic patients, no superiority was found on either patency or improvement in walking distance. PMID- 29501594 TI - Eversion Femoral Endarterectomy for Iliofemoral Occlusive Disease: A Description of Technique and Series of Cases. AB - BACKGROUND: Eversion endarterectomy (EE) is a well-described technique for the treatment of extracranial cerebrovascular disease. Longitudinal arteriotomy and closure with patch angioplasty is the standard for infrainguinal arterial occlusive disease in the iliofemoral segment. A potential drawback of this technique is the introduction of exogenous material into the field. We herein describe a technique of transverse femoral arteriotomy with primary closure for treatment of chronic limb ischemia involving the iliofemoral system. METHODS: We retrospectively evaluated all patients who underwent EE at our institution for chronic limb ischemia. Eleven patients were identified who underwent EE by a single surgeon (M.N.) at our institution from 2013 to 2014. Indications for operation included life-limiting claudication, rest pain, and tissue loss. In each case, the external iliac artery (EIA), common femoral artery (CFA), or superficial femoral artery (SFA) was divided with eversion of the proximal and distal segments and endarterectomy. Reconstruction was achieved with primary end to-end closure. Preoperative demographics were evaluated, as well as preoperative and postoperative ankle-brachial indices and Trans-Atlantic Inter-Society Consensus (TASC) II lesion classification when available. In addition, all adjunctive procedures performed both at the time of index operation and subsequently were recorded. Clinical improvement was gauged using the recommended scale for gauging change in clinical status according to Rutherford. RESULTS: Follow-up ranged from 6 weeks to 16 months. There were no amputations, deaths, or surgical site infections. Two patients required concomitant patch angioplasty in the treated segment at the index operation. There was symptom improvement in 9 of 11 patients, with 2 requiring reintervention due to poor outflow. CONCLUSIONS: In patients with arterial occlusive disease of the iliofemoral segment, EE either alone or in association with endovascular stenting or open bypass appears to be a safe and effective technique. It may obviate the need for patch closure. In our initial case series, there were no amputations, deaths, or surgical site infections. Symptoms improved in 9 of 11 patients with only 2 requiring reintervention due to recurrent symptoms during the follow-up period. PMID- 29501595 TI - Heel Wounds Predict Mortality but Not Amputation after Infrapopliteal Revascularization. AB - BACKGROUND: Ischemic heel ulcerations are generally thought to carry a poor prognosis for limb salvage. We hypothesized that patients undergoing infrapopliteal revascularization for heel wounds, either bypass or endovascular intervention, would have lower wound healing rates and amputation-free survival (AFS) than patients with forefoot wounds. METHODS: A retrospective chart review was performed on patients who presented between 2006 and 2013 to our institution with ischemic foot wounds and infrapopliteal arterial disease and underwent either pedal bypass or endovascular tibial artery intervention. Data were collected on patient demographics, comorbidities, wound characteristics, procedural details, and postoperative outcomes then analyzed by initial wound classification. The primary outcome was major amputation or death. RESULTS: Three hundred ninety-eight limbs underwent treatment for foot wounds; accurate wound data were available in 380 cases. There were 101 bypasses and 279 endovascular interventions, with mean follow-up of 24.6 and 19.9 months, respectively (P = 0.02). Heel wounds comprised 12.1% of the total with the remainder being forefoot wounds; there was no difference in treatment modality by wound type (P = 0.94). Of 46 heel wounds, 5 (10.9%) had clinical or radiographic evidence of calcaneal osteomyelitis. Patients with heel wounds were more likely to have diabetes mellitus (DM) (P = 0.03) and renal insufficiency (P = 0.004). 43.1% of wounds healed within 1 year, with no difference by wound location (P = 0.30). Major amputation rate at 1 year was 17.8%, with no difference by wound location (P = 0.81) or treatment type (P = 0.33). One- and 3-year AFS was 66.2% and 44.0% for forefoot wounds and 45.7% and 17.6% for heel wounds, respectively (P = 0.001). In a multivariate analysis, heel wounds and endovascular intervention were both predictors of death; however, there was significant interaction such that endovascular intervention was associated with higher mortality in patients with forefoot wounds (hazard ratio 2.25, P < 0.001) but not those with heel wounds (hazard ratio 0.67, P = 0.31). CONCLUSIONS: Patients presenting with heel ulceration who undergo infrapopliteal revascularization are prone to higher mortality despite equivalent rates of amputation and wound healing and regardless of treatment modality. These patients may benefit from an endovascular-first strategy. PMID- 29501596 TI - Radioprotection Measures during the Learning Curve with Hybrid Operating Rooms. AB - BACKGROUND: Endovascular procedures come with a potential risk of radiation hazards both to patients and to the vascular staff. Classically, most endovascular interventions took place in regular operating rooms (ORs) using a fluoroscopy C-arm unit controlled by a third party. Hybrid operating rooms (HORs) provide an optimal surgical suit with all the qualities of a fixed C-arm device, while allowing the device to be controlled by the surgical team. The latest studies suggest that an operator-controlled system may reduce the radiation dose. The purpose of the present study is to determine the amount of absorbed radiation using an HOR in comparison with a portable C-arm unit and to assess whether the radioprotection awareness of the surgical team influences the radiation exposure. The primary end point was the effective dose in milliSievert (mSv) for the surgical team and the average dose-area product (ADAP) in Gray-meters squared (Gym2) for patients. METHODS: The values of absorbed radiation of the surgical team's dosimeters were collected from January 2015 to May 2016. The HOR was installed in June 2015, and a radioprotection seminar was given in October 2015. The HOR-issued radiation, measured by the maximum dose-area product, ADAP, average dose (AD) per procedure, maximum dose per procedure per month, maximum fluoroscopy time, average fluoroscopic time, peak skin dose, and average skin dose (ASD), was collected monthly from September 2015 to July 2016. The timeline was divided into 3 periods: 5 months pre-HOR (Pre-HOR), 5 months after the HOR installation (PreS-HOR), and 5 months after a radioprotection seminar (PostS HOR). RESULTS: The average number of procedures per month was 22.55 (+/-4.9), including endovascular aneurysm repair/thoracic endovascular aneurysm repair, carotid, visceral, and upper and lower limb endovascular revascularization. The average amount of absorbed radiation by the surgeons during PreS-HOR was 1.07 +/- 0.4 mSv, which was higher than the other periods (Pre-HOR 0.06 +/- 0.03 mSv, P = 0.002; PostS-HOR 0.14 +/- 0.09 mSv, P = 0.000, respectively). The ADAP during PreS-HOR was 0.016 +/- 0.01 Gym2, which was lower than the PostS-HOR (0.001 +/- 0.002 Gym2) (P = 0.034). The AD during PreS-HOR was 0.78 +/- 0.3 Gy and 0.39 +/- 0.3 Gy during PostS-HOR (P = 0.098). The ASD during PreS-HOR was 0.40 +/- 0.2 Gy and 0.20 +/- 0.1 Gy during PostS-HOR (P = 0.099). CONCLUSIONS: In our experience, the HOR increases the amount of absorbed radiation for both patients and surgeons. The radioprotection seminars are of utmost importance to provide a continued training and optimize the use of ionizing radiation while using an HOR. Despite the awareness of the surgical team in the radioprotection field, the amount of absorbed radiation using an HOR is higher than the one using a C-Arm unit. PMID- 29501597 TI - The Influence of 4 or more Patent Lumbar Arteries on Persistent Type II Endoleak and Sac Expansion after Endovascular Aneurysm Repair. AB - BACKGROUND: This study aimed to review our clinical results and determine how preoperative patent lumbar arteries (LAs) influence the occurrence of type II endoleaks or aneurysm sac enlargement after endovascular aneurysm repair (EVAR) and to identify the preoperative computed tomography findings of persistent type II endoleaks from patent LAs that indicate the need for preventive procedures during EVAR. METHODS: A total of 293 patients who underwent EVAR for infrarenal abdominal aortic aneurysm (AAA) between August 2007 and July 2013 were reviewed. Follow-up data were available for 194 patients (76% male, mean age 78 +/- 6.8 years), and the mean follow-up time was 57 +/- 23 months. RESULTS: The number of patent LAs was identified as a significant positive predictor of persistent type II endoleaks (hazard ratio [HR], 1.4; 95% confidence interval [CI]: 1.2-1.7; P < 0.001) and sac enlargement (>=5 mm) at the 2-year follow-up period (HR, 1.3; 95% CI: 1.1-1.8; P = 0.009) after EVAR, using Cox regression analysis. The receiver operating characteristics curve (AUC: 0.72) showed that a cutoff of 4 patent LAs resulted in a sensitivity of 87% and specificity of 48%. The rates of freedom from sac enlargement (>=5 mm) at 3 and 5 years after EVAR were significantly lower in patients with 4 or more patent LAs than in those with fewer (90% and 76% vs. 96% and 89%; P = 0.0008). CONCLUSIONS: The number of patent LAs is associated as a significant risk factor with the development of persistent type II endoleaks and sac enlargement after EVAR. Four or more patent LAs should be recognized as the group having an elevated risk of developing late sac enlargement after EVAR. PMID- 29501598 TI - Decellularized and Secured Porcine Arteries with NaOH-based Process: Proof of Concept. AB - BACKGROUND: There is a need for small caliber vascular prosthesis. Synthetic grafts are hindered by thrombogenicity and rapid occlusion. Decellularized matrices could be an alternative. We assessed in vitro and in vivo the biocompatibility of porcine artery treated with a chemical/physical process for decellularization and graft securitization with non/conventional pathogens inactivation. METHODS: Porcine carotid arteries (PCA) were treated. First, biopsies (n = 4/tissue) were performed before/after treatment to assess decellularization (hematoxylin and eosin/-4',6-diamidino-2 phenylindole/DNA/Miller). Second, 5 rats received an abdominal aortic patch of decellularized PCA (DPCA). Four pigs received subcutaneous DPCA implants (n = 2/pig). Half were explanted at day 15 and half at day 30. Finally, 2 pigs received DPCA (n = 2) and polytetrafluoroethylene prosthesis (n = 1), respectively, as carotid interposition. Implants were removed at day 30. Inflammation (CD3 and CD68 immunostaining) calcifications (von Kossa staining), remodeling (hematoxylin and eosin), and vascular characterization (CD31 and alpha smooth muscle actin immunofluorescent staining) were investigated. RESULTS: Ninety-five percentage of decellularization was obtained without structural deterioration. No death occurred. Low inflammatory reaction was found in the 2 models for DPCA. Acquisition of vascular identity was confirmed in the rodent and porcine models. Similarity between native PCA and DPCA was observed after 30 days. In contrast, polytetrafluoroethylene graft showed severe calcifications, higher CD3 reaction, and higher intimal hyperplasia (P < 0.05). CONCLUSIONS: The physical and chemical process ensures decellularization of carotid porcine arteries and their in vivo remodeling with the presence of an endothelium and smooth-muscle-like cells as well as a low level of inflammatory cells. PMID- 29501599 TI - Associations Among Mucosal and Transmural Healing and Fecal Level of Calprotectin in Children With Crohn's Disease. AB - BACKGROUND & AIMS: Bowel healing is an important goal of therapy for patients with Crohn's disease (CD). Although there have been many studies of mucosal healing, transmural healing (ie, in the bowel wall) has not been investigated in children. We analyzed data from the ImageKids study to determine associations among mucosal, transmural healing and levels of calprotectin and C-reactive protein in children with CD. METHODS: We collected data from a multi-center study designed to develop 2 magnetic resonance enterography (MRE)-based measures for children with CD (6-18 years old). In our analysis of 151 children (mean age, 14.2 +/- 2.4 years), all patients underwent MRE and a complete ileocolonoscopic evaluation; fecal levels of calprotectin and blood levels of C-reactive protein were measured. Mucosal healing was defined as simple endoscopic severity index in CD score below 3, transmural healing as an MRE visual analogue score below 20 mm, and deep healing as a combination of transmural and mucosal healing. RESULTS: We identified mucosal healing with transmural inflammation in 9 children (6%), transmural healing with mucosal inflammation in 38 children (25%), deep healing in 21 children (14%), and mucosal and transmural inflammation in 83 children (55%). The median level of calprotectin was lowest in children with deep healing (mean level, 10 MUg/g; interquartile range, 10-190 MUg/g), followed by children with either transmural or mucosal inflammation, and highest in children with mucosal and transmural inflammation (810 MUg/g; interquartile range, 539-1737 MUg/g) (P < .001). Fecal level of calprotectin identified children with deep healing with an area under the receiver operating characteristic curve value of 0.93 (95% CI, 0.89-0.98); level of C-reactive protein identified children with deep healing with an area under the receiver operating characteristic curve value of 0.81 (95% CI, 0.71-0.9). A calprotectin cutoff value of 100 MUg/g identified children with deep healing with 71% sensitivity and 92% specificity; a cutoff value of 300 MUg/g identified children with mucosal healing with 80% sensitivity and 81% specificity. CONCLUSIONS: In a prospective study of children with CD, we found that one-third have healing in only the mucosa or the bowel wall (not both). Levels of fecal calprotectin below 300 MUg/identify children with mucosal healing, but a lower cutoff value (below 100 MUg/g) is needed to identify children with deep healing. Clinicaltrials.gov no: NCT01881490. PMID- 29501600 TI - Preparation of siRNA encapsulated nanoliposomes suitable for siRNA delivery by simply discontinuous mixing. AB - Previously a scalable and extrusion-free method has been developed for efficient liposomal encapsulation of DNA by twice stepwise mixing of lipids in ethanol and DNA solution using T-shape mixing chamber. In this study, we prepared nanoliposomes encapsulating siRNA by simply discontinuous mixing of lipids in ethanol/ether/water mixture and acidic siRNA solution without use of special equipment. The simple mixing siRNA/liposomal particles (siRNA/SMLs) prepared using ethanol/ether/water (3:1:1) mixture showed 120.4 +/- 20.2 nm particle size, 0.174 +/- 0.033 polydispersity and 86.5 +/- 2.76% siRNA encapsulation rate. In addition, the SMLs almost completely protected the encapsulated siRNA from RNase A digestion. Coupling of anti-human epidermal growth factor receptor (EGFR) Fab' to siRNA/SMLs enhanced EGFR-specific cell penetration of SMLs and induced siRNA dependent gene silencing. Unexpectedly, the Cy5.5-labeled Fab' showed almost no in vivo targeting to the xenografted A549 tumors in SCID-NOD mice. However, multiple injection of the unmodified siRNA/SMLs accumulated in the tumors and induced siRNA-dependent in vivo gene silencing. These results demonstrate that the siRNA/SMLs can be used as a siRNA delivery tool for gene therapy. PMID- 29501601 TI - pH sensing by lipids in membranes: The fundamentals of pH-driven migration, polarization and deformations of lipid bilayer assemblies. AB - Most biological molecules contain acido-basic groups that modulate their structure and interactions. A consequence is that pH gradients, local heterogeneities and dynamic variations are used by cells and organisms to drive or regulate specific biological functions including energetic metabolism, vesicular traffic, migration and spatial patterning of tissues in development. While the direct or regulatory role of pH in protein function is well documented, the role of hydrogen and hydroxyl ions in modulating the properties of lipid assemblies such as bilayer membranes is only beginning to be understood. Here, we review approaches using artificial lipid vesicles that have been instrumental in providing an understanding of the influence of pH gradients and local variations on membrane vectorial motional processes: migration, membrane curvature effects promoting global or local deformations, crowding generation by segregative polarization processes. In the case of pH induced local deformations, an extensive theoretical framework is given and an application to a specific biological issue, namely the structure and stability of mitochondrial cristae, is described. This article is part of a Special Issue entitled: Emergence of Complex Behavior in Biomembranes edited by Marjorie Longo. PMID- 29501602 TI - Prophylactic cefazolin concentrations in morbidly obese patients undergoing sleeve gastrectomy: do we achieve targets? AB - Morbid obesity is known to increase the risk of surgical site infections. Optimal concentrations of prophylactic antibacterial drugs are required. Using Monte Carlo simulations, the aim of this work was to build a population pharmacokinetics model for a morbidly obese population to assess a 4000-mg dose of cefazolin recommended by the guidelines and to propose new administration schemes. One hundred and seventeen morbidly obese patients (mean body mass index, 46.95 kg/m2) received 4000 mg of cefazolin intravenously before sleeve gastrectomy. Using population pharmacokinetics modelling and Monte Carlo simulations, probabilities of target attainment (PTAs) (subcutaneous tissue concentration of cefazolin above the minimum inhibitory concentration (MIC) throughout the surgical procedure was targeted) were determined. For Staphylococcus spp. and Streptococcus spp., which are the most frequent species isolated from post-surgical infections in bariatric surgery (MIC usually <=2 mg/L), PTA remains greater than 0.9 until 2 h after administration of 4000 mg of cefazolin. For MIC up to 4 mg/L, efficient prophylaxis was checked until 1 h after the initial administration. A 3000-mg regimen followed by a continuous infusion (1000 mg/h) achieves these two targets until 4 h after the loading dose. A 2000-mg and a 3000-mg regimen do not achieve sufficient concentrations. According to the duration of surgery and MIC values, an initial administration of 4000 mg should be sufficient, but for extended surgeries continuous infusion can be considered. PMID- 29501603 TI - Impact of polymyxin-B-associated acute kidney injury in 1-year mortality and renal function recovery. AB - The objective of this study was to evaluate the impact of polymyxin B (PMB) associated acute kidney injury (AKI) in 1-year mortality and renal function recovery. Patients >18 years old who survived the first 30 days after PMB therapy were followed for 1 year. The impact of AKI and renal failure (using RIFLE score) in 1-year mortality was analysed, along with other confounding variables. Variables with a P-value <=0.2 were included in a forward stepwise Cox regression model. In the subgroup of patients who developed AKI, we evaluated renal function recovery. A total of 234 patients were included for analyses. Of these, 108 (46.1%) died, in a median time of 63 (38.3-102.5) days. The use of other nephrotoxic drugs along with PMB (P = 0.05), renal failure (P = 0.03), dialysis (P < 0.01) and re-exposure to PMB (P<0.01), were all significantly related to 1 year mortality, while male gender had a protective effect (P = 0.01). Independent factors related to death were age (adjusted hazard ratio (aHR) 1.02, 95% confidence interval (CI) 1.00-1.03, P = 0.02), re-exposure to PMB (aHR 2.69, 95% CI 1.82-3.95, P<0.01), and male gender (aHR0.6, 95% CI 0.41-0.87, P = 0.01), when controlled for renal failure (aHR 1.28, 95% CI 0.78-2.10, P = 0.34).Thirty one of 94 (33%) patients who developed AKI had renal function recovery within 1 year. Mortality rates were high in the first year after PMB use and only one-third of patients who developed AKI returned to baseline renal function. Strategies to reduce renal toxicity are urgently needed in these patients. PMID- 29501604 TI - Monotherapy with High-Dose Once-Daily Tigecycline is Highly Effective Against Acinetobacter baumanii and other Multidrug-Resistant (MDR) Gram-Negative Bacilli (GNB). PMID- 29501605 TI - Scaling relationships for translational diffusion constants applied to membrane domain dissolution and growth. AB - We compare the way that relationships for diffusion constants scale with the size of diffusing membrane domains and the geometry of their environments. Then, we review our experimental work on the dynamics of dissolution/growth of membrane domains in crowding induced mixing, phase separation, and Ostwald ripening in a highly confined environment. Overall, the scaling relationships applied to diffusion constants obtained by fits to our dynamic data indicate that dissolution and growth is influenced by the diffusion of clusters or small domains of lipids, in addition to kinetic processes and geometrical constraints. PMID- 29501606 TI - Amyloid growth and membrane damage: Current themes and emerging perspectives from theory and experiments on Abeta and hIAPP. AB - Alzheimer's Disease (AD) and Type 2 diabetes mellitus (T2DM) are two incurable diseases both hallmarked by an abnormal deposition of the amyloidogenic peptides Abeta and Islet Amyloid Polypeptide (IAPP) in affected tissues. Epidemiological data demonstrate that patients suffering from diabetes are at high risk of developing AD, thus making the search for factors common to the two pathologies of special interest for the design of new therapies. Accumulating evidence suggests that the toxic properties of both Abeta or IAPP are ascribable to their ability to damage the cell membrane. However, the molecular details describing Abeta or IAPP interaction with membranes are poorly understood. This review focuses on biophysical and in silico studies addressing these topics. Effects of calcium, cholesterol and membrane lipid composition in driving aberrant Abeta or IAPP interaction with the membrane will be specifically considered. The cross correlation of all these factors appears to be a key issue not only to shed light in the countless and often controversial reports relative to this area but also to gain valuable insights into the central events leading to membrane damage caused by amyloidogenic peptides. This article is part of a Special Issue entitled: Protein Aggregation and Misfolding at the Cell Membrane Interface edited by Ayyalusamy Ramamoorthy. PMID- 29501607 TI - The N-terminal amphipathic helix of Pex11p self-interacts to induce membrane remodelling during peroxisome fission. AB - Pex11p plays a crucial role in peroxisome fission. Previously, it was shown that a conserved N-terminal amphipathic helix in Pex11p, termed Pex11-Amph, was necessary for peroxisomal fission in vivo while in vitro studies revealed that this region alone was sufficient to bring about tubulation of liposomes with a lipid consistency resembling the peroxisomal membrane. However, molecular details of how Pex11-Amph remodels the peroxisomal membrane remain unknown. Here we have combined in silico, in vitro and in vivo approaches to gain insights into the molecular mechanisms underlying Pex11-Amph activity. Using molecular dynamics simulations, we observe that Pex11-Amph peptides form linear aggregates on a model membrane. Furthermore, we identify mutations that disrupted this aggregation in silico, which also abolished the peptide's ability to remodel liposomes in vitro, establishing that Pex11p oligomerisation plays a direct role in membrane remodelling. In vivo studies revealed that these mutations resulted in a strong reduction in Pex11 protein levels, indicating that these residues are important for Pex11p function. Taken together, our data demonstrate the power of combining in silico techniques with experimental approaches to investigate the molecular mechanisms underlying Pex11p-dependent membrane remodelling. PMID- 29501608 TI - Stimulation of alpha-synuclein amyloid formation by phosphatidylglycerol micellar tubules. AB - alpha-Synuclein (alpha-Syn) is a presynaptic protein that is accumulated in its amyloid form in the brains of Parkinson's patients. Although its biological function remains unclear, alpha-syn has been suggested to bind to synaptic vesicles and facilitate neurotransmitter release. Recently, studies have found that alpha-syn induces membrane tubulation, highlighting a potential mechanism for alpha-syn to stabilize highly curved membrane structures which could have both functional and dysfunctional consequences. To understand how membrane remodeling by alpha-syn affects amyloid formation, we have studied the alpha-syn aggregation process in the presence of phosphatidylglycerol (PG) micellar tubules, which were the first reported example of membrane tubulation by alpha syn. Aggregation kinetics, beta-sheet content, and macroscopic protein-lipid structures were observed by Thioflavin T fluorescence, circular dichroism spectroscopy and transmission electron microscopy, respectively. Collectively, the presence of PG micellar tubules formed at a stochiometric (L/P = 1) ratio was found to stimulate alpha-syn fibril formation. Moreover, transmission electron microscopy and solid-state nuclear magnetic resonance spectroscopy revealed the co-assembly of PG and alpha-syn into fibril structures. However, isolated micellar tubules do not form fibrils by themselves, suggesting an important role of free alpha-syn monomers during amyloid formation. In contrast, fibrils did not form in the presence of excess PG lipids (>=L/P = 50), where most of the alpha syn molecules are in a membrane-bound alpha-helical form. Our results provide new mechanistic insights into how membrane tubules modulate alpha-syn amyloid formation and support a pivotal role of protein-lipid interaction in the dysfunction of alpha-syn. PMID- 29501609 TI - Effects of the Arg9Cys and Arg25Cys mutations on phospholamban's conformational equilibrium in membrane bilayers. AB - Approximately, 70% of the Ca2+ ion transport into the sarcoplasmic reticulum is catalyzed by the sarcoplasmic reticulum Ca2+-ATPase (SERCA), whose activity is endogenously regulated by phospholamban (PLN). PLN comprises a TM inhibitory region and a cytoplasmic regulatory region that harbors a consensus sequence for cAMP-dependent protein kinase (PKA). The inhibitory region binds the ATPase, reducing its apparent Ca2+ binding affinity. beta-adrenergic stimulation activates PKA, which phosphorylates PLN at Ser 16, reversing its inhibitory function. Mutations and post-translational modifications of PLN may lead to dilated cardiomyopathy (DCM) and heart failure. PLN's cytoplasmic region interconverts between a membrane-associated T state and a membrane-detached R state. The importance of these structural transitions on SERCA regulation is emerging, but the effects of natural occurring mutations and their relevance to the progression of heart disease are unclear. Here we use solid-state NMR spectroscopy to investigate the structural dynamics of two lethal PLN mutations, R9C and R25C, which lead to DCM. We found that the R25C mutant enhances the dynamics of PLN and shifts the conformational equilibrium toward the R state confirmation, whereas the R9C mutant drives the amphipathic cytoplasmic domain toward the membrane-associate state, enriching the T state population. The changes in membrane interactions caused by these mutations may explain the aberrant regulation of SERCA. PMID- 29501610 TI - Comparative Effectiveness of Initial Treatment at Trauma Center vs Neurosurgery Capable Non-Trauma Center for Severe, Isolated Head Injury. AB - BACKGROUND: Head injury is an increasing contributor to death and disability, particularly among the elderly. Older patients are less likely to be treated at trauma centers, and head injury is the most common severe injury treated at non trauma centers. We hypothesized that patients initially triaged to trauma centers would have lower rates of mortality and higher rates of discharge home without services than those treated at non-trauma centers. STUDY DESIGN: We used the State Emergency Department and Inpatient Databases (2011 to 2012) for 6 states to conduct a retrospective cohort study of patients with severe, isolated head injury. Combined, these databases capture all visits to non-federal emergency departments. We compared in-hospital mortality and discharge status for all adults and for the subgroup aged 65 years or older who initially presented to either a trauma center or a neurosurgery-capable non-trauma center. To account for selection bias, we used differential distance from patients' homes to a trauma center as an instrumental variable and performed a multivariable matched analysis. RESULTS: Of 62,198 patients who presented with severe, isolated head injury, 44.2% presented to non-trauma centers and 55.8% to trauma centers. In multivariable matched instrumental variable analysis, initial presentation to a trauma center was associated with no significant difference in overall mortality (-1.06%; 95% CI -3.36% to 1.19%), but a 5.8% higher rate of discharge home (95% CI 1.7% to 10.0%). Among patients aged 65 years or older, initial presentation to a trauma center was associated with a 3.4% reduction in mortality (95% CI 0.0% to 7.1%). CONCLUSIONS: Patients with isolated, severe head injury have better outcomes if initially treated in designated trauma centers. As 40% of such patients were triaged to non-trauma centers, there are major opportunities for improving outcomes. PMID- 29501611 TI - 12q14 microdeletion syndrome: A family with short stature and Silver-Russell syndrome (SRS)-like phenotype and review of the literature. AB - We report here on the first family with short stature and Silver-Russell-like phenotype due to a microdeletion in 12q14.3. The Netchine-Harbison clinical scoring system was used for the clinical diagnosis of Silver-Russell syndrome (SRS). The three affected first-degree relatives (index patient, mother and brother) presented with prenatal and postnatal growth retardation, feeding difficulties, a prominent forehead and a failure to thrive, but did not show relative macrocephaly. In addition, our index patient showed dysmorphic facial features, periodically increased sweating, and scoliosis. Learning problems and cardiac arrhythmia presented as additional features of her brother. Using high resolution array-CGH, heterozygosity for a 1.67 Mb deletion in 12q14.3 was detected in the index patient. The heterozygous loss was confirmed by MLPA in the index patient and the other two affected family members. The deletion includes the genes HMGA2, LLPH, TMBIM4, IRAK3, HELB, GRIP1, and the pseudogene RPSAP52. We conclude from these results and from the data of other patients reported in the literature that haploinsufficiency of HMGA2 leads to the short stature in this family. PMID- 29501612 TI - Exome sequencing reveals blended phenotype of double heterozygous FBN1 and FBN2 variants in a fetus. AB - We report a 29 week fetus with arthrogryposis multiplex congenita, multiple joint dislocations, scoliosis and dysmorphism who was detected to be double heterozygote for putatively pathogenic FBN1 (NM_000138.4:c.6004C > T; p.Pro2002Ser) and FBN2 (NM_001999.3:c.2945G > T; p.Cys982Phe) variants on exome sequencing. The de-novo status of these variants is not confirmed as parental genotypes could not be ascertained. A comparison of the post-mortem findings of the fetus with reported phenotypes of Beals and Marfan syndromes indicated overlapping clinical features suggestive of a blended phenotype. PMID- 29501613 TI - 3q29 microduplication syndrome: Description of two new cases and delineation of the minimal critical region. AB - Heterogeneous clinical and neuropsychological features, such as intellectual disability, developmental and language delay, hypotonia, and, to a lesser extent, microcephaly that is present in about the half of the reported patients, characterize the 3q29 microduplication syndrome with usually a milder phenotype compared with the corresponding 3q29 microdeletion syndrome. The duplications described so far range from 2.3 Mb to 1.6 Mb, spanning from TFRC to BDH1 genes. Here we report on two patients with overlapping interstitial duplications of the 3q29 region differing in size. Patient 1 harboured a common-seized 3q29 microduplication spanning ~1.6 Mb, while patient 2 carried a very small 3q29 microduplication of 448.8 Kb encompassing only two genes, DLG1 and BDH1. Both patients presented clinical characteristics similar to those reported in the literature in 3q29 microduplication syndrome. Interestingly, heterotopic gray matter nodules were found along the right lateral ventricle on brain MRI in patient 1, thus expanding the neuroradiological phenotype in 3q29 microduplication syndrome, while patient 2 allowed us to define with more precision the smallest region of overlap (SRO). Gene content analysis of the duplicated region suggests that gain-of-dosage of DLG1 and BDH1 may be a good candidate for the main clinical features of this syndrome. PMID- 29501614 TI - Redox control in cancer development and progression. AB - Cancer is the leading cause of death worldwide after cardiovascular diseases. This has been the case for the last few decades despite there being an increase in the number of cancer treatments. One reason for the apparent lack of drug effectiveness might be, at least in part, due to unspecificity for tumors; which often leads to substantial side effects. One way to improve the treatment of cancer is to increase the specificity of the treatment in accordance with the concept of individualized medicine. This will help to prevent further progression of an existing cancer or even to reduce the tumor burden. Alternatively it would be much more attractive and efficient to prevent the development of cancer in the first place. Therefore, it is important to understand the risk factors and the mechanisms of carcinogenesis in detail. One such risk factor, often associated with tumorigenesis and tumor progression, is an increased abundance of reactive oxygen species (ROS) arising from an imbalance of ROS-producing and -eliminating components. A surplus of ROS can induce oxidative damage of macromolecules including proteins, lipids and DNA. In contrast, ROS are essential for an adequate signal transduction and are known to regulate crucial cellular processes like cellular quiescence, differentiation and even apoptosis. Therefore, regulated ROS-formation at physiological levels can inhibit tumor formation and progression. With this review we provide an overview on the current knowledge of redox control in cancer development and progression. PMID- 29501615 TI - Glucagon-like peptide-1 mediates effects of oral galactose in streptozotocin induced rat model of sporadic Alzheimer's disease. AB - Insulin resistance and metabolic dysfunction in the brain are considered to be the pathophysiological core of sporadic Alzheimer's disease (sAD). In line with that fact, nutrients that could have therapeutic effects at this level have been investigated as possible targets in AD therapy. Galactose, an epimer of glucose, may serve as an alternative source of energy, and given orally may stimulate secretion of the incretin hormone glucagon-like peptide-1 (GLP-1). Our preliminary research indicated that oral galactose might prevent development of memory impairment in a rat model of sAD generated by intracerebroventricular administration of streptozotocin (STZ-icv). Here, we explored whether chronic oral galactose treatment could have beneficial effects on cognitive deficits already manifested at the time of initiation of galactose treatment in adult STZ icv rats (treatment initiated 1 month after STZ-icv injection). The results clearly show that a 2-month exposure to oral galactose (200 mg/kg/day administered in a drink ad libitum) normalises impaired learning and memory functions. Memory improvement was accompanied by an improvement in brain glucose hypometabolism measured by 18fluorodeoxyglucose-positron emission tomography neuroimaging and by increments in active GLP-1 plasma levels as well as by an increased expression of GLP-1 receptors in the hippocampus and hypothalamus. Our findings provide strong evidence of beneficial effects of oral galactose treatment in the STZ-icv rat model of sAD and present possible underlying mechanisms including both direct effects of galactose within the brain and indirect GLP-1-induced neuroprotective effects that might open a new, dietary based strategy in sAD treatment. PMID- 29501616 TI - Multiple nucleobase transporters contribute to boscalid sensitivity in Aspergillus nidulans. AB - The development of fungicide-resistant fungal populations represents a major challenge for the agrochemical and agri-food sectors, which threatens food supply and security. The issue becomes complex for fungi that cause quantitative and qualitative losses due to mycotoxin biosynthesis. Nonetheless, currently, the molecular details underlying fungicide action and fungal resistance mechanisms are partially known. Here, we have investigated whether plasma membrane transporters contribute to specific fungicide uptake in the model fungus Aspergillus nidulans. Independent physiological tests and toxicity screening of selected fungicides provided evidence that the antifungal activity of Succinate Dehydrogenase Inhibitors (SDHIs) is associated with the expression of several nucleobase-related transporters. In particular, it was shown that a strain genetically inactivated in all seven nucleobase-related transporters is resistant to the fungicide boscalid, whereas none of the single null mutants exhibited significant resistance level. By constructing and testing isogenic strains that over-express each one of the seven transporters, we confirmed that five of them, namely, UapC, AzgA, FycB, CntA, and FurA, contribute to boscalid uptake. Additionally, by employing metabolomics we have examined the effect of boscalid on the metabolism of isogenic strains expressing or genetically lacking boscalid related nucleobase transporters. The results confirmed the involvement of specific nucleobase transporters in fungicide uptake, leading to the discovery of corresponding metabolites-biomarkers. This work is the first report on the involvement of specific transporters in fungicide uptake and toxicity and their impact on fungal metabolism regulation and results might be further exploited towards the deeper understanding of fungal resistance to fungicides. PMID- 29501617 TI - Multifaceted immune functions of human defensins and underlying mechanisms. AB - Defensins have been long recognized as natural antimicrobial peptides, but they also possess diverse and versatile immune functions. Defensins can both induce inflammation and suppress inflammatory responses by acting on specific cells through distinct mechanisms. Defensins can also modulate the immune response by forming a complex with cellular molecules including proteins, nucleic acids, and carbohydrates. The mechanisms of defensin-mediated immune modulation appear to be cell-type and context specific. Because the levels of human defensins are often altered in response to infection or disease states, suggesting their clinical relevance, this review summarizes the complex immune functions of human defensins and their underlying mechanisms of action, which have implications for the development of new therapeutics. PMID- 29501618 TI - Candida innate immunity at the mucosa. AB - The tremendous diversity in microbial species that colonise the mucosal surfaces of the human body is only now beginning to be fully appreciated. Distinguishing between the behaviour of commensal microbes and harmful pathogens that reside at mucosal sites in the body is a complex, and exquisitely fine-tuned process central to mucosal health. The fungal pathobiont Candida albicans is frequently isolated from mucosal surfaces with an asymptomatic carriage rate of approximately 60% in the human population. While normally a benign member of the microbiota, overgrowth of C. albicans often results in localised mucosal infection causing morbidity in otherwise healthy individuals, and invasive infection that often causes death in the absence of effective immune defence. C. albicans triggers numerous innate immune responses at mucosal surfaces, and detection of C. albicans hyphae in particular, stimulates the production of antimicrobial peptides, danger-associated molecular patterns and cytokines that function to reduce fungal burdens during infection. This review will summarise our current understanding of innate immune responses to C. albicans at mucosal surfaces. PMID- 29501619 TI - Self-reported tick-borne encephalitis (TBE) vaccination coverage in Europe: Results from a cross-sectional study. AB - Adequate vaccination is effective in preventing tick-borne encephalitis (TBE). A population survey conducted in 2015 in Czech Republic, Estonia, Finland, Germany, Hungary, Latvia, Lithuania, Poland, Slovakia, Slovenia, and Sweden obtained information on TBE vaccination. Respondents answered 10 questions for themselves and household members. Data were weighted according to age and fine-tuned for geographical spread. Across the 10 countries (excluding Poland), TBE awareness was 83%; of all respondents, 68% were aware of TBE vaccines and 25% had >=1 injections. Vaccination rates were lowest in Finland and Slovakia (~10%), highest in Austria (85%, results from a separate 2015 survey), and varied widely in Germany. Across the 11 countries (excluding Austria), compliance with vaccination schedule among TBE-vaccinated respondents was 61%; 27% and 15% of respondents received first and second booster injections; strongest motivators for vaccination were fear of TBE (38%) and residence/spending time in high-risk areas (31-35%); main reasons for not receiving vaccination were beliefs that vaccination was unnecessary (33%) and that there was no risk of contracting TBE (23%). TBE vaccine uptake and compliance could be improved with effective public health information to increase TBE awareness and trust in vaccination and by updating recommendations to include all subjects visiting TBE-risk areas. PMID- 29501620 TI - PATSIM: Prediction and analysis of protein sequences using hybrid Knuth-Morris Pratt (KMP) and Boyer-Moore (BM) algorithm. AB - In phylogenomic profiling, the genomic context based methods are based on the observation that two or more proteins having the same pattern of presence or absence in many diverse genomes most likely have a functional link. In this research work, a tool (PATSIM) has been developed to predict the protein patterns based on the SOPM tool. In this tool, the secondary structure for CATH database protein sequences, predicted by the SOPM (Self Optimized Prediction Method) server is passed as input to fulfill objectives such as, (i) Predict the Amino Acid Pattern using the proposed Hybrid KMP and BM algorithm, (ii) Predict the physiochemical properties such as Hydrophobic Non-Polar ALKYL Amino Acid groups, Hydrophobic Non-Polar AROMATIC Amino Acid groups, Hydrophilic Polar Neutral Amino Acid groups, Hydrophilic Polar Acidic Amino Acid groups and Hydrophilic Polar Basic Amino Acid groups of protein sequence, (iii) Predict the secondary structure of protein where the structure of protein sequence is unknown, and (iv) Similarity analysis of protein sequence (structure unknown) with the CATH database. From the results, it is inferred that this tool effectively predicts the similarity between the sequences and also identifies the protein patterns for four secondary structural classes, namely Alpha Helix (h), Beta Sheet (e), Turn (t) and Coil (c). Based on the experimental results, it is inferred that this tool identifies the physiochemical properties of the protein sequence in an effective manner. The source code and its documentation for the PATSIM tool is freely available in the GitHub public repository (https://github.com/manimkn89/Protein-Sequence-Analysis). PMID- 29501621 TI - Shedding light on lipid metabolism in Kinetoplastida: A phylogenetic analysis of phospholipase D protein homologs. AB - Unicellular flagellates that make up the class Kinetoplastida include multiple parasites responsible for public health concerns, including Trypanosoma brucei and T. cruzi (agents of African sleeping sickness and Chagas disease, respectively), and various Leishmania species, which cause leishmaniasis. These diseases are generally difficult to eradicate, with treatments often having lethal side effects and/or being effective only during the acute phase of the diseases, when most patients are still asymptomatic. Phospholipid signaling and metabolism are important in the different life stages of Trypanosoma, including playing a role in transitions between stages and in immune system evasion, thus, making the responsible enzymes into potential therapeutic targets. However, relatively little is understood about how the pathways function in these pathogens. Thus, in this study we examined evolutionary history of proteins from one such signaling pathway, namely phospholipase D (PLD) homologs. PLD is an enzyme responsible for synthesizing phosphatidic acid (PA) from membrane phospholipids. PA is not only utilized for phospholipid synthesis, but is also involved in many other signaling pathways, including biotic and abiotic stress response. 37 different representative Kinetoplastida genomes were used for an exhaustive search to identify putative PLD homologs. The genome of Bodo saltans was the only one of surveyed Kinetoplastida genomes that encoded a protein that clustered with plant PLDs. The representatives from other Kinetoplastida species clustered together in two different clades, thought to be homologous to the PLD superfamily, but with shared sequence similarity with cardiolipin synthases (CLS), and phosphatidylserine synthases (PSS). The protein structure predictions showed that most Kinetoplastida sequences resemble CLS and PSS, with the exception of 5 sequences from Bodo saltans that shared significant structural similarities with the PLD sequences, suggesting the loss of PLD-like sequences during the evolution of parasitism in kinetoplastids. On the other hand, diacylglycerol kinase (DGK) homologs were identified for all species examined in this study, indicating that DGK could be the only pathway for the synthesis of PA involved in lipid signaling in these organisms due to genome streamlining during transition to parasitic lifestyle. Our findings offer insights for development of potential therapeutic and/or intervention approaches, particularly those focused on using PA, PLD and/or DGK related pathways, against trypanosomiasis, leishmaniasis, and Chagas disease. PMID- 29501622 TI - Panax notoginsenoside saponins Rb1 regulates the expressions of Akt/ mTOR/PTEN signals in the hippocampus after focal cerebral ischemia in rats. AB - Panax notoginsenoside saponins Rb1 (PNS-Rb1) is an important active ingredient of panax notoginseng for effective treatment of cerebrovascular diseases. However, the mechanism underlying its actions in the state of cerebral ischemia is still unclear. We asked whether the potential neuroprotection of PNS-Rb1 on the brain is due to, at least partially, its modulation of AkT/mTOR/PTEN signalling pathway along with down-regulation of caspase-3 in rats subjected to phototrombic stroke. To test this hypothesis, rats with induced photothrombotic stroke were treated with PNS-Rb1 (applied in three different doses, 25 mg/kg, 50 mg/kg,100 mg/kg, respectively) or saline, while sham operated rats injected with saline were used as the control. Our results indicate that PNS-Rb1 significantly alleviated the morphological lesion concomitant with improvement of cognitive and sensorimotor deficits induced by ischemic stroke. Moreover, immunohistochemistry and Western blot analyses showed that PNS Rb1 in a dose dependent manner increased the expressions of P-Akt, P-mTOR and reduced P-PTEN and caspase-3. The present study suggests that the improvement of cognitive and sensorimotor deficits by PNS-Rb1 is made, at least partially, by the modulation of the Akt/mTOR/PTEN signalling pathway. PMID- 29501623 TI - Adenosine A2A receptor involves in neuroinflammation-mediated cognitive decline through activating microglia under acute hypobaric hypoxia. AB - Hypobaric hypoxia (HH) at high altitudes leads to a wide range of cognitive impairments which can handicap human normal activities and performances. However, the underlying mechanism is still unclear. Adenosine A2A receptors (A2ARs) of the brain are pivotal to synaptic plasticity and cognition. Besides, insult-induced up-regulation of A2AR regulates neuroinflammation and therefore induces brain damages in various neuropathological processes. The present study was designed to determine whether A2AR-mediate neuroinflammation involves in cognitive impairments under acute HH. A2AR knock-out and wild-type male mice were exposed to a simulated altitude of 8000 m for 7 consecutive days in a hypobaric chamber and simultaneously received behavioral tests including Morris water maze test and open filed test. A2AR expression, the activation of microglia and the production of TNF-alpha were evaluated in the hippocampus by immunohistochemistry and ELISA, respectively. Behavioral tests showed that acute HH exposure caused the dysfunction of spatial memory and mood, while genetic inactivation of A2AR attenuated the impairment of spatial memory but not that of mood. Double-labeled immunofluorescence showed that A2ARs were mainly expressed on microglia and up regulated in the hippocampus of acute HH model mice. Acute HH also induced the accumulation of microglia and increased production of TNF-alpha in the hippocampus, which could be markedly inhibited by A2AR inactivation. These findings indicate that microglia-mediated neuroinflammation triggered by A2AR activation involves in acute HH-induced spatial memory impairment and that A2AR could be a new target for the pharmacotherapy of cognitive dysfunction at high altitudes. PMID- 29501624 TI - Bivalent vaccine platform based on ca influenza virus vaccine elicits protective immunity against human adenoviruses. AB - Human adenoviruses (HAdVs) are prevalent in pediatric and adult patients with severe acute respiratory disease (ARD). To date, there have been no widely used HAdV vaccines available. In this report, we developed a cold-adapted attenuated influenza virus, termed rg HAdV-Flu ca, carrying epitopes from HAdV hexon protein in the backbone of the ca influenza vaccine neuraminidase (NA) gene using reverse genetics. Rg HAdV-Flu ca virus exhibited a cold-adapted (ca) phenotype, and its morphological characteristics were observed using electron microscopy. Moreover, BALB/c mice were immunized intranasally (i.n.) with 105, 106 or 107 TCID50 rg HAdV-Flu ca. Results showed a specific, robust antibody response against influenza and HAdV in a dose-dependent manner. More importantly, potent humoral, mucosal and cellular immune responses protected against subsequent wild-type HAdV 3 or HAdV-7 challenges, as determined by a significant decrease in viral titers and a noticeable alleviation of histopathological alterations in the lung tissue of challenged mice. These findings demonstrate that rg HAdV-Flu ca warrants attention as a potential vaccine candidate against HAdV infection. PMID- 29501625 TI - Radiologic Relation of the Colon to the Trajectory of Percutaneous Nephrolithotomy Access in Prone Versus Flank-free Modified Supine Position: A Prospective Study of Intra and Interindividual Influencing Factors. AB - OBJECTIVE: To compare the distance between the colon and the trajectory of percutaneous nephrolithotomy (PCNL) access both in prone and flank-free modified supine (FFMS) positions as measured on computed tomography and to study the effect of age, gender, BMI, side, and previous renal surgery as influencing factors. PATIENTS AND METHODS: In this prospective study, we included 367 patients scheduled for PCNL. All patients underwent low dose abdominal computed tomography both in prone and FFMS positions. Patients <18 years and those with previous colonic surgery or renal congenital anomalies were excluded. The perpendicular distance between the imaginary line of the renal access and the colon was measured. Findings were correlated to different influencing factors. RESULTS: Two hundred nineteen patients were males, and 148 were females. BMI of <30 were reported in 158 patients whereas BMI >30 in 209 patients. Data analysis showed that the mean perpendicular distance between colon and the renal access in FFMS and prone positions were 35.92 +/- 0.22 mm and 17.78 +/- 0.09 mm, respectively. In prone position only obesity, age, and overall interaction effect were the significant factors on the studied distance. In FFMS position, in addition to the effect of the prior factors, previous renal surgery also significantly reduces this distance. CONCLUSION: The distance between the colon and assumed PCNL trajectory at a puncture on the posterior axillary line was influenced mainly by patient position. In FFMS position the colon appears to be farther than in prone position. BMI and age significantly influence this distance to a lesser extent. PMID- 29501626 TI - Nobiletin protects against insulin resistance and disorders of lipid metabolism by reprogramming of circadian clock in hepatocytes. AB - SCOPE: Circadian clock plays a principal role in orchestrating our daily physiology and metabolism, and their perturbation can evoke metabolic diseases such as fatty liver and insulin resistance. Nobiletin (NOB) has been demonstrated to possess antitumor and neuroprotective activities. The objective of the current study is to determine potential effects of NOB on modulating the core clock gene Bmal1 regarding ameliorating glucolipid metabolic disorders. RESULTS: Our results revealed that NOB partially reverse the relatively shallow daily oscillations of circadian clock genes and reset phase-shifting circadian rhythms in primary hepatocytes under metabolic disorders conditions. Importantly, NOB was found to be effective at amplifying glucose uptake via stimulating IRS-1/AKT signaling pathway, as well as blunting palmitate-induced lipogenesis in HepG2 cells via modulating AMPK-Sirt1 signaling pathway and key enzymes of de novo lipogenesis in a Bmal1-dependent manner. NOB attenuated palmitate-stimulated excessive secretions of ROS, restored the depletions of mitochondrial membrane potential, which is similar to the recovery in expressions of mitochondrial respiration complex I-IV. CONCLUSION: This study is the first to provide compelling evidences that NOB prevent cellular glucolipid metabolic imbalance and mitochondrial function in a Bmal1-dependent manner. Overall, NOB may serve as a nutritional preventive strategy in recovering metabolic disorders relevant to circadian clock. PMID- 29501627 TI - Orthostatic hypertension as a risk factor for age-related macular degeneration: Evidence from the Irish longitudinal study on ageing. AB - PURPOSE: Age related macular degeneration (AMD) is a leading cause of irreversible visual loss in developed countries. It is associated with vascular risk factors including hypertension. Dysregulated blood pressure (BP) behaviour including orthostatic hypertension (OHTN), hypotension (OH) and BP variability (BPV) are associated with end-organ damage, particularly in the brain. We investigated if abnormal orthostatic BP (OBP) was a risk factor for AMD, for which a vascular aetiology is implicated. METHODS: A nationally representative, cross-sectional study was carried out 2009/2010 in The Irish Longitudinal Study on Ageing (TILDA). Beat-to-beat BP data, measured by digital photoplethysmography during active stand, was used to characterise OBP behaviour in the 30-110 s after standing. OH, OHTN, BPV and normal stabilisation recovery phenotypes were defined. AMD was identified following masked grading of 45 degrees monoscopic colour retinal photographs, which were centred on the macula and taken with a NIDEK AFC-210 non-mydriatic auto-fundus camera. The relationship between OBP recovery phenotypes and AMD in 3750 adults aged >=50 years was investigated using multivariate logistic regression models, adjusted for traditional AMD risk factors. RESULTS: From 30 to 110 s post active stand, systolic and diastolic OHTN was associated with increased odds of AMD after adjustment for demographics, health behaviours including smoking, family history of AMD, self-report (SR) diabetes, SR cataracts, objective hypertension and prescribed antihypertensives. No evidence of heterogeneity of OHTN effect was found between those who were hypertensive to those who were normotensive. CONCLUSIONS: This study provides evidence that OHTN may be an independent cardiovascular risk factor for AMD. PMID- 29501628 TI - Limiting angiogenesis to modulate scar formation. AB - Angiogenesis, the process of new blood vessel formation from existing blood vessels, is a key aspect of virtually every repair process. During wound healing an extensive, but immature and leaky vascular plexus forms which is subsequently reduced by regression of non-functional vessels. More recent studies indicate that uncontrolled vessel growth or impaired vessel regression as a consequence of an excessive inflammatory response can impair wound healing, resulting in scarring and dysfunction. However, in order to elucidate targetable factors to promote functional tissue regeneration we need to understand the molecular and cellular underpinnings of physiological angiogenesis, ranging from induction to resolution of blood vessels. Especially for avascular tissues (e.g. cornea, tendon, ligament, cartilage, etc.), limiting rather than boosting vessel growth during wound repair potentially is beneficial to restore full tissue function and may result in favourable long-term healing outcomes. PMID- 29501629 TI - Synthetic resveratrol-curcumin hybrid derivative inhibits mitosis progression in estrogen positive MCF-7 breast cancer cells. AB - Curcumin (1) and resveratrol (2) are bioactive natural compounds that display wide pharmacological properties, including antitumor activity. However, their clinical application has been limited due to their low solubility and bioavailability. Nevertheless, independent studies have considered these compounds as interesting prototypes for developing new chemical structures useful for anticancer therapy. Here in, we report the synthesis of novel curcumin-like hydrazide analogues (3a and 3b), and a series of curcumin-resveratrol hybrid compounds (4a-f), and the evaluation of their cytotoxic potential on three tumor cell lines MCF-7 (breast), A549 (lung), and HepG2 (liver). Cell viability was significantly reduced in all tested cell lines when compounds 4c-4e were used. The IC50 values for these compounds on MCF-7 cells were lower than those for curcumin, resveratrol, or curcumin combined with resveratrol. We evidenced that 4c promoted a drastic increase of G2/M population. The accumulation of cells in mitosis onset in treated cultures was due to, at least in part, the ability of 4c to modulate nuclear kinase proteins, which orchestrate important events in mitosis progression. We have also observed significant reduction of the relative RNAm abundance of CCNB1, PLK1, AURKA, AURKB in samples treated with 4c, with concomitant increase of CDKN1A (p21). Thus, compound 4c is a promising multi target antitumor agent that should be considered for further in vivo studies. PMID- 29501630 TI - Workshop on acceleration of the validation and regulatory acceptance of alternative methods and implementation of testing strategies. AB - This report describes the proceedings of the BfR-RIVM workshop on validation of alternative methods which was held 23 and 24 March 2017 in Berlin, Germany. Stakeholders from governmental agencies, regulatory authorities, universities, industry and the OECD were invited to discuss current problems concerning the regulatory acceptance and implementation of alternative test methods and testing strategies, with the aim to develop feasible solutions. Classical validation of alternative methods usually involves one to one comparison with the gold standard animal study. This approach suffers from the reductionist nature of an alternative test as compared to the animal study as well as from the animal study being considered as the gold standard. Modern approaches combine individual alternatives into testing strategies, for which integrated and defined approaches are emerging at OECD. Furthermore, progress in mechanistic toxicology, e.g. through the adverse outcome pathway approach, and in computational systems toxicology allows integration of alternative test battery results into toxicity predictions that are more fine-tuned to the human situation. The road towards transition to a mechanistically-based human-focused hazard and risk assessment of chemicals requires an open mind towards stepping away from the animal study as the gold standard and defining human biologically based regulatory requirements for human hazard and risk assessment. PMID- 29501631 TI - Methamphetamine binge administration during late adolescence induced enduring hippocampal cell damage following prolonged withdrawal in rats. AB - A recent study from our laboratory demonstrated that binge methamphetamine induced hippocampal cell damage (i.e., impaired cell genesis) in rats when administered specifically during late adolescence (postnatal day, PND 54-57) and evaluated 24 h later (PND 58). The results also suggested a possible role for brain-derived neurotrophic factor (BDNF) regulating cell genesis and survival. This subsequent study evaluated whether these effects persisted in time as measured following prolonged withdrawal. Male Sprague-Dawley rats were treated (i.p.) with BrdU (2 * 50 mg/kg, 3 days, PND 48-50) followed by a binge paradigm (3 pulses/day, every 3 h, 4 days, PND 54-57) of methamphetamine (5 mg/kg, n = 14, M) or saline (0.9% NaCl, 1 ml/kg, n = 12, C). Following 34 days of forced withdrawal (PND 91), rats were killed 45 min after a challenge dose of saline (Sal: C-Sal, n = 6; M-Sal, n = 7) or methamphetamine (Meth: C-Meth, n = 6; M Meth, n = 7). Neurogenesis markers (Ki-67: cell proliferation; NeuroD: early neuronal survival; BrdU: prolonged cell survival, 41-43 days old cells) were evaluated by immunohistochemistry while neuroplasticity markers (BDNF and Fos forms) were evaluated by Western blot. The main results showed that a history of methamphetamine administration (PND 54-57) induced enduring hippocampal cell damage (i.e., observed on PND 91) by decreasing cell survival (BrdU + cells) and mature-BDNF (m-BDNF) protein content, associated with neuronal survival, growth and differentiation. Interestingly, m-BDNF regulation paralleled hippocampal c Fos protein content, indicating decreased neuronal activity, and thus reinforcing the persisting negative effects induced by methamphetamine in rat hippocampus following prolonged withdrawal. PMID- 29501632 TI - Three-step monitoring of glycan and galectin profiles in the anterior segment of the adult chicken eye. AB - A histochemical three-step approach is applied for processing a panel of sections that covers the different regions of fixed anterior segment of the adult chicken eye. This analysis gains insight into the presence of binding partners for functional pairing by galectin/lectin recognition in situ. Glycophenotyping with 11 fungal and plant lectins (step 1) revealed a complex pattern of reactivity with regional as well as glycan- and cell-type-dependent differences. When characterizing expression of the complete set of the seven adhesion/growth regulatory chicken galectins immunohistochemically (step 2), the same holds true, clearly demonstrating profiles with individual properties, even for the CG-1A/B paralogue pair. Testing this set of labeled tissue lectins as probes (step 3) detected binding sites in a galectin-type-dependent manner. The results of steps 2 and 3 reflect the divergence of sequences and argue against functional redundancy among the galectins. These data shape the concept of an in situ network of galectins. As consequence, experimental in vitro studies will need to be performed from the level of testing a single protein to work with mixtures that mimic the (patho)physiological situation, a key message of this report. PMID- 29501633 TI - Reaching the sellar region endonasally - One or both nostrils? A pilot study in body donors. AB - INTRODUCTION: The purpose of this study was to evaluate the effect of posterior septectomy size on surgical exposure and surgical freedom during the endoscopic transsphenoidal approach to the sellar and parasellar region. METHODS: A mononostril and binostril approach to the sellar region was performed on 4 formalin-fixed cadaveric heads. Predefined anatomical structures were identified. Additionally, a millimeter gauge was introduced into the surgical site and the extent of dorsal septectomy was analyzed for both approaches. Surgical freedom was defined as the distance between the ipsilateral and contralateral limit of opening of the sphenoid sinus. RESULTS: The mean extent of dorsal septectomy was 15.7+/-5.7mm using a binostril approach to achieve adequate visualization of all relevant anatomical structures. Superior results were obtained via binostril technique with respect to the ability to identify the contralateral internal carotid artery or opticocarotid recessus. No such advantage was found for all other landmarks. Surgical freedom between the ipsilateral and contralateral limit of exposure of the sphenoid sinus was measured with 15+/-0.8mm in the mononostril and 19.2+/-0.9mm in the binostril group. CONCLUSIONS: The surgical exposure increased significantly with progressively larger posterior septectomy in binostril approaches until a 20-mm posterior septectomy. Bilateral lateral opticocarotid recesses were accessible with a mean of 15mm for posterior septectomy. In the mononostril group no dorsal septectomy was necessary. Thus, the nasal mucosa is more preserved by this technique. However, the lateral exposure is partially limited and the use of angled endoscopes is recommended when adopting a mononostril approach to the sellar region. PMID- 29501634 TI - Medical students' perspective on training in anatomy. AB - Gaining sufficient knowledge of anatomy is an important part of medical education. Factors that influence how well students learn anatomical structures include available sources, learning time and study assistance. This study explores the attitude of medical students with regard to studying anatomy and evaluates possibilities for improvement of training in anatomy. Twenty medical students participated in a focus group meeting. Based on this focus group, an online survey consisting of 27 questions was developed and distributed amongst medical students of Maastricht University, the Netherlands. A total of 495 medical students (both Bachelor and Master level) participated in this survey. Master students found studying anatomy less attractive than Bachelor students (36.8% of the Master students vs. 47.9% of the Bachelor students (p=.024)). Although most students responded that they thought it is important to study anatomy, 48% of all students studied anatomy less than 10h per study block of 8 weeks. Only 47.9% of the students rated their knowledge of anatomy as adequate. Students suggested that three-dimensional techniques would help improve their knowledge of anatomy. Therefore investing in three-dimensional tools could prove beneficial in the future. PMID- 29501635 TI - A nano silicon adjuvant enhances inactivated transmissible gastroenteritis vaccine through activation the Toll-like receptors and promotes humoral and cellular immune responses. AB - Inactivated transmissible gastroenteritis virus (TGEV) vaccines are widely used in swine herds in China. These are limited, however, by the need to elicit both humoral and cellular immunity, as well as the efficiency of adjuvants. In this study, a 70-nm nano silicon particle was applied with inactivated TGEV vaccine in mice, and its immune-enhancing effects and mechanism of action investigated. We found that nano silicon applied with inactivated TGEV vaccine induced high antibody titers, increase IL-6, TNF-alpha and IFN-gamma expression, and stimulate CD3+ T cell proliferation with a high CD4+/CD8+ T lymphocyte ratio. Nano silicon could quickly activate innate and adaptive immunity by stimulating Toll-like receptor signaling pathways, indicating that the nano silicon adjuvant enhanced long-term humoral and early cellular immune responses when combined with inactivated TGEV vaccine. Nano silicon could be considered for use as an antigen- carrier and adjuvant for veterinary vaccines. PMID- 29501636 TI - Association of HCV mutated proteins and host SNPs in the development of hepatocellular carcinoma. AB - Hepatitis C virus plays a significant role in the development of hepatocellular carcinoma (HCC) globally. The pathogenic mechanisms of hepatocellular carcinoma with HCV infection are generally linked with inflammation, cytokines, fibrosis, cellular signaling pathways, and liver cell proliferation modulating pathways. HCV encoded proteins (Core, NS3, NS4, NS5A) interact with a broad range of hepatocytes derived factors to modulate an array of activities such as cell signaling, DNA repair, transcription and translational regulation, cell propagation, apoptosis, membrane topology. These four viral proteins are also implicated to show a strong conversion potential in tissue culture. Furthermore, Core and NS5A also trigger the accretion of the beta-catenin pathway as a common target to contribute viral induced transformation. There is a strong association between HCV variants within Core, NS4, and NS5A and host single nucleotide polymorphisms (SNPs) with the HCC pathogenesis. Identification of such viral mutants and host SNPs is very critical to determine the risk of HCC and response to antiviral therapy. In this review, we highlight the association of key variants, mutated proteins, and host SNPs in development of HCV induced HCC. How such viral mutants may modulate the interaction with cellular host machinery is also discussed. PMID- 29501637 TI - Predictors of Heparin Resistance Before Cardiovascular Operations in Adults. AB - BACKGROUND: Heparin resistance (HR) is often encountered during cardiovascular operations that require cardiopulmonary bypass. Clinical risk factors and the mechanism underlying heparin resistance are yet to be determined. The aim of this study was to elucidate the clinically valid preoperative predictors related to HR. METHODS: The study evaluated 489 patients undergoing cardiovascular operations. Of these, 25 patients presented with HR and received antithrombin III for the initiation of cardiopulmonary bypass with an effective activated coagulation time. The remaining 464 patients, who did not receive antithrombin III, served as controls (NHR). Preoperative patient demographic and laboratory data were analyzed to identify risk factors for HR. RESULTS: The preoperative laboratory data showed platelet count, fibrinogen, D-dimer, creatinine, and C reactive protein were significantly higher in the HR group than in the NHR group. As expected, the antithrombin III level was significantly lower overall in the HR group (86.0% vs 95.5%, p = 0.009); however, 80% of the patients in the HR group showed normal antithrombin III levels preoperatively. Multivariable logistic regression analysis identified chronic aortic dissection, chronic obstructive pulmonary disease, smoking, and elevated fibrinogen levels as independent predictors for HR. CONCLUSIONS: HR was shown to be associated with preoperative high fibrinogen levels, a smoking habit, and a preoperative diagnosis of chronic, but not acute, aortic dissection, with chronic obstructive pulmonary disease as comorbidity. Administration of antithrombin III resolved HR in all of the affected patients, even when their preoperative antithrombin III level was within the normal limit. PMID- 29501638 TI - Long-Term Outcomes for Patients With Stroke After Coronary and Valve Surgery. AB - BACKGROUND: Postoperative stroke is one of the most devastating complications of cardiac surgery. When life-threatening situations such as large infarction and hemorrhage occur, neurosurgical procedures may be performed. In this study, we analyzed the long-term medical and surgical outcomes of stroke after cardiac surgery. METHODS: We conducted a retrospective, nationwide, population-based study. All enrolled patients underwent first-time cardiac surgery and were further divided into the subgroups of nonstroke, stroke with medical treatment, and stroke with neurosurgical treatment. All-cause mortality, recurrent stroke, and readmission were analyzed. RESULTS: We included 67,051 patients in this study. Patients with postoperative stroke (2.6%, n = 1,731) exhibited an in hospital mortality rate of 12.3% (n = 213) and a 5-year mortality rate of 49.1% (n = 850). Unprecedentedly, the 83 patients who underwent neurosurgical procedures exhibited an in-hospital mortality of 16.9%; this rate increased to 65.1% at the 5-year follow-up. This neurosurgical subgroup exhibited the highest rate of long-term mortality (p < 0.001). In the neurosurgical subgroup, age was the risk factor for all-cause mortality (hazard ratio, 2.60; 95% confidence interval, 1.60-4.24; p < 0.001). CONCLUSIONS: Postoperative stroke often leads to high mortality and poor long-term outcomes. Patients who experienced a severe stroke and underwent neurosurgical procedures also exhibited poor outcomes. Patients and their families should be informed of relatively high mortality and poor long-term outcomes before neurosurgical operation. PMID- 29501639 TI - Ochronosis of Mitral Valve and Coronary Arteries. AB - Cardiac ochronosis is a rare complication of alkaptonuria, a disorder of tyrosine metabolism characterized by a triad of dark urine, pigmentation of tissues, and ochronotic arthropathies. When present, cardiac ochronosis generally affects the aortic valve, resulting in aortic stenosis. More rarely, it may affect the mitral valve and the coronary arteries. This report describes the case of a 67-year-old woman with a history of alkaptonuria with severe ochronosis of the coronary arteries and mitral valve who required coronary artery bypass and mitral valve replacement. PMID- 29501640 TI - Is Functional Independence Associated With Improved Long-Term Survival After Lung Transplantation? AB - BACKGROUND: Existing research demonstrates superior short-term outcomes (length of stay, 1-year survival) after lung transplantation in patients with preoperative functional independence. The aim of this study was to determine whether advantages remain significant in the long-term. METHODS: The United Network for Organ Sharing database was queried for adult, first-time, isolated lung transplantation records from January 2005 to December 2015. Stratification was performed based on Karnofsky Performance Status Score (3 groups) and on employment at the time of transplantation (2 groups). Kaplan-Meier and Cox analyses were performed to determine the association between these factors and survival in the long-term. RESULTS: Of 16,497 patients meeting criteria, 1,581 (9.6%) were almost completely independent at the time of transplant vs 5,662 (34.3%) who were disabled (completely reliant on others for activities of daily living). Cox models adjusting for recipient, donor, and transplant factors demonstrated a statistically significant association between disability at the time of transplant and long-term death (hazard ratio, 1.26; 95% confidence interval, 1.14 to 1.40; p < 0.001). There were 15,931 patients with available data on paid employment at the time of transplantation. Multivariable analysis demonstrated a statistically significant association between employment at the time of transplantation and death (hazard ratio, 0.86; 95% confidence interval, 0.75 to 0.91; p < 0.001). CONCLUSIONS: Preoperative functional independence and maintenance of employment are associated with superior long-term outcomes in lung recipients. The results highlight potential benefits of pretransplant functional rehabilitation for patients on the waiting list for lungs. PMID- 29501641 TI - Acute Kidney Injury Classification Underestimates Long-Term Mortality After Cardiac Valve Operations. AB - BACKGROUND: Perioperative acute kidney injury (AKI) is an important predictor of long-term all-cause mortality after coronary artery bypass (CABG). However, the effect of AKI on long-term mortality after cardiac valve operations is hitherto undocumented. METHODS: Perioperative renal injury and long-term all-cause mortality after valve operations were studied in a prospective cohort of patients undergoing solitary valve operations (n = 2,806) or valve operations combined with CABG (n = 1,260) with up to 18 years of follow-up. Postoperative serum creatinine increase was classified according to AKI staging 0 to 3. Patients undergoing solitary CABG (n = 4,938) with cardiopulmonary bypass served as reference. RESULTS: In both valve and valve+CABG operations, postoperative renal injury of AKI stage 1 or higher was progressively associated with an increase in long-term mortality (hazard ratio [HR], 2.27, p < 0.05 for valve; HR, 1.65, p < 0.05 for valve+CABG; HR, 1.56, p < 0.05 for CABG). Notably, the mortality risk increased already substantially at serum creatinine increases of 10% to 25%-that is, far below the threshold for AKI stage 1 after valve operations (HR, 1.39, p < 0.05), but not after valve operations combined with CABG or CABG only. CONCLUSIONS: An increase in serum creatinine by more than 10% during the first week after valve operation is associated with an increased risk for long-term mortality after cardiac valve operation. Thus, AKI classification clearly underestimates long-term mortality risk in patients undergoing valve operations. PMID- 29501642 TI - Implantation Depth and Rotational Orientation Effect on Valve-in-Valve Hemodynamics and Sinus Flow. AB - BACKGROUND: This study evaluated the effect of transcatheter aortic valve implantation depth and rotation on pressure gradient (PG), leakage fractions (LF), leaflet shear stress, and sinus washout in an effort to understand factors that may dictate optimal positioning for valve-in-valve (ViV) procedures. Sinus flow stasis is often associated with prosthetic leaflet thrombosis. Although recent ViV in vitro studies highlighted potential benefits of transcatheter aortic valve supraannular implantation to minimize PGs, the relationship between transcatheter aortic valve depth and other determinates of valve function remains unknown. Among these, LFs, shear stress, and poor sinus washout have been associated with poorer valve outcomes. METHODS: ViV hemodynamic performance was evaluated in vitro vs axial positions -9.8, -6.2, 0, and +6 mm and angular orientations 0, 30, 60, and 90 degrees in a degenerated surgical aortic valve. PGs, LFs, and sinus shear stress and washout were compared. Leaflet high-speed imaging and particle-image velocimetry were performed to elucidate hemodynamic mechanisms. RESULTS: (1) The PG varies as a function of axial position, with supraannular deployments yielding a maximum benefit of 7.85 mm Hg less than PGs for subannular deployments irrespective of commissural alignment (p < 0.01); (2) in contrast, LF decreased in relationship to subannular deployment; and (3) at peak systole, sinus flow shear stress increased with deployment depth as did sinus washout with and without coronary flow. CONCLUSIONS: First, supraannular axial deployment is associated with lower PGs irrespective of commissural alignment. Second, subannular deployment is associated with more favorable sinus hemodynamics and less LF. Further in vivo studies are needed to substantiate these observations and facilitate optimal prosthesis positioning during ViV procedures. PMID- 29501643 TI - Use of an Automated Suture Fastening Device in Minimally Invasive Aortic Valve Replacement. AB - BACKGROUND: Minimally invasive aortic valve replacement (mAVR) is gaining clinical acceptance; however, it is associated with increased operative times because of the limited surgical field and access. The Cor-Knot (CK; LSI Solutions, Victor, NY) is an automated fastening device designed to facilitate suture fastening, but clinical data in mAVR are lacking. METHODS: From May 2014 to February 2017, 92 patients underwent mAVR at Spectrum Health in Grand Rapids, Michigan; 39 valves were secured with manually tied sutures, and 53 valves were entirely secured with the CK device. Preoperative characteristics and 30-day outcomes data were extracted from the local The Society of Thoracic Surgeons database and the patients' electronic medical records. Survival data were obtained from the Michigan State Social Security Death Index. RESULTS: No significant differences in preoperative characteristics were noted between the two groups. Aortic cross-clamp time (72 +/- 12 minutes vs 82 +/- 15 minutes; p = 0.001) was significantly shorter with CK. There was no difference in the rate of postoperative mortality (0% vs 0%), stroke (0% vs 1.9%), atrial fibrillation (28% vs 33%), renal failure (0% vs 3.8%), or pacemaker implantation (5.1% vs 5.7%) between patients with manually tied sutures and patients with sutures fastened with the CK. Valve function on postoperative echocardiography and 1-year patient survival rates were similar. CONCLUSIONS: In mAVR, the CK device was associated with reduced aortic cross-clamp time while providing equivalent clinical outcomes. Larger studies are needed to confirm the efficacy, safety, and cost effectiveness of the CK device in minimally invasive aortic valve surgery. PMID- 29501644 TI - Timing and Risk Factors Associated With Venous Thromboembolism After Lung Cancer Resection. AB - BACKGROUND: Few studies have examined the risk factors for and timing of venous thromboembolism (VTE) in patients undergoing surgical procedures for lung cancer, and there are limited data to formulate guidelines for extended VTE prophylaxis after hospital discharge. This study sought to identify risk factors for postdischarge VTE after lung resection. METHODS: Patients undergoing anatomic resection for lung cancer were identified in the National Surgical Quality Improvement Program database from 2005 to 2015. Patients' demographic and clinical characteristics were evaluated for any association with postdischarge VTE. Predictors of postdischarge VTE were identified using multivariable analysis. RESULTS: VTE occurred in 1.6% (234) of the 14,308 patients identified; 44% (102) VTE events occurred after hospital discharge. Undergoing pneumonectomy was associated with a threefold increased risk for postdischarge VTE compared with lobectomy (2.0% versus 0.6%, p < 0.01), as was open resection compared with minimally invasive resection (0.8% versus 0.6%, p < 0.01). Prolonged operative time (>75th percentile) was also associated with an increased risk for postdischarge VTE compared with shorter operative time. Multivariable analysis identified older age, obesity, pneumonectomy, and prolonged operative time as independent predictors of postdischarge VTE. CONCLUSIONS: Significant proportions of VTE events occur after hospital discharge. Although there are data to suggest that the risk for VTE extends beyond this period, few patients are managed with postdischarge prophylaxis. These data suggest that postdischarge prophylaxis should be considered for those patients at high risk for VTE, particularly for older patients, those who are obese, and after extended or lengthy resections. PMID- 29501645 TI - Predictors for Late Reoperation After Surgical Repair of Acute Type A Aortic Dissection. AB - BACKGROUND: It is impossible to resolve all the problems of the entire diseased aorta with just one operation for acute type A aortic dissection, which requires additional surgical treatment in the long-term. METHODS: From April 2004 to March 2017, 310 patients underwent surgical repair for acute type A aortic dissection at our institution. Of these, 32 (10.3%) died in the hospital. Of the 278 hospital survivors, 38 underwent late reoperation associated with aortic dissection during the follow-up period. We compared the 240 nonreoperation patients and the 38 reoperation patients to analyze risk factors for late reoperation after operations for acute type A dissection. RESULTS: The mean duration from the initial operation to reoperation was 3.54 +/- 3.0 years. The rates of actuarial freedom from reoperation were 96.9%, 83.2%, and 64.2% at 1, 5, and 10 years, respectively. The multivariate Cox proportional hazard regression analysis revealed the following as independent predictors of late reoperation: younger age, Marfan syndrome, nonprescription of beta-blockers, greater diameter of the descending aorta, ratio of false lumen to true lumen of more than 1, limb malperfusion, and primary entry in the ascending aorta. Log-rank analysis revealed no difference in long-term survival between the two groups. CONCLUSIONS: We found several risk factors for both late reoperation and death. Specifically, aortic diameter in the early phase after the initial operation and nonuse of beta blockers were strong predictors. The ratio of the false lumen to the true lumen may also be a new and useful indicator for late reoperation. PMID- 29501646 TI - Lung Cancer Screening in the Community Setting. AB - BACKGROUND: Lung cancer has high incidence and high mortality burden, particularly because it is typically diagnosed in later stages. The National Lung Screening Trial demonstrated a lung cancer-specific mortality benefit in high risk current and former smokers with yearly low-dose chest computed tomography (CT). Lung cancer screening is thus recommended, but it is unclear whether the results of the National Lung Screening Trial can be replicated in community settings. METHODS: A retrospective review was performed of the lung screening program over its first 5 years, 2012 to 2016. Patients' demographics, initial screening results, follow-up, and management results were analyzed in relation to the National Lung Screening Trial results. Annual adherence was defined as returning for imaging within 1 year + 90 days. RESULTS: A total of 1,241 persons underwent initial screening over the 5-year period; 78.6% of findings were benign, and only annual repeat low-dose chest CT was recommended. A total of 29 cancers were identified in 26 participants (2%), of which 72% were stage I. The annual adherence rate to repeat imaging after a low-risk baseline scan was 37%, and the any follow-up rate was 51% despite programmatic efforts to follow screening recommendations. When positive findings required more intensive evaluation, most commonly by repeat chest CT scan, adherence was 88%. A total of 1.1% of all participants had invasive biopsies for benign results. Complications of biopsy were minimal. CONCLUSIONS: This review demonstrates that a community based program can approximate the results of the National Lung Screening Trial in detecting early lung cancers. Further study of the adherence phenomenon is essential. PMID- 29501647 TI - Unintended pregnancy and interpregnancy interval by maternal age, National Survey of Family Growth. AB - BACKGROUND: The relationship between unintended pregnancy and interpregnancy interval (IPI) across maternal age is not clear. METHODS: Using data from the National Survey of Family Growth, we estimated the percentages of pregnancies that were unintended among IPI groups (<6, 6-11, 12-17, 18-23, 24+ months) by maternal age at last live birth (15-19, 20-24, 25-29, 30-44 years). RESULTS: Approximately 40% of pregnancies were unintended and 36% followed an IPI<18 months. Within each maternal age group, the percentage of pregnancies that were unintended decreased as IPI increased. CONCLUSION: Unintended pregnancies are associated with shorter IPI across the reproductive age spectrum. PMID- 29501648 TI - Ultrasensitive environmental assessment of xeno-estrogens in water samples using label-free graphene immunosensors. AB - There is a growing interest in the possible environmental health impact posed by endocrine-disrupting chemicals (EDCs). A challenge to the field of endocrine disruption is that these substances are diverse and may not appear to share any structural similarity other than usually being low molecular mass (<1000 Da) compounds. Here we demonstrate the effectiveness of sensor device for the detection of low molecular weight, poorly water soluble, estrogenic compounds E1, E2 and EE2, fabricated by electropolymerization over graphene screen printed electrode (SPE). The PANI/Gr-SPE-devices displayed linear responses to estrogenic substances, in EIS assays, from 0.0975 ng/L to 200 ng/L in water samples, with a detection limit of 0.043 pg/L for E1, 0.19 ng/L for E2 and 0.070 pg/L for EE2 which is lower than other current biosensing techniques. This portable, disposable immunosensor offers a solution for immediate measurement at sample collection sites, due to its excellent sensitivity and selectivity when testing water samples obtained directly from rivers and waste water treatment facilities. The simple screen printing production method will enable the low cost, high volume production required for this type of environmental analysis. PMID- 29501650 TI - The production of nitric oxide in the coeliac ganglion modulates the effect of cholinergic neurotransmission on the rat ovary during the preovulatory period. AB - The aim of the present work was to investigate whether the nitric oxide produced by the nitric oxide/nitric oxide synthase (NO/NOS) system present in the coeliac ganglion modulates the effects of cholinergic innervation on oxidative status, steroidogenesis and apoptotic mechanisms that take place in the rat ovary during the first proestrous. An ex vivo Coeliac Ganglion- Superior Ovarian Nerve- Ovary (CG-SON-O) system was used. Cholinergic stimulation of the CG was achieved by 10 6 M Acetylcholine (Ach). Furthermore, 400 MUM Aminoguanidine (AG) - an inhibitor of inducible-NOS was added in the CG compartment in absence and presence of Ach. It was found that Ach in the CG compartment promotes apoptosis in ovarian tissue, probably due to the oxidative stress generated. AG in the CG compartment decreases the release of NO and progesterone, and increases the release of estradiol from the ovary. The CG co-treatment with Ach and AG counteracts the effects of the ganglionic cholinergic agonist on ovarian oxidative stress, increases hormone production and decreases Fas mRNA expression. These results suggest that NO is an endogenous modulator of cholinergic neurotransmission in CG, with implication in ovarian steroidogenesis and the apoptotic mechanisms that take place in the ovary during the preovulatory period in rats. PMID- 29501649 TI - Positive parenting behaviors in women who spontaneously quit smoking during pregnancy: Clues to putative targets for preventive interventions. AB - BACKGROUND: While the majority of pregnant smokers do not respond to intervention, little is known about how a subset of pregnant smokers known as spontaneous quitters achieve sustained biologically-confirmed abstinence through delivery in the absence of intervention. We explore a developmental framework to address this question by viewing spontaneous quitting as an adaptive parenting behavior, facilitated by abilities necessary for sensitive parenting, or responsiveness. Utilizing existing data, we examined responsiveness from parenting assessments in women who exhibited a variety of smoking patterns during pregnancy, including spontaneous quitting. METHODS: Participants were N = 305 pregnant women assessed for smoking prospectively and biochemically at 16 weeks, 28 weeks, delivery, and 4 weeks postpartum, then reassessed with their children 5 years later with directly-observed home- and lab-based measures of parenting. We used linear regression analysis to compare spontaneous quitters with women who exhibited other prenatal smoking patterns on parenting responsiveness, controlling for potential confounders. RESULTS: In home-based observations, spontaneous quitters (n = 22) exhibited greater responsiveness with their children relative to intermittent pregnancy smokers [n = 70; beta = 0.258, p = .022]; persistent pregnancy smokers [n = 66; beta = 0.228, p = .040]; former smokers (quit before pregnancy) [n = 78; beta = 266, p = .028]; and never smokers [n = 69; beta = 0.312, p = .009]. Hypothesized differences were not observed in lab-based and self-report measures. CONCLUSIONS: Putative protective characteristics in spontaneous quitters were captured in mother-child interactions at home, but not in lab-based and maternal report measures of responsiveness. Specification of these characteristics using prospective designs that oversample for spontaneous quitters is recommended to enable translation to preventive interventions. PMID- 29501651 TI - Regulation of brain development and brain function by the transcriptional repressor RP58. AB - The mechanisms regulating the formation of the cerebral cortex have been well studied. In the developing cortex, (also known Znf238, Zfp238, and Zbtb18), which encodes a sequence-specific transcriptional repressor, is expressed in glutamatergic projection neurons and progenitor cells. Targeted deletion of Rp58 leads to dysplasia of the neocortex and hippocampus, a reduction in the number of mature cortical neurons, and defects in laminar organization due to abnormal neuronal migration within the cortical plate. During late embryogenesis, Rp58 deficient mice have larger numbers of progenitor cells due to a delay in cell cycle exit. RP58 represses all four Id genes (Id1-Id4), which regulate cell cycle exit in the developing cerebral cortex, and is essential for transcriptional repression of Ngn2 and Rnd2, which regulate the multipolar-to-bipolar transition during neuronal migration independently of its role in cell cycle exit. PMID- 29501652 TI - Metabolic effects of light deprivation in the prefrontal cortex of rats with depression-like behavior: In vivo proton magnetic resonance spectroscopy at 7T. AB - Recent evidence suggests that the glutamate system plays an important role in the pathogenesis of major depressive disorder (MDD). The aim of this study was to investigate the effects of light deprivation (LD) in the prefrontal cortex (PFC) of animals with depression-like behavior, targeting the glutamate system, using in vivo proton magnetic resonance spectroscopy (1H MRS). Male Sprague-Dawley rats were housed in constant darkness for six weeks (n = 12; LD group), while controls (n = 8) were housed under normal light cycles. The animals were assessed with forced swim tests. Point-resolved spectroscopy was used to quantify metabolite levels in the PFC. To substantiate the validity of the use of in vivo1H MRS in this study, the spectra obtained in the in vivo1H MRS, parametrically matched spectral simulation, and in vitro experiments were analyzed. The results of the spectral analyses showed that the quantification of glutamate and glutamine was not significantly affected by spectral overlaps. Thus, these results suggested that in vivo1H MRS can be used to reliably investigate the glutamate system. The results of the forced swim test showed LD-induced behavioral despairs in the animals. The levels of glutamate, myo-inositol, phosphocreatine, and total creatine were found significantly (p < 0.010) increased in the PFC of the LD animals compared with the controls. These results suggested that the LD-induced metabolic changes were consistent with the previous findings in patients with MDD and that short-echo-time in vivo1H MRS can be used to effectively measure depression-induced alterations in glutamate systems. PMID- 29501653 TI - The epidemiology and genetics of Amyotrophic lateral sclerosis in China. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder associated with loss of motor neurons. Previous knowledge of the disease has been mainly based on studies from Caucasian ALS patients of European descent. Here we review the epidemiological characteristics of ALS among the Chinese population in order to compare the similarities and differences between Chinese ALS cases and those from other countries. We describe a potential lower incidence and prevalence of ALS, a younger age of onset and a lower proportion of familial ALS cases in the Chinese population. Additionally, we highlight potential genetic differences between Chinese and Caucasian ALS patients. Most notably, the frequency of GGGGCC repeat expansions in C9ORF72 in Chinese ALS is significantly lower than in Caucasians. Since some conclusions might not be consistent across all of the studies around China to date, we suggest that it is necessary to carry out a prospective population-based study and large-scale gene sequencing around to better define epidemiological and genetic features of Chinese ALS patients. PMID- 29501654 TI - Invited Commentary. PMID- 29501655 TI - Reply. PMID- 29501656 TI - Statistical Commentary. PMID- 29501657 TI - Invited Commentary. PMID- 29501658 TI - Reply. PMID- 29501659 TI - Reply. PMID- 29501660 TI - Invited Commentary. PMID- 29501661 TI - Invited Commentary. PMID- 29501662 TI - Towards an improved diagnosis of bloodstream infection: promises and hurdles. PMID- 29501663 TI - Characterisation of the intracellular protozoan MPX in Scottish mussels, Mytilus edulis Linnaeus, 1758. AB - Ciliates have been reported as pathogens of many species of economically important bivalves. Mussel protozoan X (MPX), is an uncharacterised intracellular ciliate of mussels and has been widely reported in Mytilus spp. around the world. In order to characterise this ciliate, Mytilus edulis samples were collected from a site on the West coast of Scotland, and four different fixatives for histological examination were tested. Fresh preparations of mussel digestive glands were also examined by laser scanning confocal microscopy. Intracellular ciliates were prepared by laser capture microdissection and partial sequences of small subunit ribosomal RNA gene and of large subunit ribosomal RNA gene were generated, using Phyllopharyngea primers. Methacarn solution proved to be the best fixative for both histological and molecular characterisation. The morphological and molecular investigations confirmed that this ciliate belongs to the class Phyllopharyngea, order Rhynchodida. However, this organism does not belong to any known family, genus or species, therefore, a new description is necessary, following further morphological analyses. Most mussel samples containing MPX displayed mild to moderate infections, with no signs of necrosis or haemocytic response, although a single sample displayed a severe infection (~103 ciliates per section). The localisation of this ciliate in tissues other than the digestive gland, the presence of necrosis in infected tissue of the most severely infected mussel and the binary fission of this ciliate have been observed here for the first time. We also report the first observation of the live ciliate isolated from tissue. Although MPX remains of unknown significance to the mussel industry, tools and protocols described here will be useful in further characterising these and other ciliates (subclass Rhynchodia) known as pathogens for bivalves. PMID- 29501664 TI - Indigenous strains of Beauveria and Metharizium as potential biological control agents against the invasive hornet Vespa velutina. AB - Alien species often miss parasites in their invaded area, and this is the case in Vespa velutina. This invasive hornet predator of bees was accidentally introduced in Europe from East China in 2004. The control of this species is still problematic. Indeed to destroy nests, applicators currently use large spectrum insecticides, which is too costly or dangerous to applicators and also to the environment, affecting non-targeted arthropods (one period). Studying the potential interest of biological control methods may help to propose alternatives in V. velutina control. We present here the bioassays in which we assessed the potential control efficiency of different indigenous French isolates of entomopathogenic fungi. We inoculated adults V. velutina by different ways: being directly, by walking on a contaminated surface, in the food, or by inter individual transfers. We tested differences between the isolates and the application methods using two parameters mortality and LT50. The direct inoculation method was the most efficient modality, then the contact, transfer and food. Considering all contamination methods, there was no difference on susceptibility or mortality among different isolates. Still the LT50 was quite short in all isolates (average 5.8+/-0.44d), and their virulence was quite high: we conclude that there is high potential in using such entomopathogens as a biological control agent against V. velutina. PMID- 29501665 TI - Elastin-driven genetic diseases. AB - Elastic fibers provide recoil to tissues that undergo repeated deformation, such as blood vessels, lungs and skin. Composed of elastin and its accessory proteins, the fibers are produced within a restricted developmental window and are stable for decades. Their eventual breakdown is associated with a loss of tissue resiliency and aging. Rare alteration of the elastin (ELN) gene produces disease by impacting protein dosage (supravalvar aortic stenosis, Williams Beuren syndrome and Williams Beuren region duplication syndrome) and protein function (autosomal dominant cutis laxa). This review highlights aspects of the elastin molecule and its assembly process that contribute to human disease and also discusses potential therapies aimed at treating diseases of elastin insufficiency. PMID- 29501667 TI - Diagnosis and management of short QT syndrome. AB - Establishing a definition of short QT syndrome (SQTS), including symptomatology and QT-interval duration, is still a work in progress. However, it is clear , that SQTS is a rare, life-threatening, inherited heart disease presenting as sudden cardiac death (SCD) or aborted SCD in 34% and a family history of SCD in 15%. Genetic testing is important in diagnosing the disease, but to date a causative mutation is found in <25%. A benign variety of the disease has been observed in children with atrial fibrillation and a KCNH2-V141M mutation, and recently a mutation in the cardiac Cl/HCO3 exchanger AE3 was found to cause SQTS. Issues related to measuring and correcting the QT interval for heart rate has made it difficult to rely entirely on QT duration for the diagnosis of SQTS. In order to establish the diagnosis on firmer grounds, symptoms, family history, and genetic testing need to be considered. Although the benefit of insertion of an implantable cardioverter-defibrillator as secondary prophylaxis against SCD in a patient with SQTS is well documented, the benefit as primary prophylaxis is controversial and not proven by solid data. In 2 recent similar studies involving 115 patients with approximately 5 years of follow-up, insertion of an implantable cardioverter-defibrillator in 40 patients saved the lives of 12, 11 who had presented with cardiac arrest and 1 with syncope. No appropriate shocks were delivered in any patients who did not have a history of either syncope or cardiac arrest. Currently quinidine is the only drug that has undergone any clinical testing. PMID- 29501666 TI - Association of regional epicardial right ventricular electrogram voltage amplitude and late gadolinium enhancement distribution on cardiac magnetic resonance in patients with arrhythmogenic right ventricular cardiomyopathy: Implications for ventricular tachycardia ablation. AB - BACKGROUND: Criteria for identification of anatomic ventricular tachycardia substrates in arrhythmogenic right ventricular cardiomyopathy (ARVC) on late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) are unclear. OBJECTIVE: The purpose of this study was to define (1) the association of regional right ventricular (RV) epicardial voltage amplitude with the distribution of LGE; and (2) appropriate image signal intensity (SI) thresholds for ventricular tachycardia substrate identification in ARVC. METHODS: Preprocedural LGE-CMR and epicardial electrogram mapping were performed in 10 ARVC patients. The locations of epicardial electrogram map points, obtained during sinus rhythm with intrinsic conduction or RV pacing, were retrospectively registered to the corresponding LGE image regions. Standardized SI z-scores (standard deviation distance from the mean) were calculated for each 10-mm region surrounding map points. RESULTS: In patient-clustered, generalized estimating equations models that included 3205 epicardial electroanatomic points and corresponding SI measures, bipolar (-1.43 mV/z-score; P <.001) and unipolar voltage amplitude (-1.22 mV/z-score; P <.001) were associated with regional SI z scores. In contrast to the QRS-late potential (LP) interval (P = .362), the LP activation index, defined as electrogram duration divided by QRS-LP, was associated with regional SI z-scores (P <.001). SI z-score thresholds >0.05 (95% confidence interval -0.05 to 0.15) and <-0.16 (95% confidence interval -0.26 to 0.06) corresponded to bipolar voltage measures <0.5 and >1.0 mV, respectively. CONCLUSION: Increased RV gadolinium uptake is associated with lower epicardial bipolar and unipolar electrogram voltage amplitude. Standardized LGE-CMR SI z scores may augment preprocedural planning for identification of low-voltage zones and abnormal myocardium in ARVC. PMID- 29501668 TI - Endocardial left ventricular pacing across the interventricular septum for cardiac resynchronization therapy: Clinical results of a pilot study. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) is an effective treatment for selected patients with heart failure, but it can be limited by the inability to place the left ventricular (LV) lead via the coronary sinus. OBJECTIVE: The purpose of this study was to develop an alternative approach, placing the LV lead endocardially via an interventricular septal puncture, and to assess the feasibility and safety of this technique. METHODS: All patients were anticoagulated with warfarin (international normalized ratio 2.5-3.5). A superior approach ventricular transseptal puncture using radiofrequency energy was performed. An active fixation pacing lead was delivered to the mapped site of latest electrical activation on the endocardial LV. RESULTS: Twenty patients were recruited, 15 with failed transvenous LV lead placement and 5 nonresponders to CRT. Mean (+/- SD) age was 67 +/- 12, with 80% male, QRS duration 157 +/- 14 ms, ischemic etiology 45%, New York Heart Association functional class 2.9 +/- 0.4, and LV ejection fraction 28% +/- 7%. The procedure was successful in all, with no serious complications. Clinical composite score improved at 6 months in 65% and worsened in 35%. LV ejection fraction improved >5% in 88%, from 28% +/- 7% to 41% +/- 9%. Six-minute walking distance improved >10% in 64%, from 248 +/- 125 m to 316 +/- 109 m. One patient suffered a lacunar ischemic stroke after 5 months with partial neurological recovery, associated with labile international normalized ratios. After 2.0 +/- 1.0 years of follow-up, 3 patients died (2 pneumonia, 1 heart failure), and 2 patients suffered transient ischemic attacks. CONCLUSION: LV endocardial pacing via interventricular septal puncture in patients for whom standard CRT is not possible is similarly effective and durable, with significant but potentially acceptable risks. PMID- 29501669 TI - Pulmonary vein activity does not predict the outcome of catheter ablation for persistent atrial fibrillation: A long-term multicenter prospective study. AB - BACKGROUND: Pulmonary vein (PV) isolation (PVI) remains the cornerstone of catheter ablation (CA) in persistent atrial fibrillation (AF) (PeAF), although less successful than for paroxysmal AF. Whether rapid or fibrillatory (PV AF) PV firing may identify patients with PeAF more likely to benefit from a PV-based ablation approach is unclear. OBJECTIVE: The purpose of this study was to determine the relationship between the PV cycle length (PVCL) and the PV AF outcome after CA. METHODS: Before ablation, the multipolar catheter was placed in each PV and the left atrial appendage (LAA) for 100 consecutive cycles. The presence of PV AF, the average PVCL of all 4 veins (PV4VAverage), the fastest vein average (PVFVAverage), the fastest cycle length (PVFast) both individually and relative to the average LAA cycle length were calculated. The ablation strategy included PVI and posterior wall isolation with a minimum of 12 months follow-up. RESULTS: A total of 123 patients underwent CA (age 62 +/- 9.1 years; CHA2DS2-VASC score 1.6 +/- 1.1; left ventricular ejection fraction 48% +/- 13%; left atrial area 31 +/- 8.7 cm2; AF duration 16 +/- 17 months). PVI was achieved in 100% of patients. Multiprocedure success (MPS; freedom from AF/atrial tachycardia episodes lasting >30 seconds) was achieved in 76% of patients at 24 +/- 8.1 months of follow-up after 1.2 +/- 0.4 procedures. PV activity was not associated with MPS either absolutely (PV4VAverage [MPS no vs yes: 178 +/- 27 ms vs 177 +/- 24 ms; P = .92], PVFVAverage [P = .69], or PVFast [P = .82]) or as a ratio relative to the LAA cycle length (PV4VAverage/LAA 1.05 +/- 0.11 vs 1.06 +/- 0.21; P = .87). The presence of PV AF (31% vs 47%; P = .13) did not predict MPS. CONCLUSION: The rapidity of PV firing or presence of fibrillation within the PV was not predictive of outcome of CA for PeAF. PV activity does not identify patients most likely to benefit from a PV-based ablation strategy. PMID- 29501670 TI - Amino acid-level signal-to-noise analysis of incidentally identified variants in genes associated with long QT syndrome during pediatric whole exome sequencing reflects background genetic noise. AB - BACKGROUND: Due to rapid expansion of clinical genetic testing, an increasing number of genetic variants of undetermined significance and unclear diagnostic value are being identified in children. Variants found in genes associated with heritable channelopathies, such as long QT syndrome (LQTS), are particularly difficult to interpret given the risk of sudden cardiac death associated with pathologic mutations. OBJECTIVE: The purpose of this study was to determine whether variants in LQTS-associated genes from whole exome sequencing (WES) represent disease-associated biomarkers or background genetic "noise." METHODS: WES variants from Baylor Genetics Laboratories were obtained for 17 LQTS associated genes. Rare variants from healthy controls were obtained from the GnomAD database. LQTS case variants were extracted from the literature. Amino acid-level mapping and signal-to-noise calculations were conducted. Clinical history and diagnostic studies were analyzed for WES subjects evaluated at our institution. RESULTS: Variants in LQTS case-associated genes were present in 38.3% of 7244 WES probands. There was a similar frequency of variants in the WES and healthy cohorts for LQTS1-3 (11.2% and 12.9%, respectively) and LQTS4-17 (27.1% and 38.4%, respectively). WES variants preferentially localized to amino acids altered in control individuals compared to cases. Based on amino acid-level analysis, WES-identified variants are indistinguishable from healthy background variation, whereas LQTS1 and 2 case-identified variants localized to clear pathologic "hotspots." No individuals who underwent clinical evaluation had clinical suspicion for LQTS. CONCLUSION: The prevalence of incidentally identified LQTS-associated variants is ~38% among WES tests. These variants most likely represent benign healthy background genetic variation rather than disease associated mutations. PMID- 29501671 TI - Heart rate variability during acute psychosocial stress: A randomized cross-over trial of verbal and non-verbal laboratory stressors. AB - Acute psychosocial stress is typically investigated in laboratory settings using protocols with distinctive characteristics. For example, some tasks involve the action of speaking, which seems to alter Heart Rate Variability (HRV) through acute changes in respiration patterns. However, it is still unknown which task induces the strongest subjective and autonomic stress response. The present cross over randomized trial sought to investigate the differences in perceived stress and in linear and non-linear analyses of HRV between three different verbal (Speech and Stroop) and non-verbal (Montreal Imaging Stress Task; MIST) stress tasks, in a sample of 60 healthy adults (51.7% females; mean age = 25.6 +/- 3.83 years). Analyses were run controlling for respiration rates. Participants reported similar levels of perceived stress across the three tasks. However, MIST induced a stronger cardiovascular response than Speech and Stroop tasks, even after controlling for respiration rates. Finally, women reported higher levels of perceived stress and lower HRV both at rest and in response to acute psychosocial stressors, compared to men. Taken together, our results suggest the presence of gender-related differences during psychophysiological experiments on stress. They also suggest that verbal activity masked the vagal withdrawal through altered respiration patterns imposed by speaking. Therefore, our findings support the use of highly-standardized math task, such as MIST, as a valid and reliable alternative to verbal protocols during laboratory studies on stress. PMID- 29501672 TI - Delivery of oat-derived phytoceramides into the stratum corneum of the skin using nanocarriers: Formulation, characterization and in vitro and ex-vivo penetration studies. AB - Deficiency or altered composition of stratum corneum (SC) lipids such as ceramides (CERs), causing skin barrier dysfunction and skin dryness, have been associated with skin diseases such as atopic dermatitis and psoriasis, and ageing. Replenishing the depleted native CERs with exogenous CERs has also been shown to have beneficial effects in restoring the skin barrier. Phyto-derived CERs such as oat CERs were shown to be potential for skin barrier reinforcement. To effect this, however, the oat CERs should overcome the SC barrier and delivered deep into the lipid matrix using the various novel formulations. In an attempt to demonstrate the potential use of oat CERs, lecithin-based microemulsions (MEs) and starch-based nanoparticles (NPs) were formulated and characterized. Besides, ME gel and NP gel were also prepared using Carbopol(r)980 as a gelling agent. The in vitro release and penetration (using artificial four layer membrane system) and ex vivo permeation (using excised human skin) of oat CERs from the various formulations were investigated. The results revealed ME enhanced the in vitro release and penetration oat CERs compared to the other formulations. On the other hand, the NPs retarded the release of oat CERs and small quantities of oat CERs incorporated into NP gel penetrated into the deeper layers of the multilayer membranes. The penetration-enhancing effect of ME was also observed in the ex vivo permeation studies where significant quantities of oat CERs were found in the acceptor compartment. Compared to the ME, the ME gel exhibited reduced depth and extent of oat CERs permeation. As compared to NP gel, ME gel enhanced the degree of permeation of oat CERs into the deeper layer of the skin. Generally the gel formulations were effective in concentrating oat CERs in the SC where they are needed to be. PMID- 29501673 TI - Lafoensia pacari A. St.-Hil.: Wound healing activity and mechanism of action of standardized hydroethanolic leaves extract. AB - ETHNOPHARMACOLOGICAL IMPORTANCE: Lafoensia pacari A. St.-Hil., (Lythraceae) is a native tree of Brazilian Cerrado and commonly known in Brazil as "mangava-brava". Its leaves are used in Brazilian folk medicine in wound healing, cutaneous mycoses, and in the treatment of gastritis and ulcers. AIM OF THE STUDY: The present study was designed to evaluate the wound healing activity and mechanism of action of the hydroethanolic extract of Lafoensia pacari A. St.-Hil. leaves (HELp), and to advance in its chemical profiling. MATERIALS AND METHODS: HELp was prepared by maceration in 70% hydroethanolic solution (1:10, w/v). The phytochemical analyses were investigated using colorimetry and electrospray ionization/mass spectrometric detection (ESI-MSn). Its in vitro cytotoxicity was evaluated in CHO-K1 and L929 cells, while the in vivo acute toxicity was performed in mice. The potential in vivo wound healing activity was assessed using excision and incision rat models and histopathology of the wounded skin (excision model) was carried out. The in vitro wound healing activity of HELp was demonstrated by scratch assay in L-929 cells, by measuring proliferation/migration rate and p-ERK 1/2 protein expression using western blot analysis. HELp's in vivo anti-inflammatory activity was evaluated by lipopolysaccharide (LPS) induced peritonitis in mice, along with the determination of nitric oxide (NO) and cytokines (TNF-alpha and IL-10) in the peritoneal lavages. Its potential in vitro antibacterial activity was performed using microbroth dilution assay, while in vitro antioxidant activities was by 1,1 diphenyl-2-picrylhydrazyl (DPPH) radical, and ferric reducing antioxidant power (FRAP) assays. RESULTS: The phytochemical analysis of HELp revealed the presence of polyphenols with ellagic acid, punicalagin, punicalin, kaempferol, quercetin-3 O-xylopyranoside and quercetin-3-O-rhamnopyranoside being the most prominent. HELp showed no toxicity on CHO-k1 and L929 cell lines. Topical treatment with HELp (10 and 30 mg/g of gel) presented increased rates of wound contraction at all the days evaluated with complete wound re-epithelialization at 22.0 +/- 1.5 (p < 0.05) and 21.7 +/- 1.6 (p < 0.01) days, respectively. Topical application of HELp (10, 30 or 100 mg/g of gel) in incised wounds caused an increase in tensile break strength at all concentrations resulting in moderate re-epithelialization and neovascularization, increased cell proliferation an accelerated remodeling phase of the wound, in a manner comparable to standard drug (Madecassol(r), 10 mg/g). In the scratch assay with L929 cells, HELp (0.1 and 0.03 mg/mL) and PDGF (5 ng/mL) resulted in the increased proliferation/migration rate of fibroblasts and higher expression of p-ERK 1/2 protein. In LPS-induced peritonitis, HELp (100 and 200 mg/kg p.o.) decreased total leukocyte migration, comparable to the dexamethasone (0.5 mg/kg p.o.). In RAW 264.7 macrophages activated by LPS, HELp produced anti-inflammatory activity dependent on increased concentrations of IL 10, reduction in NO production, without altering the TNF-alpha levels. HELp also presented potent antioxidant activity in the DPPH and FRAP, but lacks in vitro antibacterial activity. CONCLUSION: The present study results support the popular use of the leaves of L. pacari in the treatment of wounds. Its wound healing activity is multi-targeted and involves inhibition of the proliferative and anti inflammatory phases, antioxidant and positive modulation of the remodeling phase that might be involved different secondary metabolites, with emphasis on the ellagic acid, punicalagin, punicalin, kaempferol, quercetin-3-O-xylopyranoside and quercetin-3-O-rhamnopyranoside. PMID- 29501674 TI - Traditional uses, phytochemistry, pharmacology and toxicology of Codonopsis: A review. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Species of the genus Codonopsis are perennial herbs mainly distributed throughout East, Southeast and Central Asia. As recorded, they have been used as traditional Chinese medicines since the Qing Dynasty, where they were claimed for strengthening the spleen and tonifying the lung, as well as nourishing blood and engendering liquid. Some species are also used as food materials in southern China and Southeast Asia, such as tea, wine, soup, plaster, and porridge. AIM OF THE REVIEW: The review aims to assess the ethnopharmacological uses, explicit the material basis and pharmacological action, promote the safety of medical use, and suggest the future research potentials of Codonopsis. MATERIALS AND METHODS: Information on the studies of Codonopsis was collected from scientific journals, books, and reports via library and electronic data search (PubMed, Elsevier, Scopus, Google Scholar, Springer, Science Direct, Wiley, Researchgate, ACS, EMBASE, Web of Science and CNKI). Meanwhile, it was also obtained from published works of material medica, folk records, ethnopharmacological literatures, Ph.D. and Masters Dissertation. Plant taxonomy was confirmed to the database "The Plant List" (www.theplantlist.org). RESULTS: Codonopsis has been used for medicinal purposes all around the world. Some species are also used as food materials in southern China and Southeast Asia. The chemical constituents of Codonopsis mainly are polyacetylenes, polyenes, flavonoids, lignans, alkaloids, coumarins, terpenoids, steroids, organic acids, saccharides, and so on. Extract of Codonopsis exhibit extensive pharmacological activities, including immune function regulation, hematopoiesis improvement, cardiovascular protection, neuroprotection, gastrointestinal function regulation, endocrine function regulation, cytotoxic and antibacterial effects, anti-aging and anti-oxidation, etc. Almost no obvious toxicity or side effect are observed and recorded for Codonopsis. CONCLUSIONS: The traditional uses, phytochemistry, pharmacology and toxicology of Codonopsis are reviewed in this paper. Species of the genus have long been used as traditional medicines and food materials, they are reported with a large number of chemical constituents with different structures, extensive pharmacological activities in immune system, blood system, digestive system, etc. and almost no toxicity. More profound studies on less popular species, pharmacodynamic material basis and pharmacological mechanism, and quality assurance are suggested to be carried out to fulfil the research on the long-term clinical use and new drug research of Codonopsis. PMID- 29501675 TI - Paljung-San, a traditional herbal medicine, attenuates benign prostatic hyperplasia in vitro and in vivo. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Paljung-san is a traditional herbal medicine used widely for the treatment of urogenital diseases in East Asia. However, scientific evidence of the efficacy of Paljung-san and its mechanisms of action against benign prostatic hyperplasia (BPH) is not clearly established. AIM OF THE STUDY: We investigated the inhibitory effect of Paljung-san water extract (PSWE) and its mechanisms against BPH in vitro and in vivo. MATERIALS AND METHODS: Active compounds of PSWE were analyzed quantitatively by High-performance liquid chromatography (HPLC). For in vitro study, PSWE treated BPH-1 cells were used to perform western blot analysis, cell cycle analysis and enzyme-linked immunosorbent assay. For in vivo BPH model, male rats were subcutaneously injected with 10 mg/kg of testosterone propionate (TP) every day for four weeks. 200 and 500 mg/kg of PSWE was administrated daily by oral gavage with s.c. injection of TP, respectively. RESULTS: HPLC revealed that PSWE contains 1.21, 1.18, 2.27, 3.56, 4.23, 3.00, 6.78, and 0.004 mg/g of gallic acid, 5 caffeoylquinic acid, chlorogenic acid, geniposide, liquiritin apioside, liquiritin, glycyrrhizin, and chrysophanol components, respectively. In human BPH 1 cells, PSWE treatment reduced cell proliferation through arresting the cell cycle in the DNA synthesis phase. Moreover, PSWE suppressed prostaglandin E2 production with reduced cyclooxygenase-2 expression. In TP -induced BPH rat model, PSWE administration showed reduced prostate weights and dihydrotestosterone levels and led to a restoration of normal prostate morphology. PSWE also decreased TP-induced Ki-67 and cyclin D1 protein levels in the prostatic tissues. Decreased glutathione reductase activity and increased malondialdehyde levels in the BPH groups were reversed by PSWE administration. CONCLUSION: PSWE attenuates the progression of BPH through anti-proliferative, anti-inflammatory and anti-oxidant activities in vitro and in vivo. Therefore, these data provide the scientific evidence of pharmacological efficacy of PSWE against BPH. PMID- 29501677 TI - Comparative sequence alignment reveals River Buffalo genomic structural differences compared with cattle. AB - This study sought to characterize differences in gene content, regulation and structure between taurine cattle and river buffalo (one subspecies of domestic water buffalo) using the extensively annotated UMD3.1 cattle reference genome as a basis for comparisons. We identified 127 deletion CNV regions in river buffalo representing 5 annotated cattle genes. We also characterized 583 merged mobile element insertion (MEI) events within the upstream regions of annotated cattle genes. Transcriptome analysis in various tissue types on river buffalo confirmed the absence of four cattle genes. Four genes which may be related to phenotypic differences in meat quality and color, had upstream MEI predictions and were found to have significantly elevated expression in river buffalo compared with cattle. Our comparative alignment approach and gene expression analyses suggested a functional role for many genomic structural variations, which may contribute to the unique phenotypes of river buffalo. PMID- 29501676 TI - Validation of ethnopharmacology of ayurvedic sarasvata ghrita and comparative evaluation of its neuroprotective effect with modern alcoholic and lipid based extracts in beta-amyloid induced memory impairment. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Sarasvata ghrita (SG), a polyherbal formulation from ayurveda, an ancient medicinal system of India, has been used to improve intelligence and memory, treat speech delay, speaking difficulties and low digestion power in children. AIM OF THE STUDY: Study aimed to validate the ethno use of SG in memory enhancement through systematic scientific protocol. The effect of SG and modern extracts of ingredients of SG was compared on cognitive function and neuroprotection in amyloid-beta peptide 25-35(Abeta25-35) induced memory impairment in wistar rats. Further the underlying mechanism for neuroprotective activity was investigated. MATERIALS AND METHODS: SG was prepared as per traditional method, ethanolic extract (EE) was prepared by conventional method and lipid based extract was prepared by modern extraction method. All extracts were standardised by newly developed HPLC method with respect to marker compounds. SG, EE and LE were administered orally to male Wistar rats at doses of 100,200 and 400 mg/kg Body Weight by feeding needle for a period of 21 days after the intracerebroventricular administration of Abeta25-35 bilaterally. Spatial memory of rats was tested using Morris water maze (MWM) and Radial arm maze (RAM) test. The possible underlying mechanisms for the cognitive improvement exhibited by SG, EE and LE was investigated through ex-vivo brain antioxidant effect, monoamine level estimation, acetylcholine esterase (AchE) inhibitory effect and Brain-derived neurotropic factor (BDNF) levels estimation. RESULTS: SG, EE and LE were analyzed by HPLC method, results showed that EE extract has high percent of selected phytoconstituents as compared with SG and LE. SG and LE decrease escape latency and searching distance in a dose dependant manner during MWM test. In case of RAM significant decrease in number of errors and increase in number of correct choices indicate an elevation in retention and recall aspects of learning and memory after administration of SG an LE. SG and LE extract can efficiently prevent accumulation of beta-amyloid plaque in hippocampus region. There was increase in SOD, GSH, CAT and NO level and decrease in MDA levels in SG and LE administered animals. SG and LE have found to exhibit AchE inhibitiory activity and significant dose-dependant increase in BDNF level in the plasma. SG and LE significantly increased the levels of noradrenaline, dopamine and 5 hydroxytryptamine in the brain. CONCLUSION: The study validated the neuroprotective activity of SG. The study concludes the extraction efficiency of SG for selected phytoconstituents is less than modern methods. However the neuroprotective activity of SG and LE was found to be greater than EE. PMID- 29501678 TI - Comparative genomics of Mycobacterium reveals evolutionary trends of M. avium complex. AB - Mycobacterium is gram positive, slow growing, disease causing Actinobacteria. Beside potential pathogenic species, Mycobacterium also contains opportunistic pathogens as well as free living non-pathogenic species. Disease related various analyses on Mycobacterium tuberculosis are very widespread. However, genomic study of overall Mycobacterium species for understanding the selection pressure on genes as well as evolution of the organism is still illusive. MLSA and 16s rDNA based analysis has been generated for 241 Mycobacterium strains and a detailed analysis of codon and amino acid usage bias of mycobacterial genes, their functional analysis have been done. Further the evolutionary features of M. avium complex also have been revealed. Mycobacterial genes are moderately GC rich showed higher expression level in PPs and significant negative correlation with biosynthetic cost of proteins. Translational selection pressure was observed in mycobacterial genes. MAC showed close relationship with NPs and higher evolutionary rate in MAC revealed their constant evolving nature. PMID- 29501679 TI - Personalized immunosuppression in elderly renal transplant recipients. AB - The number of elderly people has increased considerably over the last decades, due to a rising life expectancy and ageing populations. As a result, an increased number of elderly with end-stage-renal-disease are diagnosed, for which the preferred treatment is renal transplantation. Over the past years the awareness of the elderly as a specific patient population has grown, which increases the importance of research in this group. Elderly patients often receive kidneys from elderly donors while younger donor kidneys are preferentially reserved for younger recipients. Although the rate of acute rejection after transplantation is lower in the elderly, these rejections may lead to graft loss more frequently, as kidneys from elderly donors have marginal reserve capacity. To prevent acute rejection, immunosuppressive therapy is needed. On the other hand, elderly patients have a higher risk to die from infectious complications, and thus less immunosuppression would be preferable. Immunosuppressive treatment in the elderly is complicated further by changes in the pharmacokinetics and pharmacodynamics, with increasing age. Adjustments in standard immunosuppressive regimes are therefore suggested for this population. An unmet need in transplantation medicine is a tool to guide a personalized approach to immunosuppression. Recently several promising biomarkers that identify injury to the graft at an early stage or predict acute rejection have been identified. Unfortunately, none of these biomarkers were tested specifically in the elderly. We believe there is an urgent need to perform clinical trials investigating novel immunosuppressive regimens in conjunction with biomarker studies in this specific population. PMID- 29501680 TI - A meta-analytic study of the factors driving the purchase of organic food. AB - Interest in the consumption of organic food has steadily risen over the past two decades. Yet after considerable research addressing a range of issues related to organic food consumption no research systematically examines which factors explain consumers' perceptions and purchase of organics. Through a meta-analysis we examine factors underpinning the purchase of organic food using a sample of 124,353 consumers reported in 150 manuscripts over the period from 1991 to 2016. The results demonstrate that credence attributes of organic food are valued more than search and experience attributes. This shows that the market is guided by the perceived benefits of organic over conventionally grown food. These findings do not diminish the importance of search and experience attributes, but suggest that credence attributes have a prominent role in consumer organic food purchases. From the perspective of organic producers and sellers an understanding of consumer perceptions, set within search, experience and credence attributes, has the potential to offer a unique selling proposition and point of differentiation in the market. PMID- 29501681 TI - What makes the hedonic experience of a meal in a top restaurant special and retrievable in the long term? Meal-related, social and personality factors. AB - Knowing what makes a top gastronomy experience unique and retrievable in the long term is of interest for scientific and economic reasons. Recent attempts to isolate predictors of the hedonic evaluation of food have afforded several factors, such as individual and social attributes, or liking/disliking profiles. However, in these studies relevant variables have been examined in isolation without an integrative perspective. Here we investigated 80 guests enjoying a 23 course meal in a top gastronomy restaurant, in groups of four. Our main question concerned the factors driving the overall evaluation of the meal at its conclusion and after three months. To this aim we administered the Big Five Personality Inventory before the meal, dish-by-dish hedonic ratings, and a multi dimensional Meal Experience Questionnaire (MEQ) at the end of the meal. Hedonic evaluations of the meal were collected immediately after the meal and three months later. Better immediate overall evaluations were predicted by both the number of peaks in dish-by-dish ratings and by positive ratings of the final dish. Both factors and the number of troughs were also critical for the long-term evaluation after three months. The MEQ dimensions overall interest, valence and distraction predicted immediate evaluations, while the long-term evaluations were determined by interest and high scores on the personality traits agreeableness and conscientiousness. High consistency of the hedonic ratings within quartets indicated the relevance of commensality for the meal experience. The present findings highlight the simultaneous relevance of food- and personality-related factors and commensality for a top gastronomy meal experience in the short and long-run. The uncovered relationships are of theoretical interest and for those involved in designing meals for consumers in various settings. PMID- 29501682 TI - Adding sodium information to casual dining restaurant menus: Beneficial or detrimental for consumers? AB - High sodium levels in restaurant food have prompted Philadelphia and New York City to require inclusion of sodium content in addition to calories on menus to "nudge" consumers toward lower sodium foods. However, taste perceptions may impact the effectiveness of this intervention. An online survey tested whether sodium and calorie menu nutrition information (MNI) influenced consumer choices from a casual dining restaurant menu, accounting for consumers' intuition about taste of food relative to sodium, calories, and healthiness. Consumer choices were assessed based on calorie and sodium content of the menu items they selected. Participants were randomized to a menu with (1) calorie MNI only, (2) calorie plus numeric sodium MNI, (3) calorie MNI plus a sodium warning symbol for foods with 2300 mg of sodium or more, or (4) no MNI. Calorie plus numeric sodium MNI was associated with selection of meals lower in sodium compared to meals from the calorie MNI only menu or no MNI menu, but only for consumers with a taste intuition that (relatively) lower sodium, lower calorie, healthy foods were tasty. Consumers with the opposite taste intuition *(foods with these characteristics are not tasty) ordered meals higher in sodium. Inclusion of the sodium warning symbol did not result in a significantly different meal sodium content compared to the other menu conditions, regardless of taste intuition. However, differing levels of taste intuition alone, without consideration of MNI, was associated with ordering meals of significantly different calorie content. Overall, findings suggest adding calorie plus numeric sodium MNI may lead to beneficial outcomes (i.e., selecting meals lower in sodium) for some consumers and detrimental outcomes (i.e., selecting meals higher in sodium) for others, depending on their taste intuition. PMID- 29501683 TI - If you build it, will they eat it? Consumer preferences for plant-based and cultured meat burgers. AB - In a hypothetical choice experiment consumers were given the option of purchasing burgers that were made from beef, plant-based protein, or cultured meat. Willingness to purchase plant-based and cultured meat burgers is linked to age, sex, views of other food technologies, and attitudes towards the environment and agriculture. Although consumers were told that all burgers tasted the same, there was a marked preference for beef burgers. A mixed-logit model predicts that, if prices were equal, 65% of consumers would purchase the beef burger, 21% would purchase the plant-based burger, 11% would purchase the cultured meat burger, and 4% would make no purchase. Preferences for plant-based and cultured meat burgers are found to be highly, but not perfectly, correlated. PMID- 29501684 TI - Transplanted human neural precursor cells integrate into the host neural circuit and ameliorate neurological deficits in a mouse model of traumatic brain injury. AB - Traumatic brain injury (TBI) is to date one of the major critical conditions causing death and disability worldwide. Exogenous neural stem/precursor cells (NSCs/NPCs) hold great promise for improving neurological dysfunction, but their functional properties in vivo remain unknown. Human neural precursor cells (hNPCs) carrying one fluorescent reporter gene (DsRed) can be observed directly in vivo using two-photon laser-scanning microscope. Therefore, we evaluated the neural integration and potential therapeutic effect of hNPCs on mice with TBI. Behavioral tests were performed by rotarod task and Morris Water Maze task. Neural integration was detected by fluorometric Ca2+ imaging and nerve tracing. We found that motor and cognition functions were significantly improved in mice with hNPCs injection compared to mice with vehicle treatment, and hNPCs integrated into the host circuit and differentiated toward neuronal lineage. Our study provided reliable evidence for further hNPCs transplantation in clinical practice. PMID- 29501685 TI - Ketamine-induced neurotoxicity blocked by N-Methyl-d-aspartate is mediated through activation of PKC/ERK pathway in developing hippocampal neurons. AB - Ketamine, a non-competitive N-methyl d-aspartate (NMDA) receptor antagonist, is widely used in pediatric clinical practice. However, prolonged exposure to ketamine results in widespread anesthetic neurotoxicity and long-term neurocognitive deficits. The molecular mechanisms that underlie this important event are poorly understood. We investigated effects of anesthetic ketamine on neuroapoptosis and further explored role of NMDA receptors in ketamine-induced neurotoxicity. Here we demonstrate that ketamine induces activation of cell cycle entry, resulting in cycle-related neuronal apoptosis. On the other hand, ketamine administration alters early and late apoptosis of cultured hippocampus neurons by inhibiting PKC/ERK pathway, whereas excitatory NMDA receptor activation reverses these effects. Ketamine-induced neurotoxicity blocked by NMDA is mediated through activation of PKC/ERK pathway in developing hippocampal neurons. PMID- 29501686 TI - Involvement of dopamine D2 receptor in a single methamphetamine-induced behavioral sensitization in C57BL/6J mice. AB - A single exposure to drugs of abuse is sufficient to induce behavioral sensitization, which is a form of long-lasting neuroplasticity. Dopamine D2 receptors are the main receptor for antipsychotic drugs, but little is known about their role in a single methamphetamine-induced behavioral sensitization. In the present study, we examined whether typical antipsychotic haloperidol and atypical antipsychotic risperidone, both targeting dopamine D2 receptor, could prevent the methamphetamine sensitization when they were given at the different phase of behavioral sensitization. A single methamphetamine exposure induced robust and reliable behavioral sensitization to the lower challenge dose of methamphetamine after 7 days of drug-free period. At doses that did not affect general locomotion, haloperidol and risperidone not only significantly attenuated methamphetamine induced hyperlocomotion, but also completely prevented the development of behavioral sensitization to methamphetamine challenge when they were pretreated before the first exposure to methamphetamine. When haloperidol and risperidone were given in the early period of transfer (2 h after the first methamphetamine exposure), they also dose-dependently attenuated the transfer to expression of methamphetamine sensitization from the hyperlocomotion. These data suggest that dopamine D2 receptors play an important role in methamphetamine sensitization, especially in protecting against the development and transfer in the earlier labile period after the methamphetamine exposure. Therefore, clinically approved dopamine D2 receptor antagonists may be useful in the treatment of methamphetamine addiction. PMID- 29501687 TI - Inter-session reliability of short-interval intracortical inhibition measured by threshold tracking TMS. AB - Paired-pulse transcranial magnetic stimulation (TMS) using fixed test stimuli suffers from marked variability of the motor evoked potential (MEP) amplitude. Threshold tracking TMS (TT-TMS) was introduced to overcome this problem. The aim of this work was to describe the absolute and relative reliability of short interval intracortical inhibition (SICI) using TT-TMS. Cortical excitability studies were performed on twenty-six healthy subjects over three sessions (two recordings on the same day and one seven days apart), with MEPs recorded over abductor pollicis brevis. Reliability was established by calculating the standard error of the measurements (SEm), minimal detectable change (MDC) and intraclass correlation coefficient (ICC). Resting motor threshold and averaged SICI presented the lowest SEm and highest ICCs. SICI at 1 ms showed a higher SEm than SICI at 3 ms, suggesting different physiological processes, but averaging SICI over a number of intervals greatly increases the reproducibility. The variability was lower for tests undertaken at the same time of day seven days apart compared to tests performed on the same day, and in both instances the ICC for averaged SICI was >=0.81. The MDC in averaged SICI was reduced from 6.7% to 2% if the number of subjects was increased from one to eleven. In conclusion, averaged SICI is the most reproducible variable across paired-pulse TT-TMS measures, showing an excellent ICC. It is recommended that, in longitudinal studies, testing be performed at the same time of day and that changes in cortical excitability should be measured and averaged over a number of interstimulus intervals to minimise variability. PMID- 29501688 TI - Comparison of reduced metagenome and 16S rRNA gene sequencing for determination of genetic diversity and mother-child overlap of the gut associated microbiota. AB - Use of the 16S rRNA gene in microbiota studies is limited by the lack of taxonomic and functional resolution. High resolution analyses are particularly important for understanding transmission and persistence of bacteria. The aim of our work was therefore to compare a novel reduced metagenome sequencing (RMS) approach with 16S rRNA gene sequencing to determine both the metagenome genetic diversity and the mother-to-child sharing of the microbiota in a cohort of 17 mother-child pairs. We found that although both approaches gave comparable results with respect to sample separation and taxonomy, RMS gave higher resolution and the potential for genomic-/functional assignment. Using RMS we estimated that the metagenome size increased from about 60 Mbp for 4-day-old children to about 225 Mbp for mothers. The 4-day-old children shared 7% of the metagenome sequences with the mothers, while the metagenome sequence sharing was >30% among the mothers. We found 15 genomes shared across >50% of the mothers, of which 10 belonged to Clostridia. Only Bacteroides showed a direct mother-child association, with B. vulgatus being abundant in both 4-day-old children and mothers. For the functional assignments, we identified a significant association between antibiotic usage during labor, and quantity of Fosfomycin resistance genes. In conclusion, our results show a higher functional and taxonomic resolution for RMS compared to 16S rRNA gene sequencing, where RMS enabled a detailed description of mother to child gut microbiota transmission - supporting a late recruitment of most gut bacteria and an effect of antibiotic treatment during labor on infant antibiotic resistance gene patterns. PMID- 29501689 TI - Evaluation of the reproducibility of a serological test for antibodies to Chlamydia trachomatis pgp3: A potential surveillance tool for trachoma programs. AB - PURPOSE: Serological testing for antibodies to Chlamydia trachomatis pgp3 is being evaluated as a tool to use for trachoma surveillance. There are limited data on the reproducibility of the test results using a multiplex platform. METHODS: We tested the reproducibility of a serologic test for C. trachomatis pgp3 in 6 dried blood spots collected from a random sample of 45 children from a trachoma endemic area. The spots were tested on a multiplex bead array platform, using one bead set twice, using another bead set at the same time as the first, and using the same bead set twice on different days separated by several months. Seropositivity was defined using ROC analyses from the same external controls for both bead sets. We compared the mean fluorescent intensity unit minus background (MFI-BG) results using the intraclass correlation coefficient (ICC), and analyzed the concordance of seropositivity designation using the kappa statistic. RESULTS: The tests using the same bead set were highly correlated, ICC = 0.997 (0.995 1.00). Even tested months apart, the slight loss of signal was not statistically significant (p = 0.06). The test of the two different bead sets showed high correlation, but the differences in MFI-BG was statistically significant. However, the serostatus of the children was unchanged comparing the seropositivity using one bead set compared to a second bead set. CONCLUSION: The reproducibility of the multiplex bead array for serological testing of antibodies to Chlamydia trachomatis pgp3 is high when the same bead set is used for testing. PMID- 29501690 TI - Identity and home: Understanding the experience of people with advanced cancer. AB - The purpose of this study was to explore how the identity of people with advanced cancer is influenced by their experiences of living at home. A total of 28 in depth interviews were conducted with 22 people with advanced cancer and four spouses. Grounded theory guided the collection and analysis of data. Home tours and associated field notes augmented the interview data. The analysis revealed that support of participants' identity was reflected in their abilities to live and occupy the home during daily activities, and in the ways the home and objects functioned as referents to themselves and their past. Threats to their identity ensued as the home environment became unmanageable during daily activities and as homecare professionals and assistive devices entered the home. By supporting people with advanced cancer in maintaining daily activities in the home and reducing changes in the home caused by homecare it is possible to reduce loss of identity. PMID- 29501691 TI - Identification and screening of potent antimicrobial peptides in arthropod genomes. AB - Using tBLASTn and BLASTp searches, we queried recently sequenced arthropod genomes and expressed sequence tags (ESTs) using a database of known arthropod cecropins, defensins, and attacins. We identified and synthesized 6 potential AMPs and screened them for antimicrobial activity. Using radial diffusion assays and microtiter antimicrobial assays, we assessed the in vitro antimicrobial effects of these peptides against several human pathogens including Gram-positive and Gram-negative bacteria and fungi. We also conducted hemolysis assays to examine the cytotoxicity of these peptides to mammalian cells. Four of the six peptides identified showed antimicrobial effects in these assays. We also created truncated versions of these four peptides to assay their antimicrobial activity. Two cecropins derived from the monarch butterfly genome (Danaus plexippus), DAN1 and DAN2, showed minimum inhibitory concentrations (MICs) in the range of 2-16 MUg/ml when screened against Gram-negative bacteria. HOLO1 and LOUDEF1, two defensin-like peptides derived from red flour beetle (Tribolium castaneum) and human body louse (Pediculus humanus humanus), respectively, exhibited MICs in the range of 13-25 MUg/ml against Gram-positive bacteria. Furthermore, HOLO1 showed an MIC less than 5 MUg/ml against the fungal species Candida albicans. These peptides exhibited no hemolytic activity at concentrations up to 200 MUg/ml. The truncated peptides derived from DAN2 and HOLO1 showed very little antimicrobial activity. Our experiments show that the peptides DAN1, DAN2, HOLO1, and LOUDEF1 showed potent antimicrobial activity in vitro against common human pathogens, did not lyse mammalian red blood cells, and indicates their potential as templates for novel therapeutic agents against microbial infection. PMID- 29501692 TI - Long non-coding RNA CRNDE as a potential prognostic biomarker in solid tumors: A meta-analysis. AB - BACKGROUND AND AIM: Long non-coding RNA colorectal neoplasia differentially expressed (CRNDE) has been demonstrated to be highly expressed in many malignant tumors; however, the role of CRNDE in cancer remains undetermined because of limitations in sample size. We conducted a meta-analysis to assess the role of CRNDE in cancer. METHODS: PubMed, Medline, Cochrane Library, Web of Science, EMBASE database, Ovid, Chinese CNKI, and Chinese WanFang database were systematically searched. The relation between CRNDE and the clinicopathological characteristics and prognosis of patients with cancer was determined using pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence interval (CI). RESULTS: Thirteen studies with 1570 patients were included. The pooled results indicated that high CRNDE expression was related to lymph node metastasis (YES vs. NO: OR = 3.50, 95% CI = [1.05, 8.09]) and TNM stage (I + II vs. III + IV: OR = 0.26, 95% CI = [0.18, 0.37]) but not to gender, tumor size, and differentiation. High CRNDE expression indicated poor overall survival (OS) (HR = 2.06, 95% CI = [1.66, 2.47]). CRNDE could be an independent predictive factor for OS (HR = 1.62, 95% CI = [1.15, 2.08]) in patients with cancer. CONCLUSION: Therefore, high CRNDE expression was associated with advanced clinicopathological characteristics, and CRNDE could be used as a reliable prognostic biomarker in human cancer. However, more high-quality studies with a large sample size are needed to support this meta-analysis. PMID- 29501693 TI - Reference measurement procedure for total bilirubin in serum re-evaluated and measurement uncertainty determined. AB - BACKGROUND: For the determination of total bilirubin in serum the candidate reference method developed by Doumas et al. has international recognition. The primary standard SRM 916a (NIST) was recommended for use as the primary reference material for calibration. Nowadays, no primary standard is anymore commercially available. Further, a description of uncertainty components was missing. METHODS: Two reference laboratories have re-investigated the candidate reference measurement procedure. Beside minor modifications, mainly the use of a molar absorption coefficient instead of calibration by use of bilirubin standard solutions has facilitated the operating, and improved the analytical performance. All relevant sources of measurement uncertainty were investigated. RESULTS: A measurement range of 5-525 MUmol/L and a CV of 0.5% to 1.4% (long term imprecision) were determined. Excellent agreement was obtained comparing to Doumas procedure (r = 0.9999) and during a two laboratory comparison participating at IFCC RELA ring trials (mean deviation: 0.6%). The combined expanded measurement uncertainty (probability 95%) for bilirubin concentrations >30 MUmol/L was estimated as 2.2%. CONCLUSION: A reference system for total bilirubin based on the described reference procedure shall enable metrological traceability and optimized standardization of the values obtained in clinical routine laboratories. PMID- 29501694 TI - Effects on haematological and serum biochemical parameters of Pangasianodon hypophthalmus to an experimental infection of Thaparocleidus sp. (Monogenea: dactylogyridae). AB - Monogenea (gill parasite) is a major problem in aquaculture that reduces the growth of cultured fish and adversely affects the economy. The present study was performed to evaluate the impact of various degrees of Thaparocleidus sp. (dactylogyrids, monogenean) infestation on haematological and serum biochemical parameters of Pangasianodon hypophthalmus. A standard cohabitation study, following complete randomized design in triplicate, was conducted to obtain low, moderate and high degrees of infestation in P. hypophthalmus along with the control (uninfested) group. Blood and serum were studied for haematological (total erythrocyte count (TEC), haemoglobin (Hb), packed cell volume (PCV), total leucocyte count (TLC) and indices viz. mean cell volume (MCV), mean cell haemoglobin (MCH), mean cell haemoglobin concentration (MCHC) and erythrocyte osmolarity brittleness (EOB)) and serum biochemical parameters (serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), lactate, total bilirubin and creatinine. Significant (p < 0.05) increase in TEC, Hb, TLC, EOB, SGOT, SGPT, LDH, lactate, bilirubin, and creatinine were noticed in moderate to high monogenean-infested group in comparison to the control group. However, significant (p < 0.05) reduction in MCH, and MCV and no difference (P > 0.05) in PCV were noticed in high degree parasitized group in comparison to the control group. The results of altered haematological and serum biochemical parameters in various degrees of monogenean-infested groups signify the density dependent physiological responses and changes in cells of the blood. The data of serum enzymes in the present study would be valuable for assessing the health status of the host and facilitate as a potential biomarker in relation to various degrees of monogenean infestation. PMID- 29501695 TI - Detection and molecular characterization of Acanthamoeba spp. in stray cats from Madrid, Spain. AB - Acanthamoeba spp. is a widespread protozoan that has been isolated from air, dust, soil, water and biological samples. An opportunistic pathogen of humans and animals, it may cause ocular keratitis, encephalitis, and even multisystem disease. The frequency of Acanthamoeba in animals is unknown. The aim of present study was determine the presence of Acanthamoeba spp. in immunocompromised stray cats - animals possibly more likely to harbour the infection given their immunocompromised status and frequenting of contaminated environments. Of 307 cats examined, 55 were positive for feline immunodeficiency virus and/or feline leukaemia virus and therefore included in the study. Corneal scrapings were obtained to isolate Acanthamoeba spp. by culture and molecular detection by conventional and real time PCR. None of the samples examined directly by molecular methods were positive for Acanthamoeba spp. However, two (3.6%) cases of the cultured samples provided positive results, which were confirmed by subsequent molecular analysis. Sequencing assigned one isolate to genotype T4 and the other to T2. Since Acanthamoeba spp. may also infect animals and humans, the present findings may raise some public health and veterinary concerns. PMID- 29501696 TI - The therapeutic strategies against Naegleria fowleri. AB - Naegleria fowleri is a pathogenic amoeboflagellate most prominently known for its role as the etiological agent of the Primary Amoebic Meningoencephalitis (PAM), a disease that afflicts the central nervous system and is fatal in more than 95% of the reported cases. Although being fatal and with potential risks for an increase in the occurrence of the pathogen in populated areas, the organism receives little public health attention. A great underestimation in the number of PAM cases reported is assumed, taking into account the difficulty in obtaining an accurate diagnosis. In this review, we summarize different techniques and methods used in the identification of the protozoan in clinical and environmental samples. Since it remains unclear whether the protozoan infection can be successfully treated with the currently available drugs, we proceed to discuss the current PAM therapeutic strategies and its effectiveness. Finally, novel compounds for potential treatments are discussed as well as research on vaccine development against PAM. PMID- 29501697 TI - Isolation and molecular identification of Acanthamoeba spp from oasis water in Tunisia. AB - In the southern Tunisia Oasis, we conducted 211 water with drawals from various water traffic sites. This water is used for agriculture, swimming or various other human activities. Acanthamoeba genus was detected in 82% of collected samples. Sequencing of the amplification products with primers P892C/P892 has allowed us to detect genotypic variation with predominance of T4 genotype (51%) and presence of the genotypes T14, T5, T3, T16, T15, T10, T11, T9 and T7. They T4, T3, T5, T15, T11 and T10 genotypes have a high potential for pathogenicity and a very high degree of virulence due to their production of serine proteases and extracellular cysteine enzymes involved in tissue degradation of the host. T4 genotype was the most abundant in the environment as well as in infections caused by Acanthamoeba spp. T5 genotype was ranked second and T3 genotype was less abundant in the environment and its pathogenicity is discussed. Acanthamoeba strains with the genotypes T16, T9 and T7 were considered non pathogenic. In fact, they have been isolated only from the environment. However, for these strains, their role as a reservoir can be a real risk to human health. PMID- 29501698 TI - Heregulin-induced cell migration is promoted by aryl hydrocarbon receptor in HER2 overexpressing breast cancer cells. AB - HER2 overexpression accounts for approximately 15-20% of all breast cancers. We have shown that HER2 overexpression leads to elevated expression of the aryl hydrocarbon receptor (AhR) in breast cancer cells. In this study, firstly, we showed that AhR expression was up-regulated by treatment with the HER3 ligand heregulin (HRG) in HER2-overexpressing breast cancer cell lines. Induction of AhR was mediated by transcriptional activation of the region of AhR promoter corresponding to - 190 to - 100 bp. In addition, HRG treatment elicited nuclear translocation of AhR. To investigate the role of AhR in HRG-HER2/HER3 signaling in HER2-overexpressing cells, we established AhR knockout (KO) HER2 overexpressing cells to perform wound-healing assays. HRG-induced cell migration was markedly attenuated by AhR KO. HRG-induced cell migration was associated with increased expression of the inflammatory cytokines interleukin (IL)-6 and IL-8 in wild type cells, but not in AhR KO cells. These results elucidate that AhR is an important factor for the malignancy in HER2 overexpressing breast cancers. PMID- 29501699 TI - Wound healing related agents: Ongoing research and perspectives. AB - Wound healing response plays a central part in chronic inflammation, affecting millions of people worldwide. It is a dynamic process that can lead to fibrosis, if tissue damage is irreversible and wound resolution is not attained. It is clear that there is a tight interconnection among wound healing, fibrosis and a variety of chronic disease conditions, demonstrating the heterogeneity of this pathology. Based on our further understanding of the cellular and molecular mechanisms underpinning tissue repair, new therapeutic approaches have recently been developed that target different aspects of the wound healing process and fibrosis. Nevertheless, several issues still need to be taken into consideration when designing modern wound healing drug delivery formulations. In this review, we highlight novel pharmacological agents that hold promise for targeting wound repair and fibrosis. We also focus on drug-delivery systems that may enhance current and future therapies. PMID- 29501700 TI - Responsive triggering systems for delivery in chronic wound healing. AB - Non-communicable diseases including cancer, cardiovascular disease, diabetes, and neuropathy are chronic in nature. Treatment of these diseases with traditional delivery systems is limited due to lack of site-specificity, non-spatiotemporal release and insufficient doses. Numerous responsive delivery systems which respond to both physiological and external stimuli have been reported in the literature. However, effective strategies incorporating a multifactorial approach are required to control these complex wounds. This can be achieved by fabricating spatiotemporal release systems, multimodal systems or dual/multi-stimuli responsive delivery systems loaded with one or more bioactive components. Critically, these next generation stimuli responsive delivery systems that are at present not feasible are required to treat chronic wounds. This review provides a critical assessment of recent developments in the field of responsive delivery systems, highlighting their limitations and providing a perspective on how these challenges can be overcome. PMID- 29501701 TI - Lumican as a multivalent effector in wound healing. AB - Wound healing, a complex physiological process, is responsible for tissue repair after exposure to destructive stimuli, without resulting in complete functional regeneration. Injuries can be stromal or epithelial, and most cases of wound repair have been studied in the skin and cornea. Lumican, a small leucine-rich proteoglycan, is expressed in the extracellular matrices of several tissues, such as the cornea, cartilage, and skin. This molecule has been shown to regulate collagen fibrillogenesis, keratinocyte phenotypes, and corneal transparency modulation. Lumican is also involved in the extravasation of inflammatory cells and angiogenesis, which are both critical in stromal wound healing. Lumican is the only member of the small leucine-rich proteoglycan family expressed by the epithelia during wound healing. This review summarizes the importance of lumican in wound healing and potential methods of lumican drug delivery to target wound repair are discussed. The involvement of lumican in corneal wound healing is described based on in vitro and in vivo models, with critical emphasis on its underlying mechanisms of action. Similarly, the expression and role of lumican in the healing of other tissues are presented, with emphasis on skin wound healing. Overall, lumican promotes normal wound repair and broadens new therapeutic perspectives for impaired wound healing. PMID- 29501702 TI - Synthetic artificial "long non-coding RNAs" targeting oncogenic microRNAs and transcriptional factors inhibit malignant phenotypes of bladder cancer cells. AB - Both oncogenic transcription factors (TFs) and microRNAs (miRNAs) play important roles in human cancers, acting as transcriptional and post-transcriptional regulators, respectively. These phenomena raise questions about the ability of an artificial device to simultaneously regulate miRNAs and TFs. In this study, we aimed to construct artificial long non-coding RNAs, "alncRNAs", and to investigate their therapeutic effects on bladder cancer cell lines. Based on engineering principles of synthetic biology, we combined tandem arrayed aptamer cDNA sequences for TFs with tandem arrayed cDNA copies of binding sites for the miRNAs to construct alncRNAs. In order to prove the utility of this platform, we chose beta-catenin and the miR-183-182-96 cluster as the functional targets and used the bladder cancer cell lines 5637 and SW780 as the test models. Dual luciferase reporter assay, real-time quantitative PCR (qRT-PCR) and related phenotypic experiments were used to test the expression of related genes and the therapeutic effects of our devices. The result of dual-luciferase reporter assay and qRT-PCR showed that alncRNAs could inhibit transcriptional activity of TFs and expression of corresponding microRNAs. Using functional experiments, we observed decreased cell proliferation, increased apoptosis, and motility inhibition in alncRNA-infected bladder cancer cells. What's more, follow-up mechanism experiments further confirmed the anti-tumor effect of our devices. In summary, our synthetic devices indeed function as anti-tumor regulators, which synchronously accomplish transcriptional and post-transcriptional regulation in bladder cancer cells. Most importantly, anti-cancer effects were induced by the synthetic alncRNAs in the bladder cancer lines. Our devices, all in all, provided a novel strategy and methodology for cancer studies, and might show a great potential for cancer therapy if the challenges of in vivo DNA delivery are overcome. PMID- 29501703 TI - Seek and Find! PCR analyses of skin infections in West-European travelers returning from abroad with an eschar. AB - BACKGROUND: Skin infections are among the leading causes of diseases in travelers. Diagnosing pathogens could be difficult. METHOD: We applied molecular assays for the diagnostic of a large collection of skin biopsies and swabs from travelers with suspected skin infections. All samples were tested by qPCR for Coxiella burnetti, Bartonella sp., Rickettsia sp., Borrelia sp., Ehrlichia sp., Tropheryma whipplei, Francisella tularensis, Mycobacteria sp., Staphylococcus aureus, Streptococcus pyogenes, Leishmania spp., Ortho poxvirus and Para poxvirus and then screened for the presence of bacteria by PCR amplification and sequencing, targeting the 16S rRNA gene. RESULTS: From January 2009 to January 2017, 100 international travelers presenting with a suspected skin infection were enrolled. We detected 51 patients with an identified pathogen on skin samples. Travelers presenting with eschars were more likely to have a positive PCR sample (n = 44/76, 57.9%) compared to other patients (n = 7/24, 29.2%). Spotted fever group Rickettsia (n = 28) was the most frequently detected pathogens (19 R. africae, 6 R. conorii, 3 R. mongolitimonae); S. aureus were detected in 11 patients; S. pyogenes in 3; Leishmania sp.; M. leprae and B. henselae in 1 patient, respectively. CONCLUSION: By targeting the most commonly encountered causative agents of travel-related skin infections, our strategy provides a sensitive and rapid diagnostic method. PMID- 29501704 TI - Effects of Guanfu total base on Bcl-2 and Bax expression and correlation with atrial fibrillation. AB - OBJECTIVE: This study sought to investigate the effects of Guanfu total base on Bcl-2 and Bax expression and the correlation of Bcl-2 and Bax expression with atrial fibrillation. METHODS: Twenty-four male Sprague-Dawley rats were randomly divided into control, model, and treatment groups (n = 8 each). A combined intravenous injection of CaCl2 (10 mg/mL) and acetylcholine (Ach; 66 MUg/mL) was administered to the model and treatment groups for 7 consecutive days to induce atrial fibrillation. After 3 days, the treatment group was administered orally with Aconitum coreanum. Controls received saline for 7 consecutive days. Atrial fibrillation duration was monitored by using an electrocardiogram. Immunohistochemical analysis was used to measure the expression and distribution of Bcl-2 and Bax in the atrial myocardial tissues, RT-PCR was used to measure the Bcl-2 and Bax mRNA expression, and western blot was used to measure Bcl-2 and Bax expression in the atrial myocardial tissue. RESULTS: The model group showed prolonged atrial fibrillation, but this was absent in the control and treatment groups, indicating that treatment with A. coreanum effectively reduced atrial fibrillation duration. Immunohistochemical analysis showed that Bcl-2 expression in the atrial muscle tissue was significantly lower, but Bax expression was significantly higher in the model group compared to that in the control group. After treatment, Bcl-2 expression increased and Bax expression decreased (P < 0.01) in the treatment group compared to those in the model group. RT-PCR and western blot presented the same trends. CONCLUSION: Bcl-2 and Bax expression was correlated with atrial fibrillation. Guanfu total base was effective in treating atrial fibrillation, upregulating Bcl-2 expression, and downregulating Bax expression. PMID- 29501705 TI - Electrocardiograms in a patient with recurrent takotsubo syndrome and comprehensive assessment of coronary circulation. PMID- 29501706 TI - Mass spectrometry in freeze-drying: Motivations for using a bespoke PAT for laboratory and production environment. AB - Mass Spectrometry has commonly been used in the semi-conductor industry where maintaining a clean environment with minimum contaminants under high vacuum is crucial for successful manufacturing. Since the technology's early usage for pharmaceutical manufacturing in the 1980 s, particularly in the freeze-drying environment, much has changed. The focus of the current work is aimed at asking some key questions regarding the maturity of the technology, its challenges and importance of having an application-specific instrument for quantitative process analyses applied to freeze-drying. Furthermore, we compare the use of mass spectrometers in early installations from the '80s with recent experiences of the technology in the production and laboratory environments comparing data from different MS technologies. In addition, the manuscript covers broad application of the technology towards detection of and sensitivity for analytes including silicone oil and Helium. It also explores the option of using MS in detecting water vapor and nitrogen concentration not just in primary drying, but also in secondary drying. The technology, when purpose built, has the potential for use as a robust, multi-purpose PAT tool in the freeze-drying laboratory and production environments. PMID- 29501707 TI - Uterine Transplantation: A Minimally Invasive Approach. PMID- 29501708 TI - Advances in glycosylation-mediated cancer-targeted drug delivery. AB - Targeted drug delivery for cancer therapy is expected to enhance therapeutic efficacy with minimized side effects, where the ligand-receptor recognition serves as a common targeting approach. Various ligands have been reported and carbohydrates, one of the crucial structures of tumor cell membranes, have been demonstrated effective for cell-selective binding. Hence, glycosylation-mediated cancer-targeted drug nanocarriers have received increasing attention in recent years. This review surveys a variety of glycosylated drug delivery systems as well as their applications for cancer therapy. Their challenges, opportunities, and future perspectives are also discussed in the end. PMID- 29501710 TI - Suppression of dsRNA response genes and innate immunity following Oct4, Stella, and Nanos2 overexpression in mouse embryonic fibroblasts. AB - The self-renewal capacity of germline derived stem cells (GSCs) makes them an ideal source for research and use in clinics. Despite the presence of active gene network similarities between embryonic stem cells (ESCs) and GSCs, there are unanswered questions regarding the roles of evolutionary conserved genes in GSCs. To determine the reprogramming potential of germ cell- specific genes, we designed a polycistronic gene cassette expressing Stella, Oct4 and Nanos2 in a lentiviral-based vector. Deep transcriptome analysis showed the activation of a set of pluripotency and germ-cell-specific markers and the downregulation of innate immune system. The global shut down of antiviral genes included MHC class I, interferon response genes and dsRNA 2'-5'-oligoadenylate synthetase are critical pathways that has been affected . Individual expression of each factor highlighted suppressive effect of Nanos2 on genes such as Isg15 and Oasl2. Collectively, to our knowledge this is the first report showing that Nanos2 could be considered as an immunosuppressive factor. Furthermore, our results demonstrate suppression of endogenous retrotransposons that harbor immune response but further analysis require to uncover the correlation between transposon suppression and immune response in germ cell development. PMID- 29501709 TI - SWATH mass spectrometry as a tool for quantitative profiling of the matrisome. AB - Proteomic analysis of extracellular matrix (ECM) and ECM-associated proteins, collectively known as the matrisome, is a challenging task due to the inherent complexity and insolubility of these proteins. Here we present sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH MS) as a tool for the quantitative analysis of matrisomal proteins in both non enriched and ECM enriched tissue without the need for prior fractionation. Utilising a spectral library containing 201 matrisomal proteins, we compared the performance and reproducibility of SWATH MS over conventional data-dependent analysis mass spectrometry (DDA MS) in unfractionated murine lung and liver. SWATH MS conferred a 15-20% increase in reproducible peptide identification across replicate experiments in both tissue types and identified 54% more matrisomal proteins in the liver versus DDA MS. We further use SWATH MS to evaluate the quantitative changes in matrisome content that accompanies ECM enrichment. Our data shows that ECM enrichment led to a systematic increase in core matrisomal proteins but resulted in significant losses in matrisome associated proteins including the cathepsins and proteins of the S100 family. Our proof-of-principle study demonstrates the utility of SWATH MS as a versatile tool for in-depth characterisation of the matrisome in unfractionated and non-enriched tissues. SIGNIFICANCE: The matrisome is a complex network of extracellular matrix (ECM) and ECM-associated proteins that provides scaffolding function to tissues and plays important roles in the regulation of fundamental cellular processes. However, due to its inherent complexity and insolubility, proteomic studies of the matrisome typically require the application of enrichment workflows prior to MS analysis. Such enrichment strategies often lead to losses in soluble matrisome associated components. In this study, we present sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH MS) as a tool for the quantitative analysis of matrisomal proteins. We show that SWATH MS provides a more reproducible coverage of the matrisome compared to data-dependent analysis (DDA) MS. We also demonstrate that SWATH MS is capable of accurate quantification of matrisomal proteins without prior ECM enrichment and fractionation, which may simplify sample handling workflows and avoid losses in matrisome-associated proteins commonly linked to ECM enrichment. PMID- 29501711 TI - Clinical Evaluation of a Safety-device to Prevent Urinary Catheter Inflation Related Injuries. AB - OBJECTIVE: To evaluate the feasibility of a novel "safety-valve" device for preventing catheter related urethral trauma during urethral catheterization (UC). To assess the opinions of clinicians on the performance of the safety-valve device. MATERIALS AND METHODS: A validated prototype "safety-valve" device for preventing catheter balloon inflation related urethral injuries was prospectively piloted in male patients requiring UC in a tertiary referral teaching hospital (n = 100). The device allows fluid in the catheter system to decant through an activated safety threshold pressure valve if the catheter anchoring balloon is misplaced. Users evaluated the "safety-valve" with an anonymous questionnaire. The primary outcome measurement was prevention of anchoring balloon inflation in the urethra. Secondary outcome measurement was successful inflation of urinary catheter anchoring balloon in the bladder. RESULTS: Patient age was 76 +/- 12 years and American Society of Anaesthesiologists grade was 3 +/- 1.4. The "safety valve" was utilized by 34 clinicians and activated in 7% (n = 7/100) patients during attempted UC, indicating that the catheter anchoring balloon was incorrectly positioned in the patient's urethra. In these 7 cases, the catheter was successfully manipulated into the urinary bladder and inflated. 31 of 34 (91%) clinicians completed the questionnaire. Ten percent (n = 3/31) of respondents had previously inflated a urinary catheter anchoring balloon in the urethra and 100% (n = 31) felt that a safety mechanism for preventing balloon inflation in the urethra should be compulsory for all UCs. CONCLUSION: The safety valve device piloted in this clinical study offers an effective solution for preventing catheter balloon inflation related urethral injuries. PMID- 29501712 TI - Phenazopyridine: A Preoperative Way to Identify Ureteral Orifices. AB - OBJECTIVE: To identify difficult to see ureteral orifices (UOs), urologists need a method to stain the urine. Phenazopyridine, a urinary analgesic which discolors the urine orange, can be administered orally preoperatively. We evaluated the usefulness of phenazopyridine in identifying the UOs and optimal timing of administration. METHODS: Adult patients undergoing endoscopic procedures at the Stratton VA were prospectively enrolled. Preoperative metabolic panels were reviewed. Exclusion criteria were renal insufficiency (creatinine clearance <50 mL/min), severe hepatitis or severe liver disease, glucose-6-phosphate dehydrogenase deficiency, previous hypersensitivity to phenazopyridine, or pregnancy. In phase 1, patients undergoing office flexible cystoscopy were administered 200 mg phenazopyridine the morning of the procedure. Because of the robust orange color of the urine, phase 2 was implemented. In phase 2, patients undergoing rigid cystoscopy in the operating room took 200 mg phenazopyridine at 7 PM the night before surgery. Upon entry into the bladder, UOs were identified and urine color was graded (0 = no dye, 1 = weak, 2 = moderate, and 3 = strong). Patients were assessed postoperatively for side effects. RESULTS: Five patients were included in phase 1. The mean time from medication to cystoscopy was 153 minutes (range 17-304 minutes). One-third of patients had excretion of grade 3 orange urine that obscured inspection of the bladder mucosa. The study design was adjusted and we transitioned to phase 2. Twenty-three patients were enrolled in phase 2. The mean time from phenazopyridine dose to cystoscopy was 14 hours (range 13-17 hours). Seventy-three percent of patients had grade 2 efflux from the UOs. CONCLUSION: Phenazopyridine can successfully identify UOs and can be administered as early as the evening before the procedure. PMID- 29501713 TI - Titanized Transobturator Sling Placement for Male Stress Urinary Incontinence Using an Inside-out Single-incision Technique: Minimum 12-Months Follow-up Study. AB - OBJECTIVE: To evaluate prospectively midterm outcomes of a new titanium-coated fixed polypropylene sling for male stress urinary incontinence. MATERIALS AND METHODS: From January 2013 to June 2016, 44 consecutive patients with incontinence caused by radical prostatectomy (39) or transurethral resection of prostate (5) underwent transobturator 2-arm titanium-coated sling (TiLOOP Male) implantation with an inside-out, single-incision technique, leaving the bulbourethral muscle in place. Patients have been assessed postoperatively with uroflowmetry, pad count, International Prostate Symptom Score-Short Form, Incontinence Impact Quetionnaire-7, Patient's Global Impression of Improvement, Overactive Bladder questionnaire, International Prostate Symptom Score, and satisfaction (yes or no). Successful outcome included cure (no pad use or 1 dry "security" pad) or improvement (reduction of at least 50% of the pad count). RESULTS: Evaluated patients had mild (11 of 44, 25%), moderate (26 of 44, 59%), or severe (7 of 44, 16%) incontinence. After a median follow-up of 25 months (range 12-55, minimum 12 months), 24 (54.6%) patients were cured and 10 (22.7%) were improved, which was a global success rate of 77.3%. There were 10 (22.7%) failures in the first 6 months. Zero pad rate was 50%. Subjective success (Patient's Global Impression of Improvement very much or much improved) was achieved in 33 (75%) patients. Mean scores of ICIQ-SF, ICIQ-QoL, and IIQ-7 improved to a statistically significant extent. Satisfaction was reported by 33 (75%) patients. Uroflowmetry parameters were unchanged postoperatively, and most of the complications were Clavien-Dindo grade I. Body mass index >=30 and previous irradiation or high-intensity focused ultrasound were independent predictors of failure. CONCLUSION: TiLOOP Male provided favorable and stable midterm continence outcomes. The inside-out approach was safe, and the tolerability of the sling and the single-incision technique was satisfactory. Patients with obesity and previous irradiation or high-intensity focused ultrasound should be aware of their higher risk of failure. PMID- 29501714 TI - Spermatic Vein Thrombosis. PMID- 29501715 TI - The effect of health insurance on sexual health: Evidence from the Affordable Care Act's dependent coverage mandate. AB - This study estimates changes in sexually transmitted disease rates for young adults in the United States following the Affordable Care Act's dependent coverage mandate; a provision that allows dependents to remain covered under their parents' health insurance plans until the age of 26. This study is the first to analyze changes in reported chlamydia and gonorrhea rates resulting from the dependent coverage mandate. Utilizing a difference-in-differences framework coupled with administrative data from the Centers for Disease Control and Prevention, I find that reported chlamydia rates increased for males and females ages 20-24 relative to comparison groups of males and females ages 15-19 and 25 29 following the mandate. I also find evidence of an increase in gonorrhea rates for females in this age group. I find no evidence that the mandate induced ex ante moral hazard. PMID- 29501716 TI - The role of community participation for sustainable integrated neglected tropical diseases and water, sanitation and hygiene intervention programs: A pilot project in Tanzania. AB - Strategies aimed at reducing the prevalence of neglected tropical diseases (NTDs) in Tanzania including those attributed to water, sanitation and hygiene (WASH) problems have been largely top-down in nature. They have focused on strengthening the governance of NTD-WASH programs by integrating different vertical disease programs and improving the efficiency of report-generation. In this paper, we argue for community participation as an effective strategy for developing sustainable village health governance. We present the results of a pilot undertaken between November 2015 and April 2016 in which we adopted a mixed methods case study approach to implement an Enhanced Development Governance (EDG) model using existing village governance structures. Our results show that the EDG model was associated with a statistically significant reduction in the prevalence of schistosomiasis and diarrhoea, and has led to an increase in awareness of WASH interventions for sustaining gains in NTD control. We identify five key social processes enacted by the EDG model that have led to improved health benefits related to frequency of meetings and attendance, promotion of health and sanitation awareness, income-generating activities, self-organising capabilities, and interaction between village bodies. These findings hold important implications for conceptualising the role of community participation in sustaining NTD-WASH intervention programs and for sensitising institutional and policy reform. PMID- 29501717 TI - Representations of race and skin tone in medical textbook imagery. AB - : Although a large literature has documented racial inequities in health care delivery, there continues to be debate about the potential sources of these inequities. Preliminary research suggests that racial inequities are embedded in the curricular edification of physicians and patients. We investigate this hypothesis by considering whether the race and skin tone depicted in images in textbooks assigned at top medical schools reflects the diversity of the U.S. POPULATION: We analyzed 4146 images from Atlas of Human Anatomy, Bates' Guide to Physical Examination & History Taking, Clinically Oriented Anatomy, and Gray's Anatomy for Students by coding race (White, Black, and Person of Color) and skin tone (light, medium, and dark) at the textbook, chapter, and topic level. While the textbooks approximate the racial distribution of the U.S. population - 62.5% White, 20.4% Black, and 17.0% Person of Color - the skin tones represented - 74.5% light, 21% medium, and 4.5% dark - overrepresent light skin tone and underrepresent dark skin tone. There is also an absence of skin tone diversity at the chapter and topic level. Even though medical texts often have overall proportional racial representation this is not the case for skin tone. Furthermore, racial minorities are still often absent at the topic level. These omissions may provide one route through which bias enters medical treatment. PMID- 29501718 TI - Generalized and particularized trust for health between urban and rural residents in Japan: A cohort study from the JAGES project. AB - Previous studies on trust and health have not fully considered the nature of trust in relation to types of trust and socio-cultural background. The present study aimed to examine whether generalized trust (trust in general people; GT) and particularized trust (trust in particular people; PT) in urban and rural areas had different associations with health. This prospective cohort study on older adults used panel data obtained in 2010 and 2013. Surveys were conducted in 24 municipalities in Japan. Of 20,209 respondents, 13,657 participants were followed up. The independent variables were GT and PT in neighbors; the dependent variable was self-rated health (SRH) at follow-up. We examined the interaction term between population density and each trust variable. Age, sex, SRH at the baseline, and other potential confounders were adjusted. The median age was 72 years (females: 53.4%). Percentages of high GT and high PT were 21.0% and 72.4%, respectively. Prevalence of poor SRH at the follow-up was 15.5% and 28.5% in high and low GT, respectively, and 16.9% and 32.8% in high and low PT, respectively. After adjusting for covariates in logistic regression models, low GT and PT were significantly associated with higher odds ratios (ORs) for poor SRH compared to high trust (GT: OR = 1.43 [95% confidence interval (95%CI) = 1.17, 1.75] and PT: OR = 1.44 [95%CI = 1.15, 1.81]). Associations of low PT with poor SRH significantly strengthened when population density increased (interaction term of low PT: OR = 1.16 [95%CI = 1.04, 1.27]). On the other hand, associations of GT with SRH were not significantly interacted by population density. The mediation analysis showed that the direct effects of PT influenced SRH in urban areas only. In urban areas with high social uncertainty, trust in particular neighbors was more beneficial to health. PMID- 29501719 TI - Gestational stress in mouse dams negatively affects gestation and postpartum hippocampal BDNF and P11 protein levels. AB - Stress during pregnancy increases the risk to develop psychological disorders such as depression during pregnancy or in the postpartum period. According to the neurotrophin hypothesis of depression, the pathophysiology of depression is caused by reduced neurotrophic activity in the brain. However, most studies only focus on the molecular changes happening to the offspring upon gestational stress. To gain insight into the potential molecular changes happening in the stressed dams, C57Bl6/J mice were stressed during their first week of gestation. At 28 days postpartum, the hippocampus and nucleus accumbens core of the dams, two brain regions heavily implicated in depression, were evaluated using immunohistochemistry to detect changes in the neurotrophin system. Gestational stress decreased the weight of the dams, increased the chance for spontaneous abortion and increased the weight of offspring. Litter size, survival rates and sex distribution were not altered as a consequence of gestational stress. Hippocampal brain-derived neurotrophic factor (BDNF) decreased following exposure to stress during pregnancy. Hippocampal protein levels of p75NTR, a low-affinity receptor for BDNF which can induce apoptosis, were increased following exposure to stress. Protein levels of p11, of which the expression is regulated by BDNF, were decreased in the hippocampus. No changes were found for TrkB immunostaining or apoptosis. Taken together, this shows that stress during pregnancy negatively affects the neurotrophin system in the hippocampus of the dams, thereby reducing hippocampal plasticity. These data confirm that gestational stress has a negative impact on pregnancy. PMID- 29501720 TI - Unconventional secretion of annexins and galectins. AB - Eukaryotic cells have a highly evolved system of protein secretion, and dysfunction in this pathway is associated with many diseases including cancer, infection, metabolic disease and neurological disorders. Most proteins are secreted using the conventional endoplasmic reticulum (ER)/Golgi network and as such, this pathway is well-characterised. However, several cytosolic proteins have now been documented as secreted by unconventional transport pathways. This review focuses on two of these proteins families: annexins and galectins. The extracellular functions of these proteins are well documented, as are associations of their perturbed secretion with several diseases. However, the mechanisms and regulation of their secretion remain poorly characterised, and are discussed in this review. This review is part of a Special Issues of SCDB on 'unconventional protein secretion' edited by Walter Nickel and Catherine Rabouille. PMID- 29501721 TI - Towards clinical translation of ligand-functionalized liposomes in targeted cancer therapy: Challenges and opportunities. AB - The development of therapeutic resistance to targeted anticancer therapies remains a significant clinical problem, with intratumoral heterogeneity playing a key role. In this context, improving the therapeutic outcome through simultaneous targeting of multiple tumor cell subtypes within a heterogeneous tumor is a promising approach. Liposomes have emerged as useful drug carriers that can reduce systemic toxicity and increase drug delivery to the tumor site. While clinically used liposomal drug formulations show marked therapeutic advantages over free drug formulations, ligand-functionalized liposomes that can target multiple tumor cell subtypes may further improve the therapeutic efficacy by facilitating drug delivery to a broader population of tumor cells making up the heterogeneous tumor tissue. Ligand-directed liposomes enable the so-called active targeting of cell receptors via surface-attached ligands that direct drug uptake into tumor cells or tumor-associated stromal cells, and so can increase the selectivity of drug delivery. Despite promising preclinical results demonstrating improved targeting and anti-tumor effects of ligand-directed liposomes, there has been limited translation of this approach to the clinic. Key challenges for translation include the lack of established methods to scale up production and comprehensively characterize ligand-functionalized liposome formulations, as well as the inadequate recapitulation of in vivo tumors in the preclinical models currently used to evaluate their performance. Herein, we discuss the utility of recent ligand-directed liposome approaches, with a focus on dual-ligand liposomes, for the treatment of solid tumors and examine the drawbacks limiting their progression to clinical adoption. PMID- 29501723 TI - In-situ NIR-laser mediated bioactive substance delivery to single cell for EGFP expression based on biocompatible microchamber-arrays. AB - Controlled drug delivery and gene expression is required for a large variety of applications including cancer therapy, wound healing, cell migration, cell modification, cell-analysis, reproductive and regenerative medicine. Controlled delivery of precise amounts of drugs to a single cell is especially interesting for cell and tissue engineering as well as therapeutics and has until now required the application of micro-pipettes, precisely placed dispersed drug delivery vehicles, or injections close to or into the cell. Here we present surface bound micro-chamber arrays able to store small hydrophilic molecules for prolonged times in subaqueous conditions supporting spatiotemporal near infrared laser mediated release. The micro-chambers (MCs) are composed of biocompatible and biodegradable polylactic acid (PLA). Biocompatible gold nanoparticles are employed as light harvesting agents to facilitate photothermal MC opening. The degree of photothermal heating is determined by numerical simulations utilizing optical properties of the MC, and confirmed by Brownian motion measurements of laser-irradiated micro-particles exhibiting similar optical properties like the MCs. The amount of bioactive small molecular cargo (doxycycline) from local release is determined by fluorescence spectroscopy and gene expression in isolated C2C12 cells via enhanced green fluorescent protein (EGFP) biosynthesis. PMID- 29501722 TI - Supramolecular self assembly of nanodrill-like structures for intracellular delivery. AB - Despite recent advances in the supramolecular assembly of cell-penetrating peptide (CPP) nanostructures, the tuning of size, shape, morphology and packaging of drugs in these materials still remain unexplored. Herein, through sequential ligation of peptide building blocks, we create cell-penetrating self-assembling peptide nanomaterials (CSPNs) with the capability to translocate inside cells. We devised a triblock array of Tat48-59 [HIV-1 derived transactivator of transcription48-59] based CPPs, conjugated to up to four Phenylalanine (Phe) residues through an amphiphilic linker, (RADA)2. We observed that the sequential addition of Phe leads to the transition of CSPN secondary structures from a random coil, to a distorted alpha-helix, a beta-sheet, or a pure alpha-helix. This transition occurs due to formation of a heptad by virtue of even number of Phe. Atomic force microscopy revealed that CSPNs form distinct shapes reminiscent of a "drill-bit". CSPNs containing two, three or four Phe, self-assemble into "nanodrill-like structures" with a coarse-twisted, non-twisted or fine-twisted morphology, respectively. These nanodrills had a high capacity to encapsulate hydrophobic guest molecules. In particular, the coarse-twisted nanodrills demonstrate higher internalization and are able to deliver rapamycin, a hydrophobic small molecule that induced autophagy and are capable of in vivo delivery. Molecular dynamics studies provide microscopic insights into the structure of the nanodrills that can contribute to its morphology and ability to interact with cellular membrane. CSPNs represent a new modular drug delivery platform that can be programmed into exquisite structures through sequence specific fine tuning of amino acids. PMID- 29501724 TI - alphaCGRP, another amyloidogenic member of the CGRP family. AB - The Calcitonin-gene related peptide (CGRP) family is a group of peptide hormones, which consists of IAPP, calcitonin, adrenomedullin, intermedin, alphaCGRP and betaCGRP. IAPP and calcitonin have been extensively associated with the formation of amyloid fibrils, causing Type 2 Diabetes and Medullary Thyroid Carcinoma, respectively. In contrast, the potential amyloidogenic properties of alphaCGRP still remain unexplored, although experimental trials have indicated its presence in deposits, associated with the aforementioned disorders. Therefore, in this work, we investigated the amyloidogenic profile of alphaCGRP, a 37-residue-long peptide hormone, utilizing both biophysical experimental techniques and Molecular Dynamics simulations. These efforts unravel a novel amyloidogenic member of the CGRP family and provide insights into the mechanism underlying the alphaCGRP polymerization. PMID- 29501725 TI - Eco-friendly preparation of zinc oxide nanoparticles using Tabernaemontana divaricata and its photocatalytic and antimicrobial activity. AB - The present work reports the green synthesis of Zinc Oxide Nanoparticles (ZnO NPs) using aqueous Tabernaemontana divaricata green leaf extract. ZnO NPs have been characterized by X-ray diffraction (XRD), Ultra Violet-Visible (UV-Vis) studies, Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM) and Fourier Transform-Infra Red (FT-IR) analysis. XRD pattern analysis confirms the presence of pure hexagonal wurtzite crystalline structure of ZnO. The TEM images reveal the formation of spherical shape ZnO NPs with the sizes ranging from 20 to 50 nm. The FT-IR analysis suggests that the obtained ZnO NPs have been stabilized through the interactions of steroids, terpenoids, flavonoids, phenyl propanoids, phenolic acids and enzymes present in the leaf extract. Mechanism for the formation of ZnO NPs using Tabernaemontana divaricata as bioactive compound is proposed. As prepared ZnO NPs reveals antibacterial activity against three bacterial strains, Salmonella paratyphi, Escherichia coli and Staphylococcus aureus. The ZnO NPs shows higher antibacterial activity against S. aureus and E. coli and lesser antibacterial activity against S. paratyphi compared to the standard pharmaceutical formulation. Photocatalytic activity of synthesized ZnO NPs was analyzed for methylene blue (MB) dye degradation with sunlight. Almost complete degradation of dye occurred in 90 min. This nano-ZnO, prepared by eco-friendly method will be much useful for dye removal and bacterial decontamination. PMID- 29501726 TI - Extracellular nucleotides enhance agonist potency at the parathyroid hormone 1 receptor. AB - Parathyroid hormone (PTH) activates the PTH/PTH-related peptide receptor (PTH1R) on osteoblasts and other target cells. Mechanical stimulation of cells, including osteoblasts, causes release of nucleotides such as ATP into the extracellular fluid. In addition to its role as an energy source, ATP serves as an agonist at P2 receptors and an allosteric regulator of many proteins. We investigated the effects of concentrations of extracellular ATP, comparable to those that activate low affinity P2X7 receptors, on PTH1R signaling. Cyclic AMP levels were monitored in real-time using a bioluminescence reporter and beta-arrestin recruitment to PTH1R was followed using a complementation-based luminescence assay. ATP markedly enhanced cyclic AMP and beta-arrestin signaling as well as downstream activation of CREB. CMP - a nucleotide that lacks a high energy bond and does not activate P2 receptors - mimicked this effect of ATP. Moreover, potentiation was not inhibited by P2 receptor antagonists, including a specific blocker of P2X7. Thus, nucleotide-induced potentiation of signaling pathways was independent of P2 receptor signaling. ATP and CMP reduced the concentration of PTH (1-34) required to produce a half-maximal cyclic AMP or beta-arrestin response, with no evident change in maximal receptor activity. Increased potency was similarly apparent with PTH1R agonists PTH (1-14) and PTH-related peptide (1-34). These observations suggest that extracellular nucleotides increase agonist affinity, efficacy or both, and are consistent with modulation of signaling at the level of the receptor or a closely associated protein. Taken together, our findings establish that ATP enhances PTH1R signaling through a heretofore unrecognized allosteric mechanism. PMID- 29501727 TI - Sonic hedgehog signaling pathway promotes INSM1 transcription factor in neuroendocrine lung cancer. AB - Neuroendocrine (NE) lung tumors account for 20% of total lung cancer cases and represent a subset of aggressive tumors with metastatic potential. High-risk NE lung cancer patients display disseminated disease, N-myc expression/amplification, and poorly differentiated tumors. In this study, we investigate the molecular mechanisms underlying a zinc-finger transcription factor, INSM1 in NE lung cancer. Our study revealed that INSM1 crosstalk with the Shh-PI3K/AKT-N-myc/Ascl1-MEK/ERK1/2 transcriptional network in NE lung cancer. The INSM1 expression pattern and functional data demonstrated that INSM1 is not only critical for NE differentiation, but also served as a NE tumor-specific marker in small cell lung carcinoma (SCLC). The Shh signaling pathway activates INSM1 expression through N-myc and Ascl1 in aggressive SCLC. The E2-box in the INSM1 promoter is the direct target recognized by N-myc and Ascl1 transcription factors. N-myc or Ascl1 activates endogenous INSM1 expression in lung cancer cells. INSM1 functions as a key player in NE lung cancer via Shh signaling that crosstalk with PI3K/AKT and MEK/ERK1/2 pathway to enhance N-myc stability in NE lung cancer. We investigate the negative effects of Shh inhibitor and knockdown of INSM1 in NE lung cancer cells. The combination of different Shh signaling pathway inhibitors targeting INSM1 and N-myc inhibits lung cancer cell growth and could be used as a new treatment option for SCLC. PMID- 29501728 TI - Targeting of cathepsin C induces autophagic dysregulation that directs ER stress mediated cellular cytotoxicity in colorectal cancer cells. AB - As Autophagy is a pivotal mechanism of cancer cell survival and the development of chemotherapeutic resistance; therefore, new approaches are warranted for its targeting which may be fulfilled by cathepsins regulation. Amongst cathepsins, cathepsin C (CTSC) is highly expressed in various cancers and possesses significant therapeutic potential in autoimmune disorders; however, its role in colorectal cancer has not been explored. Herein, we aimed to investigate the role of CTSC in autophagy regulation mediated colorectal carcinoma cell proliferation. Cathepsin C targeting through inhibitors/siRNA leads to the accumulation of light chain 3 II and p62 without affecting the lysosomal integrity, revealed dysfunctional autolysosomal degradation which is also substantiated by proteolytic studies. Cathepsin C inhibition showed comparable autophagy blockade with E64d and augmented the autophagy blockade mediated by bafilomycin. Loss of CTSC function also induced ER stress-mediated JNK phosphorylation accompanied by the translocation of mitochondrial cyt c followed by apoptotic cell death in colorectal carcinoma cells. Taken together, the study reveals that CTSC targeting plays a key role in the regulation of autophagy mediated colorectal cancer cell proliferation. Further investigations are required to determine the functional role of CTSC in other tumors also which may have implications for the therapeutic prevention of cancer in the future. PMID- 29501729 TI - STAT6 is a cargo of exportin 1: Biological relevance in primary mediastinal B cell lymphoma. AB - Primary mediastinal B-cell lymphoma (PMBL) is a distinct B-cell lymphoma subtype with unique clinicopathological and molecular features. PMBL cells are characterised by several genetic abnormalities that conduct to the constitutive activation of the Janus kinase 2/signal transducer and activator of transcription 6 (JAK2/STAT6) signalling pathway. Among recurrent genetic changes in PMBL, we previously reported that the XPO1 gene encoding exportin 1 that controls the nuclear export of cargo proteins and RNAs, is mutated (p.E571K) in about 25% of PMBL cases. We therefore hypothesized that STAT6 could be a cargo of XPO1 and that STAT6 cytoplasm/nucleus shuttle could be altered in a subset of PMBL cells. Using immunocytochemistry techniques as well as the proximity ligation assay, we showed that STAT6 bound XPO1 in PBML cell lines and in HEK-293 cells genetically engineered to produce STAT6. Moreover, XPO1-mediated export of STAT6 occurs in cells expressing either a wild-type or the E571K mutated XPO1 protein. PMID- 29501730 TI - Mobile phones and computer keyboards: unlikely reservoirs of multidrug-resistant organisms in the tertiary intensive care unit. AB - Few studies have used molecular epidemiological methods to study transmission links to clinical isolates in intensive care units. Ninety-four multidrug resistant organisms (MDROs) cultured from routine specimens from intensive care unit (ICU) patients over 13 weeks were stored (11 meticillin-resistant Staphylococcus aureus (MRSA), two vancomycin-resistant enterococci and 81 Gram negative bacteria). Medical staff personal mobile phones, departmental phones, and ICU keyboards were swabbed and cultured for MDROs; MRSA was isolated from two phones. Environmental and patient isolates of the same genus were selected for whole genome sequencing. On whole genome sequencing, the mobile phone isolates had a pairwise single nucleotide polymorphism (SNP) distance of 183. However, >15,000 core genome SNPs separated the mobile phone and clinical isolates. In a low-endemic setting, mobile phones and keyboards appear unlikely to contribute to hospital-acquired MDROs. PMID- 29501731 TI - A limit in the dynamic increase in the accuracy of group migration. AB - Many migratory animals regularly travel thousands of kilometers, exactly finding their seasonal destinations. The nature of this ability is still not fully understood. The aggregation of animals in groups and their socially coordinated movement is considered a way to eliminate navigational errors. Orientation accuracy of a group may be significantly higher as the errors caused by a variety of casual factors are averaged due to social interactions. This idea, called the "many wrongs principle," has been confirmed both in behavioral experiments and numerical simulations. However, little is known about the dependence of this effect on the number N of individuals. Until now, there were no analytical models considering this effect and its limitations. In this article, a stochastic dynamic model of group navigation is presented in terms of the course deviation angle and its variance. The N-dependence of the variance of deviations is found. The variance first decreases with N, however the decrease then slows down thus showing disagreement with the "many wrongs principle." This can be interpreted as meaning that the growth in the accuracy of migration due to the aggregation of individuals into groups is limited. The limit depends on the individual sensitivity of the animal compass, the power of the herd instinct, and the level of random noise. PMID- 29501732 TI - The role of STAG2 in bladder cancer. AB - Stromal Antigen 2 (STAG2) is one of four components of the cohesin complex and predominantly functions in sister chromatid cohesion and segregation. STAG2 is the most frequently mutated cohesin subunit and was recently identified as a gene that is commonly altered in bladder cancer. The significance of these mutations remains controversial. Some studies associate loss of STAG2 expression with low stage and low grade bladder tumors, as well as with improved clinical outcomes. In other cases, STAG2 inactivation has been shown to be a predictor of worse outcome for these patients. The role of STAG2 in aneuploidy also remains controversial. Loss of STAG2 is associated with significant changes in chromosome number in certain cell lines, while in others, aneuploidy is not induced or results remain inconclusive. At this time, little is known about the influence of STAG2 on cellular migration, invasion, proliferation, and cell death, and such studies are required to determine the role of STAG2 in bladder cancer and other malignancies. PMID- 29501733 TI - Cyclosporin A induces autophagy in cardiac fibroblasts through the NRP-2/WDFY-1 axis. AB - Cyclosporin A (CsA) is an effective immunosuppressive agent, but its myocardial toxicity limits its widespread and long-term clinical application. In this study, CsA treatment led to damages in myocardial fiber structure, an increase in myocardial fibrosis, and changes in heart size and shape; moreover, the degree of damage was exacerbated with prolonged drug application and increases in dose. However, the mechanism is not clear; therefore, the purpose of this study was to reveal the mechanism of CsA-induced myocardial fibrosis and identify a new target for the prevention and treatment of CsA-induced myocardial injury. Cardiac fibroblasts were treated with CsA (5, 10, or 20 MUg/mL) for 24 h. Autophagy was observed by electron microscopy and immunofluorescence. The expression of NRP 2/WDFY-1, autophagy-related proteins (Beclin1 and LC3B), fibrosis-related proteins (MMP2/9), and fibroblast phenotype conversion factor (alpha-SMA) was evaluated by Western blot. The expression of collagen I was determined by ELISA. Then, we used the gene interference technique to alter WDFY-1 expression with or without CsA or 3-MA treatment for 24 h, and the effects on autophagy and the expression of autophagy-related proteins, fibrosis-associated proteins, IFN alpha, TNF-alpha, and IL-6 were determined. The results showed the following: (1) CsA induced fibrosis-related protein (MMP2/9), fibroblast phenotype conversion factor (alpha-SMA), and collagen I up-regulation in a dose-dependent manner. (2) CsA induced the formation of autophagosomes and up-regulated the expression of Beclin1, LC3B, and the ERK/MAPK pathway in cardiac fibroblasts. (3) CsA induced NRP-2 down-regulation and WDFY-1 up-regulation. (4) Depletion of WDFY-1 inhibited CsA-induced autophagy, TNF-alpha and IFN-alpha up-regulation, and fibrosis. (5) The autophagy inhibitor 3-MA inhibited CsA-induced TNF-alpha and IFN-alpha up regulation and fibrosis. Overall, cyclosporin A induces autophagy in cardiac fibroblasts through the NRP-2/WDFY-1 axis, which promotes the progression of myocardial fibrosis. PMID- 29501734 TI - Arrangements of nucleotides flanking the start codon in the IRES of the hepatitis C virus in the IRES binary complex with the human 40S ribosomal subunit. AB - Genomic RNA of hepatitis C virus (HCV) has an internal ribosome entry site (IRES), a specific highly structured fragment responsible for its non-canonical translation initiation. The HCV IRES contains a major part of the 5'-untranslated region of the viral RNA and a small portion of the open reading frame (ORF). At the first step of initiation, IRES directly binds to 40S ribosomal subunits so that the AUG start codon appears at the P site region without scanning and without involving initiation factors. However, it is still not entirely clear whether the IRES ORF is correctly loaded into the 40S ribosomal mRNA binding channel in the resulting binary complex. To address this issue, we applied site directed cross-linking using HCV IRES derivatives bearing a perfluorophenyl azide cross-linker at nucleotides in definite positions relative to the adenine of the AUG start codon. We found that the modifier at the IRES position -3 cross-links to ribosomal proteins uS11 and eS26. These proteins have been identified together with uS7 as those interacting with the mRNA nucleotide in position -3 relative to the first nucleotide of the codon directed to the P site by a cognate tRNA. Thus, our results indicate a certain difference in the locations of the above parts of HCV IRES and canonical mRNAs on 40S subunits. The modifier at the IRES positions +4/5 was attached to uS19, which is specific for ribosomal complexes with the P site tRNA and similar derivatives of model canonical mRNAs when the modifier is in the same positions. However, the cross-linking efficiency of the IRES derivative was drastically lower than that previously observed with derivatives of model mRNAs. This implies that the IRES ORF portion is correctly loaded into the mRNA binding channel only in a tiny fraction of the binary complexes. PMID- 29501735 TI - Finite element model predicts the biomechanical performance of transforaminal lumbar interbody fusion with various porous additive manufactured cages. AB - In lumbar interbody fusion, a porous additive manufactured (AM) cage can provide more desirable stiffness, and may be beneficial to bone ingrowth. The biomechanical influence of porous cages on stability, subsidence, and facet contact force has not been fully described. The aim of this study was to verify biomechanical effects of porous cages. A surgical finite element (FE) model of transforaminal lumbar interbody fusion (TLIF) was constructed. Partially porous (PP) cages and fully porous (FP) cages were applied. Mechanical tests were performed to obtain the mechanical parameters of porous materials. The porous cages were compared to solid titanium (TI) cage and solid PEEK cage. Four motion modes were simulated. Range of motion (ROM), cage stress, endplate stress, and facet joint force (FJF) were compared. After interbody fusion, ROM decreased by more than 90% in flexion, bending and rotation. Compared with TI and PP cages, PEEK and FP cages substantially reduced the maximum stresses in cage and endplate in all motion modes. Compared with PEEK cages, the stresses in cage and endplate for FP cages decreased, whereas the ROM increased. Compared among three FP cages, the stresses in cage and endplate decreased with increasing porosity, whereas ROM increased with increasing porosity. FJF for various cages was substantially reduced compared to the intact model in all motion modes except for flexion. In summary, fully porous cages with a porosity of between 65% and 80% may offer an alternative to solid PEEK cages in TLIF. PMID- 29501736 TI - Effects of refractory gradients and ablation on fibrillatory activity. AB - BACKGROUND: The mechanisms involved in onset, maintenance, and termination of atrial fibrillation are not well understood. A biophysical model could be useful to determine how the events unfold. METHOD: A two-dimensional cellular automaton consisting of 576 * 576 grid nodes was implemented to demonstrate the types of electrical activity that may occur in compromised atrial substrate. Electrical activation between nodes was made anisotropic (2:1), and the refractory period (RP) was adjusted from 74 to 192 ms in the spatial domain. Presence of collagen fibers were simulated as short lines of conduction block at many random grid sites, while ablation lesions were delineated as longer lines of block. An S1-S2 pulse from one grid corner was utilized to initiate simulated electrical activity. Simulations were done in which 1. no ablation lines, 2. random ablation lines, and 3. parallel ablation lines were added to the grid to determine how this affected the formation and annihilation of rotational activity after S1-S2 stimulation. RESULTS: As the premature (S2) wavefront traversed the grid, rotational activity formed near boundaries where wavefronts propagated from shorter to longer refractory regions, causing unidirectional block, and were anchored by fiber clusters. Multiple wavelets appeared when wavefronts originating from different driving rotational features collided, and/or by their encounter with RP discontinuities. With the addition of randomly orientated simulated ablation lesions, followed by reinduction of fibrillatory activity, mean activation interval (AI) prolonged from a baseline level of 144.2 ms-160.3 ms (p < 0.001 in most comparisons). During fibrillatory activity, when parallel ablation lines were added to short RP regions, AI prolonged to 150.4 ms (p < 0.001), and when added to long RP regions, AI prolonged to 185.3 ms (p < 0.001). In all cases, AI prolongation after simulated ablation resulted from reduced number and/or from the isolation of local drivers, so that distant drivers in short RP regions activated long RP regions N:1, while distant drivers in long RP regions activated short RP regions at a relatively slow rate. CONCLUSIONS: An automaton model was found useful to generate and test hypotheses concerning fibrillatory activity, which can then be validated in the clinical electrophysiology laboratory. PMID- 29501737 TI - Transdermal delivery of raloxifene HCl via ethosomal system: Formulation, advanced characterizations and pharmacokinetic evaluation. AB - Raloxifene HCl belongs to a class of selective estrogen receptor modulators (SERMs) which is used for the management of breast cancer. The major problem reported with raloxifene is its poor bioavailability which is only up to 2%. The main objective of the present work was to formulate raloxifene loaded ethosomal preparation for transdermal application and compare it with an oral formulation of the drug. Five ethosomal formulations with different concentrations of ethanol and a conventional liposomes formulation were prepared by rotary evaporation method. The prepared systems were characterised by high resolution transmission electron microscopy (HRTEM), force emission electron microscopy (FESEM), atomic force microscopy (AFM), X-ray diffraction (XRD) and 31P NMR study. All these advanced characterization study established that the ethosome formulation was well defined by its size, shape and its bilayer formation. Transdermal flux of the optimized ethosome formulation was 22.14 +/- 0.83 ug/ml/cm2 which was 21 times higher when compared to the conventional liposomes. Confocal microscopy study revealed an enhanced permeation of coumarin-6 dye loaded ethosomes to much deeper layers of skin when compared with conventional liposomes. The gel was found to be pseudoplastic with elastic behaviour. In-vivo studies on rats showed a higher bioavailability of RXL (157% times) for ethosomal formulation when compared with the oral formulation. In conclusion, RXL loaded ethosomal formulation via transdermal route showed superior drug delivery properties as compared to oral formulation. PMID- 29501738 TI - Oral insulin delivery, the challenge to increase insulin bioavailability: Influence of surface charge in nanoparticle system. AB - Oral administration of insulin increases patient comfort and could improve glycemic control thanks to the hepatic first passage. However, challenges remain. The current approach uses poly (d, lactic-co-glycolic) acid (PLGA) nanoparticles (NPs), an effective drug carrier system with a long acting profile. However, this system presents a bioavailability of less than 20% for insulin encapsulation. In this context, physico-chemical parameters like surface charge could play a critical role in NP uptake by the intestinal barrier. Therefore, we developed a simple method to modulate NP surface charge to test its impact on uptake in vitro and finally on NP efficiency in vivo. Various NPs were prepared in the presence (+) or absence (-) of polyvinyl alcohol (PVA), sodium dodecyl sulfate (SDS), and/or coated with chitosan chloride. In vitro internalization was tested using epithelial culture of Caco-2 or using a co-culture (Caco-2/RevHT29MTX) by flow cytometry. NPs were then administered by oral route using a pharmaceutical complex vector (100 or 250 UI/kg) in a diabetic rat model. SDS-NPs (-42 +/- 2 mV) were more negatively charged than -PVA-NPs (-22 +/- 1 mV) and chitosan-coated NPs were highly positively charged (56 +/- 2 mV) compared to +PVA particles (-2 +/- 1 mV), which were uncharged. In the Caco-2 model, NP internalization was significantly improved by using negatively charged NPs (SDS NPs) compared to using classical NPs (+PVA NPs) and chitosan-coated NPs. Finally, the efficacy of insulin SDS-NPs was demonstrated in vivo (100 or 250 UI insulin/kg) with a reduction of blood glucose levels in diabetic rats. Formulation of negatively charged NPs represents a promising approach to improve NP uptake and insulin bioavailability for oral delivery. PMID- 29501739 TI - Protocol for Exercise Program in Cancer and Cognition (EPICC): A randomized controlled trial of the effects of aerobic exercise on cognitive function in postmenopausal women with breast cancer receiving aromatase inhibitor therapy. AB - : The Exercise Program in Cancer and Cognition (EPICC) Study is a randomized controlled trial designed to test the effects of moderate-intensity aerobic exercise on cognitive function in postmenopausal women with early-stage breast cancer during the first six months of aromatase inhibitor therapy. It is estimated that up to 75% of survivors of breast cancer experience cognitive impairment related to disease and treatment. At present, there are no known interventions to improve or manage cognitive function for women with breast cancer. Here, we describe a single-blinded, randomized controlled trial with allocation of 254 postmenopausal women with early-stage breast cancer to a supervised six-month aerobic exercise intervention or usual care. Prior to beginning aromatase inhibitor (AI) therapy, participants complete baseline assessments of cognitive function, cardiorespiratory fitness, blood-based biomarkers, physical activity and sleep, and symptoms (fatigue, sleep problems, depressive symptoms, anxiety). A random subset of participants (n = 150) undergoes neuroimaging procedures that include structural and functional magnetic resonance imaging assessments. All participants maintain an activity diary; physical activity and sleep monitoring is repeated three and seven months post randomization. The remaining baseline assessments are repeated seven months post randomization. If successful, exercise could be a low-cost method to improve cognitive function in women with breast cancer that is easily adaptable to the home or community. TRIAL REGISTRATION: Clinicaltrials.govNCT02793921. Registered 20 May 2016. PMID- 29501740 TI - Workplace health and safety intervention for child care staff: Rationale, design, and baseline results from the CARE cluster randomized control trial. AB - BACKGROUND: Low-wage workers suffer disproportionately high rates of chronic disease and are important targets for workplace health and safety interventions. Child care centers offer an ideal opportunity to reach some of the lowest paid workers, but these settings have been ignored in workplace intervention studies. METHODS: Caring and Reaching for Health (CARE) is a cluster-randomized controlled trial evaluating efficacy of a multi-level, workplace-based intervention set in child care centers that promotes physical activity and other health behaviors among staff. Centers are randomized (1:1) into the Healthy Lifestyles (intervention) or the Healthy Finances (attention control) program. Healthy Lifestyles is delivered over six months including a kick-off event and three 8 week health campaigns (magazines, goal setting, behavior monitoring, tailored feedback, prompts, center displays, director coaching). The primary outcome is minutes of moderate and vigorous physical activity (MVPA); secondary outcomes are health behaviors (diet, smoking, sleep, stress), physical assessments (body mass index (BMI), waist circumference, blood pressure, fitness), and workplace supports for health and safety. RESULTS: In total, 56 centers and 553 participants have been recruited and randomized. Participants are predominately female (96.7%) and either Non-Hispanic African American (51.6%) or Non-Hispanic White (36.7%). Most participants (63.4%) are obese. They accumulate 17.4 (+/ 14.2) minutes/day of MVPA and consume 1.3 (+/-1.4) and 1.3 (+/-0.8) servings/day of fruits and vegetables, respectively. Also, 14.2% are smokers; they report 6.4 (+/-1.4) hours/night of sleep; and 34.9% are high risk for depression. CONCLUSIONS: Baseline data demonstrate several serious health risks, confirming the importance of workplace interventions in child care. PMID- 29501741 TI - Together We STRIDE: A quasi-experimental trial testing the effectiveness of a multi-level obesity intervention for Hispanic children in rural communities. AB - BACKGROUND: Hispanic children are disproportionally overweight and obese compared to their non-Hispanic white counterparts in the US. Community-wide, multi-level interventions have been successful to promote healthier nutrition, increased physical activity (PA), and weight loss. Using community-based participatory approach (CBPR) that engages community members in rural Hispanic communities is a promising way to promote behavior change, and ultimately weight loss among Hispanic children. OBJECTIVES: Led by a community-academic partnership, the Together We STRIDE (Strategizing Together Relevant Interventions for Diet and Exercise) aims to test the effectiveness of a community-wide, multi-level intervention to promote healthier diets, increased PA, and weight loss among Hispanic children. METHODS: The Together We STRIDE is a parallel quasi experimental trial with a goal of recruiting 900 children aged 8-12 years nested within two communities (one intervention and one comparison). Children will be recruited from their respective elementary schools. Components of the 2-year multi-level intervention include comic books (individual-level), multi generational nutrition and PA classes (family-level), teacher-led PA breaks and media literacy education (school-level), family nights, a farmer's market and a community PA event (known as ciclovia) at the community-level. Children from the comparison community will receive two newsletters. Height and weight measures will be collected from children in both communities at three time points (baseline, 6-months, and 18-months). SUMMARY: The Together We STRIDE study aims to promote healthier diet and increased PA to produce healthy weight among Hispanic children. The use of CBPR approach and the engagement of the community will springboard strategies for intervention' sustainability. Clinical Trials Registration Number: NCT02982759 Retrospectively registered. PMID- 29501742 TI - FTO is involved in Alzheimer's disease by targeting TSC1-mTOR-Tau signaling. AB - Diabetes and obesity are commonly associated with Alzheimer's disease (AD). Accumulating evidence show that insulin signaling defects are protentional upstream driver of AD. However, the mechanism by which diabetes and insulin signaling defects contribute to AD remains unknown. Here we show that Fat mass and obesity-associated protein (FTO) is involved the insulin defects-associated AD. Defective insulin signaling in diabetes and obesity in human and mice activated Fto in the brain tissues. Lentivirus-mediated knockdown of Fto reduced the phosphorylation of Tau protein whereas overexpression of FTO promoted the level of phosphorylated Tau in neurons. Mechanism study demonstrated that FTO activated the phosphorylation of Tau in a mTOR-dependent manner because FTO activated mTOR and its downstream signaling and rapamycin blocked FTO-mediated phosphorylation of Tau. FTO promoted the activation of mTOR by increasing the mRNA level of TSC1 but not TSC2, the upstream inhibitor of mTOR. Finally, we found that conditional knockout of Fto in the neurons reduced the cognitive deficits in 3xTg AD mice. Collectively, our evidence demonstrated that FTO is critically involved in insulin defects-related AD. PMID- 29501743 TI - An ode to mitochondria biologists, new and old. PMID- 29501744 TI - LncRNA PDIA3P interacts with c-Myc to regulate cell proliferation via induction of pentose phosphate pathway in multiple myeloma. AB - Multiple myeloma (MM), the second most common hematologic malignancy, is an incurable disease characterized by the accumulation of malignant plasma cells within the bone marrow. Though great progresses have been made in understanding the mechanisms of MM, metabolic plasticity and drug resistance remain largely unknown. In this study, we found lncRNA Protein disulfide isomerase family A member 3 pseudogene 1 (PDIA3P) is highly expressed in MM and is associated with the survival rate of MM patients. PDIA3P regulates MM growth and drug resistance through Glucose 6-phosphate dehydrogenase (G6PD) and the pentose phosphate pathway (PPP). Mechanistically, we revealed that PDIA3P interacts with c-Myc to enhance its transactivation activity and binding to G6PD promoter, stimulating G6PD expression and PPP flux. Our study identified PDIA3P as a novel c-Myc interacting lncRNA and elucidated crucial roles for PDIA3P in metabolic regulation of MM, providing a potential therapeutic target for MM patients. PMID- 29501745 TI - Regulation of granulocyte colony-stimulating factor receptor-mediated granulocytic differentiation by C-mannosylation. AB - Granulocyte colony-stimulating factor (G-CSF) receptor (G-CSFR) is a type I cytokine receptor which is involved in hematopoietic cell maturation. G-CSFR has three putative C-mannosylation sites at W253, W318, and W446; however, it is not elucidated whether G-CSFR is C-mannosylated or not. In this study, we first demonstrated that G-CSFR was C-mannosylated at only W318. We also revealed that C mannosylation of G-CSFR affects G-CSF-dependent downstream signaling through changing ligand binding capability but not cell surface localization. Moreover, C mannosylation of G-CSFR was functional and regulated granulocytic differentiation in myeloid 32D cells. In conclusion, we found that G-CSFR is C-mannosylated at W318 and that this C-mannosylation has role(s) for myeloid cell differentiation through regulating downstream signaling. PMID- 29501746 TI - Partial loss of complex I due to NDUFS4 deficiency augments myocardial reperfusion damage by increasing mitochondrial superoxide/hydrogen peroxide production. AB - Recent work has found that complex I is the sole source of reactive oxygen species (ROS) during myocardial ischemia-reperfusion (IR) injury. However, it has also been reported that heart mitochondria can also generate ROS from other sources in the respiratory chain and Krebs cycle. This study examined the impact of partial complex I deficiency due to selective loss of the Ndufs4 gene on IR injury to heart tissue. Mice heterozygous for NDUFS4 (NDUFS4+/-) did not display any significant changes in overall body or organ weight when compared to wild type (WT) littermates. There were no changes in superoxide (O2?-)/hydrogen peroxide (H2O2) release from cardiac or liver mitochondria isolated from NDUFS4 +/- mice. Using selective ROS release inhibitors, we found that complex III is a major source of ROS in WT and NDUFS4 +/- cardiac mitochondria respiring under state 4 conditions. Subjecting hearts from NDUFS4 +/- mice to reperfusion injury revealed that the partial loss of complex I decreases contractile recovery and increases myocardial infarct size. These results correlated with a significant increase in O2?-/H2O2 release rates in mitochondria isolated from NDUFS4 +/- hearts subjected to an IR challenge. Taken together, these results demonstrate that the partial absence of complex I sensitizes the myocardium towards IR injury and that the main source of ROS following reperfusion is complex III. PMID- 29501747 TI - Assessment of health-related quality of life in spine treatment: conversion from SF-36 to VR-12. AB - BACKGROUND CONTEXT: Health-related quality-of-life outcomes have been collected with the Medical Outcomes Study (MOS) Short Form 36 (SF-36) survey. Boston University School of Public Health has developed algorithms for the conversion of SF-36 to Veterans RAND 12-Item Health Survey (VR-12) Physical Component Summary (PCS) and Mental Component Summary (MCS) scores. PURPOSE: The purpose of the present study is to investigate the conversion of the SF-36 to VR-12 PCS and MCS scores. STUDY DESIGN: Preoperative and postoperative SF-36 were collected from patients who underwent lumbar or cervical surgery from a single surgeon between August 1998 and January 2013. METHODS: Short Form 36 PCS and MCS scores were calculated following their original instructions. The SF-36 answers were then converted to VR-12 PCS and MCS scores following the algorithm provided by the Boston University School of Public Health. The mean score, preoperative to postoperative change, and proportions of patients who reach the minimum detectable change were compared between SF-36 and VR-12. RESULTS: A total of 1,968 patients (1,559 lumbar and 409 cervical) had completed preoperative and postoperative SF-36. The values of the SF-36 and VR-12 mean scores were extremely similar, with score differences ranging from 0.77 to 1.82. The preoperative to postoperative improvement was highly significant (p<.001) for both SF-36 and VR 12 scores. The mean change scores were similar, with a difference of up to 0.93 for PCS and up to 0.37 for MCS. Minimum detectable change (MDC) values were almost identical for SF-36 and VR-12, with a difference of 0.12 for PCS and up to 0.41 for MCS. The proportions of patients whose change in score reached MDC were also nearly identical for SF-36 and VR-12. About 90% of the patients above SF-36 MDC were also above VR-12 MDC. CONCLUSIONS: The converted VR-12 scores, similar to the SF-36 scores, detect a significant postoperative improvement in PCS and MCS scores. The calculated MDC values and the proportions of patients whose score improvement reach MDC are similar for both SF-36 and VR-12. PMID- 29501748 TI - A novel preoperative trajectory evaluation method for L5-S1 transforaminal percutaneous endoscopic lumbar discectomy. AB - BACKGROUND CONTEXT: L5-S1 transforaminal percutaneous endoscopic lumbar discectomy (PELD) is a demanding procedure because of structures such as iliac crest, L5 transverse process, hypertrophic L5-S1 facet joint, and sacral ala. There has been no definite preoperative evaluation method to evaluate the surgical validity of L5-S1 transforaminal PELD. PURPOSE: The authors report a new preoperative trajectory evaluation method for L5-S1 transforaminal PELD using magnetic resonance imaging (MRI) or computed tomography (CT) examinations. STUDY DESIGN/SETTING: This is a technical report study. PATIENT SAMPLE: Patients who were diagnosed L5-S1 soft disc herniation were included in the present study. OUTCOME MEASURES: Success rate of transforaminal PELD according to height of iliac crest was measured. METHODS: Twelve patients who were diagnosed L5-S1 disc herniation were preoperatively evaluated with this new method. A skin marker is attached to patient's back as a tentative skin entry point, which was determined by usual preoperative MRI or CT. A new tilted axial and coronal MRI or CT scan is performed according to axis of L5-S1 transforaminal working channel. The images show good relationship between working channel and iliac crest. RESULTS: Six patients underwent a transforaminal PELD, and the results were successful. The other six patients were considered to be "unsuitable" for transforaminal PELD because of the probable blockade by iliac crest. CONCLUSIONS: The tilted MRI or CT provides precise evaluation for L5-S1 transforaminal PELD trajectory and may achieve good outcome. PMID- 29501749 TI - Rod fracture in adult spinal deformity surgery fused to the sacrum: prevalence, risk factors, and impact on health-related quality of life in 526 patients. AB - BACKGROUND CONTEXT: Risk factors associated with rod fracture (RF) following adult spinal deformity (ASD) surgery fused to the sacrum remain debatable, and the impact of RF on patient-reported outcomes (PROs) after ASD surgery has not been investigated. PURPOSE: We aimed to evaluate the prevalence of and risk factors for RF and determine PROs changes associated with RF after ASD surgery fused to the sacrum. STUDY DESIGN/SETTING: A retrospective single-center cohort study was performed. PATIENT SAMPLE: Patients undergoing long-construct posterior spinal fusions to the sacrum performed at a single institution by two senior spine surgeons from 2004 to 2014 were included. OUTCOME MEASURES: Patient demographics, radiographic parameters, and surgical factors were assessed for risk factors associated with RF. Oswestry Disability Index (ODI) and Scoliosis Research Society-30 (SRS-30) scores were assessed at baseline, 1 year postoperatively, and latest follow-up. METHODS: Inclusion criteria were ASD patients age >18 who had >=5 vertebrae instrumented and fused posteriorly to the sacrum and either development of RF or no development of RF with minimum 2-year follow-up. Patient characteristics, operative data, radiographic parameters, and PROs were analyzed at baseline and follow-up. Separate Cox proportional hazard models based on rod material and diameter were used to determine factors associated with RF. RESULTS: Five hundred twenty-six patients (80%) were available for analysis. RF occurred in 97 (18.4%) patients (unilateral RF n=61 [63%]; bilateral RF n=36 [37%]). Risk factors for fracture of 5.5 mm cobalt chromium (CC) instrumentation (CC 5.5 model) included preoperative sagittal vertical axis (hazard ratio [HR] 1.07, 95% confidence interval [95% CI] 1.02-1.14 per 1-cm increase), preoperative thoracolumbar kyphosis (HR 1.02, 95% CI 1.01 1.04 per 1-degree increase), and number of levels fused for patients who received rhBMP-2 <12 mg per level fused (HR 1.48, 95% CI 1.20-1.82 per 1-level increase). Implants that were 5.5-mm CC constructs were at a higher risk for fracture than 6.35-mm stainless steel (SS) constructs (HR 8.49, 95% CI 4.26-16.89). The RF group had less overall improvement in SRS Satisfaction (0.93 vs. 1.32; p=.007) and SRS Self-image domain scores (0.72 vs. 1.02; p=.01). The bilateral RF group had less overall improvement in ODI (8.1 vs. 15.8; p=.02), SRS Subscore (0.51 vs. 0.85; p=.03), and SRS Pain domain scores (0.48 vs. 0.95; p=.02) compared with the non-RF group at final follow-up. CONCLUSIONS: The prevalence of all RF after index procedures was 18.4%, 37% for bilateral RF. Greater preoperative sagittal vertical axis, greater preoperative thoracolumbar kyphosis, increased number of vertebrae fused for patients who received rhBMP-2 <12 mg per level fused, and CC 5.5-mm rod were associated with RF. Less improvement in patient satisfaction and self-image was noted in the RF group. Furthermore, bilateral RF significantly affected PROs as measured by ODI and SRS Subscore at final follow-up. PMID- 29501750 TI - Mixed phenotype (T/B/myeloid) extramedullary blast crisis as an initial presentation of chronic myelogenous leukemia. AB - BACKGROUND: Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by the Philadelphia (Ph) chromosome generated by the reciprocal translocation t(9,22)(q34;q11). The natural progression of the disease follows a biphasic or triphasic course. Most cases of CML are diagnosed in the chronic phase. Extramedullary blast crisis rarely occurs during the course of CML, and is extremely rare as the initial presentation of CML. CASE PRESENTATION: Here, we report the case of a 32-year-old female with enlarged neck lymph nodes and fatigue. She was diagnosed with B-lymphoblastic leukemia/lymphoma with possible mixed phenotype (B/myeloid) by right neck lymph node biopsy at an outside hospital. However, review of her peripheral blood smear and her bone marrow aspirate and biopsy showed features consistent with CML, which was confirmed by PCR and karyotyping. An ultrasound-guided right cervical lymph node core biopsy showed a diffuse infiltrate of blasts, near totally replacing the normal lymph node tissue, admixed with some hematopoietic cells including megakaryocytes, erythroid precursors and maturing myeloid cells. By flow cytometry and immunohistochemistry, the blasts expressed CD2, cytoplasmic CD3, CD5, CD7, CD56, TdT, CD10 (weak, subset), CD19 (subset), CD79a, PAX-5 (subset), CD34, CD38, CD117 (subset), HLA-DR (subset), CD11b, CD13 (subset), CD33 (subset), and weak cytoplasmic myeloperoxidase, without co-expression of surface CD3, CD4, CD8, CD20, CD22, CD14, CD15, CD16 and CD64, consistent with blasts with mixed phenotype (T/B/myeloid). A diagnosis of extramedullary blast crisis of CML was made. Chromosomal analysis performed on the lymph node biopsy tissue revealed multiple numerical and structural abnormalities including the Ph chromosome (46 49,XX,add(1)(p34),add(3)(p25),add(5)(q13),-6,t(9;22)(q34;q11.2),+10, 15,add(17)(p11.2),+19, +der(22)t(9;22),+mar[cp8]). After completion of one cycle of combined chemotherapy plus dasatinib treatment, she was transferred to City of Hope National Cancer Institute for bone marrow transplantation. DISCUSSION AND CONCLUSION: Diagnosis of extramedullary blast crisis should be suspected in patients with leukocytosis and extramedullary blast proliferation. In this case study, we diagnosed extramedullary blast crisis accompanied by chronic phase of CML in the bone marrow. To our knowledge, this is the first reported case of extramedullary blast crisis as the initial presentation of CML with T/B/myeloid mixed phenotype. Other unusual features associated with this case are also discussed. PMID- 29501751 TI - Signaling pathways involved in zymosan phagocytosis induced by two secreted phospholipases A2 isolated from Bothrops asper snake venom in macrophages. AB - Phagocytosis, a process involved in host defense, requires coordination of a variety of signaling reactions. MT-II, a catalytically-inactive Lys49-PLA2 and MT-III, an active Asp49-PLA2 isolated from Bothrops asper snake venom, activate phagocytosis in macrophages. In this study the signal pathways mediating zymosan phagocytosis, focusing in lipidic second messengers, were investigated. Macrophages collected from male Swiss mouse peritoneum were obtained 96h after i.p. injection of thioglycollate. Phagocytosis was evaluated with non-opsonized zymosan in the presence or absence of specific inhibitors. Data showed that both venom PLA2s increased phagocytosis. Zileuton, Etoricoxib, PACOCF3 (5-LO, COX-2 and iPLA2 inhibitors, respectively), as well as WEB2170 (PAF receptor antagonist) significantly reduced phagocytosis induced by both venom PLA2s. However, Indomethacin (COX-1/COX-2 inhibitor) and Montelukast (CysL receptor antagonist) did not affect the toxins-induced phagocytosis. Moreover, while PACOCF3 (iPLA2 inhibitor), reduced the phagocytosis induced by MT-II and MT-III, AACOCF3 (cPLA2 inhibitor) significantly reduced the MT-II, but not MT-III-induced phagocytosis. These data suggest the effect of both sPLA2s depends on iPLA2 and that the effect of MT-II depends on activation of cPLA2. COX-2 and 5-LO-derived metabolites as well as PAF are involved in the signaling events required for phagocytosis induced by both venom sPLA2s. PMID- 29501752 TI - Mitochondrial genome characteristics of two Sphingidae insects (Psilogramma increta and Macroglossum stellatarum) and implications for their phylogeny. AB - In this study, complete mitogenomes of P. increta and M. stellatarum (Lepidoptera: Sphingidae) were sequenced and compared with other Sphingidae species. The mitogenomes containing 37 genes and a AT rich region are circular molecules with 15,252 and 15,290 base pairs in length respectively. Except cox1 all 13 protein-coding genes (PCGs) are initiated by ATN codons. Most of PCGs terminate with TAA except nad5 and cox1 in P. increta and nad5 and cox2 in M. stellatarum. Ile and Leu2 are the most frequently used codon families in both species and codons CGC, CCG, TCG and ACG are absent in P. increta while in M. stellatarum CGC, CCG, CTG, AGG are absent. All the tRNA genes could be folded into the typical cloverleaf secondary structure except the trnS1 of P. increta which lost dihydrouridine (DHU) stem. The AT-rich region of both insects includes the motif ATAGA followed by a 18-19bp polyT stretch and 2-3 short tandem repeats (STRs) of TA, and a poly-A element. Phylogenetic analyses showed that the phylogenetic relationships are (((Sphinx morio+Manduca sexta)+(P. increta+Notonagemia analis scribae))+(Agrius convolvuli)+(M. stellatarum+(Ampelophaga rubiginosa+Daphnis nerii)). PMID- 29501753 TI - Transgenic tobacco plants expressing a P1B-ATPase gene from Populus tomentosa Carr. (PtoHMA5) demonstrate improved cadmium transport. AB - Heavy metal ATPase (HMA) plays an important role in phytoremediation via long distance transportation from root to shoot. In this report, we identified a heavy metal ATPase gene, PtoHMA5, from Populus tomentosa Carr. Its encoded peptide consists of 967 amino acids and has eight trans-membrane motifs inside. Tobacco plants were transformed with this gene via Agrobacterium tumefaciens-mediated method. After exposure to 50mg/LCdCl2 for 10d, the transgenic lines displayed higher cadmium accumulation in leaves than did the wild-type plants with an absolute increase of 25.04%, while the transfer coefficient increased by 16.01% 43.25%. Physiological testing including assessment of relative electrolytic leakage (REL), malondialdehyde (MDA) content, and chlorophyll content revealed that the transgenic lines were seriously affected when compared with the wild type plants. In summary, PtoHMA5 is really involved in cadmium transport from root to shoot but is not associated with the removal of cadmium toxicity. PMID- 29501754 TI - Involvement of adenosine monophosphate activated kinase in interleukin-6 regulation of steroidogenic acute regulatory protein and cholesterol side chain cleavage enzyme in the bovine zona fasciculata and zona reticularis. AB - In bovine adrenal zona fasciculata (ZF) and NCI-H295R cells, interleukin-6 (IL-6) increases cortisol release, increases expression of steroidogenic acute regulatory protein (StAR), cholesterol side chain cleavage enzyme (P450scc), and steroidogenic factor 1 (SF-1) (increases steroidogenic proteins), and decreases the expression of adrenal hypoplasia congenita-like protein (DAX-1) (inhibits steroidogenic proteins). In contrast, IL-6 decreases bovine adrenal zona reticularis (ZR) androgen release, StAR, P450scc, and SF-1 expression, and increases DAX-1 expression. Adenosine monophosphate (AMP) activated kinase (AMPK) regulates steroidogenesis, but its role in IL-6 regulation of adrenal steroidogenesis is unknown. In the present study, an AMPK activator (AICAR) increased (P < 0.01) NCI-H295R StAR promoter activity, StAR and P450scc expression, and the phosphorylation of AMPK (PAMPK) and acetyl-CoA carboxylase (PACC) (indexes of AMPK activity). In ZR (decreased StAR, P450scc, SF-1, increased DAX-1) (P < 0.01) and ZF tissues (increased StAR, P450scc, SF-1, decreased DAX-1) (P < 0.01), AICAR modified StAR, P450scc, SF-1 and DAX-1 mRNAs/proteins similar to the effects of IL-6. The activity (increased PAMPK and PACC) (P < 0.01) of AMPK in the ZF and ZR was increased by AICAR and IL-6. In support of an AMPK role in IL-6 ZF and ZR effects, the AMPK inhibitor compound C blocked (P < 0.01) the effects of IL-6 on the expression of StAR, P450scc, SF-1, and DAX-1. Therefore, IL-6 modification of the expression of StAR and P450scc in the ZF and ZR may involve activation of AMPK and these changes may be related to changes in the expression of SF-1 and DAX-1. PMID- 29501755 TI - Stereoselective synthesis of the four 16-hydroxymethyl-3-methoxy- and 16 hydroxymethyl-3-benzyloxy-13alpha-estra-1,3,5(10)-trien-17-ol isomers and their antiproliferative activities. AB - The reduction of 16-hydroxymethylene-3-methoxy-13alpha-estra-1,3,5(10)-trien-17 one (14) and 16-hydroxymethylene-3-benzyloxy-13alpha-estra-1,3,5(10)-trien-17-one (16) yielded a mixture of two diastereomeric diols, the 16alpha hydroxymethyl,17beta-hydroxy and 16beta-hydroxymethyl,17alpha-hydroxy isomers (17a-20a) in a ratio of 6:1. We describe a straightforward synthetic route to transform the isomers with trans functional groups attached to ring D (17a-20a) into isomers with cis functional groups (25a-28a). We determined the in vitro antiproliferative activities of compounds 17a-20a and 25a-28a by means of MTT assays against a panel of human adherent cancer cell lines HeLa, A2780, MCF-7, T47D, MDA-MB-231 and MDA-MB-361. PMID- 29501757 TI - Chlorine disinfection increases both intracellular and extracellular antibiotic resistance genes in a full-scale wastewater treatment plant. AB - The emergence and spread of antibiotic resistance has posed a major threat to both human health and environmental ecosystem. Although the disinfection has been proved to be efficient to control the occurrence of pathogens, little effort is dedicated to revealing potential impacts of disinfection on transmission of antibiotic resistance genes (ARGs), particularly for free-living ARGs in final disinfected effluent of urban wastewater treatment plants (UWWTP). Here, we investigated the effects of chlorine disinfection on the occurrence and concentration of both extracellular ARGs (eARGs) and intracellular ARGs (iARGs) in a full-scale UWWTP over a year. We reported that the concentrations of both eARGs and iARGs would be increased by the disinfection with chlorine dioxide (ClO2). Specifically, chlorination preferentially increased the abundances of eARGs against macrolide (ermB), tetracycline (tetA, tetB and tetC), sulfonamide (sul1, sul2 and sul3), beta-lactam (ampC), aminoglycosides (aph(2')-Id), rifampicin (katG) and vancomycin (vanA) up to 3.8 folds. Similarly, the abundances of iARGs were also increased up to 7.8 folds after chlorination. In terms of correlation analyses, the abundance of Escherichia coli before chlorination showed a strong positive correlation with the total eARG concentration, while lower temperature and higher ammonium concentration were assumed to be associated with the concentration of iARGs. This study suggests the chlorine disinfection could increase the abundances of both iARGs and eARGs, thereby posing risk of the dissemination of antibiotic resistance in environments. PMID- 29501756 TI - Antagonism of corticotropin releasing factor in the basolateral amygdala of resilient and vulnerable rats: Effects on fear-conditioned sleep, temperature and freezing. AB - The basolateral nucleus of the amygdala (BLA) plays a significant role in mediating individual differences in the effects of fear memory on sleep. Here, we assessed the effects of antagonizing corticotropin releasing factor receptor 1 (CRFR1) after shock training (ST) on fear-conditioned behaviors and sleep. Outbred Wistar rats were surgically implanted with electrodes for recording EEG and EMG and with bilateral guide cannulae directed at BLA. Data loggers were placed intraperitoneally to record core body temperature. The CRFR1 antagonist, antalarmin (ANT; 4.82 mM) was microinjected into BLA after shock training (ST: 20 footshocks, 0.8 mA, 0.5 s duration, 60 s interstimulus interval), and the effects on sleep, freezing and the stress response (stress-induced hyperthermia, SIH) were examined after ST and fearful context re-exposure alone at 7 days (CTX1) and 21 days (CTX2) post-ST. EEG and EMG recordings were scored for non-rapid eye movement sleep (NREM), rapid eye movement sleep (REM) and wakefulness. The rats were separated into 4 groups: Vehicle-vulnerable (Veh-Vul; n = 10), Veh-resilient (Veh-Res; n = 11), ANT-vulnerable (ANT-Vul; n = 8) and ANT-resilient (ANT-Res; n = 8) based on whether, compared to baseline, the rats showed a decrease or no change/increase in REM during the first 4 h following ST. Post-ST ANT microinjected into BLA attenuated the fear-conditioned reduction in REM in ANT Vul rats on CTX1, but did not significantly alter REM in ANT-Res rats. However, compared to Veh treated rats, REM was reduced in ANT treated rats on CTX2. There were no group differences in freezing or SIH across conditions. Therefore, CRFR1 in BLA plays a role in mediating individual differences in sleep responses to stress and in the extinction of fear conditioned changes in sleep. PMID- 29501758 TI - Quantification of pathogens and markers of fecal contamination during storm events along popular surfing beaches in San Diego, California. AB - Along southern California beaches, the concentrations of fecal indicator bacteria (FIB) used to quantify the potential presence of fecal contamination in coastal recreational waters have been previously documented to be higher during wet weather conditions (typically winter or spring) than those observed during summer dry weather conditions. FIB are used for management of recreational waters because measurement of the bacterial and viral pathogens that are the potential causes of illness in beachgoers exposed to stormwater can be expensive, time consuming, and technically difficult. Here, we use droplet digital Polymerase Chain Reaction (digital PCR) and digital reverse transcriptase PCR (digital RT PCR) assays for direct quantification of pathogenic viruses, pathogenic bacteria, and source-specific markers of fecal contamination in the stormwater discharges. We applied these assays across multiple storm events from two different watersheds that discharge to popular surfing beaches in San Diego, CA. Stormwater discharges had higher FIB concentrations as compared to proximal beaches, often by ten-fold or more during wet weather. Multiple lines of evidence indicated that the stormwater discharges contained human fecal contamination, despite the presence of separate storm sewer and sanitary sewer systems in both watersheds. Human fecal source markers (up to 100% of samples, 20-12440 HF183 copies per 100 ml) and human norovirus (up to 96% of samples, 25-495 NoV copies per 100 ml) were routinely detected in stormwater discharge samples. Potential bacterial pathogens were also detected and quantified: Campylobacter spp. (up to 100% of samples, 16 504 gene copies per 100 ml) and Salmonella (up to 25% of samples, 6-86 gene copies per 100 ml). Other viral human pathogens were also measured, but occurred at generally lower concentrations: adenovirus (detected in up to 22% of samples, 14-41 AdV copies per 100 ml); no enterovirus was detected in any stormwater discharge sample. Higher concentrations of avian source markers were noted in the stormwater discharge located immediately downstream of a large bird sanctuary along with increased Campylobacter concentrations and notably different Campylobacter species composition than the watershed that had no bird sanctuary. This study is one of the few to directly measure an array of important bacterial and viral pathogens in stormwater discharges to recreational beaches, and provides context for stormwater-based management of beaches during high risk wet weather periods. Furthermore, the combination of culture-based and digital PCR derived data is demonstrated to be valuable for assessing hydrographic relationships, considering delivery mechanisms, and providing foundational exposure information for risk assessment. PMID- 29501759 TI - Seasonal performance of a full-scale wastewater treatment enhanced pond system. AB - Enhanced pond systems (EPS) consist of a series of ponds that have been designed to work in synergy to provide both cost-effective enhanced wastewater treatment and resource recovery, in the form of algal biomass, for beneficial reuse. Due to the limited number of full-scale EPS systems worldwide, our understanding of factors governing both enhanced wastewater treatment and resource recovery is limited. This paper investigates the seasonal performance of a full-scale municipal wastewater EPS with respect to nutrient removal from the liquid fraction, microalgal biomass production and subsequent removal through the system. In the high rate algal pond both microalgal productivity (determined as organic matter and chlorophyll a biomass) and NH4-N removal varied seasonally, with significantly higher biomass and removal rates in summer than in spring (p < 0.05) or winter (p < 0.01). Microalgal biomass was not successfully harvested in the algal harvester pond (AHP), most likely due to poor flocc formation coupled with relatively short hydraulic residence time (HRT). High percentage removal rates, from sedimentation and zooplankton grazing, were achieved in the maturation pond (MP) series, particularly in winter and spring. However, in summer decreased efficiency of biomass removal and the growth of new microalgal species suggests that summer-time HRT in the MPs could be shortened. Further modifications to the operation of the AHP, seasonal changes in the HRT of the MPs and potential harvesting of zooplankton grazers are all potential strategies for improving resource recovery and producing a higher quality final discharge effluent. PMID- 29501760 TI - Influence of secondary water supply systems on microbial community structure and opportunistic pathogen gene markers. AB - Secondary water supply systems (SWSSs) refer to the in-building infrastructures (e.g., water storage tanks) used to supply water pressure beyond the main distribution systems. The purpose of this study was to investigate the influence of SWSSs on microbial community structure and the occurrence of opportunistic pathogens, the latter of which are an emerging public health concern. Higher numbers of bacterial 16S rRNA genes, Legionella and mycobacterial gene markers were found in public building taps served by SWSSs relative to the mains, regardless of the flushing practice (P < 0.05). In residential buildings, genes of L. pneumomhila, Acanthamoeba and Vermamoeba vermiformis were primarily detected in tanks and taps compared to the mains. Long water retention time, warm temperature and loss of disinfectant residuals promoted microbial growth and colonization of potential pathogens in SWSSs. Varied levels of microbial community shifts were found in different types of SWSSs during water transportation from the distribution main to taps, highlighting the critical role of SWSSs in shaping the drinking water microbiota. Overall, the results provided insight to factors that might aid in controlling pathogen proliferation in real world water systems using SWSSs. PMID- 29501761 TI - UV/H2O2 process stability and pilot-scale validation for trace organic chemical removal from wastewater treatment plant effluents. AB - This study investigated the removal of 15 trace organic chemicals (TOrCs) occurring at ambient concentrations from municipal wastewater treatment plant effluent by advanced oxidation using UV/H2O2 at pilot-scale. Pseudo first-order rate constants (kobs) for photolytic as well as combined oxidative and photolytic degradation observed at pilot-scale were validated with results from a bench scale collimated beam device. No significant difference was determined between pilot- and lab-scale performance. During continuous pilot-scale operation at constant UV fluence of 800 mJ/cm2 and H2O2 dosage of 10 mg/L, the removal of various TOrCs was investigated. The average observed removal for photo susceptible (kUV>10-3 cm2/mJ; like diclofenac, iopromide and sulfamethoxazole), moderately photo-susceptible (10-4 2 were independent predictors of SSI (odds ratios: 2.29, 2.46, and 2.1 respectively, p < 0.05). CONCLUSIONS: Bile spillage is associated with SSI, and surgeons should take extra caution to avoid it during laparoscopic cholecystectomy. PMID- 29501783 TI - Extracorporeal Pringle Maneuver During Laparoscopic and Robotic Hepatectomy: Detailed Technique and First Comparison with Intracorporeal Maneuver. PMID- 29501784 TI - Impact of Prolonged Fasting on the Risk of Calcium Phosphate Precipitation in the Urine: Calcium Phosphate Lithogenesis during Prolonged Fasting in a Healthy Cohort. AB - PURPOSE: Intermittent fasting and curtailing water intake for extended periods were likely common in Paleolithic times. Today it occurs for religious and dietary reasons. This restriction in intake should cause a decrease in the urine flow rate while raising the concentration of certain substances in urine to the point of precipitation. In this study we measured the risk of CaHPO4 precipitation following 18 hours of food and water deprivation. MATERIALS AND METHODS: Urine samples were periodically collected from 15 healthy subjects who fasted and abstained from drinking any liquid for 18 hours. The urine constituents Ca2+, HPO42- and pH involved in CaHPO4 formation were measured at various times throughout the fasting day. A comparison was made with control data, which consisted of diurnal urine collections taken throughout a separate nonfasting day prior to the fasting day. RESULTS: The mean +/- SEM urine flow rate decreased significantly from 0.93 +/- 0.1 ml per minute in the control group to 0.37 +/- 0.05 ml per minute in the fasting group (p <0.05). Mean Na+ and Ca2+ excretion rates decreased significantly from 127 +/- 12 to 54 +/- 13 MUmol per minute and from 3.2 +/- 0.4 to 0.80 +/- 0.21, respectively. Mean urinary Na+ and Ca2+ concentrations also decreased from 161 +/- 11.6 to 122 +/- 16.0 mmol/l and from 3.7 +/- 0.5 to 2.0 +/- 0.55, respectively. Urinary pH and the concentration of phosphate, citrate and magnesium were not significantly affected. CONCLUSIONS: Although the steady decrease in the urine flow rate was statistically significant during 18 hours of food and water deprivation, there was no evidence that the calculated risk of CaHPO4 precipitation in the healthy subjects had increased. PMID- 29501785 TI - Using an integrated approach to identify cryptic species, divergence patterns and hybrid species in Asian ladies' tresses orchids (Spiranthes, Orchidaceae). AB - Spiranthes (~36 species, Orchidaceae) is a small genus with a global distribution. It has a center of diversity in North America with only a few species occurring in Asia. This study focuses on the Asian Spiranthes with an emphasis on understanding their biogeographic relationships and species delimitations using molecular markers. Our phylogenetic trees based on nuclear (ITS) and chloroplast (trnL-trnLF, matK and trnS-G) sequences from samples across their range in Asia revealed the Asian Spiranthes are monophyletic. Ancestral area optimization suggested that North America forms the ancestral region for the Asian Spiranthes rather than Europe suggesting that they originated from a single long-distance dispersal event. Our study also revealed the presence of a cryptic species S. himalayensis, which was discovered based on molecular data thus emphasizing the importance of wide geographical sampling in phylogenetic studies. Sequences of cloned ITS provided support for the hypothesis that natural hybridization between S. sinensis and the newly described S. himalayensis resulted in the allotetraploid S. hongkongensis, with S. himalayensis as the paternal parent. One of the species complexes known in Asia is the S. sinensis complex, which shows a wide occurrence and is known for local geographical variants. Some of these variants have been described as new species in Australia and New Zealand. Our studies show that all the sampled variants including the Australian and New Zealand species show monophyly despite having long branches. This suggests that there may be high rates of gene flow between the geographically distinct forms resulting in lack of species resolution within the S. sinensis complex. PMID- 29501786 TI - Herpes simplex virus: A rare but treatable cause of fulminant hepatitis. PMID- 29501787 TI - Genomics and emerging biomarkers for immunotherapy of colorectal cancer. AB - Colorectal cancer (CRC) is a common and lethal disease with a high therapeutic need. For most patients with metastatic CRC, chemotherapy is the only viable option. Currently, immunotherapy is restricted to the particular genetic subgroup of mismatch-repair deficient (MMRd)/microsatellite instable (MSI) CRC. Anti-PD1 therapy was recently FDA-approved as a second-line treatment in this subgroup. However, in a metastatic setting, these MMRd/MSI tumors are vastly outnumbered by mismatch-repair proficient (MMRp)/microsatellite stable (MSS) tumors. These MMRp/MSS tumors do not meaningfully respond to any traditional immunotherapy approach including checkpoint blockade, adoptive cell transfer and vaccination. This resistance to immunotherapy is due to a complex tumor microenvironment that counteracts antitumor immunity through a combination of poorly antigenic tumor cells and an immunosuppressive tumor microenvironment. To find ways of overcoming immunotherapy resistance in the majority of CRC patients, it is necessary to analyze the immunological makeup in an in-depth and personalized way and in the context of their tumor genetic makeup. Flexible, biomarker-guided early-phase immunotherapy trials are needed to optimize this workflow. In this review, we detail key mechanisms for immune evasion and emerging immune biomarkers for personalized immunotherapy in CRC. Also, we present a template for biomarker guided clinical trials that are needed to move new immunotherapy approaches closer to clinical application. PMID- 29501788 TI - 50 years of comparative biochemistry: The legacy of Peter Hochachka. AB - Peter Hochachka was an early pioneer in the field of comparative biochemistry. He passed away in 2002 after 4 decades of research in the discipline. To celebrate his contributions and to coincide with what would have been his 80th birthday, a group of his former students organized a symposium that ran as a satellite to the 2017 Canadian Society of Zoologists annual meeting in Winnipeg, Manitoba (Canada). This Special Issue of CBP brings together manuscripts from symposium attendees and other authors who recognize the role Peter played in the evolution of the discipline. In this article, the symposium organizers and guest editors look back on his career, celebrating his many contributions to research, acknowledging his role in training of generations of graduate students and post doctoral fellows in comparative biochemistry and physiology. PMID- 29501789 TI - A lesson from the oxidative metabolism of hibernator heart: Possible strategy for cardioprotection. AB - In the present study we hypothesized that myocardial adaptive phenotype in mammalian hibernation involves rearrangement of mitochondria bioenergetic pathways providing protective pattern in states of reduced metabolism and low temperature. European ground squirrels (Spermophilus citellus) were exposed to low temperature (4 +/- 1 degrees C) and then divided into two groups: (1) animals that fell into torpor (hibernating group) and (2) animals that stayed active and euthermic for 1, 3, 7, 12, or 21 days (cold-exposed group). Protein levels of selected components of the electron transport chain and ATP synthase in the heart increased after prolonged cold acclimation (mainly from day 7-21 of cold exposure) and during hibernation. Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) was also upregulated under both cold exposure and hibernating conditions. The phosphorylation state (Thr172) of 5'-AMP activated protein kinase alpha increased early in cold exposure (at day 1 and 3) along with increased protein levels of phosphofructokinase and pyruvate dehydrogenase, whereas hypoxia inducible factor 1alpha protein levels showed no changes in response to cold exposure or hibernation. Hibernation also resulted in protein upregulation of three antioxidant defense enzymes (manganese and copper/zinc superoxide dismutases and glutathione peroxidase) and thioredoxin in the heart. Cold-exposed and hibernation-related phenotypes of the heart are characterized by improved molecular basis for mitochondrial energy-producing and antioxidant capacities that are achieved in a controlled manner. The recapitulation of such adaptive mechanisms found in hibernators could have broad application for myocardial protection from ishemia/reperfusion to improve hypothermic survival and cold preservation of hearts from non-hibernating species, including humans. PMID- 29501790 TI - Social value orientation modulates context-based social comparison preference in the outcome evaluation: An ERP study. AB - Social value orientation (SVO) is a personality trait that is closely associated with social comparison preference. However, little is known about how the different types of SVO (i.e., proself vs. prosocial) modulate the behaviour and neural underpinnings of its interaction with social context. In the present study, we examined electrophysiological correlates captured when individuals with different SVOs engaged in a gambling game with two other players (a socially disliking player, person A, vs. a socially liking player, person B). Three main findings are reported in our study. 1) Social comparison effects were manifested in feedback-related negativity (FRN) (the most negative FRN was expressed in the large difference condition, and the least negative FRN was expressed in the even condition), and this effect was modulated by both the win/loss context and SVO. That is, in a self-win context, FRN exhibited a social comparison effect for both prosocials and proselfs. In the self-loss condition, only prosocials displayed this effect. 2) Both groups displayed an enhanced FRN to person A's (the disliked player's) loss compared with the FRN to A's win in the self-win context, whereas only prosocials displayed a more negative FRN to A's win compared to A's loss in the self-loss context. 3) There was a social liking effect, but not a social comparison effect, on the P300, showing that for prosocials only, winning with a socially liking player elicited an increased P300 compared to winning with a disliking player. These findings suggest that the influences of SVO on social comparison are automatic and context dependent, which is reflected by a semi automatic FRN in which prosocials are sensitive to others' wins or losses in both the self-win and self-loss contexts, whereas proselfs are not interested in others' outcomes in the self-loss context. Furthermore, interpersonal relationships affected the P300 for prosocials when they won but had no effect on the proselfs. This work sheds light on the neural basis of outcome evaluation in multiple social contexts and its individual differences in automatic social comparison situations. PMID- 29501791 TI - The roles of selective attention and desensitization in the association between video gameplay and aggression: An ERP investigation. AB - A number of studies have indicated that violent video gameplay is associated with higher levels of aggression and that desensitization and selective attention to violent content may contribute to this association. Utilizing an emotionally charged rapid serial visual presentation (RSVP) task, the current study used two event-related potentials (ERPs) - the N1 and P3 - that have been associated with selective attention and desensitization as neurocognitive mechanisms potentially underlying the connection between gameplay and higher levels of aggression. Results indicated that video game players and non-players differed in N1 and P3 activation when engaged with emotionally-charged imagery. Additionally, P3 amplitudes moderated the association between video gameplay and aggression, indicating that players who display small P3 amplitudes also showed heightened levels of aggression. Follow-up moderational analyses revealed that individuals who play games for many hours and show more negative N1 amplitudes show smaller P3 activation. Together, our results suggest that selective attention to violent content and desensitization both play key roles in the association between video gameplay and aggression. PMID- 29501792 TI - Neural basis of the crossmodal correspondence between auditory pitch and visuospatial elevation. AB - Crossmodal correspondences refer to associations between otherwise unrelated stimulus features in different sensory modalities. For example, high and low auditory pitches are associated with high and low visuospatial elevation, respectively. The neural mechanisms underlying crossmodal correspondences are currently unknown. Here, we used functional magnetic resonance imaging (fMRI) to investigate the neural basis of the pitch-elevation correspondence. Pitch elevation congruency effects were observed bilaterally in the inferior frontal and insular cortex, the right frontal eye field and right inferior parietal cortex. Independent functional localizers failed to provide strong evidence for any of three proposed mechanisms for crossmodal correspondences: semantic mediation, magnitude estimation, and multisensory integration. Instead, pitch elevation congruency effects overlapped with areas selective for visually presented non-word strings relative to sentences, and with regions sensitive to audiovisual asynchrony. Taken together with the prior literature, the observed congruency effects are most consistent with mediation by multisensory attention. PMID- 29501793 TI - Neural modulations of interference control over conscious perception. AB - The relation between attention and consciousness is a highly debated topic in Cognitive Neuroscience. Although there is an agreement about their relationship at the functional level, there is still no consensus about how these two cognitive processes interact at the neural level. According to the gateway hypothesis (Posner, 1994), attention filters the information accessing to consciousness, resulting in both neural and functional modulations. Contrary to this idea, the cumulative influence hypothesis (Tallon-Baudry, 2012) proposes that both attention and consciousness independently impact decision processes about the perception of stimuli. Accordingly, we could observe an interaction between attention and consciousness at the behavioral level, but not at the neural level. Previous studies have shown that alerting and orienting networks of attention modulate participants' ability to verbally report near-threshold visual stimuli both at behavioral and neural levels, supporting the gateway hypothesis over the cumulative influence hypothesis. The impact of the executive control network of attention on conscious perception, however, has only been explored behaviorally (Colas et al., 2017). In the present study, we employed high-density encephalography to investigate the neural basis of the interaction between executive attention and conscious perception. We presented a classical Stroop task concurrently with a detection task of near-threshold stimuli. In two separate sessions, we manipulated the proportion of congruent and incongruent Stroop stimuli. We found that the Stroop-evoked N2 potential (usually associated to conflict detection and localized in the anterior cingulate cortex) was modulated by both conflict detection and conscious perception processes. These results suggest that the relation between executive control and conscious perception lies in frontal lobe regions associated to conflict detection, supporting the gateway hypothesis over the cumulative influence hypothesis. PMID- 29501794 TI - Effect of the application of surface treatments before and after sintering on the flexural strength, phase transformation and surface topography of zirconia. AB - OBJECTIVES: To evaluate the effects of airborne-particle abrasion (APA) and Er,Cr:YSGG laser irradiation on 4-point-flexural strength, phase transformation and morphologic changes of zirconia ceramics treated at pre-sintered or post sintered stage. METHODS: Three hundred and forty-two bar shaped zirconia specimens were milled with different sizes according to the flexural strength test (n = 10), X-ray diffraction (XRD) (n = 4) and field emission scanning electron microscope (FE-SEM) (n = 4) analyses. For each test protocol, specimens were divided into 4 main groups whether the surface treatments applied before or after sintering and whether the specimens received heat treatment or not as pre sintered, post-sintered no-heat and post-sintered heat-treated groups, and a group was served as control. Main groups were further divided into 6 equal subgroups according to surface treatment method applied (2 W-, 3 W-, 4 W-, 5 W-, 6 W-laser irradiations and APA). Surface treatments were applied to pre-sintered groups before sintering and to post-sintered groups after sintering. Post sintered heat-treated groups were subjected to veneer ceramic firing simulation after surface treatments. Flexural strength and flexural modulus values were statistically analysed and monoclinic phase content was calculated. Weibull analysis was used to evaluate strength reliability and fractographic analysis was conducted. RESULTS: Highest flexural strength values were detected at post sintered no-heat APA and 4W-laser groups (P < 0.05). Pre-sintered groups showed statistically lower flexural strength values. Heat treatment decreased the strength of the specimens. Monoclinic phase content was only detected at post sintered no-heat groups and the highest amount was detected at APA group. Rougher surfaces and deeper irregularities were detected at FE-SEM images pre-sintered groups. CONCLUSIONS: Application of surface treatments at pre-sintered stage may be detrimental for zirconia ceramics in terms of flexural strength. CLINICAL SIGNIFICANCE: Treating the surface of zirconia ceramic before sintering process is not recommended due to significant decrease in flexural strength values. 2 W-4 W Er,Cr:YSGG laser irradiations can be regarded as alternative surface treatment methods when zirconia restoration would be subjected to veneer ceramic firing procedures. PMID- 29501795 TI - Preservation versus non-preservation of left colic artery in sigmoid and rectal cancer surgery: A meta-analysis. AB - BACKGROUND: The aim of this study was to conduct a meta-analysis comparing the oncological, intraoperative and safety outcomes in sigmoid and rectal cancer surgery with and without preservation of the left colic artery (LCA). METHOD: We searched Medline, Embase, China National Knowledge Infrastructure (CNKI), and PubMed databases for relevant articles published between 1962 and 2017. Randomized and non-randomized clinical trials were identified and included in the study. End-points evaluated included 5-year mortality, number of patients with retrieved positive metastatic lymph nodes (LN) at the root of inferior mesenteric artery (IMA), number of retrieved LNs, morbidity, mortality, recurrence, bowel obstruction, intraoperative blood loss, anastomotic leakage, operation time, surgical site infection and postoperative bleed. Meta-analysis was conducted using RevMan 5.3 software. The odds ratio (OR) with 95% confidence intervals (CI) was used to analyze dichotomous data. RESULTS: Seventeen studies including 6247 patients were identified for the meta-analysis. Meta-analysis revealed that preserving the LCA was associated with reduced anastomotic leakage rate (OR, 0.78; 95% CI, 0.62-0.98; P = 0.03). There were no significant differences between the two groups with respect to the 5-year mortality, number of retrieved LNs, number of patients with retrieved positive metastatic LNs at the root of IMA, morbidity, mortality, recurrence, bowel obstruction, intraoperative blood loss, operation time, surgical site infection and postoperative bleed. CONCLUSION: In comparison with ligating the left colic artery, preserving the left colic artery seems to achieve comparable success with acceptable safety outcomes and we suggest to preserve the LCA in the sigmoid and rectal cancer surgeries. However, more multicenter randomized controlled trials are required to further evaluate the efficacy and safety of preserving the left colic artery in surgeries. PMID- 29501796 TI - Biological meshes for abdominal hernia: Lack of evidence-based recommendations for clinical use. AB - BACKGROUND: In the clinical literature on abdominal hernia repair, no sound criteria have been established to support the use of biological meshes as opposed to synthetic ones. Furthermore, the information on biological meshes is quite scarce, and so their place in therapy has not yet been defined. METHODS: The treatment of primary and incisional ventral hernia was the target intervention evaluated in our analysis. Our study consisted of the following phases: a) Identification of the biologic meshes available on the market; b) Literature search focused on efficacy and safety of these meshes; c) Analysis of the findings derived from the literature search. The information collected this way was reviewed narratively, and presented according to standard meta-analysis. The main end-points of our analysis included infection of surgical wound at 1 month and recurrence at 12 months. RESULTS: Our clinical literature comprised 11 trials that evaluated 5 biological meshes: Permacol (706 patients), Strattice (324 patients), Surgisis (44 patients), Tutomesh (38 patients) and Xenmatrix (22 patients). These studies generally showed a poor methodological quality. Surgical wound infection showed a wide between-study variability (95%CI: from 12.0% to 22.9%). Also the 12-month relapse rate demonstrated a wide 95%CI (from 5.0% to 19.9%). A significantly lower rate of recurrence at 12 months was found for Permacol compared with Strattice (rate difference: -14.2%; 95%CI: -22.1% to 6.2%). DISCUSSION: Our analysis provided an overview of 5 biological meshes currently available on the market. The different types of meshes showed a marked statistical variability in the clinical outcomes. Hence, nearly all comparisons between different meshes in the two clinical end-points did not reach statistical significance. One exception was represented by the finding that cross-linked meshes had a significantly lower recurrence rate at 12 months than non-cross linked meshes. PMID- 29501797 TI - Caspase-3, a key apoptotic protein, as a prognostic marker in gastric cancer after curative surgery. AB - BACKGROUND: Caspase-3 acts as a major executioner protein in proteolytic degradation during apoptosis. The role of Caspase-3 in gastric cancer remains controversial. METHODS: A total of 366 gastric cancer patients who received curative surgery were enrolled. Caspase-3 expression in gastric tumors was examined by immunohistochemical staining. Correlations between Caspase-3 expression and the survival rates and between Caspase-3 expression and the clinicopathological parameters of the gastric cancer patients were analyzed. RESULTS: The 5-year overall survival rates of gastric cancer patients with and without Caspase-3 expression were 51.2% and 37.3%, respectively (P = 0.030). The 5-year disease-free survival rates of gastric cancer patients with and without Caspase-3 expression were 49.2% and 34.6%, respectively (P = 0.029). Analyses of the clinicopathological features showed that larger tumor size (P = 0.030), more advanced Borrmann type (P = 0.012), more aggressive stromal reaction (P = 0.001), higher classification using Ming's infiltrating histology type (P = 0.018), more lymph node involvement (P = 0.019), and more lymphovascular involvement (P = 0.045) were significantly correlated with a lack of Caspase-3 expression. The multivariate analysis showed that age (P = 0.001), Borrmann classification (P = 0.032), stromal reaction type (P = 0.018), TNM pathological T category (P = 0.002), TNM pathological N category (P < 0.001), and Caspase-3 expression (P = 0.041) were significantly correlated with the overall survival of gastric cancer patients. CONCLUSION: Caspase-3 expression in gastric cancer patients is related to favorable clinicopathological features and a positive prognosis after curative surgery. Caspase-3 may act as a tumor suppressor in human gastric cancer. PMID- 29501799 TI - New transcriptomic tools to understand testis development and functions. AB - The testis plays a central role in the male reproductive system - secreting several hormones including male steroids and producing male gametes. A complex and coordinated molecular program is required for the proper differentiation of testicular cell types and maintenance of their functions in adulthood. The testicular transcriptome displays the highest levels of complexity and specificity across all tissues in a wide range of species. Many studies have used high-throughput sequencing technologies to define the molecular dynamics and regulatory networks in the testis as well as to identify novel genes or gene isoforms expressed in this organ. This review intends to highlight the complementarity of these transcriptomic studies and to show how the use of different sequencing protocols contribute to improve our global understanding of testicular biology. PMID- 29501798 TI - Metabolic syndrome 2 years after laparoscopic gastric bypass. AB - BACKGROUND: The latest diabetes consensus identified obesity as key component of the metabolic syndrome. The role of bariatric surgery over such syndrome has been less explored with a lack of long term studies, and especially among Mexicans. METHODS: Retrospective study including patients with metabolic syndrome submitted to laparoscopic gastric bypass at a single institution with complete data after 24 months. The objective was to analyze the improvement of the syndrome and each component. Demographic, anthropometric, biochemical and clinical parameters were analyzed at 12 and 24 months. Secondarily weight loss and other parameters were also analyzed. Finally, an analysis of syndrome improvement related to weight loss was performed. RESULTS: Sixty-three patients were included. The 2 most common components associated with obesity were reduced HDL and raised glucose or Type 2 diabetes. There was a significant improvement of metabolic syndrome and its components, as well as for the rest of the analyzed data, from the first check point and throughout follow-up. Prevalence of such syndrome was 6.3% at 12 and 24 months. Hypertension and raised glucose or Type 2 diabetes were the components with the greatest and fastest improvement; HDL levels and obesity were the least improved. There was a direct relationship between percentage of excess weight loss or percentage of excess BMI loss, and syndrome's improvement. CONCLUSION: Patients with metabolic syndrome improved after gastric bypass, with results lasting after 2 years; other metabolic parameters important for cardiovascular risk were also positively affected. There was a relationship between the amount of weight loss and improvement of metabolic syndrome. PMID- 29501800 TI - Magnesium administration after experimental traumatic brain injury improves decision-making skills. AB - After sustaining a traumatic brain injury (TBI), a person's ability to make daily decisions can be affected. Simple tasks such as, deciding what to wear are no longer effortless choices, but are instead difficult decisions. This study explored the use of a discrimination task with a magnesium treatment in order to examine how decision-making skills are affected after TBI and if the treatment helped to attenuate cognitive and motor impairments. Thirty-one male rats were separated into MAG/TBI, VEH/TBI, or VEH/Sham groups. Pre-TBI, rats were trained to dig in the sand for a reinforcer. After establishment of consistent digging behavior rats received a bilateral frontal cortex injury. Rats received either an i.p. injection of 2 mmol/kg magnesium chloride or control at 4, 24, 72 h post surgery. Dig task testing began 7 days post-injury, lasting for 4 weeks. The discriminations included two scent pairings; basil (baited) versus coffee then the reversal and then cocoa (baited) versus cumin then the reversal. The results indicated that the magnesium treatment was successful at attenuating cognitive and motor deficits after TBI. The results also indicated that the dig task is a sufficient operant conditioning task in the assessment of frontal functioning after TBI. PMID- 29501801 TI - Innate lymphoid cells 3 induce psoriasis in xenotransplanted healthy human skin. PMID- 29501802 TI - Alteration of the fecal microbiota in Chinese patients with Parkinson's disease. AB - Emerging evidences suggest that gut microbiota dysbiosis plays a role in Parkinson's disease (PD). However, the alterations in fecal microbiome in Chinese PD patients remains unknown. This case-control study was conducted to explore fecal microbiota compositions in Chinese PD patients. Microbiota communities in the feces of 45 patients and their healthy spouses were investigated using high throughput Illumina Miseq sequencing targeting the V3-V4 region of 16S ribosomal RNA (rRNA) gene. The relationships between fecal microbiota and PD clinical characteristics were analyzed. The structure and richness of the fecal microbiota differed between PD patients and healthy controls. Genera Clostridium IV, Aquabacterium, Holdemania, Sphingomonas, Clostridium XVIII, Butyricicoccus and Anaerotruncus were enriched in the feces of PD patients after adjusting for age, gender, body mass index (BMI), and constipation. Furthermore, genera Escherichia/Shigella were negatively associated with disease duration. Genera Dorea and Phascolarctobacterium were negatively associated with levodopa equivalent doses (LED). Among the non-motor symptoms (NMSs), genera Butyricicoccus and Clostridium XlVb were associated with cognitive impairment. Overall, we confirmed that gut microbiota dysbiosis occurs in Chinese patients with PD. A well-controlled population involved was beneficial for the identification of microbiota associated with diseases. Additionally, the fecal microbiota was closely related to PD clinical characteristics. Elucidating these differences in the fecal microbiome will provide a foundation to improve our understanding the pathogenesis of PD and to support the potentially therapeutic options modifying the gut microbiota. PMID- 29501803 TI - The role of the dorsal striatum in extinction: A memory systems perspective. AB - The present review describes a role for the dorsal striatum in extinction. Evidence from brain lesion and pharmacological studies indicate that the dorsolateral region of the striatum (DLS) mediates extinction in various maze learning and instrumental learning tasks. Within the context of a multiple memory systems view, the role of the DLS in extinction appears to be selective. Specifically, the DLS mediates extinction of habit memory and is not required for extinction of cognitive memory. Thus, extinction mechanisms mediated by the DLS may involve response-produced inhibition (e.g. inhibition of existing stimulus response associations or formation of new inhibitory stimulus-response associations), as opposed to cognitive mechanisms (e.g. changes in expectation). Evidence also suggests that NMDA-dependent forms of synaptic plasticity may be part of the mechanism through which the DLS mediates extinction of habit memory. In addition, in some learning situations, DLS inactivation enhances extinction, suggesting a competitive interaction between multiple memory systems during extinction training. Consistent with a multiple memory systems perspective, it is suggested that the DLS represents one of several distinct neural systems that specialize in extinction of different kinds of memory. The relevance of these findings to the development of behavioral and pharmacological therapies that target the maladaptive habit-like symptoms in human psychopathology is also briefly considered. PMID- 29501804 TI - A 17-year surgical experience of the intraoral approach for ranulas. AB - INTRODUCTION: The aim of this study was to analyze the clinical features and treatment outcomes in order to determine the optimal management of ranulas in our Oral and Maxillofacial Surgery department with long-term results. PATIENTS AND METHODS: A retrospective study was performed to evaluate patients with a final diagnosis of a simple or plunging ranula at Lille Teaching Hospital from May 2000 to January 2017. Clinical data on ranulas that were reviewed included gender, age, symptoms, location of the lesion, surgical procedures, complications, recurrence and follow-up. RESULTS: The 26 patients included in the study comprised 18 males and 8 females, ranging from 3-months to 38 years of age. A total of 27 ranulas were managed: 25 oral ranula and 2 plunging ranulas. Twelve patients had undergone marsupialization (44.4%), 7 patients had complete excisions of the ranula (25.9%) or partial excisions combined with marsupialization (14.8%) and 4 patients (14.8%) had undergone excision of the sublingual gland (SLG). Seven ranulas recurred (25.9%). Not a single case recurred following the excision of the SLG. Treatments that included marsupialization were associated with the lowest recurrence rate (16.7%) after SLG excision, followed by combined marsupialization and ranula excision (25%) and by ranula excision alone (57%). There were no major complications. DISCUSSION: Long-term outcomes confirm the different surgical procedures available in the outpatient clinic for the management of ranulas based on our surgical experience. Transoral resection of the SLG should be the optimal treatment, producing the lowest recurrence rate. PMID- 29501805 TI - Are prostaglandins or calcium channel blockers efficient for free flap salvage? A review of the literature. AB - The free flap failure rate is less than 5%. The responsible mechanisms of postoperative secondary ischemia are mostly vascular. The main postoperative complication leading to flap failure is thrombosis. Different strategies have been reported to improve the reliability of flaps and decrease the risk of partial or total necrosis: thus, pharmacologic agents have been studied to reduce the risk of microvascular thrombosis. The aim of this review was to evaluate the effect of calcium channel blockers and prostaglandins on free skin flap survival. A systematic review of the literature was performed to identify articles studying the efficacy of calcium channel blockers and prostaglandins on free flap survival. After full text reading, eleven articles were finally included. Eight articles investigated the role of prostaglandins in free tissue transfers, two in rats subjects, one in rabbits, five in humans. Two articles studied the effect of calcium channel blockers on free flaps, one in rats subjects, one in rabbits. One article studied in different groups the effect of calcium channel blockers and prostaglandins on free flaps in rabbits. Literature regarding the efficacy of calcium channel blockers and prostaglandins to salvage free flap is poor and mainly based on animal models. Nevertheless, studies on prostaglandins showed a slight efficiency of these molecules for free flap salvage. Results are less reliable for calcium channel blockers and dependent on the molecule used. In conclusion, there is a lack of evidence to use them in clinical practice. PMID- 29501806 TI - Sudden Death in Heart Failure With Preserved Ejection Fraction: A Competing Risks Analysis From the TOPCAT Trial. AB - OBJECTIVES: This study investigated the rates and predictors of SD or aborted cardiac arrest (ACA) in HFpEF. BACKGROUND: Sudden death (SD) may be an important mode of death in heart failure with preserved ejection fraction (HFpEF). METHODS: We studied 1,767 patients with HFpEF (EF >=45%) enrolled in the Americas region of the TOPCAT (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function) trial. We identified independent predictors of composite SD/ACA with stepwise backward selection using competing risks regression analysis that accounted for nonsudden causes of death. RESULTS: During a median 3.0-year (25th to 75th percentile: 1.9 to 4.4 years) follow-up, 77 patients experienced SD/ACA, and 312 experienced non-SD/ACA. Corresponding incidence rates were 1.4 events/100 patient-years (25th to 75th percentile: 1.1 to 1.8 events/100 patient-years) and 5.8 events/100 patient-years (25th to 75th percentile: 5.1 to 6.4 events/100 patient-years). SD/ACA was numerically lower but not statistically reduced in those randomized to spironolactone: 1.2 events/100 patient-years (25th to 75th percentile: 0.9 to 1.7 events/100 patient years) versus 1.6 events/100 patient-years (25th to 75th percentile: 1.2 to 2.2 events/100 patient-years); the subdistributional hazard ratio was 0.74 (95% confidence interval: 0.47 to 1.16; p = 0.19). After accounting for competing risks of non-SD/ACA, male sex and insulin-treated diabetes mellitus were independently predictive of composite SD/ACA (C-statistic = 0.65). Covariates, including eligibility criteria, age, ejection fraction, coronary artery disease, left bundle branch block, and baseline therapies, were not independently associated with SD/ACA. Sex and diabetes mellitus status remained independent predictors in sensitivity analyses, excluding patients with implantable cardioverter-defibrillators and when predicting SD alone. CONCLUSIONS: SD accounted for ~20% of deaths in HFpEF. Male sex and insulin-treated diabetes mellitus identified patients at higher risk for SD/ACA with modest discrimination. These data might guide future SD preventative efforts in HFpEF. (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function [TOPCAT]); NCT00094302. PMID- 29501807 TI - Natriuretic Peptides as Biomarkers of Treatment Response in Clinical Trials of Heart Failure. AB - OBJECTIVES: This study sought to determine whether treatment-related changes in natriuretic peptides (NPs) predict longer-term therapeutic effects in clinical trials of heart failure (HF). BACKGROUND: The lack of reliable predictors of efficacy of drugs and devices in HF has presented a major hurdle to the development and evaluation of novel therapies. METHODS: The study conducted a trial-level analysis of 16 phase III chronic HF trials completed between 1987 and 2013 studying 18 therapeutic comparisons in 48,844 patients. Weighted Pearson correlation coefficients were calculated between average control- or placebo corrected changes in NPs and longer-term treatment effects on clinical endpoints (expressed as log-transformed hazard ratios). RESULTS: Median follow-up for clinical endpoints was 28 (25th to 75th percentile range: 18 to 36) months. NPs were available in a median of 748 (25th to 75th percentile range: 270 to 1,868) patients and measured at a median of 4 (25th to 75th percentile range: 3 to 6) months after randomization. Treatment-related changes in NPs were not correlated with longer-term treatment effects on all-cause mortality (r = 0.12; p = 0.63), but were correlated with HF hospitalization (r = 0.63; p = 0.008). Correlation with HF hospitalization improved when analyses were restricted to trials completed in the last decade (>2010; r = 0.92; p = 0.0095), using N-terminal pro B-type NP assays (r = 0.65; p = 0.06), and evaluating inhibitors of the renin angiotensin-aldosterone system (r = 0.97; p = 0.0002). CONCLUSIONS: When examining a broad range of interventions, therapy-related changes in NPs appeared modestly correlated with longer-term therapeutic effects on hospitalization for HF, but not with effects on all-cause mortality. These observations raise important caveats regarding the use of NPs in phase II trials for decision making regarding phase III trials. PMID- 29501808 TI - Will Biomarkers Succeed as a Surrogate Endpoint in Heart Failure Trials? PMID- 29501809 TI - Maximizing Sentinel Lymph Node Detection: Aortic Sentinel Lymph Node Detection in Endometrial Cancer. AB - STUDY OBJECTIVE: To determine the importance of a dual (cervical and fundal) indocyanine green (ICG) injection and thorough dissection for the detection of sentinel lymph nodes (SLNs). DESIGN: Description and step-by-step demonstration of the surgical procedure using video (Canadian Task Force classification III). SETTING: Hospital Universitario Donostia, San Sebastian, Spain. PATIENTS: A 60 year-old woman with a diagnosis of IAG1 endometrial adenocarcinoma (EC). INTERVENTIONS: The patient received a cervical and transcervical fundal ICG injection for para-aortic and pelvic SLN detection in the setting of a research protocol, followed by a total hysterectomy and bilateral salpingo-oophorectomy with a frozen section of the uterus as a standard approach [1]. Institutional Review Board approval was obtained for the research protocol of this study. MEASUREMENTS AND MAIN RESULTS: Dual ICG injection [2] adds the benefit of a cervical injection (that best evaluates the pelvic region [3]) to the fundal injection, with better spread to the lumboaortic pathway [4] so as not to lose the aortic drainage and aortic SLN, whose relevance is still discussed due to its low incidence of metastasis [5]. This search does not add to the associated morbidity but is associated with increased operative time. For pelvic SLN dissection, patience and good training are key; the surgeon must always be on the lookout for uncommon pathways if no SLN is detected in the classical areas. The final histological classification was upgraded to a grade IIIC2 (ie, micrometastasis in the aortic and pelvic-right pararectal space) EC, 3 cm G1 with no lymphovascular invasion. CONCLUSION: Dual ICG injection allows comprehensive mapping not only of pelvic SLNs, but also of para-aortic SLNs, in EC, maximizing the identification of all possible affected areas. Nonetheless, the relevance of its added benefit requires further evaluation. PMID- 29501810 TI - Laparoscopic Neuronavigation for Deep Lateral Pelvic Endometriosis: Clinical and Surgical Implications. AB - STUDY OBJECTIVE: To evaluate the clinical presentation and surgical outcome in patients with deep lateral pelvic endometriosis (dLPE). DESIGN: A retrospective multicentric study (Canadian Task Force classification II-2). SETTING: University tertiary referral centers. PATIENTS: One hundred forty-eight women with deep infiltrating endometriosis (DIE). INTERVENTIONS: Laparoscopic excision of DIE. Disease distribution was classified as follows: central pelvic endometriosis (CPE) when DIE involved 1 of the following anatomic sites: cervix, vagina, uterosacral ligaments, rectum, bladder, or pelvic peritoneum; superficial lateral pelvic endometriosis when parametria, ureters, or hypogastric plexus were involved; and dLPE in the presence of sacral plexus and/or sciatic nerve infiltration. MEASUREMENTS AND MAIN RESULTS: All patients showed CPE. LPE was detected in 116 cases (78.4%); among these, we observed dLPE in 41 patients (35.3%). dLPE occurred in 40% of women with CPE and in 72.7% of patients with hypogastric plexus involvement. Thirty women with dLPE (73.2%) received gastrointestinal or urologic resection in addition to gynecologic procedures compared with 40 patients (57.1%) without dLPE (p = .001). No differences were observed in terms of perioperative complications according to the presence of dLPE. According to univariate/multivariate analysis, chronic pelvic pain was the only predictor of dLPE (odds ratio = 3.041, p = .003). The median preoperative visual analog scale for dysmenorrhea (median = 8, range, 0-10) and dyspareunia (median = 5; range, 0-10) dropped to 0 after surgery. The median follow-up was 36 months (range, 6-66 months) with a recurrence rate of 8.8%. CONCLUSIONS: dLPE is not a rare event in women with DIE. Complete laparoscopic removal of endometriosis seems to ensure benefit in terms of recurrence rate without increased surgical morbidities. PMID- 29501811 TI - Laparoendoscopic Single-Site Supracervical Hysterectomy with Manual Morcellation: A Retrospective Study. AB - STUDY OBJECTIVE: To evaluate the feasibility, efficiency, and safety of manual morcellation in laparoendoscopic single-site (LESS) supracervical hysterectomy. DESIGN: Retrospective study (Canadian Task Force classification II-2). SETTING: A teaching hospital. PATIENTS: One hundred and ninety patients with symptomatic uterine leiomyomas and/or adenomyosis who underwent LESS supracervical hysterectomy. INTERVENTIONS: Manual morcellation through the umbilical wound. MEASUREMENTS AND MAIN RESULTS: Time of operation, blood loss volume, specimen weights, rate of morcellation, requirement for blood transfusion, hospital length of stay, and prevalence of postoperative cyclic spotting were recorded. The median weight of the uterine corpus was 245 g (range, 100-1960 g). The median total operation time was 69 minutes (range, 36-183 minutes). The median volume of blood loss was 50 mL (range, 10-850 mL). The median level of hemoglobin reduction was 1 g/dL (range, -1 to 3.2 g/dL). The incidence of intraoperative blood transfusion was 3.2%, and the mean manual morcellation rate was 38.9 +/- 15 g/minute. The incidence of postoperative cyclic spotting was 10.5%. CONCLUSION: Safe and effective LESS surgery requires a minimal surgical incision compared with conventional laparoscopic surgery and laparotomy. Manual morcellation was found to be effective and safe in removing solid tumors in this population. PMID- 29501812 TI - Uterine Transplantation: A Survey of Perceptions and Attitudes of American Reproductive Endocrinologists and Gynecologic Surgeons. AB - OBJECTIVE: To determine whether reproductive endocrinologists and minimally invasive surgeons support uterine transplantation as a treatment option for absolute uterine factor infertility (AUFI). DESIGN: A cross-sectional study (Canadian Task Force classification II-2). SETTING: A Web-based survey. PATIENTS: Physician members of the American Society of Reproductive Medicine (ASRM) and the American Association of Gynecologic Laparoscopists (AAGL). INTERVENTIONS: A Web based questionnaire administered between January and February 2017. MEASUREMENTS AND MAIN RESULTS: Support for (strongly agree or agree) or opposition to (strongly disagree or disagree) various aspects of uterine transplantation were described using descriptive statistics and analyzed using chi-square tests. A total of 414 physicians (ASRM: 49.5%, AAGL: 50.5%) responded to the Web-based survey; 43.7% were female, 52.4% were between the ages of 45 and 65 years, and 73.4% were white. Nearly fifty-six percent supported women being allowed to donate or receive a transplanted uterus. Fifty-four percent strongly agreed or agreed that uterine transplantation carried an acceptable risk for donors, 28.0% for the recipient and 21.0% for the infant. Forty-two percent agreed that uterine transplantation should be considered a therapeutic option for women with AUFI, whereas 19.6% felt it should be covered by insurance. Nearly 45% of respondents felt uterine transplantation to be ethical. The most common ethical concerns regarding uterine transplantation were related to medical or surgical complications to the recipient (48.8%). CONCLUSION: Just under half of the reproductive endocrinologists and minimally invasive surgeons surveyed find uterine transplantation to be an ethical option for patients with AUFI. Important concerns remain regarding the risk to donors, recipients, and resulting infants, all contributing to only a minority currently recommending it as a therapeutic option. PMID- 29501813 TI - Concomitant Laparoscopic and Thoracoscopic Resection of Recurrent High-Grade Ovarian Cancer. AB - STUDY OBJECTIVE: To describe the first case of combined endoscopic management of a thoracic and abdominal recurrence of ovarian cancer. DESIGN: An instructive video showing the combined thoracic and abdominal surgical procedure. SETTING: Department of Gynecological Oncology, Churchill Hospital, Oxford University, UK. PATIENTS: A 64-year-old woman undergoing endoscopic treatment for a third recurrence of ovarian cancer after a full surgical staging in 2007. The disease free interval from the last recurrence was 31 months. INTERVENTION: The operation was performed by a multidisciplinary team of thoracic and gynecologic oncologist surgeons. Surgery started with thoracoscopic resection of a right enlarged paracardiac lymph node of 24 mm and a small wedge of the right lung, which was attached to the lymph node. At laparoscopy, 2 nodules of 3 and 5 mm were excised from the mesosigmoid and 1 nodule of 20 mm was resected from the right hemidiaphragm. MEASUREMENTS AND MAIN RESULTS: The total operative time was 251 minutes, and no intraoperative complication occurred. No conversion to open surgery was necessary. The estimated blood loss was 50 mL. There was no visible residual disease at the end of the surgery. The patient was discharged 4 days after surgery. The final pathology report confirmed the presence of endometrioid adenocarcinoma in all specimens removed. Adjuvant chemotherapy with carboplatin/paclitaxel was started 2 weeks later. At the 60-day follow-up, no complications were recorded. A computed tomographic scan performed after 6 cycles of chemotherapy did not reveal any evidence of relapse. CONCLUSIONS: The combined endoscopic approach might be feasible in selected patients. PMID- 29501814 TI - Small RNA-mediated regulation in bacteria: A growing palette of diverse mechanisms. AB - Small RNAs (sRNAs) in bacteria have evolved with diverse mechanisms to balance their target gene expression in response to changes in the environment. Accumulating studies on bacterial regulatory processes firmly established that sRNAs modulate their target gene expression generally at the posttranscriptional level. Identification of large number of sRNAs by advanced technologies, like deep sequencing, tilling microarray, indicates the existence of a plethora of distinctive sRNA-mediated regulatory mechanisms in bacteria. Types of the novel mechanisms are increasing with the discovery of new sRNAs. Complementary base pairing between sRNAs and target RNAs assisted by RNA chaperones like Hfq and ProQ, in many occasions, to regulate the cognate gene expression is prevalent in sRNA mechanisms. sRNAs, in most studied cases, can directly base pair with target mRNA to remodel its expression. Base pairing can happen either in the untranslated regions or in the coding regions of mRNA to activate/repress its translation. sRNAs also act as target mimic to titrate away different regulatory RNAs from its target. Other mechanism includes the sequestration of regulatory proteins, especially transcription factors, by sRNAs. Numerous sRNAs, following analogous mechanism, are widespread in bacteria, and thus, has drawn immense attention for the development of RNA-based technologies. Nevertheless, typical sRNA mechanisms are also discovered to be confined in some bacteria. Analysis of the sRNA mechanisms unravels their existence in both the single step processes and the complex regulatory networks with a global effect on cell physiology. This review deals with the diverse array of mechanisms, which sRNAs follow to maintain bacterial lifestyle. PMID- 29501815 TI - Human gene expression microarray analysis of the HPV 6bE7-HaCaT stable cell line. AB - OBJECTIVE: Human papillomavirus (HPV) is the most common sexually transmitted agent in the world. HPV6b is a low-risk type of HPVs that causes benign verrucous hyperplastic lesions of the skin and anal genital mucosa. Previous research has indicated that HPV genotype 6 is sometimes associated with high-grade lesions and anal cancer. The pathogenesis of low-risk HPV infection and its relationship to high-risk HPV is not clear at present. The E7 protein, which is encoded by HPV early -expressing genes, plays an important role in HPV infection. The aim of this study is to investigate the human gene expression signature of the HPV6b E7 transfected HaCaT stable cell line. The identification of differentially expressed genes might provide a more comprehensive understanding of HPV6b infection and will allow us to explore the specific role of E7 protein. METHODS: We established a stable cell line transfected with the HPV6b E7 gene and analyzed the line's genome-wide expression profile by microarray. Quantitative real-time PCR (qRT-PCR) was used to verify the differentially expressed genes. GO enrichment analysis was applied for gene annotation according to functions. KEGG analysis, a system for analyzing gene function and genome information, was used to help us integrate differentially expressed genes into pathways. RESULTS: A total of 3519 genes were identified to be significantly differentially expressed between the HPV 6bE7-HaCaT stable cell line and a control cell line, among which 1884 genes were up-regulated and 1635 genes were down-regulated with a fold change > 2.0 between the two groups. The expression profiles of the top 20 up regulated and the top 20 down-regulated genes in the HPV 6bE7-HaCaT stable cell line as analyzed by qRT-PCR were consistent with the microarray data. The most significantly enhanced genes HPV 6bE7-HaCaT cells were SIMC1, S100A8 and S100A9, whereas PXDN expression was markedly down-regulated. GO analysis showed that HPV 6bE7 primarily affected biological processes and that the most significant difference was in heart induction (GO:0003129). Many differentially expressed genes were linked to histone H4-K20 demethylation (GO:0035574). KEGG analysis showed that the most significant changes in gene expression were related to primary bile acid biosynthesis, and the most diverse biological processes were related to systemic lupus erythematosus pathogenesis. CONCLUSIONS: The global gene expression profile of the HPV 6bE7-HaCaT stable cell line was analyzed, revealing the genes regulated by E7 protein and providing insight into the pathogenesis of HPV6b infection. PMID- 29501816 TI - Imaging transcriptional dynamics. AB - Recent advances in imaging techniques have enabled visualizations of nascent transcripts or individual protein molecules at high spatiotemporal resolution, revealing the complex nature of transcriptional regulation. Here, we highlight recent studies that have provided comprehensive insights to transcriptional dynamics using such quantitative imaging techniques. Specifically, they demonstrated that transcriptional activity is stochastic, and such transcriptional bursting is modulated by multiple components like chromatin environments, concentration of transcription factors, and enhancer-promoter interactions. Moreover, recent studies suggested that regulation of transcriptional activity is more complex than previously thought, by showing that transcription factors and RNA polymerases also move within the cell with distinct kinetics and sometimes form dynamic clusters to mediate transcriptional initiation. PMID- 29501817 TI - Manipulation of VEGF-induced angiogenesis by 2-N, 6-O-sulfated chitosan. AB - : Emerging evidence suggests that vascular endothelial growth facto (VEGF) is important in the treatment of various ischemic and cardiovascular diseases. However, it often suffers from high cost and easy deactivation with a short half life. Here, we describe a synthetic 2-N, 6-O-sulfated chitosan (26SCS) with a high affinity to VEGF promoting the binding of the signaling protein to its VEGF receptor 2 (VEGFR2), activating receptor phosphorylation and pro-angiogenic related genes expression, and further stimulating downstream VEGF-dependent endothelial cell viability, migration, tube formation and rat aortic rings outgrowth. Interestingly, the obvious recruitment of mural cells were occurred to stabilize the sprouted microvessels. In addition, the pro-angiogenic potential of 26SCS composited VEGF was confirmed in vivo using the chick embryo chorioallantoic membrane (CAM) assay with an extensive perfusable vascular network. A longer monitoring was administered subcutaneously to mice in a biocompatible gelatin sponge and showed that VEGF with 26SCS had the capability to efficiently enhance neovascularization. These findings highlight that 26SCS, the semi-synthetic natural polymer, may be a promising coagent with VEGF for vascular therapy. STATEMENT OF SIGNIFICANCE: Vascular endothelial growth factor (VEGF) is crucial for facilitating angiogenesis to supply oxygen and nutrient during wound healing and tissue regeneration. However, appropriate use of VEGF is an ongoing challenge due to its rapidly clearance and severe side effects at higher dosage. In this study, we described a synthetic 2-N, 6-O-sulfated chitosan (26SCS) with a high affinity to VEGF, which could significantly promote its binding capacity to VEGF receptor 2 and further stimulate the angiogenic behavior of endothelial cells. We further confirmed that 26SCS was spatially combined with VEGF in a "lying manner", and this spatial arrangement was more conducive to exposure of the receptor binding domain of VEGF. Additionally, it also promoted in vivo angiogenesis in a chicken chorioallantoic membrane assay and mouse subcutaneous implant model. This strategy may afford a new avenue to enhance pro angiogenic capacity of VEGF. PMID- 29501818 TI - Binary polyhydroxyalkanoate systems for soft tissue engineering. AB - : Progress in tissue engineering is dependent on the availability of suitable biomaterials. In an effort to overcome the brittleness of poly(3 hydroxybutyrate), P(3HB), a natural biodegradable polyester, and widen its biomedical applications, plasticising of P(3HB) with oligomeric substances of related structure has been studied. A biosynthesised medium-chain-length polyhydroxyalkanoate (mcl-PHA) copolymer, the plasticiser precursor, was obtained using vegetable waste frying oil as a sole carbon source. The mcl-PHA was transformed into an oligomeric derivative by acid hydrolysis. The plasticising effect of the oligomeric mcl-PHA on P(3HB) was studied via characterisation of thermal and mechanical properties of the blends in the course of ageing at ambient conditions. Addition of oligomeric mcl-PHA to P(3HB) resulted in softer and more flexible materials based entirely on PHAs. It was shown that the oligomeric mcl-PHA transformed highly crystalline P(3HB) into materials with a dominant amorphous phase when the content of oligomeric mcl-PHA exceeded 10 wt%. In vitro biocompatibility studies of the new binary PHA materials showed high viability and proliferation of C2C12 myoblast cells. Thus, the proposed approach for P(3HB) plasticisation has the potential for the generation of more pliable biomaterials based on P(3HB) which can find application in unique soft tissue engineering applications where a balance between stiffness, tensile strength and ductility is required. STATEMENT OF SIGNIFICANCE: Polyhydroxyalkanoates, a broad family of natural biodegradable and biocompatible polymers, have emerged as highly promising biomaterials both for bulk and biomedical applications. Here we describe an approach to tune the mechanical properties of stiff and brittle poly(3-hydroxybutyrate) and thereby to expand its potential biomedical applications. Plasticisation, a common practice in the plastic industry to modify polymer mechanical properties, has been used very cautiously for biomedical applications due to plasticiser toxicity and migration. We have developed a plasticiser for poly(3-hydroxybutyrate) based on a structurally related but softer and pliable medium chain length polyhydroxyalkanoate. Additives of oligomeric derivatives of this polymer improved ductility of poly(3 hydroxybutyrate), greatly widening the future applicability of this well established biomaterial. In parallel, the binary polyhydroxyalkanoate materials also exhibited improved cell attachment and proliferation, a highly desirable outcome. PMID- 29501819 TI - Emergence of NDM-5-producing Escherichia coli sequence type 167 clone in Italy. AB - The emergence of carbapenemase-producing Enterobacteriaceae (CPE) is a critical concern worldwide. In Italy, CPE isolates are very frequent, with the KPC enzyme types strongly predominant whereas the New Delhi metallo-beta-lactamase (NDM) enzymes are extremely rare. Here we report the first detection of NDM-5-producing Escherichia coli sequence type 167 (ST167) isolates from two patients with urinary tract infection (Ec001 and Ec002 from urines), including one with colonisation (Ec003 from faeces) admitted to the same hospital 2 months apart in 2017. Minimum inhibitory concentrations (MICs) were determined by broth microdilution. The carbapenemase type was identified both by phenotypic and genotypic methods. Isolate genotypes were investigated by phylogenetic typing, multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE). Next-generation sequencing (NGS) was used to obtain complete sequences of plasmids. The three E. coli isolates carried the blaNDM-5 gene, shared the same resistance phenotype and belonged to ST167. By PFGE, isolates showed the same profile, suggesting that they were the same strain. NGS revealed that the blaNDM 5 gene was located on a 99-kb multireplicon plasmid (designed pNDM-5-IT) with a peculiar scaffold constituted by four replicons of the IncF type (FIA, FIB and two copies of the FII replicon). pNDM-5-IT plasmid harboured multiple resistance and virulence determinants, including the arginine deaminase (ADI) cluster never found associated with plasmids before. Since NDM-5-producing E. coli ST167 has been regarded as a successful epidemic clone in China, the emergence of such a clone carrying a plasmid associated both with multiresistance and virulence could be a public-health threat. PMID- 29501820 TI - Identification and bioevaluation of SRI-12742 as an antimicrobial agent against multidrug-resistant Acinetobacter baumannii. AB - Multidrug-resistant Acinetobacter baumannii (MDR-Ab) is one of the most significant nosocomial pathogens that is being increasingly isolated in healthcare settings worldwide. Owing to its inherent drug-resistant nature, coupled with its ability to readily acquire resistance to other antibiotic classes, there is a real dearth of antibiotics available to treat infections with MDR-Ab. A commercially available library was screened against MDR-Ab BAA-1605 to identify novel inhibitory molecules. The selectivity index of a hit was tested against Vero cells and in vitro efficacy was profiled against a panel of clinical MDR-Ab. The bacteriostatic or bactericidal nature was determined by time-kill experiments, and synergy with clinically approved drugs was determined by the chequerboard method. Additionally, in vivo efficacy was measured in a murine neutropenic A. baumannii thigh infection model. SRI-12742 was identified as a potent active hit, with a minimum inhibitory concentration (MIC) of 4 mg/L against BAA-1605. Its activity was then profiled against a MDR-Ab clinical strain panel (MICs 4 mg/L to >64 mg/L). SRI-12742 exhibited concentration-dependent bactericidal activity and caused an ca. 16 log10 CFU/mL reduction at 10 * MIC in 24 h, which is comparable with minocycline. In a murine neutropenic thigh infection model of A. baumannii infection, SRI-12742 reduced CFU counts by ca. 0.9 log10 CFU, which is comparable with polymyxin B. In addition, SRI-12742 synergised with all classes of antibiotics tested. SRI-12742 exhibits all of the criteria necessary to be positioned as a novel lead with potential to be deployed for the treatment of infections caused by MDR-Ab. PMID- 29501821 TI - Adjunctive therapy with azithromycin for moderate and severe acute respiratory distress syndrome: a retrospective, propensity score-matching analysis of prospectively collected data at a single center. AB - Effective pharmacological therapy has not been established for patients with acute respiratory distress syndrome (ARDS). Macrolides are antibiotics with potent immunomodulatory and anti-inflammatory effects that may be beneficial in ARDS treatment. The objective of this study was to determine the adjunctive effect of azithromycin on survival for patients with ARDS. This single-center, retrospective cohort evaluation of hospitalized patients with moderate or severe ARDS was conducted to assess the impact of intravenous azithromycin on clinical outcomes using a propensity score analysis. All data were collected prospectively as part of ongoing research on the utility of high-resolution computed tomography in ARDS. The primary outcome was 90-day mortality, and the secondary analysis assessed the effect of azithromycin on time to successful discontinuation of mechanical ventilation and 28-day mortality. Of 191 eligible patients with severe or moderate ARDS, 62 were treated with azithromycin. The 62 patients treated with azithromycin and 62 not treated with azithromycin were matched and analysed. Azithromycin use was associated with a statistically significant improvement in 90-day survival rate (Hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.27 0.87; P = 0.015) and a shorter time to successful discontinuation of mechanical ventilation (HR, 1.74; 95% CI, 1.07-2.81; P = 0.026). The 28-day mortality rate tended to be higher in the azithromycin cohort than in the non-azithromycin cohort, but this was not statistically significant. Adjunctive intravenous azithromycin therapy was effective in patients with moderate or severe ARDS. Further prospective randomized controlled trials are needed to confirm this result. PMID- 29501822 TI - Hot topics in necrotising skin and soft tissue infections. PMID- 29501823 TI - Multidrug-resistant Shigella sonnei carrying the plasmid-mediated mcr-1 gene in China. AB - Since the plasmid-mediated polymyxin resistance gene mcr-1 was first reported in Escherichia coli and Klebsiella pneumoniae in China, only one mcr-1-positive isolate of Shigella sonnei, containing inactivated mcr-1, has been reported worldwide. In this study, 1650 historical S. sonnei strains isolated from 2003 2015 in China were screened for the mcr-1 gene. Antimicrobial susceptibilities and resistance genes of mcr-1-positive isolates were determined, and the transferability of polymyxin resistance by plasmid conjugation was investigated. Pulsed-field gel electrophoresis (PFGE), plasmid profiles and Southern blotting were used to analyse genetic relationships and plasmid characteristics, and mcr-1 positive plasmids were sequenced. Six mcr-1-positive S. sonnei isolates from Shanghai (2010-2012) with polymyxin B resistance (MICs 4-8 MUg/mL) were identified. Four of these exhibited multidrug resistance, including resistance to azithromycin and third-generation cephalosporins, and co-harboured blaCTX-M-14, mph(A) and blaTEM on different plasmids. mcr-1-positive plasmids shared highly similar IncI2 backbones that resembled reference plasmids, although some differences were observed, including various and abundant insertion sequences/patterns (IS1294, IS1 and ISApl1) and a diverse recombination shufflon region. mcr-1 in S. sonnei may date back to mid-2006. Here we report for the first time the presence of active mcr-1 in multidrug-resistant S. sonnei in China, which has existed since at least 2010. This study highlights the diverse mobile genetic elements on mcr-1-harboring plasmids, potentially resulting in high rates of mcr-1 horizontal transfer among Enterobacteriaceae. These findings emphasise the importance of continuous national and international surveillance of mcr-1-positive Shigella and changes in antibiotic resistance patterns. PMID- 29501825 TI - Beta-defensin genes of the Colubridae snakes Phalotris mertensi, Thamnodynastes hypoconia, and T. strigatus. AB - beta-Defensins are cationic antimicrobial peptides showing little sequence similarity but highly conserved tertiary structure stabilized by a six-cysteines motif. Using a PCR approach, we described beta-defensin sequences with two exons in three species of Colubridae snakes with high sequence similarity between them. The deduced amino acid sequence presented the characteristics of beta-defensin family. The phylogenetic analysis using beta-defensin coding sequences of different snakes grouped them in two main branches: genes organized in three or two exons. PMID- 29501824 TI - Distribution and speciation of zinc in the gills of rainbow trout (Oncorhynchus mykiss) during acute waterborne zinc exposure: Interactions with cadmium or copper. AB - We utilized micro X-ray fluorescence imaging (MU-XFI) and micro X-ray absorption near-edge spectroscopy (MU-XANES), which are both synchrotron-based techniques to investigate Zn distribution profile, its co-localization patterns with Ca, S, and Fe and speciation in the gills of rainbow trout (RBT). Fish (~100 g) were exposed to acutely toxic levels of waterborne Zn alone and in combination with waterborne Cd or Cu for 24 h (each at 1 * 96 h LC50). Gill sections were prepared and analyzed at the VESPERS beamline of the Canadian Light Source. The primary lamellae of the fish gill were found to be the primary area of Zn accumulation. These regions also correspond to the zones of mitochondria rich cells localization in fish gills, supporting the putative roles of these cells in metal uptake. Zn was also found to predominantly co-localize with Ca and S, but not with Fe, indicating the roles of Ca and S in intracellular Zn handling. Zn distribution in the gill was markedly reduced during co-exposure to Cd, but not to Cu, suggesting a competitive interaction between Zn and Cd for uptake. The speciation of Zn in the gill was dominated by Zn-phosphate, Zn-histidine and Zn cysteine species; however, the interactions of Zn with Cd or Cu resulted in the loss of Zn-cysteine. Overall, our findings provide important novel insights into the interactions of Zn, Cd and Cu in the fish gill, which may ultimately help to explain the mechanisms underlying the acute toxicity of these metals in binary mixture to fish. PMID- 29501826 TI - Adsorptive removal of microcystin-LR from surface and wastewater using tyre-based powdered activated carbon: Kinetics and isotherms. AB - Microcystin LR (MC-LR) is a highly toxic compound and it is known for its adverse health effect on both humans and animals. Due to the ineffectiveness of conventional water treatments methods, for the past decades, researchers have been developing cost-effective ways of removing MC-LR from water bodies. This study reports the application of powdered activated carbon (PAC) obtained from the waste tyre for the removal of MC-LR. The choice of the adsorbent was chosen due to its attractive properties. The prepared tyre-based PAC was found to have the large surface area (1111 m2 g-1). The detection of MC-LR was achieved using high performance liquid chromatography (HPLC) coupled with a PDA detector. The experimental parameters (such as optimum pH, dosage and contact time) affecting the removal of MC-LR using tyre based-powdered activated carbon were optimized using response surface methodology (RSM). Maximum removal of MC-LR was achieved under the following optimum conditions; sample pH 4, carbon dosage concentration 10,000 mg L-1 and contact time of 34 min. Under optimum conditions, kinetic studies and adsorption isotherms reflected better fit for pseudo-second-order rate and Langmuir isotherm model, respectively. The optimized method was applied for the removal of MC-LR in wastewater sample. The effluent and influent sample contained initial concentrations ranging from 0.52 to 8.54 MUg L-1 and the removal efficiency was 100%. PMID- 29501827 TI - In vitro study of gossypol's ovarian toxicity to rodents and goats. AB - Gossypol interferes with reproduction, causing damage to sperm, disrupting the estrous cycle and resulting in embryonic lethality. In females, gossypol administration promotes degeneration of ovarian follicles, but it is unknown whether this effect is direct or indirect. Thus, the aim of this study is to determine whether gossypol interferes with folliculogenesis in vitro in rats, mice and goats. Ovaries from rats and mice and fragments of goat ovaries were grown in cell culture for 24 h or 7 days. Four groups were tested: 0 (control), 5, 10 and 20 MUg gossypol/ml. After incubation, the ovaries were fixed and processed for histological analysis. Follicles were classified according to their stage of development as either viable or atretic. It was found that the ovaries of rats, mice and goats cultured with gossypol showed an increase in the proportion of atretic follicles and a consequent reduction in the proportion of viable follicles at all stages of follicular development. Compared to the control group, the viability of all ovarian follicles in the rat, mouse and goat groups was reduced after cultivation for 24 h by 56.9%, 56.5% and 68.0%, respectively, with the highest concentration of gossypol (20 MUg/mL), and after seven days, the respective reductions were 65.4%, 65.3% and 88.2%. Thus, it is possible that gossypol may directly affect follicular maturation, and consequently female fertility. PMID- 29501828 TI - Primary plasma cell leukemia in the era of novel agents for myeloma - a multicenter retrospective analysis of outcome. AB - Primary plasma cell leukemia (PPCL) is a rare form of multiple myeloma with a dismal prognosis. This retrospective multi-center study examines the national experience of PPCL in the era of novel agents. During 2002-2016, thirty-nine patients with PPCL were identified in 11 Israeli centers. One-fifth of them died in the first 2 months after diagnosis. The overall survival (OS) of those who survived the first 3 months was 22.5 months. About 70% of patients received at least one type of immunomodulatory drug (IMiD) and similarly proteasome inhibitor (PI) during treatment. There was a survival advantage for those who received IMiD but not for those who received PI or other type of standard dose chemotherapy. In multivariate analysis, low performance status and increased uric acid were also associated with shorter OS. In conclusion, this study demonstrates favorable impact of treatment with IMiDs and hematopoietic cell transplantation on the survival of PPCL patients. PMID- 29501830 TI - Long-term exposure to ambient air pollution (including PM1) and metabolic syndrome: The 33 Communities Chinese Health Study (33CCHS). AB - Little evidence exists about the effects of long-term exposure to ambient air pollution on metabolic syndrome (MetS). This study aimed to determine the association between long-term ambient air pollution and MetS in China. A total of 15,477 adults who participated in the 33 Communities Chinese Health Study (33CCHS) in 2009 were evaluated. MetS was defined based on the recommendation by the Joint Interim Societies. Exposure to air pollutants was assessed using data from monitoring stations and a spatial statistical model (including particles with diameters <= 1.0 um (PM1), <= 2.5 um (PM2.5), and <= 10 um (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2), and ozone (O3)). Two-level logistic regression analyses were utilized to assess the associations between air pollutants and MetS. The prevalence of MetS was 30.37%. The adjusted odds ratio of MetS per 10 ug/m3 increase in PM1, PM2.5, PM10, SO2, NO2, and O3 were 1.12 (95% CI = 1.00-1.24), 1.09 (95% CI = 1.00-1.18), 1.13 (95% CI = 1.08-1.19), 1.10 (95% CI = 1.02-1.18), 1.33 (95% CI = 1.12-1.57), and 1.10 (95% CI = 1.01-1.18), respectively. Stratified analyses indicated that the above associations were stronger in participants with the demographic variables of males, < 50 years of age, and higher income, as well as with the behavioral characteristics of smoking, drinking, and consuming sugar-sweetened soft drinks frequently. This study indicates that long-term exposure to ambient air pollutants may increase the risk of MetS, especially among males, the young to middle aged, those of low income, and those with unhealthy lifestyles. PMID- 29501829 TI - Improvements of ambient hyperglycemia and glycemic variability are associated with reduction in oxidative stress for patients with type 2 diabetes. AB - AIMS: We aimed to evaluate which parameters of improvement in glucose metabolism reduce oxidative stress for patients with Type 2 diabetes mellitus (T2DM). METHODS: Sixty-seven outpatients with T2DM underwent 72 h of continuous glucose monitoring (CGM) and were measured for oxidative stress before and after a 24 week intervention with the following targets: fasting plasma glucose (FPG), <130 mg/dl; postprandial plasma glucose (PPG), <180 mg/dl; and glycated hemoglobin (HbA1c), <7% (53 mmol/mol). The mean glucose level (MGL), mean amplitude of glycemic excursions (MAGE), mean of daily differences (MODD), percentage coefficient of variation for glucose (%CV) and area under the postprandial plasma glucose curve (AUCPP) were calculated from the CGM data. Oxidative stress was estimated using the diacron-reactive oxygen metabolites (d-ROMs) test. Finally, the association between the improvements in glucose metabolism and oxidative stress was evaluated. RESULTS: FPG, MGL, HbA1c, MAGE, MODD, %CV, AUCPP, and d ROMs significantly improved after 24 weeks of intervention. The change in d-ROMs was significantly correlated with that in FPG (r = 0.414), MGL (r = 0.402), HbA1c (r = 0.271), MAGE (r = 0.457), MODD (r = 0.371), and AUCPP (r = 0.352). The correlation of the change in d-ROMs with that in FPG, MAGE, and MODD and the use of glucose-like peptide 1 receptor agonists and statins remained significant after adjustment for other markers of diabetes control (multiple R2 = 0.406). CONCLUSIONS: Improvements in glucose metabolism, including FPG and daily and day to-day glucose variability, were all correlated with reduced oxidative stress for patients with T2DM. PMID- 29501831 TI - Urinary polycyclic aromatic hydrocarbon metabolites among 3-year-old children from Krakow, Poland. AB - Polycyclic aromatic hydrocarbons (PAHs) are widespread in the environment and can adversely affect human health. The aim of the present study is to describe the level of PAHs exposure in children living in Krakow, one of the most polluted cities in Poland, and to determine the relationship of urinary biomarkers with environmental PAHsexposure. Urinary monohydroxy metabolites (OH-PAHs) of 20 PAHs were assessed in 218 three-year old children, of which only 10 were present in nearly all the samples: monohydroxy metabolites of naphthalene, fluorene, phenantrene and pyrene. Of the metabolites analyzed, hydroxynaphthalenes were predominant and constituted almost 73% of total excreted OH-PAHs, while 1-OH PYRene was the least abundant (2.3% of total OH-PAHs). All measured urinary OH PAHs were statistically significantly correlated with each other (R = 0.165 0.880) but the highest correlation coefficients with other individual OH-PAHs and with total OH-PAHs were observed for 2-OH-FLUOR. Children exposed at home to environmental tobacco smoke (ETS) had higher concentrations of fluorene and pyrene urinary metabolites compared to those without ETS exposure; and those exposed to gas-based appliances used for cooking or heating water had higher levels of fluorene and phenanthrene metabolites than children not exposed. The use of coal, wood or oil for heating was associated with elevated levels of 1-OH PYRene. Urinary PAHs metabolites only modestly reflect high molecular weight carcinogenic PAHs exposures such as those monitored in air in the present study. None of the measured PAHs metabolites was correlated with airborne PM2.5 and only two were slightly correlated with measured higher molecular mass airborne PAHs. The average concentrations of these specific metabolites in Polish children were much higher than observed in other pediatric populations living in developed countries. Our findings suggest that to capture various sources of PAHs, in addition to 1-OH-PYRene, biomonitoring of PAHs exposure should include 2-OH-NAP and 2-OH-FLUOR. PMID- 29501832 TI - Hyperpigmentation and higher incidence of cutaneous malignancies in moderate-high PCB- and dioxin exposed individuals. AB - Polychlorinated biphenyls (PCB) are well known persistent and toxic environmental pollutants. Our aim was to identify effects of moderate-high exposure to dioxin like (dl) and non-dioxin-like (ndl)-PCBs on the skin in order to provide more insight in the pathophysiological effects of these compounds. We performed a dermatological examination on 92 former workers from a transformer recycling company with known elevated serum PCB and/or dioxin (polychlorinated dibenzo-p dioxin/polychlorinated dibenzo-p-furan (PCDD/F)) levels. In addition, we performed a skin cancer screening over a period of seven years (2010-2016) on resp. 268, 271, 210, 149, 92, 129 and 79 participants. We found a higher incidence of acne and malignancies of the skin (malignant melanoma, basal cell carcinoma and mycosis fungoides) in the workers compared to normal population. The probability of having hyperpigmentation on the skin was statistically significantly higher in workers with higher sumPCBs- (OR:1.09(1.12-2.17)), dioxin like (dl)-PCBs- (OR:1.56(1.12-2.17)) and dioxin (PCDD/Fs) (OR:1.09(1.02-1.16)) levels. Age was a confounding factor in this model. Formation of hyperpigmentation could be an indicator for (moderate-high) exposure to toxic compounds like PCBs. The higher incidence of cutaneous malignancies found in the workers might be associated with PCB- and dioxin exposure, warranting further investigation on larger cohorts. PMID- 29501833 TI - Ecological and human exposure assessment to PBDEs in Adige River. AB - The interest for environmental issues and the concern resulting from the potential exposure to contaminants were the starting point to develop methodologies in order to evaluate the consequences that those might have over both the environment and human health. Considering the feature of POPs, including PBDEs, such as bioaccumulation, biomagnification, long-range transport and adverse effects even long time after exposure, risk assessment of POPs requires specific approaches and tools. In this particular context, the MERLIN-Expo tool was used to assess the aquatic environmental exposure of Adige River to PBDEs and the accumulation of PBDEs in humans through the consumption of possible contaminated local aquatic food. The aquatic food web models provided as output of the deterministic simulation the time trend of concentrations for twenty years of BDE-47 and total PBDEs, expressed using the physico-chemical properties of BDE 47, in aquatic organisms of the food web of Adige River. For BDE-47, the highest accumulated concentrations were detected for two benthic species: Thymallus thymallus and Squalius cephalus whereas the lowest concentrations were obtained for the pelagic specie Salmo trutta marmoratus. The trend obtained for the total PBDEs, calculated using the physico-chemical properties of BDE-47, follows the one of BDE-47. For human exposure, different BDE-47 and total PBDEs concentration trends between children, adolescent, adults and elderly were observed, probably correlated with the human intake of fish products in the daily diet and the ability to metabolize these contaminants. In detail, for the adolescents, adults and elderly a continuous accumulation of the target contaminants during the simulation's years was observed, whereas for children a plateau at the end of the simulation period was perceived. PMID- 29501834 TI - Non-responsive breast cellulitis after hyaluronic acid filler injection. PMID- 29501835 TI - Evaluation of the efficacy of valproic acid and suberoylanilide hydroxamic acid (vorinostat) in enhancing the effects of first-line tuberculosis drugs against intracellular Mycobacterium tuberculosis. AB - BACKGROUND: New tuberculosis (TB) drug treatment regimens are urgently needed. This study evaluated the potential of the histone deacetylase inhibitors (HDIs) valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) to enhance the effects of first-line anti-TB drugs against intracellular Mycobacterium tuberculosis. METHODS: M. tuberculosis H37Rv cultures were exposed to VPA or SAHA over 6 days, in the presence or absence of isoniazid (INH) and rifampicin (RIF). The efficacy of VPA and SAHA against intracellular M. tuberculosis with and without INH or RIF was tested by treating infected macrophages. Bactericidal activity was assessed by counting mycobacterial colony-forming units (CFU). RESULTS: VPA treatment exhibited superior bactericidal activity to SAHA (2-log CFU reduction), while both HDIs moderately improved the activity of RIF against extracellular M. tuberculosis. The bactericidal effect of VPA against intracellular M. tuberculosis was greater than that of SAHA (1-log CFU reduction) and equalled that of INH (1.5-log CFU reduction). INH/RIF and VPA/SAHA combination treatment inhibited intracellular M. tuberculosis survival in a shorter time span than monotherapy (3days vs. 6 days). CONCLUSIONS: VPA and SAHA have adjunctive potential to World Health Organization-recommended TB treatment regimens. Clinical evaluation of the two drugs with regard to reducing the treatment duration and improving treatment outcomes in TB is warranted. PMID- 29501836 TI - Shigellosis and toxic megacolon secondary to Shigella flexneri serotype 3a: The challenges of laboratory diagnosis. AB - We present a rare case of Shigella flexneri bacteraemia and toxic megacolon, and discuss the challenges of conventional laboratory techniques versus molecular PCR platforms in differentiating between Shigella species and Escherichia coli. PMID- 29501838 TI - Adipose tissue extrinsic factor: Obesity-induced inflammation and the role of the visceral lymph node. AB - Obesity-related adverse health consequences occur predominately in individuals with upper body fat distribution commonly associated with increased central adiposity. Visceral adipose tissue accumulation is described to be the greatest driver of obesity-induced inflammation, however evidence also supports that the intestines fundamentally contribute to the development of obesity-induced metabolic disease. The visceral adipose depot shares the same vasculature and lymph drainage as the small intestine. We hypothesize that the visceral lymph node, which drains adipose tissue and the gastrointestinal tract, is central to the exacerbation of systemic pro-inflammation. Male C57BL/6 mice were fed CHOW or high fat diet (HFD) for 7 weeks. At termination the mesenteric depot, visceral lymph node and ileum, jejunum and Peyer's patches were collected. Cytokine concentration was determined in adipose tissue whereas immune cell populations where investigated in the visceral lymph node and intestinal segments by flow cytometry. Visceral adipose tissue and the gastrointestinal tract mutually influence immune cells enclosed within the visceral lymph node. HFD increased visceral lymph node immune cell number. This likely resulted from 1.) an increase in immune cells migration from the small intestines likely from activated dendritic cells that travel to the lymph node and 2.) cytokine effluent from visceral adipose tissue that promoted expansion, survival and retention of pro inflammatory immune cells. Overall, the visceral lymph node, the immune nexus of visceral adipose tissue and the small intestines, likely plays a fundamental role in exacerbation of systemic pro-inflammation by HFD-induced obesity. The research of Tim Bartness greatly enhanced the understanding of adipose tissue regulation. Studies from his laboratory significantly contributed to our awareness of extrinsic factors that influence body fatness levels. Specifically, the work he produced eloquently demonstrated that adipose tissue was more complex than an insulating storage center; it was connected to our brains via the sympathetic and sensory nervous system. Mapping studies demonstrated that adipose tissue both receives and sends information to the brain. Further, his lab demonstrated that nervous system connections contributed to lipolysis, thermogenesis and adipocyte proliferation and growth. The work of Tim Bartness will continue to influence adipose tissue research. As such, Tim Bartness directly inspired the following research. Adipose tissue extrinsic factors are not limited to the peripheral nervous system. The lymphatic system is an additional extrinsic factor that cross talks with adipose tissue, however its role in this context is under emphasized. Here we begin to elucidate how the lymphatic system may contribute to the comorbidities associated with visceral adipose tissue accumulation. PMID- 29501839 TI - Structure and conformation of alpha-glucan extracted from Agaricus blazei Murill by high-speed shearing homogenization. AB - Agaricus blazei Murill is an edible and medicinal mushroom favored in many countries, by virtue of both its delicious taste and its potential health benefits such as its purported anticancer activity. A neutral alpha-glucan (ABM40 1) with a carbohydrate content of 96% was purified from the high-speed shearing homogenization extracts of A. Blazei Murill by ethanol precipitation and column chromatography. Methylation analysis along with nuclear magnetic resonance spectroscopy revealed that ABM40-1 was an alpha-(1->4)-d-glucopyranan with O-6 position occasionally occupied with alpha-Glcp-(1->or alpha-Glcp-(1->6)-beta-Glcp (1->side chains. A weight-average molecular weight of 7.34*106Da was determined for ABM40-1 and its chain in solution was revealed as a compact sphere by size exclusion chromatography (SEC) coupled with a laser light scattering. This spherical conformation was also further confirmed by Congo red test and using atom force microscopy. These results suggest it would be worthwhile to further study the potential bioactivities of ABM40-1. PMID- 29501837 TI - Dietary influences on cognition. AB - Obesity is a world-wide crisis with profound healthcare and socio-economic implications and it is now clear that the central nervous system (CNS) is a target for the complications of metabolic disorders like obesity. In addition to decreases in physical activity and sedentary lifestyles, diet is proposed to be an important contributor to the etiology and progression of obesity. Unfortunately, there are gaps in our knowledge base related to how dietary choices impact the structural and functional integrity of the CNS. For example, while chronic consumption of hypercaloric diets (increased sugars and fat) contribute to increases in body weight and adiposity characteristic of metabolic disorders, the mechanistic basis for neurocognitive deficits in obesity remains to be determined. In addition, studies indicate that acute consumption of hypercaloric diets impairs performance in a wide variety of cognitive domains, even in normal non-obese control subjects. These results from the clinical and basic science literature indicate that diet can have rapid, as well as long lasting effects on cognitive function. This review summarizes our symposium at the 2017 Society for the Study of Ingestive Behavior (SSIB) meeting that discussed these effects of diet on cognition. Collectively, this review highlights the need for integrated and comprehensive approaches to more fully determine how diet impacts behavior and cognition under physiological conditions and in metabolic disorders like type 2 diabetes mellitus (T2DM) and obesity. PMID- 29501840 TI - Thermodynamics of a Ca2+ dependent, highly thermostable and detergent compatible purified alkaline serine protease from Nocardiopsis xinjiangensis strain OM-6. AB - Extracellular alkaline protease producing salt tolerant alkaliphilic actinobacteria, Nocardiopsis xinjiangensis strain OM-6 was isolated from Okha Madi (OM) site of coastal Gujarat, India. The purified protease was stable even at 70 degrees C in 100mM Ca2+ with Kd=20*10-3 and t1/2=34min. The activation energies (E), enthalpy (?H*) and entropy (?S*) for protease deactivation were 29.35kJ/mol, 26.68kJ/mol and -186.22J/mol, respectively in 200mM Ca2+. The ?G* for protease deactivation was 97.63kJ/mol at 50 degrees C in 100mM Ca2+. OM-6 protease exhibited enhanced residual activities up to 103%, 70%, 144% and 119% with SDS, CTAB, Tween 80 and Triton X-100, respectively after 2h of incubation at 40 degrees C. Interestingly, residual activity of OM-6 protease increased by 450% and 559% in 50mM H2O2 and 10mM beta-mercaptoethanol respectively even after 2h of incubation. Moreover, protease retained 100% of its original activity with H2O2 and beta-mercaptoethanol at highest concentration after 24h. The protease retained more than 60% of original activity with 1% w/v of each commercial detergent even after 2h at 40 degrees C. These unique properties of protease make it an ideal choice for application in detergent formulations and enzymatic peptide synthesis. PMID- 29501841 TI - Preparation optimization and protective effect on 60Co-gamma radiation damage of Pinus koraiensis pinecone polyphenols microspheres. AB - Here, the chitosan and the glutaraldehyde (GA) were used to encapsulate pinecones polyphenols of Pinus koraiensis (P. koraiensis) by emulsification cross-linking technology. First, the prepared parameters (crosslinking agent amount, stirring speed, crosslinking temperature and emulsifying time) of the pinecones polyphenols microspheres (PPMs) were optimized by the response surface methodology (RSM). When chitosan concentration and crosslinking time were 2% and 80min, respectively, the optimal conditions were 7.91mL of crosslinking agent, stirring speed of 660.98r/min, crosslinking temperature of 41.18 degrees C and emulsifying time of 198.65min. The prepared PPMs embedding rate was 73.57%. The optimized PPM possessed a distinct core-shell structure and uniform spherical distribution with a particle size value of 3.4MUm. In addition, they had the excellent sustained-release characteristics in vitro. We also evaluated the radioprotective effects of PPMs against 60Co-gamma radiation in vivo. PPMs improved significantly the activity of the antioxidant enzyme SOD and reduce MDA level in the plasma of irradiated mice. Accordingly, PPMs could also significantly enhance the immunomodulation activity by promoting the proliferation of splenocytes and monocyte phagocytosis of irradiated mice. These results suggested that PPMs exert effective protection against radiation-induced injury by improving the antioxidant and immunomodulation activities. PMID- 29501842 TI - Exploring the interaction of Azure dyes with t-RNA by hybrid spectroscopic and computational approaches and its applications toward human lung cancer cell line. AB - In the present study, in depth characterization of binding aspects of Azure A (AZA) and Azure B (AZB) with transfer Ribonucleic acid (t-RNA) from Escherichia coli (E.coli) is investigated using spectroscopic techniques. The absorbance and fluorescence properties of these dyes have been remarkably changed upon binding with t-RNA. Significant changes in the absorption maxima of the dyes evidence the t-RNA induced metachromasy and the binding clearly revealed the high affinity of AZA and AZB to t-RNA. Strong emission polarization of the bound dyes and strong energy transfer from the guanine base pairs of t-RNA suggested intercalative binding interaction. The stoichiometry of AZA and AZB with t-RNA complexes are determined by the Benesi-Hildebrand plot from emission data. The negative values of free energy change indicated the involvement of hydrophobic forces and noncovalent interactions in the complexation of both the dyes with t-RNA. The 3 (4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay in A-549 human lung cancer cell lines reveals that binding of t-RNA reduces the toxicity of AZA and AZB. The utility of the present work explores the potential binding applicability of these dyes to t-RNA for their development as effective therapeutic agents and its target at molecular level for the treatment of diseases like cancer. PMID- 29501843 TI - Characterization and immunological activity of polysaccharides from Ixeris polycephala. AB - A water-soluble polysaccharide, named KMCP, was isolated and purified from edible plant Ixeris polycephala by using DEAE-52 cellulose chromatography. Its structure was determined by chemical analysis, methylation analysis, and NMR analysis, coupled with characterization by scanning electron spectroscopy (SEM). The resulting data indicated that KMCP was an arabinogalactan, with an average molecular weight of 1.95*106Da, which was mainly composed of arabinose and galactose in a relative molar ratio of 28.1% and 70.3%, respectively. The structure of KMPC was characterized as 72.5% of (1->4)-beta-Galp residues interspersed with 27.5% of (1->4,6)-beta-Galp residues in the main chain, and the branches were composed of (1->5)-alpha-Araf moieties or alpha-Araf (1->5) alpha Araf (1->disaccharide moieties attached at O-6 of the (1->4,6)-beta-Galp residues. KMCP was revealed to be capable of exhibiting macrophage-mediated innate immune responses via enhancing phagocytosis of macrophages and increasing production of NO, activating NF-kappaB signaling pathway and promoting the mice spleen cells proliferation in a dose-dependent manner within the test concentrations (10.0-200.0MUg/mL). These results suggested that KMCP could potentially be an effective and safe immunomodulator valuable to be utilized in pharmacological fields or in the development of functional foods. PMID- 29501844 TI - Evidence of traditionality of Brazilian medicinal plants: The case studies of Stryphnodendron adstringens (Mart.) Coville (barbatimao) barks and Copaifera spp. (copaiba) oleoresin in wound healing. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The World Health Organization (WHO) recognizes the potential of plants used in secular traditional medicine and considers this an important source of evidence to assess their effectiveness and safety. Brazil is rich in biodiversity and traditional uses based on the Amerindian culture. However, many processes started with the arrival of the Portuguese in the year 1500. The successive economic cycles, for example, led to destruction of native vegetation and an intense cultural erosion. As a consequence, the information about the use of plants in the past centuries are dispersed and without interpretation. In this study a methodology to evidence the traditionality of Brazilian plants was demonstrated using data about barbatimao barks (Stryphnodendron adstringens (Mart.) Coville - Fabaceae) and Copaiba oleoresin (Copaifera spp. - Fabaceae) in wound healing, was established. MATERIAL AND METHODS: Data about use of the plants were recovered from bibliography published between 1576 and 2011. The books (101) were classified using weights, considering the date of publication and the source of Information. Older books that describe primary information received weight 10, while books written more recently and with secondary information received weight 0.4. A score for each category of medicinal use was calculated based on the books weights and the frequency of citation. A review about the current use of both plants was also performed from ethnobotanical studies published in journals. RESULTS AND DISCUSSION: The traditional secular use of barks of barbatimao and oleoresin of copaiba to treat wounds was confirmed based on the historic bibliographic research. The most frequent use of barbatimao in a timeline of 500 years of Brazil's history, was as astringent, whereas for copaiba was as healing of skin and mucosal lesions. The continuous and current use of these plants to treat wounds, confirmed by recent ethnobotanical studies, is an indicative of the resilience of these remedies and their effectiveness. CONCLUSION: The use of preparations containing barbatimao barks and copaiba oleoresin can be considered effective in the treatment of wounds. Nonetheless, it is necessary to improve the quality of the formulas as established by WHO. PMID- 29501846 TI - Quantitative proteomic characterization of the lung extracellular matrix in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. AB - Remodeling of the extracellular matrix (ECM) is a common feature in lung diseases such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Here, we applied a sequential tissue extraction strategy to describe disease-specific remodeling of human lung tissue in disease, using end stages of COPD and IPF. Our strategy was based on quantitative comparison of the disease proteomes, with specific focus on the matrisome, using data-independent acquisition and targeted data analysis (SWATH-MS). Our work provides an in-depth proteomic characterization of human lung tissue during impaired tissue remodeling. In addition, we show important quantitative and qualitative effects of the solubility of matrisome proteins. COPD was characterized by a disease specific increase in ECM regulators, metalloproteinase inhibitor 3 (TIMP3) and matrix metalloproteinase 28 (MMP-28), whereas for IPF, impairment in cell adhesion proteins, such as collagen VI and laminins, was most prominent. For both diseases, we identified increased levels of proteins involved in the regulation of endopeptidase activity, with several proteins belonging to the serpin family. The established human lung quantitative proteome inventory and the construction of a tissue-specific protein assay library provides a resource for future quantitative proteomic analyses of human lung tissues. SIGNIFICANCE: We present a sequential tissue extraction strategy to determine changes in extractability of matrisome proteins in end-stage COPD and IPF compared to healthy control tissue. Extensive quantitative analysis of the proteome changes of the disease states revealed altered solubility of matrisome proteins involved in ECM regulators and cell-ECM communication. The results highlight disease-specific remodeling mechanisms associated with COPD and IPF. PMID- 29501845 TI - Acetone fraction from Sechium edule (Jacq.) S.w. edible roots exhibits anti endothelial dysfunction activity. AB - ETHNOPHARMACOLOGICAL RELEVANCE: A recent ethnomedical survey on medicinal plants grown in Mexico revealed that Sechium edule (Jacq.) Sw. (Cucurbitaceae) is one of the most valued plant species to treat cardiovascular diseases, including hypertension. Fruits, young leaves, buds, stems, and tuberous roots of the plant are edible. Considering that endothelial dysfunction induced by Angiotensin II plays an important role in the pathogenesis of hypertension and is accompanied by a prooxidative condition, which in turn induces an inflammatory state, vascular remodeling, and tissue damage, and that S. edule has been reported to possess antioxidant, anti-inflammatory and antihypertensive activity, its capability to control endothelial dysfunction was also assessed. AIM OF THE STUDY: To assess in vivo the anti-endothelial dysfunction activity of the acetone fraction (rSe-ACE) of the hydroalcoholic extract from S. edule roots. MATERIALS AND METHODS: Endothelial dysfunction was induced in female C57BL/6 J mice by a daily intraperitoneal injection of angiotensin II for 10 weeks. Either rSe-ACE or losartan (as a control) were co-administered with angiotensin II for the same period. Blood pressure was measured at weeks 0, 5, and 10. Kidney extracts were prepared to determine IL1beta, IL4, IL6, IL10, IL17, IFNgamma, TNFalpha, and TGFbeta levels by ELISA, along with the prooxidative status as assessed by the activity of antioxidant enzymes. The expression of ICAM-1 was evaluated by immunohistochemistry in kidney histological sections. Kidney and hepatic damage, as well as vascular tissue remodeling, were studied. RESULTS: The rSe-ACE fraction administered at a dose of 10 mg/kg was able to control hypertension, as well as the prooxidative and proinflammatory status in kidney as efficiently as losartan, returning mice to normotensive levels. Additionally, the fraction was more efficient than losartan to prevent liver and kidney damage. Phytochemical characterization identified cinnamic acid as a major compound, and linoleic, palmitic, and myristic acids as the most abundant non-polar components in the mixture, previously reported to aid in the control of hypertension, inflammation, and oxidative stress, three important components of endothelial dysfunction. IN CONCLUSION: this study demonstrated that rSe-ACE has anti-endothelial dysfunction activity in an experimental model and highlights the role of cinnamic acid and fatty acids in the observed effects. PMID- 29501847 TI - Proteomics as a tool to understand Leptospira physiology and virulence: Recent advances, challenges and clinical implications. PMID- 29501848 TI - Global effect of the lack of inorganic polyphosphate in the extremophilic archaeon Sulfolobus solfataricus: A proteomic approach. AB - : Inorganic polyphosphates (polyP) are present in all living cells and several important functions have been described for them. They are involved in the response to stress conditions, such as nutrient depletion, oxidative stress and toxic metals amongst others. A recombinant strain of Sulfolobus solfataricus unable to accumulate polyP was designed by the overexpression of its endogenous ppx gene. The overall impact of the lack of polyP on this S. solfataricus polyP ( ) strain was analyzed by using quantitative proteomics (isotope-coded protein label, ICPL). Stress-related proteins, such as peroxiredoxins and heat shock proteins, proteins involved in metabolism and several others were produced at higher levels in the ppx expression strain. The polyP deficient strain showed an increased copper sensitivity and an earlier transcriptional up-regulation of copA gene coding for the P-type copper-exporting ATPase. This implies a complementary function of both copper resistance systems. These results strongly suggests that the lack of polyP makes this hyperthermophilic archaeon more sensitive to toxic conditions, such as an exposure to metals or other harmful stimuli, emphasizing the importance of this inorganic phosphate polymers in the adaptations to live in the environmental conditions in which thermoacidophilic archaea thrive. SIGNIFICANCE: Inorganic polyphosphate (polyP) are ubiquitous molecules with many functions in living organisms. Few studies related to these polymers have been made in archaea. The construction of a polyP deficient recombinant strain of Sulfolobus solfataricus allowed the study of the global changes in the proteome of this thermoacidophilic archaeon in the absence of polyP compared with the wild type strain. The results obtained using quantitative proteomics suggest an important participation of polyP in the oxidative stress response of the cells and as having a possible metabolic role in the cell, as previously described in bacteria. The polyP deficient strain also showed an increased copper sensitivity and an earlier transcriptional up-regulation of copA, implying a complementary role of both copper resistance systems. PMID- 29501849 TI - A systematic review about the epidemiology of primary progressive multiple sclerosis in Latin America and the Caribbean. AB - : Novel epidemiological data has appeared in recent years in Latin America (LATAM) regarding the epidemiology of multiple sclerosis (MS); however, most of this information is related to all MS subtypes, and no specific data was collected regarding the primary progressive form of MS (PPMS). The objective of this study was to perform an updated systematic review of the epidemiology of PPMS in LATAM. METHODS: We conducted a systematic review of published epidemiological articles of PPMS from January 1997 to June 2017. RESULTS: No incidence data were found regarding PPMS. Differentiated prevalence was reported in 7 studies and ranged from 0.13 to 1.1 cases of PPMS per 100,000 inhabitants. Regarding subtype frequency, PPMS was observed in 10% of affected patients in proportional meta-analysis. No data about mortality were found. CONCLUSION: The study provides information on discriminated epidemiological features of PPMS in the region. The frequency observed was low in terms of prevalence. Follow up studies considering survival milestones and incidence data could provide a better understanding of the disease in the region. PMID- 29501850 TI - Exploring cognitive motor interference in multiple sclerosis by the visual Stroop test. AB - BACKGROUND: The dual task paradigm (the simultaneous performance of motor and cognitive task) is used in a laboratory setting to evaluate walking impairments that affect patients' daily lives. Although promising, it is poorly standardized and neither the cognitive task nor the motor task have been validated in a matched healthy control group (HC) for multiple sclerosis (MS). OBJECTIVE: Our aim was to set up a standardized instrument to evaluate cognitive motor interference in MS using the interference test par excellence: the stroop colour word test (SCWT). METHODS: Patients with MS and HC underwent 3D gait analysis with a dual task protocol, using the SCWT as a cognitive task. Gait performance impairment during the dual task was evaluated by dual task cost (DTC). A MANOVA was used to verify the effect of status (MS, HC) on DTC, calculated for the spatiotemporal parameter of the gait. RESULTS: In MS, the DTC was higher for the following gait parameters: speed (p = .013), cadence (p = .004), stride time (p = .005) stance phase (p < .001), and swing phase duration (p = .032). CONCLUSION: DTC is present in MS and HC, but the motor cost in MS is higher. The present work provides a useful and validated basis for future studies about cognitive motor interference in MS. PMID- 29501851 TI - Presence of antibiotic residues in various environmental compartments of Shandong province in eastern China: Its potential for resistance development and ecological and human risk. AB - OBJECTIVES: To investigate the occurrence of antibiotic residues in different types of environmental samples including water samples in rural Shandong province, China. Further, to characterize the potential ecological risk for development of antibiotic resistance in the environment, and the potential direct human health risk of exposure to antibiotics via drinking water and vegetables. METHODS: Environmental samples (n = 214) (river water, waste water, drinking water, sediments, manure, soil and edible parts of vegetables) were collected in twelve villages in Shandong province in eastern China. High performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was used to determine the concentration of antibiotic residues. The ratio of the measured environmental concentrations (MEC) to the predicted no-effect concentrations (PNEC) was used to evaluate the ecological risk (risk quotient, RQ) for development of antibiotic resistance. The potential risks to human health through exposure to antibiotics in drinking water were assessed by comparing measured environmental concentrations (MEC) and predicted no-effect concentration in drinking water (PNECDW), and in vegetables by comparing estimated daily intake (EDI) to ADI. RESULTS: Sulfapyridine, sulfamethoxazole, ciprofloxacin, enrofloxacin, levofloxacin, norfloxacin, chloramphenicol, florfenicol, doxycycline, and metronidazole were detected at concentrations ranging between 0.3 and 3.9 ng/L in river water, 1.3 and 12.5 ng/L in waste water, 0.5 and 21.4 ng/L in drinking water, 0.31 and 1.21 MUg/kg in river sediment, 0.82 and 1.91 MUg/kg in pig manure, 0.1 and 11.68 MUg/kg in outlet sediment, 0.5 and 2.5 MUg/kg in soil, and 6.3 and 27.2 MUg/kg in vegetables. The RQs for resistance development were >1 for enrofloxacin, levofloxacin, and ranged between 0.1 and 1 for ciprofloxacin. MECs/PNECDW ratios were <1 from exposure to antibiotics through drinking water for both adults and children. EDI/ADI ratios were <0.1 from exposure to antibiotics by vegetable consumption. CONCLUSIONS: Antibiotic pollutants were ubiquitous in various environmental compartments of Shandong province of China. Risk estimates indicated a potential for the measured levels of enrofloxacin, levofloxacin and ciprofloxacin in waste water to pose an ecological risk for resistance selection, and further studies are needed to validate this finding. The investigated antibiotics did not appear to pose an appreciable direct human health risk from environmental exposure through drinking water or vegetables consumption. However, they might still pose a risk for resistance development. PMID- 29501852 TI - Simulated discharge of treated landfill leachates reveals a fueled development of antibiotic resistance in receiving tidal river. AB - Around 350 million tons of solid waste is disposed of in landfills every year globally, with millions of cubic meters of landfill leachates released into neighboring environment. However, to date, little is known about the variations of antimicrobial resistance (AMR) in on-site leachate treatment systems and its development in leachate-receiving water environment. Here, we quantified 7 subtypes of antibiotic resistance genes (ARGs), 3 types of culturable antibiotic resistant bacteria (ARB) and 6 subtypes of mobile genetic elements (MGEs) in the effluents from a combined leachate treatment process, including biological treatment (MBR), physical separation (UF), ultraviolet (UV) disinfection and advanced oxidation process (AOP). The contents of ARGs, ARB and MGEs were generally enriched by the MBR, but then decreased significantly along with the tertiary treatment process. However, in the effluent-receiving water samples, the abundance of dominant ARGs (i.e. ermB, sul1, blaTEM) increased by 1.5 orders of magnitude within 96 h, alongside a general increase of MGEs (~10.0 log10(copies/mL) and total ARB (~1100 CFU/mL). Structural correlation analyses reveal that target ARGs were closely associated with MGEs, particularly in effluent-receiving samples (Procrustes test; M2 = 0.49, R = 0.71, P = 0.001); and occurrences of ARB were majorly affected by ARG's distribution and environmental conditions (e.g. nitrogen speciation) in effluent and recipient groups, respectively. This study indicates that current treatment technologies and operation protocols are not feasible in countering the development of AMR in effluent-receiving water environment, particularly in tidal rivers that are capable of retaining contaminants for a long residence time. PMID- 29501853 TI - Prenatal urinary triclosan concentrations and child neurobehavior. AB - BACKGROUND: Exposure to triclosan, an antimicrobial chemical, is ubiquitous among pregnant women and may reduce thyroid hormone levels that are important for fetal neurodevelopment. Few studies have examined the association between prenatal triclosan exposure and children's neurobehavior. OBJECTIVE: We investigated the relationship of prenatal urinary triclosan concentrations with children's behavior and cognitive abilities at age three years in a prospective pregnancy and birth cohort in Canada. METHODS: We measured triclosan in urine samples collected at ~12 weeks of gestation in 794 Canadian women enrolled in a prospective pregnancy and birth cohort study (MIREC) from 2008 to 2011. Around age 3 years, we assessed children's cognitive abilities using the Wechsler Primary and Preschool Scale of Intelligence-III (WPPSI-III), and two scales of the Behavior Rating Inventory of Executive Function-Preschool (BRIEF-P). Parents reported children's problem and reciprocal social behaviors using the Behavior Assessment System for Children-2 (BASC-2) and Social Responsiveness Scale-2 (SRS 2), respectively. RESULTS: After adjusting for confounders using multivariable linear regression, triclosan was not associated with most of the 30 examined neurobehavioral scales. Each 10-fold increase in triclosan was associated with better WPPSI-III picture completion scores (beta: 0.2; 95% CI: 0,0.5) and BASC-2 externalizing (beta: -0.5; 95% CI: -1.1, 0) and hyperactivity (beta: -0.6; 95% CI: -1.2, -0.1) scores, suggesting less externalizing and hyperactive behaviors. Child sex did not modify these associations. CONCLUSIONS: In this cohort, urinary triclosan concentrations measured once in early pregnancy were not associated with most assessed aspects of neurobehavior and weakly associated with a few others, but not in the hypothesized direction. PMID- 29501854 TI - Evaluation of triclosan in the Hershberger and H295R steroidogenesis assays. AB - Triclosan (TCS) is an antibacterial widely used in personal care products that exhibits endocrine disrupting activity in several species, with reports of altered thyroid, estrogen and androgen signaling pathways. To evaluate the androgenic mode of action, TCS was evaluated for androgen receptor mediated effects in the Hershberger assay and for altered androgen synthesis in the H295R steroidogenesis assay. In the Hershberger assay, castrated males were dosed by oral gavage for 10 days with corn oil (vehicle) or TCS (50 or 200 mg/kg/day) in the presence or absence of testosterone proprionate (TP, 0.2 mg/kg/day) prior to assessing accessory sex tissues (ASTs) weights. TCS alone or in combination with TP did not alter androgen dependent AST weights. Assessment of serum thyroxine (T4) demonstrated a significant dose-dependent decrease by TCS (50 or 200 mg/kg/day) co-administered with TP and TCS (200 mg/kg) without TP, but no differences in liver or thyroid weights. In the H295R assay, TCS from 0.01 to 10 MUM had no effect on testosterone production but TCS at 3 MUM and above did induce a significant increase in estrogen production. At 10 MUM, TCS produced significant cytotoxicity which confounded the interpretation of the estrogenic effect at that concentration. Thus, TCS had no effect on androgen synthesis or activity in the models used, but did enhance estrogen production and suppress serum T4. PMID- 29501855 TI - Inflammation kinase PKR phosphorylates alpha-synuclein and causes alpha-synuclein dependent cell death. AB - Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy comprise a group of neurodegenerative diseases termed synucleinopathies. Synucleinopathie are, characterized by presence of inclusion bodies in degenerating brain cells which contain aggregated alpha-synuclein phosphorylated on Ser129. Although the inflammation-associated serine-threonine kinase, PKR (EIF2AK2), promotes cellular protection against infection, we demonstrate a pro degenerative role of activated PKR in an alpha-synuclein-dependent cell model of multiple system atrophy, where inhibition and silencing of PKR decrease cellular degeneration. In vitro phosphorylation demonstrates that PKR can directly bind and phosphorylate monomeric and filamenteous alpha-synuclein on Ser129. Inhibition and knockdown of PKR reduce Ser129 phosphorylation in different models (SH-SY5Y ASYN cells, OLN-AS7 cells, primary mouse hippocampal neurons, and acute brain slices), while overexpression of constitutively active PKR increases Ser129 alpha-syn phosphorylation. Treatment with pre-formed alpha-synuclein fibrils, proteostatic stress-promoting MG-132 and known PKR activators, herpes simplex virus-1-?ICP34.5 and LPS, as well as PKR inducer, IFN-beta-1b, lead to increased levels of phosphorylated Ser129 alpha-synuclein that is completely blocked by simultaneous PKR inhibition. These results reveal a direct link between PKR and the phosphorylation and toxicity of alpha-synuclein, and they support that neuroinflammatory processes play a role in modulating the pathogenicity of alpha synuclein. PMID- 29501856 TI - The motor features of action verbs: fMRI evidence using picture naming. AB - The processing disadvantage of verbs compared to nouns and the greater vulnerability of verbs in brain damage have been ascribed to greater processing demands of morpho-syntactical or/and semantic properties for verbs, or/and visual complexity in picture-naming studies. Using picture naming, the current functional magnetic resonance imaging study examined the neural substrates underlying the semantic distinction between nouns and verbs. Under forced (externally-elicited) or free (internally-motivated) conditions, participants named a set of pictorial stimuli as objects or actions performed on/with the objects in Chinese. Use of a language with impoverished inflectional morphology (i.e., Chinese) and the same set of pictures for naming objects and actions allows for the control of both morpho-syntactical and visual confounds. The results revealed specific neural correlates for action verbs in the cortical subcortical motor system, irrespective of the naming conditions. Plausible accounts for the motor aspects of action-verb processing were interpreted basically on a semantic basis. PMID- 29501857 TI - Representation of action semantics in the motor cortex and Broca's area. AB - Previous studies have shown that both reading action words and observing actions engage the motor cortex and Broca's area, but it is still controversial whether a somatotopic representation exists for action verbs within the motor cortex and whether Broca's area encodes action-specific semantics for verbs. Here we examined these two issues using a set of functional MRI experiments, including word reading, action observation and a movement localiser task. Results from multi-voxel pattern analysis (MVPA) showed a somatotopic organisation within the motor areas and action-specific activation in Broca's area for observed actions, suggesting the representation of action semantics for observed actions in these neural regions. For action verbs, however, a lack of finding for the somatotopic activation argues against semantic somatotopy within the motor cortex. Furthermore, activation patterns in Broca's area were not separable between action verbs and unrelated verbs, suggesting that Broca's area does not encode action-specific semantics for verbs. PMID- 29501858 TI - Comparative sensitivity and inhibitor tolerance of GlobalFiler(r) PCR Amplification and Investigator(r) 24plex QS kits for challenging samples. AB - In cases such as mass disasters or missing persons, human remains are challenging to identify as they may be fragmented, burnt, been buried, decomposed, and/or contain inhibitory substances. This study compares the performance of a relatively new STR kit in the US market (Investigator(r) 24plex QS kit; Qiagen) with the GlobalFiler(r) PCR Amplification kit (Thermo Fisher Scientific) when genotyping highly inhibited and low level DNA samples. In this study, DNA samples ranging from 1 ng to 7.8 pg were amplified to define the sensitivity of two systems. In addition, DNA (1 ng and 0.1 ng input amounts) was spiked with various concentrations of five inhibitors common to human remains (humic acid, melanin, hematin, collagen, calcium). Furthermore, bone (N = 5) and tissue samples from decomposed human remains (N = 6) were used as mock casework samples for comparative analysis with both STR kits. The data suggest that the GlobalFiler(r) kit may be slightly more sensitive than the Investigator(r) kit. On average STR profiles appeared to be more balanced and average peak heights were higher when using the GlobalFiler(r) kit. However, the data also show that the Investigator(r) kit may be more tolerant to common PCR inhibitors. While both STR kits showed a decrease in alleles as the inhibitor concentration increased, more complete profiles were obtained when the Investigator(r) kit was used. Of the 11 bone and decomposed tissue samples tested, 8 resulted in more complete and balanced STR profiles when amplified with the GlobalFiler(r) kit. PMID- 29501859 TI - Career intentions of PhD students in nursing: A cross-sectional survey. AB - BACKGROUND: Despite the rapid growth of Chinese nursing PhD programs, little is known about the career intentions of students in this field. OBJECTIVE: To investigate the career intentions of nursing PhD students. DESIGN: Online cross sectional survey. PARTICIPANTS: Nursing PhD students at Chinese universities. METHODS: An online questionnaire was designed and the data were analyzed using SPSS. RESULTS: The mean age of the participants was 31.53 +/- 4.92 years, and most were female (89.9%), married (74.2%), and had been employed previously (69.7%). Most intended to work in the city where their family lived (34.8%) or near their previous workplace (32.6%). Most (60.7%) desired to work in an educational institution (e.g., a university or college). The most common expected salary was 8000-11,999 RMB/month. The work benefits perceived as indispensable were "Five Insurances and One Fund" (77.5%), good educational resources for children (59.6%), financial allowances for PhD graduates (52.8%), staff dormitories/housing subsidies (50.6%), and tenure (50.6%). Nursing education (75.3%) and research (70.8%) were the most favored fields. The key job characteristics were the opportunity to put strengths to fullest use (79.8%), time to conduct research (60.7%), and work-life balance (51.7%). The key research conditions included a good research incentive mechanism (77.5%), a Basic Scientific Research Foundation (68.5%), opportunity to apply to conduct research projects (66.3%), and the nursing team's atmosphere regarding research (64.0%), and 91.0% were eager to study abroad (e.g., as part of an international exchange). CONCLUSIONS: Nursing PhD students would like to work in their hometown or near their previous workplace. Most preferred working in an educational institution, and the most popular fields were nursing education and research (rather than clinical care), despite the high demand of hospital management for nursing PhD graduates. Flexible work, high-quality research conditions, a certain salary, work benefits, and training were key expectations. PMID- 29501860 TI - Efficient glycosylation of natural Danshensu and its enantiomer by sugar and 2 deoxy sugar donors. AB - An efficient methodology of the glycosylation process of a secondary plant metabolite (R-Danshensu) and its enantiomer by sugar and 2-deoxy sugar donors was developed. The overall synthesis of the new sugar derivatives involved two steps, starting from the previously synthesized protected R and S Danshensu (1 and 2). The deoxy sugar derivatives of R and S Danshensu were obtained from available tri O-acetyl-2-deoxy-D-glucal and di-O-acetyl-2-deoxy-D-ramnal. The direct glycosylation of 1 and 2 using glycal activation by an acid catalyst in all cases led to the alpha-anomers of deoxy sugar derivatives with good yields. As a result, a novel group of sugar and deoxy sugar conjugates with optically pure polyphenolic acids was successfully synthesized and their cytotoxic profile against two cancer cell lines was tested. An advantageous ADME profile and antiproliferative data classified this new group of compounds as a promising scaffold for further modification of more potent and selective anticancer agents. PMID- 29501861 TI - Synthesis of novel sugar or azasugar modified anthra[1,2-d] imidazole-6,11-dione derivatives and biological evaluation. AB - A series of novel, sugar or azasugar modified anthra[1,2-d] imidazole-6,11-dione derivatives, with different side chain were synthesized, using the synthetic route of imidazole cyclization reaction of 1,2-diaminoanthraquinone with various sugar (azasugar)-derived aldehydes, and imidazole cyclization reaction of 1,2 diaminoanthraquinone with chloroacetic acid and then followed by the nucleophilic substitution of N-alkylamino azasugar. Their biological activities against HIV-RT and cytotoxic activities against A549, Hela and MCF-7 cells were preliminary evaluated, most compounds showed similar HIV-RT inhibition to the control drug (AZT). PMID- 29501862 TI - Configuration-dependent complex formation between Ca(II) and sugar carboxylate ligands in alkaline medium: Comparison of L-gulonate with D-gluconate and D heptaguconate. AB - The calcium sugar carboxylate interactions in hyperalkaline solutions are of relevance in radioactive waste repositories and in certain industrial processes. The complex formation between L-gulonate and Ca2+ ions was studied in strongly alkaline medium at 25 degrees C and 1 M ionic strength and was compared with previous results reported for D-gluconate and D-heptagluconate. The deprotonation of the ligand was confirmed by potentiometric and 13C NMR spectroscopic measurements. Pronounced pH effects were seen in the presence of Ca2+ indicating strong complex formation. By the evaluation of the experimental data, two highly stable trinuclear species, Ca3Gul2H-3+ and the Ca3Gul2H-40, are formed in alkaline aqueous solutions. Polarimetric as well as 1H NMR spectroscopic measurements attested that the increased complex stability was due to the formation of strong metal ion - alcoholate interactions. Moreover, the 1H NMR spectra of the three anions refer to the role of configuration in metal ion binding. That is, the participation of the C3-OH or C4-OH group is governed by the relative position (i.e., threo or erythro) of the C2-OH and C3-OH groups. PMID- 29501863 TI - The in vitro pharmacology and non-clinical cardiovascular safety studies of a novel 5-HT4 receptor agonist, DSP-6952. AB - The pharmacological activity of DSP-6952, a novel compound was investigated, compared to that of clinically efficacious gastrointestinal (GI) prokinetic 5 hydroxytryptamine4 (5-HT4) receptor agonists. DSP-6952 had a strong affinity of Ki = 51.9 nM for 5-HT4(b) receptor, and produced contraction in the isolated guinea pig colon with EC50 of 271.6 nM and low intrinsic activity of 57%, similar to tegaserod and mosapride. In the development of the 5-HT4 receptor agonists, cardiovascular risk was deliberately evaluated, because some related prokinetics were reported to cause with cardiovascular adverse events, such as ventricular arrhythmias or ischemia. DSP-6952 showed minimal effects up to 100 MUM in human ether-a-go-go-related gene (hERG) channels or guinea pig cardiomyocytes. In telemetered conscious monkeys, DSP-6952 did not affect blood pressure or any electrocardiogram (ECG) up to 180 mg/kg, p.o.; however, DSP-6952 transiently increased heart rate, as well as in anesthetized dogs. The positive chronotropic effects of DSP-6952 were completely antagonized by a 5-HT4 receptor antagonist, and another 5-HT4 receptor agonist, TD-5108 also increased heart rate. These effects are considered a class effect seen in clinically developing and marketed 5-HT4 receptor agonists, and have not been regarded as a critical issue in clinical use. DSP-6952 did not induce contraction in the rabbit coronary artery up to 100 MUM, which differed from tegaserod or sumatriptan. These results show that DSP-6952 does not have cardiac ischemic risk via coronary vasoconstriction. In conclusion, DSP-6952 is a promising GI prokinetic compound with partial 5-HT4 receptor agonistic activity as well as a favorable cardiovascular safety profile. PMID- 29501864 TI - Autophagy is a major mechanism for the dual effects of curcumin on renal cell carcinoma cells. AB - The aim of this study was to explore the effects of curcumin on renal cell carcinoma(RCC) through regulating autophagy. Cell viabilities were determined by MTT assay in RCC cells after treatment with curcumin at different concentrations for various durations. ATG7 silencing RCC cells were established to test the role of autophagy. The levels of key proteins on autophagy pathway were analyzed by Western blot. We found out that following 24 h curcumin treatment, the viability of RCC cells had an increase at 5 MUM and no significant change at 20 MUM but a decrease at 80 MUM. These effects were affected by the inhibition of autophagy. When pre-incubated with inhibitors of the AMPK and ER stress pathways, the LC3II levels of RCC cells at 5 MUM and 20 MUM of curcumin were significantly decreased; however, when treated with the inhibitor of the oxidative stress pathway, the LC3II levels of RCC cells at 80 MUM were significantly decreased. In conclusion, the present study indicated Curcumin protected cells from death at low concentration but promotes cell death at high concentration. Autophagy played a dual role in curcumin's effects on RCC. The AMPK and ER stress pathways might be involved at low concentrations of curcumin to protect cells, while the oxidative stress pathway might take part in toxicity at high curcumin concentration. PMID- 29501865 TI - Nitric oxide donors for prostate and bladder cancers: Current state and challenges. AB - Nitric oxide (NO) is an endogenous molecule that plays pivotal physiological and pathophysiological roles, particularly in cancer biology. Generally, low concentrations of NO (pico- to nanomolar range) lead to tumor promotion. In contrast, high NO concentrations (micromolar range) have pro-apoptotic functions, leading to tumor suppression, and in this case, NO is involved in immune surveillance. Under oxidative stress, inducible NO synthase (iNOS) produces high NO concentrations for antineoplastic activities. Prostate and bladder cancers are the most commonly detected cancers in men, and are related to cancer death in males. This review summarizes the state of the art of NO/NO donors in combating prostate and bladder cancers, highlighting the importance of NO donors in cancer treatment, and the limitations and challenges to be overcome. In addition, the combination of NO donors with classical therapies (radio- or chemotherapy) in the treatment of prostate and bladder cancers is also presented and discussed. The combination of NO donors with conventional anticancer drugs is reported to inhibit tumor growth, since NO is able to sensitize tumor cells, enhancing the efficacy of the traditional drugs. Although important progress has been made, more studies are still necessary to definitely translate the administration of NO donors to clinical sets. The purpose of this review is to inspire new avenues in this topic. PMID- 29501866 TI - The Role of Mitochondria in Methamphetamine-induced inhibitory effects on osteogenesis of Mesenchymal Stem Cells. AB - Methamphetamine (METH) abuse causes significant physical, psychological, and social concerns. Therefore, in this study, we investigated its effects on osteogenic differentiation of mesenchymal stem cells (MSCs). We found that METH dose-dependently affected MSCs viability. Upon osteogenic induction, the 3 and 30 umol/l METH dosages without deleterious effects on MSCs viability resulted in the down-regulation of osteoblastic marker genes (Alp, Bglap, and Runx2), suppression of the protein expression of RUNX2, and decreased ALP activity and mineralization ability. Mitochondria are essential during osteogenesis of MSCs. Our analysis on mitochondrial function revealed that METH decreased ATP production, suppressed the oxygen consumption rate, and depolarized the mitochondrial membrane potential, but it had no significant effects on the protein expression of the five complexes on the respiratory chain. Additionally, METH could impair mitochondrial biogenesis, as demonstrated by decreased mtDNA and down-regulated biogenesis factors. Mitochondrial fusion regulators were also decreased at the mRNA and protein levels. However, mitochondrial fission and mitophagy were not affected. In conclusion, our study revealed that exposure to METH could result in decreased mitochondrial biogenesis and fusion as well as mitochondrial dysfunction, and thus it suppressed the osteogenesis of MSCs. PMID- 29501867 TI - Levetiracetam mitigates lipopolysaccharide-induced JAK2/STAT3 and TLR4/MAPK signaling pathways activation in a rat model of adjuvant- induced arthritis. AB - Levetiracetam (LEV), a novel anti-epileptic drug that has been demonstrated with an anti-inflammatory effect, but the exact mechanisms of its action remain to be fully defined. The present study aimed to evaluate the possible effects of LEV on lipopolysaccharides (LPS)-induced Janus kinase-signal transducers and activators of transcription (JAK/STAT) as well as toll-like receptor 4 (TLR4)/ mitogen activated protein kinase (MAPK) signaling pathways activation in adjuvant induced arthritis (AIA). Rats were allocated into normal control, three arthritic control groups: Complete Freund's Adjuvant (CFA) (0.4 ml/3days/12days), LPS (100 ug/kg/day), CFA+LPS, and three treated groups: CFA+LEV, LPS+LEV and CFA+LPS+LEV. LEV was administered in a dose 50 mg/kg/day for 15 day. After 28 days, tissue samples were collected for assessment of phosphorylated JAK2, STAT3, TLR4, MAPK and cathepsin K quantitative expression in synovium. Additionally, Serum samples were used for biochemical evaluation of interleukin-6 (IL-6), interleukin-1beta (IL-1B), LPS, anti-citrullinated protein antibody (ACPA) and 8 hydroxydeoxyguanosine (8-OHdG). Histopathological and macroscopical examinations of joints were also performed to support our study. Results indicated that LEV exerted its anti-inflammatory effect through inhibiting LPS-dependent phosphorylation of JAK2/STAT3 signaling. It significantly suppressed TLR4 and MAPK expressions, thereby decreasing release of inflammatory cytokines IL-1beta, IL-6.LEV exhibited a potent inhibitory effect on cathepsin K and 8-OHdG parallel to confirmatory histopathological and macroscopical findings. In conclusion, LEV has a powerful therapeutic effect on adjuvant induced arthritis in rats and its mechanisms are strongly related to inhibiting excessive activation of JAK2-STAT3 and TLR4 pathways. This may add a new approach for treatment of RA. PMID- 29501869 TI - Pravastatin improves risk factors but not ischaemic tolerance in obese rats. AB - Statins are effective in management of dyslipidaemia, and a cornerstone of CVD prevention strategies. However, the impacts of their pleiotropic effects on other cardiovascular risk factors and myocardial responses to infarction are not well characterised. We hypothesised that pravastatin treatment in obesity improves lipid profiles, insulin-resistance and myocardial resistance to ischaemia/reperfusion (I/R) injury. Wistar rats were fed a control (C) chow or high carbohydrate and fat diet (HCFD) for 16 weeks with vehicle or pravastatin (prava 7.5 mg/kg/day) treatment for 8 weeks. At 16 weeks HOMAs were performed, blood samples collected and hearts excised for Langendorff perfusions/biochemical analyses. Anti-oxidant activity and proteins regulating mitochondrial fission/fusion and apoptosis were assessed. The HCFD increased body weight (736+/ 15 vs. 655+/-12 g for C; P<0.001), serum triglycerides (2.91+/-0.52 vs. 1.64+/ 0.26 mmol/L for C; P<0.001) and insulin-resistance (HOMA- 6.9+/-0.8 vs. 4.2+/-0.5 for C; P<0.05) while prava prevented diet induced changes and paradoxically increased lipid peroxidation. The HCFD increased infarct size (34.1+/-3.1% vs. 18.8+/-3.0% of AAR for C; P<0.05), which was unchanged by prava in C and HCFD animals. The HCFD decreased cardiac TxR activity and mitochondrial MFN-1 and increased mitochondrial DRP-1 (reducing MFN-1:DRP-1 ratio) and Bax expression, with the latter changes prevented by prava. While unaltered by diet, cytosolic levels of Bax and caspase-3 were reduced by prava in C and HCFD hearts (without changes in cleaved caspase-3). We conclude that obesity, hyper-triglyceridemia and impaired glycemic control in HCFD rats are countered by prava. Despite improved risk factors, prava did not reduce myocardial infarct size, potentially reflecting its complex pleiotropic impacts on cardiac GPX activity and MFN-1, DRP 1, caspase-3 and Bcl-2 proteins. PMID- 29501868 TI - Novel Insights on Notch signaling pathways in liver fibrosis. AB - Liver fibrosis is characterized by an increased and altered deposition of extracellular matrix (ECM) proteins that make up excessive tissue scarring and promote chronic liver injury. Activation of hepatic stellate cells (HSCs) is a pivotal cellular event in the progression of liver fibrosis. However, the mechanisms involved in the development of liver fibrosis are only now beginning to be unveiled. The Notch pathway is a fundamental and highly conserved pathway able to control cell-fate, including cell proliferation, differentiation, apoptosis, regeneration and other cellular activities. Recently, the deregulation of Notch cascade has been found involved in many pathological processes, including liver fibrosis. These data give evidence for a role for Notch signaling in liver fibrosis. In addition,more and more date are available on the role of Notch pathways in the process. Therefore, this review focuses on the current knowledge about the Notch signaling pathway, which dramatically takes part in HSC activation and liver fibrosis, and look ahead on new perspectives of Notch signaling pathway research. Furthermore, we will summarize this new evidence on the different interactions in Notch signaling pathway-regulated liver fibrosis, and support the potentiality of putative biomarkers and unique therapeutic targets. PMID- 29501870 TI - Functional characterization of alpha7 nicotinic acetylcholine and NMDA receptor signaling in SH-SY5Y neuroblastoma cells in an ERK phosphorylation assay. AB - In the present study, the functional properties of alpha7 nicotinic acetylcholine receptors (alpha7 nAChRs) and N-methyl-D-aspartate receptors (NMDARs) endogenously expressed in SH-SY5Y human neuroblastoma cells were characterized in an extracellular-signal regulated kinase (ERK) phosphorylation assay. Both choline and N-methyl-D-aspartate (NMDA) mediated robust concentration-dependent increases in ERK phosphorylation in the SH-SY5Y cells, exhibiting EC50 values in good agreement with those reported for the agonists at recombinant alpha7 nAChRs and NMDARs, respectively. Importantly, the responses evoked by choline (10 mM) and by NMDA (50 MUM) were significantly inhibited by the alpha7-selective antagonist alpha-bungarotoxin (100 nM) and by the NMDAR-selective antagonist MK 801 (50 MUM), respectively. The increased ERK phosphorylation levels observed upon co-application of choline (1, 3, 10 mM) and NMDA (50 MUM) compared to those produced by the two agonists on their own were fully reconcilable with additive effects and did not reveal substantial synergy between alpha7 nAChR and NMDAR signaling. Interestingly, however, the responses evoked by the "choline (10 mM) - NMDA (50 MUM)" combination were almost completely inhibited by alpha-bungarotoxin (100 nM) as well as by MK-801 (50 MUM), suggesting some sort of a link between alpha7 nAChR- and NMDAR-mediated ERK phosphorylation. Finally, oligomeric amyloid beta1-42 peptide (1000 nM) mediated robust inhibition of the ERK phosphorylation induced by choline (10 mM), NMDA (50 MUM) and the "choline (10 mM) - NMDA (50 MUM)" combination. In conclusion, ERK phosphorylation measurements in SH-SY5Y cells provides a robust assay for studies of alpha7 nAChR- and NMDAR-mediating signaling and putative functional interactions between the receptors. PMID- 29501872 TI - Healthcare-associated sepsis and the role of clean hands: When we do not see the trees for the forest. PMID- 29501871 TI - Hypoxia inhibits the regulatory volume decrease in red blood cells of common frog (Rana temporaria). AB - Red blood cells of vertebrates can restore their cellular volume after hyposmotic swelling. The process strictly depends on oxygen availability in the environment. However, the role of hemoglobin in regulation of cell volume recovery is not clear yet. Little is known about the osmotic reactions and regulatory volume decrease of amphibian red blood cells. We investigated volume recovery process in oxygenated (oxyhemoglobin concentration 97 +/- 3% of total hemoglobin) deoxygenated (96 +/- 2% of deoxyhemolobin) and oxidized (47 +/- 2% of methemoglobin, 41 +/- 3% of deoxyhemoglobin) red blood cells of common frog (Rana temporaria) after hyposmotic swelling. Using the low-angle light scattering method we demonstrated the regulatory volume decrease in oxygenated cells and showed that the process was eliminated in hypoxic conditions. Reoxygenation of hypoxic cells restored the regulatory volume decrease. Oxidation of cellular hemoglobin to methemoglobin inhibited the volume recovery response in hyposmotically swollen oxygenated and reoxygenated hypoxic cells. PMID- 29501873 TI - Impact of X/Y genes and sex hormones on mouse neuroanatomy. AB - Biological sex influences brain anatomy across many species. Sex differences in brain anatomy have classically been attributed to differences in sex chromosome complement (XX versus XY) and/or in levels of gonadal sex steroids released from ovaries and testes. Using the four core genotype (4CG) mouse model in which gonadal sex and sex chromosome complement are decoupled, we previously found that sex hormones and chromosomes influence the volume of distinct brain regions. However, recent studies suggest there may be more complex interactions between hormones and chromosomes, and that circulating steroids can compensate for and/or mask underlying chromosomal effects. Moreover, the impact of pre vs post-pubertal sex hormone exposure on this sex hormone/sex chromosome interplay is not well understood. Thus, we used whole brain high-resolution ex-vivo MRI of intact and pre-pubertally gonadectomized 4CG mice to investigate two questions: 1) Do circulating steroids mask sex differences in brain anatomy driven by sex chromosome complement? And 2) What is the contribution of pre- versus post pubertal hormones to sex-hormone-dependent differences in brain anatomy? We found evidence of both cooperative and compensatory interactions between sex chromosomes and sex hormones in several brain regions, but the interaction effects were of low magnitude. Additionally, most brain regions affected by sex hormones were sensitive to both pre- and post-pubertal hormones. This data provides further insight into the biological origins of sex differences in brain anatomy. PMID- 29501874 TI - Decoding the neural signatures of emotions expressed through sound. AB - Effective social functioning relies in part on the ability to identify emotions from auditory stimuli and respond appropriately. Previous studies have uncovered brain regions engaged by the affective information conveyed by sound. But some of the acoustical properties of sounds that express certain emotions vary remarkably with the instrument used to produce them, for example the human voice or a violin. Do these brain regions respond in the same way to different emotions regardless of the sound source? To address this question, we had participants (N = 38, 20 females) listen to brief audio excerpts produced by the violin, clarinet, and human voice, each conveying one of three target emotions-happiness, sadness, and fear-while brain activity was measured with fMRI. We used multivoxel pattern analysis to test whether emotion-specific neural responses to the voice could predict emotion-specific neural responses to musical instruments and vice versa. A whole-brain searchlight analysis revealed that patterns of activity within the primary and secondary auditory cortex, posterior insula, and parietal operculum were predictive of the affective content of sound both within and across instruments. Furthermore, classification accuracy within the anterior insula was correlated with behavioral measures of empathy. The findings suggest that these brain regions carry emotion-specific patterns that generalize across sounds with different acoustical properties. Also, individuals with greater empathic ability have more distinct neural patterns related to perceiving emotions. These results extend previous knowledge regarding how the human brain extracts emotional meaning from auditory stimuli and enables us to understand and connect with others effectively. PMID- 29501875 TI - Recovering task fMRI signals from highly under-sampled data with low-rank and temporal subspace constraints. AB - Recent developments in highly accelerated fMRI data acquisition have employed low rank and/or sparsity constraints for image reconstruction, as an alternative to conventional, time-independent parallel imaging. When under-sampling factors are high or the signals of interest are low-variance, however, functional data recovery can be poor or incomplete. We introduce a method for improving reconstruction fidelity using external constraints, like an experimental design matrix, to partially orient the estimated fMRI temporal subspace. Combining these external constraints with low-rank constraints introduces a new image reconstruction model that is analogous to using a mixture of subspace decomposition (PCA/ICA) and regression (GLM) models in fMRI analysis. We show that this approach improves fMRI reconstruction quality in simulations and experimental data, focusing on the model problem of detecting subtle 1-s latency shifts between brain regions in a block-design task-fMRI experiment. Successful latency discrimination is shown at acceleration factors up to R = 16 in a radial Cartesian acquisition. We show that this approach works with approximate, or not perfectly informative constraints, where the derived benefit is commensurate with the information content contained in the constraints. The proposed method extends low-rank approximation methods for under-sampled fMRI data acquisition by leveraging knowledge of expected task-based variance in the data, enabling improvements in the speed and efficiency of fMRI data acquisition without the loss of subtle features. PMID- 29501876 TI - T1 white/gray contrast as a predictor of chronological age, and an index of cognitive performance. AB - Knowing the maturational schedule of typical brain development is critical to our ability to identify deviations from it; such deviations have been related to cognitive performance and even developmental disorders. Chronological age can be predicted from brain images with considerable accuracy, but with limited spatial specificity, particularly in the case of the cerebral cortex. Methods using multi modal data have shown the greatest accuracy, but have made limited use of cortical measures. Methods using complex measures derived from voxels throughout the brain have also shown great accuracy, but are difficult to interpret in terms of cortical development. Measures based on cortical surfaces have yielded less accurate predictions, suggesting that perhaps cortical maturation is less strongly related to chronological age than is maturation of deep white matter or subcortical structures. We question this suggestion. We show that a simple metric based on the white/gray contrast at the inner border of the cortex is a good predictor of chronological age. We demonstrate this in two large datasets: the NIH Pediatric Data, with 832 scans of typically developing children, adolescents, and young adults; and the Pediatric Imaging, Neurocognition, and Genetics data, with 760 scans of individuals in a similar age-range. Further, our usage of an elastic net penalized linear regression model reveals the brain regions which contribute most to age-prediction. Moreover, we show that the residuals of age prediction based on this white/gray contrast metric are not merely random errors, but are strongly related to IQ, suggesting that this metric is sensitive to aspects of brain development that reflect cognitive performance. PMID- 29501878 TI - A case of 28 seconds asystole after a stimulus for modified electroconvulsive therapy. PMID- 29501877 TI - Comparative biological impacts of an aerosol from carbon-heated tobacco and smoke from cigarettes on human respiratory epithelial cultures: A systems toxicology assessment. AB - The biological impact of an aerosol of a potential modified-risk tobacco product, carbon heated tobacco product 1.2 (CHTP1.2), was comprehensively assessed for the first time in vitro using human small airway and nasal epithelial models following a systems toxicology approach. The potentially reduced effects of CHTP1.2 aerosol exposure were benchmarked against those of 3R4F cigarette smoke at similar nicotine concentrations. Experimental repetitions were conducted for which new batches of small airway and nasal cultures were exposed to CHTP1.2 aerosol or 3R4F smoke for 28 minutes. The biological impacts were determined based on a collection of endpoints including morphology, cytotoxicity, proinflammatory mediator profiles, cytochrome P450 1A1/1B1 activity, global mRNA and microRNA changes and proteome profiles. Alterations in mRNA expression were detected in cultures exposed to CHTP1.2 aerosol, without noticeable morphological changes and cytotoxicity, and minimal impact on proinflammatory mediator and proteome profiles. The changes linked to CHTP1.2 aerosol exposure, when observed, were transient. However, the impact of 3R4F smoke exposure persisted long post exposure and greater than CHTP1.2 aerosol. Morphological changes were observed only in cultures exposed to 3R4F smoke. The lower biological effects of CHTP1.2 aerosol than 3R4F smoke exposure were observed similarly in both small airway and nasal epithelial cultures. PMID- 29501880 TI - Controlled elevation of intraocular pressure and its impact on ocular aberrations in healthy eyes. PMID- 29501879 TI - Negative regulation of lens fiber cell differentiation by RTK antagonists Spry and Spred. AB - Sprouty (Spry) and Spred proteins have been identified as closely related negative regulators of the receptor tyrosine kinase (RTK)-mediated MAPK pathway, inhibiting cellular proliferation, migration and differentiation in many systems. As the different members of this antagonist family are strongly expressed in the lens epithelium in overlapping patterns, in this study we used lens epithelial explants to examine the impact of these different antagonists on the morphologic and molecular changes associated with fibroblast growth factor (FGF)-induced lens fiber differentiation. Cells in lens epithelial explants were transfected using different approaches to overexpress the different Spry (Spry1, Spry2) and Spred (Spred1, Spred2, Spred3) members, and we compared their ability to undergo FGF induced fiber differentiation. In cells overexpressing any of the antagonists, the propensity for FGF-induced cell elongation was significantly reduced, indicative of a block to lens fiber differentiation. Of these antagonists, Spry1 and Spred2 appeared to be the most potent among their respective family members, demonstrating the greatest block in FGF-induced fiber differentiation based on the percentage of cells that failed to elongate. Consistent with the reported activity of Spry and Spred, we show that overexpression of Spry2 was able to suppress FGF-induced ERK1/2 phosphorylation in lens cells, as well as the ERK1/2 dependent fiber-specific marker Prox1, but not the accumulation of beta crystallins. Taken together, Spry and Spred proteins that are predominantly expressed in the lens epithelium in situ, appear to have overlapping effects on negatively regulating ERK1/2-signaling associated with FGF-induced lens epithelial cell elongation leading to fiber differentiation. This highlights the important regulatory role for these RTK antagonists in establishing and maintaining the distinct architecture and polarity of the lens. PMID- 29501881 TI - Validation of IgY for the diagnosis of Streptococcus agalactiae-caused endocarditis and bacterial meningitis in Nile tilapia (Oreochromis niloticus). AB - Streptococcus agalactiae (Sta), which belongs to Lancefield group B, causes sepsis, endocarditis and bacterial meningitis in human neonates and Nile tilapia. Because the pathophysiology of Sta infection is partially similar in both species, the identification of biomarkers for the diagnosis and study of this disease is of importance for human and animal health. Therefore, in the present study, we produced an immunoglobulin Y (IgY) by immunizing laying hens with Sta proteins and evaluated its ability to detect Sta in paraffinized tilapia brain and cardiac tissue by direct immunofluorescence (IMF) and indirect immunohistochemistry (IHC). The IgY produced was effective in the diagnosis of Sta infection in Nile tilapia, justifying the use of this species as a biomodel for the study of this disease. PMID- 29501882 TI - Molecular cloning of a C-type lectin from Portunus trituberculatus, which might be involved in the innate immune response. AB - C-type lectin plays an important role in the innate immune response of crustaceans including Portunus trituberculatus which is an important marine species. In the present study, we cloned the full length of a C-type lectin (designated as PtCTL4) from P. trituberculatus via 3'RACE. The full length of the nucleic acid sequence has a length of 654 bp including an open reading frame (ORF) of 480 bp. PtCTL4 possesses conserved CTL features, while containing a CRD domain with Ca2+ binding site 2 and six conserved cysteine residues. Quantitative RT-PCR analysis showed that PtCTL4 expression level was highest in the hepatopancreas, while it was relatively low in other tissues such as hemocytes, eyestalk, muscle, and gonad. The expression level of PtCTL4 reached a maximum at 3 h after challenge with Vibrio alginolyticus, then decreased to the lowest level at 12 h, and returned to normal level at 48 h. Hemagglutination analysis showed that the recombinant PtCTL4 (rPtCTL4) can agglutinate rabbit erythrocyte. The rPtCTL4 can agglutinate Gram-positive bacteria (Bacillus aquimaris, Micrococcus lysodeik, and Staphylococcus aureus) and Gram-negative bacteria (Aeromonas hydrophila, V. alginolyticus, and Chryseobacterium indologenes) in the presence of Ca2+. This study indicated that PtCTL4 acts as a pattern recognition receptor in the innate immune response of P. trituberculatus. PMID- 29501883 TI - Positive pharmacologic provocative testing with methohexital during cerebral arteriovenous malformation embolization. AB - A middle-aged patient underwent staged endovascular embolization of a Spetzler Martin grade V right parietal arteriovenous malformation(AVM).In the fifth endovascular embolization, after methohexital 10 mg injection into a right posterior choroidal artery feeding the AVM nidus, there was an immediate change in the electroencephalogram (EEG) with simultaneous loss of motor evoked potentials (MEPs) in the bilateral upper and lower extremities and a delayed change in somatosensory evoked potential responses (SSEPs). No embolization was made and procedure was terminated. This case demonstrates the utility of intraoperative neurophysiologic monitoring (IONM) with pharmacologic provocative testing in predicting and mitigating the risks prior to the proposed embolization. PMID- 29501884 TI - Partitioning of Ag and CeO2 nanoparticles versus Ag and Ce ions in soil suspensions and effect of natural organic matter on CeO2 nanoparticles stability. AB - This study examined the solid-liquid distribution of 14.8-nm Ag and 6.2-nm CeO2 nanoparticles in soil suspensions and compared it to that of Ag+ and Ce3+ ions, to better understand their environmental behaviour and fate. After 24 h incubation, more than 51% or 29% of the spiked amounts of Ag or CeO2 nanoparticles, respectively, can be retrieved in the liquid phase of (re)suspended soils. The Ag or Ce concentration remaining in solution depends on the incubation time and was influenced by soil properties. Significant correlations are obtained between, on the one hand, the relative amounts of Ag or CeO2 nanoparticles in suspension and the soil-pH, CEC, texture, suspended matter, nitrogen, phosphorus, TOC and main and trace elements content on the other hand. The presence of dissolved natural organic matter stabilizes CeO2 nanoparticles in the aqueous phase. In soil suspensions, Ag+ and Ce3+ ions seemingly interact more strongly with soil constituents compared to their nanoparticle counterparts, rendering the Ag and CeO2 nanoparticles to be more stable and potentially bioavailable. PMID- 29501885 TI - Start-up and long-term performance of anammox moving bed biofilm reactor seeded with granular biomass. AB - Availability of granular anammox sludge is much higher than biofilm seed carriers and the sludge is easier to transport. This paper describes and investigates a formation of mature anammox biofilm originated from granular sludge and proves that an anammox moving bed biofilm reactors (MBBR) can be easily and quickly started-up by seeding with granular sludge. The reactor was fed with synthetic wastewater containing ammonium and nitrite. Successful start-up was completed in as little as 50 days when TN removal increased to more than 80%. Surface nitrogen loading rate during start-up was equal to 0.75 g m-2 d and was stepwise increased up to 5.3 g m-2 d. Biofilm thickness reached 1269 +/- 444 MUm at the end of the study with specific anammox activity of 22.0 +/- 2.1 mg N g-1 VSS h. This study shows that granular biomass can be transitioned to a biofilm relatively easily which opens a new window of opportunity for starting-up anammox MBBRs. PMID- 29501886 TI - Response of regional agricultural soil phosphorus status to net anthropogenic phosphorus input (NAPI) determined by soil pH value and organic matter content in subtropical China. AB - Exploring the relationship between net anthropogenic phosphorus input (NAPI) and soil available P (SAP) content could inform applied issues related to environmental quality and agronomic productivity and increase our knowledge of element biogeochemical cycles. Here, the NAPI was estimated and the SAP content determined in eight counties in subtropical China from 1980 to 2010. It is suggested that the NAPI ranging 318-924 km-2 yr-1 in 1980 had increased substantially to 865-3601 km-2 yr-1 in 2010 across the eight counties, in which the P fertilizer application was estimated to represent the largest individual source of NAPI, accounting for an average of 36.1-74.6% of the NAPI. The NAPI in agricultural land (NAPIa) was the largest component of the NAPI, and 60.7-77.1% of the NAPIa accumulated in the upper 20 cm layer of agricultural soils, which significantly increased soil total-P (TP) and SAP contents. The increases in SAP, resulting from 10,000 kg P km-2 of the NAPIa (IOPNAPI), were estimated to be 1.61 4.36 mg P kg-1 in the counties. Both the correlation and variation partitioning analyses (VPAs) suggested that the soil pH and organic matter content (SOM) were the most important factors influencing the variations of IOPNAPI (determination coefficient: 72.5%). Therefore, the contribution of soil pH and SOM should be considered in enriching soil SAP levels and implementing optimal P management strategies to improving the agronomic effectiveness of P fertilization and further reduce the environmental risk of P loss in subtropical region. PMID- 29501887 TI - Novel synergistic hydrous iron-nickel-manganese (HINM) trimetal oxide for hazardous arsenite removal. AB - A novel hydrous iron-nickel-manganese (HINM) trimetal oxide was successfully fabricated using oxidation and coprecipitation method for metalloid arsenite removal. The atomic ratio of Fe:Ni:Mn for this adsorbent is 3:2:1. HINM adsorbent was identified as an amorphous nanosized adsorbent with particle size ranged from 30 nm to 60 nm meanwhile the total active surface area and pore diameter of HINM area of 195.78 m2/g and 2.43 nm, respectively. Experimental data of arsenite adsorption is best fitted into pseudo-second order and Freundlich isotherm model. The maximum adsorption capacity of arsenite onto HINM was 81.9 mg/g. Thermodynamic study showed that the adsorption of arsenite was a spontaneous and endothermic reaction with enthalpy change of 14.04 kJ/mol and Gibbs energy of -12 to -14 kJ/mol. Zeta potential, thermal gravimetric (TGA) and Fourier transform infrared (FTIR) analysis were applied to elucidate the mechanism of arsenite adsorption by HINM. Mechanism of arsenite adsorption by HINM involved both chemisorption and physisorption based on the electrostatic attraction between arsenite ions and surface charge of HINM. It also involved the hydroxyl substitution by arsenite ions through the formation of inner-sphere complex. Reusability of HINM trimetal oxide was up to 89% after three cycles of testing implied that HINM trimetal oxide is a promising and practical adsorbent for arsenite. PMID- 29501888 TI - Occurrence and levels of glyphosate and AMPA in shallow lakes from the Pampean and Patagonian regions of Argentina. AB - Glyphosate (N-(phosphonomethyl)glycine) is a broad-spectrum systemic herbicide used to kill weeds that compete with commercial crops. In Argentina, the use of glyphosate-based herbicides increased dramatically (up to ~200,000 tons on 2012) since the introduction of glyphosate-resistant crops, such as transgenic soy and resistant corn, and the adoption of non-till practices in the 1990's. Sallow lakes within the Pampa region may be potentially impacted by continuous herbicide usage. We surveyed 52 shallow lakes from the Pampa region (Buenos Aires Province, Argentina) to assess the occurrence and concentrations of glyphosate and its main degradation product (AMPA). For comparison, we also sampled 24 shallow lakes from an area with no agricultural use of glyphosate (Northern Patagonia). Glyphosate and AMPA were analyzed by UPLC-MS/MS ESI (+/-) in lake water, suspended particulate matter (SPM), and sediment samples. Within the Pampa region, glyphosate residues were detected in >40% of samples. Glyphosate residues were detected more frequently in sediment and surface water than in SPM samples. The mean (maximum) concentrations of glyphosate were 2.11 (4.52) MUg l-1 for surface water; 0.10 (0.13) MUg l-1 for SPM and 10.47 (20.34) MUg kg-1 for sediment samples, respectively. Whereas, mean (maximum) concentrations of AMPA were 0.84 and (0.90) MUg l-1 for surface water; 0.07 (0.07) MUg l-1 for SPM; and 22.53 (32.89) MUg kg-1 for sediment samples. The herbicide was not detected in samples from the Patagonian region. To our knowledge, this is the first study reporting the occurrence and concentrations of the herbicide in freshwater lakes of Argentina. PMID- 29501889 TI - Signals of pollution revealed by trace elements in recent snow from mountain glaciers at the Qinghai-Tibetan plateau. AB - In order to extract pollution signal of trace elements (TEs) in glacier snow at the Qinghai-Tibetan plateau of China by human activities, concentrations of 18 TEs (Al, Ti, Fe, Rb, Sr, Ba, V, Cr, Mn, Li, Cu, Co, Mo, Cs, Sb, Pb, Tl, and U), 14 rare earth elements (La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu), Y and Th in digested snow samples from five glaciers in April-May 2013 before monsoon season were measured. Results shown that higher TEs concentrations were found in glaciers at the northern plateau while lower concentrations in glaciers at the central and southern plateau. Discussion revealed that EF values calculated from elements with mass fraction <30% such as Ti and Al, etc in traditional acid leached samples, will overestimate at least 4.6 times the contribution of other sources than dust for TEs such as Sb, Sr, As, Cu and Pb etc. Analysis indicated that most TEs mainly originated from dust sources, whereas Pb, Cu, Mo and Sb showed occasionally significant contributions from polluted sources in three snow pits and the GRHK surface snow samples. The pollution probably originated from mining and smelting, road transport emissions on the plateau and some regions outside of the plateau. Dust provenance tracing results based on REEs indicated that Taklimakan Desert, Qaidam Basin, and Tibetan surface soil were the potential dust sources for the studied glaciers, while the Indian Thar Desert was an occasional dust sources for YZF,XDKMD and GRHK snow samples. PMID- 29501890 TI - Distribution, sources, and air-soil exchange of OCPs, PCBs and PAHs in urban soils of Nepal. AB - Due to the high temperature and extensive use of organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs) and polycyclic aromatic hydrocarbons (PAHs), tropical cities could act as secondary sources of these pollutants and therefore received global concern. As compared with other tropical cities, studies on the air-soil exchange of OCPs, PCBs and PAHs in tropical Nepali cities remained limited. In the present study, 39 soil samples from Kathmandu (capital of Nepal) and 21 soil samples from Pokhara (second largest city in Nepal) were collected The soil concentrations of the sum of endosulfans (alpha- and beta endosulfans) ranged from 0.01 to 16.4 ng/g dw. Meanwhile, ?dichlorodiphenyltrichloroethane (DDTs) ranged from 0.01 to 6.5 ng/g dw; ?6PCBs from 0.01 to 9.7 ng/g dw; and ?15PAHs from 17.1 to 6219 ng/g dw. High concentrations of OCPs were found in the soil of commercial land, while, high soil PAH concentrations were found on tourist/religious and commercial land. Combined the published air concentrations, and the soil data of this study, the directions and fluxes of air-soil exchange were estimated using a fugacity model. It is clear that Nepal is a country contributing prominently to secondary emissions of endosulfans, hexachlorobenzene (HCB), and low molecular weight (LMW) PCBs and PAHs. The flux for all the pollutants in Kathmandu, with ?endosulfans up to 3553; HCB up to 5263; and ?LMW-PAHs up to 24378 ng m-2 h-1, were higher than those in Pokhara. These high flux values indicated the high strength of Nepali soils to act as a source. PMID- 29501891 TI - A phenomenological reaction kinetic model for Cu removal from aqueous solutions by zero-valent iron (ZVI). AB - Zero-valent iron (ZVI) being an inexpensive and eco-friendly catalyst has drawn great attention in removal of heavy metals from wastewaters. However, quantitative understandings of ZVI processes are significantly deficient. To compensate for the lack of quantitative analyses of removal of heavy metals by ZVI, a phenomenological reaction kinetic model was newly developed for removal of Cu chosen as a typical heavy metal from acidic aqueous solutions by ZVI. The novel kinetic model is based on the adsorption of Cu2+ and H+ onto ZVI surface and subsequent Cu2+ reduction on ZVI surface and Fe2+ elution from ZVI. Batch experiments were conducted to elucidate effects of pH and Cu loading on Cu removal by ZVI in acidic aqueous solutions and to validate the proposed phenomenological reaction kinetic model. The quick and complete removals of 1.57 mM Cu were established in the rage of pH 2-5. Although the maximum Cu removal rate was obtained at pH 4, effects of pH were insignificant. In the range of Cu loading from 0.393 to 4.72 mM, almost complete Cu removals were obtained at pH 4 within 35 min. The changes in concentrations of Cu2+, Fe2+, H+ and dissolved oxygen were strongly linked with each other. They could be successfully simulated by the proposed model with the average correlation coefficient of 0.979. The capability of the phenomenological reaction kinetic model for dynamic simulation of Cu removal by ZVI under acidic conditions was confirmed. PMID- 29501893 TI - Effects of long-term UV-exposure and plant sex on the leaf phenoloxidase activities and phenolic concentrations of Salix myrsinifolia (Salisb.). AB - The accumulation of flavonoids on the leaf surface is a well-characterized protective mechanism against UV-B radiation. Other protective mechanisms, such as the induction of antioxidative enzymes and peroxidase-mediated lignification may also be important. The effects of UV-B radiation have mainly been considered in short-term studies, whereas ecologically more relevant long-term field studies are still rare. Here we examined the effects of long-term exposure to enhanced UV B radiation on the activities of two antioxidative enzymes, polyphenol oxidase (PPO; EC 1.10.2.2 and EC 1.14.18.1) and guaiacol peroxidase (POD; EC 1.11.1.7), as well as the phenolic concentrations in two sexes of the dioecious species, Salix myrsinifolia. After three consecutive growth seasons with enhanced UV-B radiation, we found that PPO activity was decreased by UV radiation in male plants, which might explain their lower UV-B tolerance when compared to female plants. In addition, male plants had higher specific activity than did female plants under ambient conditions, supporting the idea that males of S. myrsinifolia are generally more growth-oriented than females. By contrast, neither UV treatment nor sex had significant effects on the POD activities of willows. Gender differences in the concentrations of phenolic compounds are in line with the general concept that males are less well defended than females. We suggest that the inability to increase PPO and POD activity, along with lower accumulation of UV-B absorbing compounds under UV-B exposure, might be one of the reasons why males had thinner leaves and were less tolerant of UV-B than were females. PMID- 29501892 TI - In vivo spatiotemporal dynamics of NG2 glia activity caused by neural electrode implantation. AB - Neural interface technology provides direct sampling and analysis of electrical and chemical events in the brain in order to better understand neuronal function and treat neurodegenerative disease. However, intracortical electrodes experience inflammatory reactions that reduce long-term stability and functionality and are understood to be facilitated by activated microglia and astrocytes. Emerging studies have identified another cell type that participates in the formation of a high-impedance glial scar following brain injury; the oligodendrocyte precursor cell (OPC). These cells maintain functional synapses with neurons and are a crucial source of neurotrophic support. Following injury, OPCs migrate toward areas of tissue injury over the course of days, similar to activated microglia. The delayed time course implicates these OPCs as key components in the formation of the outer layers of the glial scar around the implant. In vivo two-photon laser scanning microscopy (TPLSM) was employed to observe fluorescently-labeled OPC and microglia reactivity up to 72 h following probe insertion. OPCs initiated extension of cellular processes (2.5 +/- 0.4 MUm h-1) and cell body migration (1.6 +/- 0.3 MUm h-1) toward the probe beginning 12 h after insertion. By 72 h, OPCs became activated at a radius of about 190.3 MUm away from the probe surface. This study characterized the early spatiotemporal dynamics of OPCs involved in the inflammatory response induced by microelectrode insertion. OPCs are key mediators of tissue health and are understood to have multiple fate potentials. Detailed spatiotemporal characterization of glial behavior under pathological conditions may allow identification of alternative intervention targets for mitigating the formation of a glial scar and subsequent neurodegeneration that debilitates chronic neural interfaces. PMID- 29501894 TI - Ascophyllum nodosum extract biostimulants and their role in enhancing tolerance to drought stress in tomato plants. AB - Global changes in climate are leading to increased occurrence and duration of drought episodes with concurrent reduction in crop yields. Expansion of the irrigated land area does not appear to be a viable solution in many regions to deliver crop productivity. The development of crop drought tolerance traits by either genetic modification or plant breeding represent the principal approaches to meeting this challenge to date. Biostimulants are an emerging category of crop management products which can enhance crop productivity under abiotic stress conditions. The ability of some biostimulant products such as Ascophyllum nodosum extracts (ANE) to enhance the tolerance of crops to drought stress has been observed by growers. The objective of this study was to investigate if different commercial ANE biostimulants provided the same tolerance to tomato plants (cv. Moneymaker) subjected to a defined drought period. A compositional characterisation of the key macromolecules of ANEs was performed. In addition, the role of ANE biostimulants in inducing changes of chlorophyll and osmolytes levels, MDA production, dehydrin isoform pattern and dehydrin gene expression levels was assessed. The three ANE biostimulants evaluated were found to provide different levels of tolerance to drought stressed tomato plants. The level of drought tolerance provided was related to changes in the concentration of osmolytes and expression of tas14 dehydrin gene. Taken together, our results highlight that despite the fact all ANE biostimulants were manufactured from the same raw material, their ability to maintain crop productivity during and after drought stress was not the same. PMID- 29501895 TI - Immune profile in relation to sex steroid cyclicity in healthy women and women with multiple sclerosis. AB - To prospectively study systemic in vivo immunological effects of sex hormones, using different phases of oral combined hormonal contraceptives (CHC), and the natural menstrual cycles in both healthy women and in women with multiple sclerosis (MS), blood samples from sixty female MS patients and healthy controls with and without CHC were drawn in high and low estrogenic/progestogenic phases. Expression of Th-associated genes in blood cells was determined by qPCR and a panel of cytokines and chemokines was measured in plasma. High hormone level phases were associated with increases in Th1 (TBX21) and Th2 (GATA3) associated markers, as well as the B cell-associated chemokine CXCL13, while the inhibitory regulator CTLA-4 was decreased. These changes were not observed in MS patients, of whom most were treated with immunomodulatory drugs. Our data indicate immune activating properties in vivo of high steroid sex hormone levels during both CHC and normal menstrual cyclicity. PMID- 29501896 TI - Lumbar Arterial Bleeding Treated with Endovascular Aneurysm Repair: A Report of 4 Patients. AB - BACKGROUND: Lumbar arterial bleeding is a severe condition. Surgical exploration is not indicated because of its rich collateral flow. Transarterial embolization (TAE) is reportedly effective, but there have been cases of failure. It may be a time-consuming procedure for patients with multiple bleeding sources or those with poor vital signs. In this case series, we used endovascular aneurysm repair (EVAR) instead of TAE. METHOD: In this case series, we described 4 male patients (2 with traumatic injury, 1 with iatrogenic injury, and 1 with drug-induced hypocoagulability) with lumbar arterial bleeding. The reasons we chose EVAR are because 2 patients had poor vital signs, one patient was a technically difficult case for selective cannulation, and one patient had accompanying aortic dissection. RESULT: In all patients, EVAR was performed successfully, and hemostasis was obtained although one patient died of pneumonia on postoperative day 23. CONCLUSIONS: EVAR is an effective alternative for lumbar arterial bleeding although TAE is a first choice of treatment. PMID- 29501897 TI - Open and Endovascular Repair of Popliteal Artery Aneurysms. AB - BACKGROUND: The purpose of this study was to report midterm outcomes of open repair (OR) or endovascular repair (ER) of popliteal artery aneurysms (PAAs) and assess if outcomes of patients have changed in the endovascular era. METHODS: This monocentric and retrospective study included all consecutive patients treated for PAA between January 2004 and December 2016. Before 2010, all patients underwent OR, but ER was available since 2010, and the choice between OR or ER was made on the basis of clinical presentation and preoperative morphological assessment. Survival, primary patency, primary-assisted patency, secondary patency, and limb salvage rates were assessed regarding the surgical way of treatment (OR or ER) or regarding the period of time (before 2010 or since 2010). RESULTS: A total of 153 PAA were treated in 126 patients (103 limbs in OR and 50 limbs in ER). Mean follow-up was 3.8 years. Five-year survival was 97.7% for OR and 88.7% for ER. Five-year primary patency was 77.8% and 29.5% for OR and ER, respectively, primary-assisted patency 85.0% and 49.7%, respectively, and secondary patency 92.8% and 79.6%, respectively. Five-year limb salvage was 89.5% for OR and 87.9% for ER. No outcome difference was observed between patients who underwent surgery before or after ER was available. CONCLUSIONS: Results of OR and ER in the setting of PAA are satisfactory. Outcomes of patients did not change in the endovascular era. PMID- 29501898 TI - Modified Eversion Carotid Endarterectomy: A 14-Year Experience in a Tertiary Teaching University Hospital in Brazil (South America). AB - BACKGROUND: Carotid endarterectomy is one of the most performed vascular procedures. Since the first reports in the late 1950s, the conventional open and the eversion techniques are the popularized ones. A short extraction or partial eversion technique has been previously described and recently has been subjected to case series reports. The aim of the study was to present the experience of a teaching hospital with modified or partial eversion endarterectomy compared with the experience with conventional open procedure performed exclusively by training vascular surgeons. METHOD: A retrospective review of a consecutive series of cases from January 2002 to June 2016 was performed. RESULTS: There were 355 operations. The mean age was 70 years (range, 41-90), 72.39% were males, and 53.5% were symptomatic. There were 7.3% of contralateral occlusions and 12.1% of contralateral stenosis greater than 70%. General anesthesia was employed in 56% of cases and regional blockage in the remaining cases. A selective shunt was used in 10 patients among those operated with regional blockage (6.9%; 3.1% of the total group of patients) and 1 patient (0.5%) operated with general anesthesia. There were 73 open procedures with primary closure, 23 patch closures, and 259 partial eversion procedures. The mean operation time for the primary closure, patch closure, and eversion techniques were 129.9 min (range, 75-220), 137.5 min (range, 120-160), and 109.7 min (range, 45-230), respectively, with a significant difference (P < 0.0001, Kruskal-Wallis test). The mean clamping time for the same techniques was 23.5 min (range, 13-50), 42 min (range, 20-60), and 17.1 min (range, 9-41), respectively, with a significant difference (P < 0.0001, Kruskal Wallis test). There were 2.25% of transient ischemic events, 2.54% of cerebrovascular accidents, 1.97% of death, and a combined death/cerebrovascular accidents rate of 3.94%, with no statistical difference between the surgical techniques. The incidence of neck hematoma was 5.63% and that of cranial nerve injury was 2.54%. There were 3.66% of patients submitted to late reoperation for restenosis. When results were analyzed according to the academic period of the last year of training, there was no difference regarding time and complications. CONCLUSIONS: Modified or partial eversion endarterectomy seems to be safely performed and applicable for the teaching of new vascular surgeons. PMID- 29501899 TI - Covered Stent Treatment of a Chronically Thrombosed Popliteal Artery Aneurysm in the Setting of Critical Limb Ischemia following Multiple Failed Bypass Operations. AB - Endovascular salvage of failed surgical bypasses has been scantly reported for treatment of infrainguinal occlusive disease. Although catheter-directed thrombolysis and/or mechanical thromboembolectomy have been the mainstay of endovascular salvage of previous bypass grafts, native vessel recanalization remains seldom attempted. Herein, we present a unique approach to native vessel recanalization of a chronically thrombosed popliteal artery aneurysm for nonhealing distal ulceration. PMID- 29501900 TI - Appropriate Use of Venous Imaging and Analysis of the D-Dimer/Clinical Probability Testing Paradigm in the Diagnosis and Location of Deep Venous Thrombosis. AB - BACKGROUND: The D-dimer (DD) level combined with the pretest Wells criteria probability (WCP) score can safely exclude deep venous thrombosis (DVT). The objective of this study was to examine the correlation between DD results alongside WCP score with findings on venous duplex ultrasound (VDU). The hypothesis is that VDU remains overutilized in low-risk patients with negative DD and that higher DD levels may correlate with thrombus burden and location. METHODS: Patients who presented to a high-volume tertiary care center with lower limb swelling with or without associated pain were retrospectively examined through June and July for 4 consecutive years (2012 to 2015). After calculating WCP, patients were divided into low-, moderate-, and high-risk categories. Electronic DD results utilizing enzyme linked immunosorbent assay, WCP data, and VDU analysis data were merged and analyzed based on receiver operator characteristic curve to determine the DD cutoff point for each WCP. Abnormal DD with an average value >= 0.6 mg/L fibrinogen equivalent units (FEUs) was correlated to positive DVT to differentiate proximal DVT (above popliteal vein) from distal DVT (below popliteal vein). RESULTS: Data of 1,909 patients were analyzed, and 239 (12.5%) patients were excluded secondary to serial repeat visits or follow-ups, surveillance screens, and if they had a previous history of DVT. The average age was 62.1 +/- 16.3 years with more women (55.7%) and the majority presented with limb pain and edema (87%). DD studies were ordered and completed in 202 patients and correlated with all positive and negative DVT patients (100% sensitivity and negative predictive value, with specificity and positive predictive value of 14.9% and 15.9%, respectively). Twenty-six of 202 patients had DD that were in the normal range 0.1-0.59 mg/L (FEU), all of which were negative for DVT (100% sensitive). Fifty one of 202 patients had DD values of 0.6-1.2 mg/L FEU, of which only 3 DVTs were recorded, and all of them were distal DVTs. In addition, 685 patients with WCP <1 and negative DD were sent for VDU. Thus, 762 patients had an unnecessary immediate VDU (Wells <=1 and -DD) study during their initial presentation. Potential charge savings for VDU for all patients are 762 * $1,557 = $1,186,434 and DD for all patients are 762 * $182 = $138,684, with total potential savings of $1,047,750 (USD 2016). CONCLUSIONS: This study suggests that DD is still underutilized, and DD in conjunction with WCP could significantly reduce the number of unnecessary immediate VDUs. Higher value of DD (>1.2 mg/L FEU) may raise concern for proximal DVT. Concern on cost effectiveness exists and raises the demand for a proposed algorithm to be followed. PMID- 29501901 TI - Creation of an Arterialized Cephalic Vein as Autologous Bypass for Below-Knee Reconstruction in Critical Limb Ischemia. AB - Two cases of below-knee bypasses using an arterialized cephalic vein (CV) are presented. Both patients had critical ischemia, but no greater or lesser saphenous veins (LSVs) were usable. According to ultrasound, the CVs were thin but regularly positioned. Four weeks after wrist fistula was created, ultrasound showed adequate maturation, and the bypass operations were performed. Both patients had uneventful courses and were discharged after a few days with patent bypasses since then (35 and 18 months). As this report shows, creation of a fistula can be a useful option to gain autologous bypass material in case of critical limb ischemia. PMID- 29501902 TI - Hospital Teaching Status and Readmission after Open Abdominal Aortic Aneurysm Repair. AB - BACKGROUND: Readmission after abdominal aortic aneurysm (AAA) repair to a different (nonindex) hospital has been shown to be associated with high mortality rates. Factors influencing this association remain unknown. The objective of this study was to determine the impact of hospital teaching status on nonindex hospital readmission and mortality. METHODS: An observational analysis of the longitudinally linked California Office of Statewide Health Planning and Development database was conducted from 1995 to 2009. Patients who were readmitted within 30 days after open AAA repair were included. The primary outcome measured was mortality on readmission. RESULTS: Over the 15-year study period, 3,475 readmissions after AAA were analyzed, of which 1,020 (29.4%) were to a nonindex hospital. After adjusting for age, race, gender, insurance, comorbidities, perioperative factors, and reason for readmission, nonindex readmission for patients undergoing their initial operation at a teaching hospital did not impact mortality (odds ratio [OR] 0.78, 95% confidence interval [CI] 0.28-2.17, P = 0.63). Nonindex readmission for patients undergoing their initial operation at a nonteaching hospital, however, significantly increased mortality (OR 1.63, 95% CI 1.04-2.54, P = 0.03). CONCLUSIONS: Readmission to a different hospital is associated with a higher mortality rate for patients undergoing AAA repair at nonteaching hospitals. This effect is not seen in patients having their initial operation performed at teaching hospitals, possibly due to infrastructure at these hospitals allowing for decreased impact from fragmentation of care. In cases where triage to an index hospital for readmission is not possible, communication at a high level between the index hospital and readmission hospital is paramount. PMID- 29501903 TI - Aneurysmal Degeneration of an Aortorenal Bypass for Takayasu Renal Artery Stenosis: A Novel Endovascular Intervention. AB - We report an aneurysm degeneration of a vein graft in a previous aortorenal bypass performed 5 years earlier for severe right renal artery stenosis due to Takayasu arteritis. The patient was a 31-year-old woman who suffered from refractory hypertension. The autogenous bypass adopting great saphenous vein was performed from her infrarenal abdominal aorta to her right renal artery. Five years after the operation, the patient complained vague discomfort in her abdomen. Three-dimensional computed tomography angiography reconstruction demonstrated the existence of an aneurysm with a maximum diameter of 1.5 cm at the distal portion of a previous aortorenal vein graft, and >75% stenosis of the right renal artery. The replacement of a previous vein graft bypass with autograft or artificial graft is reported in literature. In this case, we attempted endovascular procedures by embolization of the aneurysm and revascularization of the right renal artery using coils and Viabahn stents. PMID- 29501904 TI - Distinct Vascular Remodeling Pattern of Adult Rats with Carotid-Jugular Shunt. AB - BACKGROUND: Previous research has revealed that patent vein grafts lose their venous identity Eph-B4 but do not gain arterial identity ephrin-B2 during adaptation to the arterial circulation, and vascular identity marker, for example, the Eph-B4 signaling is a critical determinant of venous wall thickness of vein grafts. But what is the remodeling pattern, especially the remodeling pattern of vascular identity in the venous segment of arteriovenous shunt at a late stage postoperation has not been fully explored. This study was conducted to characterize the remodeling pattern of shear stress, vascular identity, structural composition and morphology, and transcriptional profiles in jugular segment of carotid-jugular (CJ) shunt and/or pulmonary artery (PA), which delivers an increased amount of mixed blood at a late stage postoperation in adult rats. METHODS: CJ shunt was created in adult Wistar rats via end-to-end anastomosis of carotid artery (CA) and jugular vein (JV). At the time of 15 weeks, after hemodynamics test, remodeled jugular segment of CJ shunt, PA, and sham-operated corresponding vessels were isolated. Reverse transcription polymerase chain reaction, microarray, western blot, immunohistochemistry experiments, and morphology analyses were performed. RESULTS: CJ shunt shear stresses have been patterned to some sort of balance with no significant difference in shear stress between carotid segment and jugular segment (P > 0.05). Immunohistochemical analysis reveals that venous identity marker Eph-B4 is lost, but arterial identity markers ephrin-B2 and regulator of G-protein signaling 5 are gained in jugular segment of CJ shunt (P < 0.01), and these 2 arterial identity markers further strengthened in PA (P < 0.01) in shunted rats compared with controls. Jugular segment of CJ shunt undergoes significant intimal hyperplasia with strong expression of smooth muscle cell markers (P < 0.05) and demonstrates a distinct transcriptional profiles which reveals that transcripts of 5 arterial markers are significantly upregulated (P < 0.05 or < 0.01) compared with sham-operated JV; among them, G-protein signaling 5 is exactly the gene with the largest fold change (10.14-fold) in all genes tested by microarray experiment. CONCLUSIONS: Venous identity is lost, but arterial identity is gained in jugular segment of CJ shunt and arterial identity further strengthened in PA in adult shunted rats during late adaptation. PMID- 29501905 TI - Rupture after Previous Endovascular Aneurysm Repair due to Type IA Endoleak: Complete Endograft Preservation Is Feasible with Proximal Suturing, Aortic Neck Banding, and Sac Plication. AB - Rupture of an abdominal aortic aneurysm (AAA) after previous endovascular repair (EVAR) may require endograft explantation and replacement with a prosthetic surgical graft. Recent reports have suggested that total endograft removal during late surgical conversion in the nonruptured setting may not be necessary and that preserving functional parts of the endograft may improve results. Similar techniques may be used for ruptured cases diminishing the magnitude of an already difficult and complex procedure. We describe the successful treatment of a ruptured AAA after previous EVAR with complete endograft preservation by combining transmural endograft fixation with sutures, proximal aortic neck banding, and sac plication. PMID- 29501906 TI - Endovascular Treatment of Femoral Anastomotic Aneurysm: Case Report and Review of Published Cases. AB - Anastomotic aneurysm is a possible complication after arterial reconstruction with highest incidence at femoral anastomosis; open surgery is the standard treatment, but endovascular exclusion can be useful in selected cases. The authors report a case of femoral anastomotic aneurysm, 19 years after aortobifemoral grafting, treated successfully using stent grafts, under local anesthesia and percutaneous brachial access. Review of published articles regarding endovascular management of femoral anastomotic aneurysm was performed. Endovascular exclusion of femoral anastomotic aneurysm is safe and feasible. PMID- 29501907 TI - An Alternative Approach for Treating a Type Ia Endoleak after Conventional EVAR Using the Nellix Endovascular Aneurysm Sealing. AB - BACKGROUND: To report the use of a Nellix endovascular aneurysm sealing (EVAS) device, to successfully treat a type Ia endoleak (EL) after an endovascular aortic repair (EVAR). CASE REPORT: A 70-year-old man was diagnosed with a 90-mm aortic aneurysm, suspicious for being inflammatory. It was initially treated successfully, with a Medtronic Endurant (Medtronic, Minneapolis, MN, USA). Five years after the index endovascular repair, an asymptomatic type Ia EL was detected on duplex ultrasound and computed tomographic angiogram. Other endovascular solutions in the form of proximal cuff, chimney was considered difficult to execute due to challenges in planning, manipulation, and renal cannulation caused by the short proximal sealing zone above the existing stent graft and the constraints of the previous endograft. Thus, a relining of the previous endoprothesis was performed using the Nellix system (Endologix, Inc., Irvine, CA, USA). One-year follow-up imaging demonstrated successful resolution of the EL and persistent sealing of the Nellix device. CONCLUSIONS: Nellix EVAS system can be an alternative and safe option for relining a stent graft with a type Ia EL. Nellix platform can be added to the clinician's armamentarium for treating type Ia EL after conventional EVAR of infrarenal abdominal aortic aneurysm (AAA). PMID- 29501909 TI - Augmentation of the think aloud method with users' perspectives for the selection of a picture archiving and communication system. AB - OBJECTIVES: Users attitude toward a picture archiving and communication system (PACS) and their interaction with this system are among the most important factors that influence its acceptance. This study aimed to augment the user's interaction with the user's perspective to select a usable PACS among three systems available on the market. METHODS: We augmented the think aloud (TA) usability evaluation method with the Post-Study System Usability Questionnaire (PSSUQ) to compare user interaction problems of three PACS user interfaces. Four radiologists and four internist physicians participated in this study. Usability characteristics including efficiency, effectiveness, learnability, error, and satisfaction were used to assess the usability of each PACS. RESULTS: There was a significant difference in efficiency (p = 0.01), effectiveness (p = 0.005), learnability (p = 0.001), and satisfaction (p = 0.009). However, no significant difference in the number of errors (p = 0.18), mouse clicks and keystrokes (p = 0.12), and the number of usability problems (p = 0.6) were observed among the three PACS systems studied. CONCLUSIONS: This study showed that applying the proposed approach to augment TA with the user's perspective addresses almost all of the theoretical aspects of usability and can be employed to select the most usable PACS. PMID- 29501908 TI - Challenges and solutions implementing an SMS text message-based survey CASI and adherence reminders in an international biomedical HIV PrEP study (MTN 017). AB - BACKGROUND: We implemented a text message-based Short Message Service computer assisted self-interviewing (SMS-CASI) system to aid adherence and monitor behavior in MTN-017, a phase 2 safety and acceptability study of rectally-applied reduced-glycerin 1% tenofovir gel compared to oral emtricitabine/tenofovir disoproxil fumarate tablets. We sought to implement SMS-based daily reminders and product use reporting, in four countries and five languages, and centralize data management/automated-backup. METHODS: We assessed features of five SMS programs against study criteria. After identifying the optimal program, we systematically implemented it in South Africa, Thailand, Peru, and the United States. The system consisted of four windows-based computers, a GSM dongle and sim card to send SMS. The SMS-CASI was, designed for 160 character SMS. Reminders and reporting sessions were initiated by date/time triggered messages. System, questions, responses, and instructions were triggered by predetermined key words. RESULTS: There were 142,177 total messages: sent 86,349 (60.73%), received 55,573 (39.09%), failed 255 (0.18%). 6153 (4.33%) of the message were errors generated from either our SMS-CASI system or by participants. Implementation challenges included: high message costs; poor data access; slow data cleaning and analysis; difficulty reporting information to sites; a need for better participant privacy and data security; and mitigating variability in system performance across sites. We mitigated message costs and poor data access by federating the SMS-CASI system, and used secure email protocols to centralize data backup. We developed programming syntaxes to facilitate daily data cleaning and analysis, and a calendar template for reporting SMS behavior. Lastly, we ambiguated text message language to increase privacy, and standardized hardware and software across sites, minimizing operational variability. CONCLUSION: We identified factors that aid international implementation and operation of SMS-CASI for real-time adherence monitoring. The challenges and solutions we present can aid other researchers to develop and manage an international multilingual SMS-based adherence reminder and CASI system. PMID- 29501910 TI - The neuroprotective role of the brain opioid system in stroke injury. AB - Novel neuroprotective therapies are desperately needed to improve neuronal recovery after ischemic stroke and extend the therapeutic window or offset some of the adverse effects of tissue-type plasminogen activator (tPA). These advances could provide a more effective and safe therapeutic regimen for patients with ischemic stroke. The opioid system has gained intense interest over the past few years and is currently being investigated as a viable target for the pharmacological treatment of stroke. In this review, we focus on different opioid receptors (ORs) and their distribution in the central nervous system (CNS), and the effect of ischemic stroke on their redistribution. We also discuss studies involving the use of the selective and nonselective and/or simultaneous targeting of ORs for neuroprotection during ischemic stroke. PMID- 29501911 TI - Approved CAR T cell therapies: ice bucket challenges on glaring safety risks and long-term impacts. AB - Two autologous chimeric antigen receptor (CAR) T cell therapies (KymriahTM and YescartaTM) were recently approved by the FDA. KymriahTM is for the treatment of pediatric patients and young adults with refractory or relapse (R/R) B cell precursor acute lymphoblastic leukemia and YescartaTM is for the treatment of adult patients with R/R large B cell lymphoma. In common, both are CD19-specific CAR T cell therapies lysing CD19-positive targets. Their dramatic efficacy in the short term has been highlighted by many media reports. By contrast, their glaring safety gaps behind the miracles remain much less addressed. Here, we focus on addressing the crucial challenges in relation to the gaps. PMID- 29501912 TI - 'Bioexit': navigating the policy and regulatory pathways for the biotechnology industry in a post-Brexit landscape. AB - The withdrawal of the UK from the European Union (EU) is a complicated event. Although implications vary by industry, the biotechnology sector is especially vulnerable to the consequences of Brexit. Accordingly, here we evaluate potential repercussions under four post-Brexit political pathways: European Economic Area (EEA) affiliation (Norwegian Model); negotiated bilateral access (Swiss Model); limited participation in EU Customs Union (Turkish Model); or independence under the World Trade Organization (WTO) designation. We conclude that all four pathways fail to protect the mutually beneficial UK-EU biotechnology relationship and that alternative pathways need to be explored. Accordingly, we outline a suite of policy mechanisms aimed at ensuring continued EU-UK regulatory synergy, with the central aim of ensuring access to biomedical innovations and ensuring patient safety. PMID- 29501913 TI - The development of glutamate-based antidepressants is taking longer than expected. PMID- 29501914 TI - Foot and ankle kinematics in chronic ankle instability subjects using a midfoot strike pattern when running, including influence of taping. AB - BACKGROUND: Investigate differences in multi-segment foot kinematics between controls and participants with chronic ankle instability during running with a midfoot striking pattern and to evaluate the effect of Low-Dye and High-Dye taping. METHODS: Three-dimensional multi-segment foot kinematics of 12 controls and 15 participants with chronic ankle instability were collected while running barefoot, and in both taping conditions. Ranges of motion occurring at each joint, each sub phase of stance, were compared between groups and between taping conditions (0-dimensional inference). Kinematic data were also compared using one dimensional statistical parametric mapping. FINDINGS: The symptomatic group demonstrated while barefoot running a significantly decreased rearfoot dorsiflexion range of motion during the peak impact phase as well as a less dorsiflexed position from 6 to 12% of the running cycle. During the absorption and generation phase, the symptomatic group also showed a significantly increased rearfoot dorsiflexion and adduction motion as well as an increased midfoot inversion motion. In the peak impact phase of both taping conditions, a decreased midfoot inversion motion was found. The High-Dye taping resulted in a decreased rearfoot plantarflexion motion whereas the Low-Dye caused a decreased midfoot inversion motion. INTERPRETATION: Persons with chronic ankle instability seem to have altered rearfoot and midfoot kinematics while running with a midfoot striking index. High-Dye taping seems to have better therapeutic features than Low-Dye taping. PMID- 29501915 TI - Analysis of the kinetic chain in asymptomatic individuals with and without scapular dyskinesis. AB - BACKGROUND: This study measured strength of the trunk and hip, and compared Y Balance Test and Upper Quarter Y Balance Test in individuals without and with scapular dyskinesis. Strength and endurance of the scapulothoracic muscles were also assessed. METHODS: Forty-four individuals without shoulder pain were divided in 2 groups: without scapular dyskinesis (age 26.00, SD 4.10 years) and scapular dyskinesis (age 23.68, SD 4.20 years). Scapular dyskinesis was assessed by clinical observation of the scapular motion during arm elevation, and was classified as present or absent. A handheld dynamometer was used to measure the isometric strength of the trunk flexors and lateral flexors, hip extensors and abductors, lower trapezius, serratus anterior, and latissimus dorsi. Y and Upper Quarter Y Balance Tests were performed with the individual in single-limb and 3 point plank position, respectively. Endurance of the scapulothoracic muscles was assessed with the individuals in prone with the arm at 135 degrees abduction. Independent t-test and Mann-Witney test were used for comparison between groups. A P < 0.05 was considered significant. Effect sizes between groups were also calculated. FINDINGS: No differences (P > 0.05) were demonstrated between groups for all variables. Moderate effect size (d ~ 0.40) was found for the trunk flexors and hip extensors, and endurance of the scapulothoracic muscles, whereas the scapular dyskinesis group showed less strength and endurance in relation to the group without dyskinesis. INTERPRETATION: Strength of the trunk flexors and hip extensors, and endurance of the scapulothoracic muscles seem to have influence in scapular dyskinesis in non-athletes without shoulder pain. PMID- 29501916 TI - Fluoroquinolone resistance and gyrA mutations in Campylobacter jejuni and Campylobacter coli isolated from chicken in Egypt. PMID- 29501917 TI - Characterisation of a ST100 Staphylococcus epidermidis producing an LnuB nucleotidyltransferase: Evidence for interspecies spread of an lnuB-carrying transposon. PMID- 29501918 TI - Identification of blaDIM-1 metallo-beta-lactamase gene in Pseudomonas aeruginosa isolated from Tamil Nadu, India. PMID- 29501919 TI - Impairment of Left Atrial Mechanics Is an Early Sign of Myocardial Involvement in Systemic Sclerosis. AB - BACKGROUND: Left ventricular (LV) diastolic dysfunction is common in systemic sclerosis (SSc). Less is known, however, about left atrial (LA) mechanics in this context. The aim of this study was to investigate the correlation between LV diastolic function and LA mechanics in SSc patients with the use of volumetric and 2-dimensional speckle tracking-derived strain techniques and to compare the results with those obtained in healthy subjects. METHODS AND RESULTS: Seventy-two SSc patients and 30 healthy volunteers (H) were investigated. LV diastolic function was classified as normal (I), impaired relaxation (II), and pseudonormal pattern (III). LA reservoir (H: 51.8 +/- 7.4%; I: 45.1 +/- 8.1%; II: 42.2 +/- 6.6%; III: 36.6 +/- 7.3%; analysis of variance: P < .001) and contractile strain (H: 24.8 +/- 4.9%; I: 18.2 +/- 4.4%; II: 21.5 +/- 2.8%; III: 16.8 +/- 3.6%; P < .001) already showed significant worsening in SSc patients with preserved LV diastolic function compared with healthy subjects. LA conduit strain (H: 27.1 +/- 4.6%; I: 26.9 +/- 5.7%; II: 20.6 +/- 6.1%; III: 19.5 +/- 5.3%; P < .001) was preserved in this early phase. Further deterioration of reservoir strain was pronounced in the pseudonormal group only. LA contractile strain increased significantly in the impaired relaxation group and then decreased with the further worsening of the LV diastolic function. Regarding phasic volume indices, the differences between groups were not always statistically significant. CONCLUSION: LA mechanics strongly reflects the changes in LV diastolic function in SSc. On the other hand, strain parameters of the LA reservoir and contractile function already show significant worsening in SSc patients with preserved LV diastolic function, suggesting that impairment of the LA mechanics is an early sign of myocardial involvement in SSc. PMID- 29501920 TI - Association of Serum Zinc Level With Prognosis in Patients With Heart Failure. AB - BACKGROUND: Zinc is an essential cofactor for energy transfer and physiological heart function, has antioxidant properties, and is involved in multiple signaling pathways. We aimed to investigate the associations between serum zinc levels with prognosis, as well as underlying cardiac function and exercise capacity, in patients with heart failure (HF). METHODS AND RESULTS: We measured serum zinc levels in 968 consecutive hospitalized patients with decompensated HF, who were divided into 3 groups based on serum zinc levels (ug/dL): first (zinc >=75, n = 323), second (62<= zinc <75, n = 322), and third (zinc <62, n = 323) tertiles. We examined cardiac function and exercise capacity and followed up on all patients. Although cardiac function did not differ among the 3 groups, peak oxygen consumption was significantly lower in the third tertile than in the first and second tertiles (peak oxygen consumption, 14.2 vs 15.9 and 15.2 mL/kg/min, P = .010). In the Kaplan-Meier analysis (mean duration of follow-up 1103 days), cardiac and all-cause mortality was highest in the third tertile compared with the first and second tertiles. In the Cox proportional hazard analysis, serum zinc level was a predictor of cardiac and all-cause mortality. In the subgroup analysis, there were no interactions concerning associations between serum zinc levels with prognosis and other important variables, including age, gender, comorbidities, medications, other micronutrient levels, B-type natriuretic peptide, and left ventricular ejection fraction. The associations between zinc levels with mortality were consistent in all subgroups. CONCLUSION: Decreased serum zinc levels are associated with high mortality, accompanied by impaired exercise capacity. PMID- 29501921 TI - A clinician friendly data warehouse oriented toward narrative reports: Dr. Warehouse. AB - INTRODUCTION: Clinical data warehouses are often oriented toward integration and exploration of coded data. However narrative reports are of crucial importance for translational research. This paper describes Dr. Warehouse(r), an open source data warehouse oriented toward clinical narrative reports and designed to support clinicians' day-to-day use. METHOD: Dr. Warehouse relies on an original database model to focus on documents in addition to facts. Besides classical querying functionalities, the system provides an advanced search engine and Graphical User Interfaces adapted to the exploration of text. Dr. Warehouse is dedicated to translational research with cohort recruitment capabilities, high throughput phenotyping and patient centric views (including similarity metrics among patients). These features leverage Natural Language Processing based on the extraction of UMLS(r) concepts, as well as negation and family history detection. RESULTS: A survey conducted after 6 months of use at the Necker Children's Hospital shows a high rate of satisfaction among the users (96.6%). During this period, 122 users performed 2837 queries, accessed 4,267 patients' records and included 36,632 patients in 131 cohorts. The source code is available at this github link https://github.com/imagine-bdd/DRWH. A demonstration based on PubMed abstracts is available at https://imagine-plateforme-bdd.fr/dwh_pubmed/. PMID- 29501922 TI - Strong carcinogenic stress response induction of preneoplastic cells positive for GST-P in the rat liver: Physiological mechanism for initiation. AB - AIMS: To identify experimental conditions that induce preneoplastic cells positive for glutathione S-transferase P-form (GST-P) in the rat liver by new approaches, and analysis of the mechanism of cancer initiation based on the findings. MAIN METHODS: The experimental protocols employed to induce GST-P+ preneoplastic cells in rat liver were as follows. Protocol 1: adult rats were fed basal diet containing 2-acetylaminofluorene (AAF, 0.02% by wt) and high concentrations of N-acetyl-l-cysteine (0.5%) over 10 weeks. Protocol 2: rats were subjected to partial hepatectomy (2/3PH), followed by an AAF (0.04%) diet for two more weeks. Vibratome-prepared liver sections were then immunostained for GST-P. KEY FINDINGS: GST-P was inducible in the rat liver in response to the strong carcinogenic stress by AAF in the two experimental protocols. When examined immunocytochemically with vibratome sections, the biliary tracts of hepatocytes, GST-P+ single hepatocytes and foci were heavily positive for the marker enzyme in addition to ordinary cytosolic staining of preneoplastic cell populations. The biliary tracts of hepatocytes were severely injured, and the excretory portions of GST-P+ single hepatocytes were significantly injured. SIGNIFICANCE: The cytotoxic action of AAF that give rise to the GST-P+ single hepatocytes was suggested to be an injury to the excretory pump(s) and the duct of hepatocytes. A new physiological mechanism was hypothesized for the induction of preneoplastic cell populations in the rat liver instead of a genetic mechanism. PMID- 29501923 TI - Toll-like receptor expression and apoptosis morphological patterns in female rat hearts with takotsubo syndrome induced by isoprenaline. AB - AIMS: Toll-like receptors (TLR) and apoptosis were indicated as important factors in heart failure. Our aim was to characterize the morphological pattern of apoptosis, TLR2, TLR4, and TLR6 expression in female rat hearts in the model of takotsubo syndrome (TTS). MAIN METHODS: 60 Sprague-Dawley female rats were treated with a single dose of 150 mg/kg b.wt. of isoprenaline (ISO) or 0.9% NaCl (controls). Hearts were collected 24, 48, 72 h and 7 days post-ISO injection. 32/60 hearts were used in immunohistopathological studies and 28/60 in real time. KEY FINDINGS: Apoptosis was observed 24 h post-ISO in cardiomyocytes, 24, 48, 72 h and 7 days post-ISO in infiltrating inflammatory cells, 7 days post-ISO in endothelial cells of vessels. Diffuse TLR4CD68 (CD68, a macrophage marker) and TLR6CD68 positive cells and TLR2, TLR4, TLR6 mononuclear cells were observed in both acute and recovery phase of TTS. In the foci located in the neighborhood of damaged (necrotic/apoptotic) cardiomyocytes in TTS, high (strong) protein expression of TLR2 (TLR2high) was observed: 24, 48, 72 h post-ISO; TLR4high - 48 and 72 h post-ISO; TLR6high - 48 h post-ISO. Whereas in cardiomyocytes of remote myocardium: TLR2high - 72 h post-ISO; TLR4high - 24 and 72 h post-ISO; TLR6high - 24 h post-ISO. TLR2 mRNA was down-regulated 48 and 72 h post-ISO whereas TLR4 up regulated 7 days post-ISO. SIGNIFICANCE: The expression pattern of apoptosis and TLR differs in the course of TTS in comparison with the control rats. We hypothesize that innate immunity and apoptosis may play a crucial role in TTS pathophysiology. PMID- 29501924 TI - Biochemical characterization in Norway spruce (Picea abies) of SABATH methyltransferases that methylate phytohormones. AB - Indole-3-acetic acid (IAA), gibberellins (GAs), salicylic acid (SA) and jasmonic acid (JA) exist in methyl ester forms in plants in addition to their free acid forms. The enzymes that catalyze methylation of these carboxylic acid phytohormones belong to a same protein family, the SABATH methyltransferases. While the genes encoding these enzymes have been isolated from a small number of flowering plants, little is known about their occurrence and evolution in non flowering plants. Here, we report the systematic characterization of the SABATH family from Norway spruce (Picea abies), a gymnosperm. The Norway spruce genome contains ten SABATH genes (PaSABATH1-10). Full-length cDNA for each of the ten PaSABATH genes was cloned and expressed in Escherichia coli. Recombinant PaSABATHs were tested for activity with IAA, GA, SA, and JA. Among the ten PaSABATHs, five had activity with one or more of the four substrates. PaSABATH1 and PaSABATH2 had the highest activities with IAA and SA, respectively. PaSABATH4, PaSABATH5 and PaSABATH10 all had JA as a preferred substrate but with notable differences in biochemical properties. The structural basis of PaSABATHs in discriminating various phytohormone substrates was inferred based on structural models of the enzyme-substrate complexes. The phylogeny of PaSABATHs with selected SABATHs from other plants implies that the enzymes methylating IAA are conserved in seed plants whereas the enzymes methylating JA and SA have independent evolution in gymnosperms and angiosperms. PMID- 29501925 TI - New flavonoids from Portulaca oleracea L. and their activities. AB - Three new compounds, identified as (3S)-5-hydroxy-3-(2-hydroxybenzyl)-7 methoxychroman-4-one, oleracone C (1), 5-hydroxy-3-(2-hydroxybenzyl)-7-methoxy-4H chromen-4-one, oleracone D (2), and 1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(2 hydroxyphenyl)propan-1-one, oleracone E (4), together with one new natural product, 5,7-dimethoxy-4-O-2'-cycloflavan (3) already known from synthesis, and two known compounds, (2S)-5,2'-dihydroxy-7-methoxyflavanone (5) and 2',4' dihydroxy-4,6'-dimethoxychalcone (6) were isolated from the Portulaca oleracea L. for the first time. Their structures were elucidated using spectroscopic methods, including one- and two-dimensional nuclear magnetic resonance, high-resolution electrospray ionization time-of-flight mass spectrometry and circular dichroism spectrometry. Oleracone C (1), D (2) and E (4) presented scavenging activities in 1,1-diphenyl-2-picryl-hydrazyl (DPPH) radical quenching assay, with IC50 values of 23.27, 11.73, 13.17 MUM, respectively and anticholinesterase activities with IC50 values ranging between 59.55 and 78.85 MUM. PMID- 29501926 TI - Energy-based culture medium design for biomanufacturing optimization: A case study in monoclonal antibody production by GS-NS0 cells. AB - Demand for high-value biologics, a rapidly growing pipeline, and pressure from competition, time-to-market and regulators, necessitate novel biomanufacturing approaches, including Quality by Design (QbD) principles and Process Analytical Technologies (PAT), to facilitate accelerated, efficient and effective process development platforms that ensure consistent product quality and reduced lot-to lot variability. Herein, QbD and PAT principles were incorporated within an innovative in vitro-in silico integrated framework for upstream process development (UPD). The central component of the UPD framework is a mathematical model that predicts dynamic nutrient uptake and average intracellular ATP content, based on biochemical reaction networks, to quantify and characterize energy metabolism and its adaptive response, metabolic shifts, to maintain ATP homeostasis. The accuracy and flexibility of the model depends on critical cell type/product/clone-specific parameters, which are experimentally estimated. The integrated in vitro-in silico platform and the model's predictive capacity reduced burden, time and expense of experimentation resulting in optimal medium design compared to commercially available culture media (80% amino acid reduction) and a fed-batch feeding strategy that increased productivity by 129%. The framework represents a flexible and efficient tool that transforms, improves and accelerates conventional process development in biomanufacturing with wide applications, including stem cell-based therapies. PMID- 29501927 TI - Protein engineering of alpha-ketoisovalerate decarboxylase for improved isobutanol production in Synechocystis PCC 6803. AB - Protein engineering is a powerful tool to modify e.g. protein stability, activity and substrate selectivity. Heterologous expression of the enzyme alpha ketoisovalerate decarboxylase (Kivd) in the unicellular cyanobacterium Synechocystis PCC 6803 results in cells producing isobutanol and 3-methyl-1 butanol, with Kivd identified as a potential bottleneck. In the present study, we used protein engineering of Kivd to improve isobutanol production in Synechocystis PCC 6803. Isobutanol is a flammable compound that can be used as a biofuel due to its high energy density and suitable physical and chemical properties. Single replacement, either Val461 to isoleucine or Ser286 to threonine, increased the Kivd activity significantly, both in vivo and in vitro resulting in increased overall production while isobutanol production was increased more than 3-methyl-1-butanol production. Moreover, among all the engineered strains examined, the strain with the combined modification V461I/S286T showed the highest (2.4 times) improvement of isobutanol-to-3M1B molar ratio, which was due to a decrease of the activity towards 3M1B production. Protein engineering of Kivd resulted in both enhanced total catalytic activity and preferential shift towards isobutanol production in Synechocystis PCC 6803. PMID- 29501928 TI - The perspectives of structurally vulnerable people who use drugs on volunteer stipends and work experiences provided through a drug user organization: Opportunities and limitations. AB - BACKGROUND: While drug user organizations (DUO) have received public health attention as a means to potentially reduce the harms associated with drug use, there is a lack of research on the compensation and structural forces that promote or inhibit participation in DUO. Against the backdrop of structural vulnerability experienced by people who use drugs (PWUD), we examined the impact of monetary 'volunteer stipends' provided through a DUO and explore their role in providing low-threshold employment opportunities and shaping participation in DUO. METHODS: Participants were purposively sampled to reflect a range of perspectives and experiences volunteering at Vancouver Area Network of Drug Users (VANDU) and receiving stipends. Semi-structured qualitative interviews were conducted with 23 members of VANDU. Interview transcripts were coded in Atlas.ti 7 for key a priori themes and emergent categories from the data and analyzed thematically. RESULTS: Stipends provided participants with symbolic and material recognition of the time, effort, and expertise they contribute to the organization, and functioned to facilitate ongoing participation. Payments that rewarded, skills, labour and drug-related knowledge reduced participant's perception of stigma against PWUD. Paid work in VANDU further provided participants with non-material benefits commonly attributed to regular employment, including social connections and a sense of purpose. Participants also identified the low level of pay as a limitation of VANDU's paid participation program. The daily demands of survival (accessing shelter, food, and drugs) posed more complex structural vulnerabilities to participate in VANDU, as small stipends were not sufficient to address these needs. CONCLUSION: Low threshold employment opportunities within DUO may provide significant individual and public health benefits. However, these benefits are constrained by the small size of stipends. Therefore, to ensure better inclusion of PWUD, our findings recommend the development and expansion of equitable, accessible, well-paying employment programs for PWUD. PMID- 29501929 TI - Analysis of volatile compounds in Chinese dry-cured hams by comprehensive two dimensional gas chromatography with high-resolution time-of-flight mass spectrometry. AB - A microwave assisted extraction method coupled with solvent assisted flavor evaporation (MAE-SAFE) was used to extract the volatiles from three-selected Chinese dry-cured hams (Jinhua ham, Xuanwei ham and Rugao ham). Extracts were analyzed by comprehensive two-dimensional gas chromatography with high-resolution time-of-flight mass spectrometry (GC * GC/HR-TOFMS), gas chromatography-mass spectrometry (GC-MS), respectively. A total 165 volatile compounds were identified by GC * GC/HR-TOFMS while only 50 compounds were identified by GC-MS. Principal component analysis showed that the specific dominant volatile compounds were [S-(R*,R*)]-2,3-butanediol (26.39%) and 3-methyl-butanoic acid (7.53%) for Jinhua ham, were [R-(R*,R*)]-2,3-butanediol (16.85%) and acetic acid (8.25%) for Rugao ham and were dihydro-4-hydroxy-2(3H)-furanone (11.67%) and hexanoic acid (8.24%) for Xuanwei ham. The results not only provided a fast and mild extraction method to analyze the volatiles in non-volatile food matrices, but also represented the detailed information of volatile profiles of Chinese dry-cured hams. PMID- 29501930 TI - Distribution of fatty acids and phospholipids in different table cuts and co products from New Zealand pasture-fed Wagyu-dairy cross beef cattle. AB - Wagyu beef products are marketed as luxury goods to discerning consumers and the lipid content and composition are important drivers of wagyu product value. Wagyu beef is an extensively marbled meat product, well characterised for its tenderness and flavour. In New Zealand, pasture-fed Wagyu-dairy beef production is increasing to meet demand for ultra-premium meat products. Important for these characteristics is the composition of lipid species and their distribution across the carcass. The aim of this study was to analyse the distribution of fatty acids and phospholipids in 26 table cuts, nine co-products and three fat deposits of carcasses from New Zealand pasture-fed Wagyu-dairy cross beef carcasses (n = 5). Phospholipid and fatty acid levels varied across different cuts of the carcass, but typically cuts with high levels of phospholipids also had high levels of omega-3 fatty acids and low levels of saturated fatty acids. This work will be used in the future to examine the potential health aspects of pasture-fed Wagyu beef. PMID- 29501931 TI - The effects of bioactive edible film containing Terminalia arjuna on the stability of some quality attributes of chevon sausages. AB - The aim of this study was to assess the effectiveness of calcium alginate edible films incorporated with Terminalia arjuna on the lipid oxidative stability and storage quality of chevon sausages. Chevon sausages were aerobically packaged in the edible films containing different concentrations of T. arjuna viz. T1 (0.0%), T2 (0.50%) and T3 (1.0%) and were stored under refrigerated (4+/-1 degrees C) conditions. A significant improvement was observed in the lipid oxidative stability and microbial quality of the products. Products packaged in T2 and T3 films exhibited significantly (P < 0.05) lower values for TBARS (mg malonaldehyde/kg), microbial counts (log cfu/g) and FFA (% oleic acid). Higher (P < 0.05) sensory scores were also observed for the products packaged in T2 and T3 films. This study shows that application of a bioactive edible film incorporated with T. arjuna is an effective strategy in retarding the lipid oxidation and storage changes in meat products. PMID- 29501932 TI - Descriptive analysis of bacon smoked with Brazilian woods from reforestation: methodological aspects, statistical analysis, and study of sensory characteristics. AB - The aim of this study was to perform a descriptive analysis (DA) of bacons smoked with woods from reforestation and liquid smokes in order to investigate their sensory profile. Six samples of bacon were selected: three smoked bacons with different wood species (Eucalyptus citriodora, Acacia mearnsii, and Bambusa vulgaris), two artificially smoked bacon samples (liquid smoke) and one negative control (unsmoked bacon). Additionally, a commercial bacon sample was also evaluated. DA was developed successfully, presenting a good performance in terms of discrimination, consensus and repeatability. The study revealed that the smoking process modified the sensory profile by intensifying the "saltiness" and differentiating the unsmoked from the smoked samples. The results from the current research represent the first methodological development of descriptive analysis of bacon and may be used by food companies and other stakeholders to understand the changes in sensory characteristics of bacon due to traditional smoking process. PMID- 29501933 TI - Delayed diagnosis of post-surgical pyoderma gangrenosum: A multicenter case series and review of literature. AB - INTRODUCTION: Pyoderma gangrenosum is a chronic neutrophilic dermatosis which can occur following trauma or surgery and can mimic infection. Surgical intervention can lead to progression of disease. PRESENTATION OF CASES: This case series describes 3 cases of post-surgical pyoderma gangrenosum with delayed diagnosis from two large medical centers. DISCUSSION: Epidemiology, pathogenesis, clinical and histopathologic presentation, and management of post-surgical pyoderma gangrenosum are discussed with a review of the literature. CONCLUSION: Post surgical pyoderma gangrenosum (PSPG) can mimic ulcerative disorders including bacterial infection. The diagnosis should be suspected in post-operative wounds with negative bacterial cultures which progress despite broad-spectrum antibiotics and surgical debridement. Recognizing the clinical features of PSPG is fundamental to prevent severe destruction and deformity. PMID- 29501934 TI - Progesterone attenuates airway remodeling and glucocorticoid resistance in a murine model of exposing to ozone. AB - Airway remodeling is a vital component of chronic obstructive pulmonary disease (COPD). Despite the broad anti-inflammation effects of glucocorticoids, they exhibit relatively little therapeutic benefit in COPD, indicating the accelerating demands of new agents for COPD. We aim to explore the effect of progesterone on airway remodeling in a murine modeling of exposing to ozone and to further examine the potential effect of progesterone on glucocorticoid insensitivity. C57/BL6 mice were exposed to ozone for 12 times over 6 weeks, and were administered with progesterone alone or combined with budesonide (BUD) after each exposure until the 10th week. The peribronchial collagen deposition was measured. The protein levels of MMP8 and MMP9 in bronchoalveolar lavage fluid (BALF) and lungs were assessed. Western blot analysis was used to detect the levels of hypoxia-inducible factor-1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF), a-smooth muscle actin (alpha-SMA), glycogen synthase kinase 3beta (GSK-3beta). The expression of VEGF and histone deacetylase 2 (HDAC2) in the lung were determined by Immunohistochemical analyses. We observe that progesterone attenuates the peribronchial collagen deposition, as well as the expression of MMP8, MMP9, HIF-1alpha, VEGF, alpha-SMA, and GSK-3beta in BALF or lung tissues. Progesterone or BUD monotherapy has no effect on HDAC2 production. Progesterone combines with BUD induce dramatically enhanced effects. Thus, these results demonstrate novel roles of progesterone for the pathogenesis and airway remodeling in COPD. Progesterone plus BUD administration exerts more significant inhibition on airway remodeling with dose-independent. Additionally, progesterone may, to some extent, improve the glucocorticoid insensitivity. PMID- 29501935 TI - Socio-economic status and risk for suicide by immigration background in Norway: A register-based national study. AB - The relative importance of socio-economic factors on risk for suicide in the immigrant population may differ from that for the native population; however, few studies have addressed this issue on a national basis. With a nested case-control design and data from Norwegian population registers we identified 11,409 suicide cases in the years 1992-2012 and 191,785 sex-birthdate-matched controls. The influence of socio-economic factors on the risk for completed suicide was assessed through conditional logistic regression. Among 11,409 suicides, 1139 (10%) were individuals with an immigration background of either themselves or their parent(s). Suicide cases, as well as the controls, with an immigration background differed in several aspects of their socio-economic status from those without such a background. Being single or separated, divorced or widowed, was, however, associated with an increased risk of suicide regardless to the subjects' immigration background. Low level of education and low annual income significantly increased the risk for suicide in almost all the study subgroups. Living in the capital area was associated with a reduced risk of suicide in first generation immigrants but an increased risk in native Norwegians. In conclusion, persons with an immigration background, as well as native Norwegians, shared most common risk factors for suicide, but the strength of associations between socio economic factors and risk for suicide can differ by immigration background. PMID- 29501936 TI - Binary effect of titanium dioxide nanoparticles (nTio2) and phosphorus on microalgae (Chlorella 'Ellipsoides Gerneck, 1907). AB - The wide application of titanium dioxide nanoparticles and phosphorus in the manufacturing of many industrial products mainly used in agricultural sector has resulted in the release of considerable amounts of these compounds into freshwater aquatic ecosystem. These compounds may cause some unexpected effects to aquatic organisms. This study assessed the binary effects of Titanium nanoparticles (nTiO2) and Phosphorus on Chlorella ellipsoides. Toxicological assay test of the compounds nTiO2 (1.25 MUM) alone and the combination of Titanium dioxide (1.25 MUM) and Phosphorus (16, 32, 80, 160, 240 MUM) was assessed, after 96 h exposures, for optical density (OD680), specific growth rate, chlorophyll levels and lipid peroxidation via Malondialdehyde (MDA) activity. Superoxide dismutase (SOD), peroxidase (POD) and glutathione-s transferase (GST) activities were also measured. Two-way ANOVA showed a significant interaction (P < 0.05) between binary mixture. Co-exposure showed a decreased phosphorus bioconcentration in the microalgae with significant increase (P < 0.05) in chlorophyll a/b and total chlorophyll contents. A significant decrease (P < 0.05) in specific growth rate and optical density were recorded whereas, antioxidant enzymes (MDA, SOD, POD, GST) activities were significantly (P < 0.05) increased. These results showed that the addition of nTiO2 to Phosphorus affected the physiology of microalgae and should be of great concern for freshwater biodiversity. PMID- 29501937 TI - Evaluation of biomarkers in Mytilus galloprovincialis as an integrated measure of biofilm-membrane bioreactor (BF-MBR) system efficiency in mitigating the impact of oily wastewater discharge to marine environment: a microcosm approach. AB - The large volumes of oily wastewater discharged to marine environment cause heavy impacts on the coastal marine ecosystem. The selection of an appropriate technology to reduce these impacts should be based on the respect of the discharge limits and on the effective assessment and monitoring of its effects on biological organism preservation. To this aim, we set up a controlled microcosm scale system to compare the effects of a treated and untreated oily wastewater discharge in which the restore process is performed through a Membrane Bio Reactor. The system is completed by other three microcosms to control and isolate any possible concurrent effect on the Mytilus galloprovincialis, used as sentinel organism. Mytilus galloprovincialis have been kept in all these microcosms, and then mRNA expression and morphology were evaluated on gills and digestive gland. The genes considered in this work are Heat Shock Protein 70 and Metallothionein 10, involved in response to physicochemical sublethal stressors, Superoxide dismutase 1, Catalase, and Cytochrome P450 involved in oxidative stress response. Our results evidenced a significant overexpression, both in gills and digestive gland, of HSP70 in samples maintained in the microcosm receiving the untreated effluent, and of MT10 in those animals kept in microcosm where the effluent was treated. Even though the mRNA modifications are considered "primary" and transient responses which do not always correspond to protein content, the study of these modifications can help to gain insights into the mechanisms of action of xenobiotic exposure. Morphological analysis suggested that, although different, depending on the microcosm, the most serious damages were found in the gill epithelium accompanied with severe haemocyte infiltration, whilst in digestive gland the tissue architecture alterations and the haemocyte infiltration were less pronounced. These observations suggest that the immune system was activated as a general response to stressful stimuli such as the presence of toxic compounds. Moreover, the results indicate that the treatment process is useful. In fact, samples derived from the microcosm receiving the treated effluent, even though presenting some signs of stress, seemed to partially recover the normal structure, although their mRNA expression indicated some cellular suffering. PMID- 29501938 TI - The strong correlation between neonatal early-onset Group B Streptococcal disease and necrotizing enterocolitis. AB - BACKGROUND: Necrotizing enterocolitis (NEC) is a leading cause of newborn gastrointestinal emergencies, affecting 1-3 per 1000 live births. Although NEC has been linked to a microbial etiology, associations with maternal intrapartum and resultant newborn early-onset invasive Group B streptococcus (EO-GBS) have been weakly defined. OBJECTIVE: The study aim was to determine the relationship between EO-GBS and NEC. STUDY DESIGN: Data from 2008 to 2015 were collected from pediatric records with ICD diagnosis codes consistent with all stages of NEC, with the exception of neonatal EO-GBS data (only available 2011-2015). RESULTS: For the 131 newborns meeting inclusion criteria, the mean gestational age (GA) and birthweight at delivery was 30.2 weeks and 1449 g. Maternal comorbidities were not associated with a more advanced stage of NEC, however male gender (OR 3.2, p < .001), lower mean 1 (OR = 0.89, p = .045) and 5 min Apgar scores (OR = 0.84, p = .009) were significantly associated with higher NEC stage, after controlling for GA. Infectious morbidities including chorioamnionitis (OR = 1.5, p = .553) and intrapartum antibiotic administration (OR = 1.3, p = .524) were not significantly associated with higher NEC stage. Neither neonatal sepsis workup (OR = 0.27, p = .060) nor positive blood culture (OR = 0.97, p = .942) prior to NEC diagnosis were statistically significant. Type of feed prior to diagnosis (p = .530) was not significantly associated with NEC stage, however, expressed breast milk tended to be protective against higher stage of NEC (OR = 0.49, p = .055). Type of feed included total parenteral nutrition, mother's or donor expressed breast milk, trophic, full and high calorie feeds. Of the 579 newborns admitted from 2011 to 2015, 13 (2%) were diagnosed with EO-GBS and 64 met diagnostic criteria for NEC. GBS positive newborns had significantly higher odds of NEC (OR = 5.37, p = .009). NEC stage was not significantly different for patients with GBS positive vs. GBS negative mothers (p = .732), nor was there a significant difference in GA (p = .161). CONCLUSION: Our study is the first to describe a strong correlation between neonatal EO- GBS disease and NEC, with more than a five-fold increase in the odds of developing NEC in newborns of GBS positive mothers. PURPOSE: To investigate a possible relationship between EO-GBS disease and the neonatal diagnosis of NEC. Secondary analysis will determine if maternal antepartum and intrapartum factors along with neonatal variables contribute to a more advanced stage of NEC by retrospective chart review of patient data collected at Children's Hospital: New Orleans. PMID- 29501939 TI - Design, synthesis, DFT study and antifungal activity of the derivatives of pyrazolecarboxamide containing thiazole or oxazole ring. AB - Pyrazolecarboxamide fungicides are one of the most important classes of agricultural fungicides, which belong to succinodehydrogenase inhibitors (SDHIS). To discover new pyrazolecarboxamide analogues with broad spectrum and high activity, a class of new compounds of pyrazole carboxamide derivatives containing thiazole or oxazole ring were designed by scaffold hopping and bioisosterism, and 36 pyrazole carboxamide derivatives with antifungal activity were synthesized. Those compounds were evaluated against five phytopathogenic fungi, Gibberella zeae, Phytophythora capsici, Sclerotonia sclerotiorum, Erysiphe graminis and Puccinia sorghi. The results indicated that most of the compounds displayed good fungicidal activities, especially against E. graminis. Theoretical calculations were carried out at the B3LYP/6-31G (d, p) level and the full geometry optimization was carried out using the 6-31G (d, p) basis set, and the frontier orbital energy, atomic net charges, molecular docking were discussed, and the structure-activity relationships were also studied. PMID- 29501940 TI - Synthesis and biological evaluation of Schizandrin derivatives as potential anti cancer agents. AB - A new series of Schizandrin (1) derivatives were synthesized utilizing the C-9 position of the Schizandrin core and evaluated for their cytotoxic activities against HeLa (cervical cancer), A549 (lung cancer), MCF-7 (breast cancer) and DU 145 (prostate cancer) cell lines. Among the synthesized series, 4e, 4f, 4g and 5 showed potent activities against tested cell lines. More significantly, compound 5 exhibited most potent cytotoxic activity against DU-145 with an IC50 value of 1.38 MUM which is comparable to the standard agent, doxorubicin. Further, flow cytometry analysis indicated that 5 arrested cells in G2/M phase and consequently leading to apoptosis. Molecular docking analysis showed that 5 occupied the colchicine binding pocket of tubulin. Overall, the present study demonstrates that 5, as a mitotic-agent. PMID- 29501941 TI - Design, synthesis, and biological evaluation of stable beta6.3-Helices: Discovery of non-hemolytic antibacterial peptides. AB - Gramicidin A, a topical antibiotic made from alternating L and D amino acids, is characterized by its wide central pore; upon insertion into membranes, it forms channels that disrupts ion gradients. We present helical peptidomimetics with this characteristic wide central pore that have been designed to mimic gramicidin A channels. Mimetics were designed using molecular modeling focused on oligomers of heterochiral dipeptides of proline analogs, in particular azaproline (AzPro). Molecular Dynamics simulations in water confirmed the stability of the designed helices. A sixteen-residue Formyl-(AzPro-Pro)8-NHCH2CH2OH helix was synthesized as well as a full thirty-two residue Cbz-(AzPro-Pro)16-OtBu channels. No liposomal lysis activity was observed suggesting lack of channel formation, possibly due to inappropriate hydrogen-bonding interactions in the membrane. These peptidomimetics also did not hemolyze red blood cells, unlike gramicidin A. PMID- 29501943 TI - Novel topoisomerase I inhibitors. Syntheses and biological evaluation of phosphorus substituted quinoline derivates with antiproliferative activity. AB - This work describes the synthesis of 1,2,3,4-tetrahydroquinolinylphosphine oxides, phosphanes and phosphine sulfides as well as that of quinolinylphosphine oxides and phosphine sulfides, which were synthesized in good to high overall yield. The synthetic route involves a multicomponent reaction of (2-phosphine oxide)-, 2-phosphine- or (2-phosphine-sulfide)-aniline, aldehydes and olefins and allows the selective generation of two stereogenic centres in a short, efficient and reliable synthesis. The selective dehydrogenation of 1,2,3,4 tetrahydroquinolinylphosphine oxides and phosphine sulfides leads to the formation of corresponding phosphorus substituted quinolines. Some of the products which were prepared showed excellent activity as topoisomerase I (Top1) inhibitors. In addition, prolonged effect of the most potent compounds is maintained with the same intensity even after 3 min of the beginning of the enzymatic reaction. The cytotoxic effect on cell lines derived from human lung adenocarcinoma (A549), human ovarian carcinoma (SKOV03) and human embryonic kidney (HEK293) was also screened. 1,2,3,4-Tetrahydroquinolinylphosphine oxide 6g with an IC50 value of 0.25 +/- 0.03 MUM showed excellent activity against the A549 cell line in vitro, while 1,2,3,4-tetrahydroquinolinylphosphane 9c with an IC50 value of 0.08 +/- 0.01 MUM and 1,2,3,4-tetrahydroquinolinylphosphine sulfide derivative 10f with an IC50 value of 0.03 +/- 0.04 MUM are more active against the A549 cell line. Moreover, selectivity towards cancer cell (A549) over non malignant cells (MRC5) has been observed. According to their structure, they may be excellent antiproliferative candidates. PMID- 29501942 TI - Synthesis and biological evaluation of indole-based UC-112 analogs as potent and selective survivin inhibitors. AB - The anti-apoptotic protein survivin is highly expressed in cancer cells but has a very low expression in fully differentiated adult cells. Overexpression of survivin is positively correlated with cancer cell resistance to chemotherapy and radiotherapy, cancer cell metastasis, and poor patient prognosis. Therefore, selective targeting survivin represents an attractive strategy for the development of anticancer therapeutics. Herein, we reported the extensive structural modification of our recently discovered selective survivin inhibitor UC-112 and the synthesis of thirty-three new analogs. The structure-activity relationship (SAR) study indicated that replacement of the benzyloxy moeity in UC 112 with an indole moiety was preferred to other moieties. Among these UC-112 analogs, 10f, 10h, 10k, 10n showed the most potent antiproliferative activities. Interestingly, they were more potent against the P-glycoprotein overexpressing cancer cell lines compared with the parental cancer cell lines. Mechanistic studies confirmed that new analogs maintained their unique selectivity against survivin among the IAP family members. In vivo study using 10f in a human A375 melanoma xenograft model revealed that it effectively inhibited melanoma tumor growth without observable acute toxicity. Collectively, this study strongly supports the further preclinical development of selective survivin inhibitors based on the UC-112 scaffold. PMID- 29501944 TI - Trypanothione reductase inhibition and anti-leishmanial activity of all hydrocarbon stapled alpha-helical peptides with improved proteolytic stability. AB - Trypanothione reductase (TryR) is a well-established target in the search for novel antitrypanosomal and antileishmanial agents. We have previously identified linear and lactam-bridged 13-residue peptides derived from an alpha-helical region making up part of the dimeric interface of Leishmania infantum TryR (Li TryR) which prevent trypanothione reduction by disrupting enzyme dimerization. We now show that i,i + 4 side-chain cross-linking with an all-hydrocarbon staple stabilizes the helical structure of these peptides and significantly improves their resistance to protease cleavage relative to previous linear and cyclic lactam analogues. Interestingly, replacement of the amide bridge by the hydrocarbon staple at the same cyclization positions generates derivatives (2 and 3) that similarly inhibit oxidoreductase activity of the enzyme but unexpectedly stabilize the TryR homodimer. The most proteolytically stable peptide 2 covalently linked to oligoarginines displayed potent in vitro leishmanicidal activity against L. infantum parasites. PMID- 29501945 TI - A novel synthetic peptide inspired on Lys49 phospholipase A2 from Crotalus oreganus abyssus snake venom active against multidrug-resistant clinical isolates. AB - Currently, the evolving and complex mechanisms of bacterial resistance to conventional antibiotics are increasing, while alternative medicines are drying up, which urges the need to discover novel agents able to kill antibiotic resistant bacteria. Lys49 phospholipase A2s (PLA2s) from snake venoms are multifunctional toxins able to induce a huge variety of therapeutic effects and consequently serve as templates for new drug leads. Hence, the present study was aimed at the synthesis of oligopeptides mimicking regions of the antibacterial Lys49 PLA2 toxin (CoaTx-II), recently isolated from Crotalus oreganus abyssus snake venom, to identify small peptides able to reproduce the therapeutic action of the toxin. Five peptides, representing major regions of interest within CoaTx II, were synthesized and screened for their antibacterial properties. The 13-mer peptide pC-CoaTxII, corresponding to residues 115-129 of CoaTx-II, was able to reproduce the promising bactericidal effect of the toxin against multi-resistant clinical isolates. Peptide pC-CoaTxII is mainly composed by positively charged and hydrophobic amino acids, a typical trait in most antimicrobial peptides, and presented no defined secondary structure in aqueous environment. The physicochemical properties of pC-CoaTxII are favorable towards a strong interaction with anionic lipid membranes as those in bacteria. Additional in silico studies suggest formation of a water channel across the membrane upon peptide insertion, eventually leading to bacterial cell disruption and death. Overall, our findings confirm the valuable potential of snake venom toxins towards design and synthesis of novel antimicrobials, thus representing key insights towards development of alternative efficient antimicrobials to fight bacterial resistance to current antibiotics. PMID- 29501946 TI - Identification of Pyrazolo[3,4-e][1,4]thiazepin based CYP51 inhibitors as potential Chagas disease therapeutic alternative: In vitro and in vivo evaluation, binding mode prediction and SAR exploration. AB - American trypanosomiasis or Chagas disease (CD) is a vector borne pathology caused by the parasite Trypanosoma cruzi (T. cruzi), which remains a serious global health problem. The current available treatment for CD is limited to two nitroderivatives with limited efficacy and several side effects. The rational design of ergosterol synthetic route inhibitors (e.g. CYP51 inhibitors) represents a promising strategy for fungi and trypanosomatids, exhibiting excellent anti-T.cruzi activity in pre-clinical assays. In the present work, we evaluate through different approaches (molecular docking, structure activity relationships, CYP51 inhibitory assay, and phenotypic screenings in vitro and in vivo) the potency and selectivity of a novel CYP51 inhibitor (compound 1) and its analogues against T.cruzi infection. Regarding anti-parasitic effect, compound 1 was active in vitro with EC50 3.86 and 4.00 MUM upon intracellular (Tulahuen strain) and bloodstream forms (Y strain), respectively. In vivo assays showed that compound 1 reduced in 43% the parasitemia peak but, unfortunately failed to promote animal survival. In order to promote an enhancement at the potency and pharmacological properties, 17 new analogues were purchased and screened in vitro. Our findings demonstrated that five compounds were active against intracellular forms, highlighting compounds 1e and 1f, with EC50 2.20 and 2.70 MUM, respectively, and selectivity indices (SI) = 50 and 36, respectively. Against bloodstream trypomastigotes, compound 1f reached an EC50 value of 20.62 MUM, in a similar range to Benznidazole, but with low SI (3). Although improved the solubility of compound 1, the analogue 1f did not enhance the potency in vitro neither promote better in vivo efficacy against mouse model of acute T.cruzi infection arguing for the synthesis of novel pyrazolo[3,4 e][1,4]thiazepin derivatives aiming to contribute for alternative therapies for CD. PMID- 29501947 TI - Design and synthesis of new hybrids from 2-cyano-3,12-dioxooleana- 9-dien-28-oic acid and O2-(2,4-dinitrophenyl) diazeniumdiolate for intervention of drug resistant lung cancer. AB - To search for new drugs for intervention of drug-resistant lung cancer, a series of hybrids 4-15 from 2-cyano-3,12-dioxooleana-9-dien-28-oic acid (CDDO) and O2 (2,4-dinitrophenyl) diazeniumdiolate were designed, synthesized and biologically evaluated. The most active compound 7 produced relatively high levels of nitric oxide (NO) and reactive oxygen species (ROS) in drug-resistant lung cancer A549/Taxol cells which over-express glutathione S-transferase pi (GSTpi), and significantly inhibited the cells' proliferation (IC50 = 0.349 +/- 0.051 MUM), superior to the positive controls CDDO-Me, JS-K and Taxol. The inhibitory activity of 7 could be attenuated by an NO scavenger, ROS scavenger or GSTpi inhibitor. In addition, 7 suppressed the Lon protease expression as well as induced cell apoptosis and cycle arrest in A549/Taxol cells more strongly than CDDO-Me or JS-K. Together, our findings suggest that 7 may be worth studying further for intervention of drug-resistant lung cancer. PMID- 29501948 TI - Salivary cortisol and alpha-amylase diurnal profiles and stress reactivity in children with Attention Deficit Hyperactivity Disorder. AB - There is growing evidence for dysregulation of the stress system in individuals with Attention Deficit Hyperactivity Disorder (ADHD). The stress system includes neuroanatomical and functional components that function in concert to maintain homeostasis and its main effectors are the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic/adrenomedullary nervous system (SNS). As stress system activity demonstrates a distinct circadian variation, we aimed to describe simultaneously, diurnal rhythms of both the HPA axis and the SNS in children with ADHD and a comparison group. Moreover, we attempted to investigate stress responses to a physical stressor, venipuncture, in both groups. Sixty-two prepubertal children with ADHD combined (ADHD-C) or inattentive (ADHD-I) type and 40 typically developing children provided saliva samples at six specific time points during a day, as well as before and 10 min after a scheduled morning venipuncture. Salivary cortisol and alpha- amylase were selected as reliable noninvasive biomarkers for HPA axis and SNS function and were measured in the samples obtained. Results revealed that children with ADHD-C had lower mean cortisol values both 30 min after awakening and at 18:00 h than controls (p = 0.002 and p = 0.018 respectively), as well as lower mean Cortisol Awakening Response (CAR) and Area Under the Curve for "wake to bed" period (AUCi) values of cortisol (p = 0.004 and p = 0.001, respectively). Also, mean CAR and cortisol AUCi were lower in children with ADHD-I than the control group (p = 0.034 and p = 0.038 respectively). Alpha-amylase measurements showed an increase over time (p < 0.001), which was similar in all three groups. Interestingly, alpha-amylase changes over time were correlated with the corresponding cortisol changes (p < 0.001). Venipuncture, elicited a significant increase only in alpha-amylase levels and more so in the control group (p = 0.003). These findings suggest a partial hypofunction of the stress system in children with ADHD. PMID- 29501949 TI - There's (still) plenty of room at the bottom. AB - Motifs, circuits, and networks are core conceptual elements in modern systems and synthetic biology. While there are still undoubtedly more fascinating computations to discover at network level, there are also rich computations that we are only beginning to uncover within the diverse molecules that constitute the networks. Here we explore some work, both new and old, that showcases the incredible computational capacity of seemingly simple molecular mechanisms. A more sophisticated understanding of computations at the molecular level will inspire the development of a more nuanced toolbox for future biological engineering. PMID- 29501950 TI - Genetically encoded fluorescent voltage indicators: are we there yet? AB - In order to understand how brain activity produces adaptive behavior we need large-scale, high-resolution recordings of neuronal activity. Fluorescent genetically encoded voltage indicators (GEVIs) offer the potential for these recordings to be performed chronically from targeted cells in a minimally invasive manner. As the number of GEVIs successfully tested for in vivo use grows, so has the number of open questions regarding the improvements that would facilitate broad adoption of this technology that surpasses mere 'proof of principle' studies. Our aim in this review is not to provide a status check of the current state of the field, as excellent publications covering this topic already exist. Here, we discuss specific questions regarding GEVI development and application that we think are crucial in achieving this goal. PMID- 29501951 TI - Enhancing syntrophic associations among Clostridium butyricum, Syntrophomonas and two types of methanogen by zero valent iron in an anaerobic assay with a high organic loading. AB - The impacts of ZVI on microbial community diversity in an anaerobic assay with high organic loading were investigated. The relative abundance of bacteria, archaea, and the functional methyl coenzyme-M reductase (mcrA) gene were investigated using high-throughput sequencing, and variations in their quantity were determined by qPCR. The results showed that ZVI significantly increased both the relative abundance and quantity of Methanobacteriales and Methanosarcinales during hydrogenotrophic and acetoclastic methanogenesis. The relative abundance of syntrophic Methanobacteriales at the hydrolysis and acidogenesis stages resulted in H2 partial pressure decrease through an interspecies hydrogen transfer (IHT) network, which further induced butyric conversion to acetic by Syntrophomonas. The primary microbial metabolism then converted to acetoclastic methanogensis in the assay with ZVI addition. The short duration of this process and high relative abundance of Syntrophomonas, Clostridium butyricum and Methanosarcinales potentially indicated the existence of a novelty syntrophic mechanism for extracellular electron transfer, which promoted CH4 generation. PMID- 29501952 TI - Eco-friendly process combining acid-catalyst and thermomechanical pretreatment for improving enzymatic hydrolysis of hemp hurds. AB - The aim of this study was to investigate a pretreatment by combined H2SO4 acid catalyst and thermomechanical process to improve hemicelluloses solubilization of hemp hurds and subsequently enzymatic hydrolysis extent of potentially fermentable sugars. It was found that the sugars released were gradually increased with treatment severity. Soluble sugars generated before enzymatic hydrolysis (R1) increased up to 2.23 g/L indicating that autohydrolysis reaction occurred during pretreatment. Consequently, the solubilization of hemicelluloses was correlated with combined severity factor (CS). As a result, increase of overall reducing sugars (ORS) from 23.4% (untreated) to 81.4% was observed at optimized conditions of steaming temperature of 165 degrees C for 30 min and acid loading of 62.9 g/kg DM (dry material) corresponding to CS = 1.2, with limited production of identified by-products: 0.035 g/L and 0.46 g/L (per 100 g DM) for furfural and HMF, respectively. Structural and physicochemical modifications of biomass were observed by FTIR, ABET and SEM. PMID- 29501953 TI - Performance and bacterial diversity of biotrickling filters filled with conductive packing material for the treatment of toluene. AB - Toluene has high toxicity and mutagenicity, thus, the removal of toluene from air is necessary. In this study, two biotrickling filters (BTFs) were constructed and packed with conductive packing material to treat toluene waste gas. BTF-O exhibited good toluene removal performance even under high toluene inlet concentration, and over 80% of removal efficiency was observed. The elimination capacity reached 120.1 g/m3 h corresponding to an inlet concentration of 2.259 g/m3 under 61.5 s of empty bed retention time. During toluene biodegradation, the output voltage was observed in BTF-O and BTF-E, moreover BTF-E also showed slight power storage capacity. The applied voltage inhibited toluene removal and affected the bacterial community. The predominant bacterial genera in BTF-O were Acidovorax, Rhodococcus, Hydrogenophaga, Brevundimonas, Arthrobacter, Pseudoxanthomonas, Devosia, Gemmobacter, Rhizobium, Dokdonella and Pseudomonas. Genera Xanthobacter and Pelomonas accounted for the main bacterial community in BTF-E. PMID- 29501954 TI - Improvement of pulse-echo harmonic generation from a traction-free boundary through phase shift of a dual element transducer. AB - The practical implementation of nonlinear ultrasonic technique has been limited to the through-transmission setup for measuring the second harmonic component induced by the nonlinearity or microstructural changes of test material. A more practical technique such as the pulse-echo testing has been ruled out because a traction-free reflecting boundary destructively alters the nonlinear generation process. A focusing acoustic beam or rigid boundary condition was often employed for biomedical imaging and fluid nonlinearity in the pulse-echo inspection. In this article, we further explore a more general and efficient method to improve the generation of the second harmonic component in the pulse-echo mode with traction-free surface. A dual element planar transdcer with optimal phase shift of the input signal in one element relative to another is proposed for this purpose. The validity of the phase shift concept is confirmed by comparing the enhanced generation of second harmonic amplitudes and the resulting nonlinear parameters with the rigid-boundary case equivalent to the conventional through transmission setup. PMID- 29501955 TI - Generation of a luciferase-expressing human embryonic stem cell line: NERCe002-A 2. AB - The human embryonic stem cell line NERCe002-A-2 was generated by transduction of NERCe002-A cells with an expression vector carrying the luciferase gene. The stem cells labelled with luciferase can be transplanted into animals and detected by the bioluminescence imaging technology. This provides optimal prospects of application to in vivo stem cell tracing. Luciferin served as a substrate to detect the activity of luciferase, and luciferase expression was measured by quantitative PCR. Characterization assays suggested that the NERCe002-A-2 cell line expresses typical markers of pluripotency and can form the 3 germ layers in vivo. PMID- 29501956 TI - Verdazyl-ribose: A new radical for solid-state dynamic nuclear polarization at high magnetic field. AB - Solid-state dynamic nuclear polarization (DNP) using the cross-effect relies on radical pairs whose electron spin resonance (ESR) frequencies differ by the nuclear magnetic resonance (NMR) frequency. We measure the DNP provided by a new water-soluble verdazyl radical, verdazyl-ribose, under both magic-angle spinning (MAS) and static sample conditions at 9.4 T, and compare it to a nitroxide radical, 4-hydroxy-TEMPO. We find that verdazyl-ribose is an effective radical for cross-effect DNP, with the best relative results for a non-spinning sample. Under non-spinning conditions, verdazyl-ribose provides roughly 2* larger 13C cross-polarized (CP) NMR signal than the nitroxide, with similar polarization buildup times, at both 29 K and 76 K. With MAS at 7 kHz and 1.5 W microwave power, the verdazyl-ribose does not provide as much DNP as the nitroxide, with the verdazyl providing less NMR signal and a longer polarization buildup time. When the microwave power is decreased to 30 mW with 5 kHz MAS, the two types of radical are comparable, with the verdazyl-doped sample having a larger NMR signal which compensates for its longer polarization buildup time. We also present electron spin relaxation measurements at Q-band (1.2 T) and ESR lineshapes at 1.2 and 9.4 T. Most notably, the verdazyl radical has a longer T1e than the nitroxide (9.9 ms and 1.3 ms, respectively, at 50 K and 1.2 T). The verdazyl electron spin lineshape is significantly affected by the hyperfine coupling to four 14N nuclei, even at 9.4 T. We also describe 3000-spin calculations to illustrate the DNP potential of possible radical pairs: verdazyl-verdazyl, verdazyl-nitroxide, or nitroxide-nitroxide pairs. These calculations suggest that the verdazyl radical at 9.4 T has a narrower linewidth than optimal for cross-effect DNP using verdazyl-verdazyl pairs. Because of the hyperfine coupling contribution to the electron spin linewidth, this implies that DNP using the verdazyl radical would improve at lower magnetic field. Another conclusion from the calculations is that a verdazyl-nitroxide bi-radical would be expected to be slightly better for cross effect DNP than the nitroxide-nitroxide bi-radicals commonly used now, assuming the same spin-spin coupling constants. PMID- 29501957 TI - ADC at 3.0 T as a noninvasive biomarker for preoperative prediction of Ki67 expression in invasive ductal carcinoma of breast. AB - PURPOSE: To investigate the role of apparent diffusion coefficient (ADC) as an imaging biomarker for invasive ductal carcinoma (IDC) in the breast. METHODS: Seventy-one patients undergoing 3.0 Tesla DWI were retrospectively enrolled. Correlations between the ADC values and prognostic factors were evaluated. RESULTS: Multivariate regression analyses showed that Ki67 expression and molecular subtype were independently associated with the ADC. Discriminant analysis excluded the ADC as a good biomarker for subtype, but the mean ADC significantly distinguished Ki67-positive (low ADC) from Ki67-negative (high ADC) lesions, as observed in the in ROC curves, with a diagnostic sensitivity of 1.00 and a cut-off value of 0.97 * 10-3 mm2/s. CONCLUSION: The ADC may be helpful for predicting Ki67 expression in IDC preoperatively. PMID- 29501958 TI - Faster protein folding using enhanced conformational sampling of molecular dynamics simulation. AB - In this study, we applied swarm particle-like molecular dynamics (SPMD) approach to enhance conformational sampling of replica exchange simulations. In particular, the approach showed significant improvement in sampling efficiency of conformational phase space when combined with replica exchange method (REM) in computer simulation of peptide/protein folding. First we introduce the augmented dynamical system of equations, and demonstrate the stability of the algorithm. Then, we illustrate the approach by using different fully atomistic and coarse grained model systems, comparing them with the standard replica exchange method. In addition, we applied SPMD simulation to calculate the time correlation functions of the transitions in a two dimensional surface to demonstrate the enhancement of transition path sampling. Our results showed that folded structure can be obtained in a shorter simulation time using the new method when compared with non-augmented dynamical system. Typically, in less than 0.5 ns using replica exchange runs assuming that native folded structure is known and within simulation time scale of 40 ns in the case of blind structure prediction. Furthermore, the root mean square deviations from the reference structures were less than 2A. To demonstrate the performance of new method, we also implemented three simulation protocols using CHARMM software. Comparisons are also performed with standard targeted molecular dynamics simulation method. PMID- 29501960 TI - Transfer kinetics of phosphorus (P) in macrophyte rhizosphere and phytoremoval performance for lake sediments using DGT technique. AB - DGT (diffusive gradients in thin films) technique and DIFS (DGT induced fluxes in sediment) model are firstly designed for macrophyte-rhizobox system and in-situ macrophytes in Lake Erhai. Dynamics of phosphorus (P) transfer in Zizania latifolia (ZL) and Myriophyllum verticiilatur (MV) rhizosphere is revealed and phytoremediation performance for P in sediment is evaluated. Dynamic transfer process of P at DGT/sediment interface includes (i) diffusion flux and concentration gradients at DGT(root)/porewater interface leading to porewater concentration (C0) depletion and (ii) P desorption from labile P pool in sediment solid to resupply C0 depletion. Fe-redox controlled P release from Fe-bound P (BD P2) and then NH4Cl-P1 in rhizosphere sediment resupplies porewater depletion due to DGT (root) sink. Kd (labile P pool size in solid phase), r (resupply ratio) and kinetic exchange (Tc and k-1) lead to change characters of DIFS curves of (1) r against deployment time and (2) Csolu (dissolved concentration) against distance at 24 h. They include two opposite types of "fast" and "slow" rate of resupplies. Sediment properties and DIFS parameters control P diffusion and resupply in rhizosphere sediment. Phytoremoval ability for sediment P in lake is estimated to be 23.4 (ZL) or 15.0 t a-1 (MV) by "DGT-flux" method. PMID- 29501959 TI - Transcriptional alterations in skin fibroblasts from Parkinson's disease patients with parkin mutations. AB - Mutations in the parkin gene (PRKN) are the most common cause of autosomal recessive juvenile Parkinson's disease (PD). PRKN encodes an E3 ubiquitin ligase that is involved in multiple regulatory functions including proteasomal-mediated protein turnover, mitochondrial function, mitophagy, and cell survival. However, the precise molecular events mediated by PRKN mutations in PRKN-associated PD (PRKN-PD) remain unknown. To elucidate the cellular impact of parkin mutations, we performed an RNA sequencing study in skin fibroblasts from PRKN-PD patients carrying different PRKN mutations (n = 4) and genetically unrelated healthy subjects (n = 4). We identified 343 differentially expressed genes in PRKN-PD fibroblasts. Gene ontology and canonical pathway analysis revealed enrichment of differentially expressed genes in processes such as cell adhesion, cell growth, and amino acid and folate metabolism among others. Our findings indicate that PRKN mutations are associated with large global gene expression changes as observed in fibroblasts from PRKN-PD patients and support the view of PD as a systemic disease affecting also non-neural peripheral tissues such as the skin. PMID- 29501961 TI - Comparison of functional dyspepsia with organic dyspepsia in terms of attachment patterns. AB - AIM: Functional dyspepsia, originates from gastroduodenal region, is described as resistant and recurring dyspeptic symptoms with unknown etiology. Although there is some evidence in support of a relationship between functional dyspepsia and psychopathology, attachment patterns of functional dyspepsia patients have not been studied yet. In our study, we aimed to compare attachment patterns of functional dyspepsia patients with organic dyspepsia patients and healthy volunteers. METHOD: 43 patients diagnosed with functional dyspepsia, 38 patients with organic dyspepsia and 42 healthy volunteers matched in terms of age, sex and education were included in the study. All participants were evaluated using a socio-demographic and clinical data questionnaire, the State and Trait Anxiety Inventory, the Experiences in Close Relationships Questionnaire and the Adult Attachment Scale. RESULTS: There was no difference in sociodemographic features among the three groups. Functional dyspepsia group exhibited significantly higher Trait Anxiety scores compared to organic dyspepsia and control groups. Control group showed significantly higher secure attachment styles compared to functional dyspepsia and organic dyspepsia groups, there was no difference between groups in non-secure attachment styles according to triple attachment model. Dimensionally, functional dyspepsia group showed more avoidant attachment patterns than organic dyspepsia groups and organic dyspepsia group showed more avoidant attachment patterns than control group. CONCLUSION: According to our findings, Functional dyspepsia patients are more anxious than organic dyspepsia patients and healthy volunteers. Non-secure attachment patterns were seen generally in all dyspeptic patients while avoidant attachment patterns are more prominent in functional dyspepsia patients. PMID- 29501962 TI - RGD-Functionalized Fe3O4 nanoparticles for magnetic hyperthermia. AB - To improve the selectivity of magnetic nanoparticles for tumor treatment by hyperthermia, Fe3O4 nanoparticles have been functionalized with a peptide of the type arginine-glycine-aspartate (RGD) following a "click" chemistry approach. The RGD peptide was linked onto the previously coated nanoparticles in order to target alphavbeta3 integrin receptors over-expressed in angiogenic cancer cells. Different coatings have been analyzed to enhance the biocompatibility of magnetic nanoparticles. Monodispersed and homogeneous magnetite nanoparticles have been synthesized by the seed growth method and have been characterized using X-ray diffraction, thermogravimetric analysis, infrared spectroscopy, transmission electron microscopy and magnetic measurements. The magnetic hyperthermia efficiency of the nanoparticles has also been investigated and cytotoxicity assays have been perfomed for functionalized nanoparticles. PMID- 29501963 TI - Impact response and energy absorption of human skull cellular bones. AB - A skull fracture, due to a composition of typical lightweight cellular structures, is the most common type of traumatic brain injury. This paper presents a systematic investigation on the failure mechanism and energy absorption of skull cellular bones under low- and medium-velocity impact loadings. Non-destructive three-dimensional micro-computed tomography (Micro-CT) is utilized to scan samples of human skull cellular bones, and relevant structural parameters are obtained to reconstruct a finite element (FE) model of these bones. Micro-structures, mechanical properties, and failure process analysis of human skull cellular bones under impact loadings are investigated. The effects of some typical parameters, such as impact velocity and angle, impactor shape and density, and various reconstructed sections on the impact behavior of human skull cellular bones are investigated. Their impact properties and energy absorption are summarized. The present work will be of great significance in understanding the mechanical mystery of human skull cellular bones under impact loading. PMID- 29501964 TI - Enhanced lubricant film formation through micro-dimpled hard-on-hard artificial hip joint: An in-situ observation of dimple shape effects. AB - This study evaluates the impact of dimple shapes on lubricant film formation in artificial hip joints. Micro-dimples with 20-50 um lateral size and 1 +/- 0.2 um depths were fabricated on CrCoMo hip joint femoral heads using a picosecond laser. Tribological studies were performed using a pendulum hip joint simulator to apply continuous swing flexion-extension motions. The results revealed a significantly enhanced lubricant film thickness (>= 500 nm) with micro-dimpled prosthesis heads at equilibrium position after the lubricant film has fully developed. The average lubricant film thickness of dimpled prostheses with square and triangular-shaped dimple arrays over time is about 3.5 that of the non dimpled prosthesis (204 nm). Remarkably, the prosthesis with square-shaped dimple arrays showed a very fast lubricant film formation reaching their peak values within 0.5 s of pendulum movement, followed by prosthesis with triangular-shaped dimple arrays with a transition period of 42.4 s. The fully developed lubricant film thicknesses (>= 700 nm) are significantly higher than the surface roughness (~ 25 nm) demonstrating a hydrodynamic lubrication. Hardly any scratches appeared on the post-experimental prosthesis with square-shaped dimple array and only a few scratches were found on the post-experimental prosthesis with triangular shaped dimple arrays. Thus, prostheses with square-shaped dimple arrays could be a potential solution for durable artificial hip joints. PMID- 29501965 TI - Age-related differences in orienting attention to sound object representations. AB - We examined the effect of age on listeners' ability to orient attention to an item in auditory short-term memory (ASTM) using high-density electroencephalography, while participants completed a delayed match-to-sample task. During the retention interval, an uninformative or an informative visual retro-cue guided attention to an item in ASTM. Informative cues speeded response times, but only for young adults. In young adults, informative retro-cues generated greater event-related potential amplitude between 450 and 650 ms at parietal sites, and an increased sustained potential over the left central scalp region, thought to index the deployment of attention and maintenance of the cued item in ASTM, respectively. Both modulations were reduced in older adults. Alpha and low beta oscillatory power suppression was greater when the retro-cue was informative than uninformative, especially in young adults. Our results point toward an age-related decline in orienting attention to the cued item in ASTM. Older adults may be dividing their attention between all items in working memory rather than selectively focusing attention on a single cued item. PMID- 29501967 TI - A bilayer swellable drug-eluting ureteric stent: Localized drug delivery to treat urothelial diseases. AB - A bilayer swellable drug-eluting ureteric stent (BSDEUS) is engineered and implemented, as a sustained drug delivery platform technology that enhances localized drug delivery to the highly impermeable urothelium, for the treatment of urothelial diseases such as strictures and carcinomas. On deployment, the device swells to co-apt with the ureteric wall and ensure drug availability to these tissues. BSDEUS consists of a stent spray-coated with a polymeric drug containing polylactic acid-co-caprolactone (PLC) layer which is overlaid by a swellable polyethylene glycol diacrylate (PEGDA) based hydrogel. In-vitro quantification of released drug demonstrated a tunable time-profile, indicating sustained delivery over 1-month. The PEGDA hydrogel overlayer enhanced drug release and transport into explanted porcine ureteric tissues ex-vivo, under a simulated dynamic fluid flow. A preliminary pilot in-vivo feasibility study, in a porcine model, demonstrated that the swollen hydrogel co-apts with the urothelium and thus enables localized drug delivery to the target tissue section. Kidney functions remained unaffected and device did not result in either hydronephrosis or systemic toxicity. This successful engineering of a bilayer coated stent prototype, demonstrates its feasibility, thus offering a unique solution for drug based urological therapy. PMID- 29501966 TI - Levodopa improves response inhibition and enhances striatal activation in early stage Parkinson's disease. AB - Dopaminergic medications improve the motor symptoms of Parkinson's disease (PD), but their effect on response inhibition, a critical executive function, remains unclear. Previous studies primarily enrolled patients in more advanced stages of PD, when dopaminergic medication loses efficacy, and patients were typically on multiple medications. Here, we recruited 21 patients in early-stage PD on levodopa monotherapy and 37 age-matched controls to perform the stop-signal task during functional magnetic resonance imaging. In contrast to previous studies reporting null effects in more advanced PD, levodopa significantly improved response inhibition performance in our sample. No significant group differences were found in brain activations to pure motor inhibition or error processing (stop success vs. error trials). However, relative to controls, the PD group showed weaker striatal activations to salient events (infrequent vs. frequent events: stop vs. go trials) and fronto-striatal task-residual functional connectivity; both were restored with levodopa. Thus, levodopa appears to improve an important executive function in early-stage PD via enhanced salient signal processing, shedding new light on the role of dopaminergic signaling in response inhibition. PMID- 29501968 TI - Erythrocyte membrane bioinspired near-infrared persistent luminescence nanocarriers for in vivo long-circulating bioimaging and drug delivery. AB - Combination of biological entities with functional nanostructure would produce the excellent systemic drug-delivery vehicles that possess the ability to cross the biological barriers. Herein, from a biomimetic point of view, erythrocyte membrane bioinspired optical nanocarrier is fabricated by integrating Red blood cell (RBC) membrane vesicle with near-infrared persistent luminescence nanophosphors (PLNPs). The triple-doped zinc gallogermanate nanostructures with super-long near-infrared persistent luminescence (ZGGO) are used as optical emission center, mesoporous silica coated on the PLNPs (ZGGO@mSiO2) is employed for drug delivery, and the RBC membrane vesicle is introduced for biomimetic functionalization to ensure the developed nanocarriers bypass macrophage uptake and systemic clearance. Owing to the coating of natural erythrocyte membrane along with membrane lipids and associated membrane proteins, the proposed bioinspired nanocarriers have exhibited cell-mimicking property. Retaining the applicability of PLNPs core that favored in vitro excitation, the developed RBC ZGGO@mSiO2 biomimetic nanocarriers have demonstrated intense fluorescence, super long persistent luminescence, monodispersed nanosize, red light renewability, and excellent biocompatibility. In vivo mice bioimaging and biodistribution study demonstrate the erythrocyte membrane bioinspired nanoprobe loaded with doxorubicin as ideal nanocarriers for long-circulating bioimaging, in situ real time monitoring and drug delivery. We believe the PLNPs-based biomimetic nanocarriers offer a promising nano-platform for diagnostics and therapeutics application. PMID- 29501969 TI - Hypoxia-inducible Factor-1alpha directs renal regeneration induced by decellularized scaffolds. AB - Although mammalian kidney regeneration has been reported to occur throughout life, mature kidneys in mammals are not thought to regenerate sufficiently, particularly glomeruli. In our previous work, we found that renal regeneration could be enhanced by decellularized renal scaffolds after partial nephrectomy. In this study, we verified that the enhanced renal regeneration mediated by decellularized scaffolds could be attributed to regenerated glomeruli, which were counted both indirectly and directly under a microscope. Using the isobaric tag for relative and absolute quantitation, we performed proteomics analysis and found that hypoxia-inducible factor (HIF)-1alpha may be a key factor involved in induced renal regeneration. Dimethyloxyallyl glycine (DMOG), a propyl hydroxylase inhibitor, was applied to stabilize constitutive expression of HIF-1alpha protein, and small interfering RNA was used to inhibit gene expression. Administration of DMOG to decellularized scaffold-grafted rats improved the induced renal regeneration, whereas siHif1alpha transfection decreased the regeneration capacity. These findings revealed the critical role of HIF-1alpha in renal regeneration and provided important insights into our understanding of kidney development and the treatment of various kidney diseases. PMID- 29501971 TI - Seeing life through rose-colored spectacles: Autobiographical memory as experienced in Korsakoff's syndrome. AB - We investigated whether patients with Korsakjoff's Sybdrome (KS) would demonstrate a discrepancy between (low) autobiographical specificity and (high) sense of reliving. We invited 20 KS patients and 24 controls to retrieve personal memories. After memory retrieval, they were invited to rate subjective characteristics of their recall (e.g., reliving, travel in time, remembering, realness). Besides this rating, we analyzed memories objectively with regard to specificity. Analysis demonstrated poorer sense of reliving and memory specificity in KS patients than in controls. Critically, a discrepancy (i.e., higher level of sense of reliving than of specificity) was observed in KS participants but not in controls. We propose a hypothesis of "genuine consciousness experience" in which the discrepancy between sense of reliving and specificity mirrors how KS patients can benefit from an authentic experience of the past despite compromise in their autobiographical recall. PMID- 29501970 TI - Bacteria-like mesoporous silica-coated gold nanorods for positron emission tomography and photoacoustic imaging-guided chemo-photothermal combined therapy. AB - Mesoporous silica nanoshell (MSN) coating has been demonstrated as a versatile surface modification strategy for various kinds of inorganic functional nanoparticles, such as gold nanorods (GNRs), to achieve not only improved nanoparticle stability but also concomitant drug loading capability. However, limited drug loading capacity and low tumor accumulation rate in vivo are two major challenges for the biomedical applications of MSN-coated GNRs (GNR@MSN). In this study, by coating uniformly sized GNRs with MSN in an oil-water biphase reaction system, we have successfully synthesized a new bacteria-like GNR@MSN (i.e., bGNR@MSN) with a significantly enlarged pore size (4-8 nm) and surface area (470 m2/g). After PEGylation and highly efficient loading of doxorubicin (DOX, 40.9%, w/w), bGNR@MSN were used for positron emission tomography (PET, via facile and chelator-free 89Zr-labeling) and photoacoustic imaging-guided chemo photothermal cancer therapy in vivo. PET imaging showed that 89Zr-labeled bGNR@MSN(DOX)-PEG can passively target to the 4T1 murine breast cancer-bearing mice with high efficiency (~10 %ID/g), based on enhanced permeability and retention effect. Significantly enhanced chemo-photothermal combination therapy was also achieved due to excellent photothermal effect and near-infrared-light triggered drug release by bGNR@MSN(DOX)-PEG at the tumor site. The promising results indicate great potential of bGNR@MSN-PEG nanoplatforms for future cancer diagnosis and therapy. PMID- 29501972 TI - Reactive balance performance and neuromuscular and cognitive responses to unpredictable balance perturbations in children with developmental coordination disorder. AB - Developmental coordination disorder (DCD) is a common motor disorder affecting balance performance. However, few studies have investigated reactive balance performance and the underlying mechanisms in children with DCD. This study aimed to compare the reactive balance performance, lower limb muscle reflex contraction latency and attention level in response to unpredictable balance perturbations between 100 typically developing children and 120 children with DCD (with and without comorbid autism spectrum disorder) aged 6-9 years. Reactive balance performance was evaluated using a motor control test (MCT) conducted on a computerized dynamic posturography machine. The lower limb postural muscle responses and attention level before, during and after a MCT were measured using surface electromyography and electroencephalography, respectively. The results revealed that relative to typically developing children, those with DCD had a significantly longer MCT latency score in the backward platform translation condition (p = 0.048) but a significantly shorter latency score in the forward platform translation condition (p = 0.024). The MCT composite latency scores and the corresponding lower limb muscle onset latencies were similar between the groups. Children with DCD also demonstrated a lower attention level during and after sudden backward (p = 0.042) and forward (p = 0.031) platform translations, compared to typically developing children. Children with DCD were less attentive in response to postural threats, and their balance responses were direction specific. Balance training for children with DCD might require an additional emphasis on sudden posterior-to-anterior balance perturbations, as well as on problems with inattention. PMID- 29501974 TI - Partner reactions and task set selection: Compatibility is more beneficial in the stronger task. PMID- 29501973 TI - Safety and efficacy of the bumped kinase inhibitor BKI-1553 in pregnant sheep experimentally infected with Neospora caninum tachyzoites. AB - Neospora caninum is one of the main causes of abortion in cattle, and recent studies have highlighted its relevance as an abortifacient in small ruminants. Vaccines or drugs for the control of neosporosis are lacking. Bumped kinase inhibitors (BKIs), which are ATP-competitive inhibitors of calcium dependent protein kinase 1 (CDPK1), were shown to be highly efficacious against several apicomplexan parasites in vitro and in laboratory animal models. We here present the pharmacokinetics, safety and efficacy of BKI-1553 in pregnant ewes and foetuses using a pregnant sheep model of N. caninum infection. BKI-1553 showed exposure in pregnant ewes with trough concentrations of approximately 4 MUM, and of 1 MUM in foetuses. Subcutaneous BKI-1553 administration increased rectal temperatures shortly after treatment, and resulted in dermal nodules triggering a slight monocytosis after repeated doses at short intervals. BKI-1553 treatment decreased fever in infected pregnant ewes already after two applications, resulted in a 37-50% reduction in foetal mortality, and modulated immune responses; IFNgamma levels were increased early after infection and IgG levels were reduced subsequently. N. caninum was abundantly found in placental tissues; however, parasite detection in foetal brain tissue decreased from 94% in the infected/untreated group to 69-71% in the treated groups. In summary, BKI-1553 confers partial protection against abortion in a ruminant experimental model of N. caninum infection during pregnancy. In addition, reduced parasite detection, parasite load and lesions in foetal brains were observed. PMID- 29501975 TI - Truth is in the head. A nod and shake compatibility effect. AB - Studies from the embodiment perspective on language processing have shown facilitation or interference effects depending on the compatibility between verbal contents, concrete or abstract, and the motion of various parts of the body. The aim of the present study was to test whether such compatibility effects can be found when a higher cognitive process like truth evaluation is accomplished with head movements. Since nodding is a vertical head gesture typically performed with positive and affirmative responses, and shaking is a horizontal head gesture associated with negative and dissenting contents, faster response times can be expected when true information is evaluated by making a vertical head movement and false information by making a horizontal head movement. Three experiments were designed in order to test this motor compatibility effect. In the first experiment a series of very simple sentences were asked to be evaluated as true or false by dragging them vertically and horizontally with the head. It resulted that truth-value was assessed faster when it was compatible with the direction of the head movement, compared to when it was incompatible. In the second experiment participants were asked to evaluate the same sentences as the first experiment but by moving them with the mouse. In the third experiment, a non-evaluative classification task was given, where sentences concerning animals or objects were to be dragged by vertical and horizontal head movements. In the second and third experiment no compatibility effect was observed. Overall results support the hypothesis of an embodiment effect between the abstract processing of truth evaluation and the direction of the two head movements of nodding and shaking. Cultural aspects, cognitive implications, and the limits of these findings are discussed. PMID- 29501976 TI - Costs of screening for prostate cancer: Evidence from the Finnish Randomised Study of Screening for Prostate Cancer after 20-year follow-up using register data. AB - OBJECTIVES: Few empirical analyses of the impact of organised prostate cancer (PCa) screening on healthcare costs exist, despite cost-related information often being considered as a prerequisite to informed screening decisions. Therefore, we estimate the differences in register-based costs of publicly funded healthcare in the two arms of the Finnish Randomised Study of Screening for Prostate Cancer (FinRSPC) after 20 years. METHODS: We obtained individual-level register data on prescription medications, as well as inpatient and outpatient care, to estimate healthcare costs for 80,149 men during the first 20 years of the FinRSPC. We compared healthcare costs for the men in each trial arm and performed statistical analysis. RESULTS: For all men diagnosed with PCa during the 20-year observation period, mean PCa-related costs appeared to be around 10% lower in the screening arm (SA). Mean all-cause healthcare costs for these men were also lower in the SA, but differences were smaller than for PCa-related costs alone, and no longer statistically significant. For men dying from PCa, although the difference was not statistically significant, mean all-cause healthcare costs were around 10% higher. When analysis included all observations, cumulative costs were slightly higher in the CA; however, after excluding extreme values, cumulative costs were slightly higher in the SA. CONCLUSIONS: No major cost impacts due to screening were apparent, but the FinRSPC's 20-year follow-up period is too short to provide definitive evidence at this stage. Longer term follow-up will be required to be better informed about the costs of, or savings from, introducing mass PCa screening. PMID- 29501977 TI - Perioperative chemotherapy with or without epidermal growth factor receptor blockade in unselected patients with locally advanced oesophagogastric adenocarcinoma: Randomized phase II study with advanced biomarker program of the German Cancer Society (AIO/CAO STO-0801). AB - BACKGROUND: Perioperative chemotherapy significantly improves survival in patients with locally advanced oesophagogastric cancer (EGC). However, as approximately 60% of patients will die from their disease, new therapeutic agents such as molecular-targeted drugs are needed. PATIENTS AND METHODS: To evaluate the role of panitumumab with perioperative chemotherapy, previously untreated patients with locally advanced EGC received, in an open-label randomised phase II study (NEOPECX), standard epirubicin, cisplatin, capecitabine (ECX) chemotherapy with or without panitumumab. The primary end-point was the histological response rate after neoadjuvant therapy. The expression status and gene copy number of EGFR, HER2, and MET were determined by immunohistochemistry and fluorescence in situ hybridization (FISH). Plasma samples were collected before the first cycle of neoadjuvant chemotherapy. RESULTS: Overall, 160 patients (80 versus 80) were eligible. The majority (82% versus 80%) showed lymph node involvement. Rate of R0 resection, percentage of patients with downstaging to ypT0-2 at pathohistological evaluation, and rate of major histological response was equal in both arms. Toxicity was increased by panitumumab with regard to thromboembolic events and skin toxicity. Patients with tumour EGFR, HER2 or MET expression had shorter progression-free and overall survival. FISH positivity for these markers was associated with shorter survival independent of therapy. High levels of soluble EGFR in particular predicted poor survival in the panitumumab arm. CONCLUSION: The addition of panitumumab to ECX did not improve downstaging of locally advanced EGC. Low plasma levels of pathway-associated proteins such as sEGFR may identify a group of patients that benefit from EGFR-directed therapy. CLINICALTRIALS.GOV: NCT01234324. PMID- 29501978 TI - Ruthenium anticancer agent KP1019 binds more tightly than NAMI-A to tRNAPhe. AB - The ruthenium-based anticancer agent NAMI-A (ImH[trans-RuCl4(dmso)(Im)], where Im = imidazole) has been shown to interact with RNA in vivo and in vitro. We hypothesized that the similarly structured drug KP1019 (IndH[trans-RuCl4(Ind)2], where Ind = indazole) binds to RNA as well. Fluorescence spectroscopy was employed to assay the interactions between either NAMI-A or KP1019 and tRNAPhe through an intrinsic fluorophore wybutosine (Y) base and by extrinsic displacement of the intercalating agent ethidium bromide. In both the intrinsic Y base and extrinsic ethidium bromide studies, KP1019 exhibited tighter binding to phenylalanine-specific tRNA (tRNAPhe) than NAMI-A. In the ethidium bromide study, reducing both drugs from RuIII to RuII resulted in a significant decrease in binding. Our findings suggest that the relatively large heteroaromatic indazole ligands of KP1019 intercalate in the pi-stacks of tRNAPhe within structurally complex binding pockets. In addition, NAMI-A appears to be sensitive to destabilizing electrostatic interactions with the negative phosphate backbone of tRNAPhe. Interactions with additional tRNA molecules and other types of RNA require further evaluation to determine the role of RNA in the mechanisms of action for KP1019 and to better understand how Ru drugs fundamentally interact with biomolecules that are more structurally sophisticated than short DNA oligonucleotides. To the best of our knowledge, this is the first study to report KP1019 binding interactions with RNA. PMID- 29501979 TI - Interplay between autophagy and apoptosis in lead(II)-induced cytotoxicity of primary rat proximal tubular cells. AB - Autophagy and apoptosis are two different biological processes that determine cell fates. We previously reported that autophagy inhibition and apoptosis induction are involved in lead(II)-induced cytotoxicity in primary rat proximal tubular (rPT) cells, but the interplay between them remains to be elucidated. Firstly, data showed that lead(II)-induced elevation of LC3-II protein levels can be significantly modulated by 3-methyladenine or rapamycin; moreover, protein levels of Autophagy-related protein 5 (Atg5) and Beclin-1 were markedly up regulated by lead(II) treatment, demonstrating that lead(II) could promote the autophagosomes formation in rPT cells. Next, we applied three pharmacological agents and genetic method targeting the early stage of autophagy to validate that enhancement of autophagosomes formation can inhibit lead(II)-induced apoptotic cell death in rPT cells. Simultaneously, lead(II) inhibited the autophagic degradation of rPT cells, while the addition of autophagic degradation inhibitor bafilomycin A1 aggravated lead(II)-induced apoptotic death in rPT cells. Collectively, this study provided us a good model to know about the dynamic process of lead(II)-induced autophagy in rPT cells, and the interplay between autophagy and apoptosis highlights a new sight into the mechanism of lead(II) induced nephrotoxicity. PMID- 29501980 TI - Bioactive ruthenium(II)-arene complexes containing modified 18beta-glycyrrhetinic acid ligands. AB - Metal-arene complexes containing bioactive natural-product derived ligands can have new and unusual properties. We report the synthesis, characterization and antiproliferative activity of two new Ru(II) arene complexes with imidazole (dichlorido complex 1) or bipyridyl (chlorido complex 2) ligands conjugated to 18beta-glycyrrhetinic acid, an active triterpenoid metabolite of Glycyrrhiza glabra. In general, the conjugated ligands and complexes showed only moderate activity against HeLa (cervical), MCF-7 (breast) and A2780 (ovarian) cancer cells, although the activity of complex 2 in the former two cell lines approached that of the drug cisplatin. Complex 2 (in contrast to complex 1) also exhibited significant activity towards both Gram-positive S. aureus and Gram-negative E. coil bacteria. Complex 2 can induce condensation of DNA and enhances the generation of intracellular reactive oxygen species (ROS). The conjugation of natural products to ligands in organometallic half-sandwich complexes provides a strategy to enhance their biological activities. PMID- 29501981 TI - The neural basis of representing others' inner states. AB - Shared reality is facilitated by social mentalizing, that is, inferring the inner states such as beliefs and traits of another person. Recent advances in neuroscientific research on mentalizing have pinpointed the role of (a) the temporo-parietal junction in the switching of perspectives from self-to-other, and (b) the medial prefrontal cortex in holding stable neural representation of personality traits and the persons that hold these traits. Furthermore, the recently discovered role of the cerebellum in social mentalizing is introduced, and its potential role in inferring action sequences. These three processes are relevant preconditions for shared understanding because they allow people to adjust their own beliefs and adequately invest their talents by taking into account others' beliefs and traits, and so shape a shared reality in which differences in beliefs, opinions and talent are appreciated and integrated. PMID- 29501982 TI - Characteristics and environmental response of secondary minerals in AMD from Dabaoshan Mine, South China. AB - This article documents the new precipitates formed related to acid mine drainage (AMD) at Dabaoshan mine (South China). X-ray diffraction (XRD), Fourier Transform Infrared Spectroscopy (FTIR) and Scanning Electron Microscope & Energy Spectrometer (SEM-EDS) have been used to detect minerals in AMD impoundment and downstream creeks. The occurrences, the mineralogical species and the micro morphological characteristics of secondary minerals from different pH conditions has been carried out. Iron- hydroxysulfates and iron-oxyhydroxides are the main secondary minerals, and they occurred as both poorly and well-crystalline minerals. Jarosite nearly predominate as pseudocubic crystals at pH 2.5-4.0. Schwertmannite-rich sediments occurred at pH 3.82-4.5 as urchin-like, pin-cushion and as well as globular-like aggregates and show high concentrations of Mn, Cu, Pb and As due to adsorption and co-precipitation. Goethite formed mainly as botryoidal and flaky assemblages. Paragenesis of different types of schwertmannite indicate that pH condition is not the dominant factor controlling morphology but the main parameter for the variation of minerals species. Statistical analysis reveal obvious changing tendency in Zn, Cd and SO4 within pH. FTIR analysis show adsorption of Cu, Pb, Zn and As on secondary iron minerals. Water elements with high concentrations in the impoundment and the obvious decrease in downstream creak reflected an accumulation and evaporation in AMD impoundment and a dilution in downstream area respectively. These results indicate that secondary minerals associated with AMD can play an important role in attenuating toxic elements. PMID- 29501983 TI - Access to health services for the refugee community in Greece: lessons learned. PMID- 29501984 TI - Factors impacting antiretroviral therapy adherence among human immunodeficiency virus-positive adolescents in Sub-Saharan Africa: a systematic review. AB - OBJECTIVES: Eighty-two percent of human immunodeficiency virus (HIV)-positive adolescents live in Sub-Saharan Africa (SSA). Despite the availability of antiretroviral therapy (ART), adherence levels are suboptimal, leading to poor outcomes. This systematic review investigated factors impacting ART adherence among adolescents in SSA, including religious beliefs and intimate relationships. METHODS: A systematic review was conducted between June and August 2016 using eight electronic databases, including Cochrane and PubMed. Published, ongoing and unpublished research, conducted in SSA from 2004 to 2016, was identified and thematic analysis was used to summarise findings. RESULTS: Eleven studies from eight SSA countries, published in English between 2011 and 2016, reported on factors impacting ART adherence among adolescents living with HIV (ALHIV). Forty four barriers and 29 facilitators to adherence were identified, representing a complex web of factors. The main barriers were stigma, ART side-effects, lack of assistance and forgetfulness. Facilitators included caregiver support, peer support groups and knowledge of HIV status. CONCLUSIONS: Stigma reflects difficult relations between ALHIV and their HIV-negative peers and adults. Most interventions target only those with HIV, suggesting a policy shift towards the wider community could be beneficial. Recommendations include engaging religious leaders and schools to change negative societal attitudes. Limitations of the review include the urban settings and recruitment of predominantly vertically infected participants in most included studies. Therefore, the findings cannot be extrapolated to ALHIV residing in rural locations or horizontally infected ALHIV, highlighting the need for further research in those areas. PMID- 29501985 TI - Sociocultural barriers to maternity services delivery: a qualitative meta synthesis of the literature. AB - OBJECTIVES: Maternal and neonatal healthcare outcomes in Sub-Saharan Africa (SSA) remain poor despite decades of different health service delivery interventions and stakeholder investments. Qualitative studies have attributed these results, at least in part, to sociocultural beliefs and practices. Thus there is a need to understand, from an overarching perspective, how these sociocultural beliefs affect maternal and neonatal health (MNH) outcomes. STUDY DESIGN: A qualitative meta-synthesis of primary studies on cultural beliefs and practices associated with maternal and neonatal health care was carried out, incorporating research conducted in any country within SSA, using data from men, women and health professionals gathered through focus group discussions, structured and semistructured interviews. METHODS: A systematic search was carried out on seven electronic databases, Scopus, Ovid Medline, PubMed, CINAHL Plus, Humanities and Social Sciences (Informit), EMBASE and Web of Science, and on Google Scholar, using both manual and electronic methods, between 1st January 1990 and 1st January 2017. The terms 'cultural beliefs'; 'cultural beliefs AND maternal health'; 'cultural beliefs OR maternal health'; 'traditional practices' and 'maternal health' were used in the search. RESULTS: Key components of cultural beliefs and practices associated with adverse health outcomes on pregnancy, labour and the postnatal period were identified in five overarching factors: (a) pregnancy secrecy; (b) labour complications attributed to infidelity; (c) mothers' autonomy and reproductive services; (d) marital status, trust in traditional medicines and traditional birth attendants; and (e) intergenerational beliefs attached to the 'ordeal' of giving birth. CONCLUSION: Cultural beliefs and practices related to maternal and neonatal health care are intergenerational. Therefore, intensive community-specific education strategies to facilitate behaviour changes are required for improved MNH outcomes. Adopting practical approaches such as involving husbands/partners and communities in antenatal care services in a health facility and community settings can enhance improved MNH outcomes. PMID- 29501986 TI - Spectacles need and ownership among multiethnic students in rural China. AB - OBJECTIVES: The aim of this study is to describe the prevalence and associated factors of spectacles need and ownership among multiethnic school students in rural China. STUDY DESIGN: School-based cross-sectional study. METHODS: This school-based eye study was conducted in Yunnan province located in Southwestern China. Questionnaires were filled out by children with the help of their parents concerning demographic characteristics, spectacles usage, and myopia-related lifestyle exposures. Spectacles need was defined as participants who had an uncorrected visual acuity (VA) of less than 6/12 but could be corrected to more than 6/12 in the better-seeing eye, with myopia of less than -0.5 diopters (D), hyperopia of more than +2.0 D, or astigmatism of more than 0.75 D in both eyes. Definition of spectacles ownership was based on spectacles wearing at school on the examination day. RESULTS: Among the 7681 students aged 5-16 years participating in this study, 7166 (93.3% of the study participants) successfully completed VA tests and questionnaires. The rate of spectacles need among children with an uncorrected VA of 6/12 or worse in either eye was 68.3% (623/912). Among the students who needed spectacles, only 18.9% owned them. Multivariate analyses revealed that spectacles ownership was significantly associated with increasing age (odds ratio [OR]: 1.30; 95% confidence interval [CI]: 1.08-1.55), more time on reading and writing (OR = 1.66; 95% CI: 1.15-2.40), having myopic friend(s) (OR: 1.90; 95% CI: 1.01-3.56), self-awareness of myopia (OR: 6.67; 95% CI: 2.48 17.92), and poorer uncorrected VA (OR: 4.57; 95% CI: 2.78-7.52). CONCLUSIONS: We observed a lower rate of spectacles ownership among rural children compared with those of similar ages in urban China. These findings may have important public health implications for China and other countries regarding vision-related health resources allocation. PMID- 29501987 TI - Determinants of adolescent maternal healthcare utilization in Bangladesh. AB - OBJECTIVES: To identify the factors associated with adolescent maternal healthcare utilization in Bangladesh. STUDY DESIGN: A secondary analysis was undertaken using the latest data set from the Bangladesh Demographic and Health Survey (2014). Data were collected from the cross-sectional survey carried out from June to mid November 2014. In total, 17,863 ever-married women aged 15-49 years were interviewed. According to the definition of the World Health Organization, 2029 of these women were adolescents and therefore eligible for inclusion in this study. METHODS: Both bivariate and multivariate logistic regression models were used to determine the factors influencing adolescent pregnancy, use of contraception, use of antenatal care services, facility-based delivery and presence of a skilled birth attendant at the last birth. The results are presented in terms of adjusted odds ratio (OR) with 95% confidence interval (CI), at a significance level of 5%. RESULTS: Maternal age, education, knowledge of menstrual regulations i.e. any procedure which disrupts the intra uterine environment, awareness of community clinic, household size, socio-economic status and administrative division were found to have a significant effect on adolescent pregnancy in Bangladesh. Sexual knowledge has a significant positive role in the use of modern contraceptives. Adolescents of low socio-economic status are significantly more likely to deliver at home compared with adolescents in the richest quintile (OR 0.26, 95% CI 0.15-0.47; P < 0.001). The likelihood of delivering at a health facility was higher among adolescents who had knowledge about sexually transmitted infections (OR 1.84, 95% CI 1.28-2.65; P < 0.001) and menstrual regulations (OR 1.41, 95% CI 1.04-1.91; P < 0.05). CONCLUSIONS: Adolescent maternal healthcare utilization was associated with a number of factors including low socio-economic status, limited reproductive knowledge (e.g. menstrual regulations, sexually transmitted infections) and geographical region. The study findings will serve to inform policy and would be beneficial for introducing need-based adolescent maternal health programmes by targeting a range of maternal health services and opportunities that contribute to better health and development for adolescent mothers in Bangladesh. PMID- 29501988 TI - Impacts of using a head-worn display on gait performance during level walking and obstacle crossing. AB - Use of a head-worn display (HWD) may affect gait performance and increase slip and trip risks, though there is a lack of information on such effects. This study investigated how different display technologies (monocular and binocular HWDs, and a paper list) and visual information presentation modes affect gait performance. Twelve gender-balanced participants completed walking and obstacle crossing trials on a linear walking track under all experimental conditions and a baseline control (without using a technology). During these trials, information relevant to a simulated light assembly task was provided, as representative of a potential occupational application. Gait performance was assessed based on minimum foot clearance (MFC), required coefficient of friction, foot placement locations around the obstacle, and/or walking/obstacle crossing speed. Use of a HWD had no substantial effects on level walking performance. A more conservative/cautious obstacle crossing strategy was, however, observed with HWD use, including a decrease (~3%) in obstacle crossing speed (compared to the baseline). Gender-specific foot control strategies (lead foot MFC) were also observed that depended on the specific display technology and information modes. Foot placements around the obstacle were not influenced by use of the binocular HWD, yet a conservative strategy was observed with the monocular HWD. PMID- 29501989 TI - Investigation of short tandem repeats in major depression using whole-genome sequencing data. AB - BACKGROUND: Major depressive disorder (MDD) is a leading contributor to global disease burden. Recent studies have shown that genetic factors play significant roles in the susceptibility to this condition; however, the underlying genetic basis currently remains largely unknown. Short tandem repeat (STR) has been proposed as an explanatory factor in the "missing heritability" of complex diseases or traits. METHODS: We investigated STR variations from 15 MDD patients and 10 ethnically matched healthy controls based on their deep whole-genome sequencing (WGS) data. The lobSTR software was used to computationally determine STRs. RESULTS: The results of the Mexican-American sample showed that STRs are significantly richer in healthy controls than in MDD cases on each of the 23 chromosomes (all false discovery rates, FDR P-values < 0.0062); while for the Australian of European-ancestry sample, there was no statistically significant STRs difference between MDD cases and controls. LIMITATIONS: High quality WGS costs limited obtaining larger datasets. CONCLUSIONS: This preliminary work is the first study that STR variations are applied to investigate MDD based on WGS data. The results on Mexican-American population may imply that within the same ancestry, targeted sequencing on a specific chromosome or region of genome would be sufficient for examining the relationship between STR and MDD. Further studies should examine larger sequencing datasets on other ethnic groups. PMID- 29501991 TI - A systematic review and meta-analysis of interpersonal psychotherapy for perinatal women. AB - BACKGROUND: Interpersonal psychotherapy (IPT) has demonstrated efficacy for the prevention and treatment of perinatal depression. Previous systematic reviews have not evaluated the effects of IPT on other outcomes, most notably symptoms of anxiety and interpersonal functioning, or assessed moderators of treatment efficacy specific to IPT. METHOD: A systematic review identified 28 studies assessing the efficacy of IPT during pregnancy or the first year postpartum. Random effects meta-analyses assessed the average change in outcomes (depression, anxiety, relationship quality, social adjustment, and social support) from pre- to post-treatment, the difference in the change in outcomes between treatment and comparison conditions, and the difference in prevalence of depressive episodes between treatment and comparison conditions. Study, intervention, and sample characteristics were evaluated as potential moderators of effect sizes. RESULTS: In prevention studies, IPT was effective for reducing depressive symptoms and the prevalence of depressive episodes. In treatment studies, IPT reduced symptoms of depression and anxiety and improved relationship quality, social adjustment and social support. Few significant moderators were identified, and results of moderation analyses were inconsistent across outcomes. LIMITATIONS: There are insufficient studies to evaluate the effects of preventive IPT on anxiety and interpersonal outcomes. Analyses of potential moderators were limited by the number of studies available for subgroup comparisons. CONCLUSIONS: IPT is an effective preventive intervention for perinatal depression. IPT is clearly effective for treating depressive symptoms and promising as a treatment for anxiety and improving interpersonal functioning. Further research is necessary to assess whether adaptations to IPT enhance its efficacy. PMID- 29501990 TI - Features of dissociation differentially predict antidepressant response to ketamine in treatment-resistant depression. AB - BACKGROUND: Ketamine induces rapid and robust antidepressant effects, and many patients also describe dissociation, which is associated with antidepressant response. This follow-up study investigated whether antidepressant efficacy is uniquely related to dissociative symptom clusters. METHODS: Treatment-resistant patients with major depressive disorder (MDD) or bipolar disorder (BD) (n = 126) drawn from three studies received a single subanesthetic (0.5 mg/kg) ketamine infusion. Dissociative effects were measured using the Clinician-Administered Dissociative States Scale (CADSS). Antidepressant response was measured using the 17-item Hamilton Depression Rating Scale (HAM-D). A confirmatory factor analysis established the validity of CADSS subscales (derealization, depersonalization, amnesia), and a general linear model with repeated measures was fitted to test whether subscale scores were associated with antidepressant response. RESULTS: Factor validity was supported, with a root mean square error of approximation of .06, a comparative fit index of .97, and a Tucker-Lewis index of .96. Across all studies and timepoints, the depersonalization subscale was positively related to HAM-D percent change. A significant effect of derealization on HAM-D percent change was observed at one timepoint (Day 7) in one study. The amnesia subscale was unrelated to HAM-D percent change. LIMITATIONS: Possible inadequate blinding; combined MDD/BD datasets might have underrepresented ketamine's antidepressant efficacy; the possibility of Type I errors in secondary analyses. CONCLUSIONS: From a psychometric perspective, researchers may elect to administer only the CADSS depersonalization subscale, given that it was most closely related to antidepressant response. From a neurobiological perspective, mechanistic similarities may exist between ketamine-induced depersonalization and antidepressant response, although off-target effects cannot be excluded. PMID- 29501992 TI - A new facile approach to prepare reduced graphene oxide and MoO2/reduced graphene oxide as electrode materials for oxygen reduction reactions. AB - A facile one-pot method for the formation of MoO2/RGO has been established using Mo particles as both the reductant for graphene oxide (GO) and as the Mo source. The Mo powder efficiently reduced the GO under acidic conditions to give reduced GO (RGO) and Mo ions. These ions were then transformed into MoO2 and MoO2/RGO composites were formed by tuning the pH of the solution. Other variables such as reaction time and Mo:GO weight ratio were also investigated. The MoO2/RGO composite prepared at 3:1 (Mo:GO, called MoO2/RGO3) had the best electrochemical performance for the oxygen reduction reaction (ORR) in alkaline medium. The ORR reaction at the MoO2/RGO3 electrode mainly proceeded via a four-electron pathway and the electrode displayed superior catalytic activity and good stability. These results indicate that MoO2/RGO3 could be a promising noble metal-free electrocatalyst for fuel cells. PMID- 29501993 TI - Selective and adsorptive removal of anionic dyes and CO2 with azolium-based metal organic frameworks. AB - The positively charged azolium moieties make imidazolium linker an ideal linker for the construction of cationic metal-organic frameworks because the ligand induces cationic environments in the frameworks. Therefore, we employed two imidazolium ligands, 1,3-bis(4-carboxyphenyl)imidazolium chloride (H2L+Cl-) and 1,3-bis(3,5-dicarboxyphenyl)imidazolium chloride (H4L+Cl-), to synthesize two nickel azolium-based MOFs, 1 and 2. The as-synthesis MOFs were characterized by PXRD, TGA, FE-SEM, HR-TEM, FTIR and BET measurements. By applying 1 and 2 in liquid phase adsorption of charged molecules of dyes, they successfully exhibit remarkable efficiency for adsorptive removal of anionic dyes, Methyl orange (MO), Congo red (CR), and Orange II sodium salt (OS), from aqueous solution. The framework proves efficient in photocatalytic degradation of anionic dye. Furthermore, in the gaseous phase adsorption, 1 and 2 selectively adsorb CO2 over CH4 due to the higher quadrupole moment of CO2. Overall, the results show that azolium-based MOFs have potential applications for adsorptive removal of charged organic contaminants from both aqueous and gaseous environment. PMID- 29501994 TI - Hydrogen bond-induced bright enhancement of fluorescent silica cross-linked micellar nanoparticles. AB - This work demonstrated the synthesis and design of ultra-bright and ultra-small fluorescent nanoparticles, which were prepared by encapsulating 4 (diphenylamino)benzaldehyde (DPB) in silica cross-linked micellar nanoparticles (SCMNPs). The DPB-doped SCMNPs (DPB-SCMNPs) exhibited ultra-bright fluorescence in an aqueous medium that was 22 times brighter than that of free DPB molecules in an organic solvent. For the first time, density functional theory (DFT) and time-dependent density functional theory (TDDFT) calculations were used to confirm that the enhanced brightness of the DPB-SCMNPs was due to a hydrogen bond induced mechanism. In addition, the 3D fluorescence spectra and the Commission Internationale de L'Eclairage (CIE) diagram were employed to determine the optical properties and emission colour of the DPB-SCMNPs. Moreover, the DPB SCMNPs were water-soluble, monodisperse and ultra-small (~12 nm) and should be robust and stable in aqueous media and biological systems. PMID- 29501995 TI - Elucidating Bauhinia variegata lectin/phosphatidylcholine interactions in lectin containing liposomes. AB - Investigations focused on the interactions of nanoparticles with lectins are relevant since it is well accepted that such proteins can be recognized by carbohydrates as parts of cell membranes. This can ultimately enhance the cellular uptake of the produced assemblies. In this framework, the physical interactions of phosphatidylcholine (PC) liposomes and the Bauhinia variegate lectin (BVL) are reported here. BVL-liposome interactions were characterized by a variety of techniques to understand the influence of BVL in the structural features, thermodynamic and spectroscopic properties of the hybrid material. The produced system is composed of 56% w/w lectin, and the scattering techniques show the presence of stable vesicular structures with a mean diameter DH ~ 100 nm. The FTIR and NMR results showed a strong lectin effect on the PC choline region, restricting the rotational motion of the lipid group. The BVL-liposome interaction promoted hardening of the protein as evidenced by circular dichroism spectroscopy. The photophysics results suggest higher rigidity of the system in the presence of BVL. The BVL may be present in the inner or outer polar surface of the liposomes. The system was shown to be relatively stable and therefore potentially useful for carbohydrate recognition of nanoparticles. PMID- 29501996 TI - Electro-elastoviscous response of polyaniline functionalized nano-porous zeolite based colloidal dispersions. AB - The present article discusses the typical influence of grafted conducting polymers in the mesoscale pores of dielectric particles on the static and dynamic electrorheology and electro-viscoelastic behavior of corresponding colloids. Nanocrystalline meso-nanoporous zeolite has been prepared by chemical synthesis and subsequently polyaniline (PANI) coating has been implemented. Electrorheological (ER) suspensions have been formed by dispersing the nanoparticles in silicone oil and their viscoelastic behaviors are examined to understand the nature of such complex colloidal systems under electric fields. PANI-Zeolite ER fluids demonstrate higher static electroviscous effects and yield stress potential than untreated Zeolite, typically studied in literature. Transient electro-viscous characterizations show a stable and negligible hysteresis behavior when both the fluids are exposed to constant as well as time varying electric field intensities. Further oscillatory shear experiments of frequency and strain sweeps exhibit predominant elastic behavior in case of Zeolite based ER suspensions as compared to PANI systems. Detailed investigations reveal Zeolite based ER suspensions display enhanced relative yielding as well as electro-viscoelastic stability than the PANI-Zeolite. The steady state viscous behaviors are scaled against the non-dimensional Mason number to model the system behavior for both fluids. Experimental data of flow behaviors of both the ER fluids are compared with semi-classical models and it is found that the CCJ model possesses a closer proximity than traditional Bingham model, thereby revealing the fluids to be generic pseudo-linear fluids. The present article reveals that while the PANI based fluids are typically hailed superior in literature, it is only restricted to steady shear utilities. In case of dynamic and oscillatory systems, the traditional Zeolite based fluids exhibit superior ER caliber. PMID- 29501997 TI - Characterization of regulatory elements in OsRGLP2 gene promoter from different rice accessions through sequencing and in silico evaluation. AB - Germins and germin-like proteins from cupin superfamily contribute resistance to heat denaturation, chemical degradation and against plant pathogens, further functions in plant growth and development. In this study, from three different Oryza sativa accessions KS-282 and Pak 7178 and Pak 7865, OsRGLP2 gene promoter region was amplified, sequenced and analyzed. Sequencing data was evaluated via different computational tools. The regulatory elements were predicted by Consite tool and mapping was done. Many transcription factors binding sites were discovered in OsRGLP2 gene promoter; among these factors, HFH-1 having a significant role in germination was picked for further investigation. To study the interaction between HFH-1 and corresponding regulatory factors, HADDOCK Webserver was used. Graphical models for the interactions of HFH-1 and related regulatory elements were studied by graphic molecular system PyMOL. Mapping of cis-acting regulatory elements in OsRGLP2 gene promoter from three rice accessions showed differences in their position and copy number. Important regulatory elements found in OsRGLP2 promoter region were TATA, CAAT Box, ARR1, GATA, AGAAA, CAAT and DNA-binding One Zinc Finger (Dof) factors, few of them contribute to the regulation of plant defensive system, light responses, developmental and growth activities. Furthermore, during DNA interaction studies, it was found that HFH-1 transcription factor participates in hydrogen bonds formation with thymine and adenine bases. PMID- 29501998 TI - Destruction processes of mining on water environment in the mining area combining isotopic and hydrochemical tracer. AB - There is less research on the hydrological system and its destruction processes mechanism in the mining areas, especially combined application of isotope technology and chemical signals, which is a key scientific problem that need to be solved. This study takes Jinci spring area in Shanxi as a case study. It is based on the data of hydrology and mining condition from 1954 to 2015, combining monitoring experiments, O18, D, S34 and N15 tracing, chemical and model simulation. This study investigates the hydrological regularity and impacts of mining activities on water quantity and quality, and reveals the destruction process of hydrological system. The results show that: (1) Water chemical type shows an evolutionary trend of HCO3--Ca2+-Mg2+->SO42--HCO3--Ca2+-Mg2+->SO42--Ca2+ Mg2+, due to the influence of exploitation and fault zones. Isotope tracer shows that mine pit water is formed by a mixture of pore water, karst water and surface water. (2) Although precipitation and seepage have a certain impact on the reducing of groundwater quantity, over-exploitation of water resource is still the main reason for reducing of groundwater quantity. Under the conditions of keeping the exploitation intensity at the current level or reducing it by 10%, groundwater level shows a declining trend. Under the condition of reducing it by 30%, groundwater level starts to rise up. When reducing by 50%, groundwater level reaches its highest point. Coalmining changes the runoff, recharge and discharge paths. (3) From 1985 to 2015, Water quality in the mining area is worsening. Ca2+ increases by 35.30%, SO42- increases by 52.80%, and TDS (Total Dissolved Solid) increases by 67.50%. Nitrates come from the industrial and domestic wastewater, which is generated by mining. The percentage of groundwater coming from gypsum dissolusion is 67.51%, and the percentage from coal measure strata water is 34.49%. The water qualities of river branches are generally deteriorated. PMID- 29501999 TI - Source apportionment of PM2.5 organic carbon in the San Joaquin Valley using monthly and daily observations and meteorological clustering. AB - Two hundred sixty-three fine particulate matter (PM2.5) samples collected on 3 day intervals over a 14-month period at two sites in the San Joaquin Valley (SJV) were analyzed for organic carbon (OC), elemental carbon (EC), water soluble organic carbon (WSOC), and organic molecular markers. A unique source profile library was applied to a chemical mass balance (CMB) source apportionment model to develop monthly and seasonally averaged source apportionment results. Five major OC sources were identified: mobile sources, biomass burning, meat smoke, vegetative detritus, and secondary organic carbon (SOC), as inferred from OC not apportioned by CMB. The SOC factor was the largest source contributor at Fresno and Bakersfield, contributing 44% and 51% of PM mass, respectively. Biomass burning was the only source with a statistically different average mass contribution (95% CI) between the two sites. Wintertime peaks of biomass burning, meat smoke, and total OC were observed at both sites, with SOC peaking during the summer months. Exceptionally strong seasonal variation in apportioned meat smoke mass could potentially be explained by oxidation of cholesterol between source and receptor and trends in wind transport outlined in a Residence Time Analysis (RTA). Fast moving nighttime winds prevalent during warmer months caused local emissions to be replaced by air mass transported from the San Francisco Bay Area, consisting of mostly diluted, oxidized concentrations of molecular markers. Good agreement was observed between SOC derived from the CMB model and from non biomass burning WSOC mass, suggesting the CMB model is sufficiently accurate to assist in policy development. In general, uncertainty in monthly mass values derived from daily CMB apportionments were lower than that of CMB results produced with monthly marker composites, further validating daily sampling methodologies. Strong seasonal trends were observed for biomass and meat smoke OC apportionment, and monthly mass averages had lowest uncertainty when derived from daily CMB apportionments. PMID- 29502000 TI - Dietary grape seed proanthocyanidin extract regulates metabolic disturbance in rat liver exposed to lead associated with PPARalpha signaling pathway. AB - Lead, a pervasive environmental hazard worldwide, causes a wide range of physiological and biochemical destruction, including metabolic dysfunction. Grape seed proanthocyanidin extract (GSPE) is a natural production with potential metabolic regulation in liver. This study was performed to investigate the protective role of GSPE against lead-induced metabolic dysfunction in liver and elucidate the potential molecular mechanism of this event. Wistar rats received GSPE (200 mg/kg) daily with or without lead acetate (PbA, 0.5 g/L) exposure for 56 d. According to biochemical and histopathologic analysis, GSPE attenuated lead induced metabolic dysfunction, oxidative stress, and liver dysfunction. Liver gene expression profiling was assessed by RNA sequencing and validated by qRT PCR. Expression of some genes in peroxisome proliferator-activated receptor alpha (PPARalpha) signaling pathway was significantly suppressed in PbA group and revived in PbA + GSPE group, which was manifested by Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis and validated by western blot analysis. This study supports that dietary GSPE ameliorates lead-induced fatty acids metabolic disturbance in rat liver associated with PPARalpha signaling pathway, and suggests that dietary GSPE may be a protector against lead induced metabolic dysfunction and liver injury, providing a novel therapy to protect liver against lead exposure. PMID- 29502002 TI - Spatial and temporal trends in poly- and per-fluorinated compounds in the Laurentian Great Lakes Erie, Ontario and St. Clair. AB - The temporal and spatial trends in sediment of 22 poly- and perfluorinated (PFAS) compounds were investigated in the southern Great Lakes Erie and Ontario as well as Lake St. Clair. Surface concentrations measured by Ponar grab samples indicated a trend for greater concentrations near to urban sites. Mean concentrations ?22PFAS were 15.6, 18.2 and 19 ng g-1 dm for Lakes St. Clair, Erie and Ontario, respectively. Perfluoro-n-butanoic acid (PFBA) and Perfluoro-n hexanoic acid (PFHxA) were frequently determined in surface sediment and upper core samples indicating a shift in use patterns. Where PFBA was identified it was at relatively great concentrations typically >10 ng g-1 dm. However as PFBA and PFHxA are less likely to bind to sediment they may be indicative of pore water concentrations Sedimentation rates between Lake Erie and Lake Ontario differ greatly with greater rates observed in Lake Erie. In Lake Ontario, in general concentrations of PFAS observed in core samples closely follow the increase in use along with an observable change due to regulation implementation in the 1970s for water protection. However some of the more water soluble PFAS were observed in deeper core layers than the time of production could account for, indicating potential diffusion within the sediment. Given the greater sedimentation rates in Lake Erie, it was hoped to observe in greater resolution changes since the mid 1990s. However, though some decrease was observed at some locations the results are not clear. Many cores in Lake Erie had clearly observable gas voids, indicative of gas ebullition activity due to biogenic production, there were also observable mussel beds that could indicate mixing by bioturbation of core layers. PMID- 29502001 TI - Interactive responses of primary producers and grazers to pollution on temperate rocky reefs. AB - Macroalgal beds provide important habitat structure and support primary production for rocky reef communities, but are increasingly degraded as a result of human pressures. Various sources of pollution can have both direct and interactive effects on stressed ecosystems. In particular, interactions involving invertebrate grazers could potentially weaken or strengthen the overall impact of pollution on macroalgal beds. Using a paired impact-control experimental design, we tested the effects of multiple pollution sources (fish farms, marinas, sewerage, and stormwater) on translocated and locally established algal assemblages, while also considering the influence of invertebrate grazers. Marinas directly affected algal assemblages and also reduced densities of amphipods and other invertebrate mesograzers. Fish farms and sewerage outfalls tended to directly increase local establishment of foliose and leathery algae without any indication of changes in herbivory. Overall, pollution impacts on algae did not appear to be strongly mediated by changes in grazer abundance. Instead, mesograzer abundance was closely linked to availability of more complex algal forms, with populations likely to decline concurrently with loss of complex algal habitats. Macrograzers, such as sea urchins, showed no signs of a negative impact from any pollution source; hence, the influence of this group on algal dynamics is probably persistent and independent of moderate pollution levels, potentially adding to the direct impacts of pollution on algal beds in urbanised environments. PMID- 29502003 TI - Antibiotic and heavy metal resistance in enterococci from coastal marine sediment. AB - Sediment samples from three coastal sites - two beach resorts (Beach 1 and Beach 2 sites) and an area lying between an oil refinery and a river estuary (Estuarine site) - were analyzed for antibiotic- and heavy metal (HM)-resistant enterococci. A total of 123 enterococci, 36 E. faecium, 34 E. casseliflavus, 33 E. hirae, 5 E. faecalis, 3 E. durans, 3 E. gallinarum, and 9 Enterococcus spp, were recovered. Strains resistant to erythromycin, tetracycline and quinupristin/dalfopristin (Q/D) were recovered from all sites, whereas multidrug-resistant isolates were recovered only from "Beach 2" (14%) and "Estuarine" (3.7%). As regards HM resistance, the strains showed a high frequency (68%) of cadmium and/or copper resistance and uniform susceptibility to mercury. The prevalence of cadmium resistant strains was significantly higher among erythromycin-resistant than among erythromycin-susceptible strains. A significant association between cadmium or copper resistance and Q/D resistance was also observed at "Estuarine" site. The levels of the two HMs in sediment from all sites were fairly low, ranging from 0.070 to 0.126 MUg/g, for cadmium and from 1.00 to 7.64 MUg/g for copper. Mercury was always undetectable. These findings are consistent with reports that low HM concentrations may contribute to co-selection of antibiotic-resistant bacterial strains, including enterococci. PMID- 29502004 TI - Establishment of a dietary exposure assay for evaluating the toxicity of insecticidal compounds to Apolygus lucorum (Hemiptera: Miridae). AB - With the commercialization of transgenic cotton that expresses Bt (Bacillus thuringiensis) insecticidal proteins, mirid bugs have become key pests in cotton and maize fields in China. Genetically engineered (GE) crops for controlling mirids are unavailable owing to a lack of suitable insecticidal genes. In this study, we developed and validated a dietary exposure assay for screening insecticidal compounds and for assessing the potential effects of insecticidal proteins produced by GE plants on Apolygus lucorum, one of the main mirid pests of Bt cotton and Bt maize. Diets containing potassium arsenate (PA) or the cysteine protease inhibitor E-64 were used as positive controls for validating the efficacy of the dietary exposure assay. The results showed that with increasing concentrations of PA or E-64, A. lucorum larval development time was prolonged and adult weight and fecundity were decreased, suggesting that the dietary exposure assay was useful for detecting the toxicity of insecticidal compounds to A. lucorum. This assay was then used to assess the toxicity of Cry1Ab, Cry1Ac, Cry1F, Cry2Aa, and Cry2Ab proteins, which have been transformed into several crops, against A. lucorum. The results showed that A. lucorum did not show a negative effect by feeding on an artificial diet containing any of the purified Cry proteins. No significant changes in the activities of digestive, detoxifying, or antioxidant enzymes were detected in A. lucorum that fed on a diet containing Cry proteins, but A. lucorum fitness was reduced when the insect fed on a diet containing E-64 or PA. These results demonstrate that A. lucorum is not sensitive to the tested Cry proteins and that the dietary exposure assay is useful for evaluating the toxicity of insecticidal compounds to this species. PMID- 29502005 TI - Tracing the incorporation of carbon into benthic foraminiferal calcite following the Deepwater Horizon event. AB - Following the Deepwater Horizon (DWH) event in 2010, hydrocarbons were deposited on the continental slope in the northeastern Gulf of Mexico through marine oil snow sedimentation and flocculent accumulation (MOSSFA). The objective of this study was to test the hypothesis that benthic foraminiferal delta13C would record this depositional event. From December 2010 to August 2014, a time-series of sediment cores was collected at two impacted sites and one control site in the northeastern Gulf of Mexico. Short-lived radioisotopes (210Pb and 234Th) were employed to establish the pre-DWH, DWH, and post-DWH intervals. Benthic foraminifera (Cibicidoides spp. and Uvigerina spp.) were isolated from these intervals for delta13C measurement. A modest (0.2-0.40/00), but persistent delta13C depletion in the DWH intervals of impacted sites was observed over a two year period. This difference was significantly beyond the pre-DWH (background) variability and demonstrated that benthic foraminiferal calcite recorded the depositional event. The longevity of the depletion in the delta13C record suggested that benthic foraminifera may have recorded the change in organic matter caused by MOSSFA from 2010 to 2012. These findings have implications for assessing the subsurface spatial distribution of the DWH MOSSFA event. PMID- 29502006 TI - Diverse mechanisms drive fluoride enrichment in groundwater in two neighboring sites in northern China. AB - Excessive amounts of fluoride in drinking groundwater are harmful to human health, but the mechanisms responsible for fluoride enrichment in groundwater are not fully understood. Samples from two neighboring areas with endemic fluorosis were collected to test the hypothesis that there are distinctly different mechanisms responsible for the enrichment of fluoride in these groundwater. Hydrochemistry, stable isotopes and geochemical simulation were conducted together to investigate the fluoride spatial distribution and the diversity of responsible mechanisms. Our results showed that the spatial distributions of fluoride are different: I) high [F] in fresh shallow groundwater (SGQJ) and II) medium [F] in fresh to brackish deep groundwater (DGQJ) in the Qiji area; and III) medium [F] in brackish shallow groundwater (SGYH) and IV) low [F] in fresh deep groundwater (DGYH) in the Yanhu area. We also found that the fluoride concentration in groundwater is primarily controlled by the dissolution equilibrium of fluorite, as suggested by the correlation between [F] and [Ca]. However, there are other significant mechanisms: 1) for SGQJ, fluoride-bearing minerals (such as fluorite) dissolution, along with moderate evaporation, cation exchange and the more alkaline conditions are the driving factors; 2) for SGYH, the contributing factors are strong evaporation, the salt effect, dissolution of evaporites, gypsum and dolomite, bicarbonate-fluoride competition and anthropogenic activity; 3) for DGQJ, cation exchange, alkaline conditions and competitive adsorption are major factors; and 4) dolomite dissolution promotes the [F] increase in DGYH. Our findings suggest that the hydrogeochemical conditions play key roles in the enrichment of fluoride and that caution should be taken in the future when evaluating fluoride occurrence in groundwater, even in nearby areas. PMID- 29502007 TI - Comprehensive glycan analysis of twelve recombinant human erythropoietin preparations from manufacturers in China and Japan. AB - Recombinant, human, erythropoietin (rhEPO) is a glycoprotein hormone which is prescribed throughout the world to treat anaemia caused by chronic kidney disease or chemotherapy. rhEPO is at the forefront of the recent emergence of biosimilar medicines, with numerous products now available worldwide. Due to its complex glycosylation profile, which has a crucial influence upon biological activity, therapeutic rhEPO preparations must be closely monitored to ensure consistency, safety and efficacy. Here, we have compared twelve rhEPO preparations from eleven manufacturers in China and one in Japan, measuring in vivo biological activity and exploring its relationship with glycosylation through sialic acid content determination, isoform distribution via capillary electrophoresis (CE), O-glycan profiling, and N-glycan mapping using a novel anion-exchange/hydrophilic interaction chromatography-mass spectrometry (AEX/HILIC-MS) approach. We observed differences between glycosylation profiles, including the varying occurrence of sialic acid O-acetylation, extension of N-glycan antennae with N acetyllactosamine units, and the distribution of sialic acids across multi antennary structures. The presence of unusually high levels of suspected penta- and hexa-anionic N-glycans in several samples is consistent with elevated rhEPO isoform acidity, which is reflected by slightly elevated in vivo bioactivities. This aside, the observed differences in glycosylation profile do not appear to have a significant influence upon biological activity in mice. Nonetheless, with the continued emergence of biosimilars, the study highlights the importance of monitoring glycosylation profiles in biological medicines, in order to detect and account for divergence between products, as well as the presence of unusual or unexpected glycans. PMID- 29502009 TI - The role of visual experience in the emergence of cross-modal correspondences. AB - Cross-modal correspondences describe the widespread tendency for attributes in one sensory modality to be consistently matched to those in another modality. For example, high pitched sounds tend to be matched to spiky shapes, small sizes, and high elevations. However, the extent to which these correspondences depend on sensory experience (e.g. regularities in the perceived environment) remains controversial. Two recent studies involving blind participants have argued that visual experience is necessary for the emergence of correspondences, wherein such correspondences were present (although attenuated) in late blind individuals but absent in the early blind. Here, using a similar approach and a large sample of early and late blind participants (N = 59) and sighted controls (N = 63), we challenge this view. Examining five auditory-tactile correspondences, we show that only one requires visual experience to emerge (pitch-shape), two are independent of visual experience (pitch-size, pitch-weight), and two appear to emerge in response to blindness (pitch-texture, pitch-softness). These effects tended to be more pronounced in the early blind than late blind group, and the duration of vision loss among the late blind did not mediate the strength of these correspondences. Our results suggest that altered sensory input can affect cross-modal correspondences in a more complex manner than previously thought and cannot solely be explained by a reduction in visually-mediated environmental correlations. We propose roles of visual calibration, neuroplasticity and structurally-innate associations in accounting for our findings. PMID- 29502008 TI - Time-dependent transcriptional response of GOT1 human small intestine neuroendocrine tumor after 177Lu[Lu]-octreotate therapy. AB - INTRODUCTION: Patients with neuroendocrine tumors expressing somatostatin receptors are often treated with 177Lu[Lu]-octreotate. Despite being highly effective in animal models, 177Lu[Lu]-octreotate-based therapies in the clinical setting can be optimized further. The aims of the study were to identify and elucidate possible optimization venues for 177Lu[Lu]-octreotate tumor therapy by characterizing transcriptional responses in the GOT1 small intestine neuroendocrine tumor model in nude mice. METHODS: GOT1-bearing female BALB/c nude mice were intravenously injected with 15 MBq 177Lu[Lu]-octreotate (non-curative amount) or mock-treated with saline solution. Animals were killed 1, 3, 7 or 41 d after injection. Total RNA was extracted from the tumor samples and profiled using Illumina microarray expression analysis. Differentially expressed genes were identified (treated vs. control) and pathway analysis was performed. RESULTS: Distribution of differentially expressed transcripts indicated a time dependent treatment response in GOT1 tumors after 177Lu[Lu]-octreotate administration. Regulation of CDKN1A, BCAT1 and PAM at 1 d after injection was compatible with growth arrest as the initial response to treatment. Upregulation of APOE and BAX at 3 d, and ADORA2A, BNIP3, BNIP3L and HSPB1 at 41 d after injection suggests first activation and then inhibition of the intrinsic apoptotic pathway during tumor regression and regrowth, respectively. CONCLUSION: Transcriptional analysis showed radiation-induced apoptosis as an early response after 177Lu[Lu]-octreotate administration, followed by pro-survival transcriptional changes in the tumor during the regrowth phase. Time-dependent changes in cell cycle and apoptosis-related processes suggest different time points after radionuclide therapy when tumor cells may be more susceptible to additional treatment, highlighting the importance of timing when administering multiple therapeutic agents. PMID- 29502010 TI - Customizing the coefficients of urban domestic pollutant discharge and their driving mechanisms: Evidence from the Taihu Basin, China. AB - Discharge of urban domestic pollution has risen sharply during China's extensive urbanization. Together with understanding the complexity of influencing factors underpinning this rise, it has become a pressing issue to estimate total discharge and illustrate its driving mechanism scientifically. This paper reports on the monitoring of discharge from 36 sampling sites in selected residential districts in the heavily polluted Taihu Basin, China. The data were used to estimate the total amount of discharge, to develop corresponding urban domestic pollutant discharge coefficients and to analyse associated spatial patterns. Data from a questionnaire survey of over 1000 households in downtown, suburb and market town areas were then used to apply an econometric model in order to distinguish driving mechanisms. The urban domestic pollutant discharge coefficients developed in this paper are generally smaller than those reported nationally for China, based on more generalised data, decaying from city centres to the urban periphery. This study quantifies the amount of discharge and also demonstrates that urban domestic pollutant discharge is driven by multiple factors. For example, urban domestic pollution discharge rates were positively correlated with income and female-dominated households also tend to discharge more wastewater. Other factors were found to have negative correlations, such as sewage treatment rates, awareness of environmental protection, age and degree of education. As well as providing new and refined data on urban pollution discharge characteristics, the research in this paper also demonstrates the utility of combining household questionnaire and sample monitoring data in order to yield greater insights into the causes of typical polluting behaviour in Chinese neighbourhoods. PMID- 29502011 TI - A novel step-by-step optimization method for interplant water networks. AB - This paper evaluated the characteristics of interplant water networks along with superstructure models of such networks coordinated with intermediate pools, with the latter being assessed via nonlinear programming tools. To overcome the inherent difficulties associated with nonlinear programming models, a superstructure model was ultimately simplified according to a unidirectional characteristic. A novel step-by-step optimization method was then set forth for this simplified model. And the novel method was then applied to two examples, a single contaminant example from the literature and a multiple contaminants example located in southern China, which could demonstrate the applicability and effectiveness of the proposed method. PMID- 29502012 TI - Combining microwave irradiation with sodium citrate addition improves the pre treatment on anaerobic digestion of excess sewage sludge. AB - This study investigated the synergistic effect of sodium citrate (SC; Na3C3H5O(COO)3) and microwave (MW) treatment on the efficiency of the anaerobic digestion of excess sewage sludge. In terms of the methane yield, an increase of the digestion's efficiency was observed. Taking into account the cost for the MW energy supplied to the system, the optimum treatment conditions were a MW energy input of 20 MJ/kg TS and a SC concentration of 0.11 g/g TS, obtaining a methane yield of 218.88 ml/g VS, i.e., an increase of 147.7% compared to the control. MW treatment was found to break the sludge structure, thereby improving the release of extracellular polymeric substances (EPS) and volatile fatty acids (VFAs). The treatment of sodium citrate further strengthened the breakage of loosely bound extracellular polymeric substances (LB-EPS) and tightly bound extracellular polymeric substances (TB-EPS). The increased VFA content stressed the improved digestion by this pretreatment. Furthermore, the preliminary economic analysis showed that at this point in the research, only operational but no financial gains were achieved. PMID- 29502013 TI - Kinetics of Acid Orange 7 oxidation by using carbon fiber and reticulated vitreous carbon in an electro-Fenton process. AB - In this study, a micro-scale parallel plate reactor was built to electrochemically generate hydrogen peroxide (H2O2) and to develop the Fenton reaction in situ, for the treatment of toxic organic pollutants. Two types of carbon materials were compared and used as cathodes: unidirectional carbon fiber (CF) and reticulated vitreous carbon (RVC). As anode, a stainless steel mesh was used. The results of H2O2 were experimentally compared by means of electrogeneration process. RVC cathode with dimensions of 2.5 * 1 * 5 cm (170 mA and variable voltage V = 2.0-2.7) and 180 min produced 5.3 mM H2O2, with an H2O2 production efficiency of 54%. Unidirectional carbon fiber cathode produced 7.5 mM of H2O2 (96% of H2O2 production efficiency) when a voltage of 1.8 V was applied during 180 min to a total area of 480 cm2 of this material. Acid Orange 7 (AO7) was degraded to a concentration of 0.16 mM during the first 40 min of the process, which represented 95% of the initial concentration. Electrolysis process removed nearly 100% of the AO7 using both cathodes at the end of these experiments (180 min). PMID- 29502014 TI - Effect of hydrophobic and hydrophilic nanoparticles loaded in D2EHPA/M2EHPA - PTFE supported liquid membrane for simultaneous cationic dyes pertraction. AB - Cationic dyes mixture pertraction experiments of Rhodamine B (RhB) and Methylene Blue (MB) using a flat sheet supported liquid membrane (SLM) were performed. Mono (2-etylhexyl) ester of phosphoric acid (M2EHPA) and bis-(2-etylhexyl) ester of phosphoric acid (D2EHPA) mixture was used as carrier and Sesame oil to dilute the carrier due to its very high viscosity. Acetic acid (AA) was also used as stripper phase. Influences of hydrophobic and hydrophilic nanoparticles were loaded in a carrier at different loadings (from 0 to 6 mg mL-1) on dyes pertraction at constant operating conditions were investigated. It was found that hydrophilic nanoparticles, including ZnO and TiO2 decrease dyes pertraction, while hydrophobic nanoparticles, including ZIF-8 and Fe3O4 favorably increase this parameter. ZIF-8 was found as the most effective nanoparticles on increasing dyes pertraction and the optimum loading was 2 mg mL-1. Also, the important process parameters that influence on the dyes mixture pertraction efficiency such as feed concentration, carrier concentration, feed pH and strip concentration were studied. In order to investigate the effects of operating parameters, all experiments were performed at a constant 2 mg mL-1 ZIF-8 loading. Optimum pertraction efficiency of RhB and MB were 90.6 and 79.4%, respectively. They were obtained after 10 h pertraction at optimum experimental conditions with feed concentration of 100 mg L-1, carrier concentration of 35% (vol), strip concentration of 0.5 mol L-1, and feed pH of 6. Effect of time on pertraction efficiencies at the optimum conditions were also studied. PMID- 29502015 TI - High-rate algal pond coupled with a matrix of Spirogyra sp. for treatment of rural streams with nutrient pollution. AB - This study evaluated the unique features of a filamentous algae matrix (FAM) that can be applied to high rate algal ponds (HRAPs) as a promising way to remove nutrient from polluted rural streams. The results show that the HRAPs, coupled with the FAM, effectively removed nitrogen and phosphorus (79.8% and 81.2%, respectively), and achieved high production of DO, with a maximum of 11.0 g O2 g FAM-1 d-1. The FAM functioned wells as a screen to prevent excessive algae loss from the system and obtained relatively high biomass growth rate (0.032 mg L-1 d 1 for nitrogen and 0.344 mg L-1 d-1 for phosphorus). The harvested FAM was a useful fertilizer and the rate of addition of FAM were 1.52 kg d-1 ha-1 of nitrogen and 0.44 kg d-1 ha-1 of phosphorus. Thus, combining the HRAP with the FAM was an effective nutrient removal and resource utilization system for rural streams. PMID- 29502016 TI - Assessing the impacts of land use on downstream water quality using a hydrologically sensitive area concept. AB - Understanding the relationship between land use and water quality is essential to improve water quality through carefully managing landscape change. This study applies a linear mixed model at both watershed and hydrologically sensitive areas (HSAs) scales to assess such a relationship in 28 northcentral New Jersey watersheds located in a rapidly urbanizing region in the United States. Two models differ in terms of the geographic scope used to derive land use matrices that quantify land use conditions. The land use matrices at the watershed and HSAs scales represent the land use conditions in these watersheds and their HSAs, respectively. HSAs are the hydrological "hotspots" in a watershed that are prone to runoff generation during storm events. HSAs are derived using a soil topographic index (STI) that predicts hydrological sensitivity of a landscape based on a variable source area hydrology concept. The water quality indicators in these models are total nitrogen (TN), total phosphorus (TP) and total suspended solids (TSS) concentrations in streams observed at the watershed outlets. The modeling results suggest that presence of low density urban land, agricultural land and wetlands elevate while forest decreases TN, TP and/or TSS concentrations in streams. The watershed scale model tends to emphasize the role of agricultural lands in water quality degradation while the HSA scale model highlights the role of forest in water quality improvement. This study supports the hypothesis that even though HSAs are relatively smaller area compared to watershed, still the land uses within HSAs have similar impacts on downstream water quality as the land uses in entire watersheds, since both models have negligible differences in model evaluation parameters. Inclusion of HSAs brings an interesting perspective to understand the dynamic relationships between land use and water quality. PMID- 29502017 TI - Using Myriophyllum aquaticum (Vell.) Verdc. to remove heavy metals from contaminated water: Better dead or alive? AB - This study aimed to investigate the potential of the invasive macrophyte Myriophyllum aquaticum to remove heavy metals. The elements tested were Cd, Cr, Ni, and Zn, in single-metal trials, and experiments were performed with both the living and dead biomass of the plant. In respect of metal removal by living plants, the element that was removed the most was Zn, though Cd showed the highest concentration in plant shoots. The metal negative effect on plant growth was, therefore, more important than the level of metal concentration in plant tissue in determining the removal percentages. All the metals were mostly accumulated in the roots, where a considerable fraction of the element was simply adsorbed to root cell wall, except in the case of Cr. In shoots, the fraction of the adsorbed metal was extremely low in respect to roots, thereby implying a lower apoplastic binding capacity. As regards a possible use of the dead biomass for metal removal, we proposed the generation of a hybrid biosorbent enclosing the dried and grounded plant biomass in cotton bags to improve its handling and its adsorption capacity, in view of a valid alternative to reduce the problems of packed beds. Cadmium-and especially Zn-were the elements removed most efficiently with respect to the other metals. On comparing the removal percentages of the living biomass and the hybrid biosorbent, our data deposed in favour of the use of M. aquaticum as dead biomass for a possible application of this invasive macrophyte in the biological treatment of metal-contaminated water. Our findings may be beneficial to metal removal application accompanying wetland management, devising a possible use of M. aquaticum waste material after its removal from the invaded habitats. PMID- 29502018 TI - Ensuring food security with lower environmental costs under intensive agricultural land use patterns: A case study from China. AB - Rapid population growth and environmental deterioration make ensuring food security with lower environmental costs fundamental to realizing sustainable development in China and other developing countries. The conceptual framework used in this paper integrates the major consequences of intensive agricultural land use and the diverse objectives of policymakers and farmers. It also offers an operational approach, based on farmers' diverse performance in grain production and farmland productivity, to assess food production and environmental impacts under foci-differentiated scenarios. Using data from farmer household surveys, soil surveys, land use images, and statistical yearbooks, this approach was tested using a regional case in China. The results indicate that, among all farmer types, the medium-scale farmers had a better comprehensive performance for grain production for yield, fertilizer and pesticide inputs, labor productivity, and sustainability. Therefore, grain yields can be increased and environmental costs reduced simultaneously through the use of policy instruments that encourage the transformation of trapped farmers into medium-scale farmers and balancing the proportion of single and double cropped rice. In addition, and in order to reduce grain losses caused by natural disasters and to prevent environmental degradation, robust policy measures should be developed to avoid the currently predominant cropping patterns that erode biodiversity. PMID- 29502019 TI - Exploring the effects of nitrogen fertilization management alternatives on nitrate loss and crop yields in tile-drained fields in Illinois. AB - It is vital to manage the excessive use of nitrogen (N) fertilizer in corn production, the single largest consumer of N fertilizer in the United States, in order to achieve more sustainable agroecosystems. This study comprehensively explored the effects of N fertilization alternatives on nitrate loss and crop yields using the Root Zone Water Quality Model (RZWQM) in tile-drained fields in central Illinois. The RZWQM was tested for the prediction of tile flow, nitrate loss, and crop yields using eight years (1993-2000) of observed data and showed satisfactory model performances from statistical and graphical evaluations. Our model simulations demonstrated the maximum return to nitrogen (MRTN) rate (193 kgha-1), a newly advised N recommendation by the Illinois Nutrient Loss Reduction Strategy (INLRS), can be further reduced. Nitrate loss was reduced by 10.3% and 29.8%, but corn yields decreased by 0.3% and 1.9% at 156 and 150 kgha-1 of N fertilizer rate in the study sites A and E, respectively. Although adjustment of N fertilization timing presented a further reduction in nitrate loss, there was no optimal timing to ensure nitrate loss reduction and corn productivity. For site A, 100% spring application was the most productive and 40% fall, 10% pre plant, and 50% side dress application generated the lowest nitrate loss. For site E, the conventional N application timing was verified as the best practice in both corn production and nitrate loss reduction. Compared to surface broadcast placement, injected N fertilizer in spring increased corn yield, but may also escalate nitrate loss. This study presented the need of an adaptive N fertilizer management due to the heterogeneity in agricultural systems, and raised the importance of timing and placement of N fertilizer, as well as further reduction in fertilizer rate to devise a better in-field N management practice. PMID- 29502020 TI - Enhancing quantitative approaches for assessing community resilience. AB - Scholars from many different intellectual disciplines have attempted to measure, estimate, or quantify resilience. However, there is growing concern that lack of clarity on the operationalization of the concept will limit its application. In this paper, we discuss the theory, research development and quantitative approaches in ecological and community resilience. Upon noting the lack of methods that quantify the complexities of the linked human and natural aspects of community resilience, we identify several promising approaches within the ecological resilience tradition that may be useful in filling these gaps. Further, we discuss the challenges for consolidating these approaches into a more integrated perspective for managing social-ecological systems. PMID- 29502021 TI - The construction of feelings of justice in environmental management: An empirical study of multiple biodiversity conflicts in Calakmul, Mexico. AB - A failure to address social concerns in biodiversity conservation can lead to feelings of injustice among some actors, and hence jeopardize conservation goals. The complex socio-cultural and political context of the Calakmul Biosphere Reserve, Mexico, has historically led to multiple biodiversity conflicts. Our goal, in this case study, was to explore perceptions of justice held by local actors in relation to biodiversity conflicts. We then aimed to determine the following: 1) people's definitions of their feelings of justice; 2) the criteria used in this assessment; 3) variability in the criteria influencing them; and 4) implications for environmental management in the region and beyond. We worked with five focus groups, exploring three examples of biodiversity conflict around forest, water and jaguar management with a total of 41 ranchers, farmers and representatives of local producers. Our results demonstrated that people constructed their feelings of justice around four dimensions of justice: recognition (acknowledging individuals' rights, values, cultures and knowledge systems); ecological (fair and respectful treatment of the natural environment), procedural (fairness in processes of environmental management), distributive (fairness in the distribution of costs and benefits). We identified a list of criteria the participants used in their appraisal of justice and sources of variation such as the social scale of focus and participant role, and whom they perceived to be responsible for resource management. We propose a new framework that conceptualizes justice-as-recognition and ecological justice as forms of conditional justices, and procedural and distributive justices as forms of practical justice. Conditional justice allows us to define who is a legitimate source of justice norms and if nature should be integrated in the scope of justice; hence, conditional justice underpins other dimensions of justice. On the other hand, procedural and distributive address the daily practices of fair processes and distribution. We propose that the perception of justice is a neglected but important aspect to include in integrative approaches to managing biodiversity conflicts. Addressing demands of justice in environmental management will require us to consider more than the distribution of costs and benefits among actors. We also need to respect the plurality of fairness perspectives and to recognize the benefits of dialogical approaches to achieve more successful environmental management. PMID- 29502022 TI - Understanding perceptions of stakeholder groups about Forestry Best Management Practices in Georgia. AB - Forestry Best Management Practices (BMPs) are critical in ensuring sustainable forest management in the United States because of their effectiveness in protecting water quality, reducing soil erosion, maintaining riparian habitat, and sustaining site productivity. The success of forestry BMPs depends heavily on coordination among primary stakeholder groups. It is important to understand perceptions of such groups for a successful forest policy formulation. We used the SWOT-AHP (Strengths, Weaknesses, Opportunities, and Threats analysis with the Analytical Hierarchy Process) framework to assess perceptions of three stakeholder groups (loggers, landowners, agency foresters) about forestry BMPs in Georgia, the largest roundwood producing state in the United States. The agency and logger stakeholder groups gave the highest priority to improved reputation under the strength category, whereas the landowner stakeholder group perceived sustainable forestry as the highest priority under the same category. Lack of landowner education was the highest priority under the weakness category for landowner and agency stakeholder groups, whereas the logger stakeholder group selected lack of trained personnel as the highest priority under the same category. Agency and landowner stakeholder groups gave the highest priority to training and education while loggers indicated maintenance of forest-based environmental benefits as their highest priority under the opportunity category. Finally, landowners and agency stakeholder groups perceived more regulations and restrictions as most significant in the threat category whereas the logger stakeholder group was most concerned about the insufficient accounting of cost sharing under the same category. Overall, selected stakeholder groups recognize the importance of forestry BMPs and had positive perceptions about them. A collaborative approach based on continuous feedback can streamline expectations of stakeholder groups about forestry BMPs in Georgia and several other states that are interested in maintaining high compliance rate of forestry BMPs for ensuring sustainable forest management. PMID- 29502023 TI - Cholinesterase inhibitory alkaloids from the rhizomes of Coptis chinensis. AB - Coptis chinensis has been used as a medicinal herb in traditional oriental medicine. In this study, chemical investigation of a water extract of C. chinensis identified two new quaternary protoberberines (1, 2), a new tricyclic amide (3), together with five known compounds. Their chemical structures were elucidated by analysis with 1D and 2D NMR and high-resolution mass spectroscopy, as well as by comparison with those reported in the literature. Compounds 4, 5, and 7 showed potent inhibition against acetylcholinesterase (AChE) with IC50 values of 1.1, 5.6, and 12.9 MUM, respectively. Compounds 2 and 4 showed inhibition of butyrylcholinesterase (BChE) with IC50 values of 11.5 and 27.8 MUM, respectively. The kinetic activities were investigated to find out the type of enzyme inhibition involved. The types of AChE inhibition shown by compounds 5 and 7 were noncompetitive; BChE inhibition by compound 2 was also noncompetitive. PMID- 29502024 TI - Synthesis and biological evaluation of novel pyrazoline-based aromatic sulfamates with potent carbonic anhydrase isoforms II, IV and IX inhibitory efficacy. AB - Herein we report the synthesis of a new series of aromatic sulfamates designed considering the sulfonamide COX-2 selective inhibitors celecoxib and valdecoxib as lead compounds. These latter were shown to possess important human carbonic anhydrase (CA, EC 4.2.1.1) inhibitory properties, with the inhibition of the tumor-associated isoform hCA IX likely being co-responsible of the celecoxib anti tumor effects. Bioisosteric substitution of the pyrazole or isoxazole rings from these drugs with the pyrazoline one was considered owing to the multiple biological activities ascribed to this latter heterocycle and paired with the replacement of the sulfonamide of celecoxib and valdecoxib with its equally potent bioisoster sulfamate. The synthesized derivatives were screened for the inhibition of four human carbonic anhydrase isoforms, namely hCA I, II, IV, and IX. All screened sulfamates exhibited great potency enhancement in inhibiting isoform II and IV, widely involved in glaucoma (KIs in the range of 0.4-12.4 nM and 17.7 and 43.3 nM, respectively), compared to the lead compounds, whereas they affected the tumor-associated hCA IX as potently as celecoxib. PMID- 29502025 TI - Potent dialkyl substrate-product analogue inhibitors and inactivators of alpha methylacyl-coenzyme A racemase from Mycobacterium tuberculosis by rational design. AB - Rational approaches for the design of enzyme inhibitors furnish powerful strategies for developing pharmaceutical agents and tools for probing biological mechanisms. A new strategy for the development of gem-disubstituted substrate product analogues as inhibitors of racemases and epimerases is elaborated using alpha-methylacyl-coenzyme A racemase from Mycobacterium tuberculosis (MtMCR) as a model enzyme. MtMCR catalyzes the epimerization at C2 of acyl-CoA substrates, a key step in the metabolism of branched-chain fatty acids. Moreover, the human enzyme is a potential target for the development of therapeutic agents directed against prostate cancer. We show that rationally designed, N,N-dialkylcarbamoyl CoA substrate-product analogues inactivate MtMCR. Binding greatly exceeds that of the substrate, (S)-ibuprofenoyl-CoA, up to ~250-fold and is proportional to the alkyl chain length (4-12 carbons) with the N,N-didecyl and N,N-didodecyl species having competitive inhibition constants with values of 1.9 +/- 0.2 MUM and 0.42 +/- 0.04 MUM, respectively. The presence of two decyl chains enhanced binding over a single decyl chain by ~204-fold. Overall, the results reveal that gem disubstituted substrate-product analogues can yield extremely potent inhibitors of an epimerase with a capacious active site. PMID- 29502026 TI - Rupestrines A-D, alkaloids from the aerial parts of Corydalis rupestris. AB - Phytochemical investigation of the dichloromethane extract of the dried aerial parts of Corydalis rupestris (Papaveraceae) resulted in the identification of four new isoquinoline alkaloids rupestrines A-D and one known isoquinoline alkaloid, namely, stylopine. The structures of these compounds were characterized by extensive spectroscopic methods including 1D- (1H and 13C) and 2D NMR experiments (COSY, HSQC, HMBC, and NOESY) as well as HRESIMS analyses. In addition, the absolute configurations of rupestrines A-D were determined using modified Mosher's method. Cytotoxic effects of alkaloids and their interaction with albumin were also investigated in this study. PMID- 29502027 TI - Potent ACE inhibitors from 5-hydroxy indanone derivatives. AB - A novel triazole derivatives(+/-)-2-(hydroxymethyl)-7,8-dihydro-1H-indeno[5,4 b]furan-6(2H)-one (12a-j) were designed and synthesized by the reaction between racemic azide and terminal acetylenes under click chemistry reaction conditions followed by biological evaluation as angiotensin converting enzyme (ACE) inhibitors. beta-Amino alcohol derivatives of 1-indanone (15a-l) were synthesized from 5-hydroxy indanone, it was reacted with epichlorohydrin and followed by oxirane ring opening with various piperazine derivatives. Among the newly synthesized compounds 12b (IC50: 1.388024 uM), 12g (IC50: 1.220696 uM), 12j (IC50: 1.312428 uM) and 15k (IC50: 1.349671 uM) and 15l (IC50: 1.330764 uM) emerged as most active non-carboxylic acid ACE inhibitors with minimal toxicity comparable to clinical drug Lisinopril. PMID- 29502028 TI - UPLC-G2Si-HDMS untargeted metabolomics for identification of metabolic targets of Yin-Chen-Hao-Tang used as a therapeutic agent of dampness-heat jaundice syndrome. AB - Yin-Chen-Hao-Tang (YCHT), the classic formulae of traditional Chinese medicine (TCM), is widely used to treat dampness-heat jaundice syndrome (DHJS) and various liver diseases. However, the therapeutic mechanism of YCHT is yet to have an integrated biological interpretation. In this work, we used metabolomics technology to reveal the adjustment of small molecule metabolites in body during the treatment of YCHT. Aim to discover the serum biomarkers which are associated with the treatment of DHJS against YCHT. Pathological results and biochemical indicators showed that the hepatic injury and liver index abnormalities caused by DHJS was effectively improve after treatment with YCHT. On the basis of effective treatment, ultra-high performance liquid chromatography (UPLC-G2Si-HDMS) combined with the multivariate statistical analysis method was utilized to analyze the serum samples. Finally, 22 biomarkers were identified by using mass spectrometry and illuminated the correlative metabolic pathways which play a significant role and as therapeutic targets in the treatment of DHJS. This work demonstrated that mass spectrometry metabolomics provides a new insight to elucidate the action mechanism of formulae. PMID- 29502029 TI - Micellar electrokinetic chromatography with laser induced fluorescence detection shows increase of putrescine in erythrocytes of Parkinson's disease patients. AB - A highly sensitive method was developed to measure putrescine by micellar electrokinetic chromatography with laser induced fluorescence detection with excellent linearity in the 1 nM to 3 MUM range. The technique was tested on a drop of blood from Parkinson's disease patients obtained by finger prick. The results showed a statistically significant increase of putrescine in the erythrocytes compared to controls and a non-significant increase in plasma. This high level of putrescine does not constitute by itself proof that putrescine and polyamines are directly related to Parkinson's disease. However, the present results and several others addressed in the discussion suggest that these compounds might be causally involved in the pathophysiology of Parkinson's disease. In addition, the analytical method reported here may help to find new biomarkers for many diseases including Parkinson's disease. PMID- 29502030 TI - Intrasubject multimodal groupwise registration with the conditional template entropy. AB - Image registration is an important task in medical image analysis. Whereas most methods are designed for the registration of two images (pairwise registration), there is an increasing interest in simultaneously aligning more than two images using groupwise registration. Multimodal registration in a groupwise setting remains difficult, due to the lack of generally applicable similarity metrics. In this work, a novel similarity metric for such groupwise registration problems is proposed. The metric calculates the sum of the conditional entropy between each image in the group and a representative template image constructed iteratively using principal component analysis. The proposed metric is validated in extensive experiments on synthetic and intrasubject clinical image data. These experiments showed equivalent or improved registration accuracy compared to other state-of the-art (dis)similarity metrics and improved transformation consistency compared to pairwise mutual information. PMID- 29502031 TI - Multiscale deep neural network based analysis of FDG-PET images for the early diagnosis of Alzheimer's disease. AB - Alzheimer's disease (AD) is one of the most common neurodegenerative diseases with a commonly seen prodromal mild cognitive impairment (MCI) phase where memory loss is the main complaint progressively worsening with behavior issues and poor self-care. However, not all individuals clinically diagnosed with MCI progress to AD. A fraction of subjects with MCI either progress to non-AD dementia or remain stable at the MCI stage without progressing to dementia. Although a curative treatment of AD is currently unavailable, it is extremely important to correctly identify the individuals in the MCI phase that will go on to develop AD so that they may benefit from a curative treatment when one becomes available in the near future. At the same time, it would be highly desirable to also correctly identify those in the MCI phase that do not have AD pathology so they may be spared from unnecessary pharmocologic interventions that, at best, may provide them no benefit, and at worse, could further harm them with adverse side-effects. Additionally, it may be easier and simpler to identify the cause of the cognitive impairment in these non-AD cases, and hence proper identification of prodromal AD will be of benefit to these individuals as well. Fluorodeoxy glucose positron emission tomography (FDG-PET) captures the metabolic activity of the brain, and this imaging modality has been reported to identify changes related to AD prior to the onset of structural changes. Prior work on designing classifier using FDG PET imaging has been promising. Since deep-learning has recently emerged as a powerful tool to mine features and use them for accurate labeling of the group membership of given images, we propose a novel deep-learning framework using FDG PET metabolism imaging to identify subjects at the MCI stage with presymptomatic AD and discriminate them from other subjects with MCI (non-AD / non-progressive). Our multiscale deep neural network obtained 82.51% accuracy of classification just using measures from a single modality (FDG-PET metabolism data) outperforming other comparable FDG-PET classifiers published in the recent literature. PMID- 29502032 TI - The decomposition of deformation: New metrics to enhance shape analysis in medical imaging. AB - In landmarks-based Shape Analysis size is measured, in most cases, with Centroid Size. Changes in shape are decomposed in affine and non affine components. Furthermore the non affine component can be in turn decomposed in a series of local deformations (partial warps). If the extent of deformation between two shapes is small, the difference between Centroid Size and m-Volume increment is barely appreciable. In medical imaging applied to soft tissues bodies can undergo very large deformations, involving large changes in size. The cardiac example, analyzed in the present paper, shows changes in m-Volume that can reach the 60%. We show here that standard Geometric Morphometrics tools (landmarks, Thin Plate Spline, and related decomposition of the deformation) can be generalized to better describe the very large deformations of biological tissues, without losing a synthetic description. In particular, the classical decomposition of the space tangent to the shape space in affine and non affine components is enriched to include also the change in size, in order to give a complete description of the tangent space to the size-and-shape space. The proposed generalization is formulated by means of a new Riemannian metric describing the change in size as change in m-Volume rather than change in Centroid Size. This leads to a redefinition of some aspects of the Kendall's size-and-shape space without losing Kendall's original formulation. This new formulation is discussed by means of simulated examples using 2D and 3D platonic shapes as well as a real example from clinical 3D echocardiographic data. We demonstrate that our decomposition based approaches discriminate very effectively healthy subjects from patients affected by Hypertrophic Cardiomyopathy. PMID- 29502034 TI - A Survey of Methods for 3D Histology Reconstruction. AB - Histology permits the observation of otherwise invisible structures of the internal topography of a specimen. Although it enables the investigation of tissues at a cellular level, it is invasive and breaks topology due to cutting. Three-dimensional (3D) reconstruction was thus introduced to overcome the limitations of single-section studies in a dimensional scope. 3D reconstruction finds its roots in embryology, where it enabled the visualisation of spatial relationships of developing systems and organs, and extended to biomedicine, where the observation of individual, stained sections provided only partial understanding of normal and abnormal tissues. However, despite bringing visual awareness, recovering realistic reconstructions is elusive without prior knowledge about the tissue shape. 3D medical imaging made such structural ground truths available. In addition, combining non-invasive imaging with histology unveiled invaluable opportunities to relate macroscopic information to the underlying microscopic properties of tissues through the establishment of spatial correspondences; image registration is one technique that permits the automation of such a process and we describe reconstruction methods that rely on it. It is thereby possible to recover the original topology of histology and lost relationships, gain insight into what affects the signals used to construct medical images (and characterise them), or build high resolution anatomical atlases. This paper reviews almost three decades of methods for 3D histology reconstruction from serial sections, used in the study of many different types of tissue. We first summarise the process that produces digitised sections from a tissue specimen in order to understand the peculiarity of the data, the associated artefacts and some possible ways to minimise them. We then describe methods for 3D histology reconstruction with and without the help of 3D medical imaging, along with methods of validation and some applications. We finally attempt to identify the trends and challenges that the field is facing, many of which are derived from the cross-disciplinary nature of the problem as it involves the collaboration between physicists, histolopathologists, computer scientists and physicians. PMID- 29502033 TI - Estimating fiber orientation distribution from diffusion MRI with spherical needlets. AB - We present a novel method for estimation of the fiber orientation distribution (FOD) function based on diffusion-weighted magnetic resonance imaging (D-MRI) data. We formulate the problem of FOD estimation as a regression problem through spherical deconvolution and a sparse representation of the FOD by a spherical needlets basis that forms a multi-resolution tight frame for spherical functions. This sparse representation allows us to estimate the FOD by l1-penalized regression under a non-negativity constraint on the estimated FOD. The resulting convex optimization problem is solved by an alternating direction method of multipliers (ADMM) algorithm. The proposed method leads to a reconstruction of the FOD that is accurate, has low variability and preserves sharp features. Through extensive experiments, we demonstrate the effectiveness and favorable performance of the proposed method compared to three existing methods. Specifically, we demonstrate that the proposed method is able to successfully resolve fiber crossings at small angles and automatically identify isotropic diffusion. We also apply the proposed method to real 3T D-MRI data sets of healthy individuals. The results show realistic depictions of crossing fibers that are more accurate, less noisy, and lead to superior tractography results compared to competing methods. PMID- 29502035 TI - Assessing the prognostic value of carcinoembryonic antigen levels in stage I and II colon cancer. AB - BACKGROUND: Previous studies have shown that elevated preoperative carcinoembryonic antigen (CEA) levels are associated with worse prognosis in patients with colon cancer. These studies compared the prognosis of patients with elevated versus normal CEA levels. We sought to assess the prognostic role of increasing levels of CEA in stage I and II patients who did not receive adjuvant chemotherapy. METHODS: Using the National Cancer Database (2004-2014), we identified 45,449 individuals with stage I and II colon cancer who did not receive adjuvant chemotherapy and had preoperative CEA levels available. We estimated the optimal cut-point of CEA levels to predict survival using the Youden Index. Cox proportional hazards were used to compare individuals with CEA levels above and below the defined cut-point. In a secondary analysis, we examined the prognostic value of stage, age and tumour location. RESULTS: The optimal preoperative CEA cut-point to predict survival was 2.35 ng/mL. The adjusted HR for overall survival among individuals with preoperative CEA levels at or above compared with below 2.35 ng/mL was 1.56 (95% CI, 1.49-1.64). Individuals with CEA levels below 2.35 ng/mL had higher 3-year survival rates compared with those with CEA levels above 2.35 ng/mL (79.7% vs 64.5%, respectively). CONCLUSIONS: Preoperative CEA levels at or above 2.35 ng/mL, found within the normal range, may be used to identify stage I and II colon cancer patients harbouring worse prognosis. PMID- 29502037 TI - Targeting the microenvironment in solid tumors. AB - Tumorigenesis is a complex and dynamic process involving different cellular and non-cellular elements composed of tumor microenvironment (TME). The interaction of TME with cancer cells is responsible for tumor development, progression and drug resistance. TME consists of non malignant cells of the tumor such as cancer associated fibroblasts (CAFs), endothelial cells and pericytes composing tumor vasculature, immune and inflammatory cells, bone marrow derived cells, and the extracellular matrix (ECM) establishing a complex cross-talk with tumor. These interactions contribute towards proliferation and invasion of the tumor by producing growth factors, chemokines and matrix-degrading enzymes. ECM is a complex system containing macromolecules with distinctive physical, biochemical and biomechanical properties. During tumorigenesis this system is deregulated favoring the generation of tumorigenic microenvironment enhancing tumor associated angiogenesis and inflammation. An important step of anticancer treatment is the identification of the biological alterations present in TME in order to target these key molecular players. Multitargeted approaches, providing a simultaneous inhibition of TME components, may offer a more efficient way to treat cancer. In this manuscript we overview the function of each components of TME and the treatments targeting the key players. PMID- 29502036 TI - The impact of overdiagnosis on thyroid cancer epidemic in Italy,1998-2012. AB - AIMS: In Italy, incidence rates of thyroid cancer (TC) are among the highest worldwide with substantial intracountry heterogeneity. The aim of the study was to examine time trends of TC incidence in Italy and to estimate the proportion of TC cases potentially attributable to overdiagnosis. METHODS: Data on TC cases reported to Italian cancer registries during 1998-2012 aged <85 years were included. Age-standardised incidence rates (ASR) were computed by sex, period, and histology. TC overdiagnosis was estimated by sex, period, age, and Italian region. RESULTS: In Italy between 1998-2002 and 2008-2012, TC ASR increased of 74% in women (from 16.2 to 28.2/100,000) and of 90% in men (from 5.3 to 10.1/100,000). ASR increases were nearly exclusively due to papillary TC (+91% in women, +120% in men). In both sexes, more than three-fold differences emerged between regions with highest and lowest ASR. Among TC cases diagnosed in 1998 2012 in Italy, we estimated that overdiagnosis accounted for 75% of cases in women and 63% in men and increased over the study period leading to overdiagnosis of 79% in women and 67% in men in 2008-2012. Notably, overdiagnosis was over 80% among women aged <55 years, and substantial variations were documented across Italian regions, in both genders. CONCLUSION(S): Incidence rates of TC are steadily increasing in Italy and largely due to overdiagnosis. These findings call for an update of thyroid gland examination practices in the asymptomatic general population, at national and regional levels. PMID- 29502039 TI - High Beck Depression Inventory 21 scores in adolescents without depression are associated with negative self-image and immature defense style. AB - Beck Depression Inventory (BDI) is widely used in assessing adolescents' psychological wellbeing, but occasionally the result diverges from diagnostics. Our aim was to identify factors associated with discrepancies between BDI scores and diagnostic assessment in adolescent psychiatric patients and general population. The study comprised 206 inpatients (13-17 years old) and 203 age and gender matched non-referred adolescents. Study subjects filled self-reports on depression symptoms (BDI-21), alcohol use (AUDIT), defense styles (DSQ-40) and self-image (OSIQ-R), and on background information and adverse life events. Diagnostics was based on K-SADS-PL interview, and/or clinical interview and clinical records when available. We compared subjects who scored in BDI-21 either 0-15 points or 16-63 points firstly among subjects without current unipolar depression (n = 284), secondly among those with unipolar depression (n = 105). High BDI-21 scores in subjects without depression diagnosis (n = 48) were associated with female sex, adverse life events, parents' psychiatric problems, higher comorbidity, higher AUDIT scores, worse self-image and more immature defense styles. Low BDI-21 scores among subjects with depression diagnosis (n = 23) were associated with male sex, more positive self-image and less immature defense style. In conclusion, high BDI-21 scores in the absence of depression may reflect a broad range of challenges in an adolescent's psychological development. PMID- 29502038 TI - Epigenetic perspectives on the evolution and domestication of polyploid plant and crops. AB - Polyploidy or whole genome duplication (WGD) is a prominent feature for genome evolution of some animals and all flowering plants, including many important crops such as wheat, cotton, and canola. In autopolyploids, genome duplication often perturbs dosage regulation on biological networks. In allopolyploids, interspecific hybridization could induce genetic and epigenetic changes, the effects of which could be amplified by genome doubling (ploidy changes). Albeit the importance of genetic changes, some epigenetic changes can be stabilized and transmitted as epialleles into the progeny, which are subject to natural selection, adaptation, and domestication. Here we review recent advances for general and specific roles of epigenetic changes in the evolution of flowering plants and domestication of agricultural crops. PMID- 29502040 TI - Impact of childhood trauma on sensorimotor gating in Chinese patients with chronic schizophrenia. AB - We investigated the relationship between childhood trauma (CT) and sensorimotor gating in Chinese patients diagnosed with chronic schizophrenia. Seventy-five patients were assessed with the Childhood Trauma Questionnaire-Short Form (CTQ SF), and then the modified paradigm, perceived spatial separation-induced prepulse inhibition (PSS PPI) and the perceived spatial co-location PPI (PSC PPI or classical PPI) were applied to test sensorimotor gating. Startling stimuli (90 dB) were presented either alone or preceded by discrete prepulse stimuli of 4 dB in a background 60-dB noise level. Associations between CT and various PPI paradigms were statistically analyzed. Univariate analysis revealed the absence of a significant correlation between CT and PPI paradigms (p > 0.05). However, multiple linear regression analyses revealed that sexual abuse and the positive and negative syndrome scale (PANSS) score were negatively correlated with PSS PPI (p = 0.029 and 0.008, respectively). On the other hand, female sex and history of smoking were positively correlated with PSS PPI (p = 0.044 and 0.043, respectively). In conclusion, the results of this study suggest that CT can be a predisposing factor that affects sensorimotor gating in schizophrenia patients. PMID- 29502041 TI - Computational linguistic analysis applied to a semantic fluency task to measure derailment and tangentiality in schizophrenia. AB - Although rating scales to assess formal thought disorder exist, there are no objective, high-reliability instruments that can quantify and track it. This proof-of-concept study shows that CoVec, a new automated tool, is able to differentiate between controls and patients with schizophrenia with derailment and tangentiality. According to ratings from the derailment and tangentiality items of the Scale for the Assessment of Positive Symptoms, we divided the sample into three groups: controls, patients without formal thought disorder, and patients with derailment/tangentiality. Their lists of animals produced during a one-minute semantic fluency task were processed using CoVec, a newly developed software that measures the semantic similarity of words based on vector semantic analysis. CoVec outputs were Mean Similarity, Coherence, Coherence-5, and Coherence-10. Patients with schizophrenia produced fewer words than controls. Patients with derailment had a significantly lower mean number of words and lower Coherence-5 than controls and patients without derailment. Patients with tangentiality had significantly lower Coherence-5 and Coherence-10 than controls and patients without tangentiality. Despite the small samples of patients with clinically apparent thought disorder, CoVec was able to detect subtle differences between controls and patients with either or both of the two forms of disorganization. PMID- 29502042 TI - The perceived risk of pregnancy as a mediator of the association between prenatal depression and depression 5 years after giving birth. AB - The present study examines a mother's perception of her pregnancy as risking herself and her fetus, as a mediator of the association between depressive symptoms during pregnancy and depressive symptoms 5 years after giving birth, regardless of actual objective risk. 290 Jewish Israeli mothers filled out self reported questionnaires dealing with objective risk, subjective risk and depressive symptoms. The findings confirmed partial mediation effect, implying a potential negative impact of the preventive efforts usually made, by increasing risk perception with long-term costs for mothers, especially for those who have already developed depressive symptoms. PMID- 29502043 TI - Assessing the subjective experience of participating in a clinical trial (AVATAR). AB - This study assessed the subjective experience of participating in a clinical trial, specifically positive and negative experiences and the experience of audio recording assessment sessions. The study was cross-sectional from a single blinded randomised controlled trial. Forty participants with a primary diagnosis of non-organic psychosis completed baseline and 12-week follow-up questionnaires assessing their experiences. Participants rated research interviews as moderately helpful in facilitating their therapy and talking to the interviewer as moderately helpful at baseline and 12-week follow-up. Self-report ratings of the degree of self-realisation promoted by the research questionnaires were significantly higher at 12-week follow-up compared to baseline. Participants adjusted quickly to being audio recorded and rated interviews as not at all disruptive and not at all to slightly intrusive. On average there were neutral emotional reactions, positive gains and minimal inconveniences as a result of participation. The main reasons for taking part were: 'To help myself', 'I was curious' and 'To help others'. The findings offer support to previous research reporting that individuals with mental health problems find participating in clinical trials a beneficial experience. This may alleviate concerns that participation in similar studies may be personally intrusive or harmful. PMID- 29502044 TI - Cardiomyocyte hypertrophy induced by Endonuclease G deficiency requires reactive oxygen radicals accumulation and is inhibitable by the micropeptide humanin. AB - The endonuclease G gene (Endog), which codes for a mitochondrial nuclease, was identified as a determinant of cardiac hypertrophy. How ENDOG controls cardiomyocyte growth is still unknown. Thus, we aimed at finding the link between ENDOG activity and cardiomyocyte growth. Endog deficiency induced reactive oxygen species (ROS) accumulation and abnormal growth in neonatal rodent cardiomyocytes, altering the AKT-GSK3beta and Class-II histone deacethylases (HDAC) signal transduction pathways. These effects were blocked by ROS scavengers. Lack of ENDOG reduced mitochondrial DNA (mtDNA) replication independently of ROS accumulation. Because mtDNA encodes several subunits of the mitochondrial electron transport chain, whose activity is an important source of cellular ROS, we investigated whether Endog deficiency compromised the expression and activity of the respiratory chain complexes but found no changes in these parameters nor in ATP content. MtDNA also codes for humanin, a micropeptide with possible metabolic functions. Nanomolar concentrations of synthetic humanin restored normal ROS levels and cell size in Endog-deficient cardiomyocytes. These results support the involvement of redox signaling in the control of cardiomyocyte growth by ENDOG and suggest a pathway relating mtDNA content to the regulation of cell growth probably involving humanin, which prevents reactive oxygen radicals accumulation and hypertrophy induced by Endog deficiency. PMID- 29502046 TI - The complete mitochondrial genome of Vannella simplex (Amoebozoa, Discosea, Vannellida). AB - Vannella simplex (Amoebozoa, Discosea, Vannellida) is one of the commonest freshwater free-living lobose amoebae, known from many locations worldwide. In the present study, we describe the complete mitochondrial genome of this species. The circular mitochondrial DNA of V. simplex has 34,145obp in length and contains 27 protein-coding genes, 2 ribosomal RNAs, 16 transfer RNAs and 4 open reading frames. Mitochondiral genome of V. simplex is one of the most gene compact due to overlapping genes and reduced intergenic space. It has much in common with its closest relative, mitochondrial genome of V. croatica GenBank number MF508648. In the same time, both of them show considerable differences in length and in gene order from the next close relative - that of Neoparamoeba pemaquidensis KX611830 (deposited as Paramoeba) and even more - from other sequenced amoebozoan mitochondrial genomes. The present study confirms the opinion that the level of synteny between the mitochondrial genomes across the entire Amoebozoa clade is low. More or less considerable similarity yet was found only between members of the same clade of the genera or family level, but hardly - among more distant lineages. PMID- 29502047 TI - Reactivation of BK polyomavirus during pregnancy, vertical transmission, and clinical significance: A meta-analysis. AB - BACKGROUND: Studies have shown conflicting results on the prevalence and the risks of BK reactivation among pregnant women. In addition, the prevalence of vertical transmission and its clinical significance during pregnancy are not well studied. OBJECTIVES: The study's aims were (1) to investigate the prevalence, and (2) to assess the risk of BK Polyomavirus reactivation and its clinical significance in pregnant women and fetuses. STUDY DESIGN: A literature search was performed using MEDLINE, EMBASE and Cochrane Database from inception through May 31, 2017. We included studies that reported prevalence, relative risks, odds ratios, or hazard ratios of BK Polyomavirus reactivation during pregnancy. Pooled odds ratios (ORs) and 95% CI were calculated using a random-effect model. The protocol for this study is registered with PROSPERO (International Prospective Register of Systematic Reviews; no. CRD42017063919). RESULTS: 17 observational studies with a total of 2553 pregnant women were enrolled. The estimated prevalence of BK seropositivity and BK in urine (viruria) among pregnant women were 79.2% (95%CI: 69.6%-86.4%) and 18.9% (95%CI: 10.4%-31.8%). When compared to non-pregnant women, the pooled ORs of BK seropositivity and BK viruria in pregnant women were 1.84 (95%CI: 1.05-3.22) and 6.02 (95%CI: 2.43-14.92), respectively. The estimated prevalence of positive BK-specific IgM antibody in cord blood was 4.9% (95%CI: 0.5%-36.2%). The data on the fetal effects of BK virus were limited. Although BK was detected in fetal organs, available data suggested no association between BK infection and adverse consequences such as miscarriage during pregnancy or childhood malignancy. CONCLUSION: Our meta analysis demonstrates a significantly increased risk of BK Polyomavirus reactivation during pregnancy. Although vertical transmission can occur with an overall estimated prevalence of 4.9%, there are currently no data suggesting harm to pregnant women and fetuses from BK Polyomavirus. PMID- 29502048 TI - [Rosai-Dorfman disease in the larynx: report of a case and literature review]. AB - OBJECTIVE: Rosai-Dorfman disease (RDD) is a rare histiocytic disorder that has nodal and extranodal manifestations. Currently no guidelines are available for the management of this disease. We report a case of laryngeal RDD that did not present with classical symptoms such as fever or lymphadenopathy and could be easily misdiagnosed as malignant tumor. The patient received minimally invasive surgeries combined with steroid therapy to preserve the laryngeal function as much as possible, and a favorable clinical outcome was obtained. Reports of similar cases in literatures were reviewed to obtain a better understanding of the disease course, diagnosis and treatment of this uncommon condition. PMID- 29502045 TI - Ripk3 promotes ER stress-induced necroptosis in cardiac IR injury: A mechanism involving calcium overload/XO/ROS/mPTP pathway. AB - Receptor-interacting protein 3 (Ripk3)-mediated necroptosis contributes to cardiac ischaemia-reperfusion (IR) injury through poorly defined mechanisms. Our results demonstrated that Ripk3 was strongly upregulated in murine hearts subjected to IR injury and cardiomyocytes treated with LPS and H2O2. The higher level of Ripk3 was positively correlated to the infarction area expansion, cardiac dysfunction and augmented cardiomyocytes necroptosis. Function study further illustrated that upregulated Ripk3 evoked the endoplasmic reticulum (ER) stress, which was accompanied with an increase in intracellular Ca2+ level ([Ca2+]c) and xanthine oxidase (XO) expression. Activated XO raised cellular reactive oxygen species (ROS) that mediated the mitochondrial permeability transition pore (mPTP) opening and cardiomyocytes necroptosis. By comparison, genetic ablation of Ripk3 abrogated the ER stress and thus blocked the [Ca2+]c overload-XO-ROS-mPTP pathways, favouring a pro-survival state that ultimately resulted in the inhibition of cardiomyocytes necroptosis in the setting of cardiac IR injury. In summary, the present study helps to elucidate how necroptosis is mediated by ER stress, via the calcium overload /XO/ROS/mPTP opening axis. PMID- 29502049 TI - [A single-team experience with robotic pancreatic surgery in 1010 cases]. AB - OBJECTIVE: To assess the safety and advantages of robotic pancreatic surgery (RPS) based on the single-team experience with 1010 cases. METHODS: The clinical data of 1010 cases of RPS performed by a single team from November, 2011 to September, 2017 in our hospital were collected prospectively and analyzed. In most of cases the surgeries were performed using the third-generation da Vinci robotic surgical system. RESULTS: The 1010 cases receiving RPS included 417 cases of robotic pancreatoduodenectomy (RPD), 428 cases of robotic distal pancreatectomy, 60 cases of robotic central pancreatectomy, 53 cases of robotic pancreatic tumor enucleation, 3 cases of Appleby procedure, and 49 cases of other operations (including 4 cases of innovative robotic retroperitoneal laparoscopic surgery, 4 cases of robotic pancreatic tumor enucleation combined with main pancreatic duct bridging repair, 1 case of single incision robotic pancreatic tumor enucleation, and 2 cases of robotic central pancreatectomy combined with end-to-end anastomosis reconstruction). The median operative time was 210 min (30 720 min) with a median intraoperative blood loss of 80 mL (10-2000 mL), a conversion rate of 4.06% (41/1010), a blood transfusion rate of 6.7% (68/1010), a mean post-operative stay of 10.87?6.70 days, a complication rate (beyond grade III according to Clavien-Dindo scoring system) of 8.0% (81/1010), and a pancreatic fistula rate (beyond) grade B of 9.21% (93/1010). The mortality rate of the patients was 0.69% (7/1010) in 30 days and 1.31% (12//934) in 90 days. The application of RPS in total pancreatectomy increased steadily from the rate of 10.44% in 2012 to 72.06% in 2017. CONCLUSION: This represents to our knowledge the world largest series of robotic pancreatic resections. RPS is expected to gradually replace open procedure and laparoscopic procedure to become the primary choice of approach for pancreatectomy. After the learning curve, RPS procedure including distal pancreatectomy, robotic Appleby procedure and other operations can be safely performed, and the experiences from other centers can be beneficial to reduce severe complications in the early stage of learning. PMID- 29502050 TI - [Prognostic analysis of plantar fasciitis treated by pneumatic ballistic extracorporeal shock wave versus ultrasound guided intervention]. AB - OBJECTIVE: To compare the medium- and long-term effect of pneumatic ballistic extracorporeal shock wave versus ultrasound-guided hormone injection in the treatment of plantar fasciitis. METHODS: The clinical data were collected from patients with plantar fasciitis admitted to PLA General Hospital pain department from September, 2015 to February, 2017. The patients were randomly divided into ultrasound-guided drug injection group and shock wave group. The therapeutic parameters including the numerical rating scale (NRS) scores in the first step pain in the morning, American Orthopedic Foot and Ankle Society (AOFAS) Ankle Hindfoot Scale, and thickness of the plantar fascia were monitored before and at 1 week, 1 month, 3 months, and 6 months after the treatment. The recurrence rate, effectiveness, and patient satisfaction were compared between the two groups at 6 months after the treatment. RESULTS: Thirty-nine patients were enrolled in shock wave group and 38 patients in ultrasound group. The NRS scores in the first step pain in the morning were lowered after treatment in both groups (P<0.05), and the scores were significantly lower in ultrasound group than in shock wave group at 1 week and 1 month (P<0.01), but significantly higher in ultrasound group than in shock wave group at 3 and 6 months after treatment (P<0.05). The AOFAS functional scores were increased in both groups (P<0.05) at 6 months after treatment, was significantly lower in ultrasound group than in shock wave group than group B (90.44?13.27 vs 75.76?21.40; P<0.05). The effective rates in shock wave group and ultrasound group were 92.31% and 76.32%, respectively (P<0.05). Recurrence was found in 1 patient (2.56%) in shock wave group and in 8 (21.05%) in ultrasound group (P<0.05). The patient satisfaction scores were significantly higher in shock wave group than in ultrasound group (8.13?2.67 vs 6.63?3.75, P=0.048). CONCLUSION: Pneumatic ballistic extracorporeal shock achieves better medium- and long-term outcomes than ultrasound-guided hormone injection in the treatment of plantar fasciitis. PMID- 29502051 TI - [A method for efficient transduction of miR-483-5p in the kidney of mice]. AB - OBJECTIVE: To establish a method for gene delivery in murine renal tissue using lentivirus vector encoding miR-483-5p. METHODS: Thirty-five C57BL/6J mice were randomly divided into control group, low-dose treatment group (5 uL each kidney) , and high?dose treatment group (20 uL each kidney), and in the latter two groups, the lentivirus vector encoding miR-483-5p were injected in the renal cortex. The tissue samples were collected at 7 and 21 days after the injection. A transgenic mouse model with inducible systemic overexpression of miR-483-5p was established in TG483 mice. The Cre-loxp system was used to create a mouse model with renal tubule-specific expression of miR-483-5p. The levels of BUN in the mice were detected and HE staining and fluorometric TUNEL assay were used to observe the morphological changes of the kidneys; real-time qPCR was used to detect miR-483-5p expression in the renal cortex. RESULTS: The mice with overexpression of miR-483-5p had normal renal function without obvious pathological changes or apoptosis in the renal tissue. Renal cortex injection of 20 uL lentivirus resulted in obviously increased level of miR-483-5p at 21 days (1.2?0.43 vs 8.6?1.09, P<0.001). miR-483-5p showed a low expression (0.9?0.09 vs 1.7?0.19, P<0.05) in TG483 mice and a high expression in the kidney of the transgenic mice established using the Cre-loxp system (1.6?1.13 vs 12.36?3.89, P<0.05). CONCLUSION: The transgenic mice with renal tubule-specific expression of miR-483-5p show normal renal function, and this model facilitates further study of the role of miR-483-5p in the kidney. PMID- 29502052 TI - [Sericin regulates proliferation of human gastric cancer MKN45 cells through autophagic pathway]. AB - OBJECTIVE: To investigate the effect of sericin on the proliferation of human gastric cancer MKN45 cells and explore the underlying molecular mechanism. METHODS: MKN45 cells were transfected by LC3 double fluorescent autophagic virus, and the positive cells screened by puromycin were divided into blank group, sericin group and sericin?3-MA group. After incubation with sericin for 48 h, the cells were examined for proliferation, apoptosis and cell cycle using CCK-8 assay and flow cytometry. Cell autophagy was detected by transmission electron microscopy (TEM) and fluorescent inverted microscope, and the autophagy-related markers including LC3, p62 and Beclin proteins were detected with Western blotting. Nude mice bearing gastric cancer xenograft were treated with normal saline or sericin injections (n=5) and the changes in the tumor volume and weight were measured. RESULTS: Compared with the blank group, MKN45 cells with sericin treatment showed significantly inhibited proliferation both in vitro and in nude mice. Autophagosomes were observed in sericin-treated cells under TEM and fluorescent inverted microscope. Sericin treatment of the cells significantly increased the cell apoptosis (P<0.01), caused obvious cell cycle arrest in G2/M phase (P<0.01), up-regulated the expressions of both LC3-2 and Beclin, and down regulated the expression of p62. The autophagy inhibitor 3-MA obviously antagonized the effects of sericin on cell apoptosis, cell cycle and autophagic protein expressions. CONCLUSION: Sericin can inhibit the proliferation of human gastric cancer MKN45 cells by regulating cell autophagy to serve as potential anti-tumor agent. PMID- 29502053 TI - [A high level of high-density lipoprotein cholesterol is a protective factor against transplant renal artery stenosis]. AB - OBJECTIVE: To investigate the factors associated with the occurrence of transplant renal artery stenosis (TRAS). METHODS: A retrospective analysis was conducted in 26 recipients who developed TRAS and 40 concurrent renal recipients without TRAS. We also conducted a nested case-control study in 14 patients with TRAS (TRAS-SD group) and another 14 non-TRAS recipients who received the allograft from the same donor (non-TRAS-SD group). RESULTS: Compared with those in the concurrent recipients without TRAS, acute rejection (AR) occurred at a significantly higher incidence (P=0.004) and the warm ischemia time (WIT) was significantly longer (P=0.015) and the level of high?density lipoprotein cholesterol (HDL--C) significantly lower (P=0.009) in the recipients with TRAS. Logistic regression analysis suggested that AR (P=0.007) and prolonged WIT (P=0.046) were risk factors of TRAS while HDL-C (P=0.022) was the protective factor against TRAS. In recent years early diagnosis of TRAS had been made in increasing cases, the interval from transplantation to TRAS diagnosis became shortened steadily, and the recipients tended to have higher estimated glomerular filtration rate at the time of TRAS diagnosis. CONCLUSION: Apart from the surgical technique, AR and prolonged WIT are also risk factors of TRAS while a high HDL-C level is the protective factor against TRAS. The improvement of the diagnostic accuracy by ultrasound is the primary factor contributing to the increased rate of early TRAS diagnosis in recent years. PMID- 29502054 TI - [Changes of cerebral cortical metabolomics in rats following benzo[a]pyrene exposure]. AB - OBJECTIVE: To analyze the changes in endogenous small molecule metabolites after benzo[a]pyrene (B[a]P) exposure in rat cerebral cortex and explore the mechanism of B[a]P neurotoxicity. METHODS: Five-day-old SD rats were subjected to gavage administration of 2 mg/kg B[a]P for 7 consecutive weeks. After the exposure, the rats were assessed for spatial learning ability using Morris water maze test, ultrastructural changes of the cortical neurons under electron microscope, and metabolite profiles of the cortex using GC/MS. The differential metabolites between the exposed and control rats were identified with partial least squares discriminant analysis (PLS-DA) and the metabolic pathways related with the differential metabolites were analyzed using Cytoscape software. RESULTS: Compared with the control group, the rats exposed to B[a]P showed significantly increased escape latency (P<0.05) and decreased time spent in the target area (P<0.05). The exposed rats exhibited widened synaptic cleft, thickened endplate membrane and swollen cytoplasm compared with the control rats. Eighteen differential metabolites (VIP>1, P<0.05) in the cortex were identified between the two groups, and 9 pathways associated with B[a]P neurotoxicity were identified involving amino acid metabolism, tricarboxylic acid cycle and Vitamin B3 (niacin and nicotinamide) metabolism. CONCLUSION: B[a]P can cause disturbance in normal metabolisms and its neurotoxicity is possibly related with disorders in amino acid metabolism, tricarboxylic acid cycle and vitamin metabolism. PMID- 29502055 TI - [Protective effect of paeoniflorin against PM2.5-induced damage in BEAS-2B cells]. AB - OBJECTIVE: To investigate the protective effects of paeoniflorin against PM2.5 induced damage in BEAS-2B cells and explore the possible mechanism. METHODS: With a factorial design, this study was performed to observe the protective effects of different doses of paeoniflorin against PM2.5-induced BEAS-2B cell growth inhibition and the effects of paeoniflorin on the contents of malondialdehyde (MDA) and intracellular reactive oxygen species (ROS) in the cell cultures. RESULTS: Exposure to increased PM2.5 concentrations caused significant decrease in the cell survival rate (P<0.05) with a clear dose-response relationship (r= 0.759, P<0.05). Treatment of the cells with paeoniflorin significantly attenuated PM2.5-induced inhibition of BEAS-2B cell survival (P<0.05), but the effect of paeoniflorin was not dose-dependent (P>0.05). PM2.5 exposure also significantly increased the contents of MDA and intracellular ROS (P<0.05), and paeoniflorin obviously antagonized these effects of PM2.5. CONCLUSION: Paeoniflorin can protect BEAS-2B cells from PM2.5-induced growth inhibition, and the mechanism might be related to the anti-oxidant effects of paeoniflorin. PMID- 29502056 TI - [Efficacy of intramedullary and extramedullary decompression and lavage therapy under microscope for treatment of chronic cervical spinal cord injury]. AB - OBJECTIVE: To analyze the clinical effect of spinal cord decompression and lavage therapy on chronic cervical spinal cord injury and explore the possible mechanism. METHODS: Fifty-seven patients with chronic cervical spinal cord injury treated in our hospital from January, 2008 to January, 2015 were enrolled, including 17 with multilevel cervical disc herniation, 25 with long segmental ossification of the posterior longitudinal ligament, 13 with hypertrophy or calcification of neck ligamentum flavum, and 2 with old cervical fractures. Open door spinal canal laminoplasty via a posterior approach and decompression in simple extramedullary decompression was performed in 31 cases (group A), and open door spinal cord incision decompression via a posterior approach, saline irrigation, and spinal canal laminoplasty in intramedullary decompression was performed in 26 cases (group B). The pre-operative cerebrospinal fluid in group B patients was collected to examine the inflammatory factors. All the patients were followed up and evaluated for pre- and postoperative JOA scores to calculate the improvement rate with regular examinations by X-ray, CT or MRI. RESULTS: Imaging examinations 2 weeks after the operation showed obvious relief of the primary lesion in both groups, and the improvement of high signals was better in group B than in group A. The mean improvement rate at 12 months after the operation was 52.33% in group A and 61.52% in group B (P<0.05), and the mean JOA score was significantly higher in group B than in group A (14.80?1.51 vs 13.58?0.56; P<0.05). Cerebrospinal fluid leakage occurred in 3 cases, epidural hematoma in 2 cases, internal fixation loosening in 1 case in group A; portal shaft fracture and internal fixation loosening occurred in 1 case in group B. Postoperative recovery time was shorter in group B and entered the platform phase in 3 months. The inflammatory factors IFN-gamma, IL-17F, IL-6 and sCD40L were all significantly higher than the normal levels after spinal cord injury, and the increment of IL-6 was the most conspicuous (P<0.05). CONCLUSION: Intramedullary and extramedullary decompression can achieve better outcomes than extramedullary decompression in patients with chronic cervical cord injury. This may be related not only to relieving adhesions and secondary compression by cutting the dura under the microscope, but also to removal of local inflammatory factors. PMID- 29502057 TI - [Inhibition of CaMKII alleviates myocardial ischemia?reperfusion injury by reducing mitochondrial oxidative stress in isolated perfused rat heart]. AB - OBJECTIVE: To investigate the role of calcium/calmodulin-dependent protein kinase II (CaMKII) in myocardial ischemia-reperfusion (IR) injury in isolated perfused rat heart and explore the underlying mechanisms. METHODS: An ischemia-reperfusion (IR) model was prepared using isolated rat hearts perfused with Krebs-Henseleit solution were randomly divided into control group, 2.5 umol/L KN-93 group, IR (induced by ischemia for 45 min followed by reperfusion for 120 min) group and KN 93+IR group. The myocardial performance was evaluated by assessing the left ventricular pressure. Lactate dehydrogenase (LDH) activity and cTnI content in the coronary flow and the infarct size were determined to evaluate the myocardial injury. The phosphorylation of CaMKII (p-CaMKII) and PLN (p-PLN) and oxidation of CaMKII (ox--CaMKII) were measured with Western blotting. The activity of mitochondrial superoxide dismutase (SOD) and the content of malondialdehyde (MDA) were determined using ELISA. RESULTS: Compared with the control group, KN-93 treatment at 2.5 umol/L produced no significant effects on cardiac function or performance in rat hearts without IR injury. Myocardial IR injury significantly decreased myocardial performance and mitochondrial SOD activity in the perfused hearts (P<0.01) and caused significantly increased infarct size, LDH activity, cTnI content, expressions of p-CaMKII, ox-CaMKII and p-PLN, and also increased mitochondrial MDA content (P<0.01). KN-93 treatment at 2.5 umol/L administered before ischemia and before reperfusion markedly attenuated such changes induced by ischemia and reperfusion (P<0.01). CONCLUSION: CaMKII participates in myocardial IR injury in isolated rat heart, and inhibiting CaMKII can alleviate myocardial injury by relieving mitochondrial oxidation stress. PMID- 29502058 TI - [Effect of propofol and operative trauma on neurodevelopment and cognitive function of developing brain in rats]. AB - OBJECTIVE: To investigate the effect of propofol and operative trauma on the neurodevelopment and cognitive function of the developing brain and its mechanism. METHODS: A total of 104 postnatal day 13 Sprague-Dawley rats were randomly divided into 4 groups: control group (treated by 7.5 mL/kg saline and sham surgery), propofol group (treated by 75 mg/kg propofol), surgery group (with abdominal surgery under local anesthesia) and propofol+surgery group (with abdominal surgery under local anesthesia plus 75 mg/kg propofol anesthesia). Thirteen rats from each group were randomly selected for detecting the content of TNF-alpha in the hippocampus and the expression levels of caspase-3 and c-fos in the brain. Morris Water Maze test was used to detect the cognitive ability of the other rats at 60 days old, after which TNF-alpha content in the hippocampus and caspase-3 and c-fos expressions in the brain were detected. RESULTS: In 13 day old rats, TNF-alpha level and caspase-3 and c-fos expressions differed significantly between the surgery group and the other 3 groups (P<0.05) and were similar among the control group, propofol group and propofol+surgery group (P>0.05). In 60-day-old rats, Morris water maze test results, TNF-alpha level or expressions of caspase-3 and c-fos showed no significant differences among the 4 groups. CONCLUSION: Abdominal surgery can induce inflammation in the hippocampus and neuroapoptosis in neonatal rats rather than adult rats. Single-dose propofol anesthesia does not significantly affect neurodevelopment of young rats, and can relieve central inflammatory reaction induced by surgical trauma. PMID- 29502059 TI - [Prognostic value of preoperative serum albumin in patients with non-muscle invasive bladder cancer undergoing transurethral resection of bladder tumor]. AB - OBJECTIVE: To assess the value of preoperative serum albumin level in predicting the survival of patients with non-muscle-invasive bladder cancer (NMIBC) undergoing transurethral resection of bladder tumor (TURBT). METHODS: Two hundred and sixteen newly diagnosed patients with NMIBC who underwent TURBT between January, 2007 and April, 2012 were retrospectively analyzed. The patients were categorized into low albumin (<40 g/L) and normal albumin (>=40 g/L) groups. The patient survival was estimated using the Kaplan-Meier method, and univariate and multivariate Cox proportional analyses were used to determine the hazard ratios (HRs) for the overall survival (OS). RESULTS: Of the patients with available data, 82 (39%) and 127 (61%) patients were classified into low albumin (<40 g/L) and normal albumin (>=40 g/L) groups, respectively. Kaplan-Meier analysis showed a significantly worse 5-year OS in low albumin group than in normal albumin group (P=0.017). In the multivariate Cox regression analysis, after adjusting for confounding variables, the preoperative albumin level remained as an independent predictor for 5-year OS (HR: 3.102, 95%CI: 1.200-8.020, P=0.020). CONCLUSION: A low preoperative albumin level predicts a poor 5-year OS in patients with NMIBC who underwent TURBT. Preoperative serum albumin can be a good prognostic factor for predicting survival of the patients with NMIBC treated with TURBT. PMID- 29502060 TI - [Role of SMU.2055 gene in regulating acid resistance of Streptococcus mutans UA159]. AB - OBJECTIVE: To evaluate the effect of SMU.2055 gene on acid resistance of Streptococcus mutans. METHODS: A SMU.2055-dificient mutant strain of S. mutans was constructed using homologous recombination technique. The growth of the wild type and mutant strains was monitored in both normal and acidic conditions. The lethal pH level, glycolysis, proton permeability, cell permeability and biofilm formation of the two strains were compared. RESULTS: PCR and sequence analyses verified the successful construction of the SMU.2055-dificient mutant strain. The growth and biofilm formation capacity of the mutant strain were obviously lowered in both normal and acidic conditions. The mutant strain also showed increased lethal pH level, proton permeability, and cell permeability with impaired H+ ATPase activity in acidic conditions, but its minimum glycolytic pH remained unaffected. CONCLUSION: The SMU.2055-deficient S. mutans mutant exhibits a lowered acid resistance, which affects the growth, lethal pH, proton permeability, H+-ATPase activity, cell permeability and biofilm formation but not the minimum glycolytic pH of the mutant strain. PMID- 29502061 TI - [Establishment of an ex vivo myocardial ischemia-reperfusion model in tree shrews]. AB - OBJECTIVE: To establish an ex vivo model of myocardial ischemia reperfusion in tree shrews. METHODS: The Langendorff ex vivo heart perfusion system was used to establish the myocardial ischemia reperfusion model in tree shrews with different irrigation and reperfusion time settings. Alanine aminotransferase (ALT), aspartate transaminase (AST) and lactic dehydrogenase (LDH) levels were measured by enzyme-labeled immunosorbent assay, creatine kinase MB (CK-MB) was detected using immunosuppression method, and malondialdehyde was measured with thiobarbital staining method; the infarct size was measured using 2, 3, 5 triphenyltrazoliumchloride (TTC) method. RESULTS: Ischemia for 30 min and reperfusion for 30 and 60 min caused more significant increase in CK-MB and LDH levels in the perfusion fluid and also in the levels of ALT, CK-MB and AST in the myocardial tissue compared with other experimental settings (P<0.05), but these parameters were comparable between the former two settings (P>0.05). The mean heart rate in 30-min ischemia with 60-min reperfusion group was obviously lower than that in continuous reperfusion group, 15-min ischemia with 30-min reperfusion group and 30-min ischemia with 30-min reperfusion group (P<0.05), and the heart rate was similar between the latter 3 groups (P>0.05). ECG analysis showed that the mean heart rate in 30-min ischemia with 30-min reperfusion group was closer to the physiological heart rate of tree shrews. CONCLUSION: We successfully established an ex vivo myocardial ischemia reperfusion model using tree shrews, and ischemia for 30 min followed by reperfusion for 30 min is the optimal experimental setting. PMID- 29502062 TI - [ADS-J1 antagonizes semen-derived enhancer of virus infection-mediated enhancement of transmitted founder HIV-1 and its matched chronic control strain infection]. AB - OBJECTIVE: To investigate the effect of semen-derived enhancer of virus infection (SEVI) on the infection of transmitted/founder (TF) HIV-1 and its matched chronic control (CC) viruses and the antagonism of ADS-J1 on SEVI-mediated enhancement of TF and CC virus infection in vitro. METHODS: PAP248-286 self-assembling into SEVI amyloid fibrils was validated by ThT assay. We generated the virus stocks of TF and CC virus pair. TZM-bl cells were infected with the mixture of SEVI and TF or CC viruses for 72 h. Luciferase activity was used to observe the enhancement of SEVI. SEVI was treated with different concentrations of ADS-J1 and incubated with TF or CC viruses. TZM-bl cells were then infected with the mixture and luciferase activity was detected 72 h after infection to analyze the antagonism of ADS-J1 on the enhancing effect of SEVI. ADS-J1 was also incubated with TF and CC viruses directly and TZM-bl cells were infected for 72 h to evaluate the antiviral effect using luciferase assay. SEVI was treated with ADS-J1 and Zeta potential was determined to explore the antagonistic mechanism of ADS-J1. RESULTS: ThT assay showed that PAP248-286 was capable of self-assembly into SEVI amyloid fibrils. SEVI significantly accelerated TF and CC viruses infection (P<0.05), and ADS-J1 not only significantly antagonized the enhancement of SEVI (P<0.05) but also directly inhibited the infection of TF and CC viruses (P<0.05). ADS-J1 neutralized the positive charge of SEVI in a dose-dependent manner. CONCLUSIONS: SEVI promotes the infection of TF and CC strains, and ADS-J1 antagonizes SEVI mediated enhancement of TF and CC viruses by neutralizing the positive charge of SEVI. PMID- 29502063 TI - [Construction and bioactivity evaluation of hepatocyte growth factor-loaded poly (lactic-co-glycolic acid) nanoparticles]. AB - OBJECTIVE: To explore the optimum conditions for preparing poly(lactic-co glycolic) acid (PLGA) nanoparticles and evaluate the bioactivity of hepatocyte growth factor (HGF)-loaded PLGA nanoparticles. METHODS: Bovine serum albumin (BSA)-loaded PLGA nanoparticles were prepared using a double emulsion-solvent evaporation method. The preparation process of nanoparticles was optimized by orthogonal test with the particle size, encapsulation efficiency (EE), drug loading (DD), and recovery as the indexes. HGF-loaded nanoparticles were then prepared under the optimized conditions. The EE, DD and release characteristics of BSA?loaded nanoparticles and HGF-loaded nanoparticles were evaluated using a BCA kit and HGF ELISA kit. The bioactivity of HGF-loaded nanoparticles was evaluated using CCK8 proliferation assay. RESULTS: The HGF-loaded nanoparticles prepared under the optimized conditions had a uniform size with a mean diameter of 234.4?4.8 nm, an EE of (77.75?3.04)% and a recovery rate of (49.33?9.34)%. The in vitro release curve highlighted an initial burst drug release followed by sustained release from the nanoparticles. HGF-loaded nanoparticles obviously promoted the proliferation of Hacat keratinocytes in vitro. CONCLUSION: HGF loaded nanoparticles prepared using double emulsion?solvent evaporation method under optimized conditions possesses a high EE with a good sustained drug release profile and a good bioactivity. PMID- 29502064 TI - [Expression pattern of FAM135B and K (lysine) acetyltransferase 5 in esophageal squamous cell carcinoma in Uygur patients]. AB - OBJECTIVE: To explore the expression of the family with sequence similarity 135 member B (FAM135B) and K(lysine) acetyltransferase 5 (KAT5) in esophageal squamous cell carcinoma (ESCC) in Uygur patients. METHODS: The expression of FAM135B and KAT5 in ESCC tissues and paired adjacent tissues from 40 Uygur patients were detected using Roche Benchmark XT. The correlation of FAM135B and KAT5 and their correlation with the clinicopathological characteristics of the patients were analyzed. RESULTS: The positivity rates of FAM135B and KAT5 in ESCC tissues were 92.50% (37/40) and 15.00%(6/40) in these patients, respectively. The ESCC tissues showed a significantly higher rate of strong FAM135B expression than the adjacent tissues [45.00% (18/40) vs 22.50% (9/40); Chi2=4.528, P=0.033], but the rates of negative KAT5 expression was similar between ESCC and adjacent tissues [85.00% (34/40) vs 87.50% (35/40); Chi2=0.105, P=0.745]. Strong expressions of FAM135B in ESCC tissues and the paired adjacent tissues were well correlated (Kendall's coefficient = 0.707, P<0.001). In ESCC tissues, a strong expression of FAM135B showed a significant negative correlation with KAT5 expression (Kendall's coefficient=-0.946, P<0.001). Neither FAM135B nor KAT5 expression was associated with the patients' gender, age, tumor site, tumor differentiation, invasion, lymph node metastasis and clinical stage (all P>0.05). CONCLUSION: A strong expression of FAM135B may be an important molecular basis for the occurrence of ESCC in Uygur patients and plays its role by negatively regulating the expression of KAT5. PMID- 29502065 TI - [Application of sevoflurane and laryngeal mask in cesarean section in women with heart disease]. AB - OBJECTIVE: To compare the safety of sevoflurane anesthesia with laryngeal mask and tracheal intubation in cesarean section in women with heart disease. METHODS: Fifty-two pregnant women with heart diseases undergoing cesarean section were randomized into laryngeal mask (LAM) group and tracheal intubation group. In LAM group, 6% sevoflurane was given at the rate of 6 L/min for induction with a maintenance sevoflurane concentration of 3%. In the intubation group, 1.5 mg/kg propofol and 1 ug/kg remifentanil were injected intravenously, and after achieving D0 with Narcotrend monitoring, 0.9 mg/kg rocuronium was injected and intubation was performed 1 min later. The systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and heart rate (HR) were recorded in the two groups before anesthesia induction (T0), at intubation or laryngeal mask placement (T1), skin incision (T2), and extubation or laryngeal mask removal (T3). The surgery to fetal birth time, uterine incision to fetal childbirth time, drug discontinuation to awake time, and newborn Apgar scores were also recorded. Sevoflurane consumption and maternal comfort during hospitalization were compared between the two groups. RESULTS: In LAM group, HR and MBP at T1 and T3 were significantly lower than those in the intubation group (P<0.05). The drug discontinuation to extubation time and to awaken time were significantly shorter in LAM group than in the intubation group (P<0.05), but the operation time and fetal child birth time were comparable between the two groups (P>0.05). The women in LAM group reported better physical and psychological comforts than those in the intubation group (P<0.05). The neonatal Apgar scores and the scores of health education, satisfaction with hospital environment and service were all similar between the two groups (P>0.05). CONCLUSION: Sevoflurane anesthesia with laryngeal mask can achieve satisfactory anesthetic effects in cesarean section in women with heart disease. PMID- 29502066 TI - [Effects of raloxifene at two different doses for ovulation induction on endometrial pinopodes in mice during the implantation window]. AB - OBJECTIVE: To compare the expression of pinopodes, the marker of endometrial receptivity, during the implantation window in Kunming mice stimulated with two different doses of raloxifene (RAL). METHODS: Forty-eight 8-week-old female Kunming mice were randomly divided into 4 groups (n=12), namely saline group, clomiphene citrate (CC, 18 mg/kg) group, RAL (33 mg/kg) group and RAL (44 mg/kg group). In each group, the mice received intragastric administration of 1 mL of normal saline containing CC or RAL at the specified doses or saline only as indicated for ovulation induction, once daily for 2 days. The mice received then injection with 5 IU human chorionic gonadotropin (HCG) and mated and on day 4.5 of gestation, the pregnant mice were sacrificed for examination of the uterus with scanning electron microscopy. RESULTS: Abundant and well developed pinopodes were observed in the endometrium of the mice in the 2 RAL groups and in the saline control group. The mice in CC group showed obviously reduced endometrial pinopodes with poor development. CONCLUSIONS: RAL at two different doses does not obviously affect the expression of pinopodes in the uterine epithelium of mice, suggesting the safety of RAL at these two doses for ovulation induction without causing adverse effects on endometrial receptivity. PMID- 29502067 TI - Dual effects for lovastatin in anaplastic thyroid cancer: the pivotal effect of transketolase (TKT) on lovastatin and tumor proliferation. AB - This study tested the hypothesis that the effects of lovastatin on anaplastic thyroid cancer cell growth are mediated by upregulation of transketolase (TKT) expression. The effects of lovastatin on TKT protein levels in ARO cells were determined using western blot and proteomic analyses. After treatment with lovastatin and oxythiamine, the in vitro and in vivo growth of ARO cells was determined using 3-(4,5-Dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assays and tumor xenografts in nude mice. TKT protein expression in the ARO tumors was assessed using immunohistochemistry analysis. Proteomic analysis revealed that 25 uM lovastatin upregulated TKT expression. Co-treatment of ARO cells with 1 uM lovastatin + 1 uM oxythiamine increased TKT protein expression compared with control levels; however, no differences were observed with 10 uM lovastatin + 1 uM oxythiamine. Furthermore, treatment with either oxythiamine or lovastatin alone reduced ARO tumor expression of TKT, as well as decreased ARO cell proliferation in vitro and tumor growth in vivo. However, mice treated with both lovastatin and oxythiamine at the same time had tumor volumes similar to that of the untreated control group. We conclude that either lovastatin or oxythiamine reduced ARO cell growth; however, the combination of these drugs resulted in antagonism of ARO tumor growth. PMID- 29502068 TI - Twenty-year outcomes in patients with newly diagnosed glaucoma: mortality and visual function. AB - BACKGROUND/AIMS: To determine the mortality within 20 years of diagnosis of chronic open-angle glaucoma (COAG) and visual acuity and visual field progression of a cohort followed for 20 years. METHODS: Twenty years following the diagnosis of COAG in 68 of 436 (16%) patients seen in a glaucoma case-finding clinic, visual and mortality outcomes were audited from medical records. Causes of death were obtained from general practitioner records and death certificates. Probability of death was calculated using a Kaplan-Meier survival curve. The visual field of each eye of survivors was graded using a nine-stage severity scale. Visual outcome was analysed at the 20-year follow-up visit. RESULTS: From 68, 14 (21%) were lost to follow-up. In the remaining 54, 20 (37%) were alive 20 years after diagnosis. Of 63% who died, mean age of death was 84 years, most commonly due to vascular disease. Mean age at presentation of those who died was 73.7 years versus 63.2 years for survivors (P=0.001). The median time to death was 16 years. On visual field analysis, nearly half (48.9%) of eyes did not deteriorate, but 28.3% eyes deteriorated by more than two stages. Those who died had worse final visual acuity than survivors (P<0.001). Three who died were registered severely visually impaired mainly from macular disease, but no survivors were registered (P<0.001). CONCLUSION: In this cohort, approximately two-thirds of patients with glaucoma died within 20 years of diagnosis. In most older patients with glaucoma, the overall goal of preventing visual handicap and blindness is achievable 20 years after diagnosis. PMID- 29502069 TI - Galectin-3: role in ocular allergy and potential as a predictive biomarker. AB - AIMS: To evaluate galectin-3 (Gal-3), a beta-galactoside binding protein, as a possible biomarker in ocular allergy and further investigated the role of endogenous Gal-3 in a murine model of ovalbumin (OVA)-induced allergic conjunctivitis (AC). METHODS: Conjunctival impression cytology specimens from control and patients with severe vernal keratoconjunctivitis, treated or untreated, were used to evaluate Gal-3 expression by immunocytochemistry. To investigate the mechanism of action of Gal-3, OVA-immunised BALB/c male wild-type (WT) and Gal-3 null (Gal-3-/-) mice were challenged with eye drops containing OVA on days 14-16 with a subset of animals pretreated with 0.03% tacrolimus (TC) or dexamethasone (Dex). RESULTS: Patients with AC and OVA-sensitised WT mice exhibited increased levels of Gal-3 in the conjunctiva compared with control, an effect reverted by the action of Dex and TC therapy. Twenty-four hours after the final OVA challenge, total and anti-OVA IgE levels increased significantly in the blood of OVA-sensitised WT and Gal-3-/- mice compared with controls, supporting the efficacy of the AC model. The lack of endogenous Gal-3 exacerbated the local inflammatory response, increasing the influx of eosinophils and mast cell activation. Additionally, OVA-sensitised Gal-3-/- animals exhibited increased CD4+ expression in the eyes as well as eotaxin, IL-4, IL-13 and interferon-gamma levels in the tear fluid compared with WT animals. CONCLUSION: Gal-3 contributes to the pathogenesis of ocular allergy and represents a relevant therapeutic target. PMID- 29502070 TI - Association of genetic variations in PTPN2 and CD122 with ocular Behcet's disease. AB - BACKGROUND: Protein tyrosine phosphatases (PTPs) play critical roles in human autoimmunity. Previous studies found that PTPN2 may be the key regulatory factor in the T-cell-mediated immune response. PTPN2 regulates the Janus kinase/signal transducers and activators of transcription pathway by inhibiting signalling via the interleukin (IL)-2 receptor (CD122). An association between genetic variations in PTPN2 and CD122 with ocular Behcet's disease (BD) has not yet been addressed and was therefore the purpose of this study. METHODS: A two-stage case control study was performed in 906 patients with ocular BD and 2178 healthy controls. Genotyping analysis of 11 single nucleotide polymorphisms was carried out. The expression of PTPN2 in peripheral blood mononuclear cells (PBMCs) was quantified by real-time PCR and cytokine production was measured by ELISA. RESULTS: The frequency of the GG genotype of PTPN2-rs7234029 was significantly lower in patients with ocular BD (p=1.94*10-5, pc=8.34*10-4, OR=0.466). Stratification according to gender showed that rs7234029 was significantly associated with BD in men. A stratified analysis according to the main clinical features showed that rs7234029 was significantly associated with genital ulcers, skin lesions and a positive pathergy test. No association could be detected between BD and CD122 gene polymorphisms. Functional studies showed that rs7234029 GG genotype carriers had a higher PNPT2 mRNA expression level than those which carrying the AA or AG genotype, and a decreased secretion of IL-17 and tumour necrosis factor-alpha was seen by PBMCs from GG carriers. No significant difference could be detected concerning IL-1beta or IL-6 production by stimulated PBMCs between the different genotype groups. CONCLUSIONS: This study shows that a PTPN2-rs7234029 polymorphism is associated with ocular BD and is strongly influenced by gender. In addition, our results suggest that the genetic association with PTPN2 may involve the regulation of PTPN2 mRNA expression and cytokine secretion. PMID- 29502071 TI - Painful shoulder post fall. PMID- 29502072 TI - Electroacupuncture mitigates endothelial dysfunction via effects on the PI3K/Akt signalling pathway in high fat diet-induced insulin-resistant rats. AB - OBJECTIVE: To investigate the effect of electroacupuncture (EA) on endothelial dysfunction related to high fat diet (HFD)-induced insulin resistance through the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) signalling pathway. METHODS: Twenty-four male Sprague-Dawley rats were fed a regular diet (Control group, n=8) or a HFD (n=16) for 12 weeks to induce an insulin resistance model. HFD-fed rats were divided into two groups that remained untreated (HFD group, n=8) or received electroacupuncture (HFD+EA group, n=8). EA was applied at PC6, ST36, SP6 and BL23. At the end of the experiment, fasting blood glucose (FBG), serum insulin (FINS), serum C-peptide (C-P) and homeostatic model assessment of insulin resistance (HOMA-IR) indices were determined. Pancreatic islet samples were subjected to histopathological examination. The thoracic aorta was immunostained with anti-rat insulin receptor substrate (IRS)-1, Akt and endothelial nitric oxide synthase (eNOS) antibodies. mRNA and protein expression of IRS-1, PI3K, Akt2 and eNOS in the vascular endothelium were determined by real time PCR and Western blot analysis, respectively. RESULTS: The bodyweight increase of the HFD+EA group was smaller than that of the untreated HFD group. Compared with the HFD group, the levels of FBG, FINS, C-P and HOMA-IR in the HFD+EA group decreased significantly (P<0.01). Histopathological evaluation indicated that EA improved pancreatic islet inflammation. The expression of endothelial markers, such as IRS-1, PI3K, Akt2 and eNOS, decreased in the HFD group, while EA treatment appeared to ameliorate the negative impact of diet. CONCLUSION: EA may improve insulin resistance and attenuate endothelial dysfunction, and therefore could play a potential role in the prevention or treatment of diabetic complications and cardiovascular disease through the PI3K/Akt signalling pathway. PMID- 29502074 TI - Multiple safety warnings for ?fingolimod. PMID- 29502073 TI - Impact of acute otitis media clinical practice guidelines on antibiotic and analgesic prescriptions: a systematic review. AB - BACKGROUND: Clinical practice guidelines focusing on judicious use of antibiotics for childhood acute otitis media (AOM) have been introduced in many countries around the world. OBJECTIVE: To systematically review the effects of these guidelines on the prescription of antibiotics and analgesics for children with AOM. METHODS: Systematic searches of PubMed, Embase and Cochrane Library from inception to 6 June 2017 using broad search terms. Studies specifically aimed at evaluating the effects of introduction of national AOM practice guidelines on type of antibiotic and/or analgesic prescriptions were included, irrespective of design, setting or language. The Risk Of Bias In Non-randomized Studies of Interventions tool was used to assess risk of bias. RESULTS: Of 411 unique records retrieved, seven studies conducted in six different countries (France, Italy, Spain, Sweden, UK and USA (twice)) compared data before and after guideline introduction. All studies had an observational design, using longitudinal data of children aged under 15 years (n=200-4.6 million) from either routine care, insurance databases or electronic surveys. Risk of bias of all studies was judged serious to critical.Of the five studies reporting on antibiotic prescription rates, three showed a decline of 5%-12% up to 3 years after guideline introduction and two found no or negligible effect. In one US study, the initial 9% decline decreased to 5% after 4-6 years. The recommended first choice antibiotic was prescribed more frequently (9%-58% increase) after guideline introduction in four out of five studies reporting on this outcome. Analgesic prescription rates for AOM were reported in one US study and increased from 14% to 24% after guideline introduction. CONCLUSION: Based upon what is published, the effects of introduction of national clinical practice guidelines on antibiotic and analgesic prescribing for children with AOM seem modest at the most. REGISTRATION: PROSPERO: CRD42016050976. PMID- 29502075 TI - E-cigarettes and subsequent cigarette smoking in under-18s. PMID- 29502076 TI - Physiotherapy breathing retraining for asthma and quality of life. PMID- 29502077 TI - ADHD medication use in pregnancy and risk of congenital malformation. PMID- 29502078 TI - Clinical and cost effectiveness of longer prescriptions for chronic conditions. PMID- 29502079 TI - Effectiveness of community screening in reducing fractures in older women. PMID- 29502080 TI - MHRA: confusion over drug names. PMID- 29502081 TI - A new model of exercise referral scheme in primary care: is the effect on adherence to physical activity sustainable in the long term? A 15-month randomised controlled trial. AB - INTRODUCTION: Studies had not yet overcome the most relevant barriers to physical activity (PA) adherence. An exercise referral scheme (ERS) with mechanisms to promote social support might enhance adherence to PA in the long term. SETTING: A randomised controlled trial in 10 primary care centres in Spain. OBJECTIVE: To assess the effectiveness of a primary care-based ERS linked to municipal resources and enhancing social support and social participation in establishing adherence to PA among adults over a 15-month period. PARTICIPANTS: 422 insufficiently active participants suffering from at least one chronic condition were included. 220 patients (69.5 (8.4) years; 136 women) were randomly allocated to the intervention group (IG) and 202 (68.2 (8.9) years; 121 women) to the control group (CG). INTERVENTIONS: The IG went through a 12-week standardised ERS linked to community resources and with inclusion of mechanisms to enhance social support. The CG received usual care from their primary care practice. OUTCOMES: The main outcome measure was self-report PA with the International Physical Activity Questionnaire and secondary outcomes included stages of change and social support to PA practice. DATA COLLECTION: Participant-level data were collected via questionnaires at baseline, and at months 3, 9 and 15. BLINDING: The study statistician and research assessors were blinded to group allocation. RESULTS: Compared with usual care, follow-up data at month 15 for the ERS group showed a significant increase of self-reported PA (IG: 1373+/-1845 metabolic equivalents (MET) min/week, n=195; CG: 919+/-1454 MET min/week, n=144; P=0.009). Higher adherence (in terms of a more active stage of change) was associated with higher PA level at baseline and with social support. CONCLUSIONS: Prescription from ordinary primary care centres staff yielded adherence to PA practice in the long term. An innovative ERS linked to community resources and enhancing social support had shown to be sustainable in the long term. TRIAL REGISTRATION NUMBER: NCT00714831; Results. PMID- 29502082 TI - Economic burden of cirrhosis in Catalonia: a population-based analysis. AB - BACKGROUND: Cirrhosis is a chronic disease with high morbidity and mortality. Few studies have evaluated healthcare resource use in patients with cirrhosis. OBJECTIVE: We aimed to describe the point prevalence of cirrhosis on 31 December 2012 and the population-level distribution of healthcare resource use and expenditures in a non-selected population of patients with cirrhosis, stratified by whether their disease was compensated or decompensated, and by comorbidity burden. METHODS: This population study included all known patients aged >18 years with cirrhosis (according to International Classification of Diseases, ninth revision) in Catalonia, Spain, on 31 December 2012. We evaluated healthcare resource use and expenditure during 2013, taking into account the presence of decompensation before or during 2012. RESULTS: We documented 34 740 patients diagnosed with cirrhosis (58.7% men; mean age 61.8+/-14 years), yielding a point prevalence of 460 per 100 000 inhabitants on 31 December 2012. Annual mortality was 9.1%. During 2013, healthcare expenditures on patients with cirrhosis totalled ?142.1 million (?4234 per patient), representing 1.8% of the total 2013 healthcare budget of Catalonia. Hospitalisation costs accounted for 35.1% of the total expenditure and outpatient care accounted for 22.4%. MultivariateMultivariate logistic regression identified morbidity burden, HIV infection, hospitalisation and emergency room visits during 2012 as independent predictors of expenditure above the 85th centile (area under the receiver operating curve, 0.88 (95% CI 0.883 to 0.893, P<0.001)). CONCLUSIONS: Cirrhosis accounts for a high proportion of healthcare resource usage and expenditures; hospitalisation accounted for the highest expenditures. PMID- 29502083 TI - An electronic health records cohort study on heart failure following myocardial infarction in England: incidence and predictors. AB - OBJECTIVES: To investigate the incidence and determinants of heart failure (HF) following a myocardial infarction (MI) in a contemporary cohort of patients with MI using routinely collected primary and hospital care electronic health records (EHRs). METHODS: Data were used from the CALIBER programme, linking EHRs in England from primary care, hospital admissions, an MI registry and mortality data. Subjects were eligible if they were 18 years or older, did not have a history of HF and survived a first MI. Factors associated with time to HF were examined using Cox proportional hazard models. RESULTS: Of the 24 479 patients with MI, 5775 (23.6%) developed HF during a median follow-up of 3.7 years (incidence rate per 1000 person-years: 63.8, 95% CI 62.2 to 65.5). Baseline characteristics significantly associated with developing HF were: atrial fibrillation (HR 1.62, 95% CI 1.51 to 1.75), age (per 10 years increase: 1.45, 1.41 to 1.49), diabetes (1.45, 1.35 to 1.56), peripheral arterial disease (1.38, 1.26 to 1.51), chronic obstructive pulmonary disease (1.28, 1.17 to 1.40), greater socioeconomic deprivation (5th vs 1st quintile: 1.27, 1.13 to 1.41), ST segment elevation MI at presentation (1.19, 1.11 to 1.27) and hypertension (1.16, 1.09 to 1.23). Results were robust to various sensitivity analyses such as competing risk analysis and multiple imputation. CONCLUSION: In England, one in four survivors of a first MI develop HF within 4 years. This contemporary study demonstrates that patients with MI are at considerable risk of HF. Baseline patient characteristics associated with time until HF were identified, which may be used to target preventive strategies. PMID- 29502084 TI - Prevalence of xenobiotic substances in first-trimester blood samples from Danish pregnant women: a cross-sectional study. AB - OBJECTIVE: The aim of this study was to investigate the prevalence of xenobiotic substances, such as caffeine, nicotine and illicit drugs (eg, cannabis and cocaine), in blood samples from first-trimester Danish pregnant women unaware of the screening. DESIGN: A cross-sectional study examined 436 anonymised residual blood samples obtained during 2014 as part of the nationwide prenatal first trimester screening programme. The samples were analysed by ultra performance liquid chromatography with high-resolution time-of-flight mass spectrometry. SETTING: An antenatal clinic in a Danish city with 62 000 inhabitants, where >95% of pregnant women joined the screening programme. PRIMARY AND SECONDARY OUTCOME MEASURES: The prevalence and patterns of caffeine, nicotine, medication and illicit drug intake during the first trimester of pregnancy. RESULTS: The prevalence of prescription and over-the-counter drug detection was 17.9%, including acetaminophen (8.9%) and antidepressants (3.0%), of which citalopram (0.9%) was the most frequent. The prevalence of illegal drugs, indicators of smoking (nicotine/cotinine) and caffeine was 0.9%, 9.9%, and 76.4%, respectively. Only 17.4% of women had no substance identified in their sample. CONCLUSIONS: This study emphasises the need for further translational studies investigating lifestyle habits during pregnancy, as well as the underlying molecular mechanisms through which xenobiotic substances may affect placental function and fetal development. PMID- 29502085 TI - Prevalence of coronary artery calcification in a non-specific chest pain population in emergency and cardiology departments compared with the background population: a prospective cohort study in Southern Denmark with 12-month follow up of cardiac endpoints. AB - OBJECTIVES: To examine and compare the prevalence of coronary artery calcification (CAC) and the frequency of cardiac events in a background population and a cohort of patients with non-specific chest pain (NSCP) who present to an emergency or cardiology department and are discharged without an obvious reason for their symptom. DESIGN: A double-blinded, prospective, observational cohort study that measures both CT-determined CAC scores and cardiac events after 1 year of follow-up. SETTING: Emergency and cardiology departments in the Region of Southern Denmark. SUBJECTS: In total, 229 patients with NSCP were compared with 722 patients from a background comparator population. MAIN OUTCOMES MEASURES: Prevalence of CAC and incidence of unstable angina (UAP), acute myocardial infarction (MI), ventricular tachycardia (VT), coronary revascularisation and cardiac-related mortality 1 year after index contact. RESULTS: There was no significant difference in the prevalence of CAC (OR 0.9 (95% CI 0.6 to 1.3), P=0.546) or the frequency of cardiac endpoints (P=0.64) between the studied groups. When compared with the background population, the OR for patients with NSCP for a CAC >100 Agatston units (AU) was 1.0 (95% CI 0.6 to 1.5), P=0.826. During 1 year of follow-up, two (0.9%) patients with NSCP underwent cardiac revascularisation, while none experienced UAP, MI, VT or death. In the background population, four (0.6%) participants experienced a clinical cardiac endpoint; two had an MI, one had VT and one had a cardiac related death. CONCLUSION: The prevalence of CAC (CAC >0 AU) among patients with NSCP is comparable to a background population and there is a low risk of a cardiac event in the first year after discharge. A CAC study does not provide notable clinical utility for risk-stratifying patients with NSCP. TRIAL REGISTRATION NUMBER: NCT02422316; Pre-results. PMID- 29502087 TI - Prediabetes in pregnancy, can early intervention improve outcomes? A feasibility study for a parallel randomised clinical trial. AB - OBJECTIVE: Measurement of glycated haemoglobin (HbA1c) in early pregnancy is routine in New Zealand to identify women with diabetes and prediabetes. However, the benefit of early intervention in women with prediabetes is inconclusive. Our aim was to test the feasibility of a two-arm parallel randomised controlled trial of standard care versus early intervention in pregnancies complicated by prediabetes. SETTING: Two tertiary referral centres in New Zealand. PARTICIPANTS: Women <14 weeks' gestation and HbA1c >=5.9%-6.4% (41-46 mmol/mol) measured at booking, without pre-existing diabetes. INTERVENTIONS: Randomisation was done by remote web-based allocation into one of two groups. Women in the early intervention group attended an antenatal diabetes clinic, commenced daily home blood glucose monitoring, and medication was prescribed if lifestyle measures failed to maintain target blood glucose levels. Controls received lifestyle education, continued standard care with their midwife and/or obstetrician, and were asked to perform a 75 g oral glucose tolerance test at 24 weeks' gestation with a referral to clinic if this test was positive. Both groups received lifestyle questionnaires at recruitment and in late pregnancy. OUTCOME MEASURES: Recruitment rate, adherence to protocol and validation of potential primary outcomes. RESULTS: Recruitment rates were lower than expected, especially in Maori and Pacific women. Non-adherence to allocated treatment protocol was significant, 42% (95% CI 24% to 61%) in the early intervention group and 30% (95% CI 16% to 51%) in controls. Caesarean section and pre-eclampsia were signalled as potential primary outcomes, due to both the high observed incidence in the control group and ease of measurement. CONCLUSIONS: For a future definitive trial, extending the gestation of eligibility and stepped-wedge cluster randomisation may overcome the identified feasibility issues. Consistent with published observational data, pre-eclampsia and emergency caesarean section could be included as primary outcome measures, both of which have a significant impact on maternal and neonatal morbidity and healthcare costs. TRIAL REGISTRATION NUMBER: ACTRN12615000904572; Pre-results. PMID- 29502086 TI - Intertester reliability of clinical shoulder instability and laxity tests in subjects with and without self-reported shoulder problems. AB - OBJECTIVE: First, to investigate the intertester reliability of clinical shoulder instability and laxity tests, and second, to describe the mutual dependency of each test evaluated by each tester for identifying self-reported shoulder instability and laxity. METHODS: A standardised protocol for conducting reliability studies was used to test the intertester reliability of the six clinical shoulder instability and laxity tests: apprehension, relocation, surprise, load-and-shift, sulcus sign and Gagey. Cohen's kappa (kappa) with 95% CIs besides prevalence-adjusted and bias-adjusted kappa (PABAK), accounting for insufficient prevalence and bias, were computed to establish the intertester reliability and mutual dependency. RESULTS: Forty individuals (13 with self reported shoulder instability and laxity-related shoulder problems and 27 normal shoulder individuals) aged 18-60 were included. Fair (relocation), moderate (load and-shift, sulcus sign) and substantial (apprehension, surprise, Gagey) intertester reliability were observed across tests (kappa 0.39-0.73; 95% CI 0.00 to 1.00). PABAK improved reliability across tests, resulting in substantial to almost perfect intertester reliability for the apprehension, surprise, load-and shift and Gagey tests (kappa 0.65-0.90). Mutual dependencies between each test and self-reported shoulder problem showed apprehension, relocation and surprise to be the most often used tests to characterise self-reported shoulder instability and laxity conditions. CONCLUSIONS: Four tests (apprehension, surprise, load-and-shift and Gagey) out of six were considered intertester reliable for clinical use, while relocation and sulcus sign tests need further standardisation before acceptable evidence. Furthermore, the validity of the tests for shoulder instability and laxity needs to be studied. PMID- 29502088 TI - Risk of pyogenic liver abscess and endoscopic sphincterotomy: a population-based cohort study. AB - OBJECTIVES: To evaluate the risk of pyogenic liver abscess (PLA) in patients receiving endoscopic sphincterotomy (ES). SETTING: A population-based cohort study using data from Taiwans' National Health Insurance Research Database was conducted. Patients aged 20 or older who had undergone an ES were considered as the ES cohort. The dates for the first hospitalisation of the patients receiving ES were defined as the index dates. PARTICIPANTS: Patients in the ES and non-ES cohorts were selected by 1:1 matching ratio based on a propensity score. A total of 8174 sex-matched, age-matched and index year-matched (1:1) pairs of patients receiving ES and 8174 patients without ES served as controls. Cox proportional hazards regression was employed to calculate the HRs and 95% CIs for the association between PLA and ES. RESULTS: The overall incidence of PLA was significantly higher in the ES cohort than in the non-ES cohort (4.20 vs 0.94, respectively, per 1000 person-year) with the adjusted HR (aHR) 4.50 (95% CI 3.38 to 6.58) A stratified analysis during the follow-up years revealed that when the ES cohort was compared with the non-ES cohort, they displayed a higher risk of PLA during the first follow-up year (aHR 4.35, 95% CI 2.26 to 8.39) which continued significantly over the next 4-5 years of follow-up. CONCLUSIONS: Patients receiving ES are associated with having a higher risk of PLA. PMID- 29502089 TI - Factors affecting decisions to extend access to primary care: results of a qualitative evaluation of general practitioners' views. AB - OBJECTIVES: To report general practitioners' (GPs') views and experiences of an Enhanced Primary Care programme (EPCP) funded as part of the Prime Minister's Challenge Fund (second wave) for England which aimed to extend patient access to primary care. SETTING: Primary care in Sheffield, England. PARTICIPANTS: Semi structured interviews with a purposive sample of GPs working in 24 practices across the city. RESULTS: Four core themes were derived: GPs' receptivity to the aims of the EPCP, their capacity to support integrated care teams, their capacity to manage urgent care and the value of some new community-based schemes to enhance locality-based primary care. GPs were aware of the policy initiatives associated with out-of-hours access that aimed to reduce emergency department and hospital admissions. Due to limited capacity to respond to the programme, they selected elements that directly related to local patient demand and did not increase their own workload. CONCLUSIONS: The variation in practice engagement and capacity to manage changes in primary care services warrants a subtle and specialist approach to programme planning. The study makes the case for enhanced planning and organisational development with GPs as stakeholders within individual practices and groups. This would ensure that policy implementation is effective and sustained at local level. A failure to localise implementation may be associated with increased workloading in primary care without the sustained benefits to patients and the public. To enable GPs to become involved in systems transformation, further research is needed to identify the best methods to engage GPs in programme planning and evaluation. PMID- 29502090 TI - Cost-effectiveness of a complex workplace dietary intervention: an economic evaluation of the Food Choice at Work study. AB - OBJECTIVE: To evaluate the costs, benefits and cost-effectiveness of complex workplace dietary interventions, involving nutrition education and system-level dietary modification, from the perspective of healthcare providers and employers. DESIGN: Single-study economic evaluation of a cluster-controlled trial (Food Choice at Work (FCW) study) with 1-year follow-up. SETTING: Four multinational manufacturing workplaces in Cork, Ireland. PARTICIPANTS: 517 randomly selected employees (18-65 years) from four workplaces. INTERVENTIONS: Cost data were obtained from the FCW study. Nutrition education included individual nutrition consultations, nutrition information (traffic light menu labelling, posters, leaflets and emails) and presentations. System-level dietary modification included menu modification (restriction of fat, sugar and salt), increase in fibre, fruit discounts, strategic positioning of healthier alternatives and portion size control. The combined intervention included nutrition education and system-level dietary modification. No intervention was implemented in the control. OUTCOMES: The primary outcome was an improvement in health-related quality of life, measured using the EuroQoL 5 Dimensions 5 Levels questionnaire. The secondary outcome measure was reduction in absenteeism, which is measured in monetary amounts. Probabilistic sensitivity analysis (Monte Carlo simulation) assessed parameter uncertainty. RESULTS: The system-level intervention dominated the education and combined interventions. When compared with the control, the incremental cost-effectiveness ratio (?101.37/quality-adjusted life-year) is less than the nationally accepted ceiling ratio, so the system-level intervention can be considered cost-effective. The cost-effectiveness acceptability curve indicates there is some decision uncertainty surrounding this, arising from uncertainty surrounding the differences in effectiveness. These results are reiterated when the secondary outcome measure is considered in a cost-benefit analysis, whereby the system-level intervention yields the highest net benefit (?56.56 per employee). CONCLUSIONS: System-level dietary modification alone offers the most value per improving employee health-related quality of life and generating net benefit for employers by reducing absenteeism. While system-level dietary modification strategies are potentially sustainable obesity prevention interventions, future research should include long-term outcomes to determine if improvements in outcomes persist. TRIAL REGISTRATION NUMBER: ISRCTN35108237; Post results. PMID- 29502091 TI - Diagnostic study on an immunochromatographic rapid test for schistosomiasis: comparison between use on serum and on blood spot from fingerprick. AB - BACKGROUND: An immunochromatographic rapid test (ICT; Schistosoma ICT IgG-IgM, LDBIO Diagnostics) demonstrated high sensitivity (96%) in the diagnosis of Schistosoma mansoni and S. haematobium. To date, the test has been validated for use on serum only, but in the absence of lab equipment, blood drop from fingerprick could be a useful option. This method is acquiring more interest because of the high flow of migrants rapidly moving across Italy and other European countries. OBJECTIVE: The aim of this prospective study was to evaluate the use of ICT on whole blood obtained from fingerprick. SETTING: Centre for Tropical Diseases (CTD), Sacro Cuore Don Calabria Hospital, Negrar, Verona, Italy. PARTICIPANTS: The inclusion criteria were African migrants aged >=18 years with epidemiological risk of infection. The exclusion criteria were refusal to participate in the study and impossibility of execution of one of the two study methods, for any reason. Seventy of the 72 eligible patients completed the study, 79% of whom were male. INTERVENTIONS: The ICT was performed twice for each included patient: one on blood drop (by the research nurses, in the ward) and one on serum (by staff of CTD lab). The primary outcome was the concordance between the two methods, assessed by Cohen's kappa. RESULTS: Cohen's kappa was 0.45 (95% CI 27.0 to 63.6), indicating moderate agreement between the ICT on serum and the ICT on blood drop. Assuming the results on serum as reference standard for diagnosis, the sensitivity and specificity of ICT on blood drop were 55% (95% CI 40 to 69) and 93% (95% CI 79 to 98), respectively. CONCLUSIONS: The agreement between the two diagnostic methods is too low to support the alternative one. Implementation of the kit for using blood drop instead of the serum and/or further studies aimed to identify easy-to-use tests for schistosomiasis feasible outside referral centres for tropical diseases are needed. PMID- 29502092 TI - Management of haemothoraces in blunt thoracic trauma: study protocol for a randomised controlled trial. AB - INTRODUCTION: Haemothorax following blunt thoracic trauma is a common source of morbidity and mortality. The optimal management of moderate to large haemothoraces has yet to be defined. Observational data have suggested that expectant management may be an appropriate strategy in stable patients. This study aims to compare the outcomes of patients with haemothoraces following blunt thoracic trauma treated with either chest drainage or expectant management. METHODS AND ANALYSIS: This is a single-centre, dual-arm randomised controlled trial. Patients presenting with a moderate to large sized haemothorax following blunt thoracic trauma will be assessed for eligibility. Eligible patients will then undergo an informed consent process followed by randomisation to either (1) chest drainage (tube thoracostomy) or (2) expectant management. These groups will be compared for the rate of additional thoracic interventions, major thoracic complications, length of stay and mortality. ETHICS AND DISSEMINATION: This study has been approved by the institution's research ethics board and registered with ClinicalTrials.gov. All eligible participants will provide informed consent prior to randomisation. The results of this study may provide guidance in an area where there remains significant variation between clinicians. The results of this study will be published in peer-reviewed journals and presented at national and international conferences. TRIAL REGISTRATION NUMBER: NCT03050502. PMID- 29502093 TI - Factors influencing career progress for early stage clinician-scientists in emerging Asian academic medical centres: a qualitative study in Singapore. AB - OBJECTIVES: To explore the factors that influence career progress for early stage clinician-scientists and to identify ways to mitigate these factors in the context of emerging Asian academic medical centres (AMCs). DESIGN: Qualitative interviews and thematic data analysis based on grounded theory. SETTING AND PARTICIPANTS: Five focus group interviews comprising 29 early career clinician scientists who have received their first national-level career development award in Singapore. RESULTS: Clinical priorities represented an overarching concern with many reporting the difficulty in delineating responsibilities between clinical care and research. Additionally, there was a prevailing perception of the lack of support for research at the institutional level. Participants tended to identify mentors through their own efforts in a relatively haphazard manner, often owing to the dearth of role models and perceived inadequacy of reward systems for mentoring. Support from mentors was thought to be limited in terms of targeted scientific guidance and long-term commitments to the relationship. Most of the participants expressed concerns about how they could secure the next level of funding with diminishing confidence. Notably, the work-life balance was neither conceptualised as a 'barrier' to successful pursuit of research career nor was it translated into the reason for leaving the dual clinical-research career pathway. CONCLUSIONS: Results revealed specific limitations presented by the research environment in newly emerging Asian AMCs. To retain a vibrant clinician-scientist workforce, additional measures are needed, aiming to improve institutional culture of research, build mentoring networks, adopt effective tools for tracking career progress and provide a clear and viable career progression path for clinician-scientist. Further research might explore the cross-cultural differences in managing work-life balance in academic medicine. PMID- 29502094 TI - Cushing's sign and severe traumatic brain injury in children after blunt trauma: a nationwide retrospective cohort study in Japan. AB - OBJECTIVE: We tested whether Cushing's sign could predict severe traumatic brain injury (TBI) requiring immediate neurosurgical intervention (BI-NSI) in children after blunt trauma. DESIGN: Retrospective cohort study using Japan Trauma Data Bank. SETTING: Emergency and critical care centres in secondary and tertiary hospitals in Japan. PARTICIPANTS: Children between the ages of 2 and 15 years with Glasgow Coma Scale motor scores of 5 or less at presentation after blunt trauma from 2004 to 2015 were included. A total of 1480 paediatric patients were analysed. PRIMARY OUTCOME MEASURES: Patients requiring neurosurgical intervention within 24 hours of hospital arrival and patients who died due to isolated severe TBI were defined as BI-NSI. The combination of systolic blood pressure (SBP) and heart rate (HR) on arrival, which were respectively divided into tertiles, and its correlation with BI-NSI were investigated using a multiple logistic regression model. RESULTS: In the study cohort, 297 (20.1%) exhibited BI-NSI. After adjusting for sex, age category and with or without haemorrhage shock, groups with higher SBP and lower HR (SBP >=135 mm Hg; HR <=92 bpm) were significantly associated with BI-NSI (OR 2.84, 95% CI 1.68 to 4.80, P<0.001) compared with the patients with normal vital signs. In age-specific analysis, hypertension and bradycardia were significantly associated with BI-NSI in a group of 7-10 and 11-15 years of age; however, no significant association was observed in a group of 2-6 years of age. CONCLUSIONS: Cushing's sign after blunt trauma was significantly associated with BI-NSI in school-age children and young adolescents. PMID- 29502095 TI - Impact and acceptability of self-consent procedures for the school-based human papillomavirus vaccine: a mixed-methods study protocol. AB - INTRODUCTION: The human papillomavirus (HPV) vaccine, administered in early adolescence, can substantially reduce cervical cancer incidence and mortality. However, lack of written parental consent is a key reason why some young women do not receive the vaccine. The national legal framework allows girls to be vaccinated without parental consent provided they are deemed Gillick competent, but there is some reticence about vaccinating without written parental consent. Self-consent procedures are being implemented in Bristol and South Gloucestershire. This study will examine the implementation, acceptability and impact of these new procedures. METHODS AND ANALYSIS: Statistical analyses of routine data from Public Health England and the Child Health Information System will test if there has been an increase in HPV vaccination uptake in two ways: (a) Is there an increase when comparing before and after the change in our intervention sites? and (b) Does the percentage change in our intervention sites differ from comparison sites (similar to our intervention sites in terms of initial HPV uptake, ethnicity and deprivation levels) in England where no such intervention took place and how? For the process evaluation, we will develop a logic model and use questionnaires, observations and audio-recorded interviews with young women, school nurses, school staff and parents to examine the context, implementation of self-consent and response to the new procedures. ETHICS AND DISSEMINATION: The University of Bristol Faculty of Health Sciences Research Ethics Committee and the National Health Service Health Research Authority provided approvals for the study. We will produce a report with recommendations about self-consent procedures in conjunction with key stakeholders. At least two papers will be written for publication in peer-reviewed journals and for conference presentations. A summary of results will be shared with participating immunisation nurses, school staff, young people and parents as requested. TRIAL REGISTRATION NUMBER: ISRCTN49086105; Pre-results. PMID- 29502097 TI - Disability discrimination and misdirected criticism of the quality-adjusted life year framework. AB - Whose values should count - those of patients or the general public - when adopting the quality-adjusted life year (QALY) framework for healthcare decision making is a long-standing debate. Specific disciplines, such as economics, are not wedded to a particular side of the debate, and arguments for and against the use of patient values have been discussed at length in the literature. In 2012, Sinclair proposed an approach, grounded within patient preference theory, which sought to avoid a perceived unfair discrimination against people with disabilities when using values from the general public. Key assumptions about general public values that beget this line of thinking were that 'disabled states always tally with lower quality of life', and the use of standardised instruments means that 'you are forced into a fixed view of disability as a lower value state' (Sinclair, 2012). Drawing on recent contributions to the health economics literature, we contend that such assumptions are not inherent to the incorporation of general public values for the estimation of QALYs. In practice, whether health states of people with disabilities are of 'lower value' is, to some extent, a reflection of the health state descriptions that members of the public are asked to value. PMID- 29502096 TI - Identifying research priorities for patient safety in mental health: an international expert Delphi study. AB - OBJECTIVE: Physical healthcare has dominated the patient safety field; research in mental healthcare is not as extensive but findings from physical healthcare cannot be applied to mental healthcare because it delivers specialised care that faces unique challenges. Therefore, a clearer focus and recognition of patient safety in mental health as a distinct research area is still needed. The study aim is to identify future research priorities in the field of patient safety in mental health. DESIGN: Semistructured interviews were conducted with the experts to ascertain their views on research priorities in patient safety in mental health. A three-round online Delphi study was used to ascertain consensus on 117 research priority statements. SETTING AND PARTICIPANTS: Academic and service user experts from the USA, UK, Switzerland, Netherlands, Ireland, Denmark, Finland, Germany, Sweden, Australia, New Zealand and Singapore were included. MAIN OUTCOME MEASURES: Agreement in research priorities on a five-point scale. RESULTS: Seventy-nine statements achieved consensus (>70%). Three out of the top six research priorities were patient driven; experts agreed that understanding the patient perspective on safety planning, on self-harm and on medication was important. CONCLUSIONS: This is the first international Delphi study to identify research priorities in safety in the mental field as determined by expert academic and service user perspectives. A reasonable consensus was obtained from international perspectives on future research priorities in patient safety in mental health; however, the patient perspective on their mental healthcare is a priority. The research agenda for patient safety in mental health identified here should be informed by patient safety science more broadly and used to further establish this area as a priority in its own right. The safety of mental health patients must have parity with that of physical health patients to achieve this. PMID- 29502098 TI - Researching about us without us: exploring research participation and the politics of disability rights in the context of the Mental Capacity Act 2005. AB - The right to active participation by disabled people in academic research has been discussed at length in recent years, along with the potential for such research to function as a tool in challenging oppression and pursuing disability rights. Significant ethical, legal and methodological dilemmas arise, however, in circumstances where a disabled person loses the capacity to provide informed consent to such participation. In this article, I consider disability politics and academic research in the context of the Mental Capacity Act (MCA) 2005, which sets out in Anglo-Welsh law the circumstances and requirements for research participation by individuals lacking the capacity to provide informed consent. Drawing on my own perspective on research participation in relation to physical and psychosocial disability, I consider the implications of my potential future loss of capacity (eg, if I were to be in a vegetative or minimally conscious state following an accident) for my right to participate in disability-related research. I examine the barriers to such participation and suggest that partial solutions may be found in the advance decision-making and advance care-planning frameworks of the MCA 2005 and related policy, but that current legislative and policy frameworks nevertheless still curtail my rights with regard to research participation on loss of capacity to consent. In so doing, I seek to provoke debate concerning what this legislative provision means for the disability rights movement, and the possibilities and challenges it presents to the movement's commitment to 'nothing about us without us'. PMID- 29502099 TI - Advance euthanasia directives: a controversial case and its ethical implications. AB - Authorising euthanasia and assisted suicide with advance euthanasia directives (AEDs) is permitted, yet debated, in the Netherlands. We focus on a recent controversial case in which a Dutch woman with Alzheimer's disease was euthanised based on her AED. A Dutch euthanasia review committee found that the physician performing the euthanasia failed to follow due care requirements for euthanasia and assisted suicide. This case is notable because it is the first case to trigger a criminal investigation since the 2002 Dutch euthanasia law was enacted. Thus far, only brief descriptions of the case have been reported in English language journals and media. We provide a detailed description of the case, review the main challenges of preparing and applying AEDs for persons with dementia and briefly assess the adequacy of the current oversight system governing AEDs. PMID- 29502100 TI - Adipose-Derived Exosomes Exert Proatherogenic Effects by Regulating Macrophage Foam Cell Formation and Polarization. AB - BACKGROUND: Obesity is causally associated with atherosclerosis, and adipose tissue (AT)-derived exosomes may be implicated in the metabolic complications of obesity. However, the precise role of AT-exosomes in atherogenesis remains unclear. We herein aimed to assess the effect of AT-exosomes on macrophage foam cell formation and polarization and subsequent atherosclerosis development. METHODS AND RESULTS: Four types of exosomes isolated from the supernatants of ex vivo subcutaneous AT and visceral AT (VAT) explants that were derived from wild type mice and high-fat diet (HFD)-induced obese mice were effectively taken up by RAW264.7 macrophages. Both treatment with wild-type VAT exosomes and HFD-VAT exosomes, but not subcutaneous AT exosomes, markedly facilitated macrophage foam cell generation through the downregulation of ATP-binding cassette transporter (ABCA1 and ABCG1)-mediated cholesterol efflux. Decreased expression of liver X receptor-alpha was also observed. Among the 4 types of exosomes, only HFD-VAT exosomes significantly induced M1 phenotype transition and proinflammatory cytokine (tumor necrosis factor alpha and interleukin 6) secretion in RAW264.7 macrophages, which was accompanied by increased phosphorylation of NF-kappaB-p65 but not the cellular expression of NF-kappaB-p65 or IkappaB-alpha. Furthermore, systematic intravenous injection of HFD-VAT exosomes profoundly exacerbated atherosclerosis in hyperlipidemic apolipoprotein E-deficient mice, as indicated by the M1 marker (CD16/32 and inducible nitric oxide synthase)-positive areas and the Oil Red O/Sudan IV-stained area, without affecting the plasma lipid profile and body weight. CONCLUSIONS: This study demonstrated a proatherosclerotic role for HFD-VAT exosomes, which is exerted by regulating macrophage foam cell formation and polarization, indicating a novel link between AT and atherosclerosis in the context of obesity. PMID- 29502101 TI - Effect of beta-Blockers Beyond 3 Years After Acute Myocardial Infarction. AB - BACKGROUND: The optimal duration of beta-blocker therapy in patients with acute myocardial infarction (AMI) is unknown. We aimed to evaluate the late effect of beta-blockers in patients with AMI. METHODS AND RESULTS: We enrolled all consecutive patients who presented with AMI at Seoul National University Bundang Hospital, between June 3, 2003 and February 24, 2015. The primary end point was 5 year all-cause mortality, depending on the use of beta-blockers at discharge, 1 year after AMI, and 3 years after AMI. Of 2592 patients, the prescription rates of beta-blockers were 72%, 69%, 63%, and 60% at discharge and 1, 3, and 5 years after AMI, respectively. The patients who were receiving beta-blocker therapy had more favorable clinical characteristics, such as younger age (62 versus 65 years; P<0.001). They received reperfusion therapy more often (92% versus 80%; P<0.001) than those without beta-blocker prescription. In the univariate analysis, the patients with beta-blocker prescription had lower 5-year mortality at all time points. In the Cox model after adjustment for significant covariates, beta blocker prescription at discharge was associated with a 29% reduced mortality risk (hazard ratio, 0.71; 95% confidence interval, 0.55-0.90; P=0.006); however, beta-blocker prescriptions at 1 and 3 years after AMI were not associated with reduced mortality. CONCLUSIONS: The beneficial effect of beta-blocker therapy after AMI may be limited until 1 year after AMI. Whether late beta-blocker therapy beyond 1 year after AMI offers clinical benefits should be confirmed in further clinical trials. PMID- 29502102 TI - Combined Angiotensin Receptor-Neprilysin Inhibitors Improve Cardiac and Vascular Function Via Increased NO Bioavailability in Heart Failure. AB - BACKGROUND: There is a paucity of data about the mechanisms by which sacubitril/valsartan (also known as LCZ696) improves outcomes in patients with heart failure. Specifically, the effects of sacubitril/valsartan on vascular function and NO bioavailability have not been investigated. We hypothesized that sacubitril/valsartan therapy increases circulating NO levels and improves vascular function in the setting of heart failure. METHODS AND RESULTS: Male spontaneously hypertensive rats underwent myocardial ischemia/reperfusion surgery to induce heart failure and were followed for up to 12 weeks with serial echocardiography. Rats received sacubitril/valsartan (68 mg/kg), valsartan (31 mg/kg), or vehicle starting at 4 weeks after reperfusion. At 8 or 12 weeks of reperfusion, animals were euthanized and tissues were collected for ex vivo analyses of NO bioavailability, aortic vascular reactivity, myocardial and vascular histology, and cardiac molecular assays. Left ventricular structure and function were improved by both valsartan and sacubitril/valsartan compared with vehicle. Sacubitril/valsartan resulted in superior cardiovascular benefits, as evidenced by sustained improvements in left ventricular ejection fraction and end diastolic pressure. Ex vivo vascular function, as measured by aortic vasorelaxation responses to acetylcholine and sodium nitroprusside, was significantly improved by valsartan and sacubitril/valsartan, with more sustained improvements afforded by sacubitril/valsartan. Furthermore, myocardial NO bioavailability was significantly enhanced in animals receiving sacubitril/valsartan therapy. CONCLUSIONS: Sacubitril/valsartan offers superior cardiovascular protection in heart failure and improves vascular function to a greater extent than valsartan alone. Sacubitril/valsartan-mediated improvements in cardiac and vascular function are likely related to increases in NO bioavailability and explain, in part, the benefits beyond angiotensin receptor blockade. PMID- 29502103 TI - ADP Platelet Hyperreactivity Predicts Cardiovascular Disease in the FHS (Framingham Heart Study). AB - BACKGROUND: Platelet function is associated with adverse events in patients with cardiovascular disease (CVD). METHODS AND RESULTS: We examined associations of baseline platelet function with incident CVD events in the community-based FHS (Framingham Heart Study). Participants free of prevalent CVD and without recent aspirin treatment with available data in the Framingham Offspring cohort (1991 1995) and Omni cohort (1994-1998) were included. Platelet function was measured with light transmission aggregometry using collagen (1.9 MUg/mL), ADP (0.05-15 MUmol/L), and epinephrine (0.01-15 MUmol/L). We used proportional hazards models to analyze incident outcomes (myocardial infarction/stroke, CVD, and CVD mortality) with respect to platelet measures. The study sample included 2831 participants (average age, 54.3 years; 57% women). During follow-up (median, 20.4 years), we observed 191 composite incident myocardial infarction or stroke events, 432 incident CVD cases, and 117 CVD deaths. Hyperreactivity to ADP and platelet aggregation at ADP concentration of 1.0 MUmol/L were significantly associated with incident myocardial infarction/stroke in a multivariable model (hazard ratio, 1.68 [95% confidence interval, 1.13-2.50] [P=0.011] for hyperreactivity across ADP doses; and hazard ratio, 1.16 [95% confidence interval, 1.02-1.33] [P=0.029] for highest quartile of ADP response at 1.0 MUmol/L versus others). No association was observed for collagen lag time or any epinephrine measures with incident myocardial infarction or stroke. CONCLUSIONS: Intrinsic hyperreactivity to low-dose ADP in our community-based sample, who were free of CVD and any antiplatelet therapy, is associated with future arterial thrombosis during a 20-year follow-up. These findings reinforce ADP activation inhibition as a critical treatment paradigm and encourage further study of ADP inhibitor-refractive populations. PMID- 29502104 TI - To Have and Have Not: Intrinsic Platelet Hyperreactivity? PMID- 29502106 TI - Hypercholesterolemia-Induced Loss of Flow-Induced Vasodilation and Lesion Formation in Apolipoprotein E-Deficient Mice Critically Depend on Inwardly Rectifying K+ Channels. AB - BACKGROUND: Hypercholesterolemia-induced decreased availability of nitric oxide (NO) is a major factor in cardiovascular disease. We previously established that cholesterol suppresses endothelial inwardly rectifying K+ (Kir) channels and that Kir2.1 is an upstream mediator of flow-induced NO production. Therefore, we tested the hypothesis that suppression of Kir2.1 is responsible for hypercholesterolemia-induced inhibition of flow-induced NO production and flow induced vasodilation (FIV). We also tested the role of Kir2.1 in the development of atherosclerotic lesions. METHODS AND RESULTS: Kir2.1 currents are significantly suppressed in microvascular endothelial cells exposed to acetylated low-density lipoprotein or isolated from apolipoprotein E-deficient (Apoe-/- ) mice and rescued by cholesterol depletion. Genetic deficiency of Kir2.1 on the background of hypercholesterolemic Apoe-/- mice, Kir2.1+/-/Apoe-/- exhibit the same blunted FIV and flow-induced NO response as Apoe-/- or Kir2.1+/- alone, but while FIV in Apoe-/- mice can be rescued by cholesterol depletion, in Kir2.1+/ /Apoe-/- mice cholesterol depletion has no effect on FIV. Endothelial-specific overexpression of Kir2.1 in arteries from Apoe-/- and Kir2.1+/-/Apoe-/- mice results in full rescue of FIV and NO production in Apoe-/- mice with and without the addition of a high-fat diet. Conversely, endothelial-specific expression of dominant-negative Kir2.1 results in the opposite effect. Kir2.1+/-/Apoe-/- mice also show increased lesion formation, particularly in the atheroresistant area of descending aorta. CONCLUSIONS: We conclude that hypercholesterolemia-induced reduction in FIV is largely attributable to cholesterol suppression of Kir2.1 function via the loss of flow-induced NO production, whereas the stages downstream of flow-induced Kir2.1 activation appear to be mostly intact. Kir2.1 channels also have an atheroprotective role. PMID- 29502108 TI - Regulation of Kir2.1 Function Under Shear Stress and Cholesterol Loading. PMID- 29502107 TI - Sudden Unexplained Nocturnal Death Syndrome: The Hundred Years' Enigma. PMID- 29502111 TI - Why We Should Focus on Melanoma-Targeted Screening Strategies. PMID- 29502105 TI - Safety of Perioperative Aprotinin Administration During Isolated Coronary Artery Bypass Graft Surgery: Insights From the ART (Arterial Revascularization Trial). AB - BACKGROUND: There is still uncertainty about the safety of aprotinin for coronary artery bypass graft surgery. The ART (Arterial Revascularization Trial) was designed to compare survival after bilateral versus single internal thoracic artery grafting. Many of the ART patients (~30%) received perioperative aprotinin. We investigated the association between perioperative aprotinin administration and short-term (in-hospital) and long-term outcomes by performing a post hoc analysis of the ART. METHODS AND RESULTS: Among patients enrolled in the ART (n=3102) from 2004 to 2007, we excluded those who did not undergo surgery (n=18) and those with no information about use of perioperative aprotinin (n=9). Finally, 836 of 3076 patients (27%) received aprotinin. Propensity matching was used to select 536 pairs for final comparison. Aprotinin was also associated with an increased risk of hospital mortality (9 [1.7%] versus 1 [0.2%]; odds ratio, 9.12; 95% confidence interval [CI], 1.15-72.2; P=0.03), intra-aortic balloon pump insertion (37 [6.9%] versus 17 [3.2%]; odds ratio, 2.26; 95% CI, 1.26-4.07; P=0.006), and acute kidney injury (102 [19.0%] versus 76 [14.2%]; odds ratio, 1.42; 95% CI, 1.03-1.97; P=0.03). Aprotinin was not associated with a lower incidence of transfusion (37 [6.9%] versus 28 [5.2%]; odds ratio, 1.34; 95% CI, 0.81-2.23; P=0.25) and reexploration (26 [4.9%] versus 19 [3.5%]; hazard ratio, 1.39; 95% CI, 0.76-2.53; P=0.28). At 5 years, all-cause mortality was significantly increased in the aprotinin group (56 [10.6%] versus 38 [7.3%]; hazard ratio, 1.51; 95% CI, 1.0-2.28; P=0.045). CONCLUSIONS: In the present post hoc ART analysis, aprotinin was associated with a significantly increased risk of early and late mortality. CLINICAL TRIAL REGISTRATION: URL: http://www.isrctn.com. Unique identifier: ISRCTN46552265. PMID- 29502109 TI - Cardiopulmonary Exercise Testing in Patients Following Massive and Submassive Pulmonary Embolism. AB - BACKGROUND: Little data exist regarding the functional capacity of patients following acute pulmonary embolism. We sought to characterize the natural history of symptom burden, right ventricular (RV) structure and function, and exercise capacity among survivors of massive and submassive pulmonary embolism. METHODS AND RESULTS: Survivors of submassive or massive pulmonary embolism (n=20, age 57+/-13.3 years, 8/20 female) underwent clinical evaluation, transthoracic echocardiography, and cardiopulmonary exercise testing at 1 and 6 months following hospital discharge. At 1 month, 9/20 (45%) patients had New York Heart Association II or greater symptoms, 13/20 (65%) demonstrated either persistent RV dilation or systolic dysfunction, and 14/20 (70%) had objective exercise impairment as defined by a peak oxygen consumption (VO2) of <80% of age-sex predicted maximal values (16.25 [13.4-20.98] mL/kg per minute). At 6 months, no appreciable improvements in symptom severity, RV structure or function, and peak VO2 (17.45 [14.08-22.48] mL/kg per minute, P=NS) were observed. No patients demonstrated an exercise limitation attributable to either RV/pulmonary vascular coupling, as defined by a VE/VCO2 slope >33, or a pulmonary mechanical limit to exercise at either time point. Similarly, persistent RV dilation or dysfunction was not significantly related to symptom burden or peak VO2 at either time point. CONCLUSIONS: Persistent symptoms, abnormalities of RV structure and function, and objective exercise limitation are common among survivors of massive and submassive pulmonary embolism. Functional impairment appears to be attributable to general deconditioning rather than intrinsic cardiopulmonary limitation, suggesting an important role for prescribed exercise rehabilitation as a means toward improved patient outcomes and quality of life. PMID- 29502110 TI - Prospective, Observational, Non-Interventional, Multicentre Study on the Efficacy and Tolerability of a New Calcipotriol/Betamethasone Aerosol Foam (Enstilar(r)) in Patients with Plaque Psoriasis under Daily Practice Conditions. AB - BACKGROUND/AIMS: To assess the efficacy and tolerability of the new aerosol foam of calcipotriol 50 ug/g plus betamethasone dipropionate 0.5 mg/g (Cal/BD foam, Enstilar(r)) in psoriasis vulgaris under daily practice conditions. METHODS: 410 adult psoriasis patients (56% male) from 87 German sites were enrolled in a 4 week, open-label, prospective, non-controlled, observational, non-interventional study. RESULTS: At baseline, patients presented with a psoriasis severity of mild (41.81%), moderate (49.63%), and severe (8.31%) assessed by an investigator global assessment (IGA). After 4 weeks of treatment, 49% of the patients achieved an IGA of clear/almost clear. The mean affected body surface area was reduced from 12.91 to 7.55%, the PASI from 10.4 to 5.2 (p < 0.0001). 43% of the patients with severe IGA achieved treatment success (IGA = 0/1 and >=2-step improvement). 93% of the patients did not show any adverse events. CONCLUSION: The new Cal/BD foam showed a convincing efficacy and tolerability profile in daily practice, particularly in patients with severer disease manifestations. PMID- 29502112 TI - Hyperhidrosis - Sweating Sites Matter: Quality of Life in Primary Hyperhidrosis according to the Sweating Sites Measured by SF-36. AB - BACKGROUND: Primary hyperhidrosis has negative impacts on quality of life. The aim of this study was to investigate whether the impacts of primary hyperhidrosis on quality of life are different depending on the localisation of the sweating. METHOD: We compiled background data, Hyperhidrosis Disease Severity Scale (HDSS), and Short-Form Health Survey (SF-36) post hoc results from 2 previous studies. Cases who described only 1 site as their most problematic area of sweating were included (n = 160/188) while individuals with multifocal primary sites of hyperhidrosis were excluded (n = 28/188). RESULTS: Individuals included were 11 62 years old with a mean age of 30.2 +/- 10.4 years, and axillary hyperhidrosis (65.6%) was the most common type of hyperhidrosis. Comorbidities were more common when hyperhidrosis was reported in other than the axillary, palmar, and plantar regions. Excluding comorbidities showed the lowest SF-36 mental component summary scores for axillary (41.6 +/- 11.6), palmar (40.0 +/- 9.4), and plantar hyperhidrosis (41.1 +/- 13.7). The HDSS showed the highest proportion of severe cases in axillary (60.6%) and palmar (51.5%) hyperhidrosis (p < 0.01) while mild cases were more often observed in plantar (60%), facial (83.3%), and other sites (85.7%) in primary hyperhidrosis (p < 0.01). CONCLUSION: Our results indicate that impairments in quality of life can be different depending on the manifestation of primary hyperhidrosis on the body. This can have an influence on how patients with hyperhidrosis could be prioritised in health care. Subgroup samples affected by facial hyperhidrosis and other sites of primary hyperhidrosis were however small, and more research is required to verify our findings. PMID- 29502113 TI - Default Mode Network Disruption in Stroke-Free Patients with Atrial Fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) is a widely accepted risk for causing stroke. However, recent studies show AF as a risk factor for dementia, even without causing stroke. The mechanisms by which dementia develops in stroke-free patients with AF are still poorly understood and the association of AF with abnormal function of brain networks activities, such as the default mode network (DMN), has not been previously studied. We aimed to determine whether, in the absence of stroke and dementia, patients with AF have abnormal resting-state brain networks compared to controls without AF. METHODS: Twenty-one stroke-free patients with AF and 21 age- and sex-matched controls without AF underwent brain functional magnetic resonance imaging acquired at a 3.0 Tesla scanner. During the exam, the subjects were instructed to lie still with eyes closed. At first-level analysis, connectivity of the DMN was obtained for all subjects. Second-level analysis compared the DMN connectivity between AF patients and controls with a general linear model (two-sample t test, p < 0.05, False Discovery Rate corrected, minimum of 50 contiguous voxels). RESULTS: Patients with AF compared with controls showed decreased connectivity in regions of the DMN including the frontal lobe (left medial frontal gyrus, left superior frontal gyrus and anterior cingulate), left angular gyrus, and bilateral precuneus. CONCLUSIONS: Stroke-free patients with AF have evidence of abnormal DMN connectivity. This study adds evidence to the occurrence of cerebral dysfunction in patients with AF. PMID- 29502114 TI - The Prevalence of Multiple Sclerosis in the Metropolitan Area of Rome: A Capture Recapture Analysis. AB - BACKGROUND: Limited data are available on the prevalence of multiple sclerosis (MS) in central Italy. The objective of this study is to estimate MS prevalence in the metropolitan area of Rome. METHODS: We used the capture-recapture method to calculate prevalence estimates in the study area. The selected prevalence day was December 31, 2015. A total of 1,007 patients, with a definite diagnosis of MS according to the revised McDonald's criteria, were considered for crude, age- and sex-specific prevalence estimation. RESULTS: The overall crude prevalence rate was 146.2 cases per 100,000 (95% CI 119.9-172.5). A higher prevalence rate was recorded in females (194.1, 95% CI 149.6-238.6) than in males (93.0, 95% CI 67.2 118.8) with a female to male ratio of 1.8. Age-specific prevalence peaked in the 25-34 , 35-44 and 45-54 years class; moreover, it was found to increase up to the 45-54 years age group in females and the 35-44 years age group in males, decreasing thereafter. CONCLUSION: The results confirm that the metropolitan area of Rome is a high-risk area for MS. PMID- 29502115 TI - Anaplastic Ganglioglioma Involving the Entire Length of the Spinal Cord. PMID- 29502116 TI - Dermoscopy Improves the Diagnostic Accuracy of Melanomas Clinically Resembling Seborrheic Keratosis: Cross-Sectional Study of the Ability to Detect Seborrheic Keratosis-Like Melanomas by a Group of Dermatologists with Varying Degrees of Experience. AB - BACKGROUND: Malignant melanomas mimicking seborrheic keratosis (SK-like MMs) carry the risk of delayed diagnosis and inadequate treatment. The value of dermoscopy to improve the correct detection of these mimickers has not been previously studied. OBJECTIVE: To evaluate the diagnostic accuracy of clinically SK-like MMs with and without dermoscopy. METHODS: Clinical and dermoscopic images of histopathologically proven SK-like MMs (n = 134) intermingled with other melanomas and benign tumors were randomly presented to clinicians with different levels of experience, blinded to the diagnosis and goal of the study. Each participant classified each lesion as melanoma or benign tumor. The clinical and clinical-dermoscopic diagnostic accuracies were measured separately. RESULTS: Overall, 54 participants with a mean clinical experience of 15.8 years (SD 11.8) evaluated 231 tumors. Almost 40% of SK-like melanomas were clinically misclassified as benign tumor. Dermoscopy improved diagnostic accuracy for all participants, independently of experience, from 60.9 to 68.1% (p < 0.001), mostly due to a significant increase in the sensitivity (clinical 61.9% vs. dermoscopic 74.5%) (p < 0.001). Dermoscopy did not significantly affect specificity among the experienced participants (>=6 years of experience) compared to clinical examination (61.1 vs. 59.6%, respectively); in contrast, dermoscopy was associated with a decrease in specificity compared to clinical diagnosis among novice participants (< 6 years) (45.6 vs. 61.1%, respectively; p = 0.02). CONCLUSION: Melanomas can be clinically indistinguishable from SKs despite being evaluated by expert dermatologists. Dermoscopy, even in nonexpert hands, significantly improves their recognition. PMID- 29502117 TI - Children with a History of Premature Adrenarche Have Good Health-Related Quality of Life at the Age of 12 Years. AB - BACKGROUND/AIM: Children with premature adrenarche (PA) are taller and more overweight than their healthy peers, and PA girls have a slightly accelerated pubertal development. There is some evidence that early exposure to androgens may have an influence on psychosocial development. The aim of this cross-sectional case-control study was to evaluate health-related quality of life (HRQoL) in PA children at the age of 12 years. METHODS: The HRQoL was assessed for 43 PA (36 girls) and 63 control children (52 girls) at the median age of 12.0 years using the standardized 16D instrument, and the scores of the PA children were compared to those of the control children and reference population. RESULTS: The mean overall HRQoL scores did not differ between PA and control girls, PA and control boys, or all PA and control children or the reference population. Independently of PA, overweight girls had a lower mean overall HRQoL score than lean girls, and both overweight girls and boys were on average worse off on the dimension of appearance than their lean peers. CONCLUSIONS: PA children have as good self rated HRQoL as their peers at the age of 12 years. Overweight is associated with a worse HRQoL profile independently of PA. PMID- 29502119 TI - Use of Urinary Collection Devices in Community and Nursing Homes in Istria County. AB - INTRODUCTION: This study is aimed at assessing the use of various types of urinary catheters, appropriateness of catheter placement and factors associated with antibiotic use in a population of chronically catheterized patients in Istria County. MATERIALS AND METHODS: This cross-sectional study, conducted between March and June 2017 in Istria County, Croatia, was initiated through a network of general family medicine offices. Data were collected from general practitioners (GPs) and from medical managers in nursing homes. Participants were asked to review medical records of their patients and to complete a 10-item questionnaire designed to retrieve information on patients with urinary catheter. RESULTS: All GPs in the county were surveyed. We identified 309 patients with urinary catheter: 216 men (70%) and 93 women (30%). The overall prevalence of individuals with urinary catheters was 0.18%: 4.7% in nursing home population and 0.1% among non-institutionalized adult population. Most common indication for catheterization was chronic urinary retention (52%). One hundred eighty-six patients (60.4%) reported antibiotic usage in the previous 3 months for treating urinary infection. CONCLUSIONS: In Istria County, the prevalence of indwelling urinary catheters is highest in males, especially among patients in nursing homes. There is a need for focused education among GPs regarding urinary catheter maintenance and antibiotic prescription for suspected urinary tract infections. PMID- 29502118 TI - Inhibitory Effects of Benzaldehyde, Vanillin, Muscone and Borneol on P Glycoprotein in Caco-2 Cells and Everted Gut Sac. AB - AIMS: In clinical practice, herbal medicines have played an important role in the modulation of drug transporters through the combination of conventional prescription drugs, which necessitates the elucidation of herb-drug interactions. The present study was designed to investigate the inhibitory effects and mechanisms of benzaldehyde, vanillin, muscone, and borneol on P-glycoprotein (P gp). METHODS: The effects of the 4 compounds on the intracellular accumulation of rhodamine-123 (Rho-123) in vinblastine-treated Caco-2 (VB-Caco-2) cells were studied by monitoring fluorescence intensity through a flow cytometry assay, and the effects of these compounds on Rho-123 transport through VB-Caco-2 monolayers and Rho-123 intestinal absorption in the rat everted gut sac were investigated by high-performance liquid chromatography. Moreover, P-gp expression in VB-Caco-2 cells was assessed using flow cytometry and Western blot analysis, and the relative ABCB1 mRNA level was determined by Real-time RT-PCR. KEY FINDINGS: The results showed that benzaldehyde, vanillin, muscone, and borneol significantly increased Rho-123 uptake in VB-Caco-2 cells, increased the absorption rate and apparent permeability coefficient of Rho-123 in rat jejunum and ileum, and decreased the efflux ratio of Rho-123 from 6.52 to less than 2 during transport across VB-Caco-2 cell monolayers. In addition, these compounds reduced the protein and ABCB1 mRNA levels of P-gp in VB-Caco-2 cells. CONCLUSIONS: These data indicate that benzaldehyde, vanillin, muscone and borneol could effectively reverse multidrug resistance via inhibiting the P-gp function and expression pathway. The data provide fodder for further investigation into the interaction between the 4 compounds and other drugs transported by P-gp. PMID- 29502120 TI - A Positive Conversion in HER2 Status Might Affect Survival after Liver Resection for Breast Cancer Metastases. PMID- 29502121 TI - Effects of Hydroxychloroquine on Proteinuria in Immunoglobulin A Nephropathy. AB - BACKGROUND: Hydroxychloroquine (HCQ) is a well-known immunomodulator that is useful as in the treatment for lupus because of its inhibitory effect on toll like receptors and cytokines, which are speculated to play a role in the pathogenesis of Immunoglobulin A (IgA) nephropathy (IgAN). However, there was only one study that investigated the effect of HCQ on proteinuria in patients with IgAN. METHODS: Ninety patients with IgAN who received HCQ in addition to optimized dosage of renin-angiotensin-aldosterone system inhibitors (RAASi) were recruited for this study, and 90 matched historical controls who received RAASi alone were selected from our registry by the propensity score matching method. Their clinical data were compared at baseline and during follow-up till the termination of HCQ or addition of immunosuppressive agents. RESULTS: The median baseline proteinuria level of the 90 patients who received HCQ was comparable with the RAASi-alone group (1.5 [1.2, 2.1] vs. 1.5 [1.2, 1.9] g/day, p = 0.74). At 6 months post-study initiation, the median proteinuria level in the HCQ group was lower than that in the RAASi-alone group (0.8 [0.7, 1.2] vs. 1.2 [0.8, 1.8] g/day, p = 0.02). The percentage by which proteinuria was reduced in the HCQ group was significantly higher than that in the RAASi-alone group (-43% [-57, 12] vs. -19% [-46, 17], p = 0.01). No serious adverse effects were documented during treatment with HCQ. CONCLUSION: The addition of HCQ to RAASi resulted in a significant and safe reduction in proteinuria in patients with IgAN. PMID- 29502122 TI - Aichivirus in Children with Diarrhea in Northern Italy. AB - OBJECTIVE: Since its discovery, Aichivirus (AiV) A has been detected, with an incidence of 0.9-4.1%, primarily when studying outbreaks of diarrhea in children or young adults. In this paper, we report the first detection of AiV in Piedmont, Italy, in pediatric patients. METHODS: A total of 159 fecal specimens (from 96 males and 63 females) previously screened for rotaviruses, adenoviruses, noroviruses, human parechoviruses, saliviruses, and sapoviruses were collected from infants and children with acute gastroenteritis. RESULTS: The most commonly detected virus was norovirus GII (33.80%), fol lowed by rotavirus (21.30%), astrovirus (18.87%), boca virus (13.92%), sapovirus (10.90%), parechovirus (8%), norovirus GI (6.70%), adenovirus (1%), and salivirus (0.52%). Real-time polymerase chain reaction detected AiV A in 1 (0.62%) case subjects. AiV A was detected in monoinfection only in January. CONCLUSIONS: Our results indicate that AiV may be associated with a limited number of diarrhea cases in pediatric patients. PMID- 29502123 TI - The Overall Survival Benefit for Patients with T1 Renal Cell Carcinoma after Nephron-Sparing Surgery Depends on Gender and Age. AB - : Due to the recommendations in the urological guidelines to perform nephron sparing surgery in patients with organ-confined renal cell carcinoma (RCC), the customary therapy regimen changed, but it is not well studied yet whether partial nephrectomy (PN) especially in the elderly is beneficial. From 2000 to 2015, 3,592 patients from 7 clinics undergoing surgery in RCC were identified; 2,323 had T1 tumours. We retrospectively compared the overall survival benefit of patients with T1 RCC who underwent either PN or radical nephrectomy (RN) and studied effects of age and gender. RESULTS: In T1 RCC, PN was beneficial in male patients (p = 0.0006) independent of age, especially in those men <=75 years of age (p = 0.0005); but PN was not beneficial for female patients (p = 0.0629) regardless of age and male patients older than 75 years (p = 0.736). The OS of female patients after RN and male patients after PN is the same, regardless of age. A life expectancy of more than 45 months at least is necessary to experience an overall survival benefit after PN. CONCLUSIONS: There should be harder proven indications for PN in female patients and especially in all patients older than 75 years, particularly with regard to perioperative risk factors. PMID- 29502124 TI - A Prospective Observational Study Evaluating the Correlation of c-MET Expression and EGFR Gene Mutation with Response to Erlotinib as Second-Line Treatment for Patients with Advanced/Metastatic Non-Small-Cell Lung Cancer. AB - OBJECTIVES: We aimed to evaluate the prevalence and predictive role of c-MET expression and EGFR mutation in the efficacy of erlotinib in non-small-cell lung cancer (NSCLC). METHODS: We prospectively recruited 196 patients with stage IV or recurrent NSCLC treated with erlotinib after failure of first-line chemotherapy. Immunohistochemistry was used to evaluate c-MET overexpression, silver in situ hybridization (SISH) to assess gene copy number, and real-time polymerase chain reaction to detect EGFR mutations, respectively, in tumor tissue. RESULTS: The major histologic type was adenocarcinoma (66.8%). c-MET was overexpressed in 55.8% (87/156) and dominant in females as well as non-squamous histology. Although c-MET gene amplification and high polysomy were observed in 2.0% (3/152) and 11.2% (17/152), they did not correlate with any characteristics. EGFR mutation was detected in 13.1% (20/153). The objective response rate of erlotinib was higher (61.1 vs. 3.7%, p < 0.001) and the median progression-free survival (PFS) was longer (10.2 vs. 1.9 months, p < 0.001) in EGFR-sensitizing mutations. However, c-MET positivity did not show a significant correlation with response to erlotinib or PFS. CONCLUSION: We reconfirmed EGFR mutation as a strong predictive marker of NSCLC. However, c-MET positivity was not associated with response or PFS, although c-MET overexpression correlated with some clinical characteristics. PMID- 29502126 TI - Systematic Review and Meta-Analysis of Liver Resection for Colorectal Metastases in Elderly Patients. AB - BACKGROUND: This systematic review and meta-analysis evaluated the short- and long-term outcomes of liver resection for colorectal liver metastases (CRLM) in elderly patients. METHODS: A PubMed, EMBASE, and Cochrane Library search was performed from January 1995 to April 2017, for studies comparing both short- and long-term outcomes in younger and elderly patients undergoing liver resection for CRLM. RESULTS: Eleven studies comparing patients aged <70 years with patients aged >70 years and 4 studies comparing patients aged <75 years with patients aged >75 years were included. Postoperative morbidity was similar in patients aged >70 years (27 vs. 30%; p = 0.35) but higher in patients aged >75 years (21 vs. 32%; p = 0.001). Postoperative mortality was higher in both patients aged >70 years (2 vs. 4%; p = 0.01) and in patients aged >75 years (1 vs. 6%; p = 0.02). Mean 5 year overall survival was lower in patients aged >70 years (40 vs. 32%; p < 0.001) but equal in patients aged >75 years (42 vs. 32%; p = 0.06). CONCLUSION: Although postoperative morbidity and mortality were increased with higher age, liver resection for CRLM seems justified in selected elderly patients. PMID- 29502125 TI - Exercise Performance of Lowlanders with COPD at 2,590 m: Data from a Randomized Trial. AB - BACKGROUND: Effects of hypobaric hypoxia at altitude on exercise performance of lowlanders with chronic obstructive pulmonary disease (COPD) have not been studied in detail. OBJECTIVES: To quantify changes in exercise performance and associated physiologic responses in lowlanders with COPD travelling to moderate altitude. METHODS: A total of 31 COPD patients with a median age (quartiles) of 66 years (59; 69) and FEV1 of 56% predicted (49; 69) living below 800 m performed a constant-load bicycle exercise to exhaustion at 60% of the maximal work rate at 490 m (Zurich) and at an identical work rate at 2,590 m (Davos) in randomized order. Pulmonary gas exchange, pulse oximetry (SpO2), cerebral tissue oxygenation (CTO; near-infrared spectroscopy), and middle cerebral artery peak blood flow velocity (MCAv) by Doppler ultrasound during 30 s at end exercise were compared between altitudes. RESULTS: With ascent from 490 to 2,590 m, the median endurance time (quartiles) was reduced from 500 s (256; 795) to 205 s (139; 297) by a median (95% CI) of 303 s (150-420) (p < 0.001). End exercise SpO2 decreased from 92% (89; 94) to 81% (77; 84) and CTO from 62% (56; 66) to 55% (50; 60); end exercise minute ventilation increased from 40.6 L/min (35.5; 47.8) to 47.2 L/min (39.6; 58.7) (p < 0.05; all comparisons 2,590 vs. 490 m). MCAv increased similarly from rest to end exercise at 490 m (+25% [17; 36]) and at 2,590 m (+21% [14; 30]). However, the ratio of MCAv increase to SpO2 drop during exercise decreased from +6%/% (3; 12) at 490 m to +3%/% (2; 5) at 2,590 m (p < 0.05). CONCLUSIONS: In lowlanders with COPD travelling to 2,590 m, exercise endurance is reduced by more than half compared to 490 m in association with reductions in systemic and cerebral oxygen availability. PMID- 29502127 TI - Detection of Acute Myocardial Infarction in a Pig Model Using the SAN-Atrial-AVN His (SAAH) Electrocardiogram (ECG), Model PHS-A10, an Automated and Integrated Signals Recognition System. AB - BACKGROUND The aim of this study was to compare the use of the standard 12-lead electrocardiogram (ECG) with the SAN-Atrial-AVN-His (SAAH) ECG (Model PHS-A10), a new automated and integrated signals recognition system that detects micro waveforms within the P, QRS, and T-wave, in a pig model of acute myocardial infarction (MI). MATERIAL AND METHODS Six medium-sized domestic Chinese pigs underwent general anesthesia, and an angioplasty balloon was placed and dilated for 120 minutes in the first diagonal coronary artery arising from the left anterior descending (LAD) coronary artery. A standard ECG and a SAAH ECG (Model PHS-A10) were used to evaluate: 1) the number of wavelets in ST-T segment in lead V5; 2) the duration of the repolarization initial (Ri), or duration of the wavelets starting from the J-point to the endpoint of the wavelets in the ST interval; 3) the duration of the repolarization terminal (Rt), of the wavelets, starting from the endpoint of the wavelets in the ST interval to the cross-point of the T-wave and baseline; 4) the ratio Ri: Rt. RESULTS Following coronary artery occlusion, duration of Ri and Ri/Rt increased, and Rt decreased, which was detected by the SAAH ECG (Model PHS-A10) within 12 seconds, compared with standard ECG that detected ST segment depression at 24 seconds following coronary artery occlusion. CONCLUSIONS The findings from this preliminary study in a pig model of acute MI support the need for clinical studies to evaluate the SAAH ECG (Model PHS-A10) for the early detection of acute MI. PMID- 29502128 TI - Lon Peptidase 2, Peroxisomal (LONP2) Contributes to Cervical Carcinogenesis via Oxidative Stress. AB - BACKGROUND Lon protease is responsible for degrading proteins injured by oxidation, and has 2 isoforms, located in mitochondria and peroxisomes. Recent research showed that Lon protease was upregulated in different types of human cancer, but the role of Lon peptidase 2, peroxisomal (LONP2) in cancer is not well understood. It is known, however, that in cancer biology, reduction oxidation is one of the molecular mechanisms involved in tumorigenesis. MATERIAL AND METHODS Oncomine databases and tissue microarrays, initially using immunohistochemistry, were used to analyze LONP2 expression in cervical cancer. In order to uncover the biologic functions and mechanism(s) underlying LONP2 in cervical tumorigenesis, we downregulated the expression of LONP2 using 2 siRNAs transduced in HeLa and SiHa cells. CCK8 assays were performed to evaluate cell viability. Cell cycle and apoptosis assays were used to determine cell growth. Cell migration and invasion assays were used to study changes in cell migration and invasion capacity. Immunofluorescence and flow cytometry were performed to analyze the changes in ROS production. RESULTS We found that the expression of LONP2 was significantly upregulated in cervical cancer, and there was a significant association with pathology type, pathology grade, and clinical stage, but not with age or lymph node metastasis. Moreover, we demonstrated that knocking down LONP2 in HeLa and SiHa cells reduced cell proliferation, cell cycle, apoptosis, migration, invasion, and oxidative stress levels. CONCLUSIONS Our findings suggest that LONP2 promotes cervical tumorigenesis via oxidative stress and may be a potential biomarker and therapeutic target in cervical cancer. PMID- 29502129 TI - Secondary Syphilis with Tonsillar and Cervical Lymphadenopathy and a Pulmonary Lesion Mimicking Malignant Lymphoma. AB - BACKGROUND Syphilis is a sexually transmitted disease caused by the pathogen Treponema pallidum. Prevalence continues to rise, especially among men who have sex with men (MSM). Due to changes in patterns of sexual activity, manifestations of the disease are highly variable. CASE REPORT A 27-year-old male visited the hospital for a low-grade fever and tender 5-cm mass in the right side of his neck. His right tonsil was swollen and covered with a white coating. Levofloxacin was prescribed, but ineffective. The patient's levels of liver function enzymes increased gradually. Systemic magnetic resonance imaging (MRI) revealed bilateral cervical lymphadenopathy with right predominance, a right pulmonary nodule, and a periportal lymph node, suggestive of malignant lymphoma. However, a biopsy of the right cervical lymph node showed nonspecific inflammation. Preoperative rapid plasma reagin (RPR) and T. pallidum latex agglutination (TPLA) tests were positive. The patient was MSM and reported oral sex with many sexual partners. A diagnosis of secondary syphilis was made. Oral amoxicillin was effective, and all symptoms other than periportal lymph node resolved. CONCLUSIONS Tonsillitis, cervical lymphadenopathy, and lung lesions can be manifestations of secondary syphilis. A detailed history, pathology, and serology are crucial for diagnosis. PMID- 29502130 TI - Primary thoracic giant cell tumor of bone sensitive to steroids. AB - Spinal giant cell tumor of bone (GCTB) is a rare benign, but locally aggressive, entity. We report the case of a 40-year-old man diagnosed with GCTB of the thoracic spine. The only symptom upon presentation was progressive back pain with pain radiating to the chest. Magnetic resonance imaging showed that the soft tissue mass extended posteriorly into the spinal canal, causing severe spinal cord compression. We initially treated this case with Decadron (Fresenius kabi, Bad Homburg vor der Hohe, Germany) for 1 week. This led to a reduction of tumor size and decompression of the spinal cord. To the best of our knowledge, there have been no prior reports of primary GCTB sensitive to steroid therapy within the existing literature. PMID- 29502131 TI - Clinical, radiological, and pathological features of extraskeletal osteosarcoma. AB - OBJECTIVE: To evaluate clinical and radiological features of pathology-proven extraskeletal osteosarcomas. METHODS: This retrospective study was IRB-approved and HIPAA-compliant. Our pathology database was queried for cases of extraskeletal osteosarcoma. Tumor location, size, imaging appearance, presence of metastases, and clinical outcome were documented. RESULTS: Nineteen patients met inclusion criteria (age 59 +/- 15 (range 28-85) years; 15 male, 4 female). Tumors occurred in the lower extremities (12 out of 19, 63%), pelvis/gluteal region (3 out of 19, 16%), upper extremity (2 out of 19, 5%), thorax (1 out of 19, 5%), and neck (1 out of 19, 5%). Two out of 19 (11%) patients had undergone radiation to the tumor site previously. According to pathology, 16 out of 19 tumors were high grade (84%). Tumors presented as soft-tissue masses measuring 9.5 +/- 6.8 (2-29) cm. Tumor mineralization was present in 5 out of 19 cases (26%) and local invasion was found in 1 out of 19 cases (6%). On MRI, tumors typically appeared hyperintense on T2-weighted sequences with enhancement in 15 out of 15 (100%) contrast-enhanced studies, and with central necrosis in 10 out of 19 (53%) cases. Low-grade tumors were smaller (<4 cm; 3 out of 3, 100%) and lacked central necrosis (3 out of 3, 100%). 8 out of 19 patients (42%) had metastases, most commonly to the lung (7 out of 19, 37%) and bone (2 out of 19,11%). Two out of 8 patients (25%) with metastases and 8 out of 11 (73%) without metastases achieved recurrence-free survival (mean follow-up 3.8 +/- 4.0 [0.2-14.2]) years. No metastases or deaths occurred in patients with low-grade histology. CONCLUSIONS: Extraskeletal osteosarcomas are rare, typically high-grade malignancies that commonly metastasize to lung and bones. Low-grade tumors and those without metastases have a good prognosis. MRI appearance is nonspecific, with T2 hyperintense signal and heterogeneous enhancement. Unlike conventional osteosarcoma, mineralization is rare. PMID- 29502132 TI - Are adult carpal angle measurements applicable to the pediatric population in the trauma setting? AB - OBJECTIVE: The aim of this study is to assess the applicability of standard adult carpal angle measurements, specifically the scapholunate and capitolunate angles, in the assessment of the pediatric wrist. MATERIALS AND METHODS: The study cohort comprised male and female children who underwent a wrist radiograph for the evaluation of suspected wrist injuries following trauma. A gender- and indication matched adult cohort was also assessed. To ensure an accurate carpal angle measurement, only individuals with a sufficiently ossified carpus and an adequately positioned lateral wrist radiograph were included. RESULTS: Carpal angle measurements were performed on the lateral wrist radiographs of 256 individuals between the ages of 5 and 17 years (mean 11.2 years, SD +/- 2.5 years) and 256 individuals between the ages of 18 and 40 years (mean 28.8 years, SD +/- 6.2 years). The mean pediatric scapholunate angle was 47 degrees (SD +/- 8) and the mean pediatric capitolunate angle was 11 degrees (SD +/- 7). The mean adult scapholunate and capitolunate angles were 48 degrees (SD +/- 8 degrees ) and 10 degrees (SD +/- 6 degrees ) respectively. No statistically significant difference was observed between the scapholunate or capitolunate angle measurements in the two groups (p = 0.26 and p = 0.36). CONCLUSION: The study data supports the applicability of standard adult carpal angle values to the pediatric population provided the carpus is sufficiently ossified. PMID- 29502134 TI - Bond villain should have consulted a neuroradiologist. PMID- 29502133 TI - Bacterial Communities and Their Predicted Functions Explain the Sediment Nitrogen Changes Along with Submerged Macrophyte Restoration. AB - Submerged vegetation biomass fluctuation usually occurs during the preliminary stage of vegetation restoration in shallow lakes, which impacts the final status and duration for achieving a macrophyte-dominant state. This study uncovered the sediment N characteristics and the sediment bacterial community and their predicted functions during the preliminary stage of vegetation recovery in the West Lake, a typical subtropical degenerated shallow lake in China. Results showed increased amounts of sediment TN and NH4-N, reaching 3425.76 and 345.5 mg kg-1, respectively, when the vegetation biomass decreased from its maximum to its minimum. The maximum concentration of sediment NH4-N reached 508.60 mg kg-1 with the decline in vegetation, which might restrict further growth of the submerged macrophytes. The bacterial community structure during the high macrophyte biomass (HMB) period was distinct from that observed during the low macrophyte biomass (LMB) period. Specific taxa such as the phyla Chloroflexi and Acidobacteria and the genus Anaerolineaceae that are related to organic carbon degradation were significantly higher during the LMB period. Potential denitrifiers, such as Lactococcus and Bacillus genera decreased during the LMB period. Accumulation of sediment ammonia could be attributed to the enhanced production by assimilatory nitrate reduction, organic N degradation, and/or the decreased consumption by nitrification. Our findings highlight that the unstable preliminary stage of vegetation restoration brings drastic fluctuation of sediment N loading, of which NH4-N accumulation caused by bacterial communities prevents further growth of the submerged macrophytes. Therefore, extra management measures for the vegetation recovery areas should be taken to avoid excess NH4-N accumulation in sediments. PMID- 29502135 TI - Correlation of Patient- and Physician-Scored Dysphagia with Videofluoroscopies in Patients Treated with Radiotherapy for Head and Neck Cancer. AB - The aim of this study was to investigate the correlation between patient-scored dysphagia and physician-scored dysphagia in head and neck cancer patients treated with radiotherapy. Furthermore, we wanted to compare both patient- and physician scored dysphagia with dysphagia evaluated on swallowing videofluoroscopies. Sixty three patients from two different centers treated with radiotherapy for head and neck cancer were evaluated in the current study. Swallowing videofluoroscopies at baseline, 6, and 12 months following radiotherapy were evaluated by 2 observers using the Penetration Aspiration Scale (PAS) and Swallowing Performance Status Scale (SPS) and correlated with patient and physician scored dysphagia. We observed a significant association between physician and patient scored dysphagia (p < 0.01), pre-treatment and post-treatment. Furthermore, the risk of observing dysphagia on videofluoroscopies increased significantly with increasing scores of both physician as well as patient scored dysphagia, and this at all assessed time points. Patient-scored dysphagia correlates better with dysphagia evaluated by the PAS. Physician-scored dysphagia, however, correlates better with dysphagia as evaluated using the SPS. Both physician- and patient-scored dysphagia correlate well with dysphagia evaluated on videofluoroscopies. Since patient-scored dysphagia correlates better with PAS and changes in the PAS score, and physician scored dysphagia correlates better with SPS, we advocate to use both patient- and physician-scored dysphagia in future trials. PMID- 29502136 TI - Taxane use in breast cancer and risk of brain metastases. PMID- 29502137 TI - Effectiveness of the Remeex systemTM in Colombian women with recurrent stress urinary incontinence or intrinsic sphincter deficiency. AB - INTRODUCTION AND HYPOTHESIS: We report our experience with the Remeex systemTM in women with recurrent stress urinary incontinence (SUI) or intrinsic sphincter deficiency (ISD). METHODS: A multicenter retrospective study was conducted in women who underwent an adjustable sling procedure between 2011 and 2016. We used urodynamic studies (UDS) preoperatively and the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) and cough stress test (CST) pre- and postoperatively. Primary outcomes were subjective (no leakage reported by the patient) and objective (no leakage during CST) cure and improvement rates (reduction of >=4 points in ICIQ-SF). Descriptive and inferential statistics were employed. RESULTS: A total of 50 patients were included. Mean age was 62 years (SD +/- 11.35). Median follow-up was 19.5 months [interquartile range (IQR) 12.95 41.38]. Urinary incontinence (UI) was described as moderate and severe by 8 (16%) and 42 (84%) patients, respectively, and 25 (50%) had stress-predominant mixed urinary incontinence (MUI). Objective and subjective cure rates were 90% and 48%, respectively, while 82% of patients achieved improvement. Impact of UI on quality of life (QoL) improved from 10 (IQR 9-10) to 2 (IQR 0-5) (p < 0.0001). Clavien Dindo II complications occurred in 14 (28%) patients, and one (2%) had IIIa. Tape erosion occurred in one (2%) patient, and five (10%) required readjustments. Logistic regression identified MUI [odds ratio (OR) 3.3, 95% confidence interval (CI) 1.02-10.89] and vaginal atrophy (OR 4.2, 95% CI 1.06-16.03) as predictors of low subjective cure rate. CONCLUSIONS: Adjustable slings represent a valuable and safe option in the management of recurrent SUI or ISD, with improvement in QoL. Results should be carefully interpreted due to our small sample and retrospective design. PMID- 29502138 TI - Mapping the non-darkening trait from 'Wit-rood boontje' in bean (Phaseolus vulgaris). AB - KEY MESSAGE: A QTL for non-darkening seed coat from 'Wit-rood boontje' was mapped in pinto bean population on chromosome Pv10, comprising 40 candidate genes. The seed coat colour darkens with age in some market classes of dry beans (Phaseolus vulgaris), including pinto bean. Beans with darkened seed coats are discounted in the market place, since they are believed to be associated with lower nutritional quality, increased cooking time, and decreased palatability. The objective of this research was to map a non-darkening gene from a cranberry-like bean 'Wit rood boontje' using a recombinant inbred line population, derived from a cross between 'Wit-rood boontje' and a slow-darkening pinto bean (1533-15). The population was characterized for seed phenotype and genotyped with an Illumina BeadChip. A genetic linkage map was constructed with 1327 informative SNP markers plus an STS marker (OL4S500) and an SSR marker (Pvsd-0028), previously associated with the J gene and Sd gene, respectively, as well as non-darkening and slow darkening phenotypes. The linkage map spanned 1253.2 cM over 11 chromosomes. A major QTL for the non-darkening trait was flanked by SNP 715646341 and SNP 715646348 on chromosome Pv10. The region, which spanned 13.2 cM, explained 48% of the phenotypic variation for seed coat darkening. Forty candidate genes were identified in the QTL interval. This information can be used to develop a gene based marker to facilitate breeding non-darkening pinto beans and may lead to a better understanding of the molecular mechanism for the postharvest darkening phenomenon in pinto bean. PMID- 29502139 TI - Phase I study of chemoradiotherapy using gemcitabine plus nab-paclitaxel for unresectable locally advanced pancreatic cancer. AB - PURPOSE: For unresectable locally advanced (UR-LA) pancreatic cancer, chemoradiotherapy has been recommended by the NCCN guidelines. We designed a chemoradiotherapy protocol using nab-paclitaxel combined with gemcitabine (GnP) for patients with UR-LA pancreatic cancer. The purpose of this phase I study was to determine a recommended dose (RD) for this novel regimen. METHODS: Patients with UR-LA pancreatic cancer were eligible. The frequency of dose-limiting toxicities (DLTs) was evaluated, and the RD was determined. Patients were classified according to the designated dose levels of chemoradiotherapy using the GnP regimen. After additional 6 cycles of the GnP regimen were administered, surgery was considered if the patients had stable disease and tumor marker levels had normalized. RESULTS: DLT (grade 4 thrombocytopenia) was observed only in 1 of 12 patients, and the RD was set at level 3. Grade 3-4 leukopenia was observed in 9 (75.0%) patients, and neutropenia in 7 (58.3%). The response rate was 41.7%, and the disease control rate was 100%. Conversion surgery was performed in 6 (50%) patients, and curative resection (R0) was performed in all 6 patients (100%). Stratification according to the Evans classification system demonstrated one patient with grade 1b, one with grade 2, two with grade 3, and two with grade 4 disease. CONCLUSION: The RD for weekly administration was 800 mg/m2 for gemcitabine and 100 mg/m2 for nab-paclitaxel with a 50.4 Gy radiation. The GnP regimen at this dosage was promising with 6 of 12 patients proceeding to conversion surgery, and should be evaluated further in a phase II trial. PMID- 29502140 TI - Efficacy and safety of concurrent immunoradiotherapy in patients with metastatic melanoma after progression on nivolumab. AB - BACKGROUND: The objective of this study was to evaluate the efficacy and safety of concurrent immune checkpoint inhibitor therapy and radiotherapy (immunoradiotherapy) in patients with metastatic melanoma after progression on nivolumab. PATIENTS AND METHODS: A retrospective review was performed on 16 consecutive patients with metastatic melanoma treated with concurrent immunoradiotherapy after progression on nivolumab. Best responses to immunoradiotherapy were assessed either inside or outside of the radiation fields. The target lesions ratio (the sum of the diameters of the target lesions inside the irradiated fields/all target lesions) was also assessed. RESULTS: Among the patients, seven received ipilimumab and radiotherapy (Ipi-RT), six received nivolumab and radiotherapy (Nivo-RT), and three sequentially received Ipi-RT and Nivo-RT. The overall response rate (all patients regardless of inside or outside radiation fields) was 30%. The response rate inside the radiation fields was 68.8% for all patients combined. The response rates of Ipi-RT and Nivo RT inside the radiation fields were 37.5 and 100% (P = 0.03), respectively. Grade 3 adverse events were observed in three patients treated with Ipi-RT. The target lesions ratio was a predictive marker of disease control rate among patients treated with Nivo-RT. CONCLUSIONS: This study showed that concurrent immunoradiotherapy is an option for patients with metastatic melanoma after progression on nivolumab. PMID- 29502141 TI - Comment on Saku et al.: Reasons and risk factors for ninety day re-admission following primary total knee arthroplasty in a high-volume centre. PMID- 29502142 TI - Knee size chart nomogram for evaluation of tibial tuberosity-trochlear groove distance in knees with or without history of patellofemoral instability. AB - PURPOSE: Lateralized tibial tubercle is a cause of patellar instability. Before proceeding with reduction of the tibial tubercle-trochlear groove (TT-TG) distance, surgeons prefer to know whether this distance is pathologic. However, the pathological value remains discussed and may vary with the size of the knee. METHODS: We sought to determine variability in the traditional TT-TG distance versus the anthropometric knee size, using dimensions of the distal part of the femur and proximal part of the tibia of 85 CT scans of the knees in two groups of knees, one normal group without history of patellofemoral instability and one pathologic group with history of instability. RESULTS: The average TT-TG distance measured 13 mm in normal knees and 16.4 mm in pathologic knees. The variability in measurements between normal and pathologic knees varied respectively between +/- 5 and +/- 15 mm, with as consequence absence of threshold value between normal and pathologic knees. These measurements were supplemented by an analysis of a size ratio coefficient. In the normal group without history of instability, linear regression analysis showed that patients with larger knees tended to have higher TT-TG distances and that the values are associated with the mean ML femoro tibial width (p = 0.014; Pearson coefficient = 0.4). The knees with history of instability also keep proportional increase of TT-TG with the size of the knee as the knees without history of instability. We developed a nomogram to more appropriately represent the normal values for a given size of the knee. Application of the nomographic model on the CT scan TT-TG data of the patients who have knee instability allows the orthopaedic surgeon to associate the TT-TG distance with the knee size and to evaluate the medial transfer corresponding to the knee size. CONCLUSIONS: The average TT-TG distances in normal and pathologic knees were not identical for each size of the knees. PMID- 29502143 TI - Coronal plane alignment of the lower limbs in patients with unilateral developmental hip dislocation. AB - PURPOSE: We aimed to identify the coronal plane alignment of lower limbs in patients with unilateral developmental hip dislocation (UDHD) and observe the difference between Hartofilakidis type II and III. PATIENTS AND METHODS: The radiographic data of 76 patients who met the inclusion criteria were retrospectively reviewed, including the hip-knee-ankle angle (HKA), mechanical lateral distal femoral angle (mLDFA), anatomical lateral distal femoral angle (aLDFA), mechanical proximal tibial angle (MPTA), and lateral distal tibial angle (LDTA). RESULTS: The valgus alignment on ipsilateral side was most frequently seen in both Hartofilakidis type II (51.3%) and type III groups (67.6%), whereas for the contralateral side, the neutral alignment in type II group (69.2%) and varus alignment in type III group (51.4%) were most commonly observed. Both the mLDFA and aLDFA of the ipsilateral side were significantly smaller than the contralateral side. CONCLUSIONS: UDHD patients may present with lower limb malalignment on both sides. The ipsilateral valgus alignment is the most common deformity. On the contralateral side, Hartofilakidis type III patients may be more prone to be varus than type II patients. The lower limb malalignment and deformity of the ipsilateral distal femur should be considered during surgery involving hip, knee, or femur. PMID- 29502144 TI - Fast periodic stimulation (FPS): a highly effective approach in fMRI brain mapping. AB - Defining the neural basis of perceptual categorization in a rapidly changing natural environment with low-temporal resolution methods such as functional magnetic resonance imaging (fMRI) is challenging. Here, we present a novel fast periodic stimulation (FPS)-fMRI approach to define face-selective brain regions with natural images. Human observers are presented with a dynamic stream of widely variable natural object images alternating at a fast rate (6 images/s). Every 9 s, a short burst of variable face images contrasting with object images in pairs induces an objective face-selective neural response at 0.111 Hz. A model free Fourier analysis achieves a twofold increase in signal-to-noise ratio compared to a conventional block-design approach with identical stimuli and scanning duration, allowing to derive a comprehensive map of face-selective areas in the ventral occipito-temporal cortex, including the anterior temporal lobe (ATL), in all individual brains. Critically, periodicity of the desired category contrast and random variability among widely diverse images effectively eliminates the contribution of low-level visual cues, and lead to the highest values (80-90%) of test-retest reliability in the spatial activation map yet reported in imaging higher level visual functions. FPS-fMRI opens a new avenue for understanding brain function with low-temporal resolution methods. PMID- 29502145 TI - Functional connectivity of task context representations in prefrontal nodes of the multiple demand network. AB - A subset of regions in the lateral and medial prefrontal cortex and the anterior insula increase their activity level whenever a cognitive task becomes more demanding, regardless of the specific nature of this demand. During execution of a task, these areas and the surrounding cortex temporally encode aspects of the task context in spatially distributed patterns of activity. It is not clear whether these patterns reflect underlying anatomical subnetworks that still exist when task execution has finished. We use fMRI in 12 participants performing alternating blocks of three cognitive tasks to address this question. A first data set is used to define multiple demand regions in each participant. A second dataset from the same participants is used to determine multiple demand voxel assemblies with a preference for one task over the others. We then show that these voxels remain functionally coupled during execution of non-preferred tasks and that they exhibit stronger functional connectivity during rest. This indicates that the assemblies of task preference sharing voxels reflect patterns of underlying anatomical connections. Moreover, we show that voxels preferring the same task have more similar whole brain functional connectivity profiles that are consistent across participants. This suggests that voxel assemblies differ in patterns of input-output connections, most likely reflecting task demand-specific information exchange. PMID- 29502146 TI - Pregnant Genetic Counselors in an Era of Advanced Genomic Tests: What Do the Experts Test Prenatally? AB - Advanced genomic tests in pregnancy, such as chromosomal microarray analysis (CMA), provide higher detection rates yet often produce probabilistic and uncertain information. This study aimed to understand how the most knowledgeable patients, i.e., pregnant genetic counselors, act in their own pregnancies, thereby gaining insight into the impact of patients' knowledge on the diagnostic process. Seventeen interviews were conducted with Israeli genetic counselors, either pregnant or up to 2 years post-pregnancy. A third of the participants chose not to have CMA while two thirds underwent it despite no detected abnormalities. Although knowledge was the main motivation, counselors varied in the desired degree of information. Two thirds of those opting for CMA wished to have all findings identified whereas roughly one third asked for a targeted platform seeking to avoid uncertain results. Counselors were not quick to adopt new tests such as whole-exome sequencing. Being knowledgeable was described as promoting a sense of control yet also being a source of stress and moral dilemmas. While the basic premise of informed consent is crucial, it does not always make things easier for educated patients. Consequently, raising levels of patient knowledge is only a limited step forward in the search for best practice. PMID- 29502147 TI - Mindfulness Among Genetic Counselors Is Associated with Increased Empathy and Work Engagement and Decreased Burnout and Compassion Fatigue. AB - Genetic counselors experience high rates of compassion fatigue and an elevated risk for burnout, both of which can negatively impact patient care and retention in the profession. In other healthcare professions, mindfulness training has been successfully used to address similar negative psychological sequelae and to bolster empathy, which is the foundation of our counseling work. We aimed to assess associations between mindfulness and key professional variables, including burnout, compassion fatigue, work engagement, and empathy. Data were collected via an anonymous, online survey that included validated measures of mindfulness and these key professional variables. The survey was completed by 441 genetic counselors involved in direct patient care. Half of the respondents (50.1%) reported engaging in yoga, meditation, and/or breathing exercises. Mindfulness was positively correlated with work engagement (r = 0.24, p < 0.001) and empathy (as measured through four subscales: perspective taking (r = 0.15, p = 0.002), empathic concern (r = 0.11, p = 0.03), fantasy (r = - 0.11, p = 0.03) and personal distress (r = - 0.15, p = 0.001)). Mindfulness was negatively correlated with compassion fatigue (r = - 0.48, p < 0.001) and burnout (r = - 0.50, p < 0.001). Given these findings, mindfulness training may be a valuable addition to graduate and continuing education for genetic counselors. The integration of mindfulness into the genetic counseling field will likely improve professional morale and well-being, while promoting workforce retention and bolstering the relational and counseling aspects of our clinical work. PMID- 29502148 TI - Characterization of the genome of a novel ilarvirus naturally infecting Cape gooseberry (Physalis peruviana). AB - As part of an initiative to characterize viruses infecting Cape gooseberry in the province of Antioquia (Colombia), we report the genome sequence of a new member of the genus Ilarvirus (family Bromoviridae). This virus was identified in a Cape gooseberry plot in the municipality of Marinilla in a mixed infection with potato virus Y (PVY) as part of high-throughput sequencing initiative. Results were confirmed by nested RT-PCR and DAS-ELISA. Phylogenetic analysis suggested that the Cape gooseberry ilarvirus is a new member of subgroup 1 and it is most closely related to ageratum latent virus (AgLV). The name "Cape gooseberry ilarvirus 1" (CGIV-1) is proposed for this new ilarvirus. PMID- 29502149 TI - A teat papillomatosis case in a Damascus goat (Shami goat) in Hatay province, Turkey: a new putative papillomavirus? AB - Papillomaviruses (PVs) are epitheliotropic viruses that cause benign proliferative lesions in the skin (warts or papillomas) and mucous membranes of their natural hosts. Recently, new PVs have been found in many animal species. The most common current approach for identifying novel PV types is based on PCR, using various consensus or degenerated primer (broad-range primers), designed on the basis of the multiple alignment of nucleotide or amino acid sequences of a large number of different human papillomaviruses (HPV). PVs have been classified according to the sequence similarity of one of their capsid proteins, L1, without taking into account other regions of the genome and without considering the phenotypic characteristics of the viral infection. In this study, we performed molecular detection and typing of a PV in a goat with teat papillomatosis. Firstly, PCR was performed using the FAP59/FAP64 and MY09/MY11 primer pairs for the L1 gene region. The PV DNA was found to be positive only with the FAP59/FAP64 primer pair. PV DNA was then tested with three primer sets in four different combinations (L2Bf/FAP64, L2Bf/L1Br, FAP59/FAP64, L1Bf/LCRBr) for the gene region encoding the L1, L2 and LCR proteins. The goat teat papilloma sample was amplified using FAP59/FAP64 primers and two primer pairs (L2Bf/FAP64 and L2Bf/L1Br). We obtained products matching approximately 604 bp of the L1 region of the virus. PV DNA was used for typing using sequence analysis/PCR with some type-specific primers for bovids, caprids and cervids. The results of the sequence analysis suggested one new putative PV type with sequence identity ranging from 46.45 to 80.09% to other known papillomaviruses, including Capra hircus papillomavirus (ChPV-2), bovine papillomavirus (BPV) 6, 7, 10, 11 and 12, Rangifer tarandus papillomavirus 3 (RtPV-3) and BPV-7Z (Alpine wild ruminant papillomavirus; Cervus elaphus papillomavirus). We therefore propose that this is the first identification of a new putative type, MG523274 (HTY-goat-TR2016), in a goat with teat papillomatosis. It is essential to identify PV types in different animal species and investigate their prevalence/distribution and clinical consequences in order to develop appropriate prophylactic and/or therapeutic procedures and to determine the interspecies transmission potential and evolution of PVs. PMID- 29502150 TI - The Scientific Study of Parents and Caregivers of Children with ASD: A Flourishing Field but Still Work to be Done. AB - There is a long history of research on parents and caregivers of individuals within autism. Parents and other primary caregivers typically play the most important part in the lives of persons with ASD although the need for support as the child becomes of age varies widely. This special issue includes 30 articles on central areas related to parenting and caregiving for people with ASD. Some of the key themes include intervention and training, mental health issues related to parent and family stress, measurement and assessment, and parent-child transactional processes. Other articles in this issue consider different but equally important topics such as sibling as potential future caregivers and parent support of preschool peer relationships. PMID- 29502151 TI - Implementation of a Practice Development Model to Reduce the Wait for Autism Spectrum Diagnosis in Adults. AB - This study examined waiting times for diagnostic assessment of Autism Spectrum Disorder in 11 adult services, prior to and following the implementation of a 12 month change program. Methods to support change are reported and a multi-level modelling approach determined the effect of the change program on overall wait times. Results were statistically significant (b = - 0.25, t(136) = - 2.88, p = 0.005). The average time individuals waited for diagnosis across all services reduced from 149.4 days prior to the change program and 119.5 days after it, with an average reduction of 29.9 days overall. This innovative intervention provides a promising framework for service improvement to reduce the wait for diagnostic assessment of ASD in adults across the range of spectrum presentations. PMID- 29502153 TI - Sexual health in patients with hematological malignancies: a neglected issue. AB - Current evidence, although limited, outlines that sexual dysfunction may represent a prominent part of the symptom burden experienced by the patients with hematologic malignancies (HM). However, despite their presumed negative effects on quality of life (QoL), sexual health is not typically considered in the QoL assessment of HM patients. In addition, very few studies have been conducted in this area. Therefore, it would be important to further investigate how newer drugs developed in recent years for patients with HM, including targeted therapies and impact on sexual health, and how this influence overall patients' QoL outcomes. PMID- 29502152 TI - Adjuvant vinorelbine and cisplatin after complete resection of stage II and III non-small cell lung cancer: long-term follow-up of our study of Japanese patients. AB - PURPOSE: We reported previously a phase II study of adjuvant chemotherapy consisting of four cycles of vinorelbine (25 mg/m2) and cisplatin (40 mg/m2), given on days 1 and 8, every 4 weeks, to Japanese patients with completely resected stage II or III non-small cell lung cancer (NSCLC; UMIN 000005055). However, the follow-up was too short for us to evaluate a definitive 5-year overall survival rate and after-effects. METHODS: Between December 2006 and January 2011, 60 patients were enrolled in this study. We analyzed relapse-free and overall survival, long-lasting adverse effects, the influence of treatment on recurrent tumors, and the development of a second primary cancer, in relation with the regimen. RESULTS: After a median follow-up period of 95.8 months, the 5 year relapse-free and overall survival rates were 51.7 and 76.7%, respectively. Neuralgia developed in one patient and this was the only case of a long-lasting adverse effect. Recurrence developed in 31 patients, 29 of whom received intensive treatment. Although 16 s (or more) primary neoplasms developed among 13 patients, these were common carcinomas in Japan and did not include sarcoma or hematologic malignancies. CONCLUSION: Adjuvant vinorelbine and cisplatin chemotherapy showed encouraging relapse-free and overall survival rates, and long term safety in Japanese patients with resected NSCLC. PMID- 29502154 TI - The impact of UGT2B7 C802T and CYP3A4*1G polymorphisms on pain relief in cancer patients receiving oxycontin. AB - BACKGROUND: Single nucleotide polymorphisms (SNPs) in UGT2B7 C802T and CYP3A4*1G impact drug metabolism. This study aimed to investigate the impact of these SNPs on the efficacy of oxycontin for pain relief in cancer patients. METHODS: A total of 57 Han Chinese cancer patients (age range 20-70 years) who received oxycontin to ease pain for the first time were enrolled and divided into two groups (refractory group and remission group) according to pain relief. Peripheral blood samples were collected from each patient for sequencing analysis. The genotype and allele frequency between the two groups were analyzed using the chi-square test. RESULTS: The T allele frequency of UGT2B7 C802T was 25% among all participants, but was higher (32%) in the refractory group (P = 0.047). The variant allele frequency of CYP3A4*1G was 27% and did not differ between the refractory group and remission group. CONCLUSION: The palliative effect of oxycontin is better in patients with UGT2B7 802CC than in those with 802TT. CYP3A4*1G SNP is unlikely to affect pain relief efficacy of oxycontin. PMID- 29502155 TI - Exploring symptom meaning: perspectives of palliative care physicians. AB - CONTEXT: Understanding patients' symptom experiences is essential to providing effective clinical care. The discussion between patients and physicians of symptom meaning and its significance, however, is ill understood. OBJECTIVES: To investigate palliative care physicians' understanding of symptom meaning, and their experiences of and attitudes towards the discussion of symptom meaning with patients. METHODS: Semi-structured interviews were conducted (N = 17) across Sydney, Australia. Transcripts were analysed using framework analysis. RESULTS: Six key themes were identified: (1) definitions of symptom meaning (causal meanings, functional impact, existential impact, and cascade of meanings); (2) meanings are personal (demographic, culture, spiritual, and family differences); (3) eliciting meanings requires subtlety and trust (following the patient's cues); discussing meaning can be (4) hard (for the patient and health professional); (5) therapeutic (assuaging fears, feeling listened to and valued, increased sense of control, and reduced symptom distress); and (6) enhances clinicians' practice and work satisfaction (provision of more tailored care, reassurance through the provision of information, and strengthening of doctor patient relationship). CONCLUSIONS: Exploring symptom meaning can serve to provide information, alleviate anxiety, and facilitate individualised care, but only when patients present cues or are open to discuss symptom-related concerns. However, various barriers hinder such dialogue in consultations. Greater awareness of symptom meaning and its influence may facilitate physicians exploring symptom meaning more with patients in the future. PMID- 29502156 TI - Disruption or innovation? A qualitative descriptive study on the use of electronic patient-physician communication in patients with advanced cancer. AB - PURPOSE: In the advanced cancer context, care coordination is often inadequate, leading to suboptimal continuity of care. We evaluated an electronic web-based tool which assembles the patient, their caregivers, and their healthcare providers in a virtual space for team-based communication. We sought to understand participant perceptions on electronic communication in general and the added value of the new tool in particular. METHODS: We conducted a qualitative descriptive study with participants (patients, caregivers, cancer physicians) who participated in a 3-month pilot trial evaluating the tool. Interviews were thematically analyzed and the perspectives from patients, caregivers, and cancer physicians were triangulated. Interviews from six patients, five of their caregivers, and seven cancer physicians conducted alongside monthly outcome assessments were analyzed. RESULTS: We identified five themes relating participants' perspectives on electronic communication to their experience of care: (1) apparent gaps in care, (2) uncertainty in defining the circle of care, (3) relational aspects of communication, (4) incongruence between technology and social norms of patient-physician communication, and (5) appreciation but apprehension about the team-based communication tool for improving the experience of care. CONCLUSIONS: The potential of tools for electronic communication to bring together a team of healthcare providers with the patient and caregivers is significant but may pose new challenges to existing team structure and interpersonal dynamics. Patients and physicians were worried about the impact that electronic communication may have on the patient-physician relationship. Implementation approaches, which build on the relationship and integrate the team as a whole, could positively position electronic communication to enhance the team-based care. PMID- 29502157 TI - Social Network Analysis Identifies Key Participants in Conservation Development. AB - Understanding patterns of participation in private lands conservation, which is often implemented voluntarily by individual citizens and private organizations, could improve its effectiveness at combating biodiversity loss. We used social network analysis (SNA) to examine participation in conservation development (CD), a private land conservation strategy that clusters houses in a small portion of a property while preserving the remaining land as protected open space. Using data from public records for six counties in Colorado, USA, we compared CD participation patterns among counties and identified actors that most often work with others to implement CDs. We found that social network characteristics differed among counties. The network density, or proportion of connections in the network, varied from fewer than 2 to nearly 15%, and was higher in counties with smaller populations and fewer CDs. Centralization, or the degree to which connections are held disproportionately by a few key actors, was not correlated strongly with any county characteristics. Network characteristics were not correlated with the prevalence of wildlife-friendly design features in CDs. The most highly connected actors were biological and geological consultants, surveyors, and engineers. Our work demonstrates a new application of SNA to land use planning, in which CD network patterns are examined and key actors are identified. For better conservation outcomes of CD, we recommend using network patterns to guide strategies for outreach and information dissemination, and engaging with highly connected actor types to encourage widespread adoption of best practices for CD design and stewardship. PMID- 29502158 TI - Mitochondrial mRNA expression in fibroblasts of Down syndrome subjects. PMID- 29502159 TI - Phototherapy suppresses inflammation in human nucleus pulposus cells for intervertebral disc degeneration. AB - The etiology of intervertebral disc (IVD) degeneration accompanied by low back pain (LBP) is largely unknown, and there are no curative therapies. Painful IVD degeneration is associated with infiltrated macrophage-mediated inflammatory response of human nucleus pulposus (NP) cells. The present study aimed to address the hypothesis that pro-inflammatory cytokines derived from macrophages lead to the altered molecular phenotype of human NP cells and to investigate the effects of phototherapy (630, 525, 465 nm with 16, 32, 64 J/cm2) on pain-related cytokine interleukin (IL)-6 and chemokine IL-8 under inflammatory conditions in human NP cells. Human NP cells were treated with soluble factors derived from macrophages in an inflammatory microenvironment, similar to that found in degenerative IVD. Human NP cells were also treated with phototherapy (630, 525, 465 nm with 16, 32, 64 J/cm2), and their cytokine and chemokine levels were detected. The soluble factors caused modulated expression of IL-6, IL-8, and matrix metalloproteinases (MMPs) at the gene and protein levels, causing a shift toward matrix catabolism through the expression of MMPs and increased pain-related factors via preferential activation of the nuclear factor-kappa B (NF-kappaB) p50 protein. Importantly, phototherapy attenuated the protein and gene expression of pain related factor IL-6 at all doses and wavelengths. Interestingly, phototherapy also modulated the protein and gene expression of IL-8, which is responsible for the anabolic response, at a wavelength of 465 nm at all doses, in human NP cells. These findings suggested that phototherapy, at an optimal dose and wavelength, might be a useful therapeutic tool to treat IVD degeneration. PMID- 29502161 TI - Zebrafish as a model for kidney function and disease. AB - Kidney disease is a global problem with around three million people diagnosed in the UK alone and the incidence is rising. Research is critical to develop better treatments. Animal models can help to better understand the pathophysiology behind the various kidney diseases and to screen for therapeutic compounds, but the use especially of mammalian models should be minimised in the interest of animal welfare. Zebrafish are increasingly used, as they are genetically tractable and have a basic renal anatomy comparable to mammalian kidneys with glomerular filtration and tubular filtration processing. Here, we discuss how zebrafish have advanced the study of nephrology and the mechanisms underlying kidney disease. PMID- 29502160 TI - Evaluation of laser therapy and alpha-lipoic acid for the treatment of burning mouth syndrome: a randomized clinical trial. AB - The aim of this study was to evaluate the efficacy of low-level laser therapy (LLLT) and alpha-lipoic acid (ALA) in the treatment of burning mouth syndrome (BMS) and secondary oral burning (SOB) by unstimulated sialometry, symptom assessment, and measurement of salivary TNF-alpha levels. Forty-four patients were randomized into four treatment groups: BMS/laser (n = 10), BMS/ALA (n = 5), SOB/laser (n = 15), and SOB/ALA (n = 14). The control group consisted of eight healthy female subjects. Unstimulated salivary flow was measured before and after treatment, and the collected saliva was stored at - 20 degrees C for the analysis of TNF-alpha. Symptoms were evaluated before and after treatment using a pain visual analog scale. Most patients were women (81.8%) during menopause (72.2%). LLLT and ALA were efficient in increasing salivary flow only in BMS but provided symptom relief in both conditions. TNF-alpha levels did not differ between patients with BMS and SOB or between those patients and the control group. No differences were observed in posttreatment TNF-alpha levels in either condition. The results of this study suggest that LLLT and ALA are efficient therapies in reducing burning mouth symptoms, with LLLT being more efficient than ALA. PMID- 29502162 TI - Multimodal lipid-lowering treatment in pediatric patients with homozygous familial hypercholesterolemia-target attainment requires further increase of intensity. AB - BACKGROUND: Familial hypercholesterolemia (FH) causes premature cardiovascular disease (CVD). Lipoprotein apheresis (LA) is recommended as first-line lipid lowering treatment (LLT) for homozygous (ho) FH. METHODS: Efficacy of multimodal LLT including lifestyle counseling, drug treatment, and LA was analyzed in 17 pediatric hoFH or compound heterozygous (c-het) FH patients, who commenced chronic LA in Germany before the age of 18. RESULTS: At time of diagnosis, mean low-density lipoprotein cholesterol (LDL-C) concentration was 19.6 mmol/l (756 mg/dl). Multimodal LLT resulted in 73% reduction of mean LDL-C concentration including a 62% contribution of LA. Only three children (18%) achieved mean LDL-C concentrations below the recommended pediatric target of 3.5 mmol/l (135 mg/dl). In 13 patients (76%) during chronic LA, neither cardiovascular events occurred nor was CVD progression detected clinically or by routine imaging techniques. In four patients (24%), cardiovascular events documented progression of CVD despite weekly LA, including one death due to coronary and cerebrovascular CVD which was not stabilized after commencing LA. Based on the mutational status, only 6 out of the 17 children were candidates for proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibition. Two already responded with further LDL-C decrease by 40%. CONCLUSIONS: Next to drug therapy, regular LA is an essential component of LLT for approaching LDL-C targets in children with hoFH or c-hetFH, which was successful only in a minority of children. Progression of CVD morbidity and resulting mortality remain unresolved issues. Early and intensified multimodal LLT guided by risk factors beyond LDL-C concentration is needed to improve outcome. PMID- 29502163 TI - Patients' reported outcome measures and clinical scales in brain tumor surgery: results from a prospective cohort study. AB - BACKGROUND: This study aims to assess surgical outcome in brain tumor surgery using patient reported outcome measures (PROMs) and to compare their results with traditional clinical outcome measurements. METHOD: Neuro-oncological patients undergoing surgical removal for the lesion were enrolled; MOCA test, PROMs (EUROHIS-QoL, PGWB-S, WHODAS-12), and the clinical scale Karnofsky Performance Status (KPS) were administered to evaluate respectively cognitive status, quality of life, well-being, disability, and functional status before surgery and at 3 month follow-up. Wilcoxon test was performed to evaluate the longitudinal change of test scores, the smallest detectable difference to classify the change of patients in PROMs, the Cohen kappa to investigate the concordance between KPS and PROMs in classifying the patients' change, and Mann-Whitney U test to compare patients with complications and no complications. RESULTS: A total of 101 patients were enrolled (54 woman, mean age 50.2 +/- 14.1, range 20-85): psychological well-being improved at follow-up; 95 patients (94.1%) were improved/unchanged and 6 (5.9%) were worsened according to PROMs; functional status measured with KPS had a slight agreement with quality of life and disability and no agreement with psychological well-being questionnaires; patients with complications had a greater worsening in KPS. CONCLUSIONS: According to PROMs measuring QoL, disability, and psychological well-being, most of the patients were improved/unchanged after surgery. Since PROMs and KPS detect different aspects of the patients' health status, PROMs should be integrated in surgical outcome evaluation. Furthermore, their association with complications and with other clinical and subjective variables that could influence patient's perception of health status should be investigated. PMID- 29502164 TI - The association of increased drugs use with activities of daily living and discharge outcome among elderly stroke patients. AB - : Background Few systematic studies have evaluated the association between drugs and functional recovery for geriatric patients after strokes in the convalescent stage. Objective To assess the association of increased drugs during hospitalization with activities of daily living and outcome among geriatric stroke patients. Setting This study was conducted at the convalescent rehabilitation ward in the Hitachinaka General Hospital in Japan. Methods This retrospective cohort study included consecutive patients aged >= 65 years who had experienced stroke between 2010 and 2016. The participants were classified into two groups according to their discharge destination: home discharge group and non home discharge group. Multiple linear regression analysis and multiple logistic regression analysis were used to examine the association of increased drugs with FIM gain and home discharge, respectively. MAIN OUTCOME MEASURES: The main outcome measures were Functional Independence Measure (FIM) gain and home discharge. Results In total, 417 participants (165 males and 252 females; mean age, 78.8 years) were assessed and classified into home discharge (n = 226) and non-home discharge (n = 191) groups. The median FIM score was 77 (interquartile range 57-96). Multiple linear regression analysis revealed that increased use of drugs during hospitalization negatively correlated with FIM gain. Multiple logistic regression analysis showed that increased use of drugs was independently associated with a low possibility of home discharge. Conclusion The increased use of drugs during hospitalization was negatively associated with both functional recovery and possibility of home discharge among geriatric stroke patients in a convalescent rehabilitation ward. PMID- 29502165 TI - Dynamic imaging of adaptive stress response pathway activation for prediction of drug induced liver injury. AB - Drug-induced liver injury remains a concern during drug treatment and development. There is an urgent need for improved mechanistic understanding and prediction of DILI liabilities using in vitro approaches. We have established and characterized a panel of liver cell models containing mechanism-based fluorescent protein toxicity pathway reporters to quantitatively assess the dynamics of cellular stress response pathway activation at the single cell level using automated live cell imaging. We have systematically evaluated the application of four key adaptive stress pathway reporters for the prediction of DILI liability: SRXN1-GFP (oxidative stress), CHOP-GFP (ER stress/UPR response), p21 (p53 mediated DNA damage-related response) and ICAM1 (NF-kappaB-mediated inflammatory signaling). 118 FDA-labeled drugs in five human exposure relevant concentrations were evaluated for reporter activation using live cell confocal imaging. Quantitative data analysis revealed activation of single or multiple reporters by most drugs in a concentration and time dependent manner. Hierarchical clustering of time course dynamics and refined single cell analysis allowed the allusion of key events in DILI liability. Concentration response modeling was performed to calculate benchmark concentrations (BMCs). Extracted temporal dynamic parameters and BMCs were used to assess the predictive power of sub-lethal adaptive stress pathway activation. Although cellular adaptive responses were activated by non DILI and severe-DILI compounds alike, dynamic behavior and lower BMCs of pathway activation were sufficiently distinct between these compound classes. The high level detailed temporal- and concentration-dependent evaluation of the dynamics of adaptive stress pathway activation adds to the overall understanding and prediction of drug-induced liver liabilities. PMID- 29502166 TI - Perfluorooctanoic acid (PFOA) exposure promotes proliferation, migration and invasion potential in human breast epithelial cells. AB - Despite significant advances in early detection and treatment, breast cancer remains a major cause of morbidity and mortality. Perfluorooctanoic acid (PFOA) is a suspected endocrine disruptor and a common environmental pollutant associated with various diseases including cancer. However, the effects of PFOA and its mechanisms of action on hormone-responsive cells remain unclear. Here, we explored the potential tumorigenic activity of PFOA (100 nM-1 mM) in human breast epithelial cells (MCF-10A). MCF-10A cells exposed to 50 and 100 uM PFOA demonstrated a higher growth rate compared to controls. The compound promoted MCF 10A proliferation by accelerating G0/G1 to S phase transition of the cell cycle. PFOA increased cyclin D1 and CDK4/6 levels, concomitant with a decrease in p27. In contrast to previous studies of perfluorooctane sulfate (PFOS), the estrogen receptor antagonist ICI 182,780 had no effect on PFOA-induced cell proliferation, whereas the PPARalpha antagonist GW 6471 was able to prevent the MCF-10A proliferation, indicating that the underlying mechanisms involve PPARalpha dependent pathways. Interestingly, we also showed that PFOA is able to stimulate cell migration and invasion, demonstrating its potential to induce neoplastic transformation of human breast epithelial cells. These results suggest that more attention should be paid to the roles of PFOA in the development and progression of breast cancer. PMID- 29502167 TI - Tool-use training temporarily enhances cognitive performance in long-tailed macaques (Macaca fascicularis). AB - Tool use relies on numerous cognitive functions, including sustained attention and understanding of causality. In this study, we investigated the effects of tool-use training on cognitive performance in primates. Specifically, we applied the Primate Cognition Test Battery to three long-tailed macaques (Macaca fascicularis) at different stages of a training procedure that consisted of using a rake to retrieve out-of-reach food items. In addition, we evaluated a control group (n = 3) performing a grasping task, in order to account for possible effects related to a simple motor act. Our results showed that tool-use training enhances mean performance in the physical cognition domain, i.e. the understanding of spatial relations, numerosity and causality. In particular, causal cognition (evaluating noise- and shape-related causality and understanding of tool properties) showed significant improvement after training, whereas spatial cognition (evaluating spatial memory, object permanence, rotation and transposition) showed a trend to improvement. Despite these findings, none of our trained monkeys succeeded in the tool-use task of the Primate Cognition Test Battery, which involved an unfamiliar tool. Some training-related effects did not persist after a 35-day resting period, suggesting that continuous practice may be necessary, or that a longer training period before resting may be needed to better maintain cognitive performance. In contrast with the training group, the control group did not display any change in cognitive performance. This finding paves the way to further investigation into the link between tool-use behaviour and the evolution of primate cognition. PMID- 29502168 TI - Bone-patellar tendon-bone autograft could be recommended as a superior graft to hamstring autograft for ACL reconstruction in patients with generalized joint laxity: 2- and 5-year follow-up study. AB - PURPOSE: The present study aimed to compare 2- and 5-year outcomes of ACL reconstruction between patients with and without generalized joint laxity and to perform comparative evaluation between two types of grafts used for ACL reconstruction in patients with generalized joint laxity. METHODS: Two hundred and thirty-seven patients who underwent ACL reconstruction from 2001 to 2008 were included. Patients were classified into two groups according to the presence or the absence of generalized joint laxity, and further subdivided into two subgroups based on the type of graft used: bone-patellar tendon-bone (BPTB) or hamstring. Generalized joint laxity was assessed with the Beighton and Horan criteria using a point scoring system. Stability reflected by the Lachman test, pivot-shift test, and anterior translation measured with KT-2000, and functional outcomes reflected by Lysholm knee score, and International Knee Documentation Committee (IKDC) subjective score were investigated. IKDC objective grade and radiographic grade were also assessed. Clinical assessments were conducted preoperatively and at 2 and 5 years after operation. RESULTS: Two-year follow-up results showed that patients with generalized joint laxity receiving hamstring grafts had poorer outcomes than those without generalized joint laxity. Five-year follow-up results showed that patients with generalized joint laxity experienced poorer outcomes than patients without generalized joint laxity, irrespective of the type of graft. Comparison of grafts used showed that, in patients with generalized joint laxity, BPTB graft provided significantly better stability and functional outcomes than hamstring graft at both 2- and 5-year follow-ups. Comparisons between serial outcomes measured at 2 and 5 years demonstrated that stability and functional outcomes deteriorated over time in patients with generalized joint laxity. CONCLUSIONS: Less satisfactory stability and functional outcomes were noted in patients with generalized joint laxity, compared to patients without generalized joint laxity. Comparisons of stability and functional outcomes after ACL reconstruction in patients with generalized joint laxity between two different grafts demonstrated that BPTB graft achieves better results than hamstring graft. LEVEL OF EVIDENCE: III, a retrospective cohort study. PMID- 29502169 TI - The popliteus tendon provides a safe and reliable location for all-inside meniscal repair device placement. AB - PURPOSE: Repairs of the posterior horn of the lateral meniscus can be technically challenging. In contrast to medial meniscus repairs, the capsule around the posterior segment attachment of the lateral meniscus is quite thin. This study evaluates the clinical results of an arthroscopic all-inside repair technique for unstable, vertical, lateral meniscus tears, using a suture repair placed directly into the popliteus tendon. METHODS: A retrospective analysis of prospectively collected data from the SANTI database was performed. All patients who had undergone combined ACL reconstruction with lateral meniscus all-inside repair, using sutures placed in the popliteus tendon, between 2011 and 2015, were included. Patients were reviewed clinically at 1 and 2 years' follow-up. At final follow-up, all patients were contacted to identify if they underwent further surgery or had knee pain, locking or effusion. Symptomatic patients were recalled for clinical evaluation by a physician and Magnetic Resonance Imaging of the knee. Operative notes for those undergoing further surgery were reviewed and rates and type of re-operation, including for failed lateral meniscal repair were recorded. RESULTS: Two hundred patients (mean age 28.6 +/- 10.2 years) with a mean follow-up of 45.5 +/- 12.8 months (range 24.7-75.2) were included. The mean Subjective International Knee Documentation Committee (IKDC) at final follow-up was 85.0 +/- 11.3. The post-operative mean side-to-side laxity measured at 1 year was 0.6 +/- 1.0 mm. Twenty-six patients underwent re-operation (13%) at a mean follow-up of 14.8 +/- 7.8 months. The ACL graft rupture rate was 5.0%. Other causes for re-operation included medial meniscus tear (2.5%), cyclops lesion (1.5%) and septic arthritis (0.5%). The lateral meniscus repair failure rate was 3.5%. No specific complications relating to placement of sutures in the popliteus tendon were identified. CONCLUSION: Arthroscopic all-inside repair of unstable, vertical, lateral meniscus tears using a suture placed in the popliteus tendon is a safe technique. It is associated with a very low failure rate with no specific complications. LEVEL OF EVIDENCE: Level IV. PMID- 29502170 TI - Multiple primary non-breast tumors in breast cancer survivors. AB - PURPOSE: The aim of this study was to assess the frequency of second primary non breast cancer after breast cancer diagnosis and treatment, and its correlation with clinicopathological features. METHODS: Data from 21,527 patients with primary breast cancer were collected retrospectively in a single cancer centre; 4.1% of the women developed a second non-breast cancer. The most frequently observed second primary tumor affected the digestive tract (27.8%). The frequency of observed cancers was similar to that expected in the general population, excepting for an excess of melanoma [SIR 1.98 (1.52-2.53)], uterine cancers [SIR 1.44 (1.17-1.74)], ovarian cancers [SIR 1.67 (1.31-2.10)], thyroid tumors [SIR 1.54 (1.23-1.92)], and leukemia [SIR 1.57 (1.11-2.16)]. RESULTS: Clinicopathological breast cancer stratification showed a general increased risk of developing a second cancer in older patients, excluding ovarian cancer. An increased risk of developing ovarian cancer after breast cancer diagnosis was observed, in particular, in triple-negative [HR 3.47 (1.91-6.29)], G3 tumors [HR 2.54 (1.10-5.83)] and in positive breast cancer family history [HR 2.19 (1.22 3.94)]. Breast cancer survivors in hormonal therapy treatment are at higher risk for developing a second thyroid cancer [HR 4.00 (1.46-10.9)]. Conversely, adjuvant chemotherapy offered a protective effect on thyroid cancer risk development [HR 0.46 (0.28-0.76)]. CONCLUSIONS: Older age represents the major risk of developing a second primary non-breast cancer, excluding ovarian cancer. Clinical surveillance is required to prevent ovarian and thyroid cancers, respectively, in patients with positive family history, triple negative, G3 breast cancer and during hormonal therapy treatment in postmenopausal status. PMID- 29502171 TI - Forearm vasodilator responses to environmental stress and reactive hyperaemia are impaired in young South Asian men. AB - PURPOSE: Prevalence of cardiovascular disease (CVD) is greater in South Asians (SAs) than White Europeans (WEs). Endothelial dysfunction and blunted forearm vasodilatation to environmental stressors have been implicated in CVD. We investigated whether these features are present in young SA men. METHODS: In 15 SA and 16 WE men (19-23 years), we compared changes in forearm blood flow, arterial blood pressure (ABP), forearm vascular conductance (FVC), heart rate, and electrodermal resistance (EDR; sweating) following release of arterial occlusion (reactive hyperaemia endothelium-dependent) and 5 single sounds at 5-10 min intervals (stressors). RESULTS: All were normotensive. Peak reactive hyperaemia was smaller in SAs than WEs (FVC increase: 0.36 +/- 0.038 vs 0.44 +/- 0.038 units; P < 0.05). Furthermore, in WEs, mean FVC increased at 5, 15, and 20 s of each sound (vasodilatation), but increased at 5 s only in SAs, decreasing by 20 s (vasoconstriction). This reflected a smaller proportion of SAs showing forearm vasodilatation at 15 s (5/15 SAs vs 11/16 WEs: P < 0.01), the remainder showing vasoconstriction. Concomitantly, WEs showed greater bradycardia and EDR changes. Intra-class correlation analyses showed that all responses were highly reproducible over five sounds in both WEs and SAs. Moreover, sound-evoked changes in ABP and FVC were negatively correlated in each ethnicity (P < 0.01). However, WEs showed preponderance of forearm vasodilatation and depressor responses; SAs showed preponderance of vasoconstriction and pressor responses. CONCLUSIONS: Endothelium-dependent vasodilatation is blunted in young SA men. This could explain their impaired forearm vasodilatation and greater pressor responses to repeated environmental stressors, so predisposing SAs to hypertension and CVD. PMID- 29502172 TI - Lack of age-specific influence on leg blood flow during incremental calf plantar flexion exercise in men and women. AB - PURPOSE: Age-related exercising leg blood flow (LBF) responses during dynamic knee-extension exercise and forearm blood flow responses during handgrip exercise are preserved in normally active men but attenuated in activity-matched women. We explored whether these age- and sex-specific effects are also apparent during isometric calf plantar-flexion incremental exercise. METHODS: Normally active young men (YM, n = 15, 24 +/- 2 years), young women (YW, n = 8, 22 +/- 1 years), older men (OM, n = 13, 70 +/- 7 years) and older women (OW, n = 10, 64 +/- 7 years) were tested. LBF was measured between contractions using venous occlusion plethysmography. RESULTS: Peak force obtained was higher (P < 0.05) in men compared with women and in young compared with older individuals. However, peak LBF (YM; 971 +/- 328 ml min-1, OM; 985 +/- 504 ml min-1, YW; 844 +/- 366 ml min 1, OW; 960 +/- 244 ml min-1) and peak leg vascular conductance [LVC = LBF/(MAP + hydrostatic pressure)] responses (YM; 6.0 +/- 1.8 ml min-1 mmHg-1, OM; 5.5 +/- 2.8 ml min-1 mmHg-1, YW; 5.3 +/- 2.1 ml min-1 mmHg-1, OW; 5.5 +/- 1.6 ml min-1 mmHg-1) were similar among the four groups. Furthermore, the hyperaemic (YM; 8.8 +/- 3.7 ml min-1 %Fpeak-1 OM; 8.3 +/- 5.4 ml min-1 %Fpeak-1, YW; 8.2 +/- 3.5 ml min-1 %Fpeak-1, OW; 9.6 +/- 2.2 ml min-1 %Fpeak-1) and vasodilatory responses (YM; 0.053 +/- 0.020 ml min-1 mmHg-1 %Fpeak-1, OM; 0.048 +/- 0.028 ml min-1 mmHg 1 %Fpeak-1, YW; 0.051 +/- 0.019 ml min-1 mmHg-1 %Fpeak-1, OW; 0.055 +/- 0.014 ml min-1 mmHg-1 %Fpeak-1) were not different among the four groups. These results were accompanied by similar resting LBF responses among groups and were not affected when data were normalised to estimated leg muscle mass. CONCLUSIONS: Our results demonstrate that exercising LBF responses during isometric incremental calf muscle exercise are preserved in older men and women, suggesting that the previously observed age-related attenuations in leg and forearm hyperaemia among women may be muscle-group specific. PMID- 29502173 TI - Non-linear growth trends of toe flexor muscle strength among children, adolescents, and young adults: a cross-sectional study. AB - PURPOSE: There are only a few studies on the muscular strength of the foot in children and adolescents; thus, the developmental pattern and normative data of these populations during growth are unclear. We sought to elucidate the developmental pattern of the foot muscle strength among children, adolescents, and young adults compared with that of the hand. METHODS: A total of 747 children, adolescents, and young adults participated in this study, and their maximum isometric toe flexor strength (TFS), hand grip strength (HGS), and foot length were measured. RESULTS: TFS was correlated with HGS (r = 0.785), age (r = 0.659), height (r = 0.757), body mass (r = 0.737), and foot length (r = 0.594). Multiple regression analyses revealed that TFS was correlated with age (beta = 0.243 in boys; beta = 0.461 in girls), squared value of age (age2; beta = - 0.296 in boys; beta = - 0.260 in girls), and body mass (beta = 0.256 in boys; beta = 0.311 in girls) in both sexes, indicating a non-linear relationship between age and TFS development. In a regression model for HGS, age was a significant variable, but not age2. HGS increased linearly from childhood until young adulthood, whereas TFS increased from childhood until adolescence and then levelled off. CONCLUSION: Our results demonstrate that TFS has a different developmental pattern compared with HGS. PMID- 29502174 TI - Baricitinib for Previously Treated Moderate or Severe Rheumatoid Arthritis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal. AB - As part of its single technology appraisal process, the National Institute for Health and Care Excellence invited the manufacturer (Eli Lilly) of baricitinib (BARI; Olumiant(r); a Janus kinase inhibitor that is taken orally) to submit evidence of its clinical and cost effectiveness for the treatment of moderate to severe rheumatoid arthritis (RA) after the failure of disease-modifying antirheumatic drugs (DMARDs). The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a detailed review of the evidence for the clinical and cost effectiveness of the technology, based on the company's submission (CS) to NICE. The clinical-effectiveness evidence in the CS for BARI was based predominantly on three randomised controlled trials comparing the efficacy of BARI against adalimumab or placebo, as well as one long-term extension study. The clinical-effectiveness review identified no head-to-head evidence on the efficacy of BARI against all the comparators within the scope. Therefore, the company performed network meta analyses (NMAs) in two different populations: one in patients who had experienced an inadequate response to conventional DMARDs (cDMARD-IR), and the other in patients who had experienced an inadequate response to tumour necrosis factor inhibitors (TNFi-IR). The company's NMAs concluded BARI had comparable efficacy as the majority of its comparators in both populations. The company submitted a de novo discrete event simulation model that analysed the incremental cost effectiveness of BARI versus its comparators for the treatment of RA from the perspective of the National Health Service (NHS) in four different populations: (1) cDMARD-IR patients with moderate RA, defined as a 28-Joint Disease Activity Score (DAS28) > 3.2 and no more than 5.1; (2) cDMARD-IR patients with severe RA (defined as a DAS28 > 5.1); (3) TNFi-IR patients with severe RA for whom rituximab (RTX) was eligible; and (4) TNFi-IR patients with severe RA for whom RTX in combination with methotrexate (MTX) is contraindicated or not tolerated. In the cDMARD-IR population with moderate RA, the deterministic incremental cost effectiveness ratio (ICER) for BARI in combination with MTX compared with intensive cDMARDs was estimated to be L37,420 per quality-adjusted life-year (QALY) gained. In the cDMARD-IR population with severe RA, BARI in combination with MTX dominated all comparators except for certolizumab pegol (CTZ) in combination with MTX, with the ICER of CTZ in combination with MTX compared with BARI in combination with MTX estimated to be L18,400 per QALY gained. In the TNFi IR population with severe RA, when RTX in combination with MTX was an option, BARI in combination with MTX was dominated by RTX in combination with MTX. In the TNFi-IR population with severe RA for whom RTX in combination with MTX is contraindicated or not tolerated, BARI in combination with MTX dominated golimumab in combination with MTX and was less effective and less expensive than the remaining comparators. Following a critique of the model, the ERG undertook exploratory analyses after applying corrections to the methods used in the NMAs and two programming errors in the economic model that affected the company's probabilistic sensitivity analysis (PSA) results. The ERG's NMA results were broadly comparable with the company's results. The programming error that affected the PSA of the severe cDMARD-IR population had only a minimal impact on the results, while the error affecting the severe TNFi-IR RTX-ineligible population resulted in markedly higher costs and QALYs gained for the affected comparators but did not substantially modify the conclusions of the analysis. The NICE Appraisal Committee concluded that BARI in combination with MTX or as monotherapy is a cost-effective use of NHS resources in patients with severe RA, except in TNFi-IR patients who are RTX-eligible. PMID- 29502175 TI - Ponatinib for Treating Acute Lymphoblastic Leukaemia: An Evidence Review Group Perspective of a NICE Single Technology Appraisal. AB - As part of its single technology appraisal (STA) process, the UK National Institute for Health and Care Excellence (NICE) invited the manufacturer (Incyte Corporation) of ponatinib (Inclusig(r)) to submit evidence of its clinical and cost effectiveness for previously treated Philadelphia-chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) and chronic myeloid leukaemia. This paper focusses on Ph+ ALL. The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent evidence review group (ERG). This article presents the critical review of the company's submission by the ERG and the outcome of the NICE guidance. The clinical-effectiveness evidence in the company's submission was derived from a phase II, single-arm, open-label, non-comparative study. Given the lack of comparative evidence, a naive indirect comparison was performed against re-induction chemotherapy comparing major cytogenetic response and complete remission. Best supportive care (BSC) was assumed to produce no disease response. Despite the limited evidence and potential for biases, this study demonstrated that ponatinib was likely to be an effective treatment for patients with Ph+ ALL. The company submitted a state transition model that analysed the incremental cost effectiveness of ponatinib versus re-induction therapy and BSC for the treatment of Ph+ ALL in patients whose disease is resistant to dasatinib, who are intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate or who have the threonine-315-isoleucine mutation. This population was further subdivided into those who were suitable for allogeneic stem cell transplant (allo-SCT) and those who were not. The company's revised economic evaluation, following the clarification process, estimated incremental cost-effectiveness ratios (ICERs) in those suitable for allo-SCT of L31,123 per quality-adjusted life-year (QALY) gained for ponatinib compared with re-induction chemotherapy and L26,624 per QALY gained compared with BSC. For those for whom allo-SCT was unsuitable, the company-estimated ICER compared with BSC was L33,954 per QALY gained. Following a critique of the model, the ERG undertook exploratory analyses that, when combined, produced a range in ICERs (due to uncertainty of the most appropriate overall survival function) of dominant (being less expensive and providing more QALYs) to L11,727 per QALY gained compared with re-induction chemotherapy and between L7892 and L31,696 per QALY gained compared with BSC for those in whom allo-SCT was suitable. For those in whom allo-SCT was not suitable, the ERG estimated that ponatinib was dominant. During the consultation period, the company agreed a revised patient access scheme (PAS) that reduced the ICER ranges to L7156 to L29,995 per QALY gained versus BSC and to less than L5000 per QALY gained versus re-induction chemotherapy. In people for whom allo-SCT was unsuitable, ponatinib dominated BSC. The NICE appraisal committee concluded that ponatinib is a cost-effective use of UK NHS resources in the considered population, subject to the company providing the agreed discount in the PAS. PMID- 29502176 TI - The Role of Measurement Uncertainty in Health Technology Assessments (HTAs) of In Vitro Tests. AB - INTRODUCTION: Numerous factors contribute to uncertainty in test measurement procedures, and this uncertainty can have a significant impact on the downstream clinical utility and cost-effectiveness of testing strategies. Currently, however, there is no clear guidance concerning if or how such factors should be considered within Health Technology Assessments (HTAs) of tests. OBJECTIVE: The aim was to provide an introduction to key concepts in measurement uncertainty for the HTA community and to explore, via systematic review, current methods utilised within HTAs. METHODS: HTAs of in vitro tests including a model-based economic evaluation were identified via the Centre for Reviews and Dissemination (CRD) HTA database and key reimbursement authority websites. Data were extracted to explore the specific components of measurement uncertainty assessed and methods utilised. The findings were narratively synthesised. RESULTS: Of 107 identified HTAs, 20 (19%) attempted to assess components of measurement uncertainty: 15 did so via some form of pre-model assessment (such as a literature review or laboratory survey); four also included components within the economic model; and one considered measurement uncertainty within the model only. One study quantified the impact of measurement uncertainty on cost-effectiveness and found that this parameter significantly changed the results, but did not impact the overall decision uncertainty. CONCLUSION: A minority of HTAs identified from this review used various approaches to assess and/or incorporate the impact of measurement uncertainty, indicating that these assessments are feasible. Uncertainty remains around best practice methodology for conducting such analyses; further research is required to ensure that future HTAs are fit for purpose. PMID- 29502177 TI - The role of magnetic iron oxide nanoparticles in the bacterially induced calcium carbonate precipitation. AB - Recently, magnetic iron oxide nanoparticles (IONs) have been used to control and modify the characteristics of concrete and mortar. Concrete is one of the most used materials in the world; however, it is susceptible to cracking. Over recent years, a sustainable biotechnological approach has emerged as an alternative approach to conventional techniques to heal the concrete cracks by the incorporation of bacterial cells and nutrients into the concrete matrix. Once cracking occurs, CaCO3 is induced and the crack is healed. Considering the positive effects of IONs on the concrete properties, the effect of these nanoparticles on bacterial growth and CaCO3 biosynthesis needs to be evaluated for their possible application in bio self-healing concrete. In the present work, IONs were successfully synthesized and characterized using various techniques. The presence of IONs showed a significant effect on both bacterial growth and CaCO3 precipitation. The highest bacterial growth was observed in the presence of 150 MUg/mL IONs. The highest concentration of induced CaCO3 (34.54 g/L) was achieved when the bacterial cells were immobilized with 300 MUg/mL of IONs. This study provides new data and supports the possibility of using IONs as a new tool in designing the next generation of bio self-healing concrete. PMID- 29502178 TI - Biodegradation of dissolved humic substances by fungi. AB - Humic and fulvic acids constitute humic substances, a complex mixture of many different acids containing carboxyl and phenolate groups, which are not only the principal soil fertility factors but also the main pollutants present in landfill leachates or natural organic matter in water. Due to their low bacterial biodegradability, fungal biodegradation processes are key for their removal. The present study compiles and comments all the available literature on decomposition of aqueous humic substances by fungi or by their extracellular enzymes alone, focusing on the influence of the reaction conditions. The biodegradation extent mainly depends on the characteristics and concentration of the humic compounds, the type of microorganisms selected, the inoculation mode, the C and N sources, the presence of certain chemicals in the medium, the availability of oxygen, the temperature, and the pH. PMID- 29502179 TI - Nematode-specific cadherin CDH-8 acts as a receptor for Cry5B toxin in Caenorhabditis elegans. AB - Parasitic nematodes of animals and plants cause worldwide devastating impacts on people's lives and agricultural crops. The crystal protein Cry5B produced by Bacillus thuringiensis has efficient and specific activity against a wide range of nematodes. However, the action mode of this toxin has not yet been thoroughly determined. Here, a nematode-specific cadherin CDH-8 was demonstrated to be a receptor for Cry5B toxin by using Caenorhabditis elegans as a model, providing evidence that the cadherin mutant worm cdh-8(RB815) possesses significant resistance to Cry5B, and the CDH-8 fragments bind specifically to Cry5B. Furthermore, CDH-8 was identified to be required for the oligomerization of Cry5B toxin in vivo and contribute to the internalization and pore formation of Cry5B in nematode cells. This study will facilitate a better understanding of the action mode of nematicidal Cry toxins and help the design of Cry toxin-based products for the control of plant or animal parasitic nematodes. PMID- 29502180 TI - Role of the Group 2 Mrp sodium/proton antiporter in rapid response to high alkaline shock in the alkaline- and salt-tolerant Dietzia sp. DQ12-45-1b. AB - The six- and seven-subunit Na+/H+ antiporters (Mrp) are widely distributed in bacteria. They are reported to be integral for pH homeostasis in alkaliphilic bacteria when adapting to high pH environments. In this study, operons encoding for the six-subunit Na+/H+ antiporters were found in the genomes of all studied Dietzia strains, which have different alkaline-resistant abilities. Disruption of the operon in the strain Dietzia sp. DQ12-45-1b which leads to declined growth in presence of hypersaline and alkaline conditions suggested that the six-subunit Na+/H+ antiporter played an important role in hypersaline and alkaline resistance. Although the complexes DqMrp from DQ12-45-1b (strain with high alkaline resistance) and DaMrp from D. alimentaria 72T (strain with low alkaline resistance) displayed Na+(Li+)/H+ antiport activities, they functioned optimally at different pH levels (9.0 for DQ12-45-1b and 8.0 for 72T). While both antiporters functioned properly to protect Escherichia coli cells from salt shock, only the DqMrp-containing strain survived the high alkaline shock. Furthermore, real-time PCR results showed that the expression of mrpA and mrpD induced only immediately after DQ12-45-1b cells were subjected to the alkaline shock. These results suggested that the expression of DqMrp might be induced by a pH gradient across the cell membrane, and DqMrp mainly functioned at an early stage to respond to the alkaline shock. PMID- 29502181 TI - Streptomyces spp. in the biocatalysis toolbox. AB - About 20,100 research publications dated 2000-2017 were recovered searching the PubMed and Web of Science databases for Streptomyces, which are the richest known source of bioactive molecules. However, these bacteria with versatile metabolism are powerful suppliers of biocatalytic tools (enzymes) for advanced biotechnological applications such as green chemical transformations and biopharmaceutical and biofuel production. The recent technological advances, especially in DNA sequencing coupled with computational tools for protein functional and structural prediction, and the improved access to microbial diversity enabled the easier access to enzymes and the ability to engineer them to suit a wider range of biotechnological processes. The major driver behind a dramatic increase in the utilization of biocatalysis is sustainable development and the shift toward bioeconomy that will, in accordance to the UN policy agenda "Bioeconomy to 2030," become a global effort in the near future. Streptomyces spp. already play a significant role among industrial microorganisms. The intention of this minireview is to highlight the presence of Streptomyces in the toolbox of biocatalysis and to give an overview of the most important advances in novel biocatalyst discovery and applications. Judging by the steady increase in a number of recent references (228 for the 2000-2017 period), it is clear that biocatalysts from Streptomyces spp. hold promises in terms of valuable properties and applicative industrial potential. PMID- 29502182 TI - Wax synthase MhWS2 from Marinobacter hydrocarbonoclasticus: substrate specificity and biotechnological potential for wax ester production. AB - Wax synthases are involved in the biosynthesis of wax esters, lipids with great industrial potential. Here, we heterologously expressed the native wax synthase MhWS2 from Marinobacter hydrocarbonoclasticus in Saccharomyces cerevisiae and performed comprehensive analysis of its substrate specificity. The enzyme displayed high wax synthase (but no diacylglycerol acyltransferase) activity both in vivo and in vitro. In the presence of exogenous fatty alcohol, wax esters accounted for more than 57% of total yeast lipids. In vitro, MhWS2 produced wax esters with most of the tested substrates, showing the highest activity with 14:0 , 18:1-, 18:0-, 12:0-, and 16:0-CoA together with saturated C10-C16 fatty alcohols. Co-expression with genes encoding fatty acyl reductases resulted in the accumulation of C26-C36 wax esters. Altogether, our results provide a detailed characterization of MhWS2 which should be useful in the development of strategies for producing wax esters in various expression systems. PMID- 29502183 TI - Bioactivity and biotechnological production of punicic acid. AB - Punicic acid (PuA; 18: 3Delta 9cis,11trans,13cis ) is an unusual 18-carbon fatty acid bearing three conjugated double bonds. It has been shown to exhibit a myriad of beneficial bioactivities including anti-cancer, anti-diabetes, anti-obesity, antioxidant, and anti-inflammatory properties. Pomegranate (Punica granatum) seed oil contains approximately 80% PuA and is currently the major natural source of this remarkable fatty acid. While both PuA and pomegranate seed oil have been used as functional ingredients in foods and cosmetics for some time, their value in pharmaceutical/medical and industrial applications are presently under further exploration. Unfortunately, the availability of PuA is severely limited by the low yield and unstable supply of pomegranate seeds. In addition, efforts to produce PuA in transgenic crops have been limited by a relatively low content of PuA in the resulting seed oil. The production of PuA in engineered microorganisms with modern fermentation technology is therefore a promising and emerging method with the potential to resolve this predicament. In this paper, we provide a comprehensive review of this unusual fatty acid, covering topics ranging from its natural sources, biosynthesis, extraction and analysis, bioactivity, health benefits, and industrial applications, to recent efforts and future perspectives on the production of PuA in engineered plants and microorganisms. PMID- 29502184 TI - Survival models and health sequences. AB - Survival studies often generate not only a survival time for each patient but also a sequence of health measurements at annual or semi-annual check-ups while the patient remains alive. Such a sequence of random length accompanied by a survival time is called a survival process. Robust health is ordinarily associated with longer survival, so the two parts of a survival process cannot be assumed independent. This paper is concerned with a general technique-reverse alignment-for constructing statistical models for survival processes, here termed revival models. A revival model is a regression model in the sense that it incorporates covariate and treatment effects into both the distribution of survival times and the joint distribution of health outcomes. The revival model also determines a conditional survival distribution given the observed history, which describes how the subsequent survival distribution is determined by the observed progression of health outcomes. PMID- 29502185 TI - Expression characteristics and functional analysis of Kruppel-like factor 4 in adductor muscle and mantle of Zhikong scallop Chlamys farreri. AB - Kruppel-like factor 4 (KLF4) is an important transcription factor involving in formation and maintenance of muscles in mammals. However, no data are available on KLF4 function in shellfish muscles which play vital roles in the movement, stress response, and physiology in shellfish. In the present study, we revealed that the Klf4 mRNA of Zhikong scallop Chlamys farreri was expressed in most tissues, which has high level in adductor muscle, mantle, kidney, and testis. Positive signals of the Klf4 mRNA and protein were visible in all skeletal muscle fibers of adductor muscle, and all the cells of C. farreri mantle. Furthermore, the knockdown of Klf4 mRNA in adductor muscle and mantle by means of in vivo RNA interference led to some different phenotypes, including disordered arrangement of muscle fibers in adductor muscle and mantle, abnormal structures of skeletal muscles, and reduced muscle fibers under endepidermis of mantle. Our findings demonstrated that Klf4 plays important roles in maintenance of muscle functions in C. farreri adductor muscle and mantle, and suggested that its regulatory way in skeletal muscle may be different from the smooth muscle in shellfish. PMID- 29502187 TI - Epidemiology and correlates of osteoporotic fractures among type 2 diabetic patients. AB - : This study analyzed data on 87,224 osteoporotic patients with up to 18 years of computerized medical history. Patients with osteoporosis and type 2 diabetes had higher bone density yet more fractures than non-diabetic osteoporotic patients. Fracture incidence among the diabetic patients was associated with retinopathy and cardiovascular disease, but not with diabetes duration. PURPOSE: Little is known about the association between type 2 diabetes mellitus (T2DM) and fragility fractures or the mechanism(s) involved. We examined fracture correlates among T2DM patients with osteoporosis. METHODS: We used electronic health records of an osteoporosis (OP) registry cross-linked with a diabetes registry of a large payer provider healthcare organization in Israel. A cross-sectional analysis compared osteoporosis patients with and without T2DM, and a longitudinal Cox proportional hazard regression was used to identify incident fracture correlates. RESULTS: As of December 2015 a total of 87,224 current OP patients were identified, of whom 15,700 (18%) had T2DM. The T2DM OP patients were characterized by older age (mean 74.6 vs. 69.5), more males (20.3 vs. 14.0%), and a higher rate of chronic comorbidities compared to OP without diabetes. All major OP fractures (hip, spine, humerus, and forearm) were significantly more prevalent among T2DM OP patients (44 vs. 32%), with an overall age-standardized ratio of 1.22 (95% CI 1.19 to 1.25) and 1.15 (95% CI 1.10 to 1.21) for females and males respectively. The average T-scores were higher (femur neck - 1.8 vs. - 1.9, total hip - 1.2 vs. - 1.6, and vertebrae - 1.3 vs. - 1.7) for the T2DM OP patients compared to the non-T2DM OP patients. Among women with coexisting T2DM and osteoporosis (n = 10,812), fracture incidence was significantly associated with retinopathy (HR = 1.24, 95% CI 1.05 to 1.47) and cardiovascular disease (HR = 1.22, 95% CI 1.10 to 1.36) after controlling for age, bone mineral density T-score, rheumatoid arthritis, glucocorticoids, alcohol, and smoking). CONCLUSION: This large population-based study confirms the higher fracture risk of osteoporotic patients with T2DM, as compared to osteoporotic patients without T2DM, despite higher bone mineral density levels. The presence of micro- and macrovascular disease appears to increase this risk. PMID- 29502186 TI - Co-inoculation of Lolium perenne with Funneliformis mosseae and the dark septate endophyte Cadophora sp. in a trace element-polluted soil. AB - The presence of dark septate endophytes (DSEs) or arbuscular mycorrhizal fungi (AMF) in plant roots and their effects on plant fitness have been extensively described. However, little is known about their interactions when they are simultaneously colonizing a plant root, especially in trace element (TE)-polluted soils. We therefore investigated the effects of Cadophora sp. and Funneliformis mosseae on ryegrass (Lolium perenne) growth and element uptake in a Cd/Zn/Pb polluted soil. The experiment included four treatments, i.e., inoculation with Cadophora sp., inoculation with F. mosseae, co-inoculation with Cadophora sp. and F. mosseae, and no inoculation. Ryegrass biomass and shoot Na, P, K, and Mg concentrations significantly increased following AMF inoculation as compared to non-inoculated controls. Similarly, DSE inoculation increased shoot Na concentration, whereas dual inoculation significantly decreased shoot Cd concentration. Moreover, oxidative stress determined by ryegrass leaf malondialdehyde concentration was alleviated both in the AMF and dual inoculation treatments. We used quantitative PCR and microscope observations to quantify colonization rates. They demonstrated that DSEs had no effect on AMF colonization, while AMF colonization slightly decreased DSE frequency. We also monitored fluorescein diacetate (FDA) hydrolysis and alkaline phosphatase (AP) activity in the rhizosphere soils. FDA hydrolysis remained unchanged in the three inoculated treatments, but AMF colonization increased AP activity and P mobility in the soil whereas DSE colonization did not alter AP activity. In this experiment, we unveiled the interactions between two ecologically important fungal groups likely to occur in roots which involved a decrease of oxidative stress and Cd accumulation in shoots. These results open promising perspectives on the fungal-based phytomanagement of TE-contaminated sites by the production of uncontaminated and marketable plant biomass. PMID- 29502188 TI - Thirteen years' experience in fertility preservation for cancer patients after in vitro fertilization and in vitro maturation treatments. AB - PURPOSE: This study aims to describe the experience and outcomes of in vitro maturation without ovarian stimulation (IVM-FP) and conventional in vitro fertilization after ovarian stimulation (IVF-FP) in a fertility preservation (FP) program for women with cancer. METHODS: Retrospective cohort study from 2003 to 2015 was conducted. The study population consisted of 353 women with cancer who underwent 394 FP cycles (187 IVF-FP cycles and 207 IVM-FP) for oocytes and/or embryos cryopreservation. RESULT(S): Comparatively with IVM-FP, IVF-FP had a higher median [25th-75th percentile] number of oocytes collected-12 [8-18] vs 7 [5-13]; oocytes cryopreserved-10 [6-15] vs 5 [2-8]; and, where applicable, embryos cryopreserved-5 [3-7] vs 3 [2-5] (p < 0.000001). Following FP treatment, 32 patients (9.0%) died, 18 patients (5.6%) conceived spontaneously, and 23 patients (6.5%) returned to attempt pregnancy with a median lapse of returning of 4.6 [3.1-6.1] years. Of these, cryopreserved oocytes or embryos were used in 33 cycles (19 after IVF-FP and 14 after IVM-FP). Overall, the cumulative pregnancy rate (CPR) was 47.6% (10/21) and the live birth rate (LBR) was 38.1% (8/21). Per cycle, CPR and LBR were 37 and 31% following IVF-FP and 14 and 7% following IVM FP, although these differences did not reach statistical significance. We report the fourth live birth after IVM-FP in cancer, and the first one after IVM embryo warming resulting from in vivo oocyte retrieval and IVM procedure. CONCLUSION(S): Both IVF-FP and IVM-FP are possible options for FP women with cancer. Due to minimal data regarding ultimate outcomes, further follow-up is needed. PMID- 29502189 TI - A predictive model for high-quality blastocyst based on blastomere number, fragmentation, and symmetry. AB - PURPOSE: The aim of this study was to create a predictive model for high-quality blastocyst progression based on the traditional morphology parameters of embryos. METHODS: A total of 1564 embryos from 234 women underwent conventional in vitro fertilization and were involved in the present study. High-quality blastocysts were defined as having a grade of at least 3BB, and all embryos were divided based on the development of high-quality blastocysts (group HQ) or the failure to develop high-quality blastocysts (group NHQ). A retrospective analysis of day-3 embryo parameters, focused on blastomere number, fragmentation, the presence of a vacuole, symmetry, and the presence of multinucleated blastomeres was conducted. RESULTS: All parameters were related to high-quality blastocysts (p < 0001) in t tests, chi-square tests, or Fisher tests. The individual scores for all parameters were determined according to their distributions and corresponding rates of forming high-quality blastocysts. Parameters are indicated by s_bn (blastomere number), s_f (fragmentation), s_pv (presence of a vacuole), s_s (symmetry), and s_MNB (multinucleated blastomeres). Subsequently, univariate and multivariate logistic regression analyses were conducted to explore their relationship. In the multivariate logistic regression analysis, a predictive model was constructed, and a parameter Hc was created based on the s_bn, s_f, and s_s parameters and their corresponding odds ratios. The value of Hc in group HQ was significantly higher than that in group NHQ. A receiver operating characteristic curve was used to test the effectiveness of the model. An area under the curve of 0.790, with a 95% confidence interval of 0.766-0.813, was calculated. A dataset was used to validate the predictive utility of the model. Moreover, another dataset was used to ensure that the model can be applied to predict the implantation of day-3 embryos. CONCLUSIONS: A predictive model for high-quality blastocysts was created based on blastomere number, fragmentation, and symmetry. This model provides novel information on the selection of potential embryos. PMID- 29502190 TI - Biomolecular analysis of matrix proteoglycans as biomarkers in non small cell lung cancer. AB - Matrix proteoglycans (PGs) have shown promise as biomarker in malignancies. We employed agarose gel eletrophoresis, quantitative real- time reverse transcription-polymerase chain reaction and immunohistochemistry to evaluate the content of sulfated glicosaminoglycans (chondroitin sulfate and heparan sulfate) and expression of PG (biglycan, glypican, perlecan, syndecan e versican) in patient-matched normal and tumor tissues obtained from resected specimens of lung cancer. A significant increase of heparan sulfate (HS) and chondroitin sulfate (CS) concentrations was found in tumor tissue samples when compared to normal lung tissue samples. HS was also significantly increased in adenocarcinomas compared to squamous cell carcinomas. PG gene expression, with exception of syndecan, were significantly decreased in tumor tissue compared to normal lung, coinciding with significant decrease of PG protein levels in tumor cells and stroma compared to normal lung tissue (Kappa coefficient 0.41, 0.42 and 0,28, respectively). Women patients (p = 0.02), non smokers (p = 0.05), T stage (p = 0.009), N stage (p = 0.03) and adenocarcinoma (p = 0.05) were associated with improved overall survival (OS). Patients presenting tumors with low concentration of sulfated GAG and high PGs levels presented better OS compared to patients with high concentration of sulfated GAG and low expression of PGs. Cox regression model controlled by gender, tobacco history and histological type, showed that patients with high perlecan and versican expression in tumor presented respectively high probability of life (beta risk 11.64; 1.27 to 15.90) and low risk of death (beta risk 0.11; 0.02-0.51). The combined approach suggest matrix (PGs) as biomarkers in lung cancer. PMID- 29502192 TI - Post-traumatic Stress Disorder: A Review of Therapeutic Role of Meditation Interventions. AB - This review is an attempt to provide a comprehensive view of post-traumatic stress disorder (PTSD) and its therapy, focusing on the use of meditation interventions. PTSD is a multimodal psycho-physiological-behavioral disorder, which calls for the potential usefulness of spiritual therapy. Recent times witness a substantial scientific interest in an alternative mind-to-body psychobehavioral therapy; the exemplary of which is meditation. Meditation is a form of mental exercise that has an extensive, albeit still mostly empiric, therapeutic value. Meditation steadily gains an increasing popularity as a psychobehavioral adjunct to therapy in many areas of medicine and psychology. While the review does not provide a final or conclusive answer on the use of meditation in PTSD treatment we believe the available empirical evidence demonstrates that meditation is associated with overall reduction in PTSD symptoms, and it improves mental and somatic quality of life of PTSD patients. Therefore, studies give a clear cue for a trial of meditation-associated techniques as an adjunct to pharmacotherapy or standalone treatment in otherwise resistant cases of the disease. PMID- 29502191 TI - The glycomic effect of N-acetylglucosaminyltransferase III overexpression in metastatic melanoma cells. GnT-III modifies highly branched N-glycans. AB - N-acetylglucosaminyltransferase III (GnT-III) is known to catalyze N-glycan "bisection" and thereby modulate the formation of highly branched complex structures within the Golgi apparatus. While active, it inhibits the action of other GlcNAc transferases such as GnT-IV and GnT-V. Moreover, GnT-III is considered as an inhibitor of the metastatic potential of cancer cells both in vitro and in vivo. However, the effects of GnT-III may be more diverse and depend on the cellular context. We describe the detailed glycomic analysis of the effect of GnT-III overexpression in WM266-4-GnT-III metastatic melanoma cells. We used MALDI-TOF and ESI-ion-trap-MS/MS together with HILIC-HPLC of 2-AA labeled N glycans to study the N-glycome of membrane-attached and secreted proteins. We found that the overexpression of GnT-III in melanoma leads to the modification of a broad range of N-glycan types by the introduction of the "bisecting" GlcNAc residue with highly branched complex structures among them. The presence of these unusual complex N-glycans resulted in stronger interactions of cellular glycoproteins with the PHA-L. Based on the data presented here we conclude that elevated activity of GnT-III in cancer cells does not necessarily lead to a total abrogation of the formation of highly branched glycans. In addition, the modification of pre-existing N-glycans by the introduction of "bisecting" GlcNAc can modulate their capacity to interact with carbohydrate-binding proteins such as plant lectins. Our results suggest further studies on the biological function of "bisected" oligosaccharides in cancer cell biology and their interactions with carbohydrate-binding proteins. PMID- 29502193 TI - Subcutaneous implantable cardioverter defibrillator eligibility according to a novel automated screening tool and agreement with the standard manual electrocardiographic morphology tool. AB - PURPOSE: Since subcutaneous implantable cardioverter defibrillator (S-ICD) introduction, the pre-implant screening based on a dedicated manual ECG tool (MST) was required to assure adequate sensing by the S-ICD. A novel automated screening tool (AST) has been recently developed. We assessed and compared the pass rate with AST and MST, and we measured the agreement between screening tools. METHODS: Three electrodes were positioned at locations mimicking the placement of the S-ICD, and ECG recordings were collected in the supine and standing postures at rest. The three sensing vectors were analyzed with the MST and the AST. Eligibility was defined by the presence of at least one or two appropriate vectors in both postures. RESULTS: A total of 235 patients with an indication to ICD and no need for permanent pacing were enrolled. At least one suitable vector was identified in 214 (91%) patients with MST and 221 (94%) patients with AST (p = 0.219). At least two vectors were appropriate in 162 (69%) patients with MST and 187 (80%) patients with AST (p = 0.008). Overall, out of 1587 ECG analyzed, 1035 (65%) qualifying leads were identified with MST and 1111 (70%) with AST (p = 0.004). The agreement between the results of MST and AST ECG analysis was moderate (Kappa = 0.570; standard error = 0.022; CI = 0.526-0.613). The results were consistent regardless of the underlying cardiomyopathy. The most frequent reason for screening failure with MST was a high-amplitude T-wave (31% of failures). With AST, 23% of recordings that failed with MST for high-amplitude T-wave were classified as acceptable. CONCLUSION: The AST is associated with higher pass rate than the standard MST. It seems more tolerant of high-amplitude T-waves. Consequently, the agreement between MST and AST findings was only moderate. PMID- 29502194 TI - Incidence, predictors, and impact on outcome of increased left ventricular latency in patients undergoing cardiac resynchronization therapy. AB - PURPOSE: Latency during left ventricle (LV) pacing has been suggested as a potential cause of ineffectual biventricular pacing. We assessed the incidence, predictors, and impact on outcome of increased LV latency in 274 patients undergoing cardiac resynchronization therapy (CRT). METHODS: On implantation, the latency interval was defined as the shortest stimulus-to-QRS onset interval in any lead of the 12-lead ECG. A stimulus-to-QRS onset interval >= 40 ms was used to define the presence of increased LV latency. RESULTS: Increased LV latency was observed in 55 patients (20%). On multivariate analysis, only ischemic etiology proved to be a predictor of increased LV latency. On 12-month echocardiographic evaluation, 68% patients showed a >= 15% decrease in LV end systolic volume (74% patients with increased LV latency, 67% patients without increased LV latency (p = 0.58). The presence of increased LV latency was not associated with a different clinical response to CRT. CONCLUSIONS: Increased LV latency occurred in almost 20% of patients undergoing CRT and was more frequent in patients with ischemic heart disease. The presence of increased LV latency does not seem to have an impact on echocardiographic or clinical response to CRT. PMID- 29502195 TI - Effect of Sedation Regimen on Weaning from Mechanical Ventilation in the Intensive Care Unit. AB - BACKGROUND: Intensive care unit patients undergoing mechanical ventilation have traditionally been sedated to make them comfortable and to avoid pain and anxiety. However, this may lead to prolonged mechanical ventilation and a longer length of stay. OBJECTIVE: The aim of this retrospective study was to explore whether different sedation regimens influence the course and duration of the weaning process. PATIENTS AND METHODS: Intubated adult patients (n = 152) from 15 general intensive care units in Sweden were mechanically ventilated for >= 24 h. Patients were divided into three groups according to the sedative(s) received during the weaning period (i.e. from being assessed as 'fit for weaning' until extubation): dexmedetomidine alone (DEX group, n = 32); standard of care with midazolam and/or propofol (SOC group, n = 67); or SOC plus dexmedetomidine (SOCDEX group, n = 53). RESULTS: Patients receiving dexmedetomidine alone were weaned more rapidly than those in the other groups despite spending longer time on mechanical ventilation prior to weaning. Anxiety during weaning was present in 0, 9 and 24% patients in the DEX, SOC and SOCDEX groups, respectively. Anxiety after extubation was present in 41, 20 and 34% in the DEX, SOC and SOCDEX groups, respectively. Delirium during weaning was present in 1, 2 and 1 patient in the DEX, SOC and SOCDEX groups, respectively. Delirium at ICU discharge was present in 1, 0 and 3 patients in the DEX, SOC and SOCDEX groups, respectively. Few patients fulfilled criteria for post-traumatic stress disorder. CONCLUSION: Dexmedetomidine, used as a single sedative, may have contributed to a shorter weaning period than SOC or SOCDEX. Patients who received dexmedetomidine-only sedation tended to report better health-related quality of life than those receiving other forms of sedation. PMID- 29502197 TI - Control and Responsibility: Taking a Closer Look at the Work of Ensuring Well Being in Neoliberal Schools. AB - This paper argues that the neo-liberal work of schooling includes a focus on producing subjectivities with a high level of well-being. This is done by drawing on evidence based therapeutic techniques that are adjusted to a school setting. These are termed 'therapeutic socio-educational technologies. It is argued that these practices adhere to the neo-liberal logic of increased competition, standardization and testing, focusing on the individual child. There are a number of problems connected to these well-being enhancing technologies. These include the risk of producing passive and submissive subjectivities, that are understood as needing therapy by default; pathologizing the discomfort and struggles that are an inherent part of learning; the fragmentation of the child, focusing directly on the child rather than on the content matter at hand; producing an overly mechanic and technified pedagogy, focusing on output, as well as laying claim to much control in a risk-filled relational endeavor. PMID- 29502196 TI - Communicative Mediation by Adults in the Construction of Symbolic Uses by Infants. AB - Adult semiotic mediation in the origin and evolution of the first symbolic uses of objects by infants in contexts of triadic interactions was investigated. Six infant-parent dyads interacting together with ten objects were observed longitudinally from 9 to 15 months of age, with an interval of three months between each observation. The communicative mediators used by adults, in the form of demonstrations and ostensive gestures, decrease as infants grow up. The orchestration of these semiotic mediators also decreases and the functions of the demonstrations change. At the beginning, the adults use them merely to demonstrate the symbolic uses of object, but later they use them to evaluate, complete or correct the symbolic uses by the infants. The semiotic mediators are first used to guide the child at the level of attention and later at the level of cultural practices of symbolic uses of objects. These changes in communicative mediators and their functions reveal the educational role of adults through adjustment in communication, always in tune with the infant's knowledge and performance. PMID- 29502199 TI - Role of Laparoscopic-Assisted Gastric Per-oral Endoscopic Pyloromyotomy in Refractory Gastroparesis. PMID- 29502198 TI - Drug-Induced Liver Injury: Why is the Roussel Uclaf Causality Assessment Method (RUCAM) Still Used 25 Years After Its Launch? AB - Launched in 1993 and partially based on the results of an international consensus meeting organized under the auspices of the Council of International Organizations of Medical Sciences (CIOMS), the Roussel Uclaf Causality Assessment Method (RUCAM) is the most used causality assessment tool worldwide for the diagnosis of drug-induced liver injury (DILI) and herb-induced liver injury (HILI) in a large number of epidemiological studies, case reports, and case series. The 25-year experience of RUCAM use confirmed that the success was due to its objective, standardized, and liver-injury-specific approach structured with defined key elements derived from a series of DILI cases with positive rechallenge. Using this series, the validation procedure avoided arbitrary definitions and confirmed scores to key items. The algorithm provides a quantitative causality grading of highly probable, probable, possible, unlikely, or excluded relationship between the liver injury and the suspected product(s). Despite challenges, prospective use of RUCAM fosters case data completeness and transparent causality adjudication in real time, as opposed to subjective opinion resulting from several rounds by experts lacking defined key elements and scores. In 2016, RUCAM was updated with specification of alcohol use and Hepatitis E Virus (HEV) biomarkers and simplified item handling to further reduce inter observer variability. RUCAM-based probable and highly probable DILI and HILI cases are essential for the detection of new hepatotoxins, confirmation of new biomarkers, description of clinical features and risk factors, and determination of incidence in pharmacoepidemiological studies. This article is intended to encourage systematic use of sophisticated causality assessment methods such as RUCAM to improve DILI and HILI case evaluation and to increase confidence in published cases. PMID- 29502201 TI - Integrated neurodegenerative disease autopsy diagnosis. PMID- 29502200 TI - Differential alpha-synuclein expression contributes to selective vulnerability of hippocampal neuron subpopulations to fibril-induced toxicity. AB - The accumulation of misfolded alpha-synuclein (aSyn) and neuron loss define several neurodegenerative disorders including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). However, the precise relationship between pathology and neurotoxicity and why these processes disproportionately affect certain neuron subpopulations are poorly understood. We show here that Math2 expressing neurons in the hippocampal Cornu ammonis (CA), a region significantly affected by aSyn pathology in advanced PD and DLB, are highly susceptible to pathological seeding with pre-formed fibrils (PFFs), in contrast to dentate gyrus neurons, which are relatively spared. Math2+ neurons also exhibited more rapid and severe cell loss in both in vitro and in vivo models of synucleinopathy. Toxicity resulting from PFF exposure was dependent on endogenous aSyn and could be attenuated by N-acetyl-cysteine through a glutathione-dependent process. Moreover, aSyn expression levels strongly correlate with relative vulnerability among hippocampal neuron subtypes of which Math2+ neurons contained the highest amount. Consistent with this, antisense oligonucleotide (ASO)-mediated knockdown of aSyn reduced the neuronal pathology in a time-dependent manner. However, significant neuroprotection was observed only with early ASO intervention and a substantial reduction of aSyn pathology, indicating toxicity occurs after a critical threshold of pathological burden is exceeded in vulnerable neurons. Together, our findings reveal considerable heterogeneity in endogenous aSyn levels among hippocampal neurons and suggest that this may contribute to the selective vulnerability observed in the context of synucleinopathies. PMID- 29502202 TI - Association Between Vitamin D Metabolism Gene Polymorphisms and Risk of Tunisian Adults' Asthma. AB - INTRODUCTION: Several studies have shown a strong correlation between the serum vitamin D level and asthma severity and deficits in lung function. OBJECTIVE: Study the relationship between vitamin D and the severity of asthma by targeting five SNPs of vitamin D metabolism gene pathway in a Tunisian adult asthmatics population. METHODS: Our case-control study includes 154 adult asthmatic patients and 154 healthy Tunisian subjects. We genotyped many variants in three human genes encoding key components of the vitamin D metabolism, CYP2R1, CYP27B1, GC. The GC gene rs4588 and rs7041 polymorphisms were analysed using the PCR-RFLP method, while rs10741657 and rs12794714 for CYP2R1 gene and rs10877012 of CYP27B1 gene were investigated using TaqMan PCR genotyping techniques. RESULTS: We found that the presence of at least one copy of the rs12794714 A, allele was associated with lower risk of developing asthma (OR 0.61). Further, the rs12794714 is a protector factor against asthma severity (OR 0.5). However, the presence of rs10877012 TG genotype is a risk factor related to asthma severity (OR 1.89). When we classified the population according to sex, our results showed that rs10877012 TT genotype was a risk factor for women subjects (OR 6.7). Moreover, the expression of TT genotype was associated with a higher risk of asthma in non smoker patients (OR 7.13). We found a significant lower VD serum levels in asthmatics than controls but no impact of the polymorphisms on VD levels. CONCLUSIONS: We found that rs12794714 and rs10877012 SNPs were associated with asthma risk. PMID- 29502203 TI - Amantadine attenuates sepsis-induced cognitive dysfunction possibly not through inhibiting toll-like receptor 2. AB - : Amantadine has been shown to reduce anesthesia and surgery-induced neuroinflammation and cognitive dysfunction. It is known that sepsis can impair brain function. We determined whether amantadine-attenuated sepsis-induced neuroinflammation and dysfunction of learning and memory and whether toll-like receptors (TLRs) play a role in the effects. Six- to eight-week-old mice were subjected to cecal ligation and puncture (CLP). Amantadine at 30 mg/kg/day was injected intraperitoneally for 3 days. CU-CPT22, a TLR1/TLR2 inhibitor, at 3 mg/kg/day was injected intraperitoneally for 2 days. Mice were subjected to Barnes maze and fear conditioning tests from 1 week after CLP. CLP induced neuroinflammation and cognitive dysfunction. CLP also increased the expression of toll-like receptor 2 (TLR2), TLR4, and TLR9, three major TLRs in the brain, in CD 1 male mice. Amantadine attenuated CLP-induced neuroinflammation and dysfunction of learning and memory but did not have significant effects on the expression of TLRs. CU-CPT22 also attenuated sepsis-induced neuroinflammation and cognitive dysfunction. Similarly, sepsis induced neuroinflammation and cognitive dysfunction in the C57BL/6J mice. Interestingly, sepsis also induced neuroinflammation and cognitive dysfunction in the TLR2 knockout mice. The effects of amantadine on the neuroinflammation and cognitive dysfunction were still apparent in these knockout mice. TLR2 contributes to sepsis-induced neuroinflammation and cognitive dysfunction. However, inhibiting TLR2 may not be a major mechanism for amantadine to inhibit sepsis-induced neuroinflammation and cognitive dysfunction. KEY MESSAGES: Sepsis induces neuroinflammation and cognitive impairment, which were attenuated by amantadine. Toll-like receptors 2 mediates these sepsis effects but may not be the major target for amantadine to reduce these effects. PMID- 29502204 TI - AMPKalpha inactivation destabilizes atherosclerotic plaque in streptozotocin induced diabetic mice through AP-2alpha/miRNA-124 axis. AB - : Diabetes mellitus is one of risk factors of cardiovascular diseases including atherosclerosis. Whether and how diabetes promotes the formation of unstable atherosclerotic plaque is not fully understood. Here, we show that streptozotocin induced type 1 diabetes reduced collagen synthesis, leading to the formation of unstable atherosclerotic plaque induced by collar placement around carotid in apolipoprotein E knockout (Apoe-/-) mice. These detrimental effects of hyperglycemia on plaque stability were reversed by metformin in vivo without altering the levels of blood glucose and lipids. Mechanistically, we found that high glucose reduced the phosphorylated level of AMP-activated protein kinase alpha (AMPKalpha) and the transcriptional activity of activator protein 2 alpha (AP-2alpha), increased the expression of miR-124 expression, and downregulated prolyl-4-hydroxylase alpha 1 (P4Halpha1) protein expression and collagen biosynthesis in cultured vascular smooth muscle cells. Importantly, these in vitro effects produced by high glucose were abolished by AMPKalpha pharmacological activation or adenovirus-mediated AMPKalpha overexpression. Further, adenovirus-mediated AMPKalpha gain of function remitted the process of diabetes-induced plaque destabilization in Apoe-/- mice injected with streptozotocin. Administration of metformin enhanced pAP-2alpha level, reduced miR-124 expression, and increased P4Halpha1 and collagens in carotid atherosclerotic plaque in diabetic Apoe-/- mice. We conclude that streptozotocin induced toxic diabetes promotes the formation of unstable atherosclerotic plaques based on the vulnerability index in Apoe-/- mice, which is related to the inactivation of AMPKalpha/AP-2alpha/miRNA-124/P4Halpha1 axis. Clinically, targeting AMPKalpha/AP-2alpha/miRNA-124/P4Halpha1 signaling should be considered to increase the plaque stability in patients with atherosclerosis. KEY MESSAGES: Hyperglycemia reduced collagen synthesis, leading to the formation of unstable atherosclerotic plaque induced by collar placement around carotid in apolipoprotein E knockout mice. Hyperglycemia destabilizes atherosclerotic plaque in vivo through an AMPKalpha/AP-2alpha/miRNA-124/P4Halpha1-dependent collagen synthesis. Metformin functions as a stabilizer of atherosclerotic plaque to reduce acute coronary accent. PMID- 29502205 TI - Heterologous Expression, Purification and Characterization of an Oligopeptidase A from the Pathogen Leptospira interrogans. AB - Oligopeptidases are enzymes involved in the degradation of short peptides (generally less than 30 amino acids in size) which help pathogens evade the host defence mechanisms. Leptospira is a zoonotic pathogen and causes leptospirosis in mammals. Proteome analysis of Leptospira revealed the presence of oligopeptidase A (OpdA) among other membrane proteins. To study the role of oligopeptidase in leptospirosis, the OpdA of L. interrogans was cloned and expressed in Escherichia coli with a histidine tag (His-tag). The protein showed maximum expression at 37 degrees C with 0.5 mM of IPTG after 2 h of induction. Recombinant OpdA protein was purified to homogeneity using Ni-affinity chromatography. The purified OpdA showed more than 80% inhibition with a serine protease inhibitor but the activity was reduced to 30% with the cysteine protease inhibitor. The peptidase activity was increased significantly in the presence of Zn2+ at a neutral pH. Inhibitor assay indicate the presence of more than one active sites for peptidase activity as reported with the OpdA of E. coli and Salmonella. Over-expression of OpdA in E. coli BL21 (DE3) did not cause any negative effects on normal cell growth and viability. The role of OpdA as virulence factor in Leptospira and its potential as a therapeutic and diagnostic target in leptospirosis is yet to be identified. PMID- 29502206 TI - Silver ions increase plasma membrane permeability through modulation of intracellular calcium levels in tobacco BY-2 cells. AB - KEY MESSAGE: Silver ions increase plasma membrane permeability for water and small organic compounds through their stimulatory effect on plasma membrane calcium channels, with subsequent modulation of intracellular calcium levels and ion homeostasis. The action of silver ions at the plant plasma membrane is largely connected with the inhibition of ethylene signalling thanks to the ability of silver ion to replace the copper cofactor in the ethylene receptor. A link coupling the action of silver ions and cellular auxin efflux has been suggested earlier by their possible direct interaction with auxin efflux carriers or by influencing plasma membrane permeability. Using tobacco BY-2 cells, we demonstrate here that besides a dramatic increase of efflux of synthetic auxins 2,4-dichlorophenoxyacetic acid (2,4-D) and 1-naphthalene acetic acid (NAA), treatment with AgNO3 resulted in enhanced efflux of the cytokinin trans-zeatin (tZ) as well as the auxin structural analogues tryptophan (Trp) and benzoic acid (BA). The application of AgNO3 was accompanied by gradual water loss and plasmolysis. The observed effects were dependent on the availability of extracellular calcium ions (Ca2+) as shown by comparison of transport assays in Ca2+-rich and Ca2+-free buffers and upon treatment with inhibitors of plasma membrane Ca2+-permeable channels Al3+ and ruthenium red, both abolishing the effect of AgNO3. Confocal microscopy of Ca2+-sensitive fluorescence indicator Fluo-4FF, acetoxymethyl (AM) ester suggested that the extracellular Ca2+ availability is necessary to trigger the response to silver ions and that the intracellular Ca2+ pool alone is not sufficient for this effect. Altogether, our data suggest that in plant cells the effects of silver ions originate from the primal modification of the internal calcium levels, possibly by their interaction with Ca2+-permeable channels at the plasma membrane. PMID- 29502207 TI - Cranial morcellation decompression for refractory idiopathic intracranial hypertension in children. AB - BACKGROUND: Primary idiopathic intracranial hypertension (PIIH) in children is rare and has a poorly understood pathophysiology. It is characterized by raised intracranial pressure (ICP) in the absence of an identified brain lesion. Diagnosis is usually confirmed by the measurement of a high cerebrospinal fluid (CSF) opening pressure and exclusion of secondary causes of intracranial hypertension. Refractory PIIH may lead to severe visual impairment. The purpose of this study was to evaluate a cranial morcellation decompression (CMD) technique as a new surgical alternative to stabilize intracranial pressure in PIIH. MATERIALS AND METHODS: A literature review was carried out, disclosing only 7 pediatric cases of PIIH treated with surgical skull expansion. In addition, we describe here one case of our own experience treated by CMD. CONCLUSIONS: CMD surgery is a safe and effective option to control refractory PIIH in selected patients. PMID- 29502208 TI - Tumor-associated myeloid cells promote tumorigenesis of non-tumorigenic human and murine prostatic epithelial cell lines. AB - The etiology of prostate cancer is poorly understood, but it is a multi-step process that has been linked to environmental factors that induce inflammation within the gland. Glands of prostate cancer patients frequently contain multiple zones of disease at various stages of progression. The factors that drive disease progression from an indolent benign stage to aggressive disease are not well defined. Prostate inflammation and carcinoma are associated with high levels of myeloid cell infiltration; these cells are linked to disease progression in other cancers, but their role in prostate cancer is unclear. To determine whether myeloid cells contribute to prostate cancer progression, the ability of prostate tumor-associated CD11b+ cells (TAMC) to drive prostate epithelial cell tumorigenesis was tested. Co-culture of CD11b+ TAMC with non-tumorigenic genetically primed prostate epithelial cells resulted in stable transformation and induction of tumorigenesis. RNA sequencing identified the IL-1alpha pathway as a potential molecular mechanism responsible for tumor promotion by TAMC. Inhibition of IL-1alpha delayed growth of TAMC-induced tumors. Further analysis showed that IL-1alpha inhibition led to decreased angiogenesis within tumors, suggesting that IL-1alpha promotes prostate tumor progression, potentially through augmentation of angiogenesis. PMID- 29502209 TI - Delineation of contaminant plume for an inorganic contaminated site using electrical resistivity tomography: comparison with direct-push technique. AB - Precise delineation of contaminant plume distribution is essential for effective remediation of contaminated sites. Traditional in situ investigation methods like direct-push (DP) sampling are accurate, but are usually intrusive and costly. Electrical resistivity tomography (ERT) method, as a non-invasive geophysical technique to map spatiotemporal changes in resistivity of the subsurface, is becoming increasingly popular in environmental science. However, the resolution of ERT for delineation of contaminant plumes still remains controversial. In this study, ERT and DP technique were both conducted at a real inorganic contaminated site. The reliability of the ERT method was validated by the direct comparisons of their investigation results that the resistivity acquired by ERT method is in accordance with the total dissolved solid concentration in groundwater and the overall variation of the total iron content in soil obtained by DP technique. After testifying the applicability of ERT method for contaminant identification, the extension of contaminant plume at the study site was revealed by supplementary ERT surveys conducted subsequently in the surrounding area of the contaminant source zone. PMID- 29502210 TI - Analyzing the effects of urban expansion on land surface temperature patterns by landscape metrics: a case study of Isfahan city, Iran. AB - Urban expansion can cause extensive changes in land use and land cover (LULC), leading to changes in temperature conditions. Land surface temperature (LST) is one of the key parameters that should be considered in the study of urban temperature conditions. The purpose of this study was, therefore, to investigate the effects of changes in LULC due to the expansion of the city of Isfahan on LST using landscape metrics. To this aim, two Landsat 5 and Landsat 8 images, which had been acquired, respectively, on August 2, 1985, and July 4, 2015, were used. The support vector machine method was then used to classify the images. The results showed that Isfahan city had been encountered with an increase of impervious surfaces; in fact, this class covered 15% of the total area in 1985, while this value had been increased to 30% in 2015. Then LST zoning maps were created, indicating that the bare land and impervious surfaces categories were dominant in high temperature zones, while in the zones where water was present or NDVI was high, LST was low. Then, the landscape metrics in each of the LST zones were analyzed in relation to the LULC changes, showing that LULC changes due to urban expansion changed such landscape properties as the percentage of landscape, patch density, large patch index, and aggregation index. This information could be beneficial for urban planners to monitor and manage changes in the LULC patterns. PMID- 29502211 TI - Intraoperative optical coherence tomography in the full-thickness macular hole surgery with internal limiting membrane inverted flap placement. AB - PURPOSE: To describe the helpfulness of using intraoperative optical coherence tomography (OCT) during surgery for full-thickness macular hole (FTMH). OBSERVATIONS: This observational case series identifies three patients with FTMH who were treated with vitrectomy, internal limiting membrane (ILM) peel with inverted ILM flap, which was tucked into the MH, and air with 18% Sulfur Hexafluoride (SF6) gas tamponade. Intraoperative OCT was used to confirm positioning of the ILM flap, even after complete air-fluid exchange. The patients were followed for three months after surgery and all reached a good morphological and functional outcome. CONCLUSIONS: If confirmed by a prospective longitudinal study, the intraoperative OCT might become an important tool in assisting FTMH surgery. PMID- 29502212 TI - A comparative study of transscleral suture-fixated and scleral-fixated intraocular lens implantation. AB - PURPOSE: To compare short-term clinical outcomes between scleral-fixated and transscleral suture-fixated intraocular lens (IOL) implantation. SEETING: Hiroshima Prefectural Hospital, Japan. DESIGN: A retrospective, nonrandomized, comparative case series. METHODS: Eighty-nine eyes of 87 patients were included in this study; 45 eyes underwent transscleral suture-fixated IOL implantation (group 1), and 44 eyes underwent scleral-fixated IOL implantation (group 2) between February 2009 and June 2017 in the department of Ophthalmology, Hiroshima Prefectural Hospital, Japan. The postoperative best corrected visual acuity (BCVA), degree of astigmatism, IOL astigmatism (total astigmatism-corneal astigmatism), and refractive error were all measured at 1-week and 1-month intervals. RESULTS: The mean preoperative BCVA in logarithm of minimum angle of resolution (log MAR) was 0.39 +/- 0.56 and 0.46 +/- 0.51 in groups 1 and 2, respectively, and the mean postoperative BCVA was 0.25 +/- 0.41 and 0.34 +/- 0.49 at 1 month. The postoperative degree of astigmatism in group 2 was significantly less than that in group 1 at 1 week and 1 month (p = 0.0046 and p = 0.021, respectively). The postoperative IOL astigmatism in group 2 was significantly less than that in group 1 at 1 week (p = 0.021), while the refractive error between the two groups was not significantly different at 1 week or 1 month. CONCLUSIONS: Scleral-fixated IOL implantation has equivalent BCVA and refractive error outcomes as transscleral suture-fixated IOL implantation during the early postoperative period without serious complications. Scleral-fixated IOL implantation appears to provide more stable fixation than suture-fixated IOL implantation. PMID- 29502213 TI - Photorefractive keratectomy influences the angle of ocular deviation in strabismus patients with hyperopia. AB - PURPOSE: To evaluate refractive, binocular vision and ocular alignment outcomes of photorefractive keratectomy (PRK) for the treatment of hyperopia in esotropic patients. METHODS: Medical charts of hyperopic patients with full or partial accommodative esotropia (FAE or PAE) or consecutive exotropia (CE) undergone PRK from 2011 to 2014 were reviewed. The primary outcome was to assess the efficacy of PRK in improving ocular alignment. The secondary outcomes were the assessments of uncorrected visual acuity (UCVA), best-corrected visual acuity (BCVA), spherical equivalent (SE) and stereoacuity. RESULTS: Sixty-four eyes of 32 hyperopic patients were included. Three patients were affected by FAE, 24 by PAE and 5 by CE. All FAE patients and 4 PAE patients underwent only PRK; the remaining 25 patients underwent PRK plus strabismus surgery. After PRK, the mean corrected esodeviation decreased significantly in the overall esotropic population [7.15 +/- 9.42 prism diopters (PD) vs. 5.04 +/- 8.83 PD; p = 0.03] and in particular in the group with small-angle esodeviation (< 20 PD). Conversely, the only 2 patients with an angle of strabismus >= 20 PD as well as all CE patients did not show any postoperative variation of the deviation angle. Mean preoperative BCVA did not differ from postoperative UCVA (p = 0.19), while the mean postoperative SE decreased significantly after PRK (p < 0.0001). CONCLUSIONS: Our study confirmed that PRK eliminates the accommodative component of the deviation. In addition, this procedure seems to reduce or eliminate also the non-accommodative component of esodeviation (especially in small-angle deviation), thus suggesting to postpone strabismus surgery after PRK when esotropia and hyperopia coexist. PMID- 29502214 TI - Does diabetes increase the risk of periodontitis? A systematic review and meta regression analysis of longitudinal prospective studies. AB - AIM: Even though the association between diabetes and periodontitis is taken for granted, results on this association are conflicting within the literature. This systematic review assessed whether poorly controlled diabetes was associated with periodontitis onset or progression. METHODS: Electronic searches were performed in PubMed, Scopus and Embase databases. Hand search was carried out in the reference list of all articles included. Gray literature was investigated with a Google Scholar search. Prospective longitudinal studies on the association between diabetes and periodontitis were considered for this review. Studies should have presented at least two measurements of periodontal conditions over time. Data on study design, crude and adjusted estimates were collected. We used meta-analysis to estimate the pooled effect of hyperglycemia in people with diabetes on periodontitis onset or progression. Meta-regression and subgroup analyses were employed to investigate potential sources of heterogeneity between studies. RESULTS: Thirteen studies matched the inclusion criteria, comprising 49,262 individuals, including 3197 diagnosed with diabetes. Meta-analyses of adjusted estimates showed that diabetes increased the risk of incidence or progression of periodontitis by 86% (RR 1.86 [95% CI 1.3-2.8]). However, there is scarce information on the association between diabetes and periodontal destruction. CONCLUSIONS: This study provides evidence that diabetes is associated with increased risk of periodontitis onset and progression in adults. Upcoming prospective longitudinal studies ought to overcome methodological caveats identified in this review. PMID- 29502215 TI - Identification of a less toxic vinca alkaloid derivative for use as a chemotherapeutic agent, based on in silico structural insights and metabolic interactions with CYP3A4 and CYP3A5. AB - Vinca alkaloids are chemotherapeutic agents used in the treatment of both pediatric and adult cancer patients. Cytochrome P450 3A5 (CYP3A5) is 9- to 14 fold more efficient at clearing vincristine than cytochrome P450 3A4 (CYP3A4) is. However, patients who express an inactive form of the polymorphic CYP3A5 enzyme suffer from severe neurotoxicity during vincristine treatment, resulting in chemotherapy failure. Previous studies have found that the addition of new features to the parent drug can enhance its binding affinity to tubulin manyfold and could therefore yield novel anticancer drugs. However, there is no report of any study of the metabolic activities of CYP3A4 and CYP3A5 with respect to vincristine and vinblastine, so we studied the interactions of these two drugs and 15 vinca derivatives with CYP3A4 and CYP3A5 by performing docking studies using GOLD. Six of the vinca derivatives in complexes with CYP3A4 and CYP3A5 were further investigated in 100-ns molecular dynamic simulations. Interaction energies, hydrogen bonds, and linear interaction energies were calculated and principal component analysis was carried out to visualize the binding interface in each complex. The results indicate that the addition of dimethylurea at the C20' position in vincristine may increase its binding affinity and lead to enhanced interactions with the less polymorphic CYP3A4 rather than CYP3A5. Thus, dimethylurea vincristine may be a useful drug in cancer chemotherapy treatment as it should be significantly less likely than vincristine to induce severe neurotoxicity in patients. Graphical Abstract Proposed modification of Vinca alkaloid derivatives to decrease the neurotoxicity level in cancer patients exhibiting CYP3A4 gene rather than polymorphic CYP3A5 gene. PMID- 29502216 TI - Are cucurbiturils better drug carriers for bent metallocenes? Insights from theory. AB - Bent metallocenes (BM) have anti-tumor properties but they face a serious drug efficacy problem due to poor aqueous solubility and rapid hydrolysis under physiological conditions. These two problems can be fixed by encapsulating them in host molecules such as cyclodextrin (CD), cucurbituril (CB) etc. Experimentally, CD-BM, CB-BM host-guest complexes have been investigated to check the efficiency of the drug delivery and efficiency of the encapsulated drug. CB has been reported to be a better host than CD but the reasons for this has not been figured out. This can be done by finding out the mechanism of binding and the nature of the binding forces in both the inclusion complexes. This is exactly done here by performing a DFT study at BP86/TZP level on CB-BM host-guest systems. For comparison CD-BM with beta-cyclodextrin as host have been studied. Four BMs (Cp2MCl2, M=Ti, V, Nb, Mo) and their corresponding cations (Cp2MCl+, Cp2M2+) are chosen as guests and they are encapsulated into cucurbit-[6]-uril (CB[6]) and cucurbit-[7]-uril(CB[7]) host systems. Computations reveal that CB[7] accommodates well the BMs over CB[6] due to their larger cavity size and also CB[7] is found to be a better host than beta-cyclodextrin. BMs enter vertically rather than horizontally into the CB cavity. The reversible binding of BMs within CB[7] is controlled by various non-bonding interactions and mainly by hydrogen bonding between the portal oxygen atoms and Cp protons as revealed by QTAIM analysis. On the other hand, the interaction between the wall nitrogen atoms in CB[7] and chlorine atoms attached to the metal in BM strengthens the M-Cl bonds that prevents rapid hydrolysis of M-Cl and M-Cp bonds saving the drug. Comparatively, BMs experience less electrostatic attraction and more Pauli repulsion within beta-cyclodextrin cavity and this affects the drug binding with CD. This makes beta-cyclodextrin a less suitable drug carrier for BMs than CBs. Among the four BMs, niobocene binds strongly and titanocene binds weakly with CBs. EDA clearly shows that all the interactions between the guest and host are non-covalent in nature and electrostatic interactions outperform high-repulsion resulting in stable complexes. Cations form stronger complexes than neutral BMs. FMO analysis reveals that neutral BMs are less reactive compared to their cations and complexes are more reactive in CB[6] environment due to excess strain. QTAIM analysis helps to bring out the newer insights in these types of host-guest systems. PMID- 29502217 TI - Equisetin as potential quorum sensing inhibitor of Pseudomonas aeruginosa. AB - OBJECTIVE: To screen for the quorum-sensing (QS) inhibitors from marine-derived fungi and evaluate their anti-QS properties in Pseudomonas aeruginosa. RESULTS: QS inhibitory activity was found in secondary metabolites of a marine fungus Fusarium sp. Z10 using P. aeruginosa QSIS-lasI biosensor. The major active compound of this fungus was isolated by HPLC and identified as equisetin. Subinhibitory concentration of equisetin could inhibit the formation of biofilm, swarming motility, and the production of virulence factors in P. aeruginosa. The inhibition of las, PQS, and rhl system by equisetin were determined using Escherichia coli MG4/pKDT17, E.coli pEAL08-2, and E.coli pDSY, respectively. Real time RT-PCR assays showed that equisetin could downregulate the mRNA expression of QS-related genes. CONCLUSIONS: Equisetin proved its potential as an inhibitor against P. aeruginosa QS system and might also serve as precursor compound in development of novel therapeutics for infectious diseases by optimal design of structures. PMID- 29502218 TI - Profiles of Adolescents' Perceptions of Democratic Classroom Climate and Students' Influence: The Effect of School and Community Contexts. AB - Students' learning experiences and outcomes are shaped by school and classroom contexts. Many studies have shown how an open, democratic classroom climate relates to learning in the citizenship domain and helps nurture active and engaged citizens. However, little research has been undertaken to look at how such a favorable classroom climate may work together with broader school factors. The current study examines data from 14,292 Nordic eighth graders (51% female) who had participated in the International Civic and Citizenship Education Study in 2009, as well as contextual data from 5,657 teachers and 618 principals. Latent class analysis identifies profiles of students' perceptions of school context, which are further examined with respect to the contextual correlates at the school level using two-level fixed effects multinomial regression analyses. Five distinct student profiles are identified and labeled "alienated", "indifferent", "activist", "debater", and "communitarian". Compared to indifferent students, debaters and activists appear more frequently at schools with relatively few social problems; being in the communitarian group is associated with aspects of the wider community. Furthermore, being in one of these three groups (and not in the indifferent group) is more likely when teachers act as role models by engaging in school governance. The results are discussed within the framework of ecological assets and developmental niches for emergent participatory citizenship. The implications are that adults at school could enhance multiple contexts that shape adolescents' developmental niches to nurture active and informed citizens for democracies. PMID- 29502219 TI - Protecting High-Risk Youth in High-Risk Contexts: Neighborhoods, Parenting, and Victimization. AB - Victimization theories suggest parents can serve as guardians to protect adolescents from victimization, yet findings from studies examining the main effects of parenting variables on adolescent victimization are mixed. Prior research suggests that it is the combination of parental warmth and monitoring that produces the best results across a range of other outcomes. The current study used data collected from a sample of serious adolescent offenders as part of the Pathways to Desistance study (N = 888; 16.1% female; mean age = 15.92). Using the first two waves (baseline and 6-month time points) of data, we estimated a series of negative binomial regression models to observe the main and interactive effects of parental warmth and monitoring on adolescent victimization and the potential moderating influence of neighborhood disorder. The results indicate that the combination of warmth and monitoring reduces adolescent victimization, and that parental warmth may be particularly important for protecting adolescents in neighborhoods with moderate-high levels of disorder. PMID- 29502220 TI - Characterization of a drug-targetable allosteric site regulating vascular endothelial growth factor signaling. AB - Vascular endothelial growth factors (VEGFs) regulate blood and lymph vessel development upon activation of three receptor tyrosine kinases (VEGFRs). The extracellular domain of VEGFRs consists of seven Ig-homology domains, of which D2 3 form the ligand-binding site, while the membrane proximal domains D4-7 are involved in homotypic interactions in ligand-bound receptor dimers. Based on low resolution structures, we identified allosteric sites in D4-5 and D7 of vascular endothelial growth factor receptor 2 (VEGFR-2) accomplishing regulatory functions. Allosteric inhibition of VEGFR-2 signaling represents an attractive option for the treatment of neovascular diseases. We showed earlier that DARPin(r) binders to domains D4 or D7 are potent VEGFR-2 inhibitors. Here we investigated in detail the allosteric inhibition mechanism of the domain D4 binding inhibitor D4b. The 2.38 A crystal structure of D4b in complex with VEGFR 2 D4-5, the first high-resolution structure of this VEGFR-2 segment, indicates steric hindrance by D4b as the mechanism of inhibition of receptor activation. At the cellular level, D4b triggered quantitative internalization of VEGFR-2 in the absence of ligand and thus clearance of VEGFR-2 from the surface of endothelial cells. The allosteric VEGFR-2 inhibition was sufficiently strong to efficiently inhibit the growth of human endothelial cells at suboptimal dose in a mouse xenograft model in vivo, underlining the therapeutic potential of the approach. PMID- 29502221 TI - New equations for age estimation using four permanent mandibular teeth in Thai children and adolescents. AB - The purposes of this study were to generate new age estimation equations using two four-teeth methods and to test the accuracy of the resulting equations in comparison with Demirjian and Goldstein four-teeth methods in a Thai population. A sample of 720 digital panoramic radiographs of Thai individuals (360 males and 360 females), aged between 7 and 15 years was randomly selected and assessed for age estimation. The new equations were developed using quadratic regression analysis. The results showed the Thai population-specific equations had a strong relationship between the dental maturity score and the chronological age in both sexes (r = 0.946-0.956). The new equations revealed no statistically significant differences between the estimated and the chronological ages in either sex. On the other hand, Demirjian and Goldstein four-teeth methods showed statistically significant differences between the estimated and the chronological ages in both sexes. Moreover, we found slight differences in the mean absolute error between Demirjian and Goldstein methods and our new equations (0.01 years for males and 0.03 years for females in method I and 0.04 years for males and 0.02 years for females in method II) and the root mean square error between Demirjian and Goldstein methods and our new equations (0.02 years for males and 0.04 years for females in method I and 0.00 years for males and 0.04 years for females in method II). In summary, although Thai population-specific equations provide a slightly increased accuracy in age estimation in Thai children and adolescents, Demirjian and Goldstein methods are still relevant. PMID- 29502222 TI - Perimortem fracture pattern in ribs by blunt force trauma. AB - Literature on timing of rib trauma is scarce but remains challenging during forensic cases. This study analysed the macroscopic fracture patterns of perimortem rib fractures and compared them to experimentally reproduced rib fractures on fresh and dry ribs. Six distinctive macroscopic traits were found in ribs that might provide information about the timing of trauma, fracture mechanism and/or trauma circumstances. These traits are peels, folds, differential fracture edges, incomplete fractures, plastic deformation and longitudinal lines. Peels, folds and plastic deformation might provide information about trauma timing. Folds and different fracture edges might provide information about the fracture mechanism. Statistical analyses showed that longitudinal lines, folds and incomplete fractures might provide information about the trauma circumstances and that age might have an influence on the occurrence of complete fractures, longitudinal lines and peels (p <= 0.05). The new insights presented in this study might be valuable for forensic anthropologists in rib trauma analysis. PMID- 29502223 TI - Third molar mineralization in relation to chronologic age estimation of the Han in central southern China. AB - The purpose of this study is to provide a forensic reference data about estimating chronologic age by evaluating the third molar mineralization of Han in central southern China. The mineralization degree of third molars was assessed by Demirjian's classification with modification for 2519 digital orthopantomograms (1190 males, 1329 females; age 8-23 years). The mean ages of the initial mineralization and the crown completion of third molars were around 9.66 and 13.88 years old in males and 9.52 and 14.09 years old in females. The minimum ages of apical closure were around 16 years in both sexes. Twenty-eight at stage C and stage G and 38 and 48 at stage F occurred earlier in males than in females. There was no significant difference between maxillary and mandibular teeth in males and females except that stage C in males. Two formulas were devised to estimate age based on mineralization stages and sexes. In Hunan Province, the person will probably be over age 14, when a third molar reaches the stage G. The results of the study could provide reference for age estimation in forensic cases and clinical dentistry. PMID- 29502225 TI - Quantitative Proteomics Identify the Possible Tumor Suppressive Role of Protease Activated Receptor-4 in Esophageal Squamous Cell Carcinoma Cells. AB - Exposure to carcinogens of tobacco smoke may result in methylation of protease activated receptors-4 (PAR4) gene and further induces the loss of PAR4 expression, which is considered to be involved in carcinogenesis of esophageal squamous cell carcinoma (ESCC). Here we employed a TMT-based quantitative proteomic approach to identify PAR4-regulated changes of proteomic profiles in ESCC cells and to identify potentially therapeutic value. A total of 33 proteins were found significantly changed with 15 up-regulated and 18 down-regulated in PAR4-activating peptide (PAR4-AP) treated ESCC cells compared with controls. Bioinformatics analysis showed that key higher expressed proteins included those associated with apoptosis and tumor suppressor (e.g. CASP9), and lower expressed proteins included those associated with anti-apoptosis, autophagy and promoting cell proliferation (e.g. CHMP1B, PURA, PARG and HIST1H2AH). Western blot verified changes in five representative proteins including CASP9, CHMP1B, PURA, PARG and HIST1H2AH. Immunohistochemistry analysis showed that CHMP1B, PURA, PARG and HIST1H2AH expression in ESCC tissues were significantly higher than those in adjacent nontumorous tissues. Our findings will be helpful in further investigations into the functions and molecular mechanisms of PAR4 in ESCC. PMID- 29502224 TI - Detection of side-chain proton resonances of fully protonated biosolids in nano litre volumes by magic angle spinning solid-state NMR. AB - We present a new solid-state NMR proton-detected three-dimensional experiment dedicated to the observation of protein proton side chain resonances in nano liter volumes. The experiment takes advantage of very fast magic angle spinning and double quantum 13C-13C transfer to establish efficient (H)CCH correlations detected on side chain protons. Our approach is demonstrated on the HET-s prion domain in its functional amyloid fibrillar form, fully protonated, with a sample amount of less than 500 ug using a MAS frequency of 70 kHz. The majority of aliphatic and aromatic side chain protons (70%) are observable, in addition to Halpha resonances, in a single experiment providing a complementary approach to the established proton-detected amide-based multidimensional solid-state NMR experiments for the study and resonance assignment of biosolid samples, in particular for aromatic side chain resonances. PMID- 29502226 TI - Infrequent organ involvement of IgG4-related diseases: a literature review. AB - IgG4-related disease (IgG4-RD) is a chronic and systemic disease that can involve multiple organs. The most commonly involved organs include the salivary glands, orbital adnexal structures, paranasal sinus, thyroid, lungs, breasts, aorta, pancreas, biliary ducts, kidneys, retroperitoneum, lymph nodes, prostate, pituitary, and endocranium. Due to increased disease research, several new site specific nuances of IgG4-RD have been described. The authors have reviewed the recent literature and briefly summarize the infrequent organ involvement of IgG4 RD. PMID- 29502227 TI - Decreased IgG4 ACPA levels in responders and increased CD1c+ classical dendritic cells in non-responders of patients with rheumatoid arthritis under therapy. AB - The treatment options for patients suffering from rheumatoid arthritis expanded over the last years. However, reliable biomarkers to guide therapy decisions are still warranted. Therefore, we here evaluated the value of antibodies against citrullinated peptide antigens (ACPA) IgG subclasses and peripheral blood antigen presenting cells as biomarkers to monitor and predict therapy response of patients with rheumatoid arthritis. Thirty-four ACPA-positive RA patients were enrolled and monitored for 3 months after therapy begin. ACPA IgG1 and IgG4 serum levels were quantified by ELISA. Phenotyping of the B cell, monocytic, and dendritic cell lineages was performed via flow cytometry. Three months after therapy begin, the responders showed a significant decrease in IgG4 ACPA levels, and this was independent of the individual treatment regimen. The non-responders showed a significant increase in CD1c+ classical dendritic cells (cDC). Furthermore, the baseline disease activity score 28 and the baseline percentage of cDC allowed for some prediction of future therapy responses. We here suggest IgG4 ACPA levels as biomarkers to monitor therapy response in RA. The increase in CD1c+ cDC among non-responders to therapy remains enigmatic and requires future elucidation of the underlying mechanisms. PMID- 29502228 TI - Endoluminal vacuum-assisted therapy as treatment for anastomotic leak after ileal pouch-anal anastomosis: a pilot study. AB - BACKGROUND: Anastomotic leak after ileal pouch-anal anastomosis (IPAA) could lead to poor functional results and failure of the pouch. The aim of the present study was to analyze the outcomes of the vacuum-assisted closure therapy as the unique treatment for anastomotic leaks following IPAA without any additional surgical operations. METHODS: Consecutive patients with anastomotic leak after IPAA treated at our institution between March 2016 and March 2017 were prospectively enrolled. After diagnosis, the Endosponge(r) device was positioned in the gap and replaced until the cavity was reduced in size and covered by granulating tissue. A pouchoscopy was performed every week for the first month and monthly subsequently. No additional procedures were performed. RESULTS: Eight patients were included in the study. The leak was diagnosed at a median of 14 (6-35) days after surgery. At the time of diagnosis, seven patients had a defunctioning ileostomy performed as routine at the time of pouch formation, while one patient was diagnosed after ileostomy closure and underwent emergency diversion ileostomy. The Endosponge(r) treatment started after a median of 6.5 (1-158) days after the diagnosis of the leakage and was carried on for a median of 12 (3-42) days. The device was replaced a median of 3 (1-10) times. The median length of hospital stay after the first application of the treatment was 15.5 (6-48) days. The complete healing of the leak was documented in all patients, after a median of 60 (24-90) days from the first treatment. All patients but one had their ileostomy reversed at a median of 2.5 (1-6) months from the confirmation of the complete closure. CONCLUSIONS: Endosponge(r) is effective as the only treatment after IPAA leak. Based on the results of our prospective pilot study, application of Endosponge(r) should be the treatment of choice in selected pouch anastomotic leaks not requiring immediate surgery. These results will have to be confirmed by future prospective studies including a larger number of patients. PMID- 29502229 TI - Surgical skills: Can learning curves be computed from recordings of surgical activities? AB - PURPOSE: Surgery is one of the riskiest and most important medical acts that are performed today. The need to improve patient outcomes and surgeon training, and to reduce the costs of surgery, has motivated the equipment of operating rooms with sensors that record surgical interventions. The richness and complexity of the data that are collected call for new methods to support computer-assisted surgery. The aim of this paper is to support the monitoring of junior surgeons learning their surgical skill sets. METHODS: Our method is fully automatic and takes as input a series of surgical interventions each represented by a low-level recording of all activities performed by the surgeon during the intervention (e.g., cut the skin with a scalpel). Our method produces a curve describing the process of standardization of the behavior of junior surgeons. Given the fact that junior surgeons receive constant feedback from senior surgeons during surgery, these curves can be directly interpreted as learning curves. RESULTS: Our method is assessed using the behavior of a junior surgeon in anterior cervical discectomy and fusion surgery over his first three years after residency. They revealed the ability of the method to accurately represent the surgical skill evolution. We also showed that the learning curves can be computed by phases allowing a finer evaluation of the skill progression. CONCLUSION: Preliminary results suggest that our approach constitutes a useful addition to surgical training monitoring. PMID- 29502230 TI - Planning nonlinear access paths for temporal bone surgery. AB - PURPOSE: Interventions at the otobasis operate in the narrow region of the temporal bone where several highly sensitive organs define obstacles with minimal clearance for surgical instruments. Nonlinear trajectories for potential minimally invasive interventions can provide larger distances to risk structures and optimized orientations of surgical instruments, thus improving clinical outcomes when compared to existing linear approaches. In this paper, we present fast and accurate planning methods for such nonlinear access paths. METHODS: We define a specific motion planning problem in [Formula: see text] with notable constraints in computation time and goal pose that reflect the requirements of temporal bone surgery. We then present [Formula: see text]-RRT-Connect: two suitable motion planners based on bidirectional Rapidly exploring Random Tree (RRT) to solve this problem efficiently. RESULTS: The benefits of [Formula: see text]-RRT-Connect are demonstrated on real CT data of patients. Their general performance is shown on a large set of realistic synthetic anatomies. We also show that these new algorithms outperform state-of-the-art methods based on circular arcs or Bezier-Splines when applied to this specific problem. CONCLUSION: With this work, we demonstrate that preoperative and intra-operative planning of nonlinear access paths is possible for minimally invasive surgeries at the otobasis. PMID- 29502231 TI - Correction to: The heterologous expression of Arabidopsis PAP2 induces anthocyanin accumulation and inhibits plant growth in tomato. AB - In the original version of this article the "Acknowledgements" and the "Competing interests" were inadvertently omitted. The information missing in the original article is now given below. PMID- 29502232 TI - An analysis of ranibizumab treatment and visual outcomes in real-world settings: the UNCOVER study. AB - PURPOSE: To describe intravitreal ranibizumab treatment frequency, clinical monitoring, and visual outcomes (including mean central retinal thickness [CRT] and visual acuity [VA] changes from baseline) in neovascular age-related macular degeneration (nAMD) in real-world settings across three ranibizumab reimbursement scenarios in the Middle East, North Africa, and the Asia-Pacific region. METHODS: Non-interventional multicenter historical cohort study of intravitreal ranibizumab use for nAMD in routine clinical practice between April 2010 and April 2013. Eligible patients were diagnosed with nAMD, received at least one intravitreal ranibizumab injection during the study period, and had been observed for a minimum of 1 year (up to 3 years). Reimbursement scenarios were defined as self-paid, partially-reimbursed, and fully-reimbursed. RESULTS: More than three fourths (n = 2521) of the analysis population was partially-reimbursed for ranibizumab, while 16.4% (n = 532) was fully-reimbursed, and 5.8% was self-paid (n = 188). The average annual ranibizumab injection frequency was 4.1 injections in the partially-reimbursed, 4.7 in the fully-reimbursed and 2.6 in the self-paid populations. The average clinical monitoring frequency was estimated to be 6.7 visits/year, with similar frequencies observed across reimbursement categories. On average, patients experienced VA reduction of -0.7 letters and a decrease in CRT of -44.4 MUm. The greatest mean CRT change was observed in the self-paid group, with -92.6 MUm. CONCLUSIONS: UNCOVER included a large, heterogeneous ranibizumab-treated nAMD population in real-world settings. Patients in all reimbursement scenarios attained vision stability on average, indicating control of disease activity. PMID- 29502233 TI - Combined trabeculotomy-trabeculectomy using the modified Safer Surgery System augmented with MMC: its long-term outcomes of glaucoma treatment in Asian children. AB - BACKGROUND: This study aimed to study the long-term surgical outcomes of combined trabeculotomy-trabeculectomy (CTT) using the modified Safer Surgery System in treating childhood glaucoma at a tertiary medical center in Taiwan. METHODS: Retrospective, consecutive, noncomparative case series. We retrospectively reviewed medical records of 42 pediatric patients (age 0-18 years) who had CTT performed on their 65 eyes using the modified Safer Surgery System. The study period spanned 18 years (from January 1, 1997, to December 31, 2014). We evaluated the outcome in terms of postoperative intraocular pressure (IOP), axial length growth, disc cupping reversal, and use of antiglaucoma medications. The surgical success was rated using the Kaplan-Meier survival analysis and based on the incidence of complications. RESULTS: The mean follow-up period was 85.05 +/- 32.17 months (range 14-200). After operation, IOP dropped significantly from 35.76 +/- 9.44 mmHg (mean +/- SD) to 16.18 +/- 7.20 mmHg together with a significant reversal of optic disc cupping. Similarly, the use of antiglaucoma medications was also significantly reduced in number from 1.26 +/- 0.50 to 0.43 +/- 0.70. Most of the axial lengths of the eyes measured at the last follow-up visit showed growths within the average +/- 2 SDs in comparison with the healthy, age-matched population. After surgery, the qualified success rate was 90.77% at the end of the first year, 90.77% at the second year, 87.64% at the fifth year, 84.51% at the 10th year, and 81.38% at the 15th year. No serious intraoperative or postoperative complications were found. CONCLUSIONS: For Taiwanese children, the combined trabeculotomy-trabeculectomy using the modified Safer Surgery System offered an efficient and safe surgical option for treating glaucoma with long term satisfactory control of IOP. PMID- 29502234 TI - Concerns of anophthalmic patients-a comparison between cryolite glass and polymethyl methacrylate prosthetic eye wearers. AB - PURPOSE: To compare the concerns of experienced cryolite glass and (poly)methyl methacrylate (PMMA) prosthetic eye wearers. METHODS: One hundred six experienced cryolite glass and 63 experienced PMMA prosthetic eye wearers completed an anonymous questionnaire regarding general and specific prosthetic eye concerns at least 2 years after natural eye loss. From these independent anophthalmic populations, we identified 34 case-control pairs matched for the known influencing demographic variables of gender, occupation, age, and time since natural eye loss. RESULTS: The levels of concern were significantly lower in the cryolite glass group than those in the PMMA group for the following: loss of balance (p < 0.001), phantom sight vision (p < 0.001), pain (p < 0.001), receiving good advice (p = 0.001), fullness of orbit (p = 0.001), size (p = 0.007), direction of gaze relative to the healthy fellow eye (p = 0.005), eye lid contour (p = 0.037), comfort of the prosthetic eye (p < 0.001), colour relative to the healthy fellow eye (p < 0.001), and retention of the prosthetic eye (p < 0.001). Concerns about watering, crusting, discharge, visual perception, appearance, movement of the prosthetic eye, and health of the remaining eye were not significantly different between both groups. CONCLUSIONS: The results of this study showed that many general and specific levels of concern were significantly lower for cryolite glass prosthetic eye wearers than for PMMA prosthetic eye wearers. The question of why there are significant differences and to what extent the material of the prosthesis (cryolite glass or PMMA) has an impact on various concerns remains unanswered and should be addressed in a prospective comparative multicentre trial. PMID- 29502235 TI - Inhibition of integrin alpha5beta1 ameliorates VEGF-induced retinal neovascularization and leakage by suppressing NLRP3 inflammasome signaling in a mouse model. AB - PURPOSE: To assess the effect of inhibiting integrin alpha5beta1 by ATN-161 on vascular endothelial growth factor (VEGF)-induced neovascularization (NV) and leakage causing retinal detachment in adult Tet/opsin/VEGF transgenic mice, and characterize the underlying mechanism of its function. METHOD: Retinas from adult Tet/opsin/VEGF transgenic mice and human retinal endothelial cells (HRECs) exposed to VEGF (treated with ATN-161 or PBS) were used to carry out immunofluorescence, RT-PCR and western blot to examine expression levels of integrin alpha5beta1 and the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome. Retinal frozen section analysis was used to assess NV and leakage causing retinal detachment. RESULTS: In comparison to normal-treated mice, doxycycline-treated Tet/opsin/VEGF transgenic mice showed severe retinal detachment and higher integrin alpha5beta1 expression. Furthermore, the retinal detachment was inhibited significantly by ATN-161. Additionally, ATN-161 treatment was associated with a conspicuous reduction in NLRP3, apoptosis associated speck-like protein containing a CARD (ASC), cleaved caspase-1, and mature interleukin-1beta expression levels in the retinas of Tet/opsin/VEGF transgenic mice treated with doxycycline as well as in HRECs exposed to VEGF. CONCLUSION: ATN-161, an antagonist of integrin alpha5beta1, is a promising treatment for retinal neovascularization (RNV), and its retinal protection role appears to take effect through inhibition of NLRP3 inflammasome activity. PMID- 29502237 TI - Patient Preferences for Managing Insomnia: A Discrete Choice Experiment. AB - BACKGROUND: Despite the rapid development of effective treatments, both pharmacological and non-pharmacological, insomnia management remains suboptimal at the practice interface. Patient preferences play a critical role in influencing treatment outcomes. However, there is currently a mismatch between patient preferences and clinician recommendations, partly perpetuated by a limited understanding of the patients' decision-making process. OBJECTIVES: The aim of our study was to empirically quantify patient preferences for treatment attributes common to both pharmacological and non-pharmacological insomnia treatments. METHOD: An efficient dual-response discrete choice experiment was conducted to evaluate patient treatment preferences for managing insomnia. The sample included 205 patients with self-reported insomnia and an Insomnia Severity Index >= 14. Participants were presented with two unlabelled hypothetical scenarios with an opt-out option across 12 choice sets. Data were analyzed using a mixed multinomial logit model to investigate the influence of five attributes (i.e. time, onset of action, maintainability of improved sleep, length of treatment, and monthly cost) on treatment preferences. RESULTS: Treatments were preferentially viewed if they conferred long-term sleep benefits (p < 0.05); had an ongoing, as opposed to a predefined, duration of treatment course (p < 0.05); required some, as opposed to no, additional time commitment (p < 0.05); and had lower monthly out-of-pocket treatment costs (p < 0.001). However, treatment onset of action had no influence on preference. Age, help-seeking status, concession card status and fatigue severity significantly influenced treatment preference. CONCLUSION: Participants' prioritization of investing time in treatment and valuing the maintainability of therapeutic gains suggests a stronger inclination towards non-pharmacological treatment, defying current assumptions that patients prefer 'quick-fixes' for managing insomnia. PMID- 29502236 TI - A Review of Recent Advances Using Tocilizumab in the Treatment of Rheumatic Diseases. AB - Tocilizumab (TCZ) is the first humanized anti-interleukin-6 (IL-6) receptor monoclonal antibody approved for the treatment of patients with rheumatoid arthritis (RA), Castleman's disease, polyarticular and systemic juvenile idiopathic arthritis, and, most recently, giant cell arteritis as well as for the treatment of chimeric antigen receptor T cell therapy-induced cytokine release syndrome. The global clinical development program for TCZ provides a wealth of clinical data on intravenous TCZ, and more recent studies in patients with RA have provided evidence characterizing the role of intravenous TCZ as monotherapy in early disease and led to the introduction of a subcutaneous formulation of TCZ. In addition, recently published open-label extension and observational studies continue to support the long-term efficacy and safety of TCZ in both clinical trial and real-world settings. Given the involvement of IL-6-mediated signaling in inflammatory disorders, TCZ is also being investigated in other immunological diseases. In particular, a phase 2 trial on the safety and efficacy of subcutaneous TCZ in adults with systemic sclerosis shows clinically relevant improvements in skin sclerosis and lung function in these patients. Another anti IL-6 receptor agent, sarilumab, targeting the IL6 receptor alpha subunit, was recently approved for the treatment of patients with RA, although long-term data for this biologic are not yet published. In this article we review the placement of TCZ in current treatment guidelines; recent clinical trial data, including quality of life in patients with RA; recent updates to the TCZ safety profile; recent investigations of TCZ in other immunological diseases; and the clinical development of other novel IL-6-targeted agents. PMID- 29502238 TI - A Systematic Review of Community Health Workers' Role in Occupational Safety and Health Research. AB - We systematically reviewed the literature to describe how community health workers (CHWs) are involved in occupational health and safety research and to identify areas for future research and research practice strategies. We searched five electronic databases from July 2015 through July 2016. Inclusion criteria were as follows: (1) study took place in the United States, (2) published as a full peer-review manuscript in English, (3) conducted occupational health and safety research, and (4) CHWs were involved in the research. The majority of 17 included studies took place in the agriculture industry (76%). CHWs were often involved in study implementation/design and research participant contact. Rationale for CHW involvement in research was due to local connections/acceptance, existing knowledge/skills, communication ability, and access to participants. Barriers to CHW involvement in research included competing demands on CHWs, recruitment and training difficulties, problems about research rigor and issues with proper data collection. Involving CHWs in occupational health and safety research has potential for improving inclusion of diverse, vulnerable and geographically isolated populations. Further research is needed to assess the challenges and opportunities of involving CHWs in this research and to develop evidence-based training strategies to teach CHWs to be lay-health researchers. PMID- 29502239 TI - Feasibility of applying the LED-UV-induced TiO2/ZnO-supported H3PMo12O40 nanoparticles in photocatalytic degradation of aniline. AB - In the present study, TiO2/ZnO-supported phosphomolybdic acid nanoparticles are investigated by the impregnation method, followed by analyzing their photocatalytic activity under UV-LED light and degradation kinetics degrading aniline as an organic pollutant model. Nanoparticle characteristics and the remaining Keggin structure in the nanocomposites were confirmed by means of FESEM, FTIR, and XRD analyses. Heterogenization of phosphomolybdic acid on TiO2 and ZnO nanoparticles resulted in the improved light absorption intensity and decreased band gap of nanocomposites. Photocatalytic degradation of aniline was also improved for composite nanoparticles and reached to 25.62, 43.48, and 38.25% for TiO2/HPMo, ZnO/HPMo, and TiO2/ZnO/HPMo, respectively. Overall, the results showed a good fit to the Langmuir-Hinshelwood kinetic model. PMID- 29502240 TI - The role of charge-transfer states in the spectral tuning of antenna complexes of purple bacteria. AB - The LH2 antenna complexes of purple bacteria occur, depending on light conditions, in various different spectroscopic forms, with a similar structure but different absorption spectra. The differences are related to point changes in the primary amino acid sequence, but the molecular-level relationship between these changes and the resulting spectrum is still not well understood. We undertook a systematic quantum chemical analysis of all the main factors that contribute to the exciton structure, looking at how the environment modulates site energies and couplings in the B800-850 and B800-820 spectroscopic forms of LH2. A multiscale approach combining quantum chemistry and an atomistic classical embedding has been used where mutual polarization effects between the two parts are taken into account. We find that the loss of hydrogen bonds following amino acid changes can only explain a part of the observed blue-shift in the B850 band. The coupling of excitonic states to charge-transfer states, which is different in the two forms, contributes with a similar amount to the overall blue-shift. PMID- 29502242 TI - Smoking and bone mineral density: comprehensive analyses of the third National Health and Nutrition Examination Survey (NHANES III). AB - : Some questions remain on the relationship between smoking and bone health. Detailed analyses of the relationship between smoking and BMD are presented, essentially ruling out non-linear associations as an explanation for inconsistent results in the literature. INTRODUCTION: To provide comprehensive multiple regression and dose-response analyses of the association between smoking behavior variables and bone health as assessed by radiologically determined bone mineral density in NHANES III. METHODS: Analyzes of a representative cross-sectional survey of the noninstitutionalized population of the USA. Self-reported smoking behavior and bone mineral density of 14,510 participants were analyzed using survey design-based multiple linear regression modeling. Dose-response patterns were analyzed using restricted cubic spline regression. RESULTS: Femoral neck bone mineral density in current smokers was numerically lower than in never smokers, but this was not statistically significant after controlling for confounders. In former smokers, bone mineral density T scores were 0.064 units higher for every 10 years of abstinence, with little impact of confounder adjustment. Spline regression revealed no relevant non-linearity in the associations studied. CONCLUSIONS: Non-linearity is an unlikely explanation for inconsistent results in the literature on smoking and bone mineral density. Further and especially longitudinal studies of the complex relationship smoking with bone health would be particularly important given the still substantial prevalence of smoking in an aging global population. PMID- 29502241 TI - Evolutionary analysis of Porcine circovirus 3 (PCV3) indicates an ancient origin for its current strains and a worldwide dispersion. AB - Porcine circovirus 3 (PCV3) is an emerging virus that was identified in the United States in 2016. Since its first identification, PCV3 has been identified in Brazil, China, United States, Poland, and Republic of Korea. In this study, we used molecular phylogenetic analysis of available sequences to address questions surrounding the emergence of PCV3 in porcine world industry. Our data indicate that PCV3 did not emerge through recombination events among currently known circoviruses and that its speciation is not a recent evolutionary event. The most common recent ancestor analysis suggests that PCV3 lineages have emerged over the past 50 years. PCV3 is not genetically closely related with other Porcine circovirus and it has been evolving undetected for some time in swine and probably in bovine population. We also found groups of genetically related isolates of PCV3 originated from different countries that may be associated with dispersal routes, suggesting that PCV3 has already been circulating in pig producing countries for some time before its first detection. PMID- 29502243 TI - Thawed embryo transfer and ectopic pregnancy: a meta-analysis. AB - PURPOSE: To examine whether thawed embryo transfers can reduce the rate of EP. METHODS: The PubMed, EMBASE, Cochrane Library databases and two randomized controlled trials registration centers were thoroughly searched until March 2017. The clinical outcomes of IVF/ICSI cycles were compared between thawed and fresh embryo transfer. RESULTS: Twenty-one articles were included in this meta analysis. There were 801,464 pregnancies totally (thawed-ET: n = 158,967, fresh ET: n = 642,497). The ectopic pregnancy rate was significantly lower in the group of thawed-ET than that in the group of fresh-ET (OR 0.69, 95% CI 0.57-0.82; I2 = 83%). We subdivided the data into subgroups for D3 embryo transfer and D5 embryo transfer. We also found that the ectopic pregnancy rate was significantly lower with thawed-ET on D3 than that with fresh-ET (OR 0.67, 95% CI 0.53-0.85; I2 = 0%). The risk of ectopic pregnancy was significantly decreased with thawed-ET on D5 than that with fresh-ET (OR 0.57, 95% CI 0.50-0.64; I2 = 45%). CONCLUSION: Our results indicate that in contrast to fresh embryo transfers, thawed D3 or D5 embryo transfers can reduce the rate of EP. PMID- 29502244 TI - A rare case of hydrometrocolpos from persistent urogenital sinus in patient affected by adrenogenital syndrome. AB - Persistent urogenital sinus (PUGS) is a congenital pathological condition characterized by an abnormal communication between the urethra and vagina, which has an estimated incidence of 0.6/10,000 female births. It could be the only known malformation or part of a syndrome. PUGS is commonly shown by a pelvic mass, related to a distended bladder, hydrometrocolpos which is due to an obstruction leading to the dilation of the vagina and uterus (i.e., imperforate hymen, transverse vaginal septum or atresia, and PUGS) or both. We present a case of female patient with classical congenital adrenal hyperplasia, diagnosed on the 7th day of life, with ambiguous genitalia, untreated surgically only with hormone therapy by parental decision. The patient, at the age of 5 years and 5 months, came to our observation for a pelvic ultrasound, which revealed retrovesical neoformation with anechoic content and regular walls. We performed the ultrasound examination that showed the dilation of the cervix and the vaginal canal with anechoic finely corpuscolated content in the declining portion, compatible with hydrometrocolpos from probable persistence of the urogenital sinus. The voiding cystourethrography (VCUG) confirmed the ultrasound diagnosis, with evidence of urogenital sinus. In conclusion, ultrasound is the first diagnostic tool, but need to be completed by other technical procedures, which VCUG or magnetic resonance imaging to observe the site of fusion of the urinary and genital tract. PMID- 29502245 TI - Uncommon obstetric and gynecologic emergencies associated with pregnancy: ultrasound diagnosis. AB - INTRODUCTION: Many uncommon obstetric and gynecologic problems associated with pregnancy and the early postpartum period can lead to severe abdominal pain and be life-threatening. The patient will be in urgent need of a quick and accurate decision. The means of management will depend on the ability to differentiate between these problems to achieve an optimal diagnosis. MATERIALS AND METHODS: 30 pregnant females attended a private obstetric ultrasound clinic with clinical picture of acute abdomen with pregnancy. All were subjected to an ultrasound exam, the results were recorded, and the final diagnosis was reached based on the postoperative results. RESULTS: Patients were classified according to their duration of pregnancy into cases with acute abdomen that occurred during the first trimester, during the second trimester, during the third trimester, and in the early postpartum period. CONCLUSION: Ultrasonography is a valuable tool for detecting the etiology and guiding the management in cases of emergency situations faced by the obstetrician and gynecologist during pregnancy and the early postpartum period. PMID- 29502246 TI - On the response function and range dependence of manual estimation. AB - Manual estimates without vision of the hand are thought to constitute a form of cross-modal matching between stimulus size and finger opening. However, few investigations have systematically looked at how manual estimates relate a perceived size to the response across different ranges of stimuli. In two experiments (N = 18 and N = 14), we sought to map out the response properties for (1) manual estimates of visually presented stimuli as well as (2) visual estimates of proprioceptive stimuli, and to test whether these properties depend on the range of stimuli. We also looked at whether scalar variability is present in manual estimates, as predicted by Weber's Law for perceptual tasks. We found that manual estimates scale linearly and with a slope of close to 1 with object sizes up to 90 mm, before participants' hand size limited their responses. In contrast, we found a shallower response slope of about 0.7 when participants performed the inverse task, adjusting the size of a visual object to match a not actively chosen, induced finger opening. Our results were mixed with regards to scalar variability in large objects. We saw some indication of a plateau, but no evidence for an effect of mechanical constraints in the range studied (up to 90 mm). Participants also showed a clear tendency to overestimate small differences when a set of objects differed little in size, but not when stimulus differences were more pronounced. PMID- 29502247 TI - Vertical and sagittal combinations of concha bullosa media and paradoxical middle turbinate. AB - Common anatomic variants of the middle nasal turbinate include its pneumatization (i.e. concha bullosa media) and its paradoxical curvature. We report here two cases of differently combined variations of the middle turbinate which were documented in cone beam computed tomography (CBCT). The first report presents the vertical combination of a double or septated lamellar concha bullosa with the paradoxical curvature of middle turbinate. This combined variant associated (coincidental findings): ipsilateral paradoxical superior turbinate and contralateral paradoxical middle turbinate, concha bullosa superior and concha bullosa suprema. In the second case was found the sagittal combination of successive anterior concha bullosa media and posterior paradoxical curvature of the middle turbinate. An ethmoidal sinolith was found embedded in lamella basalis. The contralateral superior turbinate was pneumatized. These rare findings demonstrate that sound knowledge of possible anatomical variations, supported by a complete use of the tools available for the CBCT documentation of cases, is able to enrich the picture of human anatomic variations, with a direct impact on clinical and surgical practice. The septa-containing lamellar concha bullosa and paradoxical middle concha combination is a variation that affects surgical practice. PMID- 29502249 TI - Impact of Glutathione Peroxidase-1 (Gpx1) Genotype on Selenoenzyme and Transcript Expression When Repleting Selenium-Deficient Mice. AB - Glutathione peroxidase (Gpx1) is the major selenoprotein in most tissues in animals. Knockout (KO) of Gpx1 decreases Gpx1 activity to near zero and substantially reduces liver selenium (Se) levels, but has no overt effects in otherwise healthy mice. To investigate the impact of deletion of Gpx1 on Se metabolism, Se flux, and apparent Se requirements, KO, Gpx1 heterozygous (Het), and Gpx1 wild-type (WT) mice were fed Se-deficient diet for 17 weeks, then repleted with graded levels of Se (0-0.3 MUg Se/g as Na2SeO3) for 7 days, and selenoprotein activities and transcripts were determined in blood, liver, and kidney. Se deficiency decreased the activities of plasma Gpx3, liver Gpx1, liver Txnrd, and liver Gpx4 to 3, 0.3, 11, and 50% of WT Se-adequate levels, respectively, but the Gpx1 genotype had no effect on growth or changes in activity or expression of selenoproteins other than Gpx1. Se repletion increased selenoprotein transcripts to Se-adequate levels after 7 days; Se response curves and apparent Se requirements for selenoprotein transcripts were similar to those observed in studies starting with Se-adequate mice. With short-term Se repletion, selenoenzyme activities resulted in three Se response curve patterns: (1) liver and kidney Gpx1, Gpx4, and Txnrd activities were sigmoidal or hyperbolic with breakpoints (0.08-0.19 MUg Se/g) that were double those observed in studies starting with Se-adequate mice; (2) red blood cell Gpx1 activity was not significantly changed; and (3) plasma Gpx3 activity only increased substantially with 0.3 MUg Se/g. Plasma Gpx3 is secreted from kidney. In this short-term study, kidney Gpx3 mRNA reached plateau levels at 0.1 MUg Se/g, and other kidney selenoenzyme activities reached plateau levels at <= 0.2 MUg Se/g, so sufficient Se should have been present in kidney. Thus, the delayed increase in plasma Gpx3 activity suggests that newly synthesized and secreted kidney Gpx3 is preferentially retained in kidney or rapidly cleared by binding to basement membranes in kidney or in other tissues. This repletion study shows that loss of capacity to incorporate Se into Gpx1 in Gpx1 KO mice does not dramatically alter expression of other Se biomarkers, nor the short-term flux of Se from intestine to liver to kidney. PMID- 29502248 TI - Anaerobic biodegradation of partially hydrolyzed polyacrylamide in long-term methanogenic enrichment cultures from production water of oil reservoirs. AB - The increasing usage of partially hydrolyzed polyacrylamide (HPAM) in oilfields as a flooding agent to enhance oil recovery at so large quantities is an ecological hazard to the subsurface ecosystem due to persistence and inertness. Biodegradation of HPAM is a potentially promising strategy for dealing with this problem among many other methods available. To understand the responsible microorganisms and mechanism of HPAM biodegradation under anaerobic conditions, an enrichment culture from production waters of oil reservoirs were established with HPAM as the sole source of carbon and nitrogen incubated for over 328 days, and analyzed using both molecular microbiology and chemical characterization methods. Gel permeation chromatography, High-pressure liquid chromatography and Fourier-transformed infrared spectroscopy results indicated that, after 328 days of anaerobic incubation, some of the amide groups on HPAM were removed and released as ammonia/ammonium and carboxylic groups, while the carbon backbone of HPAM was converted to smaller polymeric fragments, including oligomers and various fatty acids. Based on these results, the biochemical process of anaerobic biodegradation of HPAM was proposed. The phylogenetic analysis of 16S rRNA gene sequences retrieved from the enrichments showed that Proteobacteria and Planctomycetes were the dominant bacteria in the culture with HPAM as the source of carbon and nitrogen, respectively. For archaea, Methanofollis was more abundant in the anaerobic enrichment. These results are helpful for understanding the process of HPAM biodegradation and provide significant insights to the fate of HPAM in subsurface environment and for possible bioremediation. PMID- 29502250 TI - Developmental Neurotoxicity of Arsenic: Involvement of Oxidative Stress and Mitochondrial Functions. AB - Over the last decade, there has been an increased concern about the health risks from exposure to arsenic at low doses, because of their neurotoxic effects on the developing brain. The exact mechanism underlying arsenic-induced neurotoxicity during sensitive periods of brain development remains unclear, although enhanced oxidative stresses, leading to mitochondrial dysfunctions might be involved. Here, we highlight the generation of reactive oxygen species (ROS) and oxidative stress which leads to mitochondrial dysfunctions and apoptosis in arsenic-induced developmental neurotoxicity. Here, the administration of sodium arsenite at doses of 2 or 4 mg/kg body weight in female rats from gestational to lactational (GD6 PD21) resulted to increased ROS, led to oxidative stress, and increased the apoptosis in the frontal cortex, hippocampus, and corpus striatum of developing rats on PD22, compared to controls. Enhanced levels of ROS were associated with decreased mitochondrial membrane potential and the activity of mitochondrial complexes, and hampered antioxidant levels. Further, neuronal apoptosis, as measured by changes in the expression of pro-apoptotic (Bax, Caspase-3), anti apoptotic (Bcl2), and stress marker proteins (p-p38, pJNK) in arsenic-exposed rats, was discussed. The severities of changes were found to more persist in the corpus striatum than in other brain regions of arsenic-exposed rats even after the withdrawal of exposure on PD45 as compared to controls. Therefore, our results indicate that perinatal arsenic exposure leads to abrupt changes in ROS, oxidative stress, and mitochondrial functions and that apoptotic factor in different brain regions of rats might contribute to this arsenic-induced developmental neurotoxicity. PMID- 29502251 TI - Serum Concentrations of 15 Elements Among Helicobacter Pylori-Infected Residents from Lujiang County with High Gastric Cancer Risk in Eastern China. AB - Helicobacter pylori (H. pylori) infection can interfere with the absorption of most elements, and the variations of some element levels are related to the incidence of gastric cancer. However, there have been conflicting results concerning the influence of H. pylori infection on serum element levels. The present study aimed to compare the serum element concentrations of H. pylori infected local residents with uninfected residents from Lujiang County with high gastric cancer risk in Eastern China. We used data and serum samples from the H. pylori screening-survey program which was a cross-sectional study. We took 155 samples randomly from the screening survey, identified 74 H. pylori-positive residents and 81 H. pylori-negative residents by a serological test. The serum concentrations of 15 elements (calcium, magnesium, iron, zinc, selenium, copper, molybdenum, chromium, cobalt, nickel, lead, cadmium, mercury, arsenic, and aluminum) were determined using inductively coupled plasma mass spectrometry. Serum cobalt was found at higher levels in the H. pylori-infected residents than the H. pylori-uninfected residents (0.246 vs 0.205 MUg/L, P = 0.022), but no statistically significant differences in the serum levels of other elements were found. This is the first study to report the serum concentrations of 15 elements and their relationships with the infection status of H. pylori among local residents from Lujiang County with high gastric cancer risk. Although the International Agency for Research on Cancer has classified cobalt and other soluble cobalt salts as possibly carcinogenic to human beings, our results may provide a clue to the relationships between cobalt, H. pylori, and gastric cancer. PMID- 29502253 TI - Eye-tracking and speech-generating technology to improve communication with intubated intensive care unit patients: initial experience. PMID- 29502252 TI - Assessment of ozone toxicity among 14 Indian wheat cultivars under field conditions: growth and productivity. AB - Tropospheric ozone (O3) is a well-known threat to global agricultural production. Wheat (Triticum aestivum L.) is the second most important staple crop in India, although little is known about intra-specific variability of Indian wheat cultivars in terms of their sensitivity against O3. In this study, 14 wheat cultivars widely grown in India were exposed to 30 ppb elevated O3 above ambient level using open top chambers to evaluate their response against O3 stress. Different growth and physiological parameters, foliar injury and grain yield were evaluated to assess the sensitivity of cultivars and classified them on the basis of their cumulative stress response index (CSRI). Due to elevated O3, growth parameters, plant biomass, and photosynthetic rates were negatively affected, whereas variable reductions in yield were observed among the test cultivars. Based on CSRI values, HD 2987, DBW 50, DBW 77, and PBW 550 were classified as O3 sensitive; HD 2967, NIAW 34, HD 3059, PBW 502, HUW 213, and HUW 251 as intermediately sensitive, while HUW12, KUNDAN, HUW 55, and KHARCHIYA 65 were found to be O3-tolerant cultivars. Cultivars released after year 2000 were found to be more sensitive compared to earlier released cultivars. Path analysis approach showed that leaf area, plant biomass, stomatal conductance, net assimilation rate, and absolute growth rate were the most important variables influencing yield under O3 stress. Findings of the current study highlight the importance of assessing differential sensitivity and tolerance of wheat cultivars and response of different traits in developing resistance against elevated O3. PMID- 29502254 TI - Organization model for allotransplantations of cryopreserved vascular grafts in Czech Republic. AB - The transplantation of fresh or cryopreserved vascular allografts in patients with a prosthetic graft infection or critical limb ischemia is necessary for their limb salvage and, in many cases, represents a lifesaving procedure. While transplantation of fresh allografts has a long history in the Czech Republic, the standard use of cryopreserved vascular allografts was introduced into the clinical practice in 2011 as a result of the implementation of EU Directive 2004/23/EC into national legislation (Human Cell and Tissue Act No. 296/2008 Coll.). The authors present an organizational model based on cooperation between the majority of Czech Transplant Centers with a tissue establishment licensed by the national competent authority. In various points, we are addressing individual aspects of experimental and clinical studies which affect clinical practice. Based on experimental and clinical work, the first validation of cryopreserved arterial and venous grafts for clinical use was performed between 2011 and 2013. The growing number of centers participating in this programme led to a growing number of patients who underwent transplantation of vascular allografts. In 2015 the numbers of transplanted fresh versus cryopreserved allografts in the Czech Republic were almost equal. Cooperation of the participating centers in the Czech Republic with the licensed Tissue Establishment made it possible to achieve a full compliance with the European Union Directives, and harmonized national legal norms and assured a high quality of cryopreserved vascular allografts. PMID- 29502256 TI - Genetic ancestry of families of putative Inka descent. AB - This study focuses on the descendants of the royal Inka family. The Inkas ruled Tawantinsuyu, the largest pre-Columbian empire in South America, which extended from southern Colombia to central Chile. The origin of the royal Inkas is currently unknown. While the mummies of the Inka rulers could have been informative, most were destroyed by Spaniards and the few remaining disappeared without a trace. Moreover, no genetic studies have been conducted on present-day descendants of the Inka rulers. In the present study, we analysed uniparental DNA markers in 18 individuals predominantly from the districts of San Sebastian and San Jeronimo in Cusco (Peru), who belong to 12 families of putative patrilineal descent of Inka rulers, according to documented registries. We used single nucleotide polymorphisms and short tandem repeat (STR) markers of the Y chromosome (Y-STRs), as well as mitochondrial DNA D-loop sequences, to investigate the paternal and maternal descent of the 18 alleged Inka descendants. Two Q-M3* Y-STR clusters descending from different male founders were identified. The first cluster, named AWKI-1, was associated with five families (eight individuals). By contrast, the second cluster, named AWKI-2, was represented by a single individual; AWKI-2 was part of the Q-Z19483 sub-lineage that was likely associated with a recent male expansion in the Andes, which probably occurred during the Late Intermediate Period (1000-1450 AD), overlapping the Inka period. Concerning the maternal descent, different mtDNA lineages associated with each family were identified, suggesting a high maternal gene flow among Andean populations, probably due to changes in the last 1000 years. PMID- 29502255 TI - Pathophysiology of dyskinesia and behavioral disorders in non-human primates: the role of serotonergic fibers. AB - The MPTP monkey model of Parkinson's disease (PD) has allowed huge advances regarding the understanding of the pathological mechanisms of PD and L-DOPA induced adverse effects. Among the main findings were the imbalance between the efferent striatal pathways in opposite directions between the hypokinetic and hyperkinetic states of PD. In both normal and parkinsonian monkeys, the combination of behavioral and anatomical studies has allowed the deciphering of the cortico-basal ganglia circuits involved in both movement and behavioral disorders. A major breakthrough has then been made regarding the hypothesis of the involvement of serotonergic fibers in the conversion of L-DOPA to dopamine when dopaminergic neurons are dying and to release it, in an uncontrolled manner, as serotonergic neurons are deprived from the machinery required for buffering dopamine from the synaptic cleft. The crucial involvement of serotonergic fibers underlying L-DOPA-induced dyskinesia (LID) has been demonstrated in both rodent and monkey models of PD, in which dyskinesia induced by L-DOPA is abolished following lesion of the serotonergic system. Moreover, the role of serotonergic fibers goes well beyond dyskinesia, as lesioning of such serotonergic fibers by MDMA in the monkey also decreased other L-DOPA-induced adverse effects such as impulsive compulsive behaviors and visual hallucinations. The same pathological mechanism, i.e., an imbalance between serotonin and dopamine terminals may, therefore, favor L-DOPA-induced adverse effects according to the basal ganglia territory it inhabits. Further non-human primate studies will be needed to demonstrate the role of such a pathological mechanism in both movement and behavioral disorders driven by L-DOPA therapy but also to determine the causal link between serotonin lesions and the expression of non-motor symptoms like apathy, depression and anxiety, frequently observed in PD patients. PMID- 29502257 TI - Whole genome analysis of six organophosphate-degrading rhizobacteria reveals putative agrochemical degradation enzymes with broad substrate specificity. AB - Six organophosphate-degrading bacterial strains collected from farm and ranch soil rhizospheres across the Houston-metropolitan area were identified as strains of Pseudomonas putida (CBF10-2), Pseudomonas stutzeri (ODKF13), Ochrobactrum anthropi (FRAF13), Stenotrophomonas maltophilia (CBF10-1), Achromobacter xylosoxidans (ADAF13), and Rhizobium radiobacter (GHKF11). Whole genome sequencing data was assessed for relevant genes, proteins, and pathways involved in the breakdown of agrochemicals. For comparative purposes, this analysis was expanded to also include data from deposited strains in the National Center for Biotechnology Information's (NCBI) database. This study revealed Zn-dependent metallo-beta-lactamase (MBL)-fold proteins similar to OPHC2 first identified in P. pseudoalcaligenes as the likely agents of organophosphate (OP) hydrolysis in A. xylosoxidans ADAF13, S. maltophilia CBF10-1, O. anthropi FRAF13, and R. radiobacter GHKF11. A search of similar proteins within NCBI identified over 200 hits for bacterial genera and species with a similar OPHC2 domain. Taken together, we conclude from this data that intrinsic low-level OP hydrolytic activity is likely prevalent across the rhizosphere stemming from widespread OPHC2-like metalloenzymes. In addition, P. stutzeri ODKF13, P. putida CBF10-2, O. anthropi FRAF13, and R. radiobacter GHKF11 were found to harbor glycine oxidase (GO) enzymes that putatively possess low-level activity against the herbicide glyphosate. These bacterial GOs are reported to catalyze the degradation of glyphosate to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and suggest a possible link to AMPA that can be found in glyphosate-contaminated agricultural soil. The presence of aromatic degradation proteins were also detected in five of six study strains, but are attributed primarily to components of the widely distributed beta-ketoadipate pathway found in many soil bacteria. PMID- 29502258 TI - Past, current, and future research on microalga-derived biodiesel: a critical review and bibliometric analysis. AB - Microalga-derived biodiesel plays a crucial role in the sustainable development of biodiesel in recent years. Literature related to microalga-derived biodiesel had an increasing trend with the expanding research outputs. Based on the Science Citation Index Expanded (SCI-Expanded) of the Web of Science, a bibliometric analysis was conducted to characterize the body of knowledge on microalga-derived biodiesel between 1993 and 2016. From the 30 most frequently used author keywords, the following research hotspots are extracted: lipid preparation from different microalga species, microalga-derived lipid and environmental applications, lipid-producing microalgae cultivation, microalgae growth reactor, and microalga harvest and lipid extraction. Other keywords, i.e., microalga mixotrophic cultivation, symbiotic system between microalga and other oleaginous yeast, microalga genetic engineering, and other applications of lipid-producing microalga are future focal points of research. Graphical abstract. PMID- 29502259 TI - Plant-associated bacteria mitigate drought stress in soybean. AB - Agriculture accounts for ~ 70% of all water use and the world population is increasing annually; soon more people will need to be fed, while also using less water. The use of plant-associated bacteria (PAB) is an eco-friendly alternative that can increase crop water use efficiency. This work aimed to study the effect of some PAB on increasing soybean tolerance to drought stress, the mechanisms of the drought tolerance process, and the effect of the PAB on promoting plant growth and on the biocontrol of Sclerotinia sclerotiorum. PAB were isolated from soybean rhizosphere and S. sclerotiorum sclerotia. The strains identified as UFGS1 (Bacillus subtilis), UFGS2 (Bacillus thuringiensis), UFGRB2 and UFGRB3 (Bacillus cereus) were selected on their ability to grow in media with reduced water activity. Soybean plants were inoculated with the PAB and evaluated for growth promotion, physiological and molecular parameters, after drought stress. Under drought stress, UFGS2 and UFGRB2 sustained potential quantum efficiency of PSII (Fv/Fm), while a decrease was found in the control plants. Moreover, UFGS2 and UFGRB3 maintained the photosynthetic rates in non-stressed conditions compared to the control. UFGS2-treated plants showed a higher stomatal conductance and higher transpiration than the control, after drought stress. Some PAB-treated plants also had other beneficial phenotypes, such as increases in fresh and dried biomass relative to the control. Differential gene expression analysis of genes involved in plant stress pathways shows changes in expression in PAB-treated plants. Results from this study suggest that PAB can mitigate drought stress in soybean and may improve water efficiency under certain conditions. PMID- 29502260 TI - Assessing resident awareness on e-waste management in Bangalore, India: a preliminary case study. AB - The generation of e-waste has increased significantly in India, and the informal recycling of e-waste has adverse effects on environment and public health. In this article, the E-waste management is evaluated in accordance from the resident's awareness perspective in Bangalore city, India. The survey data revealed that about 58% male and 42% female responded and 35% of the participants belong to age range between 18 and 25 years. About 60% of respondent's education level was either graduate or post graduate, 27% high school to higher school, 10% higher educated (> post graduate), and 3% primary to middle. Only 30% of the respondents were confident with e-waste rules and regulation, while 39% of the respondents were of very little information. Indian e-waste management has been improving for the last few years and it continues to develop. Therefore, the findings can be valuable for better understanding the resident's awareness for e waste management and also need to promote the environmentally sound management of e-waste in Bangalore, India. PMID- 29502261 TI - Heavy metals in soils and sediments from Dongting Lake in China: occurrence, sources, and spatial distribution by multivariate statistical analysis. AB - Heavy metal contamination in soils/sediments and its impact on human health and ecological environment have aroused wide concerns. Our study investigated 30 samples of soils and sediments around Dongting Lake to analyze the concentration of As, Cd, Cr, Cu, Fe, Mn, Ni, Pb, and Zn in the samples and to distinguish the natural and anthropogenic sources. Also, the relationship between heavy metals and the physicochemical properties of samples was studied by multivariate statistical analysis. Concentration of Cd at most sampling sites were more than five times that of national environmental quality standard for soil in China (GB 15618-1995), and Pb and Zn levels exceeded one to two times. Moreover, Cr in the soil was higher than the national environmental quality standards for one to two times while in sediment was lower than the national standard. The investigation revealed that the accumulations of As, Cd, Mn, and Pb in the soils, and sediments were affected apparently by anthropogenic activities; however, Cr, Fe, and Ni levels were impacted by parent materials. Human activities around Dongting Lake mainly consisted of industrial activities, mining and smelting, sewage discharges, fossil fuel combustion, and agricultural chemicals. The spatial distribution of heavy metal in soil followed the rule of geographical gradient, whereas in sediments, it was significantly affected by the river basins and human activities. The result of principal component analysis (PCA) demonstrated that heavy metals in soils were associated with pH and total phosphorus (TP), while in sediments, As, Cr, Fe, and Ni were closely associated with cation exchange capacity (CEC) and pH, where Pb, Zn, and Cd were associated with total nitrogen (TN), TP, total carbon (TC), moisture content (MC), soil organic matter (SOM), and ignition lost (IL). Our research provides comprehensive approaches to better understand the potential sources and the fate of contaminants in lakeshore soils and sediments. PMID- 29502262 TI - Ascidiaceibacter salegens gen. nov., sp. nov., isolated from an ascidian. AB - An aerobic, Gram-stain negative, rod-shaped, non-motile bacterium, designated as strain HQA918T, was isolated from an ascidian, Botryllus schlosseri, which was collected from the coast of Weihai in the north of the Yellow Sea, in China. The strain grew optimally at 28-30 degrees C, at pH values 7.0-8.0, and in the presence of 1.0-3.0% (w/v) sodium chloride (NaCl). A phylogenetic analysis based on 16S rRNA gene sequences showed that strain HQA918T can be affiliated with the family Flavobacteriaceae in the phylum Bacteroidetes, with 92.7% similarity to its close relatives. The major fatty acids identified were iso-C15:0, iso-C15:0 3 OH, and summed feature 3 (iso-C15:0 2-OH and/or C16:1omega7c). The major polar lipids were phosphatidylethanolamine, one unidentified aminolipid, and five unidentified polar lipids. The G+C content of the genomic DNA was 44.1 mol%. On the basis of the phylogenetic, genotypic, phenotypic, and chemotaxonomic data, this organism should be classified as a representative of a novel genus, for which the name Ascidiaceibacter gen. nov. is proposed. The type species is Ascidiaceibacter salegens sp. nov. (type strain HQA918T = KCTC 52719T = MCCC 1K03259T). PMID- 29502263 TI - Ventilatory responses of the clown knifefish, Chitala ornata, to hypercarbia and hypercapnia. AB - The aim of the present study was to determine the roles of externally versus internally oriented CO2/H+-sensitive chemoreceptors in promoting cardiorespiratory responses to environmental hypercarbia in the facultative air breathing fish, Chitala ornata (the clown knifefish). Fish were exposed to environmental acidosis (pH ~ 6.0) or hypercarbia (~ 30 torr PCO2) that produced changes in water pH equal to the pH levels of the acidotic water to distinguish the relative roles of CO2 versus H+. We also injected acetazolamide to elevate arterial levels of PCO2 and [H+] in fish in normocarbic water to distinguish between internal and external stimuli. We measured changes in gill ventilation frequency, air breathing frequency, heart rate and arterial blood pressure in response to each treatment as well as the changes produced in arterial PCO2 and pH. Exposure to normocarbic water of pH 6.0 for 1 h did not produce significant changes in any measured variable. Exposure to hypercarbic water dramatically increased air breathing frequency, but had no effect on gill ventilation. Hypercarbia also produced a modest bradycardia and fall in arterial blood pressure. Injection of acetazolamide produced similar effects. Both hypercarbia and acetazolamide led to increases in arterial PCO2 and falls in arterial pH although the changes in arterial PCO2/pH were more modest following acetazolamide injection as were the increases in air breathing frequency. The acetazolamide results suggest that the stimulation of air breathing was due, at least in part, to stimulation of internally oriented CO2/H+ chemoreceptors monitoring blood gas changes. PMID- 29502264 TI - Pulmonary hemodynamics responses to hypoxia and/or CO2 inhalation during moderate exercise in humans. AB - In this study, we hypothesized that adding CO2 to an inhaled hypoxic gas mixture will limit the rise of pulmonary artery pressure (PAP) induced by a moderate exercise. Eight 20-year-old males performed four constant-load exercise tests on cycle at 40% of maximal oxygen consumption in four conditions: ambient air, normobaric hypoxia (12.5% O2), inhaled CO2 (4.5% CO2), and combination of hypoxia and inhaled CO2. Doppler echocardiography was used to measure systolic (s)PAP, cardiac output (CO). Total pulmonary resistance (TPR) was calculated. Arterialized blood pH was 7.40 at exercise in ambient and hypoxia conditions, whereas CO2 inhalation and combined conditions showed acidosis. sPAP increases from rest in ambient air to exercise ranged as follows: ambient + 110%, CO2 inhalation + 135%, combined + 184%, hypoxia + 217% (p < 0.001). CO was higher when inhaling O2-poor gas mixtures with or without CO2 (~ 17 L min-1) than in the other conditions (~ 14 L min-1, p < 0.001). Exercise induced a significant decrease in TPR in the four conditions (p < 0.05) but less marked in hypoxia (- 19% of the resting value in ambient air) than in ambient (- 33%) and in both CO2 inhalation and combined condition (- 29%). We conclude that (1) acute CO2 inhalation did not significantly modify pulmonary hemodynamics during moderate exercise. (2) CO2 adjunction to hypoxic gas mixture did not modify CO, despite a higher CaO2 in combined condition than in hypoxia. (3) TPR was lower in combined than in hypoxia condition, limiting sPAP increase in combined condition. PMID- 29502265 TI - Aquaporin1 regulates development, secondary metabolism and stress responses in Fusarium graminearum. AB - The Ascomycete fungus Fusarium graminearum, the causal agent of Fusarium head blight of wheat and barley, has become a predominant model organism for the study of fungal phytopathogens. Aquaporins (AQPs) have been implicated in the transport of water, glycerol, and a variety of other small molecules in yeast, plants and animals. However, the role of these proteins in phytopathogenic fungi is not well understood. Here, we identified and attempted to elucidate the function of the five aquaporin genes in F. graminearum. The phylogenetic analysis revealed that FgAQPs are divided into two clades, with FgAQP1 in the first clade. The ?AQP1 mutant formed whitish colonies with longer aerial hyphae and reduced conidiation and perithecium formation. The ?AQP1 mutant conidia were morphologically abnormal and appeared to undergo abnormal germination. The ?AQP1 mutant and the wild type strain were equally pathogenic, while the mutant produced significantly higher quantities of deoxynivalenol (DON). The ?AQP1 mutant also exhibited increased resistance to osmotic and oxidative stress as well as cell-wall perturbing agents. Using FgAQP1-GFP and DAPI staining, we found that FgAQP1 is localized to the nuclear membrane in conidia. Importantly, deletion of FgAQP1 increased the severity of conidium autophagy. Taken together, these results suggest that FgAQP1 is involved in hyphal development, stress responses, secondary metabolism, and sexual and asexual reproduction in F. graminearum. Unlike the ?AQP1 mutant, the ?AQP2, ?AQP3, ?AQP4 and ?AQP5 mutants had no variable phenotypes. PMID- 29502266 TI - Loss of angiopoietin-like 4 (ANGPTL4) in mice with diet-induced obesity uncouples visceral obesity from glucose intolerance partly via the gut microbiota. AB - AIMS/HYPOTHESIS: Angiopoietin-like 4 (ANGPTL4) is an important regulator of triacylglycerol metabolism, carrying out this role by inhibiting the enzymes lipoprotein lipase and pancreatic lipase. ANGPTL4 is a potential target for ameliorating cardiometabolic diseases. Although ANGPTL4 has been implicated in obesity, the study of the direct role of ANGPTL4 in diet-induced obesity and related metabolic dysfunction is hampered by the massive acute-phase response and development of lethal chylous ascites and peritonitis in Angptl4-/- mice fed a standard high-fat diet. The aim of this study was to better characterise the role of ANGPTL4 in glucose homeostasis and metabolic dysfunction during obesity. METHODS: We chronically fed wild-type (WT) and Angptl4-/- mice a diet rich in unsaturated fatty acids and cholesterol, combined with fructose in drinking water, and studied metabolic function. The role of the gut microbiota was investigated by orally administering a mixture of antibiotics (ampicillin, neomycin, metronidazole). Glucose homeostasis was assessed via i.p. glucose and insulin tolerance tests. RESULTS: Mice lacking ANGPTL4 displayed an increase in body weight gain, visceral adipose tissue mass, visceral adipose tissue lipoprotein lipase activity and visceral adipose tissue inflammation compared with WT mice. However, they also unexpectedly had markedly improved glucose tolerance, which was accompanied by elevated insulin levels. Loss of ANGPTL4 did not affect glucose-stimulated insulin secretion in isolated pancreatic islets. Since the gut microbiota have been suggested to influence insulin secretion, and because ANGPTL4 has been proposed to link the gut microbiota to host metabolism, we hypothesised a potential role of the gut microbiota. Gut microbiota composition was significantly different between Angptl4-/- mice and WT mice. Interestingly, suppression of the gut microbiota using antibiotics largely abolished the differences in glucose tolerance and insulin levels between WT and Angptl4-/- mice. CONCLUSIONS/INTERPRETATION: Despite increasing visceral fat mass, inactivation of ANGPTL4 improves glucose tolerance, at least partly via a gut microbiota-dependent mechanism. PMID- 29502267 TI - Can insulin response patterns predict metabolic disease risk in individuals with normal glucose tolerance? Reply to Crofts CAP, Brookler K, Henderson G [letter]. PMID- 29502268 TI - Holmes tremor with impairment of the Guillain-Mollaret triangle following medullar hemorrhage. PMID- 29502269 TI - The IL-10-producing regulatory B cells (B10 cells) and regulatory T cell subsets in neuromyelitis optica spectrum disorder. PMID- 29502270 TI - Cervical disc herniation as a rare cause of intracranial hypotension: a case report. PMID- 29502271 TI - A positive conversion in hormone receptor and HER2 status might have an impact on survival after liver resection for breast cancer metastases. PMID- 29502272 TI - Shock wave lithotripsy or retrograde intrarenal surgery: which one is more effective for 10-20-mm renal stones in children. AB - OBJECTIVES: To compare shock wave lithotripsy and flexible ureteroscopy in children with renal stone's diameter of 10 to 20 mm. MATERIALS AND METHODS: This is a retrospective study including 79 children, who had renal stone and underwent either shock wave lithotripsy or flexible ureteroscopy between January 2007 and June 2017. Of those, 38 patients underwent shock wave lithotripsy assigned as group 1 and 41 patients underwent flexible ureteroscopy assigned as group 2. Stone-free rate, fluoroscopy time, procedure time, complication rates, hospitalization time, and cost-effectiveness were monitored and included in the analyses. RESULTS: The mean patient age was 4.4 +/- 3.5 in group 1 and 4.9 +/- 4.1 in group 2. Stone-free rate was not different in both groups in the first and third months of follow-up. The mean fluoroscopy time was statistically significantly longer in group 1 compared to group 2. Procedure and hospitalization times were longer in group 2 compared to group 1. No complications were seen in either groups. The expenditure was calculated as 135.23 and 869.41 Euro per patient for groups 1 and 2, respectively, which shows significant higher cost in group 2. CONCLUSIONS: In this present study, we have shown that shock wave lithotripsy is cheaper, has short hospitalization time and long fluoroscopy time and similar stone-free rate, and has the same efficiency compared to flexible ureteroscopy regarding pediatric renal stones with the diameter between 10 and 20 mm. PMID- 29502273 TI - The acute effects of cocoa flavanols on temporal and spatial attention. AB - In this study, we investigated how the acute physiological effects of cocoa flavanols might result in specific cognitive changes, in particular in temporal and spatial attention. To this end, we pre-registered and implemented a randomized, double-blind, placebo- and baseline-controlled crossover design. A sample of 48 university students participated in the study and each of them completed the experimental tasks in four conditions (baseline, placebo, low dose, and high-dose flavanol), administered in separate sessions with a 1-week washout interval. A rapid serial visual presentation task was used to test flavanol effects on temporal attention and integration, and a visual search task was similarly employed to investigate spatial attention. Results indicated that cocoa flavanols improved visual search efficiency, reflected by reduced reaction time. However, cocoa flavanols did not facilitate temporal attention nor integration, suggesting that flavanols may affect some aspects of attention, but not others. Potential underlying mechanisms are discussed. PMID- 29502274 TI - The treatment of cognitive dysfunction in dementia: a multiple treatments meta analysis. AB - OBJECTIVE: No cure is currently available for dementia; however, various treatments and interventions have been reported to be effective. The factors influencing the efficacy of dementia treatment have not been comprehensively evaluated. This study evaluated the factors influencing treatment effects on cognitive dysfunction in dementia by comparing the results obtained from a meta analysis based on meta-regression. METHODS: We searched for articles, clinical trials, and meta-analyses on the efficacy of pharmacotherapy or psychosocial treatment for dementia published between 2000 and 2016 in the MEDLINE/PubMed, Cochrane Library, SCOPUS, and Airiti Library databases. RESULTS: The 235 selected studies involved 44,854 patients with dementia (mainly vascular dementia, Alzheimer disease, and mild cognitive impairment). A preliminary random effects meta-analysis yielded a positive overall effect. The pooled standardized mean difference of the treatment effects on cognitive dysfunction was 0.439 (95% confidence interval 0.374, 0.504). The results of meta-regression showed that in young patients (beta = - 0.036, p value < 0.001) with vascular dementia (beta = 0.603, p value < 0.001), the efficacies of treatment 2 (symptomatic treatment for vascular dementia with piracetam, nimodipine, aniracetam, flunarizine, vinpocetine, hyperbaric oxygen, oxiracetam, or EGB761) and treatment 5 (treatment with other alternative therapies including acupuncture, premarin, statin, butylphthalide soft capsules, donepezil, huperzine A, and lithium treatment) were higher than those of other existing treatments for cognitive dysfunction (beta = 0.308 and 0.321, p values = 0.010 and < 0.001, respectively). CONCLUSION: The most effective intervention for dementia available is symptomatic treatment for vascular dementia. Antipsychotic treatment for dementia alleviates cognitive dysfunction less effectively than does symptomatic treatment. Alternative therapies are also effective at present. Further research on causes and very early diagnosis of Alzheimer disease is warranted. PMID- 29502275 TI - 5-HT6 receptor agonist and antagonist modulates ICV-STZ-induced memory impairment in rats. AB - RATIONALE AND OBJECTIVES: 5-HT6 receptors are mainly expressed in brain areas associated with learning and memory. Several studies have reported procognitive effects of both 5-HT6 agonist and antagonists. However, the exact mechanism 5-HT6 receptor modulation has not been properly studied especially in the context of cholinergic functions, cerebral blood flow (CBF), brain-derived neural factor (BDNF), oxidative stress, and behavioral changes. METHODS: In the present study, memory impairment was induced in albino Wistar rats by two doses of intracerebroventricular (ICV) injection of streptozotocin (STZ, 3 mg/kg) on first and third day. These rats were evaluated in a battery of behavioral tasks after 14 days from the first day of ICV-STZ. RESULTS: Significant memory impairment was seen when ICV-STZ induced rats are assessed by Morris water maze, novel object recognition, social recognition, and passive avoidance tests. There was a significant reduction in CBF, increased oxidative stress (MDA, GSH, and ROS), acetylcholinesterase (AChE) activity, and a decrease in BDNF. Treatment with selective 5-HT6 agonist EMD-386088 (5 mg/kg) and antagonist SB-399885 (10 mg/kg) prevented ICV-STZ-induced memory impairment when assessed by behavioral tests. Treatment with 5-HT6 ligands significantly prevented the change in CBF and BDNF. Further, protected from MDA and ROS and decreasing GSH in the brain compared to ICV-STZ rats. The rice in brain AChE activity was normalized by both ligands. The changes in locomotor activity by EMD-386088 and SB-399885 treatment were negligible. CONCLUSION: The findings in this study support the therapeutic potential of 5-HT6 receptor ligands in the treatment of cognitive dysfunction. PMID- 29502277 TI - Ab initio scrutiny of endohedral C20 fullerenes implanted in between gold electrodes. AB - Using the smallest non-classical fullerene, we investigate the impact of endohedral fullerene molecules on the quantum transport through molecular junctions, and then compared this with the pure C20-based molecular junction. By employing the density functional theory combined with the non-equilibrium Green's function, we contemplated different electronic parameters, namely, density of states, transmission coefficient, energy levels, molecular orbitals, conduction gaps, electron density and their charge transfer. A knowledge of these physical parameters is necessary in order to calculate current and conductance computed using Landauer-Buttiker formalism. The molecule-electrode coupling influenced by endohedral molecules affects junction devices in a unique manner. We observe that the highest quantum transport is possible in an Au-N@C20-Au and Au-O@C20-Au junction device, and is even higher than that of the intrinsic C20 fullerene junction. Another notable observation is that the F@C20 molecule exhibits the least conducting nature, being even lower than that of the endohedral molecule formed by inserting the noble element, neon. Graphical abstract Electrical characteristics of Endohedral fullerene junctions. PMID- 29502276 TI - Mining the nucleus accumbens proteome for novel targets of alcohol self administration in male C57BL/6J mice. AB - RATIONALE: There is a clear need for discovery of effective medications to treat behavioral pathologies associated with alcohol addiction, such as chronic drinking. OBJECTIVE: The goal of this preclinical study was to assess effects of chronic alcohol drinking on the nucleus accumbens (NAcb) proteome to identify and validate novel targets for medications development. MATERIALS AND METHODS: Two dimensional difference in-gel electrophoresis (2D-DIGE) with matrix-assisted laser desorption ionization tandem time-of-flight (MALDI-TOF/TOF) was used to assess effects of chronic voluntary home-cage (24-h access) alcohol drinking on the NAcb proteome of C57BL/6J mice. To extend these findings to a model of alcohol self-administration and reinforcement, we investigated potential regulation of the positive reinforcing effects of alcohol by the target protein glutathione S-transferase Pi 1 (GSTP1) using a pharmacological inhibition strategy in mice trained to self-administer alcohol or sucrose. RESULTS: Expression of 52 unique proteins in the NAcb was changed by chronic alcohol drinking relative to water control (23 upregulated, 29 downregulated). Ingenuity Pathway Analysis showed that alcohol drinking altered an array of protein networks associated with neurological and psychological disorders, molecular and cellular functions, and physiological systems and development. DAVID functional annotation analysis identified 9 proteins (SNCA, GSTP1, PRDX3, PPP3R1, EIF5A, PHB, PEBP1/RKIP, GAPDH, AND SOD1) that were significantly overrepresented in a functional cluster that included the Gene Ontology categories "response to alcohol" and "aging." Immunoblots confirmed changes in Pebp1 (RKIP) and GSTP1 in NAcb with no change in amygdala or frontal cortex, suggesting anatomical specificity. Systemic inhibition of GSTP1 with Ezatiostat (0-30 mg/kg, i.p.) dose dependently reduced the reinforcing effects of alcohol as measured by operant self-administration, in the absence of motor effects. Sucrose self-administration was also reduced but in a manner associated with nonspecific motor inhibition. CONCLUSIONS: Protein expression profiling identified an array of proteins and networks in the NAcb, including GSTP1, that are novel molecular targets of chronic alcohol drinking. Pharmacological inhibition of GSTP1 significantly reduced the positive reinforcing effects of alcohol, which regulate repetitive use and abuse liability. The observation that this protein was both upregulated after chronic drinking and that its inhibition could modulate the reinforcing properties of alcohol suggests that it is a key target for alcohol-related pathologies. Proteomic strategies combined with specific preclinical models has potential to identify and validate novel targets of alcohol that may be useful in the medical management of alcohol addiction. PMID- 29502278 TI - The Effects of Laparoscopic Sleeve Gastrectomy with Duodenojejunal Bypass on Japanese Patients with BMI < 35 kg/m2 on Type 2 Diabetes Mellitus and the Prediction of Successful Glycemic Control. AB - BACKGROUND: Laparoscopic sleeve gastrectomy with duodenojejunal bypass (LSG-DJB) is a combination of sleeve gastrectomy and proximal intestinal bypass through duodenal exclusion. This technique has shown excellent weight loss and anti diabetic effects in severely obese patients. In this retrospective study, we examined the clinical effects of LSG-DJB on mildly obese patients (body mass index (BMI) < 35 kg/m2) with type 2 diabetes mellitus (T2DM) and analyzed factors contributing to the successful postoperative glycemic control. METHODS: Seventy two consecutive Japanese patients with T2DM with a BMI of < 35 kg/m2 who underwent LSG-DJB in a single institution from September 2007 to March 2015 were included for the study. Weight loss, safety, and the impact on T2DM and metabolic syndrome were examined at 1 year after surgery when weight loss reaches an expected plateau. In addition, pre- and postoperative factors between those who achieved diabetes remission (remitters) and non-remitters were compared. RESULTS: The follow-up rate at 1 year after surgery was 93%. The mean percent total weight loss (%TWL) was 31.6 +/- 8.8%, and the mean glycosylated hemoglobin (HbA1c) dropped from 8.9 +/- 1.5 to 6.4 +/- 1.0%. There were four early- and seven late severe complications (grade III-A or more based on the Clavien-Dindo classification), which account for the 1-year morbidity rate of 15%. There was no mortality. The complete (HbA1c of < 6% without diabetes medication) and partial (HbA1c of < 6.5% without diabetes medication) remission of T2DM was achieved in 31 and 49% of the patients, respectively. Positive impacts were also observed on hypertension and dyslipidemia. Consequently, the ratio of those who achieved the composite endpoint (HbA1c of < 7%, low-density lipoprotein cholesterol < 100 mg/dL, systolic blood pressure < 130 mmHg) significantly increased from 4.2 to 22% (p = 0.003). Duration of T2DM and preoperative use of anti-hypertensive drugs were independent predictors of diabetes remission. Patients with a higher ABCD score were also at a higher rate of success in T2DM remission. CONCLUSIONS: LSG DJB for T2DM patients with a BMI of < 35 kg/m2 is a feasible and effective surgical method in achieving moderate weight loss and excellent improvement of glycemic control, metabolic syndrome, and cardiovascular risk although the T2DM remission rate was lower compared with severely obese individuals. Proper patient selection for candidates of the procedure is imperative to effectively predict poor responders. PMID- 29502279 TI - A 4-Week Preoperative Ketogenic Micronutrient-Enriched Diet Is Effective in Reducing Body Weight, Left Hepatic Lobe Volume, and Micronutrient Deficiencies in Patients Undergoing Bariatric Surgery: a Prospective Pilot Study. AB - BACKGROUND: Before bariatric surgery (BS), moderate weight loss, left hepatic lobe volume reduction, and micronutrient deficiency (MD) identification and correction are desirable. OBJECTIVES: The objective of this study was to assess the safety and the effectiveness of a 4-week preoperative ketogenic micronutrient enriched diet (KMED) in reducing body weight (BW), left hepatic lobe volume, and correcting MD in patients scheduled for BS. MATERIALS AND METHODS: In this prospective pilot study, a cohort of morbidly obese patients (n = 27, 17 females, 10 males) with a mean body mass index (BMI) of 45.2 kg/m2 scheduled for BS underwent a 4-week preoperative KMED. Their BW, BMI, fat mass (FM), fat-free mass (FFM), resting metabolic rate (RMR), left hepatic lobe volume, micronutrient status, and biochemical and metabolic patterns were measured before and after the 4-week KMED. Patient compliance was assessed by validated questionnaires (3-day estimated food records and 72-h recall). Qualitative methods (5-point Likert questionnaire) were used to measure diet acceptability and side effects. RESULTS: All patients completed the study. We observed highly significant decreases in BW (- 10.3%, p < 0.001, in males; - 8.2%, p < 0.001, in females), left hepatic lobe volume (- 19.8%, p < 0.001), and an amelioration of patient micronutrient status. All patients showed a high frequency of acceptability and compliance in following the diet. No adverse side effect was reported. CONCLUSION: This study demonstrates that a 4-week preoperative KMED is safe and effective in reducing BW, left hepatic lobe volume, and correcting MD in obese patients scheduled for BS. PMID- 29502280 TI - Depression, posttraumatic stress and relationship distress in parents of very preterm infants. AB - To determine the prevalence, associated factors, and relationships between symptoms of depression, symptoms of posttraumatic stress (PTS), and relationship distress in mothers and fathers of very preterm (VPT) infants (< 32 weeks). Mothers (n = 323) and fathers (n = 237) completed self-report measures on demographic and outcome variables at 38 days (SD = 23.1, range 9-116) postpartum while their infants were still hospitalised. Of mothers, 46.7% had a moderate to high likelihood of depression, 38.1% had moderate to severe symptoms of PTS, and 25.1% were in higher than average relationship distress. The corresponding percentages in fathers were 16.9, 23.7, and 27%. Depression was positively associated with having previous children (p = 0.01), speaking little or no English at home (p = 0.01), financial stress (p = 0.03), and recently accessing mental health services (p = 0.003) for mothers, and financial stress (p = 0.005) and not being the primary income earner (p = 0.04) for fathers. Similar associations were found for symptoms of PTS and relationship distress. Being in higher relationship distress increased the risk of depression in both mothers (p < .001) and fathers (p = 0.03), and PTS symptoms in mothers (p = 0.001). For both mothers and fathers, depression was associated with more severe PTS symptoms (p < .001). Fathers of VPT infants should be screened for mental health problems alongside mothers, and postpartum parent support programs for VPT infants should include strategies to improve the couple relationship. PMID- 29502281 TI - Women generating narratives after an unwanted prenatal diagnosis result: randomized controlled trial. AB - We have defined a psychological intervention based on cognitive narrative therapy and the Ottawa decision framework to reduce adjustment problems following a termination of pregnancy (TOP) after a positive prenatal diagnosis (PND). The intervention is composed of four sessions: decision, subjectivation, metaphorization, and projecting. This study aims to assess the effectiveness of a cognitive narrative intervention to prevent depression and anxiety symptoms after TOP. The intervention was accepted by 24 participants. The outcome is compared with a control group of 67 women who also terminated a pregnancy after PND. Participants were from several Portuguese institutions; 64.4% had a genetic and 35.6% had ultrasound diagnosis; the mean age was 30.0 years and the mean gestational age was 19 weeks. There are two evaluations: a baseline at the 15th day and a sixth month follow-up after TOP, using Beck Depression Inventory, Zung Anxiety Scale, Perinatal Grief Scale, and an instrument capturing participant satisfaction. Six months after TOP, there is a lower mean of anxiety and depression (p < 0.05), between groups, with effect sizes on the follow-up of 0.54 for depression, 0.41 for anxiety, and 0.23 for perinatal grief. This intervention has very positive effects on women mental health, and we emphasize the importance of the meaning-making process in the context of terminating a wanted pregnancy. PMID- 29502282 TI - How we do it: down to up posterior components separation. AB - BACKGROUND: Posterior component separation with transversus abdominis release technique is increasingly being used for abdominal wall reconstruction in complex abdominal wall repair. The main purpose of this study is to present a modification of the surgical technique originally described that facilitates the surgical procedure and offers additional advantages. METHODS: Based on the knowledge of the anatomy of the retromuscular space and the preperitoneal aerolar tissue distribution, we start the incision on the posterior rectus sheath from the arcuate line in a down to up direction. The posterior rectus sheath is incised 0,5-1 cm medial to the linea semilunaris and cut longitudinally as far as the fibers of transversus abdominis muscle that are divided in the superior part of the abdomen. It is also possible to avoid cutting the fibers of this muscle if we incise the posterior rectus sheath in an oblique direction to the midline from the umbilical area. Since 2012 to 2016, 69 consecutive patients with down to up TAR have been prospectively followed. Main outcome measures included demographics, perioperative details, wound complications, and recurrences. RESULTS: Between 2012 and 2016, we have operated 69 patients with down to up TAR technique. Mean operative time was 251 (range 65-566) minutes. Mean hospital stay was 9,8 (2-98) days. 10 patients presented surgical site events (14,5%): 6 patients had superficial site infection, 3 deep and 1 organ space. During follow up, 3 patients (4,3%) presented incisional hernia recurrence. CONCLUSIONS: This novel modification allows a simpler dissection of the preperitoneal retromuscular space and makes the TAR technique easier to perform. It also enables to incise only the insertion of the transversalis fascia cranially. PMID- 29502284 TI - Fertility preservation for female cancer patients. AB - An improvement in the survival rates of cancer patients and recent advancements in assisted reproductive technologies have led to remarkable progress in oncofertility and fertility preservation treatments. Currently, for adults and postpubertal girls, oocyte or embryo cryopreservation is an established method. If their cancer treatment cannot be postponed for 2 weeks, ovarian tissue cryopreservation is offered as an experimental technique. For prepubertal girls, ovarian tissue cryopreservation is the only option. As for ovarian protection, there is insufficient evidence regarding the effectiveness of GnRH agonist in fertility preservation. In the past decade, the concept of fertility preservation for cancer patients has been rapidly spreading, but at present only a small part of young cancer patients receive fertility preservation services. It is partly because of the lack of adequate provision of information on fertility preservation and the lack of referral from oncology to the fertility clinic. In Japan, the clinical practice guidelines for fertility preservation in childhood, adolescent and young adult cancer patients was issued last year by the Japan Society of Clinical Oncology (JSCO). It would help Japanese health care providers, including oncologists and reproductive specialists, to increase their knowledge on fertility preservation for cancer patients and move forward the fertility preservation services. For further progress, it is also needed to establish a national registration system of fertility preservation for cancer patients to evaluate the safety and efficacy of the current management. PMID- 29502283 TI - Acetyl Phosphate as a Primordial Energy Currency at the Origin of Life. AB - Metabolism is primed through the formation of thioesters via acetyl CoA and the phosphorylation of substrates by ATP. Prebiotic equivalents such as methyl thioacetate and acetyl phosphate have been proposed to catalyse analogous reactions at the origin of life, but their propensity to hydrolyse challenges this view. Here we show that acetyl phosphate (AcP) can be synthesised in water within minutes from thioacetate (but not methyl thioacetate) under ambient conditions. AcP is stable over hours, depending on temperature, pH and cation content, giving it an ideal poise between stability and reactivity. We show that AcP can phosphorylate nucleotide precursors such as ribose to ribose-5-phosphate and adenosine to adenosine monophosphate, at modest (~2%) yield in water, and at a range of pH. AcP can also phosphorylate ADP to ATP in water over several hours at 50 degrees C. But AcP did not promote polymerization of either glycine or AMP. The amino group of glycine was preferentially acetylated by AcP, especially at alkaline pH, hindering the formation of polypeptides. AMP formed small stacks of up to 7 monomers, but these did not polymerise in the presence of AcP in aqueous solution. We conclude that AcP can phosphorylate biologically meaningful substrates in a manner analogous to ATP, promoting the origins of metabolism, but is unlikely to have driven polymerization of macromolecules such as polypeptides or RNA in free solution. This is consistent with the idea that a period of monomer (cofactor) catalysis preceded the emergence of polymeric enzymes or ribozymes at the origin of life. PMID- 29502285 TI - Evaluation of hollow fiber culture for large-scale production of mouse embryonic stem cell-derived hematopoietic stem cells. AB - Hematopoietic stem cells (HSCs) have the ability to differentiate into all types of blood cells and can be transplanted to treat blood disorders. However, it is difficult to obtain HSCs in large quantities because of the shortage of donors. Recent efforts have focused on acquiring HSCs by differentiation of pluripotent stem cells. As a conventional differentiation method of pluripotent stem cells, the formation of embryoid bodies (EBs) is often employed. However, the size of EBs is limited by depletion of oxygen and nutrients, which prevents them from being efficient for the production of HSCs. In this study, we developed a large scale hematopoietic differentiation approach for mouse embryonic stem (ES) cells by applying a hollow fiber (HF)/organoid culture method. Cylindrical organoids, which had the potential for further spontaneous differentiation, were established inside of hollow fibers. Using this method, we improved the proliferation rate of mouse ES cells to produce an increased HSC population and achieved around a 40 fold higher production volume of HSCs in HF culture than in conventional EB culture. Therefore, the HF/organoid culture method may be a new mass culture method to acquire pluripotent stem cell-derived HSCs. PMID- 29502286 TI - Biological characterization and pluripotent identification of ovine amniotic fluid stem cells. AB - Mesenchymal stem cells derived from amniotic fluid have become one of the most potential stem cell source for cell-based therapy for the reason they can be harvested at low cost and without ethical problems. Here, we obtained amniotic fluid stem cells (AFSCs) from ovine amniotic fluid and studied the expansion capacity, cell markers expression, karyotype, and multilineage differentiation ability. In our work, AFSCs were subcultured to passage 62. The cell markers, CD29, CD44, CD73 and OCT4 which analyzed by RT-PCR were positive; CD44, CD73, CD90, CD105, NANOG, OCT4 analyzed by immunofluorescence and flow cytometry were also positive. The growth curves of different passages were all typically sigmoidal. The different passages cells took on a normal karyotype. In addition, AFSCs were successfully induced to differentiate into adipocytes, osteoblasts and chondrocytes. The results suggested that the AFSCs isolated from ovine maintained normal biological characteristics and their multilineage differentiation potential provides many potential applications in cell-based therapies and tissue engineering. PMID- 29502287 TI - Breast care problems on call: training residents to manage effectively. AB - PURPOSE: Our aim was to assess and address the challenges radiology residents face when managing breast imaging emergencies on call and to determine if targeted educational interventions improved resident confidence and knowledge. METHODS: We created surveys to determine resident comfort level with and knowledge of appropriate management of breast imaging emergencies. We also created structured educational interventions to improve resident confidence and knowledge. The effectiveness of these interventions was assessed with pre- and post-intervention surveys given to the 43 residents at our institution. RESULTS: Thirty-six of the 43 residents at our institution completed both surveys. The results showed that 33 of 36 residents (91.7%) felt an increase in their comfort level after utilizing one or both of the interventions. There was also significant improvement in resident knowledge; the average resident score on the knowledge questions improved from 40 to 68% (p < 0.0001). CONCLUSION: Managing breast imaging emergencies on call can be challenging and stressful for residents. Educational interventions such as our targeted teaching tools can significantly improve resident confidence and knowledge. Presenting dedicated teaching materials directed at a previously identified knowledge deficit and source of stress significantly improved resident knowledge base and confidence in managing breast imaging emergencies on call. PMID- 29502288 TI - Immunotherapy for Head and Neck Squamous Cell Carcinoma. AB - PURPOSE OF REVIEW: Discussion of current strategies targeting the immune system related to solid tumors with emphasis on head and neck squamous cell carcinoma (HNSCC).This review will outline the current challenges with immunotherapy and future goals for treatment using these agents. RECENT FINDINGS: Agents targeting immune checkpoint receptors (IR) such as program death 1 (PD1) have been used in the clinical realm for melanoma and non-small cell lung cancer (NSCLC), and the use of these agents for these malignancies has provided crucial information about how and why patients respond or not to inhibitory checkpoint receptor blockade therapy (ICR). The anti PD1 agent, nivolumab, was recently approved by the FDA as a standard of care regimen for patients with platinum refractory recurrent/metastatic (R/M) HNSCC. Molecular pathways leading to resistance are starting to be identified, and work is underway to understand the most optimal treatment regimen with incorporation of immunotherapy. ICR has renewed interest in the immunology of cancer, but resistance is not uncommon, and thus understanding of these mechanisms will allow the clinician to appropriately select patients that will benefit from this therapy. PMID- 29502289 TI - Comparison of meat quality characteristics and fatty acid composition of finished goat kids from indigenous and dairy breeds. AB - The aim of the study was to compare the certain carcass and meat quality traits and also fatty acid composition of goat kids from indigenous breeds (Gokceada and Hair Goat) and dairy breeds (Saanen and Maltese). A total 40 male kids from Saanen, Gokceada, Maltese and Hair Goat breeds were collected from commercial farms after weaning. Kids were finished for 56 days with grower concentrate and alfalfa hay in the sheepfold until slaughter. Higher mean values were found for Saanen kids in terms of slaughter weight, hot carcass weight and real dressing compared with Maltese, Hair Goat and Gokceada kids under the same intensive conditions. On the other hand, there were no significant differences between breeds in terms of instrumental meat quality traits, except meat colour. Meat from Gokceada and Hair Goat kids had higher lightness and Hue angle values than Saanen kids after 24 h of blooming. High meat redness values were observed for Saanen kids after 0 and 1 h of blooming. Panellist appreciated cooked meat from Saanen and Maltese kids in overall acceptability. If the fatty acid composition of meat was taken into consideration, kids from Saanen and Gokceada breeds displayed better values, because of the lower ?SFA percentage and higher desirable fatty acids (C18:0 + SigmaMUFA + SigmaPUFA) percentage than Maltese and Hair Goat kids. Our results indicate that male kids for Saanen which is dairy breed could be assessable for quality goat meat production. PMID- 29502290 TI - Effect of mixed maize-legume silages on milk quality and quantity from lactating smallholder dairy cows. AB - The study investigated the effect of the following maize:legume (70:30) mixed crop silages: maize:cowpea, maize:velvet bean, and maize:lablab on milk production during the 2016 dry season. Using a 5 * 5 double Latin square design, five Holstein-Friesian crossbred cows in early lactation (30 +/- 15 days) and five Jersey crossbred cows in early lactation (25 +/- 10 days) were given the supplementary mixed crop silage diets at 0.5 kg/l of milk produced over 105 days. Commercial dairy meal and sole maize silage were used as positive and negative controls, respectively. Milk yield was significantly higher (P < 0.05) in cows given the dairy meal compared to mixed crop silages; however, milk yield was also significantly higher (P < 0.05) for cows given the three mixed crop silages compared to cows given sole maize silage. Cows given mixed crop silages produced milk of significantly higher protein content (P < 0.05) than those given sole maize silage. There was no significant difference (P > 0.05) in butterfat content of milk across all the dietary treatments. The dietary cost of producing 1 l of milk was highest at 0.31USD/l for cows given commercial dairy meal and lowest for cows given maize:velvet bean and maize:cowpea silage at 0.19USD/kg. The highest dietary gross margins of 68% were observed when cows were given maize:velvet mixed silage compared to commercial dairy meal (47%) and sole maize silage (57%). The 70:30 maize:legume mixed crop silages showed the capability to increase milk quantity and quality at very low production costs in smallholder dairy schemes. PMID- 29502291 TI - NKCC1 Inhibition Attenuates Chronic Cerebral Hypoperfusion-Induced White Matter Lesions by Enhancing Progenitor Cells of Oligodendrocyte Proliferation. AB - Cerebral white matter is vulnerable to ischemic condition. However, no effective treatment to alleviate or restore the myelin damage caused by chronic cerebral hypoperfusion has been found. Na+-K+-Cl- cotransporter 1 (NKCC1), a Na+-K+-Cl- cotransporter widely expressed in the central nervous system (CNS), involves in regulation of cell swelling, EAA release, cell apoptosis, and proliferation. Nevertheless, the role of NKCC1 in chronic hypoperfusion-induced white matter lesions (WMLs) has not been explored. Here, mice subjected to bilateral common carotid artery stenosis (BCAS) were used as model of chronic cerebral hypoperfusion; density of progenitor cells of oligodendrocyte (OPCs), oligodendrocytes (OLs), astrocytes, and microglia was assessed by immunofluorescent staining and Western blot analysis; working memory was examined by eight-arm radial maze test; expression of MAPK signaling pathway was determined by Western blot analysis. After BCAS, white matter integrity disruption and working memory impairment were observed. NKCC1 inhibition by bumetanide administration enhanced OPC proliferation, attenuated chronic hypoperfusion-induced white matter damage, and promoted recovery of neurological function. However, NKCC1 inhibition caused no significant change in the densities of GFAP- and Iba-1-positive cells in the corpus callosum. Bumetanide administration significantly increased the expression of p-ERK and decreased the expression of p-JNK and p-p38 in comparison to vehicle-BCAS groups. In conclusion, NKCC1 inhibition might significantly ameliorate chronic cerebral hypoperfusion-induced WMLs and cognitive impairment by enhancing progenitor cells of oligodendrocyte proliferation, and this protective function of bumetanide might be mediated by modulation of the MAPK signaling pathway. PMID- 29502293 TI - Acquired resistance to pamidronate treated effectively with zoledronate in juvenile Paget's disease. AB - Juvenile Paget's disease (JPD) is a rare autosomal recessive osteopathy. There is still a question about the most effective treatment modality in long-term prognosis. A 9-month-old boy who suffered from bone pain and deformities with a very high alkaline phosphatase level was diagnosed as JPD by radiographic findings. Genetic analysis showed a homozygous large deletion in TNFRSF11B gene encoding osteoprotegerin. Clinical improvement was observed with intravenous pamidronate therapy. However, the effect of drug reduced in time so the annual dose per kilogram body weight was increased after 2 years. Despite this increment, bone fractures developed and bone pain recurred with high-ALP levels, which suggested resistance to pamidronate. Switching to zoledronate resulted a significant improvement in bone findings radiographically and ALP level. Severe hypocalcemia requiring intravenous calcium treatment complicated the first dose of zoledronate, but not recurred thereafter. Intravenous pamidronate therapy is effective in reducing bone pain, improving bone deformities and motor development in infantile onset JPD. However, this effect can be transient. Switching to another bisphosphonate like zoledronate may provide long-term clinical and biochemical improvement as an alternative treatment in case of resistance to pamidronate therapy. PMID- 29502292 TI - Whole-Genome Expression Microarray Combined with Machine Learning to Identify Prognostic Biomarkers for High-Grade Glioma. AB - The aim of our study is to build a framework for a better understanding of high grade glioma (HGG) prognostic-related biomarkers. Whole-genome gene expression microarray was performed to identify differently expressed genes between HGGs and low-grade diffuse gliomas. Several machine learning algorithms were used to filter prognostic-related genes. One hundred ninety-three HGG patients after surgical resection were selected for survival analysis. Immunohistochemistry were performed on these tumor samples to analyze IDH1 mutation status and protein expression of WEE1. qRT-PCR, western blotting, transwell assays, and scratch wound healing assays were performed to evaluate the effect of WEE1 knockdown or overexpression in HGG cells. Three prognostic-related genes (WEE1, IGF2PB3, and EMP3) were demonstrated to separate HGG patients into two different survival subgroups. The area under receiver operating characteristic curve of WEE1 was higher than that of IGF2BP3, EMP3, age, IDH status, 1p/19q status, and MGMT promoter status. WEE1 was an independent covariate compared with IDH status, age, and WHO grade. Knockdown or overexpression of WEE1 can inhibit or promote migration and invasion in U251 and U87 cell lines. WEE1, EMP3, and IGF2BP3 are reliable prognostic-related genes at the mRNA level. WEE1 is an independent prognostic biomarker in survival analysis and has potential diagnostic value for HGG patients. WEE1 can induce HGG cell migration and invasion in vitro. PMID- 29502294 TI - Identification of two novel host proteins interacting with Toxoplasma gondii 14-3 3 protein by yeast two-hybrid system. AB - Toxoplasma gondii deploys many effector proteins in order to hijack and manipulate host cell signaling pathways, allowing parasite colonization, subversion of immune responses, and disease progression. T. gondii effector protein 14-3-3 (Tg14-3-3) promotes parasite dissemination inside the body, by enhancing the migratory ability of infected microglia and dendritic cells. Understanding both the mechanism of action and the host targets of Tg14-3-3 effector is important because of their importance to the parasite's virulence. The aim of the present study was to explore the function of Tg14-3-3 by utilizing the yeast two-hybrid system (Y2HS) to identify novel Tg14-3-3 interactors/substrates in host cells. A human cDNA library was screened using Tg14-3-3 as the bait. Tg14-3-3 (RH strain, Type I) was cloned into the pGBKT7 vector and expressed in the Y2HGold yeast strain. The bait protein expression was validated by Western blotting analysis, auto-activation, and toxicity investigation compared with control (Y2HGold yeast strain transformed with empty pGBKT7 vector). Two positive Tg14-3-3 interactors identified by this screening, hCG1821272 and eIF5B (eukaryotic translation initiation factor 5B), were isolated and characterized. This approach made it possible to gain a better understanding of the function of Tg14-3-3 in regulating host proteins involved in key cellular processes, such as translational initiation and cell migration. PMID- 29502295 TI - High prevalence of chigger mite infection in a forest-specialist frog with evidence of parasite-related granulomatous myositis. AB - Amphibians are hosts for a wide variety of micro- and macro-parasites. Chigger mites from the Hannemania genus are known to infect a wide variety of amphibian species across the Americas. In Chile, three species (H. pattoni, H. gonzaleacunae and H. ortizi) have been described infecting native anurans; however, neither impacts nor the microscopic lesions associated with these parasites have been described. Here, we document 70% prevalence of chigger mite infection in Eupsophus roseus and absence of infection in Rhinoderma darwinii in the Nahuelbuta Range, Chile. Additionally, we describe the macroscopic and microscopic lesions produced by H. ortizi in one of these species, documenting previously undescribed lesions (granulomatous myositis) within the host's musculature. These findings highlight that further research to better understand the impacts of chigger mite infection on amphibians is urgently required in Chile and elsewhere. PMID- 29502296 TI - Alaria spp. mesocercariae in Eurasian badger (Meles meles) and wild boar (Sus scrofa) from the Bialowieza Forest, north-eastern Poland. AB - Alaria spp. mesocercariae are commonly found in wild boar and other omnivorous mammals. In Europe, the number of cases presenting Alaria mesocercariae infections has been on the rise in the last years. From October to December 2016, samples of muscle from tongue, neck, and mandibular regions were collected from 1 Eurasian badger (Meles meles) and 14 wild boars (Sus scrofa) hunted in the Bialowieza Forest, north-eastern Poland. Using the Alaria migration technique (AMT), Alaria mesocercariae were isolated and morphologically identified in one badger and one wild boar. To the authors' knowledge, this is the first report of Alaria mesocercariae in paratenic hosts from the Bialowieza Forest. PMID- 29502298 TI - Correction to: Contribution of transposable elements and distal enhancers to evolution of human-specific features of interphase chromatin architecture in embryonic stem cells. AB - The original version of this article unfortunately contained a mistake in publishing the panel C for Figures 3, 5 and 6. PMID- 29502297 TI - Chlorinated metronidazole as a promising alternative for treating trichomoniasis. AB - Trichomoniasis is the most common non-viral, sexually transmitted infection affecting humans worldwide. The main treatment for trichomoniasis is metronidazole (MTZ). However, adverse effects and reports of resistance have stimulated the development of therapeutic alternatives. The ease of manipulation of the side chains of MTZ coupled with its safety makes this molecule attractive for the development of new drugs. In this context, we evaluated the activity of the chlorinated MTZ derivative, MTZ-Cl, on sensitive and resistant strains of Trichomonas vaginalis. MTZ-Cl presented a remarkable activity against both sensitive and resistant strains. In vitro and in vivo toxicity assays indicated that the new molecule is safe for future clinical trials. Furthermore, we noticed different rates of free radical production between the sensitive and resistant strains. MTZ-Cl induced a higher release of nitric oxide (NO, ~ 9000 a.u.) by both sensitive and resistant strains. However, the sensitive strain produced a greater amount of H2O2 (~ 1,800,000 a.u.) and superoxide radicals (~ 350,000 a.u.) in the presence of MTZ. In the resistant strain, production of these radicals was more prominent when MTZ-Cl was used. Collectively, these results suggest that NO is an important molecule in the trichomonacidal activity against resistant and sensitive strains, suggesting an alternative pathway for MTZ-Cl activation. We highlight the high trichomonacidal potential of MTZ-Cl, improving the effectiveness of treatment and reducing side effects. In addition, MTZ-Cl is derived from a well-established drug on the world market that presents low toxicity to human cells, suggesting its safety to proceed with future clinical trials. PMID- 29502300 TI - Quality of leadership in multidisciplinary cancer tumor boards: development and evaluation of a leadership assessment instrument (ATLAS). AB - BACKGROUND: High-quality leadership and chairing skills are vital for good performance in multidisciplinary tumor boards (MTBs), but no instruments currently exist for assessing and improving these skills. OBJECTIVE: To construct and validate a robust instrument for assessment of MTB leading and chairing skills. DESIGN AND SETTING: We developed an observational MTB leadership assessment instrument (ATLAS). ATLAS includes 12 domains that assess the leadership and chairing skills of the MTB chairperson. ATLAS has gone through a rigorous process of refinement and content validation prior to use to assess the MTB lead by two urological surgeons (blinded to each other) in 7 real-live (n = 286 cases) and 10 video-recorded (n = 131 cases) MTBs. OUTCOME MEASURES AND STATISTICAL ANALYSIS: ATLAS domains were analyzed via descriptive statistics. Instrument content was evaluated for validity using the content validation index (CVI). Intraclass correlation coefficients (ICCs) were used to assess inter observer reliability. RESULTS: Instrument refining resulted in ATLAS including the following 12 domains: time management, communication, encouraging contribution, ability to summarize, ensuring all patients have treatment plan, case prioritization, keeping meeting focused, facilitate discussion, conflict management, leadership, creating good working atmosphere, and recruitment for clinical trials. CVI was acceptable and inter-rater agreement adequate to high for all domains. Agreement was somewhat higher in real-time MTBs compared to video ratings. Concurrent validation evidence was derived via positive and significant correlations between ATLAS and an established validated brief MTB leadership assessment scale. CONCLUSION: ATLAS is an observational assessment instrument that can be reliably used for assessing leadership and chairing skills in cancer MTBs (both live and video-recorded). The ability to assess and feedback on team leader performance provides the ground for promotion of good practice and continuing professional development of tumor board leaders. PMID- 29502299 TI - Comprehensive transcriptome analyses correlated with untargeted metabolome reveal differentially expressed pathways in response to cell wall alterations. AB - KEY MESSAGE: This research provides new insights into plant response to cell wall perturbations through correlation of transcriptome and metabolome datasets obtained from transgenic plants expressing cell wall-modifying enzymes. Plants respond to changes in their cell walls in order to protect themselves from pathogens and other stresses. Cell wall modifications in Arabidopsis thaliana have profound effects on gene expression and defense response, but the cell signaling mechanisms underlying these responses are not well understood. Three transgenic Arabidopsis lines, two with reduced cell wall acetylation (AnAXE and AnRAE) and one with reduced feruloylation (AnFAE), were used in this study to investigate the plant responses to cell wall modifications. RNA-Seq in combination with untargeted metabolome was employed to assess differential gene expression and metabolite abundance. RNA-Seq results were correlated with metabolite abundances to determine the pathways involved in response to cell wall modifications introduced in each line. The resulting pathway enrichments revealed the deacetylation events in AnAXE and AnRAE plants induced similar responses, notably, upregulation of aromatic amino acid biosynthesis and changes in regulation of primary metabolic pathways that supply substrates to specialized metabolism, particularly those related to defense responses. In contrast, genes and metabolites of lipid biosynthetic pathways and peroxidases involved in lignin polymerization were downregulated in AnFAE plants. These results elucidate how primary metabolism responds to extracellular stimuli. Combining the transcriptomics and metabolomics datasets increased the power of pathway prediction, and demonstrated the complexity of pathways involved in cell wall mediated signaling. PMID- 29502301 TI - Kaleido: Visualizing Big Brain Data with Automatic Color Assignment for Single Neuron Images. AB - Effective 3D visualization is essential for connectomics analysis, where the number of neural images easily reaches over tens of thousands. A formidable challenge is to simultaneously visualize a large number of distinguishable single neuron images, with reasonable processing time and memory for file management and 3D rendering. In the present study, we proposed an algorithm named "Kaleido" that can visualize up to at least ten thousand single neurons from the Drosophila brain using only a fraction of the memory traditionally required, without increasing computing time. Adding more brain neurons increases memory only nominally. Importantly, Kaleido maximizes color contrast between neighboring neurons so that individual neurons can be easily distinguished. Colors can also be assigned to neurons based on biological relevance, such as gene expression, neurotransmitters, and/or development history. For cross-lab examination, the identity of every neuron is retrievable from the displayed image. To demonstrate the effectiveness and tractability of the method, we applied Kaleido to visualize the 10,000 Drosophila brain neurons obtained from the FlyCircuit database ( http://www.flycircuit.tw/modules.php?name=kaleido ). Thus, Kaleido visualization requires only sensible computer memory for manual examination of big connectomics data. PMID- 29502302 TI - Sleep duration, body composition, dietary profile and eating behaviours among children and adolescents: a comparison between Portuguese acrobatic gymnasts. AB - : Sleep, body composition and dietary intake are crucial for athletes' health and performance but have never been investigated in acrobatic gymnasts. Thus, this study aimed to evaluate sleep, body composition, dietary intake and eating behaviours of acrobatic gymnasts. Using a cross-sectional study, 82 Portuguese acrobatic gymnasts (12.8 +/- 3.1 years, 61 females and 21 males) were evaluated during the competitive period to collect training data, sleep duration, body composition, dietary intake and eating behaviours before, during and after practices. Most of the gymnasts (91.5%) slept less than 8 h/night. Female adolescents slept significantly less on weekdays than female children (P = 0.024). Female adolescents' mean body mass was below the normal and 60.0% showed menstrual irregularities; 4.9% of females bases were overweight and 2.4% obese. Male adolescents slept significantly less on weekdays than male children (P = 0.001); significant differences were shown for fat-free mass (P = 0.014); however, 3.7% were overweight. All daily energy and macronutrient intakes were significantly different according to age and gender, with exception for fibre and energy intake in females (P = 0.057 and P = 0.052, respectively), and for protein in males (P = 0.068). Female and male adolescents demonstrated significant lower energy availability (32.8 +/- 9.4 kcal/kg FFM/day and 45.1 +/- 14.7 kcal/kg FFM/day) than children (45.8 +/- 8.7 kcal/kg FFM/day and 53.8 +/- 9.1 kcal/kg FFM/day), respectively. Significant low intakes of important vitamins and minerals were reported. Most of the participants did not eat or drink during or immediately after training sessions. CONCLUSION: Acrobatic gymnasts revealed low BF, short sleep duration and macro- and micronutrients inadequate intakes. The Female Athlete Triad was demonstrated by female adolescent gymnasts. What is Known: * Adequate dietary intake is an important resource for athletes' short and long-term health and performance. * There are no published studies in acrobatic gymnasts' sleep, body composition or dietary intake. What is New: * This study provides the first data on significant differences in energy intake and availability between acrobatic gymnasts; overweight and obesity were present in females. * Macro and micronutrients were inappropriate. Female Athlete Triad was observed in female adolescent acrobatic gymnasts. PMID- 29502303 TI - Sleep disorders during childhood: a practical review. AB - Sleep disorders are a common problem during childhood. The consequences are variable, and sleep disorders can influence medical, psychological and developmental aspects of the growing child. It is important to recognize sleep disorders and to treat them correctly. We discuss common sleep disorders during childhood using the 3rd edition of the International Classification of Sleep Disorders. We analyze the different sleep disorders from a clinical approach and provide an overview of adequate treatment options.Conlusion: This review discusses common sleep disorders during childhood using the 3rd edition of the International Classification of Sleep Disorders. We analyze the different sleep disorders from a clinical approach and provide an overview of adequate treatment options. What is known: * Sleep disorders are a common problem during childhood. * The consequences are variable, and sleep disorders can influence medical, psychological, and developmental aspects of the growing child. What is new: * Pediatricians should routinely screen for sleep and sleep disorders. * It is important to recognize sleep disorders and to treat them correctly. PMID- 29502304 TI - User Performance Evaluation of Four Blood Glucose Monitoring Systems Applying ISO 15197:2013 Accuracy Criteria and Calculation of Insulin Dosing Errors. AB - INTRODUCTION: The international standard ISO 15197:2013 requires a user performance evaluation to assess if intended users are able to obtain accurate blood glucose measurement results with a self-monitoring of blood glucose (SMBG) system. In this study, user performance was evaluated for four SMBG systems on the basis of ISO 15197:2013, and possibly related insulin dosing errors were calculated. Additionally, accuracy was assessed in the hands of study personnel. METHODS: Accu-Chek(r) Performa Connect (A), Contour(r) plus ONE (B), FreeStyle Optium Neo (C), and OneTouch Select(r) Plus (D) were evaluated with one test strip lot. After familiarization with the systems, subjects collected a capillary blood sample and performed an SMBG measurement. Study personnel observed the subjects' measurement technique. Then, study personnel performed SMBG measurements and comparison measurements. Number and percentage of SMBG measurements within +/- 15 mg/dl and +/- 15% of the comparison measurements at glucose concentrations < 100 and >= 100 mg/dl, respectively, were calculated. In addition, insulin dosing errors were modelled. RESULTS: In the hands of lay-users three systems fulfilled ISO 15197:2013 accuracy criteria with the investigated test strip lot showing 96% (A), 100% (B), and 98% (C) of results within the defined limits. All systems fulfilled minimum accuracy criteria in the hands of study personnel [99% (A), 100% (B), 99.5% (C), 96% (D)]. Measurements with all four systems were within zones of the consensus error grid and surveillance error grid associated with no or minimal risk. Regarding calculated insulin dosing errors, all 99% ranges were between dosing errors of - 2.7 and + 1.4 units for measurements in the hands of lay-users and between - 2.5 and + 1.4 units for study personnel. Frequent lay-user errors were not checking the test strips' expiry date and applying blood incorrectly. CONCLUSIONS: Data obtained in this study show that not all available SMBG systems complied with ISO 15197:2013 accuracy criteria when measurements were performed by lay-users. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (NCT02916576). FUNDING: Ascensia Diabetes Care Deutschland GmbH. PMID- 29502305 TI - Correction to: Variation in Parasympathetic Dysregulation Moderates Short-Term Memory Problems in Childhood Attention-Deficit/Hyperactivity Disorder. AB - The authors note two errors in this article. In the reference section, Musser et al. (2014) was mistakenly used whereas the following entry should have been used. PMID- 29502306 TI - Antiviral effects and mechanisms of Yinhuapinggan granule against H1N1 influenza virus infection in RAW264.7 cells. AB - Yinhuapinggan granule (YHPG), a modified prescription based on Ma-Huang-Tang (MHT), is used in traditional Chinese medicine (TCM) to treat influenza, cough, and viral pneumonia. In this study, we investigated the antiviral effects of YHPG by means of pre-, post-, and co-treatment, and its underlying mechanisms on regulating the levels of inflammatory-related cytokines, modulating the mRNA expressions of interferon-stimulated genes in influenza virus-infected murine macrophage cells (RAW264.7), and evaluating the protein expressions of key effectors in the Type I IFN and pattern recognition receptor (PRRs) signaling pathways. The results showed that YHPG markedly inhibited influenza virus (IFV) replication in pre-, post- and co-treatment assay, especially in post-treatment assay. Antiviral mechanisms studies revealed that YHPG (500 and 250 MUg/mL) significantly up-regulated levels of IFN-beta, IFN-stimulated genes (Mx-1, ISG-15 and ISG-56) compared with the IFV control group, while the levels of IL-6 and TNF alpha were significantly down-regulated. Furthermore, western blot analysis results revealed that the protein expressions of the phosphorylated forms of TBK1, IRF3, ERK1/2, P38 MAPK and NF-kappaB p65 were significantly down-regulated in RAW264.7 cells with the YHPG (500 and 250 MUg/mL) treatment, while the expression of the phosphorylated form of STAT1 was significantly enhanced. Based on these results, YHPG had antiviral effects in IFV-infected RAW264.7 cells, which might be associated with regulation of the inflammatory cytokines production, evaluation of the levels of IFN-stimulated genes, and modulation of the protein expressions of key effectors in the Type I IFN and PRRs signaling pathways. PMID- 29502307 TI - Role of the Nervous System in Tumor Angiogenesis. AB - The development of cancer involves an intricate process, wherein many identified and unidentified factors play a role. Tumor angiogenesis, growth of new blood vessels, is one of the major prerequisites for tumor growth as tumor cells rely on adequate oxygen and nutrient supply as well as the removal of waste products. Growth factors including VEGF orchestrate the development of angiogenesis. In addition, nervous system via the release of neurotransmitters contributes to tumor angiogenesis. The nervous system governs functional activities of many organs, and, as tumors are not independent organs within an organism, this system is integrally involved in tumor growth and progression via regulating tumor angiogenesis. Various neurotransmitters have been reported to play an important role in tumor angiogenesis. PMID- 29502310 TI - Clinical utility of simultaneous whole-body 18F-FDG PET/MRI as a single-step imaging modality in the staging of primary nasopharyngeal carcinoma. AB - PURPOSE: Both head and neck magnetic resonance imaging (MRI) and 18F fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) play a crucial role in the staging of primary nasopharyngeal carcinoma (NPC). In this study, we sought to prospectively investigate the clinical utility of simultaneous whole-body 18F-FDG PET/MRI for primary staging of NPC patients. METHODS: We examined 113 patients with histologically confirmed NPC who underwent pretreatment, simultaneous whole-body PET/MRI and PET/CT for primary tumor staging. The images obtained with the different imaging modalities were interpreted independently and compared with each other. RESULTS: PET/MRI increased the accuracy of head and neck MRI for assessment of primary tumor extent in four patients via addition of FDG uptake information to increase the conspicuity of morphologically subtle lesions. PET/MR images were more discernible than PET/CT images for mapping tumor extension, especially intracranial invasion. Regarding the N staging assessment, the sensitivity of PET/MRI (99.5%) was higher than that of head and neck MRI (94.2%) and PET/CT (90.9%). PET/MRI was particularly useful for distinguishing retropharyngeal nodal metastasis from adjacent nasopharyngeal tumors. For distant metastasis evaluation, PET/MRI exhibited a similar sensitivity (90% vs. 86.7% vs. 83.3%), but higher positive predictive value (93.1% vs. 78.8% vs. 83.3%) than whole-body MRI and PET/CT, respectively. CONCLUSIONS: For tumor staging of NPC, simultaneous whole-body PET/MRI was more accurate than head and neck MRI and PET/CT, and may serve as a single-step staging modality. PMID- 29502311 TI - Impact of plasma glucose level on the pattern of brain FDG uptake and the predictive power of FDG PET in mild cognitive impairment. AB - PURPOSE: Increased blood glucose level (BGL) has been reported to cause alterations of FDG uptake in the brain that mimic Alzheimer's disease (AD), even within the "acceptable" range <= 160 mg/dl. The aim of this study was (i) to confirm this in a large sample of well-characterized normal control (NC) subjects, and (ii) to analyze its impact on the prediction of AD dementia (ADD) in mild cognitive impairment (MCI). METHODS: The study included NCs from the Alzheimer's Disease Neuroimaging Initiative (ADNI) that were cognitively stable for >=36 months after PET (n = 87, 74.2 +/- 5.3 y), and ADNI MCIs with >=36 months follow-up if not progressed to ADD earlier (n = 323, 71.1 +/- 7.1 y). Seventy-three of the MCIs had progressed to ADD within 36 months. In the NCs, parenchyma-scaled FDG uptake was tested for clusters of correlation with BGL on the family-wise, error-corrected 5% level. In the MCIs, ROC analysis was used to assess the power of FDG uptake in a predefined AD-typical region for prediction of ADD. ROC analysis was repeated after correcting mean FDG uptake in the AD typical region for BGL based on linear regression in the NCs. RESULTS: In the NCs, BGL (59-149 mg/dl) was negatively correlated with FDG uptake in a cluster comprising the occipital cortex and precuneus but sparing the posterior cingulate, independent of amyloid-beta and ApoE4 status. In the MCIs, FDG uptake in the AD-typical region provided an area of 0.804 under the ROC curve for prediction of ADD. Correcting FDG uptake in the AD-typical region for BGL (55-189 mg/dl) did not change predictive performance (area = 0.808, p = 0.311). CONCLUSIONS: Increasing BGL is associated with relative reduction of FDG uptake in the posterior cortex even in the "acceptable" range <= 160 mg/dl. The BGL associated pattern is similar to the typical AD pattern, but not identical. BGL associated variability of regional FDG uptake has no relevant impact on the power of FDG PET for prediction of MCI-to-ADD progression. PMID- 29502309 TI - Dual-time point 18F-FDG PET/CT for the staging of oesophageal cancer: the best diagnostic performance by retention index for N-staging in non-calcified lymph nodes. AB - PURPOSE: The purpose of this study is to investigate the role of dual time point (DTP) 18F-FDG PET/CT in the staging of oesophageal cancer, especially in lymph node metastasis. METHODS: A total of 35 patients with oesophageal squamous cell carcinoma who underwent surgical treatment without neoadjuvant chemotherapy were enrolled as a test set and another 19 patients were enrolled as a validation set. The DTP PET/CT scans were obtained in dual time points at 60 and 120 min each, following the administration of 18F-FDG. Visual analysis was performed and semiquantitative analysis was performed using several PET parameters such as maximal standardized uptake values (SUVmax), peak SUV (SUVpeak) and retention indexes using SUVmax (RImax) and SUVpeak (RIpeak). RESULTS: Primary oesophageal lesions exhibited a significant difference for SUVmax at each time point scan (ANOVA, p < 0.001). For nodal staging, a total of 276 non-calcified nodal stations of the test set were evaluated. Sensitivity, specificity and accuracy of visual analysis were 32.0% (8 of 25), 96.8% (243 of 251) and 90.9% (251 of 276) in the test set. Using ROC analysis, RImax had the largest area under the curve (AUC) to detect metastatic lymphadenopathy at the optimal cut-off value of 6% (AUC 0.853, P < 0.001) in the test set (sensitivity, specificity and accuracy; 80.0% (20 of 25), 94.8% (238 of 251) and 93.5% (258 of 276)). In the validation set (179 non-calcified nodal stations), sensitivity, specificity and accuracy of RImax at the optimal cut-off of 6% were 71.4% (5 of 7), 99.4% (171 of 172) and 98.4% (176 of 179), whereas those of visual analysis were 14.3% (1 of 7), 98.8% (170 of 172) and 95.5% (171 of 179). CONCLUSIONS: The best diagnostic performance of nodal staging in patients with oesophageal cancer was achieved by application of RImax with a cut-off of more than 6% on DTP 18F-FDG PET/CT with the exclusion of calcified lymph nodes. Optimal clinical management in surgically-candidate oesophageal cancer patients could be achieved using the diagnostic flow on DTP 18F-FDG PET/CT. PMID- 29502308 TI - Biochemistry of proinflammatory macrophage activation. AB - In the last decade, metabolism has been recognized as a major determinant of immunological processes. During an inflammatory response, macrophages undergo striking changes in their metabolism. This metabolic reprogramming is governed by a complex interplay between metabolic enzymes and metabolites of different pathways and represents the basis for proper macrophage function. It is now evident that these changes go far beyond the well-known Warburg effect and the perturbation of metabolic targets is being investigated as a means to treat infections and auto-immune diseases. In the present review, we will aim to provide an overview of the metabolic responses during proinflammatory macrophage activation and show how these changes modulate the immune response. PMID- 29502312 TI - Prognostic value of normal stress myocardial perfusion imaging and ventricular function in Japanese patients with chronic kidney disease: a study based on the J ACCESS-3 database. AB - BACKGROUND: The purpose of this study is to test the hypothesis that a normal myocardial perfusion imaging (MPI) study in chronic kidney disease (CKD) can provide benign prognostic information for the prediction of major cardiovascular events. METHODS: The study group consisted of 431 CKD patients (males, 64%; mean age, 72 +/- 11 years) with normal SPECT imaging. Based on SPECT image and QGS data, 331 had a summed stress score of 3 or less, a summed difference score of 1 or less and normal cardiac function (males; end-systolic volume (ESV) <= 60 ml, females; ESV <= 40 ml, males, ejection fraction (EF) >= 49%; females, EF >= 50%). RESULTS: During a 3-year follow-up period, there were a total of 27 major cardiovascular events, including cardiac death (n = 3), sudden death (n = 3), and acute coronary syndrome (n = 3), and 19 were hospitalized because of congestive heart failure. Kaplan-Meier analysis showed that the number of major cardiovascular events in patients with higher eGFR of >= 15 ml/min) were very few, and regarded as low risk. According to the eGFR status, namely < 15 (n = 58), 15 to < 30 (n = 97), 30 to < 45 (n = 131), >= 45 (n = 45), the higher cardiac event rate was observed in patients with eGFR of < 15 ml/min among the four groups. The major cardiovascular event rate in patients with the lowest eGFR (< 15) was twice as much than that in patients with eGFR of >= 30 ml/min. Lower hemoglobin (males, < 12 g/dl; females, < 11 g/dl) and higher CRP (CPR >= 0.3 mg/dl) were also the predictors of increased risk. CONCLUSIONS: Normal stress SPECT images confer a benign prognosis in patients with CKD, but care must be taken for severely reduced renal function, which was associated with higher cardiac event. PMID- 29502313 TI - Epidemiology of malignant lymphoma and recent progress in research on adult T cell leukemia/lymphoma in Japan. AB - The morbidity and mortality of disease vary according to the region and may also change over time. The morbidity and mortality of malignant lymphoma are also affected by differences in ethnicity, lifestyle habits, geographical area, and time period. Increasing research on malignant lymphoma has focused on its pathophysiology, diagnosis, and therapeutic treatment. Recent improvements in the accuracy of clinical study, technologies such as next-generation sequencing, and the development of targeted molecular agents have also resulted in a number of excellent studies. This review summarizes the epidemiology of malignant lymphoma and highlights novel studies on adult T-cell leukemia/lymphoma recently published in Japan. PMID- 29502314 TI - Trends in the treatment of rectal prolapse: a population analysis. AB - PURPOSE: Rectal prolapse is a common condition, with conflicting opinions on optimal surgical management. Existing literature is predominantly composed of case series, with a dearth of evidence demonstrating current, real-world practice. This study investigated recent national trends in management of rectal prolapse in the Republic of Ireland (ROI). METHODS: This population analysis used a national database to identify patients admitted in the ROI primarily for the management of rectal prolapse, as defined by the International Classification of Diseases, 10th Revision (ICD-10). Demographics, procedures, comorbidities, and outcomes were obtained for patients admitted from 2005 to 2015 inclusive. RESULTS: There were 2648 admissions with a primary diagnosis of rectal prolapse; 39.3% underwent surgical correction. The majority were treated with either a perineal resection (47.2%) or an abdominal rectopexy +/- resection (45.1%). The population-adjusted rate of operative intervention increased over the study period, from 25 to 42 per million (p < 0.001), with no change in the mean age of patients over time (p = 0.229). The application of a laparoscopic approach increased over time (p = 0.001). Patients undergoing an abdominal rectopexy were younger than those undergoing a perineal procedure (64.1 +/- 17.3 versus 75.2 +/- 15.5 years, p < 0.001) despite having a similar Charlson Comorbidity Index (p = 0.097). The mortality rate for elective repair was 0.2%. CONCLUSIONS: Despite the popularization of ventral mesh rectopexy over the study period, perineal resection Delorme's procedure remains the most common procedure employed for the correction of rectal prolapse in the ROI, with specific approach determined by age. PMID- 29502315 TI - A solid majority remit following evidence-based OCD treatments: a 3-year naturalistic outcome study in pediatric OCD. AB - This study reports follow-up 2 and 3 years after the initial assessment of a sample of youth with a primary diagnosis of OCD. Participants were 109 children and adolescents, aged 5-17 years, recruited from a specialized, outpatient OCD clinic in Sweden. Patients were treated with cognitive behavioral therapy (CBT), augmented when indicated by selective serotonin reuptake inhibitor (SSRI). In cases where SSRIs were insufficient, augmentation with a second-generation antipsychotic (SGA) was applied. Participants were assessed with the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS), Children's OCD Impact Scale (COIS), and Children's Depressive Inventory (CDI) at follow-ups 2 and 3 years after baseline assessment. Treatment response was defined as CY-BOCS total score <= 15, and remission was defined as CY-BOCS total score <= 10. Analyzing the outcomes with linear mixed-effects models (LME) showed a decrease in OCD symptom load from 23 to 6.9 at the 3-year follow-up. Moreover, two of three (66.1%) participants were in remission, and another 19.2% had responded to treatment at the 3-year follow-up. Thus, 85.3% of participants responded to treatment. Moreover, during the follow-up period, participants' psychosocial functioning had significantly improved, and depressive symptoms had significantly decreased. The results suggest that evidence-based treatment for pediatric OCD, following expert consensus guidelines, has long-term positive effects for most children and adolescents diagnosed with OCD. The results also indicate that improvements are maintained over a 3-year period, at least, and that improvement is also found with regard to psychosocial functioning and depressive symptoms. PMID- 29502316 TI - Developmental course of anxiety and depression from adolescence to young adulthood in a prospective Norwegian clinical cohort. AB - Anxiety and depression are often co-occurring disorders, reflecting both homotypic and heterotypic continuity as possible developmental pathways. The present study aimed to examine homotypic and heterotypic continuities of anxiety and depression across 3 years in adolescence and young adulthood. Participants included patients presenting to psychiatric care with diagnoses of anxiety and/or depressive disorders aged 13-18 at T1 (N = 717, 44% initial participation rate) and aged 16-21 at T2 (N = 549, 80% follow-up participation rate). McNemar's mid-p test and ordinal proportional odds logistic regression analyses were used to assess changes in prevalence within and across diagnostic categories, respectively. More adolescents had an anxiety disorder (+ 11%), whereas fewer had a depressive disorder (- 11%), at T2 compared to T1. Of adolescents with anxiety and/or depression at T1, only 25% recovered or were non-symptomatic 3 years after referral to a psychiatric clinic. Homotypic continuity was observed for anxiety disorders in general (OR = 2.33), for phobic anxiety disorders (OR = 7.45), and for depressive disorders (OR = 2.15). For heterotypic continuity, depression predicted later anxiety (OR = 1.92), more specifically social anxiety (OR = 2.14) and phobic anxiety disorders (OR = 1.83). In addition, social anxiety predicted later generalized anxiety disorder (OR = 3.11). Heterotypic continuity was thus more common than homotypic continuity. For adolescents presenting with anxiety or depression, treatment should, therefore, target broad internalizing symptom clusters, rather than individual diagnoses. This may contribute to prevent future mental illness, particularly anxiety, in clinical samples. PMID- 29502317 TI - No laughing matter: subacute degeneration of the spinal cord due to nitrous oxide inhalation. AB - BACKGROUND: Whilst the dangers of 'legal highs' have been widely publicised in the media, very few cases of the neurological syndrome associated with the inhalation of nitrous oxide (N2O) have been reported. Here we set out to raise awareness of subacute degeneration of the spinal cord arising from recreational N2O use so that formal surveillance programs and public health interventions can be designed. METHODS: Case series documenting the clinical and investigational features of ten consecutive cases of subacute degeneration of the spinal cord presenting to a hospital with a tertiary neurosciences service in East London. RESULTS: Sensory disturbance in the lower (+/- upper) limbs was the commonest presenting feature, along with gait abnormalities and sensory ataxia. MRI imaging of the spine showed the characteristic features of dorsal column hyperintensity on T2 weighted sequences. Serum B12 levels may be normal because subacute degeneration of the spinal cord in this situation is triggered by functional rather than absolute B12 deficiency. DISCUSSION: A high index of suspicion is required to prompt appropriate investigation, make the diagnosis and commence treatment early. This is the largest reported series of patients with subacute degeneration of the spinal cord induced by recreational use of N2O. However, the number of patients admitted to hospital likely represents the 'tip of the iceberg', with many less severe presentations remaining undetected. After raising awareness, attention should focus on measuring the extent of the problem, the groups affected, and devising ways to prevent potentially long-term neurological damage. PMID- 29502318 TI - Correction to: The minimally invasive flexor carpi radialis approach: a new perspective for distal radius fractures. AB - With regards to Juan Jose Hidalgo Diaz, fifth author. The author's name is incorrectly listed on Pub-Med. The first and last name has been mixed up.Correct first name is: JJ (on PubMed: JJH.).Correct last name is: Hidalgo Diaz (on PubMed: Diaz).On SpringerLink the name is listed correctly, but on PubMed he is listed as Diaz JJH. PMID- 29502319 TI - Variation of C1 spinolaminar line and prevalence of C1 stenosis in normal population. AB - BACKGROUND: The variation of C1 spinolaminar line in normal population is not fully understood. The relative position of C1 lamina to C3-C2 spinolaminar line is reported as good screening tool for determination of C1 canal stenosis. OBJECTIVE: To determine the variation of C1 spinolaminar line and find the prevalence of C1 canal stenosis in normal population using C3-C2 spinolaminar test. MATERIALS AND METHODS: Three hundred and fifteen lateral cervical radiographs from 315 volunteers without neurological symptoms were analyzed. The relative position of C1 spinolaminar line was determined by C3-C2 spinolaminar and considered positive if C1 lamina lay ventral to C3-C2 line. C1 space available for cord (SAC) was measured from posterior border of dens to the C1 lamina to determine the sagittal diameter. RESULTS: The mean sagittal spinal canal diameter of C1 was 22.2 mm (13-26 mm). Of 315, 14 (4.4%) had positive, 184 (58.4%) had neutral, and 117 (37.1%) had negative C1 spinolaminar line in relation to C3-C2 line. The mean SAC among positive group was 14.9 mm compared to neutral and negative groups which were 22.2 and 23.3 mm, respectively. 21.4% of positive group had SAC of less than 12 mm. The 92.8% of positive C1 spinolaminar line was found in age >= 60 years. CONCLUSION: In a normal population, 4.4% has positive C1 spinolaminar line. The C1 stenosis is more prevalent in positive C1 spinolaminar line group. PMID- 29502320 TI - Cognitive Approaches for Medicine in Cloud Computing. AB - : This paper will present the application potential of the cognitive approach to data interpretation, with special reference to medical areas. The possibilities of using the meaning approach to data description and analysis will be proposed for data analysis tasks in Cloud Computing. The methods of cognitive data management in Cloud Computing are aimed to support the processes of protecting data against unauthorised takeover and they serve to enhance the data management processes. The accomplishment of the proposed tasks will be the definition of algorithms for the execution of meaning data interpretation processes in safe Cloud Computing. HIGHLIGHTS: * We proposed a cognitive methods for data description. * Proposed a techniques for secure data in Cloud Computing. * Application of cognitive approaches for medicine was described. PMID- 29502321 TI - Performance assessment of a single-layer moisture store-and-release cover system at a mine waste rock pile in a seasonally humid region (Nova Scotia, Canada). AB - Cover systems are commonly applied to mine waste rock piles (WRPs) to control acid mine drainage (AMD). Single-layer covers utilize the moisture "store-and release" concept to first store and then release moisture back to the atmosphere via evapotranspiration. Although more commonly used in semi-arid and arid climates, store-and-release covers remain an attractive option in humid climates due to the low cost and relative simplicity of installation. However, knowledge of their performance in these climates is limited. The objective of this study was to assess the performance of moisture store-and-release covers at full-scale WRPs located in humid climates. This cover type was installed at a WRP in Nova Scotia, Canada, alongside state-of-the-art monitoring instrumentation. Field monitoring was conducted over 5 years to assess key components such as meteorological conditions, cover material water dynamics, net percolation, surface runoff, pore-gas, environmental receptor water quality, landform stability and vegetation. Water balances indicate small reductions in water influx to the waste rock (i.e., 34 to 28% of precipitation) with the diminished AMD release also apparent by small improvements in groundwater quality (increase in pH, decrease in sulfate/metals). Surface water quality analysis and field observations of vegetative/aquatic life demonstrate significant improvements in the surface water receptor. The WRP landform is stable and the vegetative cover is thriving. This study has shown that while a simple store-and-release cover may not be a highly effective barrier to water infiltration in humid climates, it can be used to (i) eliminate contaminated surface water runoff, (ii) minimize AMD impacts to surface water receptor(s), (iii) maintain a stable landform, and (iv) provide a sustainable vegetative canopy. PMID- 29502322 TI - Vascular assessment after clipping surgery using four-dimensional CT angiography. AB - Recent advances in computed tomography angiography (CTA) enable repeated imaging follow up for post-clipping surgery. The purpose of this study was to clarify the critical volume and configuration of the aneurysmal clip in the postoperative evaluation using volume rendering (VR) imaging, and present four-dimensional (4D) CTA for these larger metal artifacts. A total of 44 patients with cerebral aneurysm, treated using clipping surgery, were included in this study. The metal artifact volume was assessed using CTA and the association between the type of clips and its metal artifact volume was analyzed. A VR image and a 4D-CTA were then produced, and the diagnostic accuracy of arteries around the clip or residual aneurysm on these images was evaluated. In the receiver operating characteristic (ROC) curve analysis, the cutoff value for metal artifacts was 2.32 mm3 as determined through a VR image. Patients were divided into two groups. Group 1 included patients with a simple and small clip, and group 2 included patients with multiple, large or fenestrated clips. The metal artifact volume was significantly larger in group 2, and the group incorporated the cutoff value. Post-clipping status on the VR image was significantly superior in group 1 compared with group 2. In group 2, the imaging quality of post-clipping status on 4D-CTA was superior in 92.9% of patients. The metal artifact volume was dependent on the number, size, or configuration of the clip used. In group 2, evaluation using a 4D-CTA eliminated the effect of the metal artifacts. PMID- 29502323 TI - Internal driveline damage under the costal margin several years after HeartMate II implant: a series of three cases. AB - Although the incidence of driveline failure has been significantly reduced with the major modification to the driveline connection to the HeartMate II left ventricular assist device (LVAD), internal and external driveline damage continues to be a major reason for pump exchange or driveline repair. We report three cases of internal driveline damage under the costal margin and in the adjacent abdominal wall. All three cases developed occasional electrical disruptions 2-5 years after the original LVAD implant through the median sternotomy. Two patients underwent subcostal LVAD exchange and one had driveline externalization and repair. The driveline velour was well adhered to the costal margin and wire damage was found at the costal margin as well as the subsequent segment in the abdominal wall. Repeated ante-flex bending of the abdominal wall over years appeared to cause the chronic wear and tear of the vertically located driveline under the costal margin. This report will confirm a pitfall of the LVAD driveline location which can potentially cause driveline damage in the mid-to long term. PMID- 29502324 TI - Does mammographic density mediate risk factor associations with breast cancer? An analysis by tumor characteristics. AB - BACKGROUND: Though mammographic density (MD) has been proposed as an intermediate marker of breast cancer risk, few studies have examined whether the associations between breast cancer risk factors and risk are mediated by MD, particularly by tumor characteristics. METHODS: Our study population included 3392 cases (1105 premenopausal) and 8882 (3192 premenopausal) controls from four case-control studies. For established risk factors, we estimated the percent of the total risk factor association with breast cancer that was mediated by percent MD (secondarily, by dense area and non-dense area) for invasive breast cancer as well as for subtypes defined by the estrogen receptor (ER+/ER-), progesterone receptor (PR+/PR-), and HER2 (HER2+/HER2-). Analyses were conducted separately in pre- and postmenopausal women. RESULTS: Positive associations between prior breast biopsy and risk of invasive breast cancer as well as all subtypes were partially mediated by percent MD in pre- and postmenopausal women (percent mediated = 11-27%, p <= 0.02). In postmenopausal women, nulliparity and hormone therapy use were positively associated with invasive, ER+ , PR+ , and HER2- breast cancer; percent MD partially mediated these associations (percent mediated >= 31%, p <= 0.02). Further, among postmenopausal women, percent MD partially mediated the positive association between later age at first birth and invasive as well as ER+ breast cancer (percent mediated = 16%, p <= 0.05). CONCLUSION: Percent MD partially mediated the associations between breast biopsy, nulliparity, age at first birth, and hormone therapy with risk of breast cancer, particularly among postmenopausal women, suggesting that these risk factors at least partially influence breast cancer risk through changes in breast tissue composition. PMID- 29502326 TI - Expression of concern: Biologically validating the measurement of oxytocin in western lowland gorilla (Gorilla gorilla gorilla) urine and saliva using a commercial enzyme immunoassay. PMID- 29502325 TI - Health-related quality of life of Portuguese children and adolescents according to their biological maturation and volume of physical activity. AB - PURPOSE: The purpose of this study was to analyze the relationship between biological maturation and health-related quality of life (HRQoL) in Portuguese children and adolescents of both sexes when the effect of chronological age (CA) and volume of physical activity (VPA) were removed. METHODS: HRQoL, biological maturation, CA, and VPA were assessed in 750 children and adolescents, 11-17 years old, from 3 schools in Lisbon, Portugal. The KIDSCREEN-52 was used to assess HRQoL. Maturity indicator was bone age (BA), using Tanner-Whitehouse III method (TW3). The participants were classified into three different maturity categories: late, on time, and early maturers. VPA was assessed by questionnaire (RAPIL II). An analysis of covariance (ANCOVA), using the CA and the VPA as covariates was completed. The level of significance was set at p <= 0.05. RESULTS: Analysis of covariance suggested an influence of biological maturation in physical well-being dimension in both sexes, with early-maturing girls and boys having worst perception. Maturity groups were also influent in moods and emotions for girls. CA seems to be particularly important in self-perception and parent relation and home life for girls and in school environment for boys. CONCLUSION: Biological maturation and CA have relevant impact on some HRQoL dimensions. These variables, due to their nature and effect should be considered particularly when working with specific domains of HRQoL as physical well-being in both sexes, moods and emotions and self-perception and parent relation and home life for girls and in school environment for boys. PMID- 29502327 TI - Impulsivity and Gambling Type Among Treatment-Seeking Disordered Gamblers: An Explorative Study. AB - Several studies have found that certain traits of impulsivity are associated with gambling disorder, and influence its severity. Furthermore, it has been suggested that some forms of gambling, particularly electronic gambling machines, are particularly widespread among pathological gamblers. In the present, exploratory study, we aim to clarify the role played by impulsivity in influencing the choice of specific gambling activities, by examining the relation between individual dimensions of impulsivity, and the choice of specific gambling activities in a clinical population. 100 consecutively admitted pathological gamblers at the National Problem Gambling Clinic in London (UK) in 2014 were administered the UPPS-P and BIS-11 impulsivity questionnaires, the Problem Gambling Severity Index, and underwent a structured interview concerning their gambling activities in the month and year prior to assessment. The correlation between individual gambling activities and impulsivity dimensions was analyzed both at a bivariate level, and using logistic regression. We found a significant correlation between Negative Urgency, Motor impulsivity and low-stakes machine gambling on multivariate analysis. Negative urgency (i.e. the tendency to act impulsively in response to negative affect), and Motor impulsivity (a tendency to rash action and restlessness) might be mediating factors in the choice of electronic gambling machines, particularly among patients whose gambling is escape-oriented. Structural and situational characteristics of gambling machines, particularly the widespread availability of low-stakes-rather than high-stakes-gaming machines, might concur to the choice of this form of gambling among individuals who present higher negative urgency and restlessness. PMID- 29502329 TI - Detecting aberrant opioid behavior in the emergency department: a prospective study using the screener and Opioid Assessment for Patients with Pain-Revised (SOAPP(r)-R), Current Opioid Misuse Measure (COMM)TM, and provider gestalt. AB - Emergency department (ED) providers have limited time to evaluate patients at risk for opioid misuse. A validated tool to assess the risk for aberrant opioid behavior may mitigate adverse sequelae associated with prescription opioid misuse. We sought to determine if SOAPP-R, COMM, and provider gestalt were able to identify patients at risk for prescription opioid misuse as determined by pharmacy records at 12 months. We conducted a prospective observational study of adult patients in a high volume US ED. Patients completed the SOAPP-R and COMM, and treating EM providers evaluated patients' opioid misuse risk. We performed variable-centered, person-centered, and hierarchical cluster analyses to determine whether provider gestalt, SOAPP-R, or COMM, or a combination, predicted higher misuse risk. The primary outcome was the number of opioid prescriptions at 12 months according to pharmacy records. For 169 patients (mean age 43 years, 51% female, 73% white), correlation analysis showed a strong relationship between SOAPP-R and COMM with predicting the number of opioid prescriptions dispensed at 12 months. Provider scores estimating opioid misuse were not related to SOAPP-R and only weakly associated with COMM. In our adjusted regression models, provider gestalt and SOAPP-R uniquely predicted opioid prescriptions at 6 and 12 months. Using designated cutoff scores, only SOAPP-R detected a difference in the number of opioid prescriptions. Cluster analysis revealed that provider gestalt, SOAPP R, and COMM scores jointly predicted opioid prescriptions. Provider gestalt and self-report instruments uniquely predicted the number of opioid prescriptions in ED patients. A combination of gestalt and self-assessment scores can be used to identify at-risk patients who otherwise miss the cutoff scores for SOAPP-R and COMM. PMID- 29502328 TI - Aerobic Interval vs. Continuous Training in Patients with Coronary Artery Disease or Heart Failure: An Updated Systematic Review and Meta-Analysis with a Focus on Secondary Outcomes. AB - BACKGROUND: In a previous meta-analysis including nine trials comparing aerobic interval training with aerobic continuous training in patients with coronary artery disease, we found a significant difference in peak oxygen uptake favoring aerobic interval training. OBJECTIVE: The objective of this study was to (1) update the original meta-analysis focussing on peak oxygen uptake and (2) evaluate the effect on secondary outcomes. METHODS: We conducted a systematic review with a meta-analysis by searching PubMed and SPORTDiscus databases up to March 2017. We included randomized trials comparing aerobic interval training and aerobic continuous training in patients with coronary artery disease or chronic heart failure. The primary outcome was change in peak oxygen uptake. Secondary outcomes included cardiorespiratory parameters, cardiovascular risk factors, cardiac and vascular function, and quality of life. RESULTS: Twenty-four papers were identified (n = 1080; mean age 60.7 +/- 10.7 years). Aerobic interval training resulted in a higher increase in peak oxygen uptake compared with aerobic continuous training in all patients (1.40 mL/kg/min; p < 0.001), and in the subgroups of patients with coronary artery disease (1.25 mL/kg/min; p = 0.001) and patients with chronic heart failure with reduced ejection fraction (1.46 mL/kg/min; p = 0.03). Moreover, a larger increase of the first ventilatory threshold and peak heart rate was observed after aerobic interval training in all patients. Other cardiorespiratory parameters, cardiovascular risk factors, and quality of life were equally affected. CONCLUSION: This meta-analysis adds further evidence to the clinically significant larger increase in peak oxygen uptake following aerobic interval training vs. aerobic continuous training in patients with coronary artery disease and chronic heart failure. More well designed randomized controlled trials are needed to establish the safety of aerobic interval training and the sustainability of the training response over longer periods. PMID- 29502330 TI - Clinical impact of application of risk assessment models (Padua Prediction Score and Improve Bleeding Score) on venous thromboembolism, major hemorrhage and health expenditure associated with pharmacologic VTE prophylaxis: a "real life" prospective and retrospective observational study on patients hospitalized in a Single Internal Medicine Unit (the STIME study). AB - International guidelines recommend the use of pharmacological prophylaxis in hospitalized medical patients at high risk of venous thromboembolism (VTE). The same international guidelines suggest the employment of standardized risk assessment models (RAMs) when evaluating the administration of pharmacological prophylaxis in acutely ill medical patients. The Padua Prediction Score and the Improve Bleeding Score have been indicated as the best available RAMs to predict thrombotic and haemorrhagic risk in hospitalized medical patients, but it is still unknown whether their combined use may lead to a significant reduction in thrombotic and haemorrhagic events. It is also unclear whether their extensive use can affect to some extent health expenditure associated with pharmacological VTE prophylaxis. The purpose of this single-centre, prospective and retrospective observational study is to investigate these unanswered questions. All patients admitted to our Internal Medicine Department between May 2015 and August 2015, i.e., before the introduction and extensive use of RAMs, were consecutively enrolled (retrospective group). Similarly, all patients admitted between November 2016 and February 2017-once RAMs clinical use became a consolidated practice-have also been consecutively recruited (prospective group). Consecutively, 203 patients were enrolled in the retrospective group and 210 patients were enrolled in the prospective group. Three events of major bleeding and one event of pulmonary embolism were observed in the prospective group; three events of major hemorrhage and two events of pulmonary embolism were observed in the retrospective group (p = not significant). A statistically significant decrease in pharmacological VTE prophylaxis among study groups was detected: 43.3% of prospective group patients and 56.7% of retrospective group patients received pharmacological prophylaxis (p = .028). Overall, 299 drug doses for VTE prophylaxis have been spared after RAMs introduction (p = .0001) and health expenditure decreased by 27.2% (i.e., 1.67 ? saved for each single patient). In conclusion, the extensive use of RAMs in our population of hospitalized medical patients did not statistically affect VTE rate or incidence of major bleeding, but it resulted in a significant drop in health expenditure related with pharmacological prophylaxis. Awaiting new clinical trials, a broad use of RAMs may be a safe strategy for reducing health expenditure associated with VTE prophylaxis in hospitalized medical patients. PMID- 29502331 TI - Outcomes of laparoscopic sleeve gastrectomy in Crohn's disease patients: an initial Australian experience. AB - BACKGROUND: Crohn's disease (CD) in association with obesity is becoming an increasing issue in Australia and worldwide. This report looks at outcomes for patients with CD undergoing laparoscopic sleeve gastrectomy. METHODS: This is a retrospective analysis of our database of patients undergoing laparoscopic sleeve gastrectomy from 2007 to 2016. Patients with concurrent CD were included. RESULTS: Eight patients with CD underwent laparoscopic sleeve gastrectomy with a mean preoperative body mass index of 43.8. There were no identified intraoperative or post-operative complications. The mean excess weight loss was 55.7% and 56.5% at 6 months and 1 year, respectively. CONCLUSION: Laparoscopic sleeve gastrectomy can be achieved in CD patients. No complications and effective weight loss was observed in the eight reported patients. PMID- 29502332 TI - Interventions for treating post-extraction bleeding. AB - BACKGROUND: Post-extraction bleeding (PEB) is a recognised, frequently encountered complication in dental practice, which is defined as bleeding that continues beyond 8 to 12 hours after dental extraction. The incidence of post extraction bleeding varies from 0% to 26%. If post-extraction bleeding is not managed, complications can range from soft tissue haematomas to severe blood loss. Local causes of bleeding include soft tissue and bone bleeding. Systemic causes include platelet problems, coagulation disorders or excessive fibrinolysis, and inherited or acquired problems (medication induced). There is a wide array of techniques suggested for the treatment of post-extraction bleeding, which include interventions aimed at both local and systemic causes. This is an update of a review published in June 2016. OBJECTIVES: To assess the effects of interventions for treating different types of post-extraction bleeding. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 24 January 2018), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2017, Issue 12), MEDLINE Ovid (1946 to 24 January 2018), Embase Ovid (1 May 2015 to 24 January 2018) and CINAHL EBSCO (1937 to 24 January 2018). The US National Institutes of Health Trials Registry (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. We searched the reference lists of relevant systematic reviews. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) that evaluated any intervention for treating PEB, with male or female participants of any age, regardless of type of teeth (anterior or posterior, mandibular or maxillary). Trials could compare one type of intervention with another, with placebo, or with no treatment. DATA COLLECTION AND ANALYSIS: Three pairs of review authors independently screened search records. We obtained full papers for potentially relevant trials. If data had been extracted, we would have followed the methods described in the Cochrane Handbook for Systematic Reviews of Interventions for the statistical analysis. MAIN RESULTS: We did not find any randomised controlled trial suitable for inclusion in this review. AUTHORS' CONCLUSIONS: We were unable to identify any reports of randomised controlled trials that evaluated the effects of different interventions for the treatment of post-extraction bleeding. In view of the lack of reliable evidence on this topic, clinicians must use their clinical experience to determine the most appropriate means of treating this condition, depending on patient-related factors. There is a need for well designed and appropriately conducted clinical trials on this topic, which conform to the CONSORT statement (www.consort-statement.org/). PMID- 29502333 TI - Positional complications of minimal access surgery, laparoscopic/robotic/transanal surgery. PMID- 29502334 TI - Microtubule defects in mesenchymal stromal cells distinguish patients with Progressive Supranuclear Palsy. AB - Progressive Supranuclear Palsy (PSP) is a rare neurodegenerative disease whose etiopathogenesis remains elusive. The intraneuronal accumulation of hyperphosphorylated Tau, a pivotal protein in regulating microtubules (MT), leads to include PSP into tauopathies. Pathological hallmarks are well known in neural cells but no word yet if PSP-linked dysfunctions occur also in other cell types. We focused on bone marrow mesenchymal stromal cells (MSCs) that have recently gained attention for therapeutic interventions due to their anti-inflammatory, antiapoptotic and trophic properties. Here, we aimed to investigate MSCs biology and to disclose if any disease-linked defect occurs in this non-neuronal compartment. First, we found that cells obtained from patients showed altered morphology and growth. Next, Western blotting analysis unravelled the imbalance in alpha-tubulin post-translational modifications and in MT stability. Interestingly, MT mass is significantly decreased in patient cells at baseline and differently changes overtime compared to controls, suggesting their inability to efficiently remodel MT cytoskeleton during ageing in culture. Thus, our results provide the first evidence that defects in MT regulation and stability occur and are detectable in a non-neuronal compartment in patients with PSP. We suggest that MSCs could be a novel model system for unravelling cellular processes implicated in this neurodegenerative disorder. PMID- 29502335 TI - Bronchiectasis in indigenous and non-indigenous residents of Australia and New Zealand. AB - BACKGROUND AND OBJECTIVE: Bronchiectasis not associated with cystic fibrosis is an increasingly recognized chronic lung disease. In Oceania, indigenous populations experience a disproportionately high burden of disease. We aimed to describe the natural history of bronchiectasis and identify risk factors associated with premature mortality within a cohort of Aboriginal Australians, New Zealand Maori and Pacific Islanders, and non-indigenous Australians and New Zealanders. METHODS: This was a retrospective cohort study of bronchiectasis patients aged >15 years at three hospitals: Alice Springs Hospital and Monash Medical Centre in Australia, and Middlemore Hospital in New Zealand. Data included demographics, ethnicity, sputum microbiology, radiology, spirometry, hospitalization and survival over 5 years of follow-up. RESULTS: Aboriginal Australians were significantly younger and died at a significantly younger age than other groups. Age- and sex-adjusted all-cause mortality was higher for Aboriginal Australians (hazard ratio (HR): 3.9), and respiratory-related mortality was higher for both Aboriginal Australians (HR: 4.3) and Maori and Pacific Islander people (HR: 1.7). Hospitalization was common: Aboriginal Australians had 2.9 admissions/person-year and 16.9 days in hospital/person-year. Despite Aboriginal Australians having poorer prognosis, calculation of the FACED score suggested milder disease in this group. Sputum microbiology varied with Aspergillus fumigatus more often isolated from non-indigenous patients. Airflow obstruction was common (66.9%) but not invariable. CONCLUSIONS: Bronchiectasis is not one disease. It has a significant impact on healthcare utilization and survival. Differences between populations are likely to relate to differing aetiologies and understanding the drivers of bronchiectasis in disadvantaged populations will be key. PMID- 29502336 TI - Impact of ovarian metastases on survival in patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal malignancy originating from appendiceal and colorectal cancer. AB - AIM: Ovarian metastases from gastrointestinal tract malignancies have been considered an ominous finding with poor prognosis. The aim of this project was to determine the impact on survival, and potential cure, when cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are combined to treat peritoneal malignancy in women with Krukenberg tumours. METHOD: A retrospective analysis of prospectively collected data between January 2010 and July 2015. Female patients undergoing complete CRS (macroscopic tumour removal) and HIPEC for pseudomyxoma peritonei (PMP) of appendiceal origin, or colorectal peritoneal metastases (CPM) were included. Survival was estimated using the Kaplan-Meier method and survival rates compared using the log-rank test. RESULTS: In total, 889 patients underwent surgery for peritoneal malignancy, of whom 551 were female. Of these, 504/551 (91%) underwent complete CRS and HIPEC. Overall, 405/504 (80%) had at least one involved ovary removed either during CRS and HIPEC or at their index prereferral operation. Three hundred and fifty-two patients (87%) had an appendiceal tumour and 53 (13%) had CPM. At a median follow up of 40 months, overall survival (OS) did not differ significantly between patients with or without ovarian involvement in women with a primary low-grade appendiceal tumour or CPM. In women with high-grade primary appendiceal pathology, OS was significantly lower in patients with ovarian metastases compared with those without ovarian involvement. CONCLUSION: Women with ovarian metastases from low grade appendiceal tumours or colorectal cancer treated with CRS and HIPEC have similar survival rates to patients without ovarian metastases. Long-term survival and cure is feasible in patients amenable to complete tumour removal. PMID- 29502337 TI - Reply to Lawday et al. PMID- 29502339 TI - Year in review 2017: Chronic obstructive pulmonary disease and asthma. PMID- 29502338 TI - Efficacy and safety of phosphodiesterase 4 inhibitors in patients with asthma: A systematic review and meta-analysis. AB - Phosphodiesterase 4 (PDE4) inhibitors are a novel medication approved for airway inflammatory diseases including chronic obstructive pulmonary disease. Their role and application in asthma are controversial and not defined. A comprehensive search was performed in major databases (1946-2016) using the keywords: 'phosphodiesterase 4 inhibitor' or 'roflumilast' and 'asthma'. Placebo-controlled trials reporting lung function, airway hyperresponsiveness by direct challenge, asthma control and exacerbations, and adverse events were included. Random or fixed-effects models were used to calculate odds ratios (OR) and mean differences between the two treatment groups. Statistical analyses were conducted using Mann Whitney U-tests and Cochrane systematic review software, Review Manager. Seventeen studies were included in the systematic review, of which 14 studies were included in the meta-analysis. Except for significant statistical heterogeneity in pre- and post-challenge predicted percentage of forced expiratory volume in 1 s (FEV1 %; I2 = 72%, chi2 = 3.35, P = 0.06), there was no heterogeneity in outcome measures. Roflumilast (500 MUg) significantly improved FEV1 (mean difference: 0.05, 95% CI: 0.01-0.09, Z = 2.50, P = 0.01), peak expiratory flow, asthma control and exacerbations, but showed variable effects on airway responsiveness to methacholine and a 20% fall in FEV1 .Of note, PDE4 inhibitors were accompanied with significantly higher adverse events such as headache (OR: 3.99, 95% CI: 1.65-9.66, Z = 3.07, P = 0.002) and nausea (OR: 5.53, 95% CI: 1.38-22.17, Z = 2.41, P = 0.02). In patients with mild asthma, oral PDE4 inhibitors can be considered as an alternative treatment to regular bronchodilators and inhaled controllers. PMID- 29502340 TI - Sarcopenia and Its Clinical Correlates in the General Population: The Rotterdam Study. AB - Sarcopenia, a complex multifactorial condition, is characterized by loss of muscle mass and function, which increases progressively with age. The existence of different definitions has contributed to the large variation in the prevalence estimates of sarcopenia. We aimed to estimate the prevalence of sarcopenia in the general population using the European Working Group on Sarcopenia in Older People (EWGSOP) proposed definition and compared baseline demographic and clinical characteristics between the nonsarcopenia, presarcopenia, and sarcopenia individuals, with particular emphasis on the overlap with osteoporosis and fracture risk. We studied 5911 subjects at a mean age of 69.2 years (55.8% female) with data on sarcopenia participating in the Rotterdam Study, a prospective population-based cohort study in Rotterdam, the Netherlands. Presarcopenia was defined as having only low muscle mass, whereas sarcopenia was defined based on the presence of low muscle mass, plus either low muscle strength or low physical performance. The prevalence of presarcopenia and sarcopenia was 5.9% and 4.4%, respectively. Individuals with sarcopenia were older, more often males, smokers, with less optimal dietary intake, and more often disabled with lower physical activity. Although the prevalence of fractures was higher in individuals with low lean mass (presarcopenic [16.6%] and sarcopenic [23.5%]) compared with the no sarcopenic group (15.5%), the differences were not present after correcting for age and sex. There were no statistical differences in the prevalence of chronic diseases, with the exception of a higher prevalence of COPD in presarcopenic (29.1%) and sarcopenic (26.9%) individuals compared with nonsarcopenic (13.4%) individuals. Osteoporotic individuals with (odds ratio [OR] = 2.59, 95% confidence interval [CI] 1.41-4.45) and without sarcopenia (OR = 2.75, 95% CI 2.01-3.75) had similar elevated risk of nonvertebral fractures. The presence of sarcopenia appears to be independent of chronic diseases with the exception of COPD and more related to lifestyle factors and disabilities. Sarcopenic individuals in the general population are at no greater risk of fracture than what is determined by their low bone mineral density. (c) 2018 American Society for Bone and Mineral Research. PMID- 29502341 TI - Reply to Atamanalp. PMID- 29502342 TI - Caveolin-1 down-regulation is required for Wnt5a-Frizzled 2 signalling in Ha RasV12 -induced cell transformation. AB - Caveolin-1 (Cav1) is down-regulated during MK4 (MDCK cells harbouring inducible Ha-RasV12 gene) transformation by Ha-RasV12 . Cav1 overexpression abrogates the Ha-RasV12 -driven transformation of MK4 cells; however, the targeted down regulation of Cav1 is not sufficient to mimic this transformation. Cav1-silenced cells, including MK4/shCav1 cells and MDCK/shCav1 cells, showed an increased cell area and discontinuous junction-related proteins staining. Cellular and mechanical transformations were completed when MDCK/shCav1 cells were treated with medium conditioned by MK4 cells treated with IPTG (MK4+I-CM) but not with medium conditioned by MK4 cells. Nanoparticle tracking analysis showed that Ha RasV12 -inducing MK4 cells increased exosome-like microvesicles release compared with their normal counterparts. The cellular and mechanical transformation activities of MK4+I-CM were abolished after heat treatment and exosome depletion and were copied by exosomes derived from MK4+I-CM (MK4+I-EXs). Wnt5a, a downstream product of Ha-RasV12 , was markedly secreted by MK4+I-CM and MK4+I EXs. Suppression of Wnt5a expression and secretion using the porcupine inhibitor C59 or Wnt5a siRNA inhibited the Ha-RasV12 - and MK4+I-CM-induced transformation of MK4 cells and MDCK/shCav1 cells, respectively. Cav1 down-regulation, either by Ha-RasV12 or targeted shRNA, increased frizzled-2 (Fzd2) protein levels without affecting its mRNA levels, suggesting a novel role of Cav1 in negatively regulating Fzd2 expression. Additionally, silencing Cav1 facilitated the internalization of MK4+I-EXs in MDCK cells. These data suggest that Cav1 dependent repression of Fzd2 and exosome uptake is potentially relevant to its antitransformation activity, which hinders the activation of Ha-RasV12 -Wnt5a Stat3 pathway. Altogether, these results suggest that both decreasing Cav1 and increasing exosomal Wnt5a must be implemented during Ha-RasV12 -driven cell transformation. PMID- 29502343 TI - LncRNA CCAT2 promoted osteosarcoma cell proliferation and invasion. AB - Long non-coding RNA (lncRNA) plays important roles in tumour progression. Accumulating studies demonstrated that lncRNA colon cancer-associated transcript 2 (CCAT2) acted as an oncogene in many tumours. However, the role of CCAT2 in the development of osteosarcoma has not been elucidated. In our study, we indicated that CCAT2 expression was up-regulated in osteosarcoma tissues and cell lines (SOSP-9607, MG-63, U2OS and SAOS-2). In addition, osteosarcoma cases with higher CCAT2 expression had a poorer disease-free survival and shorter the overall survival time compared to those with lower expression. Overexpression of CCAT2 promoted osteosarcoma cell proliferation, invasion and cell cycle. Furthermore, ectopic expression of CCAT2 increased the expression of mesenchymal markers N cadherin, vimentin and snail and reduced the expression of N-cadherin marker E cadherin. CCAT2 overexpression promoted the LATS2 and c-Myc expression in osteosarcoma cell. These data indicated that CCAT2 served as an oncogene in osteosarcoma and promoted osteosarcoma cell proliferation, cell cycle and invasion. PMID- 29502345 TI - Lesions associated with the use of bits, nosebands, spurs and whips in Danish competition horses. AB - BACKGROUND: Information is needed to guide sport administrators in formulating rules for equipment use in competitions. OBJECTIVES: To seek associations between spurs, bits, nosebands and whips with injuries in horses during competitions in four equestrian sports. STUDY DESIGN: Cross sectional study. METHODS: Post competition evaluations were performed in 3143 horse/rider combinations competing in Danish Equestrian Federation competitions in dressage, showjumping, eventing and endurance by trained evaluators who recorded the presence and type of spurs, bits, nosebands, and whips. Further evaluations recorded noseband tightness, (in three categories <2 cm, 2-3 cm, >3 cm), the presence of hair or blood on spurs; hair loss, lesions or blood on the ribcage behind the girth; abrasions and/or blood at the commissures of the lips; and swelling, lesions or blood on the forequarters or hindquarters. Statistical analysis was performed to determine relationships between discipline (dressage, showjumping, eventing, endurance), level of competition (level 0-7), type/tightness of equipment, and prevalence of injuries. RESULTS: The presence of hair (3.2% of horse/rider combinations) and blood (0.4% of horse/rider combinations) on spurs were highly associated. Longer spurs and lower competition levels were significantly associated with hair on the spurs and worn hair on the horse's ribcage. Oral lesions or blood were visible at the commissures of the lips in 9.2% of horses and increased with level of competition but did not differ between bit types or bitless bridles. Looser upper noseband category was associated with decreased risk of oral lesions (odds ratio [OR] 0.66, 95% confidence interval [95% CI] 0.51-0.86, P = 0.002). However, the absence of a cavesson increased the risk of lesions at the commissures of the lips 2.39 times compared with the loosest noseband (95% CI 1.4-4.11, P = 0.002). MAIN LIMITATIONS: The rules of the equestrian federation did not permit a full intraoral examination. Selection of rider/horse combination was not random. CONCLUSIONS: Lesions of the skin or mucosa at the commissures of the lips may be decreased by limiting noseband tightness and lesions on the chest wall may be decreased by limiting the length of spurs. PMID- 29502344 TI - The vulnerability of spinal motoneurons and soma size plasticity in a mouse model of amyotrophic lateral sclerosis. AB - KEY POINTS: Motoneuron soma size is a largely plastic property that is altered during amyotrophic lateral sclerosis (ALS) progression. We report evidence of systematic spinal motoneuron soma size plasticity in mutant SOD1-G93A mice at various disease stages and across sexes, spinal regions and motoneuron types. We show that disease-vulnerable motoneurons exhibit early increased soma sizes. We show via computer simulations that the measured changes in soma size have a profound impact on the excitability of disease-vulnerable motoneurons. This study reveals a novel form of plasticity in ALS and suggests a potential target for altering motoneuron function and survival. ABSTRACT: alpha-Motoneuron soma size is correlated with the cell's excitability and function, and has been posited as a plastic property that changes during cellular maturation, injury and disease. This study examined whether alpha-motoneuron somas change in size over disease progression in the G93A mouse model of amyotrophic lateral sclerosis (ALS), a disease characterized by progressive motoneuron death. We used 2D- and 3D morphometric analysis of motoneuron size and measures of cell density at four key disease stages: neonatal (P10 - with earliest known disease changes); young adult (P30 - presymptomatic with early motoneuron death); symptom onset (P90 - with death of 70-80% of motoneurons); and end-stage (P120+ - with full paralysis of hindlimbs). We additionally examined differences in lumbar vs. sacral vs. cervical motoneurons; in motoneurons from male vs. female mice; and in fast vs. slow motoneurons. We present the first evidence of plastic changes in the soma size of spinal alpha-motoneurons occurring throughout different stages of ALS with profound effects on motoneuron excitability. Somatic changes are time dependent and are characterized by early-stage enlargement (P10 and P30); no change around symptom onset; and shrinkage at end-stage. A key finding in the study indicates that disease-vulnerable motoneurons exhibit increased soma sizes (P10 and P30). This pattern was confirmed across spinal cord regions, genders and motoneuron types. This extends the theory of motoneuron size-based vulnerability in ALS: not only are larger motoneurons more vulnerable to death in ALS, but are also enlarged further in the disease. Such information is valuable for identifying ALS pathogenesis mechanisms. PMID- 29502346 TI - Past, present and future of in vitro 3D reconstructed inflammatory skin models to study psoriasis. AB - Psoriasis is a common chronic inflammatory skin disease with a significant socio economic impact that can greatly affect the patients' quality of life. The prevailing dogma in the aetiology and pathophysiology of this complex disease is that skin cells, immune cells and environmental factors contribute to psoriatic skin inflammation. For a better understanding of the disease pathogenesis, models are required that mimic the disease and which can be used to develop therapeutics. Over the last decades, in vitro human reconstructed skin models have been widely used in dermatological research and have also been developed to mimic psoriatic skin. This viewpoint summarizes the most commonly used in vitro models and the latest accomplishments for the combination of the dermal and epidermal compartments with other cell types and factors that are important players in the psoriatic skin environment. We aim to critically list the most complete and best-validated models that include major psoriasis hallmarks with regard to gene and protein expression profile and epidermal morphology, but also discuss the shortcoming of the current models. This viewpoint intends to guide the development of in vitro 3D skin models that faithfully mimic all features of psoriatic skin. Such model will enable fundamental biological studies for a better understanding of the aetiology and pathophysiology of psoriasis and aid in novel therapeutic target identification and drug development studies. PMID- 29502347 TI - Acupuncture for depression. AB - BACKGROUND: Depression is recognised as a major public health problem that has a substantial impact on individuals and on society. People with depression may consider using complementary therapies such as acupuncture, and an increasing body of research has been undertaken to assess the effectiveness of acupuncture for treatment of individuals with depression. This is the second update of this review. OBJECTIVES: To examine the effectiveness and adverse effects of acupuncture for treatment of individuals with depression.To determine:* Whether acupuncture is more effective than treatment as usual/no treatment/wait list control for treating and improving quality of life for individuals with depression.* Whether acupuncture is more effective than control acupuncture for treating and improving quality of life for individuals with depression.* Whether acupuncture is more effective than pharmacological therapies for treating and improving quality of life for individuals with depression.* Whether acupuncture plus pharmacological therapy is more effective than pharmacological therapy alone for treating and improving quality of life for individuals with depression.* Whether acupuncture is more effective than psychological therapies for treating and improving quality of life for individuals with depression.* Adverse effects of acupuncture compared with treatment as usual/no treatment/wait list control, control acupuncture, pharmacological therapies, and psychological therapies for treatment of individuals with depression. SEARCH METHODS: We searched the following databases to June 2016: Cochrane Common Mental Disorders Group Controlled Trials Register (CCMD-CTR), Korean Studies Information Service System (KISS), DBPIA (Korean article database website), Korea Institute of Science and Technology Information, Research Information Service System (RISS), Korea Med, Korean Medical Database (KM base), and Oriental Medicine Advanced Searching Integrated System (OASIS), as well as several Korean medical journals. SELECTION CRITERIA: Review criteria called for inclusion of all published and unpublished randomised controlled trials comparing acupuncture versus control acupuncture, no treatment, medication, other structured psychotherapies (cognitive-behavioural therapy, psychotherapy, or counselling), or standard care. Modes of treatment included acupuncture, electro-acupuncture, and laser acupuncture. Participants included adult men and women with depression diagnosed by Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV), Research Diagnostic Criteria (RDC), International Statistical Classification of Diseases and Related Health Problems (ICD), or Chinese Classification of Mental Disorders Third Edition Revised (CCMD-3-R). If necessary, we used trial authors' definitions of depressive disorder. DATA COLLECTION AND ANALYSIS: We performed meta-analyses using risk ratios (RRs) for dichotomous outcomes and standardised mean differences (SMDs) for continuous outcomes, with 95% confidence intervals (CIs). Primary outcomes were reduction in the severity of depression, measured by self-rating scales or by clinician-rated scales, and improvement in depression, defined as remission versus no remission. We assessed evidence quality using the GRADE method. MAIN RESULTS: This review is an update of previous versions and includes 64 studies (7104 participants). Most studies were at high risk of performance bias, at high or unclear risk of detection bias, and at low or unclear risk of selection bias, attrition bias, reporting bias, and other bias.Acupuncture versus no treatment/wait list/treatment as usualWe found low quality evidence suggesting that acupuncture (manual and electro-) may moderately reduce the severity of depression by end of treatment (SMD -0.66, 95% CI -1.06 to -0.25, five trials, 488 participants). It is unclear whether data show differences between groups in the risk of adverse events (RR 0.89, 95% CI 0.35 to 2.24, one trial, 302 participants; low-quality evidence).Acupuncture versus control acupuncture (invasive, non-invasive sham controls)Acupuncture may be associated with a small reduction in the severity of depression of 1.69 points on the Hamilton Depression Rating Scale (HAMD) by end of treatment (95% CI -3.33 to 0.05, 14 trials, 841 participants; low-quality evidence). It is unclear whether data show differences between groups in the risk of adverse events (RR 1.63, 95% CI 0.93 to 2.86, five trials, 300 participants; moderate-quality evidence).Acupuncture versus medicationWe found very low-quality evidence suggesting that acupuncture may confer small benefit in reducing the severity of depression by end of treatment (SMD -0.23, 95% CI -0.40 to -0.05, 31 trials, 3127 participants). Studies show substantial variation resulting from use of different classes of medications and different modes of acupuncture stimulation. Very low quality evidence suggests lower ratings of adverse events following acupuncture compared with medication alone, as measured by the Montgomery-Asberg Depression Rating Scale (MADRS) (mean difference (MD) -4.32, 95% CI -7.41 to -1.23, three trials, 481 participants).Acupuncture plus medication versus medication aloneWe found very low-quality evidence suggesting that acupuncture is highly beneficial in reducing the severity of depression by end of treatment (SMD -1.15, 95% CI 1.63 to -0.66, 11 trials, 775 participants). Studies show substantial variation resulting from use of different modes of acupuncture stimulation. It is unclear whether differences in adverse events are associated with different modes of acupuncture (SMD -1.32, 95% CI -2.86 to 0.23, three trials, 200 participants; very low-quality evidence).Acupuncture versus psychological therapyIt is unclear whether data show differences between acupuncture and psychological therapy in the severity of depression by end of treatment (SMD -0.5, 95% CI -1.33 to 0.33, two trials, 497 participants; low-quality evidence). Low-quality evidence suggests no differences between groups in rates of adverse events (RR 0.62, 95% CI 0.29 to 1.33, one trial, 452 participants). AUTHORS' CONCLUSIONS: The reduction in severity of depression was less when acupuncture was compared with control acupuncture than when acupuncture was compared with no treatment control, although in both cases, results were rated as providing low-quality evidence. The reduction in severity of depression with acupuncture given alone or in conjunction with medication versus medication alone is uncertain owing to the very low quality of evidence. The effect of acupuncture compared with psychological therapy is unclear. The risk of adverse events with acupuncture is also unclear, as most trials did not report adverse events adequately. Few studies included follow-up periods or assessed important outcomes such as quality of life. High-quality randomised controlled trials are urgently needed to examine the clinical efficacy and acceptability of acupuncture, as well as its effectiveness, compared with acupuncture controls, medication, or psychological therapies. PMID- 29502348 TI - Gordon Sanderson MNZM BSc(Ophthalmic Optics) FBOA. PMID- 29502349 TI - In vitro models of multiple system atrophy from primary cells to induced pluripotent stem cells. AB - Multiple system atrophy (MSA) is a rare neurodegenerative disease with a fatal outcome. Nowadays, only symptomatic treatment is available for MSA patients. The hallmarks of the disease are glial cytoplasmic inclusions (GCIs), proteinaceous aggregates mainly composed of alpha-synuclein, which accumulate in oligodendrocytes. However, despite the extensive research efforts, little is known about the pathogenesis of MSA. Early myelin dysfunction and alpha-synuclein deposition are thought to play a major role, but the origin of the aggregates and the causes of misfolding are obscure. One of the reasons for this is the lack of a reliable model of the disease. Recently, the development of induced pluripotent stem cell (iPSC) technology opened up the possibility of elucidating disease mechanisms in neurodegenerative diseases including MSA. Patient specific iPSC can be differentiated in glia and neurons, the cells involved in MSA, providing a useful human disease model. Here, we firstly review the progress made in MSA modelling with primary cell cultures. Subsequently, we focus on the first iPSC based model of MSA, which showed that alpha-synuclein is expressed in oligodendrocyte progenitors, whereas its production decreases in mature oligodendrocytes. We then highlight the opportunities offered by iPSC in studying disease mechanisms and providing innovative models for testing therapeutic strategies, and we discuss the challenges connected with this technique. PMID- 29502350 TI - Postprandial glucose-lowering effect of premeal consumption of protein-enriched, dietary fiber-fortified bar in individuals with type 2 diabetes mellitus or normal glucose tolerance. AB - AIMS/INTRODUCTION: Protein preload improves postprandial glycemia by stimulating secretion of insulin and incretin hormones. However, it requires a large dose of protein to produce a significant effect. The present study was carried out to investigate the postprandial glucose-lowering effect of a premeal protein enriched, dietary fiber-fortified bar (PFB), which contains moderate amounts of protein, in individuals with type 2 diabetes mellitus or normal glucose tolerance (NGT). MATERIALS AND METHODS: The participants (15 type 2 diabetes mellitus and 15 NGT) were randomly assigned to either a premeal or postmeal PFB group and underwent two mixed meal tolerance tests, 1 week apart in reverse order. Plasma levels of glucose, insulin, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide were measured. RESULTS: During the mixed meal tolerance tests, the incremental area under the curve from 0 to 180 min of plasma glucose levels was lower with premeal PFB than with postmeal PFB in the type 2 diabetes mellitus (14,723 +/- 1,310 mg min/dL vs 19,642 +/- 1,367 mg min/dL; P = 0.0002) and NGT participants (3,943 +/- 416 mg min/dL vs 4,827 +/- 520 mg min/dL, P = 0.0296). In the type 2 diabetes mellitus participants, insulinogenic index and the incremental area under the curve from 0 to 180 min of plasma total glucagon-like peptide-1 levels were higher with premeal PFB than with postmeal PFB, but not in the NGT participants. There was no difference in postprandial glucose-dependent insulinotropic polypeptide levels between premeal and postmeal PFB in both groups. CONCLUSIONS: Acute administration of premeal PFB decreased postprandial glucose excursion in both type 2 diabetes mellitus and NGT participants. In the type 2 diabetes mellitus participants, premeal PFB augmented the early-phase insulin secretion, possibly through enhancing glucagon-like peptide-1 secretion. PMID- 29502351 TI - Dense infraspecific sampling reveals rapid and independent trajectories of plastome degradation in a heterotrophic orchid complex. AB - Heterotrophic plants provide excellent opportunities to study the effects of altered selective regimes on genome evolution. Plastid genome (plastome) studies in heterotrophic plants are often based on one or a few highly divergent species or sequences as representatives of an entire lineage, thus missing important evolutionary-transitory events. Here, we present the first infraspecific analysis of plastome evolution in any heterotrophic plant. By combining genome skimming and targeted sequence capture, we address hypotheses on the degree and rate of plastome degradation in a complex of leafless orchids (Corallorhiza striata) across its geographic range. Plastomes provide strong support for relationships and evidence of reciprocal monophyly between C. involuta and the endangered C. bentleyi. Plastome degradation is extensive, occurring rapidly over a few million years, with evidence of differing rates of genomic change among the two principal clades of the complex. Genome skimming and targeted sequence capture differ widely in coverage depth overall, with depth in targeted sequence capture datasets varying immensely across the plastome as a function of GC content. These findings will help to fill a knowledge gap in models of heterotrophic plastid genome evolution, and have implications for future studies in heterotrophs. PMID- 29502352 TI - Surgery for women with posterior compartment prolapse. AB - BACKGROUND: Posterior vaginal wall prolapse (also known as 'posterior compartment prolapse') can cause a sensation of bulge in the vagina along with symptoms of obstructed defecation and sexual dysfunction. Interventions for prevention and conservative management include lifestyle measures, pelvic floor muscle training, and pessary use. We conducted this review to assess the surgical management of posterior vaginal wall prolapse. OBJECTIVES: To evaluate the safety and effectiveness of any surgical intervention compared with another surgical intervention for management of posterior vaginal wall prolapse. SEARCH METHODS: We searched the Cochrane Incontinence Group Specialised Register of controlled trials, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (searched April 2017). We also searched the reference lists of relevant articles, and we contacted researchers in the field. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing different types of surgery for posterior vaginal wall prolapse. DATA COLLECTION AND ANALYSIS: We used Cochrane methods. Our primary outcomes were subjective awareness of prolapse, repeat surgery for any prolapse, and objectively determined recurrent posterior wall prolapse. MAIN RESULTS: We identified 10 RCTs evaluating 1099 women. Evidence quality ranged from very low to moderate. The main limitations of evidence quality were risk of bias (associated mainly with performance, detection, and attrition biases) and imprecision (associated with small overall sample sizes and low event rates).Transanal repair versus transvaginal repair (four RCTs; n = 191; six months' to four years' follow-up)Awareness of prolapse is probably more common after the transanal approach (risk ratio (RR) 2.78, 95% confidence interval (CI) 1.00 to 7.70; 2 RCTs; n = 87; I2 = 0%; low-quality evidence). If 10% of women are aware of prolapse after transvaginal repair, between 10% and 79% are likely to be aware after transanal repair.Repeat surgery for any prolapse: Evidence is insufficient to show whether there were any differences between groups (RR 2.42, 95% CI 0.75 to 7.88; 1 RCT; n = 57; low-quality evidence).Recurrent posterior vaginal wall prolapse is probably more likely after transanal repair (RR 4.12, 95% CI 1.56 to 10.88; 2 RCTs; n = 87; I2 = 35%; moderate-quality evidence). If 10% of women have recurrent prolapse on examination after transvaginal repair, between 16% and 100% are likely to have recurrent prolapse after transanal repair.Postoperative obstructed defecation is probably more likely with transanal repair (RR 1.67, 95% CI 1.00 to 2.79; 3 RCTs; n = 113; I2 = 10%; low-quality evidence).Postoperative dyspareunia: Evidence is insufficient to show whether there were any differences between groups (RR 0.32, 95% CI 0.09 to 1.15; 2 RCTs; n = 80; I2 = 5%; moderate-quality evidence).Postoperative complications: Trials have provided no conclusive evidence of any differences between groups (RR 3.57, 95% CI 0.94 to 13.54; 3 RCTs; n = 135; I2 = 37%; low-quality evidence). If 2% of women have complications after transvaginal repair, then between 2% and 21% are likely to have complications after transanal repair.Evidence shows no clear differences between groups in operating time (in minutes) (mean difference (MD) 1.49, 95% CI -11.83 to 8.84; 3 RCTs; n = 137; I2 = 90%; very low-quality evidence).Biological graft versus native tissue repairEvidence is insufficient to show whether there were any differences between groups in rates of awareness of prolapse (RR 1.09, 95% CI 0.45 to 2.62; 2 RCTs; n = 181; I2 = 13%; moderate-quality evidence) or repeat surgery for any prolapse (RR 0.60, 95% CI 0.18 to 1.97; 2 RCTs; n = 271; I2 = 0%; moderate-quality evidence). Trials have provided no conclusive evidence of a difference in rates of recurrent posterior vaginal wall prolapse (RR 0.55, 95% CI 0.30 to 1.01; 3 RCTs; n = 377; I2 = 6%; moderate-quality evidence); if 13% of women have recurrent prolapse on examination after native tissue repair, between 4% and 13% are likely to have recurrent prolapse after biological graft. Evidence is insufficient to show whether there were any differences between groups in rates of postoperative obstructed defecation (RR 0.96, 95% CI 0.50 to 1.86; 2 RCTs; n = 172; I2 = 42%; moderate-quality evidence) or postoperative dyspareunia (RR 1.27, 95% CI 0.26 to 6.25; 2 RCTs; n = 152; I2 = 74%; low-quality evidence). Postoperative complications were more common with biological repair (RR 1.82, 95% CI 1.22 to 2.72; 3 RCTs; n = 448; I2 = 0%; low-quality evidence).Other comparisonsSingle RCTs compared site-specific vaginal repair versus midline fascial plication (n = 74), absorbable graft versus native tissue repair (n = 132), synthetic graft versus native tissue repair (n = 191), and levator ani plication versus midline fascial plication (n = 52). Data were scanty, and evidence was insufficient to show any conclusions about the relative effectiveness or safety of any of these interventions. The mesh exposure rate in the synthetic group compared with the native tissue group was 7%. AUTHORS' CONCLUSIONS: Transvaginal repair may be more effective than transanal repair for posterior wall prolapse in preventing recurrence of prolapse, in the light of both objective and subjective measures. However, data on adverse effects were scanty. Evidence was insufficient to permit any conclusions about the relative effectiveness or safety of other types of surgery. Evidence does not support the utilisation of any mesh or graft materials at the time of posterior vaginal repair. Withdrawal of some commercial transvaginal mesh kits from the market may limit the generalisability of our findings. PMID- 29502353 TI - Novel TLE4-NTRK2 fusion in a ganglioglioma identified by array-CGH and confirmed by NGS: Potential for a gene targeted therapy. AB - Gangliogliomas are rare neoplasms of the central nervous system that mostly originate in the temporal lobe and are associated with seizures. Literature mentions that BRAF mutations are most commonly associated with gangliogliomas. We discuss a unique case of ganglioglioma originating in the posterior fossa that showed multiple losses and a unique interstitial deletion at 9q21 by an array comparative genome hybridization (array-CGH). The deletion led to a novel molecular fusion (TLE4-NTRK2) which was confirmed by next generation sequencing and provides a potential for a gene-targeted therapy. PMID- 29502354 TI - Antimicrobial activity of metal oxide microspheres: an innovative process for homogeneous incorporation into materials. AB - AIMS: To investigate the potent control of microbial surface contamination of an innovative process which consists in incorporating metal oxide microspheres homogeneously into materials. METHODS AND RESULTS: Spherical microspheres containing zinc and magnesium oxides synthesized via a one-step manufacturing process (Pyrolyse Pulverisee(r) ) and incorporated into different plastic matrices were evaluated for their antimicrobial activity according to JIS Z 2801 standard. A significant activity was observed for microsphere-added polyethylene coupons with a reduction of all tested bacteria populations, including Gram negative and Gram positive even expressing acquired antibiotic resistance (Escherichia coli ESBL, Staphylococcus aureus metiR). An antiviral activity higher than 2 log of reduction was also observed on H1N1 and HSV-1 viruses. This antimicrobial effect was dose-dependent and time-dependent for both polyethylene and polypropylene matrices. Antimicrobial activity was maintained after exposition to disinfectants and totally preserved 50 months after the preparation of the coupons. CONCLUSIONS: Incorporated into plastic matrices, metal oxide microspheres showed significant antibacterial and antiviral activities. SIGNIFICANCE AND IMPACT OF STUDY: This is, to our knowledge, the first report on an original process incorporating metal oxide microspheres, which have specific physico-chemical and antimicrobial properties, into materials that could be used for surface contamination prevention. PMID- 29502355 TI - State of the art of nonthermal and thermal processing for inactivation of micro organisms. AB - Despite the constant development of novel thermal and nonthermal technologies, knowledge on the mechanisms of microbial inactivation is still very limited. Technologies such as high pressure, ultraviolet light, pulsed light, ozone, power ultrasound and cold plasma (advanced oxidation processes) have shown promising results for inactivation of micro-organisms. The efficacy of inactivation is greatly enhanced by combination of conventional (thermal) with nonthermal, or nonthermal with another nonthermal technique. The key advantages offered by nonthermal processes in combination with sublethal mild temperature (<60 degrees C) can inactivate micro-organisms synergistically. Microbial cells, when subjected to environmental stress, can be either injured or killed. In some cases, cells are believed to be inactivated, but may only be sublethally injured leading to their recovery or, if the injury is lethal, to cell death. It is of major concern when micro-organisms adapt to stress during processing. If the cells adapt to a certain stress, it is associated with enhanced protection against other subsequent stresses. One of the most striking problems during inactivation of micro-organisms is spores. They are the most resistant form of microbial cells and relatively difficult to inactivate by common inactivation techniques, including heat sterilization, radiation, oxidizing agents and various chemicals. Various novel nonthermal processing technologies, alone or in combination, have shown potential for vegetative cells and spores inactivation. Predictive microbiology can be used to focus on the quantitative description of the microbial behaviour in food products, for a given set of environmental conditions. PMID- 29502356 TI - Age-dependent leaf physiology and consequences for crown-scale carbon uptake during the dry season in an Amazon evergreen forest. AB - Satellite and tower-based metrics of forest-scale photosynthesis generally increase with dry season progression across central Amazonia, but the underlying mechanisms lack consensus. We conducted demographic surveys of leaf age composition, and measured the age dependence of leaf physiology in broadleaf canopy trees of abundant species at a central eastern Amazon site. Using a novel leaf-to-branch scaling approach, we used these data to independently test the much-debated hypothesis - arising from satellite and tower-based observations - that leaf phenology could explain the forest-scale pattern of dry season photosynthesis. Stomatal conductance and biochemical parameters of photosynthesis were higher for recently mature leaves than for old leaves. Most branches had multiple leaf age categories simultaneously present, and the number of recently mature leaves increased as the dry season progressed because old leaves were exchanged for new leaves. These findings provide the first direct field evidence that branch-scale photosynthetic capacity increases during the dry season, with a magnitude consistent with increases in ecosystem-scale photosynthetic capacity derived from flux towers. Interactions between leaf age-dependent physiology and shifting leaf age-demographic composition are sufficient to explain the dry season photosynthetic capacity pattern at this site, and should be considered in vegetation models of tropical evergreen forests. PMID- 29502357 TI - Qiliqiangxin attenuates hypoxia-induced injury in primary rat cardiac microvascular endothelial cells via promoting HIF-1alpha-dependent glycolysis. AB - Protection of cardiac microvascular endothelial cells (CMECs) against hypoxia injury is an important therapeutic strategy for treating ischaemic cardiovascular disease. In this study, we investigated the effects of qiliqiangxin (QL) on primary rat CMECs exposed to hypoxia and the underlying mechanisms. Rat CMECs were successfully isolated and passaged to the second generation. CMECs that were pre-treated with QL (0.5 mg/mL) and/or HIF-1alpha siRNA were cultured in a three gas hypoxic incubator chamber (5% CO2 , 1% O2 , 94% N2 ) for 12 hours. Firstly, we demonstrated that compared with hypoxia group, QL effectively promoted the proliferation while attenuated the apoptosis, improved mitochondrial function and reduced ROS generation in hypoxic CMECs in a HIF-1alpha-dependent manner. Meanwhile, QL also promoted angiogenesis of CMECs via HIF-1alpha/VEGF signalling pathway. Moreover, QL improved glucose utilization and metabolism and increased ATP production by up-regulating HIF-1alpha and a series of glycolysis-relevant enzymes, including glucose transport 1 (GLUT1), hexokinase 2 (HK2), 6 phosphofructokinase 1 (PFK1), pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA). Our findings indicate that QL can protect CMECs against hypoxia injury via promoting glycolysis in a HIF-1alpha-dependent manner. Lastly, the results suggested that QL-dependent enhancement of HIF-1alpha protein expression in hypoxic CMECs was associated with the regulation of AMPK/mTOR/HIF-1alpha pathway, and we speculated that QL also improved HIF-1alpha stabilization through down regulating prolyl hydroxylases 3 (PHD3) expression. PMID- 29502359 TI - FGF23 Neutralizing Antibody Partially Improves Bone Mineralization Defect of HMWFGF2 Isoforms in Transgenic Female Mice. AB - Mice overexpressing high molecular weight FGF2 isoforms (HMWTg) in osteoblast lineage phenocopy human X-linked hypophosphatemic rickets (XLH) and a Hyp murine model of XLH demonstrating increased FGF23/FGF receptor signaling and hypophosphatemic rickets/osteomalacia. Because HMWFGF2 was upregulated in bones of Hyp mice and abnormal FGF23 signaling is important in XLH, HMWTg mice were used to examine the effect of the FGF23 neutralizing antibody (FGF23Ab). Eight week-old female Vector control mice and HMWTg mice were treated with FGF23Ab or control IgG. A single injection of FGF23Ab rescued abnormal hypophosphatemia in HMWTg. The decreased type II sodium-dependent phosphate co-transporter (Npt2a) was rescued by FGF23Ab treatment. Inappropriately low serum 1,25(OH)2 D in HMWTg mice was normalized by FGF23Ab treatment, which is accompanied by increased anabolic vitamin D hydroxylase Cyp27b1 and decreased catabolic vitamin D hydroxylase Cyp24 mRNA in kidney. Long-term treatment with FGF23Ab normalized femur length and significantly increased vertebrae BMD and BMC, and femur BMC in HMWTg mice compared to IgG-treated HMWTg mice. Micro-computed tomography (MUCT) revealed increased cortical porosity and decreased cortical apparent density in the HMWTg-IgG group compared with the Vector-IgG group; however, FGF23Ab treatment rescued defective cortical mineralization, decreased porosity, and increased apparent density in HMWTg mice. Bone histomorphometry analysis showed FGF23Ab treatment decreased osteoid volume, increased intra-label thickness, mineralization apposition rate, and bone formation rate in HMWTg mice. FGF23Ab improved disorganized double labeling in femurs from HMWTg mice. Quantitative real-time PCR analysis of tibia shafts showed FGF23Ab treatment normalized the osteocalcin (Ocn) mRNA expression in HMWTg mice, but further increased expression of SIBLING protein-related and pyrophosphate-related genes that are important in matrix mineralization, suggesting that HMWFGF2 modulates these genes independent of FGF23. We conclude that FGF23Ab partially rescued hypophosphatemic osteomalacia in HMWTg. However, long-term treatment with FGF23Ab further increased SIBLING protein-related genes and pyrophosphate-related genes in bone that could contribute to incomplete rescue of the mineralization defect. (c) 2018 American Society for Bone and Mineral Research. PMID- 29502358 TI - METTL3 regulates alternative splicing of MyD88 upon the lipopolysaccharide induced inflammatory response in human dental pulp cells. AB - Dental pulp inflammation is a widespread public health problem caused by oral bacterial infections and can progress to pulp necrosis and periapical diseases. N6-methyladenosine (m6A) is a prevalent epitranscriptomic modification in mRNA. Previous studies have demonstrated that m6A methylation plays important roles in cell differentiation, embryonic development and stress responses. However, whether m6A modification affects dental pulp inflammation remains unknown. To address this issue, we investigated the expression of m6A and N6-adenosine methyltransferase (METTL3, METTL14) as well as demethylases (FTO, ALKBH5) and found that the levels of m6A and METTL3 were up-regulated in human dental pulp cells (HDPCs) stimulated by lipopolysaccharide (LPS). Furthermore, we knocked down METTL3 and demonstrated that METTL3 depletion decreased the expression of inflammatory cytokines and the phosphorylation of IKKalpha/beta, p65 and IkappaBalpha in the NF-kappaB signalling pathway as well as p38, ERK and JNK in the MAPK signalling pathway in LPS-induced HDPCs. The RNA sequencing analysis revealed that the vast number of genes affected by METTL3 depletion was associated with the inflammatory response. Previous research has shown that METTL3-dependent N6-adenosine methylation plays an important role in mRNA splicing. In this study, we found that METTL3 knockdown facilitated the expression of MyD88S, a splice variant of MyD88 that inhibits inflammatory cytokine production, suggesting that METTL3 might inhibit the LPS-induced inflammatory response of HDPCs by regulating alternative splicing of MyD88. These data shed light on new findings in epitranscriptomic regulation of the inflammatory response and open new avenues for research into the molecular mechanisms of dental pulp inflammation. PMID- 29502360 TI - Glucagon-like peptide-2: A potential role in equine insulin dysregulation. AB - BACKGROUND: Equine insulin dysregulation (ID) is a common and poorly understood disorder that increases the risk of laminitis. Recent data show that the condition may be associated with alteration of the enteroinsular axis and enhanced glucose bioavailability. Upregulation of glucagon-like peptide-2 (GLP 2), an intestinotrophic peptide, leads to enhanced nutrient uptake and metabolic dysfunction in other species. OBJECTIVES: The study aimed to 1) determine whether GLP-2 is differentially expressed in insulin-dysregulated ponies, compared with healthy ponies, and 2) confirm intestinal expression of the GLP-2 receptor in horses (eGLP-2R). STUDY DESIGN: Cohort study. METHODS: Fasting and post-prandial GLP-2 concentrations were measured in archived plasma samples obtained from 25 mixed-breed ponies during two feeding studies. Measurements were undertaken with an ELISA that was validated for equine use as part of the current study. Ponies were designated as healthy or insulin-dysregulated based on an oral glucose test, and the results were compared between groups. The gene expression of the eGLP-2R was determined with polymerase chain reaction. RESULTS: Basal, fasted plasma GLP 2 concentrations were higher in ponies with ID, compared with healthy ponies. Grazing increased GLP-2 in healthy, but not in insulin-dysregulated, ponies. The eGLP-2R gene was expressed in the small intestine and pancreas. MAIN LIMITATIONS: The study was performed with a relatively small sample size. The specificity of the GLP-2 assay could not be determined due to the lack of equine-specific assay standards. CONCLUSIONS: This study has demonstrated that GLP-2 may be important in the pathogenesis of equine ID and suggests that the eGLP-2R may be a novel therapeutic target for the treatment of equine ID. PMID- 29502362 TI - Clinical impact of healthcare-associated acquisition in cirrhotic patients with community-onset spontaneous bacterial peritonitis. AB - Background/Aims: Healthcare-associated (HCA) infection is a recently suggested new category of community-onset infections. The implications of HCA infections in terms of diagnosis, treatment, and outcomes of spontaneous bacterial peritonitis (SBP) are not well understood. We sought to delineate the differences between community-acquired (CA) SBP and HCA SBP with specific interest in the antimicrobial resistance of causative microorganisms and outcomes. Methods: We conducted a retrospective cohort study of all SBP episodes with positive ascitic culture and/or blood culture from June 2000 to August 2011. Community-onset SBP episodes were included when they occurred within 48 hours after admission and were classified as CA SBP and HCA SBP based on the predefined criteria. Results: A total of 188 episodes of community-onset SBP were analyzed (65.4% HCA SBP and 34.6% CA SBP). HCA SBP had a higher resistance rate to third-generation cephalosporin (6.8% vs. 1.6%, p = 0.168). The overall 30-day mortality was similar between both groups (37.4% vs. 41.5%, p = 0.638). The independent risk factors for 30-day all-cause mortality in community-onset SBP included high Child Pugh score, acute kidney injury, and resistance to third-generation cephalosporins; HCA infection was not associated. Conclusions: Hepatic functional status, renal dysfunction, and third-generation cephalosporin resistant pathogens more adversely affected the outcome of cirrhotic patients with community-onset SBP rather than HCA infection. The higher rate of third-generation cephalosporin resistance was notable in HCA SBP, which will require a novel approach to empirical antibiotic treatment selection in this population. PMID- 29502361 TI - Fundamental role of dendritic cells in inducing Th2 responses. AB - A mysterious puzzle in immunology is how the immune system decides what types of immune response to initiate against various stimuli. Although much is known about control of T helper 1 (Th1) and Th17 responses, the mechanisms that initiate Th2 responses remain obscure. Antigen-presenting cells, particularly dendritic cells (DCs), are mandatory for the induction of a Th cell response. Numerous studies have documented the organizing role of DCs in this process. The present review summarizes the fundamental roles of DCs in inducing Th2 responses. PMID- 29502363 TI - Performance of disposable endoscopic forceps according to the manufacturing techniques. AB - Background/Aims: Recently, to lower the production costs and risk of infection, new disposable biopsy forceps made using simple manufacturing techniques have been introduced. However, the effects of the manufacturing techniques are unclear. The aim of this study was to evaluate which types of biopsy forceps could obtain good-quality specimens according to the manufacturing techniques. Methods: By using an in vitro nitrile glove popping model, we compared the popping ability among eight different disposable biopsy forceps (one pair of biopsy forceps with cups made by a cutting method [cutting forceps], four pairs of biopsy forceps with cups made by a pressing method [pressing forceps], and three pairs of biopsy forceps with cups made using a injection molding method [molding forceps]). Using an in vivo swine model, we compared the penetration depth and quality of specimen among the biopsy forceps. Results: In the in vitro model, the molding forceps provided a significantly higher popping rate than the other forceps (cutting forceps, 25.0%; pressing forceps, 17.5%; and molding forceps, 41.7%; p = 0.006). In the in vivo model, the cutting and pressing forceps did not provide larger specimens, deeper biopsy specimen, and higher specimen adequacy than those obtained using the molding forceps (p = 0.2631, p = 0.5875, and p = 0.2147, respectively). However, the molding forceps showed significantly more common crush artifact than the others (cutting forceps, 0%; pressing forceps, 5.0%; and molding forceps, 43.3%; p = 0.0007). Conclusions: The molding forceps provided lower performance than the cutting and pressing forceps in terms of crush artifact. PMID- 29502364 TI - Time-dependent reversal of significant intrapulmonary shunt after liver transplantation. AB - Background/Aims: Although the association between intrapulmonary shunt (IPS) and liver cirrhosis is clear, data of repeated contrast echocardiography (CE) before and after liver transplantation (LT) to evaluate factors associated with IPS are limited. Methods: Hand-agitated saline was used for CE and, by assessing left chamber opacification, IPS was classified as grade 0 to 4. Grade 3/4 constituted significant IPS and hepatopulmonary syndrome (HPS) was defined as significant IPS with the arterial partial pressure of oxygen < 70 mmHg. Results: Before LT, 253 patients underwent CE and the frequency of significant IPS and HPS were 44% (n = 112) and 7% (n = 17), respectively. Child-Pugh score (odds ratio [OR], 1.345; 95% confidence interval [CI], 1.090 to 1.660; p = 0.006) and arterial oxygen content (OR, 0.838; 95% CI, 0.708 to 0.991; p = 0.039) were independent determinants of significant IPS, whereas direct bilirubin (OR, 1.076; 95% CI, 1.012 to 1.144; p = 0.019) was the only variable associated with HPS. Among 153 patients who underwent successful LT, repeated CE was performed in 97 (63%), which showed significant reductions in IPS grade (from 2.6 +/- 1.0 to 1.2 +/- 1.3, p < 0.001) and the prevalence of significant IPS (from 56% to 20%, p = 0.038). After adjustment for pre-LT IPS grade, time from LT to repeated CE presented negative linear relationship with post-LT IPS grade (r 2 = 0.366, p < 0.001) and was the only determinant of post-LT IPS grade (OR, 1.009; 95% CI, 1.003 to 1.014; p = 0.004). Conclusions: Repeated CE is useful to evaluate intrapulmonary vascular change before and after LT. Reversal of IPS after successful LT is time-dependent and follow-up duration should be considered for accurate assessment of IPS after LT. PMID- 29502365 TI - [Molecular origins of cancer and future cancer therapy]. AB - The accumulation of genomic and epigenetic changes gives rise to the tumorigenesis and progression. Currently, clonal evolution model and cancer stem cell model, two leading theories of caner origin, are becoming complementary to one another to explain the nature of tumor heterogeneity. Precision medicine that is based on the next generation sequencing and big data describes the phenomena of tumor heterogeneity more precisely. The future cancer therapy may need more comprehensive and dynamical understandings of the distinct subclones of tumor and follow the trends of cancer evolution. PMID- 29502366 TI - [Multi-channel promotion of lung cancer progress by bone marrow derived mesenchymal stem cells in tumor microenvironment]. AB - Objective: To observe the growth and metastasis of lung cancer promoted by bone marrow derived mesenchymal stem cells (BMSCs) in tumor microenvironment and investigate the underlined mechanisms. Methods: Specific chemotaxis of BMSCs towards lung cancer was observed, and the tumor growth and metastasis were assessed in vivo. Furthermore, CD34 expression determined by immunohistochemistry was used to assess the microvessel density (MVD), and the expressions of GFP and alpha-SMA determined by immunofluorescence were used to detect the BMSCs derived mesenchymal cells. We investigated the effect of BMSCs on migration, invasion of lung cancer cells including A549 and H446 cells by using scratch assays and Transwell Assay in vitro. We also explored the effect of BMSCs on epithelial mesenchymal transition of A549 and H446 cells by observing the phenotype transition and E-Cadherin protein expression detected by Western blot. At last, we screened the potentially key soluble factors by enzyme linked immunosorbent assay (ELISA). Results: In NOD mice, labeled BMSCs injected via tail vein were special chemotaxis to tumor cells, and promoted the tumor growth [the time of tumor formation in A549+ BMSCs and A549 alone was (5.0+/-1.5) days and (10.0+/ 3.6) days, respectively, P<0.05; the time of tumor formation in H446+ BMSCs and H446 alone was (5.2+/-1.5) days and (12.0+/-2.0) days, respectively, P<0.05]. The tumor incidence of A549+ BMSCs was 100%, significantly higher than 66.7% of A549 alone (P<0.05), while the tumor incidence of H446+ BMSCs was 83.0%, significantly higher than 50.0% of H446 alone (P<0.05). The BMSCs also increased the tumor volume [the tumor volume of A549+ BMSCs and A549 alone was (193.0+/-42.3) mm(3) and (97.8+/-42.9) mm(3,) respectively, P<0.05; the tumor volume of H446+ BMSCs and H446 alone was (78.6+/-34.8) mm(3) and (25.3+/-12.7) mm(3,) respectively, P<0.05] and facilitated the tumor metastasis (the tumor metastatic incidence of A549+ BMSCs and A549 alone was 100.0% and 16.7%, respectively, P<0.05; the tumor metastatic incidence of H446+ BMSCs and H446 alone was 100.0% and 0.0%, respectively, P<0.05). Furthermore, BMSCs increased tumor vessel formation (the MVD of A549+ BMSCs and A549 alone was 53.2+/-11.4 and 25.3+/-11.5, respectively, P<0.05; the MVD of H446+ BMSCs and H446 alone was 56.8+/-12.5 and 24.8+/-10.0, respectively, P<0.05). BMSCs were able to differentiate to fibroblasts in the lung squamous cell carcinoma and promoted the migration and invasion of lung cancer cells (the A of cells in the migrated lower chambers of A549+ BMSCs and A549 alone was 1.9+/-0.2 and 1.1+/-0.1, respectively, P<0.05; the A of cells in the migrated lower chambers of H446+ BMSCs and H446 alone was 1.9+/-0.3 and 0.9+/ 0.2, respectively, P<0.05). The cell shape was longer and sharper, the intercellular junctions were reduced and the relative expression level of E Cadherin protein in A549 co-cultured with BMDCs was 0.36, significantly down regulated when compared to 0.55 of A549 alone (P<0.05), and the relative expression level of E-Cadherin protein in H446 co-cultured with BMDCs was 0.28, significantly down-regulated when compared to 0.46 of H446 cells alone (P<0.05). The concentration of IL-6 in the conditional medium of BMSCs, A549 co-cultured with BMSCs and H446 co-cultured with BMSCs was 910.5, 957.2, and 963.8, respectively, significantly up-regulated when compared to 18.8 of control group (P<0.05). The expression level of PGE2 in A549 co-cultured with BMSCs and H446 co cultured with BMSCs was 130.5 and 87.2, significantly up-regulated when compared to 13.8 of control group and 23.8 of BMSCs group (P<0.05). Conclusions: Our results suggest that BMSCs contribute to the tumor growth through facilitating angiogenesis, and promote tumor metastasis through paracrine manner and down regulation of E-Cadherin protein. IL-6 and PGE2 produced by BMDCs might be the potentially important cytokines. PMID- 29502367 TI - [Triptolide reverses apatinib resistance in gastric cancer cell line MKN45 via inhibition of heat shock protein 70]. AB - Objective: To investigate the effect of triptolide, a specific inhibitor of heat shock protein 70 (HSP70), on apatinib resistance in gastric cancer cells line MKN45. Methods: The apatinib-resistant cells (MKN45/AR) and MKN45 parental cells were treated with apatinib, triptolide and apatinib combined with triptolide, respectively. CCK-8 assay was performed to determine the half maximal inhibitory concentration (IC(50)) of MKN45/AR and MKN45 cells in the presence of different treatment. The mRNA expression of heat shock protein gene (HSPA1A and HSPA1B) was detected by RT-PCR, while the protein expression of heat shock protein 70 was analyzed using Western blot in MKN45/AR and MKN45 cells. Results: The IC(50) values of apatinib-sensitive and apatinib-resistant MKN45 cells were 10.411 MUmol/L and 70.527 MUmol/L, respectively, showing a significant difference (P<0.05). The mRNA expression of HSPA1A and HSPA1B in MKN45/AR cells was significantly higher than that in MKN45 cells (P<0.001). The protein expression of heat shock protein 70 was significantly decreased after 0.25 MUmol/L triptolide treatment in MKN45/AR cells (P<0.01). When heat shock protein 70 was inhibited by triptolide, the IC(50) value of apatinib in MKN45/AR cells was reduced to 11.679 MUmol/L, which was significantly lower than cells treated with apatinib alone (P<0.05). Conclusions: The apatinib-resistant MKN45 cells have high levels of heat shock protein 70. Low doses of triptolide can significantly inhibit heat shock protein 70, leading to reverse the resistance phenotype of MKN45/AR cells. Therefore, inhibition of heat shock protein 70 provides a new therapy strategy for patients with apatinib resistance. PMID- 29502368 TI - [Relationships between the enrichment of ETBF, Fn, Hp in intestinal and colorectal cancer]. AB - Objective: To explore relationships between the enrichment of ETBF, Fn, Hp in feces, tissues and colorectal cancer. Methods: Feces, lesion tissue and adjacent tissue from 24 patients with colorectal cancer and 31 patients with adenomas were collected, and we collected Feces and tissue of 20 healthy control persons. Then the copy numbers of enterotoxigenic B. fragilis (ETBF), Fusobacterium nucleatum (Fn) and Helicobacter pylori (Hp) were determined by quantitative real-time PCR. Immunohistochemical method was used to examine the expression intensity of EGFR and p53, and the relationships between different expression intensity of EGFR, p53 and the numbers of three bacterias. Results: In the feces, copy numbers of ETBF and Fn were as follous: colorectal cancer group>adenomas group>healthy control group (P<0.05). Copy numbers of Hp were as follous: colorectal cancer group>healthy control group (P<0.01); adenomas group>healthy control group (P<0.01). In the tissue, copy numbers of ETBF, Fn were as follows: colorectal cancer group>adenomas group>healthy control group (P<0.05). Copy numbers of Hp were as follows: colorectal cancer group>healthy control group (P<0.01); adenomas group>healthy control group (P<0.01). Copy numbers of those three bacteria in the lesion tissue and the adjacent tissue had no significant difference. This happened both in colorectal cancer group and adenomas group. The different expression intensity of EGFR, p53 and the number of three bacteria showed no obviously statistical correlation(P>0.05). Conclusion: Adenomatous polyp and colorectal cancer patients show high enrichment of ETBF, Fn and Hp in both feces and tissues. ETBF, Fn and Hp probably contribute to the development of adenomatous polyp and colorectal cancer. Trial registration Chinese Clinical Trial Registry, ChiCTR-BOC-17012509. PMID- 29502369 TI - [The relationship between vimentin protein expression in endothelial cells and contrast-enhanced ultrasound characters in VETC (+ ) hepatocellular carcinoma]. AB - Objective: To detect the possible molecular mechanisms of the formation of vessels that encapsulated tumor clusters (VETC) and identify the relationship between vimentin protein expression in endothelial cells and contrast-enhanced ultrasound characters in VETC (+ ) hepatocellular carcinoma (HCC). Methods: A total of 64 paraffin embedded HCC tissue samples were collected, all of which the tumor diameters were between 2 cm and 5 cm measured by the preoperative ultrasound. Immunohistochemistry staining for CD34 was used to detect the formation of VETC and the expressions of angiopoietin-2 (Ang-2) and vimentin were also determined. Human umbilical vein endothelial cells (HUVECs) were treated with 150 ng/ml recombinant human Ang-2 protein (rhAng-2) at various times and the protein expression of vimentin was detected by western blot assay. The contrast enhanced ultrasound characters were also analyzed in both VETC (+ ) and VETC (-) HCC. Results: Tumor clusters encapsulated by vessels to form cobweb-like networks, which were identified as VETC phenotype, were observed in 27 HCC tissues (42.18%). In VETC (+ ) HCC tissues, Ang-2 was overexpressed in tumor cells and endothelial cells while vimentin was only upregulated in endothelial cells. With the treatment of 150 ng/ml rhAng-2 protein, the expression of vimentin in HUVECs was 0.878+/-0.102 and 0.918+/-0.092 at 12 h and 36 h, significantly upregulated when compared to the 0.322+/-0.061 at 6 h (P<0.01). In contrast-enhanced ultrasound, a crack and tendon-like filling character was observed in VETC (+ ) HCC during the arterial-phase, while the large scale and diffuse-like filling character was observed in VETC (-) HCC. The filling time of unit diameter in VETC (+ ) HCC was (3.95+/-0.22)s, significantly longer than (2.28+/-0.27)s of VETC (-) HCC (P<0.01). Conclusions: The overexpressions of Ang 2 and vimentin are positively correlated with the formation of VETC and considered as potential therapeutic targets of VETC (+ ) HCC. The crack and tendon-like filling characters in arterial-phase of contrast-enhanced ultrasound indicates the VETC (+ ) HCC. PMID- 29502370 TI - [Impact of the 21-gene recurrence score assay in clinical treatment and prognosis analysis for patients with hormone receptor positive early-stage breast cancer]. AB - Objective: To explore the association between the 21-gene recurrence score (RS) and clinicopathologic characteristics as well as prognosis in patients with axillary lymph node negative, hormone receptor (HR) positive breast cancer. Methods: The clinicopathologic data of 439 early breast cancer patients who underwent 21 gene RS testing was retrospectively analyzed. According to the 21 gene RS, the patients were divided into low risk (295 cases), intermediate risk (111 cases) and high-risk (33 cases) group. The relationship between the 21 gene RS and clinicopathological characteristics, treatment, recurrence and metastasis was analyzed. Univariate and multivariate statistical analyses were used to analyze the risk factors for relapse free survival (RFS). Results: Tumor grade, estrogen receptor (ER), progesterone receptor (PR) and Ki-67 index were significantly different among the 3 risk cohorts (P<0.001 for all). After a median follow-up of 32 months, the recurrence rate in low risk group (3.7%) was significantly lower than that in the intermediate-high risk group (9.0%), the locoregional recurrence (LRR) rate of low, intermediate and high risk group was 2.4%, 6.3% and 9.1%; and the distant metastasis (DM) rate in low risk group was 1.4% and 2.1% in the intermediate-high risk group. Univariate analysis showed RS, ER status and endocrine therapy were prognostic factors for RFS (P<0.05 for all). Multivariate analysis showed that RS was an independent significant predictor for RFS (P=0.04). Conclusions: The 21-gene RS is related to tumor grade, ER, PR and Ki-67 index. RS is an independent risk factor for RFS in patients with hormone receptor positive early-stage breast cancer. PMID- 29502371 TI - [Risk factor analysis of the patients with solitary pulmonary nodules and establishment of a prediction model for the probability of malignancy]. AB - Objective: This study aims to analyze the relationship among the clinical features, radiologic characteristics and pathological diagnosis in patients with solitary pulmonary nodules, and establish a prediction model for the probability of malignancy. Methods: Clinical data of 372 patients with solitary pulmonary nodules who underwent surgical resection with definite postoperative pathological diagnosis were retrospectively analyzed. In these cases, we collected clinical and radiologic features including gender, age, smoking history, history of tumor, family history of cancer, the location of lesion, ground-glass opacity, maximum diameter, calcification, vessel convergence sign, vacuole sign, pleural indentation, speculation and lobulation. The cases were divided to modeling group (268 cases) and validation group (104 cases). A new prediction model was established by logistic regression analying the data from modeling group. Then the data of validation group was planned to validate the efficiency of the new model, and was compared with three classical models(Mayo model, VA model and LiYun model). With the calculated probability values for each model from validation group, SPSS 22.0 was used to draw the receiver operating characteristic curve, to assess the predictive value of this new model. Results: 112 benign SPNs and 156 malignant SPNs were included in modeling group. Multivariable logistic regression analysis showed that gender, age, history of tumor, ground -glass opacity, maximum diameter, and speculation were independent predictors of malignancy in patients with SPN(P<0.05). We calculated a prediction model for the probability of malignancy as follow: p=e(x)/(1+ e(x)), x=-4.8029 0.743*gender+ 0.057*age+ 1.306*history of tumor+ 1.305*ground-glass opacity+ 0.051*maximum diameter+ 1.043*speculation. When the data of validation group was added to the four-mathematical prediction model, The area under the curve of our mathematical prediction model was 0.742, which is greater than other models (Mayo 0.696, VA 0.634, LiYun 0.681), while the differences between any two of the four models were not significant (P>0.05). Conclusions: Age of patient, gender, history of tumor, ground-glass opacity, maximum diameter and speculation are independent predictors of malignancy in patients with solitary pulmonary nodule. This logistic regression prediction mathematic model is not inferior to those classical models in estimating the prognosis of SPNs. PMID- 29502372 TI - [Evaluation of progression-free survival for locally advanced rectal cancer by MRI after neoadjuvant chemoradiotherapy and total mesorectal excision]. AB - Objective: To evaluate the predictive value of MRI features and pathological parameters on local recurrence, metastasis and progression free survival (PFS) for locally advanced rectal cancer after neoadjuvant chemoradiotherapy and subsequent total mesorectal excision surgery. Methods: A retrospective analysis of 95 patients with locally advanced rectal adenocarcinoma who underwent total mesorectal excision after neoadjuvant chemoradiotherapy was performed. Univariate and multivariate analyses were performed to evaluate the predictive value of MRI features before chemoradiation and postoperative pathological parameters on progression free survival. Results: Among the 95 cases, 5 cases occured local recurrence, 21 cases developed, 3 cases including both locally recurrence and distant metastasis, 19 died and 47 had no recurrence or metastasis at the last of follow-up. Univariant analysis showed that MRI signs before chemoradiation, namely, mr circumferential resection margin, mr levator ani muscle invasion, mr lymphatic vessel invasion, mr tumor deposition and postoperative pathological parameters, yp circumferential resection margin, yp lymphatic vessel invasion were related to PFS (P<0.05). Multivariate analysis of Cox proportional hazard model showed that mr lymphatic vessel invasion and mr tumor deposition were independent factors for PFS (OR=2.774 and 3.029, P<0.05). Conclusions: Lymphatic vessel invasion and tumor deposition on MRI are independent prognostic factors for progression free survival of locally advanced rectal cancer after neoadjuvant chemoradiotherapy and TME surgery. To some extent, MRI signs can assess local recurrence and distant metastasis in locally advanced rectal cancer patients after neoadjuvant chemoradiotherapy and mesorectal excision. PMID- 29502373 TI - [Effect of postoperative precision nutrition therapy on postoperative recovery for advanced gastric cancer after neoadjuvant chemotherapy]. AB - Objective: To investigate the effect of postoperative precision nutrition therapy on postoperative recovery (PR) of patients with advanced gastric cancer (AGC) after neoadjuvant chemotherapy (NC). Methods: 71 subjects were randomly divided into 2 groups. The 34 patients of research group were treated with postoperative precision nutrition treatment according to the indirect energy measurement method. The 31 patients of control group were treated with traditional postoperative nutrition treatment. All participants were measured for body mass index (BMI), NRS2002, PG-SGA and relevant laboratory test within the 1st day before surgery and 7th day after surgery. Moreover, the difference between two groups in short-term effects were evaluated. Results: The daily energy supply of control group was 30.1%-43.74% higher than that of the experimental group (P<0.05). The resting energy expenditure (REE) of the research group after surgery was lower than that before operation. The levels of prealbumin, albumin and lymphocyte count were higher in research group than the controls at the 7th day after surgery whereas the opposite was true for the creatinine, urea nitrogen, C-reactive protein and procalcitonin (P<0.05). Similarly, the rate of malnutrition and nutritional risk became lower in the research group (P<0.05). The gastrointestinal function recovery of patients in the research group was comparable to that of the control group (P>0.05). Moreover, the complication rate and hospitalization costs of in research group were significantly lower than that of in control group (P<0.05). For patients with or without nutritional risks before surgery, the nutritional index and inflammatory index in the research group were better than those in the control group. Conclusion: Postoperative precision nutrition therapy may improve the postoperative nutritional status and short-term effects of patients with AGC after NC. PMID- 29502374 TI - [A randomized controlled study of erlotinib versus pemetrexed combined with cisplatin in neoadjuvant therapy of stage IIIA EGFR-mutant lung adenocarcinoma]. AB - Objective: To evaluate the feasibility, efficacy and safety of epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs) for neoadjuvant therapy. Methods: Eighty-six patients with stage IIIA EGFR-mutant lung adenocarcinoma were assigned to 2 groups (n=43 in each group) according to the random number table method: neoadjuvant targeted therapy group (single oral dose of erlotinib 150 mg per day, for 9 weeks) and neoadjuvant chemotherapy group (2 cycles of pemetrexed combined with cisplatin chemotherapy followed by 3- week discontinuation). Surgical treatment was underwent after imaging efficacy evaluation. Results: In neoadjuvant targeted therapy group, 4 achieved complete response (CR), 25 achieved partial response (PR), giving an objective response rate (ORR) of 67.4%. In pathological response, 8 patients had grade I, 20 patients had grade II, giving a pathological response rate of 65.1%. The most frequent adverse events (AEs) were rash and diarrhea. In neoadjuvant chemotherapy group, 2 had CR and 17 had PR, giving an ORR of 44.2%. In pathological response, 3 patients had grade I, 15 patients had grade II, giving a pathological response rate of 41.9%. The main AEs were hematologic toxic effects. The ORR, histological efficacy and hematologic toxicity showed statistical significance between the two groups (P<0.05). The neoadjuvant targeted therapy group had 90.7% resection rate, (299.8+/-23.4) ml of hemorrhage volume during operation, (5.2+/-0.4) days of extubation time and 9.3% postoperative complication rate. Corresponding results were 83.7%, (308.9+/-22.7) ml, (5.4+/-0.6) days and 11.6% in neoadjuvant chemotherapy group, which showed no statistical significance (P>0.05). Conclusions: Neoadjuvant targeted treatment for stage IIIA lung adenocarcinoma harboring EGFR mutations. The regimen could be considered as a choice of neoadjuvant treatment for patients with stage IIIA EGFR-mutant lung adenocarcinoma. PMID- 29502375 TI - [Therapeutic effect of cervical Jiaji electroacupuncture on postoperative intractable hiccup of liver neoplasms]. AB - Objective: To evaluate the therapeutic effect of cervical Jiaji electroacupuncture on postoperative intractable hiccup of liver neoplasms. Methods: A total of 39 patients with postoperative intractable hiccup of liver neoplasms in The First Affiliated Hospital of Heilongjiang University of Chinese Medicine from May 2013 to May 2017 were collected and divided into 2 groups randomly. The electroacupuncture group included 20 cases, the control group included 19 cases. Patients in the electroacupuncture group were treated by cervical Jiaji electroacupuncture (located in C3-5, sympathetic ganglion), while the control group were treated by metoclopramide combined with chlorpromazine for three days. The therapeutic effects of two groups were compared and the onset time were recorded. Results: Total effective rates of electroacupuncture group and control group were 95.0% and 47.4%, respectively. The onset time in electroacupuncture group and control group were (14.8+/-3.3) h and (30.5+/-3.1) h, respectively (P<0.01). Ten cases who resisted the control treatment were then treated by electroacupuncture for 3 days, 6 cases were recovered, 3 cases became better, while 1 case demonstrated no response. No serious adverse reactions were appeared in each group. Conclusion: Cervical Jiaji electroacupuncture is an effective and safe treatment for postoperative intractable hiccup of liver neoplasms, and it can be used as a remedy for intractable hiccup patients who don't respond to drug treatment. PMID- 29502376 TI - [Outcome and prognosis of spinal myeloma surgery]. AB - Objective: To evaluate the impact of surgery in pain relief, quality of life, neurological function, survival status and prognosis of spinal myeloma patients. Methods: Twenty spinal myeloma patients from January 1990 to June 2016 who underwent surgery were reviewed. Compare the preoperative and postoperative neurological function and quality of life, via visual analogue scale (VAS), Eastern Cooperative Oncology Group (ECOG) score and Frankel classification, survival rate based follow-up were statistical analyzed by Wilcoxon and Kaplan Meier respectively, univariate and multivariate analysis with Cox regression model. Results: There were 12 males and 8 females enrolled with average age of 53.3 (range from 31 to 75 years). Lesions location distribution: cervical spine 1 case, 12 in thoracic spine, 6 in lumbar and 1 in sacral tumor. The majority of symptom was pain in 20 cases and 5 cases had incomplete paraplegia with spinal cord compression. Single posterior approach in 15 cases, single anterior in 3 cases, anterior and posterior combined approach in 2 cases. The average operation time was 225 min, average blood loss was 2 320 ml. The patients with postoperative median VAS score and ECOG score were 2.00 and 1 respectively, it is significantly decreased (P<0.001) compared with the preoperative score (7.50 and 3), the median Frankel classification was level 5 in postoperative patients and increased significantly (P<0.001) than preoperative patients (level 4). One patient had local recurrence, 2 patients had complications. The overall 5 and 10 year survival rate was 61.7% and 42.3%, respectively. The 3 years survival rate between surgery combine chemotherapy and without chemotherapy group was 87.1% and 25.0%, 5 years survival rate was 79.1% and 0 respectively (P<0.01). LDH, ALB and chemotherapy were independent prognostic factors of survival from Cox regression. The odds ratio (OR) was 1.037 (P=0.006), 0.746 (P=0.009) and 0.077 (P=0.012) respectively. Conclusion: Surgical strategy is effective to improve quality of life for spinal myeloma patients. Combine chemotherapy could improve the survival. PMID- 29502377 TI - [Clinical analysis of 138 multiple primary cancers diagnosed of digestive system malignant tumor initially]. AB - Objective: To study the clinical characteristics, strategy of treatment and prognosis of multiple primary cancers(MPC) diagnosed of digestive system malignant tumor firstly. Methods: From January, 2000 to December, 2015, the clinical, follow-up and prognostic data of 138 MPC patients diagnosed of digestive system malignant tumor firstly were retrospectively analyzed. Results: 138 cases were found in 10 580 cases with malignant tumors, and the incidence was 1.30%. There were 129 cases of duplex primary cancers, 8 cases of triple primary cancers and 1 case of quintuple primary cancers. The repetitive primary cancer was occurred in digestive system (61cases, 44.2%) most frequently, with the next in respiratory system (46 cases, 33.3%). 52.2% (72 cases) suffered second primary cancer in 2 years after first primary cancer diagnosed, and 75.4% (104 cases) in 5 years. The median overall survival in patients with all cancer lesions radically treated was 168 months, better than any other treatment (68 months, P<0.05). Conclusions: The second primary cancers of MPC cases initially diagnosed of digestive system malignant tumor most frequently occurred in the digestive system and respiratory system. More concern should be attracted in follow-up, especially in the first 5 years. The key to improve patient' prognosis was radical treatment to every primary cancer. PMID- 29502378 TI - [Screening of benign and malignant thyroid nodules in 5 196 physical examination population]. AB - Objective: To investigate the distribution characteristics of thyroid nodules and thyroid cancer in physical examination population in Tianjin, and report the outcome of ultrasonography in detection of thyroid nodules. Methods: Enrolled all of physical examination population in our hospital from Jan 1, 2014 to Dec 31, 2014 as our study subjects then the thyroid gland lesions were screened by ultrasound diagnostic technique. The risk assessment of benign and malignant thyroid nodules was assessed by ultrasonography and thyroid imaging reporting and data system (TI-RADS), and the individuals were followed up for 1 year. Results: Among the 5 196 cases, the patients with thyroid nodules was 2 068 cases (39.80%). The thyroid nodules was 35.04% in male and 44.78% in female subjects, lower in females than in male cases (P<0.001). 18 cases of thyroid cancer patients were detected (0.35%). The thyroid cancer rate were 0.34% and 0.36% in male and female respectively (P>0.05). Thyroid nodules increased with age, but the thyroid cancer patients were mainly concentrated in the 30 to 39 years old group and 50 to 59 years old group. All of the thyroid cancer patients underwent surgical treatment, better differentiation thyroid papillary carcinoma (17 cases) in major, most were early stage cancer and micro-cancer, possessing relatively low risk of recurrence. The sensitivity, specificity and accuracy of ultrasonography and TI-RADS diagnosis of thyroid cancer was 72.22%, 98.94% and 98.85%. Conclusions: The detection rate of thyroid nodules in our population is close to 40%, and there are differences between sexes and ages. Ultrasonography and TI-RADS association is an efficient method to detect the nodules in thyroid. PMID- 29502379 TI - [The option of critical patients with cancer for ICU]. AB - With the improvement of diagnosis and treatment, tumor has become a chronic disease, and an increasing number of older patients will live with tumors. This change has led to an increase in demand for intensive care unit (ICU) and a challenge to the traditional ICU treatment concept. The option of ICU consists of two parts. The first is the option for admission. Since classic predictors of mortality are no longer relevant, we suggest broadening the criteria for ICU admission. Patients during the first course of cancer therapies should be treated with a full-code status similar to that of other patients without malignancy. Patients whose clinical response to therapy was not available or undetermined should be allowed an ICU trial that consists of unlimited invasive support, including anti-cancer therapies such as ambulatory chemotherapy. Do everything that can be done to save the patients who might benefit from ICU treatment. The second is the option of therapeutic end point. An interdisciplinary meeting, including an ethics consultation, should be held after 3-6 days'ICU trial to make end-of-life decisions with relatives of patients if the SOFA score shows clinical deterioration with no available therapeutic options. The treatment goals should shift from curative or supportive therapies to end-of-life care. we could integrate hospice and palliative care with intensive care more effectively and efficiently. That would be the future of oncological ICUs. PMID- 29502380 TI - [DICER1 mutaiton identified in sisters with Ovarian Sertoli-Leydig cell tumor]. PMID- 29502381 TI - Stomach Perforation Caused by Ingesting Liquid Nitrogen: A Case Report on the Effect of a Dangerous Snack. AB - We report our experience with a case of stomach perforation after accidental ingestion of liquid nitrogen. A 13-year-old boy ate a snack at an amusement park and began to complain of sudden onset of severe abdominal pain with shortness of breath. It was determined that the snack he had ingested had been cooled with liquid nitrogen. A computed tomography scan of the abdomen and a chest X-ray showed a large volume of pneumoperitoneum. During surgery, a 4-cm perforation of the angularis incisura of the stomach was identified. Primary repair and omentopexy was performed. The patient was discharged without postoperative complications. PMID- 29502382 TI - Closing the Gaps: Endoscopic Suturing for Large Submucosal and Full-Thickness Defects. AB - This article is a systematic review of relevant literature on endoscopic suturing as a primary closure technique for large submucosal and full-thickness defects after endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), and endoscopic full-thickness resection (EFTR). A comprehensive literature search was conducted through 2016 by using PubMed, to find peer-reviewed original articles. The specific factors considered were the procedural indications and details, success rates, clinical outcomes including complications, and study limitations. Six original articles were included in the final review: two with non-human subjects and four with human subjects. The mean success rate of endoscopic suturing was 97.4% (100% for human subjects and 95.4% for non-human subjects). The procedural time ranged from 7 to 89 min. The average size and depth of lesions were 2.71 cm (3.74 cm [human] and 1.96 cm [non-human]) and 1.52 cm, respectively. The technique itself had no reported impact on mortality. In conclusion, endoscopic suturing is a minimally invasive technique for the primary closure of defects caused by EMR, ESD, and EFTR, with a high success and low complication rate. PMID- 29502383 TI - Nutritional management of preterm newborn after hospital discharge: energy and nutrients. AB - Preterm infants are at risk for poor growth while in the Neonatal Intensive Care Unit (NICU) and after discharge from the NICU. The main objective is to reach the body composition and rate of growth of a normal fetus/infant of the same post menstrual age during the first entire year of life. In case of human milk, the limited data do not provide convincing evidence that feeding preterm infants after discharge with multi-nutrient fortified human milk, compared with unfortified, affects important outcomes including growth rates during infancy. Conversely, if formula-fed, post discharge formulas produce short term advantages in growth rate but no long term advantages are demonstrated. It is very important to establish a feeding plan and a follow up for all preterm babies who are discharged from NICU in order to recognize as soon as possible any growth deficit. PMID- 29502384 TI - Weaning and complementary feeding in preterm infants: management, timing and health outcome. AB - The introduction of solid food is necessary for any infant in order to provide adequate nutrition because when they grow up milk is insufficient for their nutritional needs. Infants born preterm have increased nutritional requirements. The high nutrient demands as well as the organ immaturity of preterm infants combine to render it difficult to achieve dietary intakes that will allow preterm infants to match their in utero growth rates. Current guidelines for the introduction of solid food to term infants cannot be directly translated to preterm infants. For preterm infants such guidelines are lacking. Based on the limited available evidence, it could be concluded that a corrected age of 3 months (13 weeks) may be an appropriate age to start introducing solid food for most preterm infants. About celiac disease (CD), gluten may be introduced into the infant's diet anytime between 4 and 12 completed months of age. In children at high risk for CD, earlier introduction of gluten (4 vs 6 months or 6 vs 12 months) is associated with earlier development of CD autoimmunity (defined as positive serology) and CD, but the cumulative incidence of each in later childhood is similar. Relatively to weaning and allergies, the European Society of Pediatric Allergy and Clinical Immunology and the European Society for Paediatric Gastroenterology Hepatology and Nutrition have produced joint guidelines. They recommend exclusive breastfeeding for 4-6 months or use of hypoallergenic formulas if exclusive breastfeeding is not possible. In addition, The American Academy of Pediatrics recommendations now state that there is no evidence to recommend maternal dietary restrictions during pregnancy or breastfeeding. However, there is no evidence that delaying introduction of solids including allergenic foods after 4-6 months is protective. PMID- 29502385 TI - Nutritional problems of children with bronchopulmonary dysplasia after hospital discharge. AB - The last decades have seen significant improvements in the care of premature infants. The introduction of new approaches, especially in the ventilatory management, have led to significant increase of survival rate of low and extremely low gestational age infants. These populations of neonates, however, often experience prolonged mechanical ventilation, which is widely recognized to be closely related to bronchopulmonary dysplasia (BPD) development. The management of BPD, which is a multifactorial disease, requires a multidisciplinary approach and remains challenging for all the physicians involved. In fact, short and long-term sequelae are not only related to pulmonary performances but include neurological impairment and growth deficiency. A proper nutrition management since the very first days has shown to significantly contribute to the optimal maturation and functionality of the lung. In this paper, we aim to give an overall of the main principles of nutrition in infants born prematurely, with specific regard to the interventions, which could be relevant in infants affected by BPD. PMID- 29502386 TI - Functional nutrients in infants born by vaginal delivery or Cesarean section. AB - The development of a proper neonatal microbiota is of great importance, especially for the effects that dysbiosis has in acute and chronic diseases' onset. The microbiota, particularly the intestinal one, plays a crucial role in maintaining the health of the host, preventing colonization by pathogenic bacteria and significantly influencing the development and maturation of a normal gastrointestinal mucosal immunity. Several factors may interfere with the physiological development of microbiota, such as diseases during pregnancy, type of delivery, maternal nutrition, type of neonatal feeding, use of antibiotics, exposition to hospital environment (e.g., neonatal intensive care unit) and genetic factors. Thanks to a proper maternal and neonatal supplementation with specific functional nutrients, it is now possible to correct dysbiosis, thus reducing the risks for the newborn's health. In this review of the literature, we give an overview of the studies highlighting the composition of the maternal, fetal and neonatal microbiota, the factors potentially responsible for dysbiosis and the use of functional nutrients to prevent diseases' onset. PMID- 29502387 TI - Introducing complementary foods in the first year of life. AB - Introduction of solid foods is a fundamental step in the development of an individual. There are many implications that weaning contains not only on a nutritional plan, but also on the contingent and long-term health of an individual. Over time this nutritional passage has evolved through the acquisition of new knowledge about maturation of anatomical and neurosensory structures involved in all the phases of such a complex process. The understanding of a maturing taste of infant and cultural changes is another key to understand the evolution of introduction of solid foods in infants. What is contained in this text encapsulates thus the evolutionary path of weaning in recent years, showing current trends in the light of cultural changes and new scientific acquisitions. PMID- 29502388 TI - Horseshoe kidney and uretero-pelvic-junction obstruction in a pediatric patient. Laparoscopic vascular hitch: A valid alternative to dismembered pyeloplasty? AB - Horseshoe kidney (HSK) is a congenital defect of the urinary tract that occurs in 0.25% of the general population. Laparoscopic Vascular Hitch (LVH) according to Hellstrom-Chapman represent an alternative approach in treatment of extrinsic hydronephrosis by crossing vessels (CV) in pediatric age. In our Department from 2006 to 2016, 36 children with extrinsic-Uretero-Pelvic-Junction (UPJ) Obstruction (UPJO) underwent laparoscopic vessels transposition. Over the last 4years, we have treated three patients with extrinsic hydronephrosis in HSK; two males and one female respectively of 6, 7 and 8years. The side affected was the left in all patients; symptoms of onset: recurrent abdominal pain, vomiting with associated intermittent hydronephrosis at ultrasonography. The preoperative examinations performed were: ultrasound/Doppler scan, MAG3-renogram, functional magnetic-resonance-urography (fMRU). Mean operative time was 120'; median hospital stay 3- days. Intraoperative diuretic-test (DT) confirmed an extrinsic UPJO in all patients. No JJ-stents and drain were used and there were no perioperative complications. Clinical and ultrasound follow-up (18 months-4 years) show resolution of symptoms and decrease in hydronephrosis grade in all patients. Our series is the largest in pediatric population by a revision of the literature. We believe that LVH is feasible in patients with symptomatic hydronephrosis by CV in HSK. Intraoperative-DT and the correct selection of patients are crucial to the success of the technique. According to us, this procedure is appropriate in those cases where the UPJ-anatomy is disadvantageous to a resection/re-anastomosis between ureter and renal pelvis. Our initial results are encouraging, although long-term follow- up and a more significant patient sample are required. PMID- 29502389 TI - Second-generation antipsychotic and diabetes mellitus in children and adolescents. AB - Second generation antipsychotics (SGA) are used in children for the treatment of various psychiatric diseases, including pervasive developmental disorders. These drugs can cause metabolic effects as hyperglycemia and diabetes. A 16-year-old young-boy, diagnosed with autism, developed diabetes mellitus type 1 whilst he was on treatment with olanzapine (started 4 months before), clomipramine, valproic acid and lithium. The hypothesis of druginduced diabetes imposed olanzapine interruption and clozapine initiation. Insulin therapy was practiced, with progressive dosage reduction, until complete cessation of treatment after 13 months. Blood sugar and HbA1c levels remained stable for about a year and then increased again, requiring the introduction of metformin that improved glycemia. In children and adolescents assuming SGA serum glucose and lipid profile should always be assessed before therapy and then frequently monitored. Drug selection must consider family history and the individual risk. Molecule final choice remains equilibrium between efficacy and safety. PMID- 29502390 TI - A unique case of foreign body aspiration and recurrent pneumothorax. AB - Paediatric foreign body aspiration can be related to a high morbidity/mortality rate, especially in young children, and pneumothorax can be a severe associated issue. We describe a case of a 13-year-old girl with recurrent pneumothorax in bilateral bullous lung, twice previously treated at our institution by robotassisted bullectomy, and once again showing same signs and symptoms. At conventional thoracoscopy an inorganic foreign body was found to be located pointing upwards the apex. We believe this may have acted as a contributory cause in the persistence of the clinical picture, despite the surgical removal of the underlying pathology. PMID- 29502391 TI - Kearns-Sayre syndrome with facial and white matter extensive involvement: a (mitochondrial and nuclear gene related?) neurocristopathy? AB - The Authors report on a patient with Kearns-Sayre syndrome, large mtDNA deletion (7/kb), facial abnormalities and severe central nervous system (CNS) white matter radiological features, commonly attributed to spongy alterations. The common origin from neural crest cell (NCC) of facial structures (cartilagineous, osseous, vascular and of the peripheral nervous system) and of peripheral glia and partially of the CNS white matter are underlined and the facial and glial abnormalities are attributed to the abnormal reproduction/migration of NCC. In this view, the CNS spongy alterations in KSS may be not only a dystrophic process (leukodystrophy) but also a dysplastic condition (leukodysplasia). The Authors hypothesize that the symptoms may be related to mtDNA mutations associated to NCC nuclear gene abnormality. SOX 10 gene may be a nuclear candidate gene, as reported in some case of Waardenburg IV syndrome. PMID- 29502392 TI - Effects of Rubus coreanus byproducts on intestinal microbiota and the immune modulation. AB - OBJECTIVE: Although the efficacy of Rubus coreanus (RC) byproducts as a feed additive has been recognized, its effects on intestinal microorganisms and the immune system are still unknown. METHODS: Six-week-old male rats were treated with 0.5% RC (T1), 1.0% RC (T2), and 1.5% RC (T3) for 4 weeks. RESULTS: We found that treatment with RC byproducts significantly increased the daily gain of body weight and feed intake. Treg-cell differentiation was enhanced in the mesenteric lymph nodes and spleen from the rats fed with RC byproducts. Illumina sequencing showed that bacteria in the phylum Firmicutes decreased and while those in the phylum Bacteroidetes increased in RC-treated groups. Particularly, the pathogenic microorganisms in the family Peptococcaceae decreased, and the non-pathogenic families Lachnospiraceae and S24-7 increased. Quantitative polymerase chain reaction analysis showed that the RC byproducts increased the lactic acid bacteria Bifidobacterium spp., Oscillospira spp., Leuconostoc citreum, and Weissella cibaria in a concentration-dependent manner. CONCLUSION: RC byproducts may be effective in immunomodulation by affecting intestinal microorganisms. PMID- 29502393 TI - Hepatic transcriptional changes in critical genes for gluconeogenesis following castration of bulls. AB - OBJECTIVE: This study was performed to understand transcriptional changes in the genes involved in gluconeogenesis and glycolysis pathways following castration of bulls. METHODS: Twenty Korean bulls were weaned at average 3 months of age, and castrated at 6 months. Liver tissues were collected from bulls (n = 10) and steers (n = 10) of Korean cattle, and hepatic gene expression levels were measured using quantitative real-time polymerase chain reaction. We examined hepatic transcription levels of genes encoding enzymes for irreversible reactions in both gluconeogenesis and glycolysis as well as genes encoding enzymes for the utilization of several glucogenic substrates. Correlations between hepatic gene expression and carcass characteristics were performed to understand their associations. RESULTS: Castration increased the mRNA (3.6 fold; p<0.01) and protein levels (1.4 fold; p< 0.05) of pyruvate carboxylase and mitochondrial phosphoenolpyruvate carboxykinase genes (1.7 fold; p<0.05). Hepatic mRNA levels of genes encoding the glycolysis enzymes were not changed by castration. Castration increased mRNA levels of both lactate dehydrogenase A (1.5 fold; p<0.05) and lactate dehydrogenase B (2.2 fold; p<0.01) genes for lactate utilization. Castration increased mRNA levels of glycerol kinase (2.7 fold; p<0.05) and glycerol-3-phosphate dehydrogenase 1 (1.5 fold; p<0.05) genes for glycerol utilization. Castration also increased mRNA levels of propionyl-CoA carboxylase beta (mitochondrial) (3.5 fold; p<0.01) and acyl-CoA synthetase short chain family member 3 (1.3 fold; p = 0.06) genes for propionate incorporation. CONCLUSION: Castration increases transcription levels of critical genes coding for enzymes involved in irreversible gluconeogenesis reactions from pyruvate to glucose and enzymes responsible for incorporation of glucogenic substrates including lactate, glycerol, and propionate. Hepatic gluconeogenic gene expression levels were associated with intramuscular fat deposition. PMID- 29502394 TI - N-Alkynylpyridinium Salts: Highly Electrophilic Alkyne-Pyridine Conjugates as Precursors of Cationic Nitrogen-Embedded Polycyclic Aromatic Hydrocarbons. AB - We achieved the first synthesis of N-alkynylpyridinium salts, by reacting pyridines with alkynyl-lambda3-iodanes. The N-alkynylpyridiniums exhibit highly electron-accepting character with extended pi-conjugation. The electrophilic alkynyl groups were readily susceptible to Michael addition and 1,3-dipolar cycloaddition to afford various N-alkenylpyridiniums. Ring-fused pyridiniums were synthesized through intramolecular cyclization, demonstrating the utility of N alkynylpyridiniums for the design of various electron-deficient cationic nitrogen embedded polycyclic aromatic hydrocarbons with unique optical and electrochemical properties. PMID- 29502395 TI - Occurrence and Fate of Benzophenone-Type UV Filters in a Tropical Urban Watershed. AB - The study investigated the occurrence and fate of seven benzophenone-type UV filters (i.e., 2,4-dihydroxybenzophenone (2,4OH-BP), 2,2',4,4' tetrahydroxybenzophenone (2,2',4,4'OH-BP), 2-hydroxy-4-methoxybenzophenone (2OH 4MeO-BP), 2,2'-Dihydroxy-4,4'-dimethoxybenzophenone (2,2'OH-4,4'MeO-BP), 2,2' dihydroxy-4-methoxybenzophenone (2,2'OH-4MeO-BP), 4-hydroxybenzophenone (4OH-BP), and 4,4'-dihyroxybenzophenone (4DHB)) in a tropical urban watershed consisting of five major tributaries that discharge into a well-managed basin. Total benzophenone concentrations (?CBPs) varied from 19-230.8 ng L-1 in overlying bulk water, 48-115 ng L-1 in pore water, 295-5813 ng g-1 dry weight (d.w.) in suspended solids, and 6-37 ng g-1 d.w. in surficial sediments, respectively. The tributaries (?CBPs: 19-231 ng L-1) were the main source of benzophenone compounds entering the basin (?CBPs: 20-81 ng L-1). In the water column, the vertical concentration profile in the aqueous phase was uniform while concentrations in the suspended solids decreased with depth. Different distribution profiles were also identified for benzophenones in suspended solids and sediments. A preliminary risk assessment suggested that the seven BPs were unlikely to pose ecotoxicological risks to local aquatic organisms except for 2OH-4MeO-BP in the case of an intermittent release. PMID- 29502396 TI - Catalyst-Directed Guidance of Sulfur-Substituted Enediolates to Stereoselective Carbon-Carbon Bond Formation with Aldehydes. AB - A highly chemo-, regio-, and stereoselective glycolate aldol reaction of sulfur substituted enediolates with aldehydes was developed by employing a l cyclohexylglycine-derived chiral iminophosphorane as a catalyst. The key for establishing this protocol is the distinct ability of the iminophosphorane catalyst to precisely direct the equilibrium mixture of the enediolates toward the intermolecular carbon-carbon bond formation with simultaneous yet rigorous control of relative and absolute stereochemistry. The critical importance of the cyclohexyl substituents on the catalyst backbone in dictating the reaction pathway and the stereochemical outcome was elucidated through an extensive quantum analysis by density functional theory calculations. PMID- 29502397 TI - An In-Depth Glycosylation Assay for Urinary Prostate-Specific Antigen. AB - The concentration of prostate-specific antigen (PSA) in serum is used as an early detection method of prostate cancer (PCa); however, it shows low sensitivity, specificity, and a poor predictive value. Initial studies suggested the glycosylation of PSA to be a promising marker for a more specific yet noninvasive PCa diagnosis. Recent studies on the molecular features of PSA glycosylation (such as antenna modification and core fucosylation) were not successful in demonstrating its potential for an improved PCa diagnosis, probably due to the lack of analytical sensitivity and specificity of the applied assays. In this study, we established for the first time a high-performance PSA Glycomics Assay (PGA), allowing differentiation of alpha2,6- and alpha2,3-sialylated isomers, the latter one being suggested to be a hallmark of aggressive types of cancer. After affinity purification from urine and tryptic digestion, PSA samples were analyzed by CE-ESI-MS (capillary electrophoresis-electrospray ionization coupled to mass spectrometry). Based on positive controls, an average interday relative standard deviation of 14% for 41 N-glycopeptides was found. The assay was further verified by analyzing PSA captured from patients' urine samples. A total of 67 N glycopeptides were identified from the PSA pooled from the patients. In summary, the first PGA successfully established in this study allows an in-depth relative quantitation of PSA glycoforms from urine. The PGA is a promising tool for the determination of potential glycomic biomarkers for the differentiation between aggressive PCa, indolent PCa, and benign prostate hyperplasia in larger cohort studies. PMID- 29502398 TI - Design, Synthesis, and Evaluation of New Sulfone Derivatives Containing a 1,3,4 Oxadiazole Moiety as Active Antibacterial Agents. AB - This study aimed to synthesize some new sulfone derivatives containing a 1,3,4 oxadiazole moiety and investigate their in vitro antibacterial activities against Xanthomonas oryzae pv. oryzae ( Xoo) and Xanthomonas axonopodis pv. citri ( Xac), the pathogens of rice bacterial leaf blight and citrus canker, respectively, by performing turbidimeter tests. Antibacterial bioassay results showed that compound 6d revealed excellent bioactivities against Xoo and Xac, with the 50% effective concentration (EC50) values of 0.17 and 1.98 MUg/mL, respectively, compared with thiodiazole copper (121.82 and 77.04 MUg/mL, respectively) and bismerthiazol (92.61 and 58.21 MUg/mL, respectively). Meanwhile, greenhouse condition trials indicated that, compared with thiodiazole copper and bismerthiazol, compound 6d more effectively reduced rice bacterial leaf blight. PMID- 29502399 TI - Enhanced Photosensitized Hydrogen Production by Encapsulation of Ferrocenyl Dyes into Single-Walled Carbon Nanotubes. AB - Dye-encapsulated single-walled carbon nanotubes (SWCNTs) were employed for the construction of a coaxial three-component dye/SWCNT/C60 heterojunction. Despite the larger diameter (~1.4 nm) of the SWCNTs relative to that set by Flavel's rule (0.95 nm), the photoinduced electron transfer from dye-encapsulated SWCNTs to C60 proceeded smoothly, resulting in the photosensitized evolution of H2 from H2O using a ferrocenyl-based photosensitizer, which was confirmed by the action spectra. PMID- 29502400 TI - Lewis Acid Activation of the Ferrous Heme-NO Fragment toward the N-N Coupling Reaction with NO To Generate N2O. AB - Bacterial NO reductase (bacNOR) enzymes utilize a heme/non-heme active site to couple two NO molecules to N2O. We show that BF3 coordination to the nitrosyl O atom in (OEP)Fe(NO) activates it toward N-N bond formation with NO to generate N2O. 15N-isotopic labeling reveals a reversible nitrosyl exchange reaction and follow-up N-O bond cleavage in the N2O formation step. Other Lewis acids (B(C6F5)3 and K+) also promote the NO coupling reaction with (OEP)Fe(NO). These results, complemented by DFT calculations, provide experimental support for the cis: b3 pathway in bacNOR. PMID- 29502401 TI - Egg White Ovotransferrin Shows Osteogenic Activity in Osteoblast Cells. AB - Ovotransferrin, the major protein in egg white, is a member of transferrin family. The objective of this study was to study the effects of ovotransferrin on cell proliferation, differentiation, mineralization and osteoclastogenesis of bone osteoblast cells. Effect of ovotransferrin (concentrations ranging from 1 to 1000 MUg/mL) on the proliferation, differentiation, and mineralization of mouse osteoblast cells MC3T3-E1 was determined by 5-bromo-2-deoxyuridine (BrdU) incorporation assay, Western blot, immunofluorescence, and Alizarin-S red staining, respectively. Our results showed that ovotransferrin stimulated cell proliferation (enhanced BrdU incorporation), differentiation (enhanced expression of alkaline phosphatase and type-I collagen), and mineralization (increased calcium deposits) in a dose-dependent manner. Furthermore, ovotransferrin could increase the expression of osteoprotegerin (OPG) while decreasing the expression of receptor activator of nuclear factor kappa-B ligand (RANKL), suggesting its role in inhibition of bone resorption. This study demonstrated for the first time that ovotransferrin might promote bone formation while preventing bone resorption, which might open up a new application of egg white protein ovotransferrin as a functional ingredient in bone health management. PMID- 29502402 TI - Influence of Annulation on the Electron Spin within the 1,2,3-Triazole Ring in Annulenotriazole Anion Radicals. AB - The low temperature (-100 degrees C) single electron reduction of N1 phenylbenzotriazole in liquid ammonia, and the room temperature reduction of N1 phenylcyclooctatetraenotriazole in hexamethylphosphoramide, yields stable solutions of both anion radicals, which were studied via EPR spectroscopy. The amount of electron spin localized within the triazole ring, and how spin is distributed within this ring, is greatly influenced by the size of the annulene ring attached. UB3LYP/6-31++G(d,p) geometry optimizations using DFT methods were carried out for both anion radicals, and the calculated coupling constants (and electron spin densities) are in good agreement with the EPR spectroscopic results. Both theory and experiment show that much of the unpaired electron spin in the N1-phenylbenzotriazole anion radical is delocalized over the entire pi system of benzotriazole ring including the phenyl ring attached, but that a significant percentage of total spin is found to reside within triazole ring with much of it located on the second nitrogen (N2). With the N1 phenylcyclooctatetraenotriazole anion radical, the majority of spin is localized over the pi system of the COT ring, however a relatively small amount of total spin, found within the triazole moiety, is largely concentrated on two of the nitrogens (N1 and N3) within the ring. PMID- 29502403 TI - Selective Extraction and Purification of Azaspiracids from Blue Mussels ( Mytilus edulis) Using Boric Acid Gel. AB - Azaspiracids belong to a family of more than 50 polyether toxins originating from marine dinoflagellates such as Azadinium spinosum. All of the azaspiracids reported thus far contain a 21,22-dihydroxy group. Boric acid gel can bind selectively to compounds containing vic-diols or alpha-hydroxycarboxylic acids via formation of reversible boronate complexes. Here we report use of the gel to selectively capture and release azaspiracids from extracts of blue mussels. Analysis of the extracts and fractions by liquid chromatography-tandem mass spectrometry (LC-MS) showed that this procedure resulted in an excellent cleanup of the azaspiracids in the extract. Analysis by enzyme-linked immunoasorbent assay (ELISA) and LC-MS indicated that most azaspiracid analogues were recovered in good yield by this procedure. The capacity of boric acid gel for azaspiracids was at least 50 MUg/g, making this procedure suitable for use in the early stages of preparative purification of azaspiracids. In addition to its potential for concentration of dilute samples, the extensive cleanup provided by boric acid gel fractionation of azaspiracids in mussel samples almost eliminated matrix effects during subsequent LC-MS and could be expected to reduce matrix effects during ELISA analysis. The method may therefore prove useful for quantitative analysis of azaspiracids as part of monitoring programs. Although LC-MS data showed that okadaic acid analogues also bound to the gel, this was much less efficient than for azaspiracids under the conditions used. The boric acid gel methodology is potentially applicable to other important groups of natural toxins containing diols including ciguatoxins, palytoxins, pectenotoxins, tetrodotoxin, trichothecenes, and toxin glycosides. PMID- 29502404 TI - Increases in Phenolic, Fatty Acid, and Phytosterol Contents and Anticancer Activities of Sweet Potato after Fermentation by Lactobacillus acidophilus. AB - Phenolic, fatty acid, and phytosterol contents in sweet potato (SP) fermented by Lactobacillus acidophilus were evaluated and compared with those of raw and boiled SPs. The differences in the profiles and levels of phenolics between the raw and boiled SPs were not as significant as the differences between those and the fermented SP. The levels of caffeic acid and 3,5-dicaffeoylquinic acid in fermented SP were more than 4 times higher than those in raw and boiled SPs. Two phenolics, p-coumaric acid and ferulic acid, which were not detected in either raw or boiled SP, were found in fermented SP. The level of each fatty acid or phytosterol increased in fermented SP and decreased in boiled SP. Among the hydrophilic and lipophilic extracts obtained from raw and fermented SPs, the hydrophilic extract of fermented SP exhibited the highest capability of inhibiting cancer-cell PC-12 proliferation. However, each of the extracts had very low cytotoxicities to normal-monkey-kidney-cell growth. The results indicated that SP fermented by L. acidophilus significantly increased free antioxidant-rich phenolics and inhibited cancer-cell-proliferation activity without cytotoxicity to normal cells. PMID- 29502405 TI - 4-Amino-7,8-dihydro-1,6-naphthyridin-5(6 H)-ones as Inhaled Phosphodiesterase Type 4 (PDE4) Inhibitors: Structural Biology and Structure-Activity Relationships. AB - Rational design of a novel template of naphthyridinones rapidly led to PDE4 inhibitors with subnanomolar enzymatic potencies. X-ray crystallography confirmed the binding mode of this novel template. We achieved compounds with double-digit picomolar enzymatic potencies through further structure-based design by targeting both the PDE4 enzyme metal-binding pocket and occupying the solvent-filled pocket. A strategy for lung retention and long duration of action based on low aqueous solubility was followed. In vivo efficacies were measured in a rat lung neutrophilia model by suspension microspray and dry powder administration. Suspension microspray of potent compounds showed in vivo efficacy with a clear dose-response. Despite sustained lung levels, dry powder administration performed much less well and without proper dose-response, highlighting clear differences between the two formulations. This indicates a deficiency in the low aqueous solubility strategy for long duration lung efficacy. PMID- 29502406 TI - Ultrafast Exciton Delocalization, Localization, and Excimer Formation Dynamics in a Highly Defined Perylene Bisimide Quadruple pi-Stack. AB - An adequately designed, bay-tethered perylene bisimide (PBI) dimer Bis-PBI was synthesized by Pd/Cu-catalyzed Glaser-type oxidative homocoupling of the respective PBI building block. This newly synthesized PBI dimer self-assembles exclusively and with high binding constants of up to 106 M-1 into a discrete pi stack of four chromophores. Steady-state absorption and emission spectra show the signatures of H-type excitonic coupling among the dye units. Broadband fluorescence upconversion spectroscopy (FLUPS) reveals an ultrafast dynamics in the optically excited state. An initially coherent Frenkel exciton state that is delocalized over the whole quadruple stack rapidly (tau = ~200 fs) loses its coherence and relaxes into an excimer state. Comparison with Frenkel exciton dynamics in PBI dimeric and oligomeric H-aggregates demonstrates that in the quadruple stack coherent exciton propagation is absent due to its short length of aggregates, thereby it has only one relaxation pathway to the excimer state. Furthermore, the absence of pump-power dependence in transient absorption experiments suggests that multiexciton cannot be generated in the quadruple stack, which is in line with time-resolved fluorescence measurements. PMID- 29502407 TI - Guanidinium-Formamidinium Lead Iodide: A Layered Perovskite-Related Compound with Red Luminescence at Room Temperature. AB - Two-dimensional hybrid organic-inorganic lead halides perovskite-type compounds have attracted immense scientific interest due to their remarkable optoelectronic properties and tailorable crystal structures. In this work, we present a new layered hybrid lead halide, namely [CH(NH2)2][C(NH2)3]PbI4, wherein puckered lead iodide layers are separated by two small and stable organic cations: formamidinium, CH(NH2)2+, and guanidinium, C(NH2)3+. This perovskite is thermally stable up to 255 degrees C, exhibits room-temperature photoluminescence in the red region with a quantum yield of 3.5%, and is photoconductive. This study highlights a vast structural diversity that exists in the compositional space typically used in perovskite photovoltaics. PMID- 29502408 TI - Increased Electrical Conductivity in a Mesoporous Metal-Organic Framework Featuring Metallacarboranes Guests. AB - Nickel(IV) bis(dicarbollide) is incorporated in a zirconium-based metal-organic framework (MOF), NU-1000, to create an electrically conductive MOF with mesoporosity. All the nickel bis(dicarbollide) units are located as guest molecules in the microporous channels of NU-1000, which permits the further incorporation of other active species in the remaining mesopores. For demonstration, manganese oxide is installed on the nodes of the electrically conductive MOF. The electrochemically addressable fraction and specific capacitance of the manganese oxide in the conductive framework are more than 10 times higher than those of the manganese oxide in the parent MOF. PMID- 29502409 TI - Dietary Wheat Bran Oil Is Equally as Effective as Rice Bran Oil in Reducing Plasma Cholesterol. AB - Rice bran oil (RBO) possesses a plasma cholesterol-lowering activity, while effect of wheat bran oil (WBO) on plasma cholesterol remains unknown. The present study compared the cholesterol-lowering activity of WBO with that of RBO in hamsters. Fifty-four male hamsters were divided into seven groups fed either a noncholesterol diet (NCD) or one of six high-cholesterol diets, namely HCD diet (0.2% cholesterol +9.5% lard), HCD+C diet (0.2% cholesterol +9.5% lard +0.5% cholestyramine), WL diet (0.2% cholesterol +4.8% Lard +4.8% WBO), WH diet (0.2% cholesterol +9.5% WBO), RL diet (0.2% cholesterol +4.8% Lard +4.8% RBO), and RH diet (0.2% cholesterol +9.5% RBO). Plasma total cholesterol (TC) in HCD group was 327.4 +/- 31.8 mg/dL, while plasma TC in two WBO and two RBO groups was 242.2 +/- 20.8, 243.1 +/- 31.7, 257.1 +/- 16.3, and 243.4 +/- 46.0 mg/dL, respectively, leading to a decrease in plasma TC by 22-26% ( P < 0.01). No significant difference in cholesterol-lowering potency was seen between WBO and RBO. Plasma cholesterol-lowering activity of WBO and RBO was accompanied by down-regulation of hepatic 3-hydroxy-3-methylglutaryl-CoA reductase and fatty acid synthase, while up-regulation of cholesterol-7alpha-hydroxylase. WL, WH, RL, and RH diets increased the fecal excretion of total neutral sterols by 72.8%, 106.9%, 5.4%, and 36.8% ( P < 0.01) respectively. Results indicated WBO and RBO could inhibit cholesterol absorption via down-regulation of intestinal Niemann-Pick C1 like 1 protein, acyl CoA:cholesterol acyltransferase 2, and ATP binding cassette transporter 5. In summary, WBO was equally effective as RBO in decreasing plasma cholesterol in hypercholesterolemia hamsters. PMID- 29502410 TI - cRGD Peptide-Conjugated Pyropheophorbide-a Photosensitizers for Tumor Targeting in Photodynamic Therapy. AB - Pyropheophorbide-a (Pyro) is a highly promising photosensitizer for tumor photodynamic therapy (PDT), although its very limited tumor-accumulation ability seriously restricts its clinical applications. A higher accumulation of photosensitizers is very important for the treatment of deeply seated and larger tumors. The conjugation of Pyro with tumor-homing peptide ligands could be a very useful strategy to optimize the physical properties of Pyro. Herein, we reported our studies on the conjugation of Pyro with a cyclic cRGDfK (cRGD) peptide, an integrin binding sequence, to develop highly tumor-specific photosensitizers for PDT application. To further reduce the nonspecific uptake and, thus, reduce the background distribution of the conjugates in normal tissues, we opted to add a highly hydrophilic polyethylene glycol (PEG) chain and an extra strongly hydrophilic carboxylic acid group as the linker to avoid the direct connection of the strongly hydrophobic Pyro macrocycle and cRGD ligand. We reported here the synthesis and characterization of these conjugates, and the influence of the hydrophilic modification on the biological function of the conjugates was carefully studied. The tumor-accumulation ability and photodynamic-induced cell killing ability of these conjugates were evaluated through both in vitro cell based experiment and in vivo distribution and tumor therapy experiments with tumor-bearing mice. Thus, the synthesized conjugate significantly improved the tumor enrichment and tumor selectivity of Pyro, as well as abolished the xenograft tumors in the murine model through a one-time PDT treatment. PMID- 29502411 TI - Evaluation of an Anti-HER2 Nanobody Labeled with 225Ac for Targeted alpha Particle Therapy of Cancer. AB - Human epidermal growth factor receptor type 2 (HER2) is overexpressed in numerous carcinomas. Nanobodies (Nbs) are the smallest antibody-derived fragments with beneficial characteristics for molecular imaging and radionuclide therapy. Therefore, HER2-targeting nanobodies could offer a valuable platform for radioimmunotherapy, especially when labeled with alpha-particle emitters, which provide highly lethal and localized radiation to targeted cells with minimal exposure to surrounding healthy tissues. In this study, the anti-HER2 2Rs15d nanobody was conjugated with 2-(4-isothiocyanatobenzyl)-1,4,7,10 tetraazacyclododecane-1,4,7,10-tetraacetic acid ( p-SCN-Bn-DOTA) and radiolabeled with an alpha-emitter 225Ac with a high yield (>90%) and a radiochemical purity above 95%. The 225Ac-DOTA-Nb binding affinity was 4.12 +/- 0.47 nM with an immunoreactive fraction above 80%. Binding to low HER2-expressing MDA-MB-231 cells was negligible, whereas HER2-overexpressing SKOV-3 cells could be blocked with an excess of unlabeled nanobody, confirming the specificity of binding. Noncompeting binding to HER2 was observed in the presence of an excess of trastuzumab. The cell-associated fraction of 225Ac-DOTA-Nb was 34.72 +/- 16.66% over 24 h. In vitro, the radioconjugate was toxic in an HER2-mediated and dose dependent manner, resulting in IC50 values of 10.2 and 322.1 kBq/mL for 225Ac DOTA-Nb and the 225Ac-DOTA control, respectively, on SKOV-3 cells, and 282.2 kBq/mL for 225Ac-DOTA-Nb on MDA-MB-231 cells. Ex vivo biodistribution studies, performed in mice bearing subcutaneous HER2-overexpressing and low HER2 expressing tumors, showed a fast uptake in SKOV-3 tumors compared to MDA-MB-231 (4.01 +/- 1.58% ID/g vs 0.49 +/- 0.20% ID/g after 2 h), resulting also in high tumor-to-normal tissue ratios. In addition, coinjection of 225Ac-DOTA-Nb with Gelofusine reduced kidney retention by 70%. This study shows that 225Ac-DOTA-Nb is a promising new radioconjugate for targeted alpha-particle therapy and supports its further development. PMID- 29502412 TI - Experimental and Theoretical Investigations of Infrared Multiple Photon Dissociation Spectra of Aspartic Acid Complexes with Zn2+ and Cd2. AB - Complexes of aspartic acid (Asp) cationized with Zn2+: Zn(Asp-H)+, Zn(Asp H)+(ACN) where ACN = acetonitrile, and Zn(Asp-H)+(Asp); as well as with Cd2+, CdCl+(Asp), were examined by infrared multiple photon dissociation (IRMPD) action spectroscopy using light generated from a free electron laser. A series of low energy conformers for each complex was found using quantum chemical calculations to identify the structures formed experimentally. The main binding motif observed for the heavy-metal complex, CdCl+(Asp)[N,CO,COs], is a charge-solvated, tridentate structure, where the metal center binds to the backbone amino group and carbonyl oxygens of the backbone and side-chain carboxylic acids. Likewise, the deprotonated Zn(Asp-H)+(ACN) and Zn(Asp-H)+(Asp) complexes show comparable [N,CO-,COs](ACN) and [N,CO-,COs][N,CO,COs] coordinations, respectively. Interestingly, there was only minor spectral evidence for the analogous Zn(Asp H)+[N,CO-,COs] binding motif, even though this species is predicted to be the lowest-energy conformer. Instead, rearrangement and partial dissociation of the amino acid are observed, as spectral features most consistent with the experimental spectrum are exhibited by a four-coordinate Zn(Asp-NH4)+[CO2 ,COs](NH3) complex. Analysis of the mechanistic pathway leading from the predicted lowest-energy conformer to the isobaric deaminated complex is explored theoretically. Further, comparison of the current work to that of Zn2+ and Cd2+ complexes of asparagine (Asn) allows additional conclusions regarding populated conformers and effects of carboxamide versus carboxylic acid binding to be drawn. PMID- 29502413 TI - Electric Field Effect on Condensed-Phase Molecular Systems. VI. Field-Driven Orientation of Hydrogen Chloride in an Argon Matrix. AB - The orientation state of hydrogen chloride (HCl) molecules in a solid argon matrix was reversibly controlled by applying an external electric field of up to 4 * 108 V.m-1 using the ice film capacitor method. The rovibrational transitions of the field-oriented HCl were measured by reflection absorption infrared spectroscopy with p-polarized light. Upon application of the external field, free rotation of HCl inside the matrix gradually changed to perturbed rotation and then to a pendular state harmonically bound in the Stark potential well. Further increase in the field strength increased the degree of dipole alignment along the field direction, approaching an asymptotically perfect orientation of the molecules with an average tilt angle of <30 degrees at a field strength above 1 * 108 V.m-1. PMID- 29502414 TI - DLS Setup for in Situ Measurements of Photoinduced Size Changes of Microgel-Based Hybrid Particles. AB - Photoinduced size changes in microgel particles loaded with gold nanoparticles (AuNPs) were investigated with an extended multiangle dynamic light scattering (DLS) setup. The DLS setup was equipped with a conventional laser (lambda = 633 nm) to determine the microgel particle size. Additionally, a laser (lambda = 532 nm) is installed to study the photoresponsive behavior of the AuNP-microgel hybrids. The wavelength of 532 nm is close to the absorption maximum of the plasmon resonance of the AuNPs used in the present study (i.e. spherical AuNPs with a diameter of 14 nm). The extended DLS setup enables us to follow in situ the change in microgel size during irradiation. The light stimulus is directly correlated with the size changes of the hybrid particles and the photothermal effect depends on the intensity of the excitation laser. The increase in excitation laser intensity results in a size reduction of hybrid particles because of the ability of AuNPs to partially transform the absorbed photon energy into heat which is emitted into the surrounding microgel network. PMID- 29502415 TI - 3-Fold-Periodic Size-Dependence in Electronic Properties of Monolayer-TMDC Nanotriangles. AB - Stable nanotriangles of monolayer transitional metal dichalcogenides (referred herein as MS2 mNTs) grown via ordinary deposition conditions, where M = Mo or W, exhibit a peculiar 3-fold periodic size-dependence in electronic and chemical properties. For " k" being the number of M atoms per edge, mNTs are (a) intrinsic semiconducting when k = 3 i + 1, such as k = 7, 10, 13, 16; (b) metallic-like with no bandgap when k = 3 i; (c) n+ semiconducting when k = 3 i - 1. Besides changes in electronic properties, the catalytic properties for hydrogen evolution reaction also switch from active for k = 3 i and 3 i - 1 to inactive for k = 3 i + 1. The peculiar periodic size-dependence roots from the chemistry of edge reconstruction and the consequential evolution of band structure. Further, such chemistry and thereby the size-dependence can be manipulated by adding or depleting the atomic concentration of sulfur atoms along the mNT edges. PMID- 29502416 TI - Click-Mediated Pretargeted Radioimmunotherapy of Colorectal Carcinoma. AB - Pretargeted radioimmunotherapy (PRIT) based on the inverse electron demand Diels Alder (IEDDA) reaction between tetrazine (Tz) and trans-cyclooctene (TCO) represents a promising strategy for leveraging the affinity and specificity of antibodies without their pharmacokinetic drawbacks. Herein, we present an investigation of the in vivo efficacy and dosimetry of a PRIT strategy for colorectal carcinoma based on the ligation between a 177Lu-labeled Tz radioligand (177Lu-DOTA-PEG7-Tz) and a TCO-bearing immunoconjugate of the huA33 antibody (huA33-TCO). Biodistribution studies in tumor-bearing mice using intervals of 24, 48, and 72 h between the administration of huA33-TCO and 177Lu-DOTA-PEG7-Tz revealed that a 24 h lag time produced the most promising in vivo results: high activity concentrations in the tumor (21.2 %ID/g +/- 2.9 at 24 h postinjection), low uptake in nontarget tissues, and favorable dosimetry (an effective dose of 0.054 mSv/MBq). A subsequent longitudinal therapy study revealed striking differences between both the survival and tumor growth of the treatment and control cohorts, clearly underscoring the promise of this approach for the radiotherapy of colorectal carcinoma. PMID- 29502417 TI - Quantifying Vascular Distribution and Adhesion of Nanoparticles with Protein Corona in Microflow. AB - The protein corona has emerged as an important determinant of biological response in nanoparticle (NP) drug delivery. However, there is presently no reported study on how the protein corona affects the behavior of NPs in microflow and its subsequent interactions with the vascular endothelium, which could affect their delivery to the target tumor site regardless of its targeting mechanism. Furthermore, a consensus on the role of physical and surface characteristics of NPs in affecting the margination of NPs is lacking due to different methods of quantifying margination. In this study, we examine how the particle adhesion (PA) method and particle distribution (PD) method quantify the margination of 20, 40, 100, and 200 nm polystyrene NPs (pNPs) differently in fibronectin or pluronic F 127-coated microfluidic straight channels. We found that PA reduced with increasing pNP size, whereas the PD was similar across all pNP sizes regardless of channel coating. We then formed a protein corona on all pNPs (pNPs-PC) and found that the protein corona increased the adhesion of 40-200 nm pNPs in fibronectin-coated channels, with no size dependence between them except for 40 nm, which had significantly higher particle adhesion. The PA method was also dependent on channel coating, whereas the PD method was independent of channel coating. These results suggested that the PA method was more amenable to surface interactions between the pNPs and the channel wall while providing a measure of the amount of NPs that interacted with the channel walls, whereas the PD method provided a representation of their distribution across the channel due to margination. The two methods complement each other to elucidate a more holistic understanding of how different factors might affect a NP's margination in future studies. PMID- 29502418 TI - Two-Dimensional Lattices of VN: Emergence of Ferromagnetism and Half-Metallicity on Nanoscale. AB - Two-dimensional (2D) ferromagnets with high spin-polarization ratio and high Curie temperature are crucial for developing next-generation spintronic nanodevices. Using first-principles calculations, we predict two polymorphic modifications ( t-VN and h-VN) of 2D VN lattices that have robust intrinsic ferromagnetic properties and high Curie temperatures. Whereas t-VN has 99.9% of spin polarization at the Fermi level, h-VN possesses a half-metallic type of conductivity and keeps it after contact with semiconducting MoS2, which can be used as the substrate for h-VN synthesis and valley polarized contacts. Magnetocrystalline anisotropy energy of 2D VN polymorphs is found to be at least an order larger than those of Fe and Ni bulks. The phonon spectra and ab initio molecular dynamic simulation prove that 2D VN lattices have a high thermodynamic stability. These advantages demonstrate that the VN monolayers should be promising candidates for low-dimensional spintronic devices. PMID- 29502419 TI - Reduced Graphene Oxide-Hybridized Polymeric High-Internal Phase Emulsions for Highly Efficient Removal of Polycyclic Aromatic Hydrocarbons from Water Matrix. AB - Reduced graphene oxide (RGO)-hybridized polymeric high-internal phase emulsions (RGO/polyHIPEs) with an open-cell structure and hydrophobicity have been successfully prepared using 2-ethylhexyl acrylate and ethylene glycol dimethacrylate as the monomer and the cross-linker, respectively. The adsorption mechanism and performance of this RGO/polyHIPEs to polycyclic aromatic hydrocarbons (PAHs) were investigated. Adsorption isotherms of PAHs on RGO/polyHIPEs show that the saturated adsorption capacity is 47.5 mg/g and the equilibrium time is 8 h. Cycling tests show that the adsorption capacity of RGO/polyHIPEs remains stable in 10 adsorption-desorption cycles without observable structure change in RGO/polyHIPEs. Moreover, the PAH residues in water samples after being purified by RGO/polyHIPEs are lower than the limit values in drinking water set by the European Food Safety Authority. These results demonstrate that the RGO/polyHIPEs have great potentiality in PAH removal and water purification. PMID- 29502420 TI - Photodisruption of the Structurally Conserved Cys-Cys-Trp Triads Leads to Reduction-Resistant Scrambled Intrachain Disulfides in an IgG1 Monoclonal Antibody. AB - Photostability conditions as prescribed by ICH guidelines induced highly reduction-resistant scrambled disulfides that contribute to the population of apparent nonreducible aggregates in an IgG1 mAb. Photoinduced cross-linked species were isolated under reducing conditions using an organic phase size exclusion chromatography (OP-SEC) method, followed by O18-labeling tryptic mapping to identify cross-linked peptides. Disulfide scrambling was observed within the IgG1 structurally conserved-intrachain cysteine-cysteine-tryptophan triads (Cys-Cys-Trp), and correlated with Trp-to-kynurenine (Kyn) photodegradation within these triads. We hypothesize that intrachain disulfides protect the proximal Trp within the Cys-Cys-Trp triads from photodegradation by enabling dissipation of Trp-absorbed UV energy via electron transfer to the disulfide bond. Finally, we propose three distinct mechanisms of photochemical degradation of monoclonal antibodies mediated by Trp residues. PMID- 29502421 TI - Self-Assembling Benzothiazole-Based Gelators: A Mechanistic Understanding of in Vitro Bioactivation and Gelation. AB - Low molecular weight gelators (LMWGs) of chemotherapeutic drugs represent a valid alternative to the existing polymer-based formulations used for targeted delivery of anticancer drugs. Herein we report the design and development of novel self assembling gelators of the antitumor benzothiazole 5F 203 (1). Two different types of derivatives of 1 were synthesized, formed by an amide (2) and a carbamate (3a-3d) linker, respectively, which showed potent in vitro antitumor activity against MCF-7 mammary and IGROV-1 ovarian carcinoma cells. In contrast, MRC-5 fibroblasts were inherently resistant to the above derivatives (GI50 > 10 MUM), thus revealing stark selectivity against the malignant cell lines over the nontransformed fibroblasts. Western blots assays demonstrated induction of CYP1A1 by 1 and its derivatives only in sensitive malignant cells (MCF-7), corroborating conservation of a CYP1A1-mediated mechanism of action. The ability to form stable gels under relatively high strains was supported by rheological tests; in addition, their inner morphology was characterized as possessing a crossed-linked nanostructure, with the formation of thick aggregates with variable widths between 1100 and 400 nm and lengths from 8 to 32 MUm. Finally, in vitro dissolution studies proved the ability of hydrogel 2 to release 48% of 2 within 80 h, therefore demonstrating its ability to act as a platform for localized delivery. PMID- 29502422 TI - Morphological and Physicochemical Evaluation of Two Distinct Glibenclamide/Hypromellose Amorphous Nanoparticles Prepared by the Antisolvent Method. AB - The morphology and stability of amorphous nanoparticles of glibenclamide (GLB) prepared by the antisolvent method using different methods of adding hypromellose (HPMC) were evaluated. Nano-A was prepared by the injection of a dimethyl sulfoxide (DMSO) solution of GLB into the HPMC solution, whereas nano-B was obtained by the injection of a DMSO solution of GLB and HPMC into water. Cryogenic transmission electron microscopy, field-emission scanning electron microscopy, and field-emission transmission electron microscopy, including energy dispersive X-ray spectrometry, revealed that the particles of the nano-A and nano B samples are hollow spheres and nonspherical nanoparticles, respectively. Powder X-ray diffraction and solid-state NMR measurements showed that GLB is present in an amorphous state in both nano-A and nano-B. The weight ratios of HPMC in the GLB/HPMC nanoparticles were 11 and 16% for nano-A and nano-B, respectively, as determined by solution-state NMR. The glass transition temperatures ( Tg) of nano A and nano-B evaluated using differential scanning calorimetry were lower by about 10 degrees C compared to that of amorphous GLB, presumably because of a Tg confinement effect and the surface coverage and mixing of HPMC, as suggested by the inverse gas chromatography experiment. GLB crystallization during storage was suppressed more strongly in nano-B than nano-A, owing to the higher amount of HPMC and the higher miscibility between GLB and HPMC. It is suggested that the diffusion rate of the solvent during nanoprecipitation determined the nanoparticle properties. In nano-A, the precipitation of GLB first occurred at the outer interface because of the rapid diffusion of the solvent. Thus, hollow spherical particles with HPMC preferentially located near the surface were formed. On the other hand, the diffusion of the solvent in nano-B was suppressed because of the presence of HPMC, yielding small nonspherical nanoparticles with a high miscibility of GLB and HPMC. PMID- 29502423 TI - Systemic Administration of siRNA with Anti-HB-EGF Antibody-Modified Lipid Nanoparticles for the Treatment of Triple-Negative Breast Cancer. AB - Triple-negative breast cancer is one of the intractable cancers that are not sensitive to treatment with existing molecular-targeted drugs. Recently, there has been much interest in RNA interference-mediated treatment of triple-negative breast cancer. In the present study, we have developed lipid nanoparticles encapsulating siRNA (LNP-siRNA) decorated with an Fab' antibody against heparin binding EGF-like growth factor (alphaHB-EGF LNP-siRNA). alphaHB-EGF LNP-siRNA targeting polo-like kinase 1 (PLK1) was prepared and evaluated for its anticancer effect using MDA-MB-231 human triple-negative breast cancer cells overexpressing HB-EGF on their cell surface. Biodistribution data of radioisotope-labeled LNP and fluorescence-labeled siRNA indicated that alphaHB-EGF LNP effectively delivered siRNA to tumor tissue in MDA-MB-231 carcinoma-bearing mice. Expression of PLK1 protein in the tumors was clearly suppressed after intravenous injection of alphaHB-EGF LNP-siPLK1. In addition, tumor growth was significantly inhibited by treatment with this formulation of siRNA and an antibody-modified carrier. These findings indicate that alphaHB-EGF LNP is a promising carrier for the treatment of HB-EGF-expressing cancers, including triple-negative breast cancer. PMID- 29502424 TI - Evaluation of Pazopanib Phase Behavior Following pH-Induced Supersaturation. AB - Salts of weakly basic active pharmaceutical ingredients are widely used to improve aqueous solubility and/or dissolution rate. However, these compounds are prone to precipitation due to the lower solubility of the un-ionized species at the higher pH in the intestinal region, and this can result in poor and/or variable absorption. The goal of this study was to investigate the degree of supersaturation achieved following dissolution of different amounts of pazopanib hydrochloride at low pH, followed by rapid pH increase. Using pH solubility profiles, phase boundaries were defined for crystalline and amorphous free base forms. The resultant phase diagram was used to rationalize the observed supersaturation and phase behavior of pazopanib following pH adjustment. In the presence of a crystallization inhibitor, hydroxypropylmethyl cellulose (HPMC), the degree of supersaturation was found to be very high, approximately 600-fold, at pH 6.5. At a dose equivalent to the clinical dose, the maximum free drug concentration observed at pH 6.5 was dictated by the amorphous solubility. Solutions that exceeded the amorphous solubility upon pH increase were found to undergo glass-liquid phase separations (GLPS) with the formation of amorphous colloidal drug-rich particles. Microscopic observations confirmed that HPMC delayed the appearance of pazopanib free base crystals. The phase behavior upon pH change is thus well predicted by the phase diagram, after taking into consideration the initial dose, the extent of supersaturation generated upon pH change, and the presence or absence of a crystallization inhibitor. PMID- 29502425 TI - Single-Mode Near-Infrared Lasing in a GaAsSb-Based Nanowire Superlattice at Room Temperature. AB - Semiconductor nanowire lasers can produce guided coherent light emission with miniaturized geometry, bringing about new possibilities for a variety of applications including nanophotonic circuits, optical sensing, and on-chip and chip-to-chip optical communications. Here, we report on the realization of single mode and room-temperature lasing from 890 to 990 nm, utilizing a novel design of single nanowires with GaAsSb-based multiple axial superlattices as a gain medium under optical pumping. The control of lasing wavelength via compositional tuning with excellent room-temperature lasing performance is shown to result from the unique nanowire structure with efficient gain material, which delivers a low lasing threshold of ~6 kW/cm2 (75 MUJ/cm2 per pulse), a lasing quality factor as high as 1250, and a high characteristic temperature of ~129 K. These results present a major advancement for the design and synthesis of nanowire laser structures, which can pave the way toward future nanoscale integrated optoelectronic systems with superior performance. PMID- 29502426 TI - Immuno-PET Imaging of 89Zr Labeled Anti-PD-L1 Domain Antibody. AB - Recently, various immuno-PET tracers based on monoclonal antibodies (mAbs), engineered scaffold proteins, and peptides were developed to target either programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1), showing promise in assessment of immune checkpoints. We sought to develop an immunotherapeutic agent based PET probe that enables real-time assessment of PD L1 expression and evaluation of antibody drug biodistribution to select eligible candidates for anti-PD-1/PD-L1 immunotherapies. KN035, a 79.6 kDa size anti-PD-L1 domain antibody under analysis in clinical trials, was used to develop the immuno PET probe, 89Zr-Df-KN035. Immuno-PET studies were performed to monitor PD-L1 levels in nude mice bearing LN229 xenografts with positive expression for PD-L1, and to evaluate the whole-body biodistribution in healthy non-human primates (NHPs). LN229 xenografts were markedly visualized from 24 h after injection of 89Zr-Df-KN035, with elevated accumulation persisting for up to 120 h. Tumor radioactivity was notably reduced in the presence of excess KN035. Mouse ex vivo biodistribution studies performed at 24 and 120 h revealed tumor-to-muscle ratios as high as 5.64 +/- 0.65 and 7.70 +/- 1.37, respectively. In the NHP model, PET imaging demonstrated low background. The liver and kidney showed moderate accumulation with the highest SUVmean value of 1.15 +/- 0.15 and 2.13 +/- 0.10 at 72 h, respectively. The spleen, lymph nodes, and salivary glands were also slightly visualized. In conclusion, 89Zr-Df-KN035, a novel anti-PD-L1 domain antibody-based probe, shows the feasibility of noninvasive in vivo evaluation of PD-L1 expression. This work further provides a template for immunotherapeutic agent based imaging to evaluate human PD-L1 expression and to augment our understanding of therapeutic agent biodistribution, leading to better therapeutic strategies in the future. PMID- 29502427 TI - Pharmacology by Chemical Biology. PMID- 29502428 TI - Resistance of Aedes aegypti (Diptera: Culicidae) Populations to Deltamethrin, Permethrin, and Temephos in Cambodia. AB - Dengue fever is a major public health concern, including 185,000 annual cases in Cambodia. Aedes aegypti is the primary vector for dengue transmission and is targeted with insecticide treatments. This study characterized the insecticide resistance status of Ae aegypti from rural and urban locations. The susceptibility to temephos, permethrin, and deltamethrin of Ae aegypti was evaluated in accordance with World Health Organization instructions. All the field populations showed lower mortality rate to temephos compared with the sensitive strain with resistance ratio 50 (RR50) varying from 3.3 to 33.78 and RR90 from 4.2 to 47 compared with the sensitive strain, demonstrating a generalized resistance of larvae to the temephos in Cambodia. Ae aegypti adult populations were highly resistant to permethrin regardless of province or rural/urban classification with an average mortality of 0.02%. Seven of the 8 field populations showed resistance to deltamethrin. These results are alarming for dengue vector control, as widespread resistance may compromise the entomological impact of larval control operations. Innovative vector control tools are needed to replace ineffective pesticides in Cambodia. PMID- 29502429 TI - Modelling the Impact of Different Tuberculosis Control Interventions on the Prevalence of Tuberculosis in an Overcrowded Prison. AB - The aim of this study was to simulate the effects of tuberculosis (TB) treatment strategies interventions in an overcrowded and poorly ventilated prison with both high (5 months) and low (3 years) turnover of inmates against improved environmental conditions. We used a deterministic transmission model to simulate the effects of treatment of latent TB infection and active TB, or the combination of both treatment strategies. Without any intervention, the TB prevalence is estimated to increase to 8.8% for a prison with low turnover of inmates but modestly stabilize at 5.8% for high-turnover prisons in a 10-year period. Reducing overcrowding from 6 to 4 inmates per housing cell and increasing the ventilation rate from 2 to 12 air changes per hour combined with any treatment strategy would further reduce the TB prevalence to as low as 0.98% for a prison with low inmate turnover. PMID- 29502430 TI - Anxiety and depression symptoms in young people with perinatally acquired HIV and HIV affected young people in England. AB - Adolescents with perinatal HIV (PHIV) may be at higher risk of anxiety and depression than HIV negative young people. We investigated prevalence of anxiety and depression symptoms in 283 PHIV and 96 HIV-affected (HIV-negative) young people in England recruited into the Adolescents and Adults Living with Perinatal HIV (AALPHI) cohort. We used Hospital Anxiety and Depression Scale (HADS) scores and linear regression investigated predictors of higher (worse) scores.115 (41%) and 29 (30%) PHIV and HIV-affected young people were male, median age was 16 [interquartile range 15,18] and 16 [14,18] years and 241 (85%) and 71 (74%) were black African, respectively. There were no differences in anxiety and depression scores between PHIV and HIV-affected participants. Predictors of higher anxiety scores were a higher number of carers in childhood, speaking a language other than English at home, lower self-esteem, ever thinking life was not worth living and lower social functioning. Predictors of higher depression scores were male sex, death of one/both parents, school exclusion, lower self-esteem and lower social functioning. In conclusion, HIV status was not associated with anxiety or depression scores, but findings highlight the need to identify and support young people at higher risk of anxiety and depression. PMID- 29502435 TI - Ossicular Chain Reconstruction in a Developing Country. AB - OBJECTIVES: In Ethiopia, 2-stage operations with middle ear prostheses are economically unfavorable. We hypothesized that single-stage autologous ossiculoplasty results in acceptable tympanic membrane (TM) and hearing improvements in a setting of limited resources. METHODS: One hundred eighty-eight patients (197 ears) who underwent 1-stage autologous ossiculoplasty for ossicular dysfunction are presented. All but 14 of these ears also had perforations of the TM. Conditions of the middle ear were granulation tissue, ossicular disruption only, tympanosclerosis, and cholesteatoma. Reconstructions of the ossicular chain were performed with autologous ossicles only. RESULTS: The closure rate of TM perforations was 95%. Preoperative air bone gaps were 27 to 60 dB (mean [SD] = 44 [7] dB); postoperative air bone gaps were 0 to 50 dB (average [SD] = 23 [10] dB), for an average improvement of 21 dB across all reconstruction types ( P < .001). The largest favorable changes in air bone gaps were with incus and malleus columellas from the footplate to the TM (33 and 23 dB, respectively) ( P < .001). No patient had worsening of sensorineural hearing levels or extrusion of the reconstructed ossicles. CONCLUSION: Autologous ossiculoplasty performed well in this setting. Acceptable TM closure rates and improvement of air bone gaps were seen in 1-stage operations without the use of prostheses. PMID- 29502434 TI - Using Mismatch Negativity to Investigate the Pathophysiology of Substance Use Disorders and Comorbid Psychosis. AB - Substance use disorders (SUDs) have a devastating impact on society and place a heavy burden on health care systems. Given that alcohol, tobacco, and cannabis use have the highest prevalence, further understanding of the underlying pathophysiology of these SUDs is crucial. Electroencephalography is an inexpensive, temporally superior, and translatable technique which enables investigation of the pathobiology of SUDs through the evaluation of various event related potential components, including mismatch negativity (MMN). The goals of this review were to investigate the effects of acute and chronic alcohol, tobacco, and cannabis use on MMN among nonpsychiatric populations and patients with comorbid psychosis. A literature search was performed using the database PubMed, and 36 articles met our inclusion and exclusion criteria. We found a pattern of attenuation of MMN amplitude among patients with alcoholism across acute and chronic alcohol use, and this dysregulation was not heritable. Reports were limited, and results were mixed on the effects of acute and chronic tobacco and cannabis use on MMN. Reports on comorbid SUDs and psychosis were even fewer, and also presented mixed findings. These preliminary results suggest that MMN deficits may be associated with SUDs, specifically alcohol use disorder, and serve as a possible biomarker for treating these common disorders. PMID- 29502438 TI - Three new tetralol analogs from soil-derived fungus Myrothecium verrucaria with anti-inflammatory activity. AB - Three new tetralol analogs, myrochromanols A-C (1-3), together with 11 known trichothecenes (4-14), were isolated from a soil fungus Myrothecium verrucaria HL P-1. The structures of the three new compounds were elucidated by extensive spectroscopic analysis including HRESIMS, NMR, and ECD calculation. All of the new compounds were tested for their anti-inflammatory activity and cytotoxicity. Compounds 1 and 3 inhibited lipopolysaccharide (LPS)-induced NO production in BV2 cells with IC50 values of 26.04 and 25.80 MUM, respectively. PMID- 29502439 TI - Dyshidrotic Bullous Pemphigoid: Case Report and Review of Literature. AB - BACKGROUND: Dyshidrotic pemphigoid (DP) is a rare variant of bullous pemphigoid (BP) that affects the hands and feet and may resemble an acute vesicular eczema. While it can remain confined to hands and feet, spread that involves the entire body is described. BP and DP are associated with autoantibodies directed against hemidesmosomal proteins BP180 (collagen XVII) and BP230 (dystonin), which are transmembrane and intracellular proteins in the basement membrane zone, respectively. CASE SUMMARY: We present a case of DP in a 78-year-old woman who was diagnosed based on histopathologic and immunofluorescence findings and subsequently successfully treated. CONCLUSION: DP is an unusual form of localized BP. While the pathogenesis is still unclear, it may involve differential expression of BP antigens in the cutaneous basement membrane of the hands and feet. The clinical presentation is a diagnostic challenge, and skin biopsies with immunofluorescence studies are required for diagnosis. PMID- 29502440 TI - Filiform Verrucous Sarcoidosis of the Face: A Warty Report. AB - Sarcoidosis is a multisystem inflammatory condition of unknown etiology. Variability in the cutaneous features of sarcoidosis is profound, and its protean manifestations affirm the condition's designation as one of dermatology's "great mimics." Cutaneous phenotypes of sarcoidosis include but are by no means limited to ichthyosiform, alopecic, erythrodermic, angiolupoid, and verrucous variants. Verrucous sarcoidosis is an exceedingly rare manifestation, and previous reports of this phenotype are limited to 15 cases. Most cases in the extant literature presented on the extremities, with clinical features mimicking that of a common wart, or as verrucous crateriform nodules, ulcers, or cutaneous horns. Only 4 previous reports of facial verrucous sarcoidosis exist in the literature, and to our knowledge, no prior cases have demonstrated filiform lesion morphology. Here we present a case of filiform verrucous sarcoidosis in an otherwise healthy, middle-aged African American man, devoid of internal organ involvement and limited to the face, histopathologically confirmed by the presence of characteristic granulomata devoid of lymphocytic infiltrates. PMID- 29502442 TI - Abstracts of the Basic and Clinical Multimodal Imaging (BaCI) Conference, Annual Joint Meeting of ECNS, ISBET, ISFSI, and ISNIP, Bern, Switzerland, August 29 September 2, 2017. PMID- 29502441 TI - Uncomplicated Neonatal Linear IgA Bullous Dermatosis: A Case Report. PMID- 29502443 TI - Leucoxenols A and B, two new phenolics from Bornean medicinal plant Syzygium leucoxylon. AB - The medicinal plant, Syzygium leucoxylon or commonly known as Obah found in North Borneo was considered as traditional medicine by local committee. Two new phenolics, leucoxenols A (1) and B (2) were isolated and identified as major secondary metabolites from the leaves of S. leucoxylon. Their chemical structures were elucidated based on spectroscopic data such as NMR and HRESIMS. Furthermore, these compounds were active against selected strains of fungi. PMID- 29502444 TI - Restricted mean survival time: Does covariate adjustment improve precision in randomized clinical trials? AB - BACKGROUND: Restricted mean survival time is a measure of average survival time up to a specified time point. There has been an increased interest in using restricted mean survival time to compare treatment arms in randomized clinical trials because such comparisons do not rely on proportional hazards or other assumptions about the nature of the relationship between survival curves. METHODS: This article addresses the question of whether covariate adjustment in randomized clinical trials that compare restricted mean survival times improves precision of the estimated treatment effect (difference in restricted mean survival times between treatment arms). Although precision generally increases in linear models when prognostic covariates are added, this is not necessarily the case in non-linear models. For example, in logistic and Cox regression, the standard error of the estimated treatment effect does not decrease when prognostic covariates are added, although the situation is complicated in those settings because the estimand changes as well. Because estimation of restricted mean survival time in the manner described in this article is also based on a model that is non-linear in the covariates, we investigate whether the comparison of restricted mean survival times with adjustment for covariates leads to a reduction in the standard error of the estimated treatment effect relative to the unadjusted estimator or whether covariate adjustment provides no improvement in precision. Chen and Tsiatis suggest that precision will increase if covariates are chosen judiciously. We present results of simulation studies that compare unadjusted versus adjusted comparisons of restricted mean survival time between treatment arms in randomized clinical trials. RESULTS: We find that for comparison of restricted means in a randomized clinical trial, adjusting for covariates that are associated with survival increases precision and therefore statistical power, relative to the unadjusted estimator. Omitting important covariates results in less precision but estimates remain unbiased. CONCLUSION: When comparing restricted means in a randomized clinical trial, adjusting for prognostic covariates can improve precision and increase power. PMID- 29502445 TI - The Interrelated Physiological and Psychological Effects of EcoMeditation. AB - This study investigated changes in psychological and physiological markers during a weekend meditation workshop (N = 34). Psychological symptoms of anxiety, depression, posttraumatic stress disorder (PTSD) and happiness were assessed. Physiological markers included cortisol, salivary immunoglobulin A (SigA), heart rate variability (HRV), blood pressure (BP), and resting heart rate (RHR). On posttest, significant reductions were found in cortisol (-29%, P < .0001), RHR ( 5%, P = .0281), and pain (-43%, P = .0022). Happiness increased significantly (+11%, P = .0159) while the increase in SigA was nonsignificant (+27%, P = .6964). Anxiety, depression, and PTSD all declined (-26%, P = .0159; -32%, P = .0197; -18%, P = .1533), though changes in PTSD did not reach statistical significance. No changes were found in BP, HRV, and heart coherence. Participants were assessed for psychological symptoms at 3-month follow-up, but the results were nonsignificant due to inadequate sample size (n = 17). EcoMeditation shows promise as a stress-reduction method. PMID- 29502446 TI - Sexual and behavioral health disparities among African American sexual minority men and women. AB - INTRODUCTION: Sexual and behavioral health disparities have been consistently demonstrated between African American and White adults and between sexual minority and heterosexual communities in the United States; however, few studies using nationally representative samples have examined disparities between sexual minority and heterosexual adults within African American populations. The purpose of this study was to examine the prevalence of sexual and behavioral health outcomes between sexual minority and heterosexual African American adults and to examine whether there were different patterns of disparities for African American sexual minority men and women, respectively. METHODS: We analyzed data from 4502 African American adults who participated in the 2001-2015 waves of the National Health and Nutrition Examination Survey. Using multivariable analyses, we examined differences in HIV, sexually transmitted infections, mental health, and substance use among African American sexual minority and heterosexual men and women. RESULTS: After adjusting for sociodemographic variables, African American sexual minority men had significantly higher odds of HIV, sexually transmitted infections, and poor mental health compared to their heterosexual male counterparts, whereas African American sexual minority women had significantly higher odds of Hepatitis C, poor mental health, and substance use compared to their heterosexual female counterparts. CONCLUSIONS: These findings demonstrate notable sexual orientation disparities among African American adults. Disparities persisted beyond the role of sociodemographic factors, suggesting that further research utilizing an intersectional approach is warranted to understand the social determinants of adverse health outcomes among African American sexual minority men and women. PMID- 29502447 TI - A new flavone glucoside together with known ellagitannins and flavones with anti diabetic and anti-obesity activities from the flowers of pomegranate (Punica granatum). AB - A new flavone glucoside tricetin 4'-O-beta-glucopyranoside (1) and four known ellagitannins and flavones tricetin (2), luteolin (3), ellagic acid (4), and granatin B (5) were isolated from the flowers of Punica granatum L. (Lythraceae). Their structures were established by 1D and 2D NMR as well as mass spectrometry analyses. Among all tested compounds, tricetin (2) exhibited the strongest alpha glucosidase inhibitory activity that was comparable to the anti-diabetic drug acarbose. Comparative structure-function analysis of tri-, tetra-, and pentahydroxy flavones [apigenin, luteolin (3), and tricetin (2), respectively] suggested that a greater number of hydroxyl groups on the flavone molecule enhanced its suppression of alpha-glucosidase, alpha-amylase, and lipase activities. PMID- 29502448 TI - The independent effects of match location, match result and the quality of opposition on subjective wellbeing in under 23 soccer players: a case study. AB - This study examined if subjective wellbeing in soccer players was affected by match location, match result and opposition quality before a match (PRE), 1 day after (POST-1), and 3 days after a match (POST-3). Eleven professional male soccer players from the under 23 squad playing in the Premier League 2 division completed a wellbeing questionnaire before and after 17 matches. Match training load (session-rating perceived exertion) was not different, regardless of the location, result, or quality of opposition faced (P > 0.05). Subjective wellbeing was not different at PRE (P > 0.05); however, at POST-1 and POST-3, stress and mood were >=20% lower after playing away from home or losing (P < 0.05). Stress, mood and sleep were >=12% worse after playing against a higher-level opposition at POST-1. Coaches need to be aware that match location, match result and the quality of the opposition can influence post-match wellbeing, irrespective of match load. PMID- 29502449 TI - Rubescins I and J, further limonoid derivatives from the stem bark of Trichilia rubescens (Meliaceae). AB - Two new tetranorterpenoid derivatives named rubescins I (1) and J (2), were isolated along with six known compounds including rubescin D (3), lichexanthone (4), scopoletin (5), scopoletin O-glycoside (6), beta-sitosterol (7) and stigmasterol (8) from the stem bark of Trichilia rubescens (Meliaceae). The structures of the compounds were determined by means of MS, different NMR and by comparison with related data reported in the literature. PMID- 29502450 TI - A new dimeric secoiridoids derivative, japonicaside E, from the flower buds of Lonicera japonica. AB - A new dimeric secoiridoids derivative, named japonicaside E, together with six known compounds were isolated from the flower buds of Lonicera japonica. The structures of these compounds were elucidated by the analyses of mass spectrometry and NMR spectroscopy. All compounds were evaluated for anti inflammatory activity in vitro. PMID- 29502451 TI - Does the type of sport practised influence foot posture and knee angle? Differences between footballers and swimmers. AB - This aim of this study is to observe the differences in foot posture and the angle of the knee according to different physical activities. Seventy-eight football players and 72 swimmers were recruited, and in each case a foot posture analysis, based on the foot posture index (FPI), was conducted and the Q angle of the knee was determined. The following mean values were obtained for the lower extremities: in the swimmers, FPI 6.45 +/- 2.04 and Q angle 15.38o +/- 3.79o. In the footballers, FPI 2.23 +/- 1.72 and Q angle 13.16o +/- 1.36o. There were statistically significant differences (p < 0.001) between the two groups. The swimmers presented a foot posture with a tendency towards pronation, and a Q angle with a tendency towards valgus, while the results for the footballers were within the normal range. PMID- 29502452 TI - Auditory Mismatch Negativity and P300a Elicited by the "Optimal" Multi-feature Paradigm in Early Schizophrenia. AB - The mismatch negativity (MMN) is an EEG-derived event-related potential (ERP) elicited by any violation of a predicted auditory "rule," regardless of whether one is attending to the stimuli and is thought to reflect updating of the stimulus context. Redirection of attention toward a rare, distracting stimulus event, however, can be measured by the subsequent P3a component of the P300. Chronic schizophrenia patients exhibit robust MMN deficits, as well as reductions in P3a amplitude. While, the substantial literature on the MMN in first-episode and early phase schizophrenia in this population reports reduced amplitudes, there also exist several contradictory studies. Conversely, P3a reduction in this population is relatively consistent, although the literature investigating this is small. The primary goal of this study was to contribute to our understanding of whether auditory change detection mechanisms are altered in early phase schizophrenia and, if so, under what conditions. Event-related potentials elicited by duration, frequency, gap, intensity, and location deviants (as elicited by the "optimal" multi-feature paradigm) were recorded in 14 early phase schizophrenia (EP) patients and 17 healthy controls (HCs). Electrical activity was recorded from 15 scalp electrodes. MMN/P3a amplitudes and latencies for each deviant were compared between groups and were correlated with clinical measures in EPs. There were no significant group differences for MMN amplitudes or latencies, though EPs did exhibit reduced P3a amplitudes to gap and duration deviants. Furthermore, PANSS (Positive and Negative Syndrome Scale) positive symptom scores were correlated with intensity MMN latencies and duration P3a amplitudes in EPs. These findings suggest that MMNs may not be as robustly reduced in early phase schizophrenia (relative to chronic illness), but that alterations may be more likely in patients with increased positive symptomatology. Furthermore, these findings offer further support to previous work suggesting that the understudied P3a may have good complementary utility as a marker of early cortical dysfunction in psychosis. PMID- 29502453 TI - Brain tissue analysis of impacts to American football helmets. AB - Concussion in American football is a prevalent concern. Research has been conducted examining frequencies, location, and thresholds for concussion from impacts. Little work has been done examining how impact location may affect risk of concussive injury. The purpose of this research was to examine how impact site on the helmet and type of impact, affects the risk of concussive injury as quantified using finite element modelling of the human head and brain. A linear impactor was used to impact a helmeted Hybrid III headform in several locations and using centric and non-centric impact vectors. The resulting dynamic response was used as input for the Wayne State Brain Injury Model to determine the risk of concussive injury by utilizing maximum principal strain as the predictive variable. The results demonstrated that impacts that occur primarily to the side of the head resulted in higher magnitudes of strain in the grey and white matter, as well as the brain stem. Finally, commonly worn American football helmets were used in this research and significant risk of injury was incurred for all impacts. These results suggest that improvements in American football helmets are warranted, in particular for impacts to the side of the helmet. PMID- 29502454 TI - Health psychology in Ghana: A review of the multidisciplinary origins of a young sub-field and its future prospects. AB - This article presents a historical overview of psychology applied to health and health psychology in Ghana. A brief history of health, illness and healthcare in Ghana is introduced. Then, the history of psychology in Ghana is presented, with signposts of the major turns in the field in relation to psychology and other disciplines applied to health and the emergence of health psychology as a sub field. Selected health psychology studies are reviewed to highlight ideological trends in the field. Finally, future prospects are considered in terms of how the sub-field can transition into an established critical field with unique contributions to make to global health psychology. PMID- 29502455 TI - Health psychology in autobiography: Three Canadian critical narratives. AB - Three Canadian colleagues in health psychology recount their careers in a field of research and practice whose birth they witnessed and whose developments they have critiqued. By placing the development of health psychology in Canada in a context that is both institutional and personal, Stam, Murray, and Lubek raise a series of questions about health psychology and its propagation. While uniquely Canadian their professional careers were affected by international colleagues as well as others-patients and community members-whose views shaped their perspectives. This article is a plea for the continuing development of critical voices in health psychology. PMID- 29502456 TI - Doing Histor{y/ies} of Health Psycholog{y/ies}. AB - Academic (sub)disciplines develop in time and place when particular ideas/practices are nurtured within social, gendered, cultural, community, economic and political contexts. Different histories employ different analyses, some with external views of scientific outputs describing research and practice, and others with internal, behind-the-scenes examinations of these developments, through oral histories and personal recollections. This collection, written by historians of (social) science, or practitioners or pioneering participants, uses different historiographical methods to contextualize health-related activities within the sub-discipline of health psychology and the evolving critical and/or community approaches. The papers connect the evolving health psycholog{y/ies} with changing socio-political circumstances in different countries. PMID- 29502457 TI - Notes on the development of health psychology and behavioral medicine in the United States. AB - A "standard" historiographical overview of the development of health psychology in the United States, alongside behavioral medicine, first summarizes previous disciplinary and professional histories. A "historicist" approach follows, focussing on a collective biographical summary of accumulated contributions of one cohort (1967-1971) at State University of New York at Stony Brook. Foundational developments of the two areas are highlighted, contextualized within their socio-political context, as are innovative cross-boundary collaboration on "precursor" studies from the 1960s and 1970s, before the official disciplines emerged. Research pathways are traced from social psychology to health psychology and from clinical psychology to behavioral medicine. PMID- 29502458 TI - Project reach: Piloting a risk-tailored smoking cessation intervention for lung screening. AB - The purpose of this study was to explore the feasibility, acceptability, and efficacy of a telephone-based smoking cessation intervention for lung screening patients. Participants ( N = 39) were enrolled in a single-arm pilot study of a four-session telephone-based intervention. Self-report measures were completed at baseline, post-intervention, and 3-month follow-up. Participants were long-term smokers; 62 percent were not motivated to quit. Twenty-three percent attempted quitting, 29 percent decreased their smoking, and 11 percent reported abstinence. Confidence increased ( p < .001) and there were trends toward increased importance ( p = .09) and comparative disease risk ( p = .02). This intervention was acceptable and associated with improvements in smoking-related beliefs and behaviors. PMID- 29502459 TI - Variation of temporal order reveals deficits in categorisation of facial expressions in patients afflicted with depression. AB - INTRODUCTION: It is well established that depressive disorders are associated with abnormalities in the processing of affective information. However, type of stimuli, perceptual complexity and cognitive demand are important factors in evaluating these findings. In particular, processing mechanisms of perceptual boundaries in ecologically valid face stimuli are largely unknown in depression. METHODS: In the current study, intensity-ordered frame sequences provided a dynamic visualisation of happy or sad facial expressions fading from or to neutral expressions. Patients (n = 20) with major depression (MD) disorder and controls (n = 20) indicated their perceptual boundaries between neutral and emotional face depending on direction and emotion. The averaged time of the perceptual boundary entered a group * condition ANOVA and regression analysis. RESULTS: MD group did not systematically shift perceptual boundaries in the dynamic emotional faces but yielded altered statistics in information processing. The Gaussian distribution of boundary judgements was disturbed in depression, increasing goodness-of-fit errors in disappearing emotions. Goodness-of-fit correlated with depression symptom score (Beck Depression Inventory-II (BDI-II)) in the MD group during the disappearing sad (r(18) = 46, p = 0.04) and happy (r(18) = 51, p = 0.02) conditions. CONCLUSION: We evaluated detection of appearing and disappearing emotions in dynamic faces. A deviant distribution of categorisation responses emerged in the MD group, which was not emotion-specific. Such a perceptional uncertainty can impede individuals' functioning in interpersonal interaction. PMID- 29502460 TI - Influence of authoritarianism, vagal tone and mental fatigue on obedience to authority. AB - Recent research suggests that obedience in the Milgram paradigm is underpinned by stress vulnerability and inhibitory control over pain sharing. Because self regulatory fatigue (SRF) induction is a suited method to investigate the influence of inhibitory control on behaviour, participants (n = 99) were randomly assigned to a High vs. Low self-regulatory condition. Heart rate variability (HRV, a biomarker of stress vulnerability) was collected during 5-min baseline and continuously during the experimental procedure. Prior to the experiment, participants completed an online survey assessing right-wing authoritarianism (RWA), a well-known predictor of obedience. Using the Immersive Video Milgram Obedience Experiment, we found (i) that lower resting HRV predicted higher destructive obedience, (ii) that low self-regulatory inhibition (induced by fatigue) reduced destructive obedience, (iii) that the well-established influence of RWA on destructive obedience was suppressed in the presence of SRF. Implications for future directions in obedience research are discussed. PMID- 29502461 TI - Examining the factor structure of narrative meaning-making for stressful events and relations with psychological distress. AB - This study examined the underlying factor structure of 15 narrative meaning making indices for narratives of stressful events, and explored the incremental validity of the narrative factor solution over and above general personality traits in predicting various indices of psychological well-being. Two-hundred and twenty four undergraduates (Mage = 19.2 years, SDage = 2.1; 114 males and 110 females; 67.6% Caucasian, 12.0% East Asian, 7.6% African-American, 4.0% South Asian, 2.2% Hispanic, and 6.7% as mixed or Other origin) wrote about the most traumatic experience in their life, and completed a series of psychological questionnaires. The narratives were coded in 15 ways theoretically derived from the narrative meaning-making literature. A series of exploratory structural equation models indicated that a four-factor solution best approximated the data. The four factors were: positive processing, negative processing, integrative meaning, and structure. All four factors related differentially to indices of well-being over and above traits. There appear to be four distinct, but related, factors of narrative meaning-making for memories of stressful events, which shed light on the nuanced relations with well-being. PMID- 29502463 TI - Examination of the relevance of the ICF cores set for stroke by comparing with the Stroke Impact Scale. AB - PURPOSE: To examine if the International Classification of Functioning (ICF) core set for stoke contains problems that are relevant for the persons living with stroke as expressed in the Stroke Impact Scale (SIS). METHODS: Cross-sectional study of 242 persons with previous stroke. The agreement between the perceived problems in the SIS items and problems in the categories of Comprehensive ICF Core Set for stroke were analyzed using percent of agreement and Kappa statistic. RESULTS: The analyses between 57 items of the SIS and 31 second-level categories of the ICF were conducted. The problems in domains of "Mobility", "Activities of daily living", "Hand function", "Strength" in the SIS had moderate agreement when compared to ICF categories. The SIS domains of "Emotion" and "Communication", as well as some aspects of the "Memory" had slight or fair agreement with corresponding ICF categories. The results of the study suggest that there is acceptable agreement between persons after stroke and health professionals in the physical aspects, but rather poor agreement in the cognitive and emotional aspects of functioning. CONCLUSIONS: Health professionals do not fully capture the magnitude of emotional or social problems experienced by persons after stroke when using the ICF Core Set as a framework for evaluation. Implications for Rehabilitation The ICF Core Set for Stroke provides comprehensive list of possible health and health related outcomes for persons after stroke. Problems reported in condition-specific patient-reported outcome scales can be important in decision making in rehabilitation. Patients and health professionals tend to agree more on physical than cognitive problems. Examination of the relevance of the ICF cores set for stroke by comparing with the Stroke Impact Scale. PMID- 29502464 TI - The effect of trunk training on muscle thickness and muscle activity: a systematic review. AB - OBJECTIVE: A systematic review to examine the effect of static or dynamic trunk training compared to standard care or control therapy on muscle activity and muscle thickness of the trunk and lower limb muscles in stroke survivors. MATERIALS AND METHODS: This review was registered on PROSPERO (no: CRD42017063771) and was written according to the PRISMA guidelines. The search strategy included studies from the first indexed article until September 2017 and was performed in the electronical databases PubMed, Web of Science, Cochrane Library, Ovid Medline and PEDro. Two independent reviewers screened, assessed risk of bias by means of the PEDro scale and extracted data. RESULTS: Eight studies were included of which three investigated the effects of trunk training on muscle thickness, the remaining five investigated muscle activity. The following muscles were investigated: erector spinae, multifidi, paravertebralis, transversus abdominis, internal and external oblique abdominis, rectus abdominis, quadriceps femoris, hamstrings, soleus and tibialis anterior. Trunk exercises significantly improved the muscle activity of the internal oblique abdominis and increased muscle thickness of transversus abdominis. CONCLUSIONS: Trunk training is effective in restoring symmetry in muscle thickness to improve muscle strength. The gain in muscle thickness is specific to the applied exercise program, suggesting that therapeutic goal setting is of great importance. However, no conclusion could be made concerning changes in muscle activity due to a high risk of bias. Implications for rehabilitation: Trunk training seems to be effective in restoring symmetry in trunk muscle thickness. Not all muscle groups benefit from specific trunk exercises. Patients suffering from chronic stroke are still capable of restoring muscle function. PMID- 29502465 TI - Isolated Optic Nerve Glioma in Children With and Without Neurofibromatosis: Retrospective Characterization and Analysis of Outcomes. AB - Isolated optic nerve glioma is a rare tumor with no consensus for the best therapeutic approach. Therefore, tumor control and preservation of visual function remain a challenge. In this retrospective study, we describe our experience over 30 years in a single-institutional cohort of children with isolated optic nerve glioma, focusing on treatments and visual outcomes. Seventeen children were followed for a median period of 8 years (range, 2-22 years). Diagnosis was based on typical neuroradiologic findings, and 3 patients had histologic confirmation of their tumors. In our study, conservative management preserved the vision of most patients with neurofibromatosis type 1 (NF1). NF1-related optic nerve gliomas were less often treated but were associated with a lower probability of progression and with occasional spontaneous regression. Sporadic tumors more frequently exhibited aggressive clinical behavior with a higher propensity for posterior extension, often requiring surgical intervention. PMID- 29502462 TI - Laboratory evaluation of the IFN-gamma circuit for the molecular diagnosis of Mendelian susceptibility to mycobacterial disease. AB - The integrity of the interferon (IFN)-gamma circuit is necessary to mount an effective immune response to intra-macrophagic pathogens, especially Mycobacteria. Inherited monogenic defects in this circuit that disrupt the production of, or response to, IFN-gamma underlie a primary immunodeficiency known as Mendelian susceptibility to mycobacterial disease (MSMD). Otherwise healthy patients display a selective susceptibility to clinical disease caused by poorly virulent mycobacteria such as BCG (bacille Calmette-Guerin) vaccines and environmental mycobacteria, and more rarely by other intra-macrophagic pathogens, particularly Salmonella and M. tuberculosis. There is high genetic and allelic heterogeneity, with 19 genetic etiologies due to mutations in 10 genes that account for only about half of the patients reported. An efficient laboratory diagnostic approach to suspected MSMD patients is important, because it enables the establishment of specific therapeutic measures that will improve the patient's prognosis and quality of life. Moreover, it is essential to offer genetic counseling to affected families. Herein, we review the various genetic and immunological diagnostic approaches that can be used in concert to reach a molecular and cellular diagnosis in patients with MSMD. PMID- 29502466 TI - New Breast Cancer Radiotherapy Technology Confers Higher Complications and Costs Before Effectiveness Proven: A Medicare Data Analysis. AB - A new breast cancer treatment, brachytherapy-based accelerated partial breast radiotherapy (RT), was adopted before long-term effectiveness evidence, potentially increasing morbidity and costs compared with whole breast RT. The aim of this study was to estimate complication rates and RT-specific and 1-year costs for a cohort of female Medicare beneficiaries diagnosed with breast cancer (N = 47 969). We analyzed 2005-2007 Medicare claims using multivariable logistic regression for complications and generalized linear models (log link, gamma distribution) for costs. Overall, 11% (n = 5296) underwent brachytherapy-based RT; 9.4% had complications. Odds of any complication were higher (odds ratio [OR]: 1.62; 95% confidence interval [CI]: 1.49-1.76) for brachytherapy versus whole breast RT, similarly to seroma (OR: 2.85; 95% CI: 1.97-4.13), wound complication/infection (OR: 1.72; 95% CI: 1.52-1.95), cellulitis (OR: 1.48; 95% CI: 1.27-1.73), and necrosis (OR: 2.07; 95% CI: 1.55-2.75). Mean RT-specific and 1-year total costs for whole breast RT were $6375, and $19 917, $4886, and $4803 lower than brachytherapy ( P < .0001). Multivariable analyses indicated brachytherapy yielded 76% higher RT costs (risk ratio: 1.76; 95% CI: 1.74-1.78, P < .0001) compared with whole breast RT. Brachytherapy had higher complications and costs before long-term evidence proved its effectiveness. Policies should require treatment registries with reimbursement incentives to capture surveillance data for new technologies. PMID- 29502467 TI - Examining the Rate of Self-Reported ADHD-Related Traits and Endorsement of Depression, Anxiety, Stress, and Autistic-Like Traits in Australian University Students. AB - OBJECTIVE: To investigate the rate of ADHD-related traits among young adults in an Australian university, and to examine whether higher endorsement of ADHD related symptoms is associated with self-reported symptoms of depression, anxiety, distress, and autistic-like traits. METHOD: In total, 1,002 students aged 17 to 25 years completed the Conners' Adult ADHD Rating Scale (CAARS), the Depression, Anxiety, and Stress Scale (DASS), and the Autism Quotient (AQ). RESULTS: About 17.3% of students reported "at-risk" levels of ADHD-related symptoms. Regression analyses revealed that CAARS scores explained unique variance in self-reported levels of depression, anxiety, stress, and autism related traits. CONCLUSION: The rate of self-reported ADHD symptoms is higher in Australian undergraduate students than that reported in previous studies using the CAARS to investigate rates of diagnosed students. Problems with self-concept accounted for the most unique variance in DASS subscale scores. Hyperactivity/restlessness and inattention/memory problems accounted for the most unique variance in AQ-Social and AQ-Attention-to-Detail scores, respectively. PMID- 29502468 TI - Pharmacokinetics and tolerability of cinitapride in healthy Chinese volunteers: a randomized, open-label, single- and multiple-dose study. AB - Cinitapride (CIN) is a drug for functional dyspepsia. The purpose of the study was to investigate the pharmacokinetics and tolerability of CIN in healthy Chinese volunteers. A randomized, open-label, single- and multiple-dose study was conducted in 12 healthy volunteers. Three different doses of CIN (1, 2, 4 tablets) were given to six groups in the single-dose study, and one tablet (1 mg) of CIN was administered three times a day in the multiple-dose study. Blood samples were collected at predetermined time intervals after CIN dosing and analyzed by LC-MS/MS. Eleven volunteers completed the study. After single dose, the Cmax and AUC of plasma increased approximately linearly with dosage; no statistically significant differences were found in pharmacokinetic parameters between three dose groups. After multiple doses, there was no significant change in Tmax and t1/2 compared with the results from the single dose. After repeated doses, AUC0-t and AUC0-infinity were increased, while CLz/F slightly decreased. And no differences between male and female. The pharmacokinetic parameters of this study were consistent with study results of non-Chinese subjects. Good tolerability was demonstrated in both single- and multiple-dose studies with dosage range from 1 to 4 mg in healthy Chinese subjects. PMID- 29502469 TI - Excitatory and inhibitory priming by attended and ignored non-recycled words with monolinguals and bilinguals. AB - Experiments examining identity priming from attended and ignored novel words (words that are used only once except when repetition is required due to experimental manipulation) in a lexical decision task are reported. Experiment 1 tested English monolinguals whereas Experiment 2 tested Twi (a native language of Ghana, Africa)-English bilinguals. Participants were presented with sequential pairs of stimuli composed of a prime followed by a probe, with each containing two items. The participants were required to name the target word in the prime display, and to make a lexical decision to the target item in the probe display. On attended repetition (AR) trials the probe target item was identical to the target word on the preceding attentional display. On ignored repetition (IR) trials the probe target item was the same as the distractor word in the preceding attentional display. The experiments produced facilitated (positive) priming in the AR trials and delayed (negative) priming in the IR trials. Significantly, the positive and negative priming effects also replicated across both monolingual and bilingual groups of participants, despite the fact that the bilinguals were responding to the task in their non-dominant language. PMID- 29502470 TI - Relationship between smartphone addiction of nursing department students and their communication skills. AB - BACKGROUND: The use of technological devices today is widespread. One of these devices is the smartphone. It can be argued that when smartphones are thought of as a means of communication, they can influence communication skills. AIM: The aim of this study is to determine the effect of nursing students' smartphone addiction on their communication skills. METHODS: A relational screening model was used for the study. The study's data were obtained from 214 students studying in the nursing department. RESULTS: Smartphone addiction levels of students are below average (86.43 +/- 29.66). Students think that their communication skills are at a good level (98.81 +/- 10.88). Correlation analysis results show that students have a negative, significant and very weak relationship between the smartphone addiction of students and communication skills (r = -.149). Smartphone addiction explains 2.2% of the variance in communication skills. CONCLUSIONS: Communication skills of nursing students is affected negatively by smartphone addiction. PMID- 29502471 TI - Sources of variability in quantifying circulating thymosin beta-4: literature review and recommendations. AB - INTRODUCTION: Thymosin beta-4 (TB4) is an endogenous peptide with protective and regenerative effects in models of cellular and organ injury. TB4 is increasingly measured as a potential plasma or serum biomarker in human cardiovascular, liver, infectious, and autoimmune disease. Areas covered: The focus of this review is the quantification of TB4 in clinical cohort studies and whether reported TB4 concentrations differ with respect to method of sample preparation. We survey current literature for studies measuring TB4 in human serum or plasma and compare reported concentrations in healthy controls. Expert opinion: We find substantial intra- and inter- study variability in healthy controls, and a lack of protocol standardization. We further highlight three factors that may confound TB4 clinical measurements and should be considered in future study design: 1) residual platelets remaining in suspension after centrifugation, 2) TB4 release following ex vivo platelet activation, and 3) specificity of assays towards posttranslational modifications. Accordingly, we put forth our recommendations to minimize residual and activated platelets during sample collection, and to cross validate TB4 measurements using both antibody-based and mass spectrometry-based methods. PMID- 29502472 TI - Rules of engagement in mobile health: what does mobile health bring to research and theory? AB - BACKGROUND: The effectiveness of mobile health (mHealth) is a controversial issue. For its wide-scale adoption and successful integration to the healthcare system, theoretical, methodological, and practical issues of mHealth should be well understood. OBJECTIVES: The purpose of the study was to review the essential characteristics of mHealth and discuss what mHealth presents to research and theory. METHOD: This review synthesized the studies focused on the adoption, design, and implementation of mHealth. The search strategy included reviewing electronic databases, key journals, web-based research and knowledge centers, and manual searching reference lists of the main studies. RESULTS: mHealth's core characteristics were specified as accessibility, inclusivity, patient's autonomy, customizability, increasing the accuracy of diagnostics and treatment, improvement in service quality, and testability. Opportunities and challenges in regards to theory and research were discussed. CONCLUSIONS AND IMPLICATIONS: Using an integrated approach, this study identified and summarized the key issues to understand mHealth. Implications and recommendations for research and practice were provided. PMID- 29502473 TI - Defining and treating moderate plaque psoriasis: a dermatologist survey. AB - PURPOSE: Patients with moderate plaque psoriasis are often undertreated and may experience unsatisfactory clinical outcomes. Undertreatment may stem partly from a lack of consensus on the definition of moderate psoriasis and appropriate treatments for patients with moderate disease severity. MATERIALS AND METHODS: An online survey was conducted during October 2015 to determine how US dermatologists in the clinical setting define and treat moderate psoriasis. RESULTS: A total of 150 dermatologists responded to the survey (mean time in practice: 13.5 years). On average, they saw 72 patients with psoriasis per month; 40% of these patients were considered to have moderate psoriasis. Most (95%) reported assessing disease severity based on the percentage of psoriasis-affected body surface area (BSA); 59% also considered location of the affected area. BSA cutoffs used to define moderate psoriasis varied widely (median low and high cutoffs: 5-10%; range: 1-70%). Similarly, wide variation in cutoff ranges was observed for the Psoriasis Area and Severity Index (PASI), Physician Global Assessment (PGA), and Dermatology Life Quality Index (DLQI). Primary therapy comprised biologics (47%), prescription topicals (28%), and oral systemics (18%). CONCLUSIONS: The current findings indicate lack of consensus surrounding the definition of moderate psoriasis among US dermatologists. PMID- 29502474 TI - Psychological factors and subjective cognitive complaints after stroke: Beyond depression and anxiety. AB - Subjective Cognitive Complaints (SCC) are common after stroke and adversely affect quality of life. In the present study, we determined the associations of depression, anxiety, perceived stress and fatigue with post-stroke SCC, and whether these associations were independent of objective cognitive functioning, stroke characteristics and individual differences in personality traits and coping styles. Using a cross-sectional design, SCC and psychological measures were obtained in 208 patients (mean 3.3 +/- 0.5 months after stroke; 65.9% men; mean age 64.9 +/- 12.4 years). SCC were assessed using the Checklist for Cognitive and Emotional consequences following stroke (CLCE) inventory. Validated questionnaires were used to measure depression and anxiety (Hospital Anxiety and Depression Scale), perceived stress (Perceived Stress Scale), fatigue (Fatigue Assessment Scale), personality traits (Eysenck Personality Questionnaire Revised Short Scale) and coping style (Utrecht Coping List). Multivariate hierarchical linear regression analyses were used to adjust for covariates. Depression (beta = 0.35), anxiety (beta = 0.38), perceived stress (beta = 0.39), and fatigue (beta = 0.39) were associated with CLCE scores, independent of demographic, cognitive performance and stroke-related covariates. After including personality traits and coping styles in the model, independent associations with CLCE scores were found for fatigue (beta = 0.26, p = .003) and neuroticism (beta = 0.21, p = .05). Interventions aimed at improving psychological resilience and increasing energy levels might be a worthwhile addition to stroke rehabilitation programmes by reducing SCC and improving quality of life. PMID- 29502475 TI - Differentiating Adults With Mixed Age Victims From Those Who Exclusively Sexually Assault Children or Adults. AB - Although adults who have sexually offended against both child and adult victims (i.e., adults with mixed aged sexual offense victims [MASOVs]) have been found at increased risk to reoffend, they have been a neglected and rarely studied group of individuals who have sexually offended. The present study explored their differentiating characteristics by comparing them with adults who had sexually offended exclusively against children (child sex offense victims [CSOVs]) or adults (adult sex offense victims [ASOVs]). Using an extensive database gathered on offenders examined for civil commitment, we found that although MASOVs were not distinguished from the other types of offenders by any specific developmental trauma, they cumulatively tended to be higher across traumas. They evidenced lower self-esteem relative to both other offender types. In addition, MASOVs, like ASOVs, exhibited higher levels of psychopathy relative to CSOVs. The implications of these findings for etiology and treatment are discussed. PMID- 29502476 TI - The Prevalence of Sexual Abuse in Institutions: Results From a Representative Population-Based Sample in Germany. AB - The lifetime prevalence of sexual abuse in institutional settings in Germany was examined in a sample representative of the general adult population ( N = 2,437). Participants completed a survey on whether they had ever experienced such abuse, its nature (contact, noncontact, forced sexual, intercourse), the type of institution (e.g. school, club), and the relationship of perpetrator to victim (peer, caregiver, staff member). Overall, 3.1% of adult respondents (women: 4.8%, men: 0.8%) reported having experienced some type of sexual abuse in institutions. Adult women reported higher rates of all types than did men, with rates of 3.9% versus 0.8% for contact sexual abuse, 1.2% versus 0.3% for noncontact sexual abuse, and 1.7% versus 0.2% for forced sexual intercourse. We conclude that a remarkable proportion of the general population experiences sexual abuse in institutions, underscoring the need for development of protective strategies. Especially, schools seem to represent good starting points for primary prevention strategies. PMID- 29502477 TI - Early intervention of N-acetylcysteine better improves insulin resistance in diet induced obesity mice. AB - Reactive oxygen species (ROS) plays a crucial role in pathogenesis of insulin resistance (IR) and type 2 diabetes. In the United Kingdom Prospective Diabetes Study and its 10-year post-trial monitoring, a beneficial effect of early optimization of blood glucose control is clearly demonstrated. In this study, we investigated whether ROS scavenger N-acetylcysteine (NAC) and the time point of intervention can affect IR in a diet-induced obesity mouse model. Male C57B/L6 mice were fed chow diet (CD), high-fat high-sucrose diet (HFD), CD+NAC1-6 (NAC intervention 1st-6th month), HFD+NAC1-6, and HFD+NAC3-6 (NAC intervention 3rd-6th month) for a 6-month treatment course. HFD group showed significantly increased body weight (BW) and body fat, decreased motor activity (MA), impaired intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance test (IPITT) throughout the study. HFD+NAC1-6, as compared with HFD group, had increased MA, improved IPGTT and IPITT since first month, followed by decreased BW and body fat. HFD+NAC3-6 group, although showed improved IPGTT and IPITT than HFD group, still had higher BW, decreased MA, and impaired IPGTT and IPITT as compared with HFD+NAC1-6 at the end of the study. NAC significantly increased MA, and ameliorated the HFD induced mitochondrial and intracellular ROS expression, DNA and protein oxidative damage, and adipose tissue inflammation. We concluded that ROS scavenger can improve IR and chronic inflammation in diet-induced obesity mice. This action is likely better expressed through early intervention. The mechanism is probably through a virtuous circle of suppressed oxidative stress, and increased motor activity, which helps to reduce body fat. PMID- 29502478 TI - [Multitasking: An Asset or a "Time Trap"? Overview of Media Multitasking in Children and Adolescents]. AB - : Multitasking: An Asset or a "Time Trap"? Overview of Media Multitasking in Children and Adolescents Abstract. OBJECTIVE: The development of modern digital media, especially smartphones, has contributed to a fundamental change in the leisure activities and communication practices of adolescents. Besides the technical possibilities, the amount of multitasking, i.e., the parallel use of several media alone or in combination with nonmedia activities, has gained in importance. This article addresses the bidirectional relationships between multitasking and cognitive processes, consequences for performance, and the potentially negative effects on psychosocial health. METHODS: This review article is based on a Medline research involving studies and reviews published on multitasking in digital media since 2000 concerning adolescents and adults. RESULTS: Multitasking is involved in specific neuropsychological processes of the frontal cortex and, in part, the corpus striatum. Up to an individually defined level and an objectively defined performance capacity, multitasking does not necessarily haven a negative impact on the quality of work. However, if excessive individual or objective stress occurs, especially in very young children, respective reactions and negative consequences for psychosocial health occur. CONCLUSION: According to present research results, multitasking should not be exercised in tasks requiring complex cognitive conditions. Many further studies will be required to assess the relationship between multitasking and specific psychiatric diseases, especially addictive disorders and ADHD, but also its useful implementation in educational settings has to be explored. PMID- 29502479 TI - Public Trust in Physicians-Health Care Commodification as a Possible Deteriorating Factor: Cross-sectional Analysis of 23 Countries. AB - Trust in physicians has declined, and surveys of public opinion show a poor level of public trust in physicians. Commodification of health care has been speculated as a plausible driving force. We used cross-national data of 23 countries from the International Social Survey Programme 2011 to quantify health care commodification and study its role in the trust that patients generally place in physicians. A modified health care index was used to quantify health care commodification. There were 34 968 respondents. A question about the level of general trust in physicians and a 4-item "general trust in physicians" scale were used as our major and minor outcomes. The results were that compared with those in the reference countries, the respondents in the health care-commodified countries were approximately half as likely to trust physicians (odds ratio: 0.47, 95% confidence interval [CI]: 0.31-0.72) and scored 1.13 (95% CI: 1.89 0.37) less on the general trust scale. However, trust in physicians in the health care-decommodified countries did not differ from that in the reference countries. In conclusion, health care commodification may play a meaningful role in the deterioration of public trust in physicians. PMID- 29502480 TI - Postsurgical Treatment of Split Skin Graft Donor Sites in Dermatological Departments. AB - The surgical removal of split skin grafts (SSGs) leads to superficial wounds that can be covered with different wound dressings. Currently, international guidelines that recommend a standard treatment of the donor sites are not yet established. We developed a questionnaire to evaluate the treatment of SSG donor sites and sent it to all dermatological departments in Germany. Altogether 78 of the 115 contacted departments in Germany participated in our cross-sectional trial. Our analysis reveals that multiple wound dressings with different frequencies of replacement are used. On an average, complete reepithelialization of the donor site takes 14-21 days. Foams and coated gauzes are used in 73% of all surgical procedures for postsurgical treatment of SSG donor sites. Still, neither a significant faster reepithelialization nor a lower rate of wound healing disorders can be assigned to any of the wound dressings. The results of our study indicate that a large number of wound care products and treatment strategies are currently applied on SSG donor sites in dermatological departments in Germany. The selection of the wound dressing is not based on scientific data but rather on the experience of individual experts. PMID- 29502481 TI - A Successful Pharmacist-Based Quality Initiative to Reduce Inappropriate Stress Ulcer Prophylaxis Use in an Academic Medical Intensive Care Unit. AB - Stress ulcer prophylaxis (SUP) is often inappropriately utilized, particularly in critically ill patients. The objective of this study is to find an effective way of reducing inappropriate SUP use in an academic medical intensive care unit (ICU). Medical ICU patients receiving SUP were identified over a 1-month period, and their charts were reviewed to determine whether American Society of Health System Pharmacists guidelines were followed. Inappropriate usage was calculated as inappropriate patient-days and converted to incidence per 100 patient-days. Two interventions were implemented: (1) Pharmacists reviewed indications for SUP on each patient during daily team rounds and daily medication reconciliation and (2) residents rotating on ICU services were educated on a bimonthly basis. Postintervention data were obtained in a similar fashion. Prior to intervention, the incidence of inappropriate SUP usage was calculated to be 26.75 per 100 patient-days (n = 1099 total patient-days). Total cost attributable to the inappropriate use was $2433. Post intervention, we were able to decrease the inappropriate incidence of SUP usage to 7.14 per 100 patient-days (n = 1149 total patient-days). In addition, total cost of inappropriate use was reduced to $239.80. Our study highlights an effective multidisciplinary approach to reduce the inappropriate use of SUP in an academic medical ICU. We were able to reduce the incidence of inappropriate use of SUP by 73.31% ( P < .001). Furthermore, we were able to decrease the costs by approximately $2200/month. PMID- 29502482 TI - Lycium barbarum polysaccharide protects against LPS-induced ARDS by inhibiting apoptosis, oxidative stress, and inflammation in pulmonary endothelial cells. AB - Acute respiratory distress syndrome (ARDS) is a heterogenous syndrome characterised by diffuse alveolar damage, with an increase in lung endothelial and epithelial permeability. Lycium barbarum polysaccharide (LBP), the most biologically active fraction of wolfberry, possesses antiapoptotic and antioxidative effects in distinct situations. In the present study, the protective effects and potential molecular mechanisms of LBP against lipopolysaccharide (LPS)-induced ARDS were investigated in the mice and in the human pulmonary microvascular endothelial cells (HPMECs). The data indicated that pretreatment with LBP significantly attenuated LPS-induced lung inflammation and pulmonary oedema in vivo. LBP significantly reversed LPS-induced decrease in cell viability, increase in apoptosis and oxidative stress via inhibiting caspase-3 activation and intracellular reactive oxygen species (ROS) production in vitro. Moreover, the scratch assay verified that LBP restored the dysfunction of endothelial cells (ECs) migration induced by LPS stimulation. Furthermore, LBP also significantly suppressed LPS-induced NF-kappaB activation, and subsequently reversed the release of cytochrome c. These results showed the antiapoptosis and antioxidant LBP could partially protect against LPS-induced ARDS through promoting the ECs survival and scavenging ROS via inhibition of NF-kappaB signalling pathway. Thus, LBP could be potentially used for ARDS against pulmonary inflammation and pulmonary oedema. PMID- 29502483 TI - Recurrent perseverations on semantic verbal fluency tasks as an early marker of cognitive impairment. AB - INTRODUCTION: Our objective was to examine the association between perseverations produced on the semantic verbal fluency (SVF) task in asymptomatic individuals and the future diagnosis of cognitive impairment (CI). METHOD: Participants were individuals participating in the Mayo Clinic Study of Aging (N = 1269, Mage = 79.3 years, SD = 5.1; 51% men). All were cognitively normal at baseline and were followed in 15-month intervals for up to 6 visits. Each neurocognitive assessment included SVF tasks ("animals," "fruits," and "vegetables"). Cox modeling was used to test for associations between perseverations and time to CI diagnosis. RESULTS: Perseverations on the "animals" SVF task were associated with incident CI (hazard ratio = 1.35; 95% confidence interval, CI [1.10, 1.66]). No significant association was found with perseverations on the "fruits" or "vegetables" SVF tasks. Mixed-effects modeling in cognitively normal participants revealed that the number of perseverations at baseline is significantly associated with decline in memory and visuospatial cognitive domains but is not associated with decline in attention. CONCLUSIONS: Assessing perseverations together with standard SVF scores on the "animals" SVF task can help in early identification of asymptomatic individuals at an increased risk for CI. Perseverations are not associated with attention, but rather visual and verbal working memory mechanisms. In longitudinal settings aimed at early detection of signs of CI in presymptomatic individuals, SVF testing with scoring that includes counting of perseverations may potentially serve as a practical alternative to the more cumbersome memory tests. PMID- 29502485 TI - The Etiology of Risk in Sexual Offenders: A Preliminary Model. AB - Sexual offender risk assessment practice is considered by many to be atheoretical. The identification of the most predictive risk factors and tools has typically overshadowed questions about etiology. To gain insight into the origins of criminal behavior among sexual offenders, we developed and validated an etiological model of risk based on the theoretical framework of Beech and Ward. Our model focused on persistence rather than onset, and encompassed both the sexual and nonsexual criminal activity of these offenders. It comprised two pathways. The first was characterized by sexual victimization, social isolation, and early deviant sexual fantasies. It led to a prolific involvement in sexual criminality (especially toward children) and predicted sexual recidivism. The second pathway was characterized by externalization problems, sexual promiscuity, and physical/psychological victimization, and was associated with nonsexual offending and serious sexual offenses directed (mostly) toward women. It predicted all types of recidivism. PMID- 29502486 TI - Images in Vascular Medicine. The case of the blue-gray fingernails. PMID- 29502484 TI - Developing and implementing national health identifiers in resource limited countries: why, what, who, when and how? AB - Many resource-limited countries are scaling up health services and health information systems (HISs). The HIV Cascade framework aims to link treatment services and programs to improve outcomes and impact. It has been adapted to HIV prevention services, other infectious and non-communicable diseases, and programs for specific populations. Where successful, it links the use of health services by individuals across different disease categories, time and space. This allows for the development of longitudinal health records for individuals and de identified individual level information is used to monitor and evaluate the use, cost, outcome and impact of health services. Contemporary digital technology enables countries to develop and implement integrated HIS to support person centred services, a major aim of the Sustainable Development Goals. The key to link the diverse sources of information together is a national health identifier (NHID). In a country with robust civil protections, this should be given at birth, be unique to the individual, linked to vital registration services and recorded every time that an individual uses health services anywhere in the country: it is more than just a number as it is part of a wider system. Many countries would benefit from practical guidance on developing and implementing NHIDs. Organizations such as ASTM and ISO, describe the technical requirements for the NHID system, but few countries have received little practical guidance. A WHO/UNAIDS stake-holders workshop was held in Geneva, Switzerland in July 2016, to provide a 'road map' for countries and included policy-makers, information and healthcare professionals, and members of civil society. As part of any NHID system, countries need to strengthen and secure the protection of personal health information. While often the technology is available, the solution is not just technical. It requires political will and collaboration among all stakeholders to be successful. PMID- 29502487 TI - Aspergillus section Flavi and aflatoxins in dried figs and nuts in Algeria. AB - The presence of Aspergillus section Flavi and aflatoxin (AF) contamination was investigated in 112 samples of peanuts, almonds and dried figs collected in Algeria. The occurrence of aflatoxin B1 (AFB1), B2 (AFB2), G1 (AFG1) and G2 (AFG2) in different commodities has been determined with a sensitive method based on high performance liquid chromatography (HPLC) coupled with fluorescence detection with post-column photochemical derivatisation. Analytical results indicated that 28 samples of peanuts, 16 samples of almonds and 26 samples of dried figs contained detectable levels of AFs. A total of 69 samples (61.6%) were contaminated with AFB1 ranging from the limit of quantification to 174 ug kg-1. AFB2 was found in 12 samples (10.7%) and varied from 0.18 to 193 ug kg-1. Seven samples revealed AF concentrations lower than the limit of quantification. Eleven peanut and fourteen dried fig samples exceeded the European maximum limits for AFB1. PMID- 29502488 TI - Identification of new benzamide inhibitor against alpha-subunit of tryptophan synthase from Mycobacterium tuberculosis through structure-based virtual screening, anti-tuberculosis activity and molecular dynamics simulations. AB - Multi-drug-resistant tuberculosis and extensively drug-resistant tuberculosis has emerged as global health threat, causing millions of deaths worldwide. Identification of new drug candidates for tuberculosis (TB) by targeting novel and less explored protein targets will be invaluable for antituberculosis drug discovery. We performed structure-based virtual screening of eMolecules database against a homology model of relatively unexplored protein target: the alpha subunit of tryptophan synthase (alpha-TRPS) from Mycobacterium tuberculosis essential for bacterial survival. Based on physiochemical properties analysis and molecular docking, the seven candidate compounds were selected and evaluated through whole cell-based activity against the H37Rv strain of M. tuberculosis. A new Benzamide inhibitor against alpha-subunit of tryptophan synthase (alpha-TRPS) from M. tuberculosis has been identified causing 100% growth inhibition at 25 MUg/ml and visible bactericidal activity at 6 MUg/ml. This benzamide inhibitor displayed a good predicted binding score (-48.24 kcal/mol) with the alpha-TRPS binding pocket and has logP value (2.95) comparable to Rifampicin. Further refinement of docking results and evaluation of inhibitor-protein complex stability were investigated through Molecular dynamic (MD) simulations studies. Following MD simulations, Root mean square deviation, Root mean square fluctuation and secondary structure analysis confirmed that protein did not unfold and ligand stayed inside the active pocket of protein during the explored time scale. This identified benzamide inhibitor against the alpha-subunit of TRPS from M. tuberculosis could be considered as candidate for drug discovery against TB and will be further evaluated for enzyme-based inhibition in future studies. PMID- 29502489 TI - Chitosan oligosaccharide promotes osteoclast formation by stimulating the activation of MAPK and AKT signaling pathways. AB - Chitosan Oligosaccharide (COS) has been widely used for the systemic treatment of clinical diseases such as bone tissue engineering. However, its influence on osteoclast formation, which plays a critical role in bone homeostasis, has never been investigated. The aim of this study was to investigate the effect of chitosan oligosaccharide on differentiation of osteoclast. Using cell counting kit-8, tartrate-resistant acid phosphatase staining, reverse transcription quantitative polymerase chain reaction assay and western blot analysis, we demonstrated that chitosan oligosaccharide cannot inhibit RANKL-induced osteoclast precursor proliferation but does promote osteoclast differentiation by stimulating the activation of p38/mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK)/MAPK, extracellular signal-regulated kinase (ERK)/MAPK and protein kinase B (AKT) without affecting nuclear factor kappaB (NF-kB) signaling pathways. Based on the promoting effect of chitosan oligosaccharide on osteoclast differentiation, we suggest that this property of chitosan oligosaccharide may have potential detrimental effect on bone homeostasis. PMID- 29502490 TI - Carnosine in health and disease. AB - Carnosine was originally discovered in skeletal muscle, where it exists in larger amounts than in other tissues. The majority of research into the physiological roles of carnosine have been conducted on skeletal muscle. Given this and the potential for muscle carnosine content to be increased with supplementation, there is now a large body of research examining the ergogenic effects (or otherwise) of carnosine. More recent research, however, points towards a potential for carnosine to exert a wider range of physiological effects in other tissues, including the brain, heart, pancreas, kidney and cancer cells. Taken together, this is suggestive of a potential for carnosine to have therapeutic benefits in health and disease, although this is by no means without complication. Herein, we will provide a review of the current literature relating to the potential therapeutic effects of carnosine in health and disease. PMID- 29502491 TI - Cause-specific mortality in the Kombewa health and demographic surveillance systems site, rural Western Kenya from 2011-2015. AB - BACKGROUND: The vast majority of deaths in the health and Kombewa demographic surveillance system (HDSS) study area are not registered and reported through official systems of vital registration. As a result, few data are available regarding causes of death in this population. OBJECTIVES: To describe causes of death among residents of all ages in the Kombewa HDSS, located in rural Western Kenya. METHODS: Verbal autopsy (VA) interviews at the site were conducted using the modified 2007 and later 2012 standardized WHO questionnaires. Assignment of causes of death was made using the InterVA-4 model version 4.02. Cox regression model, adjusted for sex, was built to evaluate the influence of age on mortality. RESULTS: There were a total of 5196 deaths recorded between 2011 and 2015 at the site. VA interviews were successfully completed for 3903 of these deaths (75.1%). Mortality rates were highest among neonates HR = 38.54 (<0.001) and among Infants HR = 2.07 (<0.006) in the Kombewa HDSS. Among those deaths in which VA was performed, the top causes of death were HIV/AIDS (12.6%), Malaria (10.3%), Pneumonia (10.1%), Acute abdomen (7.0%), Stroke (5.2%) and TB (4.9%) for the whole population in general. Stroke, acute abdomen heart diseases and Pneumonia were common causes of death (CODs) among the elderly over the age of 65. CONCLUSIONS: The analysis established the main CODs among people of all ages within the area served by the Kombewa HDSS. We hope that information generated from this study will help better address preventable deaths in the surveyed community as well as help mitigate negative health impacts in other rural communities throughout the Western Kenya region. PMID- 29502492 TI - Endovascular iliocaval reconstruction for the treatment of iliocaval thrombosis: From imaging to intervention. AB - Thrombosis of the inferior vena cava and iliac veins, known as iliocaval thrombosis, is a common cause of significant morbidity. Patients with chronic iliocaval obstruction often present with life-limiting occlusive symptoms secondary to recurrent lower extremity deep venous thrombosis, swelling, pain, venous stasis ulcers, or phlegmasia. Endovascular iliocaval reconstruction is a technically successful procedure that results in favorable clinical outcomes and stent patency rates with few complications and is often able to relieve debilitating symptoms in affected patients. This review presents an approach to endovascular iliocaval stent reconstruction in patients suffering from chronic iliocaval thrombosis, including background, patient selection, timing of intervention, procedural steps, technical considerations, patient follow-up, and a brief review of outcomes. Schematic illustrations and clinical cases outlining iliocaval stent reconstruction and crossing chronic venous occlusions have been provided. PMID- 29502493 TI - Carotid Consensus Panel duplex criteria can replace modified University of Washington criteria without affecting accuracy. AB - The decision to intervene for internal carotid stenosis often depends on the degree of stenosis seen on duplex ultrasound (US). The aim of this study is to compare the diagnostic accuracy of two criteria: modified University of Washington (UW) and 2003 Carotid Consensus Panel (CCP). All patients undergoing US in an accredited (IAC) vascular laboratory from January 2010 to June 2015 were reviewed ( n=18,772 US exams). Patients receiving a neck computed tomography angiography (CTA) within 6 months of the US were included in the study ( n=254). The degree of stenosis was determined by UW/CCP criteria and confirmed on CTA images using North American Symptomatic Carotid Endarterectomy Trial (NASCET)/European Carotid Surgery Trial (ECST) schema. Kappa analysis with 95% confidence intervals (CIs) were utilized to determine duplex-CTA agreement. A total of 417 carotid arteries from 221 patients were assessed in this study. The modified UW criteria accurately classified 266 (63.9%, kappa = 0.321, 95% CI 0.255 to 0.386) cases according to NASCET-derived measurements. The sensitivity, specificity, and accuracy at >= 60% stenosis were 65.7%, 81.3%, and 81.9%. The CCP criteria resulted in 296 (70.9%) accurate diagnoses (kappa = 0.359, 95% CI 0.280 to 0.437). At >= 70% stenosis, the sensitivity, specificity and accuracy were 38.8%, 91.6%, and 87.1% for NASCET. Comparison of the duplex results to ECST derived CTA measurements revealed a similar trend (UW 53.1%, kappa = 0.301 vs CCP 62.1%, kappa = 0.315). The CCP criteria demonstrate a higher concordance rate with measurements taken from CTAs. The CCP criteria may be more sensitive in classifying clinically significant degrees of stenosis without a loss in diagnostic accuracy. PMID- 29502494 TI - Electric vehicle recycling 2020: Key component power electronics. AB - Electromobility will play a key role in order to reach the specified ambitious greenhouse gas reduction targets in the German transport sector of 42% between 1990 and 2030. Subsequently, a significant rise in the sale of electric vehicles (EVs) is to be anticipated in future. The amount of EVs to be recycled will rise correspondingly after a delay. This includes the recyclable power electronics modules which are incorporated in every EV as an important component for energy management. Current recycling methods using car shredders and subsequent post shredder technologies show high recycling rates for the bulk metals but are still associated with high losses of precious and strategic metals such as gold, silver, platinum, palladium and tantalum. For this reason, the project 'Electric vehicle recycling 2020 - key component power electronics' developed an optimised recycling route for recycling power electronics modules from EVs which is also practicable in series production and can be implemented using standardised technology. This 'WEEE recycling route' involves the disassembly of the power electronics from the vehicle and a subsequent recycling in an electronic end-of life equipment recycling plant. The developed recycling process is economical under the current conditions and raw material prices, even though it involves considerably higher costs than recycling using the car shredder. The life cycle assessment shows basically good results, both for the traditional car shredder route and the developed WEEE recycling route: the latter provides additional benefits from some higher recovery rates and corresponding credits. PMID- 29502495 TI - Developing a national programme for textiles and clothing recovery. AB - Textiles waste is relatively small in terms of weight as compared to other waste streams, but it has a large impact on human health and environment, and its rate is increasing due to the 'fast fashion' model. In this paper, we examine the French national programme for managing post-consumer textiles and clothing through a case study research. To date, France is the only country in the world implementing an extended producer responsibility (EPR) policy for end-of-use clothing, linen and shoes. The case highlights the benefits of using an EPR policy and provides interesting insights about the challenges faced by the textiles waste sector. For instance, the EPR policy has contributed to a threefold increase in the collection and recycling rates of post-consumer textiles since 2006. In addition, the material recovery rate of the post-consumer textiles can reach 90%, 50% of which can be directly reused. However, the 'reuse' stream is facing some challenges because its main market is in Africa and many African countries are considering banning the import of used textiles to encourage a competitive textiles industry locally and internationally. The EPR policy shows a great potential to identify new markets for 'reuse' and to improve the textiles waste sector. Such an EPR policy also could drive societies to financially support innovation and research to provide feasible solutions for fashion producers to adopt eco-design and design for recycling practices. This paper provides guidance for policy makers, shareholders, researchers and practitioners interested in diverting post-consumer textiles and clothing waste from landfills and promoting circular textiles transition. PMID- 29502496 TI - Investigation of biomass production, crude protein and starch content in laboratory wastewater treatment systems planted with Lemna minor and Lemna gibba. AB - The use of duckweed-based wastewater treatment systems for producing biomass with high crude protein and starch content was investigated in the current study. For this reason, three lab-scale systems were used; System 1 was planted with Lemna minor, System 2 with Lemna gibba and System 3 with the combination of the two duckweeds. The studied duckweeds were cultivated using secondary treated wastewater as substrate (Phase A), in the presence of excess NH4-N (Phase B) and using water with no nutrients (Phase C). All systems achieved average NH4-N removal higher that 90%. The specific duckweeds growth rates and the specific duckweeds growth rates normalized to the area ranged between 0.14 d-1 and 8.9 g m 2 d-1 (System 1) to 0.19 d-1 and 14.9 g m-2 d-1(System 3). The addition of NH4-N resulted in a significant increase of biomass protein content, reaching 44.4% in System 3, 41.9% in System 2 and 39.4% in System 1. The transfer of biomass in water containing no nutrients resulted in the gradual increment of the starch content up to the end of the experiment. The highest starch content was achieved for the combination of the two duckweeds (46.1%), followed by L. gibba (44.9%) and L. minor (43.9%). PMID- 29502497 TI - A Descriptive Study of Musculoskeletal Injuries in Long-Haul Truck Drivers: A NIOSH National Survey. AB - Long-haul truck drivers are significantly affected by musculoskeletal injuries with incidence rates 3.5 times higher than the national average. Yet, little is known about injuries that affect long-haul trucks drivers. In 2010, interviewers collected data from 1,265 long-haul truck drivers at 32 truck stops across the United States. These surveys were analyzed to describe all self-reported musculoskeletal injuries. Injuries to the arm (26.3%) and back (21.1%) were the two areas most reported in the survey. Musculoskeletal injuries were most often caused by falls (38.9%) and contact with an object or equipment (33.7%) resulting most commonly in sprains/strains (60%). This large scale survey highlights the significance of musculoskeletal injuries in long-haul truck drivers and suggests the need to develop interventions to prevent injuries and improve recovery once injuries occur. PMID- 29502498 TI - Perfusion imaging and recurrent cerebrovascular events in intracranial atherosclerotic disease or carotid occlusion. AB - Background Large vessel disease stroke subtype carries the highest risk of early recurrent stroke. In this study we aim to look at the association between impaired perfusion and early stroke recurrence in patients with intracranial atherosclerotic disease or total cervical carotid occlusion. Methods This is a retrospective study from a comprehensive stroke center where we included consecutive patients 18 years or older with intracranial atherosclerotic disease or total cervical carotid occlusion admitted with a diagnosis of ischemic stroke within 24 h from symptom onset with National Institute Health Stroke Scale < 15, between 1 December 2016 and 30 June 2017. Patients with (1) evidence of >= 50% stenosis of a large intracranial artery or total carotid artery occlusion, (2) symptoms referable to the territory of the affected artery, and (3) perfusion imaging data using the RAPID processing software were included. The primary predictor was unfavorable perfusion imaging defined as Tmax > 6 s mismatch volume (penumbra volume-infarct volume) of 15 ml or more. The outcome was recurrent cerebrovascular events at 90 days defined as worsening or new neurological symptoms in the absence of a nonvascular cause attributable to the decline, or new infarct or infarct extension in the territory of the affected artery. We used Cox proportional hazards models to determine the association between impaired perfusion and recurrent cerebrovascular events. Results Sixty-two patients met our inclusion criteria; mean age 66.4 +/- 13.1 years, 64.5% male (40/62) and 50.0% (31/62) with intracranial atherosclerotic disease. When compared to patients with favorable perfusion pattern, patients with unfavorable perfusion pattern were more likely to have recurrent cerebrovascular events (55.6% (10/18) versus 9.1% (4/44), p < 0.001). This association persisted after adjusting for potential confounders (adjusted hazard ratio 10.44, 95% confidence interval 2.30 47.42, p = 0.002). Conclusion Perfusion mismatch predicts recurrent cerebrovascular events in patients with ischemic stroke due to intracranial atherosclerotic disease or total cervical carotid occlusion. Studies are needed to determine the utility of revascularization strategies in this patient population. PMID- 29502500 TI - Dynamic Risk Factors Characterizing Aggressive Sexual Initiation by Female College Students. AB - Past research has supported that community women engage in sexually coercive strategies as a means to initiate sexual intercourse with men. However, at the present state of the knowledge, there is a great lack of scientific information on the psychological characterization of these women. In accordance, the aim of the present study was to characterize the psychopathological and personality profile of a sample of college women reporting sexual initiation by coercive approaches, and to predict membership in the categories of sexually abusive strategies that were used by these women. Findings revealed that 32.7% of women reported to have used some kind of sexually coercive strategy in the past; these women were characterized by the endorsement of more psychopathology symptoms (e.g., depression, anxiety, somatization), and a maladaptive personality style (e.g., neuroticism, impulsiveness, negative trait-affect), in relation to the nonaggressive peers. Also, among the sexually aggressive group, extraversion predicted membership in the category of physical force (i.e., women using physical force to initiate sexual interaction). Findings add to the literature by showing that college women reporting sexually aggressive strategies as a means to initiate sexual intercourse with men present a set of psychopathological and personality features that are qualitatively similar to those features that were previously found to characterize samples of convicted sexual offenders. PMID- 29502501 TI - The Effect of Moral Disengagement on Bullying: Testing the Moderating Role of Personal and Social Factors. AB - Bullying is a subset of aggressive behavior that has severe consequences in children's psychosocial development. Bullying behaviors can be influenced by personal and social factors, such as gender, age, school type, and sport participation, as well as psychological constructs, such as moral disengagement. The present study was designed to investigate the effect of moral disengagement on bullying behaviors and the moderating role of personal and social factors. In this study, 2,252 students ( M = 13.57, SD = 1.17; 1,125 girls, and 1,127 boys) attending the sixth grade of primary school and secondary education have participated. Participants completed the revised Olweus Bully/Victim Questionnaire and Bandura's Moral Disengagement Questionnaire along with general questions about their demographic characteristics. The results of the analyses demonstrated moderation effects of gender on the moral disengagement-physical bullying relationship and of age on the moral disengagement-verbal bullying relationship. No significant moderating effect emerged for school type and sport participation. The findings of the present study provide valuable information about the role of personal and social factors on bullying behavior. PMID- 29502499 TI - Biophysics Model of Heavy-Ion Degradation of Neuron Morphology in Mouse Hippocampal Granular Cell Layer Neurons. AB - Exposure to heavy-ion radiation during cancer treatment or space travel may cause cognitive detriments that have been associated with changes in neuron morphology and plasticity. Observations in mice of reduced neuronal dendritic complexity have revealed a dependence on radiation quality and absorbed dose, suggesting that microscopic energy deposition plays an important role. In this work we used morphological data for mouse dentate granular cell layer (GCL) neurons and a stochastic model of particle track structure and microscopic energy deposition (ED) to develop a predictive model of high-charge and energy (HZE) particle induced morphological changes to the complex structures of dendritic arbors. We represented dendrites as cylindrical segments of varying diameter with unit aspect ratios, and developed a fast sampling method to consider the stochastic distribution of ED by delta rays (secondary electrons) around the path of heavy ions, to reduce computational times. We introduce probabilistic models with a small number of parameters to describe the induction of precursor lesions that precede dendritic snipping, denoted as snip sites. Predictions for oxygen (16O, 600 MeV/n) and titanium (48Ti, 600 MeV/n) particles with LET of 16.3 and 129 keV/MUm, respectively, are considered. Morphometric parameters to quantify changes in neuron morphology are described, including reduction in total dendritic length, number of branch points and branch numbers. Sholl analysis is applied for single neurons to elucidate dose-dependent reductions in dendritic complexity. We predict important differences in measurements from imaging of tissues from brain slices with single neuron cell observations due to the role of neuron death through both soma apoptosis and excessive dendritic length reduction. To further elucidate the role of track structure, random segment excision (snips) models are introduced and a sensitivity study of the effects of the modes of neuron death in predictions of morphometric parameters is described. An important conclusion of this study is that delta rays play a major role in neuron morphological changes due to the large spatial distribution of damage sites, which results in a reduced dependence on LET, including modest difference between 16O and 48Ti, compared to damages resulting from ED in localized damage sites. PMID- 29502502 TI - Intimate Partner Violence and Pet Abuse: Responding Law Enforcement Officers' Observations and Victim Reports From the Scene. AB - The risk of harm/injury in homes where intimate partner violence (IPV) occurs is not limited to humans; animals reside in as many as 80% of these homes and may be at substantial risk of suffering severe or fatal injury. Gaining a better understanding of IPV-pet abuse overlap is imperative in more accurately identifying the risks of harm for all individuals and animals residing in these homes. The objectives of this study were to utilize law enforcement officers' observations and IPV victim reports from the scene of the incident to (a) determine the prevalence of pet abuse perpetration among suspects involved in IPV incidents, (b) compare characteristics of IPV incidents and the home environments in which they occur when the suspect has a history of pet abuse with incidents involving suspects with no reported history of pet abuse, and (c) compare IPV incident outcomes involving suspects with a history of pet abuse with those involving suspects with no reported history of pet abuse. IPV victims residing in homes with a suspect who has a history of pet abuse often describe "extremely high-risk" environments. With nearly 80% reporting concern that they will eventually be killed by the suspect, victims in these environments should be considered at significant risk of suffering serious injury or death. In addition, IPV victims involved in incidents with a suspect that has a history of pet abuse were significantly more likely to have had at least one prior unreported IPV incident with the suspect (80%) and to have ever been strangled (76%) or forced to have sex with the suspect (26%). Effective prevention/detection/intervention strategies are likely to require multidisciplinary collaboration and safety plans that address the susbstantial risk of harm/injury for all adults, children, and animals residing in the home. PMID- 29502503 TI - Risk Factors for Forced, Incapacitated, and Coercive Sexual Victimization Among Sexual Minority and Heterosexual Male and Female College Students. AB - Although college students are at high risk for sexual victimization, the majority of research has focused on heterosexual students and often does not differentiate by victimization type. Thus, little is known about prevalence rates and risk factors for sexual victimization among sexual minority college students and whether the interaction between gender and sexual orientation differs by victimization type. To address these gaps, we examine whether risk factors for three types of sexual victimization (i.e., forced, incapacitated, and coerced) differ by gender ( n = 681 males; n = 732 females) and sexual orientation ( n = 1,294 heterosexual; n = 119 sexual minority) and whether the intersection of gender and sexual orientation is correlated with these three types of sexual victimization among 1,413 college students. Prevalence rate results revealed significant differences between gender and sexual orientation: Sexual minority females had the highest rates of coerced sexual victimization (58%), and their mean was significantly different from the other three groups (i.e., heterosexual females, heterosexual males, and sexual minority males). For both forced and incapacitated sexual victimization, heterosexual males had significantly lower means than the other three groups. Logistic regression results revealed that child sexual abuse increased the odds of experiencing both forced and coerced sexual victimization for both heterosexual and sexual minority students, whereas increased rates of risky sexual behavior were associated with forced and incapacitated sexual victimization but only for heterosexuals. Finally, heavy drinking increased the odds of experiencing incapacitated sexual victimization for both heterosexuals and sexual minorities. PMID- 29502504 TI - Structured Spatial Modeling and Mapping of Domestic Violence Against Women of Reproductive Age in Rwanda. AB - The main objective of this study was to assess the risk factors and spatial correlates of domestic violence against women of reproductive age in Rwanda. A structured spatial approach was used to account for the nonlinear nature of some covariates and the spatial variability on domestic violence. The nonlinear effect was modeled through second-order random walk, and the structured spatial effect was modeled through Gaussian Markov Random Fields specified as an intrinsic conditional autoregressive model. The data from the Rwanda Demographic and Health Survey 2014/2015 were used as an application. The findings of this study revealed that the risk factors of domestic violence against women are the wealth quintile of the household, the size of the household, the husband or partner's age, the husband or partner's level of education, ownership of the house, polygamy, the alcohol consumption status of the husband or partner, the woman's perception of wife-beating attitude, and the use of contraceptive methods. The study also highlighted the significant spatial variation of domestic violence against women at district level. PMID- 29502505 TI - "We Boil at Different Degrees": Factors Associated With Severity of Attack in Sexual Killing. AB - Degree of injury, as measured by the Homicide Injury Scale (HIS), was examined to advance understanding of the dynamics of sexual killing. A total of 350 nonserial, male sexual killers were included, and the different ways that the sexual element of their offenses and the act of killing were connected was accounted for by determining that cases were either directly sexual (the sexual element and killing were closely bound), or indirectly sexual (killing was not a source of sexual stimulation). The two groups, direct and indirect sexual killers, were each subjected to multiple linear regression analyses to examine the group-specific relationship between level of injury and predictor variables previously found to be associated with increased severity of attack. No differences in the mean total HIS scores between the indirect and the direct cases were found, suggesting a comparable emotional intensity between the groups. However, given that the groups differed in terms of the functional role of fatal violence, severity of attack could not be sufficiently explained as driven by anger. In line with this hypothesis, different predictors appeared to be associated with increased degree of injury sustained by victims of indirect compared with direct sexual killers. As such, situational components appear to play a role in the behavior of indirect sexual killers, whereas the behavior of direct perpetrators tends to be linked with the enactment of existing deviant fantasies. The role of anger in sexual homicide is discussed further, and overall, it is argued that irrespective of whether violence was initially driven by anger, evidence of sexual arousal to severe violence must be scrutinized within sexual homicide research as well as in psycholegal contexts. PMID- 29502506 TI - Association Among Television and Computer/Video Game Use, Victimization, and Suicide Risk Among U.S. High School Students. AB - With the increasing popularity of mobile Internet devices, the exposure of adolescents to media has significantly increased. There is limited information about associations between the types and frequency of media use and experiences of violence victimization and suicide risk. The current study sought to examine the association of bullying and teen dating violence (TDV) victimization, suicide risk with different types of media use (i.e., television and computer/video game use), and number of total media use hours per school day. Data from the nationally representative 2015 Youth Risk Behavior Survey ( n = 15,624) were used to examine the association between media use and violence victimization and suicide risk. Logistic regression models generated prevalence ratios adjusted for demographic characteristics and substance use behaviors to identify significant associations between media use and victimization and suicide risk, stratified by gender. Media use was associated with TDV victimization for male students only, while media use was related to experiences of bullying and suicide risk for both male and female students. In addition, limited (2 or fewer hours) and excessive (5 or more hours) media use emerged as significant correlates of suicide risk and bullying victimization, with limited media use associated with decreased risk and excessive media use with increased risk. Comprehensive, cross-cutting efforts to prevent different forms of victimization should take into account media use and its potential association with adolescent victimization and suicide risk. The current study results suggest limiting adolescent media use, as part of comprehensive prevention programming, might relate to reductions in risk for victimization and suicide. PMID- 29502507 TI - Abusive Relationship and Its Associated Factors Between Deployed and Un-Deployed Veterans in College. AB - This study is to examine the effect of student veteran status on abusive relationships, namely, emotional, physical, and sexual abuse. In addition, this study divided student veterans into two groups, deployed and un-deployed veterans, to see whether two groups demonstrate different results on abusive relationships. Logistic regression models were employed as a statistical strategy using the 2011-2014 American College Health Association National College Health Assessment II (ACHA-NCHA-II) data. The results found that deployed veterans were more likely to experience physical abuse, while un-deployed veterans were more likely to experience emotional abuse. Student veterans did not show any significant relationship with sexual abuse regardless deployment experience. It would be appropriate to consider the results of this study to address abusive relationships among student veterans, which help them to not only adjust college life but also succeed in careers and have healthy family relationships. PMID- 29502508 TI - Sexual Assault Disclosure: The Effect of Victim Race and Perpetrator Type on Empathy, Culpability, and Service Referral for Survivors in a Hypothetical Scenario. AB - The aftermath of sexual assault warrants further attention surrounding the responses provided by those to whom survivors disclose, especially when perpetrator type or victim race may affect whether the bystander response is supportive or attributes culpability to the victim. Disclosure responses have significant consequences for survivors' posttrauma mental health and formal help seeking behavior. The current study used a sample of 348 self-report, paper-and pencil surveys administered during the fall 2015 semester to a purposive sample of undergraduate students with a mean age of 20.94 years old at a midsized, Southern public university. Survey design included a randomly assigned 2 * 2 hypothetical sexual assault disclosure vignette. The objective of the study was to assess the effect of perpetrator type (stranger vs. acquaintance) and victim race (White vs. Black) on empathic concern, culpability attributions, and resource referral. Between-subjects factorial ANOVA and multivariate ordinary least squares (OLS) regression models were estimated to identify the role of vignette manipulations, participant-sexual victimization history, and rape myth acceptance on empathy, culpability, and resource referral for the sexual assault survivor portrayed in the vignette. Multivariate analyses included main effects and moderation models. Findings revealed increased culpability and decreased resource referral for victims of acquaintance rape as compared with stranger rape, independent of victim race. Although no direct victim race effects emerged in the multivariate analyses, race moderated the effect of culpability on resource referral indicating culpability attributions decreased resource referral, but only when the victim was Black . Implications from the results presented here include a continued focus on bystander intervention strategies, empathy-building techniques, and educational programming targeting potential sexual assault disclosees and race stereotypes that disadvantage victims of color. PMID- 29502509 TI - Psychometric Properties of the Dating Violence Questionnaire: Reviewing the Evidence in Chilean Youths. AB - The Dating Violence Questionnaire (DVQ) is a 42-item questionnaire that measures victimization in romantic relationships between young people, through eight interrelated scales assessing detachment, humiliation, coercion, emotional punishment, gender-based, sexual, physical, and instrumental violence. It has been validated in a myriad of countries and languages and is commonly used in Spanish-speaking countries; however, two scales (emotional punishment and instrumental violence) have shown reliability issues. The aim of present study is to analyze the psychometric proprieties of the adapted version of the DVQ for the Chilean population, reviewing evidence of structure validity, external validity, and reliability-using polychoric and ordinal analysis-and including new items to improve instrumental and emotional punishment scales (DVQ+). Eight hundred forty six high school and university students (14-24 years old) participated in the study. Results showed that both DVQ and DVQ+ versions had an adequate fit with the original correlated eight-factor model (root mean square error of approximation [RMSEA] = .023; comparative fit index [CFI] = .97, in both cases), as well as with a more parsimonious second-order factor model (RMSEA = .024-.025; CFI = .97-.97, respectively). Reliability analysis also showed both version presented satisfactory values for internal consistency. Finally, scores of DVQ were correlated-as expected-negatively with quality of the relationship and positively with fear, perceived abuse, and attachment-related anxiety, thus providing new evidences of validity. PMID- 29502510 TI - A Dyadic Analysis of PTSD and Psychological Partner Aggression Among U.S. Iraq and Afghanistan Veterans: The Impact of Gender and Dual-Veteran Couple Status. AB - Posttraumatic stress disorder (PTSD) symptoms have been repeatedly linked to intimate partner aggression (IPA), and previous research has suggested that this association may be stronger among veterans and men. However, few studies have examined veteran status and gender as moderators of the association between PTSD and psychological IPA, taking both partners' perspectives into account (i.e., within a dyadic framework). The current study aimed to address this limitation by using dyadic multilevel modeling to examine the association between PTSD symptoms and psychological IPA perpetration among a sample of 159 Operation Iraqi Freedom and Operation Enduring Freedom veterans and their partners ( N = 318 participants). Findings revealed that both one's own and one's partner's PTSD symptoms were positively associated with greater psychological IPA. In addition, the effects of partner PTSD symptoms on psychological IPA perpetration differed across gender and veteran status. Results suggested that the association of partner PTSD and IPA perpetration may be stronger for male veterans than for female veterans. Findings from the current study are consistent with previous research showing associations between PTSD and IPA, and have clinical implications for treatment of PTSD and IPA among Operation Iraqi Freedom and Operation Enduring Freedom veterans. PMID- 29502511 TI - Stranger Harassment ("Piropo") and Women's Self-Objectification: The Role of Anger, Happiness, and Empowerment. AB - According to objectification theory, women's habitual exposure to sexually objectifying situations can lead them to internalize a third-person perspective of themselves in physical terms, leading women to adopt an observer's viewpoint of themselves as a body or collection of body parts that is valued principally for use or consumption by others (i.e., self-objectification). The frequency and/or intensity of situations of female objectification have generally been studied as precedents of self-objectification. Our research analyzes whether direct exposure to a particular objectifying situation, as in the case of verbal stranger harassment (called piropos in Spain), could have these same effects. We tested the consequences of exposure to piropos (vs. a control situation) on body surveillance and body shame in a sample of 329 Spanish women. The impact of verbal harassment on women's anger, anxiety, happiness, and sense of empowerment was also analyzed. The results of a moderated mediation analysis showed that exposure to piropos increased body shame through body surveillance but only in women who reacted to the piropo with happiness, empowerment, or low levels of anger. The negative effects that objectifying situations (e.g., stranger harassment) may have on women, and the importance of women's reactions and perceptions of such situations are discussed. PMID- 29502512 TI - Molecular epidemiology of Giardia duodenalis infection in humans in Southern Ethiopia: a triosephosphate isomerase gene-targeted analysis. AB - BACKGROUND: Giardia duodenalis is a species complex consisting of multiple genetically distinct assemblages. The species imposes a major public health crisis on developing countries. However, the molecular diversity, transmission dynamics and risk factors of the species in these countries are indeterminate. This study was conducted to determine the molecular epidemiology of G. duodenalis infection in asymptomatic individuals in Southern Ethiopia. METHODS: From March to June 2014, fresh stool samples were collected from 590 randomly selected individuals. Socio-demographic data were gathered using a pre-tested structured questionnaire. The genotyping was done using triosephosphate isomerase gene-based nested polymerase chain reaction and DNA sequencing. The genetic identity and relatedness of isolates were determined using the basic local alignment search tool and phylogenetic analysis. Risk factors associated with G. duodenalis infection were analysed using binary and multinomial logistic regression models. RESULTS: The results showed that 18.1% (92/509) of the study subjects were infected by G. duodenalis. Among the isolates, 35.9% (33/92) and 21.7% (20/92) were sub-typed into assemblages A and B, respectively, whereas 42.4% (39/92) showed mixed infections of A and B. Most of the assemblage A isolates (94%,31/33) were 100% identical to sequences registered in GenBank, of which the majority belonged to sub-assemblage AII. However, the high genetic variability and frequency of double peaks made sub-genotyping of assemblage B more problematic and only 20% (4/20) of the isolates matched 100% with the sequences. The risk factors of age (P = 0.032) and type of drinking water source (P = 0.003) both showed a significant association with the occurrence G. duodenalis infection. CONCLUSIONS: This study established the endemicity of G. duodenalis in Southern Ethiopia. Infection with assemblage A was more frequent than with assemblage B, and the rate of infection was higher in children and in municipal/tap and open spring water consumers than the other groups. Sub-typing of assemblage B and determining the origin of double peaks were challenging. The present study confirms the need for further inclusive studies to be conducted focusing on sub types of assemblage B and the origin of heterogeneity. PMID- 29502513 TI - PM2.5 obtained from urban areas in Beijing induces apoptosis by activating nuclear factor-kappa B. AB - BACKGROUND: Particulate matter (PM), which has adverse effects on citizen health, is a major air pollutant in Beijing city. PM2.5 is an indicator of PM in urban areas and can cause serious damage to human health. Many epidemiological studies have shown that nuclear factor-kappa B (NF-kappaB) is involved in PM2.5-induced cell injury, but the exact mechanisms are not well understood. METHODS: The cytotoxic effects of PM2.5 at 25-1600 MUg/ml for 24 h were determined by MTT assay in Chinese hamster ovary cells (CHO) cells. Flow cytometry was used to determine the apoptosis rate induced by PM2.5. The destabilized enhanced green fluorescent protein (d2EGFP) green fluorescent protein reporter system was used to determine the NF-kappaB activity induced by PM2.5. The expression of pro apoptotic Bcl-2-associated death promoter (BAD) proteins induced by PM2.5 was determined by western blotting to explore the relationship between PM2.5 and the NF-kappaB signaling pathway and to determine the toxicological mechanisms of PM2.5. RESULTS: PM2.5 collected in Beijing urban districts induces cytotoxic effects in CHO cells according to MTT assay with 72.28% cell viability rates even at 200 MUg/ml PM2.5 and flow cytometry assays with 26.97% apoptosis rates at 200 MUg/ml PM2.5. PM2.5 increases the activation levels of NF-kappaB, which have maintained for 24 h. 200 MUg/ml PM2.5 cause activation of NF-kappaB after exposure for 4 h, the activation peak appears after 13.5 h with a peak value of 25.41%. The average percentage of NF-kappaB activation in whole 24 h is up to 12.9% by 200 MUg/ml PM2.5. In addition, PM2.5 decreases the expression level of the pro-apoptotic protein BAD in a concentration-dependent manner. CONCLUSIONS: PM2.5 induces NF-kappaB activation, which persists for 24 h. The expression of pro-apoptotic protein BAD decreased with increased concentrations of PM2.5. These findings suggest that PM2.5 plays a major role in apoptosis by activating the NF kappaB signaling pathway and reducing BAD protein expression. PMID- 29502515 TI - Radiation-induced chondrosarcoma of the scapula after radiotherapy for lung cancer: a case report and review of the literature. AB - BACKGROUND: Radiotherapy associated with chemotherapy is a well-established treatment modality for locally advanced non-small cell lung cancers. Radiation induced second malignancies, particularly radiation-induced sarcomas, are rare. Some authors reported a recent increase in the incidence of this rare complication, especially because of the improved prognosis and survival of patients after radiotherapy. Pathogenic mechanisms of radiation-induced sarcomas are poorly understood. However, diagnosis criteria are well established. Treatment options must be discussed and adapted to the patient's profile. Surgery in irradiated tissue is challenging, with limited treatment options with chemotherapy and radiotherapy. CASE PRESENTATION: We report the case of a 62-year old Moroccan man diagnosed as having chondrosarcoma of his right scapula, who was irradiated 10 years ago for stage IIIB non-small cell lung cancer. This case was managed by a complete resection of the tumor with good functional and oncological outcomes. To the best of our knowledge, the scapular location of radiation induced sarcoma after irradiation for lung cancer has never been described in the literature. CONCLUSION: Radiation-induced sarcoma of the scapula represents a rare situation that must be actively researched to have access to an optimal therapeutic approach. PMID- 29502514 TI - Recent advances in the effects of microwave radiation on brains. AB - This study concerns the effects of microwave on health because they pervade diverse fields of our lives. The brain has been recognized as one of the organs that is most vulnerable to microwave radiation. Therefore, in this article, we reviewed recent studies that have explored the effects of microwave radiation on the brain, especially the hippocampus, including analyses of epidemiology, morphology, electroencephalograms, learning and memory abilities and the mechanisms underlying brain dysfunction. However, the problem with these studies is that different parameters, such as the frequency, modulation, and power density of the radiation and the irradiation time, were used to evaluate microwave radiation between studies. As a result, the existing data exhibit poor reproducibility and comparability. To determine the specific dose-effect relationship between microwave radiation and its biological effects, more intensive studies must be performed. PMID- 29502516 TI - What priorities should be considered for Iranian veterans with ankle-foot injuries? A health needs assessment study, 25 years post-conflict. AB - Despite the passage of time, a large number of veterans are still affected by injuries acquired during Iran-Iraq war. In addition to their primary injuries, the majority of veterans also experience difficulty with long-term, secondary effects. Studies have shown that the most common of these include a range of disabilities, pain, and dramatic decline in mental health and quality of life. Improving living conditions and providing rehabilitation services to veterans has always been a main priority of authorities. The goal of this study was to explain the methods and materials with which these priorities were explored. PMID- 29502517 TI - Strategy and technology to prevent hospital-acquired infections: Lessons from SARS, Ebola, and MERS in Asia and West Africa. AB - Hospital-acquired infections (HAIs) are serious problems for healthcare systems, especially in developing countries where public health infrastructure and technology for infection preventions remain undeveloped. Here, we characterized how strategy and technology could be mobilized to improve the effectiveness of infection prevention and control in hospitals during the outbreaks of Ebola, Middle East respiratory syndrome (MERS), and severe acute respiratory syndrome (SARS) in Asia and West Africa. Published literature on the hospital-borne outbreaks of SARS, Ebola, and MERS in Asia and West Africa was comprehensively reviewed. The results showed that healthcare systems and hospital management in affected healthcare facilities had poor strategies and inadequate technologies and human resources for the prevention and control of HAIs, which led to increased morbidity, mortality, and unnecessary costs. We recommend that governments worldwide enforce disaster risk management, even when no outbreaks are imminent. Quarantine and ventilation functions should be taken into consideration in architectural design of hospitals and healthcare facilities. We also recommend that health authorities invest in training healthcare workers for disease outbreak response, as their preparedness is essential to reducing disaster risk. PMID- 29502518 TI - Establishment and evaluation of a theater influenza monitoring platform. AB - BACKGROUND: Influenza is an acute respiratory infectious disease with a high incidence rate in the Chinese army, which directly disturbs military training and affects soldiers' health. Influenza surveillance systems are widely used around the world and play an important role in influenza epidemic prevention and control. METHODS: As a theater centers for disease prevention and control, we established an influenza monitoring platform (IMP) in 2014 to strengthen the monitoring of influenza-like illness and influenza virus infection. In this study, we introduced the constitution, influenza virus detection, and quality control for an IMP. The monitoring effect was also evaluated by comparing the monitoring data with data from national influenza surveillance systems. The experiences and problems associated with the platform also were summarized. RESULTS: A theater IMP was established based on 3 levels of medical units, including monitoring sites, testing laboratories and a checking laboratory. A series of measures were taken to guarantee the quality of monitoring, such as technical training, a unified process, sufficient supervision and timely communication. The platform has run smoothly for 3 monitoring years to date. In the 2014-2015 and 2016-2017 monitoring years, sample amount coincided with that obtained from the National Influenza Surveillance program. In the 2015-2016 monitoring year, due to the strict prevention and control measures, an influenza epidemic peak was avoided in monitoring units, and the monitoring data did not coincide with that of the National Influenza Surveillance program. Several problems, including insufficient attention, unreasonable administrative intervention or subordination relationships, and the necessity of detection in monitoring sites were still observed. CONCLUSIONS: A theater IMP was established rationally and played a deserved role in the prevention and control of influenza. However, several problems remain to be solved. PMID- 29502519 TI - Identifying prognostic factors for conservative treatment outcomes in servicemen with chronic exertional compartment syndrome treated at a rehabilitation center. AB - BACKGROUND: Chronic exertional compartment syndrome (CECS) is a condition of pain induced by exercise, and it is characterized by muscle swelling and impaired muscle function in the lower leg. Given the diversity in the diagnosis and treatment of CECS, it is desirable to determine variables pertaining to prognosis and recovery. The purpose of this study is to identify prognostic factors for conservative treatment outcomes in servicemen with CECS who were treated at a Military Rehabilitation Center. METHODS: Patients from all military services were referred from the special unit for lower leg pain at the Central Military Hospital, Utrecht, the Netherlands. Descriptive analysis was used to report the characteristics of the participants and their baseline measurements. Group differences were analyzed using a Student's t-test or Mann-Whitney U test, according to the normality of the data distribution. Differences between the pre- and post-intervention outcomes were evaluated using the Wilcoxon signed rank test. To evaluate the magnitude of prognostic factors, a univariate logistic regression analysis was performed. The prognostic factors included age, body mass index, body fat percentage, self-efficacy beliefs, foot malalignment, intramuscular pressure, other comorbidities, protein and creatine use, smoking, alcohol use, complaint duration, physical demands, and duration of military service. RESULTS: After the rehabilitation period, we observed 25 patients with a successful outcome, which was defined as a reduction in pain (>= 2 points) during the capacity test measured using a verbal rating scale and 20 patients with an unsuccessful outcome. Factors demonstrating a limited increased odds ratio for an unsuccessful outcome included smoking, alcohol use, intramuscular pressure, a complaint duration of more than 6 months, and physical demands of service. However, these factors did not reach significance. CONCLUSION: This study did not identify any prognostic factors that predict the outcome of a rehabilitation program for CECS. A larger sample using an identical design might provide further evidence regarding prognostic factors, which would facilitate development of a model that predicts the outcomes of a rehabilitation program for CECS. PMID- 29502520 TI - Mental health among Iranian combat veterans with ankle-foot neuromusculoskeletal injuries. AB - BACKGROUND: Veterans with purely physical disorders, such as ankle-foot neuromusculoskeletal disorders, are often neglected in psychological assessments because mental health evaluations are usually focused on those with a psychological disturbance or with a high percentage of injury. The purpose of this study was to evaluate the psychological condition of veterans with ankle foot neuromusculoskeletal disorders. METHODS: A cross-sectional study was performed between 2014 and 2016 on veterans with war-related ankle-foot injuries living in two provinces of Iran. An information form for demographic data and injury-related factors was used. Additionally, the previously validated Persian version of the Symptom Checklist-90-Revision (SCL-90-R) questionnaire was used for data collection. RESULTS: The respondents were 215 male veterans with a mean age of 51.7 +/- 7.5 years. The most common mental health problems were observed for the somatization (24.7%), obsessions-compulsions (14.4%), and anxiety (12.6%). Based on the Global Severity Index (GSI), 48.6% of individuals had a possible psychiatric/psychological illness. According to the multivariate regression analysis, GSI scores were significantly higher among veterans who were older than 27 years at the time of injury (P = 0.005), had an associated injury (P = 0.002), and had a history of hospitalization within the past 12 months for reasons other than their injury (P = 0.035). CONCLUSIONS: Approximately half of the combat veterans with ankle-foot neuromusculoskeletal disorders likely had psychological problems. The evaluation of the patterns and predicting factors of psychological conditions may inform strategic planning efforts and decision making, which, in turn, may provide a better quality of life for veterans. Further studies that utilize longitudinal designs are needed to evaluate and compare the psychological status of different groups of veterans and other groups in the general population. PMID- 29502521 TI - Beneficial effects of a novel shark-skin collagen dressing for the promotion of seawater immersion wound healing. AB - BACKGROUND: Wounded personnel who work at sea often encounter a plethora of difficulties. The most important of these difficulties is seawater immersion. Common medical dressings have little effect when the affected area is immersed in seawater, and only rarely dressings have been reported for the treatment of seawater-immersed wounds. The objective of this study is to develop a new dressing which should be suitable to prevent the wound from seawater immersion and to promote the wound healing. METHODS: Shark skin collagen (SSC) was purified via ethanol de-sugaring and de-pigmentation and adjusted for pH. A shark skin collagen sponge (SSCS) was prepared by freeze-drying. SSCS was attached to an anti-seawater immersion polyurethane (PU) film (SSCS + PU) to compose a new dressing. The biochemical properties of SSC and physicochemical properties of SSCS were assessed by standard methods. The effects of SSCS and SSCS + PU on the healing of seawater-immersed wounds were studied using a seawater immersion rat model. For the detection of SSCS effects on seawater-immersed wounds, 12 SD rats, with four wounds created in each rat, were divided into four groups: the 3rd day group, 5th day group, 7th day group and 12th day group. In each group, six wounds were treated with SSCS, three wounds treated with chitosan served as the positive control, and three wounds treated with gauze served as the negative control. For the detection of the SSCS + PU effects on seawater-immersed wounds, 36 SD rats were divided into three groups: the gauze (GZ) + PU group, chitosan (CS) + PU group and SSCS + PU group, with 12 rats in each group, and two wounds in each rat. The wound sizes were measured to calculate the healing rate, and histomorphology and the immunohistochemistry of the CD31 and TGF-beta expression levels in the wounded tissues were measured by standard methods. RESULTS: The results of Ultraviolet-visible (UV-vis) spectrum, Fourier-transform infrared (FTIR) spectrum, circular dichroism (CD) spectra, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and amino acid composition analyses of SSC demonstrated that SSC is type I collagen. SSCS had a homogeneous porous structure of approximately 200 MUm, porosity rate of 83.57% +/- 2.64%, water vapor transmission ratio (WVTR) of 4500 g/m2, tensile strength of 1.79 +/- 0.41 N/mm, and elongation at break of 4.52% +/- 0.01%. SSCS had significant beneficial effects on seawater-immersed wound healing. On the 3rd day, the healing rates in the GZ negative control, CS positive control and SSCS rats were 13.94% +/- 5.50%, 29.40% +/- 1.10% and 47.24% +/- 8.40%, respectively. SSCS also enhanced TGF-beta and CD31 expression in the initial stage of the healing period. The SSCS + PU dressing effectively protected wounds from seawater immersion for at least 4 h, and accelerated re-epithelialization, vascularization and granulation formation of seawater-immersed wounds in the earlier stages of wound healing, and as well as significantly promoted wound healing. The SSCS + PU dressing also enhanced expression of TGF-beta and CD31. The effects of SSCS and SSCS + PU were superior to those of both the chitosan and gauze dressings. CONCLUSIONS: SSCS has significant positive effects on the promotion of seawater immersed wound healing, and a SSCS + PU dressing effectively prevents seawater immersion, and significantly promotes seawater-immersed wound healing. PMID- 29502522 TI - Management of dog bites by frontline service providers in primary healthcare facilities in the Greater Accra Region of Ghana, 2014-2015. AB - BACKGROUND: Dog bites are common in developing countries including Ghana, with the victims often being children. Although some breeds of dogs have been identified as being more aggressive than others, all dog bites carry a risk of infection. Immediate and initial assessment of the risk for tetanus and rabies infection with appropriate interventions such as wound management and subsequent selection of prophylactic antibiotics are essential in the management of dog bites. This study examined the management of patients with dog bites by frontline service providers at primary healthcare facilities in the Greater Accra Region, Ghana. METHODS: We conducted a cross-sectional study in 66 public health facilities in the Greater Accra Region from July 2014 to April 2015. Up to four frontline service providers were randomly selected to participate from each facility. A structured questionnaire was administered to all consenting participants. Continuous variables were presented as means and standard deviations. The frontline service providers' knowledge was assessed as a discrete variable and values obtained presented as percentages and proportions. The chi square test of proportions was used to determine any significant associations between the various categories of the frontline service providers and their knowledge about the management of rabies. RESULTS: Regarding the frontline service providers' knowledge about rabies, 57.8% (134/232) were correct in that the rabies virus is the causative agent of rabies, 39.2% (91/232) attributed it to a dog bite, 2.6% (6/232) did not know the cause, and one person (0.4%) attributed it to the herpes virus. Only 15.5% (36/232) knew the incubation period in dogs and the period required to observe for signs of a rabies infection. With respect to the administration of rabies immunoglobulin, 42.2% (98/232) of the frontline service providers did not know how to administer it. Of the facilities visited, 76% (50/66) did not have the rabies vaccines and 44% (102/232) of frontline service providers did not know where to get the rabies vaccines from. Most of the service providers (87.9%; 204/232) had never reported either a dog bite or a suspected case of rabies. Overall, there was gross underreporting of dog bites and suspected rabies cases at public healthcare facilities in the Greater Accra Region of Ghana. CONCLUSIONS: In view of the high morbidity and mortality associated with bites from rabid dogs and the poor knowledge and practices of frontline service providers, there is an urgent need for capacity building such as training in the management of dog bites and subsequent potential rabies infection. PMID- 29502523 TI - Self-reported dietary supplement use in deployed United States service members pre-deployment vs. during deployment, Afghanistan, 2013-2014. AB - BACKGROUND: Dietary supplement use (protein/amino acids, weight-loss supplements, performance enhancers) is common among U.S. military members. Reported dietary supplement use in deployed troops is limited and is of concern in settings where troops are exposed to high ambient temperatures, increased physical demands, and dehydration. Our objective was to describe dietary supplement use and adverse events (AEs) among deployed U.S. service members compared with their pre deployment use. METHODS: We conducted an institutional review board (IRB) approved, descriptive study in Afghanistan using a written questionnaire and collected demographic information, dietary supplement use before and during deployment, AEs associated with supplement use, and physical workout routines. Participants were U.S. military personnel of all branches of service deployed to Afghanistan. They were recruited in high-traffic areas in the combat theater. We analyzed the data with descriptive statistics. Paired t-test/Wilcoxon signed-rank test was conducted to examine the before/during deployment changes for continuous data, and McNemar's chi-square test was conducted for categorical data. We constructed separate logistic regression models to determine the best predictors of increases or decreases in dietary supplement use, with demographic information, reasons for using supplements, and education requested/received as covariates in each model. All statistical tests were two-sided at a significance level of 5% (P < 0.05). RESULTS: Data were collected on 1685 participants. Ninety seven of the participants were in the Army or Air Force. The participants were more likely to work out daily or more than once a day during deployment. Thirty five percent of the participants reported no supplement use before or during deployment. The remaining 65% of participants reported increased use and increased frequency of use of supplements (e.g., daily) during deployment compared with pre-deployment. Additionally, more people followed label instructions strictly during deployment vs. pre-deployment. Overall, the frequency of self-reported AEs among supplement users remained consistent before and during deployment. The only significant difference noted was in problems falling or staying asleep, which increased during deployment. In the adjusted logistic regression models, the level of formal education, military branch, occupational specialty, education about dietary supplements, and certain reasons for using supplements (to boost energy, lose weight, gain muscle strength and mass, and as a meal replacement) were significant predictors of changes in supplement use. CONCLUSION: Deployed U.S. service members were more likely to use dietary supplements, use more than one supplement and use supplements more frequently during deployment than pre-deployment. No serious AEs were reported, but problems falling or staying asleep increased during deployment. PMID- 29502524 TI - Silodosin 8 mg improves benign prostatic obstruction in Caucasian patients with lower urinary tract symptoms suggestive of benign prostatic enlargement: results from an explorative clinical study. AB - BACKGROUND: To preliminary investigate the effects of silodosin 8 mg once daily on obstruction urodynamic parameters and subjective symptoms in Caucasian patients with lower urinary tract symptoms suggestive of benign prostatic enlargement. METHODS: We performed a single-center, open-label, single-arm, post marketing interventional clinical trial. Inclusion criteria were: Caucasian subjects aged >=50 years waiting to undergo surgery for lower urinary tract symptoms suggestive of benign prostatic enlargement, international prostate symptom total score >= 13, international prostate symptom-quality of life score >= 3, prostate volume >= 30 ml, maximum urine flow rate <= 15 mL/s, bladder outlet obstruction index > 40. Eligible subjects received one capsule of silodosin 8 mg once daily for 8 weeks. Invasive urodynamic evaluations were performed at baseline and at 8-weeks follow-up. International prostate symptom questionnaire was administered at baseline, after 4-weeks and 8-weeks of treatment. RESULTS: Overall, 34 subjects were included. Mean bladder outlet obstruction index significantly decreased from 70.6 to 39.2 and bladder outlet obstruction index class improved in 16 patients (53.3%). Statistically significant improvements of mean total international prostate symptom score, mean storage sub-score, mean voiding sub-score and mean quality of life sub-score were evident after 4-weeks of treatment with further improvements after 8-weeks. At the end of the treatment, all patients declared that their condition improved enough to spare or delay surgery. CONCLUSIONS: Silodosin 8 mg once daily significantly improves benign prostatic obstruction in Caucasian patients with lower urinary tract symptoms suggestive of benign prostatic enlargement waiting for surgery. TRIAL REGISTRATION: EudraCT n. 2015-002277-38 Date of registration: 15th December 2017. PMID- 29502525 TI - Health-related quality of life and the ability to perform activities of daily living: a cross-sectional study on 1079 war veterans with ankle-foot disorders. AB - BACKGROUND: The ankle-foot injuries are among the war-related injuries that cause many serious secondary problems for a lifetime. This nationwide study aimed to assess health-related quality of life and the ability to perform activities of daily living in veterans with ankle-foot injuries due to the Iran-Iraq war. METHODS: A total of 1079 veterans with ankle-foot injuries were enrolled in a cross-sectional study from 2014 to 2016. Demographic characteristics, including age, gender, marital status, disability percent, educational level, employment and additional injuries, were collected. The ability to perform daily activities was assessed using the Barthel activities of daily living (ADL) and Lawton instrumental activities of daily living (IADL) Indexes. Physical and mental health-related quality of life (HRQOL) data were measured via the SF-36 subscales. The data were compared with those of bilateral lower limb amputees (BLLAs) and of the general Iranian population. Statistical analyses, including Pearson's correlation coefficient, one-sample t-test and analysis of variance (ANOVA), were performed using SPSS16.0. A multiple linear regression model was used to determine the contribution of independent variables to the Physical Component Summary (PCS) and Mental Component Summary (MCS). RESULTS: The highest and lowest scores were observed for mental health (48.93 +/- 20.69) and bodily pain (28.16 +/- 21.74), respectively. The mean scores of veterans with ankle-foot injuries on the SF-36 were significantly lower on all eight measures than those of the general Iranian male population and of the bilateral lower limb amputees (P < 0.001). The mean scores of ADLs and IADLs were 83.9 +/- 16.3 and 5.3 +/- 2.0, respectively. The higher dependency in ADLs (P < 0.001) and IADLs (P < 0.001), the higher disability rate (P < 0.001) and additional injury (P < 0.001) were significant determinants of the PCS. ADL (P < 0.001) and IADL (P < 0.001) limitations, additional injury (P < 0.001), history of hospitalization in the year preceding the study (P = 0.007) and employment (P = 0.001) were reported as determinants of the MCS. CONCLUSION: The results strongly suggest that veterans with ankle-foot injuries suffer from critically poor health-related quality of life. The main predicting factors of HRQOL were the disability to perform ADLs/IADLs, suffering two or more injuries, a history of hospitalization in the year preceding the study and unemployment. PMID- 29502526 TI - A hypothesis study on a four-period prevention model for high altitude disease. AB - BACKGROUND: High altitude disease (HAD) can reduce combat effectiveness and damage the health of soldiers at high altitudes. The objective of this hypothesis study is to build a four-period prevention model for high altitude disease that can be applied at high altitudes of over 3000 m. PRESENTATION OF THE HYPOTHESIS: We divided the time at high altitude into nine periods, with three stages from the ascent preparation to the descent to the plain, and applied a continuous dynamic and systematic four-period prevention model across the nine periods. Each period of three stages has its own different measures and targets high altitude health care services for the prevention of high altitude disease. A standard four period prevention model for high altitude disease was constructed for the high altitude health services at the population level. TESTING THE HYPOTHESIS: Our hypothesized HAD prevention model represents a continuous dynamic and systematic four-period prevention model across the nine periods. This hypothesis can be tested from three aspects. The first one isassessment of soldiers' operating efficacies. The second is comparison of the long-term high altitude population health basic data and development and utilization of big data. The third is descent population health status comparative study and historical retrospective study on prevention. IMPLICATIONS: As we know, it is necessary to protect soldiers' health through the ascent and descent. Through the standard four-period model, we can protect soldiers' health by preventing high altitude diseases, screening the susceptible population, securely tracking their location and maintaining soldiers' health statuses; we also maintain their operational capabilities, eliminate their psychological fears and ease their family troubles. PMID- 29502528 TI - Application of stem cells in tissue engineering for defense medicine. AB - The dynamic nature of modern warfare, including threats and injuries faced by soldiers, necessitates the development of countermeasures that address a wide variety of injuries. Tissue engineering has emerged as a field with the potential to provide contemporary solutions. In this review, discussions focus on the applications of stem cells in tissue engineering to address health risks frequently faced by combatants at war. Human development depends intimately on stem cells, the mysterious precursor to every kind of cell in the body that, with proper instruction, can grow and differentiate into any new tissue or organ. Recent reports have suggested the greater therapeutic effects of the anti inflammatory, trophic, paracrine and immune-modulatory functions associated with these cells, which induce them to restore normal healing and tissue regeneration by modulating immune reactions, regulating inflammation, and suppressing fibrosis. Therefore, the use of stem cells holds significant promise for the treatment of many battlefield injuries and their complications. These applications include the treatment of injuries to the skin, sensory organs, nervous system tissues, the musculoskeletal system, circulatory/pulmonary tissues and genitals/testicles and of acute radiation syndrome and the development of novel biosensors. The new research developments in these areas suggest that solutions are being developed to reduce critical consequences of wounds and exposures suffered in warfare. Current military applications of stem cell-based therapies are already saving the lives of soldiers who would have died in previous conflicts. Injuries that would have resulted in deaths previously now result in wounds today; similarly, today's permanent wounds may be reduced to tomorrow's bad memories with further advances in stem cell-based therapies. PMID- 29502527 TI - Expert consensus on the evaluation and diagnosis of combat injuries of the Chinese People's Liberation Army. AB - The accurate assessment and diagnosis of combat injuries are the basis for triage and treatment of combat casualties. A consensus on the assessment and diagnosis of combat injuries was made and discussed at the second annual meeting of the Professional Committee on Disaster Medicine of the Chinese People's Liberation Army (PLA). In this consensus agreement, the massive hemorrhage, airway, respiration, circulation and hypothermia (MARCH) algorithm, which is a simple triage and rapid treatment and field triage score, was recommended to assess combat casualties during the first-aid stage, whereas the abbreviated scoring method for combat casualty and the MARCH algorithm were recommended to assess combat casualties in level II facilities. In level III facilities, combined measures, including a history inquiry, thorough physical examination, laboratory examination, X-ray, and ultrasound examination, were recommended for the diagnosis of combat casualties. In addition, corresponding methods were recommended for the recognition of casualties needing massive transfusions, assessment of firearm wounds, evaluation of mangled extremities, and assessment of injury severity in this consensus. PMID- 29502529 TI - Effects of therapeutic horseback riding on post-traumatic stress disorder in military veterans. AB - BACKGROUND: Large numbers of post-deployment U.S. veterans are diagnosed with post-traumatic stress disorder (PTSD) and/or traumatic brain injury (TBI), leading to an urgent need for effective interventions to reduce symptoms and increase veterans' coping. PTSD includes anxiety, flashbacks, and emotional numbing. The symptoms increase health care costs for stress-related illnesses and can make veterans' civilian life difficult. METHODS: We used a randomized wait list controlled design with repeated measures of U.S. military veterans to address our specific aim to test the efficacy of a 6-week therapeutic horseback riding (THR) program for decreasing PTSD symptoms and increasing coping self efficacy, emotion regulation, social and emotional loneliness. Fifty-seven participants were recruited and 29 enrolled in the randomized trial. They were randomly assigned to either the horse riding group (n = 15) or a wait-list control group (n = 14). The wait-list control group experienced a 6-week waiting period, while the horse riding group began THR. The wait-list control group began riding after 6 weeks of participating in the control group. Demographic and health history information was obtained from all the participants. PTSD symptoms were measured using the standardized PTSD Checklist-Military Version (PCL-M). The PCL-M as well as other instruments including, The Coping Self Efficacy Scale (CSES), The Difficulties in Emotion Regulation Scale (DERS) and The Social and Emotional Loneliness Scale for Adults-short version (SELSA) were used to access different aspects of individual well-being and the PTSD symptoms. RESULTS: Participants had a statistically significant decrease in PTSD scores after 3 weeks of THR (P <= 0.01) as well as a statistically and clinically significant decrease after 6 weeks of THR (P <= 0.01). Logistic regression showed that participants had a 66.7% likelihood of having lower PTSD scores at 3 weeks and 87.5% likelihood at 6 weeks. Under the generalized linear model(GLM), our ANOVA findings for the coping self-efficacy, emotion regulation, and social and emotional loneliness did not reach statistical significance. The results for coping self-efficacy and emotion regulation trended in the predicted direction. Results for emotional loneliness were opposite the predicted direction. Logistic regression provided validation that outcome effects were caused by riding longer. CONCLUSION: The findings suggest that THR may be a clinically effective intervention for alleviating PTSD symptoms in military veterans. PMID- 29502531 TI - Assistive technologies for pain management in people with amputation: a literature review. AB - The prevalence of limb amputation is increasing globally as a devastating experience that can physically and psychologically affect the lifestyle of a person. The residual limb pain and phantom limb pain are common disabling sequelae after amputation surgery. Assistive devices/technologies can be used to relieve pain in people with amputation. The existing assistive devices/technologies for pain management in people with amputation include electrical nerve block devices/technologies, TENS units, elastomeric pumps and catheters, residual limb covers, laser systems, myoelectric prostheses and virtual reality systems, etc. There is a great potential to design, fabricate, and manufacture some portable, wireless, smart, and thin devices/technologies to stimulate the spinal cord or peripheral nerves by electrical, thermal, mechanical, and pharmaceutical stimulus. Although some preliminary efforts have been done, more attention must be paid by researchers, clinicians, designers, engineers, and manufacturers to the post amputation pain and its treatment methods. PMID- 29502530 TI - Successful use of closed-loop allostatic neurotechnology for post-traumatic stress symptoms in military personnel: self-reported and autonomic improvements. AB - BACKGROUND: Military-related post-traumatic stress (PTS) is associated with numerous symptom clusters and diminished autonomic cardiovascular regulation. High-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM(r)) is a noninvasive, closed-loop, allostatic, acoustic stimulation neurotechnology that produces real-time translation of dominant brain frequencies into audible tones of variable pitch and timing to support the auto-calibration of neural oscillations. We report clinical, autonomic, and functional effects after the use of HIRREM(r) for symptoms of military-related PTS. METHODS: Eighteen service members or recent veterans (15 active-duty, 3 veterans, most from special operations, 1 female), with a mean age of 40.9 (SD = 6.9) years and symptoms of PTS lasting from 1 to 25 years, undertook 19.5 (SD = 1.1) sessions over 12 days. Inventories for symptoms of PTS (Posttraumatic Stress Disorder Checklist - Military version, PCL-M), insomnia (Insomnia Severity Index, ISI), depression (Center for Epidemiologic Studies Depression Scale, CES-D), and anxiety (Generalized Anxiety Disorder 7-item scale, GAD-7) were collected before (Visit 1, V1), immediately after (Visit 2, V2), and at 1 month (Visit 3, V3), 3 (Visit 4, V4), and 6 (Visit 5, V5) months after intervention completion. Other measures only taken at V1 and V2 included blood pressure and heart rate recordings to analyze heart rate variability (HRV) and baroreflex sensitivity (BRS), functional performance (reaction and grip strength) testing, blood and saliva for biomarkers of stress and inflammation, and blood for epigenetic testing. Paired t-tests, Wilcoxon signed-rank tests, and a repeated-measures ANOVA were performed. RESULTS: Clinically relevant, significant reductions in all symptom scores were observed at V2, with durability through V5. There were significant improvements in multiple measures of HRV and BRS [Standard deviation of the normal beat to normal beat interval (SDNN), root mean square of the successive differences (rMSSD), high frequency (HF), low frequency (LF), and total power, HF alpha, sequence all, and systolic, diastolic and mean arterial pressure] as well as reaction testing. Trends were seen for improved grip strength and a reduction in C-Reactive Protein (CRP), Angiotensin II to Angiotensin 1-7 ratio and Interleukin-10, with no change in DNA n-methylation. There were no dropouts or adverse events reported. CONCLUSIONS: Service members or veterans showed reductions in symptomatology of PTS, insomnia, depressive mood, and anxiety that were durable through 6 months after the use of a closed loop allostatic neurotechnology for the auto-calibration of neural oscillations. This study is the first to report increased HRV or BRS after the use of an intervention for service members or veterans with PTS. Ongoing investigations are strongly warranted. TRIAL REGISTRATION: NCT03230890 , retrospectively registered July 25, 2017. PMID- 29502532 TI - Risk factors for 90-day readmission in veterans with inflammatory bowel disease Does post-discharge follow-up matter? AB - BACKGROUND: Repeat hospitalizations in veterans with inflammatory bowel disease (IBD) are understudied. The early readmission rate and potentially modifiable risk-factors for 90-day readmission in veterans with IBD were studied to avert avoidable readmissions. METHODS: A retrospective cohort study was conducted using the data from veterans who were admitted to the Minneapolis VA Medical Center (MVMC) between January 1, 2007, and December 31, 2013, for an IBD-related problem. All-cause readmissions within 30 and 90 days were recorded to calculate early readmission rates. The multivariate logistic regression was used to identify the potential risk factors for 90-day readmission. RESULTS: There were 130 unique patients (56.9% with Crohn's disease and 43.1% with ulcerative colitis) with 202 IBD-related index admissions. The mean age at the time of index admission was 59.8 +/- 15.2 years. The median time to re-hospitalization was 26 days (IQR 10-49), with 30- and 90-day readmission rates of 17.3% (35/202) and 29.2% (59/202), respectively. Reasons for all-cause readmission were IBD-related (71.2%), scheduled surgery (3.4%) and non-gastrointestinal causes (25.4%). The following reasons were independently associated with 90-day readmission: Crohn's disease (OR 3.90; 95% CI 1.82-8.90), use of antidepressants (OR 2.19; 95% CI 1.12 4.32), and lack of follow-up within 90 days with a primary care physician (PCP) (OR 2.63; 95% CI 1.32-5.26) or a gastroenterologist (GI) (OR 2.44; 95% CI 1.20 5.00). 51.0% and 49.0% of patients had documentation of a recommended outpatient follow-up with PCP and/or GI, respectively. CONCLUSIONS: Early readmission in IBD is common. Independent risk factors for 90-day readmission included Crohn's disease, use of antidepressants and lack of follow-up visit with PCP or GI. Further research is required to determine if the appropriate timing of post discharge follow-up can reduce IBD readmissions. PMID- 29502533 TI - The prevalence rates of major chronic diseases in retired and in-service Chinese military officers (2000-2016): a meta-analysis. AB - BACKGROUND: Chronic diseases cause a tremendous burden to the military medical system. However, the prevalence rates of major chronic diseases among military officers remain unclear in China. METHODS: China National Knowledge Infrastructure (CNKI), Wanfang Database, VIP Database for Chinese Technical Periodicals (VIP), PubMed and Web of Science were searched for studies (from 2000 to 2016) concerning 6 major chronic diseases: hypertension, hyperlipidemia, diabetes mellitus, heart diseases, cerebrovascular diseases, and chronic obstructive pulmonary diseases (COPD) in Chinese military officers following strict inclusion and exclusion criteria. Three researchers independently extracted data from the included studies, and a fourth researcher reviewed and solved every disagreement. Statistical analysis was performed with STATA 14.0 and R 3.3.2. Heterogeneity was evaluated by the I 2 value. A random effect model was performed to combine the heterogeneous data. The Egger test was performed to test the publication bias. RESULTS: A total of 90,758 military officers derived from 75 articles were pooled together. Publication bias was only observed in 37 studies reporting heart disease (P Egger test = 0.01). The overall prevalence rates of hypertension, hyperlipidemia, diabetes mellitus, heart diseases, cerebrovascular diseases, and COPD were 46.6% (95% CI 41.8-51.5%), 30.9% (26.4 35.7%), 20.7% (16.5-25.7%), 48.2% (41.7-54.9%), 20.2% (14.8-26.9%) and 16.6% (12.9-21.0%), respectively. The prevalence rates of hypertension, diabetes, heart disease, cerebrovascular disease, and COPD, rather than hyperlipidemia, increased with age in Chinese military officers. Heart diseases (P Q-test < 0.001) and hypertension (P Q-test < 0.001) increased sharply in retired officers compared with officers in service. Cerebrovascular disease was more frequent in Northern Theater Command than in any other theater command (P Q-test < 0.001). CONCLUSIONS: Major chronic diseases heavily affect Chinese military officers, especially retirees. Medical intervention should be enforced on the prevention of cerebrovascular diseases in those working in cold areas in the north, as well as hypertension and heart diseases in retirees. PMID- 29502534 TI - A hypothesis study on bionic active noise reduction of auditory organs. AB - BACKGROUND: Noise exposure can lead to hearing loss and multiple system dysfunctions. As various forms of noise exist in our living environments, and our auditory organs are very sensitive to acoustic stimuli, it is a challenge to protect our hearing system in certain noisy environments. PRESENTATION OF THE HYPOTHESIS: Herein, we propose that our hearing organ could serve as a noise eliminator for high intensity noise and enhance acoustic signal processing abilities by increasing the signal-noise ratio. For suprathreshold signals, the hearing system is capable of regulating the middle ear muscles and other structures to actively suppress the sound level to a safe range. TESTING THE HYPOTHESIS: To test our hypothesis, both mathematic model analyses and animal model studies are needed. Based on a digital 3D reconstructed model, every structure in the auditory system can be analyzed and tested for its contribution to the process of noise reduction. Products manufactured by this bionic method could be used and verified in animal models and volunteers. IMPLICATIONS: By mimicking the noise-reduction effect of the sophisticated structures in the hearing system, we may be able to provide a model that establishes a new active sound-suppression mode. This innovative method may overcome the limited capabilities of current noise protection options and become a promising possibility for noise prevention. PMID- 29502535 TI - From nuclear submarines to graduate medical education: applying David Marquet's intent-based leadership model. AB - L. David Marquet, a decorated Navy Captain, transformed an underperforming submarine crew by empowering his subordinates to be leaders and reach their full potential. He called this intent-based leadership (IBL). What would happen if Marquet's model were implemented in Graduate Medical Education (GME)?In this letter to the editor, we summarize the potential of the IBL model in graduate medical education as opposed to the traditional leader-follower method. IBL harnesses human productivity toward the shared goals of GME, which are patient care and trainee learning. This shift in mindset could lead both teachers and trainees to focus more on the real reason that we undertake GME and change behaviors for the better. We suggest that IBL can and should be adopted in GME and propose that both patients and providers will benefit from this action. PMID- 29502536 TI - Metabolomics analysis of serum in a rat heroin self-administration model undergoing reinforcement based on 1H-nuclear magnetic resonance spectra. AB - BACKGROUND: Understanding the process of relapse to abused drugs and ultimately developing treatments that can reduce the incidence of relapse remains the primary goal for the study of substance dependence. Therefore, exploring the metabolite characteristics during the relapse stage is valuable. METHODS: A heroin self-administered rat model was employed, and analysis of the 1H-nuclear magnetic resonance-based metabolomics was performed to investigate the characteristic metabolite profile upon reintroduction to the drug after abstinence. RESULTS: Sixteen metabolites in the serum of rats, including phospholipids, intermediates in TCA (Tricarboxylic Acid Cycle) cycle, keto bodies, and precursors for neurotransmitters, underwent a significant change in the reinstatement stage compared with those in the control group. In particular, energy production was greatly disturbed as evidenced by different aspects such as an increase in glucose and decrease in intermediates of glycolysis and the TCA cycle. The finding that the level of 3-hydroxybutyrate and acetoacetate increased significantly suggested that energy production was activated from fatty acids. The concentration of phenylalanine, glutamine, and choline, the precursors of major neurotransmitters, increased during the reinstatement stage which indicated that an alteration in neurotransmitters in the brain might occur along with the disturbance in substrate supply in the circulatory system. CONCLUSIONS: Heroin reinforcement resulted in impaired energy production via different pathways, including glycolysis, the TCA cycle, keto body metabolism, etc. A disturbance in the substrate supply in the circulatory system may partly explain heroin toxicity in the central nervous system. These findings provide new insight into the mechanism underlying the relapse to heroin use. PMID- 29502537 TI - Association of tribbles homologue 1 gene expression in human umbilical vein endothelial cells with duration of intrauterine exposure to hyperglycaemia. AB - Maternal gestational diabetes mellitus (GDM) is considered to be an important factor that epigenetically predisposes offspring to metabolic and cardiovascular diseases. However, the mechanisms of how intrauterine hyperglycaemia affects offspring have not been thoroughly studied. The mammalian tribbles homologue 1 (TRIB1) gene is associated with plasma lipid concentrations and coronary artery disease (CAD). Our aim was to study the effect of GDM and its treatment terms on the level of TRIB1 gene expression in human umbilical vein endothelial cells (HUVECs) of newborns from women with and without GDM. The study included 50 women with GDM and 25 women without GDM (control group). Women with GDM were divided into three groups according to their gestational age when the treatment of GDM started: 24-28 weeks (GDM1, N = 16), 29-32 weeks (GDM2, N = 25) and >34 weeks (GDM3, N = 9). The levels of TRIB1 gene expression in GDM3, GDM2, GDM1 and control groups were 2.8 +/- 1.1, 4.2 +/- 2.4, 6.0 +/- 3.4 and 8.1 +/- 6.1, respectively (p = 0.001). After comparison in pairs the difference was significant for the following pairs: GDM2-control (p = 0.004), GDM3-control (p = 0.002), GDM1-GDM3 (p = 0.012). Notably, if treatment had been started before the 28th week of gestation, the difference in TRIB1 gene expression in HUVECs was not significant (p = 0.320 for comparison between GDM1 and control groups). Our findings support the hypothesis that TRIB1 gene expression in HUVECs depends on the duration of intrauterine exposure to hyperglycaemia. PMID- 29502538 TI - Maternal high-salt diet alters redox state and mitochondrial function in newborn rat offspring's brain. AB - Excessive salt intake is a common feature of Western dietary patterns, and has been associated with important metabolic changes including cerebral redox state imbalance. Considering that little is known about the effect on progeny of excessive salt intake during pregnancy, the present study investigated the effect of a high-salt diet during pregnancy and lactation on mitochondrial parameters and the redox state of the brains of resulting offspring. Adult female Wistar rats were divided into two dietary groups (n 20 rats/group): control standard chow (0.675 % NaCl) or high-salt chow (7.2 % NaCl), received throughout pregnancy and for 7 d after delivery. On postnatal day 7, the pups were euthanised and their cerebellum, hypothalamus, hippocampus, prefrontal and parietal cortices were dissected. Maternal high-salt diet reduced cerebellar mitochondrial mass and membrane potential, promoted an increase in reactive oxygen species allied to superoxide dismutase activation and decreased offspring cerebellar nitric oxide levels. A significant increase in hypothalamic nitric oxide levels and mitochondrial superoxide in the hippocampus and prefrontal cortex was observed in the maternal high-salt group. Antioxidant enzymes were differentially modulated by oxidant increases in each brain area studied. Taken together, our results suggest that a maternal high-salt diet during pregnancy and lactation programmes the brain metabolism of offspring, favouring impaired mitochondrial function and promoting an oxidative environment; this highlights the adverse effect of high salt intake in the health state of the offspring. PMID- 29502539 TI - Dietary inflammatory index and risk of oesophageal cancer in Xinjiang Uyghur Autonomous Region, China. AB - Diet has been shown to have an effect on both inflammation and oesophageal cancer. This study investigated the association between the dietary inflammatory index (DII(r)) and the risk of oesophageal cancer in Xinjiang Uyghur Autonomous Region, China. A case-control study was conducted during 2008-2009 in Urumqi and Shihezi. DII scores were calculated based on dietary intake assessed by a validated FFQ administered to 359 incident oesophageal cancer patients and 380 hospital-based controls. Higher DII scores indicate more pro-inflammatory diets. Logistic regression analyses were performed to assess the association between DII scores and oesophageal cancer risk. Oesophageal cancer patients had a significantly higher median DII score (-0.35; interquartile range (IQR)=-2.25, 1.86) than that of controls (-1.41; IQR -3.07, 0.40). Multivariable logistic analysis revealed a positive association between higher DII scores and oesophageal cancer risk (ORQuartile 4 v. 1 2.55; 95 % CI 1.61, 4.06; P trend<0.001). A pro-inflammatory diet appears to be associated with an increased risk of oesophageal cancer in Xinjiang Uyghur Autonomous Region. Specific carcinogenic mechanisms are discussed. Accumulating evidence, to which the study contributes, indicates that encouraging the intake of more anti-inflammatory foods may be a strategy to protect against oesophageal cancer in this high-risk area of China. PMID- 29502540 TI - Early changes in tissue amino acid metabolism and nutrient routing in rats fed a high-fat diet: evidence from natural isotope abundances of nitrogen and carbon in tissue proteins. AB - Little is known about how diet-induced obesity and insulin resistance affect protein and amino acid (AA) metabolism in tissues. The natural relative abundances of the heavy stable isotopes of C (delta 13C) and N (delta 15N) in tissue proteins offer novel and promising biomarkers of AA metabolism. They, respectively, reflect the use of dietary macronutrients for tissue AA synthesis and the relative metabolic use of tissue AA for oxidation v. protein synthesis. In this study, delta 13C and delta 15N were measured in the proteins of various tissues in young adult rats exposed perinatally and/or fed after weaning with a normal- or a high-fat (HF) diet, the aim being to characterise HF-induced tissue specific changes in AA metabolism. HF feeding was shown to increase the routing of dietary fat to all tissue proteins via non-indispensable AA synthesis, but did not affect AA allocation between catabolic and anabolic processes in most tissues. However, the proportion of AA directed towards oxidation rather than protein synthesis was increased in the small intestine and decreased in the tibialis anterior muscle and adipose tissue. In adipose tissue, the AA reallocation was observed in the case of perinatal or post-weaning exposure to HF, whereas in the small intestine and tibialis anterior muscle the AA reallocation was only observed after HF exposure that covered both the perinatal and post-weaning periods. In conclusion, HF exposure induced an early reorganisation of AA metabolism involving tissue-specific effects, and in particular a decrease in the relative allocation of AA to oxidation in several peripheral tissues. PMID- 29502541 TI - Is there any difference between the iodine statuses of breast-fed and formula-fed infants and their mothers in an area with iodine sufficiency? AB - Despite substantial progress in the global elimination of iodine deficiency, lactating mothers and their infants remain susceptible to insufficient iodine intake. This cross-sectional study was conducted to compare iodine statuses of breast-fed and formula-fed infants and their mothers at four randomly selected health care centres in Tehran. Healthy infants <3 months old and their mothers were randomly selected for inclusion in this study. Iodine was measured in urine and breast milk samples from each infant and mother as well as commercially available infant formula. The study included 124 postpartum mothers (29.2 (sd 4.9) years old) and their infants (2.0 (sd 0.23) months old). The iodine concentrations were 50-184 ug/l for infant formula, compared with a median breast milk iodine concentration (BMIC) of 100 ug/l in the exclusive breast-feeding group and 122 ug/l in the partial formula feeding group. The median values for urinary iodine concentration in the exclusive breast-feeding group were 183 ug/l (interquartile range (IQR) 76-285) for infants and 78 ug/l (IQR 42-145) for mothers, compared with 140 ug/l (IQR 68-290) for infants and 87 ug/l (IQR 44-159) for mothers in the formula feeding group. These differences were not statistically significant. After adjustment for BMIC, ANCOVA revealed that feeding type (exclusive breast-feeding v. partial formula feeding) did not significantly affect the infants' or mother's urinary iodine levels. Thus, in an area with iodine sufficiency, there was no difference in the iodine statuses of infants and mothers according to their feeding type. PMID- 29502542 TI - Household-level factors associated with relapse following discharge from treatment for moderate acute malnutrition. AB - Factors associated with relapse among children who are discharged after reaching a threshold denoted 'recovered' from moderate acute malnutrition (MAM) are not well understood. The aim of this study was to identify factors associated with sustained recovery, defined as maintaining a mid-upper-arm circumference>=12.5 cm for 1 year after release from treatment. On the basis of an observational study design, we analysed data from an in-depth household (HH) survey on a sub-sample of participants within a larger cluster randomised controlled trial (cRCT) that followed up children for 1 year after recovery from MAM. Out of 1497 children participating in the cRCT, a subset of 315 children participated in this sub study. Accounting for other factors, HH with fitted lids on water storage containers (P=0.004) was a significant predictor of sustained recovery. In addition, sustained recovery was better among children whose caregivers were observed to have clean hands (P=0.053) and in HH using an improved sanitation facility (P=0.083). By contrast, socio-economic status and infant and young child feeding practices at the time of discharge and HH food security throughout the follow-up period were not significant. Given these results, we hypothesise that improved water, sanitation and hygiene conditions in tandem with management of MAM through supplemental feeding programmes have the possibility to decrease relapse following recovery from MAM. Furthermore, the absence of associations between relapse and nearly all HH-level factors indicates that the causal factors of relapse may be related mostly to the child's individual, underlying health and nutrition status. PMID- 29502543 TI - A review and update of the Health of the Nation Outcome Scales (HoNOS). AB - : Aims and method The Health of the Nation Outcome Scales (HoNOS) and its older adults' version (HoNOS 65+) have been used widely for 20 years, but their glossaries have not been revised to reflect clinicians' experiences or changes in service delivery. The Royal College of Psychiatrists convened an international advisory board, with UK, Australian and New Zealand expertise, to identify desirable amendments. The aim was to improve rater experience by removing ambiguity and inconsistency in the glossary rather than more radical revision. RESULTS: Changes proposed to the HoNOS are reported. HoNOS 65+ changes will be reported separately. Based on the views and experience of the countries involved, a series of amendments were identified. Clinical implications While effective clinician training remains critically important, these revisions aim to improve intra- and interrater reliability and improve validity. Next steps will depend on feedback from HoNOS users. Reliability and validity testing will depend on funding. Declaration of interest None. PMID- 29502544 TI - Helminth endoparasites of the smooth newt Lissotriton vulgaris: linking morphological identification and molecular data. AB - The helminth endoparasites of many European amphibian species are often known exclusively from morphological descriptions. A molecular library of DNA sequence data linked to morphological identifications is still in its infancy. In this paper, we aim to contribute to such a library on the smooth newt Lissotriton vulgaris, the intermediate and definitive host of 31 helminth parasites, according to evidence published so far. Newts (n = 69) were collected at two study sites in western Germany and examined for the presence of helminths. A total of five helminth species were detected in 56 (81%) of the newts, but only one or two species infected a single host. Four out of five helminth species were identified morphologically and based on DNA sequences as Parastrigea robusta (metacercariae), Oswaldocruzia filiformis, Megalobatrachonema terdentatum (adults and larvae) and Cosmocerca longicauda, and the corresponding sequences were provided subsequently. Oswaldocruzia molgeta was confirmed to be a junior synonym of O. filiformis. Molecular data on a fifth species (a cosmocercid nematode) that could not be identified at species level were added to GenBank. These findings increased the molecular library on morphologically identified smooth newt parasites significantly, from 12 to 15 entries. PMID- 29502545 TI - Urban rodent reservoirs of Borrelia spp. in Warsaw, Poland. AB - The anticipated worldwide surge in urban environments is generating ever-greater interest in the study of host-pathogen interactions in this specific type of habitat. We investigated the potential of city-inhabiting rodents to serve as the main Lyme borreliosis agents (Borrelia spp.) reservoir. We also tried to verify if anthropogenic disturbances changing the vertebrate species community composition may also alter the scheme of Borrelia spp. circulation. A total of 252 Apodemus mice (A. agrarius, A. flavicollis, A. sylvaticus) were captured in Warsaw (Poland), at sites classified into different zones of anthropogenic disturbance, ranging from suburban forests to municipal parks strictly in the city centre. Borrelia spp. infection, ascertained based on bacterium DNA presence in the rodents' blood, was found only in A. agrarius and A. flavicollis (7.6 and 6%, respectively). Only one species from the Borrelia genus - the mammal associated species B. afzelii - was found in the mice studied. We found no statistical evidence of a correlation between infection in Apodemus mice and the zone of anthropogenic disturbance where the mice were caught. Non-homogeneous concentrations of Borelia spp. infected specimens within the strict city centre area suggest a lack of contact between members of particular mice subpopulations, and their responsibility for relatively high, but local Borrelia spp. infection. PMID- 29502546 TI - IS FERTILITY AFTER THE DEMOGRAPHIC TRANSITION MALADAPTIVE? AB - Fitness is always relative to the fitness of others in the group or breeding population. Even in very low-fertility societies, individual fitness as measured by the share of genes in subsequent generations may still be maximized. Further, sexual selection theory from evolutionary biology suggests that the relationship between status and fertility will differ for males and females. For this reason it is important to examine the relationship between status and fertility separately for males and females-something few demographic studies of fertility do. When male fertility is measured separately, high-status men (as measured by their wealth and personal income) have higher fertility than low-status men, even in very low-fertility societies, so individual males appear to be maximizing their fitness within the constraints posed by a modern society. Thus male fertility cannot be considered maladaptive. When female fertility is measured separately, in both very high- and very low-fertility societies, there is not much variance across women of different statuses in completed fertility. Only in societies currently changing rapidly (with falling fertility rates) is somewhat high variance across women of different statuses in completed fertility found. What is seen across all phases of the demographic transition appears to be a continuation of two somewhat different evolved human reproductive strategies-one male, one female-in changing social and material contexts. Whether contemporary female fertility is maladaptive remains an open question. PMID- 29502547 TI - 'Hello, you're not supposed to be here': homeless emerging adults' experiences negotiating food access. AB - OBJECTIVE: We aimed to examine the food-seeking experiences of homeless emerging adults (age 18-24 years) in a US urban context. DESIGN: The study used a qualitative descriptive design, combining semi-structured interviews with a standardized quantitative measure of food insecurity. Interview data were coded using constant comparative methods to identify patterns across and within interviews. Emerging themes were confirmed and refined through member checking. SETTING: Buffalo, a mid-sized city in the Northeastern USA. SUBJECTS: A sample of thirty participants was recruited through community-based methods. Eligibility criteria specified that participants were aged 18-24 years and did not have a stable place to live. The sample was demographically diverse and included participants who were couch-surfing, staying on the streets and/or using shelters. RESULTS: Participants' food access strategies varied across their living circumstances. Common strategies included purchasing food with cash or benefits (reported by 77 %), using free meal programmes (70 %) and eating at friends' or relatives' homes (47 %). Although 70 % of participants received Supplemental Nutrition Assistance Program benefits, several reported access barriers, including initial denials of eligibility due to being listed on a parent's application even when the participant no longer resided in the household. Participants described a stigma associated with using food pantries and free meal programmes and expressed preference for less institutionalized programmes such as Food Not Bombs. CONCLUSIONS: Given endemic levels of food insecurity among homeless youth and young adults, policy modifications and service interventions are needed to improve food access for this population. PMID- 29502548 TI - Increased hippocampal engagement during learning as a marker of sensitivity to psychotomimetic effects of delta-9-THC. AB - BACKGROUND: Cannabis and its main psychoactive ingredient delta-9 tetrahydrocannibidiol (THC) can induce transient psychotic symptoms in healthy individuals and exacerbate them in those with established psychosis. However, not everyone experience these effects, suggesting that certain individuals are particularly susceptible. The neural basis of this sensitivity to the psychotomimetic effects of THC is unclear. METHODS: We investigated whether individuals who are sensitive to the psychotomimetic effects of THC (TP) under experimental conditions would show differential hippocampal activation compared with those who are not (NP). We studied 36 healthy males under identical conditions under the influence of placebo or THC (10 mg) given orally, on two separate occasions, in a pseudo-randomized, double-blind, repeated measures, within-subject, cross-over design, using psychopathological assessments and functional MRI while they performed a verbal learning task. They were classified into those who experienced transient psychotic symptoms (TP; n = 14) following THC administration and those who did not (NP; n = 22). RESULTS: Under placebo conditions, there was significantly greater engagement of the left hippocampus (p < 0.001) in the TP group compared with the NP group during verbal encoding, which survived leave-one-out analysis. The level of hippocampal activation was directly correlated (Spearman's rho = 0.44, p = 0.008) with the severity of transient psychotic symptoms induced by THC. This difference was not present when we compared two subgroups from the same sample that were defined by sensitivity to anxiogenic effects of THC. CONCLUSIONS: These results suggest that altered hippocampal activation during verbal encoding may serve as a marker of sensitivity to the acute psychotomimetic effects of THC. PMID- 29502549 TI - Infant-directed speech from seven to nineteen months has similar acoustic properties but different functions. AB - This longitudinal study assessed three acoustic components of maternal infant directed speech (IDS) - pitch, affect, and vowel hyperarticulation - in relation to infants' age and their expressive vocabulary size. These three individual components were measured in IDS addressed to infants at 7, 9, 11, 15, and 19 months (N = 18). All three components were exaggerated at all ages in mothers' IDS compared to their adult-directed speech. Importantly, the only significant predictor of infants' expressive vocabulary size at 15 and 19 months was vowel hyperarticulation, but only at 9 months and beyond, not at 7 months, and not pitch or affect at any age. These results set apart vowel hyperarticulation in IDS to infants as the critical IDS component for vocabulary development. Thus IDS, specifically the degree of vowel hyperarticulation therein, is a vehicle by which parents can provide the most optimal speech quality for their infants' linguistic and communicative development. PMID- 29502550 TI - Parasites in space and time: a novel method to assess and illustrate host searching behaviour of trematode cercariae. AB - The transmission from one host to another constitutes a challenging obstacle for parasites and is a key determinant of their fitness. Due to their complex life histories involving several different hosts, the free-living dispersal stages (cercariae) of digenean trematodes show a huge diversity in morphology and behaviour. On a finer scale, we still have an extremely limited understanding of the inter- and intraspecific variation in transmission strategies of many trematode species. Here, we present a novel method to study the movement patterns of cercariae of four New Zealand trematode species (Coitocaecum parvum, Maritrema poulini, Apatemon sp. and Aporocotylid sp. I.) via automated video tracking. This approach allows to quantify parameters otherwise not measurable and clearly illustrates the individual strategies of parasites to search for their respective target hosts. Cercariae that seek out an evasive fish target hosts showed higher swimming speeds (acceleration and velocity) and travelled further distances, compared with species searching for high-density crustacean hosts. Automated video tracking provides a powerful tool for such detailed analyses of parasites' host-searching strategies and can enhance our understanding of complex host parasite interactions, ranging from parasite community structure to the transmission of potential disease agents. PMID- 29502551 TI - Coronary occlusion in a child masquerading as dilated cardiomyopathy: the sequelae of missed Kawasaki disease. AB - If coronary artery sequelae are the only suggestive signs of previous Kawasaki disease, the diagnosis may easily be missed. We describe a rare case of a child with severe occlusive coronary disease likely owing to missed Kawasaki disease. This diagnosis was not initially considered given the age and absence of suggestive history. Careful echocardiographic assessment and low-radiation coronary CT angiogram resulted in successful diagnosis and treatment. PMID- 29502552 TI - Helminths of zoonotic importance in slaughtered food animals in Nigeria: a systematic review and meta-analysis. AB - Knowledge of endemic helminths in a resource-limited country such as Nigeria is essential for their diagnosis, treatment and cost-effective control. In the present study, the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guideline was employed to determine the prevalence and geographical distribution of zoonotic helminths in food animals slaughtered in Nigerian abattoirs between 1970 and 2016. Pooled prevalence estimate (PPE) was determined by the random-effects model while heterogeneity was evaluated using the Cochran's Q-test. Results from 42 eligible studies reported across 19 Nigerian states revealed 85,466 cases of zoonotic helminths from 3,771,832 slaughtered food animals. Overall PPE was 2.27% (95% confidence interval (CI): 2.25, 2.28). PPEs for sub-groups ranged between 0.51% (95% CI: 0.46, 0.56) and 18.05% (95% CI: 17.12, 19.01) across regions, hosts, study periods and diagnostic methods. Ascaris suum had the highest pooled prevalence of 25.46% (95% CI: 24.04, 26.92). Overall prevalence estimates for cestodes, nematodes and trematodes were 0.60% (95% CI: 0.59, 0.61), 21.51% (95% CI: 20.73, 22.30) and 1.86% (95% CI: 1.84, 1.87), respectively. A high degree of heterogeneity 99.97% (95% CI: 2.25, 2.28, P: 0.000) was observed. Zoonotic helminths were prevalent in slaughtered food animals, with higher prevalence estimates in the north-central region, pigs and during the last decade reviewed. Ascaris suum was the most prevalent helminth, while Fasciola gigantica had the widest geographical distribution. It is envisaged that the present information will help in the formulation of disease control policies, encourage on-farm good agricultural practices, and adequate hygiene and sanitation in abattoirs and meat-processing plants, with the aim of protecting public health. PMID- 29502553 TI - Characteristics and outcomes of older emergency department patients assigned a low acuity triage score. AB - CLINICIAN'S CAPSULE What is known about the topic? Little is known about the outcomes of older patients who are classified as "low acuity" at triage. What did this study ask? What are the differences in outcome of ED patients ages 65 years and older who received a CTAS score of 4 or 5, compared with patients 40 to 55 years old. What did this study find? Older patients were significantly more likely to be admitted; patients aged 85 years and older were particularly at risk. Why does this study matter to clinicians? Consideration should be given to triage modifiers for age, given the higher admission and re-presentation rates in older patients. PMID- 29502554 TI - GENDER DIFFERENCES IN INTELLIGENCE OF 5- to 11-YEAR-OLDS ON THE COLOURED PROGRESSIVE MATRICES IN EGYPT. AB - This study was based on data for a sample of 1756 Egyptian primary school children (863 boys and 893 girls) aged 5-11 years assessed for intelligence with Raven's Coloured Progressive Matrices (CPM). The results showed that boys obtained a slightly higher IQ than girls and had greater variance. PMID- 29502555 TI - Molecular analysis of human- and pig-derived Ascaris in Honduras. AB - Ascaris sp. is a soil-transmitted helminth (STH) significantly affecting the health of human and swine populations. Health inequities and poverty, with resulting deficiencies in water, sanitation and hygiene, are directly associated with Ascaris lumbricoides prevalence in humans. Resource constraints also lead to small-scale livestock production under unsanitary conditions. Free-ranging pigs, for instance, are exposed to a number of infectious agents, among which Ascaris suum is one of the most common. Under these conditions, close proximity between people and pigs can result in cross-contamination; that is, pigs harbouring human Ascaris and vice versa. Moreover, the potential interbreeding between these two Ascaris species has been demonstrated. The present study analysed Ascaris worms obtained from children and pigs in Honduras. Adult worms were collected from stool samples of children after pharmacological treatment, and from pigs' intestines after slaughter for commercial purposes at a local abattoir. A nuclear ribosomal internal transcribed spacer (ITS) region was amplified by polymerase chain reaction (PCR) and digested with a restriction enzyme in order to separate putative human- and pig-derived Ascaris isolates. PCR products were also sequenced, and cladograms were constructed. All parasites isolated from children showed the typical human-derived genotype of Ascaris, whereas 91% of parasites from pigs showed the expected pig-derived genotype. Cross-infections between hosts were not demonstrated in this study. Nine per cent of pig-derived worms showed a restriction band pattern highly suggestive of a hybrid human-pig Ascaris genotype. These results contribute to the understanding of ascariasis epidemiology and its zoonotic potential in a highly endemic region. PMID- 29502557 TI - Editorial. PMID- 29502556 TI - Indirect detection in solid state NMR: An illustrious history and a bright future. PMID- 29502558 TI - Beyond Supply: How We Must Tackle the Opioid Epidemic. PMID- 29502559 TI - Over-the-Counter Adrenal Supplements: More Than Meets the Eye. PMID- 29502560 TI - Over-the-Counter "Adrenal Support" Supplements Contain Thyroid and Steroid-Based Adrenal Hormones. AB - OBJECTIVE: To assess whether dietary supplements that are herbal and/or animal derived products, marketed for enhancing metabolism or promoting energy, "adrenal fatigue," or "adrenal support," contain thyroid or steroid hormones. METHODS: Twelve dietary adrenal support supplements were purchased. Pregnenolone, androstenedione, 17-hydroxyprogesterone, cortisol, cortisone, dehydroepiandrosterone sulfate, synthetic glucocorticoids (betamethasone, dexamethasone, fludrocortisone, megestrol acetate, methylprednisolone, prednisolone, prednisone, budesonide, and triamcinolone acetonide) levels were measured twice in samples in a blinded fashion. This study was conducted between February 1, 2016, and November 1, 2016. RESULTS: Among steroids, pregnenolone was the most common hormone in the samples. Budesonide, 17-hydroxyprogesterone, androstenedione, cortisol, and cortisone were the others in order of prevalence. All the supplements revealed a detectable amount of triiodothyronine (T3) (63 394.9 ng/tablet), 42% contained pregnenolone (66.12-205.2 ng/tablet), 25% contained budesonide (119.5-610 ng/tablet), 17% contained androstenedione (1.27 7.25 ng/tablet), 8% contained 17-OH progesterone (30.09 ng/tablet), 8% contained cortisone (79.66 ng/tablet), and 8% contained cortisol (138.5 ng/tablet). Per label recommended doses daily exposure was up to 1322 ng for T3, 1231.2 ng for pregnenolone, 1276.4 ng for budesonide, 29 ng for androstenedione, 60.18 ng for 17-OH progesterone, 277 ng for cortisol, and 159.32 ng for cortisone. CONCLUSION: All the supplements studied contained a small amount of thyroid hormone and most contained at least 1 steroid hormone. This is the first study that measured thyroid and steroid hormones in over-the-counter dietary "adrenal support" supplements in the United States. These results may highlight potential risks of hidden ingredients in unregulated supplements. PMID- 29502563 TI - Active Smoking and Hematocrit and Fasting Circulating Erythropoietin Concentrations in the General Population. AB - Cigarette smoking continues to be one of the major risk factors for increased morbidity and mortality worldwide. Among many adverse health effects, smoking can induce erythrocytosis, which is commonly believed to result from elevated serum erythropoietin (EPO) levels. Currently, however, this notion is only alleged, without data available to substantiate it. Hence, we analyzed data from the Prevention of Renal and Vascular End-Stage Disease study, a prospective population-based cohort study. Smoking behavior was quantified as number of cigarettes smoked per day and as 24-hour urinary cotinine excretion levels, an objective and quantitative measure of nicotine exposure. In 6808 community dwelling participants, the prevalence of nonsmokers, former smokers, and current smokers were 29%, 43%, and 28%, respectively. Hematocrit levels were higher in current smokers (41.4%+/-3.6%) than in nonsmokers (40.3%+/-3.6%) (P<.001). In contrast, median EPO levels were lower in current smokers (7.5 IU/L; interquartile range [IQR], 5.7-9.6 IU/L) than in nonsmokers (7.9 IU/L; IQR, 6.0 10.7 IU/L) (P<.001). In multivariate linear regression analysis, current smoking, compared with nonsmoking, was independently positively associated with hematocrit levels (beta=.12; P<.001) and hemoglobin levels (beta=.11; P<.001), but inversely associated with EPO levels (beta=-.09; P<.001). In sensitivity analyses, we observed a dose-dependent inverse association of smoking exposure reflected by 24 hour urinary cotinine excretion levels with EPO levels. Contrary to common belief, we identified that in the general population, smoking is inversely associated with EPO levels. Future mechanistic insight is needed to unravel the currently identified association, and if reproduced in other studies, guidelines for diagnosis of secondary erythrocytosis may need to be revisited. PMID- 29502562 TI - Younger Adults Initiating Hemodialysis: Antidepressant Use for Depression Associated With Higher Health Care Utilization. AB - OBJECTIVE: To examine associations between antidepressant use and health care utilization in young adults beginning maintenance hemodialysis (HD) therapy. PATIENTS AND METHODS: Antidepressant use, hospitalizations, and emergency department (ED) visits were examined in young adults (N=130; age, 18-44 years) initiating HD (from January 1, 2001, through December 31, 2013) at a midwestern US institution. Primary outcomes included hospitalizations and ED visits during the first year. RESULTS: Depression diagnosis was common (47; 36.2%) at HD initiation, yet only 28 patients (21.5%) in the cohort were receiving antidepressant therapy. The antidepressant use group was more likely to have diabetes mellitus (18 [64.3%] vs 33 [32.4%]), coronary artery disease (8 [28.6%] vs 12 [11.8%]), and heart failure (9 [32.1%] vs 15 [14.7%]) (P<.05 for all) than the untreated group. Overall, 68 (52.3%) had 1 or more hospitalizations and 33 (25.4%) had 1 or more ED visits in the first year. The risk of hospitalization during the first year was higher in the antidepressant use group (hazard ratio, 2.35; 95% CI, 1.39-3.96; P=.001), which persisted after adjustment for diabetes, coronary artery disease, and heart failure (hazard ratio, 1.94; 95% CI, 1.22 3.10; P=.006). Emergency department visit rates were similar between the groups. CONCLUSION: Depression and antidepressant use for mood indication are common in young adult incident patients initiating HD and and are associated with higher hospitalization rates during the first year. Further research should determine whether antidepressants are a marker for other comorbidities or whether treated depression affects the increased health care use in these individuals. PMID- 29502564 TI - How Good Intentions Contributed to Bad Outcomes: The Opioid Crisis. AB - The opioid crisis that exists today developed over the past 30 years. The reasons for this are many. Good intentions to improve pain and suffering led to increased prescribing of opioids, which contributed to misuse of opioids and even death. Following the publication of a short letter to the editor in a major medical journal declaring that those with chronic pain who received opioids rarely became addicted, prescriber attitude toward opioid use changed. Opioids were no longer reserved for treatment of acute pain or terminal pain conditions but now were used to treat any pain condition. Governing agencies began to evaluate doctors and hospitals on their control of patients' pain. Ultimately, reimbursement became tied to patients' perception of pain control. As a result, increasing amounts of opioids were prescribed, which led to dependence. When this occurred, patients sought more in the form of opioid prescriptions from providers or from illegal sources. Illegal, unregulated sources of opioids are now a factor in the increasing death rate from opioid overdoses. Stopping the opioid crisis will require the engagement of all, including health care providers, hospitals, the pharmaceutical industry, and federal and state government agencies. PMID- 29502565 TI - Practical Strategies for Engaging Individuals With Obesity in Primary Care. AB - Although widely recognized as a chronic disease that requires long-term, structured, and multidisciplinary management, obesity remains largely underdiagnosed and undertreated. The prevalence of obesity continues to increase dramatically, with the highest rates seen in the United States. Despite the availability of several clinical practice guidelines, published studies suggest that health care professionals (HCPs) infrequently and inconsistently follow guideline recommendations. Barriers to HCP participation in obesity management are likely to inhibit obesity counseling in primary care. Improving HCP obesity related practices and counseling is important. This article discusses current practices, barriers to effective obesity management, and recommendations to improve HCP obesity management and counseling, based on findings from a PubMed search and clinical experience. The aim of the article is to share best-practice strategies for engaging patients. PMID- 29502566 TI - Aerobic Exercise: Evidence for a Direct Brain Effect to Slow Parkinson Disease Progression. AB - No medications are proven to slow the progression of Parkinson disease (PD). Of special concern with longer-standing PD is cognitive decline, as well as motor symptoms unresponsive to dopamine replacement therapy. Not fully recognized is the substantial accumulating evidence that long-term aerobic exercise may attenuate PD progression. Randomized controlled trial proof will not be forthcoming due to many complicating methodological factors. However, extensive and diverse avenues of scientific investigation converge to argue that aerobic exercise and cardiovascular fitness directly influence cerebral mechanisms mediating PD progression. To objectively assess the evidence for a PD exercise benefit, a comprehensive PubMed literature search was conducted, with an unbiased focus on exercise influences on parkinsonism, cognition, brain structure, and brain function. This aggregate literature provides a compelling argument for regular aerobic-type exercise and cardiovascular fitness attenuating PD progression. PMID- 29502567 TI - Atrial Fibrillation: Beyond Rate Control. AB - Atrial fibrillation is the most common cardiac dysrhythmia encountered in the primary care setting. Although a rate control strategy is pursued by physicians for the initial treatment of atrial fibrillation, the efficacy of a rhythm control approach is often undervalued despite offering effective treatment options. There are many pharmacological therapies available to patients, with drug choice often dictated by safety concerns (toxicities and proarrhythmic adverse effects) as well as patient characteristics and comorbidities. This article presents a simplified approach to understanding the rhythm control strategy, including the advantages and disadvantages of various antiarrhythmic drugs and common drug-drug interactions encountered in the primary care setting. PMID- 29502568 TI - COL1A1 Mutations Presenting as Descending Perineum Syndrome in a Young Patient With Hypermobility Syndrome. AB - A 22-year-old woman presented with 12 years of progressive constipation; she had increased joint flexibility, hyperextensible skin, and excessive perineal descent on examination. Radiological studies confirmed evidence of rectal evacuation disorder due to descending perineum syndrome, enterocele, and rectocele. In a wide genetic screen (~611,000 single nucleotide polymorphisms), 4 variations were identified in COL1A1 gene ([rs72656352, Chr17: 50,185,535-50,185,539, deletion], [rs72654794, Chr17: 50,188,575, deletion], [rs72667023, Chr17: 50,198,170, deletion], [rs67828806, Chr17: 50,198,177 G->C]). These mutations result in an increase in the number of base pairs in the C' end, as well as replacement of the glycine amino acid in the N' end, leading to incomplete cleavage of procollagen by proteases and resulting in collagen weakness. Our observations suggest that COL1A1 gene mutations are plausible biological factors predisposing to descending perineum syndrome in association with joint hypermobility in this patient. PMID- 29502569 TI - Serum Calcium and Risk of Sudden Cardiac Arrest in the General Population. PMID- 29502570 TI - In Reply-Serum Calcium and Risk of Sudden Cardiac Arrest in the General Population. PMID- 29502571 TI - Preexposure Prophylaxis Is for Women, Too. PMID- 29502561 TI - MyD88 and TLR4 Expression in Epithelial Ovarian Cancer. AB - OBJECTIVE: To evaluate myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 (TLR4) expression in relation to clinical features of epithelial ovarian cancer, histologic subtypes, and overall survival. PATIENTS AND METHODS: We conducted centralized immunohistochemical staining, semi quantitative scoring, and survival analysis in 5263 patients participating in the Ovarian Tumor Tissue Analysis consortium. Patients were diagnosed between January 1, 1978, and December 31, 2014, including 2865 high-grade serous ovarian carcinomas (HGSOCs), with more than 12,000 person-years of follow-up time. Tissue microarrays were stained for MyD88 and TLR4, and staining intensity was classified using a 2-tiered system for each marker (weak vs strong). RESULTS: Expression of MyD88 and TLR4 was similar in all histotypes except clear cell ovarian cancer, which showed reduced expression compared with other histotypes (P<.001 for both). In HGSOC, strong MyD88 expression was modestly associated with shortened overall survival (hazard ratio [HR], 1.13; 95% CI, 1.01-1.26; P=.04) but was also associated with advanced stage (P<.001). The expression of TLR4 was not associated with survival. In low-grade serous ovarian cancer (LGSOC), strong expression of both MyD88 and TLR4 was associated with favorable survival (HR [95% CI], 0.49 [0.29-0.84] and 0.44 [0.21-0.89], respectively; P=.009 and P=.02, respectively). CONCLUSION: Results are consistent with an association between strong MyD88 staining and advanced stage and poorer survival in HGSOC and demonstrate correlation between strong MyD88 and TLR4 staining and improved survival in LGSOC, highlighting the biological differences between the 2 serous histotypes. PMID- 29502572 TI - Correction. PMID- 29502573 TI - Perihilar Cholangiocarcinoma. PMID- 29502574 TI - Calcium Embolus to the Brain. PMID- 29502575 TI - Christian Albert Theodor Billroth: Founder of Abdominal Surgery. PMID- 29502576 TI - Wall Sculpture by Linda Leviton. AB - Recognizing the contribution art has had in the Mayo Clinic environment since the original Mayo Clinic Building was finished in 1914, Mayo Clinic Proceedings features some of the numerous works of art displayed throughout the buildings and grounds on Mayo Clinic campuses as interpreted by the author. PMID- 29502578 TI - Anatomy of the Volar Retinacular Elements of the Hand: A Unified Nomenclature. AB - Many investigators have described the anatomy of the volar retinacular structures of the hand over the last 60 years. As a result, multiple terms have been assigned to 1 anatomical structure and 1 name designated to more than 1 structure. Our purpose is to review the detailed anatomy and key components of the volar retinacular elements of the hand, their etymology, and their most recent descriptions. The objective also is to organize these structures into systems, which can be helpful for learners to assimilate into a practical anatomical guide. Lastly, the goal is to create a common nomenclature for identifying the volar retinacular structures of the hand in order to facilitate clear communication about them across languages. PMID- 29502577 TI - The Teleology of the Thumb: On Purpose and Design. AB - The Andrew J. Weiland Medal is presented by the American Society for Surgery of the Hand to a midcareer researcher dedicated to advancing patient care in the field of hand surgery. The Weiland Medal for 2017 was presented to the author at the annual meeting of the American Society for Surgery of the Hand. The purpose of this article is to present current evidence on how biomechanics and morphology influence the pathophysiology of thumb carpometacarpal joint osteoarthritis. PMID- 29502579 TI - Partial Wrist Denervation: The Evidence Behind a Small Fix for Big Problems. AB - Wrist denervation addresses symptomatic wrist pain without the morbidity and complication profile of more extensive surgical procedures aimed to correct the underlying pathology. The concept of wrist denervation is not new, but its practical application has been modified over the past 50 years. A variety of techniques have been described for various indications, with generally good results. In the United States, a simple, single incision partial denervation consisting of neurectomies of the anterior and posterior interosseous nerves is most commonly performed. Although data on this procedure are limited, most patients are satisfied with pain relief in the short term. There is no evidence that partial denervation procedures alter proprioception of the wrist, and this procedure shows promise as a good option for palliating pain without prolonged postoperative immobilization or leave from work. Preoperative injections do not seem to correlate well with postoperative results. Future studies are needed to assess the duration of relief and possible acceleration of underlying pathology. PMID- 29502580 TI - First Commentary on "Partial Wrist Denervation: The Evidence Behind a Small Fix for Big Problems". PMID- 29502581 TI - Second Commentary on "Partial Wrist Denervation: The Evidence Behind a Small Fix for Big Problems". PMID- 29502582 TI - Radialization With Ulnar Cuff Osteotomy: A Technique for Deformity Correction in Radial Longitudinal Deficiency. AB - Various procedures described for deformity correction in radial longitudinal deficiency (RLD) have encountered problems of stiffness, instability, and inadequate correction. Many surgical modifications of these procedures have still resulted in deformity recurrence, shortening, and damage to the epiphysis. To align the hand with the forearm, the deforming forces from both soft tissues and skeletal growth should be addressed without damaging the ulnar epiphysis or the carpus. To achieve this, we propose a metaphyseal ulnar cuff osteotomy during radialization. After soft tissue release, the overlap of carpus to ulna is shortened at the metaphysis in the form of a subperiosteal cuff along with additional tendon balancing. This procedure has helped us in correcting the deformity without damaging the epiphysis or the carpus and has maintained correction through the initial critical growth period of the child. PMID- 29502583 TI - Data Science: Big Data, Machine Learning, and Artificial Intelligence. PMID- 29502584 TI - "Radiology" Is Going Away . . . and That's Okay: Titles Change, A Profession Evolves. PMID- 29502585 TI - Role of Big Data and Machine Learning in Diagnostic Decision Support in Radiology. AB - The field of diagnostic decision support in radiology is undergoing rapid transformation with the availability of large amounts of patient data and the development of new artificial intelligence methods of machine learning such as deep learning. They hold the promise of providing imaging specialists with tools for improving the accuracy and efficiency of diagnosis and treatment. In this article, we will describe the growth of this field for radiology and outline general trends highlighting progress in the field of diagnostic decision support from the early days of rule-based expert systems to cognitive assistants of the modern era. PMID- 29502586 TI - [Editorial orientations for La Presse Medicale]. PMID- 29502587 TI - [Peripheral arterial disease in 2018]. PMID- 29502588 TI - Clinical Applications of Ultrasonic Enhancing Agents in Echocardiography: 2018 American Society of Echocardiography Guidelines Update. PMID- 29502589 TI - Intraoperative Two- and Three-Dimensional Transesophageal Echocardiography in Combined Myectomy-Mitral Operations for Hypertrophic Cardiomyopathy. AB - Transesophageal echocardiography is essential in guiding the surgical approach for patients with obstructive hypertrophic cardiomyopathy. Septal hypertrophy, elongated mitral valve leaflets, and abnormalities of the subvalvular apparatus are prominent features, all of which may contribute to left ventricular outflow tract obstruction. Surgery aims to alleviate the obstruction via an extended myectomy, often with an intervention on the mitral valve and subvalvular apparatus. The goal of intraoperative echocardiography is to assess the anatomic pathology and pathophysiology in order to achieve a safe intraoperative course and a successful repair. This guide summarizes the systematic evaluation of these patients to determine the best surgical plan. PMID- 29502590 TI - Echo Core Labs: Gold Standard or Fools' Gold? PMID- 29502591 TI - What is Twitter? How Do I Get Started? Why Should I Become a User? PMID- 29502592 TI - Sonographer Career Development. PMID- 29502593 TI - Evolution of Nuclear Medicine in the diagnosis and treatment of prostate cancer. PMID- 29502595 TI - Reducing the environmental impact of cataract surgery: Sustainability versus safety: A tradeoff? PMID- 29502594 TI - Interim PET Response-adapted Strategy in Untreated Advanced Stage Hodgkin Lymphoma: Results of GOELAMS LH 2007 Phase 2 Multicentric Trial. AB - BACKGROUND: Patients with advanced stage Hodgkin lymphoma still present unsatisfactory outcomes. PATIENTS AND METHODS: The Groupe d'etude des Leucemies Aigues et des Maladies du Sang (GOELAMS) group conducted a prospective multicentric trial (NCT00920153) for advanced stage Hodgkin lymphoma to evaluate a positron emission tomography (PET)-adapted strategy. Patients received an intensive regimen (VABEM [vindesine, doxorubicin, carmustine, etoposide, and methylprednisolone]) in front-line and interim 18FFDG-PET evaluation after 2 courses (PET-2). Patients with negative PET-2 findings received 1 additional course. Patients with positive PET-2 findings underwent early salvage therapy followed by high-dose therapy/autologous stem cell transplantation. RESULTS: Fifty-one patients were included. The final complete remission rate was 88%. With a median follow up of 5.3 years, 5-year event-free survival and overall survival rates were 75.3% and 85.3%, respectively, for the whole cohort. Patients who were PET-2-negative had 5-year event-free survival and overall survival rates of, respectively, 77.8% and 88.2% versus 85.1% and 91.7% for patients who were PET-2 positive. CONCLUSION: A PET-guided strategy with early salvage therapy and high dose therapy/autologous stem cell transplantation for patients with interim PET-2 positive findings is safe and feasible and provide similar outcome as patients with a negative PET-2. PMID- 29502596 TI - Retinal detachment after acute posterior vitreous detachment resulting from posterior chamber phakic intraocular lens implantation. AB - A 39-year-old woman presented with an early posterior vitreous detachment (PVD) after the implantation of an Implantable Collamer Lens phakic intraocular lens (pIOL). The patient detected PVD, noticing metamorphopsia early after surgery; it was confirmed with optical coherence tomography 5 days postoperatively. She was examined by a retinal expert, and no retinal tears were found. However, 15 days postoperatively, the patient had a retinal tear; 38 days later, a retinal detachment (RD) occurred despite treatment with argon laser photocoagulation. Prompt treatment and adequate patient cooperation achieved a final good uncorrected distance visual acuity (20/20). To our knowledge, this is the first description of the whole sequence involving early PVD leading to RD after pIOL implantation. This case highlights the importance of a fundus examination before and after surgery and of informing patients about the small chance of RD and visual symptoms. PMID- 29502597 TI - Descemet membrane endothelial keratoplasty for corneal decompensation caused by herpes simplex virus endotheliitis. AB - We report a case of corneal decompensation caused by recurrent herpetic endotheliitis that was treated successfully with Descemet membrane endothelial keratoplasty (DMEK). A 62-year-old woman presented with a history of recurrent herpetic infections in the right cornea. After topical and systemic treatment with antivirals and steroids for 5 months, DMEK combined with cataract surgery was performed. Two weeks after DMEK, the corrected distance visual acuity (CDVA) in the affected eye was 0.3 (20/60). One year postoperatively, the CDVA was 1.0 (20/20) and the slitlamp biomicroscopy showed no signs of graft rejection or herpetic recurrence. Corneal decompensation caused by herpetic endotheliitis used to be treated exclusively with penetrating keratoplasty. Descemet membrane endothelial keratoplasty combined with cataract surgery seems to be a favorable surgical option in the treatment of corneal endothelial decompensation after recurrent herpetic endotheliitis. PMID- 29502599 TI - January consultation #2. PMID- 29502598 TI - Astigmatic overcorrection and axis flip for targeting minimal remaining refractive astigmatism with toric intraocular lenses. PMID- 29502600 TI - Coincident cataract and glaucoma surgery in an anticoagulated patient: January consultation #1. PMID- 29502601 TI - January consultation #3. PMID- 29502602 TI - January consultation #4. PMID- 29502603 TI - January consultation #5. PMID- 29502604 TI - January consultation #6. PMID- 29502605 TI - January consultation #7. PMID- 29502606 TI - Editor's Comment. PMID- 29502607 TI - Steroid-induced ocular hypertension after photorefractive keratectomy. PMID- 29502608 TI - Reply. PMID- 29502609 TI - Reply. PMID- 29502611 TI - Erratum. PMID- 29502610 TI - Discrepancy in statistical analysis of pediatric cataract surgery comparative study. PMID- 29502612 TI - Erratum. PMID- 29502613 TI - Wang-Koch formula for optimization of intraocular lens power calculation: Evaluation at a Canadian center. AB - PURPOSE: To externally validate the Wang-Koch method for optimization of intraocular lens (IOL) formulas. SETTING: TLC Laser Eye Centre, Mississauga, Ontario, Canada. DESIGN: Retrospective case series. METHODS: Consecutive cataract patients with an axial length (AL) of 25.0 mm or longer were recruited. The predicted postoperative spherical equivalents (SEs) calculated from the Holladay 1 formula were compared with the 3-week postoperative SEs to yield prediction errors for Wang-Koch adjusted and unadjusted ALs. A mixed linear model was used to compare the proportion of eyes with a prediction error of +/-0.25 diopter (D) or worse, +/-0.50 D or worse, and +/-1.00 D or worse between groups. The secondary outcomes of mean absolute error and median absolute error were also analyzed. A subgroup analysis was performed based on AL subgroups. RESULTS: Two hundred sixty-two eyes were selected for inclusion with a balanced sex distribution, a mean age of 62.49 years +/- 9.13 (SD), and a preoperative AL of 26.49 +/- 1.10 mm. Subgroup prediction error comparisons of +/-0.50 D or worse favored unadjusted eyes with ALs between 25.0 mm and 26.0 mm (n = 105; P < .001), no difference in eyes with ALs between 26.0 mm and 27.0 mm (n = 91; P = .43), adjusted eyes with ALs between 27.0 mm and 28.0 mm (n = 36; P = .003), and adjusted eyes with ALs of 28.00 mm or longer (n = 30; P < .001). CONCLUSION: The Wang-Koch adjustment should only be applied in eyes with ALs longer than 27.0 mm that have IOL power calculation with the Holladay 1 formula. PMID- 29502614 TI - Toxic retinopathy after phacoemulsification when the cefuroxime dilution is correct. AB - PURPOSE: To determine the clinical characteristics and outcomes of patients with toxic retinopathy after phacoemulsification and intraocular lens implantation when the correct cefuroxime dilution is administered. SETTING: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China. DESIGN: Prospective case series. METHODS: Patients developing toxic retinopathy after phacoemulsification between January 2016 and April 2017 were observed. All patients received an anterior chamber injection of correctly diluted cefuroxime at the end of the surgery. RESULTS: The study evaluated 20 patients (20 eyes). At the 1-day follow-up, the mean logarithm of the minimum angle of resolution (logMAR) corrected distance visual acuity (CDVA) decreased to 0.78 logMAR +/- 0.31 (SD) with no significant difference compared with the preoperative CDVA of 0.71 +/- 0.34 logMAR (P = .535). Spectral-domain optical coherence tomography (SD-OCT) showed cystoid macular edema (CME) with extensive serous neurosensory retinal detachment (RD) at the posterior pole. At the 1-week follow-up, the mean CDVA improved to 0.13 +/- 0.80 logMAR and the improvement was significant compared with the preoperative and 1-day postoperative logMAR CDVA (P < .001). The SD-OCT showed regression of CME and recovery of RD. CONCLUSIONS: When the drug dilution is correct, there is still a possibility of sporadic cefuroxime toxic maculopathy after intracameral injection of cefuroxime. This toxicity might be related to transient retinal pigment epithelium sodium potassium pump dysfunction resulting from a large injection volume of a standard dose concentration or individual differences in conventional drug dose tolerance. PMID- 29502615 TI - Small-aperture corneal inlay repositioning. AB - We describe a technique used to recenter a small-aperture corneal inlay (Kamra). Repositioning the inlay is performed to achieve the best presbyopic correction while maintaining distance visual acuity. PMID- 29502616 TI - Supervised resident manual small-incision cataract surgery outcomes at large urban United States residency training program. AB - PURPOSE: To examine the outcomes of resident-performed manual small-incision cataract surgery (SICS) in an urban academic setting. SETTING: Parkland Memorial Hospital, Dallas, Texas, USA. DESIGN: Retrospective case series. METHODS: Manual SICS was used only in selected cases for which phacoemulsification was expected to be difficult, namely for mature or brunescent cataracts, traumatic cataracts, and pseudoexfoliation syndrome or other causes of zonular weakness. All manual SICS cases performed by resident physicians as the primary surgeon over a 5-year period were reviewed. Postoperative visual acuity, intraoperative complications, and early postoperative complications were the main outcomes measured. RESULTS: For the 52 cases identified, the mean preoperative visual acuity was 2.165 logarithm of the minimum angle of resolution (logMAR) +/- 0.141 (SD) (95% confidence interval) (slightly better than had motion acuity), improving to 0.278 +/- 0.131 logMAR (Snellen 20/38) corrected visual acuity postoperatively. Of the 52 cases, the most frequent intraoperative complications were iris prolapse (5 cases [9.6%]) and zonular dialysis (4 cases [7.7%]), with vitreous loss occurring in 1 case (1.9%). The most frequent postoperative complications were cystoid macular edema (3 cases [5.8%]), retained ophthalmic viscosurgical device (2 cases [3.8%]), intraocular lens displacement (2 cases [3.8%]), and microhyphema (2 cases [3.8%]). CONCLUSIONS: Although the more advanced wound construction in manual SICS might be challenging to surgeons unfamiliar with the technique, it was a safe and efficacious technique in the hands of learning residents. With several advantages over phacoemulsification, such as cost and ability to remove very dense nuclei, manual SICS will play a valuable role in modern cataract surgery. PMID- 29502617 TI - Trabecular microbypass stents as minimally invasive approach after conventional glaucoma filtration surgery. AB - PURPOSE: To evaluate long-term efficacy and safety of 2 trabecular microbypass stents in patients with advanced primary open-angle glaucoma (POAG) and insufficient intraocular pressure (IOP) after previous filtration surgery. SETTING: Vivantes Klinikum Neukolln, Augenklinik, Berlin, Germany. DESIGN: Retrospective case series. METHODS: Eyes with uncontrolled and advanced POAG since 2014 were assessed. All eyes previously had at least 1 filtration surgery procedure. The anatomical landmarks and configuration of the anterior chamber angle had to be identified easily. Two iStents were placed nasally into Schlemm canal. RESULTS: The study comprised 42 patients (42 eyes); 18 eyes had 1 previous glaucoma filtration surgery. During the follow-up of 12 months, the mean IOP in cases of primary failure of filtration surgery decreased from preoperative 23.8 mm Hg +/- 3.9 (SD) to 15.2 +/- 2.7 mm Hg. For cases with more than 1 previous filtration surgery, the mean IOP decreased from preoperative 26.1 +/- 5.7 mm Hg to 16.3 +/- 3.3 mm Hg. Medications were reduced from 2.7 +/- 0.9 to 2.0 +/- 1.1. No intraoperative or perioperative complications occurred. CONCLUSIONS: For eyes with previous filtration surgery and medically uncontrolled IOP, the implantation of 2 stents provided a minimally invasive and safe reduction of mean IOP to less than 18 mm Hg at 12 months. The number of medications was also reduced. PMID- 29502618 TI - Safety and efficacy of intravitreal injection of steroid and antibiotics in the setting of cataract surgery and trabecular microbypass stent. AB - PURPOSE: To evaluate the safety and efficacy of intravitreal administration of a steroid and antibiotics during cataract surgery compared with the typical postoperative topical regimen in preventing postoperative inflammation, pain, cystoid macular edema (CME), and endophthalmitis. SETTING: Private practice, Sioux Falls, South Dakota, USA. DESIGN: Retrospective case series. METHODS: The study group included eyes that had an intravitreal injection of triamcinolone moxifloxacin-vancomycin at the time of cataract surgery with concomitant trabecular microbypass stent insertion. The control eyes had the same procedure but were prescribed topical antibiotics, steroids, and nonsteroidal antiinflammatory drugs postoperatively. Data were recorded preoperatively and 1 day, 1 week, 1 month, and 3 months postoperatively. Primary outcomes included the number of glaucoma medications, intraocular pressure (IOP), and IOP spikes of at least 15 mm Hg from baseline. RESULTS: There were 234 eyes in the study group and 249 eyes in the control group. The mean reduction in glaucoma medications was 0.24 drops in the study group and 0.80 drops in the control group 3 months postoperatively, whereas the mean IOP reduction was 2.59 mm Hg in the study group and 3.63 mm Hg in the control group. Pressure spikes were detected at 54 (5.7%) of 936 postoperative visits in the study group and at 37 (3.7%) of 996 visits in the control group. There were no cases of severe inflammation, CME, infection, or retinal detachments. CONCLUSIONS: Both groups had similar postoperative pressure reductions and incidence of IOP spikes. The results indicate that intravitreal injections of a steroid and antibiotics might be a safe option for glaucomatous eyes having cataract surgery with trabecular microbypass stent insertion. PMID- 29502619 TI - Surgical management of negative dysphotopsia. AB - PURPOSE: To evaluate curative and preventative surgical strategies for negative dysphotopsia. SETTING: Private practice, Los Angeles, California, USA. DESIGN: Retrospective case series. METHODS: Patients with self-reported chronic negative dysphotopsia had corrective surgery as the therapeutic group. Second eye surgery, in cases with negative dysphotopsia in the previously operated eye, comprised the preventative group. Chronologically, several surgical strategies were used, including bag-to-bag intraocular lens (IOL) exchange, reducing posterior chamber depth, piggyback secondary IOL placement, bag-to-sulcus IOL exchange, and reverse optic capture. The primary outcome measure was improvement of negative dysphotopsia by 3 months postoperatively. RESULTS: The therapeutic group comprised 40 eyes of 37 patients; 76.6% of causative IOLs were acrylic and 23.4% were silicone and all were bag-fixated. There were 21 eyes in the preventative group of which 11 were second eyes from the therapeutic group; the remaining 10 did not require surgery for the symptomatic eye. Successful outcomes for each surgical strategy were as follows: bag-to-bag IOL exchange (0/5), a reduction in posterior chamber depth with iris suture fixation of the bag-haptic complex (0/1), piggyback secondary IOL (8/11), secondary reverse optic capture (21/22), ciliary sulcus posterior chamber IOL exchange (7/8), and primary reverse optic capture (21/21). CONCLUSIONS: Negative dysphotopsia was associated with acrylic or silicone IOLs of either square- or round-edge design. Negative dysphotopsia was reduced, eliminated, or prevented when the IOL optic overlaid the anterior capsulotomy rather than when the capsule edge overlaid the optic. Bag-to-sulcus IOL exchange and reverse optic capture were highly successful in managing or preventing negative dysphotopsia. PMID- 29502620 TI - Repeatability and reliability of ectasia display and topometric indices with the Scheimpflug system in normal and keratoconic eyes. AB - PURPOSE: To evaluate the repeatability and reliability of Belin-Ambrosio Enhanced Ectasia Display-III indices and topometric indices with a Scheimpflug system (Pentacam HR) in normal eyes and keratoconic eyes. SETTING: Ulucanlar Eye Research and Training Hospital, Ankara, Turkey. DESIGN: Prospective case series. METHODS: The same operator performed 3 consecutive successive measurements with the Scheimpflug device in the eyes of patients with keratoconus (keratoconus group) and healthy volunteers (normal group). The keratoconus group was further classified into the following 3 subgroups according to the topographic keratoconus classification: early, moderate, and severe. One eye of each volunteer was assigned randomly to a repeatability test. The maximum keratometry (K), 6-parameter topometric indices, and 9 parameter ectasia display indices were recorded. The within-subject standard deviation, precision, repeatability indices, coefficient of variation, and intraclass correlation coefficient (ICC) values were calculated for repeatability and reliability assessments. RESULTS: There were 100 patients in the keratoconus group and 100 healthy volunteers in the normal group. The maximum K, topometric indices except for index of height asymmetry, ectasia display indices except for deviation of normality of the front elevation, and deviation of normality of the back elevation were repeatable in normal eyes and keratoconic eyes. The repeatability indices of all parameters increased as the severity of keratoconus increased. The maximum K value and all indices showed good to excellent reliability in both groups (ICC values between 0.750 and 1.0 for all values). CONCLUSION: The maximum K value, most topometric indices, and ectasia display indices were repeatable and reliable in normal eyes and keratoconic eyes. PMID- 29502621 TI - Direct measurement of anterior corneal curvature changes attributable to epithelial removal in keratoconus. AB - PURPOSE: To compare the tomography of the corneal epithelium and Bowman layer in eyes with moderate to severe keratoconus before and after epithelial debridement. SETTING: University hospital tertiary referral center. DESIGN: Prospective case series. METHODS: Dual-channel Scheimpflug combined with Placido-disk tomography was used to measure the corneal variables in eyes with keratoconus having corneal crosslinking immediately before and after epithelial debridement. The differences in pachymetry, axial keratometry, astigmatism magnitude, asphericity, total corneal power, and spherical aberrations were computed. RESULTS: The study comprised 30 eyes of 30 patients. After epithelial removal, the central (0.0 to 4.0 mm) and midperipheral (4.0 to 7.0 mm) corneal zones were significantly thinner mean (21 MUm +/- 14 [SD] and 35 +/- 44 MUm, respectively). The mean anterior axial flat keratometry (K) (+1.71 diopters [D]), steep K (+2.14 D), maximum K (+2.13 D), corneal astigmatism (+1.11 D), asphericity (-0.31), and total corneal power changes (+2.03 D) were significantly different after epithelial debridement. There were no significant changes in posterior corneal flat K or steep K, posterior corneal astigmatism, or posterior asphericity. There were no significant differences in the mean astigmatic axis (anterior or posterior corneal surface) or spherical aberration after epithelial debridement. CONCLUSIONS: In eyes with moderate to severe keratoconus, the tomography of Bowman layer was significantly steeper than that of the epithelium; thus, epithelial debridement increased the magnitude of anterior corneal keratometry, astigmatism, and prolateness. These data suggest that the corneal epithelium smooths the underlying Bowman layer irregularity in keratoconus. PMID- 29502622 TI - Comparison of visual outcomes and flap morphology using 2 femtosecond-laser platforms. AB - PURPOSE: To compare the 3-month postoperative refractive results and flap thickness homogeneity after correction of myopia using the Intralase femtosecond platform and the Victus dual femtosecond laser platform. SETTING: Novovision Clinic, Madrid, Spain. DESIGN: Prospective case series. METHODS: Eyes treated with a 60 kHz femtosecond laser (Group 1) and eyes treated with a dual femtosecond laser (Group 2) were included. The refractive results 3 months postoperatively were compared. The differences between the maximum and the minimum thickness point of each flap, the intraflap standard deviation (SD), and the achieved and the targeted central flap thickness were evaluated in each group. RESULTS: The study comprised 31 eyes in Group 1 and 20 eyes in Group 2. Three months postoperatively, the uncorrected distance visual acuity, residual refraction, efficacy, safety, and predictability were significantly better in Group 1. The dual femtosecond laser induced a significantly greater increase in higher-order aberrations than the conventional femtosecond laser. The mean central flap thickness was 123.2 MUm +/- 9.2 (SD) in Group 1 and 116.3 +/- 14.4 MUm in Group 2 (P = .005). The mean difference between the maximum and the minimum flap thickness points in each flap was significantly lower in Group 1 than in Group 2 (22 +/- 8.3 MUm versus 35.7 +/- 16.9 MUm) (P = .0007). The intraflap SD was significantly lower in Group 1 than in Group 2 (6.1 MUm versus 10.8 MUm) (P = .0001). CONCLUSION: The conventional femtosecond laser provided better efficacy, safety, predictability, and flap thickness homogeneity than the dual femtosecond laser for the correction of myopia. PMID- 29502623 TI - Refractive and visual outcomes after surgery for pediatric traumatic cataract. AB - PURPOSE: To describe refractive and visual outcomes of pediatric traumatic cataract requiring surgery and evaluate the factors influencing success. SETTING: Hospital for Sick Children, Toronto, Ontario, Canada. DESIGN: Retrospective case series. METHODS: Charts of children having lensectomy for traumatic cataract between January 1, 2000, and June 30, 2015, were reviewed for demographic information, visual and refractive outcomes, complications, and surgical details. RESULTS: One hundred six children (mean age 7.6 years +/- 3.9 [SD]) were included. The median follow-up was 41 months (range 3 to 155 months). Seventy nine children had open-globe injuries and 27 had closed-globe injuries. Patients with open-globe injuries were younger than those with closed-globe injuries (mean age 6.9 versus 10.4 years; P < .05). The final corrected distance visual acuity (CDVA) was 20/40 or better in 47 children. In the 94 children who had intraocular lens placement, 54% with open-globe injuries and 55% with closed-globe injuries achieved a mean absolute prediction error of 1.0 diopter or less in the early postoperative period. Open-globe injuries and amblyopia were associated with worse visual outcomes (odds ratio [OR], 2.8 and P = .03 versus OR, 2.4 and P = .04) and refractive outcomes (OR, 3.1 and P = .02 versus OR, 3.8 and P = .04). Age younger than 5 years was associated with worse refractive outcomes (OR, 2.88; P = .02). CONCLUSIONS: Children requiring surgery for traumatic cataract can have good visual and refractive outcomes. Those with open-globe and those with closed globe injuries both had good early postoperative refractive accuracy. Sixty-three percent of children with closed-globe injuries attained a CDVA of 20/40 or better at the final follow-up. PMID- 29502624 TI - Comparison of different types of phacoemulsification tips. III. Morphological changes induced after multiple uses in an ex vivo model. AB - PURPOSE: To assess the ultrastructural morphologic changes in the surface's micro roughness for single-use and multiple-use phaco tips after multiple phacoemulsification cycles in an ex vivo animal model. SETTING: John A. Moran Eye Center and Utah Nanofab, College of Engineering, University of Utah, Salt Lake City, Utah, USA. DESIGN: Experimental study. METHODS: Eight types of phaco tips were studied using an identical experimental protocol. Two tips of each type were used to emulsify porcine cataractous lenses of moderate hardness for 2 minutes. This cycle was then repeated 5 consecutive times for each phaco tip. Scanning electron microscopy and white-light interferometry were used to analyze each tip for potential ultrastructural damage. RESULTS: No significant structural damage was noted on either single- or multiple-use tips after 5 cycles of experimental use. There was a trend toward increased surface micro-roughness at the tip opening after multiple procedures. Most tips had salt crystals on their surface and deposits of organic material composed of carbon and oxygen, which were consistent with porcine tissue that had not been cleaned from the tip surface. CONCLUSIONS: No significant ultrastructural damage was detected after repeated experimental use of phaco tips in a porcine cataract model. There was no significant difference when phaco tips labeled for single use or multiple uses were compared. PMID- 29502625 TI - Histopathological trabecular meshwork remodeling after cataract surgery detected with an advanced image analyzer. AB - PURPOSE: To compare the histopathological morphometry of the trabecular meshwork and ciliary processes in pseudophakic eyes and phakic eyes using advanced image analyzer technology. SETTING: McGill University, Montreal, Quebec, Canada. DESIGN: Retrospective case series. METHODS: Thirty-five pseudophakic eyes and 25 phakic eyes were sectioned and converted into digital slides. The total trabecular meshwork area and the ciliary body stroma were demarcated. The area of the trabecular meshwork, cellular and noncellular trabecular meshwork compartments, trabecular space, distance from scleral spur to inner uveal trabecular portion, and degree of fibrosis of the ciliary processes were evaluated. RESULTS: The trabecular meshwork area was larger in the pseudophakic group than the phakic group (P = .03). Furthermore, a trend of larger trabecular space recorded was seen in the pseudophakic group than the phakic group (P = .14). No differences in the proportion of cellular (P = .88) and noncellular trabecular meshwork compartments (P = .4) were seen between groups. The scleral spur to inner uveal trabecular portion distance was longer in the pseudophakic group than the phakic group (P = .008) and correlate with the trabecular meshwork area (P = .0001, r = 0.56). In the ciliary processes, a higher degree of fibrosis was measured in the pseudophakic group than the phakic group (P = .02). CONCLUSIONS: There were significant histopathological changes in the trabecular meshwork and higher fibrosis in the ciliary processes in pseudophakic eyes compared with phakic eyes. These findings support the hypothesis that trabecular meshwork remodeling after cataract surgery is involved in lowering intraocular pressure. PMID- 29502626 TI - Improving Human Papillomavirus Vaccination in the United States: Executive Summary. PMID- 29502627 TI - Can School-Located Vaccination Have a Major Impact on Human Papillomavirus Vaccination Rates in the United States? AB - School-local vaccination (SLV) has been a highly effective method of increasing rates of human papillomavirus (HPV) vaccination in many countries internationally in which vaccines are purchased by national, regional, or local public health authorities and offered free of charge within schools. However, the effectiveness of SLV for increasing HPV vaccination rates in the United States is likely to be substantially limited due to a number of identified barriers, the most significant of which is with the need to bill for vaccines among adolescents not covered under the Vaccines for Children Program. HPV vaccination within school based health centers (SBHCs) has been much more effective than SLV, but SBHCs exist in only 2% of schools in the United States. The opportunity gap between the United States and other countries will remain unless reimbursement issues related to HPV delivery in schools can be addressed in a sustainable manner or SBHCs become much more common. PMID- 29502628 TI - Creating a National Coalition to Increase Human Papillomavirus Vaccination Coverage. PMID- 29502629 TI - Advancing Human Papillomavirus Vaccine Delivery: 12 Priority Research Gaps. PMID- 29502630 TI - The End of Human Papillomavirus Vaccine Exceptionalism. PMID- 29502631 TI - Social Media in the Exam Room: Stories of Human Papillomavirus Disease and Prevention. PMID- 29502632 TI - Beyond the Statistics: What HPV Means to Women's Lives. PMID- 29502633 TI - Human Papillomavirus Vaccination: Narrative Review of Studies on How Providers' Vaccine Communication Affects Attitudes and Uptake. AB - The burden of human papillomavirus (HPV) infections is substantial, causing thousands of cancers and deaths in the United States yearly. Safe and effective vaccines exist, yet remains underutilized, particularly among younger adolescents for whom the vaccine is targeted. Provider communication techniques are known to affect parents' and adolescents' acceptance of this vaccine. In this review, we examine the influence that provider communication techniques have on parental attitudes regarding HPV vaccine, as well as how those techniques affect vaccination uptake. We explore the limited literature that has directly measured the influence of provider communication techniques on parental attitudes, which suggests that the strength of a provider recommendation strongly influences parents' perceptions regarding the safety of HPV vaccine, and that brief recommendations might be best for parents without significant concerns. We also review the literature regarding the use of so-called 'presumptive' recommendations, and how these types of recommendations are associated with increased HPV vaccine uptake. Finally, we present new information regarding the use of motivational interviewing as a provider communication technique to improve vaccination uptake, particularly among vaccine-hesitant parents. We close with suggestions for 'best practices' that include using brief, strong, unambiguous language to introduce the HPV vaccine, followed by more nuanced communication techniques, such as motivational interviewing, when encountering resistance. PMID- 29502634 TI - Evaluation of Pediatric Human Papillomavirus Vaccination Provider Counseling Written Materials: A Health Literacy Perspective. AB - BACKGROUND AND OBJECTIVES: Despite recommendations supporting human papillomavirus (HPV) vaccination, pediatric vaccination rates remain suboptimal in the United States; lack of tools to support provider counseling is one barrier. We sought to evaluate HPV-related counseling materials for readability, suitability, and content, and assess parent perceptions of materials, using a health literacy perspective. METHODS: A systematic search was conducted for written materials developed for HPV vaccination counseling by examining state Department of Health Web sites and associated links to local and national organizations. Materials were assessed for the following: 1) readability (Flesch Reading Ease, Flesch-Kincaid, Gunning Fog, Simple Measure of Gobbledygook, Fry), 2) suitability (understandability and actionability) (Suitability Assessment of Materials; Patient Education Materials Assessment Tool for Printable Materials), and 3) coverage of 8 key content areas (recommended by Centers for Disease Control and Prevention). Semistructured interviews were conducted with English speaking parents or caregivers of children 9 to 17 years of age from 3 pediatric clinics (New York, Ohio, Illinois) serving predominantly low-income families to assess perceptions and usefulness of 4 handouts selected for review. RESULTS: Thirty-eight documents were assessed. Mean +/- standard deviation (SD) reading grade level was 9.4 +/- 2; 10.5% (n = 4) had a reading level of 6th grade or below; 68.4% (n = 26) were considered not suitable. Mean understandability was 41.7% and mean actionability was 20.7%. Only 5.3% (n = 2) addressed all 8 content areas mean +/- SD (number of areas = 6.7 +/- 1.2). Brochure comprehensiveness and inclusion of a personal story were cited as factors that would be helpful in influencing parents to vaccinate against HPV. CONCLUSIONS: Few written materials for HPV vaccination counseling were optimal from a health literacy best practices perspective. Content comprehensiveness was important for informed decision making. PMID- 29502635 TI - Ten Years of Human Papillomavirus Vaccination in the United States. AB - Since human papillomavirus (HPV) vaccine was first introduced for females in the United States in 2006, vaccination policy has evolved as additional HPV vaccines were licensed and new data became available. The United States adopted a gender neutral routine HPV immunization policy in 2011, the first country to do so. Vaccination coverage is increasing, although it remains lower than for other vaccines recommended for adolescents. There are various reasons for low coverage, and efforts are ongoing to increase vaccine uptake. The safety profile of HPV vaccine has been well established from 10 years of postlicensure monitoring. Despite low coverage, the early effects of the HPV vaccination program have exceeded expectations. PMID- 29502637 TI - Synergistically Improving Resident Education and Rates of Human Papillomavirus Vaccination. PMID- 29502636 TI - Parents Who Decline HPV Vaccination: Who Later Accepts and Why? AB - OBJECTIVE: Parental declination contributes to low human papillomavirus (HPV) vaccination coverage among US adolescents, resulting in missed opportunities for cancer prevention. We sought to characterize parents' acceptance of HPV vaccination after declination ("secondary acceptance"). METHODS: In September 2016, we conducted an online survey with a national sample of parents of children ages 11 to 17 years. For those who reported having ever declined HPV vaccination for their children (n = 494), our survey assessed whether they accepted the vaccine at a subsequent visit. We used multivariable logistic regression to assess correlates of secondary acceptance. RESULTS: Overall, 45% of parents reported secondary acceptance of HPV vaccination, and an additional 24% intended to vaccinate in the next 12 months. In multivariable analyses, secondary acceptance was associated with receiving follow-up counseling about HPV vaccination from a health care provider (odds ratio, 2.16; 95% confidence interval, 1.42-3.28). However, only 53% of parents overall reported receiving such counseling. Secondary acceptance was also associated with receiving a higher quality HPV vaccine recommendation from a provider during the initial discussion and greater satisfaction with provider communication, as well as higher vaccination confidence. Among the reasons for secondary acceptance, parents most commonly reported the child getting older (45%), learning more about HPV vaccine (34%), and receiving a provider recommendation (33%). CONCLUSIONS: Our findings suggest secondary acceptance of HPV vaccination is common, with more than two thirds of parents in this national sample accepting or intending to accept HPV vaccination after declination. Providers should seek to motivate secondary acceptance by delivering repeated, high-quality recommendations for HPV vaccination. PMID- 29502639 TI - US Health Care Clinicians' Knowledge, Attitudes, and Practices Regarding Human Papillomavirus Vaccination: A Qualitative Systematic Review. AB - Clinicians' recommendation for the human papillomavirus (HPV) vaccine appears to be an important driver of parental decisions about vaccination. Our aim was to synthesize the best available evidence exploring the perceptions and experiences regarding HPV vaccination, from the perspective of the US clinician. We conducted a comprehensive literature search of Academic Search Complete, CINAHL Plus, Communication & Mass Media Complete, Consumer Health Complete (EBSCOhost), ERIC, Health and Psychosocial Instruments, MEDLINE with full text, and PsycINFO databases. We identified 60 eligible articles: 48 quantitative and 12 qualitative. We extracted the following information: study purpose, use of theory, location, inclusion criteria, and health care provider classification. Results were organized into 5 categories: 1) clinicians' knowledge and beliefs about HPV and the HPV vaccine, 2) clinicians' attitudes and beliefs about recommending HPV vaccines, 3) clinicians' intention to recommend HPV vaccines, 4) clinicians' professional practices regarding HPV vaccination, and 5) patient HPV vaccination rates. Although clinicians were generally supportive of HPV vaccination, there was a discrepancy between clinicians' intentions, recommendation practices, and patient vaccination rates. Studies reported that clinicians tended not to provide strong, consistent recommendations, and were more likely to recommend HPV vaccines to girls versus boys and to older versus younger adolescents. Analyses revealed a number of facilitating factors and barriers to HPV vaccination at the clinician, parent/patient, and systems levels, including clinician knowledge, clinician beliefs, and office procedures that promote vaccination. This review provides an evidence base for multilevel interventions to improve clinician HPV vaccine recommendations and vaccination rates. PMID- 29502638 TI - A Learning Collaborative Model to Improve Human Papillomavirus Vaccination Rates in Primary Care. AB - OBJECTIVE: Human papillomavirus (HPV) vaccination rates remain low, in part because of missed opportunities (MOs) for vaccination. We used a learning collaborative quality improvement (QI) model to assess the effect of a multicomponent intervention on reducing MOs. METHODS: Study design: pre-post using a QI intervention in 33 community practices and 14 pediatric continuity clinics over 9 months to reduce MOs for HPV vaccination at all visit types. MEASURES: outcome measures comprised baseline and postproject measures of 1) MOs (primary outcome), and 2) HPV vaccine initiation and completion. Process measures comprised monthly chart audits of MOs for HPV vaccination for performance feedback, monthly Plan-Do-Study-Act surveys and pre-post surveys about office systems. INTERVENTION: providers were trained at the start of the project on offering a strong recommendation for HPV vaccination. Practices implemented provider prompts and/or standing orders and/or reminder/recall if desired, and were provided monthly feedback on MOs to assess their progress. ANALYSES: chi square tests were used to assess changes in office practices, and logistic regression used to assess changes in MOs according to visit type and overall, as well as HPV vaccine initiation and completion. RESULTS: MOs overall decreased (from 73% to 53% in community practices and 62% to 55% in continuity clinics; P < .01, and P = .03, respectively). HPV vaccine initiation increased for both genders in community practices (from 66% to 74% for female, 57% to 65% for male; P < .01), and for male patients in continuity clinics (from 68% to 75%; P = .05). Series completion increased overall in community practices (39% to 43%; P = .04) and for male patients in continuity clinics (from 36% to 44%; P = .03). CONCLUSIONS: Office systems changes using a QI model and multicomponent interventions decreased rates of MO for HPV vaccination and increased initiation and completion rates among some gender subgroups. A learning collaborative model provides an effective forum for practices to improve HPV vaccine delivery. PMID- 29502640 TI - Simple and Elaborated Clinician Reminder Prompts for Human Papillomavirus Vaccination: A Randomized Clinical Trial. AB - OBJECTIVE: To evaluate the effects of simple and elaborated health care provider (HCP) reminder prompts on human papillomavirus (HPV) vaccine initiation rates. METHODS: Twenty-nine pediatric HCPs serving 5 pediatric clinics were randomized to 1 of 3 arms: 1) usual practice control, 2) simple reminder prompt, and 3) elaborated reminder prompt, which included suggested language for recommending the early adolescent platform vaccines. Prompts were delivered via a computer based clinical decision support system deployed in the 5 clinics. Eligible patients were ages 11 to 13 years, had not received HPV vaccine, and were due for meningococcal ACWY (MenACWY) vaccine and/or the tetanus, diphtheria, and pertussis booster (Tdap). Receipt of HPV vaccine was determined via automated queries sent to the Indiana immunization registry. Data were analyzed via logistic regression models, with generalized estimating equations used to account for the clustering of patients within HCPs. RESULTS: Ten HCPs in the control group saw 301 patients, 8 HCPs in the simple prompt group saw 124, and 11 HCPs in the elaborated prompt group saw 223. The elaborated prompt arm had a higher rate of HPV vaccination (62%) than the control arm (45%): adjusted odds ratio, 2.76; 95% confidence interval, 1.07 to 7.14. The simple prompt arm did not differ significantly from the control arm with respect to HPV vaccine initiation, which might have been because of the small sample size for this arm. MenACWY and Tdap rates did not vary across the 3 arms. CONCLUSIONS: Results suggest that an elaborated HCP-targeted reminder prompt, with suggested recommendation language, might improve rates of HPV vaccine initiation. PMID- 29502641 TI - Patterns of Primary Care Physician Visits for US Adolescents in 2014: Implications for Vaccination. AB - OBJECTIVE: Because most adolescent vaccinations are delivered in primary care, opportunities to vaccinate depend on the presence of visits and types of visits. We evaluated: 1) national visit patterns (having an annual preventive visit with a physician, provider type seen, visit types) for adolescents across the United States, and 2) the type of physician visits at which vaccines are administered for this age group. METHODS: We performed a secondary data set analysis of the 2014 Medical Expenditure Panel Survey. Data are collected through interviews of caregivers of a nationally representative sample of the noninstitutionalized US population. We used descriptive analyses to examine use of health care according to age and gender, and visit types at which vaccines were given according to age. RESULTS: During a 12-month period, almost half of participants had no primary care physician (PCP) visits, and one-third had a preventive visit to a PCP. An additional 19% had only nonpreventive care visits to a PCP. Uninsured participants had the highest rate of no care, and the lowest rate of preventive care. Most preventive care visits by adolescents 11 to 17 years of age were to pediatricians, and most visits among those 18 to 21 years of age were to family/general practitioners. Overall, 67% of non-check-up PCP visits were for acute care, 10% were for follow-up, and 7% for immunization only. Nationally, 61%, 26%, and 12% of vaccines were given at preventive, immunization-only, and acute/follow-up visits, respectively. CONCLUSIONS: Fewer than half of adolescents receive preventive care, and many have no PCP visits. This reinforces the need to offer outreach to adolescents to improve rates of preventive visits, and to take advantage of all primary care visits for vaccinations. Because pediatricians and family practice/general practice physicians vaccinate most adolescents, these providers should remain the target audience for vaccine education and quality improvement activities. PMID- 29502642 TI - Early Outcomes of a Multilevel Human Papillomavirus Vaccination Pilot Intervention in Federally Qualified Health Centers. AB - OBJECTIVE: Human papillomavirus (HPV) vaccine coverage in the United States remains low compared with other adolescent vaccines. As the largest primary care network in the United States, safety net clinics such as federally qualified health centers (FQHCs) serve patients at a disproportionate risk of HPV-related cancers. In this pilot project, the American Cancer Society (ACS) leveraged its primary care workforce to implement quality improvement interventions in the unique context of 30 FQHC systems across the country, including 130 clinic sites reaching >20,000 adolescents in a variety of geographic settings. METHODS: FQHC systems were randomly selected to receive either a $90,000 2-year grant, a $10,000 3-month grant, or training and technical assistance without funding. All 3 intervention groups conducted provider training and education, completed a capacity assessment tool, and measured HPV vaccination rates. Annual HPV vaccine series initiation and completion rates for active, 11- to 12-year-old patients were measured to evaluate project outcomes. RESULTS: HPV vaccine series initiation rates among 11- to 12-year-old patients increased by 14.6 percentage points from a baseline of 41.2% before the intervention (2014) to the intervention year (2015). Changes in HPV second dose and series completion rates were not statistically significant. Meningococcal and tetanus, diphtheria, and acellular pertussis vaccination rates also increased significantly, by 13.9 and 9.9 percentage points from baseline rates of 49.1% and 52.5%, respectively. CONCLUSIONS: The first year of this pilot project showed early success, particularly with HPV vaccine series initiation. On the basis of these promising results, ACS is expanding clinical quality improvement projects to increase HPV vaccination across the country. PMID- 29502643 TI - Human Papillomavirus Vaccine Coverage and Prevalence of Missed Opportunities for Vaccination in an Integrated Healthcare System. AB - BACKGROUND: Human papillomavirus (HPV) vaccination has been recommended in the United States for female and male adolescents since 2006 and 2011, respectively. Coverage rates are lower than those for other adolescent vaccines. The objective of this study was to evaluate an assessment and feedback intervention designed to increase HPV vaccination coverage and quantify missed opportunities for HPV vaccine initiation at preventive care visits. METHODS: We examined changes in HPV vaccination coverage and missed opportunities within the adolescent (11-17 years) population at 9 Oregon-based Kaiser Permanente Northwest outpatient clinics after an assessment and feedback intervention. Quarterly coverage rates were calculated for the adolescent populations at the clinics, according to age group (11-12 and 13-17 years), sex, and department (Pediatrics and Family Medicine). Comparison coverage assessments were calculated at 3 nonintervention (control) clinics. Missed opportunities for HPV vaccine initiation, defined as preventive care visits in which a patient eligible for HPV dose 1 remained unvaccinated, were examined according to sex and age group. RESULTS: An average of 29,021 adolescents were included in coverage assessments. Before the intervention, 1 dose and 3-dose quarterly coverage rates were increasing at intervention as well as at control clinics in both age groups. Postimplementation quarterly trends in 1-dose or 3-dose coverage did not differ significantly between intervention and control clinics for either age group. One-dose coverage rates among adolescents with Pediatrics providers were significantly higher than those with Family Medicine providers (56% vs 41% for 11- to 12-year-old and 82% vs 69% for 13- to 17-year-old girls; 55% vs 40% for 11- to 12-year-old and 78% vs 62% for 13- to 17 year-old boys). CONCLUSIONS: No significant differences in HPV vaccine coverage were identified at intervention clinics. However, coverage rates were increasing before the start of the intervention and might have been influenced by ongoing health system best practices. HPV vaccine coverage rates varied significantly according to department, which could allow for targeted improvement opportunities. PMID- 29502645 TI - Artificial Intelligence for Operations: The Untold Story. PMID- 29502644 TI - Successful Use of Interventions in Combination to Improve Human Papillomavirus Vaccination Coverage Rates Among Adolescents-Chicago, 2013 to 2015. AB - In 2013, National Immunization Survey-Teen data indicated that >40% of female adolescents had not initiated the human papillomavirus (HPV) vaccine series and >60% had not completed the series, documenting vaccination rates much lower than those for other vaccines recommended for adolescents. The Chicago Department of Public Health (CDPH) was 1 of 22 jurisdictions nationwide to receive a Prevention and Public Health Fund award through the Centers for Disease Control and Prevention to improve HPV vaccination rates among adolescents. The CDPH implemented 5 interventions targeting the public, clinicians and their staff, and diverse immunization and cancer prevention stakeholders. Compared with 2013 jurisdiction-specific HPV vaccination rates among all adolescents, Chicago's HPV vaccination rates were increased significantly in 2014 and 2015. This article details the methods and results of Chicago's successful interventions, the particular strengths as well as barriers encountered, and future steps necessary for sustaining improvement. PMID- 29502646 TI - Data Science and the Future of Radiology: A New Pillar for JACR. PMID- 29502647 TI - Arbitrary Radiation Dose "Limits" Must Not Set Standard of Care. PMID- 29502648 TI - Author's Response. PMID- 29502649 TI - Point: The Existential Threat to Nuclear Medicine. PMID- 29502650 TI - Counterpoint: Nuclear Medicine's Decline: Radiology Is the Solution, Not the Problem. PMID- 29502651 TI - Determining Adherence to Follow-up Imaging Recommendations. AB - PURPOSE: Radiology reports often contain follow-up imaging recommendations. However, these recommendations are not always followed up by referring physicians and patients. Failure to comply in a timely manner can lead to delayed treatment, poor patient outcomes, unnecessary testing, lost revenue, and legal liability. Therefore, the primary objective of this research was to determine adherence rates to follow-up recommendations. METHODS: We extracted radiology examination related data, including report text, for examinations performed between January 1, 2010, and February 28, 2017, from the radiology information system at an academic institution. The data set contained 2,972,164 examinations. The first 6 years were used as the period during which a follow-up recommendation was to be detected, allowing for a maximum of 14 months for a follow-up examination to be performed. RESULTS: At least one recommendation for follow-up imaging was present in 10.6% of radiology reports. Overall, the follow-up imaging adherence rate was 58.14%. Mammography had the highest follow-up adherence rate at 69.03%, followed by MRI at 67.54%. Of the modalities, nuclear medicine had the lowest adherence rate at 37.93%. CONCLUSIONS: This study confirms that follow-up imaging adherence rates are inherently low and vary by modality and that appropriate interventions may be needed to improve compliance to follow-up imaging recommendations. PMID- 29502652 TI - Unpopular Opinions. PMID- 29502653 TI - Firefighting Versus Long-Term Planning. PMID- 29502654 TI - Discussion of: Peri-operative emergency department utilization in inpatient and outpatient Medicare laparoscopic cholecystectomy. PMID- 29502655 TI - Discussion of: The benefits of a low-dose complex carbohydrate/citrulline electrolyte solution for preoperative carbohydrate loading: Focus on glycemic variability. PMID- 29502656 TI - Discussion of: Endoscopic and histopathological analysis of incidental focal colorectal 18F-fluorodeoxyglucose uptake in PET/CT scan: Colonoscopic evaluation is warranted. PMID- 29502657 TI - Discussion of: Surgical resection improves median overall survival with marginal improvement in long-term survival when compared with definitive radiotherapy in Merkel cell carcinoma: A propensity score matched analysis of the National Cancer Database. PMID- 29502658 TI - Discussion of: Can parathyroid hyperplasia be predicted preoperatively? PMID- 29502659 TI - Discussion of: Accurate surgical skills evaluation: Does it mandate raters have a medical background? PMID- 29502660 TI - Discussion of: A novel modality for intraoperative margin assessment and its impact on re-excision rates in breast conserving surgery. PMID- 29502661 TI - Discussion of: Coagulation profile following liver resection: Does liver cirrhosis affect thrombelastography? PMID- 29502662 TI - Discussion of: Seeing the forest beyond the trees: Predicting survival in burn patients with machine learning. PMID- 29502663 TI - Discussion of: Is it safe to discharge geriatric trauma patients with anemia? PMID- 29502664 TI - Discussion of: The impact of the repeal of Michigan's universal helmet law on traumatic brain injury: A statewide analysis. PMID- 29502665 TI - Discussion of: Risk-adjusted regional outcomes in elective medicare colorectal surgery. PMID- 29502666 TI - Discussion of: Outcomes of rectal resection following neoadjuvant therapy in the elderly: Can rectal cancer patients be too old for a neoadjuvant approach? PMID- 29502667 TI - Discussion of: Individual surgeon practice is the most important factor influencing diverting ileostomy creation for patients undergoing sigmoid colectomy for diverticulitis. PMID- 29502668 TI - Discussion of: Do not break up the surgical team! Familiarity and expertise affect operative time in complex surgery. PMID- 29502669 TI - Discussion of: Decreasing length of stay in bariatric surgery: The power of suggestion. PMID- 29502670 TI - Discussion of: Robotic and hybrid robotic transversus abdominis release may be performed with low length of stay and wound morbidity. PMID- 29502671 TI - Discussion of: Is there a role for Ytrrium-90 in the treatment of unresectable and metastatic intrahepatic cholangiocarcinoma? PMID- 29502672 TI - Discussion of: The diagnosis and staging of pancreatic cancer: A comparison of endoscopic ultrasound and computed tomography with pancreas protocol. PMID- 29502673 TI - Discussion of: Utility of Sequential Organ Failure Assessment score in predicting bacteremia in critically ill burn patients. PMID- 29502674 TI - Discussion of: Early versus delayed appendectomy: A comparison of outcomes. PMID- 29502675 TI - Discussion of: Effect of intra-operative single dose of dexamethasone for control of post-operative nausea and vomiting on the control of blood glucose levels in diabetic patients. PMID- 29502676 TI - Discussion of: DRG migration: A novel measure of inefficient surgical care in a value-based world. PMID- 29502677 TI - Discussion of: Efficacy and safety of transversus abdominis plane block versus thoracic epidural anesthesia in patients undergoing major abdominal oncologic resections: A prospective, randomized controlled trial. PMID- 29502678 TI - Discussion of: Do psoas muscle area and volume correlate with postoperative complications in patients undergoing rectal cancer resection? PMID- 29502679 TI - Discussion of: Neoadjuvant systemic therapy in invasive lobular breast cancer: Is it indicated? PMID- 29502680 TI - The value of neuron-specific enolase in prognostication after cardiac arrest. PMID- 29502681 TI - Reply to: "The value of neuron-specific enolase in prognostication after cardiac arrest". PMID- 29502682 TI - Point-of-care ultrasound use in patients with cardiac arrest: More harmful than useful? PMID- 29502684 TI - Conjunctivodacryocystorhinostomy. PMID- 29502683 TI - Reply to: Point-of-care ultrasound use in patients with cardiac arrest: More harmful than useful? PMID- 29502685 TI - Erratum. PMID- 29502686 TI - Big Data: Progress or a Big Headache? AB - Large administrative database, or "big data" research studies can include an immense number of patients. Strengths of research based on big data include generalizability resulting from diverse patients, diverse providers, and diverse clinical settings. Limitations of research based on large administrative databases may include indeterminate quality and obscure purpose of data entry, lack of information regarding confounding variables, and suboptimal clinical outcome measures. Thus, research conclusions based on big data must be scrutinized in a discerning and critical manner. PMID- 29502687 TI - Editorial Commentary: Are We Running Out of Treatments for Osteoarthritis of the Knee? AB - A considerable body of literature with high-level evidence has been published in the past 15 years calling into question the value of arthroscopic surgery in treating osteoarthritis of the knee (OAK). This, plus recent guidelines advising against the use of conservative treatments such as hyaluronic viscosupplementation, threatens to limit patient access to treatment for a chronic disease state with no known cure. The disease burden of OAK is considerable and represents one of the largest health care dollar expenditures in the United States and the world. Orthopaedic surgeons are the primary specialty dealing with OAK and manage this disease from inception to the final endpoint of total joint arthroplasty. As the population ages and the incidence of OAK increases, we must find ways to improve our ability to show efficacy in our treatments and also promote innovative modalities and applications to ameliorate the disability and dysfunction associated with OAK. Arthroscopy is recognized as a global leader in the presentation of evidence and debate surrounding all treatments for OAK and plays an important role in improving knowledge and treatment efficacy. PMID- 29502688 TI - Editorial Commentary: The Krackow Stitch: More Than 30 Years of Tendon Repair and Still Holding Strong. AB - Security at the suture-tendon interface is a critical component of soft tissue fixation. For more than 3 decades, the Krackow stitch has been considered the gold standard for soft tissue fixation. Modifications of the original configuration have withstood the test of time. Many have been evaluated in preclinical and clinical studies for multiple musculoskeletal applications. Most recently, double Krackow suture configurations have been shown to increase the ultimate failure load of the suture-tendon construct. I have learned this stitch and will add it to my soft tissue fixation arsenal. PMID- 29502689 TI - Editorial Commentary: Want to Play in the National Football League? Not For Long If You Have an Untreated Cartilage Defect of the Knee. AB - Although the epidemiology and risk factors for chondral injuries of the knee among prospective National Football League athletes have been reported, the effect of previously untreated chondral injuries on players' early National Football League career performance has been unclear to this point. Despite not requiring surgical treatment, players with these untreated injuries were drafted later, played and started fewer games, and exhibited lower fantasy scores-a surrogate marker for performance. Untreated chondral injuries of the knee can have potentially deleterious effects on the playing careers (and financial prospects) of professional American football players. PMID- 29502690 TI - Editorial Commentary: Posterolateral Corner Injuries in Elite Athletes Remain a Challenging Diagnostic Problem. AB - Posterolateral corner injuries are rare, and the examination to quantitate these injuries is very challenging. Careful examination comparing the involved and uninvolved knees, considering stress radiographs, and combining this with magnetic resonance imaging findings is currently our most accurate way to grade these injuries. PMID- 29502691 TI - Editorial Commentary: Understanding Anterior Cruciate Ligament Failure: New Questions Emerge as Existing Ones Are Answered. AB - Cartilage injuries are prevalent in patients undergoing knee anterior cruciate ligament revision surgery. PMID- 29502692 TI - Editorial Commentary: Anterior Cruciate Ligament Augmentation: A Bold, Technically Demanding Surgical Technique... But Don't Forget to Evaluate the Benefit-Risk Ratio! AB - Preserving the remnant tissues in anterior cruciate ligament reconstruction, commonly referred to as anterior cruciate ligament augmentation, is an option in the "surgery a la carte" menu that the surgeon may choose from to adapt the surgical technique depending on each patient's specific needs. When possible, preserving this remnant offers definite benefits: improved vascularization, presence of neurosensors, and even mechanical advantages. However, this technique may prove to be tricky, especially when the intercondylar notch is not clearly visible and when the surgeon lacks experience. The benefit-risk ratio must be carefully weighed for each case. PMID- 29502693 TI - Editorial Commentary: Is Magnetic Resonance Imaging Imaged Knee Patellar Tracking Relevant in Assessing the Patient With Patellar Instability? AB - Patellar pain and instability are common presentations to surgeons, yet assessment is more a static art than a dynamic science. In addition to resource intensive gait laboratory, computed tomography (CT) and magnetic resonance imaging (MRI) have been used to measure patellar tracking. CT has the limitation of radiation and MRI has the limitation of software processing times. With an updated MRI protocol and software, it is now possible to dynamically view patellar tracking. Determining how this will be used to help in the diagnosis and treatment of patients will be the next goal. PMID- 29502694 TI - Editorial Commentary: Revision Multiligament Knee Reconstruction Can Restore Stability in a High Percentage of the Cases When Well Executed. AB - A thorough and comprehensive evaluation of failed multiligament knee reconstructions is a key component for optimal outcomes of revision cases. Addressing all associated injuries during surgery, either staged or not, will potentially guarantee better subjective and objective scores. Older age and high energy mechanism of injury are associated with worse functional outcomes. PMID- 29502695 TI - Editorial Commentary: The Shoulder Biceps Tendon and Baseball Continue Their Controversial Relationship. AB - The optimal treatment of shoulder SLAP tears in high-level baseball players remains highly controversial. In pitchers, many SLAP lesions are found incidentally on magnetic resonance imaging and may in fact be adaptive to the baseball pitcher's mechanics of throwing. Surgical repair of SLAP lesions requires lengthy rehabilitation, and outcomes have been similar to or worse than the results after nonoperative treatment. The treatment option of biceps tenodesis is an appealing alternative to SLAP repair, but the indications and technique of biceps tenodesis in the elite pitcher still need to be defined. PMID- 29502696 TI - Editorial Commentary: Go Ahead and Repair That Shoulder Rotator Cuff Tear in Your Obese Patient: Just Be Prepared to Admit Them. AB - Arthroscopic rotator cuff repair in the obese patient offers functional outcomes and rates of complications comparable to those seen in nonobese patients. Future prospective studies with better methodology, as well as including larger numbers of severely obese patients with a body mass index of 40 or greater, will help to further elucidate if obesity truly affects outcomes in rotator cuff repair. In the meantime, be sure to consider admission of your obese rotator cuff repair patients. PMID- 29502697 TI - Editorial Commentary: Lateral Acromioplasty Is Clinically Safe and Has the Potential to Reduce the Risk for Rotator Cuff Re-tears. AB - The critical shoulder angle and lateral acromioplasty are areas of controversy that are being studied in association with rotator cuff tears both as potential pathogenic variables and as surgically modifiable variables that could improve clinical outcomes. Current clinical evidence regarding the effectiveness and potential benefit of lateral acromioplasty support the hypothesis that modification of the bony anatomy may influence the integrity of the rotator cuff. PMID- 29502698 TI - Editorial Commentary: Evaluating the Epidemiology of Shoulder Stabilization Surgery: An Opinion on Causation. AB - Epidemiology originates from the Greek words "epi" meaning upon and "demos" meaning people. Hence, epidemiology is the study of what is "upon the people" or the analysis of the patterns of disease in a defined population. Epidemiological studies are important in defining "at-risk" patient populations so research can be directed toward these groups. It is important to understand that epidemiology does not determine causation. However, it is reasonable for clinicians (me) to opine on the reasons for these epidemiological trends. I believe that the major factors responsible for the changing incidence in shoulder stabilization are the use of the arthroscope and the surgical management of the first time dislocator. PMID- 29502699 TI - Editorial Commentary: Shoulder Anatomy, Finding the Axillary Nerve: Measure Twice, Cut Once. AB - Most descriptions of shoulder anatomy note that the axillary nerve lies approximately 5 cm below the anterolateral corner of the acromion, and the nerve has been reported to range from 2 to 7 cm from the acromial edge, depending on the patient and measuring technique. The safe trans-deltoid operable area has been described as up to 4 cm below the acromion. A useful clinical guide I use is that the inferior extent of the subacromial bursa ends above the axillary nerve. PMID- 29502700 TI - Editorial Commentary: Shoulder Subpectoral Biceps Tenodesis Significantly Increases the Humeral Fracture Risk-Is This a Reason to Look for Alternatives? AB - Subpectoral tenodesis is performed at the surgical neck of the humerus. In a cadaveric study, the insertion of a unicortical PEEK (polyether ether ketone) screw decreased the torsional load to failure (fracture) by 30% compared with intact control specimens but was similar to unicortical reaming without screw insertion. Placing the biceps tendon into the tunnel and securing it with a unicortical screw reduced the torsional load to failure by 20%. Whether these facts are significant is currently unknown, but the creation of a stress riser is a concern and may possibly result in surgical neck fractures. PMID- 29502701 TI - Editorial Commentary: Changing Times in Sports Biomechanics: Baseball Pitching Injuries and Emerging Wearable Technology. AB - Research has shown relations between amount of baseball pitching and overuse injuries, as well as between poor mechanics and high loads on the elbow and shoulder. However, overuse injuries continue to be a problem from youth to professional sports. Emerging wearable technology may enable players, parents, coaches, leagues, and clinicians to monitor biomechanics during competition and training, reducing the risk of serious injury. PMID- 29502702 TI - Editorial Commentary: Platelet-Rich Fibrin Matrix-Is This Stuff for Real?! AB - The use of biologic augments such as platelet-rich plasma and platelet-rich fibrin for tendon pathology has skyrocketed within the past 5-7 years amongst orthopaedic patients. Many retrospective series exist with small sample sizes and variable clinical applications. Patient psyche, price of product, and outcomes may be more intimately related than once thought. In this commentary, we briefly review the placebo and psychometric effect of medicine. PMID- 29502703 TI - Editorial Commentary: The Importance of Capsular Closure in Hip Arthroscopy: Is There a Limit to the Benefit? AB - Capsular closure is an important concept in hip arthroscopy and should be performed in nearly all patients. However, in patients with stiff hips and borderline arthritic changes, leaving the capsule unrepaired or performing a partial repair in the setting of a T-capsulotomy could result in successful outcomes. PMID- 29502704 TI - Editorial Commentary: Paving a Road Requires a Well-Mixed Cement Stem Cells, Platelet-Rich Plasma, and Shoulder Rotator Cuff Healing. AB - The process of healing in musculoskeletal tissues is complex, and the addition of devices, including platelet-rich plasma and mesenchymal stem cells, to biologically enhance it may favor its optimization. This work shows in a compelling fashion that it is possible to produce the right admixture of physical and biological factors to make it happen in rotator cuff repair. PMID- 29502705 TI - Editorial Commentary: Narrow Knee Intercondylar Notch Width Is a Risk Factor for Anterior Cruciate Ligament Injury, and Hetrogeneous Methods Are a Risk Factor for "Between Study" Error in Meta-analyses. AB - The anatomic dimensions of the intercondylar notch have been associated with and anterior cruciate ligament (ACL) injury; however, these findings have been shown to be highly heterogeneous in a previous systematic review. Early studies used conventional radiographs to image the knee, whereas recent studies have employed magnetic resonance imaging. The different imaging techniques are a potential source of heterogeneity, prompting a systematic review of magnetic resonance imaging studies only. Although a narrower intercondylar notch width and intercondylar index were again associated with ACL injury, statistical heterogeneity remains persistent. Subgroup analysis successfully identified sources of between-study error among studies measuring notch width but was unable to account for differences in studies examining notch width index. These findings have provided greater insight into the relation between the anatomic dimensions of the intercondylar notch and ACL as well as the importance of between-study error in meta-analysis. PMID- 29502706 TI - Editorial Commentary: Reviewing the Science of Our Unscientific Criteria for Return to Sports After Shoulder Stabilization. AB - In contrast to anterior cruciate ligament reconstruction, there is a paucity of primary studies that address the issue of return to play after anterior shoulder stabilization for glenohumeral instability. Most studies focused on clinical outcomes after anterior shoulder stabilization provide little detail on the authors' assessment protocols used in determining return to sport readiness. In fact, many issues germane to the postoperative rehabilitation process (biologic healing, motion recovery, strength recovery, and sport-specific considerations) remain poorly defined, and are not typically addressed using validated shoulder outcomes instruments. Sports medicine surgeons need more objective criteria on which to base their clinical decision making with athletes treated for anterior glenohumeral instability. PMID- 29502707 TI - Editorial Commentary: Safe Innovation? Arthroscopy After Traumatic Hip Dislocation. AB - Hip arthroscopy can be helpful relative to conventional imaging when diagnosing (and treating) intra-articular injuries after a hip dislocation, but more evidence is required before adopting this approach diagnostic and therapeutic strategy. PMID- 29502708 TI - Editorial Commentary: The Downstream Effects of Limited Hip Rotation and Femoroacetabular Impingement on the Anterior Cruciate Ligament: Could a Little Hip Stretching Every Day (or Surgery) Keep the Knee Doctor Away? AB - Patients with radiographic evidence of femoroacetabular impingement and decreased hip internal rotation have a higher rate of anterior cruciate ligament (ACL) tears. Limited internal rotation of the hip increases strain and potentially resultant fatigue failure of the ACL. Although causation has not been proven, a better understanding of the lower extremity kinetic chain may allow improved ACL prevention strategies through measures (operative or nonoperative) to improve rotation of the hip. PMID- 29502709 TI - Editorial Commentary: Graft Removal Versus Retention for Septic Arthritis After Anterior Cruciate Ligament Reconstruction: Accounting for Patient Preference Flips the Script on Current Practice. AB - Septic arthritis is a rare but potentially devastating complication after anterior cruciate ligament (ACL) reconstruction. Studies examining surgical treatment options including graft retention and removal are largely inconclusive. Although the literature indicated that 43.8% of patients who have the graft removed later go on to have a revision ACL reconstruction compared with only 6.5% among those whose graft is retained, this expected-value decision analysis found removal to be the optimal treatment for patients with septic arthritis after ACL reconstruction. This is largely based on patient preference to avoid a late reoperation for residual knee infection. These findings support the concept of utility when considering treatment options for patients with a septic knee. For some, avoiding a late reoperation for a persistent infection is the most important factor and as such graft removal may be the most appropriate treatment to produce a positive outcome among these patients despite the fact that currently, an attempt at graft retention could represent the generally preferred treatment option among practicing surgeons. PMID- 29502710 TI - Editorial Commentary: Does It Matter Which Way I Fuse Your Ankle: Arthroscopically or Open? I Hope So! AB - Arthroscopic ankle arthrodesis is the treatment method of choice to achieve good clinical scores, faster time to union, fewer complications, and shorter hospital stay. However, the union rate, reoperation rate, and operative time are similar to open arthrodesis. The choice of which method to use for arthrodesis is influenced by surgeon preference and experience, clinical presentation, and equipment availability. Overall, we must choose the method of ankle arthrodesis that gives the best result with the least morbidity to the patient. PMID- 29502711 TI - Pathophysiology and Management of Intracranial Hypertension and Tissular Brain Hypoxia After Severe Traumatic Brain Injury: An Integrative Approach. AB - Monitoring intracranial pressure in comatose patients with severe traumatic brain injury (TBI) is considered necessary by most experts. Acute intracranial hypertension (IHT), when severe and sustained, is a life-threatening complication that demands emergency treatment. Yet, secondary anoxic-ischemic injury after brain trauma can occur in the absence of IHT. In such cases, adding other monitoring modalities can alert clinicians when the patient is in a state of energy failure. This article reviews the mechanisms, diagnosis, and treatment of IHT and brain hypoxia after TBI, emphasizing the need to develop a physiologically integrative approach to the management of these complex situations. PMID- 29502712 TI - Management of Traumatic Brain Injury: An Update. AB - The care of patients with traumatic brain injury can be one of the most challenging and rewarding aspects of clinical neurocritical care. This article reviews the approach to unique aspects specific to the care of this patient population. These aspects include appropriate use of sedation and analgesia, and the principles and the clinical use of intracranial monitors. Common clinical challenges encountered in these patients are also discussed, including the treatment of intracranial hypertension, temperature management, and control of sympathetic hyperactivity. PMID- 29502713 TI - Cortical Spreading Depression and Ischemia in Neurocritical Patients. AB - Spreading depolarization in cerebral cortex is associated with swelling of neurons, distortion of dendritic spines, massive ion translocation with a large change of the slow electrical potential, and silencing of brain electrical activity. The term spreading depression represents a wave of spontaneous activity of the electrocorticogram that propagates through contiguous cerebral gray matter at a characteristic velocity. Spreading depression is a consequence of cortical spreading depolarization. Therefore, spreading depolarization is not always accompanied by spreading depression and the terms are not synonymous. PMID- 29502714 TI - Targeted Temperature Management in Brain Injured Patients. AB - Evidence from animal models indicates that lowering temperature by a few degrees can produce substantial neuroprotection. In humans, hypothermia has been found to be neuroprotective with a significant impact on mortality and long-term functional outcome only in cardiac arrest and neonatal hypoxic-ischemic encephalopathy. Clinical trials have explored the potential role of maintaining normothermia and treating fever in critically ill brain injured patients. This review concentrates on basic concepts to understand the physiologic interactions of thermoregulation, effects of thermal modulation in critically ill patients, proposed mechanisms of action of temperature modulation, and practical aspects of targeted temperature management. PMID- 29502715 TI - Aneurysmal Subarachnoid Hemorrhage: Unanswered Questions. AB - Optimizing outcomes after aneurysmal subarachnoid hemorrhage remains a challenge for neurosurgeons and neurointensivists alike. Although we have learned a lot about the pathophysiology of this disease, many clinical questions are still unanswered. In this review, the authors discuss some of these questions, including the current diagnostic value of lumbar puncture in patients with negative computed tomography scans, the treatment value of blood pressure reduction and antifibrinolytics for prevention of early rebleeding, the indication for antiseizure medications, the optimal management of hydrocephalus and intracranial pressure, the role of clipping, and the options for diagnosis and treatment of delayed cerebral ischemia. PMID- 29502716 TI - Recent Advances in the Acute Management of Intracerebral Hemorrhage. AB - Primary intracerebral hemorrhage (ICH) is a common, devastating disease that lacks an effective specific treatment. Mortality is high, functional outcomes are poor, and these have not substantially changed for decades. There is, therefore, considerable opportunity for advancement in the management of ICH. In recent years, a significant amount of research has begun to address this gap. This article is aimed at updating neurologists on the most clinically relevant contemporary research. PMID- 29502717 TI - New Developments in Refractory Status Epilepticus. AB - Status epilepticus (SE) is a medical emergency and presents with either a continuous prolonged seizure or multiple seizures without full recovery of consciousness in between them. The goals of treatment are prompt recognition, early seizure termination, and simultaneous evaluation for any potentially treatable cause. Improved understanding of the pathophysiology has led to a more practical definition. New data have emerged regarding the safety and efficacy of alternative agents, which are increasingly used in the management of these patients. Continuous electroencephalogram monitoring is more widely used and has revealed a higher incidence of subclinical seizures than was previously thought. PMID- 29502718 TI - Acute Cardiac Complications in Critical Brain Disease. AB - Acute cardiac complications in critical brain disease should be understood as a clinical condition representing an intense brain-heart crosstalk and might mimic ischemic heart disease. Two main entities (neurogenic stunned myocardium [NSM] and stress cardiomyopathy) have been better characterized in the neurocritically ill patients and they portend worse clinical outcomes in these cases. The pathophysiology of NSM remains elusive. However, significant progress has been made on the early identification of neurocardiac compromise following acute critical brain disease. Effective prevention and treatment interventions are yet to be determined. PMID- 29502719 TI - Nosocomial Infections in the Neurointensive Care Unit. AB - Infectious complications in the neurointensive care unit (neuro-ICU) are common, including pneumonia, urinary tract infection, bloodstream infection, and intracranial infection. The neuro-ICU population poses a specific challenge in the diagnosis of infections, because of the high incidence of fever in acutely brain-injured patients. Furthermore, susceptibility to infections is likely enhanced by brain-injury (induced immune modulation). This article reviews the concept of brain injury-induced immune modulation, and summarizes available data and knowledge on nosocomial meningitis and ventriculitis, and systemic infectious complications in patients with traumatic brain injury, ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, and status epilepticus. PMID- 29502720 TI - Shared Decision Making in Neurocritical Care. AB - Shared decision making is a collaborative decision-making process between health care providers and patients or their surrogates, taking into account the best scientific evidence available while considering the patient's values, goals, and preferences. Decision aids are tools enabling SDM. This article discusses shared decision making in general and in the intensive care unit in particular and facilitators and barriers for the creation and implementation of International Patient Decision Aids Standards Collaboration-compliant decision aids for the intensive care unit and neuro-intensive care unit. PMID- 29502721 TI - Neurocritical Care: Growth from Interdisciplinary Collaboration. PMID- 29502722 TI - History of Otosclerosis and Stapes Surgery. AB - The current advancements in otosclerosis therapy cannot be fully appreciated without studying the history, rediscovery, and modification of a once-forgotten procedure. The evolution of stapes surgery can be best summarized into 4 noteworthy eras: the preantibiotic era (which was forgotten and then rediscovered), the fenestration era (mainstreamed by Julius Lempert), the mobilization era (led by Samuel Rosen), and the modern stapedectomy era (revived and revolutionized by John Shea). Each era is unique with its own challenges and ingenious techniques to overcome what used to be among the leading causes of deafness. PMID- 29502723 TI - Otosclerosis: From Genetics to Molecular Biology. AB - Over the past several years, with the evolution of genetic and molecular research, several etiologic factors have been implicated in the pathogenesis of otosclerosis. Overall, current evidence suggests that otosclerosis is a complex disease with a variety of potential pathways contributing to the development of abnormal bone remodeling in the otic capsule. These pathways involved in the pathogenesis of otosclerosis are influenced by both genetic and environmental factors. PMID- 29502724 TI - Impact of Imaging in Management of Otosclerosis. AB - The use of imaging in otosclerosis for diagnosis, preoperative assessment, and follow-up has the potential to give the clinician an additional tier of patient evaluation and validation of diagnosis. Before stapes surgery, imaging may help avoid unnecessary middle ear explorations in nonotosclerotic cases, prevent potential complications, and assist in appropriate patient counseling regarding management expectations. Postoperatively, following unsuccessful air-bone gap closure in stapes surgery or conductive hearing deterioration following initial successful closure of the air bone gap, imaging can be used to determine the prosthesis position in the middle ear. PMID- 29502725 TI - The Stapes Prosthesis: Past, Present, and Future. AB - Since the original carved Teflon stapes over vein graft, stapedectomy prostheses have undergone evolution. Prostheses shapes, materials, and surgical techniques for placement have reflected advances in biomaterials and surgical tools. The variability in prostheses has reflected alternative techniques of stapedectomy and stapedotomy and differing strategies for attachment to the incus. Although many iterations of stapes prostheses have been proposed, excellent results can be achieved with various prostheses designed to rest on tissue grafts in stapedectomy techniques or pass through the footplate in stapedotomy techniques when used by surgeons experienced with technique details specific to the selected prosthesis. PMID- 29502726 TI - Use of Lasers in Otosclerosis Surgery. AB - Lasers were introduced as an atraumatic modality for accomplishing several of the crucial steps in otosclerosis surgery. Advances in laser technology have spurred coevolution of refinements in the technique of the operation. Several varieties of laser systems are available to suit individual preference and to augment a surgeon's armamentarium; however, a clear advantage in terms of surgical outcome or patient safety remains to be demonstrated. PMID- 29502727 TI - Advanced Otosclerosis: Stapes Surgery or Cochlear Implantation? AB - Diagnosis and treatment of advanced otosclerosis can be controversial. In 1961, House and Sheehy defined advanced otosclerosis as hearing loss in air conduction threshold by 85 dB with nonmeasurable bone conduction. Recently, the definition of advanced otosclerosis is mostly based on the decrease of speech recognition. There are some treatment modalities: stapes surgery and hearing aids, cochlear implantation, or direct acoustic cochlear implant. The authors propose a new algorithm for treatment. If the patient is treated with cochlear implantation, the surgeon should be cautious for facial nerve stimulation after surgery because it is the most prevalent complication. PMID- 29502728 TI - Medical Management of Otosclerosis. AB - Otosclerosis/otospongiosis is a primary osteodystrophy of the otic capsule that affects genetically predisposed individuals and leads to progressive hearing loss. Diagnosis is usually clinical, based on the findings of anamnesis, physical examination, and audiometric evaluation. However, high-resolution computed tomography scan and MRI have played an important role in the diagnosis and therapeutic approach of otosclerosis and in assisting in the differential diagnosis. The therapeutic approach is aimed at preventing, or at least minimizing, disease progression while attempting to restore hearing. The use of sodium fluoride and bisphosphonates can be an important adjunct, perhaps even primary treatment, in managing active lesions. PMID- 29502729 TI - Revision Surgery for Otosclerosis. AB - This article is an overview of the care of patients requiring revision surgery for otosclerosis. Preoperative evaluation of the patient including surgical history, audiologic results, and physical findings is discussed, and the causes of failure of primary surgery are reviewed. A discussion of evidence-based surgical technique and postoperative care then follows. PMID- 29502730 TI - Potential of Robot-Based Surgery for Otosclerosis Surgery. AB - Otosclerosis surgery is performed through a transcanal approach and requires long, thin instruments with submillimetric precision and precise amplitude of motion. The functional outcomes and complications of otosclerosis surgery depend on the experience of the surgeon. Thus, any technological assistance that can enhance the surgeon's dexterity and rapidly reduce the learning curve could yield an even safer surgical procedure. One of the options is to use robotic assistance to achieve this goal. An overview of different robots designed for otosclerosis surgery is presented focusing on the RobOtol system that we have designed as a multitask platform for ear surgery. PMID- 29502731 TI - Controversies in the Evaluation and Management of Otosclerosis. AB - Controversies have been associated with the etiology, diagnosis, evaluation, and management of otosclerosis since Valsalva first described stapes fixation as a cause of hearing loss. Although the exact mechanism of the bone remodeling associated with otosclerosis remains uncertain, stapedotomy has been accepted as the surgical treatment of most patients with stapedial otosclerosis. There remains a disparity of opinion, however, regarding the role of preoperative imaging, surgical technique, implant selection, and medical therapy for cochlear otosclerosis. In addition, opinions vary regarding the optimal postoperative care of patients undergoing stapedotomy and a patient's ability to participate in activities that may result in barotrauma. PMID- 29502732 TI - Otosclerosis and Stapes Surgery. PMID- 29502733 TI - Metformin: Prevention of genomic instability and cancer: A review. AB - The diabetes drug metformin can mitigate the genotoxic effects of cytotoxic agents and has been proposed to prevent or even cure certain cancers. Metformin reduces DNA damage by mechanisms that are only incompletely understood. Metformin scavenges free radicals, including reactive oxygen species and nitric oxide, which are produced by genotoxicants such as ionizing or non-ionizing radiation, heavy metals, and chemotherapeutic agents. The drug may also increase the activities of antioxidant enzymes and inhibit NADPH oxidase, cyclooxygenase-2, and inducible nitric oxide synthase, thereby limiting macrophage recruitment and inflammatory responses. Metformin stimulates the DNA damage response (DDR) in the homologous end-joining, homologous recombination, and nucleotide excision repair pathways. This review focuses on the protective properties of metformin against genomic instability. PMID- 29502734 TI - Corrosion potential in artificial saliva and possible genotoxic and cytotoxic damage in buccal epithelial cells of patients who underwent Ni-Cr based porcelain fused-to-metal fixed dental prostheses. AB - Nickel-chromium(Ni-Cr) based alloys account for the majority of the porcelain fused-to-metal fixed dental prostheses(PFM-FDPs) on account of their superior properties despite both nickel and chromium being known as human carcinogens. Understanding the genotoxicity and the cytotoxicity alongside the characteristics of corrosion behavior of the alloy is vital for understanding their biocompatibility. This study has evaluated whether the Ni-Cr based alloys corroded in artificial saliva by analyzing alloy decomposition at different pH levels and immersion durations(7, 14, 21, and 28 days) using inductively coupled plasma-optic emission spectrophotometry(ICP-OES). The principal aim of the study was to determine the possible genotoxicity and cytotoxicity using micronucleus(MN) and other nuclear anomaly frequencies [nuclear bud(NBUD), binucleated(BNC), condensed chromatin(CC), karyorrhectic(KhC), pyknotic(PC) and karyolytic(KC) cells] and various cytome parameters [basal cells(BC), differentiated cells(DF)] with the buccal epithelial cell(BEC) micronucleus cytome assay(BMCyt). This test was administered at 1 pre- and 3 post-treatment time points to 40 patients who underwent installation of PFM-FDPs made of Ni-Cr based alloy. Furthermore, at the final post-treatment time point, saliva cotinine levels were measured with salivary cotinine quantitative enzyme immunoassay(EIA) kit and information obtained by questionnaire prior to the first pre-treatment time point was confirmed. The highest greatest release of Ni and Cr ions were seen at pH 2.3. MN and micronucleated cell frequencies, and BNC cell frequencies were significantly elevated at post-treatment time points(p < 0.03). BC, CC, KhC, PC and KC cell frequencies however were not significantly different between pre and post-treatment time points(p > 0.05). MN frequency was significantly lower in non-smokers than in current and former smokers(p < 0.001) at the pre-treatment time point. There was no significant correlation between the unit number of PFM FDPs and MN frequencies. Our results revealed that Ni-Cr based alloys are prone to corrosion and that PFM-FDPs fabricated with Ni-Cr based alloys may induce genotoxic effects rather than cytotoxic effect. PMID- 29502735 TI - Validation of the 3D Skin Comet assay using full thickness skin models: Transferability and reproducibility. AB - Recently revised OECD Testing Guidelines highlight the importance of considering the first site-of-contact when investigating the genotoxic hazard. Thus far, only in vivo approaches are available to address the dermal route of exposure. The 3D Skin Comet and Reconstructed Skin Micronucleus (RSMN) assays intend to close this gap in the in vitro genotoxicity toolbox by investigating DNA damage after topical application. This represents the most relevant route of exposure for a variety of compounds found in household products, cosmetics, and industrial chemicals. The comet assay methodology is able to detect both chromosomal damage and DNA lesions that may give rise to gene mutations, thereby complementing the RSMN which detects only chromosomal damage. Here, the comet assay was adapted to two reconstructed full thickness human skin models: the EpiDermTM- and Phenion(r) Full-Thickness Skin Models. First, tissue-specific protocols for the isolation of single cells and the general comet assay were transferred to European and US American laboratories. After establishment of the assay, the protocol was then further optimized with appropriate cytotoxicity measurements and the use of aphidicolin, a DNA repair inhibitor, to improve the assay's sensitivity. In the first phase of an ongoing validation study eight chemicals were tested in three laboratories each using the Phenion(r) Full-Thickness Skin Model, informing several validation modules. Ultimately, the 3D Skin Comet assay demonstrated a high predictive capacity and good intra- and inter-laboratory reproducibility with four laboratories reaching a 100% predictivity and the fifth yielding 70%. The data are intended to demonstrate the use of the 3D Skin Comet assay as a new in vitro tool for following up on positive findings from the standard in vitro genotoxicity test battery for dermally applied chemicals, ultimately helping to drive the regulatory acceptance of the assay. To expand the database, the validation will continue by testing an additional 22 chemicals. PMID- 29502736 TI - Mechanism of oxidative DNA damage induced by metabolites of carcinogenic naphthalene. AB - Naphthalene is a carcinogenic polycyclic aromatic hydrocarbon, to which humans are exposed as an air pollutant. Naphthalene is metabolized in humans to reactive intermediates such as 1,2-hydroxynaphthalene (1,2-NQH2), 1,4-NQH2, 1,2 naphthoquinone (1,2-NQ), and 1,4-NQ. We examined oxidative DNA damage by these naphthalene metabolites using 32P-labeled DNA fragments from human cancer relevant genes. 1,2-NQH2 and 1,4-NQH2 induced DNA damage in the presence of Cu(II). The DNA-damaging activity of 1,2-NQH2 was significantly increased in the presence of the reduced form of nicotinamide adenine dinucleotide (NADH), whereas that of 1,4-NQH2 was not. In the presence of NADH, 1,2-NQ induced Cu(II) dependent DNA damage, whereas 1,4-NQ did not. The calculated energy of the lowest unoccupied molecular orbital (LUMO), which corresponds to the reduction potential, was estimated to be -0.67 eV for 1,2-NQ and -0.75 eV for 1,4-NQ. These results suggest that 1,2-NQ was reduced more easily than 1,4-NQ. Furthermore, 1,2 NQH2, 1,4-NQH2, and 1,2-NQ plus NADH formed 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) as an oxidative DNA marker. Catalase and bathocuproine inhibited DNA damage, suggesting that H2O2 and Cu(I) were involved. These results indicate that NQH2s are oxidized to the corresponding NQs via semiquinone radicals, and that H2O2 and Cu(I) are generated during oxidation. 1,2-NQ is reduced by NADH to form the redox cycle, resulting in enhanced DNA damage. The formation of the corresponding semiquinone radicals was supported by an electron paramagnetic resonance (EPR) study. In conclusion, the redox cycle of 1,2-NQ/1,2-NQH2 may play a more important role in the carcinogenicity of naphthalene than that of 1,4 NQ/1,4-NQH2. PMID- 29502737 TI - Kinetics of ROS generation induced by polycyclic aromatic hydrocarbons and organic extracts from ambient air particulate matter in model human lung cell lines. AB - Polycyclic aromatic hydrocarbons (PAHs) associated with particulate matter (PM) may induce oxidative damage via reactive oxygen species (ROS) generation. However, the kinetics of ROS production and the link with antioxidant response induction has not been well studied. To elucidate the differences in oxidative potential of individual PAH compounds and extractable organic matter (EOM) from PM containing various PAH mixtures, we studied ROS formation and antioxidant response [total antioxidant capacity (TAC) and expression of HMOX1 and TXNRD1] in human alveolar basal epithelial cells (A549 cells) and human embryonic lung fibroblasts (HEL12469 cells). We treated the cells with three concentrations of model PAHs (benzo[a]pyrene, B[a]P; 3-nitrobenzanthrone, 3-NBA) and EOM from PM <2.5 MUm (PM2.5). ROS levels were evaluated at 8 time intervals (30 min-24 h). In both cell lines, B[a]P treatment was associated with a time-dependent decrease of ROS levels. This trend was more pronounced in HEL12469 cells and was accompanied by increased TAC. A similar response was observed upon 3-NBA treatment in HEL12469 cells. In A549 cells, however, this compound significantly increased superoxide levels. This response was accompanied by the decrease of TAC as well as HMOX1 and TXNRD1 expression. In both cell lines, a short-time exposure to EOMs tended to increase ROS levels, while a marked decrease was observed after longer treatment periods. This was accompanied by the induction of HMOX1 and TXNRD1 expression in HEL12469 cells and increased TAC in A549 cells. In summary, our data indicate that in the studied cell lines B[a]P and EOMs caused a time dependent decrease of intracellular ROS levels, probably due to the activation of the antioxidant response. This response was not detected in A549 cells following 3-NBA treatment, which acted as a strong superoxide inducer. Pro-oxidant properties of EOMs are limited to short-time exposure periods. PMID- 29502738 TI - Assessment of the predictive capacity of the optimized in vitro comet assay using HepG2 cells. AB - Evaluation of DNA damage is critical during the development of new drugs because it is closely associated with genotoxicity and carcinogenicity. The in vivo comet assay to assess DNA damage is globally harmonized as OECD TG 489. However, a comet test guideline that evaluates DNA damage without sacrificing animals does not yet exist. The goal of this study was to select an appropriate cell line for optimization of the in vitro comet assay to assess DNA damage. We then evaluated the predictivity of the in vitro comet assay using the selected cell line. In addition, the effect of adding S9 was evaluated using 12 test chemicals. For cell line selection, HepG2, Chinese hamster lung (CHL/IU), and TK6 cell lines were evaluated. We employed a method for the in vitro comet assay based on that for the in vivo comet assay. The most appropriate cell line was determined by% tail DNA increase after performing in vitro comet assays with 6 test chemicals. The predictivity of the in vitro comet assay using the selected cell line was measured with 10 test chemicals (8 genotoxins and 2 non-genotoxic chemicals). The HepG2 cell line was found to be the most appropriate, and in vitro comet assays using HepG2 cells exhibited a high accuracy of 90% (9/10). This study suggests that HepG2 is an optimal cell line for the in vitro comet assay to assess DNA damage. PMID- 29502739 TI - Corrigendum to "Relationship between spontaneous gammaH2AX foci formation and progenitor functions in circulating hematopoietic stem and progenitor cells among atomic-bomb survivors" [Mutat. Res. - Genet. Toxicol. Environ. Mutagen. 802 (2016) 59-65]. PMID- 29502740 TI - Genotoxicity evaluation of multi-component mixtures of polyaromatic hydrocarbons (PAHs), arsenic, cadmium, and lead using flow cytometry based micronucleus test in HepG2 cells. AB - Some polyaromatic hydrocarbons (PAHs) and metals are known human carcinogens and the combined toxicity data of these co-contaminants are important for assessing their health risk. In this study, we have evaluated the combined genotoxicity, AhR activity and cell cycle parameters of four PAHs (benzo[a]pyrene (Ba]P), naphthalene (Nap), phenanthrene (Phe) and pyrene (Pyr)) and three metals (arsenic (As), cadmium (Cd), and lead (Pb)) in HepG2 cells using a flow cytometry based micronucleus (MN) test CAFLUX assay and nuclear fluorescence assay, respectively. The mixtures of B[a]P and metals induced a maximum of four fold increase in the MN formation compared to B[a]P alone. The higher combination of PAHs and metals did not significantly increase the MN formation. The mixtures of metals or non carcinogenic PAHs were found to increase or decrease the aryl hydrocarbon receptor (AhR) activation of B[a]P in HepG2 cell based CAFLUX assay. Overall, the results showed that combined genotoxicity of PAHs and metals in HepG2 cells vary depending on the concentrations and number of the chemicals that are present in the mixtures and the effects of higher order combinations appear to be largely unpredictable from binary combinations. In this study, we have demonstrated the use of flow cytometry based MN test to screen the genotoxicity of environmental chemicals and its mixtures. PMID- 29502741 TI - Assessment of Digital Media Use in the Adolescent Psychiatric Evaluation. AB - Digital media (also called "new media") have become an important ecosystem in which adolescents develop biologically, psychologically, and socially. When assessing adolescents in the psychiatric interview, a nuanced understanding of digital media use can inform a more accurate formulation. However, there are few published resources to help the psychiatrist assess the impact of digital media during the initial adolescent interview. The authors propose an innovation on the traditional psychiatric assessment that addresses teen Internet use and digital media habits. Through this enhanced assessment, mental health clinicians can improve upon current interviewing practices of twenty-first century adolescents. PMID- 29502742 TI - Digital Media Use in Families: Theories and Strategies for Intervention. AB - Family dynamics are increasingly being influenced by digital media. Three frameworks are described to help clinicians to understand and respond to this influence. First, a social-ecological framework shows how media has both a direct and indirect impact on individuals, relationships, communities, and society. Next, family systems theory is introduced to demonstrate digital media-related interactions within families. Finally, a developmental framework explores the role of digital media in shaping parenting. These theories are then integrated into practical strategies that clinicians can use, including recommendations and resources from the American Academy of Pediatrics. PMID- 29502743 TI - Relationship Between Adolescent Suicidality, Self-Injury, and Media Habits. AB - Media has changed the daily lives of most Americans, especially adolescents. The interplay between development and media habits is complex. There is a link between excessive media use and risk-taking behaviors, with an alarming increase in adolescent nonsuicidal self-injury, suicidal behavior, and completed suicide. The link is complex and not necessarily causal. Clinicians should routinely take a media history that distinguishes types and extent of use, content, and psychological impact. Media is a significant part of adolescents' lives and exploring their engagement with media is a critical piece of the initial assessment, risk assessment, and ongoing treatment. PMID- 29502744 TI - #KidsAnxiety and Social Media: A Review. AB - This article reviews the available literature regarding the interaction between child and adolescent anxiety and electronic media. It reviews current research contributing to understanding of the correlation of youth anxiety with engagement in social media and other online platforms, including risk and protective factors. mHealth and eHealth prevention and treatment options, available via various digital resources, are discussed. Suggestions for mental health clinicians' assessment of client's online behaviors and a review of novel treatment options are provided. The article concludes with proposing healthy online technology interventions, including popups for overuse and identification of digitally enhanced posts. PMID- 29502745 TI - Inattention to Problematic Media Use Habits: Interaction Between Digital Media Use and Attention-Deficit/Hyperactivity Disorder. AB - As digital media (DM) access among youths continues to surge, caregivers and clinicians are concerned about problems associated with its excessive use. Children with attention-deficit/hyperactivity disorder (ADHD) have an increased risk of experiencing negative effects on sleep, academic achievement, attention, and cognitive skills. ADHD symptom severity and circumstances of DM access are among the factors that mediate these negative effects. Key interventions for parents and clinicians to assist youths with problematic DM habits and opportunities for advocacy groups and the DM industry for public health interventions are discussed. PMID- 29502746 TI - The Interplay of Media Violence Effects and Behaviorally Disordered Children and Adolescents: Guidelines for Practitioners. AB - A robust body of scientific research explores the effects of violent media on youths. For practitioners, the volume of interdisciplinary research and controversial findings can be confusing and difficult to generalize for best practice. This article briefly reviews the literature and presents guidelines for parenting and treating youths exposed and enmeshed in violent media. Attention is given to at-risk populations and children presenting with aggressive, violent, and antisocial behavior. Guidelines assume a family based, cognitive-behavioral approach suitable for the eclectic practitioner, with a focus on the complex, developmental, and ecological factors that contribute to presenting symptoms. PMID- 29502747 TI - Electronic Screen Media Use in Youth With Autism Spectrum Disorder. AB - Electronic and social media play a prominent role in the lives of children and teenagers. Evidence suggests youth with autism spectrum disorder (ASD) use media differently than typically developing peers, and some of these differences place them at greater risk for negative health outcomes related to unhealthy and improper use of media. Such outcomes include physiologic, cognitive, social, emotional, and legal/safety problems. However, several technology-aided interventions have emerged to help youth with ASD across multiple domains. Parents of youth with ASD may benefit from several recommendations and resources from the American Academy of Pediatrics and the American Academy of Child and Adolescent Psychiatry. PMID- 29502748 TI - Adolescent Eating Disorder Risk and the Online World. AB - The proliferation of social media and rapid increase in the use of the Internet by adolescents generates new dynamics and new risks for the development and maintenance of eating disorders. Here, the authors review different types of online content and how they are relevant to eating disorders within different theoretic frameworks, before examining the empirical evidence for the risks posed by online content in the development and maintenance of eating disorders. They describe pro-eating disorder content specifically and examine the research related to it, before considering its implications, and considering directions for future research, and prevention and intervention strategies. PMID- 29502750 TI - Geeks, Fandoms, and Social Engagement. AB - The Internet changed the way the global community interacts and communicates. This cultural shift allows like-minded individuals to connect and share ideas. It creates spaces for stigmatized communities to gather in a virtual presence. Youth now have greater options to explore identity, and to reach peers with niche interests. From a clinical perspective, it is helpful to understand the nature of communities our patients join on the Internet. This article focuses on the broad umbrella of "geek" culture, exploring a variety of interests such as cosplay, fanfiction, and gaming. PMID- 29502751 TI - Media Engagement and Identity Formation Among Minority Youth. AB - Clinicians who work with youth should understand how they engage with screen media, including differences between ethnic groups, and how to maximize its positive potential and minimize negative consequences. This article presents data summarizing patterns of media use by youth, with an emphasis on European Americans, African Americans, and Hispanic Americans. The authors explain how identity formation and social identity theory relate to online influences, benefits, and risks of online engagement, including those specific to minority populations. The authors clarify how child mental health professionals may use this information to better treat patients and their families. PMID- 29502752 TI - Risky Business: Talking with Your Patients About Cyberbullying and Sexting. AB - This article reviews cyberbullying and sexting research and presents new research exploring relatively neglected areas of cyberbullying and cell phone ownership among children and outcomes following sexting in college. Two samples are studied: 4584 elementary school children and 1332 college freshman. Findings include: owning a cell phone increased the risk of becoming involved in cyberbullying in grades 3, 4, and 5; and, of college freshman who sexted, 61% reported no outcomes, 19% reported negative outcomes, 13% reported positive outcomes, and 7% reported mixed outcomes. This information may be useful when considering discussing these digital technology risks with patients. PMID- 29502749 TI - Youth Screen Media Habits and Sleep: Sleep-Friendly Screen Behavior Recommendations for Clinicians, Educators, and Parents. AB - With the widespread use of portable electronic devices and the normalization of screen media devices in the bedroom, insufficient sleep has become commonplace. In a recent literature review, 90% of included studies found an association between screen media use and delayed bedtime and/or decreased total sleep time. This pervasive phenomenon of pediatric sleep loss has widespread implications. There is a need for basic, translational, and clinical research examining the effects of screen media on sleep loss and health consequences in children and adolescents to educate and motivate clinicians, teachers, parents and youth themselves to foster healthy sleep habits. PMID- 29502753 TI - Internet and Video Game Addictions: Diagnosis, Epidemiology, and Neurobiology. AB - In the past 2 decades, there has been substantial increase in availability and use of digital technologies, including the Internet, computer games, smart phones, and social media. Behavioral addiction to use of technologies spawned a body of related research. The recent inclusion of Internet gaming disorder as a condition for further study in the DSM-V invigorated a new wave of researchers, thereby expanding our understanding of these conditions. This article reviews current research, theory, and practice regarding the diagnosis, epidemiology, and neurobiology of Internet and video game addictions. PMID- 29502754 TI - Treatment Considerations in Internet and Video Game Addiction: A Qualitative Discussion. AB - Internet and video game addiction has been a steadily developing consequence of modern living. Behavioral and process addictions and particularly Internet and video game addiction require specialized treatment protocols and techniques. Recent advances in addiction medicine have improved our understanding of the neurobiology of substance and behavioral addictions. Novel research has expanded the ways we understand and apply well-established addiction treatments as well as newer therapies specific to Internet and video game addiction. This article reviews the etiology, psychology, and neurobiology of Internet and video game addiction and presents treatment strategies and protocols for addressing this growing problem. PMID- 29502755 TI - The Interplay Between Digital Media Use and Development. AB - Today's youth develop immersed in a digital media world and the effects are specific to their developmental stage. Clinicians and caretakers should be mindful regarding digital media use patterns; however, this complex and reciprocal relationship defies simple linear descriptions. The impacts of digital media can be powerful. It is important to be cautious but not over-pathologize media use because digital media enables social connections, allows self-soothing in some children, and fills needs for stimulation and self-expression. Young children or those with psychiatric disorders or developmental delays should be considered vulnerable to harmful effects of media content and overuse. PMID- 29502756 TI - Child Psychiatry in the Age of the Internet. PMID- 29502757 TI - Duration of untreated illness in patients with somatoform disorders. AB - OBJECTIVE: A long duration of untreated mental illness (DUI) has been found to be associated with negative long-term outcomes. Although somatic symptom and related disorders are frequent in the general population and in primary care, data regarding the DUI of these disorders is scarce. The aim of this study was to investigate the DUI in patients with somatoform disorders. METHODS: In a cross sectional study, primary care patients at high risk of having a somatoform disorder were identified using the Patient Health Questionnaire (PHQ). In a second step, life-time somatoform disorder diagnosis was established using the Composite International Diagnostic Interview (CIDI). Additionally, DUI was retrospectively assessed via self-reporting and sociodemographic information was collected. Survival analysis was used to estimate the DUI and to identify patient related predictors of DUI. RESULTS: A total of 139 patients with somatoform disorders were included in the analyses. The mean DUI in these patients was 25.2years (median 23.1years). Higher education significantly predicted shorter DUI, whereas gender and age of onset were unrelated to DUI. CONCLUSIONS: The results reveal a substantial delay in adequate treatment of patients with somatoform disorders. The reported DUI emphasizes the importance of improvements in the management of patients with these disorders. PMID- 29502758 TI - Mindfulness skills during pregnancy: Prospective associations with mother's mood and neonatal birth weight. AB - OBJECTIVES: Mindfulness skills have been associated with better mood and several health related outcomes. Because depressed mood during pregnancy has been related to worse child outcomes, the aim was to examine the association of mindfulness skills during pregnancy with the mother's depressive symptoms, gestational age, and neonatal birth weight. METHODS: A subsample of 905 pregnant women who participated in the longitudinal cohort HAPPY study (Holistic Approach to Pregnancy and the first Postpartum Year) completed the 12-item Three Facet Mindfulness-Questionnaire-Short Form at 22weeks of gestation. The Edinburgh Depression Scale was completed to assess depressive symptoms at 12, 22 and 32weeks. The obstetric medical records were examined for gestational age and birth weight. RESULTS: Mindfulness skills Acting with Awareness and Nonjudging at 22weeks were associated with less depressive symptoms at 22weeks and at 32weeks. When controlled for depressive symptoms at 22weeks, the association was still significant for Nonjudging predicting depressive symptoms at 32weeks (Beta=-0.12, p<0.01). Regarding the obstetric medical records, only Nonreacting was (positively) associated with birth weight (Beta=0.09, p<0.01). Controlling for gestational age, sex, parity, depressive symptoms, and health behavior, Nonreacting predicted a normal birth weight (OR=1.12, 95% CI=1.06-1.19), in contrast to low birth weight. CONCLUSION: It seems that different mindfulness skills during pregnancy are important in predicting mother's depressive symptoms compared to the prediction of child's birth weight. Potential mechanisms are discussed. PMID- 29502759 TI - Relationships among personality traits, metabolic syndrome, and metabolic syndrome scores: The Kakegawa cohort study. AB - OBJECTIVE: Metabolic syndrome and the presence of metabolic syndrome components are risk factors for cardiovascular disease (CVD). However, the association between personality traits and metabolic syndrome remains controversial, and few studies have been conducted in East Asian populations. METHODS: We measured personality traits using the Japanese version of the Eysenck Personality Questionnaire (Revised Short Form) and five metabolic syndrome components elevated waist circumference, elevated triglycerides, reduced high-density lipoprotein cholesterol, elevated blood pressure, and elevated fasting glucose-in 1322 participants aged 51.1+/-12.7years old from Kakegawa city, Japan. Metabolic syndrome score (MS score) was defined as the number of metabolic syndrome components present, and metabolic syndrome as having the MS score of 3 or higher. We performed multiple logistic regression analyses to examine the relationship between personality traits and metabolic syndrome components and multiple regression analyses to examine the relationship between personality traits and MS scores adjusted for age, sex, education, income, smoking status, alcohol use, and family history of CVD and diabetes mellitus. We also examine the relationship between personality traits and metabolic syndrome presence by multiple logistic regression analyses. RESULTS: "Extraversion" scores were higher in those with metabolic syndrome components (elevated waist circumference: P=0.001; elevated triglycerides: P=0.01; elevated blood pressure: P=0.004; elevated fasting glucose: P=0.002). "Extraversion" was associated with the MS score (coefficient=0.12, P=0.0003). No personality trait was significantly associated with the presence of metabolic syndrome. CONCLUSIONS: Higher "extraversion" scores were related to higher MS scores, but no personality trait was significantly associated with the presence of metabolic syndrome. PMID- 29502760 TI - Mental health assessment of altruistic non-directed kidney donors: An EAPM consensus statement. PMID- 29502761 TI - Association between postpartum physical symptoms and mood. AB - OBJECTIVE: Postpartum depression may be associated with higher levels of postpartum pain, but the association with discomfort in general is unclear. We sought to describe an association between postpartum mood disturbances and quantitatively measured physical symptoms at the time of the routine postpartum encounter. METHODS: We designed a novel quantitative measurement of postpartum symptoms, the Postpartum Symptom Inventory (PSI), to allow comparison to scores of postpartum mood. Women presenting for a routine postpartum visit were asked to complete a brief questionnaire about their delivery, the 20-item PSI, and an Edinburgh Postnatal Depression Scale (EPDS). Depression scores were compared with symptom inventory scores and demographic data. RESULTS: Two hundred six women responded, of whom 77% had a vaginal delivery. The most common physical symptoms experienced to a bothersome degree were fatigue (35.3%), back/hip pain (22.4%), and headache (13.2%). Twenty-nine women (14.3%) had an EPDS score of 10 or more, thereby screening positive for possible depression. Women screening positive had significantly greater total PSI scores than women who did not screen positive (20.2 vs 12.2, p < 0.001). After adjustment for history of depression and age, the odds of screening positive for depression were 3.6 times higher in women with PSI scores over 10 compared to women with lower scores [95% CI: (1.1, 11.4); p = 0.03]. CONCLUSION: Data suggest that a high level of physical symptomatology as measured by a PSI score >10 at six weeks post-delivery is associated with increased odds of screening positive for postpartum depression. PMID- 29502762 TI - The role of emotion regulation in chronic pain: A systematic literature review. AB - OBJECTIVE: Emotion regulation (ER) includes a set of cognitive and attentional processes used to change or maintain emotional state. A small but growing body of research suggests that maladaptive ER might be a risk factor for the development of chronic pain. This review aims to summarize existing literature on the association between ER and chronic pain, and to determine whether the construct of ER may further enhance our understanding of the risk and protective factors that may contribute to the onset and maintenance of chronic pain. METHODS: A systematic search was conducted using the search terms "chronic pain" and "emotion regulation." Studies that measured both constructs across all age groups were included. RESULTS: We found 15 studies that met our inclusion criteria. Nine studies were completed within the last five years, suggesting that the evaluation of ER as it relates to pain is a new line of research. Studies that measured "response-focused" ER found associations between maladaptive ER and pain. Studies that measured "antecedent-focused" ER strategies were less likely to show a direct association with pain. CONCLUSION: Maladaptive response-focused ER may be an important risk factor in the development and maintenance of chronic pain, as it is associated with pain and psychological comorbidities. Adding ER to chronic pain investigations may help to further explain individual differences in the risk and protective mechanisms that are known to influence chronic pain. Importantly, this line of research has potential to directly inform future interventions for patients with chronic pain. PMID- 29502763 TI - Specific, but not general beliefs about medicines are associated with medication adherence in patients with COPD, but not asthma: Cohort study in a population of people with chronic pulmonary disease. AB - BACKGROUND: Beliefs about medicines are regarded as influencing factors on medication adherence (Horne, 1997). Adherence levels in patients with chronic pulmonary diseases are low (Bourbeau and Bartlett, 2008; Sumino and Cabana, 2013). A better understanding of the predictive role of patients' beliefs about medicines for adherence might be a crucial step to improve medication adherence. OBJECTIVE: This prospective study investigated the association between beliefs about medicines and medication adherence in patients with asthma and COPD. METHODS: The Beliefs about Medicines Questionnaire (BMQ) and the Medication Adherence Rating Scale (MARS) were administered to 402 patients (49% asthma, 51% COPD, 50% female, mean age 56.7 years (SD = 15.9)) at baseline. Follow-ups were carried out after 3 (N = 255) and 12 months (N = 171). Multivariable logistic regression analyses were performed analysing the association between the BMQ subscales at baseline and adherence at each follow-up inquiry. Sociodemographic, psychosocial, and disease related factors were considered as potential confounders. RESULTS: One third of the patients showed adherent behavior (18% and 46% of people with asthma and COPD). In the COPD sample, the subscale Specific necessity showed a significant positive association with adherence at the 3 months-follow-up (OR = 2.6, 95% CI 1.4-5.1) and the subscale Specific-concerns showed a significant inverse association with adherence at the 3-months-follow-up (OR = 0.6, 95% CI 0.3-0.95) and the 12-months-follow-up (OR = 0.4, 95% CI 0.2 0.8). No significant association was found for the asthmatic sample. CONCLUSIONS: Beliefs about medicines are important factors predicting future medication adherence in patients with COPD, but not asthma. Physicians should primarily focus on the specific beliefs of their patients in order to diminish medication non-adherence. PMID- 29502764 TI - Limited evidence to measure the impact of chronic pain on health outcomes of Indigenous people. PMID- 29502766 TI - Psychometric properties of the Fear of Progression Questionnaire for parents of children with cancer (FoP-Q-SF/PR). AB - OBJECTIVE: Psychometric properties of the Fear of Progression Questionnaire - Short Form (FoP-Q-SF) were shown to be good in samples of adult cancer patients and their partners but have so far not been investigated in parents of children with cancer. This study therefore aimed to examine psychometric properties of the previously adapted parent version of the Fear of Progression Questionnaire (FoP-Q SF/PR) in pediatric oncology. METHODS: N=181 parents (119 mothers, 62 fathers) of n=128 children with diverse cancer entities, up to ten years after diagnosis were recruited at six hospitals and six registered parent associations in Germany and Austria between 06/2015 and 05/2016 (cross-sectional design). Parents provided medical information about their child and completed standardized questionnaires (Hospital Anxiety and Depression Scale, HADS; State-Trait Anxiety Inventory, STAI; Impact of Event Scale-Revised, IES-R; Ulm Quality of Life Inventory for Parents, ULQIE; Giessen Physical Complaints Inventory for children and adolescents, GBB-KJ). RESULTS: Exploratory factor analysis yielded two factors (50.2% explained variance) and internal consistency was good (Cronbach's alpha=0.89). Significant medium to large correlations of the FoP-Q-SF/PR were observed with anxiety (HADS: r=0.68; STAI: r=0.60-0.61), depression (HADS: r=0.58), posttraumatic stress (IES-R: r=0.42-0.64) and quality of life (ULQIE: r= 0.59). The FoP-Q-SF/PR discriminated between sub-groups, e.g. parents with and without clinical anxiety levels (Cohen's d=1.26). CONCLUSION: The FoP-Q-SF/PR demonstrated good reliability and validity for parents of children with cancer. The FoP-Q-SF/PR is a feasible screening instrument, which is suitable for the assessment of parental FoP in pediatric oncology. PMID- 29502765 TI - Resilience linked to personality dimensions, alexithymia and affective symptoms in motor functional neurological disorders. AB - OBJECTIVE: Reduced resilience, a construct associated with maladaptive stress coping and a predisposing vulnerability for Functional Neurological Disorders (FND), has been under-studied compared to other neuropsychiatric factors in FND. This prospective case-control study investigated self-reported resilience in patients with FND compared to controls and examined relationships between resilience and affective symptoms, personality traits, alexithymia, health status and adverse life event burden. METHODS: 50 individuals with motor FND and 47 healthy controls participated. A univariate test followed by a logistic regression analysis investigated group-level differences in Connor-Davidson Resilience Scale (CD-RISC) scores. For within-group analyses performed separately in patients with FND and controls, univariate screening tests followed by multivariate linear regression analyses examined factors associated with self reported resilience. RESULTS: Adjusting for age, gender, education status, ethnicity and lifetime adverse event burden, patients with FND reported reduced resilience compared to controls. Within-group analyses in patients with FND showed that individual-differences in mental health, extraversion, conscientiousness, and openness positively correlated with CD-RISC scores; post traumatic stress disorder symptom severity, depression, anxiety, alexithymia and neuroticism scores negatively correlated with CD-RISC scores. Extraversion independently predicted resilience scores in patients with FND. In control subjects, univariate associations were appreciated between CD-RISC scores and gender, personality traits, anxiety, alexithymia and physical health; conscientiousness independently predicted resilience in controls. CONCLUSION: Patients with FND reported reduced resilience, and CD-RISC scores covaried with other important predisposing vulnerabilities for the development of FND. Future research should investigate if the CD-RISC is predictive of clinical outcomes in patients with FND. PMID- 29502767 TI - Duplex Ultrasound for the Diagnosis of Acute and Chronic Venous Diseases. AB - Venous diseases are highly prevalent, mostly caused by valve incompetence and/or obstruction of the vein lumen. Signs and symptoms are diverse and unspecific. Careful clinical assessment and imaging interpretation are crucial to diagnosis. Duplex ultrasound is the first choice and often the gold standard imaging technique for this purpose, providing information on the anatomy and function of the veins. This article describes the sonographic anatomic and hemodynamic criteria used for the diagnosis of venous reflux, venous obstruction, and the most frequent complications after interventions in the superficial, perforating, and deep venous systems. PMID- 29502769 TI - Evidence-Based Therapies for Pharmacologic Prevention and Treatment of Acute Deep Vein Thrombosis and Pulmonary Embolism. AB - Venous thromboembolism (VTE) remains a significant mortal and morbid disease. The major risks have not changed and many patients present with unprovoked VTE disease. Prevention of VTE in hospitalized patients depends on comprehensive risk factor assessment, with an individual risk score. Proper and timely prophylaxis with mechanical, pharmacologic, or both is then effective. Treatment of VTE with parenteral anticoagulation followed by either a direct oral anticoagulant or warfarin is standard to reduce risk of VTE recurrence and death. Selected cases of iliofemoral deep vein thrombosis may be treated by pharmacomechanical thrombolysis, but more data are needed before this is standard of care. PMID- 29502768 TI - New Trends in Anticoagulation Therapy. AB - Anticoagulation pharmacy has been dramatically altered with US Food and Drug Administration (FDA) approval of 5 direct oral anticoagulants, 1 novel reversal agent and, a second designated for fast-track approval. Trial data surrounding current trends in anticoagulant choice for VTE, reversal, and bridging are constantly redefining practice. Extended therapy for unprovoked VTE has expanded to include low-dose direct oral anticoagulants, aspirin, and the use of the HERDOO2 system to identify women who can stop anticoagulant therapy without increased risk of recurrent VTE. Trends in thromboprophylaxis include extended duration low-dose direct oral anticoagulants to prevent VTE in high-risk patients. PMID- 29502770 TI - Catheter-Directed Therapy Options for Iliofemoral Venous Thrombosis. AB - Proximal deep venous thrombosis (DVT) is linked to a 50% risk of pulmonary embolism and a 50% risk of postthrombotic syndrome. This article reviews catheter directed thrombolysis options for iliofemoral DVT and discusses the risks, benefits, and techniques commonly used in performing endovascular procedures for iliofemoral DVT. PMID- 29502771 TI - Advances in Operative Thrombectomy for Lower Extremity Venous Thrombosis. AB - Lower extremity deep venous thrombosis is a leading cause of morbidity and mortality. The mainstay of therapy is medical. However, anticoagulation does not remove the thrombus and restore venous patency. In select patients, early thrombus removal and anticoagulation can restore venous patency, preserve venous valve function, and may reduce the incidence of postthrombotic syndrome. Catheter directed therapies are minimally invasive with low complication rates. However, in patients with a contraindication to thrombolytic agents who can receive anticoagulation, open thrombectomy should be considered if indications for thrombus removal are met and patients are good operative risks. PMID- 29502772 TI - Pulmonary Embolism: Current Role of Catheter Treatment Options and Operative Thrombectomy. AB - Pulmonary embolism remains a leading cause of death in the United States, with an estimated 180,000 deaths per year. Guideline-based treatment in most cases recommends oral anticoagulation for 3 months. However, in a small subset of patients, the "submassive, high-risk" by current nomenclature, with hemodynamic instability, more advanced therapeutic options are available. Treatment modalities to extract the thromboembolism and reduce pressure overload in the cardiopulmonary system include use of intravenous or catheter-directed thrombolytic agents, catheter-directed mechanical thrombectomy, and surgical embolectomy. This article discusses current minimally invasive and surgical methods for reducing embolic burden in patients with submassive, high-risk pulmonary embolism. PMID- 29502773 TI - Inferior Vena Cava Filters: Current Indications, Techniques, and Recommendations. AB - The vena cava filter (VCF) is intended to prevent the progression of deep venous thrombosis to pulmonary embolism. Recently, the indications for VCF placement have expanded, likely due in part to newer retrievable inferior vena caval filters and minimally invasive techniques. This article reviews the available VCFs, the indications for use, the techniques for placement, and possible outcomes and complications. PMID- 29502774 TI - Endovenous and Operative Treatment of Superior Vena Cava Syndrome. AB - Few areas of venous disease provide a more satisfying experience for both the patient and the vascular specialist than reconstruction for superior vena cava (SVC) syndrome. Relief from severe, frequently incapacitating symptoms of venous congestion of the head and neck is almost instantaneous, and benefit after reconstruction is generally long lasting. This article reviews the etiologic factors, clinical presentation, and diagnostic evaluation of SVC syndrome, and current techniques and results for the endovascular and open surgical treatment of SVC occlusion. PMID- 29502775 TI - Pathophysiology of Chronic Venous Disease and Venous Ulcers. AB - Chronic venous disease and venous leg ulceration are a common disease affecting millions of individuals. The fundamental problem is venous hypertension with resultant clinical manifestations of venous disease including varicose veins, skin changes, and venous leg ulceration. The pathophysiology leading to venous hypertension is complex and multifactorial, involving genetic predisposition, environmental factors, hormones, endothelial dysfunction, inflammatory cells and molecules and activation on the endothelium and vein wall, and disturbances in the balance of cytokines and matrix metalloproteinases. Understanding the pathophysiology of chronic venous disease and venous leg ulcers identifies cellular pathways, biomarkers, metabolic signatures, and cellular cross-talk for targeted therapy. PMID- 29502776 TI - Optimal Compression Therapy and Wound Care for Venous Ulcers. AB - Venous leg ulcers remain a major public health issue with significant economic impact. Two main components of the management of patients with venous leg ulcers are compression therapy and wound care. This article addresses principles and specific aspects of compression therapy and focal wound care for patients with venous leg ulcers. PMID- 29502777 TI - Role of Venous Stenting for Iliofemoral and Vena Cava Venous Obstruction. AB - Venous stenting for CVD is being increasingly used as more evidence accumulates supporting the open vein hypothesis and supporting the safety, efficacy, and durability of these interventions. As such, they can be offered to patients with advanced age and complex comorbidities. Future studies should focus on reporting outcomes specific to the underlying venous pathologic condition (thrombotic vs nonthrombotic and acute vs chronic) to provide better evidence for stenting in CVD, and the outcomes of new stent design with dedicated venous indications. PMID- 29502778 TI - Open Surgical Reconstruction for Deep Venous Occlusion and Valvular Incompetence. AB - This article considers the potential options for open deep venous reconstructions based on pathologic complication (obstruction vs insufficiency), anatomic location, presence of disease-free venous architecture, and patient need. Other things being equal, less invasive techniques and disease locations will be attempted as first-line therapy. When other options fail and symptoms persist, open venous surgery by means of bypass for obstructive disease and valve repair or replacement for deep venous insufficiency remains a viable option. The basic techniques available and overall success rates of each are considered. PMID- 29502779 TI - Thermal and Nonthermal Endovenous Ablation Options for Treatment of Superficial Venous Insufficiency. AB - Open saphenous removal, phlebectomy, and venous ligation were historic mainstays of surgical treatment of venous disease. Duplex ultrasound has become standard to diagnose venous insufficiency. Percutaneous modalities have allowed treatments to include thermal and nonthermal endovenous ablation. These treatments vary in preoperative planning, procedural steps, and postprocedural care, but all are safe and effective. An individualized approach should be taken in determining which modality is offered to each patient. Endovenous options, which often are minimally invasive and safely performed in an outpatient setting, allow access to effective treatments with low risk and discomfort. PMID- 29502780 TI - Phlebectomy Techniques for Varicose Veins. AB - Ambulatory phlebectomy is a well-known and widely used procedure for residual symptomatic venous disease. Tumescent anesthesia complements the procedure, providing the ability to perform this intervention in a wide range of practice settings. The procedures are well tolerated by most patients, and complications are rare. They include venous thromboembolism, infection, and hematoma and are generally simple to manage. Alternative and emerging techniques of powered phlebectomy and cyanoacrylate glue are providing alternative forms for treatment and will advance the practice further. PMID- 29502781 TI - Liquid and Foam Sclerotherapy for Spider and Varicose Veins. AB - Sclerotherapy has wide applicability in treating venous disease at every stage of clinical disease. The various sclerosant drugs and formulations each have unique properties, utilities, and side effects. Treating physicians should be aware of the differences between agents, accounting for disease presentation, vein characteristics, and patient comorbidities when selecting the appropriate sclerosing agents. Successful outcomes rely on proper patient evaluation and assessment for contraindications to sclerotherapy. Thorough patient education regarding realistic expectations with sclerotherapy in terms of symptoms relief, recurrence, and improvement in appearance is of chief importance. PMID- 29502782 TI - Foreword. PMID- 29502783 TI - Current Concepts and Treatments for Venous Disease. PMID- 29502784 TI - Between activity and solidarity: Comprehending retirement and extended working lives in Swedish rural areas. AB - The expected costs of population ageing have generally led to perceived needs to postpone the age of retirement. Drawing on 20 semi-structured interviews, the aim of this paper is to describe the ways that the possibility of an extended working life is comprehended by persons over the age of 60 living in sparsely populated areas in northern Sweden. While defining themselves as active, the interviewees argued strongly in favour of the right to retire. What are often described as opposing retiree subject positions - healthy and active vs. vulnerable and dependent - were partly transgressed in the interviews. The interviewees performed a solidarity that had the potential of including their future selves as possible objects of solidarity. Another important result was that in comprehending the possibility of an extended working life, morally charged notions of geographic place became central. PMID- 29502785 TI - Exploring the path to death through Barnes's older characters: Between irony and melancholic meditation. AB - This article aims at analysing four of Julian Barnes's novels with protagonists either entering or in their old age in order to discern to what extent conceptions of ageing, old age and death are depicted in Barnes's fiction and develop throughout his writing career. Barnes's memoir Nothing to Be Frightened Of (2008) will also be central in the discussion, since, in it, the author reflects on conceptions of old age and death from different philosophers and authors intermingling them with his own personal experience and that of his family, specially his parents. For Barnes, death represents another part of life, even though he himself has confessed to have been obsessed with death since his early adolescence. On the other hand, in Barnes's novels, and from the point of view of his protagonists, ageing and old age is not that different from other life stages, since, one's essence does not change throughout one's life course. By resourcing to irony and imbuing the narrative voice of his novels with what he calls melancholic meditation, Barnes approaches the reader to the experience of ageing, old age and death pointing to the fact that existential questions and life concerns are intrinsic to human beings rather than to specific ages. PMID- 29502786 TI - The art of doing good. Aging, creativity and wisdom in the Isabel Dalhousie novels. AB - Several studies have examined the interaction between the aging process and literary creativity, either to confirm the stereotype that wisdom and experience do not compensate for the inevitable decline of intellectual (and all) capacities (Lehman 1953; de Beauvoir 1972) or to highlight the empowering possibilities of embracing the knowledge and insight of a lifetime to continue developing creativity in maturity (Wyatt-Brown and Rossen 1993; Cohen-Shalev 2002; Casado Gual, Dominguez-Rue and Worsfold 2016). Not so much emphasis, however, has been put on how this new creative stage and the wisdom gained in a lifetime can contribute to improving the author's personal and/or intellectual fulfilment and, by extension, benefit readers by the sharing of that experience. Since wisdom is a quality often associated with old age, it would not be odd to assume that the lessons learned from life and career can not only lead the artist to a period of renewed engagement, but the sharing of that awareness can also inspire readers to get a glimpse of "the good life". One such example is the Scottish writer Alexander McCall-Smith (1948). McCall-Smith is currently one of the best-loved and most prolific authors in English, having written more than a hundred volumes, mostly after the age of fifty. Among such an extensive production, this article concentrates on his Sunday Philosophy Club series, featuring middle-aged philosopher and amateur detective Isabel Dalhousie, whose deep philosophical interrogations and intensely human dimension interrogate fundamental notions about ethical living and life at large. PMID- 29502787 TI - Suffering: The darker side of ageing. AB - Much of the literature on ageing is presaged upon a model of advocacy that seeks to combat what is seen as the negative stereotyping of old age and old people. One consequence is that ageing studies has difficulty in confronting the darker side of ageing except in so far as age associated disability and distress can be attributed to extrinsic disadvantage, such as low income, poor housing and inadequate services. The pain and suffering associated with age itself tend to be neglected as subject experiences. This paper seeks to shed some light on these topics, considered under the general heading of 'suffering'. Suffering can be viewed from the perspective of moral philosophy of medicine and of the social sciences. Serving as a witness to suffering has been proposed as the basis for an ethics of human dignity and as a call upon the collective moral agency of the community. Whether or not one accepts such an ethical viewpoint, it seems important for students of ageing to acknowledge document and explore the place of suffering in later life. PMID- 29502788 TI - Too many 'false dichotomies'? Investigating the division between ageing and disability in social care services in Ireland: A study with statutory and non statutory organisations. AB - Initiatives that bridge the fields of ageing and disability are considered critical internationally but to be limited in practice. Taking Ireland as a case, and focusing on social care, this article reports on a study investigating the separate organization of older people's and disability services as perceived by those working in policy-making, service provision and advocacy. In Ireland, as in many countries, social care is administered separately for disabled people and older people. Perceptions of those working in social care are thought to play a role in successful boundary-crossing initiatives. This study suggests that while participants often perceived the administrative and funding boundary between the fields of ageing and disability as illogical, inflexible, and not delivering person-centred care or support, the divide between the two sectors is underpinned by conceptual issues, including the lack of a concept of disability with ageing. The article argues that ways are needed of articulating what it is to experience disability in older age that are shared between older people's and disability sectors. It discusses bio-psychosocial models of disability as a means of doing so, one that avoids a return to an equation between older age and impairment, disability or decline. It concludes that more interrogation is needed of the separate philosophical underpinnings of disability and older people's sectors, argues for greater linkages between the two fields and for more exploration of social constructions of the experience of disability in later life. PMID- 29502789 TI - Stigma, discrimination and agency: Diagnostic disclosure as an everyday practice shaping social citizenship. AB - The importance of stigma in shaping the experiences of people living with dementia and challenging their social citizenship emerges repeatedly as a powerful and negative force. In a recent participatory action research (PAR) study focused on understanding what people with dementia need to know to live well, this link between stigma, discrimination and social citizenship emerged once again. A group of people living with dementia (n=8) met monthly for 16months to discuss their experiences and advise on the curriculum of a proposed self management program. From the first introduction, stigma was identified as a defining feature of the experience of living well with dementia. This paper analyses this group's talk around stigma and discrimination, drawing attention to the critical role that diagnostic disclosure has in both positioning people with dementia in a stigmatizing way and, also, acting as a strategy of resistance that facilitates full social citizenship. PMID- 29502790 TI - Social research and co-production with older people: Developing age-friendly communities. AB - The aging of the population, together with the need for more inclusive and responsive policies and services, has contributed to a burgeoning interest in co production and co-research with older people. To date, however, only a limited number of studies have addressed how the participation of older persons as research partners can be practically realized in community-based research. The purpose of this article is to provide insights into the process of co-producing a research project with older residents living in low-income neighborhoods in Manchester, United Kingdom. The project was unique in involving and training eighteen older people as co-researchers who took a leading role in all phases of a study aimed at developing "age-friendly" communities. The co-researchers also completed 68 interviews with residents aged 60 and over who were experiencing social isolation within their neighborhood. This paper describes the methodological approach developed for the study together with a description of the recruitment and training of co-researchers. It then presents findings based upon four reflection meetings with the co-researchers, focusing on their motivations for working on the project and their relationship with the interviewees. The article concludes with a discussion of the implications of the findings for developing co-production work with older people in age-friendly research, policy and practice. PMID- 29502791 TI - Quality of life in the contemporary politics of healthcare: ... but what is a life? AB - 'Quality of life' (QoL) is a ubiquitous phrase in medicine. There is considerable literature on the meaning of 'quality' in 'quality of life', but little on the meaning of 'life'. And yet, rooted in measurements of QoL, is a conceptualization of 'a life' used to judge 'quality'. In this article I focus on 'life' within institutional healthcare, arguing that for patients who are considered elderly, their life is defined against functionality. I use an autoethnographic method to enter this conversation, underlining the disjuncture between patients' understanding of 'a life', and that of healthcare professionals. I draw on the writings of the Italian philosopher Georgio Agamben to interrogate 'life', shifting the conversation of QoL from one of measurement and administration to one of political order. I discuss both the formal, evidence-based tools and the nature of their application. I conclude by arguing that QoL tools and their application, produce a particular kind of life, and that what is at stake in the invocation of 'quality of life' in health care is our very experience of aging and our embodiment. PMID- 29502792 TI - Relation of Coronary Artery Diameters With Cardiorespiratory Fitness. AB - Cardiorespiratory fitness is associated with reduced cardiovascular morbidity and mortality when adjusted for traditional risk factors. Mechanisms by which fitness reduces risk have been studied but remain incompletely understood. We hypothesize that higher fitness is associated with larger coronary artery diameters independent of its effect on traditional risk factors. Two independent measurements of the proximal diameters of the left main, left anterior descending, left circumflex, and right coronary arteries were obtained from gated multidetector computed tomography scans in 500 men from the Cooper Center Longitudinal Study (CCLS). Men with coronary artery calcium scores >=10 were excluded. Fitness was measured with a maximal exercise treadmill test and reported by quintiles and as a function of METs. We then evaluated the relation between coronary artery diameters and fitness using mixed effect regression models. Higher fitness was associated with larger coronary artery diameters after adjustment for body surface area, smoking status, low-density lipoprotein and high-density lipoprotein cholesterol, resting systolic blood pressure, and serum glucose. When examined continuously, each MET increase in fitness was associated with a mean 0.03 +/- 0.01 mm larger diameter of the left main, a 0.04 +/- 0.01 mm larger diameter of the left anterior descending, a 0.05 +/- 0.01 mm larger diameter of the left circumflex, and a 0.07 +/- 0.01 mm larger diameter of the right coronary artery (p = 0.002). This correlation between fitness and coronary artery diameters was most prominent for fitness levels above 10 METs. In conclusion, higher fitness is associated with larger coronary artery diameters. PMID- 29502793 TI - A Meta-Analysis Comparing Percutaneous Coronary Intervention With Drug-Eluting Stents Versus Coronary Artery Bypass Grafting in Unprotected Left Main Disease. AB - Coronary artery bypass grafting (CABG) is the preferred revascularization strategy for unprotected left main disease (UPLMD). Multiple small-scale trials and registry data showed that percutaneous coronary intervention (PCI) with drug eluting stents (DES) is a noninferior strategy with a Class IIa American College of Cardiology/American Heart Association recommendation in patients with high surgical risk and favorable anatomy. However, 2 recent large-scale randomized trials showed conflicting evidence. We conducted a meta-analysis of the existing data to compare outcomes of PCI with DES versus CABG for UPLMD. Four randomized and 8 nonrandomized trials involving 10,284 patients were included. Primary end point was composite of death, stroke, or myocardial infarction (MI) at 3 years or longer. Secondary end points were MACCE (Major Adverse Cardiac and Cerebrovascular Events) and its individual components (death, stroke, MI, or repeat revascularization). Mantel-Haenszel random effects model was used to calculate combined odds ratio for outcomes. A separate analysis of randomized data was also performed. There was no significant difference in primary composite outcome between PCI and CABG. However, MACCE was significantly higher in PCI, primarily driven by significantly high repeat revascularization. A subgroup analysis stratified by Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) score showed that MACCE and repeat revascularization were not significantly different between PCI and CABG in low to intermediate SYNTAX score (<33), whereas they were significantly higher in PCI with higher SYNTAX score. Thus, although CABG remains the preferred method of treatment in UPLMD, PCI with DES can be considered as a reasonable alternative in patients with favorable anatomy and high surgical risk. PMID- 29502794 TI - Azathioprine reduces the risk of audiometric relapse in immune-mediated hearing loss. AB - INTRODUCTION: Current schemes for treatment of immune-mediated hearing loss with sporadic short-course, low-dose corticosteroids, are insufficient. METHODS: To determine the role of azathioprine in the control of auditory impairment, a longitudinal, observational, descriptive study was performed with 20 patients treated with azathioprine (1.5-2.5mg/kg/day into two doses) for 1year. The loss of 10dB on two consecutive frequencies or 15dB on an isolated frequency was considered as relapse. RESULTS: The mean age of the patients was 52.50years (95%CI: 46.91-58.17), half were women. Bilateral affectation was 65%. 75% had organ specific disease and 25% had systemic autoimmune disease. The difference between baseline PTA (46.49dB; DS18.90) and PTA at 12months (45.47dB; DS18.88) did not reach statistical significance (P=.799). There was a moderate positive correlation between female sex and the presence of systemic disease (R=.577). By applying Student's t for paired data, a significant difference (P=.042) was obtained between the PTA in frequencies up to 1000 Hz (PTA125-1000Hz). The relative incidence rate of relapse per year was .52 relapses/year (95%CI: .19 1.14]). The median time to audiometric relapse-free was 9.70months (DS1.03). CONCLUSIONS: Azathioprine maintains the hearing threshold, decreases the risk of relapse, and slows down the rate at which patients relapse, altering the course of immune-mediated inner ear disease. PMID- 29502795 TI - [Management for locally advanced dermatofibrosarcoma protuberans in Togo]. PMID- 29502796 TI - Pulmonary hypertension in congenital diaphragmatic hernia patients: Prognostic markers and long-term outcomes. AB - : Prenatal observed/expected lung-to-head ratio (O/E LHR) by ultrasound correlates with postnatal mortality for congenital diaphragmatic hernia (CDH) patients. The aim of this study is to determine if O/E LHR correlates with pulmonary hypertension (PH) outcomes for CDH patients. METHODS: A single center retrospective chart review was performed for CDH neonates from January 1, 2006, to December 31, 2015, (REB #1000053124) to include prenatal O/E LHR, liver position, first arterial blood gas, repair type, echocardiogram (ECHO), and lung perfusion scan (LPS) results up to 5years of age. RESULTS: Of 153 newborns, 123 survived (80.4%), 58 (37.9%) had prenatal O/E LHR, and 42 (27.5%) had postnatal ECHO results. High mortality risk neonates (O/E LHR <=45%) correlated with higher right ventricular systolic pressure (RVsp) at birth. Generally PH resolved by age 5years. LPS results did not change over time (p>0.05) regardless of initial PH severity, suggesting that PH resolution did not correlate with increased ipsilateral lung perfusion to offload the right ventricle. CONCLUSION: Prenatal prognostic markers correlated with initial PH severity for CDH newborns, but PH resolved over time despite fixed perfusion bias to the lungs. These results suggest favorable PH outcomes for CDH patients who survive beyond infancy. TYPE OF STUDY: Retrospective Cohort Study. LEVEL OF EVIDENCE: 3b. PMID- 29502797 TI - Liver damage, proliferation, and progenitor cell markers in experimental necrotizing enterocolitis. AB - BACKGROUND: Necrotizing enterocolitis (NEC) is a disease known to cause injury to multiple organs including the liver. Liver regeneration is essential for the recovery after NEC-induced liver injury. Our aim was to investigate hepatic proliferation and progenitor cell marker expression in experimental NEC. METHODS: Following ethical approval (#32238), NEC was induced in mice by hypoxia, gavage feeding of hyperosmolar formula, and lipopolysaccharide. Breastfed pups were used as control. We analyzed serum ALT level, liver inflammatory cytokines, liver proliferation markers, and progenitor cell marker expression. Comparison was made between NEC and controls. RESULTS: Serum ALT level was higher in NEC (p<0.05). The mRNA expression of inflammatory cytokines in the liver was also higher in NEC (IL6: p<0.05, TNF-alpha: p<0.01). Conversely, mRNA expression of proliferation markers in the liver was lower in NEC (Ki67; p<0.01, PCNA: p<0.01). LGR5 expression was also significantly decreased in NEC as demonstrated by mRNA (p<0.05) and protein (p<0.01) levels. CONCLUSIONS: Inflammatory injury was present in the liver during experimental NEC. Proliferation and LGR5 expression were impaired in the NEC liver. Modulation of progenitor cell expressing LGR5 may result in stimulation of liver regeneration in NEC-induced liver injury and improved clinical outcome. LEVEL OF EVIDENCE: Level IV. PMID- 29502798 TI - Correlation of preoperative findings in computed axial tomography with the presence of difficult airway in patients undergoing head and neck otorhinolaryngological surgery. AB - OBJECTIVES: To establish a correlation between 4 measurements made on preoperative computed axial tomography and the presence of difficult airway, as well as its clinical prediction in patients undergoing otorhinolaryngological surgery. MATERIAL AND METHODS: A retrospective, observational study was carried out using the information gathered from the clinical notes of 104 patients undergoing general anaesthesia and endotracheal intubation for oncological otorhinolaryngological surgery over a period of 36 months. Based on the findings in the preoperative imaging tests, a multivariate logistic regression analysis was performed, where the dependent variable was the presence of extreme grades of visualization of the glottis visualisation (Cormack III-IV) or the presence of predictors of difficult intubation (Mallampati III-IV). This resulted in a total of 4 tomographic and clinical factors of difficult airway being introduced in this model. RESULTS: In the Cormack III-IV group, the results were not statistically significant in the multivariate model when compared to the tomography predictors, distance from epiglottis to posterior pharyngeal wall (95% CI; 0.030 - 2.31, P<.05), and the distance from the base of the tongue to the posterior pharyngeal wall (95% CI; 0.018-1.37, P<.05). In the Mallampati III-IV group, in the multivariate model only the distance from the vocal cords to the posterior pharyngeal wall showed clinically significant results (95% CI; 0.104 - 8.53, P<.05). CONCLUSIONS: In the approach to the airway, reliance on predictors is based on physical examination to anticipate situations that put oxygenation and ventilation of the patients at risk. There are still insufficient data to recommend imaging tests in this area, however it seems that in the future they may be added to the diagnostic performance of physical examination as predictors of difficult airway. PMID- 29502799 TI - Genetics of tardive dyskinesia: Promising leads and ways forward. AB - Tardive dyskinesia (TD) is a potentially irreversible and often debilitating movement disorder secondary to chronic use of dopamine receptor blocking medications. Genetic factors have been implicated in the etiology of TD. We therefore have reviewed the most promising genes associated with TD, including DRD2, DRD3, VMAT2, HSPG2, HTR2A, HTR2C, and SOD2. In addition, we present evidence supporting a role for these genes from preclinical models of TD. The current understanding of the etiogenesis of TD is discussed in the light of the recent approvals of valbenazine and deutetrabenazine, VMAT2 inhibitors, for treating TD. PMID- 29502800 TI - Paternal exposure to antirheumatic drugs-What physicians should know: Review of the literature. AB - Reproduction capacity and long-term preserved hormonal function are important aspects with big impacts on patients' quality of life. Updated information on the interaction between drug therapy and reproductive function is essential when discussing family planning with patients. Currently, limited data is published regarding paternal exposure to different medications. Thus, it may be a challenge for the practitioner to choose the right therapy for a young male patient. Therefore we reviewed the literature, for effects of antirheumatic drugs on male gonadal function with a focus on spermatogenesis and offspring. PMID- 29502801 TI - [Factors influencing the acceptability of pediatric galenic formulations]. AB - BACKGROUND AND GOAL OF THIS STUDY: Few available galenic formulations of drugs have pediatric doses, so that many of them are used off label in children. The influence of such pharmaceutical formulation on therapeutic adherence was evaluated in a systematic review of the literature. MATERIALS AND METHODS: This search was performed in 4 data bases: Medline, the Cochrane Library, Web of Science and Science Direct. Included articles were in French or English and focused on therapeutic adherence and route of administration. RESULTS: Overall, 51 articles were included in the study: 46 from Medline (27 selected), 1 from The Cochrane Library (1 duplicate), 61 from Web of Science (13 selected) and 23 articles from Science Direct (11 selected). The two main pharmaceutical formulations studied were liquid dosage form 51% (n=28) and solid oral form 35% (n=19). DISCUSSION: Easy use of liquid forms (n=18) (easy dose adjustment and administration) was associated with good adherence. Optimization of organoleptic properties was found to improve adherence (n=20). The main limitations to the use of solid oral formulations are the risk of choking in a child under 6 and difficulty adapting doses for pediatric use. Commercialization of minitablets should help solve these problems (n=3) and therapeutic education sessions could make it possible to prescribe selected pills to children aged 4 or older (n=2). A risk of misuse because of incorrect administration seems to be the reason that aerosols are underused. CONCLUSION: Drug formulation influences therapeutic adherence in children, which is a cornerstone for successful pharmacotherapeutic management. PMID- 29502802 TI - Infection of monocytes with European porcine reproductive and respiratory syndrome virus (PRRSV-1) strain Lena is significantly enhanced by dexamethasone and IL-10. AB - Monocytes are considered refractory to porcine reproductive and respiratory syndrome virus type 1 (PRRSV-1) infection. However, monocytes are only short lived in blood, being able to differentiate into macrophages and dendritic cells (DC). It was therefore merited to revisit PRRSV-1 interaction with monocytes, particularly those treated with cytokines influencing monocyte biology. Thus, several factors were screened, particularly those modulating monocyte differentiation and expression of putative PRRSV-1 receptors (CD169 and CD163). M CSF, known to stimulate macrophage differentiation, did not increase their susceptibility to PRRSV-1. Nor did GM-CSF or IL-4, known drivers for monocyte derived DC (MoDC) differentiation. In contrast, monocyte treatment with IL-10 or the corticosteroid, dexamethasone, known to be potent suppressors of monocyte differentiation, was correlated with increased susceptibility to PRRSV-1 infection. While this effect was strongly correlated to CD163 and CD169 expression, our data suggest that receptor expression is not the only factor driving successful infection of PPRSV-1 in monocytes. PMID- 29502803 TI - Aminopeptidase-N-independent entry of porcine epidemic diarrhea virus into Vero or porcine small intestine epithelial cells. AB - A monkey cell line Vero (ATCC CCL-81) is commonly used for porcine epidemic diarrhea virus (PEDV) propagation in vitro. However, it is still controversial whether the porcine aminopeptidase N (pAPN) counterpart on Vero cells (Vero-APN) confers PEDV entry. We found that endogenous expression of Vero-APN was undetectable in the mRNA and the protein levels in Vero cells. We cloned the partial Vero-APN gene (3340-bp) containing exons 1 to 9 from cellular DNA and subsequently generated two APN-knockout Vero cell lines by CRISPR/Cas9 approach. PEDV infection of two APN-knockout Vero cells had the same efficiency as the Vero cells with or without neuraminidase treatment. A Vero cells stably expressing pAPN did not increase PEDV production. SiRNA-knockdown of pAPN in porcine jejunum epithelial cells had no effects on PEDV infection. The results suggest that there exists an additional cellular receptor on Vero or porcine jejunal cells independent of APN for PEDV entry. PMID- 29502804 TI - Effect of Automated Bolus Calculation on Glucose Variability and Quality of Life in Patients With Type 1 Diabetes on CSII Treatment. AB - PURPOSE: Automated bolus calculation may benefit patients with poorly controlled type 1 diabetes who are relatively new to continuous subcutaneous insulin infusion (CSII). This study investigated the effect of automated bolus calculation on glucose variability, glucose control, and diabetes-related quality of life in patients with reasonably well-controlled type 1 diabetes, accustomed to treatment with CSII for several years. METHODS: This open-label, single-center study included 32 patients (mean age, 45.9 [15.1] years; 34% male; disease duration, 27.3 [12.9] years; glycosylated hemoglobin [HbA1c] level, 64.6 [12.5] mmol/mol [8.1% (1.1%)]; CSII treatment, 9.0 [7.8] years) who were randomly assigned to receive 4 months' treatment with a bolus calculator (n = 14) or continuation of standard care without a bolus calculator (n = 18). All participants received dietary counseling on carbohydrate counting. Primary outcome was glucose variability, as assessed by the SD of 7-point glucose profiles. Secondary outcomes included HbA1c, rate of (severe) hypoglycemia, and diabetes-related quality of life. FINDINGS: After 4 months of follow-up, glucose variability had improved in the bolus calculator group compared with the control group (change, -0.8 [0.9] vs 0.1 [0.9] mmol/L; P = 0.030). Mean glucose levels did not change in either group (0.4 [1.1] vs 0.3 [0.9] mmol/L; P = 0.95). There were also no differences in change in hypoglycemia rate (-0.6 [1.6] vs -0.4 [1.6] event per patient per week; P = 0.67), HbA1c value (-0.5 [6.6] vs -4.9 [10.6] mmol/mol; P = 0.21), or diabetes-related quality of life between the bolus calculator group and the control group. IMPLICATIONS: Use of a bolus calculator modestly improved glucose variability in this relatively small group of patients with longstanding type 1 diabetes on CSII but did not affect other parameters of glycemic control or diabetes-related quality of life. PMID- 29502805 TI - A Randomized Phase I Study Comparing the Pharmacokinetics of HD201, a Trastuzumab Biosimilar, With European Union-sourced Herceptin. AB - PURPOSE: This first-in-human study of HD201 was designed to evaluate the pharmacokinetic (PK) equivalence between this biosimilar candidate and trastuzumab sourced in the European Union (EU-trastuzumab)*. METHODS: In this randomized, blinded, single-dose comparative PK study, healthy male subjects were randomized to receive a single 6 mg/kg IV dose of HD201 or EU-trastuzumab. The primary PK end point was AUC0-infinity. Equivalence was determined by using the predefined margins of 0.8 to 1.25. Other PK parameters were included as secondary end points. FINDINGS: Baseline demographic characteristics for the 73 randomized subjects were similar across the 2 groups: median age 29 and 30 years old (ranges 19 - 45), median weight 78.6 and 81.7 kg (ranges 60.2 - 101). The 90% CIs for the geometric least squares mean of the AUC0-infinity were included within the margins of 0.8 to 1.25. All other PK parameters were comparable for both HD201 and EU-trastuzumab. The proportions of subjects who experienced adverse events related to the study drug were 61.8% and 82.9% in the HD201 and EU-trastuzumab groups, respectively. The most frequently reported adverse events related to the study drug were infusion-related reactions. No subjects had positive results for antidrug antibodies after a single dose. IMPLICATIONS: This study reported the PK equivalence between HD201 and EU-trastuzumab. HD201 was well tolerated with no safety concerns after single-dose administration in healthy male subjects. EudraCT No.: 2012-000805-56. PMID- 29502806 TI - Imperforate syringocele of the Cowper's gland. Diagnosis by urethrosonography. PMID- 29502807 TI - Rapid voltammetric method for quinine determination in soft drinks. AB - A novel voltammetric assay for quinine (QN) determination using an electrochemically pretreated pencil graphite electrode is described. The detection limit of QN was 2 * 10-7 M. The method possesses some obvious advantages including extreme simplicity, rapid response, and low cost. PMID- 29502808 TI - Purification and identification of anti-inflammatory peptides from spent hen muscle proteins hydrolysate. AB - Spent hens have low market value and incur significant costs for disposal. This study explored the use of spent hens as a source of bioactive peptides. Spent hen hydrolysates prepared by Protease M or Protex 50FP exhibited interleukin (IL)-6 inhibitory activity in endotoxin-activated macrophage-like U937 cells (p < .05). The potential peptides from Protex 50FP hydrolysate were further fractionated using a combination of ultrafiltration, solid-phase extraction and high performance liquid chromatography; 17 novel peptides encoded in major muscle proteins were identified by mass spectrometry analysis, of which 7 were chemically synthesized and assayed for the IL-6 inhibitory activity. At a concentration of 100 ug/mL, peptide FLWGKSY induced a 79% reduction of IL-6 production in endotoxin-activated macrophage-like U937 cells, which is comparable to results reported from other food sources. Our results indicate that spent hens have potential to be a source of bioactive peptides for anti-inflammatory applications. PMID- 29502809 TI - Identification of the free phenolic profile of Adlay bran by UPLC-QTOF-MS/MS and inhibitory mechanisms of phenolic acids against xanthine oxidase. AB - Adlay bran free phenolic extract has been previously demonstrated to possess potent xanthine oxidase (XOD) inhibitory activity. The aims of this study were to characterize the free phenolic profile of adlay bran and investigate the structure-activity relationship, underlying mechanism and interaction of phenolic acids as XOD inhibitors. A total of twenty phenolics including ten phenolic acids, two coumarins, two phenolic aldedhyes and six flavonoids were identified in a phenolic compound-guided separation by UPLC-QTOF-MS/MS. Adlay bran free phenolic extract possessed strong XOD inhibitory activity related to hydroxycinnamic acids with methoxyl groups. The hydrogen bonding and hydrophobic interactions were the main forces in the binding of adlay phenolics to XOD. Sinapic acid, identified in adlay bran for the first time, possessed strong XOD inhibitory activity in a mixed non-competitive manner, and synergistic effects with other adlay phenolic acids at low concentrations, and would be a promising agent for preventing and treating hyperuricemia. PMID- 29502810 TI - Effect of acorn meal-water combinations on technological properties and fine structure of gluten-free bread. AB - Gluten-free breads were developed from rice flour and corn starch at a constant ratio 1:1 with acorn meal addition (5, 15, 25%), at three levels of water (65, 70, 75%). Acorn supplemented gluten free breads better met sensory preference than rice breads in terms of colour (brown hue was enhanced) and were also nutritionally improved in terms of total phenolics. The specific volume of breads significantly decreased with increasing acorn addition while crumb hardness was also increased. SEM images confirmed that the decrease in the DeltaH values at low water level (65%) was due to less swelling of starch as observed from large starch granule remnants present after baking. XRD measurements revealed coexistence of "B" and "V" type starch structures. Increasing of acorn concentration enhanced the intensity of FTIR bands at 994, 1016 and 1077 cm-1. PMID- 29502811 TI - In-silico prediction of sweetness using structure-activity relationship models. AB - Quantitative structure activity relationship (QSAR) models appear to be an ideal tool for quick screening of promising candidates from a vast library of molecules, which can then be further designed, synthesized and tested using a combination of rigorous first principle simulations, such as molecular docking, molecular dynamics simulation and experiments. In this study, QSAR models have been built with an extensive dataset of 487 compounds to predict the sweetness potency relative to sucrose (ranging 0.2-220,000). The whole dataset was randomly split into training and test sets in a 70:30 ratio. The models were developed using Genetic Function Approximation (Rtest2 = 0.832) and Artificial Neural Network (Rtest2 = 0.831). Our models thus offer a convenient route for fast screening of molecules prior to synthesis and testing. Additionally, this study can supplement a molecular modelling approach to improve binding of molecules with sweet taste receptors, leading to design of novel sweeteners. PMID- 29502812 TI - Effect of lavender (Lavandula angustifolia) and melissa (Melissa Officinalis) waste on quality and shelf life of bread. AB - The effect of lavender (Lavandula angustifolia) and melissa (Melissa Officinalis) waste on preparation, characteristics and shelf life of bread was investigated. It was found that lavender and melissa waste, generated yearly in large amounts, were rich on polyphenols (especially rosmarinic acid) and aroma compounds, and exhibited high antioxidant and antimicrobial activity. The bread with 2.5% lavender waste was characterized with the highest loaf volume and loaf specific volume. The total dietary fiber increased three times and the polyphenols and flavonoids increased more than four times for breads with added 5% lavender and melissa waste, compared to control sample. The breads with 2.5% and 5% added lavender waste had increased shelf life (up to 96 h) compared to control, and no fungal or bacterial spoilage was observed during storage at 22 degrees C, 30 degrees C and 37 degrees C for four days. The sensory evaluation demonstrated that the consumers preferred mainly bread with 2.5% lavender waste. PMID- 29502813 TI - Grape pomace as a source of phenolic compounds and diverse bioactive properties. AB - The bio-residues resulting from the wine industry (grape pomace made up of skins, seeds and stems) are often undervalued but constitute a potential source of bioactive phenolic compounds that can be applied in several industries. In this context, the aim of the present study was to evaluate the phenolic profile of Vitis vinifera L. grape pomace (skins, seeds and their mixture), and correlate them with its antioxidant, cytotoxic and antibacterial activities. The seeds showed the highest amount of phenolic compounds and also the highest antioxidant, cytotoxic and antibacterial activities. The skins revealed the highest levels of anthocyanins and p-coumaric acid hexoside. Strong correlations were observed between the presence of phenolic compounds and all the bioactivities studied. These by-products are good sources of phenolic compounds with high antioxidant and antibacterial activity, and also presenting a moderate cytotoxicity activity. These added-value by-products have great applicability in food, pharmaceutical and cosmetic industries. PMID- 29502814 TI - Expression and characterization of a novel cold-adapted chitosanase suitable for chitooligosaccharides controllable preparation. AB - Chitooligosaccharide is widely used as a functional food additive and a valuable pharmacological agent. The transformation of chitinous biomass into valuable bioactive chitooligosaccharides is one of the most exciting applications of chitosanase. A novel glycoside hydrolase (GH) family 46 chitosanase (GsCsn46A) from rhizobacterium Gynuella sunshinyii was cloned and heterologously expressed in Escherichia coli. GsCsn46A showed maximal activity at pH 5.5 and 30 degrees C. GsCsn46A featured remarkable cold-adapted property, which controllably hydrolyzed chitosan to three types of chitooligosaccharides at the mild reaction condition (reaction condition: pH 5.5 at 30 degrees C; method for stopping the reaction: 50 degrees C for 30 min). The yields of three types of chitooligosaccharides products (degree of polymerization (DP): 2-7, 2-5 and 2-3) were 70.9%, 87.1% and 94.6% respectively. This novel cold-adapted chitosanase provides a cleaner production process for the controllable preparation of chitooligosaccharides with the specific DP. PMID- 29502815 TI - Effects of glutenin and gliadin modified by protein-glutaminase on pasting, rheological properties and microstructure of potato starch. AB - Glutenin and gliadin were treated with protein-glutaminase in order to obtain soluble glutenin (PG-Glu) and gliadin (PG-Gli). PG-Glu or PG-Gli was added to potato starch at various concentrations (0.5%, 1.0%, and 1.5% of starch weight, w/w), and the physicochemical properties and microstructure of starch/protein mixtures were investigated. The results showed that the presence of PG-Glu or PG Gli decreased the viscosity parameters and yield stress and consistency coefficient of mixed pastes. The starch/protein mixed pastes exhibited a pseudoplastic and shear-thinning behavior under yield stress condition, and the storage modulus and loss modulus increased. Moreover, the To, Tp, Tc, and DeltaH of starch/protein mixtures varied insignificantly compared with native starch. CLSM results confirmed the inhibition of PG-Glu and PG-Gli on the gelatinization of starch, and the morphology of starch granules became more compact. These results suggest that the physicochemical properties and microstructure of potato starch are effectively influenced by PG-Glu or PG-Gli. PMID- 29502816 TI - Arabinoxylan-starch-protein interactions in specially modified rye dough during a simulated fermentation process. AB - The purpose of the work was to determine which processes occur during fermentation of rye dough beside progressive hydrolysis of biopolymers and production of gases, and also to determine which compounds are most responsible for them. The study was conducted with a specially modified dough containing starch, arabinoxylan preparations (non-modified, hydrolysed and cross-linked) and protein obtained from rye wholemeal. Despite the same consistency of the dough samples, their viscosity and values of rheological parameters depended on the amount of arabinoxylan preparations and their molecular weight. Already at the stage of mixing the dough, high molecular complexes of arabinoxylan-protein and arabinoxylan-arabinoxylan were formed. Complex formation was confirmed in the modified dough preparation with rye starch including only arabinoxylan or rye protein as well as a combination of arabinoxylan and rye protein. The highest amount and molecular dimension of complexes were found in the sample composed of starch, cross-linked arabinoxylan and rye protein. PMID- 29502817 TI - Foliar applications of iron promote flavonoids accumulation in grape berry of Vitis vinifera cv. Merlot grown in the iron deficiency soil. AB - Flavonoids are important compounds for grape and wine quality. Foliar fertilization with iron compounds has been reported to have a substantial impact on grape composition in the grapevines growing in calcareous soil. However, much less is known about its real impact on flavonoid composition. In the present study, Ferric ethylenediamine di (O-hydroxyphenylacetic) acid (Fe-EDDHA) was foliar applied to Merlot (Vitis vinifera L.) grapevines growing in calcareous soil over two consecutive vintages in order to study its effect on grape flavonoid composition. Fe-EDDHA foliar supply tended to increase grape sugar, anthocyanin and flavonol content, decrease acid content and enhance the juice pH when compared to the control. Principal component analysis showed that the vintage also had influence on grape quality. The results suggested that Fe-EDDHA foliar application had an enhancement effect on grape secondary metabolism, and the effect increased the nutritional value of the consequent grapes and wines. PMID- 29502818 TI - Herbal distillates: A new era of grape marc distillates with enriched antioxidant profile. AB - Grape marc distillates are traditional alcoholic beverages, produced mostly in the Mediterranean countries. The present study proposes the enrichment of a Greek traditional grape marc distillate (tsikoudia) with selected herbs to enhance its natural antioxidants and functional properties. Total phenolic content, the antiradical and antioxidant activities, as well as the phenolic and sugar profiles using NMR and FT-IR spectroscopy were evaluated. The enrichment of distillates with Syzygium aromaticum L., Jasminum officinale L. and Eucalyptus globulus Labill. exhibited the highest total phenolic content as well as the highest antioxidant and antiradical activities, whereas the lowest values were observed with Hippophae rhamnoides L. and Lycium Barbarum Mill. The implementation of NMR and FT-IR spectroscopies attested to the presence of phenolic compounds and of specific carbohydrates in herbal distillates, postulating their migration from selected herbal species to tsikoudia and probably contributing to their organoleptic characteristics. The target of this approach leads to new added-value distillates with enhanced characteristics. PMID- 29502819 TI - Optimization of mixed surfactants-based beta-carotene nanoemulsions using response surface methodology: An ultrasonic homogenization approach. AB - In the present study, food grade mixed surfactant-based beta-carotene nanoemulsions were prepared without using any co-surfactant. Response surface methodology (RSM) along with central composite design (CCD) was used to investigate the effect of independent variables (surfactant concentration, ultrasonic homogenization time and oil content) on response variables. RSM analysis results revealed that experimental results were best fitted into a quadratic polynomial model with regression coefficient values of more than 0.900 for all responses. Optimized preparation conditions for beta-carotene nanoemulsions were 5.82% surfactant concentration, 4 min ultrasonic homogenization time and 6.50% oil content. The experimental values at optimized preparation conditions were 119.33 nm droplet size, 2.67p-Anisidine value and 85.63% beta-carotene retention. This study will be helpful for the fortification of aqueous products with beta-carotene. PMID- 29502820 TI - Preparation, characterization and catalytic behavior of pectinase covalently immobilized onto sodium alginate/graphene oxide composite beads. AB - Pectinase was immobilized onto sodium alginate/graphene oxide beads via amide bonds by using N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide as the activating agent. The immobilized pectinase was characterized by Fourier transform infrared spectra and scanning electron microscopy analyses. Immobilization conditions were optimized by Box-Behnken design and the response surface method. The activity of the immobilized pectinase prepared under optimal conditions reached 1236.86 +/- 40.21 U/g, with an enzyme activity recovery of 83.5%. The optimal pH of free pectinase was 4.5, while that of immobilized pectinase was shifted to 4.0. The optimal temperature of immobilized pectinase was increased to 60 degrees C, which was 10 degrees C higher than that of free form. Furthermore, the immobilized pectinase possessed a superior thermal stability and storage stability to those of free pectinase. Reusability studies indicated that the immobilized pectinase retained 73% of initial activity after six times cycles. Due to these good properties, such immobilized pectinase may find application in food industry. PMID- 29502821 TI - Comparison of the influence of pH on the selectivity of free and immobilized trypsin for beta-lactoglobulin hydrolysis. AB - Although immobilized trypsin is a viable alternative to the free one in solution for producing protein hydrolysates, the change of selectivity introduced by immobilization is unclear. In this study, we compared the selectivity of free and immobilized trypsin towards different cleavage sites of beta-lactoglobulin (beta Lg) with a focus on the impact of environmental pH. Both free and immobilized trypsin exhibited greater accessibility to native beta-Lg at elevated pH (from pH 7.2 to 8.7). Additionally, free trypsin preferred to attack cleavage sites located at the C-terminus at pH 7.8, whereas an opposite preference for the N terminus was observed at pH 8.7. Regarding the immobilized trypsin, the pH did not significantly influence its preference for the C- or N-terminus. Generally, immobilization of trypsin resulted in more focused cleavage within its specificity during the initial stage of hydrolysis, and some peptides were formed more rapidly by the immobilized trypsin. PMID- 29502822 TI - Functionality of ovalbumin during Chinese steamed bread-making processing. AB - Hen egg is commonly used in some cereal-based food, including cakes and bread. Ovalbumin, one of the major components of egg white protein, can affect the performance of the food product. The interaction between ovalbumin and gluten protein and its effect on property of dough and quality of Chinese steamed bread was investigated in this study. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) patterns indicated that ovalbumin was surprisingly not incorporated in glutenins by covalent bond, whereas size-exclusion high performance liquid chromatography showed that glutenin macropolymer content in glutenins increased slightly. Furthermore, dynamic rheology experiments indicated ovalbumin led to a decrease inG' andG" of dough. Based on molecular dynamic simulation and SDS-PAGE results, it was inferred that ovalbumin was not hydrolyzed by endopeptidases during dough fermentation and crosslinked to gluten proteins during steaming. Finally, ovalbumin improved maximum dough height (Hm) during dough development and specific volume of Chinese steamed bread. PMID- 29502823 TI - Synthesis and antibacterial activity of C2 or C5 modified and D ring rejiggered canthin-6-one analogues. AB - Thirty-one canthin-6-one analogues, mainly including C2 or C5 or D ring modified canthin-6-ones, were designed and synthesized in order to study their antibacterial activity and structure-activity relationships. The analogue 28 with the highest bioactivity had a peak minimum inhibitory concentration of 4 MUg/ml and showed low cytotoxicity against L02 cells and good "drug-like" properties. The antibacterial effect of 28 was characterized further by scanning electron microscopy, cytoplasmic beta-galactosidase leakage assay, molecular docking evaluation, UV-visible analysis and isothermal titration calorimetry (ITC) measurement. The results showed that 28 may exert its bactericidal effect by damaging bacterial cell membranes and disrupting the function of DNA topoisomerases, both of which could lead to rapid cell death. PMID- 29502824 TI - A comparative study of ultra-sonication and agitation extraction techniques on bioactive metabolites of green tea extract. AB - The aim of this study was to compare methods for efficient extraction of green tea metabolites. Aqueous green tea leaf powder extracts were prepared by ultra sonication extraction (UE), agitation extraction (AE), and the conventional extraction method (control) at different temperatures (60, 70, and 80 degrees C) and times (5-30 min). Compared to the control, both UE and AE techniques significantly increased the yields of polyphenols (three-fold), catechins (two fold), and flavonoids (two-fold), and resulted in higher antioxidant activity. For both techniques, highest extraction efficiency of bioactive metabolites occurred at 80 degrees C for 20 min. Caffeine, total free amino acid, vitamin C, and total soluble solid contents were also significantly increased using either technique compared to the control. Thus, AE and UE have similar extraction efficiencies and could be used to prepare antioxidant-rich green tea extract or green tea extract powder. PMID- 29502825 TI - Accounting for the effect of degree of milling on rice protein extraction in an industrial setting. AB - The by-products of rice milling (BRM), which are predominately rice bran, are a potential source of soluble protein that has been underexploited due to difficulties in extraction. Significant advances have been made understanding how protein content changes with degree of milling (DOM) at the laboratory scale. However, these results cannot be compared due to the lack of information on how DOM affects protein extractability in industrially produced BRM. The colorimetry or particle size analysis may estimate milling degree in industrial scale, and protein extractability changes due to a series of abrasive milling passes. Both colorimetry and particle size could differentiate the industrial abrasive passes and correlated with the amount of bran/protein present. Both the 1st and 2nd pass of milling were suitable sources for the extraction. While the relative amount of protein extracted in each fraction changed, the protein profile of the major fractions was conserved between mill passes. PMID- 29502826 TI - The influence of yeast on chemical composition and sensory properties of dry white wines. AB - This study evaluates the impact on two varietal white wines from 'Chardonnay' and 'Verdejo' cultivars of different fermentative strategies: inoculation with Saccharomyces cerevisiae yeast (CT), sequential inoculation (Torulaspora delbrueckii/Saccharomyces cerevisiae) (SI), and spontaneous fermentation (SP). The wines' chemical composition was characterized by oenological parameters, organic acids, metals, major volatile compounds, ester compounds and sensory analyses. The fermentative strategy (CT, SI and SP) was found to be a key factor for assessing different styles of white wines. SI wines showed enhanced 'mature fruit' nuances and a chemical profile characterized by higher content of ethyl propanoate, ethyl isobutyrate and ethyl dihydrocinnamate. Meanwhile, the SP wines presented enhanced "stone fruit" nuances possible related to the higher contents of 2-phenyl acetate and isobutyl acetate. After a chemometric approach the above esters were identified as the markers of each fermentative strategy, independently of the variety. PMID- 29502827 TI - Biochemical characterization of two GH70 family 4,6-alpha-glucanotransferases with distinct product specificity from Lactobacillus aviarius subsp. aviarius DSM 20655. AB - Nine GtfB-like 4,6-alpha-glucanotransferases (4,6-alpha-GTs) (represented by GtfX of L. aviarius subsp. aviarius DSM 20655) were identified to show distinct characteristics in conserved motifs I-IV. In particular, the "fingerprint" Tyr in motif III of these nine GtfB-type 4,6-alpha-GTs was found to be replaced by a Trp. In L. aviarius subsp. aviarius DSM20655, a second GtfB-like protein (GtfY), containing the canonical GtfB Tyr residue in motif III, was located directly upstream of GtfX. Biochemical characterization revealed that both GtfX and GtfY showed GtfB-like 4,6-alpha-GT activity, cleaving (alpha1->4) linkages and catalyzing the synthesis of (alpha1->6) linkages. Nonetheless, they differ in product specificity; GtfY only synthesizes consecutive (alpha1->6) linkages, yielding linear alpha-glucan products, but GtfX catalyzes the synthesis of (alpha1->6) linkages predominantly at branch points (22%) rather than in linear segments (10%). The highly branched alpha-glucan produced by GtfX from amylose V is resistant to digestion by alpha-amylase, offering great potential as dietary fibers. PMID- 29502828 TI - Screening and profiling of natural ketocarotenoids from environmental aquatic bacterial isolates. AB - Ketocarotenoids are high-value natural pigments. The red diketocarotenoid astaxanthin particularly exhibits an extraordinary antioxidant activity, which raises its market demand for foods and nutraceuticals. We screened for ketocarotenoid-producing bacteria from both marine and freshwater environments. Phylogenetic analysis, based on 16S rRNA gene sequence, revealed 37 potential producers of ketocarotenoids that are related to alpha-proteobacteria, comprising 32 strains of Brevundimonas and 5 strains of Erythrobacter. Carotenoids analysis by HPLC-DAD and HPLC-MS revealed two groups; astaxanthin-producers (28 Brevundimonas strains) and adonixanthin-producers (Five Brevundimonas and 5 Erythrobacter strains). Strain FrW-Asx16 exhibited the highest carotenoid production (1060 ug g-1 dry cells with 16.6% astaxanthin). Strain FrW-Asx-5 producing 946.1 ug g-1 dry cells carotenoid exhibited the highest astaxanthin content (~46%). The most intriguing result is the potential of producing natural colorants from freshwater bacterial isolates, and with high productivity and selectivity, suggesting a great promise for their application in food. PMID- 29502829 TI - Structural consequences of the interaction of puroindolines with gluten proteins. AB - The effect of puroindolines (PINs) on structural characteristics of wheat proteins was investigated in Triticum turgidum ssp. durum (cv. Svevo) and Triticum aestivum (cv. Alpowa) and in their respective derivatives in which PIN genes were expressed (Soft Svevo) or the distal end of the short arm of chromosome 5D was deleted and PINs were not expressed (Hard Alpowa). The presence of PINs decreased the amount of cold-SDS extractable proteins and the accessibility of protein thiols to specific reagents, but resulted in facilitated solvation of gluten proteins, as detected by tryptophan fluorescence measurements carried out on minimally mixed flour/water mixtures. We propose that PINs and gluten proteins are interacting in the grain or flour prior to mixing. Hydrophobic interactions between PINs and some of the gluten proteins modify the pattern of interactions among gluten proteins, thus providing an additional mechanistic rationale for the effects of PINs on kernel hardness. PMID- 29502830 TI - Study of the role of bran water binding and the steric hindrance by bran in straight dough bread making. AB - This study investigates the effect of the physical presence and water binding of wheat bran during bread making, and the possible mechanisms behind this effect. Regular bran, pericarp-enriched bran and synthetic bran-like particles with different water binding capacities and particle sizes were used. Incorporation of regular and pericarp-enriched bran in dough (15% dm) led to a lower oven rise than the control dough. Bread volumes decreased with 11% and 30%, respectively. Dough with synthetic bran, having a low water binding capacity, displayed a near to normal leavening and oven rise and resulted in a bread volume decrease of only 5% compared to the control. Particle size reduction of regular bran and synthetic bran to an average size of 200 um did not affect final bread quality. Results indicate that water binding by bran affects bread quality the most, whereas steric hindrance by physical presence of bran particles is less determinative. PMID- 29502831 TI - Stabilization of immature rice grain using infrared radiation. AB - Immature rice grain is one of the underutilized by-products of paddy milling process. Despite its high potential of use as a food ingredient, it is mainly utilized as feed due to the rancidity problem. In the present study, the composition of immature rice grain, the potential of using infrared (IR) radiation for stabilization, and the effects of IR stabilization on color, fatty acid composition, tocopherol and gamma-oryzanol contents of the grain were investigated. The free fatty acid (FFA) value of the unprocessed immature rice grain was 5.49% and increased to 35.71% at the end of 3 months of storage at room temperature. However, FFA content of the grains stabilized with IR radiation at specific conditions remained unchanged throughout the storage period. Moreover, IR stabilization did not caused a negative effect on the noted components of the immature rice grain. PMID- 29502832 TI - A highly selective and sensitive ultrasonic assisted dispersive liquid phase microextraction based on deep eutectic solvent for determination of cadmium in food and water samples prior to electrothermal atomic absorption spectrometry. AB - A simple, fast, green, sensitive and selective ultrasonic assisted deep eutectic solvent liquid-phase microextraction technique was used for preconcentration and extraction of cadmium (Cd) in water and food samples by electrothermal atomic absorption spectrometry (ETAAS). In this technique, a synthesized reagent (Z)-N (3,5-diphenyl-1H-pyrrol-2-yl)-3,5-diphenyl-2H-pyrrol-2-imine (Azo) was used as a complexing agent for Cd. The main factors effecting the pre-concentration and extraction of Cd such as effect of pH, type and composition of deep eutectic solvent (DES), volume of DES, volume of complexing agent, volume of tetrahydrofuran (THF) and ultrasonication time have been examined in detail. At optimum conditions the value of pH and molar ratio of DES were found to be 6.0 and 1:4 (ChCl:Ph), respectively. The detection limit (LOD), limit of quantification (LOQ), relative standard deviation (RSD) and preconcentration factor (PF) were observed as 0.023 ng L-1, 0.161 ng L-1, 3.1% and 100, correspondingly. Validation of the developed technique was observed by extraction of Cd in certified reference materials (CRMs) and observed results were successfully compared with certified values. The developed procedure was practiced to various food, beverage and water samples. PMID- 29502833 TI - An integrated approach combining HPLC, GC/MS, NIRS, and chemometrics for the geographical discrimination and commercial categorization of saffron. AB - In the present study, an integrated approach combining HPLC/DAD, GC/MS, near infrared (NIR) spectroscopy, and chemometrics was used to geographically discriminate saffron samples from Iran and China. Chinese and Iranian samples can be well-separated based on HPLC data analysed by a principal component analysis and an orthogonal partial least squares discriminant analysis. Picrocrocin and two types of crocins were found to be the discriminating variables, and the Chinese samples had higher contents of safranal and picrocrocin but lower cis crocin 3Gg, kaempferol-3-O-sophoroside and isophorone. Furthermore, an NIR method was successfully established to rapidly distinguish the Chinese and Iranian samples. The relationship between an ISO standard and the contents of the chemical indices was also studied. The results indicated that the ISO standard should be revised, especially for analysing safranal. PMID- 29502834 TI - Effects of polyol type and particle size on flavor release in chewing gum. AB - The influence of polyol type and particle size on the flavor release profile of chewing gum was investigated in vivo. Four chewing gum samples with an average particle size of 62 or 246 MUm for sorbitol and 57 or 184 MUm for mannitol were analyzed. Chewing gum formulated with mannitol, in general, had a higher aroma release than chewing gum formulated with sorbitol. Polyol type did not influence the release profile of the high intensity sweeteners (HIS) aspartame and acesulfame K. However, a smaller particle size resulted in a significantly higher release of HIS. The release rate of polyol was not significantly changed by particle size. Sensory analysis was also in agreement with the HIS delivery; the smaller particle size polyol gum was significantly higher in perceived sweetness intensity. In summary, two physical attributes of polyols (solubility and surface area) were reported to uniquely alter the delivery of aroma and taste stimuli. PMID- 29502835 TI - Enhancement of Z-aspartame synthesis by rational engineering of metalloprotease. AB - Metalloprotease PT121Y114S, an effective catalyst for Z-aspartame synthesis under the substrate (Z-Asp:l-Phe-OMe) molar ratio of 1:5, was obtained previously. Herein, a computational strategy combining molecular dynamics simulation of the enzyme-substrate complex with binding free energy (DeltaG) calculations was established to guide the further engineering of PT121Y114S. One His224 residue proximal to the PT121Y114S active site was selected on the basis of the difference in DeltaG decomposition of PT121Y114S toward l-Phe-NH2 and l-Phe-OMe. Site-saturation mutagenesis of His224 resulted in the mutants H224D, H224N, and H224S, which showed great improvement in Z-aspartame synthesis under an economical substrate molar ratio approaching 1:1. Furthermore, the kinetic constants of PT121Y114S and its mutants revealed that the affinity of mutants toward the l-Phe-OMe was significantly higher than that of PT121Y114S. Molecular dynamic simulation revealed that the enhanced synthetic activity may be attributed to the mutation stabilizing the transient state of the enzyme-l-Phe OMe complex. PMID- 29502836 TI - An instrument-free method based on visible chemical waves for quantifying the ethanol content in alcoholic beverages. AB - An alternative approach using visible chemical waves for ethanol determination is presented. The method is based on the dynamic change of chemical waves in the Belousov-Zhabotinsky (BZ) reaction by perturbation with ethanol. The observablepropagating waves, generatedina Petri dish, can be recorded by using a smartphone camera. The propagating distances are measured from photographic images and then plotted as a function of time to attain the wave velocity. It is found that wave velocities are inversely proportional to ethanol concentrations. By using this linear relationship, the ethanol content can be efficiently quantified with good intra-day and inter-day precision (<3% RSD). Validated by the GC technique, the developed method is highly reliable and successfully applied for quantifying the ethanol content in beer, colored whisky, and vodka samples. Hence, this new method provides an alternative practical strategy for simple quantitative detection of ethanol without the need for instruments. PMID- 29502837 TI - Seed characteristics and physicochemical properties of powders of 25 edible dry bean varieties. AB - Information on the physicochemical variability in dry bean seeds from different varieties grown over distinct crop years is lacking. This study was designed to investigate the relationship between the environment and the seed characteristics of 25 edible dry bean varieties and to expand the knowledge on their proximate composition, starch digestibility, solvent retention capacity, and pasting and thermal properties. The impact of bean genotype (25 varieties), growing environment (two crop years), and powder particle size (<=0.5 mm, <=1.0 mm) was investigated. Statistical differences (P > 0.05) in seed characteristics and in starch, amylose and protein contents were found among the 25 varieties. Unique pasting and thermal properties were observed, and genotype and particle size greatly affected these properties. The accumulated information can be used in breeding programs to select bean lines possessing unique properties for food ingredients while increasing the market value of the crop and enhancing human health. PMID- 29502838 TI - Characterization of laccase from apple fruit during postharvest storage and its response to diphenylamine and 1-methylcyclopropene treatments. AB - To gain better understanding on laccase in apples and reveal its role in browning color formation during storage, laccases in apples were investigated. The full length complementary DNAs encoding laccase genes were obtained from different tissues of apple including flowers, calyx, leaves and fruit peel of 'Red Delicious' and 'Cortland'. The apple laccases were compared to those in other plant species and found to have up to 99% homology to Arabidopsis and litchi. qRT PCR analysis revealed changes in transcript abundance of LAC genes (2, 7, 9, 12, 14, 15 and 16) during storage and in response to DPA and 1-MCP treatments. Enzyme activity of laccase protein in apple peel increased with storage in control fruit, while decreased significantly with DPA or 1-MCP. Changes in phenolic compounds in pericarp tissues decreased generally during storage, but no significant effect of DPA and 1-MCP treatments on the phenolic compounds was found. PMID- 29502839 TI - Corrigendum to "Composition and morphology of cuticular wax in blueberry (Vaccinium spp.) fruits" [Food Chemistry 219 (2017) 436-442]. PMID- 29502840 TI - Corrigendum to "Evaluation of estrogenic activity of red clover (Trifolium pratense L.) sprouts cultivated under different conditions by content of isoflavones, calorimetric study and molecular modelling" [Food Chem. 245 (2018) 324-336]. PMID- 29502841 TI - Phytochemicals and nutritional composition in accessions of Kei-apple (Dovyalis caffra): Southern African indigenous fruit. AB - Current study was initiated to identify the phytochemicals and the nutritional profile of eleven Kei-apple fruit accessions. Accession FH29 showed the highest level (492.45 mg 100 g-1 fresh weight) of total phenolic content, higher than the referral fruit, blueberry. Pyrogallol was identified as the predominant phenolic compound in all accessions. Accession FH 29 showed the highest (49.75 umol TEAC g 1 fresh weight) antioxidant capacity. Catechin content was higher in accessions; FH151, FH15, FH14, FH29, FH243, FH 239 and FH 231. Accessions, FH14 and FH232 exhibited higher levels of beta-carotene than the referral fruit apples (cv. Top red) and peaches (cv. Excellence). The total sugar (glucose and fructose) was highest (50 mg g-1 fresh weight) in accession FH240. Asparagine (3122.18 mg L-1) and gamma-aminobutyric (1688.87 mg L-1) were higher in accessions FH239 and FH243 respectively. Overall, the accession Kei-apple FH236 can be regarded as a good source of essential amino acids. PMID- 29502842 TI - Subcritical water extraction of phenolic and antioxidant constituents from pistachio (Pistacia vera L.) hulls. AB - Pistachio hulls, important by-products of pistachio processing, were extracted using an environmentally friendly process with subcritical water (SCW) at a pressure of 6.9 MPa in the range of 110 and 190 degrees C, and a flow rate of 4 ml/min. Detailed HPLC-DAD-ESI/MSn analyses allowed the identification of 49 phenolic compounds in the SCW extracts. Total gallotannin yields up to 33 g/kg were reached at 150-170 degrees C, where gallic acid (22.2 g/kg) and penta-O galloyl-beta-d-glucose (9.77 g/kg) levels were 13.2- and 10.6-fold higher than those in the aqueous methanol extracts. Flavonols were also effectively extracted at 110-150 degrees C (4.37-5.65 g/kg), while anacardic acid recovery was poor (1.13-2.77 g/kg). Accordingly, high amounts of anacardic acids (up to 50.7 g/kg) were retained in the extraction residue, revealing that SCW extraction allowed selective extraction of gallotannins and flavonols. Antioxidant capacities ranged from 0.68 to 1.20 mmol Trolox equivalents (TE)/g for SCW extracts increasing with temperature up 190 degrees C. PMID- 29502843 TI - The antioxidant activity and genotoxicity of isogarcinol. AB - The antioxidant activity and genotoxicity of isogarcinol were assessed by several in vitro tests. Its IC50 values for DPPH and ABTS were 36.3 +/- 3.35 uM and 16.6 +/- 3.98 uM, respectively, which were all lower than those of VC and BHT. Isogarcinol had no cyctotoxic or promotional activities at 1-10 uM in the CCK-8 assay, and negligible genotoxic effects at 50-500 uM on HepG2 cells by the single cell gel electrophoresis assay. Pre-incubation of the cells with 0.5-1.5 uM isogarcinol, before exposure to H2O2, significantly increased cell viability in a concentration-dependent manner. Isogarcinol also reduced intercellular reactive oxygen species accumulation, lactate dehydrogenase release and malondialdehyde levels, and increased superoxide dismutase activity and glutathione levels. Western-blot analysis revealed that it up-regulated pro-caspase-3 and reduced cleaved caspase-3 during H2O2-induced oxidative stress. All the above results indicate that isogarcinol promises to be useful as a natural antioxidant. PMID- 29502844 TI - Selection of the best active modified atmosphere packaging with ethylene and moisture scavengers to maintain quality of guava during low-temperature storage. AB - In modified atmosphere packaging of guava, moisture scavenger (MS) sachet containing 30-50 g of coarse silica gel and ethylene scavenger (ES) sachet containing 0-4 g of potassium permanganate was added as per central composite rotatable design. The headspace O2 and CO2 of the packages were studied at 4, 8 and 12 degrees C for 30 days and thereafter the guava were left for two days to ripen at 30 degrees C. After that the chilling injuries, percentage acceptable guava, peel color and pulp texture was analyzed. After two days ripening at 30 degrees C the samples with 3 g ES and 46 g MS registered higher L*, lower a* value & firmness (16.65 N), lowest chilling injury score. About 95% of guava was found acceptable in this treatment with 1.89-2.79% reducing sugar, 0.95-1.1% titrable acidity, 59% and 46.61% retention of total phenols and ascorbic acid respectively, resulting 32 days shelf-life of guava. PMID- 29502845 TI - Physical stability, microstructure and micro-rheological properties of water-in oil-in-water (W/O/W) emulsions stabilized by porcine gelatin. AB - Water-in-oil-in-water (W/O/W) emulsions could be utilized for fat-reduced food formulation and delivery of bioactive nutrients. However, due to thermodynamic instability, it is difficult to prepare stable double emulsions. The purpose of this study was to improve the stability of W/O/W double emulsions containing 2.0 M MgCl2 by adding porcine gelatin in the inner water phase. The impact of gelatin on the physical stability, microstructure and micro-rheological properties of W/O/W emulsions was investigated. It was found that, when the concentration of porcine gelatin exceeded 4.0 wt%, the stability of emulsions was improved, due to increased viscoelasticity of emulsion droplets. When MgCl2 concentration increased to 2.0 M, the particle size of emulsions increased, due to the osmotic pressure gradient, and the presence of gelatin further increased the droplet size. Confocal microscopy results showed that the presence of gelatin could improve the stability of W/O/W emulsions against coalescence?. PMID- 29502846 TI - Double emulsions as potential fat replacers with gallic acid and quercetin nanoemulsions in the aqueous phases. AB - The development of fat replacers to obtain healthier/functional foods is a constant challenge. With this aim, double emulsions (DE) with a blend of olive, linseed and fish oils as oil phase were developed. To prevent the oxidation of these oils, gallic acid and quercetin were incorporated in the internal and the external aqueous phase (W2), respectively, according to a factorial design. Considering the low solubility of quercetin in water, it was included in O/W nanoemulsions (QN), thus being freely dispersible in W2. The antioxidant activity in DE was attributed to QN, which significantly improved the oxidative stability of DE/QN. Furthermore, DE/QN showed good physical stability with a limited coalescence during storage at 4 degrees C for 28 days, significantly longer than time usually required for food ingredients. Therefore, DE/QN could be used as potential fat replacer in a variety of food formulations, providing blends of fatty acids consistent with dietary recommendations. PMID- 29502847 TI - Mechanisms of astringency: Structural alteration of the oral mucosal pellicle by dietary tannins and protective effect of bPRPs. AB - The interaction of tannins with salivary proteins is involved in astringency. This paper focussed on saliva lining oral mucosae, the mucosal pellicle. Using a cell-based model, the impact of two dietary tannins (EgC and EgCG) on the mucosal pellicle structure and properties was investigated by microscopic techniques. The role of basic Proline-Rich-Proteins (bPRPs) in protecting the mucosal pellicle was also evaluated. At low (0.05 mM) tannin concentration, below the sensory detection threshold, the distribution of salivary mucins MUC5B on cells remained unaffected. At 0.5 and 1 mM, MUC5B-tannin aggregates were observed and their size increased with tannin concentration and with galloylation. In addition, 3 mM EgCG resulted in higher friction forces measured by AFM. In presence of bPRPs, the size distribution of aggregates was greatly modified and tended to resemble that of the "no tannin" condition, highlighting that bPRPs have a protective effect against the structural alteration induced by dietary tannins. PMID- 29502848 TI - Persistence of thiacloprid and deltamethrin residues in tea grown at different locations of North-East India. AB - In order to examine the residues of thiacloprid (90 and 180 g a.i./ha) and deltamethrin (10 and 20 g a.i./ha) in fresh tea leaves, made tea and tea infusion, field experiments were conducted at three different locations viz. Kamalpur tea estate, Darjeeling; West Bengal, Teok tea Estate and AAU, Jorhat; Assam in India. Regardless of location and doses, residues of both the insecticides dissipated following first order kinetics. The half-life of Thiacloprid (4.93-5.38 days) was longer than that of deltamethrin (1.78-1.94 days). Processing of green tea leaves reduced the residue level of thiacloprid and deltamethrin in made tea. No residues of both these insecticides could be detected in tea infusion. With respect to the phenolic distribution in tea, a marked increase in total catechin monomers with thiacloprid and greater accumulation of EGCG and ECG (indices of phenol quality) with deltamethrin were observed. PMID- 29502849 TI - Analysis of avenanthramides in oat products and estimation of avenanthramide intake in humans. AB - Avenanthramides are phenolic compounds found only in oats, and are of interest due to suggested bioactivities, including anti-inflammatory effects and induction of apoptosis. The objective of this work was to optimise a high performance liquid chromatography (HPLC) method for analysis of avenanthramides in food, and analyse the avenanthramide content in 45 oat fractions and products. The optimised HPLC method was based on triplicate extraction of 100 mg sample with 1 ml 80% ethanol in phosphate buffer (pH 2.8) and used gallacetophenone as an internal standard. Avenalumic acid-derived avenanthramide homologues 2fd and 2pd were also present, making up to 20% of the total avenanthramides detected in oats. The amounts of avenanthramides detected in oat products was 2-82 ug/g. It was estimated that mean avenanthramide intake among oat consumers ranges from 0.3 to 2.1 mg/day, considerably lower than the amount used in studies that have investigated biological effects of avenanthramides in humans. PMID- 29502850 TI - Effect of increased groundwater viscosity on the remedial performance of surfactant-enhanced air sparging. AB - The effect of groundwater viscosity control on the performance of surfactant enhanced air sparging (SEAS) was investigated using 1- and 2-dimensional (1-D and 2-D) bench-scale physical models. The viscosity of groundwater was controlled by a thickener, sodium carboxymethylcellulose (SCMC), while an anionic surfactant, sodium dodecylbenzene sulfonate (SDBS), was used to control the surface tension of groundwater. When resident DI water was displaced with a SCMC solution (500 mg/L), a SDBS solution (200 mg/L), and a solution with both SCMC (500 mg/L) and SDBS (200 mg/L), the air saturation for sand-packed columns achieved by air sparging increased by 9.5%, 128%, and 154%, respectively, (compared to that of the DI water-saturated column). When the resident water contained SCMC, the minimum air pressure necessary for air sparging processes increased, which is considered to be responsible for the increased air saturation. The extent of the sparging influence zone achieved during the air sparging process using the 2-D model was also affected by viscosity control. Larger sparging influence zones (de saturated zone due to air injection) were observed for the air sparging processes using the 2-D model initially saturated with high-viscosity solutions, than those without a thickener in the aqueous solution. The enhanced air saturations using SCMC for the 1-D air sparging experiment improved the degradative performance of gaseous oxidation agent (ozone) during air sparging, as measured by the disappearance of fluorescence (fluorescein sodium salt). Based on the experimental evidence generated in this study, the addition of a thickener in the aqueous solution prior to air sparging increased the degree of air saturation and the sparging influence zone, and enhanced the remedial potential of SEAS for contaminated aquifers. PMID- 29502851 TI - Symptom-based network classification identifies distinct clinical subgroups of liver diseases with common molecular pathways. AB - BACKGROUND AND OBJECTIVE: Liver disease is a multifactorial complex disease with high global prevalence and poor long-term clinical efficacy and liver disease patients with different comorbidities often incorporate multiple phenotypes in the clinic. Thus, there is a pressing need to improve understanding of the complexity of clinical liver population to help gain more accurate disease subtypes for personalized treatment. METHODS: Individualized treatment of the traditional Chinese medicine (TCM) provides a theoretical basis to the study of personalized classification of complex diseases. Utilizing the TCM clinical electronic medical records (EMRs) of 6475 liver inpatient cases, we built a liver disease comorbidity network (LDCN) to show the complicated associations between liver diseases and their comorbidities, and then constructed a patient similarity network with shared symptoms (PSN). Finally, we identified liver patient subgroups using community detection methods and performed enrichment analyses to find both distinct clinical and molecular characteristics (with the phenotype genotype associations and interactome networks) of these patient subgroups. RESULTS: From the comorbidity network, we found that clinical liver patients have a wide range of disease comorbidities, in which the basic liver diseases (e.g. hepatitis b, decompensated liver cirrhosis), and the common chronic diseases (e.g. hypertension, type 2 diabetes), have high degree of disease comorbidities. In addition, we identified 303 patient modules (representing the liver patient subgroups) from the PSN, in which the top 6 modules with large number of cases include 51.68% of the whole cases and 251 modules contain only 10 or fewer cases, which indicates the manifestation diversity of liver diseases. Finally, we found that the patient subgroups actually have distinct symptom phenotypes, disease comorbidity characteristics and their underlying molecular pathways, which could be used for understanding the novel disease subtypes of liver conditions. For example, three patient subgroups, namely Module 6 (M6, n = 638), M2 (n = 623) and M1 (n = 488) were associated to common chronic liver disease conditions (hepatitis, cirrhosis, hepatocellular carcinoma). Meanwhile, patient subgroups of M30 (n = 36) and M36 (n = 37) were mostly related to acute gastroenteritis and upper respiratory infection, respectively, which reflected the individual comorbidity characteristics of liver subgroups. Furthermore, we identified the distinct genes and pathways of patient subgroups and the basic liver diseases (hepatitis b and cirrhosis), respectively. The high degree of overlapping pathways between them (e.g. M36 with 93.33% shared enriched pathways) indicates the underlying molecular network mechanisms of each patient subgroup. CONCLUSIONS: Our results demonstrate the utility and comprehensiveness of disease classification study based on community detection of patient network using shared TCM symptom phenotypes and it can be used to other more complex diseases. PMID- 29502852 TI - Consistency between subjectively and objectively measured hazard perception skills among young male drivers. AB - Young male drivers have lower hazard perception skills (HPS) than older and more experienced drivers and a tendency to overestimate their skills in hazardous situations. Both factors contribute to an over-representation in traffic accidents. Based on a sample of 63 drivers aged 18-24, this study compares the consistency of HPS measured by objective and subjective measures and the link between these measures is the key contribution of the study. Both visible and hidden hazards are included. Objective measures of HPS include responsiveness and eye movements while driving in a driving simulator. Subjective measures of HPS include self-reports derived based on the Hazard Perception Questionnaire (HPQ), Driving Skill Questionnaire (DSQ), and Brief Sensation Seeking Scale (BSSS). Results show that drivers who respond to the hazards on time, as compared to drivers who do not respond, have higher scores on subjective measures of HPS and higher driving skills in the visible but not in the hidden condition. Eye movement analysis confirms the difference and shows that response in time to hazards indicate higher HPS and young drivers are poor at detecting hidden hazards. Drivers with a response in time locate the hazard faster, have more fixations, but dwell less on the hazard. At the same time, those who do not respond have a later first fixation and fewer but longer fixations on the hazard. High sensation seeking drivers respond to visible hazards on time, suggesting that sensation seeking does not affect HPS negatively when the hazard is visible. To enhance the HPS among young drivers, the results of this study suggest that specific hazard perception training is relevant, especially for hazards that require more advanced HPS. PMID- 29502853 TI - Assessing rear-end crash potential in urban locations based on vehicle-by-vehicle interactions, geometric characteristics and operational conditions. AB - Rear-end crashes are one of the most frequently occurring crash types, especially in urban networks. An understanding of the contributing factors and their significant association with rear-end crashes is of practical importance and will help in the development of effective countermeasures. The objective of this study is to assess rear-end crash potential at a microscopic level in an urban environment, by investigating vehicle-by-vehicle interactions. To do so, several traffic parameters at the individual vehicle level have been taken into consideration, for capturing car-following characteristics and vehicle interactions, and to investigate their effect on potential rear-end crashes. In this study rear-end crash potential was estimated based on stopping distance between two consecutive vehicles, and four rear-end crash potential cases were developed. The results indicated that 66.4% of the observations were estimated as rear-end crash potentials. It was also shown that rear-end crash potential was presented when traffic flow and speed standard deviation were higher. Also, locational characteristics such as lane of travel and location in the network were found to affect drivers' car following decisions and additionally, it was shown that speeds were lower and headways higher when Heavy Goods Vehicles lead. Finally, a model-based behavioral analysis based on Multinomial Logit regression was conducted to systematically identify the statistically significant variables in explaining rear-end risk potential. The modeling results highlighted the significance of the explanatory variables associated with rear-end crash potential, however it was shown that their effect varied among different model configurations. The outcome of the results can be of significant value for several purposes, such as real-time monitoring of risk potential, allocating enforcement units in urban networks and designing targeted proactive safety policies. PMID- 29502854 TI - Evaluating variability in foot to pedal movements using functional principal components analysis. AB - There are reasons why the driver's foot may not be applied to the correct pedal while driving and this can lead to unintended consequences. In this study, we seek to capture common and unique patterns of variations in drivers' foot movements using functional principal components analysis (FPCA). This analysis technique was used to analyze three categories of pedal response types (direct hits, corrected trajectories, and pedal errors) based on the various foot to pedal trajectories. Data from a driving simulator study with video data of foot movements for 45 drivers was used for analyses. Most foot movements show common patterns associated with direct hits and corrected trajectories with some level of variation. However, those foot movements associated with unique patterns might be early indicators of pedal errors. The findings of this study can be used with collision mitigation systems to provide early detection of foot trajectories that are more likely to result in a pedal error. PMID- 29502855 TI - Interactive online learning on perioperative management of elderly patients. AB - INTRODUCTION: Surgical specialists and residents lack knowledge to adequately manage frail older patients. This study aims to evaluate the effects of an interactive online course regarding attitude, self-confidence and knowledge in perioperative management of the elderly patient. METHODS: The six-weeks course consisted of expert videos, literature readings, quizzes and forum discussions. Surgical consultants with geriatric expertise and geriatricians moderated online discussions and stimulated interaction. Knowledge, self-confidence and attitude of course participants were compared at the beginning and end of the course. RESULTS: 206 medical practitioners started the course. Knowledge scores improved significantly from 49% to 65% (p < 0.005). Participants felt more secure (p < 0.005) in the treatment of the older patient at the end of the course. A better attitude correlated with a higher total knowledge score in surgeons and surgical residents (p = 0.02). CONCLUSION: A six-week interactive online course on perioperative management of elderly patients increases relevant geriatric knowledge and improves self-confidence of residents and faculty. PMID- 29502856 TI - Differences between palpable and nonpalpable tumors in early-stage, hormone receptor-positive breast cancer. AB - BACKGROUND: We compared characteristics and outcomes of palpable versus nonpalpable, hormone-sensitive, early-stage breast cancers. METHODS: Patients from the North American Fareston vs. Tamoxifen Adjuvant (NAFTA) trial were divided into palpable (n = 513) and nonpalpable (n = 1063) tumor groups. Differences in pathological features, loco-regional therapy, disease-free survival (DFS) and overall survival (OS) were analyzed. RESULTS: Patients with palpable tumors were older, had larger tumors, and higher rates of lymph-node involvement. The tumors were more likely to be poorly differentiated, of high nuclear grade, and display lymphovascular invasion. After mean followup of 59 months, DFS and OS were significantly lower for palpable than nonpalpable tumors (DFS 93.5% vs. 98.4%, p < 0.001, OS 88.5% vs. 95.6%, p < 0.001). Controlling for age, size and nodal status, palpability was an independent factor for DFS (OR = 2.56; 95%CI, 1.37-4.79, p = 0.003) and OS (OR = 2.12; 95%CI, 1.38-3.28, p < 0.001). CONCLUSIONS: In a group of hormone-sensitive, mostly postmenopausal early stage breast cancer patients, palpable tumors were more likely to have more aggressive features and metastatic potential, which translated in to a higher incidence of breast cancer-related events and worse overall survival. PMID- 29502858 TI - Cellular therapies and stem cell applications in trauma. AB - BACKGROUND: As the leading cause of mortality in the United States, trauma management have improved drastically over the past few decades with improved resuscitation and hemorrhage control. Stem cells are being used in an attempt to augment healing from trauma. DATA SOURCES: PubMed and ClinicalTrials.gov were searched for published and registered pre-clinical and clinical trials for the application of stem cells to AKI, ARDS, shock, infection, TBI, wound healing, and bone healing. CONCLUSIONS: Stem cell therapy for augmentation of healing traumatic injuries appears safe, as demonstrated by completed phase I/II trials. Further large scale studies are needed to assess the clinical efficacy. PMID- 29502859 TI - Surgical Treatment of Popliteal Venous Aneurysm in a Young Patient. PMID- 29502857 TI - Stratifying SLN incidence in intermediate thickness melanoma patients. AB - BACKGROUND: Guidelines for melanoma recommend sentinel lymph node biopsy (SLNB) in patients with melanomas >=1 mm thickness. Recent single institution studies have found tumors <1.5 mm a low-risk group for positive SLNB. METHODS: A retrospective review of the Sentinel Lymph Node Working Group multicenter database identified patients with intermediate thickness melanoma (1.01-4.00 mm) who had SLNB, and assessed predictors for positive SLNB. RESULTS: 3460 patients were analyzed, 584 (17%) had a positive SLNB. Univariate factors associated with a positive SLNB included age <60 (p < .001), tumor on the trunk/lower extremity (p < .001), Breslow depth >=2 mm (p < .001), ulceration (p < .001), mitotic rate >=1/mm2 (p = .01), and microsatellitosis (p < .001). Multivariate analysis revealed age, location, and Breslow depth as significant predictors. Patients >=75 with lesions 1.01-1.49 mm on the head/neck/upper extremity and 1.5-1.99 mm without high-risk features had <5% risk of SLN positivity. CONCLUSIONS: Intermediate thickness melanoma has significant heterogeneity of SLNB positivity. Low-risk subgroups can be found among older patients in the absence of high-risk features. PMID- 29502860 TI - Long-term outcome of scleral-fixated posterior chamber intraocular lens implantation with the knotless Z-suture technique. AB - PURPOSE: To assess the long-term results and complications of scleral-fixated posterior chamber intraocular lenses (PC IOLs) with the knotless Z-suture technique. SETTING: University Eye Hospital, Tubingen, Germany. DESIGN: Retrospective case series. METHODS: Records of consecutive patients who had implantation of scleral-fixated PC IOLs with the knotless Z-suture technique with a minimum follow-up of 3 years were reviewed. RESULTS: Sixty-six eyes of 62 patients were included. The mean preoperative corrected distance visual acuity (CDVA) was 0.71 logarithm of the minimum angle of resolution (logMAR) +/- 0.58 (SD). The mean CDVA was 0.67 +/- 0.54 logMAR (P = .257; n = 66) after 3 years, 0.73 +/- 0.55 logMAR (P = .399; n = 60) after 5 years, 0.8 +/- 0.68 logMAR (P = .348; n = 30) after 8 years, and 1.09 +/- 0.76 logMAR (P = .069; n = 13) after 10 years. Failure because of suture breakage was observed in 11 eyes (16.7%) after a mean of 7.5 years. Kaplan-Meier time-to-event analysis showed a 40% failure probability after 10 years. Traumatic aphakia was the only risk factor for failure (odds ratio 4.1; 95% confidence interval, 1.0-18.3; P = .049). Complications included retinal detachment (15%), cystoid macular edema (9%), increased intraocular pressure requiring surgical intervention (7.6%), corneal edema (4.5%), and posterior iris-chafing syndrome with microhyphema (3%). CONCLUSIONS: Implantation of scleral-fixated PC IOLs using the knotless Z-suture was a safe technique resulting in good visual outcomes. The long-term success of the procedure was dependent on the material properties of the suture. PMID- 29502861 TI - New surgical approach for intrascleral fixation using an intraocular lens with hook-shaped haptics. AB - We report a new surgical technique of intrascleral posterior chamber intraocular lens (PC IOL) fixation using a newly developed hook-shaped haptic IOL (NX-70CH) and a 25-gauge loop-shaped haptic manipulator. Previous techniques of intrascleral PC IOL fixation had 2 major technical challenges; that is, externalization of the haptic and fixation of the haptic into the scleral tunnel. The new IOL and manipulator can facilitate externalization and secure fixation of the IOL haptic and can be used for suture fixation or implantation in the capsular bag in cases with presumed subluxated lens. PMID- 29502863 TI - Quality Activity or Research: Does it matter? PMID- 29502862 TI - Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 Alpha as a Novel Target for Bipolar Disorder and Other Neuropsychiatric Disorders. AB - Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) is a protein that regulates metabolism and inflammation by activating nuclear receptors, especially the family of peroxisome proliferator-activated receptors (PPARs). PGC-1 alpha and PPARs also regulate mitochondrial biogenesis, cellular energy production, thermogenesis, and lipid metabolism. Brain energy metabolism may also be regulated in part by the interaction between PGC-1 alpha and PPARs. Because neurodegenerative diseases (Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis) and bipolar disorder have been associated with dysregulated mitochondrial and brain energy metabolism, PGC-1 alpha may represent a potential drug target for these conditions. The purpose of this article is to review the physiology of PGC-1 alpha, PPARs, and the role of PPAR agonists to target PGC-1 alpha to treat neurodegenerative diseases and bipolar disorder. We also review clinical trials of repurposed antidiabetic thiazolidines and anti-triglyceride fibrates (PPAR agonists) for neurodegenerative diseases and bipolar disorder. PGC-1 alpha and PPARs are innovative potential targets for bipolar disorder and warrant future clinical trials. PMID- 29502864 TI - Hemoptysis? Try Inhaled Tranexamic Acid. AB - BACKGROUND: Tranexamic acid (TXA) is a synthetic anti-fibrinolytic agent used to prevent and treat various bleeding complications. In many studies, investigators have evaluated its utility and safety orally, intravenously, and topically, but few studies have described the potential benefits of nebulized TXA. CASE REPORT: We present a case of massive hemoptysis treated with nebulized TXA in the emergency department (ED) that led to the cessation of bleeding and avoidance of endotracheal intubation. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: In massive hemoptysis, rapidly available nebulized TXA may be considered a therapeutic option, serving either as primary therapy or as a bridge until other definitive therapies can be arranged. PMID- 29502865 TI - Use of the d-dimer for Detecting Pulmonary Embolism in the Emergency Department. AB - BACKGROUND: Assessment for pulmonary embolism (PE) in the emergency department (ED) remains complex, involving clinical decision tools, blood tests, and imaging. OBJECTIVE: Our objective was to examine the test characteristics of the high-sensitivity d-dimer for the diagnosis of PE at our institution and evaluate use of the d-dimer and factors associated with a falsely elevated d-dimer. METHODS: We retrospectively collected data on adult patients evaluated with a d dimer and computed tomography (CT) pulmonary angiogram or ventilation perfusion scan at two EDs between June 4, 2012 and March 30, 2016. We collected symptoms (dyspnea, unilateral leg swelling, hemoptysis), vital signs, and medical and social history (cancer, recent surgery, medications, history of deep vein thrombosis or PE, chronic obstructive pulmonary disease, smoking). We calculated test characteristics, including sensitivity, specificity, and likelihood ratios for the assay using conventional threshold and with age adjustment, and performed a univariate analysis. RESULTS: We found 3523 unique visits with d-dimer and imaging, detecting 198 PE. Imaging was pursued on 1270 patients with negative d dimers, revealing 9 false negatives, and d-dimer was sent on 596 patients for whom negative Pulmonary Embolism Rule-Out Criteria (PERC) were documented with 2% subsequent radiographic detection of PE. The d-dimer showed a sensitivity of 95.7% (95% confidence interval [CI] 91-98%), specificity of 40.0% (95% CI 38 42%), negative likelihood ratio of 0.11 (95% CI 0.06-0.21), and positive likelihood ratio of 1.59 (95% CI 1.53-1.66) for the radiographic detection of PE. With age adjustment, 347 of the 2253 CT scans that were pursued in patients older than 50 years with an elevated d-dimer could have been avoided without missing any additional PE. Many risk factors, such as age, history of PE, recent surgery, shortness of breath, tachycardia and hypoxia, elevated the d-dimer, regardless of the presence of PE. CONCLUSIONS: Many patients with negative d-dimer and PERC still received imaging. Our data support the use of age adjustment, and perhaps adjustment for other factors seen in patients evaluated for PE. PMID- 29502866 TI - A novel germline PIGA mutation causes early-onset epileptic encephalopathies in Chinese monozygotic twins. AB - We report a case of 14-month-old male monozygotic twins showing early-onset intractable epilepsy, delayed psychomotor development, hypotonia, opisthotonus, and dysmorphism. They presented with refractory partial and secondary generalized tonic-clonic or myoclonic seizures since age of 6 months. Electroencephalograms mainly revealed fast activity in left occipital region and generalized high amplitude polyspikes and wave. Brain MRI was normal. A de novo germline hemizygous mutation, C.110 T > C (p.37 M > T), in exon 2 of PIGA was confirmed, which indicated that a novel germline mutation in PIGA leads to early-onset epileptic encephalopathies. PMID- 29502867 TI - Clustering on Membranes: Fluctuations and More. AB - Clustering of extracellular ligands and proteins on the plasma membrane is required to perform specific cellular functions, such as signaling and endocytosis. Attractive forces that originate in perturbations of the membrane's physical properties contribute to this clustering, in addition to direct protein protein interactions. However, these membrane-mediated forces have not all been equally considered, despite their importance. In this review, we describe how line tension, lipid depletion, and membrane curvature contribute to membrane mediated clustering. Additional attractive forces that arise from protein-induced perturbation of a membrane's fluctuations are also described. This review aims to provide a survey of the current understanding of membrane-mediated clustering and how this supports precise biological functions. PMID- 29502868 TI - Surgical implants and business ethics? PMID- 29502869 TI - Immunomodulatory activities of Acacia catechu, a traditional thirst quencher of South India. AB - BACKGROUND: Acacia catechu has been widely used in Ayurveda for treating many diseases. Its heartwood extract is used in asthma, cough, bronchitis, colic, diarrhea, dysentery, boils, skin afflictions, sores and for stomatitis. The decoction of heartwood is used for drinking purpose in southern part of India especially in Kerala. OBJECTIVE: The current study was carried out to scientifically evaluate immunomodulatory effects of heartwood extracts of A. catechu in Swiss albino mice. MATERIAL AND METHODS: In vivo immunomodulatory activity was analyzed by hemagglutinating antibody (HA) titer, plaque forming cell assay and delayed type hypersensitivity (DTH). In vitro immunomodulatory potential of the extracts was studied using peritoneal macrophages and splenocytes from mice. Effect of extracts on phagocytic activity of macrophages was analyzed by nitroblue tetrazolium (NBT) reduction assay and cellular lysosomal enzyme assay. Anti-inflammatory activity was studied by nitric oxide (NO) assay and production of TNF-alpha and IL-10. RESULTS: A dose dependent increase in antibody titer was observed with extracts treatment. Treatment with extracts produced an enhancement in the number of antibody producing cells in the spleen. DTH reaction was significantly decreased with extracts treatment. An increased phagocytic response was shown by peritoneal macrophages on treatment with the extracts as evidenced by its effect on NBT reduction and cellular lysosomal enzyme activity. The extracts inhibited the release of pro-inflammatory cytokine TNF-alpha and the production of NO. IL-10 production was significantly increased after extract treatment. CONCLUSION: The results of the present study indicate the immunomodulatory effects of A. catechu extracts on humoral, cell mediated and non-specific immune functions. PMID- 29502870 TI - Cardiac amyloidosis and aortic stenosis: Great masquerader back again! PMID- 29502871 TI - The gap between currently available evidence and awareness in clinical practice of wound care: It is the time to shower earlier. AB - BACKGROUND: A postoperative water-forbidden strategy has been used for many decades. However, evidence shows that early contact with water postoperatively does not increase the infection rate. Our study evaluated the gap between currently available evidence and awareness in clinical practice of postoperative wound care. METHODS: We conducted a systematic review to compare the outcomes between postoperative water-contact and water-forbidden groups. PubMed, EMBASE, and Cochrane databases were searched. A meta-analysis was conducted to calculate a pooled effect size by using random-effects models. On the basis of pooling results, a questionnaire survey was conducted to evaluate the gap from systematic review to clinical practice by clinical staff and patients. RESULTS: We reviewed 12 trials including 4,086 patients. Incidence of infection and wound complications did not differ significantly between water-contact and water forbidden groups. Satisfaction was significantly higher in water-contact group than in water-forbidden group (risk ratio: 17.33; 95% confidence interval, 11.11 27.03). A survey of clinicians showed that awareness, acceptance of the evidence, and the current water-contact strategy differed among departments. However, many clinicians showed no willingness to apply the water-contact strategy for various reasons. A survey of patients showed low awareness of the issue and variety in willingness to contact water. CONCLUSION: Water-forbidden strategy causes inconvenience to patients. However, a majority of patients and clinicians still hesitated to apply the early water-contact strategy, even after viewing the results of the current review. Establishment of local clinical practice guidelines, advocacy from authorities, and promotion by social media for this strategy are warranted. PMID- 29502873 TI - Of Mice and Men....and Plants: Comparative Genomics of the Dual Lifestyles of Enteric Pathogens. AB - Outbreaks of gastrointestinal illness, linked to the consumption of fruits, vegetables, and sprouts, continue to capture the attention of the general public and scientists. The recurrence of these outbreaks, despite heightened producer and consumer awareness, combined with improved sanitation protocols and technology, can be explained by the hypothesis that enteric pathogens, such as nontyphoidal Salmonella spp. and enterovirulent Escherichia coli, have evolved to exploit plants as alternative hosts. This review explores the genetic and genomic context for this hypothesis. Even though gastroenteritis outbreaks associated with the consumption of produce have been caused by a limited number of strains or serovars, robust evidence in support of the polymorphism hypothesis is lacking. While some housekeeping genes with additional virulence functions in animal models contribute to the fitness of enterics within plants, canonical virulence determinants required for animal infections, such as the type III secretion system (T3SS) and effectors, by and large, are of little consequence in interactions with plants. Conversely, despite possessing some functions more commonly found in phytobacteria, human enteric pathogens do not appear to rely on the same strategies for plant colonization. Instead, it is likely that nontyphoidal Salmonella and enterovirulent E. coli have evolved a set of functions distinct from its virulence regulon and from those used by phytopathogens. PMID- 29502872 TI - Natural history of portal vein embolization before liver resection: a 23-year analysis of intention-to-treat results. AB - BACKGROUND: Portal vein embolization (PVE) use is nowadays debated due to the risk of technical or biological unresectability after the period of time needed to achieve future liver remnant (FLR) hypertrophy. We evaluated the safety and efficacy of PVE in a single high-volume hepatobiliary center, with emphasis in the feasibility to achieve tumor resection. METHODS: Patients undergoing PVE before major hepatectomy at our institution between 1993 and 2015 were retrospectively analyzed. RESULTS: A total of 431 patients formed the study population. Morbidity and mortality rates of PVE were 16.7% and 0.2% respectively. Morbidity was similar between percutaneous and ileocolic approaches or between histoacryl and ethanol as embolization materials (P > 0.05). On the contrary, the percutaneous ipsilateral approach was associated with significantly less complications than the contralateral approach (10.3% vs 19.4%; P = 0.024). Almost all patients (96%) achieved sufficient FLR volume after embolization, but only 66% finally underwent planned liver resection. Disease progression was the most common cause of unresectability (67%). Patients with extrahepatic biliary tumors experienced significantly higher unresectability rates compared to other entities (45.1% vs 31.4%; P = 0.019). CONCLUSION: PVE was not followed by hepatectomy in 34% of our patients. Biliary tumors displayed the higher dropout rates after PVE and the higher chances of tumor progression preventing curative resection. Although PVE may be performed with acceptable morbidity, PVE-related complications prevented curative resection in 5% of patients. Careful multidisciplinary selection is crucial to avoid PVE overuse in technically resectable patients who will experience a not negligible risk of futile use and non-therapeutic laparotomy. PMID- 29502874 TI - The neural correlates of visual imagery: A co-ordinate-based meta-analysis. AB - Visual imagery is a form of sensory imagination, involving subjective experiences typically described as similar to perception, but which occur in the absence of corresponding external stimuli. We used the Activation Likelihood Estimation algorithm (ALE) to identify regions consistently activated by visual imagery across 40 neuroimaging studies, the first such meta-analysis. We also employed a recently developed multi-modal parcellation of the human brain to attribute stereotactic co-ordinates to one of 180 anatomical regions, the first time this approach has been combined with the ALE algorithm. We identified a total 634 foci, based on measurements from 464 participants. Our overall comparison identified activation in the superior parietal lobule, particularly in the left hemisphere, consistent with the proposed 'top-down' role for this brain region in imagery. Inferior premotor areas and the inferior frontal sulcus were reliably activated, a finding consistent with the prominent semantic demands made by many visual imagery tasks. We observed bilateral activation in several areas associated with the integration of eye movements and visual information, including the supplementary and cingulate eye fields (SCEFs) and the frontal eye fields (FEFs), suggesting that enactive processes are important in visual imagery. V1 was typically activated during visual imagery, even when participants have their eyes closed, consistent with influential depictive theories of visual imagery. Temporal lobe activation was restricted to area PH and regions of the fusiform gyrus, adjacent to the fusiform face complex (FFC). These results provide a secure foundation for future work to characterise in greater detail the functional contributions of specific areas to visual imagery. PMID- 29502875 TI - Is the homophone advantage influenced by post-lexical effects? PMID- 29502876 TI - Value-based care: the preference of outcome over prediction. PMID- 29502877 TI - Clinical Predictors of Residual Sleep Apnea after Weight Loss Therapy in Obese Adolescents. AB - OBJECTIVE: To investigate clinical factors that could predict residual sleep disordered breathing (SDB) after weight loss. STUDY DESIGN: Obese subjects between 10 and 19 years of age were recruited while entering an in-patient weight loss treatment program. All subjects underwent anthropometry and sleep screening using a portable device at baseline and after 4-6 months of therapy. Sleep and International Study of Asthma and Allergies in Childhood questionnaires were completed at baseline. RESULTS: A total of 339 patients were included. Median age was 15.4 years (10.1-19.1). Body mass index z score at baseline was 2.75 +/- 0.42, and 35% of subjects were boys. SDB was present in 32%. After a mean decrease in body mass index z score of 32%, residual SDB was found in 20% of subjects with SDB at baseline. Subjects with more severe SDB (OR 1.18; CI 1.01 1.34; P = .02) and respiratory allergies (OR 7.85; CI 1.20-51.39; P = .03) were at higher risk of developing residual SDB, unlike age, sex, and anthropometric variables. CONCLUSIONS: Weight loss was successful for treating SDB in 80% of patients. More severe SDB and the presence of respiratory allergies at baseline were associated with a higher risk of residual SDB after weight loss. PMID- 29502878 TI - The prognostic value of a novel magnetic resonance imaging/magnetic resonance spectroscopy score after hypoxic ischemic encephalopathy: methodological concerns. PMID- 29502879 TI - Not a Hydrocele! PMID- 29502881 TI - Head imaging in suspected non accidental injury in the paediatric population. In the advent of volumetric CT imaging, has the skull X-ray become redundant? AB - AIM: To assess whether the inclusion of skull radiography, as part of the skeletal survey performed in suspected non-accidental injury (NAI), is still justified when volume computed tomography (CT) of the head has also been performed. MATERIALS AND METHODS: This was a retrospective study which included 94 patients aged between 24 days and 23 months who presented to the Emergency Department between August 2014 to July 2016 and had subsequent investigations for suspected NAI. Patients were identified from the local radiology systems (Carestream PACS and CRIS) using strict inclusion and exclusion criteria. Inclusion criteria were any suspected NAI patient who had both unenhanced volume CT head and skull radiography during the same episode of presentation. Any child with suspected NAI who only had one of either CT or radiographs of the skull (and not both) were excluded. RESULTS: None of the cases reviewed demonstrated additional findings on skull X-rays that were not demonstrated on the CT head. Due to the starkness of this result, the confidence interval is 0-3.9%. In two cases, additional bony findings were demonstrated on the CT head which were not evident on the skull X-rays. CONCLUSION: Skull X-rays could be excluded from the NAI skeletal survey without missing intracranial injuries or skull fractures in cases where a contemporaneous volumetric CT head is also performed. PMID- 29502880 TI - Pulmonary Hypertension Associated with Hypoxic-Ischemic Encephalopathy-Antecedent Characteristics and Comorbidities. AB - OBJECTIVE: To determine the characteristics of term infants with persistent pulmonary hypertension of the newborn (PPHN) associated with moderate or severe hypoxic ischemic encephalopathy (HIE). METHODS: We compared infants with and without PPHN enrolled in 2 randomized trials of therapeutic hypothermia: the induced hypothermia trial of cooling to 33.5 degrees C for 72 hours vs normothermia, and the "usual-care" arm (33.5 degrees C for 72 hours) of the optimizing cooling trial. RESULTS: Among 303 infants with HIE from these 2 studies, 67 (22%) had PPHN and 236 (78%) did not. We compared infants with PPHN with those without PPHN. The proportion of patients treated with therapeutic hypothermia was similar in PPHN and no-PPHN groups (66% vs 65%). Medication use during resuscitation (58% vs 44%), acidosis after birth (pH: 7.0 +/- 0.2 vs 7.1 +/- 0.2), severe HIE (43% vs 28%), meconium aspiration syndrome (39% vs 7%), pulmonary hemorrhage (12% vs 3%), culture-positive sepsis (12% vs 3%), systemic hypotension (65% vs 28%), inhaled nitric oxide therapy (64% vs 3%), and extracorporeal membrane oxygenation (12% vs 0%) were more common in the PPHN group. Length of stay (26 +/- 21 vs 16 +/- 14 days) and mortality (27% vs 16%) were higher in the PPHN group. CONCLUSIONS: PPHN is common among infants with moderate/severe HIE and is associated with severe encephalopathy, lung disease, sepsis, systemic hypotension, and increased mortality. The prevalence of PPHN was not different between those infants receiving therapeutic hypothermia at 33.5 degrees C in these 2 trials (44/197 = 22%) compared with infants receiving normothermia in the induced hypothermia trial (23/106 = 22%). PMID- 29502882 TI - Effect of electronic real-time prompting on hand hygiene behaviors in health care workers. AB - BACKGROUND: Poor hand hygiene by health care workers is a major cause of nosocomial infections. This research evaluated the ability of an electronic monitoring system with real-time prompting capability to change hand hygiene behaviors. METHODS: Handwashing activity was measured by counting dispenser activations on a single nursing unit before, during, and after installation of the system. The effect of changing the prompt duration on hand hygiene performance was determined by a cluster-randomized trial on 3 nursing units with 1 acting as control. Sustainability of performance and participation was observed on 4 nursing units over a year. All staff were eligible to participate. RESULTS: Between June 2015 and December 2016, a total of 459,376 hand hygiene opportunities and 330,740 handwashing events from 511 staff members were recorded. Dispenser activation counts were significantly influenced by use of the system (chi2[3] = 75.76; P < .0001). Hand hygiene performance dropped from 62.61% to 24.94% (odds ratio, 0.36; 95% confidence interval, 0.34-0.38) when the prompting feature was removed. Staff participation had a negative trajectory of 0.72% (P < .001), whereas change in average performance was -0.18% (P < .001) per week for the year. CONCLUSIONS: Use of electronic monitoring with real-time prompts of 20 seconds' duration nearly doubles handwashing activity and causes handwashing to occur sooner after entering a patient room. These improvements are sustainable over a year. PMID- 29502883 TI - Use of a verbal electronic audio reminder with a patient hand hygiene bundle to increase independent patient hand hygiene practices of older adults in an acute care setting. AB - BACKGROUND: We hypothesized that the addition of a novel verbal electronic audio reminder to an educational patient hand hygiene bundle would increase performance of self-managed patient hand hygiene. METHODS: We conducted a 2-group comparative effectiveness study randomly assigning participants to patient hand hygiene bundle 1 (n = 41), which included a video, a handout, and a personalized verbal electronic audio reminder (EAR) that prompted hand cleansing at 3 meal times, or patient hand hygiene bundle 2 (n = 34), which included the identical video and handout, but not the EAR. The primary outcome was alcohol-based hand sanitizer use based on weighing bottles of hand sanitizer. RESULTS: Participants that received the EAR averaged significantly more use of hand sanitizer product over the 3 days of the study (mean +/- SD, 29.97 +/- 17.13 g) than participants with no EAR (mean +/- SD, 10.88 +/- 9.27 g; t73 = 5.822; P <= .001). CONCLUSIONS: The addition of a novel verbal EAR to a patient hand hygiene bundle resulted in a significant increase in patient hand hygiene performance. Our results suggest that simple audio technology can be used to improve patient self-management of hand hygiene. Future research is needed to determine if the technology can be used to promote other healthy behaviors, reduce infections, and improve patient centered care without increasing the workload of health care workers. PMID- 29502884 TI - Duration of influenza outbreaks in long-term care facilities after antiviral prophylaxis initiation: Fraser Health, British Columbia, 2014-2017. AB - To assess the duration of antiviral prophylaxis (AP), we conducted a retrospective outbreak review over 3 seasons, looking for acute respiratory illness (ARI) onset after 5 days of AP. Of 114 facility-level outbreaks with 352 unit-level outbreaks, we found only 1 case of laboratory-confirmed influenza after 5 days of AP. New cases of ARI after 5 days of AP should be investigated, and recommendations for AP duration could be shortened to 7-8 days or less. PMID- 29502885 TI - Legionella pneumophila contamination of hospital dishwashers. AB - In a tertiary hospital, Legionella spp were isolated from taps and from ward dishwashers connected to contaminated tap piping. Our investigation revealed favorable conditions for growth of Legionella, and showed that Legionella pneumophila SG6 isolates from the taps and dishwashers were all genetically identical by repetitive-element polymerase chain reaction. These results suggest that contaminated dishwashers might be a potential reservoir for the spread of Legionella in health care facilities. PMID- 29502886 TI - Nurses' experiences of care for patients with Middle East respiratory syndrome coronavirus in South Korea. AB - BACKGROUND: This study aimed to identify nurses' experiences of care for patients with Middle East respiratory syndrome-coronavirus (MERS-CoV). Their experiences can be useful to establish a safer healthcare system in preparation for infectious disease outbreaks. METHODS: Data were collected through in-depth individual interviews and analyzed using Colaizzi's phenomenological method. Participants were 12 nurses. RESULTS: Nurses' experiences of care for patients with MERS-CoV were categorized as follows: "Going into a dangerous field," "Strong pressure because of MERS-CoV," "The strength that make me endure," "Growth as a nurse," and "Remaining task." CONCLUSIONS: It is necessary to examine the difficulties and demands of healthcare providers for establishing a safe healthcare system to respond effectively when national disasters occur. In addition, it is necessary to develop strategies to protect healthcare providers from severe physical and psychological stress. PMID- 29502887 TI - Prosarcopenic Effects of Statins May Limit Their Effectiveness in Patients with Heart Failure. AB - Some studies using small doses of statins revealed significant benefits for patients with chronic heart failure (HF). However, the results of large randomized studies did not confirm these advantages. Along with the primary effect of cholesterol lowering, statins have many ancillary actions that may be relevant for body wasting. In this context, the fear of muscle-related side effects needs to be put into clinical context and assessed appropriately before statins are either withheld or withdrawn in patients with sarcopenia (muscle wasting). Some of the mechanistic bases of statin-mediated muscle dysfunction correspond with mechanisms of sarcopenia observed in HF with reduced ejection fraction patients, connected with insulin-like growth factor 1, inflammation, the ubiquitin-proteasome pathway, apoptosis, and myostatin. Here we present the hypothesis of potential prosarcopenic properties of statins as a possible explanation of the lack of effectiveness of these drugs in HF patients. PMID- 29502888 TI - Subcapsular hepatic haematoma after endoscopic retrograde cholangiopancreatography. A rare complication with high morbidity and mortality. PMID- 29502889 TI - Intensive care admission and hospital mortality in the elderly after non-cardiac surgery. AB - OBJECTIVE: To assess whether patient age is independently associated to Intensive Care Unit (ICU) admission after non-cardiac surgery. DESIGN: An observational cohort study of the Spanish subset of the European Surgical Outcome Study (EuSOS) was carried out. SETTING: Hospitals of the public National Health Care System and private hospitals in Spain. INTERVENTION: None. PATIENTS AND METHODS: All patients over 16 years of age undergoing inpatient non-cardiac surgery in the participating hospitals during a 7-day period in the month of April 2011 were consecutively included. MAIN VARIABLES OF INTEREST: ICU admission rate, factors associated with ICU admission and hospital mortality were assessed using logistic regression analysis and fractional polynomial regression. RESULTS: Out of 5412 patients, 677 (12.5%) were admitted to the ICU after surgery. The adjusted odds ratio (95% confidence interval [CI]) for ICU admission was 1.1 (0.8-1.4) for patients aged 65-74 years, 0.7 (0.5-1) for patients aged 75-85 years, and 0.4 (0.2-0.8) for patients over 85 years, respectively. Age, ASA score, grade of surgery (minor, intermediate, major), urgent surgery, surgical specialty, laparoscopic surgery and metastatic disease were independent factors for ICU admission. Global risk-adjusted mortality was 1.4 (95% CI 0.9-2.2). The ASA score, urgent surgery, surgical specialty and diabetes were predictors of hospital mortality. CONCLUSIONS: Elderly patients (over 80 years) appear less likely to be admitted to ICU after non-cardiac surgery in Spanish hospitals. There was no significant association between age and postoperative mortality in this cohort. PMID- 29502890 TI - Issues to resolve with the use of extracorporeal membrane oxygenation during interfacility transportation. AB - Extracorporeal membrane oxygenation (ECMO) support is indicated in patients who are refractory to treatment, those with cardiogenic shock or respiratory failure and those with exacerbations eligible for heart and lung transplantation. Physician experience and quantity of necessary resources are reasons why regionalization could benefit patients of this kind, establishing ECMO reference centers and integrating a transportation network specialized in ECMO. This type of transportation is a challenge for healthcare systems and physicians, given its greater complexity, requiring a multidisciplinary and inter-territorial approach. ECMO transportation is safer than without mechanical support, though there are currently no criteria for starting such therapy in patients being transferred. Criteria of lesser severity might be necessary for these patients. The training and specialization of the team in extracorporeal support therapies, interfacility transport and the systemization of transfer can improve the outcomes. There are no studies on the conditions that must be met by the transportation media, although space and stability are important characteristics. Air transfer with ECMO is an increasingly frequent option. Although there are data on its safety, there are none on the physiology of patients undergoing ECMO at high altitudes. Such information could be of help in the indication and management of this type of transportation. PMID- 29502891 TI - Hemolysis, hyperkalemia and the transfusion of packed old red blood cells in critically ill patients. PMID- 29502892 TI - Uncommon EGFR G724S mutations arise in non-small-cell lung cancer patients with acquired resistance to first-generation EGFR-TKIs. PMID- 29502893 TI - Strategic Purchasing in Practice: Comparing Ten European Countries. AB - Strategic purchasing of health care services is widely recommended as a policy instrument. We conducted a review of literature of material drawn from the European Observatory on Health Systems and Policies Health Systems in Transition series, other European Observatory databases, and selected country-specific literature to augment the comparative analysis by providing the most recent healthcare trends in ten selected countries. There is little evidence of purchasing being strategic according to any of the established definitions. There is little or no literature suggesting that existing purchasing mechanisms in Europe deliver improved population health, citizen empowerment, stronger governance and stewardship, or develop purchaser organization and capacity. Strategic purchasing has not generally been implemented. Policymakers considering adopting strategic purchasing policies should be aware of this systemic implementation problem. Policymakers in systems with strategic purchasing built into policy should not assume that a purchasing system is strategic or that it is delivering any expected objectives. However, there are individual components of strategic purchasing that are worth pursuing and can provide benefits to health systems. PMID- 29502894 TI - [Thoracic endometriosis complicated with pneumopericard and iterative pneumothorax due to bullous dystrophy]. AB - Thoracic endometriosis is a rare entity characterized by presence of endometrial tissue in pleura, lung parenchyma or airways. Most frequent manifestations are catamenial pneumothorax, hemothorax, hemoptysis and pulmonary nodules. We report here a rare case of a woman with thoracic endometriosis who developed iterative pneumothorax and pneumopericardium on bilateral bullous pulmonary dystrophy. She was a 37-year-old woman without any tobacco exposure and with previous history of pleural tuberculosis treated 5 years earlier. She was first referred to our centre for right pleuro-pneumothorax and hemorrhagic ascites. Pleural fluid examinations did not show any tuberculosis relapse, the evolution was favorable after thoracic drainage and there was no parenchymal lung abnormality on CT scan after surgery. Celioscopic peritoneal examination revealed stage IV peritoneal endometriosis. One year later, she was admitted for left catamenial pneumothorax. Thoracic CT scan showed apparition of large subpleural bulla. She underwent thoracotomy for bulla resection and left partial pleurectomy. Two years later, she was hospitalized for right pneumothorax and compressive pneumopericardium. Surgical lung biopsies confirmed pleuropulmonary endometriosis. Thoracotomy was performed for talcage pleurodesis and diaphragmatic leakages sutures. Lung bulla are rare in thoracic endometriosis, mechanism of their formation remains unknown. Pericardial involvement is rare in endometriosis; we report here a unique case of pneumopericardium. PMID- 29502895 TI - [Effectiveness of therapeutic education against "nicotinophobia" in smokers hospitalized for cardiovascular and pulmonary rehabilitation]. AB - INTRODUCTION: Nicotine replacement therapies remain the main validated treatment to stop smoking. Nevertheless, treatment acceptance deals with patients negative representations. This "nicotinophobia" could be the main barrier to treatment acceptance and as a consequence would be at the origin of numerous failures of smoking cessation. MATERIALS AND METHODS: We estimated the efficiency of an educational collective workshop to fight against nicotinophobia in patients smokers hospitalized for cardiovascular and pulmonary rehabilitation. RESULTS: Smoking cessation was significantly improved in patients who participated at the workshop (81 vs. 48 %), associated with a significant decrease of anxiety depression scores, and without significant weight gain (average loss of 2.8kg). CONCLUSION: Educational approaches seem to help a majority of patient smokers to stop smoking, without anxiety and without weight gain. These results encourage the creation of a real therapeutic educational program dedicated to smoking cessation. PMID- 29502896 TI - Effects of coenzyme Q10 on semen cryopreservation of stallions classified as having good or bad semen freezing ability. AB - This study aimed to evaluate the antioxidant properties of coenzyme Q10 (CoQ10) during cryopreservation of semen obtained from stallions having good and bad semen freezing ability (GFA vs. BFA, respectively). Forty ejaculates (n = 20 stallions) were split into five centrifugation and five freezing extenders containing different concentrations of CoQ10 (0, 25, 50, 75 and 100 MUmols/L). If CoQ10 was added to the centrifugation extender, the freezing extender had no CoQ10 added; similarly, if CoQ10 was added to the freezing extender, the centrifugation extender had no CoQ10. Semen cryopreserved on extenders containing no CoQ10 served as the control. After post-thaw total sperm motility (TM) assessments, the stallions were classified as GFA (i.e., decrease of <=25% in TM, n = 7) or BFA (i.e., decrease of >=40% in TM, n = 5). Stallions not fitting (n = 8) this enrollment criteria had samples discarded. After that, two straws for each extender were thawed at 37 degrees C for 30 s; one straw was immediately used for evaluation of sperm kinetics, plasma membrane integrity, non-capacitated spermatozoa, reactive oxygen species production, mitochondrial activity and lipid peroxidation. The second straw was kept at 37 degrees C for 30 min and subjected to the same assessments. Expectedly, sperm motility parameters were significantly lower for stallions with BFA. There were no effects of CoQ10 concentration or time for all parameters evaluated in the group with GFA when compared with the control extender (p > 0.05), except lipid peroxidation (p < 0.05). However, stallions with BFA had improved sperm parameters for samples processed with extenders containing CoQ10 (particularly 75 MUmols/L) (p < 0.05), except for the reactive oxygen species production and mitochondrial potential (T0) in which there were no differences between the groups (p > 0.05). In summary, 75 MUmols/L appears to be the optimal dose of Co-Q10, particularly, when added to the centrifugation extender. PMID- 29502897 TI - A highly selective dispersive liquid-liquid microextraction approach based on the unique fluorous affinity for the extraction and detection of per- and polyfluoroalkyl substances coupled with high performance liquid chromatography tandem-mass spectrometry. AB - In the present study, a highly selective fluorous affinity-based dispersive liquid-liquid microextraction (DLLME) technique was developed for the extraction and analysis of per- and polyfluoroalkyl substances (PFASs) followed by high performance liquid chromatography tandem-mass spectrometry. Perfluoro-tert butanol with multiple C-F bonds was chosen as the extraction solvent, which was injected into the aqueous samples with a dispersive solvent (acetonitrile) in a 120:800 (MUL, v/v) mixture for PFASs enrichment. The fluorous affinity-based extraction mechanism was confirmed by the significantly higher extraction recoveries for PFASs containing multiple fluorine atoms than those for compounds with fewer or no fluorine atoms. The extraction recoveries of medium and long chain PFASs (CF2 > 5) exceeded 70%, except perfluoroheptanoic acid, while those of short-chain PFASs were lower than 50%, implying that the proposed DLLME may not be suitable for their extraction due to weak fluorous affinity. This highly fluoroselective DLLME technique can greatly decrease the matrix effect that occurs in mass spectrometry detection when applied to the analysis of urine samples. Under the optimum conditions, the relative recoveries of PFASs with CF2 > 5 ranged from 80.6-121.4% for tap water, river water and urine samples spiked with concentrations of 10, 50 and 100 ng/L. The method limits of quantification for PFASs in water and urine samples were in the range of 0.6-8.7 ng/L. Furthermore, comparable concentrations of PFASs were obtained via DLLME and solid phase extraction, confirming that the developed DLLME technique is a promising method for the extraction of PFASs in real samples. PMID- 29502898 TI - Separation of enantiomers of selected chiral sulfoxides with cellulose tris(4 chloro-3-methylphenylcarbamate)-based chiral columns in high-performance liquid chromatography with very high separation factor. AB - The present study reports successful separations of enantiomers of selected chiral sulfoxides with very high separation factor in high-performance liquid chromatography by using chiral columns prepared with the chiral selector cellulose tris(4-chloro-3-methylphenylcarbamate). High separation factors were observed in polar organic, as well as in hydrocarbon-alcohol-type mobile phases. The key structural components of the solute for obtaining high chiral recognition are discussed as well as thermodynamic quantities of analyte adsorption on the chiral stationary phase were determined. Experiment aimed at the enantioselective extraction of racemates from solution are also described. PMID- 29502899 TI - Simultaneous determination of trace concentrations of aldehydes and carboxylic acids in particulate matter. AB - Carboxylic acids and aldehydes are present in ambient air particulate matter (PM) originating from both primary emission and secondary production in air and may, due to their polarity have, an impact on formation of cloud condensation nuclei. Their simultaneous determination may provide improved understanding of atmospheric processes. We developed a new analytical method allowing for a single step determination of majority of carboxylic acids and aldehydes (+95 compounds). This sample preparation employed O-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine (PFBHA.HCl) in methanol to yield oximes (for aldehydes) and methyl esters (for majority of acids); with the limits of detection of 0.02-1 ng per injection, corresponding to approximately 0.4-20 MUg/gPM. Subsequent trimethylsilylation with N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) was employed only for aromatic acids, which were not completely esterified, and for hydroxyl groups. Our method, in contrast to previous primarily qualitative studies, based on derivatization with an aqueous PFBHA followed by BSTFA derivatization, is less labor-intesive and reduces sample losses caused by an evaporation. The method was tested with a broad range of functionalized compounds (95), including monocarboxylic, dicarboxylic and aromatic acids, ketoacids, hydroxyacids and aldehydes. The developed protocol was applied to wood smoke (WS) and urban air standard reference material 1648b (UA) PM. The observed concentrations of aldehydes were 10-3000 MUg/gPM in WS PM and 10-900 MUg/gPM in UA PM, while those of acids were 20-1800 MUg/gPM in WS PM and 15-1200 MUg/gPM in UA PM. The most prominent aldehydes were syringaldehyde and vanillin in WS PM and glyoxal in UA PM. The most abundant acids in both PM samples were short-chain dicarboxylic acids (<=C10). WS PM had a high abundance of hydroxyacids (vanillic and malic acids) as well as ketoacids (glutaric and oxalacetic) while UA PM also featured a high abundance of long-chain monocarboxylic acids (>=C16). PMID- 29502900 TI - On-line solid phase extraction-liquid chromatography-tandem mass spectrometry for insect repellent residue analysis in surface waters using atmospheric pressure photoionization. AB - Insect repellents (IRs) are a group of organic chemicals whose function is to prevent the ability of insects of landing in a surface. These compounds have been found in the environment and may pose a risk to non-target organisms. In this study, an on-line solid phase extraction - high performance liquid chromatography tandem mass spectrometry multiresidue method was developed using an atmospheric photoionization source (SPE-HPLC-(APPI)-MS/MS). The use of the APPI as an alternative ionization technique to electrospray (ESI) and atmospheric pressure chemical ionization (APCI) allowed expanding the range of analytical techniques suitable for the analysis of IRs, so far relied in gas chromatography. High sensitivity and precision was reached with method limits of quantification between 0.2 and 4.6 ng l-1 and interday and intraday precision equal or below 15%. The validated method was applied to the study of surface water samples from three European river basins with different flow regime (Adige River in Italy, Sava River in the Balkans, and Evrotas River in Greece). The results showed that two IRs (DEET and Bayrepel) were ubiquitous in the Sava and Evrotas basins, reaching concentrations as high as 105 MUg l-1 of Bayrepel in the Sava River, and 5 MUg l-1 of DEET in the Evrotas River. Densely populated areas and effluent waste waters are pointed out as the responsible for this pollution. In the alpine river Adige, only three samples showed low levels of IRs (6.01-37.8 ng l-1). The concentrations measured were used to perform an environmental risk assessment based on the hazard quotients (HQs) estimation approach by using the chronic and acute eco-toxicity data available. The results revealed that despite the high frequency and eventually high concentrations of these IRs determined in the three basins, only few sites were at risk, with 1 < HQs < 3.3. PMID- 29502902 TI - WASP (Write a Scientific Paper) using Excel - 10: Contingency tables. AB - Contingency tables may be required to perform chi-test analyses. This provides pointers as to how to do this in Microsoft Excel and explains how to set up methods to calculate confidence intervals for proportions, including proportions with zero numerators. PMID- 29502901 TI - The Mexican consensus on the diagnosis and treatment of ulcerative colitis. AB - The guidelines presented herein are an updated version of the recommendations published in 2007. Since then, there has been a rapid advance in the knowledge about the pathophysiology of ulcerative colitis and its therapeutic options. New drugs have been approved, novel targeted therapies have emerged, and new strategies have been developed to improve the previously available approaches to the disease. The aim of the present consensus is to promote the current knowledge of and Mexican perspective on the epidemiology, diagnosis, and medical and surgical treatment of chronic idiopathic ulcerative colitis. The final vote on the statements and their ultimate modifications were carried out at the consensus working group meeting. Evidence was evaluated through the GRADE classification. PMID- 29502903 TI - The role of disengagement in the psychology of competence drift. AB - BACKGROUND: The framing of competence as a binary "either-or" process may be shaped by the measurement tools and assessment methods used to define it. Blunt measures such as passing or failing a licensure examination, or revoking/suspending a license after a single dispensing error fosters anxiety amongst professionals and potentially leads to behaviours where learning needs are actually hidden from educators, employers or regulators. Such framing may not accurately capture the lived experience of those labelled "incompetent" and in fact may be counterproductive to remediation and skills enhancement. OBJECTIVES: To examine the construct of competence as a lived experience amongst pharmacists who had been identified and labelled as incompetent by their regulatory body. METHODS: A multiple single-case research design (described by Kratochwill and Levin) involving 14 practicing pharmacists identified as not meeting competence standards by their regulatory body in Ontario, Canada was used for this research. Constant-comparative qualitative analysis of semi-structured interview data was coded, categorized and used to identify and describe major research themes. RESULTS: Two major themes were identified, related to the personal and professional consequences of being labelled "incompetent" by one's regulatory body, and the importance of psychological engagement in one's own profession in facilitating maintenance of competence. CONCLUSIONS: This study highlighted the importance of disengagement as both a cause and consequence of competence drift and pointed to the impact of regulatory policies, practices, and assessment systems that may actually inadvertently contribute to this disengagement. PMID- 29502904 TI - Assessing for Occult Suicidality at Triage: Experiences of Emergency Nurses. AB - INTRODUCTION: Screening for suicidality is a critical nursing function at the initial ED encounter. Suicide is the tenth leading cause of death in the United States, and a substantial percentage of people who die by suicide present for health care in the year before their deaths. The emergency department provides health care professionals with a critical opportunity to identify patients at risk for suicide and intervene appropriately. METHODS: Qualitative exploratory study using focus-group data. FINDINGS: Effective and accurate suicidality assessment occurs not by asking a single question but also with the assessment of patient behaviors and presentation (appearance, hygiene, etc). When emergency nurses suspected occult suicidality, additional actions (finding private space, keeping patients safe, and passing on information), took priority. DISCUSSION: The Joint Commission recommends using clinical judgment tools for the final determination of safety for a patient at suspected risk of suicide, as research findings suggest that a screening tool can identify persons at risk for suicide more reliably than a clinician's personal judgment. Our participants report that when they assessed suicide risk at triage, it was usually by asking a single question such as "Do you have thoughts or plans to harm yourself?" and they expressed concern about the effectiveness of doing so. Participants described their efforts to improve suicide screening across the duration of the patient's ED stay through an iterative process of assessment that included further probing and eliciting, evaluating, and reacting to the patient's response. PMID- 29502906 TI - Taking aim at cholera. PMID- 29502905 TI - Mapping the burden of cholera in sub-Saharan Africa and implications for control: an analysis of data across geographical scales. AB - BACKGROUND: Cholera remains a persistent health problem in sub-Saharan Africa and worldwide. Cholera can be controlled through appropriate water and sanitation, or by oral cholera vaccination, which provides transient (~3 years) protection, although vaccine supplies remain scarce. We aimed to map cholera burden in sub Saharan Africa and assess how geographical targeting could lead to more efficient interventions. METHODS: We combined information on cholera incidence in sub Saharan Africa (excluding Djibouti and Eritrea) from 2010 to 2016 from datasets from WHO, Medecins Sans Frontieres, ProMED, ReliefWeb, ministries of health, and the scientific literature. We divided the study region into 20 km * 20 km grid cells and modelled annual cholera incidence in each grid cell assuming a Poisson process adjusted for covariates and spatially correlated random effects. We combined these findings with data on population distribution to estimate the number of people living in areas of high cholera incidence (>1 case per 1000 people per year). We further estimated the reduction in cholera incidence that could be achieved by targeting cholera prevention and control interventions at areas of high cholera incidence. FINDINGS: We included 279 datasets covering 2283 locations in our analyses. In sub-Saharan Africa (excluding Djibouti and Eritrea), a mean of 141 918 cholera cases (95% credible interval [CrI] 141 538 146 505) were reported per year. 4.0% (95% CrI 1.7-16.8) of districts, home to 87.2 million people (95% CrI 60.3 million to 118.9 million), have high cholera incidence. By focusing on the highest incidence districts first, effective targeted interventions could eliminate 50% of the region's cholera by covering 35.3 million people (95% CrI 26.3 million to 62.0 million), which is less than 4% of the total population. INTERPRETATION: Although cholera occurs throughout sub Saharan Africa, its highest incidence is concentrated in a small proportion of the continent. Prioritising high-risk areas could substantially increase the efficiency of cholera control programmes. FUNDING: The Bill & Melinda Gates Foundation. PMID- 29502907 TI - Cortical plasticity with bimodal hearing in children with asymmetric hearing loss. AB - This longitudinal study aimed to identify auditory plasticity promoted by a cochlear implant in children with asymmetric hearing loss. Participants included 10 children who experienced (mean +/- SD) 3.1 +/- 3.6 years of asymmetric hearing (difference of 47.2 +/- 47.6 dB) before receiving an implant at age 8.7 +/- 5.1 years. Multi-channel electroencephalography was measured at initial implant use (5.8 +/- 3.2 days) and after 10.2 +/- 4.1 months in each child. Monaurally presented stimuli consisted of 36 ms trains of 9 acoustic clicks/biphasic electric pulses at a rate of 250 Hz, repeated at 1 Hz. The time-restricted artifact and coherent source suppression (TRACS) beamformer was used to locate sources underlying peak amplitudes of cortical responses. Results indicated consistent activity from the non-implanted ear but significant implant-driven changes to the auditory cortices. Initially, the newly implanted ear evoked activity which strongly lateralized to the ipsilateral auditory cortex and contributed to a significant aural preference for implant stimulation in children with limited acoustic experience pre-implantation. Cochlear implant use reversed these abnormalities, but the resolution was limited in children with longer periods of asymmetric hearing. These findings suggest that early implantation of children with asymmetric hearing rapidly restores hemispheric representations of bilateral auditory input in the auditory cortex. Most recorded changes were isolated to pathways stimulated by the cochlear implant, potentially reflecting an abnormal independence of the bilateral pathways with possible consequences for binaural integration in these bimodal listeners. PMID- 29502908 TI - Design and synthesis of a fragment set based on twisted bicyclic lactams. AB - Current fragment sets tend to be dominated by flatter molecules, and their shape diversity does not reflect that of the fragments that are theoretically possible. The design and synthesis of a set of bridged fragments containing a bridgehead nitrogen is described. Many of these fragments contain twisted lactams whose modulated electronic properties may present unusual opportunities for interaction with target proteins. The demonstrated novelty, three-dimensionality and molecular properties of the set of 22 fragments may provide valuable, and highly distinctive, starting points for fragment-based drug discovery. PMID- 29502909 TI - Inborn Errors of Metabolism Overview: Pathophysiology, Manifestations, Evaluation, and Management. AB - The specialty of inherited metabolic disease is at the forefront of progress in medicine, with new methods in metabolomics and genomics identifying the molecular basis for a growing number of conditions and syndromes. This review presents an updated pathophysiologic classification of inborn errors of metabolism and a method of clinical screening in neonates, late-onset emergencies, neurologic deterioration, and other common clinical scenarios. When and how to investigate a metabolic disorder is presented to encourage physicians to use sophisticated biochemical investigations and not miss a treatable disorder. PMID- 29502910 TI - Inborn Errors of Metabolism with Acidosis: Organic Acidemias and Defects of Pyruvate and Ketone Body Metabolism. AB - When a child presents with high-anion gap metabolic acidosis, the pediatrician can proceed with confidence by recalling some basic principles. Defects of organic acid, pyruvate, and ketone body metabolism that present with acute acidosis are reviewed. Flowcharts for identifying the underlying cause and initiating life-saving therapy are provided. By evaluating electrolytes, blood sugar, lactate, ammonia, and urine ketones, the provider can determine the likelihood of an inborn error of metabolism. Freezing serum, plasma, and urine samples during the acute presentation for definitive diagnostic testing at the provider's convenience aids in the differential diagnosis. PMID- 29502911 TI - Inborn Errors of Metabolism with Hyperammonemia: Urea Cycle Defects and Related Disorders. AB - The urea cycle disorders are a group of inherited biochemical diseases caused by a complete or partial deficiency of any one of the enzymes or transport proteins required to convert toxic ammonia into urea and to produce arginine and citrulline. The clinical manifestations of these disorders are mostly the result of acute or chronic hyperammonemia, which affects the central nervous system. Affected individuals can also develop hepatic dysfunction. These disorders can present at any age from the immediate newborn to later in life. Early diagnosis and treatment are key to improving outcomes. PMID- 29502912 TI - Inborn Errors of Metabolism with Hypoglycemia: Glycogen Storage Diseases and Inherited Disorders of Gluconeogenesis. AB - Although hyperinsulinism is the predominant inherited cause of hypoglycemia in the newborn period, inborn errors of metabolism are the primary etiologies after 1 month of age. Disorders of carbohydrate metabolism often present with hypoglycemia when fasting occurs. The presentation, diagnosis, and management of the hepatic glycogen storage diseases and disorders of gluconeogenesis are reviewed. PMID- 29502913 TI - Inborn Errors of Metabolism with Cognitive Impairment: Metabolism Defects of Phenylalanine, Homocysteine and Methionine, Purine and Pyrimidine, and Creatine. AB - Phenylketonuria is a defect in phenylalanine metabolism resulting in the excretion of phenylketones and severe intellectual disability. The principle of eliminating the offending amino acid from the diet as a successful treatment strategy was demonstrated. The development of a low methionine diet to treat homocystinuria was established after identifying the transsulfuration pathway resulting in cysteine synthesis. Both conditions are examples of disorders of amino acid metabolism. Lesch-Nyhan syndrome, a rare disorder of purine metabolism resulting in intellectual disability and self-injurious behavior, is a classical inborn error of metabolism. Disorders of creatine biosynthesis are relatively newly described and less known diseases. PMID- 29502914 TI - Inborn Errors of Metabolism with Seizures: Defects of Glycine and Serine Metabolism and Cofactor-Related Disorders. AB - Inborn errors of metabolism (IEM) are relatively uncommon causes for seizures in children; however, they should be considered in the differential diagnosis because several IEM are potentially treatable and seizures can be resolved if appropriate treatment is initiated. Clues from clinical presentation, physical examination, laboratory tests, and brain imaging can raise the possibility of IEM. Several IEM can present with seizures, either as the main presenting finding or as a part of a more complex phenotype. These include cofactor-related disorders, glycine and serine metabolism defects, and other disorders. PMID- 29502915 TI - Inborn Errors of Metabolism with Movement Disorders: Defects in Metal Transport and Neurotransmitter Metabolism. AB - Movement disorders in the pediatric age group are largely of the hyperkinetic type. Metal ion accumulation in the central nervous system presents predominantly with movement disorders and over time leads to psychomotor decline. Abnormalities in monoamine and amino acidergic neurotransmitter metabolism present in individuals with a combination of abnormal movements, epilepsy, and cognitive and motor delay. Detailed clinical history, careful examination, appropriate diagnostic work-up with metabolic screening, cerebrospinal fluid neurotransmitters, and targeted genetic testing help with accurate diagnosis and appropriate treatment. This article provides an overview on movement disorders present in childhood secondary to inborn errors of metal transport and neurotransmitter metabolism. PMID- 29502916 TI - Inborn Errors of Metabolism with Myopathy: Defects of Fatty Acid Oxidation and the Carnitine Shuttle System. AB - Fatty acid oxidation disorders (FAODs) and carnitine shuttling defects are inborn errors of energy metabolism with associated mortality and morbidity due to cardiomyopathy, exercise intolerance, rhabdomyolysis, and liver disease with physiologic stress. Hypoglycemia is characteristically hypoketotic. Lactic acidemia and hyperammonemia may occur during decompensation. Recurrent rhabdomyolysis is debilitating. Expanded newborn screening can detect most of these disorders, allowing early, presymptomatic treatment. Treatment includes avoiding fasting and sustained extraneous exercise and providing high-calorie hydration during illness to prevent lipolysis, and medium-chain triglyceride oil supplementation in long-chain FAODs. Carnitine supplementation may be helpful. However, conventional treatment does not prevent all symptoms. PMID- 29502917 TI - Inborn Errors of Metabolism with Hepatopathy: Metabolism Defects of Galactose, Fructose, and Tyrosine. AB - The liver is one of the most essential organs in metabolism and is responsible for metabolizing a wide variety of molecules from amino acids to sugars. Although it is responsible for many essential metabolic processes, it is one of the most severely affected by metabolic disease because, in many cases, it is the first to be exposed to the toxic intermediates. The metabolism of galactose, fructose, and tyrosine involve the liver and although there are systemic findings in metabolic disease involved with these substrates, severe hepatopathy is a common presenting aspect of galactosemia, hereditary fructose intolerance, and tyrosinemia type I. PMID- 29502918 TI - Inborn Errors of Metabolism Involving Complex Molecules: Lysosomal and Peroxisomal Storage Diseases. AB - Peroxisomes and lysosomes are distinct subcellular compartments that underlie several pediatric metabolic disorders. Knowledge of their function and cell biology leads to understanding how the disorders result from genetic defects. Diagnostic and therapeutic approaches for the disorders take advantage of the cell biology mechanisms. Whereas peroxisomal disorders are characterized by enzymatic defects in peroxisomal pathways leading to metabolic and lipid changes, lysosomal storage disorders are marked by accumulation of substrates of lysosomal pathways inside the lysosome. The human diseases related to these two organelles are reviewed, focusing on general disease patterns and underlying diagnosis and treatment principles. PMID- 29502919 TI - Complex Phenotypes in Inborn Errors of Metabolism: Overlapping Presentations in Congenital Disorders of Glycosylation and Mitochondrial Disorders. AB - Congenital disorders of glycosylation (CDG) and mitochondrial disorders have overlapping clinical features, including central nervous system, cardiac, gastrointestinal, hepatic, muscular, endocrine, and psychiatric disease. Specific abnormalities orienting the clinician toward the right diagnostic approach include abnormal fat distribution, coagulation abnormalities, together with anticoagulation abnormalities, hyperinsulinism, and congenital malformations in CDG. Diabetes, sensorineural deafness, and depression are very rare in CDG but common in mitochondrial disease. Chronic lactic acidosis is highly suggestive of mitochondrial dysfunction. Serum transferrin isoform analysis is specific for glycosylation abnormalities but not abnormal in all types of CDG. PMID- 29502920 TI - Newborn Screening: History, Current Status, and Future Directions. AB - Newborn screening programs aim to achieve presymptomatic diagnosis of treatable disorders allowing for early initiation of medical care to prevent or reduce significant morbidity and mortality. Many of the conditions included in the newborn screening panels are inborn errors of metabolism; however, screening for endocrine, hematologic, immunologic, and cardiovascular diseases, and hearing loss is also included in many panels. Newborn screening tests are not diagnostic and therefore diagnostic testing is needed to confirm or exclude the suspected diagnosis. Further advancement in technology is expected to allow continuous expansion of newborn screening. PMID- 29502921 TI - Approach to Inborn Errors of Metabolism in Pediatrics. PMID- 29502922 TI - Erratum. PMID- 29502923 TI - New Understanding of Mechanisms and New Hope for Treatments. PMID- 29502924 TI - Head-to-head comparison of the accuracy of Abbott FreeStyle Libre and Dexcom G5 mobile. PMID- 29502925 TI - High serum levels of C-reactive protein (CRP) predict beneficial decrease of visceral fat in obese females after sleeve gastrectomy. AB - BACKGROUND & AIMS: Gender-related differences represent an emerging investigation field to better understand obesity heterogeneity and paradoxically associated cardiovascular (CV) risk. Here, we investigated if high-sensitivity C-reactive protein (hs-CRP) might differently affect adiposity and predict the clinical response to bariatric surgery in obese males and females. METHODS AND RESULTS: In 110 morbidly obese patients undergoing laparoscopic sleeve gastrectomy, hs-CRP as well as anthropometric assessment of adiposity, completed by electric bioimpedance and ultrasonography quantification of visceral fat area (VFA), were measured before and one year after surgery. As compared to males, obese female showed less severe overweight and prevalent subcutaneous fat deposition, but higher circulating hs-CRP. In obese females, hs-CRP was associated with VFA at baseline, independently of body mass index (BMI) and visceral adiposity index (OR 1.022 [95% CI 1.001-1.044]; p = 0.039). Based on decreases and increases in hs CRP levels after surgery, two distinct subgroups of females were identified. Post surgery decreases in hs-CRP was predominantly observed in patients with higher baseline levels of hs-CRP and associated with greater reduction of weight, BMI, fat and lean mass, VFA and visceral to subcutaneous fat ratio. Finally, we observed that high baseline values of hs-CRP were able to predict VFA reduction one-year after surgery, independently of BMI and visceral adiposity index (VAI) loss (OR 1.031 [95% CI 1.009-1.053]; p = 0.005). CONCLUSION: In obese females, hs CRP levels might be a promising biomarker of visceral fat amount and dysfunction, in addition to predict the effectiveness of bariatric surgery in terms of loss of VFA one-year after surgery. PMID- 29502926 TI - Phenylketonuric diet negatively impacts on butyrate production. AB - BACKGROUND AND AIMS: Phenylalanine (Phe) restricted diet, combined with Phe-free l-amino acid supplementation, is the mainstay of treatment for phenylketonuria (PKU). Being the diet a key factor modulating gut microbiota composition, the aim of the present paper was to compare dietary intakes, gut microbiota biodiversity and short chain fatty acids (SCFAs) production in children with PKU, on low-Phe diet, and in children with mild hyperphenylalaninemia (MHP), on unrestricted diet. METHODS AND RESULTS: We enrolled 21 PKU and 21 MHP children matched for gender, age and body mass index z-score. Dietary intakes, including glycemic index (GI) and glycemic load (GL), and fecal microbiota analyses, by means of denaturing gradient gel electrophoresis (DGGE) and Real-time PCR were assessed. Fecal SCFAs were quantified by gas chromatographic analysis. RESULTS: We observed an increased carbohydrate (% of total energy), fiber and vegetables intakes (g/day) in PKU compared with MHP children (p = 0.047), as well a higher daily GI and GL (maximum p < 0.001). Compared with MHP, PKU showed a lower degree of microbial diversity and a decrease in fecal butyrate content (p = 0.02). Accordingly, two of the most abundant butyrate-producing genera, Faecalibacterium spp. and Roseburia spp., were found significantly depleted in PKU children (p = 0.02 and p = 0.03, respectively). CONCLUSION: The low-Phe diet, characterized by a higher carbohydrate intake, increases GI and GL, resulting in a different quality of substrates for microbial fermentation. Further analyses, thoroughly evaluating microbial species altered by PKU diet are needed to better investigate gut microbiota in PKU children and to eventually pave the way for pre/probiotic supplementations. PMID- 29502927 TI - Laryngeal nerve injury during thyroid surgery. PMID- 29502928 TI - [Benign metastasizing leiomyoma: An unusual cause of aggressive femoral bone tumor]. AB - BACKGROUND: Benign metastasizing leiomyoma (BML) is a rare condition characterized by histologically benign "metastatic" smooth muscle tumors, which can affect women with history of uterine surgery. We report the case of a patient with bone metastases of BML. CASE REPORT: A 78-year-old woman who had undergone uterine surgery six years before hospital admission, was diagnosed with large pulmonary and pleural metastases that necessitated surgical removal. Pathological examination allowed the diagnosis of BML with positive staining for estrogen and progesterone receptors. Three years later, a BML metastasis in the right femoral diaphysis was unexpectedly discovered and treated by osteosynthesis because of a high risk of fracture. Despite an aromatase-inhibitor treatment, new lungs lesions appeared in the next few months. CONCLUSION: BML is a potential cause of aggressive, although histologically benign, bone tumor in women with a history of uterine surgery. PMID- 29502929 TI - [An unusual cause of abdominal pain]. PMID- 29502930 TI - A comparison of compliance in the estimation of body fluid status using daily fluid balance charting and body weight changes during continuous renal replacement therapy. PMID- 29502931 TI - Effect of Radiation Treatment Volume Reduction on Lymphopenia in Patients Receiving Chemoradiotherapy for Glioblastoma. AB - PURPOSE: To evaluate whether reduction in glioblastoma radiation treatment volume can reduce risk of acute severe lymphopenia (ASL). METHODS AND MATERIALS: A total of 210 patients with supratentorial/nonmetastatic glioblastoma were treated with radiation therapy (RT) plus temozolomide from 2007 to 2016 and had laboratory data on total lymphocyte counts. Before 2015, 164 patients were treated with standard-field RT (SFRT), and limited-field RT (LFRT) was implemented thereafter for 46 patients to reduce treatment volume. Total lymphocyte counts were evaluated at baseline, during RT, and at approximately week 12 from initiating RT. Acute severe lymphopenia was defined as any total lymphocyte count < 500 cells/MUL within 3 months (by week 12) of initiating RT. Multivariate analysis for overall survival (OS) was performed with Cox regression and with logistic regression for ASL. Propensity score matching was performed to adjust for variability between cohorts. Acute severe lymphopenia, progression-free survival (PFS), and OS were compared using the Kaplan-Meier method. RESULTS: Limited-field RT patients had higher gross tumor volume than SFRT patients yet lower brain dose volume parameters, including volume receiving 25 Gy (V25 Gy: 41% vs 53%, respectively, P < .01). Total lymphocyte count at week 12 was significantly higher for LFRT than for SFRT (median: 1100 cells/MUL vs 900 cells/MUL, respectively, P = .02). On multivariate analysis, ASL was an independent predictor of OS, and brain V25 Gy was an independent predictor of ASL. The ASL rate at 3 months was 15.5% for LFRT and 33.8% for SFRT (P = .12). In a propensity matched comparison of 45 pairs of LFRT and SFRT patients, PFS (median: 5.9 vs 6.2 months, respectively, P = .58) and OS (median: 16.2 vs 13.9 months, respectively, P = .69) were not significantly different. CONCLUSIONS: Limited-field RT is associated with less lymphopenia after RT plus temozolomide and does not adversely affect PFS or OS. Brain V25 Gy is confirmed as an important dosimetric predictor for ASL. PMID- 29502932 TI - Machine Learning on a Genome-wide Association Study to Predict Late Genitourinary Toxicity After Prostate Radiation Therapy. AB - PURPOSE: Late genitourinary (GU) toxicity after radiation therapy limits the quality of life of prostate cancer survivors; however, efforts to explain GU toxicity using patient and dose information have remained unsuccessful. We identified patients with a greater congenital GU toxicity risk by identifying and integrating patterns in genome-wide single nucleotide polymorphisms (SNPs). METHODS AND MATERIALS: We applied a preconditioned random forest regression method for predicting risk from the genome-wide data to combine the effects of multiple SNPs and overcome the statistical power limitations of single-SNP analysis. We studied a cohort of 324 prostate cancer patients who were self assessed for 4 urinary symptoms at 2 years after radiation therapy using the International Prostate Symptom Score. RESULTS: The predictive accuracy of the method varied across the symptoms. Only for the weak stream endpoint did it achieve a significant area under the curve of 0.70 (95% confidence interval 0.54 0.86; P = .01) on hold-out validation data that outperformed competing methods. Gene ontology analysis highlighted key biological processes, such as neurogenesis and ion transport, from the genes known to be important for urinary tract functions. CONCLUSIONS: We applied machine learning methods and bioinformatics tools to genome-wide data to predict and explain GU toxicity. Our approach enabled the design of a more powerful predictive model and the determination of plausible biomarkers and biological processes associated with GU toxicity. PMID- 29502933 TI - Trueness and precision of digital impressions obtained using an intraoral scanner with different head size in the partially edentulous mandible. AB - PURPOSE: It remains unclear whether digital impressions obtained using an intraoral scanner are sufficiently accurate for use in fabrication of removable partial dentures. We therefore compared the trueness and precision between conventional and digital impressions in the partially edentulous mandible. METHODS: Mandibular Kennedy Class I and III models with soft silicone simulated mucosa placed on the residual edentulous ridge were used. The reference models were converted to standard triangulated language (STL) file format using an extraoral scanner. Digital impressions were obtained using an intraoral scanner with a large or small scanning head, and converted to STL files. For conventional impressions, pressure impressions of the reference models were made and working casts fabricated using modified dental stone; these were converted to STL file format using an extraoral scanner. Conversion to STL file format was performed 5 times for each method. Trueness and precision were evaluated by deviation analysis using three-dimensional image processing software. RESULTS: Digital impressions had superior trueness (54-108MUm), but inferior precision (100 121MUm) compared to conventional impressions (trueness 122-157MUm, precision 52 119MUm). The larger intraoral scanning head showed better trueness and precision than the smaller head, and on average required fewer scanned images of digital impressions than the smaller head (p<0.05). On the color map, the deviation distribution tended to differ between the conventional and digital impressions. CONCLUSIONS: Digital impressions are partially comparable to conventional impressions in terms of accuracy; the use of a larger scanning head may improve the accuracy for removable partial denture fabrication. PMID- 29502934 TI - Association of Tricuspid Regurgitation With Transcatheter Aortic Valve Replacement Outcomes: A Report From The Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. AB - BACKGROUND: The purpose of this study is to evaluate the association of tricuspid regurgitation (TR) severity with outcomes after transcatheter aortic valve replacement (TAVR). METHODS: We analyzed data from 34,576 patients who underwent TAVR at 365 US hospitals from November 2011 through March 2015 submitted to The Society of Thoracic Surgeon/American College of Cardiology Transcatheter Valve Therapy Registry. We examined unadjusted mortality and heart failure readmission stratified by degree of preoperative TR and used multivariable models for 1-year mortality and heart failure readmission. RESULTS: Tricuspid regurgitation was present in 80% (n = 27,804) of TAVR patients, with mild TR in 56% (n = 19,393), moderate TR in 19% (n = 6687), and severe TR in 5% (n = 1,724). Increasing TR severity was associated with a number of comorbidities and The Society of Thoracic Surgeons predicted risk of mortality increased (p < 0.001): no TR (7.3 +/- 5.4); mild TR (8.0 +/- 5.7); moderate TR (9.6 +/- 6.8); and severe TR (10.7 +/- 7.4). In unadjusted analysis, moderate and severe TR were associated with increased use of cardiopulmonary bypass, longer intensive care unit and hospital stays, new dialysis, inhospital major adverse cardiac event, inhospital mortality, observed-to-expected inhospital mortality ratio, long-term heart failure readmission, and mortality (p < 0.001). Adjusted mortality at 1 year was significantly worse for patients with severe TR when left ventricular ejection fraction greater than 30% (hazard ratio 1.29, 95% confidence interval: 1.11 to 1.50) as was heart failure readmission (hazard ratio 1.27, 95% confidence interval: 1.04 to 1.54). CONCLUSIONS: Tricuspid regurgitation was common among patients undergoing TAVR. Increasing TR severity was associated with higher risk patients and increased mortality and readmission-particularly for patients with severe TR and left ventricular ejection fraction greater than 30%. The effectiveness of TAVR alone in patients with aortic stenosis and concomitant severe TR may warrant further consideration, particularly for lower risk patients. PMID- 29502935 TI - Robotic Versus Video-Assisted Thoracoscopic Lung Resection During Early Program Development. AB - BACKGROUND: The objective of this study is to compare robotic portal (RP) to video-assisted thoracoscopic surgery (VATS) pulmonary resections for early stage non-small cell lung cancer with respect to health care resource utilization during the first year of a robotic surgery program in thoracic oncology. METHODS: Patients who underwent anatomic lung resections using RP (n = 42) or VATS (n = 96) for early stage non-small cell lung cancer between April 2014 and March 2015 at a single institution were identified. Patient-level case costing data for hospital and home care-associated resource variables were recorded. We adopted a health care payer perspective and 30-day posthospital discharge/death time horizon. Parametric or nonparametric tests were used as appropriate and incremental cost difference using 10,000 bootstrap samples using bias-corrected and accelerated method to generate 95% confidence intervals for total cost. RESULTS: Baseline demographic and clinical characteristics were comparable between the two groups. The median total hospital cost per patient was $15,247 (95% confidence interval: $15,643 to $18,945) in the RP cohort, compared with $12,131 (95% confidence interval: $13,218 to $15,879) in the VATS cohort (n = 96; p < 0.001). Longer operating times in the RP group were the main driver of higher hospital costs. Post-hoc analysis of mean operating room time for first 20 RP procedures versus remaining 22 RP procedures found a mean difference of 71 minutes (p = 0.004), resulting in an intraoperative cost difference of $883.38 (p = 0.036). CONCLUSIONS: A micro-costing analysis demonstrates that RP pulmonary resection for early stage non-small cell lung cancer utilizes more health care resource dollars when compared with VATS during early program development, but offers similar perioperative outcomes. PMID- 29502936 TI - Preface: Clinical relevance of respiratory mechanics and flows. PMID- 29502938 TI - Short dental implants in patients with oral lichen planus: a long-term follow-up. AB - Oral lichen planus is associated with the Koebner phenomenon, and trauma may exacerbate oral lesions. Short dental implants, as alternatives to bony augmentation, would reduce the number of interventions and their morbidity. However, we know of no studies that have analysed the long-term outcomes of short implants in patients with oral lichen planus. We have therefore designed a retrospective study of such patients treated with short implants (<=8.5mm long), with survival of implants as the main outcome. The secondary outcomes were marginal bone loss and the development of complications. We calculated the implants' survival and compared the outcomes statistically between erosive and reticular oral lichen planus. Sixty-six short implants were placed in 23 patients with a mean (SD) age of 58 (7) years. The mean (SD) peri-implant bone loss was 0.96 (0.89) mm mesially and 0.99 (1.1) mm distally. Sixty-five of the 66 implants survived with a mean (SD) follow-up of 68 (32) months, and there were no significant differences between erosive and reticular disease. Stable long-term outcomes can be expected for short implants placed in patients with oral lichen planus, and graftless rehabilitation of missing teeth could be possible in these patients if short implants were used. PMID- 29502939 TI - So-called "bad split" may not be "bad" when the split is on the buccal side: technical note. PMID- 29502937 TI - Managing latent tuberculosis infection and tuberculosis in children. AB - Tuberculosis (TB) is a major cause of childhood morbidity and mortality worldwide. The aim of this review is to describe the management of the child with TB and latent tuberculosis infection (LTBI). To develop this article, a working group reviewed relevant epidemiological and other scientific studies and established practices in conducting LBTI and TB in children. The article describes how to manage the child with LTBI, considering transmission and infectiousness of tuberculosis, contact screening and prioritization of contacts and recommendations on treatment of children with LTBI and how to manage the child with TB considering the susceptibility of children to developing tuberculosis, epidemiology and classification of tuberculosis in children, diagnosis and treatment. PMID- 29502940 TI - Genome-wide association study identifies polymorphisms associated with the analgesic effect of fentanyl in the preoperative cold pressor-induced pain test. AB - Opioid analgesics are widely used for the treatment of moderate to severe pain. The analgesic effects of opioids are well known to vary among individuals. The present study focused on the genetic factors that are associated with interindividual differences in pain and opioid sensitivity. We conducted a multistage genome-wide association study in subjects who were scheduled to undergo mandibular sagittal split ramus osteotomy and were not medicated until they received fentanyl for the induction of anesthesia. We preoperatively conducted the cold pressor-induced pain test before and after fentanyl administration. The rs13093031 and rs12633508 single-nucleotide polymorphisms (SNPs) near the LOC728432 gene region and rs6961071 SNP in the tcag7.1213 gene region were significantly associated with the analgesic effect of fentanyl, based on differences in pain perception latency before and after fentanyl administration. The associations of these three SNPs that were identified in our exploratory study have not been previously reported. The two polymorphic loci (rs13093031 and rs12633508) were shown to be in strong linkage disequilibrium. Subjects with the G/G genotype of the rs13093031 and rs6961071 SNPs presented lower fentanyl-induced analgesia. Our findings provide a basis for investigating genetics-based analgesic sensitivity and personalized pain control. PMID- 29502941 TI - Nuclear magnetic resonance- and gas chromatography/mass spectrometry-based metabolomic characterization of water-soluble and volatile compound profiles in cabbage vinegar. AB - Non-targeted metabolomic analyses employing nuclear magnetic resonance- and gas chromatography/mass spectrometry-based techniques were applied for an in-depth characterization of cabbage vinegar, an original agricultural product made from cabbage harvested in Tsumagoi, Japan. Water-soluble and volatile metabolite profiles of cabbage vinegar were compared with those of various vinegars: rice vinegar, grain vinegar, apple vinegar, and black vinegar (Japanese kurozu made of brown rice). Principal component analysis (PCA) of the water-soluble metabolites indicated that cabbage vinegars belonged to an isolated class by the contributions of fructose, pyroglutamic acid, choline, and methiin (S methylcysteine sulfoxide). Regarding the volatile compounds, the PCA data represented that rice, black, and apple vinegars were characterized by most of the dominant volatiles, such as acetate esters, alcohols, ketones, and acids. Cabbage and grain vinegars were included in the same class although these two vinegars have different flavors. Orthogonal partial least squares-discrimination analysis exhibited the differences in volatile compound profile between cabbage and grain vinegars, revealing that cabbage vinegars were characterized by the presence of sulfides (dimethyl sulfide, dimethyl disulfide, and dimethyl trisulfide), nitriles (allyl cyanide and 4-methylthio-butanenitrile), 3-hexene-1 ol, and crotonic acid. The time-course changes in these highlighted compounds during the acetic acid fermentation of cabbage vinegar suggested that pyroglutamic and crotonic acids were produced through fermentation, whereas choline, methiin, sulfides, nitriles, and 3-hexene-1-ol were derived from cabbage, suggesting the key role of these compounds in the unique taste and flavor of cabbage vinegar. PMID- 29502942 TI - Development of a perfusable 3D liver cell cultivation system via bundling-up assembly of cell-laden microfibers. AB - Although the reconstruction of functional 3D liver tissue models in vitro presents numerous challenges, it is in great demand for drug development, regenerative medicine, and physiological studies. Here we propose a new approach to perform perfusion cultivation of liver cells by assembling cell-laden hydrogel microfibers. HepG2 cells were densely packed into the core of sandwich-type anisotropic microfibers, which were produced using microfluidic devices. The obtained microfibers were bundled up and packed into a perfusion chamber, and perfusion cultivation was performed. We evaluated cell viability and functions, and also monitored the oxygen consumption. Furthermore, fibers covered with vascular endothelial cells were united during the perfusion culture, to form vascular network-like conduits between fibers. The presented technique can structurally mimic the hepatic lobule in vivo and could prove to be a useful model for various biomedical research applications. PMID- 29502943 TI - Rejoinder to "Visibility of healthcare research institutes through the Web of Science database". PMID- 29502944 TI - Registry of Japanese patients with atrial fibrillation focused on anticoagulant therapy in the new era: The RAFFINE registry study design and baseline characteristics. AB - BACKGROUND: The management of atrial fibrillation (AF) has evolved with the development of direct oral anticoagulants (DOACs), but data on their clinical effectiveness and safety outside clinical trial settings are limited. METHOD: The RAFFINE registry is an observational, multicenter, prospective registry of Japanese patients with AF, designed to follow clinical events over 3 years. Patient enrollment was conducted from 2013 to 2015 at university hospitals, general hospitals, and private clinics to ensure inclusion of a broad spectrum of representative AF patients. The primary outcome events in this study will be ischemic stroke, systemic embolism, and major bleeding. RESULT: We enrolled 3901 ambulatory patients with AF from 4 university hospitals and 50 general hospitals/clinics in Japan. The mean patient age was 72.6 years and 68.5% were male. The type of AF was paroxysmal in 37.8%, persistent in 9.3%, and permanent in 51.7%. Major coexisting diseases were hypertension (72.7%), diabetes mellitus (30.3%), congestive heart failure (23.8%), history of ischemic stroke or transient ischemic attack (15.1%), and coronary artery disease (13.7%). Of the entire cohort, 44.6% were treated with warfarin and 43.0% were treated with DOACs. The prescription of DOACs exceeded that of warfarin in the general hospitals and clinics. Risk scores such as CHADS2 score, CHA2DS2-VASc score, and HAS-BLED score were higher in patients at university hospitals than in patients at general hospitals or clinics. CONCLUSION: The RAFFINE registry at baseline described the current status of anticoagulation therapy in Japan and long-term follow-up data will identify how outcomes vary between stratified groups in patients with AF in the DOAC era (UMIN Clinical Trials Registry UMIN000009617). PMID- 29502945 TI - Corrigendum to "The Selvester QRS score as a predictor of cardiac events in nonischemic dilated cardiomyopathy" [J. Cardiol. 71 (2018) 284-290]. PMID- 29502946 TI - Proprioceptive Distance Cues Restore Perfect Size Constancy in Grasping, but Not Perception, When Vision Is Limited. AB - Our brain integrates information from multiple modalities in the control of behavior. When information from one sensory source is compromised, information from another source can compensate for the loss. What is not clear is whether the nature of this multisensory integration and the re-weighting of different sources of sensory information are the same across different control systems. Here, we investigated whether proprioceptive distance information (position sense of body parts) can compensate for the loss of visual distance cues that support size constancy in perception (mediated by the ventral visual stream) [1, 2] versus size constancy in grasping (mediated by the dorsal visual stream) [3-6], in which the real-world size of an object is computed despite changes in viewing distance. We found that there was perfect size constancy in both perception and grasping in a full-viewing condition (lights on, binocular viewing) and that size constancy in both tasks was dramatically disrupted in the restricted-viewing condition (lights off; monocular viewing of the same but luminescent object through a 1-mm pinhole). Importantly, in the restricted-viewing condition, proprioceptive cues about viewing distance originating from the non-grasping limb (experiment 1) or the inclination of the torso and/or the elbow angle of the grasping limb (experiment 2) compensated for the loss of visual distance cues to enable a complete restoration of size constancy in grasping but only a modest improvement of size constancy in perception. This suggests that the weighting of different sources of sensory information varies as a function of the control system being used. PMID- 29502947 TI - Spontaneous Changes in Ploidy Are Common in Yeast. AB - Changes in ploidy are relatively rare, but play important roles in the development of cancer and the acquisition of long-term adaptations. Genome duplications occur across the tree of life, and can alter the rate of adaptive evolution. Moreover, by allowing the subsequent loss of individual chromosomes and the accumulation of mutations, changes in ploidy can promote genomic instability and/or adaptation. Although many studies have been published in the last years about changes in chromosome number and their evolutionary consequences, tracking and measuring the rate of whole-genome duplications have been extremely challenging. We have systematically studied the appearance of diploid cells among haploid yeast cultures evolving for over 100 generations in different media. We find that spontaneous diploidization is a relatively common event, which is usually selected against, but under certain stressful conditions may become advantageous. Furthermore, we were able to detect and distinguish between two different mechanisms of diploidization, one that requires whole genome duplication (endoreduplication) and a second that involves mating-type switching despite the use of heterothallic strains. Our results have important implications for our understanding of evolution and adaptation in fungal pathogens and the development of cancer, and for the use of yeast cells in biotechnological applications. PMID- 29502949 TI - Spatial Rule Learning and Corresponding CA1 Place Cell Reorientation Depend on Local Dopamine Release. AB - Incentives drive goal-directed behavior; however, how they impact the formation and stabilization of goal-relevant hippocampal maps remains unknown. Since dopamine is involved in reward processing, affects hippocampal-dependent behavior, and modulates hippocampal plasticity, we hypothesized that local dopaminergic transmission in the hippocampus serves to mold the formation and updating of hippocampal cognitive maps to adaptively represent reward-predicting space of sensory inputs. We recorded CA1 place cells of rats throughout training on a spatial extra-dimensional set-shift task. After learning to rely on one of two orthogonal sets of cues, we introduced a rule shift and infused locally the D1/5 receptor (D1/5R) antagonist SCH23390. Successful learning was accompanied by place cell reorientation to represent rule-relevant spatial dimension. SCH23390 infusion prevented this remapping and, consequently, impaired learning, causing perseveration. These findings suggest that dopaminergic innervation provides reward information to the hippocampus and is critical for the stabilization of goal-related hippocampal representation, contributing to successful goal-directed behavior. PMID- 29502948 TI - Mps1 Phosphorylates Its N-Terminal Extension to Relieve Autoinhibition and Activate the Spindle Assembly Checkpoint. AB - Monopolar spindle 1 (Mps1) is a conserved apical kinase in the spindle assembly checkpoint (SAC) that ensures accurate segregation of chromosomes during mitosis. Mps1 undergoes extensive auto- and transphosphorylation, but the regulatory and functional consequences of these modifications remain unclear. Recent findings highlight the importance of intermolecular interactions between the N-terminal extension (NTE) of Mps1 and the Hec1 subunit of the NDC80 complex, which control Mps1 localization at kinetochores and activation of the SAC. Whether the NTE regulates other mitotic functions of Mps1 remains unknown. Here, we report that phosphorylation within the NTE contributes to Mps1 activation through relief of catalytic autoinhibition that is mediated by the NTE itself. Moreover, we find that this regulatory NTE function is independent of its role in Mps1 kinetochore recruitment. We demonstrate that the NTE autoinhibitory mechanism impinges most strongly on Mps1-dependent SAC functions and propose that Mps1 activation likely occurs sequentially through dimerization of a "prone-to-autophosphorylate" Mps1 conformer followed by autophosphorylation of the NTE prior to maximal kinase activation segment trans-autophosphorylation. Our observations underline the importance of autoregulated Mps1 activity in generation and maintenance of a robust SAC in human cells. PMID- 29502950 TI - Equatorial Assembly of the Cell-Division Actomyosin Ring in the Absence of Cytokinetic Spatial Cues. AB - The position of the division site dictates the size and fate of daughter cells in many organisms. In animal cells, division-site placement involves overlapping mechanisms, including signaling from the central spindle microtubules, astral microtubules, and spindle poles and through polar contractions [1-3]. In fission yeast, division-site positioning requires overlapping mechanisms involving the anillin-related protein Mid1 and the tip complex (comprising the Kelch-repeat protein Tea1, the Dyrk-kinase Pom1, and the SH3-domain protein Tea4) [4-11]. In addition to these factors, cell shape has also been shown to participate in the maintenance of the position of the actomyosin ring [12-14]. The first principles guiding actomyosin ring placement, however, have not been elucidated in any organism. Because actomyosin ring positioning, ring assembly, and cell morphogenesis are genetically separable in fission yeast, we have used it to derive actomyosin ring placement mechanisms from first principles. We report that, during ring assembly in the absence of cytokinetic cues (anillin-related Mid1 and tip-complex proteins), actin bundles follow the path of least curvature and assemble actomyosin rings in an equatorial position in spherical protoplasts and along the long axis in cylindrical cells and compressed protoplasts. The equatorial position of rings is abolished upon treatment of protoplasts with an actin-severing compound or by slowing down actin polymerization. We propose that the physical properties of actin filaments/bundles play key roles in actomyosin ring assembly and positioning, and that key cytokinetic molecules may modulate the length of actin filaments to promote ring assembly along the short axis. PMID- 29502951 TI - Size Laws and Division Ring Dynamics in Filamentous Escherichia coli cells. AB - Our understanding of bacterial cell size control is based mainly on stress-free growth conditions in the laboratory [1-10]. In the real world, however, bacteria are routinely faced with stresses that produce long filamentous cell morphologies [11-28]. Escherichia coli is observed to filament in response to DNA damage [22 25], antibiotic treatment [11-14, 28], host immune systems [15, 16], temperature [17], starvation [20], and more [18, 19, 21], conditions which are relevant to clinical settings and food preservation [26]. This shape plasticity is considered a survival strategy [27]. Size control in this regime remains largely unexplored. Here we report that E. coli cells use a dynamic size ruler to determine division locations combined with an adder-like mechanism to trigger divisions. As filamentous cells increase in size due to growth, or decrease in size due to divisions, its multiple Fts division rings abruptly reorganize to remain one characteristic cell length away from the cell pole and two such length units away from each other. These rules can be explained by spatiotemporal oscillations of Min proteins. Upon removal of filamentation stress, the cells undergo a sequence of division events, randomly at one of the possible division sites, on average after the time required to grow one characteristic cell size. These results indicate that E. coli cells continuously keep track of absolute length to control size, suggest a wider relevance for the adder principle beyond the control of normally sized cells, and provide a new perspective on the function of the Fts and Min systems. PMID- 29502952 TI - Stress Accelerates Defensive Responses to Looming in Mice and Involves a Locus Coeruleus-Superior Colliculus Projection. AB - Defensive responses to threatening stimuli are crucial to the survival of species. While expression of these responses is considered to be instinctive and unconditional, their magnitude may be affected by environmental and internal factors. The neural circuits underlying this modulation are still largely unknown. In mice, looming-evoked defensive responses are mediated by the superior colliculus (SC), a subcortical sensorimotor integration center. We found that repeated stress caused an anxiety-like state in mice and accelerated defensive responses to looming. Stress also induced c-fos activation in locus coeruleus (LC) tyrosine hydroxylase (TH)+ neurons and modified adrenergic receptor expression in SC, suggesting a possible Th::LC-SC projection that may be involved in the accelerated defensive responses. Indeed, both anterograde and retrograde neural tracing confirmed the anatomical Th::LC-SC projection and that the SC projecting TH+ neurons in LC were activated by repeated stress. Optogenetic stimulation of either LC TH+ neurons or the Th::LC-SC fibers also caused anxiety like behaviors and accelerated defensive responses to looming. Meanwhile, chemogenetic inhibition of LC TH+ neurons and the infusion of an adrenergic receptor antagonist in SC abolished the enhanced looming defensive responses after repeated stress, confirming the necessity of this pathway. These findings suggest that the Th::LC-SC pathway plays a key role in the sophisticated adjustments of defensive behaviors induced by changes in physiological states. PMID- 29502953 TI - Identification of a Single Pair of Interneurons for Bitter Taste Processing in the Drosophila Brain. AB - Drosophila has become an excellent model system for investigating the organization and function of the gustatory system due to the relatively simple neuroanatomical organization of its brain and the availability of powerful genetic and transgenic technology. Thus, at the molecular and cellular levels, a great deal of insight into the peripheral detection and coding of gustatory information has already been attained. In contrast, much less is known about the central neural circuits that process this information and induce behaviorally appropriate motor output. Here, we combine functional behavioral tests with targeted transgene expression through specific driver lines to identify a single bilaterally homologous pair of bitter-sensitive interneurons that are located in the subesophageal zone of the brain. Anatomical and functional data indicate that these interneurons receive specific synaptic input from bitter-sensitive gustatory receptor neurons. Targeted transgenic activation and inactivation experiments show that these bitter-sensitive interneurons can largely suppress the proboscis extension reflex to appetitive stimuli, such as sugar and water. These functional experiments, together with calcium-imaging studies and calcium modulated photoactivatable ratiometric integrator (CaMPARI) labeling, indicate that these first-order local interneurons play an important role in the inhibition of the proboscis extension reflex that occurs in response to bitter tastants. Taken together, our studies present a cellular identification and functional characterization of a key gustatory interneuron in the bitter sensitive gustatory circuitry of the adult fly. PMID- 29502954 TI - ORY-1001, a Potent and Selective Covalent KDM1A Inhibitor, for the Treatment of Acute Leukemia. AB - The lysine-specific demethylase KDM1A is a key regulator of stem cell potential in acute myeloid leukemia (AML). ORY-1001 is a highly potent and selective KDM1A inhibitor that induces H3K4me2 accumulation on KDM1A target genes, blast differentiation, and reduction of leukemic stem cell capacity in AML. ORY-1001 exhibits potent synergy with standard-of-care drugs and selective epigenetic inhibitors, reduces growth of an AML xenograft model, and extends survival in a mouse PDX (patient-derived xenograft) model of T cell acute leukemia. Surrogate pharmacodynamic biomarkers developed based on expression changes in leukemia cell lines were translated to samples from patients treated with ORY-1001. ORY-1001 is a selective KDM1A inhibitor in clinical trials and is currently being evaluated in patients with leukemia and solid tumors. PMID- 29502956 TI - The current landscape for the treatment of mitochondrial disorders. AB - The mitochondrial organelle is crucial to the energy metabolism of the eukaryotic cell. Defects in mitochondrial function lie at the core of a wide range of disorders, including both rare primary mitochondrial disorders and more common conditions such as Parkinson's disease and diabetes. Inherited defects in mitochondrial function can be found in both the nuclear genome and the mitochondrial genome, with the latter creating unique challenges in the treatment and understanding of disease passed on through the mitochondrial genome. In this review, we will describe the limited treatment regimens currently used to alleviate primary mitochondrial disorders, as well as the potential for emerging technologies (in particular, those involving direct manipulation of the mitochondrial genome) to more decisively treat this class of disease. We will also emphasize the critical parallels between primary mitochondrial disorders and more common ailments such as cancer and diabetes. PMID- 29502957 TI - Genetic profiling of cancer with circulating tumor DNA analysis. AB - Circulating cell-free tumor DNA (ctDNA) in the blood is DNA released from apoptotic, circulating, and living tumor cells. ctDNA is about 140 nt in length and has a half-life of about 1.5 h. ctDNA analysis provides a noninvasive means to assess the genetic profile of cancer in real time. With the advent of molecular technologies, including digital PCR and massively parallel sequencing (MPS), ctDNA analysis has shown promise as a highly sensitive and specific alternative to conventional tissue biopsy in cancer detection, longitudinal monitoring, and precision therapy. This review provides an overview of the latest development in our understanding of the biologic characteristics, detection methodologies, and potential clinical implications of ctDNA, as well as the challenges in translating ctDNA analysis from the research arena to patient care. PMID- 29502958 TI - AQR is a novel type 2 diabetes-associated gene that regulates signaling pathways critical for glucose metabolism. AB - Type 2 diabetes mellitus (T2DM) is a common metabolic disease influenced by both genetic and environmental factors. In this study, we performed an in-house genotyping and meta-analysis study using three independent GWAS datasets of T2DM and found that rs3743121, located 1 kb downstream of AQR, was a novel susceptibility SNP associated with T2DM. The risk allele C of rs3743121 was correlated with the increased expression of AQR in white blood cells, similar to that observed in T2DM models. The knockdown of AQR in HepG2 facilitated the glucose uptake, decreased the expression level of PCK2, increased the phosphorylation of GSK-3beta, and restored the insulin sensitivity. Furthermore, the suppression of AQR inhibited the mTOR pathway and the protein ubiquitination process. Our study suggests that AQR is a novel type 2 diabetes-associated gene that regulates signaling pathways critical for glucose metabolism. PMID- 29502955 TI - The SS18-SSX Oncoprotein Hijacks KDM2B-PRC1.1 to Drive Synovial Sarcoma. AB - Synovial sarcoma is an aggressive cancer invariably associated with a chromosomal translocation involving genes encoding the SWI-SNF complex component SS18 and an SSX (SSX1 or SSX2) transcriptional repressor. Using functional genomics, we identify KDM2B, a histone demethylase and component of a non-canonical polycomb repressive complex 1 (PRC1.1), as selectively required for sustaining synovial sarcoma cell transformation. SS18-SSX1 physically interacts with PRC1.1 and co associates with SWI/SNF and KDM2B complexes on unmethylated CpG islands. Via KDM2B, SS18-SSX1 binds and aberrantly activates expression of developmentally regulated genes otherwise targets of polycomb-mediated repression, which is restored upon KDM2B depletion, leading to irreversible mesenchymal differentiation. Thus, SS18-SSX1 deregulates developmental programs to drive transformation by hijacking a transcriptional repressive complex to aberrantly activate gene expression. PMID- 29502959 TI - Proximal embolic protection versus distal filter protection versus combined protection in carotid artery stenting: A systematic review and meta-analysis. AB - OBJECTIVE: Proximal embolic protection devices (P-EPD) and distal filters (DF) are used to prevent distal cerebral embolizations during carotid artery stenting (CAS). We compared their comparative effectiveness in regards to prevention of intraprocedural and periprocedural adverse events, including ischemic lesions (ipsilateral and contralateral), stroke, transient ischemic attacks (TIA) and death. We also compared the combination of the two neuroprotection strategies vs. a single strategy in regards to ischemic lesions and stroke. MATERIALS & METHODS: This study was performed according to the PRISMA and MOOSE guidelines and eligible studies were identified through search of PubMed, Scopus and Cochrane Central. A meta-analysis was conducted with the use of a random effects model. The I-square statistic was used to assess for heterogeneity. RESULTS: Twenty-nine studies involving 16,307 patients were included. There was a significant reduction in ischemic lesions with the use of P-EPD among observational studies (RR: 0.66 [0.45-0.97]). There were no statistically significant differences for the other outcomes between the two treatment groups. CONCLUSIONS: There is a number of studies reporting outcomes on the comparison between P-EPD and DF for CAS. P-EDP can reduce distal embolization phenomena resulting into ischemic lesions when compared to DF based on the results from real-world studies. P-EPD was not superior however, in regards to periprocedural stroke, TIA and death. Further studies are anticipated to provide a clear answer to this debate. PMID- 29502960 TI - Spontaneous coronary artery dissection and takotsubo syndrome: An often overlooked association; review. AB - Spontaneous coronary artery dissection (SCAD) and takotsubo syndrome (TS) are two cardiovascular syndromes with predilection for women. Both conditions may be preceded by an emotional stress or, for the affected individual, an unusual severe physical exercise. "Restitution ad integrum" occurs in most cases suffering from SCAD or TS with complete angiographic resolution of the dissected vessel and left ventricular dysfunction respectively. Recently, many cases, which were initially diagnosed as TS because of typical left ventricular ballooning pattern showed to have SCAD, have been reported; these cases were deemed to be "SCAD misdiagnosed as TS". The left ventricular wall motion abnormality has been attributed to the ischemia caused by SCAD-affected coronary vessel especially in the left anterior descending artery (LAD) with "wrap-around course". However, the left ventricular ballooning pattern have occurred in patients with SCAD in non long-wrap-around LAD and SCAD in other coronary branches where coronary ischemia on its own cannot explain the left ventricular ballooning. In this review, sufficient data supporting the evidence for the possibility of coexistence of SCAD and TS is provided. Misdiagnosis of the association of the two conditions may result in mismanagement of the patient with undesirable consequences. Furthermore, the causal links between SCAD and TS is discussed. PMID- 29502961 TI - A Pilot Study of Augmented Reality Technology Applied to the Acetabular Cup Placement During Total Hip Arthroplasty. AB - BACKGROUND: We developed an acetabular cup placement device, the AR-HIP system, using augmented reality (AR). The AR-HIP system allows the surgeon to view an acetabular cup image superimposed in the surgical field through a smartphone. The smartphone also shows the placement angle of the acetabular cup. This preliminary study was performed to assess the accuracy of the AR-HIP system for acetabular cup placement during total hip arthroplasty (THA). METHODS: We prospectively measured the placement angles using both a goniometer and AR-HIP system in 56 hips of 54 patients undergoing primary THA. We randomly determined the order of intraoperative measurement using the 2 devices. At 3 months after THA, the placement angle of the acetabular cup was measured on computed tomography images. The primary outcome was the absolute value of the difference between intraoperative and postoperative computed tomography measurements. RESULTS: The measurement angle using AR-HIP was significantly more accurate in terms of radiographic anteversion than that using a goniometer (2.7 degrees vs 6.8 degrees , respectively; mean difference 4.1 degrees ; 95% confidence interval, 3.0-5.2; P < .0001). There was no statistically significant difference in terms of radiographic inclination (2.1 degrees vs 2.6 degrees ; mean difference 0.5 degrees ; 95% confidence interval, -1.1 to 0.1; P = .13). CONCLUSION: In this pilot study, the AR-HIP system provided more accurate information regarding acetabular cup placement angle than the conventional method. Further studies are required to confirm the utility of the AR-HIP system as a navigation tool. PMID- 29502962 TI - Evidence-Based Thresholds for the Volume and Length of Stay Relationship in Total Hip Arthroplasty: Outcomes and Economies of Scale. AB - BACKGROUND: Several studies have indicated that high-volume surgeons and hospitals deliver higher value care. However, no evidence-based volume thresholds currently exist in total hip arthroplasty (THA). The primary objective of this study was to establish meaningful thresholds taking patient outcomes into consideration for surgeons and hospitals performing THA. A secondary objective was to examine the market share of THAs for each surgeon and hospital strata. METHODS: Using 136,501 patients undergoing hip arthroplasty, we used stratum specific likelihood ratio (SSLR) analysis of a receiver-operating characteristic curve to generate volume thresholds predictive of increased length of stay (LOS) for surgeons and hospitals. Additionally, we examined the relative proportion of annual THA cases performed by each surgeon and hospital strata established. RESULTS: SSLR analysis of LOS by annual surgeon THA volume produced 3 strata: 0 69 (low), 70-121 (medium), and 121 or more (high). Analysis by annual hospital THA volume produced strata at: 0-120 (low), 121-357 (medium), and 358 or more (high). LOS decreased significantly (P < .05) in progressively higher volume categories. High-volume hospitals performed the majority of cases, whereas low volume surgeons performed the majority of THAs. CONCLUSION: Our study validates economies of scale in THA by demonstrating a direct relationship between volume and value for THA through risk-based volume stratification of surgeons and hospitals using SSLR analysis of receiver-operating characteristic curves to identify low-, medium-, and high-volume surgeons and hospitals. While the majority of primary THAs are performed at high-volume centers, low-volume surgeons are performing the majority of these cases, which may offer room for improvement in delivering value-based care. PMID- 29502963 TI - Changes in Antibiotic Susceptibility of Staphylococcus aureus Between the Stages of 2-Stage Revision Arthroplasty. AB - BACKGROUND: Staphylococcus aureus is the predominant cause of periprosthetic joint infection (PJI) and can persist at the time of planned second stage of 2 stage revision arthroplasty, despite antibiotic cement spacer insertion and parenteral antibiotic therapy. Given the rapid emergence of antibiotic resistance, it is important to determine whether the antibiotic susceptibility of microorganisms changes between the stages of a 2-stage revision. METHODS: A total of 1614 2-stage revision hip/knee arthroplasties performed for PJI at 2 academic institutions from 2000 to 2015 were identified. S aureus (methicillin susceptible and/or resistant) was isolated by culture in 402 (24.9%) cases during the first stage (resection arthroplasty). S aureus persisted and was cultured in 30 cases (knees = 18, hips = 12) during the second stage. Minimum inhibitory concentrations (MICs), demographics, antibiotic therapy, and surgical history were collected. The MICs at the time of the first-stage and second-stage surgeries were compared. RESULTS: Nine (30%) revisions had an increase in vancomycin MIC. Six had an increase from <=0.5 to 1 MUg/mL, 2 had an increase from <=0.5 to 2 MUg/mL, and 1 had an increase from 1 to 2 MUg/mL. All of the 9 revisions with an increase in vancomycin MIC had vancomycin in spacer. CONCLUSION: Increases in the MICs were observed for vancomycin, the antibiotic widely used in cement spacers, in about one-third of the revisions. Despite the small sample size, the data from this preliminary study raise concern about the potential for emergence of resistant organisms between the stages of a 2-stage revision. PMID- 29502964 TI - Diagnosing Taper Corrosion: When Is It the Taper and When Is It Something Else? AB - There has been an increasing use of modularity at the head-neck junction in total hip arthroplasty to more closely mimic the native anatomy, allowing for optimal leg length and stability. Corrosion at this junction in metal-on-polyethylene bearings can lead to an adverse local tissue reaction (ALTR). This increasingly prevalent condition should be considered in the differential diagnosis of hip pain and difficulty ambulating. A recent symposium by the American Academy of Hip and Knee Surgeons described the diagnosis, etiology, management, and prevention of taper corrosion. This article describes the history, physical, plain and advanced imaging findings, laboratory tests, and other diagnoses that should be taken into consideration when diagnosing taper corrosion. The presence of ALTR due to taper corrosion can mimic other diagnoses such as periprosthetic joint infection, instability, or aseptic loosening. Serum metal levels have been found to be the most effective screening tool for identifying corrosion, but other common causes of hip pain and difficulty ambulating should always be ruled out with the use of radiographs and common laboratory techniques before diagnosing ALTR due to corrosion. PMID- 29502965 TI - Similar Superior Patient-Reported Outcome Measures for Anterior and Posterolateral Approaches After Total Hip Arthroplasty: Postoperative Patient Reported Outcome Measure Improvement After 3 months in 12,774 Primary Total Hip Arthroplasties Using the Anterior, Anterolateral, Straight Lateral, or Posterolateral Approach. AB - BACKGROUND: Patient-reported outcome measures (PROMs) are used to evaluate the outcome of total hip arthroplasty (THA). We determined the effect of surgical approach on PROMs after primary THA. METHODS: All primary THAs, with registered preoperative and 3 months postoperative PROMs were selected from the Dutch Arthroplasty Register. Based on surgical approach, 4 groups were discerned: (direct) anterior, anterolateral, direct lateral, and posterolateral approaches. The following PROMs were recorded: Hip disability and Osteoarthritis Outcome Score Physical function Short form (HOOS-PS); Oxford Hip Score; EQ-5D index score; EQ-5D thermometer; and Numeric Rating Scale measuring pain, both active and in rest. The difference between preoperative and postoperative scores was calculated (delta-PROM) and used as primary outcome measure. Multivariable linear regression analysis was performed for comparisons. Cohen's d was calculated as measure of effect size. RESULTS: All examined 4 approaches resulted in a significant increase of PROMs after primary THA in the Netherlands (n = 12,274). The anterior and posterolateral approaches were associated with significantly more improvement in HOOS-PS scores compared with the anterolateral and direct lateral approaches. Furthermore, the posterolateral and anterior approaches showed greater improvement on Numeric Rating Scale pain scores compared with the anterolateral approach. No relevant differences in delta-PROM were seen between the anterior and posterolateral surgical approaches. CONCLUSION: Anterior and posterolateral surgical approaches showed more improvement in self-reported physical functioning (HOOS-PS) compared with anterolateral and direct lateral approaches in patients receiving a primary THA. However, clinical differences were only small. PMID- 29502966 TI - Letter to the Editor on "Acetabular Revision Using Trabecular Metal Augments for Paprosky Type 3 Defects". PMID- 29502967 TI - Using Patient Demographics and Statistical Modeling to Predict Knee Tibia Component Sizing in Total Knee Arthroplasty. AB - BACKGROUND: Preoperative planning is important to achieve successful implantation in primary total knee arthroplasty (TKA). However, traditional TKA templating techniques are not accurate enough to predict the component size to a very close range. METHODS: With the goal of developing a general predictive statistical model using patient demographic information, ordinal logistic regression was applied to build a proportional odds model to predict the tibia component size. The study retrospectively collected the data of 1992 primary Persona Knee System TKA procedures. Of them, 199 procedures were randomly selected as testing data and the rest of the data were randomly partitioned between model training data and model evaluation data with a ratio of 7:3. Different models were trained and evaluated on the training and validation data sets after data exploration. RESULTS: The final model had patient gender, age, weight, and height as independent variables and predicted the tibia size within 1 size difference 96% of the time on the validation data, 94% of the time on the testing data, and 92% on a prospective cadaver data set. CONCLUSION: The study results indicated the statistical model built by ordinal logistic regression can increase the accuracy of tibia sizing information for Persona Knee preoperative templating. This research shows statistical modeling may be used with radiographs to dramatically enhance the templating accuracy, efficiency, and quality. In general, this methodology can be applied to other TKA products when the data are applicable. PMID- 29502968 TI - Reducing Pericyte-Derived Scarring Promotes Recovery after Spinal Cord Injury. AB - CNS injury often severs axons. Scar tissue that forms locally at the lesion site is thought to block axonal regeneration, resulting in permanent functional deficits. We report that inhibiting the generation of progeny by a subclass of pericytes led to decreased fibrosis and extracellular matrix deposition after spinal cord injury in mice. Regeneration of raphespinal and corticospinal tract axons was enhanced and sensorimotor function recovery improved following spinal cord injury in animals with attenuated pericyte-derived scarring. Using optogenetic stimulation, we demonstrate that regenerated corticospinal tract axons integrated into the local spinal cord circuitry below the lesion site. The number of regenerated axons correlated with improved sensorimotor function recovery. In conclusion, attenuation of pericyte-derived fibrosis represents a promising therapeutic approach to facilitate recovery following CNS injury. PMID- 29502969 TI - Brain-wide Electrical Spatiotemporal Dynamics Encode Depression Vulnerability. AB - Brain-wide fluctuations in local field potential oscillations reflect emergent network-level signals that mediate behavior. Cracking the code whereby these oscillations coordinate in time and space (spatiotemporal dynamics) to represent complex behaviors would provide fundamental insights into how the brain signals emotional pathology. Using machine learning, we discover a spatiotemporal dynamic network that predicts the emergence of major depressive disorder (MDD)-related behavioral dysfunction in mice subjected to chronic social defeat stress. Activity patterns in this network originate in prefrontal cortex and ventral striatum, relay through amygdala and ventral tegmental area, and converge in ventral hippocampus. This network is increased by acute threat, and it is also enhanced in three independent models of MDD vulnerability. Finally, we demonstrate that this vulnerability network is biologically distinct from the networks that encode dysfunction after stress. Thus, these findings reveal a convergent mechanism through which MDD vulnerability is mediated in the brain. PMID- 29502970 TI - Regulated Stochasticity in a Bacterial Signaling Network Permits Tolerance to a Rapid Environmental Change. AB - Microbial populations can maximize fitness in dynamic environments through bet hedging, a process wherein a subpopulation assumes a phenotype not optimally adapted to the present environment but well adapted to an environment likely to be encountered. Here, we show that oxygen induces fluctuating expression of the trimethylamine oxide (TMAO) respiratory system of Escherichia coli, diversifying the cell population and enabling a bet-hedging strategy that permits growth following oxygen loss. This regulation by oxygen affects the variance in gene expression but leaves the mean unchanged. We show that the oxygen-sensitive transcription factor IscR is the key regulator of variability. Oxygen causes IscR to repress expression of a TMAO-responsive signaling system, allowing stochastic effects to have a strong effect on the output of the system and resulting in heterogeneous expression of the TMAO reduction machinery. This work reveals a mechanism through which cells regulate molecular noise to enhance fitness. PMID- 29502972 TI - Corrigendum to "The resistance of cortical bone tissue to failure under cyclic loading is reduced with alendronate"[Bone 64 (2014) 57-64]. PMID- 29502973 TI - Corrigendum to novel approaches for two and three dimensional multiplexed imaging of osteocytes Bone 76 (2015) [129-140]. PMID- 29502971 TI - Regulation of Cell Cycle to Stimulate Adult Cardiomyocyte Proliferation and Cardiac Regeneration. AB - Human diseases are often caused by loss of somatic cells that are incapable of re entering the cell cycle for regenerative repair. Here, we report a combination of cell-cycle regulators that induce stable cytokinesis in adult post-mitotic cells. We screened cell-cycle regulators expressed in proliferating fetal cardiomyocytes and found that overexpression of cyclin-dependent kinase 1 (CDK1), CDK4, cyclin B1, and cyclin D1 efficiently induced cell division in post-mitotic mouse, rat, and human cardiomyocytes. Overexpression of the cell-cycle regulators was self limiting through proteasome-mediated degradation of the protein products. In vivo lineage tracing revealed that 15%-20% of adult cardiomyocytes expressing the four factors underwent stable cell division, with significant improvement in cardiac function after acute or subacute myocardial infarction. Chemical inhibition of Tgf-beta and Wee1 made CDK1 and cyclin B dispensable. These findings reveal a discrete combination of genes that can efficiently unlock the proliferative potential in cells that have terminally exited the cell cycle. PMID- 29502974 TI - The effect of fibrinogen concentrate and fresh frozen plasma on the outcome of patients with acute traumatic coagulopathy: A quasi-experimental study. AB - INTRODUCTION: The debate on replacing coagulation factors and its effect on the final outcome of the patients with acute traumatic coagulopathy (ATC) in need of transfusion is still ongoing. Therefore, the present study is designed with the aim of comparing the outcome of patients with acute traumatic coagulopathies receiving fibrinogen and fresh frozen plasma (FFP). METHODS: In this quasi experimental randomized controlled study, patients with severe blunt trauma (ISS>16) and in need of packed cells transfusion were divided into 3 groups of receiving fibrinogen, receiving FFP, and control, and their final outcome was compared. RESULTS: 90 patients with the mean age of 33.16+/-16.32years were randomly allocated to one of the 3 study groups (82.2% male). The 3 groups were similar regarding baseline characteristics. Patients receiving fibrinogen needed significantly less packed cells (p=0.044) and intravenous fluid in the initial 24h of hospitalization (p=0.022). In addition, mortality rate (p=0.029), need for admission to intensive care unit (p=0.020) and duration of hospitalization (p=0.045) were also lower in the group receiving fibrinogen. The number of sepsis cases in patients receiving fibrinogen and control group was lower than those who received FFP (p=0.001). The number of multiple organ failure cases in patients receiving fibrinogen was about one fourth of the other 2 groups (p=0.106), and a fewer number of them needed mechanical ventilation (p=0.191). No case of venous thrombosis was detected in any of the 3 groups. CONCLUSION: Multiple trauma patients in need of transfusion who received fibrinogen along with packed cells had significantly better outcomes regarding mortality, sepsis, need for admission to the intensive care unit, need for receiving packed cells, need for receiving intravenous fluids in the initial 24h, and duration of hospitalization. PMID- 29502975 TI - Grit, anxiety, and stress in emergency physicians. AB - INTRODUCTION: The personality traits of emergency physicians are infrequently studied, though interest in physician wellness is increasing. The objective of this study is to acquire pilot data about the amount of grit, anxiety, and stress in emergency physicians using established psychological survey instruments, and to examine their associations of each of these traits with each other. METHODS: Thirty-six emergency medicine resident and attending physicians from an urban academic medical center consented for enrollment. Participants were administered the Duckworth 12-point Grit Scale, the State-Trait Anxiety Inventory (STAI), and the Perceived Stress Scale (PSS), which measure grit, anxiousness, and perceived stress, respectively. These are the gold standard psychological instruments for each of their areas. We analyzed the results with descriptive statistics, Spearman correlations, and linear regression. RESULTS: Nineteen residents and 17 attending physicians completed the surveys during the first quarter of a new academic year. The mean grit score was 3.7 (95% CI 3.5-3.8, SD: 0.56), the mean trait-anxiety score was 32.61 (95% CI 30.15-35.07, SD: 7.26), and the mean PSS score was 12.28 (95% CI 10.58-13.97, SD: 4.99). Only trait-anxiety and perceived stress were significantly correlated (Spearman's rho: 0.70, p<0.01). CONCLUSIONS: In this pilot study at a single institution, emergency physicians demonstrated a range of grit, trait-anxiety, and perceived stress. Trait-anxiety and stress were strongly associated, and individuals who were more anxious reported more stress. Levels of grit were not associated with trait-anxiety. These psychological concepts should be studied further as they relate to the function and health of emergency medicine providers. PMID- 29502976 TI - Real-time elastography evaluation of differential penetrating liver trauma in a rabbit model. AB - BACKGROUND: Real-time ultrasound elastography (RTE) is used to examine liver fibrosis and benign and malignant lesions, but its use for the diagnosis of liver trauma has not been examined. The purpose of this study was to examine the use of RTE for the evaluation of differential penetrating liver trauma in a rabbit model. MATERIAL AND METHODS: Eighty New Zealand rabbits were divided into 2 groups. In one group, a single incision (type "-" lesion) was made, and in the other group a hash mark incision (type "#" lesion) was made (about 0.5cm in depth; 1.0-2.0cm in length). RTE was performed at 10, 30, and 60min after injury. RESULTS: There were no differences in mean RTE scores between the 2 types of lesions at 10 and 30min. However, the mean values for the 2 types of lesions increased from 10min to 60min (type '-' lesion: 0.88+/-0.32 to 2.06+/-0.88; type '#' lesion: 0.89+/-0.34 to 2.63+/-1.16). At 60min, the mean elasticity score in the type '#' lesion group was significantly higher than in the type '-' lesion group (P<.001). Strain ratios were not different between the groups at each time point, but in each group the values decreased from the 10min time point to the 60min time point (P-value for the trends, <.001). CONCLUSIONS: RTE may be able to distinguish mild or severe penetrating liver trauma at 60min or more after injury. PMID- 29502977 TI - Future of Genetic Studies in Women's Sexual Health. PMID- 29502978 TI - Combined Transplantation of Mesenchymal Stem Cells and Endothelial Progenitor Cells Restores Cavernous Nerve Injury-Related Erectile Dysfunction. AB - BACKGROUND: Whether combined transplantation of mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) is more effective than transplantation of a single cell type in the restoration of erectile function is unknown. AIM: To investigate the effect of combined transplantation of MSCs and EPCs on restoration of erectile function in rats with cavernous nerve injury (CNI). METHODS: MSCs were isolated from human bone marrow and EPCs were isolated from human umbilical cord blood. MSCs and EPCs were identified by flow cytometry and in vitro differentiation or immunofluorescence staining. 25 8-week-old male Sprague-Dawley rats were allocated to 1 of 5 groups: sham operation group, bilateral CNI group receiving periprostatic implantation of MSCs plus EPCs, MSCs, EPCs, or phosphate buffered saline (control group). 2 weeks after CNI and treatment, erectile function of rats was measured by electrically stimulating the CN. The penis and major pelvic ganglia were harvested for histologic examinations. RNA and protein levels of neurotrophin factors (vascular endothelial growth factor, nerve growth factor, and brain-derived neurotrophic factor) in mono- or coculture MSCs and EPCs were assessed by real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. OUTCOMES: Intracavernous pressure and mean arterial pressure were measured to evaluate erectile function. Histologic examinations of the penis and major pelvic ganglia and RNA and protein levels of neurotrophin factors in MSCs and EPCs were performed. RESULTS: MSCs and EPCs expressed the specified cell markers and exhibited the typical appearance and characteristics. Treatments using MSCs and/or EPCs could increase endothelial and smooth muscle contents of the corpus cavernosum, decrease caspase-3 expression and increase penile neuronal nitric oxide synthase expression, and restore the neural component of the major pelvic ganglia in rats with CNI. Combined transplantation of MSCs and EPCs had a better effect on improving erectile function than single transplantation of MSCs or EPCs. Expression levels of vascular endothelial growth factor and nerve growth factor in coculture MSCs and EPCs were significantly higher than those of primary MSCs or EPCs. CLINICAL TRANSLATION: Combined transplantation of MSCs and EPCs was more effective in restoring erectile function in CNI-related erectile dysfunction models. STRENGTHS AND LIMITATIONS: The study, for the 1st time, proved that combined transplantation of MSCs and EPCs was more effective in restoring erectile function in rats with CNI. The rat model might not represent the human condition. CONCLUSION: Combined periprostatic transplantation of MSCs and EPCs could restore erectile function in rats with CNI more effectively. MSCs might restore CN fibers by secreting neurotrophin factors such as vascular endothelial growth factor and nerve growth factor, and EPCs could enhance the paracrine activity of MSCs. Fang J-f, Huang X-n, Han X-y, et al. Combined Transplantation of Mesenchymal Stem Cells and Endothelial Progenitor Cells Restores Cavernous Nerve Injury-Related Erectile Dysfunction. J Sex Med 2018;15:284-295. PMID- 29502979 TI - Amelioration of Cavernosal Fibrosis and Erectile Function by Lysyl Oxidase Inhibition in a Rat Model of Cavernous Nerve Injury. AB - BACKGROUND: Cavernous nerve injury (CNI) causes fibrosis and loss of smooth muscle cells (SMCs) in the corpus cavernosum and leads to erectile dysfunction, and lysyl oxidase (LOX) activation has been found to play an important role in fibrotic diseases. AIM: To evaluate the role of LOX in penile fibrosis after bilateral CNI (BCNI). METHODS: Rats underwent BCNI or a sham operation and were treated with vehicle or beta-aminopropionitrile, a specific LOX activity inhibitor. 30 days after BCNI, rats were tested for erectile function before penile tissue harvest. LOX and extracellular matrix component expression levels in the corpus cavernosum, including matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), fibronectin (FN), collagen (COL) I, and COL IV, were evaluated by real-time quantitative polymerase chain reaction and western blot. Corporal fibrosis was evaluated by Masson trichrome staining. Localization of LOX and SMC content in the corpus cavernosum were assessed by immunohistochemistry. OUTCOMES: Ratio of intracavernous pressure to mean arterial blood pressure; LOX, MMPs, TIMPs, COL I, COL IV, and FN expression; penile fibrosis; penile SMC content. RESULTS: After BCNI, there was an increase in penile LOX expression and activity, increased penile fibrosis, decreased SMC content, and impaired erectile function. TIMP1, TIMP2, COL I, COL IV, and FN expression was markedly upregulated, whereas the enzyme activity of MMPs was decreased after BCNI. beta-Aminopropionitrile treatment, at least in part, prevented a decrease in the ratio of intracavernous pressure to mean arterial blood pressure, decreased penile expression of TIMP1, TIMP2, COL I, COL IV, and FN, increased MMP activity, prevented corporal fibrosis, and preserved SMC content. CLINICAL TRANSLATION: LOX over-activation contributes to penile fibrosis and LOX inhibition could be a promising strategy in preventing the progression of CNI-induced erectile dysfunction. STRENGTHS AND LIMITATIONS: This is the 1st study to demonstrate the role of LOX activation in penile fibrosis. However, the exact mechanism of how LOX influences extracellular matrix protein synthesis and SMC content preservation awaits further investigation. CONCLUSION: CNI induced LOX over-activation in cavernous tissue, and inhibition of LOX preserved penile morphology and improved erectile function in a rat model of BCNI. Wan Z-H, Li G H, Guo Y-L, et al. Amelioration of Cavernosal Fibrosis and Erectile Function by Lysyl Oxidase Inhibition in a Rat Model of Cavernous Nerve Injury. J Sex Med 2018;15:304-313. PMID- 29502980 TI - Male Sexuality, Fertility, and Urinary Continence in Bladder Exstrophy-Epispadias Complex. AB - BACKGROUND: The bladder exstrophy-epispadias complex is a rare congenital malformation associated with severe dysfunction of the genital and urinary tracts and requiring a staged surgical reconstruction. AIM: The primary aims of this study were to report the sexuality, infertility, and urinary incontinence outcomes in a cohort of men born with bladder exstrophy-epispadias complex. The secondary aim was to highlight some predictive factors of infertility in this population. METHODS: We conducted a descriptive, cross-sectional study of men diagnosed with classic presentations of bladder exstrophy or epispadias. OUTCOMES: Patients were asked to complete 4 validated questionnaires: the International Index of Erectile Function (IIEF)-5, the Erection Hardness Score (EHS), the Self-Esteem and Relationship, and the International Consultation Incontinence modular Questionnaire-Short Form. Fertility potential was assessed with semen analysis and a non-validated questionnaire. RESULTS: 38 Patients 18-64 years old (M [mean] = 32.2) completed the questionnaires. The average IIEF-5 score was 18.1/25 (ranging from 3-25; SE = 7.62), with results indicating that 55% of the sample had normal erectile function. Results also showed higher scores for patients with normal spermatozoa concentration (M = 22.75, SE = 1.89, P = .08) than for those with oligospermia (M = 17.30, SE = 8.53, P = .08). Results on the IIEF-5 also indicated higher scores for patients who conceived children without assisted reproductive technologies (ART) (M = 22.83, SE = 2.317, P = .02) than for patients without children (M = 15.76, SE = 8.342, P = .02). The average EHS was 3.43/4 (ranging from 1-4, SE = 0.9). EHS was higher for patients who had reconstruction than for patients who had cystectomy (M = 3.88, SE = 1.07 and 2.78, SE = 1.09, P = .02). The average total Self-Esteem and Relationship score was 67.04/100 (ranging from 10.71-96.43, SE = 22.11). The average total International Consultation Incontinence modular Questionnaire-Short Form score was 4.97/21 (ranging from 0-18, SE = 5.44), higher score indicating more urinary incontinence. Among the patients surveyed, 31.6% were parents at the time of study and 50% of them benefited from ART. With regards to the 14 semen analyses performed, only 7.1% produced normal results and 44.7% indicated that ejaculation was weak and dribbling. CLINICAL TRANSLATION: Erectile function appears to be decreased and psychological aspects of sexuality indicate low self-esteem about sexual relationship. Although ethical problems could not allow prospective spermograms, our cohort is large enough to provide significant data. CONCLUSIONS: Early sperm storage for future ART, sexual medicine management, and complementary genital reconstruction in adulthood constitute potential treatment options for this population. Reynaud N, Courtois F, Mouriquand P, et al. Male Sexuality, Fertility, and Urinary Continence in Bladder Exstrophy-Epispadias Complex. J Sex Med 2017;15:314-323. PMID- 29502981 TI - Sexual Activity, Sexual Dysfunction, and Sexual Life Quality Among Psychiatric Hospital Inpatients With Schizophrenia. AB - BACKGROUND: Sexual dysfunction occurs commonly in patients with psychiatric illness and may be related to the primary mental disorder, comorbidity with sexual disorders or medical illness, or medications used for mental disorders treatment, but the magnitude of this problem is unknown. AIM: To estimate the prevalence of current sexual activity, sexual dysfunction, and sexual attitude and influence of factors on patients with schizophrenia. METHODS: This study used a cross-sectional design with a total of 317 patients diagnosed with schizophrenia. The subjects completed a demographic questionnaire, sexual attitude scale, sexual dysfunction scale, and sexual behavior scale. Descriptive analysis, difference analysis, and logistic regression model were used to identify relevant variables that may affect sexual life quality. OUTCOMES: Age, sexual satisfaction, and patient symptoms may predict sexual life quality on patients with schizophrenia. RESULTS: The mean age of patients was 47.71 +/- 9.54 years old. About the sexual activities, 53% of subjects had sexual intercourse experience, and 41.3% reported currently having sexual intercourse. The mean +/- SD age for first sexual intercourse was 20.83 +/- 5.95 years old (median was 20.0 years old). Moreover, women older than 50 years had significantly higher medians for the Brief Psychiatric Rating Scale (BPRS) score, higher proportions of sexual dysfunction, and lower proportions of feeling important to sexual life quality than men. For participants with age <=50 years old, there was a significant relationship among BPRS group (mean score >2.5 vs <=2.5), sexual dysfunction (P < .001), sexual life quality (P < .001), and sexual satisfaction (P = .006). Among the predictors of feeling important to sexual life quality, sexual satisfaction (odds ratio = 7.005, 95% CI = 4.126-11.892, P < .001) and BPRS score (odds ratio = 4.501, 95% CI = 2.042-9.923, P < .001) were significant independent factors after adding the interaction of age group and BPRS group. CLINICAL TRANSLATION: This study also reveals the close relationship between sexual satisfaction and BPRS score, which may predict sexual life quality of patients with schizophrenia. Limitations include the possibility of underreporting and bias associated with self-report measurement. CONCLUSION: Sexual life quality and sexual dysfunction on patients with schizophrenia are associated with interaction among psychological, sociological, and biochemical-pharmacological factors. Ma M-C, Chao J-K, Hung J-Y, et al. Sexual Activity, Sexual Dysfunction, and Sexual Life Quality Among Psychiatric Hospital Inpatients With Schizophrenia. J Sex Med 2018;15:324-333. PMID- 29502982 TI - Relationships Between 3-Dimensional Transperineal Ultrasound Imaging and Digital Intravaginal Palpation Assessments of the Pelvic Floor Muscles in Women With and Without Provoked Vestibulodynia. AB - BACKGROUND: Digital intravaginal palpation remains the favored method for clinical assessment of pelvic floor muscle (PFM) function in women; however, there is growing interest in using transperineal ultrasound imaging (TPUSI). TPUSI does not involve vaginal penetration, making it particularly relevant for PFM assessment in women with genito-pelvic pain and penetration disorders. AIMS: To study the relations between measures of PFM morphology and function assessed using 3-dimensional (3D) TPUSI and PFM assessment through intravaginal palpation. METHODS: 77 nulliparous premenopausal women with (n = 38) and without (n = 39) PVD participated. 3D TPUSI was used to measure levator hiatal dimensions at rest, at maximal voluntary contraction (MVC) of the PFMs, and at maximal Valsalva maneuver (MVM). Intravaginal palpation was used to assess PFM strength, PFM tone, PFM relaxation after contraction, and vaginal flexibility; each was scored using an ordinal grading scale. Ultrasound and palpation outcomes were compared using Spearman correlation coefficients and Kruskal-Wallis 1-way analyses of variance by rank. OUTCOMES: Outcomes included ultrasound measures of the levator hiatal area, anteroposterior diameter, and left-right transverse diameter at rest, at MVC, and at MVM; raw and relative changes in hiatal dimensions between rest and MVC and between rest and MVM; and palpation measures of PFM strength, tone, and relaxation after contraction, and vaginal flexibility. RESULTS: Weak to fair correlations were found between ultrasound and palpation measures. A smaller levator hiatus at rest was associated with greater PFM tone, less PFM relaxation, and less vaginal flexibility. Greater levator hiatal constriction and shortening of the hiatal anteroposterior diameter at MVC were associated with greater palpated PFM strength. Greater hiatal distention at MVM was associated with lower PFM tone and greater relaxation. CLINICAL TRANSLATION: 3D TPUSI and intravaginal palpation provide related but distinct information about PFM function in young women with and without PVD with high functioning PFMs. STRENGTHS AND LIMITATIONS: This was the first study to compare PFM assessment using 3D TPUSI and intravaginal palpation in nulliparous premenopausal women. A main strength of the study was the inclusion of women with PVD and asymptomatic controls, which provided a wide range in outcomes because differences in PFM morphology and function exist between women with and without PVD. The lack of inclusion of older women and women with weaker and/or hypotonic PFMs limits the generalizability of the findings. CONCLUSION: Although TPUSI has several advantages, including painless application, it is not recommended as a replacement for digital palpation in the clinical assessment of PFM function. Thibault-Gagnon S, Goldfinger C, Pukall C, et al. Relationships Between 3-Dimensional Transperineal Ultrasound Imaging and Digital Intravaginal Palpation Assessments of the Pelvic Floor Muscles in Women With and Without Provoked Vestibulodynia. J Sex Med 2018;15:346-360. PMID- 29502983 TI - A Network Approach to Hypersexuality: Insights and Clinical Implications. AB - BACKGROUND: In spite of a growing interest in research on hypersexuality, consensus about its etiology and best treatment strategy has not been achieved. AIM: To further the empirical and clinical understanding of hypersexuality by exploring the structure of its symptoms using a network analytic approach. METHODS: In 2014, an online survey advertised as focusing on Internet pornography, sexual health, and relationships was carried out among Croatian men and women aged 18-60 years (Mage = 31.1 years, SD = 9.67). In a sample of 3,028 participants, we applied a network analytic approach to explore the structure of hypersexuality symptoms. In the network, nodes represented hypersexuality symptoms and associated sexual behaviors, while their connections were operationalized as partial correlations. 4 Research questions were addressed: (1) does the hypersexuality network differ between genders; (2) which symptoms are centrally positioned; (3) what is the topological location of pornography use; and (4) are there distinct clusters ("communities") of symptoms in the network? OUTCOMES: We estimated and plotted hypersexuality networks by gender using items from the Hypersexual Disorder Screening Inventory and the Hypersexual Behavioral Consequences Scale, as well as indicators of sexual desire, pornography use, sexual intercourse, and masturbation frequency. RESULTS: The structure of the hypersexuality network was surprisingly similar in women and men, both in terms of symptom centrality and the clustering of symptoms. Psychological distress and negative emotions triggered by sexual fantasies and/or behaviors, together with a loss of control over sexual feelings, occupied central positions in the networks. Pornography use was located peripherally in both the men's and women's hypersexuality networks. CLINICAL TRANSLATION: Psychological distress and negative emotions triggered by sexual fantasies and/or behaviors constituted the core of the hypersexuality network, which makes them potential prime targets for clinical intervention and calls for normalization of (presumably self stigmatized) sexual expression through affirmative therapy and interventions that enhance self-care, self-compassion, and adaptive coping mechanisms. STRENGTHS & LIMITATIONS: This is the first network analytic approach to hypersexuality. Apart from its novel insights about the structure of hypersexuality, the study employed several methods to assure reliability and robustness of findings. Considering that networks were estimated in a convenience-based community sample, the findings might not generalize to clinically distressed individuals. CONCLUSION: Our results demonstrate the usefulness of network analytics to hypersexuality in a non-clinical sample and we encourage future clinical and longitudinal explorations of hypersexuality using this novel approach. Werner M, Stulhofer A, Waldorp L, et al. A Network Approach to Hypersexuality: Insights and Clinical Implications. J Sex Med 2018;15:373-386. PMID- 29502984 TI - Flibanserin for Hypoactive Sexual Desire Disorder: An Open-Label Safety Study. AB - BACKGROUND: To evaluate the safety of flibanserin in premenopausal and naturally postmenopausal women with hypoactive sexual desire disorder (HSDD) in an open label extension (OLE) study. AIM: To examine the safety and tolerability of flibanserin 100 mg once daily at bedtime in the treatment of premenopausal and naturally postmenopausal women with HSDD in a multicenter 28-week OLE study. METHODS: Patients entering this study received flibanserin or placebo in the double-blinded, placebo-controlled trials of premenopausal and postmenopausal women and in a pharmacokinetic study of postmenopausal women. OUTCOMES: The primary end point of this OLE study was the incidence of adverse events (AEs). Secondary exploratory efficacy measures included the Female Sexual Distress Scale Revised (FSDS-R) total score and FSDS-R item 13 (distress owing to low desire) score and the Female Sexual Function Index (FSFI) total score. Because the sponsor terminated the study early at discontinuation of the development of flibanserin, only descriptive statistics were calculated. RESULTS: Of the 595 patients receiving study medication, 346 and 249 patients were premenopausal and postmenopausal, respectively. The mean number of days of exposure to flibanserin was 72.8 (SD = 41.6). AEs were reported by 352 patients (59.2%), and most AEs (93.8%) were mild or moderate. The most common AEs (>=5%) were dizziness (9.6%), somnolence (8.6%), insomnia (6.2%), and nausea (5.7%). There were no flibanserin related serious AEs and no instances of suicidal ideation. The safety profile of flibanserin was similar for premenopausal and postmenopausal women. The FSDS-R total scores and FSDS-R item 13 scores were numerically lower at weeks 4, 12, and 20 than at baseline (decrease in distress owing to low desire) for premenopausal and postmenopausal women. Mean FSFI total scores were numerically higher at weeks 4, 12, and 20 than at baseline, irrespective of menopausal status of the patients. CLINICAL IMPLICATIONS: The results of this study support the safety and tolerability of flibanserin for the treatment of HSDD in premenopausal and naturally postmenopausal women. STRENGTHS AND LIMITATIONS: Although this open label study was designed to be 28 weeks long, it was discontinued early by the sponsor, and patients' maximum duration of exposure to flibanserin was 23.9 weeks. The open-label design and lack of a placebo-controlled arm are other study limitations. CONCLUSION: In this open-label study, flibanserin 100 mg once daily at bedtime was generally safe and well tolerated by premenopausal and naturally postmenopausal women with HSDD. Simon JA, Derogatis L, Portman D, et al. Flibanserin for Hypoactive Sexual Desire Disorder: An Open-Label Safety Study. J Sex Med 2018;15:387-395. PMID- 29502985 TI - Editorial Comment: "Glucose Modulates Human Ventral Tegmental Activity in Response to Sexual Stimuli". PMID- 29502986 TI - Diverse effects of interleukin-22 on pancreatic diseases. AB - Interleukin-22 (IL-22) is involved in the development of lymphocytes and serves as a rapid and early source of the effector cytokines that are released in response to pathogen-induced changes in the microenvironment. Recent research has implicated IL-22 as a potential contributing factor to the spectrum of inflammation-related pancreatic diseases, particularly pancreatitis, fibrosis, carcinoma and diabetes. In this review, we summarize the current knowledge on the roles of IL-22 in the various pancreatic pathogenesis, providing insights into the underlying cellular and signaling mechanisms that will help guide future research into promising interventional targets with therapeutic potential. PMID- 29502987 TI - The prevalence of small intestinal bacterial overgrowth in non-surgical patients with chronic pancreatitis and pancreatic exocrine insufficiency (PEI). AB - BACKGROUND: Small intestinal bacterial overgrowth (SIBO) is a condition characterised by symptoms similar to pancreatic exocrine insufficiency (PEI) in chronic pancreatitis patients. SIBO is thought to complicate chronic pancreatitis in up to 92% of cases; however, studies are heterogeneous and protocols non standardised. SIBO may be determined by measuring lung air-expiration of either hydrogen or methane which are by-products of small bowel bacterial fermentation of intraluminal substrates such as carbohydrates. We evaluated the prevalence of SIBO among a defined cohort of non-surgical chronic pancreatitics with mild to severe PEI compared with matched healthy controls. METHODS: Thirty-five patients and 31 age-, gender- and smoking status-matched healthy controls were evaluated for SIBO by means of a fasting glucose hydrogen breath test (GHBT). The relationship between SIBO and clinical symptoms in chronic pancreatitis was evaluated. RESULTS: SIBO was present in 15% of chronic pancreatitis patients, while no healthy controls tested positive (P = 0.029). SIBO was more prevalent in those taking pancreatic enzyme replacement therapy (PERT) (P = 0.016), with proton pump inhibitor use (PPI) (P = 0.022) and in those with alcohol aetiology (P = 0.023). Patients with concurrent diabetes were more often SIBO-positive and this was statistically significant (P = 0.009). There were no statistically significant differences in reported symptoms between patients with and without SIBO, with the exception of 'weight loss', with patients reporting weight loss more likely to have SIBO (P = 0.047). CONCLUSION: The prevalence of SIBO in this study was almost 15% and consistent with other studies of SIBO in non-surgical chronic pancreatitis patients. These data support the testing of patients with clinically-relevant PEI unresolved by adequate doses of PERT, particularly in those patients with concurrent diabetes. SIBO can be easily diagnosed therefore allowing more specific and more targeted symptom treatment. PMID- 29502988 TI - Widespread distribution of ticks and selected tick-borne pathogens in Kentucky (USA). AB - The geographical distribution of Ixodes scapularis and Amblyomma maculatum ticks is poorly understood in Kentucky. We conducted a convenience survey of wildlife species (white-tailed deer (Odocoileus virginianus), elk (Cervus canadensis) and black bears (Ursus americanus)) for ticks from October 2015 to January 2017. We detected four tick species including Amblyomma americanum, Dermacentor albipictus, I. scapularis and A. maculatum. Although the former two tick species were previously known to be widely distributed in Kentucky, we also found that I. scapularis and A. maculatum were also widespread. Because of the limited data available for pathogens from I. scapularis and A. maculatum, we tested them for Borrelia and Rickettsia spp. by polymerase chain reaction assays. Prevalence of Borrelia burgdorferi sensu stricto and Rickettsia parkeri were 11% and 3%, respectively. These data indicate that public health measures are important to prevent tick-borne diseases in Kentucky. PMID- 29502989 TI - Subclinical Lyme borreliosis is common in south-eastern Sweden and may be distinguished from Lyme neuroborreliosis by sex, age and specific immune marker patterns. AB - BACKGROUND: Determinants of a subclinical course of Lyme borreliosis (LB) remain largely unknown. The aim of this study was to assess the extent, sex and age profiles of subclinical Borrelia seroconversion in a LB endemic area in Sweden and to map blood cellular Borrelia-specific immune marker patterns in individuals with a previous subclinical LB course compared with patients previously diagnosed with Lyme neuroborreliosis (LNB). METHODS: A large group of 1113 healthy blood donors was screened for multiple IgG anti-Borrelia antibodies and asked to complete a health inquiry regarding previous LB. A group of subjects with anti Borrelia-specific IgG antibodies but no previous history of LB (subclinical LB, n = 60) was identified together with 22 cases of previous LNB. Whole Borrelia spirochetes, strains B. afzelii ACA1 and B. garinii Ip90, were used for ex vivo whole blood stimulations, whereas outer surface protein enriched fractions of the same strains were used for stimulation of peripheral blood mononuclear cells (PBMCs). An extensive panel of immune markers was analysed in the supernatants after stimulation using multiplex bead arrays, and Borrelia-specific secretion was determined by subtracting the spontaneous secretion. RESULTS: A total of 125/1113 blood donors reported previous clinical LB. In contrast, 66 donors denied previous LB but showed multiple IgG anti-Borrelia antibodies; these were defined as subclinical subjects, of whom 60 were available for further studies. The subclinical subjects consisted of significantly more men and had a younger age compared with the LNB patients (p <= 0.01). Discriminant analysis revealed a distinct pattern of sex, age and PBMC B. garinii-specific levels of IL-10, IL-17A and CCL20 discriminating subclinical subjects from LNB patients. CONCLUSIONS: This study confirms that subclinical Borrelia seroconversion is common in south eastern Sweden. The findings further suggest that male sex, younger age together with B. gariniii induced levels of IL-10, IL-17A and CCL20 may be associated with a subclinical course. PMID- 29502990 TI - Examination of Skill Acquisition and Grader Bias in a Distal Radius Fracture Fixation Model. AB - OBJECTIVES: Primary: Assess the ability of faculty graders to predict the objectively measured strength of distal radius fracture fixation. Secondary: Compare resident skill variation and retention related to other knowable training data. DESIGN: Residents were allowed 60 minutes to stabilize a standardized distal radius fracture using an assigned fixed-angle volar plate. Faculty observed and subjectively graded the residents without providing real-time feedback. Objective biomechanical evaluation (construct strength and stiffness) was compared to subjective grades. Resident-specific characteristics (sex, PGY, and ACGME case log) were also used to compare the objective data. SETTING: A simulated operating room in our laboratory. PARTICIPANTS: Post-graduate year 2, 3, 4, and 5 orthopedic residents. RESULTS: Primary: Faculty were not successful at predicting objectively measured fixation, and their subjective scoring suggests confirmation bias as PGY increased. Secondary: Resident year-in-training alone did not predict objective measures (p = 0.53), but was predictive of subjective scores (p < 0.001). Skills learned were not always retained, as 29% of residents objectively failed subsequent to passing. Notably, resident-reported case-specific experience alone was inversely correlated with objective fixation strength. CONCLUSIONS: This testing model enabled the collection of objective and subjective resident skill scores. Faculty graders did not routinely predict objective measures, and their subjective assessment appears biased related to PGY. Also, in vivo case volume alone does not predict objective results. Familiar faculty teaching consistency, and resident grading by external faculty unfamiliar with tested residents, might alter these results. PMID- 29502991 TI - Neuraxial block for delivery among women with low platelet counts: a retrospective analysis. AB - BACKGROUND: Laboring women with low platelet counts may be denied neuraxial block due to concerns about causing a spinal-epidural hematoma. AIMS: To assess the anesthetic management, complications and outcome variables of women with low platelet counts, and to expand the existing data regarding the safety of neuraxial blocks in this patient population. METHODS: This is a retrospective analysis of anesthetic and obstetric data from women with platelet counts <100 000/MUL, who were admitted to a single referral center during 2011-2014. The rate of neuraxial block and related complications were examined in relation to the platelet count and the results combined with published data to assess the risk of spinal-epidural hematoma. RESULTS: During the study period, 471 of 45 462 women (1%) had a low platelet count (<100 000/MUL). The rate of neuraxial block was significantly higher in women with platelet counts of 70-99 000/MUL (280/394, 71.1%) when compared to women with platelet counts of 50-69 000/MUL and 0 to 49 000/MUL (23/59, 38.9% and 5/18, 27.8%, respectively, P <0.0001). Women in the lower platelet count ranges had a higher risk of cesarean delivery under general anesthesia and longer hospital stay. No neuraxial hematoma were reported. CONCLUSIONS: This study contributes a substantial series of neuraxial blocks among women with low platelet counts. The findings support that the risk of hematoma is low if the platelet count is <100 000/MUL, specifically between 70 and 99 000/MUL. Risk assessment in the lower count ranges requires a much larger sample. PMID- 29502992 TI - A study of factors influencing surgical cesarean delivery times in an academic tertiary center. AB - BACKGROUND: Knowledge of hospital-specific average cesarean delivery operative times, and factors influencing length of surgery, can serve as a guide for anesthesiologists when choosing the optimal anesthetic technique. The aim of this study was to determine operative times and the factors influencing those times for cesarean delivery. METHODS: We conducted a retrospective review of all 1348 cesarean deliveries performed at an academic hospital in 2011. The primary outcome was mean operative time for first, second, third and fourth or more cesarean deliveries. The secondary goal was to identify factors influencing operative time. Variables included age, body mass index, previous surgery, gestational age, urgency of cesarean delivery, anesthesia type, surgeon's seniority, layers closed, and performance of tubal ligation. RESULTS: Mean (standard deviation) operative times for first (n=857), second (n=353), third (n=108) and fourth or more (n=30) cesarean deliveries were 56 (19), 60 (19), 69 (28) and 82 (31) minutes, respectively (P <0.0001, all groups different). Emergency status of the case and later gestational age were associated with shorter operative times. Higher body mass index, a less senior surgeon, the number of layers closed, and tubal ligation, increased operative times. These factors accounted for 18% of the variability. CONCLUSIONS: Third and fourth cesarean delivery or the presence of other factors that could increase operative time may warrant catheter-based anesthetic techniques or the addition of adjunctive medications to prolong spinal anesthetic block. Institutional and individual surgeon factors may play an even more important role in determining surgical time. PMID- 29502993 TI - Intraperitoneal chloroprocaine is a useful adjunct to neuraxial block during cesarean delivery: a case series. AB - BACKGROUND: Use of intraperitoneal local anesthetic to treat intraoperative pain during cesarean delivery has not been described previously. The aim of this study was to determine if intraperitoneal chloroprocaine may be useful as an adjunct to neuraxial block in reducing the proportion of patients with severe intraoperative pain that requires conversion to general anesthesia. Intraperitoneal chloroprocaine was administered during cesarean delivery as a potential alternative, when the anesthesiologist considered performing a general anesthetic due to severe intraoperative pain. METHODS: A keyword search for "chloroprocaine" was performed for patients on labor and delivery between November 2013 and March 2017. Patients were included if cesarean delivery was initiated with neuraxial anesthesia and there was documented intraoperative intraperitoneal instillation of chloroprocaine. RESULTS: Among 2479 patients who had cesarean delivery with neuraxial anesthesia, 32 received intraperitoneal chloroprocaine (mean dose 11.8 mg/kg). No patients exhibited signs of local anesthetic systemic toxicity or required conversion to general anesthesia. Among the 32 patients who received chloroprocaine, 17 had improved pain scores documented after instillation. CONCLUSION: Intraperitoneal chloroprocaine may be useful as part of a multimodal approach to managing intraoperative pain during cesarean delivery. PMID- 29502994 TI - Factors affecting patients' functional status and their impact on outcomes of ruptured abdominal aortic aneurysms. AB - OBJECTIVE: Despite advances in surgical techniques, ruptured abdominal aortic aneurysm (rAAA) remains associated with extremely high mortality. Several preoperative risk factors have been shown to predict poor prognosis after rAAA repair. Notably, a preoperative dependent functional status has previously been shown to be associated with poor outcomes after several vascular surgery procedures. The purpose of this study was to examine the effect of preoperative functional status on postoperative outcomes for patients undergoing repair of rAAA. METHODS: Patients with rAAA were identified in the American College of Surgeons National Surgical Quality Improvement Program database for the year 2013. The patients' demographics, procedural data, and postoperative outcomes were analyzed. Patients were then divided into two groups: dependent functional status and independent functional status. Preoperative variables and outcomes were compared between these two groups. A multivariate logistic regression analysis was then conducted to assess independent risk factors that predispose to dependent functional status. RESULTS: A total of 1239 patients underwent repair of rAAAs. Of these, 34 patients did not have a recorded functional status. The total number of patients analyzed was therefore 1205 (male, 78%; female; 22%; group I, dependent functional status, n = 62 [5%]; group II, independent functional status, n = 1143 [95%]). Bivariate analysis identified the following variables as having a significant association with dependent functional status: age >80 years (odds ratio [OR], 8.70; confidence interval [CI] 1.18-64.43; P = .002), female sex (OR, 2.89; CI, 1.71-4.87; P < .001), dyspnea (OR, 3.77; CI, 2.0 7.13; P < .001), dialysis (OR, 7.55; CI, 3.21-17.73; P < .001), insulin-dependent diabetes mellitus (vs nondiabetic: OR, 3.76; CI, 1.39-10.21; P = .033), current smoker (OR, 0.41; CI, 0.22-0.77; P = .005), and hypertension (OR, 2.86; CI, 1.4 5.87; P = .004). Preoperative functional status had no effect on the following postoperative outcomes: surgical site infection, cardiac arrest, unplanned intubation, readmission, return to the operating room, and death. Dependent functional status was associated with increased length of hospital stay (group I, median of 10 days; group II, median of 7 days). CONCLUSIONS: Dependent functional status is considered to be strongly associated with poor outcomes after surgical operations. Our study shows that functional status has little or no bearing on the outcomes of operations for rAAA and that preoperative dialysis, female sex, advanced age, and dyspnea are strong predictors of dependent functional status. Dependent functional status should not be used to exclude patients with rAAA from being offered surgical treatment. PMID- 29502995 TI - Epidemiology, treatment, and outcomes of acute limb ischemia in the pediatric population. AB - OBJECTIVE: Acute limb ischemia (ALI) in a pediatric patient is a rare condition but may result in lifelong disability. A paucity of evidence exists to derive treatment guidelines; some surgeons advocate conservative management over invasive measures. The purpose of this study was to evaluate the role of surgical revascularization in the pediatric population and outcomes of conservative vs surgical management. METHODS: The Healthcare Cost and Utilization Project State Inpatient Database (California, Iowa, and New York) between 2007 and 2013 was queried using International Classification of Diseases, Ninth Revision codes. Patients were stratified into two cohorts: conservative management and surgical management. Each group was further subdivided into three age groups: infant (<24 months), child (<12 years), and adolescent (<18 years). Outcome variables included mortality, amputation status, length of hospital stay, and hospital charge. RESULTS: A total of 1576 pediatric patients with ALI were identified among 6,122,535 pediatric admissions (26 per 100,000 admissions). Average age was 9.9 +/- 7.1 years. There were 263 patients who underwent surgical revascularization. The conservative management group was younger (5.8 +/- 6.2 vs 9.2 +/- 6.1 years; P < .01). Otherwise, baseline characteristics were similar between the two groups. Overall, the amputation rate was low (<2%; n = 28), especially in the upper extremities (<0.2%). Outcomes of conservative management and surgical revascularization were similar for mortality (5.0% vs 3.4%; P = .34), amputation (1.9% vs 1.1%; P = .46), length of hospital stay (15.4 vs 12.9 days; P = .07), and hospital charge ($281,794 vs $288,507; P = .28). In subgroup analysis, infants had less concomitant orthopedic injury than other age groups. Children demonstrated a higher likelihood of associated upper extremity injury and operative revascularization (P < .01) than infants or adolescents. In infants, mortality was higher and surgical intervention was associated with longer hospital stay (29.5 +/- 34.4 days vs 45.6 +/- 31.6 days; P = .02) and larger health care expenditure ($467,885 +/- $638,653 vs $1,099,343 +/- $695,872; P < .01). CONCLUSIONS: Pediatric ALI is a rare entity and is associated with low amputation and mortality rates. Among the pediatric age cohorts, infants with ALI are at higher risk of in-hospital mortality than older age groups are. Surgical intervention is not associated with improved limb salvage or mortality. Nonoperative management may be considered an initial treatment modality, but further research is needed to elucidate which important subset of pediatric patients benefit from open or endovascular operative intervention. PMID- 29502996 TI - Fenestrated-branched endografts and visceral debranching plus stenting (hybrid) for complex aortic aneurysm repair. AB - OBJECTIVE: The aim of this study was to assess the immediate postoperative and midterm outcome of complex aortic aneurysm treatment necessitating four-vessel revascularization with either a total endovascular approach (fenestrated-branched stent graft [FBSG]) or a hybrid technique of visceral debranching plus stenting. METHODS: The clinical data of consecutively treated patients presenting with a complex aortic aneurysm that necessitated four-vessel revascularization between 2010 and 2015 were retrospectively analyzed. RESULTS: There were 98 patients (65 men [68%]) with a mean age of 70.65 +/- 4 years who presented with aortic aneurysm (Crawford type I, 12; type II, 18; type III, 12; type IV, 24; type V, 6; and juxtarenal and suprarenal, 26) and were treated with either FBSG (76/98 [77.5%]) or hybrid repair (22/98 [22.4%]). Twenty-six patients were symptomatic (16, pain; 10, contained rupture). The mean maximum aneurysm diameter was 65 +/- 15 mm, and 53% of the patients had a prior aortic intervention. In FBSG-treated patients, 15 off-the-shelf multibranched stent grafts, 3 surgeon-modified fenestrated stent grafts, and 58 custom-made devices tailored to the patient's anatomy were used. Four fenestrations, four branches, and their combination were used in 38 cases, 30 cases, and 8 cases, respectively. A total of 304 target vessels were addressed, with technical success rate of 96% (292/304). In most hybrid cases (18/22 [82%]), a two-stage procedure was undertaken. All target vessels were successfully revascularized with 88 bypasses. The 30-day mortality was 15.3% (15/98), and the early target vessel occlusion was 9.1% (2 in FBSG, 7 in hybrid). After multivariate analysis, type of procedure (hybrid) was independently associated with higher early mortality (odds ratio, 6.3; P = .01). The morbidity was mainly attributed to pulmonary complications (16.3%), lower extremity weakness (16.3%), mesenteric ischemia (6.1%), dialysis on discharge (6.1%), and complete paraplegia (4.3%). Acute renal failure (2.6% vs 18%; P = .03) and mesenteric ischemia (3% vs 23%; P = .001) presented more commonly in the hybrid group. The mean follow-up was 16.4 +/- 5 months, and the mortality rate was 19.4% (12% in the FBSG group vs 45% in the hybrid group; P = .05). The graft and stent graft patency rate was 87.8% (three branches and nine bypasses were occluded). CONCLUSIONS: FBSG and hybrid technique seem to be feasible treatment options for complex aortic aneurysms that necessitate four-vessel revascularization. FBSG may be associated with lower mortality and morbidity rates in comparison to the hybrid procedure. FBSG should be the treatment of choice for complex aneurysms in patients with comorbidities, whereas hybrid repair should be considered for acute cases unsuitable for endovascular repair. PMID- 29502997 TI - Neoplastic embolization to systemic and pulmonary arteries. AB - OBJECTIVE: Arterial neoplastic emboli are uncommon, accounting for <1% of thromboemboli in the current literature. Nonetheless, this event may be associated with significant morbidity and mortality. Herein, we report a series of 11 cases of arterial neoplastic emboli from a single tertiary care center along with a comprehensive review of the literature to date. The aim of this study was to document the incidence, clinical presentations, and complications of arterial neoplastic emboli as well as to highlight the importance of routine histologic examination of thrombectomy specimens. METHODS: Pathology archives from a single tertiary care institution were queried to identify cases of surgically resected arterial emboli containing neoplasm (1998-2014). Histopathology was reviewed for confirmation of diagnosis. Patient demographics and oncologic history were abstracted from the medical record. Comprehensive literature review documented 332 patients in 275 reports (1930-2016). RESULTS: Eleven patients (six men) with a median age of 63 years (interquartile range, 42 71 years) were identified through institutional archives. Embolism was the primary form of diagnosis in seven (64%) cases. Cardiac involvement (primary or metastasis) was present in more than half of the cohort. Comprehensive literature review revealed that pulmonary primaries were the most common anatomic origin of arterial neoplastic emboli, followed by gastrointestinal neoplasia. Cardiac involvement was present in 18% of patients, and sentinel identification of neoplasia occurred in 30% of cases. Postmortem evaluation was the primary means of diagnosis in 27%. CONCLUSIONS: This study highlights the importance of routine histopathologic evaluation of embolectomy specimens in patients with and without documented neoplasia. PMID- 29502998 TI - Ambulation and functional outcome after major lower extremity amputation. AB - OBJECTIVE: Major lower extremity amputations (MLEAs) remain a significant source of disability. It is unknown whether postamputation functional outcomes and outcome predictability have changed with a population of increasingly aging and obese patients. Accordingly, we sought to evaluate contemporary trends. METHODS: A retrospective chart review was performed to identify patients undergoing MLEA using Current Procedural Terminology codes in a university hospital. Demographics, comorbidities, perioperative variables, and outcomes were obtained. Descriptive statistics, t-tests, and chi2 and multivariate logistic regression modeling were used where appropriate. Survival analyses were performed with the Kaplan-Meier method. RESULTS: From October 2005 to November 2016, 206 patients (147 male; mean age, 63 +/- 13.5 years) underwent 256 MLEAs (90.9% below-knee amputations, 1.3% through-knee amputations, and 7.8% above-knee amputations [AKAs]) related to acute and critical limb ischemia, infection, or other causes. Mean follow-up was 178.7 +/- 266.9 days. Conversion from below-knee amputation to AKA was 3.5%. Estimated 1-year survival was 83%, and it was 15% lower in nonambulatory patients (75% vs 90%; P = .04). Overall 1-year postamputation ambulatory rate was 46.1%. Nonambulatory patients had a higher body mass index (30.9 +/- 8.0 vs 25.6 +/- 5.4; P < .001), lower preoperative hematocrit (31.0% +/ 7.4% vs 33.3% +/- 8.1%; P < .05), higher modified frailty index (mFI; 8.4 +/- 1.0 vs 5.4 +/- 1.2; P < .0001), higher chronic alcohol use (9% vs 1%; P = .01), dependent preoperative functional status (29% vs 2.1%; P < .01), and lack of family support (66.3% vs 17.9%; P < .01); they were less likely to be married (83.2% vs 35.8%; P < .01) and more likely to have an AKA (20% vs 52.6%; P = .004). There were no patients with dementia, on dialysis, or with bilateral MLEAs who were ambulatory after amputation. Factors predictive of nonambulatory status after MLEA with multivariate logistic regression analysis included increased body mass index (odds ratio [OR], 0.88; 95% confidence interval [CI], 0.81-0.98; P = .017) and an increased mFI (OR, 0.23; 95% CI, 0.16-0.34; P < .0001); a higher hemoglobin level was protective (OR, 1.3; 95% CI, 1.03-1.62; P = .019). CONCLUSIONS: Patients should be counseled that <50% of patients receiving MLEAs are ambulatory after amputation. Educating patients about the deleterious effects of obesity on ambulatory status after MLEA may motivate patients to improve their level of fitness to achieve successful ambulation. Patients with an elevated mFI, patients with dementia, and those on dialysis should be considered for AKAs. PMID- 29502999 TI - Outcomes and management costs of peripheral arterial disease in France. AB - BACKGROUND: Little is known about the characteristics and prognosis of patients with peripheral arterial disease (PAD) and related real-life health costs in France. METHODS: A cohort of patients diagnosed with PAD between 2007 and 2011 was extracted from the French Echantillon Generaliste des Beneficiaires (EGB) claims database. The patients were followed up from the date of PAD diagnosis. Their characteristics, incidence of death and other events, treatments, and costs were analyzed by comparison with age- and gender-matched PAD-free controls. RESULTS: There were 5889 patients with PAD identified. Mean age was 70.8 years, and 68.1% of patients were male. Diabetes was present in 28.9% of patients (13.2% of controls), hypercholesterolemia in 52.9% (28.7%), and hypertension in 46.6% (12.3%); 4.9% of patients had a history of unstable angina or myocardial infarction (0.5%), and 6.0% had a history of stroke or transient ischemic attack (1.4%). At inclusion, 69.3% of patients were receiving antiplatelet drugs (17.3%), 52.3% statins (21.9%), 26.7% angiotensin-converting enzyme inhibitors (13.7%), and 24.2% angiotensin receptor blockers (16.6%). Cumulative mortality rates were 13.2% at 1 year and 19.4% at 2 years (3.2% and 6.5% in controls). Cumulative incidence rates of death and major cardiovascular events (myocardial infarction and ischemic stroke) were 15.7% (95% confidence interval [CI], 14.8% 16.6%) at 1 year and 22.9% (95% CI, 21.9%-24.0%) at 2 years vs 3.9% (95% CI, 3.4% 4.4%) and 7.8% (95% CI, 7.1%-8.5%) in controls. All differences were statistically significant (P < .05). Total annual management costs were ?14,949 in the PAD group and ?3812 in the control group. CONCLUSIONS: Mortality is elevated and cardiovascular events are frequent among French PAD patients. PAD drug treatment guidelines are not fully implemented in France. PMID- 29503000 TI - Increasing the number of integrated vascular surgery residency positions is important to address the impending shortage of vascular surgeons in the United States. AB - OBJECTIVE: The demand for vascular surgeons is expected to far exceed the current supply. In an attempt to decrease the training duration and to address the impending shortage, integrated vascular surgery residencies were approved and have expanded nationally. Meanwhile, vascular fellowships have continued to matriculate approximately 120 trainees annually. We sought to evaluate the supply and demand for integrated vascular residency positions as well as changes in the quality of applicants. METHODS: We conducted a retrospective review of national data compiled by the Association of American Medical Colleges and the National Resident Matching Program regarding integrated vascular surgery residency programs (2008-2015) and fellowships (2007-2016). Variables reviewed included the total number of applicants, sex, U.S. vs international medical school enrollment, applications per program, and applicants per position. In addition, we conducted a retrospective review of applicants to the University of Massachusetts Medical School integrated vascular surgery residency program from 2008 to 2015 to examine these variables and United States Medical Licensing Examination Step 1 and Step 2 CK scores over time. RESULTS: The number of vascular surgery integrated residency positions increased from 4 in 2008 to 56 in 2015. Concurrently, the number of integrated residency applicants grew from 112 in 2008 to 434 in 2015. This increase has been predominantly driven by a 575% increase in U.S. graduate applicants and a 170% increase in women applicants. The percentage of international medical graduates has decreased by 17% during the study period. The total number of applicants per residency position increased from 5.9 to 7.8. Meanwhile, the number of vascular surgery fellowship positions remained stable with an applicant to position ratio near 1:1. At the University of Massachusetts Medical School, the mean United States Medical Licensing Examination Step 1 (226 to 235) and Step 2 CK (237 to 243) scores among integrated residency applicants have improved annually and typically exceed the national average among U.S. applicants who have matched in their preferred specialty. CONCLUSIONS: Since the approval of a primary certificate in vascular surgery and the subsequent rollout of integrated vascular residency programs, the number of residency programs and the quality of residency applicants have continued to increase. Demand from medical school applicants vastly outweighs the current supply of training positions by eightfold. In contrast, demand from fellowship applicants matches the supply of fellowship positions. The matriculation of additional trainees must be met with continued expansion of the integrated vascular surgery residency pathway to manage future public health needs. PMID- 29503001 TI - Scoring system to predict early carotid restenosis after eversion endarterectomy by analysis of inflammatory markers. AB - BACKGROUND: Inflammation is one of the mechanisms that leads to carotid restenosis (CR). The aim of this study was to examine the influence of increased values of inflammation markers (high-sensitivity C-reactive protein [hs-CRP], C3 complement, and fibrinogen) on CR development after eversion carotid endarterectomy (CEA). METHODS: A consecutive 300 patients were included in the study, in which eversion CEA was performed between March 1 and August 1, 2010. Demographic data, atherosclerosis risk factors, comorbidities, and ultrasound plaque characteristics were listed in relation to potential risk factors for CR. Serum concentrations of hs-CRP, fibrinogen, and C3 complement were taken just before surgery (6 hours); 48 hours after CEA; and during regular checkups at 1 month, 6 months, 1 year, and 2 years. An "inflammatory score" was also created, which consisted of six predictive values of inflammatory markers (hs-CRP just before and just after CEA, fibrinogen just before and just after CEA, and C3 complement just before and just after CEA) with a maximum score of 6 and a minimum score of 0. At every follow-up visit to the outpatient clinic, ultrasound assessment of the carotid artery for restenosis was done. RESULTS: Our results showed an increased risk of early CR within 1 year in patients with increased hs CRP before CEA (6 hours) and increased fibrinogen 48 hours after surgery and in patients not taking aspirin after CEA. Sex was determined to be an independent predictor of CR, with female patients having a higher risk (P = .002). Male patients taking aspirin with an inflammatory score >2 had an increased risk for restenosis compared with male patients with inflammatory score <2. Not taking aspirin after CEA and fibrinogen (48 hours) were the strongest predictors, and the Fisher equation incorporating these predictors was used to predict CR. A computer program was created to calculate whether the patient was at high or low risk for CR by selecting whether the patient was taking aspirin (yes or no) and whether fibrinogen was increased 48 hours after CEA (yes or no) and to display the recommended therapeutic algorithm consisting of aspirin, clopidogrel, cilostazol, and statins. CONCLUSIONS: Increased hs-CRP before CEA, increased fibrinogen 48 hours after CEA, and not taking aspirin were the main predictors of early CR. With the clinical implementation of the Fisher equation, it is possible to identify patients at high risk for early CR and to apply an aggressive therapeutic algorithm, finally leading to a decreased CR rate. PMID- 29503002 TI - Retrograde popliteal access to treat femoropopliteal artery occlusive disease. AB - OBJECTIVE: Retrograde popliteal artery (RPA) access to treat superficial femoral artery and popliteal artery disease is an option when treatment through common femoral artery (CFA) access is not possible. Our goal was to compare the safety and efficacy of RPA access with CFA access for treatment of femoral and popliteal artery lesions. METHODS: The Vascular Quality Initiative was queried for all patients undergoing RPA access from 2010 to 2016 for symptomatic peripheral arterial disease. These were compared with standard CFA access. Patients with acute limb ischemia were excluded. Preoperative, operative, and postoperative data were analyzed. Perioperative and 6-month outcomes were analyzed. Multivariable analysis was used to assess the effect of RPA access on amputation or death, major adverse limb event (MALE) or death, patency, and death. RESULTS: There were 30,074 patients with isolated superficial femoral and popliteal artery disease treated, 148 of whom had RPA access. Indications overall included claudication (56.3%), rest pain (13.9%), and tissue loss (29.8%). RPA access had a significantly lower rate of technical success compared with CFA access (80.4% vs 93.8%; P < .001). RPA access and CFA access were similar for rates of arterial dissection (8.3% vs 6.3%; P = .333), distal embolization (0% vs 1.2%; P = .183), access site hematoma (3.4% vs 3.1%; P = .849), and 30-day mortality (1.4% vs 1.1%; P = .789). There were no differences between RPA access and CFA access for unadjusted 6-month amputation-free survival (94.8% vs 96%; P = .747) or survival (934.3% vs 95.6%; P = .845). MALE-free survival (74.5% vs 83.5%; P = .016) and patency (70.3% vs 83.1%; P < .001) were significantly lower in the RPA access group. Multivariable analysis showed no differences between patients who were successfully treated by RPA access and CFA access for amputation-free survival (hazard ratio [HR], 1.24; 95% confidence interval [CI], 0.46-3.32; P = .669), MALE-free survival (HR, 1.57; 95% CI, 0.99-2.5; P = .057), and survival (HR, 0.86; 95% CI, 0.43-1.73; P = .675). RPA access was independently associated with loss of primary patency (HR, 1.91; 95% CI, 1.24-2.94; P = .003). CONCLUSIONS: RPA access had lower technical success and primary patency compared with antegrade access at 6 months. There were no differences demonstrated between the two access techniques in perioperative morbidity and mortality or 6-month amputation, MALE, and survival. This technique should be considered when CFA access cannot be accomplished. PMID- 29503003 TI - Quantitative analysis and predictors of embolic filter debris load during carotid artery stenting in asymptomatic patients. AB - OBJECTIVE: The objective of this study was to perform a quantitative analysis and to identify predictors of embolic filter debris (EFD) load during carotid artery stenting (CAS) in asymptomatic patients. METHODS: All patients with asymptomatic carotid stenosis >70% undergoing CAS between 2008 and 2016 were included in a prospective database. A distal filter protection device was used in all patients. At the end of the procedure, the filter was fixed in formalin and then analyzed with a stereomicroscope. Morphometric analysis was performed with Image-Pro Plus software (Media Cybernetics, Rockville, Md). The total area of the filter membrane and the area covered by particulate material were quantified. The quantity of membrane occupied by debris was expressed as percentage of covered surface area. Anatomic and clinical variables were evaluated for their association with EFD load using multiple logistic regression. RESULTS: Among the 278 patients undergoing CAS, an open-cell stent was implanted in 211 patients (76%); 67 patients (24%) received a closed-cell stent. Overall technical success and clinical success were both 99%; no perioperative death was reported. Stroke rate was 1.8% (major, n = 1 [0.4%]; minor, n = 4 [1.4%]); transient ischemic attacks occurred in 5% of cases (n = 14). The quantitative analysis of the filter revealed that EFD was present in 74% of cases (n = 207). The mean EFD load was 10% of the filter surface (median, 1; range, 0-80); it was <10% in 203 patients (73%), between 11% and 20% in 39 patients (14%), between 21% and 30% in 14 patients (5%), and >31% in 22 (8%). Patients with any type of ischemic neurologic event after CAS (stroke and transient ischemic attack) had a significantly higher mean EFD load compared with uneventful cases (26.7% +/- 19.0% vs 8.5% +/- 13.5%; P < .001). The observational frequency distribution analysis identified the presence of >12.5% EFD load as the optimal cutoff for the association with clinically relevant perioperative ischemic events (sensitivity, 78%; specificity, 77%; area under the curve, 0.81). The multivariate analysis demonstrated that age >75 years (odds ratio [OR], 2.56; P = .003), pre-existing ipsilateral ischemic cerebral lesions (OR, 2.09; P = .047), hypoechogenic plaque on the preoperative duplex ultrasound examination (OR, 6.05; P < .001), and plaque length >15 mm (OR, 1.79; P = .049) were independent predictors of EFD load >12.5%. CONCLUSIONS: The majority of asymptomatic carotid stenoses treated with CAS have detectable embolic debris in the protecting filter. Age >75 years, pre-existing ipsilateral cerebral ischemic lesions, hypoechogenic plaque, and plaque length >15 mm should be taken into consideration as independent predictors of clinically relevant embolic debris during the procedure. PMID- 29503004 TI - Ethnic minorities with critical limb ischemia derive equal amputation risk reduction from autologous cell therapy compared with whites. AB - OBJECTIVE: Ethnic minorities (nonwhites) with critical limb ischemia (CLI) have historically performed worse compared with whites with regard to major amputation risk reduction and amputation-free survival (AFS) after peripheral vascular intervention. This post hoc analysis was completed to determine whether this precedent also extended to treatment of CLI without a suitable revascularization option with intramuscular injections of concentrated bone marrow aspirate (cBMA). METHODS: The treatment arm of the randomized, double-blind, multicenter MarrowStim PAD Kit for the Treatment of Critical Limb Ischemia in Subjects with Severe Peripheral Arterial Disease (MOBILE) trial was stratified by ethnicity and evaluated for demographics, comorbidities, and outcomes. The primary and therapeutic end point was 1-year AFS and major amputation, respectively. Noninferiority analysis was performed with the margin set at historically reported hazard ratios. RESULTS: Thirty-seven minority (African American, Hispanic, other) CLI patients (9 placebo, 28 cBMA) with no suitable revascularization option were randomized to cBMA or placebo at a 3:1 ratio during the MOBILE trial. At 1-year follow-up for the treatment group, overall AFS was 80%. Of the 28 minority patients randomized to cBMA intervention, an 89% AFS rate was observed compared with 77% in whites. Specifically, 22 of 24 (92%) African Americans survived amputation free at 1-year follow-up. Noninferiority testing confirmed no difference between whites and the ethnic minority treated with cBMA with respect to major amputation reduction; however, noninferiority could not be confirmed with regard to AFS. No significant differences favoring whites treated with cBMA were noted in the secondary end points of vascular quality of life, limb pain, ankle-brachial index, toe-brachial index, transcutaneous oximetry, and 6-minute walk testing. CONCLUSIONS: This post hoc analysis of the MOBILE trial demonstrates noninferiority of cBMA intervention in minorities with no-option CLI for the therapeutic end point of major amputation prevention. cBMA represents a novel treatment paradigm and should be explored for minorities with poor revascularization options who face impending amputation secondary to progressive CLI. PMID- 29503005 TI - Optimization of rifampin coating on covered Dacron endovascular stent grafts for infected aortic aneurysms. AB - OBJECTIVE: In the treatment of an infected aorta, open repair and replacement with a rifampin-impregnated Dacron vascular graft decrease the risk of prosthetic graft infections, with several protocols available in the literature. We hypothesize that the same holds true for endovascular aneurysm repair, and after studying and optimizing rifampin solution concentration and incubation period to maximize the coating process of rifampin on Dacron endovascular stent grafts (ESGs), we propose a rapid real-time perioperative protocol. METHODS: Several prepared rifampin solutions, including a negative control solution, were used to coat multiple triplicate sets of Dacron endovascular aortic stent grafts at different but set incubation periods. Rifampin elution from the grafts was studied by spectroscopic analysis. Once an optimized solution concentration and incubation time were determined, the elution of rifampin over time from the graft and the graft's surface characteristics were studied by ultraviolet-visible spectroscopy and atomic force microscopy. RESULTS: All coated ESGs with any concentration of prepared rifampin solution, regardless of incubation time, immediately demonstrated a visible bright orange discoloration and subsequently after elution procedures returned to the original noncolored state. At the 25 minute incubation time (standard flush), there was no statistical difference in the amount of rifampin coated to the ESGs with 10-mg/mL, 30-mg/mL, and 60-mg/mL solutions (0.06 +/- 0.01, 0.07 +/- 0.05, and 0.044 +/- 0.01, respectively; P > .05). This was also true for a 10-minute incubation time (express flush) of 10 mg/mL and 60-mg/mL rifampin solution concentrations (0.04 +/- 0.007 and 0.066 +/- 0.014, respectively; P = .22). The elution-over-time of coated rifampin ESG, although not statistically significant, did seem to plateau and to reach a steady state by 50 hours and was confirmed by surface characteristics using atomic force microscopy. CONCLUSIONS: Having studied two variables of rifampin coating techniques to Dacron ESGs, the authors propose a rapid real-time perioperative coating protocol by using a 10-mg/mL rifampin solution for a 10-minute incubation period. As rifampin loosely binds to Dacron ESGs by weak intermolecular forces, a rifampin-coated ESG would need to be inserted in a timely fashion to treat the diseased aorta and to deliver its antibiotic affect. A rapid perioperative coating protocol followed by immediate deployment makes our proposed technique especially useful in an urgent and unstable clinical scenario. PMID- 29503006 TI - Percutaneous axillary artery access for fenestrated and branched thoracoabdominal endovascular repair. AB - OBJECTIVE: The aim of this study was to assess the safety and effectiveness of upper extremity access (UEA) with percutaneous closure of the axillary artery (AxA) during endovascular treatment of thoracoabdominal aortic aneurysms with fenestrated and branched endografts. METHODS: Between January 2014 and 2017, 34 out of 37 patients (92%) required UEA during a staged branched and fenestrated endovascular approach. A percutaneous AxA (pAxA) approach was used in 14 consecutive patients (41%) with the off-label use of two Perclose ProGlide (Abbott Vascular, Santa Clara, Calif) devices. The results of patients who had received a pAxA access were analyzed; technical success was defined as successful arterial closure with no evidence of persistent bleeding or arterial occlusion requiring secondary interventions. Early (30 days) and short-term (6 months) success rates were recorded. The anatomic characteristics of the AxA of the entire cohort (34 cases) were studied. RESULTS: Primary technical success of pAxA was 100%; in one case, an adjunctive Perclose ProGlide device was used to achieve complete closure. No secondary open or endovascular procedures were required. At predischarge computed tomography, no intimal defects, pseudoaneurysms, or signs of bleeding were observed, and all patients were discharged without neurologic deficits related to the AxA puncture site. All 14 patients are alive at follow up, and 9 of 14 patients completed a 6-month clinical follow-up with computed tomography examination; no late complications were observed at the site of UEA percutaneous repair. With regard to the anatomic characteristics of the AxA, the vessel diameters in the first and third segments were statistically different (P < .001) with a median difference of 1.5 mm (1.0-2.0 mm), with no differences between the right and left sides. The distance between the end of the first segment of the AxA and the origin from the aortic arch was statistically different between the right and left sides, with a median difference of 36 mm (17 50 mm). A positive linear correlation was found between the diameter of the AxA and the height of the patients. CONCLUSIONS: AxA is adequate in terms of both caliber and lack of calcifications as an access vessel for large-sheath catheterizations, and it might be considered an alternative UEA for complex aortic endovascular procedures thanks to its proximity to visceral target vessels. In this preliminary experience, percutaneous closure of AxA access with the Perclose ProGlide device is clinically safe and technically feasible with high rates of success. PMID- 29503007 TI - Rate and factors influencing the conversion of abstracts presented at the argentinian congress of hypertension meetings to indexed full peer-reviewed publications. AB - INTRODUCTION: Publication rates vary significantly among different scientific meetings, with many abstracts never being published as peer-reviewed articles. This issue has never been investigated in the Hypertension field in Argentina. Our purpose was to determine the proportion of abstracts presented at the Argentinian Congress of Hypertension meetings that were published as full articles in peer-reviewed indexed journals, the time lag to publication and the factors associated with successful publication. METHODS: we conducted a PubMed search to identify peer-reviewed publications of abstracts presented at the Argentinian Congress of Hypertension meetings between 2006 and 2015, assessing publication rate along with the time lag to publication. We also extracted information about several abstract characteristics and, for those that got published, we recorded the date of publication and journal name with its impact factor and H index. Predictors of publication were analyzed using a multivariable model. RESULTS: a total of 619 abstracts were presented between 2006 and 2015. The rate of conversion to full-text peer-reviewed articles by June 2017 was 28.1% (95%CI 24.7-31.8%), with a median time to publication of 15.7 months (IQR 8 30.9). On multivariable analysis, the independent predictors of publication were basic science category (OR 5 [95%CI 2.3-10.8], p<0.001), oral presentation (OR 2.8 [95%CI 1.6-4.9], p<0.001) and being an award winner for the presentation (OR 3 [95%CI 1.3-6.8], p=0.01). CONCLUSION: conversion rate to full peer-reviewed articles of abstracts presented at the Argentinian Congress of Hypertension meetings is far from ideal, with potential areas where efforts should be concentrated to improve dissemination of knowledge. PMID- 29503008 TI - [Contributions of the First International Consensus on grade 1 Hypertension with low to moderate cardiovascular risk]. PMID- 29503009 TI - Dynamic surface fault tolerant control for underwater remotely operated vehicles. AB - In this paper, we present a two stages actuator Fault Tolerant Control (FTC) strategy for the trajectory tracking of a Remotely Operated Vehicle (ROV). Dynamic Surface Control (DSC) is used to generate the moment and forces required by the vehicle to perform the desired motion. In the second stage of the control system, a fault tolerant thruster allocation policy is employed to distribute moment and forces among the thrusters. Exhaustive simulations have been carried out in order to compare the performance of the proposed solution with respect to different control techniques (i.e., PID, backstepping and sliding mode approaches). Saturations, actuator dynamics, sensor noises and time discretization are considered, in fault-free and faulty conditions. Furthermore, in order to provide a fair and exhaustive comparison of the control techniques, the same meta-heuristic approach, namely Artificial Bee Colony algorithm (ABC), has been employed to tune the controllers parameters. PMID- 29503010 TI - Event-triggered fault detection for discrete-time T-S fuzzy systems. AB - This paper is concerned with the design of piecewise fuzzy diagnostic observers for discrete-time T-S fuzzy systems under an event-triggered (ET) communication mechanism. Considering that the premise variables of the fuzzy diagnostic observer and the system may belong to different local space regions due to the introduction of ET mechanism, a partition method-based piecewise fuzzy diagnostic observer is designed to detect faults. The two-term approximation approach is introduced to approximate the time-varying delay. By transforming the augmented system into an input-output form consisting of two interconnected subsystems, the design condition of the piecewise fuzzy diagnostic observer is obtained by using the scaled small gain (SSG) theorem and a piecewise Lyapunov-Krasovskii functional. Furthermore, the Linfinity/L2 and Linfinity fault detection (FD) scheme is used to optimize the FD performance. Finally, two simulation examples are provided to show the efficiency of the proposed design method. PMID- 29503011 TI - Tick borne illness - Anaplasmosis. PMID- 29503012 TI - Eccentric knee flexor strength profiles of 341 elite male academy and senior Gaelic football players: Do body mass and previous hamstring injury impact performance? AB - OBJECTIVE: Report eccentric knee flexor strength values of elite Gaelic football players from underage to adult level whilst examining the influence of body mass and previous hamstring injury. DESIGN: Cross-sectional study. SETTING: Team's training facility. PARTICIPANTS: Elite Gaelic football players (n = 341) from under 14 years to senior age-grades were recruited from twelve teams. MAIN OUTCOME MEASURES: Absolute (N) and relative (N.kg-1) eccentric hamstring strength as well as corresponding between-limb imbalances (%) were calculated for all players. RESULTS: Mean maximum force was 329.4N (95% CI 319.5-340.2) per limb. No statistically significant differences were observed in relative force values (4.4 N .kg-1, 95% CI 4.2-4.5) between age-groups. Body mass had moderate-to-large and weak associations with maximum force in youth (r = 0.597) and adult (r =0 .159) players, respectively. Overall 40% (95 CI 31.4-48.7) presented with a maximum strength between-limb imbalance >10%. Players with a hamstring injury had greater relative maximum force (9.3%, 95% CI 7.0-11.8; p > 0.05) and a 28% (95% CI 10.0 38.0) higher prevalence of between-limb imbalances >=15% compared to their uninjured counterparts. CONCLUSIONS: Overlapping strength profiles across age groups, combined with greater strength in previously injured players, suggests difficulties for establishing cut-off thresholds associated with hamstring injury risk. PMID- 29503013 TI - Platelet rich concentrate enhances mesenchymal stem cells capacity to repair focal cartilage injury in rabbits. AB - BACKGROUND: It has been previously suggested that the use of regenerative promoters, which include bone marrow-derived mesenchymal stem cells (MSCs) or natural growth factors supplement such as platelet-rich concentrate (PRC) could promote cartilage regeneration. However, the notion that the concurrent use of both promoters may provide a synergistic effect that improves the repair outcome of focal cartilage injury has not been previously demonstrated. This study was thus conducted to determine whether the concomitant use of PRC could further enhance the reparative potential of MSCs encapsulated in alginate transplanted into focal cartilage injury in rabbits. METHODS: Artifically created full thickness cartilage defects were made on the weight-bearing region of medial femoral condyles in bilateral knees of New Zealand White rabbits (N = 30). After one month, the right knee was treated with either i) PRC (n = 10), ii) MSCs (n = 10), or, iii) a combination of PRC and MSCs (PRC + MSC) (n = 10), all encapsulated in alginate. The left knee remained untreated (control). Rabbits were sacrificed at 3 and 6 months after treatment. Cartilage tissue regeneration was accessed using ICRS morphologic scoring, histologic grading by O'Driscoll scoring, immunohistochemical staining and quantitative analysis of glycosaminoglycans (GAG) per total protein content. RESULTS: At 3 months, transplantation using PRC alone was equally effective as MSCs in inducing the repair of cartilage defects. However, PRC + MSC resulted in significantly higher ICRS and O'Driscoll scores (p < 0.05) as compared to other groups. The regenerated tissues from the PRC + MSC group also had stronger staining for Safranin-O and collagen type II. By 6 months, in addition to superior ICRS and O'Driscoll scores as well as stronger staining, glycosaminoglycan per total protein content was also significantly higher (p < 0.05) in the PRC + MSC group (3.4 +/- 0.3 MUg/mg) as compared to the MSC (2.6 +/- 0.2 MUg/mg) or PRC (2.1 +/- 0.2 MUg/mg) groups. CONCLUSION: PRC enhances the reparative effects of MSC in treating focal articular cartilage injuries. PMID- 29503014 TI - High incidence of screw penetration in the proximal and distal tibiofibular joints after intramedullary nailing of tibial fractures-A prospective cohort and mapping study. AB - BACKGROUND: Intramedullary-nails (IMN) are the treatment of choice for most tibial shaft fractures due to their minimally-invasive nature and non-demanding surgical technique. However, a potential iatrogenic pitfall is intra-articular interlocking screw positioning within the proximal (PTFJ) and distal (DTFJ) tibiofibular joints that may go unrecognized. OBJECTIVE: To evaluate the incidence of intra-articular screw penetration of the PTFJ and DTFJs after interlocking of IMN for tibial fractures. INTERVENTION: Reamed IMN using modern techniques, including proximal interlocking via standard aiming jig and distal interlocking either freehand or using SureShot(r). METHODS: Prospective series of 165 consecutive patients with a tibial shaft fracture managed with an IMN. Diagnosis and incidence of penetration of the PTFJ and DTFJ was assessed on protocolled low-dose postoperative CT-scans (standardized clinical practice for assessing rotational alignment). The degree of penetration of the TFJ's was graded as: Grade 1-slight breach of the tibial cortex; Grade 2-clear penetration of the tibial cortex with intra-articular screw tip; and Grade 3-penetration of both tibial- and fibular cortices with screw tip in fibula. RESULTS: Of the 165 tibial shaft fractures, using the AO/OTA classification, 69% were simple, 16% wedge and 15% complex fractures. Following IMN 42% of patients had intra articular screw penetration of their PTFJ whilst 39% had penetration of their DTFJ. 66% of patients had penetration of either one- or both of their TFJs. The grading of PTFJ violation was distributed as follows: Grade 1 in 24 patients; Grade 2 in 26 patients and Grade 3 in 19 patients. DTFJ violation was graded as: Grade 1 in 21 patients; 40 patients had Grade 2 violation; and four patients had a Grade 3 penetration. CONCLUSIONS: This diagnostic imaging study reports a high rate of intra-articular screw penetration of the PTFJ and DTFJ after interlocking of IMN for tibia shaft fractures. A prospective cohort study is underway to evaluate its clinical significance. Changes to enable alteration in forced angle of interlocking screw trajectory and avoidance of the anteromedial to posterolateral locking screw may reduce the incidence of TJF violation. LEVEL OF EVIDENCE: Level II - Diagnostic Imaging Study. PMID- 29503015 TI - Incidence of intracranial injury in orbital wall fracture patients not classified as traumatic brain injury. AB - OBJECTIVE: The detection of intracranial injury in patients with facial injury rather than traumatic brain injury (TBI) remains a challenge for emergency physicians. This study aimed to evaluate the incidence and risk factors of intracranial injury in patients with orbital wall fracture (OWF), who were classified with a chief complaint of facial injury rather than TBI. METHODS: This retrospective case-control study enrolled adult OWF patients (age >=18 years) who presented at the hospital between January 2004 and March 2016. Patients with definite TBI were excluded because non-contrast head computed tomography (CT) is recommended for such patients. RESULTS: A total of 1220 patients with OWF were finally enrolled. CT of the head was performed on 677 patients, and the incidence of concomitant intracranial injury was found to be 9% (62/677). Patients with definite TBI were excluded. Symptoms raising a suspicion of TBI, such as loss of consciousness, alcohol intoxication, or vomiting, were present in 347 of the patients, with 44 of these patients (13%) showing a concomitant intracranial injury. Of the 330 patients without such symptoms, 18 (6%) demonstrated a concomitant intracranial injury. In OWF patients, superior wall fracture (odds ratio [OR], 4.15; 95% confidence interval [CI], 2.06-8.34; P < 0.001), associated frontal bone fracture (OR, 4.38; 95% CI, 2.08-9.23; P < 0.001), and older age (decades) (OR, 1.03; 95% CI, 1.01-1.04; P = 0.002) were independent risk factors for concomitant intracranial injury. CONCLUSIONS: Emergency physicians should maintain a high degree of suspicion of TBI, even when their primary concern is facial trauma with OWF. Head CT is recommended for OWF patients with a superior OWF, frontal bone fracture, or increased age. PMID- 29503016 TI - Vibration loading promotes osteogenic differentiation of bone marrow-derived mesenchymal stem cells via p38 MAPK signaling pathway. AB - Low magnitude high frequency vibration (LMHFV) exhibits effectively anabolic effects on the bone tissue, and can promote osteogenic differentiation of mesenchymal stem cells (MSCs) in vitro. The role of p38 MAPK signaling in LMHFV induced osteogenesis remains unclear. In this current study, LMHFV loading was applied to BMSCs in vitro, and cell proliferation, alkaline phosphatase (ALP), matrix mineralization, as well as osteogenic genes expression were assayed. The mechanism of mechanical signal transduction was analysed using PCR array, qRT-PCR and Western blot. LMHFV increased cell proliferation in the growth medium, while inhibited proliferation in the osteogenic medium. ALP activity, matrix mineralization and osteogenic genes expression of Runx2, Col-I, ALP, OPN and OC were increased by LMHFV. p38 and MKK6 genes expression, and p38 phosphorylation were promoted in LMHFV-induced osteogenesis. Inhibition of p38 MAPK with SB203580 and targeted p38 siRNA blunted the increased ALP activity and osteogenic genes expression by LMHFV. These findings suggest that LMHFV promotes osteogenic differentiation of BMSCs, and p38 MAPK signaling shows an important function in LMHFV-induced osteogenesis. PMID- 29503017 TI - A method to measure predictive ability of an injury risk curve using an observation-adjusted area under the receiver operating characteristic curve. AB - Area under the receiver operating characteristic curve (AROC) is commonly used to choose a biomechanical metric from which to construct an injury risk curve (IRC). However, AROC may not handle censored datasets adequately. Survival analysis creates robust estimates of IRCs which accommodate censored data. We present an observation-adjusted ROC (oaROC) which uses the survival-based IRC to estimate the AROC. We verified and evaluated this method using simulated datasets of different censoring statuses and sample sizes. For a dataset with 1000 left and right censored observations, the median AROC closely approached the oaROCTrue, or the oaROC calculated using an assumed "true" IRC, differing by a fraction of a percent, 0.1%. Using simulated datasets with various censoring, we found that oaROC converged onto oaROCTrue in all cases. For datasets with right and non censored observations, AROC did not converge onto oaROCTrue. oaROC for datasets with only non-censored observations converged the fastest, and for a dataset with 10 observations, the median oaROC differed from oaROCTrue by 2.74% while the corresponding median AROC with left and right censored data differed from oaROCTrue by 9.74%. We also calculated the AROC and oaROC for a published side impact dataset, and differences between the two methods ranged between -24.08% and 24.55% depending on metric. Overall, when compared with AROC, we found oaROC performs equivalently for doubly censored data, better for non-censored data, and can accommodate more types of data than AROC. While more validation is needed, the results indicate that oaROC is a viable alternative which can be incorporated into the metric selection process for IRCs. PMID- 29503018 TI - Assessment of Systemic Adenosine Effect Using Color Doppler Ultrasound of the Splenic Artery-Feasibility and Potential Clinical Utility for Coronary Interventions. AB - Adenosine induces coronary vasodilation and simultaneously reduces splanchnic perfusion. This effect can be absent in adenosine non-responders. Imaging of splanchnic arteries under adenosine assessing this effect has not been performed in humans previously. In 26 patients, splenic artery color Doppler was performed during an infusion of adenosine. Peak velocity in the splenic artery was measured before the infusion and at 2 min. Results were compared qualitatively with perfusion imaging in magnetic resonance. A total of 24 patients showed a drop of splenic artery peak velocity from 62.3 +/- 18.1 to 40.4 +/- 15.7 cm/s (p <0.001), which corresponded to perfusion restriction in magnetic resonance. Two patients with constant splenic artery velocity did not show perfusion restriction. We showed feasibility of assessing changes in splenic artery velocity under adenosine for the first time in humans. Further studies are needed to investigate whether this novel application is a robust tool to rule out inadequate adenosine effect during measurement of fractional flow reserve in coronary catheterization. PMID- 29503019 TI - The Assessment of Diagnostic Accuracy for Basilar Artery Stenosis by Transcranial Color-Coded Sonography. AB - This study aimed to determine the optimal criteria for evaluating basilar artery stenosis (BAS) by transcranial color-coded sonography (TCCS). A total of 403 cases with both TCCS and digital subtraction angiography (DSA) were enrolled. Peak systolic velocity (PSV), end diastolic velocity (EDV) and mean flow velocity (MFV) of the basilar artery (BA), intracranial vertebral artery (IVA) and posterior cerebral artery (PCA) were measured. The ratios PSVBA/PSVIVA and PSVBA/PSVPCA were calculated. With DSA as the reference, the optimal criteria for grading BAS were determined by receiver operating characteristic analysis. They were as follows: PSV >=110 cm/s, MFV >=70 cm/s and PSVBA/PSVIVA >=1.5 for <50% BAS; PSV >=150 cm/s, MFV >=90 cm/s and PSVBA/PSVIVA >=2.0 for 50%-69% BAS; PSV >=210 cm/s, MFV >=120 cm/s and PSVBA/PSVIVA >=3.0 for 70%-99% BAS. The combination of PSV, MFV and PSVBA/PSVIVA may increase the accuracy for diagnosing 70%-99% BAS. PMID- 29503020 TI - Prediction of Tubulointerstitial Injury in Chronic Kidney Disease Using a Non Invasive Model: Combination of Renal Sonography and Laboratory Biomarkers. AB - The goal of the study described here was to evaluate the degree of tubulointerstitial injury in patients with chronic kidney disease (CKD) using a more accurate model that combines renal sonographic parameters and laboratory biomarkers. A total of 308 patients were enrolled. The study protocol included conventional ultrasound, contrast-enhanced ultrasonography and renal biopsy. CKD patients were divided into normal and mild (<=25%), moderate (26%-50%) and severe (>50%) tubulointerstitial injury groups. We created a model comprising peak intensity, time to peak, urinary retinol-binding protein and beta2-microglobulin that could discriminate severe (>50%) tubulointerstitial injury. The area under the receiver operating characteristic curve of this model was 0.832, which had better accuracy than other individual indexes, and the sensitivity and specificity were 74.2% and 82.8%, respectively. Therefore, this model may be used to evaluate the severity of tubulointerstitial injury and may have the potential to serve as an effective auxiliary method to help nephrologists evaluate patients with CKD. PMID- 29503021 TI - Asymmetric oxidative coupling of hydroxycarbazoles: Facile synthesis of (+)-bi-2 hydroxy-3-methylcarbazole. AB - Asymmetric oxidative coupling reactions of hydroxycarbazoles have been established using a chiral dinuclear vanadium complex. To demonstrate the utility of vanadium-catalyzed reactions, we have used them to synthesize (+)-bi-2-hydroxy 3-carbazole in three steps from cyclohexanone and commercially available aniline derivatives. PMID- 29503022 TI - Synthetic efforts towards the stereoselective synthesis of NF00659B1. AB - NF00659B1 is a novel alpha-pyrone diterpenoid natural product with potent anti colon cancer activity. A stereoselective approach to the 2,2-dimethyl oxepanol core of NF00659B1 is described enlisting a sequence of olefinic ester ring closing metathesis, epoxidation, and Grignard addition. This strategy paves the way to a total synthesis of NF00659B1 for further biological studies. PMID- 29503023 TI - Chemical synthesis of an indomethacin ester prodrug and its metabolic activation by human carboxylesterase 1. AB - It is necessary to consider the affinity of prodrugs for metabolic enzymes for efficient activation of the prodrugs in the body. Although many prodrugs have been synthesized with consideration of these chemical properties, there has been little study on the design of a structure with consideration of biological properties such as substrate recognition ability of metabolic enzymes. In this report, chemical synthesis and evaluation of indomethacin prodrugs metabolically activated by human carboxylesterase 1 (hCES1) are described. The synthesized prodrugs were subjected to hydrolysis reactions in solutions of human liver microsomes (HLM), human intestine microsomes (HIM) and hCES1, and the hydrolytic parameters were investigated to evaluate the hydrolytic rates of these prodrugs and to elucidate the substrate recognition ability of hCES1. It was found that the hydrolytic rates greatly change depending on the steric hindrance and stereochemistry of the ester in HLM, HIM and hCES1 solutions. Furthermore, in a hydrolysis reaction catalyzed by hCES1, the Vmax value of n-butyl thioester with chemically high reactivity was significantly lower than that of n-butyl ester. PMID- 29503024 TI - Cathepsin B inhibitors: Further exploration of the nitroxoline core. AB - Human cathepsin B is a cysteine protease with many house-keeping functions, such as intracellular proteolysis within lysosomes. Its increased activity and expression have been strongly associated with many pathological processes, including cancers. We present here the design and synthesis of novel derivatives of nitroxoline as inhibitors of cathepsin B. These were prepared either by omitting the pyridine part, or by modifying positions 2, 7, and 8 of nitroxoline. All compounds were evaluated for their ability to inhibit endopeptidase and exopeptidase activities of cathepsin B. For the most promising inhibitors, the ability to reduce extracellular and intracellular collagen IV degradation was determined, followed by their evaluation in cell-based in vitro models of tumor invasion. The presented data show that we have further defined the structural requirements for cathepsin B inhibition by nitroxoline derivatives and provided additional knowledge that could lead to non-peptidic compounds with usefulness against tumor progression. PMID- 29503025 TI - Clinical, echocardiographic and analytical parameters in patients with atrioventricular septal defect with and without Down syndrome. PMID- 29503026 TI - Impact of anticoagulation and platelet antiaggregation on anaemia and haemorragic events in patients with chronic kidney disease stages 3 and 4. AB - BACKGROUND AND OBJECTIVE: There is controversy concerning the risk/benefit of anticoagulation/antiaggregation in chronic kidney disease (CKD) patients. We analysed the impact of anticoagulation/antiaggregation on anaemia and haemorrhagic events in CKD patients. PATIENTS AND METHODS: A total of 232 CKD patients stages 3 and 4 were followed during a mean follow-up time of 36.7 +/- 11.6 months: 81 patients did not receive any anticoagulation or antiaggregation treatment, 91 received anticoagulation treatment and 60 patients received platelet antiaggregation. Haemorrhagic and cardiovascular events were recorded. RESULTS: Haemoglobin and ferritine levels were significantly higher in patients who did not receive anticoagulation or antiaggregation (Hb 13.7 +/- 1.6, 13.3 +/- 1.8 and 12.7+/-1.9g/dl, p=0.004; ferritine 170 +/- 145, 140 +/- 138, 105 +/- 99MUg/l, p=0.023). During follow up, 36 haemorrhagic events were registered: 4in the control group, 23 in the anticoagulation group and 9in the antiaggregation group (log rank 12.5; p=0.002). In a Cox model adjusted by age, renal function and haemoglobin levels, the anticoagulation increased the risk of bleeding by 4times (HR 4.180, 1.955-8.937); p=0,001) and antiaggregation by almost 3times (HR 2.780, 1.257-6.149, p=0.012). A total of 64 cardiovascular events were registered, 21 of which were classified as atherosclerotic events: 10 in the antiaggregation group, 8in the control group and 3in the anticoagulation group (log rank: 8.351; p=0.015). Anticoagulation treatment showed a reduction in the risk of atherosclerotic events (HR 0.136, 0.033-0.551, p=0.005) while platelet antiaggregation did not modified this risk (HR 1,566, 0.569-4.308). CONCLUSIONS: Anticoagulation and antiaggregation increase haemorrhagic risk in patients with CKD and worsen anaemia. Anticoagulation reduces atherosclerotic events by more than 85% while platelet antiaggregation does not modify this risk. PMID- 29503027 TI - The decline of the incidence of meningococcal disease in Barcelona between 1988 and 2015: the influence of the vaccine against serogroup C. AB - INTRODUCTION AND OBJECTIVE: The purpose of this study was to describe the evolution of meningococcal disease (MD) in the city of Barcelona between 1988 and 2015 and to assess the impact of the vaccine against serogroup C. MATERIALS AND METHODOLOGY: The evolution of MD and by serogroup was analysed using the information included in the mandatory notification diseases registry. Incidences of all serogroups between the periods of before and after the implementation of the serogroup C vaccine in 2000 were compared. Vaccination coverage among cases, serogroup among vaccinated cases and mortality and case fatality rates were analysed. RESULTS: MD has evolved from an incidence rate in children aged under 1 of 63.09 cases per 100,000 in 1997-2000 to 15.44 per 100,000 in 2001-2015. All MD serogroups incidences decreased after the implementation of the vaccine, especially for serogroup C among children aged between 1 and 4. Since 2000 vaccine coverage in MD cases by this serogroup was 7.6% while in those affected by serogroup B it was 35.0% (p<.01). Among those vaccinated, 66.4% of cases were serogroup B and 5.2% were C (p<.01). Mortality and case fatality rates were 7.7% and 0.19/100,000 respectively, without significant changes in time regarding case fatality. CONCLUSIONS: Incidence caused by serogroups B and C has decreased after the systematic vaccination against serogroup C. Vaccination against serogroup B could further reduce the impact of this lethal disease which has not decreased during this period. PMID- 29503028 TI - [Is the orientation of patients suffering from depressive disorder to the psychiatric emergencies by a general practitioner associated with the decision to hospitalize?] AB - INTRODUCTION: Depressive disorders affect nearly 350 million people worldwide and are the world's leading cause of incapacity. Patients who are depressed preferentially approach their general practitioner (GP), who is their first point of contact, in 50-60% of cases. The aim of our study is to assess whether the orientation of patients suffering from anxiety-depressive disorder towards a GP in a general emergency is a factor associated with hospitalization when compared to patients who present themselves spontaneously for the same disorders. Our secondary objective was to identify the different profiles of patients who were hospitalized for these disorders as an emergency. MATERIALS AND METHODS: We conducted a cross-sectional study for the year 2015, targeting patients who presented as general emergencies at the centre hospitalier de Troyes and who had received a psychiatric diagnosis in the context of an anxiety or depressive disorder. RESULTS: Five hundred and twenty four patients were included. A univariate analysis showed that referral by the attending physician was associated with hospitalization in 57.9% vs. 42.1% cases (P=0.007), at an odds ratio at 1.98 [1.22-3.21] by multivariate analysis. Analysis by ascending hierarchical classification made it possible to identify 3 profiles for hospitalized patients: 1) patients with a known psychiatric history, a history of past or current follow-ups directed by a psychiatrist, with at least one psychotropic treatment, the presence of psychotic symptoms and a low suicidal risk compared to the rest of the study population; 2) patients without a psychiatric history, or a history of past or ongoing psychiatric follow-up and the absence of ongoing psychotropic treatment. These patients were referred by a GP (67% vs 23%, P<0.001) and their suicidal risk was higher (59% vs 26%, P<0.001); 3) patients about whom the psychiatrist had little information at the time of the emergency consultation. CONCLUSIONS: The relevance of GPs in orientation towards emergencies pleads in favor of a partnership and an early exchange between treating physicians and the psychiatrists. PMID- 29503029 TI - Minimally invasive resection of lumbosacral pseudojoint resulting in complete resolution of a lower back pain - A case report and review of Bertolotti syndrome. AB - Bertolotti syndrome describes lower back pain secondary to an anatomical lumbosacral transitional vertebrae. We present the case of a 37 year old female with chronic lower back pain with radiological evidence of an anatomical lumbosacral pseudojoint. The patient underwent minimally invasive resection of her pseudojoint with complete resolution of symptoms postoperatively. We, as the authors would like to highlight that in patients with pain secondary to an aberrant lumbosacral articulation, consideration should be given to treatment via a minimally invasive technique. PMID- 29503030 TI - Crozier's penguin: An object history of maritime and museum science. AB - In November 1843 John Cassidy, curator in the Belfast Museum received, perhaps rather dolefully, a collection of bird skins. The Museum was barely managing to cope with the constant flow of donations from the 'four quarters of the globe'. But the gift of bird skins could not be ignored. Sent by Captain Francis Crozier, recently returned from the British Antarctic Expedition, the bequest contained 150 species of Southern Ocean birds, including the remains of two immature 'great penguins'. Taking the one surviving specimen as a focal point, this paper compares and contrasts the ways in which Aptenodytes forsteri, or the emperor penguin, was differently scripted on board ship and in the museum. The lively interpretations and close encounters with emperor penguins on the ice and on board the two naval bomb vessels are set alongside the more constrained meanings and fleeting attention given to them in a metropolitan and a provincial museum. PMID- 29503032 TI - The Use of Sexually Explicit Material and Its Relationship to Adolescent Sexual Activity. AB - PURPOSE: There is growing concern that sexually explicit material (SEM) may influence young people's sexual activity. The present study aimed to assess the longitudinal association between frequency of SEM use and adolescent sexual debut. METHOD: The present study used two independent panel samples of Croatian adolescents (with four and five data collection waves, respectively). We employed discrete-time event history approach and propensity matching score analysis to explore the target association. RESULTS: A consistent lack of significant association between SEM use and sexual debut was observed among male adolescents. Among female adolescents, the findings were inconclusive. We also found some evidence for the role of timing of first exposure to SEM. CONCLUSIONS: Our findings are relevant for educational and adolescent health specialists, as well as concerned parents. Considering that this study focused on middle adolescence, future research should address a potential link between SEM use and early sexual debut. PMID- 29503031 TI - Attitudes Toward Fertility and Reproductive Health Among Transgender and Gender Nonconforming Adolescents. AB - PURPOSE: Little is known about the reproductive desires of transgender and gender nonconforming (TGNC) adolescents who may seek gender-affirming medical care that leads to infertility. The current study addressed this gap by examining attitudes toward fertility and family formation in a diverse sample of TGNC youth. METHOD: An online survey about sexual/reproductive health in sexual and gender minority (SGM) adolescents ages 14-17 years was conducted from September to October 2016. RESULTS: A total of 156 TGNC adolescents (Mage = 16.1 years; 83.3% assigned female at birth; 58.3% youth of color) responded. Overall, 70.5% of TGNC adolescents were interested in adoption and 35.9% in biological parenthood; more gender-nonconforming youth (43.8%) than transgender youth (25.8%) expressed interest in biological fertility. Discussions with health-care providers about fertility and reproductive health were uncommon-only 20.5% of youth had discussed fertility in general and only 13.5% had discussed effects of hormones on fertility. However, 60.9% of respondents were interested in learning more about their fertility and family building options. Key themes emerging from qualitative comments included concerns related to fertility/reproductive health (e.g., stigma of SGM parenthood, effect of gender-affirming treatments on fertility), and the need for additional reproductive health information both tailored to their individual experience and for SGM individuals more generally. DISCUSSION: TGNC adolescents expressed interest in multiple family building options, including adoption and biological parenthood, and identified a need for more information about these options. Thus, clinicians working with adolescents should be aware of the unique fertility and reproductive health needs of TGNC youth. PMID- 29503033 TI - Impacts of Immigration Actions and News and the Psychological Distress of U.S. Latino Parents Raising Adolescents. AB - PURPOSE: U.S. Latino parents of adolescents face unprecedented threats to family stability and well-being due to rapid and far-reaching transformations in U.S. immigration policy. METHODS: Two hundred thirteen Latino parents of adolescents were recruited from community settings in a suburb of a large mid-Atlantic city to complete surveys assessing parents' psychological distress and responses to immigration actions and news. Univariate and bivariate analyses were conducted to describe the prevalence of parents' responses to immigration news and actions across diverse residency statuses. Multiple logistic regression models examined associations between immigration-related impacts and the odds of a parent's high psychological distress. RESULTS: Permanent residents, temporary protected status, and undocumented parents reported significantly more negative immigration impacts on psychological states than U.S. citizens. Parents reporting frequent negative immigration-related impacts had a significantly higher likelihood of high psychological distress than did other parents, and these associations were maintained even when accounting for parents' residency status, gender, education, and experience with deportation or detention. The odds of a parent reporting high psychological distress due to negative immigration impacts ranged from 2.2 (p < .05) to 10.4 (p < .001). CONCLUSIONS: This is one of the first empirical accounts of how recent immigration policy changes and news have impacted the lives of Latino families raising adolescent children. Harmful impacts were manifest across a range of parent concerns and behaviors and are strong correlates of psychological distress. Findings suggest a need to consider pathways to citizenship for Latina/o parents so that these parents, many of whom are legal residents, may effectively care for their children. PMID- 29503034 TI - Alterations in cholesterol metabolism-related genes in sporadic Alzheimer's disease. AB - Genome-wide association studies have identified several cholesterol metabolism related genes as top risk factors for late-onset Alzheimer's disease (LOAD). We hypothesized that specific genetic variants could act as disease-modifying factors by altering the expression of those genes. Targeted association studies were conducted with available genomic, transcriptomic, proteomic, and histopathological data from 3 independent cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Quebec Founder Population (QFP), and the United Kingdom Brain Expression Consortium (UKBEC). First, a total of 273 polymorphisms located in 17 cholesterol metabolism-related loci were screened for associations with cerebrospinal fluid LOAD biomarkers beta amyloid, phosphorylated tau, and tau (from the ADNI) and with amyloid plaque and tangle densities (from the QFP). Top polymorphisms were then contrasted with gene expression levels measured in 134 autopsied healthy brains (from the UKBEC). In the end, only SREBF2 polymorphism rs2269657 showed significant dual associations with LOAD pathological biomarkers and gene expression levels. Furthermore, SREBF2 expression levels measured in LOAD frontal cortices inversely correlated with age at death; suggesting a possible influence on survival rate. PMID- 29503035 TI - Pisiform malalignment associated with distal radius fractures. AB - BACKGROUND: The association of scaphoid or other carpal bone fractures with distal radius fractures is frequently reported, whereas few studies have described pisiform malalignment associated with distal radius fractures. The purpose of this study was to investigate the frequency and characteristics of pisiform malalignment associated with distal radius fractures. METHODS: We performed a retrospective study by reviewing the data of 152 consecutive patients with a mean age of 63 years who were treated surgically for distal radius fractures during a five-year period. We evaluated the pisotriquetral joint via preoperative sagittal computed tomography (CT) and assessed pisiform malalignment. Pisiform malalignment was defined as follows: (1) wide type, joint space >=4.0 mm; (2) non-parallel type, loss of parallelism of the joint surface of >=20 degrees ; or (3) overriding type, proximal or distal overriding of the pisotriquetral joint >=2.0 mm. We investigated the relationship between pisiform malalignment and the patterns of distal radius fractures. Pisiform malalignment was assessed using postoperative CT to determine whether it had been reduced. RESULTS: Pisiform malalignment was observed in 48 cases involving 44 patients with a mean age of 58 (17-81) years. The patients included 16, 17, and 15 cases of the wide type, non-parallel type, and overriding type, respectively. Distal radius fractures with dorsal displacement exhibited pisiform malalignment significantly more frequently than those with volar displacement. No significant difference was noted between intra- and extra-articular fractures or between patients with and without distal ulnar fractures. Among the 22 pisiform malalignment cases assessed via postoperative CT, 15 cases were reduced, and 7 cases remained malaligned. The non-parallel type exhibited the lowest reduction rate among the 3 types. CONCLUSIONS: Among distal radius fractures, 29% were complicated by pisiform malalignment. Distal radius fractures with dorsal displacement exhibited a significantly increased frequency of pisiform malalignment compared to those with volar displacement. PMID- 29503036 TI - Randomized open-labbel non-inferiority trial of acetaminophen or loxoprofen for patients with acute low back pain. AB - BACKGROUND: Current worldwide clinical practice guidelines recommend acetaminophen as the first option for the treatment of acute low back pain. However, there is no concrete evidence regarding whether acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) is more effective for treating acute low back pain (LBP) in Japan. The present study aimed to investigate whether acetaminophen treatment for acute musculoskeletal pain was comparable with loxoprofen (a traditional NSAID in Japan) treatment. METHODS: Of the 140 patients with acute LBP who visited out-patient hospitals, 127 were considered eligible and were randomly allocated to a group taking acetaminophen or one taking loxoprofen. As primary outcome measure, pain intensity was measured using a 0-10-numeric rating scale (NRS). Moreover, pain disability, pain catastrophizing, anxiety, depression, and quality of life, as well as adverse events, were assessed as secondary outcomes. The primary outcome was tested with a noninferiority margin (0.84 on changes in pain-NRS), and the secondary outcomes were compared using conventional statistical methods at week 2 and week 4. RESULTS: Seventy patients completed the study (acetaminophen: 35, loxoprofen: 35). The dropout rates showed no significant difference between the two medication-groups. We found that the mean differences of changes in pain-NRS from baseline to week 2 or 4 between the two medication groups were not statistically beyond the noninferiority margin (mean [95% confidence interval]: -0.51 [-1.70, 0.67], at week 2 and -0.80 [-2.08, 0.48] at week 4). There were no consistent differences between the two medication groups in terms of secondary outcomes. CONCLUSIONS: The results suggest that acetaminophen has comparable analgesic effects on acute LBP, based on at least a noninferiority margin, compared with loxoprofen at 4 weeks. Acetaminophen seems to be a reasonable first-line option for patients with acute LBP in Japan. PMID- 29503038 TI - Nonunion of the sternum treated with cervical locking plate: A case report. PMID- 29503037 TI - Long-term retrospective study on the placement of the cementless acetabular cup and clinical outcomes in patients undergoing femoral head autografting for hip dysplasia and total hip arthroplasty. AB - BACKGROUND: Placement of acetabular cup in the dysplastic hip is a challenging procedure. Using bulk femoral head autograft to increase the bony coverage of the cup is one of the techniques, which have been described. The impact of cup position on cup and autograft survival is a controversial issue. We aimed to determine whether the position of cementless acetabular cup used in conjunction with femoral head autograft in dysplastic hips affected the autograft-host incorporation with its final radiographic appearance and the cup survivorship into the second decade. METHODS: Thirty-eight dysplastic hips with varying Crowe types in 31 patients (30 women and one man) were included. The mean age was 47 years (range, 29-64 years) and the mean follow-up was 20.3 years (range, 14.8 25.9 years). The initial postoperative and final radiographs were evaluated. The survival rate of the cups was analysed using Kaplan-Meier statistics and the log rank test. Multivariate analysis was used to evaluate the effect of variables (Crowe type, radiographic initial host bone coverage over the cup and position of the cup) on survivorship. RESULTS: The acetabular cups were positioned anatomical in 27/38 hips according to Ranawat measurement technique. Trabecular bridging at graft-host interface was seen in all cases at an average 22.1 months. Neither acetabular cup position nor initial host bone coverage over acetabular cup less than 50% had any significant effect on either cup survival or final radiographic appearance of the graft. The 20-year cup survival rate without aseptic revision was 66% (95 CI, 52%-84%). No revision was performed due to graft resorption. CONCLUSION: Twenty-year survival rate of the cementless cup combination with femoral head autograft showed no significant differences whether it was placed at high or anatomic hip centre. The final radiographic appearance of the autograft was not affected from either the cup location or the initial radiographic horizontal host bone coverage. PMID- 29503039 TI - Implementing the International Committee on Mental Health in Cystic Fibrosis (ICMH) guidelines: Screening accuracy and referral-treatment pathways. AB - BACKGROUND: The International Committee on Mental Health (ICMH) published screening guidelines in Cystic Fibrosis (CF). This work 1) evaluated the sensitivity of the recommended screening tools against the 'gold standard' clinical psychological assessment and 2) investigated referral and treatment pathways. METHODS: Ninety-six participants (79 caregivers; 17 adolescents with CF) completed the screening tools prior to formal assessment. Agreement between screening data and psychological assessment was evaluated, sensitivity analyses performed and referral pathways tracked. RESULTS: All participants with an elevated screen (moderate/severe range) were subsequently assessed as requiring treatment for major depression/anxiety disorders. However, many were referred for treatment without elevated scores. Hence, sensitivity was poor with the recommended threshold score of 10, but with a threshold of 5 the sensitivity was 76% for adults and 46% for adolescents. The area under the ROC curve (diagnostic test ability) was 0.89 for caregivers but lower at 0.68 for adolescents. CONCLUSION: Mental health screening is complex, particularly in adolescents. Nonetheless, it is a first valuable step to improve mental health care in CF. The need for psychological support is greater than anticipated by the TIDES study. PMID- 29503040 TI - Inflection point analysis: A machine learning approach for extraction of IEGM active intervals during atrial fibrillation. AB - OBJECTIVE: In this paper, we propose a novel algorithm to extract the active intervals of intracardiac electrograms during atrial fibrillation. METHODS: First, we show that the characteristics of the signal waveform at its inflection points are prominent features that are implicitly used by human annotators for distinguishing between active and inactive intervals of IEGMs. Then, we show that the natural logarithm of features corresponding to active and inactive intervals exhibits a mixture of two Gaussian distributions in three dimensional feature space. An Expectation Maximization algorithm for Gaussian mixtures is then applied for automatic clustering of the features into two categories. RESULTS: The absolute error in onset and offset estimation of active intervals is 6.1ms and 10.7ms, respectively, guaranteeing a high resolution. The true positive rate for the proposed method is also 98.1%, proving the high reliability. CONCLUSION: The proposed method can extract the active intervals of IEGMs during AF with a high accuracy and resolution close to manually annotated results. SIGNIFICANCE: In contrast with some of the conventional methods, no windowing technique is required in our approach resulting in significantly higher resolution in estimating the onset and offset of active intervals. Furthermore, since the signal characteristics at inflection points are analyzed instead of signal samples, the computational time is significantly low, ensuring the real-time application of our algorithm. The proposed method is also robust to noise and baseline variations thanks to the Laplacian of Gaussian filter employed for extraction of inflection points. PMID- 29503041 TI - Effectiveness of an educational intervention and physical exercise on the functional capacity of patients on haemodialysis. AB - OBJECTIVE: To describe the impact of a standard hospital educational intervention including active physical exercises on personal well-being, functional capacity and knowledge of the benefits of prescribed physical activity for patients undergoing haemodialysis. METHOD: An uncontrolled, quasi-experimental, before-and after study with repeated measures of response variables at 4, 8 and 12 weeks after participating in an educational and physical exercise hospital intervention. It was performed at the Nephrology Unit at the Hospital Complex in Vic within september and december 2014. The patients' well-being, functional capacity and knowledge were assessed. Assessment tools: NOC nursing indicators, Barthel index scale, FAC Holden, Timed Get Up and Go test and Daniels scale. RESULTS: We included 68 (80.0%) patients and 58 (85.3%) completed, with a mean age of 70.16+/-13.5 years; 62.1% were males. After 12 weeks, the patients had better scores of personal well-being (2.33+/-1.2, 3.88+/-0.8), more autonomy to perform activities of daily living (Barthel: 92.8+/-12.8; 93.5+/-13.9), more muscle strength (Daniels Scale: 3.81+/-0.7, 4.19+/-0.6) and walked more briskly (Get Up and Go test: 14.98+/-8.5; 15.65+/-10.5). All of the score differences were statistically significant (P<05) except the Barthel Index. CONCLUSIONS: The standard educational intervention and active exercise performed at hospital level improved the personal well-being, knowledge and functional capacity of patients on haemodialysis. PMID- 29503042 TI - Engrafting human regulatory T cells with a flexible modular chimeric antigen receptor technology. AB - As regulatory T cells (Tregs) play a fundamental role in immune homeostasis their adoptive transfer emerged as a promising treatment strategy for inflammation related diseases. Preclinical animal models underline the superiority of antigen specific Tregs compared to polyclonal cells. Here, we applied a modular chimeric antigen receptor (CAR) technology called UniCAR for generation of antigen specific human Tregs. In contrast to conventional CARs, UniCAR-endowed Tregs are indirectly linked to their target cells via a separate targeting module (TM). Thus, transduced Tregs can be applied universally as their antigen-specificity is easily adjusted by TM exchange. Activation of UniCAR-engrafted Tregs occurred in strict dependence on the TM, facilitating a precise control over Treg activity. In order to augment efficacy and safety, different intracellular signaling domains were tested. Both 4-1BB (CD137) and CD28 costimulation induced strong suppressive function of genetically modified Tregs. However, in light of safety issues, UniCARs comprising a CD137-CD3zeta signaling domain emerged as constructs of choice for a clinical application of redirected Tregs. In that regard, Tregs isolated from patients suffering from autoimmune or inflammatory diseases were, for the first time, successfully engineered with UniCAR 137/zeta and efficiently suppressed patient-derived effector cells. Overall, the UniCAR platform represents a promising approach to improve Treg-based immunotherapies for tolerance induction. PMID- 29503043 TI - Origins and specificity of auto-antibodies in Sm+ SLE patients. AB - Systemic lupus erythematosus (SLE) is a complex autoimmune disease accompanied by production of autoantibodies directed to a variety of self-proteins and nucleic acids. The genetic basis of SLE is also complex with at least 40 susceptibility loci identified. This complexity suggests that there are a variety of SLE manifestations; nevertheless, SLE is treated as a single disease clinically. One unique SLE target is the Smith antigen (Sm), a nuclear ribonucleoprotein complex. Sm response occurs in 25% of patients with SLE. To simplify analysis of the disease and its associated autoantibody repertoire, we focused on this subset [referred to here as "Sm positive", Sm+]. We analyzed the memory B cell repertoire and identified a V region, Vkappa4-1, which was significantly overrepresented in the Sm+ SLE subset. Antibodies that express Vkappa4-1 are enriched in antinuclear (ANA) positive specificities and often associated with speckled ANA pattern that is a characteristic of Sm binding. In healthy individuals Vkappa4-1 B cells are enriched in the unswitched memory population. Unswitched memory B cells resemble mouse marginal zone B cells and this population is decreased in all SLE patients. Moreover, we found a similar decrease in healthy African American donors. African Americans have a significantly higher prevalence of SLE compared to Caucasians. Thus, reduced unswitched memory B cell compartment may represent a new susceptibility marker for SLE. PMID- 29503044 TI - Specialist Advice Support for Management of Severe Hereditary Angioedema Attacks: A Multicenter Cluster-Randomized Controlled Trial. AB - STUDY OBJECTIVE: Hereditary angioedema is a rare disease associated with unpredictable, recurrent attacks of potentially life-threatening edema. Management of severe attacks is currently suboptimal because emergency medical teams are often unaware of new specific treatments. The objective of this trial is to test whether a dedicated national telephone care-management strategy would reduce resource use during severe hereditary angioedema attacks. METHODS: We conducted a cluster-randomized multicenter prospective trial of patients with a documented diagnosis of hereditary angioedema (type I, II or FXII hereditary angioedema). Participants were enrolled between March 2013 and June 2014 at 8 participating reference centers. The randomized units were the reference centers (clusters). Patients in the intervention arm were given a national free telephone number to call in the event of a severe attack. Emergency physicians in the SOS hereditary angioedema (SOS-HAE) call center were trained to advise or prescribe specific treatments. The primary outcome was number of admissions for angioedema attacks. Economic evaluation was also performed. RESULTS: We included 100 patients in the SOS-HAE group and 100 in the control group. During the 2 years, there were 2,368 hereditary angioedema attacks among 169 patients (85%). Mean number of hospital admissions per patient in the 2-year period was significantly greater in the usual-practice group (mean 0.16 [range 0 to 2] versus 0.03 [range 0 to 1]); patient risk difference was significant: -0.13 (95% confidence interval -0.22 to -0.04; P=.02). Probabilistic sensitivity graphic analysis indicated a trend toward increased quality-adjusted life-years in the SOS-HAE group. CONCLUSION: A national dedicated call center for management of severe hereditary angioedema attacks is associated with a decrease in hospital admissions and may be cost-effective if facilities and staff are available to deliver the intervention alongside existing services. PMID- 29503045 TI - Thermal injuries from exploding electronic cigarettes. AB - INTRODUCTION: There are an estimated 2.75 million electronic cigarette (EC) users in the United States. ECs have become the most commonly used nicotine-containing product in young adults ages 18-24 years. Thermal, blast, and missile injuries from EC explosions has grown rapidly in recent years. Burn surgeons must remain up to date regarding management and treatment of burn injuries related to EC device ignition. METHODS: An IRB approved retrospective review of all patients admitted to the Massachusetts General Hospital Burn Center from January 2015 to April 2017 was performed. Fourteen patients with injuries associated with EC use were identified. Patient demographics, injury location, size and degree of burn, treatments required, length of stay (LOS), time to 95% closure, associated complications and injuries, and the circumstances that led to the injury were identified. RESULTS: The mean age was 28.6+/-8.6 years with a range of 19-50 years (n=14). EC burns occurred in males 93% (13/14) of the time. The majority of EC explosions caused 2nd and 3rd degree burns (57%) within the same wound bed, followed by deep 2nd degree (29%), and superficial 2nd degree (14%). The average TBSA from EC burns was 4.7+/-2.4% with a range of 1-10%. The most common location of the device or battery at the time of the injury was a pant pocket 86% (12/14), followed by 7% hand (1/14) and 7% purse (1/14). Isolated lower extremity burns occurred in 43% (6/14) of patients, while lower extremity and hand burns occurred in 21% (3/14) of patients. Nine of 14 patients required an operating room encounter under general anesthesia. Eight of 14 patients required skin grafting for definitive wound closure. The mean hospital length of stay was 6.6+/-4.7 days with a range of 0-15 days. Time to 95% wound closure was 18.4+/-10.8 with a range of 8-40 days. CONCLUSION: Thermal and blast injuries associated with EC device failure tend to cause small TBSA burns that are deep 2nd and 3rd degree wounds. The most common location for EC device storage among males was the front pants pocket. EC device users should be made aware of the dangers associated with EC use and advised to carry EC devices away from their body in dedicated carrying cases without loose metallic items. PMID- 29503046 TI - Families with newborns: Using a cartographic model to identify those who are at risk for fires. AB - We assessed whether a home fire safety intervention targeting families with newborn children in Jefferson County, Kentucky, reached those at severe risk using a cartographic model. Demographic and economic factors of 61 families were compared by census tract. Using geographic information systems (GIS), families were assigned a risk level (low, medium, high, or severe) based on the risk model. Families who participated differed from census tracts in that of being minority race (p=0.01). The median risk category of the families was medium risk. Sixty-five tracts were identified as high or severe risk and in need of future intervention. The model yielded a way to prioritize at-risk families. GIS is a useful tool for examining whether prevention interventions reached those in the severe risk category. PMID- 29503047 TI - Arterial infection caused by Listeria monocytogenes: Report of two cases. The efficacy of an early combined approach and oral suppressive treatment. PMID- 29503048 TI - Congenital cytomegalovirus infection. AB - Each year, thousands of children are born with or develop permanent disabilities such as hearing loss, vision loss, motor and cognitive deficits from congenital CMV infection (cCMV). However, awareness of cCMV and its associated sequelae is very low in pregnant women and healthcare providers. Both targeted and universal approaches to screen newborns for CMV infection are now achievable due to recent scientific advances including the development of a rapid, high-throughput method for detecting CMV in saliva, the efficacy of antiviral treatment in symptomatic infants, and the demonstration of cost effectiveness of CMV screening. Future studies are needed to address gaps in our understanding on the role of non primary maternal CMV infections, the evaluation of antiviral treatment in asymptomatic infants, and the implementation of prevention strategies for cCMV. PMID- 29503049 TI - Survival and Long-Term Outcomes of Thumb Metacarpal Extension Osteotomy for Symptomatic Carpometacarpal Laxity and Early Basal Joint Arthritis. AB - PURPOSE: To evaluate the survival and long-term outcomes of thumb metacarpal extension osteotomy for early carpometacarpal (CMC) arthritis. METHODS: Patients who underwent a thumb extension osteotomy between years 2000 and 2011 were identified. Patient demographics, complications, and reoperations were recorded. The Kaplan-Meier survival analysis was used with subsequent CMC surgery defined as failure. Patients who had undergone surgery 10 years or more before the study date underwent radiographic assessment, grip and pinch strength testing, and completed the Patient Rated Wrist/Hand Evaluation (PRWHE) and the Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) questionnaires. RESULTS: Thirty-two procedures in 7 males and 21 females were performed (mean age, 44.8 y). There were no cases of nonunion. Nine of 32 thumbs developed pin site erythema and were treated with oral antibiotics. Two thumbs developed osteomyelitis. Seven of 32 thumbs (22%) required reoperation. The Kaplan-Meier analysis indicated a 70% probability that patients who have this procedure will not require additional CMC surgery up to 14 years. Seven patients with a mean follow-up of 12.3 years (minimum 10 y) returned for clinical evaluation. The mean PRWHE and QuickDASH scores were 32.1 and 27.7, respectively. Examination revealed 124% pinch and 98% grip strength relative to the preoperative values. One thumb did not progress from stage II disease; 2 thumbs progressed from stage I to stage II; 1 thumb progressed from stage II to stage III; 1 thumb progressed from stage II to stage IV; 1 thumb did not have disease progression at the CMC joint, but developed scaphotrapeziotrapezoidal arthritis. CONCLUSIONS: Although reoperation rates and superficial infections with the described method of fixation were relatively high, thumb metacarpal osteotomy provides some degree of pain relief and improvement of function. This procedure may have utility as a temporizing measure in younger patients as it does not compromise future reconstructive procedures. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 29503050 TI - On the trail of the perfect prognosticator in advanced heart failure patients. PMID- 29503051 TI - Impact of cardiac resynchronization therapy on inflammatory biomarkers and cardiac remodeling: The paradox of functional and echocardiographic response. AB - INTRODUCTION: Response to cardiac resynchronization therapy (CRT) can currently be assessed by clinical or echocardiographic criteria, and there is no strong evidence supporting the use of one rather than the other. Reductions in B-type natriuretic peptide (BNP) and C-reactive protein (CRP) have been shown to be associated with CRT response. This study aims to assess variation in BNP and CRP six months after CRT and to correlate this variation with criteria of functional and echocardiographic response. METHODS: Patients undergoing CRT were prospectively enrolled between 2011 and 2014. CRT response was defined by echocardiography (15% reduction in left ventricular end-systolic volume) and by cardiopulmonary exercise testing (10% increase in peak oxygen consumption) from baseline to six months after device implantation. RESULTS: A total of 115 patients were enrolled (68.7% male, mean age 68.6+/-10.5 years). Echocardiographic response was seen in 51.4% and 59.2% were functional responders. There was no statistical correlation between the two. Functional response was associated with a significantly greater reduction in BNP (-167.6+/ 264.1 vs. -24.9+/-269.4 pg/ml; p=0.044) and CRP levels (-1.6+/-4.4 vs. 2.4+/-9.9 mg/l; p=0.04). Nonetheless, a non-significant reduction in BNP and CRP was observed in echocardiographic responders (BNP -144.7+/-260.2 vs. -66.1+/-538.2 pg/ml and CRP -7.1+/-24.3 vs. 0.8+/-10.3 mg/l; p>0.05). CONCLUSION: An increase in exercise capacity after CRT implantation is associated with improvement in myocardial remodeling and inflammatory biomarkers. This finding highlights the importance of improvement in functional capacity after CRT implantation, not commonly considered a criterion of CRT response. PMID- 29503052 TI - Stabilized landfill leachate treatment by coagulation-flocculation coupled with UV-based sulfate radical oxidation process. AB - In this work, the feasibility of coagulation-flocculation coupled with UV-based sulfate radical oxidation process (UV/SRAOP) in the removal of chemical oxygen demand (COD) of stabilized landfill leachate (SLL) was evaluated. For coagulation flocculation, ferric chloride (FeCl3) was used as the coagulant. The effect of initial pH of SLL and COD:FeCl3 ratio on the COD removal was evaluated. The result revealed that COD:FeCl3 ratio of 1:1.3 effectively removed 76.9% of COD at pH 6. The pre-treated SLL was then subjected to UV/SRAOP treatment. For UV/SRAOP, the sulfate radical (SR) was generated using UV-activated persulfate (UV/PS) and peroxymonosulfate (UV/PMS). The dosage of oxidant and reaction time were found to be the main parameters that influence the efficiency of COD removal. On the other hand, the effect of initial pH (3-7) and the type of oxidant (PS and PMS) was found to have no significant influence on COD removal efficiency. At optimum conditions, approximately 90.9 and 91.5% of COD was successfully removed by coagulation-flocculation coupled with UV/PS and UV/PMS system, respectively. Ecotoxicity study using zebrafish showed a reduction in toxicity of SLL from 10.1 to 1.74 toxicity unit (TU) after coagulation-flocculation. The TU remained unchanged after UV/PS treatment but slightly increased to 1.80 after UV/PMS treatment due to the presence of residual sulfate ion in the treated effluent. In general, it can be concluded that coagulation-flocculation coupled with UV/SRAOP could be a potential water treatment method for SLL treatment. PMID- 29503053 TI - A simple awareness campaign to promote food waste reduction in a University canteen. AB - Food waste has important environmental, social and economic impacts and increasing attention has been given lately to the unparalleled scale of food waste in the food supply chain worldwide. An initiative aiming to reduce food waste was tested at the School of Agriculture canteen (University of Lisbon, Portugal). The "Clean dish, clean conscience!" initiative consisted of a simple and inexpensive education campaign to raise awareness of reducing plate waste, by establishing the connection between food waste and personal behaviour. As a first stage plate waste from canteen users was measured over a 10 day period. After this period, a waste consumption index and per capita waste consumption were calculated to evaluate the level of satisfaction of the consumer and the related concern about food wastage, and was classified as Bad. After this first stage it was concluded that the users did not have strong convictions about avoiding food waste. During the second stage of the project an education campaign was implemented with plate waste being monitored for a further 16 days to assess the effectiveness of the campaign. The approach consisted of displaying simple and affordable informative posters in strategic areas of the canteen with simple messages reminding not to accept food they knew they would not eat. This led to a mean reduction in the waste consumption index of ~15%. A parallel action encouraging separation of organic and inorganic waste was implemented as well, with an active participation of >70% of the users. The initiative achieved its objective of reducing plate waste by raising awareness of the daily food waste problem at the institution's canteen and by suggesting "how-to" actions for reducing such waste. This study showed how avoidable waste can be reduced simply by making students aware of the topic of food waste. Simple strategies may be useful to improve behaviours and increase sustainability of the canteens at Universities although this proved to be only efficient with the collaboration of the canteen staff that needs solid education. From the results, a set of measures was presented to the University Social Services for adoption to ensure a permanent reduction of food waste and recyclables in the University canteens. PMID- 29503054 TI - Life cycle assessment of bottled water: A case study of Green2O products. AB - This study conducted a full life cycle analysis of bottled water on four types of bottles: ENSO, PLA (corn based), recycled PET, and regular (petroleum based) PET, to discern which bottle material is more beneficial to use in terms of environmental impacts. PET bottles are the conventional bottles used that are not biodegradable and accumulate in landfills. PLA corn based bottles are derived from an organic substance and are degradable under certain environmental conditions. Recycled PET bottles are purified PET bottles that were disposed of and are used in a closed loop system. An ENSO bottle contains a special additive which is designed to help the plastic bottle degrade after disposed of in a landfill. The results showed that of all fourteen impact categories examined, the recycled PET and ENSO bottles were generally better than the PLA and regular PET bottles; however, the ENSO had the highest impacts in the categories of global warming and respiratory organics, and the recycled PET had the highest impact in the eutrophication category. The life cycle stages that were found to have the highest environmental impacts were the bottle manufacturing stage and the bottled water distribution to storage stage. Analysis of the mixed bottle material based on recycled PET resin and regular PET resin was discussed as well, in which key impact categories were identified. The PLA bottle contained extremely low impacts in the carcinogens, respiratory organics and global warming categories, yet it still contained the highest impacts in seven of the fourteen categories. Overall, the results demonstrate that the usage of more sustainable bottles, such as biodegradable ENSO bottles and recycled PET bottles, appears to be a viable option for decreasing impacts of the bottled water industry on the environment. PMID- 29503055 TI - Vitamin D nutritional status and bone turnover markers in childhood acute lymphoblastic leukemia survivors: A PETALE study. AB - BACKGROUND: The remarkable progress in the treatment of childhood acute lymphoblastic leukemia (cALL) has led to a survival rate reaching 90%. This success story is unfortunately linked to increased risk of impaired skeletal mass accumulation during childhood and adolescence, predisposing the patients to osteoporosis and pathological fractures at adulthood. OBJECTIVE: This study aims at characterizing the vitamin D status and bone health biomarkers in a well characterized cohort of cALL survivors. RESULTS: Food frequency questionnaires reveal that (i) the total vitamin D intake varies greatly (44-2132 IU/d), (ii) only 16.8% of the participants consume vitamin D supplements, and (iii) 74% of survivors' intakes are below the Recommended Daily Intakes (400 IU/d). For the 42 participants taking vitamin D supplements, the median (2.5-97.5%iles) intake is 600 IU/d (21.2-1972 IU/d). Sixteen participants are vitamin D deficient (<30 nM) and 66 insufficient (>=30 - <50 nM). Serum 24,25(OH)2D3 concentrations are directly related to those of 25OHD3, and those of 3-epi-25OHD3 below the Lower Limit of Quantification in most samples. The participants' serum concentrations of cross-linked C-telopeptide of type-I collagen and intact amino-terminal pro peptide of type-I collagen decrease steadily with age, leveling at adulthood, and are at all times higher in males. CONCLUSION: The present study shows that the prevalence of vitamin D insufficiency or deficiency is not greater in cALL survivors compared to the general Canadian population despite low vitamin D food and supplement intakes. Furthermore, there seem to be no overt imbalance in the gender- and age-adjusted serum bone turnover marker concentrations. PMID- 29503056 TI - Comparing Western and Eastern criteria for sarcopenia and their association with survival in patients with pancreatic cancer. AB - BACKGROUND & AIMS: Sarcopenia and cachexia are associated with pancreatic cancer and serve as important adverse prognostic factors. Body composition can be analyzed by routine computed tomography (CT) for cancer staging and has been used to study many types of cancer. The CT measurements are robust, but the diagnostic criteria for sarcopenia vary among different studies. Age, sex and race are important factors that affect muscle and fat masses. This study aimed to analyze the effect of different sarcopenia diagnostic criteria on the prognosis of patients with pancreatic cancer. METHODS: Patients with newly diagnosed pancreatic cancer at National Taiwan University Hospital between October 2013 and October 2016 were retrospectively reviewed in this study. Body composition was assessed using cross-sectional CT images to calculate the total skeletal muscle (TSM) index. The concordance and interobserver variability of the TSM measurements were evaluated using both the Western criteria and the Eastern criteria. Kaplan-Meier analyses and the Cox proportional hazard ratio with two different diagnostic criteria for sarcopenia were used to compare the effect on overall survival (OS). RESULTS: A total of 146 patients with pancreatic cancer were enrolled. The TSM index measured by the Western institute was highly correlated with that measured by the Eastern institute (r = 0.953, p < 0.001). The prevalence of sarcopenia in the patient group at baseline was 66.4% (97/146) by the Western criteria and 11.0% (16/146) by the Eastern criteria, and only low agreement was found between the Western and Eastern criteria (Kappa value = 0.028, p = 0.149). Patients who were sarcopenic by the Western criteria showed no significant difference in OS versus those who were not sarcopenic (p = 0.807). However, patients who were sarcopenic by the Eastern criteria showed a significant difference in OS versus those who were not sarcopenic in a univariate analysis (p = 0.008) and multivariate analysis after adjustment for AJCC stage (p = 0.014). CONCLUSIONS: Our study demonstrates that different diagnostic criteria may result in different diagnoses and that sarcopenia is an important poor prognostic factor for pancreatic cancer when appropriate diagnostic criteria are selected. PMID- 29503057 TI - Prognostic significance of perioperative nutritional parameters in patients with gastric cancer. AB - BACKGROUND & AIMS: It has been suggested that nutritional status is related to the survival outcomes of cancer patients. The purpose of the current research is to evaluate the importance of the prognosis of various nutritional parameters during the perioperative period in patients with gastric cancer. METHODS: This study enrolled patients with gastric cancer who underwent D2 gastrectomy at the Department of Surgery, Samsung Medical Center, in 2008. The prognostic significance of nutritional parameters was analyzed, along with other clinical and pathological variables, preoperatively and postoperatively at 3, 6, and 12 months. RESULTS: The total number of patients was 1415. The mean values of nutritional parameters, weight, body mass index (BMI), hemoglobin, total cholesterol, and total lymphocyte count (TLC) decreased significantly over time after surgery. On the contrary, albumin and prognostic nutritional index (PNI) score increased significantly during the postoperative follow-up period. Preoperatively, low BMI (<18.5 kg/m2) and low TLC level (<1000 per mm3) were revealed as independent prognostic factors in multivariate analysis. Low preoperative TLC level and decline in PNI (DeltaPNI < -2.2) at postoperative 3 months; low preoperative TLC level and decline in TLC (DeltaTLC < -279.9 per mm3) at postoperative 6 months; and low preoperative BMI, albumin, and TLC levels at postoperative 12 months were independent nutritional prognostic indicators. CONCLUSION: Various perioperative nutritional parameters were confirmed as independent prognostic factors in patients with gastric cancer. Our results imply prognostic benefit from careful nutritional support for patients with poor nutritional parameters. PMID- 29503058 TI - Do patterns of nutrient intake predict self-reported anxiety, depression and psychological distress in adults? SEPAHAN study. AB - BACKGROUND & AIMS: Despite the growing evidence about dietary patterns, this study aimed at the association between patterns of nutrients intake and psychological disorders. METHODS: In this cross-sectional study, diet and psychological factors including anxiety, depression, and general health (GHQ) were assessed through self-administered questionnaires in 3846 Iranian adults. Daily intakes of 57 nutrients and bioactive compounds were calculated. Nutrient patterns (NPs) were derived using factor analysis. RESULTS: Three NPs were identified: 1) high in individual amino acids, cobalamin, zinc, phosphorus, saturated fatty acids, cholesterol and pantothenic acid named as "omnivore"; 2) high in thiamin, folate, selenium, iron, starch, maltose, betaine, calcium, riboflavin, and niacin; named as "grains and dairy". Mono-unsaturated fats, vitamin E and polyunsaturated fats were inversely associated with this pattern; 3) "fruits and vegetables" NP high in copper, vitamin C, glucose, fructose, potassium, dietary fiber, sucrose, vitamin A, magnesium and vitamin K. After adjustment for confounders, men in the top tertile of the omnivore NP had lower anxiety score than those in the bottom tertile (P = 0.04). Men in the highest tertile of the first NP were less likely to be depressed (OR = 0.50, 95%CI: 0.26 0.96; P-trend = 0.04). Women in the highest tertile of this pattern had lower GHQ scores than those in the bottom tertile (P = 0.01) and had lower odds of psychological distress (OR = 0.75, 95%CI: 0.57-0.99, P-trend = 0.0.04). CONCLUSIONS: An "omnivore" like diet high in amino acids, cobalamin, zinc, phosphorus, saturated fat, cholesterol and pantothenic acid is associated with reduced psychological disorders. Prospective studies are recommended to confirm our results. PMID- 29503059 TI - Clinical nutrition education in medical schools - Comment on the ESPEN survey. PMID- 29503060 TI - Impact of 3-week citrulline supplementation on postprandial protein metabolism in malnourished older patients: The Ciproage randomized controlled trial. AB - BACKGROUND: Citrulline (CIT), is not extracted by the splanchnic area, can stimulate muscle protein synthesis and could potentially find clinical applications in conditions involving low amino acid (AA) intake, such as in malnourished older subjects. OBJECTIVE: Our purpose was to research the effects of CIT supplementation on protein metabolism in particular on non-oxidative leucine disposal (NOLD, primary endpoint), and splanchnic extraction of amino acids in malnourished older patients. DESIGN: This prospective randomized multicenter study determined whole-body and liver protein synthesis, splanchnic protein metabolism and appendicular skeletal muscle mass (ASMM) in 24 malnourished older patients [80-92 years; 18 women and 6 men] in inpatient rehabilitation units. All received an oral dose of 10 g of CIT or an equimolar mixture of six non-essential amino acids (NEAAs), as isonitrogenous placebo, for 3 weeks. RESULTS: NOLD and albumin fractional synthesis rates were not different between the NEAA and CIT groups. Splanchnic extraction of dietary amino acid tended to decrease (p = 0.09) in the CIT group (45.2%) compared with the NEAA group (60.3%). Total differences in AA and NEAA area under the curves between fed state and postabsorptive-state were significantly higher in the CIT than in the NEAA group. There were no significant differences for body mass index, fat mass (FM), lean mass (LM) or ASMM in the whole population except for a tendential decrease in FM for the citrulline group (p = 0.089). Compared with Day 1, lean mass and ASMM significantly increased (respectively p = 0.016 and p = 0.018) at Day 20 in CIT-treated women (mean respective increase of 1.7 kg and 1.1 kg), and fat mass significantly decreased (p = 0.001) at Day 20 in CIT-group women (mean decrease of 1.3 kg). CONCLUSIONS: Our results demonstrate that CIT supplementation has no effect on whole-body protein synthesis or liver protein synthesis in malnourished older subjects. However, CIT supplementation was associated with a higher systemic AA availability. In the subgroup of women, CIT supplementation increased LM and ASMM, and decreased FM. PMID- 29503061 TI - Cystatin immunoreactivity in cornifying layers of the epidermis suggests a role in the formation of the epidermal barrier in amniotes. AB - The presence and localization of cystatin, a cysteine protease inhibitor involved in barrier formation in human and mice epidermis, has been studied in the epidermis of piscine and terrestrial vertebrates using a mouse monoclonal antibody. Cystatin has been localized by Immunostaining in the pre-corneous and corneous layers of monotreme, marsupial and placental mammals, and sparsely in the thin corneous layer of birds. Cystatin-immunolabeling is present in the pre corneous and corneous layer of crocodilian and turtle epidermis, in the alpha corneous layer and likely also in the beta-corneous layer of the epidermis in lizards, snakes and the tuatara. In keratinocytes of the pre-corneous (transitional) layers the protein initially shows a peripheral distribution that becomes compacted in mature corneocytes. The protein is not detected using the antibody in the epidermis of cyclostome, teleosts, sarcopterigian fish, and in amphibians. The study concludes that while in fish and amphibians cystatin is absent or however uncertainly localized in the epidermis, the protein instead appears present in the more external pre-corneous and corneous layers of amniotes. This special regionalization suggests a specific role of cystatin in the formation of the corneous epidermal barrier and regulation of desquamation originally evolved in the terrestrial environment. PMID- 29503062 TI - Measuring cancer in indigenous populations. AB - It is estimated that there are 370 million indigenous peoples in 90 countries globally. Indigenous peoples generally face substantial disadvantage and poorer health status compared with nonindigenous peoples. Population-level cancer surveillance provides data to set priorities, inform policies, and monitor progress over time. Measuring the cancer burden of vulnerable subpopulations, particularly indigenous peoples, is problematic. There are a number of practical and methodological issues potentially resulting in substantial underestimation of cancer incidence and mortality rates, and biased survival rates, among indigenous peoples. This, in turn, may result in a deprioritization of cancer-related programs and policies among these populations. This commentary describes key issues relating to cancer surveillance among indigenous populations including 1) suboptimal identification of indigenous populations, 2) numerator-denominator bias, 3) problems with data linkage in survival analysis, and 4) statistical analytic considerations. We suggest solutions that can be implemented to strengthen the visibility of indigenous peoples around the world. These include acknowledgment of the central importance of full engagement of indigenous peoples with all data-related processes, encouraging the use of indigenous identifiers in national and regional data sets and mitigation and/or careful assessment of biases inherent in cancer surveillance methods for indigenous peoples. PMID- 29503063 TI - Physical Activity in COPD. Significance, Prognosis, Measurement and Therapeutic Interventions. PMID- 29503064 TI - Giant Cervical and Mediastinal Hemangioendothelioma Arising from Subclavian Vein. PMID- 29503065 TI - Methotrexate Pneumonitis in Crohn's Disease: A Rare Case Report and Review of Literature. PMID- 29503066 TI - Risk Stratification in Chronic Obstructive Pulmonary Disease. Can the Spanish Guidelines be Improved? PMID- 29503067 TI - Orotracheal Intubation in a Patient with Known Tracheal Diverticulum. PMID- 29503068 TI - Pulmonary Hyalinizing Granuloma: A Diagnostic Challenge. PMID- 29503070 TI - Middle-aged man with symmetrical lesions in his throat. PMID- 29503069 TI - Risk Factors Influencing Outcome of Acute Leukemia Patients Who Experience Relapse After Allogeneic Hematopoietic Stem-Cell Transplantation. AB - BACKGROUND: Prognosis of acute leukemia patients who experience relapse after hematopoietic stem-cell transplantation (HSCT) remains poor. Identifying risk factors influencing outcome of these patients is essential. PATIENTS AND METHODS: Follow-up of 234 acute leukemia patients who underwent allogeneic HSCT from matched related donor was performed for occurrence of posttransplantation relapse. Statuses of remission and survival were assessed at 6 months after treatment of relapse. Analysis of risk factors influencing postrelapse overall survival (prOS), complete remission (CR), and nonrelapse mortality (NRM) was carried out. RESULTS: Posttransplantation relapse occurred in 43 patients (17.9%). After treatment, 11 patients (25.6%) experienced postrelapse remission, the prOS rate was 20.9% (9 patients), and the NRM rate was 25.6% (11 patients). Older age (P = .007) and failure to experience remission after relapse treatment (P = .027) were associated with lower prOS in multivariate analysis. Female sex (P = .027), posttransplantation extramedullary relapse (P = .001), and absence of postrelapse graft-versus-host disease P = .025) were associated with lower CR rate. Also, presence of extramedullary relapse (P = .011) was associated with lower risk of NRM whereas treatment of posttransplantation relapse with donor lymphocyte infusion with or without chemotherapy (P = .002) and occurrence of postrelapse graft-versus-host disease (P = .025) were associated with higher risk of NRM. CONCLUSION: Survival of acute leukemia patients who experience relapse after allogeneic HSCT is poor, especially in elderly patients and those who do not experience remission after relapse treatment. PMID- 29503071 TI - A young man with acute onset epigastric pain after the ingestion of Japanese sushi. PMID- 29503072 TI - Dementia, cardiomyopathy and pseudo-obstruction in a 63-year-old female. PMID- 29503073 TI - An elderly woman with progressive odynophagia, epigastralgia and nausea. PMID- 29503074 TI - Dimerization of the Pragmin Pseudo-Kinase Regulates Protein Tyrosine Phosphorylation. AB - The pseudo-kinase and signaling protein Pragmin has been linked to cancer by regulating protein tyrosine phosphorylation via unknown mechanisms. Here we present the crystal structure of the Pragmin 906-1,368 amino acid C terminus, which encompasses its kinase domain. We show that Pragmin contains a classical protein-kinase fold devoid of catalytic activity, despite a conserved catalytic lysine (K997). By proteomics, we discovered that this pseudo-kinase uses the tyrosine kinase CSK to induce protein tyrosine phosphorylation in human cells. Interestingly, the protein-kinase domain is flanked by N- and C-terminal extensions forming an original dimerization domain that regulates Pragmin self association and stimulates CSK activity. A1329E mutation in the C-terminal extension destabilizes Pragmin dimerization and reduces CSK activation. These results reveal a dimerization mechanism by which a pseudo-kinase can induce protein tyrosine phosphorylation. Further sequence-structure analysis identified an additional member (C19orf35) of the superfamily of dimeric Pragmin/SgK269/PEAK1 pseudo-kinases. PMID- 29503076 TI - Ultrasound, endoscopic ultrasound elastography, and the strain ratio in differentiating benign from malignant lymph nodes. AB - BACKGROUND AND STUDY AIMS: Endoscopic ultrasound elastography (EUS-elastography), or sono-elastography, has emerged in the past 2 decades as a qualitative method of estimating tissue stiffness. Strain elastography allows for semi-quantitative measurements of the average elasticity of a lesion, and previous studies have proposed the strain ratio (SR) for overcoming the limitations of the elasticity score. The main objective of this study is to assess the specificity, sensitivity and predictive values of the SR measured by EUS-elastography in differentiating benign from malignant lymph nodes (LNs). This study also aims to find significant ultrasonographic features other than the SR which could help in predicting LN malignancy. PATIENTS AND METHODS: This prospective study included 126 Egyptian patients with lymphadenopathy. US and EUS-elastography and the SR were assessed, in addition to detailed sonographic features, including size, longest diameter, shortest diameter, ratio of shortest/longest diameter, echotexture (echogenic or echo-poor) and hilum (lost or preserved). RESULTS: The SR cut-off value of 4.61 showed a sensitivity and specificity of 89.8% and 83.3%, respectively. This parameter had high positive and negative predictive values of 82.5% and 90.2%, respectively, for predicting malignant LNs. Univariate regression analysis showed that echogenicity, hilum preservation, elastography, the shortest dimension, the ratio of the shortest/longest dimension, ultrasound diagnosis and SR could be potential predictors of the final lymph node diagnosis. Sono-diagnosis depending on echogenicity, the shortest/longest diameter ratio and a preserved hilum in combination was the only predictive parameter in multivariate regression analysis. CONCLUSION: EUS-elastography and the SR could be excellent prognostic indices in differentiating benign from malignant lymph nodes if combined with other US features. PMID- 29503075 TI - Antibiotic prophylaxis in transarterial chemoembolization of hepatocellular carcinoma. AB - BACKGROUND AND STUDY AIMS: Transarterial chemoembolization remains a common treatment option in unresectable hepatocellular carcinoma. However, protocols for pre- and post-procedure care and the role of antibiotic prophylaxis have not been evaluated. The aim of this work was to compare 3 different groups of prophylactic antibiotics in patients undergoing chemoembolization and to compare the efficacy of intravenous versus oral route. PATIENTS AND METHODS: 180 hepatocellular carcinoma patients undergoing transarterial chemoembolization were selected. Patients were classified into 3 groups; Group 1: 60 patients; 30 received intravenous ceftriaxone, and 30 received oral cefixime. Group 2: 60 patients; 30 patients received intravenous levofloxacin and 30 received oral levofloxacin. Group 3: 60 patients; 30 received intravenous ciprofloxacin and 30 received oral ciprofloxacin. All antibiotics were given one day before intervention and for 4 days afterwards. Complete blood count, C-reactive protein, liver and renal function tests were assessed 1 and 5 days and then 1 month after the procedure. RESULTS: The ciprofloxacin group gave better results than the other 2 groups regarding total and differential leucocytic count and C-reactive protein level. No significant difference was found between oral and intravenous routes among the 3 groups. None of the studied patients developed infections or liver abscess after chemoembolization. CONCLUSION: Third generation cephalosporin, levofloxacin or ciprofloxacin all are effective as prophylaxis against post-chemoembolization infections. No significant difference between oral and intravenous administration among the 3 groups. Oral ciprofloxacin is an effective, safe and relatively inexpensive prophylaxis regimen. PMID- 29503077 TI - The prevalence of occult hepatitis B in chronic hepatitis C patients treated with interferon-based antiviral therapy. AB - BACKGROUND AND STUDY AIMS: Occult hepatitis B infection (OBI) is known to be mostly prevalent in chronic hepatitis C (CHC) patients and OBI reactivation might be life-threatening in patients undergoing interferon (IFN)-free direct acting antiviral (DAA) therapy. As previous studies have revealed a relationship between OBI and non-response to IFN-based antiviral therapy, the aim of the current study was to determine if there was a higher prevalence of OBI in IFN non-responders than responders. PATIENTS AND METHODS: This retrospective cross-sectional study was conducted in CHC patients who had previously received IFN-based antiviral therapy. Serum samples of 100 HBsAg negative CHC patients were tested for HBV DNA, anti-HBc IgG, anti-HBs, ALT and AST. The presence of OBI was compared between 50 IFN responders and 50 IFN non-responders. Patients with a history of previous HBV infection, patients with evidence of cirrhosis and patients who had received IFN therapy within the last one year were excluded from the study. RESULTS: Anti-HBc IgG positivity was determined in 53% of the patients. HBV DNA positivity, indicating OBI was determined in 1 (1%) patient. This patient was anti-HBc IgG positive, anti-HBs negative, ALT and AST levels were normal. The HBV DNA and anti-HBc IgG positivity rates were higher in the non-responder group than in the responder group, but the difference was not statistically significant (p = 0.31 and p = 0.07 respectively). CONCLUSION: According to the results of this study, the prevalence of OBI is lower than expected amongst CHC patients in Turkey and it may not be necessary to apply routine screening to IFN non responders for OBI infection before DAA therapy. However, there is a need for multicentre studies with larger patient series. PMID- 29503078 TI - Intraoperative evaluation of polymorphonuclear leukocyte during second-stage revision surgery promote overdiagnosis of persistent periprosthetic joint infection. AB - OBJECTIVE: The aim of this study was to evaluate whether intraoperative histopathological examination could predict the risk of relapse of infection in periprosthetic joint infections (PJI). METHODS: The study included 25 patients (14 women and 11 men, with a mean age of 67.0 years (range, 37-83 years)), who had two-staged revision surgery for a PJI. Following prosthetic removal in the first stage, all patient underwent an intraoperative histopathological examination during the second stage. The patients were divided into PMNs-positive group (>=five PMNs per high-powered field) or -negative group (0.3 * 106/mouse) at >50% endocrine purity and (2) their maturation to a functional state comparable with human pancreatic beta cells, as judged by their secretory responses during perifusion, their content in typical secretory vesicles, and their nuclear NKX6.1-PDX1-MAFA co-expression. Assessment of FBM in implants and its correlation with in vivo metabolic markers will guide clinical translation of stem cell-derived grafts in diabetes. PMID- 29503088 TI - BCL11B Drives Human Mammary Stem Cell Self-Renewal In Vitro by Inhibiting Basal Differentiation. AB - The epithelial compartment of the mammary gland contains basal and luminal cell lineages, as well as stem and progenitor cells that reside upstream in the differentiation hierarchy. Stem and progenitor cell differentiation is regulated to maintain adult tissue and mediate expansion during pregnancy and lactation. The genetic factors that regulate the transition of cells between differentiation states remain incompletely understood. Here, we present a genome-scale method to discover genes driving cell-state specification. Applying this method, we identify a transcription factor, BCL11B, which drives stem cell self-renewal in vitro, by inhibiting differentiation into the basal lineage. To validate BCL11B's functional role, we use two-dimensional colony-forming and three-dimensional tissue differentiation assays to assess the lineage differentiation potential and functional abilities of primary human mammary cells. These findings show that BCL11B regulates mammary cell differentiation and demonstrate the utility of our proposed genome-scale strategy for identifying lineage regulators in mammalian tissues. PMID- 29503089 TI - Neonatal Apex Resection Triggers Cardiomyocyte Proliferation, Neovascularization and Functional Recovery Despite Local Fibrosis. AB - So far, opposing outcomes have been reported following neonatal apex resection in mice, questioning the validity of this injury model to investigate regenerative mechanisms. We performed a systematic evaluation, up to 180 days after surgery, of the pathophysiological events activated upon apex resection. In response to cardiac injury, we observed increased cardiomyocyte proliferation in remote and apex regions, neovascularization, and local fibrosis. In adulthood, resected hearts remain consistently shorter and display permanent fibrotic tissue deposition in the center of the resection plane, indicating limited apex regrowth. However, thickening of the left ventricle wall, explained by an upsurge in cardiomyocyte proliferation during the initial response to injury, compensated cardiomyocyte loss and supported normal systolic function. Thus, apex resection triggers both regenerative and reparative mechanisms, endorsing this injury model for studies aimed at promoting cardiomyocyte proliferation and/or downplaying fibrosis. PMID- 29503090 TI - Stabilizing the Retromer Complex in a Human Stem Cell Model of Alzheimer's Disease Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein. AB - Developing effective therapeutics for complex diseases such as late-onset, sporadic Alzheimer's disease (SAD) is difficult due to genetic and environmental heterogeneity in the human population and the limitations of existing animal models. Here, we used hiPSC-derived neurons to test a compound that stabilizes the retromer, a highly conserved multiprotein assembly that plays a pivotal role in trafficking molecules through the endosomal network. Using this human-specific system, we have confirmed previous data generated in murine models and show that retromer stabilization has a potentially beneficial effect on amyloid beta generation from human stem cell-derived neurons. We further demonstrate that manipulation of retromer complex levels within neurons affects pathogenic TAU phosphorylation in an amyloid-independent manner. Taken together, our work demonstrates that retromer stabilization is a promising candidate for therapeutic development in AD and highlights the advantages of testing novel compounds in a human-specific, neuronal system. PMID- 29503091 TI - Establishment of Immunodeficient Retinal Degeneration Model Mice and Functional Maturation of Human ESC-Derived Retinal Sheets after Transplantation. AB - Increasing demand for clinical retinal degeneration therapies featuring human ESC/iPSC-derived retinal tissue and cells warrants proof-of-concept studies. Here, we established two mouse models of end-stage retinal degeneration with immunodeficiency, NOG-rd1-2J and NOG-rd10, and characterized disease progress and immunodeficient status. We also transplanted human ESC-derived retinal sheets into NOG-rd1-2J and confirmed their long-term survival and maturation of the structured graft photoreceptor layer, without rejection or tumorigenesis. We recorded light responses from the host ganglion cells using a multi-electrode array system; this result was consistent with whole-mount immunostaining suggestive of host-graft synapse formation at the responding sites. This study demonstrates an application of our mouse models and provides a proof of concept for the clinical use of human ESC-derived retinal sheets. PMID- 29503093 TI - Contractile Work Contributes to Maturation of Energy Metabolism in hiPSC-Derived Cardiomyocytes. AB - Energy metabolism is a key aspect of cardiomyocyte biology. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a promising tool for biomedical application, but they are immature and have not undergone metabolic maturation related to early postnatal development. To assess whether cultivation of hiPSC-CMs in 3D engineered heart tissue format leads to maturation of energy metabolism, we analyzed the mitochondrial and metabolic state of 3D hiPSC-CMs and compared it with 2D culture. 3D hiPSC-CMs showed increased mitochondrial mass, DNA content, and protein abundance (proteome). While hiPSC-CMs exhibited the principal ability to use glucose, lactate, and fatty acids as energy substrates irrespective of culture format, hiPSC-CMs in 3D performed more oxidation of glucose, lactate, and fatty acid and less anaerobic glycolysis. The increase in mitochondrial mass and DNA in 3D was diminished by pharmacological reduction of contractile force. In conclusion, contractile work contributes to metabolic maturation of hiPSC-CMs. PMID- 29503092 TI - YY1 Positively Regulates Transcription by Targeting Promoters and Super-Enhancers through the BAF Complex in Embryonic Stem Cells. AB - Yin Yang 1 (YY1) regulates early embryogenesis and adult tissue formation. However, the role of YY1 in stem cell regulation remains unclear. YY1 has a Polycomb group (PcG) protein-dependent role in mammalian cells. The PcG independent functions of YY1 are also reported, although their underlying mechanism is still undefined. This paper reports the role of YY1 and BAF complex in the OCT4-mediated pluripotency network in mouse embryonic stem cells (mESCs). The interaction between YY1 and BAF complex promotes mESC proliferation and pluripotency. Knockdown of Yy1 or Smarca4, the core component of the BAF complex, downregulates pluripotency markers and upregulates several differentiation markers. Moreover, YY1 enriches at both promoter and super-enhancer regions to stimulate transcription. Thus, this study elucidates the role of YY1 in regulating pluripotency through its interaction with OCT4 and the BAF complex and the role of BAF complex in integrating YY1 into the core pluripotency network. PMID- 29503095 TI - Plastic surgery in bariatric patients: a nationwide study of 17,000 patients on the national administrative database. AB - BACKGROUND: Bariatric patients are often candidates for plastic surgery. However, the rate of postbariatric procedures is not known. OBJECTIVES: The aim of this study was to analyze the rate of plastic surgery, and factors related to surgery, in bariatric patients. SETTING: University hospital, France. METHODS: This was a cohort study based on administrative data. All adult patients who received bariatric surgery in France between 2007 and 2013 were included to estimate the rate of plastic surgery and related predictive factors. Data are reported according to the reporting of studies conducted using observational routinely collected data guidelines for observational studies on administrative data. RESULTS: Among the 183,514 patients who underwent bariatric surgery in the study period, 23,120 plastic surgeries were performed on 17,695 patients, including abdominoplasty (62%), dermolipectomy of the upper or lower limbs (25%), and reconstruction of the breast (14%). The rates of plastic surgery were 13%, 18%, and 21% at 3, 5, and 7 years post-bariatric surgery, respectively. Multivariate analysis revealed that patients who had a biliopancreatic diversion or a gastric bypass had a hazard ratio of 2.67 and 2.67 for subsequent plastic surgery, respectively, compared with patients who had adjustable gastric banding. Women had a 2-fold probability of surgery compared with men (hazard ratio 2.02). Important variability in the rate of surgery was found among different hospitals; rates ranged from 6.1% to 41.3% at 5 years. CONCLUSIONS: This study showed that 21% of bariatric patients undergo plastic surgery. Large variability exists among hospitals, suggesting that several unmeasured factors may limit access to contouring surgery. PMID- 29503094 TI - Prospective Isolation of ISL1+ Cardiac Progenitors from Human ESCs for Myocardial Infarction Therapy. AB - The LIM-homeodomain transcription factor ISL1 marks multipotent cardiac progenitors that give rise to cardiac muscle, endothelium, and smooth muscle cells. ISL1+ progenitors can be derived from human pluripotent stem cells, but the inability to efficiently isolate pure populations has limited their characterization. Using a genetic selection strategy, we were able to highly enrich ISL1+ cells derived from human embryonic stem cells. Comparative quantitative proteomic analysis of enriched ISL1+ cells identified ALCAM (CD166) as a surface marker that enabled the isolation of ISL1+ progenitor cells. ALCAM+/ISL1+ progenitors are multipotent and differentiate into cardiomyocytes, endothelial cells, and smooth muscle cells. Transplantation of ALCAM+ progenitors enhances tissue recovery, restores cardiac function, and improves angiogenesis through activation of AKT-MAPK signaling in a rat model of myocardial infarction, based on cardiac MRI and histology. Our study establishes an efficient method for scalable purification of human ISL1+ cardiac precursor cells for therapeutic applications. PMID- 29503096 TI - Which postoperative complications matter most after bariatric surgery? Prioritizing quality improvement efforts to improve national outcomes. AB - BACKGROUND: National quality programs have been implemented to decrease the burden of adverse events on key outcomes in bariatric surgery. However, it is not well understood which complications have the most impact on patient health. OBJECTIVE: To quantify the impact of specific bariatric surgery complications on key clinical outcomes. SETTING: The Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) database. METHODS: Data from patients who underwent primary bariatric procedures were retrieved from the MBSAQIP 2015 participant use file. The impact of 8 specific complications (bleeding, venous thromboembolism [VTE], leak, wound infection, pneumonia, urinary tract infection, myocardial infarction, and stroke) on 5 main 30-day outcomes (end-organ dysfunction, reoperation, intensive care unit admission, readmission, and mortality) was estimated using risk-adjusted population attributable fractions. The population attributable fraction is a calculated measure taking into account the prevalence and severity of each complication. The population attributable fractions represents the percentage reduction in a given outcome that would occur if that complication were eliminated. RESULTS: In total, 135,413 patients undergoing sleeve gastrectomy (67%), Roux-en-Y gastric bypass (29%), adjustable gastric banding (3%), and duodenal switch (1%) were included. The most common complications were bleeding (.7%), wound infection (.5%), urinary tract infection (.3%), VTE (.3%), and leak (.2%). Bleeding and leak were the largest contributors to 3 of 5 examined outcomes. VTE had the greatest effect on readmission and mortality. CONCLUSION: This study quantifies the impact of specific complications on key surgical outcomes after bariatric surgery. Bleeding and leak were the complications with the largest overall effect on end-organ dysfunction, reoperation, and intensive care unit admission after bariatric surgery. Furthermore, our findings suggest that an initiative targeting reduction of post bariatric surgery VTE has the greatest potential to reduce mortality and readmission rates. PMID- 29503097 TI - Comment on: repeat sleeve gastrectomy/optimization of outcomes by modifying the indications and technique. PMID- 29503099 TI - Do we choose control diets wisely? AB - In a recent article in Cell Reports, Dalby and colleagues convincingly demonstrate that choosing an inadequate control diet in animal experiments that investigate the interaction of nutrition, gut microbiota, and obesity development may lead to the wrong conclusions. The authors systematically compared the effects of refined high- and low-fat diets (rHFD and rLFD) with those of a standard chow diet on mouse physiology, microbiota composition, cecal fermentation, and intestinal morphology. The results obtained in this study question the conclusions drawn from animal studies that compared the effects of HFDs with those of chow diets. PMID- 29503100 TI - The management of infected elbow arthroplasty by two-stage revision. AB - BACKGROUND: Deep prosthetic infection is a potentially devastating complication after total elbow arthroplasty, with an incidence of up to 12%. This study examined the demographics, microbiologic profile, and outcomes of infected total elbow arthroplasty treated with 2-stage revision in a tertiary referral unit. METHODS: We identified 19 consecutive patients (mean age, 65 years) undergoing revision arthroplasty for deep prosthetic infection. All patients underwent a first-stage procedure with removal of implants, debridement, and insertion of an antibiotic-loaded cement spacer, followed by at least 6 weeks of intravenous antibiotics. Fourteen patients required a second-stage revision. RESULTS: Five patients did not undergo a second-stage procedure because of patient choice (n = 2), medical or surgical risk factors (n = 2), and death from an unrelated cause (n = 1). Of the 19 patients undergoing a first-stage procedure, 16 (84%) remained infection free, and 11 of the 14 patients (79%) undergoing reimplantation of an elbow prosthesis remained infection free. Six patients required further surgery (3 for recurrent infection, 3 for noninfective indications). The commonest infecting organism was Staphylococcus aureus (47%). A degree of postoperative ulnar nerve dysfunction occurred in 37% of patients, but all resolved fully without further treatment. CONCLUSIONS: Management of prosthetic joint infection using 2-stage revision can result in high rates of eradication, although rates of reoperation and transient ulnar nerve dysfunction are high. PMID- 29503101 TI - Comparison of trophic factors secreted from human adipose-derived stromal vascular fraction with those from adipose-derived stromal/stem cells in the same individuals. PMID- 29503102 TI - Can Listeners Hear Who Is Singing? The Development of Voice Category Perception. AB - OBJECTIVE AND HYPOTHESIS: This study sought to investigate if a small amount of training in identification of voices elicits the development of prototypical vocal categories. STUDY DESIGN: This study used a between-group design. METHODS: This study used an ABX paradigm where listeners heard two different singers singing "ah" at the same pitch. Listeners identified which of the two singers was the producer of a third "ah" at a different pitch. Stimuli were recorded from two baritones, two tenors, two mezzo-sopranos, and two sopranos across a 1.5-octave range. Participants were randomly assigned to two groups, one group that received a training session using voices that were different from those in the experimental session, but of the same voice category, and one group that received no training. RESULTS: Training listeners with voices that are different from those of singers presented in the experiment did not significantly improve the ability to discriminate individual voices of the same voice category, but did significantly improve that ability to discriminate individual voices when the voices being compared were of different voice categories. CONCLUSIONS: Small amounts of purposeful exposure to human voices appear to result in the beginnings of listener voice category formation, providing listeners with prototypical categories that can aid them in discrimination of novel voices of those same categories. PMID- 29503103 TI - Eliminating bias and accelerating the clinical translation of oral microbiome research in oral oncology. PMID- 29503104 TI - Associations between fish and cold-water coral habitats on the Icelandic shelf. AB - The association between fish assemblages and cold-water coral habitats was evaluated based on analysis of longline catches in the Lonsdjup trough, SE Iceland. In 2009 and 2010, longlines were set in locations with varying coral cover within the trough. The study site is characterised by a depression (50-100 m deep), intersected by several ridges. Colonies of the cold-water coral Lophelia pertusa and other coral species were mainly found on the ridges. Among the fifteen fish species recorded, tusk (Brosme brosme) contributed ~80% to the total fish abundance in both surveys and their catch per unit effort was twofold greater on the ridges than in adjacent flat areas. Multivariate analyses showed differences between the structure of fish communities on and off the ridges. Constrained redundancy ordinations followed by variance partitioning revealed that the structure of the fish community varied with seabed complexity, cold water coral coverage and geographical position. It was not possible to separate between the effects of seabed complexity and coral cover, as these were strongly correlated. PMID- 29503098 TI - The tetrapartite synapse: a key concept in the pathophysiology of schizophrenia. AB - Growing evidence points to synaptic pathology as a core component of the pathophysiology of schizophrenia (SZ). Significant reductions of dendritic spine density and altered expression of their structural and molecular components have been reported in several brain regions, suggesting a deficit of synaptic plasticity. Regulation of synaptic plasticity is a complex process, one that requires not only interactions between pre- and post-synaptic terminals, but also glial cells and the extracellular matrix (ECM). Together, these elements are referred to as the 'tetrapartite synapse', an emerging concept supported by accumulating evidence for a role of glial cells and the extracellular matrix in regulating structural and functional aspects of synaptic plasticity. In particular, chondroitin sulfate proteoglycans (CSPGs), one of the main components of the ECM, have been shown to be synthesized predominantly by glial cells, to form organized perisynaptic aggregates known as perineuronal nets (PNNs), and to modulate synaptic signaling and plasticity during postnatal development and adulthood. Notably, recent findings from our group and others have shown marked CSPG abnormalities in several brain regions of people with SZ. These abnormalities were found to affect specialized ECM structures, including PNNs, as well as glial cells expressing the corresponding CSPGs. The purpose of this review is to bring forth the hypothesis that synaptic pathology in SZ arises from a disruption of the interactions between elements of the tetrapartite synapse. PMID- 29503105 TI - Living at the margins - The response of deep-water seagrasses to light and temperature renders them susceptible to acute impacts. AB - Seagrasses inhabit environments where light varies at different timescales, nonetheless are acutely sensitive to reductions in light beyond some conditional bounds. Two tropical deep-water seagrasses, Halophila decipiens and Halophila spinulosa, from the Great Barrier Reef were tested for their response to defined light and temperature regimes to identify their growth requirements and potential thresholds of mortality. Species were exposed to two light intensities, saturating (75 MUmol photons m-2 s-1) and limiting (25 MUmol photons m-2 s-1) light and two temperature treatments (26 degrees C and 30 degrees C) over a four-week period. Wavelength-specific parameters of PSII photochemistry were evaluated for seagrass leaves, as well as shoot density, gas exchange, and pigment content. Both species were sustained under saturating light levels (3.2 mol photons m-2 d-1) while limiting light led to decreased shoot density for H. decipiens and H. spinulosa after two and four weeks, respectively. Wavelength specific photochemistry was also affected under light-limiting treatments for both species while the functional absorption cross section was highly conserved. Photoacclimation and physiological adjustments by either species was not adequate to compensate for reduced irradiance suggesting these plants reside at the margins of their functional limits. As such, relatively short periods of light attenuating events, like dredging or flood plumes, may be detrimental to deep water seagrass populations. PMID- 29503106 TI - Benthic foraminifera in transitional environments in the English Channel and the southern North Sea: A proxy for regional-scale environmental and paleo environmental characterisations. AB - On the basis of the available databases including 700 sampling stations from subtidal to salt marsh areas, the purpose of this paper is to synthesise the regional distribution of living benthic foraminifera in transitional environments along the English Channel and southern North Sea. Indicator species analyses assign 37 foraminiferal taxa to high salt marsh, middle salt marsh, low salt marsh, tidal flat, tidal channel, and subtidal environmental units. Species are indicator of a single unit (e.g., Elphidium gunteri for tidal flat) up to four units (e.g., Haynesina germanica from tidal flat to middle marsh). The outcomes of the present study enhance future high-resolution paleo-environmental interpretations based on benthic foraminifera in transitional environments. PMID- 29503107 TI - Bioturbation activity of three macrofaunal species and the presence of meiofauna affect the abundance and composition of benthic bacterial communities. AB - Given concerns of increasing rates of species extinctions, the relationship between biodiversity and ecosystem functioning has become a major research focus over the past two decades. Many studies have shown that biodiversity per se (e.g. species richness) or species-specific traits may be good predictors of changes in ecosystem function. Although numerous studies on this subject have focused on terrestrial systems, few have evaluated benthic marine systems. We used the Limecola balthica community as a model to test whether the number or identity of three well-studied macrofaunal species influence the sediment bacterial compartment, which drives important biogeochemical processes and influence ecosystem functioning. We also investigated the poorly known role of meiofauna in the interactions between macrofauna and bacteria. Eight combinations of 0-3 species were maintained in microcosms for 34 days in the presence or absence of meiofauna. The abundance and composition of the bacterial community, defined by the relative percentage of cells with a high (HNA) vs low (LNA) nucleic acid content, were measured. Species identity of macrofauna was a better indicator of changes in the microbial compartment than was species richness per se. In particular, the gallery-diffuser behaviour of the polychaete Alitta virens likely induced strong changes in sediment physical and geochemical properties with a major impact on the bacterial compartment. Moreover, the presence of meiofauna modulated the influence of macrofauna on bacterial communities. This study provides evidence that species identity provides greater explanatory power than species richness to predict changes in the bacterial compartment. We propose that multi-compartment approaches to describe interactions amongst different size classes of organisms and their ecological roles should be further developed to improve our understanding of benthic ecosystem functioning. PMID- 29503108 TI - Can benthic foraminifera serve as proxies for changes in benthic macrofaunal community structure? Implications for the definition of reference conditions. AB - Benthic macrofauna is one of the most widely used biological groups to assess the ecological status of marine systems. Lately, attention has been paid to similar use of benthic foraminifera. In this study, distribution patterns of benthic foraminiferal and macrofaunal species were investigated simultaneously in 11 fjords in southeastern Norway in order to assess correlations and responses to environmental conditions. Selected fjords allowed to investigate contrasted environmental conditions from low total organic carbon (TOC) content (sediment TOC < 2.7%) in normoxia (bottom-water [O2] > 2 mL O2.L-1) up to high TOC content (> 3.4%) in severe hypoxia (< 0.5 mL O2.L-1). Environmental parameters comprised bottom-water dissolved oxygen, grain size, total organic carbon, total nitrogen (TN), pigments and depth below threshold (DBT). Foraminiferal and macrofaunal community data were significantly correlated (Procrustes analysis m2 = 0.66, p = 0.001). Hence, benthic foraminiferal distribution patterns mirror those of benthic macrofauna. However, as opposed to the foraminifera, macrofauna was not recorded at the most oxygen-depleted stations and, hence, was more sensitive to severe oxygen depletion. With regard to assigning species to ecological groups for ecological quality status assessment, the results suggest that species, e.g. Spiroplectammina biformis (foraminifera), Scalibregma inflatum (macrofauna), may exhibit different ecological requirements depending on their habitat. Considering the observed congruent patterns of benthic foraminifera and macrofauna, palaeo communities of benthic foraminifera could be used as indicators of reference conditions for benthic macrofaunal community structure. This would however need further developments of algorithms to perform such a translation. PMID- 29503109 TI - Oxidative stress induced by titanium dioxide nanoparticles increases under seawater acidification in the thick shell mussel Mytilus coruscus. AB - Biochemical responses of the mussel Mytilus coruscus exposed to different concentrations of titanium dioxide nanoparticles (nano-TiO2) (0, 2.5, 10 mg L-1) and two pH levels (pH 8.1 and pH 7.3) for 14 days. Mussel responses were also investigated after a 7 days recovery period (pH 8.1 and no nanoparticle). Exposure to nano-TiO2 led changes in antioxidant indexes (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione (GSH)), biotransformation enzyme activity (GST) and malondialdehyde level (MDA) in gills and digestive glands. An increase in MDA level and a decrease in SOD and GSH activities were observed in gill of mussels exposed to 10 mg L-1 nano-TiO2. This effect was more severe in mussels kept at pH 7.3 as compared to pH 8.1. A different response was observed in the digestive gland as SOD, CAT and GSH levels increased in mussels exposed to nano-TiO2. These contrasting results in digestive glands and gills were only evident at high concentration of nano-TiO2 and low pH. A 7 days recovery period was not sufficient to fully restore SOD, GPx, GST, GSH and MDA levels to levels before exposure to nano-TiO2 and low pH. Overall, our results confirmed that seawater acidification modulates effects of nanoparticles in mussels, and that gills are more sensitive to these stressors as compared with digestive glands. PMID- 29503110 TI - Vaccine-preventable disease incidence of pneumococcal conjugate vaccine in the Finnish invasive pneumococcal disease vaccine trial. AB - Estimation of the full disease burden caused by Streptococcus pneumoniae is challenging due to the difficulties in assigning the aetiology especially in lower and upper respiratory infections. We estimated the pneumococcal disease burden by using the vaccine-preventable disease incidence (VPDI) of PHiD-CV10 vaccine (GSK) in our clinical trial setting. Finnish Invasive Pneumococcal disease (FinIP) trial was a cluster-randomized, double-blind trial in children <19 months who received PHiD-CV10 in 52 clusters or hepatitis B/A vaccine as control in 26 clusters according to 3+1 or 2+1 schedules (infants < 7 months) or catch-up schedules (children 7-18 months). Outcome data were collected using Finnish routine health-care registers, consisting of THL National Infectious Diseases Register, THL Care register, and Benefits Register of Social Insurance Institution of Finland. Blinded follow-up lasted from the date of first vaccination (trial enrolment Feb-2009 through Aug-2010) to January 31, 2012 for Invasive Pneumococcal Disease (IPD) and to end of December 2011 for four other outcomes: non-laboratory-confirmed IPD, hospital-diagnosed pneumonia, tympanostomy tube placements, and antimicrobial purchases. VPDI was estimated as difference in disease incidences between PHiD-CV10 clusters and control clusters. Altogether >47,000 children were enrolled. In 30,527 vaccinated infants <7 months at first dose, the VPDIs per 100,000 person-years were 75 for laboratory confirmed IPD, 210 for non-laboratory-confirmed IPD, 271 for hospital-diagnosed pneumonia, 1143 for any tympanostomy tube placements and 11,381 for antimicrobial outpatient prescription, mainly due to otitis media. In a European developed country setting, over 95% of the disease episode reductions in vaccinated children were seen in mild upper respiratory infections. The VPDIs of severe diseases are underestimated, because the majority of invasive disease goes undetected with routine blood-culture-based definitions. Evaluation of the absolute reduction achievable with vaccinations using sensitive case detection is essential for understanding the full disease burden, for valid cost-effectiveness analyses and for appropriate vaccination policy decisions. Registration: ClinicalTrials.gov, NCT00861380 and NCT00839254. PMID- 29503111 TI - Lack of nervous necrosis virus (NNV) neutralizing antibodies in convalescent sevenband grouper Hyporthodus septemfasciatus after NNV infection. AB - Viral nervous necrosis (VNN) is caused by nervous necrosis viruses (NNVs) belonging to genus Betanodavirus (Nodaviridae). It is one of the most serious diseases in aquaculture industry worldwide. In the present study, the kinetics of NNV-infectivity and NNV-specific antibodies in convalescent sevenband grouper Hyporthodus septemfasciatus after NNV infection was determined. When fish were infected with NNV at 17.5 degrees C, and reared for 84 days at natural seawater temperature (increasing rate: approximately 0.1 degrees C/day), NNV infectivity peaked on day 14 with 107.80 TCID50/g at the highest, and declined to below the detection limit. When convalescent fish were reared at 27 degrees C, and re infected with NNV at 104.3 or 106.3 TCID50/fish, no mortality was observed although NNV multiplied up to 108.80 and 107.80 TCID50/g at the highest, respectively, suggesting NNV-specific immune response. It also revealed that convalescent fish were re-infected by NNV although NNV multiplication was strongly regulated. Interestingly, NNV-specific antibodies were detectable in 20% and >=80% of convalescent fish before and after re-infection with NNV, respectively. However, no NNV-neutralizing activity was detected before and after re-infection in almost all of the convalescent fish. Therefore, NNV-neutralizing antibodies might not be necessary for the protection of convalescent fish against NNV re-infection after previous NNV infection. PMID- 29503112 TI - Immunogenicity and safety of one or two doses of the quadrivalent meningococcal vaccine MenACWY-TT given alone or with the 13-valent pneumococcal conjugate vaccine in toddlers: A phase III, open-label, randomised study. AB - BACKGROUND: We evaluated the immunogenicity and safety of 1 and 2 doses of quadrivalent meningococcal serogroup A, C, W and Y tetanus toxoid-conjugate vaccine (MenACWY-TT) given alone or co-administered with 13-valent pneumococcal conjugate vaccine (PCV13) in toddlers. METHODS: In this phase III, open-label, controlled, multicentre study (NCT01939158), healthy toddlers aged 12-14 months were randomised into 4 groups to receive 1 dose of MenACWY-TT at month (M) 0 (ACWY_1), 2 doses of MenACWY-TT at M0 and M2 (ACWY_2), MenACWY-TT and PCV13 at M0 (Co-ad), or PCV13 at M0 and MenACWY-TT at M2 (PCV13/ACWY). Immune responses were assessed 1 month post-each vaccination. Solicited and unsolicited symptoms were recorded for 4 and 31 days post-each vaccination, respectively; serious adverse events (SAEs) and new onset of chronic illnesses (NOCIs) up to M9 from first vaccination. RESULTS: 802 toddlers were vaccinated. Post-dose 1 of MenACWY-TT, >=92.8% of toddlers had rSBA titres >=1:8, and >=62.5% had hSBA titres >=1:4 for each meningococcal serogroup. Post-dose 2 of MenACWY-TT, rSBA titres >=1:8 were observed in >=98.0% and hSBA titres >=1:4 in >=95.3% of toddlers. Percentages of toddlers with hSBA titres >=1:4 were higher after 2 doses versus 1 dose of MenACWY-TT for MenW (97.1% versus 62.5-68.9%) and MenY (95.3% versus 64.3-67.6%). Non-inferiority of immune responses to co-administered MenACWY-TT and PCV13 over their separate administration was demonstrated. AEs incidence was comparable among groups. SAEs were reported for 4.9%, 5.1%, 5.5% and 7.5%, and NOCIs for 2.0%, 3.0%, 0.5% and 3.5% of toddlers in the ACWY_1, ACWY_2, Co-ad and PCV13/ACWY groups, respectively; 4 SAEs reported in 3 toddlers were vaccine-related. Two fatal vaccine-unrelated SAEs were reported. CONCLUSION: MenACWY-TT was immunogenic when administered as a single dose at 12-14 months of age. A second dose in toddlers increased hSBA responses against MenW and MenY. MenACWY-TT and PCV13 can be co-administered without impairing the immunogenicity or safety profile of either vaccine. PMID- 29503114 TI - Factors contributing to declination of annual influenza vaccination by healthcare workers caring for cancer patients: An Australian experience. AB - Healthcare workers (HCWs) at an Australian cancer centre were evaluated using a voluntary declination form program to determine factors contributing to declination of annual influenza vaccination. Overall, 1835/2041 HCWs (89.9%) completed a consent or declination form; 1783 were vaccinated and 52 declined. Staff roles with minimal patient contact were significantly associated with lower vaccine uptake (adjusted odds ratio 0.48, 95% confidence interval 0.23-0.99). Reasons for vaccine refusal included personal choice (41%), previous side effect/s (23.1%), and medical reasons (23.1%). Of these, a large proportion may not be amenable to intervention, and this must be considered in setting threshold targets for future campaigns. PMID- 29503113 TI - H5N2 vaccine viruses on Russian and US live attenuated influenza virus backbones demonstrate similar infectivity, immunogenicity and protection in ferrets. AB - The continued detection of zoonotic influenza infections, most notably due to the avian influenza A H5N1 and H7N9 subtypes, underscores the need for pandemic preparedness. Decades of experience with live attenuated influenza vaccines (LAIVs) for the control of seasonal influenza support the safety and effectiveness of this vaccine platform. All LAIV candidates are derived from one of two licensed master donor viruses (MDVs), cold-adapted (ca) A/Ann Arbor/6/60 or ca A/Leningrad/134/17/57. A number of LAIV candidates targeting avian H5 influenza viruses derived with each MDV have been evaluated in humans, but have differed in their infectivity and immunogenicity. To understand these differences, we generated four H5N2 candidate pandemic LAIVs (pLAIVs) derived from either MDV and compared their biological characteristics in vitro and in vivo. We demonstrate that all candidate pLAIVs, regardless of gene constellation and derivation, were comparable with respect to infectivity, immunogenicity, and protection from challenge in the ferret model of influenza. These observations suggest that differences in clinical performance of H5 pLAIVs may be due to factors other than inherent biological properties of the two MDVs. PMID- 29503115 TI - Assessment of treatment factors and clinical outcomes in cervical cancer in older women compared to women under 65 years old. AB - OBJECTIVE: This study aims to understand the treatment patterns and clinical outcomes of older women with cervical cancer compared to younger women. METHODS: Women undergoing care for cervical cancer between 2000 and 2013 at two academic institutions were identified. The cohort of older patients was defined as >65 years old at diagnosis. Patient charts were retrospectively reviewed, and clinical variables were extracted. Fisher's exact tests, logistic regression, and Kaplan-Meier analyses were performed. RESULTS: From 2000 to 2013 1119 women with cervical cancer were identified. Of these, 191 (17.0%) were >65 years old at the time of diagnosis. Older women were more likely to present with higher stage disease (p < 0.001). Controlling for stage, older women were less likely to undergo surgery during their treatment course (38% versus 70%, p < 0.001) and more likely to undergo radiation (77% versus 52%, p < 0.001), but no more likely to receive chemotherapy (p = 0.34). If they did undergo surgery, older women were less likely to have a pelvic lymph node dissection performed (41% versus 61%, p = 0.04), though the rate of positive pelvic lymph nodes was not different (p = 0.80). Overall survival was decreased in the older cohort (p < 0.001). A multivariate model identified age > 65 (HR 1.76, 95%CI 1.30-2.40), stage (HR 2.77, 95%CI 2.40-3.21), and ever undergoing surgery (HR 0.60, 95%CI 0.44-0.82) as independently associated with overall survival. CONCLUSIONS: Women over age 65 with cervical cancer are less likely to undergo surgical management and were observed to have a decreased overall survival, even when controlling for use of surgery and stage of disease. PMID- 29503117 TI - Assessment of Heparin Anticoagulation Measured Using i-STAT and Hemochron Activated Clotting Time. AB - OBJECTIVE: Adequate anticoagulation, measured using activated clotting time (ACT), is important during vascular and cardiac surgeries. Unfractionated heparin is the most common anticoagulant used. The purpose of this analysis was to compare the i-STAT ACT (iACT) to the Hemochron ACT (hACT), both of which were then compared to anti-factor Xa (anti-Xa) assay, a representation of heparin level and activity. DESIGN: Prospective study. SETTING: Tertiary care cardiovascular center. PARTICIPANTS: Eleven consecutive elective adult cardiac surgical patients. INTERVENTIONS: Prior to cardiopulmonary bypass, ACTs were measured using i-STAT and Hemochron technologies and compared to each other and to anti-Xa assay prior to and during a cumulative administration of heparin. Data were compared using bias analyses. MEASUREMENTS AND MAIN RESULTS: Heparin (300 U/kg) was administered in quarterly doses. Coagulation labs were collected prior to and 3 minutes after each quarterly dose of heparin. The baseline ACTs for i STAT and Hemochron were 147 and 142 seconds, respectively. A significant association was found between iACT and hACT (p = 0.002). The iACT measurements underestimated hACT at ACT levels >180 seconds or anti-Xa levels >0.75 U/mL. No significant difference was found between ACT data at anti-Xa levels <0.5 U/mL. CONCLUSION: There was a good association between the iACT and hACT; however, the 2 tests are not equivalent. Overall, the iACT underestimated the hACT. Agreement between the ACT technologies was good at lower ACTs and anti-Xa levels, but declined with an anti-Xa >0.75 U/mL. PMID- 29503118 TI - Delayed Onset Aorto-Right Ventricular Fistula Complicating Sutureless Aortic Valve Replacement. PMID- 29503116 TI - Physical therapists familiarity and beliefs about health services utilization and health seeking behaviour. AB - BACKGROUND: Physical therapists' familiarity, perceptions, and beliefs about health services utilization and health seeking behaviour have not been previously assessed. OBJECTIVES: The purposes of this study were to identify physical therapists' characteristics related to familiarity of health services utilization and health seeking behaviour, and to assess what health seeking behaviour factors providers felt were related to health services utilization. METHODS: We administered a survey based on the Andersen behavioural model of health services utilization to physical therapists using social media campaigns and email between March and June of 2017. In addition to descriptive statistics, we performed binomial logistic regression analysis. We asked respondents to rate familiarity with health services utilization and health seeking behaviour and collected additional characteristic variables. RESULTS: Physical therapists are more familiar with health services utilization than health seeking behaviour. Those who are familiar with either construct tend to be those who assess for health services utilization, use health services utilization for a prognosis, and believe that health seeking behaviour is measurable. Physical therapists rated need and enabling factors as having more influence on health services utilization than predisposing and health belief factors. CONCLUSION: Physical therapists are generally familiar with health services utilization and health seeking behaviour; however, there appears to be a disconnect between what is familiar, what is perceived to be important, and what can be assessed for both health services utilization and health seeking behaviour. PMID- 29503119 TI - An Alternative Technique for Radial Arterial Catheterization. PMID- 29503120 TI - Invited Commentary: A Case of Multiple Ventricular Gradients. PMID- 29503121 TI - Enhanced Recovery for Cardiac Surgery. AB - Enhanced Recovery After Surgery (ERAS(r) Society, Stockholm, Sweden) programs are developing rapidly in multiple specialties, fueled by the promising outcomes in colorectal surgery. There currently are no Enhanced Recovery After Surgery guidelines for cardiac surgery. The elevated burden of mortality, morbidity, and high resource expenditures associated with cardiac surgery present a tremendous opportunity for enhanced recovery. This narrative review sets out to examine the literature involving enhanced recovery in cardiac surgery and explores additional potential areas of interest. PMID- 29503122 TI - Formation of banded vegetation patterns resulted from interactions between sediment deposition and vegetation growth. AB - This research investigates the formation of banded vegetation patterns on hillslopes affected by interactions between sediment deposition and vegetation growth. The following two perspectives in the formation of these patterns are taken into consideration: (a) increased sediment deposition from plant interception, and (b) reduced plant biomass caused by sediment accumulation. A spatial model is proposed to describe how the interactions between sediment deposition and vegetation growth promote self-organization of banded vegetation patterns. Based on theoretical and numerical analyses of the proposed spatial model, vegetation bands can result from a Turing instability mechanism. The banded vegetation patterns obtained in this research resemble patterns reported in the literature. Moreover, measured by sediment dynamics, the variation of hillslope landform can be described. The model predicts how treads on hillslopes evolve with the banded patterns. Thus, we provide a quantitative interpretation for coevolution of vegetation patterns and landforms under effects of sediment redistribution. PMID- 29503123 TI - High-mobility group nucleosome binding domain 1 (HMGN1) functions as a Th1 polarizing alarmin. AB - High-mobility group (HMG) nucleosome binding domain 1 (HMGN1), which previously was thought to function only as a nucleosome-binding protein that regulates chromatin structure, histone modifications, and gene expression, was recently discovered to be an alarmin that contributes extracellularly to the generation of innate and adaptive immune responses. HMGN1 promotes DC recruitment through interacting with a Galphai protein-coupled receptor (GiPCR) and activates DCs predominantly through triggering TLR4. HMGN1 preferentially promotes Th1-type immunity, which makes it relevant for the fields of vaccinology, autoimmunity, and oncoimmunology. Here, we discuss the alarmin properties of HMGN1 and update recent advances on its roles in immunity and potential applications for immunotherapy of tumors. PMID- 29503124 TI - The immunological functions of the Appendix: An example of redundancy? AB - Biological redundancy ensures robustness in living organisms at several levels, from genes to organs. In this review, we explore the concept of redundancy and robustness through an analysis of the caecal appendix, an organ that is often considered to be a redundant remnant of evolution. However, phylogenic data show that the Appendix was selected during evolution and is unlikely to disappear once it appeared. In humans, it is highly conserved and malformations are extremely rare, suggesting a role for that structure. The Appendix could perform a dual role. First, it is a concentrate of lymphoid tissue resembling Peyer's patches and is the primary site for immunoglobulin A production which is crucial to regulate the density and quality of the intestinal flora. Second, given its shape and position, the Appendix could be a unique niche for commensal bacteria in the body. It is extremely rich in biofilms that continuously shed bacteria into the intestinal lumen. The Appendix contains a microbiota as diverse as that found in the colon and could replenish the large intestine with healthy flora after a diarrhea episode. In conditions of modern medicine hygiene, and people live healthy without their appendix. However, several reports suggest that the effects of appendectomy could be subtler and associated with the development of inflammatory conditions such as inflammatory bowel disease (IBD), heart disease but also in less expected disorders such as Parkinson's disease. Lack of an Appendix also predicts a worsen outcome for recurrent Clostridium difficile infection, which is the first nosocomial infection in hospitals. Here, we review the literature and in combination with our own data, we suggest that the Appendix might be redundant in its immunological function but unique as a reservoir of microbiota. PMID- 29503126 TI - Endometrial stem/progenitor cells and their role in the pathogenesis of endometriosis. AB - Human endometrium regenerates on a cyclical basis each month, likely mediated by endometrial stem/progenitor cells. Several types of stem/progenitor cells have been identified: CD140b+CD146+ or SUSD2+ endometrial mesenchymal stem cells (eMSCs), N-cadherin+ endometrial epithelial progenitor cells (eEPs), and side population (SP) cells, a heterogeneous population predominantly comprising endothelial cells. eMSCs reside in a perivascular niche and likely mediate angiogenesis and stromal regeneration. Human eEPs are located in the bases of glands in the basalis and are likely more primitive than SSEA-1+ basalis epithelial cells. Endometrial stem/progenitor cells may contribute to the pathogenesis of endometriosis by their retrograde shedding into the pelvic cavity, either after menarche or as a result of neonatal uterine bleeding. eMSCs may have a role in the generation of progesterone-resistant phenotype of endometrial stromal fibroblasts (eSFs) in endometriosis. In future clinical practice, endometrial stem/progenitor cells may be used to establish diagnosis of endometriosis or as therapeutic targets. PMID- 29503127 TI - Constitution of traditional chinese medicine and related factors in women of childbearing age. AB - BACKGROUND: This study investigates the constitution of traditional Chinese medicine (TCM) among women who want to be pregnant in one year and explores factors related to TCM constitution. METHODS: This study was conducted on women who participated in free preconception check-ups provided by the Zhabei District Maternity and Child Care Center in Shanghai, China. The information regarding the female demographic characteristics, physical condition, history of pregnancy and childbearing, diet and behavior, and social psychological factors was collected, and TCM constitution assessment was performed. The Chi-square test, t-test, logistic regression analysis, and multinomial logistic regression analysis were used to explore the related factors of TCM constitution. RESULTS: The participants in this study were aged 28.3 +/- 3.0 years. Approximately fifty-five women in this study had Unbalanced Constitution. Logistic regression analysis showed that Shanghai residence, dysmenorrhea, gum bleeding, aversion to vegetables, preference for raw meat, job stress, and economic stress were significantly and negatively associated with Balanced Constitution. Multinomial logistic analysis showed that Shanghai residence was significantly associated with Yang-deficiency, Yin-deficiency, and Stagnant Qi Constitutions; gum bleeding was significantly associated with Yin-deficiency, Stagnant Blood, Stagnant Qi, and Inherited Special Constitutions; aversion to vegetables was significantly associated with Damp-heat Constitution; job stress was significantly associated with Yang-deficiency, Phlegm-dampness, Damp-heat, Stagnant Blood, and Stagnant Qi Constitutions; and economic stress was significantly associated with Yang deficiency, and Stagnant Qi Constitutions. CONCLUSION: The application of TCM constitution to preconception care would be beneficial for early identification of potential TCM constitution risks and be beneficial for early intervention (e.g., health education, and dietary education), especially during the women who do not have a medical condition and those who have related factors found in this study. PMID- 29503125 TI - Disorders of sex development. AB - Normal sex development depends on the precise spatio-temporal sequence and coordination of mutually antagonistic activating and repressing factors. These factors regulate the commitment of the unipotential gonad into the binary pathways governing normal sex development. Typically, the presence of the SRY gene on the Y chromosome triggers the cascade of molecular events that lead to male sex development. Disorders of sex development comprise a heterogeneous group of congenital conditions associated with atypical development of internal and external genitalia. These disorders are generally attributed to deviations from the typical progression of sex development. Disorders of sex development can be classified into several categories including chromosomal, gonadal, and anatomic abnormalities. Genetic tools such as microarray analyses and next-generation sequencing techniques have identified novel genetic variants among patients with disorders of sexual development. Most importantly, patient management needs to be individualized, especially for decisions related to sex of rearing, surgical interventions, hormone treatment, and potential for fertility preservation. PMID- 29503128 TI - Mesothelin and osteopontin as circulating markers of diffuse malignant peritoneal mesothelioma: A preliminary study. AB - BACKGROUND: The differential diagnosis between diffuse malignant peritoneal mesothelioma (DMPM) and other peritoneal surface malignancies (PSM) is still challenging. Serum mesothelin and osteopontin are increasingly used as markers of pleural mesothelioma, but their role in DMPM is unclear. We assessed the diagnostic and prognostic values of mesothelin, osteopontin, CEA, CA19.9, CA125, and CA15.3 in DMPM patients. METHODS: Markers were dosed before cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) by enzyme-linked immunosorbent assay (ELISA) in 30 DMPM patients and 14 controls with other PSMs. Receiver-operating characteristics (ROC) curve were plotted. The performance of each marker was assessed by the area under the ROC curve (AUC-ROC). RESULTS: Mean mesothelin levels were 7.84 ng/dl (SD = 5.14) in DMPM group and 3.00 ng/dl (SD = 1.25) in controls (P = 0.001). Mean CEA levels were 5.3 ng/dl (SD = 4.7), and 61.96 ng/dl (SD = 112.5) in the two groups (P = 0.008). No statistical difference was seen for osteopontin (P = 0.738), CA19.9 (P = 0.081), CA125 (P = 0.600), and CA15.3 (P = 0.365). AUC-ROC was 0.836 for CA19.9, 0.812 for mesothelin, 0.793 for CEA, and lower for CA125 (0.652), osteopontin (0.531), and CA15.3 (0.481). Using diagnostic cut-offs selected by ROC methodology, sensitivity, specificity, positive and negative predictive values were 70.0%, 100.0%, 100.0%, and 60.9% for mesothelin >5.21 ng/dl, and 90.0%, 85.7%, 93.1%, and 80.0% for CA19.9 < 8.8 U/dl. At multivariate analysis, osteopontin correlated with survival (hazard rate 6.46; 95%CI 1.81-23.05; P = 0.004). CONCLUSION: When assessing PSMs of unknown origin, elevated mesothelin with low CA19.9 may increase the suspicion index for DMPM. Ospeopontin warrants further investigations as a prognostic marker for DMPM. PMID- 29503130 TI - ECCO essential requirements for quality cancer care for oesophageal and gastric cancer: Defining how to organise care. PMID- 29503129 TI - Surgical morbidity and mortality after neoadjuvant chemotherapy in the CRITICS gastric cancer trial. AB - BACKGROUND: In order to determine the optimal combination of perioperative chemotherapy and chemoradiotherapy for Western patients with advanced resectable gastric cancer, the international multicentre CRITICS trial (ChemoRadiotherapy after Induction chemotherapy In Cancer of the Stomach) was initiated. In this trial, patients with resectable gastric cancer were randomised before start of treatment between adjuvant chemotherapy or adjuvant chemoradiotherapy following neoadjuvant chemotherapy plus gastric cancer resection. The purpose of this study was to report on surgical morbidity and mortality in this trial, and to identify factors associated with surgical morbidity. METHODS: Patients who underwent a gastrectomy with curative intent were selected. Logistic regression analyses were used to assess risk factors for developing postoperative complications. RESULTS: Between 2007 and 2015, 788 patients were included in the CRITICS trial, of whom 636 patients were eligible for current analyses. Complications occurred in 296 patients (47%). Postoperative mortality was 2.2% (n = 14). Complications due to anastomotic leakage was cause of death in 5 patients. Failure to complete preoperative chemotherapy (OR = 2.09, P = 0.004), splenectomy (OR = 2.82, P = 0.012), and male sex (OR = 1.55, P = 0.020) were associated with a greater risk for postoperative complications. Total gastrectomy and oesophago-cardia resection were associated with greater risk for morbidity compared with subtotal gastrectomy (OR = 1.88, P = 0.001 and OR = 1.89, P = 0.038). CONCLUSION: Compared to other Western studies, surgical morbidity in the CRITICS trial was slightly higher whereas mortality was low. Complications following anastomotic leakage was the most important factor for postoperative mortality. Important proxies for developing postoperative complications were failure to complete preoperative chemotherapy, splenectomy, male sex, total gastrectomy, and oesophago-cardia resection. PMID- 29503131 TI - The treatment of ANCA-associated rapidly-progressive glomerulonephritis and Goodpasture syndrome with therapeutic apheresis. AB - Therapeutic plasma aphresis (plasmapheresis) is one form of treatment that is frequently used in practice of Nephrology. Plasmapheresis is the most important part of the therapies for Goodpasture's syndrome and anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis which are causes of rapidly progressive glomerulonephritis. The reason why the effectiveness of plasmapheresis therapy cannot be clearly demonstrated in renal involvement in these diseases is that it does not appear to be possible to recruit an adequate number of patients and plasmapheresis is not effective in advanced disease if early treatment is not initiated. PMID- 29503132 TI - A multicenter experience of thrombotic microangiopathies in Turkey: The Turkish Hematology Research and Education Group (ThREG)-TMA01 study. AB - Thrombotic microangiopathies (TMAs) are rare, but life-threatening disorders characterized by microangiopathic hemolytic anemia and thrombocytopenia (MAHAT) associated with multiorgan dysfunction as a result of microvascular thrombosis and tissue ischemia. The differentiation of the etiology is of utmost importance as the pathophysiological basis will dictate the choice of appropriate treatment. We retrospectively evaluated 154 (99 females and 55 males) patients who received therapeutic plasma exchange (TPE) due to a presumptive diagnosis of TMA, who had serum ADAMTS13 activity/anti-ADAMTS13 antibody analysis at the time of hospital admission. The median age of the study cohort was 36 (14-84). 67 (43.5%), 32 (20.8%), 27 (17.5%) and 28 (18.2%) patients were diagnosed as thrombotic thrombocytopenic purpura (TTP), infection/complement-associated hemolytic uremic syndrome (IA/CA-HUS), secondary TMA and TMA-not otherwise specified (TMA-NOS), respectively. Patients received a median of 18 (1-75) plasma volume exchanges for 14 (153) days. 81 (52.6%) patients received concomitant steroid therapy with TPE. Treatment responses could be evaluated in 137 patients. 90 patients (65.7%) achieved clinical remission following TPE, while 47 (34.3%) patients had non responsive disease. 25 (18.2%) non-responsive patients died during follow-up. Our study present real-life data on the distribution and follow-up of patients with TMAs who were referred to therapeutic apheresis centers for the application of TPE. PMID- 29503133 TI - A Consecutive Case Series of 166 First Metatarsophalangeal Joint Fusions Using a Combination of Cup and Cone Reamers and Crossed Cannulated Screws. AB - Fusion of the first metatarsophalangeal joint (MTPJ) is the reference standard surgery for significant hallux rigidus. A number of different techniques for first MTPJ fusion have been reported. We describe our technique of first MTPJ fusion using cup and cone reamers for joint surface preparation and 2 crossed cannulated screws for fixation. To the best of our knowledge, this is the single largest series using this technique. The present study reports on a single surgeon, consecutive series of 166 consecutive cases in 147 patients who had undergone first MTPJ fusion. The demographic data and comorbidities of the patients were collected from the digital medical records, and the radiographs were evaluated by 2 of us (S.Q., M.A.) independently to document fusion status. Radiologic nonunion was seen in 11 of 166 cases (6.6%). The mean duration of follow up was 60 +/- 29.5 (minimum 26, maximum 183) days. However, only 4 of the 11 cases (36%) of nonunion were clinically symptomatic and underwent revision using a bone graft and locking plate. A statistically significant difference was found in union rates among males and females (p = .01). Other factors, such as diabetes (p = .2), inflammatory arthritis (p = .5), steroids (p = .6), smoking (p = .5), hallux valgus deformity (p = .5), and concomitant forefoot surgery, did not have a statistically significant (p = .3) effect on union in our study. The union rate of first MTPJ fusion with our technique was comparable to that of others, with the advantage of being simple and less expensive compared with the use of a plate. PMID- 29503134 TI - Squamous Cell Carcinoma From Marjolin's Ulcer of the Foot in a Diabetic Patient: Case Study. AB - Squamous cell carcinoma (SCC) has been commonly reported by foot and ankle specialists. Marjolin's ulcer is a malignancy that involves a posttraumatic scar or ulceration that can develop into SCC from chronic neuropathic pedal wounds, venous stasis, or decubitus ulcerations. Most Marjolin's ulcers are found in the lower extremity, specifically the feet, and it is twice as common in females as males. Biopsy of the tumor is the reference standard to diagnose SCC, and wide excision of SCC is the most common treatment option. The present case study describes an 83-year-old diabetic wheelchair-bound female who presented to the wound care clinic with a right heel nonhealing pressure ulceration. After biopsy and surgical excision, the patient was found to have SCC. This case was followed up for 5 years in which the patient had successful excision of the tumor with no recurrence. The clinical significance of our case study is to assist in the diagnosis, management, and prognosis of patients with SCC. In addition, this study has shown that adequate excision of the tumor margins and depth is necessary to prevent potential recurrence and metastasis. PMID- 29503135 TI - A Prospective Cohort Study of Symptomatic Venous Thromboembolic Events in Foot and Ankle Trauma: The Need for Stratification in Thromboprophylaxis? AB - The incidence of venous thromboembolic (VTE) events (deep vein thrombophlebitis [DVT] or pulmonary embolism [PE]) in foot and ankle trauma has been low, and the risk/benefit ratio associated with chemoprophylaxis is controversial. We compared the 90-day incidence of VTE events in 3 cohorts: group 1, tendo-Achillis (TA) ruptures managed with full weightbearing in a walker boot; group 2, ankle fractures immobilized non-weightbearing in a below-the-knee cast; and group 3, ankle fractures managed surgically, followed by non-weightbearing in a below-the knee cast. Data were extracted from 2 prospectively collected trust databases for acute TA ruptures and ankle fractures. VTE risk was assessed using a U.K. national assessment tool. Chemoprophylaxis was prescribed for high-risk patients. The 90-day incidence of symptomatic VTE events was drawn from a trust-wide radiology database. In group 1 (n = 291), the incidence of VTE events was 4.8% (11 [3.8%] DVT, 3 [1.0%] PE) at a mean of 16.1 +/- 6.8 days. In group 2 (n = 227), the incidence of VTE events was 2.2% (5 [2.2%] DVT) at a mean of 33.4 +/- 11.3 days. In group 3 (n = 199), the incidence of VTE events was 3.0% (5 [2.5%] DVT, 1 [0.5%] PE) at a mean of 37.2 +/- 14.2 days. Patients with symptomatic VTE events presented significantly earlier after acute TA rupture compared with after ankle fracture (p = .002). We found the overall incidence of VTE events in foot and ankle trauma was low, with a relatively greater incidence of symptomatic VTE events, which occurred earlier, in acute TA ruptures compared with ankle fractures. PMID- 29503136 TI - Foot and Ankle Osteoid Osteomas. AB - Foot and ankle osteoid osteomas (OOs) are often cancellous or subperiosteal and rarely present with a periosteal reaction. Additionally, the large number of disorders included in the differential diagnosis and the nonspecific findings on radiographs complicate the diagnosis. We performed a manual search of the senior surgeon's hospitals' operating room records for the terms "benign bone tumor," "foot," "ankle," and "osteoid osteoma" from January 2003 until December 2014. Of 87 surgically treated patients with lower extremity OOs, 9 patients (11%) with foot or ankle OOs were included. The mean age at presentation was 21 (range 6 to 30) years; all 9 (11%) patients were male. The patients were evaluated for swelling, pain, trauma history, night pain, response to pain relievers, duration of complaints, and interval to diagnosis. The mean follow-up period was 48 +/- 24 months, and no recurrences had developed. The mean American Orthopaedic Foot and Ankle Society scale score was 59.04 +/- 11 before surgery and 91.56 +/- 6 after surgery. The difference was statistically significant at p <= .0003. Most previous studies have been limited to case reports. The need for findings from a case series was an essential determinant of our decision to report our results. Patients usually have been treated conservatively, often for a long period. However, delays in treatment cause social, economic, and psychological damage. In conclusion, the presence of atypical findings on radiographs has resulted in a preference for magnetic resonance imaging instead of computed tomography; however, the diffuse soft tissue edema observed on MRI can lead to the use of long-term immobilization and a delay in the diagnosis. PMID- 29503137 TI - Sagittal Ankle and Midfoot Range of Motion Before and After Revision Total Ankle Replacement: A Retrospective Comparative Analysis. AB - The most common reason for a revision total ankle replacement procedure is a painful, stiff ankle even after the initial surgery. Limited and conflicting data are available regarding the change in sagittal foot and ankle range of motion after revision total ankle replacement surgery. We sought to determine whether revision total ankle replacements would reduce compensatory midfoot range of motion. In determining this, a novel radiographic measurement system with stable osseous landmarks is used. A retrospective medical record review of patients who had undergone revision total ankle replacement from January 2009 to June 2016 was performed. Thirty-three patients (33 ankles) underwent revision total ankle replacement surgery and met the inclusion criteria with a mean follow-up period of 28.39 +/- 14.68 (range 2 to 59) months. Investigation of preoperative and postoperative weightbearing lateral radiographic images was performed to determine the global foot and ankle, isolated ankle, and isolated midfoot sagittal ranges of motion. Statistical analysis revealed a significant increase in ankle range of motion (p = .046) and a significant decrease in midfoot range of motion (p < .001) from preoperatively to postoperatively. The change in global foot and ankle range of motion was not significant (p = .53). For this patient population, the increased ankle range of motion effectively resulted in less compensatory midfoot range of motion. PMID- 29503138 TI - Quantification of the Learning Curve for Arthroscopic Os Trigonum Excision. AB - The purpose of the present study was to quantify the learning curve for arthroscopic os trigonum excision using the log-linear model. Twenty-three consecutive feet underwent arthroscopic os trigonum excision and release of the flexor hallucis longus. The required time from the beginning of shaving of the soft tissue until completion of os trigonum excision and release of the flexor hallucis longus (van Dijk time) was recorded. Regression analysis was applied to predict the required time on the basis of the cumulative case volume after logarithmic transformation of both statistics. The mean required time was 35.2 (range 9 to 90) minutes. After logarithmic transformation, a significant linear correlation was observed between the required time and the cumulative case volume (p = .0043). The best-fit linear equation was calculated as log (y, estimated required time) = -0.41 log (x, case volume) + 1.86, resulting in an estimated learning rate of 75.3% (= 2-0.41). The results showed an overall time reduction in arthroscopic os trigonum excision in support of a learning curve effect with an ~75% learning rate, indicating that the required time for arthroscopic os trigonum excision can decrease by <=25% when the cumulative volume of cases has doubled. PMID- 29503139 TI - Bilateral Common Peroneal Nerve Entrapment After Excessive Weight Loss: Case Report and Review of the Literature. AB - We report a case of excessive weight loss causing bilateral common peroneal nerve entrapment in a 60-year-old patient. The bilateral peroneal involvement suggested a systemic cause. Excessive weight loss during a relatively short period can cause changes in the tissues surrounding the common peroneal nerve and lead to its entrapment in the peroneal tunnel. Our patient underwent successful surgical decompression with significant improvement. PMID- 29503140 TI - Reduction of Morbidity With a Reverse-Flow Sural Flap: A Two-Stage Technique. AB - The reverse sural flap has often been used for cutaneous coverage of the distal region of the leg and ankle. When the flap is performed in 2 stages, the vascular pedicle is exteriorized and later resected. Our goal was to assess the reverse sural flap performed in 2 stages regarding its viability and low morbidity along the flap-donor area. Eleven patients with cutaneous coverage loss found in the area between the distal third of the leg and ankle underwent cutaneous coverage surgery with a reverse-flow sural flap with an exteriorized pedicle, without violation of the skin between the base of the flap pedicle to the margin of the wound. After a minimum period of 15 days with flap autonomy, the pedicle was resected. The flap dimensions, its viability before and after the pedicle ligature, and the distance from the intact skin between the flap base and the margin of the wound were evaluated. Any losses were measured as a percentage of the total flap size. The respective length and width of the flap were a mean average of 7.45 cm * 4.18 cm. All the flaps survived. Partial loss of the flap occurred in 3 patients, ranging from 20% to 30%. The mean average distance of the intact skin between the pedicle base and the margin of the wound was 5.59 (range 4 to 8) cm. Our results showed that the 2-stage reverse sural flap ensures good flap survival and low morbidity. PMID- 29503141 TI - Null association between androgen-deprivation therapy and nonprostate cancer mortality among older men with nonmetastatic prostate cancer. AB - BACKGROUND: Androgen-deprivation therapy (ADT) has been associated with cardiovascular risk factors and the development of cardiovascular disease in men with metastatic prostate cancer. We sought to examine the effect of ADT on nonprostate cancer mortality among patients with nonmetastatic prostate cancer. METHODS: We performed a population-based, retrospective cohort study of men aged 66 years and older treated with surgery or radiotherapy for nonmetastatic prostate cancer in Ontario, Canada from 2002 to 2009 using administrative datasets (including the Ontario Cancer Registry, Ontario Drug Benefit, and Ontario Health Insurance Plan). Analysis was performed between September 2016 and April 2017. ADT exposure was operationalized as a time-varying binary and cumulative dose exposure. Primary and secondary outcomes were nonprostate cancer mortality and cardiovascular mortality, respectively. The Fine and Gray subdistribution method with generalized estimating equations was used to calculate subdistribution hazard ratios (sdHR), while accounting for competing risks. RESULTS: We examined 20,651 men treated for nonmetastatic prostate cancer. Median follow-up was 7.4 years and median ADT exposure was 6.4 months. ADT was not significantly associated with nonprostate cancer mortality (sdHR = 0.75, 95% CI: 0.37-1.50) or cardiovascular mortality (sdHR = 1.16, 95% CI: 0.37-3.63) when operationalized as a binary time-varying exposure. Similar results were obtained when we examined ADT cumulative dose exposure. CONCLUSIONS: ADT is not associated with nonprostate cancer mortality or cardiovascular mortality in a large, population-based cohort of older men with localized prostate cancer treated by surgery or radiation therapy. PMID- 29503143 TI - The effect of fluoride varnish in preventing enamel demineralization around and under orthodontic bracket. AB - AIM: The aim of this study was to evaluate in vitro the effectiveness of fluoride VanishTM in preventing enamel demineralization around and under orthodontic brackets, using a laser fluorescence monitoring device on a group of teeth, using a laser fluorescence monitoring device on a group of extracted teeth with bonded brackets. METHODS: Orthodontic brackets were bonded to 32 extracted premolars. Buccal surfaces of teeth were divided into two halves: mesial and distal, fluoride VanishTM (3M Unitek, Monrovia, CA, USA) was applied only on the distal half while the mesial one served as control half. Teeth were subjected to two demineralization cycles in standard demineralization solution. Enamel demineralization was measured on both varnished and non-varnished halves at baseline, after first and second demineralization cycles and under the brackets after debonding using laser fluorescence device Diagnodent pen. Data were analyzed using Friedman test followed by Wilcoxon test. Differences were considered statistically significant at P<0.001. RESULTS: Statistically significant differences were observed between the varnished and non-varnished halves after the first and second demineralization cycles at P<0.001. No significant difference was found between baseline readings and under the brackets in both halves. CONCLUSION: Fluoride varnish application is effective in preventing enamel demineralization around orthodontic brackets. Fluoride varnish has insignificant effect on enamel mineral content under orthodontic brackets. PMID- 29503142 TI - Acetyl-CoA synthetase 2 enhances tumorigenesis and is indicative of a poor prognosis for patients with renal cell carcinoma. AB - BACKGROUND: Acetyl-CoA synthetase 2 (ACSS2) is highly expressed in various cancers, whereas ACSS2 expression and function in renal cell carcinoma (RCC) are unknown. METHODS: We investigated ACSS2 expression in 198 human RCC tissues using immunohistochemistry, and analyzed its clinicopathological correlation and prognostic relevance. Overexpression and knockdown of ACSS2 were used to investigate the proliferation, migration and invasion of human RCC 786-O, 769-P, and ACHN cell lines. RESULTS: High-ACSS2 expression was associated with advanced T stage (P = 0.008), advanced tumor-node-metastasis stage (P = 0.015) and high University of California, Los Angeles, Integrated Staging System score category (P = 0.009). Multivariate analysis identified high-ACSS2 expression as a poor prognostic factor for recurrence-free survival (hazard ratio [HR] = 1.83, P = 0.038) and overall survival (HR = 1.60, P = 0.043). Cell-based functional assays showed that ACSS2 knockdown inhibited RCC cell growth, migration, and invasion, whereas overexpression of ACSS2 enhanced these effects. ACSS2 silencing inhibited PI3K/AKT signaling pathway. CONCLUSION: ACSS2 may increase tumor progression and aggressive behavior and be an independent prognostic factor in RCC. PMID- 29503144 TI - ? PMID- 29503145 TI - Statin dose reduction with complementary diet therapy: A pilot study of personalized medicine. AB - OBJECTIVE: Statin intolerance, whether real or perceived, is a growing issue in clinical practice. Our aim was to evaluate the effects of reduced-dose statin therapy complemented with nutraceuticals. METHODS: First phase: Initially, 53 type 2 diabetic statin-treated patients received a supplementation with fish oil (1.7 g EPA + DHA/day), chocolate containing plant sterols (2.2 g/day), and green tea (two sachets/day) for 6 weeks. Second phase: "Good responders" to supplementation were identified after multivariate analysis (n = 10), and recruited for a pilot protocol of statin dose reduction. "Good responders" were then provided with supplementation for 12 weeks: standard statin therapy was kept during the first 6 weeks and reduced by 50% from weeks 6-12. RESULTS: First phase: After 6 weeks of supplementation, plasma LDL-C (-13.7% +/- 3.7, P = .002) and C-reactive protein (-35.5% +/- 5.9, P = .03) were reduced. Analysis of lathosterol and campesterol in plasma suggested that intensity of LDL-C reduction was influenced by cholesterol absorption rate rather than its synthesis. Second phase: no difference was observed for plasma lipids, inflammation, cholesterol efflux capacity, or HDL particles after statin dose reduction when compared to standard therapy. CONCLUSIONS: Although limited by the small sample size, our study demonstrates the potential for a new therapeutic approach combining lower statin dose and specific dietary compounds. Further studies should elucidate "good responders" profile as a tool for personalized medicine. This may be particularly helpful in the many patients with or at risk for CVD who cannot tolerate high dose statin therapy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02732223. PMID- 29503147 TI - The Effect of a Technologist-Centered Electronic Review and Feedback System on Image Quality. PMID- 29503146 TI - Raised Anxiety Levels Among Outpatients Preparing to Undergo a Medical Imaging Procedure: Prevalence and Correlates. AB - PURPOSE: To examine the percentage of patients with raised state anxiety levels before undergoing a medical imaging procedure; their attribution of procedural related anxiety or worry; and sociodemographic, health, and procedural characteristics associated with raised state anxiety levels. MATERIALS AND METHODS: This prospective cross-sectional study was undertaken in the outpatient medical imaging department at a major public hospital in Australia, with institutional board approval. Adult outpatients undergoing a medical imaging procedure (CT, x-ray, MRI, ultrasound, angiography, or fluoroscopy) completed a preprocedural survey. Anxiety was measured by the short-form state scale of the six-item State-Trait Anxiety Inventory (STAI: Y-6). The number and percentage of participants who reported raised anxiety levels (defined as a STAI: Y-6 score >= 33.16) and their attribution of procedural-related anxiety or worry were calculated. Characteristics associated with raised anxiety were examined using multiple logistic regression analysis. RESULTS: Of the 548 (86%) patients who consented to participate, 488 (77%) completed all STAI: Y-6 items. Half of the participants (n = 240; 49%) experienced raised anxiety, and of these, 48% (n = 114) reported feeling most anxious or worried about the possible results. Female gender, imaging modality, medical condition, first time having the procedure, and lower patient-perceived health status were statistically significantly associated with raised anxiety levels. CONCLUSION: Raised anxiety is common before medical imaging procedures and is mostly attributed to the possible results. Providing increased psychological preparation, particularly to patients with circulatory conditions or neoplasms or those that do not know their medical condition, may help reduce preprocedural anxiety among these subgroups. PMID- 29503148 TI - A Retrospective Comparison of Creatinine Changes Among Patients Receiving, Not Receiving, and Not Yet Receiving Contrast Administration. AB - OBJECTIVE: We sought to compare variability in serum creatinine among inpatients in our institution receiving contrast imaging studies and among inpatients not receiving such studies. MATERIALS AND METHODS: This retrospective, single-site, multiple-cohort study in a 550-bed academic medical center in October 2016 used the electronic medical record data to analyze the greatest absolute and relative changes in serum creatinine over periods no longer than 48 hours (1) during the admission for 1,134 patients who did not receive a contrast imaging study, (2) before the earliest contrast study for 155 patients who had not yet had a scheduled contrast examination, and (3) straddling the time when 266 patients received their earliest contrast study. We compared creatinine changes in the first cohort with those in the second and the third using histograms and t tests. RESULTS: Among those who did not receive contrast, 18.3% had a creatinine increase of greater than 0.3 mg/dL, and before contrast, 14.2% had such increases (P = .22). After contrast, 6.4% had increases at least this great (P < .001). Patients with increases in creatinine before contrast tended to have such increases after as well (Pearson's 0.48, P < .001). CONCLUSIONS: Physiological variability may explain the similar increases among patients who did not receive contrast versus patients who had not yet received contrast. Hydration therapy may explain the milder and fewer increases after contrast. Only a randomized clinical trial can determine whether acute kidney injuries are caused by contrast; these results support equipoise for such a trial. PMID- 29503149 TI - Recent Changes in Student Loans: What Early-Career Radiologists Need to Know. PMID- 29503150 TI - Improved Quality of Thyroid Ultrasound Reports After Implementation of the ACR Thyroid Imaging Reporting and Data System Nodule Lexicon and Risk Stratification System. AB - PURPOSE: The aim of this study was to compare the description and management recommendations for thyroid nodules before and after implementing a structured reporting template based on the ACR Thyroid Imaging Reporting and Data System (TI RADS). METHODS: Thyroid ultrasound reports for seven private practice radiologists were analyzed in three phases. In phase 1, radiologists dictated in a free-text format. In phase 2, they used a structured reporting template based on the ACR TI-RADS lexicon, but without the ACR TI-RADS recommendations for nodule management. In phase 3, ACR TI-RADS management recommendations were added. The most suspicious thyroid nodule in each report was analyzed for size, features, and management recommendations in all three phases. RESULTS: Seventy one thyroid ultrasound reports were reviewed for each phase, for a total of 213 reports. In phase 1, reports did not describe the features of the majority of nodules. In particular, shape and margin were not reported for 100% and 92% of nodules, respectively. Ninety-six percent to 100% of nodules had descriptions of all five features in phases 2 and 3. The number of nodules without management recommendations was 34% in phase 1 and 31% in phase 2. It decreased to 6% in phase 3 (P < .0005). CONCLUSIONS: Implementing an ACR TI-RADS structured reporting template improved the quality of thyroid ultrasound reports in two key ways. A structured reporting template led to better description of features that are predictive of malignancy. The use of ACR TI-RADS management guidelines substantially improved the number of reports with definitive management recommendations. PMID- 29503151 TI - Management-Based Structured Reporting of Posttreatment Glioma Response With the Brain Tumor Reporting and Data System. PMID- 29503153 TI - Correction in article "Comments on the 2017 ESC Guidelines for the Management of Acute Myocardial Infarction in Patients Presenting With ST-segment Elevation", Rev Esp Cardiol. 2017;70:1039-1045. PMID- 29503152 TI - Impact of Delayed Time to Advanced Imaging on Missed Appointments Across Different Demographic and Socioeconomic Factors. AB - PURPOSE: The aim of this study was to investigate the impact of wait days (WDs) on missed outpatient MRI appointments across different demographic and socioeconomic factors. METHODS: An institutional review board-approved retrospective study was conducted among adult patients scheduled for outpatient MRI during a 12-month period. Scheduling data and demographic information were obtained. Imaging missed appointments were defined as missed scheduled imaging encounters. WDs were defined as the number of days from study order to appointment. Multivariate logistic regression was applied to assess the contribution of race and socioeconomic factors to missed appointments. Linear regression was performed to assess the relationship between missed appointment rates and WDs stratified by race, income, and patient insurance groups with analysis of covariance statistics. RESULTS: A total of 42,727 patients met the inclusion criteria. Mean WDs were 7.95 days. Multivariate regression showed increased odds ratio for missed appointments for patients with increased WDs (7 21 days: odds ratio [OR], 1.39; >21 days: OR, 1.77), African American patients (OR, 1.71), Hispanic patients (OR, 1.30), patients with noncommercial insurance (OR, 2.00-2.55), and those with imaging performed at the main hospital campus (OR, 1.51). Missed appointment rate linearly increased with WDs, with analysis of covariance revealing underrepresented minorities and Medicaid insurance as significant effect modifiers. CONCLUSIONS: Increased WDs for advanced imaging significantly increases the likelihood of missed appointments. This effect is most pronounced among underrepresented minorities and patients with lower socioeconomic status. Efforts to reduce WDs may improve equity in access to and utilization of advanced diagnostic imaging for all patients. PMID- 29503154 TI - Deep brain stimulation of the pedunculopontine nucleus for treatment of gait and balance disorder in progressive supranuclear palsy: Effects of frequency modulations and clinical outcome. AB - BACKGROUND: The pedunculopontine nucleus has been suggested as a potential deep brain stimulation target for axial symptoms such as gait and balance impairment in idiopathic Parkinson's disease as well as atypical Parkinsonian disorders. METHODS: Seven consecutive patients with progressive supranuclear palsy received bilateral pedunculopontine nucleus deep brain stimulation. Inclusion criteria comprised of the clinical diagnosis of progressive supranuclear palsy, a levodopa resistant gait and balance disorder, age <75 years, and absence of dementia or major psychiatric co-morbidities. Effects of stimulation frequencies at 8, 20, 60 and 130 Hz on motor scores and gait were assessed. Motor scores were followed up for two years postoperatively. Activities of daily living, frequency of falls, health-related quality of life, cognition and mood at 12 months were compared to baseline parameters. Surgical and stimulation related adverse events were assessed. RESULTS: Bilateral pedunculopontine nucleus deep brain stimulation at 8 Hz significantly improved axial motor symptoms and cyclic gait parameters, while high frequency stimulation did not ameliorate gait and balance but improved hypokinesia. This improvement however did not translate into clinically relevant benefits. Frequency of falls was not reduced. Activities of daily living, quality of life and frontal cognitive functions declined, while mood remained unchanged. CONCLUSION: Bilateral pedunculopontine nucleus deep brain stimulation in progressive supranuclear palsy generates frequency-dependent effects with improvement of cyclic gait parameters at low frequency and amelioration of hypokinesia at high frequency stimulation. However, these effects do not translate into a clinically important improvement. PMID- 29503155 TI - Phenotypic heterogeneity in seven Italian cases of aceruloplasminemia. AB - INTRODUCTION: Aceruloplasminemia is an ultra-rare hereditary disorder characterized by iron-restricted microcytic anemia and tissue iron overload associated with diabetes, retinal and progressive neurological degeneration. We describe genotypes and phenotypes at diagnosis, and disease evolution of seven Italian patients. METHODS: Anagraphical, biochemical, genetic, clinical and instrumental data were collected at diagnosis and during a long-term follow-up. Mutations, ferroxidase activity and Western Blot analysis of ceruloplasmin were performed according to standard protocols. RESULTS: Three mutations were already described (p.Phe217Ser, deletions of exon 11 and 12), p.Ile991Thr is a very rare variant, p.Cys338Ser and IVS6+1G > A were novel mutations. In silico analyses suggested they were highly likely or likely to be damaging. At diagnosis, 100% had microcytosis, 86% had mild-moderate anemia, low serum iron and high serum ferritin. Four (57%) had type 1 diabetes or glucose intolerance, 3/7 had neurological manifestations, and only one had early diabetic retinopathy. All but one underwent iron chelation therapy requiring temporary discontinuation because of anemia worsening. At the end of follow-up, three patients aggravated and 2 developed neurological symptoms; only two patients were free of neurological manifestations and showed mild or absent brain iron. CONCLUSION: Aceruloplasminemia phenotypes ranged from classical characterized by progressive neurologic derangement to milder in which signs of systemic iron overload prevailed over brain iron accumulation. Within this large heterogeneity, microcytosis with or without anemia, low serum iron and high serum ferritin were the early hallmarks of the disease. Therapeutic approaches other than iron chelation should be explored to reduce morbidity and improve life expectancy. PMID- 29503156 TI - Pallidal dopaminergic denervation and rest tremor in early Parkinson's disease: PPMI cohort analysis. AB - BACKGROUND: s: Over recent years there have been some conflicting reports upon the role of pallidal dopaminergic denervation in rest tremor in Parkinson's disease. OBJECTIVES: To clarify this issue we analyzed the clinical and 123I-FP CIT SPECT data of a large cohort of early Parkinson's disease patients enrolled in the PPMI study. METHODS: Pallidal and striatal dopamine transporter uptake ratios were calculated in 382 patients (120 no-tremor, 60 tremor-dominant, and 202 indeterminate) and 150 controls. A region of interest (ROI) approach was used to estimate DAT uptake ratios from 123I-FP-CIT SPECT scans in the caudate nucleus, putamen, and globus pallidus after normalization to a DAT template. DAT uptake ratios for each region were compared between subgroups using ANCOVA and linear regression analyses were performed to evaluate the relationship between severity of rest tremor and regional DAT uptake ratios. RESULTS: PD patients had significantly lower DAT uptake ratios in the pallidum, putamen and caudate as compared to healthy controls (p < 0.001). ANCOVA showed inter-PD subgroup differences in DAT uptake ratios in the putamen and pallidum (p < 0.05) after adjustment for age and disease duration, with post-hoc comparisons revealing significantly higher DAT uptake ratios for the tremor-dominant subgroup as compared to non-tremor and indeterminate subgroups (p < 0.016). There was no significant relationship between rest tremor severity and pallidal DAT either in the tremor-dominant subgroup or in the total PD population. CONCLUSIONS: Pallidal dopaminergic denervation appears unrelated to rest tremor severity in early Parkinson's disease. PMID- 29503157 TI - Chaperone-Independent Peripheral Quality Control of CFTR by RFFL E3 Ligase. AB - The peripheral protein quality control (QC) system removes non-native membrane proteins, including DeltaF508-CFTR, the most common CFTR mutant in cystic fibrosis (CF), from the plasma membrane (PM) for lysosomal degradation by ubiquitination. It remains unclear how unfolded membrane proteins are recognized and targeted for ubiquitination and how they are removed from the apical PM. Using comprehensive siRNA screens, we identified RFFL, an E3 ubiquitin (Ub) ligase that directly and selectively recognizes unfolded DeltaF508-CFTR through its disordered regions. RFFL retrieves the unfolded CFTR from the PM for lysosomal degradation by chaperone-independent K63-linked poly-ubiquitination. RFFL ablation enhanced the functional expression of cell-surface DeltaF508-CFTR in the presence of folding corrector molecules, and this effect was further improved by inhibiting the Hsc70-dependent ubiquitination machinery. We propose that multiple peripheral QC mechanisms evolved to dispose of non-native PM proteins and to preserve cellular proteostasis, even at the cost of eliminating partially functional polypeptides. PMID- 29503158 TI - Enteroid Monolayers Reveal an Autonomous WNT and BMP Circuit Controlling Intestinal Epithelial Growth and Organization. AB - The intestinal epithelium maintains a remarkable balance between proliferation and differentiation despite rapid cellular turnover. A central challenge is to elucidate mechanisms required for robust control of tissue renewal. Opposing WNT and BMP signaling is essential in establishing epithelial homeostasis. However, it has been difficult to disentangle contributions from multiple sources of morphogen signals in the tissue. Here, to dissect epithelial-autonomous morphogenic signaling circuits, we developed an enteroid monolayer culture system that recapitulates four key properties of the intestinal epithelium, namely the ability to maintain proliferative and differentiated zones, self-renew, polarize, and generate major intestinal cell types. We systematically perturb intrinsic and extrinsic sources of WNT and BMP signals to reveal a core morphogenic circuit that controls proliferation, tissue organization, and cell fate. Our work demonstrates the ability of intestinal epithelium, even in the absence of 3D tissue architecture, to control its own growth and organization through morphogen mediated feedback. PMID- 29503160 TI - [What is the goal blood pressure in non-diabetic chronic kidney disease?] AB - High blood pressure during renal disease is highly prevalent and an important risk factor for cardiovascular disease and renal progression. Its optimal management is therefore necessary to improve the prognosis of patients. Several trials concerning the blood pressure target in patients with chronic non-diabetic kidney disease have been published in recent years, we will detail them in this article in order to determine which blood pressure target provides the best benefit in terms of progression of renal diseases and cardiovascular prevention. PMID- 29503159 TI - Importin-beta Directly Regulates the Motor Activity and Turnover of a Kinesin-4. AB - Spatiotemporal regulation of kinesins is essential for microtubule-dependent intracellular transport. In plants, cell wall deposition depends on the FRA1 kinesin, whose abundance and motility are tightly controlled to match cellular growth rate. Here, we show that an importin-beta, IMB4, regulates FRA1 activity in a developmental manner. IMB4 physically interacts with a PY motif in the FRA1 motor domain and inhibits its motility by preventing microtubule binding, while also protecting FRA1 against proteasome-mediated degradation, thus providing a mechanism to couple the motility and stability of FRA1. This regulatory mechanism is likely to be broadly applicable, based on the conservation of the PY motif in the motor domains of plant and animal kinesins and the direct interaction of multiple plant kinesins with IMB4. Together, our data establish IMB4 as a multi functional regulator of FRA1 and reveal a mechanism for how plants control the magnitude of cargo transport needed for cell wall assembly. PMID- 29503161 TI - Interrater reliability of the injury reporting of the injury surveillance system used in international athletics championships. AB - OBJECTIVES: The quality of epidemiological injury data depends on the reliability of reporting to an injury surveillance system. Ascertaining whether all physicians/physiotherapists report the same information for the same injury case is of major interest to determine data validity. The aim of this study was therefore to analyse the data collection reliability through the analysis of the interrater reliability. DESIGN: Cross-sectional survey. METHODS: During the 2016 European Athletics Advanced Athletics Medicine Course in Amsterdam, all national medical teams were asked to complete seven virtual case reports on a standardised injury report form using the same definitions and classifications of injuries as the international athletics championships injury surveillance protocol. The completeness of data and the Fleiss' kappa coefficients for the inter-rater reliability were calculated for: sex, age, event, circumstance, location, type, assumed cause and estimated time-loss. RESULTS: Forty-one team physicians and physiotherapists of national medical teams participated in the study (response rate 89.1%). Data completeness was 96.9%. The Fleiss' kappa coefficients were: almost perfect for sex (k=1), injury location (k=0.991), event (k=0.953), circumstance (k=0.942), and age (k=0.870), moderate for type (k=0.507), fair for assumed cause (k=0.394), and poor for estimated time-loss (k=0.155). CONCLUSIONS: The injury surveillance system used during international athletics championships provided reliable data for "sex", "location", "event", "circumstance", and "age". More caution should be taken for "assumed cause" and "type", and even more for "estimated time-loss". This injury surveillance system displays satisfactory data quality (reliable data and high data completeness), and thus, can be recommended as tool to collect epidemiology information on injuries during international athletics championships. PMID- 29503162 TI - The genetics of antipsychotic response in schizophrenia. PMID- 29503164 TI - Wound irrigation and the lack of evidence-based practice. PMID- 29503163 TI - Five novel loci associated with antipsychotic treatment response in patients with schizophrenia: a genome-wide association study. AB - BACKGROUND: Antipsychotic drugs improve schizophrenia symptoms and reduce the frequency of relapse, but treatment response is highly variable. Little is known about the genetic factors associated with treatment response. We did a genome wide association study of antipsychotic treatment response in patients with schizophrenia. METHODS: The discovery cohort comprised patients with schizophrenia from 32 psychiatric hospitals in China that are part of the Chinese Antipsychotics Pharmacogenomics Consortium. Patients who met inclusion criteria were randomly assigned (1:1:1:1:1:1) to six groups (olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone, and haloperidol or perphenazine; those assigned to haloperidol or perphenazine were subsequently assigned [1:1] to one or the other) for 6 weeks. Antipsychotic response was quantified with percentage change on the Positive and Negative Syndrome Scale. Single-nucleotide polymorphisms (SNPs) were tested for their association with treatment response. Linkage-disequilibrium-independent SNPs that exhibited potential associations (ie, p<1 * 10-5) were tested in a validation cohort comprising patients from the Chinese Antipsychotics Pharmacogenetics Consortium from five collaborative hospitals, who were treated with olanzapine, risperidone, or aripiprazole for 8 weeks. FINDINGS: The discovery cohort contained 2413 patients and the validation cohort 1379 patients. In the discovery cohort, we identified three novel SNPs (rs72790443 in MEGF10 [p=1.37 * 10-8], rs1471786 in SLC1A1 [p=1.77 * 10-8], and rs9291547 in PCDH7 [p=4.48 * 10-8]) that were associated with antipsychotic treatment response at a genome-wide significance level. These associations were confirmed in the validation cohort (p<0.05). In the combined sample of the discovery and validation cohorts, we identified five novel loci showing genome wide significant associations with general antipsychotic treatment response (rs72790443 in MEGF10 [p=1.40 * 10-9], rs1471786 in SLC1A1 [p=2.33 * 10-9], rs9291547 in PCDH7 [p=3.24 * 10-9], rs12711680 in CNTNAP5 [p=2.12 * 10-8], and rs6444970 in TNIK [p=4.85 * 10-8]). In antipsychotic-specific groups, after the combination of results from both samples, the rs2239063 SNP in CACNA1C was associated with treatment response to olanzapine (p=1.10 * 10-8), rs16921385 in SLC1A1 was associated with treatment response to risperidone (p=4.40 * 10-8), and rs17022006 in CNTN4 was associated with treatment response to aripiprazole (p=2.58 * 10-8). INTERPRETATION: We have identified genes related to synaptic function, neurotransmitter receptors, and schizophrenia risk that are associated with response to antipsychotics. These findings improve understanding of the mechanisms underlying treatment responses, and the identified biomarkers could eventually guide choice of antipsychotic in patients with schizophrenia. FUNDING: National Key Technology R&D Program of China, National Natural Science Foundation of China. PMID- 29503165 TI - Factors predicting health-related quality of life following necrotizing fasciitis. AB - BACKGROUND: Necrotizing fasciitis (NF) is a debilitating soft tissue infection that results in disfiguring scars and often amputations. While mortality rates have improved, long-term outcomes in survivors of NF are poorly understood. OBJECTIVES: The objective of this study is to analyze the impact of NF on survivors' health-related quality of life (HRQoL) influenced by age, sex, comorbidities, %TBSA, and confidence with appearance. METHODS: We surveyed 56 adult patients with NF treated at either of two regional referral centers in Manitoba, Canada, between January 1, 2004, and December 31, 2014. Necrotizing soft tissue infections involving the fascial planes were identified during surgical debridement. HRQoL was measured by the Medical Outcomes Short Form-36. Derriford Appearance Scale-24, age, sex, comorbidities, and %TBSA were recorded, and group comparisons and stepwise regression models were developed for the mental and physical component scores separately. RESULTS: Mean Mental Component Score (MCS) was 44.5 +/- 14.3 and mean Physical Component Score (PCS) was 36.5 +/ 11.5; both means were lower than the Canadian population norm of 50. Although stepwise linear regression analyses with block entry indicated influence from age, sex, and comorbid conditions for the MCS and PCS, the only factors that were statistically significant in the final models were confidence with appearance for the MCS and %TBSA for the PCS. CONCLUSIONS: NF has long-term impact on mental and physical health-related quality of life. Distress regarding confidence with appearance affects mental quality of life, whereas the size of the injured area impacted physical quality of life. These findings can help guide targeted interventions that could potentially improve recovery from NF. PMID- 29503166 TI - A retrospective study of closed extension block pinning for mallet fractures: Analysis of predictors of postoperative range of motion. AB - BACKGROUND: Extension block pinning is a simple and reliable technique for mallet fractures, but poor results are sometimes obtained. The predictors of postoperative range of motion after extension block pinning of mallet fingers were investigated. METHODS: The outcomes for postoperative active motion of the distal interphalangeal (DIP) joint, such as flexion angle, extension loss, and total range of motion, were examined. Predictors such as age, gender, finger, fragment size, joint subluxation, the time from injury to operation, procedure, fixation angle, the time from operation to wire removal, and joint step-off were evaluated statistically. RESULTS: With a mean 12.2-month follow-up, according to Crawford's criteria, 49 of 116 fingers (42%) had an excellent result, 37 (32%) had a good result, 29 (25%) had a fair result, and 1 (1%) had a poor result. The mean flexion angle was 62.9 +/- 13.2 degrees , extension loss was -6.6 +/- 7.3 degrees , and total range of motion was 55.8 +/- 17.0 degrees in the DIP joint. Pin tract infections were confirmed in 7 fingers with poor results. There were no complaints about nail deformity or skin abnormality. On multivariate analysis, significant predictors of poor postoperative motion were increased age chronic case, remained joint step-off, excess flexed fixation angle, and long-term wire placement. CONCLUSIONS: Extremely flexed fixation and chronic case easily causes extension loss in the DIP joint. In closed extension block pinning, joint fixation with an extreme flexion angle should be avoided and the pinning wire should be removed as soon as possible after confirming bony union. PMID- 29503167 TI - Qualitative Analysis of Mini Mental State Examination Pentagon in Vascular Dementia and Alzheimer's Disease: A Longitudinal Explorative Study. AB - BACKGROUND: Vascular dementia and Alzheimer's disease are the most diffuse forms of dementia. Sometimes, they are difficult to distinguish due to overlaps in symptomatology, pathophysiology, and comorbidity. Visual constructive apraxia is very common in dementia and impairment in these abilities can provide clinical information for differential diagnosis. MATERIALS AND METHODS: All patients underwent Mini Mental State Examination (MMSE) at basal visit (T0) and after 1 year (T1). We analyzed differences in Qualitative Scoring Method for the Pentagon Copying Test and we explored the visual constructive apraxia evolution in these 2 types of dementia. RESULTS: In intragroup analysis, we found a significant difference in each group between T0 and T1 in MMSE score (P < .001) and total qualitative scores (P < .001). In intergroup analysis, at T0, we found significance difference in total qualitative scores (P < .001), in numbers of angles (P = .005), in distance/intersection (P < .001), in closure/opening (P = .01), in rotation (P < .001), and in closing-in (P < .001). At T1, we found significance difference in total qualitative scores (P < .001), in particular, in numbers of angles (P < .001), in distance/intersection (P < .001), in closure/opening (P < .001), in rotation (P < .001), and in closing-in (P < .001). The total score showed the highest classification accuracy (.90, 95%CI = .81 0.96) in differentiating patients with Alzheimer's disease from patients with vascular dementia. The optimal threshold value was k = 5. with .84 (95%CI = .69 0.93) sensitivity and .81 (95%CI = .64-0.93) specificity. CONCLUSION: Patients with vascular dementia showed more accuracy errors and graphic difficulties than patients with Alzheimer's disease. Qualitative analysis of copy provided a sensitive measure of visual constructive abilities in differentiating dementias, underlining a particularly vulnerability of visuoconstructive functions in vascular dementia compared with Alzheimer's disease. PMID- 29503168 TI - Multiple Thrombi in the Heart in Trousseau Syndrome Caused by Pancreatic Carcinoma. AB - A 65-year-old woman presented to our emergency room because of sudden onset of right hemiparesis with severe fatigue. Neurological examination revealed right hemiparesis with right facial numbness and an extensor planter response on the right side.Magnetic resonance imaging with diffusion-weighted imaging revealed multiple highintensity areas in both cerebral hemispheres and the right cerebellum. A diagnosis of acute stage of multiple brain infarctions caused by emboli was made. An abdominal computed tomography showed a pancreatic tumor with multiple liver metastases. High D-dimer and serum carbohydrate antigen 19-9 concentration strongly suggested Trousseau syndrome associated with pancreatic cancer. The patient had another large embolic stroke and died on day 47. Autopsy was performed. There were large thrombi in the left ventricular apex and in the left atrial appendage There was also a papillary-shaped vegetation on the aortic valve that consisted mainly of fibrin without any inflammatory cells or destruction of the valve, these findings being characteristic of NBTE. This case is remarkable in that the patient had 3 different types of cardiac thrombi in her heart associated with Trousseau syndrome. PMID- 29503169 TI - Assessment of the Efficiency of Stroke Awareness Campaigns in Hungary. AB - BACKGROUND: The critical period of stroke management lies between the disease onset and the time of the emergency call, relying on stroke-related knowledge of the population. Public campaigns play a role in spreading relevant health information. Due to the substantial expenses of these campaigns, the assessment of their efficiency is reasonable. METHODS: We assessed the number of thrombolytic treatments performed in Hungary, subjected to national media coverage and in particular in Budapest, being the location of the Stroke Day campaign, in the period between 2008 and 2015. We compared the change in the daily mean number of thrombolytic treatments performed during the preceding and following day, week, and month. Data were also compared with annual means. RESULTS: No meaningful changes can be seen in the number of thrombolytic treatments on the days immediately following Stroke Days, and casual differences can be seen in the following week. The comparison of the numbers of thrombolytic treatments performed in the postcampaign months with the monthly means in the corresponding years revealed a positive effect in each year except for 2012, 2014, and 2015. Regarding the whole examined period, however, the effect is not statistically significant, neither for data obtained from Hungary nor from Budapest. CONCLUSIONS: Better outcomes were observed 1 month after a campaign than more immediately. This can be partly explained by ongoing media coverage in a given period rather than exposure of the public on a single Stroke Day. PMID- 29503170 TI - Optimal oncologic treatment of rectal cancer in patients over 75 years old: Results of a strategy based on oncogeriatric evaluation. AB - BACKGROUND: Few data are available on the management of elderly rectal cancer patients, and especially on the ability to provide optimal oncological treatment. The aim of this study was to determine the feasibility and results of multimodality treatment for rectal cancer in patients 75years and older after simplified comprehensive geriatric assessment (CGA) according to Balducci score. METHODS: We reviewed the charts of elderly patients who underwent surgery for localized middle or low rectal cancer. Patients were classified into three CGA groups depending on their functional reserve, comorbidities, geriatric syndromes, and life expectancy. RESULTS: Neoadjuvant therapy was discussed for 27 patients (47%), but only 56% of them were treated, including 8, 7, and 1 patient from CGA groups 1, 2, and 3, respectively. Fifty-three patients (93%) underwent sphincter preserving surgical resection and four patients underwent abdominoperineal resection (7%). Postoperative complications were observed in 21 patients (37%). The postoperative complication rate was correlated non-significantly with age (<85years: 40.6%; >=85years: 57.1%; P=0.3), and with the CGA (P=0.64). In total, 10 patients (18%) had definitive colostomy, including five anastomotic leakages (9%), and one incontinence (2%). The total rate of sphincter preservation was 82% (n=47). The risk of secondary definitive colonic stoma formation was not correlated with CGA (group 1: 14%; group 2/3: 16%; P=0.8). Estimated OS at five years was 52%. CONCLUSIONS: After routine geriatric assessment, elderly rectal cancer patients have good rates of sphincter conservation and acceptable morbidity/mortality. PMID- 29503171 TI - The many faces of diabetes: addressing heterogeneity of a complex disease. PMID- 29503172 TI - Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables. AB - BACKGROUND: Diabetes is presently classified into two main forms, type 1 and type 2 diabetes, but type 2 diabetes in particular is highly heterogeneous. A refined classification could provide a powerful tool to individualise treatment regimens and identify individuals with increased risk of complications at diagnosis. METHODS: We did data-driven cluster analysis (k-means and hierarchical clustering) in patients with newly diagnosed diabetes (n=8980) from the Swedish All New Diabetics in Scania cohort. Clusters were based on six variables (glutamate decarboxylase antibodies, age at diagnosis, BMI, HbA1c, and homoeostatic model assessment 2 estimates of beta-cell function and insulin resistance), and were related to prospective data from patient records on development of complications and prescription of medication. Replication was done in three independent cohorts: the Scania Diabetes Registry (n=1466), All New Diabetics in Uppsala (n=844), and Diabetes Registry Vaasa (n=3485). Cox regression and logistic regression were used to compare time to medication, time to reaching the treatment goal, and risk of diabetic complications and genetic associations. FINDINGS: We identified five replicable clusters of patients with diabetes, which had significantly different patient characteristics and risk of diabetic complications. In particular, individuals in cluster 3 (most resistant to insulin) had significantly higher risk of diabetic kidney disease than individuals in clusters 4 and 5, but had been prescribed similar diabetes treatment. Cluster 2 (insulin deficient) had the highest risk of retinopathy. In support of the clustering, genetic associations in the clusters differed from those seen in traditional type 2 diabetes. INTERPRETATION: We stratified patients into five subgroups with differing disease progression and risk of diabetic complications. This new substratification might eventually help to tailor and target early treatment to patients who would benefit most, thereby representing a first step towards precision medicine in diabetes. FUNDING: Swedish Research Council, European Research Council, Vinnova, Academy of Finland, Novo Nordisk Foundation, Scania University Hospital, Sigrid Juselius Foundation, Innovative Medicines Initiative 2 Joint Undertaking, Vasa Hospital district, Jakobstadsnejden Heart Foundation, Folkhalsan Research Foundation, Ollqvist Foundation, and Swedish Foundation for Strategic Research. PMID- 29503173 TI - Shear Wave Speed of the Lesion in Preoperative Breast Ultrasonography: Association with Disease-free Survival of Patients with Primary Operable Invasive Breast Cancer. AB - RATIONALE AND OBJECTIVES: We aimed to investigate the relationship between shear wave speed (SWS) of the lesion on preoperative breast ultrasonography (US) and disease-free survival of patients with primary operable invasive breast cancer. MATERIALS AND METHODS: This retrospective study was approved by our Institutional Review Board. The requirement for informed consent was waived. A total of 195 consecutive newly diagnosed invasive breast cancer patients (age 33-83 years; mean 54.0 years) with preoperative breast US with SWS measurement of the lesion were identified. They underwent surgery between May 2012 and May 2013. SWS was measured at the center and three marginal zones in the main tumors, and the maximum value was used for analyses. For 35 patients who underwent primary systemic therapy (PST), the maximum SWS before PST was used. Cox proportional hazards modeling was used to identify the relationship between clinical pathologic factors and disease-free survival. RESULTS: Fourteen recurrences occurred at 6-47 months (mean 22.3 months) after surgery. On multivariate analysis, a positive history of PST (hazard ratio [HR] = 4.93; 95% confidence interval [CI]: 1.66, 14.70; P = .004), adjuvant chemotherapy (HR = 3.67; 95% CI: 1.11, 12.1; P = .033), and higher maximum SWS (HR = 1.55; 95% CI: 1.07, 2.23; P = .020) were associated with poorer disease-free survival. CONCLUSION: Higher maximum SWS on preoperative US, in addition to a positive history of PST and adjuvant chemotherapy, was significantly associated with poorer disease-free survival of patients with invasive breast cancer. PMID- 29503174 TI - Posterior Inferior Cerebellar Artery Aneurysm: Have You Ever Been Misdiagnosed? AB - RATIONALE AND OBJECTIVES: The posterior inferior cerebellar artery aneurysm (PICAA), especially distal PICAA, is easily missed by a doctor, leading to misdiagnosis and treatment delays. The objective of this article is to report the computed tomography angiography (CTA) presentations of 30 cases of PICAA proved by digital subtraction angiography (DSA) or surgical operation, and analyze the causes of misdiagnosis of PICAA by CTA. MATERIALS AND METHODS: Thirty cases of patients with PICAA that were proved by DSA or surgical operation were included in this study, all of whom underwent CTA before surgical procedure. The relationship between the locations of PICAA and the rates of missed diagnosis by CTA was analyzed. The detection rates of the PICAA by volume rendering (VR) images and original thin axial images of CTA were compared. RESULTS: Twelve cases (12 of 30, 40%) of aneurysm lied on the proximal end of posterior inferior cerebellar artery (PICA) (border with vertebral artery) and all of them (12 of 12,100%) were clearly displayed on the VR images of CTA and correctly diagnosed by doctors. Eighteen cases (18 of 30, 60%) of aneurysm lied on the distal part of the PICA, whereas only 2 of them (2/18, 11.1%) were displayed on the VR images and correctly diagnosed before surgical procedure. After surgical operation, the respective review of the CTA images demonstrated that all aneurysms (30 of 30, 100%) can be found on the thin axial images after careful observation and are shown on VR images after adjusting the display threshold when the locations of the PICAA through thin axial images were known, including the distal PICAA. CONCLUSIONS: Thin axial CT images are most important and reliable for the detection of distal PICAA. Overdependence on three-dimensional VR images of CTA is the main cause of misdiagnosis. PMID- 29503175 TI - CT-based Radiomics Signature to Discriminate High-grade From Low-grade Colorectal Adenocarcinoma. AB - RATIONALE AND OBJECTIVES: To develop and validate a computed tomography-based radiomics signature for preoperatively discriminating high-grade from low-grade colorectal adenocarcinoma (CRAC). MATERIALS AND METHODS: This retrospective study was approved by our institutional review board, and the informed consent requirement was waived. This study enrolled 366 patients with CRAC (training dataset: n = 222, validation dataset: n = 144) from January 2008 to August 2015. A radiomics signature was developed with the least absolute shrinkage and selection operator method in training dataset. Mann-Whitney U test was applied to explore the correlation between radiomics signature and histologic grade. The discriminative power of radiomics signature was investigated with the receiver operating characteristics curve. An independent validation dataset was used to confirm the predictive performance. We further performed a stratified analysis to validate the predictive performance of radiomics signature in colon adenocarcinoma and rectal adenocarcinoma. RESULTS: The radiomics signature demonstrated discriminative performance for high-grade and low-grade CRAC, with an area under the curve of 0.812 (95% confidence interval [CI]: 0.749-0.874) in training dataset and 0.735 (95%CI: 0.644-0.826) in validation dataset. Stratified analysis demonstrated that radiomics signature also showed distinguishing ability for histologic grade in both colon adenocarcinoma and rectal adenocarcinoma, with area under the curve of 0.725 (95%CI: 0.653-0.797) and 0.895 (95%CI: 0.838 0.952), respectively. CONCLUSIONS: We developed and validated a radiomics signature as a complementary tool to differentiate high-grade from low-grade CRAC preoperatively, which may make contribution to personalized treatment. PMID- 29503176 TI - Prevalence and Reporting Rates of Incidental Dental Disease on Head CT Examinations. AB - RATIONALE AND OBJECTIVES: Routine head computed tomography (CT) examinations often inadvertently include dental pathology which is often overlooked. The purpose of this study is to examine the prevalence of dental disease incidentally present and detected on head CT examinations, and to determine the effect of the institution of a dental disease field or macro in a standardized head CT dictation template on the rate of reporting dental disease. MATERIALS AND METHODS: Head CT examinations were retrospectively and randomly selected from all examinations performed 6 months before, and 6 months after the institution of a dental disease field in a standardized head CT template. Dental findings were recorded from the initial finalized report. Examination images were subsequently reviewed for the presence of dental disease by two neuroradiologists who were blinded to the original reports and to each other's findings. RESULTS: One hundred examinations were reviewed in the analysis. At our institution, 33% of the randomly selected head CT examinations included the level of the teeth (100/307). Dental disease was determined to be present in 40%-41% of these cases. Only 11% of the initial reports mentioned dental disease (P < .01). Addition of a dental disease field in the dictation template resulted in no significant difference in reporting dental disease (14% vs 8%, P = .371). CONCLUSIONS: Incidental dental disease is common and frequently underreported. Inclusion of a dental disease field in a standardized template does not significantly improve the rate of reporting dental disease. PMID- 29503177 TI - Native RNA-Sequencing Throws its Hat into the Transcriptomics Ring. AB - De novo sequence-level surveys of transcriptomes have previously relied on sequencing via a DNA intermediate. While such methods can yield massive data sets, various problems mean that these do not always accurately reflect the true innate composition of transcriptomes. Enter Garalde et al., who present for the first time highly parallel native RNA-Sequencing (RNA-seq), with potentially disruptive future-implications for the transcriptomics field. PMID- 29503178 TI - Relationship Between Work Productivity and Clinical Characteristics in Rheumatoid Arthritis. AB - OBJECTIVE: This study assesses the relationship between the ability to perform productive activities and the clinical characteristics of RA, such as disease activity, quality of life, functional capacity, workload, pharmacotherapy, and comorbidities. MATERIALS AND METHODS: A cross-sectional, observational and descriptive study was conducted. Patients aged 18-75years with a diagnosis of RA according to ACR/EULAR 2010 criteria who attended regularly to the Rheumatology service in the period between January and March 2017 were included. The questionnaires, WPAI-AR, HAQ-DI and RAQoL, were applied. RA disease activity was measured by DAS28-PCR. Correlations were made between the clinical data obtained and work productivity and activity impairment measured by WPAI-AR. RESULTS: Two hundred four patients with a diagnosis of RA were included, of whom 92.6% were women. Mean age was 54.46+/-9.3years. Regarding the percentage of impairment of daily life activities, we found a significant difference between employed and unemployed patients (P<=.002). A positive correlation was found between RA activity measured by DAS28-PCR, quality of life, and functional ability with the percentages of absenteeism, presenteeism, overall productivity loss, and impairment of daily life activities. CONCLUSION: A correlation between RA disease activity, functional capacity, quality of life, and working impairment was found. The strongest association was established with the degree of functional capacity. PMID- 29503179 TI - Inflammation-Modulated Metabolic Reprogramming Is Required for DUOX-Dependent Gut Immunity in Drosophila. AB - DUOX, a member of the NADPH oxidase family, acts as the first line of defense against enteric pathogens by producing microbicidal reactive oxygen species. DUOX is activated upon enteric infection, but the mechanisms regulating DUOX activity remain incompletely understood. Using Drosophila genetic tools, we show that enteric infection results in "pro-catabolic" signaling that initiates metabolic reprogramming of enterocytes toward lipid catabolism, which ultimately governs DUOX homeostasis. Infection induces signaling cascades involving TRAF3 and kinases AMPK and WTS, which regulate TOR kinase to control the balance of lipogenesis versus lipolysis. Enhancing lipogenesis blocks DUOX activity, whereas stimulating lipolysis via ATG1-dependent lipophagy is required for DUOX activation. Drosophila with altered activity in TRAF3-AMPK/WTS-ATG1 pathway components exhibit abolished infection-induced lipolysis, reduced DUOX activation, and enhanced susceptibility to enteric infection. Thus, this work uncovers signaling cascades governing inflammation-induced metabolic reprogramming and provides insight into the pathophysiology of immune-metabolic interactions in the microbe-laden gut epithelia. PMID- 29503182 TI - Comparison of proximal interphalangeal arthroplasty outcomes with Swanson implant performed by volar versus dorsal approach. AB - No study has compared the QuickDASH score after Swanson implant arthroplasty performed by dorsal versus volar approaches. This study compared the outcomes of PIP arthroplasties through a volar approach as described by Schneider versus a dorsal approach as described by Chamay by determining the QuickDASH score, pain and range of motion. Our series included 21 Swanson implant arthroplasty cases in 17 patients aged 62 years on average, among which 12 were females. A volar approach was performed in 9 cases (group I) and a dorsal approach was performed in 12 cases (group II). The difference between the average QuickDASH score preoperatively and at the last follow-up was strong (group I: -16.584; group II: 1.444), the difference between the average pain level preoperatively and at the last follow up was very strong (group I: -2.098; group II: -4.506), the difference in average PIP extension was not different from 0 (group: I -5.805; group II: -11.332), the difference in average PIP flexion was very strong (group I: -2.716; group II: -2.007). There were four recurrences of swan neck deformity (3 in group, 1 in group II) and one implant fracture in each group. For Swanson implant arthroplasty, the volar approach leads to better QuickDASH scores and PIP flexion compared to the dorsal approach. The volar approach did not improve PIP extension, or pain, and did not lead to dysesthesia. PMID- 29503180 TI - Dicer-2-Dependent Generation of Viral DNA from Defective Genomes of RNA Viruses Modulates Antiviral Immunity in Insects. AB - The RNAi pathway confers antiviral immunity in insects. Virus-specific siRNA responses are amplified via the reverse transcription of viral RNA to viral DNA (vDNA). The nature, biogenesis, and regulation of vDNA are unclear. We find that vDNA produced during RNA virus infection of Drosophila and mosquitoes is present in both linear and circular forms. Circular vDNA (cvDNA) is sufficient to produce siRNAs that confer partially protective immunity when challenged with a cognate virus. cvDNAs bear homology to defective viral genomes (DVGs), and DVGs serve as templates for vDNA and cvDNA synthesis. Accordingly, DVGs promote the amplification of vDNA-mediated antiviral RNAi responses in infected Drosophila. Furthermore, vDNA synthesis is regulated by the DExD/H helicase domain of Dicer-2 in a mechanism distinct from its role in siRNA generation. We suggest that, analogous to mammalian RIG-I-like receptors, Dicer-2 functions like a pattern recognition receptor for DVGs to modulate antiviral immunity in insects. PMID- 29503183 TI - Retrograde fixation of metacarpal fractures with intramedullary cannulated headless compression screws. AB - : We analyzed the results of 20 unstable metacarpal fractures in 15 patients treated with a cannulated compression screw and no immobilization. All fractures healed within 6 weeks. One patient with multiple fractures and a flexion deficit required arthrolysis of two metacarpophalangeal joints. Another patient had an extension lag. There were no other complications. This fast and easy technique results in good outcomes for unstable metacarpal fractures. The advantages are early active motion without immobilization and stable fixation. Surgical removal of the screw is rarely needed. LEVEL OF EVIDENCE: IV (therapeutic). PMID- 29503181 TI - Comparative Heterochromatin Profiling Reveals Conserved and Unique Epigenome Signatures Linked to Adaptation and Development of Malaria Parasites. AB - Heterochromatin-dependent gene silencing is central to the adaptation and survival of Plasmodium falciparum malaria parasites, allowing clonally variant gene expression during blood infection in humans. By assessing genome-wide heterochromatin protein 1 (HP1) occupancy, we present a comprehensive analysis of heterochromatin landscapes across different Plasmodium species, strains, and life cycle stages. Common targets of epigenetic silencing include fast-evolving multi gene families encoding surface antigens and a small set of conserved HP1 associated genes with regulatory potential. Many P. falciparum heterochromatic genes are marked in a strain-specific manner, increasing the parasite's adaptive capacity. Whereas heterochromatin is strictly maintained during mitotic proliferation of asexual blood stage parasites, substantial heterochromatin reorganization occurs in differentiating gametocytes and appears crucial for the activation of key gametocyte-specific genes and adaptation of erythrocyte remodeling machinery. Collectively, these findings provide a catalog of heterochromatic genes and reveal conserved and specialized features of epigenetic control across the genus Plasmodium. PMID- 29503184 TI - Activity-Dependent Downscaling of Subthreshold Synaptic Inputs during Slow-Wave Sleep-like Activity In Vivo. AB - Activity-dependent synaptic plasticity is critical for cortical circuit refinement. The synaptic homeostasis hypothesis suggests that synaptic connections are strengthened during wake and downscaled during sleep; however, it is not obvious how the same plasticity rules could explain both outcomes. Using whole-cell recordings and optogenetic stimulation of presynaptic input in urethane-anesthetized mice, which exhibit slow-wave-sleep (SWS)-like activity, we show that synaptic plasticity rules are gated by cortical dynamics in vivo. While Down states support conventional spike timing-dependent plasticity, Up states are biased toward depression such that presynaptic stimulation alone leads to synaptic depression, while connections contributing to postsynaptic spiking are protected against this synaptic weakening. We find that this novel activity dependent and input-specific downscaling mechanism has two important computational advantages: (1) improved signal-to-noise ratio, and (2) preservation of previously stored information. Thus, these synaptic plasticity rules provide an attractive mechanism for SWS-related synaptic downscaling and circuit refinement. PMID- 29503185 TI - Activation of Striatal Neurons Causes a Perceptual Decision Bias during Visual Change Detection in Mice. AB - The basal ganglia are implicated in perceptual decision-making, although their specific contributions remain unclear. Here, we tested the causal role of the basal ganglia by manipulating neuronal activity in the dorsal striatum of mice performing a visual orientation-change detection (yes/no) task. Brief unilateral optogenetic stimulation caused large changes in task performance, shifting psychometric curves upward by increasing the probability of "yes" responses with only minor changes in sensitivity. For the direct pathway, these effects were significantly larger when the visual event was expected in the contralateral visual field, demonstrating a lateralized bias in responding to sensory inputs rather than a generalized increase in action initiation. For both direct and indirect pathways, the effects were specific to task epochs in which choice relevant visual stimuli were present. These results indicate that the causal link between striatal activity and decision-making includes an additive perceptual bias in favor of expected or valued visual events. PMID- 29503186 TI - Rapid Rebalancing of Excitation and Inhibition by Cortical Circuitry. AB - Excitation is balanced by inhibition to cortical neurons across a wide range of conditions. To understand how this relationship is maintained, we broadly suppressed the activity of parvalbumin-expressing (PV+) inhibitory neurons and asked how this affected the balance of excitation and inhibition throughout auditory cortex. Activating archaerhodopsin in PV+ neurons effectively suppressed them in layer 4. However, the resulting increase in excitation outweighed Arch suppression and produced a net increase in PV+ activity in downstream layers. Consequently, suppressing PV+ neurons did not reduce inhibition to principal neurons (PNs) but instead resulted in a tightly coordinated increase in both excitation and inhibition. The increase in inhibition constrained the magnitude of PN spiking responses to the increase in excitation and produced nonlinear changes in spike tuning. Excitatory-inhibitory rebalancing is mediated by strong PN-PV+ connectivity within and between layers and is likely engaged during normal cortical operation to ensure balance in downstream neurons. PMID- 29503187 TI - Insm1 Induces Neural Progenitor Delamination in Developing Neocortex via Downregulation of the Adherens Junction Belt-Specific Protein Plekha7. AB - Delamination of neural progenitor cells (NPCs) from the ventricular surface is a crucial prerequisite to form the subventricular zone, the germinal layer linked to the expansion of the mammalian neocortex in development and evolution. Here, we dissect the molecular mechanism by which the transcription factor Insm1 promotes the generation of basal progenitors (BPs). Insm1 protein is most highly expressed in newborn BPs in mouse and human developing neocortex. Forced Insm1 expression in embryonic mouse neocortex causes NPC delamination, converting apical to basal radial glia. Insm1 represses the expression of the apical adherens junction belt-specific protein Plekha7. CRISPR/Cas9-mediated disruption of Plekha7 expression suffices to cause NPC delamination. Plekha7 overexpression impedes the intrinsic and counteracts the Insm1-induced, NPC delamination. Our findings uncover a novel molecular mechanism underlying NPC delamination in which a BP-genic transcription factor specifically targets the integrity of the apical adherens junction belt, rather than adherens junction components as such. PMID- 29503189 TI - Volitional Modulation of Primary Visual Cortex Activity Requires the Basal Ganglia. AB - Animals acquire behaviors through instrumental conditioning. Brain-machine interfaces have used instrumental conditioning to reinforce patterns of neural activity directly, especially in frontal and motor cortices, which are a rich source of signals for voluntary action. However, evidence suggests that activity in primary sensory cortices may also reflect internally driven processes, instead of purely encoding antecedent stimuli. Here, we show that rats and mice can learn to produce arbitrary patterns of neural activity in their primary visual cortex to control an auditory cursor and obtain reward. Furthermore, learning was prevented when neurons in the dorsomedial striatum (DMS), which receives input from visual cortex, were optogenetically inhibited, but not during inhibition of nearby neurons in the dorsolateral striatum. After learning, DMS inhibition did not affect production of the rewarded patterns. These data demonstrate that cortico-basal ganglia circuits play a general role in learning to produce cortical activity that leads to desirable outcomes. PMID- 29503188 TI - Neural Mechanisms Mediating Motion Sensitivity in Parasol Ganglion Cells of the Primate Retina. AB - Considerable theoretical and experimental effort has been dedicated to understanding how neural circuits detect visual motion. In primates, much is known about the cortical circuits that contribute to motion processing, but the role of the retina in this fundamental neural computation is poorly understood. Here, we used a combination of extracellular and whole-cell recording to test for motion sensitivity in the two main classes of output neurons in the primate retina-midget (parvocellular-projecting) and parasol (magnocellular-projecting) ganglion cells. We report that parasol, but not midget, ganglion cells are motion sensitive. This motion sensitivity is present in synaptic excitation and disinhibition from presynaptic bipolar cells and amacrine cells, respectively. Moreover, electrical coupling between neighboring bipolar cells and the nonlinear nature of synaptic release contribute to the observed motion sensitivity. Our findings indicate that motion computations arise far earlier in the primate visual stream than previously thought. PMID- 29503190 TI - Gamma Oscillation Dysfunction in mPFC Leads to Social Deficits in Neuroligin 3 R451C Knockin Mice. AB - Neuroligins (NLs) are critical for synapse formation and function. NL3 R451C is an autism-associated mutation. NL3 R451C knockin (KI) mice exhibit autistic behavioral abnormalities, including social novelty deficits. However, neither the brain regions involved in social novelty nor the underlying mechanisms are clearly understood. Here, we found decreased excitability of fast-spiking interneurons and dysfunction of gamma oscillation in the medial prefrontal cortex (mPFC), which contributed to the social novelty deficit in the KI mice. Neuronal firing rates and phase-coding abnormalities were also detected in the KI mice during social interactions. Interestingly, optogenetic stimulation of parvalbumin interneurons in the mPFC at 40 Hz nested at 8 Hz positively modulated the social behaviors of mice and rescued the social novelty deficit in the KI mice. Our findings suggest that gamma oscillation dysfunction in the mPFC leads to social deficits in autism, and manipulating mPFC PV interneurons may reverse the deficits in adulthood. PMID- 29503191 TI - Attentional Changes in Either Criterion or Sensitivity Are Associated with Robust Modulations in Lateral Prefrontal Cortex. AB - Visual attention is associated with neuronal changes across the brain, and these widespread signals are generally assumed to underlie a unitary mechanism of attention. However, using signal detection theory, attention-related effects on performance can be partitioned into changes in either the subject's criterion or sensitivity. Neuronal modulations associated with only sensitivity changes were previously observed in visual cortex, raising questions about which structures mediate attention-related changes in criterion and whether individual neurons are involved in multiple components of attention. Here, we recorded from monkey lateral prefrontal cortex (LPFC) and found that, in contrast to visual cortex, neurons in LPFC changed their firing rates, pairwise correlation, and Fano factor when subjects changed either their criterion or their sensitivity. These results indicate that attention-related neuronal modulations in separate brain regions are not a monolithic signal and instead can be linked to distinct behavioral changes. PMID- 29503193 TI - Safety First: Perspective on Patient-Centered Development of AAV Gene Therapy Products. PMID- 29503192 TI - Structural Basis for Draxin-Modulated Axon Guidance and Fasciculation by Netrin-1 through DCC. AB - Axon guidance involves the spatiotemporal interplay between guidance cues and membrane-bound cell-surface receptors, present on the growth cone of the axon. Netrin-1 is a prototypical guidance cue that binds to deleted in colorectal cancer (DCC), and it has been proposed that the guidance cue Draxin modulates this interaction. Here, we present structural snapshots of Draxin/DCC and Draxin/Netrin-1 complexes, revealing a triangular relationship that affects Netrin-mediated haptotaxis and fasciculation. Draxin interacts with DCC through the N-terminal four immunoglobulin domains, and Netrin-1 through the EGF-3 domain, in the same region where DCC binds. Netrin-1 and DCC bind to adjacent sites on Draxin, which appears to capture Netrin-1 and tether it to the DCC receptor. We propose the conformational flexibility of the single-pass membrane receptor DCC is used to promote fasciculation and regulate axon guidance through concerted Netrin-1/Draxin binding. VIDEO ABSTRACT. PMID- 29503194 TI - Neonatal Systemic AAV-Mediated Gene Delivery of GDF11 Inhibits Skeletal Muscle Growth. AB - Growth and differentiation factor 11 (GDF11; BMP11) is a circulating cytokine in the transforming growth factor beta (TGF-beta) superfamily. Treatment with recombinant GDF11 (rGDF11) protein has previously been shown to reverse skeletal muscle dysfunction in aged mice. However, the actions of GDF11 in skeletal muscle are still not fully understood. Because GDF11 activates the TGF-beta-SMAD2/3 pathway, we hypothesized that GDF11 overexpression would inhibit skeletal muscle growth. To test this hypothesis, we generated recombinant adeno-associated virus serotype 9 (AAV9) vectors harboring the gene for either human GDF11 (AAV9-GDF11) or human IgG1 Fc-fused GDF11 propeptide (AAV9-GDF11Pro-Fc-1) to study the effects of GDF11 overexpression or blockade on skeletal muscle growth and function in vivo. After intravenous administration of AAV9-GDF11 into neonatal C57BL/6J mice, we observed sustained limb muscle growth inhibition along with reductions in forelimb grip strength and treadmill running endurance at 16 weeks. Conversely, treatment with AAV9-GDF11Pro-Fc-1 led to increased limb muscle mass and forelimb grip strength after 28 weeks, although a difference in the total body mass/muscle mass ratio was not observed between treatment and control groups. In sum, our results suggest GDF11 overexpression has an inhibitory effect on skeletal muscle growth. PMID- 29503195 TI - Adoptive Transfer of IL13Ralpha2-Specific Chimeric Antigen Receptor T Cells Creates a Pro-inflammatory Environment in Glioblastoma. AB - In order to fully harness the potential of immunotherapy with chimeric antigen receptor (CAR)-modified T cells, pre-clinical studies must be conducted in immunocompetent animal models that closely mimic the immunosuppressive malignant glioma (MG) microenvironment. Thus, the goal of this project was to study the in vivo fate of T cells expressing CARs specific for the MG antigen IL13Ralpha2 (IL13Ralpha2-CARs) in immunocompetent MG models. Murine T cells expressing IL13Ralpha2-CARs with a CD28.zeta (IL13Ralpha2-CAR.CD28.zeta) or truncated signaling domain (IL13Ralpha2-CAR.Delta) were generated by retroviral transduction, and their effector function was evaluated both in vitro and in vivo. IL13Ralpha2-CAR.CD28.zeta T cells' specificity toward IL13Ralpha2 was confirmed through cytokine production and cytolytic activity. In vivo, a single intratumoral injection of IL13Ralpha2-CAR.CD28.zeta T cells significantly extended the survival of IL13Ralpha2-expressing GL261 and SMA560 glioma-bearing mice; long-term survivors were resistant to re-challenge with IL13Ralpha2 negative and IL13Ralpha2-positive tumors. IL13Ralpha2-CAR.CD28.zeta T cells proliferated, produced cytokines (IFNgamma, TNF-alpha), and promoted a phenotypically pro-inflammatory glioma microenvironment by inducing a significant increase in the number of CD4+ and CD8+ T cells and CD8alpha+ dendritic cells and a decrease in Ly6G+ myeloid-derived suppressor cells (MDSCs). Our data underline the significance of CAR T cell studies in immunocompetent hosts and further validate IL13Ralpha2-CAR T cells as an efficacious therapeutic strategy for MG. PMID- 29503196 TI - Combined Ectopic Expression of Homologous Recombination Factors Promotes Embryonic Stem Cell Differentiation. AB - Homologous recombination (HR), which ensures accurate DNA replication and strand break repair, is necessary to preserve embryonic stem cell (ESC) self-renewal. However, little is known about how HR factors modulate ESC differentiation and replication stress-associated DNA breaks caused by unique cell-cycle progression. Here, we report that ESCs utilize Rad51-dependent HR to enhance viability and induce rapid proliferation through a replication-coupled pathway. In addition, ESC differentiation was shown to be enhanced by ectopic expression of a subset of recombinases. Abundant expression of HR proteins throughout the ESC cycle, but not during differentiation, facilitated immediate HR-mediated repair of single stranded DNA (ssDNA) gaps incurred during S-phase, via a mechanism that does not perturb cellular progression. Intriguingly, combined ectopic expression of two recombinases, Rad51 and Rad52, resulted in efficient ESC differentiation and diminished cell death, indicating that HR factors promote cellular differentiation by repairing global DNA breaks induced by chromatin remodeling signals. Collectively, these findings provide insight into the role of key HR factors in rapid DNA break repair following chromosome duplication during self renewal and differentiation of ESCs. PMID- 29503197 TI - Local Delivery of miR-21 Stabilizes Fibrous Caps in Vulnerable Atherosclerotic Lesions. AB - miRNAs are potential regulators of carotid artery stenosis and concordant vulnerable atherosclerotic plaques. Hence, we analyzed miRNA expression in laser captured micro-dissected fibrous caps of either ruptured or stable plaques (n = 10 each), discovering that miR-21 was significantly downregulated in unstable lesions. To functionally evaluate miR-21 in plaque vulnerability, miR-21 and miR 21/apolipoprotein-E double-deficient mice (Apoe-/-miR-21-/-) were assessed. miR 21-/- mice lacked sufficient smooth muscle cell proliferation in response to carotid ligation injury. When exposing Apoe-/-miR-21-/- mice to an inducible plaque rupture model, they presented with more atherothrombotic events (93%) compared with miR-21+/+Apoe-/- mice (57%). We discovered that smooth muscle cell fate in experimentally induced advanced lesions is steered via a REST-miR-21-REST feedback signaling pathway. Furthermore, Apoe-/-miR-21-/- mice presented with more pronounced atherosclerotic lesions, greater foam cell formation, and substantially higher levels of arterial macrophage infiltration. Local delivery of a miR-21 mimic using ultrasound-targeted microbubbles into carotid plaques rescued the vulnerable plaque rupture phenotype. In the present study, we identify miR-21 as a key modulator of pathologic processes in advanced atherosclerosis. Targeted, lesion site-specific overexpression of miR-21 can stabilize vulnerable plaques. PMID- 29503198 TI - Efficient Non-viral Gene Delivery into Human Hematopoietic Stem Cells by Minicircle Sleeping Beauty Transposon Vectors. AB - The Sleeping Beauty (SB) transposon system is a non-viral gene delivery platform that combines simplicity, inexpensive manufacture, and favorable safety features in the context of human applications. However, efficient correction of hematopoietic stem and progenitor cells (HSPCs) with non-viral vector systems, including SB, demands further refinement of gene delivery techniques. We set out to improve SB gene transfer into hard-to-transfect human CD34+ cells by vectorizing the SB system components in the form of minicircles that are devoid of plasmid backbone sequences and are, therefore, significantly reduced in size. As compared to conventional plasmids, delivery of the SB transposon system as minicircle DNA is ~20 times more efficient, and it is associated with up to a 50% reduction in cellular toxicity in human CD34+ cells. Moreover, providing the SB transposase in the form of synthetic mRNA enabled us to further increase the efficacy and biosafety of stable gene delivery into hematopoietic progenitors ex vivo. Genome-wide insertion site profiling revealed a close-to-random distribution of SB transposon integrants, which is characteristically different from gammaretroviral and lentiviral integrations in HSPCs. Transplantation of gene-marked CD34+ cells in immunodeficient mice resulted in long-term engraftment and hematopoietic reconstitution, which was most efficient when the SB transposase was supplied as mRNA and nucleofected cells were maintained for 4-8 days in culture before transplantation. Collectively, implementation of minicircle and mRNA technologies allowed us to further refine the SB transposon system in the context of HSPC gene delivery to ultimately meet clinical demands of an efficient and safe non-viral gene therapy protocol. PMID- 29503199 TI - Immunological Synapse Predicts Effectiveness of Chimeric Antigen Receptor Cells. AB - Chimeric antigen receptor (CAR)-modified T cell therapy has the potential to improve the overall survival of patients with malignancies by enhancing the effectiveness of CAR T cells. Precisely predicting the effectiveness of various CAR T cells represents one of today's key unsolved problems in immunotherapy. Here, we predict the effectiveness of CAR-modified cells by evaluating the quality of the CAR-mediated immunological synapse (IS) by quantitation of F actin, clustering of tumor antigen, polarization of lytic granules (LGs), and distribution of key signaling molecules within the IS. Long-term killing capability, but not secretion of conventional cytokines or standard 4-hr cytotoxicity, correlates positively with the quality of the IS in two different CAR T cells that share identical antigen specificity. Xenograft model data confirm that the quality of the IS in vitro correlates positively with performance of CAR-modified immune cells in vivo. Therefore, we propose that the quality of the IS predicts the effectiveness of CAR-modified immune cells, which provides a novel strategy to guide CAR therapy. PMID- 29503200 TI - Autologous Cell Therapy Approach for Duchenne Muscular Dystrophy using PiggyBac Transposons and Mesoangioblasts. AB - Duchenne muscular dystrophy (DMD) is a lethal muscle-wasting disease currently without cure. We investigated the use of the PiggyBac transposon for full-length dystrophin expression in murine mesoangioblast (MABs) progenitor cells. DMD murine MABs were transfected with transposable expression vectors for full-length dystrophin and transplanted intramuscularly or intra-arterially into mdx/SCID mice. Intra-arterial delivery indicated that the MABs could migrate to regenerating muscles to mediate dystrophin expression. Intramuscular transplantation yielded dystrophin expression in 11%-44% of myofibers in murine muscles, which remained stable for the assessed period of 5 months. The satellite cells isolated from transplanted muscles comprised a fraction of MAB-derived cells, indicating that the transfected MABs may colonize the satellite stem cell niche. Transposon integration site mapping by whole-genome sequencing indicated that 70% of the integrations were intergenic, while none was observed in an exon. Muscle resistance assessment by atomic force microscopy indicated that 80% of fibers showed elasticity properties restored to those of wild-type muscles. As measured in vivo, transplanted muscles became more resistant to fatigue. This study thus provides a proof-of-principle that PiggyBac transposon vectors may mediate full-length dystrophin expression as well as functional amelioration of the dystrophic muscles within a potential autologous cell-based therapeutic approach of DMD. PMID- 29503202 TI - Overcoming Limitations Inherent in Sulfamidase to Improve Mucopolysaccharidosis IIIA Gene Therapy. AB - Sulfamidase (SGSH) deficiency causes mucopolysaccharidosis type IIIA (MPS IIIA), a lysosomal storage disease (LSD) that affects the CNS. In earlier work in LSD mice and dog models, we exploited the utility of adeno-associated viruses (AAVs) to transduce brain ventricular lining cells (ependyma) for secretion of lysosomal hydrolases into the cerebrospinal fluid (CSF), with subsequent distribution of enzyme throughout the brain resulting in improved cognition and extending lifespan. A critical feature of this approach is efficient secretion of the expressed enzyme from transduced cells, for delivery by CSF to nontransduced cells. Surprisingly, we found that SGSH was poorly secreted from cells, resulting in retention of the expressed product. Using site-directed mutagenesis of native SGSH, we identified an improved secretion variant that also displayed enhanced uptake properties that were mannose-6-phosphate receptor independent. In studies in MPS IIIA-deficient mice, ependymal transduction with AAVs expressing variant SGSH improved spatial learning and reduced memory deficits, substrate accumulation, and astrogliosis. Secondary lysosomal enzyme elevations in the CSF and brain parenchyma were also resolved. In contrast, ependymal transduction with AAVs expressing wild-type SGSH had significantly lower CSF SGSH levels and limited impacts on behavior. These results demonstrate the utility of a previously undescribed SGSH variant for improved MPS IIIA brain gene therapy. PMID- 29503201 TI - Translation of MicroRNA-Based Huntingtin-Lowering Therapies from Preclinical Studies to the Clinic. AB - The single mutation underlying the fatal neuropathology of Huntington's disease (HD) is a CAG triplet expansion in exon 1 of the huntingtin (HTT) gene, which gives rise to a toxic mutant HTT protein. There have been a number of not yet successful therapeutic advances in the treatment of HD. The current excitement in the HD field is due to the recent development of therapies targeting the culprit of HD either at the DNA or RNA level to reduce the overall mutant HTT protein. In this review, we briefly describe short-term and long-term HTT-lowering strategies targeting HTT transcripts. One of the most advanced HTT-lowering strategies is a microRNA (miRNA)-based gene therapy delivered by a single administration of an adeno-associated viral (AAV) vector to the HD patient. We outline the outcome measures for the miRNA-based HTT-lowering therapy in the context of preclinical evaluation in HD animal and cell models. We highlight the strengths and ongoing queries of the HTT-lowering gene therapy as an HD intervention with a potential disease-modifying effect. This review provides a perspective on the fast developing HTT-lowering therapies for HD and their translation to the clinic based on existing knowledge in preclinical models. PMID- 29503203 TI - Altered Peptide Ligands Impact the Diversity of Polyfunctional Phenotypes in T Cell Receptor Gene-Modified T Cells. AB - The use of T cell receptor (TCR) gene-modified T cells in adoptive cell transfer has had promising clinical success, but often, simple preclinical evaluation does not necessarily accurately predict treatment efficacy or safety. Preclinical studies generally evaluate one or a limited number of type 1 cytokines to assess antigen recognition. However, recent studies have implicated other "typed" T cells in effective anti-tumor/viral immunity, and limited functional evaluations may underestimate cross-reactivity. In this study, we use an altered peptide ligand (APL) model and multi-dimensional flow cytometry to evaluate polyfunctionality of TCR gene-modified T cells. Evaluating six cytokines and the lytic marker CD107a on a per cell basis revealed remarkably diverse polyfunctional phenotypes within a single T cell culture and among peripheral blood lymphocyte (PBL) donors. This polyfunctional assessment identified unexpected phenotypes, including cells producing both type 1 and type 2 cytokines, and highlighted interferon gammaneg (IFNgammaneg) antigen-reactive populations overlooked in our previous studies. Additionally, APLs skewed functional phenotypes to be less polyfunctional, which was not necessarily related to changes in TCR-peptide-major histocompatibility complex (pMHC) affinity. A better understanding of gene-modified T cell functional diversity may help identify optimal therapeutic phenotypes, predict clinical responses, anticipate off-target recognition, and improve the design and delivery of TCR gene-modified T cells. PMID- 29503204 TI - In Vivo Expansion and Antitumor Activity of Coinfused CD28- and 4-1BB-Engineered CAR-T Cells in Patients with B Cell Leukemia. AB - Several recent clinical trials have successfully incorporated a costimulatory domain derived from either CD28 or 4-1BB with the original CD3zeta T cell activating domain to form second-generation chimeric antigen receptors (CARs) that can increase the responsiveness and survival of CAR-engineered T (CAR-T) cells. However, a rigorous assessment of the individual benefits of these costimulatory components relative to the in vivo performance of infused T cells in patients is still lacking. Therefore, we have designed a study that allows us to investigate and compare the impact of different costimulatory signal domains on CAR-T cells in vivo. Patients with B cell leukemia were infused with a mixture of two types of CD19-specific CAR-T cells, individually bearing CD28 (28zeta) and 4-1BB (BBzeta) costimulatory signaling domains. We found that such a clinical procedure was feasible and safe. Complete remission (CR) was observed in five of seven enrolled patients, with two patients exhibiting durable CR lasting more than 15 months. The in vivo expansion pattern of 28zeta and BBzeta CAR-T cells varied significantly among individual patients. These results confirm a feasible method of comparing different CAR designs within individual patients, potentially offering objective insights that may facilitate the development of optimal CAR-T cell-based immunotherapies. PMID- 29503205 TI - Poly(lactic-co-glycolic acid)(PLGA)/TiO2 nanotube bioactive composite as a novel scaffold for bone tissue engineering: In vitro and in vivo studies. AB - The aim of this study was to synthesize and characterize novel three-dimensional porous scaffolds made of poly (lactic-co-glycolic acid)/TiO2 nanotube (TNT) composite microspheres for bone tissue engineering applications. The incorporation of TNT greatly increases mechanical properties of PLGA/TNT microsphere-sintered scaffold. The experimental results exhibit that the PLGA/0.5 wt% TNT scaffold sintered at 100 degrees C for 3 h showed the best mechanical properties and a proper pore structure for tissue engineering. Biodegradation test ascertained that the weight of both PLGA and PLGA/PLGA/0.5 wt% TiO2 nanotube composites slightly reduced during the first 4 weeks following immersion in SBF solution. Moreover, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and alkaline phosphatase activity (ALP activity) results represent increased cell viability for PLGA/0.5%TNT composite scaffold in comparison to the control group. In vivo studies show the amount of bone formation for PLGA/TNT was approximately twice of pure PLGA. Vivid histologic images of the newly generated bone on the implants further supported our test results. Eventually, a mathematical model showed that both PLGA and PLGA/TNT scaffolds' mechanical properties follow an exponential trend with time as their degradation occurs. By a three-dimensional finite element model, a more monotonous distribution of stress was present in the scaffold due to the presence of TNT with a reduction in maximum stress on bone. PMID- 29503206 TI - Novel RNA-Affinity Proteogenomics Dissects Tumor Heterogeneity for Revealing Personalized Markers in Precision Prognosis of Cancer. AB - To discriminate the patient subpopulations with different clinical outcomes within each breast cancer (BC) subtype, we introduce a robust, clinical practical, activity-based proteogenomic method that identifies, in their oncogenically active states, candidate biomarker genes bearing patient-specific transcriptomic/genomic alterations of prognostic value. First, we used the intronic splicing enhancer (ISE) probes to sort ISE-interacting trans-acting protein factors (trans-interactome) directly from a tumor tissue for subsequent mass spectrometry characterization. In the retrospective, proteogenomic analysis of patient datasets, we identified those ISE trans-factor-encoding genes showing interaction-correlated expression patterns (iCEPs) as new BC-subtypic genes. Further, patient-specific co-alterations in mRNA expression of select iCEP genes distinguished high-risk patient subsets/subpopulations from other patients within a single BC subtype. Function analysis further validated a tumor-phenotypic trans interactome contained the drivers of oncogenic splicing switches, representing the predominant tumor cells in a tissue, from which novel personalized biomarkers were clinically characterized/validated for precise prognostic prediction and subsequent individualized alignment of optimal therapy. PMID- 29503207 TI - Snapshots of C-S Cleavage in Egt2 Reveals Substrate Specificity and Reaction Mechanism. AB - Sulfur incorporation in the biosynthesis of ergothioneine, a histidine thiol derivative, differs from other well-characterized transsulfurations. A combination of a mononuclear non-heme iron enzyme-catalyzed oxidative C-S bond formation and a subsequent pyridoxal 5'-phosphate (PLP)-mediated C-S lyase reaction leads to the net transfer of a sulfur atom from a cysteine to a histidine. In this study, we structurally and mechanistically characterized a PLP dependent C-S lyase Egt2, which mediates the sulfoxide C-S bond cleavage in ergothioneine biosynthesis. A cation-pi interaction between substrate and enzyme accounts for Egt2's preference of sulfoxide over thioether as a substrate. Using mutagenesis and structural biology, we captured three distinct states of the Egt2 C-S lyase reaction cycle, including a labile sulfenic intermediate captured in Egt2 crystals. Chemical trapping and high-resolution mass spectrometry were used to confirm the involvement of the sulfenic acid intermediate in Egt2 catalysis. PMID- 29503208 TI - Repurposing High-Throughput Image Assays Enables Biological Activity Prediction for Drug Discovery. AB - In both academia and the pharmaceutical industry, large-scale assays for drug discovery are expensive and often impractical, particularly for the increasingly important physiologically relevant model systems that require primary cells, organoids, whole organisms, or expensive or rare reagents. We hypothesized that data from a single high-throughput imaging assay can be repurposed to predict the biological activity of compounds in other assays, even those targeting alternate pathways or biological processes. Indeed, quantitative information extracted from a three-channel microscopy-based screen for glucocorticoid receptor translocation was able to predict assay-specific biological activity in two ongoing drug discovery projects. In these projects, repurposing increased hit rates by 50- to 250-fold over that of the initial project assays while increasing the chemical structure diversity of the hits. Our results suggest that data from high-content screens are a rich source of information that can be used to predict and replace customized biological assays. PMID- 29503209 TI - In-vitro regulation of primordial follicle activation: challenges for fertility preservation strategies. AB - Ovarian tissue is increasingly being collected from cancer patients and cryopreserved for fertility preservation. While the only available option to restore fertility is autologous transplantation, this treatment is not appropriate for all patients due to the risk of reintroducing cancer cells and causing disease recurrence. Harnessing the full reproductive potential of this tissue to restore fertility requires the development of culture systems that support oocyte development from the primordial follicle stage. While this has been achieved in the mouse, the goal of obtaining oocytes of sufficient quality to support embryo development has not been reached in higher mammals despite decades of effort. In vivo, primordial follicles gradually exit the resting pool, whereas when primordial follicles are placed into culture, global activation of these follicles occurs. Therefore, the addition of a factor(s) that can regulate primordial follicle activation in vitro may be beneficial to the development of culture systems for ovarian tissue from cancer patients. Several factors have been observed to inhibit follicle activation, including anti-Mullerian hormone, stromal-derived factor 1 and members of the c-Jun-N-terminal kinase pathway. This review summarizes the findings from studies of these factors and discusses their potential integration into ovarian tissue culture strategies for fertility preservation. PMID- 29503210 TI - Human embryonic curvature studied with 3D ultrasound in ongoing pregnancies and miscarriages. AB - Embryonic growth is often impaired in miscarriages. It is postulated that derangements in embryonic growth result in abnormalities of the embryonic curvature. This study aims to create first trimester reference charts of the human embryonic curvature and investigate differences between ongoing pregnancies and miscarriages. Weekly ultrasonographic scans from ongoing pregnancies and miscarriages were used from the Rotterdam periconceptional cohort and a cohort of recurrent miscarriages. In 202 ongoing pregnancies and 33 miscarriages, first trimester crown rump length and total arch length were measured to assess the embryonic curvature. The results show that the total arch length increases and shows more variation with advanced gestation. The crown rump length/total arch length ratio shows a strong increase from 8+0 to 10+0 weeks and flattening thereafter. No significant difference was observed between the curvature of embryos of ongoing pregnancies and miscarriages. The majority of miscarried embryos could not be measured. Therefore, this technique is too limited to recommend the measurement of the embryonic curvature in clinical practice. PMID- 29503211 TI - A demographic projection of the contribution of assisted reproductive technologies to world population growth. AB - Enormous unmet needs for infertility treatment exist because access to assisted reproductive technologies is demographically skewed. Since the first IVF baby in 1978, the number of people conceived by reproductive technology has grown much faster than expected, reaching several million today and rapidly approaching 0.1% of the total world population. As more patients build families, and their children in turn become parents, the number owing their existence to assisted reproductive technologies, either directly or indirectly, will expand tremendously in future decades, but no attempts have been made hitherto to project the magnitude. We have projected growth to the year 2100, along with the fractional contribution to world population. The chief variable driving growth is access to fertility services. If it stagnates at current levels of about 400,000 babies per year, an estimated 157 million people alive at the end of the century will owe their lives to assisted reproductive technologies (1.4% of global population), but at an arbitrary upper limit of 30,000 extra births annually there will be 394 million additional people alive (3.5%). As the conquest of infertility continues, individuals who owe their lives to assisted reproductive technologies will quietly make a significant contribution to demographic growth as well as social progress. PMID- 29503212 TI - Human oocyte maturation in vitro is improved by co-culture with cumulus cells from mature oocytes. AB - The conventional method of human oocyte maturation in vitro in the presence of gonadotrophins continues to be a relatively low-success procedure in the assisted conception programme owing to suboptimal maturation conditions in the absence of an ovarian 'niche' and poor understanding of this procedure at the molecular level in oocytes. In this study, the gene expression profiles of human oocytes were analysed according to their manner of maturation: in vivo (in the ovaries) or in vitro (matured either by the conventional method or by a new approach - co cultured with cumulus cells of mature oocytes from the same patient). Our results show that the in-vitro maturation procedure strongly affects the gene expression profile of human oocytes, including several genes involved in transcriptional regulation, embryogenesis, epigenetics, development, and the cell cycle. The in vitro maturation of oocytes co-cultured with cumulus cells from mature oocytes provides an ovarian 'niche' to some degree, which improves oocyte maturation rates and their gene expression profile to the extent that they are more comparable to oocytes that naturally mature in the ovarian follicle. PMID- 29503213 TI - A Canadian Survey of Self-Management Strategies and Satisfaction with Ability to Control Pain: Comparison of Community Dwelling Adults with Neuropathic Pain versus Adults with Non-neuropathic Chronic Pain. AB - BACKGROUND: Individuals with chronic pain with neuropathic characteristics (CPNC) describe a different pain experience compared with those with chronic pain without neuropathic characteristics (CP). AIMS: The aim of this study was to describe and compare pain, self-management strategies, and satisfaction with ability to control pain between adults with CPNC versus CP. PARTICIPANTS: Seven hundred and ten community-dwelling adults with chronic pain participated in a cross-sectional survey. METHODS: CPNC was defined as a score >=12 on the Self Report Leeds Assessment of Neuropathic Symptoms and Signs Pain Scale. Self management and pain control was compared between participants with CPNC and CP using frequency, percent, relative risk (RR), odds ratios (ORs), and 95% confidence intervals (CIs). RESULTS: Participants with CPNC (188/710) reported lower socioeconomic status, poorer general health, and more intense, frequent, and widespread pain. They were more likely to use prescription medications to manage pain (adjusted OR = 2.25, CI = 1.47-3.42). They were more likely to use potentially negative strategies to ease the emotional burden of living with chronic pain, including substance use (adjusted OR = 1.58, CI = 1.06-2.35), denial (adjusted OR = 2.21, CI = 1.49-3.28), and behavioral disengagement (adjusted OR = 1.68, CI = 1.16-2.45), and they were more likely to be completely dissatisfied with their ability to control pain (RR = 1.77, CI = 1.21-2.58). CONCLUSIONS: Individuals with CPNC have distinct pain and self-management experiences compared with those with CP that may lead to negative coping strategies and dissatisfaction with ability to control pain. Therefore, self management assessment and support should be tailored by pain condition. PMID- 29503214 TI - Nurse Practitioner-Administered Chloroprocaine in Children with Postoperative Pain. AB - BACKGROUND: Pain is a complex physical and emotional experience. Therefore, assessment of acute pain requires self-report when possible, observations of emotional and behavioral responses and changes in vital signs. Peripheral nerve and epidural catheters often provide postoperative analgesia in children. Administration of chloroprocaine (a short acting local anesthetic) via a peripheral nerve or epidural catheter allows for a comparison of pain scores, observations of emotional and behavioral responses and changes in vital signs to determine catheter function. AIMS: The aims of this study are to describe the use chloroprocaine injections for testing catheters; patient response; and how changes to pain management are guided by the patient response. METHODS: This study describes the use of chloroprocaine injections to manage pain and assess the function of peripheral nerve or epidural catheters in a pediatric population. We examined 128 surgical patients, (0-25 years old), who received chloroprocaine injections for testing peripheral nerve or epidural catheters. Patient outcomes included: blood pressure, respiratory rate, heart rate and pain intensity scores. RESULTS: There were no significant adverse events. The injection guided intervention by determining the function of regional analgesia in the majority (98.5%) of patients. DISCUSSION: Chloroprocaine injections appear to be useful to evaluate functionality of peripheral nerve and epidural catheters after surgery in a pediatric population. PMID- 29503215 TI - The Relationship of Age and Postoperative Pain in Women after Surgery for Breast Cancer. AB - BACKGROUND: In the past, elderly women with breast cancer were not offered surgery because of beliefs that they would experience serious complications from comorbidities and increased chronological age. Today the decision to offer surgery is based on a woman's fitness rather than her age. OBJECTIVE: The purpose of this study is to compare the experience of postoperative nausea and vomiting (PONV), anxiety, and reported pain levels in women who represent four different age groups after breast cancer surgery. This study employed a prospective comparative design. A large women's hospital which houses a Comprehensive Breast Care Program. Women diagnosed with early stage breast cancer and scheduled for surgical resection. METHODS: Postoperative pain was measured in the postanesthesia care unit using an 11-point verbal pain scale, PONV was measured categorically, and if present, severity of nausea was assessed. Anxiety was measured preoperatively by the short-form Profile of Mood States. FINDINGS: A total of 97 women aged 37-78 participated in this study. Overall, 35% of all women experienced PONV; only two women (18%) in the highest age range (70-79) experienced PONV, yet they reported significantly more pain than women in the other age groups. Understanding the difference in postoperative symptoms experienced by older woman after surgery for breast cancer will support the development of age-specific strategies. PMID- 29503216 TI - The AVPR1A Gene and Its Single Nucleotide Polymorphism rs10877969: A Literature Review of Associations with Health Conditions and Pain. AB - BACKGROUND: Pain is the quintessential symptom for individuals suffering from sickle cell disease (SCD). Although the degree of suffering and the cost of treatment are staggering, SCD continues to be grossly understudied, including a lack of data for pain-related genes and prevalence of polymorphisms in this population. This lack of data adds to the inadequacy of pain therapy in this population. Pain genetics investigators have recently examined allele frequencies of single-nucleotide polymorphisms from candidate genes in people who have SCD. One of the genes identified was the arginine vasopressin receptor 1A gene (AVPR1A) and its associated single-nucleotide polymorphism (SNP) rs10877969. Progress in explaining pain-related polymorphisms associated with SCD can be facilitated by understanding the literature. Aim/Design: The purpose of this literature review was to describe mechanisms of the polymorphic gene AVPR1A and the phenotypic variations associated with its SNPs relative to health conditions and pain. METHODS: Published studies were included if the research addressed AVPR1A and was a full article in a peer-reviewed journal, in the English language, a human or animal study, and published 2009 to present. Abstracts were included if they were in English and provided information not found in a full article. RESULTS: The results of this review revealed that AVPR1A is associated with behavioral phenotypes, which include pair bonding, autism spectrum disorder, musical aptitude, infidelity, altruism, monogamy, mating, substance abuse, and alcohol preference. In addition, there were associations with pain, stress pain by sex, and sickle cell pain. CONCLUSION: Summary of this literature could provide insights into future pain research of this SNP in people with SCD. PMID- 29503217 TI - Estimating the Frequency, Severity, and Clustering of SPADE Symptoms in Chronic Painful Chemotherapy-Induced Peripheral Neuropathy. AB - BACKGROUND: Patients undergoing treatment for cancer commonly experience symptoms such as sleep disturbance, pain, anxiety, depression, and low energy/fatigue (SPADE), subsequently altering physical function and complicating effective symptom management. However, little is known about the frequency, severity, and clustering of SPADE symptoms in individuals with chronic painful chemotherapy induced peripheral neuropathy (CIPN). Aims/Design: The purpose of this cross sectional, secondary analysis was to describe the frequency, severity, and clustering of SPADE symptoms and their association with physical function in individuals with chronic painful CIPN. Participants/Subjects: Sixty individuals with chronic painful CIPN were recruited from five academic and community oncology outpatient center to participate in a randomized controlled pilot trial designed to test the efficacy of a cognitive behavioral therapy-based pain management program. METHODS: Participants completed the 0-10 Average CIPN Pain Numerical Rating Scale and Patient-Reported Outcome Measurement Information System measures for sleep-related impairment, anxiety, depression, fatigue, and pain interference via tablet before being randomly assigned to a study arm. The frequency, severity, and clustering of SPADE symptoms were calculated via descriptive statistics and Partitioning Around Medoids cluster analysis. Spearman rank correlation was performed to determine the association between number of SPADE symptoms and pain interference severity. RESULTS AND CONCLUSIONS: Results revealed that participants (n = 59) experienced at least two symptoms concurrently. The cluster analysis revealed high (n = 36) and low (n = 23) severity subgroups. There was a moderate correlation (r = 0.48) between the number of SPADE symptoms and pain interference severity. Determining the clustering of SPADE symptoms in individuals with chronic painful CIPN may lead to targeted multifaceted interventions to improve physical function. PMID- 29503218 TI - Longitudinal Analysis of Parent Communication Behaviors and Child Distress during Cancer Port Start Procedures. AB - BACKGROUND: The roles parents play in supporting their child during painful cancer procedures have been studied as communication strategies versus a broader caring framework and from a cross-sectional versus longitudinal perspective. OBJECTIVES: To examine the longitudinal change in parent communication behaviors over repeated cancer port start procedures experienced by their children. METHODS: This study used a longitudinal design. Two trained raters coded 104 recorded videos of port starts from 43 children being treated for cancer. This included 25 children with two video-recorded port starts and 18 children with three (T1, T2, T3). The Parent Caring Response Scoring System derived from Swanson's Caring Theory was used to code parent communication behaviors as caring responses during their children's port starts. Three 3- to 5-minute slices (pre port start, during, and post-port start) were coded for each video. Mixed modeling with generalized estimating equations and Friedman test were used to analyze longitudinal change in parent behaviors. RESULTS: Significant differences were found between T1 versus T3 in eye contact (beta = -1.05, p = .02), distance close-enough-to-touch (beta = -0.81, p = .03), nonverbal comforting (beta = 1.34, p = .04), and availability (beta = -0.92, p = .036), suggesting that more parents used communication behaviors at T3 compared with T1. Parent burdensome or intrusive questions (e.g., Why do you cry? beta = -1.11, p = .03) and nonverbal comforting (beta = -1.52, p = .047) increased from T2 to T3. The median values of parent communication behaviors overall had no significant changes from T1 to T3. CONCLUSION: Parents adjusted to use more nonverbal caring behaviors as their child experienced additional port starts. Experimental studies should be designed to help parents use caring behaviors to better support their children during cancer procedures. PMID- 29503219 TI - Sleep quality at 3 months postpartum considering maternal age: A comparative study. AB - BACKGROUND: Poor sleep quality is related to old age among the general population, but few studies have focused on postpartum women of advanced maternal age. The present study aimed to describe and compare sleep quality between women younger or older than 35 years of age at 3 months postpartum, and to examine the related factors. METHODS: A cross-sectional survey was conducted with 160 postpartum women who had given birth at a teaching hospital in Taiwan. The participants were assigned to two groups according to age (>=35 years, n=80; and 20-34 years, n=80). Sleep quality was measured using the Pittsburgh Sleep Quality Index with a cut-off score of 5. RESULTS: The prevalence of poor sleep quality at 3 months postpartum was higher in older mothers (61.6%) than in younger mothers (38.4%, p<0.01). Multiple logistic regression revealed that poor sleep quality was positively correlated with the severity of postpartum physical symptoms, lack of exercise, and room-sharing with infants. After adjustment for those variables, older mothers were three times more likely to have poor sleep quality than younger mothers (odds ratio=3.08; 95% confidence interval 1.52-6.23). CONCLUSION: Health care providers should pay attention to sleep problems among postpartum women, especially mothers of advanced maternal age. In particular, health care providers should evaluate sleep quality among postpartum women, instruct them not to share the bed with their infants at night, perform exercise, and manage their postpartum physical symptoms to improve the sleep quality. PMID- 29503220 TI - Prospective multicenter study on robot-assisted laparoscopic extravesical ureteral reimplantation (RALUR-EV): Outcomes and complications. AB - BACKGROUND: Robot-assisted laparoscopic extravesical ureteral reimplantation (RALUR-EV) is a minimally invasive alternative to open surgery. We have previously reported retrospective outcomes from our study group, and herein provide an updated prospective analysis with a focus on success rate, surgical technique, and complications among surgeons who have overcome the initial learning curve. OBJECTIVE: To assess the safety and efficacy of RALUR-EV in children, among experienced surgeons. DESIGN AND METHODS: We reviewed our prospective database of children undergoing RALUR-EV by pediatric urologists at eight academic centers from 2015 to 2017. Radiographic success was defined as absence of vesicoureteral reflux (VUR) on postoperative voiding cystourethrogram. Complications were graded using the Clavien scale. Univariate regression analysis was performed to assess for association among various patient and technical factors and radiographic failure. RESULTS: In total, 143 patients were treated with RALUR-EV for primary VUR (87 unilateral, 56 bilateral; 199 ureters). The majority of ureters (73.4%) had grade III or higher VUR preoperatively. Radiographic resolution was present in 93.8% of ureters, as shown in the summary table. Ureteral complications occurred in five ureters (2.5%) with mean follow-up of 7.4 months (SD 4.0). Transient urinary retention occurred in four patients following bilateral procedure (7.1%) and in no patients after unilateral. On univariate analysis, there were no patient or technical factors associated with increased odds of radiographic failure. DISCUSSION: We report a radiographic success rate of 93.8% overall, and 94.1% among children with grades III-V VUR. In contemporary series, alternate management options such as endoscopic injection and open UR have reported radiographic success rates of 90% and 93.5% respectively. We were unable to identify specific patient or technical factors that influenced outcomes, although immeasurable factors such as tissue handling and intraoperative decision-making could not be assessed. Ureteral complications requiring operative intervention were rare and occurred with the same incidence reported in a large open series. Limitations include lack of long-term follow-up and absence of radiographic follow-up on a subset of patients. CONCLUSIONS: Radiographic resolution of VUR following RALUR is on par with contemporary open series, and the incidence of ureteral complications is low. RALUR should be considered as one of several viable options for management of VUR in children. PMID- 29503222 TI - A brief description of study design. PMID- 29503221 TI - Collaborating with our adult colleagues: A case series of robotic surgery for suspicious and cancerous lesions in children and young adults performed in a free standing children's hospital. AB - BACKGROUND: In adult urologic oncology the use of robotics has become commonplace; in pediatric urology it is rare. Herein, we describe a collaboration between an adult and a pediatric urologist performing robotic surgery for children and young adults with suspicious or cancerous genitourinary (GU) lesions. OBJECTIVES: To evaluate clinical and oncologic outcomes in children and young adults undergoing robotic surgery for suspicious or cancerous lesions of the GU tract; to describe our collaborative model between an adult and pediatric surgeon at a free-standing children's hospital. DESIGN: We retrospectively reviewed all robotic cases performed at our institution from 2014 to 2016 for patients with a GU malignancy or a suspicious mass. The surgeries were performed by a pediatric urologist with robotic experience and a fellowship-trained MIS adult urologist specializing in oncology. Perioperative and oncologic outcomes were recorded. RESULTS: A total of eight robotic cases were performed: four partial nephrectomies (PN) with retroperitoneal lymph node dissection (LND) (OT 269-338 min, EBL 5-300 mL, LOS 3-6 days), one adrenalectomy with LND (6.4 cm mass; OT 172 min, EBL 5 mL, LOS 3 days), one nephrectomy with pericaval LND (9.8 cm mass; 234 min, EBL 25 mL, LOS 3 days), and two retroperitoneal LNDs (OT 572 and 508 min, EBL 250 and 100, LOS 3 and 4 days). Patient weights ranged from 14 to 79 kg (mean 53.4 kg). There were no major complications (Clavien 3-5). Pathology results for PN included papillary RCC (AJCC pT1aNx) and two cases of segmental cystic renal dysplasia with nephrogenic rests. Bilateral template RPLNDs yielded paratesticular rhabdomyosarcoma (43 nodes; COG low risk group II stage I) and mixed non-seminomatous germ cell tumor (74 nodes; COG stage III). The nephrectomy yielded an undifferentiated sarcoma, low grade; the adrenalectomy favorable-type ganglioneuroma. DISCUSSION: In pediatrics, urologic oncology cases are often managed with open surgery. Our series demonstrates the feasibility of using the robotic approach in carefully selected cases. In doing so, the patient benefits from a minimally invasive surgery, while the surgeon benefits from robotic surgical dexterity. We seamlessly advanced these new techniques through a step-wise collaboration between an adult urologist who routinely performs robotic oncology procedures and a pediatric urologist experienced in robotics for benign conditions. CONCLUSION: In this small series, we safely and effectively adapted adult robotic techniques for genitourinary oncology cases in children and young adults. PMID- 29503223 TI - Outbreak of recombinant coxsackievirus A2 infection and polio-like paralysis of children, Taiwan, 2014. PMID- 29503224 TI - Identification of one novel homozygous mutation in the NPR2 gene in a patient from Taiwan with acromesomelic dysplasia Maroteaux type. PMID- 29503226 TI - Mycobacterium heckeshornense lung infection diagnosed by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). AB - Identification of microorganisms by matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS) has been widely accepted. However, the significance of MALDI-TOF MS for identifying mycobacteria, particularly rare nontuberculous mycobacteria, has not been established. M. heckeshornense is one such bacteria, and distinguishing it from M. xenopi is difficult. The patient was a 40-year-old man with Behcet's disease who had started treatment with prednisolone and azathioprine. A lung nodule in the right lower lobe was pointed out, and it increased in size 6 months later. Bronchoscopy was performed, and was culture positive for mycobacteria. It was identified as M. heckeshornense by MALDI-TOF MS with a score value of 1.928. Analysis of the 16S rRNA, rpoB, and hsp65 genes confirmed the result of MALDI-TOF MS. MALDI-TOF MS seems reliable for the diagnosis of M. heckeshornense infection. PMID- 29503225 TI - Reciprocal modulation of mesenchymal stem cells and tumor cells promotes lung cancer metastasis. AB - Metastasis is a multi-step process in which direct crosstalk between cancer cells and their microenvironment plays a key role. Here, we assessed the effect of paired tumor-associated and normal lung tissue mesenchymal stem cells (MSCs) on the growth and dissemination of primary human lung carcinoma cells isolated from the same patients. We show that the tumor microenvironment modulates MSC gene expression and identify a four-gene MSC signature that is functionally implicated in promoting metastasis. We also demonstrate that tumor-associated MSCs induce the expression of genes associated with an aggressive phenotype in primary lung cancer cells and selectively promote their dissemination rather than local growth. Our observations provide insight into mechanisms by which the stroma promotes lung cancer metastasis. PMID- 29503228 TI - Early linezolid-associated lactic acidosis in a patient with Child's class C liver cirrhosis and end stage renal disease. AB - Linezolid, an oxazolidinone antibiotic, does not required dose adjustment in patients with Child's class A and B liver cirrhosis. The dose adjustment data for Child's class C liver cirrhosis is inadequate. We reported a case of Child's class C liver cirrhosis, in which lactic acidosis, an adverse effect related to prolonged use, occurred only after two weeks of linezolid treatment. A 63-year old male had underlying diseases, such as end-stage renal disease (ESRD) and Child's class C liver cirrhosis, and was admitted for hepatic encephalopathy management and liver transplantation evaluation. Spontaneous bacterial peritonitis and septic shock occurred during admission. Because ascites culture revealed vancomycin-resistant Enterococci (VRE), daptomycin was initially prescribed. Subsequently, VRE bacteremia occurred, and infective endocarditis was confirmed. Following treatment failure with daptomycin use, intravenous linezolid (600 mg q12h) was added for synergic effect. VRE bacteremia quickly resolved following linezolid treatment, and vasopressor use was reduced. Despite stable hemodynamics, lactic acidosis still persisted, and linezolid therapeutic drug monitoring was ordered. High linezolid trough concentration (49 mg/L) was found by therapeutic drug monitoring, and linezolid-associated lactic acidosis was highly suspected. Therefore, linezolid treatment was stopped and patient's lactic acid level returned to normal after one week. VRE bacteremia recurred after discontinuation of linezolid; therefore, linezolid was re-prescribed at the lower dose (600 mg). Linezolid trough concentration was within the therapeutic range this time (6.1 mg/L), and lactic acidosis did not occur when linezolid dose was reduced. Therefore, empirically decreased dose and therapeutic drug monitoring should be considered in patients with Child's class C liver cirrhosis and ESRD. PMID- 29503227 TI - Characteristics of health problems in returned overseas travelers at a tertiary teaching hospital in a suburban area in Japan. AB - Few studies have analyzed the characteristics of patients who develop physical disorders after overseas travel. We retrospectively reviewed the medical records of 183 patients who visited Nara Medical University Hospital from 2008 to 2016 because of physical problems after traveling abroad. The main travel destinations were Southeast Asia (n = 100), Africa (n = 27), and South Asia (n = 23). The main reasons for the travel were leisure (n = 96), business (n = 51), and volunteer work (n = 19). The most common final diagnosis was gastrointestinal disease (n = 72), followed by febrile disease (n = 59) and respiratory disease (n = 19). There were eight malaria cases, including one patient who was infected after <14 days of overseas travel. Additionally, 61 of 71 cases of travelers' diarrhea and 15 of 21 cases of dengue fever occurred after <14 days travel. 26 cases of vaccine preventable diseases, such as hepatitis A, typhoid fever, and influenza, were observed. Consequently, healthcare providers should notify Japanese overseas travelers that there is a non-negligible health risk inherent to short-term travel, while stressing on the importance of pre-travel medical consultation. PMID- 29503229 TI - The 2016 JAID/JSC guidelines for clinical management of infectious disease Odontogenic infections. PMID- 29503230 TI - Effects of a lifestyle intervention on psychosocial well-being of severe mentally ill residential patients: ELIPS, a cluster randomized controlled pragmatic trial. AB - Large studies investigating the psychosocial effects of lifestyle interventions in patients with a severe mental illness (SMI) are scarce, especially in residential patients. This large, randomized controlled, multicentre pragmatic trial assessed the psychosocial effects of a combined diet-and-exercise lifestyle intervention targeting the obesogenic environment of SMI residential patients. Twenty-nine sheltered and clinical care teams were randomized into intervention (n=15) or control (n=14) arm. Team tailored diet-and-exercise lifestyle plans were set up to change the obesogenic environment into a healthier setting, and team members were trained in supporting patients to make healthier choices. The control group received care-as-usual. The Calgary Depression Scale for Schizophrenia (CDSS), Positive and Negative Syndrome Scale (PANSS), Health of the Nation Outcome Scales (HoNOS) and the Manchester Short Assessment of Quality of Life (MANSA) were assessed at baseline and after three and twelve months. Data were available for 384 intervention and 386 control patients (48.6+/-12.5years old, 62.7% males, 73.7% psychotic disorder). Linear mixed model analysis showed no psychosocial improvements in the intervention group compared to care-as-usual; the intervention group showed a slightly reduced quality of life (overall) and a small increase in depressive symptoms (clinical care facilities) and psychotic symptoms (sheltered facilities). This may be due to difficulties with implementation, the intervention not being specifically designed for improvements in mental well-being, or the small change approach, which may take longer to reach an effect. Further research might elucidate what type of lifestyle intervention under what circumstances positively affects psychosocial outcomes in this population. PMID- 29503231 TI - Second-to-fourth digit length ratio is associated with negative and affective symptoms in schizophrenia patients. AB - BACKGROUND: Higher levels of circulating oestrogens in women and testosterone in men have been shown to have a protective effect against the clinical manifestations of schizophrenia, mostly with respect to negative symptomatology. Certain studies suggest that they also have a protective effect against the neuropsychological impairment observed in the disease. We investigated whether greater prenatal exposure to estrogens in women and to testosterone in men, reflected by the 2D:4D ratio, was similarly associated with decreased negative symptomatology and improved neuropsychological functioning in patients. METHOD: 51 schizophrenia patients and 50 healthy participants were administered a neuropsychological battery. The 2D:4D ratio was measured in all participants. Positive, negative, and affective symptoms were assessed in patients. Regression analyses were conducted separately in male and female subgroups. RESULTS: No associations with positive symptoms were revealed. In male patients, the 2D:4D ratio was positively associated with avolition and inversely associated with anxiety. In female patients, it was inversely associated with alogia, and tended to be positively associated with depression. No association between higher prenatal concentration of the relevant sex hormone and improved neuropsychological performance emerged in patients. CONCLUSIONS: Higher concentrations of prenatal testosterone in male patients, and prenatal oestrogens in female patients, are associated with a decrement in certain aspects of negative symptomatology. In addition, prenatal sex hormone concentration seems to be associated with predisposition to anxiety in male patients, and to depression in female patients. PMID- 29503232 TI - Potentially fatal outcomes associated with clozapine. AB - Clozapine has been shown to be the most efficacious therapy for treatment resistant schizophrenia, estimated at one third of all schizophrenia cases. There is significant morbidity and mortality associated with clozapine including risk of agranulocytosis, aspiration pneumonia, bowel ischemia, myocarditis, seizures, and weight gain. Here we present a case of a 62-year-old man with chronic paranoid schizophrenia refractory to numerous antipsychotics who was started on clozapine therapy during an acute inpatient psychiatric admission. Within three weeks of starting clozapine, the patient developed flu-like symptoms, pleuritic chest pain, and was sent to a medical hospital for evaluation. After transfer, the patient had a rapidly deteriorating course with newly developed congestive heart failure, acute respiratory failure requiring intubation, and cardiovascular collapse requiring vasopressors. The patient expired within two days of transfer and four days after initial symptoms developed. The underlying etiology in this case is likely clozapine induced myocarditis leading to rapid cardiovascular collapse and death. Mortality with clozapine induced myocarditis has been estimated up to 24%. Given that 90% of clozapine cardiotoxic sequelae are seen in the first month post-initiation, more rigorous post-initiation surveillance is recommended for the first four weeks of clozapine with weekly cardiac enzymes (troponins, creatinine kinase-MB), EKG, and acute inflammatory markers (C reactive protein, and erythrocyte sedimentation rate). PMID- 29503233 TI - Critically Appraised Papers: Moderate-intensity walking for people with severe knee osteoarthritis does not decrease pain but may have cardiovascular benefits [commentary]. PMID- 29503234 TI - Consensus on insulin treatment in type 2 diabetes. PMID- 29503235 TI - Tricuspid annular plane systolic excursion-to-aortic ratio provides a bodyweight independent measure of right ventricular systolic function in dogs. AB - OBJECTIVES: To evaluate whether tricuspid annular plane systolic excursion (TAPSE) can be normalized to aortic valve (Ao) measurements in dogs. To determine TAPSE:Ao reference intervals for healthy dogs and examine diagnostic performance of TAPSE:Ao in dogs with pulmonary hypertension (PH). ANIMALS: One hundred and thirty-seven healthy adult dogs; 115 dogs with myxomatous mitral valve disease (MMVD) but no PH; 91 dogs with PH. METHODS: A combined prospective and retrospective study. Full echocardiographic evaluations were performed on all dogs; TAPSE was indexed to Ao to produce a unitless TAPSE:Ao. Reference intervals for TAPSE:Ao were generated, and TAPSE:Ao was regressed on tricuspid regurgitant jet velocity in dogs with PH and on LA:Ao in dogs with MMVD without PH. Diagnostic test analysis was used to examine the ability of TAPSE:Ao to identify severe PH. An adjusted TAPSE:Ao (TAPSE:Ao(adj)) was derived to account for MMVD in dogs with PH. RESULTS: The ratio, TAPSE:Ao, removed the effect of bodyweight from TAPSE measurements. Healthy dogs had TAPSE:Ao > 0.65. The ratio, TAPSE:Ao, showed a linear negative relationship with tricuspid regurgitation velocity and positive relationship with LA:Ao. The adjusted ratio, TAPSE:Ao(adj), increased the sensitivity of diagnosis of PH in dogs with moderate-severe MMVD without affecting the diagnosis of PH in dogs with PH and with no or mild MMVD. CONCLUSIONS: The ratios, TAPSE:Ao and TAPSE:Ao(adj), are a bodyweight-independent means of assessing right ventricular systolic function in dogs and for identifying severe PH in dogs with or without MMVD. PMID- 29503236 TI - Society of Interventional Radiology Reporting Standards for Thoracic Central Vein Obstruction: Endorsed by the American Society of Diagnostic and Interventional Nephrology (ASDIN), British Society of Interventional Radiology (BSIR), Canadian Interventional Radiology Association (CIRA), Heart Rhythm Society (HRS), Indian Society of Vascular and Interventional Radiology (ISVIR), Vascular Access Society of the Americas (VASA), and Vascular Access Society of Britain and Ireland (VASBI). PMID- 29503237 TI - [Management of assisted reproductive technology (ART) in case of endometriosis related infertility: CNGOF-HAS Endometriosis Guidelines]. AB - The management of endometriosis related infertility requires a global approach. In this context, the prescription of an anti-gonadotropic hormonal treatment does not increase the rate of non-ART (assisted reproductive technologies) pregnancies and it is not recommended. In case of endometriosis related infertility, the results of IVF management in terms of pregnancy and birth rates are not negatively affected by the existence of endometriosis. Controlled ovarian stimulation during IVF does not increase the risk of endometriosis associated symptoms worsening, nor accelerate the intrinsic progression of endometriosis and does not increase the rate of recurrence. However, in the context of IVF management for women with endometriosis, pre-treatment with GnRH agonist or with oestrogen/progestin contraception improve IVF outcomes. There is currently no evidence of a positive or negative effect of endometriosis surgery on IVF outcomes. Information on the possibilities of preserving fertility should be considered, especially before surgery. PMID- 29503238 TI - [Endometrioma and management by assisted reproductive technology: CNGOF-HAS Endometriosis Guidelines]. AB - Could the presence of an endometrioma change the management of Assisted Reproductive Technology? The presence of an endometrioma (<6cm) at the time of stimulation or an endometrioma operated prior to stimulation have no impact on the quality of the embryos and the final results of IVF about the pregnancy and live birth rates despite a possible decrease in the number of oocytes retrieved and potentially higher doses of gonadotropins used. The discovery of an endometrioma during IVF stimulation should not lead to an interruption of the attempt. Their surgical treatment before IVF is not recommended just to improve fertility. It is discussed in case of painful symptomatology, depending on the size and/or in case of diagnosis doubt. The associated indications for ART management and surgical history for endometrioma should also be taken into account. There is no benefit of prophylactic surgery to decrease the risk of tubo ovarian abscess post ovarian retrieval. It is not recommended to make a systematic trans-vaginal ultrasound guided aspiration with or without sclerotherapy of endometriomas before IVF in order to increase pregnancy rates, but it is reserved in case of endometrioma that may hinder the oocyte retrieval. Ethanol sclerotherapy decreases the recurrence rate of endometriomas without altering the results of IVF while a second surgery would have a deleterious effect. PMID- 29503239 TI - Exercise Training Potentiates The Cardioprotective Effects of Stem Cells Post infarction. AB - BACKGROUND: Preconditioning of cell recipients may exert a significant role in attenuating the hostility of the infarction milieu, thereby enhancing the efficacy of cell therapy. This study was conducted to examine whether exercise training potentiates the cardioprotective effects of adipose-derived stem cell (ADSC) transplantation following myocardial infarction (MI) in rats. METHODS: Four groups of female Fisher-344 rats were studied: Sham; non-trained rats with MI (sMI); non-trained rats with MI submitted to ADSCs transplantation (sADSC); trained rats with MI submitted to ADSCs (tADSC). Rats were trained 9 weeks prior to MI and ADSCs transplantation. Echocardiography was applied to assess cardiac function. Myocardial performance was evaluated in vitro. Protein expression analyses were carried out by immunoblotting. Periodic acid-Schiff staining was used to analyse capillary density and apoptosis was evaluated with terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay. RESULTS: Echocardiography performed 4 weeks after the infarction revealed attenuated scar size in the both sADSC and tADSC groups compared to the sMI group. However, fractional shortening was improved only in the tADSC group. In vitro myocardial performance was similar between the tADSC and Sham groups. The expression of phosphoSer473Akt1 and VEGF were found to be higher in the hearts of the tADSC group compared to both the sADSC and sMI groups. Histologic analysis demonstrated that tADSC rats had higher capillary density in the remote and border zones of the infarcted sites compared to the sMI rats. CONCLUSIONS: Preconditioning with exercise induces a pro-angiogenic milieu that may potentiate the therapeutic effects of ADSCs on cardiac remodelling following MI. PMID- 29503240 TI - Coronary Artery Fistulae: Anatomy, Diagnosis and Management Strategies. AB - Coronary artery fistula (CAF) is a relatively rare anatomic abnormality of the coronary arteries that afflicts 0.002% of the general population and represents 14% of all the anomalies of coronary arteries. Its clinical relevance focusses mainly on the mechanism of "coronary steal phenomenon", causing myocardial functional ischaemia even in the absence of stenosis, hence common symptoms are angina or effort dyspnoea. The suggested diagnostic approach is guided by the patient's symptoms and consists of a number of instrumental examinations like ECG, treadmill test, echocardiography, computed tomography scan, cardiac magnetic resonance and coronary angiography. If it is not an incidental finding, coronary angiography is required in view of the optimal therapeutic planning. Small-sized fistulae are usually asymptomatic and have an excellent prognosis if managed medically with clinical follow-up with echocardiography every 2 to 5 years. In the case of symptomatic, large-sized or giant fistulae an invasive treatment, by transcatheter approach or surgical ligation, is usually a reasonable choice, and both strategies show equivalent results at long-term follow-up. Antibiotic prophylaxis for the prevention of bacterial endocarditis is recommended in all patients with coronary artery fistulae who undergo dental, gastrointestinal or urological procedures. A life-long follow-up is always essential to ensure that the patient is not undergoing progression of disease or further cardiac complications. PMID- 29503241 TI - Increased Admissions Due to Cardiac Complications of Thyrotoxicosis in Maori. AB - BACKGROUND: As thyrotoxicosis is a risk factor for atrial fibrillation, current guidelines recommend measuring a thyroid-stimulating hormone level in patients with this disorder. Hyperthyroidism may also be associated with other heart diseases including cardiac ischaemia and cardiac failure. Currently, the prevalence of thyrotoxicosis in cardiac admissions in the absence of a rhythm disorder is unknown. AIMS: The aims of this study were: 1) to calculate the prevalence of admissions for thyrotoxicosis-associated cardiac disease, 2) determine the type of cardiac disease i.e. dysrhythmic, ischaemic or cardiac failure, and 3) to assess whether Maori are over-represented amongst patients admitted to hospital with cardiac complications of thyrotoxicosis. METHODS: A retrospective review of admissions with both thyrotoxicosis and cardiac disease from 1 January 2005 to 31 December 2012 inclusive. RESULTS: Seventy-two patients were identified as being admitted for a cardiac complication of thyrotoxicosis, giving a mean of nine admissions per year. Dysrhythmia was the cause for admission in 32 patients, ischaemia in 12, cardiac failure in 11 and mixed cardiac disease in 17. Graves' disease and amiodarone-induced were the most common causes of the thyrotoxicosis (25 and 19 cases, respectively). Of the cohort 26 (36.1%) were Maori (compared to 16.8% of all cardiac admissions over the same period). Maori were more likely to present with cardiac failure than non Maori (57.7% vs. 26.1%, p=0.008 respectively). CONCLUSIONS: Maori are over represented amongst patients admitted with cardiac complications of thyrotoxicosis and more often present with cardiac failure than non-Maori. Measurement of thyroid function should be considered in patients presenting not only with atrial fibrillation but also in patients presenting with cardiac failure, particularly if they are Maori. PMID- 29503242 TI - Increased Survival Time With SS-31 After Prolonged Cardiac Arrest in Rats. AB - Cardiac arrest is one of the leading causes of death with a very high mortality rate. No therapeutic drug that can be administered during resuscitation has been reported. Mitochondrial dysfunction is believed to play an important role for the pathogenesis of cardiac arrest. SS-31, a tetra-peptide, has been shown to protect mitochondria from ischaemia/reperfusion injury. Therefore, we tested whether SS 31 improves rat survival after prolonged cardiac arrest. Rats were randomised into two groups. After 25minutes of asphyxia-induced cardiac arrest, rats were resuscitated with or without SS-31 using cardiopulmonary bypass resuscitation. Rat survival was followed for additional 4.5hours using haemodynamic monitoring. The blood gas was analysed for surviving rats at multiple time points. After 5hours, 5 of 10 rats survived in the SS-31 group whereas only 1 of 10 rats survived in the control group (p=0.026). At 90minutes after resuscitation, the blood lactate level in the SS-31 treated rats (4.29+/-2.5mmol/L) was significantly lower than in control rats (7.36+/-3.1mmol/L, p=0.026), suggesting mitochondrial aerobic respiration was improved with SS-31 treatment. Overall, our data show the potential of SS-31 as a novel therapeutic in cardiac arrest. PMID- 29503243 TI - Manual Braiding of GoreTex Neochords to Ensure Correct Length in Mitral Valve Repair. AB - Ascertaining the correct length of neochords during mitral valve repair is challenging. We describe a modified technique of chordal replacement where a GoreTex (W.L. Gore and Assoc, Inc, Flagstaff, AZ, USA) sutures are repeatedly tied so as to braid the suture to the optimal length before sutures are passed through the mitral leaflet. The length of the braided chord remains fixed when tying on the atrial side. For bileaflet repairs, a second suture is incorporated into the initial chord to create a "Y" braided neo-chord configuration. This technique facilitates precision in mitral repair. PMID- 29503244 TI - Larotrectinib in TRK fusion-positive cancers. PMID- 29503245 TI - Pattern of Care Study in Metastatic Renal-Cell Carcinoma in the Preimmunotherapy Era in Switzerland. AB - INTRODUCTION: In metastatic renal-cell carcinoma (mRCC), physicians have a plethora of therapeutic choices, with the latest addition of checkpoint inhibitors. However, many questions regarding the best use of the respective drugs remain unanswered. Therefore, it is important to examine and summarize the outcome of real-world experiences to understand the practical value of the various drugs in daily use and foster optimal treatment algorithms for patients with renal-cell carcinoma. We sought to describe the pattern of care in mRCC under circumstances with access to all therapeutic options for patients. PATIENTS AND METHODS: We examined the outcome of patients with mRCC who were treated at 8 major centers in Switzerland, mainly with vascular endothelial growth factor targeted therapy and mammalian target of rapamycin inhibitors. Data from 110 patients with mRCC who had undergone more than one systemic therapy were collected and analyzed. We assessed the pattern of care for patients with mRCC in an unrestricted health care system and outcomes with regard to the respective treatment sequences. We also studied the compliance of individual therapies with published guidelines and correlated the adherence to outcome. Finally, immediate versus deferred treatment and the number of received therapeutic drug lines were analyzed. RESULTS: Median survival of patients treated with targeted agents for mRCC was 2.0 years. CONCLUSION: Exposure to more than 2 lines of systemic drugs did not improve outcome of patients with mRCC. PMID- 29503246 TI - Polymorphisms in the Von Hippel-Lindau Gene Are Associated With Overall Survival in Metastatic Clear-Cell Renal-Cell Carcinoma Patients Treated With VEGFR Tyrosine Kinase Inhibitors. AB - BACKGROUND: Clear-cell renal-cell carcinoma (ccRCC) is characterized by loss of a functional Von Hippel-Lindau (VHL) protein. We investigated the potential of 3 single nucleotide polymorphisms (SNPs) in VHL as biomarkers in metastatic ccRCC (m-ccRCC) patients treated with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs). PATIENTS AND METHODS: We genotyped 3 VHL SNPs in 199 m-ccRCC patients: rs1642742 T > C, rs1642743 A > G, and rs1678607 C > A. Primary end points were response rate (RR), progression-free survival (PFS), and overall survival (OS) after start of first-line TKI. RR was compared with Fisher's exact test, and PFS and OS with Kaplan-Meier analysis and multivariable Cox regression. Secondary end points were association with VHL promotor hypermethylation, VHL mutation status, VHL loss of heterozygosity, >= 25% sarcomatoid dedifferentiation, and expression of genes implicated in angiogenesis and immunoresponse (Fisher's exact test and unpaired t tests). RESULTS: The minor alleles of rs1642742 and rs1642743, known to be in close linkage disequilibrium, were associated with poor outcome, following a recessive pattern. For the rs1642742 CC versus TT/TC genotype, OS was 11 versus 26 months (hazard ratio = 2.3; 95% confidence interval, 1.2-6.6; P = .015). For the rs1642743 GG versus AA/AG genotype, OS was 15 versus 28 months (hazard ratio = 2.6; 95% confidence interval, 1.4-5.0; P = .004). After multivariable analysis, both remained linked with poor OS (P = .018 and P = .009, respectively). There was a trend toward shorter PFS and poorer RR. Both SNPs were associated with >= 25% sarcomatoid dedifferentiation (P = .037 and .006, respectively). No significant results were found for rs1678607. CONCLUSION: rs1642742 and rs1642743 are candidate biomarkers for poor OS in m-ccRCC patients receiving first-line VEGFR-TKI. They are associated with higher levels of sarcomatoid dedifferentiation. PMID- 29503248 TI - Microwave or radiofrequency ablation: clinically equivalent? PMID- 29503249 TI - Successful Rescue Cerclage in a Monochorionic Diamniotic Twin Pregnancy at 20 Weeks: Case Report and Overview of Literature. AB - BACKGROUND: In twin pregnancies, elective cerclage placement based on obstetrical history or ultrasound findings has been shown to be ineffective and even harmful. There are currently no guidelines for the use of rescue cervical cerclage in twin pregnancies. CASE: The current report presents the case of a 33-year-old patient with monochorionic diamniotic twins (MCDA) found to have dilated cervix at 3.5cm with exposed membranes upon physical examination at 19 weeks and 3 days. An emergency McDonald cerclage was placed at 20 weeks and the patient carried the current pregnancy until 35weeks 6 days. CONCLUSION: Rescue cerclage represents an important option to consider in order to preserve twin pregnancies regardless of chorionicity. PMID- 29503247 TI - Efficacy of microwave ablation versus radiofrequency ablation for the treatment of hepatocellular carcinoma in patients with chronic liver disease: a randomised controlled phase 2 trial. AB - BACKGROUND: Radiofrequency ablation is the recommended treatment for patients with hepatocellular carcinoma who have lesions smaller than 3 cm and are therefore not candidates for surgery. Microwave ablation is a more recent technique with certain theoretical advantages that have not yet been confirmed clinically. We aimed to compare the efficacy of both techniques in the treatment of hepatocellular carcinoma lesions of 4 cm or smaller. METHODS: We did a randomised controlled, single-blinded phase 2 trial at four tertiary university centres in France and Switzerland. Patients with chronic liver disease and hepatocellular carcinoma with up to three lesions of 4 cm or smaller who were not eligible for surgery were randomised to receive microwave ablation (experimental group) or radiofrequency ablation (control group). Randomisation was centralised and done by use of a fixed block method (block size 4). Patients were randomly assigned by a co-investigator by use of the sealed opaque envelope method and were masked to the treatment; physicians were not masked to treatment, since the devices used were different. The primary outcome was the proportion of lesions with local tumour progression at 2 years of follow-up. Local tumour progression was defined as the appearance of a new nodule with features typical of hepatocellular carcinoma in the edge of the ablation zone. All analyses were done in the per-protocol population. The study is completed, but patients will continue to be followed up for 5 years. This study is registered with ClinicalTrials.gov, number NCT02859753. FINDINGS: Between Nov 15, 2011, and Feb 27, 2015, 152 patients were randomly assigned: 76 patients to receive microwave ablation and 76 patients to receive radiofrequency ablation. For the per-protocol analysis, five patients were excluded from the microwave ablation group as were three patients from the radiofrequency ablation group. Median follow-up was 26 months (IQR 18-29) in the microwave ablation group and 25 months (18-34) in the radiofrequency ablation group. At 2 years, six (6%) of 98 lesions had local tumour progression in the microwave ablation group as did 12 (12%) of 104 in the radiofrequency ablation group (risk ratio 1.62, 95% CI 0.66-3.94; p=0.27). Complications were infrequent, with only two grade 4 complications (two events of arterial bleeding requiring embolisation, both in the microwave ablation group) and three grade 3 complications (pneumothorax; lesion of the umbilical vein; and intrahepatic segmental necrosis, all in the radiofrequency ablation group). No treatment-related deaths were reported. INTERPRETATION: Although we did not find that microwave ablation was more effective than radiofrequency ablation for treatment of hepatocellular carcinoma lesions of 4 cm or smaller, our results show that the proportion of lesions with local tumour progression at 2 years of follow-up was low with both tested percutaneous methods. FUNDING: Microsulis (AngioDynamics). PMID- 29503250 TI - Incidence and Carrier Frequency of CFTR Gene Mutations in Pregnancies With Echogenic Bowel in Nova Scotia and Prince Edward Island. AB - OBJECTIVE: Fetal echogenic bowel (echogenic bowel) is associated with cystic fibrosis (CF), with a reported incidence ranging from 1% to 13%. Prenatal testing for CF in the setting of echogenic bowel can be done by screening parental or fetal samples for pathogenic CFTR variants. If only one pathogenic variant is identified, sequencing of the CFTR gene can be undertaken, to identify a second pathogenic variant not covered in the standard screening panel. Full gene sequencing, however, also introduces the potential to identify variants of uncertain significance (VUSs) that can create counselling challenges and cause parental anxiety. To provide accurate counselling for families in the study population, the incidence of CF associated with echogenic bowel and the carrier frequency of CFTR variants were investigated. METHODS: All pregnancies for which CF testing was undertaken for the indication of echogenic bowel (from Nova Scotia and Prince Edward Island) were identified (January 2007-July 2017). The CFTR screening and sequencing results were reviewed, and fetal outcomes related to CF were assessed. RESULTS: A total of 463 pregnancies with echogenic bowel were tested. Four were confirmed to be affected with CF, giving an incidence of 0.9% in this cohort. The carrier frequency of CF among all parents in the cohort was 5.0% (1 in 20); however, when excluding parents of affected fetuses, the carrier frequency for the population was estimated at 4.1% (1 in 25). CFTR gene sequencing identified an additional VUS in two samples. CONCLUSION: The incidence of CF in pregnancies with echogenic bowel in Nova Scotia and Prince Edward Island is 0.9%, with an estimated population carrier frequency of 4.1%. These results provide the basis for improved counselling to assess the risk of CF in the pregnancy, after parental carrier screening, using Bayesian probability. Counselling regarding VUSs should be undertaken before gene sequencing. PMID- 29503251 TI - No. 357-Immunization in Pregnancy. AB - OBJECTIVE: To review the evidence and provide recommendations on immunization in pregnancy. OUTCOMES: Outcomes evaluated include effectiveness of immunization and risks and benefits for mother and fetus. EVIDENCE: The Medline and Cochrane databases were searched for articles published up to January 2017 on the topic of immunization in pregnancy. VALUES: The evidence obtained was reviewed and evaluated by the Infectious Diseases Committee of the SOGC under the leadership of the principal authors, and recommendations were made according to guidelines developed by the Canadian Task Force on Preventive Health Care (Table 1). BENEFITS, HARMS, AND COSTS: Implementation of the recommendations in this guideline should result in more appropriate immunization of pregnant and breastfeeding women, decreased risk of contraindicated immunization, and better disease prevention. RECOMMENDATIONS: PMID- 29503252 TI - SCUBA Diving in Pregnancy. AB - OBJECTIVE: Obstetrical care providers may occasionally encounter women with questions about the safety of Self-Contained Underwater Breathing Apparatus (SCUBA) diving in pregnancy. This article provides an overview of safety issues associated with basic SCUBA diving and offers guidance to practitioners about how to evaluate and counsel pregnant women about the associated maternal and fetal risks. Basic diving physiology is reviewed and the implications of SCUBA diving during pregnancy are discussed. A literature review examined available animal and human data about the potential adverse effects of the physiological changes of pregnancy on divers, the impact of pressure changes during diving, and possible consequences of hyperbaric gas exposure and rapid decompression on mother and fetus. DATA SOURCES: Studies were found by searching the terms "scuba diving," "pregnancy," "fetus," "decompression illness," "hyperbaric medicine," and "animal studies" in the databases Medline, Pubmed, and Embase. Reference lists from existing articles and reports from identified diving magazines were also reviewed. Studies were limited to the English language and included publications until 2016. STUDY SELECTION: All relevant human studies were selected. Five retrospective studies and one prospective study assessing the antenatal and postnatal outcomes of women who participated in SCUBA diving while pregnant were reviewed. DATA SYNTHESIS: Published data was limited in both quantity and quality. The authors' experience with SCUBA diving together with a background in obstetrics allowed themes to be explored and recommendations developed. CONCLUSIONS: In addition to established risks of SCUBA diving, pregnant women are at increased risk due to changes in body habitus (affecting equipment fitting and balance). Animal data suggest possible adverse fetal effects due to fetal decompression illness (DCI) and hyperbaric oxygen exposure. Human data, though generally reassuring, are of poor quality and thus do not completely exclude adverse outcomes. In general, women should be cautioned to avoid diving during pregnancy, but inadvertent exposure to recreational diving in early pregnancy is not a reason for pregnancy termination. PMID- 29503253 TI - No 357 - Immunisation pendant la grossesse. PMID- 29503254 TI - Factors Associated with Trial of Labour and Mode of Delivery in Robson Group 5: A Select Group of Women With Previous Caesarean Section. AB - OBJECTIVE: To determine the proportion of women in Robson group 5 (RG5) who were eligible for a trial of labour after Caesarean (TOLAC) and, among eligible candidates, identify determinants of having a TOLAC and subsequent vaginal delivery (VD). METHODS: This population-based cohort study used data derived from the Nova Scotia Atlee Perinatal Database. Deliveries from 1998-2014 to women in RG5 (>=1 previous CS with a singleton term cephalic fetus) were included. Eligibility for a TOLAC was based on SOGC criteria. Multivariable logistic regression was used to identify characteristics independently associated with TOLAC and VD. The characteristics associated with VD were used in a logistic model to predict the theoretical probability of VD in women who did not have a TOLAC. RESULTS: Of the 15 111 deliveries in RG5, 75.3% were by CS. Of the 14 763 eligible women, 5488 (37.2%) had a TOLAC, of which 3739 (68.1%) resulted in VD. Predictors of VD included high area-level income and either a CS without labour or a spontaneous VD in the preceding pregnancy. While mode of previous delivery also predicted TOLAC among eligible women, high area-level income was associated with reduced odds of TOLAC. The probability of VD in women who did not undergo TOLAC was estimated to be 47.1%, and the lowest CS rate attainable in RG5 was estimated at 46.3%. CONCLUSIONS: Sociodemographic factors such as income and previous mode of delivery were associated with the rates of TOLAC and subsequent VD in eligible women, and suggest that the Caesarean section rate in RG5 could be safely reduced. PMID- 29503255 TI - Impact of energy devices on the post-operative systemic immune response in women undergoing total laparoscopic hysterectomy for benign disease of the uterus. AB - OBJECTIVE: Laparoscopic surgery is associated with reduced surgical stress response, lesser post- operative immune function, and consequent early recovery compared with conventional open surgery. There is a lack of evidence regarding the inflammatory stress response with the use of different energy devices. The present study was conducted to evaluate and compare the inflammatory response in total laparoscopic hysterectomy (TLH) using three different energy devices. MATERIAL AND METHODS: A prospective randomized controlled study was conducted in 60 women with abnormal uterine bleeding undergoing TLH. They were divided into three groups based on the energy devices used, namely integrated bipolar and ultrasonic energy (Thunderbeat), ultrasonic (Harmonic) and electrothermal bipolar vessel sealing system (Ligasure). Cytokines and chemokines were measured in all three groups at different time points. RESULTS: Serum levels of interleukin (IL) 6 and tumor necrosis factor-alpha (TNF-alpha) increased postsurgery in all three groups and gradually declined by 72 hours. The geometric mean serum (IL)-6 levels was highest with Ligasure at 24 hours as compared with the other groups. Levels of TNF-alpha, macrophage inflammatory protein (MIP-1) alpha, MIP-1 beta were also higher at 3 hours in the Ligasure group. When the differences between the groups were measured at different time points, there was a significantly greater increase in serum IL-6 levels in the Ligasure group at 24 hours (p=0.010). No significant difference was found in the post-operative course between the groups. CONCLUSION: A greater inflammatory response was seen after the use of Ligasure indicating greater tissue damage. However, this response was not correlated with any difference in postoperative recovery. PMID- 29503256 TI - Short-term results of the efficacy of percutaneous tibial nerve stimulation on urinary symptoms and its financial cost. AB - OBJECTIVE: Overactive bladder (OAB) affects 16.9% of women in the United States. Percutaneous tibial nerve stimulation (PTNS) is a third-line treatment for patients who are refractory to behavioral and pharmacologic therapies. We aimed to evaluate the effects of PTNS on urinary symptoms in patients diagnosed as having refractory OAB and investigate the cost of medications and clinical visits before and after PTNS treatment. MATERIAL AND METHODS: We reviewed 60 women with refractory OAB treated with PTNS. Episodes of urinary frequency, leakage, urgency, and nocturia; number of follow-up visits; and medications were recorded. The mean quarterly drug, physician, nurse, and provider costs were calculated. The episodes of urinary symptoms, numbers of follow-up visits, and costs of medications and visits before and after PTNS were compared. RESULTS: Of the 60 patients with refractory OAB, 24 patients who completed 12 weekly sessions of initial PTNS were evaluated. The number of urinary symptoms and follow-up visits significantly decreased after PTNS (p<0.05). The average quarterly medication cost decreased from $656.36+/-292.45 to $375.51+/-331.79 after PTNS (p=0.001). After PTNS, quarterly physician and nurse visit costs decreased from $81.73+/ 70.39 to $25.89+/-54.40 and from $55.23+/-38.32 to $15.53+/-19.58, respectively (p<0.05). The quarterly total provider cost was similar before and after PTNS. CONCLUSION: PTNS treatment significantly improved urinary symptoms of patients with refractory OAB and reduced the costs of medications and physician and nurse visits. PMID- 29503259 TI - The effect of progesterone use in the first trimester on fetal nuchal translucency. AB - OBJECTIVE: To evaluate the possible association between progesterone use in the first trimester of pregnancy and fetal nuchal translucency (NT). MATERIAL AND METHODS: This is an observational case-control study, which was conducted with patients who underwent nuchal scans between March 2015 and February 2016 and consequently delivered live and healthy babies. The study group was composed of assisted reproductive technology pregnancies and used intravaginal progesterone 180 mg/day until gestational week 12. The control group comprised pregnant women who became pregnant spontaneously without using any progesterone preparation in the first trimester. RESULTS: One hundred sixty-four (57.5%) of 285 patients were in the control group and 121 (42.5%) were in the progesterone group. Age, bodyweight, gravidity, and parity number of previous births and abortus, gestational week, crown-rump lengths, free beta-human chorionic gonadotropin, pregnancy-associated plasma protein A, and NT values of the progesterone and control groups were recorded and we investigated whether there was a statistically significant difference between the two groups in terms of these parameters; maternal weight was found to be higher in the progesterone group than in the control group and the difference between the groups was statistically significant (p=0.019 and p=0.025). Whether the difference in NT was caused by the effect of maternal weight was investigated using the covariance analysis test and maternal weight was not found to be statistically significant in the model (p=0.284). CONCLUSION: Fetal NT was increased in the progesterone group compared with the untreated group in healthy pregnancies. PMID- 29503260 TI - Hysterectomy by vaginal-assisted natural orifice transluminal endoscopic surgery: Initial experience with twelve cases. AB - OBJECTIVE: To declare our initial experience on hysterectomy cases performed using vaginally-assisted natural orifice transluminal endoscopic surgery. MATERIAL AND METHODS: The study was conducted with data from 12 patients in our department who were recommended for hysterectomies for various indications between January 2017 and May 2017. The following data were collected retrospectively: age, body mass index (BMI), parity, previous abdominal or pelvic surgery, total operating time, preoperative hemoglobin (Hb), postoperative Hb, peri-operative complications and Visual Analogue Scale scores for evaluating postoperative pain. All patients were laid in the dorsal lithotomy position under general anesthesia. A cervical circumcision, as well as anterior and posterior colpotomy were performed. A self-constructed glove port was then inserted through the anterior and posterior colpotomy openings into the abdominal cavity. After pneumoperitoneum was achieved, a 10-mm rigid zero-degree telescope, disposable conventional laparoscopic grasping forceps, and a tissue sealer were used as standard equipment. After exploration of the abdominal cavity, all uterine vessels and ligaments were sealed and transected using the tissue sealer. After removing the uterus, the vaginal opening was closed using a Vicryl 1-0 suture. RESULTS: The following are the mean values for each variable: patients' age: 55.75+/-9.8 years (range, 43-72 years), BMI: 29.4+/-5.4 kg/m2 (range, 21-42 kg/m2), operation duration: 66.8+/-25.3 min (range, 42-120 min), decrease in Hb: 1.5+/-1 (0-4) gr/dL, and hospital stay: 2.1+/-0.3 (2-3) days. There were no vaginal wound infections or dehiscence, and no patients reported pain during postoperative pelvic examinations. CONCLUSION: Although these findings are from our initial experience, we can affirm the feasibility of this technique. PMID- 29503261 TI - Zika virus and pregnancy in Brazil: What happened? AB - The recent epidemic of Zika virus (ZIKV) infection in Central and South America is one of the most serious global public health emergencies since the Ebola outbreak in West Africa. In Brazil, especially in the north, northeast, and southeast parts of the country, the ZIKV outbreak is a cause of concern for pregnant women because ZIKV intrauterine infection has been found to be associated with multiple brain malformations and microcephaly. In Brazil, the number of newborns with confirmed microcephaly per year recorded during the ZIKV outbreak, has been approximately 15 times greater than previously reported. Considering that the infection is self-limiting and symptomatic, it is usually diagnosed at the time of routine prenatal scan, especially in the third trimester. In other cases, the disease is detected after childbirth through neuroimaging. This study provides an insight into the history and evolution of ZIKV in Brazil, including current knowledge concerning the transmission, diagnosis, and pathogenesis of the infection. In addition, this review describes the pre- and postnatal neuroimaging findings obtained using ultrasound, magnetic resonance imaging, and computed tomography. PMID- 29503263 TI - What is your diagnosis? PMID- 29503262 TI - The implications of male human papilloma virus infection in couples seeking assisted reproduction technologies. AB - Human papilloma virus (HPV) is one of the most common viral sexually-transmitted diseases worldwide. The prevalence of HPV is higher in infertile males when compared with fertile men and ranges between 10 and 35.7% in men affected by unexplained infertility. HPV can bind to spermatozoa and can potentially be transferred to fertilized oocytes. Viral detection in blastocysts and trophoblastic cells is associated with impaired embryo development and poor pregnancy outcomes. Nevertheless, attempts to eliminate HPV-DNA from sperm samples through routine washing techniques have failed. In assisted reproduction technologies (ART), intracytoplasmic sperm injection involves no natural selection of the sperm cell, which means that these procedures have a plausible risk of injecting sperm containing HPV. The possible detrimental effects of HPV on ART in couples with infected male partners are summarized in this review. PMID- 29503264 TI - Communication, orientation, coordination: A model for a laparoscopy team. PMID- 29503265 TI - Temporal Trends of High-Intensity Statin Therapy Among Veterans Treated With Percutaneous Coronary Intervention. AB - BACKGROUND: The 2013 American College of Cardiology/American Heart Association blood cholesterol guideline recommends high-intensity statin therapy among certain groups of patients, but full implementation of the guideline has not yet been satisfactory. We aimed to investigate the temporal trends and predictors of high-intensity statin therapy among veterans who had been treated with percutaneous coronary intervention (PCI) and followed up by cardiologists within the Veterans Health Administrative system. METHODS AND RESULTS: A retrospective cohort study was conducted at the Veterans Health Administrative system including all patients >18 years old who had their PCI procedure between October 2010 and September 2016. National Veterans Health Administrative databases were used to retrieve study participant's demographics, comorbid conditions, statin type and dose within 90 days before and after the PCI procedure. There were 48 862 patients who underwent a PCI procedure during the study period. High-intensity statin use at 90 days post-PCI rose from 23% in 2010 to 37% before release of the 2013 American College of Cardiology/American Heart Association cholesterol guideline, then rose sharply to 80% by 2016. The projected 10-year risk of arteriosclerotic cardiovascular disease events among our study population was projected to be ~1841 fewer if the cohort had received high-intensity statin therapy versus moderate-intensity statin. CONCLUSIONS: By 2016, the 2013 American College of Cardiology/American Heart Association blood cholesterol guideline was well implemented among veterans who had a PCI procedure in the Veterans Health Administrative system, suggesting systems of care can be improved to increase rates of high-intensity statin initiation. PMID- 29503266 TI - 55th National Conference of Indian Academy of Pediatrics 4-7 January 2018, Nagpur. PMID- 29503267 TI - Assisted Physical Exercise for Preterm Neonates. PMID- 29503268 TI - Prevention of Neurocognitive Impairment in Children Through Newborn Screening for Congenital Hypothyroidism. PMID- 29503269 TI - Neurodevelopmental Status of Children aged 6-30 months with Severe Acute Malnutrition. AB - OBJECTIVE: This cross sectional study was done to assess the developmental status in children (6-30 mo old) with severe acute malutrition (SAM). METHODS: Study subjects were enrolled from children in SAM therapeutic unit, and controls were selected from well-baby clinic of the institute. Neurodevelopment of both groups was assessed using the Developmental assessment scale of Indian infants (DASII). Developmental quotient (DQ) <=70 was considered delayed. RESULTS: Mean (SE) motor DQ 59.04 (0.74) and mental DQ 62.1 (0.57) was lower in SAM as compared to controls (both P<0.0001). Clusters of early age were normal but clusters with items of later infancy were delayed. CONCLUSION: Children with SAM show significant delay in development, and motor DQ is affected more than mental DQ. PMID- 29503270 TI - Diagnosis and Management of Gaucher Disease in India - Consensus Guidelines of the Gaucher Disease Task Force of the Society for Indian Academy of Medical Genetics and the Indian Academy of Pediatrics. AB - JUSTIFICATION: Gaucher disease (GD) is amongst the most frequently occurring lysosomal storage disorder in all ethnicities. The clinical manifestations and natural history of GD is highly heterogeneous with extreme geographic and ethnic variations. The literature on GD has paucity of information and optimal management guidelines for Indian patients. PROCESS: Gaucher Disease Task Force was formed under the auspices of the Society for Indian Academy of Medical Genetics. Invited experts from various specialties formulated guidelines for the management of patients with GD. A writing committee was formed and the draft guidelines were circulated by email to all members for comments and inputs. The guidelines were finalized in December 2016 at the annual meeting of the Indian Academy of Medical Genetics. OBJECTIVES: These guidelines are intended to serve as a standard framework for treating physicians and the health care systems for optimal management of Gaucher disease in India and to define unique needs of this patient population. RECOMMENDATIONS: Manifestations of GD are protean and a high index of suspicion is essential for timely diagnosis. Patients frequently experience diagnostic delays during which severe irreversible complications occur. Leucocyte acid b-glucosidase activity is mandatory for establishing the diagnosis of Gaucher disease; molecular testing can help identify patients at risk of neuronopathic disease. Enzyme replacement therapy for type 1 and type 3 Gaucher disease is the standard of care. Best outcomes are achieved by early initiation of therapy before onset of irreversible complications. However, in setting of progressive neurological symptoms such as seizures and or/ neuroregression, ERT is not recommended, as it cannot cross the blood brain barrier. The recommendations herein are for diagnosis, for initiation of therapy, therapeutic goals, monitoring and follow up of patients. We highlight that prevention of recurrence of the disease through genetic counseling and prenatal diagnosis is essential in India, due to uniformly severe phenotypes encountered in our population. PMID- 29503271 TI - Oral Dexamethasone versus Oral Prednisolone in Acute Asthma: A New Randomized Controlled Trial and Updated Meta-analysis: Evidence-based Medicine Viewpoint. PMID- 29503272 TI - Oral Dexamethasone versus Oral Prednisolone in Acute Asthma: A New Randomized Controlled Trial and Updated Meta-analysis: Pediatric Pulmonologist's Viewpoint. PMID- 29503273 TI - Multiple Pulmonary Nodules in an Immunocompetent Adolescent with Infectious Mononucleosis. AB - BACKGROUND: Infectious mononucleosis is usually a self-limiting illness, but can be rarely associated with complications. CASE CHARACTERISTICS: A 17-year-old boy with Epstein-Barr virus related infectious mononucleosis and cold antibody mediated autoimmune hemolytic anemia with incidentally noted multiple pulmonary nodules. OBSERVATIONS: Nodules regressed over the next few weeks without specific therapy. MESSAGE: Pediatricians need to be aware of this rare clinical presentation of infectious mononucleosis so that further invasive testing can be avoided. PMID- 29503274 TI - Cytomegalovirus Enterocolitis in a Term Neonate. AB - BACKGROUND: Cytomegalovirus (CMV) enterocolitis is rare in term neonates. CASE CHARACTERISTICS: A term newborn with persistent pneumonia from birth developed enterocolitis on day 18 of life. OUTCOME: Polymerase chain reaction (PCR) for CMV DNA was positive in urine sample. Antiviral therapy for six weeks resulted in successful treatment without any stricture formation. MESSAGE: CMV enterocolitis should be considered as a differential diagnosis in atypical cases of necrotizing enterocolitis in neonates. PMID- 29503275 TI - Feasibility of Helmet-delivered Continous Positive Airway Pressure in Very Low Birthweight Infants. AB - We describe our experience with helmet-delivered continuous positive airway pressure in five preterm newborns. We analyzed oxygen requirement, arterial oxygen saturation, respiratory rate, medium arterial pressure, heart rate, apneic spells and patient's comfort. The patients' vital signs or pain scale were not different before and after treatment. PMID- 29503276 TI - Recall Type vs Problem-based Tests for Formative Assessment in Undergraduate Medical Students. AB - We studied two types of formative assessment: recall type, and problem-based questions, with summative scores and previous grades in 77 fourth-year medical students. We found that the formative scores did not correlate well with the summative scores, but were associated with the Grade point average in the preclinical period. PMID- 29503277 TI - Ketotic Hypoglycemia in Children with Previous Transient Congenital Hyperinsulinism. AB - Congenital Hyperinsulinism (CHI) is a major cause of neonatal hypoglycemia characterised by non-ketotic hypoglycemia. We describe the occurrence and higher prevalence of ketotic hypoglycemia (KH) in 5 children with transient CHI. Four children had required diazoxide to control the persistent hypoglycemia that was discontinued at a mean age of 11.25 (+5.25) months. KH developed after an average time period of 6.7 months following the resolution of CHI. Children with transient CHI may be at risk of subsequently developing KH at a variable age period. PMID- 29503278 TI - Recurrent UTI - Make the Child Smile! PMID- 29503279 TI - Interpretation of Physical Growth among Healthy Late Preterm Neonates. PMID- 29503280 TI - Synthesis spherical porous hydroxyapatite/graphene oxide composites by ultrasonic assisted method for biomedical applications. AB - Spherical porous hydroxyapatite (SHA)/graphene oxide (GO) composites with different GO (w/w) content of 16%, 40%, and 71% have been fabricated through a facile and controllable ultrasonic-assisted method at room temperature. The products were characterized by x-ray diffraction, field emission scanning electron microscopy, thermogravimetric analysis, mechanical testing and biomimetic mineralization. Results showed SHA were covered by GO, and SHA/GO composites had an irregular surface with different degrees of wrinkles. The elastic modulus and hardness of SHA/GO-3 composites were up to 12.45 +/- 0.33 GPa and 686.67 +/- 26.95 MPa, which indicated that the contents of GO had an effect on SHA/GO composites. And the mechanical properties of SHA/GO-2 composites were similar to SHA particles. The biomimetic mineralization in SBF solution showed the bone-like apatite layer on composites surface, which demonstrated that the SHA/GO materials had osseointegration property. Moreover, in vitro cytocompatibility of SHA/GO-2 composites and pure GO were evaluated by cell adhesion and proliferation tests using MC3T3-E1 cells, which demonstrated that the SHA/GO composites can act as a good template for the cells growth and adhesion. These results suggested that the SHA/GO composites will be a promising material for biomedical application. PMID- 29503281 TI - From Syrian Refugee to Dishwasher to Heart Doctor: The Inspirational Story of Hero and Humanitarian Dr. Heval Kelli. AB - It has been said that those with the least are often the ones with the most to give. This proved to be true for a Syrian refugee turned cardiologist who provides care in communities that are poor and underserved including refugees, immigrants, minorities, those of low socioeconomic status, and other vulnerable populations. Dr. Heval Kelli is the epitome of a kind-hearted, humble, genuine hero, through his dedication to serving humanity. Between providing health care to those in need, educating future generations of doctors, mentoring high school students, and advocating for the less fortunate, his life is truly his message to the world. PMID- 29503282 TI - Getting King's Words Right. PMID- 29503283 TI - Strategies for Achieving Diversity through Medical School Admissions. AB - The relative lack of diversity in medicine is a rate limiting factor in efforts to eliminate health care disparities. Many medical schools struggle to matriculate student bodies that reflect the diversity of this country. Actively recruiting is one tactic to diversify a medical school's applicant pool, but in isolation is not enough. Our medical school admissions committee made a number of programmatic changes that contributed to our current compositional diversity that may be instructive to others. This report from the field on the experience of one U.S. medical school describes several admissions committee initiatives that can be undertaken to increase the yield of students from groups underrepresented in medicine who matriculate to medical school. PMID- 29503284 TI - Racial/Ethnic Health Disparities Among Rural Adults-United States, 2012-2015: MMWR Surveillance Summaries / November 17, 2017 / 66(23);1-9. AB - PROBLEM/CONDITION: Rural communities often have worse health outcomes, have less access to care, and are less diverse than urban communities. Much of the research on rural health disparities examines disparities between rural and urban communities, with fewer studies on disparities within rural communities. This report provides an overview of racial/ethnic health disparities for selected indicators in rural areas of the United States. REPORTING PERIOD: 2012-2015. DESCRIPTION OF SYSTEM: Self-reported data from the 2012-2015 Behavioral Risk Factor Surveillance System were pooled to evaluate racial/ethnic disparities in health, access to care, and health-related behaviors among rural residents in all 50 states and the District of Columbia. Using the National Center for Health Statistics 2013 Urban-Rural Classification Scheme for Counties to assess rurality, this analysis focused on adults living in noncore (rural) counties. RESULTS: Racial/ethnic minorities who lived in rural areas were younger (more often in the youngest age group) than non-Hispanic whites. Except for Asians and Native Hawaiians and other Pacific Islanders (combined in the analysis), more racial/ethnic minorities (compared with non-Hispanic whites) reported their health as fair or poor, that they had obesity, and that they were unable to see a physician in the past 12 months because of cost. All racial/ethnic minority populations were less likely than non-Hispanic whites to report having a personal health care provider. Non-Hispanic whites had the highest estimated prevalence of binge drinking in the past 30 days. INTERPRETATION: Although persons in rural communities often have worse health outcomes and less access to health care than those in urban communities, rural racial/ethnic minority populations have substantial health, access to care, and lifestyle challenges that can be overlooked when considering aggregated population data. This study revealed difficulties among non-Hispanic whites as well, primarily related to health related risk behaviors. Across each population, the challenges vary. PUBLIC HEALTH ACTION: Stratifying data by different demographics, using community health needs assessments, and adopting and implementing the National Culturally and Linguistically Appropriate Services Standards can help rural communities identify disparities and develop effective initiatives to eliminate them, which aligns with a Healthy People 2020 overarching goal: achieving health equity. PMID- 29503285 TI - Racism and Health in Rural America. AB - This commentary responds to the recent article by Dr. James et al. on racial and ethnic health disparities in rural America, published in the November 16 issue of Morbidity and Mortality Weekly Report. We applaud Dr. James and colleagues for their important contribution uncovering intra-rural racial and ethnic disparities and build on their paper by discussing potential mechanisms, including structural racism. We also discuss several pragmatic steps that can be taken in research, policy, and practice to address racial and ethnic disparities in rural communities and to work toward health equity for all rural residents. PMID- 29503286 TI - Social Support Networks: An Underutilized Resource for the Prevention of HIV and other Sexually Transmitted Diseases among Hispanic/Latino Migrants and Immigrants. AB - Hispanic/Latino migrants and immigrants are vulnerable to infection by HIV and other sexually transmitted diseases (STDs). Participation in social support networks helps them cope with circumstances in the U.S. Studies of Hispanic/Latino migrants suggest that participation may also be protective against HIV/STD infection. However the studies do not satisfactorily explain how participation leads to protective actions, and recommend externally-induced interventions for HIV/STD prevention rather than incorporating the spontaneously occurring forms of social support they describe. Given the potential protective effects of support networks, a database search was conducted to ascertain the extent to which published HIV/STD prevention interventions for these populations incorporate their support networks. Very few interventions were identified and fewer still incorporate support networks. This commentary calls for research to understand more fully how support networks affect HIV/STD risks among Hispanic/Latino migrants and immigrants and identifies potential benefits of incorporating these networks in HIV/STD prevention for these vulnerable populations. PMID- 29503287 TI - The Electronic Health Record and Health IT to Decrease Racial/Ethnic Disparities in Care. AB - The Electronic Health Record (EHR) now has high penetration in both ambulatory and hospital care. How can this technology be utilized to reduce racial and ethnic disparities in health care quality? We suggest a three-step process. First, routinely obtain accurate, detailed, and complete race and ethnicity data. Second, use these data to identify and monitor inequities in care, and explore the contributing factors. The third and most important step, is to employ the power of the EHR and its associated digital tools for interventions to actively reduce the extent of these disparities. PMID- 29503288 TI - Implementing a Course Review Process for a Continuous Quality Improvement Model for a Medical School Curriculum. AB - In 1901, Abraham Flexner, a research scholar at the Carnegie Foundation for the Advancement of Teaching, visited 155 medical schools in the United States and Canada to assess medical education. Flexner's recommendations became the foundation for the Liaison Committee on Medical Education accreditation, a voluntary, peer-reviewed quality assurance process to determine whether a medical education program meets established standards. The Meharry Medical College School of Medicine, a historically Black college/university (HBCU) established the Office of Curriculum Evaluation and Effectiveness in 2013 to ensure the consistent monitoring of the medical education program's compliance with accreditation standards. The motto and logo, LCME 24/7, highlight the school's emphasis on meeting accreditation standards. The school uses the 1994 Plan-Do Study-Act Cycle for Learning and Improvement for continuous review of course content, outcomes, and evaluations. This process identifies strengths, challenges, and opportunities for innovative steps for continuous quality improvements to the curriculum. PMID- 29503289 TI - Rural Cancer Screening and Faith Community Nursing in the Era of the Affordable Care Act. AB - Rural populations often face higher cancer rates and have lower cancer screening rates than urban populations. Screening disparities may be mediated by limited access to care, less knowledge of screening, and psychosocial factors. While the improved insurance rates and more comprehensive coverage under the Affordable Care Act may address some of these barriers, rural-urban disparities in cancer screening may not be fully attenuated. Faith-based interventions have been an effective approach to improving cancer screening among rural and underserved populations. Similarly, faith community nurses (FCNs) may be an effective agents for implementing evidence-based cancer screening strategies in rural communities. We provide a model for how FCNs standards of professional performance and practice can enable them to implement screening strategies. We also posit two recommendations of services that FCNs can provide to improve cancer screening in rural areas: educational messaging and patient navigation. PMID- 29503290 TI - Measuring the Effect of Social Determinants on Patient Outcomes: A Systematic Literature Review. AB - Given the movement towards value-based purchasing in the United States, health care leaders need methods to characterize and address the complex effect that social determinants have on health care outcomes. This systematic literature review was specifically designed to understand current research on the effect that patient material and social deprivation has on health care delivery outcomes and the potential benefit of clinical interventions designed to mediate this effect. A total of 310 studies were identified for review with 80 studies included in the final synthesis. Results highlight significant variation in the methods used to measure the effect of social determinants on health care outcomes and the need for common measurement standards. More robust identification of deprivation-sensitive diseases or conditions is needed to channel scarce program resources to effected conditions. Finally, further research is needed to evaluate the benefits of data-driven, tailored clinical interventions designed to serve the needs of materially-deprived patient populations. PMID- 29503291 TI - Diagnosis and Management of Pneumocystis Pneumonia in Resource-poor Settings. AB - Globally, Pneumocystis pneumonia (PCP) remains a common and lethal infection in both HIV-positive and HIV-negative patients, particularly in developing countries where rates of PCP increases with rising GDP. Pneumocystis jirovecii cannot be cultured in routine clinical laboratories; thus diagnosis relies on microscopy, histology, serology and/or polymerase chain reaction (PCR) of the Pneumocystis DNA. Most of these methods are expensive and require training. Accessing lower respiratory tract specimens in young children is often challenging and only PCR testing of nasopharyngeal aspirates is useful. Early treatment with high-dose co trimoxazole is effective therapy; however, adverse reactions are common along with reports of emerging resistance. Improved outcomes are associated with adding corticosteroid to treatment in those with moderate/severe PCP, although this has not been studied in resource-poor settings. This review compares the available diagnostic techniques in relation to their suitability for use in resource-poor settings. We also addressed the non-availability of the alternative medications in these regions. PMID- 29503292 TI - Mental Health Interventions with Community Health Workers in the United States: A Systematic Review. AB - Mental health conditions are common in the United States, yet the mental health workforce is limited in its capacity to reach disadvantaged populations. While a number of recent reviews demonstrate that community health worker (CHW)-supported physical health interventions are effective, and increase access to services, there are no recent reviews that systematically assess CHW-supported mental health interventions. To address this gap, the authors conducted a systematic review of mental health interventions with CHWs in the United States, and assessed the methodological rigor of such studies. Nine studies met review criteria. Though most of the studies reviewed showed inadequate methodological rigor, findings suggest CHW-supported mental health interventions show promise, particularly given evidence of feasibility and acceptability with underserved populations. The authors describe the rationale for mental health CHWs in the workforce, offer recommendations to strengthen the evidence base, and discuss implications of mental health interventions with CHWs for underserved populations. PMID- 29503293 TI - Successes, Challenges, and Considerations for Integrating Referral into Food Insecurity Screening in Pediatric Settings. AB - Food insecurity, lack of access to enough food for an active and healthy life, is associated with poor child health. Three pediatric clinics implemented a two question food insecurity screening of 7,284 families with children younger than five years. Over one thousand (1,133, 15.6%) reported food insecurity and 630 (55.6%) were referred to a benefits access organization for connection to public benefits and community resources. This study evaluated the efficacy of screening and referral through process evaluation, key informant interviews, and focus groups with 19 caregivers and 11 clinic staff. Using grounded theory, transcript themes were coded into facilitators and barriers of screening and referral. Facilitators included trust between caregivers and staff, choice of screening methods, and assistance navigating benefits application. Barriers included complex administration of referral, privacy and stigma concerns, and caregivers' current benefit enrollment or ineligibility. Results demonstrate importance of integrated screening and referral consent processes, strong communication, and convenient outreach for families. PMID- 29503294 TI - Antihypertensive Medication Use: Implications for Inequities in Cardiovascular Risk and Opportunities for Intervention. AB - Antihypertensive medication use protects against adverse health effects of hyper tension. Residents of low-income urban communities are disproportionately Black and Latino, and may experience heightened cardiovascular health risks due to reduced medication use. We estimate the odds of antihypertensive medication use by race/ethnicity and socioeconomic position. Data are from the Healthy Environments Partnership Community Survey, restricted to 377 hypertensive participants. Antihypertensive medication use was defined as people with hypertension who were taking antihypertensive medication. Racial/ethnic and socioeconomic differences in medication use were examined using multivariate logistic regression. Odds of antihypertensive medication use were lower for people with incomes 1.00-1.99 times the poverty level (OR=0.75, p=.05) compared with those >=2.00 times poverty, and for Latinos (OR=0.48, p<.01) and Whites (OR=0.50, p<.01) compared with Blacks. Findings suggest a need to improve hypertension screening and treatment for residents of low-to moderate-income urban communities, with attention to subgroups who may have limited health care access. PMID- 29503295 TI - A Practical Risk Stratification Approach for Implementing a Primary Care Chronic Disease Management Program in an Underserved Community. AB - The use of value metrics is often dependent on payer-initiated health care management incentives. There is a need for practices to define and manage their own patient panels regardless of payer to participate effectively in population health management. A key step is to define a panel of primary care patients with high comorbidity profiles. Our sample included all patients seen in an urban academic family medicine clinic over a two-year period. The simplified risk stratification was built using internal electronic health record and billing system data based on ICD-9 codes. There were 347 patients classified as high-risk out of the 5,364 patient panel. Average age was 59 years (SD 15). Hypertension (90%), hyperlipidemia (62%), and depression (55%) were the most common conditions among high-risk patients. Simplified risk stratification provides a feasible option for our team to understand and respond to the nuances of population health in our underserved community. PMID- 29503296 TI - Perceived Unmet Mental Health Treatment Need Among Adults with Criminal Justice System Involvement. AB - Research shows criminal justice system involved individuals are more likely to have behavioral health needs. This study analyzes nationally representative data on non-incarcerated individuals with mental disorders. It examines whether having past year criminal justice system involvement was associated with perceiving an unmet need for mental health treatment and the reasons for that unmet need. Results show criminal justice system involved individuals were more likely to report perceived unmet need for mental health treatment (OR = 1.20, p <.001). Among those not receiving mental health treatment, criminal justice system involvement yielded a higher relative risk of identifying affordability as the primary reason for having unmet mental health treatment need (RRR = 1.92, p <.001). Among those receiving mental health treatment, having criminal justice system involvement yielded a higher relative risk of identifying stigma as the primary reason for having unmet need (RRR = 1.99, p <.001). PMID- 29503297 TI - "Birth Control can Easily Take a Back Seat": Challenges Providing IUDs in Community Health Care Settings. AB - OBJECTIVE: To assess community health centers' (CHCs) capacity to offer streamlined intrauterine devices (IUDs) services. METHODS: Prior to implementing a contraceptive training project, we surveyed health care staff (N=97) from 11 CHC sites that offer IUDs onsite. Twenty interviews with clinicians explored more deeply their challenges offering IUDs in the CHC setting. RESULTS: Most practices required multiple visits for IUD placement, most (66%) clinician survey respondents had placed an IUD and 19% had placed an IUD as emergency contraception. Need for screening tests, scheduling challenges, pressures to meet patient quotas, and lack of priority given to women's health hindered streamlined IUD provision. CONCLUSIONS: Although access to IUDs has increased, significant barriers to provision in CHC settings persist. Clinic policies may need to address a variety of system and provider-level barriers to meet the needs of patients. PMID- 29503298 TI - Indian Health Service Care System and Cancer Stage in American Indians and Alaska Natives. AB - PURPOSE: We aimed to determine whether the association between late-stage cancer and American Indian/Alaska Native (AI/AN) race differed by enrollment in the Indian Health Service Care System (IHSCS). METHODS: We used Surveillance, Epidemiology, and End Results (SEER) data linked to Medicare files to compare the odds of late-stage breast, colorectal, lung, or prostate cancer between non Hispanic Whites (NHWs) (n=285,993) and AI/ANs with (n=581) and without (n=543) IHSCS enrollment. RESULTS: For AI/ANs without IHSCS enrollment, the odds of late stage disease were higher in AI/ANs compared with NHWs for breast (OR=3.17, 95%CI: 1.82-5.53) and for prostate (OR=2.59, 95%CI:1.55-4.32) cancer, but not for colorectal or lung cancers. Among AI/ANs with IHSCS enrollment, there was not a significant association between late-stage disease and AI/AN race for any of the four cancers evaluated. CONCLUSION: Our results suggest that enrollment in the IHSCS reduced the disparity between AI/ANs and NHWs with respect to late-stage cancer diagnoses. PMID- 29503299 TI - "We feel like it was better back home:" Stress, Coping, and Health in a U.S. Dwelling African Immigrant Community. AB - BACKGROUND: This study examines stress and stress management from the perspective of African immigrants in southwestern Pennsylvania. Our research questions explore how participants define stress, the most common causes of stress, manifestations of stress, and common strategies for stress management. METHODS: We conducted a descriptive, cross-sectional, qualitative study with 34 African immigrants. Data were collected via three focus groups. Qualitative data were audio-recorded, transcribed verbatim, and analyzed to identify common themes. RESULTS: Five major types of stressors included: remittances, financial and job related challenges, children, disconnected families, and unrealized expectations. Participants reported both physical and mental manifestations of stress and used both group-based and individual-focused coping strategies. DISCUSSION: African immigrants suffer from sources of stress that are uniquely attributed to their cultural background, immigration modalities, acculturation processes, and unrealized expectations. Health care providers must be aware of these sources of stress and potential management strategies. PMID- 29503300 TI - Delayed Diagnosis of HIV among Non-Latino Black Caribbean Immigrants in Florida 2000-2014. AB - Prompt HIV diagnosis decreases the risk of HIV transmission and improves health outcomes. The study objective was to examine rates of delayed HIV diagnosis among non-Latino Black Caribbean immigrants in Florida. The sample included 39,008 Black HIV-positive individuals, aged 13 or older from the Caribbean and the mainland U.S. Delayed HIV diagnosis was defined as AIDS diagnosis within three months of HIV diagnosis. After adjusting for demographic factors, year of HIV diagnosis, transmission mode, neighborhood level socioeconomic status, and rural urban residence, a disparity persisted for Caribbean-born Blacks in the Bahamas and Haiti compared with U.S.-born Blacks. Male Jamaican-Bahamian-Haitian-born Blacks were more likely to have delayed diagnosis (aOR 2.17, 95% confidence interval [CI] 1.53-3.03; aOR 1.88, 95% CI 1.01-3.44; aOR 1.58, 95%CI 1.58). Findings suggest the need for targeted, culturally relevant interventions to reduce delayed diagnosis incidence among specific Caribbean-born Blacks. PMID- 29503301 TI - Examining Long-Term Mental Health in a Rural Community Post-Disaster: A Mixed Methods Approach. AB - Psychological stressors have been observed immediately following disasters, yet less is known about the long-term effects on the mental health of vulnerable communities. In 2005, Graniteville, S.C. was ravaged by a train derailment that leaked approximately 60 tons of chlorine gas and left several people dead in the small community. The purpose of this study was to examine the mental health of Graniteville-area residents in the nine years following the train disaster using a mixed methods approach. Using the photovoice method, participants reported compromised mental health with symptoms consistent with depression, post traumatic stress disorder, fear, and anxiety. Medical records analysis indicated that mental health-related hospital encounters generally increased post-disaster. Mental health concerns should be anticipated in the long-term aftermath of disasters. Addressing these concerns is particularly vital in resource-poor communities. Our findings can be useful in developing mental health disaster management protocols and policies for communities in the long-term post-disaster period. PMID- 29503302 TI - Medical School Performance of Socioeconomically Disadvantaged and Underrepresented Minority Students Matriculating after a Multiple Mini-Interview. AB - Multiple Mini-Interviews (MMIs) are increasingly used in medical school admissions. We previously reported that while under-represented minority (URM) status was not associated with MMI scores, self-designated disadvantaged applicants had lower MMI scores, possibly affecting their matriculation prospects. No studies have examined how URM status or socioeconomic disadvantage (SED) are associated with academic performance following admission through an MMI. We examined the adjusted associations of MMI scores, SED, and URM status with U.S. Medical Licensing Examination Steps 1 and 2 performance and third-year clerkship Honors, measures affecting residency matching. While URM status was not associated with the measures, students with greater SED had lower Step 1 scores and fewer Honors. Students with higher MMI scores had more Step 1 failures, but more Honors. The findings identify areas to address in medical school admissions, student support, and evaluation processes, which is important given the need for a more representative physician workforce. PMID- 29503303 TI - Water, Sanitation and Hygiene Situation in Kenya's Urban Slums. AB - Kenya has undergone rapid urbanization as people migrate to the cities in search of economic opportunities. This has given rise to informal settlements characterized by overcrowding, poor infrastructure, and inadequate social amenities. A cross-sectional study on water, sanitation, and hygiene (WASH) status was carried out in Mathare, an informal settlement in Nairobi. A random sample of 380 households was used. The average household size was five people, and 26% of the household heads had completed secondary or higher level of education. The main source of income (70%) was self-employment with 41% of the households living on less than 1.5 USD per day. The WASH situation in the urban slums is below the minimum standard recommended by the World Health Organization (WHO). There is need to improve the situation by improving and installing basic infrastructure including water, sanitation, and solid waste collection. PMID- 29503304 TI - Health and Well-being of Women Migrating from Predominantly Muslim Countries to the United States. AB - The purpose of this study was to examine the health and well-being of women migrating from predominantly Muslim countries to the U.S. Women from predominantly Muslim countries completed a paper survey on the following topics from June to December in 2016 (N=102): depression; physical functioning; self reported general health; experiences with health care; and demographic characteristics. There were several women's health-related issues: low rates for mammography and Pap smear screening, and preference for female physicians and/or physicians from the same culture. Only one-third of the participants had received a physical exam in the past year, and having done so was related to higher levels of depression and worse physical functioning. The participants who were not in a refugee camp reported higher levels of depression than those who were. PMID- 29503306 TI - Healing Skills from the Underserved Patient Perspective. AB - The purpose of this study was to identify physician actions that facilitate meaningful doctor-patient relationships, from the perspective of the medically underserved patient. Twenty-five patients were interviewed at the United Neighborhood Health Services Northeast Clinic in Nashville, Tennessee, which serves an underinsured patient population. Patients were asked to identify the qualities of engagement with their doctor that move beyond simple diagnosis and treatment. Interviews were audio-recorded, professionally transcribed, made anonymous, and analyzed by the grounded theory method of qualitative research. Six physician actions emerged as vital to the doctor-patient relationship. As presented in the words of the patient, they are: Sits down with me; Treats me like family; Cares about me as a person; Takes the time; Gets to the root of it; Will not push me away. How the doctor made the patient feel was vitally important to the clinical encounter. PMID- 29503305 TI - Chuma na Uchizi: A Livelihood Intervention to Increase Food Security of People Living with HIV in Rural Zambia. AB - The objective of this study was to evaluate the impact of Chuma na Uchizi, a livelihood intervention for people living with HIV (PLHIV) in rural Eastern Province, Zambia, on food security. The intervention included cash transfers to purchase income-generating assets, access to a savings account, and life-skills training. The study employed a non-equivalent groups design to compare intervention (n = 50) and control participants (n = 51) who were receiving outpatient care from two comparable health facilities in distinct constituencies in the same geographic area. We collected data before and after implementation of the intervention. Chuma na Uchizi improved access to food. At follow-up, the intervention group reported lower food insecurity scores compared with the control group (beta = -5.65; 95% CI - 10.85 --0.45). Livelihood programs for PLHIV are practical and may be a promising approach to address food insecurity and its adverse effects. PMID- 29503308 TI - Spirituality and Willingness to Participate in Health-Related Research Among African Americans. AB - African Americans remain underrepresented in health-related research. We examined the association between spirituality using the Self-Rating Spirituality Scale (range 6-24) and self-reported willingness to participate in health-related research studies among African Americans. Covariates included gender, education level, employment status, and previous research experience. Adjusted associations were calculated with logistic regression models, with multiple imputation to account for missing data. Results from the logistic regression model show that each one-point increase in the Self-Rating Spirituality Scale was associated with a 24% increase in the odds of being very likely to participate in research (OR: 1.24, 95% CI: 1.07-1.44). Those with less than a college degree (OR: 3.59, 95% CI: 1.51-8.54), who were unemployed (OR: 2.34, 95% CI: 1.03-5.33), and had previous research experience (OR: 2.92, 95% CI: 1.22-6.99) reported increased willingness to participate. This work offers new insight for developing recruitment initiatives within African American spiritual communities. PMID- 29503307 TI - Neighborhood Crime and Sexual Transmission Risk Behavior among Black Men Living with HIV. AB - Here, we examined the association of exposure to neighborhood crime with sexual risk-taking behavior among Black men living with HIV. HIV-positive Black men on antiretroviral therapy in California completed an audio computer-assisted self interview. Crime risk per census block group was derived from the Federal Bureau of Investigation's Uniform Crime Report. Among 193 men, the mean (SD) number of sexual partners among those who were sexually active was 2.7 (3.3). 49% reported condomless sex, and 23% reported sex with an HIV-negative or unknown-serostatus partner. In multivariate analysis, illicit drug use ([IRR=1.86; 95%CI: 1.20-2.89] p=.006), depressive symptoms ([IRR=1.59; 95%CI: 1.03-2.44] p=.03), an undetectable viral load ([IRR=1.91; 95%CI: 1.22-3.00] p=.005), and neighborhood total crime risk ([IRR=1.02; 95%CI: 1.01-1.04] p=.007) remained significant. Among Black men living with HIV, exposure to neighborhood crime is associated with having multiple sexual partners whose HIV status was negative or unknown. PMID- 29503309 TI - Higher Perceived Clinic Capacity to Address Patients' Social Needs Associated with Lower Burnout in Primary Care Providers. AB - PURPOSE: Primary care physicians (PCP) experience high rates of professional burnout. These symptoms may be magnified in underserved populations. This study explores relationships between clinic capacity to address patients' social needs (SN) and PCP burnout. METHODS: We conducted a cross-sectional survey of PCPs from three delivery systems in San Francisco. Surveys included three components of burnout, measured by the Maslach Burnout Inventory (MBI) and a four-item instrument exploring attitudes, confidence, individual skills and organizational capacity to address patients' SN. RESULTS: Provider perception of higher clinic capacity to address patients' SN was the strongest independent predictor of lower burnout. Providers who perceived high clinic capacity and resources to address SN reported significantly greater professional efficacy (p <.01), lower emotional exhaustion (p <.05), and lower cynicism (p <.05). CONCLUSIONS: Provider perceptions of greater clinic capacity to address SN are significantly associated with lower burnout. Devoting organizational resources to address SN may reduce PCP burnout. PMID- 29503310 TI - Effectiveness of a Retention Program to Improve Performance During the First Semester of a Doctor of Physical Therapy Program. AB - BACKGROUND: To meet the expanding need for physical therapists universities are under increasing pressure to enroll, educate, and train physical therapists. Poor academic performance can result in student dismissal from a physical therapy program. The purpose of this study is to determine if implementation of a retention program would improve student academic performance in the foundational science curriculum in a physical therapy program. METHODS: A prospective observational cohort design was used. The retention program centered on three approaches: 1. Early identification of at-risk students. 2. Supplemental instruction in Human Anatomy. 3. Offering peer tutoring for the foundational science courses. RESULTS: A significant association existed between the implementation of the retention program and the reduction of dismissals from the Fall Semester of 2012 to the fall 2013 semesters. CONCLUSION: Implementation of a retention program had a beneficial effect on decreasing student dismissals in a physical therapy program. PMID- 29503311 TI - Time to Clinical Follow-up after Abnormal Mammogram among African American and Hispanic Women. AB - BACKGROUND: Time to clinical follow-up after an abnormal mammogram may be a significant factor contributing to breast cancer health disparities. OBJECTIVE: Evaluate time to follow-up in a cross-sectional cohort of African American and Hispanic women who obtained mammogram screening at a county facility. METHODS: Time to follow-up was assessed in days after an abnormal mammogram to subsequent clinical care in a cross-sectional study of 74 women. RESULTS: The median number of days until clinical follow-up after an abnormal mammogram for women in the study was 30 days (Range: 0-357 days). There was a statistically significant difference in the time-to-biopsy among women who had incomplete mammograms and women who had comorbid conditions. CONCLUSIONS: This data indicates that county services provide clinical follow-up in compliance with recommended guidelines of 30 days. However, women with incomplete mammograms and comorbid conditions may be at a higher risk of experiencing delays in diagnosis and treatment. PMID- 29503312 TI - One Message, Many Voices: Mobile Audio Counselling in Health Education. AB - Health workers' use of counselling information on their mobile phones for health education is a central but little understood phenomenon in numerous mobile health (mHealth) projects in Sub-Saharan Africa. Drawing on empirical data from an interpretive case study in the setting of the Millennium Villages Project in rural Malawi, this research investigates the ways in which community health workers (CHWs) perceive that audio-counselling messages support their health education practice. Three main themes emerged from the analysis: phone-aided audio counselling (1) legitimises the CHWs' use of mobile phones during household visits; (2) helps CHWs to deliver a comprehensive counselling message; (3) supports CHWs in persuading communities to change their health practices. The findings show the complexity and interplay of the multi-faceted, sociocultural, political, and socioemotional meanings associated with audio-counselling use. Practical implications and the demand for further research are discussed. PMID- 29503313 TI - Provider Perceptions of the Organization's Cultural Competence Climate and Their Skills and Behaviors Targeting Patient-Centered Care for Socially At-Risk Populations. AB - As part of a cultural competence needs assessment study at a large academic health care system, we conducted a survey among 1,220 practicing physicians to assess their perceptions of the organization's cultural competence climate and their skills and behaviors targeting patient-centered care for culturally and socially diverse patients. Less than half of providers reported engaging in behaviors to address cultural and social barriers more than 75% of the time. In multivariable logistic regression models, providers who reported moderate or major structural problems were more likely to report low skillfulness in identifying patient mistrust (aOR: 2.01; 95% CI: 1.23-3.28, p<0.01), how well patients read and write English (aOR: 1.63; 95% CI: 1.03-2.57, p=0.03), and socioeconomic barriers (aOR: 2.14; 95% CI: 1.14-4.01, p=0.01), than providers who reported only small or no structural problems. Improved structural support for socially and culturally complex medical encounters is needed to enhance care for socially at-risk patients. PMID- 29503314 TI - In-Hospital Paternity Establishment: Experiences and Meaning Perceived by Unmarried Parents. AB - Voluntary paternity establishment was placed in birthing hospitals by an act of Congress, but little is known about how unmarried parents experience this process. This study presents reactions from 81 racially/ethnically diverse, low income parents. A qualitative analysis of semi-structured interviews revealed three overall themes and six subthemes: (1) paternity establishment process [subthemes: variety of experiences, strong emotional experience, and poor timing]; (2) meaning of paternity establishment [subthemes: responsible fatherhood, symbol of commitment to child, and importance of the child knowing his father's identity]; and (3) paternity establishment decision-making. Many parents either did not recall receiving the requisite information or found it difficult to focus on technical materials immediately after childbirth. For parents, the symbolic value of the father's name on the birth certificate overrode other considerations. Parents' perspectives may help administrators of paternity establishment programs better tailor procedures and timing to the needs of unmarried parents. PMID- 29503315 TI - Affluence Does Not Influence Breast Cancer Outcomes in African American Women. AB - The aim of this study was to determine the impact of race and socioeconomic status on breast tumor clinicopathological features and survival outcomes. This study used breast cancer data from the Washington D.C. Cancer Registry (2000- 2010). Logistic regression and survival analysis assessed the association between race, socioeconomic (SES) variables, clinicopathological variables, recurrence free survival and overall survival. African American (AA) breast cancer patients had an increased risk for stage III, ER-, and PR-breast cancer compared with White and Hispanic breast cancer patients. Additionally, D.C. geographical areas of lower socioeconomic status had higher incidences of stage III and stage IV breast cancer. A nested analysis demonstrated that AAs with higher median incomes compared with AAs with lower incomes revealed no differences for clinicopathological variables, nor were differences found between overall and recurrence-free survival. This study suggests that the biology of breast cancer in AAs could be driving breast cancer disparities. PMID- 29503316 TI - Physicians, Physician Extenders and Health Outcomes: Race, Gender and Patient Health Provider Concordance in North Carolina Medicaid. AB - BACKGROUND: No studies were found that consider the role of race and gender concordance in patient-physician extender relationships. METHODS: A telephone survey in summer 2012 allowed measures of the relationship between physicians and physician extenders with race and gender concordance. Randomized stratified sampled adults (n = 1,401) enrolled in North Carolina Medicaid's managed care networks met the study's criteria. FINDINGS: The analysis determined the association of provider type and race and gender concordance. It also explored the association of race and gender concordance with trust, satisfaction, and decision-making propensity. Separate logistic regression models were constructed for each dependent variable. Race concordance was associated with significantly higher trust scores among respondents in the physician subgroup when race was not included in the predictive model. However, in those models where race and gender were included as control variables, provider type was not associated with race and gender concordance in the logistic regressions. PMID- 29503317 TI - The Racial and Ethnic Composition and Distribution of Primary Care Physicians. AB - Racial and ethnic minority physicians are more likely to practice primary care and serve in underserved communities. However, there are micro-practice patterns within primary care specialties that are not well understood. To examine the differences among primary care physician practice locations by specialty and race/ethnicity, a retrospective study was conducted on U.S. medical graduates who were direct patient care physicians in 2012. The group-specific contributions to primary care accessibility were decomposed by individual group of minorities underrepresented in medicine (URM). Results confirm significant differences not only in their distribution across underserved areas but also in their racial/ethnic composition by primary care specialties, with internist most diverse and family physicians least diverse. However, stratified analysis shows that within each primary care subspecialty, URM physicians were more likely to practice in underserved areas than their White peers regardless of specific specialties. PMID- 29503319 TI - The cover page. PMID- 29503320 TI - Movement disorders: The genesis and progression in India: Neurological perspective. PMID- 29503321 TI - Neurosurgery for movement disorders in India: Balloons to Electrodes. PMID- 29503322 TI - The rise of movement disorders. PMID- 29503323 TI - Classification of movement disorders: The problem of terminology. PMID- 29503324 TI - Parkinsonian syndromes: A review. AB - Since James Parkinson published his remarkable clinical observations in the "An Essay On The Shaking Palsy" in 1817, the number of diseases included in the spectrum of parkinsonian syndromes (a group of diseases that have some part of their clinical features resembling those seen in Parkinson's disease), are growing. Careful history taking, comprehensive neurological examination, and utilization of proper investigations will lead the physicians to make an accurate diagnosis of the specific disease entity present. In this recent review, we cover the issue of classification of parkinsonian syndromes, and comprehensively review the characteristic features of the commonly encountered diseases that present with this syndrome. The salient aspects of the epidemiology, key clinical features, proper investigations, and possible treatment options of these diseases have also been addressed. PMID- 29503325 TI - Parkinson's disease: A review. AB - Parkinson's disease is a common movement disorder seen in neurological practice, but the diagnosis and management is challenging. The diagnosis is clinical and sometimes difficult, considering a large number of motor and non-motor symptoms in PD patients. The medical management of PD patients is difficult, as choices of drugs are limited and levodopa is the mainstay of treatment. However, levodopa induced dyskinesia (LID) is commonly seen in Parkinson's disease patients treated with levodopa. This side effect is usually encountered after a long duration of treatment, but occasionally, this may be seen even after a few days or months of treatment. Different types of surgical approaches, including unilateral pallidotomy and deep brain stimulation, have given very good results in PD patients, who cannot be managed by medications alone. PMID- 29503326 TI - Tremor syndromes: A review. AB - Among the involuntary movement disorders, tremor is a common phenomenology seen in clinical practice. The important factors that need to be determined while assessing a patient with tremor include the phenomenology of tremor, presence or absence of other neurologic signs, and the effect of medications or alcohol. Tremor can broadly be classified based on the circumstances under which it occurs, i.e., rest or action. The basal ganglia-cerebello-thalamic and dentate olivary circuits are involved in the generation of tremor. Experimental data have suggested the olivocerebellar system as the site of the central oscillator in essential tremor. Generation of tremor in Parkinson's disease results from loss of dopaminergic neurons of the retrorubral area causing dysfunction of the globus pallidus, which finally leads to abnormal firing pattern of the ventrolateral posterior neurons of the thalamus. Involvement of the cerebello-thalamic pathways leads to orthostatic tremor. Palatal tremor is thought to be generated by the cells of the inferior olive. Holmes tremor usually results from the disruption of the dentate-rubro-thalamic circuit and also the nigro-striatal circuit. Multiple drugs can cause tremors. Demyelinating neuropathies are associated with tremors. Involvement of the deep cerebellar nuclei, cerebellar outflow tracts and the cerebrocerebellar loops has been postulated in the cerebellar tremor production. Electrophysiological methods are valuable in characterizing tremors. In addition to the pharmacological therapy including botulinum toxin therapy, surgical therapies in form of DBS or lesional surgeries are beneficial in reducing the symptoms. PMID- 29503327 TI - Dystonia: A review. AB - Dystonia is a hyperkinetic movement disorder characterized by sustained or intermittent muscle contractions that cause abnormal repetitive movements, abnormal postures, or both. The new consensus classifies dystonia into two axes to characterize clinical characteristics, and etiology. This system allows correct identification of isolated and combined forms of dystonia and retains the description of generalized and focal dystonia which is very useful in planning investigations and management. The characterization of dystonia for its better identification and a brief overview of its management are discussed in this article. The treatment options for dystonia include drugs, botulinum toxin and deep brain stimulation surgery. PMID- 29503328 TI - Pediatric movement disorders. AB - Pediatric movement disorders are commonly encountered clinical entities in the pediatric outpatient department. These disorders are a heterogenous group of disorders and may represent an underlying genetic disorder, a metabolic disorder or a hypoxic-ischemic insult during the perinatal period. Hyperkinetic movement disorders are more common as compared to hypokinetic disorders. This is unlike the situation in adult movement disorders where hypokinetic disorders are more often seen. A child's nervous system is more prone to hypoxic-ischemic insults due to its higher metabolic demands and the presence of an immature blood-brain barrier. The commonest movement disorders seen are tics, dystonia and chorea. Myoclonus is commonly associated with epilepsy syndromes. The aetiology of paediatric movement disorders depends on their course, their static or progressive nature, and whether an isolated symptom or an association with other neurological symptoms is present. The clue to the diagnosis is the proper recognition of the movement prevalent in the disorder. PMID- 29503329 TI - Neuroimaging in Parkinsonian Disorders. AB - Neuroimaging (NI) in Parkinson's disease (PD) includes functional techniques like positron emission tomography (PET) and single photon emission computed tomography (SPECT), and morphological imaging using magnetic resonance imaging (MRI) and transcranial sonography to probe different aspects of the neurobiology of PD. Changes in neurotransmitters in various regions of the brain and their influence on brain networks is the basis for the motor symptoms of PD which are interrogated by NI. The recent Movement Disorders Society Clinical Diagnostic Criteria for PD (MDS-PD) have included the results of a few of these neuroimaging techniques to serve as single supportive criteria or absolute exclusion criteria for the diagnosis of PD. While dopaminergic imaging is useful in the early stages of disease to differentiate the neurodegenerative versus non-degenerative causes of parkinsonism like essential tremors, it has also been used for the differential diagnosis of dementia with Lewy bodies (DLB) from Alzheimer's disease (AD), for inclusion of PD patients into clinical trials and for evaluating response to cell-replacement therapies in PD. Metabolic patterns on F 18 fluorodeoxyglucose positron emission tomography have been used effectively for the classification and differential diagnosis of the parkinsonian syndromes using visual and quantitative approaches. Disease related network-patterns have been used for a completely automated approach to differential diagnosis of parkinsonian syndromes on a single case basis. Structural MRI and advanced MR techniques have been used for the classification of PD and the atypical parkinsonian syndromes. Thus, multimodal imaging in PD may aid in an early, accurate and objective diagnostic classification by highlighting the underlying neurochemical and neuroanatomical changes that underlie this spectrum of disorders. The present challenge in PD is to develop radioligands which could bind selectively to alphasynuclein in-vivo. PMID- 29503330 TI - Botulinum toxin in movement disorders. AB - Botulinum toxin has gained immense popularity since its introduction for therapeutic use. It is used in a variety of movement disorders like hemi-facial spasm, focal dystonias like blepharospasm, cervical dystonia, oromandibular dystonia, limb dystonias. It is also being used in patients with tremors, tics and for a variety of indications in Parkinson's disease as well. There are eight subtypes of toxins available, but type A and B are the ones used in movement disorder clinics. The toxin mainly acts by inhibiting the release of acetylcholine at the neuromuscular junction and causing weakness. Type B toxin has more effect over the autonomic nervous system and hence is preferred for hyper-secretory disorders. The use of electromyography and ultrasound further improve the accuracy of the procedure. It is a relatively safe therapeutic option with its effect lasting for around three months. It has very few side effects. The key is to start with the lowest possible dose and then gradually increase the dose depending upon the patient's response. Selecting the right muscles for injection is of utmost importance and is guided by the knowledge of anatomy of the muscles. PMID- 29503331 TI - Deep brain stimulation for movement disorders. AB - Deep Brain Stimulation (DBS) was introduced into clinical practice nearly four decades ago and is currently the standard of care for patients with Parkinson's disease experiencing motor complications. Apart from this, it has several other established and emerging applications in movement disorders. The exact mechanisms by which DBS provides relief in movement disorders are still unclear; disruption of pathological neuronal synchrony and abnormal information flow through the neuronal circuits involved, are the most likely underlying mechanisms. DBS has been established to be a relatively safe procedure if patients are carefully selected and followed up by experienced multidisciplinary teams. Alternatives to the traditional stereotactic frame based techniques of lead implantation are emerging, and these, along with the other recent technological advances, are likely to extend the availability of this therapy to an increasing number of patients in the future. PMID- 29503332 TI - Expanding indications for deep brain stimulation. AB - It has been three decades since the first application of deep brain stimulation (DBS) for tremors was described by Benabid. Over the years, the indications for the performance of DBS have been expanding. There are now more than 1,50,000 patients around the world who have undergone DBS for various disorders. The main appeal of DBS is in its reversibility and titratability. Though the initial interest in DBS was for pain, the main indications for DBS have been movement disorders. Despite its wide appeal and "perceived" advantage, United States Food and Drug Administration, the nodal agency for approving therapies, has been cautious and guarded in providing approvals. Only two indications, i.e., Parkinson's disease and tremors, have been approved; the two other indications, i.e., dystonia and obsessive compulsive disorder (OCD), have been granted exemption under the humanitarian device usage. However, the European community has been more liberal and several of these indications have CE (Conformite Europeene) approval. Most of them will be reviewed in this article. There have been numerous indications for which DBS has been applied, which in turn has helped to change the lives of several patients. Unfortunately, due to the paucity of the number of procedures performed and the inherent difficulty in conducting "surgical" double blind randomized trials, Class 1 or Class 2 evidence for several of these indications is lacking. Hence, it is advisable that one does not embark on using each and any target for each and any indication without having the understanding or the team backup. It is cautionary that most of these therapies should be conducted in an institutional setting with an ethics and scientific committee backup and ably assisted by an experienced team. PMID- 29503333 TI - Newer advances in lesional surgery for movement disorders. AB - An analysis of the existing literature on lesioning for movement disorders was undertaken to review lesion therapy and its advances. Advances in imaging technology and electrophysiological techniques used for localization of brain structures and its functions, such as microelectrode recordings and macrostimulation, have greatly improved the ability to accurately identify the target nuclei such as the ventrointermediate nucleus (Vim), globus pallidus interna (GPi) and subthalamic nucleus (STN). Many important changes are happening in the understanding of lesion making. Its application as a cheaper modality of treatment; being less cumbersome; having a wider geographical appeal; and more options to create a lesion, appeals to the clinician. The procedure is undergoing a revival. PMID- 29503334 TI - Deep brain stimulation for movement disorders: Surgical nuances. AB - Parkinson's disease (PD) and dystonia are common indications for the deep brain stimulation (DBS) procedure. It is very important to be diligent about target localization and execution of the procedure. The single most important predictor of a good postoperative outcome is proper patient selection. The various steps of performing DBS include taking a preoperative non - stereotactic MRI, stereotactic frame fixation, fusion of MRI with stereotactic CT scan images, planning of the target and trajectory, lead placement at target through the planned trajectory, implantation of pulse generator/ battery and programming of the implanted device. Utmost care and precision are required to execute the procedure, which decide the final outcome of the surgical procedure. PMID- 29503335 TI - Lateralized hyperkinetic motor behavior. AB - Seizures are followed by a post-ictal period, which is characterized by usual slowing of brain activity. This case report describes a 68-year old woman who presented with right-sided rhythmic, non-voluntary, semi-purposeful motor behavior that started 2 days after an episode of generalized seizure. Her initial electroencephalogram (EEG) showed beta activity with no evidence of epileptiform discharges. Computed tomography scan showed hypodensity in the left parieto occipital region. Magnetic resonance imaging (MRI) showed restricted diffusion/fluid-attenuated inversion recovery hyperintensities in the left precentral and post-central gyrus. Unilateral compulsive motor behavior during the post-ictal state should be considered, and not confused with partial status epilepticus to avoid unnecessary treatment. Abnormal magnetic resonance imaging (MRI) findings, which are reversible, can help with the diagnostic and therapeutic approach. PMID- 29503336 TI - Implications of secondary unresponsiveness to dopaminergic drugs with preserved response to subthalamic nucleus stimulation in Parkinson's disease. AB - Improvement in motor symptoms with levodopa is one of the hallmark features of Parkinson's disease (PD). The response to levodopa may reduce during the course of the illness. Few studies have also reported reduced response to levodopa in patients with PD several years after deep brain stimulation (DBS) of the subthalamic nucleus (STN) on both the sides. In this study, we report an extreme unresponsiveness to levodopa in the presence of a good response to STN stimulation in a patient 5 years after the DBS proceudre had been carried out. The implications of this phenomenon are also discussed. PMID- 29503337 TI - Interleaving pallidal deep brain stimulation improves the degree of benefit obtained in a patient with dystonia. PMID- 29503338 TI - ADCY5-related dyskinesia. PMID- 29503339 TI - Hemimyoclonus: A rare presentation of hemimegalencephaly. PMID- 29503340 TI - Reversible "hemiparkinsonism" following surgery for a lateral ventricle liponeurocytoma in a 24-year old student. PMID- 29503341 TI - Expanding the phenotypic spectrum of type III GM1 gangliosidosis: Progressive dystonia with auditory startle. PMID- 29503342 TI - Risperidone induced rabbit syndrome. PMID- 29503343 TI - Does cerebral infarction ameliorate essential tremor? A mini-review. PMID- 29503344 TI - Unusual sites of primary dystonia in adults: A series of three patients. PMID- 29503345 TI - Belly dancer's dyskinesia: A rare movement disorder. PMID- 29503346 TI - Weight loss due to feeding dyskinesia: A presenting symptom of neuroacanthocytosis. PMID- 29503347 TI - Protein Tyrosine Phosphatase SHP-2 Is Involved in the Interleukin-21-Induced Activation of Extracellular Signal-Regulated Kinase 1/2. AB - The cytokine interleukin-21 (IL-21) is mainly produced from activated CD4+ T cells and natural killer T (NKT) cells. IL-21 enhances the proliferation and differentiation of T cells and B cells and also increases cytotoxicity of CD8+ T cells and NK cells through the IL-21 receptor and its downstream signaling molecules such as signal transducers and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase 1/2 (ERK1/2). SH2 domain-containing tyrosine phosphatase (SHP-2) is ubiquitously expressed, including hematopoietic cells. SHP-2 has been implicated in the regulation of IL-6 and IL-3 signaling, but its function in IL-21 signaling has not been investigated. Therefore, we studied the role of SHP-2 in IL-21 signaling by SHP-2 overexpression and knockdown experiments. For the SHP-2 overexpression, we used 293T human embryonic kidney cells, in which the IL-21 receptor system were easily reconstituted and high amounts of exogenous SHP-2 were expressed by vector transfection. In 293T cells, overexpressed SHP-2 caused the increase in the degree of the IL-21-induced ERK1/2 activation. Subsequently, SHP-2 knockdown experiments were performed in the mouse pro-B cell line, BAF21RWT-1, which constitutively expresses human IL-21 receptor and proliferates in an IL-21-dependent manner. SHP-2 knockdown reduced the degree of the IL-21-induced ERK1/2 activation and suppressed cell proliferation. These results suggest that SHP-2 may augment the ERK1/2 activity and cell proliferation activity in IL-21 signaling. We propose that SHP-2 is involved in the IL-21-mediated ERK1/2 activation and cell proliferation. PMID- 29503348 TI - Trematode infections in farm animals and their vector snails in Saint Martin's Island, the southeastern offshore area of Bangladesh in the Bay of Bengal. AB - The prevalence of snail-borne trematode (SBT) infections in farm animals on the offshore Saint (St.) Martin's Island of Bangladesh were 68.9% for cattle, 76.7% for buffaloes, 56.3% for goats, respectively. Examination of fecal samples showed that paramphistomes infection was the most common at 50.5% followed by schistosomes at 23.7% and Fasciola at 2.3%. Fasciola infection was found in cattle (1.9%) and buffaloes (16.7%) but not in goats. Schistosome infection in cattle, buffaloes and goats were 31.1, 6.7 and 17.5%, respectively. Prevalence of SBTs was higher in older animals. Thiara tuberculata (Melanoides tuberculata) were found to serve as vector for paramphistomes and Indoplanorbis exustus for schistosomes and paramphistomes, respectively. Our results suggest that SBT and their vector snails are highly endemic on St. Martin's Island of Bangladesh, and proper attention is needed to control these infections. PMID- 29503349 TI - Characterization of gizzards and grits of wild cranes found dead at Izumi Plain in Japan. AB - We analyzed the gizzards, and grits retained in the gizzards of 41 cranes that migrated to the Izumi Plain during the winter of 2015/2016 and died there, either due to accident or disease. These included 31 Hooded Cranes (Grus monacha) and 10 White-naped Cranes (G. vipio). We determined body weight, gizzard weight, total grit weight and number per gizzard, and size, shape, and surface roundness of the grits. Average gizzard weights were 92.4 g for Hooded Cranes and 97.1 g for White naped Cranes, and gizzard weight positively correlated with body weight in both species. Average total grit weights per gizzard were 19.7 g in Hooded Cranes and 25.7 g in White-naped Cranes, and were significantly higher in the latter. Average percentages of body weight to grit weight were 0.8% in Hooded Cranes and 0.5% in White-naped Cranes. Average grit number per gizzard was 693.5 in Hooded Cranes and 924.2 in White-naped Cranes, and were significantly higher in the latter. The average grit size was 2.8 mm in both species. No differences were found in the shape and surface roundness of grits between the two species. To the best of our knowledge, this is the first study on the grits retained in the gizzards of Hooded and White-naped Cranes. PMID- 29503351 TI - [Essence and Perspective of the JGS/JDS Clinical Practice Guideline for the Treatment of Diabetes in the Elderly]. PMID- 29503350 TI - Partial exposure of frog heart to high-potassium solution: an easily reproducible model mimicking ST segment changes. AB - By simply inducing burn injuries on the bullfrog heart, we previously reported a simple model of abnormal ST segment changes observed in human ischemic heart disease. In the present study, instead of inducing burn injuries, we partially exposed the surface of the frog heart to high-potassium (K+) solution to create a concentration gradient of the extracellular K+ within the myocardium. Dual recordings of ECG and the cardiac action potential demonstrated significant elevation of the ST segment and the resting membrane potential, indicating its usefulness as a simple model of heart injury. Additionally, from our results, Na+/K+-ATPase activity was thought to be primarily responsible for generating the K+ concentration gradient and inducing the ST segment changes in ECG. PMID- 29503352 TI - [The development of care farming for elderly people with cognitive impairment to enhance social inclusion: A feasibility study of rice-farming care for elderly people with cognitive impairment]. AB - AIM: The aim of this study was to assess the feasibility of rice-farming care among elderly people with cognitive impairment as a tool for social inclusion. METHODS: Eight elderly individuals with cognitive impairment (7 men, 1 woman, mean age 68.3 years old) participated in the program over 25 weeks. The cognitive function, well-being, and depression were assessed before and after the program period. The degree of participants' independence during the program was also assessed. Semi-structured interviews with the participants and caregivers were held after the program period. RESULTS: The average participation rate was 93.0%. There were no unexpected events, and the subjects carried out farmwork almost independently. Regarding their well-being, two participants who scored below the cut-off criterion of mental health before the study scored above the cut-off after the study. Regarding depression, two participants who scored positive with a two-question case-finding instrument no longer scored positive after the study. Interviews with the participants showed that they enjoyed the program, especially because they had peers, a role, and gained positive emotions. Interviews with the caregivers showed that they had recognized for the first time what people can do with their skills. CONCLUSION: The results of the present study indicate that rice-farming was a feasible method of care with a positive impact on the well being and depression of elderly people with cognitive impairment and enhanced their social participation, drawing out their individual strengths. PMID- 29503353 TI - [Aging and verbal memory -an experimental study using structured and non structured word lists]. AB - AIM: Typical neuropsychological methods for measuring the verbal memory function include the Rey Auditory Verbal Learning Test (AVLT) and the California Verbal Learning Test (CVLT). The stimulus words of the CVLT are structured according to their semantic categories, and many researchers have claimed that the CVLT can also evaluate subjects' memory strategy. However, the stimulus words of these tests do not have equal difficulty, which is necessary when comparing their performances directly, and there are no standard word lists for them in Japanese. In this study, we developed two word lists with the same number and difficulty of stimulus words in order to examine the effects of aging on the comprehension of structured word lists. METHODS: A non-structured (NS) verbal memory test to represent the AVLT and a structured (S) test to represent the CVLT were developed. The subjects were 40 healthy young adults (18-25 years of age) and 40 healthy elderly individuals (65-80 years of age). RESULTS: The results revealed that the elderly group correctly recalled significantly fewer words than the young group. The elderly group demonstrated a significantly higher rate of word loss due to interference. The number of correctly recalled words in the elderly group was significantly more for the S test than for the NS test, which was not the case in the young group. CONCLUSIONS: Since elderly people have a poorer verbal memory than younger people, they gain more benefit from the S test, in which the word list is structured and subjects may be able to use memory strategies more easily. This is the first study in Japan to present standardized word lists for list-learning tasks and their normative data in different age groups. PMID- 29503354 TI - [The characteristics of frail elderly patients in acute care hospitals]. AB - AIM: Efforts to improve the treatment of frail elderly patients in acute care hospitals are urgently needed because a low physical activity level due to hospitalization is reported to be associated with a risk of disability. The aim of this study was to clarify the characteristics of frail elderly patients in acute care hospitals. METHODS: We assessed 198 elderly patients who were admitted to acute care hospitals. The factors that were evaluated included the presence of frailty, the age, gender, and nutritional status of the patients, and complications that developed during hospitalization. In this study, frailty was evaluated using the Kihon checklist (KCL), and was defined by a total KCL score of >=7 points. RESULTS: A total of 87 (43.9%) subjects met the definition of frailty and there was a female predominance (63.2%). The nutritional status of the subjects with frailty was significantly worse than that of the non-frail patients. In comparison to the non-frail subjects, the frail subjects were significantly older and the onset of complications during hospitalization was observed significantly more frequently. Moreover, a large number of frail subjects showed low scores on the KCL items related to their social activity, physical and oral functions, and psychological status. CONCLUSION: These findings suggest that efforts to improve the treatment of frail elderly patients in acute care hospitals are important because of the high incidence of frailty. Multifaceted assessments and the promotion of physical activity to prevent the onset of complications during hospitalization may be needed for frail elderly patients in acute care hospitals. PMID- 29503355 TI - [Molecular mechanism of sarcopenia]. PMID- 29503356 TI - [Eight cases of Percutaneous Endoscopic Gastrostomy (PEG) in patients taking oral anticoagulants]. AB - Patients who undergo percutaneous endoscopic gastrostomy (PEG) placement are often on antiplatelet therapy. There is a potential risk of infarction if these medications are discontinued.The guidelines of the Japan Gastroenterological Endoscopy Society, classify PEG as an operation associated with a high risk of bleeding; however, it is known that surgery can be performed without interruption when patients are treated with low-dose aspirin alone. Nevertheless, we experienced the case of severe bleeding at the incision site, which was accompanied by massive hematemesis and hemorrhagic shock the night after PEG using the modified introducer method in an 87-year-old male patient. The patient was being treated with Bayer aspirin (100 mg/day, oral). The patient's platelet count, PT, and APTT were within the normal levels. Thus, we decided to investigate the pull method as the effective method for pressure hemostasis comparing with the modified introducer method, to reduce the risks associated with bleeding after surgery when patients are being treated with antiplatelet drugs.PEG was performed by the pull method on eight patients who were being treated with oral antiplatelet drugs (including four patients receiving dual antiplatelet therapy [DAPT]). All patients had previously suffered strokes, and they all presented with normal platelet counts, PT, and APTT values.Only slight bleeding was observed in one out of eight patients (bleeding had stopped by the following day using an alginate patch on the abdominal wall at the incision site, along with direct pressure using a stationary plate). None of the patients showed infection at the incision site.Although the study population was small, the present study showed that PEG using the pull method is safe while patients are being treated with oral antiplatelet drugs. PMID- 29503357 TI - [The development of pneumothorax in an elderly woman during treatment for nontuberculous mycobacterium]. AB - We report the case of an 82-year-old woman who developed pneumothorax during treatment for nontuberculous mycobacterium (NTM). In year X, she was diagnosed with NTM at another hospital after abnormalities were pointed out on a chest X ray. She received no treatment for NTM at that time. Antibiotic treatment was introduced at the department of respiratory medicine in our hospital in year X+15. The regimen was composed of clarithromycin (800 mg/day), ethambutol (750 mg/day) and rifampicin (600 mg/day); however, treatment with the three-drug antibiotic regimen was canceled at her request and changed to erythromycin. She was then referred to our department. However, right-side cavity wall thickening was detected on chest CT in year X+17.We resumed clarithromycin (600 mg/day), ethambutol (750 mg/day) and rifampicin (450 mg/day). On the 43rd day after treatment with three types of antibiotics, she felt dyspnea and she was admitted to the hospital and was diagnosed with right-side pneumothorax. The pneumothorax was thought to have been caused by a break in the adhesion of the cavity wall. The visceral pleura was weakened by the exacerbation of NTM and the thickness of the cavity wall was improved after the resumption of antibiotic therapy. This report is considered to be an important case in which pneumothorax developed as a complication in an elderly patient during treatment for NTM. PMID- 29503358 TI - [Pyothorax-associated lymphoma with the expression of Epstein-Barr virus latent genes]. AB - An 84-year-old man, who had received artificial pneumothorax for pulmonary tuberculosis 67 years previously, complained of severe chest pain. Chest CT revealed chronic pyothorax with multiple heterogeneously enhanced cavity lesions in the wall of the right intrathoracic space. 18FDG-PET revealed that the lesions showed an abnormal uptake. CT-guided biopsy was performed and he was diagnosed with pyothorax-associated lymphoma (PAL); the histological diagnosis was diffuse large B cell lymphoma (DLBCL). Furthermore, immunohistochemical staining revealed that the tumor cells were positive for EBNA-2 and LMP-1, suggesting that the latent gene products of Epstein-Barr virus were associated with the development of PAL. The patient was treated with chemotherapy, including rituximab; however, the treatment was discontinued due to the development of severe delirium after chemotherapy. We should keep in mind that elderly patients with a long history of chronic pyothorax are at risk of developing malignant lymphoma. We report the present case with a brief review of the literature. PMID- 29503359 TI - ? PMID- 29503360 TI - ? PMID- 29503361 TI - ? PMID- 29503362 TI - ? PMID- 29503363 TI - [Information]. PMID- 29503364 TI - ? PMID- 29503365 TI - [Catheter intervention for valvular heart disease]. PMID- 29503366 TI - [Heart failure in the elderly focused on the heart failure with preserved ejection fraction]. PMID- 29503367 TI - [Anticoagulation in older AF patients]. PMID- 29503368 TI - [Percutaneous Coronary Intervention]. PMID- 29503369 TI - [The nutritional and dietary intake among community-dwelling elderly female users of mobile vendor vehicles]. AB - AIM: We compared the nutritional and dietary intakes of users of mobile vendor vehicles and users of stores to clarify the problems in the nutritional intake of users of mobile vendor vehicles. METHODS: We conducted a questionnaire about the food accessibility among 257 elderly women (age: >=65 years) who used mobile vendor vehicles and/or stores to shop. The nutritional intake was assessed using the 24-hour recall method. We used an analysis of covariance (ANCOVA) to calculate the age-adjusted mean values for the total nutritional intake. RESULTS: The nutritional intake among users of mobile vendor vehicles included significantly lower intakes of energy (168 kcal), green vegetables, other vegetables, and meats. Furthermore, those who only shopped at mobile vendor vehicles consumed less energy and fewer nutrients than those who shopped at places other than mobile vendor vehicles. The comparison of the shopping frequency and nutritional intake of the subjects who used mobile vendor vehicles alone revealed that the energy and protein intakes of those who shopped once per week was significantly lower in comparison to those who shopped twice per week. CONCLUSIONS: Users of mobile vendor vehicles had lower intakes of macronutrients and various minerals and vitamins. Among the food groups, intakes of vegetables, meat, and dairy products were low. These findings suggest that the lack of means of shopping other than mobile vendor vehicles and shopping once per week may be associated with an inadequate dietary intake among users of mobile vendor vehicles. It would be desirable to develop the shopping environment is desirable. PMID- 29503370 TI - [Factors related to the life space of daycare center users]. AB - PURPOSE: We examined the factors related to life space and changes in the care level after one year in daycare center users. METHODS: The participants were 83 older adults (age, > 65 years; mean age, 79.5+/-6.8 years) with MMSE scores of >=20, who could walk independently, who needed support (1-2) or care (1), and who underwent rehabilitation at a daycare center. The life space was evaluated by the Life Space Assessment (LSA). The subjects' basic information (i.e., age, medical history.) was collected, and their physical function (i.e., grip strength, timed up and go test [TUG]), mental function (i.e., vitality, fear of falls), and social function (i.e., friends, hobbies, public transportation) were assessed to investigate the factors associated with their LSA scores. In addition, a follow up survey was conducted on the care level at approximately one year later. RESULTS: A multiple regression analysis indicated that TUG scores (beta=-0.33), hobbies (beta=0.30), friends (beta=0.29), public transportation (beta=0.26), and grip strength (beta=0.24) were related to the life space. Next, the participants were divided into LSA-high and LSA-low groups, and changes in the care level (improvement, maintenance, deterioration) at approximately one year after the initial assessment were examined using a chi-squared test. A significant difference was observed in the distribution of the groups (p=0.03). CONCLUSIONS: Multiple factors were related to the life space. Moreover, it is possible that improvements in the level of care may be achieved by improving the life space. PMID- 29503371 TI - [The effective of facial exercises on the mental health in elderly adults]. AB - AIM: Although it is well documented that exercising is good for the mental health and cognitive function as well as the physical condition in elderly people, exercising is difficult in elderly individuals with a low motor function. To develop an exercise program targeting elderly individuals unsuited for whole-body exercises, we assessed the effects of facial exercises on the mental health in healthy elderly people. METHODS: Community-dwelling older adults (N = 75, age range = 65-87 years) were randomly divided into a facial exercises group and a wait-listed control group. A facial exercises program of 30 min was given twice a week for 12 weeks. This program consisted of rhythmic facial movement, muscle stretching, facial yoga, and Tanden breathing. The GHQ-12 for mental health were administered to both groups before and after the 12-week study period. In addition, the facial expression and tongue muscle power were measured. RESULTS: Fifty-three participants completed the protocol. In the intervention group, the GHQ-12, facial expression, and tongue muscle power improved post-intervention. CONCLUSIONS: These results suggest that facial exercises are effective in improving the mental health, facial expression, tongue muscle power of elderly people, and that exercises may be useful as a therapeutic modality in this population. PMID- 29503372 TI - [Development of a Japanese Version of the Short-Form FAMCARE Scale for family caregivers of terminal cancer patients at home in Japan]. AB - AIM: To develop a Japanese version of the short-form FAMCARE Scale (Ornstein, 2015) for family caregivers of terminal cancer patients at home. METHODS: The survey was conducted with 316 family caregivers of terminal cancer patients at home selected as eligible participants in 11 major regions in Japan (the Tokyo metropolitan area, and the prefectures of Tochigi, Ibaraki, Saitama, Chiba, Kanagawa, Nara, Hyogo, Kagawa, Ehime, and Saga). Construct validity was confirmed using a confirmatory factor analysis, and the Caregiver Quality of Life Index Cancer (CQOLC) scale was administered to assess criterion-related validity. RESULTS: A total of 120 family caregivers provided valid responses. The mean+/ standard deviation of the age of the family caregivers was 64.6+/-12.0 years, and 91 (75.8%) were female. A factor analysis of the results showed that the Japanese version of the 10-item and 5-item short-form FAMCARE Scale was a unidimensional construct, and a confirmatory factor analysis demonstrated a goodness of fit index of 0.910 and 0.972, an adjusted goodness of fit index of 0.835 and 0.916, a comparative fit index of 0.968 and 0.992, and a root mean square error of approximation of 0.095 and 0.081, respectively. The Cronbach's alpha coefficients of the 10- and 5-item scales were 0.95 and 0.93, respectively. The scale scores were significantly correlated with the family caregiver's quality of life (CQOLC) (10-item r=0.304, P<0.01; 5-item r=0.311, P<0.01). CONCLUSION: The Japanese version of the 10-item and 5-item short-form FAMCARE Scale was found to have sufficient reliability and validity for assessing family satisfaction with terminal cancer patient at home in Japan. PMID- 29503373 TI - [Dietary approach to improving the nutritional status in institutionalized elderly hemodialysis patients with a poor dietary intake: a single-arm pilot study]. AB - OBJECTIVE: The hemodialysis (HD) diet, which is a high-calorie and high-fat regimen, may inadvertently lead to an inadequate dietary intake, resulting in undernutrition among elderly HD patients. Therefore, an attempt was made to improve the dietary intake by implementing a modified diet regimen in eligible elderly HD patients. SUBJECTS: Elderly HD patients who had ingested < 50% of the meals provided and were diagnosed with undernutrition among all elderly patients institutionalized at the special elderly nursing home annexed to Nagasaki Kidney Hospital between June and November 2012. RESULTS: Of the elderly HD patients in the nursing home (n = 27), the study included a total of 7 consecutive patients (male/female, 1/6; mean age, 84.1+/-6.4 years old; duration of HD, 4.3+/-3.8 years; geriatric nutritional index [GNRI], 83.5+/-8.3; normalized protein catabolic ratio [nPCR], 0.78+/-0.14). The modified diet regimen, which involved reducing food portion sizes and incorporating a liquid diet, led to a significant increase in their dietary intake from 48.1% at baseline to 97.1% of the meals provided 3 months after the start of the modified HD diet regimen. Their GNRI also significantly increased from 83.5+/-8.3 to 86.1+/-10.2, and their serum albumin levels significantly increased from 3.2+/-0.2 g/dL to 3.4+/-0.4 g/dL, suggesting improvements in their nutritional status. CONCLUSIONS: The attempted dietary approach for elderly HD patients was shown to potentially increase their dietary intake and improve their nutritional status without affecting the efficiency of HD being implemented. PMID- 29503374 TI - [Agreement in the responses to self-reported and proxy-reported versions of QOL HC: a new quality-of-life scale for patients receiving home-based medical care]. AB - AIM: We developed quality-of-life (QOL) scales for patients receiving home medical care. The objective of this study was to examine the agreement between the scores of the scales answered by patients and those answered by their proxy, as cognitive decline may interfere with one's ability to understand complex topics, such as the QOL. METHODS: Participants were pairs of patients receiving home medical care and their proxy. The patients were asked to complete self reported QOL scales (QOL-HC), and their proxies were asked to complete proxy reported versions of the QOL scales (QOL-HC for caregivers). We then statistically examined the extent of agreement between the self- and proxy reported QOL-HC scores using contingency tables and Spearman's rank correlation coefficient. The SPSS software program, version 24, was used for all statistical analyses. RESULTS: The concordance rate between patients and caregivers for questions 1 ( "Do you have peace of mind?" ), 2 ( "Do you feel satisfied with your life when you reflect on it?" ), 3 ( "Do you have someone that you spend time talking with?" ), and 4 ( "Are you satisfied with the home care service system?" ) were 52.3%, 52.3%, 79.5%, and 81.8%, respectively. The total scores for the patients and caregivers were significantly correlated (Spearman's rho=0.364*). CONCLUSIONS: We created the first QOL scale for patients receiving home-based medical care and for caregivers. The findings of this study suggest that the QOL-HC can be used in clinical practice for the assessment of patients receiving professional home care. PMID- 29503375 TI - [Notice]. PMID- 29503376 TI - [Table of Contents]. PMID- 29503377 TI - Two Cases of Endovascular Repair with the Stent Graft for Retrograde Type A Acute Aortic Dissection with Complications. AB - Thoracic endovascular aortic repair (TEVAR) is used to treat retrograde type A acute aortic dissection (RTAAD). In case 1, a 52-year-old man, who was conservatively managed, reported worsening back pain. Emergency TEVAR was performed 7 days after onset. After deploying two GORE Conformable TAG (CTAG) in the descending aorta, his symptoms disappeared. In case 2, a 52-year-old man with progressive worsening resistant hypertension, renal dysfunction, and respiratory failure despite maximal medical therapy underwent TEVAR 8 days after onset. A CTAG was deployed from the left subclavian artery under rapid pacing, and two Zenith Dissection stents were placed, which resolved complications. In both cases, after 6 months, computed tomography (CT) scan showed complete resorption of the false lumen in the ascending aorta. TEVAR for RTAAD with complete thrombosis of false lumen in the ascending aorta can be an alternative to surgery when the primary tear is located in descending aorta. PMID- 29503378 TI - Preface for the Special Issue "Cardiovascular Risk Factors and Socioeconomic Status in Japan: NIPPON DATA2010". PMID- 29503379 TI - Relationship Between Socioeconomic Status and the Prevalence of Underweight, Overweight or Obesity in a General Japanese Population: NIPPON DATA2010. AB - BACKGROUND: Socioeconomic status (SES) imbalances in developed and developing countries may result in individuals being overweight and obese. However, few studies have investigated this issue in Japan. We herein examined the relationship between SES and being underweight, overweight or obese according to sex and age groups (20-64 or >=65 years) in Japan. METHODS: In 2010, we established a cohort of participants in the National Health and Nutrition Survey of Japan. We divided 2,491 participants (1,081 men and 1,410 women) according to the WHO definitions of underweight, overweight or obesity and performed multinomial logistic analyses using BMI <18.5 kg/m2 (underweight), BMI 25.0-29.9 kg/m2 (overweight), and BMI >=30.0 kg/m2 (obese) versus BMI 18.5-24.9 kg/m2 (normal) as the outcome, with SES groups as the main explanatory variables. RESULTS: In adult men, a lower education level relative to a higher education level was inversely associated with obesity after adjustments for other SESs (odds ratio [OR] 0.41; 95% confidence interval [CI], 0.18-0.96). However, in adult women, lower education level was positively associated with being overweight and obese (OR 1.67; 95% CI, 1.07-2.49 for overweight and OR 2.66; 95% CI, 1.01-7.01 for obese). In adult women, a lower household income was positively associated with being overweight and obese (obese: OR 4.84; 95% CI, 1.36-17.18 for those with a household income <2 million JPY relative to those with >=6 million JPY). CONCLUSIONS: In adult women, a lower education level and lower household income were positively associated with being overweight or obese. In contrast, in adult men, a lower education level was inversely associated with obesity. Gender and age differences in SESs affect the prevalence of being overweight or obese. PMID- 29503380 TI - Macronutrient Intake and Socioeconomic Status: NIPPON DATA2010. AB - BACKGROUND: This study examined the relationships among household income, other SES indicators, and macronutrient intake in a cross-sectional study of a representative Japanese population. METHODS: In 2010, we established a cohort of participants in the National Health and Nutrition Survey (NHNS) from 300 randomly selected areas throughout Japan. A total of 2,637 participants (1,145 men and 1,492 women) were included in the study. Data from NHNS2010 and the Comprehensive Survey of Living Conditions 2010 (CSCL2010) were merged, and relationships among macronutrient intake and SES were evaluated. Additionally, socioeconomic factors associated with a risk of a higher carbohydrate/lower fat intake beyond dietary recommendations were evaluated. RESULTS: Household income was positively associated with fat intake (P = 0.001 for men and <0.001 for women) and inversely associated with carbohydrate intake (P = 0.003 for men and <0.001 for women) after adjustments for age and other SES variables. Similar relationships were observed between equivalent household expenditure (EHE) and macronutrient intake; however, these relationships were weaker than those of household income. Older age was the factor most strongly associated with a high carbohydrate/low fat intake, followed by household income, EHE, education levels, and occupation type. CONCLUSIONS: Older age was the factor most strongly associated with a high carbohydrate/low fat intake, and some aspects of SES, such as household income, EHE, education levels, and occupation type, were independently associated with an imbalanced macronutrient intake. SES may affect the health status of individuals through the intake of macronutrients. PMID- 29503381 TI - The National Integrated Project for Prospective Observation of Non-communicable Disease and its Trends in the Aged 2010 (NIPPON DATA2010): Objectives, Design, and Population Characteristics. AB - BACKGROUND: The structure and risk factors for cardiovascular diseases (CVD) in Japan may change because lifestyle, particularly nutrition, socioeconomic status, and medical care, which affect CVD, may markedly change over time. Therefore, a new prospective cohort study on a representative general Japanese population based on national surveys is required. METHODS: In November 2010, the baseline survey of the National Integrated Project for Prospective Observation of Non communicable Disease and its Trends in the Aged 2010 (NIPPON DATA2010) was performed with the National Health and Nutrition Survey of Japan (NHNS2010) in 300 randomly selected districts throughout Japan. The survey included a questionnaire, electrocardiogram, urinalysis, and blood biomarkers added to the NHNS2010 examinations. Physical measurements, blood biomarkers, and dietary data were also obtained in NHNS2010. Socioeconomic factors were obtained by merging with the Comprehensive Survey of Living Conditions 2010 (CSLC2010) dataset. Participants are followed annually for the incidence of diabetes mellitus, CVD events (acute coronary events, heart failure, atrial fibrillation, and stroke), and cause-specific mortality. The activities of daily living are followed every 5 years. RESULTS: A total of 2,898 individuals aged 20 years or older agreed to participate in the baseline survey of NIPPON DATA2010. The participation rate was 74.6%. Of these, data from NHNS2010 was merged for 2,891 participants (1,236 men and 1,655 women). The data of 2,807 participants were also merged with CSLC2010 data. CONCLUSIONS: We established NIPPON DATA2010 as a cohort study on a representative general Japanese population that covers all of Japan. PMID- 29503382 TI - Relationships among Food Group Intakes, Household Expenditure, and Education Attainment in a General Japanese Population: NIPPON DATA2010. AB - BACKGROUND: A lower socioeconomic status (SES) may be related to the intake of unhealthy food; however, this relationship has not been examined in detail. This study was undertaken to examine relationships among food group intakes and SES in a representative Japanese population. METHODS: This was a cross-sectional study using the baseline data of NIPPON DATA2010, which is a prospective cohort study of the National Health and Nutrition Survey in Japan. A total of 2,898 participants were included in the baseline survey in 2010. The effects of age (<65 years and >=65 years), equivalent household expenditure (EHE), and education attainment on food group intakes (gram per 1,000 kcal) were analyzed using a two way analysis of variance. RESULTS: When EHE was lower, cereal intake was higher in men and women. Among men, fish, milk, and alcohol intakes were reduced with lower EHE. Among women, vegetable intake was reduced with lower EHE. In men and women, cereal intake was higher with lower education attainment. In contrast, meat intake was reduced with lower education attainment. CONCLUSIONS: Lower SES was associated with a higher cereal intake and lower vegetable, fish, meat, and milk intakes in a representative Japanese population. Socioeconomic discrepancies need to be considered in order to promote healthier dietary habits. PMID- 29503383 TI - Socioeconomic Status Associated With Urinary Sodium and Potassium Excretion in Japan: NIPPON DATA2010. AB - BACKGROUND: Although socioeconomic status (SES) may affect food and nutrient intakes, few studies have reported on sodium (Na) and potassium (K) intakes among individuals with various SESs in Japan. We investigated associations of SES with Na and K intake levels using urinary specimens in a representative Japanese population. METHODS: This was a cross-sectional study of 2,560 men and women (the NIPPON DATA2010 cohort) who participated in the National Health and Nutrition Survey Japan in 2010. Casual urine was used to calculate estimated excretion in 24-hour urinary Na (E24hr-Na) and K (E24hr-K). The urinary sodium-to-potassium (Na/K) ratio was calculated from casual urinary electrolyte values. An analysis of covariance was performed to investigate associations of aspects of SES, including equivalent household expenditure (EHE), educational attainment, and job category, with E24hr-Na, E24hr-K, and the Na/K ratio for men and women separately. A stratified analysis was performed on educational attainment and the job category for younger (<65 years) and older (>=65 years) participants. RESULTS: In men and women, average E24hr-Na was 176.2 mmol/day and 172.3, average E24hr-K was 42.5 and 41.3, and the average Na/K ratio was 3.61 and 3.68, respectively. Lower EHE was associated with a higher Na/K ratio in women and lower E24hr-K in men and women. A shorter education was associated with a higher Na/K ratio in women and younger men, and lower E24hr-K in older men and women. CONCLUSION: Lower EHE and a shorter education were associated with a lower K intake and higher Na/K ratio estimated from casual urine specimens in Japanese men and women. PMID- 29503384 TI - Differences in Lifestyle Improvements With the Intention to Prevent Cardiovascular Diseases by Socioeconomic Status in a Representative Japanese Population: NIPPON DATA2010. AB - BACKGROUND: The relationships among socioeconomic status and lifestyle improvements have not yet been examined in a representative Japanese population. METHODS: We analyzed data from 2,647 participants (1,087 men and 1,560 women) who participated in NIPPON DATA2010. This survey inquired about lifestyle improvements and socioeconomic status. Education was categorized as low (<=9 years), middle (10-12 years), and high (>=13 years). Marital status was categorized as married, divorced, widowed, and never married/other. A multivariable logistic regression model was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) of lifestyle improvements with the intention of preventing cardiovascular diseases for educational attainment and marital status, with adjustments for age and awareness of cardiovascular disease risk factors. RESULTS: Overall, 1,507 (56.9%) participants practiced prevention and improvements in hypertension, diabetes, elevated cholesterol, and metabolic syndrome, and the OR of lifestyle improvements was significantly higher with a high education than with a low education in men (OR 2.86; 95% CI, 1.96-4.17) and women (OR 2.36; 95% CI, 1.67-3.33). The number of participants who practiced prevention and improvements in hypertension, diabetes, elevated cholesterol, and metabolic syndrome was significantly lower in divorced than in married men (OR 0.46; 95% CI, 0.22-0.95) and women (OR 0.53; 95% CI, 0.33-0.86). CONCLUSIONS: Specific differences caused by educational attainment and marital status may exist in lifestyle improvements. PMID- 29503385 TI - Passive Smoking at Home by Socioeconomic Factors in a Japanese Population: NIPPON DATA2010. AB - BACKGROUND: Long-term passive exposure to cigarette smoke has been reported to affect the health of non-smokers. This study aims to investigate the relationships among socioeconomic factors and passive smoking at home in the non current smokers of a representative sample from a general Japanese population. METHODS: Data are from NIPPON DATA2010. Among 2,891 participants, 2,288 non current smokers (1,763 never smokers and 525 past smokers) were analyzed in the present study. Cross-sectional analyses were performed on the relationships among socioeconomic factors and passive smoking at home (several times a week or more) in men and women separately. Socioeconomic factors were employment, length of education, marital status, and equivalent household expenditure. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a multivariable logistic regression model. RESULTS: The multivariable-adjusted model showed that employed women had a higher risk of passive smoking than unemployed women (OR 1.44; 95% CI, 1.06-1.96). Women with 9 years or less of education had a higher risk of passive smoking at home than women with 13 years and more of education (OR 2.37; 95% CI, 1.49-3.78). Single women had a lower risk of passive smoking at home (OR 0.53; 95% CI, 0.37-0.77) than married women. No significant associations were observed in men. CONCLUSIONS: An employed status, lower education, and being single were associated with passive smoking at home in the non-current smoking women of a representative Japanese population. PMID- 29503386 TI - Socioeconomic Status and Knowledge of Cardiovascular Risk Factors: NIPPON DATA2010. AB - BACKGROUND: The relationship between socioeconomic status (SES) and knowledge of cardiovascular risk factors remains unknown in a general Japanese population. METHODS: Of 8,815 participants from 300 randomly selected areas throughout Japan, 2,467 participants who were free of cardiovascular disease and who provided information on SES in the National Health and Nutrition Survey of Japan 2010 were enrolled in this cross-sectional analysis. SES was classified according to the employment status, length of education, marital and living statuses, and equivalent household expenditure (EHE). Outcomes were ignorance of each cardiovascular risk factor (hypertension, diabetes, hypercholesterolemia, low high-density lipoprotein [HDL] cholesterol, arrhythmia, and smoking) and insufficient knowledge (number of correct answers <4 out of 6). RESULTS: A short education and low EHE were significantly associated with a greater ignorance of most cardiovascular risk factors. A short education (<10 years) was also associated with insufficient knowledge of overall cardiovascular risk factors: age- and sex-adjusted odds ratios (OR) were 1.92 (95% confidence interval [CI], 1.51-2.45) relative to participants with >=13 years of education. Low EHE was also associated with insufficient knowledge (age- and sex-adjusted OR 1.24; 95% CI, 1.01-1.51 for the lowest quintile vs the upper 4 quintiles). These relationships remained significant, even after further adjustments for regular exercise, smoking, weekly alcohol consumption, body mass index, hypertension, diabetes mellitus, hypercholesterolemia, and low HDL cholesterol. CONCLUSION: Participants with a short education and low EHE were more likely to have less knowledge of cardiovascular risk factors. PMID- 29503387 TI - Factors Related to Participation in Health Examinations for Japanese National Health Insurance: NIPPON DATA2010. AB - BACKGROUND: This study investigated relationships among socioeconomic factors and participation in health examinations for Japanese National Health Insurance (NHI) using a representative Japanese population. METHODS: We used the linkage database of NIPPON DATA2010 and Comprehensive Survey of Living Conditions 2010. Participants with NHI aged 40-74 years were included in the analysis. Prevalence ratios (PRs) for participation in health examinations in the past year were set as an outcome. Participant characteristics, including sex, age, socioeconomic factors (educational attainment, employment, equivalent household expenditure [EHE], house ownership, and marital status), laboratory measures, and lifestyle were included in an age-stratified modified Poisson regression analysis to examine relationships. RESULTS: The number of study participants was 812, and 564 (69.5%) participated in health examinations in the past year. Among those aged 40 64 years, there was no significant PR for socioeconomic factors. Among those aged 65-74 years, high (>=13 years) educational attainment (adjusted PR, 1.22; 95% confidence interval [CI], 1.05-1.41) and house ownership (PR 1.40; 95% CI, 1.11 1.77) were positively associated with participation, while high (4th quartile) EHE (PR 0.84; 95% CI, 0.73-0.97) was negatively associated. CONCLUSION: These results suggest that high educational attainment, house ownership, and low EHE were positive factors for participation in health examinations among those aged 65-74 years. PMID- 29503388 TI - Socioeconomic Inequalities in Oral Health among Middle-Aged and Elderly Japanese: NIPPON DATA2010. AB - BACKGROUND: Most studies on socioeconomic inequalities in oral health have not considered the effects of behavioral and biological factors and age differences. Furthermore, the nationwide status of inequalities remains unclear in Japan. METHODS: We analyzed data from 2,089 residents aged >=40 years throughout Japan. The lowest quartile of the number of remaining teeth for each 10-year age category was defined as poor oral health. Behavioral and biological factors included smoking status, obesity, diabetes mellitus, high-sensitivity C-reactive protein, and the use of dental devices. Multiple logistic regression analyses were conducted to examine the associations of educational attainment and equivalent household expenditure (EHE) with oral health, and stratified analyses by age category were also conducted (40-64 years and >=65 years). RESULTS: Lower education and lower EHE were significantly associated with an increased risk of poor oral health after adjusting for age, sex, employment status, marital and living statuses, and EHE/education; the odds ratio for junior high school education compared with >=college education was 1.84 (95% confidence interval [CI], 1.36-2.49), and the odds ratio of the lowest compared with the highest EHE quartile was 1.91 (95% CI, 1.43-2.56). Further adjustments for behavioral and biological factors attenuated but did not eliminate these associations. EHE was significantly associated with oral health among elderly adults only, with a significant interaction by age category. CONCLUSIONS: Those with a lower education and those with lower EHE had a significantly higher risk of poor oral health, even after adjustments for behavioral and biological factors. PMID- 29503389 TI - Relationships among Socioeconomic Factors and Self-rated Health in Japanese Adults: NIPPON DATA2010. AB - BACKGROUND: The distributions of socioeconomic status (SES) factors have been changing in Japan. We examined the relationships among SES and self-rated health (SRH) in Japanese adults. METHODS: We analyzed 1,178 men and 1,555 women. We showed the distribution of SRH by sex and age and examined cross-sectional relationships among educational attainment, marital/living statuses, working status, household income and expenditure, and fine SRH (defined as excellent, very good, or good). We adjusted for age, subjective symptoms, visiting doctors, monthly equivalent household expenditure (EHE), and living in their own house. RESULTS: The age-standardized prevalence of fine SRH was 79% and 73% among men and women, respectively. Among men, graduating from high school (adjusted odds ratio [aOR] 1.53; 95% confidence interval [CI], 1.07-2.19, relative to graduating from elementary or junior high school) and university or junior college (aOR 1.74; 95% CI, 1.15-2.62) was associated with fine SRH. Among women, graduating from university or junior college was associated with fine SRH (aOR 1.65; 95% CI, 1.12-2.46). Neither marital/living status nor working status was associated with SRH after adjustments for age in either sex. Among women, high EHE and income were associated with fine SRH (the highest expenditure group: aOR 1.80; 95% CI, 1.22-2.65; the highest income group: aOR 2.15; 95% CI, 1.34-3.46, relative to the corresponding lowest group). These simple relationships were not observed for men. CONCLUSIONS: High educational attainment was associated with fine SRH. Relationships among household income, EHE, and fine SRH differed by sex. PMID- 29503390 TI - Exposure reconstruction of trichloroethylene among patients with occupational trichloroethylene hypersensitivity syndrome. AB - Occupational trichloroethylene (TCE) exposure can induce life-threatening generalized dermatitis accompanied by hepatitis: TCE hypersensitivity syndrome (HS). Since the patients' exposure levels have not been fully clarified, this study estimated end-of-shift urinary concentrations of trichloroacetic acid (TCA) and their lower limit below which the disease occurrence was rare. TCA concentration was measured in 78 TCE HS patients whose urine was collected at admission between 2nd and 14th d after their last shift. Then a linear regression model was used to calculate the mean TCA concentration with 95% confidence interval (95% CI) and 95% prediction interval (95% PI) in the end-of-shift urine. The estimated mean concentration was 83 (95% CI, 49-140) mg/l with 95% PI 9.6-720 mg/l. TCA concentrations were also measured in the end-of-shift urine of 38 healthy workers involved in the same job as were the patients. The geometric mean and its 95% CI were 127 mg/l and 16-984 mg/l, respectively. The exposure levels in HS patients might have thus overlapped with those in workers without HS. Accordingly, it was suggested that HS occurred in the environment where the workers were exposed to the TCE concentration corresponding to the urinary TCA concentration as low as 10 mg/l. PMID- 29503391 TI - Standing balance on inclined surfaces with different friction. AB - Working and walking environments often involve standing positions on different surfaces with inclination and different friction. In this study, standing balance of thirteen participants during sudden and irregular external perturbation to calf muscles was investigated. The aim of the study was to evaluate the combined effect of surface inclination and friction on standing balance. The main findings when eyes closed revealed that the standing utilised coefficient of friction (MUSUCOF) increased when the surface was inclined for both high and low friction materials. The anterior-posterior torque increased more anteriorly when the surface was inclined toes down and when the surface friction was low. The results indicate that the anterior-posterior torque is a sensitive parameter when evaluating standing balance ability and slip risk. On inclined surface, particularly on the surface with lower friction, the potential slip and fall risk is higher due to the increase of standing utilised coefficient of friction and increased forward turning torque. PMID- 29503392 TI - Individual, physical, and organizational risk factors for musculoskeletal disorders among municipality solid waste collectors in Shiraz, Iran. AB - In Iran-Shiraz, municipal solid waste is collected manually requiring strenuous physical activities. This study was conducted to determine the prevalence rate of musculoskeletal disorders (MSDs) and its associated risk factors. Two hundred male waste collectors participated in this cross-sectional study, in which task analysis followed by motion and timeline analysis were performed. The data were collected using demographic, occupation-specific physical and organizational demands, and Nordic musculoskeletal questionnaires. Logistic regression analysis was used for identifying independent risk factors for MSDs. Ten motions observed during waste collection, and the most physical and organizational demands were related to the running along with bag carriage, and the time pressure, respectively. About 39% and 36.5% of the workers reported very high physical and psychological workloads, respectively. Totally, 92.5% of waste collectors reported MSDs symptom at least in one body region during the last 12 months. Lower back and knee injuries were more prevalent and more severe. Some individual factors (age, body weight, and waste collecting duration), physical demands (lifting bag/bucket, pulling/pushing waste container, walking along with bag/bucket carriage, and jumping up/down on the garbage truck), and organizational demands (low vacation and high decision authority) were the most important risk factors for developing MSDs. PMID- 29503393 TI - Treatment Strategy Based on Plaque Vulnerability and the Treatment Risk Evaluation for Internal Carotid Artery Stenosis. AB - Carotid endarterectomy (CEA) and carotid artery stenting (CAS) are not appropriate treatment procedure for internal carotid artery stenosis (ICAS) in some patients. The importance of plaque vulnerability and the treatment risk evaluation has been reported. We analyzed whether treatment selection contributes to the outcome. We retrospectively examined 121 patients who underwent CEA or CAS. Treatment was selected based on plaque vulnerability and the treatment risk evaluation. We selected CAS for patients with stable plaques and CEA for patients with unstable plaques, and considered the other treatment for high-risk patients. The patients were classified as the stable plaque (Stable: n = 42), the unstable plaque and CEA low risk (Unstable/Low: n = 30), and the CEA high-risk (Unstable/High: n = 49). Frequency of perioperative stroke, myocardial infarction, death, and systemic complications was examined. CEA and CAS were performed in 35 and 86 patients, respectively. One patient (2.9%) had a stroke in CEA and five patients (5.8%) in CAS (P = 0.50). Systemic complications were observed in two patients (5.7%) in CEA and six (7.1%) in CAS (P = 0.80). There were no differences in stroke (Stable; 2.4%, Unstable/Low; 3.2%, and Unstable/High; 8.2%) and systemic complications (Stable; 9.5%, Unstable/Low; 3.3%, and Unstable/High; 6.1%) among three groups (P = 0.44 and P = 0.59, respectively). The treatment selection based on plaque vulnerability and the treatment risk evaluation could provide good treatment outcome for high-risk patients. It is ideal to select an appropriate treatment for ICAS by one neurovascular team. PMID- 29503394 TI - Copayment Exemption Policy and Healthcare Utilization after the Great East Japan Earthquake. AB - Healthcare utilization after natural disasters remains understudied. In general, people in Japan pay 10%-30% of total amount of costs, according to their health insurance plan. A policy exempting survivors from copayments was introduced after the Great East Japan Earthquake in March 2011, which had a magnitude of 9.0 on the Richter scale and followed by devastating tsunamis. Among the disaster affected areas, Miyagi prefecture experienced the largest number of deaths and the greatest extent of damage. However, the exemption was suspended in Miyagi prefecture from April, 2013, because of the huge governmental financial burden due to the immensity of damage from the disaster. Subsequently, in April 2014, the exemption was re-introduced, with smaller coverage. We, therefore, evaluated the influence of this policy change on monthly healthcare utilization in Miyagi prefecture between April 2008 and June 2015. We also evaluated the association between the proportion of people exempted from copayment in each municipality and the difference in healthcare utilization before and after the suspension using multivariable linear regression. Healthcare utilization in Miyagi increased immediately after the institution of the exemption policy and it peaked after one year. In March 2013, just before the suspension, a rapid increment in healthcare utilization was observed, suggesting that the copayment may be a barrier for people in the disaster-affected area to access to healthcare. The exemption policy did help the survivors to use healthcare utilization in Miyagi. After devastating natural disasters, policymakers should guarantee that all survivors can utilize healthcare services on demand. PMID- 29503395 TI - Inhibition of 2-arachydonoylgycerol degradation attenuates orofacial neuropathic pain in trigeminal nerve-injured mice. AB - Current therapeutics are not effective for orofacial neuropathic pain, and better options are needed. The present study used inferior orbital nerve (ION)-injured mice to investigate the effect of inhibiting monoacylglycerol lipase (MAGL), an enzyme that degrades the major endocannabinoid 2-arachydonoylgycerol (2-AG) in orofacial neuropathic pain. The head-withdrawal threshold to mechanical stimulation of the whisker pad was reduced on days 3, 5, and 7 after ION injury. Injection of JZL184, a selective inhibitor of MAGL, on day 7 after ION injury attenuated the reduction in head-withdrawal threshold at 2 h after administration. Moreover, the numbers of MAGL-immunoreactive neurons in the trigeminal subnucleus caudalis (Vc) and upper cervical spinal cord (C1-C2) were significantly greater in ION-injured mice than in sham-operated mice but were reduced after administration of JZL184. The increase in MAGL immunoreactivity suggests that increased 2-AG production is followed by rapid enzymatic degradation of 2-AG. JZL184 inhibited this degradation and thus increased 2-AG concentration in the brain, particularly in the Vc and C1-C2 regions, thus attenuating pain. Our findings suggest that inhibition of 2-AG degradation by MAGL inhibitors is a promising therapeutic option for treatment of orofacial neuropathic pain. PMID- 29503396 TI - Shox2: The Role in Differentiation and Development of Cardiac Conduction System. AB - The formation and conduction of electrocardiosignals and the synchronous contraction of atria and ventricles with rhythmicity are both triggered and regulated by the cardiac conduction system (CCS). Defect of this system will lead to various types of cardiac arrhythmias. In recent years, the research progress of molecular genetics and developmental biology revealed a clearer understanding of differentiation and development of the cardiac conduction system and their regulatory mechanisms. Short stature homeobox 2 (Shox2) transcription factor, encoded by Shox2 gene in the mouse, is crucial in the formation and differentiation of the sinoatrial node (SAN). Shox2 drives embryonic development processes and is widely expressed in the appendicular skeleton, palate, temporomandibular joints, and heart. Mutations of Shox2 can lead to dysembryoplasia and abnormal phenotypes, including bradycardiac arrhythmia. In this review, we provide a summary of the latest research progress on the regulatory effects of the Shox2 gene in differentiation and development processes of the cardiac conduction system, hoping to deepen the knowledge and understanding of this systematic process based on the cardiac conduction system. Overall, the Shox2 gene is intimately involved in the differentiation and development of cardiac conduction system, especially sinoatrial node. We also summarize the current information about human SHOX2. This review article provides a new direction in biological pacemaker therapies. PMID- 29503397 TI - Identification and Quantification of Alkaloid in KHR98 and Fragmentation Pathways in HPLC-Q-TOF-MS. AB - Uncaria rhynchophylla is woody climber plant distributed mainly in China and Japan, the stems and hooks of which can be collected as "Gou-Teng" for the treatment of hyperpyrexia, epilepsy and preeclampsia. Fudan University first manufactured KHR98, the extract of Uncaria rhynchophylla. In order to study the active components and structural information of KHR98, we established a HPLC coupled with quadrupole time-of-flight (Q-TOF)-MS method for rapid analysis of alkaloids. In qualitative analysis, a total of eight compounds, including four known alkaloids and four unknown components, were detected and identified. The fragmentation behaviors, such as the fragment ion information and the fragmentation pathways of the eight components were summarized simultaneously, and the concentration of the above components was determined by HPLC-MS method. The quantitative method was proved to be reproducible, precise and accurate. This study shed light on the standardization and quality control of the KHR98 and provided a foundation for the further research on pharmacology, follow-up clinical research and New Drug Applications. PMID- 29503398 TI - Peroxiredoxin as a functional endogenous antioxidant enzyme in pronuclei of mouse zygotes. AB - Antioxidant mechanisms to adequately moderate levels of endogenous reactive oxygen species (ROS) are important for oocytes and embryos to obtain and maintain developmental competence, respectively. Immediately after fertilization, ROS levels in zygotes are elevated but the antioxidant mechanisms during the maternal to-zygotic transition (MZT) are not well understood. First, we identified peroxiredoxin 1 (PRDX1) and PRDX2 by proteomics analysis as two of the most abundant endogenous antioxidant enzymes eliminating hydrogen peroxide (H2O2). We here report the cellular localization of hyperoxidized PRDX and its involvement in the antioxidant mechanisms of freshly fertilized oocytes. Treatment of zygotes at the pronuclear stage with H2O2 enhanced pronuclear localization of hyperoxidized PRDX in zygotes and concurrently impaired the generation of 5 hydroxymethylcytosine (5hmC) on the male genome, which is an epigenetic reprogramming event that occurs at the pronuclear stage. Thus, our results suggest that endogenous PRDX is involved in antioxidant mechanisms and epigenetic reprogramming during MZT. PMID- 29503400 TI - Antioxidant Activity of Ge-132, a Synthetic Organic Germanium, on Cultured Mammalian Cells. AB - Ge-132 is a synthetic organic germanium that is used as a dietary supplement. The antioxidant activity of Ge-132 on cultured mammalian cells was investigated in this study. First, Ge-132 cytotoxicity on mammalian cultured cells was determined by measuring lactate dehydrogenase (LDH) levels. Ge-132 had no cytotoxic effect on three different cell lines. Second, the cell proliferative effect of Ge-132 was determined by measuring ATP content of whole cells and counting them. Ge-132 treatment of Chinese hamster ovary (CHO-K1) and SH-SY5Y cells promoted cell proliferation in a dose-dependent manner. Finally, antioxidant activity of Ge-132 against hydrogen peroxide-induced oxidative stress was determined by measuring the levels of intracellular reactive oxygen species (ROS) and carbonylated proteins. Pre-incubation of CHO-K1 and SH-SY5Y cells with Ge-132 suppressed intracellular ROS production and carbonylated protein levels induced by hydrogen peroxide. Our results suggest that Ge-132 has antioxidant activity against hydrogen peroxide-induced oxidative stress. PMID- 29503399 TI - Effect of pre-in vitro maturation with cAMP modulators on the acquisition of oocyte developmental competence in cattle. AB - The administration of follicle-stimulating hormone (FSH) prior to oocyte retrieval improves oocyte developmental competence. During bovine embryo production in vitro, however, oocytes are typically derived from FSH-unprimed animals. In the current study, we examined the effect of pre-in vitro maturation (IVM) with cAMP modulators, also known as the second messengers of FSH, on the developmental competence of oocytes derived from small antral follicles (2-4 mm) of FSH-unprimed animals. Pre-IVM with N6,2'-O-dibutyryladenosine 3',5' cyclicmonophosphate (dbcAMP) and 3-isobutyl-1-methylxanthine (IBMX) for 2 h improved the blastocyst formation in oocytes stimulated by FSH or amphiregulin (AREG). Furthermore, pre-IVM enhanced the expression of the FSH- or AREG stimulated extracellular matrix-related genes HAS2, TNFAIP6, and PTGS2, and epidermal growth factor (EGF)-like peptide-related genes AREG and EREG. Additionally, pre-IVM with dbcAMP and IBMX enhanced the expression of EGFR, and also increased and prolonged cumulus cell-oocyte gap junctional communication. The improved oocyte development observed using the pre-IVM protocol was ablated by an EGF receptor phosphorylation inhibitor. These results indicate that pre-IVM with cAMP modulators could contribute to the acquisition of developmental competence by bovine oocytes from small antral follicles through the modulation of EGF receptor signaling and oocyte-cumulus/cumulus-cumulus gap junctional communication. PMID- 29503401 TI - Variation in Patient Backgrounds, Practice Patterns, and Outcomes of High-Risk Pulmonary Embolism in Japan. AB - High-risk pulmonary embolism (PE) with hypotension, circulatory failure, or cardiac arrest is a rare, but life-threating condition. Many guidelines recommend that thrombolytic therapy is the first-line therapy for this condition and surgical embolectomy is an alternative treatment. However, nationwide data have been lacking on patient characteristics and practice patterns for high-risk PE in a real-world clinical setting.We defined high-risk PE patients as those who received noradrenaline and underwent surgical embolectomy or thrombolysis within one day after admission. Using a Japanese national inpatient database, we identified high-risk PE patients from July 2010 to March 2014, and divided them into patients with and without embolectomy and those with and without cardiopulmonary arrest (CPA) at admission. We examined variation in patient backgrounds, procedures, and outcomes in this population.We identified 361 patients were eligible. Among those, including 266 received thrombolysis and 95 received embolectomy. The 30-day mortality was 41.4% in 266 patients with thrombolysis, and 14 patients died in 95 patients with embolectomy. Among the thrombolysis group, 30-day mortality was 35% in 187 patients without CPA thrombolysis and was 56% in 79 patients with CPA. Among the embolectomy group, 30 day mortality was 14% in 81 patients without CPA, and 21% patients died in 14 patients with CPA.The present nationwide study showed that surgical embolectomy had a relatively low mortality. Further studies are needed to verify the comparative effectiveness of embolectomy. PMID- 29503402 TI - A Vaginal Stillbirth after Aortic Surgery of Type B Aortic Dissection in a Pregnant Woman. AB - Acute aortic dissection occurring during pregnancy poses great danger to both the mother and fetus. Cesareans are usually performed before or after the aortic repair depending on the conditions of the mother and fetus. Here we report our experience in treating a 32-week pregnant woman with a type B aortic dissection, whose baby had died before admission. A cesarean section was initially arranged after emergency aortic repair. However, the patient started to deliver the fetus vaginally after the aortic surgery and the stillborn baby was delivered vaginally. This case report provides new insight into the method of delivery in a pregnant woman with an aortic dissection. PMID- 29503403 TI - Pulmonary Tumor Thrombotic Microangiopathy due to Advanced Gastric Cancer with Virchow's Node Metastasis. AB - Pulmonary tumor thrombotic microangiopathy (PTTM) is a fatal cancer-related complication characterized by severe progressive pulmonary hypertension. Antemortem diagnosis is difficult owing to the rapid progression of the condition, especially when the patient has no known malignancies and initially presents with pulmonary hypertension. Here we report a case of PTTM due to occult gastric cancer with metastasis in the left supraclavicular lymph node, also known as Virchow's node. Enlarged Virchow's node is an important indicator of advanced gastric cancer. In patients with progressive pulmonary hypertension of unknown origin, enlarged Virchow's node can be an important indicator for the diagnosis of PTTM. PMID- 29503405 TI - Novel Understanding of Takotsubo Syndrome. AB - Takotsubo cardiomyopathy is described as a transient reversible cardiomyopathy which typically occurs in older women after emotional or physical stress. This cardiomyopathy is also recognized as a "syndrome" because it develops in conjunction with various diseases. Since the clinical presentation of takotsubo syndrome (TTS) is similar to acute coronary syndrome (ACS), TTS should be distinguished from ischemic heart disease. Although the pathophysiology of TTS has not well been established, a number of its specific features have been suggested. The predictor of mortality in TTS is still unknown. In this review article, we describe a series of treatment decisions in TTS. PMID- 29503404 TI - Rationale and Design of Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) Trial. AB - Large-scale clinical trials in patients in Western countries with coronary artery disease (CAD) have found that aggressive lipid-lowering therapy using high-dose statins reduces cardiovascular (CV) events further than low-dose statins. However, such evidence has not yet been fully established in Asian populations, including in Japan. The Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study addresses whether intensification of statin therapy improves clinical outcomes in Japanese patients with CAD.REAL-CAD is a prospective, multicenter, randomized, open-label, blinded-endpoint, physician-initiated phase 4 trial in Japan. The study will recruit up to 12,600 patients with stable CAD. Patients are assigned to receive either pitavastatin 1 mg/day or pitavastatin 4 mg/day. LDL-C levels are expected to reach approximate mean values of 100 mg/dL in the low-dose pitavastatin group and 80 mg/dL in the high-dose group. The primary endpoint is the time to occurrence of a major CV event, including CV death, non-fatal myocardial infarction, non-fatal ischemic stroke, and unstable angina requiring emergency hospitalization during an average of 5 years. The large number of patients and the long follow-up period in the REAL-CAD study should ensure that there is adequate power to definitively determine if reducing LDL-C levels to approximately 80 mg/dL by high-dose statin can provide additional clinical benefit.After the study is completed, we will have categorical evidence on the optimal statin dose and target LDL-C level for secondary prevention in Japanese patients. PMID- 29503406 TI - Comparison of the Acute and Long-Term Outcomes of Patients With Multivessel Coronary Artery Disease After Angiographic Complete and Incomplete Revascularization With Drug-Eluting Stents. AB - BACKGROUND: Data regarding the long-term outcomes of a large patient population with multivessel coronary artery disease (MV-CAD) after complete revascularization (CR) and incomplete revascularization (IR) with drug-eluting stent (DES) implantation are controversial. The objective of this study was to evaluate differences between the clinical outcomes of CR and IR in such patients.Methods and Results:A total of 1,502 patients with MV-CAD who received DES between April 2005 and August 2016 were enrolled in this study after propensity score matching. The CR group had 751 patients with 1,368 stents implanted in 1,215 lesions, and the IR group had 751 patients with 1,077 stents implanted in 948 lesions. The CR group had a similar rate of in-hospital major adverse cardiovascular events to the IR group (1.9% vs. 1.6%, P=0.844). Follow-up angiography at 9 months showed no significant difference between the 2 groups for restenosis. The CR group had a higher cardiovascular event-free survival rate than the IR group during a mean follow-up period of 71+/-62 months (81.8% vs. 72.0%, P<0.001). Kaplan-Meier survival analysis also showed better results in the CR group than in the IR group. CONCLUSIONS: Angiographic CR was associated with more favorable long-term cardiovascular outcomes than angiographic IR in patients with MV-CAD after DES implantation. PMID- 29503407 TI - Survey on the Status of Smoking Inside Eating Establishments in the Cities of Kobe and Amagasaki. AB - BACKGROUND: The Hyogo Prefectural Government has been enforcing a smoking ban ordinance since April 2013. The present survey was conducted to determine the extent to which the smoking ban has been successfully implemented in eating establishments in Kobe City and Amagasaki City.Methods and Results:The Health and Welfare Department of the Hyogo Prefectural Government provided a list of eating establishments in Kobe and Amagasaki City. From these, we chose 1,300 from each city using random number generation. Responses were obtained from 310 establishments in Kobe City (response rate: 23.8%) and 297 in Amagasaki City (22.8%). Overall, 58.1% of the establishments surveyed in Kobe City were aware of the ordinance, a recognition rate significantly higher than that of Amagasaki City, where only 45.5% of eateries were aware of the ordinance (P=0.003). Of the Kobe City eateries, 31.7% had succeeded in implementing a complete ban on smoking. In Amagasaki City, the rate was significantly lower, at just 13.4% (P<0.001). A logistic regression analysis showed that coffee shops, Japanese style taverns, bars, and eating establishments that served alcohol were the independent significant predictors of low compliance. Kobe City restaurants, women, and families were the independent significant predictors of high compliance with the complete smoking ban. CONCLUSIONS: The rates of recognition and implementation of the complete smoking ban were significantly lower in Amagasaki City than in Kobe City. There needs to be a strong and continuous socialization campaign to promote the ordinance. PMID- 29503408 TI - The Unraveled Link Between Antiviral Therapy and Heart Failure Hospitalization in Chronic Hepatitis C Virus Infection - A Nationwide Cohort Study. AB - BACKGROUND: Although hepatitis C virus (HCV) is a known risk factor for cardiovascular disease, whether antiviral therapy (AVT) can reduce heart failure (HF) hospitalizations is unknown.Methods and Results:In this population-based cohort study, we used data from the Taiwan National Health Insurance Research Database to evaluate the effect of interferon-based therapy (IBT) on cardiovascular events in patients with chronic HCV infection. Clinical outcomes evaluated included HF hospitalizations; a composite of acute myocardial infarction, ischemic stroke, and peripheral artery disease; all-cause death; and cardiovascular death. Of 83,229 eligible patients with chronic HCV infection, we compared 16,284 patients who received IBT with untreated subjects after propensity score matching. Patients who received IBT were less likely to be hospitalized for HF compared with untreated subjects (incidence density.ID, 0.9 vs. 1.5 events per 103person-years; hazard ratio.HR, 0.58; 95% confidence interval.CI, 0.42-0.79; P=0.001). Compared with untreated subjects, the treated group had significantly lower risk of composite vascular events (ID, 3.7 vs. 5.0 events per 103person-years; P<0.001), all-cause death (ID, 5.6 vs. 17.2 events per 103person-years; P<0.001), and cardiovascular death (ID, 0.2 vs. 0.6 events per 103person-years; P=0.001). CONCLUSIONS: AVT for chronic HCV infection might offer protection against HF hospitalizations, critical vascular events, and cardiovascular death beyond known beneficial effects. PMID- 29503409 TI - Best Treatment Strategies With Statins to Maximize the Cardiometabolic Benefits. AB - Statins are important for preventing adverse cardiovascular events in patients with both high and low risk of vascular disease, by reducing the levels of low density lipoprotein cholesterol (LDL-C). However, statins dose-dependently increase adverse effects and increase the risk of type 2 diabetes. Previously, it was hypothesized this was caused by to off-target effects, but recent studies demonstrate it is caused by on-target effects. Nonetheless, the American guidelines recommend the use of high-intensity statin therapy, and extend its use to most people at risk of vascular diseases, particularly older people. In contrast, European, Korean, and Japanese committees have expressed concerns about the potential adverse effects of using high-intensity statins for lifelong periods in a large fraction of the population. Patients who have achieved LDL-C levels below currently recommended targets may still experience cardiovascular events, resulting from residual risk. Ezetimibe, PCSK9 inhibitors, inclisiran, and ANGPTL3 antisense oligonucleotides are promising alternative non-statin drugs. Of interest, cross-talk between hypercholesterolemia and the renin angiotensin-system exists at multiple levels of insulin resistance and endothelial dysfunction. There are still unanswered questions on how to maximize the cardiometabolic benefits of statins in patients. We will discuss the results of randomized clinical trials, meta-analysis, and recent clinicopharmacogenetic studies, and propose practical guidelines to maximize the cardiometabolic benefits while reducing adverse effects and overcoming residual risk. PMID- 29503410 TI - Investigation of Obstructive Sleep Apnea Using Portable Monitors and Health Check Data in Japanese Drivers. AB - AIMS: The identification and appropriate management of commercial motor vehicle (CMV) drivers with unrecognized obstructive sleep apnea (OSA) is a major public health concern and priority; OSA among drivers has not been fully investigated in Japan, and a better understanding of this undiagnosed disease is warranted. Therefore, we evaluated the prevalence of OSA and the factors related to apnea hypopnea index (AHI) in Japanese CMV drivers. METHODS: This retrospective study included 1309 Japanese CMV drivers aged 40-69 years. All the subjects received type IV portable sleep monitors (PMs) with Epworth Sleepiness Scale (ESS) and a periodic health check including anthropometrical and laboratory measurements, and a questionnaire of medical history, smoking status, and life style, following which variables related to AHI were analyzed. RESULTS: Of all the subjects, 23.9% had moderate to severe OSA (AHI >=15). Age, body mass index (BMI), LogeHbA1c and diastolic blood pressure (DBP) showed significance with AHI in 1309 subjects. The following factors were found to have significant odds ratio (OR) for AHI of >=15 in 1309 subjects: age, ESS, DBP, and LogeHbA1c. CONCLUSION: Notably, drivers with undiagnosed OSA exist. In these subjects, AHI was related to obesity, hypertension, and diabetes. For the early diagnosis and intervention of OSA, BMI, blood pressure, and HbA1c measurements may be helpful, particularly for drivers. Furthermore, when performing an objective assessment of the suspected OSA, evaluating these parameters during routine medical check-ups may be useful and feasible in the detection of drivers with latent OSA. PMID- 29503411 TI - Low Levels of Plasma Osteoglycin in Patients with Complex Coronary Lesions. AB - AIM: Osteoglycin is one of proteoglycans that are biologically active components of vascular extracellular matrix. However, the role of osteoglycin in atherosclerosis remains unclear. METHODS: We investigated plasma osteoglycin levels and the presence, severity, and lesion morphology of coronary artery disease (CAD) in 462 patients undergoing elective coronary angiography. RESULTS: Of 462 patients, 245 had CAD. Osteoglycin levels were higher in patients with CAD than without CAD (median 29.7 vs. 25.0 ng/mL, P<0.05). However, osteoglycin levels did not differ among patients with one-vessel, two-vessel, or three-vessel disease (30.8, 30.6, and 29.4 ng/mL, respectively) and did not correlate with the number of stenotic segments. Among 245 CAD patients, 41 had complex coronary lesions, and 70 had total occlusion, of whom 67 had good collateralization. Between 70 patients with occlusion and 175 without occlusion, osteoglycin levels did not differ (30.4 vs. 29.5 ng/mL). Notably, osteoglycin levels were lower in 41 patients with complex lesions than in 204 without such lesions (24.2 vs. 31.6 ng/mL, P<0.02). In multivariate analysis, osteoglycin levels were an independent factor for complex lesion but not for CAD. Odds ratio for complex lesion was 0.80 (95%CI=0.67-0.96) for each 10 ng/mL increase in osteoglycin levels (P<0.02). CONCLUSION: Although plasma osteoglycin levels were high in patients with CAD, they did not correlate with the severity of CAD and were not an independent factor for CAD. Notably, osteoglycin levels were low in patients with complex lesions and were a factor for complex lesions, suggesting that osteoglycin plays a role in coronary plaque stabilization. PMID- 29503413 TI - ? PMID- 29503412 TI - Evaluation of Lenticulostriate Arteries Changes by 7 T Magnetic Resonance Angiography in Type 2 Diabetes. AB - AIM: Progress in neuroimaging techniques allows us to investigate the microvasculature characteristics including lenticulostriate arteries (LSA), which are closely associated with lacunar infarction. Because ischemic stroke is a more critical health problem in East Asian than in other populations, in order to clarify pathological changes underlying cerebral small vessel disease (SVD), we projected an imaging analysis of LSA using high-resolution brain magnetic resonance imaging (MRI) in middle-aged Japanese subjects with type 2 diabetes. METHODS: Twenty-five subjects with type 2 diabetes and 25 non-diabetic control subjects underwent 7 Tesla (7 T) brain MRI. The prevalences of SVD and LSA structural changes were determined in each group. RESULTS: SVD prevalence did not differ significantly between the type 2 diabetes and control groups. The average numbers of stems, as well as numbers of branches, of LSA were significantly smaller in diabetic subjects than non-diabetic control subjects. The signal intensity of LSA was markedly decreased, indicating reduced blood flow in type 2 diabetes. CONCLUSION: In spite of the prevalence of SVD being similar, structural changes and decreased signal intensity of LSA were highly detected in diabetic subjects compared with non-diabetic controls, suggesting that 7 T MRA enables us to determine LSA impairment prior to the development of SVD. Early detection of LSA impairment allows us earlier interventions aimed at the prevention of atherosclerotic events. PMID- 29503414 TI - [Pharmaceutical Compounds in the Environment-Distribution, Ecological Effects, and Purification Technologies]. PMID- 29503415 TI - [Antibiotic Residue in Environmental Water in Vietnam]. AB - The increasing prevalence of antimicrobial resistance (AMR) has caused intractable infections worldwide. Nearly 50% of the healthy population of Southeast Asia carries extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli. The overuse of antimicrobial agents in the agriculture, aquaculture, and medical care sectors causes environmental pollution, facilitating the spread of AMR. However, there is a lack of data pertaining to antimicrobial residues in environmental water in such regions. We investigated a total of 49 chemicals, including beta-lactams, sulfonamides, quinolones, and tetracyclines. Water samples were collected from rivers in city centers, and ponds in livestock and aquaculture farms, in Ha Noi, Thai Binh, and Can Tho in Vietnam. We detected antimicrobial agents at 87 of 111 sampling sites (78.4%). Among the target analytes, sulfamethoxazole, sulfamethazine, trimethoprim, cephalexin, and ofloxacin were detected frequently. The residual levels of each antimicrobial agent ranged from 0.1 to 10000 ng/L. Moreover, we detected multi drug resistant E. coli in fishes sampled from these rivers, suggesting unwanted effects of antimicrobial residues in the environment. PMID- 29503416 TI - [Effect of Environmental Factors on the Ecotoxicity of Pharmaceuticals and Personal Care Products]. AB - In recent years, pharmaceuticals and personal care products (PPCPs) have emerged as significant pollutants of aquatic environments and have been detected at levels in the range of ng/L to MUg/L. The source of PPCPs is humans and livestock that have been administered pharmaceuticals and subsequently excreted them via urine and feces. Unlike agricultural chemicals, the environmental dynamics of PPCPs is not examined and they would undergo structural transformation by environmental factors, e.g., sunlight, microorganisms and treatments in sewage treatment plants (STPs). Processing at STPs can remove various PPCPs; however, they are not removed completely and some persist in the effluents. In this study, we examined the degradation of 9 pharmaceuticals (acetaminophen, amiodarone, dapsone, dexamethasone, indomethacin, raloxifene, phenytoin, naproxen, and sulindac) by sunlight or UV, and investigated the ecotoxicological variation of degradation products. Sunlight (UVA and UVB) degraded most pharmaceuticals, except acetaminophen and phenytoin. Similar results were obtained with UVB and UVA. All the pharmaceuticals were photodegraded by UVC, which is used for sterilization in STPs. Ecotoxicity assay using the luminescent bacteria test (ISO11348) indicated that UVC irradiation increased the toxicity of acetaminophen and phenytoin significantly. The photodegraded product of acetaminophen was identified as 1-(2-amino-5-hydroxyphenyl)ethanone and that of phenytoin as benzophenone, and the authentic compounds showed high toxicity. Photodegraded products of PPCPs are a concern in ecotoxicology. PMID- 29503417 TI - [Detection of Physiological Activity of Pharmaceuticals in Wastewater and River Water]. AB - Pharmaceuticals are widely found in aquatic environments worldwide. Concern about their potential risks to aquatic species has been raised because they are designed to be biologically active. To address this concern, we must know whether biological activity of pharmaceuticals can be detected in waters. Nearly half of all marketed pharmaceuticals act by binding to the G protein-coupled receptor (GPCR). In this study, we measured the physiological activity of GPCR-acting pharmaceuticals in effluent from a wastewater treatment plant (WWTP) and upstream and downstream of its outfall in Japan during 2 years. We used the in vitro transforming growth factor-alpha (TGFalpha) shedding assay, which accurately and sensitively detects GPCR activation, to investigate the antagonistic activities of water extracts against receptors for dopamine (D2) and histamine (H1). Activities detected in waters were quantified as antagonist equivalent quantities (EQs). In WWTP effluent extracts, antagonistic activity was detected at several hundred ng/L of sulpiride-EQ (D2) and several MUg/L of diphenhydramine (DIP)-EQ (H1). In downstream river water extracts, antagonistic activity against H1 was around several hundred ng/L of DIP-EQ, higher than that upstream owing to the WWTP effluent. This review discusses the research needed to resolve the concern about potential risks of pharmaceuticals in waters to aquatic species. PMID- 29503418 TI - [Newly Designed Water Treatment Systems for Hospital Effluent]. AB - Pharmaceuticals are indispensable to contemporary life. Recently, the emerging problem of pharmaceutical-based pollution of river environments, including drinking water sources and lakes, has begun to receive significant attention worldwide. Because pharmaceuticals are designed to perform specific physiological functions in targeted regions of the human body, there is increasing concern regarding their toxic effects, even at low concentrations, on aquatic ecosystems and human health, via residues in drinking water. Pharmaceuticals are consistently employed in hospitals to treat disease; and Japan, one of the most advanced countries in medical treatment, ranks second worldwide in the quantity of pharmaceuticals employed. Therefore, the development of technologies that minimize or lessen the related environmental risks for clinical effluent is an important task as well as that for sewage treatment plants (STPs). However, there has been limited research on clinical effluent, and much remains to be elucidated. In light of this, we are investigating the occurrence of pharmaceuticals, and the development of water treatment systems for clinical effluent. This review discusses the current research on clinical effluent and the development of advanced water treatment systems targeted at hospital effluent, and explores strategies for future environmental risk assessment and risk management. PMID- 29503419 TI - [New Development of the Risk Benefit Communication-For Safety Information to Be Communicated and Understood Sufficiently]. PMID- 29503420 TI - [Risk/Benefit Communication: International Developments and Prospects for the Future]. AB - While expectations for the benefits of pharmaceuticals are high, the occurrence of health damage from adverse drug reactions remains a problem. One of the reasons for this seems to be insufficient risk communication among stakeholders. Healthcare professionals (HCPs), relevant agencies, and pharmaceutical companies have responsibilities to communicate useful information on the risks/benefits of the pharmaceuticals they provide in addition to basic policies and services. Four years have passed since the risk management plan system was introduced in Japan. Although relevant materials for patients and HCPs are offered, it is still difficult to determine whether they are being utilized effectively. The provision of drug information to patients is necessary to allow them to take medicine safely, while maximizing the benefits and minimizing the risks associated with pharmacotherapy. By incorporating survey results on patients' level of understanding of drug risks/benefits, a system to provide information emphasizing the perspectives of patients has been promoted in Europe and North America. In the study of safety issues on a scientific basis, risk communication will become an increasingly important subject. This is a field to which pharmacologists and pharmacists can contribute during this symposium. This paper introduces research activities on risk communication that have been carried out in Japan as well as internationally. PMID- 29503421 TI - [The Pharmaceuticals and Medical Devices Agency's Approach to Facilitate Risk Communication and Its Challenges]. AB - The issue of drug lag in Japan has been rapidly reduced in recent years, and newly approved drugs now become available on Japanese and international markets at the same time. In this context, the risk management plan (RMP) system was introduced in 2012. RMPs describe important safety concerns recognized by Japan's Pharmaceuticals and Medical Devices Agency (PMDA) and marketing authorization holders (MAHs), as well as safety measures that MAHs request healthcare professionals (HCPs) to follow. The publication of RMPs is expected to support the sharing of drug risk management among HCPs during the postmarketing phase. In addition, to encourage risk communication between HCPs and patients, the PMDA website provides drug guides for patients and other information to promote proper understanding of drugs by patients and their families and enable them to identify serious adverse drug reactions at an early stage. However, the results of surveys conducted by the PMDA in FY2014 and FY2015 revealed low levels of awareness of RMPs and drug guides for patients in hospitals and other healthcare institutions. The surveys also showed that information regarding the proper use of drugs from MAHs and the PMDA was not incorporated into practice at healthcare institutions, resulting in the repeated release of identical safety alerts. To facilitate the increased utilization of risk communication tools, the PMDA has been providing and disseminating these tools through its website. This study addresses those efforts and the associated challenges. PMID- 29503422 TI - [Making Patient-focused Information Provision a Reality: One Company's Approach]. AB - In recent years, as the market has seen the appearance of innovative medical products with novel mechanisms of action, adverse reactions that cannot be expected from the approved product label are being detected in the postmarketing phase. It is increasingly important to undertake timely product label updates and other drug safety measures through the monitoring, early detection, and reporting of adverse reactions. In 2013, the risk management plan (RMP) system was introduced in Japan. An RMP documents efforts to ensure the safety of a medical product, and sharing the RMP with stakeholders results in enhanced postmarketing safety measures. Healthcare providers have already started to utilize RMPs, but issues with perception and utilization remain. The industry, regulators, and academia are also working together to facilitate the use of RMPs. With the implementation of the RMP requirement, pharmaceutical companies are seeking to improve safety assurance by enhancing their drug safety functions, including the collection, assessment, and dissemination of drug safety information. Chugai Pharmaceutical is starting a completely new approach to patient-focused information provision, exemplified by the "PMS & SAFETY DB Tools," designed to give healthcare providers quick access to its extensive database of real-world drug safety information. This paper introduces Chugai Pharmaceutical's new efforts to manage adverse reactions and raises issues for future consideration. PMID- 29503423 TI - [Current Status and Issues of Electronic Information Provision for Risk Minimization: Coordination between Electronic Medicine Notebook and Patient Drug Information]. AB - In the collaboration between community pharmacies and hospitals or clinics, the use of electronic medicine notebook may allow information sharing, including among out-of-network hospitals, clinics, and community pharmacies. For risk minimization, mobile or smart phones, which patients always carry with them, should be used as a tool allowing drug information to be accessed at any time. An advantage of the electronic conversion of patient drug information is that it allows patients not only to obtain round-the-clock information on drugs, etc. that they are receiving but also to check patient-oriented information selected and made easier to understand by pharmacists. In the collaboration between community pharmacies and hospitals or clinics, if, for example, patient discharge summaries are conveyed to community pharmacies via electronic medicine notebook, patients will feel reassured about the medical alliance and place more trust in pharmacists overall. This can improve patient drug awareness, thus contributing effectively to risk minimization. Drug information in electronic medicine notebook with 24-h access requires not only patients but also pharmacists to be proactive in its use. In addition, a system to facilitate the proactive use of that information needs to be established. For the electronic conversion of patient drug information and the establishment of a system promoting electronic medicine notebook use, the current status and issues need to be thoroughly examined from the viewpoint of risk communication. PMID- 29503424 TI - [Evidence-based Risk and Benefit Communication for Shared Decision Making]. AB - Evidence-based medicine (EBM) can be defined as "the integration of the best research evidence with clinical expertise and a patient's unique values and circumstances". However, even with the best research evidence, many uncertainties can make clinical decisions difficult. As the social requirement of respecting patient values and preferences has been increasingly recognized, shared decision making (SDM) and consensus development between patients and clinicians have attracted attention. SDM is a process by which patients and clinicians make decisions and arrive at a consensus through interactive conversations and communications. During the process of SDM, patients and clinicians share information with each other on the goals they hope to achieve and responsibilities in meeting those goals. From the clinician's standpoint, information regarding the benefits and risks of potential treatment options based on current evidence and professional experience is provided to patients. From the patient's standpoint, information on personal values, preferences, and social roles is provided to clinicians. SDM is a sort of "wisdom" in the context of making autonomous decisions in uncertain, difficult situations through interactions and cooperation between patients and clinicians. Joint development of EBM and SDM will help facilitate patient-clinician relationships and improve the quality of healthcare. PMID- 29503425 TI - [Knowledge of Drug Interactions to Take Advantage in the Pharmacist]. PMID- 29503426 TI - [Quantitative Prediction of Drug-Drug Interaction Caused by CYP Inhibition and Induction from In Vivo Data and Its Application in Daily Clinical Practices Proposal for the Pharmacokinetic Interaction Significance Classification System (PISCS)]. AB - Drug-drug interactions (DDIs) can affect the clearance of various drugs from the body; however, these effects are difficult to sufficiently evaluate in clinical studies. This article outlines our approach to improving methods for evaluating and providing drug information relative to the effects of DDIs. In a previous study, total exposure changes to many substrate drugs of CYP caused by the co administration of inhibitor or inducer drugs were successfully predicted using in vivo data. There are two parameters for the prediction: the contribution ratio of the enzyme to oral clearance for substrates (CR), and either the inhibition ratio for inhibitors (IR) or the increase in clearance of substrates produced by induction (IC). To apply these predictions in daily pharmacotherapy, the clinical significance of any pharmacokinetic changes must be carefully evaluated. We constructed a pharmacokinetic interaction significance classification system (PISCS) in which the clinical significance of DDIs was considered in a systematic manner, according to pharmacokinetic changes. The PISCS suggests that many current 'alert' classifications are potentially inappropriate, especially for drug combinations in which pharmacokinetics have not yet been evaluated. It is expected that PISCS would contribute to constructing a reliable system to alert pharmacists, physicians and consumers of a broad range of pharmacokinetic DDIs in order to more safely manage daily clinical practices. PMID- 29503427 TI - [Dynamic Simulation of Drug-Drug Interactions by Using Multi-level Physiological Modeling & Simulation Platforms]. AB - Drug-drug interactions mediated by drug metabolizing enzymes are serious, clinically relevant issues. Prediction and evaluation of the probability and consequences of drug-drug interactions are essential during drug development, as well as during clinical application. A physiologically based pharmacokinetic (PBPK) model, which considers the hierarchical structure of the physiological behavior of drugs, has been demonstrated to be effective for in vitro-in vivo extrapolation of the phenomena of drug-drug interaction (DDI). While commercial software that implements PBPK models is now available, increasing attention has been given to developing similar models on open platforms for systems biology modeling and simulation. Open simulation model development environments, including CellDesigner and PhysioDesigner, have been developed and improved with the advent of research fields associated with systems biology or synthetic biology. Model developers implement their models using the platform, then publish the models in public databases. Through sharing and reuse among researchers, these models can become more generalized and sophisticated. This review article aims to discuss the attractive features and potential of these open platforms, and to evaluate the prediction effectiveness for enzyme induction-based drug-drug interactions via integrating the PBPK models of inducers and substrates and the dynamic models of enzyme induction kinetics. PMID- 29503428 TI - [Effect of Food Thickeners on the Disintegration, Dissolution, and Drug Activity of Rapid Oral-disintegrating Tablets]. AB - For patients with dysphagia in medical facilities and nursing homes, food thickeners are routinely used to aid the ingestion of medicines such as tablets. However, some types of thickeners affect the disintegration and dissolution of tablets, such as rapidly-disintegrating magnesium oxide tablets and donepezil hydrochloride orally disintegrating tablets. Additionally, delayed disintegration and dissolution of tablets affect a drug's efficacy. As an example, with Voglibose orally disintegrating tablets, marked differences are observed in changes in glucose levels during glucose tolerance testing. When using food thickeners to aid tablet ingestion, it is therefore necessary to select a product that has little effect on drug disintegration, dissolution, and activity. PMID- 29503429 TI - [Metabolism of Sesamin and Drug-Sesamin Interaction]. AB - Sesamin, derived from sesame seeds, is known to have various biological effects. Since some of these effects appear to be derived from its metabolites, the elucidation of sesamin metabolism is essential to understanding the molecular mechanism of its effects. In addition, it is important to clarify drug-sesamin interactions in order to address safety concerns, as some food factors are known to affect drug metabolism. Our previous studies revealed that sesamin was sequentially metabolized by cytochrome P450 (CYP) and UDP-glucuronosyltransferase or sulfotransferase. Whereas sesamin metabolism is mainly mediated by CYP2C9 in human liver, sesamin causes a mechanism-based inhibition (MBI) of CYP2C9. However, we found that the metabolite-intermediate complex between CYP2C9 and sesamin was unstable, and the effects of sesamin appeared to be minimal. To confirm this assumption, in vivo studies using rats were conducted. After the administration of sesamin to rats for 3 d, diclofenac (an NSAID) was administered to measure the time course of plasma concentration of diclofenac. No significant differences were observed in the diclofenac Cmax, Tmax, and AUC0-24 h between the group that was administered sesamin and the group that was not. Based on these results, it could be concluded that no significant interaction occurs in people who take sesamin supplements at a standard dose. PMID- 29503430 TI - [Drug-Drug Interactions with Consideration of Pharmacogenetics]. AB - Elderly patients often suffer from a variety of diseases and therefore may be prescribed several kinds of drugs. Interactions between these drugs may cause problems in some patients. Guidelines for drug interactions were released on July 8, 2014 "Drug Interaction Guideline for Drug Development and Labeling Recommendations (Final Draft)". These guidelines include the theoretical basis for evaluating the mechanisms of drug interaction, the possible extent of drug interactions, and take into consideration special populations (e.g., infants, children, elderly patients, patients with hepatic or renal dysfunction, and subjects with minor deficient alleles for drug metabolizing enzymes and drug transporters). In this symposium article, I discuss this last special population: altered drug metabolism and drug interactions in subjects with minor alleles of genes encoding deficient drug metabolizing enzymes. I further discuss a drug label for eliglustat (Cerdelga) with instructions for patients with ultra-rapid, extensive, intermediate, and poor metabolizer phenotypes that arise from different CYP2D6 gene alleles. PMID- 29503431 TI - [Bioinorganic Chemistry of Iron]. AB - The X-ray crystallographic analysis of the single-crystal mugineic acid-Cu(II) complex showed that mugineic acid acts as a hexadentate ligand. Mugineic acid, a typical phytosiderophore, shows a marked stimulating effect on 59Fe-uptake and chlorophyll synthesis in rice plants. A salient feature is the higher reduction potential of the mugineic acid-Fe(III) complex than those of bacterial siderophores. X-ray diffraction study of the structurally analogous Co(III) complex of the mugineic acid-Fe(III) complex demonstrates that the azetidine nitrogen and secondary amine nitrogen, and both terminal carboxylate oxygens, coordinate as basal planar donors, and the hydroxyl oxygen and intermediate carboxylate oxygen bind as axial donors in a nearly octahedral configuration. The iron-transport mechanism in gramineous plants appears to involve the excretion of mugineic acid from the roots, which aids Fe(III)-solubilization and reduction of Fe(III) to Fe(II). Manganese peroxidase (MnP) is a component of the lignin degradation system of the basidiomycetous fungus, Phanerochaete chrysosporium. To elucidate the heme environment of this novel Mn(II)-dependent extracellular enzyme, we studied its ESR and resonance Raman spectroscopic properties. Consequently, it is most likely that the heme environment of MnP resembles that of cytochrome c peroxidase. In addition, degradation methods using basidiomycetous fungi or Fe3+-H2O2 mixed reagent were developed for dioxins and polychlorinated biphenyls. The complete amino acid sequences of respective [2Fe 2S] ferredoxins were determined and compared with those of other higher plants. Finally, the toxic effects of iron on human health and the development of novel antibacterial drugs capable of inhibiting the iron transport system of Vibrio vulnificus are described. PMID- 29503432 TI - [Pharmacological Mechanisms of Boiogito and Bofutsushosan in Diabetes and Obesity Models]. AB - The antihyperglycemic activities of extracts of boiogito (BOT) and bofutsushosan (BTS) were investigated in streptozotocin-induced (STZ)-diabetic mice. BOT extract containing Stephania tetrandra S. MOORE root (stephania), has more potent antihyperglycemic activity than BOT extract containing sinomenium stem (sinomenium). Extracts of stephania and astragalus root (astragalus) exert combined effects in the antihyperglycemic and insulinotropic activities of BOT extract. Fangchinoline, but not tetrandrine, in stephania plays a role in its activity. Formononetin in astragalus potentiates the actions of fangchinoline. Tetrandrine has antiangiogenic effects on choroidal vessels in STZ-diabetic rats, which are associated with the inhibition of tumor necrosis factor (TNF)-alpha induced nuclear factor (NF)-kappaB activation. BTS extract has shown antihyperglycemic and insulinotropic activities whereas gardenia fruit (gardenia) extract in BTS has antihyperglycemic, but not insulinotropic, activity in the diabetic mice. Gardenia extract decreased the HOMA-IR level and increased insulin stimulated 2-deoxyglucose (2-DG) uptake to skeletal muscle. The effects of gardenia extract on 2-DG uptake were associated with the upregulation of glucose transporter type 4 and Akt phosphorylation. Gardenia extract was also shown to have antihyperglycemic and insulinotropic actions in high-fat diet (HFD)-fed and STZ-diabetic mice. In addition, gardenia extract decreased the production of TNF alpha and leptin, and increased the production of adiponectin in the visceral adipose tissues. In the early administration period, BTS extract increased mRNA expression levels of leptin, adiponectin, and UCP1 in brown adipose tissues in HFD-fed obese mice. With a longer duration of administration, BTS extract improved insulin resistance and subsequently reduced serum leptin and triglyceride levels in parallel with visceral adipose tissue volume and size. PMID- 29503433 TI - [Enzymological Studies on the Mechanisms of Pathogenesis of Diabetic Complications]. AB - Aldose reductase (AR) is involved in the pathogenesis of complications in diabetes. In this study, the enzymatic properties of AR isolated from various sources and a recombinant human AR (rh-AR) were analyzed in detail. The sensitivity of different forms of AR to several AR inhibitors (ARIs) was compared. Our findings enabled us to propose that human AR should be used as the target enzyme in the development of ARIs. An enzyme-linked immunosorbent assay (ELISA) for human AR which employed monoclonal antibodies against rh-AR was created, and this method was used to demonstrate the distribution of AR in human tissues. AR was widely distributed in various organs and blood cell components. The levels of erythrocyte AR (e-AR) were 10.1+/-1.9 ng/mg Hb and 10.5+/-3.0 ng/mg Hb in healthy volunteers and diabetic patients, respectively, and thus there was no significant difference between them. The e-AR levels of diabetic patients were assayed using the ELISA developed to investigate the potential correlation between AR levels and the onset of diabetic complications. There were significant correlations between the incidence of diabetic neuropathy and e-AR levels in patients with disease duration of less than 10 years, and between the incidence of diabetic retinopathy and e-AR levels in patients with disease duration of 10 20 years. Our results suggest that measurement of e-AR levels in patients could help optimize drug therapy with ARIs and be a useful method to predict the onset of complications due to the upregulation of the polyol pathway. PMID- 29503434 TI - [A Questionnaire Survey on Cooperation between Community Pharmacies and Hospitals in Outpatient Chemotherapy-Comparison of Roles of Pharmacists in Community Pharmacy and Hospitals]. AB - Previous reports suggested that sharing outpatient information during chemotherapy is very important for managing pharmaceutical usage between community pharmacies and hospitals. We herein examined using a questionnaire survey whether pharmaceutical management for outpatient chemotherapy is desired by community and hospital pharmacists. The response rates were 44.3% (133/300) for pharmacists in community pharmacies and 53.7% (161/300) for pharmacists in hospitals. Prescriptions for outpatients during chemotherapy were issued at 88.2% of the hospitals. Currently, 28.9% of hospital pharmacists rarely provide pharmaceutical care, such as patient guidance and adverse effect monitoring, for outpatients receiving oral chemotherapy. Furthermore, whereas 93.7% of hospital pharmacists conducted prescription audits based on the chemotherapy regimen, audits were only performed by 14.8% of community pharmacists. Thus, outpatients, particularly those on oral regimens, were unable to receive safe pharmaceutical care during chemotherapy. Community pharmacists suggested that hospital pharmacists should use "medication notebooks" and disclose prescription information when providing clinical information to community pharmacists. They also suggested sending clinical information to hospital pharmacists by fax. On the other hand, hospital pharmacists suggested the use of "medication notebooks" and electronic medical records when providing clinical information to community pharmacists. In addition, they suggested for community pharmacists to use electronic medical records when providing clinical information to hospital pharmacists. As there may be differences in opinion between community and hospital pharmacists, mutual preliminary communication is important for successful outpatient chemotherapy. PMID- 29503435 TI - [Role of Pharmacists in Completion of Adjuvant Cisplatin-Vinorelbine Chemotherapy in Japanese Patients with Non-small Cell Lung Cancer]. AB - Adjuvant cisplatin-vinorelbine chemotherapy has been shown to be effective in patients with completely resected non-small cell lung cancer (NSCLC) in several Phase III trials, but not yet in the Japanese population. Pharmacists are expected to assist patients with completion of adjuvant chemotherapy. The aim of this retrospective study was to evaluate the compliance with and safety of adjuvant cisplatin-vinorelbine chemotherapy in Japanese patients and to evaluate the contribution of pharmacists to completion of treatment. Thirty-four patients with NSCLC who received adjuvant cisplatin-vinorelbine chemotherapy at Kyorin University Hospital between January 2006 and June 2015 were reviewed. The treatment schedule comprised cisplatin 80 mg/m2 on day 1 and vinorelbine 25 mg/m2 on days 1 and 8 every 3 weeks. Four 3-week cycles were planned. A pharmacist provided guidance to all patients and monitored them for adverse effects thereafter. The pharmacist intervened with advice to doctors as necessary. The 4 cycles were administered in 67.6% of cases. There were no treatment-related deaths. The main grade 3 or 4 toxicities were neutropenia (76.5%) and anorexia (38.2%). The most common reason for discontinuation and dose reduction was anorexia. There were 56 instances of pharmacist intervention. In total, 96.4% of the pharmacist interventions were implemented by doctors, which included administration of an antiemetic on 15 occasions and hot fomentation for prevention of vasculitis on 7 occasions. Adjuvant cisplatin-vinorelbine chemotherapy was tolerated by most patients but was discontinued because of adverse events in some. Pharmacist intervention aids completion of planned chemotherapy and management of treatment-related adverse events. PMID- 29503436 TI - Prognostic Risk Factors in Ventilator-Associated Pneumonia. AB - BACKGROUND Ventilator-associated pneumonia (VAP) is a nosocomial infection commonly seen in patients in intensive care units (ICU). This study aimed to analyze factors affecting prognosis of patients diagnosed with VAP. MATERIAL AND METHODS Critically ill patients with VAP were retrospectively evaluated between June 2002 and June 2011 in the ICU. VAP diagnosis was made according to 2005 ATS/IDSA (Infectious Diseases Society of America/American Thoracic Society) criteria. First pneumonia attacks of patients were analyzed. RESULTS When early- and late-onset pneumonia causes were compared according to ICU and hospital admittance, resistant bacteria were found to be more common in pneumonias classified as early-onset according to ICU admittance. APACHE II score of >21 (p=0.016), SOFA score of >6 (p<0.001) on admission to ICU and SOFA score of >6 (p<0.001) on day of diagnosis are risk factors affecting mortality. Additionally, low PaO2/FIO2 ratio at onset of VAP had a negative effect on prognosis (p<0.001). SOFA score of >6 on the day of VAP diagnosis was an independent risk factor for mortality [(p<0.001; OR (95%CI): 1.4 (1.2-1.6)]. CONCLUSIONS Resistant bacteria might be present in early-onset VAP. Especially, taking LOS into consideration may better estimate the presence of resistant bacteria. Acinetobacter baumannii, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus (MRSA) were the most frequent causative microorganisms for VAP. SOFA score might be more valuable than APACHE II score. Frequently surveilling SOFA scores may improve predictive performance over time. PMID- 29503437 TI - Bilateral Pneumothoraces in a Trauma Patient After Dobhoff Tube Insertion. AB - BACKGROUND Dobhoff tube insertion is a common procedure used in the clinical setting to deliver enteral nutrition. Although it is often viewed as an innocuous bedside procedure, there are risks for numerous complications such as tracheobronchial insertion, which could lead to deleterious consequences. We present to our knowledge the first reported case of bilateral pneumothoraces caused by the insertion of a Dobhoff tube. In addition, we also discuss common pitfalls for confirming the positioning of Dobhoff tubes, as well as risk factors that can predispose a patient to improper tube placement. CASE REPORT We present the case of a 74-year-old male patient with multiple orthopedic injuries following an auto-pedestrian collision. Five attempts were made to place a Dobhoff tube to maintain enteral nutrition. Follow-up abdominal x-ray revealed displacement of the Dobhoff tube in the left pleural space. After removal of the tube, a follow-up chest x-ray revealed iatrogenic bilateral pneumothoraces. Acute hypoxemic respiratory failure ensued; therefore, bilateral chest tubes were placed. Over the next three weeks, the patient's respiratory status improved and both chest tubes were removed. The patient was eventually discharged to a skilled nursing facility. CONCLUSIONS Improper placement of Dobhoff tubes can lead to rare complications such as bilateral pneumothoraces. This unique case report of bilateral pneumothoraces after Dobhoff tube placement emphasizes the necessity of using proper diagnostic techniques for verifying proper tube placement, as well as understanding the risk factors that predispose a patient to a malpositioned tube. PMID- 29503440 TI - TBK1 as a regulator of autoimmunity and antitumor immunity. PMID- 29503439 TI - Vaccine-induced autoimmunity: the role of molecular mimicry and immune crossreaction. AB - Since the early 1800s vaccines have saved numerous lives by preventing lethal infections. However, during the past two decades, there has been growing awareness of possible adverse events associated with vaccinations, cultivating heated debates and leading to significant fluctuations in vaccination rates. It is therefore pertinent for the scientific community to seriously address public concern of adverse effects of vaccines to regain public trust in these important medical interventions. Such adverse reactions to vaccines may be viewed as a result of the interaction between susceptibility of the vaccinated subject and various vaccine components. Among the implicated mechanisms for these reactions is molecular mimicry. Molecular mimicry refers to a significant similarity between certain pathogenic elements contained in the vaccine and specific human proteins. This similarity may lead to immune crossreactivity, wherein the reaction of the immune system towards the pathogenic antigens may harm the similar human proteins, essentially causing autoimmune disease. In this review, we address the concept of molecular mimicry and its application in explaining post vaccination autoimmune phenomena. We further review the principal examples of the influenza, hepatitis B, and human papilloma virus vaccines, all suspected to induce autoimmunity via molecular mimicry. Finally, we refer to possible implications on the potential future development of better, safer vaccines. PMID- 29503438 TI - Wnt/beta-catenin signaling stimulates the expression and synaptic clustering of the autism-associated Neuroligin 3 gene. AB - Synaptic abnormalities have been described in individuals with autism spectrum disorders (ASD). The cell-adhesion molecule Neuroligin-3 (Nlgn3) has an essential role in the function and maturation of synapses and NLGN3 ASD-associated mutations disrupt hippocampal and cortical function. Here we show that Wnt/beta catenin signaling increases Nlgn3 mRNA and protein levels in HT22 mouse hippocampal cells and primary cultures of rat hippocampal neurons. We characterized the activity of mouse and rat Nlgn3 promoter constructs containing conserved putative T-cell factor/lymphoid enhancing factor (TCF/LEF)-binding elements (TBE) and found that their activity is significantly augmented in Wnt/beta-catenin cell reporter assays. Chromatin immunoprecipitation (ChIP) assays and site-directed mutagenesis experiments revealed that endogenous beta catenin binds to novel TBE consensus sequences in the Nlgn3 promoter. Moreover, activation of the signaling cascade increased Nlgn3 clustering and co- localization with the scaffold PSD-95 protein in dendritic processes of primary neurons. Our results directly link Wnt/beta-catenin signaling to the transcription of the Nlgn3 gene and support a functional role for the signaling pathway in the dysregulation of excitatory/inhibitory neuronal activity, as is observed in animal models of ASD. PMID- 29503442 TI - Siglec genes confer resistance to systemic lupus erythematosus in humans and mice. AB - A recent meta-analysis revealed the contribution of the SIGLEC6 locus to the risk of developing systemic lupus erythematosus (SLE). However, no specific Siglec (sialic acid-binding immunoglobulin-like lectin) genes (Siglecs) have been implicated in the pathogenesis of SLE. Here, we performed in silico analysis of the function of three major protective alleles in the locus and found that these alleles were expression quantitative trait loci that enhanced expression of the adjacent SIGLEC12 gene. These data suggest that SIGLEC12 may protect against the development of SLE in Asian populations. Consistent with human genetic data, we identified two missense mutations in lupus-prone B6.NZMSle1/Sle2/Sle3 (Sle1-3) mice in Siglece, which is the murine Siglec with the greatest homology to human SIGLEC12. Since the mutations resulted in reduced binding of Siglec E to splenic cells, we evaluated whether Siglece-/- mice had SLE phenotypes. We found that Siglece-/- mice showed increased autoantibody production, glomerular immune complex deposition and severe renal pathology reminiscent of human SLE nephropathy. Our data demonstrate that the Siglec genes confer resistance to SLE in mice and humans.Cellular and Molecular Immunology advance online publication, 5 March 2018; doi:10.1038/cmi.2017.160. PMID- 29503441 TI - Characterization and allergic role of IL-33-induced neutrophil polarization. AB - Neutrophils are involved in the pathogenesis of allergy. However, the contribution of the different functionally polarized neutrophils in allergy needs to be clarified. We sought to define the characteristics of interleukin (IL)-33 induced neutrophils and the involvement of this subset of polarized neutrophils in allergic pathogenesis. Freshly isolated neutrophils were treated with different cytokines and the cytokine expression levels were detected by real-time PCR. The gene expression profile of IL-33-induced neutrophils was determined by microarray assay. Adoptive transfer assay was used to investigate the function of IL-33-induced neutrophils in an ovalbumin (OVA)-induced allergic asthma model. IL 33-treated neutrophils selectively produced IL-4, IL-5, IL-9 and IL-13 (referred as to N(IL-33) cells) and displayed a distinctive gene expression profile in sharp contrast to resting and lipopolysaccharide (LPS)-treated neutrophils. IL-33 induced neutrophils expressed high Levels of IL-1R2 on cell surface, whereas resting and LPS-treated neutrophils did not, indicating IL-1R2 might be used as a biomarker for N(IL-33) cells. Importantly, N(IL-33) neutrophils exist in the lungs of OVA-induced allergic asthma mice. Adoptive transfer of N(IL-33) neutrophils significantly promotes the severity of the lung pathogenesis in this model. IL-33 induces neutrophil polarization through c-Jun N-terminal kinase- and nuclear factor-kappaB-dependent pathways. A previously unappreciated neutrophil polarization driven by IL-33 with unique cell surface markers and cytokine/chemokine-producing gene profile was defined. The newly identified N(IL 33) subpopulation may have significant contribution to IL-33-related pathogenesis. PMID- 29503443 TI - New insights into the roles of RGC-32. PMID- 29503445 TI - Lymphatic endothelial cells regulate B-cell homing to lymph nodes via a NIK dependent mechanism. AB - B cells home to the lymph nodes (LNs) via high endothelial venules (HEVs) under the guidance of chemokines, particularly CXCL13. However, as CXCL13 is not directly made in HEVs, the molecular mechanism mediating B-cell homing to LNs has remained unclear. We show here that nuclear factor (NF)-kappaB-inducing kinase (NIK), a kinase mediating activation of the noncanonical NF-kappaB pathway, functions in lymphatic endothelial cells (LECs) to regulate B-cell homing to LNs. LEC-conditional deletion of NIK in mice did not affect the integrity or global function of lymphatic vessels but caused a severe reduction in the frequency of B cells in LNs. The LEC-specific NIK deficiency did not affect the survival of B cells or the frequency of B cells in the spleen. B-cell adoptive transfer studies revealed that the LEC-specific NIK deletion impairs the ability of LNs to recruit B cells. We further show that NIK mediates expression of the chemokines CXCL13 and CCL19 in LECs. Although CCL19 is also expressed in blood endothelial cells (BECs), CXCL13 is not produced in BECs. These results suggest that NIK regulates naive B-cell homing to LNs via mediating production of the B-cell homing chemokine CXCL13 in LECs.Cellular and Molecular Immunology advance online publication, 5 March 2018; doi:10.1038/cmi.2017.167. PMID- 29503446 TI - Immune regulation by CD8+ Treg cells: novel possibilities for anticancer immunotherapy. PMID- 29503444 TI - Genetic and epigenetic influences on the loss of tolerance in autoimmunity. AB - Immunological tolerance loss is fundamental to the development of autoimmunity; however, the underlying mechanisms remain elusive. Immune tolerance consists of central and peripheral tolerance. Central tolerance, which occurs in the thymus for T cells and bone marrow for B cells, is the primary way that the immune system discriminates self from non-self. Peripheral tolerance, which occurs in tissues and lymph nodes after lymphocyte maturation, controls self-reactive immune cells and prevents over-reactive immune responses to various environment factors. Loss of tolerance results in autoimmune disorders, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), type 1 diabetes (T1D) and primary biliary cirrhosis (PBC). The etiology and pathogenesis of autoimmune diseases are highly complicated. Both genetic predisposition and epigenetic modifications are implicated in the loss of tolerance and autoimmunity. In this review, we will discuss the genetic and epigenetic influences on tolerance breakdown in autoimmunity. Genetic and epigenetic influences on autoimmune diseases, such as SLE, RA, T1D and PBC, will also be briefly discussed. PMID- 29503447 TI - LIN28B enhanced tumorigenesis in an autochthonous KRASG12V-driven lung carcinoma mouse model. AB - LIN28B is a RNA-binding protein regulating predominantly let-7 microRNAs with essential functions in inflammation, wound healing, embryonic stem cells, and cancer. LIN28B expression is associated with tumor initiation, progression, resistance, and poor outcome in several solid cancers, including lung cancer. However, the functional role of LIN28B, especially in non-small cell lung adenocarcinomas, remains elusive. Here, we investigated the effects of LIN28B expression on lung tumorigenesis using LIN28B transgenic overexpression in an autochthonous KRASG12V-driven mouse model. We found that LIN28B overexpression significantly increased the number of CD44+/CD326+ tumor cells, upregulated VEGF A and miR-21 and promoted tumor angiogenesis and epithelial-to-mesenchymal transition (EMT) accompanied by enhanced AKT phosphorylation and nuclear translocation of c-MYC. Moreover, LIN28B accelerated tumor initiation and enhanced proliferation which led to a shortened overall survival. In addition, we analyzed lung adenocarcinomas of the Cancer Genome Atlas (TCGA) and found LIN28B expression in 24% of KRAS-mutated cases, which underscore the relevance of our model. PMID- 29503448 TI - Association of Chlamydia trachomatis ompA genovar with trachoma phenotypes. PMID- 29503450 TI - Prevalence of diabetic retinopathy and visual impairment in patients with diabetes mellitus in Zambia through the implementation of a mobile diabetic retinopathy screening project in the Copperbelt province: a cross-sectional study. AB - AIMS: A paucity of literature exists on prevalence of diabetic retinopathy (DR) in sub-Saharan Africa. We aim to estimate the prevalence of DR and visual impairment in Zambia's Copperbelt province through a cross-sectional study. METHODS: All patients with a diagnosis of diabetes mellitus attending a DR screening programme were eligible to participate. Fundus photographs were graded in accordance with the DR grading system used in the UK National Health service (NHS). Visual impairment data were collected from visual acuity measurements recorded using Snellen chart. RESULTS: A total of 2689 patients were screened and of these, 2153 patients had a least one eye of gradable quality for analysis. Fifty-five per cent (1190/2153) of patients were male. Mean age was 56 (SD 11). Fifty-two per cent (1113/2153) showed evidence of diabetic retinopathy (DR). Thirty-six per cent of patients graded (779/2153) had sight threatening DR. Proliferative DR was found in 7% (14/208) of type 1 diabetics compared to 5% (42/921) type 2 diabetics (p = <0.001). Duration of diabetes, random blood glucose, systolic and diastolic BP, and use of insulin and oral hypoglycaemics were strongly associated with DR in univariate analysis. The associations of increased systolic BP, random blood glucose, duration of diabetes and insulin use with DR were maintained in multivariate analysis. CONCLUSION: We observed a high prevalence of sight threatening DR which is close to the upper range of estimates that currently exist on DR. This study represents further evidence of global health inequality and the scale of the epidemic which sub-Saharan African countries now face. PMID- 29503452 TI - Regeneration: Interstitial-epithelial crosstalk. PMID- 29503451 TI - Angiomyolipoma: A link between stemness and tumorigenesis in the kidney. PMID- 29503453 TI - Antibodies: Septic shock absorbers. PMID- 29503454 TI - Stem cells: Escape from the Jedi. PMID- 29503455 TI - Vaccines: Stem cell hope for cancer treatment. PMID- 29503449 TI - Cellular regeneration strategies for macular degeneration: past, present and future. AB - Despite considerable effort and significant therapeutic advances, age-related macular degeneration (AMD) remains the commonest cause of blindness in the developed world. Progressive late-stage AMD with outer retinal degeneration currently has no proven treatment. There has been significant interest in the possibility that cellular treatments may slow or reverse visual loss in AMD. A number of modes of action have been suggested, including cell replacement and rescue, as well as immune modulation to delay the neurodegenerative process. Their appeal in this enigmatic disease relate to their generic, non-pathway specific effects. The outer retina in particular has been at the forefront of developments in cellular regenerative therapies being surgically accessible, easily observable, as well as having a relatively simple architecture. Both the retinal pigment epithelium (RPE) and photoreceptors have been considered for replacement therapies as both sheets and cell suspensions. Studies using autologous RPE, and to a lesser extent, foetal retina, have shown proof of principle. A wide variety of cell sources have been proposed with pluripotent stem cell-derived cells currently holding the centre stage. Recent early-phase trials using these cells for RPE replacement have met safety endpoints and hinted at possible efficacy. Animal studies have confirmed the promise that photoreceptor replacement, even in a completely degenerated outer retina may restore some vision. Many challenges, however, remain, not least of which include avoiding immune rejection, ensuring long-term cellular survival and maximising effect. This review provides an overview of progress made, ongoing studies and challenges ahead. PMID- 29503456 TI - Comparative genomics: Blood, guts and vampire bats. PMID- 29503458 TI - Resurrection of a poxvirus causes alarm. PMID- 29503459 TI - Bacterial physiology: Bridging the gap for lipopolysaccharides. PMID- 29503461 TI - Immigrants and Italian labor market: statistical or taste-based discrimination? AB - Types of discrimination are usually distinguished by economic theory in statistical and taste-based. Using a correspondence experiment, we analyze which of the two affects Italian labor market the most. In this respect, we studied the difference in discrimination reserved to first- and second-generation immigrants, taking gender differences into account. Even if we want to admit a rational discrimination based on perceived productivity differences (statistical discrimination) against first-generation immigrants (concerning language and education gaps), the same would not be reasonable for second-generation ones. Since they are born and educated in Italy, where they have always lived, the associated discrimination must be taste-based. PMID- 29503457 TI - Bacterial microcompartments. AB - Bacterial microcompartments (BMCs) are self-assembling organelles that consist of an enzymatic core that is encapsulated by a selectively permeable protein shell. The potential to form BMCs is widespread and found across the kingdom Bacteria. BMCs have crucial roles in carbon dioxide fixation in autotrophs and the catabolism of organic substrates in heterotrophs. They contribute to the metabolic versatility of bacteria, providing a competitive advantage in specific environmental niches. Although BMCs were first visualized more than 60 years ago, it is mainly in the past decade that progress has been made in understanding their metabolic diversity and the structural basis of their assembly and function. This progress has not only heightened our understanding of their role in microbial metabolism but is also beginning to enable their use in a variety of applications in synthetic biology. In this Review, we focus on recent insights into the structure, assembly, diversity and function of BMCs. PMID- 29503460 TI - Protected area connectivity: Shortfalls in global targets and country-level priorities. AB - Connectivity of protected areas (PAs) is crucial for meeting their conservation goals. We provide the first global evaluation of countries' progress towards Aichi Target 11 of the Convention on Biological Diversity that is to have at least 17% of the land covered by well-connected PA systems by 2020. We quantify how well the terrestrial PA systems of countries are designed to promote connectivity, using the Protected Connected (ProtConn) indicator. We refine ProtConn to focus on the part of PA connectivity that is in the power of a country to influence, i.e. not penalizing countries for PA isolation due to the sea and to foreign lands. We found that globally only 7.5% of the area of the countries is covered by protected connected lands, which is about half of the global PA coverage of 14.7%, and that only 30% of the countries currently meet the Aichi Target 11 connectivity element. These findings suggest the need for considerable efforts to improve PA connectivity globally. We further identify the main priorities for improving or sustaining PA connectivity in each country: general increase of PA coverage, targeted designation of PAs in strategic locations for connectivity, ensuring permeability of the unprotected landscapes between PAs, coordinated management of neighbouring PAs within the country, and/or transnational coordination with PAs in other countries. Our assessment provides a key contribution to evaluate progress towards global PA connectivity targets and to highlight important strengths and weaknesses of the design of PA systems for connectivity in the world's countries and regions. PMID- 29503462 TI - Early Parenting and the Reduction of Educational Inequality in Childhood and Adolescence. AB - Socio-economic status (SES) differences in parenting are often implicated in widening the SES-achievement gap. Using nationally representative data (N = 12,887), this study tests for variation across SES in the types and intensity of parenting behaviors utilized and then examines SES differences in the relationship between parenting and student achievement growth from kindergarten through eighth grade. Exploratory factor analysis identifies three dimensions of early parenting: Educational Engagement, Stimulating Parent-Child Interaction, and Discursive Discipline. Regression results indicate that all three dimensions are used most heavily by high-SES families. However, only Educational Engagement consistently predicts achievement growth. Surprisingly, it is positively associated with achievement for lower-, but not higher-SES students in first through eighth grades. Further, Educational Engagement is beneficial for low-SES children because it is particularly beneficial for low-achieving students, consistent with a compensatory hypothesis. PMID- 29503463 TI - How Different Forms of Health Matter to Political Participation. AB - Physical and mental health is known to have wide influence over most aspects of social life-be it schooling and employment or marriage and broader social engagement-but has received limited attention in explaining different forms of political participation. We analyze a unique dataset with a rich array of objective measures of cognitive and physical well-being and two objective measures of political participation, voting and contributing money to campaigns and parties. For voting, each aspect of health has a powerful effect on par with traditional predictors of participation such as education. In contrast, health has little to no effect on making campaign contributions. We recommend additional attention to the multifaceted affects of health on different forms of political participation. PMID- 29503464 TI - Buckling Instabilities in Polymer Brush Surfaces via Postpolymerization Modification. AB - We report a simple route to engineer ultrathin polymer brush surfaces with wrinkled morphologies using post-polymerization modification (PPM), where the length scale of the buckled features can be tuned from hundreds of nanometers to one micrometer using PPM reaction time. We show that partial crosslinking of the outer layer of the polymer brush under poor solvent conditions is critical to obtain wrinkled morphologies upon swelling. Characterization of the PPM kinetics and swelling behavior via ellipsometry and the through-thickness composition profile via time-of-flight secondary ion mass spectroscopy (ToF-SIMS) provided keys insight into parameters influencing the buckling behavior. PMID- 29503465 TI - A paper-based competitive lateral flow immunoassay for multi beta-agonist residues by using a single monoclonal antibody labelled with red fluorescent nanoparticles. AB - An ultrasensitive paper based lateral flow assay is described for rapid and simultaneous fluorometric detection of several beta-agonists including clenbuterol and its chemical analogues (mabuterol, brombuterol, cimaterol, cimbuterol, bromchlorbuterol and banbuterol). A nonspecific monoclonal antibody (mAb) against clenbuterol and its analogues was prepared and employed in a competitive immunoassay where mAb conjugated to fluorescent nanoparticles and free beta-agonists compete for the binding sites. This enables rapid screening for the 7 beta-agonists in a single run that takes about 8 min. Detection limits for the seven beta-agonists are <50 pg g-1 of pork. Recoveries ranged from 69.5% to 102.4%, and relative standard deviations were +/-15%. The assay was applied to the analysis of both using spiked and unspiked pork for beta-agonists, and the results compare well to those obtained by HPLC-MS. Graphical abstractSchematic presentation of an ultra sensitive fluorescent nanoparticle based paper based assay for rapid detection of multi beta-agonists in pork tissue. PMID- 29503466 TI - On polarimetric radar signatures of deep convection for model evaluation: columns of specific differential phase observed during MC3E. AB - The representation of deep convection in general circulation models is in part informed by cloud-resolving models (CRMs) that function at higher spatial and temporal resolution; however, recent studies have shown that CRMs often fail at capturing the details of deep convection updrafts. With the goal of providing constraint on CRM simulation of deep convection updrafts, ground-based remote sensing observations are analyzed and statistically correlated for four deep convection events observed during the Midlatitude Continental Convective Clouds Experiment (MC3E). Since positive values of specific differential phase (KDP) observed above the melting level are associated with deep convection updraft cells, so-called "KDP columns" are analyzed using two scanning polarimetric radars in Oklahoma: the National Weather Service Vance WSR-88D (KVNX) and the Department of Energy C-band Scanning Atmospheric Radiation Measurement (ARM) Precipitation Radar (C-SAPR). KVNX and C-SAPR KDP volumes and columns are then statistically correlated with vertical winds retrieved via multi-Doppler wind analysis, lightning flash activity derived from the Oklahoma Lightning Mapping Array, and KVNX differential reflectivity (ZDR). Results indicate strong correlations of KDP volume above the melting level with updraft mass flux, lightning flash activity, and intense rainfall. Analysis of KDP columns reveals signatures of changing updraft properties from one storm event to another as well as during event evolution. Comparison of ZDR to KDP shows commonalities in information content of each, as well as potential problems with ZDR associated with observational artifacts. PMID- 29503467 TI - Design of angle-resolved illumination optics using nonimaging bi-telecentricity for 193 nm scatterfield microscopy. AB - Accurate optics-based dimensional measurements of features sized well-below the diffraction limit require a thorough understanding of the illumination within the optical column and of the three-dimensional scattered fields that contain the information required for quantitative metrology. Scatterfield microscopy can pair simulations with angle-resolved tool characterization to improve agreement between the experiment and calculated libraries, yielding sub-nanometer parametric uncertainties. Optimized angle-resolved illumination requires bi telecentric optics in which a telecentric sample plane defined by a Kohler illumination configuration and a telecentric conjugate back focal plane (CBFP) of the objective lens; scanning an aperture or an aperture source at the CBFP allows control of the illumination beam angle at the sample plane with minimal distortion. A bi-telecentric illumination optics have been designed enabling angle-resolved illumination for both aperture and source scanning modes while yielding low distortion and chief ray parallelism. The optimized design features a maximum chief ray angle at the CBFP of 0.002 degrees and maximum wavefront deviations of less than 0.06 lambda for angle-resolved illumination beams at the sample plane, holding promise for high quality angle-resolved illumination for improved measurements of deep-subwavelength structures using deep-ultraviolet light. PMID- 29503468 TI - Culturable mycobiota from Karst caves in China, with descriptions of 20 new species. AB - Karst caves are distinctly characterised by darkness, low to moderate temperatures, high humidity, and scarcity of organic matter. During the years of 2014-2015, we explored the mycobiota in two unnamed Karst caves in Guizhou province, China, and obtained 563 fungal strains via the dilution plate method. Preliminary ITS analyses of these strains suggested that they belonged to 246 species in 116 genera, while 23.5 % were not identified to species level. Among these species, 85.8 % (211 species) belonged to Ascomycota; 7.3 % (18 species) belonged to Basidiomycota; 6.9 % (17 species) belonged to Mucoromycotina. The majority of these species have been previously known from other environments, mostly from plants or animals as pathogens, endophytes or via a mycorrhizal association. We also found that 59 % of these species were discovered for the first time from Karst caves, including 20 new species that are described in this paper. The phylogenetic tree based on LSU sequences revealed 20 new species were distributed in six different orders. In addition, ITS or multi-locus sequences were employed to infer the phylogenetic relationships of new taxa with closely related allies. We conclude that Karst caves encompass a high fungal diversity, including a number of previously unknown species. Novel species described include: Amphichorda guana, Auxarthronopsis guizhouensis, Biscogniauxia petrensis, Cladorrhinum globisporum, Collariella quadrum, Gymnoascus exasperatus, Humicola limonisporum, Metapochonia variabilis, Microascus anfractus, Microascus globulosus, Microdochium chrysanthemoides, Paracremonium variiforme, Pectinotrichum chinense, Phaeosphaeria fusispora, Ramophialophora globispora, Ramophialophora petraea, Scopulariopsis crassa, Simplicillium calcicola, Volutella aeria, and Wardomycopsis longicatenata. PMID- 29503469 TI - High species diversity in Colletotrichum associated with citrus diseases in Europe. AB - Species of Colletotrichum are considered important plant pathogens, saprobes, and endophytes on a wide range of plant hosts. Several species are well-known on citrus, either as agents of pre- or post-harvest infections, such as anthracnose, postbloom fruit drop, tear stain and stem-end rot on fruit, or as wither-tip of twigs. In this study we explored the occurrence, diversity and pathogenicity of Colletotrichum spp. associated with Citrus and allied genera in European orchards, nurseries and gardens. Surveys were carried out during 2015 and 2016 in Greece, Italy, Malta, Portugal and Spain. A total of 174 Colletotrichum strains were isolated from symptomatic leaves, fruits, petals and twigs. A multi-locus phylogeny was established based on seven genomic loci (ITS, GAPDH, ACT, CAL, CHS 1, HIS3 and TUB2), and the morphological characters of the isolates determined. Preliminary pathogenicity tests were performed on orange fruits with representative isolates. Colletotrichum strains were identified as members of three major species complexes. Colletotrichum gloeosporioides s.str. and two novel species (C. helleniense and C. hystricis) were identified in the C. gloeosporioides species complex. Colletotrichum karstii, C. novae-zelandiae and two novel species (C. catinaense and C. limonicola) in the C. boninense species complex, and C. acutatum s.str. was also isolated as member of C. acutatum species complex. Colletotrichum gloeosporioides and C. karstii were the predominant species of Colletotrichum isolated. This study represents the first report of C. acutatum on citrus in Europe, and the first detection of C. novae zelandiae from outside New Zealand. Pathogenicity tests revealed C. gloeosporioides s.str. to be the most virulent species on fruits. The present study improves our understanding of species associated with several disease symptoms on citrus fruits and plants, and provides useful information for effective disease management. PMID- 29503470 TI - Revision of Lophiotremataceae (Pleosporales, Dothideomycetes): Aquasubmersaceae, Cryptocoryneaceae, and Hermatomycetaceae fam. nov. AB - The family Lophiotremataceae (Pleosporales, Dothideomycetes) is taxonomically revised on the basis of morphological observations and phylogenetic analyses of sequences of nuclear rDNA SSU, ITS, and LSU regions and tef1 and rpb2 genes. A total of 208 sequences were generated from species of Lophiotremataceae and its relatives. According to phylogenetic analyses, Lophiotremataceae encompasses the genus Lophiotrema and five new genera: Atrocalyx, Crassimassarina, Cryptoclypeus, Galeaticarpa, and Pseudocryptoclypeus. These genera are characterised by ascomata with or without a slit-like ostiole and pycnidial conidiomata. Three new families, Aquasubmersaceae, Cryptocoryneaceae, and Hermatomycetaceae, are proposed. Two genera previously recognised as members of Lophiotremataceae, namely, Aquasubmersa having ascomata with a papillate ostiolar neck and pycnidial conidiomata and Hermatomyces possessing sporodochial conidiomata and dimorphic (lenticular and cylindrical) conidia, are included in Aquasubmersaceae and Hermatomycetaceae, respectively. Cryptocoryneum, characterised by the presence of stromatic sporodochia, cheiroid conidia, and conidial arms developed downward from the cap cells, is placed in Cryptocoryneaceae. Two new genera, Antealophiotrema and Pseudolophiotrema, are established, but their familial placements remain unresolved. Antealophiotrema bears ascomata morphologically similar to those of Lophiotrema, but is differentiated from the latter by having ascomata with a well-developed peridium and a monodictys-like asexual morph. Pseudolophiotrema is also similar to Lophiotrema, but can be distinguished by ascomata with a thin peridium. A total of three new families, seven new genera, eight new species, and two new combinations are described and illustrated. PMID- 29503471 TI - Phylogeny of the order Phyllachorales (Ascomycota, Sordariomycetes): among and within order relationships based on five molecular loci. AB - The order Phyllachorales (Pezizomycotina, Ascomycota) is a group of biotrophic, obligate plant parasitic fungi with a tropical distribution and high host specificity. Traditionally two families are recognised within this order: Phyllachoraceae and Phaeochoraceae, based mostly on morphological and host characteristics. Currently, the position of the order within the class Sordariomycetes is inconclusive, as well as the monophyly of the order, and its internal phylogenetic structure. Here we present a phylogeny of the order Phyllachorales based on sequence data of 29 species with a broad host range resulting from a wide geographical sampling. We inferred Maximum Likelihood and Bayesian phylogenies from data of five DNA regions: nrLSU rDNA, nrSSU rDNA, ITS rDNA, and the protein coding genes RPB2, and TEF1. We found that the order Phyllachorales is monophyletic and related to members of the subclass Sordariomycetidae within Sordariomycetes. Within the order, members of the family Phaeochoraceae form a monophyletic group, and the family Phyllachoraceae is split into two lineages. Maximum Likelihood ancestral state reconstructions indicate that the ancestor of Phyllachorales had a monocotyledonous host plant, immersed perithecia, and a black stroma. Alternative states of these characters evolved multiple times independently within the order. Based on our results we redefine the family Phyllachoraceae and propose the new family Telimenaceae with Telimena erythrinae as type species, resulting in three families in the order. Species of Telimena spp. occur in several monocotyledonous and eudicotyledonous host plants except Poaceae, and generally have enlarged black pseudostroma around the perithecia, a character not present in species of Phyllachoraceae. PMID- 29503472 TI - Phylogenetic placement within Lecanoromycetes of lichenicolous fungi associated with Cladonia and some other genera. AB - Though most of the lichenicolous fungi belong to the Ascomycetes, their phylogenetic placement based on molecular data is lacking for numerous species. In this study the phylogenetic placement of 19 species of lichenicolous fungi was determined using four loci (LSU rDNA, SSU rDNA, ITS rDNA and mtSSU). The phylogenetic analyses revealed that the studied lichenicolous fungi are widespread across the phylogeny of Lecanoromycetes. One species is placed in Acarosporales, Sarcogyne sphaerospora; five species in Dactylosporaceae, Dactylospora ahtii, D. deminuta, D. glaucoides, D. parasitica and Dactylospora sp.; four species belong to Lecanorales, Lichenosticta alcicorniaria, Epicladonia simplex, E. stenospora and Scutula epiblastematica. The genus Epicladonia is polyphyletic and the type E. sandstedei belongs to Leotiomycetes. Phaeopyxis punctum and Bachmanniomyces uncialicola form a well supported clade in the Ostropomycetidae. Epigloea soleiformis is related to Arthrorhaphis and Anzina. Four species are placed in Ostropales, Corticifraga peltigerae, Cryptodiscus epicladonia, C. galaninae and C. cladoniicola comb. nov. (= Lettauia cladoniicola). Three new species are described, Dactylospora ahtii, Cryptodiscus epicladonia and C. galaninae. PMID- 29503473 TI - Phylogenetic reassessment of Nigrospora: Ubiquitous endophytes, plant and human pathogens. AB - Species of Nigrospora commonly occur as plant pathogens, endophytes or saprobes, and have been shown to be extremely interesting for the discovery of novel metabolites. The familial placement, as well as phylogenetic relationships among Nigrospora species remain ambiguous. In this study, Nigrospora (= Khusia) is confirmed as a monophyletic genus belonging to Apiosporaceae (Xylariales), based on a phylogeny inferred from LSU sequence data. A multi-locus phylogeny based on ITS, TEF1-alpha and TUB2, in conjunction with morphological characters, host associations, and ecological data was employed for species delimitation in Nigrospora, as well as identification of 165 recently collected isolates from China, and three from Europe. In total 13 novelties are proposed including 12 new species and 1 new combination. Five species are re-described based on an examination of type specimens and/or fresh collections. New species described in this paper include: N. aurantiaca, N. bambusae, N. camelliae-sinensis, N. chinensis, N. guilinensis, N. hainanensis, N. lacticolonia, N. osmanthi, N. pyriformis, N. rubi, N. vesicularis and N. zimmermanii. Furthermore, N. vietnamensis is transferred to Arthrinium. Our results indicate a high level of species diversity within Nigrospora, with a general lack in host specificity. Taxa that cluster basal in Nigrospora have wide host ranges, whereas those that diverged later tend to have narrow host ranges. The currently available data suggest, therefore, that the general evolutionary direction in the genus Nigrospora is from a wide to a narrow host range. PMID- 29503475 TI - Cortinarius section Bicolores and section Saturnini (Basidiomycota, Agaricales), a morphogenetic overview of European and North American species. AB - Cortinarius is the largest genus of ectomycorrhizal fungi worldwide. Recent molecular studies have shown high levels of morphological homoplasy within the genus. Importantly, DNA phylogenies can reveal characteristics that have been either over- or underemphasized in taxonomic studies. Here we sequenced and phylogenetically analysed a large set of pan-European and North American collections taxonomically studied and placed in Cortinarius sect. Bicolores and sect. Saturnini, according to traditional morpho-anatomical criteria. Our goal was to circumscribe the evolutionary boundaries of the two sections, to stabilize both the limits and nomenclature of relevant species, and to identify described taxa which, according to our current understanding, belong to other lineages. Our analysis resolves two clades: /Bicolores, including 12 species, one of which is new to science, and /Saturnini, including 6 species. Fifteen binomials, traditionally treated in these two sections based on morphology, do not belong to the above two phylogenetic clades. Instead, six of these latter are clearly placed in other clades that represent sect. Bovini, sect. Sciophylli, sect. Duracini and sect. Brunneotincti. The presence or absence of blue pigments and the detection of specific odours emerge as clearly misleading taxonomic features, but more surprisingly, spore size and ecology can be misleading as well. A total of 63 type specimens were sequenced, 4 neotypes and 2 epitypes are proposed here, and 1 new combination is made. PMID- 29503474 TI - Nothophytophthora gen. nov., a new sister genus of Phytophthora from natural and semi-natural ecosystems. AB - During various surveys of Phytophthora diversity in Europe, Chile and Vietnam slow growing oomycete isolates were obtained from rhizosphere soil samples and small streams in natural and planted forest stands. Phylogenetic analyses of sequences from the nuclear ITS, LSU, beta-tubulin and HSP90 loci and the mitochondrial cox1 and NADH1 genes revealed they belong to six new species of a new genus, officially described here as Nothophytophthora gen. nov., which clustered as sister group to Phytophthora. Nothophytophthora species share numerous morphological characters with Phytophthora: persistent (all Nothophytophthora spp.) and caducous (N. caduca, N. chlamydospora, N. valdiviana, N. vietnamensis) sporangia with variable shapes, internal differentiation of zoospores and internal, nested and extended (N. caduca, N. chlamydospora) and external (all Nothophytophthora spp.) sporangial proliferation; smooth-walled oogonia with amphigynous (N. amphigynosa) and paragynous (N. amphigynosa, N. intricata, N. vietnamensis) attachment of the antheridia; chlamydospores (N. chlamydospora) and hyphal swellings. Main differing features of the new genus are the presence of a conspicuous, opaque plug inside the sporangiophore close to the base of most mature sporangia in all known Nothophytophthora species and intraspecific co-occurrence of caducity and non-papillate sporangia with internal nested and extended proliferation in several Nothophytophthora species. Comparisons of morphological structures of both genera allow hypotheses about the morphology and ecology of their common ancestor which are discussed. Production of caducous sporangia by N. caduca, N. chlamydospora and N. valdiviana from Valdivian rainforests and N. vietnamensis from a mountain forest in Vietnam suggests a partially aerial lifestyle as adaptation to these humid habitats. Presence of tree dieback in all forests from which Nothophytophthora spp. were recovered and partial sporangial caducity of several Nothophytophthora species indicate a pathogenic rather than a saprophytic lifestyle. Isolation tests from symptomatic plant tissues in these forests and pathogenicity tests are urgently required to clarify the lifestyle of the six Nothophytophthora species. PMID- 29503476 TI - A synopsis of the saddle fungi (Helvella: Ascomycota) in Europe - species delimitation, taxonomy and typification. AB - Helvella is a widespread, speciose genus of large apothecial ascomycetes (Pezizomycete: Pezizales) that are found in terrestrial biomes of the Northern and Southern Hemispheres. This study represents a beginning on assessing species limits and applying correct names for Helvella species based on type material and specimens in the university herbaria (fungaria) of Copenhagen (C), Harvard (FH) and Oslo (O). We use morphology and phylogenetic evidence from four loci - heat shock protein 90 (hsp), translation elongation factor alpha (tef), RNA polymerase II (rpb2) and the nuclear large subunit ribosomal DNA (LSU) - to assess species boundaries in an expanded sample of Helvella specimens from Europe. We combine the morphological and phylogenetic information from 55 Helvella species from Europe with a small sample of Helvella species from other regions of the world. Little intraspecific variation was detected within the species using these molecular markers; hsp and rpb2 markers provided useful barcodes for species delimitation in this genus, while LSU provided more variable resolution among the pertinent species. We discuss typification issues and identify molecular characteristics for 55 European Helvella species, designate neo- and epitypes for 30 species, and describe seven Helvella species new to science, i.e., H. alpicola, H. alpina, H. carnosa, H. danica, H. nannfeldtii, H. pubescens and H. scyphoides. PMID- 29503477 TI - Morphological reassessment and molecular phylogenetic analyses of Amauroderma s.lat. raised new perspectives in the generic classification of the Ganodermataceae family. AB - Ganodermataceae is a remarkable group of polypore fungi, mainly characterized by particular double-walled basidiospores with a coloured endosporium ornamented with columns or crests, and a hyaline smooth exosporium. In order to establish an integrative morphological and molecular phylogenetic approach to clarify relationship of Neotropical Amauroderma s.lat. within the Ganodermataceae family, morphological analyses, including scanning electron microscopy, as well as a molecular phylogenetic approach based on one (ITS) and four loci (ITS-5.8S, LSU, TEF-1alpha and RPB1), were carried out. Ultrastructural analyses raised up a new character for Ganodermataceae systematics, i.e., the presence of perforation in the exosporium with holes that are connected with hollow columns of the endosporium. This character is considered as a synapomorphy in Foraminispora, a new genus proposed here to accommodate Porothelium rugosum (= Amauroderma sprucei). Furtadoa is proposed to accommodate species with monomitic context: F. biseptata, F. brasiliensis and F. corneri. Molecular phylogenetic analyses confirm that both genera grouped as strongly supported distinct lineages out of the Amauroderma s.str. clade. PMID- 29503480 TI - Synthesis of N-alkoxy-substituted 2H-benzimidazoles. AB - Treatment of 2-nitro-N-(2-methyl-1-propen-1-yl)benzenamines with potassium tert butoxide in tert-butanol followed by the addition of an electrophile affords N alkoxy-2H-benzimidazoles. Electrophiles including methyl iodide, allylic bromides, propargylic bromides, benzyl bromide, and acetyl chloride gave good to excellent yields of product while 1-iodo- and 2-iodo-butane afforded very low yields. PMID- 29503481 TI - Absolute Configurations of Griseorhodins A and C. AB - The known antibiotic and cytotoxic compounds griseorhodin A (1) and griseorhodin C (2) were produced in solid culture by Streptomyces puniceus AB10, which was isolated from the leaf-cutter ant Acromyrmex rugosus rugosus. Their absolute configurations were unambiguously established as 6S,6aR,7S,8S and 6R,6aR,7S,8R, respectively, using vibrational circular dichroism (VCD) and density functional theory (DFT) calculations. PMID- 29503482 TI - Developmental Toxicity of Diethylnitrosamine in Zebrafish Embryos/Juveniles Related to Excessive Oxidative Stress. AB - Diethylnitrosamine (DEN) is present in food, water, and daily supplies and is regarded as a toxicant of carcinogenicity. The developmental toxicity of DEN has been rarely reported as yet. In this study, zebrafish were exposed to different concentrations of DEN at 6 h post-fertilization (hpf) to access embryonic toxicity of the compound. The results show that DEN resulted in negative effects of hatching rate, heartbeat, body length, and spontaneous movement. Deformities, including notochord malformation, pericardium edema, embryonic membrane turbidity, tail hypoplasia, yolk sac deformity, and growth retardation, happened during exposure period. Moreover, production of reactive oxygen species (ROS) significantly increased after DEN treatment. Then, alterations of the expression level of oxidative stress-related genes were observed in our results. To our knowledge, this is the first study concerning the effect of DEN on zebrafish. And from the information of our research, we speculated that development toxicity of DEN should be related to the excessive oxidative stress. PMID- 29503483 TI - THE ROLE OF NEIGHBORHOOD COLLECTIVE EFFICACY AND FEAR OF CRIME IN SOCIALIZATION OF COPING WITH VIOLENCE IN LOW-INCOME COMMUNITIES. AB - The influences of public housing, caregiver fear of crime, and collective efficacy on messages caregivers relay to their offspring regarding coping with community and peer violence were examined using a 3-wave prospective design. Caregivers (N = 358; 92% African American/Black) living in moderate to high violence areas of a midsized southern city completed face-to-face interviews. Coping suggestions were coded at Wave 3 from audiotaped responses to a vignette measure depicting five neighborhood-based and five school-based situations involving violence or aggression. Path models indicated that residing in public or Section 8 housing was associated with greater fear of crime and lower collective efficacy. Fear of crime was associated with more suggestions to use active coping strategies for neighborhood-based situations involving violence; collective efficacy was associated with messages to use less aggression for school-based situations. These findings extend our understanding of caregiver socialization of coping processes in poor and underresourced neighborhoods. PMID- 29503484 TI - Re-examining the Non-Linear Moisture-Precipitation Relationship over the Tropical Oceans. AB - Bretherton et al. (2004) used the Special Sensor Microwave Imager (SSM/I) version 5 product to derive an exponential curve that describes the relationship between precipitation and column relative humidity (CRH) over the tropical oceans. The curve, which features a precipitation pickup at a CRH of about 0.75 and a rapid increase of precipitation with CRH after the pickup, has been widely used in the studies of the tropical atmosphere. This study re-examines the moisture precipitation relationship by using the version 7 SSM/I data, in which several biases in the previous version are corrected, and evaluates the relationship in the Coupled Model Intercomparison Project phase 5 (CMIP5) models. In the revised exponential curve derived using the updated satellite data, the precipitation pick-up occurs at a higher CRH (~0.8), and precipitation increases more slowly with CRH than in the previous curve. In most CMIP5 models, the precipitation pickup is too early due to the common model bias of overestimated (underestimated) precipitation in the dry (wet) regime. PMID- 29503479 TI - Optically polarized 3He. AB - This article reviews the physics and technology of producing large quantities of highly spin-polarized 3He nuclei using spin-exchange (SEOP) and metastability exchange (MEOP) optical pumping. Both technical developments and deeper understanding of the physical processes involved have led to substantial improvements in the capabilities of both methods. For SEOP, the use of spectrally narrowed lasers and K-Rb mixtures has substantially increased the achievable polarization and polarizing rate. For MEOP nearly lossless compression allows for rapid production of polarized 3He and operation in high magnetic fields has likewise significantly increased the pressure at which this method can be performed, and revealed new phenomena. Both methods have benefitted from development of storage methods that allow for spin-relaxation times of hundreds of hours, and specialized precision methods for polarimetry. SEOP and MEOP are now widely applied for spin-polarized targets, neutron spin filters, magnetic resonance imaging, and precision measurements. PMID- 29503485 TI - Fractal approaches to characterize the structure of capillary suspensions using rheology and confocal microscopy. AB - The rheological properties of a particle suspension can be substantially altered by adding a small amount of a secondary fluid that is immiscible with the bulk phase. The drastic change in the strength of these capillary suspensions arises due to the capillary forces, induced by the added liquid, leading to a percolating particle network. Using rheological scaling models, fractal dimensions are deduced from the yield stress and from oscillatory strain amplitude sweep data as function of the solid volume fraction. Exponents obtained using aluminum-oxide-based capillary suspensions, with a preferentially wetting secondary fluid, indicate an increase in the particle gel's fractal dimension with increasing particle size. This may be explained by a corresponding relative reduction in the capillary force compared to other forces. Confocal images using a glass model system show the microstructure to consist of compact particle flocs interconnected by a sparse backbone. Thus, using the rheological models two different fractal dimensionalities are distinguished - a lower network backbone dimension (D = 1.86-2.05) and an intrafloc dimension (D = 2.57-2.74). The latter is higher due to the higher local solid volume fraction inside of the flocs compared to the sparse backbone. Both of these dimensions are compared with values obtained by analysis of spatial particle positions from 3D confocal microscopy images, where dimensions between 2.43 and 2.63 are computed, lying between the two dimension ranges obtained from rheology. The fractal dimensions determined via this method corroborate the increase in structural compactness with increasing particle size. PMID- 29503478 TI - Fungal Planet description sheets: 625-715. AB - Novel species of fungi described in this study include those from various countries as follows: Antarctica: Cadophora antarctica from soil. Australia: Alfaria dandenongensis on Cyperaceae, Amphosoma persooniae on Persoonia sp., Anungitea nullicana on Eucalyptus sp., Bagadiella eucalypti on Eucalyptus globulus, Castanediella eucalyptigena on Eucalyptus sp., Cercospora dianellicola on Dianella sp., Cladoriella kinglakensis on Eucalyptus regnans, Cladoriella xanthorrhoeae (incl. Cladoriellaceae fam. nov. and Cladoriellales ord. nov.) on Xanthorrhoea sp., Cochlearomyces eucalypti (incl. Cochlearomyces gen. nov. and Cochlearomycetaceae fam. nov.) on Eucalyptus obliqua, Codinaea lambertiae on Lambertia formosa, Diaporthe obtusifoliae on Acacia obtusifolia, Didymella acaciae on Acacia melanoxylon, Dothidea eucalypti on Eucalyptus dalrympleana, Fitzroyomyces cyperi (incl. Fitzroyomyces gen. nov.) on Cyperaceae, Murramarangomyces corymbiae (incl. Murramarangomyces gen. nov., Murramarangomycetaceae fam. nov. and Murramarangomycetales ord. nov.) on Corymbia maculata, Neoanungitea eucalypti (incl. Neoanungitea gen. nov.) on Eucalyptus obliqua, Neoconiothyrium persooniae (incl. Neoconiothyrium gen. nov.) on Persoonia laurina subsp. laurina, Neocrinula lambertiae (incl. Neocrinulaceae fam. nov.) on Lambertia sp., Ochroconis podocarpi on Podocarpus grayae, Paraphysalospora eucalypti (incl. Paraphysalospora gen. nov.) on Eucalyptus sieberi, Pararamichloridium livistonae (incl. Pararamichloridium gen. nov., Pararamichloridiaceae fam. nov. and Pararamichloridiales ord. nov.) on Livistona sp., Pestalotiopsis dianellae on Dianella sp., Phaeosphaeria gahniae on Gahnia aspera, Phlogicylindrium tereticornis on Eucalyptus tereticornis, Pleopassalora acaciae on Acacia obliquinervia, Pseudodactylaria xanthorrhoeae (incl. Pseudodactylaria gen. nov., Pseudodactylariaceae fam. nov. and Pseudodactylariales ord. nov.) on Xanthorrhoea sp., Pseudosporidesmium lambertiae (incl. Pseudosporidesmiaceae fam. nov.) on Lambertia formosa, Saccharata acaciae on Acacia sp., Saccharata epacridis on Epacris sp., Saccharata hakeigena on Hakea sericea, Seiridium persooniae on Persoonia sp., Semifissispora tooloomensis on Eucalyptus dunnii, Stagonospora lomandrae on Lomandra longifolia, Stagonospora victoriana on Poaceae, Subramaniomyces podocarpi on Podocarpus elatus, Sympoventuria melaleucae on Melaleuca sp., Sympoventuria regnans on Eucalyptus regnans, Trichomerium eucalypti on Eucalyptus tereticornis, Vermiculariopsiella eucalypticola on Eucalyptus dalrympleana, Verrucoconiothyrium acaciae on Acacia falciformis, Xenopassalora petrophiles (incl. Xenopassalora gen. nov.) on Petrophile sp., Zasmidium dasypogonis on Dasypogon sp., Zasmidium gahniicola on Gahnia sieberiana.Brazil: Achaetomium lippiae on Lippia gracilis, Cyathus isometricus on decaying wood, Geastrum caririense on soil, Lycoperdon demoulinii (incl. Lycoperdon subg. Arenicola) on soil, Megatomentella cristata (incl. Megatomentella gen. nov.) on unidentified plant, Mutinus verrucosus on soil, Paraopeba schefflerae (incl. Paraopeba gen. nov.) on Schefflera morototoni, Phyllosticta catimbauensis on Mandevilla catimbauensis, Pseudocercospora angularis on Prunus persica, Pseudophialophora sorghi on Sorghum bicolor, Spumula piptadeniae on Piptadenia paniculata.Bulgaria: Yarrowia parophonii from gut of Parophonus hirsutulus. Croatia: Pyrenopeziza velebitica on Lonicera borbasiana.Cyprus: Peziza halophila on coastal dunes. Czech Republic: Aspergillus contaminans from human fingernail. Ecuador: Cuphophyllus yacurensis on forest soil, Ganoderma podocarpense on fallen tree trunk. England: Pilidium anglicum (incl. Chaetomellales ord. nov.) on Eucalyptus sp. France: Planamyces parisiensis (incl. Planamyces gen. nov.) on wood inside a house. French Guiana: Lactifluus ceraceus on soil. Germany: Talaromyces musae on Musa sp. India: Hyalocladosporiella cannae on Canna indica, Nothophoma raii from soil. Italy: Setophaeosphaeria citri on Citrus reticulata, Yuccamyces citri on Citrus limon.Japan: Glutinomyces brunneus (incl. Glutinomyces gen. nov.) from roots of Quercus sp. Netherlands (all from soil): Collariella hilkhuijsenii, Fusarium petersiae, Gamsia kooimaniorum, Paracremonium binnewijzendii, Phaeoisaria annesophieae, Plectosphaerella niemeijerarum, Striaticonidium deklijnearum, Talaromyces annesophieae, Umbelopsis wiegerinckiae, Vandijckella johannae (incl. Vandijckella gen. nov. and Vandijckellaceae fam. nov.), Verhulstia trisororum (incl. Verhulstia gen. nov.). New Zealand: Lasiosphaeria similisorbina on decorticated wood. Papua New Guinea: Pseudosubramaniomyces gen. nov. (based on Pseudosubramaniomyces fusisaprophyticus comb. nov.). Slovakia: Hemileucoglossum pusillum on soil. South Africa: Tygervalleyomyces podocarpi (incl. Tygervalleyomyces gen. nov.) on Podocarpus falcatus.Spain: Coniella heterospora from herbivorous dung, Hymenochaete macrochloae on Macrochloa tenacissima, Ramaria cistophila on shrubland of Cistus ladanifer.Thailand: Polycephalomyces phaothaiensis on Coleoptera larvae, buried in soil. Uruguay: Penicillium uruguayense from soil. Vietnam: Entoloma nigrovelutinum on forest soil, Volvariella morozovae on wood of unknown tree. Morphological and culture characteristics along with DNA barcodes are provided. PMID- 29503486 TI - Sparse Regression Incorporating Graphical Structure among Predictors. AB - With the abundance of high dimensional data in various disciplines, sparse regularized techniques are very popular these days. In this paper, we make use of the structure information among predictors to improve sparse regression models. Typically, such structure information can be modeled by the connectivity of an undirected graph using all predictors as nodes of the graph. Most existing methods use this undirected graph edge-by-edge to encourage the regression coefficients of corresponding connected predictors to be similar. However, such methods do not directly utilize the neighborhood information of the graph. Furthermore, if there are more edges in the predictor graph, the corresponding regularization term will be more complicate. In this paper, we incorporate the graph information node-by-node, instead of edge-by-edge as used in most existing methods. Our proposed method is very general and it includes adaptive Lasso, group Lasso, and ridge regression as special cases. Both theoretical and numerical studies demonstrate the effectiveness of the proposed method for simultaneous estimation, prediction and model selection. PMID- 29503487 TI - Wide-ranging Absolute Viscosity Measurements of Sub- and Supercritical 1,1,1 trifluoroethane (R143a). AB - The viscosity of 1,1,1-trifluoroethane (R143a) was measured with a piezoelectrically actuated, torsionally vibrating quartz sensor. The measurements extended over a temperature range from 300 K to 440 K with pressures to 68 MPa and covered states from the dilute gas to the compressed liquid. The influence of the drive voltage on the torsional displacement of the vibrator in fluid and in vacuum was systematically investigated. Since R143a is highly polar, the sample conductance and susceptance were also monitored with the sensor to detect possible electroviscous contributions in the measured viscosities. None were identified so that the estimated uncertainty of the measurements remains at 2 % at a 95 % confidence level (coverage factor k = 2). The results agree well within this margin with literature data that were determined with four other viscometric techniques. PMID- 29503488 TI - Studies of Expertise and Experience. AB - I describe the program of analysis of expertise known as 'Studies of Expertise and Experience', or 'SEE' and contrast it with certain philosophical approaches. SEE differs from many approaches to expertise in that it takes the degree of 'esotericity' of the expertise to be one of its characteristics: esotericity is not a defining characteristic of expertise. Thus, native language speaking is taken to be an expertise along with gravitational wave physics. Expertise is taken to be acquired by socialisation within expert communities. Various methods of analysis are described. PMID- 29503489 TI - Relationships between Borda voting and Zermelo ranking. AB - There are many situations wherein a group of individuals (e.g., voters, experts, sports writers) must produce an ordered list of 'best' alternatives selected from a given group of alternatives (e.g., candidates, proposals, sports teams). Two long established mechanisms that have been used for this task are 'Zermelo's Ranking Method' (1929) and 'Borda's Voting Scheme' (1781). The main purpose of this paper is to point out that they are, under certain common circumstances, identical. We then show that Zermelo's Method can be used in situations that Borda's Method is not designed to handle. PMID- 29503491 TI - Candida auris for the clinical microbiology laboratory: Not your grandfather's Candida species. AB - Candida auris is a newly emerging species that was first identified in Asia in 2009 but has rapidly spread across the world. C. auris differs from most other Candida species in that antifungal resistance is the norm rather than the exception, it is a commensal of human skin rather than the human gut, and it can be easily transmitted from person to person in a healthcare setting. This review discusses the emergence of C. auris, global epidemiology, identification, antifungal susceptibility testing, and precautions to be taken when it is identified from a patient specimen. PMID- 29503490 TI - Developmental Pathways from Child Maltreatment to Adolescent Substance Use: The Roles of Posttraumatic Stress Symptoms and Mother-Child Relationships. AB - While many studies have identified a significant relation between child maltreatment and adolescent substance use, the developmental pathways linking this relation remain sparsely explored. The current study examines posttraumatic stress (PTS) symptoms, mother-child relationships, and internalizing and externalizing problems as potential longitudinal pathways through which child maltreatment influences adolescent substance use. Structural equation modeling was conducted on 883 adolescents drawn from the Longitudinal Studies of Child Abuse and Neglect (LONGSCAN). The pathways of PTS symptoms linked physical and sexual abuse to substance use, and the pathways of mother-child relationships linked emotional abuse and neglect to substance use. None of the four types of maltreatment affected substance use via internalizing or externalizing problems. The findings suggest that intervention efforts aimed at addressing posttraumatic stress symptoms and improving mother-child relationship quality may be beneficial in reducing substance use among adolescents with child maltreatment histories. PMID- 29503492 TI - Land ownership and technology adoption revisited: Improved maize varieties in Ethiopia. AB - The lack of land ownership can discourage agricultural technology adoption, yet there is scarce evidence of the impact of land rental contracts on the adoption of improved crop varieties in developing countries. The current study investigates such impact using a nationally representative survey of Ethiopian maize farmers. In contrast to many previous studies, we show in a simple model that cash-renters are as likely to adopt improved maize varieties as owner operators, while sharecroppers are more likely to adopt given that such varieties are profitable. Empirical analysis reveals a significant impact of sharecropping on improved maize variety adoption, and no significant impact from cash-rental, lending support to the above hypotheses. These results imply that improvements in land rental markets can potentially enhance household welfare through crop variety adoption in agrarian economies where land sales markets are incomplete or missing. PMID- 29503493 TI - Reflectance confocal microscopy of oral epithelial tissue using an electrically tunable lens. AB - We present the use of a commercially available electrically tunable lens to achieve axial scanning in a reflectance confocal microscope. Over a 255 MUm axial scan range, the lateral and axial resolutions varied from 1-2 MUm and 4-14 MUm, respectively, dependent on the variable focal length of the tunable lens. Confocal imaging was performed on normal human biopsies from the oral cavity ex vivo. Sub-cellular morphologic features were seen throughout the depth of the epithelium while axially scanning using the focus tunable lens. PMID- 29503494 TI - Radical polymerization of capillary bridges between micron-sized particles in liquid bulk phase as a low temperature route to produce porous solid materials. AB - We present a generic and versatile low temperature route to produce macro-porous bodies with porosity and pore size distribution that are adjustable in a wide range. Capillary suspensions, where the minor fluid is a monomer, are used as pre cursors. The monomer is preferentially located between the particles, creating capillary bridges, resulting in a strong, percolating network. Thermally induced polymerization of these bridges at temperatures below 100 degrees C for less than 5 hours and subsequent removal of the bulk fluid yields macroscopic, self supporting solid bodies with high porosity. This process is demonstrated using methylmethacrylate and hydroxyethylmethacrlyate with glass particles as a model system. The produced PMMA had a molecular weight of about 500.000 g/mol and dispersity about three. Application specific porous bodies, including PMMA particles connected by PMMA bridges, micron-sized capsules containing phase change material with high inner surface, and porous graphite membranes with high electrical conductivity, are also shown. PMID- 29503495 TI - Economic Status and Adult Mortality in India: Is the Relationship Sensitive to Choice of Indicators? AB - Research on economic status and adult mortality is often stymied by the reciprocity of this relationship and lack of clarity on which aspect of economic status matters. While financial resources increase access to healthcare and nutrition and reduce mortality, sickness also reduces labor force participation, thereby reducing income. Without longitudinal data, it is difficult to study the linkage between economic status and mortality. Using data from a national sample of 132,116 Indian adults aged 15 years and above, this paper examines their likelihood of death between wave 1 of the India Human Development Survey (IHDS), conducted in 2004-2005 and wave 2, conducted in 2011-2012. The results show that mortality between the two waves is strongly linked to the economic status of the household at wave 1 regardless of the choice of indicator for economic status. However, negative relationship between economic status and mortality for individuals already suffering from cardiovascular and metabolic conditions varies between three markers of economic status - income, consumption and ownership of consumer durables - varies, reflecting two-way relationship between short and long term markers of economic status and morbidity. PMID- 29503496 TI - Secondary and 2-Year Outcomes of a Sexual Assault Resistance Program for University Women. AB - We report the secondary outcomes and longevity of efficacy from a randomized controlled trial that evaluated a novel sexual assault resistance program designed for first-year women university students. Participants (N = 893) were randomly assigned to receive the Enhanced Assess, Acknowledge, Act (EAAA) program or a selection of brochures (control). Perception of personal risk, self-defense self-efficacy, and rape myth acceptance was assessed at baseline; 1-week postintervention; and 6-, 12-, 18-, and 24-month postrandomization. Risk detection was assessed at 1 week, 6 months, and 12 months. Sexual assault experience and knowledge of effective resistance strategies were assessed at all follow-ups. The EAAA program produced significant increases in women's perception of personal risk, self-defense self-efficacy, and knowledge of effective (forceful verbal and physical) resistance strategies; the program also produced decreases in general rape myth acceptance and woman blaming over the entire 24 month follow-up period. Risk detection was significantly improved for the intervention group at post-test. The program significantly reduced the risk of completed and attempted rape, attempted coercion, and nonconsensual sexual contact over the entire follow-up period, yielding reductions between 30% and 64% at 2 years. The EAAA program produces long-lasting changes in secondary outcomes and in the incidence of sexual assault experienced by women students. Universities can reduce the harm and the negative health consequences that young women experience as a result of campus sexual assault by implementing this program. Online slides for instructors who want to use this article for teaching are available on PWQ's website at http://journals.sagepub.com/page/pwq/suppl/index. PMID- 29503497 TI - Robust Separation of Multiple Sets. AB - Given K finite disjoint sets {Ak }, k = 1, ..., K in Euclidean n-space, a general problem with numerous applications is to find K simple nontrivial functions fk (x) which separate the sets {Ak } in the sense that fk (a) <= fi (a) for all a ? Ak and i ? k, k = 1, ..., K. This can always be done (e.g., with the piecewise linear function obtained by the Voronoi Partition defined for the points in [Formula: see text]). However, typically one seeks linear functions fk (x) if possible, in which case we say the sets {Ak } are piecewise linear separable. If the sets are separable in a linear sense, there are generally many such functions that separate, in which case we seek a 'best' (in some sense) separator that is referred as a robust separator. If the sets are not separable in a linear sense, we seek a function which comes as close as possible to separating, according to some criterion. PMID- 29503498 TI - Set Separation Problems and Global Optimization. AB - Given a pair of finite, disjoint sets A and B in Rn , a fundamental problem with numerous applications is to find a simple function f(x) defined over Rn which separates the sets in the sense that f(a) > 0 for all a ? A and f(b) < 0 for all b ? B. This can always be done (e.g., with the piecewise linear function defined by the Voronoi partition implied by the points in A ? B). However typically one seeks a linear (or possibly a quadratic) function f if possible, in which case we say that A and B are linearly (quadratically) separable. If A and B are separable in a linear or quadratic sense, there are generally many such functions which separate. In this case we seek a 'robust' separator, one that is best in a sense to be defined. When A and B are not separable in a linear or quadratic sense we seek a function which comes as close as possible to separating, according to some well defined criterion. In this paper we examine the optimization problems associated with the set separation problem, characterize them (convex or non convex) and suggest algorithms for their solutions. PMID- 29503499 TI - Robust Set Separation Via Exponentials. AB - Given a pair of finite disjoint sets A and B in Euclidean n-space, a fundamental problem with numerous applications is to efficiently determine a hyperplane H(omega, gamma) which separates these sets when they are separable, or 'nearly' separates them when they are not. We seek a hyperplane that separates them in the sense that a measure of the Euclidean distance between the separating hyperplane and all of the points is as large as possible. This is done by 'weighting' points relative to A ? B according to their distance to H(omega, gamma), with the closer points getting a higher weight, but still taking into account the points distant from H(omega, gamma). The negative exponential is chosen for that purpose. In this paper we examine the optimization problem associated with this set separation problem and characterize it (convex or non-convex). PMID- 29503500 TI - Resistance and tolerance to the brown planthopper, Nilaparvata lugens (Stal), in rice infested at different growth stages across a gradient of nitrogen applications. AB - High resource availability can reduce anti-herbivore resistance (a plant's ability to defend against herbivores and reduce damage) in rice, Oryza sativa L, but may also increase tolerance (a plant's ability to withstand damage by, for example, compensatory growth). Through a series of greenhouse, screenhouse and field experiments, this study examines fitness (survival and development * reproduction) of the brown planthopper, Nilaparvata lugens (Stal), on resistant (IR62) and susceptible (IR22) rice varieties and age-related rice tolerance to planthopper damage under varying resource (nitrogenous fertilizer) availability. Planthoppers reared on IR62 in the greenhouse had lower fitness than planthoppers on IR22. IR62 became increasingly resistant as plants aged. IR22 was generally more tolerant of planthopper damage, and tolerance increased in IR22, but declined in IR62, as the plants aged. Rice plants infested at pre-tillering stages (3-4 leaf stage) in the screenhouse had greater losses to root, shoot and grain yield per unit weight of planthopper than plants infested at tillering stages, particularly in IR22. These trends were mainly due to the impact of planthoppers during pre-tillering stages and the length of exposure to the planthoppers. High nitrogen compromised IR62 resistance, particularly in tillering plants in the greenhouse study; however, high nitrogen did not increase planthopper biomass-density on IR62 in greenhouse or field cages. Tolerance to damage in IR62 at mid-tillering stages declined under increasing levels of nitrogen, but nitrogen increased tolerance during late-tillering stages. Planthopper damage to IR22 in field cages was severe and hopperburn (plant death) occurred in 83% of IR22 plants under high nitrogen (60-150 kg N ha-1). In contrast, despite planthopper infestations, damage to IR62 was low in field-grown plants and productivity (tillers, roots, shoots and grain) increased in IR62 under increasing nitrogen. Our results indicate that, whereas nitrogenous fertilizer increases planthopper fitness on susceptible and resistant varieties, the net effects of high nitrogen on IR62 include decreased planthopper biomass density (apparent in all experiments) and higher tolerance to damage during later growth stages (observed in the greenhouse, and during one of two seasons in field cages). PMID- 29503501 TI - "Cause That's the Only Skills in School You Need": A Qualitative Analysis of Revenge Goals in Poor Urban Youth. AB - Revenge goals are correlated with maladjustment, and retaliation is a factor driving youth violence. However, revenge might be an important social tool adolescents use to achieve (self-)justice in environments where institutionalized interventions from authorities such as teachers or police are limited. This qualitative secondary analysis of 50 revenge scenarios from a larger study (N = 358 youth-caregiver dyads) expands one-dimensional knowledge from closed-answer vignettes to the rich real-world experiences of youth (aged 10-16; 30 boys, 20 girls), from an urban community sample. Ten patterns of qualitative differences in cognition and emotion of revenge scenarios emerged and are discussed within the revised model of social information processing (SIP). Importance of reputation, confidence in non-violent solutions, and the influence of intense emotions were among the themes. Gender differences and implications for prevention are discussed. PMID- 29503502 TI - The company objects keep: Linking referents together during cross-situational word learning. AB - Learning the meanings of words involves not only linking individual words to referents but also building a network of connections among entities in the world, concepts, and words. Previous studies reveal that infants and adults track the statistical co-occurrence of labels and objects across multiple ambiguous training instances to learn words. However, it is less clear whether, given distributional or attentional cues, learners also encode associations amongst the novel objects. We investigated the consequences of two types of cues that highlighted object-object links in a cross-situational word learning task: distributional structure - how frequently the referents of novel words occurred together - and visual context - whether the referents were seen on matching backgrounds. Across three experiments, we found that in addition to learning novel words, adults formed connections between frequently co-occurring objects. These findings indicate that learners exploit statistical regularities to form multiple types of associations during word learning. PMID- 29503503 TI - Effects of Force Field Selection on the Computational Ranking of MOFs for CO2 Separations. AB - Metal-organic frameworks (MOFs) have been considered as highly promising materials for adsorption-based CO2 separations. The number of synthesized MOFs has been increasing very rapidly. High-throughput molecular simulations are very useful to screen large numbers of MOFs in order to identify the most promising adsorbents prior to extensive experimental studies. Results of molecular simulations depend on the force field used to define the interactions between gas molecules and MOFs. Choosing the appropriate force field for MOFs is essential to make reliable predictions about the materials' performance. In this work, we performed two sets of molecular simulations using the two widely used generic force fields, Dreiding and UFF, and obtained adsorption data of CO2/H2, CO2/N2, and CO2/CH4 mixtures in 100 different MOF structures. Using this adsorption data, several adsorbent evaluation metrics including selectivity, working capacity, sorbent selection parameter, and percent regenerability were computed for each MOF. MOFs were then ranked based on these evaluation metrics, and top performing materials were identified. We then examined the sensitivity of the MOF rankings to the force field type. Our results showed that although there are significant quantitative differences between some adsorbent evaluation metrics computed using different force fields, rankings of the top MOF adsorbents for CO2 separations are generally similar: 8, 8, and 9 out of the top 10 most selective MOFs were found to be identical in the ranking for CO2/H2, CO2/N2, and CO2/CH4 separations using Dreiding and UFF. We finally suggested a force field factor depending on the energy parameters of atoms present in the MOFs to quantify the robustness of the simulation results to the force field selection. This easily computable factor will be highly useful to determine whether the results are sensitive to the force field type or not prior to performing computationally demanding molecular simulations. PMID- 29503504 TI - Network Coding in Relay-based Device-to-Device Communications. AB - Device-to-Device (D2D) communications has been realized as an effective means to improve network throughput, reduce transmission latency, and extend cellular coverage in 5G systems. Network coding is a well-established technique known for its capability to reduce the number of retransmissions. In this article, we review state-of-the-art network coding in relay-based D2D communications, in terms of application scenarios and network coding techniques. We then apply two representative network coding techniques to dual-hop D2D communications and present an efficient relay node selecting mechanism as a case study. We also outline potential future research directions, according to the current research challenges. Our intention is to provide researchers and practitioners with a comprehensive overview of the current research status in this area and hope that this article may motivate more researchers to participate in developing network coding techniques for different relay-based D2D communications scenarios. PMID- 29503505 TI - Wireless Infrastructure M2M Network For Distributed Power Grid Monitoring. AB - With the massive integration of distributed renewable energy sources (RESs) into the power system, the demand for timely and reliable network quality monitoring, control, and fault analysis is rapidly growing. Following the successful deployment of Phasor Measurement Units (PMUs) in transmission systems for power monitoring, a new opportunity to utilize PMU measurement data for power quality assessment in distribution grid systems is emerging. The main problem however, is that a distribution grid system does not normally have the support of an infrastructure network. Therefore, the main objective in this paper is to develop a Machine-to-Machine (M2M) communication network that can support wide ranging sensory data, including high rate synchrophasor data for real-time communication. In particular, we evaluate the suitability of the emerging IEEE 802.11ah standard by exploiting its important features, such as classifying the power grid sensory data into different categories according to their traffic characteristics. For performance evaluation we use our hardware in the loop grid communication network testbed to access the performance of the network. PMID- 29503506 TI - Highlighting the Importance of Surface Grafting in Combination with a Layer-by Layer Approach for Fabricating Advanced 3D Poly(l-lactide) Microsphere Scaffolds. AB - A combined surface treatment (i.e., surface grafting and a layer-by-layer (LbL) approach) is presented to create advanced biomaterials, i.e., 3D poly(l-lactide) (PLLA) microsphere scaffolds, at room temperature. The grafted surface plays a crucial role in assembling polyelectrolyte multilayers (PEMs) onto the surface of the microspheres, thus improving the physicochemical properties of the 3D microsphere scaffolds. The grafted surface of the PLLA microspheres demonstrates much better PEM adsorption, improved surface coverage at low pH, and smoother surfaces at high pH compared with those of nongrafted surfaces of PLLA microspheres during the assembly of PEMs. They induce more swelling than nongrafted surfaces after the assembly of the PEMs and exhibit blue emission after functionalization of the microsphere surface with a fluorescent dye molecule. The 3D scaffolds functionalized with and without nanosheets not only exhibit good mechanical performance similar to the compressive modulus of cancellous bone but also exhibit the porosity required for cancellous bone regeneration. The magnetic nanoparticle-functionalized 3D scaffolds result in an electrical conductivity in the high range of semiconducting materials (i.e., 1 250 S cm-1). Thus, these 3D microsphere scaffolds fabricated by surface grafting and the LbL approach are promising candidates for bone tissue engineering. PMID- 29503507 TI - Electrochemistry and Spectroelectrochemistry of Lead Halide Perovskite Films: Materials Science Aspects and Boundary Conditions. AB - The unique optoelectronic properties of lead halide perovskites have triggered a new wave of excitement in materials chemistry during the past five years. Electrochemistry, spectroelectrochemistry, and photoelectrochemistry could be viable tools both for analyzing the optoelectronic features of these materials and for assembling them into hybrid architectures (e.g., solar cells). At the same time, the instability of these materials limits the pool of solvents and electrolytes that can be employed in such experiments. The focus of our study is to establish a stability window for electrochemical tests for all-inorganic CsPbBr3 and hybrid organic-inorganic MAPbI3 perovskites. In addition, we aimed to understand the reduction and oxidation events that occur and to assess the damage done during these processes at extreme electrochemical conditions. In this vein, we demonstrated the chemical, structural, and morphological changes of the films in both reductive and oxidative environments. Taking all these results together as a whole, we propose a set of boundary conditions and protocols for how electrochemical experiments with lead halide perovskites should be carried out and interpreted. The presented results will contribute to the understanding of the electrochemical response of these materials and lead to a standardization of results in the literature so that comparisons can more easily be made. PMID- 29503508 TI - Area-Selective Atomic Layer Deposition of Metal Oxides on Noble Metals through Catalytic Oxygen Activation. AB - Area-selective atomic layer deposition (ALD) is envisioned to play a key role in next-generation semiconductor processing and can also provide new opportunities in the field of catalysis. In this work, we developed an approach for the area selective deposition of metal oxides on noble metals. Using O2 gas as co reactant, area-selective ALD has been achieved by relying on the catalytic dissociation of the oxygen molecules on the noble metal surface, while no deposition takes place on inert surfaces that do not dissociate oxygen (i.e., SiO2, Al2O3, Au). The process is demonstrated for selective deposition of iron oxide and nickel oxide on platinum and iridium substrates. Characterization by in situ spectroscopic ellipsometry, transmission electron microscopy, scanning Auger electron spectroscopy, and X-ray photoelectron spectroscopy confirms a very high degree of selectivity, with a constant ALD growth rate on the catalytic metal substrates and no deposition on inert substrates, even after 300 ALD cycles. We demonstrate the area-selective ALD approach on planar and patterned substrates and use it to prepare Pt/Fe2O3 core/shell nanoparticles. Finally, the approach is proposed to be extendable beyond the materials presented here, specifically to other metal oxide ALD processes for which the precursor requires a strong oxidizing agent for growth. PMID- 29503509 TI - Atomic Structure of Intrinsic and Electron-Irradiation-Induced Defects in MoTe2. AB - Studying the atomic structure of intrinsic defects in two-dimensional transition metal dichalcogenides is difficult since they damage quickly under the intense electron irradiation in transmission electron microscopy (TEM). However, this can also lead to insights into the creation of defects and their atom-scale dynamics. We first show that MoTe2 monolayers without protection indeed quickly degrade during scanning TEM (STEM) imaging, and discuss the observed atomic-level dynamics, including a transformation from the 1H phase into 1T', 3-fold rotationally symmetric defects, and the migration of line defects between two 1H grains with a 60 degrees misorientation. We then analyze the atomic structure of MoTe2 encapsulated between two graphene sheets to mitigate damage, finding the as prepared material to contain an unexpectedly large concentration of defects. These include similar point defects (or quantum dots, QDs) as those created in the nonencapsulated material and two different types of line defects (or quantum wires, QWs) that can be transformed from one to the other under electron irradiation. Our density functional theory simulations indicate that the QDs and QWs embedded in MoTe2 introduce new midgap states into the semiconducting material and may thus be used to control its electronic and optical properties. Finally, the edge of the encapsulated material appears amorphous, possibly due to the pressure caused by the encapsulation. PMID- 29503510 TI - Tilapia fish microbial spoilage monitored by a single optical gas sensor. AB - As consumption of fish and fish-based foods increases, non-destructive monitoring of fish freshness also becomes more prominent. Fish products are very perishable and prone to microbiological growth, not always easily detected by organoleptic evaluation. The analysis of the headspace of fish specimens through gas sensing is an interesting approach to monitor fish freshness. Here we report a gas sensing method for monitoring Tilapia fish spoilage based on the application of a single gas sensitive gel material coupled to an optical electronic nose. The optical signals of the sensor and the extent of bacterial growth were followed over time, and results indicated good correlation between the two determinations, which suggests the potential application of this simple and low cost system for Tilapia fish freshness monitoring. PMID- 29503511 TI - Experimental aspects of buoyancy correction in measuring reliable highpressure excess adsorption isotherms using the gravimetric method. AB - Addressing reproducibility issues in adsorption measurements is critical to accelerating the path to discovery of new industrial adsorbents and to understanding adsorption processes. A National Institute of Standards and Technology Reference Material, RM 8852 (ammonium ZSM-5 zeolite), and two gravimetric instruments with asymmetric two-beam balances were used to measure high-pressure adsorption isotherms. This work demonstrates how common approaches to buoyancy correction, a key factor in obtaining the mass change due to surface excess gas uptake from the apparent mass change, can impact the adsorption isotherm data. Three different approaches to buoyancy correction were investigated and applied to the subcritical CO2 and supercritical N2 adsorption isotherms at 293 K. It was observed that measuring a collective volume for all balance components for the buoyancy correction (helium method) introduces an inherent bias in temperature partition when there is a temperature gradient (i.e. analysis temperature is not equal to instrument air bath temperature). We demonstrate that a blank subtraction is effective in mitigating the biases associated with temperature partitioning, instrument calibration, and the determined volumes of the balance components. In general, the manual and subtraction methods allow for better treatment of the temperature gradient during buoyancy correction. From the study, best practices specific to asymmetric two beam balances and more general recommendations for measuring isotherms far from critical temperatures using gravimetric instruments are offered. PMID- 29503512 TI - Influence of Substrate Moisture State and Roughness on Interface Microstructure and Bond Strength: Slant Shear vs. Pull-Off Testing. AB - There are conflicting views in the literature concerning the optimum moisture state for an existing substrate prior to the application of a repair material. Both saturated-surface-dry (SSD) and dry substrates have been found to be preferable in a variety of studies. One confounding factor is that some studies evaluate bonding of the repair material to the substrate via pull-off (direct tension) testing, while others have employed some form of shear specimens as their preferred testing configuration. Available evidence suggests that dry substrate specimens usually perform equivalently or better in shear testing, while SSD ones generally exhibit higher bond strengths when a pull-off test is performed, although exceptions to these trends have been observed. This paper applies a variety of microstructural characterization tools to investigate the interfacial microstructure that develops when a fresh repair material is applied to either a dry or SSD substrate. Simultaneous neutron and X-ray radiography are employed to observe the dynamic microstructural rearrangements that occur at this interface during the first 4 h of curing. Based on the differences in water movement and densification (particle compaction) that occur for the dry and SSD specimens, respectively, a hypothesis is formulated as to why different bond tests may favor one moisture state over the other, also dependent on their surface roughness. It is suggested that the compaction of particles at a dry substrate surface may increase the frictional resistance when tested under slant shear loading, but contribute relatively little to the bonding when the interface is submitted to pull-off forces. For maximizing bond performance, the fluidity of the repair material and the roughness and moisture state of the substrate must all be given adequate consideration. PMID- 29503513 TI - Assessment of agroforestry residue potentials for the bioeconomy in the European Union. AB - The biobased chemical industry is characterised by strong growth. Innovative products and materials such as biopolymers have been developed, and current European demand for biopolymers exceeds the domestic supply. Agroforestry residues can serve as main sources of the basic building blocks for chemicals and materials. This work assesses sustainably available agroforestry residues to feed a high added-value materials and product bioeconomy. To evaluate bioeconomic potential, a structured three-step approach is applied. Cultivation practices, sustainability issues, legislative restrictions, technical limitations and competitive applications are considered. All data regarding bioeconomic potential are processed on a regional level and mapped by ArcGIS. Our results identify wheat straw as the most promising source in the agricultural sector, followed by maize stover, barley straw and rape straw, which all contain a total concentration of lignocellulose of more than 80% of dry matter. In the forestry sector, residue bark from two coniferous species, spruce and pine, is the most promising source, with approximately 70% lignocellulose. Additionally, coniferous bark contains considerable amounts of tannin, which has attracted increasing interest for industrial utilisation. A sensitivity analysis concerning removal rates, residue-to-crop ratios, changes in farming technologies and competing applications is applied at the end of the study to consolidate our results. PMID- 29503514 TI - New insights for mesospheric OH: multi-quantum vibrational relaxation as a driver for non-local thermodynamic equilibrium. AB - The question of whether mesospheric OH(upsilon) rotational population distributions are in equilibrium with the local kinetic temperature has been debated over several decades. Despite several indications for the existence of non-equilibrium effects, the general consensus has been that emissions originating from low rotational levels are thermalized. Sky spectra simultaneously observing several vibrational levels demonstrated reproducible trends in the extracted OH(upsilon) rotational temperatures as a function of vibrational excitation. Laboratory experiments provided information on rotational energy transfer and direct evidence for fast multi-quantum OH(high-upsilon) vibrational relaxation by O atoms. We examine the relationship of the new relaxation pathways with the behavior exhibited by OH(upsilon) rotational population distributions. Rapid OH(high-upsilon) + O multi-quantum vibrational relaxation connects high and low vibrational levels and enhances the hot tail of the OH(low-upsilon) rotational distributions. The effective rotational temperatures of mesospheric OH(upsilon) are found to deviate from local thermodynamic equilibrium for all observed vibrational levels. PMID- 29503515 TI - Riccati-Regularized Precision Matrices for Neuroimaging. AB - The introduction of graph theory in neuroimaging has provided invaluable tools for the study of brain connectivity. These methods require the definition of a graph, which is typically derived by estimating the effective connectivity between brain regions through the optimization of an ill-posed inverse problem. Considerable efforts have been devoted to the development of methods extracting sparse connectivity graphs. The present paper aims at highlighting the benefits of an alternative approach. We investigate low-rank L2 regularized matrices recently introduced under the denomination of Riccati regularized precision matrices. We demonstrate their benefits for the analysis of cortical thickness map and the extraction of functional biomarkers from resting state fMRI scans. In addition, we explain how speed and result quality can be further improved with random projections. The promising results obtained using the Human Connectome Project dataset, as well as, the numerous possible extensions and applications suggest that Riccati precision matrices might usefully complement current sparse approaches. PMID- 29503517 TI - Geovisualizing attribute uncertainty of interval and ratio variables: a framework and an implementation for vector data. AB - Geovisualization of attribute uncertainty helps users to recognize underlying processes of spatial data. However, it still lacks an availability of uncertainty visualization tools in a standard GIS environment. This paper proposes a framework for attribute uncertainty visualization by extending bivariate mapping techniques. Specifically, this framework utilizes two cartographic techniques, choropleth mapping and proportional symbol mapping based on the types of attributes. This framework is implemented as an extension of ArcGIS in which three types of visualization tools are available: overlaid symbols on a choropleth map, coloring properties to a proportional symbol map, and composite symbols. PMID- 29503516 TI - Approximation degree of Durrmeyer-Bezier type operators. AB - Recently, a mixed hybrid operator, generalizing the well-known Phillips operators and Baskakov-Szasz type operators, was introduced. In this paper, we study Bezier variant of these new operators. We investigate the degree of approximation of these operators by means of the Lipschitz class function, the modulus of continuity, and a weighted space. We study a direct approximation theorem by means of the unified Ditzian-Totik modulus of smoothness. Furthermore, the rate of convergence for functions having derivatives of bounded variation is discussed. PMID- 29503518 TI - Enhancing Social Inclusion of Children With Externalizing Problems Through Classroom Seating Arrangements: A Randomized Controlled Trial. AB - Inclusive education has brought new challenges for teachers, including the search for a suitable place in the classroom for children with externalizing problems. In the current study, we examined whether a careful rearrangement of the classroom seats could promote social acceptance and more prosocial behaviors for children with externalizing problems, and limit the potential negative consequences for classmates sitting next to them. The sample of this randomized controlled trial consisted of 64 classrooms with 221 fourth- to sixth-grade children selected by their teachers because of elevated levels of externalizing behavior. Results showed that over time children with externalizing behavior were better liked by their seatmates and showed fewer externalizing problems according to the teacher. This was particularly the case when students sat next to a well liked and prosocial buddy, or when they were initially disliked. Classmates who sat next to a child with externalizing problems did not become more aggressive or less prosocial over time. Yet their social status did decrease slightly over time as a result of the rearrangement. We discuss implications and future directions for research on classroom seating arrangements to support children with externalizing problems. PMID- 29503519 TI - A case study exploring field-level risk assessments as a leading safety indicator. AB - Health and safety indicators help mine sites predict the likelihood of an event, advance initiatives to control risks, and track progress. Although useful to encourage individuals within the mining companies to work together to identify such indicators, executing risk assessments comes with challenges. Specifically, varying or inaccurate perceptions of risk, in addition to trust and buy-in of a risk management system, contribute to inconsistent levels of participation in risk programs. This paper focuses on one trona mine's experience in the development and implementation of a field-level risk assessment program to help its organization understand and manage risk to an acceptable level. Through a transformational process of ongoing leadership development, support and communication, Solvay Green River fostered a culture grounded in risk assessment, safety interactions and hazard correction. The application of consistent risk assessment tools was critical to create a participatory workforce that not only talks about safety but actively identifies factors that contribute to hazards and potential incidents. In this paper, reflecting on the mine's previous process of risk-assessment implementation provides examples of likely barriers that sites may encounter when trying to document and manage risks, as well as a variety of mini case examples that showcase how the organization worked through these barriers to facilitate the identification of leading indicators to ultimately reduce incidents. PMID- 29503520 TI - Hysteresis Bearingless Slice Motors with Homopolar Flux-biasing. AB - We present a new concept of bearingless slice motor that levitates and rotates a ring-shaped solid rotor. The rotor is made of a semi-hard magnetic material exhibiting magnetic hysteresis, such as D2 steel. The rotor is radially biased with a homopolar permanent-magnetic flux, on which the stator can superimpose 2 pole flux to generate suspension forces. By regulating the suspension forces based on position feedback, the two radial rotor degrees of freedom are actively stabilized. The two tilting degrees of freedom and the axial translation are passively stable due to the reluctance forces from the bias flux. In addition, the stator can generate a torque by superimposing 6- pole rotating flux, which drags the rotor via hysteresis coupling. This 6-pole flux does not generate radial forces in conjunction with the homopolar flux or 2-pole flux, and therefore the suspension force generation is in principle decoupled from the driving torque generation. We have developed a prototype system as a proof of concept. The stator has twelve teeth, each of which has a single phase winding that is individually driven by a linear transconductance power amplifier. The system has four reflective-type optical sensors to differentially measure the two radial degrees of freedom of the rotor. The suspension control loop is implemented such that the phase margin is 25 degrees at the cross-over frequency of 110 Hz. The prototype system can levitate the rotor and drive it up to about 1730 rpm. The maximum driving torque is about 2.7 mNm. PMID- 29503521 TI - Microflow High-p,T Intensification of Vitamin D3 Synthesis Using an Ultraviolet Lamp. AB - Herewith a new process concept for synthesis is presented which combines both UV photoirradiation and high-p,T intensification (photo-high-p,T) in continuous flow. The application of this procedure to Vitamin D3 synthesis promotes thermal shifting of the equilibrium from the reaction intermediate to the product. This is enabled by microreactors which allow operation under harsh conditions such as the high temperature used here. This provides, to our best knowledge, a new kind of process combination (novel process window). As a result, in less than 1 min, 42% conversion of 7-dehydrocholesterol can be achieved giving a 17% yield and 40% selectivity of Vitamin D3. This approach enhances productivity by up to 2 orders of magnitude compared with the current capillary based vitamin D3 synthesis, because, under the microflow conditions, photochemistry can be performed at fairly high concentration and up to 20 times faster. PMID- 29503522 TI - Posttraumatic Growth and Sexual Violence: A Literature Review. AB - Posttraumatic growth (PTG) is the positive psychological growth that a person might experience after enduring a traumatic event. PTG is a relatively new area of research identified by researchers because it represents a shift in thinking. Rather than focusing on the negative consequences of trauma, it explores the potential for positive outcomes associated with trauma. Although PTG is well documented across different types of traumas, it is unclear how this kind of growth stems from sexual violence, specifically. This review provides an overview of the literature concerning PTG that is associated with sexual violence. Results across the literature indicate that sexual violence is consistently associated with PTG. However, given the inconsistency in research designs, assessment, and operational definitions used to study PTG, many researchers suggest that it might be difficult to determine how and when PTG occurs. This study provides a literature review of the research on PTG in the aftermath of sexual violence. Important implications for future directions and trauma-based therapy are discussed and include the identification of relevant predictors, the importance of context, and how service providers might benefit from a better understanding of PTG. PMID- 29503523 TI - Familial Influences on Dating Violence Victimization Among Latino Youth. AB - Despite theoretical and empirical evidence suggesting that the family environment plays a central role in Latino youth development, relatively little is known about how family processes influence dating violence victimization among Latino adolescents. To address this gap in the literature, we used data from 210 Latino parents and their 13- to 15-year-old adolescents to examine associations between several different family processes, including both parenting practices (parent monitoring, parent-adolescent communication) and aspects of the family relational climate (family cohesion, family conflict, acculturation conflict) and psychological, physical, and sexual dating violence victimization. Consistent with expectations, lower levels of family cohesion and higher levels of family and acculturation conflict were associated with risk for dating violence victimization, although associations varied depending on victimization type. In contrast, neither parental monitoring nor parent-adolescent communication was significantly associated with any type of dating violence victimization. In addition, we found that parent, but not teen, Anglo-American acculturation was associated with higher dating violence victimization risk. Findings suggest that family-based dating abuse prevention programs for Latino youth should seek to increase family cohesion and decrease family conflict, including acculturation based conflict. PMID- 29503524 TI - Visual acuity loss associated with excessive "dry macula" in exudative age related macular degeneration. AB - Purpose: To investigate the correlation between visual acuity and central macular thickness (CMT) and choroidal thickness (CCT) in patients with wet age-related macular degeneration (AMD). Methods: In this retrospective analysis, 14 eyes that received >10 ranibizumab injections (based on pro re nata [PRN] regimen) and maintained initial visual acuity gain were analyzed. The following 5 parameters were measured at the foveal center: CMT (distance from the inner limiting membrane [ILM] to Bruch's membrane); central retinal thickness (CRT; distance from the ILM to the inner limit of the retinal pigment epithelium or subretinal fluid [SRF]); SRF thickness (SRFT); pigment epithelium detachment thickness (PEDT); and CCT. The correlation between the logarithm of the minimum angle of resolution (logMAR) best-corrected visual acuity (BCVA) and the 5 parameters was examined with generalized estimating equations. Results: CMT, CRT, and CCT were negatively correlated with logMAR BCVA (P=0.031, 0.023, and 0.036, respectively) when only CMT values less than the thickness that maximized visual acuity for each eye were used for the analysis. Each 100-MUm reduction in CMT, CRT, or CCT improved logMAR BCVA by -0.1, -0.08, or -0.07, respectively. SRFT and PEDT were not correlated with BCVA. The median CMT that maximized the visual acuity was 230 MUm. Conclusion: Dry macula with CMT <230 MUm was associated with temporary decrease in visual acuity in AMD patients whose visual acuity was maintained with PRN regimen. PMID- 29503525 TI - Identifying risk factors for blindness from primary open-angle glaucoma by race: a case-control study. AB - Purpose: To examine the factors associated with blindness from primary open-angle glaucoma (POAG) among black and white patients at our institution. Patients and methods: For this retrospective, case-control study, patients legally blind from POAG ("cases") were matched on age, race, and gender with non-blind POAG patients ("controls"). Thirty-seven black case-control pairs and 19 white case-control pairs were included in this study. Clinical variables were compared at initial presentation and over the course of follow-up. Results: Black case-control pairs and white case-control pairs had similar characteristics at presentation, including cup-to-disc ratio and number of glaucoma medications. However, over the course of follow-up, black cases underwent significantly more glaucoma surgeries than matched controls (2.4 versus 1.2, p=0.001), whereas white cases and controls had no significant difference in glaucoma operations (0.9 versus 0.6, p=0.139). Our analysis found that glaucoma surgery is associated with blindness in black patients (odds ratio [OR] 1.6, 95% CI 1.1-2.2) but not in white patients (OR 1.5, 95% CI 0.7-3.2). Conclusion: Black and white case-control pairs with POAG shared similar risk factors for blindness at presentation. However, over the follow-up period, black cases required significantly more glaucoma surgeries compared to black controls, whereas there was no significant difference in surgery between white cases and controls. There was no difference in medication changes in either case-control set. PMID- 29503526 TI - Comparison of two laboratory-based systems for evaluation of halos in intraocular lenses. AB - Purpose: Multifocal intraocular lenses (IOLs) can be associated with unwanted visual phenomena, including halos. Predicting potential for halos is desirable when designing new multifocal IOLs. Halo images from 6 IOL models were compared using the Optikos modulation transfer function bench system and a new high dynamic range (HDR) system. Materials and methods: One monofocal, 1 extended depth of focus, and 4 multifocal IOLs were evaluated. An off-the-shelf optical bench was used to simulate a distant (>50 m) car headlight and record images. A custom HDR system was constructed using an imaging photometer to simulate headlight images and to measure quantitative halo luminance data. A metric was developed to characterize halo luminance properties. Clinical relevance was investigated by correlating halo measurements to visual outcomes questionnaire data. Results: The Optikos system produced halo images useful for visual comparisons; however, measurements were relative and not quantitative. The HDR halo system provided objective and quantitative measurements used to create a metric from the area under the curve (AUC) of the logarithmic normalized halo profile. This proposed metric differentiated between IOL models, and linear regression analysis found strong correlations between AUC and subjective clinical ratings of halos. Conclusion: The HDR system produced quantitative, preclinical metrics that correlated to patients' subjective perception of halos. PMID- 29503527 TI - Relationship between preoperative axial length and myopic shift over 3 years after congenital cataract surgery with primary intraocular lens implantation at the National Institute of Ophthalmology of Peru, 2007-2011. AB - Objective: To determine the relationship between the preoperative axial length and the myopic shift over 3 years after congenital cataract surgery with primary intraocular lens implantation and other related factors. Methods: In this retrospective cohort study, the axial length was measured and assigned into 2 groups (>21.5 mm and <=21.5 mm), visual axis obscuration, laterality of cataract, age of surgery and follow-up time were assessed and compared to the myopic shift. Results: The mean myopic shift was 3.6 (standard deviation [SD]: 2.3) diopters (D) in all patients; 3.2 (3.3) and 3.9 (3.2) D for each group respectively (p=0.359). In unilateral cataracts the mean myopic shift was 6.3 D and in bilateral cases was 3.0 D (p=0.001). In bilateral cataracts, the shift was 2.6 D (SD: 2.0) and 3.4 D (SD: 1.8), respectively (p=0.098). Conclusion: There was no relationship between the initial axial length and the myopic shift in all patients. Unilateral cataracts had a greater myopic shift over 3 years. PMID- 29503528 TI - Formulation design and development of matrix diffusion controlled transdermal drug delivery of glimepiride. AB - Background: The present work was conducted to prepare and evaluate transdermal patches with optimization of suitable polymeric blend of poly(meth) acrylates (Eudragit(r)) (Ammonio Methacrylate Copolymer Ph Eur) for sustained transdermal delivery of glimepiride. Method: Polymeric matrix transdermal films were prepared by using Ammonio Methacrylate Copolymer Ph Eur RL 100 and Ammonio Methacrylate Copolymer Ph Eur RS 100 as the film former, and dibutyl phthalate (30% w/w) as the plasticizer. Patches were characterized by physical appearance, thickness, weight variation, folding endurance, percentage erosion, swelling index, moisture content, and moisture uptake capacity. Fourier transform infrared spectroscopic studies and differential scanning calorimetry analysis of physical mixtures of contents were performed to identify any chemical and physical interaction between drug and excipients. Five different enhancers (isopropyl myristate [IPM], Span(r) 80, Tween(r) 20, eucalyptus oil, and limonene) were employed at three different concentrations of polymer (2%, 5%, and 10% w/w) in order to enhance permeation through rabbit skin. In vitro drug release studies were performed at pH 7.4, and scanning electron microscopy was conducted to elucidate surface morphology before and after the drug release. In vitro permeation studies through rabbit skin were performed on Franz diffusion cells and permeation kinetics followed the Higuchi model. Results: Results of in vitro permeation studies revealed that these enhancers not only increased drug release but also augmented the skin permeation of glimepiride. Conclusion: IPM was the most effective enhancer with the highest permeation flux of 51.763 MUg/cm2/hr, and the enhancement effect of different enhancers on glimepiride permeation through rabbit skin was in the rank order of IPM > eucalyptus oil > Span(r) 80 > Tween(r) 20> limonene. PMID- 29503529 TI - Therapeutic potential of bimatoprost for the treatment of eyebrow hypotrichosis. AB - Eyebrows serve as a key feature of the face and have many roles, including cosmetic appearance and social communication. Eyebrow hypotrichosis, which refers to reduction or absence of the eyebrow hair, could be a major problem that leads to negative functional, psychological, and social consequences. Bimatoprost is an ophthalmic prostamide analog that is approved by the United States Food and Drug Administration for the treatment of eyelash hypotrichosis. Its proposed mechanism is stimulation of the prostaglandin receptor in dermal papilla and melanocyte, thus leading to a prolonged anagen phase and increased melanogenesis. The hair follicle then increases in thickness, length, and darkness. The efficacy of bimatoprost for the treatment of eyebrow hypotrichosis has been supported by well controlled studies. Bimatoprost, which is noninvasive, effective, and well tolerated, is worth considering as a treatment option for eyebrow hypotrichosis. PMID- 29503530 TI - Fasudil inhibits proliferation and migration of Hep-2 laryngeal carcinoma cells. AB - Background: Rho-kinase signal pathway is a new target for cancer therapy. Fasudil, a selective Rho-kinase inhibitor, is found to exert antitumor effects on several types of cancer, but whether fasudil has antitumor effects on laryngeal carcinoma is still unknown. The aim of this study was to determine the effects of fasudil on laryngeal carcinoma and explore the underlying molecular mechanisms in this process. Methods: After treatment with fasudil, changes in biological behaviors, including the growth, proliferation, clone formation, apoptosis, and migration of human laryngeal carcinoma cells (Hep-2 cells) were observed. The influences on apoptotic protease activity factor-1 (APAF-1)-mediated apoptosis pathway and the activities of matrix metalloproteinases (MMP-2 and MMP-9) were measured by Western blotting and gelatin zymography assay. Results: Half-maximal inhibitory concentration of fasudil to Hep-2 cells was ~3.40*103 uM (95% CI: 2.53 4.66*103 uM). Moreover, fasudil treatment significantly decreased the ability of growth, proliferation, clone formation, and migration of Hep-2 cells, while remarkably increased the apoptosis rate. Furthermore, the expressions of APAF-1, caspase-9, and caspase-3 significantly increased in fasudil treatment group. Meanwhile, fasudil led to a remarkable decrease in the expressions and activities of MMP-2 and MMP-9. Conclusion: Our findings first demonstrate that fasudil not only inhibits the proliferation of laryngeal carcinoma cells through activating APAF-1-mediated apoptosis pathway, but also prevents migration by inhibiting the activities of MMP-2 and MMP-9. Therefore, fasudil is an attractive antitumor drug candidate for the treatment of laryngeal carcinoma. PMID- 29503531 TI - A novel ocular delivery of brinzolamide based on gellan gum: in vitro and in vivo evaluation. AB - Background: The aim of the study was to develop a sustained ocular delivery of brinzolamide (BLZ) based on gellan gum. Methods: The formulations were characterized for clarity, gelling capacity, rheological studies, pH, drug content, and in vitro drug-release behavior. In vivo rabbit eye irritation test was conducted to evaluate irritation of the BLZ gel drug-delivery system. The prepared BLZ formulations were then investigated in vivo and compared with commercially available BLZ eyedrops with regard to pharmacodynamics. Results: The results showed that the optimum concentration of gellan gum was 0.25% w/v; the prepared liquid was converted into a flowing gel after the addition of simulated tear fluid. In vitro release profiles showed that the release of BLZ from the in situ gel exhibited sustained characteristics. Draize test results showed that BLZ in situ gels did not stimulate signs of eye tissue activity and were less irritating than BLZ solutions and commercial Azopt. Conclusion: The results of pharmacodynamics implied that the novel preparation of BLZ in situ gel effectively prolonged the intraocular pressure-lowering effect after administration. PMID- 29503532 TI - Skepticism and pharmacophobia toward medication may negatively impact adherence to psychiatric medications: a comparison among outpatient samples recruited in Spain, Argentina, and Venezuela. AB - Background: Cultural differences in attitudes toward psychiatric medications influence medication adherence but transcultural studies are missing. The objective of this study was to investigate how attitudes and beliefs toward psychotropic medications influence treatment adherence in psychiatric outpatients in Spain, Argentina, and Venezuela. Methods: A cross-sectional, cross-cultural psychopharmacology study was designed to assess psychiatric outpatients' attitudes toward their prescribed medication. Patients completed the Drug Attitude Inventory - 10 Item (DAI-10), the Beliefs about Medicines Questionnaire Specific Scale (BMQ-Specific), the Sidorkiewicz adherence tool, and sociodemographic and clinical questionnaires. The study included 1,291 adult psychiatric outpatients using 2,308 psychotropic drugs from three Spanish speaking countries, the Canary Islands (Spain) (N=588 patients), Argentina (N=508), and Venezuela (N=195). Results: The univariate analyses showed different mean scores on the DAI-10 and the BMQ - Necessity and Concerns subscales but, on the other hand, the percentages of non-adherent and skeptical patients were relatively similar in three countries. Argentinian patients had a very low level of pharmacophobia. Multivariate analyses (logistic regression and chi-squared automatic interaction detector segmentation) showed that pharmacophobia in general and skepticism about specific medications (high concern about adverse reactions and low belief in their necessity) were associated with non-adherence. Pharmacophobia was the major factor associated with non-adherence (Spain and Venezuela) but when pharmacophobia was rare (Argentina), skepticism was the most important variable associated with non-adherence. Conclusion: Psychiatric patients' attitudes and beliefs about their psychiatric treatment varied in these three Spanish-speaking countries, but pharmacophobia and skepticism appeared to play a consistent role in lack of adherence. PMID- 29503534 TI - Vascular aging processes accelerate following a cubic kinetic: pulse wave velocity as an objective counterpart that time, as we age, goes by faster. PMID- 29503533 TI - Urologic symptoms and burden of frailty and geriatric conditions in older men: the Aging Study of PyeongChang Rural Area. AB - Purpose: Frailty is an important consideration in the management of lower urinary tract symptoms and erectile dysfunction in older men; frailty increases vulnerability to treatment-related adverse outcomes, but its burden is not known. The authors aimed to examine the burden of frailty and associated geriatric conditions in community-dwelling older men. Patients and methods: A cross sectional study was conducted with 492 community-dwelling older men (mean age, 74.2 years; standard deviation, 5.6 years). All the participants were administered the International Prostate Symptom Score (IPSS) (range: 0-35) and a five-item version of the International Index of Erectile Function (IIEF-5) (range: 5-25). Frailty phenotype was assessed based on exhaustion, inactivity, slowness, weakness, and weight loss. Prevalence of frailty phenotype and geriatric conditions were assessed by the IPSS severity category (mild, 0-7; moderate, 8-19; severe, 20-35 points) and the first IIEF-5 question, which assesses the confidence in erectile function (low, 1-2; moderate, 3; high, 4-5 points). Results: Older men with severe urologic symptoms had a high prevalence of frailty. According to the IPSS questionnaire, the prevalence of frailty was 7.3% (21/288) in the mild category, 16.3% (26/160) in the moderate category, and 43.2% (19/44) in the severe category. Participants in the severe IPSS category showed high prevalence of dismobility (45.5%), multimorbidity (43.2%), malnutrition risk (40.9%), sarcopenia (40.9%), and polypharmacy (31.8%). According to erectile confidence based on the first IIEF-5 question, the prevalence of frailty was 18.7% (56/300) for low confidence, 5.3% (6/114) for moderate confidence, and 5.1% (4/78) for high confidence. Participants with low confidence in erectile function showed high prevalence of sarcopenia (39.0%), multimorbidity (37.7%), dismobility (35.7%), malnutrition risk (33.3%), and polypharmacy (23.0%). Conclusion: The prevalence of frailty and geriatric conditions was higher in older men with severe urologic symptoms. A frailty screening should be routinely administered in urology practices to identify older men who are vulnerable to treatment-related adverse events. PMID- 29503535 TI - Feasibility of a community-based Functional Power Training program for older adults. AB - Purpose: Community-based programs can increase and sustain physical activity participation in older adults, even for those who are physically frail. We studied the feasibility and potential effect of a 12-week structured Functional Power Training (FPT) program involving high velocities and low loads for older adults conducted in a common area of their housing estate. Patients and methods: The structured FPT program was conducted in collaboration with a health promotion social enterprise and a community service provider based in a public housing site. We recruited nine inactive residents as participants to the single, group based, twice-weekly program. Attendance and adverse event(s) were recorded throughout the program. The Short Physical Performance Battery, Timed Up and Go (TUG), and 30s Sit-to-Stand tests were used to assess functional outcomes pre- and postprogram. The FRAIL Scale was used to assess their frailty status, and a postprogram experience survey was conducted. Results: Eight subjects (aged 74+/ 10 years) completed the program with an average overall attendance of 90.3%, with at least five participants present for each session. Changes in functional outcomes showed a moderate-to-large effect with significant improvement in TUG (p<0.01). In addition, participants either reversed or maintained their frailty status (p<0.01). Overall, the program was perceived to be well structured, engaging, as well as providing physical and psychosocial benefits. No exercise related adverse events occurred during the program, and participants were keen to recommend this program to others. Conclusion: Community-based structured FPT is safe and feasible for frail older adults, with the potential to improve function and reverse frailty status. PMID- 29503536 TI - Reference values of hand-grip dynamometry and the relationship between low strength and mortality in older Chileans. AB - Aim: This study was aimed to set reference values of hand-grip strength by age and sex and validate cut points for risk of functional limitation and mortality in older Chileans. Methods: This was a pooled analysis of four studies including 6,426 people >=60 years of nondependent community-dwelling Chileans. After exclusion criteria, the final sample included 5,250 subjects, from whom 2,193 were followed to study all-cause mortality associated with low hand-grip strength. Face-to-face interviews registering sociodemographic characteristics, self-reported chronic diseases, and functional limitations were conducted. Anthropometric measurements and observed mobility were performed by trained professionals. Hand-grip strength was measured with a hand dynamometer T-18 (Country Technology, Inc.) before 2008 or with JAMAR brand from 2008 onwards. Percentiles were calculated through descriptive analysis and quantile regression models for specific groups of age and sex. Adjusted Cox regression hazard models for mortality risk according to low dynamometry condition and covariates were developed. Results: We deliver reference values of hand-grip strength for older Chileans proposing the 25th percentile as the cut-off point for low dynamometry risk: men <=27 kg, women <=15 kg. Low hand-grip strength was associated with Instrumental Activities of Daily Living limitations (p=0.001), and altered physical performance evaluated through the Timed Up and Go test (p=0.0001), grasping (p=0.001), bending (p<0.0001), and lifting (p<0.0001). After Cox proportional hazard regression models were assessed with a median follow-up of 9.2 years, the adjusted risk of all-cause mortality associated with a hand-grip strength lower than the 25th percentile in older Chileans showed a hazard ratio of 1.39 (95% confidence interval: 1.13-1.71). Conclusion: The cut-off points of dynamometry validated for the older Chileans allow the incorporation in the geriatric evaluation in primary health care of an easy-to-use, inexpensive indicator to identify older adults at risk of sarcopenia, frailty, and dismobility. In addition this also helps to optimize the evaluation of intervention strategies focused on the maintenance of functionality. PMID- 29503537 TI - Relationship of annual change in bone mineral density with extent of emphysematous lesions and pulmonary function in patients with COPD. AB - Background: Osteoporosis is a well-known comorbidity in COPD. It is associated with poor health status and prognosis. Although the exact pathomechanisms are unclear, osteoporosis is suggested to be either a comorbidity due to shared risk factors with COPD or a systematic effect of COPD with a cause-effect relationship. This study aimed to evaluate whether progression of osteoporosis is synchronized with that of COPD. Materials and methods: Data from 103 patients with COPD included in the Hokkaido COPD cohort study were analyzed. Computed tomography (CT) attenuation values of thoracic vertebrae 4, 7, and 10 were measured using custom software, and the average value (average bone density; ABD4,7,10) was calculated. The percentage of low attenuation volume (LAV%) for each patient was also calculated for evaluation of emphysematous lesions. Annual change in thoracic vertebral CT attenuation, which is strongly correlated with dual-energy X-ray absorptiometry-measured bone mineral density, was compared with that in FEV1.0 or emphysematous lesions. Results: In the first CT data set, ABD4,7,10 was significantly correlated with age (rho=-0.331; p=0.0006), body mass index (BMI; rho=0.246; p=0.0136), St George's Respiratory Questionnaire (SGRQ) activity score (rho=-0.248; p=0.0115), eosinophil count (rho=0.229; p=0.0198), and LAV% (rho=-0.372; p=0.0001). However, ABD4,7,10 was not associated with FEV1.0. After adjustment for age, BMI, SGRQ activity score, and eosinophil count, no significant relationship was found between ABD4,7,10 and LAV%. Annual change in ABD4,7,10 was not associated with annual change in LAV% or FEV1.0. Conclusion: Progression of osteoporosis and that of COPD are not directly related or synchronized with each other. PMID- 29503538 TI - The outcome and the influencing factors of the age of onset in post-mortem of chronic bronchitis patients: a retrospective study. AB - Purpose: Chronic bronchitis is thought to occur in elderly patients, and smoking seems to be an important risk factor. The outcomes related to the age of onset in patients with chronic bronchitis are still unclear. Patients and methods: A retrospective study was conducted on deceased patients whose diagnosis included bronchitis from 2010 to 2016. Patients were separated into two groups according to the age of onset (Group I, age <=50 years old; Group II, age >50 years old). Information regarding disease course, smoking history, death age, number of admissions per year, Hugh Jones Index, and self-reported comorbidities of the patients was recorded. Results: The courses of chronic cough and sputum were 33.38+/-7.73 years and 14.44+/-8.60 years in Group I and Group II, respectively (p<0.05). The death ages of Group I and Group II were 77.65+/-7.87 years and 84.69+/-6.67 years, respectively (p<0.05). There was a significant negative correlation between the number of hospital admissions per year and the age of onset. The age of onset was negatively associated with daily smoking count (r= 0.210) and total smoking count (r=-0.146). In Group I, there were fewer cases of coronary heart disease (OR =0.41 [0.24-0.71]), neurological diseases (OR =0.48 [0.24-0.97]), and total comorbidities (OR =0.67 [0.54-0.85]) than in Group II. Conclusion: Patients with early onset chronic bronchitis had a longer history, younger death age, poorer health status, and lower incidence of comorbidities. PMID- 29503539 TI - Real-life evaluation of COPD treatment in a Bulgarian population: a 1-year prospective, observational, noninterventional study. AB - Introduction: This was the first study designed to prospectively evaluate treatment patterns in chronic obstructive pulmonary disease (COPD) and the degree of adherence with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy recommendations in routine clinical practice in Bulgaria. Methods: The study was conducted in an outpatient setting and enrolled patients of both genders, aged >40 years, who were diagnosed with COPD (as per GOLD 2013). Evaluations were performed at baseline and at 6- and 12-month visits. Results: Of the 811 enrolled patients, 719 were assessed and completed the 12-month observation period. Overall, a substantial number of patients experienced moderate airflow limitation (~49% patients, GOLD 2 as per GOLD 2013; mean postbronchodilator forced expiratory volume in 1 second value was ~50% of the predicted value), belonged to GOLD group D (~51% patients), and had COPD assessment test score >=10 or modified Medical Research Council score >=2 (~79% patients), and <=1 exacerbation in the past 1 year (~80% patients). Short-acting beta2-agonists (~63% patients), inhaled corticosteroids/long-acting beta2-agonist fixed-dose combination (~62% patients), and long-acting muscarinic antagonists (~59% patients) were the most frequently used medications at all visits, regardless of severity. High levels of deviation from GOLD recommendations were observed in GOLD groups A and B patients. The deviation comprised high use of inhaled corticosteroid-containing regimens in ~45% and 63% of patients in GOLD groups A and B, respectively. Only 25 (3%) of the 796 patients reported at least one adverse event. Conclusion: The routine clinical practice for COPD in Bulgaria deviates from the GOLD recommendations largely in patients at a low risk (GOLD groups A and B), while the deviation was lesser in those at a higher risk (GOLD groups C and D). PMID- 29503540 TI - Origanum vulgare mediated green synthesis of biocompatible gold nanoparticles simultaneously possessing plasmonic, antioxidant and antimicrobial properties. AB - Purpose: The leaves and flowering stem of Origanum vulgare contain essential oils, flavonoids, phenolic acids and anthocyanins. We propose a new, simple, one pot, O. vulgare extract (OVE) mediated green synthesis method of biocompatible gold nanoparticles (AuNPs) possessing improved antioxidant, antimicrobial and plasmonic properties. Materials and methods: Different concentrations of OVEs were used to reduce gold ions and to synthetize biocompatible spherical AuNPs. Their morphology and physical properties have been investigated by means of transmission electron microscopy, ultraviolet-visible absorption spectroscopy, photon correlation spectroscopy and Fourier transform infrared spectroscopy, whereas their plasmonic properties have been tested using surface-enhanced Raman spectroscopy (SERS). The antioxidant properties of nanoparticles (NPs) have been evaluated by 2,2-diphenyl-1-picrylhydrazyl radical scavenging assay, and the antimicrobial tests were performed using the disk diffusion assay. Their cytotoxicity has been assessed by means of 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. Results: The experimental results confirmed the successful synthesis of biocompatible, spherical, plasmonic NPs having a mean diameter of ~40 nm and an outstanding aqueous stability. This new class of NPs exhibits a very good antioxidant activity and presents interesting inhibitory effects against Staphylococcus aureus and Candida albicans. Due to their plasmonic properties, AuNPs are used as SERS substrates for the detection of a test molecule (methylene blue) up to a concentration of 10-7 M and a pharmaceutical compound (propranolol) in solution. Cytotoxicity assays revealed that AuNPs are better tolerated by normal human dermal fibroblast cells, while the melanoma cancer cells are more sensitive. Conclusion: The biocompatible AuNPs synthetized using OVEs showed significant bactericidal and antimycotic activities, the most sensitive microorganisms being S. aureus and C. albicans, both commonly involved in various dermatological infections. Moreover, the significant antioxidant effect might recommend their use for protective and/or preventive effect in various skin inflammatory conditions, including the reduction in side effects in dermatological infections. Meanwhile, the as synthesized biocompatible AuNPs can be successfully used as SERS substrates for the detection of pharmaceutical compounds in aqueous solutions. PMID- 29503541 TI - Pivotal role of Acitretin nanovesicular gel for effective treatment of psoriasis: ex vivo-in vivo evaluation study. AB - The goal of the current study was to explore the potential benefits of Acitretin (Act) nanovesicular gel as a prospective antipsoriatic topical delivery system counteracting the drug challenges in terms of its extremely low aqueous solubility, instability, skin irritation, and serious systemic adverse effects. Act-loaded niosomes were successfully developed, entirely characterized, and optimized. Further evaluation of the optimized formula was conducted regarding its stability and ex vivo cytotoxicity on different cell lines. The optimized niosomal vesicles were then incorporated in gel base matrix and investigated by sequential ex vivo (skin permeation and deposition) and in vivo (skin irritation and antipsoriatic activity using mouse tail model) experiments. The optimized Act loaded niosomes (span 60:cholesterol molar ratio 1:1) were spherical in shape and exhibited the highest entrapment efficiency (90.32+/-3.80%) with appropriate nanosize and zeta potential of 369.73+/-45.45 nm and -36.33+/-1.80 mV, respectively. Encapsulation of the drug in the nanovesicles was further emphasized by differential scanning calorimetric and powder X-ray diffraction studies. After 3 months storage at 4+/-1 degrees C, the optimized formula preserved its stability. Act nano niosomal gel produced a remarkable enhanced ex vivo permeation profile up to 30 h and significant drug deposition in the viable epidermal-dermal layers compared with those of Act gel. The pronounced antipsoriatic activity of the medicated nano niosomes was proved ex vivo in HaCaT cells (a keratinocyte cell line). Topical application of Act nano niosomal gel to mouse tail model further established its distinct in vivo antipsoriatic superiority in terms of significantly higher orthokeratosis, drug activity, and reduction in epidermal thickness compared with the control and other gel formulations. Also, negligible skin irritation and better skin tolerability of Act nanovesicular gel were revealed by primary irritation index and histopathologic examination. PMID- 29503542 TI - Adhesion, proliferation, and apoptosis in different molecular portraits of breast cancer treated with silver nanoparticles and its pathway-network analysis. AB - Background: Silver nanoparticles (AgNPs) have attracted considerable attention due to the variety of their applications in medicine and other sciences. AgNPs have been used in vitro for treatment of various diseases, such as hepatitis B and herpes simplex infections as well as colon, cervical, and lung cancers. In this study, we assessed the effect on proliferation, adhesion, and apoptosis in breast cancer cell lines of different molecular profiles (MCF7, HCC1954, and HCC70) exposed to AgNPs (2-9 nm). Methods: Breast cancer cell lines were incubated in vitro; MTT assay was used to assess proliferation. Adhesion was determined by real-time analysis with the xCELLingence system. Propidium iodide and fluorescein isothiocyanate-Annexin V assay were used to measure apoptosis. The transcriptome was assessed by gene expression microarray and Probabilistic Graphical Model (PGM) analyses. Results: The results showed a decreased adhesion in breast cancer cell lines and the control exposed to AgNPs was noted in 24 hours (p<=0.05). We observed a significant reduction in the proliferation of MCF7 and HCC70, but not in HCC1954. Apoptotic activity was seen in all cell lines exposed to AgNPs, with an apoptosis percentage of more than 60% in cancer cell lines and less than 60% in the control. PGM analysis confirmed, to some extent, the effects of AgNPs primarily on adhesion by changes in the extracellular matrix. Conclusion: Exposure to AgNPs causes an antiproliferative, apoptotic, and anti-adhesive effect in breast cancer cell lines cultured in vitro. More research is needed to evaluate the potential use of AgNPs to treat different molecular profiles of breast cancer in humans. PMID- 29503543 TI - IQ discrepancy differentiates levels of fine motor skills and their relationship in children with autism spectrum disorders. AB - Purpose: We investigated 1) the impact of differences in intelligence quotient discrepancy (IQD) on motor skills of preschool-aged children with autism spectrum disorders (ASD); 2) the relationships between IQD and motor skills in preschool aged children with ASD. Methods: A total of 127 ASD preschool-aged children were divided into three groups according to the size of the IQD: IQD within 1 standard deviation (1SD; EVENIQ; n=81), discrepantly higher verbal intelligence quotient (VIQ; n=22; VIQ>performance intelligence quotient [PIQ] above 1SD [>=15 points]), and discrepantly higher PIQ (n=24; PIQ>VIQ above 1SD [>=15 points]). Children's IQD and motor skills were determined with the Wechsler Preschool and Primary Scale of IntelligenceTM - Fourth Edition and the motor subtests of the Comprehensive Developmental Inventory for Infants and Toddlers (CDIIT), respectively. Results: One-way analysis of variance revealed significant group differences for the fine motor domain of the CDIIT and the visual-motor coordination subtest (F=3.37-4.38, p<0.05). Children with discrepantly higher PIQ were associated with better fine motor skills than were children with even IQD and those with discrepantly higher VIQ, and vice versa. IQD (PIQ - VIQ) had significant positive correlations with the fine motor domain and fine motor subtests of the CDIIT (r=0.18-0.29, p<0.05). Conclusion: The IQD can identify different levels of fine motor skills in preschool-aged children with ASD. This study suggests important implications for clinicians, therapists, and researchers: discrepantly higher PIQ could be related to better visual-motor coordination, and discrepantly higher VIQ could be related to poor visual-motor coordination. Furthermore, the results support that when therapists are working with preschool-aged children with ASD who are developing fine motor skills or undertaking fine motor tasks related to visual-motor coordination, they may need to pay attention to the children's IQD. PMID- 29503544 TI - Successful switch from bilateral brief pulse to right unilateral ultrabrief pulse electroconvulsive therapy after failure to induce seizures. AB - Inducing adequate therapeutic seizures during electroconvulsive therapy (ECT) is sometimes difficult due to a high seizure threshold, even at the maximum stimulus charge. Previous studies have demonstrated that seizure threshold is lower in patients treated with right unilateral ultrabrief pulse (RUL-UBP) ECT than in those treated with bilateral or brief pulse (BL-BP) ECT. Therefore, switching to RUL-UBP ECT may be beneficial for patients in whom seizure induction is difficult with conventional ECT. In the present report, we discuss the case of a patient suffering from catatonic schizophrenia in whom BL-BP ECT failed to induce seizures at the maximum charge. However, RUL-UBP ECT successfully elicited therapeutic seizures and enabled the patient to achieve complete remission. This case illustrates that, along with other augmentation strategies, RUL-UBP ECT represents an alternative for seizure induction in clinical practice. PMID- 29503545 TI - Treatment patterns, health care resource utilization, and costs in Japanese adults with attention-deficit hyperactivity disorder treated with atomoxetine. AB - Objective: To describe the characteristics and medication treatment patterns of adult patients with attention-deficit/hyperactivity disorder (ADHD) prescribed atomoxetine in Japan. Materials and methods: A retrospective analysis of insurance claims data was conducted using the Japan Medical Data Center database. Adults (>=18 years) with ADHD who had >=1 atomoxetine claim from January 1, 2013 to December 31, 2014, and >=180 to <=900 days of follow-up were included. First atomoxetine claim defined the index date. Patient characteristics included age, gender, and comorbid conditions. Treatment patterns assessed included rates of atomoxetine discontinuation, switching, persistence, adherence (assessed via the medication possession ratio), and use of concomitant medications. Results: A total of 457 adults met all the inclusion criteria. Mean (SD) age was 32.7 (10.4) years, and 61.0% of patients were male. Nearly 72.0% of the patients had at least one comorbid mental health condition in the baseline period; depression (43.8%) and insomnia (40.7%) were the most common mental health comorbidities. Most common physical comorbidities were chronic obstructive pulmonary disease (14.4%) and diabetes (12.9%). Non-ADHD-specific psychotropics were prescribed to 59.7% of patients during the baseline period and to 65.9% during the follow-up period; 6.6% were prescribed non-ADHD-specific psychotropics concomitantly with atomoxetine. Overall, 40.0% of adults discontinued atomoxetine during the entire follow-up period and 65.9% were persistent with atomoxetine therapy at 3 months post-index date. Mean (SD) atomoxetine medication possession ratio was 0.57 (0.25), and 25.4% switched to an alternative ADHD therapy; methylphenidate (22.4%) and non-ADHD-specific psychotropics (77.6%) were the most common medication alternatives. Nearly 8% augmented atomoxetine with methylphenidates, non-stimulants, or non-ADHD-specific psychotropics. Conclusion: In this observational study, a majority of adults with ADHD treated with atomoxetine were still persistent with therapy at 3 months post-index date, with one quarter switching to alternative ADHD therapy. High proportions of mental health comorbidities, along with high use of non-ADHD-specific psychotropic medications in both the baseline and follow-up periods, were observed among patients with ADHD prescribed atomoxetine. PMID- 29503546 TI - The effectiveness of parent participation in occupational therapy for children with developmental delay. AB - Introduction: This study aims to explore the impact of Parent Participation Program on the development of developmental delay children. Methods: Pretest posttest equivalent-group experimental design study was used in this paper. A total of 30 pairs of developmental delay children aged 0-72 months and their parents participated into this study. They were divided into two groups, namely control group and experimental group, according to parents' wishes. The objects of study in control group received 16 courses of direct rehabilitation therapy; those in experimental group received 8 courses of direct rehabilitation therapy and 8 courses of instruction and tracking of Parent Participation Program. The duration of the intervention was 8 weeks. All cases should be evaluated before and after the intervention, to analyze the difference before and after intervention and among groups. The statistical methods in this paper included descriptive analysis, Chi-square test, independent sample t-test, pair-sample t test. Results and conclusion: The intervention of Parent Participation Occupational Program has positive impact on the development of developmental delay children in various fields. Among all the intervention results, the progress of the experimental group is 1.895 times more than that of the control group. With parent involvement, Parent Participation Occupational Therapy can promote the cognitive ability, language ability, action ability (gross and fine movement), social competence and self-care ability of children with developmental delay. Finally, the researcher presents suggestions and directions for future research in accordance with the results. PMID- 29503547 TI - Pediatric-onset multiple sclerosis in Egypt: a multi-center registry of 186 patients. AB - Introduction: Although the frequency of pediatric-onset multiple sclerosis (POMS) has increased in recent decades, it is still highly uncommon, which creates a need for the involvement of more registries from various clinical centers. Objective: To characterize the demographic, clinical, and paraclinical features of Egyptian patients with POMS. Patients and methods: A retrospective chart review study was undertaken on 237 Egyptian patients with demyelinating events which started before the age of 18 years who attended one of five tertiary referral centers in Cairo, Egypt. Results: Multiple sclerosis was diagnosed in 186 patients, 47 (25.27%) patients had disease onset before the age of 12 years; "early-onset pediatric multiple sclerosis (EOPMS)". The mean age of disease onset was (14.13+/-2.49 years), with a female:male ratio of 1.62:1, none of the enrolled patients had a primary progressive course (PPMS), whereas 10 patients (5.38%) had a secondary progressive form. Approximately two-thirds of the patients had monofocal disease onset, and less than 10% presented with encephalopathy; most of them had EOPMS. Motor weakness was the presenting symptom in half of the patients, whereas cerebellar presentation was detected in 34.95%, mainly in EOPMS. Seizures (not related to encephalopathy) were more frequent in those with EOPMS. Initial brain magnetic resonance images were positive in all patients, with detected atypical lesions in 29.03%, enhanced lesions in 35.48%, black holes in 13.98%, and infratentorial in 34.41%. Cervical cord involvement was found in 68.28%. More than two-thirds of the patients received either immunomodulatory or immunosuppressant (IS) treatment throughout their disease course, and about half of them received their treatment within the first year from symptoms onset, with a more favorable outcome, and patients with highly active disease received natalizumab, fingolimod, or other IS. Conclusion: The results from this registry - the largest for MS in the Arab region to date - are comparable to other registries. Immunomodulatory therapies in POMS are well tolerated and efficacious and they can improve the long-term outcome in children. PMID- 29503548 TI - Childhood trauma and dissociation among women with genito-pelvic pain/penetration disorder. AB - Objective: Causes such as childhood trauma, negative attitude about sexuality, inadequate sexual knowledge and education, relationship problems, and unconscious motivation are reported about psychosexual development in the etiology of genito pelvic pain/penetration disorder (GPP/PD). There are few studies that focus directly on research etiology of GPP/PD and use structured scales. The aim of this study was to research childhood trauma and dissociation forms among women with GPP/PD. Patients and methods: Fifty-five women with GPP/PD according to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders and 61 healthy women with no complaints of sexual function as a control group, in the age range of 18-60 years, were included in this study. Sociodemographic data form, Childhood Trauma Questionnaire (CTQ-28), Dissociative Experiences Scale (DES), and Somatoform Dissociation Questionnaire (SDQ-20) were administered to all participants. Results: Sexual abuse, emotional abuse, and emotional neglect scores, which comprise the subgroups of CTQ, were found high among women with GPP/PD compared with the control group (p=0.003, p=0.006, p=0.001). While a significant difference between the two groups' SDQ scores was obtained (p=0.000), no significant difference was detected between the two groups' DES scores (p=0.392). Discussion: The results evoke the question are genitopelvic pain conditions, vaginismus and dyspareunia, that cannot be explained with a medical cause and that cause penetration disorder, a kind of dissociative symptom prone to develop in some women with childhood psychogenic trauma. PMID- 29503549 TI - Single-stage procedure for the treatment of cholecysto-choledocolithiasis: a surgical procedures review. AB - While laparoscopic cholecystectomy is generally accepted as the treatment of choice for simple gallbladder stones, in cases in which common bile duct stones are also present, clinical and diagnostic elements, along with intraoperative findings, define the optimal means of treatment. All available options must be accessible to the surgical team which must necessarily be multidisciplinary and include a surgeon, an endoscopist, and a radiologist in order to identify the best option for a truly personalized surgery. This review describes the different techniques and approaches used based on distinctive recommendations and factors, according to the specific cases treated and the results achieved. PMID- 29503550 TI - Safety and efficacy of the perioperative administration of recombinant human brain natriuretic peptide (rhBNP): a systematic review and meta-analysis. AB - Objective: Retrospective studies and a meta-analysis were performed to evaluate the safety and effectiveness of the perioperative administration of recombinant human brain natriuretic peptide (rhBNP) during cardiac surgery under extracorporeal circulation. Methods: Computerized literature searches were performed in Medline, Embase, The Cochrane Library, CNKI, CBM, and WANFANG to find randomized controlled trials (RCTs) related to the perioperative administration of rhBNP during cardiac surgery starting from the database inception until December 2016. Two researchers independently performed study screening, information extraction, and quality evaluation according to the inclusion/exclusion criteria, and a meta-analysis was performed using RevMan 5.2 software. Results: A total of 12 studies were analyzed, including 12 RCTs and 727 patients. The meta-analysis results indicated that the perioperative administration of rhBNP could reduce the occurrence rate of postoperative complications, length of intensive care unit (ICU) stay, length of hospital stay, and serum creatinine (Scr) levels, and increase the 24-hour urine volume; however, it did not affect the postoperative mortality rate. Conclusion: The perioperative administration of rhBNP during cardiac surgery was safe and effective, and could improve the prognosis of the patients. PMID- 29503551 TI - Developments in the treatment of carcinoid syndrome - impact of telotristat. AB - Carcinoid syndrome occurs in 20% of patients with neuroendocrine tumors, and serotonin is usually the main causative hormonal peptide. Carcinoid syndrome, and particularly diarrhea, can significantly impact patients' quality of life. Somatostatin analogs (SSAs) are the mainstay of treatment, but are unable to ameliorate symptoms in all patients due to dose-limiting side effects and tachyphylaxis. Telotristat is a novel oral inhibitor of tryptophan hydroxylase, which is the rate-limiting enzyme in serotonin synthesis. A Phase III placebo controlled trial of telotristat etiprate (orally at 250 mg three times a day) showed a significant decrease in the frequency of bowel motions in treated patients with diarrhea from carcinoid syndrome. The main side effects were gastrointestinal symptoms, deranged liver function tests and depression. Treatment with 500 mg three times a day also decreased stool frequency, but was associated with more nausea and mood disturbances. Telotristat, therefore, represents a valuable option in the management of carcinoid syndrome diarrhea refractory to SSAs, and the US Food and Drugs administration approved its use for this indication in March 2017. However, its role in somatostatin-naive patients and in the treatment of other carcinoid syndrome symptoms (flushing and abdominal pain) remains unknown. Further research should focus on these issues as well as the safety of continuing telotristat in the context of other systemic antineoplastic therapies. PMID- 29503552 TI - Comparison between the long-axis/in-plane and short-axis/out-of-plane approaches for ultrasound-guided vascular catheterization: an updated meta-analysis and trial sequential analysis. AB - Background: A long-axis in-plane (LA-IP) approach and a short-axis out-of-plane (SA-OOP) approach are the two main approaches used in ultrasound (US)-guided vascular catheterization. However, the efficacy and safety of these approaches remain controversial. Therefore, we performed this meta-analysis to compare the two techniques in vascular catheterization. Materials and methods: Relevant studies were searched in PubMed, Embase, and the Cochrane Library databases from database inception until August 2017. Randomized controlled trials comparing a long-axis approach with a short-axis approach for US-guided vascular cannulation were selected. The RevMan software was used to analyze the results, and trial sequential analysis (TSA) was further applied to determine whether the currently available evidence was sufficient and conclusive. Results: Eleven studies met the inclusion criteria. Overall, 1,210 patients were included. The total success rate was similar between the SA-OOP and LA-IP approaches for US-guided vascular catheterization (risk ratio [RR], 1.01; 95% CI, 0.99-1.04; P=0.35; I2=48%). In the radial artery (RA; RR, 1.00; 95% CI, 0.96-1.05; P=0.88; I2=49%) and internal jugular vein (IJV; RR, 1.00; 95% CI, 0.98-1.02; P=0.99; I2=0%) subgroups, the total success rate was also similar and was confirmed by the TSA. For populations with subclavian vein (SCV) and axillary vein catheterization, the SA-OOP approach showed a benefit for first-attempt success rate. No significant differences in first-attempt success rate, cannulation times, or complications were found between the two approaches. Conclusion: Despite a similar total success rate between the SA-OOP approach and the LA-IP approach when used for RA and IJV catheterization (as confirmed by TSA), further robust well-designed trials are warranted to evaluate other outcomes. There is insufficient evidence to definitively state that the SA-OOP approach was superior to the LA-IP approach when used for SCV and axillary vein catheterization. High-quality trials are needed to confirm or refute this finding. PMID- 29503553 TI - Potential risk factors for poor outcome after anterior surgery for patients with cervical ossification of the posterior longitudinal ligament. AB - Objective: Our purpose here was to identify risk factors of poor outcome after anterior operation in patients with cervical ossification of the posterior longitudinal ligament (OPLL). Methods: This study retrospectively reviewed 98 patients who underwent anterior surgery for improving neurological symptoms. The Japanese Orthopedic Association (JOA) recovery rate <50% was defined as poor surgical outcome. We investigated the relationship between various predictors and outcome by logistic regression analysis and receiver operating characteristic curves. To explore the cause of cerebrospinal fluid (CSF) leakage, we used the Mann-Whitney U-test, chi2 test, or independent t-test. Results: Multivariate logistic regression analysis showed that age (odds ratio [OR] =1.1, 95% confidence interval [CI] =1.03-1.18, P=0.005), occupying ratio of OPLL (OR =1.08, 95% CI =1.03-1.12, P=0.001), and residual ratio of OPLL (OR =1.07, 95% CI =1.02 1.13, P=0.008) were independently associated with poor outcome. The cutoffs of the above risk factors were set at 63.5 years, 39.65%, and 25.165%, respectively. Predictors for CSF leakage were occupying ratio of OPLL, the K-line, and shape of the ossified lesion (P<0.001, P=0.019, and P=0.003). Conclusion: These findings suggest that advanced age, high occupying ratio of OPLL, and high residual ratio of OPLL were risk factors for postoperative poor outcome in patients with OPLL. In addition, the high occupying ratio of OPLL, the K-line (-), and hill-shape ossification were potential causes of CSF leakage. PMID- 29503554 TI - Computed tomography colonography versus colonoscopy for the diagnosis of colorectal cancer: a systematic review and meta-analysis. AB - Colorectal cancer (CRC) is a significant cause of morbidity and mortality. Optical colonoscopy (OC) is the first choice of investigation for assessing the state of the colon and it is excellent for CRC screening. Newer technologies such as computed tomography colonography (CTC) may also be useful in CRC screening. This systematic review compares the benefits of CTC and OC for CRC screening. This review includes all the available randomized clinical trials comparing CTC and OC for CRC screening in asymptomatic patients. Three studies were included in the systematic review and were submitted for meta-analysis. In the analysis of participation rates, only 2,333 of 8,104 (29%) patients who were invited for screening underwent the CTC, and only 1,486 of the 7,310 (20%) patients who were invited for screening underwent OC. The absolute risk difference in participation rate in the two procedures was 0.1 (95% CI, 0.05-0.14) in favor of CTC. In the analysis of advanced colorectal neoplasia (ACN) detection rates, 2,357 patients undergoing CTC and 1,524 patients undergoing OC were included. Of these, 135 patients (5.7%) who underwent a CTC and 130 patients (8.5%) who underwent an OC were diagnosed with ACN. The absolute risk difference in ACN detection rate in the two procedure types was -0.02 (with a 95% CI between -0.04 and -0.00) in favor of OC. CTC is an option for CRC screening in asymptomatic patients. However, as CTC was inferior in detecting ACN, it should not replace OC, which remains the gold standard. PMID- 29503555 TI - Tanezumab: a selective humanized mAb for chronic lower back pain. AB - Chronic lower back pain is a significant disease that affects nearly 20% of the worldwide population. Along with hindering patients' quality of life, chronic lower back pain is considered to be the second most common cause of disability among Americans. Treating chronic lower back pain is often a challenge for providers, especially in light of our current opioid epidemic. With this epidemic and an increased aging population, there is an imminent need for development of new pharmacologic therapeutic options, which are not only effective but also pose minimal adverse effects to the patient. With these considerations, a novel therapeutic agent called tanezumab has been developed and studied. Tanezumab is a humanized monoclonal immunoglobulin G2 antibody that works by inhibiting the binding of NGF to its receptors. NGF is involved in the function of sensory neurons and fibers involved in nociceptive transduction. It is commonly seen in excess in inflammatory joint conditions and in chronic pain patients. Nociceptors are dependent on NGF for growth and ongoing function. The inhibition of NGF binding to its receptors is a mechanism by which pain pathways can be interrupted. In this article, a number of recent randomized controlled trials are examined relating to the efficacy and safety of tanezumab in the treatment of chronic lower back pain. Although tanezumab was shown to be an effective pain modulator in major trials, several adverse effects were seen among different doses of the medication, one of which led to a clinical hold placed by the US Food and Drug Administration. In summary, tanezumab is a promising agent that warrants further investigation into its analgesic properties and safety profile. PMID- 29503556 TI - Renoprotective effect of remote ischemic postconditioning in patients with ST elevation myocardial infarction undergoing primary percutaneous coronary intervention. AB - Background: Whether upper arm remote ischemic postconditioning (RIPostC) exerts protection to kidney in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI) remains unknown. Methods: Sixty-four patients with STEMI were randomized to PPCI + RIPostC (n=29) and PPCI (n=35) groups. RIPostC consisting of 4 cycles of 5 minutes occlusion/reperfusion by cuff inflation/deflation of the upper arm was started within 1 minute after the first balloon dilatation. Peripheral venous blood samples were collected before PPCI and at 0.5, 8, 24, 48, and 72 hours after PPCI to detect serum creatinine (SCr) and creatine kinase-MB (CK-MB). Acute kidney injury (AKI) rate and estimated glomerular filtration rate (eGFR) were calculated. The transthoracic echocardiography was performed 7 days after PPCI to assess left ventricular ejection fraction (LVEF). Results: The patients in the PPCI + RIPostC group had a lower AKI rate compared with those in the PPCI group (P=0.04). The eGFR after PPCI increased in the PPCI + RIPostC group compared to the PPCI group (P<0.01). The peak of CK-MB concentration in the PPCI + RIPostC group was significantly lower than that in the PPCI group (P<0.01). The area under the curve of CK-MB decreased in the PPCI + RIPostC group compared with that in the PPCI group. LVEF in the PPCI + RIPostC group was significantly higher than that in the PPCI group (P=0.04). Conclusion: Upper arm RIPostC exerts renal and cardiac protection following cardiac ischemia-reperfusion in patients with STEMI. PMID- 29503557 TI - The clinical course of symptomatic deep vein thrombosis after 3 months of anticoagulant therapy using fondaparinux/edoxaban or fondaparinux/vitamin K antagonist. AB - Background: For the management of venous thromboembolism (VTE), providing anticoagulant therapy within the therapeutic range has been a major challenge, as conventional therapy with unfractionated heparin (UFH) and vitamin K antagonist (VKA) requires frequent laboratory monitoring and dose adjustment. Recently, fondaparinux and edoxaban are being used as beneficial alternatives to UFH and VKA. Methods: We evaluated the clinical course of symptomatic deep vein thrombosis (DVT) in patients who received the 3-month anticoagulation therapy with fondaparinux/edoxaban (Group A; n=40) in comparison with the findings from our previous experience of patients who received the fondaparinux/VKA combination (Group B; n=33). Results: In both Groups A and B, serum D-dimer was significantly improved after treatment (p<0.001). The thrombus volume assessed by quantitative ultrasound thrombosis (QUT) score was significantly reduced in both groups (p<0.001). There was no difference in the proportion of patients who were normalized (ie, disappearance of DVT) between the groups, although Group A had significantly more patients who were normalized or improved (ie, disappearance and reduction of DVT) (p<0.001). No bleeding event was observed in either group. However, in one patient in Group B, worsening of DVT and development of symptomatic PE were observed. Conclusion: Fondaparinux/edoxaban therapy is as effective as fondaparinux/VKA. This treatment has the possible advantage in thrombus regression. This would be a beneficial therapeutic option for both patients and physicians. PMID- 29503558 TI - The frequency, risk factors, and complications of gastrointestinal dysfunction during enteral nutrition in critically ill patients. AB - Background: Gastrointestinal (GI) motility disorders in intensive care patients remain relatively unexplored. Nowadays, the frequency, risk factors and complications of GI dysfunction during enteral nutrition (EN) become more questionable. Aim: To evaluate the frequency, risk factors and complications of GI dysfunction during EN in the first 2 weeks of the intensive care unit (ICU) stay and to identify precautions to prevent the development of GI dysfunction and avoid complications. Methods: In this prospective observational study, we deliberately targeted at-risk patients. A total of 137 patients who received nasogastric tube feeding in an ICU of a tertiary hospital were enrolled. Results: The incidence of GI dysfunction that was found to be 63% which was associated mainly between MDR bacteria positivity and negative fluid balance. Diarrhea was observed in 36 patients (26%) and on 147 patient-days (incidence rate, 5.5 per 100 patient-days). The median day of diarrhea onset was 6 days after the initiation of EN. Forty patients (29%) presented with constipation (85% during the first week). Fifty patients (36%) exhibited upper digestive intolerance on 212 patient-days (incidence rate, 7.9 per 100 patient-days), after a median EN duration of 6 days (range, 2-14 days). Logistic regression analysis revealed MDR bacteria growth in the culture (OR, 1.75; 95% CI, 1.15-2.67; P=0.008) and negative fluid balance (OR, 0.57; 95% CI, 0.34-0.94; P=0.03) as the risk factors for GI dysfunction. We also showed that GI dysfunction was associated with high SOFA score, hypoalbuminemia, catecholamine use, and prolonged length of stay (LOS). GI dysfunction, on the other hand, can cause some complications including inadequate nutrition, and newly developed decubitus ulcers. Conclusion: GI dysfunction should be considered a clinical predictor of inadequate nutrition and prolonged LOS. In addition, the most dramatic risk for GI dysfunction was observed in patients with MDR bacteria growth in the culture and patients in negative fluid balance. Intensivists provide appropriate nutrition for patients, as well as prompt intervention and the development of treatment strategies in the event of GI dysfunction. PMID- 29503559 TI - Specialty-care access for community health clinic patients: processes and barriers. AB - Introduction: Community health clinics/centers (CHCs) comprise the US's core health-safety net and provide primary care to anyone who walks through their doors. However, access to specialty care for CHC patients is a big challenge. Materials and methods: In this descriptive qualitative study, semistructured interviews of 37 referral coordinators of CHCs were used to describe their perspectives on processes and barriers to patients' access to specialty care. Analysis of data was done using content analysis. Results: The process of coordinating care referrals for CHC patients is complex and begins with a provider's order for consultation and ends when the referring provider receives the specialist's note. Poverty, specialist and referral coordinator shortages, lack of insurance, insurance acceptability by providers, transport and clinic location factors, lack of clinic-hospital affiliations, and poor communication between primary and specialty providers constitute critical barriers to specialty care access for patients. Conclusion: Understanding the complexities of specialty care coordination processes and access helps determine the need for comprehensive and uninterrupted access to quality health care for vulnerable populations. Guaranteed access to primary care at CHCs has not translated into improved access to specialty care. It is critical that effective policies be pursued to address the barriers and minimize interruptions in care, and to ensure continuity of care for all patients needing specialty care. PMID- 29503560 TI - Hospital-based child protection teams that care for parents who abuse or neglect their children recognize the need for multidisciplinary collaborative practice involving perinatal care and mental health professionals: a questionnaire survey conducted in Japan. AB - Background: Child abuse and/or neglect is a serious issue, and in many cases, parents are the perpetrators. Hospital-based child protection teams (CPTs) play pivotal roles in the management of not only abused and/or neglected children but also of their parents; this is generally conducted through multidisciplinary practice. The aim of this study is to survey hospital-based CPT members to determine the professions they perceive to be most applicable to participation in CPTs. Participants and methods: The participants were members of CPTs affiliated with hospitals that had pediatric emergency departments and which were located in Chiba Prefecture; specifically, 114 CPT members from 23 hospitals responded to this survey. The two main questionnaire items concerned are as follows: 1) each respondent's evaluation of conducting assessments, providing support, and implementing multidisciplinary collaborative practice in the treatment of abusive and negligent parents, and 2) each CPT member's opinion on the professions that are most important for CPT activities. An exploratory factor analysis (EFA) was performed to explore the factor structure of the data, and a correlation analysis was performed using the result obtained. Results: The EFA returned two factors: multidisciplinary collaborative practice (alpha = 0.84) and assessment and support (alpha = 0.89). A correlational analysis showed that multidisciplinary collaborative practice had a positive correlation for obstetricians (r = 0.315, p = 0.001), neonatologists (r = 0.261, p = 0.007), midwives (r = 0.248, p = 0.011), and psychiatrists (r = 0.194, p = 0.048); however, assessment and support was only significantly correlated with midwives (r = 0.208, p = 0.039). Conclusion: This study showed that hospital-based CPT members highly evaluate multidisciplinary collaborative practice for the management of abusive and/or negligent parents, and they believe that, in addition to pediatric physicians and nurses, perinatal care and mental health professionals are the most important participants in advanced CPT activities. PMID- 29503561 TI - Appearance and potential predictors of poorly controlled hypertension at the primary care level in an urban community. AB - Purpose: Hypertension (HT) is the major risk factor for cardiovascular diseases because of its poor control. To control HT at the primary care level in urban communities, there is a demand for deeper comprehension of the manifestations of poorly controlled HT. This study aimed to examine appearance of HT, including the association between the appearance and home blood pressure (HBP) control at the primary care level in urban communities. Patients and methods: A cross-sectional study was conducted in July-October 2017 in an urban community in Thailand. The total sample size from randomization was 125 poorly controlled HT patients who were diagnosed with an average clinic blood pressure >=140/90 mmHg in their last three visits. Data were collected by face-to-face interviews, HBP monitoring (HBPM), and blood and urine testing. Data analysis was conducted via descriptive statistics and the chi-square tests, with a significance level of p<0.05. Results: HBPM revealed that 58.4% of patients with poorly controlled blood pressure from clinic measurement had a systolic blood pressure and diastolic blood pressure that were below the HBP target. Most patients were overweight/obese, but they were nonsmokers and nondrinkers. As comorbidities, they had hyperlipidemia (64.0%) and diabetes mellitus (53.0%). One-quarter of them had good levels of knowledge and literacy. Nearly half had good health self care literacy. Only 13% exhibited adequate self-management behaviors, but more than half had biochemistry results within normal limits. There were significant associations of smoking history and having hyperlipidemia as a comorbidity with HBP control (p =0.010 and 0.046, respectively). Conclusion: The role of HBPM is important in practice when it comes to monitoring HT control at the primary care level in an urban context. Smoking cessation and control of the blood lipid levels should be highlighted not only at the practice, but also at the policy level. PMID- 29503562 TI - Women's experience of acute skin toxicity following radiation therapy in breast cancer. AB - Purpose: Acute skin toxicity is experienced by 70%-100% of patients receiving radiation therapy following breast cancer. Most studies focus on skin appearances and treatment of such reactions, not the experience. Increased knowledge about patients' experience will contribute to provide tailored patient care. Thus, the purpose was to investigate patients' experiences of acute skin toxicity following radiation therapy for breast cancer. Patients and methods: Semi-structured in depth interviews were conducted with seven women, 2-3 weeks post-treatment. Five broad areas of inquiry were investigated: 1) experiences from the development of skin reactions; 2) experiences in day-to-day life; 3) coping strategies; 4) experiences of information; and 5) experiences from the aftercare. The interviews were analyzed in line with qualitative content analysis. Results: The main theme "Not so bad itself, but it comes on top of everything else" was identified, based upon three categories: 1) unique experience of the skin; 2) it is something about the psychological aspect; and 3) experience of information. Conclusion: Acute skin toxicity following breast cancer treatment may affect many dimensions of patients' lives. Experiences are complex, individual, and not necessarily consistent with visible changes of the skin. A holistic approach is necessary to provide treatment and support according to patients' individual needs. PMID- 29503563 TI - The association of sociodemographic characteristics and sexual risk behaviors with health literacy toward behaviors for preventing unintended pregnancy among university students. AB - Purpose: The aim of this study was to determine whether there is an associated effect between sociodemographic characteristics and sexual risk behaviors with health literacy in preventing unintended pregnancy among university students in Chon Buri province, Thailand. Participants and methods: A cross-sectional study design was used. The data were collected between February and May, 2017. A self administered questionnaire was developed by the Ministry of Public Health and supported by the evolving concept of health literacy of Nutbeam. This questionnaire was then applied to collect data from 418 university students. Descriptive statistical and binary logistic regression methods were used for data analysis in this study. Results: Half the students exhibited inappropriate behaviors to prevent unintended pregnancies. However, half the respondents had been educated to prevent unintended pregnancies. Nearly one-third of the students had experienced sexual intercourse. Binary logistic regression was used to analyze an association between the behavior for unintended-pregnancy prevention with sociodemographic characteristics and the health literacy of university students. The factors assessed were current residence type (the adjusted odds ratio [aOR]=1.897, 95% CI=1.123-3.205), previous sexual intercourse (aOR=3.263, 95% CI=1.735-6.139), cognitive health to prevent unintended pregnancy (aOR=1.095, 95% CI=1.019-1.176), decision skills in choosing appropriate practices to prevent unintended pregnancy (aOR=1.289, 95% CI=1.182-1.405), and self-management to prevent unintended pregnancy (aOR=1.113, 95% CI=1.005-1.232). Conclusion: This study indicated that university students who had experienced sexual intercourse and had low health literacy were more likely to exhibit inappropriate behaviors concerning the lack of prevention of unintended pregnancies. The results will provide health professionals with information to develop more effective prevention and intervention programs. PMID- 29503564 TI - CDCA5 regulates proliferation in hepatocellular carcinoma and has potential as a negative prognostic marker. AB - Background: CDCA5 plays an important role in the development of various human cancers, but the associated mechanisms have not been investigated in hepatocellular carcinoma (HCC). Materials and methods: We evaluated expression levels and functions of CDCA5 in HCC and showed that CDCA5 is upregulated in HCC tissues compared with paired or unpaired normal liver tissues. Results: Increased CDCA5 expression in HCCs was significantly associated with shorter survival of patients. Knockdown of CDCA5 using lentivirus-mediated shRNA significantly inhibited cell proliferation and suppressed cell survival, as well as induced cell cycle arrest at the G2/M phase and cell apoptosis of HCC cells. The tumor suppression effects of CDCA5 knockdown were mediated by decreased expression of cyclin-dependent kinase 1 (CDK1) and CyclinB1, which were increased in HCC tissues comparing with adjacent normal liver tissues. Moreover, upregulation of CDCA5 was positively associated with increased CDK1 and CyclinB1 expression in HCC tissues. Conclusion: The present data warrant consideration of CDCA5 as a prognostic biomarker and therapeutic target for HCC. PMID- 29503565 TI - Postoperative hepatic arterial infusion chemotherapy improved survival of pancreatic cancer after radical pancreatectomy: a retrospective study. AB - Objective: To determine the effect of postoperative hepatic arterial infusion chemotherapy (HAIC) on long-term survival of patients with pancreatic cancer (PC) after radical pancreatectomy. Methods: A total of 87 patients with PC underwent radical pancreatectomy in the First People's Hospital affiliated to Huzhou Normal College between June 2008 and May 2013. Among these patients, after surgery, 43 received two sessions of HAIC followed by four sessions of systemic chemotherapy (HAIC group), while 44 received six sessions of systemic chemotherapy alone (control group). Both the HAIC and systemic chemotherapy regimen included 5 fluorouracil (1,000 mg/m2) as a 5-h infusion on day 1, and gemcitabine (800 mg/m2) as an over 30-min infusion on days 1 and 8. The toxicity, complication, and long-term survival were retrospectively compared. Results: No significant difference in patient characteristics between the two groups was found. No chemotherapy-related deaths were recorded, and no significant difference in toxicities was observed between the two groups. The 5-year disease-free survival probability did not differ between the two groups (P=0.2029, hazard ratio for recurrence=0.7561; 95% CI=0.4768-1.1989, by the log-rank test). The HAIC group had significantly higher 5-year overall survival probability (P=0.0288, hazard ratio for death=0.6059; 95% CI=0.3734-0.9832, by the log-rank test) and higher 5 year hepatic metastases-free survival probability (P=0.0321, hazard ratio for hepatic metastases=0.5006; 95% CI=0.2546-0.9843, by the log-rank test) than the control group. Conclusions: Postoperative HAIC has the potential to prevent hepatic metastases and increase long-term survival probability of patients with PC after radical pancreatectomy. PMID- 29503566 TI - Low levels of tumor suppressor candidate 3 predict poor prognosis of patients with hepatocellular carcinoma. AB - Purpose: The tumor suppressor candidate 3 (TUSC3) has been considered to be closely associated with the occurrence, development and invasion of various malignant tumors. However, the expression of TUSC3 in hepatocellular carcinoma (HCC) tissues remains ambiguous. The purpose of this research was to investigate the expression of TUSC3 in HCC tissues and analyze the relationship between TUSC3 levels and clinicopathological characteristics and prognosis of HCC patients. Materials and methods: Immunohistochemistry was used to detect the expression of TUSC3 in HCC and the corresponding para-cancerous tissues from 92 samples of HCC patients. mRNA and protein expression levels of TUSC3 were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot assays in 25 paired HCC and corresponding adjacent nontumor tissues. Furthermore, statistical analysis was applied to evaluate the correlation between TUSC3 level and the clinicopathological features and prognosis of HCC patients. Results: Immunohistochemical assay indicated that the expression of TUSC3 was significantly lower in HCC tissues when compared with the corresponding para cancerous tissues (chi2=11.512, P=0.001). The analysis of clinicopathological characteristics showed that low expression of TUSC3 in HCC tissues was significantly associated with Edmondson grade, Barcelona Clinic Liver Cancer stage and tumor size (P=0.008, 0.009 and 0.020, respectively). Univariate analysis showed that the expression of TUSC3 was strongly correlated with overall survival (OS) and disease-free survival (DFS) after radical surgery in HCC patients (P<0.001, P<0.001, respectively). Multivariate analysis revealed that the TUSC3 level was an independent risk factor for OS and DFS in HCC patients (P=0.001, P<0.001, respectively). Results of qRT-PCR and Western blot assays indicated that the level of TUSC3 in HCC tissues was significantly lower than that in the corresponding adjacent noncancerous tissues (P<0.01, P<0.001). Conclusion: The expression of TUSC3 in HCC was significantly downregulated and was correlated with tumor progression and prognosis, which could be used as an independent predictor of prognosis in HCC patients. PMID- 29503567 TI - The investigation for potential modifier genes in patients with neurofibromatosis type 1 based on next-generation sequencing. AB - Introduction: Neurofibromatosis type 1 (NF1) is a common Mendelian multi-system disorder that is characterized by cafe-au-lait spots (CLS), axillary freckling, optic glioma and plexiform neurofibroma. Various mutations of the NF1 gene are widely accepted to be the main cause of this disease, while whether there are still certain other modifier genes that could influence the phenotypes of NF1 is our concern. Patients and Methods: One proband and his father are involved, who are characterized by plexiform neurofibroma and cutaneous neurofibroma, respectively. Enhanced Computed tomography (CT) and Positron emission tomography CT (PET-CT) were taken to collect the radiographic data, and the specimens of this neurofibroma as well as the blood samples from the father and son were sent for panel mutation screening of 295 tumor-related genes based on next-generation screening. Furthermore, the NF1 gene mutations were referred with Canis lupus familiaris, Rattus norvegicus, Gallus gallus, Danio rerio, and Drosophila melanogaster NF1 sequencing for evolutionary conservativeness and then analyzed in Condel databases for pathogenicity prediction. Results: The radiography indicated that the benign plexiform neurofibroma only occurred in the son. Also, TP53, FANCA, BCL6, PIK3C2G, RNF43, FGFR4, FLT3, ERBB2, PAK7, NSD1, MEN1 and TSC1 were uniquely found mutated in the son, which could be candidates as new modifier genes; besides, RNF43 was also mutated in public neurofibroma seuquencing data. By KEGG pathway annotation, phosphoinositide-3-kinase-Akt pathway was altered in both the public plexiform neurofibroma sample and in our proband patient. Conclusion: This study reexamined the background germline mutations and suggested their potential value as modifier genes that may influence the phenotype heterogenity. PMID- 29503568 TI - Characterization of luteinizing hormone-releasing hormone receptor type I (LH-RH I) as a potential molecular target in OCM-1 and OCM-3 human uveal melanoma cell lines. AB - Introduction: Uveal melanoma (UM) is the most common primary intraocular malignancy with very poor prognosis. Conventional chemotherapy only rarely prolongs the survival, therefore patients require novel treatment modalities. The discovery of specific receptors for hypothalamic hormones on cancer cells has led to the development of radiolabeled and cytotoxic hormone analogs. Materials and methods: In the present study, our aim was to investigate the expression of mRNA for receptors of luteinizing hormone-releasing hormone type I (LH-RH-I) and LH-RH ligand in OCM-1 and OCM-3 human uveal melanoma cell lines. The presence and binding characteristics of LH-RH-I receptor protein was further studied by Western blot, immunocytochemistry and ligand competition assay. The expression of mRNA and protein for LH-RH-I receptors has been also studied using tumor samples originating from nude mice xenografted with OCM-1 or OCM-3 cells. Results: The mRNA for LH-RH-I receptor has been detected in OCM-1 and OCM-3 cell lines and was found markedly higher in OCM-3 cells. The mRNA for LH-RH-I receptors was also observed in both UM xenograft models in vivo with higher levels in OCM-3. The presence of LH-RH-I receptor protein was found in both cell lines in vitro by immunocytochemistry and Western blot, and also in tumor tissue samples grown in nude mice by Western blot. Both human uveal melanoma models investigated showed specific high affinity receptors for LH-RH-I using ligand competition assay. The mRNA for LH-RH ligand has also been detected in OCM-1 and OCM-3 cell lines and cancer tissues. Conclusion: The demonstration of the expression of LH-RH-I receptors in OCM-1 and OCM-3 human UM cell lines suggests that they could serve as potential molecular target for therapy. Our findings support the development of new therapeutic approaches based on cytotoxic LH-RH analogs or modern powerful antagonistic analogs of LH-RH targeting LH-RH-I receptors in UM. PMID- 29503569 TI - Role of ubenimex as an anticancer drug and its synergistic effect with Akt inhibitor in human A375 and A2058 cells. AB - Background: Malignant melanoma (MM) is a malignant tumor produced by changes in melanocytes in the skin or other organs. In the classification of skin tumor mortality, skin melanoma ranks the highest. Ubenimex, an Aminopeptidase N (APN) inhibitor, is now widely used for cancer as an adjunct therapy, conferring antitumor effects. Apoptosis and the induction of autophagy have both been found to be closely associated with tumor cell death. Methods: In this study, the A375 and A2058 cell lines were treated with ubenimex. Cell viability was measured using the Cell Counting Kit 8 assay. Apoptosis and autophagic cell death were assessed using flow cytometry and acridine orange/ethidium bromide staining. Protein expression was assessed by Western blot analyses and immunofluorescence. Matrigel invasion and migration assays were used to examine the metastatic ability of melanoma cells. Results: The results revealed that ubenimex inhibited the expression of APN in melanoma cells, which may be connected with the inhibition of metastasis. In addition, it increased melanoma cell death by inducing apoptosis and autophagic cell death. This effect was accompanied by increased levels of p-JNK. Moreover, treatment with ubenimex induced protective Akt activation, and combined use of an Akt inhibitor with ubenimex provided a better effect for inducing tumor cell death. Conclusion: As an effective anti tumor drug in vitro, ubenimex might be an excellent adjunctive therapy for the treatment of melanoma, with greater effects when combined with the use of an Akt inhibitor. PMID- 29503570 TI - Prognostic utility of baseline neutrophil-to-lymphocyte ratio in patients receiving immune checkpoint inhibitors: a review and meta-analysis. AB - Introduction: Systemic inflammation is associated with prognosis in solid tumors. The neutrophil-to-lymphocyte ratio (NLR) is a marker for the general immune response to various stress stimuli. Studies have shown correlation of NLR to outcomes in immune checkpoint blockade, peripheral neutrophil count to intratumor neutrophil population, and NLR to intratumoral levels of myeloid-derived suppressor cells. Studies have shown elevated peripheral blood regulator T cells accompanied by elevated NLR are associated with poor outcomes further highlighting the importance of inflammation in the prognosis of cancer patients. Methods: We performed a meta-analysis of published articles on the utility of baseline NLR in predicting outcomes in patients treated with immune checkpoint inhibitors (ICIs) using Review Manager, version 5.3. Seven studies on the prognostic utility of NLR in ICI treatment were included in this analysis. For outcomes of interest, the hazard ratios (HRs) were computed. Subgroup analyses were planned based on type of malignancy and type of immune checkpoint inhibitor. Results/discussion: A high NLR resulted in worse overall survival (OS) (HR, 1.92; 95% CI, 1.29-2.87; p=0.001) and progression-free survival (PFS; HR, 1.66; 95% CI, 1.38-2.01; p<0.00001) across types of malignancies studied (melanoma, non-small cell lung cancer, and genitourinary cancer). Subgroup analysis across different types of malignancies treated with ICI showed similar results for OS and PFS. The single study on genitourinary cancers also showed worse OS and PFS (OS: HR, 1.82; 95% CI, 1.29-2.87; p=0.001 and PFS: HR, 1.83; 95% CI, 0.97-3.44; p=0.06). A high NLR also showed worse OS and PFS across all ICIs (ipilimumab, nivolumab, and unspecified or pooled pembrolizumab and nivolumab; OS: HR, 1.92; 95% CI, 1.29 2.87; p=0.001 and PFS: HR, 1.66; 95% CI, 1.38-2.01; p<0.00001). Subgroup analysis by type of ICI showed similar results. Conclusion: A high NLR is associated with poorer outcomes across studies. This shows that NLR has the potential as a readily available prognostic indicator for patients receiving ICI based on available studies. Studies utilizing more stringent design may serve to better determine the utility of this tool. PMID- 29503571 TI - Prognostic significance of mucinous component in gastric adenocarcinoma after radical D2 gastrectomy. AB - Background: The mucinous component is a special histologic factor in gastric adenocarcinoma. The aim of this study was to assess the prognostic significance of mucinous component in gastric adenocarcinoma according to proportion. Patients and methods: Candidate patients with gastric adenocarcinoma were given radical D2 gastrectomies from September 2008 to May 2015 in our division. Clinicopathologic data and prognosis were monitored and analyzed among gastric adenocarcinoma patients with various proportions of mucinous component. Results: A total of 690 gastric adenocarcinomas with various proportions of mucinous component from 6,025 gastric adenocarcinoma patients were included. Higher numbers of patients with mucinous component came from: young patients, females, those with drinking history, at lower locations, Borrmann type III and IV, T4 stage, and positive for dissected lymph nodes. Tumors and pathological molecular markers showed more positivity in CEA, CA19-9, S100, and CD34. As the various proportions increased, more mucinous component seemed to be accompanied by more Borrmann type III and IV, T4 stage, and more positive expression of CEA and CA19-9. However, no significant difference in 5-year overall survival rate was observed among various proportions or existence of mucinous component. Also, proportion or existence of mucinous component was not an independent prognostic factor in multivariate analysis. Conclusion: Mucinous component was not a prognostic factor for gastric adenocarcinoma after radical D2 gastrectomy, no matter what proportion the component comprised. However, gastric adenocarcinoma with mucinous component showed specific clinicopathological characteristics, such as more advanced tumor stage, different age and sex, and more positive rate of molecular markers, which might provide a new strategy for optimal individual diagnosis and therapies. PMID- 29503572 TI - Role of palliative resection of the primary pancreatic neuroendocrine tumor in patients with unresectable metastatic liver disease: a systematic review and meta analysis. AB - Background: Treatment for pancreatic neuroendocrine tumors (PNETs) in patients with unresectable metastatic liver disease has long been a controversial issue. This systematic review aims to summarize the existing evidence concerning the value of primary tumor resection in this group of patients. Methods: A systematic review of the literature and a meta-analysis were performed. The PubMed and Cochrane databases were searched to identify articles that compared palliative primary tumor resection and nonsurgical regimens in patients with PNETs and unresectable liver metastases. Relevant articles were identified in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The primary outcome was overall survival. The included studies were evaluated for heterogeneity and publication bias. Results: Overall, 10 studies were included in the analysis. No randomized controlled trials (RCTs) were identified. These studies included 1,226 patients who underwent a resection of the primary tumor and 1,623 patients who did not undergo surgery. The median overall survival was 36-137 and 13.2-65 months in the surgical and nonsurgical groups, respectively, and the 5-year overall survival rate was 35.7-83 and 5.4% 50%, respectively, in these two groups. The meta-analysis demonstrated that there was no significant difference in liver tumor burden (odds ratio [OR] =1.51, 95% CI: 0.59-3.89, P=0.39) or tumor grade (OR =2.88, 95% CI: 0.92-9.04, P=0.07) among patients who underwent surgery and nonsurgical therapy. Furthermore, patients who underwent an aggressive surgical approach appeared to have a higher tumor grade. However, the meta-analysis demonstrated that patients who underwent primary tumor resection had better overall survival (P<0.001), with a pooled hazard ratio of 0.36 (95% CI: 0.30-0.45). No publication bias was detected. Conclusion: This meta analysis demonstrates that the palliative resection of the primary tumor in patients with PNETs and unresectable liver metastases can increase survival, although a bias toward a more aggressive surgical approach in patients with better performance status, less advanced disease, or a tumor located in the body or tail of the pancreas appears likely. RCTs with longer follow-up periods are required to confirm the advantages of palliative primary tumor resection for PNETs. PMID- 29503573 TI - Second-line anti-tuberculosis drug resistance testing in Ghana identifies the first extensively drug-resistant tuberculosis case. AB - Background: Drug resistance surveillance is crucial for tuberculosis (TB) control. Therefore, our goal was to determine the prevalence of second-line anti TB drug resistance among diverse primary drug-resistant Mycobacterium tuberculosis complex (MTBC) isolates in Ghana. Materials and methods: One hundred and seventeen MTBC isolates with varying first-line drug resistance were analyzed. Additional resistance to second-line anti-TB drugs (streptomycin [STR], amikacin [AMK] and moxifloxacin [MOX]) was profiled using the Etest and GenoType MTBDRsl version 2.0. Genes associated with resistance to AMK and MOX (gyrA, gyrB, eis, rrs, tap, whiB7 and tlyA) were then analyzed for mutation. Results: Thirty seven (31.9%) isolates had minimum inhibitory concentration (MIC) values >=2 ug/mL against STR while 12 (10.3%) isolates had MIC values >=1 ug/mL for AMK. Only one multidrug-resistant (MDR) isolate (Isolate ID: TB/Nm 919) had an MIC value of >=0.125 ug/mL for MOX (MIC = 3 ug/mL). This isolate also had the highest MIC value for AMK (MIC = 16 ug/mL) and was confirmed as resistant to AMK and MOX by the line probe assay GenoType MTBDRsl version 2.0. Mutations associated with the resistance were: gyrA (G88C) and rrs (A514C and A1401G). Conclusion: Our findings suggest the need to include routine second-line anti-TB drug susceptibility testing of MDR/rifampicin-resistant isolates in our diagnostic algorithm. PMID- 29503574 TI - Emergence and spread of worldwide Staphylococcus aureus clones among cystic fibrosis patients. AB - Background: The aim of this study was to assess the relatedness of molecular types of Staphylococcus aureus isolates colonizing cystic fibrosis (CF) patients with their antimicrobial resistance and prevalence of toxin genes. Methods: A total of 215 isolates from the airways of 107 patients with CF were tested for spa and SCCmec type, antimicrobial resistance and carriage of toxin genes. Results: t015, t084, t091, t700 and t002 were the largest group (approximately 25%) among all 69 identified spa types. Five new spa types, t14286, t14287, t14288, t14289 and t14290, were identified and registered. Isolates from CF patients were clustered into 11 multi-locus sequence typing clonal complexes, with CC30, CC22, CC97, CC45, CC15 and CC5 being the most frequent ones. Twelve (5.6%) methicillin-resistant S. aureus (MRSA) isolates and 102 (47.7%) multidrug resistant isolates were identified, along with three SCCmec types (I, III and V). All isolates (both MRSA and methicillin-sensitive S. aureus) were Panton Valentine leucocidin-negative, and 56.7% harbored egc genes. This was the first study documenting the presence of ST398-V-t571 livestock-associated MRSA in a European patient with CF. Conclusion: These findings imply that individuals with CF can also be colonized with animal-related ST398 MRSA, and justify constant monitoring of staphylococcal colonization and identification of epidemic S. aureus clones in this group. PMID- 29503575 TI - Clinical benefit of ertapenem compared to flomoxef for the treatment of cefotaxime-resistant Enterobacteriaceae bacteremia. AB - Objectives: Cefotaxime-resistant Enterobacteriaceae (CE) infections are intractable, with limited treatment options. Though carbapenems are frequently prescribed for CE infections, the emergence of carbapenem-resistant Enterobacteriaceae is of huge concern. Flomoxef is effective against CE in vitro, and some clinical data on its demonstrated effectiveness against CE bloodstream infections (BSIs) exists. Patients and methods: We conducted a retrospective study on adults with BSI caused by flomoxef-susceptible CE to investigate the efficacy of flomoxef compared with that of ertapenem. The outcome was evaluated with propensity score-based matching and logistic regression analysis. Results: Demographic and clinical characteristics of patients treated with flomoxef (n = 58) or ertapenem (n = 188) were compared. In the multivariate analysis, severe sepsis (adjusted odds ratio [AOR] = 3.84; 95% confidence interval [CI], 1.16 12.78; p = 0.03), high BSI mortality score (AOR = 5.59; 95% CI, 2.37-13.21; p < 0.01), ultimately or rapidly fatal comorbidity (AOR = 10.60; 95% CI, 3.43-32.75; p < 0.01), and pneumonia (AOR = 10.11; 95% CI, 3.43-29.81; p < 0.01) were independently associated with 28-day mortality. Using propensity scores, 58 flomoxef-treated patients were matched to 116 ertapenem-treated patients. There were no intergroup differences in BSI severity, comorbidity, or BSI sources. The 28-day mortality rates (20.7% vs 13.8%, p = 0.28) did not differ significantly. However, hospitalization length was shorter in the ertapenem group (10.2 +/- 8.5 vs. 14.6 +/- 9.4 days, p < 0.01). Conclusion: Although similar outcomes were observed between the groups, ertapenem therapy was associated with a shorter hospitalization time in adults after CE BSI. PMID- 29503576 TI - Clinical and economic burden of idiopathic pulmonary fibrosis in Quebec, Canada. AB - Background: Idiopathic pulmonary fibrosis (IPF), although rare, is a severe and costly disease. Objective: To estimate the clinical and economic burden of IPF over multiple years before and after diagnosis using comprehensive administrative databases for the province of Quebec, Canada. Methods: Several administrative databases from Quebec, providing information on hospital care, community care, and pharmaceuticals, were linked over a 5-year period ending March 31, 2011, which was before approval of antifibrotic drugs in Canada. Prevalent and incident IPF cases were defined using International Classification Disease-10-CA codes and International Classification Disease-9-CM codes. We used a broad definition that excluded cases with subsequent diagnosis of other interstitial lung diseases and a narrow definition that required further diagnostic testing to confirm IPF diagnosis. Incident cases had an IPF code in a particular year without any IPF code in the 2 previous years. Health care resource utilization before and after the index diagnosis date was determined and costs calculated. Costs were expressed in 2016 Canadian dollars. Results: Over 5-years, 10,579 (mean age: 76.4; 58% male) satisfied the broad definition of IPF and 8,683 (mean age: 74.5; 57% male) satisfied the narrow definition (82% of broad). Incidences of IPF overall were 25.8 and 21.7/100,000 population for broad and narrow definitions, respectively. Three-year survival was 40% and 37% in broad and narrow cohorts, respectively. For both cohorts, health care resource utilization and costs increased several years before diagnosis ($2,721 and $7,049/patient 5 years and 2 years prior to diagnosis using a broad definition, respectively) and remained elevated for multiple years post diagnosis ($12,978 and $8,267 at 2 and 3 years postdiagnosis). Conclusion: Health care resource utilization and costs of IPF increase many years prior to diagnosis. Incorporating multiyear annual costs before and after diagnosis results in a higher estimate of the economic burden of IPF than previous studies using a 1-year time frame. PMID- 29503577 TI - Risk factors associated with postoperative pain and discomfort in oculoplastic surgery with general anesthesia: a prospective study. AB - Purpose: To evaluate patient pain and discomfort following oculoplastic surgery performed under general anesthesia and to assess key factors associated with postoperative pain and discomfort. Methods: A prospective observational cohort study was conducted among 212 consecutive patients who underwent oculoplastic surgery performed under general anesthesia. The patients were assessed according to quantified levels of pain and discomfort postoperatively. Analgesic requests were recorded, and responses were statistically analyzed. Results: Pain and discomfort after oculoplastic surgery under general anesthesia were reported by 32.1% and 28.3% of the patients, respectively; 2.8% of the patients requested analgesic medication within 18 hours after surgery. The patients who underwent orbital decompression, secondary orbital implantation, and orbital fracture repair were more likely to develop significant postoperative pain and discomfort (P<0.001), and the patients who underwent enucleation/evisceration during orbital implantation were more likely to develop postoperative discomfort (P<0.001). The predictors of pain were smoking history, prior surgery on the operative eye, and anxiety (P<0.05), and the predictor of discomfort was anxiety (P<0.05). Conclusion: Patients undergoing oculoplastic surgery tend to experience postoperative pain and discomfort. Anxiety is a risk factor for both postoperative pain and discomfort, while smoking history and prior surgery on the operative eye may be associated with postoperative pain. PMID- 29503578 TI - Patient perspectives on improving osteoarthritis management in urban and rural communities. AB - Introduction: Although there is no cure for osteoarthritis (OA), there are lifestyle modifications that can mitigate symptoms such as pain, and improve management of the disease. This information is not always translated to community dwelling seniors. Individuals in rural areas often face additional challenges due to geographic isolation and decreased access to community services. Methods: We used qualitative research methodology (hermeneutic phenomenology) to better understand the lived experiences of urban and rural community-dwelling seniors diagnosed with OA. We explored their sources of information about OA, how they manage their OA pain, and how OA management could be improved in the community. Purposeful sampling was used to recruit 20 information-rich participants (11 urban, 9 rural) in Ontario, Canada. All participants were aged >65 and diagnosed with OA. Semi-structured interviews were conducted, audio recorded, and transcribed verbatim. NVivo 11 Pro qualitative software was used to code transcripts. Results: Thematic analysis revealed 9 key themes where 8 were common to urban and rural participants, and 1 was unique to rural participants. Most significant among the common themes was the description of the social network as a source of OA information, the trial-and-error approach used for OA management, and the individual contextualization of OA management. Our results suggest that there are several common experiences among urban- and rural-dwelling seniors living with OA, including the desire for support over time, but also a unique experience to rural-dwelling seniors, namely lack of access to local care. Conclusion: These findings can be used to improve translation of OA information in both urban and rural communities in Canada, highlighting that common strategies may be effective in different contexts for this disease. PMID- 29503579 TI - A randomized study of the efficacy and safety of parecoxib for the treatment of pain following total knee arthroplasty in Korean patients. AB - Purpose: Parecoxib is an injectable cyclooxygenase-2 inhibitor with proven postoperative analgesic efficacy in a variety of settings, including total knee arthroplasty (TKA). The effect of ethnicity on the efficacy of parecoxib for post TKA pain has not been studied. Patients and methods: This was a parallel-group, double-blind, randomized, placebo- controlled study of ethnically Korean patients aged >=18 years who had unilateral TKA. Patients who reported moderate or severe pain 6 hours after the end of postoperative opioid analgesia were randomized to receive a single intravenous dose of parecoxib sodium 40 mg or placebo. Patients were evaluated for 24 hours postdose. The primary efficacy endpoints included time-specific pain intensity difference (PID), time-specific pain relief (PR), and time to rescue medication. The incidence and nature of adverse events (AEs) assessed safety. Results: Of the 116 patients randomized, 58 received parecoxib and 58 placebo. Mean (SD) PID was significantly greater for parecoxib vs placebo 1 hour postdose (0.69 [0.67] vs 0.40 [0.59], respectively; p<0.05), and for each time point up to 24 hours. Similarly, mean (SD) PR was significantly greater for parecoxib vs placebo 1.5 hours postdose (1.63 [0.85] vs 1.07 [0.90], respectively; p=0.001), and for each time point up to 24 hours. The median time (hours:minutes) to rescue medication was significantly longer for parecoxib vs placebo (21:30 vs 4:08, respectively; p<0.001). Generally, fewer AEs were reported with parecoxib than placebo, and the AE profile was consistent with previous studies. These results are comparable to the findings from a similarly designed study in a Caucasian patient population. Conclusion: Parecoxib 40 mg significantly improved postoperative pain vs placebo in Korean patients after TKA. The efficacy and safety of parecoxib in Korean patients is similar to that seen in Caucasian patients. PMID- 29503580 TI - Quantitative sensory testing is feasible and is well-tolerated in patients with sickle cell disease following a vaso-occlusive episode. AB - Introduction: Sickle cell disease (SCD) is an inherited blood disorder characterized by abnormally shaped sickle cells. The hallmark of this disease is intermittent, painful vaso-occlusive episodes (VOE), but a subset of individuals with SCD experience chronic pain. The mechanism of transition to chronic pain is not well understood in SCD, but there is evidence of altered pain processing in individuals with SCD. The impact of VOE on pain sensitivity is not established. The objective of this study was to determine the feasibility and tolerability of quantitative sensory testing (QST) in SCD following a VOE to better understand the contribution of VOE to the development of chronic pain. Methods: As part of a larger pain sensitivity study, pediatric patients with SCD were offered QST following a VOE-related Emergency Room visit or inpatient hospitalization. The feasibility of recruitment and completion of QST was measured, and tolerability of QST was determined using post-QST assessments of pain, and compared with measurements at steady state. Results: Ten participants completed QST following a VOE. The median age was 16.5, and 60% were female. Overall, 10 of 16 (62.5%) patients approached for QST following VOE completed QST. This included 8 of 12 patients who had previously completed QST at steady state. There were no statistically significant differences in pain intensity and Gracely Box scores after QST following a VOE, when compared to steady-state QST. Conclusion: QST is feasible and is well-tolerated following a VOE in patients with SCD. Large prospective studies are needed to determine the impact of VOE on experimental pain sensitivity and must take into account all factors contributing to pain sensitivity. PMID- 29503581 TI - Neck/shoulder function in tension-type headache patients and the effect of strength training. AB - Introduction: Muscle pain has been associated with reduced maximal muscle strength, and reduced rate of force development (RFD). Strength training (ST) has shown an effect in not only normalizing muscle function but also reducing neck muscle pain. Aim: The aims of this study were to compare muscle function in terms of strength, force steadiness in neck flexion, as well as extension, and rate of RFD of the shoulder in tension-type headache (TTH) patients and healthy controls and to examine the correlation to tenderness. Furthermore, the aim of the study was to examine the effect of ST on neck and shoulder functions in TTH patients. Participants and methods: In all, 60 TTH patients and 30 sex- and age-matched healthy controls were included for a case-control comparison. The 60 patients with TTH were randomized into an ST and an ergonomic and posture correction (EP) control group. The ST group trained for 10 weeks with elastic bands. Results: TTH patients had a lower extension force steadiness with a significant 15% higher coefficient of variation (CoV) compared to healthy controls (p=0.047). A significantly lower RFD (25%) was noted in the TTH group than in the healthy controls (p=0.031). A significant (p<0.01) and moderate correlation to muscle tenderness was found. In the intervention, 23 patients completed ST and 21 patients completed EP. No significant between-group effect was observed, but at 22 weeks follow-up, both groups had a significant within-group effect of improved extension force steadiness (ST: p=0.011 and EP: p<0.01). Conclusion: TTH patients showed a deteriorated muscle function, indicated by a lower force steadiness and RFD, compared to the healthy controls. The effect of ST was not larger than EP as both groups of TTH patients showed some improvement in neck and shoulder functions during the 10 weeks intervention and at follow-up. Future interventions are needed to elucidate if normalization of muscle function can lead to a reduction in headache. PMID- 29503582 TI - Effect of warming anesthetic on pain perception during dental injection: a split mouth randomized clinical trial. AB - Background: The purpose of this study is to determine the effectiveness of warming anesthesia on the control of the pain produced during the administration of dental anesthesia injection and to analyze the role of Transient Receptor Potential Vanilloid-1 nociceptor channels in this effect. Patients and methods: A double-blind, split-mouth randomized clinical trial was designed. Seventy-two volunteer students (22.1+/-2.45 years old; 51 men) from the School of Dentistry at the Universidad Austral de Chile (Valdivia, Chile) participated. They were each administered 0.9 mL of lidocaine HCl 2% with epinephrine 1:100,000 (Alphacaine(r)) using two injections in the buccal vestibule at the level of the upper lateral incisor teeth. Anesthesia was administered in a hemiarch at 42 degrees C (107.6 degrees F) and after 1 week, anesthesia was administered by randomized sequence on the contralateral side at room temperature (21 degrees C 69.8 degrees F) at a standardized speed. The intensity of pain perceived during the injection was compared using a 100 mm visual analog scale (VAS; Wilcoxon test p<0.05). Results: The use of anesthesia at room temperature produced an average VAS for pain of 35.3+/-16.71 mm and anesthesia at 42 degrees C produced VAS for pain of 15+/-14.67 mm (p<0.001). Conclusion: The use of anesthesia at 42 degrees C significantly reduced the pain during the injection of anesthesia compared to its use at room temperature during maxillary injections. The physiological mechanism of the temperature on pain reduction could be due to a synergic action on the permeabilization of the Transient Receptor Potential Vanilloid-1 channels, allowing the passage of anesthetic inside the nociceptors. PMID- 29503583 TI - Surgical resection improves long-term survival of patients with hepatocellular carcinoma across different Barcelona Clinic Liver Cancer stages. AB - Objectives: Surgical resection remains a controversial treatment for hepatocellular carcinoma (HCC) within different Barcelona Clinic Liver Cancer (BCLC) stages. The objective of this study was to evaluate the long-term outcome of patients undergoing surgical resection (SR) compared to non-surgical treatments across different BCLC stages. Patients and methods: One thousand four hundred forty-three HCC patients within BCLC 0, A, B and C stages were identified. Overall survival was compared by log-rank test among patients within different BCLC stages and among patients receiving different treatments (SR vs locoregional therapy [LRT] vs best supportive care). Propensity score matching analysis was introduced to mitigate the confounding biases between the groups. Results: The median survival time of the patients diminished from early, intermediate to advanced BCLC stages (BCLC 0-A 43 [range 0-100] months vs BCLC B 32 [range 0-100] months vs BCLC C 27 [range 0-90] months, all p<0.05). Patients undergoing SR presented with better liver function and more favorable tumor status and, consequently, displayed significant better overall survival than patients receiving LRT or best supportive care at different BCLC stages. In adjusted cohort after propensity score matching, patients who were surgically treated consistently had more favorable outcome than those who were non curatively treated across different BCLC stages (median survival [range]: BCLC stage B: resection 45 [0-100] months vs LRT 36 [0-81] months, p=0.002; BCLC stage C: resection 39 [3-77] months vs LRT 27 [0-54] months, p=0.003). Conclusion: Surgical resection should be considered as a radical treatment for selected HCC patients regardless of the BCLC stages when appropriate. PMID- 29503584 TI - High C-reactive protein/albumin ratio predicts unfavorable distant metastasis free survival in nasopharyngeal carcinoma: a propensity score-matched analysis. AB - Background: Recent studies have indicated that the C-reactive protein/albumin (CRP/ALB) ratio (CAR) may represent a simple inflammation-based index for assessing the host inflammatory response. In this study, the prognostic value of the CAR for distant metastasis-free survival (DMFS) in nasopharyngeal carcinoma (NPC) was assessed. Methods: A total of 1,168 non-metastatic NPC patients from Sun Yat-sen University Cancer Center were retrospectively included. The optimal cutoff value for CAR was defined by the Cutoff Finder online tool. Propensity case-matched analysis was performed to adjust for potential differences in baseline characteristics. Subsequently, the prognostic value of the CAR for DMFS was validated in a 756 validation cohort with NPC. Results: The optimal CAR cutoff value was 0.081. Patients with high CAR values had significantly poorer DMFS than those with low CAR in univariate and multivariate analyses before propensity score matching. The CAR could also significantly stratify patients into different risks of developing distant metastasis in subgroup analysis. Propensity score analyses showed that CAR remained a prognostic factor for DMFS, thus excluding other interpretations and selection bias. Moreover, the prognostic value of the CAR was robustly confirmed in the external validation cohort. Conclusion: CAR is an inexpensive and easy-to-measure inflammatory index that may aid clinicians in the development of individualized treatment and follow-up strategies for patients with non-metastatic NPC. PMID- 29503585 TI - Quality of life of young Chinese breast cancer patients after adjuvant chemotherapy. AB - Introduction: Understanding of quality of life (QoL) of young Chinese breast cancer patients after adjuvant cytotoxic chemotherapy is limited. This study aims to assess the QoL of premenopausal Chinese breast cancer women after receiving adjuvant chemotherapy. Patients and methods: Eligibility criteria included stage I-III breast cancer, premenopausal and age <=45 years at cancer diagnosis and having received adjuvant chemotherapy within 3-10 years before entry to the present study. Patients' background demographics at the time of breast cancer diagnosis, together with tumor characteristics and anticancer treatments, were collected. At the time of study entry, the menopausal status based on menstrual history, body mass index, and QoL (assessed using Functional Assessment of Cancer Therapy-Breast +4) were recorded. Results: Two hundred and eighty patients were recruited. Ninety-five patients (33.9%) underwent breast-conserving surgery, and nearly all (98.6%) underwent axillary dissection. For adjuvant therapies, 249 patients (88.9%) received anthracycline-containing chemotherapy and 79 (28.2%) received taxane-containing chemotherapy, while 68 (24.3%) received both. One hundred and eighty six patients (66.4%) received adjuvant radiotherapy, and 214 (76.4%) received adjuvant tamoxifen. The median time from breast cancer diagnosis to study entry was 5.01 years. QoL assessment at study entry revealed that older patients had worse social well-being (SWB; mean scores for age <=40, 41-45, 46-50 and >50 years were 22.0, 19.3, 19.1 and 18.1, respectively, P=0.0442). Patients who underwent axillary dissection had worse scores for breast cancer sub-scale (BCS; mean score 22.2 vs. 28.3, P=0.0212). Patients who underwent taxane containing chemotherapy had worse scores for arm subscale (mean score 13.8 vs. 15.3, P=0.0053). Conclusion: At a median follow-up of 5 years post-diagnosis, patients who were younger had fewer disturbances in their SWB. Patients who had axillary dissection had worse BCS scores, while those who received taxane had worse scores for arm subscale. Further studies are warranted for breast-specific QoL to address the specific issues encountered by breast cancer patients. PMID- 29503586 TI - Spotlight on the utility of the Oncotype DX(r) breast cancer assay. AB - The Oncotype DX(r) assay was developed to address the need for optimizing the selection of adjuvant systemic therapy for patients with estrogen receptor (ER) positive, lymph node-negative breast cancer. It has ushered in the era of genomic based personalized cancer care for ER-positive primary breast cancer and is now widely utilized in various parts of the world. Together with several other genomic assays, Oncotype DX has been incorporated into clinical practice guidelines on biomarker use to guide treatment decisions. The Oncotype DX result is presented as the recurrence score which is a continuous score that predicts the risk of distant disease recurrence. The assay, which provides information on clinicopathological factors, has been validated for use in the prognostication and prediction of degree of adjuvant chemotherapy benefit in both lymph node positive and lymph node-negative early breast cancers. Clinical studies have consistently shown that the Oncotype DX has a significant impact on decision making in adjuvant therapy recommendations and appears to be cost-effective in diverse health care settings. In this article, we provide an overview of the validation and clinical impact studies for the Oncotype DX assay. We also discuss its potential use in the neoadjuvant setting, as well as the more recent prospective validation trials, and the economic and utility implications of studies that use a lower cutoff score to define low-risk disease. PMID- 29503587 TI - Anxiety and depression during pregnancy in women attending clinics in a University Hospital in Eastern province of Saudi Arabia: prevalence and associated factors. AB - Background: Anxiety and depression during the antenatal period is a growing problem with major effects on the mother, the developing fetus, and the neonate. Objectives: To assess the prevalence of anxiety and depression during pregnancy in women attending the hospital for antenatal care and assess the associated factors. Methods: This is a prospective cohort study conducted in the University Hospital of Imam Abdulrahman Bin Faisal University. Anxiety was evaluated using State Trait Anxiety Inventory. Depression was assessed using Edinburgh Postnatal Depression Scale (EPDS). Results: Complete data were available for 575 women. The mean EPDS score was 10.5 (SD 5.5). The prevalence of depression was 26.8%. The mean state-anxiety score was 38.4 (SD 11.4) and mean trait-anxiety score was 38.2 (SD 9.5). The prevalence of anxiety using state-anxiety scale was 23.6%, while using the trait scale it was 23.9%. The risk is higher among unemployed women with history of miscarriage and unplanned pregnancy. Conclusion: Anxiety and depression are common during pregnancy. PMID- 29503588 TI - The relationship of wearing a wetsuit in long-distance open-water swimming with sex, age, calendar year, performance, and nationality - crossing the "Strait of Gibraltar". AB - Aim: The aim of the present study was to investigate the relationship of wearing a wetsuit with sex, age group, nationality, calendar year, and performance in crossing the "Strait of Gibraltar"(14.3 km). Materials and methods: A sample of 1,130 open-water (females, n=180, age 35.9+/-11.9 years; males, n=950, age 40.0+/ 10.2 years) ultra-distance swimmers crossing the "Strait of Gibraltar" since 1950 was analyzed. Results: Male, older, and Spanish swimmers used wetsuits more often than female, younger, and athletes of other nationalities, respectively, and the use of the wetsuit has increased during the past three decades. Swimmers with wetsuits were faster than those without. Male athletes aged 30-34 years were faster than athletes >60 years. Female athletes were younger than male athletes, and swimmers with wetsuits were older than those without. The Spanish were faster than the American swimmers and athletes from other nationalities, and the American swimmers were the oldest. Conclusion: In summary, swimmers were faster when using a wetsuit, and local Spanish swimmers were the fastest and also used wetsuits most frequently. Male and older swimmers used wetsuits more often than other swimmers, and the use of wetsuits has increased in the last three decades. PMID- 29503590 TI - Direct oral anticoagulants for extended thromboprophylaxis in medically ill patients: meta-analysis and risk/benefit assessment. AB - Background: Standard-duration (7-10 days) thromboprophylaxis with low molecular weight heparin, low dose unfractionated heparin, or fondaparinux in hospitalized medically ill patients is associated with ~50% reduction in venous thromboembolism (VTE) risk. However, these patients remain at high risk for VTE post-discharge. The direct oral anticoagulants (DOACs) apixaban, rivaroxaban and betrixaban have been evaluated for extended-duration (30-42 days) thromboprophylaxis in this population. Methods: We review the efficacy and safety results from the 3 pivotal trials of extended-duration DOAC thromboprophylaxis in medically ill patients. We performed a meta-analysis of these pivotal trials focusing on 6 VTE (efficacy) and three bleeding outcomes (safety). These results were integrated into a quantitative risk/benefit assessment. Results: The trials evaluating extended-duration DOAC thromboprophylaxis in medically ill patients failed to establish clear efficacy and/or safety signals for each agent. Our meta analysis shows that, as a class, DOACs have selective and partial extended duration prophylactic activity in preventing VTE events. However, this is associated with a marked increase in the risk of various bleeding events. The risk/benefit analyses fail to show a consistent net clinical benefit of extended duration DOAC prophylaxis in medically ill patients. Conclusion: At this time, the evidence of safe and effective extended-duration thromboprophylaxis with DOACs in this population is inconclusive. PMID- 29503589 TI - Cost and quality of life of overlooked eye care needs of children. AB - Background: The objective of this research was to conduct a systematic review and cost analysis to summarize, from the Ministry of Health perspective, the costs families might incur because of their child's prescription for refractive errors and amblyopia correction. Methods: Databases including MEDLINE, Embase, BIOSIS, CINAHL, HEED, ISI Web of Science, and the Cochrane Library as well as the gray literature were searched. Systematic review was conducted using EPPI-Reviewer 4. Percentage difference in cost of glasses and patches per patient per various diagnoses were computed. The cost of glasses and patches was projected over a 5 year time horizon. Cost-utility analysis was performed. Results: In total, 302 records were retrieved from multiple databases and an additional 48 records were identified through gray literature search. From these, a total of 14 studies (10,388 subjects) were eligible for quantitative analysis. The cost of glasses increased significantly for congenital cataract patients to US$1,820, esotropia patients to US$840, myopes to US$411, amblyopes (mixed) to US$916, anisometropes to US$521, and patients with strabismus to US$728 over a 5-year period making them unaffordable for low-income families. Incremental cost of glasses of congenital cataract patients with delayed treatment was computed to be US$1,690 per health utility gained. Incremental cost of glasses for high refractive error was US$93 per health utility gained in non-compliant children. For amblyopia patients, incremental cost of glasses per quality-adjusted life years gained was US$3,638. Conclusion: Cost of corrective lenses is associated with significant financial burden and thus other means of mitigating costs should be considered. Eyesight problems in children are perceived as low-priority health needs. Thus, educational interventions on substantial visual deficits of not wearing glasses should be offered to families and governmental health agencies. PMID- 29503591 TI - Surgical simulation training in orthopedics: current insights. AB - Background: While the knowledge required of residents training in orthopedic surgery continues to increase, various factors, including reductions in work hours, have resulted in decreased clinical learning opportunities. Recent work suggests residents graduate from their training programs without sufficient exposure to key procedures. In response, simulation is increasingly being incorporated into training programs to supplement clinical learning. This paper reviews the literature to explore whether skills learned in simulation-based settings results in improved clinical performance in orthopedic surgery trainees. Materials and methods: A scoping review of the literature was conducted to identify papers discussing simulation training in orthopedic surgery. We focused on exploring whether skills learned in simulation transferred effectively to a clinical setting. Experimental studies, systematic reviews, and narrative reviews were included. Results: A total of 15 studies were included, with 11 review papers and four experimental studies. The review articles reported little evidence regarding the transfer of skills from simulation to the clinical setting, strong evidence that simulator models discriminate among different levels of experience, varied outcome measures among studies, and a need to define competent performance in both simulated and clinical settings. Furthermore, while three out of the four experimental studies demonstrated transfer between the simulated and clinical environments, methodological study design issues were identified. Conclusion: Our review identifies weak evidence as to whether skills learned in simulation transfer effectively to clinical practice for orthopedic surgery trainees. Given the increased reliance on simulation, there is an immediate need for comprehensive studies that focus on skill transfer, which will allow simulation to be incorporated effectively into orthopedic surgery training programs. PMID- 29503592 TI - An evaluation of medical student-led podcasts: what are the lessons learnt? AB - Background: Student-led podcasts were developed by 5th year Peninsula Medical School students as part of an educational grant. The students completed 35 video podcasts using PREZI software, and based on clinical indicative presentations of the Peninsula Medical School curriculum. Methods: Third, 4th and 5th year medical students were invited to complete the evaluation of the indicative presentation video podcasts they watched. Both quantitative and qualitative data were collected through anonymized questionnaires. A thematic analysis of qualitative data was carried out. Results: Seven hundred and fifty students were invited to evaluate the podcasts of which 142 responded to the email. One hundred and forty two students were assigned podcasts, of whom 122 completed the podcast questionnaire (85.9%), with 20 students dropping out for unknown reasons. The majority of the students found the podcasts to be clear, of an appropriate length, targeted at the right academic level and providing a good method of learning. However, there were mixed views in relation to the preference of podcasts over conventional learning methods. The thematic analysis identified positive comments and areas of improvement for the podcasts. Conclusion: Podcasts conducted in an interview style with an engaging voice and images are thought to help maintain student engagement from their perspective. Further evaluation/research is required to help establish the correct depth and breadth of information to be included in podcasts. PMID- 29503593 TI - Seeing and sensing the railways: A phenomenological view on practice-based learning. AB - This article explores the role of embodied, sensible knowledge in practice-based learning. Despite recent efforts to conceptualize how practitioners become skillful through corporeal and sensible learning, it still seems under-theorized and hard to understand what this exactly entails. The aim of this article is to account for the inherently embodied and sensible nature of knowledge by drawing on a 2-year ethnographic study of train dispatchers in a railway control room. Embodied and sensible knowledge is developed through the work of Merleau-Ponty and Heidegger, as phenomenology is a way to theorize the body beyond being an object to, instead, account for embodiment as lived and experienced. The data show that such knowledge can be understood as a matter of 'attunement': dispatchers become progressively skillful in bringing their bodies and senses in tune with practical situations and perturbations in the environment. The article contributes to a richer understanding of embodiment, especially in the relation between knowledge and practices, in organization studies and management learning. PMID- 29503594 TI - A systematic meta-review of evaluations of youth violence prevention programs: Common and divergent findings from 25 years of meta-analyses and systematic reviews. AB - Violence among youth is a pervasive public health problem. In order to make progress in reducing the burden of injury and mortality that result from youth violence, it is imperative to identify evidence-based programs and strategies that have a significant impact on violence. There have been many rigorous evaluations of youth violence prevention programs. However, the literature is large, and it is difficult to draw conclusions about what works across evaluations from different disciplines, contexts, and types of programs. The current study reviews the meta-analyses and systematic reviews published prior to 2009 that synthesize evaluations of youth violence prevention programs. This meta review reports the findings from 37 meta-analyses and 15 systematic reviews; the included reviews were coded on measures of the social ecology, prevention approach, program type, and study design. A majority of the meta-analyses and systematic reviews were found to demonstrate moderate program effects. Meta analyses yielded marginally smaller effect sizes compared to systematic reviews, and those that included programs targeting family factors showed marginally larger effects than those that did not. In addition, there are a wide range of individual/family, program, and study moderators of program effect sizes. Implications of these findings and suggestions for future research are discussed. PMID- 29503595 TI - Gangs and a global sociological imagination. AB - Across the globe, the phenomenon of youth gangs has become an important and sensitive public issue. In this context, an increasing level of research attention has focused on the development of universalized definitions of gangs in a global context. In this article, we argue that this search for similarity has resulted in a failure to recognize and understand difference. Drawing on an alternative methodology we call a 'global exchange', this article suggests three concepts-homologies of habitus, vectors of difference and transnational reflexivity-that seek to re-engage the sociological imagination in the study of gangs and globalization. PMID- 29503597 TI - The moral economy of home construction in late socialist Yugoslavia. AB - Housing shortages in Yugoslav cities were a perennial concern for authorities and citizens alike. They disproportionately affected Yugoslav workers who as a consequence were the demographic most likely to independently construct a family home. This article explores how informal builders justified home construction in moral terms, legitimizing it on the basis of physical labour that was invested in home construction. This was couched in both the language register of Yugoslav socialism and patriarchal custom (according to which a male-headed household should enjoy the right to a family home). Construction was also conditioned by the opportunities and constraints of late socialist temporalities. PMID- 29503596 TI - Recruiting, Retaining and Engaging Men in Social Interventions: Lessons for Implementation Focusing on a Prison-based Parenting Intervention for Young Incarcerated Fathers. AB - Recruiting, retaining and engaging men in social interventions can be challenging. The focus of this paper is the successful implementation of a parenting programme for incarcerated fathers, delivered in a Young Offender Institution (YOI) in Scotland. Reasons for high levels of recruitment, retention and engagement are explored, with barriers identified. A qualitative design was employed using ethnographic approaches including participant observation of the programme, informal interactions, and formal interviews with programme participants, the facilitators and others involved in managing the programme. Framework analysis was conducted on the integrated data set. The prison as the setting for programme delivery was both an opportunity and a challenge. It enabled easy access to participants and required low levels of effort on their part to attend. The creation of a nurturing and safe environment within the prison classroom facilitated engagement: relationships between the facilitators and participants, and between the participants themselves were key to understanding high levels of retention and engagement. The most fundamental challenge to high engagement levels arose from clashes in embedded institutional ways of working, between the host institution and the organisation experienced in delivering such intervention work. This threatened to compromise trust between the participants and the facilitators. Whilst adding specifically to the very sparse literature on reaching incarcerated young fathers and engaging them in parenting work, the findings have transferability to other under-researched areas: the implementation of social interventions generally in the prison setting, and engaging marginalised fathers in parenting/family work in community settings. The paper highlights ways of overcoming some of the challenges faced. PMID- 29503598 TI - Dupilumab: an evidence-based review of its potential in the treatment of atopic dermatitis. AB - Introduction: Atopic dermatitis (AD) is a recurrent, pruritic inflammatory skin disease with complex immunopathogenesis characterized by a dominant TH2 response. Dupilumab is an interleukin (IL)-4 receptor alpha antagonist that subsequently blocks IL-4 and IL-13 signaling. It has recently been approved for the treatment of adult patients with moderate-to-severe AD whose current treatment options are limited. Aim: This article reviews the evidence of clinical efficacy, safety, and patient-reported out-come (PRO) measures from Phase I-III trials of dupilumab in adult patients with moderate-to-severe AD. Evidence review: Results from clinical trials of dupilumab in adults with moderate-to-severe AD have shown that weekly or biweekly dupilumab injections significantly improve clinical and PROs. Transcriptome and serum analyses also found that dupilumab significantly modulates the AD molecular signature and other TH2-associated biomarkers, compared with placebo. Additionally, concomitant use of dupilumab with topical corticosteroids (TCS) results in a greater improvement in signs and symptoms of AD than with dupilumab use alone. Throughout the trials, common adverse events were headaches, conjunctivitis, and injection site reactions. These were consistently mild-moderate and occurred with similar frequency between the treatment and placebo groups. Place in therapy: In adult patients with moderate to-severe refractory AD, monotherapy or concomitant use of dupilumab with TCS holds great promise to significantly improve clinical outcomes and quality of life of the patient. Ongoing studies of dupilumab will help determine the clinical efficacy and safety profile of its long-term use. Finally, further economic evidence is warranted to compare the long-term costs and benefits of dupilumab with other currently available treatments for moderate-to-severe AD. PMID- 29503599 TI - Structure-Function Relationships in Pectin Emulsification. AB - The emulsifying characteristics of pectins isolated from six different okra genotypes were investigated and their structure-function relationships have been evaluated. Emulsion formation and stabilization of acidic oil-in-water emulsions (pH 2.0, phi = 0.1) were studied by means of droplet size distribution, zeta potential measurements, viscometry, interfacial composition analysis and fluorescence microscopy. Fresh and aged emulsions differed in terms of droplet size distribution, interfacial protein and pectin concentrations (Gamma) depending on the molecular properties of pectin that was used. Specifically, pectins with intermediate length of RG-I branching with molar ratio of (Ara + Gal)/Rha between 2 and 3 exhibit the optimum emulsification capacity whereas samples with the molar ratio outside this range do not favour emulsification. Additionally, low amounts of RG-I segments (HG/RG-I > 2) improve long term stability of emulsions as opposed to the samples that contain high amounts of RG I (HG/RG-I < 2) which lead to long term instability. Protein was not found to be the controlling factor for the stability of the dispersions. The present results show that rational design of pectin should be sought before application as functional ingredient in food and/or pharmaceutical systems. PMID- 29503600 TI - Review: Secondary Metabolites of Aquilaria, a Thymelaeaceae Genus. AB - Background: Aquilaria, a genus belonging to the Thymelaeaceae, produces fragrant resinous agarwood, also known as eaglewood, which has been used as incense since old times. The intense fra-grance is the result of the presence of a wide variety of secondary metabolites. Objective: This genus was reported contained sesquiterpenes, chromones, flavonoids, benzophenones, diterpenoids, triterpenoids, and lignans. Conclusion: Here, we review the different secondary metabolites that have been identified in Aquilaria to show their diversity and to allow comparison with other Thymelaeaceae genera. PMID- 29503601 TI - Surface Charge and Overlayer pH Influence the Dynamics of Supported Phospholipid Films. AB - Understanding the thermodynamics and kinetics of interactions between model lipid bilayers and planar supports is of critical importance in the furtherance of biosensing and the creation of biomimetic devices. Evaluating these properties can be accomplished through understanding the diffusional properties of the bilayer constituents. In this report, the dynamics of a model DMPC bilayer supported on a phosphorylated silica surface are studied in the presence and absence of interfacial Ca2+ as a function of pH of the aqueous overlayer. The data for this system reveal the importance of the balance of ionic interactions between the interfacial species, and the dependence of the diffusional, kinetic and thermodynamic properties of the system on pH. The thermodynamic data suggest that interactions between the bilayer and surface are mediated enthalpically rather than entropically. PMID- 29503603 TI - Hidden concerns of sharing research data by low/middle-income country scientists. AB - There has considerable interest in bringing low/middle-income countries (LMIC) scientists into discussions on Open Data - both as contributors and users. The establishment of in situ data sharing practices within LMIC research institutions is vital for the development of an Open Data landscape in the Global South. Nonetheless, many LMICs have significant challenges - resource provision, research support and extra-laboratory infrastructures. These low-resourced environments shape data sharing activities, but are rarely examined within Open Data discourse. In particular, little attention is given to how these research environments shape scientists' perceptions of data sharing (dis)incentives. This paper expands on these issues of incentivizing data sharing, using data from a quantitative survey disseminated to life scientists in 13 countries in sub Saharan Africa. This interrogated not only perceptions of data sharing amongst LMIC scientists, but also how these are connected to the research environments and daily challenges experienced by them. The paper offers a series of analysis around commonly cited (dis)incentives such as data sharing as a means of improving research visibility; sharing and funding; and online connectivity. It identifies key areas that the Open Data community need to consider if true openness in research is to be established in the Global South. PMID- 29503602 TI - From correlation to causation: analysis of metabolomics data using systems biology approaches. AB - Introduction: Metabolomics is a well-established tool in systems biology, especially in the top-down approach. Metabolomics experiments often results in discovery studies that provide intriguing biological hypotheses but rarely offer mechanistic explanation of such findings. In this light, the interpretation of metabolomics data can be boosted by deploying systems biology approaches. Objectives: This review aims to provide an overview of systems biology approaches that are relevant to metabolomics and to discuss some successful applications of these methods. Methods: We review the most recent applications of systems biology tools in the field of metabolomics, such as network inference and analysis, metabolic modelling and pathways analysis. Results: We offer an ample overview of systems biology tools that can be applied to address metabolomics problems. The characteristics and application results of these tools are discussed also in a comparative manner. Conclusions: Systems biology-enhanced analysis of metabolomics data can provide insights into the molecular mechanisms originating the observed metabolic profiles and enhance the scientific impact of metabolomics studies. PMID- 29503604 TI - Engineering Immunological Tolerance Using Quantum Dots to Tune the Density of Self-Antigen Display. AB - Treatments for autoimmunity - diseases where the immune system mistakenly attacks self-molecules - are not curative and leave patients immunocompromised. New studies aimed at more specific treatments reveal development of inflammation or tolerance is influenced by the form self-antigens are presented. Using a mouse model of multiple sclerosis (MS), we show for the first time that quantum dots (QDs) can be used to generate immunological tolerance by controlling the density of self-antigen on QDs. These assemblies display dense arrangements of myelin self-peptide associated with disease in MS, are uniform in size (<20 nm), and allow direct visualization in immune tissues. Peptide-QDs rapidly concentrate in draining lymph nodes, co-localizing with macrophages expressing scavenger receptors involved in tolerance. Treatment with peptide-QDs reduces disease incidence 10-fold. Strikingly, the degree of tolerance - and the underlying expansion of regulatory T cells - correlates with the density of myelin molecules presented on QDs. A key discovery is that higher numbers of tolerogenic particles displaying lower levels of self-peptide are more effective for inducing tolerance than fewer particles each displaying higher densities of peptide. QDs conjugated with self-antigens could serve as a new platform to induce tolerance, while visualizing QD therapeutics in tolerogenic tissue domains. PMID- 29503605 TI - Commentary: Cortical activity in the null space: permitting preparation without movement. PMID- 29503606 TI - Deep Brain Stimulation to Alleviate Freezing of Gait and Cognitive Dysfunction in Parkinson's Disease: Update on Current Research and Future Perspectives. AB - Freezing of gait (FOG) is a gait disorder featured by recurrent episodes of temporary gait halting and mainly found in advanced Parkinson's disease (PD). FOG has a severe impact on the quality of life of patients with PD. The pathogenesis of FOG is unclear and considered to be related to several brain areas and neural circuits. Its close connection with cognitive disorder has been proposed and some researchers explain the pathogenesis using the cognitive model theory. FOG occurs concurrently with cognitive disorder in some PD patients, who are poorly responsive to medication therapy. Deep brain stimulation (DBS) proves effective for FOG in PD patients. Cognitive impairment plays a role in the formation of FOG. Therefore, if DBS works by improving the cognitive function, both two challenging conditions can be ameliorated by DBS. We reviewed the clinical studies related to DBS for FOG in PD patients over the past decade. In spite of the varying stimulation parameters used in different studies, DBS of either subthalamic nucleus (STN) or pedunculopontine nucleus (PPN) alone or in combination can improve the symptoms of FOG. Moreover, the treatment efficacy can last for 1-2 years and DBS is generally safe. Although few studies have been conducted concerning the use of DBS for cognitive disorder in FOG patients, the existing studies seem to indicate that PPN is a potential therapeutic target to both FOG and cognitive disorder. However, most of the studies have a small sample size and involve sporadic cases, so it remains uncertain which nucleus is the optimal target of stimulation. Prospective clinical trials with a larger sample size are needed to systematically assess the efficacy of DBS for FOG and cognitive disorder. PMID- 29503607 TI - Effect of Somatic Experiencing Resiliency-Based Trauma Treatment Training on Quality of Life and Psychological Health as Potential Markers of Resilience in Treating Professionals. AB - Background: Individuals who treat trauma are at significant risk of vicarious traumatization and burnout. Somatic Experiencing(r) (SE(r)) is a resiliency focused trauma treatment modality designed to address autonomic nervous system (ANS) dysregulation and its impacted physical health and mental health symptoms e.g., anxiety, depression, post-traumatic stress disorder, migraines, fibromyalgia, and chronic fatigue, etc. The SE(r) training supports the development of clinical skills to reduce physical health/mental health symptoms as well as increase clinician resilience. Individuals who display resilience often have increased experiences of well-being (quality of life) and decreased levels of self-reported psychological symptoms. Greater resilience could mitigate the risks to providers and the clients they treat. Materials and Methods: This within-groups, longitudinal study assessed students (N = 18) over the course of a 3-year SE(r) practitioner training. This training focuses on increased ANS, physical, and emotional regulation skills. The convenience of a web-based survey allowed for: measures of a general quality of life (WHOQOL-BREF), psychological symptoms, somatic, anxiety, and depressive symptoms (PHQ-SADS), as well as a measure of early life exposure to adversity (CDC/Kaiser Permanente ACE Score Calculator Questionnaire). The clinician survey was conducted yearly for 3 years. Future studies would do well to also include laboratory-based objective measures of ANS functioning. Results: ANOVA with repeated measures showed that there were significant reductions in anxiety symptoms (GAD7, p < 0.001) and somatization symptoms (PHQ15, p < 0.001). Health-related quality of life (a measure of physical well-being) and social quality of life (a measure of interpersonal well being) both increased significantly (Health QoL p = 0.028; Social QoL p = 0.046). Conclusions: Results suggest that professionals attending the 3-year SE(r) training course experience a significant improvement in self-reported measures associated with resiliency including: quality of life (well-being) and psychological symptoms (anxiety and somatization). Our results support the importance of future research in a larger sample and support the exploration, cross-sectionally and prospectively, of the relationship of clinician resiliency and changes in clinician resiliency with SE(r) training and clinical outcomes. These data have implications for other professions at risk of exposure to vicarious trauma (VT) including nurses, medical providers, and paramedics. PMID- 29503608 TI - Silencing of Glucocerebrosidase Gene in Drosophila Enhances the Aggregation of Parkinson's Disease Associated alpha-Synuclein Mutant A53T and Affects Locomotor Activity. AB - Background: Mutations in glucocerebrosidase (GBA), a lysosomal enzyme are the most common genetic risk factor for developing Parkinson's disease (PD). We studied how reduced GCase activity affects alpha-synuclein (alpha-syn) and its mutants (A30P and A53T) aggregation, neurodegeneration, sleep and locomotor behavior in a fly model of PD. Methods: We developed drosophila with GBA gene knockdown (RNAi) (with reduced GCase activity) that simultaneously expresses either wildtype (WT) or mutants such as A30P or A53T alpha-syn. Western blot and confocal microscopy were performed to study the alpha-syn aggregation and neurodegeneration in these flies. We also studied the sleep and locomotor activity of those flies using Drosophila activity monitor (DAM) system. Results: Western blot analysis showed that GBA RNAi A53T alpha-syn flies (30 days old) had an increased level of Triton insoluble synuclein (that corresponds to alpha-syn aggregates) compared to corresponding A53T flies without GBA RNAi (control), while mRNA expression of alpha-syn remained unchanged. Confocal imaging of whole brain staining of 30 days old drosophila showed a statistically significant decrease in neuron numbers in PPL1 cluster in flies expressing alpha-syn WT, A30P and A53T in the presence GBA RNAi compared to corresponding control. Staining with conformation specific antibody for alpha-syn aggregates showed an increased number of neurons staining for alpha-syn aggregates in A53T fly brain with GBA RNAi compared to control A53T flies, thus confirming our protein analysis finding that under decreased GBA enzyme activity, mutant A53T aggregates more than the control A53T without GBA silencing. Sleep analysis revealed decreased total activity in GBA silenced flies expressing mutant A53T compared to both A53T control flies and GBA RNAi flies without synuclein expression. Conclusion: In A53T flies with reduced GCase activity, there is increased alpha-syn aggregation and dopamine (DA) neuronal loss. This study demonstrates that reduced GCase activity both in the context of heterozygous GBA1 mutation associated with PD and in old age, contribute to increased aggregation of mutant alpha-syn A53T and exacerbates the phenotype in a fly model of PD. PMID- 29503609 TI - It's All about Timing: The Involvement of Kir4.1 Channel Regulation in Acute Ischemic Stroke Pathology. AB - An acute ischemic stroke is characterized by the presence of a blood clot that limits blood flow to the brain resulting in subsequent neuronal loss. Acute stroke threatens neuronal survival, which relies heavily upon proper function of astrocytes. Neurons are more susceptible to cell death when an astrocyte is unable to carry out its normal functions in supporting the neuron in the area affected by the stroke (Rossi et al., 2007; Takano et al., 2009). For example, under normal conditions, astrocytes initially swell in response to changes in extracellular osmotic pressure and then reduce their regulatory volume in response to volume-activated potassium (K+) and chloride channels (Vella et al., 2015). This astroglial swelling may be overwhelmed, under ischemic conditions, due to the increased levels of glutamate and extracellular K+ (Lai et al., 2014; Vella et al., 2015). The increase in extracellular K+ contributes to neuronal damage and loss through the initiation of harmful secondary cascades (Nwaobi et al., 2016). Reducing the amount of extracellular K+ could, in theory, limit or prevent neuronal damage and loss resulting in an improved prognosis for individuals following ischemic stroke. Kir4.1, an inwardly rectifying K+ channel, has demonstrated an ability to regulate the rapid reuptake of this ion to return the cell to basal levels allowing it to fire again in rapid transmission (Sibille et al., 2015). Despite growing interest in this area, the underlying mechanism suggesting that neuroprotection could occur through modification of the Kir4.1 channel's activity has yet to be described. The purpose of this review is to examine the current literature and propose potential underlying mechanisms involving Kir4.1, specially the mammalian target of rapamycin (mTOR) and/or autophagic pathways, in the pathogenesis of ischemic stroke. The hope is that this review will instigate further investigation of Kir4.1 as a modulator of stroke pathology. PMID- 29503610 TI - Laminar Distribution of Subsets of GABAergic Axon Terminals in Human Prefrontal Cortex. AB - In human prefrontal cortex (PFC), ~85% of gamma-aminobutyric acid (GABA) expressing neurons can be subdivided into non-overlapping groups by the presence of calbindin (CB), calretinin (CR) or parvalbumin (PV). Substantial research has focused on the differences in the laminar locations of the cells bodies of these neurons, with limited attention to the distribution of their axon terminals, their sites of action. We previously reported that in non-human primates subtypes of these cells are distinguishable by differences in terminal protein levels of the GABA synthesizing enzymes glutamic acid decarboxylase 65 (GAD65) and GAD67. Here we used multi-label fluorescence microscopy in human PFC to assess: (1) the laminar distributions of axon terminals containing CB, CR, or PV; and (2) the relative protein levels of GAD65, GAD67 and vesicular GABA transporter (vGAT) in CB, CR and PV terminals. The densities of the different CB, CR and PV terminal subpopulations differed across layers of the PFC. PV terminals comprised two subsets based on the presence of only GAD67 (GAD67+) or both GADs (GAD65/GAD67+), whereas CB and CR terminals comprised three subsets (GAD65+, GAD67+, or GAD65/GAD67+). The densities of the different CB, CR and PV GAD terminal subpopulations also differed across layers. Finally, within each of the three calcium-binding protein subpopulations intra-terminal protein levels of GAD and vGAT differed by GAD subpopulation. These findings are discussed in the context of the laminar distributions of CB, CR and PV cell bodies and the synaptic targets of their axons. PMID- 29503611 TI - Estimating the Integrated Information Measure Phi from High-Density Electroencephalography during States of Consciousness in Humans. AB - The integrated information theory (IIT) proposes a quantitative measure, denoted as Phi, of the amount of integrated information in a physical system, which is postulated to have an identity relationship with consciousness. IIT predicts that the value of Phi estimated from brain activities represents the level of consciousness across phylogeny and functional states. Practical limitations, such as the explosive computational demands required to estimate Phi for real systems, have hindered its application to the brain and raised questions about the utility of IIT in general. To achieve practical relevance for studying the human brain, it will be beneficial to establish the reliable estimation of Phi from multichannel electroencephalogram (EEG) and define the relationship of Phi to EEG properties conventionally used to define states of consciousness. In this study, we introduce a practical method to estimate Phi from high-density (128-channel) EEG and determine the contribution of each channel to Phi. We examine the correlation of power, frequency, functional connectivity, and modularity of EEG with regional Phi in various states of consciousness as modulated by diverse anesthetics. We find that our approximation of Phi alone is insufficient to discriminate certain states of anesthesia. However, a multi-dimensional parameter space extended by four parameters related to Phi and EEG connectivity is able to differentiate all states of consciousness. The association of Phi with EEG connectivity during clinically defined anesthetic states represents a new practical approach to the application of IIT, which may be used to characterize various physiological (sleep), pharmacological (anesthesia), and pathological (coma) states of consciousness in the human brain. PMID- 29503612 TI - Brain Activity Related to the Judgment of Face-Likeness: Correlation between EEG and Face-Like Evaluation. AB - Faces represent important information for social communication, because social information, such as face-color, expression, and gender, is obtained from faces. Therefore, individuals' tend to find faces unconsciously, even in objects. Why is face-likeness perceived in non-face objects? Previous event-related potential (ERP) studies showed that the P1 component (early visual processing), the N170 component (face detection), and the N250 component (personal detection) reflect the neural processing of faces. Inverted faces were reported to enhance the amplitude and delay the latency of P1 and N170. To investigate face-likeness processing in the brain, we explored the face-related components of the ERP through a face-like evaluation task using natural faces, cars, insects, and Arcimboldo paintings presented upright or inverted. We found a significant correlation between the inversion effect index and face-like scores in P1 in both hemispheres and in N170 in the right hemisphere. These results suggest that judgment of face-likeness occurs in a relatively early stage of face processing. PMID- 29503613 TI - Extremely Scalable Spiking Neuronal Network Simulation Code: From Laptops to Exascale Computers. AB - State-of-the-art software tools for neuronal network simulations scale to the largest computing systems available today and enable investigations of large scale networks of up to 10 % of the human cortex at a resolution of individual neurons and synapses. Due to an upper limit on the number of incoming connections of a single neuron, network connectivity becomes extremely sparse at this scale. To manage computational costs, simulation software ultimately targeting the brain scale needs to fully exploit this sparsity. Here we present a two-tier connection infrastructure and a framework for directed communication among compute nodes accounting for the sparsity of brain-scale networks. We demonstrate the feasibility of this approach by implementing the technology in the NEST simulation code and we investigate its performance in different scaling scenarios of typical network simulations. Our results show that the new data structures and communication scheme prepare the simulation kernel for post-petascale high performance computing facilities without sacrificing performance in smaller systems. PMID- 29503614 TI - Increased Degradation Rates in the Components of the Mitochondrial Oxidative Phosphorylation Chain in the Cerebellum of Old Mice. AB - Brain structures differ in the magnitude of age-related neuron loss with the cerebellum being more affected. An underlying cause could be an age-related decline in mitochondrial bioenergetics. Successful aging of mitochondria reflects a balanced turnover of proteins involved in mitochondrial biogenesis and mitophagy. Thus, an imbalance in mitochondrial turnover can contribute to the diminution of cellular function seen during aging. Mitochondrial biogenesis and mitophagy are mediated by a set of proteins including MFN1, MFN2, OPA1, DRP1, FIS1 as well as DMN1l and DNM1, all of which are required for mitochondrial fission. Using N15 labeling, we report that the turnover rates for DMN1l and FIS1 go in opposite directions in the cerebellum of 22-month-old C57BL6j mice as compared to 3-month-old mice. Previous studies have reported decreased turnover rates for the mitochondrial respiratory complexes of aged rodents. In contrast, we found increased turnover rates for mitochondrial proteins of the oxidative phosphorylation chain in the aged mice as compared to young mice. Furthermore, the turnover rate of the components that are most affected by aging -complex III components (ubiquinol cytochrome C oxidoreductase) and complex IV components (cytochrome C oxidase)- was significantly increased in the senescent cerebellum. However, the turnover rates of proteins involved in mitophagy (i.e., the proteasomal and lysosomal degradation of damaged mitochondria) were not significantly altered with age. Overall, our results suggest that an age-related imbalance in the turnover rates of proteins involved in mitochondrial biogenesis and mitophagy (DMN1l, FIS1) in conjunction with an age-related imbalance in the turnover rates of proteins of the complexes III and IV of the electron transfer chain, might impair cerebellar mitochondrial bioenergetics in old mice. PMID- 29503615 TI - Metabolomics Based Profiling of Dexamethasone Side Effects in Rats. AB - Dexamethasone (Dex) is a synthetic glucocorticoid that has anti-inflammatory and immunosuppressant effects and is used in several conditions such as asthma and severe allergy. Patients receiving Dex, either at a high dose or for a long time, might develop several side effects such as hyperglycemia, weight change, or osteoporosis due to its in vivo non-selectivity. Herein, we used liquid chromatography-tandem mass spectrometry-based comprehensive targeted metabolomic profiling as well as radiographic imaging techniques to study the side effects of Dex treatment in rats. The Dex-treated rats suffered from a ~20% reduction in weight gain, hyperglycemia (145 mg/dL), changes in serum lipids, and reduction in total serum alkaline phosphatase (ALP) (~600 IU/L). Also, compared to controls, Dex-treated rats showed a distinctive metabolomics profile. In particular, serum amino acids metabolism showed six-fold reduction in phenylalanine, lysine, and arginine levels and upregulation of tyrosine and hydroxyproline reflecting perturbations in gluconeogenesis and protein catabolism which together lead to weight loss and abnormal bone metabolism. Sorbitol level was markedly elevated secondary to hyperglycemia and reflecting activation of the polyol metabolism pathway causing a decrease in the availability of reducing molecules (glutathione, NADPH, NAD+). Overexpression of succinylacetone (4,6-dioxoheptanoic acid) suggests a novel inhibitory effect of Dex on hepatic fumarylacetoacetate hydrolase. The acylcarnitines, mainly the very long chain species (C12, C14:1, C18:1) were significantly increased after Dex treatment which reflects degradation of the adipose tissue. In conclusion, long-term Dex therapy in rats is associated with a distinctive metabolic profile which correlates with its side effects. Therefore, metabolomics based profiling may predict Dex treatment related side effects and may offer possible novel therapeutic interventions. PMID- 29503617 TI - Endonuclease from Gram-Negative Bacteria Serratia marcescens Is as Effective as Pulmozyme in the Hydrolysis of DNA in Sputum. AB - One of the approaches to effective airway cleansing is the degradation of DNA into smaller fragments. For this purpose Pulmozyme(r) is used with high efficacy because it contains recombinant DNase I as its active component. The aim of the study was to comparatively analyze DNase activity of Pulmozyme(r) and the nuclease from gram-negative bacteria Serratia marcescens, because at optimal conditions the catalytic efficiency of the nuclease is much higher than the efficiency of DNase I. Highly polymerized DNA and purulent-mucous sputum were used as substrates. The examination showed that both S. marcescens nuclease and Pulmozyme(r) hydrolyzed DNA in sputum. Also S. marcescens nuclease was found capable of hydrolyzing DNA in conditions that are standard for Pulmozyme(r) and suitable for its therapeutic application. For manifesting the similar hydrolytic activity the nuclease amount in the assay mixture containing highly polymerized DNA or the sonicated sputum and NaCl together with calcium- or magnesium- cations can be about 10- time lower than that of the recombinant DNase I. In the presence of magnesium cations the DNase activity of both S. marcescens nuclease and Pulmozyme(r) was higher than in the presence of calcium cations. PMID- 29503616 TI - Moringa Genus: A Review of Phytochemistry and Pharmacology. AB - Moringa is a genus of medicinal plants that has been used traditionally to cure wounds and various diseases such as colds and diabetes. In addition, the genus is also consumed as a source of nutrients and widely used for purifying water. The genus consists of 13 species that have been widely cultivated throughout Asia and Africa for their multiple uses. The purpose of this review is to provide updated and categorized information on the traditional uses, phytochemistry, biological activities, and toxicological research of Moringa species in order to explore their therapeutic potential and evaluate future research opportunities. The literature reviewed for this paper was obtained from PubMed, ScienceDirect, and Google Scholar journal papers published from 1983 to March 2017. Moringa species are well-known for their antioxidant, anti-inflammatory, anticancer, and antihyperglycemic activities. Most of their biological activity is caused by their high content of flavonoids, glucosides, and glucosinolates. By documenting the traditional uses and biological activities of Moringa species, we hope to support new research on these plants, especially on those species whose biological properties have not been studied to date. PMID- 29503618 TI - New Perspectives on the Potential Role of Aquaporins (AQPs) in the Physiology of Inflammation. AB - Aquaporins (AQPs) are emerging, in the last few decades, as critical proteins regulating water fluid homeostasis in cells involved in inflammation. AQPs represent a family of ubiquitous membrane channels that regulate osmotically water flux in various tissues and sometimes the transport of small solutes, including glycerol. Extensive data indicate that AQPs, working as water channel proteins, regulate not only cell migration, but also common events essential for inflammatory response. The involvement of AQPs in several inflammatory processes, as demonstrated by their dysregulation both in human and animal diseases, identifies their new role in protection and response to different noxious stimuli, including bacterial infection. This contribution could represent a new key to clarify the dilemma of host-pathogen communications, and opens up new scenarios regarding the investigation of the modulation of specific AQPs, as target for new pharmacological therapies. This review provides updated information on the underlying mechanisms of AQPs in the regulation of inflammatory responses in mammals and discusses the broad spectrum of options that can be tailored for different diseases and their pharmacological treatment. PMID- 29503619 TI - Bactericidal and Bioactive Dental Composites. AB - Aim: Antimicrobial and bioactive restorative materials are needed to develop a bacteria free environment and tight bond with the surrounding tissue, preventing the spread of secondary caries and thus extending the lifetime of dental restorations. The characteristic properties of new dental bioactive and antibacterial composites are presented in this work. The new composites have been microstructurally characterized and both long and short term properties have been studied. Methods: The Ag-doped sol-gel derived bioactive glass (Ag-BG) was incorporated into resin composite in concentrations 5, 10, and 15 wt.%, to fabricate new Ag-doped bioactive and antibacterial dental composites (Ag-BGCOMP). The microstructural properties and elemental analysis of the developed Ag-BGCOMP was observed. The total bond strength (TBS) was measured immediately and after long term of immersion in medium using microtensile testing. The capability of Ag BGCOMPs to form apatite layer on their surface after immersion in Simulated Body Fluid (SBF) as well as the bacteria growth inhibition in a biofilm formed by Streptococcus mutans (S. mutans) were evaluated. Results: Homogeneous distribution of Ag-BG particles into the resin composite was observed microstructurally for all Ag-BGCOMPs. The TBS measurements showed non statistically significant difference between control samples (Ag-BG 0 wt.%) and Ag-BGCOMP specimens. Moreover, the total bond strength between the surrounding tooth tissue and the material of restoration does not present any statistically significant change for all the cases even after 3 months of immersion in the medium. The bioactivity of the Ag-BGCOMPs was also shown by the formation of a calcium-phosphate layer on the surface of the specimens after immersion in SBF. Antibacterial activity was observed for all Ag-BGCOMPs, statistically significant differences were observed between control samples and Ag-BGCOMPs. Accordingly, the number of dead bacteria in the biofilm found to increase significantly with the increase of Ag-BG concentration in the Ag-BGCOMPs. Conclusions: New resin composites with antibacterial and remineralizing properties have been manufactured. Characterization of these materials provides a rationale for future clinical trials to evaluate clinical benefits and outcomes in comparison with currently used dental materials. Significance: The new developed composites could ultimately prevent restoration failure and could advance patients' wellbeing. PMID- 29503621 TI - When Learning Disturbs Memory - Temporal Profile of Retroactive Interference of Learning on Memory Formation. AB - Introduction: Consolidation is defined as the time necessary for memory stabilization after learning. In the present study we focused on effects of interference during the first 12 consolidation minutes after learning. Participants had to learn a set of German - Japanese word pairs in an initial learning task and a different set of German - Japanese word pairs in a subsequent interference task. The interference task started in different experimental conditions at different time points (0, 3, 6, and 9 min) after the learning task and was followed by subsequent cued recall tests. In a control experiment the interference periods were replaced by rest periods without any interference. Results: The interference task decreased memory performance by up to 20%, with negative effects at all interference time points and large variability between participants concerning both the time point and the size of maximal interference. Further, fast learners seem to be more affected by interference than slow learners. Discussion: Our results indicate that the first 12 min after learning are highly important for memory consolidation, without a general pattern concerning the precise time point of maximal interference across individuals. This finding raises doubts about the generalized learning recipes and calls for individuality of learning schedules. PMID- 29503620 TI - Oxidative Stress and Renal Fibrosis: Recent Insights for the Development of Novel Therapeutic Strategies. AB - Chronic kidney disease (CKD) is a significant worldwide healthcare problem. Regardless of the initial injury, renal fibrosis is the common final pathway leading to end stage renal disease. Although the underlying mechanisms are not fully defined, evidence indicates that besides inflammation, oxidative stress plays a crucial role in the etiology of renal fibrosis. Oxidative stress results from an imbalance between the production of free radicals that are often increased by inflammation and mitochondrial dysfunction, and reduced anti-oxidant defenses. Several studies have demonstrated that oxidative stress may occur secondary to activation of transforming growth factor beta1 (TGF-beta1) activity, consistent with its role to increase nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) activity. A number of other oxidative stress-related signal pathways have also been identified, such as nuclear factor erythroid-2 related factor 2 (Nrf2), the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-cGMP dependent protein kinase 1-phosphodiesterase (cGMP-cGK1-PDE) signaling pathway, and the peroxisome proliferator-activated receptor gamma (PPARgamma) pathway. Several antioxidant and renoprotective agents, including cysteamine bitartrate, epoxyeicosatrienoic acids (EETs), and cytoglobin (Cygb) have demonstrated ameliorative effects on renal fibrosis in preclinical or clinical studies. The mechanism of action of many traditional Chinese medicines used to treat renal disorders is based on their antioxidant properties, which could form the basis for new therapeutic approaches. This review focuses on the signaling pathways triggered by oxidative stress that lead to renal fibrosis and provides an update on the development of novel anti-oxidant therapies for CKD. PMID- 29503623 TI - Job Satisfaction, Organizational Commitment and Job Involvement: The Mediating Role of Job Involvement. AB - We conducted an empirical study aimed at identifying and quantifying the relationship between work characteristics, organizational commitment, job satisfaction, job involvement and organizational policies and procedures in the transition economy of Serbia, South Eastern Europe. The study, which included 566 persons, employed by 8 companies, revealed that existing models of work motivation need to be adapted to fit the empirical data, resulting in a revised research model elaborated in the paper. In the proposed model, job involvement partially mediates the effect of job satisfaction on organizational commitment. Job satisfaction in Serbia is affected by work characteristics but, contrary to many studies conducted in developed economies, organizational policies and procedures do not seem significantly affect employee satisfaction. PMID- 29503622 TI - The Influence of Emotional Material on Encoding and Retrieving Intentions: An ERP Study in Younger and Older Adults. AB - Prospective memory is a cognitive process that comprises the encoding and maintenance of an intention until the appropriate moment of its retrieval. It is of highly relevance for an independent everyday life, especially in older adults; however, there is ample evidence that prospective memory declines with increasing age. Because most studies have used neutral stimuli, it is still an open question how emotional factors influence age-related differences in prospective remembering. The aim of the study was to investigate the influence of emotional material on prospective memory encoding, monitoring, maintaining, and retrieval in younger and older adults using behavioral and electrophysiological measures. We tested 24 younger adults (M = 26.4 years) and 20 older adults (M = 68.1 years) using a picture one-back task as ongoing activity with an embedded prospective memory instruction. The experimental task consisted of three sessions. In each session, participants had to encode series of images that represented the prospective memory cues for the consecutive block. The images were either of pleasant, unpleasant, or neutral valence. The pictures used in the ongoing task were likewise of pleasant, unpleasant, or neutral valence. Event-related potentials (ERPs) were recorded to assess the neural correlates of intention encoding, maintenance, and self-initiated retrieval. We did not find age differences between younger and older adults on the behavioral level. However, the ERP results revealed an interesting pattern that suggested for both age groups elevated attentional processing of emotional cues during encoding indicated by an elevated LPP for the emotional cues. Additionally, younger adults showed increased activity for unpleasant cues. During the maintenance phase, both age groups engaged in strategic monitoring especially for pleasant cues, which led to enhanced sustained positivity. During retrieval, older adults showed increased activity of ERP components related to cue detection and retrieval mainly for pleasant cues indicating enhanced relevance for those cues. In conclusion, emotional material may influence prospective remembering in older adults differently than in younger adults by supporting a mixture of top-down and bottom-up controlled processing. The results demonstrated a negativity bias in younger adults and a positivity bias in older adults. PMID- 29503624 TI - Individual Differences in Reward Sensitivity Modulate the Distinctive Effects of Conscious and Unconscious Rewards on Executive Performance. AB - Executive control can be driven by conscious and unconscious monetary cues. This has raised the exciting question regarding the role of conscious and unconscious reward in the regulation of executive control. Similarities and differences have been uncovered between unconscious and conscious processing of monetary rewards. In the present study, we explored whether individual differences associated with reward sensitivity foster these variations on memory-updating-a core component process of executive control. Participants (N = 60) with low, medium, and high reward sensitivity were selected and performed a numerical memory-updating task. At the beginning of each trial, a high (1 euro) or a low (5 cents) reward was presented subliminally (24 ms) or supraliminally (300 ms). Participants earned the reward by responding correctly. Participants with low reward sensitivity performed better for the high reward only in the subliminal condition. For participants with medium reward sensitivity, performance improved with high reward in both subliminal and supraliminal conditions. When participants had high reward sensitivity scores, the effect of reward was stronger in the supraliminal condition than the subliminal condition. These results show that the distinctive effects of conscious and unconscious rewards on executive performance are modulated by individual differences in reward sensitivity. We discuss this finding with reference to models of conscious/unconscious processing of reward stimuli. PMID- 29503625 TI - A Comparison of Change Blindness in Real-World and On-Screen Viewing of Museum Artefacts. AB - Change blindness is a phenomenon of visual perception that occurs when a stimulus undergoes a change without this being noticed by its observer. To date, the effect has been produced by changing images displayed on screen as well as changing people and objects in an individual's environment. In this experiment, we combine these two approaches to directly compare the levels of change blindness produced in real-world vs. on-screen viewing of museum artefacts. In the real-world viewing condition, one group of participants viewed a series of pairs of similar but slightly different artefacts across eye saccades, while in the on-screen viewing condition, a second group of participants viewed the same artefacts across camera pans on video captured from a head-mounted camera worn by the first set of participants. We present three main findings. First, that change blindness does occur in a museum setting when similar ancient artefacts are viewed briefly one after another in both real-world and on-screen viewing conditions. We discuss this finding in relation to the notion that visual perceptual performance may be enhanced within museums. Second, we found that there was no statistically significant difference between the mean levels of change blindness produced in real-world and on-screen viewing conditions (real world 42.62%, on-screen 47.35%, X2 = 1.626, p > 0.05 1 d.f.). We discuss possible implications of these results for understanding change blindness, such as the role of binocular vs. monocular vision and that of head and eye movements, as well as reflecting on the evolution of change detection systems, and the impact of the experimental design itself on our results. Third, we combined the data from both viewing conditions to identify groups of artefacts that were independently associated with high and low levels of change blindness, and show that change detection rates were influenced mainly by bottom-up factors, including the visible area and contrast of changes. Finally, we discuss the limitations of this experiment and look to future directions for research into museum perception, change blindness, real-world and on-screen comparisons, and the role of bottom-up and top-down factors in the perception of change. PMID- 29503626 TI - Does Individual Gambling Behavior Vary across Gambling Venues with Differing Numbers of Terminals? An Empirical Real-World Study using Player Account Data. AB - Research examining gambling behavior via experiments, self-report, and/or observation presents many methodical challenges particularly in relation to objectivity. However, the use of player account-based gambling data provides purely objective data. Based on this real-world data, the primary aim of the present study was to examine gambling behavior in gambling venues with different numbers of gambling terminals (i.e., venues with one terminal; 2-5 terminals; 6 10 terminals; 11-16 terminals). Player account-based gambling data aggregated over a year (2015) amounting to 153,379 observations within 93,034 individual gamblers (males = 74%; mean age = 44.1, SD = 16.4 years) were analyzed. Gambling frequency was highest in venues with 2-5 terminals (54.5%) and lowest in venues with 11-16 terminals (1.6%). Approximately half of the sample (52.5%) gambled in only one venue category, with the majority (81.5%) preferring venues with 2-5 terminals present. Only 0.8% of the sample gambled in all four venue categories. Compared to venues with one terminal, venues with two or more terminals were associated with gamblers placing more bets, and spending more time and money per session. However, gamblers had higher losses (albeit small) in venues with one terminal compared to venues with 2-5 terminals. No differences in net outcome were found between venues with one terminal and those with 6-10 and 11-16 terminals. Overall, the present study demonstrates that in the natural gambling environment, gambling behavior is reinforced in venues with multiple terminals. PMID- 29503628 TI - Editorial: Intrinsic Clocks. PMID- 29503627 TI - False Belief Reasoning in Adults with and without Autistic Spectrum Disorder: Similarities and Differences. AB - A central diagnostic criteria for autism spectrum disorder (ASD) is the qualitative impairment in reciprocal social interaction and a prominent hypotheses that tried to explain this impairment is the Theory of Mind (ToM) deficit hypotheses. On a behavioral level the critical test for having a ToM, the understanding of false beliefs (FB), is often used for testing ToM abilities in individuals with ASD. Investigating the neural underpinnings several neuroimaging studies revealed a network of areas involved in FB reasoning in neurotypical individuals. For ASD individuals the neural correlates of false belief processing are largely unknown. Using functional magnetic resonance imaging and an adapted unexpected transfer task, that makes it possible to distinguish between the computation of diverging beliefs and the selection of a belief-associated response, we investigated a group of adult high-functioning individuals with ASD (N = 15) and an age and IQ matched group of neurotypical adults (NT; N = 15). On the behavioral level we found no group differences. On the neural level, results were two-fold: In the story phase, in which participants had to compute whether the character's belief is congruent or incongruent to their own belief, there were no differences between neurotypical participants and those diagnosed with ASD. But, in the subsequent question phase, participants with ASD showed increased activity in the bilateral anterior prefrontal cortex, the left posterior frontal cortex, the left superior temporal gyrus, and the left temporoparietal area. These results suggest that during the story phase in which the participants processed observable actions the neural correlates do not differ between adult individuals with ASD and NT individuals. But in the question phase in which participants had to infer an unobservable mental state results revealed neural differences between the two groups. Possibly, these subtle neural processing differences may contribute to the fact that adult ASD individuals are able to master explicit false belief tasks but fail to apply their strategies during everyday social interaction. PMID- 29503629 TI - A Score for Risk of Thrombolysis-Associated Hemorrhage Including Pretreatment with Statins. AB - Background: Symptomatic intracranial hemorrhage (sICH) after intravenous thrombolysis with recombinant tissue-plasminogen activator (rt-PA) for acute ischemic stroke is associated with a poor functional outcome. We aimed to develop a score assessing risk of sICH including novel putative predictors-namely, pretreatment with statins and severe renal impairment. Methods: We analyzed our local cohort (Berlin) of patients receiving rt-PA for acute ischemic stroke between 2006 and 2016. Outcome was sICH according to ECASS-III criteria. A multiple regression model identified variables associated with sICH and receiver operating characteristics were calculated for the best discriminatory model for sICH. The model was validated in an independent thrombolysis cohort (Basel). Results: sICH occurred in 53 (4.0%) of 1,336 patients in the derivation cohort. Age, baseline National Institutes of Health Stroke Scale, systolic blood pressure on admission, blood glucose on admission, and prior medication with medium- or high-dose statins were associated with sICH and included into the risk of intracranial hemorrhage score. The validation cohort included 983 patients of whom 33 (3.4%) had a sICH. c-Statistics for sICH was 0.72 (95% CI 0.66-0.79) in the derivation cohort and 0.69 (95% CI 0.60-0.77) in the independent validation cohort. Inclusion of severe renal impairment did not improve the score. Conclusion: We developed a simple score with fair discriminating capability to predict rt-PA-related sICH by adding prior statin use to known prognostic factors of sICH. This score may help clinicians to identify patients with higher risk of sICH requiring intensive monitoring. PMID- 29503630 TI - A Longitudinal Study of a Chinese Man Presenting with Non-Fluent/Agrammatic Variant of Primary Progressive Aphasia. AB - Primary progressive aphasia (PPA) is a neurodegenerative disease characterized by declining language ability. However, the difficulty in defining the central clinical features in its earliest stage and establishing the dynamics of its progression has led to controversy. We report a 71-year-old man with Han language suffering from non-fluent/agrammatic variant of PPA but presenting as typical Alzheimer's disease (AD) and confused with logopenic variant of PPA in its early stage, longitudinally describing his clinical characteristics, neuroanatomical basis, and genetic associations, and exploring the underlying pathology. This case highlights a longitudinal data for reliably discriminating among AD and PPA variants and helps to deepen our understanding of Han language non fluent/agrammatic variant of PPA. PMID- 29503632 TI - Plant Rhizosphere Selection of Plasmodiophorid Lineages from Bulk Soil: The Importance of "Hidden" Diversity. AB - Microbial communities closely associated with the rhizosphere can have strong positive and negative impacts on plant health and growth. We used a group specific amplicon approach to investigate local scale drivers in the diversity and distribution of plasmodiophorids in rhizosphere/root and bulk soil samples from oilseed rape (OSR) and wheat agri-systems. Plasmodiophorids are plant- and stramenopile-associated protists including well known plant pathogens as well as symptomless endobiotic species. We detected 28 plasmodiophorid lineages (OTUs), many of them novel, and showed that plasmodiophorid communities were highly dissimilar and significantly divergent between wheat and OSR rhizospheres and between rhizosphere and bulk soil samples. Bulk soil communities were not significantly different between OSR and wheat systems. Wheat and OSR rhizospheres selected for different plasmodiophorid lineages. An OTU corresponding to Spongospora nasturtii was positively selected in the OSR rhizosphere, as were two genetically distinct OTUs. Two novel lineages related to Sorosphaerula veronicae were significantly associated with wheat rhizosphere samples, indicating unknown plant-protist relationships. We show that group-targeted eDNA approaches to microbial symbiont-host ecology reveal significant novel diversity and enable inference of differential activity and potential interactions between sequence types, as well as their presence. PMID- 29503631 TI - Insulin- like Growth Factor-Binding Protein Action in Bone Tissue: A Key Role for Pregnancy- Associated Plasma Protein-A. AB - The insulin-like growth factor (IGF) axis is required for the differentiation, development, and maintenance of bone tissue. Accordingly, dysregulation of this axis is associated with various skeletal pathologies including growth abnormalities and compromised bone structure. It is becoming increasingly apparent that the action of the IGF axis must be viewed holistically taking into account not just the actions of the growth factors and receptors, but also the influence of soluble high affinity IGF binding proteins (IGFBPs).There is a recognition that IGFBPs exert IGF-dependent and IGF-independent effects in bone and other tissues and that an understanding of the mechanisms of action of IGFBPs and their regulation in the pericellular environment impact critically on tissue physiology. In this respect, a group of IGFBP proteinases (which may be considered as ancillary members of the IGF axis) play a crucial role in regulating IGFBP function. In this model, cleavage of IGFBPs by specific proteinases into fragments with lower affinity for growth factor(s) regulates the partition of IGFs between IGFBPs and cell surface IGF receptors. In this review, we examine the importance of IGFBP function in bone tissue with special emphasis on the role of pregnancy associated plasma protein-A (PAPP-A). We examine the function of PAPP-A primarily as an IGFBP-4 proteinase and present evidence that PAPP-A induced cleavage of IGFBP-4 is potentially a key regulatory step in bone metabolism. We also highlight some recent findings with regard to IGFBP-2 and IGFBP-5 (also PAPP-A substrates) function in bone tissue and briefly discuss the actions of the other three IGFBPs (-1, -3, and -6) in this tissue. Although our main focus will be in bone we will allude to IGFBP activity in other cells and tissues where appropriate. PMID- 29503634 TI - Excision of Nucleopolyhedrovirus Form Transgenic Silkworm Using the CRISPR/Cas9 System. AB - The CRISPR/Cas9-mediated genome engineering has been shown to efficiently suppress infection by disrupting genes of the pathogen. We recently constructed transgenic lines expressing CRISPR/Cas9 and the double sgRNA target Bombyx mori nucleopolyhedrovirus (BmNPV) immediate early-1 (ie-1) gene in the silkworm, respectively, and obtained four transgenic hybrid lines by G1 generation hybridization: Cas9(-)/sgRNA(-), Cas9(+)/sgRNA(-), Cas9(-)/sgRNA(+), and Cas9(+)/sgRNA(+). We demonstrated that the Cas9(+)/sgRNA(+) transgenic lines effectively edited the target site of the BmNPV genome, and large fragment deletion was observed after BmNPV infection. Further antiviral analysis of the Cas9(+)/sgRNA(+) transgenic lines shows that the median lethal dose (LD50) is 1,000-fold higher than the normal lines after inoculation with occlusion bodies. The analysis of economic characters and off-target efficiency of Cas9(+)/sgRNA(+) transgenic hybrid line showed no significant difference compared with the normal lines. Our findings indicate that CRISPR/Cas9-mediated genome engineering more effectively targets the BmNPV genomes and could be utilized as an insect antiviral treatment. PMID- 29503633 TI - Regulation of the Interferon Response by lncRNAs in HCV Infection. AB - The interferon (IFN) response is a critical component of the innate immunity antiviral pathways in mammalians. IFN signaling results in increased expression of cellular factors that block key steps in the viral replication cycle. Many IFN induced antiviral factors act through decreasing viral entry, replication, transcription, translation, packaging and release. However, these effects are also deleterious for the viability of the cell, which necessitates a tight control over the magnitude and duration of the IFN response. This is partially achieved through the IFN-mediated activation of negative regulatory factors that help in termination of the IFN response and return to a normal homeostatic state. Such built-in negative regulatory mechanisms are frequently hijacked by viruses such as the Hepatitis C virus (HCV) to increase viral replication and productive infections. We and others have shown that long non-coding RNAs (lncRNAs) play prominent roles in regulation of the IFN response. Activation of the IFN cascade alters the expression of a large number of lncRNAs, many of which are directly induced by the JAK/STAT pathway and thus, resemble the well-studied protein coding interferon-stimulated genes (ISGs). While only a handful of IFN- and virally induced lncRNAs have been characterized, recent studies have identified several lncRNAs that act as positive or negative regulators of expression of ISGs during the IFN response. A number of such regulatory lncRNAs have multiple ISG targets, while others act on a single neighboring ISG. Another group of studied lncRNAs act further upstream and regulate the expression of IFN genes or factors that sense the presence of viral genome or replication products. The large number of unstudied IFN- and virally induced lncRNAs makes it highly likely that future studies will reveal a much greater share for this class of transcripts in regulation of the antiviral response. In addition to their physiological roles, the expression of such lncRNAs is frequently modulated by virally encoded factors to interfere with the antiviral response and promote viral replication, thus making them ideal targets for therapeutic intervention. PMID- 29503635 TI - Comparative Genomic Analysis of a Clinical Isolate of Klebsiella quasipneumoniae subsp. similipneumoniae, a KPC-2 and OKP-B-6 Beta-Lactamases Producer Harboring Two Drug-Resistance Plasmids from Southeast Brazil. AB - The aim of this study was to unravel the genetic determinants responsible for multidrug (including carbapenems) resistance and virulence in a clinical isolate of Klebsiella quasipneumoniae subsp. similipneumoniae by whole-genome sequencing and comparative analyses. Eighty-three clinical isolates initially identified as carbapenem-resistant K. pneumoniae were collected from nosocomial infections in southeast Brazil. After RAPD screening, the KPC-142 isolate, showing the most divergent DNA pattern, was selected for complete genome sequencing in an Illumina HiSeq 2500 instrument. Reads were assembled into scaffolds, gaps between scaffolds were resolved by in silico gap filling and extensive bioinformatics analyses were performed, using multiple comparative analysis tools and databases. Genome sequencing allowed to correct the classification of the KPC-142 isolate as K. quasipneumoniae subsp. similipneumoniae. To the best of our knowledge this is the first complete genome reported to date of a clinical isolate of this subspecies harboring both class A beta-lactamases KPC-2 and OKP-B-6 from South America. KPC-142 has one 5.2 Mbp chromosome (57.8% G+C) and two plasmids: 190 Kbp pKQPS142a (50.7% G+C) and 11 Kbp pKQPS142b (57.3% G+C). The 3 Kbp region in pKQPS142b containing the blaKPC-2 was found highly similar to that of pKp13d of K. pneumoniae Kp13 isolated in Southern Brazil in 2009, suggesting the horizontal transfer of this resistance gene between different species of Klebsiella. KPC-142 additionally harbors an integrative conjugative element ICEPm1 that could be involved in the mobilization of pKQPS142b and determinants of resistance to other classes of antimicrobials, including aminoglycoside and silver. We present the completely assembled genome sequence of a clinical isolate of K. quasipneumoniae subsp. similipneumoniae, a KPC-2 and OKP-B-6 beta-lactamases producer and discuss the most relevant genomic features of this important resistant pathogen in comparison to several strains belonging to K. quasipneumoniae subsp. similipneumoniae (phylogroup II-B), K. quasipneumoniae subsp. quasipneumoniae (phylogroup II-A), K. pneumoniae (phylogroup I), and K. variicola (phylogroup III). Our study contributes to the description of the characteristics of a novel K. quasipneumoniae subsp. similipneumoniae strain circulating in South America that currently represent a serious potential risk for nosocomial settings. PMID- 29503636 TI - Metagenomic Study Suggests That the Gut Microbiota of the Giant Panda (Ailuropoda melanoleuca) May Not Be Specialized for Fiber Fermentation. AB - Bamboo-eating giant panda (Ailuropoda melanoleuca) is an enigmatic species, which possesses a carnivore-like short and simple gastrointestinal tract (GIT). Despite the remarkable studies on giant panda, its diet adaptability status continues to be a matter of debate. To resolve this puzzle, we investigated the functional potential of the giant panda gut microbiome using shotgun metagenomic sequencing of fecal samples. We also compared our data with similar data from other animal species representing herbivores, carnivores, and omnivores from current and earlier studies. We found that the giant panda hosts a bear-like gut microbiota distinct from those of herbivores indicated by the metabolic potential of the microbiome in the gut of giant pandas and other mammals. Furthermore, the relative abundance of genes involved in cellulose- and hemicellulose-digestion, and enrichment of enzymes associated with pathways of amino acid degradation and biosynthetic reactions in giant pandas echoed a carnivore-like microbiome. Most significantly, the enzyme assay of the giant panda's feces indicated the lowest cellulase and xylanase activity among major herbivores, shown by an in-vitro experimental assay of enzyme activity for cellulose and hemicellulose degradation. All of our results consistently indicate that the giant panda is not specialized to digest cellulose and hemicellulose from its bamboo diet, making the giant panda a good mammalian model to study the unusual link between the gut microbiome and diet. The increased food intake of the giant pandas might be a strategy to compensate for the gut microbiome functions, highlighting a strong need of conservation of the native bamboo forest both in high- and low-altitude ranges to meet the great demand of bamboo diet of giant pandas. PMID- 29503638 TI - A Damaged Oxidative Phosphorylation Mechanism Is Involved in the Antifungal Activity of Citral against Penicillium digitatum. AB - Citral exhibits strong antifungal activity against Penicillium digitatum. In this study, 41 over-expressed and 84 repressed proteins in P. digitatum after 1.0 MUL/mL of citral exposure for 30 min were identified by the iTRAQ technique. The proteins were closely related with oxidative phosphorylation, the TCA cycle and RNA transport. The mitochondrial complex I, complex II, complex III, complex IV and complex V, which are involved in oxidative phosphorylation were drastically affected. Among of them, the activities of mitochondrial complex I and complex IV were apparently suppressed, whereas those of mitochondrial complex II, complex III and complex V were significantly induced. Meanwhile, citral apparently triggered a reduction in the intracellular ATP, the mitochondrial membrane potential (MMP) and glutathione content, in contrast to an increase in the glutathione S-transferase activity and the accumulation of reactive oxygen species (ROS). Addition of exogenous cysteine decreased the antifungal activity. In addition, cysteine maintained the basal ROS level, deferred the decrease of MMP and the membrane damage. These results indicate that citral inhibited the growth of P. digitatum by damaging oxidative phosphorylation and cell membranes through the massive accumulation of ROS. PMID- 29503637 TI - Host and Environmental Factors Affecting the Intestinal Microbiota in Chickens. AB - The initial development of intestinal microbiota in poultry plays an important role in production performance, overall health and resistance against microbial infections. Multiplexed sequencing of 16S ribosomal RNA gene amplicons is often used in studies, such as feed intervention or antimicrobial drug trials, to determine corresponding effects on the composition of intestinal microbiota. However, considerable variation of intestinal microbiota composition has been observed both within and across studies. Such variation may in part be attributed to technical factors, such as sampling procedures, sample storage, DNA extraction, the choice of PCR primers and corresponding region to be sequenced, and the sequencing platforms used. Furthermore, part of this variation in microbiota composition may also be explained by different host characteristics and environmental factors. To facilitate the improvement of design, reproducibility and interpretation of poultry microbiota studies, we have reviewed the literature on confounding factors influencing the observed intestinal microbiota in chickens. First, it has been identified that host related factors, such as age, sex, and breed, have a large effect on intestinal microbiota. The diversity of chicken intestinal microbiota tends to increase most during the first weeks of life, and corresponding colonization patterns seem to differ between layer- and meat-type chickens. Second, it has been found that environmental factors, such as biosecurity level, housing, litter, feed access and climate also have an effect on the composition of the intestinal microbiota. As microbiota studies have to deal with many of these unknown or hidden host and environmental variables, the choice of study designs can have a great impact on study outcomes and interpretation of the data. Providing details on a broad range of host and environmental factors in articles and sequence data repositories is highly recommended. This creates opportunities to combine data from different studies for meta-analysis, which will facilitate scientific breakthroughs toward nutritional and husbandry associated strategies to improve animal health and performance. PMID- 29503639 TI - Comprehensive Molecular Characterization of Escherichia coli Isolates from Urine Samples of Hospitalized Patients in Rio de Janeiro, Brazil. AB - Urinary tract infections (UTIs) are often caused by Escherichia coli. Their increasing resistance to broad-spectrum antibiotics challenges the treatment of UTIs. Whereas, E. coli ST131 is often multidrug resistant (MDR), ST69 remains susceptible to antibiotics such as cephalosporins. Both STs are commonly linked to community and nosocomial infections. E. coli phylogenetic groups B2 and D are associated with virulence and resistance profiles making them more pathogenic. Little is known about the population structure of E. coli isolates obtained from urine samples of hospitalized patients in Brazil. Therefore, we characterized E. coli isolated from urine samples of patients hospitalized at the university and three private hospitals in Rio de Janeiro, using whole genome sequencing. A high prevalence of E. coli ST131 and ST69 was found, but other lineages, namely ST73, ST648, ST405, and ST10 were also detected. Interestingly, isolates could be divided into two groups based on their antibiotic susceptibility. Isolates belonging to ST131, ST648, and ST405 showed a high resistance rate to all antibiotic classes tested, whereas isolates belonging to ST10, ST73, ST69 were in general susceptible to the antibiotics tested. Additionally, most ST69 isolates, normally resistant to aminoglycosides, were susceptible to this antibiotic in our population. The majority of ST131 isolates were ESBL-producing and belonged to serotype O25:H4 and the H30-R subclone. Previous studies showed that this subclone is often associated with more complicated UTIs, most likely due to their high resistance rate to different antibiotic classes. Sequenced isolates could be classified into five phylogenetic groups of which B2, D, and F showed higher resistance rates than groups A and B1. No significant difference for the predicted virulence genes scores was found for isolates belonging to ST131, ST648, ST405, and ST69. In contrast, the phylogenetic groups B2, D and F showed a higher predictive virulence score compared to phylogenetic groups A and B1. In conclusion, despite the diversity of E. coli isolates causing UTIs, clonal groups O25:H4-B2-ST131 H30-R, O1:H6-B2-ST648, and O102:H6-D-ST405 were the most prevalent. The emergence of highly virulent and MDR E. coli in Brazil is of high concern and requires more attention from the health authorities. PMID- 29503640 TI - A Pilin Region Affecting Host Range of the Pseudomonas aeruginosa RNA Phage, PP7. AB - The host range of a phage is determined primarily by phage-receptor interaction. Here, we profiled the host range of an RNA leviphage, PP7 that requires functional type IV pilus (TFP) in order to enter into its host bacterium, Pseudomonas aeruginosa. Out of 25 twitching-proficient P. aeruginosa strains, 4 with group I pilin and 7 with group III pilin displayed PP7-resistance. The remaining 14 possessed group II pilin, which included 10 PP7-sensitive and 4 PP7 resistant strains, suggesting that only the strains with TFP consisted of a subset of group II (hence, group IIa) pilin were susceptible to PP7. The co expression of the PAO1 (group IIa) pilin rendered all the strains susceptible to PP7, with the exception of the 4 strains with group I pilin. Moreover, the expression of PA14 (group III) and PAK (group IIb) pilin in the PAO1 pilA mutant restored the twitching motility but not the PP7-suceptibility. Site-directed and random mutation analyses of PAO1 pilin enabled us to identify a pilin mutant (G96S) that is fully functional but resistant to PP7 infection. This is due to the lack of any phage-receptor interactions, suggesting the structural properties of the beta1-beta2 loop in the variable region 2 of the group II pilin might be involved in PP7 infection. PMID- 29503641 TI - New Insights into the Biosynthesis Pathway of Polyketide Alkaloid Argimycins P in Streptomyces argillaceus. AB - Argimycins P are a recently identified family of polyketide alkaloids encoded by the cryptic gene cluster arp of Streptomyces argillaceus. These compounds contain either a piperideine ring, or a piperidine ring which may be fused to a five membered ring, and a polyene side chain, which is bound in some cases to an N acetylcysteine moiety. The arp cluster consists of 11 genes coding for structural proteins, two for regulatory proteins and one for a hypothetical protein. Herein, we have characterized the post-piperideine ring biosynthesis steps of argimycins P through the generation of mutants in arp genes, the identification and characterization of compounds accumulated by those mutants, and cross-feeding experiments between mutants. Based in these results, a biosynthesis pathway is proposed assigning roles to every arp gene product. The regulation of the arp cluster is also addressed by inactivating/overexpressing the positive SARP-like arpRI and the negative TetR-like arpRII transcriptional regulators and determining the effect on argimycins P production, and through gene expression analyses (reverse transcription PCR and quantitative real-time PCR) of arp genes in regulatory mutants in comparison to the wild type strain. These findings will contribute to deepen the knowledge on the biosynthesis of piperidine-containing polyketides and provide tools that can be used to generate new analogs by genetic engineering and/or biocatalysis. PMID- 29503642 TI - Prevalence and Genetic Basis of Antimicrobial Resistance in Non-aureus Staphylococci Isolated from Canadian Dairy Herds. AB - Emergence and spread of antimicrobial resistance is a major concern for the dairy industry worldwide. Objectives were to determine: (1) phenotypic and genotypic prevalence of drug-specific resistance for 25 species of non-aureus staphylococci, and (2) associations between presence of resistance determinants and antimicrobial resistance. Broth micro-dilution was used to determine resistance profiles for 1,702 isolates from 89 dairy herds. Additionally, 405 isolates were sequenced to screen for resistance determinants. Antimicrobial resistance was clearly species-dependent. Resistance to quinupristin/dalfopristin was common in Staphylococcus gallinarum (prevalence of 98%), whereas S. cohnii and S. arlettae were frequently resistant to erythromycin (prevalence of 63 and 100%, respectively). Prevalence of resistance was 10% against beta-lactams and tetracyclines. In contrast, resistance to antimicrobials critically important for human medicine, namely vancomycin, fluoroquinolones, linezolid and daptomycin, was uncommon (< 1%). Genes encoding multidrug-resistance efflux pumps and resistance-associated residues in deducted amino acid sequences of the folP gene were the most frequent mechanisms of resistance, regardless of species. The estimated prevalence of the mecA gene was 17% for S. epidermidis. Several genes, including blaZ, mecA, fexA, erm, mphC, msrA, and tet were associated with drug specific resistance, whereas other elements were not. There were specific residues in gyrB for all isolates of species intrinsically resistant to novobiocin. This study provided consensus protein sequences of key elements previously associated with resistance for 25 species of non-aureus staphylococci from dairy cattle. These results will be important for evaluating effects of interventions in antimicrobial use in Canadian dairy herds. PMID- 29503643 TI - Multidrug-Resistant Escherichia albertii: Co-occurrence of beta-Lactamase and MCR 1 Encoding Genes. AB - Escherichia albertii is an emerging member of the Enterobacteriaceae causing human and animal enteric infections. Antimicrobial resistance among enteropathogens has been reported to be increasing in the past years. The purpose of this study was to investigate antibiotic resistance and resistance genes in E. albertii isolated from Zigong city, Sichuan province, China. The susceptibility to 21 antimicrobial agents was determined by Kirby-Bauer disk diffusion method. The highest prevalence was tetracycline resistance with a rate of 62.7%, followed by resistance to nalidixic acid and streptomycin with a rate of 56.9 and 51.0%, respectively. All isolates were sensitive or intermediate susceptible to imipenem, meropenem, amoxicillin-clavulanic acid, and levofloxacin. Among 51 E. albertii isolates, 15 were extended-spectrum beta-lactamase-producing as confirmed by the double disk test. The main beta-lactamase gene groups, i.e., blaTEM, blaSHV, and blaCTX-M, were detected in17, 20, and 22 isolates, respectively. Furthermore, four colistin-resistant isolates with minimum inhibitory concentrations of 8 mg/L were identified. The colistin-resistant isolates all harbored mcr-1 and blaCTX-M-55. Genome sequencing showed that E. albertii strain SP140150 carried mcr-1 and blaCTX-M-55 in two different plasmids. This study provided significant information regarding antibiotic resistance profiles and identified the co-occurrence of beta-lactamase and MCR-1 encoding genes in E. albertii isolates. PMID- 29503644 TI - Bacteria-Derived Carbon Dots Inhibit Biofilm Formation of Escherichia coli without Affecting Cell Growth. AB - Biofilms are deleterious in many biomedical and industrial applications and prevention of their formation has been a pressing challenge. Here, carbon dots, CDs-LP that were easily synthesized from the biomass of Lactobacillus plantarum by one-step hydrothermal carbonization, were demonstrated to prevent biofilm formation of E. coli. CDs-LP did not thwart the growth of E. coli, indicating the anti-biofilm effect was not due to the bactericidal effect. Moreover, CDs-LP did not affect the growth of the animal cell AT II, showing low cytotoxicity, good safety and excellent biocompatibility. Therefore, CDs-LP could overcome the cytotoxicity issue found in many current antibiofilm agents. CDs-LP represent a new type of anti-biofilm materials, opening up a novel avenue to the development of biofilm treatment. PMID- 29503645 TI - Autoantibodies in Autoimmune Hepatitis: Can Epitopes Tell Us about the Etiology of the Disease? AB - Autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) are serious autoimmune liver diseases that are characterized by a progressive destruction of the liver parenchyma and/or the hepatic bile ducts and the development of chronic fibrosis. Left untreated autoimmune liver diseases are often life-threatening, and patients require a liver transplantation to survive. Thus, an early and reliable diagnosis is paramount for the initiation of a proper therapy with immunosuppressive and/or anticholelithic drugs. Besides the analysis of liver biopsies and serum markers indicating liver damage, the screening for specific autoantibodies is an indispensable tool for the diagnosis of autoimmune liver diseases. Such liver autoantigen-specific antibodies might be involved in the disease pathogenesis, and their epitope specificity may give some insight into the etiology of the disease. Here, we will mainly focus on the generation and specificity of autoantibodies in AIH patients. In addition, we will review data from animal models that aim toward a better understanding of the origins and pathogenicity of such autoantibodies. PMID- 29503646 TI - Pentose Phosphate Shunt Modulates Reactive Oxygen Species and Nitric Oxide Production Controlling Trypanosoma cruzi in Macrophages. AB - Metabolism provides substrates for reactive oxygen species (ROS) and nitric oxide (NO) generation, which are a part of the macrophage (Mphi) anti-microbial response. Mphis infected with Trypanosoma cruzi (Tc) produce insufficient levels of oxidative species and lower levels of glycolysis compared to classical Mphis. How Mphis fail to elicit a potent ROS/NO response during infection and its link to glycolysis is unknown. Herein, we evaluated for ROS, NO, and cytokine production in the presence of metabolic modulators of glycolysis and the Krebs cycle. Metabolic status was analyzed by Seahorse Flux Analyzer and mass spectrometry and validated by RNAi. Tc infection of RAW264.7 or bone marrow derived Mphis elicited a substantial increase in peroxisome proliferator activated receptor (PPAR)-alpha expression and pro-inflammatory cytokine release, and moderate levels of ROS/NO by 18 h. Interferon (IFN)-gamma addition enhanced the Tc-induced ROS/NO release and shut down mitochondrial respiration to the levels noted in classical Mphis. Inhibition of PPAR-alpha attenuated the ROS/NO response and was insufficient for complete metabolic shift. Deprivation of glucose and inhibition of pyruvate transport showed that Krebs cycle and glycolysis support ROS/NO generation in Tc + IFN-gamma stimulated Mphis. Metabolic profiling and RNAi studies showed that glycolysis-pentose phosphate pathway (PPP) at 6-phosphogluconate dehydrogenase was essential for ROS/NO response and control of parasite replication in Mphi. We conclude that IFN-gamma, but not inhibition of PPAR-alpha, supports metabolic upregulation of glycolytic PPP for eliciting potent ROS/NO response in Tc-infected Mphis. Chemical analogs enhancing the glucose-PPP will be beneficial in controlling Tc replication and dissemination by Mphis. PMID- 29503647 TI - The Host Restriction Factor Interferon-Inducible Transmembrane Protein 3 Inhibits Vaccinia Virus Infection. AB - Interferons (IFNs) establish dynamic host defense mechanisms by inducing various IFN-stimulated genes that encodes many antiviral innate immune effectors. IFN inducible transmembrane (IFITM) proteins have been identified as intrinsic antiviral effectors, which block the entry of a broad spectrum of enveloped RNA viruses by interrupting virus-endosomal fusion. However, antiviral activity of IFITM proteins against mammalian DNA virus has not been demonstrated till date. Here, we sought to investigate the antiviral activities and mechanisms of interferon-inducible transmembrane protein 3 (IFITM3) protein against poxvirus infection. Analysis of expression kinetics of cell endogenous IFITM3 protein indicated that vaccinia virus (VACV) infection suppressed its translation, which was independent of IRF3 phosphorylation triggered by VACV. Although silencing of endogenous IFITM proteins did not affect their baseline antiviral effects in the cell, it has reduced the IFN-alpha-mediated inhibition of VACV infection, and also modulated VACV-induced cell death. Moreover, we discovered that overexpression of IFITM3 significantly restricted VACV infection, replication and proliferation mainly by interfering with virus entry processes prior to the virus nucleocapsid entry into the cytoplasm. Interestingly, IFITM3 overexpression showed an impact on virus binding. Furthermore, IFITM3 interfered with the cytosolic entry of virus through low pH-dependent fashion. Taken together, our findings provide the first evidence of exogenously expressed IFITM3 protein restricting infection of an enveloped DNA virus, thus expanding their antiviral spectrum. This study further explores the complex mechanism and provides novel insights into the interaction between virus infection and host defense. PMID- 29503648 TI - The Rac Activator DOCK2 Mediates Plasma Cell Differentiation and IgG Antibody Production. AB - A hallmark of humoral immune responses is the production of antibodies. This process involves a complex cascade of molecular and cellular interactions, including recognition of specific antigen by the B cell receptor (BCR), which triggers activation of B cells and differentiation into plasma cells (PCs). Although activation of the small GTPase Rac has been implicated in BCR-mediated antigen recognition, its precise role in humoral immunity and the upstream regulator remain elusive. DOCK2 is a Rac-specific guanine nucleotide exchange factor predominantly expressed in hematopoietic cells. We found that BCR-mediated Rac activation was almost completely lost in DOCK2-deficient B cells, resulting in defects in B cell spreading over the target cell-membrane and sustained growth of BCR microclusters at the interface. When wild-type B cells were stimulated in vitro with anti-IgM F(ab')2 antibody in the presence of IL-4 and IL-5, they differentiated efficiently into PCs. However, BCR-mediated PC differentiation was severely impaired in the case of DOCK2-deficient B cells. Similar results were obtained in vivo when DOCK2-deficient B cells expressing a defined BCR specificity were adoptively transferred into mice and challenged with the cognate antigen. In addition, by generating the conditional knockout mice, we found that DOCK2 expression in B-cell lineage is required to mount antigen-specific IgG antibody. These results highlight important role of the DOCK2-Rac axis in PC differentiation and IgG antibody responses. PMID- 29503650 TI - Dried Blood Spots, an Affordable Tool to Collect, Ship, and Sequence gDNA from Patients with an X-Linked Agammaglobulinemia Phenotype Residing in a Developing Country. AB - Background: New sequencing techniques have revolutionized the identification of the molecular basis of primary immunodeficiency disorders (PID) not only by establishing a gene-based diagnosis but also by facilitating defect-specific treatment strategies, improving quality of life and survival, and allowing factual genetic counseling. Because these techniques are generally not available for physicians and their patients residing in developing countries, collaboration with overseas laboratories has been explored as a possible, albeit cumbersome, strategy. To reduce the cost of time and temperature-sensitive shipping, we selected Guthrie cards, developed for newborn screening, to collect dried blood spots (DBS), as a source of DNA that can be shipped by regular mail at minimal cost. Method: Blood was collected and blotted onto the filter paper of Guthrie cards by completely filling three circles. We enrolled 20 male patients with presumptive X-linked agammaglobulinemia (XLA) cared for at the Vietnam National Children's Hospital, their mothers, and several sisters for carrier analysis. DBS were stored at room temperature until ready to be shipped together, using an appropriately sized envelope, to a CLIA-certified laboratory in the US for sequencing. The protocol for Sanger sequencing was modified to account for the reduced quantity of gDNA extracted from DBS. Result: High-quality gDNA could be extracted from every specimen. Bruton tyrosine kinase (BTK) mutations were identified in 17 of 20 patients studied, confirming the diagnosis of XLA in 85% of the study cohort. Type and location of the mutations were similar to those reported in previous reviews. The mean age when XLA was suspected clinically was 4.6 years, similar to that reported by Western countries. Two of 15 mothers, each with an affected boy, had a normal BTK sequence, suggesting gonadal mosaicism. Conclusion: DBS collected on Guthrie cards can be shipped inexpensively by airmail across continents, providing sufficient high-quality gDNA for Sanger sequencing overseas. By using this method of collecting gDNA, we were able to confirm the diagnosis of XLA in 17 of 20 Vietnamese patients with the clinical diagnosis of agammaglobulinemia. PMID- 29503651 TI - Antigen Loading (e.g., Glutamic Acid Decarboxylase 65) of Tolerogenic DCs (tolDCs) Reduces Their Capacity to Prevent Diabetes in the Non-Obese Diabetes (NOD)-Severe Combined Immunodeficiency Model of Adoptive Cotransfer of Diabetes As Well As in NOD Mice. AB - : Tolerogenic DCs (tolDCs) are being researched as a promising intervention strategy also in autoimmune diseases including type 1 diabetes (T1D). T1D is a T cell-mediated, organ-specific disease with several well-defined and rather specific autoantigens, i.e., proinsulin, insulin, glutamic acid decarboxylase 65 (GAD65), that have been used in animal as well as human intervention trials in attempts to achieve a more efficient, specific immunotherapy. In this study, we have tested tolerogenic DCs for their effectiveness to prevent adoptive transfer of diabetes by diabetogenic splenocytes into non-obese diabetes (NOD)-severe combined immunodeficiency (NOD-SCID) recipients. While i.p. application of tolDCs prepared from bone marrow of prediabetic NOD mice by vitamin D2 and dexamethasone significantly reduced diabetes transfer into the NOD-SCID females, this effect was completely abolished when tolDCs were loaded with the mouse recombinant GAD65, but also with a control protein-ovalbumin (OVA). The effect was not dependent on the presence of serum in the tolDC culture. Similar results were observed in NOD mice. Removal of possible bystander antigen-presenting cells within the diabetogenic splenocytes by negative magnetic sorting of T cells did not alter this surprising effect. Tolerogenic DCs loaded with an immunodominant mouse GAD65 peptide also displayed diminished diabetes-preventive effect. Tolerogenic DCs were characterized by surface maturation markers (CD40, CD80, CD86, MHC II) and the lipopolysaccharide stability test. Data from alloreactive T cell proliferation and cytokine induction assays (IFN-gamma) did not reveal the differences observed in the diabetes incidence. Migration of tolDCs, tolDCs-GAD65 and tolDCs-OVA to spleen, mesenteric- and pancreatic lymph nodes displayed similar, mucosal pattern with highest accumulation in pancreatic lymph nodes present up to 9 days after the i.p. APPLICATION: These data document that mechanisms by which tolDCs operate in vivo require much better understanding for improving efficacy of this promising cell therapy, especially in the presence of an antigen, e.g., GAD65. PMID- 29503649 TI - Features of Effective T Cell-Inducing Vaccines against Chronic Viral Infections. AB - For many years, the focus of prophylactic vaccines was to elicit neutralizing antibodies, but it has become increasingly evident that T cell-mediated immunity plays a central role in controlling persistent viral infections such as with human immunodeficiency virus, cytomegalovirus, and hepatitis C virus. Currently, various promising prophylactic vaccines, capable of inducing substantial vaccine specific T cell responses, are investigated in preclinical and clinical studies. There is compelling evidence that protection by T cells is related to the magnitude and breadth of the T cell response, the type and homing properties of the memory T cell subsets, and their cytokine polyfunctionality and metabolic fitness. In this review, we evaluated these key factors that determine the qualitative and quantitative properties of CD4+ and CD8+ T cell responses in the context of chronic viral disease and prophylactic vaccine development. Elucidation of the mechanisms underlying T cell-mediated protection against chronic viral pathogens will facilitate the development of more potent, durable and safe prophylactic T cell-based vaccines. PMID- 29503653 TI - Aerial Images and Convolutional Neural Network for Cotton Bloom Detection. AB - Monitoring flower development can provide useful information for production management, estimating yield and selecting specific genotypes of crops. The main goal of this study was to develop a methodology to detect and count cotton flowers, or blooms, using color images acquired by an unmanned aerial system. The aerial images were collected from two test fields in 4 days. A convolutional neural network (CNN) was designed and trained to detect cotton blooms in raw images, and their 3D locations were calculated using the dense point cloud constructed from the aerial images with the structure from motion method. The quality of the dense point cloud was analyzed and plots with poor quality were excluded from data analysis. A constrained clustering algorithm was developed to register the same bloom detected from different images based on the 3D location of the bloom. The accuracy and incompleteness of the dense point cloud were analyzed because they affected the accuracy of the 3D location of the blooms and thus the accuracy of the bloom registration result. The constrained clustering algorithm was validated using simulated data, showing good efficiency and accuracy. The bloom count from the proposed method was comparable with the number counted manually with an error of -4 to 3 blooms for the field with a single plant per plot. However, more plots were underestimated in the field with multiple plants per plot due to hidden blooms that were not captured by the aerial images. The proposed methodology provides a high-throughput method to continuously monitor the flowering progress of cotton. PMID- 29503652 TI - Therapeutic Potential of Gene-Modified Regulatory T Cells: From Bench to Bedside. AB - Regulatory T cells (Tregs) are an important subset of adaptive immune cells and control immune reactions for maintaining homeostasis. Tregs are generated upon their encounter with self or non-self-antigen and mediate tolerance or suppress aberrant immune responses. A high level of specificity of Tregs to recognize antigen(s) suggested their instrumental potential to treat various inflammatory diseases. This review will first introduce seminal basic research findings in the field of Tregs over the last two decades pertinent to therapeutic approaches in progress. We will then discuss the previous approaches to use Tregs for therapeutic purposes and the more recent development of gene-modification approaches. The suppressive function of Tregs has been studied intensively in clinical settings, including cancer, autoimmunity, and allotransplantation. In cancer, Tregs are often aberrantly increased in their number, and their suppressor function inhibits mounting of effective antitumor immune responses. We will examine potential approaches of using gene-modified Tregs to treat cancer. In autoimmunity and allotransplantation, chronic inflammation due to inherent genetic defects in the immune system or mismatch between organ donor and recipient results in dysfunction of Tregs, leading to inflammatory diseases or rejection, respectively. Since the recognition of antigen is a central part in Treg function and their therapeutic use, the modulation of T cell receptor specificity will be discussed. Finally, we will focus on future novel strategies employing the therapeutic potential of Tregs using gene modification to broaden our perspective. PMID- 29503655 TI - Arbuscular Mycorrhiza Alleviates Restrictions to Substrate Water Flow and Delays Transpiration Limitation to Stronger Drought in Tomato. AB - Arbuscular mycorrhizal fungi (AMF) proliferate in soil pores, on the surface of soil particles and affect soil structure. Although modifications in substrate moisture retention depend on structure and could influence plant water extraction, mycorrhizal impacts on water retention and hydraulic conductivity were rarely quantified. Hence, we asked whether inoculation with AMF affects substrate water retention, water transport properties and at which drought intensity those factors become limiting for plant transpiration. Solanum lycopersicum plants were set up in the glasshouse, inoculated or not with Funneliformis mosseae, and grown for 35 days under ample water supply. After mycorrhizal establishment, we harvested three sets of plants, one before (36 days after inoculation) and the second (day 42) and third (day 47) within a sequential drying episode. Sampling cores were introduced into pots before planting. After harvest, moisture retention and substrate conductivity properties were assessed and water retention and hydraulic conductivity models were fitted. A root water uptake model was adopted in order to identify the critical substrate moisture that induces soil derived transpiration limitation. Neither substrate porosity nor saturated water contents were affected by inoculation, but both declined after substrates dried. Drying also caused a decline in pot water capacity and hydraulic conductivity. Plant available water contents under wet (pF 1.8-4.2) and dry (pF 2.5-4.2) conditions increased in mycorrhizal substrates and were conserved after drying. Substrate hydraulic conductivity was higher in mycorrhizal pots before and during drought exposure. After withholding water from pots, higher substrate drying rates and lower substrate water potentials were found in mycorrhizal substrates. Mycorrhiza neither affected leaf area nor root weight or length. Consistently with higher substrate drying rates, AMF restored the plant hydraulic status, and increased plant transpiration when soil moisture declined. The water potential at the root surface and the resistance to water flow in the rhizosphere were restored in mycorrhizal pots although the bulk substrate dried more. Finally, substrates colonized by AMF can be more desiccated before substrate water flux quantitatively limits transpiration. This is most pronounced under high transpiration demands and complies with a difference of over 1,000 hPa in substrate water potential. PMID- 29503654 TI - Potentials, Challenges, and Genetic and Genomic Resources for Sugarcane Biomass Improvement. AB - Lignocellulosic biomass has become an emerging feedstock for second-generation bioethanol production. Sugarcane (Saccharum spp. hybrids), a very efficient perennial C4 plant with a high polyploid level and complex genome, is considered a top-notch candidate for biomass production due to its salient features viz. fast growth rate and abilities for high tillering, ratooning, and photosynthesis. Energy cane, an ideal type of sugarcane, has been bred specifically as a biomass crop. In this review, we described (1) biomass potentials of sugarcane and its underlying genetics, (2) challenges associated with biomass improvement such as large and complex genome, narrow gene pool in existing commercial cultivars, long breeding cycle, and non-synchronous flowering, (3) available genetic resources such as germplasm resources, and genomic and cell wall-related databases that facilitate biomass improvement, and (4) mining candidate genes controlling biomass in genomic databases. We extensively reviewed databases for biomass related genes and their usefulness in biofuel generation. This review provides valuable resources for sugarcane breeders, geneticists, and broad scientific communities involved in bioenergy production. PMID- 29503656 TI - Visualization of the Nucleolus Using Ethynyl Uridine. AB - Thanks to recent innovative methodologies, key cellular processes such as replication or transcription can be visualized directly in situ in intact tissues. Many studies use so-called click iT chemistry where nascent DNA can be tracked by 5-ethynyl-2'-deoxyuridine (EdU), and nascent RNA by 5-ethynyl uridine (EU). While the labeling of replicating DNA by EdU has already been well established and further exploited in plants, the use of EU to reveal nascent RNA has not been developed to such an extent. In this article, we present a protocol for labeling of nucleolar RNA transcripts using EU and show that EU effectively highlights the nucleolus. The method is advantageous, because the need to prepare transgenic plants expressing fluorescently tagged nucleolar components when the nucleolus has to be visualized can be avoided. PMID- 29503657 TI - Arabidopsis EMB1990 Encoding a Plastid-Targeted YlmG Protein Is Required for Chloroplast Biogenesis and Embryo Development. AB - In higher plants, embryo development originated from fertilized egg cell is the first step of the life cycle. The chloroplast participates in many essential metabolic pathways, and its function is highly associated with embryo development. However, the mechanisms and relevant genetic components by which the chloroplast functions in embryogenesis are largely uncharacterized. In this paper, we describe the Arabidopsis EMB1990 gene, encoding a plastid-targeted YlmG protein which is required for chloroplast biogenesis and embryo development. Loss of the EMB1990/YLMG1-1 resulted in albino seeds containing abortive embryos, and the morphological development of homozygous emb1990 embryos was disrupted after the globular stage. Our results showed that EMB1990/YLMG1-1 was expressed in the primordia and adaxial region of cotyledon during embryogenesis, and the encoded protein was targeted to the chloroplast. TEM observation of cellular ultrastructure showed that chloroplast biogenesis was impaired in emb1990 embryo cells. Expression of certain plastid genes was also affected in the loss-of function mutants, including genes encoding core protein complex subunits located in the thylakoid membrane. Moreover, the tissue-specific genes of embryo development were misexpressed in emb1990 mutant, including genes known to delineate cell fate decisions in the SAM (shoot apical meristem), cotyledon and hypophysis. Taken together, we propose that the nuclear-encoded YLMG1-1 is targeted to the chloroplast and required for normal plastid gene expression. Hence, YLMG1-1 plays a critical role in Arabidopsis embryogenesis through participating in chloroplast biogenesis. PMID- 29503659 TI - Composite Transport Model and Water and Solute Transport across Plant Roots: An Update. AB - The present review examines recent experimental findings in root transport phenomena in terms of the composite transport model (CTM). It has been a well accepted conceptual model to explain the complex water and solute flows across the root that has been related to the composite anatomical structure. There are three parallel pathways involved in the transport of water and solutes in roots - apoplast, symplast, and transcellular paths. The role of aquaporins (AQPs), which facilitate water flows through the transcellular path, and root apoplast is examined in terms of the CTM. The contribution of the plasma membrane bound AQPs for the overall water transport in the whole plant level was varying depending on the plant species, age of roots with varying developmental stages of apoplastic barriers, and driving forces (hydrostatic vs. osmotic). Many studies have demonstrated that the apoplastic barriers, such as Casparian bands in the primary anticlinal walls and suberin lamellae in the secondary cell walls, in the endo- and exodermis are not perfect barriers and unable to completely block the transport of water and some solute transport into the stele. Recent research on water and solute transport of roots with and without exodermis triggered the importance of the extension of conventional CTM adding resistances that arrange in series (epidermis, exodermis, mid-cortex, endodermis, and pericycle). The extension of the model may answer current questions about the applicability of CTM for composite water and solute transport of roots that contain complex anatomical structures with heterogeneous cell layers. PMID- 29503658 TI - Contribution of NtZIP1-Like to the Regulation of Zn Homeostasis. AB - Tobacco has frequently been suggested as a candidate plant species for use in phytoremediation of metal contaminated soil but knowledge on the regulation of its metal-homeostasis is still in the infancy. To identify new tobacco metal transport genes that are involved in Zn homeostasis a bioinformatics study using the tobacco genome information together with expression analysis was performed. Ten new tobacco metal transport genes from the ZIP, NRAMP, MTP, and MRP/ABCC families were identified with expression levels in leaves that were modified by exposure to Zn excess. Following exposure to high Zn there was upregulation of NtZIP11-like, NtNRAMP3, three isoforms of NtMTP2, three MRP/ABCC genes (NtMRP5 like, NtMRP10-like, and NtMRP14 like) and downregulation of NtZIP1-like and NtZIP4. This suggests their involvement in several processes governing the response to Zn-related stress and in the efficiency of Zn accumulation (uptake, sequestration, and redistribution). Further detailed analysis of NtZIP1-like provided evidence that it is localized at the plasma membrane and is involved in Zn but not Fe and Cd transport. NtZIP1-like is expressed in the roots and shoots, and is regulated developmentally and in a tissue-specific manner. It is highly upregulated by Zn deficiency in the leaves and the root basal region but not in the root apical zone (region of maturation and absorption containing root hairs). Thus NtZIP1-like is unlikely to be responsible for Zn uptake by the root apical region but rather in the uptake by root cells within the already mature basal zone. It is downregulated by Zn excess suggesting it is involved in a mechanism to protect the root and leaf cells from accumulating excess Zn. PMID- 29503660 TI - Correlations between Risk Factors for Breast Cancer and Genetic Instability in Cancer Patients-A Clinical Perspective Study. AB - Molecular epidemiological studies have identified several risk factors linking to the genes and external factors in the pathogenesis of breast cancer. In this sense, genetic instability caused by DNA damage and DNA repair inefficiencies are important molecular events for the diagnosis and prognosis of therapies. Therefore, the objective of this study was to analyze correlation between sociocultural, occupational, and lifestyle risk factors with levels of genetic instability in non-neoplastic cells of breast cancer patients. Total 150 individuals were included in the study that included 50 breast cancer patients submitted to chemotherapy (QT), 50 breast cancer patients submitted to radiotherapy (RT), and 50 healthy women without any cancer. Cytogenetic biomarkers for apoptosis and DNA damage were evaluated in samples of buccal epithelial and peripheral blood cells through micronuclei and comet assay tests. Elder age patients (61-80 years) had higher levels of apoptosis (catriolysis by karyolysis) and DNA damage at the diagnosis (baseline damage) with increased cell damage during QT and especially during RT. We also reported the increased frequencies of cytogenetic biomarkers in patients who were exposed to ionizing radiation as well as for alcoholism and smoking. QT and RT induced high levels of fragmentation (karyorrhexis) and nuclear dissolution (karyolysis) and DNA damage. Correlations were observed between age and karyorrhexis at diagnosis; smoking and karyolysis during RT; and radiation and karyolysis during QT. These correlations indicate that risk factors may also influence the genetic instability in non neoplastic cells caused to the patients during cancer therapies. PMID- 29503662 TI - Gene Expression Meta-Analysis of Seven Candidate Gene Sets for Diabetes Traits Following a GWAS Pathway Study. AB - Seven gene sets were significantly enriched for SNP associations with diabetes, and considered as potential diabetes pathways in a previous meta-analysis of diabetes GWAS. This study aims to examine if these gene sets also have expression associations with diabetes. The analysis was conducted using pooled data from 23 diabetes gene expression studies. Gene associations were examined using linear modeling with an empirical Bayes approach, and pathway associations were investigated by testing enrichment for significant genes. Meta-analyses were performed to investigate gene and pathway associations in all studies and tissue types. The analysis showed that six gene sets and three member genes of ACADSB, RASSF2, and KLF12 had significant associations with diabetes traits. The findings suggest that these gene sets are related to diabetes regulation, and their functions tend to be tissue non-specific. PMID- 29503663 TI - Fast dictionary learning from incomplete data. AB - This paper extends the recently proposed and theoretically justified iterative thresholding and K residual means (ITKrM) algorithm to learning dictionaries from incomplete/masked training data (ITKrMM). It further adapts the algorithm to the presence of a low-rank component in the data and provides a strategy for recovering this low-rank component again from incomplete data. Several synthetic experiments show the advantages of incorporating information about the corruption into the algorithm. Further experiments on image data confirm the importance of considering a low-rank component in the data and show that the algorithm compares favourably to its closest dictionary learning counterparts, wKSVD and BPFA, either in terms of computational complexity or in terms of consistency between the dictionaries learned from corrupted and uncorrupted data. To further confirm the appropriateness of the learned dictionaries, we explore an application to sparsity-based image inpainting. There the ITKrMM dictionaries show a similar performance to other learned dictionaries like wKSVD and BPFA and a superior performance to other algorithms based on pre-defined/analytic dictionaries. PMID- 29503664 TI - Computable performance guarantees for compressed sensing matrices. AB - The null space condition for l1 minimization in compressed sensing is a necessary and sufficient condition on the sensing matrices under which a sparse signal can be uniquely recovered from the observation data via l1 minimization. However, verifying the null space condition is known to be computationally challenging. Most of the existing methods can provide only upper and lower bounds on the proportion parameter that characterizes the null space condition. In this paper, we propose new polynomial-time algorithms to establish upper bounds of the proportion parameter. We leverage on these techniques to find upper bounds and further develop a new procedure-tree search algorithm-that is able to precisely and quickly verify the null space condition. Numerical experiments show that the execution speed and accuracy of the results obtained from our methods far exceed those of the previous methods which rely on linear programming (LP) relaxation and semidefinite programming (SDP). PMID- 29503665 TI - The diversity of human RNA viruses. AB - We still cannot answer the very basic question "how many kinds of RNA viruses are there?" even for those that infect humans. It is often suggested that there remains a large number of viruses in humans that we have not yet discovered or recognised, and that there is a much larger and rapidly evolving pool of potential new viruses in mammalian and avian reservoirs that humans are continually being exposed to. However, a careful examination of discovery rates of new human RNA virus species, genera and families challenges this view, raising the possibility that the diversity is much more limited. Moreover, there is some evidence that the cast of human viruses is dynamic, with existing viruses disappearing (at least from humans) and new viruses appearing (perhaps evolving) over timescales of decades. Most of these new viruses, however, remain rare; only a small (but highly significant) minority are capable of spreading extensively through human populations. PMID- 29503661 TI - Identification of Shared Molecular Signatures Indicate the Susceptibility of Endometriosis to Multiple Sclerosis. AB - Women with endometriosis (EMS) appear to be at a higher risk of developing other autoimmune diseases predominantly multiple sclerosis (MS). Though EMS and MS are evidently diverse in their phenotype, they are linked by a common autoimmune condition or immunodeficiency which could play a role in the expansion of endometriosis and possibly increase the risk of developing MS in women with EMS. However, the common molecular links connecting EMS with MS are still unclear. We conducted a meta-analysis of microarray experiments focused on EMS and MS with their respective controls. The GEO2R web application discovered a total of 711 and 1516 genes that are differentially expressed across the experimental conditions in EMS and MS, respectively with 129 shared DEGs between them. The functional enrichment analysis of DEGs predicts the shared gene expression signatures as well as the overlapping biological processes likely to infer the co occurrence of EMS with MS. Network based meta-analysis unveiled six interaction networks/crosstalks through overlapping edges between commonly dysregulated pathways of EMS and MS. The PTPN1, ERBB3, and CDH1 were observed to be the highly ranked hub genes connected with disease-related genes of both EMS and MS. Androgen receptor (AR) and nuclear factor-kB p65 (RelA) were observed to be the most enriched transcription factor in the upstream of shared down-regulated and up-regulated genes, respectively. The two disease sample sets compared through crosstalk interactions between shared pathways revealed commonly up- and down regulated expressions of 10 immunomodulatory proteins as probable linkers between EMS and MS. This study pinpoints the number of shared genes, pathways, protein kinases, and upstream regulators that may help in the development of biomarkers for diagnosis of MS and endometriosis at the same time through improved understanding of shared molecular signatures and crosstalk. PMID- 29503666 TI - Continuity and Stability in Development. AB - Developmental science is centrally concerned with both consistency and change in characteristics through time. Consistency and change in development are tracked by group mean level continuity and individual order stability. Group mean level and individual order consistency and change are both developmentally informative and can co-exist conceptually and empirically as the two are partially orthogonal perspectives on development. Continuity and stability are broadly applicable to characteristics of the individual, dyad, and environment. Significantly, absent the distinctions we draw between mean level continuity and individual order stability, researchers who use the terms willy-nilly leave their readers in the dark as to which key feature of development is meant. In this article, we distinguish the two types of consistency and change, their measurement, importance, moderation, and implications. PMID- 29503667 TI - Cationic branched polymers for cellular delivery of negatively charged cargo. AB - Receptor-independent cellular uptake of small molecule therapeutics is limited by their physical interaction with the negatively charged surface of cellular membranes. Passive diffusion through the hydrophobic membrane bilayer follows this process. Unless specific carriers exist in the biological membrane, such interactions limit therapeutics to those that are hydrophobic with modest positive charge at physiological pH. Small negatively charged molecules are therefore not efficient as therapeutics. To enable delivery of such molecules into eukaryotic cells, cationic branched polymers with tetraalkylammonium pendant groups were synthesized by copolymerization of a functional monomer (glycidyl methacrylate) with degradable and non-degradable divinyl crosslinkers in the presence of an efficient chain transfer agent, CBr4, followed by reaction of the multiple pendant epoxide groups and most of the alkyl bromide chain ends with amines. Cationic branched polymers with covalently attached fluorescent labels entered human cancerous and non-cancerous cells. The non-labeled analogues were able to carry anionic cargo (carboxyfluorescein) into the cells, while no uptake was observed in the absence of the cationic carriers. Most of the polymers were not significantly toxic at the concentrations used. This pilot study showed that cellular uptake of anionic small molecules can be promoted even in the absence of natural uptake mechanisms. PMID- 29503668 TI - Recent strategies of increasing metal tolerance and phytoremediation potential using genetic transformation of plants. AB - Avoidance and reduction of soil contamination with heavy metals is one of the most serious global challenges. Nowadays, science offers us new opportunities of utilizing plants to extract toxic elements from the soil by means of phytoremediation. Plant abilities to uptake, translocate, and transform heavy metals, as well as to limit their toxicity, may be significantly enhanced via genetic engineering. This paper provides a comprehensive review of recent strategies aimed at the improvement of plant phytoremediation potential using plant transformation and employing current achievements in nuclear and cytoplasmic genome transformation. Strategies for obtaining plants suitable for effective soil clean-up and tolerant to excessive concentrations of heavy metals are critically assessed. Promising directions in genetic manipulations, such as gene silencing and cis- and intragenesis, are also discussed. Moreover, the ways of overcoming disadvantages of phytoremediation using genetic transformation approachare proposed. The knowledge gathered here could be useful for designing new research aimed at biotechnological improvement of phytoremediation efficiency. PMID- 29503669 TI - Cochlear implant - state of the art. AB - Cochlear implants are the treatment of choice for auditory rehabilitation of patients with sensory deafness. They restore the missing function of inner hair cells by transforming the acoustic signal into electrical stimuli for activation of auditory nerve fibers. Due to the very fast technology development, cochlear implants provide open-set speech understanding in the majority of patients including the use of the telephone. Children can achieve a near to normal speech and language development provided their deafness is detected early after onset and implantation is performed quickly thereafter. The diagnostic procedure as well as the surgical technique have been standardized and can be adapted to the individual anatomical and physiological needs both in children and adults. Special cases such as cochlear obliteration might require special measures and re implantation, which can be done in most cases in a straight forward way. Technology upgrades count for better performance. Future developments will focus on better electrode-nerve interfaces by improving electrode technology. An increased number of electrical contacts as well as the biological treatment with regeneration of the dendrites growing onto the electrode will increase the number of electrical channels. This will give room for improved speech coding strategies in order to create the bionic ear, i.e. to restore the process of natural hearing by means of technology. The robot-assisted surgery will allow for high precision surgery and reliable hearing preservation. Biological therapies will support the bionic ear. Methods are bio-hybrid electrodes, which are coded by stem cells transplanted into the inner ear to enhance auto-production of neurotrophins. Local drug delivery will focus on suppression of trauma reaction and local regeneration. Gene therapy by nanoparticles will hopefully lead to the preservation of residual hearing in patients being affected by genetic hearing loss. Overall the cochlear implant is a very powerful tool to rehabilitate patients with sensory deafness. More than 1 million of candidates in Germany today could benefit from this high technology auditory implant. Only 50,000 are implanted so far. In the future, the procedure can be done under local anesthesia, will be minimally invasive and straight forward. Hearing preservation will be routine. PMID- 29503671 TI - Childhood Bullying, Paranoid Thinking and the Misappraisal of Social Threat: Trouble at School. AB - Experiences of bullying predict the development of paranoia in school-age adolescents. While many instances of psychotic phenomena are transitory, maintained victimization can lead to increasingly distressing paranoid thinking. Furthermore, paranoid thinkers perceive threat in neutral social stimuli and are vigilant for environmental risk. The present paper investigated the association between different forms of bullying and paranoid thinking, and the extent to which school-age paranoid thinkers overestimate threat in interpersonal situations. Two hundred and thirty participants, aged between eleven and fourteen, were recruited from one secondary school in the UK. Participants completed a series of questionnaires hosted on the Bristol Online Survey tool. All data were collected in a classroom setting in quiet and standardized conditions. A significant and positive relationship was found between experiences of bullying and paranoid thinking: greater severity of bullying predicted more distressing paranoid thinking. Further, paranoid thinking mediated the relationship between bullying and overestimation of threat in neutral social stimuli. Exposure to bullying is associated with distressing paranoid thinking and subsequent misappraisal of threat. As paranoid thinkers experience real and overestimated threat, the phenomena may persist. PMID- 29503673 TI - Superconformal Bottom-Up Nickel Deposition in High Aspect Ratio Through Silicon Vias. AB - This work demonstrates void-free nickel filling of 56 MUm tall, annular Through Silicon Vias (TSVs) using a mechanism that couples suppression breakdown and surface topography to achieve controlled superconformal, void-free deposition. The chemistry, a Watts electrolyte containing a dilute suppressing additive, and processes are fully detailed. The impact of deposition potential and additive concentration on the filling of the patterned features is presented. Voltammetric measurements on planar substrates, including the impact of rotation rate and suppressor concentration on the rate of metal deposition and potential of suppression breakdown, are used to quantify the interplay between metal deposition and suppressor adsorption. The derived kinetics are then used to quantitatively predict the observed bottom-up filling in the TSVs using the S shaped negative differential resistance (S-NDR) mechanism for superconformal deposition; the predictions capture the experimental observations. This work extends understanding and application of the additive-derived S-NDR mechanism developed with non-ferrous metals. PMID- 29503670 TI - Diagnostics and therapy of sudden hearing loss. AB - This article reviews recent aspects of diagnostics, differential diagnostics, and evidence in systemic and local therapy of idiopathic sudden sensorineural hearing loss (ISSHL). Since a number of disorders can be accompanied by sudden hearing loss, a meaningful and targeted diagnostic strategy is of utmost importance. An important differential diagnosis of sudden hearing loss are intralabyrinthine schwannomas (ILS). The incidence of ILS is probably significantly underestimated. This may be due to the lack of awareness or lack of explicit search for an intralabyrinthine tumor on MRI or an inappropriate MRI technique for the evaluation of sudden hearing loss ("head MRI" instead of "temporal bone MRI" with too high slice thicknesses). Therefore, the request to the radiologist should specifically include the question for (or exclusion of) an ILS. With special MRI techniques, it is possibly today to visualize an endolymphatic hydrops. The evidence in the therapy of ISSHL is - with respect to the quality and not quantity of studies - unsatisfying. The value of systemically (low dose) or intratympanically applied corticosteroids in the primary treatment of ISSHL is still unclear. In order to investigate the efficacy and safety of high dose corticosteroids as primary therapy for ISSHL, a national, multicenter, three armed, randomized, triple-blind controlled clinical trial is currently performed in Germany (http://hodokort-studie.hno.org/). After insufficient recovery of the threshold with systemic therapy of ISSHL, intratympanic corticosteroid therapy appears to be associated with a significantly higher chance of an improved hearing threshold than no therapy or placebo. Both, hearing gain and final hearing threshold, however, appear to be independent from the onset of secondary therapy. Based on currently available data from clinical studies, no recommendation can be made with respect to the type of corticosteroid and specifics of the intratympanic application protocol. PMID- 29503672 TI - Pd-catalyzed versus uncatalyzed, PhI(OAc)2-mediated cyclization reactions of N6 ([1,1'-biaryl]-2-yl)adenine nucleosides. AB - In this work we have assessed reactions of N6-([1,1'-biaryl]-2-yl)adenine nucleosides with Pd(OAc)2 and PhI(OAc)2, via a PdII/PdIV redox cycle. The substrates are readily obtained by Pd/Xantphos-catalyzed reaction of adenine nucleosides with 2-bromo-1,1'-biaryls. In PhMe, the N6-biarylyl nucleosides gave C6-carbazolyl nucleoside analogues by C-N bond formation with the exocyclic N6 nitrogen atom. In the solvent screening for the Pd-catalyzed reactions, an uncatalyzed process was found to be operational. It was observed that the carbazolyl products could also be obtained in the absence of a metal catalyst by reaction with PhI(OAc)2 in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP). Thus, under Pd catalysis and in HFIP, reactions proceed to provide carbazolyl nucleoside analogues, with some differences. If reactions of N6-biarylyl nucleoside substrates were conducted in MeCN, formation of aryl benzimidazopurinyl nucleoside derivatives was observed in many cases by C-N bond formation with the N1 ring nitrogen atom of the purine (carbazole and benzimidazole isomers are readily separated by chromatography). Whereas PdII/PdIV redox is responsible for carbazole formation under the metal-catalyzed conditions, in HFIP and MeCN radical cations and/or nitrenium ions can be intermediates. An extensive set of radical inhibition experiments was conducted and the data are presented. PMID- 29503674 TI - Confined Electrochemical Deposition in Sub-15 nm Space for Preparing Nanogap Electrodes. AB - Electrode gaps with nanoscale separation offer great promise for molecular electronics and biosensing. Previous electrochemical methods to prepare nanogaps by depositing metal on pre-defined electrode tips have suffered from lack of control in the thickness direction and reproducible control of gap size. Here we report a new process wherein the electrochemical deposition is confined by a cavity to produce a nanogap with thickness smaller even than that of the initial electrodes. Using this process, we demonstrate controlled and reversible electrochemical deposition in a sub-15 nm space, to produce a nano-fluidic channel with finely tunable nanogap control electrodes for biosensing applications. PMID- 29503675 TI - Endoscopic Spine Surgery: Current State of Art and the Future Perspective. PMID- 29503676 TI - Comparison of the Pullout Strength of Different Pedicle Screw Designs and Augmentation Techniques in an Osteoporotic Bone Model. AB - Study Design: Mechanical study. Purpose: To compare the pullout strength of different screw designs and augmentation techniques in an osteoporotic bone model. Overview of Literature: Adequate bone screw pullout strength is a common problem among osteoporotic patients. Various screw designs and augmentation techniques have been developed to improve the biomechanical characteristics of the bone-screw interface. Methods: Polyurethane blocks were used to mimic human osteoporotic cancellous bone, and six different screw designs were tested. Five standard and expandable screws without augmentation, eight expandable screws with polymethylmethacrylate (PMMA) or calcium phosphate augmentation, and distal cannulated screws with PMMA and calcium phosphate augmentation were tested. Mechanical tests were performed on 10 unused new screws of each group. Screws with or without augmentation were inserted in a block that was held in a fixture frame, and a longitudinal extraction force was applied to the screw head at a loading rate of 5 mm/min. Maximum load was recorded in a load displacement curve. Results: The peak pullout force of all tested screws with or without augmentation was significantly greater than that of the standard pedicle screw. The greatest pullout force was observed with 40-mm expandable pedicle screws with four fins and PMMA augmentation. Augmented distal cannulated screws did not have a greater peak pullout force than nonaugmented expandable screws. PMMA augmentation provided a greater peak pullout force than calcium phosphate augmentation. Conclusions: Expandable pedicle screws had greater peak pullout forces than standard pedicle screws and had the advantage of augmentation with either PMMA or calcium phosphate cement. Although calcium phosphate cement is biodegradable, osteoconductive, and nonexothermic, PMMA provided a significantly greater peak pullout force. PMMA-augmented expandable 40-mm four-fin pedicle screws had the greatest peak pullout force. PMID- 29503677 TI - An Ovariectomy-Induced Rabbit Osteoporotic Model: A New Perspective. AB - Study Design: Experimental Animal Model. Purpose: The aim of our study was to validate a pure bilateral ovariectomy (OVX) female New Zealand white rabbit model of postmenopausal osteoporosis utilizing animal-sparing in vivo techniques for evaluating bone mineral density (BMD). We also sought to demonstrate that bilateral OVX in female New Zealand white rabbits can produce diminished BMD in the spinal column and simulate osteoporosis, without the need for adjuvant chemotherapeutic agents (i.e., no additional glucocorticosteroids or other drugs were used for stimulating accelerated BMD loss), which can be assessed by in vivo BMD testing. Overview of Literature: Multiple animal models of postmenopausal osteoporosis have been described. Rat ovariectomy models have been successful, but are limited by rats' inability to achieve true skeletal maturity and a slight morphology that limits surgical instrumentation. Rabbit models have been described which do not have these limitations, but previous models have relied on adjunctive steroid therapy to achieve osteoporosis and have required animal sacrifice for bone mineral density assessment. Methods: Thirty-six skeletally mature female rabbits underwent bilateral OVX. BMD was measured using dual-energy X-ray absorptiometry on the metaphysis of the proximal tibia and distal femur, at baseline and 17 weeks postoperatively. Results: Mean BMD values were significantly reduced by 21.9% (p<0.05) in the proximal tibia and 11.9% (p<0.001) in the distal femur at 17 weeks. Conclusions: This study is the first to demonstrate a significant bone loss within four months of pure OVX in rabbits using animal-sparing validation techniques. We believe that this OVX model is safe, reproducible, and can be employed to longitudinally evaluate the effect of anti-osteoporosis therapeutics and surgical interventions. PMID- 29503678 TI - Computed Tomography- and Radiography-Based Morphometric Analysis of the Lateral Mass of the Subaxial Cervical Spine in the Indian Population. AB - Study Design: This was a double-blinded cross-sectional study, which obtained no financial support for the research. Purpose: To obtain a detailed morphometry of the lateral mass of the subaxial cervical spine. Overview of Literature: The literature offers little data on the dimensions of the lateral mass of the subaxial cervical spine. Methods: We assessed axial, sagittal, and coronal computed tomography (CT) cuts and anteroposterior and lateral X-rays of the lateral mass of the subaxial cervical spine of 104 patients (2,080 lateral masses) who presented to a tertiary care public hospital (King Edward Memorial Hospital, Mumbai) in a metropolitan city in India. Results: For a majority of the parameters, males and females significantly differed at all levels (p<0.05). Females consistently required higher (p<0.05) minimum lateral angulation and lateral angulation. While the minimum lateral angulation followed the order of C560 years. On axial T2-weighted imaging at the mid-disc level, LF thickness was measured perpendicular to the lamina border, either at half the length of LF or at maximum thickness, whichever was greater. Results: We found that LF thickness does not increase significantly with increasing age and there was no significant disparity in LF thickness between the sides and sexes. We also found that there was a significant increase in LF thickness at the T10-T11 level (mean value, 3.27+/ 0.94 mm). Conclusions: LF thickness does not appear to have any side/sex dominance. LF thickening has a predominant tendency to occur specifically at the T10-T11 level. This may be due to maximum tensile strength and mobility at this level. Because there is an increased tendency for LF thickening at the T10-T11 level, this may be used as a reference point for counting the vertebral levels. PMID- 29503682 TI - Minimally Invasive Transforaminal Lumbar Interbody Fusion: An Attractive Option for Select Failed Backs. AB - Study Design: Retrospective case series. Purpose: To compare minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) outcomes in primary and revision surgeries. Overview of Literature: Revision spinal fusion is often associated with an increased risk of approach-related complications. Patients can potentially benefit from the decreased approach-related morbidity associated with MI-TLIF. Methods: Sixty consecutive MI-TLIF patients (20 failed back [Fa group], 40 primary [Pr group]) who underwent surgery between January 2011 and May 2012 were reviewed after Institutional Review Board approval to compare operative times, blood loss, complications, Oswestry Disability Index (ODI) scores, and Visual Analog Scale (VAS) scores for back and leg pain before surgery and at the last follow-up. Results: Nineteen revision surgeries were compared with 36 primary surgeries. One failed back and four primary patients were excluded because of inadequate data. The mean follow-up times were 28 months and 24 months in the Pr and Fa groups, respectively. The mean pre- and postoperative ODI scores were 53.18 and 20.23 in the Pr group and 52.01 and 25.72 in the Fa group, respectively (ODI percentage change: Pr group, 60.36%+/-29.73%; Fa group, 69.32%+/-13.72%; p=0.304, not significant). The mean pre- and postoperative VAS scores for back pain were 4.77 and 1.75 in the Pr group and 4.1 and 2.0 in the Fa group, respectively, and the percentage changes were statistically significant (VAS back pain percentage change: Pr group, 48.78+/-30.91; Fa group, 69.32+/ 13.72; p=0.027). The mean pre- and postoperative VAS scores for leg pain were 6.52 and 1.27 in the Pr group and 9.5 and 1.375 in the Fa group, respectively (VAS leg pain percentage change: Pr group, 81.07+/-29.39; Fa group, 75.72+/ 15.26; p=0.538, not significant). There were no statistically significant differences in operative time and estimated blood loss and no complications. Conclusions: MI-TLIF outcomes were comparable between primary and revision surgeries. The inherent technique of MI-TLIF is particularly suitable for select failed backs because it exploits the intact paramedian corridor. PMID- 29503683 TI - Risk Factors for Posterior Cage Migration after Lumbar Interbody Fusion Surgery. AB - Study Design: A retrospective clinical case series. Purpose: To determine the strength of association between cage retropulsion and its related factors. Overview of Literature: Lumbar interbody fusion with cage can obtain a firm union and can restore the disc height with normal sagittal and coronal alignment. Although lumbar interbody fusion procedures have satisfactory clinical outcomes, peri- and postoperative complications regarding the cage remain challenging. Methods: From January 2006 to June 2016, 1,047 patients with lumbar degenerative disc disease who underwent posterior lumbar interbody fusion or transforaminal interbody fusion at Gyeongsang National University Hospital were enrolled. Medical records and pre- and postoperative radiographs were reviewed to identify significant cage retropulsion-related factors. The associations between cage retropulsion with various risk factors were evaluated by calculating odds ratios (ORs) and 95% confidence intervals (CIs) using multiple logistic regression analysis. Results: Of 1,229 disc levels, 16 cases (1.3%, 10 men and 6 women) had cage retropulsion. Univariate analysis revealed no significant differences between the cage retropulsion group and the no cage retropulsion group with regard to demographic data such as age, sex, weight, height, body mass index (BMI), smoking habits, presence of osteoporosis, and duration of follow-up. Multivariate analysis revealed that low BMI (OR, 0.875; 95% CI, 0.771-0.994; p=0.040), presence of screw loosening (OR, 27.400; 95% CI, 7.818-96.033; p<0.001), and pear-shaped disc (OR, 9.158; 95% CI, 2.455-34.160; p=0.001) were significantly associated with cage retropulsion. Conclusions: This study demonstrated that low BMI, loosening of posterior instrumentation, and pear shaped disc were associated with cage retropulsion after lumbar interbody fusion. Therefore, when performing lumbar interbody fusion with a cage, surgeons should have skillful surgical techniques for firm fixation to prevent cage retropulsion, particularly in non-obese patients. PMID- 29503684 TI - Biceps-Related Physical Findings Are Useful to Prevent Misdiagnosis of Cervical Spondylotic Amyotrophy as a Rotator Cuff Tear. AB - Study Design: Case-control study. Purpose: The aim of the present study was to identify physical findings useful for differentiating between cervical spondylotic amyotrophy (CSA) and rotator cuff tears to prevent the misdiagnosis of CSA as a rotator cuff tear. Overview of Literature: CSA and rotator cuff tears are often confused among patients presenting with difficulty in shoulder elevation. Methods: Twenty-five patients with CSA and 27 with rotator cuff tears were enrolled. We included five physical findings specific to CSA that were observed in both CSA and rotator cuff tear patients. The findings were as follows: (1) weakness of the deltoid muscle, (2) weakness of the biceps muscle, (3) atrophy of the deltoid muscle, (4) atrophy of the biceps muscle, and (5) swallow-tail sign (assessment of the posterior fibers of the deltoid). Results: Among 25 CSA patients, 10 (40.0%) were misdiagnosed with a rotator cuff tear on initial diagnosis. The sensitivity and specificity of each physical finding were as follows: (1) deltoid weakness (sensitivity, 92.0%; specificity, 55.6%), (2) biceps weakness (sensitivity, 80.0%; specificity, 100%), (3) deltoid atrophy (sensitivity, 96.0%; specificity, 77.8%), (4) biceps atrophy (sensitivity, 88.8%; specificity, 92.6%), and (5) swallow-tail sign (sensitivity, 56.0%; specificity, 74.1%). There were statistically significant differences in each physical finding. Conclusions: CSA is likely to be misdiagnosed as a rotator cuff tear; however, weakness and atrophy of the biceps are useful findings for differentiating between CSA and rotator cuff tears to prevent misdiagnosis. PMID- 29503685 TI - The Relationship between Sacral Kyphosis and Pelvic Incidence. AB - Study Design: Retrospective cohort study. Purpose: Evaluate the fixed anatomical parameter of sacral kyphosis (SK) and its relationship with pelvic incidence (PI). Overview of Literature: Pelvic parameters determine pelvic and lumbar spinal position. Studies have defined normative values, and have evaluated the role of these parameters in clinical practice. It has been suggested that a ratio of sacral slope (SS)/PI <0.5 predisposes to spinal pathology. PI=SS+pelvic tilt (PT) and therefore for a given PI, patients with a higher SS due to an elevated SK will potentially predispose to an unfavourable SS/PI ratio. Methods: CT measurements of SS and PI were made in 100 consecutive patients from our database. Imagings without clear landmarks were excluded. PI and SK were measured using standardised techniques. Pearson's correlation was used to assess association between PI and SK, in addition to the correlation between age and the pelvic parameters. Gender specific values for PI and SK were compared using an unpaired Student t-test. Results: Ninety-five patients (52 females) with a mean age 51.3 years were available for analysis. A strong positive correlation between the PI and the SK was identified (Pearson's coefficient=0.636, R2 value=0.404). Neither PI nor SK had a statistically significant correlation with age (p=0.721 and p=0.572, respectively). The mean values of both the PI and SK were statistically significantly lower in females when compared to males (p=0.0461 and p=0.0031, respectively). Conclusions: A strong correlation between PI and SK exists and is a reflection of different pelvic morphologies. SK partially determines SS and a relatively high SK compared to PI will result in less ability to change PT and a potentially unfavourable SS/PI ratio, which could theoretically contribute to clinical pathology. PMID- 29503686 TI - Reliability and Accuracy of Palpable Anterior Neck Landmarks for the Identification of Cervical Spinal Levels. AB - Study Design: A descriptive experimental study. Purpose: The purpose of this study was to describe the reliability and accuracy of palpable anterior neck landmarks (angle of the mandible, hyoid bone, thyroid cartilage, and cricoid cartilage) for the identification of cervical spinal levels in a slight neck extended position as in anterior approach cervical spinal surgery. Overview of Literature: Standard, palpable anatomical landmarks for the identification of cervical spinal levels were described by Hoppenfeld using the midline palpable anterior structures (angle of the mandible [C2 body], hyoid bone [C3 body], thyroid cartilage [C4-C5 disc], cricoid cartilage [C6 body], and carotid tubercle [C6 body]) to determine the approximate level for skin incisions. However, in clinical practice, patients are positioned with a slight neck extension to achieve cervical lordosis. This positioning (neck extension) may result in changes in the locations of anatomical landmarks compared with those reported in previous studies. Methods: This experimental study was conducted on 96 volunteers. Each volunteer was palpated for locating four anatomical landmarks three times by three different orthopedic surgeons. We collected data from the level of the vertebral body or the vertebral disc matching the surface anatomical landmarks from the vertical reference line. Results: Accuracy of the angle of the mandible located at the C2 vertebral body was 95.5%, the hyoid bone located at the C2/3 intervertebral disc was 51.7%, the thyroid cartilage located at the C4 vertebral body was 42%, and the cricoid cartilage located at the C5/6 intervertebral disc was 43.4%. Conclusions: With the neck in a slightly extended position to achieve cervical lordosis, the angle of the mandible, the hyoid bone, the thyroid cartilage, and the cricoid cartilage were most often located at the C2 body, the C2/3 disc, the C4 body, and the C5/6 disc, respectively. The angle of the mandible and the hyoid bone are highly reliable surface anatomical landmarks for the identification of cervical spinal levels than the thyroid cartilage and the cricoid cartilage. PMID- 29503687 TI - Does Subcutaneous Infiltration of Liposomal Bupivacaine Following Single-Level Transforaminal Lumbar Interbody Fusion Surgery Improve Immediate Postoperative Pain Control? AB - Study Design: Retrospective case-control study using prospectively collected data. Purpose: Evaluate the impact of liposomal bupivacaine (LB) on postoperative pain management and narcotic use following standardized single-level low lumbar transforaminal lumbar interbody fusion (TLIF). Overview of Literature: Poor pain control after surgery has been linked with decreased pain satisfaction and increased economic burden. Unfortunately, opioids have many limitations and side effects despite being the primary treatment of postoperative pain. LB may be a form of pre-emptive analgesia used to reduce the use of postoperative narcotics as evidence in other studies evaluating its use in single-level microdiskectomies. Methods: The infiltration of LB subcutaneously during wound closure was performed by a single surgeon beginning in July 2014 for all single level lumbar TLIF spinal surgeries at Landstuhl Regional Medical Center. This cohort was compared against a control cohort of patients who underwent the same surgery by the same surgeon in the preceding 6 months. Statistical analysis was performed on relevant variables including: morphine equivalents of narcotic medication used (primary outcome), length of hospitalization, Visual Analog Scale pain scores, and total time spent on a patient-controlled analgesia (PCA) pump. Results: A total of 30 patients were included in this study; 16 were in the intervention cohort and 14 were in the control cohort. The morphine equivalents of intravenous narcotic use postoperatively were significantly less in the LB cohort from day of surgery to postoperative day 3. Although the differences lost their statistical significance, the trend remained for total (oral and intravenous) narcotic consumption to be lower in the LB group. The patients who received the study intervention required an acute pain service consult less frequently (62.5% in LB cohort vs. 78.6% in control cohort). The amount of time spent on a PCA pump in the LB group was 31 hours versus 47 hours in the control group (p=0.1506). Conclusions: Local infiltration of LB postoperatively to the subcutaneous tissues during closure following TLIF significantly decreased the amount of intravenous narcotic medication required by patients. Well-powered prospective studies are still needed to determine optimal dosing and confirm benefits of LB on total narcotic consumption and other measures of pain control following major spinal surgery. PMID- 29503688 TI - Quantitative Magnetic Resonance Imaging Analysis of the Cervical Spine Extensor Muscles: Intrarater and Interrater Reliability of a Novice and an Experienced Rater. AB - Study Design: Reliability study. Purpose: To examine the reliability of novice and experienced raters for measurements of the size and composition of the cervical extensor muscles using a thresholding technique. Overview of Literature: Although some authors have reported on the dependability of magnetic resonance imaging (MRI) measurements of the cervical muscles, there remains some variability regarding intrarater and interrater reliabilities, and few studies have examined the associated measurement error. Whether the rater's experience noticeably influences the reliability and precision of such measurements has also not been examined. Methods: A sample of 10 patients with cervical pathologies was selected. Muscle cross-sectional area (CSA), functional cross-sectional area (FCSA), and signal intensity of the cervical extensor muscles were acquired from axial T2-weighted MRIs by a novice and an experienced rater. All measurements were obtained twice, at least 5 days apart, while the raters were blinded to all earlier measurements. Results: Interrater reliability estimates (intraclass correlation coefficients) varied between 0.84 and 0.99 for the novice rater and between 0.94 and 0.99 for the experienced rater, indicating excellent reliability. The standard error of measurement for the novice rater was, however, noticeably higher for all cervical muscle measurements. Most of the interrater estimates showed excellent agreement with the exception of CSA measurement of the semispinalis cervicis at C4-C7 and FCSA measurement of the multifidus and semispinalis cervicis at C4-C7, which showed poor interrater reliability. Conclusions: The proposed method of investigating cervical muscle measurements was highly reliable; however, novice raters should receive adequate training before using this method for diagnostic, research, and clinical purposes. PMID- 29503689 TI - Analysis of Spinopelvic Parameters with L5 as the New Sacrum after Fusion in High Grade Spondylolisthesis: A Possible Explanation for Satisfactory Results with In Situ Fusion. AB - Study Design: Retrospective case series. Purpose: To correlate functional outcomes with spinopelvic parameters in patients with high-grade spondylolisthesis (HGS) treated with instrumented in-situ surgery or reduction and fusion. Overview of Literature: Satisfactory functional outcomes are reported with reduction and in-situ fusion strategies in HGS. However, reasons for this are unclear. We hypothesize that following lumbosacral fusion, the L5 becomes part of the sacrum, which improves spinopelvic parameters, resulting in equivalent functional outcomes in both surgical methods. Methods: Twenty-six patients undergoing HGS (reduction group A, 13; in-situ group B, 13) were clinically evaluated using the Oswestry Disability Index (ODI), short form-12 (SF 12), and Visual Analogue Scale (VAS) scores. Spinopelvic parameters, including pelvic incidence, pelvic tilt (PT), sacral slope (SS), lumbar lordosis (LL), lumbosacral kyphosis (LSK) angle, and sacrofemoral distance (SFD) were measured preoperatively from S1 and postoperatively from L5 as the new sacrum at 1 year follow-up. Sagittal alignment was assessed using the sagittal vertical axis. Results: Both groups were comparable in terms of age, sex, severity of slip, and preoperative spinopelvic parameters (p>0.05). Postoperative VAS, SF-12, and ODI scores significantly improved in both groups (p<0.05). Compared with preoperative values, the mean postoperative PT, SFD, and LSK significantly changed in both groups. In reduction group, PT changed from 26.98 degrees to 10.78 degrees , SFD from 61.24 to 33.56 mm, and LSK from 74.76 degrees to 109.61 degrees (p<0.05). In in-situ fusion group PT changed from 26.78 degrees to 11.08 degrees , SFD from 62.9 to 36.99 mm, and LSK from 67.23 degrees to 113.38 degrees (p<0.05 for all). In both groups, SS and LL did not change significantly (p>0.05). Conclusions: After fusion, the L5 becomes the new sacrum and influences spinopelvic parameters to change favorably. This possibly explains why reduction and in-situ fusion achieve equivalent functional outcomes in HGS. PMID- 29503690 TI - Efficacy of Platelet-Rich Plasma for Bone Fusion in Transforaminal Lumbar Interbody Fusion. AB - Study Design: Retrospective case series. Purpose: To examine the efficacy of platelet-rich plasma (PRP) for bone fusion in transforaminal lumbar interbody fusion (TLIF) using local bone grafting. Overview of Literature: Several authors have reported the efficacy of PRP for bone union in animal models. However, the use of PRP for bone fusion in TLIF surgery has not been fully explored. Methods: Twenty patients underwent single-level TLIF surgery because of L4 spondylolisthesis. An interbody fusion cage and local bone were used in nine patients (control group) and an interbody fusion cage, local bone, and PRP were used in 11 patients (PRP group). PRP was prepared from the patients' blood samples (400 mL) immediately before surgery. The duration of bone union and postoperative bone fusion rate were assessed using plain radiography at every 3 months postoperatively and computed tomography at 12 or 24 months postoperatively, respectively. Lower back pain, leg pain, and leg numbness were evaluated using the visual analog scale preoperatively and at 3, 6, 12, and 24 months postoperatively. Results: The platelet count was 8.7 times higher in PRP than in blood. The bone union rate was significantly superior in the PRP group than in the control group (91% and 77%, respectively; p=0.035), whereas the average duration of bone union was not significantly different between the groups (7.7+/-0.74 and 10.0+/-2.00 months, respectively; p=0.131). There was no significant difference in lower back pain, leg pain, and leg numbness in both groups during follow-up (p>0.05). Conclusions: Our study suggests that the use of PRP in TLIF surgery increases bone fusion rate. PMID- 29503691 TI - A New Modified Method for Inserting Iliosacral Screw versus the Conventional Method. AB - Study Design: Methodological study. Purpose: To our knowledge, this is the first study to introduce a new modified method for inserting iliosacral screws and to compare its results with those of a conventional method. Overview of Literature: Previous techniques, such as open reduction and internal fixation, are associated with perioperative hemorrhage, postoperative infection, and neurological deficits. Although percutaneous iliosacral screw insertion confers the advantage of being minimally invasive, leading to less blood loss and a low postoperative infection rate, it harbors the risk of screw malpositioning due to narrow sacral proportions and a high interindividual variability. Methods: Nine cadaveric pelvises were included in this study, with one hemipelvis of each being assigned to the new modified method and the other to the conventional iliosacral screw insertion method. In the new modified method, the guidewire entry point was determined using a lateral sacral X-ray. To do so, we first identified the anterosuperior quadrant of the S1 body on one hemipelvis. The anterosuperior quadrant was further divided into four imaginary quadrants, and the guidewire was inserted into the posteroinferior quadrant. The guidewire trajectory was perpendicular to the sagittal plane so that the guidewire resembled a single point in the lateral sacral view. Guidewires were inserted into corresponding hemipelves using the conventional method as described in the literature. Subsequently, an axial computed tomography scan with 1-mm fine cuts was obtained, and sagittal and coronal views were reconstructed. The distance of the guidewire from the sacral canal, anterior sacral cortex, and first sacral foramen was measured in axial, sagittal, and coronal views. The minimum measurement among different views was defined as the safety index of the insertion methods. The conventional and new modified methods were then compared in terms of safety and duration of the procedure. Results: The minimum distance of the guidewire from the S1 foramen and anterior sacral cortex was not significantly different between the two methods. However, the minimum distance between the guidewire and sacral canal was significantly greater in the new modified method than in the conventional method. The duration of guidewire insertion was significantly shorter in the new modified method than in the conventional method. Conclusions: This new modified method of iliosacral screw insertion could be safely and simply implemented while taking less surgical time than the conventional methods. PMID- 29503692 TI - Effects of Psychiatric Factors on Patient-Reported Outcomes after Surgical Correction of Lumbar Degenerative Kyphosis. AB - Study Design: A prospective study. Purpose: To identify associations between psychiatric factors and patient-reported outcomes after corrective surgery in patients with lumbar degenerative kyphosis (LDK). Overview of Literature: Thus far, to the best of our knowledge, patient factors that may help predict patient reported outcomes after corrective surgery for LDK have not been studied. Methods: We prospectively investigated 46 patients with LDK who underwent surgical correction with a minimum follow-up of 2 years. Demographic data were collected. Short form-36, mental component scores (MCS), physical component scores (PCS), Scoliosis Research Society-22 (SRS-22) scores, and Roland-Morris Disability Questionnaire (RMDQ) scores were determined before the surgery and after 2 years of follow-up. Psychiatric conditions were preoperatively evaluated using the Zung depression scale (ZDS) and Zung anxiety scale (ZAS). Patients were divided into two groups (with or without psychiatric issues), according to baseline ZDS and ZAS scores. Results: Patients included 43 women and 3 men. Twelve patients were deemed to have psychiatric problems (P group) and 34 patients had no psychiatric problems (NP group). No significant intergroup differences were found in MCS, PCS, SRS-22, and RMDQ scores preoperatively. However, at the 2-year follow-up, a significant intergroup difference was observed between PCS and RMDQ scores. Multiple regression analysis revealed that only the presence of a preoperative psychiatric problem can predict PCS and RMDQ scores. Other factors, such as, gender, age, body mass index, bone mineral density, osteotomy site, number of fusion segments, and instrumented levels did not affect PCS or RMDQ scores. Conclusions: The presence of a psychiatric factor may be an important risk factor underlying poor physical and pain scores after corrective surgery in patients with LDK. The findings presented here suggest that psychiatric factors should be evaluated prior to surgery for determining the risk of a poor outcome. PMID- 29503693 TI - Degenerative Lumbar Spondylolisthesis with Spinal Stenosis: A Comparative Study of 5-Year Outcomes Following Decompression with Fusion and Microendoscopic Decompression. AB - Study Design: Retrospective review of prospectively collected outcome data. Purpose: To compare 5-year outcomes following decompression with fusion (FU) and microendoscopic decompression (MED) in patients with degenerative lumbar spondylolisthesis (DLS) and to define surgical indication limitations regarding the use of MED for this condition. Overview of Literature: There have been no comparative studies on mid- or long-term outcomes following FU and MED for patients with DLS. Methods: Forty-one consecutive patients with DLS were surgically treated. Sixteen patients first underwent FU (FU group), and 25 then underwent MED (MED group). The 5-year clinical outcomes following the two surgical methods were compared using the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire. Results: The degree of improvement (DOI) for social life function was significantly greater in the MED group than in the FU group. Although not statistically significant, DOIs for the other four functional scores were also greater in the MED group than in the FU group. However, patients with a large percentage of slippage in the neutral position might experience limited improvement in low back pain, those with a large percentage of slippage at maximal extension might experience limited improvement in three functional scores, and those with a small intervertebral angle at maximal flexion might have limited improvement in three functional scores after MED for DLS. Therefore, we statistically compared the DOIs between the FU and MED groups regarding the preoperative percentage of slippage in the neutral position among patients with greater than 20% slippage, the preoperative percentage of slippage at maximal extension among patients with greater than 15% slippage, and the intervertebral angle at flexion among patients with angles lesser than -5 degrees ; however, there were no statistically significant differences between the two groups. Conclusions: MED is a useful minimally invasive surgical procedure that possibly offers better clinical outcomes than FU for DLS. PMID- 29503694 TI - Analysis of Revision Surgery of Microsurgical Lumbar Discectomy. AB - Study Design: A retrospective study. Purpose: Our objectives were to determine the association between the pathological changes of disc herniation and the interval between primary and revision surgeries and to investigate the frequency and site of the dural laceration in the primary and revision surgeries. Overview of Literature: Among 382 patients who underwent microsurgical lumbar discectomy, we investigated 29 who underwent revision surgery to analyze recurrent herniation pathologies and complications to determine the manner in which lumbar disc herniation can be more efficiently managed. Methods: Of 29 patients, 22 had recurrent disc herniation at the same level and site. The pathological changes associated with compression factors were classified into the following two types depending on intraoperative findings: (1) true recurrence and (2) minor recurrence with peridural fibrosis (>4 mm thickness). The sites of dural laceration were examined using video footage and operative records. Results: The pathological findings and days between the primary and revision surgeries showed no statistical difference (p=0.14). Analysis of multiple factors, revealed no significant difference between the primary and revision surgery groups with regard to hospital days (p=0.23), blood loss (p=0.99), and operative time (p=0.67). Dural lacerations obviously increased in the revision surgery group (1.3% vs. 16.7%, p<0.01) and were mainly located near the herniated disc in the primary surgery group and near the root shoulder in the revision surgery group, where severe fibrosis and adhesion were confirmed. To avoid dural laceration during revision surgery, meticulous decompressive manipulation must be performed around the root sleeve. Conclusions: We recommend that meticulous epidural dissection around the scar formation must be performed during revision surgery to avoid complications. PMID- 29503695 TI - Influence of Distal Fusion Level on Sagittal Spinopelvic and Spinal Parameters in the Surgical Management of Adolescent Idiopathic Scoliosis. AB - Study Design: Retrospective analysis of adolescent idiopathic scoliosis. Purpose: This study aimed to investigate the influence of distinct distal fusion levels on spinopelvic parameters in patients with adolescent idiopathic scoliosis (AIS) who underwent posterior instrumentation and fusion surgery. Overview of Literature: The distal fusion level selection in treatment of AIS is the one of milestone to effect on surgical outcome. Most of the paper focused on the coronal deformity correction and balance. The literature have lack of knowledge about spinopelvic changing after surgical treatment and the relation with distal fusion level. We evaluate the spinopelvic and pelvic parameter alteration after fusion surgery in treatment of AIS. Methods: A total of 100 patients with AIS (88 females and 12 males) were retrospectively reviewed. Patients were assigned into the following three groups according to the distal fusion level: lumbar 2 (L2), lumbar 3 (L3), and lumbar 4 (L4). Using a lateral plane radiograph of the whole spine, spinopelvic angular parameters such as thoracic kyphosis (TK), lumbar lordosis (LL), pelvic incidence (PI), sacral slope (SS), and pelvic tilt (PT) were radiologically assessed. Results: The mean age was 15+/-2.4 years, and the mean follow-up period was 24.27+/-11.69 months. Regarding the lowest instrumented vertebra, patients were categorized as follows: 30 patients in L2 (group 1), 40 patients in L3 (group 2), and 30 patients in L4 (group 3). TK decreased from 36.60+/-13.30 degrees preoperatively to 26.00+/-7.3 degrees postoperatively in each group (p=0.001). LL decreased from 52.8+/-9.4 degrees preoperatively to 44.30+/-7.50 degrees postoperatively (p=0.001). Although PI showed no difference preoperatively among the groups, it was statistically higher postoperatively in group 3 than in the other groups (p<0.05). In addition, in group 2, PI decreased from 50.60+/-8.74 degrees preoperatively to 48.00+/-6.84 degrees postoperatively (p=0.027). SS decreased from 35.20+/-6.40 degrees preoperatively to 33.40+/-5.80 degrees postoperatively (p=0.08, p>0.05). However, mean SS was significantly higher in group 3 (p=0.042, p<0.05). PT decreased from 15.50+/-7.90 degrees preoperatively to 15.2+/-7.10 degrees postoperatively. The positive relationship (28.5%) between LL and PI measurements was statistically significant (r=0.285; p=0.004, p<0.01). Furthermore, the positive relationship (36.5%) between LL and SS measurements was statistically significant (r=0.365; p=0.001, p<0.01). Conclusions: When the distal instrumentation level in AIS surgery is below L3, a significant change in PT and SS (pelvic parameters) is anticipated. PMID- 29503696 TI - Preventing Construct Subsidence Following Cervical Corpectomy: The Bump-stop Technique. AB - Cervical corpectomy is a viable technique for the treatment of multilevel cervical spine pathology. Despite multiple advances in both surgical technique and implant technology, the rate of construct subsidence can range from 6% for single-level procedures to 71% for multilevel procedures. In this technical note, we describe a novel technique, the bump-stop technique, for cervical corpectomy. The technique positions the superior and inferior screw holes such that the vertebral bodies bisect them. This allows for fixation in the dense cortical bone of the endplate while providing a buttress to corpectomy cage subsidence. We then discuss a retrospective case review of 24 consecutive patients, who were treated using this approach, demonstrating a lower than previously reported cage subsidence rate. PMID- 29503697 TI - Do Dose-Dependent Microbial Changes Occur during Spine Surgery as a Result of Applying Intrawound Vancomycin Powder?: A Systematic Literature Review. AB - We analyzed dose-dependent effects of vancomycin on wound infection bacteria and investigated the relationship between dose and microbial imbalances in patients treated with intrawound vancomycin powder during spine surgery. Numerous trials have confirmed that using intrawound vancomycin powder during spine surgery may decrease postoperative wound infection rates. However, potential risks include changes in wound infection bacteria, inhibition of bone fusion, and systemic toxicity. We searched PubMed for articles published since October 2016 with the following terms: "local vancomycin" or "intrawound vancomycin" or "intraoperative vancomycin" or "intrawound vancomycin" or "topical vancomycin" and "spinal surgery" or "spine surgery." We also screened the reference lists of included articles for additional studies and extracted data related to dose, infecting bacteria, sample size, infection rate and types, location of spine surgery, and perioperative antibiotics used. Our review includes one prospective and nine retrospective studies. Overall, 1 or 2 g local vancomycin powder was used in 2,394 patients. Gram-negative bacteria were dominant in patients in whom 1 g vancomycin powder was used, whereas gram-positive bacteria were dominant in those in whom 2 g powder was used. The exact mechanism underlying this dose-dependent trend remains unclear, although it may be attributed to the pharmacological characteristics of vancomycin. The included studies showed that trends in infection bacteria may change after the use of topical vancomycin powder. In addition, the observed increase in gram-negative bacteria when intrawound vancomycin powder is used has generated considerable attention. The present results differ from previous results but do not provide additional information regarding vancomycin dose and microbial changes in infected wounds. Additional large randomized controlled trials are needed to determine the relationship between vancomycin dose and the types of wound infection bacteria in patients treated with intrawound vancomycin powder during spine surgery. PMID- 29503698 TI - A Review of Current Clinical Applications of Three-Dimensional Printing in Spine Surgery. AB - Three-dimensional (3D) printing is a transformative technology with a potentially wide range of applications in the field of orthopaedic spine surgery. This article aims to review the current applications, limitations, and future developments of 3D printing technology in orthopaedic spine surgery. Current preoperative applications of 3D printing include construction of complex 3D anatomic models for improved visual understanding, preoperative surgical planning, and surgical simulations for resident education. Intraoperatively, 3D printers have been successfully used in surgical guidance systems and in the creation of patient specific implantable devices. Furthermore, 3D printing is revolutionizing the field of regenerative medicine and tissue engineering, allowing construction of biocompatible scaffolds suitable for cell growth and vasculature. Advances in printing technology and evidence of positive clinical outcomes are needed before there is an expansion of 3D printing applied to the clinical setting. PMID- 29503700 TI - T1 Slope in the Cervical Spine Magnetic Resonance Imaging: A Novel Concept. PMID- 29503701 TI - Response to: "T1 Slope in the Cervical Spine Magnetic Resonance Imaging: A Novel Concept". PMID- 29503699 TI - Are Controversial Issues in Cervical Total Disc Replacement Resolved or Unresolved?: A Review of Literature and Recent Updates. AB - Since the launch of cervical total disc replacement (CTDR) in the early 2000s, many clinical studies have reported better outcomes of CTDR compared to those of anterior cervical discectomy and fusion. However, CTDR is still a new and innovative procedure with limited indications for clinical application in spinal surgery, particularly, for young patients presenting with soft disc herniation with radiculopathy and/or myelopathy. In addition, some controversial issues related to the assessment of clinical outcomes of CTDR remain unresolved. These issues, including surgical outcomes, adjacent segment degeneration (ASD), heterotopic ossification (HO), wear debris and tissue reaction, and multilevel total disc replacement (TDR) and hybrid surgeries are a common concern of spine surgeons and need to be resolved. Among them, the effect of CTDR on patient outcomes and ASD is theoretically and clinically important; however, this issue remains disputable. Additionally, HO, wear debris, multilevel TDR, and hybrid surgery tend to favor CTDR in terms of their effects on outcomes, but the potential of these factors for jeopardizing patients' safety postoperatively and/or to exert harmful effects on surgical outcomes in longer-term follow-up cannot be ignored. Consequently, it is too early to determine the therapeutic efficacy and cost-effectiveness of CTDR and will require considerable time and studies to provide appropriate answers regarding the same. For these reasons, CTDR requires longer-term follow-up data. PMID- 29503702 TI - Acid-resistant genes of oral plaque microbiome from the functional metagenomics. AB - Acid resistance is one of key properties assisting the survival of cariogenic bacteria in a dental caries environment, but only a few genes conferring acid resistance have been identified to data. Functional metagenomics provides a systematic method for investigating commensal DNA to identify genes that encode target functions. Here, the host strain Escherichia coli DH10B and a constructed bidirectional transcription vector pSKII+-lacZ contributed to the construction of a metagenomic library, and 46.6 Mb of metagenomic DNA was cloned from carious supragingival plaque of 8children along with screening for lethal functionality. The screen identified 2 positive clones that exhibited a similar aciduric phenotype to that of the positive controls. Bioinformatic analysis revealed that these two genes encoded an ATP/GTP-binding protein and a malate dehydrogenase. Moreover, we also performed functional screening of Streptococcus mutans, since it is one of the predominant cariogenic strains but was not identified in our initial screening. Five positive clones were retrieved. In conclusion, our improved functional metagenomics screening method helped in the identification of important acid resistance genes, thereby providing new insights into the mechanism underlying caries formation as well as in the prevention and treatment of early childhood caries (ECC). PMID- 29503703 TI - Longitudinal comparison of Streptococcus mutans-induced aggravation of non alcoholic steatohepatitis in mice. AB - Background: We previously reported that intravenous administration of Streptococcus mutans strain TW871 caused typical non-alcoholic steatohepatitis (NASH)-like findings in a high-fat diet (HFD) mouse model at 16 weeks after initiating the experiment. Objective: The purpose of the present study was to analyse mice administered S. mutans TW871 fed a HFD for various periods of time. Methods: First, 6-week-old C57BL/6J mice were fed an HFD for 4 weeks, then TW871 (1 * 107 CFU) or phosphate-buffered saline (PBS) were intravenously administered. Mice were euthanized 12, 16, 20, and 48 weeks after starting the experiment, and conventional clinical and histopathological evaluations were performed. Results: Typical NASH-like findings were not identified in the mice at 12 weeks, while they were observed in the TW871 group at 16 weeks, and the severity of NASH symptoms were increased at 20 weeks. Furthermore, signs of severe NASH were also observed at 48 weeks. In contrast, in the PBS-administered group, the NASH findings were identified only at 48 weeks and no typical NASH features were observed at 12, 16, or 20 weeks. Conclusion: These results suggest that intravenous administration of a specific S. mutans strain aggravates NASH in a time-dependent manner in the mice in contrast to mice without S. mutans exposure. PMID- 29503704 TI - Organization of supragingival plaque at the micron scale. PMID- 29503705 TI - Importance of heterogeneity in Porhyromonas gingivalis lipopolysaccharide lipid A in tissue specific inflammatory signalling. AB - Lipopolysaccharide (LPS) of Porphyromonas gingivalis exists in at least two known forms, O-LPS and A-LPS. A-LPS shows heterogeneity in which two isoforms designated LPS1,435/1,449 and LPS1,690 appear responsible for tissue-specific immune signalling pathways activation and increased virulence. The modification of lipid A to tetra-acylated1,435/1,449 and/or penta-acylated1,690 fatty acids indicates poor growth conditions and bioavailability of hemin. Hemin protects P. gingivalis from serum resistance and the lipid A serves as a site for its binding. The LPS1,435/1,449 and LPS1,690 isoforms can produce opposite effects on the human Toll-like receptors (TLR) TLR2 and TLR4 activation. This enables P. gingivalis to select the conditions for its entry, survival, and that of its co habiting species in the host, orchestrating its virulence to control innate immune pathway activation and biofilm dysbiosis. This review describes a number of effects that LPS1,435/1,449 and LPS1,690 can exert on the host tissues such as deregulation of the innate immune system, subversion of host cell autophagy, regulation of outer membrane vesicle production, and adverse effects on pregnancy outcome. The ability to change its LPS1,435/1,449 and/or LPS1,690 composition may enable P. gingivalis to paralyze local pro-inflammatory cytokine production, thereby gaining access to its primary location in periodontal tissue. PMID- 29503706 TI - Antimicrobial peptide GH12 suppresses cariogenic virulence factors of Streptococcus mutans. AB - Cariogenic virulence factors of Streptococcus mutans include acidogenicity, aciduricity, and extracellular polysaccharides (EPS) synthesis. The de novo designed antimicrobial peptide GH12 has shown bactericidal effects on S. mutans, but its interaction with virulence and regulatory systems of S. mutans remains to be elucidated. The objectives were to investigate the effects of GH12 on virulence factors of S. mutans, and further explore the function mechanisms at enzymatic and transcriptional levels. To avoid decrease in bacterial viability, we limited GH12 to subinhibitory levels. We evaluated effects of GH12 on acidogenicity of S. mutans by pH drop, lactic acid measurement and lactate dehydrogenase (LDH) assay, on aciduricity through survival rate at pH 5.0 and F1F0-ATPase assay, and on EPS synthesis using quantitative measurement, morphology observation, vertical distribution analyses and biomass calculation. Afterwards, we conducted quantitative real-time PCR to acquire the expression profile of related genes. GH12 at 1/2 MIC (4 mg/L) inhibited acid production, survival rate, EPS synthesis, and biofilm formation. The enzymatic activity of LDH and F1F0-ATPase was inhibited, and ldh, gtfBCD, vicR, liaR, and comDE genes were significantly downregulated. In conclusion, GH12 inhibited virulence factors of S. mutans, through reducing the activity of related enzymes, downregulating virulence genes, and inactivating specific regulatory systems. PMID- 29503707 TI - Oral microbiota in autoimmune polyendocrine syndrome type 1. AB - Background: Autoimmune polyendocrine syndrome type-1 (APS-1) is a rare, childhood onset disease caused by mutations in the Autoimmune Regulator gene. The phenotypic expression is highly variable and includes disease manifestations in the oral cavity, including mucocutaneous candidiasis. Increasing evidence suggests a potential role of the skin, oral and gut microbiotas in the pathogenesis of autoimmunity. To date, no information exists regarding the oral microbiota in APS-1. Objective: To assess the bacterial microbiota of whole saliva in APS-1 patients by using high throughput sequencing. Design: Whole unstimulated saliva was collected from 10 APS-1 patients and 17 healthy controls and examined by high throughput sequencing of the hypervariable region V1-V2 of 16S rRNA using the 454 GS Junior system. Metastats (http://cbcb.umd.edu/software/metastats) was used to analyse the pyrosequencing reads. Results: A reduction in the total number of bacterial genera and species was detected in APS-1 compared to healthy controls. The proportion of the major phyla Firmicutes was higher (60% vs 41%, p = 0.002) and Bacteroidetes lower (15% vs 28%, p = 0.007) in APS-1 compared to healthy controls. On the genus level, Streptococcus and Gemella were prevalent in APS-1. Conclusion: Our findings indicate a significantly altered oral microbiota in APS-1. PMID- 29503708 TI - Effects of abutment diameter, luting agent type, and re-cementation on the retention of implant-supported CAD/CAM metal copings over short abutments. AB - PURPOSE: The aim of this study was to evaluate the effects of abutment diameter, cement type, and re-cementation on the retention of implant-supported CAD/CAM metal copings over short abutments. MATERIALS AND METHODS: Sixty abutments with two different diameters, the height of which was reduced to 3 mm, were vertically mounted in acrylic resin blocks with matching implant analogues. The specimens were divided into 2 diameter groups: 4.5 mm and 5.5 mm (n=30). For each abutment a CAD/CAM metal coping was manufactured, with an occlusal loop. Each group was sub-divided into 3 sub-groups (n=10). In each subgroup, a different cement type was used: resin-modified glass-ionomer, resin cement and zinc-oxide-eugenol. After incubation and thermocycling, the removal force was measured using a universal testing machine at a cross-head speed of 0.5 mm/min. In zinc-oxide eugenol group, after removal of the coping, the cement remnants were completely cleaned and the copings were re-cemented with resin cement and re-tested. Two-way ANOVA, post hoc Tukey tests, and paired t-test were used to analyze data (alpha=.05). RESULTS: The highest pulling force was registered in the resin cement group (414.8 N), followed by the re-cementation group (380.5 N). Increasing the diameter improved the retention significantly (P=.006). The difference in retention between the cemented and recemented copings was not statistically significant (P=.40). CONCLUSION: Resin cement provided retention almost twice as strong as that of the RMGI. Increasing the abutment diameter improved retention significantly. Re-cementation with resin cement did not exhibit any difference from the initial cementation with resin cement. PMID- 29503709 TI - Accuracy and reproducibility of 3D digital tooth preparations made by gypsum materials of various colors. AB - PURPOSE: The study aimed to identify the accuracy and reproducibility of preparations made by gypsum materials of various colors using quantitative and semi-quantitative three-dimensional (3D) approach. MATERIALS AND METHODS: A titanium maxillary first molar preparation was created as reference dataset (REF). Silicone impressions were duplicated from REF and randomized into 6 groups (n=8). Gypsum preparations were formed and grouped according to the color of gypsum materials, and light-scanned to obtain prepared datasets (PRE). Then, in terms of accuracy, PRE were superimposed on REF using the best-fit-algorithm and PRE underwent intragroup pairwise best-fit alignment for assessing reproducibility. Root mean square deviation (RMSD) and degrees of similarity (DS) were computed and analyzed with SPSS 20.0 statistical software (alpha=.05). RESULTS: In terms of accuracy, PREs in 3D directions were increased in the 6 color groups (from 19.38 to 20.88 um), of which the marginal and internal variations ranged 51.36 - 58.26 um and 18.33 - 20.04 um, respectively. On the other hand, RMSD value and DS-scores did not show significant differences among groups. Regarding reproducibility, both RMSD and DS-scores showed statistically significant differences among groups, while RMSD values of the 6 color groups were less than 5 um, of which blue color group was the smallest (3.27 +/- 0.24 um) and white color group was the largest (4.24 +/- 0.36 um). These results were consistent with the DS data. CONCLUSION: The 3D volume of the PREs was predisposed towards an increase during digitalization, which was unaffected by gypsum color. Furthermore, the reproducibility of digitalizing scanning differed negligibly among different gypsum colors, especially in comparison to clinically observed discrepancies. PMID- 29503710 TI - Survival rate of modern all-ceramic FPDs during an observation period from 2011 to 2016. AB - PURPOSE: In literature, many studies compare survival rates of different types of FPDs. Most of them compared restorations, which originated from one university, but from different clinicians. Data about restoration survival rates by only one experienced dentist are very rare. The aim of this study was to evaluate the survival rate of allceramic FPDs without the blurring effects of different clinicians. MATERIALS AND METHODS: 153 veneeredzirconia FPDs were observed for follow-up. 22 patients received 131 single crowns and 22 bridges. Because of the different bridge lengths, one unit was defined as a restored or replaced tooth. In total, 201 units were included. Only the restorations performed by the same clinician and produced in the same dental laboratory from 2011 to 2016 were included. Considered factors were defined as "type of unit", "type of abutment", "intraoral region", and "vitality". Modified UHPHS criteria were used for evaluation. Statistical analysis was performed using cox-regression. RESULTS: 189 units (94.0%) showed no kind of failure. 5 chippings (2.4%) could be corrected by intraoral polishing. 4 units (1.9%) exhibited spontaneous decementation. These polishable and recementable restorations are still in clinical use. Chippings or decementations, which lead to total failure, did not occur. One unit was completely fractured (0.5 %). Biological failures (caries, periodontitis or periimplantitis) did not occur. The statistical analysis of the factors did not reveal any significant differences. CONCLUSION: Modern all-ceramic FPDs seem to be an appropriate therapy not only for single restorations but for complex occlusal rehabilitations. PMID- 29503711 TI - Metal-ceramic bond strength between a feldspathic porcelain and a Co-Cr alloy fabricated with Direct Metal Laser Sintering technique. AB - PURPOSE: The aim of the present study was to record the metal-ceramic bond strength of a feldspathic dental porcelain and a Co-Cr alloy, using the Direct Metal Laser Sintering technique (DMLS) for the fabrication of metal substrates. MATERIALS AND METHODS: Ten metal substrates were fabricated with powder of a dental Co-Cr alloy using DMLS technique (test group) in dimensions according to ISO 9693. Another ten substrates were fabricated with a casing dental Co-Cr alloy using classic casting technique (control group) for comparison. Another three substrates were fabricated using each technique to record the Modulus of Elasticity (E) of the used alloys. All substrates were examined to record external and internal porosity. Feldspathic porcelain was applied on the substrates. Specimens were tested using the three-point bending test. The failure mode was determined using optical and scanning electron microscopy. The statistical analysis was performed using t-test. RESULTS: Substrates prepared using DMLS technique did not show internal porosity as compared to those produced using the casting technique. The E of control and test group was 222 +/- 5.13 GPa and 227 +/- 3 GPa, respectively. The bond strength was 51.87 +/- 7.50 MPa for test group and 54.60 +/- 6.20 MPa for control group. No statistically significant differences between the two groups were recorded. The mode of failure was mainly cohesive for all specimens. CONCLUSION: Specimens produced by the DMLS technique cover the lowest acceptable metal-ceramic bond strength of 25 MPa specified in ISO 9693 and present satisfactory bond strength for clinical use. PMID- 29503712 TI - Comparative color and surface parameters of current esthetic restorative CAD/CAM materials. AB - PURPOSE: The purpose of this study was to derive and compare the inherent color (hue angle, chroma), translucency (TPSCI), surface gloss (DeltaE*SCE-SCI), and surface roughness (Ra) amongst selected shades and brands of three hybrid CAD/CAM blocks [GC Cerasmart (CS); Lava Ultimate (LU); Vita Enamic (VE)]. MATERIALS AND METHODS: The specimens (N = 225) were prepared into square-shaped (12 * 12 mm2) with different thicknesses and shades. The measurements of color, translucency, and surface gloss were performed by a reflection spectrophotometer. The surface roughness and surface topography were assessed by white light interferometry. RESULTS: Results revealed that hue and chroma values were influenced by the material type, material shade, and material thickness (P < .001). The order of hue angle amongst the materials was LU > CS > VE, whereas the order of chroma was VE > CS > LU. TPSCI results demonstrated a significant difference in terms of material types and material thicknesses (P <= .001). TPSCI values of the tested materials were ordered as LU > CS > VE. DeltaE*SCE-SCI and Ra results were significantly varied amongst the materials (P < .001) and amongst the shades (P < .05). The order of DeltaE*SCE-SCI amongst the materials were as follows LU > VE >= CS, whereas the order of Ra was CS >= VE > LU. CONCLUSION: Nano-ceramic and polymer-infiltrated-feldspathic ceramic-network CAD/CAM materials exhibited different optical, inherent color and surface parameters. PMID- 29503713 TI - Influence of nano alumina coating on the flexural bond strength between zirconia and resin cement. AB - PURPOSE: The purpose of this in vitro study is to examine the effects of a nano structured alumina coating on the adhesion between resin cements and zirconia ceramics using a four-point bending test. MATERIALS AND METHODS: 100 pairs of zirconium bar specimens were prepared with dimensions of 25 mm * 2 mm * 5 mm and cementation surfaces of 5 mm * 2 mm. The samples were divided into 5 groups of 20 pairs each. The groups are as follows: Group I (C) - Control with no surface modification, Group II (APA) - airborne-particle-abrasion with 110 um high-purity aluminum oxide (Al2O3) particles, Group III (ROC) - airborne-particle-abrasion with 110 um silica modified aluminum oxide (Al2O3 + SiO2) particles, Group IV (TCS) - tribochemical silica coated with Al2O3 particles, and Group V (AlC) - nano alumina coating. The surface modifications were assessed on two samples selected from each group by atomic force microscopy and scanning electron microscopy. The samples were cemented with two different self-adhesive resin cements. The bending bond strength was evaluated by mechanical testing. RESULTS: According to the ANOVA results, surface treatments, different cement types, and their interactions were statistically significant (P<.05). The highest flexural bond strengths were obtained in nanostructured alumina coated zirconia surfaces (50.4 MPa) and the lowest values were obtained in the control group (12.00 MPa), both of which were cemented using a self-adhesive resin cement. CONCLUSION: The surface modifications tested in the current study affected the surface roughness and flexural bond strength of zirconia. The nano alumina coating method significantly increased the flexural bond strength of zirconia ceramics. PMID- 29503714 TI - The effect of glazing and aging on the surface properties of CAD/CAM resin blocks. AB - PURPOSE: To investigate the effect of accelerated aging on surface properties of glazed CAD/CAM resin blocks using a 2D surface profilometer and a 3D non-contact optical profilometer. MATERIALS AND METHODS: Three types of CAD/CAM resin restorative materials, LAVA Ultimate (3M ESPE, St Paul, MN, USA), VITA Enamic (Vita Zahnfabrik H. Rauter, Bad Sackingen, Germany), and Cerasmart (GC Corparation, Tokyo, Japan) were used for this study. CAD/CAM blocks were cut in 3 mm thickness slabs and divided into three groups; Group 1: control group (specimens polished with 600 grit SCI paper); Group 2: specimens sandblasted, silanized, and glazed with Optiglaze Color (GC); Group 3: glazed specimens subjected to 5000 thermocycles (n=15). The surface roughness (Ra and Rz) was evaluated using a profilometer and a 3D scanning instrument. Data were analyzed using two-way ANOVA and Tukey's post-hoc test (P<.05). RESULTS: LAVA, VITA, and Cerasmart exhibited statistically similar Ra and Rz values for each group (P>.05). For VITA and Cerasmart, the specimens in Group 1 exhibited significantly higher Ra values than Group 2 (P<.05). Group 1 (0.502 Ra), Group 2 (0.384 Ra), and Group 3 (0.431 Ra) exhibited statistically similar Ra values for LAVA (P=.062). After 5000 thermocycles, surface roughness values did not change significantly for glazed LAVA, VITA, and Cerasmart (P>.05). CONCLUSION: Glaze material Optiglaze Color makes CAD/CAM resin surfaces smooth and glazed CAD/CAM surfaces seem resistant to deterioration under 5000 thermocycles. PMID- 29503715 TI - A comparison of the accuracy of intraoral scanners using an intraoral environment simulator. AB - PURPOSE: The aim of this study was to design an intraoral environment simulator and to assess the accuracy of two intraoral scanners using the simulator. MATERIALS AND METHODS: A box-shaped intraoral environment simulator was designed to simulate two specific intraoral environments. The cast was scanned 10 times by Identica Blue (MEDIT, Seoul, South Korea), TRIOS (3Shape, Copenhagen, Denmark), and CS3500 (Carestream Dental, Georgia, USA) scanners in the two simulated groups. The distances between the left and right canines (D3), first molars (D6), second molars (D7), and the left canine and left second molar (D37) were measured. The distance data were analyzed by the Kruskal-Wallis test. RESULTS: The differences in intraoral environments were not statistically significant (P>.05). Between intraoral scanners, statistically significant differences (P<.05) were revealed by the Kruskal-Wallis test with regard to D3 and D6. CONCLUSION: No difference due to the intraoral environment was revealed. The simulator will contribute to the higher accuracy of intraoral scanners in the future. PMID- 29503716 TI - Fracture resistance of implant- supported monolithic crowns cemented to zirconia hybrid-abutments: zirconia-based crowns vs. lithium disilicate crowns. AB - PURPOSE: The aim of this in vitro study was to investigate the fracture resistance under chewing simulation of implant-supported posterior restorations (crowns cemented to hybrid-abutments) made of different all-ceramic materials. MATERIALS AND METHODS: Monolithic zirconia (MZr) and monolithic lithium disilicate (MLD) crowns for mandibular first molar were fabricated using computer aided design/computer-aided manufacturing technology and then cemented to zirconia hybrid-abutments (Ti-based). Each group was divided into two subgroups (n=10): (A) control group, crowns were subjected to single load to fracture; (B) test group, crowns underwent chewing simulation using multiple loads for 1.2 million cycles at 1.2 Hz with simultaneous thermocycling between 5C and 55C. Data was statistically analyzed with one-way ANOVA and a Post-Hoc test. RESULTS: All tested crowns survived chewing simulation resulting in 100% survival rate. However, wear facets were observed on all the crowns at the occlusal contact point. Fracture load of monolithic lithium disilicate crowns was statistically significantly lower than that of monolithic zirconia crowns. Also, fracture load was significantly reduced in both of the all-ceramic materials after exposure to chewing simulation and thermocycling. Crowns of all test groups exhibited cohesive fracture within the monolithic crown structure only, and no abutment fractures or screw loosening were observed. CONCLUSION: When supported by implants, monolithic zirconia restorations cemented to hybrid abutments withstand masticatory forces. Also, fatigue loading accompanied by simultaneous thermocycling significantly reduces the strength of both of the all-ceramic materials. Moreover, further research is needed to define potentials, limits, and long-term serviceability of the materials and hybrid abutments. PMID- 29503717 TI - Comparison of removal torques between laser-etched and modified sandblasted acid etched Ti implant surfaces in rabbit tibias. AB - PURPOSE: The purpose of this study was to analyze the effects of two different implant surface treatments on initial bone connection by comparing the Removal Torque Values (RTQs) at 7 and 10 days after chemically modified, sandblasted, large-grit and acid-etched (modSLA), and Laser-etched (LE) Ti implant placements. MATERIALS AND METHODS: Twenty modSLA and 20 LE implants were installed on the left and right tibias of 20 adult rabbits. RTQs were measured after 7 and 10 days in 10 rabbits each. Scanning electron microscope (SEM) photographs of the two implants were observed by using Quanta FEG 650 from the FEI company (Hillsboro, OR, USA). Analyses of surface elements and components were conducted using energy dispersive spectroscopy (EDS, Horiba, Kyoto, Japan). RESULTS: The mean RTQs were 12.29 +/- 0.830 and 12.19 +/- 0.713 Ncm after 7 days (P=.928) and 16.47 +/- 1.324 and 16.17 +/- 1.165 Ncm after 10 days (P=.867) for LE and modSLA, respectively, indicating no significant inter-group differences. Pore sizes in the LE were 40 um and consisted of numerous small pores, whereas pore sizes in the modSLA were 5 um. In the EDS analysis, Ti, O, and C were the only three elements found in the LE surfaces. Na, Ca, Cl, and K were also observed in modSLA, in addition to Ti, O, and C. CONCLUSION: The implants showed no significant difference in biomechanical bond strength to bone in early-stage osseointegration. LE implant can be considered an excellent surface treatment method in addition to the modSLA implant and can be applied to the early loading of the prosthesis clinically. PMID- 29503718 TI - Uncertainty in multispectral lidar signals caused by incidence angle effects. AB - Multispectral terrestrial laser scanning (TLS) is an emerging technology. Several manufacturers already offer commercial dual or three wavelength airborne laser scanners, while multispectral TLS is still carried out mainly with research instruments. Many of these research efforts have focused on the study of vegetation. The aim of this paper is to study the uncertainty of the measurement of spectral indices of vegetation with multispectral lidar. Using two spectral indices as examples, we find that the uncertainty is due to systematic errors caused by the wavelength dependency of laser incidence angle effects. This finding is empirical, and the error cannot be removed by modelling or instrument modification. The discovery and study of these effects has been enabled by hyperspectral and multispectral TLS, and it has become a subject of active research within the past few years. We summarize the most recent studies on multi wavelength incidence angle effects and present new results on the effect of specular reflection from the leaf surface, and the surface structure, which have been suggested to play a key role. We also discuss the consequences to the measurement of spectral indices with multispectral TLS, and a possible correction scheme using a synthetic laser footprint. PMID- 29503719 TI - Comparing terrestrial laser scanning and unmanned aerial vehicle structure from motion to assess top of canopy structure in tropical forests. AB - Terrestrial laser scanning (TLS) and unmanned aerial vehicles (UAVs) equipped with digital cameras have attracted much attention from the forestry community as potential tools for forest inventories and forest monitoring. This research fills a knowledge gap about the viability and dissimilarities of using these technologies for measuring the top of canopy structure in tropical forests. In an empirical study with data acquired in a Guyanese tropical forest, we assessed the differences between top of canopy models (TCMs) derived from TLS measurements and from UAV imagery, processed using structure from motion. Firstly, canopy gaps lead to differences in TCMs derived from TLS and UAVs. UAV TCMs overestimate canopy height in gap areas and often fail to represent smaller gaps altogether. Secondly, it was demonstrated that forest change caused by logging can be detected by both TLS and UAV TCMs, although it is better depicted by the TLS. Thirdly, this research shows that both TLS and UAV TCMs are sensitive to the small variations in sensor positions during data collection. TCMs rendered from UAV data acquired over the same area at different moments are more similar (RMSE 0.11-0.63 m for tree height, and 0.14-3.05 m for gap areas) than those rendered from TLS data (RMSE 0.21-1.21 m for trees, and 1.02-2.48 m for gaps). This study provides support for a more informed decision for choosing between TLS and UAV TCMs to assess top of canopy in a tropical forest by advancing our understanding on: (i) how these technologies capture the top of the canopy, (ii) why their ability to reproduce the same model varies over repeated surveying sessions and (iii) general considerations such as the area coverage, costs, fieldwork time and processing requirements needed. PMID- 29503720 TI - On the utilization of novel spectral laser scanning for three-dimensional classification of vegetation elements. AB - The Dual-Wavelength Echidna Lidar (DWEL), a full waveform terrestrial laser scanner (TLS), has been used to scan a variety of forested and agricultural environments. From these scanning campaigns, we summarize the benefits and challenges given by DWEL's novel coaxial dual-wavelength scanning technology, particularly for the three-dimensional (3D) classification of vegetation elements. Simultaneous scanning at both 1064 nm and 1548 nm by DWEL instruments provides a new spectral dimension to TLS data that joins the 3D spatial dimension of lidar as an information source. Our point cloud classification algorithm explores the utilization of both spectral and spatial attributes of individual points from DWEL scans and highlights the strengths and weaknesses of each attribute domain. The spectral and spatial attributes for vegetation element classification each perform better in different parts of vegetation (canopy interior, fine branches, coarse trunks, etc.) and under different vegetation conditions (dead or live, leaf-on or leaf-off, water content, etc.). These environmental characteristics of vegetation, convolved with the lidar instrument specifications and lidar data quality, result in the actual capabilities of spectral and spatial attributes to classify vegetation elements in 3D space. The spectral and spatial information domains thus complement each other in the classification process. The joint use of both not only enhances the classification accuracy but also reduces its variance across the multiple vegetation types we have examined, highlighting the value of the DWEL as a new source of 3D spectral information. Wider deployment of the DWEL instruments is in practice currently held back by challenges in instrument development and the demands of data processing required by coaxial dual- or multi-wavelength scanning. But the simultaneous 3D acquisition of both spectral and spatial features, offered by new multispectral scanning instruments such as the DWEL, opens doors to study biophysical and biochemical properties of forested and agricultural ecosystems at more detailed scales. PMID- 29503721 TI - Estimation of vegetation water content at leaf and canopy level using dual wavelength commercial terrestrial laser scanners. AB - Vegetation water content, quantified as the leaf equivalent water thickness (EWT), can serve as an indicator of vegetation stress. The intensity data recorded by terrestrial laser scanning (TLS) instruments, operating at shortwave infrared wavelengths, can be used to estimate the three-dimensional distribution of EWT, after a full and rigorous calibration for the range and incidence angle effects. However, TLS instruments do not record the incidence angles automatically, making calibration challenging. In this study, intensity data from two commercially available TLS instruments (Leica P40, 1550 nm shortwave infrared wavelength, and Leica P20, 808 nm near-infrared wavelength) were combined in a normalized difference index (NDI). The NDI was found to minimize the incidence angle effects with no need for further calibration. A dry-down experiment was conducted using deciduous and conifer canopies. The NDI was found to be highly correlated to EWT at leaf level (R2 of 0.91 and 0.74) and at canopy level (R2 of 0.89 and 0.74) for the deciduous and conifer canopies, respectively. Three dimensional distributions of EWT at canopy level were generated, which revealed some vertical heterogeneity. PMID- 29503722 TI - Bounding uncertainty in volumetric geometric models for terrestrial lidar observations of ecosystems. AB - Volumetric models with known biases are shown to provide bounds for the uncertainty in estimations of volume for ecologically interesting objects, observed with a terrestrial laser scanner (TLS) instrument. Bounding cuboids, three-dimensional convex hull polygons, voxels, the Outer Hull Model and Square Based Columns (SBCs) are considered for their ability to estimate the volume of temperate and tropical trees, as well as geomorphological features such as bluffs and saltmarsh creeks. For temperate trees, supplementary geometric models are evaluated for their ability to bound the uncertainty in cylinder-based reconstructions, finding that coarser volumetric methods do not currently constrain volume meaningfully, but may be helpful with further refinement, or in hybridized models. Three-dimensional convex hull polygons consistently overestimate object volume, and SBCs consistently underestimate volume. Voxel estimations vary in their bias, due to the point density of the TLS data, and occlusion, particularly in trees. The response of the models to parametrization is analysed, observing unexpected trends in the SBC estimates for the drumlin dataset. Establishing that this result is due to the resolution of the TLS observations being insufficient to support the resolution of the geometric model, it is suggested that geometric models with predictable outcomes can also highlight data quality issues when they produce illogical results. PMID- 29503723 TI - The potential to characterize ecological data with terrestrial laser scanning in Harvard Forest, MA. AB - Contemporary terrestrial laser scanning (TLS) is being used widely in forest ecology applications to examine ecosystem properties at increasing spatial and temporal scales. Harvard Forest (HF) in Petersham, MA, USA, is a long-term ecological research (LTER) site, a National Ecological Observatory Network (NEON) location and contains a 35 ha plot which is part of Smithsonian Institution's Forest Global Earth Observatory (ForestGEO). The combination of long-term field plots, eddy flux towers and the detailed past historical records has made HF very appealing for a variety of remote sensing studies. Terrestrial laser scanners, including three pioneering research instruments: the Echidna Validation Instrument, the Dual-Wavelength Echidna Lidar and the Compact Biomass Lidar, have already been used both independently and in conjunction with airborne laser scanning data and forest census data to characterize forest dynamics. TLS approaches include three-dimensional reconstructions of a plot over time, establishing the impact of ice storm damage on forest canopy structure, and characterizing eastern hemlock (Tsuga canadensis) canopy health affected by an invasive insect, the hemlock woolly adelgid (Adelges tsugae). Efforts such as those deployed at HF are demonstrating the power of TLS as a tool for monitoring ecological dynamics, identifying emerging forest health issues, measuring forest biomass and capturing ecological data relevant to other disciplines. This paper highlights various aspects of the ForestGEO plot that are important to current TLS work, the potential for exchange between forest ecology and TLS, and emphasizes the strength of combining TLS data with long-term ecological field data to create emerging opportunities for scientific study. PMID- 29503724 TI - Non-intersecting leaf insertion algorithm for tree structure models. AB - We present an algorithm and an implementation to insert broadleaves or needleleaves into a quantitative structure model according to an arbitrary distribution, and a data structure to store the required information efficiently. A structure model contains the geometry and branching structure of a tree. The purpose of this work is to offer a tool for making more realistic simulations of tree models with leaves, particularly for tree models developed from terrestrial laser scanning (TLS) measurements. We demonstrate leaf insertion using cylinder based structure models, but the associated software implementation is written in a way that enables the easy use of other types of structure models. Distributions controlling leaf location, size and angles as well as the shape of individual leaves are user definable, allowing any type of distribution. The leaf generation process consist of two stages, the first of which generates individual leaf geometry following the input distributions, while in the other stage intersections are prevented by carrying out transformations when required. Initial testing was carried out on English oak trees to demonstrate the approach and to assess the required computational resources. Depending on the size and complexity of the tree, leaf generation takes between 6 and 18 min. Various leaf area density distributions were defined, and the resulting leaf covers were compared with manual leaf harvesting measurements. The results are not conclusive, but they show great potential for the method. In the future, if our method is demonstrated to work well for TLS data from multiple tree types, the approach is likely to be very useful for three-dimensional structure and radiative transfer simulation applications, including remote sensing, ecology and forestry, among others. PMID- 29503725 TI - Close-range laser scanning in forests: towards physically based semantics across scales. AB - Laser scanning with its unique measurement concept holds the potential to revolutionize the way we assess and quantify three-dimensional vegetation structure. Modern laser systems used at close range, be it on terrestrial, mobile or unmanned aerial platforms, provide dense and accurate three-dimensional data whose information just waits to be harvested. However, the transformation of such data to information is not as straightforward as for airborne and space-borne approaches, where typically empirical models are built using ground truth of target variables. Simpler variables, such as diameter at breast height, can be readily derived and validated. More complex variables, e.g. leaf area index, need a thorough understanding and consideration of the physical particularities of the measurement process and semantic labelling of the point cloud. Quantified structural models provide a framework for such labelling by deriving stem and branch architecture, a basis for many of the more complex structural variables. The physical information of the laser scanning process is still underused and we show how it could play a vital role in conjunction with three-dimensional radiative transfer models to shape the information retrieval methods of the future. Using such a combined forward and physically based approach will make methods robust and transferable. In addition, it avoids replacing observer bias from field inventories with instrument bias from different laser instruments. Still, an intensive dialogue with the users of the derived information is mandatory to potentially re-design structural concepts and variables so that they profit most of the rich data that close-range laser scanning provides. PMID- 29503726 TI - Weighing trees with lasers: advances, challenges and opportunities. AB - Terrestrial laser scanning (TLS) is providing exciting new ways to quantify tree and forest structure, particularly above-ground biomass (AGB). We show how TLS can address some of the key uncertainties and limitations of current approaches to estimating AGB based on empirical allometric scaling equations (ASEs) that underpin all large-scale estimates of AGB. TLS provides extremely detailed non destructive measurements of tree form independent of tree size and shape. We show examples of three-dimensional (3D) TLS measurements from various tropical and temperate forests and describe how the resulting TLS point clouds can be used to produce quantitative 3D models of branch and trunk size, shape and distribution. These models can drastically improve estimates of AGB, provide new, improved large-scale ASEs, and deliver insights into a range of fundamental tree properties related to structure. Large quantities of detailed measurements of individual 3D tree structure also have the potential to open new and exciting avenues of research in areas where difficulties of measurement have until now prevented statistical approaches to detecting and understanding underlying patterns of scaling, form and function. We discuss these opportunities and some of the challenges that remain to be overcome to enable wider adoption of TLS methods. PMID- 29503727 TI - Spectral and spatial information from a novel dual-wavelength full-waveform terrestrial laser scanner for forest ecology. AB - The Salford Advanced Laser Canopy Analyser (SALCA) is an experimental terrestrial laser scanner designed and built specifically to measure the structural and biophysical properties of forest canopies. SALCA is a pulsed dual-wavelength instrument with co-aligned laser beams recording backscattered energy at 1063 and 1545 nm; it records full-waveform data by sampling the backscattered energy at 1 GHz giving a range resolution of 150 mm. The finest angular sampling resolution is 1 mrad and around 9 million waveforms are recorded over a hemisphere above the tripod-mounted scanner in around 110 min. Starting in 2010, data pre-processing and calibration approaches, data analysis and information extraction methods were developed and a wide range of field experiments conducted. The overall objective is to exploit the spatial, spectral and temporal characteristics of the data to produce ecologically useful information on forest and woodland canopies including leaf area index, plant area volume density and leaf biomass, and to explore the potential for tree species identification and classification. This paper outlines the key challenges in instrument development, highlights the potential applications for providing new data for forest ecology, and describes new avenues for exploring information-rich data from the next generation of terrestrial laser scanners instruments like SALCA. PMID- 29503728 TI - New perspectives on the ecology of tree structure and tree communities through terrestrial laser scanning. AB - Terrestrial laser scanning (TLS) opens up the possibility of describing the three dimensional structures of trees in natural environments with unprecedented detail and accuracy. It is already being extensively applied to describe how ecosystem biomass and structure vary between sites, but can also facilitate major advances in developing and testing mechanistic theories of tree form and forest structure, thereby enabling us to understand why trees and forests have the biomass and three-dimensional structure they do. Here we focus on the ecological challenges and benefits of understanding tree form, and highlight some advances related to capturing and describing tree shape that are becoming possible with the advent of TLS. We present examples of ongoing work that applies, or could potentially apply, new TLS measurements to better understand the constraints on optimization of tree form. Theories of resource distribution networks, such as metabolic scaling theory, can be tested and further refined. TLS can also provide new approaches to the scaling of woody surface area and crown area, and thereby better quantify the metabolism of trees. Finally, we demonstrate how we can develop a more mechanistic understanding of the effects of avoidance of wind risk on tree form and maximum size. Over the next few years, TLS promises to deliver both major empirical and conceptual advances in the quantitative understanding of trees and tree-dominated ecosystems, leading to advances in understanding the ecology of why trees and ecosystems look and grow the way they do. PMID- 29497493 TI - CellMap visualizes protein-protein interactions and subcellular localization. AB - Many tools visualize protein-protein interaction (PPI) networks. The tool introduced here, CellMap, adds one crucial novelty by visualizing PPI networks in the context of subcellular localization, i.e. the location in the cell or cellular component in which a PPI happens. Users can upload images of cells and define areas of interest against which PPIs for selected proteins are displayed (by default on a cartoon of a cell). Annotations of localization are provided by the user or through our in-house database. The visualizer and server are written in JavaScript, making CellMap easy to customize and to extend by researchers and developers. PMID- 29503730 TI - A new triazine bearing a pyrazolone group capable of copper, nickel, and zinc chelation. AB - Interests in inorganic applications of triazines is growing. In this report, metal complexes of copper(II), nickel(II), and zinc(II) and a novel class of chelates comprising a triazine ring substituted with a hydrazine group and pyralozone are evaluated using spectrophotometric methods, single crystal X-ray diffractometry, and electrochemistry. Complexes with copper(II) include a single chelate and two chloride atoms to satisfy a trigonal bipryamidal coordination sphere. The nickel(II) and zinc(II) complexes are comprised of two chelating groups that adopt an octahedral geometry around the metal ion. Irreversible redox activity was observed with the copper(II) complex but no redox activity was observed with the ligand alone or zinc(II) and nickel(II) complexes. Use of the coumarin carboxylic acid assay shows that the ligand motif is capable of preventing redox cycling of copper in biological conditions and could thus serve as an antioxidant preventative agent. Cellular toxicity studies show that the new triazine molecule could have therapeutic applications in the uM concentration range based on the measured EC50=1.183+/-2 mM. Altogether this work shows that by merging triazine chemistry into inorganic compounds, there is potential to explore a range applications thanks to the new architecture. PMID- 29503731 TI - Social influence on 5-year survival in a longitudinal chemotherapy ward co presence network. AB - Chemotherapy is often administered in openly designed hospital wards, where the possibility of patient-patient social influence on health exists. Previous research found that social relationships influence cancer patient's health; however, we have yet to understand social influence among patients receiving chemotherapy in the hospital. We investigate the influence of co-presence in a chemotherapy ward. We use data on 4,691 cancer patients undergoing chemotherapy in Oxfordshire, United Kingdom who average 59.8 years of age, and 44% are Male. We construct a network of patients where edges exist when patients are co-present in the ward, weighted by both patients' time in the ward. Social influence is based on total weighted co-presence with focal patients' immediate neighbors, considering neighbors' 5-year mortality. Generalized estimating equations evaluated the effect of neighbors' 5-year mortality on focal patient's 5-year mortality. Each 1,000-unit increase in weighted co-presence with a patient who dies within 5 years increases a patient's mortality odds by 42% (beta = 0.357, CI:0.204,0.510). Each 1,000-unit increase in co-presence with a patient surviving 5 years reduces a patient's odds of dying by 30% (beta = -0.344, CI: 0.538,0.149). Our results suggest that social influence occurs in chemotherapy wards, and thus may need to be considered in chemotherapy delivery. PMID- 29503732 TI - Sociodemographic and behavioral characteristics associated with self-reported diagnosed diabetes mellitus in adults aged 50+ years in Ghana and South Africa: results from the WHO-SAGE wave 1. AB - Objective: The objective is to identify and describe the sociodemographic and behavioral characteristics of adults, aged 50 years and over, who self-reported having been diagnosed and treated for diabetes mellitus (DM) in Ghana and South Africa. Research design and methods: This is a cross-sectional study based on the WHO Study on global AGEing and adult health (SAGE) wave 1. Information on sociodemographic factors, health states, risk factors and chronic conditions is captured from questionnaires administered in face-to-face interviews. Self reported diagnosed and treated DM is confirmed through a 'yes' response to questions regarding1 having previously been diagnosed with DM, and2 having taken insulin or other blood sugar lowering medicines. Crude and adjusted logistic regressions test associations between candidate variables and DM status. Analyses include survey sampling weights. The variance inflation factor statistic tested for multicollinearity. Results: In this nationally representative sample of adults aged 50 years and over in Ghana, after adjusting for the effects of sex, residence, work status, body mass index, waist-hip and waist-height ratios, smoking, alcohol, fruit and vegetable intake and household wealth, WHO-SAGE survey respondents who were older, married, had higher education, very high-risk waist circumference measurements and did not undertake high physical activity, were significantly more likely to report diagnosed and treated DM. In South Africa, respondents who were older, lived in urban areas and had high-risk waist circumference measurements were significantly more likely to report diagnosed and treated DM. Conclusions: Countries in sub-Saharan Africa are challenged by unprecedented ageing populations and transition from communicable to non communicable diseases such as DM. Information on those who are already diagnosed and treated needs to be combined with estimates of those who are prediabetic or, as yet, undiagnosed. Multisectoral approaches that include socioculturally appropriate strategies are needed to address diverse populations in SSA countries. PMID- 29503733 TI - Clinicopathological and immunological characteristics and outcome of concomitant coeliac disease and non-alcoholic fatty liver disease in adults: a large prospective longitudinal study. AB - Objective: Concomitant non-alcoholic fatty liver disease (NAFLD) and coeliac disease (CD) have not been adequately studied. This study investigated the frequency of CD among NAFLD patients and the clinicopathological and immunological patterns and outcome of concomitant NAFLD and CD. Design: This prospective longitudinal study screened patients with NAFLD for CD (tissue transglutaminase antibodies (TTGA); anti-TTGA and antiendomysial antibodies (EMA)). Patients with concomitant NAFLD and CD and patients with either NAFLD or CD were enrolled and followed. Duodenal biopsy, transient elastography, tumour necrosis factor (TNF)-alpha, transforming growth factor-beta, interleukins (ILs) 1, 6, 10, 15 and 17, folic acid and vitamins B12 and D were performed at baseline and 1 year after gluten-free diet (GFD). Results: CD was confirmed in 7.2% of patients with NAFLD. Refractory anaemia and nutritional deficiencies were frequent in patients with concomitant NAFLD and CD who had advanced intestinal and hepatic lesions, higher levels of TNF-alpha, IL-15 and IL-17 compared with patients with CD and NAFLD. Patients concomittant CD and NAFLD showed clinical response to GFD, but intestinal histological improvement was suboptimal. Combining EMA-IgA or anti-TTGA with either IL-15 or IL-17 enhances the prognostic performance of both tests in predicting histological response to GFD. Conclusion: Concomitant NAFLD and CD is not uncommon. Recurrent abdominal symptoms, refractory anaemia, nutritional deficiencies in patients with NAFLD warrant screening for CD. The study has important clinical implications since failure in diagnosing CD in patients with NAFLD patients results in marked intestinal and hepatic damage and suboptimal response to GFD that can be alleviated by early diagnosis and initiation of GFD. PMID- 29503734 TI - Oral rehydration solution (OS-1) as a substitute of intravenous hydration after cisplatin administration in patients with lung cancer: a prospective multicenter trial. AB - Background: The aim of this trial was to evaluate the safety and efficacy of oral hydration as a substitute for intravenous hydration after cisplatin (CDDP) administration. Methods: The major eligibility criteria included patients with lung cancer, indications for a CDDP-based regimen at a dose of 60 mg/m2 or higher, an age of between 20 and 74 years and adequate renal function. Antiemetic prophylaxis consisted of an appropriate dose of palonosetron, aprepitant, dexamethasone and magnesium sulfate (8 mEq). Five hundred millilitres of commercially available oral hydration solution (OS-1: Otsuka Pharmaceutical Factory, Tokushima, Japan) was used as a substitute for intravenous posthydration. The planned sample size was 46 to reject a proportion of 70% under an expectation of 88% with a power of 90% and an alpha error of 5%. Results: Between May and November 2013, 31 men and 15 women with a median (range) age of 65 (33-74) years were enrolled from three institutions. Of these, five received adjuvant chemotherapy, 17 received definitive chemoradiotherapy and 24 received chemotherapy for advanced diseases. The median (range) number of chemotherapy cycles was 4 (1-5). After the first cycle of CDDP administration, none of the patients experienced a creatinine elevation of grade 2 or higher, thereby meeting the primary endpoint. Of the 46 patients, 45 (97.8%, 95% CI 88.2 to 99.9) completed the CDDP-based chemotherapy without grade 2 or higher renal dysfunction. Conclusion: Oral hydration can be used as a safe and convenient substitute for intravenous posthydration for CDDP administration at the standard dose. Trial registration number: UMIN000010201. PMID- 29503735 TI - The Evolving Collaborative Relationship between Practice-Based Research Networks (PBRNs) and Clinical and Translational Science Awardees (CTSAs). AB - Purpose: Clinical and Translational Science Awards (CTSAs) and Practice-based Research Networks (PBRNs) have complementary missions. We replicated a 2008 survey of CTSA-PBRN leaders to understand how organizational relationships have evolved. Methods: We surveyed 60 CTSA community engagement (CE) Directors and 135 PBRN Directors and analyzed data using between and within-group comparisons. Results: Forty-three percent of CTSA CE Directors (26/60) and forty-two percent of PBRN Directors (57/135) responded. Quantitative responses revealed growing alignment between CTSA/PBRN perceptions, with a few areas of discordance. CE Directors noted declining financial support for PBRNs. PBRN Directors identified greater CTSA effectiveness in PBRN engagement, consultation, and collaborative grant submissions. Qualitative data revealed divergent experiences across CTSA/PBRN programs. Conclusions: Relationships between CTSAs and PBRNs are maturing; for some that means strengthening and for others a growing vulnerability. Findings suggest a mutual opportunity for PBRNs and CTSAs around applied research. Studies to characterize exemplar CTSA-PBRN collaborations are needed. PMID- 29503736 TI - Control of Innate and Adaptive Lymphocytes by the RAR-Retinoic Acid Axis. AB - Lymphocytes, such as T cells, B cells, and innate lymphoid cells (ILCs), play central roles in regulating immune responses. Retinoic acids (RAs) are vitamin A metabolites, produced and metabolized by certain tissue cells and myeloid cells in a tissue-specific manner. It has been established that RAs induce gut-homing receptors on T cells, B cells, and ILCs. A mounting body of evidence indicates that RAs exert far-reaching effects on functional differentiation and fate of these lymphocytes. For example, RAs promote effector T cell maintenance, generation of induced gut-homing regulatory and effector T cell subsets, antibody production by B cells, and functional maturation of ILCs. Key functions of RAs in regulating major groups of innate and adaptive lymphocytes are highlighted in this article. PMID- 29503737 TI - Regulation of Cellular Antiviral Signaling by Modifications of Ubiquitin and Ubiquitin-like Molecules. AB - The initiation of cellular antiviral signaling depends on host pattern recognition receptors (PRRs)-mediated recognition of viral nucleic acids that are known as classical pathogen-associated molecular patterns (PAMPs). PRRs recruit adaptor proteins and kinases to activate transcription factors and epigenetic modifiers to regulate transcription of hundreds of genes, the products of which collaborate to elicit antiviral responses. In addition, PRRs-triggered signaling induces activation of various inflammasomes which leads to the release of IL 1beta and inflammation. Recent studies have demonstrated that PRRs-triggered signaling is critically regulated by ubiquitin and ubiquitin-like molecules. In this review, we first summarize an updated understanding of cellular antiviral signaling and virus-induced activation of inflammasome and then focus on the regulation of key components by ubiquitin and ubiquitin-like molecules. PMID- 29503738 TI - Tissue-specific Role of CX3CR1 Expressing Immune Cells and Their Relationships with Human Disease. AB - Chemokine (C-X3-C motif) ligand 1 (CX3CL1, also known as fractalkine) and its receptor chemokine (C-X3-C motif) receptor 1 (CX3CR1) are widely expressed in immune cells and non-immune cells throughout organisms. However, their expression is mostly cell type-specific in each tissue. CX3CR1 expression can be found in monocytes, macrophages, dendritic cells, T cells, and natural killer (NK) cells. Interaction between CX3CL1 and CX3CR1 can mediate chemotaxis of immune cells according to concentration gradient of ligands. CX3CR1 expressing immune cells have a main role in either pro-inflammatory or anti-inflammatory response depending on environmental condition. In a given tissue such as bone marrow, brain, lung, liver, gut, and cancer, CX3CR1 expressing cells can maintain tissue homeostasis. Under pathologic conditions, however, CX3CR1 expressing cells can play a critical role in disease pathogenesis. Here, we discuss recent progresses of CX3CL1/CX3CR1 in major tissues and their relationships with human diseases. PMID- 29503739 TI - Regulation of Osteoclast Differentiation by Cytokine Networks. AB - Cytokines play a pivotal role in maintaining bone homeostasis. Osteoclasts (OCs), the sole bone resorbing cells, are regulated by numerous cytokines. Macrophage colony-stimulating factor and receptor activator of NF-kappaB ligand play a central role in OC differentiation, which is also termed osteoclastogenesis. Osteoclastogenic cytokines, including tumor necrosis factor-alpha, IL-1, IL-6, IL 7, IL-8, IL-11, IL-15, IL-17, IL-23, and IL-34, promote OC differentiation, whereas anti-osteoclastogenic cytokines, including interferon (IFN)-alpha, IFN beta, IFN-gamma, IL-3, IL-4, IL-10, IL-12, IL-27, and IL-33, downregulate OC differentiation. Therefore, dynamic regulation of osteoclastogenic and anti osteoclastogenic cytokines is important in maintaining the balance between bone resorbing OCs and bone-forming osteoblasts (OBs), which eventually affects bone integrity. This review outlines the osteoclastogenic and anti-osteoclastogenic properties of cytokines with regard to osteoimmunology, and summarizes our current understanding of the roles these cytokines play in osteoclastogenesis. PMID- 29503740 TI - Toll-like Receptor 1/2 Agonist Pam3CSK4 Suppresses Lipopolysaccharide-driven IgG1 Production while Enhancing IgG2a Production by B Cells. AB - Interaction between pathogen-associated molecular patterns and pattern recognition receptors triggers innate and adaptive immune responses. Several studies have reported that toll-like receptors (TLRs) are involved in B cell proliferation, differentiation, and Ig class switch recombination (CSR). However, roles of TLRs in B cell activation and differentiation are not completely understood. In this study, we investigated the direct effect of stimulation of TLR1/2 agonist Pam3CSK4 on mouse B cell viability, proliferation, activation, Ig production, and Ig CSR in vitro. Treatment with 0.5 ug/ml of Pam3CSK4 only barely induced IgG1 production although it enhanced B cell viability. In addition, high dosage Pam3CSK4 diminished IgG1 production in a dose-dependent manner, whereas the production of other Igs, cell viability, and proliferation increased. Pam3CSK4 additively increased TLR4 agonist lipopolysaccharide (LPS)-induced mouse B cell growth and activation. However, interestingly, Pam3CSK4 abrogated LPS induced IgG1 production but enhanced LPS-induced IgG2a production. Further, Pam3CSK4 decreased LPS-induced germline gamma1 transcripts (GLTgamma1)/GLTepsilon expression but increased GLTgamma2a expression. On the other hand, Pam3CSK4 had no effect on LPS-induced plasma cell differentiation. Taken together, these results suggest that TLR1/2 agonist Pam3CSK4 acts as a potent mouse B cell mitogen in combination with TLR4 agonist LPS, but these 2 different TLR agonists play diverse roles in regulating the Ig CSR of each isotype, particularly IgG1/IgE and IgG2a. PMID- 29503741 TI - Beyond the Role of CD55 as a Complement Component. AB - The complement is a part of the immune system that plays several roles in removing pathogens. Despite the importance of the complement system, the exact role of each component has been overlooked because the complement system was thought to be a nonspecific humoral immune mechanism that worked against pathogens. Decay-accelerating factor (DAF or CD55) is a known inhibitor of the complement system and has recently attracted substantial attention due to its role in various diseases, such as cancer, protein-losing enteropathy, and malaria. Some protein-losing enteropathy cases are caused by CD55 deficiency, which leads to complement hyperactivation, malabsorption, and angiopathic thrombosis. In addition, CD55 has been reported to be an essential host receptor for infection by the malaria parasite. Moreover, CD55 is a ligand of the seven span transmembrane receptor CD97. Since CD55 is present in various cells, the functional role of CD55 has been expanded by showing that CD55 is associated with a variety of diseases, including cancer, malaria, protein-losing enteropathy, paroxysmal nocturnal hemoglobinuria, and autoimmune diseases. This review summarizes the current understanding of CD55 and the role of CD55 in these diseases. It also provides insight into the development of novel drugs for the diagnosis and treatment of diseases associated with CD55. PMID- 29503742 TI - Ectopically Expressed Membrane-bound Form of IL-9 Exerts Immune-stimulatory Effect on CT26 Colon Carcinoma Cells. AB - IL-9 is a known T cell growth factor with pleiotropic immunological functions, especially in parasite infection and colitis. However, its role in tumor growth is controversial. In this study, we generated tumor clones expressing the membrane-bound form of IL-9 (MB-IL-9) and investigated their influences on immune system. MB-IL-9 tumor clones showed reduced tumorigenicity but shortened survival accompanied with severe body weight loss in mice. MB-IL-9 expression on tumor cells had no effect on cell proliferation or major histocompatibility complex class I expression in vitro. MB-IL-9 tumor clones were effective in amplifying CD4+ and CD8+ T cells and increasing cytotoxic activity against CT26 cells in vivo. We also observed a prominent reduction in body weights and survival period of mice injected intraperitoneally with MB-IL-9 clones compared with control groups. Ratios of IL-17 to interferon (IFN)-gamma in serum level and tumor mass were higher in mice implanted with MB-IL-9 tumor clones than those observed in mice implanted with control cells. These results indicate that the ectopic expression of the MB-IL-9 on tumor cells exerts an immune-stimulatory effect with toxicity. To exploit its benefits as a tumor vaccine, a strategy to control the toxicity of MB-IL-9 tumor clones should be developed. PMID- 29503743 TI - Out-sourcing for Trans-presentation: Assessing T Cell Intrinsic and Extrinsic IL 15 Expression with Il15 Gene Reporter Mice. AB - IL-15 is a cytokine of the common gamma-chain family that is critical for natural killer (NK), invariant natural killer T (iNKT), and CD8 memory T cell development and homeostasis. The role of IL-15 in regulating effector T cell subsets, however, remains incompletely understood. IL-15 is mostly expressed by stromal cells, myeloid cells, and dendritic cells (DCs). Whether T cells themselves can express IL-15, and if so, whether such T cell-derived IL-15 could play an autocrine role in T cells are interesting questions that were previously addressed but answered with mixed results. Recently, three independent studies described the generation of IL-15 reporter mice which facilitated the identification of IL-15-producing cells and helped to clarify the role of IL-15 both in vitro and in vivo. Here, we review the findings of these studies and place them in context of recent reports that examined T cell-intrinsic IL-15 expression during CD4 effector T cell differentiation. PMID- 29503744 TI - The Role of Reactive Oxygen Species in Regulating T Cell-mediated Immunity and Disease. AB - T lymphocytes rely on several metabolic processes to produce the high amounts of energy and metabolites needed to drive clonal expansion and the development of effector functions. However, many of these pathways result in the production of reactive oxygen species (ROS), which have canonically been thought of as cytotoxic agents due to their ability to damage DNA and other subcellular structures. Interestingly, ROS has recently emerged as a critical second messenger for T cell receptor signaling and T cell activation, but the sensitivity of different T cell subsets to ROS varies. Therefore, the tight regulation of ROS production by cellular antioxidant pathways is critical to maintaining proper signal transduction without compromising the integrity of the cell. This review intends to detail the common metabolic sources of intracellular ROS and the mechanisms by which ROS contributes to the development of T cell mediated immunity. The regulation of ROS levels by the glutathione pathway and the Nrf2-Keap1-Cul3 trimeric complex will be discussed. Finally, T cell-mediated autoimmune diseases exacerbated by defects in ROS regulation will be further examined in order to identify potential therapeutic interventions for these disorders. PMID- 29503746 TI - A New Online Journal Management System. PMID- 29503745 TI - Regulation of Allergic Immune Responses by Microbial Metabolites. AB - Emerging evidence demonstrates that the microbiota plays an essential role in shaping the development and function of host immune responses. A variety of environmental stimuli, including foods and commensals, are recognized by the host through the epithelium, acting as a physical barrier. Two allergic diseases, atopic dermatitis and food allergy, are closely linked to the microbiota, because inflammatory responses occur on the epidermal border. The microbiota generates metabolites such as short-chain fatty acids and poly-gamma-glutamic acid (gammaPGA), which can modulate host immune responses. Here, we review how microbial metabolites can regulate allergic immune responses. Furthermore, we focus on the effect of gammaPGA on allergic T helper (Th) 2 responses and its therapeutic application. PMID- 29503748 TI - Scenario-Based Assessment of User Needs for Point-of-Care Robots. AB - Objectives: This study aimed to derive specific user requirements and barriers in a real medical environment to define the essential elements and functions of two types of point-of-care (POC) robot: a telepresence robot as a tool for teleconsultation, and a bedside robot to provide emotional care for patients. Methods: An analysis of user requirements was conducted; user needs were gathered and identified, and detailed, realistic scenarios were created. The prototype robots were demonstrated in physical environments for envisioning and evaluation. In all, three nurses and three clinicians participated as evaluators to observe the demonstrations and evaluate the robot systems. The evaluators were given a brief explanation of each scene and the robots' functionality. Four major functions of the teleconsultation robot were defined and tested in the demonstration. In addition, four major functions of the bedside robot were evaluated. Results: Among the desired functions for a teleconsultation robot, medical information delivery and communication had high priority. For a bedside robot, patient support, patient monitoring, and healthcare provider support were the desired functions. The evaluators reported that the teleconsultation robot can increase support from and access to specialists and resources. They mentioned that the bedside robot can improve the quality of hospital life. Problems identified in the demonstration were those of space conflict, communication errors, and safety issues. Conclusions: Incorporating this technology into healthcare services will enhance communication and teamwork skills across distances and thereby facilitate teamwork. However, repeated tests will be needed to evaluate and ensure improved performance. PMID- 29503747 TI - Enchanted Life Space: Adding Value to Smart Health by Integrating Human Desires. AB - Objectives: Developments in advanced technology have unlocked an era of smart health, transforming healthcare practices inside and outside hospitals for both medical staff and patients. It is now possible for patients to collect detailed health data using smartphones and wearable devices, regardless of their physical location or time zone. The use of these patient-generated data holds great promise for future healthcare advancements in many ways; however, current strategies for smart-health technologies tend to focus on the smartness of the technology itself and on managing a particular disease or condition. Moreover, opportunities for people within the healthcare system to experience the benefits of these innovations are still limited. Methods: An expert workshop was held to discuss the current limitations of smart health, where each expert gave a presentation on their particular expertise, followed by an exchange of ideas for the purpose of drawing conclusions. Results: 'Smartness' should not be the ultimate value for patients using smart technologies; instead of focusing on individual smart devices, we should consider the space around people and their relation to each object so that the combination of space and objects brings an 'enchanted' experience to user. Conclusions: An 'enchanted' experience can only be possible when monitoring provides the user with a comfortable life and satisfies their needs and desires sufficiently. Only when the novelty of the device's smartness effectively connects people with the space around them and focuses on human desires can it be cost effective and value creating. PMID- 29503749 TI - Bayesian-Based Decision Support System for Assessing the Needs for Orthodontic Treatment. AB - Objectives: In this study, a clinical decision support system was developed to help general practitioners assess the need for orthodontic treatment in patients with permanent dentition. Methods: We chose a Bayesian network (BN) as the underlying model for assessing the need for orthodontic treatment. One thousand permanent dentition patient data sets chosen from a hospital record system were prepared in which one data element represented one participant with information for all variables and their stated need for orthodontic treatment. To evaluate the system, we compared the assessment results based on the judgements of two orthodontists to those recommended by the decision support system. Results: In a BN decision support model, each variable is modelled as a node, and the causal relationship between two variables may be represented as a directed arc. For each node, a conditional probability table is supplied that represents the probabilities of each value of this node, given the conditions of its parents. There was a high degree of agreement between the two orthodontists (kappa value = 0.894) in their diagnoses and their judgements regarding the need for orthodontic treatment. Also, there was a high degree of agreement between the decision support system and orthodontists A (kappa value = 1.00) and B (kappa value = 0.894). Conclusions: The study was the first testing phase in which the results generated by the proposed system were compared with those suggested by expert orthodontists. The system delivered promising results; it showed a high degree of accuracy in classifying patients into groups needing and not needing orthodontic treatment. PMID- 29503750 TI - Comparison of Models for the Prediction of Medical Costs of Spinal Fusion in Taiwan Diagnosis-Related Groups by Machine Learning Algorithms. AB - Objectives: The aims of this study were to compare the performance of machine learning methods for the prediction of the medical costs associated with spinal fusion in terms of profit or loss in Taiwan Diagnosis-Related Groups (Tw-DRGs) and to apply these methods to explore the important factors associated with the medical costs of spinal fusion. Methods: A data set was obtained from a regional hospital in Taoyuan city in Taiwan, which contained data from 2010 to 2013 on patients of Tw-DRG49702 (posterior and other spinal fusion without complications or comorbidities). Naive-Bayesian, support vector machines, logistic regression, C4.5 decision tree, and random forest methods were employed for prediction using WEKA 3.8.1. Results: Five hundred thirty-two cases were categorized as belonging to the Tw-DRG49702 group. The mean medical cost was US $4,549.7, and the mean age of the patients was 62.4 years. The mean length of stay was 9.3 days. The length of stay was an important variable in terms of determining medical costs for patients undergoing spinal fusion. The random forest method had the best predictive performance in comparison to the other methods, achieving an accuracy of 84.30%, a sensitivity of 71.4%, a specificity of 92.2%, and an AUC of 0.904. Conclusions: Our study demonstrated that the random forest model can be employed to predict the medical costs of Tw-DRG49702, and could inform hospital strategy in terms of increasing the financial management efficiency of this operation. PMID- 29503751 TI - Evaluating the Dietary and Nutritional Apps in the Google Play Store. AB - Objectives: The objective of this study was to evaluate the features of diet and nutrition apps available in the Google Play Store. Methods: A search was conducted in August 2017 using the Google Play Store database to identify apps related to diet and nutrition. Terms entered into the app search engine included 'diet apps' and 'nutrition apps'. The first 50 apps resulting from each search term was assessed. Duplicates were removed, and a comparative analysis was performed on the remaining diet and nutrition apps. Results: A total of 86 diet and nutrition apps were identified. One hundred percent (n = 86) of the apps retrieved were freely available. More than half of the apps were applicable to a target user group of all ages (94%, n = 81). Stratified analysis across unique diet and nutrition apps (total, n = 72) showed a higher average rating for the diet apps (4.4) in comparison to that for the nutrition apps (4.3). Diet apps were more likely to be recently updated than the nutrition apps (72% vs. 66%), and diet apps were more likely to feature app purchase than nutrition apps (36% vs. 19%). The average rating was slightly higher for diet apps not featuring in app purchases, but ratings were similar for the nutrition apps. Conclusions: A centralized resource is needed that can provide information on health-related apps to allow for systematic evaluation of their effectiveness. Further research needs to examine improved methods of designing app-store platforms and presenting the available apps to properly guide users in app selection. PMID- 29503752 TI - Comparison and Analysis of ISO/IEEE 11073, IHE PCD-01, and HL7 FHIR Messages for Personal Health Devices. AB - Objectives: Increasing use of medical devices outside of healthcare facilities inevitably requires connectivity and interoperability between medical devices and healthcare information systems. To this end, standards have been developed and used to provide interoperability between personal health devices (PHDs) and external systems. ISO/IEEE 11073 standards and IHE PCD-01 standard messages have been used the most in the exchange of observation data of health devices. Recently, transmitting observation data using the HL7 FHIR standard has been devised in the name of DoF (Devices on FHIR) and adopted very fast. We compare and analyze these standards and suggest that which standard will work best at the different environments of device usage. Methods: We generated each message/resource of the three standards for observed vital signs from blood pressure monitor and thermometer. Then, the size, the contents, and the exchange processes of these messages are compared and analyzed. Results: ISO/IEEE 11073 standard message has the smallest data size, but it has no ability to contain the key information, patient information. On the other hand, PCD-01 messages and FHIR standards have the fields for patient information. HL7 DoF standards provide reusing of information unit known as resource, and it is relatively easy to parse DoF messages since it uses widely known XML and JSON. Conclusions: ISO/IEEE 11073 standards are suitable for devices having very small computing power. IHE PCD-01 and HL7 DoF messages can be used for the devices that need to be connected to hospital information systems that require patient information. When information reuse is frequent, DoF is advantageous over PCD-01. PMID- 29503753 TI - Automatic Glaucoma Detection Method Applying a Statistical Approach to Fundus Images. AB - Objectives: Glaucoma is an incurable eye disease and the second leading cause of blindness in the world. Until 2020, the number of patients of this disease is estimated to increase. This paper proposes a glaucoma detection method using statistical features and the k-nearest neighbor algorithm as the classifier. Methods: We propose three statistical features, namely, the mean, smoothness and 3rd moment, which are extracted from images of the optic nerve head. These three features are obtained through feature extraction followed by feature selection using the correlation feature selection method. To classify those features, we apply the k-nearest neighbor algorithm as a classifier to perform glaucoma detection on fundus images. Results: To evaluate the performance of the proposed method, 84 fundus images were used as experimental data consisting of 41 glaucoma image and 43 normal images. The performance of our proposed method was measured in terms of accuracy, and the overall result achieved in this work was 95.24%, respectively. Conclusions: This research showed that the proposed method using three statistics features achieves good performance for glaucoma detection. PMID- 29503754 TI - Trends in Research on the Security of Medical Information in Korea: Focused on Information Privacy Security in Hospitals. AB - Objectives: Information technology involves a risk of privacy violation in providing easy access to confidential information,such as personal information and medical information through the Internet. In this study, we investigated medical information security to gain a better understanding of trends in research related to medical information security. Methods: We researched papers published on '????' and 'medical information' in various Korean journals during a 10-year period from 2005 to 2015. We also analyzed these journal papers for each fiscal year; these papers were categorized into the areas of literature research and empirical research, and were further subdivided according to themes and subjects. Results: It was confirmed that 48 papers were submitted to 35 academic journals. There were 33 (68.8%) literature review articles, and analysis of secondary data was not carried out at all. In terms of empirical research, 8 (16.7%) surveys and 7 (14.6%) program developments were studied. As a result of analyzing these papers according to the research theme by research method, 17 (35.4%) papers on laws, systems, and policies were the most numerous. It was found that among the literature research papers on medical personnel were the most common, and among the empirical research papers, research on experts in information protection and medical personnel were the most common. Conclusions: We suggest that further research should be done in terms of social perception, human resource development, and technology development to improve risk management in medical information systems. PMID- 29503755 TI - Effects of Flipped Learning Using Online Materials in a Surgical Nursing Practicum: A Pilot Stratified Group-Randomized Trial. AB - Objectives: This study examined the effect of flipped learning in comparison to traditional learning in a surgical nursing practicum. Methods: The subjects of this study were 102 nursing students in their third year of university who were scheduled to complete a clinical nursing practicum in an operating room or surgical unit. Participants were randomly assigned to either a flipped learning group (n = 51) or a traditional learning group (n = 51) for the 1-week, 45-hour clinical nursing practicum. The flipped-learning group completed independent e learning lessons on surgical nursing and received a brief orientation prior to the commencement of the practicum, while the traditional-learning group received a face-to-face orientation and on-site instruction. After the completion of the practicum, both groups completed a case study and a conference. The student's self-efficacy, self-leadership, and problem-solving skills in clinical practice were measured both before and after the one-week surgical nursing practicum. Results: Participants' independent goal setting and evaluation of beliefs and assumptions for the subscales of self-leadership and problem-solving skills were compared for the flipped learning group and the traditional learning group. The results showed greater improvement on these indicators for the flipped learning group in comparison to the traditional learning group. Conclusions: The flipped learning method might offer more effective e-learning opportunities in terms of self-leadership and problem-solving than the traditional learning method in surgical nursing practicums. PMID- 29503756 TI - Customer Discovery as the First Essential Step for Successful Health Information Technology System Development. AB - Objectives: Customer discovery (CD) is a method to determine if there are actual customers for a product/service and what they would want before actually developing the product/service. This concept, however, is rather new to health information technology (IT) systems. Therefore, the aim of this paper was to demonstrate how to use the CD method in developing a comprehensive health IT service for patients with knee/leg pain. Methods: We participated in a 6-week I Corps program to perform CD, in which we interviewed 55 people in person, by phone, or by video conference within 6 weeks: 4 weeks in the United States and 2 weeks in Korea. The interviewees included orthopedic doctors, physical therapists, physical trainers, physicians, researchers, pharmacists, vendors, and patients. By analyzing the interview data, the aim was to revise our business model accordingly. Results: Using the CD approach enabled us to understand the customer segments and identify value propositions. We concluded that a facilitating tele-rehabilitation system is needed the most and that the most suitable customer segment is early stage arthritis patients. We identified a new design concept for the customer segment. Furthermore, CD is required to identify value propositions in detail. Conclusions: CD is crucial to determine a more desirable direction in developing health IT systems, and it can be a powerful tool to increase the potential for successful commercialization in the health IT field. PMID- 29503757 TI - Applying Deep Learning in Medical Images: The Case of Bone Age Estimation. AB - Objectives: A diagnostic need often arises to estimate bone age from X-ray images of the hand of a subject during the growth period. Together with measured physical height, such information may be used as indicators for the height growth prognosis of the subject. We present a way to apply the deep learning technique to medical image analysis using hand bone age estimation as an example. Methods: Age estimation was formulated as a regression problem with hand X-ray images as input and estimated age as output. A set of hand X-ray images was used to form a training set with which a regression model was trained. An image preprocessing procedure is described which reduces image variations across data instances that are unrelated to age-wise variation. The use of Caffe, a deep learning tool is demonstrated. A rather simple deep learning network was adopted and trained for tutorial purpose. Results: A test set distinct from the training set was formed to assess the validity of the approach. The measured mean absolute difference value was 18.9 months, and the concordance correlation coefficient was 0.78. Conclusions: It is shown that the proposed deep learning-based neural network can be used to estimate a subject's age from hand X-ray images, which eliminates the need for tedious atlas look-ups in clinical environments and should improve the time and cost efficiency of the estimation process. PMID- 29503758 TI - Correction: Development and Evaluation of an Obesity Ontology for Social Big Data Analysis. AB - [This corrects the article on p. 159 in vol. 23, PMID: 28875050.]. PMID- 29503760 TI - Semi-Autonomous Electrosurgery for Tumor Resection Using a Multi-Degree of Freedom Electrosurgical Tool and Visual Servoing. AB - This paper specifies a surgical robot performing semi-autonomous electrosurgery for tumor resection and evaluates its accuracy using a visual servoing paradigm. We describe the design and integration of a novel, multi-degree of freedom electrosurgical tool for the smart tissue autonomous robot (STAR). Standardized line tests are executed to determine ideal cut parameters in three different types of porcine tissue. STAR is then programmed with the ideal cut setting for porcine tissue and compared against expert surgeons using open and laparoscopic techniques in a line cutting task. We conclude with a proof of concept demonstration using STAR to semi-autonomously resect pseudo-tumors in porcine tissue using visual servoing. When tasked to excise tumors with a consistent 4mm margin, STAR can semi-autonomously dissect tissue with an average margin of 3.67 mm and a standard deviation of 0.89mm. PMID- 29503762 TI - Primitive Path Analysis and Stress Distribution in Highly Strained Macromolecules. AB - Polymer material properties are strongly affected by entanglement effects. For long polymer chains and composite materials, they are expected to be at the origin of many technically important phenomena, such as shear thinning or the Mullins effect, which microscopically can be related to topological constraints between chains. Starting from fully equilibrated highly entangled polymer melts, we investigate the effect of isochoric elongation on the entanglement structure and force distribution of such systems. Theoretically, the related viscoelastic response usually is discussed in terms of the tube model. We relate stress relaxation in the linear and nonlinear viscoelastic regimes to a primitive path analysis (PPA) and show that tension forces both along the original paths and along primitive paths, that is, the backbone of the tube, in the stretching direction correspond to each other. Unlike homogeneous relaxation along the chain contour, the PPA reveals a so far not observed long-lived clustering of topological constraints along the chains in the deformed state. PMID- 29503761 TI - A Spectrum Graph-Based Protein Sequence Filtering Algorithm for Proteoform Identification by Top-Down Mass Spectrometry. AB - Database search is the main approach for identifying proteoforms using top-down tandem mass spectra. However, it is extremely slow to align a query spectrum against all protein sequences in a large database when the target proteoform that produced the spectrum contains post-translational modifications and/or mutations. As a result, efficient and sensitive protein sequence filtering algorithms are essential for speeding up database search. In this paper, we propose a novel filtering algorithm, which generates spectrum graphs from subspectra of the query spectrum and searches them against the protein database to find good candidates. Compared with the sequence tag and gaped tag approaches, the proposed method circumvents the step of tag extraction, thus simplifying data processing. Experimental results on real data showed that the proposed method achieved both high speed and high sensitivity in protein sequence filtration. PMID- 29503759 TI - Functional ferritin nanoparticles for biomedical applications. AB - Ferritin, a major iron storage protein with a hollow interior cavity, has been reported recently to play many important roles in biomedical and bioengineering applications. Owing to the unique architecture and surface properties, ferritin nanoparticles offer favorable characteristics and can be either genetically or chemically modified to impart functionalities to their surfaces, and therapeutics or probes can be encapsulated in their interiors by controlled and reversible assembly/disassembly. There has been an outburst of interest regarding the employment of functional ferritin nanoparticles in nanomedicine. This review will highlight the recent advances in ferritin nanoparticles for drug delivery, bioassay, and molecular imaging with a particular focus on their biomedical applications. PMID- 29503763 TI - Perceptions of Chronic Disease Among Older African Americans: A Qualitative Analysis. AB - Research has documented that African Americans suffer disproportionately from chronic diseases when compared to the general population. Yet, limited research examines older African Americans' perceptions about having chronic diseases. Accordingly, the first aim of the study provided insight into this disparity with the intent of revealing how older African Americans feel about their overall health, and how much they understand about their individual chronic disease(s). The second aim was to gather information about strategies and coping mechanisms older African Americans use to manage their chronic diseases. The purpose of this aim was to determine if any of the strategies they employed were related to the positive health outcomes. Two focus groups were conducted with African American older adults who live in community settings. The results from the focus groups indicate that older African Americans are aware of the conditions they have and have developed strong coping methods to help them manage. Recommendations are provided for future research studies and chronic disease management programs. PMID- 29503764 TI - Improving the Efficiency of Electrical Stimulation Activities After Spinal Cord Injury. AB - In order to enhance spinal cord injury (SCI) rehabilitation programs using neuromuscular electrical stimulation (NMES) and functional electrical stimulation (FES) it is important to examine the manner in which muscle fibers are recruited and the dose-response relationship. A review of the literature suggests that premature force decline and early fatigue with NMES and FES activities may be alleviated with decreased current frequency and increased current intensity. Dose response relationships with NMES and FES are dependent on the goals of interest as reversing muscle atrophy can be achieved with activities 2-3 times per week for 6 or more weeks while increasing bone mass is more limited and requires more intense activity with greater exercise frequency and duration, e.g., 3-5 days per week for at least 6-12 months. The best known protocol to elicit neurological improvement is massed practice activities-based restorative therapies (ABRT) (3-5 h per day for several weeks). PMID- 29503766 TI - Anther development in tribe Epidendreae: orchids with contrasting pollination syndromes. AB - Background: Epidendreae is one of the most diverse tribes among the orchids with remarkable variation in life form, floral morphology and pollination syndromes. Its circumscription was recently revised and subtribes Agrostophyllinae and Calypsoinae were transferred into this tribe. One of the principal floral characters utilized in classification of orchids is the incumbency or bending of the column. This study records and compares late stages of anther, column and lip development, and discusses anther characters in fifteen representative taxa of five of the six subtribes in Epidendreae with respect to classification and pollination biology. Methods: A series of late floral stages were sampled and fixed for examination under scanning electron microscope. Results: Anther incumbency or bending in this group varies from 90 degrees to almost 180 degrees . Incumbency in the late stages of development is reached in Bletiinae, Ponerinae, Pleurothallidinae and Laeliinae whereas incumbency is reached early in its development in Corallorhiza and Govenia of Calypsoinae. Discussion: Our observations indicate that the position of Chysis in subtribe Bletiinae needs revision based on differences in a number floral, and in particular of anther characters; and that Coelia only shares the early anther incumbency with Calypsoinae members, but not the rest of floral and anther characters. Anatomical characters such as crystals around the actinocytic stomata on the anther cap and sugar crystals in Laeliinae; lack of rostellum in Bletiinae; coalescent anther with the column, lack of trichomes and papillae on lip keels, and underdeveloped rostellum in Chysis; a mechanism by which the anther cap comes off (it is joined with the grooved lip by a claw) in Isochilus are all related to pollination syndromes and reproductive biology. PMID- 29503765 TI - Genetic and Environmental Associations Between Procrastination and Internalizing/Externalizing Psychopathology. AB - Recent work on procrastination has begun to unravel the genetic and environmental correlates of this problematic behavior. However, little is known about how strongly procrastination is associated with internalizing and externalizing psychopathology, and the extent to which shared genetic/environmental factors or relevant personality constructs (e.g., fear of failure, impulsivity, and neuroticism) can inform the structure of these associations. The current study examined data from 764 young adult twins who completed questionnaires assessing procrastination and personality and structured interviews regarding psychopathology symptoms. Results indicated that procrastination was positively correlated with both internalizing and externalizing latent variables, and that these correlations were driven by shared genetic influences. Moreover, the association between procrastination and internalizing was accounted for by fear of failure and neuroticism, whereas the association between procrastination and externalizing was primarily explained by impulsivity. The role of procrastination in psychopathology is discussed using a framework that highlights common and broadband-specific variance. PMID- 29503767 TI - Pharmacokinetics and safety of oral glyburide in dogs with acute spinal cord injury. AB - Background: Glyburide (also known as glibenclamide) is effective in reducing the severity of tissue destruction and improving functional outcome after experimental spinal cord injury in rodents and so has promise as a therapy in humans. There are many important differences between spinal cord injury in experimental animals and in human clinical cases, making it difficult to introduce new therapies into clinical practice. Spinal cord injury is also common in pet dogs and requires new effective therapies, meaning that they can act as a translational model for the human condition while also deriving direct benefits from such research. In this study we investigated the pharmacokinetics and safety of glyburide in dogs with clinical spinal cord injury. Methods: We recruited dogs that had incurred an acute thoracolumbar spinal cord injury within the previous 72 h. These had become acutely non-ambulatory on the pelvic limbs and were admitted to our veterinary hospitals to undergo anesthesia, cross sectional diagnostic imaging, and surgical decompression. Oral glyburide was given to each dog at a dose of 75 mcg/kg. In five dogs, we measured blood glucose concentrations for 10 h after a single oral dose. In six dogs, we measured serum glyburide and glucose concentrations for 24 h and estimated pharmacokinetic parameters to estimate a suitable dose for use in a subsequent clinical trial in similarly affected dogs. Results: No detrimental effects of glyburide administration were detected in any participating dog. Peak serum concentrations of glyburide were attained at a mean of 13 h after dosing, and mean apparent elimination half-life was approximately 7 h. Observed mean maximum plasma concentration was 31 ng/mL. At the glyburide dose administered there was no observable association between glyburide and glucose concentrations in blood. Discussion: Our data suggest that glyburide can be safely administered to dogs that are undergoing anesthesia, imaging and surgery for treatment of their acute spinal cord injury and can attain clinically-relevant serum concentrations without developing hazardous hypoglycemia. Serum glyburide concentrations achieved in this study suggest that a loading dose of 150 mcg/kg followed by repeat doses of 75 mcg/kg at 8-hourly intervals would lead to serum glyburide concentrations of 25-50 ng/mL within an acceptably short enough period after oral administration to be appropriate for a clinical trial in canine spinal cord injury. PMID- 29503768 TI - Impact of parents' physical activity on preschool children's physical activity: a cross-sectional study. AB - Purpose: This study examined the associations of physical activity levels between parents and their pre-school children based on gender and weekday/weekend. Method: A total of 247 parent-preschool child triads from Shanghai, China were analyzed. The children had a mean age of 57.5 +/- 5.2 months. Both sedentary behavior and physical activity were measured in all participants using an ActiGraph GT3X+ accelerometer over seven consecutive days from Monday through the following Sunday. A multivariate regression model was derived to identify significant relationships between parental and child physical activity according to gender and weekday/weekend. Results: There was a significant correlation between mothers' and girls' moderate-to-vigorous physical activity (MVPA) and total physical activity (TPA) on weekdays. Fathers' MPVA levels correlated significantly with those of boys and girls, with paternal influence appearing to be stronger than maternal influence. However, there was not a significant correlation between fathers' and children's TPA. TPA levels of both mothers and fathers correlated with those of girls, but not with those of boys. Parental sedentary levels on the weekend correlated significantly with girls' levels, but not with boys' levels. Children's physical activity levels on weekends were influenced more by fathers' activity levels than by mothers', while the opposite was observed on weekdays. Conclusion: Sedentary behavior and physical activity levels of parents can strongly influence those of their preschool children, with maternal influence stronger during the weekdays and paternal influence stronger on the weekends. Parents' activity levels influence girls' levels more strongly than they influence boys' levels. PMID- 29503769 TI - Crystal structure correlations with the intrinsic thermodynamics of human carbonic anhydrase inhibitor binding. AB - The structure-thermodynamics correlation analysis was performed for a series of fluorine- and chlorine-substituted benzenesulfonamide inhibitors binding to several human carbonic anhydrase (CA) isoforms. The total of 24 crystal structures of 16 inhibitors bound to isoforms CA I, CA II, CA XII, and CA XIII provided the structural information of selective recognition between a compound and CA isoform. The binding thermodynamics of all structures was determined by the analysis of binding-linked protonation events, yielding the intrinsic parameters, i.e., the enthalpy, entropy, and Gibbs energy of binding. Inhibitor binding was compared within structurally similar pairs that differ by para- or meta-substituents enabling to obtain the contributing energies of ligand fragments. The pairs were divided into two groups. First, similar binders-the pairs that keep the same orientation of the benzene ring exhibited classical hydrophobic effect, a less exothermic enthalpy and a more favorable entropy upon addition of the hydrophobic fragments. Second, dissimilar binders-the pairs of binders that demonstrated altered positions of the benzene rings exhibited the non-classical hydrophobic effect, a more favorable enthalpy and variable entropy contribution. A deeper understanding of the energies contributing to the protein ligand recognition should lead toward the eventual goal of rational drug design where chemical structures of ligands could be designed based on the target protein structure. PMID- 29503770 TI - Merging cranial histology and 3D-computational biomechanics: a review of the feeding ecology of a Late Triassic temnospondyl amphibian. AB - Finite Element Analysis (FEA) is a useful method for understanding form and function. However, modelling of fossil taxa invariably involves assumptions as a result of preservation-induced loss of information in the fossil record. To test the validity of predictions from FEA, given such assumptions, these results could be compared to independent lines of evidence for cranial mechanics. In the present study a new concept of using bone microstructure to predict stress distribution in the skull during feeding is put forward and a correlation between bone microstructure and results of computational biomechanics (FEA) is carried out. The bony framework is a product of biological optimisation; bone structure is created to meet local mechanical conditions. To test how well results from FEA correlate to cranial mechanics predicted from bone structure, the well-known temnospondyl Metoposaurus krasiejowensis was used as a model. A crucial issue to Temnospondyli is their feeding mode: did they suction feed or employ direct biting, or both? Metoposaurids have previously been characterised either as active hunters or passive bottom dwellers. In order to test the correlation between results from FEA and bone microstructure, two skulls of Metoposaurus were used, one modelled under FE analyses, while for the second one 17 dermal bone microstructure were analysed. Thus, for the first time, results predicting cranial mechanical behaviour using both methods are merged to understand the feeding strategy of Metoposaurus. Metoposaurus appears to have been an aquatic animal that exhibited a generalist feeding behaviour. This taxon may have used two foraging techniques in hunting; mainly bilateral biting and, to a lesser extent, lateral strikes. However, bone microstructure suggests that lateral biting was more frequent than suggested by Finite Element Analysis (FEA). One of the potential factors that determined its mode of life may have been water levels. During optimum water conditions, metoposaurids may have been more active ambush predators that were capable of lateral strikes of the head. The dry season required a less active mode of life when bilateral biting is particularly efficient. This, combined with their characteristically anteriorly positioned orbits, was optimal for ambush strategy. This ability to use alternative modes of food acquisition, independent of environmental conditions, might hold the key in explaining the very common occurrence of metoposaurids during the Late Triassic. PMID- 29503771 TI - Regenerative agriculture: merging farming and natural resource conservation profitably. AB - Most cropland in the United States is characterized by large monocultures, whose productivity is maintained through a strong reliance on costly tillage, external fertilizers, and pesticides (Schipanski et al., 2016). Despite this, farmers have developed a regenerative model of farm production that promotes soil health and biodiversity, while producing nutrient-dense farm products profitably. Little work has focused on the relative costs and benefits of novel regenerative farming operations, which necessitates studying in situ, farmer-defined best management practices. Here, we evaluate the relative effects of regenerative and conventional corn production systems on pest management services, soil conservation, and farmer profitability and productivity throughout the Northern Plains of the United States. Regenerative farming systems provided greater ecosystem services and profitability for farmers than an input-intensive model of corn production. Pests were 10-fold more abundant in insecticide-treated corn fields than on insecticide-free regenerative farms, indicating that farmers who proactively design pest-resilient food systems outperform farmers that react to pests chemically. Regenerative fields had 29% lower grain production but 78% higher profits over traditional corn production systems. Profit was positively correlated with the particulate organic matter of the soil, not yield. These results provide the basis for dialogue on ecologically based farming systems that could be used to simultaneously produce food while conserving our natural resource base: two factors that are pitted against one another in simplified food production systems. To attain this requires a systems-level shift on the farm; simply applying individual regenerative practices within the current production model will not likely produce the documented results. PMID- 29503772 TI - Feature-by-feature comparison and holistic processing in unfamiliar face matching. AB - Identity comparisons of photographs of unfamiliar faces are prone to error but imperative for security settings, such as the verification of face identities at passport control. Therefore, finding techniques to improve face-matching accuracy is an important contemporary research topic. This study investigates whether matching accuracy can be enhanced by verbal instructions that address feature comparisons or holistic processing. Findings demonstrate that feature-by-feature comparison strategy had no effect on face matching. In contrast, verbal instructions focused on holistic processing made face matching faster, but they impaired accuracy. Given the recent evidence for the heredity of face perception and the previously reported small or no improvements of face-matching ability, it seems reasonable to suggest that improving unfamiliar face matching is not an easy task, but it is presumably worthwhile to explore new methods for improvement nonetheless. PMID- 29503773 TI - Toward "Green" Hybrid Materials: Core-Shell Particles with Enhanced Impact Energy Absorbing Ability. AB - Restrained properties of "green" degradable products drive the creation of materials with innovative structures and retained eco-attributes. Herein, we introduce the creation of impact modifiers in the form of core-shell (CS) particles toward the creation of "green" composite materials. Particles with CS structure constituted of PLA stereocomplex (PLASC) and a rubbery phase of poly(epsilon-caprolactone-co-d,l-lactide) (P[CL-co-LA]) were successfully achieved by spray droplet atomization. A synergistic association of the soft P[CL co-LA] and hard PLASC domains in the core-shell structure induced unique thermo mechanical effects on the PLA-based composites. The core-shell particles enhanced the crystallization of PLA matrices by acting as nucleating agents. The core shell particles functioned efficiently as impact modifiers with minimal effect on the composites stiffness and strength. These findings provide a new platform for scalable design of polymeric-based structures to be used in the creation of advanced degradable materials. PMID- 29503775 TI - Cracking the Crack Dance: A Case Report on Cocaine-induced Choreoathetosis. AB - Movement disorders represent one of the less common presentations of cocaine toxicity observed in clinical practice. Given the magnitude of crack cocaine use, it is vital to understand the underlying pathogenesis. We present a case of a patient who clinically exhibited cocaine-induced choreoathetosis. The diagnosis was confirmed after ruling out all other organic causes of de novo choreoathetoid movement. This case highlights the association of cocaine with choreoathetoid movements. We propose a preliminary understanding of the underlying pathogenesis, which may help intensivists better recognize this uncommon phenomenon. PMID- 29503774 TI - Patient-Specific Flow Descriptors and Normalized wall index in Peripheral Artery Disease: a Preliminary Study. AB - Background and Aims: MRI-based hemodynamics have been applied to study the relationship between time-averaged wall shear stresses (TAWSS), oscillatory shear index (OSI) and atherosclerotic lesions in the coronary arteries, carotid artery, and human aorta. However, the role of TAWSS and OSI are poorly understood in lower extremity arteries. The aim of this work was to investigate the feasibility of hemodynamic assessment of the superficial femoral artery (SFA) in patients with peripheral artery disease (PAD) and we hypothesized that there is an association between TAWSS and OSI, respectively, and atherosclerotic burden expressed as the normalized wall index (NWI). Methods: Six cases of 3D vascular geometries of the SFA and related inlet/outlet flow conditions were extracted from patient-specific MRI data including baseline, 12 and 24 months. Blood flow simulations were performed to compute flow descriptors, including TAWSS and OSI, and NWI. Results: NWI was correlated positively with TAWSS (correlation coefficient: r = 0.592; p < 0.05). NWI was correlated negatively with OSI (correlation coefficient: r = -0.310, p < 0.01). Spatially averaged TAWSS and average NWI increased significantly between baseline and 24-months, whereas OSI decreased over 2-years. Conclusions: In this pilot study with a limited sample size, TAWSS was positively associated with NWI, a measure of plaque burden, whereas OSI showed an inverse relationship. However, our findings need to be verified in a larger prospective study. MRI-based study of hemodynamics is feasible in the superficial femoral artery. PMID- 29503777 TI - Arthroscopic Treatment of Synovial Chondromatosis in the Ankle Joint. AB - Synovial chondromatosis of the ankle is rare and sparsely documented. Traditional surgical intervention is open loose body excision and synovectomy. Upon literature review, only two other cases were found to be managed arthroscopically. We report a case of synovial chondromatosis in a 54-year-old man leading to pain and limited range of motion of his ankle. This unique case of extensive nodule formation was treated via a three-port arthroscopic approach. Removal of loose bodies and synovectomy were successfully performed arthroscopically. A total of 76 loose bodies were removed and synovectomy performed using a 3.5 mm diameter full radius shaver. This case demonstrates that a three-port arthroscopic approach can provide adequate treatment while maintaining the superior risk profile inherent to arthroscopic intervention. PMID- 29503776 TI - Deep Vein Thrombosis in Acute Stroke - A Systemic Review of the Literature. AB - We present a systemic review of available literature on the complications of deep venous thrombosis that develops in patients presenting with acute stroke. There are several pharmacological and physical treatment options available and used. We aim to summarize the management plans currently used at different centers. In conclusion, low-dose anticoagulant therapy for ischemic stroke is recommended. In the case of intracerebral hemorrhage, pneumatic sequential compression devices should be placed initially, followed by the administration of ultra-fractioned heparin on the next day, and then oral anticoagulant therapy to replace the heparin after a week in high-risk patients. Similar prophylactic treatment recommendations are used for subarachnoid hemorrhage. PMID- 29503778 TI - Transgender Associations and Possible Etiology: A Literature Review. AB - Transgender or gender dysphoria has been defined in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), as distress resulting from the incongruence between one's experienced gender and one's assigned gender, along with a persistent and strong desire to be of another gender, and accompanied by clinically significant distress. Adolescents referred for evaluation often want hormonal therapy and several among them also express a desire for gender reassignment surgery. Furthermore, evidence shows that adolescents and adults with gender dysphoria without a sex development disorder, before gender reassignments, are at increased risk for suicide. For this review, a search of the English language scientific literature was conducted using the PubMed database. This summary discusses the associations and comorbidities of gender dysphoria and reiterates the evidence that its etiology is multifactorial. Transsexualism involves prenatal neuroanatomical changes, has a psychiatric association, and is found to be more prevalent in conjunction with schizophrenia and autism spectrum disorders. Childhood adversities and neglect are also linked to having a transgender identity. Moreover, the evidence favors a genetic predisposition. Likewise, there seems to be a growing concern with regards to the relationship between endocrine disruptors and transsexuals as well as other gender minority populations. More research needs to be done to understand the exact pathways. PMID- 29503779 TI - Fractionated Radiosurgery Alone for Thirty-seven Brain Metastases: Not Everything that can be Counted Counts. AB - There is an ongoing debate as to the maximum number of brain metastases that can safely and practically be treated with a single course of radiosurgery. Despite evidence of durable local control and favorable overall survival when treating 10 or more brain metastases with radiosurgery alone, some institutions and guidelines still limit radiosurgery to an arbitrary number of metastases. As demonstrated by this case report, the number of lesions is not so important when the patient's life expectancy is otherwise good and body tumors are controllable. In the current era of effective targeted therapies, multi-year survival with brain metastases is increasingly common. Treating 37 brain metastases simultaneously in a five-fraction stereotactic course is technically feasible and in this case, resulted in 100% local and distant control in the brain for 18 months ongoing without any additional brain radiation. We discuss patient selection factors when treating large numbers of brain metastases, and present a possible class solution when using five daily fractions of 6 Gray (Gy) with a single plan and isocenter. PMID- 29503780 TI - Double Burden of Malnutrition among Bangladeshi Women: A Literature Review. AB - A narrative review was carried out of existing literature comprising nationally representative data. We searched PubMed, Google Scholar, and Banglajol databases. Quantitative studies reporting the prevalence and risk factors of the double burden of malnutrition (DBM) among Bangladeshi women based on nationally representative data were considered for this review. We included studies published between 1st May 2007 and 30th April 2017 in English language. Two researchers individually searched and screened all the relevant articles and separately extracted data using a data extraction table created in Microsoft Excel. Another researcher cross-checked the whole process to maintain consistency. Any sort of disagreement was resolved by group consensus. Thematic analysis was performed for data analysis. According to the included studies, the prevalence of underweight and stunting dramatically reduced among Bangladeshi women in last 10 years, though, nearly one-fourth of women are underweight and one-fifth of women are stunted in Bangladesh. Additionally, nearly half of the country's women are suffering from different micronutrient deficiencies. This immense burden of undernutrition is accompanied by the presence of overweight or obesity among nearly half of the adult women. Women's age, area of residence, education and wealth index have a significant influence on determining their nutritional status. DBM is an inevitable reality among Bangladesh women. The adverse health consequences of women's undernutrition and overnutrition have been well documented. As women's nutritional status is a multifaceted issue, effective implementation of very specific and focused public health interventions with inclusive multi-sectoral and multi-stakeholder approaches are indispensable to combat this problem. PMID- 29503781 TI - Preoperative Stereotactic Radiosurgery of Brain Metastases: Preliminary Results. AB - INTRODUCTION: Preoperative stereotactic radiosurgery (pre-SRS) is a recent advancement in the strategy for brain metastasis (BM) management, and available data demonstrate the advantages of pre-SRS before postoperative radiation treatment, including lower rates of local toxicity, leptomeningeal progression, and a high percentage of local control. The authors presented the results of pre SRS in patients with BM. MATERIALS AND METHODS: Nineteen patients with BM (11 female and eight male) have been treated at N.N. Burdenko Medical Research Center for Neurosurgery (Moscow, Russia) and Gamma-Knife Center (Moscow, Russia) using pre-SRS. A total of 22 symptomatic metastatic lesions were preoperatively irradiated in the series. Eight patients had multiple BM (number of metastases ranged between two and seven). The median target volume for combined treatment was 14.131 cc (volumes varied between 2.995 and 57.098 cc; mean - 19.986 cc). The median of the mean target dose was 18 Gy, ranging between 12.58 and 24.36 Gy. Results: All patients tolerated pre-SRS well, without any neurological deterioration, and surgical treatment was performed as scheduled. The median follow-up period was 6.3 months (ranging between five weeks and 22.9 months). In 17 out of 19 patients, follow-up magnetic resonance (MR) images obtained two or three months after the combined treatment demonstrated the postoperative cavity without any signs of postradiation alterations in the perifocal tissues. In two observations, peritumoral edema was present. Local recurrences were found in two cases, 5.5 and 17.4 months after treatment. Radionecrosis was present in one observation after 4.6 months of follow-up. Two patients died of disease progression and are presented as illustrative cases. CONCLUSION: The combined treatment of secondary brain tumors has proved to be the best treatment option. Preoperative stereotactic radiosurgery may decrease radiation-induced toxicity and rates of local tumor progression. The potential hazards of pre-SRS associated with the postoperative healing of irradiated soft tissues of the head were not confirmed in our study. The decision of pre-SRS should be made by the tumor board, including specialists in neurosurgery, neuro-oncology, and radiation oncology, if the diagnosis of BM is based on oncological history and visualization data. PMID- 29503782 TI - Missing Globe: A Case of Severe Head Trauma, Eyelid Laceration, and Traumatic Enucleation. AB - We report an unusual periocular injury in a 19-year-old motorcycle rider during an accident. The patient had lacerations on the right upper and lower eyelids and the globe was enucleated en bloc. Despite disorganization of the eyelids and orbit, reconstruction of the eyelids and anophthalmic socket was successful. The primary reconstruction of the anophthalmic socket in the traumatic enucleation is a real challenge, especially when the conjunctival and the orbital tissues are missing or disorganized. It is proposed to utilize the optic nerve regeneration techniques in the cases of traumatic enucleation when the globe is intact. However, in the current case, the globe was unavailable. PMID- 29503783 TI - Surface Microbiology of Smartphone Screen Protectors Among Healthcare Professionals. AB - BACKGROUND: The use of smartphones with touch screens has become a norm for healthcare professionals (HCP). The risk of smart screen contamination has been proven, and guidelines are available to deal with possible contamination. A large number of smartphone users apply plastic or glass screen protectors onto their mobile phone screens to prevent scratches. However, these materials are not scratch proof, and their antipathogenic properties have not been studied. METHODS: We have conducted a study to determine the frequency of smartphone screen protector contamination and compared the data with contamination on the bare area on the same mobile screens. The sample size included only HCPs working in acute care settings and having at least eight hours of exposure time every day. RESULTS: A total of 64 samples were collected, which reported 62.5% (n = 40/64) positive culture swabs from the protected areas of the screen and 45.3% (n = 29/64) from the unprotected area of the screen. Micrococcus and Gram-negative rods grew only on samples taken from the protected area whereas the bare area showed no such growth. There was no statistically significant difference in the frequency based on smart screen size, duration of use during duty hours, or the setting where it was used. CONCLUSIONS: Smartphone screen protectors from healthcare providers may harbor pathogenic bacteria, especially in acute care settings. Coagulase-negative Staphylococci followed by Bacillus species were the most commonly yielded bacteria among house officers and postgraduate trainees in the present study. PMID- 29503784 TI - Management of Cold Water-induced Hypothermia: A Simulation Scenario for Layperson Training Delivered via a Mobile Tele-simulation Unit. AB - Newfoundland and Labrador (NL) has one of the highest provincial drowning rates in Canada, largely due to the many rural communities located near bodies of water. Factor in the province's cold climate (average NL's freshwater temperature is below 5.4 degrees C)and the prevalence of winter recreational activities among the population, there exists an inherent risk of ice-related injuries and subsequent hypothermia. Oftentimes, these injuries occur in remote/rural settings where immediate support from Emergency Medical Services (EMS) may not be available. During this critical period, it frequently falls on individuals without formal healthcare training to provide lifesaving measures until help arrives. Training individuals in rural communities plays an important role in ensuring public safety. In recent years, simulation-based education has become an essential tool in medical, marine and first aid training. It provides learners with a safe environment to hone their skills and has been shown to be superior to traditional clinical teaching methods. The following case aims to train laypeople from rural settings in the immediate management of an individual who becomes hypothermic following immersion into cold water. However, reaching these individuals to provide training can be a challenge in a province with such a vast geography. To assist with overcoming this, the development of a simulation center that is portable between communities (or Mobile Tele-Simulation Unit) has occurred. By utilizing modern technology, this paper also proposes an innovative method of connecting with learners in more difficult to reach regions. PMID- 29503785 TI - Grooming Future Physician-scientists: Evaluating the Impact of Research Motivations, Practices, and Perceived Barriers Towards the Uptake of an Academic Career Among Medical Students. AB - PURPOSE: To evaluate the research trends and underlying motivations that shape intentions for the future uptake of an academic career among medical students. Further, to investigate the barriers and sought-after interventions which may optimise research outcomes in a resource-limited setting. METHODS: A cross sectional study was conducted among 294 undergraduate (UG) medical students in Karachi, Pakistan. A self-administered questionnaire was employed to assess current research practices and future intentions, and to evaluate related motivations, barriers, and sought-after interventions. RESULTS: Almost two-thirds of medical students reported some form of involvement in medical research and expressed positive attitudes towards the same. However, intentions to pursue research at a professional level not only remained low (19.7%) but were found to decrease with each passing year of study (p<0.01). The most commonly expressed motivation for pursuing research was "admission into a residency program" (71.8%), and was associated with a decreased likelihood of pursuing research professionally. The most cited barriers to conducting UG research were a "lack of time" (72.4%), "lack of supervisors" (50.3%) and a "lack of opportunities in the university" (48.3%). A dichotomy in sought-after interventions was observed among research-naive and research-experienced students. CONCLUSIONS: Despite promising trends in UG medical research, the intentions for uptake of an academic career remain low. Research practices driven by career enhancement alone may be detrimental. Interventions to increase research output must promote the capacity building of research-naive students and facilitate the ongoing practices of research-experienced students. PMID- 29503786 TI - A Mexican Honeymoon Marred by Gastrointestinal Upset: A Case of Dientamoeba fragilis Causing Post-infectious Irritable Bowel Syndrome. AB - Dientamoeba fragilis (D. fragilis) is an anaerobic intestinal protozoan parasite that has been associated with irritable bowel syndrome (IBS)-like symptoms. We report a case of post-infectious IBS caused by D. fragilis treated successfully with metronidazole. A 33-year-old African American male with an unremarkable past medical history was seen in the office with a three-month history of intermittent, generalized, crampy abdominal pain with bloating and flatulence without associated weight loss. He visited Mexico for his honeymoon four months ago. Initial lab work was normal. Dietary changes including fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet and loperamide were prescribed with the presumptive diagnosis of IBS; however, his symptoms persisted. Three samples of stool for ova and parasites (O&P) were positive for D. fragilis. The patient was treated with metronidazole for 14 days. Repeat fecal O&P were negative. Upon follow-up, the patient' symptoms substantially improved with a resolution of abdominal pain and flatulence. Infection caused by D. fragilis may be symptomatic or asymptomatic. It is transmitted by the fecal-oral route. Symptoms include abdominal pain, bloating, and alteration of bowel movements, resembling IBS. The diagnosis is made via the detection of D. fragilis trophozoites in appropriately fixed and stained stool samples or by a polymerase chain reaction. Treatment options include tetracyclines, paromomycin, metronidazole, and Iodoquinol. Further epidemiologic studies may help in elucidating the association between D. fragilis and IBS. PMID- 29503787 TI - Components of Effective Cognitive-Behavioral Therapy for Pediatric Headache: A Mixed Methods Approach. AB - Internet-delivered treatment has the potential to expand access to evidence-based cognitive-behavioral therapy (CBT) for pediatric headache, and has demonstrated efficacy in small trials for some youth with headache. We used a mixed methods approach to identify effective components of CBT for this population. In Study 1, component profile analysis identified common interventions delivered in published RCTs of effective CBT protocols for pediatric headache delivered face-to-face or via the Internet. We identified a core set of three treatment components that were common across face-to-face and Internet protocols: 1) headache education, 2) relaxation training, and 3) cognitive interventions. Biofeedback was identified as an additional core treatment component delivered in face-to-face protocols only. In Study 2, we conducted qualitative interviews to describe the perspectives of youth with headache and their parents on successful components of an Internet CBT intervention. Eleven themes emerged from the qualitative data analysis, which broadly focused on patient experiences using the treatment components and suggestions for new treatment components. In the Discussion, these mixed methods findings are integrated to inform the adaptation of an Internet CBT protocol for youth with headache. PMID- 29503788 TI - Chasing balance and other recommendations for improving nonparametric propensity score models. PMID- 29503789 TI - Managing the Burden of Non-NASH NAFLD. AB - Purpose of Review: The purpose of this review article is to raise awareness of the significance of steatosis that exist within the spectrum of nonalcoholic fatty liver disease (NAFLD). While the impact of nonalcoholic steatohepatitis (NASH), and its potential for histologic progression to cirrhosis and hepatocellular carcinoma is widely appreciated, the impact of non-NASH NAFLD (steatosis) on morbidity and mortality is less well recognized. Recent Findings: NAFLD is a spectrum of hepatic pathology with a rising prevalence worldwide. Steatosis without fibrosis carries a low risk of progression to cirrhosis but likely confers an increased risk of diabetes mellitus and cardiovascular disease. Summary: About a quarter of the world population is affected by NAFLD. NAFLD represents a burden to affected individuals, economics of the health care system and contributes significantly to morbidity and mortality worldwide. An increased level of awareness and knowledge about risk factors and diagnostic strategies is needed to identify patients affected with disease. PMID- 29503791 TI - Prosocial Behavior and Depression: a Case for Developmental Gender Differences. AB - Purpose of Review: Prosocial behavior and depression are related constructs that both increase during adolescence and display gender-specific effects. The current review surveys literature examining the association between depressive symptoms and prosociality, measured with behavioral economic paradigms, across development and proposes a theoretical model explaining a mechanism through which adolescent girls have higher risk for depression than boys. Recent Findings: Relative to healthy controls, prosocial behavior is reduced in adults with major depressive disorder (MDD) but may be increased in adolescents with MDD. The relationship between non-clinical levels of depressive symptoms and prosocial behavior remains to be studied experimentally; however, self-reported prosocial behavior is negatively associated with depressive symptoms in non-clinical adolescents, which may suggest a shift in the relation of prosocial behavior and depressive symptoms across the non-clinical (i.e., negative) to clinical range (i.e., positive). Summary: The effect of gender on these developmental and clinical status shifts has not been studied but could have important implications for understanding the emergence of higher rates of depression in girls than boys during adolescence. We propose that girls are at heightened risk for depression due to higher social evaluative concern and other-oriented prosocial motivation that emphasize the needs of others over the self, leading to more altruistic prosocial behavior (despite personal cost) and a higher burden that enables depressive symptoms. PMID- 29503792 TI - The Burden of Influenza: a Complex Problem. PMID- 29503790 TI - Mechanisms Underlying Sex Differences in Cannabis Use. AB - Purpose of the Review: Cannabis is the most commonly used illicit substance worldwide. In recent decades, highly concentrated products have flooded the market, and prevalence rates have increased. Gender differences exist in cannabis use, as men have higher prevalence of both cannabis use and cannabis use disorder (CUD), while women progress more rapidly from first use to CUD. This paper reviews findings from preclinical and human studies examining the sex-specific neurobiological underpinnings of cannabis use and CUD, and associations with psychiatric symptoms. Recent Findings: Sex differences exist in the endocannabinoid system, in cannabis exposure effects on brain structure and function, and in the co-occurrence of cannabis use with symptoms of anxiety, depression and schizophrenia. In female cannabis users, anxiety symptoms correlate with larger amygdala volume and social anxiety disorder symptoms correlate with CUD symptoms. Female cannabis users are reported to be especially vulnerable to earlier onset of schizophrenia, and mixed trends emerge in the correlation of depressive symptoms with cannabis exposure in females and males. Summary: As prevalence of cannabis use may continue to increase given the shifting policy landscape regarding marijuana laws, understanding the neurobiological mechanisms of cannabis exposure in females and males is key. Examining these mechanisms may help inform future research on sex-specific pharmacological and behavioral interventions for women and men with high-risk cannabis use, comorbid psychiatric disease, and CUD. PMID- 29503794 TI - Silica sol as grouting material: a physio-chemical analysis. AB - At present there is a pressing need to find an environmentally friendly grouting material for the construction of tunnels. Silica nanoparticles hold great potential of replacing the organic molecule based grouting materials currently used for this purpose. Chemically, silica nanoparticles are similar to natural silicates which are essential components of rocks and soil. Moreover, suspensions of silica nanoparticles of different sizes and desired reactivity are commercially available. However, the use of silica nanoparticles as grouting material is at an early stage of its technological development. There are some critical parameters such as long term stability and functionality of grouted silica that need to be investigated in detail before silica nanoparticles can be considered as a reliable grouting material. In this review article we present the state of the art regarding the chemical properties of silica nanoparticles commercially available, as well as experience gained from the use of silica as grouting material. We give a detailed description of the mechanisms underlying the gelling of silica by different salt solutions such as NaCl and KCl and how factors such as particle size, pH, and temperature affect the gelling and gel strength development. Our focus in this review is on linking the chemical properties of silica nanoparticles to the mechanical properties to better understand their functionality and stability as grouting material. Along the way we point out areas which need further research. PMID- 29503793 TI - Treatment of psychiatric symptoms among offspring of parents with bipolar disorder. AB - Purpose of Review: Bipolar disorder is highly familial and has a protracted and diagnostically confusing prodrome. This review critically evaluates recently published literature relevant to the treatment of psychiatric symptoms in high risk offspring of parents with Bipolar Disorder. Recent Findings: Non pharmacological treatment options including psychotherapy, resilience promotion through good sleep, diet, and exercise hygiene, and omega-3 fatty acid supplementation are important first line interventions for high-risk offspring. There has been some success in treating this population with open-label trials with mood stabilizers and atypical antipsychotics; however, these results have not been replicated in randomized controlled trails. Summary: Despite some progress in early identification of symptoms in offspring of parents with Bipolar Disorder, there is scarce evidence supporting the treatment of these high-risk youth to prevent psychiatric symptoms from progressing to threshold bipolar or other psychiatric disorders. There is a need for prospective and randomized trials and research that identifies reliable biomarkers to individualize treatments for these youth. PMID- 29503795 TI - Recent advances in cholinergic imaging and cognitive decline-Revisiting the cholinergic hypothesis of dementia. AB - Purpose of review: Although the cholinergic hypothesis of dementia provided a successful paradigm for the development of new drugs for dementia, this hypothesis has waned in popularity. Cholinergic brain imaging may provide novel insights into the viability of this hypothesis. Recent findings: Cholinergic receptor and forebrain volumetric studies suggest an important role of the cholinergic system in maintaining brain network integrity that may deteriorate with cognitive decline in Alzheimer disease (AD) and Lewy body disorders (LBD). Bidirectional changes in regional receptor expression may suggest the presence of compensatory responses to neurodegenerative injury. Cholinergic system changes are more complex in LBD because of additional subcortical degenerations compared to AD. Cholinergic-dopaminergic interactions affect attentional, verbal learning and executive functions, and impairments in these two transmitter systems may jointly increase the risk of dementia in Parkinson disease. Summary: The cholinergic hypothesis is evolving from a primary focus on memory toward expanded cognitive functions modulated by regionally more complex and interactive brain networks. Cholinergic network adaptation may serve as a novel research target in neurodegeneration. PMID- 29503797 TI - Self-Reported Arrests Among Indigenous Adolescents: a Longitudinal Analysis of Community, Family, and Individual Risk Factors. AB - Purpose: North American indigenous (American Indian/Canadian First Nations) adolescents are overrepresented in the juvenile justice systems in the USA and Canada. One explanation advanced for disproportionate numbers of racial and ethnic minorities in the justice systems is the unequal distribution of risk factors across groups. The purpose of this study is to investigate the prevalence of and risk factors for first arrest within a population sample of indigenous adolescents. Methods: The data come from an 8-year longitudinal panel study of indigenous youth (n = 641) from the northern Midwest and Canada, spanning ages 10 to 19 years. We used a discrete-time survival model to estimate the overall hazard of first arrest and change in the arrest hazard over time and included both time-invariant and time varying risk factors. Results: The risk of arrest increased over time, although the largest increase occurred between waves 3 and 4, when the adolescents averaged 13.1 and 14.3 years, respectively. The youth had a 55 % probability of being arrested at least once by the end of the study. Of the time-invariant risk factors, exposure to violence, parent arrest, age, and income were associated with overall risk of first arrest. Three time-varying risk factors (alcohol use, marijuana use, and peer delinquency) were associated with changes in the risk of first arrest. Conclusions: Being arrested carries significant repercussions for young people, including involvement in the juvenile justice system as well as consequences into adulthood. Communities must go beyond programs that target problem behaviors because community, family, and peer factors are also important. PMID- 29503796 TI - Epigenetic Therapeutics and Their Impact in Immunotherapy of Lung Cancer. AB - Lung cancer is the leading cause of cancer-related death in the United States and worldwide. Novel therapeutic developments are critically necessary to improve outcomes for this disease. Aberrant epigenetic change plays an important role in lung cancer development and progression. Therefore, drugs targeting the epigenome are being investigated in the treatment of lung cancer. Monotherapy of epigenetic therapeutics such as DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi) have so far not shown any apparent benefit while one of the clinical trials with the combinations of DNMTi and HDACi showed a small positive signal for treating lung cancer. Combinations of DNMTi and HDACi with chemotherapies have some efficacy but are often limited by increased toxicities. Preclinical data and clinical trial results suggest that combining epigenetic therapeutics with targeted therapies might potentially improve outcomes in lung cancer patients. Furthermore, several clinical studies suggest that the HDACi vorinostat could be used as a radiosensitizer in lung cancer patients receiving radiation therapy. Immune checkpoint blockade therapies are revolutionizing lung cancer management. However, only a minority of lung cancer patients experience long-lasting benefits from immunotherapy. The role of epigenetic reprogramming in boosting the effects of immunotherapy is an area of active investigation. Preclinical studies and early clinical trial results support this approach which may improve lung cancer treatment, with potentially prolonged survival and tolerable toxicity. In this review, we discuss the current status of epigenetic therapeutics and their combination with other antineoplastic therapies, including novel immunotherapies, in lung cancer management. PMID- 29503798 TI - A Joint Exercise against Intentional Biothreats. PMID- 29503799 TI - Multilevel Analysis of the Risk Factors in High-Risk Health Behavior among Korean Adolescents. AB - Objectives: To examine health behaviors among Korean adolescents with a focus on both individual and school-based factors, specifically in relation to predictors of high-risk groups. Methods: Secondary data analysis was conducted with data from the 8th Korea Youth Risk Behavior Web-Based Survey, using descriptive statistics, t tests, chi2 test, and multilevel logistic regression analysis. Health Practice Index was calculated and a range of 0 to 2 was classified as a high-risk group. Results: The results revealed that the individual-level variables of sex, age, stress, depression, subjective health status, school performance, health education, father's level of education, and living situation were significant predictors of high-risk behaviors. The risk was greater in girls, greater with higher age and higher stress scores, greater in adolescents with depression, greater with lower paternal educational level, and greater in adolescents who did not live with both parents, as were the school-level variables of school grade and school affluence score. The possibility of being in the high-risk group in health behavior was greater if a student attended a school where the Family Affluence Score (FAS) was lower. Conclusion: School health education should be expanded to manage students' high-risk health behaviors, especially in schools that have many students from families with a low affluence status. PMID- 29503800 TI - Prevalence of Fecal Carriage of CTX-M-15 Beta-Lactamase-Producing Escherichia coli in Healthy Children from a Rural Andean Village in Venezuela. AB - Objectives: Antimicrobial resistant extended-spectrum-beta-lactamase-producing Enterobacteriaceae (ESBL-PE) have been shown to be present in healthy communities. This study examined healthy children from the rural Andean village of Llano del Hato, Merida, Venezuela, who have had little or no antibiotic exposure to determine the prevalence of fecal carriage of ESBL-producing Escherichia coli (ESBL-EC). Methods: A total of 78 fecal samples were collected in healthy children aged from 1 to 5 years. ESBL-EC were selected in MacConkey agar plates with cefotaxime and further confirmed by the VITEK 2 system. ESBL were phenotypically detected and presence of bla genes and their variants were confirmed by molecular assays. Determination of phylogenetic groups was performed by PCR amplification. Risk factors associated with fecal carriage of ESBL-EC positive isolates were analyzed using standard statistical methods. Results: Of the 78 children studied, 27 (34.6%) carried ESBL-EC. All strains harbored the blaCTX-M-15 allele. Of these, 8 were co-producers of blaTEM-1, blaTEM-5, blaSHV-5 or blaSHV-12. Co-resistance to aminoglycosides and/or fluoroquinolones was observed in 9 strains. 51.9% of ESBL-EC isolates were classified within phylogroup A. A significant, positive correlation was found between age (>=2.5 - <=5 years), food consumption patterns and ESBL-EC fecal carriage. Conclusion: This is the first study describing the high prevalence of fecal carriage of ESBL EC expressing CTX-M-15- among very young, healthy children from a rural Andean village in Venezuela with scarce antibiotic exposure, underlining the importance of this population as a reservoir. PMID- 29503801 TI - Associations between Social and Physical Environments, and Physical Activity in Adults from Urban and Rural Regions. AB - Objectives: This study investigates investigated the relationship between social and physical environments, and moderate to vigorous physical activity (MVPA) amongst adults in both rural and urban areas within Korea. Methods: A sample of 128,735 adults from the 2013 Community Health Survey (CHS) was analyzed using a multilevel logistic analysis. Results: Urban residents with higher satisfaction in public transportation satisfaction and rural residents with more access to sports parks, hiking trails, and bike cycle paths were more likely to be active. The MVPA of adults from rural areas correlated urban adults was uncorrelatedwith neighborhood factors, but that of rural adults was whereas no correlations were observed in adults from urban areas. Conclusion: These differences should be considered when developing interventions strategies to enhance adult physical activity in different communities. PMID- 29503802 TI - Perception and Practice of Road Safety among Medical Students, Mansoura, Egypt. AB - Objectives: To assess the knowledge and attitude of medical students towards road safety and to determine their driving behavior and its relation to different related factors. Methods: This cross-sectional study involved 480 medical students at Mansoura University, Egypt. A self-administered questionnaire was used to collect student personal data, knowledge about road safety, attitude towards road safety, and driving practices. Results: More than 40% of students experienced an injury in the previous year, mainly as a pedestrian (56%), and 15.2% practiced driving, although only 9.6% had a driving licence. Most of the students had correct road safety knowledge except for awareness that the safe time to read maps is when your vehicle is parked (44%), one should drive in the left lane (29.6%), and one should overtake from the right-hand lane only (25.8%). The majority of the students reported that road traffic injuries can be prevented (89.2%). The mean score of the driving practices of the students ranged from 0.66+/-1.04 to 2.44+/-6.28 and rural residents showed significantly higher score regarding errors and lapses. Conclusion: Good road safety knowledge and a favorable, low risk attitude, did not translate into improved road traffic behavior and this highlights the importance of stricter implementation of the existing rules and including road safety in medical education programs. PMID- 29503803 TI - Enhancing 'Whole-of-Government' Response to Biological Events in Korea: Able Response 2014. AB - Since 2011, the Republic of Korea (ROK) and United States (U.S.) have been collaborating to conduct inter- and intra-governmental exercises to jointly respond to biological events in Korea. These exercises highlight U.S. interest in increasing its global biosurveillance capability and the ROK's interest in improving cooperation among ministries to respond to crises. With Able Response (AR) exercises, the ROK and U.S. have improved coordination among US and ROK government and defense agencies responding to potential bio-threats and identified additional areas on which to apply refinements in policies and practices. In 2014, the AR exercise employed a Biosurveillance Portal (BSP) to facilitate more effective communication among participating agencies and countries including Australia. In the present paper, we seek to provide a comprehensive assessment of the AR 2014 (AR14) exercise and make recommendations for future improvements. Incorporating a more realistic response in future scenarios by integrating a tactical response episode in the exercise is recommended. PMID- 29503804 TI - Evaluation of Hypertension Prevention and Control Programs in Lima, Peru. AB - Objectives: The Korea International Cooperation Agency (KOICA) established 4 health centers to provide hypertension screening and a health support program in a deprived urban area of Lima, Peru. This case report provides a mid-term evaluation of the KOICA's hypertension prevention and control programs. Methods: A follow up study was performed on 663 residents who were diagnosed with prehypertension or hypertension (Stage 1 and 2) in the 4 KOICA health centers. Patients participated in programs designed to prevent and control hypertension through education sessions over the course of 6 months. Using simple descriptive statistics and computer simulations, we evaluated the effect of hypertension prevention and control programs on the participants. Results: The KOICA health programs appeared to significantly contribute to lowering the blood pressure (BP) of the participants. The total number of participants with normal BP increased from none to 109. Overall, the female and younger patients responded better to the KOICA programs than the male and older participants. In addition, the average systolic BP, diastolic BP, and body mass index of all participants was significantly reduced. Conclusion: The KOICA programs were effective at lowering blood pressure, particularly amongst the prehypertension group than the Stage 1 and 2 hypertension groups. This suggests that providing an extensive screening service for adults with prehypertension will help control hypertension in the early stages. PMID- 29503805 TI - Comparing EPA production and fatty acid profiles of three Phaeodactylum tricornutum strains under western Norwegian climate conditions. AB - Microalgae could provide a sustainable alternative to fish oil as a source for the omega-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). However, growing microalgae on a large-scale is still more cost-intensive than fish oil production, and outdoor productivities vary greatly with reactor type, geographic location, climate conditions and microalgae species or even strains. The diatom Phaeodactylum tricornutum has been intensively investigated for its potential in large-scale production, due to its robustness and comparatively high growth rates and EPA content. Yet, most research have been performed in southern countries and with a single commercial P. tricornutum strain, while information about productivities at higher latitudes and of local strains is scarce. We examined the potential of the climate conditions in Bergen, western Norway for outdoor cultivation of P. tricornutum in flat panel photobioreactors and cultivated three different strains simultaneously, one commercial strain from Spain (Fito) and two local isolates (M28 and B58), to assess and compare their biomass and EPA productivities, and fatty acid (FA) profiles. The three strains possessed similar biomass productivities (average volumetric productivities of 0.20, 0.18, and 0.21 g L- 1 d- 1), that were lower compared to productivities reported from southern latitudes. However, EPA productivities differed between the strains (average volumetric productivities of 9.8, 5.7 and 6.9 mg L- 1 d- 1), due to differing EPA contents (average of 4.4, 3.2 and 3.1% of dry weight), and were comparable to results from Italy. The EPA content of strain Fito of 4.4% is higher than earlier reported for P. tricornutum (2.6-3.1%) and was only apparent under outdoor conditions. A principal component analysis (PCA) of the relative FA composition revealed strain-specific profiles. However, including data from laboratory experiments, revealed more significant differences between outdoor and laboratory grown cultures than between the strains, and higher EPA contents in outdoor grown cultures. PMID- 29503806 TI - BIO-PRECIPITATES PRODUCED BY TWO AUTOCHTHONOUS BORON TOLERANT STREPTOMYCES STRAINS. AB - Boron is widespread in the environment. Although contaminated soils are hard to recover different strategies have been investigated in the recent years. Bioremediation is one of the most studied because it is eco-friendly and less costly than other techniques. The aim of this research was to evaluate whether two Streptomyces strains isolated from boron contaminated soils in Salta, Argentina, may help remove boron from such soils. For this, they were grown in different liquid media with two boric acid concentrations and their specific growth rate and specific boric acid consumption rate were determined. Both strains showed great capacity to remove boron from the media. Increasing boric acid concentrations affected negatively the specific growth rate, however the specific boric acid consumption rate was superior. Boron bio-precipitates were observed when the strains grew in the presence of boric acid, probably due to an adaptive response developed by the cells to the exposure, for which many proteins were differentially synthetized. This strategy to tolerate high concentrations of boron by immobilizing it in bio-precipitates has not been previously described, to the best of our knowledge, and may have a great potential application in remediating soils contaminated with boron compounds. PMID- 29503807 TI - Measuring UV Curing Parameters of Commercial Photopolymers used in Additive Manufacturing. AB - A testing methodology was developed to expose photopolymer resins and measure the cured material to determine two key parameters related to the photopolymerization process: Ec (critical energy to initiate polymerization) and Dp (penetration depth of curing light). Five commercially available resins were evaluated under exposure from 365 nm and 405 nm light at varying power densities and energies. Three different methods for determining the thickness of the cured resin were evaluated. Caliper measurements, stylus profilometry, and confocal laser scanning microscopy showed similar results for hard materials while caliper measurement of a soft, elastomeric material proved inaccurate. Working curves for the five photopolymers showed unique behavior both within and among the resins as a function of curing light wavelength. Ec and Dp for the five resins showed variations as large as 10*. Variations of this magnitude, if unknown to the user and not controlled for, will clearly affect printed part quality. This points to the need for a standardized approach for determining and disseminating these, and perhaps, other key parameters. PMID- 29503808 TI - Microstructure Characterization of Bone Metastases from Prostate Cancer with Diffusion MRI: Preliminary Findings. AB - Purpose: To examine the usefulness of rich diffusion protocols with high b-values and varying diffusion time for probing microstructure in bone metastases. Analysis techniques including biophysical and mathematical models were compared with the clinical apparent diffusion coefficient (ADC). Methods: Four patients were scanned using 13 b-values up to 3,000 s/mm2 and diffusion times ranging 18 52 ms. Data were fitted to mono-exponential ADC, intravoxel incoherent motion (IVIM), Kurtosis and Vascular, extracellular, and restricted diffusion for cytometry in tumors (VERDICT) models. Parameters from the models were compared using correlation plots. Results: ADC and IVIM did not fit the data well, failing to capture the signal at high b-values. The Kurtosis model best explained the data in many voxels, but in voxels exhibiting a more time-dependent signal, the VERDICT model explained the data best. The ADC correlated significantly (p < 0.004) with the intracellular diffusion coefficient (r = 0.48), intracellular volume fraction (r = -0.21), and perfusion fraction (r = 0.46) parameters from VERDICT, suggesting that these factors all contribute to ADC contrast. The mean kurtosis correlated with the intracellular volume fraction parameter (r = 0.26) from VERDICT, consistent with the hypothesis that kurtosis relates to cellularity, but also correlated weakly with the intracellular diffusion coefficient (r = 0.18) and cell radius (r = 0.16) parameters, suggesting that it may be difficult to attribute physical meaning to kurtosis. Conclusion: Both Kurtosis and VERDICT explained the diffusion signal better than ADC and IVIM, primarily due to poor fitting at high b-values in the latter two models. The Kurtosis and VERDICT models captured information at high b using parameters (Kurtosis or intracellular volume fraction and radius) that do not have a simple relationship with ADC and that may provide additional microstructural information in bone metastases. PMID- 29503809 TI - Impact of Phosphoproteomics in the Era of Precision Medicine for Prostate Cancer. AB - Prostate cancer is the most common malignancy in men in the United States. While androgen deprivation therapy results in tumor responses initially, there is relapse and progression to metastatic castration-resistant prostate cancer. Currently, all prostate cancer patients receive essentially the same treatment, and there is a need for clinically applicable technologies to provide predictive biomarkers toward personalized therapies. Genomic analyses of tumors are used for clinical applications, but with a paucity of obvious driver mutations in metastatic castration-resistant prostate cancer, other applications, such as phosphoproteomics, may complement this approach. Immunohistochemistry and reverse phase protein arrays are limited by the availability of reliable antibodies and evaluates a preselected number of targets. Mass spectrometry-based phosphoproteomics has been used to profile tumors consisting of thousands of phosphopeptides from individual patients after surgical resection or at autopsy. However, this approach is time consuming, and while a large number of candidate phosphopeptides are obtained for evaluation, limitations are reduced reproducibility, sensitivity, and precision. Targeted mass spectrometry can help eliminate these limitations and is more cost effective and less time consuming making it a practical platform for future clinical testing. In this review, we discuss the use of phosphoproteomics in prostate cancer and other clinical cancer tissues for target identification, hypothesis testing, and possible patient stratification. We highlight the majority of studies that have used phosphoproteomics in prostate cancer tissues and cell lines and propose ways forward to apply this approach in basic and clinical research. Overall, the implementation of phosphoproteomics via targeted mass spectrometry has tremendous potential to aid in the development of more rational, personalized therapies that will result in increased survival and quality of life enhancement in patients suffering from metastatic castration-resistant prostate cancer. PMID- 29503810 TI - Metastatic Extramammary Paget's Disease: Pathogenesis and Novel Therapeutic Approach. AB - Extramammary Paget's disease (EMPD) is a rare, slow-growing, cutaneous adenocarcinoma that usually originates in the anogenital area and axillae outside the mammary glands. EMPD mostly progresses slowly and is often diagnosed as carcinoma in situ; however, upon becoming invasive, it promptly and frequently metastasizes to regional lymph nodes, leading to subsequent distant metastasis. To date, several chemotherapy regimens have been used to treat metastatic EMPD; however, they present limited effect and patients with distant metastasis exhibit a poor prognosis. Recently, basic and translational investigative research has elucidated factors and molecular mechanisms underlying the promotion of metastasis, which can lead to targeted therapy-based emerging treatment strategies. Here, we aim to discuss current therapies and their limitations; advancements in illustrating mechanisms promoting invasion, migration, and proliferation of EMPD tumor cells; and future therapeutic approaches for metastatic EMPD that may enhance clinical outcomes. PMID- 29503811 TI - Systematic Identification of Intracellular-Translocated Candidate Effectors in Edwardsiella piscicida. AB - Many bacterial pathogens inject effectors directly into host cells to target a variety of host cellular processes and promote bacterial dissemination and survival. Identifying the bacterial effectors and elucidating their functions are central to understanding the molecular pathogenesis of these pathogens. Edwardsiella piscicida is a pathogen with a wide host range, and very few of its effectors have been identified to date. Here, based on the genes significantly regulated by macrophage infection, we identified 25 intracellular translocation positive candidate effectors, including all five previously reported effectors, namely EseG, EseJ, EseH, EseK, and EvpP. A subsequent secretion analysis revealed diverse secretion patterns for the 25 effector candidates, suggesting that multiple transport pathways were involved in the internalization of these candidate effectors. Further, we identified two novel type VI secretion system (T6SS) putative effectors and three outer membrane vesicles (OMV)-dependent putative effectors among the candidate effectors described above, and further analyzed their contribution to bacterial virulence in a zebrafish model. This work demonstrates an effective approach for screening bacterial effectors and expands the effectors repertoire in E. piscicida. PMID- 29503812 TI - Tularemia in Germany-A Re-emerging Zoonosis. AB - Tularemia, also known as "rabbit fever," is a zoonosis caused by the facultative intracellular, gram-negative bacterium Francisella tularensis. Infection occurs through contact with infected animals (often hares), arthropod vectors (such as ticks or deer flies), inhalation of contaminated dust or through contaminated food and water. In this review, we would like to provide an overview of the current epidemiological situation in Germany using published studies and case reports, an analysis of recent surveillance data and our own experience from the laboratory diagnostics, and investigation of cases. While in Germany tularemia is a rarely reported disease, there is evidence of recent re-emergence. We also describe some peculiarities that were observed in Germany, such as a broad genetic diversity, and a recently discovered new genus of Francisella and protracted or severe clinical courses of infections with the subspecies holarctica. Because tularemia is a zoonosis, we also touch upon the situation in the animal reservoir and one-health aspects of this disease. Apparently, many pieces of the puzzle need to be found and put into place before the complex interaction between wildlife, the environment and humans are fully understood. Funding for investigations into rare diseases is scarce. Therefore, combining efforts in several countries in the framework of international projects may be necessary to advance further our understanding of this serious but also scientifically interesting disease. PMID- 29503814 TI - The Pathophysiology of Low Systemic Blood Flow in the Preterm Infant. AB - Assessment and treatment of the VLBW infant with cardiovascular impairment requires understanding of the underlying physiology of the infant in transition. The situation is dynamic with changes occurring in systemic blood pressure, pulmonary pressures, myocardial function, and ductal shunt in the first postnatal days. New insights into the role of umbilical cord clamping in the transitional circulation have been provided by large clinical trials of early versus later cord clamping and a series of basic science reports describing the physiology in an animal model. Ultrasound assessment is invaluable in assessment of the physiology of the transition and can provide information about the size and shunt direction of the ductus arteriosus, the function of the myocardium and its filling as well as measurements of the cardiac output and an estimate of the state of peripheral vascular resistance. This information not only allows more specific treatment but it will often reduce the need for treatment. PMID- 29503813 TI - Potential of oncolytic viruses in the treatment of multiple myeloma. AB - Multiple myeloma (MM) is a clonal malignancy of plasma cells that is newly diagnosed in ~30,000 patients in the US each year. While recently developed therapies have improved the prognosis for MM patients, relapse rates remain unacceptably high. To overcome this challenge, researchers have begun to investigate the therapeutic potential of oncolytic viruses as a novel treatment option for MM. Preclinical work with these viruses has demonstrated that their infection can be highly specific for MM cells and results in impressive therapeutic efficacy in a variety of preclinical models. This has led to the recent initiation of several human trials. This review summarizes the current state of oncolytic therapy as a therapeutic option for MM and highlights a variety of areas that need to be addressed as the field moves forward. PMID- 29503815 TI - Using Routine Data Sources to Feed an Immunization Information System for High Risk Patients-A Pilot Study. AB - Background: Vaccine-preventable diseases among high-risk patients are a public health priority in high-income countries. Most national immunization programs have included vaccination recommendations for these population groups but they remain hard-to-reach and coverage data are poorly available. In a pilot study, we developed and tested an automated approach for identifying individuals with underlying medical conditions to feed an immunization information system (IIS). Methods: We reviewed published recommendations on medical conditions that indicate vaccination against influenza, pneumococcal disease, meningococcal disease, hepatitis A, and hepatitis B. For each medical condition, we identified the International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis and procedure codes, the user fee exempt codes and the Anatomical Therapeutic Chemical Classification System codes and we reported these data in correspondence tables. Using these tables, we extracted three lists of patients recorded in three current data sources between 2001 and 2010 in the Apulia region of Italy: the hospital discharge registry, the user fee exempt registry, and the drug prescription registry. Using a unique personal identification number, we linked these three lists of patients with the regional IIS (2012 database), obtaining a list of patients with chronic diseases eligible for vaccination. We tested completeness, sensitivity, and positive predictive value (PPV) of this approach by asking a sample of 28 general practitioners (GPs) to evaluate the matching between a sublist of patients with clinical recommendations for influenza vaccination and the GPs individual subjects medical records. Results: We included a total of 1,204,496 subjects with underlying medical conditions eligible to receive any of the aforementioned vaccinations. Of these, 9% were identified in all three data sources, 18% in two sources, and 73% in one source. The completeness of this automated process in identifying GPs high risk patients eligible for influenza vaccination was 88.9% [95% confidence intervals (95% CI): 88.1-89.8%], with a sensitivity of 69.2% (95% CI: 67.7-70.6%) and a PPV of 85.7% (95% CI: 84.4-86.8%). Conclusion: The high completeness of the methodology used for identifying high-risk patients in current data sources encouraged us to apply this approach for feeding the regional IIS. PMID- 29503817 TI - Cystathionine beta-Synthase Is Necessary for Axis Development in Vivo. AB - The cystathionine beta-synthase (CBS) is a critical enzyme in the transsulfuration pathway and is responsible for the synthesis of cystathionine from serine and homocysteine. Cystathionine is a precursor to amino acid cysteine. CBS is also responsible for generation of hydrogen sulfide (H2S) from cysteine. Mutation in CBS enzyme causes homocysteine levels to rise, and gives rise to a condition called hyperhomocysteinuria. To date, numerous mouse knockout models for CBS enzyme has been generated, which show panoply of defects, reflecting the importance of this enzyme in development. In zebrafish, we and others have identified two orthologs of cbs, which we call cbsa and cbsb. Previous gene knockdown studies in zebrafish have reported a function for cbsb ortholog in maintaining ion homeostasis in developing embryos. However, its role in maintaining H2S homeostasis in embryos is unknown. Here, we have performed RNA analysis in whole zebrafish embryos that showed a wide expression pattern for cbsa and cbsb primarily along the embryonic axis of the developing embryo. Loss of-function analysis using a combination of approaches which include splice morpholinos and CRISPR/Cas9 genomic engineering show evidence that cbsb ortholog is responsible for anterior-posterior axis development, and cbsa function is redundant. Cbsb loss of function fish embryos show shortened and bent axis, along with less H2S and more homocysteine, effects resulting from loss of Cbsb. Using a chemical biology approach, we rescued the axis defects with betaine, a compound known to reduce homocysteine levels in plasma, and GYY4137, a long term H2S donor. These results collectively argue that cells along the axis of a developing embryo are sensitive to changes in homocysteine and H2S levels, pathways that are controlled by Cbsb, and thus is essential for development. PMID- 29503818 TI - Hereditary Angioedema: The Economics of Treatment of an Orphan Disease. AB - This review will discuss the cost burden of hereditary angioedema on patients, healthcare systems, and society. The impact of availability of and access to novel and specific therapies on morbidity, mortality, and the overall burden of disease will be explored along with potential changes in treatment paradigms to improve effectiveness and reduce cost of treatment. The prevalence of orphan diseases, legislative incentives to encourage development of orphan disease therapies and the impact of orphan disease treatment on healthcare payment systems will be discussed. PMID- 29503819 TI - Granulin Secreted by the Food-Borne Liver Fluke Opisthorchis viverrini Promotes Angiogenesis in Human Endothelial Cells. AB - The liver fluke Opisthorchis viverrini is a food-borne, zoonotic pathogen endemic to Thailand and adjacent countries in Southeast Asia. The adult developmental stage of the O. viverrini parasite excretes and secretes numerous proteins within the biliary tract including the gall bladder. Lesions caused by the feeding activities of the liver fluke represent wounds that undergo protracted cycles of healing and re-injury during chronic infection, which can last for decades. Components of the excretory/secretory (ES) complement released by the worms capably drive proliferation of bile duct epithelial cells and are implicated in establishing the oncogenic milieu that leads to bile duct cancer, cholangiocarcinoma. An ES protein, the secreted granulin-like growth factor termed Ov-GRN-1, accelerates wound resolution in mice and in vitro. To investigate angiogenesis (blood vessel development) that may contribute to wound healing promoted by liver fluke granulin and, by implication, to carcinogenesis during chronic opisthorchiasis, we employed an in vitro tubule formation assay (TFA) where human umbilical vein endothelial cells were grown on gelled basement matrix. Ten and 40 nM Ov-GRN-1 significantly stimulated angiogenesis as monitored by cellular proliferation and by TFA in real time. This demonstration of potent angiogenic property of Ov-GRN-1 bolsters earlier reports on the therapeutic potential for chronic non-healing wounds of diabetics, tobacco users, and the elderly and, in addition, showcases another of the hallmark of cancer characteristic of this carcinogenic liver fluke. PMID- 29503820 TI - Tools for the Assessment of Comorbidity Burden in Rheumatoid Arthritis. AB - Introduction: Comorbidities influence the prognosis, clinical outcomes, disease activity, and treatment response in rheumatoid arthritis (RA). RA patients have a high-comorbidity burden necessitating their study. Comorbidity indices are used to measure comorbidities and to study their impacts on different outcomes. A large number of such indices are used in clinical research. Some indices have been specifically developed in RA patients. Aim: This review aims to provide an overview of generic and specific comorbidity indices commonly used in RA research. Methods: We performed a critical literature review of comorbidity indices in RA using the PubMed database. Results/discussion: This non-systematic literature review provides an overview of generic and specific comorbidity indices commonly used in RA studies. Some of the older but commonly used comorbidity indices like the Charlson comorbidity index and the Elixhauser comorbidity measure were primarily developed to estimate mortality risk from comorbid diseases. They were not specifically developed for RA patients but have been widely used in rheumatology comorbidity measurement. Of the many comorbidity indices available, only the rheumatic disease comorbidity index (RDCI) and the multimorbidity index have been specifically developed in RA patients. The functional comorbidity index was developed to look at functional disability and has been used in RA patients considering that morbidity is more important than mortality in such patients. While there is limited data comparing these indices, available evidence seems to favor the use of RDCI as it predicts mortality, hospitalization, disability, and healthcare utilization. The choice of the index, however, depends on several factors such as the population under study, outcome of interest, and sources of data. More research is needed to study the RA specific comorbidity measures to make evidence-based recommendations for the choice of a comorbidity measure. PMID- 29503821 TI - Selective Mesh Augmentation to Prevent Incisional Hernias in Open Colorectal Surgery Is Safe and Cost-Effective. PMID- 29503822 TI - Outcome of Stromal Vascular Fraction-Enriched Fat Grafting Compared to Intramuscular Transposition in Painful End-Neuromas of Superficial Radial Nerve: Preliminary Results. AB - Introduction: The management of painful end-neuromas of the superficial branch of the radial nerve (SBRN) remains challenging due to high levels of pain relapse. The novel technique of stromal vascular fraction (SVF)-enriched fat grafting showed continuous pain relief, although failed to prove statistically significant. Besides acting as a mechanical barrier, SVF-enriched fat grafting might also affect the cellular level. The aim of this study was to compare clinical outcomes of SVF to the widely popular intramuscular transposition technique. Patients and methods: In this cohort study, 10 consecutive patients treated for painful end-neuromas of the SBRN between 2010 and 2013 were analyzed retrospectively. Microsurgical resection of end-neuromas was performed in all patients. Five patients were treated with subsequent intramuscular transposition into the brachioradialis muscle and five patients received SVF-enriched fat grafting. Five different pain modalities and various predictors were compared pre and up to 36 months post-operatively. Results: In the transposition group, sustained pain reduction was not observed after an initial significant reduction 2 months' post-surgery, resulting in pain relapse at 36 months and comparable to the preoperative assessment. In the graft group, some degree of pain reduction was observed at 2 months after the surgery and proved to be constant in the long term outcome, although not statistically significant compared to preoperative levels. Conclusion: Both SVF-enriched fat grafting and intramuscular transposition failed to prove statistical significant pain reduction in treating symptomatic neuromas of peripheral nerves. PMID- 29503823 TI - Editorial: Pathologic Conditions of the Human Nervous and Muscular Systems Associated with Mutant Chaperones: Molecular and Mechanistic Aspects. PMID- 29503816 TI - A Salutary Role of Reactive Oxygen Species in Intercellular Tunnel-Mediated Communication. AB - The reactive oxygen species, generally labeled toxic due to high reactivity without target specificity, are gradually uncovered as signaling molecules involved in a myriad of biological processes. But one important feature of ROS roles in macromolecule movement has not caught attention until recent studies with technique advance and design elegance have shed lights on ROS signaling for intercellular and interorganelle communication. This review begins with the discussions of genetic and chemical studies on the regulation of symplastic dye movement through intercellular tunnels in plants (plasmodesmata), and focuses on the ROS regulatory mechanisms concerning macromolecule movement including small RNA-mediated gene silencing movement and protein shuttling between cells. Given the premise that intercellular tunnels (bridges) in mammalian cells are the key physical structures to sustain intercellular communication, movement of macromolecules and signals is efficiently facilitated by ROS-induced membrane protrusions formation, which is analogously applied to the interorganelle communication in plant cells. Although ROS regulatory differences between plant and mammalian cells exist, the basis for ROS-triggered conduit formation underlies a unifying conservative theme in multicellular organisms. These mechanisms may represent the evolutionary advances that have enabled multicellularity to gain the ability to generate and utilize ROS to govern material exchanges between individual cells in oxygenated environment. PMID- 29503824 TI - Fatty Images of the Heart: Spectrum of Normal and Pathological Findings by Computed Tomography and Cardiac Magnetic Resonance Imaging. AB - Ectopic cardiac fatty images are not rarely detected incidentally by computed tomography and cardiac magnetic resonance, or by exams focused on the heart as in general thoracic imaging evaluations. A correct interpretation of these findings is essential in order to recognize their normal or pathological meaning, focusing on the eventually associated clinical implications. The development of techniques such as computed tomography and cardiac magnetic resonance allowed a detailed detection and evaluation of adipose tissue within the heart. This pictorial review illustrates the most common characteristics of cardiac fatty images by computed tomography and cardiac magnetic resonance, in a spectrum of normal and pathological conditions ranging from physiological adipose images to diseases presenting with cardiac fatty foci. Physiologic intramyocardial adipose tissue may normally be present in healthy adults, being not related to cardiac affections and without any clinical consequence. However cardiac fatty images may also be the expression of various diseases, comprehending arrhythmogenic right ventricular dysplasia, postmyocardial infarction lipomatous metaplasia, dilated cardiomyopathy, and lipomatous hypertrophy of the interatrial septum. Fatty neoplasms of the heart as lipoma and liposarcoma are also described. PMID- 29503826 TI - Predictive Factors of Mortality in Acute Amphetamine Type Stimulants Poisoning; a Review of 226 Cases. AB - Introduction: Amphetamine type stimulants (ATS) such as amphetamine and methamphetamine (MA) are one of the most important causes of poisoning in the world. In this study we aimed to define the predictive factors of mortality in acute ATS poisoning patients. Methods: This is a retrospective cross-sectional study on all cases with acute ATS poisoning who were referred to a referral center for poisoning, Tehran, Iran, from April 2011 to March 2014. Using patients' medical records, demographic data, route of exposure, type and amount of ATS, the cause of poisoning, clinical presentations, and electrocardiogram (ECG) and laboratory findings, as well as patient's outcomes were collected and analyzed regarding the independent predictive factors of mortality. Results: 226 cases with the mean age of 32.9 +/- 10.9 years were studied (77% male). MA was the most abused ATS (97.4%) and the most frequent route of exposure was oral (55.3%). The mortality rate was 5.4%. There was a significant association between agitation (p = 0.002), seizure (p = 0.001), loss of consciousness (p < 0.001), creatine phosphokinase level (p = 0.002), serum pH (p = 0.002), serum HCO3 (p = 0.02), and PCO2 (p = 0.01) with mortality. However, serum HCO3 [OR=1.27 (95% CI: 1.07-1.50); p value=0.005], PCO2 [OR=0.89 (95% CI: 0.84-0.96); p value=0.002], and loss of consciousness [OR=0.019 (95% CI: 0.003-0.106); p value=0.000] were the only independent predictive factors of mortality. Conclusion: PCO2 >= 51 mmHg, serum bicarbonate <= 22.6 mEq/L, and loss of consciousness on admission could be considered as prognostic factors of mortality in acute ATS poisoning cases presenting to emergency department. PMID- 29503825 TI - Real Time Assessment of Young Adults' Attitudes toward Tobacco Messages. AB - Objectives: We used ecological momentary assessment (EMA) to examine young adults' attitudes towards pro-tobacco messages encountered in real time and their association with intentions to use tobacco. Methods: Young adults (N = 92, ages 18-29) recorded sightings of marketing or social media related to tobacco in real time via mobile app for 28 days. Participants reported message characteristics, their attitudes towards the message, and intentions to use the depicted product for each submission. We used generalized linear mixed models to examine factors related to attitude towards message and intentions to use tobacco. Results: Messages depicting e-cigarettes (p < .001) or hookah (p < .05) were associated with significantly more favorable attitudes compared with traditional cigarettes. Positive attitude towards the message was significantly associated with intention to use the depicted product (p < .001). Messages depicting e-cigarettes and hookah were significantly associated with higher intention to use. Message source was not significantly related to attitudes towards the message or product use intentions. Conclusions: Marketing featuring e-cigarettes and hookah is an important target for future regulation. Given that pro-tobacco and e-cigarette messages are prevalent online, future research should consider the Internet and social media as important venues for counter-marketing and intervention efforts. PMID- 29503827 TI - Urinary Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Cystatin C in Early Detection of Pediatric Acute Kidney Injury; a Diagnostic Accuracy Study. AB - Introduction: There is a controversy regarding accuracy of neutrophil gelatinase associated lipocalin (NGAL) and Cystatin C in early detection of acute kidney injury (AKI). The present study aimed to compare the diagnostic value of two biomarkers in this regard. Method: In the present diagnostic accuracy study, all children between the ages of 1 month to 14 years were entered. Pediatric Risk, Injury Failure, Loss, End-stage renal disease (pRIFLE) criteria was used for identification of children with AKI as the reference test. Blood samples were taken from all patients at baseline and 48 hours after admission to assess serum creatinine and Cystatin C level. In addition, a urine sample was obtained within 6 hours of admission in order to measure NGAL level. In the end, area under the receiving operating characteristics (ROC) curve, sensitivity, and specificity of urine NGAL (uNGAL) and Cystatin C in early detection of AKI were compared. Results: Data from 96 children with the mean age of 27.31+/-36.24 months were entered (56.25% girls). Area under the ROC curve of uNGAL level in diagnosis of AKI in children was 0.91 (95% CI: 0.80 to 1.00) and area under the ROC of Cystatin C was 0.90 (95% CI: 0.77 to 1.00). Both tests had the same value in diagnosis of AKI (p=0.89). The best cut-off point of uNGAL for diagnosing AKI was 125 mg/L. uNGAL had a sensitivity and specificity of 0.92 (0.62 to 0.99) and 0.69 (0.57 to 0.78), respectively. The best cut-off point of serum Cystatin C level was 0.4 mg/L. Cystatin C had a sensitivity and specificity of 0.92 (0.62 to 0.99) and 0.64 (0.52 to 0.74), respectively. Conclusion: The present study showed that uNGAL level has the same value as serum Cystatin C level in early diagnosis of AKI. PMID- 29503828 TI - Using Intra-Aortic Balloon Pump for Management of Cardiogenic Shock Following Aluminum Phosphide Poisoning; Report of 3 Cases. AB - Introduction: Aluminium phosphide (Alp) poisoning mortality rate has been reported as high as 70-100%, and refractory hypotension and cardiogenic shock are the two most common presentations leading to death. Due to lack of specific antidote, all treatments are focused on supportive care and recently, intra aortic balloon pump (IABP) has been suggested to treat cardiogenic shock resulting from toxic myocarditis. In the current paper, we introduce three Alp poisoned patients for whom IABP was applied to manage their refractory shock. Case presentation: Two men and one woman who were admitted to emergency department (ED) of Imam Reza academic Hospital, Mashhad, Iran due to intentional Alp poisoning are reported. The cases visited the ED shortly after ingestion and nearly all of them showed hypotension, tachycardia and metabolic acidosis during early hospitalization. Due to persistent shock state, despite receiving intravenous fluid therapy and vasopressor agents, IABP insertion was performed in these cases. Finally, one of them survived and the other two died. Conclusion: It still cannot be decided whether IABP insertion is effective in cases of Alp poisoning or not. It might be reasonable to try this intervention along with other conservative treatments in patients who survive more than 12 hours and consistently suffer from refractory hypotension. PMID- 29503829 TI - Pro-BNP versus MEDS Score in Determining the Prognosis of Sepsis Patients; a Diagnostic Accuracy Study. AB - Introduction: Pro-brain natriuretic peptide (Pro-BNP) can act as an independent predictor of mortality in septic patients. This study aimed to compare the diagnostic accuracy of pro-BNP and Mortality in Emergency Department Sepsis (MEDS) score in this regard. Method: This cross-sectional study was conducted on > 14 years old sepsis patients of an emergency department (ED), during 2 years. The level of Pro-BNP and MEDS score were measured for all eligible patients and considering one month mortality as reference, screening performance characteristics of the two tests were compared using SPSS 21 and STATS 11. Results: 121 patients with the mean age of 75.87+/-11.82 years were studied (55.4% male). 85 (70.25%) patients had moderate to high probability of mortality according to MEDS score. The mean Pro-BNP levels of survivor and non-survivor patients were 489.69 +/- 327.47 and 3954.98 +/- 2717.85 pg/ml, respectively (p < 0.0001). Sensitivity and specificity of Pro-BNP (in 1000 pg/ml cut off) and MEDS score (in level 3) in prediction of 1-month mortality were 93.6 (83.7-97.9), 94.8 (84.7-98.6), 65.0 (51.9-76.3), and 98.2 (89.5-99.9), respectively. Area under the ROC curve of the two tests were 97.36 (95% CI: 92.92-94.48) and 92.31 (95% CI: 86.35-96.53), respectively (p = 0.0543). Conclusion: Pro-BNP and MEDS score both have excellent diagnostic accuracy in predicting 1-month mortality of sepsis patients. However, considering the higher sensitivity as well as availability and ease of calculation, it seems that Pro-BNP can be considered an appropriate tool for screening patients with high risk of mortality following sepsis in ED. PMID- 29503831 TI - Specialist Physicians' Attitude towards Emergency Medicine; a Semi-Structured Qualitative Study. AB - Introduction: The present study is a survey to assess the pros and cons of emergency medicine (EM) from the viewpoint of the scholars from other medicine disciplines to improve the efficiency of EM in the healthcare system. Methods: This is a semi-structured qualitative study. Face-to-face interviews with various physicians with different specialties were performed to gather information on their viewpoints. Study population was selected mainly based on their history of collaboration with emergency medicine specialists in several educational hospitals in Tehran, Iran. All interviews were recorded and then transcribed to paper. Data were mainly categorized and reported into four themes: 1) general aspects of emergency medicine, goals and policies 2) Management of emergency department 3) Educational aspects 4) therapeutic aspects. Results: 22 specialist physicians with the mean age of 47.3+/-7.6 years were studied (77.3% male). The average of their work experience as a specialist was 13.6+/-7.5 years. From the viewpoint of other experts, the establishment of EM and training of EM specialists is accompanied with relative disadvantages and advantages regarding goals and policies, patient management, therapeutic interventions and student education in the emergency department. Initiating resuscitation and maintaining hemodynamic stability and appropriate triage of the patients can add to the benefits of EM by preventing unreasonable hospitalization, and reducing the workload and difficulty of the work of other professionals working in the hospital. Conclusions: Based on the results of the current study, it seems that most Iranian specialist physicians have a positive attitude towards emergency medicine and think that emergency medicine could have beneficial effects for the health system and hospital management system. PMID- 29503830 TI - Applications of End-Tidal Carbon Dioxide (ETCO2) Monitoring in Emergency Department; a Narrative Review. AB - Capnograph is an indispensable tool for monitoring metabolic and respiratory function. In this study, the aim was to review the applications of end-tidal carbon dioxide (ETCO2) monitoring in emergency department, multiple databases were comprehensively searched with combination of following keywords: "ETCO2", "emergency department monitoring", and "critical monitoring" in PubMed, Google Scholar, Scopus, Index Copernicus, EBSCO and Cochrane Database. PMID- 29503832 TI - Workplace Violence against Residents in Emergency Department and Reasons for not Reporting Them; a Cross Sectional Study. AB - Introduction: Due to the stressful nature of emergency Department (ED), residents in ED are at risk of violence from patients or their associates. This study aimed to determine the prevalence of workplace violence against ED residents and the reasons for not reporting them. Methods: This cross-sectional study was conducted on ED residents of three educational hospitals, Tehran, Iran, during 2015. The national questionnaire about workplace violence was used for data gathering. In addition, prevalence of reporting the violence and the reasons for not reporting them were determined. Results: 280 questionnaires were analyzed. The mean age of residents was 32.2 +/- 4.6 years (58.4% female). 224 (80%) residents stated that they had not passed any educational courses on violence management. The most prevalent type of violence was verbal (90.7%) and patients' associates (85.4%) were the most common source of aggression. The frequency of physical violence was higher in male aggressors (p = 0.001), resident age > 30 years (p = 0.044), aggressor age > 30 years (p = 0.001), and night shift (p = 0.001). The same trend was observed regarding verbal and racial-ethnic violence. There was no significant relationship between residents' sex, resident's specialty, and presence of security and police with frequency of violence. 214 (76.4%) residents did not report the violence, and the main reasons for not reporting from their viewpoint were uselessness of reporting (37.4%) and insignificance of the violence (36.9%). Conclusion: Based on the findings of the present study more than 90% of ED residents had experienced at least one type of verbal, physical, or racial-ethnic violence during their shifts. It is necessary for residents in EDs to be trained about violence control and also report and follow these issues through legal channels. PMID- 29503833 TI - Accuracy of Neck stiffness, Kernig, Brudzinski, and Jolt Accentuation of Headache Signs in Early Detection of Meningitis. AB - Introduction: The diagnostic value of clinical signs in early diagnosis of meningitis has been evaluated but the existing results are contradicting. The present study aimed to evaluate the accuracy of Kernig, Brudzinski, neck stiffness, and Jolt Accentuation of Headache (JAH) signs in this regard. Methods: In this diagnostic accuracy study, patients with suspected meningitis who were referred to the emergency department were examined regarding presence or absence of the mentioned clinical signs and screening performance characteristics of the signs were calculated. Cerebrospinal fluid analysis was used as the reference test. Results: 120 cases with mean age of 48.79 +/- 21.68 years (18 - 93) were studied (63.3% male). Diagnosis of meningitis was confirmed for 45 (37.5%) cases. Neck stiffness (p < 0.001), Kernig (p < 0.001), Brudzinski (p < 0.001), and JAH (p < 0.001) had significantly higher frequency among patients with meningitis. The accuracy of neck stiffness, Kernig, Brudzinski, and JAH signs in early detection of meningitis were 0.676 (95% CI: 0.575-0.776), 0.667 (95% CI: 0.552 0.782), 0.720 (95% CI: 0.619-0.821), 0.749 (95% CI: 0.659-839), respectively. Conclusions: It seems that diagnostic value of JAH is higher than other clinical signs but the accuracy of all signs is in poor to fair range. JAH had the highest sensitivity and Kernig and Brudzinski had the highest specificity. PMID- 29503834 TI - Methamphetamine-Induced Cardiomyopathy (MACM) in a Middle-Aged Man; a Case Report. AB - The development of methamphetamine-associated cardiomyopathy (MACM) represents a severe complication of chronic methamphetamine abuse. MACM-induced irreversible structural and functional changes in the heart can eventually lead to decompensated heart failure, ultimately requiring heart transplantation. In this case report we present a 47-year old male with a previous history of chronic amphetamine abuse who presented to the emergency room with severe dyspnea at rest associated with mild substernal non-radiating chest pain. He denied any previous cardiac history but had a positive urinary toxicology for methamphetamine. A complete cardiac workup ruled out all other etiologies. The patient required a 3 week intensive pharmacotherapy intervention to stabilize acute heart failure symptoms. At discharge he was classified as having New York Association Class III (NYHA-III) heart failure. His medical symptoms did not improve and he was considered for heart transplantation. With the increase in availability and abuse of methamphetamine, case of MACM such as ours are more frequently being encountered in the emergency departments. In addition to raising awareness, our case provides an outline of how MACM patients likely may present and the subsequent morbid sequela. Clinicians should maintain a high degree of suspicion when assessing all patients with a history of methamphetamine abuse. Early cardiac evaluation can help identify ventricular compromise in asymptomatic patients providing an opportunity to intervene prior to the development of irreversible MACM. PMID- 29503835 TI - Dexmedetomidine-Fentanyl versus Midazolam-Fentanyl in Pain Management of Distal Radius Fractures Reduction; a Randomized Clinical Trial. PMID- 29503836 TI - Emergency Department Bedside Ultrasonography for Diagnosis of Acute Cholecystitis; a Diagnostic Accuracy Study. AB - Introduction: Using bedside ultrasound in diagnosing acute cholecystitis in the emergency department (ED) can save time, help the decision making process and allocate resources wisely. This study aimed to evaluate the diagnostic accuracy of bedside right upper quadrant (RUQ) ultrasonography in detection of acute cholecystitis. Method: In this diagnostic accuracy study, patients presenting to ED, suffering from RUQ pain in favor of acute cholecystitis underwent RUQ ultrasonography in emergency and radiology departments and interrater agreement between reports was calculated. Results: 342 patients with the mean age of 53.92 +/- 11.18 (20 - 83) years were studied (63.2% female). The number of patients with at least one sonographic finding of acute cholecystitis were 53 (15.50%) and 48 (14.00%) based on ED and radiology reports (Kappa = 0.826). Sensitivity, specificity, positive and negative predictive values, as well as positive and negative likelihood ratios of bedside sonography were 89.58 (95%CI: 76.55 - 96.10), 96.59 (95%CI: 93.63 - 98.29), 81.13 (95%CI: 67.58 - 90.11), 98.26 (95%CI: 95.77 - 99.36), 4.30 (95%CI: 2.42 - 7.62) and 0.017 (95%CI: 0.007 - 0.041), respectively. Conclusion: There was a very good agreement between ED and radiology departments' sonography reports regarding the presence or absence of acute cholecystitis. Sensitivity and specificity of bedside RUQ sonography were 89.58 and 96.59, respectively. PMID- 29503837 TI - Brain Natriuretic Peptides in Screening of Syncope with Cardiac Origin; a Commentary. PMID- 29503838 TI - Dissimilarity in the Frequency of Venous Thromboembolism Risk Factors among Studies, a Commentary. PMID- 29503839 TI - Key Performance Indicators of Chest Pain Management in Emergency Department; a Letter to the Editor. PMID- 29503840 TI - The Accuracy of Ultrasonography in Detection of Ulnar Collateral Ligament of Thumb Injuries; a Cross-Sectional Study. AB - Introduction: Timely diagnosis and treatment of traumatic injury to ulnar collateral ligament (UCL) of thumb is of special importance for preserving the full function of the hand. Therefore, the present study has been designed with the aim of evaluating the accuracy of ultrasonography in detection of these injuries. Methods: The present diagnostic accuracy study was performed on trauma patients over 15 years old who had clinical evidence of injury to UCL of thumb and were admitted to the emergency department. All patients were evaluated regarding injury to the mentioned ligament via ultrasonography and MRI and finally, the accuracy of ultrasonography in this regard was measured considering MRI as the reference test. Results: 20 individuals with the mean age of 38.60 +/- 13.45 (16 - 64) years were evaluated (60% male). Based on ultrasonography and MRI findings 7 (35%) individuals and 7 (35%), respectively had complete ligament rupture (kappa: 0.560 (95% CI: 0.179 - 0.942)). Sensitivity, specificity, positive and negative predictive value, and positive and negative likelihood ratio of ultrasonography in detecting injuries of the mentioned ligament were 71.42 (30.25 - 94.88), 84.61 (53.66 - 97.28), 71.42 (30.25 - 94.88), 84.61 (53.66 - 97.28), 2.5 (0.71 - 8.82), and 0.18 (0.04 - 0.67), respectively. Conclusion: Based on the findings of the present study, performance of ultrasonography by a radiologist in the emergency department has 80% accuracy in detecting traumatic injuries of UCL of the thumb. PMID- 29503841 TI - Current perspectives on incentive salience and applications to clinical disorders. AB - Affective neuroscience research has revealed that reward contains separable components of 'liking', 'wanting', and learning. Here we focus on current 'liking' and 'wanting' findings and applications to clinical disorders. 'Liking' is the hedonic impact derived from a pleasant experience, and is amplified by opioid and related signals in discrete sites located in limbic-related brain areas. 'Wanting' refers to incentive salience, a motivation process for reward, and is mediated by larger systems involving mesocorticolimbic dopamine. Deficits in incentive salience may contribute to avolitional features of depression and related disorders, whereas deficits in hedonic impact may produce true anhedonia. Excesses in incentive salience, on the other hand, can lead to addiction, especially when narrowly focused on a particular target. Finally, a fearful form of motivational salience may even contribute to some paranoia symptoms of schizophrenia and related disorders. PMID- 29503842 TI - Anhedonia in depression: biological mechanisms and computational models. AB - Anhedonia is a severe condition that describes a near-complete absence of enjoyment, motivation, and interest. A core feature of depression, clinical manifestations of anhedonia can include deficits in experiencing pleasure, approach-related motivated behavior, and learning how to match expectations to the environment. To date, the precise neurobiological mechanisms of anhedonia in major depression are still poorly understood. We have previously argued that contradictory findings and the inability to identify specific neurobiological substrates for anhedonic symptoms may result from sample heterogeneity, suboptimal methods of assessment, and the challenge of dissociating between different components of anhedonia. Recently, however, computational advances to the operationalization of psychiatric symptoms have enhanced the ability to evaluate the neurobiology of constituent elements of this symptom domain. In this paper, we review (1) advances in behavioral and computational methods of assessing reward processing and motivation and (2) the development of new self report, neurological, and biological methods of subtyping that may be useful in future pursuits to expand our understanding of the neurobiology of anhedonia in depression. PMID- 29503844 TI - Diagnostic timeliness in adolescents and young adults with cancer: a cross sectional analysis of the BRIGHTLIGHT cohort. AB - Background: Adolescents and young adults (AYAs) are thought to experience prolonged intervals to cancer diagnosis, but evidence quantifying this hypothesis and identifying high-risk patient subgroups is insufficient. We aimed to investigate diagnostic timeliness in a cohort of AYAs with incident cancers and to identify factors associated with variation in timeliness. Methods: We did a cross-sectional analysis of the BRIGHTLIGHT cohort, which included AYAs aged 12 24 years recruited within an average of 6 months from new primary cancer diagnosis from 96 National Health Service hospitals across England between July 1, 2012, and April 30, 2015. Participants completed structured, face-to-face interviews to provide information on their diagnostic experience (eg, month and year of symptom onset, number of consultations before referral to specialist care); demographic information was extracted from case report forms and date of diagnosis and cancer type from the national cancer registry. We analysed these data to assess patient interval (time from symptom onset to first presentation to a general practitioner [GP] or emergency department), the number of prereferral GP consultations, and the symptom onset-to-diagnosis interval (time from symptom onset to diagnosis) by patient characteristic and cancer site, and examined associations using multivariable regression models. Findings: Of 1114 participants recruited to the BRIGHTLIGHT cohort, 830 completed a face-to-face interview. Among participants with available information, 204 (27%) of 748 had a patient interval of more than a month and 242 (35%) of 701 consulting a general practitioner had three or more prereferral consultations. The median symptom onset-to-diagnosis interval was 62 days (IQR 29-153). Compared with male AYAs, female AYAs were more likely to have three or more consultations (adjusted odds ratio [OR] 1.6 [95% CI 1.1-2.3], p=0.0093) and longer median symptom onset-to diagnosis intervals (adjusted median interval longer by 24 days [95% CI 11-37], p=0.0005). Patients with lymphoma or bone tumours (adjusted OR 1.2 [95% CI 0.6 2.1] compared with lymphoma) were most likely to have three or more consultations and those with melanoma least likely (0.2 [0.1-0.7] compared with lymphoma). The adjusted median symptom onset-to-diagnosis intervals were longest in AYAs with bone tumours (51 days [95% CI 29-73] longer than for lymphoma) and shortest in those with leukaemia (33 days [17-49] shorter than for lymphoma). Interpretation: The findings provide a benchmark for diagnostic timeliness in young people with cancer and help to identify subgroups at higher risk of a prolonged diagnostic journey. Further research is needed to understand reasons for these findings and to prioritise and stratify early diagnosis initiatives for AYAs. Funding: National Institute for Health Research, Teenage Cancer Trust, and Cancer Research UK. PMID- 29503843 TI - Sox9 augments BMP2-induced chondrogenic differentiation by downregulating Smad7 in mesenchymal stem cells (MSCs). AB - Cartilage injuries caused by arthritis or trauma pose formidable challenges for effective clinical management due to the limited intrinsic proliferative capability of chondrocytes. Autologous stem cell-based therapies and transgene enhanced cartilage tissue engineering may open new avenues for the treatment of cartilage injuries. Bone morphogenetic protein 2 (BMP2) induces effective chondrogenesis of mesenchymal stem cells (MSCs) and can thus be explored as a potential therapeutic agent for cartilage defect repair. However, BMP2 also induces robust endochondral ossification. Although the precise mechanisms through which BMP2 governs the divergence of chondrogenesis and osteogenesis remain to be fully understood, blocking endochondral ossification during BMP2-induced cartilage formation may have practical significance for cartilage tissue engineering. Here, we investigate the role of Sox9-donwregulated Smad7 in BMP2 induced chondrogenic differentiation of MSCs. We find that overexpression of Sox9 leads to a decrease in BMP2-induced Smad7 expression in MSCs. Sox9 inhibits BMP2 induced expression of osteopontin while enhancing the expression of chondrogenic marker Col2a1 in MSCs. Forced expression of Sox9 in MSCs promotes BMP2-induced chondrogenesis and suppresses BMP2-induced endochondral ossification. Constitutive Smad7 expression inhibits BMP2-induced chondrogenesis in stem cell implantation assay. Mouse limb explant assay reveals that Sox9 expands BMP2 stimulated chondrocyte proliferating zone while Smad7 promotes BMP2-intitated hypertrophic zone of the growth plate. Cell cycle analysis indicates that Smad7 induces significant early apoptosis in BMP2-stimulated MSCs. Taken together, our results strongly suggest that Sox9 may facilitate BMP2-induced chondrogenesis by downregulating Smad7, which can be exploited for effective cartilage tissue engineering. PMID- 29503845 TI - Evaluation of agonist and antagonist radioligands for somatostatin receptor imaging of breast cancer using positron emission tomography. AB - Background: The somatostatin receptor subtype 2 (sstr2) is expressed on a majority of luminal breast cancers, however SPECT and scintigraphy imaging with agonistic sstr2 probes has been sub-optimal. High affinity antagonists can access more binding sites on the cell surface, resulting in higher tumor uptake and improved sensitivity. We compared the tumor uptake and biodistribution of the antagonist 68Ga-NODAGA-JR11 with two agonists 68Ga-DOTA-Tyr3-octreotide (68Ga DOTATOC) and 68Ga-DOTA-Tyr3-octreotate (68Ga-DOTATATE), in the human, sstr2 positive, luminal breast cancer model: ZR-75-1. Results: Peptides were assayed for binding affinity using a filtration-based competitive assay to sstr2. natGa DOTATOC and natGa-DOTATATE had excellent affinity (inhibition constant Ki: 0.9 +/ 0.1 nM and 1.4 +/- 0.3 nM respectively) compared to natGa-NODAGA-JR11 (25.9 +/- 0.2 nM). The number of binding sites on ZR-75-1 cells was determined in vitro by saturation assays. Agonist 67/natGa-DOTATOC bound to 6.64 +/- 0.39 * 104 sites/cells, which was 1.5-fold higher than 67/natGa-NODAGA-JR11 and 2.3-fold higher than 67/natGa-DOTATATE. All three 68Ga-labeled peptides were obtained in good decay-corrected radiochemical yield (61-68%) and were purified by high performance liquid chromatography to ensure high specific activity (137 - 281 MBq/nmol at the end of synthesis). NOD scid gamma mice bearing ZR-75-1 tumors were injected intravenously with the labeled peptides and used for PET/CT imaging and biodistribution at 1 h post-injection. We found that 68Ga-DOTATOC had the highest tumor uptake (18.4 +/- 2.9%ID/g), followed by 68Ga-DOTATATE (15.2 +/- 2.2%ID/g) and 68Ga-NODAGA-JR11 (12.2 +/- 0.8%ID/g). Tumor-to-blood and tumor-to muscle ratios were also higher for the agonists (>40 and >150 respectively), compared to the antagonist (15.6 +/- 2.2 and 45.2 +/- 11.6 respectively). Conclusions: The antagonist 68Ga-NODAGA-JR11 had the lowest tumor uptake and contrast compared to agonists 68Ga-DOTATOC and 68Ga-DOTATATE in ZR-75-1 xenografts.The main contributing factor to this result could be the use of an endogenously expressing cell line, which may differ from previously published transfected models in the number of low-affinity, antagonist-specific binding sites. The relative merit of agonists versus antagonists for sstr2 breast cancer imaging warrants further investigation, first in preclinical models with other sstr2-positive breast cancer xenografts, and ultimately in luminal breast cancer patients. PMID- 29503846 TI - 47Sc as useful beta--emitter for the radiotheragnostic paradigm: a comparative study of feasible production routes. AB - Background: Radiotheragnostics makes use of the same molecular targeting vectors, labeled either with a diagnostic or therapeutic radionuclide, ideally of the same chemical element. The matched pair of scandium radionuclides, 44Sc and 47Sc, satisfies the desired physical aspects for PET imaging and radionuclide therapy, respectively. While the production and application of 44Sc was extensively studied, 47Sc is still in its infancy. The aim of the present study was, therefore, to investigate and compare two different methods of 47Sc production, based on the neutron irradiation of enriched 46Ca and 47Ti targets, respectively. Methods: 47Sc was produced by thermal neutron irradiation of enriched 46Ca targets via the 46Ca(n,gamma)47Ca -> 47Sc nuclear reaction and by fast neutron irradiation of 47Ti targets via the 47Ti(n,p)47Sc nuclear reaction, respectively. The product was compared with regard to yield and radionuclidic purity. The chemical separation of 47Sc was optimized in order to obtain a product of sufficient quality determined by labeling experiments using DOTANOC. Finally, preclinical SPECT/CT experiments were performed in tumor-bearing mice and compared with the PET image of the 44Sc labeled counterpart. Results: Up to 2 GBq 47Sc was produced by thermal neutron irradiation of enriched 46Ca targets. The optimized chemical isolation of 47Sc from the target material allowed formulation of up to 1.5 GBq 47Sc with high radionuclidic purity (>99.99%) in a small volume (~700 MUL) useful for labeling purposes. Three consecutive separations were possible by isolating the in-grown 47Sc from the 46/47Ca-containing fraction. 47Sc produced by fast neutron irradiated 47Ti targets resulted in a reduced radionuclidic purity (99.95-88.5%). The chemical purity of the separated 47Sc was determined by radiolabeling experiments using DOTANOC achievable at specific activities of 10 MBq/nmol. In vivo the 47Sc-DOTANOC performed equal to 44Sc DOTANOC as determined by nuclear imaging. Conclusion: The production of 47Sc via the 46Ca(n,gamma)47Ca nuclear reaction demonstrated significant advantages over the 47Ti production route, as it provided higher quantities of a radionuclidically pure product. The subsequent decay of 47Ca enabled the repeated separation of the 47Sc daughter nuclide from the 47Ca parent nuclide. Based on the results obtained from this work, 47Sc shows potential to be produced in suitable quality for clinical application. PMID- 29503848 TI - An updated radiosynthesis of [18F]AV1451 for tau PET imaging. AB - Background: [18F]AV1451 is a commonly used radiotracer for imaging tau deposits in Alzheimer's disease (AD) and related non-AD tauopathies. Existing radiosyntheses of [18F]AV1451 require complex purifications to provide doses suitable for use in clinical imaging studies. To address this issue, we have modified the synthesis of [18F]AV1451 to use only 0.5 mg precursor, optimized the Boc-deprotection step and developed a simplified method for HPLC purification of the radiotracer. Results: An optimized [18F]AV1451 synthesis using a TRACERLab FXFN module led to high radiochemical yield (202 +/- 57 mCi per synthesis) and doses with excellent radiochemical purity (98 +/- 1%) and good specific activity (2521 +/- 623 Ci/mmol). Conclusion: An updated and operationally simple synthesis of [18F]AV1451 has been developed that is fully automated and prepares radiotracer doses suitable for use in clinical tau PET studies. PMID- 29503847 TI - Pretargeting for imaging and therapy in oncological nuclear medicine. AB - Background: Oncological pretargeting has been implemented and tested in several different ways in preclinical models and clinical trials over more than 30 years. Despite highly promising results, pretargeting has not achieved market approval even though it could be considered the ultimate theranostic, combining PET imaging with short-lived positron emitters and therapy with radionuclides emitting beta or alpha particles. Results: We have reviewed the pretargeting approaches proposed over the years, discussing their suitability for imaging, particularly PET imaging, and therapy, as well as their limitations. The reviewed pretargeting modalities are the avidin-biotin system, bispecific anti-tumour x anti-hapten antibodies and bivalent haptens, antibody-oligonucleotide conjugates and radiolabelled complementary oligonucleotides, and approaches using click chemistry. Finally, we discuss recent developments, such as the use of small binding proteins for pretargeting that may offer new perspectives to cancer pretargeting. Conclusions: While pretargeting has shown promise and demonstrated preclinical and clinical proof of principle, full-scale clinical development programs are needed to translate pretargeting into a clinical reality that could ideally fit into current theranostic and precision medicine perspectives. PMID- 29503849 TI - Guidance on validation and qualification of processes and operations involving radiopharmaceuticals. AB - Background: Validation and qualification activities are nowadays an integral part of the day by day routine work in a radiopharmacy. This document is meant as an Appendix of Part B of the EANM "Guidelines on Good Radiopharmacy Practice (GRPP)" issued by the Radiopharmacy Committee of the EANM, covering the qualification and validation aspects related to the small-scale "in house" preparation of radiopharmaceuticals. The aim is to provide more detailed and practice-oriented guidance to those who are involved in the small-scale preparation of radiopharmaceuticals which are not intended for commercial purposes or distribution. Results: The present guideline covers the validation and qualification activities following the well-known "validation chain", that begins with editing the general Validation Master Plan document, includes all the required documentation (e.g. User Requirement Specification, Qualification protocols, etc.), and leads to the qualification of the equipment used in the preparation and quality control of radiopharmaceuticals, until the final step of Process Validation. Conclusions: A specific guidance to the qualification and validation activities specifically addressed to small-scale hospital/academia radiopharmacies is here provided. Additional information, including practical examples, are also available. PMID- 29503850 TI - Sulfur - fluorine bond in PET radiochemistry. AB - The importance of the sulfur-fluorine bond is starting to increase in modern medicinal chemistry literature. This is due to a better understanding of the stability and reactivity of this moiety depending on the various oxidation states of sulfur. Furthermore, several commercial reagents used for mild and selective fluorination of organic molecules are based on the known reactivity of S-F groups. In this review, we will show how these examples are translating into the 18F field, both for use as stable tags in finished radiopharmaceuticals and as mildly reactive fluoride-relay intermediates. Finally, we also discuss current opportunities where examples of non-radioactive S-F applications/chemistry may be translated into future 18F radiochemistry applications. PMID- 29503852 TI - Comparing the use of radiolabeled SSTR agonists and an SSTR antagonist in breast cancer: does the model choice influence the outcome? PMID- 29503851 TI - An efficient preparation of labelling precursor of [11C]L-deprenyl-D2 and automated radiosynthesis. AB - Background: The synthesis of [11C]L-deprenyl-D2 for imaging of astrocytosis with positron emission tomography (PET) in neurodegenerative diseases has been previously reported. [11C]L-deprenyl-D2 radiosynthesis requires a precursor, L nordeprenyl-D2, which has been previously synthesized from L-amphetamine as starting material with low overall yields. Here, we present an efficient synthesis of L-nordeprenyl-D2 organic precursor as free base and automated radiosynthesis of [11C]L-deprenyl-D2 for PET imaging of astrocytosis. The L nordeprenyl-D2 precursor was synthesized from the easily commercial available and cheap reagent L-phenylalanine in five steps. Next, N-alkylation of L-nordeprenyl D2 free base with [11C]MeOTf was optimized using the automated commercial platform GE TRACERlab(r) FX C Pro. Results: A simple and efficient synthesis of L nordeprenyl-D2 precursor of [11C]L-deprenyl-D2 as free base has been developed in five synthetic steps with an overall yield of 33%. The precursor as free base has been stable for 9 months stored at low temperature (-20 degrees C). The labelled product was obtained with 44 +/- 13% (n = 12) (end of synthesis, decay corrected) radiochemical yield from [11C]MeI after 35 min synthesis time. The radiochemical purity was over 99% in all cases and specific activity was (170 +/- 116) GBq/MUmol. Conclusions: A high-yield synthesis of [11C]L-deprenyl-D2 has been achieved with high purity and specific activity. L-nordeprenyl-D2 precursor as free amine was applicable for automated production in a commercial synthesis module for preclinical and clinical application. PMID- 29503853 TI - Position statement on radiopharmaceutical production for clinical trials. AB - The EU regulation 536/2014 aims to facilitate the experimental use of diagnostic radiopharmaceuticals in particular for GMP requirements and needs to be applied in EU countries. As definitely clarified by this survey, the application is still far from being completed due to national restrictions that are conflicting with the content of the above EU regulation. Although the nuclear medicine centers are obliged to be compliant with national regulatory, national authorities have to be required to work towards full application of the regulation. On the other hand, an update of 536/2014 that includes therapeutic radiopharmaceuticals would also be beneficial to a rational and safe advance of nuclear medicine. PMID- 29503854 TI - Improving the stability of 11C-labeled L-methionine with ascorbate. AB - Background: Carbon-11 labeled L-methionine (11C-MET) is a popular tracer used in the clinic for imaging brain tumors with positron emission tomography. However, the stability of 11C-MET in its final formulation is not well documented in literature. Recently, we observed fast degradation of HPLC-purified 11C-MET over time, and systematic investigation was conducted to identify the cause. Results: In this study, we verified the degraded product as 11C-labeled methionine sulfoxide (11C-METSO). To minimize oxidation, ascorbate (100 ppm) was added to the HPLC eluant, and the resulting HPLC-purified 11C-MET was stable in the final formulation solution without noticeable degradation for up to 1 h after the end of synthesis. Conclusions: Our data suggest that to minimize degradation, ascorbate can be added to the 11C-MET formulation solution especially if it is not administered into patients soon after the end of synthesis. PMID- 29503855 TI - Production and separation of 43Sc for radiopharmaceutical purposes. AB - Background: The favorable decay properties of 43Sc and 44Sc for PET make them promising candidates for future applications in nuclear medicine. An advantage 43Sc (T1/2 = 3.89 h, Ebeta+av = 476 keV [88%]) exhibits over 44Sc, however, is the absence of co-emitted high energy gamma-rays. While the production and application of 44Sc has been comprehensively discussed, research concerning 43Sc is still in its infancy. This study aimed at developing two different production routes for 43Sc, based on proton irradiation of enriched 46Ti and 43Ca target material. Results: 43Sc was produced via the 46Ti(p,alpha)43Sc and 43Ca(p,n)43Sc nuclear reactions, yielding activities of up to 225 MBq and 480 MBq, respectively. 43Sc was chemically separated from enriched metallic 46Ti (97.0%) and 43CaCO3 (57.9%) targets, using extraction chromatography. In both cases, ~90% of the final activity was eluted in a small volume of 700 MUL, thereby, making it suitable for direct radiolabeling. The prepared products were of high radionuclidic purity, i.e. 98.2% 43Sc were achieved from the irradiation of 46Ti, whereas the product isolated from irradiated 43Ca consisted of 66.2% 43Sc and 33.3% 44Sc. A PET phantom study performed with 43Sc, via both nuclear reactions, revealed slightly improved resolution over 44Sc. In order to assess the chemical purity of the separated 43Sc, radiolabeling experiments were performed with DOTANOC, attaining specific activities of 5-8 MBq/nmol, respectively, with a radiochemical yield of >96%. Conclusions: It was determined that higher 43Sc activities were accessible via the 43Ca production route, with a comparatively less complex target preparation and separation procedure. The product isolated from irradiated 46Ti, however, revealed purer 43Sc with minor radionuclidic impurities. Based on the results obtained herein, the 43Ca route features some advantages (such as higher yields and direct usage of the purchased target material) over the 46Ti path when aiming at 43Sc production on a routine basis. PMID- 29503856 TI - Generation of fluorescently labeled tracers - which features influence the translational potential? AB - Given the increasing exploration of fluorescent tracers in the field of nuclear medicine, a need has risen for practical development guidelines that can help improve the translation aspects of fluorescent tracers. This editorial discusses the does and don'ts in developing fluorescence tracers. It has been put forward by the European Association of Nuclear Medicine (EANM) Translational Molecular Imaging & Therapy committee and has been approved by the EANM board. PMID- 29503857 TI - Convergent synthesis of 13N-labelled Peptidic structures using aqueous [13N]NH3. AB - Background: Nitrogen-13 has a 10-min half-life which places time constraints on the complexity of viable synthetic methods for its incorporation into PET imaging agents. In exploring ways to overcome this limitation, we have used the Ugi reaction to develop a rapid one-pot method for radiolabelling peptidic molecules using [13N]NH3 as a synthetic precursor. Methods: Carrier-added [13N]NH3 (50 MUL) was added to a solution of carboxylic acid, aldehyde, and isocyanide in 2,2,2-TFE (200 MUL). The mixture was heated in a microwave synthesiser at 120 degrees C for 10 min. Reactions were analysed by radio-HPLC and radio-LCMS. Isolation of the target 13N-labelled peptidic Ugi compound was achieved via semi-preparative radio-HPLC as demonstrated for Ugi1. Results: Radio-HPLC analysis of each reaction confirmed the formation of radioactive products co-eluting with their respective reference standards with radiochemical yields of the crude products ranging from 11% to 23%. Two cyclic gamma-lactam structures were also achieved via intra-molecular reactions. Additional radioactive by-products observed in the radio-chromatogram were identified as 13N-labelled di-imines formed from the reaction of [13N]NH3 with two isocyanide molecules. The desired 13N-labelled Ugi product was isolated using semi-preparative HPLC. Conclusion: We have developed a one-pot method that opens up new routes to radiolabel complex, peptidic molecules with 13N using aqueous [13N]NH3 as a synthetic precursor. PMID- 29503858 TI - Radiosynthesis and evaluation of an 18F-labeled silicon containing exendin-4 peptide as a PET probe for imaging insulinoma. AB - Background: Analogues of exendin-4 have been radiolabeled for imaging the glucagon-like peptide type 1 receptors (GLP-1R) which are overexpressed in insulinoma. The aim of this research was to synthesize an 18F-labeled silicon containing exendin-4 peptide (18F-2) and to evaluate its in vitro and in vivo behavior in CHL-GLP-1 receptor positive tumor-bearing mice. 18F-labeled silicon containing exendin-4 peptide (18F-2) was prepared via one-step nucleophilic substitution of a silane precursor with 18F-fluoride in the presence of acetic acid and K222. 18F-2 was then administered to tumor-bearing mice for PET imaging and ex vivo biodistribution experiments. Results: 18F-2 was produced in a radiochemical yield (decay corrected) of 1.5% and a molar activity of max. 16 GBq/MUmol. The GLP-1R positive tumors were clearly visualized by PET imaging. Biodistribution studies showed reduced uptake of 18F-2 in the kidneys compared to radiometal labeled exendin-4 derivatives. The radiotracer showed specific tumour uptake which remained steady over 2 h. Conclusions: This exendin-4 analogue, 18F 2, is a potential probe for imaging GLP-1R positive tumors. PMID- 29503859 TI - Metabolite profiling with HPLC-ICP-MS as a tool for in vivo characterization of imaging probes. AB - Background: Current analytical methods for characterizing pharmacokinetic and metabolic properties of positron emission tomography (PET) and single photon emission computed tomography (SPECT) probes are limited. Alternative methods to study tracer metabolism are needed. The study objective was to assess the potential of high performance liquid chromatography - inductively coupled plasma mass spectrometry (HPLC-ICP-MS) for quantification of molecular probe metabolism and pharmacokinetics using stable isotopes. Methods: Two known peptide-DOTA conjugates were chelated with natGa and natIn. Limit of detection of HPLC-ICP-MS for 69Ga and 115In was determined. Rats were administered 50-150 nmol of Ga- and/or In-labeled probes, blood was serially sampled, and plasma analyzed by HPLC ICP-MS using both reverse phase and size exclusion chromatography. Results: The limits of detection were 0.16 pmol for 115In and 0.53 pmol for 69Ga. Metabolites as low as 0.001 %ID/g could be detected and transchelation products identified. Simultaneous administration of Ga- and In-labeled probes allowed the determination of pharmacokinetics and metabolism of both probes in a single animal. Conclusions: HPLC-ICP-MS is a robust, sensitive and radiation-free technique to characterize the pharmacokinetics and metabolism of imaging probes. PMID- 29503860 TI - Production of novel diagnostic radionuclides in small medical cyclotrons. AB - The global network of cyclotrons has expanded rapidly over the last decade. The bulk of its industrial potential is composed of small medical cyclotrons with a proton energy below 20 MeV for radionuclides production. This review focuses on the recent developments of novel medical radionuclides produced by cyclotrons in the energy range of 3 MeV to 20 MeV. The production of the following medical radionuclides will be described based on available literature sources: Tc-99 m, I 123, I-124, Zr-89, Cu-64, Ga-67, Ga-68, In-111, Y-86 and Sc-44. Remarkable developments in the production process have been observed in only some cases. More research is needed to make novel radionuclide cyclotron production available for the medical industry. PMID- 29503861 TI - Synthesis of an Al18F radiofluorinated GLU-UREA-LYS(AHX)-HBED-CC PSMA ligand in an automated synthesis platform. AB - Background: Overexpression of prostatic membrane antigen (PSMA) is associated with the progression and prognosis of prostate cancer. There are numerous studies using this peptide with the 68Ga radionuclide. Previous methods to synthetize 18F labeled PSMA ligands with complexes [18F]AlF2+ have been achieved. However, these reported syntheses were performed manually, using small volumes. Therefore it is only possible to have the radiopharmaceutical on a small scale, for use in preclinical studies. 18F-labelled tracers allow higher doses increasing the number of examined patients. In addition, late images can be acquired in the case of uptake in lymph nodes, to discard inflammation. It is important to transfer the manual synthesis to an automatic module, producing a batch of the radiopharmaceutical with high activity in a safe and effective way. The aim of this work was to optimize the labeling of [18F]AlF-[GLU-UREA-LYS(AHX)-HBED-CC] in a Tracerlab FXFN(r) (GE) platform. Results: The labeling up to the reactor corroborates the formation of the complex [18F]AlF-PSMA. After purification by HPLC, the radiopharmaceutical was achieved with a radiochemical purity higher than 90%. The quality control of the final product fulfilled all the requirements in agreement with USP, such as radiochemical purity (greater than 90%) and residual solvents. [18F]AlF-PSMA was obtained with a yield of 18 +/- 3% (n = 7), not decay corrected (NCD) starting off from 500 to 2000 mCi the 18F and with a radiochemical purity of 95 +/- 3% (n = 7). The product verified stability in the final formulation vial during 4 hs and in human plasma up to 1 h. Conclusion: The proposed method allowed the production of [18F]AlF-PSMA with suitable radiochemical purity in a commercial platform. High activities were achieved, with a simple and robust methodology appropriate for clinical purposes. PMID- 29503862 TI - Implementing Goal-Directed Foraging Decisions of a Simpler Nervous System in Simulation. AB - Economic decisions arise from evaluation of alternative actions in contexts of motivation and memory. In the predatory sea-slug Pleurobranchaea the economic decisions of foraging are found to occur by the workings of a simple, affectively controlled homeostat with learning abilities. Here, the neuronal circuit relations for approach-avoidance choice of Pleurobranchaea are expressed and tested in the foraging simulation Cyberslug. Choice is organized around appetitive state as a moment-to-moment integration of sensation, motivation (satiation/hunger), and memory. Appetitive state controls a switch for approach vs. avoidance turn responses to sensation. Sensory stimuli are separately integrated for incentive value into appetitive state, and for prey location (stimulus place) into mapping motor response. Learning interacts with satiation to regulate prey choice affectively. The virtual predator realistically reproduces the decisions of the real one in varying circumstances and satisfies optimal foraging criteria. The basic relations are open to experimental embellishment toward enhanced neural and behavioral complexity in simulation, as was the ancestral bilaterian nervous system in evolution. PMID- 29503864 TI - Undermining subsistence: Barren-ground caribou in a "tragedy of open access". AB - Sustaining arctic/subarctic ecosystems and the livelihoods of northern Indigenous peoples is an immense challenge amid increasing resource development. The paper describes a "tragedy of open access" occurring in Canada's north as governments open up new areas of sensitive barren-ground caribou habitat to mineral resource development. Once numbering in the millions, barren-ground caribou populations (Rangifer tarandus groenlandicus/Rangifer tarandus granti) have declined over 70% in northern Canada over the last two decades in a cycle well understood by northern Indigenous peoples and scientists. However, as some herds reach critically low population levels, the impacts of human disturbance have become a major focus of debate in the north and elsewhere. A growing body of science and traditional knowledge research points to the adverse impacts of resource development; however, management efforts have been almost exclusively focused on controlling the subsistence harvest of northern Indigenous peoples. These efforts to control Indigenous harvesting parallel management practices during previous periods of caribou population decline (for example, 1950s) during which time governments also lacked evidence and appeared motivated by other values and interests in northern lands and resources. As mineral resource development advances in northern Canada and elsewhere, addressing this "science-policy gap" problem is critical to the sustainability of both caribou and people. PMID- 29503863 TI - Vascular Network Formation by Human Microvascular Endothelial Cells in Modular Fibrin Microtissues. AB - Microvascular endothelial cells (MVEC) are a preferred cell source for autologous revascularization strategies, since they can be harvested and propagated from small tissue biopsies. Biomaterials-based strategies for therapeutic delivery of cells are aimed at tailoring the cellular microenvironment to enhance the delivery, engraftment, and tissue-specific function of transplanted cells. In the present study, we investigated a modular tissue engineering approach to therapeutic revascularization using fibrin-based microtissues containing embedded human MVEC and human fibroblasts (FB). Microtissues were formed using a water-in oil emulsion process that produced populations of spheroidal tissue modules with a diameter of 100-200 um. The formation of MVEC sprouts within a fibrin matrix over 7 days in culture was dependent on the presence of FB, with the most robust sprouting occurring at a 1:3 MVEC:FB ratio. Cell viability in microtissues was high (>90%) and significant FB cell proliferation was observed over time in culture. Robust sprouting from microtissues was evident, with larger vessels developing over time and FB acting as pericyte-like cells by enveloping endothelial tubes. These neovessels were shown to form an interconnected vascular plexus over 14 days of culture when microtissues were embedded in a surrounding fibrin hydrogel. Vessel networks exhibited branching and inosculation of sprouts from adjacent microtissues, resulting in MVEC-lined capillaries with hollow lumens. Microtissues maintained in suspension culture aggregated to form larger tissue masses (1-2 mm in diameter) over 7 days. Vessels formed within microtissue aggregates at a 1:1 MVEC:FB ratio were small and diffuse, whereas the 1:3 MVEC:FB ratio produced large and highly interconnected vessels by day 14. This study highlights the utility of human MVEC as a cell source for revascularization strategies, and suggests that the ratio of endothelial to support cells can be used to tailor vessel characteristics. The modular microtissue format may allow minimally invasive delivery of populations of prevascularized microtissues for therapeutic applications. PMID- 29503866 TI - Coral reef structural complexity provides important coastal protection from waves under rising sea levels. AB - Coral reefs are diverse ecosystems that support millions of people worldwide by providing coastal protection from waves. Climate change and human impacts are leading to degraded coral reefs and to rising sea levels, posing concerns for the protection of tropical coastal regions in the near future. We use a wave dissipation model calibrated with empirical wave data to calculate the future increase of back-reef wave height. We show that, in the near future, the structural complexity of coral reefs is more important than sea-level rise in determining the coastal protection provided by coral reefs from average waves. We also show that a significant increase in average wave heights could occur at present sea level if there is sustained degradation of benthic structural complexity. Our results highlight that maintaining the structural complexity of coral reefs is key to ensure coastal protection on tropical coastlines in the future. PMID- 29503865 TI - Variant ribosomal RNA alleles are conserved and exhibit tissue-specific expression. AB - The ribosome, the integration point for protein synthesis in the cell, is conventionally considered a homogeneous molecular assembly that only passively contributes to gene expression. Yet, epigenetic features of the ribosomal DNA (rDNA) operon and changes in the ribosome's molecular composition have been associated with disease phenotypes, suggesting that the ribosome itself may possess inherent regulatory capacity. Analyzing whole-genome sequencing data from the 1000 Genomes Project and the Mouse Genomes Project, we find that rDNA copy number varies widely across individuals, and we identify pervasive intra- and interindividual nucleotide variation in the 5S, 5.8S, 18S, and 28S ribosomal RNA (rRNA) genes of both human and mouse. Conserved rRNA sequence heterogeneities map to functional centers of the assembled ribosome, variant rRNA alleles exhibit tissue-specific expression, and ribosomes bearing variant rRNA alleles are present in the actively translating ribosome pool. These findings provide a critical framework for exploring the possibility that the expression of genomically encoded variant rRNA alleles gives rise to physically and functionally heterogeneous ribosomes that contribute to mammalian physiology and human disease. PMID- 29503867 TI - Mapping a functional cancer genome atlas of tumor suppressors in mouse liver using AAV-CRISPR-mediated direct in vivo screening. AB - Cancer genomics consortia have charted the landscapes of numerous human cancers. Whereas some mutations were found in classical oncogenes and tumor suppressors, others have not yet been functionally studied in vivo. To date, a comprehensive assessment of how these genes influence oncogenesis is lacking. We performed direct high-throughput in vivo mapping of functional variants in an autochthonous mouse model of cancer. Using adeno-associated viruses (AAVs) carrying a single guide RNA (sgRNA) library targeting putative tumor suppressor genes significantly mutated in human cancers, we directly pool-mutagenized the livers of Cre inducible CRISPR (clustered regularly interspaced short palindromic repeats) associated protein 9 (Cas9) mice. All mice that received the AAV-mTSG library developed liver cancer and died within 4 months. We used molecular inversion probe sequencing of the sgRNA target sites to chart the mutational landscape of these tumors, revealing the functional consequence of multiple variants in driving liver tumorigenesis in immunocompetent mice. AAV-mediated autochthonous CRISPR screens provide a powerful means for mapping a provisional functional cancer genome atlas of tumor suppressors in vivo. PMID- 29503870 TI - Development of a Meso-Scale Fiberoptic Rotation Sensor for a Torsion Actuator. AB - This paper presents the development of a meso-scale fiberoptic rotation sensor for a shape memory alloy (SMA) torsion actuator for neurosurgical applications. Within the sensor, a rotary head with a reflecting surface is capable of modulating the light intensity collected by optical fibers when the rotary head is coupled to the torsion actuator. The mechanism of light intensity modulation is modeled, followed by experimental model verification. Meanwhile, working performances for different rotary head designs, optical fibers, and fabrication materials are compared. After the calibration of the fiberoptic rotation sensor, the sensor is capable of precisely measuring rotary motion and controlling the SMA torsion actuator with feedback control. PMID- 29503869 TI - TADs are 3D structural units of higher-order chromosome organization in Drosophila. AB - Deciphering the rules of genome folding in the cell nucleus is essential to understand its functions. Recent chromosome conformation capture (Hi-C) studies have revealed that the genome is partitioned into topologically associating domains (TADs), which demarcate functional epigenetic domains defined by combinations of specific chromatin marks. However, whether TADs are true physical units in each cell nucleus or whether they reflect statistical frequencies of measured interactions within cell populations is unclear. Using a combination of Hi-C, three-dimensional (3D) fluorescent in situ hybridization, super-resolution microscopy, and polymer modeling, we provide an integrative view of chromatin folding in Drosophila. We observed that repressed TADs form a succession of discrete nanocompartments, interspersed by less condensed active regions. Single cell analysis revealed a consistent TAD-based physical compartmentalization of the chromatin fiber, with some degree of heterogeneity in intra-TAD conformations and in cis and trans inter-TAD contact events. These results indicate that TADs are fundamental 3D genome units that engage in dynamic higher-order inter-TAD connections. This domain-based architecture is likely to play a major role in regulatory transactions during DNA-dependent processes. PMID- 29503871 TI - Probe-Based Confocal Laser Endomicroscopy Using Acrinol as a Novel Dye Can Be Used to Observe Cancer Nuclei of Bladder Carcinoma In Situ. AB - Background: Cystoscopy using white light is a standard procedure for diagnosing bladder cancer; however, white light can result in missed lesions that are present, but not visible, such as in cases of carcinoma in situ (CIS). In this case report, we describe observing the nuclei of urothelial carcinoma cells in situ that were not visible with cystoscopy under white light using probe-based confocal laser endomicroscopy (pCLE) with acrinol and fluorescein during transurethral resection of a bladder tumor (TURBT). Case Presentation: A 59-year old male with a medical history of neurogenic bladder dysfunction with multiple bladder diverticula was referred to the urology department for gross hematuria. TURBT was performed with the assistance of pCLE, using acrinol as a novel dye. Standard cystoscopy under white light could not detect any bladder tumor; however, pCLE using acrinol could detect the abnormal nuclei of bladder CIS. Subsequent histopathologic analysis of the specimen confirmed a diagnosis of bladder CIS. To our knowledge, this is the first reported case of bladder CIS diagnosed with the assistance of pCLE using acrinol in a patient undergoing a TURBT. Conclusion: pCLE using acrinol as a novel dye can help observe the cancerous nuclei of bladder CIS that cannot be detected using conventional cystoscopy under white light. Therefore, pCLE using acrinol is one possible modality for performing an optical biopsy during TURBT. PMID- 29503872 TI - Outpatient Tubeless Percutaneous Nephrolithotomy Performed in a Freestanding Ambulatory Surgery Center. AB - Background: Percutaneous nephrolithotomy (PNL) is a procedure that has traditionally been performed in an inpatient or hospital setting. Many surgical procedures have evolved over time from an inpatient/hospital setting to outpatient procedures performed in surgical centers. Outpatient PNL has become an accepted standard in select patients, but to date, the procedure has not been performed in an outpatient surgical center. Case Presentation: We describe our initial experience managing large renal stone burden with PNL performed completely outpatient in a freestanding ambulatory surgery center. The patient was carefully selected as a young, healthy, thin patient with straightforward renal stone burden and favorable anatomy per CT. Access was achieved with a combination of fluoroscopic and endoscopic needle guidance. The procedure was performed with several modifying factors to enable an effective outpatient discharge. Conclusion: Our experience reinforces the outpatient feasibility of PNL and incites the possibility of transitioning the procedure to an ambulatory surgical center in select patients to provide healthcare savings and an improved patient experience. PMID- 29503873 TI - Exploring Healthcare Experiences for Incarcerated Individuals Who Identify as Transgender in a Southern Jail. AB - Purpose: To document the health-related experiences and needs of jail detainees who self-identified as transgender women. Methods: Semistructured interviews with 10 transgender women of color were conducted in a county jail in a mid-sized southern city between 2015 and 2016. Interviews were recorded and transcribed, and later analyzed using a general inductive approach. Results: Participants experienced high levels of abuse and harassment, solitary confinement, mental health issues, and lack of access to hormone treatment. Participants described discrimination (both by other inmates-particularly while in special housing units and correctional officers); harsh correctional conditions, which exacerbated mental health issues; and a marked lack of access to healthcare, including hormone treatments. Conclusion: Policy changes are needed to address housing and placement issues, and to increase access to healthcare for transgender women jail detainees. Training is needed for jail staff and medical care professionals in correctional settings to better understand the unique needs and experiences of transgender people. PMID- 29503868 TI - Einstein@Home discovers a radio-quiet gamma-ray millisecond pulsar. AB - Millisecond pulsars (MSPs) are old neutron stars that spin hundreds of times per second and appear to pulsate as their emission beams cross our line of sight. To date, radio pulsations have been detected from all rotation-powered MSPs. In an attempt to discover radio-quiet gamma-ray MSPs, we used the aggregated power from the computers of tens of thousands of volunteers participating in the Einstein@Home distributed computing project to search for pulsations from unidentified gamma-ray sources in Fermi Large Area Telescope data. This survey discovered two isolated MSPs, one of which is the only known rotation-powered MSP to remain undetected in radio observations. These gamma-ray MSPs were discovered in completely blind searches without prior constraints from other observations, raising hopes for detecting MSPs from a predicted Galactic bulge population. PMID- 29503874 TI - Evaluation of the Luminex xTAG Respiratory Viral Panel FAST v2 assay for detection of multiple respiratory viral pathogens in nasal and throat swabs in Vietnam. AB - BACKGROUND: Acute respiratory infections (ARI) are among the leading causes of hospitalization in children <=5 years old. Rapid diagnostics of viral pathogens is essential to avoid unnecessary antibiotic treatment, thereby slowing down antibiotic-resistance. We evaluated the diagnostic performance of the Luminex xTAG Respiratory Viral Panel FAST v2 against viral specific PCR as reference assays for ARI in Vietnam. METHODS: Four hundred and forty two nose and throat swabs were collected in viral transport medium, and were tested with Luminex xTAG Respiratory Viral Panel FAST v2. Multiplex RT-PCR and single RT-PCR were used as references. Results: Overall, viral pathogens were detected in a total count of 270/294 (91.8%, 95% CI 88.1-94.7) by the Luminex among reference assays, whilst 112/6336 (1.8%, 95% CI, 1.4-2.1) of pathogens were detected by the Luminex, but not by reference assays. Frequency of pathogens detected by Luminex and reference assays was 379 and 292, respectively. The diagnostic yield was 66.7% (295/442, 95%CI 62.1-71.1%) for the Luminex assay and 54.1% (239/442, 95% CI, 49.3-58.8%) for reference assays. The Luminex kit had higher yields for all viruses except influenza B virus, respiratory syncytial virus, and human bocavirus. High agreements between both methods [mean (range): 0.91 (0.83-1.00)] were found for 10/15 viral agents. CONCLUSIONS: The Luminex assay is a high throughput multiplex platform for rapid detection of common viral pathogens causing ARI. Although the current high cost may prevent Luminex assays from being widely used, especially in limited resource settings where ARI are felt most, its introduction in clinical diagnostics may help reduce unnecessary use of antibiotic prescription. PMID- 29503876 TI - PIK3CA mutation is associated with increased local failure in lung stereotactic body radiation therapy (SBRT). AB - Objectives: Hyperactivation of the phosphatidylinositol-3-kinase (PI3K) pathway has been associated with radioresistance. It is unclear whether such mutations confer suboptimal local control for patients who receive lung stereotactic body radiation therapy (SBRT). Our objective was to examine whether mutations in the EGFR/AKT/PIK3CA signaling pathway are associated with local failure (LF) after lung SBRT. Methods: We retrospectively reviewed 166 patients who underwent SBRT to primary or metastatic lung lesions from 2007-2015 for whom genetic testing data was available for EGFR, AKT, and PIK3CA genes. Association between clinical factors, including molecular mutation status, and LF was evaluated. Results: Six patients (4%) had PIK3CA mutation, 36 patients (22%) had EGFR mutation, and one patient (0.6%) had AKT1 mutation. Median lesion size was 2.0 cm (range, 0.6-5.6 cm); median dose was 48Gy in 4 fractions (range, 30-70Gy in 3-10 fractions). Median follow-up for survivors was 27.3 months (range, 3.8-66.7 months). LF occurred in 16 patients (10%). On univariate analysis, PIK3CA mutation was associated with LF (HR 10.44 [95% CI 2.16-50.46], p=0.003), while tumor histology, tumor size, primary tumor site, BED and EGFR mutation were not. At one year, probability of LF in lesions with PIK3CA mutation was 20.0% vs. 2.9% in lesions without mutation (p<0.001 by log rank test). Conclusion: Although the number of patients affected was small, PIK3CA mutation was significantly associated with higher risk of LF in patients undergoing lung SBRT. This association has not previously been reported for lung SBRT and indicates the need for further validation. PMID- 29503875 TI - High-Speed Tracer Analysis of Metabolism (HS-TrAM). AB - Tracing the fate of stable isotopically-enriched nutrients is a sophisticated method of describing and quantifying the activity of metabolic pathways. Nuclear Magnetic Resonance (NMR) offers high resolution data, yet is under-utilised due to length of time required to collect the data, quantification requiring multiple samples and complicated analysis. Here we present two techniques, quantitative spectral filters and enhancement of the splitting due to J-coupling in 1H, 13C HSQC NMR spectra, which allow the rapid collection of NMR data in a quantitative manner on a single sample. The reduced duration of HSQC spectra data acquisition opens up the possibility of real-time tracing of metabolism including the study of metabolic pathways in vivo. We show how these novel techniques can be used to trace the fate of labelled nutrients in a whole organ model of kidney preservation prior to transplantation using a porcine kidney as a model organ, and also show how the use of multiple nutrients, differentially labelled with 13C and 15N, can be used to provide additional information with which to profile metabolic pathways. PMID- 29503877 TI - Evaluating the Efficacy of a Registry linked to a Consent to Re-Contact Program and Communication Strategies for Recruiting and Enrolling Participants into Clinical Trials. AB - Introduction: Although registries can rapidly identify clinical study participants, it is unknown which follow up methods for recruiting are most effective. Our goal is to examine the efficacy of three communication strategies for recruiting and enrolling patients who were identified via a contact registry (i.e., registry linked to a consent to re-contact program). Methods: Patients who met the study criteria were identified via the contact registry and targeted for recruitment. In condition 1, patients established in the university hepatology specialty clinics were contacted one time via phone call by the study coordinator and asked to participate (C1). In condition 2, non-established specialty clinic patients were mailed an IRB-approved letter with study information and instructions for calling the study coordinator to participate (C2). Condition 2A included patients who called within two weeks of receiving the letter (C2A); condition 2B included patients who did not call after receiving the letter but were subsequently contacted via phone call. Results: A registry identified 1,060 patients, of which 661were eligible and targeted for recruiting. All 37 patients were reached in C1 and 17 (45.9%) were recruited. Nineteen of the 624 patients in C2A were reached and 10 were recruited whereas 120 of the 605 patients in C2B were reached and 53 (8.7%) were recruited. Seventy patients enrolled with C2B being the most effective (total, cost) recruitment strategy (n = 50) (p < .001). Conclusion: The efficacy of enrolling patients identified via a contact registry into clinical trials varies based on the communication strategies used for recruiting. PMID- 29503878 TI - Rationale, design, and baseline findings from a pilot randomized trial of an IVR Supported physical activity intervention for cancer prevention in the Deep South: the DIAL study. AB - Telephone-delivered interventions do not require frequent clinic visits, literacy, or costly technology and thus may represent promising approaches to promoting physical activity in the Deep South, a largely rural U.S. region, with generally lower physical activity, income, and education levels. Building on past Interactive Voice Response (IVR) system-based HIV studies and extensive formative research (11 focus groups on physical activity intervention needs/preferences in the Deep South), the resulting IVR-supported physical activity intervention is now being tested in a randomized controlled trial with a waitlist control. The sample (n=63) includes mostly obese (Mean BMI=30.1) adults (Mean age=43 years) in Birmingham, AL. Both genders (55.6% male) and African Americans (58.7%) are well represented. Most participants reported at least some college (92%), full time employment (63.5%), and household income <$50,000 per year (61.9%). Baseline physical activity (Mean=39.6 minutes/week, SD=56.4), self-efficacy, self regulation, and social support were low. However, high physical activity enjoyment and outcome expectations bode well. Self-report physical activity was associated with physical activity enjoyment (r=.36) and social support (friends r=.25, p's<.05) at baseline. Consequently, these may be important variables to emphasize in our program. Depression and anxiety were negatively correlated with some early indicators of behavior change (e.g., physical activity self regulation; r's =-.43 and -.46, respectively, p's<.01) and thus may require additional attention. Such technology-supported strategies have great potential to reach underserved populations and address physical activity-related health disparities in this region. PMID- 29503879 TI - Swept-source optical coherence tomography angiography for choroidal neovascularization after bevacizumab and photodynamic therapy. AB - Purpose: To report the swept-source optical coherence tomography angiography (SS OCTA) findings after bevacizumab anti-vascular endothelial growth factor (anti VEGF) and full-fluence photodynamic therapy (PDT) for choroidal neovascularization. Design: Case report. Methods: An 87-year-old, Chinese male presented with a shadow and decreased vision to 20/160 in his left eye (OS). Clinical examination, color photographs, swept-source optical coherence tomography (SS-OCT), widefield dye-fluorescein angiography (FA) and SS-OCTA revealed an extrafoveal, subretinal choroidal neovascularization (CNV) in the superior macula. Bevacizumab anti-VEGF and full-fluence PDT was initiated. Results: Initial imaging with conventional color photography and FA demonstrated a classic CNV with significant early hyperfluorescence and late leakage. SS-OCT demonstrated subretinal hyperreflective material, fluid and hemorrhage emanating from a subretinal, type 2 neovascularization (NV). SS-OCTA showed a mixed lesion with a type 2, subretinal component with segmentation above the retinal pigment epithelium (RPE) and a type 1, sub-RPE component below. Treatment with anti-VEGF and PDT led to immediate regression of the CNV. One month after treatment, SS OCTA demonstrated significant resolution of the type, 2 subretinal component and decreased flow and size of the type 1 sub-RPE lesion. Conclusion: We report the first SS-OCTA images of successfully treated extrafoveal NV after combination PDT and ant-VEGF therapy. Early treatment of extrafoveal NV may improve our ability to treat mixed type 1 and 2 NV before these neovascular complexes mature from repetitive anti-VEGF treatment. PMID- 29503880 TI - Orbital compartment syndrome following retrobulbar injection of amphotericin B for invasive fungal disease. AB - Purpose: To describe a complication of retrobulbar amphotericin B injections in the treatment of invasive rhino-orbital asperigillosis. Observations: 27 year-old renal transplant recipient presented with a two-week history of headache, binocular diplopia and proptosis of the left eye. Endonasal biopsy on hospital day 3 confirmed the diagnosis of rhino-orbital invasive Aspergillus fumigatus involving the left orbital apex.In addition to systemic antifungal treatment and cessation of immunosuppression, retrobulbar amphotericin B injections (3.5 mg/1 ml) combined with endoscopic local debridement were initiated when the patient developed progressive visual loss. Retrobulbar injections were administered on hospital days 8, 10, 14, 17, and 20. Endoscopic debridement occurred on hospital days 10 and 16.After the fifth retrobulbar amphotericin B injection, the patient developed acute orbital compartment syndrome with intraocular pressures ranging from 47 to 86 mmHg and vision declined to 20/200, requiring emergent lateral canthotomy and superior and inferior cantholysis. Close observation without further intervention resulted in return of vision to 20/20 and normalization of intraocular pressure. Conclusion and importance: Retrobulbar amphotericin B in combination with local debridement may be considered an alternative to exenteration for invasive aspergillosis secondary to reversible immunosuppression. To the authors' knowledge, orbital compartment syndrome secondary to retrobulbar amphotericin B administration has not previously been reported. Patients should be counseled on the risk of severe local inflammation due to amphotericin B. More research is needed to establish the most appropriate dosing, frequency, and duration of retrobulbar amphotericin B injections in the treatment of life-threatening Aspergillus infections. PMID- 29503881 TI - Femtosecond laser-assisted cataract surgery in a patient with posterior chamber phakic intraocular lens. AB - We describe a case of modified femtosecond laser settings for cataract extraction in a patient with a posterior chamber phakic intraocular lens (PIOL), to avoid incomplete treatment patterns and treatment displacement. Modification of laser settings (increased depth for the capsulotomy, increased vertical spot spacing for the capsulotomy and increased anterior and posterior capsule safety margins for lens fragmentation) seems to make femtosecond laser-assisted cataract surgery feasible in patients with posterior chamber PIOLs, as complete treatment patterns are achieved. PMID- 29503882 TI - Recovery of outer retina in acute idiopathic blind spot enlargement (AIBSE). AB - Purpose: To report the anatomic and functional recovery of the ellipsoid zone in a case of acute idiopathic blind spot enlargement (AIBSE), which was documented by serial high-resolution optical coherence tomography imaging. Observations: The patient's clinical presentation and follow up visits were documented via Humphrey's Visual Fields, fundus autofluorescence, and high resolution spectral domain optical coherence tomography (SD-OCT). At presentation, Humphrey's Visual Field testing showed an enlarged blind spot in the right eye. Fundus autofluorescence and optical coherence tomography showed an increased peripapillary autofluorescence and loss of the outer retinal layers, respectively. At 3 months a modest improvement in the visual field was observed. This improvement was stable at both the 7 and the 15 month follow up visits. SD OCT corresponding to the areas of visual field improvement demonstrated recovery of the outer retina. Conclusion and importance: Serial OCT imaging demonstrated anatomic evidence of ellipsoid zone recovery in isolated AIBSE. Anatomic recovery was consistent with the functional gain detected by visual field improvement. PMID- 29503883 TI - Parafoveal cone abnormalities and recovery on adaptive optics in posterior uveitis. AB - Purpose: To determine if adaptive optics (AO) flood illumination imaging can detect subclinical changes in 4 cases of posterior uveitis affecting the outer retina. Observations: In all 4 cases, the affected eye showed altered areas in the photoreceptor mosaic on AO that corresponded to changes on other imaging modalities. Abnormalities not apparent on other imaging modalities were also noted. In one case of multifocal choroiditis with acute outer retinal atrophy, AO revealed decreased visualization of photoreceptors in the unaffected eye that was not noted on spectral domain-optical coherence tomography. In the patient with multiple evanescent white dot syndrome, focal photoreceptor abnormalities were more apparent on AO compared to other imaging modalities, and these areas normalized on AO during follow-up. Five weeks after initiation of high dose prednisone and azathioprine in a patient with serpiginous choroidopathy, AO images showed recovery in apparent parafoveal cone density. Conclusions and importance: AO detects subclinical changes in the photoreceptor layer in posterior uveitis that can recover over time. AO may be useful in following outer retinal inflammatory conditions. PMID- 29503884 TI - High-resolution dacryoendoscopy for observation for pediatric lacrimal duct obstruction. AB - Purpose: The aim of this study was to describe high-resolution dacryoendoscopy findings for nasolacrimal duct obstruction (NLDO) in three representative pediatric cases with different etiologies. Observations: In a case of congenital NLDO, a mucosal membranous obstruction was observed at the distal end of the nasolacrimal duct (NLD), and a slit-shaped opening of the NLD was observed after perforation. In a case of acquired NLDO secondary to an adenoviral infection, a membranous obstruction was observed at the proximal NLD. In a case of NLDO with chronic dacryocystitis in a patient with Down syndrome, diffuse fibrous obstruction was observed. Conclusion and importance: High-resolution dacryoendoscopy enables a clearer visualization of pediatric lacrimal duct obstructions, leading to an improved understanding of their features. PMID- 29503885 TI - Management of orbital emphysema secondary to rhegmatogenous retinal detachment repair with hyperbaric oxygen therapy. AB - Purpose: To describe the case of orbital subcutaneous emphysema who was successfully treated with hyperbaric oxygen therapy. Observations: Case report. Retrospective analysis of medical records and computer tomography images. A 40 years-old female, with retinal detachment who was seen at the emergency department, two weeks after undergoing a combined procedure of pars plana vitrectomy, scleral buckle and Sulfur hexafluoride tamponade. The patient complained of pain, decrease eye movement and edema of the upper eyelid. Clinical examination revealed periorbital crepitus. She was treated immediately with soft tissue decompression with small-gauge needle. Orbital emphysema recurred quickly, indicating possible gas trapped in the soft tissue. Using the US NAVY decompression protocol we were able to achieve fast clinical improvement. The protocol was repeated in several occasions until complete resolution. Conclusion and importance: Hyperbaric oxygen therapy is an effective treatment for orbital and periorbital emphysema, due to its property of helping accelerate N2 elimination from adipose tissue. PMID- 29503886 TI - Acute angle closure in the setting of high axial myopia: A case report. AB - Acute angle closure is common in hyperopic eyes but uncommon in myopic eyes. Here, we report a case of angle closure attack in a 59-year-old female patient with high axial myopia. The patient presented without underlying medical history or drug history with marked congestion and progressively blurred vision in her right eye (RE) for 1 week. Initial intraocular pressure (IOP) was 40 mmHg in the RE and 19 mmHg in the left eye. Slit lamp examination revealed a very shallow anterior chamber in both eyes and marked corneal microcytic edema in the RE. Acute angle closure of the RE was diagnosed. Conservative IOP-lowering management followed by laser iridotomy was effective in managing acute high IOP crisis; however, early cataract extraction was necessary for long-term IOP control. Clinicians should be mindful of the possibility of acute angle closure even in highly axially myopic eyes. PMID- 29503887 TI - Ophthalmic considerations in patients with Pfeiffer syndrome. AB - Purpose: We report here a newborn male infant with striking features consistent with severe Pfeiffer syndrome type II, including cloverleaf skull deformity with pansynostosis, extreme proptosis, upper extremity contractures, broad big toes and thumbs with varus deviation and genetic mutation in the FGFR2 gene. The authors review the ophthalmic complications in Pfeiffer syndrome and discuss the unique surgical strategies used for obtaining adequate corneal coverage in these unique patients. Observations: Ophthalmic considerations in Type 2 Pfeiffer Syndrome include vision loss secondary to increased intracranial pressure, and extreme proptosis as a result of orbitostenosis and midfacial retrusion. Our patient has undergone multiple ophthalmic/oculoplastic, neurosurgical, and midfacial surgeries as a result of corneal deterioration due to extreme exorbitism. Conclusions and importance: It is important for ophthalmologists to be aware of the ophthalmic complications associated with patients with craniosynostosis syndromes. Our case identifies the importance of close communication between ophthalmology and plastic reconstructive surgery to help formulate the most successful plan in treating corneal decompensation and proptosis in Pfeiffer Syndrome patients. PMID- 29503888 TI - Electroretinographic improvement after rituximab therapy in a patient with autoimmune retinopathy. AB - Purpose: To describe the effect of rituximab on full-field electroretinography (ERG) in a patient with nonparaneoplastic autoimmune retinopathy (npAIR). Observations: A 58-year-old male patient with visual complaints, positive anti retinal antibodies and negative work-up for cancer was diagnosed with npAIR. Visual acuity and ancillary tests were normal except abnormal ERG in both eyes. The patient was given one course of rituximab 375 mg/m2/week for 4 weeks and cyclophosphamide 1 gr/m2/month for 6 months. A second course of rituximab was necessary as autoantibody titers showed no change and as new antibodies were noted after treatment with rituximab and cyclophosphamide. Electroretinography was repeated after the first course of rituximab, after cyclophosphamide, and the second course of rituximab therapy. Conclusions and importance: Rituximab therapy led to marked improvement in full-field ERG readings and regression of symptoms was reported by the patient after rituximab infusions. The effect of rituximab in npAIR was objectively demonstrated with ERG. PMID- 29503889 TI - Delayed bilateral fibrinous anterior chamber reaction following autologous bone marrow transplant and cataract surgery. AB - Purpose: Immune reconstitution uveitis (IRU) is a well-described phenomenon that by definition occurs in patients with AIDS who undergo highly active antiretroviral therapy resulting in a rebound inflammatory response to the presence of clinically latent cytomegalovirus (CMV). We hypothesize that similar phenomena may exist in other cohorts who undergo transient immunosuppression with rapid white blood cell count recovery. Observations: A patient developed rebound inflammation a few months after cataract surgery with intraocular lens placement characterized by photophobia, significant anterior chamber cell and fibrinous deposits. She had a history of multiple myeloma treated with chemotherapy and a recovery of white blood cell counts following autologous bone marrow transplant. She underwent a thorough work-up for infectious etiologies, as well as the presence of intraocular CMV, which were negative. Her vision and symptoms improved to baseline with the use of topical steroids and at one year her exam remained stable. Conclusions and Importance: With a negative work-up for infectious etiologies, and the timing and clinical presentation, the patient's inflammation was likely the result of rapid white blood cell count recovery following iatrogenic immunosuppression similar to the mechanism described for IRU. PMID- 29503890 TI - Retinitis pigmentosa associated with a mutation in BEST1. AB - Purpose: There is only one prior report associating mutations in BEST1 with a diagnosis of retinitis pigmentosa (RP). The imaging studies presented in that report were more atypical of RP and shared features of autosomal recessive bestrophinopathy and autosomal dominant vitreoretinochoroidopathy. Here, we present a patient with a clinical phenotype consistent with classic features of RP. Observations: The patient in this report was diagnosed with simplex RP based on clinically-evident bone spicules with characteristic ERG and EOG findings. The patient had associated massive cystoid macular edema which resolved following a short course of oral acetazolamide. Genetic testing revealed that the patient carries a novel heterozygous deletion mutation in BEST1 which is not carried by either parent. While this suggests BEST1 is causative, the patient also inherited heterozygous copies of several mutations in other genes known to cause recessive retinal degenerative disease. Conclusions and Importance: How some mutations in BEST1 associate with peripheral retinal degeneration phenotypes, while others manifest as macular degeneration phenotypes is currently unknown. We speculate that RP due to BEST1 mutation requires mutations in other modifier genes. PMID- 29503891 TI - A case study of choroideremia carrier - Use of multi-spectral imaging in highlighting clinical features. AB - Purpose: To report the use of non-invasive multi-spectral imaging of a female choroideremia (CHM) carrier with mild visual symptoms and extensive fundus mottling. Observation: This was an observational case report study. A symptomatic 42-year-old female with a history of binocular CHM presented for routine ocular examination and underwent review of her clinical and photographic records, optical coherence tomography (OCT), intravenous fluorescein angiography (IVFA) and multi-spectral imaging (MSI). Dilated fundus examination and photography revealed similar outcomes of diffuse mottling with normal looking vessels. IVFA showed large irregular and confluent patches of RPE atrophy in the peripapillary and parapapillary areas as well as the midperiphery, corresponding to the OCT findings. The entire range of MSI imaging (520-940 nm) clearly illustrated the anomalies of the fundus including retinal pigment epithelium (RPE) mottling with melanin clumping not readily seen with the other imaging modalities. MSI fundus autofluorescence (MSI-FAF) showed a spotty hypo and hyperautofluorescent appearance of the fundus, consistent with the observations seen on IVFA and OCT images. Conclusion and Importance: MSI significantly improves visualization of the retinal pigment epithelium in choroideremia. The non-invasive nature of MSI technique is a valuable tool in monitoring the effect of retinal and choroidal presentation in patients with CHM. PMID- 29503892 TI - A case of recurrent bilateral uveitis independently associated with dabrafenib and pembrolizumab therapy. AB - Purpose: To report the case of an adult female who presented on different occasions with recurrent uveitis provoked by initiating therapy of two recently approved agents, dabrafenib and pembrolizumab, for treatment of metastatic melanoma. Observations: A 61 year old female presented with bilateral anterior uveitis after initiating therapy with dabrafenib for advanced metastatic melanoma. Her symptoms resolved and exam improved with oral and topical steroid therapy. Months later, she was started on pembrolizumab and transitioned off dabrafenib. Within days of starting pembrolizumab, she developed recurrent bilateral uveitis. This responded to escalating doses of topical and oral corticosteroid therapy and resolved following discontinuation of pembrolizumab. Nine months later, our patient received her third dose of pembrolizumab due to further progression of melanoma and within three days developed blurry vision, photophobia and subsequent ophthalmologic exam demonstrated bilateral panuveitis. Conclusions and importance: Dabrafenib and pembrolizumab therapy have both previously been associated with uveitis. Here, we document a case of a woman who developed acute uveitis in response to beginning therapy with dabrafenib and then later developed acute uveitis soon after initiating pembrolizumab. To our knowledge, this is the first time this uncommon side-effect has been reported in the same patient after receiving sequential targeted agents and checkpoint inhibitors. PMID- 29503893 TI - Vasculitic central retinal vein occlusion: The presenting sign of seronegative rheumatoid arthritis. AB - Purpose: To report the case of a patient who presented with a vasculitic central retinal vein occlusion (CRVO), which was the result of an undiagnosed systemic inflammatory condition, seronegative rheumatoid arthritis (RA). Observations: The patient presented with reduced vision in the left eye and polyarthralgia. Fundoscopic examination revealed a central retinal vein occlusion (CRVO) with concurrent evidence of vasculitis. Work-up for polyarthralgia included comprehensive serologic testing for connective tissue disease, including Vectra(r) disease activity (DA) testing. Results of these studies confirmed the diagnosis of seronegative rheumatoid arthritis (RA). Systemic steroid therapy was initiated with subsequent anatomic and visual improvement. Conclusions and importance: We hypothesize that the systemic inflammation-a hallmark of RA-led to the development of a vasculitic CRVO and, thus, the retinal manifestations served as the disease marker that prompted thorough work-up of the patient's disease, even in the face of initial seronegativity. This case serves as a reminder that, in the setting of CRVO and polyarthralgia, systemic inflammatory conditions must be considered as the underlying etiology. Further, this case report highlights our evolving understanding of the role that serologic markers play in the diagnosis and monitoring of RA. PMID- 29503894 TI - En face swept-source optical coherence tomographic analysis of X-linked juvenile retinoschisis. AB - Purpose: To clarify the area of retinoschisis by X-linked juvenile retinoschisis (XLRS) using swept-source optical coherence tomography (SS-OCT) en face images. Observations: We report two cases of XLRS in the same family. The patients presented with bilateral blurred vision. The posterior segment examination showed a spoked-wheel pattern in the macula. SS-OCT cross-sectional images revealed widespread retinal splitting at the level of the inner nuclear layer bilaterally. We diagnosed XLRS. To evaluate the area of retinoschisis, we obtained en face SS OCT images, which clearly visualized the area of retinoschisis seen as a sunflower-like structure in the macula. Conclusion and Importance: We report the findings on en face SS-OCT images from patients with XLRS. The en face images using SS-OCT showed the precise area of retinoschisis compared with the SS-OCT thickness map and are useful for managing patients with XLRS. PMID- 29503895 TI - Idiopathic retinal vasculitis, aneurysms and neuroretinitis case report. AB - Purpose: To report a case of idiopathic retinal vasculitis, aneurysms and neuroretinitis (IRVAN) in a young woman. Observations: A 21-year-old white female patient was referred to retina clinic with decreased vision in the left eye. On examination, best corrected visual acuity was 20/20 in the right eye and counting fingers in the left eye. Fundus examination revealed bilateral optic disc edema, peripapillary and macular exudates, retinal arterial aneurysms, and venous beading. In the left eye, there was a large focus of exudative material in the central macula. Examination of the peripheral retina was unremarkable, bilaterally. Fluorescein angiography demonstrated arterial aneurysms and venous beading in both eyes, with optic nerve activity and vascular sheathing noted on late frames in both eyes. In the left eye, there was a large central area of blockage corresponding to hard exudates surrounding a more central area of hyperfluorescence with leakage, representing retinal neovascularization. Review of systems and extensive laboratory workup were negative. The patient was diagnosed with IRVAN. She was observed, and her exam at 6-month follow-up revealed low grade inflammation for which the patient was started on oral prednisone. Conclusions and Importance: Management of IRVAN remains challenging because of its idiopathic nature and the lack of controlled clinical trials for such a rare entity. Bilateral involvement in IRVAN is variable and close follow up is crucial. PMID- 29503896 TI - Changes in the thickness of the macular ganglion cell complex and retinal nerve fiber layer over time after surgery in a case of juvenile glaucoma. AB - Purpose: To report longitudinal changes over time after surgery in the topography of the optic disc, thickness of the circum papillary retinal nerve fiber layer (c RNFL), and thickness of the macular ganglion cell complex (m-GCC) in a case of juvenile open angle glaucoma. Observations: Case report based on one patient. After significant edema of the optic disc for 2 months, the cup depth and cup volume measured by Heidelberg retina tomograph images showed reversal, which lasted for 3 years. The c-RNFL thickness and m-GCC thickness measured by spectral domain optical coherence tomography first increased for a week and then continued to decrease until 6 months after operation. These two parameters reached a plateau after 3 years. The mean deviation of global visual field indices of the Humphrey visual field revealed a very mild reduction for this 3 year period. Conclusions and importance: In juvenile onset glaucoma, changes in c-RNFL thickness and m-GCC thickness after operation were not consistent with changes in optic disc cupping. Changes in the thicknesses of the c-RNFL or m-GCC, rather than changes in the optic disc changes, may be good surrogate measures to confirm the effectiveness of glaucoma surgery. PMID- 29503897 TI - Delayed fungal endophthalmitis secondary to Curvularia. AB - Purpose: To describe a case of fungal endophthalmitis secondary to Curvularia after cataract surgery. Observations: This case showed delayed and recalcitrant fungal endophthalmitis secondary to Curvularia despite treatment with pars plana vitrectomy, intravitreal antifungal therapy, and systemic antifungals. Conclusions and importance: Curvularia-associated endophthalmitis should be considered in the differential diagnosis of delayed post-cataract endophthalmitis, especially in tropical or subtropical geographical areas. Awareness and early identification, timely removal of the nidi of sequestration, and prolonged antifungal treatments are important for the eradication of Curvularia-associated endophthalmitis. PMID- 29503898 TI - Delayed presentation of retained acrylic intraocular lens (IOL) fragment after uncomplicated cataract surgery. AB - Purpose: To report a case of delayed presentation of a severed acrylic single piece intraocular lens (IOL) haptic fragment causing corneal edema after uneventful phacoemulsification surgery. Observations: An 85-year-old male presented with inferior corneal decompensation six months after a reportedly uneventful phacoemulsification in his left eye. A distal haptic fragment of an acrylic single-piece posterior chamber intraocular lens was found in the inferior anterior chamber angle. Intraoperative examination revealed that the dislocated fragment originated from the temporal haptic, the remainder of which was adherent to the anterior surface of the capsular bag. The clipped edge of the haptic fragment showed a clean, flat surface, suggesting it was severed by a sharp object. The findings were considered consistent with cutting of the fragment during implantation presumably from improper lens loading, improper implantation technique, or defective implantation devices. Conclusions and Importance: This is the first case report of a foldable acrylic intraocular lens severed during routine uncomplicated cataract surgery that was not noted at the time of the surgery or in the immediate postoperative period. Delayed presentation of severed IOL fragments should be considered in cases of late onset corneal edema post operatively, when other causes have been ruled out. Careful implantation technique and thorough examination of the intraocular lens after implantation to assess for lens damage intraoperatively is essential to avoid such rare complications. PMID- 29503899 TI - The tipping point: Tamoxifen toxicity, central serous chorioretinopathy, and the role of estrogen and its receptors. AB - Purpose: To describe a case of tamoxifen toxicity superimposed on central serous chorioretinopathy (CSCR). We review the role of estrogen and the effect of tamoxifen on ocular tissues. Observations: A 32-year-old Hispanic female with infiltrating ductal carcinoma of the left breast (T2N1M0, triple-positive), status post chemotherapy and bilateral mastectomy, presented with complaint of a floater and decreased central vision of the right eye (OD). Symptoms began three weeks after initiating tamoxifen and five months after the last cycle of chemotherapy and dexamethasone. Visual acuity (VA) was 20/30 OD at presentation. Clinical examination and multimodal imaging revealed subretinal fluid (SRF) and pigment epithelial detachment (PED) suggestive of CSCR. After one month of monitoring, VA improved to 20/20; there was SRF resolution, small PED, and focal ellipsoid zone (EZ) band loss. Two weeks later, after undergoing surgery and starting a topical steroid, she returned with count fingers (CF) VA and large SRF OD. Steroid cessation improved SRF after one month, but VA was unchanged. Tamoxifen was discontinued, and VA improved to 20/100 with near-complete resolution of SRF at three weeks, and significant reduction in choroidal thickness at two months. At final follow-up, VA was 20/200, and there was focal EZ band loss sub-foveally, minimal SRF, and small PED. Conclusions and Importance: Treatment with tamoxifen may lead to ocular toxicity and can complicate the recovery course of patients affected with CSCR. Variations in levels of the estrogen receptor-alpha (ER-alpha) and treatment with tamoxifen (ER alpha partial agonist) may lead to loss of the protective effect of estrogen in the retinal pigment epithelial cells in premenopausal women. Furthermore, tamoxifen toxicity can lead to focal photoreceptor loss. Treatment in these cases should be coordinated together with the oncologist. PMID- 29503900 TI - Utility of anterior segment swept-source optical coherence tomography for imaging eyes with antecedent ocular trauma. AB - Purpose: To evaluate the utility of swept source optical coherence tomography (SS OCT) for the analysis of anterior segment structures in cases with previous traumatic eye injuries. Observations: We report three eyes of three patients with anterior segment traumatic eye injury and highlight the role of SS-OCT in their evaluation and management. This technology enabled us to visualize the structural details of anterior segment of the eye and augment the clinical examination in our patients. Given that it is non-invasive and that there is no contact involved, it may be an ideal imaging modality for traumatic eye injuries for viewing the details before and after any clinical intervention especially in the sub-acute setting. Conclusions: The anterior segment SS-OCT is a useful device allowing non-invasive, non-contact, real-time, cross-sectional anterior segment images of eyes with previous ocular trauma. PMID- 29503901 TI - Topical difluprednate for the treatment of retinal vasculitis associated with birdshot chorioretinitis. AB - Purpose: To report a case of retinal vasculitis associated with birdshot chorioretinitis which was responsive to topical difluprednate alone. Observations: Two months after initiation of topical difluprednate, fluorescein angiography demonstrated resolution of retinal vasculitis in both treated eyes. Worsening of vasculitis with attempted taper of difluprednate and subsequent control with prior dosing confirmed the response. Conclusions and importance: Despite potential adverse effects of steroid-induced glaucoma and cataract formation, topical difluprednate in the treatment of retinal vasculitis and other posterior uveitides may have efficacy. PMID- 29503902 TI - Retinal and choroidal hyperreflective foci on spectral-domain optical coherence tomographic images in a patient with retinitis pigmentosa accompanied by diabetic retinopathy. AB - Purpose: To report the detailed macular morphology documented by spectral-domain optical coherence tomography (SD-OCT) in a patient with retinitis pigmentosa (RP) and diabetic retinopathy (DR). Observations: A 54-year-old man with a hemoglobin A1c level of 11.4% was referred for decreased visual acuity (VA) bilaterally (right eye, 20/100; left eye, 20/40). Funduscopy showed typical retinal findings of RP bilaterally. The macular area of both fundi showed retinal dot-and-blot hemorrhages, hard exudates. Time-domain OCT revealed macular edema in the right eye. The patient was diagnosed with RP accompanied by DR bilaterally. Five years after the first visit, the BCVAs remained 20/100 in the right eye and 20/40 in the left eye. SD-OCT showed that the retinas were thinner temporal to the maculas. The external limiting membrane line (ELM) and the ellipsoid zone of the photoreceptors line (EZ) was not visible in the foveal region in the right eye and temporal to the macula in both eyes. The image revealed the characteristic intraretinal and intrachoroidal hyrerreflective foci, the number of which increased corresponding to the extent of the disappearance of the ELM and EZ line with thinning of the outer nuclear layer (ONL). In addition, the image also showed a great number of the hyperreflective foci in the ONL and the choriocapillaris in the foveal region in the right eye compared with the left eye. Conclusions: In the current case, the SD-OCT findings suggested that the characteristic hyrerreflective foci clinically observed in the fundi of a patient with RP accompanied by DR are present in the retinal layers and the choroid. In addition, the foci in the retinal and choroidal layers in the foveal region may increase as vision declines corresponding to the disappearance of the ELM and EZ line. PMID- 29503903 TI - Pediatric conjunctival lymphoma associated with oral carbamazepine use. AB - Purpose: To report a case of a pediatric patient diagnosed with conjunctival lymphoma associated with oral carbamazepine use. Observation: An 11-year-old boy who presented with 5-month history of a small nasal conjunctival mass in the left eye that failed therapy with topical corticosteroids. Upon excision and molecular analysis, diagnosis of Follicular Lymphoma was favored. The patient was healthy and did not have any known risk factors except for a history of epilepsy treated with systemic carbamazepine. Conclusion and importance: We report a case of a rare childhood conjunctival lymphoma. Conjunctival lymphomas may masquerade as chronic conjunctivitis, or scleritis that fail therapy with topical corticosteroids. Furthermore, our patient did not have any known risk factors such as old age, systemic lymphoma or immunosuppression. The patient did have a history long-term use of systemic carbamazepine. This is to our knowledge the first case conjunctival lymphoma that may be associated to the use of carbamazepine. PMID- 29503904 TI - Remarkable visual recovery after severe open globe injury. AB - Purpose: To describe a case of remarkable visual recovery after severe open globe injury. Observations: We present a case of a 70-year-old man with an open globe injury with no light perception vision before and after primary repair of his ruptured globe and before secondary vitreoretinal surgery to repair a total retinal detachment with a 360 degrees giant retinal tear and retinal incarceration in a posterior scleral wound who proceeded to recover vision to the 20/60 pinhole to 20/50 level. Conclusions and importance: Poor presenting acuity is a known risk factor for poor visual outcome after open globe injury. We hypothesize this remarkable visual recovery could be attributable to the presence of a massive choroidal hemorrhage and limited intraocular hemorrhage elsewhere. In rare cases, vision can improve from the no light perception level after secondary vitreoretinal surgery. PMID- 29503905 TI - Chemotherapy-induced anterior necrotising scleritis: A case report. AB - Purpose: We describe a case of anterior necrotising scleritis secondary to Gemcitabine and Carboplatin chemotherapy agents in a patient with metastatic breast cancer, which has not been previously reported. Observations: A 50-year old lady with recurrent metastatic breast cancer presented with unilateral subconjunctival haemorrhage secondary to severe thrombocytopenia eight days following palliative chemotherapy in the form of Gemcitabine and Carboplatin. Twelve days following the initial presentation, the subconjunctival haemorrhage had resolved, however there was evidence of anterior necrotising scleritis with anterior chamber reaction and hypotony with choroidal effusion. This resolved with three days of intravenous Methylprednisolone along with topical steroids and the area of necrosis remained stable. Conclusions and importance: Due to the chronological order of events, we infer a Gemcitabine and Carboplatin-induced anterior necrotising scleritis, which has not been previously reported. PMID- 29503906 TI - NOD2 genetic variants and sarcoidosis-associated uveitis. AB - Purpose: Identifying genetic risk factors for developing sarcoidosis-associated uveitis could provide insights into its pathogenesis which is poorly understood.We determine if variants in NOD2 confer an increased risk of developing uveitis in adults with sarcoidosis. Methods: In this genetic case control study, 51 total subjects were enrolled: 39 patients diagnosed with sarcoid-related uveitis and 12 patients with systemic sarcoidosis without ocular involvement as controls. Sanger sequencing of the eleven exons of the NOD2 gene was performed on DNA obtained from whole blood. Sanger sequencing data were aligned against the NOD2 NCBI-RefSeq reference sequence to identify novel mutations in uveitis patients. For common variants, allele frequencies in cases versus controls were compared using the chi-square test. Results: There were no significant differences in NOD2 common variant allele frequencies between sarcoidosis patients with and without uveitis, and none of the pathogenic NOD2 mutations associated with Blau syndrome were found in this cohort. However, four rare, non-synonymous variants were identified in four patients with ocular sarcoidosis and none of the controls. Variants rs149071116, rs35285618, and 16:g.50745164T > C have never been previously reported to be associated with any disease and may be pathogenic. The fourth variant, rs2066845, is associated with Crohn's disease and psoriatic arthritis. Conclusions: Despite the phenotypic overlap between sarcoidosis and Blau syndrome, none of the established pathogenic NOD2 variants were present in adults with sarcoidosis. However, four novel, rare, non-synonymous variants were identified in four cases with ocular sarcoidosis. Further investigation is needed to explore the potential clinical significance of these polymorphisms. PMID- 29503907 TI - Retinopathy in lupus transitioned to Kikuchi-Fujimoto disease. AB - Purpose: We present a patient with systemic lupus erythematosus with significant vaso-occlusive retinal findings mimicking antiphospholipid antibody syndrome, who developed Kikuchi-Fujimoto disease. Observations: Our patient was initially diagnosed with systemic lupus erythematosus with antiphospholipid antibody syndrome given consistent serologic markers and profound retinal vascular ischemia. However, on subsequent follow up, she presented with fever and lymphadenopathy and underwent lymph node biopsy, which declared histologic findings of Kikuchi-Fujimoto disease. Repeat markers for antiphospholipid antibody syndrome were negative and she was taken off lifelong anticoagulation. Conclusions and importance: Systemic lupus erythematosus and Kikuchi-Fujimoto disease may have many similar features and even biomarkers, and given the potential overlap of presentation, clinicians must carefully distinguish between these diseases to prevent unnecessary treatment. PMID- 29503908 TI - Unilateral surgically induced Necrotizing Scleritis after trabeculectomy with Ologen in a patient with pigmentary glaucoma. AB - Purpose: In this report we record the first surgically induced Necrotizing Scleritis case related to trabeculectomy with the use of Ologen Collagen Matrix Implant. Observations: Surgically induced Necrotizing Scleritis is a rare pathological entity that complicates ocular (sclera) surgery. Conclusions and importance: Prompt management of surgically induced Necrotizing Scleritis related to trabeculectomy with the use of Ologen and close follow up is very important to prevent its destructive nature on the globe. PMID- 29503909 TI - Radiation optic neuropathy and retinopathy with low dose (20 Gy) radiation treatment. AB - Purpose: To report a case of optic neuropathy and retinopathy from a dose of radiation traditionally thought to be safe to the visual system and discuss strategies for preventing vision loss when using radiation to treat intraocular tumors. Observations: A 44-year-old woman presented with new, painless vision loss in the left eye eighteen months after receiving proton beam radiotherapy (20 Gy dose delivered in two 10 Gy fractions) for a uveal metastasis of lung cancer. The dilated funduscopic examination revealed optic disc swelling and retinal hemorrhages and an MRI of the brain and orbits demonstrated enhancement of the left optic nerve head, findings consistent with radiation optic neuropathy (RON) and retinopathy. Risk factors for developing RON included coincident use of oral chemotherapy and relatively large fractionated doses of radiation. Conclusions and importance: Though cumulative radiation doses to the anterior visual pathway of less than 50 Gy are traditionally felt to be safe, it is important to consider not just the total exposure but also the size of individual fractions. The single dose threshold for RON in proton beam treatment has yet to be defined. Our case suggests that fractions of less than 10 Gy should be delivered to minimize the risk of optic nerve injury. PMID- 29503910 TI - Morphological changes after trabeculectomy in highly myopic eyes with high intraocular pressure by using swept-source optical coherence tomography. AB - Purpose: To investigate the effects of intraocular pressure (IOP) reduction on the eyeball shape in highly myopic eyes with high IOP. Methods: This study included patients with an axial length >=26.5 mm and high IOP >=22 mmHg after receiving maximum medication, with successful trabeculectomy by a single surgeon, and who underwent swept-source optical coherence tomography (SS-OCT) examinations on preoperative and postoperative >=3 months periods. Eight eyes of 7 patients were included in the analysis. The morphological changes in the eyeball that occurred pre- and post-operation were analyzed from the SS-OCT images. Results: In 6 out of 8 examined eyes, the following apparent morphological changes in the posterior pole and/or peripapillary sclera were postoperatively detected on SS OCT images: peripapillary scleral shrinkage, decrease in the lamina cribrosa depth, flattening of the peripapillary scleral insertion into the optic disc, decrease in the angle of the scleral protrusion temporal to the optic disc, and inhomogeneous change in scleral curvature of the posterior pole. Conclusions and importance: We found that the shape of some eyes with high myopia and high IOP changed owing to the decrease in IOP. Eyeball deformities may be affected by high IOP, and IOP reduction might reduce scleral deformation in highly myopic eyes with high IOP. PMID- 29503911 TI - Erlotinib-associated severe bilateral recalcitrant keratouveitis after corneal EDTA chelation. AB - Purpose: We report a case of erlotinib-associated severe recalcitrant bilateral keratouveitis after uneventful corneal ethylenediaminetetraacetic acid (EDTA) chelation in a patient with non-small cell lung cancer (NSCLC); discontinuation of erlotinib led to complete resolution. Observations: An elderly person presented with band keratopathy (BSK) of undetermined etiology in the both eyes, associated with foreign body sensation and constant tearing. The patient was on oral erlotinib treatment 150 mg PO daily for 1 year for NSCLC status post radiation therapy. Corneal EDTA chelation was performed in both eyes under topical anesthesia for BSK. Four days after surgery, the patient presented with severe pain in both eyes. Slit lamp evaluation revealed 5 mm * 7 mm epithelial defect with clear margins in the right eye and 6 * 7 mm epithelial defect with thick central corneal infiltrate in the left eye. Hypopyon was noticed in both eyes and intense inflammation obscured the details of anterior segment. Intense antibiotic treatment was initiated. After discussion with the oncology services, oral erlotinib was temporarily discontinued. This resulted in resolution of keratitis and hypopyon in both eyes, within one week. Conclusions: and importance: Systemic use of erlotinib suppresses local immunity, facilitates infection and enhances inflammatory reaction in the eye. Clinicians should be cautious and plan any ocular interventional treatment in collaboration with oncology team to prevent adverse outcomes. PMID- 29503912 TI - Combined rhegmatogenous and traction detachment associated with vasoproliferative tumor secondary to sickle cell retinopathy. AB - Purpose: To report the surgical management of a combined rhegmatogenous and traction retinal detachment associated with a vasoproliferative tumor secondary to sickle cell retinopathy. Observations: A 29 year old man from Ghana presented with unilateral vision loss, ischemic retina and sea fan neovascularization in both eyes and a retinal detachment nearby a vasoproliferative tumor (VPT) in the left eye. Hemoglobin electrophoresis led to the diagnosis of sickle cell disease. The patient underwent vitrectomy with scleral buckle surgery, resection of the tumor, and removal of subretinal membranes in the left eye. Laser photocoagulation was targeted to areas of ischemic retina in both eyes. Conclusions: and Importance: To our knowledge, this is the first report of a combined rhegmatogenous and traction retinal detachment associated with a VPT in sickle cell retinopathy managed by modern vitrectomy techniques. Prompt recognition of the condition and surgical management addressing both rhegmatogenous and tractional components can lead to improved outcome. PMID- 29503913 TI - Intravitreal ranibizumab for treatment of choroidal neovascularization secondary to a bilateral choroidal osteoma. AB - Purpose: Choroidal osteomas are benign intraocular tumors that classically present in females. Despite their benign nature, significant visual acuity loss can occur due to retinal pigment epithelium degeneration. We report an unusual case of bilateral choroidal osteoma in a young boy. Observation: A 16 year old boy presented to the Aga Khan University Hospital with a history of painless, bilateral deteriorating vision over past few months. Examination showed best corrected visual acuity as 20/200 in the right eye and 20/400 in the left eye. Funduscopy revealed a well-defined lesion in the juxtafoveal region of both eyes. A diagnosis of (bilateral) choroidal osteoma was subsequently made on the basis of optical coherence tomography, fundus fluorescein angiography, Indocyanine green and B-scan ultrasonography. The presence of choroidal neovascularization with sub retinal fluid was also established on OCT. The patient was treated with three intravitreal Ranizumab injections. At the follow up visit, vision had improved to 20/50 in the right eye and 20/200 in the left. Sub retinal fluid had also resolved. Conclusions: and importance: Intravitreal Ranizumab may be an effective alternative in the management of choroidal neovascularization secondary to choroidal osteoma. PMID- 29503914 TI - A case of Granulomatosis with Polyangiitis presenting with significant ocular cicatricial scarring and symblepharon formation. AB - Purpose: To report a case of Granulomatosis with Polyangiitis presenting with rare findings of cicatricial entropion progressing to significant symblepharon and fornix obliteration. Observations: An otherwise healthy patient with initial presentation findings of lower lid entropion with minimal cicatricial changes and a corneal ulcer. Management with an entropion Jones procedure repair produced good early postoperative results. 2 months post entropion repair, this patient represented with rapid progression to severe corneal ulceration, symblepharon formation and total obliteration of lower fornix and near complete obliteration of upper fornix of the left eye with concurrent acute kidney injury. He fulfilled diagnostic criteria for Granulomatosis with Polyangiitis (GPA). Systemic immunosuppressive treatment with prednisone and cyclophosphamide allowed acute kidney injury to recover however progressive cicatricial scarring ensued. Conclusions and importance: Cicatricial entropion is a very rare presentation of GPA which can take years to progress however with surgical intervention, rapid recurrence and severe tarsal-conjunctival disease progression can ensue despite systemic immunosuppressive therapy. To prevent such unexpected surgical complication, we recommend a thorough systemic evaluation prior to consideration of lid surgery in any cases of cicatrising conjunctivitis presentation. PMID- 29503915 TI - Ipsilateral supraorbital nerve transfer in a case of recalcitrant neurotrophic keratopathy with an intact ipsilateral frontal nerve: A novel surgical technique. AB - Purpose: To report a case of regained corneal sensation and function in a patient with neurotrophic keratopathy due to direct damage to the long ciliary nerves by performing a corneal neurotization procedure using ipsilateral supraorbital nerve. Surgical technique is described in detail as well as a review of the literature on corneal neurotization. Observations: A patient with devastating corneal anesthesia and poor visual acuity refractory to other treatments underwent a new surgical technique involving an ipsilateral supraorbital nerve transfer to the surrounding limbus to restore corneal sensation. At 8 months follow up, there was resolution of corneal stromal opacification documented with photographs and greatly improved corneal sensation by testing with a wisp of cotton in all 4 quadrants. Her visual acuity had improved, and at two years she was stable with even more improvement in visual acuity and ocular surface health. Conclusions and importance: We present the first successful case of corneal neurotization with ipsilateral supraorbital nerve in a patient with corneal anesthesia from a local injury to the long ciliary nerves. Our case demonstrates that the described method of corneal neurotization is a viable option for patients with recalcitrant neurotrophic keratopathy and an intact ipsilateral frontal nerve. PMID- 29503916 TI - Pneumatic retinopexy for displaced macular laceration from intraocular foreign body. AB - Purpose: To report a case of macular laceration from intraocular foreign body (IOFB) treated with pneumatic retinopexy. Observations: A 74 year old man sustained penetrating injury to his left globe with retained metallic intraocular foreign body (IOFB). The patient underwent prompt pars plana vitrectomy, intravitreal antibiotics and removal of IOFB. The posterior point of impact left a displaced foveo-macular laceration which was recognized postoperatively and treated with pneumatic retinopexy for re-approximation of the foveal tissue. Optical coherence tomography confirmed acute traumatic laceration and edema, closure of the tissue and subsequent healing and adjacent retinal and retinal pigment epithelial atrophy. He regained visual acuity of 20/30. Conclusions and importance: Traumatic macular lacerations can be treated with pneumatic retinopexy, after pars plana vitrectomy, with potentially good visual result. PMID- 29503917 TI - Amaurosis fugax due to pleomorphic sarcoma in the left atrium. AB - Purpose: This report describes a case of amaurosis fugax due to a rare primary cardiac sarcoma. Observations: A patient who was recently diagnosed with left atrial pleomorphic sarcoma presented with a chief complaint of multiple episodes of intermittent vision loss in the right eye during the course of radiation therapy. Conclusions and importance: The authors postulate emboli from the left atrial sarcoma entered systemic circulation and subsequently caused brief episodes of transient occlusion to retinal, ophthalmic and/or ciliary arteries leading to momentary retinal hypoxia. We believe this is a novel finding, previously unreported in the literature, of transient embolic occlusion without permanent visual sequelae due to a malignant primary cardiac pleomorphic sarcoma. PMID- 29503918 TI - Iris abscess a rare presentation of intravenous drug abuse associated Candida endophthalmitis. AB - Purpose: To describe an unusual case of intravenous drug abuse associated endogenous endophthalmitis presenting with an iris abscess. Observations: A 30 year old female with history of intravenous drug use presented with a two-week history of redness and blurry vision in the right eye. An initial diagnosis of anterior uveitis was made. However, she worsened on topical steroids and mydriatics. She was found to have a hypopyon and an iris abscess. She received broad spectrum antibiotic and antifungal treatment with voriconazole, this lead to significant clinical improvement. She was discharged on oral fluconazole and lost to follow up. The patient was noncompliant with the antifungal treatment. The hypopyon and iris abscess recurred, and she required a vitrectomy with iridectomy, along with intravitreal and systemic antifungal treatment. The vitreous cultures and surgical specimen of iris issue were positive for Candida albicans, and she received voriconazole. This led to resolution of the condition with a final visual acuity of 20/20 at six month follow up. Conclusions and importance: An iris abscess is a rare clinical presentation of intravenous drug use-associated endogenous endophthalmitis and as a result may present a diagnostic challenge as it requires a high level of clinical suspicion and a detailed social history to elicit the drug abuse. Early diagnosis and aggressive therapy is the key to better visual outcomes in these patients. PMID- 29503919 TI - Choroidal blood flow impairment demonstrated using laser speckle flowgraphy in a case of commotio retinae. AB - Purpose: To report the time course of choroidal blood flow (CBF) in a commotio retinae case using laser speckle flowgraphy (LSFG). Observations: A 58-year-old Japanese man with complaints of worsening left visual acuity after blunt eye trauma was diagnosed with commotio retinae. A funduscopic examination showed macular opacity, and LSFG results demonstrated CBF impairment in the affected eye.Optical coherence tomography also showed disruption of the photoreceptor outer segment. Seven months after the initial visit, CBF was significantly increased, along with improvement in the photoreceptor outer segment. Conclusion: and importance: We revealed CBF impairment in a case of commotio retinae for the first time. CBF impairment may be involved in the pathogenesis of commotio retinae, and LSFG may be useful for examining CBF in commotio retinae. PMID- 29503920 TI - Orbital myeloid sarcoma in adult mimicking nasolacrimal duct obstruction: A case report. AB - Purpose: To describe an orbital myeloid sarcoma in adult presenting with a swollen mass at inferomedial canthal area and epiphora which was misdiagnosed as nasolacrimal duct obstruction. Observations: A 45-year-old male presented with a swollen right lower eyelid around medial canthal area for 2 months with tearing for 6 month-period earlier. Eye examination demonstrated a high tear meniscus, slightly erythematous eyelid with palpable mass closed to the lacrimal sac along the inferior orbital rim. Computed tomography scan depicted infiltrative mass at the inferomedial aspect of right orbit with bony erosion, extended to adjacent paranasal sinuses. An incisional biopsy was performed. Histopathological study revealed soft tissue which was diffusely infiltrated by monotonous medium-sized round cells resembling blasts with lymphoglandular bodies, focally positive myeloperoxidase and negative lymphoid markers. The findings were consistent with myeloid sarcoma. No systemic involvement was found. The patient underwent chemotherapy and radiation without systemic leukemic disease progression. Conclusions and importance: Although orbital myeloid sarcoma is rare and difficult to diagnose, it can mimic nasolacrimal duct obstruction. We should consider this condition in our differential diagnosis. PMID- 29503921 TI - Ozurdex completely located inside a crystallized lens - Results of 14 months. AB - Purpose: To report the therapeutic efficacy and results of an accidentally injected intralenticular sustained-release dexamethasone implant (Ozurdex) in a patient with macular edema secondary to central retinal vein occlusion at 14 months after injection. Observations: We present a 70-year-old female patient with central retinal vein occlusion who underwent an Ozurdex injection. Patient discontinued from the treatment period during the 14-month and there was no ophthalmologic examination of the patient. Detailed ophthalmological examination was performed. Ozurdex localization was determined by Pentacam rotating Scheimpflug System. The implant was accidentally injected into the crystalline lens. It did not cause a totally lens opacification but did result only in a posterior subcapsular cataract. The macular edema did not resolve, and the patient underwent phacoemulsification surgery. Conclusions and importance: Ozurdex that totally located inside the crystallize lens may not have the therapeutic effects. PMID- 29503922 TI - A rare case of unifocal, unilateral pigmented paravenous retinochoroidal atrophy (PPRCA). AB - Purpose: To report an atypical case of unifocal, unilateral pigmented paravenous retinochoroidal atrophy (PPRCA) characterized by thickening and cystic degeneration of the retinal nerve fiber layer (RNFL). Observations: A 79-year old Asian woman presented with a large area of atrophic, pigmented change along the inferior arcade of her right eye. She denied nyctalopia and any other visual complaints. Visual acuity was 20/40 in both eyes and visual fields were significant for a large absolute peripheral scotoma superiorly in the affected eye corresponding to the atrophic area. Spectral domain optical coherence tomography through the lesion showed loss of choroid except for largest Haller's layer vessels, significant retinal pigment epithelium atrophy with migration and pigment clumping, outer retinal layer loss and RNFL thickening with cystic degeneration. Fundus autofluorescence imaging showed a large area of hypoautofluorescence corresponding to the area of atrophy. Full field electroretinogram demonstrated normal scotopic response and reduced photopic response in the right eye. Conclusions and importance: PPRCA is typically bilateral and symmetric, affecting primarily the outer retina and choroid. However, in rare cases, this disease can present unilaterally and/or unifocally, with degeneration extending to the inner retinal layers. PMID- 29503923 TI - Suprachoroidal hemorrhage during femtosecond laser assisted cataract surgery. AB - Purpose: To describe a case of suprachoroidal hemorrhage that occurred during femtosecond laser assisted cataract surgery (FLACS). Observations: A 67-year-old woman with high myopia underwent FLACS. Following two unsuccessful attempts at docking due to interface air bubbles, the third attempt was successful. Laser treatment and cataract surgery proceeded uneventfully until intraocular lens (IOL) implantation. While positioning the IOL within the capsular bag, the anterior chamber began to shallow, intraocular pressure became high by palpation, and the optic of the IOL prolapsed partially out of the bag. A segmental suprachoroidal hemorrhage was identified in the superior peripheral retina by intraoperative indirect ophthalmoscopy. Following an hour of waiting in the recovery room, the anterior chamber deepened and the intraocular pressure was low enough to position the IOL centrally within the bag. Her subsequent postoperative course was uneventful. Conclusions and Importance: To our knowledge, this is the first report of suprachoroidal hemorrhage during FLACS. We speculate that repeated sudden drops in intraocular pressure associated with multiple undockings triggered the suprachoroidal hemorrhage in this case. PMID- 29503924 TI - A case of Acute Myeloid Leukemia masquerading as unilateral exudative detachment. AB - Purpose: Leukemias can involve almost every part of the human eye. Ophthalmic manifestations of leukemias can be divided into direct infiltration, secondary vascular changes and neuro-ophthalmological changes. Our case presented with exudative retinal detachment mimicking Vogt Koyanagi Harada's disease (VKH). Observations: A 30-years old Asian (Indian) female presented with insidious onset of painless diminution of vision from her right eye for one month. She gave history of fever and severe headache at the time of onset of ocular symptoms. Fundus examination revealed exudative retinal detachment at the posterior pole of her right eye. Fundus fluorescein angiography showed early stippled pin point hyperfluorescence, placoid pooling of the dye and late disc staining in both the eyes. A provisional diagnosis of Vogt Koyanagi Harada disease was made and routine blood investigations and a physician check-up for fitness for systemic steroids was done. Peripheral blood smear showed the presence of blast cells. The patient was diagnosed to have Acute Myeloid Leukemia (AML) and was started on chemotherapy. Conclusions and Importance: Acute myeloid leukemia can present as an exudative retinal detachment and can mimic similarly presenting conditions like VKH. Hence, this very important differential diagnosis should be kept in mind and it stresses the importance of simple laboratory investigations like whole and differential blood counts. PMID- 29503925 TI - Atypical presentation of neuronal ceroid lipofuscinosis type 8 in a sibling pair and review of the eye findings and neurological features. AB - Purpose: To report atypical presentation of neuronal ceroid lipofuscinoses type 8 (CLN8) to the eye clinic and review clinical features of CLN8. Observations: Detailed eye exam by slit lamp exam, indirect ophthalmoscopy, fundus photography, optical coherence tomography, visual fields and electroretinogram (ERG). Molecular genetic testing using Next Generation Sequencing panel (NGS) and array Comparative Genomic Hybridization (aCGH).The siblings in this study presented to the eye clinic with retinitis pigmentosa and cystoid macular edema, and a history of seizures but no severe neurocognitive deficits or regression. Genetic testing identified a c.200C > T (p.A67V) variant in the CLN8 gene and a deletion encompassing the entire gene. Electron microscopy of lymphocytes revealed fingerprint inclusions in both siblings. Conclusions: and Importance: Pathogenic variants in CLN8 account for the retinitis pigmentosa and seizures in our patients however, currently, they do not have regression or neurocognitive decline. The presentation of NCL can be very diverse and it is important for ophthalmologists to consider this in the differential diagnosis of retinal disorders with seizures or other neurological features. Molecular genetic testing of multiple genes causing isolated and syndromic eye disorders using NGS panels and aCGH along with additional complementary testing may often be required to arrive at a definitive diagnosis. PMID- 29503926 TI - Floaters and reduced contrast sensitivity after successful pharmacologic vitreolysis with ocriplasmin. AB - Purpose: To describe the onset of floaters and reduction in contrast sensitivity (CS) following successful pharmacologic vitreolysis with ocriplasmin for the treatment of vitreo-macular traction (VMT) in a patient with previously normal CS. Observations: A 65-year-old woman with a past ocular history of normal visual acuity (VA = 20/26) and contrast sensitivity (1.81% Weber) presents with a 4 month history of distortions. VA decreased to 20/40 and Optical Coherence Tomography (OCT) demonstrated VMT. Pharmacologic vitreolysis was performed with intravitreal ocriplasmin. Ten weeks later the patient complained of floaters and was found to have a PVD and complete resolution of VMT. VA was still 20/40, but contrast sensitivity decreased by more than 100% to 3.77%Weber. After 6 months of attempted coping, this did not improve, so limited vitrectomy was performed. Post operative VA = 20/26 and CS improved by 46% from 3.77%W to 2.03%W (normal). Conclusion: and importance: This case highlights a little discussed consequence of PVD induction by successful pharmacologic vitreolysis - the development of clinically significant floaters. The resulting reduction of contrast sensitivity was normalized by limited vitrectomy, strongly suggesting that the detached vitreous was the cause. PMID- 29503927 TI - Bedside repair of congenital upper eyelid entropion: A variation of the Quickert suture technique. AB - Purpose: The current literature is void of any lasting bedside treatments for congenital upper eyelid entropion repair. Observations: A six-day old male was born with bilateral upper eyelid entropion associated with a duplication of the long arm of chromosome 3q11.1-q24. Conservative management with ocular lubrication and observation did not yield spontaneous resolution, and surgical intervention was performed at the bedside with a Quickert suture technique. Conclusions and importance: We discuss the novel use of this technique and review the relevant literature. Our technique is something not previously described in the literature for congenital upper eyelid entropion. It obtained satisfactory and sustained resolution. PMID- 29503928 TI - Acute posterior multifocal placoid pigment epitheliopathy and granulomatous uveitis following influenza vaccination. AB - Purpose: To report a case of acute placoid multifocal posterior pigment epitheliopathy (APMPPE) following influenza vaccination. The patient exhibited granulomatous uveitis during the recovery phase. Observations: A woman in her thirties developed flu-like symptoms seven days after receiving an influenza vaccination. Approximately 2 weeks later, the patient reported with conjunctival injection, blurred vision, and pain in her left eye. She was examined in our clinic, and the best-corrected visual acuity was 20/15 OD and 20/20 OS. Multiple whitish spots were observed bilaterally in the deep retinal layer along with edema of the left optic disc. Both indocyanine green and fluorescein angiographic findings suggested a diagnosis of APMPPE. Although APMPPE lesions were gradually resolved after one month, keratic precipitates, anterior chamber and vitreous cellular infiltration, iris and angle nodules, and macular edema were observed and were treated with topical steroid eye drops. No systemic disorders including sarcoidosis, tuberculosis, and Wegener's granulomatosis were present. Conclusion and importance: As influenza vaccinations are administered worldwide, ophthalmologists should be aware of the ocular side effects following vaccination. Although rare, the possibility of APMPPE occurrence following influenza vaccination should be considered; additionally, the recovery phase of APMPPE may be associated with granulomatous uveitis that requires steroid therapy. PMID- 29503929 TI - Cutaneous horn masquerading as a seborrheic keratosis. AB - Purpose: To report a case of seborrheic keratosis of the inner canthus presenting as cutaneous horn. Observation: A 67-year-old Asian male presented with a rod shaped, pedunculated mass on his inner canthus. The mass grew rapidly and within 2 months measured 3.0 cm in length and 0.5 cm in diameter. It was completely excised and submitted for microscopic examination. The specimen consisted of a proliferation of basaloid cells arranged in a papillary pattern and associated with significant hyperkeratosis and parakeratosis of the overlying squamous epithelium. The pathological diagnosis was reported as seborrheic keratosis from the skin of the inner canthus. Conclusions and importance: Seborrheic keratosis can develop into a rapidly expanding lesion such as a cutaneous horn and can be found in unusual locations. To our knowledge, this is the first report of a seborrheic keratosis from the skin of the inner canthus. PMID- 29503930 TI - Acute onset of fingolimod-associated macular edema. AB - Purpose: Fingolimod is among the first oral disease-modifying agents for the treatment of relapsing-remitting multiple sclerosis (MS). Despite its favorable safety profile, fingolimod may cause macular edema, a significant adverse event, which occurs within the first 4 months of therapy. Macular edema usually resolves upon discontinuation of fingolimod; however, the time required for resolution of this condition is unknown. Observations: A 42-year-old white male with a history of relapsing-remitting MS presented with blurring of vision in his left eye 24 h after the first dose of fingolimod. Dilated fundus examination of the left eye revealed an increased retinal thickness and mild optic disc pallor. Spectral domain optical coherence tomography (SD-OCT) confirmed the diagnosis of cystoid macular edema. Topical nonsteroidal anti-inflammatory drug (NSAID) was initiated immediately after the diagnosis, and fingolimod therapy was discontinued shortly thereafter. Seven weeks after the initial presentation, intermediate uveitis was noted in the inferior periphery of the left eye, and SD-OCT revealed worsening of macular edema. Acetazolamide therapy was added to the topical NSAID to control the edema. Three weeks after initiation of acetazolamide, macular thickness reduced significantly. The patient then stopped all medications, and 3 weeks later macular edema rebounded. Systemic steroid was employed to control both the intermediate uveitis and macular edema. Conclusions and importance: We report a case of acute and very rapid onset of fingolimod-associated macular edema (FAME). Acetazolamide may have a beneficial effect on macular edema secondary to fingolimod. It is unclear if intermediate uveitis is associated with the rapid development of FAME. PMID- 29503931 TI - Corneal ulceration and episcleritis associated with Wiskott-Aldrich syndrome. AB - Purpose: To present anterior segment ophthalmic manifestations of Wiskott-Aldrich syndrome (WAS), a rare X-linked primary immune-deficiency. Observations: A 15 year old male with WAS presented with multiple corneal ulcers of the left eye. Once resolved, this was followed by separate episodes of episcleritis in the left eye and corneal infiltrates of the right eye. Successful treatment included topical antibiotics and anti-inflammatories. Conclusions: Ocular manifestations of WAS, due to secondary infection and inflammation, may be severe. This case report emphasizes the importance of prompt ophthalmic evaluation and treatment of these patients. PMID- 29503932 TI - Detection of retrobulbar blood vessels in optical coherence tomography angiographic images in eyes with pathologic myopia. AB - Purpose: To report the detection of retrobulbar blood vessel in the optical coherence tomography angiographic (OCTA) images of two eyes with pathologic myopia. Observations: Two eyes of 2 cases with pathologic myopia were examined by OCTA (RTVue XR Avanti, Optovue, and Cirrus 5000, Zeiss). Case 1 was a 64-year-old man, and Case 2 was a 65-year-old woman. In Case 1, the thickness of the subfoveal choroid was 38 MUm and the sclera was 274 MUm, and they were 17 MUm and 214 MUm, respectively, in Case 2. The axial length was 35.8 mm in Case 1 and 29.5 mm in Case 2. The choroidal vessels were clearly visible in the choriocapillary slab in both the RTVue and the Cirrus images. The vessels were visible in the area of the retinal pigment epithelial and choriocapillaris atrophy due to the pathologic myopia. The retrobulbar blood vessels temporal to fovea were seen in the OCTA images at the level of the outer aspect of the sclera in both cases. Cross sectional images of the retrobulbar blood vessel in both cases were observed under the sclera in serial scan images overlaid with blood flow. Conclusions: and Importance: These in situ images of the retrobulbar blood vessels that were obtained by OCTA was possible because of the thinness of the choroid and sclera and atrophy of the choriocapillaris in these eyes with pathologic myopia. We conclude that OCTA might have utility to study the retrobulbar vascular alterations in eyes with pathologic myopia. PMID- 29503933 TI - Subcutaneous repository corticotropin gel for non-infectious panuveitis: Reappraisal of an old pharmacologic agent. AB - Purpose: To describe the clinical course of a patient with non-infectious idiopathic unilateral panuveitis and retinal vasculitis treated with subcutaneous repository adrenocorticotropic hormone (ACTH) gel. Observations: A 33-year-old male presented with blurry vision and floaters in the left eye (OS). The best corrected visual acuity was 20/20 in the right eye (OD) and 20/50 in OS at the time of initial presentation. Slit-lamp examination revealed mild anterior segment inflammation in OS. There were 1 + vitreous haze and 2 + cells noted in OS. Clinical examination and ancillary imaging assessment including fluorescein angiography revealed retinal vasculitis and optic nerve head inflammation. After infectious etiologies were ruled out, the patient was started on oral corticosteroids and enrolled in a clinical trial employing intravenous tocilizumab therapy. Six months after completion of the tocilizumab trial, the patient demonstrated recurrence of disease. Twice weekly subcutaneous ACTH gel was initiated and the patient demonstrated improvement of retinal vascular inflammation. Conclusions and importance: Repository subcutaneous ACTH gel formulation may be a safe and viable therapeutic option for patients with non infectious uveitis and retinal vasculitis. Clinical trials using this formulation in a larger patient cohort with longer monitoring are indicated to evaluate its tolerability and bioactivity. PMID- 29503934 TI - Ocular findings in a patient with fucosidosis. AB - Purpose: To describe the ocular findings in a patient with fucosidosis, a rare inborn lysosomal storage disease. Observations: A 14 year-old female presented with angiokeratomas corporis diffusum, coarse facial features, poor verbal skills, hearing impairment and mild developmental delay. A lysosomal storage enzyme screen confirmed absent activity of alpha-l-fucosidase consistent with a diagnosis of fucosidosis. Her eye exam was remarkable for telangiectatic vessels in the inferior conjunctiva and mild corneal stromal haze bilaterally. Spectral domain-optical coherence tomography scans of the macula and a full-field electroretinogram were normal. Conclusions and importance: We describe the findings in a 14 year-old patient with fucosidosis and review the systemic and ocular manifestations of this rare lysosomal storage disease. PMID- 29503935 TI - Lacrimal gland enlargement as an early clinical or radiological sign in thyroid orbitopathy. AB - Purpose: Characteristic ophthalmic signs of Thyroid Orbitopathy (TO) include exophthalmos, eyelid retraction, eyelid edema, restrictive extraocular myopathy, and optic neuropathy. In addition lacrimal gland (LG) enlargement can be observed in these patients. However TO has not usually been considered in the differential diagnosis of cases of isolated LG enlargement. Observations: A female patient at our institution (Texas Tech) was seen over a period from 2006 to 2012. This patient presented initially with LG enlargement as the primary clinical or radiologic sign of what later was diagnosed as TO. Computerized tomography and/or magnetic resonance imaging of the orbits were obtained and demonstrated isolated LG enlargement. Conclusions and importance: This case represents, to our knowledge, the first report of LG enlargement as an initial presenting sign of TO. Further clinical and radiological studies looking at the natural history of TO would be useful to better understand the timing of LG involvement. In patients presenting with lacrimal gland enlargement, thyroid orbitopathy should be strongly considered in the differential diagnosis together with other causes of dacryoadenitis and LG tumors. This may save unnecessary and extensive diagnostic testing or even LG biopsies. PMID- 29503936 TI - Epibulbar osseous choristoma: A case report. AB - Purpose: To present the case of a 12-year-old female with an epibulbar osseous choristoma. Observations: The patient presented with right-sided conjunctival mass, which caused her discomfort. Slit lamp examination revealed a 5*5-mm, firm nodule in the superotemporal quadrant of the bulbar conjunctiva. The nodule had feeder vessels, adhered firmly to the sclera, and lacked signs of malignancy. The patient underwent excisional biopsy under general anesthesia. During this procedure, great care was taken to avoid perforation of the globe. The pathologic sections were significant for well-circumscribed osseous tissue without atypia. Conclusions and importance: We describe diagnosis and successful surgical management of osseous choristoma the rarest subtype of ocular choristoma. With only 65 cases reported since mid-19th century, the condition remains poorly described. This report provides additional information on diagnosis and treatment of this rare condition. PMID- 29503937 TI - Malignant solitary fibrous tumor of the orbit: Spectrum of histologic features. AB - Purpose: Primary malignant solitary fibrous tumor (SFT) of the orbit is a rare spindle cell neoplasm that requires excisional biopsy for histopathological diagnosis. We present a clinical case using contemporary immunohistochemical stains, report on the latest World Health Organization classification, and provide a review of the literature. Observations: Report of a single case of a 65 year old male who presented with right-sided proptosis, limited adduction, ptosis, lateral globe displacement, and cheek festooning. Neuroimaging revealed a 2.2 cm, extraconal heterogeneous mass that diffusely enhanced.En-bloc tumor resection confirmed SFT malignancy based upon nuclear atypia, hypercellularity, and increased mitotic activity (13 mitotic figures/10 high powered fields). Ki-67 showed 2% nuclear staining in the benign tumor and 10-15% staining in the malignant counterpart. Immunohistochemical analysis revealed diffuse Stat6 positivity, CD 34 positivity with partial lack of staining within the malignant portion, S-100 positivity in the malignant portion, and overall negativity for CAM 5.2, desmin, actin, CD 31, and CD 117. Conclusions and importance: Immunoprofiling is helpful to making the diagnosis of malignant solitary fibrous tumor of the orbit. Complete tumor resection continues to be the preferred treatment. The behavior of extrathoracic SFT is unpredictable, and patients with SFT in all locations require careful, long-term follow-up. PMID- 29503938 TI - Simultaneous central retinal artery occlusion and optic nerve vasculitis in Crohn disease. AB - Purpose: To describe a case of Crohn disease presenting as occlusive vasculitis resulting in a central retinal artery occlusion (CRAO) in one eye and transient ischemic optic neuropathy in the fellow eye. Observations: An 18-year-old patient recently diagnosed with biopsy-proven Crohn disease presented with CRAO OD after a previous episode of transient visual loss OS. Extensive workup was negative for other autoimmune or infectious etiologies. The patient was started on intravenous methylprednisolone for 72 h followed by maintenance dose of azathioprine and oral prednisone. Signs of inflammation resolved gradually with some improvement of visual acuity despite developing optic atrophy. Conclusions and importance: To our knowledge, this is the first case of unilateral CRAO and bilateral optic nerve occlusive vasculitis in Crohn disease, which should be considered as an etiology of retinal vascular occlusive disorders especially in young patients. It is important for ophthalmologists to be aware of the ophthalmic risks associated with Crohn disease as aggressive treatment with systemic steroids and immunosuppressive agents is often needed. PMID- 29503939 TI - Anterior infectious necrotizing scleritis secondary to Pseudomonas aeruginosa infection following intravitreal ranibizumab injection. AB - Purpose: To report the occurrence and management of severe infectious scleritis in a 75 year-old woman following intravitreal ranibizumab injection. Observations: A 75 year-old monocular woman receiving monthly intravitreal ranibizumab injection for wet age related macular degeneration in the left eye presented with severe dull pain, decreased vision, and scleral melt with discharge 2 weeks after her last injection. The dilated fundus exam was devoid of vitritis. The patient was admitted to our hospital for both diagnostic and therapeutic purposes. She was initially started on aggressive oral and topical antibiotics, but showed no significant improvement. The scleral cultures were positive for Pseudomonas aeruginosa. In view of the aggressive nature of her infection, intravenous antibiotics were added to the treatment regimen. The patient recovered her baseline visual function after two weeks of intravenous, oral and, topical antibiotics. Conclusions and importance: To our knowledge, this is the first case of anterior infectious necrotizing scleritis secondary to Pseudomonas aeruginosa infection following intravitreal ranibizumab injection. Clinicians performing intravitreal injections should have a high index of suspicion for iatrogenic infections including scleritis and endophthalmitis, as these infections require aggressive topical and systemic antibiotics as well as possible hospitalization. PMID- 29503940 TI - Preoperative and postoperative features of macular holes on en face imaging and optical coherence tomography angiography. AB - Purpose: To characterize and quantify the pre- and postoperative foveal structural and functional patterns in full-thickness macular holes. Methods: Subjects presenting with a full-thickness macular hole that had pre- and postoperative imaging were included. En face optical coherence tomography (OCT) and OCT angiography (OCTA) was performed. Foveal avascular zone (FAZ) area, macular hole size, number and size of perifoveal cysts were measured. Results: Five eyes from 5 patients were included in the study. The hole was closed in all eyes after the initial surgery. OCTA showed enlargement of the FAZ and delineation of the holes within the FAZ. Mean preoperative FAZ area was 0.41 +/- 0.104 mm2. Visual acuity was improved and mean FAZ area was reduced to 0.27 +/- 0.098 mm2 postoperatively (P < 0.05) with resolution of the macular hole and adjacent cystic areas. En face images of the middle retina showed a range of preoperative cystic patterns surrounding the hole. Smaller holes showed fewer but larger cystic areas and larger holes had more numerous but smaller cystic areas. Conclusions and importance: Quantitative evaluation of vascular and cystic changes following macular hole repair demonstrates the potential for recovery due to neuronal and vascular plasticity. Perifoveal microstructural patterns and their quantitative characteristics may serve as useful anatomic biomarkers for assessment of macular holes. PMID- 29503941 TI - Case series: Two cases of eyeball tattoos with short-term complications. AB - Purpose: To report two cases of eyeball tattoos with short-term post procedural complications. Observations: Case 1 is a 26-year-old Mexican man that developed orbital cellulitis and posterior scleritis 2 h after an eyeball tattoo. Patient responded satisfactorily to systemic antibiotic and corticosteroid treatment. Case 2 is a 17-year-old Mexican man that developed two sub-episcleral nodules in the ink injection sites immediately after the procedure. Conclusions and importance: Eyeball tattoos are performed by non-ophthalmic trained personnel. There are a substantial number of short-term risks associated with this procedure. Long-term effects on the eyes and vision are still unknown, but in a worst case scenario could include loss of vision or permanent damage to the eyes. PMID- 29503942 TI - Drainage and analysis of suprachoroidal fluid in a patient with acute systemic lupus erythematous. AB - Purpose: To describe a case of a patient with acute systemic lupus erythematous (SLE) causing choroidal effusions and to report a novel technique for evaluation of the choroidal fluid which sheds light on effusion pathogenesis. Observations: A 37 year-old woman was referred for decreased vision, eye pain and shortness of breath. The patient had bilateral angle closure glaucoma from choroidal effusions and bilateral pleural effusions. Work-up revealed new onset acute SLE. A technique for obtaining suprachoroidal fluid is described, and the fluid was analyzed using Light's criteria and found to be exudative in nature. Conclusions and importance: There has been speculation as to pathogenesis of choroidal effusions in a variety of conditions, and many authors believe the most likely process to be transudative. The exudative nature of the fluid in our patient suggests that choroidal effusions in acute SLE are likely caused by inflammation, and not secondary to hypoalbuminemia or another transudative process. Similar analyses of suprachoroidal fluid in other disease processes may help elucidate the underlying pathogenesis and may possibly guide treatment. PMID- 29503943 TI - Androgen receptor-positive ductal adenocarcinoma of the nasolacrimal duct: A case report. AB - Purpose: Primary ductal adenocarcinoma arising in the structures of the lacrimal apparatus is extremely rare, and the entity is considered a lacrimal counterpart of salivary duct carcinoma, of which the majority are known to express androgen receptor (AR). Less than 10 cases of AR-positive carcinomas of lacrimal gland or lacrimal sac have been described. Observations: We present a primary ductal adenocarcinoma with AR expression involving the nasolacrimal duct of a middle aged patient who had suffered from right eyelid swelling, diplopia and epiphora for 4 months. Although the tumor histologically resembled oncocytic carcinoma, electron microscopic examination did not show cytoplasmic accumulation of mitochondria, which excluded the diagnosis of oncocytic carcinoma with AR positivity. Conclusions and importance: We concluded that this is the first case of AR-positive ductal adenocarcinoma arising from nasolacrimal duct. It is possible that some of the previously documented oncocytic carcinomas of the lacrimal drainage system may include ductal adenocarcinomas with oncocytic features. PMID- 29503944 TI - Primary hepatoid adenocarcinoma of the orbit. AB - Purpose: To report a case of primary hepatoid adenocarcinoma of the orbit. Observations: An adult patient was referred for evaluation of an orbital mass. Histopathology of the orbital biopsy indicated a carcinoma with hepatoid features. Laboratory studies revealed normal liver function tests, elevated serum alpha-fetoprotein, and whole-body positron emission tomography/computed tomography scan showed no evidence of liver involvement or an alternative primary origin. Conclusions and importance: To the authors' knowledge, this is the first reported case of primary hepatoid adenocarcinoma of the orbit. PMID- 29503945 TI - Atypical Tolosa Hunt syndrome with bilateral sclerokeratitis and optic atrophy in Takayasu's arteritis. AB - Purpose: We report an interesting case of atypical Tolosa Hunt syndrome with bilateral Sclerokeratitis and optic atrophy in a patient with Takayasu's arteritis. Observations: A 31-year- old lady presented with severe retroorbital pain in the right eye and right sided headache of 2 weeks duration. She had a history of 6th and 7th nerve palsies which improved with oral corticosteroids. Her BCVA was no perception of light in OD and 6/6 in OS. Slitlamp examination showed bilateral old sclerokeratitis and fundus examination showed bilateral optic atrophy. Systemic examination revealed BP of 240/100 mm of hg in the right upper limb with absent pulsations in the left radial, bilateral femoral and dorsalis pedis arteries noted. CT aortic angiography confirmed the diagnosis of Takayasu's arteritis. Symptoms improved with oral corticosteroids and azathioprine, which was followed by a renal stenting procedure. At 1 year followup, she is doing well with no recurrences. Conclusions and importance: This case report presents a unique manifestation of atypical Tolosa Hunt syndrome in Takayasu's arteritis. To our knowledge, atypical Tolosa Hunt syndrome in Takayasu'arteritis has not been described in literature. PMID- 29503946 TI - Giant retinal pigment epithelial tear associated with fluid overload due to end stage diabetic kidney disease. AB - Purpose: To report a case of a giant retinal pigment epithelial (RPE) tear associated with fluid overload in a patient with diabetic macular edema (DME) and kidney disease. Observations: A 60-year-old man with type 2 diabetes mellitus and end-stage diabetic kidney disease who had gained weight because of fluid overload complained of a visual disturbance in the left eye that had started a few days earlier. The left fundus showed a RPE defect in two temporal quadrants under an extensive serous retinal detachment (SRD) with exacerbation of the original DME. Seven days later, he was admitted for severe edema and pleural effusion. No overt signs of congestive heart failure were noted. On admission, the RPE defect had markedly widened to involve the macula. Spectral-domain optical coherence tomography images showed substantial intraretinal fluid and an extensive SRD with rolled edges of the retinal pigment epithelium, which led to the diagnosis of a RPE tear. The fluid under the SRD was absorbed on the fourth hospital day and the substantial intraretinal fluid resolved on the eleventh day after systemic management of fluid overload only without ophthalmic treatment. The change in the appearance of the RPE area was minimal and the visual field defect remained even after 6 months. Conclusions and importance: A RPE tear may develop in association with fluid overload in patients with diabetes. PMID- 29503947 TI - Juvenile X-linked retinoschisis responsive to intravitreal corticosteroids. AB - Purpose: To report the case of an adult male with X-linked retinoschisis (XLRS) who presented with cystoid macular edema (CME) that responded consistently to treatment with intravitreal steroids. Observations: A 39 year old male with unilateral presentation of CME after repair of a retinal detachment secondary to XLRS responded initially to an injection of intravitreal triamcinolone acetonide (IVTA). Central subfield thickness on OCT was reduced. Three months later, the CME recurred and he was unresponsive to topical treatment so repeat IVTA was given, and the CME once again was reduced dramatically. After the next recurrence, intravitreal dexamethasone implant treatment was initiated and successful at treating recurrences in 3 month intervals for 5 additional injections. Finally, an intravitreal fluocinolone acetonide implant was surgically placed with control of CME. Conclusions and importance: Corticosteroids have never been reported to be effective in CME related to XLRS. Here, we document a case of a man who successfully had decrease of intraretinal fluid and schisis with treatment of intravitreal corticosteroids as demonstrated by spectral domain optical coherence tomography. PMID- 29503948 TI - Nonarteritic anterior ischemic optic neuropathy associated with interferon and ribavirin in a patient with hepatitis C. AB - Purpose: To report a case of a temporal artery biopsy negative anterior ischemic optic neuropathy associated with a recently completed course of pegylated interferon 2 alpha with ribavirin for chronic hepatitis C. Observations: Despite the early presentation with symptoms and prompt treatment with systemic intravenous steroids the patient experienced deterioration of their optic neuropathy over the following few days. Although nonarteritic anterior ischemic optic neuropathy is a common disorder with known risk factors, the timing of onset of symptoms in our patient was suggestive of a possible etiology related to treatment with ribavirin and interferon 2 alpha, as found in the previously reported cases. Conclusions and importance: There have been a few reported cases of the association between the use of interferon/ribavirin for treatment of chronic hepatitis with nonarteritic anterior ischemic optic neuropathy. In these cases stopping the drug caused some improvement of symptoms or halting the progression of optic neuropathy. Having reviewed the literature on previous cases, we postulate that there may be a dose related reaction to explain the delay and deterioration of vision in some cases despite stopping the drugs. We also advise that any person who is started on this treatment for chronic hepatitis are appropriately counselled as to the potential optic nerve side effect of the drug, based on the evidence reported in the literature. PMID- 29503949 TI - Cystic mucosa-associated lymphoid tissue lymphoma of lacrimal gland associated with vision loss: A case report. AB - Purpose: To report an atypical case of cystic extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) of lacrimal gland associated with vision loss. Observations: An 89-year-old woman was presented with a rapidly progressing proptosis, lagophthalmos, and vision loss. Endophthalmitis was also present. Computed tomography scan images showed a hyperdense mass with hypodense cystic areas occupying the superolateral orbit, which displaced the globe antero-inferiorly with optic nerve compression and stretching. An erosion to the adjacent superior and lateral orbital walls was also demonstrated. Complete tumor excision was performed via upper transconjunctival orbitotomy concurrently with enucleation. The immunohistopathological diagnosis was MALT lymphoma. Conclusions and importance: This case emphasizes the importance of considering lymphoma in the differential diagnosis of a cystic superolateral orbital mass. PMID- 29503950 TI - Surgical interventions for late ocular complications of relapsing polychondritis. AB - Purpose: To report a case of surgical interventions for a patient with relapsing polychondritis who presented with late ocular complications. Observations: A 44 year-old male was diagnosed to have relapsing polychondritis on the basis of recurrent acute auricular chondritis, deformity of the ear, saddle nose deformity and painful nasal chondritis, acute ocular inflammation with conjunctivitis, episcleritis and keratouveitis, laryngotracheal chondritis, erythema nodosum in the skin, a history of polyarthritis, and abnormal blood examination findings. The acute ocular and auricular inflammation was resolved with oral corticosteroid treatment. Intraocular pressure (IOP) of the left eye was 60 mmHg as measured by Goldmann applanation tonometer. Gonioscopic observation revealed the presence of peripheral anterior synechiae and plateau iris configuration. Express drainage screw implantation was applied to the left eye, because topical and systemic medicines failed to decrease the IOP. After 12 months, complicated cataract aggravated in the right eye, and phacoemulsification operation was performed with corticosteroids administered during the perioperative period. His corrected visual acuity was 20/20 for the right eye, and the IOP remained below 21 mmHg for the left eye. The patient has been healthy, without any recurrence, for 36 months. Conclusions and importance: The present case of relapsing polychondritis is the first to be reported wherein late ocular complications were alleviated by surgical interventions. Routine use of corticosteroids is necessary for successful anti-glaucoma and phacoemulsification operations. PMID- 29503951 TI - Intraocular juvenile xanthogranuloma of the iris in an adult patient. AB - Purpose: Juvenile xanthogranuloma (JXG) is a rare histiocytic skin disease primarily of young children, which may also affect ocular structures and in particular the iris. Observations: This is a case report of a fifty-year-old patient without skin lesions showing a progressive decrease of visual acuity, iris vascularization and a yellowish iris tumor in the iridocorneal angle of his right eye. Treatment with topical and systemic prednisolone led to full recovery of visual acuity, tumor regression and restitutio ad integrum. Conclusions and importance: Although the juvenile xanthogranuloma is a very rare skin disease of young children, it may also affect the eye and in particular the iris in adult patients. There exists no standard treatment, the first-line therapy in most cases, however, is topical and systemic prednisolone application. PMID- 29503952 TI - Clinical features of a toddler with bilateral bullous retinoschisis with a novel RS1 mutation. AB - Purpose: To report the clinical and genetic findings of a male toddler who presented bilateral bullous retinoschisis with a novel RS1 mutation. Observations: This is an observational case report of a patient referred to our hospital with esotropia. A comprehensive ophthalmic examination was performed with the boy (age, 1 year 4 months) under general anesthesia that included fundus examinations, fluorescein angiography (FA), swept-source optical coherence tomography (SS-OCT), and full-field electroretinography (FF-ERG). Genetic analysis of the coding region in the RS1 gene was performed by Sanger sequencing for the patient and mother. There was a family history of X-linked retinoschisis (XLRS). Fundus examinations and FA showed bullous retinoschisis bilaterally in the inferior retina. The SS-OCT images showed two kinds of schisis in the inner nuclear layer (INL) and more proximally. In general, the inner plexiform layer, ganglion cell layer, and retinal nerve fiber layer are in the proximal INL; however, in this case there was hyperreflective tissue with a rough surface instead of normal retinal layers. In addition, in the schisis cavity between the hyperreflective tissue and separated retina, a number of hyperreflective fiber like strands arose from the hyperreflective tissue and extended to the schisis cavity. During the follow-up period, the bullous retinoschisis collapsed spontaneously in the right eye. FF-ERG showed a reduced b-wave and relatively preserved a-wave in all components. Genetic analysis showed a novel RS1 mutation (c.185_186insT, p.E62DfsX24 in exon 4) in the patient and mother. Conclusions and importance: We report the detailed retinal structure in a genetically identified case of bullous retinoschisis. The notable finding was that the cavity of bullous retinoschisis contained a number of fiber-like strands as observed in the cavity of typical retinoschisis. PMID- 29503953 TI - A rare case of Phialemonium obovatum keratitis. AB - Purpose: We report a rare case of Phialemonium obovatum fungal keratitis in a patient sustaining a corneal laceration from impact with a piece of moldy plaster. Observations: The patient was treated with topical voriconazole with resolution of active keratitis and formation of a stromal scar. The patient's final visual acuity was 20/20 in the affected eye. Conclusions and importance: There is only one other case of Phialemonium obovatum keratitis reported in the literature. The patient in the previous case required amniotic membrane transplantation for persistent stromal melting with resultant visual acuity of hand motions only. The present case demonstrates that the early use of topical antifungal medication with close follow-up can prevent corneal perforation and result in excellent visual acuity. PMID- 29503954 TI - Mucogenic glaucoma in a child. AB - Purpose: We describe a case of secondary open-angle glaucoma due to mucin producing congenital iris stromal cyst in a 4 year old patient. Observations: A 4 year old female patient with a history of unilateral congenital iris stromal cyst presented with sudden-onset eye pain and redness, with markedly elevated intraocular pressure and evidence of early optic nerve damage. During the examination under anesthesia, the anterior chamber angle was open and there was no evidence of pupillary block. Ultrasound biomicroscopy revealed mildly echogenic substance filling the anterior chamber suspicious of mucoid material, which was verified by the inability to aspirate the material through a 25 gauge needle. The iris cyst was excised, and the intraocular pressure normalized spontaneously. Pathologic examination confirmed a mucin-secreting iris cyst lined with goblet cells and confirmed the mucogenic mechanism. Conclusions and importance: This is the first reported case of mucogenic glaucoma in a pediatric patient. This rare entity should remain on the differential diagnoses of childhood glaucoma associated with nonacquired ocular anomalies. Surgical excision of the iris cyst may be curative. PMID- 29503955 TI - Nonorganic visual loss in a child due to school bullying. AB - Purpose: To describe a case of a child with nonorganic visual loss due to school bullying. Observations: An eight-year-old boy presented with bilateral painless vision loss for a few days. His best corrected visual acuity (BCVA) was 20/200 in the right eye and 20/140 in the left eye. Color vision was normal. Fundoscopy, visual fields, electroretinography, electrooculography and visual evoked potentials were within normal limits. A nonorganic (psychogenic) cause of visual loss was suspected. A conversation with his parents and school teachers revealed that he was undergoing intense school bullying. Discussion between the boy and his parents and teachers' awareness helped in relieving the boy's stress. After two weeks BCVA was 20/20 bilaterally. Conclusions and importance: School bullying is a potential cause of nonorganic vision loss in children. Correct diagnosis, and support by the parents and teachers might rapidly alleviate the symptoms. PMID- 29503956 TI - Multifocal choroiditis as the first sign of systemic sarcoidosis associated with pembrolizumab. AB - Purpose: To report a case of bilateral panuveitis with multifocal choroiditis associated with a systemic sarcoidosis unmasked by pembrolizumab. Case report: A 68-years old woman with a history of metastatic melanoma treated by pembrolizumab consulted for bilateral blurred vision. The ophthalmologic examination revealed a bilateral anterior uveitis with cells in the anterior chamber and granulomatous keratic precipitates, vitreous cells and multifocal choroiditis confirmed by indocyanine green angiography. The systemic workup revealed pulmonary sarcoidosis confirmed by biopsy. Conclusions and importance: Pembrolizumab is an immune checkpoint inhibitor therapy used in the treatment of metastatic melanoma. We report a pembrolizumab-associated sarcoidosis revealed by a panuveitis with multifocal choroiditis. Physicians should be aware of the potential inflammatory and autoimmune disease that may be induced by immunomodulatory therapies. PMID- 29503957 TI - Extraocular muscle damage from dental implant penetration to the orbit. AB - Purpose: To demonstrate an unusual case of orbital trauma due to dental surgery complication. Observations: An elderly patient who underwent dental implantation to the zygomatic bone was hospitalized in the ophthalmology department with impaired abduction of her right eye, also evident on ocular examination. Head computed tomography demonstrated damage to the lateral rectus and to the inferior oblique muscles. Clinical assessment determined these muscles could not be repaired and reattached. The extent of irreversible damage in the patient was permanent limitation in movement of her affected eye with subsequent strabismus. Conclusions and importance: Accurate pre-operative planning of dental zygomatic implant insertion, as well as selecting the size and direction of the implant, are imperative. Moreover, performing surgery in multidisciplinary centers with oculofacial plastic surgeons in such cases, may reduce risk of this complication, make it a safer procedure, and allow immediate treatment when required. PMID- 29503958 TI - Deer tick masquerading as pigmented conjunctival lesion. AB - Purpose: Conjunctival adherence of a tick is an uncommon event with few reports previously cited in the literature. We report a unique case of tick penetration, specifically a black-legged deer tick (Ixodes scapularis), into the conjunctiva. Observations: This patient experienced a 3-week history of unilateral mild ocular pain, decreased vision, and pigmented lesion of her right eye. Slit lamp examination demonstrated a tick attached to the conjunctiva. Pathology confirmed the insect exoskeleton. Visual appreciation of the tick demonstrated probable deer tick larval stage given the shape, size, pigmentation pattern and geographic location of the specimen. Polymyxin-trimethoprim eye drops were prescribed for use three times daily and loteprednol twice daily. Conclusions and importance: Despite the low risk for Lyme disease, which is endemic to the Adirondack region where the patient was affected, doxycycline was prescribed for prophylaxis. In any case of suspected tick penetration to the ocular surface, immediate ophthalmologic consultation and prompt removal via the method mentioned above is recommended, as well as attention paid to the Infectious Diseases Society of America guidelines regarding prophylaxis. PMID- 29503959 TI - Ocular histopathology in Eastern equine encephalitis: A case report. AB - Purpose: To describe the ophthalmic symptoms and histopathological findings in a human case of Eastern equine encephalitis (EEE). Observations: The patient was a septuagenarian male whose presentation and clinical course were thought to be most consistent with viral meningoencephalitis. ELISA suggested recent infection with EEE virus. Microscopic analysis of the brain demonstrated perivascular lymphohistiocytic cuffing which was consistent with viral type encephalitis. Similarly, both eyes manifested a lymphohistiocytic infiltrate in the retina and optic nerve and a reduced number of ganglion cells. Conclusions and importance: To our knowledge, this is the first report of ophthalmological and ocular pathology observations in an EEE patient. Interestingly, the inflammatory findings in the retina are reminiscent of the central nervous system effects of EEE virus. These findings are relevant given the recent epidemic of microcephaly and ophthalmic complications secondary to another arboviral virus, the Zika virus. PMID- 29503960 TI - A case of fungal keratitis and endophthalmitis post penetrating keratoplasty resulting from fungal contamination of the donor cornea. AB - Purpose: Fungal infections post keratoplasty due to contamination of the donor corneal graft have become important issues that need to be addressed. Here we report a case of fungal keratitis and endophthalmitis post penetrating keratoplasty (PKP) due to fungal contamination of the donor corneal graft. Observations: We present a 52-year-old male who underwent PKP with a donor corneal graft that was later found to be contaminated with fungus. At 4-weeks postoperative, infectious infiltrates suddenly appeared at the border between the host and donor corneal graft, and endophthalmitis concomitantly occurred. A culture of the remnant donor corneoscleral rims and the vitreous fluid obtained during vitreous surgery was found to be positive for Candida albicans. At 6 months post vitreous surgery and intensive anti-fungal medical treatment, both corneal infiltrates and vitreous opacity completely disappeared, and the patient's best-corrected visual acuity recovered to 20/40, with a transparent cornea. Conclusions and importance: The findings of this case show that prompt intensive medical treatment and surgical intervention effectively saved the vision in a patient with fungal keratitis and endophthalmitis due to contamination of the donor corneal graft. PMID- 29503961 TI - Shingles as the underlying cause of orbital myositis in an adolescent: A case report. AB - Purpose: Orbital myositis is characterized by pain with eye movements, gaze restriction, diplopia, and enlargement of extraocular muscles on imaging. Varicella zoster virus (VZV) is an extremely rare cause of the disease in the elderly and has never been reported in a patient younger than forty-five years old such as the adolescent described herein. We present this case to raise awareness of an entity that will likely become more prevalent due to current vaccine strategies. Observation: We present the case of a 13-year-old girl with VZV-associated orbital myositis and meningitis that had a quick and complete recovery following IV acyclovir and oral steroids. Conclusions and importance: In conclusion, orbital myositis is an extremely rare complication of facial VZV infections. Our case highlights the importance of prompt detection and treatment in the pediatric population. PMID- 29503962 TI - Intraocular and extraocular hemorrhage associated with ligature release of non valved glaucoma drainage implant. AB - Purpose: To report a rare complication of non-valved glaucoma drainage device surgery. Observations: An 85-year-old pseudophakic white male presented with painless vision loss and bloody tears. He was 5 weeks removed from uncomplicated non-valved glaucoma drainage device (Baerveldt 101-350, [AMO, Santa Clara, CA]). There was serosanguinous discharge without apparent source and a 25% layering hyphema in the anterior chamber. The tube was unobstructed in the anterior chamber and not abutting the iris. There was no presence of neovascularization or other abnormal vessels in the angle. After clearing of the hyphema, the patient had persistent vitreous hemorrhage necessitating pars plana vitrectomy. No source of hemorrhage was identified. Conclusions and importance: This is the first report of a rare occurrence of intraocular and extraocular hemorrhage associated following spontaneous release of ligature of a non-valved glaucoma drainage implant. The presumed mechanism was sudden shallowing of the anterior chamber resulting in the tube irritating uveal vasculature. We do not have an explanation for the extraocular blood. PMID- 29503963 TI - Amiodarone: A potential risk factor for retinal phototoxicity. AB - Purpose: To report the only known case, to our knowledge, of amiodarone induced retinal phototoxicity following vitrectomy surgery. Observations: A 66-year-old male presented with visual acuity of 20/150 OS secondary to an epiretinal membrane (ERM). Patient was on oral amiodarone for atrial fibrillation. Baseline spectral domain optical coherence tomography (SD-OCT) revealed an ERM with retinal thickening and schisis. The patient underwent an uncomplicated pars plana vitrectomy and membrane peel using standard vitrectomy settings and illumination. Triamcinolone was used to stain the ERM intraoperatively. ICG was not used. On post-operative day one, vision was count finger (CF) at 1'. At post-operative week one, vision was unchanged and SD-OCT showed macular edema. At post-operative month one, vision remained CF at 1' and macular edema resolved with residual pigmentary changes and subretinal fibrosis resembling phototoxic damage. SD-OCT at one month showed resolution of macular edema, retinal pigment epithelium hyperplasia and an indistinct ellipsoid layer. Fluorescein angiography did not show any neovascularization. At three month follow-up, patient's vision, exam and OCT findings remained unchanged. Conclusions and importance: Many pharmacologic agents have the ability to alter a patient's sensitivity to solar or artificial radiation. Drugs act as photosensitizers that lead to photochemical damage. Amiodarone has been reported to have such photosensitizing properties in humans. This report describes a case of retinal phototoxicity from intraoperative light exposure photosensitized by systemic amiodarone use. PMID- 29503964 TI - Choroidal neovascularization secondary to tuberculosis: Presentation and management. AB - Purpose: While there are many known etiologies of choroidal neovascularization (CNV), tuberculosis is not a well-known causative agent. In this case series, we highlight CNV occurring secondary to tuberculous chorioretinitis, its presentation, and its management. Observations: We retrospectively reviewed the charts and imaging of four patients who presented with presumed tuberculous chorioretinitis and CNV. Three of these patients had signs of intraocular inflammation and were also found to have active macular CNV. The one remaining patient had chorioretinal scars from prior posterior uveitis and previously treated macular CNV membranes. The three patients with active disease were started on anti-tuberculosis medications and oral corticosteroids, and they also received intravitreal anti-vascular endothelial growth factor (VEGF) injections as needed for the CNV. There was a significant improvement in the clinical course of all three patients with active disease-the intraocular inflammation subsided, and CNV recurrences were mitigated. Upon completion of systemic treatment, all patients have remained quiescent. Conclusions and importance: Our findings demonstrate that CNV may occur in the course of tuberculous chorioretinitis with marked loss of vision, and management with anti-tuberculosis medications, oral corticosteroids, and intravitreal anti-VEGF injections results in notable improvement in their clinical course. PMID- 29503965 TI - Unusually very late-onset new growth of intraocular retinoblastoma: A case report and review of literature. AB - Purpose: To report a patient who presented with a very late-onset new growth of intraocular retinoblastoma, which occurred 11 years after the initial combined treatment. Observations: A 12-year-old monoophthalmic female patient presented with bilateral familial retinoblastoma showing new growth of intraocular tumor after 11 years of complete regression following combined local and systemic treatments. The new tumor growth was treated with diode laser transpupillary thermotherapy, ruthenium-106 plaque radiotherapy and adjuvant intravenous chemotherapy and the tumor regressed. Conclusions and importance: Despite initial satisfactory treatment and complete regression of the tumor, very late-onset new growth of intraocular retinoblastoma can occur. Hence, life-long follow-up in all patients with retinoblastoma is warranted, given the risk for new tumor formation even later in life. To our knowledge, this is the first report of new growth of intraocular retinoblastoma after regression for more than a decade. PMID- 29503966 TI - Abnormality of retinal arterial velocity profiles using Doppler Fourier-domain optical coherence tomography in a case of Takayasu's arteritis with aortic regurgitation. AB - Purpose: To evaluate the retinal microcirculation using a segmental-scanning Doppler optical coherence tomography (DOCT) flowmeter in a patient with Takayasu's arteritis (TA) with aortic valve regurgitation (AR). Observations: We measured the retinal blood velocity (V), retinal blood flow (RBF), and retinal blood velocity profiles (RBVP) of the major retinal arterioles using a DOCT flowmeter. The arteries were measured at the straight portion 1 disc diameter from the optic disc. Horizontal velocity profiles were extracted to evaluate the RBVP during one cardiac cycle. A patient with TA with stage 2 Takayasu retinopathy (TR) and AR, had normal RBF and V, and the RBVP had a parabolic pattern in the systolic phase. However, the V was very slow and the RBVP had an abnormal pattern in the diastolic phase. Conclusions and importance: The current study showed for the first time that segmental-scanning DOCT flowmeter enables evaluation of an abnormal flow pattern of the RVBP in the retinal arterioles in a patient with TA and AR. Measurement of the retinal arterial blood flow may detect aortic valve dysfunction and shed light on the pathogenesis of TR. PMID- 29503967 TI - Improvements of visual function and outer retinal morphology following spontaneous regression of cancer in anti-recoverin cancer-associated retinopathy. AB - Purpose: To report an anti-recoverin antibody-positive cancer-associated retinopathy (anti-recoverin CAR) patient with remarkable improvements of visual function and outer retinal morphology following spontaneous regression of cancer. Observations: A 65-year-old woman with small cell lung carcinoma developed progressive, bilateral vision loss with diffuse loss of the ellipsoid zone at the macula on optical coherence tomography and marked reduced responses of a- and b waves on electroretinography. Western blot analysis led to a diagnosis of anti recoverin CAR. The visual function and outer retinal morphology gradually improved following spontaneous regression of the cancer and the initiation of systemic corticosteroid. Subsequent intermittent chemotherapy and continuation of corticosteroid maintained reduction of the cancer and prevented the recurrence of CAR, with preservation of improvements of the visual function and macular outer retinal morphology. Conclusions and importance: These results suggest that requirement for obtaining good visual prognosis in CAR patients is to make the cancer regress prior to falling into photoreceptor apotosis. PMID- 29503968 TI - Environmental Xenobiotic Exposure and Autoimmunity. AB - Susceptibility to autoimmune diseases is dependent on multigenic inheritance, environmental factors, and stochastic events. Although there has been substantial progress in identifying predisposing genetic variants, a significant challenge facing autoimmune disease research is the identification of the specific events that trigger loss of tolerance, autoreactivity and ultimately autoimmune disease. Accordingly, studies have indicated that a wide range of extrinsic factors including drugs, chemicals, microbes, and other environmental factors can induce autoimmunity, particularly systemic autoimmune diseases such as lupus. This review describes a class of environmental factors, namely xenobiotics, epidemiologically linked to human autoimmunity. Mechanisms of xenobiotic autoimmune disease induction are discussed in terms of human and animal model studies with a focus on the role of inflammation and the innate immune response. We argue that localized tissue damage and chronic inflammation elicited by xenobiotic exposure leads to the release of self-antigens and damage-associated molecular patterns as well as the appearance of ectopic lymphoid structures and secondary lymphoid hypertrophy, which provide a milieu for the production of autoreactive B and T cells that contribute to the development and persistence of autoimmunity in predisposed individuals. PMID- 29503969 TI - Factors Associated with Prevalent Diabetic Retinopathy in Chinese Americans: The Chinese American Eye Study. AB - Objective: To identify factors associated with prevalent diabetic retinopathy (DR) among Chinese American adults with type 2 diabetes mellitus (T2DM), and to compare these factors to ones previously described for a population-based sample of Latinos with a higher DR prevalence. Design: Population-based cross-sectional study. Participants: 4582 Chinese Americans aged 50 or older residing in Monterey Park, California. Methods: Participants completed an in-home questionnaire on socio-demographic status and medical history, and a comprehensive clinical eye examination, using the same protocol implemented in the Los Angeles Latino Eye Study. Fundus photographs from 7 Early Treatment Diabetic Retinopathy fields were graded in a masked manner using a modified Airlie House grading system to assess presence and severity of DR. Logistic regression analyses based on a conceptual model of DR risk identified factors associated with prevalent DR. Main Outcome Measures: Odds ratios (ORs) and 95% confidence intervals (CIs) for factors associated with DR and vision-threatening DR (VTDR). Results: In total, 238 participants were diagnosed with any DR; 27 of these were classified as having VTDR. Both, any DR and VTDR showed statistically significant positive associations with T2DM duration (OR5-9 years = 1.24, OR10-14 years = 2.07, OR15+years = 3.99), glycosylated hemoglobin (HbA1c) (OR6.5-6.9% = 1.33, OR7-7.9% = 1.86, OR8%+ = 3.22), systolic blood pressure (SBP) (ORper 10mmHg+ = 1.19), and insulin treatment (ORinsulin+ = 2.44). For VTDR, we also found novel associations with antihypertensive drugs (OR: 0.18; 95% CI: 0.06-0.61) and statins (OR: 4.96; 95% CI: 1.60-16.41). Chinese Americans and Latinos had a nearly identical DR probability based on HbA1c and SBP. However, Latinos had a higher DR probability at every year of duration of T2DM (>= 5 years). Conclusions: While we observed an overall lower DR prevalence in Chinese Americans than in Latinos (35.8% of individuals with TD2M in Chinese Americans versus 42.0% in Latinos), our data indicate that the impact of increasing HbA1c and SBP on DR probability is incrementally the same in both populations. However, increasing T2DM duration is associated with higher DR probability in Latinos than Chinese Americans, even after controlling for other known predictors. Novel factors associated with VTDR include antihypertensive drugs and statins. However, to determine if these drugs impact VTDR susceptibility, we need longitudinal data and more cases. PMID- 29503970 TI - Aptamer-Based Impedimetric Assay of Arsenite in Water: Interfacial Properties and Performance. AB - In this work, we explore the use of electrochemical methods (i.e., impedance) along with the arsenic-specific aptamer (ArsSApt) to fabricate and study the interfacial properties of an arsenic (As(III)) sensor. The ArsSApt layer was self assembled on a gold substrate, and upon binding of As(III), a detectable change in the impedimetric signal was recorded because of conformational changes at the interfacial layer. These interfacial changes are linearly correlated with the concentration of arsenic present in the system. This target-induced signal was utilized for the selective detection of As(III) with a linear dynamic range of 0.05-10 ppm and minimum detectable concentrations of ca. 0.8 MUM. The proposed system proved to be successful mainly because of the combination of a highly sensitive electrochemical platform and the recognized specificity of the ArsSApt toward its target molecule. Also, the interaction between the ArsSApt and the target molecule (i.e., arsenic) was explored in depth. The obtained results in this work are aimed at proving the development of a simple and environmentally benign sensor for the detection of As(III) as well as in elucidating the possible interactions between the ArsSApt and arsenic molecules. PMID- 29503971 TI - NLL-Assisted Multilayer Graphene Patterning. AB - The range of applications of diverse graphene-based devices could be limited by insufficient surface reactivity, unsatisfied shaping, or null energy gap of graphene. Engineering the graphene structure by laser techniques can adjust the transport properties and the surface area of graphene, providing devices of different nature with a higher capacitance. Additionally, the created periodic potential and appearance of the active external/inner/edge surface centers determine the multifunctionality of the graphene surface and corresponding devices. Here, we report on the first implementation of nonlinear laser lithography (NLL) for multilayer graphene (MLG) structuring, which offers a low cost, single-step, and high-speed nanofabrication process. The NLL relies on the employment of a high repetition rate femtosecond Yb fiber laser that provides generation of highly reproducible, robust, uniform, and periodic nanostructures over a large surface area (1 cm2/15 s). NLL allows one to obtain clearly predesigned patterned graphene structures without fabrication tolerances, which are caused by contacting mask contamination, polymer residuals, and direct laser exposure of the graphene layers. We represent regularly patterned MLG (p-MLG) obtained by the chemical vapor deposition method on an NLL-structured Ni foil. We also demonstrate tuning of chemical (wettability) and electro-optical (transmittance and sheet resistance) properties of p-MLG by laser power adjustments. In conclusion, we show the great promise of fabricated devices, namely, supercapacitors, and Li-ion batteries by using NLL-assisted graphene patterning. Our approach demonstrates a new avenue to pattern graphene for multifunctional device engineering in optics, photonics, and bioelectronics. PMID- 29503972 TI - Chemical Reactive Anchoring Lipids with Different Performance for Cell Surface Re engineering Application. AB - Introduction of selectively chemical reactive groups at the cell surface enables site-specific cell surface labeling and modification opportunity, thus facilitating the capability to study the cell surface molecular structure and function and the molecular mechanism it underlies. Further, it offers the opportunity to change or improve a cell's functionality for interest of choice. In this study, two chemical reactive anchor lipids, phosphatidylethanolamine poly(ethylene glycol)-dibenzocyclooctyne (DSPE-PEG2000-DBCO) and cholesterol-PEG dibenzocyclooctyne (CHOL-PEG2000-DBCO) were synthesized and their potential application for cell surface re-engineering via lipid fusion were assessed with RAW 264.7 cells as a model cell. Briefly, RAW 264.7 cells were incubated with anchor lipids under various concentrations and at different incubation times. The successful incorporation of the chemical reactive anchor lipids was confirmed by biotinylation via copper-free click chemistry, followed by streptavidin fluorescein isothiocyanate binding. In comparison, the cholesterol-based anchor lipid afforded a higher cell membrane incorporation efficiency with less internalization than the phospholipid-based anchor lipid. Low cytotoxicity of both anchor lipids upon incorporation into the RAW 264.7 cells was observed. Further, the cell membrane residence time of the cholesterol-based anchor lipid was evaluated with confocal microscopy. This study suggests the potential cell surface re-engineering applications of the chemical reactive anchor lipids. PMID- 29503973 TI - Novel FR-900493 Analogues That Inhibit the Outgrowth of Clostridium difficile Spores. AB - The spectrum of antibacterial activity for the nucleoside antibiotic FR-900493 (1) can be extended by chemical modifications. We have generated a small focused library based on the structure of 1 and identified UT-17415 (9), UT-17455 (10), UT-17460 (11), and UT-17465 (12), which exhibit anti-Clostridium difficile growth inhibitory activity. These analogues also inhibit the outgrowth of C. difficile spores at 2* minimum inhibitory concentration. One of these analogues, 11, relative to 1 exhibits over 180-fold and 15-fold greater activity against the enzymes, phospho-MurNAc-pentapeptide translocase (MraY) and polyprenyl phosphate GlcNAc-1-phosphate transferase (WecA), respectively. The phosphotransferase inhibitor 11 displays antimicrobial activity against several tested bacteria including Bacillus subtilis, Clostridium spp., and Mycobacterium smegmatis, but no growth inhibitory activity is observed against the other Gram-positive and Gram-negative bacteria. The selectivity index (Vero cell cytotoxicity/C. difficileantimicrobial activity) of 11 is approximately 17, and 11 does not induce hemolysis even at a 100 MUM concentration. PMID- 29503974 TI - Spectroscopic Study of a Cinchona Alkaloid-Catalyzed Henry Reaction. AB - A spectroscopic study of an organocatalytic Henry reaction between nitroalkanes and aldehydes catalyzed by a quinidine-derived Cinchona alkaloid is described. The binding modes of the reaction substrates are investigated using electronic absorption and fluorescence spectroscopy and further corroborated by nuclear magnetic resonance measurements. Aldehydes are shown to associate with both the 6'-OH group and the basic quinuclidine nitrogen of the catalyst, whereas nitroalkanes do not exhibit a clear binding mode. Reaction progress kinetic analysis reveals that the reaction is first-order in both of the substrates and the catalyst. Second, the reaction proceeds approximately five times faster in the excess of the nitroalkanes than in the excess of the aldehydes, suggesting that binding of the aldehydes results in the inhibition of the catalyst. Aldehydes deactivate the basic quinuclidine site, thus suppressing the deprotonation of the nitroalkanes which is the proposed initial step in the reaction cycle. PMID- 29503975 TI - Manipulation of the Geometry and Modulation of the Optical Response of Surfactant Free Gold Nanostars: A Systematic Bottom-Up Synthesis. AB - Among plasmonic nanoparticles, surfactant-free branched gold nanoparticles have exhibited exceptional properties as a nanoplatform for a wide variety of applications ranging from surface-enhanced Raman scattering sensing and imaging applications to photothermal treatment and photoimmunotherapy for cancer treatments. The effectiveness and reliability of branched gold nanoparticles in biomedical applications strongly rely on the consistency and reproducibility of physical, chemical, optical, and therapeutic properties of nanoparticles, which are mainly governed by their morphological features. Herein, we present an optimized bottom-up synthesis that improves the reproducibility and homogeneity of the gold-branched nanoparticles with desired morphological features and optical properties. We identified that the order of reagent addition is crucial for improved homogeneity of the branched nature of nanoparticles that enable a high batch-to-batch reproducibility and reliability. In addition, a different combination of the synthesis parameters, in particular, additive halides and concentration ratios of reactive Au to Ag and Au to Au seeds, which yield branched nanoparticle of similar localized surface plasmon resonances but with distinguishable changes in the dimensions of the branches, was realized. Overall, our study introduces the design parameters for the purpose-tailored manufacturing of surfactant-free gold nanostars in a reliable manner. PMID- 29503976 TI - Role of Polymorphism and Thin-Film Morphology in Organic Semiconductors Processed by Solution Shearing. AB - Organic semiconductors (OSCs) are promising materials for cost-effective production of electronic devices because they can be processed from solution employing high-throughput techniques. However, small-molecule OSCs are prone to structural modifications because of the presence of weak van der Waals intermolecular interactions. Hence, controlling the crystallization in these materials is pivotal to achieve high device reproducibility. In this perspective article, we focus on controlling polymorphism and morphology in small-molecule organic semiconducting thin films deposited by solution-shearing techniques compatible with roll-to-roll systems. Special attention is paid to the influence that the different experimental deposition parameters can have on thin films. Further, the main characterization techniques for thin-film structures are reviewed, highlighting the in situ characterization tools that can provide crucial insights into the crystallization mechanisms. PMID- 29503977 TI - Preclinical and Clinical Evidence of DNA Methylation Changes in Response to Trauma and Chronic Stress. AB - Exposure to chronic stress, either repeated severe acute or moderate sustained stress, is one of the strongest risk factors for the development of psychopathologies such as post-traumatic stress disorder and depression. Chronic stress is linked with several lasting biological consequences, particularly to the stress endocrine system but also affecting intermediate phenotypes such as brain structure and function, immune function, and behavior. Although genetic predisposition confers a proportion of the risk, the most relevant molecular mechanisms determining those susceptible and resilient to the effects of stress and trauma may be epigenetic. Epigenetics refers to the mechanisms that regulate genomic information by dynamically changing the patterns of transcription and translation of genes. Mounting evidence from preclinical rodent and clinical population studies strongly support that epigenetic modifications can occur in response to traumatic and chronic stress. Here, we discuss this literature examining stress-induced epigenetic changes in preclinical models and clinical cohorts of stress and trauma occurring early in life or in adulthood. We highlight that a complex relationship between the timing of environmental stressors and genetic predispositions likely mediate the response to chronic stress over time, and that a better understanding of epigenetic changes is needed by further investigations in longitudinal and postmortem brain clinical cohorts. PMID- 29503978 TI - The Neurobiological Mechanisms of Generalized Anxiety Disorder and Chronic Stress. AB - Two classification systems are now at the forefront of clinical psychiatric research: (1) Diagnostic and Statistical Manual, Fifth Edition and (2) the National Institutes of Mental Health Research Domain Criteria. Herein, we propose that these two classification systems are complementary rather than mutually exclusive, and when combined provide important information for understanding aspects of the pathophysiology related to Generalized Anxiety Disorder (GAD). The neurobiological literature for GAD and one relevant research domain criteria component, sustained threat, are reviewed from multiple units of analysis (genetic, neuroimaging, neuroendocrine, and psychophysiological). It is hypothesized that generating a comprehensive, biologically based understanding of the relationship between GAD, sustained threat, and the measureable units of analysis will provide information critical to design the most effective treatments. PMID- 29503980 TI - Biochemical and Histopathological Evaluation of Graphene Oxide in Sprague-Dawley Rats. AB - Graphene and its derivatives are promising material for important biomedical applications due to their versatility. A detailed comprehensive study of the toxicity of these materials is required in context with the prospective use in biological setting. We investigated toxicity of Graphene Oxide (GO) in rats following exposure with respect to hepatotoxicity and oxidative stress biomarkers. Four groups of five male rats were orally administered GOs, once a day for five days, with doses of 10, 20 and 40mg/Kg GO. A control group consisted of five rats. Blood and liver were collected 24h after the last treatment following standard protocols. GO's exposure increased induction of Reactive Oxygen Species (ROS), activities of liver enzymes (Alanine ALT, Aspartate AST, Alkaline Phosphates ALP), concentration of Lipid Hydro Peroxide (LHP) and morphological alterations of liver tissue in exposed groups compared to control. The highest two doses, 20 and 40mg/kg, showed statistically significant (p<0.05) increases in the induction of ROS, activities of ALT, ALP, LHP concentration, and morphological alterations of liver tissue compared to control. However, AST activity showed no effect. The results of this study demonstrate that GO may be hepatotoxic, and its toxicity might be mediated through oxidative stress. PMID- 29503979 TI - Whole exome analyses to examine the impact of rare variants on left ventricular traits in African American participants from the HyperGEN and GENOA studies. AB - Left ventricular (LV) hypertrophy, highest in prevalence among African Americans, is an established risk factor heart failure. Several genome wide association studies have identified common variants associated with LV-related quantitative traits in African Americans. To date, however, the effect of rare variants on these traits has not been extensively studied, especially in minority groups. We therefore investigated the association between rare variants and LV traits among 1,934 African Americans using exome chip data from the Hypertension Genetic Epidemiology Network (HyperGEN) study, with replication in 1,090 African American from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. We used single-variant analyses and gene-based tests to investigate the association between 86,927 variants and six structural and functional LV traits including LV mass, LV internal dimension-diastole, relative wall thickness, left atrial dimension (LAD), fractional shortening (FS), and the ratio of LV early-to-late transmitral velocity (E/A ratio). Only rare variants (MAF <1% and <5%) were considered in gene-based analyses. In gene-based analyses, we found a statistically significant association between potassium voltage-gated channel subfamily H member 4 (KCNH4) and E/A ratio (P=8.7*10-8 using a burden test). Endonuclease G (ENDOG) was associated with LAD using the Madsen Browning weighted burden (MB) test (P=1.4*10-7). Neither gene result was replicated in GENOA, but the direction of effect of single variants in common was comparable. G protein coupled receptor 55 (GPR55) was marginally associated with LAD in HyperGEN (P=3.2*10-5 using the MB test) and E/A ratio in GENOA, but with opposing directions of association for variants in common (P=0.03 for the MB test). No single variant was statistically significantly associated with any trait after correcting for multiple testing. The findings in this study highlight the potential cumulative contributions of rare variants to LV traits which, if validated, could improve our understanding of heart failure in African Americans. PMID- 29503981 TI - From Pressure to Path: Barometer-based Vehicle Tracking. AB - Pervasive mobile devices have enabled countless context-and location-based applications that facilitate navigation, life-logging, and more. As we build the next generation of smart cities, it is important to leverage the rich sensing modalities that these numerous devices have to offer. This work demonstrates how mobile devices can be used to accurately track driving patterns based solely on pressure data collected from the device's barometer. Specifically, by correlating pressure time-series data against topographic elevation data and road maps for a given region, a centralized computer can estimate the likely paths through which individual users have driven, providing an exceptionally low-power method for measuring driving patterns of a given individual or for analyzing group behavior across multiple users. This work also brings to bear a more nefarious side effect of pressure-based path estimation: a mobile application can, without consent and without notifying the user, use pressure data to accurately detect an individual's driving behavior, compromising both user privacy and security. We further analyze the ability to predict driving trajectories in terms of the variance in barometer pressure and geographical elevation, demonstrating cases in which more than 80% of paths can be accurately predicted. PMID- 29503982 TI - [Micro and Macro Social Work Practice in the Context of Tuberculosis]. AB - The study of tuberculosis (TB) in the U.S.-Mexico border involves the consideration of three key components, which are complex and interrelated: the difficulty tracking and providing appropriate TB care due to the epidemiological and pathological characteristics of TB; the border itself is a geographical and epidemiological area that interweaves two nations, two cultures, two health systems and different laws; and the need for prevention and treatment approaches to TB that involve comprehensive clinical care and prevention while also taking into consideration stigma, social context and knowledge. This manuscript describes the work of ten studies conducted in Mexico and in the U.S.-Mexico border region from 2006 to 2013. It also provides an understanding of the social and public health implications of TB, the environment and communities, as well as the identification and application of advocacy and social mobilization practices. The work presented provides an understanding of different interventions related to adherence, stigma reduction, person-centered approaches, and effective micro and macro practices in social work. PMID- 29503983 TI - High-resolution monochromator for iron nuclear resonance vibrational spectroscopy of biological samples. AB - A new high-resolution monochromator for 14.4-keV X-rays has been designed and developed for the Fe nuclear resonance vibrational spectroscopy of biological samples. Higher flux and stability are especially important for measuring biological samples, because of the very weak signals produced due to the low concentrations of Fe-57. A 24% increase in flux while maintaining a high resolution below 0.9 meV is achieved in the calculation by adopting an asymmetric reflection of Ge, which is used as the first crystal of the three-bounce high resolution monochromator. The small cost resulting from a 20% increase of the exit beam size is acceptable to our biological applications. The higher throughput of the new design has been experimentally verified. A fine rotation mechanics that that combines a weak-link hinge with a piezoelectric actuator was used for controlling the photon energy of the monochromatic beam. The resulting stability is sufficient to preserve the intrinsic resolution. PMID- 29503985 TI - SARA: A Mobile App to Engage Users in Health Data Collection. AB - Despite the recent progress in sensor technologies, many relevant health data can be only captured with manual input (e.g., food intake, stress appraisal, subjective emotion, substance use). A common problem of manual logging is that users often disengage within a short time because of high burden. In this work, we propose SARA, a novel app to engage users with ongoing tracking using timely rewards thereby reinforcing users for data input. SARA is developed for adolescents and emerging adults at risk for substance abuse. The rewards in SARA are designed to be developmentally and culturally appropriate to the target demographic and are theoretically grounded in the behavioral science literature. In this paper, we describe SARA and its rewards to increase data collection. We also briefly discuss future plans to evaluate SARA and develop just in time adaptive interventions for engagement and behavior change. PMID- 29503986 TI - Decolonising drugs in Asia: the case of cocaine in colonial India. AB - This article examines a drugs trade in Asia that has been largely forgotten by historians and policy-makers, that in cocaine. It will briefly trace some of the contours of this commerce and the efforts to control it. It will also assess how successful these efforts were. The article is designed to contribute fresh perspectives on recent controversies in the historiography of drugs in Asia to argue that the agendas and agency of consumers are central to understanding why markets have formed there for psychoactive substances in the modern period. PMID- 29503987 TI - Thermal properties of lauric acid filled in carbon nanotubes as shape-stabilized phase change materials. AB - Carbon nanotubes (CNTs) filled with lauric acid (LA) as a kind of shape stabilized phase change material were prepared and their structures and phase change properties were characterized. The results showed that the melting point and latent heat of LA confined in carbon nanotubes were lower than those of the bulk material, and both decrease as the diameters of CNTs and the filling ratios of LA decrease. Molecular dynamics (MD) simulations indicated that LA molecules form a liquid layer near pore walls and crystallize at the pore center. When the LA filling ratio was reduced to a certain value, all LA molecules were attached to the inner walls of CNTs, hindering their crystallization. A linear relationship between the melting temperature shift and structural properties was obtained based on the modified Gibbs-Thomson equation, which gives a reliable interpretation of the size effect of nanochannels in phase change materials. We also found that the thermal conductivity of the composite CNTs/LA was four times larger than that of pure LA. This study will provide insights into the design of novel composite phase change materials with better thermal properties by the selection of suitable porous materials and tailoring their pore structures. PMID- 29503988 TI - Reply to the 'Comment on "Revisiting the definition of local hardness and hardness kernel"' by C. Morell, F. Guegan, W. Lamine, and H. Chermette, Phys. Chem. Chem. Phys., 2018, 20, DOI. AB - This reply complements the comment of Guegan et al. about our recent work on the revision of the local hardness and the hardness kernel concepts. Guegan et al. analyze our work using a Taylor series expansion of the energy as a functional of the electron density, to show that our procedure opens a new way to define local descriptors. In this contribution we show that the strategy we followed for the local hardness and the hardness kernel is even more general, and that it can be used to derive from a global response function its corresponding local and non local counterparts by: (1) requiring that the integral over one of the two variables that characterizes the non-local function leads to the local function, and that the integral over the local function leads to the global response index, and (2) assuming that the global and local functions are related through the electronic density, by making use of the chain rule for functional derivatives. PMID- 29503989 TI - Tailoring the mechanical properties by molecular integration of flexible and stiff polymer networks. AB - Designing a multiple-network structure at the molecular level to tailor the mechanical properties of polymeric materials is of great scientific and technological importance. Through the coarse-grained molecular dynamics simulation, we successfully construct an interpenetrating polymer network (IPN) composed of a flexible polymer network and a stiff polymer network. First, we find that there is an optimal chain stiffness for a single network (SN) to achieve the best stress-strain behavior. Then we turn to study the mechanical behaviors of IPNs. The result shows that the stress-strain behaviors of the IPNs appreciably exceed the sum of that of the corresponding single flexible and stiff network, which highlights the advantage of the IPN structure. By systematically varying the stiffness of the stiff polymer network of the IPNs, optimal stiffness also exists to achieve the best performance. We attribute this to a much larger contribution of the non-bonded interaction energy. Last, the effect of the component concentration ratio is probed. With the increase of the concentration of the flexible network, the stress-strain behavior of the IPNs is gradually enhanced, while an optimized concentration (around 60% molar ration) of the stiff network occurs, which could result from the dominant role of the enthalpy rather than the entropy. In general, our work is expected to provide some guidelines to better tailor the mechanical properties of the IPNs made of a flexible network and a stiff network, by manipulating the stiffness of the stiff polymer network and the component concentration ratio. PMID- 29503990 TI - Thermal, electrochemical and radiolytic stabilities of ionic liquids. AB - Research on ionic liquids has achieved rapid progress in the last several decades. Stability is a prerequisite for the application of ionic liquids. Ionic liquids may be used at elevated temperature, as electrolytes, or under irradiation. Therefore, the thermal, electrochemical, and radiolytic stabilities of ionic liquids are important and need to be known before their usage. Many research papers and some reviews on the stabilities of ionic liquids have been published. However, new results are continuously being published and a comprehensive review and perspective on this topic are still urgently needed. In this perspective, we intend to provide a comprehensive review including characterization methods, the effects of chemical composition of the ionic liquids on the thermal, electrochemical, and radiolytic stabilities of ionic liquids, respectively. Moreover, the thermal stability of some special types of ionic liquids such as poly(ionic liquids) and mixed ionic liquids, and the thermal and electrochemical stabilities of protic ionic liquids are discussed too. For thermal stability, the interactions between ions are less important than the individual anions and cations. The decomposition temperature is mainly determined by the less-stable ion, usually the anion. For electrochemical stability, the electrochemical window is determined by both the cation and anion. The less stable ion could influence the stability by interaction between the generated species from the decomposition with the more stable ion (opposite ion). This perspective is helpful for people to avoid using unstable ionic liquids and choose suitable ionic liquids. PMID- 29503991 TI - A novel Schiff base derivative of pyridoxal for the optical sensing of Zn2+ and cysteine. AB - An easy to prepare novel vitamin B6 cofactor derivative 3-hydroxy-N'-((3 hydroxy 5-(hydroxymethyl)-2-methylpyridin-4-yl)methylene)-2-naphthohydrazide (NPY) was synthesized by a one pot condensation reaction of pyridoxal with 3-hydroxy-2 naphthoic hydrazide and applied for the optical detection of Zn2+ and cysteine in the aqueous DMSO medium. The addition of Zn2+ ions leads to a selective blue shift in the fluorescence emission spectrum of NPY from 530 nm to 475 nm, which allowed ratiometric detection of Zn2+ ions down to 8.73 * 10-7 M without any interference from other tested metal ions. This system was also successfully applied to detect intracellular Zn2+ ions in live HeLa cells. Further, when the in situ generated NPY.Zn2+ complex was interacted with various amino acids, the addition of cysteine resulted in an instantaneous colour change from light yellow to colourless and the absorbance at 435 nm of the complex was quenched selectively. Also, the fluorescence of the NPY.Zn2+ complex was quenched, which allowed the detection of cysteine down to 6.63 * 10-7 M. PMID- 29503992 TI - A study of the diffusion dynamics and concentration distribution of gold nanospheres (GNSs) without fluorescent labeling inside live cells using fluorescence single particle spectroscopy. AB - Colloidal gold nanospheres (GNSs) have become important nanomaterials in biomedical applications due to their special optical properties, good chemical stability, and biocompatibility. However, measuring the diffusion coefficients or concentration distribution of GNSs within live cells accurately without any extra fluorescent labeling in situ has still not been resolved. In this work, a single particle method is developed to study the concentration distribution of folic acid-modified GNSs (FA-GNSs) internalized via folate receptors, and investigates their diffusion dynamics within live cells using single particle fluorescence correlation spectroscopy (FCS). We optimized the experimental conditions and verified the feasibility of 30 nm GNSs without extra fluorescence labeling being used for single particle detection inside live cells. Then, the FCS characterization strategy was used to measure the concentration and diffusion coefficient distributions of GNSs inside live cells and the obtained results were basically in agreement with those obtained by TEM. The results demonstrate that our strategy is characterized as an in situ, nondestructive, rapid and dynamic method for the assay of live cells, and it may be widely used in the further design of GNP-based drug delivery and therapeutics. PMID- 29503993 TI - Competitive calcium ion binding to end-tethered weak polyelectrolytes. AB - We have developed a molecular model to describe the structural changes and potential collapse of weak polyelectrolyte layers end-tethered to planar surfaces and spherical nanoparticles as a function of pH and divalent ion concentration. In particular, we describe the structural changes of polymer-coated nanoparticles end-tethered to copolymers of poly(acrylic acid) (pAA) and poly arcrylamido-2 methylpropane sulfonate (pAMPS) in the presence of Ca2+ ions. We find that end grafted poly(acrylic acid) layers will collapse in aqueous solutions containing sufficient amounts of Ca2+ ions, while polymers and copolymers with sufficient AMPS monomers will not collapse. The collapse of end-tethered pAA is due to the formation of calcium bridges between two acrylic acid monomers and one calcium ion. On the other hand pAMPS layers do not collapse due to the lack of calcium bridges. The collapse of pAA layers is strongly dependent on the pH as well as divalent and monovalent salt concentrations of the environment. The collapse is also strongly influenced by the curvature of the tethering surface. PMID- 29503994 TI - Probing the impact of magnetic interactions on the lattice dynamics of two dimensional Ti2X (X = C, N) MXenes. AB - Dynamical properties of the two-dimensional Ti2C and Ti2N MXenes were investigated using density functional theory and discussed in connection with their structures and electronic properties. To elucidate the influence of magnetic interactions on the fundamental properties of these systems, the nonmagnetic, ferromagnetic and three distinct antiferromagnetic spin arrangements on titanium sublattice were considered. Each magnetic configuration was also studied at two directions of the spin magnetic moment with respect to the MXene layer. The zero-point energy motion, following from the phonon calculations, was taken into account while analyzing the energetic stability of the magnetic phases against the nonmagnetic solution. This contribution was found not to change a sequence of the energetic stability of the considered magnetic structures of Ti2X (X = C, N) MXenes. Both Ti2X (X = C, N) systems are shown to prefer antiferromagnetic arrangement of spins between Ti layers and the ferromagnetic order within each layer. This energetically privileged phase is semiconducting for Ti2C and metallic for Ti2N. The type of magnetic order as well as the in plane or out-of-plane spin polarizations have a relatively small impact on the structural parameters, Ti-X bonding length, force constants and phonon spectra of both Ti2X systems, leading to observable differences only between the nonmagnetic and any other magnetic configurations. Nonetheless, a noticeable effect of the spin orientation on degeneracy of the Ti-3d orbitals is encountered. The magnetic interactions affect to a great extent the positions and intensities of the Raman active modes, and hence one could exploit this effect for experimental verification of the theoretically predicted magnetic state of Ti2X monolayers. Theoretical phonon spectra of Ti2X (X = C, N) MXenes exhibit a linear dependence on energy in the long-wavelength limit, which is typical for a 2D system. PMID- 29503995 TI - Dilution induced coacervation in polyelectrolyte-micelle and polyelectrolyte protein systems. AB - "Self-suppression", the instability of complex coacervates at high concentration, is well-known for polycation-polyanion systems, but the transient nature of those complexes impedes development of a convincing model. The stable polyelectrolyte micelle complexes of the polycation poly(diallyldimethylammonium chloride) (PDADMAC) with mixed micelles of sodium dodecyl sulfate (SDS)/Triton X-100 (TX100); and the stable complexes of PDADMAC with bovine serum albumin (BSA) can be characterized and identified as coacervate precursors. We observe liquid liquid phase separation upon isoionic dilution, a common facet of self suppression. While complex coacervation usually involves association of near neutral inter-polymer complexes, dilution-induced coacervation (DIC) proceeds differently: for both systems studied, complex size decreases near the biphasic region: inter-macromolecular complexes with hydrodynamic radius Rh~ 100 nm dissociate to intra-polyelectrolyte complexes with Rh<= 30 nm. Such small complexes with <=5 bound micelles are unlikely to be net neutral. In the polyelectrolyte-protein system, complexes are even less likely to be net neutral and the effect of dilution on size is less significant, with complex size diminishing from 50 nm to 35 nm. PMID- 29503996 TI - The electrocatalytic characterization and mechanism of carbon nanotubes with different numbers of walls for the VO2+/VO2+ redox couple. AB - Carbon nanotubes (CNTs) have been applied as catalysts in the VO2+/VO2+ redox, whereas the mechanism of CNTs for the redox reaction is still unclear. In this work, the mechanism of the VO2+/VO2+ redox is investigated by comparing the electrocatalytic performance of CNTs with different distributions. For different CNTs, the peak current density of the VO2+/VO2+ redox increases with increasing content of oxygen-functional groups on the surface of CNTs, especially the carboxyl group which is proved as active sites for the redox reaction. Moreover, the reversibility of the VO2+/VO2+ redox decreases with increasing defects of CNTs, as the defects affect the charge transfer of the catalytic reaction. Nevertheless, when a multi-walled CNT sample is oxidized to achieve a high content of oxygen functional groups and defects, the peak current density of the redox reaction increases from 38.5 mA mg-1 to 45.4 mA mg-1 whilst the peak potential separation (DeltaEp) also increases from 0.176 V to 0.209 V. Overall, a balance between the oxygen functional groups and the defects of CNTs affects the peak current and the reversibility for the VO2+/VO2+ redox. PMID- 29503997 TI - Interaction of gas phase copper(ii) acetylacetonate with slow electrons. AB - Understanding the fundamental processes underlying the interaction of organometallic compounds with low energy electrons is desirable for optimizing methodologies for nanoscale applications. In this work, we couple experimental measurements with theories to investigate the interaction of gas phase copper(ii) acetylacetonate, Cu(acac)2, with low energy (<12 eV) electrons. Near 0 eV, a multipole-bound anion is likely to act as the doorway for the formation of a transitory molecular anion which then undergoes stabilization via a 90 degrees rotation of one of the acac units. The production of the parent anion competes with the dissociation processes, generating preferentially the acetylacetonate negative ion. Moreover, at incident electron energies above 3.5 eV, the electron driven fragmentation of Cu(acac)2 is likely to produce atomic Cu. These results can suggest some potential strategies for the deposition of pure copper using an appropriate electron irradiation technique. PMID- 29503998 TI - beta-Functionalized trans-A2B2 push-pull tetrabenzoporphyrins. AB - A series of beta-functionalized trans-A2B2 tetrabenzoporphyrins have been successfully designed and synthesized through newly developed regioselective bromination chemistry of porphyrins and a Pd(0) catalyzed three-step-one pot reaction. These benzoporphyrins exhibit unique patterns of UV-Vis absorptions and emissions. PMID- 29503999 TI - Two-dimensional gold trisoctahedron nanoparticle superlattice sheets: self assembly, characterization and immunosensing applications. AB - Nanoparticles were called "artificial atoms" about two decades ago due to their ability to organize into regular lattices or supracrystals. Their self-assembly into free-standing, two-dimensional (2D) nanoparticle arrays enables the generation of 2D metamaterials for novel applications in sensing, nanophotonics and energy fields. However, their controlled fabrication is nontrivial due to the complex nanoscale forces among nanoparticle building blocks. Here, we report a new type of 2D plasmonic superlattice from high-index gold trisoctahedron (TOH) nanoparticles. TOH is an anisotropic polyhedron with 24 facets and 14 vertices. By using polymer ligands in conjunction with drying-mediated self-assembly, we obtained highly ordered 2D superlattices as quantified by synchrotron based grazing-incidence small-angle X-ray scattering (GISAXS). The plasmonic properties were optimized by adjusting the ligand length and particle size. The excellent surface-enhanced Raman scattering (SERS) performance enables us to demonstrate TOH superlattices as uniform SERS immunosubstrates with a detection limit down to 1 pg ml-1 and a dynamic range from 1 pg ml-1 to 100 ng ml-1. PMID- 29504000 TI - Supramolecular self-assemblies for bacterial cell agglutination driven by directional charge-transfer interactions. AB - Two supramolecular amphiphiles are fabricated through directional charge-transfer interactions, which self-assemble into nanofibers and nanoribbons. Due to the existence of galactose on their surface, these self-assemblies act as a cell glue to agglutinate E. coli, benefiting from multivalent interactions. PMID- 29504001 TI - Dynamics-based assessment of nanoscopic polymer-network mesh structures and their defects. AB - Polymer-network gels often exhibit complex nanoscopic architectures. First, the polymer-network mesh topology on scales of 1-10 nm is usually not uniform and regular, but disordered and irregular. Second, on top of that, many swollen polymer networks display spatial inhomogeneity of their polymer segmental density and crosslinking density on scales of 10-100 nm. This multi-scale structural complexity affects the permeability, mechanical strength, and optical clarity of the polymer gels, which is of central relevance for their performance in popular applications. As a result, there is a need to characterize the polymer network structures on multiple scales. On the scale of the spatial inhomogeneity of crosslinking, 10-100 nm, scattering of neutrons, X-rays, and light has extraordinary utility and is well established. On the scale of the mesh topology, 1-10 nm, in contrast, experimental techniques are less established. This review intends to close this gap by reviewing two intrinsically dynamic methods that yield information on polymer network mesh structures. First, NMR-based assessment of residual dipolar proton-spin couplings, which arise upon the introduction of crosslinks into a liquidlike polymer system to impart partial solidlike characteristics, is suitable to quantitatively assess network meshes and local network defects. Second, diffusive penetration of molecular, macromolecular, and mesoscopic colloidal probes through a polymer gel provides insight into its obstructing network mesh structure and its potential irregularity. Either method is highly synergistic to scattering-based assessment of the network structures on larger scales, and in concert, a rich picture on the nano- and mesoscopic gel topology is obtained. PMID- 29504002 TI - A monoclonal antibody acts as a migratory cue via Ca2+ re-wiring. AB - As monoclonal antibodies have two epitopes for their target ligand, they should theoretically dimerize target receptors upon binding. In particular, the dimerization of the vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) stimulates early events occurring within minutes (e.g. Ca2+ signal generation) and late events occurring over hours and days (e.g. cell migration in angiogenesis). Although studies have noted that antibodies targeting VEGFR2 (anti VEGFR2) inhibited cell migration in angiogenesis, we show in this paper that an anti-VEGFR2 stimulus nevertheless triggered a Ca2+ signal in VEGFR2 expressing cells. This Ca2+ signal was then re-wired to promote cell migration by co expressing an engineered Ca2+ activated RhoA (called CaRQ), thereby engineering the opposite anticipated effect of an anti-VEGFR2 antibody. In these cells, the anti-VEGFR2 antibody stimulus induced cellular blebbing, migration across a membrane, and in vitro scratch wound healing. This work expands the utility of monoclonal antibodies to induce tailored responses in engineered cells such as changes in cell fluorescence via Ca2+ reporters or migration patterns via CaRQ. PMID- 29504003 TI - An MS-CASPT2 study of the photodecomposition of 4-methoxyphenyl azide: role of internal conversion and intersystem crossing. AB - The photochemical decomposition of 4-methoxyphenyl azide (CH3O-Ph-N3) is investigated using multiconfigurational second-order perturbation theory (MS CASPT2). In addition, the multi-state resonance Raman spectra of the reactant, intermediates, and product are computed with a multi-state version of the vibronic theory of Albrecht. The results support that the key step of the photolysis of the parent azide is a 21A'/23A'' intersystem crossing which in a second step decays through a 23A''/13A'' conical intersection to give directly the formation of triplet 4-methoxyphenyl nitrene (CH3O-Ph-N) in its lowest electronic state, 13A''. It is found that the efficiency of the cited intersystem crossing is enhanced by the close presence of a 21A'/21A'' conical intersection. On the other hand, the calculated spectra suggest that the only two species which would be observed in the gas phase experiments are the triplet nitrene plus 4,4' dimethoxyazobenzene. PMID- 29504004 TI - Polyaromatic molecular tubes: from strategic synthesis to host functions. AB - Ring- and tube-shaped molecules like crown ethers and cyclodextrins play a fundamental role in supramolecular chemistry since their initial discovery. To date, numerous intriguing properties and reactivities have been reported based on their unique inner microenvironments. While inner spaces encircled by aliphatic and/or small aromatic frameworks have been heavily investigated, tubular structures that feature polyaromatic frameworks remained largely unexplored until 2010, despite their undisputable potential. Polyaromatic rings provide appealing photophysical and electrochemical properties and thus allow for the construction of new functional cylindrical nanospaces. This feature article describes the recent progress in the synthesis and application of short tubular molecules bearing multiple (>=3) polyaromatic rings (e.g., anthracene, pyrene, chrysene, and HBC). The polyaromatic tubes reported herein display characteristic properties such as strong fluorescent emission, a selective molecular binding ability, efficient host-guest energy transfer and open-closed structural transformations. PMID- 29504005 TI - Supramolecular complex of a fused zinc phthalocyanine-zinc porphyrin dyad assembled by two imidazole-C60 units: ultrafast photoevents. AB - A new zinc phthalocyanine-zinc porphyrin dyad (ZnPc-ZnP) fused through a pyrazine ring has been synthesized as a receptor for imidazole-substituted C60 (C60Im) electron acceptor. Self-assembly via metal-ligand axial coordination and the pertinent association constants in solution were determined by 1H-NMR, UV-Vis and fluorescence titration experiments at room temperature. The designed host was able to bind up to two C60Im electron acceptor guest molecules to yield C60Im:ZnPc-ZnP:ImC60 donor-acceptor supramolecular complex. The spectral data showed that the two binding sites behave independently with binding constants similar in magnitude. Steady-state fluorescence studies were indicative of an efficient singlet-singlet energy transfer from zinc porphyrin to zinc phthalocyanine within the fused dyad. Accordingly, the transient absorption studies covering a wide timescale of femto-to-milli seconds revealed ultrafast energy transfer from 1ZnP* to ZnPc (kEnT ~ 1012 s-1) in the fused dyad. Further, a photo induced electron transfer was observed in the supramolecularly assembled C60Im:ZnPc-ZnP:ImC60 donor-acceptor complex leading to charge separated states, which persisted for about 200 ns. PMID- 29504006 TI - Mercury behaviour and C, N, and P biogeochemical cycles during ecological restoration processes of old mining sites in French Guiana. AB - Several decades of gold mining extraction activities in the Amazonian rainforest have caused deforestation and pollution. While ecological rehabilitation is essential for restoring biodiversity and decreasing erosion on deforested lands, few studies note the behaviour or toxicity of trace elements during the rehabilitation process. Our original study focused on the potential use of microbial activity and Hg speciation and compared them with As, Cu, Zn and Cr speciation in assessing the chemical and biological quality of ecological restoration efforts. We sampled two sites in French Guyana 17 years after rehabilitation efforts began. The former site was actively regenerated (R) with the leguminous species Clitoria racemosa and Acacia mangium, and the second site was passively regenerated with spontaneous vegetation (Sv). We also sampled soil from a control site without a history of gold mining (F). We performed microcosm soil experiments for 30 days, where trace element speciation and enzyme activities (i.e., FDA, dehydrogenase, beta-glucosidase, urease, alkaline and acid phosphatase) were estimated to characterise the behaviour of trace elements and the soil microbial activity. As bioindicators, the use of soil microbial carbon biomass and soil enzyme activities related to the carbon and phosphorus cycles seems to be relevant for assessing soil quality in rehabilitated and regenerated old mining sites. Our results showed that restoration with leguminous species had a positive effect on soil chemical quality and on soil microbial bioindicators, with activities that tended toward natural non-degraded soil (F). Active restoration processes also had a positive effect on Hg speciation by reducing its mobility. While in Sv we found more exchangeable and soluble mercury, in regenerated sites, Hg was mostly bound to organic matter. These results also suggested that enzyme activities and mercury cycles are sensitive to land restoration and must be considered when evaluating the efficiency of restoration processes. PMID- 29504007 TI - Thermal stability of iron-sulfur clusters. AB - The thermal decomposition of free cationic iron-sulfur clusters FexSy+ (x = 0-7, y = 0-9) is investigated by collisional post-heating in the temperature range between 300 and 1000 K. With increasing temperature the preferential formation of stoichiometric FexSy+ (y = x) or near stoichiometric FexSy+ (y = x +/- 1) clusters is observed. In particular, Fe4S4+ represents the most abundant product up to 600 K, Fe3S3+ and Fe3S2+ are preferably formed between 600 K and 800 K, and Fe2S2+ clearly dominates the cluster distribution above 800 K. These temperature dependent fragment distributions suggest a sequential fragmentation mechanism, which involves the loss of sulfur and iron atoms as well as FeS units, and indicate the particular stability of Fe2S2+. The potential fragmentation pathways are discussed based on first principles calculations and a mechanism involving the isomerization of the cluster prior to fragmentation is proposed. The fragmentation behavior of the iron-sulfur clusters is in marked contrast to the previously reported thermal dissociation of analogous iron-oxide clusters, which resulted in the release of O2 molecules only, without loss of metal atoms and without any tendency to form particular prominent and stable FexOy+ clusters at high temperatures. PMID- 29504008 TI - On the contribution of f electrons to the quadratic hyperpolarizability: the case of lanthanide terpyridyl complexes. AB - Over the last decades, trivalent lanthanide ions (Ln3+) have gained much attention due to their peculiar luminescence, which opened the way to a broad range of applications, from medical diagnostic to lasers. Their impact on nonlinear optical (NLO) properties also attracted interest, especially in the framework of lanthanide complexes. Several experimental studies demonstrated that the quadratic hyperpolarizability varies with the number of 4f-electrons, with a stronger effect on dipolar than octupolar components. The main interpretation put forward to explain the observed trends relied on the polarizable character of the 4f-electrons. We report here a first step towards understanding the role of 4f electrons in NLO responses, considering a series of dipolar terpyridyl-trinitro lanthanide complexes LLn(NO3)3 (Ln = Gd, Dy, Yb, Lu as well as La and Y; L = terpyridil-like ligand). Using DFT and TD-DFT we investigate their linear and non linear optical properties. Consistently with earlier experimental findings, simulated UV-visible spectra show minor changes by varying Ln. The same holds for dipole moments and polarizabilities, whereas the nature of the lanthanide affects hyperpolarizabilities. It is shown that the observed changes are not a direct effect of the 4f-electrons that behave like core electrons. PMID- 29504009 TI - Single layer porous media with entrapped minerals for microscale studies of multiphase flow. AB - The behaviour of minerals (i.e. salts) such as sodium chloride and calcite in porous media is very important in various applications such as weathering of artworks, oil recovery and CO2 sequestration. We report a novel method for manufacturing single layer porous media in which minerals can be entrapped in a controlled way in order to study their dissolution and recrystallization. In addition, our manufacturing method is a versatile tool for creating monomodal, bimodal or multimodal pore size microporous media with controlled porosity ranging from 25% to 50%. These micromodels allow multiphase flows to be quantitatively studied with different microscopy techniques and can serve to validate numerical models that can subsequently be extended to the 3D situation where visualization is experimentally difficult. As an example of their use, deliquescence (dissolution by moisture absorption) of entrapped NaCl crystals is studied; our results show that the invasion of the resulting salt solution is controlled by the capillary pressure within the porous network. For hydrophilic porous media, the liquid preferentially invades the small pores whereas in a hydrophobic network the large pores are filled. Consequently, after several deliquescence/drying cycles in the hydrophilic system, the salt is transported towards the outside of the porous network via small pores; in hydrophobic micromodels, no salt migration is observed. Numerical simulations based on the characteristics of our single layer pore network agree very well with the experimental results and give more insight into the dynamics of salt transport through porous media. PMID- 29504011 TI - Correction: Stereoselective synthesis of natural product inspired carbohydrate fused pyrano[3,2-c]quinolones as antiproliferative agents. AB - Correction for 'Stereoselective synthesis of natural product inspired carbohydrate fused pyrano[3,2-c]quinolones as antiproliferative agents' by Priti Kumari et al., Org. Biomol. Chem., 2018, DOI: 10.1039/c7ob03186f. PMID- 29504010 TI - From 2D to 3D patches on multifunctional particles: how microcontact printing creates a new dimension of functionality. AB - A straightforward approach for the precise multifunctional surface modification of particles with three-dimensional patches using microcontact printing is presented. By comparison to previous works it was possible to not only control the diameter, but also to finely tune the thickness of the deposited layer, opening up the way for three-dimensional structures and orthogonal multifunctionality. The use of PEI as polymeric ink, PDMS stamps for microcontact printing on silica particles and the influence of different solvents during particle release on the creation of functional particles with three-dimensional patches are described. Finally, by introducing fluorescent properties by incorporation of quantum dots into patches and by particle self-assembly via avidin-biotin coupling, the versatility of this novel modification method is demonstrated. PMID- 29504012 TI - Selenide-containing organic resonance molecules as turn-on fluorescent probes for the selective detection of hypochlorous acid. AB - A new series of N-P[double bond, length as m-dash]Se resonance-based fluorescent molecules were developed and used for the detection of hypochlorous acid (HClO) with rapid response and high selectivity. These Se-containing molecules can selectively detect trace amounts of HClO in nM, showing significantly strengthened fluorescence due to the enhanced resonance variation with an increased distance between the fluorophore and Se. The design of N-P[double bond, length as m-dash]Se resonance molecules in donor-resonance-acceptor (D-r-A) architectures could be an important way to develop high-performance turn-on fluorescent probes for HClO detection. PMID- 29504013 TI - Trends in Research and Publication. AB - Each year, the Journal of Allied Health is successful in attracting approximately 20% of article submissions from other nations. This development is gratifying in many ways because it signifies the utility and importance of obtaining viewpoints from other lands in ways that enhance the understanding of American educators and clinicians about common issues and challenges involving the preparation of a highly competent health workforce. Also discussed are wider trends in research and publishing including "registered reports" and authorship criteria. PMID- 29504014 TI - Kolb's Experiential Learning Theory as a Theoretical Underpinning for Interprofessional Education. AB - It is imperative to incorporate education on interprofessional competencies into the curriculum of healthcare provider students in order to meet the individual program accreditation standards. However, what is missing is a theoretical foundation for the education. The purpose of this paper was to examine if the qualitative data from a mixed-methods study using low-fidelity simulation of a case study that demonstrated changes in interprofessional attitudes and behaviors in healthcare provider students aligned with Kolb's Experiential Learning Theory (ELT). First-year students (n=515) from 8 professional healthcare programs participated in the 90-minute study which included a scripted scenario of the patient care rounding process. Using thematic analysis, the qualitative results demonstrated a significant alignment with the four stages of Kolb's ELT. Based on the results of this study, ELT appears to provide a solid theoretical underpinning for the education through which to teach interprofessional competencies to healthcare provider students. PMID- 29504015 TI - Physical and Occupational Therapy Practice Improvement Following Interprofessional Evidence-Based Falls Prevention Training. AB - AIMS: Evaluate changes in physical therapy (PT) and occupational therapy (OT) practice following evidence-based practice (EBP) interprofessional modules that teach assessments and interventions to reduce falls in community-dwelling older adults. METHODS: Medical records of post-fall patients in three Programs of All Inclusive Care for the Elderly (PACE) sites were analyzed to assess differences in documented falls and the OT and PT use of EBP assessment and interventions implemented following fall prevention training. RESULTS: In training year 1, PT demonstrated a 34.6% practice improvement in risk assessments performed (z=3.0, p<0.005). In training year 2, PT demonstrated a 66.7% practice change in the implementation of EBP interventions (z=2.1, p<0.05) and OT demonstrated a 22.2% practice improvement in the implementation of recommended EBP interventions (z=2.0, p<0.05). In training year 3, OT achieved a 6.8% increase in the execution of home environment modifications (z=2.0, p<0.05), and PT demonstrated a 23.3% practice improvement in the implementation of recommended EBP interventions (z=3.1, p<0.005). CONCLUSION: The delivery of EBP assessment and intervention training modules for falls prevention resulted in PT and OT practice changes and improved adherence to published guidelines. PMID- 29504016 TI - A Novel Interprofessional Faculty Approach for Integrating Oral Health Promotion Competencies into a Physical Therapist Curriculum. AB - AIMS: Oral health is integral to overall health and wellness. All healthcare providers can contribute to improving health by including an oral health screening (OHS) in the physical examination. The aims of this study were to 1) develop and test a novel oral health curriculum and 2) compare the effectiveness of two distinct methods of instruction, a) simulation with physical therapists (PT) and dental professional co-debriefing and b) video observation with PT faculty- only instruction. METHODS: PT students (n=202) completed one of two educational experiences to learn how to perform an OHS, evaluate oral health findings, provide oral health education, and make an appropriate dental referral. Four distinct patient-specific cases were tested. RESULTS: Results indicated multiple teaching strategies, including a simulation with co-debriefing, improved PT student performance in OHS. Between-case analysis indicated that students performed better in making appropriate referrals for pathology-based cases than preventative care-based cases. Conversely students' patient education was better for preventative cases than pathology-based cases. Curricular revisions improved student performance in providing relevant patient education. A comparison of student performance using simulation with co-debriefing vs video observation with PT faculty-only instruction found no statistically significant difference. CONCLUSIONS: This novel oral health curriculum is a useful approach for teaching PT and other health professions students how to execute an OHS. PMID- 29504017 TI - Organizational Dimensions of Innovative Practice: A Qualitative Investigation of the Processes Supporting Innovation Adoption in Outpatient Physical Therapy Practice. AB - BACKGROUND: The ability to innovate and adapt practice is a requirement of the progressive healthcare provider. Innovative practice by rehabilitation providers has largely been approached as personal professional development; this study extends that perspective by examining innovation uptake from the organizational level. The varied professions can be expected to have distinct qualities of innovation adoption that reflect professional norms, values, and expectations. The purpose of this qualitative study was to describe the organizational processes of innovation uptake in outpatient physical therapy practice. DESIGN: Through nomination, two outpatient, privately owned physical therapy clinics were identified as innovation practices. Eighteen physical therapists, three owners, and a manager participated in the study. METHODS: The two clinics served as case studies within a grounded theory approach. Data were collected through observation, unstructured questioning, work flow analysis, focus group sessions, and artifact analysis. Data were analyzed and coded among the investigators. RESULTS: A theoretical model of the innovation adoption process in outpatient physical therapy practice was developed. Elements of the model included (1) change grounded in relationship-centered care, (2) clinic readiness to accept change, and (3) clinic adaptability and resilience. CONCLUSIONS: A social paradigm of innovation adoption informed through this research complements the concentration on personal professional development. PMID- 29504018 TI - Determinants of Course Grades in Allied Health Sciences Programs. AB - Past research has shown that there is a pattern of systematic grade inflation in higher education in the U.S. As a result, it is difficult for prospective employers and graduate school admission directors to distinguish bright candidates when recruiting new graduates. The purpose of this study was two-fold: 1) to determine the grading patterns of four academic departments (i.e., rehabilitation services, communication science and disorders, social work, and nursing) in an allied health college at a large public university over time, and 2) to consider which instructor demographic factors and course characteristics might influence the grading patterns. Using an archival data set, the grades for 1,892 course sections over 12 semesters were examined. The results showed that the Department of Social Work had the highest semester GPAs, and that approximately 20% of the variance in course GPAs was due to course characteristics, with instructor characteristics only explaining 3% of the variance. Implications and directions for future research are discussed. PMID- 29504019 TI - Assessing the Impact of a Virtual Lab in an Allied Health Program. AB - Competency-based education in health care requires rigorous standards to ensure professional proficiency. Demonstrating competency in hands-on laboratories calls for effective preparation, knowledge, and experience, all of which can be difficult to achieve using traditional teaching methods. Virtual laboratories are an alternative, cost-effective approach to providing students with sufficient preparatory information. Research on the use of virtual labs in allied health education is limited. The current study investigated the benefits, challenges, and perceived impact of a virtual lab in an allied health program. The sample consisted of 64 students (55 females, 9 males) enrolled in a university medical laboratory science program. A convergent mixed-methods approach (Likert survey, open-ended questions, think-aloud protocol data) revealed that students had positive attitudes towards visual learning, authenticity, learner control, organization, and scaffolding afforded by the virtual lab. Challenges reported included navigational difficulties, an absence of control over content selection, and lack of understanding for certain concepts. Over 90% of students agreed that the virtual lab helped them prepare for hands-on laboratory sessions and that they would use this format of instruction again. Overall, 84% of the students agreed that the virtual lab helped them to achieve greater success in learning. PMID- 29504020 TI - Paramedic Learning Style Preferences and Continuing Medical Education Activities: A Cross-Sectional Survey Study. AB - BACKGROUND: Paramedics participate in continuing medical education (CME) to maintain their skills and knowledge. An understanding of learning styles is important for education to be effective. This study examined the preferred learning styles of ground ambulance paramedics and describes how their preferred learning styles relate to the elective CME activities these paramedics attend. METHODS: All paramedics (n=1,036) employed in a provincial ground ambulance service were invited to participate in a survey containing three parts: demographics, learning style assessed by the Kolb Learning Style Inventory (LSI), and elective CME activity. RESULTS: 260 paramedics (25%) participated in the survey. Preferred learning styles were: assimilator, 28%; diverger, 25%; converger, 24%; and accommodator, 23%. Advanced life support (ALS) providers had a higher proportion of assimilators (36%), and basic life support (BLS) providers had a higher proportion of divergers (30%). The learning style categories of CME activities attended by paramedics were: assimilators, 25%; divergers, 26%; convergers, 25%; and accommodators, 24%. CONCLUSION: These results suggest that paramedics are a diverse group of learners, and learning style differs within their demographics. Paramedics attend CME activities that complement all learning styles. Organizations providing education opportunities to paramedics should consider paramedics a diverse learning group when designing their CME programs. PMID- 29504021 TI - Facilitating Racial and Ethnic Diversity in the Health Workforce. AB - Racial and ethnic diversity in the health workforce can facilitate access to healthcare for underserved populations and meet the health needs of an increasingly diverse population. In this study, we explored 1) changes in the racial and ethnic diversity of the health workforce in the United States over the last decade, and 2) evidence on the effectiveness of programs designed to promote racial and ethnic diversity in the U.S. health workforce. Findings suggest that although the health workforce overall is becoming more diverse, people of color are most often represented among the entry-level, lower-skilled health occupations. Promising practices to help facilitate diversity in the health professions were identified in the literature, namely comprehensive programs that integrated multiple interventions and strategies. While some efforts have been found to be promising in increasing the interest, application, and enrollment of racial and ethnic minorities into health profession schools, there is still a missing link in understanding persistence, graduation, and careers. PMID- 29504022 TI - Teaching Theory in Occupational Therapy Using a Cooperative Learning: A Mixed Methods Study. AB - Cooperative learning provides an important vehicle for active learning, as knowledge is socially constructed through interaction with others. This study investigated the effect of cooperative learning on occupational therapy (OT) theory knowledge attainment in professional-level OT students in a classroom environment. Using a pre- and post-test group design, 24 first-year, entry-level OT students participated while taking a theory course in their second semester of the program. Cooperative learning methods were implemented via in-class group assignments. The students were asked to complete two questionnaires regarding their attitudes toward group environments and their perception toward group learning before and after the semester. MANCOVA was used to examine changes in attitudes and perceived learning among groups. Students' summary sheets for each in-class assignment and course evaluations were collected for content analysis. Results indicated significant changes in students' attitude toward working in small groups regardless of their prior group experience. PMID- 29504023 TI - Effect of Payment Model on Patient Outcomes in Outpatient Physical Therapy. AB - Although the literature has well recognized the effectiveness of physical therapy for treating musculoskeletal injuries, reimbursement is evolving towards value based or alternative payment models and away from procedure orientated, fee-for service in the outpatient setting. Alternative models include cased-based clinics, pay-for-performance, out-of-network services, accountable care organizations, and concierge practices. There is the possibility that alternative payment models could produce different and even superior patient outcomes. Physical therapists should be alert to this possibility, and research is warranted in this area to conclude if outcomes in patient care are related to method of reimbursement. PMID- 29504024 TI - Paired Athletic Training Preceptors' and Students' Perceptions of Effective Preceptor Characteristics. AB - BACKGROUND: Preceptors are important contributors to the professional development of students in allied healthcare programs. Considering their role in supervising and teaching students during clinical education, it is important that preceptors understand and embody effective characteristics and behaviors. Most existing research on preceptor effectiveness in nursing, medicine, and dietetics professions has examined preceptor and student perceptions of effective behaviors independently. OBJECTIVE: The purpose of our study was to investigate effective preceptor behaviors from perspectives of paired preceptors and students affiliated with athletic training programs. PROCEDURES: This qualitative study included interviews of eight paired groups of preceptors (n=8) and athletic training students (n=13) within collegiate, rehabilitation clinic, and high school settings. Data were analyzed using a general inductive approach using open, axial, and selective coding. RESULTS: Our participants concurred that effective preceptors: 1) communicate expectations early and often, 2) demonstrate approachability and openness towards students, 3) provide hands-on patient care responsibilities, and 4) take the time to actively instruct students. CONCLUSIONS: Preceptors are encouraged to exhibit these effective instructional and interpersonal behaviors. Based on these themes, allied health program administrators should provide preceptor trainings that encourage these behaviors to enhance student learning and professional preparation. PMID- 29504025 TI - Impact of Implementing a Competency-Based Clinical Curriculum: Transitioning a Dental Hygiene Program. AB - PURPOSE: Competency-based education is employed to ensure students are prepared to perform tasks required by entry-level practitioners. The American Dental Education Association's curriculum for dental hygiene programs states that students should learn skills consistently performed by dental hygienists to the level of competence. The purpose of this study was to assess the implementation of a competency- based dental hygiene clinical program at University of Arkansas for Medical Sciences. The program included components such as the development of competencies, assessment techniques, portfolios (self-assessment/reflection), mock boards, faculty feedback, remediation, and competency notebooks. METHODS: To evaluate the competency-based clinical program, surveys were conducted on 30 students and 5 faculty members who experienced the transition from a traditional grade-based clinical program to a non-graded competency-based program. Survey questions included Likert-type questions, ranking aspects of the competency- based program in order of importance, and open-ended questions. Frequency/descriptive statistics were stated in aggregate form to evaluate the students' and faculty's perceptions of the competency-based program. RESULTS: Survey results showed that the majority of students and faculty members felt confident in the students' skills to practice as entry-level hygienists. Students and faculty thought the most valuable aspect of the competency- based program was quad scale experiences. The least beneficial aspect was reflection/ self assessment. CONCLUSION: There were many challenges involved in implementing a newly established non-graded competency- based clinical program. Although there was resistance from students and faculty, their overall perceptions of the program were positive. PMID- 29504026 TI - Sensory Evaluation of Cucumbers Treated with Blue Light. AB - Blue light delivered at wavelengths of 405 to 470 nm has been demonstrated to inhibit growth of bacteria on foodstuffs. This study investigated the effect of a narrow band of visible light on the color, texture, and flavor (organoleptic) properties of cucumbers. Previous research in this area has focused on either broad-spectrum light or specifically the UV bands of energy. Two experiments were performed, a sensory evaluation and a discriminative test. in both experiments, half of the cucumbers were irradiated with 464 nm at 18 J/cm2 and half were left untreated. For the sensory evaluation, each evaluator received a treated cucumber slice and an untreated cucumber slice, then rated each slice based on organoleptic properties using a 9-item scoring sheet. For the two-out-of-five test, each evaluator received five slices, two slices of treated cucumber and three slices of untreated cucumber. The evaluators were asked to group the cucumber slices based on how the slices were prepared. Statistical analysis revealed that trained sensory evaluators were unable to distinguish between treated and untreated samples using sensory assessment. Blue light does not diminish the organoleptic qualities of the tested vegetables and appears to be at least as acceptable, from an organoleptic perspective, as other light decontamination methods. PMID- 29504027 TI - Best Practices in Bridging Education: Multiple Case Study Evaluation of Postsecondary Bridging Programs for Internationally Educated Health Professionals. AB - AIMS: Bridging education for internationally trained professionals has grown in popularity, but little is known about promising practices for bridging education in allied health professions. This paper addresses this gap by examining the expected outcomes of effective bridging programs, the key features that contribute to their effectiveness, challenges faced by bridging programs, and the appropriate role of regulatory colleges, government, employers, and professional associations in bridging education. METHODS: We conducted a mixed-methods multiple case study analysis of seven bridging programs in Ontario, Canada, in five allied health professions: medical laboratory technology, medical radiation technology, diagnostic medical sonography, respiratory therapy, and physical therapy. RESULTS: Effective bridging programs are accessible and flexible in content and format. The key challenges include developing curricula tailored to participants' needs, identifying appropriate format for program delivery, obtaining clinical placements for participants, and achieving financial sustainability. Government, professional, and educational stakeholders should play a central role in bridging education planning and delivery. CONCLUSION: The success of a bridging program relies on two key components-program design and infrastructure. Partnerships with government, professional, and educational stakeholders facilitate the development of good bridging programs. PMID- 29504028 TI - What Constitutes Academic Dishonesty in Physical Therapy Education: Do Faculty and Learners Agree? AB - BACKGROUND: Academic dishonesty (AD) has been widely reported as an increasing concern in higher education. The primary purpose of the current study was to investigate the perceptions of what faculty and learners consider acts of AD and the level of seriousness within physical therapist (PT) education. Secondary aims included examining the incidence of AD reported by both groups. METHODS: A survey of 16 scenarios that constitute AD, with 4 questions for each scenario. Subjects included learners and faculty members of accredited PT programs in the southeastern United States. RESULTS: Statistically significant differences were found between groups for 5 of the 16 scenarios regarding what constituted an act of AD. For perception of the seriousness of an act of AD, faculty differed significantly from learners. Faculty also differed from learners in responding that someone in their classes had committed the act of AD when compared to learner's response. DISCUSSION: The results of our survey support that there is disagreement between what faculty and learners perceive to constitute AD. CONCLUSION: The stark contrast in views between faculty and learners regarding AD suggests the need for more clear and consistent academic policy awareness for both groups. PMID- 29504029 TI - 10 Reasons to Assign Seats in Allied Health Program Classrooms. AB - The topic of assigned seating likely is one that every allied health educator has considered at some point in time. Despite a great deal of informal discussions about the topic, surprisingly, not a great deal of scholarship has explored the role of assigned seating for students in allied health and medical education. While educators can readily recite reasons not to assign seats, rarely can educators provide reasons for doing so. in truth, however, there are many benefits to be reaped from assigned seating in college and medical school classrooms. Thus, the purpose of this paper is to present 10 reasons why allied health educators should consider assigning seats. PMID- 29504030 TI - Predictive Factors for Weight Loss Following Pancreatic Resection. AB - BACKGROUND: In pancreatic cancer, postoperative weight loss is associated with higher mortality. This study assessed preoperative factors associated with postoperative weight loss so that at-risk patients can be identified for intervention. METHOD: A retrospective review of patients who underwent pancreatic surgery was completed. Demographics and routine blood work were analyzed to determine association with postoperative weight loss. RESULTS: Of 74 patients, 85% lost weight after surgery. Weight loss was associated with time since surgery, preoperative weight, and preoperative albumin, making patients who appear best nourished the most at-risk. CONCLUSIONS: Weight loss was prevalent. in contrast to conventional assessment, patients who weighed more and had higher serum albumin lost the most weight. An interprofessional team may help to address this disparity. PMID- 29504031 TI - Relative and Absolute Reliability of the Professionalism in Physical Therapy Core Values Self-Assessment Tool. AB - Development of professional behaviors in Doctor of Physical Therapy (DPT) students is an important part of professional education. The American Physical Therapy Association (APTA) has developed the Professionalism in Physical Therapy Core Values Self-Assessment (PPTCV-SA) tool to increase awareness of personal values in practice. The PPTCV-SA has been used to measure growth in professionalism following a clinical or educational experience. There are few studies reporting psychometric properties of the PPTCV-SA. The purpose of this study was to establish properties of relative reliability (intraclass correlation coefficient, iCC) and absolute reliability (standard error of measurement, SEM; minimal detectable change, MDC) of the PPTCV-SA. in this project, 29 first-year students in a DPT program were administered the PPTCVA-SA on two occasions, 2 weeks apart. Paired t-tests were used to examine stability in PPTCV-SA scores on the two occasions. iCCs were calculated as a measure of relative reliability and for use in the calculation of the absolute reliability measures of SEM and MDC. Results of paired t-tests indicated differences in the subscale scores between times 1 and 2 were non-significant, except for three subscales: Altruism (p=0.01), Excellence (p=0.05), and Social Responsibility (p=0.02). iCCs for test retest reliability were moderate-to-good for all subscales, with SEMs ranging from 0.30 to 0.62, and MDC95 ranging from 0.83 to 1.71. These results can guide educators and researchers when determining the likelihood of true change in professionalism following a professional development activity. PMID- 29504032 TI - Correction to: Predictors of cerclage failure in patients with singleton pregnancy undergoing prophylactic cervical cerclage. AB - The original version of this article unfortunately contained a mistake. The presentation of Table 3 was incorrect. The corrected Table 3 is given below. PMID- 29504033 TI - Complication analysis of complete versus partial coverage of tissue expanders using serratus anterior musculofascial flaps in immediate breast reconstruction. AB - PURPOSE: To prevent tissue expander (TE) exposure following mastectomy flap necrosis in immediate breast reconstruction, the TE is usually covered completely or partially with a musculofascial (MF) flap. This study compares the complications of the two coverage methods. METHODS: We reviewed, retrospectively, 106 cases of immediate TE-based breast reconstruction. The patients were divided into two groups according to whether complete or partial TE coverage was done. In the complete coverage group, the serratus anterior MF flap was dissected and sutured to the pectoralis major muscle to cover the TE completely. In the partial coverage group, the serratus anterior MF flap was not dissected, and the lateral border of the pectoralis major muscle was sutured to the mastectomy skin flaps. RESULTS: The TEs were covered completely in 60 breasts and partially in 46 breasts. The mastectomy flap necrosis rate was significantly higher in the complete coverage group (p < 0.01), but there was no incidence of TE exposure in either groups. The lateral migration rate was significantly higher in the partial coverage group (p = 0.033). There were no significant differences in the cranial migration rate (p = 0.133). CONCLUSIONS: The complete coverage method is a better option if there is a high risk of mastectomy flap necrosis; however, surgeons should monitor carefully for cranial migration. PMID- 29504034 TI - Y-reconstruction could be better for ACL reconstruction in knee hyperextension versus double-bundle double-tunnel technique: a retrospective comparative study of 56 patients. AB - PURPOSE: To compare the clinical outcomes of double-bundle (DB) single-tibial tunnel technique and double-tunnel technique for ACL reconstruction in patients with knee hyperextension. METHODS: Defined as having constitutional hyperextension of greater than 10 degrees , 56 patients with knee hyperextension who underwent ACL reconstruction were included in this study. To exclude concomitant lesions, preoperative magnetic resonance imaging (MRI) was performed in all knees. 24 patients (Group A) were treated with the anatomic DB/single tibial tunnel ACL reconstruction and 32 patients (Group B) were treated with DB/double-tibial tunnel ACL reconstruction, all the included patients had knee hyperextension. Clinical results were evaluated by the extension angle, ROM, IKDC 2000 subjective score, rotational stability, pivot-shift test and anterior posterior translation test before the operation and at the end of follow-up. MRI scan of the knee positioned in full extension was performed after 6 months post operation. Location of tibial tunnels and graft signal intensity were assessed according to the MRI. RESULTS: Postoperative extension deficit was detected in Group B, ROM of the injured knee in Group A was from extension angle 8.91 +/- 3.16 degrees to flexion angle 115.58 +/- 10.53 degrees . ROM of the injured knee in Group B was from extension angle - 2.13 +/- 5.88 degrees to flexion angle 119.25 +/- 12.63 degrees . Flexion angles of two groups did not show any significant difference (p = 0.24), while extension angles were quite different (p < 0.0001). Group A was slightly higher than Group B in IKDC subjective scores, but without significant difference (Group A 45.1 +/- 6.5, Group B 42.4 +/- 4.8, p = 0.09). There was no significant difference between two groups in pivot-shift test. Post-operational MRI showed more anterior located tibial tunnel and higher graft signal intensity in Group B when compared with Group A. One patient in the Group B had ligament retear, and required revision surgery. CONCLUSION: DB/single tibial tunnel technique restored the knee stability and overcame the shortcomings (such as knee extension deficit and graft impingement) of DB/double tibial tunnel, which might be more suitable for ACL reconstruction in knees with hyperextension. LEVEL OF EVIDENCE: Level II to III. PMID- 29504035 TI - Correction to: Selenium mitigates cadmium-induced oxidative stress in tomato (Solanum lycopersicum L.) plants by modulating chlorophyll fluorescence, osmolyte accumulation, and antioxidant system. AB - The original paper was published online bearing incorrect headings for Table 1. Headers "change 0 by C" which appear in columns 2 and 3, should be C only. Corrected table is provided below. PMID- 29504036 TI - Injury potential of one-litre beer steins. AB - Injuries resulting from blows with beer steins are a frequent occurrence during annual autumn fairs or at beer halls in South Germany and Austria. The majority of these cases are tried in court and thus being assessed by a forensic medicine expert. The article at hand gives a short overview on the injury potential of one litre beer steins and explains the key variables to consider when analyzing beer stein injuries. On the basis of representative cases, which were assessed by specialists from the Institute of Legal Medicine of the Munich University over the last 5 years, the main biomechanical aspects and resulting injuries of one litre beer stein assaults are discussed. Several severe and potentially life threatening injuries have been observed after an assault with a one-litre beer stein. There is a discrepancy between the mechanical stability of brand new and used steins and the corresponding injuries, which can be explained by a decrease in impact tolerance of the steins with their use. In general, a blow with a one litre glass or stonework beer stein to the head can cause severe and even life threatening blunt as well as sharp trauma injuries. PMID- 29504037 TI - Ecological responses to forest age, habitat, and host vary by mycorrhizal type in boreal peatlands. AB - Despite covering vast areas of boreal North America, the ecological factors structuring mycorrhizal fungal communities in peatland forests are relatively poorly understood. To assess how these communities vary by age (younger vs. mature), habitat (fen vs. bog), and host (conifer trees vs. ericaceous shrub), we sampled the roots of two canopy trees (Larix laricina and Picea mariana) and an ericaceous shrub (Ledum groenlandicum) at four sites in northern Minnesota, USA. To characterize the specific influence of host co-occurrence on mycorrhizal fungal community structure, we also conducted a greenhouse bioassay using the same three hosts. Root samples were assessed using Illumina-based high-throughput sequencing (HTS) of the ITS1 rRNA gene region. As expected, we found that the relative abundance of ectomycorrhizal fungi was high on both Larix and Picea, whereas ericoid mycorrhizal fungi had high relative abundance only on Ledum. Ericoid mycorrhizal fungal richness was significantly higher in mature forests, in bogs, and on Ledum hosts, while ectomycorrhizal fungal richness did not differ significantly across any of these three variables. In terms of community composition, ericoid mycorrhizal fungi were more strongly influenced by host while ectomycorrhizal fungi were more influenced by habitat. In the greenhouse bioassay, the presence of Ledum had consistently stronger effects on the composition of ectomycorrhizal, ericoid, and ericoid-ectomycorrhizal fungal communities than either Larix or Picea. Collectively, these results suggest that partitioning HTS-based datasets by mycorrhizal type in boreal peatland forests is important, as their responses to rapidly changing environmental conditions are not likely to be uniform. PMID- 29504039 TI - Comparison of Recent Oil and Gas, Wind Energy, and Other Anthropogenic Landscape Alteration Factors in Texas Through 2014. AB - Recent research assessed how hydrocarbon and wind energy expansion has altered the North American landscape. Less understood, however, is how this energy development compares to other anthropogenic land use changes. Texas leads U.S. hydrocarbon production and wind power generation and has a rapidly expanding population. Thus, for ~47% of Texas (~324,000 km2), we mapped the 2014 footprint of energy activities (~665,000 oil and gas wells, ~5700 wind turbines, ~237,000 km oil and gas pipelines, and ~2000 km electrical transmission lines). We compared the footprint of energy development to non-energy-related activities (agriculture, roads, urbanization) and found direct landscape alteration from all factors affects ~23% of the study area (~76,000 km2), led by agriculture (~16%; ~52,882 km2). Oil and gas activities altered <1% of the study area (2081 km2), with 838 km2 from pipelines and 1242 km2 from well pad construction-and that the median Eagle Ford well pad is 7.7 times larger than that in the Permian Basin (16,200 vs. 2100 m2). Wind energy occupied <0.01% (~24 km2), with ~14 km2 from turbine pads and ~10 km2 from power transmission lines. We found that edge effects of widely-distributed energy infrastructure caused more indirect landscape alteration than larger, more concentrated urbanization and agriculture. This study presents a novel technique to quantify and compare anthropogenic activities causing both direct and indirect landscape alteration. We illustrate this landscape-mapping framework in Texas for the Spot-tailed Earless Lizard (Holbrookia lacerata); however, the approach can be applied to a range of species in developing regions globally. PMID- 29504038 TI - Transcriptome analysis of wheat seedling and spike tissues in the hybrid Jingmai 8 uncovered genes involved in heterosis. AB - MAIN CONCLUSION: Transcriptome analysis was carried out for wheat seedlings and spikes from hybrid Jingmai 8 and both inbred lines to unravel mechanisms underlying heterosis. Heterosis, known as one of the most successful strategies for increasing crop yield, has been widely exploited in plant breeding systems. Despite its great importance, the molecular mechanism underlying heterosis remains elusive. In the present study, RNA sequencing (RNA-seq) was performed on the seedling and spike tissues of the wheat (Triticum aestivum) hybrid Jingmai 8 (JM8) and its homozygous parents to unravel the underlying mechanisms of wheat heterosis. In total, 1686 and 2334 genes were identified as differentially expressed genes (DEGs) between the hybrid and the two inbred lines in seedling and spike tissues, respectively. Gene Ontology analysis revealed that DEGs from seedling tissues were significantly enriched in processes involved in photosynthesis and carbon fixation, and the majority of these DEGs expressed at a higher level in JM8 compared to both inbred lines. In addition, cell wall biogenesis and protein biosynthesis-related pathways were also significantly represented. These results confirmed that a combination of different pathways could contribute to heterosis. The DEGs between the hybrid and the two inbred progenitors from the spike tissues were significantly enriched in biological processes related to transcription, RNA biosynthesis and molecular function categories related to transcription factor activities. Furthermore, transcription factors such as NAC, ERF, and TIF-IIA were highly expressed in the hybrid JM8. These results may provide valuable insights into the molecular mechanisms underlying wheat heterosis. PMID- 29504041 TI - Correction to: Two-hour post-challenge glucose is a better predictor of adverse outcome after myocardial infarction than fasting or admission glucose in patients without diabetes. AB - Unfortunately, name of co-author "Thozhukat" was misspelled in the original publication and the same is corrected here. The original article has been corrected. PMID- 29504040 TI - Incomplete and false tract insertions in cochlear implantation: retrospective review of surgical and auditory outcomes. AB - OBJECTIVES: To evaluate incidence, demographics, surgical, and radiological correlates of incomplete and false tract electrode array insertions during cochlear implantation (CI). To evaluate outcomes in patients with incomplete electrode insertion (IEI). STUDY DESIGN: Retrospective analysis. SETTING: Otology and skull base center. PATIENTS AND METHODS: Charts of 18 patients (19 ears) with incomplete or false tract insertions of the electrode array were evaluated who underwent CI, with at least 1 year follow-up (from 470 cases). Demographic findings, etiologies, pre-operative radiologic findings, operative records, post operative plain radiographic assessment for extent of electrode insertion, and switch-on mapping were evaluated. Audiological outcomes were evaluated using maximum and last recorded vowel, word, sentence, and comprehension scores for patients with IEI. RESULTS: Incidence of insertional abnormalities was 4.25% with 17 instances of incomplete and 2 cases of insertion into superior semicircular canal. Mean age and duration of deafness were 55.18 +/- 4.62 and 22.12 +/- 5.71 years. Etiologies in the IEI group were idiopathic, otosclerosis, meningitis, chronic otitis media (COM), temporal bone fractures, and Neurofibromatosis-2. 29.4% cases had cochlear luminal obstruction. Mean radiological and active electrophysiological length of insertion was 20.49 +/- 0.66 and 19.49 +/- 0.88 mm, respectively. No significant correlation was observed between audiological outcomes and insertional length except in time to achieve maximum word scores (p = 0.04). Age at implantation had significant correlations with last recorded word and comprehension scores at mean follow-up of 42.9 months, and with time to achieve maximum auditory scores. CONCLUSIONS: IEI during cochlear implantation using straight electrodes can occur with or without cochlear luminal obstruction. Age plays an important role in the auditory rehabilitation in this patient subset. PMID- 29504042 TI - Bone mineral density and nutritional status in children with quadriplegic cerebral palsy. AB - : This study demonstrated the relationship of low bone mineral density (BMD) with the degree of motor impairment, method of feeding, anthropometric indicators, and malnutrition in children with quadriplegic cerebral palsy (CP). The control of these factors could optimize adequate bone mineralization, avoid the risk of osteoporosis, and would improve the quality of life. PURPOSE: The purpose of the study is to explore the relationship between low BMD and nutritional status in children with quadriplegic CP. METHODOLOGY: A cross-sectional analytical study included 59 participants aged 6 to 18 years with quadriplegic CP. Weight and height were obtained with alternative measurements, and weight/age, height/age, and BMI/age indexes were estimated. The BMD measurement obtained from the lumbar spine was expressed in grams per square centimeter and Z score (Z). Unpaired Student's t tests, chi-square tests, odds ratios, Pearson's correlations, and linear regressions were performed. RESULTS: The mean of BMD Z score was lower in adolescents than in school-aged children (p = 0.002). Patients with low BMD were at the most affected levels of the Gross Motor Function Classification System (GMFCS). Participants at level V of the GMFCS were more likely to have low BMD than levels III and IV [odds ratio (OR) = 5.8 (confidence interval [CI] 95% 1.4, 24.8), p = 0.010]. There was a higher probability of low BMD in tube-feeding patients [OR = 8.6 (CI 95% 1.0, 73.4), p = 0.023]. The probability of low BMD was higher in malnourished children with weight/age and BMI indices [OR = 11.4 (1.3, 94), p = 0.009] and [OR = 9.4 (CI 95% 1.1, 79.7), p = 0.017], respectively. CONCLUSION: There was a significant relationship between low BMD, degree of motor impairment, method of feeding, and malnutrition. Optimizing these factors could reduce the risk of osteopenia and osteoporosis and attain a significant improvement of quality of life in children with quadriplegic CP. PMID- 29504043 TI - Gene expression in retinal ischemic post-conditioning. AB - PURPOSE: The pathophysiology of retinal ischemia involves mechanisms including inflammation and apoptosis. Ischemic post-conditioning (Post-C), a brief non lethal ischemia, induces a long-term ischemic tolerance, but the mechanisms of ischemic post-conditioning in the retina have only been described on a limited basis. Accordingly, we conducted this study to determine the molecular events in retinal ischemic post-conditioning and to identify targets for therapeutic strategies for retinal ischemia. METHODS: To determine global molecular events in ischemic post-conditioning, a comprehensive study of the transcriptome of whole retina was performed. We utilized RNA sequencing (RNA-Seq), a recently developed, deep sequencing technique enabling quantitative gene expression, with low background noise, dynamic detection range, and discovery of novel genes. Rat retina was subjected to ischemia in vivo by elevation of intraocular pressure above systolic blood pressure. At 24 h after ischemia, Post-C or sham Post-C was performed by another, briefer period of ischemia, and 24 h later, retinas were collected and RNA processed. RESULTS: There were 71 significantly affected pathways in post-conditioned/ischemic vs. normals and 43 in sham post conditioned/ischemic vs. normals. Of these, 28 were unique to Post-C and ischemia. Seven biological pathways relevant to ischemic injury, in Post-C as opposed to sham Post-C, were examined in detail. Apoptosis, p53, cell cycle, JAK STAT, HIF-1, MAPK and PI3K-Akt pathways significantly differed in the number as well as degree of fold change in genes between conditions. CONCLUSION: Post-C is a complex molecular signaling process with a multitude of altered molecular pathways. We identified potential gene candidates in Post-C. Studying the impact of altering expression of these factors may yield insight into new methods for treating or preventing damage from retinal ischemic disorders. PMID- 29504044 TI - Weekly regimen of vitamin D supplementation is more efficacious than stoss regimen for treatment of vitamin D deficiency in children with chronic liver diseases. AB - : There are no evidence-based recommendations on the ideal dose and regimen for supplementation of vitamin D in children with chronic liver disease (CLD). This study aimed to compare the safety and efficacy of weekly and stoss regimens for treatment of vitamin D deficiency in these children. Children between the ages of 1 to 18 years with CLD and hypovitaminosis D defined by 25-OH vitamin D (25(OH)D) < 30ug/l were included. They were randomized to receive either stoss regimen (600,000 IU on day 1) or weekly (60,000 IU weekly) regimen of vitamin D. The 25(OH)D levels at 3 and 6 months were compared in the two groups. A total of 210 suspected cases of CLD were assessed for eligibility. Of a total of 67 children satisfying the inclusion criteria, 33 and 34 were randomized to receive stoss and weekly regimen, respectively. Final analysis included 28 children in each group. Clinical rickets was seen in 25.4% of children with hypovitaminosis D. The rise in levels of 25(OH)D at 3 months was higher with weekly regimen (34.3 +/- 30.7 ug/l) as compared to stoss regimen (17.2 +/- 11.5 ug/l) (p = 0.009). Rise at 6 months as compared to baseline was significantly higher with weekly regimen (30.7 +/- 24ug/l) as compared to stoss regimen (11 +/- 8.4 ug/l) (p < 0.001). Normal levels of 25(OH)D at 6 months were achieved in 24/28 (85.7%) of those receiving weekly regimen and 9/28 (32.1%) of those receiving stoss regimen (p < 0.001). With stoss therapy, 25(OH)D increased at 3 months as compared to baseline but thereafter dropped significantly at 6 months (p = 0.008). CONCLUSION: Weekly regimen of vitamin D supplementation is more effective than stoss regimen for treatment of hypovitaminosis D in children with CLD. Once normal levels are achieved, child should be shifted to 60,000 IU per month as maintenance dose. What is Known: * Vitamin D deficiency is more common and severe in children with chronic liver diseases. * Currently used doses fail to achieve normal vitamin D levels in these children. What is New? * Weekly regimen of 60,000 IU of vitamin D3 is the most effective regimen for treating vitamin D deficiency in children with CLD. * Children with CLD should further receive maintenance dose of 60,000 IU every month. PMID- 29504045 TI - Human Genetics of Addiction: New Insights and Future Directions. AB - PURPOSE OF REVIEW: With the advent of the genome-wide association study (GWAS), our understanding of the genetics of addiction has made significant strides forward. Here, we summarize genetic loci containing variants identified at genome wide statistical significance (P < 5 * 10-8) and independently replicated, review evidence of functional or regulatory effects for GWAS-identified variants, and outline multi-omics approaches to enhance discovery and characterize addiction loci. RECENT FINDINGS: Replicable GWAS findings span 11 genetic loci for smoking, eight loci for alcohol, and two loci for illicit drugs combined and include missense functional variants and noncoding variants with regulatory effects in human brain tissues traditionally viewed as addiction-relevant (e.g., prefrontal cortex [PFC]) and, more recently, tissues often overlooked (e.g., cerebellum). GWAS analyses have discovered several novel, replicable variants contributing to addiction. Using larger sample sizes from harmonized datasets and new approaches to integrate GWAS with multiple 'omics data across human brain tissues holds great promise to significantly advance our understanding of the biology underlying addiction. PMID- 29504046 TI - Advances in Drug Discovery and Development in Geriatric Psychiatry. AB - PURPOSE OF REVIEW: This article reviews recent advances in drug discovery and development for geriatric psychiatry. Drug discovery for disorders of the central nervous system is a long and challenging process, with a high attrition rate from the preclinical stages through to marketing a compound. Developing drugs for geriatric neuropsychiatric conditions presents additional challenges, due to the complexity of the symptoms, comorbid diagnoses, and the variability of the population. Despite there being limited success over the past two decades, a number of new approaches have identified potential targets for preclinical development and ultimately clinical testing. RECENT FINDINGS: Recent approaches have tried to address specific mechanisms that relate to the disease progression. These approaches include combining a number of ligands into to multi-target compounds, or targeting specific types of cells such as protein kinases or myeloid cells. In addition, the increased use of induced pluripotent stem cell cultures has enabled new compounds to be tested on disease-specific tissues, increasing the success rate of the lead compounds going through the preclinical stages. New pharmacological agents designed with advanced screening techniques and the shift towards systems pharmacology is changing the landscape of drug discovery in geriatric psychiatry. There is potential for these new agents to produce targeted effects in the framework of disorders that have long been untreatable. PMID- 29504048 TI - The Interplay Between Marijuana-Specific Risk Factors and Marijuana Use Over the Course of Adolescence. AB - Permissive attitudes and norms about marijuana use and perceptions of low harm from use are considered risk factors for adolescent marijuana use. However, the relationship between risk and use may be reciprocal and vary across development and socializing domains. We examined the bidirectional relationships between marijuana-specific risk factors in individual, parent, peer, and community domains and adolescent marijuana use. Longitudinal data came from a sample of 2002 adolescents in 12 communities. Controlling for sociodemographic covariates and communities in which the individuals resided, autoregressive cross-lagged models examined predictive associations between the risk factors and marijuana use. After accounting for concurrent relationships between risk and use and stability in behavior over time, early adolescence and the transition to high school were particularly salient developmental time points. Specifically, higher risk in all four domains in grades 7 and 9 predicted greater use 1 year later. Moreover, youth's perception of lax community enforcement of laws regarding adolescent use at all time points predicted increases in marijuana use at the subsequent assessment, and perceived low harm from use was a risk factor that prospectively predicted more marijuana use at most of the time points. Finally, greater frequency of marijuana use predicted higher levels of risk factors at the next time point in most socializing domains throughout adolescence. Prevention programs should take into account developmental transitions, especially in early adolescence and during the transition to high school. They also should focus on the reciprocal relationships between use and risk across multiple socializing domains. PMID- 29504050 TI - Coming to terms with the imperfectly normal child: attitudes of Israeli parents of screen-positive infants regarding subsequent prenatal diagnosis. AB - This study examines the interface between newborn screening and prenatal diagnosis from the point-of-view of parents of screen-positive children. Many conditions covered by newborn screening represent classic (autosomal recessive) Mendelian disorders. Parents of screen-positive infants therefore often come to learn that they are carriers of the disease, and face a decision whether to test for it in future pregnancies. Semi-structured interviews were conducted in 2015 2017 with 34 Israeli parents whose child was screen positive. Three major themes emanated from the parents' attitudes toward prenatal testing for the disease in prospective hypothetical pregnancies: rejection of prenatal testing for the disease associated with the screen positive, and relying instead on newborn screening to reveal if a future baby is also sick (18/34, 53%); support of prenatal testing to get more information (7/34, 21%) and support of prenatal testing in order to abort in case of a test positive (9/34, 26%). We discuss the importance of newborn screening for reproductive decision-making, highlighting the arguments associated with positive and negative parental views of the possibility of having another child with the same condition associated with the screen-positive of the child that had already been born. The conclusions challenge the common assertion that parents pursue the dream of the "perfect child" through prenatal diagnosis that "naturally" leads to selective abortion. The diversity of views expressed by Israeli parents of screen-positive children highlights the diversity of normative scripts of "genetic responsibility" in the context of parenthood. PMID- 29504047 TI - Sex Differences in Autism Spectrum Disorder: a Review. AB - PURPOSE OF REVIEW: Neurodevelopmental disorders disproportionately affect males. The mechanisms underlying male vulnerability or female protection are not known and remain understudied. Determining the processes involved is crucial to understanding the etiology and advancing treatment of neurodevelopmental disorders. Here, we review current findings and theories that contribute to male preponderance of neurodevelopmental disorders, with a focus on autism. RECENT FINDINGS: Recent work on the biological basis of the male preponderance of autism and other neurodevelopmental disorders includes discussion of a higher genetic burden in females and sex-specific gene mutations or epigenetic changes that differentially confer risk to males or protection to females. Other mechanisms discussed are sex chromosome and sex hormone involvement. Specifically, fetal testosterone is involved in many aspects of development and may interact with neurotransmitter, neuropeptide, or immune pathways to contribute to male vulnerability. Finally, the possibilities of female underdiagnosis and a multi hit hypothesis are discussed. This review highlights current theories of male bias in developmental disorders. Topics include environmental, genetic, and epigenetic mechanisms; theories of sex chromosomes, hormones, neuroendocrine, and immune function; underdiagnosis of females; and a multi-hit hypothesis. PMID- 29504049 TI - Future Pharmacotherapy for Obesity: New Anti-obesity Drugs on the Horizon. AB - PURPOSE OF REVIEW: Obesity is a global health crisis with detrimental effects on all organ systems leading to worsening disease state and rising costs of care. Persons with obesity failing lifestyle therapies need to be escalated to appropriate pharmacological treatment modalities, medical devices, and/or bariatric surgery if criteria are met and more aggressive intervention is needed. The progression of severe obesity in the patient population coupled with related co-morbidities necessitates the development of novel therapies for the treatment of obesity. This development is preceded by increased understanding of the underpinnings of energy regulation and neurohormonal pathways involved in energy homeostasis. RECENT FINDINGS: Though there are approved anti-obesity drugs available in the USA, newer drugs are now in the pipeline for development given the urgent need. This review focuses on anti-obesity drugs in the pipeline including centrally acting agents (setmelanotide, neuropeptide Y antagonist [velneperit], zonisamide-bupropion [Empatic], cannabinoid type-1 receptor blockers), gut hormones and incretin targets (new glucagon-like-peptide-1 [GLP-1] analogues [semaglutide and oral equivalents], amylin mimetics [davalintide, dual amylin and calcitonin receptor agonists], dual action GLP-1/glucagon receptor agonists [oxyntomodulin], triple agonists [tri-agonist 1706], peptide YY, leptin analogues [combination pramlintide-metreleptin]), and other novel targets (methionine aminopeptidase 2 inhibitor [beloranib], lipase inhibitor [cetilistat], triple monoamine reuptake inhibitor [tesofensine], fibroblast growth factor 21), including anti-obesity vaccines (ghrelin, somatostatin, adenovirus36). With these new drugs in development, anti-obesity therapeutics have potential to vastly expand allowing better treatment options and personalized approach to obesity care. PMID- 29504052 TI - Displacement of the Intragastric Balloon from the Fundus to the Antrum Results in Enhanced Weight Loss. AB - BACKGROUND: The BioEnterics Intragastric Balloon [BIB] is a reliable, non invasive technique to manage obesity for subjects who refuse or are unsuitable for bariatric surgery. In a prior study, BIB placed in the antrum [A] was found to have significantly better results on weight loss in relation to that in fundus [F], but many balloons initially placed in the F were eventually found in the A. The aim of the present analysis was to evaluate whether the balloon position [firmly in F, firmly in A, or transient from F to A [FA]] influences the 3- and 6 month weight loss. MATERIAL: Six hundred sixty-eight patients that underwent successful BIB treatment were assigned into three groups: group F [n = 354], group A [n = 159], and group AF [n = 155]. Weight loss parameters were recorded and analyzed at 3 and 6 months. RESULTS: In all three groups, there was a significant, progressive reduction of BMI at 3 and 6 months. At 6 months, BMI reduction between groups F and A, and F and FA [p = 0.001] and groups A and FA [p = 0.018] was prominent. CONCLUSION: The position of the BIB affects its effectiveness: better results when antrum is involved. This observation seems to give a great perspective to newly established gastric space-occupying devices, which aim to have a compartment constantly present in the antrum. However, further studies have to be performed in order to validate the results and more importantly to clarify the mechanisms implied. PMID- 29504051 TI - Updated Meta-Analysis of BIN1, CR1, MS4A6A, CLU, and ABCA7 Variants in Alzheimer's Disease. AB - Genome-wide association studies (GWAS) have associated several genetic variants with late-onset Alzheimer's disease (LOAD), a neurodegenerative disease. Among those, rs3764650 ABCA7, rs6656401 CR1, and rs744373 BIN1 were associated as risk factors for LOAD, while rs11136000 CLU and rs610932 MS4A6A were protective. Recently, several case-control studies have investigated the association of these polymorphisms with AD. However, not all meta-analyses analyzed these variants across different ethnic groups. Therefore, we performed an updated meta-analysis of rs3764650 ABCA7, rs6656401 CR1, rs744373 BIN1, rs11136000 CLU, and rs610932 MS4A6A variants associated with LOAD, considering different ethnic populations. We utilized samples from 38 articles, comprising a total of 24,771 patients and 35,324 controls obtained through the PubMed database. Odds ratios (ORs) with 95% confidence intervals (CI) for polymorphisms were calculated by allelic comparison as an additive genetic model. We validated the risk for LOAD with BIN1 (rs744373), CR1 (rs6656401), and ABCA7 (rs376465), as well as the protective association for MS4A6A (rs610932) and CLU (rs11136000) variants. PMID- 29504053 TI - Trends in BMI, Glycemic Control and Obesity-Associated Comorbidities After Explantation of the Duodenal-Jejunal Bypass Liner (DJBL). AB - BACKGROUND: A novel-approach for treatment of obesity and diabetes mellitus type 2 (T2DM) is represented by the endoscopic duodenal-jejunal bypass liner (DJBL). Recent data from the German DJBL registry provide evidence for substantial efficacy of the DJBL during the implantation period in obese patients with T2DM. However, little is known about the trends of glycemic control, BMI, and comorbidities after explantation of the DJBL, which have been investigated in the registry in this report. METHODS: Patients were selected from the registry if they had a dataset at implantation, explantation, and at least one time point after explantation of the DJBL (n = 77). We also investigated a subgroup of patients with available data at least 1 year (-2 weeks) after explantation of the DJBL (n = 32). RESULTS: For a mean BMI at implantation and a mean follow-up period, an increase of BMI of 2.1 kg/m2 (CI 0.8-3.2; p = 0.013) had to be expected (for HbA1c 0.3% (CI - 0.0-0.7; p = n.s.), respectively). In the subgroup analysis, HbA1c and BMI increased after explantation of the DJBL but stayed significantly below baseline levels. Meanwhile, the mean number of antidiabetic drugs slightly increased. There was deterioration seen for blood pressure and LDL cholesterol over the postexplantation period to approximately baseline levels (or higher). CONCLUSION: With this data, we show that improvement of HbA1c and BMI can be partly maintained over a time of nearly 1-year postexplantation of the DJBL. However, for HbA1c, this may be biased by intensified medical treatment and effects deteriorated with time after explantation. These results suggest that implantation of the DJBL needs to be integrated in a long-term weight management program as most of other interventions in obese patients with T2DM. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02731859. PMID- 29504054 TI - Higher prevalence of periprosthetic fractures with ceramic on polyethylene hip bearing compared with ceramic on ceramic on the contralateral side: a forty year experience with hip osteonecrosis. AB - PURPOSE: It is unclear whether late THA periprosthetic femoral fractures are related to a mechanical mechanism that decreases strength of the femur (for example, loosening) or to a biological problem as osteolysis. It is also unknown if ceramic on ceramic bearing couples decrease the risk of late periprosthetic fractures as a result of the absence of wear and osteolysis. MATERIAL AND METHODS: We therefore asked whether the cumulative long-term fractures were different according to the couple of friction ceramic on ceramic or ceramic on polyethylene in 327 patients (654 hips) with bilateral THA (one ceramic-ceramic, and the contralateral ceramic-polyethylene) who had THA with cemented stems performed between from 1978 to 2000 for osteonecrosis. RESULTS: There were two intra-operative fractures (0.3%). The median follow-up was 22 years (range, 15-40 years), and at the most recent follow-up, the cumulative number of late (after 7 years of follow-up) post-operative fractures was 32 (5% of 654 hips). Fractures were unilateral, which means for the 327 patients, a 10% rate of fractures. Periprosthetic fractures increased in number with follow-up: seven fractures (1% of 654 hips) occurred within ten years of THA implantation, 20 (3%) within 20 years, 26 (4%) within 30 years, and 32 (5%) within 40 years. The risk of fracture was influenced (p < 0.001) by the bearing surfaces at the time of prosthetic implantation, low (0.3%) for ceramic on ceramic (1/32 fractures; 1/327 hips), high (10%) for ceramic on PE (31/32 fractures; 31/327 hips). CONCLUSION: In summary, when the contralateral hip of the same patient is the control, after 40 years of follow-up, post-operative fractures occur 30 times more often on the side with PE cup than on the side with ceramic/ceramic bearing. PMID- 29504055 TI - Vitamin D: part I; from plankton and calcified skeletons (500 million years ago) to rickets. AB - The vitamin D history started early in the evolution of life (billion years ago) as a photochemical reaction producing an inert molecule. During the early evolution of vertebrates, this molecule became essential for calcium and bone homeostasis of terrestrial animals and arrived to the status of hormone. Phytoplankton, zooplankton, and most plants and animals that are exposed to sunlight have the capacity to make vitamin D. Vitamin D is critically important for the development, growth, and maintenance of a healthy skeleton from birth until death. The major function of vitamin D is to maintain calcium homeostasis. It accomplishes this by increasing the efficiency of the intestine to absorb dietary calcium. When there is inadequate calcium in the diet to satisfy the body's calcium requirement, vitamin D communicates to the osteoblasts that signal osteoclast precursors to mature and dissolve the calcium stored in the bone. The typical "vitamin D-deficiency" disorder was observed for growing children in the west and south of England in the early 1600s. This disease was described by Glisson and named "rickets" (known also as "the English disease") and was observed with epidemic proportions in northern Europe and North America. The corrections of deformities of rickets were at the origin of the name "orthopedia" and of the technique of osteotomies. PMID- 29504056 TI - Evaluation of the Fecal Incontinence Quality of Life Scale (FIQL) using item response theory reveals limitations and suggests revisions. AB - PURPOSE: The Fecal Incontinence Quality of Life Scale (FIQL) is a commonly used patient-reported outcome measure for fecal incontinence, often used in clinical trials, yet has not been validated in English since its initial development. This study uses modern methods to thoroughly evaluate the psychometric characteristics of the FIQL and its potential for differential functioning by gender. METHODS: This study analyzed prospectively collected patient-reported outcome data from a sample of patients prior to colorectal surgery. Patients were recruited from 14 general and colorectal surgeons in Vancouver Coastal Health hospitals in Vancouver, Canada. Confirmatory factor analysis was used to assess construct validity. Item response theory was used to evaluate test reliability, describe item-level characteristics, identify local item dependence, and test for differential functioning by gender. RESULTS: 236 patients were included for analysis, with mean age 58 and approximately half female. Factor analysis failed to identify the lifestyle, coping, depression, and embarrassment domains, suggesting lack of construct validity. Items demonstrated low difficulty, indicating that the test has the highest reliability among individuals who have low quality of life. Five items are suggested for removal or replacement. Differential test functioning was minimal. CONCLUSIONS: This study has identified specific improvements that can be made to each domain of the Fecal Incontinence Quality of Life Scale and to the instrument overall. Formatting, scoring, and instructions may be simplified, and items with higher difficulty developed. The lifestyle domain can be used as is. The embarrassment domain should be significantly revised before use. PMID- 29504058 TI - Correction to: Deleterious Effects of VEGFR2 and RET Inhibition in a Preclinical Model of Parkinson's Disease. AB - The authors found a terrible mistake in the manuscript. The legends from the Fig. 5 and 6 are interchanged. The Fig. 5 should be appeared with the legend from the Fig. 6 and Fig. 6 should be appeared with the legend from the Fig. 5. PMID- 29504057 TI - Rapid Identification of Seven Waterborne Exophiala Species by RCA DNA Padlock Probes. AB - The black yeast genus Exophiala includes numerous potential opportunistic species that potentially cause systematic and disseminated infections in immunocompetent individuals. Species causing systemic disease have ability to grow at 37-40 degrees C, while others consistently lack thermotolerance and are involved in diseases of cold-blooded, waterborne vertebrates and occasionally invertebrates. We explain a fast and sensitive assay for recognition and identification of waterborne Exophiala species without sequencing. The ITS rDNA region of seven Exophiala species (E. equina, E. salmonis, E. opportunistica, E. pisciphila, E. aquamarina, E. angulospora and E. castellanii) along with the close relative Veronaea botryosa was sequenced and aligned for the design of specific padlock probes for the detection of characteristic single-nucleotide polymorphisms. The assay demonstrated to successfully amplify DNA of target fungi, allowing detection at the species level. Amplification products were visualized on 1% agarose gels to confirm specificity of probe-template binding. Amounts of reagents were reduced to prevent the generation of false positive results. The simplicity, tenderness, robustness and low expenses provide padlock probe assay (RCA) a definite place as a very practical method among isothermal approaches for DNA diagnostics. PMID- 29504059 TI - Influence of a brisk walking program on postural responses in sedentary older women: a randomised trial. AB - This study analyzes the evolution in kinematic and non-linear stabilometric parameters in elderly sedentary women selected to participate in a brisk walking program. Ninety-four women were randomly selected for a program of 78 sessions over 6 months, with three sessions of 60 min per week. On the force platform, participants were assessed with both eyes opened as well as eyes closed during a period of 51.2 s and the sampling frequency was 40 Hz. The main dependent kinematic variables were the length, stabilogram surface, and the mean position in anteroposterior as well as medio-lateral directions. For the dynamic approach, we have selected the parameters of recurrence quantification analysis, sample entropy, and multiscale entropy. The kinematic and the time series analysis of group * time interactions demonstrated that 6 months of walk-training lacked influence on kinematic postural responses and on dynamical measurements. The weekly brisk walking program was situated on flat ground and consisted of three 60-min weekly sessions lasting 6 months, leading to no significant effect on postural responses. In regards to international recommendations brisk walking is a pertinent exercise. However, in older sedentary women, our study indicated a systemic lack of influence of 6 months' walk-training on flat ground on kinematic postural responses and on dynamical measures obtained by time series analysis. PMID- 29504060 TI - Author Correction: Predictors for Intracranial Hemorrhage Following Intravenous Thrombolysis in Posterior Circulation Stroke. AB - In the original publication of the article, there was a switched order of author names. PMID- 29504061 TI - Effect of pad-fan cooling and dietary organic acid supplementation during late gestation and lactation on reproductive performance and antioxidant status of multiparous sows in hot weather. AB - A 2 * 2 factorial arrangement (rearing room with or without pad-fan cooling * diet with or without 2.5 kg/t organic acid) was used to evaluate the effect of pad-fan cooling and dietary organic acid supplementation during perinatal period on reproductive performance and antioxidant status of sows in hot weather. This study was conducted in a subtropical city in Guangdong Province in South China between August and October, 2015. At day 85 of gestation, a total of 112 sows were randomly assigned to the four treatments with 28 sows per treatment, and maintained until day 21 of lactation, and the feeding trial lasted for 51 days. During the experimental period, room temperature and humidity were recorded hourly. The lactation feed intake of sows (P = 0.109) and stillbirths (P < 0.05) increased when the sows were reared in the room with the pad-fan cooling against the room without pad-fan cooling. The number of weak newborns per litter and the malondialdehyde content in days 14 and 21 milk decreased (P < 0.05), while the lactation feed intake of sows, weaned litter weights, and individual pig weights increased when the sows were fed the organic acid (P < 0.05). In conclusion, pad fan cooling in rearing room improved the lactation feed intake of sows, and dietary organic acid supplementation improved reproductive performance and milk antioxidant status of sows. Pad-fan cooling is recommended in farrowing room, but not in gestating room. PMID- 29504063 TI - Serious Non-AIDS Conditions in HIV: Benefit of Early ART. AB - PURPOSE OF REVIEW: Optimal control of HIV can be achieved by early diagnosis followed by the initiation of antiretroviral therapy (ART). Two large randomised trials (TEMPRANO and START) have recently been published documenting the clinical benefits to HIV-positive adults of early ART initiation. Main findings are reviewed with a focus on serious non-AIDS (SNA) conditions. RECENT FINDINGS: Data from the two trials demonstrated that initiating ART early in the course of HIV infection resulted in marked reductions in the risk of opportunistic diseases and invasive bacterial infections. This indicates that HIV causes immune impairment in early infection that is remedied by controlling viral replication. Intriguingly, in START, a marked reduction in risk of cancers, both infection related and unrelated types of cancers, was observed. Like the findings for opportunistic infections, this anti-cancer effect of early ART shows how the immune system influences important pro-oncogenic processes. In START, there was also some evidence suggesting that early ART initiation preserved kidney function, although the clinical consequence of this remains unclear. Conversely, while no adverse effects were evident, the trials did not demonstrate a clear effect on metabolic-related disease outcomes, pulmonary disease, or neurocognitive function. HIV causes immune impairment soon after acquisition of infection. ART reverses this harm at least partially. The biological nature of the immune impairment needs further elucidation, as well as mechanisms and clinical impact of innate immune activation. Based on the findings from TEMPRANO and START, and because ART lowers the risk of onward transmission, ART initiation should be offered to all persons following their diagnosis of HIV. PMID- 29504064 TI - Media Effects in Youth Exposed to Terrorist Incidents: a Historical Perspective. AB - PURPOSE OF REVIEW: This paper reviews the evidence on the relationship between contact with media coverage of terrorist incidents and psychological outcomes in children and adolescents while tracing the evolution in research methodology. RECENT FINDINGS: Studies of recent events in the USA have moved from correlational cross-sectional studies examining primarily television coverage and posttraumatic stress reactions to longitudinal studies that address multiple media forms and a range of psychological outcomes including depression and anxiety. Studies of events in the USA-the 1995 Oklahoma City bombing, the September 11 attacks, and the 2013 Boston Marathon bombing-and elsewhere have used increasingly sophisticated research methods to document a relationship between contact with various media forms and adverse psychological outcomes in children with different event exposures. Although adverse outcomes are associated with reports of greater contact with terrorism coverage in cross-sectional studies, there is insufficient evidence at this time to assume a causal relationship. Additional research is needed to investigate a host of issues such as newer media forms, high-risk populations, and contextual factors. PMID- 29504062 TI - Sex Differences in HIV Infection. AB - PURPOSE OF REVIEW: This review will outline the multilevel effects of biological sex on HIV acquisition, pathogenesis, treatment response, and prospects for cure. Potential mechanisms will be discussed along with future research directions. RECENT FINDINGS: HIV acquisition risk is modified by sex hormones and the vaginal microbiome, with the latter acting through both inflammation and local metabolism of pre-exposure prophylaxis drugs. Female sex associates with enhanced risk for non-AIDS morbidities including cardiovascular and cerebrovascular disease, suggesting different inflammatory profiles in men and women. Data from research on HIV cure points to sex differences in viral reservoir dynamics and a direct role for sex hormones in latency maintenance. Biological sex remains an important variable in determining the risk of HIV infection and subsequent viral pathogenesis, and emerging data suggest sex differences relevant to curative interventions. Recruitment of women in HIV clinical research is a pathway to both optimize care for women and to identify novel therapeutics for use in both men and women. PMID- 29504065 TI - Influence of temperature and light-dark cycle on hatching of Eylais extendens. AB - Little research has been done on egg diapause and the embryonic development of water mites. The aim of this study was to check the impact of temperature and periods of light on hatching of larvae of Eylais extendens. Three batches of eggs which were spawned on 30 July were placed at one of three temperatures (4, 10 and 20 degrees C) and two periods of light (7 and 14 h per day). Egg hatching (both, percentage of hatched larvae and rate of hatching) was found to differ between 4 versus 10 degrees C and between 4 versus 20 degrees C, but not between 10 versus 20 degrees C. The periods of light had no influence on hatching. This synchronization of hatching, enabling the eggs to emerge from diapause in the spring, could be considered an evolutionary adaptation aimed at postponing hatching of late-spawned eggs until a time allowing for completion of the full development cycle, including the parasitic larval stage. PMID- 29504066 TI - Anticonvulsive effects of endocannabinoids; an investigation to determine the role of regulatory components of endocannabinoid metabolism in the Pentylenetetrazol induced tonic- clonic seizures. AB - 2-Arachidonoylglycerol (2-AG) and anandamide are two major endocannabinoids produced, released and eliminated by metabolic pathways. Anticonvulsive effect of 2-AG and CB1 receptor is well-established. Herein, we designed to investigate the anticonvulsive influence of key components of the 2-AG and anandamide metabolism. Tonic-clonic seizures were induced by an injection of Pentylenetetrazol (80 mg/kg, i.p.) in adult male Wistar rats. Delay and duration for the seizure stages were considered for analysis. Monoacylglycerol lipase blocker (JJKK048; 1 mg/kg) or alpha/beta hydroxylase domain 6 blocker (WWL70; 5 mg/kg) were administrated alone or with 2-AG to evaluate the anticonvulsive potential of these enzymes. To determine the CB1 receptor involvement, its blocker (MJ15; 3 mg/kg) was administrated associated with JJKK048 or WWL70. To assess anandamide anticonvulsive effect, anandamide membrane transporter blocker (LY21813240; 2.5 mg/kg) was used alone or associated with MJ15. Also, fatty acid amide hydrolase blocker (URB597; 1 mg/kg; to prevent intracellular anandamide hydrolysis) were used alone or with AMG21629 (transient receptor potential vanilloid; TRPV1 antagonist; 3 mg/kg). All compounds were dissolved in DMSO and injected i.p., before the Pentylenetetrazol. Both JJKK048 and WWL70 revealed anticonvulsive effect. Anticonvulsive effect of JJKK048 but not WWL70 was CB1 receptor dependent. LY2183240 showed CB1 receptor dependent anticonvulsive effect. However, URB597 revealed a TRPV1 dependent proconvulsive effect. It seems extracellular accumulation of 2-AG or anandamide has anticonvulsive effect through the CB1 receptor, while intracellular anandamide accumulation is proconvulsive through TRPV1. PMID- 29504067 TI - Electron probe micro-analysis reveals the complexity of mineral deposition mechanisms in urinary stones. AB - Urinary stones are complex mineralogical formations in the urinary system often impairing the kidney function. Several studies have attempted to understand the mechanisms of stone formation and growth; however, it remains to be fully explored. Here, we present a detailed investigation on the morphological and mineralogical characterizations of urinary stones. Structural properties of different types of urinary stones were done by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and field-emission scanning electron microscope (FE-SEM) analyses. X-ray maps of major and the trace elements were obtained using electron microprobe (EPMA) technique. Basic metabolic panel and urinary parameters of the patients were used for comparing mineral compositions among stone types. The study included five major types of stones identified based on the FTIR spectra. FTIR and XRD helped in identifying the major components of these stones. FE-SEM images revealed distinct microstructure and morphology of the stones among the stone types. EPMA analysis showed the presence of many metals other than calcium and certain non-metals within the urinary stone matrix at measurable levels, sometimes with distinct distribution patterns. The study demonstrates the characteristic micro-structure, morphology, distribution, and composition of elements in different stone types. Findings of the study provide scope for understanding the complex mechanisms involved in the urolithogenesis and association of trace elements in it. PMID- 29504068 TI - Histone deacetylase inhibitor chidamide induces growth inhibition and apoptosis in NK/T lymphoma cells through ATM-Chk2-p53-p21 signalling pathway. AB - We investigated the anti-tumour effects and the underlying molecular mechanisms of a new oral histone deacetylase inhibitor (HDACi), chidamide, in NK/T cell lymphoma (NKTCL), a rare and highly aggressive non-Hodgkin lymphoma with poor outcomes. SNT-8 and SNK-10 NKTCL cell lines were exposed to different concentrations of chidamide for the indicated time. The treated cells were analysed for cell proliferation, cell cycle progression, and cell apoptosis. Proteins in the AKT/mTOR and MAPK signalling pathways and the DNA damage response (DDR) cell cycle checkpoint pathway were measured by Western blotting. Chidamide inhibited cell proliferation in a dose- and time-dependent manner, arrested cell cycle progression at the G0/G1 phase, and induced apoptosis in the NKTCL cell lines. In addition, we found that chidamide suppressed the phosphorylation levels of proteins in the AKT/mTOR and MAPK signalling pathways and activated the DDR cell cycle checkpoint pathway, that is, the ATM-Chk2-p53-p21 pathway. Expression of EBV genes was also assessed by Real-Time PCR. Chidamide induced EBV lytic phase gene expression in EBV-positive NKTCL. Our results provide evidence that chidamide shows antitumour effects by inhibiting the AKT/mTOR and MAPK signalling pathways and activating the ATM-Chk2-p53-p21 signalling pathway in vitro. PMID- 29504069 TI - PIK3CA mutation sensitizes breast cancer cells to synergistic therapy of PI3K inhibition and AMPK activation. AB - Breast cancer has been emerging as a most common threat among women, thus many efforts were made to find drugs for fighting breast cancer. So far, PI3K (Phosphatidylinositol-4,5-bisphosphate 3-kinase) inhibitors have been believed to be effective drugs until frequent resistance emerged. Recently, PI3K H1047R mutation has been reported to sensitize breast cancer cells to PI3K inhibition by aspirin. Considering aspirin activates AMPK (AMP-activated protein kinase) simultaneously, it is possible that AMPK activators and PI3K inhibitors can synergistically inhibit breast cancers. Here we clearly observed synergistic suppression of cell growth in all three breast cancer cell lines (MCF-7, MDA-MB 361 and HCC38) when co-treating cells with PI3K inhibitor GDC-0941 and AMPK activator AICAR (5-Aminoimidazole-4-carboxamide ribonucleotide). What is more, it is rather remarkable that the synergistic effect was much more dramatic in PIK3CA (PI3K catalytic subunit alpha) mutated (E545K) cells (MCF-7 and MDA-MB-361) than in PIK3CA wild-type cells (HCC38), which implied there is a relationship between PI3K genetic status and the efficacy of combination therapy. By using PIK3CA wild type isogenic MCF-7 cell line, which exhibited attenuated cell proliferation compared with the parental MCF-7 cell line, we found endogenous reverse mutation of PIK3CA E545K alleles to wild-type sequence in MCF-7 cells dramatically impaired the synergy of PI3Ki&Ka (combinatorial PI3K inhibition and AMPK activation). Furthermore, PI3Ki&Ka significantly attenuated tumorigenesis of parental MCF-7 cells but not PIK3CA wild-type isogenic MCF-7 cells in tumor xenograft models. Taken together, our results suggest a promising precision therapy of PI3Ki&Ka in PIK3CA mutant breast cancers. PMID- 29504071 TI - A 3-DOF hemi-constrained wrist motion/force detection device for deploying simultaneous myoelectric control. AB - For describing the state of the wrist, either the force or movement of wrist can be measured as the training target in the simultaneous electromyography control. However, the relationship between the force and movement is so complex that only the force or movement is not precise enough to describe its actual situations. In this paper, we propose a novel platform that can acquire three degrees of freedom (DOF) wrist motion/force synchronously with multi-channel electromyography signals in a hemi-constraint way. The self-made wrist force-movement mapping device establishes a stable relationship between the wrist movement and force. Meanwhile, the elicited wrist movement can be directly fed back to the subjects via laser cursor. The information of the cursor can directly reflect the 3-DOF movement of the wrist without any decoupling algorithms. Through this platform, the support vector regression model learned from the training data can well predict the arbitrary combinations of 3-DOF wrist movements. The cross-validation result indicates that the regression accuracy of free 3-DOF movements can reach a similar performance to that of 2-DOF regular movements (in terms of R2, regular movement vs. free movement, p > 0.1). Graphical abstract The hemi-constrained platform used for detecting 3-DOF wrist movements. PMID- 29504072 TI - An Assessment of Sub-Meter Scale Spatial Variability of Arcellinida (Testate Lobose Amoebae) Assemblages in a Temperate Lake: Implications for Limnological Studies. AB - Arcellinida (testate lobose amoebae), a group of benthic protists, were examined from 46 sediment-water interface samples collected from oligotrophic Oromocto Lake, New Brunswick, Canada. To assess (1) assemblage homogeneity at a sub-meter spatial scale and (2) the necessity for collecting samples from multiple stations during intra-lake surveys; multiple samples were collected from three stations (quadrats 1, 2, and 3) across the north basin of Oromocto Lake, with quadrat 1 (n = 16) being the furthest to the west, quadrat 2 (n = 15) situated closer to the center of the basin, and quadrat 3 (n = 15) positioned 300 m south of the mouth of Dead Brook, an inlet stream. Results from cluster analysis and non-metric multidimensional scaling (NMDS) analysis identified two major Arcellinida assemblages, A1 and A2, the latter containing two sub-assemblages (A2a and A2b). Redundancy analysis and variance partitioning results indicated that seven statistically significant environmental variables (K, S, Sb, Ti, Zn, Fe, and Mn) explained 41.5% of the total variation in the Arcellinida distribution. Iron, Ti and K, indicators of detrital runoff, had the greatest influence on assemblage variance. The results of this study reveal that closely spaced samples (~ 10 cm) in an open-water setting are comprised of homogenous arcellinidan assemblages, indicating that replicate sampling is not required. The results, however, must be tempered with respect to the various water properties and physical characteristics that comprise individual lakes as collection of several samples may likely be necessary when sampling multiple sites of a lake basin characterized by varying water depths (e.g., littoral zone vs. open water), or lakes impacted by geogenic or anthropogenic stressors (e.g., eutrophication, or industrial contamination). PMID- 29504070 TI - Continuous remote monitoring of COPD patients-justification and explanation of the requirements and a survey of the available technologies. AB - Remote patient monitoring should reduce mortality rates, improve care, and reduce costs. We present an overview of the available technologies for the remote monitoring of chronic obstructive pulmonary disease (COPD) patients, together with the most important medical information regarding COPD in a language that is adapted for engineers. Our aim is to bridge the gap between the technical and medical worlds and to facilitate and motivate future research in the field. We also present a justification, motivation, and explanation of how to monitor the most important parameters for COPD patients, together with pointers for the challenges that remain. Additionally, we propose and justify the importance of electrocardiograms (ECGs) and the arterial carbon dioxide partial pressure (PaCO2) as two crucial physiological parameters that have not been used so far to any great extent in the monitoring of COPD patients. We cover four possibilities for the remote monitoring of COPD patients: continuous monitoring during normal daily activities for the prediction and early detection of exacerbations and life threatening events, monitoring during the home treatment of mild exacerbations, monitoring oxygen therapy applications, and monitoring exercise. We also present and discuss the current approaches to decision support at remote locations and list the normal and pathological values/ranges for all the relevant physiological parameters. The paper concludes with our insights into the future developments and remaining challenges for improvements to continuous remote monitoring systems. Graphical abstract ?. PMID- 29504073 TI - Application of Physicochemical Treatment Allows Reutilization of Arthrospira platensis Exhausted Medium : An Investigation of Reusing Medium in Arthrospira platensis Cultivation. AB - Since cultivations of Arthrospira platensis have a high water demand, it is necessary to develop treatment methods for reusing the exhausted medium that may prevent environmental problems and obtaining useful biomass. The exhausted Schlosser medium obtained from A. platensis batch cultivation in bench-scale mini tanks was treated by varying concentrations of different coagulants, ferric chloride (6, 10, and 14 mg L-1) or ferric sulfate (15, 25, and 35 mg L-1) and powdered activated carbon (PAC, 30 and 50 mg L-1). Such treated effluent was restored with NaNO3 and reused in new cultivations of A. platensis performed in Erlenmeyer flasks. Reusing media through the cultivation of A. platensis showed satisfactory results, particularly in the medium treated with ferric chloride and PAC. The maximum cell concentration obtained in the flasks was 1093 mg L-1, which corresponded to the medium treated with ferric chloride (6 mg L-1) and PAC (30 mg L-1). This cellular growth was higher than in the medium treated with ferric sulfate and PAC, in which values of maximum cell concentration did not exceed 796 mg L-1. The cultures in the media after treatment did not modify the biomass composition. Thus, combined coagulation/adsorption processes, commonly used in water treatment processes, can be efficient and viable for treating exhausted medium of A. platensis, allowing the production of such biomass with the reduction of production cost and saving water. PMID- 29504074 TI - Loop-Mediated Isothermal Amplification Using a Lab-on-a-Disc Device with Thin film Phase Change Material. AB - The design and fabrication of temperature measurement systems that facilitate successful realization of DNA amplification using a lab-on-a-disc (LOD) device are a highly challenging task. The major challenge lies in the fact that such a system must be directly attached to a heating chamber in a way that enables the accurate measurement of temperature of the chamber while allowing the LOD to rotate. This paper presents a temperature control system for implementing isothermal amplification of DNA samples using an LOD device. The proposed system utilizes a thin-film phase change material and non-contact heating system to remotely measure the actual temperature of the chamber and, if required, rapidly heat it to the desired temperature. The results of the experiments performed in this study demonstrate that the proposed system provides an automated platform for molecular amplification and exhibits an operational performance comparable to that of traditional microcentrifuge tube-based isothermal amplification systems. PMID- 29504075 TI - Purification and Characterization of Agarase from Marine Bacteria Acinetobacter sp. PS12B and Its Use for Preparing Bioactive Hydrolysate from Agarophyte Red Seaweed Gracilaria verrucosa. AB - Acinetobacter strain PS12B was isolated from marine sediment and was found to be a good candidate to degrade agar and produce agarase enzyme. The extracellular agarase enzyme from strain PS12B was purified by ammonium sulfate precipitation followed by DEAE-cellulose ion-exchange chromatography. The specific activity of the crude enzyme which was 1.52 U increased to 45.76 U, after two-stage purification, with an enzyme yield of 9.76%. Purified enzyme had a molecular mass of 24 kDa. The optimum pH and temperature for activity of purified agarase were found to be 8.0 and 40 degrees C, respectively. The Km and Vmax values for agarase were 4.69 mg/ml and 0.5 MUmol/min, respectively. Treatment with EDTA reduced the agarase activity by 58% at 5 mM concentration. The enzyme activity was stimulated by the presence of Fe2+, Mn2+, and Ca2+ ions while reducing reagents (beta-mercaptoethanol and dithiothreitol, DTT) enhanced its activity by 30-40%. The purified agarase exhibited tolerance to both detergents and organic solvents. Major hydrolysis products of agar were DP4 and also a mixture of longer oligosaccharides DP6 and DP7. The enzyme hydrolysed seaweed (Gracilaria verrucosa) exhibited strong antioxidant activity in vitro. Successful hydrolysis of seaweed indicates the potential use of the enzyme to produce seaweed hydrolysate having health benefits as well as the industrial application like the production of biofuels. PMID- 29504077 TI - Assessment of heavy metal pollution risks and enzyme activity of meadow soils in urban area under tourism load: a case study from Zakopane (Poland). AB - Effect of tourism, especially skiing activities, and urbanization on chemical and biochemical properties of soils in touristy town-Zakopane-was investigated. The concentration of heavy metals, nutrients, soil organic matter (SOM), dehydrogenase (DHA), invertase (IA) and urease (Ure) activities in soils from the town centre and out of the town centre was compared with the respective values of adjacent soils in protected areas (TNP). In order to evaluate a degree of contamination and risks of degradation enrichment factor (EF), ecological risk index (RI), Nemerov Pollution Index (PINemerov) as well as enzyme activity index (EAI) were calculated. Soils in the centre of Zakopane were polluted with Zn, Pb, Cd and Cu in a moderate degree when those of skiing areas were polluted with Pb and Cd in a high degree. Strong positive correlation between these metals and negative correlation between them and a distance from the main roundabout in town indicated their anthropogenic origin. Soils of both locations were also enriched in P, but depleted in SOM when compared to TNP soils. Soils of touristy areas (out of the centre) were additionally enriched in N. Activity of studied enzymes was also lowered in soils of Zakopane when compared to soils of TNP. Pollution indices, RI, PINemerov as well as EAI, indicated that soils of Zakopane are at risk of degradation. Soils of touristy areas are under stronger negative impact than soils of the centre because of the cumulative effect of transport of heavy metals from the city centre, pollution by skiing machinery and melting water from the artificial snow. PMID- 29504076 TI - Ecotoxicological assessment of perchlorate using in vitro and in vivo assays. AB - Perchlorate is an inorganic ion widespread in the environment, generated as a natural and anthropogenic pollutant, with known endocrine disruption properties in the thyroid gland. Nonetheless, there are few reports of its ecotoxicological impact on wildlife. The aim of this study was to evaluate the adverse effects of KClO4 exposure on different cell lines, HEK, N2a, and 3T3, as well as in ecological models such as Vibrio fischeri, Pseudokirchneriella subcapitata, Daphnia magna, and Eisenia fetida. Perchlorate exhibited similar toxicity against tested cell lines, with LC50 values of 19, 15, and 19 mM for HEK, N2a, and 3T3, respectively; whereas in V. fischeri, the toxicity, examined as bioluminescence reduction, was considerably lower (EC50 = 715 mM). The survival of the freshwater algae P. subcapitata was significatively impaired by perchlorate (LC50 = 72 mM), and its effect on the lethality in the crustacean D. magna was prominent (LC50 = 5 mM). For the earthworm E. fetida, the LC50 was 56 mM in soil. In this organism, perchlorate induced avoidance behavior, weight loss, and decreased egg production and hatchling, as well as morphological and histopathological effects, such as malformations, dwarfism, and necrosis. In conclusion, perchlorate toxicity varies according to the species, although E. fetida is a sensitive model to generate information regarding the toxicological impact of KClO4 on biota. PMID- 29504078 TI - The potential of foodwaste leachate as a phycoremediation substrate for microalgal CO2 fixation and biodiesel production. AB - Foodwaste leachate (FWL) is often generated during foodwaste treatment processes. Owing to its high nutrient content, FWL has high potential for phycoremediation, a microalgal technology application for water treatment while acting as CO2 fixation tank. Additionally, the end product of microalgal from phycoremediation can be potentially used for biodiesel production. Therefore, the phycoremediation has drawn a lot of attention in recent decades. This study evaluates the performance of microalgal foodwaste leachate treatment and the potential of utilizing FWL as medium for microalgal biodiesel production. Two microalgal species, Dunaliella tertiolecta and Cyanobacterium aponinum, were selected. For each species, two experimental levels of diluted FWL were used: 5 and 10% FWL. The partial inhibition growth model indicates that some inhibit factors such as ammonia; total suspended solids and oil and grease (O&G) content suppress the microalgal growth. Most of the nutrient such as nitrogen and phosphorus (> 80%) can be removed in the last day of phycoremediation by D. tertiolecta. C. aponinum also show considerable removal rate on total nitrogen ammonia and nitrate (> 60%). Biomass (0.4-0.5 g/L/day) of D. tertiolecta and C. aponinum can be produced though cultivated in diluted FWL. The bio-CO2 fixation rates of the two species were 610.7 and 578.3 mg/L/day of D. tertiolecta and C. aponinum. The strains contain high content of saturated fatty acid such as C16 and C18 making them having potential for producing good quality biodiesel. PMID- 29504079 TI - Eco-industrial zones in the context of sustainability development of urban areas. AB - Industry is one of the main activities in the city and in many cities of the world, and the dominant industrial zones are the most significant morphological forms of concentration of industrial facilities in the city and are concentrated industrial and business activity. Industrial parks combine activities related to energy and resource consumption, emissions, waste generation, economic benefits, and regional development. The focus of this work is the path of transformation between the present and the vision of a sustainable city in the future. The problem and the subject of research related to two related objects of research: the city and sustainable development. In this paper, the co-author's industrial symbiosis parks, modern tendencies of the spatial distribution of productive activities, circular economy, to attract leading corporations and open the way for new ventures while preserving the living environment in an urban area. PMID- 29504081 TI - Analysis of a variety of inorganic and organic additives in food products by ion pairing liquid chromatography coupled to high-resolution mass spectrometry. AB - A reversed-phase ion-pairing chromatographic method was developed for the detection and quantification of inorganic and organic anionic food additives. A single-stage high-resolution mass spectrometer (orbitrap ion trap, Orbitrap) was used to detect the accurate masses of the unfragmented analyte ions. The developed ion-pairing chromatography method was based on a dibutylamine/hexafluoro-2-propanol buffer. Dibutylamine can be charged to serve as a chromatographic ion-pairing agent. This ensures sufficient retention of inorganic and organic anions. Yet, unlike quaternary amines, it can be de-charged in the electrospray to prevent the formation of neutral analyte ion-pairing agent adducts. This process is significantly facilitated by the added hexafluoro-2 propanol. This approach permits the sensitive detection and quantification of additives like nitrate and mono-, di-, and triphosphate as well as citric acid, a number of artificial sweeteners like cyclamate and aspartame, flavor enhancers like glutamate, and preservatives like sorbic acid. This is a major advantage, since the currently used analytical methods as utilized in food safety laboratories are only capable in monitoring a few compounds or a particular category of food additives. Graphical abstract Deptotonation of ion pair agent in the electrospray interface. PMID- 29504080 TI - Can Prostate Imaging Reporting and Data System Version 2 reduce unnecessary prostate biopsies in men with PSA levels of 4-10 ng/ml? AB - PURPOSE: To explore the value of Prostate Imaging Reporting and Data System Version 2 (PI-RADS v2) for predicting prostate biopsy results in patients with prostate specific antigen (PSA) levels of 4-10 ng/ml. METHODS: We retrospectively reviewed multi-parameter magnetic resonance images from 528 patients with PSA levels of 4-10 ng/ml who underwent transrectal ultrasound-guided prostate biopsies between May 2015 and May 2017. Among them, 137 were diagnosed with prostate cancer (PCa), and we further subdivided them according to pathological results into the significant PCa (S-PCa) and insignificant significant PCa (Ins PCa) groups (121 cases were defined by surgical pathological specimen and 16 by biopsy). Age, PSA, percent free PSA, PSA density (PSAD), prostate volume (PV), and PI-RADS score were collected. Logistic regression analysis was performed to determine predictors of pathological results. Receiver operating characteristic curves were constructed to analyze the diagnostic value of PI-RADS v2 in PCa. RESULTS: Multivariate analysis indicated that age, PV, percent free PSA, and PI RADS score were independent predictors of biopsy findings, while only PI-RADS score was an independent predictor of S-PCa (P < 0.05). The areas under the receiver operating characteristic curve for diagnosing PCa with respect to age, PV, percent free PSA, and PI-RADS score were 0.570, 0.430, 0.589 and 0.836, respectively. The area under the curve for diagnosing S-PCa with respect to PI RADS score was 0.732. A PI-RADS score of 3 was the best cutoff for predicting PCa, and 4 was the best cutoff for predicting S-PCa. Thus, 92.8% of patients with PI-RADS scores of 1-2 would have avoided biopsy, but at the cost of missing 2.2% of the potential PCa cases. Similarly, 83.82% of patients with a PI-RADS score <= 3 would have avoided biopsy, but at the cost of missing 3.3% of the potential S PCa cases. CONCLUSIONS: PI-RADS v2 could be used to reduce unnecessary prostate biopsies in patients with PSA levels of 4-10 ng/ml. PMID- 29504082 TI - Inhibition mechanisms of hemoglobin, immunoglobulin G, and whole blood in digital and real-time PCR. AB - Blood samples are widely used for PCR-based DNA analysis in fields such as diagnosis of infectious diseases, cancer diagnostics, and forensic genetics. In this study, the mechanisms behind blood-induced PCR inhibition were evaluated by use of whole blood as well as known PCR-inhibitory molecules in both digital PCR and real-time PCR. Also, electrophoretic mobility shift assay was applied to investigate interactions between inhibitory proteins and DNA, and isothermal titration calorimetry was used to directly measure effects on DNA polymerase activity. Whole blood caused a decrease in the number of positive digital PCR reactions, lowered amplification efficiency, and caused severe quenching of the fluorescence of the passive reference dye 6-carboxy-X-rhodamine as well as the double-stranded DNA binding dye EvaGreen. Immunoglobulin G was found to bind to single-stranded genomic DNA, leading to increased quantification cycle values. Hemoglobin affected the DNA polymerase activity and thus lowered the amplification efficiency. Hemoglobin and hematin were shown to be the molecules in blood responsible for the fluorescence quenching. In conclusion, hemoglobin and immunoglobulin G are the two major PCR inhibitors in blood, where the first affects amplification through a direct effect on the DNA polymerase activity and quenches the fluorescence of free dye molecules, and the latter binds to single stranded genomic DNA, hindering DNA polymerization in the first few PCR cycles. Graphical abstract PCR inhibition mechanisms of hemoglobin and immunoglobulin G (IgG). Cq quantification cycle, dsDNA double-stranded DNA, ssDNA single-stranded DNA. PMID- 29504083 TI - An ultrasensitive hollow-silica-based biosensor for pathogenic Escherichia coli DNA detection. AB - A novel electrochemical DNA biosensor for ultrasensitive and selective quantitation of Escherichia coli DNA based on aminated hollow silica spheres (HSiSs) has been successfully developed. The HSiSs were synthesized with facile sonication and heating techniques. The HSiSs have an inner and an outer surface for DNA immobilization sites after they have been functionalized with 3 aminopropyltriethoxysilane. From field emission scanning electron microscopy images, the presence of pores was confirmed in the functionalized HSiSs. Furthermore, Brunauer-Emmett-Teller (BET) analysis indicated that the HSiSs have four times more surface area than silica spheres that have no pores. These aminated HSiSs were deposited onto a screen-printed carbon paste electrode containing a layer of gold nanoparticles (AuNPs) to form a AuNP/HSiS hybrid sensor membrane matrix. Aminated DNA probes were grafted onto the AuNP/HSiS modified screen-printed electrode via imine covalent bonds with use of glutaraldehyde cross-linker. The DNA hybridization reaction was studied by differential pulse voltammetry using an anthraquinone redox intercalator as the electroactive DNA hybridization label. The DNA biosensor demonstrated a linear response over a wide target sequence concentration range of 1.0*10-12-1.0*10-2 MUM, with a low detection limit of 8.17*10-14 MUM (R2 = 0.99). The improved performance of the DNA biosensor appeared to be due to the hollow structure and rough surface morphology of the hollow silica particles, which greatly increased the total binding surface area for high DNA loading capacity. The HSiSs also facilitated molecule diffusion through the silica hollow structure, and substantially improved the overall DNA hybridization assay. Graphical abstract Step-by-step DNA biosensor fabrication based on aminated hollow silica spheres. PMID- 29504085 TI - Electronic nicotine delivery system (ENDS) battery-related burns presenting to US emergency departments, 2016. AB - BACKGROUND: Currently, an estimated 7.9 million US adults use electronic nicotine delivery systems (ENDS). Although published reports have identified fires and explosions related to use of ENDS since 2009, these reports do not provide national estimates of burn injuries associated with ENDS batteries in the US. FINDINGS: We analyzed nationally representative data provided in the National Electronic Injury Surveillance System (NEISS) to estimate the number of US emergency department (ED) visits for burn injuries associated with ENDS batteries. We reviewed the case narrative field to gain additional insights into the circumstances of the burn injury. In 2016, 26 ENDS battery-related burn cases were captured by NEISS, which translates to a national estimate of 1007 (95%CI: 357-1657) injuries presenting in US EDs. Most of the burns were thermal burns (80.4%) and occurred to the upper leg/lower trunk (77.3%). Examination of the case narrative field indicated that at least 20 of the burn injuries occurred while ENDS batteries were in the user's pocket. CONCLUSIONS: Our study provides valuable information for understanding the current burden of ENDS battery-related burn injuries treated in US EDs. The nature and circumstances of the injuries suggest these incidents were unintentional and would potentially be prevented through battery design requirements, battery testing standards and public education related to ENDS battery safety. PMID- 29504084 TI - Larval Diet Affects Male Pheromone Blend in a Laboratory Strain of the Medfly, Ceratitis capitata (Diptera: Tephritidae). AB - The Mediterranean fruit fly (medfly) Ceratitis capitata is a polyphagous pest of fruits and crops with a worldwide distribution. Its ability to use different larval hosts may have multiple effects, including impacts on adult reproductive biology. The male sex pheromone, which plays a key role in attracting both other males to lekking arenas and females for mating, is a mixture of chemical compounds including esters, acids, alkanes and terpenes known to differ between laboratory strains and wild-type populations. The relationship between larval diet and adult pheromone composition remains unexplored. Here, we investigated the effect of larval diet, including laboratory media and fresh fruits, on the composition of the male pheromone mixture. Using Headspace Solid Phase Microextraction we collected the pheromone emitted by males reared as larvae on different substrates and found both qualitative and quantitative differences. A number of alkanes appeared to be typical of the pheromone of males reared on wheat bran-based larval medium, and these may be cuticular hydrocarbons involved in chemical communication. We also detected differences in pheromone composition related to adult male age, suggesting that variations in hormonal levels and/or adult diet could also play a role in determining the chemical profile emitted. Our findings highlight the plasticity of dietary responses of C. capitata, which may be important in determining the interactions of this pest with the environment and with conspecifics. These results also have applied relevance to increase the mating competitiveness of mass-reared C. capitata used in Sterile Insect Technique programs. PMID- 29504086 TI - Objective Assessment of the Utility of Chromoendoscopy with a Support Vector Machine. AB - PURPOSE: The utility of chromoendoscopy for early gastric cancer (GC) was determined by machine learning using data of color differences. METHODS: Eighteen histopathologically confirmed early GC lesions were examined. We prepared images from white light endoscopy (WL), indigo carmine (Indigo), and acetic acid-indigo carmine chromoendoscopy (AIM). A border between cancerous and non-cancerous areas on endoscopic images was established from post-treatment pathological findings, and 2000 pixels with equivalent luminance values were randomly extracted from each image of cancerous and non-cancerous areas. Each pixel was represented as a three-dimensional vector with RGB values and defined as a sample. We evaluated the Mahalanobis distance using RGB values, indicative of color differences between cancerous and non-cancerous areas. We then conducted diagnosis test using a support vector machine (SVM) for each image. SVM was trained using the 100 training samples per class and determined which area each of 1900 test samples per class came from. RESULTS: The means of the Mahalanobis distances for WL, Indigo, and AIM were 1.52, 1.32, and 2.53, respectively and there were no significant differences in the three modalities. Diagnosability per endoscopy technique was assessed using the F1 measure. The means of F1 measures for WL, Indigo, and AIM were 0.636, 0.618, and 0.687, respectively. AIM images were better than WL and Indigo images for the diagnosis of GC. CONCLUSION: Objective assessment by SVM found AIM to be suitable for diagnosis of early GC based on color differences. PMID- 29504087 TI - The diagnostic utility of D-dimer and other clinical variables in pregnant and post-partum patients with suspected acute pulmonary embolism. AB - BACKGROUND: Pulmonary embolism (PE) during pregnancy remains one of the leading causes of maternal morbidity and mortality in the developed world. However, there is a paucity of high-quality evidence resulting in a lack of consensus in managing this group of patients. The aims of the study were to address the diagnostic utility of D-dimer for suspected PE in pregnant and post-partum patients and to identify any clinical presentation variables that are predictors of PE in this group of patients. METHODS: A retrospective case note review of 152 pregnant and post-partum patients who underwent diagnostic imaging (ventilation/perfusion (V/Q) or computed tomographic pulmonary angiography (CTPA)) for suspected PE at a tertiary teaching hospital from 2007 to 2011 was conducted. The reference range for D-dimer was less than 0.5 mg/L as being normal. The following variables were also assessed in terms of their predictive capability for PE diagnosis in pregnancy: heart rate (HR), mean arterial pressure (MAP), shock index (SI) and A-a gradient. RESULTS: The application of D-dimer testing for suspected PE in this study population had a sensitivity of 100% (95% CI, 73-100%), specificity of 42% (95% CI, 31-53%) and a likelihood negative ratio of 0. None of the clinical variables were significant predictors of PE according to regression analyses. CONCLUSIONS: There is supportive evidence that a negative D-dimer result is useful as a means of ruling out PE in pregnant and post-partum patients. However, we need a larger prospective observational study to collaborate the findings. PMID- 29504088 TI - Psychiatry and Pain Management: at the Intersection of Chronic Pain and Mental Health. AB - PURPOSE OF REVIEW: Chronic pain impacts millions of people in the USA. At the heart of the problem of chronic pain remains the complex psychosocial aspects associated with living with chronic pain. Given the overlap between chronic pain and mental health, a promising treatment approach is to improve how we integrate psychiatry into pain management. RECENT FINDINGS: Treatment of chronic pain and comorbid mental health issues requires a multidisciplinary approach. Advancements in how pain is understood, especially centralized pain, have helped inform both pharmacological and behavioral interventions for pain. Given the growing concerns about the opioid epidemic and the lack of data supporting the use of opioids for long-term pain management, new treatment approaches are needed. Psychiatrist may be uniquely suited to help address comorbid mental health disorders and addiction in the context of chronic pain management. Addressing the psychiatric needs of chronic pain patients remains challenging and there is much room to improve how we address the complex issues associated with living with chronic pain. We believe psychiatrists are an important piece of the pain management puzzle. PMID- 29504089 TI - Co-Culturing of Multipotent Mesenchymal Stromal Cells with Autological and Allogenic Lymphocytes. AB - We studied the effect of autologous and allogeneic lymphocytes on multipotent mesenchymal stromal cells in co-culture. It is shown that changes in multipotent mesenchymal stromal cells and in lymphocytes did not depend on the source of lymphocytes. Contact with lymphocytes triggers expression of HLA-DR molecules on multipotent mesenchymal stromal cells and these cells lose their immune privilege. In multipotent mesenchymal stromal cells, the relative level of expression of factors involved in immunomodulation (IDO1, PTGES, and IL-6) and expression of adhesion molecule ICAM1 increased, while expression of genes involved in the differentiation of multipotent mesenchymal stromal cells remained unchanged. Priming of multipotent mesenchymal stromal cells with IFN did not affect these changes. In turn, lymphocytes underwent activation, expression of HLA-DR increased, subpopulation composition of lymphocytes changed towards the increase in the content of naive T cells. These findings are important for cell therapy. PMID- 29504090 TI - Some Peculiarities of Local Distribution of Multipotent Mesenchymal Stromal Cells after Their Injection into Intact Muscle Tissue in Experiment. AB - Changes in the muscular tissue after subcutaneous injection of autologous bone marrow multipotent mesenchymal stromal cells transfected with GFP gene and additionally stained with cell membrane dye Vybrant CM-Dil in the projection of ligated femoral vein were studied by light microscopy with luminescence. Stromal cells injected through the skin can appear not only in the damaged tissue where acceleration of regeneration processes is required, but also in intact structures located in superficial or deeper layers. In intact muscular tissue, stromal cells spreading in the perivascular tissue initiate inflammation and migration of macrophages, activate and even trigger sclerotic processes due to differentiation into connective tissue cells (fibroblasts) and stimulation of proliferation and collagen synthesis by host fibroblasts. Injected multipotent mesenchymal stromal cells are gradually phagocytized by macrophages. PMID- 29504091 TI - In Vitro Modeling of Co-Transplantation of Multipotent Stromal Mesenchymal Cells from Orbital Fat Pad and Lipoaspirate of Human Subcutaneous Adipose Tissue in Organ Culture in Collagen Gel. AB - The interplay of multipotent stromal cells derived from the orbital fat pads and cells of the lipoaspirate from the subcutaneous adipose tissue was studied using in vitro co-transplantation model in an organ culture in a collagen gel. Microscopy findings and intensity of apoptosis and cell proliferation in cultures of lipoaspirate with and without multipotent stromal cells showed that the cells maintained their viability, proliferation capacity, and cytokine secretion activity. Higher proliferatitive activity of cells in cocultures promotes renewal of fat transplant cells and can help to maintain its stable volume in delayed terms after transplantation. PMID- 29504092 TI - Measuring of Adhesion Force in the Cell-Cell System Based on Atomic Force Microscopy Technology. AB - We developed and tested a method for fabrication of a biosensor chip based on native human whole blood lymphocyte and a titanium tipless cantilever. The biosensor can be used for measuring intermolecular adhesion forces in the cell cell system by using atomic force spectroscopy. The developed biosensor chip was applied for measuring adhesion force between lymphocyte and granulocyte and between lymphocyte and erythrocyte in healthy individuals and in patients with acute lymphoblastic leukemia (before treatment, during standard treatment, and during relapse). It was found that adhesion force between lymphocyte and granulocyte and between lymphocyte and erythrocyte increased almost twice during relapse, which is an important diagnostic marker of early cytological abnormalities indicating progression of the disease. PMID- 29504093 TI - Isolation and Characterization of Human Myoblast Culture In Vitro for Technologies of Cell and Gene Therapy of Skeletal Muscle Pathologies. AB - We analyzed cultures of 5 independent myoblast lines from human skeletal muscles. It was shown that the content of desmin-positive cells in cultures at early passages exceeds 90%. Typical morphofunctional signs of myogenic differentiation disturbances were identified and their dynamics was studied. Signs of alternative adipogenic and chondrogenic differentiation of cells were revealed. Based on these data, limitations for the use of myoblast cultures of certain passages for biomedical research and cell therapy were evaluated. PMID- 29504094 TI - Specificity of Good Manufacturing Practice (GMP) for Biomedical Cell Products. AB - The article describes special aspects of Good Manufacturing Practice (GMP) for biomedical cell products (BMCP) that imply high standards of aseptics throughout the entire productio process, strict requirements to donors and to the procedure of biomaterial isolation, guaranty of tracing BMCP products, defining processing procedures which allow to identify BMCP as minimally manipulated; continuous quality control and automation of the control process at all stages of manufacturing, which will ensure product release simultaneously with completion of technological operations. PMID- 29504095 TI - KrioBlast TM as a New Technology of Hyper-fast Cryopreservation of Cells and Tissues. Part I. Thermodynamic Aspects and Potential Applications in Reproductive and Regenerative Medicine. AB - Kinetic (dynamic) vitrification is a promising trend in cryopreservation of biological materials because it allows avoiding the formation of lethal intracellular ice and minimizes harmful effects of highly toxic penetrating cryoprotectants. A uniform cooling protocol and the same instruments can be used for practically all types of cells. In modern technologies, the rate of cooling is essentially limited by the Leidenfrost effect. We describe a novel platform for kinetic vitrification of biological materials KrioBlast TM that realizes hyper-fast cooling and allows overcoming the Leidenfrost effect. This opens prospects for creation of a novel technology of cell cryopreservation for reproductive and regenerative medicine. PMID- 29504096 TI - Peculiarities of Cyto- and Chemoarchitectonics of Human Entorhinal Cortex during the Fetal Period. AB - We studied peculiarities of the structure of human entorhinal cortex at weeks 20 26 of gestation (10 hemispheres). The samples were Nissl-stained and immunohistochemically treated with antibodies to parvalbumin, calretinin, calbindin, and cytoskeleton proteins (MAP2 and N200). 3D-reconstruction of the entorhinal cortex from serial sections was performed, caudomedial and rostrolateral areas were isolated. Parvalbumin+ cells in layer I, discrete distribution of layer II cells with colocalization of MAP2 and calretinin at the border with layer I, and two sublayers Va and Vb with MAP2+ neurons were typical for the caudomedial area. Rostrolateral area was characterized by the homogenous layer II with big amount of cells, high density of MAP2+ neurons only in layer III, and the unique layer V. Reelin+ Cajal-Retzius cells and N200+ fiber plexus in layer I were observed in the caudomedial and rostrolateral areas of the entorhial cortex. Layer IV was represented by a cell-free desiccant. PMID- 29504097 TI - Changes in Canonical beta-Catenin/Wnt Signaling Activation in the Adrenal Cortex of Rats Exposed to Endocrine Disruptor Dichlorodiphenyltrichloroethane (DDT) during Prenatal and Postnatal Ontogeny. AB - Prenatal and postnatal exposure to low doses of the endocrine disruptor dichlorodiphenyltrichloroethane (DDT) leads to delayed activation of the canonical beta-catenin/Wnt signaling in zona glomerulosa and zona reticularis of the adrenal cortex in rats, which changed the rate of their postnatal development. Suppression of the Wnt pathway in zona fasciculata promotes its regeneration after DDT-induced blood circulation disorders and cell death. PMID- 29504098 TI - Experimental Evaluation of the Effects of Low-Dose Heparin on the Behavior and Morphofunctional Status of the Liver in Wistar Rats with Posttraumatic Stress Disorders. AB - Posttraumatic stress disorders were induced in Wistar rats by modeling predatory stress. Animals tested in elevated plus-maze demonstrated signs of high anxiety and difficulties in space orientation. Behavioral disorders were paralleled by degenerative changes in hepatocytes. A course of low-dose high-molecular heparin after stress exposure promoted effective adaptation and normalization of behavioral and morphofunctional disorders. Analysis of the results indicated good prospects of heparin as an effective drug under conditions of exposure to extreme factors of psychotraumatic type. PMID- 29504099 TI - Role of Endogenous Melatonin in the Regulation of Th17/Treg Balance during Pregnancy. AB - We studied the role of endogenous melatonin in the development and functioning of T cells that produce IL-17 (Th17) and regulatory T cells (Treg) during pregnancy. The study was performed ex vivo and in vitro with auto-serum as the source of endogenous melatonin under conditions of blockade of melatonin-dependent signaling. Participation of the hormone in the regulation of differentiation of both CD4+RORgammat+ and CD4+FoxP3+T cells and their key products IL-17A and TGF beta was demonstrated. It is known that the normal gestational process is accompanied by a decrease in Th17/Treg ratio due to hormonal changes. The sensitivity of the studied subpopulations to melatonin during pregnancy can affect its outcome. PMID- 29504100 TI - L-Lysine-alpha-Oxidase: Acidovorax citrulli Bacterium Inhibitor. AB - Studies of the effects of Trichoderma harzianum Rifai F-180 culture fluid concentrate containing L-lysine-alpha-oxidase antitumor enzyme produced by the fungus and the homogenous enzyme, on ultrahazardous bacterium Acidovorax citrulli demonstrated the antibacterial activity of the concentrate. Trichoderma harzianum Rifai F-180 producing L-lysine-alpha-oxidase was cultured in a technological device at G. K. Skryabin Institute of Biochemistry and. Physiology of Microorganisms, Russian Academy of Sciences. Activity of L-lysine-alpha-oxidase in the resulted culture fluid concentrate was 0.54 U/ml, activity of the homogenous enzyme was 50 U/mg. PMID- 29504101 TI - Studying the Phenotypic and Genotypic Expression of Antibiotic Resistance in Campylobacter jejuni under Stress Conditions. AB - Specific features for the development of resistance in Campylobacter jejuni strains were studied after treatment with antibiotics of 6 pharmacological groups. Populations of 18 native strains of C. jejuni (isolated from raw poultry products) and their subcultures (obtained after 2-3-fold stress exposures to antimicrobial agents in subinhibitory doses) were examined to evaluate the expression of phenotypic antibiotic resistance. Genotypic properties of strains were studied by the PCR with primers that detect the presence of genes for resistance to aminoglycosides (aphA-1, aphA-3, and aphA-7), tetracyclines (tetO), and quinolones (GZgyrA). The majority of test strains of C. jejuni exhibited a high resistance to nalidixic acid, ciprofloxacin, and tetracycline, which reached the maximum value after numerous passages. The expression of antibiotic resistance was greatest in the presence of nalidixic acid and tetracycline. Ciprofloxacin resistance of 33% strains, which were initially resistant to this antibiotic, was increased after 2-3-fold treatment. We revealed a high degree of correspondence between phenotypic and genotypic profiles of antibiotic resistance in food isolates of Campylobacter. One, two, or more genes of aphA were identified in 85% strains phenotypically resistant to aminoglycosides. The tetO gene was found nearly in all strains resistant to tetracycline. Studying the biofilm matrix in C. jejuni after culturing with antibiotics in subinhibitory doses showed that quinolones (particularly nalidixic acid) and tetracyclines potentiate the formation of biofilms and increase the tolerance of Campylobacter to stress exposures. The intensity of biofilm growth was shown to depend little on the effect of macrolides and aminoglycosides. Therefore, the presence of these agents in residual concentrations is associated with a lower risk for the development of antibiotic resistance in C. jejuni populations. PMID- 29504102 TI - Role of Matrix Metalloproteinase-2 in the Development of Cyclophosphamide-Induced Cardiomyopathy. AB - Immunohistochemical assay was employed to determine localization of MMP-2 in cardiomyocytes of WAG rats and changes in MMP-2 expression during modeled cardiomyopathy induced by single intraperitoneal injection of cyclophosphamide (125 mg/kg) alone or in combination with preventive intraperitoneal administration of an equal dose of asparcam-L (potassium-magnesium asparaginate) 30 min prior to the cytostatic. In the myocardium of control and experimental rats, MMP-2 was mostly located in cardiomyocyte nuclei. During the development of cyclophosphamide-induced cardiomyopathy (in 3 days after injection), the index of MMP-2-positive cardiomyocyte nuclei increased by 76%. In contrast to control hearts, MMP-2 was also expressed in the cardiomyocyte sarcoplasm. Preventive injection of asparcam-L moderated the cardiotoxic effect of cyclophosphamide, which manifested in less pronounced increase in the volume density of cardiomyocytes with lytic changes (by 42%) and index of MMP-2+ cardiomyocyte nuclei (by 23%) in comparison with the rats exposed to cyclophosphamide alone. PMID- 29504103 TI - Induction of Alternative Splicing and Inhibition of Activity of Telomerase Catalytic Subunit by Apoptotic Endonuclease EndoG in Human T, B, and NK Cells. AB - The effect of apoptotic endonuclease EndoG on alternative splicing of mRNA of human telomerase catalytic subunit hTERT (human telomerase reverse transcriptase) and telomerase activity in normal human lymphocytes were studied. Human CD4+, CD8+, B, and NK cells were transfected with a plasmid pEndoG-GFP containing EndoG gene or control plasmid pGFP. The levels of mRNA of EndoG or hTERT splicing variants were analyzed by real-time PCR. Protein content was assessed by Western blotting. Telomerase activity was measured by the telomere repeats amplification protocol. EndoG overexpression reduced the expression of active full-length hTERT and increased the expression of inactive splice variant. Shifted balance of hTERT splice variants in cells led to a significant decrease in telomerase activity within 72 h after transfection. PMID- 29504104 TI - Analysis of IL-1alpha, bFGF, TGF-beta1, IFNgamma, MMP-1, and CatD Expression in Multinuclea Macrophages In Vitro. AB - The incidence of mono- and multinuclear cells and their expression of pro- and antifibrotic factors were studied in cultured peritoneal macrophages from intact and BCG-infected mice. Generally, the expression of factors increased with an increase in the number of nuclei per cell. However, the expression was higher in macrophages from BCG infected mice, except the cells with 3 and more nuclei, extremely rarely expressing IL-1alpha in cultures from intact and BCG-infected animals. The number of macrophages with 3 and more nuclei, expressing CatD, was comparable with the number of mono- and binuclear macrophages. Presumably, this was determined by various mechanisms of formation of multinuclear (3-5 and more nuclei) macrophages, for example, by amitosis. PMID- 29504105 TI - Monocytes with Oncogenic Mutation JAK2 V617F as a Tool for Studies of the Pathogenic Mechanisms of Myelofibrosis. AB - We analyzed previously generated stable monocyte-derived cell line carrying mutation JAK2 V617F. Evaluation of the expression of pro- and antifibrotic factors revealed changes in the production of MMPs and their inhibitors, growth factors, galectin-3, and pentraxin 3 in cells carrying mutation JAK2 in comparison with control non-modified cells. PMID- 29504106 TI - Expression of Adhesion Molecules in Activated Endothelium after Interaction with Mesenchymal Stromal Cells. AB - The studied the expression of intercellular adhesion molecules and transcription of the corresponding genes in intact and activated endothelial cells both in monoculture and during interaction with mesenchymal stromal cells. It was found that the levels of integrin-alpha1 and VE-cadherin mRNA increased during co culturing. TNFalpha-induced activation of endothelial cells enhanced expression of integrin-alpha1 both at the mRNA and protein synthesis stages and had no effect on the level of VE-cadherin. Direct contact with mesenchymal stromal cells did not eliminate the effect of endothelial cell activation, but expression of integrin-alpha1 and VE-cadherin in activated endothelial cells tended to decrease. PMID- 29504107 TI - Survival of Mesenchymal Stem Cells in Different Methods of Nebulization. AB - We compared survival of bone marrow mesenchymal stem cells after compressor, ultrasound, and mesh nebulization of the cell suspension over 10 min. Viability of stromal cells was best preserved after compressor nebulization (72%). Cell survival after ultrasonic nebulization was significantly lower (20%). After mesh nebulization, no live cells were found. Thus, compressor nebulization is the most preferable method of the production of cell aerosol for their delivery to the lower respiratory tract. PMID- 29504108 TI - Analysis of Dynamic Geometric Configuration of the Aortic Channel from the Perspective of Tornado-Like Flow Organization of Blood Flow. AB - Analysis of the data of morphometry of aortic casts, aortography at different pressures, and multispiral computer tomography of the aorta with contrast and normal pulse pressure showed that geometric configuration of the flow channel of the aorta during the whole cardiac cycle corresponded to the conditions of self organization of tornado-like quasipotential flow described by exact solutions of the Navier-Stokes equation and continuity of viscous fluid typical for this type of fluid flows. Increasing pressure in the aorta leads to a decrease in the degree of approximation of the channel geometry to the ratio of exact solution and increases the risk of distortions in the structure of the flow. A mechanism of evolution of tornado-like flow in the aorta was proposed. PMID- 29504109 TI - Infrared Fluorescent Angiography during Experimental Trachea Transplantation. AB - Indocyanine green fluorescence was used for evaluation of the degree of trachea revascularization after its autotransplantation in rabbits (transplantation of 1- and 2-cm segment of the trachea). Intravenous administration of indocyanine green was followed by a significant fluorescence of the substance in microvessels of the trachea over 30-40 sec. Immediately after surgery, fluorescence in the implanted segment was absent, but within 7 days it was completely restored in rabbits receiving transplantation of a 1-cm segment. After transplantation of 2 cm segment of the trachea, fluorescence did not recover, which corresponded to the clinical picture and autopsy results. Thus, fluorescent angiography is an informative method for evaluation of trachea revascularization. PMID- 29504110 TI - Preparation of Human Olfactory Ensheathing Cells for the Therapy of Spinal Cord Injuries. AB - We developed an optimal protocol for preparing and culturing of olfactory ensheathing cells from human olfactory mucosa. Using this protocol, we obtained a culture enriched with human olfactory ensheathing cells. Immunofluorescence analysis by simultaneous expression of GFAP and p75NTR markers showed that the content of ensheathing cells was maximum in passage 3 and 4 cultures (94 and 89.5%, respectively). The developed protocol can be recommended for obtaining autologous preparations of human ensheathing cells for cell therapy of spinal cord injuries. PMID- 29504111 TI - Matrix Metalloproteinases MMP-1 and MMP-9 and Their Inhibitor TIMP-1 as Markers of Dilated Cardiomyopathy in Patients of Different Age. AB - We studied the expression of MMP-2, MMP-9, and inhibitor TIMP-1 in myocardial autopsy samples from subjects of different age and in cardiomyocyte cultures in the norm and in dilated cardiomyopathy. In autopsy samples of normal myocardium and in cardiomyocyte cultures, expression of molecules involved in extracellular matrix remodeling did not change during aging. In dilation cardiomyopathy, expression of MMP-2, MMP-9, and TIMP-1 and their ratios in autopsy material and in cultures was elevated by 1.5-9 times. Remodeling of extracellular matrix plays an important role in the pathogenesis of dilated cardiomyopathy. MMP-2, MMP-9, and their inhibitor TIMP-1 and the MMP/TIMP ratios can be regarded as promising predictors of dilated cardiomyopathy and used for evaluation of the effectiveness of treatment of this conditions in patients of different ages. PMID- 29504112 TI - Analysis of the Basic Characteristics of Osteogenic and Chondrogenic Cell Lines Important for Tissue Engineering Implants. AB - We isolated and characterized cultures of bone and cartilage tissue cells of laboratory minipigs. The size and morphological features of adherent osteogenic and chondrogenic cells were specified. During long-term culturing under standard conditions, the studied cultures expressed specific markers that were detected by immunohistochemical staining: alkaline phosphatase and calcium deposits in osteoblasts and type II collagen and cartilage extracellular matrix in chondrogenic cells. Proliferative potential (mitotic index) of both cell types was 4.64% of the total cell number. Cell motility, i.e. the mean velocity of cell motion was 49 pixels/h for osteoblasts and 47 pixels/h for chondroblasts; the mean migration distance was 2045 and 2118 pixels for chondroblasts and osteoblasts, respectively. The obtained cell lines are now used as the control for evaluation of optimal biocompatibility of scaffold materials in various models. Characteristics of the motility of the bone and cartilage tissue cells can be used for modeling and estimation of the rate of cells population of 3D scaffolds made of synthetic and biological polymers with different internal structure and physicochemical properties during designing in vitro tissue implants. PMID- 29504113 TI - Effect of Vitrification on Functional Morphology and Viability of the Ovarian Tissue. AB - The results of a complex morphofunctional study with markers of proliferation (PCNA and Ki-67), angiogenesis (CD31 and CD34), and structural integrity of mesenchymal cells (vimentin) suggest that the pool of primordial follicles was well preserved in vitrified ovarian tissue and that viability of its cellular components can be rapidly restored during incubation at 37 degrees C within 4 h after thawing. PMID- 29504114 TI - Intracellular Reorganization of Cardiomyocytes in Dyslipidemic Cardiomyopathies. AB - The study examined the myocardial ultrastructural alterations in rats maintained on various atherogenic diets. It revealed the complex ultrastructural alterations of cardiomyocytes and endotheliocytes (including the lytic and destructive changes of the intracellular organelles, upregulation of the autophagocytosis in the cardiomyocytes, and necrobiosis with apoptosis of endotheliocytes) reflecting the cytopathic features of circulating cholesterol and lipoproteins, whose elevation determined the intensity of destructive processes. The revealed peculiarities in the changes of lipid inclusions (their osmiophilic transformation) in cardiomyocytes can be provoked by entry of cholesterol into the cells and its further metabolic modifications. During moderate dyslipidemia, the cardiomyocytes demonstrated the ultrastructural signs of induction of intracellular regeneration (marked with the clusters of polysomes in the intermyofibrillar and subsarcolemmal spaces with appearance of neogenic myofilaments) and upregulated pinocytotic activity. In all cases, up-regulated autophagocytosis in cardiomyocytes was accompanied by accumulation of myelin- and vacuole-like structures in the intercellular spaces and capillary lumens paralleled with appearance of activated forms of macrophages and fibroblasts in the myocardium. PMID- 29504115 TI - Claudin-1 role in colon cancer: An update and a review. AB - Tight junction proteins are essential for sealing the cellular sheets and controlling para-cellular ion flux. Our understanding of the role that tight junction proteins, particularly claudins, play in cellular functions and pathologic conditions is continuously expanding. Particularly, the role of claudin-1 in oncogenesis in multiple locations in the human body is coming to light. This review will shed light on the role of claudin-1 in colon cancer. It will address the mechanisms through which claudin-1 becomes dysregulated in colon cancer. This will provide a platform to address results of claudin-1 expression in the third most common malignant tumour worldwide. Furthermore, it will provide updates about possible use of this biomarker in the surveillance of difficult colon maladies, such as inflammatory bowel disease. The use of claudin-1 as a biomarker of diagnostic and prognostic values will provide Medicine with much needed ammunition in the fight against cancer and will bring about, with added refinements, a new chapter in the era of personalized medicine to tackle this disease and match its destructive course with equally powerful and specifically targeted therapies. PMID- 29504116 TI - Cancer immunotherapy in mice and humans: personal observations. AB - An experiment involving active immunotherapy of leukemia in mice and its extension to human patients with chronic lymphocytic leukemia is described. First, anticancer activation of the immune system, how it is achieved, and observations of the central blockade of the immune system in leukemia are discussed. Clinical results of antileukemia immune activation are then presented, along with a description of new attempts to remove the immune checkpoint blockade. Personal observations are presented on possible further steps to achieving more effective active immunotherapy of cancer. PMID- 29504118 TI - Wisdom of the social versus non-social crowd in face identification. AB - Face identification is more accurate when people collaborate in social dyads than when they work alone (Dowsett & Burton, 2015, Br. J. Psychol., 106, 433). Identification accuracy is also increased when the responses of two people are averaged for each item to create a 'non-social' dyad (White, Burton, Kemp, & Jenkins, 2013, Appl. Cogn. Psychol., 27, 769; White et al., 2015, Proc. R. Soc. B Biol. Sci., 282, 20151292). Does social collaboration add to the benefits of response averaging for face identification? We compared individuals, social dyads, and non-social dyads on an unfamiliar face identity-matching test. We also simulated non-social collaborations for larger groups of people. Individuals and social dyads judged whether face image pairs depicted the same- or different identities, responding on a 5-point certainty scale. Non-social dyads were constructed by averaging the responses of paired individuals. Both social and non social dyads were more accurate than individuals. There was no advantage for social over non-social dyads. For larger non-social groups, performance peaked at near perfection with a crowd size of eight participants. We tested three computational models of social collaboration and found that social dyad performance was predicted by the decision of the more accurate partner. We conclude that social interaction does not bolster accuracy for unfamiliar face identity matching in dyads beyond what can be achieved by averaging judgements. PMID- 29504117 TI - Why and how to use virtual reality to study human social interaction: The challenges of exploring a new research landscape. AB - As virtual reality (VR) technology and systems become more commercially available and accessible, more and more psychologists are starting to integrate VR as part of their methods. This approach offers major advantages in experimental control, reproducibility, and ecological validity, but also has limitations and hidden pitfalls which may distract the novice user. This study aimed to guide the psychologist into the novel world of VR, reviewing available instrumentation and mapping the landscape of possible systems. We use examples of state-of-the-art research to describe challenges which research is now solving, including embodiment, uncanny valley, simulation sickness, presence, ethics, and experimental design. Finally, we propose that the biggest challenge for the field would be to build a fully interactive virtual human who can pass a VR Turing test - and that this could only be achieved if psychologists, VR technologists, and AI researchers work together. PMID- 29504119 TI - Mind perception of God in Japanese children. AB - There is a theoretical debate regarding whether children represent God with reference to a human. Most previous studies have assessed this issue focusing on knowledge/omniscience in western children. This study used a theoretical framework characterising mental capacities in terms of motivational/emotional (experience) and cognitive (agency) mental capacities and tested whether Japanese children discriminated between God, a human, a baby and an invisible agent according to these capacities. Three- to 6-year-old children were asked about the experience and agency of the agents. The results revealed that children discriminated God from a human in terms of mental capacities including experience and agency in 3-year-old children. On the other hand, 4- to 6-year-old children, but not 3-year-old children, discriminated a human from a baby and an invisible person. The results suggest that the Japanese children's representations of God differed from their representation of a human during preschool years. PMID- 29504120 TI - Development and evolution of tooth renewal in neoselachian sharks as a model for transformation in chondrichthyan dentitions. AB - A defining feature of dentitions in modern sharks and rays is the regulated pattern order that generates multiple replacement teeth. These are arranged in labio-lingual files of replacement teeth that form in sequential time order both along the jaw and within successively initiated teeth in a deep dental lamina. Two distinct adult dentitions have been described: alternate, in which timing of new teeth alternates between two adjacent files, each erupting separately, and the other arranged as single files, where teeth of each file are timed to erupt together, in some taxa facilitating similarly timed teeth to join to form a cutting blade. Both are dependent on spatiotemporally regulated formation of new teeth. The adult Angel shark Squatina (Squalomorphii) exemplifies a single file dentition, but we obtained new data on the developmental order of teeth in the files of Squatina embryos, showing alternate timing of tooth initiation. This was based on micro-CT scans revealing that the earliest mineralised teeth at the jaw margin and their replacements in file pairs (odd and even jaw positions) alternate in their initiation timing. Along with Squatina, new observations from other squalomorphs such as Hexanchus and Chlamydoselachus, together with representatives of the sister group Galeomorphii, have established that the alternate tooth pattern (initiation time and replacement order) characterises the embryonic dentition of extant sharks; however, this can change in adults. These character states were plotted onto a recent phylogeny, demonstrating that the Squalomorphii show considerable plasticity of dental development. We propose a developmental-evolutionary model to allow change from the alternate to a single file alignment of replacement teeth. This establishes new dental morphologies in adult sharks from inherited alternate order. PMID- 29504122 TI - Corrigendum. PMID- 29504121 TI - Transcranial Doppler velocity among Jamaican children with sickle cell anaemia: determining the significance of haematological values and nutrition. AB - This study investigated the association of nutritional and haematological variables with maximum time-averaged mean velocity (TAMV) measured by transcranial Doppler (TCD) velocity and the agreement of classification between two protocols. TCD categories included: normal (<170 cm/s), conditional (170-199 cm/s) and abnormal (>=200 cm/s) based on TAMV in distal internal carotid artery (dICA), middle cerebral artery (MCA), internal carotid bifurcation, anterior and posterior cerebral arteries. Of 358 children with sickle cell anaemia (SCA) examined, the mean age (+/-standard deviation) was 7.4 +/- 2.7 years; 13.1% and 6.7% had conditional and abnormal velocities, respectively. Children with abnormal TCD velocities had higher prevalence of prior stroke (P = 0.006). Increased TAMV was associated with younger age (P = 0.001), lower weight (P = 0.001), height (P = 0.007) and oxygen saturation (P = 0.005). There was no association of TAMV with height-age or body mass index (BMI) z-scores. Adjusting for gender, BMI z-score, age, previous stroke and oxygen saturation, mean corpuscular volume (P = 0.005) and reticulocyte count (P = 0.013) were positively associated with TAMV, while haemoglobin concentration (P = 0.009) was negatively associated. There was good agreement [99%; weighted Kappa 0.98 (95% confidence interval 0.89-1), P = 0.0001] in TCD classification using data from five vessels versus two vessels (dICA and MCA). Haematological variables, rather than nutritional status, may be useful markers that identify high-risk children with SCA. PMID- 29504123 TI - Editorial April 2018. PMID- 29504124 TI - Autoimmune diseases, infections, use of antibiotics and the risk of acute myeloid leukaemia: a national population-based case-control study. AB - Previous studies reported increased risk of acute myeloid leukaemia (AML) in individuals with inflammatory conditions. However, it is unclear whether this association is explained by preceding cytotoxic therapy or haematological diseases. We conducted a nationwide case-control study that included 3053 AML patients, diagnosed in Denmark between 2000 and 2013, and 30 530 sex- and age matched population controls. We retrieved information on autoimmune disease, infections, and use of antibiotics and computed odds ratios for AML (conditional logistic regression). Results were stratified by AML type, sex, and age. Autoimmune diseases were associated with an overall increased risk of AML {odds ratio [OR] 1.3 [95% confidence interval (CI) = 1.1-1.5]}. However, the risk was confined to patients with previous haematological disease or cytotoxic therapy exposure [secondary/therapy-related AML (sAML/tAML0) OR 2.0 (95% CI = 1.6-2.6)] and not de novo AML [OR 1.1 (95% CI = 0.9-1.3)]. Similarly, any prior infection requiring hospitalization was associated with a higher risk of AML [OR 1.3 (95% CI = 1.1-1.4)]. Again, this association was evident for sAML/tAML [OR 1.8 (95% CI = 1.5-2.2)], and not de novo AML [OR 1.1 (95% CI = 1.0-1.2)]. In conclusion, autoimmune diseases and infections were associated with an increased AML risk only in subjects with prior haematological disease and/or cytotoxic treatment. These observations suggest, that inflammation plays - if any - a minor role for the development of de novo AML. PMID- 29504125 TI - Greater prevalence of post-traumatic stress disorder and depression in deployed Canadian Armed Forces personnel at risk for moral injury. AB - BACKGROUND: A link between moral injury (i.e., the psychological distress caused by perceived moral transgressions) and adverse mental health outcomes (AMHO) has been recently proposed. However, the prevalence of exposure to morally injurious events and the associated risk of experiencing AMHO remains understudied. METHOD: The impact of exposure to potentially morally injurious experiences (PMIEs) was explored in relation to past-year PTSD and MDD, using the 2013 Canadian Armed Forces Mental Health Survey dataset of Afghanistan mission deployed regular force and reserve personnel. A series of logistic regressions were conducted, controlling for relevant sociodemographic, military, deployment, and trauma related variables. RESULTS: Over half of the deployed personnel endorsed at least one PMIE. Several demographic and military variables were associated with exposure to PMIEs. Those exposed to PMIEs demonstrated a greater likelihood of having past-year PTSD and MDD; feeling responsible for the death of Canadian or ally personnel demonstrated the strongest association with PTSD and MDD. Mental health training was not a moderator for PMIE exposure and AMHO. CONCLUSIONS: Exposure to PMIEs during deployments is common and represents an independent risk factor for past-year PTSD and MDD. Improved training that targets moral-ethical dilemmas and treatment interventions that address moral injury expressions is warranted. PMID- 29504126 TI - Readmissions for surgical site infections following caesarean section. AB - This retrospective study was conducted to identify the incidence and characteristics associated with readmissions for surgical site infections following caesarean section in a tertiary hospital from 2012 to 2015. Of 6334 patients who underwent caesarean section, 165 (2.6%) were readmitted, most commonly for surgical site infection (25.5%, n = 42). Thirty-seven of these patients (88%) had an emergency caesarean compared to five (12%) following an elective caesarean section. Of the women with surgical site infections, 69% were overweight and 14% had diabetes. Emergency caesarean sections were responsible for the majority of readmissions, particularly in women with co-morbidities that predisposed them to infection. PMID- 29504127 TI - Patient-controlled hospital admission for patients with severe mental disorders: a nationwide prospective multicentre study. AB - OBJECTIVE: To assess whether implementing patient-controlled admission (PCA) can reduce coercion and improve other clinical outcomes for psychiatric in-patients. METHODS: During 2013-2016, 422 patients in the PCA group were propensity score matched 1:5 with a control group (n = 2110) that received treatment as usual (TAU). Patients were followed up for at least one year using the intention to treat principle utilising nationwide registers. In a paired design, the outcomes of PCA patients during the year after signing a contract were compared with the year before. RESULTS: No reduction in coercion (risk difference = 0.001; 95% CI: 0.038; 0.040) or self-harming behaviour (risk difference = 0.005; 95% CI: -0.008; 0.018) was observed in the PCA group compared with the TAU group. The PCA group had more in-patient bed days (mean difference = 28.4; 95% CI: 21.3; 35.5) and more medication use (P < 0.0001) than the TAU group. Before and after analyses showed reduction in coercion (P = 0.0001) and in-patient bed days (P = 0.0003). CONCLUSION: Implementing PCA did not reduce coercion, service use or self-harm behaviour when compared with TAU. Beneficial effects of PCA were observed only in the before and after PCA comparisons. Further research should investigate whether PCA affects other outcomes to better establish its clinical value. PMID- 29504128 TI - The use of acute normovolemic hemodilution in paediatric cardiac surgery. AB - BACKGROUND: Acute normovolemic hemodilution (ANH) is considered safe and effective in decreasing perioperative transfusion in paediatric populations undergoing high blood-loss surgeries. We determined the association between ANH and the intraoperative use of allogeneic blood products in paediatric cardiac surgery patients. METHODS: This is a single-centre retrospective cohort study including paediatric patients between 0 and 36 months of age undergoing surgical repair or palliation of their cardiac defect with the use of cardiopulmonary bypass between November 2013 and November 2014. Our primary endpoint was the volume per kilogram of body weight of any blood product administered. Secondary endpoints were postoperative bleeding, coagulation profile, creatinine, vasoactive support, duration of mechanical ventilation, and hospital stay. RESULTS: In all, 50 patients met eligibility criteria and were included. Of those, seven were exposed to ANH and while 43 patients were treated according to usual care. Baseline characteristics were similar in both groups. After adjustment for baseline characteristics including age, American Society of Anaesthesiologists (ASA) classification, and Risk Adjusted Congenital Heart Surgery score, ANH was associated with reduced administration of allogenic blood products, with the mean difference between groups of 57.5 ml/kg (95% CI: 34.8, 80.2). The ANH group had lower blood losses at 6 and 24 h postoperatively. There were no differences in the duration of ICU or hospital stay. CONCLUSION: We found a reduction in the administration of blood products and lower postoperative blood losses associated with the use of ANH in paediatric cardiac surgery patients. The data suggest that ANH might be beneficial in reducing perioperative morbidity in this patient population. PMID- 29504129 TI - Gender differences in the development of cardiac complications: a multicentre study in a large cohort of thalassaemia major patients to optimize the timing of cardiac follow-up. AB - We assessed whether male gender was associated with a higher risk of cardiac iron accumulation and fibrosis, heart dysfunction and complications in a large, multicentre cohort of thalassaemia major (TM) patients, in order to optimize the timing in cardiac follow-up. We considered 1711 TM patients (899 females, 31.09 +/- 9.08 years), enrolled in the Myocardial Iron Overload in Thalassaemia Network. Clinical/instrumental data are recorded from birth to the first Cardiovascular Magnetic Resonance Imaging scan. Although having a similar risk of accumulating iron, males showed a significantly higher risk of developing cardiac dysfunction, heart failure, arrhythmias and cardiac complications overall, when compared to females (P < 0.0001). Up to 20-30 years of follow-up, the Kaplan Meier curves for the outcomes for which the male sex was a significant prognosticator almost overlapped, whereas they clearly diverged after this period. In patients with follow-up longer than 20 years, males exhibited a significantly higher risk of ventricular dysfunction, heart failure, arrhythmias, and cardiac complications. Female patients may have an intrinsically better tolerance for iron toxicity. International guidelines suggest annual cardiac evaluation for thalassaemia patients. It is possible that female patients can be evaluated at longer intervals, thus reducing health costs. PMID- 29504130 TI - Embryonic and larval development and fatty-acid profile of Epinephelus marginatus spawned in captivity: tools applied to captive rearing. AB - Development, ontogeny of the digestive system and the fatty-acid (FA) profile, were analysed during development of Epinephelus marginatus. Larvae were analysed 7 and 17 days post fertilization (dpf) to evaluate fatty-acid profile and morphological variables, respectively. Epinephelus marginatus larvae have relatively slow development of digestive structures, but were able to capture, ingest and digest prey by 5 dpf. Eggs were composed of high percentages of polyunsaturated fatty acids (PUFA) in phospholipids. The percentage of n3 PUFAs was higher than n6, especially docosahexaenoic acid (DHA), which exhibited higher levels compared with other marine species during the first 3 days of development, both in terms of phospholipids and triglycerides. The larvae present a high content of docosahexaenoic acid-eicosapentaenoic acid (DHA-EPA) and, during this phase, live food of small size was required (copepods or SS-strain Brachionus rotundiformes), enriched with DHA-EPA. These results may guide future studies on the contribution of FAs required during this stage of the life cycle of E. marginatus, to advance knowledge of the use of these FAs throughout ontogeny and contribute to the culture of this species commercial production or restocking. PMID- 29504131 TI - Theoretical study of nitrogen-doped graphene nanoflakes: Stability and spectroscopy depending on dopant types and flake sizes. AB - As nitrogen-doped graphene has been widely applied in optoelectronic devices and catalytic reactions, in this work we have investigated where the nitrogen atoms tend to reside in the material and how they affect the electron density and spectroscopic properties from a theoretical point of view. DFT calculations on N doped hexagonal and rectangular graphene nanoflakes (GNFs) showed that nitrogen atoms locating on zigzag edges are obviously more stable than those on armchair edges or inside flakes, and interestingly, the N-hydrogenated pyridine moiety could be preferable to pure pyridine moiety in large models. The UV-vis absorption spectra of these nitrogen-doped GNFs display strong dependence on flake sizes, where the larger flakes have their major peaks in lower energy ranges. Moreover, the spectra exhibit different connections to various dopant types and positions: the graphitic-type dopant species present large variety in absorption profiles, while the pyridinic-type ones show extraordinary uniform stability and spectra independent of dopant positions/numbers and hence are hardly distinguishable from each other. (c) 2018 Wiley Periodicals, Inc. PMID- 29504132 TI - Use of a modified Boari flap for the treatment of a proximal ureteral obstruction in a cat. AB - OBJECTIVE: To describe the use and long term outcome of a novel surgical technique developed to treat a proximal ureteral obstruction in a cat. STUDY DESIGN: Case report. ANIMALS: A 3-year-old female spayed Russian blue cat. METHODS: A 3-year-old female spayed Russian blue cat presented with a fever, decreased appetite, vomiting, and abdominal discomfort. A proximal left ureteral obstruction was noted on ultrasonographic examination. No filling defect was noted on antegrade pyelography. Due to the proximal location of the obstruction, a modification of a Boari flap was performed. In the current technique, the ureter was cut proximal to the level of obstruction, and the distal ureter was resected. A flap was created on the ventral surface of the bladder, the cut end of the ureter was pulled through the flap, and a ureteroneocystostomy was performed. The bladder was closed in a simple interrupted pattern. RESULTS: At re evaluation 2 and 4 weeks after surgery, azotemia had resolved. According to ultrasonography, the ureteroneocystostomy site appeared to be healing, and pelvic dilation had resolved. One year later, the cat continued to do well, with no lower urinary tract signs and no abnormality noted on blood tests or ultrasonography. CONCLUSION: The tubularized bladder flap originally described by Boari was modified to create a tension-free ureteroneocystostomy, without complication. This technique relied on surrounding native tissues and resulted in long-term resolution of the ureteral obstruction. CLINICAL SIGNIFICANCE: A modified Boari flap can lead to long-term resolution of proximal ureteral obstruction in cats, without requiring stents or permanent implants. PMID- 29504133 TI - Accurate lattice energies of organic molecular crystals from periodic turbomole calculations. AB - Accurate lattice energies of organic crystals are important i.e. for the pharmaceutical industry. Periodic DFT calculations with atom-centered Gaussian basis functions with the Turbomole program are used to calculate lattice energies for several non-covalently bound organic molecular crystals. The accuracy and convergence of results with basis set size and k-space sampling from periodic calculations is evaluated for the two reference molecules benzoic acid and naphthalene. For the X23 benchmark set of small molecular crystals accurate lattice energies are obtained using the PBE-D3 functional. In particular for hydrogen-bonded systems, a sufficiently large basis set is required. The calculated lattice energy differences between enantiopure and racemic crystal forms for a prototype set of chiral molecules are in good agreement with experimental results and allow the rationalization and computer-aided design of chiral separation processes. (c) 2018 Wiley Periodicals, Inc. PMID- 29504134 TI - Azobenzene-bridged diradical janus nucleobases with photo-converted magnetic properties between antiferromagnetic and ferromagnetic couplings. AB - We computationally design a series of azobenzene (AB)-bridged double radicalized nucleobases, a novel kind of diradical Janus-type nucleobases, and explore their spin coupling characteristics. Calculations prove that such diradical Janus-bases not only normally match with their complementary bases, but also exhibit well defined diradical character with photo-convertible intramolecular magnetic couplings (antiferromagnetic vs. ferromagnetic). Combination of four radical nucleobases (rG, rA, rC, rT) and photoswitch AB can yield 10 diradical Janus bases with different magnetic characteristics in which AB functions a bridge to mediate the spin coupling between two radical bases. The trans-form supports mild antiferromagnetic couplings with the spin coupling constants (J) ranging from 153.6 cm-1 to -50.91 cm-1 while the cis-form has weak magnetic couplings with ferromagnetic (0.22-8.50 cm-1 ) for most of them or antiferromagnetic (-0.77, 1.73, -3.30 cm-1 ) properties for only three. Further structural examination and frontier molecular orbital analyses indicate that the extended pi conjugation for better spin polarization provides an effective through-pi-bond pathway to mediate the spin coupling in the trans conformation while nonplanarity of the cis conformation weakens the through-bond coupling and causes a competitive through space pathway and as an overall result inhibits the spin coupling between two spin moieties. Meanwhile, we also find that the J values of the cis conformation vary with their angle between the radical base and its linked phenylene. Furthermore, the magnetic properties of the diradical Janus-bases can be significantly increased by interacting with metal ions. They also maintain a good UV absorption characteristics and there is a clear redshift compared with AB. This work provides a promising strategy for the rational design of photo convertible Janus-base magnets as the magnetism-tunable DNA building blocks. (c) 2018 Wiley Periodicals, Inc. PMID- 29504135 TI - Behavioural salinity preference of juvenile yellow perch Perca flavescens. AB - The present study determined the behavioural salinity preference of a freshwater stock of juvenile yellow perch Perca flavescens acclimated to salinities of 0 and 10. The preferred salinities ranged between 7.3 and 13.0 (mean +/- s.d. = 10.4 +/ 1.7; n = 13) with no significant effect of acclimation salinity. The results showed that juvenile P. flavescens prefers near isoosmotic salinities, which could be due to a lowered energetic cost of osmoregulation. PMID- 29504136 TI - A proposed new low-frequency antigen in the Augustine blood group system associated with a severe case of hemolytic disease of the fetus and newborn. PMID- 29504137 TI - DNA Conformation Regulates Gene Expression: The MYC Promoter and Beyond. AB - Emerging evidence suggests that DNA topology plays an instructive role in cell fate control through regulation of gene expression. Transcription produces torsional stress, and the resultant supercoiling of the DNA molecule generates an array of secondary structures. In turn, local DNA architecture is harnessed by the cell, acting within sensory feedback mechanisms to mediate transcriptional output. MYC is a potent oncogene, which is upregulated in the majority of cancers; thus numerous studies have focused on detailed understanding of its regulation. Dissection of regulatory regions within the MYC promoter provided the first hint that intimate feedback between DNA topology and associated DNA remodeling proteins is critical for moderating transcription. As evidence of such regulation is also found in the context of many other genes, here we expand on the prototypical example of the MYC promoter, and also explore DNA architecture in a genome-wide context as a global mechanism of transcriptional control. PMID- 29504138 TI - Plant water use responses along secondary forest succession during the 2015-2016 El Nino drought in Panama. AB - Tropical forests are increasingly being subjected to hotter, drier conditions as a result of global climate change. The effects of drought on forests along successional gradients remain poorly understood. We took advantage of the 2015 2016 El Nino event to test for differences in drought response along a successional gradient by measuring the sap flow in 76 trees, representing 42 different species, in 8-, 25- and 80-yr-old secondary forests in the 15-km2 'Agua Salud Project' study area, located in central Panama. Average sap velocities and sapwood-specific hydraulic conductivities were highest in the youngest forest. During the dry season drought, sap velocities increased significantly in the 80 yr-old forest as a result of higher evaporative demand, but not in younger forests. The main drivers of transpiration shifted from radiation to vapor pressure deficit with progressing forest succession. Soil volumetric water content was a limiting factor only in the youngest forest during the dry season, probably as a result of less root exploration in the soil. Trees in early successional forests displayed stronger signs of regulatory responses to the 2015 2016 El Nino drought, and the limiting physiological processes for transpiration shifted from operating at the plant-soil interface to the plant-atmosphere interface with progressing forest succession. PMID- 29504139 TI - Ab initio potential energy surface and vibration-rotation energy levels of germanium dicarbide, GeC2. AB - The accurate ground-state potential energy surface of germanium dicarbide, GeC2 , has been determined from ab initio calculations using the coupled-cluster approach. The core-electron correlation, higher-order valence-electron correlation, and scalar relativistic effects were taken into account. The potential energy surface of GeC2 was shown to be extraordinarily flat near the T shaped equilibrium configuration. The potential energy barrier to the linear CCGe configuration was predicted to be 1218 cm-1 . The vibration-rotation energy levels of some GeC2 isotopologues were calculated using a variational method. The vibrational bending mode nu3 was found to be highly anharmonic, with the fundamental wavenumber being only 58 cm-1 . Vibrational progressions due to this mode were predicted for the v1=1, v2=1, and v2=2 states of GeC2 . (c) 2018 Wiley Periodicals, Inc. PMID- 29504140 TI - Automated reaction path searches for spin-forbidden reactions. AB - Many catalytic and biomolecular reactions containing transition metals involve changes in the electronic spin state. These processes are referred to as "spin forbidden" reactions within nonrelativistic quantum mechanics framework. To understand detailed reaction mechanisms of spin-forbidden reactions, one must characterize reaction pathways on potential energy surfaces with different spin states and then identify crossing points. Here we propose a practical computational scheme, where only the lowest mixed-spin eigenstate obtained from the diagonalization of the spin-coupled Hamiltonian matrix is used in reaction path search calculations. We applied this method to the 6,4 FeO+ + H2 -> 6,4 Fe+ + H2 O, 6,4 FeO+ + CH4 -> 6,4 Fe+ + CH3 OH, and 7 Mn+ + OCS -> 5 MnS+ + CO reactions, for which crossings between the different spin states are known to play essential roles in the overall reaction kinetics. (c) 2018 Wiley Periodicals, Inc. PMID- 29504141 TI - HIF1alpha protein and mRNA expression as a new marker for post mortem interval estimation in human gingival tissue. AB - Estimating the post mortem interval (PMI) is still a crucial step in Forensic Pathology. Although several methods are available for assessing the PMI, a precise estimation is still quite unreliable and can be inaccurate. The present study aimed to investigate the immunohistochemical distribution and mRNA expression of hypoxia inducible factor (HIF-1alpha) in post mortem gingival tissues to establish a correlation between the presence of HIF-1alpha and the time since death, with the final goal of achieving a more accurate PMI estimation. Samples of gingival tissues were obtained from 10 cadavers at different PMIs (1-3 days, 4-5 days and 8-9 days), and were processed for immunohistochemistry and quantitative reverse transcription-polymerase chain reaction. The results showed a time-dependent correlation of HIF-1alpha protein and its mRNA with different times since death, which suggests that HIF-1alpha is a potential marker for PMI estimation. The results showed a high HIF-1alpha protein signal that was mainly localized in the stratum basale of the oral mucosa in samples collected at a short PMI (1-3 days). It gradually decreased in samples collected at a medium PMI (4-5 days), but it was not detected in samples collected at a long PMI (8-9 days). These results are in agreement with the mRNA data. These data indicate an interesting potential utility of Forensic Anatomy based techniques, such as immunohistochemistry, as important complementary tools to be used in forensic investigations. PMID- 29504143 TI - A case report of ovotesticular disorder of sex development (OT-DSD) in a baboon (Papio spp.) and a brief review of the non-human primate literature. AB - Disorders of sexual development are rare in non-human primates. We report a case of true hermaphroditism in a 19-year-old, nulliparous, female baboon (Papio spp.). At necropsy, the animal was obese with adequate muscle mass and hydration. Reproductive organs appeared normal with the exception of 2 firm nodular structures in the myometrium (1-1.5 cm diameter) and a thickened, dark endocervical mucosa. Histologically, both gonads were ovotestes and contained discrete areas of ovarian and testicular tissue. There were follicles in various stages of development surrounded by ovarian stroma. Other areas contained hypoplastic seminiferous tubules lined by Sertoli cells, but lacked germ cells and spermatozoa. The uterine lesions were consistent with adenomyosis and cystic endometrial hyperplasia. Cervical lesions were consistent with atypical glandular hyperplasia and squamous metaplasia with dysplasia. We report the first case of ovotesticular disorder of sexual development (OT-DSD), or true hermaphroditism in a baboon. PMID- 29504144 TI - PRO-QUEST: a rapid assessment method based on progressive saturation for quantifying exchange rates using saturation times in CEST. AB - PURPOSE: To develop a new MRI technique to rapidly measure exchange rates in CEST MRI. METHODS: A novel pulse sequence for measuring chemical exchange rates through a progressive saturation recovery process, called PRO-QUEST (progressive saturation for quantifying exchange rates using saturation times), has been developed. Using this method, the water magnetization is sampled under non-steady state conditions, and off-resonance saturation is interleaved with the acquisition of images obtained through a Look-Locker type of acquisition. A complete theoretical framework has been set up, and simple equations to obtain the exchange rates have been derived. RESULTS: A reduction of scan time from 58 to 16 minutes has been obtained using PRO-QUEST versus the standard QUEST. Maps of both T1 of water and B1 can simply be obtained by repetition of the sequence without off-resonance saturation pulses. Simulations and calculated exchange rates from experimental data using amino acids such as glutamate, glutamine, taurine, and alanine were compared and found to be in good agreement. The PRO QUEST sequence was also applied on healthy and infarcted rats after 24 hours, and revealed that imaging specificity to ischemic acidification during stroke was substantially increased relative to standard amide proton transfer-weighted imaging. CONCLUSION: Because of the reduced scan time and insensitivity to nonchemical exchange factors such as direct water saturation, PRO-QUEST can serve as an excellent alternative for researchers and clinicians interested to map pH changes in vivo. PMID- 29504145 TI - Effect of a 1800 MHz electromagnetic field emitted during embryogenesis on chick development and hatchability. AB - The level of artificial electromagnetic field (EMF) has steadily increased with the development of human civilization. The developing chicken embryo has been considered a good model to study the effects of EMF on living organisms. The aim of the study was to determine the effect of a 1800 MHz electromagnetic field during embryogenesis on the frequency of chick embryo malformations, morphometric parameters of the heart and liver and concentration of corticosterone in blood plasma, lipid and glycogen content in the liver of newly hatched chicks. A 1800 MHz EMF was found to shorten the duration of embryogenesis (earlier pipping and hatching of chicks) while having no effect on the quantity and quality of chicks and on increasing the incidence of embryo malformations. Exposure of chick embryos to EMF caused decreases in relative heart weight and right ventricle wall thickness. The pipping and hatching of chicks can be accelerated by stressful impact of EMF, which is confirmed by a significant increase in plasma corticosterone concentrations and decrease in fat and glycogen in the liver of chicks exposed during embryogenesis on the electromagnetic field with a frequency of 1800 MHz. PMID- 29504146 TI - Perceptions of risk characteristics of earthquakes compared to other hazards and their impact on risk tolerance. AB - People tolerate different levels of risk owing to a variety of hazards. Previous research shows that the psychometric properties of hazards predict people's tolerance of them. However, this work has not taken into account events such as earthquakes. The present study tested how earthquakes score vis-a-vis risk properties and risk tolerance as compared to five other familiar hazards. Participants from Wellington, New Zealand (N=139) rated these six hazards using measures of risk characteristics and risk tolerance. Participants demonstrated different levels of risk tolerance for the different hazards and viewed earthquakes as having similar risk features to nuclear power. They also preferred different risk mitigation strategies for earthquakes (more government funding) to the other five hazards (stronger legislation). In addition, earthquake risk tolerance was predicted by different risk characteristics than the other five hazards. These findings will help risk communicators in identifying which risk characteristics to target to influence citizens' risk tolerance. PMID- 29504147 TI - Self-Criticism as a Transdiagnostic Process in Nonsuicidal Self-Injury and Disordered Eating: Systematic Review and Meta-Analysis. AB - Nonsuicidal self-injury (NSSI) and disordered eating (DE) are highly comorbid and may be regarded as belonging to a spectrum of self-harm behaviors. We investigated self-criticism as a transdiagnostic correlate of these behaviors, in keeping with etiological theories of both NSSI and DE. We reviewed the literature and meta-analyzed the relation of self-criticism to both NSSI (15 studies; 17 effect sizes) and DE (24 studies; 29 effect sizes). Results showed equivalent, moderate-to-large effects for the relation of self-criticism to NSSI (r = .38; CI: .29-.46) and DE (r = .40; CI: .34-.45). The relation of NSSI to self criticism generalized across multiple potential moderators. DE behavior type moderated the relation of self-criticism to DE, with a stronger relation emerging for purging than restriction. Findings support self-criticism as a possible candidate for transdiagnostic pathways to self-harm. PMID- 29504149 TI - Control or rescue at sea? Aims and limits of border surveillance technologies in the Mediterranean Sea. AB - The matter of boat migrants crossing the Mediterranean Sea, seeking to reach Europe, is interchangeably defined as a 'security issue', requiring stricter border controls, and as a humanitarian issue with corresponding rescue and protection requirements. This paper seeks to understand what role various surveillance technologies, such as radar, satellites, and unmanned aerial vehicles, can play in this respect (legally and technically), in comparison to the role that they are assigned (that is, political expectations). To unravel what surveillance technologies can and cannot do vis-a-vis the aims of control and rescue, there is a need to comprehend what information can be collected and what information is needed to fulfil these objectives. The paper contends that there is a mismatch between the information sought to 'control' borders, but which cannot be gathered effectively by or processed using surveillance technologies, and the valuable information needed to perform rescue operations, which these surveillance technologies can supply. PMID- 29504148 TI - The immune characterization of interferon-beta responses in tuberculosis patients. AB - We aimed to assess the immunoregulatory effects of IFN-beta in patients with tuberculous pleurisy. IFN-beta, IFN-gamma and IL-17 expression levels were detected, and correlations among these factors in different culture groups were analyzed. Pleural fluid mononuclear cells (PFMC) from tuberculous pleural effusions, but not peripheral blood mononuclear cells (PBMC) from healthy donors, spontaneously expressed IFN-beta, IL-17 and IFN-gamma. Moreover, exogenous IFN beta significantly inhibited the expression of IL-17 in PFMC. By contrast, IFN beta simultaneously enhanced the levels of IFN-gamma. To further investigate the regulation of IL-17 and IFN-gamma by endogenous IFN-beta, an IFN-beta neutralizing antibody was simultaneously added to bacillus Calmette-Guerin (BCG) stimulated PFMC. IL-17 expression was significantly increased, but IFN-gamma production was markedly decreased in the experimental group supplemented with the IFN-beta neutralizing antibody. Simultaneously, IL-17 production was remarkably increased in the experimental group supplemented with the IFN-gamma neutralizing antibody. Taken together, in our study, we first found that freshly isolated PFMC, but not PBMC from healthy donors, spontaneously expressed IFN-beta, IL-17 and IFN-gamma in vivo. Moreover, IFN-beta suppressed IL-17 expression and increased IFN-gamma production. Furthermore, both IFN-beta and IFN-gamma down regulated IL-17 expression. These observations suggest that caution is required when basing anti-tuberculosis treatment on the inhibition of IFN-beta signaling. PMID- 29504150 TI - Reconstruction of diabetic lower leg and foot soft tissue defects using thoracodorsal artery perforator chimeric flaps. AB - BACKGROUND: Reconstruction of complicated diabetic lower leg and foot defects involving multiple tissue components remains a challenge. The purpose of this report is to introduce thoracodorsal artery perforator (TDAP) chimeric flaps for reconstructing diabetic lower leg and foot soft tissue defects. PATIENTS AND METHODS: Between April 2010 and August 2016, 17 patients with multiple diabetic lower leg and foot defects underwent reconstruction with TDAP chimeric flaps. Nine were women and the mean age of the patients was 57.7 years (range 35-73 years). One patient had 3 separate defects, 14 patients had 2 separate defects, and 2 patients had defects with dead space. The size of the defects ranged from 5 * 3 cm to 20 * 10 cm. RESULTS: Fifteen patients received TDAP chimeric flaps with two components (skin and muscle components), and two received three components (skin, latissimus dorsi (LD), and serratus anterior [SA] components). The skin paddle ranged from 10 * 3 cm to 25 * 14 cm. The LD components ranged from 3 * 5 cm to 20 * 10 cm and SA components ranged from 5 * 2 cm to 8 * 7 cm. All flaps survived except for partial loss of one muscle component. Four patients suffered postoperative complications including wound disruption and infection, all of which healed conservatively. The mean follow-up was 31.3 months (range 8-60 months). Fifteen patients were able to walk, one patient walked with walker, and one patient who had amputation due to Charcot joint infection walked with prosthesis. CONCLUSIONS: The TDAP chimeric flap may be another option for the complicated and complex wound coverage required to reconstruct diabetic lower leg and foot soft tissue defects. PMID- 29504151 TI - Bone vascularized composite allotransplantation model in swine tibial defect: Evaluation of surgical angiogenesis and transplant viability. AB - INTRODUCTION: In prior small animal studies, we maintained vascularized bone allotransplant viability without long-term immunotherapy. Instead, an autogenous neoangiogenic circulation is created from implanted vessels, sufficient to maintain bone viability with only 2 weeks immunosupression. Blood flow is maintained despite rejection of the allogeneic vascular pedicle thereafter. We have previously described a large animal (swine) pre-clinical model, reconstructing tibial defects with vascularized tibial allotransplants. In this manuscript, autologous angiogenesis is evaluated in this model and correlated with bone viability. MATERIALS AND METHODS: Allogeneic tibial segments were transplanted across a major swine leukocyte antigen mismatch. Microvascular repair of the bone VCA pedicle was combined with intraosseous implantation of an autogenous arteriovenous (AV) bundle. The bundle was ligated in group 1 (n = 4), and allowed to perfuse in group 2 (n = 4). Three-drug immunotherapy was given for 2 weeks. At 16 weeks micro-CT angiography quantified neoangiogenic vessel volume. Bone viability, rejection grade, and bone healing were analyzed. RESULTS: A substantial neoangiogenic circulation developed from the implanted AV-bundle in group 2, with vessel density superior to ligated AV-bundle controls (0.11 +/- 0.05 vs. 0.01 +/- 0.01, P = .029). Bone allotransplant viability was also significantly enhanced by neoangiogenesis (78.7 +/- 4.4% vs. 27.7 +/- 5.8%, P = .028) with higher bone healing scores (21.4 +/- 2.9 vs. 12.5 +/- 3.7, P = .029). Ligated control tibias demonstrated disorganized bone morphology and higher local inflammation (P = .143). CONCLUSION: Implantation of autogenous AV bundles into vascularized bone allotransplants resulted in the rapid formation of a neoangiogenic autogenous blood supply in a swine tibia model that maintained bone viability, improved bone healing, and minimized rejection. PMID- 29504152 TI - The adverse effects of interferon-free regimens in 149 816 chronic hepatitis C treated Egyptian patients. AB - BACKGROUND: Interferon-free regimens are associated with high sustained virological response; however, associated adverse effects have yet to be fully reported. AIM: To evaluate the adverse effects associated with the different direct-acting antiviral drug (DAA) regimens in Egyptian patients. METHODS: This multicenter retrospective study included all adverse effects during and after treatment with DAA regimens of 149 816 chronic hepatitis C treated Egyptian patients. Patients received sofosbuvir (SOF)/ribavirin (RBV) (n = 21 835), SOF/simeprevir (n = 24 215) SOF/daclatasvir (DCV) (n = 58 477), SOF/DCV/RBV (n = 45 188) and paritaprevir/ombitasvir/ritonavir/RBV (n = 101). The duration of treatment varied between 12 and 24 weeks. All changes in the treatment regimens, discontinuation, mortality, and serious side effects were reported. RESULTS: Adverse effects developed in 2475 (1.7%) (mean age [54 +/- 9], male gender [53%]) patients. Serious side effects developed in 68% of these patients, and SOF/RBV was the most common causing regimen (73%, P < 0.001). Anaemia and hyperbilirubinemia were the most common side effects (731/149816, 0.5% and 463/149816, 0.3%, respectively) and SOF/RBV (588/21835, 3% and 353/21835, 1.6%, respectively) showed the highest incidence in the treated patients. Hepatocellular carcinoma and mortality were reported in 0.02% and 0.06% of all treated patients, respectively. Patients with liver cirrhosis showed higher incidence of serious side effects (Log rank P = 0.045) and mortality (Log rank P = 0.025) than patients without liver cirrhosis. Male gender (P = 0.012), lower haemoglobin (P < 0.001), platelets (P < 0.001) and albumin (P = 0.001), higher bilirubin (P = 0.002) and cirrhosis (P < 0.001) were factors associated with serious side effects development. CONCLUSION: Adverse effects associated with DAAs are few, anaemia being the most common. SOF/RBV regimen showed the highest rate of side effects while SOF/DCV showed the least. PMID- 29504153 TI - Relevance of CYP3A4*20, UGT1A1*37 and UGT1A1*28 variants in irinotecan-induced severe toxicity. AB - Severe irinotecan-induced toxicity is associated with UGT1A1 polymorphisms. However, some patients develop side-effects despite harbouring a normal UGT1A1 genotype. As CYP3A4 is also an irinotecan-metabolizing enzyme, our study aimed to elucidate the influence of the CYP3A4*20 loss-of-function allele in the toxicity profile of these patients. Three-hundred and eight metastatic colorectal cancer patients treated with an irinotecan-containing chemotherapy were studied. The presence of CYP3A4*20, UGT1A1*37 and UGT1A1*28 alleles was tested. Associations between these genetic variants and toxicity were evaluated. UGT1A1*28 was significantly associated with severe diarrhoea, neutropenia and asthenia (P = 0.002, P = 0.037 and P = 0.041, respectively). One patient with the UGT1A1*28/*37 genotype presented with grade IV neutropenia and lethal septic shock. One heterozygous UGT1A1 (*1/*28) patient also carried the CYP3A4*20 allele but did not develop toxicity. We confirm that UGT1A1*37 and UGT1A1*28 are associated with severe toxicity and suggest that the CYP3A4*20 allele does not play a role in irinotecan-induced toxicity. PMID- 29504154 TI - Transcriptome changes induced in vitro by alcohol-containing mouthwashes in normal and dysplastic oral keratinocytes. AB - BACKGROUND: The role of alcohol-containing mouthwash as a risk factor for the development of oral cancer is a subject of conflicting epidemiological evidence in the literature despite alcohol being a recognised carcinogen. The aim of this study was to use in vitro models to investigate mechanistic and global gene expression effects of exposure to alcohol-containing mouthwash. METHODS: Two brands of alcohol-containing mouthwash and their alcohol-free counterparts were used to treat two oral cell lines derived from normal (OKF6-TERT) and dysplastic (DOK) tissues. Genotoxicity was determined by Comet assay. RNA-seq was performed using the Ion Torrent platform. Bioinformatics analysis used R/Bioconductor packages with differential expression using DEseq2. Pathway enrichment analysis used EnrichR with the WikiPathways and Kegg databases. RESULTS: Both cell lines displayed dose-dependent DNA damage in response to acute exposure to ethanol and alcohol-containing mouthwashes as well as alcohol-free mouthwashes reconstituted with ethanol as shown by Comet assay. The transcriptomic effects of alcohol containing mouthwash exposure were more complex with significant differential gene expression ranging from >2000 genes in dysplastic (DOK) cells to <100 genes in normal (OKF6-TERT) cells. Pathway enrichment analysis in DOK cells revealed alcohol-containing mouthwashes showed common features between the two brands used including DNA damage response as well as cancer-associated pathways. In OKF6-TERT cells, the most significantly enriched pathways involved inflammatory signalling. CONCLUSIONS: Alcohol-containing mouthwashes are genotoxic in vitro to normal and dysplastic oral keratinocytes and induce widespread changes in gene expression. Dysplastic cells are more susceptible to the transcriptomic effects of mouthwash. PMID- 29504155 TI - Oxidoreductase-Initiated Radical Polymerizations to Design Hydrogels and Micro/Nanogels: Mechanism, Molding, and Applications. AB - Due to their 3D cross-linked networks and tunable physicochemical properties, polymer hydrogels with different sizes are applied widely in tissue engineering, drug-delivery systems, pollution regulation, ionic conducting electrolytes, agricultural drought-resistance, cosmetics, and the food industry. Novel, environmentally friendly, and efficient oxidoreductase-initiated radical polymerizations to design hydrogels and micro/nanogels have gained increasing attention. Herein, the recent advances on the use of novel enzyme-initiated systems for hydrogel polymerization, including the mechanisms, and molding of polymeric and hybrid-polymeric networks are reviewed. Preliminary progress related to interfacial enzymatic polymerization for the generation of hybrid micro/nanogels is introduced as an emerging initiating approach. In addition, certain biological applications in tissue engineering, bioimaging, and therapy are demonstrated step by step. Finally, some perspectives on the safety profile of enzymatic formed hydrogels, new enzymatic systems, and potential theranostic applications are discussed. PMID- 29504156 TI - Immunolocalization of angiogenic growth factors in the ovine uterus during the oestrus cycle and in response to Steroids. AB - The vascular changes associated with endometrial maturation in preparation for embryo implantation depend on numerous growth factors, known to regulate key angiogenic events. Primarily, the vascular endothelial growth factor (VEGF) family promotes vascular growth, whilst the angiopoietins maintain blood vessel integrity. The aim was to analyse protein levels of VEGFA ligand and receptors, Angiopoietin-1 and 2 (ANG1/2) and endothelial cell receptor tyrosine kinase (TIE 2) in the ovine endometrium in the follicular and luteal phases of the oestrus cycle and in response to ovarian steroids. VEGFA and its receptors were localized in both vascular cells and non-vascular epithelium (glandular and luminal epithelium) and stroma cells. VEGFA and VEGFR2 proteins were elevated in vascular cells in follicular phase endometrium, compared to luteal phase, most significantly in response to oestradiol. VEGFR1 was expressed by epithelial cells and endothelial cells and was stimulated in response to oestradiol. In contrast, Ang-1 and Ang-2 proteins were elevated in luteal phase endometrium compared to follicular phase, and in response to progesterone, evident in vascular smooth muscle cells and glands which surround TIE-2-expressing blood vessels. Our findings indicate that VEGFA is stimulated by oestradiol, most predominantly in follicular phase endometrium, and Ang-1 and 2 are stimulated by progesterone and were increased during the luteal phase of the oestrus cycle, during the time of vascular maturation. PMID- 29504157 TI - Chemical and Morphological Control of Interfacial Self-Doping for Efficient Organic Electronics. AB - Solution-based processing of materials for electrical doping of organic semiconductor interfaces is attractive for boosting the efficiency of organic electronic devices with multilayer structures. To simplify this process, self doping perylene diimide (PDI)-based ionene polymers are synthesized, in which the semiconductor PDI components are embedded together with electrolyte dopants in the polymer backbone. Functionality contained within the PDI monomers suppresses their aggregation, affording self-doping interlayers with controllable thickness when processed from solution into organic photovoltaic devices (OPVs). Optimal results for interfacial self-doping lead to increased power conversion efficiencies (PCEs) of the fullerene-based OPVs, from 2.62% to 10.64%, and of the nonfullerene-based OPVs, from 3.34% to 10.59%. These PDI-ionene interlayers enable chemical and morphological control of interfacial doping and conductivity, demonstrating that the conductive channels are crucial for charge transport in doped organic semiconductor films. Using these novel interlayers with efficient doping and high conductivity, both fullerene- and nonfullerene-based OPVs are achieved with PCEs exceeding 9% over interlayer thicknesses ranging from ~3 to 40 nm. PMID- 29504158 TI - Template Conversion of Covalent Organic Frameworks into 2D Conducting Nanocarbons for Catalyzing Oxygen Reduction Reaction. AB - Progress over the past decades in porous materials has exerted great effect on the design of metal-free carbon electrochemical catalysts in fuel cells. The carbon material must combine three functions, i.e., electrical conductivity for electron transport, optimal pores for ion motion, and abundant heteroatom sites for catalysis. Here, an ideal carbon catalyst is achieved by combining two strategies-the use of a 2D covalent organic framework (COF) and the development of a suitable template to guide the pyrolysis. The COF produces nanosized carbon sheets that combine high conductivity, hierarchical porosity, and abundant heteroatom catalytic edges. The catalysts achieve superior performance to authentic Pt/C with exceptional onset potential (0 V vs -0.03 V), half-wave potentials (-0.11 V vs -0.16 V), high limit current density (7.2 mA cm-2 vs 6.0 mA cm-2 ), low Tafel slope (110 mV decade-1 vs 121 mV decade-1 ), long-time stability, and methanol tolerance. These results reveal a novel material platform based on 2D COFs for designing novel 2D carbon materials. PMID- 29504159 TI - Nanomaterials for Cancer Precision Medicine. AB - Medical science has recently advanced to the point where diagnosis and therapeutics can be carried out with high precision, even at the molecular level. A new field of "precision medicine" has consequently emerged with specific clinical implications and challenges that can be well-addressed by newly developed nanomaterials. Here, a nanoscience approach to precision medicine is provided, with a focus on cancer therapy, based on a new concept of "molecularly defined cancers." "Next-generation sequencing" is introduced to identify the oncogene that is responsible for a class of cancers. This new approach is fundamentally different from all conventional cancer therapies that rely on diagnosis of the anatomic origins where the tumors are found. To treat cancers at molecular level, a recently developed "microRNA replacement therapy" is applied, utilizing nanocarriers, in order to regulate the driver oncogene, which is the core of cancer precision therapeutics. Furthermore, the outcome of the nanomediated oncogenic regulation has to be accurately assessed by the genetically characterized, patient-derived xenograft models. Cancer therapy in this fashion is a quintessential example of precision medicine, presenting many challenges to the materials communities with new issues in structural design, surface functionalization, gene/drug storage and delivery, cell targeting, and medical imaging. PMID- 29504160 TI - The "Rust" Challenge: On the Correlations between Electronic Structure, Excited State Dynamics, and Photoelectrochemical Performance of Hematite Photoanodes for Solar Water Splitting. AB - In recent years, hematite's potential as a photoanode material for solar hydrogen production has ignited a renewed interest in its physical and interfacial properties, which continues to be an active field of research. Research on hematite photoanodes provides new insights on the correlations between electronic structure, transport properties, excited state dynamics, and charge transfer phenomena, and expands our knowledge on solar cell materials into correlated electron systems. This research news article presents a snapshot of selected theoretical and experimental developments linking the electronic structure to the photoelectrochemical performance, with particular focus on optoelectronic properties and charge carrier dynamics. PMID- 29504161 TI - Advanced Materials through Assembly of Nanocelluloses. AB - There is an emerging quest for lightweight materials with excellent mechanical properties and economic production, while still being sustainable and functionalizable. They could form the basis of the future bioeconomy for energy and material efficiency. Cellulose has long been recognized as an abundant polymer. Modified celluloses were, in fact, among the first polymers used in technical applications; however, they were later replaced by petroleum-based synthetic polymers. Currently, there is a resurgence of interest to utilize renewable resources, where cellulose is foreseen to make again a major impact, this time in the development of advanced materials. This is because of its availability and properties, as well as economic and sustainable production. Among cellulose-based structures, cellulose nanofibrils and nanocrystals display nanoscale lateral dimensions and lengths ranging from nanometers to micrometers. Their excellent mechanical properties are, in part, due to their crystalline assembly via hydrogen bonds. Owing to their abundant surface hydroxyl groups, they can be easily modified with nanoparticles, (bio)polymers, inorganics, or nanocarbons to form functional fibers, films, bulk matter, and porous aerogels and foams. Here, some of the recent progress in the development of advanced materials within this rapidly growing field is reviewed. PMID- 29504162 TI - Esthetic treatment of altered passive eruption. AB - Altered passive eruption is described as a condition in which the relationship between teeth, alveolar bone and soft tissues creates an excessive display of gingiva, commonly known as a 'gummy smile'. While there are authors who consider altered passive eruption to be a risk to periodontal health, its impact is greatest in terms of oral esthetics. The aim of periodontal management in such cases is not only to improve patient esthetics but also to restore periodontal health by re-establishing the normal relationship between the gingival margin, alveolar bone crest and cemento-enamel junction. The aim of this article is to present a narrative review of the etiology, classification and management of altered passive eruption. PMID- 29504163 TI - Metal-Organic-Framework-Assisted In Vivo Bacterial Metabolic Labeling and Precise Antibacterial Therapy. AB - Bacterial infection is one of the most serious physiological conditions threatening human health. There is an increasing demand for more effective bacterial diagnosis and treatment through noninvasive theranostic approaches. Herein, a new strategy is reported to achieve in vivo metabolic labeling of bacteria through the use of MIL-100 (Fe) nanoparticles (NPs) as the nanocarrier for precise delivery of 3-azido-d-alanine (d-AzAla). After intravenous injection, MIL-100 (Fe) NPs can accumulate preferentially and degrade rapidly within the high H2 O2 inflammatory environment, releasing d-AzAla in the process. d-AzAla is selectively integrated into the cell walls of bacteria, which is confirmed by fluorescence signals from clickable DBCO-Cy5. Ultrasmall photosensitizer NPs with aggregation-induced emission characteristics are subsequently designed to react with the modified bacteria through in vivo click chemistry. Through photodynamic therapy, the amount of bacteria on the infected tissue can be significantly reduced. Overall, this study demonstrates the advantages of metal-organic framework-assisted bacteria metabolic labeling strategy for precise bacterial detection and therapy guided by fluorescence imaging. PMID- 29504164 TI - Corrigendum. PMID- 29504166 TI - Esthetic evaluation and patient-centered outcomes in root-coverage procedures. AB - Treatment of buccal gingival recession is performed for esthetic concerns, root sensitivity, root caries and cervical abrasion resulting from incorrect toothbrushing. Over the years, clinicians and researchers have improved surgical techniques to achieve surrogate end points, such as complete root coverage, gingival recession reduction or keratinized tissue increase, ignoring the input from the patient regarding the true indications for treatment. In the past few years there has been an emphasis to include patient-centered outcomes in the evaluation of root-coverage procedures. The aim of this narrative review is to describe the professional objective assessment of the esthetic results after root coverage procedures and the patient perception of outcome in terms of esthetics, postoperative morbidity and dentinal hypersensitivity resolution after the treatment of gingival recessions. The need to align professional (surrogate) end points with patient-centered outcomes (true end points) in the future is emphasized. PMID- 29504165 TI - Electroconductive Biohybrid Collagen/Pristine Graphene Composite Biomaterials with Enhanced Biological Activity. AB - Electroconductive substrates are emerging as promising functional materials for biomedical applications. Here, the development of biohybrids of collagen and pristine graphene that effectively harness both the biofunctionality of the protein component and the increased stiffness and enhanced electrical conductivity (matching native cardiac tissue) obtainable with pristine graphene is reported. As well as improving substrate physical properties, the addition of pristine graphene also enhances human cardiac fibroblast growth while simultaneously inhibiting bacterial attachment (Staphylococcus aureus). When embryonic-stem-cell-derived cardiomyocytes (ESC-CMs) are cultured on the substrates, biohybrids containing 32 wt% graphene significantly increase metabolic activity and cross-striated sarcomeric structures, indicative of the improved substrate suitability. By then applying electrical stimulation to these conductive biohybrid substrates, an enhancement of the alignment and maturation of the ESC-CMs is achieved. While this in vitro work has clearly shown the potential of these materials to be translated for cardiac applications, it is proposed that these graphene-based biohybrid platforms have potential for a myriad of other applications-particularly in electrically sensitive tissues, such as neural and neural and musculoskeletal tissues. PMID- 29504167 TI - Lithiation/Delithiation Synthesis of Few Layer Silicene Nanosheets for Rechargeable Li-O2 Batteries. AB - Silicene has recently received increasing interest due to its unique properties. However, the synthesis of silicene remains challenging, which limits its wide applications. In this work, a top-down lithiation and delithiation process is developed to prepare few layer silicene-like nanosheets from ball-milled silicon nanopowders. It is found that delithiation solvent plays a critical role in the structure evolution of the final products. The use of isopropyl alcohol renders 2D silicene-like products 30-100 nm in length and ~2.4 nm in thickness. The electrochemical characterization analysis suggests that the product shows high performance for rechargeable Li-O2 batteries with 73% energy efficiency and high stability. The top-down synthesis strategy proposed in this work not only provides a new solution to the challenging preparation issue of few layer silicene but also demonstrates the feasibility of producing 2D materials from nonlayered starting structures. PMID- 29504168 TI - Sequential surveillance for drug safety in a regulatory environment. PMID- 29504169 TI - Gliosarcoma with primitive neuronal, chondroid, osteoid and ependymal elements. AB - A 51-year-old man presented with a 2-week history of malaise. MRI revealed a large solid and cystic lesion with ring enhancement measuring 6.5 cm in diameter in the right frontal lobe. Histologically, the tumor consisted of various components: diffuse growth of atypical astrocytic cells consistent with glioblastoma, fascicular proliferation of atypical spindle cells such as fibrosarcoma, clusters of primitive neuronal cells, and foci of ependymal cells. The sarcomatous component also focally exhibited chondroid and osteoid differentiation. Immunohistochemically, tumor cells in the primitive neuronal component were immunoreactive for synaptophysin and CD56. The spindle cells were immunopositive for Slug and Twist, regulators of epithelial-mesenchymal transition. Direct DNA sequencing demonstrated C228T mutation in the TERT promoter in astrocytic, sarcomatous and primitive neuronal components, suggesting their identical origin. Although a few cases of gliosarcoma with primitive neuronal differentiation have previously been described, the finding that neuronal, glial and sarcomatous components share an identical mutation of the TERT promoter has not been reported. The tumor recurred at the original site 11 months after the first surgery. Interestingly, the recurrent tumor was composed exclusively of a glioblastomatous component, unlike past cases of recurrent gliosarcoma. PMID- 29504170 TI - Alternative Thieno[3,2-b][1]benzothiophene Isoindigo Polymers for Solar Cell Applications. AB - This work reports the synthesis, characterization, photophysical, and photovoltaic properties of five new thieno[3,2-b][1]benzothiophene isoindigo (TBTI)-containing low bandgap donor-acceptor conjugated polymers with a series of comonomers and different side chains. When TBTI is combined with different electron-rich moieties, even small structural variations can have significant impact on thin film morphology of the polymer:phenyl C70 butyric acid methyl ester (PCBM) blends. More importantly, high-resolution electron energy loss spectroscopy is used to investigate the phase-separated bulk heterojunction domains, which can be accurately and precisely resolved, enabling an enhanced correlation between polymer chemical structure, photovoltaic device performance, and morphology. PMID- 29504171 TI - Evaluation of noncontrast MR enterography for pediatric inflammatory bowel disease assessment. AB - BACKGROUND: Gadolinium deposition in normal tissues is being increasingly recognized. Children with inflammatory bowel disease (IBD) undergo frequent imaging with contrast-enhanced MR enterography (MRE). PURPOSE: To determine the impact of intravenous (IV) gadolinium in assessment of pediatric IBD by MRE. STUDY TYPE: Retrospective, case series. POPULATION: Radiology information system was searched to identify all children who underwent MRE and endoscopy within 30 days in 2016. FIELD STRENGTH/SEQUENCE: 1.5T and 3T. ASSESSMENT: Imaging studies were evaluated for bowel inflammation interpreted by two blinded radiologists in two sessions 6 weeks apart (session 1 pre-MRE; session 2 pre/postcontrast-MRE). Endoscopic histology was the reference standard. STATISTICAL TESTS: A logistic regression model was evaluated using receiver operating characteristics curves and expressed by c-statistics. Agreement between readers was evaluated using Cohen's or weighted kappa statistic, as appropriate. Two-sided P < 0.05 was considered statistically significant. Descriptive statistics were used for assessment of IBD complications. RESULTS: In all, 52 children (46% female), mean age 13.2 (SD 3.42) years formed the study cohort. 77% (40/52) had inflammation on endoscopic biopsy. Pre/post-MRE showed no significant increase in the c-statistic compared to pre-MRE for assessment of small bowel (Reader 1 P = 0.56, Reader 2 P = 1.00) or large bowel inflammation (Reader 1 P = 0.42, Reader 2 P = 1.00)). Intravenous contrast showed no improvement in interobserver agreement for assessment of inflammation in small (kappa 0.92 pre-MRE, 0.88 pre/post-MRE) or large bowel (kappa 0.83 pre-MRE, 0.73 pre/post-MRE). IV contrast had no meaningful impact on interobserver agreement for length of small bowel inflamed (intraclass correlation coefficient 0.90 pre-MRE, 0.95 pre/post-MRE). Assessment of IBD complications was improved with IV contrast, with 3/5 cases with perianal penetrating disease not recognized on pre-MRE. DATA CONCLUSION: Routine administration of IV gadolinium has no impact on the assessment of bowel inflammation. However, there is potential for missing perianal complications using a noncontrast MRE protocol without dedicated pelvic imaging. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2018;48:341-348. PMID- 29504172 TI - Light-Responsive Shape: From Micrometer-Long Nanocylinders to Compact Particles in Electrostatic Self-Assembly. AB - A light-triggered shape change of supramolecular nanostructures is achieved through electrostatically self-assembly of linear polyelectrolytes and oppositely charged dyes in aqueous solution: Upon UV-irradiation, 1-um-long, flexible cylinders with a cross-section of 10 nm convert into ellipsoids of 400 nm * 40 nm. The nano-object shape is encoded in the molecular dye structure. PMID- 29504173 TI - Decision making in root-coverage procedures for the esthetic outcome. AB - The primary indication for treatment of gingival recessions is esthetics. In the last decades, patients have become increasingly more demanding in the esthetic outcome expected. In order to obtain a successful final result, periodontal plastic surgery should provide not only complete root coverage but also perfect blending in terms of color and texture. In the literature, many techniques have been demonstrated to be effective in obtaining complete root coverage, and the selection of one surgical technique over another depends on several factors related to the anatomic characteristics of the defect. The purpose of this paper was to suggest a decision-making process which starts from the clinical observation of the defects and is structured in progressive nodes that will guide the clinician through the most suitable surgical technique to achieve the ideal esthetic outcome. PMID- 29504174 TI - Controlled Polymerization of Isoprene with Chromium-Based Metal-Organic Framework Catalysts: Switching from Cyclic to cis-1,4-Selectivity Depending on Activator. AB - Chromium-based metal-organic framework (MOF) Cr-MIL-100/101 activated by activator and aluminum trialkyl compound serve as unique, highly efficient heterogeneous single-site catalysts for the controlled polymerization of isoprene, which not only exhibit quasi-living nature in isoprene polymerization but also unprecedentedly switch from cyclic to cis-1,4-selectivity depending on the activator used to yield low molecular weight cyclic PIPs or extremely high molecular weight cis-1,4-PIPs. Such heterogeneous Cr-MOF catalysts can be recycled approximately five times. Based on nitrogen sorption isotherm tests and powder X-ray diffraction, a cationic mechanism is suggested, in which the polymerization takes place inside the open nanochannels of MOF catalysts and the space confinement effect of narrow open nanochannels originated from the coordination of PhNMe2 from activator [PhNHMe2 ][B(C6 F5 )4 ] with the multiple metal centers of MOF catalysts might give a rational explanation for such controlled adjustment on the PIP's structure and properties. PMID- 29504175 TI - Do governing body and CSU nurses on clinical commissioning groups really lead a nursing agenda? Findings from a 2015 Survey of the Commissioning Nurse Leaders' Network Membership. AB - AIMS: This paper reports the findings from a 2015 survey of the Commissioning Nurse Leaders' Network. Our aim was to understand how governing body nurses perceive their influence and leadership on clinical commissioning groups. METHODS: An online survey method was used with a census sample of 238 governing body nurses and nurses working in Commissioning Support Units, who were members of the Commissioning Nurse Leaders' Network. The response rate was 40.7% (n = 97). RESULTS: While most governing body nurses felt confident in their leadership role, this was less so for non-executive governing body nurses. Nurses in Commissioning Support Units were much less positive than governing body nurses about their influence on clinical commissioning groups. CONCLUSION: Governing body nurses were satisfied with their impact on clinical commissioning groups and so could be said to be leading a nursing agenda but this evidence is limited to their own perceptions and more objective or diverse measures of impact are needed. The purpose of such roles to 'represent nursing, and ensure the patient voice is heard' may be a flawed aspiration, conflating nursing leadership and patient voice. IMPLICATIONS FOR NURSING MANAGEMENT: This is the first study to explore explicitly the differences between executive and non-executive governing body nurses and nurses working in commissioning support units. Achieving clinical commissioning groups' goals, including developing and embedding nursing leadership roles in clinical commissioning groups, may be threatened if the contributions of governing body nurses, and other nurses supporting clinical commissioning groups, go unrecognised within the profession, or if general practitioners or other clinical commissioning group executive members dominate decision-making on clinical commissioning groups. PMID- 29504176 TI - Fak-Mapk, Hippo and Wnt signalling pathway expression and regulation in distraction osteogenesis. AB - OBJECTIVES: To investigate the mechanism of mechanical stimulation in bone formation and regeneration during distraction osteogenesis. MATERIALS AND METHODS: In this study, microarray technology was used to investigate the time course of bone-related molecular changes in distraction osteogenesis in rats. Real-time PCR and Western-blot analyses were used to confirm the expression of genes identified in microarrays. Meanwhile, we used a lentivirus vector to inhibit Fak expression, in order to identify the osteogenic effect of Fak and Fak Mapk pathway during distraction osteogenesis. RESULTS: Several components of the Wnt and Hippo pathways were found to be up- or down-regulated during distraction osteogenesis by microarray. Meanwhile, it was found that Fak, Src, Raf-1, Erk1, Jnk and p38-Mapk were up-regulated during gradual distraction, compared with consolidation. To further determine whether Fak-Mapk pathway played an important role in distraction osteogenesis, Fak was disrupted with a lentivirus vector. The expressions levels of p-Fak, p-Erk1/2, p-JNK and p-p38Mapk were decreased. Meanwhile, a poor early and late osteogenesis effect was found in the shRNA-Fak group. CONCLUSION: It was inferred that the mechanical stimulus induces increased expression of Fak and activates Fak-Mapk pathway, by activation of Erk, Jnk and p38-Mapk pathway, and that Fak at least, in part, plays an important role in maintaining osteogenic effect by activating Fak-Mapk pathway during distraction osteogenesis. PMID- 29504177 TI - The influence of personal and organisational factors on entrepreneurship intention: An application in the health care sector. AB - AIMS: This study sought to contribute to research on entrepreneurial intention by identifying which constructs of the entrepreneurial profile and internal conditions of health care organisations support entrepreneurship and contribute to the entrepreneurial intention of these organisations' employees. BACKGROUND: In addition to psychological attributes, cognitive processes, motivations, sociodemographic and professional characteristics, and entrepreneurial skills, the literature indicates that internal conditions of organisations also contribute to explaining entrepreneurial intention. METHODS: To evaluate this model empirically, the primary data were collected with questionnaires distributed to nurses in two public hospitals-the Tras-os-Montes and Alto Douro Hospital Center and the Local Health Unit of the Northeast. A total of 638 nurses filled out the questionnaire. The data were analysed using inferential and regression analyses. RESULTS: The results suggest that the dimensions related to personal attributes, namely, motivation and entrepreneurial skills, are the constructs that best explain the entrepreneurial intention of these professionals within their organisations. CONCLUSIONS: A broad discussion is needed about how to implement internal conditions that promote an intrapreneurial and innovative culture in health care organisations. IMPLICATIONS FOR NURSING MANAGEMENT: Health care organisation administrators need to prioritise intrapreneurship while structuring their management strategies, thereby creating favourable internal conditions (e.g., support, autonomy, rewards, time availability and appropriate organisational procedures) that enhance their nurses' entrepreneurial intention. PMID- 29504178 TI - Tissue characterization of uterine fibroids with an intravoxel incoherent motion model: The need for T2 correction. AB - BACKGROUND: Diminished signal intensity of uterine fibroids in T2 -weighted images is routinely used as a qualitative marker of fibroid hypoperfusion. However, quantitative classification of fibroid perfusion with intravoxel incoherent motion (IVIM) model-based metrics is not yet clinically accepted. PURPOSE: To investigate the influence of T2 correction on the estimation of IVIM model parameters for characterizing uterine fibroid tissue. STUDY TYPE: Prospective. POPULATION: Fourteen women with 41 fibroids (12 Type I and 29 Type II, per Funaki classification) underwent diffusion-weighted imaging and T2 mapping. FIELD STRENGTH: Diffusion-weighted images (b values: 0, 20, 40, 60, 100, 200, 400, 600, 800, 1000 s/mm2 ) and T2 maps were obtained at 1.5T. ASSESSMENT: The effect of uterine fibroid T2 variation on IVIM model parameters (diffusion coefficient, perfusion coefficient, and perfusion volume fraction) were numerically modeled and experimentally evaluated without (D, D*, f) and with (Dc , STATISTICAL TEST: D-values and f-values estimated with and without T2 correction were compared by using a two-tailed Student's t-test. RESULTS: Type II fibroids had higher D and f than Type I fibroids, but the differences were not significant (Type I vs. Type II, D: 0.83 +/- 0.20 vs. 0.80 +/- 0.25 mm2 /s, P = 0.78; f: 23.64 +/- 4.87% vs. 25.27 +/- 7.46%, P = 0.49). For Type I and Type II fibroids, fc was lower than f, and fc of Type II fibroids was significantly higher than that of Type I fibroids (Type I vs. Type II, fc : 7.80 +/- 1.88% vs. 11.82 +/- 4.13%, P = 0.003). Both D and fc exponentially increased with the increase of fibroid T2 as functions: DATA CONCLUSION: T2 correction is important when using IVIM-based models to characterize uterine fibroid tissue. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;48:994-1001. PMID- 29504179 TI - High Signal in Bone Marrow on Diffusion-Weighted Imaging of Female Pelvis: Correlation With Anemia and Fibroid-Associated Symptoms. AB - BACKGROUND: The diffusion-weighted imaging (DWI) signals of the female pelvic bone marrow show great variability and are usually high in female patients with fibroid-associated symptoms and anemia. PURPOSE: To ascertain clinical factors contributing to high signal intensity in the bone marrow of the female pelvis on DWI. STUDY TYPE: Retrospective case-control study. SUBJECTS: A single-institution review of 221 female patients underwent a pelvic magnetic resonance study from December 2012 to July 2014. FIELD STRENGTH/SEQUENCE: 1.5T/DWI (b = 0 and 1000) and apparent diffusion coefficient (ADC). ASSESSMENT: The ADC of pelvic bone marrow and the muscle-normalized signal intensity (SI) on DWI (mnDWI) were measured. A brightness grading scale ranging from 0 to 4 was used for pelvic bone assessment. Clinical factors, namely, age, the lowest hemoglobin level in the last 6 months, the presence of large uterine fibroids, and/or adenomyosis and fibroid-associated symptoms were recorded. STATISTICAL TESTS: The relationships between the brightness grade and clinical factors were evaluated through multinomial logistic regression, and correlations of mnDWI and the ADC with the clinical factors were analyzed through the Kruskal-Wallis test, Jonckheere's trend test, and the Mann-Whitney U-test with Bonferroni correction. RESULTS: Age and the hemoglobin level were inversely associated with the bone marrow brightness grade on DWI (both P < 0.05), whereas the presence of fibroid associated symptoms showed a positive association (P = 0.028). The ADC and mnDWI in women younger than 50 years were significantly higher than those in older women (both P < 0.0001). The ADC had no significant correlation with anemia (P = 0.511), whereas mnDWI increased as the severity of anemia increased (P = 0.00154). DATA CONCLUSION: Our study showed an association of high DWI SI of pelvic bone marrow with anemia in premenopausal women. LEVEL OF EVIDENCE: 4 Technical Efficacy Stage 3 J. Magn. Reson. Imaging 2018;48:1024-1033. PMID- 29504180 TI - Decreased body mass index during treatment with sodium oxybate in narcolepsy type 1. AB - Narcolepsy type 1 is characterised by an increase in body weight after disease onset, frequently leading to obesity. It was suggested that this weight gain may be counteracted by treatment with sodium oxybate. We here provide longitudinal body mass index data of patients with narcolepsy type 1 after starting treatment with sodium oxybate, compared with patients in whom treatment with modafinil was initiated. Eighty-one individuals with narcolepsy type 1 fulfilled the entry criteria for this retrospective study: 59 had newly started treatment with sodium oxybate and 22 had newly started modafinil. Gender-specific differences between both treatment groups were compared using Student's t tests and mixed effect modeling. Patients using sodium oxybate lost weight, with a mean body mass index decrease of 2.56 kg/m2 between the first and last measurement (women; p = .001) and 0.84 kg/m2 (men; p = .006). Patients using modafinil, however, gained weight, with a mean body mass index increase of 0.57 kg/m2 (women; p = .033) and 0.67 kg/m2 (men; p = .122). Medication (p = .006) and baseline body mass index (p = .032) were predictors for body mass index decrease. In conclusion, treatment with sodium oxybate is associated with a body mass index reduction in narcolepsy type 1, whereas modafinil treatment is not. This effect is most pronounced in those who already have a higher baseline body mass index. PMID- 29504182 TI - Reduced corticostriatal functional connectivity in temporomandibular disorders. AB - Although temporomandibular disorders (TMD) have been associated with abnormal gray matter volumes in cortical areas and in the striatum, the corticostriatal functional connectivity (FC) of patients with TMD has not been studied. Here, we studied 30 patients with TMD and 20 healthy controls that underwent clinical evaluations, including Helkimo indices, pain assessments, and resting-state functional magnetic resonance imaging scans. The FCs of the striatal regions with the other brain areas were examined with a seed-based approach. As seeds, we used the dorsal caudate, ventral caudate/nucleus accumbens, dorsal caudal putamen, and ventral rostral putamen regions. Voxel-wise comparisons with controls revealed that the patients with TMD exhibited reduced FCs in the ventral corticostriatal circuitry, between the ventral striatum and ventral frontal cortices, including the anterior cingulate cortex and anterior insula; in the dorsal corticostriatal circuitry, between the dorsal striatum and the dorsal cortices, including the precentral gyrus and supramarginal gyrus; and also within the striatum. Additionally, we explored correlations between the reduced corticostriatal FCs and clinical measurements. These results directly supported the hypothesis that TMD is associated with reduced FCs in brain corticostriatal networks and that these reduced FCs may underlie the deficits in motor control, pain processing, and cognition in TMD. Our findings may contribute to the understanding of the etiologies and pathologies of TMD. PMID- 29504183 TI - A Paper Sensor Printed with Multifunctional Bio/Nano Materials. AB - We report a paper-based aptasensor platform that uses two reaction zones and a connecting bridge along with printed multifunctional bio/nano materials to achieve molecular recognition and signal amplification. Upon addition of analyte to the first zone, a fluorescently labelled DNA or RNA aptamer is desorbed from printed graphene oxide, rapidly producing an initial fluorescence signal. The released aptamer then flows to the second zone where it reacts with printed reagents to initiate rolling circle amplification, generating DNA amplicons containing a peroxidase-mimicking DNAzyme, which produces a colorimetric readout that can be read in an equipment-free manner or with a smartphone. The sensor was demonstrated using an RNA aptamer for adenosine triphosphate (a bacterial marker) and a DNA aptamer for glutamate dehydrogenase (Clostridium difficile marker) with excellent sensitivity and specificity. These targets could be detected in spiked serum or feacal samples, demonstrating the potential for testing clinical samples. PMID- 29504181 TI - Comparison of 3 He and 129 Xe MRI for evaluation of lung microstructure and ventilation at 1.5T. AB - BACKGROUND: To support translational lung MRI research with hyperpolarized 129 Xe gas, comprehensive evaluation of derived quantitative lung function measures against established measures from 3 He MRI is required. Few comparative studies have been performed to date, only at 3T, and multisession repeatability of 129 Xe functional metrics have not been reported. PURPOSE/HYPOTHESIS: To compare hyperpolarized 129 Xe and 3 He MRI-derived quantitative metrics of lung ventilation and microstructure, and their repeatability, at 1.5T. STUDY TYPE: Retrospective. POPULATION: Fourteen healthy nonsmokers (HN), five exsmokers (ES), five patients with chronic obstructive pulmonary disease (COPD), and 16 patients with nonsmall-cell lung cancer (NSCLC). FIELD STRENGTH/SEQUENCE: 1.5T. NSCLC, COPD patients and selected HN subjects underwent 3D balanced steady-state free precession lung ventilation MRI using both 3 He and 129 Xe. Selected HN, all ES, and COPD patients underwent 2D multislice spoiled gradient-echo diffusion weighted lung MRI using both hyperpolarized gas nuclei. ASSESSMENT: Ventilated volume percentages (VV%) and mean apparent diffusion coefficients (ADC) were derived from imaging. COPD patients performed the whole MR protocol in four separate scan sessions to assess repeatability. Same-day pulmonary function tests were performed. STATISTICAL TESTS: Intermetric correlations: Spearman's coefficient. Intergroup/internuclei differences: analysis of variance / Wilcoxon's signed rank. Repeatability: coefficient of variation (CV), intraclass correlation (ICC) coefficient. RESULTS: A significant positive correlation between 3 He and 129 Xe VV% was observed (r = 0.860, P < 0.001). VV% was larger for 3 He than 129 Xe (P = 0.001); average bias, 8.79%. A strong correlation between mean 3 He and 129 Xe ADC was obtained (r = 0.922, P < 0.001). MR parameters exhibited good correlations with pulmonary function tests. In COPD patients, mean CV of 3 He and 129 Xe VV% was 4.08% and 13.01%, respectively, with ICC coefficients of 0.541 (P = 0.061) and 0.458 (P = 0.095). Mean 3 He and 129 Xe ADC values were highly repeatable (mean CV: 2.98%, 2.77%, respectively; ICC: 0.995, P < 0.001; 0.936, P < 0.001). DATA CONCLUSION: 129 Xe lung MRI provides near-equivalent information to 3 He for quantitative lung ventilation and microstructural MRI at 1.5T. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage 2 J. Magn. Reson. Imaging 2018. PMID- 29504184 TI - Successful off-label sulfonylurea treatment of neonatal diabetes mellitus due to chromosome 6 abnormalities. AB - Chromosome 6 abnormalities such as paternal uniparental isodisomy, paternal 6q24 duplication, and maternal DMR (differentially methylated region) hypomethylation are a common cause of transient neonatal diabetes mellitus (TNDM). Oral sulfonylurea (SU) is used off-label to treat permanent neonatal diabetes mellitus owing to potassium channel mutation but has not been evaluated in TNDM. Our objective was to evaluate the efficacy and safety of SU therapy in chromosome 6 related TNDM. Description of 3 case reports and literature review was the subject of the study. SU therapy was successful in 2 patients (initiated during neonatal life in 1 patient and during relapse in the other) but failed in the other despite the use of high dosage. The literature review identified 11 cases of patients with chromosome 6-related TNDM treated with SU, including 4 treated before remission and 7 after the relapse. SU therapy was consistently effective, although 4 patients treated after the relapse required multiple oral medications. None of the patients needed associated insulin therapy. No side effects of SU or complications of diabetes were reported. SU seems effective and safe in chromosome 6-related TNDM treatment when used to treat the initial episode of diabetes or the relapse. It improves patients' and families' quality of life. SU is available only as oral tablets. A pediatric dosage form would facilitate the treatment of neonates and infants. PMID- 29504185 TI - A phase I study of anti-inflammatory therapy with rilonacept in adolescents and adults with type 1 diabetes mellitus. AB - BACKGROUND: The innate immune system may be activated around the time of diagnosis of type 1 diabetes (T1D). Components of this system, including cytokines such as interleukin-1beta (IL-1beta) represent potential therapeutic targets for disease modifying therapy. OBJECTIVE: We conducted a phase 1 trial of rilonacept, an IL-1 cytokine trap, in patients with T1D. SUBJECTS AND METHODS: Thirteen T1D patients (10 males) with median age (interquartile range, IQR) of 17 years (16-18), a median (IQR) of 5 months (5-7) since diagnosis. Rilonacept was administered subcutaneously for 26 weeks. Incidence of infections was the primary end-point. RESULTS: There were 85 adverse events; 13 were Grade 2, of which 9 (8 infectious) were judged "possibly related" to the drug. The mean (SD) C-peptide on 2-hour mixed meal tolerance tests decreased from 0.87 (0.42) to 0.59 (0.29) ng/mL (P = .01 by paired t test) during 6 months on treatment. Hemoglobin A1c (HbA1c) increased from 6.8 (1.1) to 7.3 (1.1) (P = .05), but there was not a significant change in daily insulin dose (0.41 +/- 0.23 to 0.47 +/- 0.18), or in insulin dose-adjusted HbA1c (IDAA1c, 8.4 +/- 1.8 to 9.0 +/- 1.5). Subjects in "remission," defined as HbA1c <6.5 and a total daily insulin dose <0.5 units/kg/24 h, decreased from 5 to 4. There were no significantly differentially expressed genes in peripheral blood leukocytes before and after rilonacept. CONCLUSIONS: Rilonacept treatment for 6 months is well-tolerated in individuals with T1D of recent onset, but is unlikely to be efficacious as a single agent in preserving beta cell function. PMID- 29504187 TI - Clinical testing of three novel transient receptor potential cation channel subfamily V member 1 antagonists in a pharmacodynamic intradermal capsaicin model. AB - BACKGROUND: The transient receptor potential cation channel subfamily V 1 (TRPV1) is involved in nociception and has thus been of interest for drug developers, as a target for novel analgesics. However, several oral TRPV1 antagonists have failed in development, and novel approaches to target TRPV1 with innovative chemistry are needed. METHOD: This work describes an intradermal microdosing approach in humans for pharmacodynamic deductions and pharmacological profiling of compounds. First, a human capsaicin model was developed, to generate pharmacodynamic translational data (Study Part A, n = 24). Then, three small molecule TRPV1 antagonists (AZ11760788, AZ12048189 and AZ12099548) were investigated in healthy volunteers (Study Part B, n = 36), applying the established model. Pain and flare were assessed by Visual Analogue Score and laser Doppler, respectively. RESULTS: The developed model proved useful for pharmacologic deductions; all compounds caused a dose-dependent inhibition of capsaicin-induced pain and flare responses, with a rank order potency of AZ11760788 > AZ12048189 ? AZ12099548. In addition, the dose-response data showed that the minimal antagonist concentrations needed to inhibit TRPV1 was >=6-7 times the equilibrium dissociation constant for each compound. CONCLUSION: With careful design of a pharmacodynamic translational human pain model, it was possible to rank order TRPV1 efficacy among three investigational TRPV1 antagonists, and to estimate human efficacious concentrations. SIGNIFICANCE: This fast and cost-effective translational approach allows for generation of human target engagement information early in drug development. This could be of value for other development programmes where pharmacological targets are expressed in peripheral sensory nerves. PMID- 29504188 TI - Anticoagulation in heart failure without atrial fibrillation: gaps and dilemmas in current clinical practice. AB - Data from observational and post-hoc analyses suggest that heart failure (HF) itself may be associated with higher risk of thromboembolic events compared to populations without HF. Although oral anticoagulants (OACs) might be a therapeutic option in individual cases, anticoagulation therapy in HF patients in sinus rhythm is not generally recommended, as the implementation of OACs in clinical practice in this HF population is not supported by large randomized clinical trials to date. Indeed, the available data suggest that the risk of major bleeding overshadows the potential anti-thromboembolic benefit of OACs in HF patients in sinus rhythm with no net beneficial effect on mortality rates. In this review we explore the current available evidence for the clinical outcomes of anticoagulation therapy in patients with HF in sinus rhythm, highlighting the current gaps in knowledge, which may guide the design of future randomized clinical trials focusing on the efficacy and safety of anticoagulant therapy in this HF population. PMID- 29504186 TI - Brain dynamics in ASD during movie-watching show idiosyncratic functional integration and segregation. AB - To refine our understanding of autism spectrum disorders (ASD), studies of the brain in dynamic, multimodal and ecological experimental settings are required. One way to achieve this is to compare the neural responses of ASD and typically developing (TD) individuals when viewing a naturalistic movie, but the temporal complexity of the stimulus hampers this task, and the presence of intrinsic functional connectivity (FC) may overshadow movie-driven fluctuations. Here, we detected inter-subject functional correlation (ISFC) transients to disentangle movie-induced functional changes from underlying resting-state activity while probing FC dynamically. When considering the number of significant ISFC excursions triggered by the movie across the brain, connections between remote functional modules were more heterogeneously engaged in the ASD population. Dynamically tracking the temporal profiles of those ISFC changes and tying them to specific movie subparts, this idiosyncrasy in ASD responses was then shown to involve functional integration and segregation mechanisms such as response inhibition, background suppression, or multisensory integration, while low-level visual processing was spared. Through the application of a new framework for the study of dynamic experimental paradigms, our results reveal a temporally localized idiosyncrasy in ASD responses, specific to short-lived episodes of long range functional interplays. PMID- 29504189 TI - "KiDS and Diabetes in Schools" project: Experience with an international educational intervention among parents and school professionals. AB - BACKGROUND: Although it is known that school care is a major challenge in diabetes treatment, there is still no published international initiative. OBJECTIVES: The aims of this study were to introduce an international educational intervention tool, the International Diabetes Federation (IDF) KiDS and Diabetes in Schools project (KiDS project), and to describe its impact on diabetes knowledge and behavior of caregivers and school professionals. METHODS: The KiDS project was developed with the support of IDF and the International Society for Pediatric and Adolescent Diabetes and provides online free material in 10 languages, directed to caregivers and school personnel. A pilot evaluation of the KiDS intervention was performed in Brazil. An educational intervention was conducted in 5 primary schools, with 42 parents and school staff, followed by 2 individual interviews after 1 and 3 months. The results were evaluated in a qualitative study with a descriptive design based on content analysis. RESULTS: School staff acquired new knowledge on diabetes and its treatment. They felt more confident when helping students with diabetes and said the educational intervention promoted a positive impact on the teacher-student relationship, on the caring for health, and on school infrastructure. Family members of children with diabetes stated that the educational intervention gave them an opportunity to strengthen and update information on treatment and improve their knowledge. CONCLUSIONS: The KiDS project is the first international tool directed to foster a safe and supportive environment and a better understanding of diabetes in schools. In this pilot evaluation, it achieved the goal of informing and changing the behavior of parents and school staff, thus improving the care provided to children with diabetes in schools. PMID- 29504190 TI - Advancing Transcranial Magnetic Stimulation Methods for Complex Regional Pain Syndrome: An Open-Label Study of Paired Theta Burst and High-Frequency Stimulation. AB - INTRODUCTION: Complex Regional Pain Syndrome (CRPS), a rare and severe chronic pain condition, often responds poorly to existing treatments. Previous studies demonstrated Transcranial Magnetic Stimulation (TMS) provided short-term pain relief for upper extremity CRPS. METHODS: Building on previous methodologies, we employed a TMS protocol that may lead to significant pain relief for upper and lower extremity CRPS in a nonrandomized open label pilot trial involving 21 participants. We individualized TMS coil positioning over motor cortex of somatic pain location, and administered intermittent theta-burst stimulation followed by 10 Hz high-frequency stimulation using a deeper targeting coil. We assessed response (>=30% pain reduction) from a single session (n = 5) and five consecutive daily sessions (n = 12) and compared change in pain from baseline, after one treatment and one-week posttreatment between groups using a mixed ANVOA. RESULTS: Both groups demonstrated significant pain reduction after one session and one-week posttreatment; however, no group differences were present. From a single session, 60% of participants responded at Week 1. From five sessions, 58% and 50% of participants responded at Weeks 1 and 2, respectively. Two from each group achieved >50% pain reduction beyond six to eight weeks. No serious adverse events occurred. Though headache and nausea were the most common side-effects, we urge careful monitoring to prevent seizures with this protocol. CONCLUSIONS: We used a TMS protocol that, for the first time, led to significant pain relief in upper and lower extremity CRPS, and will soon examine our protocol in a larger, controlled trial. PMID- 29504192 TI - 20th Annual Conference of the International Society for Bipolar Disorders, Mexico City, Mexico, 7-10 March 2018. PMID- 29504191 TI - Facilitating a dedicated focus on the human dimensions of care in practice settings: Development of a new humanised care assessment tool (HCAT) to sensitise care. AB - There is limited consensus about what constitutes humanly sensitive care, or how it can be sustained in care settings. A new humanised care assessment tool may point to caring practices that are up to the task of meeting persons as humans within busy healthcare environments. This paper describes qualitative development of a tool that is conceptually sensitive to human dimensions of care informed by a life-world philosophical orientation. Items were generated to reflect eight theoretical dimensions that constitute what makes care feel humanly focused. An action research group process in 2014-2015 with researchers, service users, healthcare professionals in two diverse clinical settings (stroke rehabilitation and dermatology) was used. Feedback on conceptual content, transparency of meaning and readability was then gained from a panel in Sweden and third-year student nurses in the UK. The tool can be applied to attune staff to human dimensions of care, offering items which point to concrete examples of humanising and dehumanising features of practice in ways that have not yet been fully captured in the caring literature. Based on theoretically led experiential items, with dedicated focus on what makes people feel more, or less than human, it may offer improvement on available assessments of care. PMID- 29504195 TI - Corrigendum to "Schmidingerothrix salinarum nov. spec. is the Molecular Sister of the Large Oxytrichid Clade (Ciliophora, Hypotricha) by Foissner et al. 2014". PMID- 29504196 TI - Corrigendum: "Morphology and Ontogenesis of Psilotrichides hawaiiensis nov. gen., nov. spec. and Molecular Phylogeny of the Psilotrichidae (Ciliophora, Hypotrichia)" by Heber et al. 2014. PMID- 29504193 TI - Functional MRI registration with tissue-specific patch-based functional correlation tensors. AB - Population studies of brain function with resting-state functional magnetic resonance imaging (rs-fMRI) rely on accurate intersubject registration of functional areas. This is typically achieved through registration using high resolution structural images with more spatial details and better tissue contrast. However, accumulating evidence has suggested that such strategy cannot align functional regions well because functional areas are not necessarily consistent with anatomical structures. To alleviate this problem, a number of registration algorithms based directly on rs-fMRI data have been developed, most of which utilize functional connectivity (FC) features for registration. However, most of these methods usually extract functional features only from the thin and highly curved cortical grey matter (GM), posing great challenges to accurate estimation of whole-brain deformation fields. In this article, we demonstrate that additional useful functional features can also be extracted from the whole brain, not restricted to the GM, particularly the white-matter (WM), for improving the overall functional registration. Specifically, we quantify local anisotropic correlation patterns of the blood oxygenation level-dependent (BOLD) signals using tissue-specific patch-based functional correlation tensors (ts PFCTs) in both GM and WM. Functional registration is then performed by integrating the features from different tissues using the multi-channel large deformation diffeomorphic metric mapping (mLDDMM) algorithm. Experimental results show that our method achieves superior functional registration performance, compared with conventional registration methods. PMID- 29504198 TI - Erratum. PMID- 29504197 TI - Legal Barriers to the Growth of Health Information Exchange-Boulders or Pebbles? AB - : Policy Points: Historically, in addition to economic and technical hurdles, state and federal health information privacy laws have been cited as a significant obstacle to expanding electronic health information exchange (HIE) in the United States. Our review finds that over the past decade, several helpful developments have ameliorated the legal barriers to HIE, although variation in states' patient consent requirements remains a challenge. Today, health care providers' complaints about legal obstacles to HIE may be better understood as reflecting concerns about the economic and competitive risks of information sharing. CONTEXT: Although the clinical benefits of exchanging patients' health information electronically across providers have long been recognized, participation in health information exchange (HIE) has lagged behind adoption of electronic health records. Barriers erected by federal and state health information privacy law have been cited as a leading reason for the slow progress. A comprehensive assessment of these issues has not been undertaken for nearly a decade, despite a number of salient legal developments. METHODS: Analysis of federal and state health information privacy statutes and regulations and secondary materials. FINDINGS: Although some legal barriers to HIE persist, many have been ameliorated-in some cases, simply through improved understanding of what the law actually requires. It is now clear that the Health Insurance Portability and Accountability Act presents no obstacles to electronically sharing protected health information for treatment purposes and does not hold providers who properly disclose information liable for privacy breaches by recipients. The failure of federal efforts to establish a unique patient identifier number does slow HIE by inhibiting optimal matching of patient records, but other action to facilitate matching will be taken under the 21st Century Cures Act. The Cures Act also creates the legal architecture to begin to combat "information blocking." Varying patient consent requirements under federal and state law are the most important remaining legal barrier to HIE progress. However, federal rules relating to disclosure of substance-abuse treatment information were recently liberalized, and development of a technical standard, Data Segmentation for Privacy, or DS4P, now permits sensitive data requiring special handling to be segmented within a patient's record. Even with these developments, state-law requirements for patient consent remain daunting to navigate. CONCLUSIONS: Although patient consent requirements make HIE challenging, providers' expressed worries about legal barriers to participating in HIE likely primarily reflect concerns that are economically motivated. Lowering the cost of HIE or increasing financial incentives may boost provider participation more than further reducing legal barriers. PMID- 29504200 TI - A Health Policy Sonnet. PMID- 29504202 TI - States Protecting the Public Interest in the Era of Trump. PMID- 29504199 TI - Transformation of the Health Care Industry: Curb Your Enthusiasm? AB - : Policy Points: Policymakers seek to transform the US health care system along two dimensions simultaneously: alternative payment models and new models of provider organization. This transformation is supposed to transfer risk to providers and make them more accountable for health care costs and quality. The transformation in payment and provider organization is neither happening quickly nor shifting risk to providers. The impact on health care cost and quality is also weak or nonexistent. In the longer run, decision makers should be prepared to accept the limits on transformation and carefully consider whether to advocate solutions not yet supported by evidence. CONTEXT: There is a widespread belief that the US health care system needs to move "from volume to value." This transformation to value (eg, quality divided by cost) is conceptualized as a two fold movement: (1) from fee-for-service to alternative payment models; and (2) from solo practice and freestanding hospitals to medical homes, accountable care organizations, large hospital systems, and organized clinics like Kaiser Permanente. METHODS: We evaluate whether this transformation is happening quickly, shifting risk to providers, lowering costs, and improving quality. We draw on recent evidence on provider payment and organization and their effects on cost and quality. FINDINGS: Data suggest a low prevalence of provider risk payment models and slow movement toward new payment and organizational models. Evidence suggests the impact of both on cost and quality is weak. CONCLUSIONS: We need to be patient in expecting system improvements from ongoing changes in provider payment and organization. We also may need to look for improvements in other areas of the economy or to accept and accommodate prospects of modest improvements over time. PMID- 29504203 TI - The Effect of Medicaid on Management of Depression: Evidence From the Oregon Health Insurance Experiment. AB - : Policy Points: We take advantage of Oregon's Medicaid lottery to gauge the causal effects of Medicaid coverage on mental health care, how effectively it addresses unmet needs, and how those effects differ for those with and without a history of depression. Medicaid coverage reduced the prevalence of undiagnosed depression by almost 50% and untreated depression by more than 60%. It increased use of medications and reduced the share of respondents reporting unmet mental health care needs by almost 40%. There are likely to be substantial mental health consequences of policy decisions about Medicaid coverage for vulnerable populations. CONTEXT: Expanding Medicaid to previously uninsured adults has been shown to increase detection and reduce the prevalence of depression, but the ways that Medicaid affects mental health care, how effectively it addresses unmet needs, and how those effects differ for those with and without a history of depression remain unclear. METHODS: We take advantage of Oregon's Medicaid lottery to gauge the causal effects of Medicaid coverage using a randomized controlled design, drawing on both primary and administrative data sources. FINDINGS: Medicaid coverage reduced the prevalence of undiagnosed depression by almost 50% and untreated depression by more than 60%. It increased use of medications frequently prescribed to treat depression and related mental health conditions and reduced the share of respondents reporting unmet mental health care needs by almost 40%. The share of respondents screening positive for depression dropped by 9.2 percentage points overall, and by 13.1 for those with preexisting depression diagnoses, with greatest relief in symptoms seen primarily in feeling down or hopeless, feeling tired, and trouble sleeping-consistent with the increase observed not just in medications targeting depression but also in those targeting sleep. CONCLUSIONS: Medicaid coverage had significant effects on the diagnosis, treatment, and outcomes of a population with substantial unmet mental health needs. Coverage increased access to care, reduced the prevalence of untreated and undiagnosed depression, and substantially improved the symptoms of depression. There are likely to be substantial mental health consequences of policy decisions about Medicaid coverage for vulnerable populations. PMID- 29504204 TI - On Creating a National Health Conversation. PMID- 29504205 TI - Geographic Variation in Household and Catastrophic Health Spending in India: Assessing the Relative Importance of Villages, Districts, and States, 2011-2012. AB - : Policy Points: Per-capita household health spending was higher in economically developed states and was associated with ability to pay, but catastrophic health spending (CHS) was equally high in both poorer and more developed states in India. Based on multilevel modeling, we found that the largest geographic variation in health spending and CHS was at the state and village levels, reflecting wide inequality in the accessibility to and cost of health care at these levels. Contextual factors at macro and micro political units are important to reduce health spending and CHS in India. CONTEXT: In India, health care is a local good, and households are the major source of financing it. Earlier studies have examined diverse determinants of health care spending, but no attempt has been made to understand the geographical variation in household and catastrophic health spending. We used multilevel modeling to assess the relative importance of villages, districts, and states to health spending in India. METHODS: We used data on the health expenditures of 101,576 households collected in the consumption expenditure schedule (68th round) carried out by the National Sample Survey in 2011-2012. We examined 4 dependent variables: per-capita health spending (PHS), per-capita institutional health spending (PIHS), per-capita noninstitutional health spending (PNHS), and catastrophic health spending (CHS). CHS was defined as household health spending exceeding 40% of its capacity to pay. We used multilevel linear regression and logistic models to decompose the variation in each outcome by state, region, district, village, and household levels. FINDINGS: The average PHS was 1,331 Indian rupees (INR), which varied by state-level economic development. About one-fourth of Indian households incurred CHS, which was equally high in both the economically developed and poorer states. After controlling for household level factors, 77.1% of the total variation in PHS was attributable to households, 10.1% to states, 9.5% to villages, 2.6% to districts, and 0.7% to regions. The pattern in variance partitioning was similar for PNHS. The largest interstate variation was found for CHS (15.9%), while the opposite was true for PIHS (3.2%). CONCLUSIONS: We observed substantial variations in household health spending at the state and village levels compared with India's districts and regions. The large variation in CHS attributable to states indicates interstate inequality in the accessibility to and cost of health care. Our findings suggest that contextual factors at the macro and micro political units are important to reduce India's household health spending and CHS. PMID- 29504206 TI - The Role of HIPAA Omnibus Rules in Reducing the Frequency of Medical Data Breaches: Insights From an Empirical Study. AB - : Policy Points: Frequent data breaches in the US health care system undermine the privacy of millions of patients every year-a large number of which happen among business associates of the health care providers that continue to gain unprecedented access to patients' data as the US health care system becomes digitally integrated. Implementation of the HIPAA Omnibus Rules in 2013 has led to a significant decrease in the number of privacy breach incidents among business associates. CONTEXT: Frequent data breaches in the US health care system undermine the privacy of millions of patients every year. A large number of such breaches happens among business associates of the health care providers that continue to gain unprecedented access to patients' data as the US health care system becomes digitally integrated. The Omnibus Rules of the Health Insurance Portability and Accountability Act (HIPAA), which were enacted in 2013, significantly increased the regulatory oversight and privacy protection requirements of business associates. The objective of this study is to empirically examine the effects of this shift in policy on the frequency of medical privacy breaches among business associates in the US health care system. The findings of this research shed light on how regulatory efforts can protect patients' privacy. METHODS: Using publicly available data on breach incidents between October 2009 and August 2017 as reported by the Office for Civil Rights (OCR), we conducted an interrupted time-series analysis and a difference-in differences analysis to examine the immediate and long-term effects of implementation of HIPAA omnibus rules on the frequency of medical privacy breaches. FINDINGS: We show that implementation of the omnibus rules led to a significant reduction in the number of breaches among business associates and prevented 180 privacy breaches from happening, which could have affected nearly 18 million Americans. CONCLUSIONS: Implementation of HIPAA omnibus rules may have been a successful federal policy in enhancing privacy protection efforts and reducing the number of breach incidents in the US health care system. PMID- 29504207 TI - Advancing diabetes management in adolescents: Comparative effectiveness of mobile self-monitoring blood glucose technology and family-centered goal setting. AB - BACKGROUND: As adolescents gain autonomy, it remains important for parents to be involved with diabetes management to avoid deterioration in glycemic control. Technologies for self-monitoring of blood glucose (SMBG) allow for remote monitoring in real-time by parents. This research compared 3 strategies for improving SMBG and diabetes self-care in the short-term. These strategies were: (1) health information technology (HIT)-enhanced blood glucose meter that shared blood glucose data among patients, their parent, and care providers, and allowed for text messaging; (2) family-centered goal setting; and (3) a combination of (1) and (2). METHODS: One hundred twenty-eight participants enrolled; 97 adolescent-parent pairs attended clinic at 3-month intervals during the 6-month intervention. Differences between treatment groups were evaluated using analysis of variance (ANOVAs) for continuous variables and chi2 tests for frequencies. Within patient changes were evaluated using paired t tests. RESULTS: Participants in the HIT-enhanced SMBG group had no change in mean glycosylated hemoglobin (HbA1c). Participants assigned to family-centered goal setting had a non significant decrease in HbA1c of -0.3% (P = .26) from baseline to 6 months. Participants in the combined approach had a significant decrease in HbA1c of 0.6% (P = .02) from baseline to 3 months, but the decrease of -0.4% at 6 months was non-significant (P = .51). The change in HbA1c from baseline to 3 months was greater for the combined approach than for the HIT-enhanced SMBG (P = .05) or family-centered goal setting (P = .01). CONCLUSIONS: Our data suggest that utilizing the family-centered goal setting strategy when implementing HIT enhanced diabetes technology deserves further study. PMID- 29504208 TI - Hepatomegaly in a boy with ARID1B-related Coffin-Siris syndrome. PMID- 29504209 TI - Brief report: Lactobacillus bulgaricus GLB44 (ProvioticTM ) plus esomeprazole for Helicobacter pylori eradication: A pilot study. AB - BACKGROUND: Recent studies of Lactobacillus delbrueckii subsp. bulgaricus GLB44 plus a proton-pump inhibitor (PPI) reported cures of more than 90% of patients with active Helicobacter pylori infections. AIM: To confirm the high H. pylori cure rates reported previously. METHOD: A pilot study was done in healthy H. pylori-infected volunteers using 3-gram sachet (3 billion cells) of L. delbrueckii GLB44 plus 22.3 mg of esomeprazole b.i.d., for 14 days. The result was determined by urea breath testing 4 weeks after therapy. Stopping rules required for ending enrollment if less than 3 of the first 10 subjects were cured. RESULTS: Nine subjects were entered and because all failed to achieve negative urea breath test, the stopping rule required the study to end. CONCLUSION: We were unable to confirm reports of achieving a high H. pylori cure rate with L. delbrueckii GLB44 plus a PPI. PMID- 29504211 TI - Lifelong learning and professional practice. PMID- 29504212 TI - A single-center clinical trial to evaluate the efficacy of a tripeptide/hexapeptide antiaging regimen. AB - INTRODUCTION: An antiaging regimen that aids in clearing the matrix of waste products and stimulating neocollagenesis and neoelastogenesis was tested among a group of subjects over the course of 12 weeks to assess its efficacy in women with mild to moderate wrinkles and skin sagging on the face. MATERIALS AND METHODS: The efficacy of the product regimen was tested in 22 subjects using investigator clinical grading measurements, raking light imaging, 3D imaging, biopsies, and self-assessment questionnaires at baseline and weeks 4, 8, and 12. RESULTS: Clinical grading indicated that use of the antiaging regimen for 12 weeks produced a statistically significant improvement in scores for all evaluated parameters; the raking light image analysis demonstrated a statistically significant improvement in values for length, width, and area of wrinkles when compared with baseline values as did 3D imaging. Biopsy results in the 5 patients tested showed improvement in solar elastosis, collagen stimulation, and improvement in cornified layers in all 5 patients. Elastin stimulation was evident in 3 of 5 patients. Results from the self-assessment questionnaire analysis indicated favorable responses in a statistically significant proportion of subjects after 12 weeks of use for all inquiries. CONCLUSION: Use of this facial antiaging regimen was effective in improving visual facial photoaging conditions and well-perceived when used by women with mild to moderate wrinkles and skin sagging on the face under the conditions of this study. PMID- 29504210 TI - Trans-species synthetic gene design allows resistance pyramiding and broad spectrum engineering of virus resistance in plants. AB - To infect plants, viruses rely heavily on their host's machinery. Plant genetic resistances based on host factor modifications can be found among existing natural variability and are widely used for some but not all crops. While biotechnology can supply for the lack of natural resistance alleles, new strategies need to be developed to increase resistance spectra and durability without impairing plant development. Here, we assess how the targeted allele modification of the Arabidopsis thaliana translation initiation factor eIF4E1 can lead to broad and efficient resistance to the major group of potyviruses. A synthetic Arabidopsis thaliana eIF4E1 allele was designed by introducing multiple amino acid changes associated with resistance to potyvirus in naturally occurring Pisum sativum alleles. This new allele encodes a functional protein while maintaining plant resistance to a potyvirus isolate that usually hijacks eIF4E1. Due to its biological functionality, this synthetic allele allows, at no developmental cost, the pyramiding of resistances to potyviruses that selectively use the two major translation initiation factors, eIF4E1 or its isoform eIFiso4E. Moreover, this combination extends the resistance spectrum to potyvirus isolates for which no efficient resistance has so far been found, including resistance breaking isolates and an unrelated virus belonging to the Luteoviridae family. This study is a proof-of-concept for the efficiency of gene engineering combined with knowledge of natural variation to generate trans-species virus resistance at no developmental cost to the plant. This has implications for breeding of crops with broad-spectrum and high durability resistance using recent genome editing techniques. PMID- 29504213 TI - Prolonged breastfeeding and dental caries. PMID- 29504214 TI - Headache and vomiting in a 15-year-old boy with hyperimmunoglobulin E syndrome. PMID- 29504215 TI - Headache and vomiting in a 15-year-old boy with hyperimmunoglobulin E syndrome. PMID- 29504216 TI - The Meaning of Screening. PMID- 29504217 TI - Maternal pertussis immunisation. PMID- 29504218 TI - Multiple grouped papules and vesicles on the finger of a 2-year-old girl. PMID- 29504219 TI - Multiple grouped papules and vesicles on the finger of a 2-year-old girl. PMID- 29504220 TI - Influenza vaccine saves children's lives. PMID- 29504221 TI - Migraine and cognitive behavioural therapy. PMID- 29504222 TI - What Medications are Australian Children Prescribed? Evidence from the Longitudinal Study of Australian Children. PMID- 29504223 TI - Consensus guidelines on the use of bisphosphonate therapy in children and adolescents. AB - Bisphosphonate therapy is the mainstay of pharmacological intervention in young people with skeletal fragility. The evidence of its use in a variety of conditions remains limited despite over three decades of clinical experience. On behalf of the Australasian Paediatric Endocrine Group, this evidence-based consensus guideline presents recommendations and discusses the graded evidence (using the GRADE system) for these recommendations. Primary bone fragility disorders such as osteogenesis imperfecta are considered separately from osteoporosis secondary to other clinical conditions (such as cerebral palsy, Duchenne muscular dystrophy). The use of bisphosphonates in non-fragility conditions, such as fibrous dysplasia, avascular necrosis, bone cysts and hypercalcaemia, is also discussed. While these guidelines provide an evidence based approach where possible, further research is required in all clinical applications in order to strengthen the recommendations made. PMID- 29504224 TI - Function and underlying mechanisms of seasonal colour moulting in mammals and birds: what keeps them changing in a warming world? AB - Animals that occupy temperate and polar regions have specialized traits that help them survive in harsh, highly seasonal environments. One particularly important adaptation is seasonal coat colour (SCC) moulting. Over 20 species of birds and mammals distributed across the northern hemisphere undergo complete, biannual colour change from brown in the summer to completely white in the winter. But as climate change decreases duration of snow cover, seasonally winter white species (including the snowshoe hare Lepus americanus, Arctic fox Vulpes lagopus and willow ptarmigan Lagopus lagopus) become highly contrasted against dark snowless backgrounds. The negative consequences of camouflage mismatch and adaptive potential is of high interest for conservation. Here we provide the first comprehensive review across birds and mammals of the adaptive value and mechanisms underpinning SCC moulting. We found that across species, the main function of SCC moults is seasonal camouflage against snow, and photoperiod is the main driver of the moult phenology. Next, although many underlying mechanisms remain unclear, mammalian species share similarities in some aspects of hair growth, neuroendocrine control, and the effects of intrinsic and extrinsic factors on moult phenology. The underlying basis of SCC moults in birds is less understood and differs from mammals in several aspects. Lastly, our synthesis suggests that due to limited plasticity in SCC moulting, evolutionary adaptation will be necessary to mediate future camouflage mismatch and a detailed understanding of the SCC moulting will be needed to manage populations effectively under climate change. PMID- 29504225 TI - Replicative stress and alterations in cell cycle checkpoint controls following acetaminophen hepatotoxicity restrict liver regeneration. AB - OBJECTIVES: Acetaminophen hepatotoxicity is a leading cause of hepatic failure with impairments in liver regeneration producing significant mortality. Multiple intracellular events, including oxidative stress, mitochondrial damage, inflammation, etc., signify acetaminophen toxicity, although how these may alter cell cycle controls has been unknown and was studied for its significance in liver regeneration. MATERIALS AND METHODS: Assays were performed in HuH-7 human hepatocellular carcinoma cells, primary human hepatocytes and tissue samples from people with acetaminophen-induced acute liver failure. Cellular oxidative stress, DNA damage and cell proliferation events were investigated by mitochondrial membrane potential assays, flow cytometry, fluorescence staining, comet assays and spotted arrays for protein expression after acetaminophen exposures. RESULTS: In experimental groups with acetaminophen toxicity, impaired mitochondrial viability and substantial DNA damage were observed with rapid loss of cells in S and G2/M and cell cycle restrictions or even exit in the remainder. This resulted from altered expression of the DNA damage regulator, ATM and downstream transducers, which imposed G1/S checkpoint arrest, delayed entry into S and restricted G2 transit. Tissues from people with acute liver failure confirmed hepatic DNA damage and cell cycle-related lesions, including restrictions of hepatocytes in aneuploid states. Remarkably, treatment of cells with a cytoprotective cytokine reversed acetaminophen-induced restrictions to restore cycling. CONCLUSIONS: Cell cycle lesions following mitochondrial and DNA damage led to failure of hepatic regeneration in acetaminophen toxicity but their reversibility offers molecular targets for treating acute liver failure. PMID- 29504226 TI - Impact of hospital volume and surgeon volume on robot-assisted partial nephrectomy outcomes: a multicentre study. AB - OBJECTIVE: To assess the impact of hospital volume (HV) and surgeon volume (SV) on perioperative outcomes of robot-assisted partial nephrectomy (RAPN). PATIENTS AND METHODS: All consecutive patients who underwent a RAPN from 2009 to 2015, at 11 institutions, were included in a retrospective study. To evaluate the impact of HV, we divided RAPN into four quartiles according to the caseload per year: low HV (<20/year), moderate HV (20-44/year), high HV (45-70/year), and very high HV (>70/year). The SV was also divided into four quartiles: low SV (<7/year), moderate SV (7-14/year), high SV (15-30/year), and very high SV (>30/year). The primary endpoint was the Trifecta defined as the following combination: no complications, warm ischaemia time (WIT) <25 min, and negative surgical margins. RESULTS: In total, 1 222 RAPN were included. The mean (sd) caseload per hospital per year was 44.9 (26.7) RAPNs and the mean (sd) caseload per surgeon per year was 19.2 (14.9) RAPNs. The Trifecta achievement rate increased significantly with SV (69.9% vs 72.8% vs 73% vs 86.1%; P < 0.001) and HV (60.3% vs 72.3% vs 86.2% vs 82.4%; P < 0.001). The positive surgical margins (PSM) rate (P = 0.02), length of hospital stay (LOS; P < 0.001), WIT (P < 0.001), and operative time (P < 0.001), all decreased significantly with increasing SV. The PSM rate (P = 0.02), LOS (P < 0.001), WIT (P < 0.001), operative time (P < 0.001), and major complications rate (P = 0.01), all decreased significantly with increasing HV. In multivariate analysis adjusting for HV and SV (model 3), HV remained the main predictive factor of Trifecta achievement (odds ratio [OR] 3.70 for very high vs low HV; P < 0.001), whereas SV was not associated with Trifecta achievement (OR 1.58 for very high vs low SV; P = 0.34). CONCLUSION: In this multicentre study HV and SV both greatly influenced RAPN perioperative outcomes, but HV appeared to have a greater impact than SV. PMID- 29504227 TI - Engineering Single-Atom Cobalt Catalysts toward Improved Electrocatalysis. AB - The development of cost-effective catalysts to replace noble metal is attracting increasing interests in many fields of catalysis and energy, and intensive efforts are focused on the integration of transition-metal sites in carbon as noble-metal-free candidates. Recently, the discovery of single-atom dispersed catalyst (SAC) provides a new frontier in heterogeneous catalysis. However, the electrocatalytic application of SAC is still subject to several theoretical and experimental limitations. Further advances depend on a better design of SAC through optimizing its interaction with adsorbates during catalysis. Here, distinctive from previous studies, favorable 3d electronic occupation and enhanced metal-adsorbates interactions in single-atom centers via the construction of nonplanar coordination is achieved, which is confirmed by advanced X-ray spectroscopic and electrochemical studies. The as-designed atomically dispersed cobalt sites within nonplanar coordination show significantly improved catalytic activity and selectivity toward the oxygen reduction reaction, approaching the benchmark Pt-based catalysts. More importantly, the illustration of the active sites in SAC indicates metal-natured catalytic sites and a media-dependent catalytic pathway. Achieving structural and electronic engineering on SAC that promotes its catalytic performances provides a paradigm to bridge the gap between single-atom catalysts design and electrocatalytic applications. PMID- 29504229 TI - Corrigendum. PMID- 29504228 TI - Molecular profiling of aged neural progenitors identifies Dbx2 as a candidate regulator of age-associated neurogenic decline. AB - Adult neurogenesis declines with aging due to the depletion and functional impairment of neural stem/progenitor cells (NSPCs). An improved understanding of the underlying mechanisms that drive age-associated neurogenic deficiency could lead to the development of strategies to alleviate cognitive impairment and facilitate neuroregeneration. An essential step towards this aim is to investigate the molecular changes that occur in NSPC aging on a genomewide scale. In this study, we compare the transcriptional, histone methylation and DNA methylation signatures of NSPCs derived from the subventricular zone (SVZ) of young adult (3 months old) and aged (18 months old) mice. Surprisingly, the transcriptional and epigenomic profiles of SVZ-derived NSPCs are largely unchanged in aged cells. Despite the global similarities, we detect robust age dependent changes at several hundred genes and regulatory elements, thereby identifying putative regulators of neurogenic decline. Within this list, the homeobox gene Dbx2 is upregulated in vitro and in vivo, and its promoter region has altered histone and DNA methylation levels, in aged NSPCs. Using functional in vitro assays, we show that elevated Dbx2 expression in young adult NSPCs promotes age-related phenotypes, including the reduced proliferation of NSPC cultures and the altered transcript levels of age-associated regulators of NSPC proliferation and differentiation. Depleting Dbx2 in aged NSPCs caused the reverse gene expression changes. Taken together, these results provide new insights into the molecular programmes that are affected during mouse NSPC aging, and uncover a new functional role for Dbx2 in promoting age-related neurogenic decline. PMID- 29504230 TI - Broken bridges: The isolation of Kilimanjaro's ecosystem. AB - Biodiversity studies of global change mainly focus on direct impacts such as losses in species numbers or ecosystem functions. In this study, we focus on the long-term effects of recent land-cover conversion and subsequent ecological isolation of Kilimanjaro on biodiversity in a paleobiogeographical context, linking our findings with the long-standing question whether colonization of African mountains mainly depended on long-distance dispersal, or whether gradual migration has been possible through habitat bridges under colder climates. For this, we used Orthoptera as bioindicators, whose patterns of endemism and habitat demands we studied on about 500 vegetation plots on Kilimanjaro and Mt. Meru (Tanzania) since 1996. Land-cover changes in the same area were revealed using a supervised classification of Landsat images from 1976 to 2000. In 1976, there was a corridor of submontane forest vegetation linking Kilimanjaro with Mt. Meru, replaced by human settlements and agriculture after 2000. Until recently, this submontane forest bridge facilitated the dispersal of forest animals, illustrated by the large number of endemic submontane forest Orthoptera shared by both mountains. Furthermore, the occurrence of common montane endemics suggests the existence of a former forest corridor with montane vegetation during much earlier times under climatic conditions 2-7 degrees C cooler and 400-1,700 mm wetter than today. Based on the endemicity patterns of forest Orthoptera, negative consequences are predicted due to the effects of isolation, in particular for larger forest animals. Kilimanjaro is becoming an increasingly isolated ecosystem with far reaching consequences for diversity and endemism. Forest bridges between East African mountains acted as important migratory corridors and are not only a prehistoric phenomenon during periods with other climatic conditions but also disappeared in some places recently due to increasing and direct anthropogenic impact. PMID- 29504231 TI - Silk fibroin produced by transgenic silkworms overexpressing the Arg-Gly-Asp motif accelerates cutaneous wound healing in mice. AB - We investigated the effect of silk fibroin (SF) on wound healing in mice. SF or an amorphous SF film (ASFF) prepared from silk produced by the wild-type silkworm Bombyx mori (WT-SF, WT-ASFF) or by transgenic worms that overexpress the Arg-Gly Asp (RGD) sequence (TG-SF, TG-ASFF) was placed on 5-mm diameter full-thickness skin wounds made by biopsy punch on the back of 8-12 week-old BALB/c mice. Each wound was covered with WT-ASFF and urethane film (UF), TG-ASFF plus UF, or UF alone (control). Wound closure, histological thickness, the area of granulation tissue, and neovascularization were analyzed 4, 8, and 12 days later. The effect of SF on cell migration and proliferation was examined in vitro by scratch- and MTT-assay using human dermal fibroblasts. Wound closure was prompted by TG-ASFF, granulation tissue was thicker and larger in ASFF-treated wounds than the control, and neovascularization was promoted significantly by WT-ASFF. Both assays showed that SF induced the migration and proliferation of human dermal fibroblasts. The effects of TG-ASFF and TG-SF on wound closure, granulation formation, and cell proliferation were more profound than that of WT-ASFF and WT SF. We document that SF accelerates cutaneous wound healing, and this effect is enhanced with TG-SF. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2018. PMID- 29504232 TI - Morphological and transcriptomic analyses reveal three discrete primary stages of postembryonic development in the common fire salamander, Salamandra salamandra. AB - The postembryonic development of amphibians has been characterized as divided into three predominant periods, hereafter named primary developmental stages: premetamorphosis (PreM), prometamorphosis (ProM), metamorphic climax (Meta), and completion of metamorphosis (PostM), largely based on examination of anuran development. Here, we categorized the postembryonic development of larvae of a poisonous fire salamander (Salamandra salamandra) by integrating morphology and gene expression (transcriptomic) data. Morphological analysis revealed three distinct clusters suggestive of PreM, ProM, and Meta, which were confirmed in parallel by microarray-derived gene expression analysis. In total, 3,510 probes targeted transcripts differentially expressed between the clusters we identified. Genes upregulated in PreM related to organogenesis, and those upregulated in Meta underlie structural proteins and related to development of anatomical structures and pigmentation. Biosynthesis pathways of pigments (pteridines and melanin) were upregulated during late ProM and Meta. Gas chromatographic analysis of alkaloids indicated the onset of steroidal alkaloid biosynthesis at ProM. When comparing gene expression in the fire salamander to that in other amphibians-three anurans, Xenopus laevis, X. tropicalis, and Michrohyla fissipes, and one caudate, Ambystoma mexicanum- we identified genes with conserved expression patterns involved in basic metamorphic processes such as skin restructuring and tail fin resorption. Our results support that primary stages of postembryonic development in caudates are homologous to those of anurans, and offer a baseline for the study of the evolution of developmental modes. PMID- 29504233 TI - Treatment of hypertension in CKD patients with azilsartan/chlorthalidone vs olmesartan/hydrochlorothiazide. PMID- 29504235 TI - Cytokine profile (IL-2, IL-6, IL-17, IL-22, and TNF-alpha) in vitiligo-New insight into pathogenesis of disease. AB - BACKGROUND: Vitiligo is an autoimmune disease associated with alteration in levels of various cytokines. However, there are very few studies in this regard. OBJECTIVES: To assess the serum levels of cytokines secreted by Th1 (IL-2, TNF alpha), Th2 (IL-6), and Th17 cells (IL-17, IL-22) in patients with localized vitiligo and generalized vitiligo and to correlate their levels with the extent, duration, and activity of disease. MATERIAL AND METHODS: Sixty patients of vitiligo (30 each of localized and generalized) and 30 controls were recruited in the study. Serum IL-2, -6, -17, -22, and TNF-alpha levels were measured by enzyme linked immunosorbent assay (ELISA) in all patients and healthy controls, and their levels were correlated with the extent, duration, and activity of vitiligo. RESULTS: We observed significantly raised levels of IL-2, -6, -17, -22, and TNF alpha in both localized vitiligo and generalized vitiligo (P < .05). IL-2 was significantly raised (P = .028) in localized vitiligo, whereas IL-17 and IL-22 were significantly raised in generalized vitiligo (P = .00 and P = .019, respectively). Activity of disease showed positive correlation with serum TNF alpha levels (P = .015) in localized vitiligo. Positive correlation of IL-17 (R = .238) with body surface area (BSA) was observed in patients with generalized vitiligo. CONCLUSIONS: Our study shows that cytokines secreted by Th17 cells play an important role in maintenance and spread of vitiligo as they increase in line with extent of disease. Also TNF-alpha increases in proportion with activity of disease, hence may act as biomarker for identifying patient with aggressive disease. PMID- 29504234 TI - Statins do not Increase the Rate of Bleeding Among Warfarin Users. AB - Clinical significance of potential interaction between warfarin and statins is unclear. Our objective was to determine whether use of statins as a class or use of simvastatin modulates the rate of bleeding requiring hospitalization among new warfarin users. Using Finnish healthcare databases, we identified a cohort of 101,588 warfarin initiators between 1 January 2009 and 30 June 2012. By the end of 2012, these patients accumulated 92,695 person-years of exposure to warfarin only and 60,253 years of exposure to warfarin-with-statin. The outcome was a composite of gastrointestinal, intracranial or other bleeding leading to hospitalization. A Poisson generalized estimating equation model was employed to estimate rate ratios (RR) and their 95% confidence intervals (CI) for exposure to warfarin-with-statin compared to warfarin-only and to allow multiple episodes per patient and time-dependent covariates. In multivariable models, we found no difference in the bleeding rate in association with exposure to any statin (multivariable-adjusted RR = 0.98, 95% CI 0.89-1.07) or to simvastatin (RR = 1.01, 95% CI 0.91-1.11) with warfarin compared to exposure to warfarin-only. We conclude that concomitant use of statins and warfarin was not associated with an increased rate of bleeding requiring hospitalization. PMID- 29504236 TI - The effect of mesenchymal stem cells combined with platelet-rich plasma on skin wound healing. AB - INTRODUCTION: Mesenchymal stem cells (MSCs) are multipotent stem cells that have the potential of proliferation, high self-renewal, and the potential of multilineage differentiation. The differentiation potential of the MSCs in vivo and in vitro has caused these cells to be regarded as potentially appropriate tools for wound healing. After the burn, trauma or removal of the tumor of wide wounds is developed. Although standard treatment for skin wounds is primary healing or skin grafting, they are not always practical mainly because of limited autologous skin grafting. EVIDENCE ACQUISITIONS: Directory of Open Access Journals (DOAJ), Google Scholar, PubMed (NLM), LISTA (EBSCO), and Web of Science have been searched. EVIDENCE SYNTHESIS: For clinical use of the MSCs in wound healing, two key issues should be taken into account: First, engineering biocompatible scaffolds clinical use of which leads to the least amount of side effects without any immunologic response and secondly, use of stem cells secretions with the least amount of clinical complications despite their high capability of healing damage. CONCLUSION: In light of the MSCs' high capability of proliferation and multilineage differentiation as well as their significant role in modulating immunity, these cells can be used in combination with tissue engineering techniques. Moreover, the MSCs' secretions can be used in cell therapy to heal many types of wounds. The combination of MSCs and PRP aids wound healing which could potentially be used to promote wound healing. PMID- 29504237 TI - Morphology and surface properties of high strength siloxane poly(urethane-urea)s developed for heart valve application. AB - A series of siloxane poly(urethane-urea) (SiPUU) were developed by incorporating a macrodiol linked with a diisocyanate to enhance mixing of hard and soft segments (SS). The effect of this modification on morphology, surface properties, surface elemental composition, and creep resistance was investigated. The linked macrodiol was prepared by reacting alpha,omega-bis(6-hydroxyethoxypropyl) poly(dimethylsiloxane)(PDMS) or poly(hexamethylene oxide) (PHMO) with either 4,4' methylenediphenyl diisocyanate (MDI), hexamethylene diisocyanate (HDI), or isophorone diisocyanate (IPDI). SiPUU with PHMO-MDI-PHMO and PHMO-IPDI-PHMO linked macrodiols showed enhanced creep resistance and recovery when compared with a commercial biostable polyurethane, Elast-EonTM 2A. Small and wide-angle X ray scattering data were consistent with significant increase of hydrogen bonding between hard and SS with linked-macrodiols, which improved SiPUU's tensile stress and tear strengths. These SiPUU were hydrophobic with contact angle higher than 101 degrees and they had low water uptake (0.7%.w/w of dry mass). They also had much higher siloxane concentration on the surface compared to that in the bulk. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2018. PMID- 29504238 TI - Fingerprint-Inspired Flexible Tactile Sensor for Accurately Discerning Surface Texture. AB - Inspired by the epidermal-dermal and outer microstructures of the human fingerprint, a novel flexible sensor device is designed to improve haptic perception and surface texture recognition, which is consisted of single-walled carbon nanotubes, polyethylene, and polydimethylsiloxane with interlocked and outer micropyramid arrays. The sensor shows high pressure sensitivity (-3.26 kPa 1 in the pressure range of 0-300 Pa), and it can detect the shear force changes induced by the dynamic interaction between the outer micropyramid structure on the sensor and the tested material surface, and the minimum dimension of the microstripe that can be discerned is as low as 15 um * 15 um (interval * width). To demonstrate the texture discrimination capability, the sensors are tested for accurately discerning various surface textures, such as the textures of different fabrics, Braille characters, the inverted pyramid patterns, which will have great potential in robot skins and haptic perception, etc. PMID- 29504239 TI - Development of a M cell-targeted microparticulate platform, BSK02TM, for oral immunization against the ovarian cancer antigen, sperm protein 17. AB - Although it only accounts for approximately 5% of all female cancer cases, ovarian cancer (OC) ranks as the fifth leading cause of death due to cancer in women. We have evaluated the potential of an orally administered microparticulate vaccine incorporating an immunodominant epitope peptide derived from the cancer/testis antigen sperm protein 17 (SP17) aberrantly expressed in OC, to retard the progression of the disease. The peptide antigen and the immune stimulatory toll-like receptor 9 ligand CpG oligonucleotide were incorporated into spray dried microparticles composed of enteric and sustained release polymers together with the Aleuria aurantia lectin targeting microfold cells present in the gut-associated lymphoid tissue. These particles were administered via oral route to mice challenged week prior with SP17-expressing ID8 OC cells. Analysis of splenocytes harvested from vaccinated mice revealed strong activation of IFN-gamma+/CD8+ lymphocytes in response to re-stimulation with the SP17 antigen. Moreover, vaccinated animals showed significant retardation of ascites/tumor volume in comparison to placebo-treated animals four weeks after the tumor challenge (p = 0.005). Taken together, our results suggest that vaccination against SP17 using orally administered microparticles could potentially be used as an effective consolidation strategy for OC patients with residual tumor or high probability for relapse following first-line treatments. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2018. PMID- 29504241 TI - Fatigue resistance, electrochemical corrosion and biological response of Ti-15Mo with surface modified by amorphous TiO2 nanotubes layer. AB - The objective of this work was a systemic evaluation of the anodizing treatment in a beta-type Ti-15Mo alloy to grow a TiO2 nanostructured layer for osseointegration improvement. The technical viability of the surface modification was assessed based on the resistance to mechanical fatigue, electrochemical corrosion, and biological response. By using an organic solution of NH4 F in ethylene glycol, a well-organized array of 90 nm diameter nanotubes was obtained with a potential of 40 V for 6 h, while undefined nanotubes of 25 nm diameter were formed with a potential of 20 V for 1 h. Nevertheless, the production of the 90 nm diameter nanotubes was followed by micrometer pits that significantly reduced the fatigue performance. The undefined nanotubes of 25 nm diameter, besides the greater cell viability and improved osteoblastic cell differentiation in comparison to the as-polished surface, were not deleterious to the fatigue and corrosion properties. This result strengthens the necessity of an overall evaluation of the anodizing treatment, particularly the fatigue resistance, before suggesting it for the design of implants. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2018. PMID- 29504240 TI - The changing role of ornamental horticulture in alien plant invasions. AB - The number of alien plants escaping from cultivation into native ecosystems is increasing steadily. We provide an overview of the historical, contemporary and potential future roles of ornamental horticulture in plant invasions. We show that currently at least 75% and 93% of the global naturalised alien flora is grown in domestic and botanical gardens, respectively. Species grown in gardens also have a larger naturalised range than those that are not. After the Middle Ages, particularly in the 18th and 19th centuries, a global trade network in plants emerged. Since then, cultivated alien species also started to appear in the wild more frequently than non-cultivated aliens globally, particularly during the 19th century. Horticulture still plays a prominent role in current plant introduction, and the monetary value of live-plant imports in different parts of the world is steadily increasing. Historically, botanical gardens - an important component of horticulture - played a major role in displaying, cultivating and distributing new plant discoveries. While the role of botanical gardens in the horticultural supply chain has declined, they are still a significant link, with one-third of institutions involved in retail-plant sales and horticultural research. However, botanical gardens have also become more dependent on commercial nurseries as plant sources, particularly in North America. Plants selected for ornamental purposes are not a random selection of the global flora, and some of the plant characteristics promoted through horticulture, such as fast growth, also promote invasion. Efforts to breed non-invasive plant cultivars are still rare. Socio-economical, technological, and environmental changes will lead to novel patterns of plant introductions and invasion opportunities for the species that are already cultivated. We describe the role that horticulture could play in mediating these changes. We identify current research challenges, and call for more research efforts on the past and current role of horticulture in plant invasions. This is required to develop science-based regulatory frameworks to prevent further plant invasions. PMID- 29504242 TI - Vasomotor symptoms and the risk of incident venous thrombosis in postmenopausal women. AB - : Essentials Vasomotor symptoms have been proposed as markers of changing cardiovascular risk. In this cohort study, we evaluated these symptoms as markers of venous thrombosis (VT) risk. We found no evidence that vasomotor symptom presence or severity were associated with VT risk. Among these postmenopausal women, vasomotor symptoms are not a useful marker of VT risk. SUMMARY: Background Vasomotor symptoms may be markers of changes in cardiovascular risk, but it is unknown whether these symptoms are associated with the risk of venous thrombosis (VT). Objective To evaluate the association of vasomotor symptom presence and severity with incident VT risk among postmenopausal women, independent of potential explanatory variables. Methods This cohort study included participants of the Women's Health Initiative (WHI) Hormone Therapy Trials (n = 24 508) and Observational Study (n = 87 783), analyzed separately. At baseline, women reported whether hot flashes or night sweats were present and, if so, their severity. Using Cox proportional hazards models, we estimated the VT risk associated with vasomotor symptom presence and severity, adjusted for potential explanatory variables: age, body mass index, smoking status, race/ethnicity, and time-varying current hormone therapy use. Results At baseline, WHI Hormone Therapy Trial participants were aged 64 years and WHI Observational Study participants were aged 63 years, on average. In the WHI Hormone Therapy Trials over a median of 8.2 years of follow-up, 522 women experienced a VT event. In the WHI Observational Study, over 7.9 years of follow-up, 1103 women experienced a VT event. In adjusted analyses, we found no evidence of an association between vasomotor symptom presence (hazard ratio [HR]adj 0.91, 95% confidence interval [CI] 0.75-1.1 in the WHI Hormone Therapy Trials; HRadj 1.1, 95% CI 0.99-1.3 in the WHI Observational Study) or severity (HRadj for severe versus mild 0.99, 95% CI 0.53-1.9 in the WHI Hormone Therapy Trials; HRadj 1.3, 95% CI 0.89-2.0) in the WHI Observational Study) and the risk of incident VT. Conclusions Although vasomotor symptoms have been associated with the risk of other cardiovascular events in published studies, our findings do not suggest that vasomotor symptoms constitute a marker of VT risk. PMID- 29504243 TI - Young children with type 1 diabetes can achieve glycemic targets without hypoglycemia: Results of a novel intensive diabetes management program. AB - BACKGROUND: Young children with type 1 diabetes (T1D) present unique challenges for intensive diabetes management. We describe an intensive diabetes program adapted for young children and compare glycemic control, anthropometry, dietary practices and insulin regimens before and after implementation. METHODS: Cross sectional data from children with T1D aged >=0.5 to <7.0 years attending the John Hunter Children's Hospital (JHCH), Australia in 2004, 2010 and 2016 were compared. Outcome measures were glycemic control assessed by hemoglobin A1c (HbA1c ); severe hypoglycemia episodes; body mass index standard deviation scores (BMI-SDS); diabetes ketoacidosis (DKA) episodes; and insulin regimen-twice daily injections, multiple daily injections, or continuous subcutaneous insulin infusion. RESULTS: Mean HbA1c declined by 12 mmol/mol over the study period (P < .01). The proportion of children achieving a mean HbA1c < 58 mmol/mol increased significantly from 31% in 2004 to 64% in 2010 (P < .01), and from 64% in 2010 to 83% in 2016 (P = .04). The mean BMI-SDS was significantly lower in 2010 when compared with 2004 (P<.01); however, this trend plateaued between 2010 and 2016 (P = .97). Severe hypoglycemia and DKA occurred infrequently. The prevalence of overweight or obesity increased from 2010 to 2016 (P = .03). CONCLUSIONS: The JHCH intensive diabetes management program has resulted in 83% of young children in 2016 achieving target glycemia without an increase in severe hypoglycemia or DKA. Overweight remains a challenge in this population warranting action to reduce weight and protect these children from future obesity-related health risks. PMID- 29504245 TI - Photonic Potentiation and Electric Habituation in Ultrathin Memristive Synapses Based on Monolayer MoS2. AB - Monolayer of 2D transition metal dichalcogenides, with a thickness of less than 1 nm, paves a feasible path to the development of ultrathin memristive synapses, to fulfill the requirements for constructing large-scale high density 3D stacking neuromorphic chips. Herein, memristive devices based on monolayer n-MoS2 on p-Si substrate with a large self-rectification ratio, exhibiting photonic potentiation and electric habituation, are successfully fabricated. Versatile synaptic neuromorphic functions, such as potentiation/habituation, short-term/long-term plasticity, and paired-pulse facilitation, are successfully mimicked based on the inherent persistent photoconductivity performance and the volatile resistive switching behavior. These findings demonstrate the potential applications of ultrathin transition metal dichalcogenides for memristive synapses. These memristive synapses with the combination of photonic and electric neuromorphic functions have prospective in the applications of synthetic retinas and optoelectronic interfaces for integrated photonic circuits based on mixed-mode electro-optical operation. PMID- 29504244 TI - Distinct chromatin signatures of DNA hypomethylation in aging and cancer. AB - Cancer is an aging-associated disease, but the underlying molecular links between these processes are still largely unknown. Gene promoters that become hypermethylated in aging and cancer share a common chromatin signature in ES cells. In addition, there is also global DNA hypomethylation in both processes. However, the similarity of the regions where this loss of DNA methylation occurs is currently not well characterized, and it is unknown if such regions also share a common chromatin signature in aging and cancer. To address this issue, we analyzed TCGA DNA methylation data from a total of 2,311 samples, including control and cancer cases from patients with breast, kidney, thyroid, skin, brain, and lung tumors and healthy blood, and integrated the results with histone, chromatin state, and transcription factor binding site data from the NIH Roadmap Epigenomics and ENCODE projects. We identified 98,857 CpG sites differentially methylated in aging and 286,746 in cancer. Hyper- and hypomethylated changes in both processes each had a similar genomic distribution across tissues and displayed tissue-independent alterations. The identified hypermethylated regions in aging and cancer shared a similar bivalent chromatin signature. In contrast, hypomethylated DNA sequences occurred in very different chromatin contexts. DNA hypomethylated sequences were enriched at genomic regions marked with the activating histone posttranslational modification H3K4me1 in aging, while in cancer, loss of DNA methylation was primarily associated with the repressive H3K9me3 mark. Our results suggest that the role of DNA methylation as a molecular link between aging and cancer is more complex than previously thought. PMID- 29504246 TI - ZIF-8 with Ferrocene Encapsulated: A Promising Precursor to Single-Atom Fe Embedded Nitrogen-Doped Carbon as Highly Efficient Catalyst for Oxygen Electroreduction. AB - The oxygen reduction reaction (ORR) plays an important role in the fields of energy storage and conversion technologies, including metal-air batteries and fuel cells. The development of nonprecious metal electrocatalysts with both high ORR activity and durability to replace the currently used costly Pt-based catalyst is critical and still a major challenge. Herein, a facile and scalable method is reported to prepare ZIF-8 with single ferrocene molecules trapped within its cavities (Fc@ZIF-8), which is utilized as precursor to porous single atom Fe embedded nitrogen-doped carbon (Fe-N-C) during high temperature pyrolysis. The catalyst shows a half-wave potential (E1/2 ) of 0.904 V, 67 mV higher than commercial Pt/C catalyst (0.837 V), which is among the best compared with reported results for ORR. Significant electrochemical properties are attributed to the special configuration of Fc@ZIF-8 transforming into a highly dispersed iron-nitrogen coordination moieties embedded carbon matrix. PMID- 29504248 TI - ANSYS-MATLAB co-simulation of mucus flow distribution and clearance effectiveness of a new simulated cough device. AB - Coughing is an irritable reaction that protects the respiratory system from infection and improves mucus clearance. However, for the patients who cannot cough autonomously, an assisted cough device is essential for mucus clearance. Considering the low efficiency of current assisted cough devices, a new simulated cough device based on the pneumatic system is proposed in this paper. Given the uncertainty of airflow rates necessary to clear mucus from airways, the computational fluid dynamics Eulerian wall film model and cough efficiency (CE) were used in this study to simulate the cough process and evaluate cough effectiveness. The Ansys-Matlab co-simulation model was set up and verified through experimental studies using Newtonian fluids. Next, model simulations were performed using non-Newtonian fluids, and peak cough flow (PCF) and PCF duration time were analyzed to determine their influence on mucus clearance. CE growth rate (lambda) was calculated to reflect the CE variation trend. From the numerical simulation results, we find that CE rises as PCF increases while the growth rate trends to slow as PCF increases; when PCF changes from 60 to 360 L/min, CE changes from 3.2% to 51.5% which is approximately 16 times the initial value. Meanwhile, keeping a long PCF duration time could greatly improve CE under the same cough expired volume and PCF. The results indicated that increasing the PCF and PCF duration time can improve the efficiency of mucus clearance. This paper provides a new approach and a research direction for control strategy in simulated cough devices for airway mucus clearance. PMID- 29504247 TI - Anti-Helicobacter pylori therapy in localized gastric mucosa-associated lymphoid tissue lymphoma: A prospective, nationwide, multicenter study in Japan. AB - BACKGROUND: Helicobacter pylori eradication therapy was approved in Japan for the first-line, standard treatment of H. pylori-positive gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Although several retrospective studies or small scale single-center studies have been reported, a prospective, large-scale, nationwide, multicenter study has not been reported from Japan. MATERIALS AND METHODS: We conducted a prospective, nationwide, multicenter study to evaluate the clinical efficacy of rabeprazole-based triple H. pylori eradication therapy for patients with localized gastric MALT lymphoma in practice-based clinical trial. A total of 108 H. pylori-positive patients with stage I/II1 gastric MALT lymphoma underwent H. pylori eradication therapy. The primary endpoints were complete remission (CR) rate and the rate of transfer to secondary treatment. The secondary endpoints were CR maintenance duration and overall survival (OS). RESULTS: CR of lymphoma was achieved in 84 of 97 patients (86.6%), during the period 2.0-44.7 months (median, 5.3 months) after starting H. pylori eradication treatment. CR was maintained in 77 of 81 patients (95.1%) for 0.4-53.2 months (median, 33.1 months). Secondary treatments (radiotherapy, rituximab, or gastrectomy) for gastric MALT lymphoma were needed in 10 of the 97 patients (10.31%). During follow-up, OS rate was 96.9% (94/97) and the causes of 3 deaths were not related to lymphoma. CONCLUSIONS: Rabeprazole-based H. pylori eradication therapy demonstrated a high CR rate, long CR maintenance, and a good OS for patients with localized gastric MALT lymphoma in this prospective, practice-based, multicenter study. PMID- 29504249 TI - Gender equality is crucial to the fight for better HIV treatment access and outcomes in the MENA region. PMID- 29504250 TI - Effect of hyperbaric oxygen on the process of hypertrophic scar formation in rabbit ears. AB - OBJECTIVE: To explore the influence of hyperbaric oxygen on scar formation in rabbit ears. METHODS: A total of 20 New Zealand rabbits were selected to establish the hypertrophic scar model on the ears. The rabbits were randomly divided into control group and experimental group (7d, 14d, 21d, and 28d group according to different HBO treatment days),each experimental group received hyperbaric oxygen treatment after the operation at the same time everyday for 1 hour. After the day 29, the scars were collected. Histomorphological change in scars was observed by hematoxylin-eosin staining, Masson staining, and transmission electrical microscope. The expression of bax, bcl-2, and the cell apoptosis rate was detected by immunohistochemical method. RESULTS: (i) Both number of fibroblast and amount of collagen fibrils in experimental group were significantly reduced compared with those in control group. In Masson staining, arrangement of collagen fibrils in experimental group was much more irregular and coarse than control groups. (ii) HI value can be found much smaller in the experimental groups than the control (P < .05). Among the four experimental groups, there is significant difference among 7d, 14d, and 21d groups (P < .05), while there is no difference between 21d and 28d groups (P > .05). (iii) Expression of Bax could be detected up-regulated in experimental group (P < .05). While the expression of Bcl-2 is detected significantly down-regulated in experimental group than that in control group (P < .05). Compared with the 7d group, the expression of Bax and Bcl-2 has significant difference in 14d group (P < .05), and the expression of this two factors in 21d group has significant difference comparing with 14d group(P < .05),but there is no significant difference between 28d group and 21d group(P > .05). (iv) Significant difference of cell apoptosis rate can be detected between the experimental groups and the control group (P < .05). Among the four experimental groups, there is significant difference among 7d, 14d, and 21d groups (P < .05), while there is no difference between 21d and 28d groups (P > .05). CONCLUSION: The hyperbaric oxygen can up regulate bax/bcl-2 value, increase the cell apoptosis rate, and inhibit the early hypertrophic scar in rabbit ears. PMID- 29504252 TI - Long-term efficacy and tolerability of azilsartan medoxomil/chlorthalidone vs olmesartan medoxomil/hydrochlorothiazide in chronic kidney disease. AB - An open-label, long-term study evaluated safety and tolerability of azilsartan medoxomil/chlorthalidone (AZL-M/CLD) vs olmesartan/hydrochlorothiazide (OLM/HCTZ) in hypertensive participants with stage 3 chronic kidney disease. Initial therapy was AZL-M/CLD 20/12.5 mg (n = 77) or OLM/HCTZ 20/12.5 mg (n = 76), but could be up-titrated (AZL-M/CLD to 40/25 mg; OLM/HCTZ to 40/25 mg [US] or 20/25 mg [Europe]) with other agents added during weeks 4-52. Primary endpoint was proportion of participants with >= 1 adverse event (AE) through week 52. Baseline demographics were similar. AEs did not differ between groups (88.3%, AZL-M/CLD vs 76.3%, OLM/HCTZ; P = .058). AZL-M/CLD showed greater systolic BP reductions after initial dosing (P = .037) but not during long-term follow-up (P = .588). A greater proportion of participants up-titrated to the highest dose with OLM/HCTZ (48.7%) vs AZL-M/CLD (29.9%) (P = .021) and were taking additional antihypertensive medications (26.3% vs 16.9%). Both AZL-M/CLD and OLM/HCTZ showed similar efficacy and tolerability. PMID- 29504251 TI - Identification and characterization of a novel alkalistable and salt-tolerant esterase from the deep-sea hydrothermal vent of the East Pacific Rise. AB - A novel esterase gene selected from metagenomic sequences of deep-sea hydrothermal vents was successfully expressed in Escherichia coli. The recombinant protein (est-OKK), which belongs to the lipolytic enzyme family V, exhibited high activity toward pNP-esters with short acyl chains and especially p nitrophenyl butyrate. Site-mutagenesis results confirmed that est-OKK contains the nonclassical catalytic tetrad predicted by alignment and computational modeling. The est-OKK protein is a moderately thermophilic enzyme that is relatively thermostable, and highly salt-tolerant, which remained stable in 3 mol/L NaCl for 6 hr. The est-OKK protein showed the considerable alkalistability, displayed optimal activity at pH 9.0 and maintained approximately 70% of its residual activity after incubation at pH 10 for 4 hr. Furthermore, the est-OKK activity was strongly resistant to a variety of metal ions such as Co2+ , Zn2+ , Fe2+ , Na+ , and K+ ; nonionic detergents such as Tween-20, Tween-80; and organic solvents such as acetone and isopropanol. Taken together, the novel esterase with unique characteristics may give us a new insight into the family V of lipolytic enzymes, and could be a highly valuable candidate for biotechnological applications such as organic synthesis reactions or food and pharmaceutical industries. PMID- 29504253 TI - Interplay between Porphyromonas gingivalis and EGF signalling in the regulation of CXCL14. AB - Porphyromonas gingivalis is a keystone pathogen in chronic periodontitis. Its expression of gingipain proteases (Kgp and RgpA/B) is central to the stimulation of chronic inflammation. In this study, we investigated the inflammatory response of oral epithelial cells to P. gingivalis. The cells responded by upregulating the expression of the orphan chemokine CXCL14. The stimulation of CXCL14 expression was largely triggered by the gingipain proteases and was dependent on the host protease-activated receptor PAR-3. Significantly, CXCL14 expression was transcriptionally repressed in response to epidermal growth factor (EGF)-induced activation of the MEK-ERK1/2 pathway. P. gingivalis overcomes the repression of CXCL14 via the gingipain protease-mediated degradation of EGF. Therefore, P. gingivalis not only directly stimulates CXCL14 expression via PAR-3 but also promotes its expression by antagonising EGF signalling. In addition to chemotactic activity, some chemokines also have antimicrobial activities. CXCL14 was demonstrated to have bactericidal activity, against commensal oral streptococci associated with health. Notably though, P. gingivalis was not susceptible to killing by CXCL14, potentially because the gingipain proteases can degrade CXCL14. This suggests that the stimulation of dysregulated CXCL14 expression by P. gingivalis may help promote dysbiosis and the development of chronic periodontitis. PMID- 29504254 TI - Effect of Vitamin D Supplementation on Obesity-Induced Insulin Resistance: A Double-Blind, Randomized, Placebo-Controlled Trial. AB - OBJECTIVE: The aim was to investigate whether vitamin D supplementation, combined with a hypocaloric diet, could have an independent effect on insulin sensitivity in subjects with both overweight and hypovitaminosis D. Changes from baseline in anthropometric parameters, body composition, glucose tolerance, and insulin secretion were considered as secondary outcomes. METHODS: Eighteen volunteers who were nondiabetic and vitamin D deficient and had BMI > 25 kg/m2 were randomized (1:1) in a double-blind manner to a hypocaloric diet + either oral cholecalciferol at 25,000 IU/wk or placebo for 3 months. Hyperinsulinemic euglycemic clamp to measure insulin sensitivity was performed at baseline and after intervention. RESULTS: Body weight in both groups decreased significantly ( 7.5% in the vitamin D group and -10% in the placebo group; P < 0.05 for both), with no between-group differences. Serum 25-hydroxyvitamin D levels in the vitamin D group increased considerably (from 36.7 +/- 13.2 nmol/L to 74.8 +/- 18.7 nmol/L; P < 0.001). Insulin sensitivity in the vitamin D group improved (from 4.6 +/- 2.0 to 6.9 +/- 3.3 mg.kg-1 .min-1 ; P < 0.001), whereas no changes were observed in the placebo group (from 4.9 +/- 1.1 to 5.1 +/- 0.3 mg.kg-1 .min 1 ; P = 0.84). CONCLUSIONS: Cholecalciferol supplementation, combined with a weight loss program, significantly improves insulin sensitivity in healthy subjects with obesity and might represent a personalized approach for insulin resistant subjects with obesity. PMID- 29504255 TI - The Components of Age-Dependent Effects of Dietary Methionine Restriction on Energy Balance in Rats. AB - OBJECTIVE: Dietary methionine restriction (MR) improves biomarkers of metabolic health, in part through coordinated increases in energy intake and energy expenditure (EE). Some metabolic benefits of dietary MR are secondary to its effects on energy balance, so this study's purpose was to examine how age at initiation of MR influences its effects on energy balance and body composition. METHODS: Energy balance was examined in rats provided control or MR diets for 9 months after weaning or in rats between 6 and 12 months of age. RESULTS: Rats provided the control diet for 9 months after weaning increased their body weight (BW) and fat mass by five- and eightfold, respectively, while BW and fat accumulation in the MR group were reduced to 50% of that of controls. In adult rats fed the respective diets between 6 and 12 months of age, dietary MR increased energy intake by ~23%, but the 15% increase in EE was sufficient to prevent increases in BW or fat mass. CONCLUSIONS: Dietary MR produces comparable increases in EE in young, growing animals and in mature animals, but young animals continue to deposit new tissue because of the proportionately larger effect of MR on energy intake relative to maintenance requirements. PMID- 29504256 TI - Trends in the incidence rate of lung cancer by histological type and gender in Sichuan, China, 1995-2015: A single-center retrospective study. AB - BACKGROUND: In recent years, lung cancer incidence has been increasing; however the impact of different histological types of lung cancer is not yet clear. METHODS: Trends in the lung cancer incidence rate by histological type were examined based on data of 36 658 primary lung cancer patients from West China Hospital between 1995 and 2015. RESULTS: The most common histological type of lung cancer in our hospital was adenocarcinoma (ADC) in both genders, followed by squamous cell carcinoma (SQCC), and small cell carcinoma (SCLC), which is consistent with general worldwide trends. The proportion of young patients with SCLC showed a downward trend. In the overall population with lung cancer, the number of elderly patients with lung cancer increased significantly, while the proportion of elderly patients increased gradually. The mean age at diagnosis also increased. The number of women with ADC increased sharply in recent years, especially in young patients, and the incidence rate in women is now greater than in men. CONCLUSION: Significant increases in the number of patients with ADC and the rate of lung cancer in women over recent years were observed, indicating that research on the pathogenesis of disease in these patients is urgent. PMID- 29504257 TI - Correlation of retinal neurodegeneration with measures of peripheral autonomic neuropathy in type 1 diabetes. AB - PURPOSE: To evaluate the relationship of neuroretinal layer thickness with sensitive measures of cardiovascular autonomic neuropathy in diabetic patients with non-proliferative diabetic retinopathy (NPDR). METHODS: Twenty-seven eyes of 27 patients with type 1 diabetes presenting with mild-to-moderate NPDR were compared to 27 healthy control (HC) eyes matched for age and gender. The total macular volume (TMV) and the volumes of individual neurosensory layers in the macula were analysed from spectral domain optical coherence tomography using automated layer segmentation. Cardiovascular autonomic regulation was assessed by short-term power spectrum analysis of heart rate variability (HRV) before, during and after an orthostatic challenge. RESULTS: The patients had an age of 46 +/- 12 years and diabetes since 28 +/- 9 years. Diastolic and mean arterial pressure was lower in the patients compared to HCs. TMV (r = 0.58, p = 0.002), inner plexiform layer volume (IPLV; r = 0.39, p = 0.047) and inner nuclear layer volume (INLV; r = 0.60, p = 0.001) were associated with reduced recovery of low-frequency (LF) spectral power of HRV after orthostatic load in diabetic patients but not in HCs. The response of LF spectral power during the orthostatic manoeuvre was blunted in patients compared to HCs (p = 0.02). Diabetes duration was negatively associated with TMV and INLV, whereas IPLV was significantly reduced in eyes with moderate NPDR compared to HCs. CONCLUSION: The results indicate a correlation between inner retinal tissue loss and diminished autonomic regulation in type 1 diabetic patients with mild-to-moderate NPDR. The observed changes can be interpreted as congruent early signs of retinal and systemic neuropathy in diabetes. PMID- 29504258 TI - Recombinant erythropoietin acutely decreases renal perfusion and decouples the renin-angiotensin-aldosterone system. AB - The effect of recombinant erythropoietin (rhEPO) on renal and systemic hemodynamics was evaluated in a randomized double-blinded, cross-over study. Sixteen healthy subjects were tested with placebo, or low-dose rhEPO for 2 weeks, or high-dose rhEPO for 3 days. Subjects refrained from excessive salt intake, according to instructions from a dietitian. Renal clearance studies were done for measurements of renal plasma flow, glomerular filtration rate (GFR) and the segmentel tubular handling of sodium and water (lithium clearance). rhEPO increased arterial blood pressure, total peripheral resistance, and renal vascular resistance, and decreased renal plasma flow in the high-dose rhEPO intervention and tended to decrease GFR. In spite of the decrease in renal perfusion, rhEPO tended to decrease reabsorption of sodium and water in the proximal tubule and induced a prompt decrease in circulating levels of renin and aldosterone, independent of changes in red blood cell mass, blood volumes, and blood pressure. We also found changes in biomarkers showing evidence that rhEPO induced a prothrombotic state. Our results suggest that rhEPO causes a direct downregulation in proximal tubular reabsorption that seems to decouple the activity of the renin-angiotensin-aldosterone system from changes in renal hemodynamics. This may serve as a negative feed-back mechanism on endogenous synthesis of EPO when circulating levels of EPO are high. These results demonstrates for the first time in humans a direct effect of rhEPO on renal hemodynamics and a decoupling of the renin-angiotensin-aldosterone system. PMID- 29504259 TI - Rapid specific and visible detection of porcine circovirus type 3 using loop mediated isothermal amplification (LAMP). AB - In this study, a rapid and specific assay for the detection of porcine circovirus type 3 (PCV3) was established using loop-mediated isothermal amplification (LAMP). Four primers were specifically designed to amplify PCV3. The LAMP assay was effectively optimized to amplify PCV3 by water bath at 60 degrees C for 60 min. The detection limit was approximately 1 * 101 copy in this LAMP assay. Compared to porcine circovirus type 2 (PCV2), both gE and gD genes of pseudorabies virus (PRV) and porcine parvovirus (PPV), the LAMP assay showed a high specific detection of PCV3. A visible detection method was developed using SYBR Green I to recognize the results rapidly. Based on the detection of 20 clinical tissue samples, the LAMP assay was more practical and convenient than classical PCR due to its simplicity, high sensitivity, rapidity, specificity, visibility and cost efficiency. PMID- 29504260 TI - Dietary Tryptophan Restriction Dose-Dependently Modulates Energy Balance, Gut Hormones, and Microbiota in Obesity-Prone Rats. AB - OBJECTIVE: To determine the effects of graded dietary restriction of tryptophan on food intake, energy expenditure, body composition, gut hormones, and select fecal bacterial populations in obesity-prone rats. METHODS: Obesity-prone rats were randomized to isocaloric diets with varying degrees of tryptophan restriction: control (100% requirements), 70% tryptophan (70TRP), 40% tryptophan (40TRP), or 10% tryptophan (10TRP) for 21 days. The sympathetic system was challenged with a subcutaneous injection of propranolol on days 15 to 17. Measurements included food intake, energy expenditure, body composition, metabolic hormones, and fecal concentrations of select bacteria. RESULTS: Moderate tryptophan restriction (70TRP) induced thermogenesis without altering body composition, whereas severe degrees of restriction (40TRP, 10TRP) produced profound hypophagia and decreased energy expenditure and body weight. The thermogenic effects of moderate tryptophan restriction were sympathetically mediated. Severe tryptophan restriction decreased fasting circulating concentrations of glucose, insulin, C-peptide, and leptin, but increased glucagon, pancreatic polypeptide, and glucagon-like peptide-1. Severe tryptophan restriction decreased fecal concentrations of Enterobacteriaceae, Lactobacillus, Bacteroides, and Clostridium coccoides while increasing Roseburia groups. CONCLUSIONS: Our findings demonstrate that dietary tryptophan restriction dose dependently modulates energy balance, with severe restriction causing hypophagia and weight loss and moderate restriction promoting sympathetically driven thermogenesis as well as concurrent changes in gut microbiota and hormones. PMID- 29504261 TI - Detection of Individual Molecules and Ions by Carbon Nanotube-Based Differential Resistive Pulse Sensor. AB - This paper presents a new method of sensing single molecules and cations by a carbon nanotube (CNT)-based differential resistive pulse sensing (RPS) technique on a nanofluidic chip. A mathematical model for multichannel RPS systems is developed to evaluate the CNT-based RPS signals. Individual cations, rhodamine B dye molecules, and ssDNAs are detected successfully with high resolution and high signal-to-noise ratio. Differentiating ssDNAs with 15 and 30 nucleotides are achieved. The experimental results also show that translocation of negatively charged ssDNAs through a CNT decreases the electrical resistance of the CNT channel, while translocation of positively charged cations and rhodamine B molecules increases the electrical resistance of the CNT. The CNT-based nanofluidic device developed in this work provides a new avenue for single molecule/ion detection and offers a potential strategy for DNA sequencing. PMID- 29504263 TI - Biodiversity of fungi in hot desert sands. AB - The fungal community of six sand samples from Saudi Arabia and Jordan deserts was characterized by culture-independent analysis via next generation sequencing of the 18S rRNA genes and by culture-dependent methods followed by sequencing of internal transcribed spacer (ITS) region. By 18S sequencing were identified from 163 to 507 OTUs per sample, with a percentage of fungi ranging from 3.5% to 82.7%. The identified fungal Phyla were Ascomycota, Basal fungi, and Basidiomycota and the most abundant detected classes were Dothideomycetes, Pezizomycetes, and Sordariomycetes. A total of 11 colonies of filamentous fungi were isolated and cultured from six samples, and the ITS sequencing pointed toward five different species of the class Sordariomycetes, belonging to genera Fusarium (F. redolens, F. solani, F. equiseti), Chaetomium (C. madrasense), and Albifimbria (A. terrestris). The results of this study show an unexpectedly large fungal biodiversity in the Middle East desert sand and their possible role and implications on human health. PMID- 29504262 TI - High Fat and Sugar Consumption During Ad Libitum Intake Predicts Weight Gain. AB - OBJECTIVE: To determine how macronutrients accompanying foods with high energy density (EnDen) affect energy intake and weight gain. METHODS: A total of 214 subjects (130 males, BMI: 32 +/- 7 kg/m2 ) ate ad libitum for 3 days. Food intake was expressed as the mean daily intake (in kilocalories) and the percentage of weight-maintaining energy needs (%WMEN). EnDen was expressed as the ratio of intake (in kilocalories) to food weight (in grams). Food choices were expressed as absolute and percent intake (kilocalories), categorized as high in fat (HF; >= 45% kcal) or low in fat (LF; < 20% kcal), and further categorized as high in complex carbohydrates (>= 30% kcal), high in simple sugars (HSS; >= 30% kcal), or high in protein (HP; >= 13% kcal). Follow-up weights were available from 99 subjects (65 males, range: 6 months to 11 years). RESULTS: EnDen was associated with BMI (r = 0.28, P < 0.0001), percent body fat (r = 0.18, P = 0.007), and percent intake from HF/HP (r = 0.34, P < 0.0001), HF/HSS (r = 0.31, P < 0.0001), LF/HP (r = -0.37, P < 0.0001) and LF/HSS (r = -0.68, P < 0.0001). The %WMEN was associated with EnDen (r = 0.16, P = 0.01), HF/HSS (r = 0.33, P < 0.0001), and LF/HP intake (r = -0.25, P = 0.0002). In a multivariate model, only HF/HSS intake remained a significant predictor of %WMEN (beta = 1.4% per 1% change, P < 0.0001). The percent intake from HF/HSS (r = 0.23, P = 0.02), not EnDen (P = 0.54), was associated with weight gain, even after adjusting for follow-up time (in years) and covariates. CONCLUSIONS: Relatively greater consumption of HF/HSS foods independently predicted overeating and weight gain. Nutrient compositions of high-EnDen foods may be important for weight management. PMID- 29504264 TI - Machine learning-aided exploration of relationship between strength and elastic properties in ascending thoracic aneurysm. AB - Machine learning was applied to classify tension-strain curves harvested from inflation tests on ascending thoracic aneurysm samples. The curves were classified into rupture and nonrupture groups using prerupture response features. Two groups of features were used as the basis for classification. The first was the constitutive parameters fitted from the tension-strain data, and the second was geometric parameters extracted from the tension-strain curve. Based on the importance scores provided by the machine learning, implications of some features were interrogated. It was found that (1) the value of a constitutive parameter is nearly the same for all members in the rupture group and (2) the strength correlates strongly with a tension in the early phase of response as well as with the end stiffness. The study suggests that the strength, which is not available without rupturing the tissue, may be indirectly inferred from prerupture response features. PMID- 29504265 TI - Retinoic acid receptor-alpha regulates synthetic events in human platelets: comment. PMID- 29504266 TI - Prevention of pressure ulcers with a static air support surface: A systematic review. AB - The aims of this study were to identify, assess, and summarise available evidence about the effectiveness of static air mattress overlays to prevent pressure ulcers. The primary outcome was the incidence of pressure ulcers. Secondary outcomes included costs and patient comfort. This study was a systematic review. Six electronic databases were consulted: Cochrane Library, EMBASE, PubMed (Medline), CINAHL (EBSCOhost interface), Science direct, and Web of Science. In addition, a hand search through reviews, conference proceedings, and the reference lists of the included studies was performed to identify additional studies. Potential studies were reviewed and assessed by 2 independent authors based on the title and abstract. Decisions regarding inclusion or exclusion of the studies were based on a consensus between the authors. Studies were included if the following criteria were met: reporting an original study; the outcome was the incidence of pressure ulcer categories I to IV when using a static air mattress overlay and/or in comparison with other pressure-redistribution device(s); and studies published in English, French, and Dutch. No limitation was set on study setting, design, and date of publication. The methodological quality assessment was evaluated using the Critical Appraisal Skills Program Tool. Results were reported in a descriptive way to reflect the exploratory nature of the review. The searches included 13 studies: randomised controlled trials (n = 11) and cohort studies (n = 2). The mean pressure ulcer incidence figures found in the different settings were, respectively, 7.8% pressure ulcers of categories II to IV in nursing homes, 9.06% pressure ulcers of categories I to IV in intensive care settings, and 12% pressure ulcers of categories I to IV in orthopaedic wards. Seven comparative studies reported a lower incidence in the groups of patients on a static air mattress overlay. Three studies reported a statistical (P < .1) lower incidence compared with a standard hospital mattress (10 cm thick, density 35 kg/m3 ), a foam mattress (15 cm thick), and a viscoelastic foam mattress (15 cm thick). No significant difference in incidence, purchase costs, and patient comfort was found compared with dynamic air mattresses. This review focused on the effectiveness of static air mattress overlays to prevent pressure ulcers. There are indications that these mattress overlays are more effective in preventing pressure ulcers compared with the use of a standard mattress or a pressure-reducing foam mattress in nursing homes and intensive care settings. However, interpretation of the evidence should be performed with caution due to the wide variety of methodological and/or reporting quality levels of the included studies. PMID- 29504267 TI - Overexpression of long non-coding RNA KCNQ1OT1 is related to good prognosis via inhibiting cell proliferation in non-small cell lung cancer. AB - BACKGROUND: Lung cancer (LC) is the most common malignancy in the world. Many long non-coding RNAs (lncRNAs) have been reported to be associated with LC; however, the function of KCNQ1OT1 in LC requires exploration. METHODS: We conducted in silico analysis with data from The Cancer Genome Atlas to investigate the association between KCNQ1OT1 and LC. A Kaplan-Meier plotter was used to analyze the function of KCNQ1OT1 on LC patient prognosis. Quantitative reverse transcription-PCR (qRT-PCR) was performed to confirm previous results. An A549 lung cancer cell was transfected with pcDNA-KCNQ1OT1, and methyl thiazolyl tetrazolium assay was performed to investigate the function of KCNQ1OT1 on cell proliferation. in vivo assay was performed with nude mice. RESULTS: Bioinformatics analysis and qRT-PCR indicated that KCNQ1OT1 expression was higher in stage I LC patients (P < 0.01), and survival analysis showed that high expression of KCNQ1OT1 in LC patients was associated with better prognosis (P < 0.05). qRT-PCR showed a negative correlation between KCNQ1OT1 and Ki67 expression and tumor size (P < 0.01), which indicated that KCNQ1OT1 is associated with tumor growth in LC. There was no significant correlation between KCNQ1OT1 level and lymph node metastasis (P > 0.05). KCNQ1OT1 overexpression significantly inhibited cell proliferation and tumor growth in vitro and in vivo (P < 0.05). CONCLUSION: Our preliminary data showed that KCNQ1OT1 is overexpressed in early stage LC and is correlated with better prognosis in LC patients, possibly by suppressing cell proliferation. PMID- 29504268 TI - Differential effects of long-term slow-pressor and subpressor angiotensin II on contractile and relaxant reactivity of resistance versus conductance arteries. AB - Vascular reactivity was evaluated in three separate arteries isolated from rats after angiotensin II (Ang II) was infused chronically in two separate experiments, one using a 14-day high, slow-pressor dose known to produce hypertension and the other using a 7-day low, subpressor but hypertensive sensitizing dose. There were three new findings. First, there was no evidence of altered vascular reactivity in resistance arteries that might otherwise explain the hypertension due to the high Ang II or the hypertensive-sensitizing effect of the low Ang II dose. Second, the high Ang II dose exerted a novel differential effect on arterial contractile responsiveness to the sympathetic neurotransmitter, norepinephrine, depending on the level of sympathetic innervation. It clearly enhanced that responsiveness in the sparsely innervated aorta but not in small mesenteric resistance arteries or the proximal (conductance) portion of the caudal artery, both of which are densely innervated. This suggests that the increased expression of alpha adrenergic receptors after long-term exposure to Ang II as previously reported for aortic smooth muscle, is prevented in densely innervated arteries, likely due to long-term Ang II-mediated increase in sympathetic neural traffic to those vessels. Third, the same high dose of Ang II impaired aortic relaxation in response to the nitric oxide (NO) donor nitroprusside without impairing aortic endothelium-dependent relaxation. NO is the main relaxing substance released by aortic endothelium. Accordingly, it is possible that this dose of Ang II is also associated with enhanced release of and/or enhanced smooth muscle responsiveness to other endothelial relaxing substances in a compensatory capacity. PMID- 29504269 TI - Brazilian network for HIV Drug Resistance Surveillance (HIV-BresNet): a survey of treatment-naive individuals. AB - INTRODUCTION: In Brazil, more than 487,450 individuals are currently undergoing antiretroviral treatment. In order to monitor the transmission of drug-resistant strains and HIV subtype distribution in the country, this work aimed to estimate its prevalence and to characterize the nationwide pretreatment drug resistance in individuals recently diagnosed with HIV between 2013 and 2015. METHODS: The HIV threshold survey methodology (HIV-THS, WHO) targeting antiretroviral-naive individuals with recent HIV diagnosis was utilized, and subjects were selected from 51 highly populated cities in all five Brazilian macroregions. The HIV pol genotypic test was performed by genomic sequencing. RESULTS: We analysed samples from 1568 antiretroviral-naive individuals recently diagnosed with HIV, and the overall transmitted drug resistance (TDR) prevalence was 9.5% (150 sequences). The regional prevalence of resistance according to Brazilian geographical regions was 9.4% in the northeast, 11.2% in the southeast, 6.8% in the central region, 10.2% in the north and 8.8% in the south. The inhibitor-specific TDR prevalence was 3.6% for nucleoside reverse transcriptase inhibitors (NRTIs), 5.8% for non nucleoside reverse transcriptase inhibitors (NNRTIs) and 1.6% for protease inhibitors (PIs); 1.0% of individuals presented resistance to more than one class of inhibitors. Overall, subtype B was more prevalent in every region except for the southern, where subtype C prevails. CONCLUSIONS: To the best of our knowledge, this is the first TDR study conducted in Brazil with nationwide representative sampling. The TDR prevalence revealed a moderate rate in the five Brazilian geographical regions, although some cities presented higher TDR prevalence rates, reaching 14% in Sao Paulo, for example. These results further illustrate the importance of surveillance studies for designing future strategies in primary antiretroviral therapy, aiming to mitigate TDR, as well as for predicting future trends in other regions of the globe where mass antiretroviral (ARV) treatment was implemented. PMID- 29504273 TI - Surface-Enhanced Raman Scattering for Rapid Detection and Characterization of Antibiotic-Resistant Bacteria. AB - As the prevalence of antibiotic-resistant bacteria continues to rise, biosensing technologies are needed to enable rapid diagnosis of bacterial infections. Furthermore, understanding the unique biochemistry of resistance mechanisms can facilitate the development of next generation therapeutics. Surface-enhanced Raman scattering (SERS) offers a potential solution to real-time diagnostic technologies, as well as a route to fundamental, mechanistic studies. In the current review, SERS-based approaches to the detection and characterization of antibiotic-resistant bacteria are covered. The commonly used nanomaterials (nanoparticles and nanostructured surfaces) and surface modifications (antibodies, aptamers, reporters, etc.) for SERS bacterial detection and differentiation are discussed first, and followed by a review of SERS-based detection of antibiotic-resistant bacteria from environmental/food processing and clinical sources. Antibiotic susceptibility testing and minimum inhibitory concentration testing with SERS are then summarized. Finally, recent developments of SERS-based chemical imaging/mapping of bacteria are reviewed. PMID- 29504270 TI - Sensitivity of the circadian system to evening bright light in preschool-age children. AB - Although the light-induced melatonin suppression response is well characterized in adults, studies examining the dynamics of this effect in children are scarce. The purpose of this study was to quantify the magnitude of evening light-induced melatonin suppression in preschool-age children. Healthy children (n = 10; 7 females; 4.3 +/- 1.1 years) participated in a 7-day protocol. On days 1-5, children followed a strict sleep schedule. On day 6, children entered a dim light environment (<15 lux) for 1-h before providing salivary samples every 20- to 30 min from the afternoon until 50-min after scheduled bedtime. On day 7, subjects remained in dim light conditions until 1-h before bedtime, at which time they were exposed to a bright light stimulus (~1000 lux) for 1-h and then re-entered dim light conditions. Saliva samples were obtained before, during, and after bright light exposure and were time anchored to samples taken the previous evening. We found robust melatonin suppression (87.6 +/- 10.0%) in response to the bright light stimulus. Melatonin levels remained attenuated for 50-min after termination of the light stimulus (P < 0.008). Furthermore, melatonin levels did not return to 50% of those observed in the dim light condition 50-min after the light exposure for 7/10 children. Our findings demonstrate a robust light-induced melatonin suppression response in preschool-age children. These findings have implications for understanding the role of evening light exposure in the development of evening settling difficulties and may serve as experimental evidence to support recommendations regarding light exposure and sleep hygiene practices in early childhood. PMID- 29504271 TI - Influence of nitrate and nitrite concentration on N2 O production via dissimilatory nitrate/nitrite reduction to ammonium in Bacillus paralicheniformis LMG 6934. AB - Until now, the exact mechanisms for N2 O production in dissimilatory nitrate/nitrite reduction to ammonium (DNRA) remain underexplored. Previously, we investigated this mechanism in Bacillus licheniformis and Bacillus paralicheniformis, ubiquitous gram-positive bacteria with many industrial applications, and observed significant strain dependency and media dependency in N2 O production which was thought to correlate with high residual NO2- . Here, we further studied the influence of several physicochemical factors on NO3- (or NO2- ) partitioning and N2 O production in DNRA to shed light on the possible mechanisms of N2 O production. The effects of NO3- concentrations under variable or fixed C/N-NO3- ratios, NO2- concentrations under variable or fixed C/N-NO2- ratios, and NH4+ concentrations under fixed C/N-NO3- ratios were tested during anaerobic incubation of soil bacterium B. paralicheniformis LMG 6934 (previously known as B. licheniformis), a strain with a high nitrite reduction capacity. Monitoring of growth, NO3- , NO2- , NH4+ concentration, and N2 O production in physiological tests revealed that NO3- as well as NO2- concentration showed a linear correlation with N2 O production. Increased NO3- concentration under fixed C/N-NO3- ratios, NO2- concentration, and NH4+ concentration had a significant positive effect on NO3- (or NO2- ) partitioning ([N-NH4+ ]/[N-N2 O]) toward N2 O, which may be a consequence of the (transient) accumulation and subsequent detoxification of NO2- . These findings extend the information on several physiological parameters affecting DNRA and provide a basis for further study on N2 O production during this process. PMID- 29504274 TI - Nutrient intake in women before conception and risks of anophthalmia and microphthalmia in their offspring. AB - BACKGROUND: We previously explored associations between nutrients including folate and other macro and micronutrients and risks of anophthalmia or microphthalmia in the National Birth Defects Prevention Study. In the current study, we expand those previous results with larger sample sizes and conduct analyses with an additional diet quality index using more recent data. METHODS: The National Birth Defects Prevention Study is a population-based, multicenter case-control study of over 30 major birth defects, with estimated due dates from October 1997 to December 2011. Cases were 224 infants diagnosed with anophthalmia or microphthalmia. Controls were 11,109 live-born, nonmalformed infants randomly selected by each study center. Mothers completed a standardized, computer assisted telephone interview between 6 weeks and 24 months after delivery. Mothers responded to a shortened food frequency questionnaire, assessing their nutrient intake for the year before pregnancy, and questions about periconceptional (2 months before to 2 months after conception) vitamin supplement use. Nutrient intake quartiles were based on the intake among controls. RESULTS: Among vitamin supplement users, odds of anophthalmia/microphthalmia were decreased for women with intake levels in the highest quartile of folate (0.56, 95% confidence interval [CI] 0.32-0.98), magnesium (0.42, 95% CI 0.22-0.82), and vitamin E (0.50, 95% CI 0.29-0.89). Among women not reporting vitamin supplement use, the odds were significantly increased for beta-carotene (2.5, 95% CI 1.10-5.68) and decreased for retinol (0.37, 95% CI 0.19-0.73). CONCLUSIONS: In this expanded analysis, we observed associations for a few nutrients, specifically forms of vitamin A. However, the heterogeneity of results by form and vitamin use necessitates further inquiry. PMID- 29504275 TI - Changes in glycaemic control, blood pressure and lipids 5 years following laparoscopic adjustable gastric banding combined with medical care in patients with type 2 diabetes: a longitudinal analysis. AB - The long-term outcomes of weight loss maintenance induced by laparoscopic adjustable gastric band (LAGB) followed by multidisciplinary medical care in patients with type 2 diabetes mellitus (T2DM) (beyond 3 years) are scarcely reported. Study aims were to determine the longer term metabolic outcomes following LAGB combined with medical care in patients with T2DM. This is a longitudinal analysis of 200 adults with T2DM who had LAGB between 2003 and 2008 and were followed up till 2013 at a single bariatric unit in a tertiary UK centre. A total of 200 patients (age 47 +/- 9.7 years; body mass index [BMI] 52.8 +/- 9.2 kg m-2 ; glycosylated haemoglobin (HbA1c) 7.9 +/- 1.9% [62.8 mmol mol-1 ]; women, n = 123 [61.5%]; insulin treatment, n = 71 [35.5%]) were included. The mean follow-up was 62.0 +/- 13.0 months (range 18-84 months). There were significant reductions in body weight (-24.4 +/- 12.3% [38 +/- 22.7 kg]), HbA1c ( 1.4 +/- 2.0%), systolic blood pressure [BP] (-11.7 +/- 23.5 mmHg), total cholesterol and triglyceride levels. The proportion of patients requiring insulin reduced from 36.2% to 12.3%. The overall band complication rate was 21% (21 patients). LAGB when combined with multidisciplinary medical care significantly improved metabolic outcomes in patients with T2DM independent of diabetes duration, and baseline BMI over 5 years. Diabetes duration and baseline BMI did not predict changes in glycaemic control, BP or lipids following LAGB. PMID- 29504276 TI - Endoscopic ultrasound guided brush/fine-needle aspiration cytology: A 15-month study. AB - BACKGROUND: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has become increasingly popular for the diagnosis and staging of gastrointestinal diseases and peri-gastrointestinal lesions. The application of FNA/Brush has dramatically expanded the clinical utility of EUS. AIMS AND OBJECTIVE: To evaluate the diagnostic accuracy, study the spectrum of lesions encountered in EUS-FNAC/brush cytology of gastrointestinal and peri-gastrointestinal lesions. MATERIALS AND METHODS: Total of 124 patients during the period from August 2015 to November 2016 was included in the study. Routine staining was done. RESULTS: A total of 124 cases were studied with 86% (107 cases) being satisfactory for evaluation. M:F ratio was 1:1.03, mean age of 50.5 years. The most common site was common bile duct (CBD) (37%) followed by lymph node (21%), pancreas (17.7%), esophagus (17%), stomach (3.5%), liver (1.8%), gallbladder (1%), and spleen (1%). In total, 53.4% lesions were benign, in 6.5% atypical cells were seen, 12.1% were suspicious for malignancy, and 28% cases were positive for malignancy. Follow-up was available in 102 cases with cyto-histopathological concordance rate of 90%. CONCLUSION: EUS-FNA/Brush is a reliable, sensitive, specific and minimally invasive way to establish a diagnosis. It can be utilized as a pre-operative procedure for the management of many intra-abdominal lesions and prevent unnecessary invasive procedures. PMID- 29504278 TI - Body mass index increase before 3 years-of-age augments the degree of insulin resistance corresponding to body mass index in adolescent girls. PMID- 29504277 TI - Donor pretreatment with nebulized complement C3a receptor antagonist mitigates brain-death induced immunological injury post-lung transplant. AB - Donor brain death (BD) is an inherent part of lung transplantation (LTx) and a key contributor to ischemia-reperfusion injury (IRI). Complement activation occurs as a consequence of BD in other solid organ Tx and exacerbates IRI, but the role of complement in LTx has not been investigated. Here, we investigate the utility of delivering nebulized C3a receptor antagonist (C3aRA) pretransplant to BD donor lungs in order to reduce post-LTx IRI. BD was induced in Balb/c donors, and lungs nebulized with C3aRA or vehicle 30 minutes prior to lung procurement. Lungs were then cold stored for 18 hours before transplantation into C57Bl/6 recipients. Donor lungs from living donors (LD) were removed and similarly stored. At 6 hours and 5 days post-LTx, recipients of BD donor lungs had exacerbated IRI and acute rejection (AR), respectively, compared to recipients receiving LD lungs, as determined by increased histopathological injury, immune cells, and cytokine levels. A single pretransplant nebulized dose of C3aRA to the donor significantly reduced IRI as compared to vehicle-treated BD donors, and returned IRI and AR grades to that seen following LD LTx. These data demonstrate a role for complement inhibition in the amelioration of IRI post-LTx in the context of donor BD. PMID- 29504279 TI - Intrinsic insulin secretion capacity might be preserved by discontinuing anti programmed cell death protein 1 antibody treatment in 'anti-programmed cell death protein 1 antibody-induced' fulminant type 1 diabetes. AB - Intrinsic insulin secretion capacity may be preserved by discontinuing anti-PD-1 antibody treatment in 'anti-PD-1 antibody-induced'fulminant type 1 diabetes. PMID- 29504281 TI - Abstracts from ASMIRT 2018 - the Australian Society of Medical Imaging and Radiation Therapy's 13th National Conference, Canberra, Australia, 15-18 March 2018. PMID- 29504280 TI - Serum uric acid to creatinine ratio correlates with beta-cell function in type 2 diabetes. AB - BACKGROUND: The correlation between serum uric acid (SUA) and beta-cell function remains controversial. The present study aims to use a new index, renal function normalized SUA, to observe its correlation with beta-cell function in patients with type 2 diabetes (T2DM). METHODS: A total of 713 patients with T2DM received standard 75-g oral glucose tolerance and insulin release test. Renal function normalized SUA was calculated using SUA/creatinine and beta-cell function was assessed by HOMA-B. Binary logistic regression analysis was used to estimate the association between SUA/creatinine and beta-cell function. RESULTS: There are positive correlations between SUA/creatinine and HOMA-B (r = 0.143, P < 0.001), as well as other indexes of beta-cell function including modified beta-cell function index (r = 0.104, P = 0.007), InsAUC30 (r = 0.100, P = 0.008), and InsAUC120 (r = 0.124, P = 0.001). SUA/creatinine also positively correlates with insulin resistance (HOMA-IR: r = 0.161, P < 0.001). Moreover, multivariate analysis revealed that SUA/creatinine was significantly associated with preserved beta-cell function, independently of potential confounders including sex, BMI, and renal function. CONCLUSIONS: SUA to creatinine ratio correlates with beta cell function in T2DM patients. PMID- 29504283 TI - Graphene Materials in Antimicrobial Nanomedicine: Current Status and Future Perspectives. AB - Graphene materials (GMs), such as graphene, graphene oxide (GO), reduced GO (rGO), and graphene quantum dots (GQDs), are rapidly emerging as a new class of broad-spectrum antimicrobial agents. This report describes their state-of-the-art and potential future covering both fundamental aspects and biomedical applications. First, the current understanding of the antimicrobial mechanisms of GMs is illustrated, and the complex picture of underlying structure-property activity relationships is sketched. Next, the different modes of utilization of antimicrobial GMs are explained, which include their use as colloidal dispersions, surface coatings, and photothermal/photodynamic therapy agents. Due to their practical relevance, the examples where GMs function as synergistic agents or release platforms for metal ions and/or antibiotic drugs are also discussed. Later, the applicability of GMs in the design of wound dressings, infection-protective coatings, and antibiotic-like formulations ("nanoantibiotics") is assessed. Notably, to support our assessments, the existing clinical applications of conventional carbon materials are also evaluated. Finally, the key hurdles of the field are highlighted, and several possible directions for future investigations are proposed. We hope that the roadmap provided here will encourage researchers to tackle remaining challenges toward clinical translation of promising research findings and help realize the potential of GMs in antimicrobial nanomedicine. PMID- 29504282 TI - The effect of xanthine oxidase and hypoxanthine on the permeability of red cells from patients with sickle cell anemia. AB - Red cells from patients with sickle cell anemia (SCA) are under greater oxidative challenge than those from normal individuals. We postulated that oxidants generated by xanthine oxidase (XO) and hypoxanthine (HO) contribute to the pathogenesis of SCA through altering solute permeability. Sickling, activities of the main red cell dehydration pathways (Psickle , Gardos channel, and KCl cotransporter [KCC]), and cell volume were measured at 100, 30, and 0 mmHg O2 , together with deoxygenation-induced nonelectrolyte hemolysis. Unexpectedly, XO/HO mixtures had mainly inhibitory effects on sickling, Psickle , and Gardos channel activities, while KCC activity and nonelectrolyte hemolysis were increased. Gardos channel activity was significantly elevated in red cells pharmacologically loaded with Ca2+ using the ionophore A23187, consistent with an effect on the transport system per se as well as via Ca2+ entry likely via the Psickle pathway. KCC activity is controlled by several pairs of conjugate protein kinases and phosphatases. Its activity, however, was also stimulated by XO/HO mixtures in red cells pretreated with N-ethylmaleimide (NEM), which is thought to prevent regulation via changes in protein phosphorylation, suggesting that the oxidants formed could also have direct effects on this transporter. In the presence of XO/HO, red cell volume was better maintained in deoxygenated red cells. Overall, the most notable effect of XO/HO mixtures was an increase in red cell fragility. These findings increase our understanding of the effects of oxidative challenge in SCA patients and are relevant to the behavior of red cells in vivo. PMID- 29504284 TI - Long-term programming effects on blood pressure following gestational exposure to the IKr blocker Dofetilide. AB - A slow embryonic heart rate in early-mid gestation is associated with increased risk of embryonic death and malformation, however, the long-term consequences remain unknown. We administered Dofetilide (Dof, 2.5 mg/kg), a drug that produces embryo-specific bradycardia, to pregnant rats from gestational days 11-14. Embryonic heart rate and rhythm were determined using embryo culture. Cardiovascular function was assessed in surviving adult offspring at rest, during acute psychological stress (air jet stress, AJS), and after 7 days of repeated AJS. Dof reduced embryonic HR by 40% for ~8 h on each of the treatment days. On postnatal day 3, Dof offspring were ~10% smaller. Blood pressure was elevated in adult Dof rats (systolic blood pressure, night: 103.8 +/- 3.9 vs. 111.2 +/- 3.0 mmHg, P = 0.01). While the pressor response to AJS was similar in both groups (control 17.7 +/- 3.4; Dof 18.9 +/- 0.9 mmHg, P = 0.74), after 7 days repeated AJS, clear habituation was present in control (P = 0.0001) but not Dof offspring (P = 0.48). Only Dof offspring showed a small increase in resting blood pressure after 7 days repeated stress (+3.9 +/- 1.7 mmHg, P = 0.05). The results indicate that embryonic bradycardia programs hypertension and impaired stress adaptation, and have implications for the maternal use of cardioactive drugs during pregnancy. PMID- 29504285 TI - Phylogenetic analysis of ORF5 and ORF7 of porcine reproductive and respiratory syndrome (PRRS) virus and the frequency of wild-type PRRS virus in Mexico. AB - Porcine reproductive and respiratory syndrome (PRRS) is caused by a genetically diverse RNA virus and is an economically significant disease in the swine industry. In this study, a total of 8,126 serum samples were obtained from 275 technified and semi-technified farms belonging to 30 of the 32 states of Mexico and representative of the eight regions of the country. Anti-PRRSv antibodies against the PRRS vaccine and an isolated wild Mexican virus were tested by ELISA. Antibodies were found in 15%-49% of the tested sera, with 2.4%-9.8% against the vaccine and 7.7%-26% against the wild virus. The PRRSv virus was detected by RT PCR in 77 of the 1,630 pooled samples tested, representing seven of the eight geographic regions into which the Mexican Republic is divided. The complete sequences of open reading frames 5 and 7 from 20 PRRSv-positive samples were determined. The analysis of the sequences together with the previously published sequences of historic strains revealed that all the strains belonged to the one, five and eight lineages of the PRRSV2. Striking differences, particularly in ORF5 and ORF7, were found between sequences of the strains and the reference virus, due to insertions and substitutions in positions that play key roles in the recognition, structure and function of the virus. Overall, these results established the magnitude of PRRS virus genetic diversity, and the most frequent virus strain that predominates in Mexico. The PRRSV2 is presented in the porcine population of Mexico; the circulating strains have important changes in ORF5 and ORF7, which probably explain the results obtained in the serological analysis of the wild virus and vaccine strains. PMID- 29504286 TI - Cold acclimation reduces hepatic protein Kinase B and AMP-activated protein kinase phosphorylation and increases gluconeogenesis in Rats. AB - This study investigated the molecular and metabolic responses of the liver to cold-induced thermogenesis. To accomplish that, male Wistar rats were exposed to cold (4 degrees C) for 7 days. Livers were then extracted and used for the determination of glucose and fatty acid oxidation, glycogen content, the expression and content of proteins involved in insulin signaling, as well as in the regulation of gluconeogenesis and de novo lipid synthesis. Despite being hyperphagic, cold-acclimated rats displayed normoglycemia with reduced insulinemia, which suggests improved whole-body insulin sensitivity. However, liver protein kinase B (AKT) and glycogen synthase kinase 3 (GSK3) phosphorylations were markedly reduced along with the expressions of the insulin receptor (IR) and its substrates IRS1 and IRS2, whereas glycogen synthase (GS) phosphorylation increased. Thus, major signaling steps of the glycogen synthesis pathway in the liver were inhibited. Furthermore, glucagonemia and hepatic glucose and fatty acid oxidation were increased, whereas liver glycogen content was reduced by cold acclimation. This was accompanied by significantly elevated expressions of the gluconeogenic transcription regulators CRTC2, PGC-1alpha, and FoxO1, as well as of major gluconeogenic enzymes (G6Pase, FBP1, and PEPCK). Conversely, phosphorylation and contents of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) content were markedly downregulated in livers of cold-acclimated rats. In conclusion, cold acclimation suppressed hepatic glycogen synthesis and promoted profound metabolic changes in the liver so the organ could sustain its ability to regulate whole body glucose and lipid metabolism under conditions of high-energy demand in thermogenic tissues. PMID- 29504287 TI - Morphological evolution of various fungal species in the presence and absence of aluminum oxide microparticles: Comparative and quantitative insights into microparticle-enhanced cultivation (MPEC). AB - The application of microparticle-enhanced cultivation (MPEC) is an attractive method to control mycelial morphology, and thus enhance the production of metabolites and enzymes in the submerged cultivations of filamentous fungi. Unfortunately, most literature data deals with the spore-agglomerating species like aspergilli. Therefore, the detailed quantitative study of the morphological evolution of four different fungal species (Aspergillus terreus, Penicillium rubens, Chaetomium globosum, and Mucor racemosus) based on the digital analysis of microscopic images was presented in this paper. In accordance with the current knowledge, these species exhibit different mechanisms of agglomerates formation. The standard submerged shake flask cultivations (as a reference) and MPEC involving 10 MUm aluminum oxide microparticles (6 g.L-1 ) were performed. The morphological parameters, including mean projected area, elongation, roughness, and morphology number were determined for the mycelial objects within the first 24 hr of growth. It occurred that heretofore observed and widely discussed effect of microparticles on fungi, namely the decrease in pellet size, was not observed for the species whose pellet formation mechanism is different from spore agglomeration. In the MPEC, C. globosum developed core-shell pellets, and M. racemosus, a nonagglomerative species, formed the relatively larger, compared to standard cultures, pellets with distinct cores. PMID- 29504288 TI - Expression of striated activator of rho-signaling in human skeletal muscle following acute exercise and long-term training. AB - The striated activator of rho-signaling (STARS) protein acts as a link between external stimuli and exercise adaptation such as muscle hypertrophy. However, the acute and long-term adaptational response of STARS is still unclear. This study aimed at investigating the acute and long-term endurance training response on the mRNA and protein expression of STARS and its related upstream and downstream factors in human skeletal muscle. mRNA and protein levels of STARS and related factors were assessed in skeletal muscle of healthy young men and women following an acute bout of endurance exercise (n = 15) or 12 weeks of one-legged training (n = 23). Muscle biopsies were obtained before (acute and long-term), at 30 min, 2, and 6 h following acute exercise, and at 24 h following both acute exercise and long-term training. Following acute exercise, STARS mRNA was significantly elevated 3.9-fold at 30 min returning back to baseline 24 h after exercise. STARS protein levels were numerically but nonsignificantly increased 7.2-fold at 24 h. No changes in STARS or ERRalpha mRNA or STARS protein expression were seen following long-term training. PGC-1alpha mRNA increased 1.7-fold following long term training. MRTF-A mRNA was increased both following acute exercise and long term training, in contrast to SRF mRNA and protein which did not change. STARS mRNA is acutely upregulated with exercise, but there is no cumulative effect to long-term training as seen in PGC-1alpha mRNA expression. Exercise intensity might play a role in manifestation of protein expression, suggesting a more complex regulation of STARS. PMID- 29504289 TI - Methods for evidence synthesis in the case of very few studies. AB - In systematic reviews, meta-analyses are routinely applied to summarize the results of the relevant studies for a specific research question. If one can assume that in all studies the same true effect is estimated, the application of a meta-analysis with common effect (commonly referred to as fixed-effect meta analysis) is adequate. If between-study heterogeneity is expected to be present, the method of choice is a meta-analysis with random effects. The widely used DerSimonian and Laird method for meta-analyses with random effects has been criticized due to its unfavorable statistical properties, especially in the case of very few studies. A working group of the Cochrane Collaboration recommended the use of the Knapp-Hartung method for meta-analyses with random effects. However, as heterogeneity cannot be reliably estimated if only very few studies are available, the Knapp-Hartung method, while correctly accounting for the corresponding uncertainty, has very low power. Our aim is to summarize possible methods to perform meaningful evidence syntheses in the situation with only very few (ie, 2-4) studies. Some general recommendations are provided on which method should be used when. Our recommendations are based on the existing literature on methods for meta-analysis with very few studies and consensus of the authors. The recommendations are illustrated by 2 examples coming from dossier assessments of the Institute for Quality and Efficiency in Health Care. PMID- 29504290 TI - Myoblast mitochondrial respiration is decreased in chronic binge alcohol administered simian immunodeficiency virus-infected antiretroviral-treated rhesus macaques. AB - Work from our group demonstrated that chronic binge alcohol (CBA)-induces mitochondrial gene dysregulation at end-stage disease of simian immunodeficiency virus (SIV) infection in antiretroviral therapy (ART) naive rhesus macaques. Alterations in gene expression can disrupt mitochondrial homeostasis and in turn contribute to the risk of metabolic comorbidities characterized by loss of skeletal muscle (SKM) functional mass that are associated with CBA, human immunodeficiency virus (HIV) infection, and prolonged ART. The aim of this study was to examine the interaction of CBA and ART on SKM fiber oxidative capacity and myoblast mitochondrial respiration in asymptomatic SIV-infected macaques. SKM biopsies were obtained and myoblasts isolated at baseline and 11 months post-SIV infection from CBA/SIV/ART+ and from sucrose (SUC)-treated SIV-infected (SUC/SIV/ART+) macaques. CBA and ART decreased succinate dehydrogenase (SDH) activity in type 1 and type 2b fibers as determined by immunohistochemistry. Myoblasts isolated from CBA/SIV/ART+ macaques showed decreased maximal oxygen consumption rate (OCR) compared to myoblasts from control macaques. Maximal OCR was significantly increased in control myoblasts following incubation with formoterol, a beta adrenergic agonist, and this was associated with increased PGC 1alpha expression and mtDNA quantity. Additionally, formoterol treatment of myoblasts isolated from CBA/SIV/ART+ macaques partially restored maximal OCR to levels not significantly different from control. These results show that CBA in combination with ART impairs myoblast mitochondrial homeostasis in SIV-infected macaques. Moreover, our findings suggest that adrenergic agonists can potentially ameliorate mitochondrial dysfunction. Future studies will elucidate whether physical exercise in HIV patients with alcohol use disorder can improve mitochondrial health. PMID- 29504291 TI - Increased Risk of Ischemic Stroke during Sleep in Apneic Patients. AB - BACKGROUND AND PURPOSE: The literature indicates that obstructive sleep apnea (OSA) increases the risk of ischemic stroke. However, the causal relationship between OSA and ischemic stroke is not well established. This study examined whether preexisting OSA symptoms affect the onset of acute ischemic stroke. METHODS: We investigated consecutive patients who were admitted with acute ischemic stroke, using a standardized protocol including the Berlin Questionnaire on symptoms of OSA prior to stroke. The collected stroke data included the time of the stroke onset, risk factors, and etiologic subtypes. The association between preceding OSA symptoms and wake-up stroke (WUS) was assessed using multivariate logistic regression analysis. RESULTS: We identified 260 subjects with acute ischemic strokes with a definite onset time, of which 25.8% were WUS. The presence of preexisting witnessed or self-recognized sleep apnea was the only risk factor for WUS (adjusted odds ratio=2.055, 95% confidence interval=1.035 4.083, p=0.040). CONCLUSIONS: Preexisting symptoms suggestive of OSA were associated with the occurrence of WUS. This suggests that OSA contributes to ischemic stroke not only as a predisposing risk factor but also as a triggering factor. Treating OSA might therefore be beneficial in preventing stroke, particularly that occurring during sleep. PMID- 29504293 TI - Electroencephalographic Abnormalities in the Screening for Pilot Applicants in Korea. AB - BACKGROUND AND PURPOSE: Electroencephalography (EEG) is often used as a screening tool for selecting pilots despite controversy regarding its contribution to aviation safety. We investigated EEG abnormalities in Korean commercial pilot applicants in order to identify the usefulness of EEG screening in this population. METHODS: We retrospectively analyzed the EEG results of 740 unselected pilot applicants who underwent waking EEG at Inha University Hospital from January 2013 to May 2017. EEG recording was performed for 30 minutes, which included 3 minutes of hyperventilation and intermittent photic stimulation. RESULTS: The pilot applicants were predominantly male (95.3%) and had a mean age of 27.8 years (range: 16-40 years). Nine of them (1.2%) exhibited EEG abnormalities; the most common abnormality (six applicants) was a small amount of generalized irregular slow activities, while the other three applicants (0.4%) exhibited epileptiform discharges, with two showing generalized spike-and-wave complexes and one showing a few spike-and-wave complexes in the left frontotemporal area. The two applicants with generalized spike-and-wave complexes were found to have experienced clinical seizures by a neurologist during detailed history-taking. CONCLUSIONS: This study found that 2 of 740 pilot applicants (0.3%) were diagnosed with epilepsy by routine EEG screening in an unselected population. Considering the low predictive value of EEG without the relevant clinical history in an unselected healthy young population, our findings raise questions regarding the cost-effectiveness of the current EEG screening protocol applied to pilot applicants. We suggest that a more-targeted and standardized EEG screening approach be applied to pilot applicants with epilepsy risk factors or a seizure history as determined by thorough medical history-taking. PMID- 29504292 TI - Current Clinical Applications of Diffusion-Tensor Imaging in Neurological Disorders. AB - Diffusion-tensor imaging (DTI) is a noninvasive medical imaging tool used to investigate the structure of white matter. The signal contrast in DTI is generated by differences in the Brownian motion of the water molecules in brain tissue. Postprocessed DTI scalars can be used to evaluate changes in the brain tissue caused by disease, disease progression, and treatment responses, which has led to an enormous amount of interest in DTI in clinical research. This review article provides insights into DTI scalars and the biological background of DTI as a relatively new neuroimaging modality. Further, it summarizes the clinical role of DTI in various disease processes such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's dementia, epilepsy, ischemic stroke, stroke with motor or language impairment, traumatic brain injury, spinal cord injury, and depression. Valuable DTI postprocessing tools for clinical research are also introduced. PMID- 29504294 TI - Predictors of Institutionalization in Patients with Alzheimer's Disease in South Korea. AB - BACKGROUND AND PURPOSE: We investigated predictors of institutionalization in patients with Alzheimer's disease (AD) in South Korea. METHODS: In total, 2,470 patients with AD aged 74.5+/-7.8 years (mean+/-standard deviation, 68.1% females) were enrolled from November 2005 to December 2013. The dates of institutionalization were identified from the public Long-Term-Care Insurance program in January 2014. We used a Cox proportional-hazards model to identify predictors for future institutionalization among characteristics at the time of diagnosis in 2,470 AD patients. A similar Cox proportional-hazards model was also used to investigate predictors among variables that reflected longitudinal changes in clinical variables before institutionalization in 816 patients who underwent follow-up testing. RESULTS: A lower Mini Mental State Examination score [hazard ratio (HR)=0.95, 95% confidence interval (CI)=0.92-0.97] and higher scores for the Clinical Dementia Rating and Neuro-Psychiatric Inventory (HR=1.01, 95% CI=1.00-1.01) at baseline were independent predictors of institutionalization. The relationship of patients with their main caregivers, presence of the apolipoprotein E e4 allele, and medication at baseline were not significantly associated with the rate of institutionalization. In models with variables that exhibited longitudinal changes, larger annual change in Clinical Dementia Rating Sum of Boxes score (HR=1.15, 95% CI=1.06-1.23) and higher medication possession ratio of antipsychotics (HR=1.89, 95% CI=1.20-2.97) predicted earlier institutionalization. CONCLUSIONS: This study shows that among Korean patients with AD, lower cognitive ability, higher dementia severity, more severe behavioral symptoms at baseline, more-rapid decline in dementia severity, and more-frequent use of antipsychotics are independent predictors of earlier institutionalization. PMID- 29504295 TI - Optical Coherence Tomography versus Visual Evoked Potentials for Detecting Visual Pathway Abnormalities in Patients with Neuromyelitis Optica Spectrum Disorder. AB - BACKGROUND AND PURPOSE: Optical coherence tomography (OCT) and visual evoked potentials (VEPs) can be used to detect optic neuritis (ON). However, the comparative sensitivities of OCT and VEPs for detecting ON in neuromyelitis optica spectrum disorder (NMOSD) are unclear, and so we assessed these sensitivities. METHODS: This cross-sectional study included 73 patients with aquaporin-4 antibody-seropositive NMOSD, and 101 eyes with ON. The clinical characteristics, visual acuity (VA), Expanded Disability Status Scale (EDSS) scores, OCT peripapillary retinal nerve fiber layer (RNFL) thickness, and VEPs of the patients were evaluated. RESULTS: OCT and VEPs were abnormal in 68% and 73% of eyes with a history of ON, respectively, and in 2% and 9% of eyes without ON. Test sensitivities were influenced by the number of ON episodes: the OCT RNFL thickness and VEPs were abnormal in 50% and 67% of the eyes with first-ever ON episode, respectively (p=0.041), with the combination of both tests detecting abnormalities in up to 75% of the eyes. The sensitivities of the OCT RNFL thickness and VEPs increased to 95% and 83%, respectively, after the second or subsequent ON episode (p=0.06), with the combination of both tests detecting abnormalities in 95% of cases. The OCT RNFL thickness and VEP latency/amplitude were correlated with EDSS scores and VA. CONCLUSIONS: VEPs were superior for detecting subclinical or first-ever ON, while OCT was better for detecting eyes with multiple ON episodes. The correlations of OCT and VEPs with clinical disability measures indicate that these tests are potential markers of the disease burden in NMOSD. PMID- 29504296 TI - Medial-Vowel Writing Difficulty in Korean Syllabic Writing: A Characteristic Sign of Alzheimer's Disease. AB - BACKGROUND AND PURPOSE: Korean-speaking patients with a brain injury may show agraphia that differs from that of English-speaking patients due to the unique features of Hangul syllabic writing. Each grapheme in Hangul must be arranged from left to right and/or top to bottom within a square space to form a syllable, which requires greater visuospatial abilities than when writing the letters constituting an alphabetic writing system. Among the Hangul grapheme positions within a syllable, the position of a vowel is important because it determines the writing direction and the whole configuration in Korean syllabic writing. Due to the visuospatial characteristics of the Hangul vowel, individuals with early onset Alzheimer's disease (EOAD) may experiences differences between the difficulties of writing Hangul vowels and consonants due to prominent visuospatial dysfunctions caused by parietal lesions. METHODS: Eighteen patients with EOAD and 18 age-and-education-matched healthy adults participated in this study. The participants were requested to listen to and write 30 monosyllabic characters that consisted of an initial consonant, medial vowel, and final consonant with a one-to-one phoneme-to-grapheme correspondence. We measured the writing time for each grapheme, the pause time between writing the initial consonant and the medial vowel (P1), and the pause time between writing the medial vowel and the final consonant (P2). RESULTS: All grapheme writing and pause times were significantly longer in the EOAD group than in the controls. P1 was also significantly longer than P2 in the EOAD group. CONCLUSIONS: Patients with EOAD might require a higher judgment ability and longer processing time for determining the visuospatial grapheme position before writing medial vowels. This finding suggests that a longer pause time before writing medial vowels is an early marker of visuospatial dysfunction in patients with EOAD. PMID- 29504297 TI - Demographic and Clinical Correlates of Seizure Frequency: Findings from the Managing Epilepsy Well Network Database. AB - BACKGROUND AND PURPOSE: Epilepsy is a chronic neurological disease that represents a tremendous burden on both patients and society in general. Studies have addressed how demographic variables, socioeconomic variables, and psychological comorbidity are related to the quality of life (QOL) of people with epilepsy (PWE). However, there has been less focus on how these factors may differ between patients who exhibit varying degrees of seizure control. This study utilized data from the Managing Epilepsy Well (MEW) Network of the Centers for Disease Control and Prevention with the aim of elucidating differences in demographic variables, depression, and QOL between adult PWE. METHODS: Demographic variables, depression, and QOL were compared between PWE who experience clinically relevant differences in seizure occurrence. RESULTS: Gender, ethnicity, race, education, income, and relationship status did not differ significantly between the seizure-frequency categories (p>0.05). People with worse seizure control were significantly younger (p=0.039), more depressed (as assessed using the Patient Health Questionnaire) (p=0.036), and had lower QOL (as determined using the 10-item Quality of Life in Epilepsy for Adults scale) (p<0.001). CONCLUSIONS: The present results underscore the importance of early screening, detection, and treatment of depression, since these factors relate to both seizure occurrence and QOL in PWE. PMID- 29504298 TI - Swallowing and Aspiration Risk: A Critical Review of Non Instrumental Bedside Screening Tests. AB - BACKGROUND AND PURPOSE: The presence of dysphagia and aspiration in stroke patients is associated with increased mortality and morbidity. Early recognition and management of these two conditions via reliable, minimally invasive bedside procedures before complications arise remains challenging in everyday clinical practice. This study reviews the available bedside screening tools for detecting swallowing status and aspiration risk in acute stroke by qualitatively observing reference population study design, clinical flexibility, reliability and applicability to acute-care settings. METHODS: The primary search was conducted using the PubMed, Embase, and Cochrane Library databases. The search was limited to papers on humans written in English and published from 1991 to 2016. Eligibility criteria included the consecutive enrollment of acute-stroke inpatients and the development of a protocol for screening aspiration risk during oral feeding in this population. RESULTS: Of the 652 sources identified, 75 articles were reviewed in full however, only 12 fulfilled the selection criteria. Notable deficiencies in most of the bedside screening protocols included poor methodological designs and inadequate predictive values for aspiration risk which render clinicians to be more conservative in making dietary recommendations. CONCLUSIONS: The literature is dense with screening methods for assessing the presence of dysphagia but with low predictive value for aspiration risk after acute stroke. A standard, practical, and cost-effective screening tool that can be applied at the bedside and interpreted by a wide range of hospital personnel remains to be developed. This need is highlighted in settings where neither trained personnel in evaluating dysphagia nor clinical instrumentation procedures are available. PMID- 29504300 TI - Bilateral Radiation-Induced Hypoglossal Nerve Palsy Responsive to Steroid Treatment. PMID- 29504299 TI - Neutralizing Antibodies Against Interferon-Beta in Korean Patients with Multiple Sclerosis. AB - BACKGROUND AND PURPOSE: Patients treated with interferon-beta (IFN-beta) can develop neutralizing antibodies (NAbs) against IFN-beta that can negatively affect the therapeutic response. This study assessed the prevalence of NAbs and the impact of NAb positivity on the therapeutic response to IFN-beta in Korean patients with multiple sclerosis (MS). METHODS: This was a multicenter study involving 150 MS patients from 9 Korean medical centers who were treated with IFN beta for at least 6 months. Sera that had not been influenced by acute treatment were assessed for NAbs using a luciferase reporter gene assay. To evaluate the association between persistent positivity for NAbs and disease activity, NAbs were tested at 2 different time points in 75 of the 150 patients. Disease activity was defined as the presence of clinical exacerbations and/or active MRI lesions during a 1-year follow-up after NAb positivity was confirmed. RESULTS: NAbs were found in 39 of the 150 (26%) MS patients: 30 of the 85 (35%) who were treated with subcutaneous IFN-beta-1b, 9 of the 60 (15%) who were treated with subcutaneous IFN-beta-1a, and 0 of the 5 (0%) who were treated with intramuscular IFN-beta-1a. Thirty of the 39 patients exhibiting NAb positivity were tested at different time points, and 20 of them exhibited persistent NAb positivity. Disease activity was observed more frequently in patients with persistent NAb positivity than in those with transient positivity or persistent negativity [16/20 (80%) vs. 4/55 (7%), respectively; p<0.001]. When disease activity was compared between patients with persistent and transient NAb positivity, the difference was unchanged and remained statistically significant [16/20 (80%) vs. 2/10 (20%), p=0.004]. CONCLUSIONS: These results further support that persistent NAb positivity is associated with disease activity in MS patients treated with IFN-beta. PMID- 29504301 TI - A Short but Long Journey with You. PMID- 29504303 TI - Being Metabolically Healthy, the Most Responsible Factor for Vascular Health. AB - The prevalence of obesity is rapidly increasing worldwide. One-thirds of world population is suffering from the deleterious effects of excessive fat and adipose tissue in their body. At the same time, the average life expectancy is becoming higher and higher every decade. Therefore, living healthy and longer is the dream for everyone. Simply being obese is not the primary cause for the consequence of obesity; rather, the depot where the fat is accumulated, is the primary key for the deleterious effects of obesity. Results from historical research suggest that visceral fat increases the risk for cardiovascular and metabolic diseases, such as diabetes, myocardial infarction and ischemic stroke, not subcutaneous fat. Therefore, body mass index (BMI), which reflects body weight relative to height might not reflect the appropriate size of metabolic burden of fat in our body. In contrast, waist circumference, which reflects abdominal obesity, would mirror the metabolic burden of fat better than BMI. Visceral fat is the marker of ectopic fat accumulation. In this review, I will introduce my researches mainly involved in uncovering the clues to the link between metabolic health and cardiovascular disease. PMID- 29504302 TI - Recent Updates on Type 1 Diabetes Mellitus Management for Clinicians. AB - Type 1 diabetes mellitus (T1DM) is a chronic autoimmune condition that requires life-long administration of insulin. Optimal management of T1DM entails a good knowledge and understanding of this condition both by the physician and the patient. Recent introduction of novel insulin preparations, technological advances in insulin delivery and glucose monitoring, such as continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring and improved understanding of the detrimental effects of hypoglycaemia and hyperglycaemia offer new opportunities and perspectives in T1DM management. Evidence from clinical trials suggests an important role of structured patient education. Our efforts should be aimed at improved metabolic control with concomitant reduction of hypoglycaemia. Despite recent advances, these goals are not easy to achieve and can put significant pressure on people with T1DM. The approach of physicians should therefore be maximally supportive. In this review, we provide an overview of the recent advances in T1DM management focusing on novel insulin preparations, ways of insulin administration and glucose monitoring and the role of metformin or sodium-glucose co-transporter 2 inhibitors in T1DM management. We then discuss our current understanding of the effects of hypoglycaemia on human body and strategies aimed at mitigating the risks associated with hypoglycaemia. PMID- 29504304 TI - Self-Monitoring of Blood Glucose in Patients with Insulin-Treated Type 2 Diabetes Mellitus. PMID- 29504305 TI - Patient Understanding of Hypoglycemia in Tertiary Referral Centers. AB - BACKGROUND: Hypoglycemia is an important complication in the treatment of patients with diabetes. We surveyed the insight by patients with diabetes into hypoglycemia, their hypoglycemia avoidance behavior, and their level of worry regarding hypoglycemia. METHODS: A survey of patients with diabetes, who had visited seven tertiary referral centers in Daegu or Gyeongsangbuk-do, Korea, between June 2014 and June 2015, was conducted. The survey contained questions about personal history, symptoms, educational experience, self-management, and attitudes about hypoglycemia. RESULTS: Of 758 participants, 471 (62.1%) had experienced hypoglycemia, and 250 (32.9%) had experienced hypoglycemia at least once in the month immediately preceding the study. Two hundred and forty-two (31.8%) of the participants had received hypoglycemia education at least once, but only 148 (19.4%) knew the exact definition of hypoglycemia. Hypoglycemic symptoms identified by the participants were dizziness (55.0%), sweating (53.8%), and tremor (40.8%). They mostly chose candy (62.1%), chocolate (37.7%), or juice (36.8%) as food for recovering hypoglycemia. Participants who had experienced hypoglycemia had longer duration of diabetes and a higher proportion of insulin usage. The mean scores for hypoglycemia avoidance behavior and worry about hypoglycemia were 21.2+/-10.71 and 23.38+/-13.19, respectively. These scores tended to be higher for participants with higher than 8% of glycosylated hemoglobin, insulin use, and experience of emergency room visits. CONCLUSION: Many patients had experienced hypoglycemia and worried about it. We recommend identifying patients that are anxious about hypoglycemia and educating them about what to do when they develop hypoglycemic symptoms, especially those who have a high risk of hypoglycemia. PMID- 29504306 TI - Color Doppler Ultrasonography Is a Useful Tool for Diagnosis of Peripheral Artery Disease in Type 2 Diabetes Mellitus Patients with Ankle-Brachial Index 0.91 to 1.40. AB - BACKGROUND: The clinical utility of ankle-brachial index (ABI) is not clear in subjects with less severe or calcified vessel. Therefore, we investigated the usefulness of color Doppler ultrasonography for diagnosing peripheral artery disease (PAD) in type 2 diabetes mellitus (T2DM) subjects. METHODS: We analyzed 324 T2DM patients who concurrently underwent ABI and carotid intima-media thickness (CIMT) measurements and color Doppler ultrasonography from 2003 to 2006. The degree of stenosis in patients with PAD was determined according to Jager's criteria, and PAD was defined as grade III (50% to 99% stenosis) or IV stenosis (100% stenosis) by color Doppler ultrasonography. Logistic regression analysis and receiver operating characteristic curve analysis were performed to evaluate the risk factors for PAD in patients with ABI 0.91 to 1.40. RESULTS: Among the 324 patients, 77 (23.8%) had ABI 0.91 to 1.40 but were diagnosed with PAD. Color Doppler ultrasonography demonstrated that suprapopliteal arterial stenosis, bilateral lesions, and multivessel involvement were less common in PAD patients with ABI 0.91 to 1.40 than in those with ABI <=0.90. A multivariate logistic regression analysis demonstrated that older age, current smoking status, presence of leg symptoms, and high CIMT were significantly associated with the presence of PAD in patients with ABI 0.91 to 1.40 after adjusting for conventional risk factors. CIMT showed significant power in predicting the presence of PAD in patients with ABI 0.91 to 1.40. CONCLUSION: Color Doppler ultrasonography is a useful tool for the detection of PAD in T2DM patients with ABI 0.91 to 1.40 but a high CIMT. PMID- 29504307 TI - Lack of Evidence of the Role of APOA5 3'UTR Polymorphisms in Iranian Children and Adolescents with Metabolic Syndrome. AB - BACKGROUND: Metabolic syndrome (MetS) is a complex and multifactorial disorder characterized by insulin resistance, dyslipidaemia, hyperglycemia, abdominal obesity, and elevated blood pressure. The apolipoprotein A5 (APOA5) gene variants have been reported to correlate with two major components of MetS, including low levels of high density lipoprotein cholesterol (HDL-C) and high levels of triglyceride. In the present study, we explored the associations between five single nucleotide polymorphisms (SNPs) of APOA5 gene and the MetS risk. METHODS: In a case-control design, 120 Iranian children and adolescents with/without MetS were genotyped by polymerase chain reaction-sequencing for these SNPs. Then, we investigated the association of SNPs, individually or in haplotype constructs, with MetS risk. RESULTS: The rs34089864 variant and H1 haplotype (harboring the two major alleles of rs619054 and rs34089864) were associated with HDL-C levels. However, there was no significant association between different haplotypes/individual SNPs and MetS risk. CONCLUSION: These results presented no association of APOA5 3'UTR SNPs with MetS. Further studies, including other polymorphisms, are required to investigate the involvement of APOA5 gene in the genetic susceptibility to MetS in the pediatric age group. PMID- 29504308 TI - Single Sensor Gait Analysis to Detect Diabetic Peripheral Neuropathy: A Proof of Principle Study. AB - This study explored the potential utility of gait analysis using a single sensor unit (inertial measurement unit [IMU]) as a simple tool to detect peripheral neuropathy in people with diabetes. Seventeen people (14 men) aged 63+/-9 years (mean+/-SD) with diabetic peripheral neuropathy performed a 10-m walk test instrumented with an IMU on the lower back. Compared to a reference healthy control data set (matched by gender, age, and body mass index) both spatiotemporal and gait control variables were different between groups, with walking speed, step time, and SDa (gait control parameter) demonstrating good discriminatory power (receiver operating characteristic area under the curve >0.8). These results provide a proof of principle of this relatively simple approach which, when applied in clinical practice, can detect a signal from those with known diabetes peripheral neuropathy. The technology has the potential to be used both routinely in the clinic and for tele-health applications. Further research should focus on investigating its efficacy as an early indicator of or effectiveness of the management of peripheral neuropathy. This could support the development of interventions to prevent complications such as foot ulceration or Charcot's foot. PMID- 29504309 TI - Letter: Adipokines and Insulin Resistance According to Characteristics of Pregnant Women with Gestational Diabetes Mellitus (Diabetes Metab J 2017;41:457 65). PMID- 29504310 TI - Response: Adipokines and Insulin Resistance According to Characteristics of Pregnant Women with Gestational Diabetes Mellitus (Diabetes Metab J 2017;41:457 65). PMID- 29504311 TI - Roles of flotillins in tumors. AB - The identification and use of molecular biomarkers have greatly improved the diagnosis and treatment of malignant tumors. However, a much deeper understanding of oncogenic proteins is needed for the benefit to cancer patients. The lipid raft marker proteins, flotillin-1 and flotillin-2, were first found in goldfish retinal ganglion cells during axon regeneration. They have since been found in a variety of cells, mainly on the inner surface of cell membranes, and not only act as a skeleton to provide a platform for protein-protein interactions, but also are involved in signal transduction, nerve regeneration, endocytosis, and lymphocyte activation. Previous studies have shown that flotillins are closely associated with tumor development, invasion, and metastasis. In this article, we review the functions of flotillins in relevant cell processes, their underlying mechanisms of action in a variety of tumors, and their potential applications to tumor molecular diagnosis and targeted therapy. PMID- 29504313 TI - In vitro antioxidant activity of phenolic-enriched extracts from Zhangping Narcissus tea cake and their inhibition on growth and metastatic capacity of 4T1 murine breast cancer cells. AB - Phenolics, as the main bioactive compounds in tea, have been suggested to have potential in the prevention of various human diseases. However, little is known about phenolics and their bioactivity in Zhangping Narcissue tea cake which is considered the most special kind of oolong tea. To unveil its bioactivity, three phenolic-enriched extracts were obtained from Zhangping Narcissue tea cake using ethyl acetate, n-butanol, and water. Their main chemical compositions and in vitro bioactivity were analyzed by high-performance liquid chromatography (HPLC) and ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). The ethyl acetate fraction (ZEF) consisted of higher content of phenolics, flavonoids, procyanidins, and catechin monomers (including epigallocatechin gallate (EGCG), epicatechin gallate (ECG), and gallocatechin gallate (GCG)) than n-butanol fraction (ZBF) and water fraction (ZWF). ZEF exhibited the strongest antioxidant capacity in vitro due to its abundant bioactive compounds. This was validated by Pearson correlation and hierarchical clustering analyses. ZEF also showed a remarkable inhibition on the growth, migration, and invasion of 4T1 murine breast cancer cells. PMID- 29504312 TI - Role of exosome-associated microRNA in diagnostic and therapeutic applications to metabolic disorders. AB - Metabolic disorders are classified clinically as a complex and varied group of diseases including metabolic syndrome, obesity, and diabetes mellitus. Fat toxicity, chronic inflammation, and oxidative stress, which may change cellular functions, are considered to play an essential role in the pathogenetic progress of metabolic disorders. Recent studies have found that cells secrete nanoscale vesicles containing proteins, lipids, nucleic acids, and membrane receptors, which mediate signal transduction and material transport to neighboring and distant cells. Exosomes, one type of such vesicles, are reported to participate in multiple pathological processes including tumor metastasis, atherosclerosis, chronic inflammation, and insulin resistance. Research on exosomes has focused mainly on the proteins they contain, but recently the function of exosome associated microRNA has drawn a lot of attention. Exosome-associated microRNAs regulate the physiological function and pathological processes of metabolic disorders. They may also be useful as novel diagnostics and therapeutics given their special features of non-immunogenicity and quick extraction. In this paper, we summarize the structure, content, and functions of exosomes and the potential diagnostic and therapeutic applications of exosome-associated microRNAs in the treatment of metabolic disorders. PMID- 29504314 TI - Diagnostic value of computed tomography (CT) histogram analysis in thyroid benign solitary coarse calcification nodules. AB - This study was to investigate the diagnostic value of the computed tomography (CT) histogram in thyroid benign solitary coarse calcification nodules (BSCNs). A total of 89 thyroid solitary coarse calcification nodules (coarse calcification >=5 mm, no definite soft tissue around calcification) confirmed either by surgery or histopathological examination in 86 cases enrolled from January 2009 to December 2015 were evaluated. These included 56 BSCNs and 33 malignant solitary coarse calcification nodules (MSCNs). Overall, 27 cut-off values were calculated by N (4<=N<=30) times of 50 Hounsfield units (HU) in the range of 200 to 1500 HU, and each cut-off value and the differences in the corresponding area percentages in the CT histogram were recorded for BSCN and MSCN. The optimal cut-off value and the corresponding area percentage were established by receiver operating characteristic (ROC) curve analysis. In the 19 groups with an ROC area under curve (AUC) of more than 0.7, at a cut-off value of 800 HU and at an area percentage of no more than 93.8%, the ROC AUC reached the maximum of 0.79, and the accuracy, sensitivity, and specificity were 75.3%, 80.4%, and 66.7%, respectively. At a cut-off value of 1050 HU and at an area percentage of no more than 93.6%, the accuracy, sensitivity, and specificity were 71.9%, 60.7%, and 90.9%, respectively. At a cut-off of 1150 HU and area of no more than 98.4%, the accuracy, sensitivity, and specificity were 70.8%, 57.1%, and 93.9%, respectively. At a cut-off of 600 HU and area of no more than 12.1%, the accuracy, sensitivity, and specificity were 61.8%, 39.3%, and 100.0%, respectively. Compared with the cut-off value of 800 HU and an area percentage of no more than 93.8%, the sensitivity of cut-off values and minimum areas of 1050 HU and 93.6%, of 1150 HU and 98.4%, and of 600 HU and 12.1%, was gradually decreasing; however, their specificity was gradually increasing. This can provide an important basis for reducing the misdiagnosis and unnecessary surgical trauma. PMID- 29504315 TI - Assessments of tear meniscus height, tear film thickness, and corneal epithelial thickness after deep anterior lamellar keratoplasty. AB - OBJECTIVE: To assess the lower tear meniscus height (LTMH), central tear film thickness (CTFT), and central corneal epithelial thickness (CCET) after deep anterior lamellar keratoplasty (DALK). METHODS: This was a retrospective cross sectional study of 20 patients who had DALK in one eye over a three-month period. LTMH, CTFT, and CCET of the operated eyes and the unoperated fellow eyes were measured using high-definition optical coherence tomography (HD-OCT). Correlations between three OCT assessments and age, time following surgery, graft size, bed size, and the number of residual sutures were analyzed. RESULTS: Compared to patients with keratoconus, patients with other corneal conditions had significantly higher CCET in the fellow eye (P=0.024). For all patients, CCET in the operated eye was significantly negatively correlated with the number of residual sutures (R=-0.579, P=0.008), and was significantly positively correlated with time following surgery (R=0.636, P=0.003). In the fellow eye, a significant positive correlation was found between age and CCET (R=0.551, P=0.012), and a significant negative correlation between age and CTFT (R=-0.491, P=0.028). LTMH was found to be significantly correlated between operated and fellow eyes (R=0.554, P=0.011). There was no significant correlation between LTMH and age, bed/graft size, time following surgery, or residual sutures (all possible correlations, P>0.05). CONCLUSIONS: Patients with keratoconus tend to have a thinner central corneal epithelium. Corneal epithelium keeps regenerating over time after DALK. DALK did not induce a significant change in tear volume compared with the fellow eye. Postoperative tear function might depend on an individual's general condition, rather than on age, gender, bed/graft size, time following surgery, or residual sutures. PMID- 29504316 TI - Metabolic profile of danshen in rats by HPLC-LTQ-Orbitrap mass spectrometry. AB - Danshen, the dried root of Salvia miltiorrhiza Bunge (Lamiaceae), is one of the traditional Chinese medicines (TCMs) most commonly used for the treatment of cardiovascular and cerebrovascular diseases. However, little is known about the chemical and metabolic profiles of danshen in vitro or in vivo. In particular, more information is needed in relation to the 50% ethanol extracts usually used in danshen formulations such as Fufang Xueshuantong Capsules and Fufang Danshen tablets. High-performance liquid chromatography coupled with a linear ion trap Orbitrap mass spectrometer (HPLC-LTQ-Orbitrap) provides a sensitive and accurate method for analyzing the composition of samples. This method was used to determine the in vitro and in vivo chemical and metabolic profiles of danshen. Sixty-nine components of danshen extract and 118 components of danshen in rat plasma, urine, feces, and bile were unambiguously or tentatively identified. These results not only revealed the material composition of danshen, but also provided a comprehensive research approach for the identification of multi constituents in TCMs. PMID- 29504318 TI - The Rising Menace Of Smog: Time To Act Now. PMID- 29504317 TI - Supplementation with turmeric residue increased survival of the Chinese soft shelled turtle (Pelodiscus sinensis) under high ambient temperatures. AB - Turmeric residue (TR), containing residual levels of curcumin, is a solid by product waste generated after the extraction and separation of curcumin from turmeric root. A feeding trial was conducted to evaluate the effects of TR on the survival of Chinese soft-shelled turtles (SSTs), Pelodiscus sinensis, under a high ambient temperature. A total of 320 female SSTs were assigned randomly to two diets: basal diet (the control group, n=160) and an interventional diet supplemented with 10% TR (the TR group, n=160). Our results demonstrated that supplementation of TR increased the SST survival rate by 135.5%, and superoxide dismutase (SOD) activity of SST liver by 112.8%, and decreased the malondialdehyde (MDA) content of SST liver by 36.4%, compared to the control group. The skin of the SST fed TR showed a golden color. High-performance liquid chromatography (HPLC) analysis indicated that the concentrations of curcumin in TR and the skin of the SST fed TR were (1.69+/-0.30) and (0.14+/-0.03) MUg/g, respectively. Our observation suggests that supplementation of TR increased the survival rate of SST under high ambient temperatures. We speculated that the increased survival rate and tolerance at the high ambient temperature were associated with the anti-oxidation activity of curcumin from TR. Moreover, curcumin in TR could be deposited in SST skin, which made it more favored in the market of China. Our findings provide new knowledge and evidence to effectively reuse TR as a feed additive in animal and aquatic farming. PMID- 29504319 TI - Anti-Arthritic Effect Of Thymoquinone In Comparison With Methotrexate On Pristane Induced Arthritis In Female Sprague Dawley Rats. AB - Background: Rheumatoid arthritis inflammatory joint disease which is chronic in nature. Since long various researches are carried out to find the remedy of this disease but still a lot of work needed to be done. Methods: This comparative study was performed from March to August 2013 at Postgraduate Medical Institute, Lahore. A total of thirty-two female Sprague-Dawley rats were randomly divided into four equal groups (n=8); group A was kept as healthy control, group B was kept as positive control, group C was treated with thymoquinone and group D was treated with methotrexate. Arthritis developed within two weeks in group B, group C and group D after giving a single shot of pristane intradermally. Treatment was started on day 15. At day 30 (time of dissection) paw weight and histopathological sections of ankle joints of all the animals were taken. Results: The results shown significant rise in paw weight and score of histopathological parameters in group B, group C and group D when compared with healthy control rats. Thymoquinone and methotrexate treated groups shown reduction in paw weight and score of histopathological parameters when compared to positive control rats with p-value 0.001each. The difference between groups C and D was insignificant (p-value 0.062). Conclusions: Study results supported the anti-inflammatory and disease modifying activities of thymoquinone as it significantly reduces both paw weight and histological parameters of joint inflammation. PMID- 29504320 TI - Effectiveness Of Plain Shoulder Radiograph In Detecting Degenerate Rotator Cuff Tears. AB - BACKGROUND: Studies have demonstrated radiographic findings of sclerosis and cortical irregularity at the greater tuberosity can suggest a rotator cuff tear. Plain radiographs are the most easily attainable first-line investigations in evaluating shoulder injuries. This study determines the effectiveness in predicting degenerate rotator cuff tears by detecting radiographic changes on shoulder x-rays. METHODS: Retrospective cross-sectional study with a consecutive series of patients conducted in Hinchingbrooke Hospital, Huntingdon, United Kingdom from January 2015 to June 2017. Anteroposterior shoulder radiographs of 150 symptomatic patients who underwent shoulder arthroscopy were independently analysed by surgeons who were blinded from the arthroscopic results. Patients aged fewer than 30 and over 70 years were excluded. Patients with advanced osteoarthritis and cuff tear arthropathy evident on x-rays were also excluded. Sixty-five patients included in the study had rotator cuff tears on arthroscopy. Radiographic changes were correlated with arthroscopic findings to determine this test's ability to predict degenerate rotator cuff tears. RESULTS: When both cortical irregularity and sclerosis were present on the plain radiograph, these signs had a sensitivity of 78.8% [95% CI 65.7, 87.8%] and specificity 77.4% [95% CI 67.2, 85.0%] with a positive predictive value of 68.3%, using contingency table analysis. The presence of cortical irregularity was found to be a better predictor of a tear as compared to sclerosis. CONCLUSIONS: This study concludes that plain radiograph are good modality for initial evaluation of rotator cuff tears and detecting when both cortical irregularity and sclerosis. Consideration of these radiographic findings serves as a useful adjunct in diagnostic workup and can guide subsequent investigations and treatment when evaluating rotator cuff tears of the shoulder. PMID- 29504321 TI - Analgesic Effect Of Bilateral Subcostal Tap Block After Laparoscopic Cholecystectomy. AB - BACKGROUND: Pain after laparoscopic cholecystectomy is mild to moderate in intensity. Several modalities are employed for achieving safe and effective postoperative analgesia, the benefits of which adds to the early recovery of the patients. As a part of multimodal analgesia, various approaches of Transversus abdominis plane (TAP) block has been used for management of parietal and incisional components of pain after laparoscopic cholecystectomy. This study was designed to compare the analgesic efficacy of two different approaches of ultrasound guided TAP block, i.e., Subcostal-TAP block technique with ultrasound guided Posterior-TAP block for postoperative pain management in patients undergoing laparoscopic cholecystectomy under general anaesthesia. METHODS: In this double blinded randomized controlled study, consecutive nonprobability sampling was done and a total of 126 patients admitted for elective laparoscopic cholecystectomy fulfilling the inclusion criteria were selected. After induction of general anaesthesia, patients were randomized through draw method and received either ultrasound guided posterior TAP block with 0.375% bupivacaine (20ml volume) on each side of the abdomen or subcostal TAP block bilaterally with the same. Up to 24 hours postoperatively, static and dynamic numeric rating pain scores were assessed. RESULTS: We found statistically significant difference in mean static pain scores over 24 hours postoperatively in subcostal TAP group, suggesting improved analgesia. However, mean dynamic postoperative pain scores were comparable between the two groups. Whereas, patients in both groups were satisfied with pain management. CONCLUSIONS: Ultrasound guided subcostal TAP block provides better postoperative analgesia as compared to the Posterior TAP block in laparoscopic cholecystectomy. Otherwise both of the approaches improve patient outcomes towards early recovery and discharge from hospital. PMID- 29504322 TI - Factors Affecting Treatment Duration - A Dilemma In Orthodontics. AB - BACKGROUND: One of the first concerns of new orthodontic patients, apart from the outcome, is the duration of treatment. A better understanding of orthodontic treatment duration as well as factors affecting the treatment duration is useful for efficient patient counselling and improved clinical practice. Hence, the objectives of this study are to compare the treatment durations of subjects with Class I and Class II division 1 (II/1) malocclusions, and to identify the factors affecting the treatment duration of these malocclusions. METHODS: This was a chart review conducted in the orthodontic department of the Aga Khan University Hospital, Karachi. The study sample comprised of 120 subjects and data were recorded from their treatment records. ANOVA and Bonferroni post-hoc were performed to determine the difference in treatment durations of Class I and Class II/1 malocclusions, whereas multiple linear regression was applied to identify the factors affecting the treatment duration. A level of significance (p<=0.05) was used for the statistical tests. RESULTS: A statistically significant difference was found between the treatment durations of Class I and Class II/1 non-extraction (p=0.007), Class I non-extraction and Class II/1 extraction (p=0.001), and Class I and II/1 extraction (p=0.004) groups. The factors significantly increasing the treatment duration included missed appointments, breakages, and lower incisor proclination. CONCLUSIONS: Orthodontic treatment of Class II/1 malocclusion lasts longer than that of Class I malocclusion. Prolonged treatment time is associated with missed appointments, band/bracket debonds and increased lower incisor inclination. The variance in treatment time can be explained most significantly by number of missed appointments and breakages. PMID- 29504323 TI - Electrocardiographic Manifestations In Paediatric Wilson Disease. AB - BACKGROUND: Wilson disease (WD) is one of the most common metabolic liver diseases in older children. It has a strong genetic background with autosomal recessive inheritance. WD is a multisystem disorder with predominant hepatic and neurological manifestations and variable age of presentation. The data on cardiac manifestations in children is very limited and only few adult studies are available in the literature. This study was planned to determine the frequency and spectrum of Electrocardiographic (ECG) changes in pediatric WD. METHODS: This was an observational cross-sectional study conducted at The Children Hospital & the Institute of Child Health, Lahore, from January 2015 to January 2017. The children diagnosed as Wilson disease were enrolled for the recording of resting ECG. The ECG changes were seen and discussed with an experienced pediatric cardiologist who was involved and explained about the objectives of study. RESULTS: Total 55 patients were enrolled but record of ECG was missing for 4 patients and excluded from the study. Out of 51 patients 22 had at least one ECG abnormality. Most frequent findings seen were T wave abnormality in 18 patients (35.2%) followed by sinus tachycardia and sinus bradycardia in 12 and 8 patients respectively. Other abnormalities included bifid P waves, ST segment changes each of 2 patients, and one premature ventricular contraction. QRS details including axis, complex, amplitude ratio and QT interval was normal in all the patients. There was no mortality during the study period due to cardiac cause. CONCLUSIONS: ECG abnormalities are not uncommon in pediatric WD but of mild nature. These are presumably related to underlying cardiomyopathy due to deposition of copper in heart which can be quantified by cardiac magnetic resonance imaging (MRI) and echocardiography is required to confirm ECG abnormalities detected. PMID- 29504324 TI - Whipple Resection: Concordance Between Frozen Section And Permanent Section Diagnosis Of Surgical Margins. AB - BACKGROUND: Margin assessment is done in Whipple procedures which are usually performed to resect tumours of head of pancreas and ampullary/periampullary region. Aims and objective of the study are to determine the concordance between frozen sections (FS) and permanent sections (PS) of surgical margins in Whipple resections. METHODS: It is a retrospective study, from January 2008 to January 2015 (07 years). It includes the specimen with malignancy in final report and for which FS of pancreatic and/or CBD margin(s) were requested. Data was retrieved from Laboratory information system (LIS) database. RESULTS: Of the 41 bile duct margins in cases of ampullary tumours, 03 were positive on FS as well as PS, 35 were negative on FS as well as on PS. Results showed 100% sensitivity, 92.1% specificity, 50% PPV and 100% NPV. Results of 36 pancreatic margins in cases of ampullary showed 100% sensitivity, 97.1% specificity, 50% PPV and 100% NPV. In pancreatic carcinoma cases, none of CBD margins were reported as positive on FS, 02 margins reported as negative were found positive on PS, while 17 were negative on FS as well as PS. Results showed 100% specificity and 89.5% NPV. Of the 27 pancreatic margins tested in pancreatic tumours 100% sensitivity, 94.1% specificity, 88.9% PPV and 100% NPV was found. CONCLUSIONS: Factors such as absent prior tissue diagnosis and/or inflammatory processes make margin diagnosis difficult. However, a high concordance was observed between our FS and PS diagnosis. PMID- 29504326 TI - Evaluation Of Micro Leakage Of Root Canals Filled With Different Obturation Techniques: An In Vitro Study. AB - BACKGROUND: Despite a plethora of studies done comparing different obturation techniques using gutta-percha, there is no consensus as to which obturation technique results in a 'better' sealing of root canal space. Aims of the study are to compare mean apical micro leakage in root canals of extracted teeth obturated with cold laterally compacted gutta-percha and thermoplasticised injectable gutta-percha using calcium hydroxide based sealer. METHODS: It was an in-vitro experimental study carried out using extracted teeth. After access cavity preparation and canal preparation in 70 teeth, they were randomly divided into 2 groups and filled with two different obturation techniques using Sealapex sealer. Teeth were placed in 2.0% methylene blue solution, sectioned longitudinally, observed under microscope and images were captured using microscope attached camera. Amount of dye penetration was measured in millimetre from apex to most coronal part of dye penetration. Data was analysed using SPSS 20.0. Mean and standard deviation of continuous variables was computed. Independent Sample t- test was applied to compare micro leakage values in the two study groups. Level of significance was kept at 0.05. RESULTS: According to the measurements, obturation with Obtura-II and Sealapex was leakier than the other group, with a mean dye penetration of 1.91+/-1.15 mm. There was a statistically significant difference in dye penetration among the two groups.. CONCLUSIONS: Cold lateral compaction plus Sealapex was the best combination for obturation as it exhibited least microleakage. Obtura IISealapex combination should be used with caution as it showed maximum microleakage. For obturation of single rooted teeth, we recommend cold lateral condensation with Sealapex sealer as it showed better sealability. Obtura-II and Sealapex should be used with caution in single rooted teeth as this group showed the maximum leakage.. PMID- 29504325 TI - Comparison Of Biliary Stenting And Surgical Bypass In Palliative Management Of Irresectable Periampullary Carcinoma. AB - BACKGROUND: Some 20-40% of the periampullary carcinoma is irresectable at the time of diagnosis. Biliary stenting and surgical bypass are commonly used palliative procedure. There is no consensus favouring one procedure over the other. This study compares the both procedures. METHODS: This Randomized Controlled Trial included 47 patients who presented with diagnosis of obstructive jaundice due to periampullary carcinoma to the Department of Surgery, Federal General Hospital, Islamabad from July 2012 to December 2014. RESULTS: Out of total 47 patients 27 (57.44%) were males and 20 (42.55%) were females. Group-A included 25 (53.19%) patients while group-B included 22 (46.81%) patients. The mean age in both groups was 62.34 years (SD=+/-5.01). All patients died during the study. The mean survival time for the stent patients was 7.5 months while the mean survival time for surgical bypass patients was 8.3 months. The jaundice was relived in all surgical (22, 100%) of the patients as compared to (18, 72%) of the patients in stent group. CONCLUSIONS: We concluded that surgical bypass as a primary procedure in selected patients provided better jaundice relieve as compared to biliary stenting.. PMID- 29504327 TI - Dengue Knowledge In Indoor Dengue Patients From Low Socioeconomic Class; Aetiology, Symptoms, Mode Of Transmission And Prevention. AB - BACKGROUND: Dengue fever has emerged as an emerging public health issue during last decade bearing significant morbidity and economic burden particularly in third world countries. Current study aims to assess various domains of knowledge of indoor dengue patients.. METHODS: This descriptive crosssectional study was conducted at Medicine dept. Rawal Institute of Health Sciences Islamabad and BBH Rawalpindi over 6 months. One hundred & twenty-five adult indoor confirmed cases of dengue from lower socioeconomic class were included after ethical approval. The 25-item dengue knowledge questionnaire including aetiology, symptoms, modes of transmission and prevention of dengue was filled. RESULTS: Among 125 cases (77% males and 23% females), mean age was 30+/-13 years. Mean knowledge score was 11+/-5 points; with excellent knowledge in 6%, good knowledge (22%), moderate knowledge (23%), fair knowledge (34%) and poor knowledge (17%). Mosquito being a vector of dengue was identified by 78%, with peak time in afternoon (48%). Symptoms identified include fever (95%), headache (55%), muscle pain (44%), rash (33%), retro-orbital pain (32%), joint pains (28%) and abdominal pain (18%). Flies and ticks aren't the vectors of dengue according to 61% and 74% respectively, special mosquito is vector (54%), i.e., Aedes aegypti (18%) that breeds in standing water (53%). Preventive measures identified were netting (56%), insecticide sprays (54%), covering water containers (38%), removing standing water (36%), mosquito repellents (17%), cutting down bushes (22%) and pouring chemicals in standing water (18%). CONCLUSIONS: Our patients from lower socioeconomic class, though aware of vector and mode of transmission, have insufficient knowledge of prevention and vector control measures. There is need to strengthen dengue awareness through community-based programs, social media, schools and health care centres for high risk people well before the expected epidemic season about mode of transmission, vector control, screening and early approach to health care facility. PMID- 29504328 TI - Use Of Steroids In Rhinoplasty With Lateral Osteotomies For Reducing Post Operative Oedema. AB - BACKGROUND: TPostoperative periorbital oedema is a commonly encountered side effect of rhinoplasties in which lateral osteotomies have been incorporated. It dissatisfies the surgeon as well as the patient. Osteotomies are done at the end of all soft tissue manipulation to reduce the development of oedema. The aim of this study was to determine the efficacy of intravenous dexamethasone in reducing oedema in patients who undergo rhinoplasty with lateral osteotomies. METHODS: A Prospective randomized controlled trial was done at department of plastic and reconstructive surgery, Shifa International Hospital Islamabad. Sixty patients age between 16-55 requiring open rhinoplasty were taken for this study and divided in two groups. One group received dexamethasone 8mg intravenously preoperatively and second dose 4 hours postoperatively. The second group did not receive anything. Both groups were assessed on first post-operative day and 7th day for periorbital oedema. RESULTS: The overall decrease in oedema in patients who received steroid was by 50% while in control group was 33.3%. By the 7th day control group 13.3% patients had grade III oedema as compared to 3.33% in steroid group. Chi test was applied and p-value of 0.0289 was obtained which was found to be statistically very significant. CONCLUSIONS: Dexamethasone used in minimal dosage showed significant advantage in reducing periorbital oedema after rhinoplasty with no evidence of any side effects secondary to steroid administration. PMID- 29504329 TI - Outcome Of Trans Rectal Ultrasound Guided Twelve Core Biopsy Of Prostate For The Detection Of Prostate Cancer- A Single Centre Experience. AB - BACKGROUND: This study was conducted to determine the outcome of trans-rectal ultrasound (TRUS) guided biopsy of prostate for the detection of prostatic carcinoma in a single tertiary care hospital in Pakistan. METHODS: This is a retrospective study including three hundred and eightythree patients who underwent trans rectal ultrasound guided biopsy of prostate in a single tertiary care hospital. Indications for biopsy were raised prostate specific antigen (PSA), abnormal digital rectal examination (DRE) and/or both. Twelve core biopsy of prostate was done.. RESULTS: The overall detection rate of prostate cancer was 59%. Prostate cancer detection in various PSA ranges of 0-3.99, 4-9.99, 10-19.99 and >20 ng/ml are 22.22%, 37.88%, 50.0% and 89.9%. PSA density >0.15ng/ml2 can diagnose 74.5% of patients with cancer. Prostate cancer detection rate based on abnormal DRE is 64.6% compared to 60.8% detected by PSA>4 ng/ml. CONCLUSIONS: In conclusion raised PSA, smaller prostate volume, abnormal DRE and raised PSA density are associated with greater chances of detection of prostate carcinoma. PMID- 29504330 TI - Correlation Between Severity Of Portal Hypertensive Gastropathy And Size Of Oesophageal Varices In Cirrhotic Hepatitis-C Patients. AB - BACKGROUND: Portal hypertension can lead to oesophageal varices (EV) and portal hypertensive gastropathy (PHG). The aim of this study is to determine the relationship between severity of Portal hypertensive gastropathy and size of oesophageal varices. METHODS: One hundred and ninety-five patients of hepatitis C positive chronic liver disease having oesophageal varices were assessed for severity of portal hypertensive gastropathy. RESULTS: Mild Portal Hypertensive Gastropathy was observed in 16 (8.2 %), moderate in 54 (27.7 %) and severe in 120 (61.6 %) patients. Grade 1 Oesophageal Varices were present in 79 (40.5%) patients, grade 2 in 44 (21.9%) patients, grade 3 in 62 (31.8%) and grade 4 in 10 (5.2%) patients. No significant correlation was observed between grades of gastropathy and size of varices. CONCLUSIONS: The frequency of portal hypertensive gastropathy was 97.5% in Hepatitis C positive cirrhotic patients having oesophageal varices. Severity of gastropathy is not related to the grade or size of oesophageal varices. PMID- 29504331 TI - Neurological Recovery In Traumatic Spinal Cord Injuries After Surgical Intervention. AB - BACKGROUND: Spinal injuries are the most devastating injuries and affect every aspect of patients' lives. This may cause lifelong disability due to spinal cord injury. Recovery of neurological functions is highly desirable. Early or late surgical intervention is still debatable, but majority recommend early intervention. The result of late surgical intervention in term of neurological recovery is not clear. This study focuses on neurological recovery after late surgical intervention. The objective of this study was to assess neurological recovery in term of ASIA grading in patients with traumatic spinal cord injury. METHODS: This descriptive cross-sectional study was performed from June 2013 to June 2016. All patients treated for spinal trauma with spinal cord injury, operated after 24 hrs of injury were included in the study. Neurology was assessed according to ASIA scale preoperative and at 6 months. Data was analysed with the help of SPSS. RESULTS: Total of 149 patients, 32 (21.5%) were female and 117 (78.5%) male were included. mean age was 32+/-13.11 years. Ninety-six (64.4%) patients presented with fall while 53 (35.6%) presented with motor vehicular accidents (MVA). according to AO comprehensive classification 76 (51.1%) patients were type C, 47 (31.5) were type B and 26 (17.4%) were type A. preoperative neurology was ASIA A 65 (43.6%), B12 (8.1%), C 59 (39.6%) and D 13 (8.7%). Mean delay in surgery was 3.6+/-1.8 days with minimum of 1 and maximum 14 days. ASIA grading on 6 months was ASIA "A" 61 (40.9%), B4 (2.7%), C 26 (17.4%), D 33 (22.1%) and E 25 (16.8%). the overall improvement in neurology was in 67 (45%) of patients. improvement by one grade was documented in 49 (32.9%) patients, by two grades in 17 (11.4%) and by three grades in one patient (.7%). CONCLUSIONS: fall from height is a major cause of spine injuries in our set up followed by RTA. Preventive measures need to be instituted to lessen the devastating outcome. PMID- 29504332 TI - Gastro Oesophageal Reflux Diseases In Chronic Obstructive Pulmonary Disease Patients. AB - BACKGROUND: There is an association of Gastroesophageal reflux disease (GERD) with chronic obstructive pulmonary disease (COPD). This study was designed to determine the frequency of GERD in COPD patients. METHODS: This descriptive, cross-sectional study was conducted in the Pulmonology Unit Ayub Teaching Hospital Abbottabad. Patients more than 40 years of age of both genders presenting with features of COPD such as cough and breathlessness for more than 6 months and confirmed by spirometry were included in the study. A total of 118 consecutive patients were included in the study. Patients who had spirometry showing FEV1 <70% predicted & FEV1/FVC ratio <70% were included. Patients of asthma, with known oesophageal disease such as cancer, stricture, achalasia or active peptic ulcer disease, Pregnancy (precipitates GERD) and those patients who had used proton pump inhibitors (PPI) in the last 15 days were excluded. RESULTS: The mean age of COPD patients was 65.25 years. Among COPD patients 89 (75.4%) were males. Fifty-five (46.6%) patients had moderate COPD (FEV1:50-69%). Frequency of smokers was 68.6% with mean duration of 12.5years and mean number of cigarettes smoke per day were 13.4. Thirty-five (29.75%) had GERD; 27% in males and 30% in females. CONCLUSIONS: Our study shows that a higher proportion of gastro oesophageal reflux (GERD) symptoms are present in COPD patients and it also shows that GERD is more common in severe COPD patients. PMID- 29504333 TI - Spectrum Of Congenital Heart Disease In Full Term Neonates. AB - BACKGROUND: Congenital heart disease is a significant problem world over especially in neonates. Early diagnosis and prompt interventions in neonatal period precludes the mortality associated with this disorder. The objective of this study was to highlight the diversity of congenital cardiac defects in our region so that appropriate interventions are devised to minimize significant morbidity and mortality associated with this disorder. METHODS: This descriptive cross-sectional study was conducted at the Neonatology Unit of Department of Paediatrics, Ayub Teaching Hospital from January 2015 to December 2016. Approval of ethical committee was taken. All fullterm neonates of either gender who presented in department of neonatology including those delivered in hospital or received from other sources (private settings, home deliveries), diagnosed as having congenital heart disease on echocardiography were included in the study. Preterm neonates of either gender were excluded from the study. Patient characteristics were recorded in a designed proforma. Data was entered in SPSS version 20 and analysed. RESULTS: A total of 89 neonates were included in the study. Mean age of presentation was 6.34+/-7.058 days and range of 1-28 days. There was a male preponderance with 57 (64%) male patients as compared to 32 (36%) female patients. Ventricular septal defect (VSD) was the commonest cardiac lesion being present in 34 (38.2%) patients. Other defects included complex congenital heart disease in 8 (9%), atrial septal defect (ASD) and transposition of great arteries (TGA) in 7 (7.9%) each, atrioventricular septal defect (AVSD) in 6 (6.7%) and Fallots's tetralogy (TOF) and hypoplastic left heart syndrome in 5 (5.6%) each.. CONCLUSIONS: Congenital heart disease is a problem of profound importance. It constitutes approximately one third of the total major congenital malformations. There is a diversity of cardiac lesions in our region that warrant early and prompt interventions so that the disease is recognized and treated at the earliest to reduce morbidity and mortality. PMID- 29504334 TI - Circadian Variation In The Onset Of Acute Myocardial Infarction In Diabetics. AB - BACKGROUND: It has been shown in previous studies there is circadian variation in the onset of acute myocardial infarction. The objective of this study was to evaluate the relation of circadian variation in onset of Acute Myocardial infarction in Diabetic subjects. METHODS: This study was conducted at the Services Institute of Medical Sciences Lahore and Punjab Institute of Cardiology from January 2015 to February 2016. Hundred diabetic and 100 Non-diabetic patients with Myocardial infarction were included in the study. Among diabetics those were included in the study that had diabetes for >=5 years. The time of onset of symptoms to determine the circadian rhythm was noted. In order to determine the frequency of acute myocardial infarction associated with circadian rhythm, 24 hours of the day were divided into four equal sections of 6 hours each. We noted time of onset of acute MI. Thereafter, patients were bracketed in their respective six-hour time periods. These six-hour periods were 0-6, 6:01-12, 12:01-18, and 18:01-24 hours. RESULTS: In this study patients' mean age was 59.16+/-13.81. Forty-two (71.2%) non-diabetic patients had acute myocardial infarction (AMI) during 6:00-12:00 hours whereas 17 (28.8%) diabetic patients presented with AMI during this time. CONCLUSIONS: Incidence of AMI is significantly increased in the morning 6:01-12:00 hours in non-diabetics. However, diabetic subjects did not show significant increased incidence of AMI during this time rather there was increased incidence of AMI during 0-6:00 hours. PMID- 29504335 TI - Can The Anterolateral Thigh Flap Replace The Rectus Abdominis Free Flap In The Reconstruction Of Complex Maxillary Defects? AB - BACKGROUND: Maxilla is perhaps the most essential and visible part of the mid face. It is a threedimensional structure and when reconstructing maxillectomy defects the principles of aesthetics as well as the best functional outcomes are taken into account. The aim of this study is to compare the Anterolateral Thigh Flap (ALTF) to the standard option like the Rectus Abdominis Free Flap (RAMFF) for the reconstruction of complex maxillary defects. METHODS: This descriptive case series was conducted at the Department of Plastic and Reconstructive Surgery, Shifa International Hospital Islamabad, Pakistan from 2009 to 2016. Patients of all age groups with complex maxillectomy defects, (Type III and IV according to Cordeiro classification) resulting from tumour resection, trauma, osteoradionecrosis or infection, underwent reconstruction with the free anterolateral thigh flap and the rectus abdominis free flap. RESULTS: Over a period of 8 years, 49 Rectus Abdominis free flaps and 32 Anterolateral thigh free flaps were performed for reconstruction of Type III and IV maxillectomy defects. The follow up was weekly for 1 month and then 3 monthly for the 1st year, 6 monthly for 2nd year and then yearly. All the patients had an uneventful immediate recovery. CONCLUSIONS: ALTF has advantages over the RAMFF in terms of the donor site morbidity, operative time and postoperative recovery in the reconstruction of complex maxillectomy defects. PMID- 29504336 TI - Vitamin D Deficiency In Pakistan: Tip Of Iceberg. AB - BACKGROUND: Vitamin D deficiency is becoming a public health problem and involves every segment of the population irrespective of age and gender. This study was conducted to assess its status in patients presenting with generalized body aches and pains.. METHODS: This cross-sectional study was conducted at Ayub Teaching Hospital Abbottabad from March 2015 to October 2016. A sample of 202 patients presenting with generalized body aches and pains were enrolled for the study using convenient sampling technique. Blood samples were taken and serum vitamin D levels were measured. The data was analysed using SPSS-16. RESULTS: Out of 202 patients, 165 (81.7%) women and 37 (18.3%) men. The mean age was 42.39+/-15.89 years. The mean serum vitamin D level was 25.15+/-18.97 ng/ml with a minimum and maximum value of 9.60 ng/ml and 98.0 ng/ml respectively. Deficient serum vitamin D levels (<20 ng/ml) was found in 128 (63.4%) patients, 30 (14.9%) patients showed insufficiency (20 to 30 ng/ml) while only 44 (21.8%) had normal levels (>30 ng/ml). There was no statistically significant difference in the levels of the vitamin D deficiency with respect to gender and age groups. CONCLUSIONS: Vitamin D deficiency is affecting the Pakistani population irrespective of age and gender, and the results of this study have demonstrated that vitamin D deficiency in Pakistan is the tip of iceberg.. PMID- 29504337 TI - Red Cell Alloimmunization In Multitransfused Thalassaemia Major Patients. AB - BACKGROUND: Lifelong transfusions are life savers for thalassaemia patients but are associated with many complications. Alloimmunization is a major problem for blood banks. Antigens of foreign red blood cells induce the formation of antibodies in patients suffering from thalassaemia. The purpose of this study was to examine the frequency of red cell alloantibodies and to express the type of these antibodies in thalassaemia patients. METHODS: Patients that have received multiple transfusions were included in this study. Those with the positive Coombs test (DAT) results were excluded from the study and remaining patients were screened for antibodies. A panel of known blood group antigens was used for the patients who had a positive antibody screening test because they had alloantibodies in their serum. First, three cell panel was applied. If the screen was positive then eleven cell panels was used to identify the specific antibody. Both the cell panels were applied at room-temperature, liss (low ionic strength saline) and coombs phase. RESULTS: Three hundred & two patients were selected out of which 65.6% (n=198) were males and 34.4% (n=104) females. Patient's age ranged from 1.5 years to 26 years +/-5.40 years. All of the patients were given regular red cell transfusion at 2-4 weeks interval. They were given non leukodepleted transfusions. It is not the practice in any thalassaemia Centre in Pakistan to give phenotypically matched blood for Kell, Kidd, Duffy or any other minor group antigens to patients on regular blood transfusion. Alloimmunization was positive in 12 (4.0%) of the 302 patients studied. Male were 66.67% (n=8) and female were 33.33% (n=4). Samples of these positive patients were further tested to determine specificity of alloantibodies. Anti Cw was most common, detected in 4 out of 12 (1.3%) patients. Anti K, k, S and Lua were detected in 2 out of 12 (0.7%) each. CONCLUSIONS: Thalassemia major patients on regular blood transfusions can develop red cell alloantibodies. Detailed pretransfusion screening would add towards better management of these patients. PMID- 29504338 TI - Efficacy Of A Single-Injection Sodium Hyaluronate Treatment In Lateral Epicondylitis. AB - BACKGROUND: Lateral epicondylitis or tennis elbow is a disease of tendons arising from common extensor origin at the lateral epicondyle of elbow and is commonly characterized by pain on supination of forearms as well as extension of fingers and wrists. METHODS: This descriptive case series aims to determine the efficacy of a single-injection sodium hyaluronate treatment for lateral epicondylitis. The study was conducted at the Department of Orthopaedics. Ayub Teaching Hospital Abbottabad. From February 1 to August 31, 2014. Patients diagnosed with lateral epicondylitis were administered 1 cc of 1% Sodium hyaluronate 1 cm from the lateral epicondyle into the soft tissue. RESULTS: Hyaluronic acid is more effective in patients with moderate pain of lateral epicondylitis (VAS score <=7 than in patients with severe pain (VAS score >7). Paired sample t-test was used to compared the means of the pre- and post-procedure VAS score and the difference was found to be statistically very significant (p=0.00) with a mean+/-SD change in VAS of 2.31+/-1.35 at 4 weeks. CONCLUSIONS: A single injection of sodium hyaluronate is effective in management of moderate, but not severe pain of lateral epicondylitis. PMID- 29504339 TI - Perceptions Of Health Professional Students Regarding Waterpipe Smoking And Its Effects On Oral Health. AB - BACKGROUND: Globally approximately 100 million people are waterpipe smokers and this trend also prevails in Pakistan. It has detrimental effects on general health and oral health. The objective of the study was to determine the perception of health professional students regarding waterpipe smoking (WPS) and to assess their awareness about adverse effects of WPS on oral health. METHODS: A selfadministered questionnaire based cross-sectional study was conducted among health professional students in three medical and dental institutes of Karachi from December 2015 to February 2016. RESULTS: Study sample comprised 342 students with mean age of 21.36+/-1.609 years. About 40% of participants ever had shisha and 10% were current smokers; 237 (69.3%) claimed that waterpipe smoking had detrimental effects on oral and general health. A proportion of 33.6% of the total respondents were unaware that waterpipe smoking was the reason for stained teeth, whereas 51.5% did not know that waterpipe smoking was related to dental caries, and 52% and 48% were unaware that waterpipe smoking was the reason for bad taste and halitosis respectively. Approximately 10% of the respondents did not know that waterpipe smoking was a risk factor for the development of oral diseases and oral cancer. CONCLUSIONS: There was a scarce knowledge about the hazardous effects of waterpipe smoking on general and especially on oral health. Health professionals need to be aware of hazardous effects of waterpipe smoking so they may play a role in reducing this habit in masses. PMID- 29504340 TI - Immunohistochemical Analysis Of Breast Cancer Subtypes And Their Correlation With Ki 67 Index. AB - BACKGROUND: Breast cancer is the second most common cancer in females including Pakistan. Nowadays immunohistochemistry has revolutionized management of breast cancer. In this study, we determined the frequency of various subtypes of breast cancer on the basis of immunohistochemical staining and their correlation with ki 67 index. METHODS: Fifty consecutive diagnosed breast cancers cases received during the period February 2014 to February 2016, at Ayub Medical College, Pathology Department were included in this cross-sectional study. Immunohistochemistry for Oestrogen receptor (ER), Progesterone receptor (PgR), Her2neu and ki 67 index were applied and the results were recorded. RESULTS: Out of 50 cases, 34 (68%) were positive for ER and PgR, 6 (12%) were positive for her 2 neu while 6 (12%) were triple positive and 4 (8%) were triple negative. CONCLUSIONS: Low risk Luminal A was the most frequently encountered breast cancer category. PMID- 29504341 TI - Perspective About Mental Illnesses: A Survey Of Health Care Providers Of Abbottabad. AB - BACKGROUND: Mental Health problems are widespread globally and are the leading causes of disability. The lives of people living with mental illnesses are often drastically altered by the symptoms of the illness and made worse by the society's reaction. Stigmatizing attitude among general population is prevalent. Relatively less research has been done to explore the attitude of health care providers towards mental illness especially so in Pakistan. This study aims to investigate views of healthcare providers of Abbottabad regarding mental illnesses. METHODS: A cross-sectional study was conducted in major hospitals and medical institutes of Abbottabad wherein 640 selfadministered questionnaires based on Opening Minds Scale for Healthcare Providers (OMS-HC) were distributed among healthcare providers selected through non-probability convenience sampling; 553 (86.41%) were returned. Data was collected from June to September 2016 and analyzed using SPSS-16.0. RESULTS: The mean age of the participants is 26.12 years+/-7.612. Majority 346 (62%) were medical students, 60 (10.8%) were teachers, 50 (9%) were house officers, 70 (12.7%) were trainee medical officers, 27 (4.9%) were consultants. There were 313 (56.6%) females. The highest degree of stigma was observed among the 'Attitudes' of the people while it was relatively lower in Disclosure and Help Seeking domain and least in the factor of Social Distance. CONCLUSIONS: Stigma associated with mental illness is prevalent among healthcare providers.. PMID- 29504342 TI - Measure Of Frequency Of Alveolar Osteitis Using Two Different Methods Of Osteotomy In Mandibular Third Molar Impactions: A Double-Blind Randomized Clinical Trial. AB - BACKGROUND: Dento-alveolar surgical procedures involving third molar teeth are the most common surgical procedure in the field of surgery. The objective of this research was to analyse the impact of surgery on the incidence of alveolar osteitis after surgical removal of mandibular third molar and to compare two different bone cutting methods following impacted mandibular third molar surgery.. METHODS: This double blinded randomized clinical trial was executed at the OPD of Department of Oral and Maxillofacial Surgery, Dow University of Health Sciences, Karachi. The study duration was four months. It was conducted on 60 patients needing unilateral mandibular third molar impaction removal. Patients were randomized to two groups (i.e., physio dispenser group and slow speed handpiece group) before surgery. The surgical procedure was performed under local anaesthesia by using standardized cross infection protocol. The frequency of alveolar osteitis was evaluated on thirdday postoperatively. Alveolar osteitis was diagnosed and confirmed by patient's history and clinical evaluation. Post operative sequelae were observed and recorded objectively. RESULTS: Out of 60 patients', five patients experienced alveolar osteitis, and the incidence rate was 8.3%. A significant pvalue of 0.000 was calculated using binomial test for comparison of alveolar osteitis among both groups. Inter-examiner reliability was assessed by kappa and good (62%) agreement, which was found among the examiners, who diagnosed alveolar osteitis clinically. Post-operative sequelae were insignificant in slow speed hand piece group. CONCLUSIONS: It was observed that alveolar osteitis was reported in physio-dispenser group; similarly, post operative complications were also more in this group as compared with slow speed hand piece group. No surgical complications were observed in slow speed-hand piece group suggesting slow speed hand piece mode of osteotomy to be safer for third molar extraction as compared with physio-dispenser. PMID- 29504343 TI - Factors Associated With Knowledge, Perception, And Practice Toward Self-Care Among Elderly Patients Suffering From Type 2 Diabetes Mellitus In Rural Thailand. AB - BACKGROUND: Globally, diabetes caused 4.6 million deaths during 2011 and burdened health care systems worldwide with $465 billion. The diabetes prevalence rate in Thailand has risen dramatically in recent years, from just 2.3% in 1991 to 6.9% in 2009. The objective of this study was to explore factors associated with knowledge, perception, and practice toward self-care among elderly type 2 diabetes mellitus patients aged 50-70 years. METHODS: A cross sectional study design was conducted by enrolling 140 aged people of both gender suffering from type 2 diabetes mellitus and registered at three clinics of Primary healthcare at Taladnoi, Horathep, and Khokyai, Saraburi, Thailand. Participants whose age was 50-70 were rechecked through laboratory testing like Hba1c, FBS, and BMI were included. Data was analysed by using descriptive statistics and chi-square. RESULTS: The participants mean age was 62.11+/-0.59 years and 69.4% were female, 27.8% belonged to indigenous caste and 82.6% were married. About one-fourth of the participants were housewives, 15.2% government employee and 12.1% were farmer. Participants suffering from diabetes since1-5 years were 48.5%. Among the diabetic patients, 51.5% reported to have family history of diabetes. The mean knowledge score of the respondents was 3.61 (+/-1.80), perception was 4.34 (+/ 1.41), practice was 12.14 (+/-4.47). A significant different existed between gender with Hba1c (<0.05), knowledge, and work status with Hba1c (<0.05).. CONCLUSIONS: Study concluded that the knowledge, perception, and practice about type 2 diabetes mellitus among patient were significantly poor. However, the factors like; gender, work and practice were found significantly correlated with glycated haemoglobin. PMID- 29504344 TI - Do We Need To Give Measles Vaccine To Children Earlier Than The Currently Recommended Age? AB - BACKGROUND: Measles is a leading cause of death among children. No specific drug has yet been discovered to treat measles but an available vaccine can effectively prevent the infection. In Pakistan children are vaccinated against measles by two doses given at age of nine months onward. The last few years have witnessed an increasing number of measles cases at age lower than nine months. METHODS: Secondary data analysis of the records of Expanded Program on Immunization from all districts of Sindh was performed from January-April 2016. Data included all patients of any age or gender, fulfilling the World Health Organization case definition of measles, along with positive IgM antibodies for measles in their blood. Data was analysed using windows SPSS version 21.0. RESULTS: Analysis of 658 confirmed measles cases showed an age range of 3 months to 336 months with a mean of 32.82. Most patients (41.4%) belonged to age group 10-24months. Some noteworthy18% of cases were <=9 months old including 1.8% patients who were <=6 months age. An unexpected 76 (11.6%) were >60 months of age. 50.6% of the cases were male while 49.4% were female. Most of the patients (73.9%) belonged to urban areas. CONCLUSIONS: We conclude that a sizeable number of children are infected by measles before reaching the age of first recommended inoculation against measles. It is affecting people at both extremes of life ranging from as young as three months up to 28 years of age. PMID- 29504345 TI - Role Of Bedside Ultrasound In Detection Of Bone Fractures In Pediatrics And Adults. AB - During medical devices evolution many modalities and techniques like Computerized tomography, magnetic resonance imaging, wireless capsule endoscopy and double balloon endoscopy were applied to provide enough evidences for final detection of diseases. As well as current procedures, sonography is a method that individuals are satisfied with it because of various conditions like non-invasive and cheap. Ultrasound is one of the procedures which can be used in diagnosis of fractures and has its own unique feature including different views at the same time with no radiation effects. It can show bones and plays an important role in initiation of disease, follow up of the patients. The aim of this investigation was to evaluate the Role of bedside ultrasound findings in patients with fractures. We concluded that ultrasound should be used as well as other methods to reach better outcomes. PMID- 29504346 TI - Myxedema Coma. AB - Myxedema may be the first presentation of patients with undiagnosed hypothyroidism. Definitive management is with thyroid hormone but supportive measures, identification and treatment of precipitating factors in an appropriately safe environment are vital. There is no consensus about preferred thyroid hormone regimen. Corticosteroid therapy is given until adrenal insufficiency has been excluded. We present here a case of seventy-four years old woman of myxodema coma. PMID- 29504348 TI - Ectopic Enterobius Vermicularis Infestation; An Extremely Rare Cause Of Mesenteric Lymphadenopathy Mimicking Tuberculous Lymphadenitis. AB - Enterobius vermicularis (EV) is a pinworm which commonly resides in the lumen of the intestinal tract and lays eggs on the perianal skin. However, rarely the worm can infest various other sites in the body and cases with infestation of such ectopic sites have been reported in literature. Rare cases of mesenteric lymph node involvement have also been reported. We report a case in a young male who presented with signs and symptoms of acute appendicitis. During surgery, enlarged mesenteric lymph nodes were identified. Histological examination revealed adult worm in the appendiceal lumen. Histological examination of mesenteric lymph node revealed degenerated worm surrounded by caseating chronic granulomatous inflammation. We conclude that EV infestation should be considered in the differential diagnosis of enlarged mesenteric lymph node with chronic granulomatous inflammation, especially in young patients and when accompanying bowel tissue also reveal the helminth. PMID- 29504347 TI - Case Of Iatrogenic Cushing's Syndrome By Topical Triamcinolone. AB - Cushing's syndrome is a collection of signs and symptoms due to hypercortisolism. Prolong use of topical steroid may cause this syndrome and suppression of hypothalamic and pituitary function, however such events are more common with oral and parenteral route. There are very few cases of Cushing's syndrome with a topical application amongst which triamcinolone is the rarest drug. We report a case of 11-year-old boy is presented who developed Cushing's disease by topical application. The child had body rashes for which the caregiver consulted a local quack, a topical cream of triamcinolone was prescribed. After application for three months, the patient became obese and developed a moon-like face. A thorough biochemical workup and diagnostic test for Cushing's disease was done to confirm. The following case report a dramatic example of development of the syndrome from chronic topical application of the least potent corticosteroid. PMID- 29504349 TI - Choledochal Cyst And Biliary Stone. AB - Choledochal cyst is not an uncommonly seen entity in children. Presentation may be varied and at different age groups. Abnormal pancreaticobiliary junction is usually a phenomenon in acquired type of choledochal cyst. A four years old child presented with symptoms of acute viral hepatitis A but persistence of symptoms beyond the usual time necessitated other conditions to be considered. Choledochal cyst was the final diagnosis complicating with biliary stone which was managed by surgical excision. PMID- 29504350 TI - Accidental Ingestion Of Toothbrush: An Unusual Foreign Body. AB - Toothbrush is a rare foreign body to be ingested accidentally. The unusual shape of the toothbrush with no theoretical possibility of spontaneous passage mandates an interventional approach. If left untreated, it can lead to pressure necrosis, bleeding, perforation and ulceration. An endoscopic attempt in an expert clinic if available is the ideal approach. If failed, surgical management by laparoscope or mini laparotomy should be done. The evaluation for underlying psychiatric disorders like bulimia, schizophrenia or generalized eating disorder should be considered to prevent such recurrence. Here, we present a case of 55 years of age, male living a normal life with no known comorbid, who ingested accidentally a toothbrush two weeks prior to presentation and was managed at our surgical department after a failed endoscopic attempt. PMID- 29504351 TI - Could It Be Schistosomiasis? AB - Schistosomiasis may cause diverse symptoms and it is usually not considered as a cause of disease especially in patients with normal immune system. We are reporting an eleven-year-old child who was initially diagnosed as a case of lymphoma but later on proved to be a case of acute schistosomiasis. PMID- 29504352 TI - Sprengel's Deformity. AB - Various shoulder bone deformities have been identified in the pediatric age group, with the most common being undescended scapula. Sprengel's deformity is dysplasia and malposition of the scapula, especially in the supraspinatus portion, mainly due to abnormal descent in the embryonic period. The clavicle is shorter and has a different contour. In some patients cervical spine deformities are also noted. This is a case of 3 years old girl presented to the clinic with difficulty in abducting right shoulder and sleeping with an internal rotation of the right arm. With physical examinations and radiological investigations sprengel's deformity was diagnosed. Sprengel's deformity is a male predominant disease which almost never occurs in isolation and is usually associated with deformities in the thoracic rib cage and the cervical and thoracic vertebrae. Our patient also had hyperpigmentation along the lines of Blaschko, which has never been previously reported with Sprengel's deformity. Sprengel's may have an association with cutaneous mosacism syndrome. PMID- 29504353 TI - A Case Of Thrombosis Due To Paroxysmal Nocturnal Haemoglobinuria Presenting At An Early Age. AB - Paroxysmal Nocturnal Haemoglobinuria (PNH) is an acquired, rare life-threatening disorder characterised by compliment mediated hemolytic anemia, thrombosis and impaired bone marrow function. It occasionally presents in childhood or adolescence. This is a case of a 14-year old female presented with complaints of shortness of breath, palpitation and abdominal pain whose laboratory test results were consistent with Coomb's test negative haemolytic anaemia. Contrast enhanced Computed Tomography Scan (CT scan) of abdomen revealed splanchnic circulation thrombosis as well as partially occluding thrombus in the inferior vena cava. Flow cytometry showed loss of CD59 expression on erythrocytes confirming the diagnosis of paroxysmal nocturnal hemogloubinuria. Supportive treatment was given with haematinics, blood transfusions and anticoagulants. After that, hematopoietic stem cell transplantation was conducted successfully as a permanent treatment. PNH can present at an earlier age and therefore should be included in differential diagnosis of haemolytic anaemia. PMID- 29504354 TI - Outcome Of Traumatic Brain Injury In Children By Using Rotterdam Score On Computed Tomography. AB - BACKGROUND: The Rotterdam Score (RS) on CT head is a new evolving clinical tool as a predictor of mortality in Traumatic Brain Injury (TBI). The objective of this study is to assess the outcome of children with TBI admitted in paediatric intensive care unit (PICU) of a tertiary-care, university hospital by using RS. METHODS: This was a prospective observational study conducted on children (age: 1mo -16yr) with TBI admitted in PICU of Aga Khan University Hospital from 2013 to 2016. RS on CT was calculated by a radiologist. All patients were managed according to according to Paediatric Brain Trauma Foundation Guidelines 2012.Demographic data, clinical variables and outcomes were recorded. Logistic regression analysis was applied to assess the association between outcome and R.. RESULTS: Ninety-two cases were enrolled during four years. The median age was 77 months (3 months to 16 years) and 73 (79%) were male. The main cause of injury was RTA (60.9%) followed by fall (39.1%). Sixty-two patients (67%) had a post resuscitation GCS of 8 or less. 54% (51) patients were managed conservatively. The RS of 1, 2, 3, 4 and 5 were present in 19, 36,19,15 and 3 patients. The mean RS was 2.4. The higher mortality rate was observed in high RS. The RS was significantly associated with mortality (OR 1.75, 95% CI 1.03-2.95; p<0.04). CONCLUSIONS: Rotterdam Score on CT head can be used to predict mortality in paediatric patients with TBI. PMID- 29504355 TI - Profile Of 'Original Articles' Published In 2016 By The Journal Of Ayub Medical College, Pakistan. AB - Journal of Ayub Medical College (JAMC) is the only Medline indexed biomedical journal of Pakistan that is edited and published by a medical college. Assessing the trends of study designs employed, statistical methods used, and statistical analysis software used in the articles of medical journals help understand the sophistication of research published. The objectives of this descriptive study were to assess all original articles published by JAMC in the year 2016. JAMC published 147 original articles in the year 2016. The most commonly used study design was crosssectional studies, with 64 (43.5%) articles reporting its use. Statistical tests involving bivariate analysis were most common and reported by 73 (49.6%) articles. Use of SPSS software was reported by 109 (74.1%) of articles. Most 138 (93.9%) of the original articles published were based on studies conducted in Pakistan. The number and sophistication of analysis reported in JAMC increased from year 2014 to 2016. PMID- 29504356 TI - Lymphangioma Of Tongue. PMID- 29504357 TI - The Apathetic Gut. PMID- 29504358 TI - Haematopoiesis: ?living in the shadow? of stem cell differentiation. AB - Haematopoiesis is one of the most well understood stem-cell associated processes. It is a process in which pluripotent hematopoietic stem cells (HSCs) self proliferate and differentiate into all types of blood cells. The process takes place in marrow of the flat bones in adults, however its location changes several times through embryonic and foetal development. Given the broad range of blood cells and the major differences in their build and function, together with the fact that their numbers need to be maintained within relatively narrow margins in order to maintain homeostasis despite changing environmental conditions, makes the whole process of haematopoiesis highly regulated and depending on a variety of growth factors. When influenced by those, HSCs undergo several irreversible steps, with every next one committing them to an even more specialised fate, ending with all the specific types of mostly short-lived blood cells, that are unable to proliferate on their own and need constant replenishment from the HSC pool. Because the process of haematopoiesis is the only source of all the members of the group of cells performing a range of highly important roles in functioning of the organism, significant damage to the underlying stem cells can cause a range of severe diseases. Many treatments are suggested for managing their symptoms or slowing progress, with bone marrow transplant being one of the only ones that offer possible permanent solution and, despite being a relatively risky procedure, is being widely performed, with the methods constantly improving in order to achieve progressively better results in both treatability and survivability of the patients. PMID- 29504359 TI - Crohn?s disease and extra intestinal granulomatous lesions. AB - Crohn?s disease (CD) is an inflammatory bowel disease with a multifactorial etiology. Clinical features include mucosal erosion, diarrhea, weight loss and other complications such as formation of granuloma. In CD, granuloma is a non neoplastic epithelioid lesion, formed by a compact aggregate of histiocytes with the absence of a central necrosis, however, the correlation among CD and the formation of granulomas is unknown. Many cases of granulomas in the extracellular site, related to CD, have been reported in the literature. These granulomas, at times, represented the only visible manifestation of the pathology. Extra intestinal granulomas have been found on ovaries, lungs, male genitalia, female genitalia, orofacial regions and skin. From the data in the literature it could be hypothesized that there is a cross-reaction of the immune system with similar antigenic epitopes belonging to different sites. This hypothesis, if checked, can place CD not only among inflammatory bowel disease but also among inflammatory diseases with systemic involvement. PMID- 29504360 TI - Different signals induce mast cell inflammatory activity: inhibitory effect of Vitamin E. AB - Vitamin supplementation in disease reduces morbidity and mortality in humans by promoting the activation of different genes which influence several pathways. The purpose of this article is to clarify the role of vitamin E in mast cell inflammation. Vitamin E is a fat soluble antioxidant which protects from low density lipoprotein (LDL) oxidation. Vitamin E promotes a barrier function and anti-inflammatory responses by binding the regulatory domain of protein kinase Calpha (pkcalpha) (a regulator and antagonist of heart failure) and decreases the activation of NF-?b, a proinflammatory transcription factor, causing the generation of cytokines/chemokines and mast cell activation. Mast cells participate in innate and acquired immunity and inflammation. Several factors, including cytokines and chemokines, regulate the development and migration of activated mast cells. Mast cells generate and release inflammatory compounds in asthma and allergic diseases and have a detrimental effect on the vessel wall, which can be inhibited by vitamin E. Vitamin E inhibits histamine release generated in activated mast cells, increases calcium Ca2+ uptake and prevents the oxidation of unsaturated fatty acids. Vitamin E is relatively non-toxic, however, administered at very high doses may suppress normal hematological response as well as causing other adverse effects. Therefore, vitamin E may be beneficial in the prevention of diseases mediated by mast cells and can have special value in the treatment of asthma and allergic diseases; however, the exact mechanism by which vitamin E acts is still unclear, thus warranting future research. PMID- 29504361 TI - Relationship between methylation status of RASSF2A gene promoter and endometriosis-associated ovarian cancer. AB - Relationship between the methylation status of the RASSF2A gene promoter and endometriosis-associated ovarian cancer (EAOC) was explored. Between January 2013 and January 2016, tissue samples were collected from 30 patients diagnosed with ovarian endometriosis cyst (EC group), 30 patients diagnosed with ovarian endometrial adenocarcinoma (OEA group) and 30 patients diagnosed with ovarian clear cell carcinoma (OCC group). Additionally, 30 cases of normal endometrium tissues were collected for the control group. The methylation status of the RASSF2A promoter was evaluated by combined bisulfite restriction enzyme analysis (COBRA). RT-PCR was used to detect the expression level of RASSF2A mRNA in tissues. Relationship between methylation status and RASSF2A mRNA expression level and the patient age, tumor clinical stage, tumor grading and pathological type were analyzed. Results showed that in the OEA and OCC groups, the methylation degrees of the RASSF2A promoter were obviously higher than that of the other two groups. The expression level of RASSF2A mRNA in the OEA and OCC groups was lower than that of the other two groups. The methylation degree of the RASSF2A promoter was related to clinical staging and grading. No relationship between the methylation degree of the RASSF2A promoter and patient?s age and the pathological type of the tissue was detected. We concluded that the methylation status of the RASSF2A gene promoter could be considered an excellent indicator for early detection of ovarian cancers. PMID- 29504362 TI - Immunomodulatory effects of T helper 17 cells and regulatory T cells on cerebral ischemia. AB - The aim of the present study was to analyze the relationship between cerebral ischemia and immune effects. A total of 70 Kunming mice were randomly divided into two groups: a model group (60 mice) and a sham group (10 mice). The model group was divided into six subgroups (10 mice per group) which were categorized according to the following time periods of treatment: 6 h, 12 h, 24 h, 48 h, 72 h and 5 days. The temporary middle cerebral artery occlusion (tMCAO) mouse model was established using intracavitary suture. The degree of brain injury was evaluated by detecting the neurological deficit score (NDS). Following cerebral ischemia reperfusion, the edema of the brain tissue was aggravated, and the infarction area was increased. At 48 h, the volume of the cerebral infarction reached a peak (44.4+/-3.2%) and then it decreased. The NDS score gradually decreased, and the nerve function was gradually restored. At 6 h, the NDS score was 4.6+/-0.55, whereas at the 5 d time point, it was significantly decreased (P less than 0.05) to 2.2+/-0.45. Flow cytometry analysis indicated that the percentage of Th17 cells increased gradually following ischemia. At 24 h, the percentage of Th17 cells reached its maximum value (0.70+/-0.10%) compared with the sham and the 5 d groups (P less than 0.05). At 24 h, the percentage of Th17 cells reached the lowest value (0.9+/-0.29%), whereas at the 5 d time point it increased significantly (3.2+/-0.49%) compared with the normal level (P less than 0.05). The secretion of Th17 and Treg-associated cytokines was consistent with the number of Th17 and Treg cells following ischemia. However, the levels of IL 17A in the brain tissues and the serum indicated a tendency to increase following the prolongation of ischemia. This marker reached the maximum levels on day 5. The IL-17 brain level was 77.9+/-5.11pg/ml, whereas the serum level was 29.44+/ 3.06pg/ml. The changes in the secretion of the Th17 and Treg-related inflammatory cytokines were consistent with the changes in the cell ratio of Th17 and Treg cells. A significant correlation was noted between the two groups and the degree of ischemic brain injury. The results suggested that the functional status of Th17/Treg cells was imbalanced following cerebral ischemia. PMID- 29504363 TI - Follow-up of patients with systemic immunological diseases undergoing fatty degenerative osteolysis of the jawbone surgery and treated with RANTES 27CH. AB - Regulated-on-activation, normal T cell expressed and secreted (also called RANTES, CCL5 or R/C) is a chemotactic cytokine that plays a key role in recruiting immune cells to inflammatory sites. R/C is involved in the pathogenesis of many systemic immune-mediated diseases (SIDs) and is upregulated in fatty-degenerative osteolysis jawbone (FDOJ) cavitations. Surgical cleaning of degenerative areas reduces the source of chronic R/C but might not be sufficient to re-establish the altered immunological patterns. The aim of the present study was to collect clinical data from patients suffering from sids who underwent dental surgery of FDOJ areas (n=46), by measuring R/C serum levels at the first visit (V0) prior to surgery, and at the second visit (V1). The majority of patients (n=41) were treated one month with ultra-low dose RANTES (27CH), a medicine used in micro-immunotherapy, while five patients were not. Mean and standard deviation of R/C serum levels at V0 in treated and untreated patients were respectively 48.5+/-25.8ng/ml and 42.48+/-22.22ng/ ml. Untreated patients had a tendency towards higher R/C levels at V1 (68.36+/-30.7ng/ml; p=0.062), while an opposite tendency was observed in treated patients (40.9+/-20.3ng/ml; p=0.129). Investigators observed that a cut-off set at 40ng/ml at V0 seemed to be predictive of the efficacy of the dental surgery/treatment (p=0.0013, n=26) and that gender could influence R/C levels and patient's responsiveness. The Authors, being aware that this is a preliminary follow-up, wanted to lay the basis for forthcoming studies, in which a larger cohort of patients and well-defined inclusion/exclusion criteria will be established. PMID- 29504364 TI - Protective effects of Nano-elemental selenium against chromium-vi-induced oxidative stress in broiler liver. AB - The valuable role of selenium in mitigation of oxidative stress and heavy metal toxicity is well-known. Thus, the aim of the current study on broiler chickens was to examine whether nano elemental selenium (Nano-Se) supplementation can reduce the effects of chromium VI (K2Cr2O7) toxicity. For this purpose, a total of 150, one-day-old broiler chickens were allotted to five groups with three replicates: control group (standard diet), poisoned group (K2Cr2O7 via drinking water), protection group (K2Cr2O7 + Nano- Se), cure group (K2Cr2O7 for initial 2 weeks and then Nano-Se), and prevention group (opposite to the cure group). The broilers were detected by the activities of marker enzymes and oxidative stress markers including, aspartate aminotransferase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (GGT) and superoxide dismutase (SOD), glutathione peroxidase (GSH-px), malondialdehyde (MDA), respectively. The (K2Cr2O7 administration caused histopathological damage in the liver of the chickens. Moreover, changes in serum biochemical indicators and oxidative stress parameters were also observed. Nano-Se supplementation increased the levels of GSH-px but reduced the activities of SOD, MDA, GGT, ALT and AST in the experimental groups (P less than 0.05). Our results showed that Nano-Se plays a protective role by preventing the oxidative stress induced by the chromium VI in broiler chickens. PMID- 29504365 TI - Layering Poly (lactic-co-glycolic acid)-based electrospun membranes and co culture cell sheets for engineering temporomandibular joint disc. AB - The temporomandibular joint disk (TMJD) lacks blood vessels and is characterized by slow self-repair. Qualitative lesions in TMJD are difficult to repair. In this study, electrospun poly (lactic-co-glycolic acid) (PLGA) scaffolds were used to reconstruct temporomandibular joint discs by tissue engineering. Rabbit temporomandibular joint disc cells (TMJDCs) and rabbit synovium-derived mesenchymal stem cells (SMSCs) were co-cultured in 1:1 ratios. Cell sheets were induced by ascorbic acid incubated with electrospun PLGA scaffolds for 14 days in the presence (10 ng/ml in culture medium) or absence of TGF-beta3. Dimethylmethylene Blue Assay (DMMB) was used to determine the content of glycosaminoglycans in the extracellular matrix. The expression of Col1a1, Col2a1, Sox-9 and Runx-2 was quantified by RT-PCR, and the expression of type II collagen was observed by immunofluorescent staining. After 14 days of cultivation, the electrospun PLGA scaffold-loaded cell sheets could form an articular disc tissue with certain morphological characteristics. The expression of chondrogenic related genes (Col2a1, Sox-9) and the secretion of extracellular matrix (GAG, type II collagen) in the co-culture group were close to those in the TMJDC group alone. The results suggest that PLGA electrospun scaffold-loaded co-cultured cell membrane could be used in the tissue engineering reconstruction of the temporomandibular joint disc. PMID- 29504366 TI - The relationship between IGF-2, IGFBP-2, and IGFBP-3 levels in patients suffering from pre-diabetes. AB - Many studies have shown that intervention in the early stages of diabetes may have a pivotal role in reducing the risk of cardiovascular diseases. This study was designed to assess possible relationships between insulin-like growth factor 2 (IGF-2), insulin-like growth factor binding proteins 2 and 3 (IGFBP-2, IGFBP-3) and pre-diabetes. A total of sixty clinically ascertained pre-diabetes cases and twenty-five healthy controls were included. Serum IGF-2 and binding proteins were estimated using commercially available ELISA kit. All groups had a positive correlation between all serum parameters. Multinomial logistic regression showed that all the study parameters directly affected each other. The results could not prove any correlation between IGF-2 and its binding proteins during pre-diabetes stage. Further assessments of these factors in larger groups of males and females in diabetic individuals could be useful to support our hypothesis that these factors change only in diabetes mellitus. PMID- 29504367 TI - The role of osteopontin and its receptor in meningioma development and progression. AB - Meningiomas are common in intracranial tumors, the majority of which are benign with slow growth and low recurrence rate. The aim of the present study was to assess the role of osteopontin and its receptor CD44 (Cluster of differentiation 44) in meningioma development and progression. A total of 2 groups were included, namely an experimental group with 54 meningioma patients and a control group with 30 patients with internal and external decompression. The disease group included subjects, from whom meningioma tissue specimens were collected during surgery for tumor excision, whereas the control group included subjects who were subjected to scalp laceration and provided normal meninx tissues. The expression of osteopontin and CD44 was determined by immunohistochemistry. Osteopontin expression was negative in normal meninx, and its expression was increased in meningioma tissues (P less than 0.05). The positive expression of osteopontin increased according to the histological grade of meningioma (r=0.417, P less than 0.001). A highly significant difference was noted between non-invasive and invasive meningiomas (P less than 0.001). The positive expression of CD44 correlated with the grade of meningioma and its invasiveness (P less than 0.05), although it exhibited no correlation with the degree of peritumoral edema (r=0.033, P>0.05). The increased expressions of osteopontin and CD44 were observed in all grades of meningioma, and correlated with its development (r=0.961, P less than 0.001). Osteopontin and CD44 play important roles in the development and progression of meningioma and can be used as prognostic markers for tumor recurrence and progression as well as therapeutic targets for the development of new drugs. PMID- 29504368 TI - The implication of diabetes metabolomics in the early diagnosis and pathogenesis of pancreatic cancer. AB - The aim of this study was to analyze metabolite differences in pancreatic cancer and diabetic patients, to better diagnose these diseases. Gas chromatography-mass spectrometry was used to evaluate the metabolomic differences in blood samples of 50 pancreatic patients, 50 diabetic patients and 50 healthy people. Metabonomic data was analyzed with primary component analysis and discriminant analysis. The results show that pancreatic cancer patients, diabetic patients and healthy people can have significantly distinct metabolite profiles. Upregulated metabolites in the serum of the diabetic group included sugars (glucose, fructose), cholesterol, tyrosine and phosphoric acid and other substances, and down-regulation was observed in lactic acid, glycine, alanine, glutamine, proline, citric acid and other substances. It is indicated that identification of the most common changes in specific markers between the two diseases, can provide a new perspective and experimental basis for a better understanding of the metabolic differences and the pathogenesis of the two diseases in future. The present study sheds new light on the diagnosis of pancreatic cancer and diabetes. PMID- 29504369 TI - House dust mite sublingual-swallow immunotherapy in perennial rhinitis: a double blind, placebo-controlled Iranian study. AB - Sensitivity to house dust mite allergens in the development of allergic rhinitis has a key role. In this study, the clinical and immunological effects of high dose Dermatophagoides farinae sublingual immunotherapy (SLIT) versus placebo were compared. Forty poly-sensitized patients, ages 6-33 years, with allergic rhinitis and positive allergic reaction to the mites were enrolled in the study. Twenty one patients were placed in the SLIT group and 19 in the placebo group. Expression levels of IL-10, TGF-beta, FOXP3 and IL-17 were measured by using real time PCR before and after the administration of sublingual immunotherapy. Clinical efficacy was estimated by the reduction rate of symptom/medication scores in the SLIT group compared with placebo treatment. After 6 months of SLIT, TGF-beta expression levels were increased compared to pre-treatment (P less than 0.05). SLIT with D. Farinae extract is an effective treatment for poly-sensitized patients with allergic rhinitis. TGF-beta mediated T-cell suppression may be an important mechanism in the first 6 months of SLIT. PMID- 29504370 TI - FK228 recovers thiram-induced tibial dyschondroplasia in chicken via hypoxia inducible factor-1alpha. AB - Tibial dyschondroplasia (TD) is a disease of many avian species characterized by an enlarged and avascular lesion in the proximal tibiotarsal bone. The aim of present study was to evaluate the effects of hypoxia-inducible factor-1alpha(HIF 1alpha) inhibition on thiram- induced TD using synthetic medicine FK228 and the association between HIF-1alpha and heat-shock protein 90 (Hsp90). One hundred and fifty broiler chicks were equally divided into 3 groups: control; thiram fed; and FK228 treatment. Expressions of HIF-1alpha and Hsp90 genes were analyzed by real time quantitative polymerase chain reaction (RT-qPCR) on day 10 and 14 post hatch. Western blot analysis of HIF-1alpha and Hsp90 gene was performed to measure the protein levels at the end of the experiment. Results showed that HIF 1alpha and Hsp90 levels were significantly (P less than 0.05) up-regulated in the thiram group as compared to the control group. Meanwhile, FK228 (HIF-1alpha inhibitor) significantly (P less than 0.05) down- regulated the mRNA and protein levels of HIF-1alpha and Hsp90, restored the size of growth plate and diminished lameness. In conclusion, HIF-1alpha and Hsp90 play an important role in the formation of avascular growth plate and there is a direct relationship between HIF-1alpha and Hsp90 for the progression of TD pathogenesis. Therefore, HIF- 1alpha may prevent and control TD in broiler chickens. PMID- 29504371 TI - Eyes in pituitary disorders. AB - The eye is a vital sense organ related to vision, conveying the underlying physical and mental state of well-being of an individual. Eye signs are often associated with endocrinal disorders such as exophthalmos in thyro-toxicosis. However, a thorough eye evaluation may lead to the identification of the early features that help in the diagnosis of various endocrine disorders. This is of vital importance especially in the central nervous system lesions. This is observed more in cases of pituitary mass lesions, which often present with functional hormonal alterations rather than visual symptoms. The definitive therapy has to be provided before it reaches the late stage of the disease which might lead to permanent visual disabilities. Hence, ophthalmologists, endocrinologists, neuro-radiologists and neurosurgeons need to intervene with combined efforts. In this review, we highlight the eye signs in pituitary disorders, along with a brief description of uncommon ocular-pituitary syndromes. PMID- 29504372 TI - In-vitro antibacterial and antioxidant potential of winged prickly ash, green tea and thyme. AB - Herbs and plants are mostly used as antimicrobials and antioxidants owing to the harmfulness and linked side-effects of synthetic chemical constituents. Plants and spices produce various metabolites with antibacterial and antioxidant potential. These metabolites are principally revealed as encouraging healing components or mediators which control ailments in human beings. The present study was aimed to characterize the extracts from selected medicinal plants through in vitro activities. Winged prickly ash, green tea and thyme were selected and extracted through ethanol and methanol solutions. The extracts were assessed for antibacterial and antioxidant activities. The antibacterial potential of extracts showed the significant extent of the activity against Bacillus subtilis and E. coli. The maximum activity was noted in 80% methanolic fraction of Thymus vulgaris (15.20+/-0.64 mm) against Bacillus subtilis. Antioxidant potential exhibited the highest phenolic and flavonoid content in Camellia sinensis . The total phenolic content was significantly higher (1456.26+/-12.05 mg gallic acid) in 80% ethanolic fraction of Camellia sinensis. The flavonoid content in different plant extracts ranged from 8.17+/-2.02 to 376.29+/-7.11 mg/g. The radical scavenging DPPH assay also showed the significant antioxidant capacity of selected plants with the methanolic (50%) extract of Camellia sinensis found to be the most potent (78.95+/-7.12%). It was concluded that the alcoholic extracts of selected medicinal plants revealed the effective antibacterial and antioxidant activity, showing protective prospective against oxidative injury. PMID- 29504373 TI - An insight into nutritional profile of selected Pleurotus species. AB - The global demand for good quality food indicates that consumers are more concerned about a particular diet associated with good health and lower risk for certain ailments. Mushrooms are widely used as healthy nutritious food. In the present study, the nutritional composition of four different Pleurotus sp. was determined. Prior to extraction, all the selected mushrooms were subjected for proximate composition analysis. The protein, fat, ash, total carbohydrate, fiber and energy contents were in the range of (16.07- 25.15%), (0.64-2.02%), (2.1 9.14%), (65.66-82.47%), (6.21-54.12%) and (342.20-394.30Kcal/100g), respectively. The spectrophotometric analysis showed that the concentration of protein was in the range of 45.78-33.47 mg/g in all Pleurotus sp. High performance liquid chromatographic analysis of sugars showed six different mono and disaccharides in all the selected mushrooms. The fatty acid profile by gas chromatography-mass spectrometry revealed that the main fatty acids in selected mushrooms were present in the order linoliec acid> oleic acid> palmitic acid. The results suggested that all the Pleurotus sp. could be considered as a rich source of nutrients. PMID- 29504374 TI - A versatile method for gene dosage quantification: multiplex PCR and single base extension for copy number and gene-conversion identification of SMN genes. AB - A comparison of the individual genomes within a species demonstrates that structural variation, including copy number variation (CNV), is a major contributor to phenotypic diversity and evolutionary adaptation. CNVs lead to the under/over-expression of a gene, according to the changes in the gene dosage, which account for the development of a number of genomic disorders. Thus, the development of efficient, rapid and accurate CNV screening is of fundamental importance. We report a method that enables the simultaneous determination of the copy numbers of several different targets as well as the discrimination among highly similar/almost identical targets that differ by only one single nucleotide variant, which establishes their copy numbers. The PCR co-amplification and single-base extension technologies are used to identify the copy number of a target sequence relative to a reference sequence of known genomic copy number in a given sample. This efficient and accurate quantification platform was successfully used to quantify the copy numbers of the primary spinal muscular atrophy-determining gene, SMN1, and the disease modifier gene, SMN2. The reliability, low-cost and potential for high-throughput make our method suitable for screening large populations as well as for use as a tool in clinical settings for genetic diagnosis/prognosis. PMID- 29504375 TI - Transvaginal color doppler sonography combined with colposcopy for diagnosis of early stage cervical cancer and precancerous lesions. AB - This study aims to assess the value of transvaginal color Doppler sonography (TVCD) combined with colposcopy for diagnosis of early stage cervical cancer and precancerous lesions. From January 2015 to September 2016, one hundred patients, diagnosed as having early stage cervical cancer and precancerous lesions by histopathological study, were selected as the observation subjects. All patients were examined by TVCD and colposcopy, and the results were compared with histopathological findings. The diagnostic accuracy, sensitivity and specificity of TVCD alone, colposcopy alone, and TVCD combined with colposcopy in early stage of cervical cancer and precancerous lesion were compared. The sensitivity, specificity and accuracy of TVCD combined with colposcopy were significantly higher than that of TVCD (P < 0.05), and the sensitivity was significantly higher than that of colposcopy (P < 0.05). The high sensitivity, specificity and accuracy of TVCD combined with colposcopy on the diagnosis of invasive cervical carcinoma (ICC) and cervical intraepithelial neoplasia (CIN) can provide a scientific basis for its use in clinical diagnosis. PMID- 29504376 TI - Analysis of quality nursing of postoperative incision infection in urological patients. AB - To study the effect of quality nursing on postoperative incision infection in urological patients, 200 subjects admitted to our hospital between June 2016 and June 2017 were included in this study and divided into a quality nursing group (group A) and a general nursing group (group B), 100 in each group. Blood loss, blood transfusion, hospital stay, incision healing, incision infection, and self rating depression scale (SDS) scores in both groups were compared. It was found that the bleeding volume in group A was significantly less than that in group B, and there was significant difference between the two groups (P less than 0.05) while the difference in blood transfusion rate and hospital stay between the two groups was not significant (P> 0.05); the number of patients of level 1 healing in group A was larger than that of group B while the number of patients of level 2 and level 3 healing was smaller than that of group B, with significant differences (P less than 0.05); the number of infection cases in group A was significantly lower than that in group B, and the difference was significant (P less than 0.05); the SDS score of group A was lower than that of group B, with significant differences (P less than 0.05). Therefore, quality nursing had a certain effect on the infection of postoperative incision of urological patients, which had positive significance for incision healing. Reducing the effect of bacterial infections in operated patients is important for rapid healing and patient health. Using a long-lasting antibacterial can protect the patient and reduce the incidence of other infections. PMID- 29504377 TI - Effect of polydatin on expression of p53 and Notch1 in brain tissue of ischemic cerebrovascular disease. AB - Secondary injury of brain tissue following cerebral infarction exhibits a complicated pathogenesis that is attributed to the induction of apoptosis and inflammatory response. The present study aimed to investigate the polydatin neuroprotective effects and their mode of action in cerebral ischemic injury. A total of 80 healthy adult male Sprague-Dawley rats were randomly divided into a Sham operated group, a permanent middle cerebral artery occlusion (MCAO) group, a Polydatin low dose group and a Polydatin high dose group. A total of 20 rats were used in each group. The right MCAO model of rats was established using the modified Longa suture method. The animals in the intervention group were injected intraperitoneally with 12.5mg/kg and/or 50mg/kg of polydatin following infarction. The expression levels of p53 and Notch 1 were measured by immunohistochemical techniques. The degree of left limb hemiplegia in the MCAO group was different compared with that of the low and high dose group of polydatin. The score for the neurological function in the high-dose group of polydatin was lower than that in the MCAO group (High vs MCAO: 2.4+/-0.31 vs 3.9+/-0.23, P less than0.05). The results indicated that high dose polydatin could reduce brain edema following cerebral infarction and improve the behavioral score in rats. PMID- 29504378 TI - Effect of dexmedetomidine on stress reactions and cellular immune function of patients in perioperative period following radial resection for rectal carcinoma. AB - The study aimed to assess the effects and the further mechanism of action of dexmedetomidine with regard to stress reactions and cellular immune function of patients during the perioperative period following radical resection for rectal carcinoma. A total of 36 patients with rectal carcinoma were selected for radical resection under general anesthesia. The patients were divided into two groups, namely an experimental and a control group. In the experimental group (dexmedetomidine group) 1 MUg/ kg/bw dexmedetomidine was injected intravenously 10 min prior to the induction of general anesthesia, and then infusion was carried out at a rate of 0.2 MUg.kg-1.h-1 for 30 min prior to the end of surgery. With regard to the control group, the same amount of normal saline (NS) was infused with the same method as the experimental group. Controlled intravenous analgesia was conducted following surgery to all of the patients. Regarding the effect of dexmedetomidine on the reaction of stress, a decrease of VAS scores was noted in the experimental group following extubation compared with the control group (P less than 0.05). Furthermore, a significant decrease in the consumption of morphine in the first 24 h was observed that was accompanied by a decrease of plasma cortisol levels at 6 and 24 h following surgery compared with the control group. The levels of IFN-gamma/IL-10 in the experimental group were lower than those of the control group (P less than 0.05). The percentages of CD8+ and CD4+/CD8+ cells in the experimental group were increased compared with those of the control group (P less than 0.05). By infusing dexmedetomidine continuously, stress reactions during the perioperative period were significantly decreased, whereas the analgesic effects of opioid were increased. PMID- 29504379 TI - Methylmercury-l-Cysteine targeting L-type amino acid transporter conjugate cytotoxicity on C6 glioma cells. AB - Glioma is the most common primary tumor in the brain, accounting for about 40~50% of intracranial primary tumors. Most chemotherapeutic drugs have difficulty in penetrating the blood-brain barrier, and their clinical applications are greatly limited. We evaluated the effects of methylmercury-L-cysteine (MeHg-L-cys) and methylmercury chloride (MMC) on apoptosis of C6 glioma cells. L-type amino acid transporter (LAT1) was used to investigate the targeted transport function and cytotoxicity of MeHg- L-cys in glioma. MeHg-L-cys enhanced the ability of targeting glioma cells and reduced the adverse reactions to normal brain tissues. Therefore, it is significantly important to develop new anti-glioma drugs targeting the blood-brain barrier. PMID- 29504380 TI - Perioperative nursing intervention on patients undergoing laparoscopic gastric stromal tumor resection. AB - This study aimed to investigate the effectiveness of perioperative nursing intervention on patients undergoing laparoscopic gastric stromal tumor resection. Sixty patients with gastric stromal tumor were selected from our hospital and evenly divided into group A and group B. Patients in both groups underwent laparoscopic resection. Patients in group A were given conventional nursing intervention before and after surgery, while those in group B were given comprehensive nursing intervention. Various indicators were compared between the two groups. The amount of bleeding of group B was less than that of group A, and the first anal exsufflation of group B was also earlier than that of group A; the differences had statistical significance (p less than 0.05). Patients in group B felt less pain than patients in group A; except for 72 h after surgery, difference of pain degree between group A and B had statistical significance in other periods (p less than 0.05); the number of cases with complications and categories of complications of group B were less than those of group A, and the difference had statistical significance (p less than 0.05). The efficacy satisfaction of group B was also higher than that of group A, and the difference was statistically significant (p less than 0.05). Perioperative nursing intervention is beneficial and positive and has bright development prospects. PMID- 29504381 TI - The role of subcutaneous adipose tissue in psoriasis. AB - It is widely accepted that obesity is a systemic comorbidity factor in psoriasis. At the same time, there is rapidly growing evidence that the adipose tissue is not only systemically but also locally involved in the pathophysiology of psoriasis and in response to successful anti-psoriatic treatment. PMID- 29504382 TI - Malnutrition is prevalent in patients with cardiorenal syndrome and negatively influences clinical outcome. AB - Cardiorenal syndrome (CRS) describes the concurrent failure of cardiac and renal function, each influencing the other. Malnutrition and cachexia frequently develop in patients with heart failure or kidney failure. However, no information is currently available on the prevalence of malnutrition in CRS patients. We studied CRS patients admitted to an internal medicine ward during a 5-month period and evaluated their clinical characteristics and nutritional status. Malnutrition risk was assessed by using the validated screening tool NRS-2002 whilst body composition was assessed by bioimpedance analysis and muscle function was measured by handgrip (HG) strength. Cardiac mass was also recorded. Length of stay, hospital readmission and 6-month mortality were registered. During the study period, 22 CRS patients were studied. Twenty patients were diagnosed with either CRS type 1 or CRS type 5. In CRS patients, fat-free mass showed a trend toward representing a protective factor for 6-month mortality (OR=0.904; p=0.06). Also, fat-free mass correlated with HG strength and cardiac ejection fraction. Malnutrition risk was diagnosed in 45% of the patients, whereas 8 patients met the definition of cachexia. Even without statistical significance, CRS patients with malnutrition had lower BMI (Body Mass Index) (p=0.038) and fat-free mass (p= n.s.). However, CRS malnutrition was associated to higher 6-month mortality (p= 0.05), and appears to negatively influence the outcome in CRS (OR= 9; p= 0.06). Our results show that malnutrition is prevalent in CRS patients and influences the clinical outcome. The assessment of nutritional status, and particularly body composition, should be implemented in daily practice of patients with CRS. PMID- 29504383 TI - Omalizumab a new prospective: a nasal polyposis. AB - Omalizumab, a monoclonal antibody against IgE, may be effective on nasal polyps, but its use is not currently authorized to treat that disease. We report the cases of three patients who were given omalizumab for asthma after undergoing nasal surgical polypectomy. Although such procedure is frequently followed by polyp recurrence, none of the three patients developed this complication, and in one subject the regression of initial polyp return was registered after starting omalizumab. Our data support the hypothesis that omalizumab may be useful to treat nasal polyposis. PMID- 29504384 TI - The role of lipofilling in reconstructions with dermal regeneration template: clinical and histological assessment. AB - Skin and soft tissue reconstruction represents one of the most debated issues of plastic surgery. The advent of regenerative medicine has shown new pathways with the use of lipofilling and dermal regeneration templates. The aim of this study was to investigate the histological and clinical modifications occurring after lipofilling in the areas previously reconstructed with Integra(r) and an autologous thin dermal-epidermal graft. Histological and immunohistochemical analysis were performed on nine patients to compare skin before and after lipofilling. Pre- and post-operative examinations (POSAS, VAS scale) were carried out as well as taking clinical photographs. The authors detected an overall clinical and histological improvement in all cases. Data obtained from POSAS and VAS scale showed a statistically significant (p less than 0.05) improvement concerning all variables investigated before surgery. The biopsies revealed qualitative modifications with hematoxylin-eosin and Masson trichrome stain. Immunohistochemistry with CD31 antibody also demonstrated quantitative changes with an increased number of vessels. The photographs enabled to compare the clinical situation before and after lipofilling with better aesthetic outcomes. Lipofilling gave good functional and aesthetic results in the areas treated with Integra(r) and autologous thin dermal-epidermal grafts. PMID- 29504385 TI - Diagnosis of a neonatal ophthalmic discharge, Ophthalmia neonatorum, in the ?molecular age?: investigation for a correct therapy. AB - An early double case of acute Ophthalmia neonatorum in 3-day-old twins is reported. Culture of eye swabs showed a wide bacterial polymorphism, in which common bacteria, such as Klebsiella pneumoniae, Streptococcus pneumoniae, Corynebacterium ulcerans and other Enterobacteriaceae, coexisted with atypical Mycoplasmataceae and Chlamydiaceae from resident cervical-vaginal maternal microbiota. The neonates were in an apparently healthy state, but showed red eyes with abundant greenish-yellow secretion, mild chemosis and lid edema. The maternal cervical-vaginal ecosystem resulted differently positive to the same common cultivable, atypical bacteria culturally and molecularly determined. This suggested a direct maternal-foetal transmission or a further foetal contamination before birth. An extended culture analysis for common bacteria to atypical ones was decisive to describe the involvement of Mycoplasmas (M. hominis and U. urealyticum) within the scenario of the Ophthalmia neonatorum in a Caucasian couple. The introduction of a routine PCR molecular analysis for Chlamydiaceae and N. gonorrhoeae allowed to establish which of these were present at birth, and contributed to determine the correct laboratory diagnosis and to define an adequate therapeutic protocol obtaining a complete resolution after one year for culture and atypical bacteria controls. This study suggests to improve the quality of laboratory diagnosis as unavoidable support to a correct clinical diagnosis and therapy, in a standardized modality both for swabbing and scraping, to check the new-born microbial programming starting in uterus, overtaking the ?cultural age? to the ?molecular age?, and to revise the WHO guidelines of ?SAFE Strategy? for trachoma eye disease, transforming it into ?SAFES Strategy? where the ?S? letter is the acronym of ?Sexual ecosystem and behavioural valuation/education?. PMID- 29504386 TI - Extracorporeal shockwave therapy on muscle tissue: the effects on healthy athletes. AB - The aim of this study is to investigate the effects of extracorporeal shock wave therapy (ESWT) on muscle rheological and functional properties in a population of young athletes. Thirty-two football and basketball players were recruited and randomized into two groups. The athletes underwent three sessions of therapy administered every five days to the thigh muscles. The treatment consisted of ESWT (electromagnetic generator, Energy Flux Density=0.03 mJ/mm2) or a placebo treatment bilaterally on the quadricep and femoral bicep muscles. Monitoring was carried out at recruitment (T0), at the end of treatment (15 days, T1) and at 30 days (T2) with myometric evaluation (measuring elasticity, stiffness and muscular tone) and electromiography exam (recording the Motor Unit Amplitude Potential values). The results showed a significant increase in the treated athletes in the elasticity (lateral vastus muscle, p=0.007), in muscular tone (femoral rectus, p=0.031) and in muscular recruitment (the lateral vastus, p<0.005; medial vastus muscle, p=0.055). These results could represent a translational interpretation of the known biological effect on connective tissue: an increase in blood flow, oxygenation, metabolic process activation and proliferative effect. The effects found may represent the justification for verifying the usefulness of using of shockwave therapy to reduce muscular fatigue and improve performance during the sport season. PMID- 29504387 TI - HIV Drug Resistance. PMID- 29504388 TI - HIV Drug Resistance. PMID- 29504389 TI - HIV Drug Resistance. PMID- 29504390 TI - Nanoscale Mobility of Aqueous Polyacrylic Acid in Dental Restorative Cements. AB - Hydrogen dynamics in a time range from hundreds of femtoseconds to nanoseconds can be directly analyzed using neutron spectroscopy, where information on the inelastic and quasi-elastic scattering, hereafter INS and QENS, can be obtained. In this study, we applied these techniques to understand how the nanoscale mobility of the aqueous solution of polyacrylic acid (PAA) used in conventional glass ionomer cements (GICs) changes under confinement. Combining the spectroscopic analysis with calorimetric results, we were able to separate distinct motions within both the liquid and the GICs. The QENS analysis revealed that the self-diffusion translational motion identified in the liquid is also visible in the GIC. However, as a result of the formation of the cement matrix and its setting, both translational diffusion and residence time differed from the PAA solution. When comparing the local diffusion obtained for the selected GIC, the only noticeable difference was observed for the slow dynamics associated with the polymer chain. Additionally, over short-term aging, progressive water binding to the polymer chain occurred in one of the investigated GICs. Finally, a considerable change in the density of the GIC without progressive water binding indicates an increased polymer cross-linking. Taken together, our results suggest that accurate and deep understanding of polymer-water binding, polymer cross linking, as well as material density changes occurring during the maturation process of GIC are necessary for the development of advanced dental restorative materials. PMID- 29504391 TI - Biomimetic Persistent Luminescent Nanoplatform for Autofluorescence-Free Metastasis Tracking and Chemophotodynamic Therapy. AB - Metastasis is the main cause of death in people with cancer. Early diagnosis and targeted therapy for metastasis is crucial for the survival of the cancer patients. However, metastasis is hard to trace for its small size, dispersed distribution and unvascularized anatomy. Here we report a biomimetic persistent luminescent nanoplatform for noninvasive high-sensitive diagnosis and 808 nm laser controlled photodynamics assisted chemotherapy of metastasis. The nanoplatform is composed of a photosensitizer functionalized persistent luminescent nanoparticle core, a doxorubicin loaded hollow silica interlayer and a cancer cell membrane shell for effective metastasis theranostic. The cancer cell membrane shell prevents drug leakage and endows the nanoplatform with targeting ability to metastasis. The reactivatable persistent luminescence of persistent luminescent nanoparticles not only enables long-term in vivo metastasis tracking, but also provides internal light source for singlet oxygen generation to kill cancer cells and further break the membrane shell for drug release. This work provides a promising strategy to develop persistent luminescence imaging guided theranostic nanoplatforms for early metastasis. PMID- 29504392 TI - Ultraspecific Multiplexed Detection of Low-Abundance Single-Nucleotide Variants by Combining a Masking Tactic with Fluorescent Nanoparticle Counting. AB - To be able to detect simultaneously multiple single-nucleotide variants (SNVs) with both ultrahigh specificity and low-abundance sensitivity is of pivotal importance for molecular diagnostics and biological research. In this contribution, we for the first time developed a multiplex SNV detection method that combines the masking tactic with fluorescent nanoparticle (FNP) counting based on the sandwich design. The method presents a rivaling performance due to its advantageous features: the masking reagent was designed to hybridize with an extremely large amount of the wild-type sequence to render the assay with high specificity; FNP counting provides a sensitive multiplexed SNV detection; the sandwich design facilitates an easy separation to make the detection free of interferences from the matrix. For single SNV target discrimination, including the 6 most frequently occurring DNA KRAS gene mutations and 2 possible RNA KRAS gene mutations as well as 11 artificial mutations, the discrimination factor ranged from 204 to 1177 with the median being 545. Among the tested 19 SNVs, abundances as low as 0.05% were successfully identified in 14 cases, and an abundance as low as 0.1% was identified for the remaining 5 cases. For multiplexed detection of SNVs in the KRAS gene, abundances as low as 0.05-0.1% were achieved for multiple SNVs occurring at the same and different codons. As low as 0.05% low-abundance detection sensitivity was also achieved for PCR amplicons of human genomic DNA extracted from cell samples. This proposed method presents the potential for ultrahigh specific multiplexed detection of SNVs with low-abundance detection capability, which may be applied to practical applications. PMID- 29504393 TI - Supercapacitor Electrodes from the in Situ Reaction between Two-Dimensional Sheets of Black Phosphorus and Graphene Oxide. AB - Two-dimensional materials show considerable promise as high surface area electrodes for energy-storage applications such as supercapacitors. A single sheet of graphene possesses a large specific surface area because of its atomically thin thickness. However, to package this area efficiently in a device, it must be confined within a finite three-dimensional volume without restacking of the sheet faces. Herein, we present a method of maintaining the high surface area through the use of a hybrid thin film in which few-layer-exfoliated black phosphorus (BP) reduces graphene oxide (GO) flakes. When the film is exposed to moisture, a redox reaction between the BP and the GO forms an interpenetrating network of reduced GO (RGO) and a liquid electrolyte of intermediate phosphorus acids H xPO y. The presence of the liquid H xPO y electrolyte in the RGO/H xPO y film stabilizes and preserves an open-channel structure enabling rapid ion diffusion, leading to an excellent charging rate capability (up to 500 mV s-1 and retaining 62.3% of initial capacitance at a large current density of 50 A g-1) when used as electrodes in supercapacitors. PMID- 29504394 TI - Unlocking the Potential of Phenacyl Protecting Groups: CO2-Based Formation and Photocatalytic Release of Caged Amines. AB - Orthogonal protection and deprotection of amines remain important tools in synthetic design as well as in chemical biology and material research applications. A robust, highly efficient, and sustainable method for the formation of phenacyl-based carbamate esters was developed using CO2 for the in situ preparation of the intermediate carbamates. Our mild and broadly applicable protocol allows for the formation of phenacyl urethanes of anilines, primary amines, including amino acids, and secondary amines in high to excellent yields. Moreover, we demonstrate the utility by a mild and convenient photocatalytic deprotection protocol using visible light. A key feature of the [Ru(bpy)3](PF6)2 catalyzed method is the use of ascorbic acid as reductive quencher in a neutral, buffered, two-phase acetonitrile/water mixture, granting fast and highly selective deprotection for all presented examples. PMID- 29504395 TI - Scalable and Automated Fabrication of Conductive Tough-Hydrogel Microfibers with Ultrastretchability, 3D Printability, and Stress Sensitivity. AB - Creating complex three-dimensional structures from soft yet durable materials enables advances in fields such as flexible electronics, regenerating tissue engineering, and soft robotics. Tough hydrogels that mimic the human skin can bear enormous mechanical loads. By employing a spider-inspired biomimetic microfluidic nozzle, we successfully achieve continuous printing of tough hydrogels into fibers, two-dimensional networks, and even three-dimensional structures without compromising their extreme mechanical properties. The resultant thin fibers demonstrate a stretch up to 21 times of their original length at a water content of 52%, and are intrinsically transparent, biocompatible, and conductive at high stretches. Moreover, the printed robust tough-hydrogel networks can sense strain that are orders of magnitude lower than stretchable conductors by percolations of conductive particles. To demonstrate their potential application, we use printed tough-hydrogel fiber networks as wearable sensors for detecting human motions. The capability to shape tough hydrogels into complex structures by scalable continuous printing opens opportunities for new areas of applications such as tissue scaffolds, large-area soft electronics, and smart textiles. PMID- 29504396 TI - Addressing Drug Resistance in Cancer with Macromolecular Chemotherapeutic Agents. AB - Drug resistance to chemotherapeutics is a recurrent issue plaguing many cancer treatment regimens. To circumvent resistance issues, we have designed a new class of macromolecules as self-contained chemotherapeutic agents. The macromolecular chemotherapeutic agents readily self-assemble into well-defined nanoparticles and show excellent activity in vitro against multiple cancer cell lines. These cationic polymers function by selectively binding and lysing cancer cell membranes. As a consequence of this mechanism, they exhibit significant potency against drug-resistant cancer cells and cancer stem cells, prevent cancer cell migration, and do not induce resistance onset following multiple treatment passages. Concurrent experiments with the small-molecule chemotherapeutic, doxorubicin, show aggressive resistance onset in cancer cells, a lack of efficacy against drug-resistant cancer cell lines, and a failure to prevent cancer cell migration. Additionally, the polymers showed anticancer efficacy in a hepatocellular carcinoma patient derived xenograft mouse model. Overall, these results demonstrate a new approach to designing anticancer therapeutics utilizing macromolecular compounds. PMID- 29504397 TI - Pharmacokinetics and Bioavailability of the Isoflavones Formononetin and Ononin and Their in Vitro Absorption in Ussing Chamber and Caco-2 Cell Models. AB - Formononetin and its glycoside ononin are bioactive isoflavones widely present in legumes. The present study investigated the pharmacokinetics, bioavailability, and in vitro absorption of formononetin and ononin. After an oral administration to rats, formononetin showed a higher systemic exposure over ononin. The oral bioavailability of formononetin and ononin were 21.8% and 7.3%, respectively. Ononin was more bioavailable than perceived, and its bioavailability reached 21.7% when its metabolite formononetin was taken into account. Both formononetin and ononin exhibited better absorption in large intestine segments than that in small intestine segments. Formononetin displayed a better permeability in all intestinal segments over ononin. Transport of formononetin across Caco-2 cell monolayer was mainly through passive diffusion, while ononin was actively pumped out by MRP2 but not P-gp. The results provide evidence for better understanding of the pharmacological actions of formononetin and ononin, which advocates more in vivo evaluations or human trials. PMID- 29504398 TI - Biomimetic Viruslike and Charge Reversible Nanoparticles to Sequentially Overcome Mucus and Epithelial Barriers for Oral Insulin Delivery. AB - Nanoparticles (NPs) for oral delivery of peptide/protein drugs are largely limited due to the coexistence of intestinal mucus and epithelial barriers. Sequentially overcoming these two barriers is intractable for a single nanovehicle due to the requirements of different or even contradictory surface properties of NPs. To solve this dilemma, a mucus-penetrating virus-inspired biomimetic NP with charge reversal ability (P-R8-Pho NPs) was developed by densely coating poly(lactic- co-glycolic acid) NPs with cationic octa-arginine (R8) peptide and specific anionic phosphoserine (Pho). The small size (81.81 nm) and viruslike neutral charged surface (-2.39 mV) of the biomimetic NPs achieved rapid mucus penetration, which was almost equal to that of the conventional PEGylated mucus-penetrating nanoparticles. The hydrolysis of surface-anchored anionic Pho was achieved by intestinal alkaline phosphatase, which led to the turnover of zeta potential to positive (+7.37 mV). This timely charge reversal behavior also exposed cationic R8 peptide and induced efficient cell-penetrating peptide (CPP)-mediated cellular uptake and transepithelial transport on Caco 2/E12 cocultured cell model. What's more, P-R8-Pho NPs showed excellent stability in simulated gastrointestinal conditions and enhanced absorption in intestine in vivo. Finally, oral administration of insulin-loaded P-R8-Pho NPs enabled to induce a preferable hypoglycemic effect and a 1.9-fold higher oral bioavailability was achieved compared with single CPP-modified P-R8 NPs on diabetic rats. The combinative application of biomimetic mucus-penetrating strategy and enzyme-responsive charge reversal strategy in a single nanovehicle could sequentially overcome mucus and epithelial barriers, thus showing great potential for the oral peptide/protein delivery. PMID- 29504399 TI - Direct Observation of Activated Kinetics and Downhill Dynamics in DNA Dehybridization. AB - We have studied two model DNA oligonucleotide sequences that display contrasting degrees of heterogeneous melting using an optical temperature jump to trigger dehybridization and a nonlinear infrared (IR) spectroscopy probe to track the response of the helix ensemble. This approach offers base-sensitive structural insight through the unique vibrational fingerprint characteristic of each nucleobase as well as time resolution capable of following unfolding across nanoseconds to milliseconds. We observe predissociation unzipping of the helical termini, loss of final dimer contacts, and rehybridization of the dissociated strands all in a single measurement. Complete dissociation of the dimer is found to be well described by Arrhenius kinetics for both sequences, with dissociation barriers in the range of 160-190 kJ/mol. A sequence with terminal adenine-thymine (AT) base pairs and a guanine-cytosine core returns a large-amplitude fast response ranging from 70 to 170 ns, originating only from the AT base pairs. Variable temperature jump ( T-jump) experiments in which the final temperature ( Tf) is fixed and the initial temperature ( Ti) is varied such that different starting ensembles all evolve on the same final free-energy surface were employed to explore the features of the underlying potential that dictates hybridization. These experiments reveal that the unzipping of the AT termini is an essentially barrierless process and that both activated and downhill events are necessary to describe the dehybridization mechanism. Although our results are largely consistent with the classic nucleation-zipper picture, new insights regarding the nature of base pair zippering refine the mechanistic details of the fastest DNA hybridization dynamics. PMID- 29504400 TI - Recycling Spent Cr Adsorbents as Catalyst for Eliminating Methylmercaptan. AB - Waste adsorbents generated from treating Cr(VI)-containing wastewater are hazardous materials and generally landfilled or treated by acid or base desorption, with concomitant high cost and toxic effects. The present work shows that these Cr adsorbents can be reused as highly efficient catalysts for treating sulfur-containing VOCs (CH3SH), not only avoiding the economic and environmental impact from the conventional approaches, but also achieving the efficient treatment of sulfur-containing waste gas. Importantly, these reused Cr adsorbents exhibit enhanced activity and stability compared with the catalysts reported elsewhere, indicating a new avenue of green chemistry. The highly toxic adsorbed Cr(VI) species are reduced to a Cr2O3 crystalline phase by calcination and finally immobilized as a Cr2S3 solid phase while converting and eliminating CH3SH. Still, the presence of Cr(VI) species on the reused Cr adsorbent provides enough reactive sites for reaction, but high concentration of Cr(VI) species causes serious accumulation of coke deposit on the catalyst, leading to fast deactivation of the catalyst. PMID- 29504401 TI - Pd(II)-Catalyzed Denitrogenative and Desulfinative Addition of Arylsulfonyl Hydrazides with Nitriles. AB - A Pd(II)-catalyzed denitrogenative and desulfinative addition of arylsulfonyl hydrazides with nitriles has been successfully achieved under mild conditions. This transformation is a new method for the addition reaction to nitriles with arylsulfonyl hydrazides as arylating agent, thus providing an alternative synthesis of aryl ketones. The reported addition reaction is tolerant to many common functional groups, and works well in the presence of electron-donating and electron-withdrawing substituents. Notably, the reported denitrogenative and desulfinative addition was also appropriate for alkyl nitriles, making this newly developed transformation attractive. PMID- 29504402 TI - The Structural Revision and Total Synthesis of Carambolaflavone A. AB - The synthesis of both enantiomers of carambolaflavone A, the antidiabetic and flavonoid C-glycoside, was achieved for the first time via a 12-longest-linear step with 16% (l-fucose) and 11% (d-fucose) overall yields. Through the synthetic investigation, the adverse effect of 4A MS in Suzuki C-glycosylation was disclosed, the mechanism of hydrogen-bonded-phenol involved Suzuki C glycosylation was clarified, and the authentic structure of carambolaflavone A was also determined. PMID- 29504404 TI - Role of Hole Trap Sites in MoS2 for Inconsistency in Optical and Electrical Phenomena. AB - Because of strong Coulomb interaction in two-dimensional van der Waals-layered materials, the trap charges at the interface strongly influence the scattering of the majority carriers and thus often degrade their electrical properties. However, the photogenerated minority carriers can be trapped at the interface, modulate the electron-hole recombination, and eventually influence the optical properties. In this study, we report the role of the hole trap sites on the inconsistency in the electrical and optical phenomena between two systems with different interfacial trap densities, which are monolayer MoS2-based field-effect transistors (FETs) on hexagonal boron nitride (h-BN) and SiO2 substrates. Electronic transport measurements indicate that the use of h-BN as a gate insulator can induce a higher n-doping concentration of the monolayer MoS2 by suppressing the free-electron transfer from the intrinsically n-doped MoS2 to the SiO2 gate insulator. Nevertheless, optical measurements show that the electron concentration in MoS2/SiO2 is heavier than that in MoS2/h-BN, manifested by the relative red shift of the A1g Raman peak. The inconsistency in the evaluation of the electron concentration in MoS2 by electrical and optical measurements is explained by the trapping of the photogenerated holes in the spatially modulated valence band edge of the monolayer MoS2 caused by the local strain from the SiO2/Si substrate. This photoinduced electron doping in MoS2/SiO2 is further confirmed by the development of the trion component in the power-dependent photoluminescence spectra and negative shift of the threshold voltage of the FET after illumination. PMID- 29504403 TI - Synthesis of Nitroolefins and Nitroarenes under Mild Conditions. AB - 1,3-Disulfonic acid imidazolium nitrate {[Dsim]NO3} was prepared and characterized as a new ionic liquid and nitrating agent for the ipso-nitration of various arylboronic acids and nitro-Hunsdiecker reaction of different alpha,beta unsaturated acids and benzoic acid derivatives, by in situ generation of NO2 to give various nitroarenes and nitroolefins without using any cocatalysts and solvents under mild conditions. PMID- 29504405 TI - Optimised care of elderly patients with acute coronary syndrome. PMID- 29504407 TI - Scripted-IMPROV: Interactive Improvisational Drama With Persons With Dementia Effects on Engagement, Affect, Depression, and Quality of Life. AB - Scripted-IMPROV (SI) is a nonpharmacological (ecopsychosocial) intervention that consists of semi-improvised drama performances specifically designed for persons with dementia (PWD). In this 12-site study, 178 PWD took part in the SI intervention. Levels of engagement/affect were assessed at baseline and again during SI performances; quality of life (via the Dementia Quality of Life scale) and depression (via the Geriatric Depression Scale-Short Form [GDS-SF]) were assessed at baseline and post-treatment. Positive forms of engagement/affect increased, while negative forms of engagement decreased. Regarding depression, for a subsample of 29 participants who scored in the depressed range on the GDS SF at baseline, depressive symptoms were reduced at post-treatment. Although overall quality of life did not change, the increase in positive affect during SI suggests that quality of life was higher during the intervention itself. In conclusion, SI possesses the characteristics of a high-quality intervention for PWD and seems worthy of further investigation in future research. PMID- 29504408 TI - Aging With Down Syndrome: The Dual Diagnosis: Alzheimer's Disease and Down Syndrome. AB - BACKGROUND: People with Down syndrome (DS) enjoy a longer life expectancy now than they ever have before and are therefore at greater risk of developing conditions associated with aging, including dementia. OBJECTIVES: To explore the phenomenon of dementia in DS. METHODS: Medline and Google Scholar searches were conducted for relevant articles, chapters, and books published until 2017. Search terms included Alzheimer's disease, cognitive impairment, dementia, DS, and trisomy 21. Publications found through this indexed search were reviewed for further references. RESULTS AND CONCLUSIONS: Virtually, all subject aged 35 to 40 show key neuropathologic changes characteristic of Alzheimer's disease, but only a part of them show clinical signs of dementia, usually around the age of 50 years. Early signs of dementia in people with DS may be different from those experienced by the general population. Failure to recognize this can delay diagnosis and subsequent interventions. PMID- 29504409 TI - Monocyte to High-Density Lipoprotein Ratio Predicts Contrast-Induced Nephropathy in Patients With Acute Coronary Syndrome. AB - Contrast-induced nephropathy (CIN) is associated with worse prognosis in patients with acute coronary syndrome (ACS). Early identification and intervention for patients with a high risk of CIN are very important to improve clinical outcomes. Inflammation plays important role in the development of CIN in the setting of ACS. The monocyte to high-density lipoprotein ratio (MHR) is a novel inflammatory marker. Bleeding is also associated with worse prognosis in such patients. We aimed to investigate whether the preprocedural MHR had a predictive role for CIN development in such patients. In addition, using the thrombolysis in myocardial infarction classification, we aimed to assess whether there was any relationship between bleeding and CIN. A total of 647 patients (496 males; age: 63.3 +/- 12.7 years) with ACS who underwent percutaneous coronary intervention (PCI) were included in the study. Seventy patients (10.8%) had developed CIN. Age, diabetes mellitus, contrast volume, estimated glomerular filtration rate, and MHR were independent predictors for CIN. Preprocedural MHR may be used as a simple marker of CIN. It may help with the early identification of patients with ACS who underwent PCI who are at high risk of CIN thus allowing the planning of protective measures. PMID- 29504410 TI - Prevention of Radial Artery Occlusions Following Coronary Procedures: Forward and Backward Steps in Improving Radial Artery Patency Rates. AB - Radial artery (RA) occlusion (RAO) remains the Achilles heel of transradial coronary procedures. Although of silent nature, RAO is relatively frequent, results in graft shortage for future coronary artery bypass surgery, and may occur even after short-lasting, 5F coronary angiography (CAG). The most frequent predictors of RAO are RA size, body size, female gender, and periprocedural anticoagulation intensity. Methods to detect RAO are variable, of which the Barbeau test and ultrasonography have similar diagnostic accuracy. Data indicate that late RAO recanalization may occur. Meticulous handling of RA and the use of appropriate hemostatic devices and techniques along with sufficient heparin dose appear important measures to reduce RAO rates. Recent contradictory studies indicate that the decreasing incidence of RAO overtime is not as uniform as previously thought. In 2 meta-analyses, the benefit of higher over lower anticoagulation intensity became evident. As "it may all be appropriate anticoagulation" for a simplified approach against RAO, the results of an ongoing trial comparing 100 with 50 IU/kg body weight in transradial CAG are eagerly awaited. PMID- 29504411 TI - Inducible nitric oxide synthase as a target for osteoarthritis treatment. AB - INTRODUCTION: Inducible nitric oxide synthase (iNOS) is the enzyme responsible for the production of nitric oxide (NO), a major proinflammatory and destructive mediator in osteoarthritis (OA). Areas covered: This is a comprehensive review of the recent literature on the involvement of iNOS in osteoarthritis and its potential to be used as a target for OA treatment. Evidence from in vitro, in vivo and human studies was systematically collected using medical search engines. Preclinical studies have focused on the effect of direct and indirect iNOS inhibitors in both animal and human tissues. Apart from direct inhibitors, common pharmacological agents, herbal and dietary medicines as well as hyperbaric oxygen, low level laser and low intensity pulsed ultrasound have been shown to exhibit a chondroprotective effect by inhibiting the expression of iNOS. Expert opinion: Data support the further investigation of iNOS inhibitors for the treatment of OA in human studies and clinical trials. Indirect iNOS inhibitors such as interleukin 1 inhibitors also need to be studied in greater detail. Finally, human studies need to be conducted on the herbal and dietary medicines and on the non-invasive, non-pharmacological treatments. PMID- 29504412 TI - Extreme variability in succinylcholine dose for muscle relaxation in electroconvulsive therapy. AB - OBJECTIVES: To determine what dose of succinylcholine falls outside the range of 2 SD above or below the mean optimal dose of 0.9 mg/kg used for electroconvulsive therapy (ECT). METHODS: In this retrospective chart review, for all patients who received ECT at our institution within the 5-year study period, the initial dose of succinylcholine in milligrams per kilogram was compared with subsequent doses after adjustments were made for individual patient responses. Mean and SD were calculated using the dose of succinylcholine, once the optimal dose for each patient had been determined, based on clinical response. RESULTS: Five hundred patients treated during the 5-year period met inclusion criteria, 180 (36%) of whom required an adjustment of the succinylcholine dosing either above (119 patients) or below (61 patients) the 0.9 mg/kg standard after their first treatment. CONCLUSIONS: In those patients who required an adjustment of 2 SD either above or below the mean dose of succinylcholine (29 patients, 5.8%), adequate neuromuscular blockade was only achieved with either an increased dose of up to 2.10 mg/kg or a decreased dose as low as 0.29 mg/kg. PMID- 29504413 TI - Data spanning three decades illustrate racial disparities in likelihood of obesity. AB - Obesity rates have risen significantly in recent decades, with underprivileged Americans associated with higher rates of the condition. Risks associated with obesity, furthermore, appear unequally distributed across different racial/ethnic groups, according to the literature. The present study examined racial disparities in obesity as a function of socioeconomic factors, using a sample of American adults from a 32-year longitudinal study. We accounted for the time factor as we evaluated obesity's associations with selected socioeconomic factors; we also examined race/ethnicity's moderating role in obesity socioeconomic status associations over time. We used data from the National Longitudinal Survey of Youth (NLSY) to obtain a final sample of 118,749 person waves for analysis. A subsample of person-waves numbering 65,702 represented data from White respondents; one numbering 31,618 represented data from Black respondents; and one numbering 21,429 represented data from Hispanic respondents. Needing to consider repeated measures of the same variables over time, we chose generalized estimated equations (GEE) for use in the data analysis. Speaking generally, the obtained results suggested that for the two smaller subsamples, minority race/ethnicity could have introduced disadvantages that helped explain links between obesity and race/ethnicity. Results also showed that White-Black disparities in obesity have widened slightly in the past three decades, while White-Hispanic disparities have stabilized during the same time period. PMID- 29504414 TI - Irish School Entry Screening referral trends and cohort comparison with preschool specialist referrals. AB - OBJECTIVE: To analyse referral cohorts from School Entry Screening, Hearing (SHS) and Vision Screening (SVS) before and after documented changes. To compare referrals to pre-school specialists with subsequent group SHS outcomes. DESIGN: Randomized cohort, audit analysis of Community Nursing Developmental and SES records (CHRs), plus Audiology file review for SHS referrals. STUDY SAMPLE: Six hundred and sixty-eight mainstream pupils' CHRs were analysed in four birth cohorts, post-SES, using coded anonymized records. RESULTS: Significant referral rate differences existed between SHS and SVS. SHS, not SVS, referrals were impacted by nursing staff changes but not by SHS protocol changes. Preschool Audiology referrals outnumbered SHS referrals. All PCHI children with amplification were detected prior to SHS. SHS program yielded conductive hearing loss only. Similar SHS referral rates occurred for pre-school Speech Language Therapy referrals compared to children not referred; just 16% of pre-school Speech Language Therapy primary referrals were referred on to Audiology. CONCLUSIONS: SHS referral percentage fell slightly; SVS referral percentage remained unchanged. Low referral rates and low SHS hearing loss yield has modest impact upon Audiology services, but audiometrically screened referrals deserve higher priority. UNHS children born after 2011 create bigger Audiology service impact. International comparisons and European SHS research collaboration are encouraged. PMID- 29504415 TI - Cardiovascular Safety of the Selective MU-Opioid Receptor Antagonist Naloxegol: A Novel Therapy for Opioid-Induced Constipation. AB - BACKGROUND: Naloxegol is a novel selective, peripherally acting MU-opioid receptor antagonist for treating opioid-induced constipation (OIC) in patients with chronic pain syndromes. We analyzed the cardiovascular (CV) safety of naloxegol based on data from its development program prior to approval by the US Food and Drug Administration in 2015. METHODS: Comprehensive CV safety analyses were performed in 4 clinical studies of naloxegol (12.5 and/or 25 mg) in patients with noncancer pain and OIC: two 12-week, double-blind, randomized studies; a 12 week, double-blind, extension study; and a 52-week, randomized, open-label study versus usual care. Evaluations of baseline CV risk were obtained from medical histories and clinical findings at the time of study initiation. RESULTS: Across the 4 studies (N = 2135), 68% of patients had >=1 CV risk factor and 41% had a history of CV disease, diabetes, or >=2 other CV risk factors. There were no increases in blood pressure, heart rate, or the rate-pressure product with naloxegol versus placebo. The rates of major adverse cardiovascular events (MACE) per 100 patient-years of exposure were 1.13 (95% confidence interval [CI], 0.31 2.89) for placebo/usual care and 0.75 (95% CI, 0.24-1.75) for naloxegol. The relative risk of MACE for all doses of naloxegol versus placebo was 0.67 (95% CI, 0.14-3.36). CONCLUSION: These data demonstrate that naloxegol has a CV safety profile comparable to placebo/usual care in patients with OIC. Although the observed number of events was low, the data show no CV signal in patients with OIC treated with naloxegol. PMID- 29504416 TI - Effect of continuous progressive resistance training during hemodialysis on body composition, physical function and quality of life in end-stage renal disease patients: a randomized controlled trial. AB - OBJECTIVE: This study aimed to investigate the effect of continuous progressive resistance training on body composition, functional capacity and self-reported quality of life in end-stage renal disease patients. DESIGN: A randomized controlled trial. SUBJECTS: The study included 52 hemodialysis patients (aged 55.7 +/- 14.03 years) randomized into exercise (progressive resistance training (PRT), n = 28) or control (CON, n = 24) groups. INTERVENTION: Patients randomized into the PRT group received prescribed strength exercises in two sets of 15-20 repetitions, in a repetition maximum training zone regime, thrice a week for 12 weeks, during hemodialysis. Patients randomized into the CON group received a sham-exercise with active mobilization of the arms and legs without load and progression. MAIN OUTCOME MEASURE: Body composition using dual-energy X-ray absorptiometry (DXA), strength using handgrip dynamometry (HGS), repeated sit-to stand test (STT), 6-minute walk test, flexibility and the SF-36 questionnaire (quality of life (QoL)) were assessed at baseline and at 12 weeks. RESULTS: Leg lean mass ( P = 0.04, effect size (ES) of 0.56), bone mineral content ( P = 0.02, ES of 0.65), leg strength in STT repetitions ( P = 0.01, ES of 0.66) and flexibility ( P < 0.01, ES of 1.03) were significantly improved in the PRT group compared to the CON group. Walking capacity, HGS and QoL were not different between the groups. CONCLUSION: 12 weeks of PRT with a repetition maximum training zone regime provided significant load to increase leg lean mass and STT performance as well as bone mineral content, compared to the CON, which continued to deteriorate. There was lack of efficacy on walking test, HGS and QoL. PMID- 29504417 TI - Techniques for lung surgery: a review of robotic lobectomy. AB - INTRODUCTION: Robotic lobectomy is an increasingly common surgical approach for anatomic lung resection. Over the last decade, robotic lobectomy has shown to be safe, with oncologic efficacy similar to lobectomy via thoracotomy or video assisted thoracoscopic surgery (VATS). Comparative analysis between these modalities is an active area of investigation. While initially expensive, the costs of a robotic platform decrease as the number of operations performed increases, length of stay is shortened, and postoperative morbidity is reduced. Moreover, the added cost has value which is defined over long periods of time. Areas covered: The clinical technique and optimal conduct of lobectomy is explained in granular detail for all five types of lobectomies. The advantages and disadvantages of a robotic platform are analyzed, including a review of the recent literature. Expert commentary: The number of robotic pulmonary resections performed has tripled in the past two years. Anticipated developments in robotic surgery include improvements in robotic training, continued refinement of robotic instrumentation, and additional adjunctive technologies. The overall costs of robotic surgery will decrease, in part, due to increasing competition as additional companies enter the market. PMID- 29504418 TI - [Changes in the clinicopathological features of surgically treated lung cancer around the millennium]. AB - INTRODUCTION: Lung cancer is the most common malignant tumor in Europe and Hungary. In 2010, 10 557 new cases were registered in Hungary; 80-85% of these cases were associated with smoking. AIM: In our work we analyzed the data of lung cancer patients of the last 15 years retrospectively. METHOD: We examined the demographic characteristics, the histological type, the stage of the lung cancer, the type of the surgical procedure used, other supplemental treatment and survival retrospectively. RESULTS: Lung cancer has occurred 50 per cent more often among females in the last decade. This growth is due to the increase of adenocarcinoma cases. Thanks to the improving diagnostic modalities and the routine follow-up of oncological patients, the number of I/A cases has been doubled recently and the preoperative staging and physical condition check-up have become more accurate. Neoadjuvant treatment has been introduced, the proportion of sublobar resections has risen, the ratio of pneumonectomy and sleeve lobectomy has become equal, so many previously unresectable cases turned to be resectable and the tolerance of adjuvant therapy has also improved. Videothoracoscopic lobectomy has become an everyday practice, leading to a decrease in the operative stress on patients. CONCLUSION: In spite of this development, the five-year survival has not changed significantly, staying around 50%. Orv Hetil. 2018; 159(10): 391-396. PMID- 29504419 TI - [Vaginal mesh operations in the urogynecological practice after the FDA warnings. Use or not to use mesh?] AB - INTRODUCTION: The prevalence of pelvic organ prolapse (POP) with aging is escalating alarmingly, and now becoming a growing epidemic among the elderly. Synthetic transvaginal mesh (TVM) has been employed with increasing popularity in the treatment of POP until the end of the last decade. After the U.S. Drug and Food Administration (FDA) warnings in the years 2008 and 2011, the number of vaginal mesh operations has decreased dramatically. AIM: The aim of the study was to evaluate and compare the anti-POP effectivity, the anti-stress incontinence (anti-SUI) efficacy, and the late (36 months) post-operative complications of the anterior vaginoplasty and the TVM operations. METHOD: We analysed the clinical data from 120 patients with stage II-III anterior prolapse and concomitant SUI who had undergone surgery at a tertiary referral centre in Hungary between January 2013 and January 2014. Sixty patients underwent Kelly-Stoeckel vaginoplasty and the other 60 cases had TVM operation. The surgical complications were classified using the Clavien-Dindo (CD) classification system. RESULTS: The anti-POP (91.6% vs. 63.3%; p<0.001) and the anti-SUI efficacy (90% vs. 55%, p<0.001) were significantly higher in the TVM group than in the vaginoplasty group, while the overall extrusion rate was found 8.3% after a 3-year follow-up. The Clavien-Dindo score (CD) proved that the early post-operative complication profile was similar among the TVM patients as compared to the vaginoplasty group (p = 0.405). CONCLUSION: Vaginal mesh surgery represents an effective procedure for prolapse and concomitant SUI with a decreased risk of short- and long-term complications. Orv Hetil. 2018; 159(10): 397-404. PMID- 29504421 TI - [Milestones in liver surgery]. AB - Numerous outstanding summarizing publications on the milestones of the rapid development of liver surgery in the twentieth century came to light around the year 2000, therefore in this summary only the newest principles and novelties of liver surgery after the second millennium are presented. Among the new principles, the newest indications, the bloodless surgery and the vascular exclusion of the liver, the "associating liver partition and portal vein occlusion for staged hepatectomy" (ALPPS) - as presently the fastest and most successful method for liver regeneration, and the "downsizing of tumors" treatment for the interest of resection of unresectable tumours are analyzed and evaluated. Open, laparoscopic, and robotic liver surgery are discussed by comparing blood loss, operating time, cost, and long-term results. Laparoscopic liver surgery on the basis of evidences has become "the method of choice" in our days. Robotic liver surgery needs further evidence-based data for determination of its place in the clinical practice. An intention is also composed in terms of place-determination of liver surgery between gastrointestinal, hepatopancreatobiliary, liver transplantation, and oncologic surgery. The mortality rate has decreased to 1% recently; the data regarding morbidity are variable; the modified Clavien-Dindo, the modified Accordion complication system and the comprehensive complication index are intended to move the different evaluations to a common ground. The up-to-date idea of hepatic surgeon, liver center and liver surgery are defined in close cooperation with international theoretical and practical outcome, in the limelight of multidisciplinarity and multimodality. The internationally observed inequalities in liver surgery are also discussed from the point of view of tackling with the inequalities existing in the universal healthcare systems on a local, national and global level by collecting and controlling the results systematically, and developing and implying international guidelines on the basis of evidences. Orv Hetil. 2018; 159(10): 375-383. PMID- 29504422 TI - [Acute appendicitis in a patient with perianal Crohn's disease receiving infliximab]. AB - The differential diagnosis of acute abdominal complaints is challenging in Crohn's disease. This is particularly true in patients in remission induced by biological therapy. In addition to the acute relapse of Crohn's disease, other common causes, such as acute appendicitis exhibiting similar and often atypical course, should be taken into consideration irrespective of the age. An ileocecal flare-up is unlikely to occur in patients with perianal Crohn's disease in remission induced by infliximab even if laboratory and radiological findings point towards this diagnosis. We report the case of a middle-aged woman in remission induced by infliximab who developed acute abdominal symptoms due to perforated appendicitis. Orv Hetil. 2018; 159(10): 405-409. PMID- 29504423 TI - [Caffeine: traditional and new therapeutic indications and use as a dermatological model drug]. AB - Coffee consumption had already been described in the 15th century. The spreading of coffee drinking was not only a consequence of its delicious aromatic taste, but also of its pharmacological effects, especially due to its caffeine content. In this review, the mechanisms behind its complex stimulatory effects and the latest studies on the possible new therapeutic indications of caffeine are summarized. Several papers reported the neuroprotective (in Alzheimer's and Parkinson's disease) and hepatoprotective profiles of caffeine, and we show the most promising new results about its preventive properties in dermal malignancies. These findings were described both in cell cultures and in vivo. The application of caffeine and coffee in cosmetology and dermatological products is based on their antioxidant property and on the above-mentioned beneficial effects. Caffeine is also presented here as a dermatological model drug due to its hydrophilic profile. It can be used for designing and comparing different novel drug formulations, although beside the transcellular route, the follicular and transappendageal pathways play also important roles in its skin penetration. Taken together, caffeine molecule has many recently discovered beneficial pharmacological effects, but one should be careful with its excessive consumption. It can result in several adverse events if overdosed and in case of regular intake of high doses, after abandonment, withdrawal symptoms may appear. Orv Hetil. 2018; 159(10): 384-390. PMID- 29504424 TI - What constitutes meaningful engagement for patients and families as partners on research teams? AB - Objective There is growing emphasis on health care organizations to ensure that lay people are meaningfully engaged as partners on research teams. Our aim was to explore the perspectives of patients, family members and informal caregivers who have been involved on health care research teams in Canada and elicit their recommendations for meaningful engagement. Methods We conducted a qualitative study guided by thematic analysis of transcripts of focus groups and interviews of 19 experienced patient research partners in Canada. Results We identified four main themes: research environment, expectations, support and value, which highlight participants' combined perspectives on important factors to ensure their engagement in research is meaningful. Conclusions Our findings add to the evolving evidence base on the perspectives of lay people involved in health care research and their recommendations for research leaders on meaningful engagement. Our study suggests that research leaders should provide a welcoming research environment, outline appropriate expectations for patient research partners on research teams, support patient research partners' engagement in projects and recognize the value patient research partners bring to health research. PMID- 29504425 TI - Proteasome 20S in multiple myeloma: comparison of concentration and chymotrypsin like activity in plasma and serum. AB - The ubiquitin-proteasome system is relevant in the pathobiology of many haematological malignancies, including multiple myeloma. The assessment of proteasome concentration and chymotrypsin-like (ChT-L) activity might constitute a new approach to diagnosis, prognosis and monitoring of anticancer treatment of patients with haematological malignancies and other diseases. The aim of our study was to determine which material, plasma or serum, is better for measuring chymotrypsin-like (ChT-L) activity and proteasome concentration. We analysed proteasome concentration and chymotrypsin-like (ChT-L) activity in 70 plasma and serum samples drawn from 28 patients at different treatment stages for multiple myeloma (MM) and 31 healthy volunteers. Proteasome ChT-L activity and concentration in multiple myeloma patients were significantly higher in plasma compared to serum. In this group we observed significant and positive correlations both between the plasma and serum proteasome ChT-L activity and plasma and serum proteasome concentration. The higher values of proteasome concentration and ChT-L activity in plasma than in serum and their better correlations with parameters of tumour load and prognosis suggest that plasma constitutes a better biological material for measuring ChT-L activity and proteasome concentration than serum in multiple myeloma patients. PMID- 29504426 TI - Simultaneous determination of AM80 (tamibarotene) and WJD-A-1 in rat plasma by ultra high-performance liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study. AB - A compound (WJD-A-1) was previously reported as a candidate prodrug of Am80 (tamibarotene), which was approved in Japan in 2005 as a therapeutic agent for recurrent refractory acute promyelocytic leukaemia. A rapid, selective and sensitive ultra high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed for the first time to simultaneously determine WJD-A-1 and its major phase-I metabolites AM80 in rat plasma. After a simple sample preparation procedure by protein precipitation with methanol and acetonitrile, WJD-A-1, AM80 and the internal standard were chromatographed on an ACQUITY UPLCTM BEH C18 column. The mobile phase consisted of methanol-0.1% formic acid (80:20, v/v) and the flow rate was 0.20 mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode via electrospray ionization (ESI) source. Each plasma sample was chromatographed within 2.6 min. The linear calibration curves for WJD-A-1 and the AM80 were obtained in the concentration range of 5.40-5.40 * 103 and 5.08-5.08 * 103 ng/mL, respectively (r >= 0.99). The intra- and inter-day precision (relative standard deviation, RSD) values were less than 8% and the accuracy (relative error, RE) was within +/-6.8%, determined from quality control (QC) samples for the analytes. The method herein described was fully validated and successfully applied to pharmacokinetic study of WJD-A-1 following an intravenous administration of 300 MUg/kg WJD-A-1 to rats. PMID- 29504427 TI - A randomized study comparing the pharmacokinetics of the potential biosimilar PF 06438179/GP1111 with Remicade(r) (infliximab) in healthy subjects (REFLECTIONS B537-01). AB - BACKGROUND: To demonstrate pharmacokinetic (PK) similarity of PF-06438179/GP1111, a potential biosimilar to Remicade(r), to Remicade(r) sourced from European Union (infliximab-EU) and United States (infliximab-US), and of infliximab-EU to infliximab-US. METHODS: In this phase I, parallel-group, three-arm trial, healthy adult subjects were randomized to receive a single 10-mg/kg intravenous infusion of PF-06438179/GP1111, infliximab-EU, or infliximab-US. PK, and safety and immunogenicity evaluations were performed over 8 and 12 weeks, respectively. PK similarity was established if the 90% confidence intervals (CIs) of the test-to reference ratios for PK parameters, Cmax, AUCT, and AUCinf, were within the 80.00 125.00% pre-specified equivalence window. RESULTS: Of 151 subjects randomized, 146 received study treatment; 130 were eligible for PK similarity assessment. Serum concentration-time profiles were similar across the three treatments. The 90% CIs for test-to-reference ratios for Cmax, AUCT, and AUCinf were within 80.00 125.00% for comparison of PF-06438179/GP1111 to infliximab-EU and infliximab-US, and of infliximab-EU to infliximab-US. Similar numbers of subjects across treatment groups experienced adverse events. Anti-drug and neutralizing antibody profiles were largely similar among groups. CONCLUSIONS: This study demonstrated PK similarity of PF-06438179/GP1111 to infliximab-EU and infliximab-US, and of infliximab-EU to infliximab-US. All three products displayed comparable safety and immunogenicity profiles. TRIAL REGISTRATION: CT.gov identifier NCT01844804. PMID- 29504428 TI - Through the Eyes of the User: Evaluating Neonatal Intensive Care Unit Design. AB - OBJECTIVE: This article presents a pilot study that employed a user-centered methodology for evaluating and quantifying neonatal intensive care unit (NICU) designs based on the needs of the primary users. BACKGROUND: The design of NICUs has begun to shift from open-bay to single-family rooms. Both designs present unique advantages and challenges that impact babies, families, and caregivers. METHODS: One NICU design was analyzed using the functional scenario (FS) analysis method. For the FS, users' needs were determined through literature review, interviews with NICU providers and parents, and a review of published design guidelines. Quantitative metrics were developed for each FS, so that characteristics of the NICU design could be analyzed to determine how successful they were in meeting the users' needs. The results were graphically represented to visualize the success and considerations of the design. RESULTS: A total of 23 FSs and 61 spatial metrics were developed. FSs for babies focused on infection prevention, minimizing exposure to environmental stimuli, and supporting enriching care activities. FSs for family members focused on direct access to the baby, and privacy and adequate space for daily activities. FSs for providers and caregivers focused on infection prevention, care activities, care zones, and visibility. CONCLUSION: Using an FS approach highlights design characteristics in the NICU that need to be addressed during the design process to more successfully meet the needs of the different users. Additionally, using this approach can inform design professionals' decision-making by presenting them with the design characteristics that impact the needs of the user groups. PMID- 29504429 TI - Relationship between illness representations and mental health among HIV-positive men who have sex with men. AB - Illness representations play a significant role on mental health across various health conditions. The present study explores the associations between illness representations of HIV and mental health (suicidal ideation and depression), and the mediation effects of emotional representations on the associations between cognitive representations and mental health among men who have sex with men who were newly diagnosed with HIV (ND-MSM) in China. A total of 225 ND-MSM were recruited from a non-governmental organisation and were invited to complete a cross-sectional survey. Results showed that 48.0% had suicidal ideation since HIV diagnosis and 48.4% scored higher than the cut-off for mild depression or above. Stepwise regression analyses showed that higher levels of emotional representations of HIV and lower levels of treatment control were associated with both suicidal ideation and depression. Emotional representations were shown to mediate the associations between some cognitive representations variables and mental health. Findings suggest that both cognitive and emotional representations of HIV were important factors of mental health among ND-MSM. Interventions to promote the mental health of ND-MSM are warranted and should seek to improve their cognitive and emotional representations of HIV. PMID- 29504431 TI - Regarding "anti-Mullerian hormone levels before and after uterine artery embolization". PMID- 29504430 TI - Lymph node metastases: importance of detection and treatment strategies. AB - INTRODUCTION: Lymphatic vessels are the preferential route of most solid tumors to spread their metastases in the body. The onset of metastatic nests in draining lymph nodes (LNs) are a significant indicator of cancer progression and a dismaying sign of worsen staging. Therefore, the individuation and elimination of cancer cells within the lymphatic system (LS) are an important goal. Nevertheless, the targeting of the LS with traditional contrast agents and/or chemotherapeutics is difficult, due to its anatomical structure. For this reason, many studies on new lymphatic delivery systems have been carried out, both to improve lymphatic imaging and to selectively carry chemotherapeutics to LNs, reducing the exposure of healthy tissues to the cytotoxic substances. This is an overview of the present situation in the field of detection and treatment strategies of lymphatic metastases, taking into account the use of nano-drug delivery systems. Nanocarriers, thanks to their small size and other physicochemical characteristics, are suitable vectors for imaging and chemotherapy of the LS. Areas covered: The role of the LS in tumor progression and importance of treatment and imaging strategies of lymphatic metastases. Expert opinion: The nanoparticles are a promising approach for treatment and detection of lymphatic metastases. However further studies are necessary in order to evaluate their efficacy in human clinical application. PMID- 29504432 TI - Corrigendum. AB - Hani Haider, Joel N Weisenburger, Kevin L Garvin. Simultaneous measurement of friction and wear in hip simulators. Proc IMechE, Part H: Journal of Engineering in Medicine; 230(5): 373-388. DOI: 10.1177/0954411916644476 On page 379 of this article, there is an error in the equation "[Formula: see text]". The corrected equation is as follows: [Formula: see text] The online version of the article has been updated. PMID- 29504433 TI - Therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy: magnetic resonance imaging findings and neurological outcomes in a Brazilian cohort. AB - OBJECTIVE: To determine the neurodevelopment outcomes after therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy (HIE) and identify the neonatal magnetic resonance imaging (MRI) findings associated with neurological outcome in a middle-income country. STUDY DESIGN: All infants born after 35 completed weeks' gestation with signs of moderate to severe encephalopathy and evidence of perinatal asphyxia before 6 hours of life were submitted to whole body hypothermia and were imaged at 18 +/- 8.4 days of life (range 7-33 days) after birth. Surviving infants had the neurodevelopment outcome assessed at 12 to 18 months of age by trained professional masked to MRI findings. RESULTS: Forty eight infants included, MRI scans were obtained from 34 infants; 14 (29.1%) patients died during hospitalization before MRI was performed. Nine (64.3%) of 14 patients were classified as severe encephalopathy presented Posterior Limb Internal Capsule (PLIC) sign at the MRI, 10 (71.4%) thalamus and basal ganglia (TBG) lesion, 9 (64.3%) white matter (WM) lesion, and 7 (50.0%) cortical lesion. Severe encephalopathy was associated with the motor delay at 12-18 months by Bayley III, Alberta Infant Motor Scale (AIMS), and Gross Motor Function Classification System (GMFCS) scores (p = .020, p = .048, p = .033, respectively), but not for the cognitive (p = .167) or language skills (p = .309). Lower BSID-III motor, cognitive, and language composite scores were associated with PLIC sign (p = .047; p = .006 and p = .003, respectively). TBG lesion (p = .051) and cortical lesion (p = .030) were associated with lower language composite score. Motor delay by AIMS and the presence of PLIC sign, TBG lesion, WM lesion, and Cortical lesion on MRI were observed (p < .001; p = .002; p = .001 and p = .027, respectively); as well as higher GMFCS score were associated with the presence of PLIC sign, TBG lesion, WM lesion, and Cortical lesion on MRI (p < .001; p = .001; p = .001, and p = .011, respectively). CONCLUSIONS: Brain MRI in neonates with HIE after therapeutic hypothermia is a valuable tool for diagnosis of encephalopathy cerebral abnormalities and is an early predictor of outcome in infants treated with whole body hypothermia for HIE in the Brazilian experience. PMID- 29504434 TI - Threshold monitoring of intraoperative auditory steady-state responses for ossiculoplasty surgery. AB - OBJECTIVE: The objective of this study is to establish a reliable intraoperative auditory threshold monitoring system for ossiculoplasty surgery. DESIGN: The chirp signal of self-designed sound field earphone (SFE) was calibrated physically and psychophysically. The interaural attenuation of the SFE was tested in patients with unilateral complete deafness and contralateral normal hearing (10 patients). Self-designed SFEs were used to measure the chirp-evoked auditory steady-state responses (Chirp-ASSR) threshold of patients (14 cases and 15 ears) with conductive hearing loss after anesthesia but before surgery. RESULTS: The response threshold of Chirp-ASSR under anesthesia displayed a strong correlation with the hearing threshold for pure tones: the Pearson coefficients at various frequencies (1, 2, and 4 kHz) were 0.56 (p = .03), 0.82 (p < .001), and 0.90 (p < .001), respectively, and the intragroup correlation coefficients were 0.70 (p = 0.02), 0.90 (p < 0.001), and 0.95 (p < 0.001), respectively. The average test time was 7.0 +/- 0.7 min. CONCLUSIONS: By combining Chirp-ASSR with self-designed SFE, we obtained objective multi-frequency intraoperative auditory thresholds that correlate well with the pure tone audiometry threshold. This reliable system can be applied to future intraoperative auditory threshold monitoring for ossiculoplasty surgery. PMID- 29504436 TI - Tocilizumab in the treatment of giant cell arteritis. AB - Giant cell arteritis is a systemic vasculitis of large vessels, manifesting mainly as temporal arteritis or large vessel vasculitis of the aorta and its branches. Glucocorticoid therapy is essential and so far had to be continued over a period of 1.5-2 years, resulting in relevant morbidity through adverse effects. With the approval of tocilizumab, an effective glucocorticoid sparing option is now available. In two randomized controlled trials, a profound reduction of cumulative glucocorticoid dose, prolonged relapse-free remission and reduced number of adverse events in the treatment groups have been demonstrated. Therefore, tocilizumab constitutes a novel therapeutic option in giant cell arteritis. Its differential role in different subgroups, timing of tocilizumab therapy and optimal treatment duration remain to be determined. PMID- 29504437 TI - Moving a mountain: Practical insights into mastering a major curriculum reform at a large European medical university. AB - AIM: Undergraduate medical education is currently in a fundamental transition towards competency-based programs around the globe. A major curriculum reform implies a dual challenge: the change of the curriculum and the delivering organization. Both are closely interwoven. In this article, we provide practical insights into our approach of managing such a fundamental reform of the large undergraduate medical program at the Charite - Universitatsmedizin Berlin. METHODS: Members of the project management team summarized the key features of the process with reference to the literature. RESULTS: Starting point was a traditional, discipline-based curriculum that was reformed into a fully integrated, competency-based program. This change process went through three phases: initiation, curriculum development and implementation, and sustainability. We describe from a change management perspective, their main characteristics, and the approaches that were employed to manage them successfully. CONCLUSIONS: Our report is intended to provide practical insights and guidance for those institutions which are yet considering or have already started to undergo a major reform of their undergraduate programs towards competency medical education. PMID- 29504438 TI - Re to: Tale of rudimentary horn pregnancy and literature review. PMID- 29504439 TI - Studying the blood-brain barrier will provide new insights into neurodegeneration - No. PMID- 29504440 TI - Effects of a Community-Based Exercise Program on Older Adults' Physical Function, Activities of Daily Living, and Exercise Self-Efficacy: Feeling Fit Club. AB - Community-based exercise programs have demonstrated feasibility, yet many lack controlled studies examining their efficacy. This study examined the efficacy of a community-based exercise program, using a controlled design. Participants ( N = 262, Mage = 74.0 years, SD = 8.4) were women (77%) and men recruited from senior centers served by the county Area Agency on Aging. Intervention participants ( n = 133) were newly enrolled in classes. Controls ( n = 129) were recruited from matched sites not offering classes. Validated measures of physical function, exercise self-efficacy, balance, and activities of daily living (ADL) confidence were administered at baseline and 3 months. Significant improvements in upper and lower body strength, aerobic endurance, mobility, exercise self-efficacy, and balance were found in the exercisers but not controls. No changes in ADL confidence occurred in exercisers, while significant decreases occurred in controls. Findings support the efficacy of the county-wide program. Building an evidence base for community-delivered programs should provide impetus for increased dissemination through state and national agencies thereby increasing program impact. PMID- 29504441 TI - Maternal serum AMP-activated protein kinase levels in mild and severe preeclampsia. AB - OBJECTIVE: To investigate Phosphorylated adenosine monophosphate activated protein kinase (AMPK) levels in healthy pregnant women and pregnant women with preeclampsia (PE). METHODS: Twenty-eight women with mild-PE, 22 with severe-PE, and 30 normotensive controls were included in this cross-sectional study. The serum AMPK levels of these patients were analyzed. The patients were followed up to delivery. RESULTS: No statistically significant difference was found between the groups for age, gravida, parity, and gestational age at the time the blood samples were obtained (p > .05). No significant difference between the group with mild-PE and the control group was found, while in the severe-PE group, serum AMPK levels were significantly higher relative to both the mild-PE and control groups (p < .001 and p < .001, respectively). No correlation was detected between serum AMPK levels and age, body mass index (BMI), and gestational age at the time the blood samples were collected. A negative correlation was found between AMPK levels and gestational week and birthweight at delivery, while a positive correlation was detected between systolic and diastolic blood pressures and AMPK levels. CONCLUSIONS: Serum AMPK was higher in patients with severe-PE compared with healthy pregnant women and patients with PE without severe features so it might be a new biomarker for the prediction of disease and its severity. PMID- 29504442 TI - Educational leadership during a decade of medical curricular innovation and renewal. AB - BACKGROUND: The past decade has witnessed successful expansion, distribution and curricular renewal at the University of British Columbia (UBC) medical school. The expansion and distribution of the medical program doubled enrollment and established the first North American medical school training students across multiple geographical locations. The more recent competency-based curriculum renewal demonstrates sustained innovation within UBC medicine. AIMS: This paper describes that a significant contributor to these successes has been a team of teaching faculty whose exclusive roles have been providing curricular support. Over the past decade, this group has evolved into a vital component of the day-to day operations and performance of the distributed medical curriculum; they now provide continuity in leadership and innovation across multiple educational facets of the program. METHOD/RESULTS: This paper reports on the evolution and significance of these faculty members. The descriptions establish the success of an investment in teaching faculty and underscore the importance of engaging faculty whose primary commitments are to teaching, educational pedagogy, and student support. CONCLUSIONS: This efficacious model of supporting and advancing a complex distributed medical program over more than a decade of pivotal change will be of interest to faculties and programs that are contemplating or navigating similar pursuits. PMID- 29504443 TI - Variation in prognosis of early laryngeal carcinoma after different types of cordectomy with transoral laser microsurgery. AB - BACKGROUND: The lack of standardized treatment is problematic in laser surgery for laryngeal cancer, and may result in an increased recurrence rate. This study analyzed the prognosis of early laryngeal carcinoma after different types of cordectomy with laser surgery. METHODS: A cohort of 818 patients with stage Tis or T1 primary early glottic squamous cell carcinoma treated with CO2 laser surgery was retrospectively analyzed. RESULTS: Of the 818 patients, According to the Kaplan-Meier method, the rate of 5-year overall survival was 92.8%, and the rates for 5-year disease-specific survival and 5-year locoregional control were 96.9% and 91.3%, respectively. Among the T1 patients, type II cordectomy with laser surgery had a significant impact on the 5-year locoregional control rate, but no obvious impact on the 5-year overall survival rate. CONCLUSIONS: There must be sufficient depth and extent of excision in T1 patientsand in early carcinoma especially those with possible microinvasive carcinoma. PMID- 29504444 TI - A new classification of vocal fold leukoplakia by morphological appearance guiding the treatment. AB - OBJECTIVE: To provide a reference for classification and treatment of vocal cords leukoplakia. METHODS: 640 cases of patients with vocal cords leukoplakia were divided into three groups based on the appearances. There were respectively 81 smooth flat lesions, 155 smooth hypertrophy lesions and 13 rough lesions were treated with conservative methods and 26, 153 and 212 cases were resected surgically for biopsy. RESULTS: A majority of smooth flat leukoplakia lesions were cured by non-operational methods and no atypical hyperplasia. Most of rough lesions were invalid and even progressed treated with conservative therapy and were severe dysplasia or canceration. Although 67.6% smooth hypertrophy lesions were cured or improved by conservative methods and 47% lesions had no or mild dysplasia, over 30% of lesions were still invalid or progressed and over 50% had moderate, severe dysplasia and canceration. By statistical analysis, the appearance of leukoplakia was concordant with pathological changes. CONCLUSIONS: It is suggested that smooth flat vocal cords leukoplakia could be treated with conservative methods and rough lesions should be resected operationally, while for smooth hypertrophy vocal cords leukoplakia could be first followed-up and then adopt measures based on the appearance changes. PMID- 29504445 TI - Effect of postoperative pneumatic compression after volar plate fixation of distal radial fractures: a randomized controlled trial. AB - : We investigated the difference between postoperative rehabilitation with or without adjunctive intermittent pneumatic compression therapy following distal radial fracture treated with volar plating. A total of 115 patients were randomized to a control or to an experimental group. After 4 weeks of immobilization the experimental group received intermittent pneumatic compression therapy in addition to conventional postoperative rehabilitation. Primary outcome up to 1 year postoperatively was assessed using the Canadian Occupational Performance Measure. No significant differences between groups were found. There were no clinically relevant differences regarding the secondary outcome measures swelling, strength, pain and flexibility. We conclude that postoperative intermittent pneumatic compression treatment had no major benefits. The results of the present study do not support general use of intermittent pneumatic compression initiated 4 weeks following volar plating surgery for distal radial fracture. LEVEL OF EVIDENCE: I. PMID- 29504446 TI - The clinical significance of B-cell maturation antigen as a therapeutic target and biomarker. AB - INTRODUCTION: B-cell maturation antigen (BCMA) is a cell membrane bound tumor necrosis factor receptor family member that is expressed exclusively on late stage normal and malignant B-cells and plasma cells. Addition of two of its ligands, B-cell activating factor and a proliferation inducting ligand, to normal B-cells cause B-cell proliferation and antibody production. Serum BCMA is elevated among patients with multiple myeloma (MM) and chronic lymphocytic leukemia (CLL), and is a prognostic and monitoring tool for these patients. The first anti-BCMA antibody (Ab) was developed in 2007. Recently, biotech and pharmaceutical companies have created various forms of BCMA-directed Abs (naked Abs, Ab drug conjugates, and bispecific Abs) and cellular therapies (chimeric antigen receptor T-cells) with promising clinical results. Areas covered: This BCMA review encompasses full-text publications of original research articles and abstracts presented at hematology/oncology meetings. Expert commentary: The limited preclinical and ongoing clinical studies published to date evaluating BCMA-directed therapies have shown great promise. It has also been demonstrated that BCMA is solubilized and elevated in the blood of MM, Waldenstrom's macroglobulinemia and CLL patients, and is also responsible for the immune deficiency in MM. Reducing circulating levels may improve the efficacy of these treatments. PMID- 29504447 TI - The Impacts of Weight Change and Weight Change Intention on Health-Related Quality of Life in the Korean Elderly. AB - OBJECTIVE: This study aimed to identify the impacts of weight change and weight change intention on health-related quality of life (HRQL) among community dwelling Korean elderly individuals. METHOD: Data on those aged 75 years and above from the Korean National Health and Nutrition Examination Survey were analyzed using multiple regression analysis. RESULTS: Compared with no weight change, unintentional weight loss was associated with significantly lower adjusted overall HRQL and lower scores in the subdimensions of mobility, pain/discomfort, usual activities, and self-care (in order), whereas intentional weight loss was associated with significantly poorer scores for anxiety/depression. Weight gain showed no statistically significant differences in comparison with no weight change. DISCUSSION: These findings suggest that weight maintenance or weight gain should be recommended rather than weight loss, whether unintentional or intentional, regardless of weight status, to improve HRQL among the elderly. PMID- 29504448 TI - Studying the blood-brain barrier will provide new insights into neurodegeneration - Yes. PMID- 29504449 TI - Psychometric Adaptation of the Beck Hopelessness Scale as a Self-Rated Suicide Risk Screening Instrument Among Nigerian University Students. AB - BACKGROUND: Globally, suicide is the most important cause of mortality among adolescents and young adults. The factor that correlates most significantly with suicide is hopelessness. OBJECTIVE: The aim is to explore the psychometric adaptation of the Beck Hopelessness Scale (BHS) as a suicide risk evaluation tool among Nigerian university students. DESIGN: A total of 554 Nigerian students completed the BHS and the Depression Anxiety Stress Scale (DASS). Suicide risk level among them was determined by interviewing them with the Mini International Neuropsychiatric Interview Suicidality module. RESULTS: Cronbach's alpha for the 16-item BHS was 0.87. It exhibited satisfactory concurrent validity with the Mini International Neuropsychiatric Interview (MINI) Suicidality module and the subscales of the DASS among the students. The 2-factor model of the BHS-16 exhibited satisfactory indices of fitness (goodness of fit index = 0.930; parsimonious goodness of fit index = 0.601; comparative fit index = 0.934; incremental fit index = 0.936; Tucker-Lewis index = 0.910; root mean square error of approximation = 0.059; chi2/ df = 1.9). Receiver operating characteristics curve indicated that the best cutoff score for those categorized as high suicide risk was 7 (sensitivity 0.700, specificity 0.908, AUC = 0.897). CONCLUSIONS: The BHS has satisfactory psychometric properties as a suicide risk screening tool among Nigerian university students. PMID- 29504450 TI - Motivational Interviewing-Based Compliance/Adherence Therapy Interventions to Improve Psychiatric Symptoms of People With Severe Mental Illness: Meta-Analysis. AB - BACKGROUND: Nonadherence is the leading cause of relapse in mental illness. No quantitative synthesis of multiple studies has been conducted to determine the effect of motivational interviewing (MI)-based compliance/adherence therapy (CAT) interventions on people with severe mental illness. OBJECTIVE: To synthesize the studies that examined the effectiveness of MI-based CAT interventions to improve psychiatric symptoms. DESIGN: Quantitative meta-analysis. RESULTS: Sixteen primary studies were retrieved ( N =1267 participants). MI-based CAT interventions significantly improved psychiatric symptoms with a moderate effect size (ES) of .45. Longer sessions and higher intervention doses showed significantly greater ESs than shorter sessions and lower doses. ESs were significantly lower when participants were older and when there was a longer period between the intervention and outcome measurement. CONCLUSIONS: These findings support the effectiveness of MI-based CAT interventions. Session length and dose effect should be considered when tailoring MI to clients. PMID- 29504451 TI - Studying the blood-brain barrier will provide new insights into neurodegeneration - Commentary. PMID- 29504452 TI - Witnesses' memory for events and faces under elevated levels of intoxication. AB - Research on alcohol and witness memory has burgeoned over the last decade. However, most studies have tested participants at relatively low breath alcohol concentration (BAC) levels, unrepresentative of those encountered by officers in the field. To examine how higher intoxication levels might impair witness memory for events and faces, the current research tested participants' ability to recall a mock crime at elevated BAC levels (>.08%). The BAC levels of bar patrons (N = 138) were recorded before witnessing a video-taped mock crime. Participants were then interviewed using free recall and cued questions and shown a six-person target-present or target-absent lineup. Results show that alcohol negatively affected both the quantity and quality of recall. Regardless of question format, alcohol also reduced the percentage of accurate information elicited from witnesses; however, only cued questions increased the percentage of inaccurate information reported. Intoxication had no effect on identification accuracy. These findings suggest that the encoding and storage systems for faces and events may be impacted differently by alcohol. Our results also highlight the importance of including higher BAC levels when examining the effects of alcohol on witness memory. PMID- 29504453 TI - Molecular Characterization of Mx1 Gene in Native Indian Breeds of Chicken. AB - The genetic polymorphism of Mx1 gene was explored in Indian chicken breeds. PCR RFLP analysis in 102 bp fragment of partial intron 13 and partial exon 14 of Mx1 gene revealed two genotypes viz. RS and SS with two alleles viz. R and S both in Naked Neck and Tellicherry breeds of chicken. The homozygous genotype RR was not identified. When deduced amino acid sequences were compared, the asparagine amino acid was found to be substituted in "R" allele for serine in "S" allele. PCR-SSCP analysis of 284 bp fragment in 5'-UTR and partial promoter region revealed three genotypes viz. CC, CG, and CH with three different alleles viz. C, G, and H in Naked Neck breed of chicken and five genotypes viz. DI, JK, KK, KL, and KM with six different alleles viz. D, I, J, K, L, and M in Tellicherry breed of chicken. The homozygous genotypes viz. GG and HH in Naked Neck and DD, II, JJ, LL, and MM in Tellicherry chicken was not identified. The nucleotide substitution rate estimated to be in the range of 0.004-0.011. The identified genetic variation can be helpful for better insight to disease resistance property of the Mx1 gene. PMID- 29504454 TI - Corrigendum. AB - van Wijngaarden, E., van der Meide, H., and Dahlberg, K. (2017): Researching health care as a meaningful practice: Toward a nondualistic view on evidence for qualitative research. Qualitative Health Research, 27, 1738 -1747. Doi: 10.1177/1049732317711133 In this article, on page 1739, left column, line 7 of second full paragraph is incorrect. In this line, the word " qualitatively" should read as "quantitatively". The correct paragraph is mentioned below; Here we want to mention three widely acknowledged limitations to using quantitative research as a model for qualitative research. First, quantitative approaches are population oriented: homogeneous groups of patients from the same clinical conditions are in focus, whereas in real life, many issues and problems are chaotic, heterogeneous, and "too complex to tackle quantitatively" (Morse, 2006b). A reason for qualitative research is the urge to be person oriented. PMID- 29504455 TI - Identification of novel DHFR inhibitors for treatment of tuberculosis by combining virtual screening with in vitro activity assay. PMID- 29504456 TI - Young, talented and injured: Injury perceptions, experiences and consequences in adolescent elite athletes. AB - Even though injury is common in elite sports, there is still a lack of knowledge of young athletes' injury perception both during and after injury. The aim of this mixed-method study was, therefore, to explore, in-depth, data on injury consequences and adolescent elite athletes' perceptions and experience of injury. Three hundred and forty adolescent elite athletes (age range 15-19), from 16 different sports, were bi-weekly monitored over 52 weeks using a valid questionnaire. Twenty athletes from the same cohort were interviewed in focus groups about injury experience and perceptions. The results show that the average bi-weekly prevalence of injury was 38.7% (95% CI 37.3-40.1), with 30.0% (n = 102) of the athletes injured for more than half of all reporting times. An overarching theme from the focus groups highlighted the risk among young athletes of a loss of identity while injured. The findings support several suggestions that may improve the rehabilitation process and enhance rehabilitation outcomes: (a) provide clear pathways to the medical team, (b) recognize the identity loss, (c) involve the injured athletes with the rest of the teammates and (d) educate athletes about how to interpret pain signals. Future research should explore and evaluate the effectiveness and generalization of such interventions. PMID- 29504457 TI - Investigating belief falsehood. Fear appeals do change behaviour in experimental laboratory studies. A commentary on Kok et al. (2018). PMID- 29504458 TI - Beyond JNC 8: implications for evaluation and management of hypertension in underserved populations. AB - In the United States, hypertension is a significant medical problem that affects nearly 1 in 3 adults, causes thousands of deaths annually, and costs the nation billions of dollars annually for medical management in terms of hospitalisations, lost wages, and pharmacotherapy. The management guidelines of hypertension have greatly varied between different healthcare organisations including the American College of Cardiology (ACC), the European Society of Cardiology (ESC) and the Joint National Committee (JNC-7, 8). One of the points of contention is the generalisability of the guidelines to all individuals despite empirical evidence suggesting racial sensitivities to pharmacotherapy and high clinical adversities with elevations in blood pressure (BP). This manuscript will aim to review a brief history of the guidelines, the adjustment of the BP goals with pharmacotherapy for the management of hypertension, and discuss several socioeconomic factors attributing to higher clinical risks for certain minority racial groups susceptible to the new BPs goals for management under the JNC-8. PMID- 29504459 TI - A New "Shield of the Weak": Continued Paternalism of Domestic Violence Services in Uruguay. AB - Drawing on ethnographic and historical research, this article illuminates the limitations of the Uruguayan domestic violence services system. In spite of how advocates in Uruguay successfully used a human rights platform to secure legislation and services, this system now faces significant critique. Using Iris Marion Young's work on the "logic of masculinist protection" and historical parallels in Uruguay's welfare system, I discuss how a paternalistic approach may be to blame. I highlight how this paternalism contributes to the paternalism that problematically underlies gendered violence-reinforcing rather than addressing oppressive ideologies and structures that impede improving conditions for women. PMID- 29504460 TI - Gonorrhoea in Greenland: geographic differences in diagnostic activity and incidence of gonorrhoea in 2015. AB - For decades the spread of sexually transmitted infections (STIs) has been a health concern in Greenland, especially within the age group of 15-34 year olds. However, no overview exists of the potential differences in regional incidence and management of STIs. This study investigates the age, gender and region specific diagnostic activity and incidence of gonorrhoea in Greenland in 2015. The study design was an observational cross sectional register study with inclusion of patients tested for gonorrhoea in 2015. Patients above 15 years of age were included. Data was obtained from the laboratory system used at The Central Laboratory at Queen Ingrid's Hospital in Nuuk. We found, in 2015, a total of 17,911 tests for gonorrhoea were performed on both men and women. Women accounted for 68% of the tests, while men accounted for 32%. The positivity rate was 7,878 pr. 100,000 of which 56% were women and 44% were men. The regional distribution showed a disparity of the testing rate and the rate of positive gonorrhoea tests.. Thus, we have documented a high diagnostic activity and high incidence of gonorrhoea in Greenland in 2015 among both women and men. We also found significant regional differences in both diagnostic activity and gonorrhoea incidence. PMID- 29504461 TI - State of the Science: Using Telomeres as Biomarkers During the First 1,000 Days of Life. AB - Telomere biology shows promise as an integrative biomarker of exposures and increased occurrence of chronic disease and early mortality. This integrative review examined the state of the science regarding toxicokinetic risks and maternal factors in humans and in vivo models that are correlated with telomere length during the first 1,000 days of life. The Preferred Reporting Items of Systematic Reviews and Meta-Analyses framework assisted in guiding this integrative by aiding researchers in identifying, selecting, and critically appraising the literature. Ovid MEDLINE, CINAHL, Cochrane Systematic Reviews, Web of Science, and SCOPUS databases were searched. The initial search yielded a total of 381 published articles. Full-text screening resulted in 19 articles retained for review (14 quasi-experimental studies and five experimental studies). Findings suggest a relationship between toxicokinetic exposures creating inflammation or oxidative stress (i.e., smoking) and maternal health conditions such as sleep apnea to shorter telomere length in children below 2 years old. PMID- 29504462 TI - Speaker-specific processing of anomalous utterances. AB - Existing work shows that readers often interpret grammatical errors (e.g., The key to the cabinets *were shiny) and sentence-level blends ("without-blend": Claudia left without her headphones *off) in a non-literal fashion, inferring that a more frequent or more canonical utterance was intended instead. This work examines how interlocutor identity affects the processing and interpretation of anomalous sentences. We presented anomalies in the context of "emails" attributed to various writers in a self-paced reading paradigm and used comprehension questions to probe how sentence interpretation changed based upon properties of the item and properties of the "speaker." Experiment 1 compared standardised American English speakers to L2 English speakers; Experiment 2 compared the same standardised English speakers to speakers of a non-Standardised American English dialect. Agreement errors and without-blends both led to more non-literal responses than comparable canonical items. For agreement errors, more non-literal interpretations also occurred when sentences were attributed to speakers of Standardised American English than either non-Standardised group. These data suggest that understanding sentences relies on expectations and heuristics about which utterances are likely. These are based upon experience with language, with speaker-specific differences, and upon more general cognitive biases. PMID- 29504463 TI - Memory for staged events: Supporting older and younger adults' memory with SenseCam. AB - Two experiments measured the effect of retrieval support provided by a wearable camera, SenseCam, on older and younger adults' memory for a recently experienced complex staged event. In each experiment, participants completed a series of tasks in groups, and the events were recalled 2 weeks later, after viewing SenseCam images (experimental condition) or thinking about the event (control condition). When IQ and education were matched, young adults recalled more event details than older adults, demonstrating an age-related deficit for novel autobiographical material. Reviewing SenseCam images increased the number of details recalled by older and younger adults, and the effect was similar for both groups. These results suggest that memory can be supported by the use of SenseCam, but the age-related deficit is not eliminated. PMID- 29504464 TI - Adults have moderate-to-good insight into their face recognition ability: Further validation of the 20-item Prosopagnosia Index in a Portuguese sample. PMID- 29504465 TI - Twenty-three-year trend in firearm deaths in the Transkei subregion of South Africa (1993-2015). AB - Background Firearm-related deaths are a serious public-health problem in South Africa, which has the second-highest rate of firearm-related deaths in the world. Objective The aim of this study was to examine the trend in firearm deaths in the Transkei subregion of South Africa. Method An autopsy record review study was conducted at the Forensic Pathology Laboratory at Mthatha over a period of 23 years (1993-2015). Results Over a 23-year period (1993-2015), 27,036 autopsies were performed at the Mthatha Forensic Pathology Laboratory on people who had died from unnatural causes. Of these, 3935 (14.2%) deaths were related to firearm injuries. The average gunshot death rate during the study period was 29/100,000 of the population annually. The majority (3236; 82%) were males, among whom the death rate was 24.4/100,000 of the population per year. The rate of gunshot deaths was 27/100,000 of the population in 1993, while in 2015 it was 12.8/100,000. About a third (1207; 31%) of victims were between 21 and 30 years of age. Conclusion The gunshot death rate is at an unacceptably high level in the Transkei subregion of South Africa, especially among young people. PMID- 29504466 TI - Social Environmental Correlates of Health Behaviors in a Faith-Based Policy and Environmental Change Intervention. AB - Diet and physical activity are behavioral risk factors for many chronic diseases, which are among the most common health conditions in the United States. Yet most Americans fall short of meeting established dietary and physical activity guidelines. Faith-based organizations as settings for health promotion interventions can affect members at multiple levels of the social ecological model. The present study investigated whether change in the church social environment was associated with healthier behavior at church and in general at 1 year follow-up. Six churches received mini-grants and technical assistance for 1 year to support policy and environmental changes for healthy eating (HE) and physical activity (PA). Socioenvironmental (social support and social norms) and behavioral (HE and PA at church and in general) outcomes were derived from baseline and 1-year follow-up church member surveys ( n = 258). Three of six churches demonstrated significant improvements in all three socioenvironmental aspects of HE. Two of five churches exhibited significant socioenvironmental improvements for PA at follow-up. Church social environmental changes were related to health behaviors at church and in general ( p < .05). Change in social support for HE, social support for PA, and social norms for PA were each associated with three church-based and general behavioral outcomes. Social norms for healthy eating were related to two general behavior outcomes and social norms for unhealthy eating to one general behavioral outcome. Study findings demonstrate that socioenvironmental characteristics are essential to multilevel interventions and merit consideration in designing policy and environmental change interventions. PMID- 29504467 TI - A Mixed Methods Examination of Sleep Throughout the Alcohol Recovery Process Grounded in the Social Cognitive Theory: The Role of Self-Efficacy and Craving. AB - Sleep disturbances can accompany alcohol use disorders during various phases of the disease. This analysis utilized a mixed methods approach to assess whether sleep-related beliefs and/or behavior of individuals who are alcohol dependent were associated with sleep quality both pre- and postdischarge from a clinical research facility providing inpatient alcohol rehabilitation treatment. Individuals with higher self-efficacy for sleep (SE-S) reported better sleep quality at both time points. Individuals with fewer dysfunctional beliefs about sleep had poorer sleep quality at both time points. Individuals with higher unhealthy sleep-related safety behaviors had poorer sleep quality at both time points. In a linear regression model, only the difference in SE-S scores from pre to postdischarge (beta = -.396, p = .01) and the postdischarge Penn Alcohol Craving Score (beta = .283, p = .019) significantly predicted the change in sleep quality. Thus, those whose SE-S scores increased and those with lower postdischarge craving scores were more likely to experience a decrease on Pittsburgh Sleep Quality Index scores from pre- to postdischarge even after controlling for covariates. References to behavior or personal factors were often discussed during the qualitative interviews in tandem with the environment. Participants reported both (1) self-medicating anxiety with alcohol and (2) self medicating the inability to fall asleep with alcohol. Given the success of behavioral sleep interventions in various populations and the unique potential contributions of mixed methods approaches to examine sleep and alcohol use, assessing sleep-related cognitions and behaviors of individuals with severe alcohol use disorders may be important in understanding sleep quality and subsequent relapse. PMID- 29504469 TI - Comparisons Between Smoking Patterns Among Sexual Minority Females and Males in Romantic Relationships. AB - PURPOSE: Several studies have noted sexual minority disparities in tobacco smoking; however, few studies have examined the role of intimate partners in these different smoking behaviors among sexual minority men and women. Furthermore, few studies distinguish between intermittent and daily smokers. Thus, this study sought to examine whether perceptions of their partner's smoking behaviors were associated with their own smoking behaviors in a sample of sexual minority adults in romantic relationships. METHOD: In total, 898 participants (413 sexual minority females and 485 sexual minority males) completed a one-time online anonymous survey. RESULTS: Approximately one third of the sample reported smoking, with 21.2% daily smokers and 9.8% intermittent smokers. Multinomial regression results revealed that for both sexual minority females and males having a partner who was a daily or intermittent smoker was associated with an increased odds of being a daily smoker, whereas having a partner who was an intermittent smoker was associated with an increased odds of being an intermittent smoker. CONCLUSIONS: These findings provide valuable information on the need to attend to romantic partners and consider tailored programming to account for different smoking patterns and partners' potential role in reinforcing smoking. PMID- 29504468 TI - Comparing Weight Loss-Maintenance Outcomes of a Worksite-Based Lifestyle Program Delivered via DVD and Face-to-Face: A Randomized Trial. AB - BACKGROUND: Native Hawaiians and other Pacific Islanders have high rates of overweight and obesity compared with other ethnic groups in Hawai'i. Effective weight loss and weight loss-maintenance programs are needed to address obesity and obesity-related health inequities for this group. AIMS: Compare the effectiveness of a 9-month, worksite-based, weight loss-maintenance intervention delivered via DVD versus face-to-face in continued weight reduction and weight loss maintenance beyond the initial weight loss phase. METHOD: We tested DVD versus face-to-face delivery of the PILI@Work Program's 9-month, weight loss maintenance phase in Native Hawaiian-serving organizations. After completing the 3-month weight loss phase, participants ( n = 217) were randomized to receive the weight loss-maintenance phase delivered via trained peer facilitators or DVDs. Participant assessments at randomization and postintervention included weight, height, blood pressure, physical functioning, exercise frequency, and fat intake. RESULTS: Eighty-three face-to-face participants were retained at 12 months (74.1%) compared with 73 DVD participants (69.5%). There was no significant difference between groups in weight loss or weight loss maintenance. The number of lessons attended in Phase 1 of the intervention (beta = 0.358, p = .022) and baseline systolic blood pressure (beta = -0.038, p = .048) predicted percent weight loss at 12 months. DISCUSSION AND CONCLUSION: Weight loss maintenance was similar across groups. This suggests that low-cost delivery methods for worksite based interventions targeting at-risk populations can help address obesity and obesity-related disparities. Additionally, attendance during the weight loss phase and lower baseline systolic blood pressure predicted greater percent weight loss during the weight loss-maintenance phase, suggesting that early engagement and initial physical functioning improve long-term weight loss outcomes. PMID- 29504470 TI - Artificial Versus Video-Based Immersive Virtual Surroundings: Analysis of Performance and User's Preference. AB - INTRODUCTION: Immersive virtual reality (VR) laparoscopy simulation connects VR simulation with head-mounted displays to increase presence during VR training. The goal of the present study was the comparison of 2 different surroundings according to performance and users' preference. METHODS: With a custom immersive virtual reality laparoscopy simulator, an artificially created VR operating room (AVR) and a highly immersive VR operating room (IVR) were compared. Participants (n = 30) performed 3 tasks (peg transfer, fine dissection, and cholecystectomy) in AVR and IVR in a crossover study design. RESULTS: No overall difference in virtual laparoscopic performance was obtained when comparing results from AVR with IVR. Most participants preferred the IVR surrounding (n = 24). Experienced participants (n = 10) performed significantly better than novices (n = 10) in all tasks regardless of the surrounding ( P < .05). Participants with limited experience (n = 10) showed differing results. Presence, immersion, and exhilaration were significantly higher in IVR. Two thirds assumed that IVR would have a positive influence on their laparoscopic simulator use. CONCLUSION: This first study comparing AVR and IVR did not reveal differences in virtual laparoscopic performance. IVR is considered the more realistic surrounding and is therefore preferred by the participants. PMID- 29504471 TI - Transanal Hemorrhoidal Dearterialization Versus Stapled Hemorrhoidopexy: Long Term Follow-up of a Prospective Randomized Study. AB - AIM: This study aims to compare the early and late outcomes of transanal hemorrhoidal dearterialization (THD) versus stapled hemorrhoidopexy (SH) for the treatment of hemorrhoidal disease. METHODS: From January 2013 to December 2014, 100 patients-50 patients on each arm-were randomly allocated to THD or SH groups. The inclusion criteria were grade III and IV hemorrhoids diagnosed by clinical examination and proctoscopy. The primary outcome was to compare the recurrence rate with a minimum follow-up of 2 years, and the secondary outcome was to compare complications rate, time to return to work postsurgery, procedure length, and patient's satisfaction between the 2 techniques. RESULTS: The mean follow-up period was 33.7 +/- 7.6. The recurrence rate was 4% in the SH group and 16% in the THD group ( P = .04). There was no difference in the intraoperative and postoperative complications rate; the pain score was significantly higher in the THD group. The mean operative time was significantly shorter in the SH group compared with the THD group. Patients in the THD group returned to work or routine activities significantly later compared with patients in the SH group. The overall satisfaction rate was also higher in the SH group. CONCLUSION: Both procedures are simple and easy to perform for the treatment of grade III and IV hemorrhoids. SH showed better results in terms of lower rate of recurrence, lower postoperative pain, quicker return to work, and higher patient satisfaction. PMID- 29504472 TI - The Effects of Exposure to Negative Social Reactions and Participant Gender on Attitudes and Behavior Toward a Rape Victim. AB - Research has shown that judgments of a rape victim could be influenced by exposure to negative social reactions: students indicated less willingness to provide sympathy and support to a hypothetical rape victim when they learned she had been blamed and stigmatized. The current study, which utilized a sample of 100 college students, replicated and extended these results and showed that men were affected by others' negative social reactions in their hypothetical judgments and in their behavioral responses to a rape victim (sitting farther away). This study demonstrates the potentially far-reaching detrimental influence of negative social reactions. PMID- 29504473 TI - Buying Time: Long-Term Results of Wrist Denervation and Time to Repeat Surgery. AB - BACKGROUND: This study reviews long-term outcomes of partial wrist denervation focusing on need for and time to revision procedure. METHODS: A retrospective study was conducted of all patients undergoing partial wrist denervation between 1994 and 2014. At average latest follow-up of 6.75 years (range, 1-21 years), clinical and radiographic data and need for revision surgery were recorded. RESULTS: There were 100 wrists in 89 patients (61 male, 28 female) with average age at surgery of 54 years (range, 26-80). Principal diagnoses were arthritis (58%), inflammatory (19%), and posttraumatic arthritis (7%). Average flexion extension arc was 83% and grip strength 75% of unaffected extremity. Average Mayo Wrist Scores improved from 48 preoperatively to 77 postoperatively. Sixty-nine percent of patients did not undergo other procedures during the time interval studied. Thirty-one percent underwent revision at an average of 26 months following denervation (range, 2-165). CONCLUSIONS: Partial wrist denervation is a motion-preserving procedure for patients with refractory wrist pain with 69% in this series requiring no further procedures. The remaining 31% experienced average symptom relief for 2 years prior to ultimately undergoing revision operation. PMID- 29504474 TI - Patient Satisfaction in the Preoperative Period: Preparing for Hand Surgery. AB - BACKGROUND: The potential impact of the number and type of preoperative encounters on satisfaction rates prior to elective surgical procedures is unclear, specifically scheduling and medical clearance encounters. METHODS: Questionnaires investigating satisfaction with the preoperative process were collected for 200 patients presenting for elective hand surgery. The number of telephone, surgeon, and medical clearance encounters were recorded, and satisfaction was determined for each type based on a 4-category Likert scale. All patients 18 years or older were included, while only patients providing incomplete questionnaires were excluded. Outcome data were assessed for associations between different encounter totals or types and satisfaction rates. RESULTS: Among 200 patients, 197 completed the questionnaire and were included. Overall satisfaction with the preoperative process was 92.9%, with only 3% of patients dissatisfied. There was a significant association between satisfaction and the number of telephone and total encounters. Satisfaction fell below 90% after 4 or more telephone calls (66.6%, P = 0.005) and 5 or more total encounters (80%, P = 0.008). When considered individually, there was no significant association between satisfaction and the number of surgeon ( P = 0.267) or medical office encounters ( P = 0.087), or a patient's perceived health status ( P = 0.14). CONCLUSIONS: Greater than 3 telephone or 4 total encounters significantly decreases patient satisfaction, while surgeon and medical office visits are not associated with satisfaction rates when considered individually. This suggests the number, not the type, of preoperative encounters impact satisfaction and highlight the importance of efficient communication between patients and providers. PMID- 29504475 TI - Morbidity of First Rib Resection in the Surgical Repair of Thoracic Outlet Syndrome. AB - BACKGROUND: Thoracic outlet syndrome (TOS) is a complex entity resulting in neurogenic or vascular manifestations. A wide array of procedures has evolved, each with its own benefits and drawbacks. The authors hypothesized that treatment of TOS with first rib resection (FRR) may lead to increased complication rates. METHODS: A retrospective case control study was performed on the basis of the National Surgical Quality Improvement Program database from 2005 to 2014. All cases involving the operative treatment of TOS were extracted. Primary outcomes included surgical and medical complications. Analyses were primarily stratified by FRR and secondarily by other procedure types. RESULTS: A total of 1853 patients met inclusion criteria. The most common procedures were FRR (64.0%), anterior scalenectomy with cervical rib resection (32.9%), brachial plexus decompression (27.2%), and anterior scalenectomy without cervical rib resection (AS, 8.9%). Factors associated with increased medical complications included American Society of Anesthesiologists (ASA) classification of 3 or greater and increased operative time. The presence or absence of FRR did not influence complication rates. CONCLUSIONS: FRR is not associated with an increased risk of medical or surgical complications. Medical complications are associated with increased ASA scores and longer operative time. PMID- 29504476 TI - Unplanned Reoperation After Surgery for Scapholunate Interosseous Ligament Insufficiency: A Retrospective Review of 316 Patients. AB - BACKGROUND: The purpose of this study was to identify factors associated with unplanned reoperation after surgery for scapholunate interosseous ligament (SLIL) insufficiency. METHODS: Using Current Procedural Terminology (CPT) codes from 3 hand surgery centers across 2 metropolitan areas, we identified 316 patients undergoing surgery for SLIL insufficiency from 2000 to 2014. Medical records were manually reviewed to collect data on factors that might be associated with unplanned reoperation, including age, sex, tobacco use, occupation, acuity of treatment, and reconstruction method. RESULTS: Thirty-eight patients (12%) had an unplanned reoperation; most of them (65%) were a secondary reconstruction or salvage procedure (eg, 6 proximal row carpectomies, 9 revision reconstruction, and 10 partial carpal arthrodeses), while 5 (13%) were for unplanned screw removal. The median time between the index and second surgery was 16 months (range, 2-97 months). The type of index procedure was not associated with reoperation. The only factor associated with reoperation was cigarette smoking, and this association persisted when looking specifically at reoperations for revision or salvage. CONCLUSIONS: Patients should be counseled that smoking is associated with reoperation after SLIL surgery. Smoking cessation or decreasing nicotine usage may be beneficial prior to surgery. With the numbers available, there was no association between surgical technique and reoperation. PMID- 29504477 TI - Surface Replacement Proximal Interphalangeal Joint Arthroplasty: A Case Series. AB - BACKGROUND: In 2012, our unit published our experience with a pyrocarbon proximal interphalangeal joint (PIPJ) implant. Due to high subsidence rates, a decision was made to change to a cemented surface replacement proximal interphalangeal joint (SR-PIPJ) implant. The purpose of this study was to assess whether the change to a cemented implant would improve the subsidence rates. METHODS: Retrospective review of all patients who had a cemented SR-PIPJ arthroplasty performed from 2011 to 2013 with at least 12 months follow-up. RESULTS: A total of 43 joints were included with an average follow-up of 26.5 months. There was a significant ( P = .02) improvement in arc of motion with an average satisfaction score of 3.3 (satisfied patient). Subsidence was noted in 26% of joints with a significant difference in range of motion ( P = .003) and patient satisfaction ( P = .001) between the group with and without subsidence. CONCLUSIONS: The change to a cemented implant resulted in satisfied patients with an improvement in range of motion. The rate of subsidence improved but remains unacceptably high. PMID- 29504479 TI - Featured Article: TGF-beta1 dominates extracellular matrix rigidity for inducing differentiation of human cardiac fibroblasts to myofibroblasts. AB - Cardiac fibroblasts and their activated derivatives, myofibroblasts, play a critical role in wound healing after myocardial injury and often contribute to long-term pathological outcomes, such as excessive fibrosis. Thus, defining the microenvironmental factors that regulate the phenotype of cardiac fibroblasts and myofibroblasts could lead to new therapeutic strategies. Both chemical and biomechanical cues have previously been shown to induce myofibroblast differentiation in many organs and species. For example, transforming growth factor beta 1, a cytokine secreted by neutrophils, and rigid extracellular matrix environments have both been shown to promote differentiation. However, the relative contributions of transforming growth factor beta 1 and extracellular matrix rigidity, two hallmark cues in many pathological myocardial microenvironments, to the phenotype of human cardiac fibroblasts are unclear. We hypothesized that transforming growth factor beta 1 and rigid extracellular matrix environments would potentially have a synergistic effect on the differentiation of human cardiac fibroblasts to myofibroblasts. To test this, we seeded primary human adult cardiac fibroblasts onto coverslips coated with polydimethylsiloxane of various elastic moduli, introduced transforming growth factor beta 1, and longitudinally quantified cell phenotype by measuring expression of alpha-smooth muscle actin, the most robust indicator of myofibroblasts. Our data indicate that, although extracellular matrix rigidity influenced differentiation after one day of transforming growth factor beta 1 treatment, ultimately transforming growth factor beta 1 superseded extracellular matrix rigidity as the primary regulator of myofibroblast differentiation. We also measured expression of POSTN, FAP, and FSP1, proposed secondary indicators of fibroblast/myofibroblast phenotypes. Although these genes partially trended with alpha-smooth muscle actin expression, they were relatively inconsistent. Finally, we demonstrated that activated myofibroblasts incompletely revert to a fibroblast phenotype after they are re-plated onto new surfaces without transforming growth factor beta 1, suggesting differentiation is partially reversible. Our results provide new insights into how microenvironmental cues affect human cardiac fibroblast differentiation in the context of myocardial pathology, which is important for identifying effective therapeutic targets and dictating supporting cell phenotypes for engineered human cardiac disease models. Impact statement Heart disease is the leading cause of death worldwide. Many forms of heart disease are associated with fibrosis, which increases extracellular matrix (ECM) rigidity and compromises cardiac output. Fibrotic tissue is synthesized primarily by myofibroblasts differentiated from fibroblasts. Thus, defining the cues that regulate myofibroblast differentiation is important for understanding the mechanisms of fibrosis. However, previous studies have focused on non-human cardiac fibroblasts and have not tested combinations of chemical and mechanical cues. We tested the effects of TGF-beta1, a cytokine secreted by immune cells after injury, and ECM rigidity on the differentiation of human cardiac fibroblasts to myofibroblasts. Our results indicate that differentiation is initially influenced by ECM rigidity, but is ultimately superseded by TGF-beta1. This suggests that targeting TGF-beta signaling pathways in cardiac fibroblasts may have therapeutic potential for attenuating fibrosis, even in rigid microenvironments. Additionally, our approach can be leveraged to engineer more precise multi-cellular human cardiac tissue models. PMID- 29504478 TI - Targeting dysfunctional beta-cell signaling for the potential treatment of type 1 diabetes mellitus. AB - Since its discovery and purification by Frederick Banting in 1921, exogenous insulin has remained almost the sole therapy for type 1 diabetes mellitus. While insulin alleviates the primary dysfunction of the disease, many other aspects of the pathophysiology of type 1 diabetes mellitus are unaffected. Research aimed towards the discovery of novel type 1 diabetes mellitus therapeutics targeting different cell signaling pathways is gaining momentum. The focus of these efforts has been almost entirely on the impact of immunomodulatory drugs, particularly those that have already received FDA-approval for other autoimmune diseases. However, these drugs can often have severe side effects, while also putting already immunocompromised individuals at an increased risk for other infections. Potential therapeutic targets in the insulin-producing beta-cell have been largely ignored by the type 1 diabetes mellitus field, save the glucagon-like peptide 1 receptor. While there is preliminary evidence to support the clinical exploration of glucagon-like peptide 1 receptor-based drugs as type 1 diabetes mellitus adjuvant therapeutics, there is a vast space for other putative therapeutic targets to be explored. The alpha subunit of the heterotrimeric Gz protein (Galphaz) has been shown to promote beta-cell inflammation, dysfunction, death, and failure to replicate in the context of diabetes in a number of mouse models. Genetic loss of Galphaz or inhibition of the Galphaz signaling pathway through dietary interventions is protective against the development of insulitis and hyperglycemia. The multifaceted effects of Galphaz in regards to beta-cell health in the context of diabetes make it an ideal therapeutic target for further study. It is our belief that a low-risk, effective therapy for type 1 diabetes mellitus will involve a multidimensional approach targeting a number of regulatory systems, not the least of which is the insulin-producing beta-cell. Impact statement The expanding investigation of beta-cell therapeutic targets for the treatment and prevention of type 1 diabetes mellitus is fundamentally relevant and timely. This review summarizes the overall scope of research into novel type 1 diabetes mellitus therapeutics, highlighting weaknesses or caveats in current clinical trials as well as describing potential new targets to pursue. More specifically, signaling proteins that act as modulators of beta-cell function, survival, and replication, as well as immune infiltration may need to be targeted to develop the most efficient pharmaceutical interventions for type 1 diabetes mellitus. One such beta-cell signaling pathway, mediated by the alpha subunit of the heterotrimeric Gz protein (Galphaz), is discussed in more detail. The work described here will be critical in moving the field forward as it emphasizes the central role of the beta-cell in type 1 diabetes mellitus disease pathology. PMID- 29504480 TI - Association of neurologist care with headache expenditures: A population-based, longitudinal analysis. AB - Objective To assess the association of neurologist ambulatory care with healthcare utilization and expenditure in headache. Methods This was a longitudinal cohort study from two-year duration panel data, pooled from 2002 2013, of adult respondents identified with diagnostic codes for headache in the Medical Expenditure Panel Survey. Those with a neurologist ambulatory care visit in year one of panel participation were compared with those who did not for the change in annual aggregate direct headache-related health care costs from year one to year two of panel participation, inflated to 2015 US dollars. Results were adjusted via multiple linear regression for demographic and clinical variables, utilizing survey variables for accurate estimates and standard errors. Results Eight hundred and eighty-seven respondents were included, with 23.3% (207/887) seeing a neurologist in year one. The neurologist group had higher year-one mean headache-related expenditures ($3032 vs. $1636), but nearly equal mean year-two expenditures compared to controls ($1900 vs. $1929). Adjusted association between neurologist care and difference in mean annual expenditures from year two to year one was -$1579 (95% CI -$2468, -$690, p < 0.001). Conclusion Among headache sufferers, particularly those with higher headache-related healthcare expenditures, neurologist care is associated with a significant reduction in costs over two years. PMID- 29504481 TI - Alien hand syndrome and migraine with aura: A case report. AB - BACKGROUND: Alien Hand Syndrome (AHS) is an uncontrollable, involuntary, but in appearance, purposeful motor control disorder of the upper extremity. CASE REPORT: A 42-year-old male patient was admitted to our clinic complaining of involuntary motor activity in his right hand. He had a previous history of migraine with visual aura. The uncontrollable motor control disorder was compatible with Alien Hand Syndrome, which was appearing immediately after the visual aura and before the beginning of headache. CONCLUSION: Alien Hand Syndrome is usually observed with anterior cerebral artery infarction, midline tumors, trauma and several neurodegenerative diseases, but is rarely seen in paroxysmal conditions such as migraine with aura. PMID- 29504482 TI - Guidelines of the International Headache Society for controlled trials of preventive treatment of chronic migraine in adults. AB - Background Quality clinical trials form an essential part of the evidence base for the treatment of headache disorders. In 1991, the International Headache Society Clinical Trials Standing Committee developed and published the first edition of the Guidelines for Controlled Trials of Drugs in Migraine. In 2008, the Committee published the first specific guidelines on chronic migraine. Subsequent advances in drug, device, and biologicals development, as well as novel trial designs, have created a need for a revision of the chronic migraine guidelines. Objective The present update is intended to optimize the design of controlled trials of preventive treatment of chronic migraine in adults, and its recommendations do not apply to trials in children or adolescents. PMID- 29504484 TI - Responsive Aggression Regulation Therapy (Re-ART): An Evaluation Study in a Dutch Juvenile Justice Institution in Terms of Recidivism. AB - This article describes a quasi-experimental study of the effectiveness of Responsive Aggression Regulation Therapy (Re-ART) in terms of recidivism for 16- to 21-year-old juveniles with aggression problems and high risk of recidivism. In a Dutch juvenile justice institution, an experimental group received Re-ART ( n = 63, Re-ART group) and a waitlist control group received Treatment as Usual ( n = 28, TAU group). Results indicated that Re-ART is significantly more effective than TAU in reducing the juveniles' recidivism risk for violent offending. Compared with the TAU group, the Re-ART group showed significantly less violent crimes after 2 and 3 years, less property crimes after 2 years, and less general recidivism after 2 and 3 years. There was no significant difference between groups in recidivism of property crimes with violence. Ethnicity, mild intellectual disabilities, substance abuse, and age did not moderate the effects on recidivism outcome, which indicates that Re-ART was equally effective for various groups. PMID- 29504483 TI - A multicenter, prospective, single arm, open label, observational study of sTMS for migraine prevention (ESPOUSE Study). AB - Objective To evaluate the efficacy and tolerability of single pulse transcranial magnetic stimulation (sTMS) for the preventive treatment of migraine. Background sTMS was originally developed for the acute treatment of migraine with aura. Open label experience has suggested a preventive benefit. The objective of this trial was to evaluate the efficacy and tolerability of sTMS for migraine prevention. Methods The eNeura SpringTMS Post-Market Observational U.S. Study of Migraine (ESPOUSE) Study was a multicenter, prospective, open label, observational study. From December 2014 to March 2016, patients with migraine (n = 263) were consented to complete a 1-month baseline headache diary followed by 3 months of treatment. The treatment protocol consisted of preventive (four pulses twice daily) and acute (three pulses repeated up to three times for each attack) treatment. Patients reported daily headache status, medication use, and device use with a monthly headache diary. The primary endpoint, mean reduction of headache days compared to baseline, was measured over the 28-day period during weeks 9 to 12. The primary endpoint was compared to a statistically-derived placebo estimate (performance goal). Secondary endpoints included: 50% responder rate, acute headache medication consumption, HIT-6, and mean reduction in total headache days from baseline of any intensity. Results Of a total of 263 consented subjects, 229 completed a baseline diary, and 220 were found to be eligible based on the number of headache days. The device was assigned to 217 subjects (Safety Data Set) and 132 were included in the intention to treat Full Analysis Set. For the primary endpoint, there was a -2.75 +/- 0.40 mean reduction of headache days from baseline (9.06 days) compared to the performance goal (-0.63 days) ( p < 0.0001). The 50% responder rate of 46% (95% CI 37%, 56%) was also significantly higher ( p < 0.0001) than the performance goal (20%). There was a reduction of -2.93 (5.24) days of acute medication use, headache impact measured by HIT-6, -3.1 (6.4) ( p < 0.0001), and total headache days of any intensity -3.16 days (5.21) compared to the performance goal (-0.63 days) ( p < 0.0001). The most common adverse events were lightheadedness (3.7%), tingling (3.2%), and tinnitus (3.2%). There were no serious adverse events. Conclusions This open label study suggests that sTMS may be an effective, well-tolerated treatment option for migraine prevention. Trial registration number NCT02357381. PMID- 29504485 TI - Framing the Mind-Body Problem in Contemporary Neuroscientific and Sunni Islamic Theological Discourse. AB - Famously posed by seventeenth-century French philosopher Rene Descartes, the mind body problem remains unresolved in western philosophy and science, with both disciplines unable to move convincingly beyond the dualistic model. The persistence of dualism calls for a reframing of the problem through interdisciplinary modes of inquiry that include non-western points of view. One such perspective is Islamic theology of the soul, which, while approaching the problem from a distinct point of view, also adopts a position commensurate with (substance) dualism. Using this point of convergence as a conceptual starting point, we argue that bringing into dialogue contemporary neuroscientific, philosophy of mind, and Sunni Islamic theological discourses may provide a fruitful way of reframing the age-old mind-body problem. This paper provides an overview of how these three discourses have approached the issue of the mind-body (-soul) problem. Juxtaposing these three discourses, we hope, may ignite further scholarly dialogue and investigation. PMID- 29504486 TI - Early fecal microbiota composition in children who later develop celiac disease and associated autoimmunity. AB - OBJECTIVES: Several studies have reported that the intestinal microbiota composition of celiac disease (CD) patients differs from healthy individuals. The possible role of gut microbiota in the pathogenesis of the disease is, however, not known. Here, we aimed to assess the possible differences in early fecal microbiota composition between children that later developed CD and healthy controls matched for age, sex and HLA risk genotype. MATERIALS AND METHODS: We used 16S rRNA gene sequencing to examine the fecal microbiota of 27 children with high genetic risk of developing CD. Nine of these children developed the disease by the age of 4 years. Stool samples were collected at the age of 9 and 12 months, before any of the children had developed CD. The fecal microbiota composition of children who later developed the disease was compared with the microbiota of the children who did not have CD or associated autoantibodies at the age of 4 years. Delivery mode, early nutrition, and use of antibiotics were taken into account in the analyses. RESULTS: No statistically significant differences in the fecal microbiota composition were found between children who later developed CD (n = 9) and the control children without disease or associated autoantibodies (n = 18). CONCLUSIONS: Based on our results, the fecal microbiota composition at the age of 9 and 12 months is not associated with the development of CD. Our results, however, do not exclude the possibility of duodenal microbiota changes or a later microbiota-related trigger for the disease. PMID- 29504487 TI - Parallel stent grafts for the treatment of complex aortic aneurysms: A single center study. AB - Background "Chimney" techniques with parallel grafts used in order to extend the landing zones in endovascular aneurysm repair (ch-EVAR) are increasingly being reported. Conflicting data has been reported regarding the success and durability of the repair. We report a single center experience using ch-EVAR in treating complex aortic pathologies. Methods We performed a retrospective review of all patients treated with ch-EVAR in our institution between 2013 and 2017. Data collected included patients demographics, indications for surgery, configuration of parallel grafts, technical success, and perioperative morbidity and mortality. Follow-up data included aortic sac size, reintervention rate, and overall mortality. Results Thirty-five patients underwent treatment of their aneurysms with parallel grafts. Sixty parallel grafts were placed. Mean age was 75 years (range 59-93) and 30 (85%) were male. Technical success was achieved in 32 (91%) patients. Mean follow up was 12 months. Sac size decreased in diameter or remained unchanged in 26 of the 30 (86.6%) patients. Four patients were found to have enlarging aneurysms due to gutter endoleaks. All were treated successfully with endovascular methods. The estimated primary patency was 95% at 12 months. Probability of freedom from intervention was 75% at 12 months. No late aneurysm related mortality occurred. Conclusion The use of ch-EVAR in treating complex aortic aneurysms is technically feasible and safe. Gutter endoleaks are encountered only in a minority of the cases, and can be treated with minimally invasive techniques. Longer term follow up is required to evaluate the patency of these parallel grafts and the durability of the aneurysm exclusion. PMID- 29504488 TI - "It's Like a Cyber-Security Blanket": The Utility of Remote Activity Monitoring in Family Dementia Care. AB - Technologies have emerged that aim to help older persons with Alzheimer's disease and related dementias (ADRDs) remain at home while also supporting their caregiving family members. However, the usefulness of these innovations, particularly in home-based care contexts, remains underexplored. The current study evaluated the acceptability and utility of an in-home remote activity monitoring (RAM) system for 30 family caregivers of persons with ADRD via quantitative survey data collected over a 6-month period and qualitative survey and interview data collected for up to 18 months. A parallel convergent mixed methods design was employed. The integrated qualitative and quantitative data suggested that RAM technology offered ongoing monitoring and provided caregivers with a sense of security. Considerable customization was needed so that RAM was most appropriate for persons with ADRD. The findings have important clinical implications when considering how RAM can supplement, or potentially substitute for, ADRD family care. PMID- 29504489 TI - An Action Research to Optimize the Well-Being of Older People in Nursing Homes: Challenges and Strategies for Implementing a Complex Intervention. AB - Few studies have been conducted on strategies to promote the implementation of complex interventions in nursing homes (NHs). This article presents a pilot study intended to assess the strategies that would enable the optimal implementation of a complex intervention approach in NHs based on the meanings of screams of older people living with Alzheimer's disease. An action research approach was used with 19 formal and family caregivers from five NHs. Focus groups and individual interviews were held to assess different implementation strategies. A number of challenges were identified, as were strategies to overcome them. These latter included interactive training, intervention design, and external support. This study shows the feasibility of implementing a complex intervention to optimize older people's well-being. The article shares strategies that may promote the implementation of these types of interventions in NHs. PMID- 29504490 TI - Does postauricular fascial flap reduce suture complications in otoplasty? AB - Numerous suture techniques and covering flaps have been described to minimize complications related to sutures in otoplasty. The split postauricular fascial flap is one of such techniques, and it has been used to pad otoplasty suture. The aim of this study was to evaluate complications related to nonabsorbable cartilage sutures in otoplasty, using a variation of the split postauricular fascial flap. In this retrospective case series, we analyzed otoplasty patients in whom simplified split postauricular fascial flap was utilized. A postauricular skin ellipse was de-epithelialized (preserving dermis) and a longitudinally split in half. Flaps were dissected, and they were positioned on the cartilage to promote additional soft tissue coverage to the sutures. The lateral flap covered conchoscaphal sutures while the medial flap covered the conchomastoid sutures. Both the flaps were not sutured to cartilage. Early and late postoperative complications were evaluated. A total of 142 patients were included. Twenty-four (16.9%) patients developed late complications: 13 (9.1%) patients had palpable and visible sutures, nine (6.3%) had suture extrusion and two (1.4%) had hypertrophic scars. In this case series, the simplified split postauricular flap did not prevent or reduce late complications related to suture extrusion in otoplasty. It is possible that suturing the entire length of the flaps may play a role in our results. So, anchoring the flap and possibly tightening it a little may be an important technical step to prevent extrusion of sutures whenever the postauricular flap is used. PMID- 29504491 TI - Unbound bilirubin measurements by a novel probe in preterm infants. AB - BACKGROUND: Hyperbilirubinemia occurs in over 80% of newborns and severe bilirubin toxicity can lead to neurological dysfunction and death, especially in preterm infants. Currently, the risk of bilirubin toxicity is assessed by measuring the levels of total serum bilirubin (TSB), which are used to direct treatments including immunoglobulin administration, phototherapy, and exchange transfusion. However, free, unbound bilirubin levels (Bf) predict the risk of bilirubin neurotoxicity more accurately than TSB. OBJECTIVE: To examine Bf levels in preterm infants and determine the frequency with which they exceed reported neurotoxic thresholds. METHODS: One hundred thirty preterm infants (BW 500-2000 g; GA 23-34 weeks) were enrolled and Bf levels measured during the first week of life by the fluorescent Bf sensor BL22P1B11-Rh. TSB and plasma albumin were measured by standard techniques. Bilirubin-albumin dissociation constants (Kd) were calculated based on Bf and plasma albumin. RESULTS: Five hundred eighty samples were measured during the first week of life, with an overall mean Bf of 13.6 +/- 9.0 nM. A substantial number of measurements exceeded potential toxic thresholds levels as reported in the literature. The correlation between Bf and TSB was statistically significant (r2 0.17), but this weak relationship was lost at high Bf levels. Infants <28-week gestations had more hearing screening failures than infants >=28-week gestation. CONCLUSIONS: Unbound (free) bilirubin values are extremely variable during the first week of life in preterm infants. A significant proportion of these values exceeded reported neurotoxic thresholds. PMID- 29504492 TI - Coinheritance of 2 New Potentially Damaging Heterozygous COL7A1 Variants in a Family With Autosomal Dominant Epidermolysis Bullosa Pruriginosa. AB - Epidermolysis bullosa pruriginosa (EBP) is a rare subtype of EB which is characterized by intense pruritus with blistering and nodular or lichenoid lesions most prominent on the lower extremities. It is caused by variants in COL7A1 which encodes for type VII collagen. There is wide phenotypic and genotypic variability between affected individuals. We report 2 potentially pathogenic variants in COL7A1 occurring on the same allele in a family with EBP and autosomal dominant inheritance. Late-onset EBP and incomplete penetrance may lead to delayed presentation in affected family members with the same variants. The broad phenotypic variability seen in EBP suggests that further genotypic and environmental factors may influence presentation. Genetic and histopathological diagnosis is essential, given the considerable overlap with clinically similar presentations such as hypertrophic lichen planus. PMID- 29504493 TI - Epithelium Lining Rat Renal Papilla: Nomenclature and Association with Chronic Progressive Nephropathy (CPN). AB - Chronic progressive nephropathy (CPN) occurs commonly in rats, more frequently and severely in males than females. High-grade CPN is characterized by increased layers of the renal papilla lining, designated as urothelial hyperplasia in the International Harmonization of Nomenclature and Diagnostic Criteria classification. However, urothelium lining the pelvis is not equivalent to the epithelium lining the papilla. To evaluate whether the epithelium lining the renal papilla is actually urothelial in nature and whether CPN-associated multicellularity represents proliferation, kidney tissues from aged rats with CPN, from rats with multicellularity of the renal papilla epithelium of either low-grade or marked severity, and from young rats with normal kidneys were analyzed and compared. Immunohistochemical staining for uroplakins (urothelial specific proteins) was negative in the papilla epithelium in all rats with multicellularity or not, indicating these cells are not urothelial. Mitotic figures were rarely observed in this epithelium, even with multicellularity. Immunohistochemical staining for Ki-67 was negative. Papilla lining cells and true urothelium differed by scanning electron microscopy. Based on these findings, we recommend that the epithelium lining the papilla not be classified as urothelial, and the CPN-associated lesion be designated as vesicular alteration of renal papilla instead of hyperplasia and distinguished in diagnostic systems from kidney pelvis urothelial hyperplasia. PMID- 29504494 TI - A 3-month Safety Assessment of Human Bone Marrow Derived Mesenchymal Stromal Cells Administered Once by the Intramuscular Route to Immunodeficient Mice. AB - Critical limb ischemia (CLI) represents the severest manifestation of peripheral arterial disease and is a major unmet medical need. This disease occurs when the arterial blood supply within the limb fails to meet the metabolic demands of the resting muscle or tissue, resulting in chronic ischemic rest pain and/or tissue necrosis. Human mesenchymal stromal cells, termed hMSCs, represent an exciting therapeutic modality for the treatment of this disease due to their immunomodulatory and tissue reparative functions. The aim of the study was to assess the preclinical toxicity profile of human bone marrow-derived MSCs in support of their use as a treatment for CLI. A 3-month toxicity study was carried out under good laboratory practices in immunodeficient mice who received, intramuscularly, a single dose of 3 * 105 (approximately 15 * 106 cells/kg) hMSCs manufactured under good manufacturing practices. No significant changes in body weight, food consumption, clinical signs, or histopathological changes were observed in the hMSC-treated mice in comparison to the controls. These results highlight that the administration of hMSCs during the 3-month study period was well tolerated and not associated with any test item-related tumors. This data set supported the initiation of a phase 1b first in human study in "no option" for revascularization patients with CLI. PMID- 29504495 TI - Shoulder muscular activity in individuals with low back pain and spinal cord injury during seated manual load transfer tasks. AB - This study aimed to compare the activity of four shoulder muscles in individuals with low back pain (LBP), spinal cord injuries (SCI) and a control group, during one-handed load transfer trials. Nine individuals with minimum one-year of LBP, eleven with thoracic/lumbar SCI and nine healthy controls participated in this study. The activations of anterior deltoid, upper trapezius, infraspinatus and pectoralis major were recorded by surface EMG during one-handed transferring of a cylinder from a home shelve to six spatially distributed target shelves. The integrated EMG values were compared using repeated measure ANOVA. Both LBPs and SCIs had higher anterior deltoid activation and LBPs required more upper trapezius activation than controls (p < 0.05). The spatial position of the targets also significantly influenced demands for these two muscles. The anterior deltoid and upper trapezius in LBP and SCI individuals are under higher demand during occupational load transfer tasks. Practitioner Summary: This study aimed to compare the activation of four shoulder muscles in individuals with low back pain, spinal cord injuries and healthy condition. EMG analysis showed that the injured groups required more upper trapezius and anterior deltoid activation during load transfer tasks, which may predispose them to muscle overexertion. PMID- 29504496 TI - On improving child health: a commentary on the Scottish GP paediatric scholars project. PMID- 29504497 TI - Mechanisms of inflammatory responses to radiation and normal tissues toxicity: clinical implications. AB - PURPOSE: Cancer treatment is one of the most challenging diseases in the present era. Among a few modalities for cancer therapy, radiotherapy plays a pivotal role in more than half of all treatments alone or combined with other cancer treatment modalities. Management of normal tissue toxicity induced by radiation is one of the most important limiting factors for an appropriate radiation treatment course. The evaluation of mechanisms of normal tissue toxicity has shown that immune responses especially inflammatory responses play a key role in both early and late side effects of exposure to ionizing radiation (IR). DNA damage and cell death, as well as damage to some organelles such as mitochondria initiate several signaling pathways that result in the response of immune cells. Massive cell damage which is a common phenomenon following exposure to a high dose of IR cause secretion of a lot of inflammatory mediators including cytokines and chemokines. These mediators initiate different changes in normal tissues that may continue for a long time after irradiation. In this study, we reviewed the mechanisms of inflammatory responses to IR that are involved in normal tissue toxicity and considered as the most important limiting factors in radiotherapy. Also, we introduced some agents that have been proposed for management of these responses. CONCLUSIONS: The early inflammation during the radiation treatment is often a limiting factor in radiotherapy. In addition to the limiting factors, chronic inflammatory responses may increase the risk of second primary cancers through continuous free radical production, attenuation of tumor suppressor genes, and activation of oncogenes. Moreover, these effects may influence non-irradiated tissues through a mechanism named bystander effect. PMID- 29504500 TI - Escalating Inhaled Glucocorticoids to Prevent Asthma Exacerbations. PMID- 29504499 TI - Quadrupling Inhaled Glucocorticoid Dose to Abort Asthma Exacerbations. AB - BACKGROUND: Asthma exacerbations are frightening for patients and are occasionally fatal. We tested the concept that a plan for patients to manage their asthma (self-management plan), which included a temporary quadrupling of the dose of inhaled glucocorticoids when asthma control started to deteriorate, would reduce the incidence of severe asthma exacerbations among adults and adolescents with asthma. METHODS: We conducted a pragmatic, unblinded, randomized trial involving adults and adolescents with asthma who were receiving inhaled glucocorticoids, with or without add-on therapy, and who had had at least one exacerbation in the previous 12 months. We compared a self-management plan that included an increase in the dose of inhaled glucocorticoids by a factor of 4 (quadrupling group) with the same plan without such an increase (non-quadrupling group), over a period of 12 months. The primary outcome was the time to a first severe asthma exacerbation, defined as treatment with systemic glucocorticoids or an unscheduled health care consultation for asthma. RESULTS: A total of 1922 participants underwent randomization, of whom 1871 were included in the primary analysis. The number of participants who had a severe asthma exacerbation in the year after randomization was 420 (45%) in the quadrupling group as compared with 484 (52%) in the non-quadrupling group, with an adjusted hazard ratio for the time to a first severe exacerbation of 0.81 (95% confidence interval, 0.71 to 0.92; P=0.002). The rate of adverse effects, which were related primarily to local effects of inhaled glucocorticoids, was higher in the quadrupling group than in the non-quadrupling group. CONCLUSIONS: In this trial involving adults and adolescents with asthma, a personalized self-management plan that included a temporary quadrupling of the dose of inhaled glucocorticoids when asthma control started to deteriorate resulted in fewer severe asthma exacerbations than a plan in which the dose was not increased. (Funded by the Health Technology Assessment Programme of the National Institute for Health Research; Current Controlled Trials number, ISRCTN15441965 .). PMID- 29504501 TI - Structural barriers to South African volunteer home-based caregivers providing quality care: the need for a policy for caregivers not affiliated to primary healthcare clinics. AB - Community home-based care (CHBC) is a critical component of non-formal care in communities in Africa that have a high prevalence of HIV and tuberculosis (TB). Community carers consisting primarily of volunteers are critical role players in African healthcare systems and particularly in South Africa's strategy to fight HIV and AIDS. This paper explores the structural barriers volunteer caregivers need to overcome to provide quality CHBC. The researchers used two focus group discussions with key informants (each with four participants), and semi structured interviews with six key informants to collect data relating to the meaning of quality CHBC. The data were coded using Tesch's data analysis technique. A major theme that emerged from the results was "Addressing structural challenges to improve the quality of CHBC". Subthemes underpinning this theme were: 1) lack of standardised training of volunteer caregivers; 2) the need for a scope of practice, parameters and legal boundaries; 3) lack of monitoring and evaluation (M&E) of CHBC; and 4) the importance of mentoring and supervision in CHBC. CHBC policy should address the need for standardised training programmes for caregivers, so that they are equipped with multiple skills. Furthermore CHBC policy must emphasise mentoring as well as M&E to encourage quality care. Finally, the policy should provide a clear scope of practice for caregivers to regulate their competencies and boundaries. PMID- 29504502 TI - Teenage pregnancies in Mozambique: the experience of "Servicios Amigos dos Adolescentes" clinics in Beira. AB - The purpose of this article is to provide insights into the demand for pregnancy related health services by adolescent girls and young women in Mozambique. We analysed the patient registers for the first year of operation (2014) of the Servicios Amigos dos Adolescentes (SAAJ) [Friendly Services for Adolescents] clinics in Beira, Mozambique. These registers provide details of the service demands of, and services provided to the 8 290 adolescent girls and young women who accessed the 6 SAAJ clinics in 2014. Analysis of that record, with disaggregation of the patients according to age (9 years or less; 10-14; 15-19; 20-24; 25 and older), show that 3 021 (36%) were pregnant or had previously been pregnant; most being girls in the 15-19 age band (59%). Being pregnant or having been pregnant previously was associated with dropping out of school. Of all the girls and women, 60% agreed to HIV testing and counselling; the HIV prevalence rate amongst this group was 4-5% amongst adolescents and 25% amongst women 25 years and older. A minority of the girls and women who were pregnant or had been pregnant previously agreed to HIV testing and counselling. Notwithstanding the limitations for analysis, the results were alarming: substantially high HIV prevalence rates were indicated (2% amongst 10-14 year old girls; 8% amongst 15 19 year olds; 10% amongst 20-24 year olds; and 28% amongst >24 year olds). The data from the SAAJ clinics and results pertain only to conditions in Beira. However, as the first empirical assessment of pregnancy-related service demand amongst adolescent girls and young women in the country and involving a relatively large sample, we contend that this study affirms the need for expansion of sexual and reproductive health (SRH) services, including HIV services, for adolescent girls and young women in Mozambique. PMID- 29504503 TI - Managing HIV-positive sero-status in Ghana's most HIV concentrated district: self perceived explanations and theoretical discourse. AB - As of December 2015 there were 37 million persons living with HIV/AIDS (PLWHAs), 70% of whom are in sub-Saharan Africa. Ghana, which contributes a relatively small number to Africa's HIV burden, has a generalised HIV epidemic. The current national prevalence is 1.47%. Agormanya, one of the HIV sentinel sites in the county and where this study was conducted, has current prevalence of 11.6%. This makes it critical to explore how persons infected with HIV manage their lives, especially in the midst of entrenched stigma and discrimination. However, available information on how PLWHAs in sub-Saharan Africa handle their day-to-day lives mostly dwell on food and nutrition. Thus, there is dearth of information on how PLWHAs in Ghana particularly handle the circumstances of their daily lives which are mostly coloured by their HIV-positive statuses, given their stigmatised identity. We explore how PLWHAs respond to the experiences and challenges of living with HIV/AIDS in Lower Manya Krobo, consistently most HIV-infected district in Ghana. Data were collected from 38 combined purposive and randomly selected HIV-positive persons in two leading hospitals (St Martins Depores Agormanya and Atua Government hospitals which provide specialised HIV care in the district. Using in-depth interviews, we studied how PLWHAs managed their routine livelihoods in the midst of extreme stigma. We combined the social capital and resilience theoretical frameworks to show that our respondents were mostly resilient and strategically mostly drew upon extended family social support to cope with their livelihood challenges. We recommend that community opinion leaders and other stakeholders sensitise community members in Lower Manya Krobo to better understand the mode of HIV infection and encourage/strengthen family and community cohesion and social support. PMID- 29504504 TI - The role of community health workers in supporting South Africa's HIV/ AIDS treatment programme. AB - Community health workers deployed around South Africa's primary health care clinics, supply indispensable support for the world's largest HIV/AIDS treatment programme. Interviews with these workers illuminated the contribution they make to anti-retroviral treatment (ART) of HIV/AIDS patients and the motivations that sustain their engagement. Their testimony highlights points of stress in the programme and supplies insights into the quality of its implementation. Finally, the paper addresses issues about the sustainability of a programme that depends on a group of workers who are not yet fully incorporated into the public sector. PMID- 29504498 TI - Quintupling Inhaled Glucocorticoids to Prevent Childhood Asthma Exacerbations. AB - BACKGROUND: Asthma exacerbations occur frequently despite the regular use of asthma-controller therapies, such as inhaled glucocorticoids. Clinicians commonly increase the doses of inhaled glucocorticoids at early signs of loss of asthma control. However, data on the safety and efficacy of this strategy in children are limited. METHODS: We studied 254 children, 5 to 11 years of age, who had mild to-moderate persistent asthma and had had at least one asthma exacerbation treated with systemic glucocorticoids in the previous year. Children were treated for 48 weeks with maintenance low-dose inhaled glucocorticoids (fluticasone propionate at a dose of 44 MUg per inhalation, two inhalations twice daily) and were randomly assigned to either continue the same dose (low-dose group) or use a quintupled dose (high-dose group; fluticasone at a dose of 220 MUg per inhalation, two inhalations twice daily) for 7 days at the early signs of loss of asthma control ("yellow zone"). Treatment was provided in a double-blind fashion. The primary outcome was the rate of severe asthma exacerbations treated with systemic glucocorticoids. RESULTS: The rate of severe asthma exacerbations treated with systemic glucocorticoids did not differ significantly between groups (0.48 exacerbations per year in the high-dose group and 0.37 exacerbations per year in the low-dose group; relative rate, 1.3; 95% confidence interval, 0.8 to 2.1; P=0.30). The time to the first exacerbation, the rate of treatment failure, symptom scores, and albuterol use during yellow-zone episodes did not differ significantly between groups. The total glucocorticoid exposure was 16% higher in the high-dose group than in the low-dose group. The difference in linear growth between the high-dose group and the low-dose group was -0.23 cm per year (P=0.06). CONCLUSIONS: In children with mild-to-moderate persistent asthma treated with daily inhaled glucocorticoids, quintupling the dose at the early signs of loss of asthma control did not reduce the rate of severe asthma exacerbations or improve other asthma outcomes and may be associated with diminished linear growth. (Funded by the National Heart, Lung, and Blood Institute; STICS ClinicalTrials.gov number, NCT02066129 .). PMID- 29504505 TI - Estimating risk factors for HIV infection among women in Mozambique using population-based survey data. AB - The use of population-based survey data together with sound statistical methods can enhance better estimation of HIV risk factors and explain variations across subgroups of the population. The distribution and determinants of HIV infection in populations must be taken into consideration. We analysed data from the HIV Prevalence and Behaviour Survey in Mozambique aiming to find risk factors associated with HIV infection among Mozambican women. The paper provides a complex survey logistic regression model to explain the variation in HIV seropositivity using demographic, socio-economic and behavioural factors. Results show that women aged 25-29 years, living in female-headed households, living in richer households and those widowed, divorced or not living with a partner have higher odds of being HIV-positive. Findings from our study provide a unique and integrated perspective on risk factors for being HIV-positive among Mozambican women and could support the implementation of programmes aiming to reduce HIV infection in Mozambique. PMID- 29504506 TI - The role of children in their HIV-positive parents' management of antiretroviral therapy in Uganda. AB - Adjustment to life on antiretroviral therapy (ART) and living with HIV as a long term chronic condition, pose significant medical, social and economic challenges. We investigated children's role in supporting HIV-positive parents to self-manage life on ART. Between 2010 and 2012, we conducted a qualitative study using semi structured interviews with 38 HIV-positive parents who had been on ART for over a year. They were randomly selected from people accessing ART from three delivery sites in Wakiso district, Uganda. Data were analysed thematically. Participants reported children between the ages of 1 and 47 years providing support. Children were a source of happiness, self-worth, encouragement, and comfort. Both younger and older children supported parents' adherence to treatment through reminding them to take the drugs and honour clinic appointments. Older children provided money to buy medication, food and shelter. Parents reported that the encouragement they received after they disclosed to their children enhanced their survival. After HIV disclosure to their children many of their fears about the future were allayed. Thinking about their children's future brought hope. However, looking after younger children while on ART could be burdensome since some parents could not work to their full capacity due to reduced physical health. Children are an important resource in their parents' adjustment to living with HIV while taking ART. There is a need for children to be supported by appropriate policy and other social and health development structures. PMID- 29504507 TI - Community perceptions of the socio-economic structural context influencing HIV and TB risk, prevention and treatment in a high prevalence area in the era of antiretroviral therapy. AB - Following calls for targeted HIV prevention interventions in so-called "hotspots", we explored subjective perceptions of community members in places considered to be high HIV and tuberculosis (TB) transmission areas and those with low prevalence. Although more people now have access to antiretroviral therapy (ART), some areas are still experiencing high HIV transmission rates, presenting a barrier to the elimination of HIV. A rapid qualitative assessment approach was used to access a sample of 230 people who contributed narratives of their experiences and perceptions of transmission, treatment and prevention of HIV and TB in their communities. Theoretical propositions case study strategy was used to inform and guide the thematic analysis of the data with Research Department of Epidemiology & Public Health, University College London, London, UK. Our results support the concept of linking perceived control to health through the identification of structural factors that increase communities' sense of agency. People in these communities did not feel they had the efficacy to effect change in their milieu. The few socio-economic opportunities promote social mobility in search of better prospects which may have a negative impact on community cohesion and prevention strategies. Communities were more concerned with improving their immediate social and economic situations and prioritised this above the prevention messages. Therefore approaches that focus on changing the structural and environmental barriers to prevention may increase people's perceived control. Multifaceted strategies that address the identified constructs of perceived control may influence the social change necessary to make structural interventions successful. PMID- 29504509 TI - Chronic hepatitis E in a heart transplant patient: sofosbuvir and ribavirin regimen not fully effective. AB - Hepatitis E virus (HEV) can induce chronic infections in the case of immunosuppression, which are sometimes not cured with ribavirin. Furthermore, sofosbuvir is a highly potent inhibitor of HCV polymerase and was shown to inhibit HEV genotype-3 replication in vitro. We report here the outcome of sofosbuvir/ribavirin therapy on a chronic HEV infection in a heart transplant recipient non-responder to ribavirin. After 24 weeks, the regimen failed to cure the persistent HEV infection, highlighting the need of therapeutic options for HEV-infected immunosuppressed patients. PMID- 29504510 TI - HCV genotype-3h, a difficult-to-diagnose sub-genotype in the DAA era. AB - BACKGROUND: No data are available on the clinical presentation and virological pattern in the case of failure of interferon (IFN)-free regimens in patients with genotype-3h. In this paper authors identified the virological and clinical characteristics of patients with genotype-3h treated with suboptimal or not indicated IFN-free regimens for the misclassification of HCV genotype. METHODS: A total of 87 consecutive patients with failure to an IFN-free regimen were re tested for HCV genotype by HCV NS5B sequencing; the 26 patients identified as harbouring HCV-3 were enrolled. RESULTS: Of the 26 patients enrolled, 4 (15.4%) harboured sub-genotype-3h and 22 (84.6%) 3a. All patients were Italian. Patients with genotype-3a infection were younger (median age 56 years, range 47-78) compared to those with genotype-3h infection (median 74 years, range 65-79; P<0.006). With regard to the failed direct-acting antiviral (DAA)-regimens, three of the four patients with genotype-3h (75%) had been treated with an ineffective DAA regimen (paritaprevir, ombitasvir, dasabuvir +/- ribavirin for 3 months) more frequently than those with genotype-3a (13.6%; P=0.02), because of previous erroneous identification of HCV-1 genotype. NS5A resistance-associated substitutions (RASs) were observed in 10 (45.4%) genotype-3a-infected patients and in 2 (50%) with genotype-3h. NS5B RASs were observed in only two genotype-3a infected patients and in none of the 3h-infected patients. CONCLUSIONS: This is the first time genotype-3h has been identified in Italian patients failing an IFN free regimen, in the majority of cases because of a misclassification of the HCV genotype. PMID- 29504511 TI - Tunable conductivity in mesoporous germanium. AB - Germanium-based nanostructures have attracted increasing attention due to favourable electrical and optical properties, which are tunable on the nanoscale. High densities of germanium nanocrystals are synthesized via electrochemical etching, making porous germanium an appealing nanostructured material for a variety of applications. In this work, we have demonstrated highly tunable electrical conductivity in mesoporous germanium layers by conducting a systematic study varying crystallite size using thermal annealing, with experimental conductivities ranging from 0.6 to 33 (*10-3) Omega-1 cm-1. The conductivity of as-prepared mesoporous germanium with 70% porosity and crystallite size between 4 and 10 nm is shown to be ~0.9 * 10-3 Omega-1 cm-1, 5 orders of magnitude smaller than that of bulk p-type germanium. Thermal annealing for 10 min at 400 degrees C further reduced the conductivity; however, annealing at 450 degrees C caused a morphological transformation from columnar crystallites to interconnecting granular crystallites and an increase in conductivity by two orders of magnitude relative to as-prepared mesoporous germanium caused by reduced influence of surface states. We developed an electrostatic model relating the carrier concentration and mobility of p-type mesoporous germanium to the nanoscale morphology. Correlation within an order of magnitude was found between modelled and experimental conductivities, limited by variation in sample uniformity and uncertainty in void size and fraction after annealing. Furthermore, theoretical results suggest that mesoporous germanium conductivity could be tuned over four orders of magnitude, leading to optimized hybrid devices. PMID- 29504512 TI - Nano-black phosphorus for combined cancer phototherapy: recent advances and prospects. AB - Black phosphorus (BP), emerging as a new member of two-dimensional nanomaterials, has attracted growing research interests for its amazing photoelectric properties and promising application in electronic devices. Recently, BP has been confirmed to be a desirable candidate for phototherapy against cancer, including photothermal therapy and photodynamic therapy. By regulating the number of layers, the bandgap of BP nanosheets (NSs) can be finely tuned to present near infrared light triggered phototherapeutic behaviors. Furthermore, the exfoliated nano-sized BP also exhibits excellent tumor-targeting property as a nanomedicine via the enhanced permeability and retention effect. With biodegradable nature and outstanding therapeutic performance, BP is highly expected to be developed as novel anti-cancer agents as well as a potential carrier for advanced cancer theranostics. In this review, on the basis of summarizing the recent advances of BP in biomedical applications, the size and layer effects of BP on its targeting effect and phototherapeutic performance are discussed. Then, the rationally designed multifunctional nanoplatforms based on BP are introduced. And, the remaining challenges and prospects of nano-BP for clinic applications against cancer are discussed and outlooked. PMID- 29504513 TI - Non-invasive approach to diagnosis of pulmonary tuberculosis using microdroplets collected from exhaled air. AB - In this report we present a proof-of-principle study aimed at developing non invasive diagnostics for pulmonary TB that are based on analyzing TB biomarkers in exhaled microdroplets of lung fluid (MLFs). Samples were collected on electrospun filters recently developed by the authors, and then tested for the presence of Mycobacterium tuberculosis (Mtb) cells, Mtb DNA, and protein biomarkers (secreted Mtb antigens and antigen-specific antibodies). The latter were detected using rapid ultra-sensitive immunochemistry methods developed in our laboratory. Neither Mtb cells (limit of detection, LOD = 1 cell) nor Mtb DNA (LOD ~ 10 CFU) were found in the MLF samples exhaled by TB patients. However, immunoglobulin A (IgA) was found in over 90% of samples from TB patients and healthy volunteers. Antigen-specific IgA were detected at higher rates in the patient samples as compared to those from nominally healthy volunteers resulting in a modest discrimination level of 72% sensitivity and 58% specificity. As such, this novel, non-invasive and fast breath diagnostic method shows promise for further development. PMID- 29504514 TI - Modulation of electronic and magnetic properties in InSe nanoribbons: edge effect. AB - Quite recently, the two-dimensional (2D) InSe nanosheet has become a hot material with great promise for advanced functional nano-devices. In this work, for the first time, we perform first-principles calculations on the structural, electronic, magnetic and transport properties of 1D InSe nanoribbons with/without hydrogen or halogen saturation. We find that armchair ribbons, with various edges and distortions, are all nonmagnetic semiconductors, with a direct bandgap of 1.3 (1.4) eV for bare (H-saturated) ribbons, and have the same high electron mobility of about 103 cm2V-1s-1 as the 2D InSe nanosheet. Zigzag InSe nanoribbons exhibit metallic behavior and diverse intrinsic ferromagnetic properties, with the magnetic moment of 0.5-0.7 MU B per unit cell, especially for their single-edge spin polarization. The edge spin orientation, mainly dominated by the unpaired electrons of the edge atoms, depends sensitively on the edge chirality. Hydrogen or halogen saturation can effectively recover the structural distortion, and modulate the electronic and magnetic properties. The binding energy calculations show that the stability of InSe nanoribbons is analogous to that of graphene and better than in 2D InSe nanosheets. These InSe nanoribbons, with novel electronic and magnetic properties, are thus very promising for use in electronic, spintronic and magnetoresistive nano-devices. PMID- 29504515 TI - Synthesis and atomic scale characterization of Er2O3 nanoparticles: enhancement of magnetic properties and changes in the local structure. AB - In the investigation reported in this paper a modified thermal decomposition method was developed to produce very small Er2O3 nanoparticles (NPs). Particles structure, shape and size were characterized by x-ray diffraction and transmission electron microscopy which showed that the synthesis by thermal decomposition under O2 atmosphere produced very small and monodisperse NPs, allowing the investigation of finite-size and surface effects. Results of magnetization measurements showed that the smallest particles present the highest values of susceptibility that decrease as particle size increases. Specific heat measurements indicate that the sample with the smallest NPs (diameter ~5 nm) has a Neel temperature of 0.54 K. The local structure of particles was investigated by measurements of hyperfine interactions with perturbed angular correlation spectroscopy using 111Cd as probe nuclei replacing the cationic sites. Results showed that the relative population of sites 8b increases in both the core and surface layer of particles. PMID- 29504516 TI - High sensitive position-dependent photodetection observed in Cu-covered Si nanopyramids. AB - Silicon nanopyramids with the excellent ability of light absorption have been mostly reported in solar cells. Here, we report an obviously enhanced lateral photovoltaic effect (LPE) in copper-nanoparticle-covered random Si nanopyramids (Cu@Si-pyramid). Remarkable photoelectric responses are achieved in broadband from 405 to 780 nm. Furthermore, a prominent LPE is double-enhanced from 74.0 to 157.9 mV mm-1 when the linear region decreases from 3 to 1 mm. Finite-difference time-domain simulation is applied to investigate the origin of the exceptional results. This work declares a position-sensitive property of Si-nanopyramid systems and proposes promising applications to photodetections based on LPE. PMID- 29504517 TI - Broken detailed balance and non-equilibrium dynamics in living systems: a review. AB - Living systems operate far from thermodynamic equilibrium. Enzymatic activity can induce broken detailed balance at the molecular scale. This molecular scale breaking of detailed balance is crucial to achieve biological functions such as high-fidelity transcription and translation, sensing, adaptation, biochemical patterning, and force generation. While biological systems such as motor enzymes violate detailed balance at the molecular scale, it remains unclear how non equilibrium dynamics manifests at the mesoscale in systems that are driven through the collective activity of many motors. Indeed, in several cellular systems the presence of non-equilibrium dynamics is not always evident at large scales. For example, in the cytoskeleton or in chromosomes one can observe stationary stochastic processes that appear at first glance thermally driven. This raises the question how non-equilibrium fluctuations can be discerned from thermal noise. We discuss approaches that have recently been developed to address this question, including methods based on measuring the extent to which the system violates the fluctuation-dissipation theorem. We also review applications of this approach to reconstituted cytoskeletal networks, the cytoplasm of living cells, and cell membranes. Furthermore, we discuss a more recent approach to detect actively driven dynamics, which is based on inferring broken detailed balance. This constitutes a non-invasive method that uses time-lapse microscopy data, and can be applied to a broad range of systems in cells and tissue. We discuss the ideas underlying this method and its application to several examples including flagella, primary cilia, and cytoskeletal networks. Finally, we briefly discuss recent developments in stochastic thermodynamics and non-equilibrium statistical mechanics, which offer new perspectives to understand the physics of living systems. PMID- 29504518 TI - Synchronous and metachronous breast cancer in Ukraine. AB - AIM: This study aims to describe the current state of multiple primary malignant neoplasms (MPMNs) breast cancer patients management, evaluate the predictive impact of different factors, optimise approaches to diagnosis and treatment of these patients and improve their life quality. METHODS: The study included 2,032 patients who received special treatment at the Department of Breast Tumours and it Reconstructive Surgery of the National Cancer Institute from 2008 to 2015 within an open randomized controlled trial. The sample included 195 patients with synchronous cancer or metachronous breast cancer. RESULTS: A more aggressive course of breast cancer is observed in patients exposed to radiation from the Chornobyl accident. The clinical course of disease in patients with synchronous breast cancer is worse and prognostically unfavourable comparing to metachronous one. The influence on clinical course of disease of primary localization, type of settlement, blood group and Rh factor, type of special treatment, and age in patients with synchronous and metachronous cancer was not statistically proven. The impact of operative intervention scope in patients with synchronous and metachronous breast cancer was statistically proven, i.e. the course of the underlying disease in patients who underwent mastectomy is worse comparing to patients who underwent conservative surgery. Plastic and reconstructive surgery in patients with synchronous cancer was statistically proven in this study as reasonable. The influence of local recurrence rates on overall survival in patients with synchronous cancer was proven. However, the influence of local recurrence rates in patients with metachronous cancer was not statistically proven. CONCLUSIONS: There should be paid a great attention to synchronous and metachronous breast cancer patients in order to find and provide the best options of their management. This is crucial to continue researches in this field of oncology. PMID- 29504519 TI - Metaplastic carcinoma of the breast with mesenchymal differentiation (carcinosarcoma). A unique presentation of an aggressive malignancy and literature review. AB - Metaplastic carcinoma of the breast with mesenchymal differentiation (MCMD), previously known as carcinosarcoma, is a very rare and aggressive tumor that has been recently classified as a subtype of metaplastic breast carcinoma. It accounts for 0.08%-0.2% of all breast cancers, with only a few cases reported in the literature. Histologically, MCMD is characterized by a biphasic pattern of malignant epithelial and sarcomatous components without evidence of a transition zone between the two elements. We herein describe a unique case of metaplastic carcinoma of the breast with chondrosarcomatous differentiation in a postmenopausal woman who presented with a large, rapidly growing, ulcerated, bleeding mass and signs of impending sepsis. Metaplastic breast carcinomas (MBC) are rare and aggressive tumors. They are characterized by larger size, lower rates of axillary node involvement, higher rates of triple negativity and distal metastases, earlier local recurrence and poorer survival compared with classic invasive breast cancer. Because of the rarity of MBC, the optimal treatment has not been well defined. Surgery is the main curative treatment modality since MBC has shown a suboptimal response to standard chemotherapy. Patients with MBC may be appropriate candidates for novel targeted therapies. PMID- 29504520 TI - Forkhead box M1 (FOXM1) expression predicts disease free survival and may mediate resistance to chemotherapy and hormonotherapy in male breast cancer. AB - BACKGROUND: Male breast cancer (MBC) is a rare and neglected disease. Prognostic and predictive factors in MBC are extrapoled from trials conducted on its female counterpart. OBJECTIVE: Since the relationship between the transcription factor Forkhead box M1 (FOXM1) expression and the clinical response to chemotherapy and hormonotherapy in MBC remains unknown, we sought to investigate the predictive value of FOXM1 in MBC. METHODS: FOXM1 expression was assessed in 130 MBC cases. Clinical significance was analyzed by Kaplan Meier curves, log-rank test and multivariate Cox regression analyses. RESULTS: Patients with high FOXM1 expression had a significantly lower response rate to chemotherapy (P = 0.045) and hormonotherapy (P = 0.029) than those with low FOXM1 expression. Multivariate analyses indicated that FOXM1 was an independent prognostic factor for disease free survival in MBC patients (P < 0.001). CONCLUSIONS: FOXM1 may have a reliable predictive significance in male breast cancer and thus may become an important target for male breast cancer therapy in the near future. PMID- 29504521 TI - Relationship of work disability between the disease activity, depression and quality of life in patients with ankylosing spondylitis. AB - OBJECTIVES: In this study, our objective was to determine the work productivity and work disability of the patients with ankylosing spondylitis (AS) and to investigate the relation of these parameters with disease activity, anxiety, depression and quality of life. PATIENTS AND METHODS: Fifty patients with the diagnosis of AS and 30 healthy control were included in the study. In patients with AS, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was used to evaluate the disease activity; Bath Ankylosing Spondylitis Metrology Index (BASMI) was used to evaluate the spinal mobility and Bath Ankylosing Spondylitis Functional Index (BASFI) was used to determine the functional status. In addition, the Ankylosing Spondylitis Quality of Life (ASQoL) questionnaire and The Short Form (SF-36) Health Survey was used to evaluate the health status, Hospital Anxiety and Depression Scale (HADS) was used for the evaluation of depression and anxiety and Work Productivity and Activity Impairment Questionnaire: Specific Health Problem v2.0 (WPAI:SHP) was used to evaluate the work productivity. RESULTS: In AS patients duration of disease at the diagnosis was 7.24 +/- 6.23 years. The time lost at work due to the disease, decrease in the work productivity and impairment in the time off daily activities were worse in the patient group compared with the control group (p< 0.05). The impairment in the work productivity was correlated with BASDAI and depression; difficulty in time-off activities was correlated with BASFI and anxiety and depression was correlated with BASDAI (p< 0.05). While the impairment in work productivity was correlated with the subparameter vitality in SF-36, difficulty in time off activities was correlated with general health status, social functions, vitality and mental health (p< 0.05). CONCLUSION: In this study, we determined that AS had a significant influence on the working conditions and the factors related to the disease had a significant correlation with work productivity. Factors related to the psychology and the disease were also correlated with the working conditions. PMID- 29504522 TI - Comparison of sit-to-stand and static standing balance ability between patients with total knee arthroplasty and elderly healthy subjects. AB - BACKGROUND: Identifying the functional status of patients after total knee arthroplasty is important. This study aimed to examine the differences in sit-to stand and static standing ability balance between patients who underwent total knee arthroplasty and healthy participants. METHODS: Twenty patients (mean age 70.05 years) who underwent total knee arthroplasty and 20 healthy participants (mean age 69.20 years) participated in this study. To assess the participants' sit-to-stand, the Good Balance System (Metitur Ltd, Finland) was used to measure each participant's mediolateral center of pressure (COP) displacement and time required to complete the sit-to-stand movement. To assess the participants' static standing balance, the Good Balance System was used to measure each patient's mediolateral COP displacement, anteroposterior COP displacement, and velocity moment when standing with eyes open and with eyes closed. RESULTS: A significant difference was found in the mediolateral COP displacement and the time required to complete the sit-to-stand movement in the two groups (P< 0.05). A significant difference was also found in the mediolateral and anteroposterior COP displacement and the velocity moment when standing with eyes open and with eyes closed in the two groups (P< 0.05). CONCLUSIONS: Patients who had total knee arthroplasty showed decreased sit-to-stand and static standing balance ability compared with the control group in the initial period after surgery. PMID- 29504523 TI - Correlation of ARHI upregulation with growth suppression and STAT3 inactivation in resveratrol-treated ovarian cancer cells. AB - BACKGROUND: Aplysia ras homology member I/ARHI is known as ovarian cancer suppressor gene and potential inhibitor of signal transducer and activator of transcription 3/STAT3 signaling. Resveratrol suppresses growth and STAT3 activation of ovarian cancer cells, while its influence in ARHI expression remains unknown. OBJECTIVE: The current study aims to elucidate the status of ARHI expression and its relevance with growth suppression and STAT3 inactivation of resveratrol-treated cells. METHODS: ARHI expression patterns of three ovarian cancer cell lines (human CAOV-3, OVCAR-3 and rat NUTU-19) without and with 100 MUM resveratrol treatment were checked by immunocytochemical staining, Western blotting and RT-PCR. The involvement of ARHI in the growth inhibition and STAT3 inactivation of resveratrol-treated OVCAR-3 cells was investigated by transfection of ARHI-specific siRNA. RESULTS: ARHI is expressed in low levels in three ovarian cancer cell lines, which is upregulated upon resveratrol treatment accompanied with growth arrest, extensive apoptosis, increased autophagic activity and inactivated STAT3 signaling. Specific siRNA transfection efficiently knocked down ARHI expression in resveratrol-treated CAOV-3 and OVCAR-3 cells and increased the total cell number in limited extents (P> 0.05) in comparison with that of resveratrol-treated ovarian cancer cells without any transfection or transfected with mock oligonucleotides. ARHI knockdown failed to prevent resveratrol-caused STAT3 inactivation and cell crisis. CONCLUSION: ARHI upregulation is another molecular event caused by resveratrol and one of the elements related with resveratrol's anti-ovarian cancer efficacy. Resveratrol may inactivate STAT3 signaling of ovarian cancer cells in ARHI unrelated pattern(s). PMID- 29504524 TI - Geriatric nutritional risk index is not an independent predictor in patients with diffuse large B-cell lymphoma. AB - BACKGROUND: The prognostic value of geriatric nutritional risk index (GNRI) for diffuse large B-cell lymphoma (DLBCL) treated in the rituximab era was not clear. OBJECTIVE: To investigate the prognostic impact of GNRI in patients with DLBCL in our hospital. METHODS: DLBCL patients were recruited and classified into two groups with and without malnutrition based on GNRI. Clinical features, concentration of T-helper cell type (Th1/Th2/Th17) cytokine profiles and overall survival were compared between these two groups. RESULTS: One hundred and five (39%) out of 267 patients were classified into malnutrition group. Patients with malnutrition had lower levels of albumin and hemoglobin, but older age, higher lactate dehydroxygenase (LDH) level, higher frequencies of advanced stage, poor performance status, B symptoms and extranodal involvement, higher scores of NCCN IPI and higher level of INF-gamma. Moreover, patients with malnutrition had poor overall survival in univariate analyses. But these significances did not stand after stratified analyses by NCCN-IPI, or in the context of NCCN-IPI in the multivariate analyses. CONCLUSIONS: GNRI is not an independent predictor for DLBCL patients. PMID- 29504525 TI - Expressions of IGF-1, ERK, GLUT4, IRS-1 in metabolic syndrome complicated with colorectal cancer and their associations with the clinical characteristics of CRC. AB - BACKGROUND: Epidemiological data have revealed that colorectal cancer (CRC) risk is increased in patients with Metabolic syndrome. OBJECTIVE: To explore the expressions of IGF-1, ERK, GLUT4, IRS-1 in MS patients with CRC and their associations with the clinical characteristics of CRC. METHODS: We investigated the expressions of IGF-1, ERK, GLUT4 and IRS-1 in greater omental adipose tissues of 168 MS patients with/without CRC, 85 CRC patients without MS and 98 healthy controls by RT-PCR, and analyzed the relationships between their expressions and clinical characteristics of CRC. RESULTS: The expression levels of IGF-1 and ERK in MS patients with/without CRC were higher while the expression levels of GLUT4 were lower compared with CRC patients without MS and healthy controls (P< 0.01). The expression levels of IGF-1 and ERK in MS patients with CRC were higher while expression levels of GLUT4 were lower compared to MS patients without CRC (P< 0.01). Expression levels of ERK, IGF-1, GLUT4 were associated with clinical characteristics of CRC, including tumor size, distant metastasis and advanced stages (III/IV) (P< 0.05). CONCLUSIONS: Expressions of IGF-1, ERK and GLUT4 in greater omental adipose tissues might be useful biomarkers and predictive targets in the diagnosis of CRC. PMID- 29504526 TI - The expression of CCL18 in diffuse large B cell lymphoma and its mechanism research. AB - BACKGROUND: Molecular target therapy has become a hot spot in cancer treatment, finding effective targets for diffuse large B cell lymphoma (DLBCL) is an urgent problem. OBJECTIVE: To detect the expression level of C-C motif chemokine ligand 18 (CCL18) in DLBCL and clarify its potential role in the progression of DLBCL. METHODS: Gene expression datas of DLBCL were obtained from TCGA and GEO databases. The relationship between CCL18 and clinicopathologic information of DLBCL was assessed using meta-analysis method. Then we conducted bioinformatics analysis to uncover the biological function of CCL18 and its co-expression genes. Immunohistochemistry was applied to detect expression of CCL18 in DLBCL and reactive hyperplasia lymphoid tissues. RESULTS: The expression of CCL18 in DLBCL was higher than negative control group. The levels of CCL18 were distinct in different molecular subtypes and ages, and patients with higher level of CCL18 had a shorter overall survival than those with lower level. CCL18 and its co expression genes were enriched in biological function such as cell proliferation, migration, apoptotic, and correlated with NF-kappaB, pathway in cancer, PI3K-AKT pathway. CONCLUSIONS: CCL18 was up-regulated in DLBCL and related to poor prognosis. CCL18 may act as a valuable target for diagnosis and treatment of DLBCL. PMID- 29504527 TI - Obesity, blood rheology and angiogenesis. AB - Adipose tissue is actively involved in angiogenesis through secretion of biologically active substances. This topic has been the subject of many recent publications concerning the pathophysiology and treatment of obesity. We discuss the relationship between obesity, angiogenesis and blood rheology. PMID- 29504528 TI - Trends of the treatment of Critical Limb Ischemia during the last two decades. AB - In this review 14 studies were identified reporting the treatment strategy in 4891 patients with Critical Limb Ischemia (CLI) with the aim to investigate if the strategy of treatment of the first episode of CLI has changed during the last 15-20 years. A computer research has been performed on PubMed and Scopus databases on November 2016. The used terms for the investigation about studies evaluating the strategy of treatment of CLI at the first-time presentation, have been "critical leg ischemia", "critical limb ischemia", "critical lower limb ischemia" along with the terms "placebo", "medical treatment" and/or "conservative" revascularisation, surgical revascularisation, endovascular revascularisation, hybrid revascularisation and primary amputation. Studies were included if they were either retrospective or prospective and reporting the rate of patients who underwent to any form of revascularization, conservative treatment and primary amputation. The one-year limb and life survival rates have been reported as major outcomes. The pooled rate of revascularization was 72.5% (95% CI 80-64.96) of which 54.5%, surgical, 38.3% endovascular and 7.1% hybrid. The bivariate regression of revascularisation procedures has been with not significant increase, from 68% in 1993 to 88% in 2015. The endovascular procedures have shown a significant increase of the trend, from 2% to more the 50% (p 0.007), while surgical and hybrid procedures have not. The pooled rate of conservative treatment was 18% (95% CI 11.6-24.5%) with a not significant increasing trend and primary amputation pooled rate was 8.7% (95% CI 12.0-5,4) with a significant decreasing trend (p 0.009). The one-year limb survival rate was 75,4% (95% CI 81.5-69.3%) and the life survival was 76%. (95% CI 85.4-66.1%) both with a not significant increasing trend. In conclusion, this review highlights how the treatment strategy of the first CLI manifestation has changed over the last 15-20 years. It has shown an increase of the rate of revascularization procedures, particularly for endovascular and a significant reduction of the rate of primary amputations. The rate of patients treated conservatively appears to be unchanged and maybe influencing the rate of limb and life survival, that have remained unchanged. PMID- 29504530 TI - Exploring the Role of Cognitive Factors in a New Instrument for Elders' Financial Capacity Assessment. AB - BACKGROUND: The influence of cognitive factors on financial capacity across the dementia spectrum of cognitive aging, Alzheimer's disease (AD), and mild cognitive impairment (MCI) has been little investigated, while it has not been investigated at all in other types of dementia as well as in extended samples of elders in Greece. OBJECTIVE: The aim of this study is to investigate financial capacity, to develop a tool, test its psychometric properties, validate, and then test the tool in groups of healthy controls compared to elders with dementia, while examining other facets of their cognitive performance. METHODS: 719 elders from Greece including healthy participants and patients with different types of dementia were examined with Legal Capacity for Property Law Transactions Assessment Scale (LCPLTAS) and a battery of neuropsychological tests concerning various cognitive functions. RESULTS: Significantly different profiles in the scores and subscores of LCPLTAS for all the groups of dementia patients were found, with a general incapacity finding for all the dementia groups including the MCI patients. Logistic regression showed that Mini-Mental State Examination (MMSE), Geriatric Depression Scale, and Trail Making Part B predicted competence on LCPLTAS for the dementia patients. Persons with MCI and dementia had lower financial knowledge scores than those without cognitive impairment, with MMSE scores below 27 suggestive as an indication of financial incapacity. CONCLUSION: The LCPLTAS provides information for a strong positive correlation with MMSE, while the use both of MMSE and LCPLTAS as adequate measures of financial (in)capacity is discussed for the Greek legal procedures regarding elder guardianship cases. PMID- 29504529 TI - [18F]-Flutemetamol Uptake in Cortex and White Matter: Comparison with Cerebrospinal Fluid Biomarkers and [18F]-Fludeoxyglucose. AB - Flutemetamol (18F-Flut) is an [18F]-labelled amyloid PET tracer with increasing availability. The main objectives of this study were to investigate 1) cerebrospinal fluid (CSF) Abeta 1-42 (Abeta42) concentrations associated with regional 18F-Flut uptake, 2) associations between cortical 18F-Flut and [18F] fludeoxyglucose (18F-FDG)-PET, and 3) the potential use of 18F-Flut in WM pathology. Cognitively impaired, nondemented subjects were recruited (n = 44). CSF was drawn, and 18F-Flut-PET, 18F-FDG-PET, and MRI performed. Our main findings were: 1) Different Alzheimer's disease predilection areas showed increased 18F-Flut retention at different CSF Abeta42 concentrations (posterior regions were involved at higher concentrations). 2) There were strong negative correlations between regional cortical 18F-Flut and 18F-FDG uptake. 3) Increased 18F-Flut uptake were observed in multiple subcortical regions in amyloid positive subjects, including investigated reference regions. However, WM hyperintensity 18F-Flut standardized uptake value ratios (SUVr) were not significantly different, thus we cannot definitely conclude that the higher uptake in 18F Flut(+) is due to amyloid deposition. In conclusion, our findings support clinical use of CSF Abeta42, putatively relate decreasing CSF Abeta42 concentrations to a sequence of regional amyloid deposition, and associate amyloid pathology to cortical hypometabolism. However, we cannot conclude that 18F-Flut-PET is a suitable marker for WM pathology due to high aberrant WM uptake. PMID- 29504531 TI - Induction of Amyloid-beta42 Production by Fipronil and Other Pyrazole Insecticides. AB - Generation of amyloid-beta peptides (Abetas) by proteolytic cleavage of the amyloid-beta protein precursor (AbetaPP), especially increased production of Abeta42/Abeta43 over Abeta40, and their aggregation as oligomers and plaques, represent a characteristic feature of Alzheimer's disease (AD). In familial AD (FAD), altered Abeta production originates from specific mutations of AbetaPP or presenilins 1/2 (PS1/PS2), the catalytic subunits of gamma-secretase. In sporadic AD, the origin of altered production of Abetas remains unknown. We hypothesize that the 'human chemical exposome' contains products able to favor the production of Abeta42/Abeta43 over Abeta40 and shorter Abetas. To detect such products, we screened a library of 3500 + compounds in a cell-based assay for enhanced Abeta42/Abeta43 production. Nine pyrazole insecticides were found to induce a beta- and gamma-secretase-dependent, 3-10-fold increase in the production of extracellular Abeta42 in various cell lines and neurons differentiated from induced pluripotent stem cells derived from healthy and FAD patients. Immunoprecipitation/mass spectrometry analyses showed increased production of Abetas cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and shorter. Strongly supporting a direct effect on gamma-secretase activity, pyrazoles shifted the cleavage pattern of another gamma-secretase substrate, alcadeinalpha, and shifted the cleavage of AbetaPP by highly purified gamma-secretase toward Abeta42/Abeta43. Focusing on fipronil, we showed that some of its metabolites, in particular the persistent fipronil sulfone, also favor the production of Abeta42/Abeta43 in both cell-based and cell-free systems. Fipronil administered orally to mice and rats is known to be metabolized rapidly, mostly to fipronil sulfone, which stably accumulates in adipose tissue and brain. In conclusion, several widely used pyrazole insecticides enhance the production of toxic, aggregation prone Abeta42/Abeta43 peptides, suggesting the possible existence of environmental "Alzheimerogens" which may contribute to the initiation and propagation of the amyloidogenic process in sporadic AD. PMID- 29504532 TI - Generation and Partial Characterization of Rabbit Monoclonal Antibody to Pyroglutamate Amyloid-beta3-42 (pE3-Abeta). AB - N-terminally truncated pyroglutamate amyloid-beta (Abeta) peptide starting at position 3 represents a significant fraction of Abeta peptides (pE3-Abeta) in amyloid plaques of postmortem brains from patients with Alzheimer's disease (AD) and older persons with Down syndrome (DS). Studies in transgenic mouse models of AD also showed that pE3-Abeta is a major component of plaques, and mouse monoclonal antibody to pE3-Abeta appears to be a desirable therapeutic agent for AD. Since small peptides do not typically elicit a good immune response in mice, but do so favorably in rabbits, our aims were to generate and partially characterize a rabbit monoclonal antibody (RabmAb) to pE3-Abeta. The generated RabmAb was found to be specific for pE3-Abeta, since it showed no reactivity with Abeta16, Abeta40, Abeta42, Abeta3-11, and pE11-17 Abeta peptides in an enzyme linked immunosorbent assay (ELISA). The isotype of the antibody was found to be IgG class. The antibody possesses high affinity to pE3-Abeta with dissociation constant (KD) for the antibody of 1 nM. The epitope of the antibody lies within the sequence of pE3-FRHD. In dot blotting, the optimal detection of pE3-Abeta was at an antibody concentration of 0.5 MUg/ml. The threshold of pE3-Abeta detection was 2 fmol. The antibody was sensitive enough to detect 10 pg/ml of pE3-Abeta in sandwich ELISA. pE3-Abeta was detected in AD and DS brain extracts in ELISA and immunoblotting. Immunohistological studies showed immunolabeling of plaques and blood vessels in brains from patients with AD, and DS showing AD pathology. Thus, the antibody can be widely applied in AD and DS research, and therapeutic applications. PMID- 29504533 TI - Associations between the Frailty Index and Brain Atrophy: The Treviso Dementia (TREDEM) Registry. AB - BACKGROUND: Frailty is a condition which is characterized by a reduction in the homeostatic reserves of the individual and which entails an increased vulnerability to stressful endogenous and exogenous agents. The Frailty Index (FI), proposed by Rockwood, was designed following an accumulation of deficits model: the greater the number of deficits in a given individual, the greater the degree of frailty. OBJECTIVE: The aim of this study was to verify the existence of associations between FI and cerebral atrophy. METHODS: The TREDEM Register (Treviso Dementia) provided retrospective observational data from 1,584 patients. The FI was calculated based on 50 variables comprising diseases, disability, behavioral disturbances, and blood chemistry parameters. The severity of atrophy in the cortical and subcortical regions, such as the amplitude of the lateral ventricles, were detected by computerized axial tomography (CAT). Multiple logistic regression models using the stepwise backward method were used to analyze possible associations between FI and atrophy. RESULTS: For each increment of one hundredth of the FI, the probability of cortical atrophy increases by 2%. The female gender is a protective factor for cortical and subcortical atrophy. At each increase of one percent of the FI, the probability of a severe degree of cortical atrophy increases by 3%. The FI was significantly associated with frontal and temporal cortical atrophy. The relationship between overall subcortical atrophy and the FI was not significant, whereas it was the one with the severe degree of subcortical atrophy. The FI is significantly associated with the atrophy of the peri-insular subcortical region. Similar associations were found considering only demented patients. CONCLUSION: The FI is associated with the presence, degree, and some localization of cerebral atrophy in a population of cognitive-decline patients. PMID- 29504534 TI - Innovative Biomarkers for Alzheimer's Disease: Focus on the Hidden Disease Biomarkers. AB - The criteria for the clinical diagnosis of AD include the analysis of biomarkers of the underlying brain disease pathology; a set of cerebrospinal fluid (CSF) tests, amyloid-beta1-42 (Abeta42), total-tau (t-tau), and phosphorylated tau (p tau), are available and their performance in a clinical setting has been assessed in several studies. Thus, in dementia research, great advances have been made in the discovery of putative biomarkers; however, disappointingly, few of them have been translated into clinically applicable assays. To find biomarkers able to reliably detect AD pathology already at prodromal stages and in blood is even more important. Recent technical breakthroughs have provided ultrasensitive methods that allow the detection of brain-specific proteins in blood. In the present review, we will focus on the usefulness of ultrasensitive technologies for biomarker discovery and trace elements detection; moreover, we will review studies on circulating nano-compartments, a promising novel source of material for molecular diagnostics. PMID- 29504535 TI - Crosstalk between Peripheral Small Vessel Properties and Anxious-like Profiles: Sex, Genotype, and Interaction Effects in Mice with Normal Aging and 3*Tg-AD mice at Advanced Stages of Disease. AB - Cardiovascular disease resulting from oxidative stress and inflammation can exacerbate Alzheimer's disease. This brief report provides the first evidence of compromised small peripheral mesenteric resistance artery (MRA) properties in 15 month-old 3xTg-AD mice. Females showed worse physiologically relevant MRA structural (increased passive external and internal diameters, cross sectional area) and functional (increased active internal diameters) alterations suggesting sex-dependent dysfunctions. At both physiological and high intraluminal pressures, vascular alterations correlated with the anxious-like behavioral profile, in a sex-dependent manner. Finally, the results unveil a crosstalk between peripheral small vessel properties and behavior in both 3xTg-AD mice and age-matched counterparts with normal aging. PMID- 29504537 TI - Alzheimer's Amyloid-beta is an Antimicrobial Peptide: A Review of the Evidence. AB - The amyloid-beta (Abeta) peptide has long been considered to be the driving force behind Alzheimer's disease (AD). However, clinical trials that have successfully reduced Abeta burden in the brain have not slowed the cognitive decline, and in some instances, have resulted in adverse outcomes. While these results can be interpreted in different ways, a more nuanced picture of Abeta is emerging that takes into account the facts that the peptide is evolutionarily conserved and is present throughout life in cognitively normal individuals. Recent evidence indicates a role for Abeta as an antimicrobial peptide (AMP), a class of innate immune defense molecule that utilizes fibrillation to protect the host from a wide range of infectious agents. In humans and in animal models, infection of the brain frequently leads to increased amyloidogenic processing of the amyloid-beta protein precursor (AbetaPP) and resultant fibrillary aggregates of Abeta. Evidence from in vitro and in vivo studies demonstrates that Abeta oligomers have potent, broad-spectrum antimicrobial properties by forming fibrils that entrap pathogens and disrupt cell membranes. Importantly, overexpression of Abeta confers increased resistance to infection from both bacteria and viruses. The antimicrobial role of Abeta may explain why increased rates of infection have been observed in some of the AD clinical trials that depleted Abeta. Perhaps progress toward a cure for AD will accelerate once treatment strategies begin to take into account the likely physiological functions of this enigmatic peptide. PMID- 29504538 TI - Perspectives on Oxidative Stress in Alzheimer's Disease and Predictions of Future Research Emphases. AB - Oxidative stress, an overproduction of free radicals or a diminution of free radical scavenging ability relative to those of cognitively aged-matched controls, is widely recognized as a critical component of the pathogenesis and progression of Alzheimer's disease (AD). This recognition arose in significant part from the work in the author's laboratory, complemented by research from others' laboratories. The Butterfield laboratory discovered the oxidative stress associated with oligomeric amyloid-beta peptide manifested primarily as elevated oxidative modification of proteins and peroxidation of lipids. Such oxidative damage caused neuronal death, which undoubtedly underlies the progressive loss of cognition in AD. Identification of specific oxidatively modified brain proteins in subjects with AD or amnestic mild cognitive impairment was achieved by the methods of redox proteomics, pioneered in the author's laboratory. The importance and significance of the research emanating from the Butterfield laboratory rest on the paradigm shift of thinking regarding the roles of oxidative stress and resulting damage to key proteins and biochemical pathways in the pathogenesis and progression of AD. Predictions of future research directions also are presented. Given the enormous financial and personal burden placed upon citizens (and governments) of the US from AD, and the surety that the number of AD patients will greatly increase over the next 20-30 years, greater understanding of the molecular basis of pathogenesis and progression of AD is essential. Our laboratory is privileged to have contributed to better understanding of AD and provided rationales to identify effective therapeutic targets for this devastating dementing disorder. PMID- 29504536 TI - Progress and Challenges in Frontotemporal Dementia Research: A 20-Year Review. AB - The landscape of frontotemporal dementia (FTD) has evolved remarkably in recent years and is barely recognizable from two decades ago. Knowledge of the clinical phenomenology, cognition, neuroimaging, genetics, pathology of the different subtypes of FTD, and their relations to other neurodegenerative conditions, has increased rapidly, due in part, to the growing interests into these neurodegenerative brain conditions. This article reviews the major advances in the field of FTD over the past 20 years, focusing primarily on the work of Frontier, the frontotemporal dementia clinical research group, based in Sydney, Australia. Topics covered include clinical presentations (cognition, behavior, neuroimaging), pathology, genetics, and disease progression, as well as interventions and carer directed research. This review demonstrates the improvement in diagnostic accuracy and capacity to provide advice on genetic risks, prognosis, and outcome. The next major challenge will be to capitalize on these research findings to develop effective disease modifying drugs, which are currently lacking. PMID- 29504539 TI - Mitochondrial Function, Dynamics, and Permeability Transition: A Complex Love Triangle as A Possible Target for the Treatment of Brain Aging and Alzheimer's Disease. AB - Because of the failure of all amyloid-beta directed treatment strategies for Alzheimer's disease (AD), the concept of mitochondrial dysfunction as a major pathomechanism of the cognitive decline in aging and AD has received substantial support. Accordingly, improving mitochondrial function as an alternative strategy for new drug development became of increasing interest and many different compounds have been identified which improve mitochondrial function in preclinical in vitro and in vivo experiments. However, very few if any have been investigated in clinical trials, representing a major drawback of the mitochondria directed drug development. To overcome these problems, we used a top down approach by investigating several older antidementia drugs with clinical evidence of therapeutic efficacy. These include EGb761(r) (standardized ginkgo biloba extract), piracetam, and Dimebon. All improve experimentally many aspects of mitochondrial dysfunction including mitochondrial dynamics and also improve cognition and impaired neuronal plasticity, the functionally most relevant consequences of mitochondrial dysfunction. All partially inhibit opening events of the mitochondrial permeability transition pore (mPTP) which previously has mainly been discussed as a mechanism relevant for the induction of apoptosis. However, as more recent work suggests the mPTP as a master regulator of many mitochondrial functions, our data suggest the mPTP as a possible relevant drug target within the love triangle between mPTP regulation, mitochondrial dynamics, and mitochondrial function including regulation of neuronal plasticity. Drugs interfering with mPTP function will improve not only mitochondrial impairment in aging and AD but also will have beneficial effects on impaired neuronal plasticity, the pathomechanism which correlates best with functional deficits (cognition, behavior) in aging and AD. PMID- 29504540 TI - Past to Future: What Animal Models Have Taught Us About Alzheimer's Disease. AB - Alzheimer's disease (AD) impairs memory and causes significant cognitive deficits. The disease course is prolonged, with a poor prognosis, and thus exacts an enormous economic and social burden. Over the past two decades, genetically engineered mouse models have proven indispensable for understanding AD pathogenesis, as well as for discovering new therapeutic targets. Here we highlight significant studies from our laboratory that have helped advance the AD field by elucidating key pathogenic processes operative in AD and exploring a variety of aspects of the disease which may yield novel therapeutic strategies for combatting this burdensome disease. PMID- 29504541 TI - Prevention Matters: Time for Global Action and Effective Implementation. AB - During the last few years, dementia prevention based on modifiable lifestyle factors has gained increasing attention. Cohort studies with follow-ups extending up to decades have identified several risk and protective factors, and very recently new randomized controlled trials with multidomain approach have provided promising evidence by showing that modifying simultaneously several risk factors, it is possible to maintain and improve cognitive capacity among older at-risk persons. Several lifestyle-based multidomain trials are under preparation or ongoing and to facilitate international collaboration and effective worldwide dementia prevention, the World Wide FINGERS interdisciplinary network (http://wwfingers.com) was recently initiated. Additionally, several new implementation projects are taking the first steps from trial setting to real life implementation of a dementia prevention program. This paper highlights the recent perspectives from the field of Alzheimer's disease and reflects the implications and importance of current achievements. Finally, predictions for the future work especially in terms of global collaboration and implementation will be discussed. PMID- 29504542 TI - Multimodal Neuroimaging in Alzheimer's Disease: Early Diagnosis, Physiopathological Mechanisms, and Impact of Lifestyle. AB - Over the last ten years, we have conducted research in Alzheimer's disease (AD) using multimodal neuroimaging techniques to improve diagnosis, further our understanding of the pathological mechanisms underlying the disease, and support the development of innovative non-pharmacological preventive strategies. Our works emphasized the interest of hippocampal subfield volumetry in early diagnosis and the need for further development in this field including optimization, standardization, and automatization of the techniques. Also, we conducted several studies in cognitively intact at-risk elderly (e.g., subjective cognitive decline patients and APOE4 carriers) to better identify biomarkers associated with increased risk of developing AD. Regarding the physiopathological mechanisms, specific multimodal neuroimaging techniques allowed us to highlight the relevance of diaschisis, the mismatch between neurodegeneration and local Abeta deposition and the regional variation in the mechanisms underlying structural or functional alterations. Further works integrating other biomarkers known to play a role in the physiopathology of AD (tau, TDP-43, inflammation, etc.) in a longitudinal design would be useful to get a comprehensive understanding of their relative role, sequence, and causal relationships. Our works also highlighted the relevance of functional connectivity in further understanding the specificity of cognitive deficits in AD and how connectivity differentially influences the propagation of the different AD biomarkers. Finally, we conducted several studies on the links between lifestyle factors and neuroimaging biomarkers to unravel mechanisms of reserve. Further efforts are needed to better understand which lifestyle factor, or combination of factors, impact on AD pathology, and when, to help translating our knowledge to training programs that might prevent or delay brain and cognitive changes leading to AD dementia. PMID- 29504544 TI - Circular Inference in Dementia Diagnostics. AB - Referring to recent international articles stating that amyloid imaging or detection has a high additive value in making a diagnosis of Alzheimer's disease (AD) when previous investigations are inconclusive, the authors of this editorial argue that this statement is based on circular reasoning and, hence, misleading. Since autopsy findings and other potential indicators fit poorly with amyloid PET, they conclude that this examination has no role in the diagnosis of AD. PMID- 29504543 TI - Targeting Alzheimer's Disease at the Right Time and the Right Place: Validation of a Personalized Approach to Diagnosis and Treatment. AB - Cautious optimism is appropriate for a near future (five years) time frame for a number of drugs acting on the different pathophysiological components of Alzheimer's disease (amyloid deposition, tau hyperphosphorylation, neuroinflammation, vascular changes, to name the most important known so far). Since the relative weight of these components will be different between individuals and will even change over time for each individual, a 'one drug fit for all' approach is no longer defensible. Precision medicine using biomarkers in the diagnosis and treatment of Alzheimer's disease is the new strategy. PMID- 29504545 TI - Editorial on Clinical Trial's Corner. PMID- 29504546 TI - The relationship between trunk control and upper limb function in children with cerebral palsy. AB - BACKGROUND: Trunk control ability greatly influences functional movement of the upper limbs. PURPOSE: Our primary aims were to assess trunk control ability, sway, and upper limb functions in children with cerebral palsy (CP), and to investigate the relationship between trunk control ability and upper limb function. METHODS: We included 15 children (8 boys and 7 girls) with CP. We used the Trunk Control Measurement Scale (TCMS) to evaluate trunk control ability and sway. We employed the Jebsen-Taylor Hand Function Test (JTHFT), the Quality of Upper Extremity Skills Test (QUEST), the Box and Blocks Test (BBT), and the ABILHAND-Kids questionnaire to explore upper limb function and arm movement acceleration. We calculated correlations between trunk control ability and parameters of upper limb function. RESULTS: TCMS scores correlated positively with the QUEST, BBT, and ABILHAND-Kids data, but negatively with the JTHFT findings. Anteroposterior acceleration correlated positively with JTHFT data, but negatively with QUEST, BBT, and ABILHAND-Kids data. Mediolateral acceleration correlated positively with the JTHFT outcomes, but negatively with those of QUEST, BBT, and ABILHAND-Kids. CONCLUSIONS: Upper limb function test data exhibited moderate to strong correlations with trunk control ability, as measured via the TCMS and triaxial accelerometry, in children with CP. Our results suggest that trunk control ability should be assessed when evaluating upper limb function in such children. PMID- 29504547 TI - Electro therapy facial and laser skin whitening: Clients' perspective. AB - There are so many beauty salons in Metropolis who provide services to women exclusively [1]. These beauty salons depend mostly on electricity for their services to customers, without it there is no effective means of operation [2]. These beauty salons are definitely leading to women empowerment. The beauty salons are run by the women for women. Since they fall under the category of micro and small enterprises, these salons may avail so many financial and non- financial advantages from the Government of India. They also provide employment opportunities to the women employees. The development of such beauty salons rests on the clients' satisfaction on the provision of their services. Hence it is essential to measure the clients attitude towards the services offered by the beauty salons, especially electro therapy facial, laser skin whitening and laser hair removal treatments, which are coming under micro current treatment as a cosmetic tool. PMID- 29504548 TI - Measurement of upper limb movement acceleration and functions in children with cerebral palsy. AB - OBJECTIVE: The main purpose of this study was to measure the peak acceleration of the upper limb (UL) during reaching, and to calculate correlations between peak acceleration data and functional test results in children with cerebral palsy (CP). METHODS: We recruited 15 children with CP (8 boys and 7 girls) and measured peak acceleration and function as revealed by the Jebsen Taylor Hand Function Test (JTHF), the Quality of Upper Extremity Skills Test (QUEST), the Box and Blocks Test (BBT), and the ABILHAND-Kids questionnaire. We calculated correlations between peak acceleration data and scores on the functional tests. RESULTS: The peak acceleration of the more-affected UL was significantly higher than that of the less-affected UL (p< 0.05). The peak acceleration data were positively correlated with JTHFT scores. On the other hand, the peak acceleration data were negatively correlated with QUEST, BBT, and ABILHAND-Kids scores. The test-retest reliability of the peak acceleration was excellent, with an intra class correlation coefficient (ICC) 0.87-0.98. CONCLUSIONS: Peak acceleration data correlated with UL functional test results; as this proved to be reliable, the tri-axial accelerometer is a clinically useful assessment tool for evaluating UL movement. Therefore, our results suggest that measurement of acceleration using a tri-axial accelerometer is appropriate when clinicians quantify UL movement during therapeutic rehabilitation in clinical settings. PMID- 29504549 TI - An iterative reconstruction algorithm for digital breast tomosynthesis imaging using real data at three radiation doses. AB - BACKGROUND: Iterative image reconstruction in Digital Breast Tomosynthesis (DBT) is a developing modality that produces three-dimensional (3D) reconstructed images of a breast to detect suspicious lesions. Algebraic reconstruction technique (ART), one of the iterative image reconstruction methods, was applied to reconstruct 3D data of breast and is becoming as one alternative method for the conventional image reconstruction techniques such as filtered back projection (FBP) in DBT imaging. OBJECTIVE: A new majorization-minimization (MM) algorithm was presented for TV denoising of signals. In the field of DBT, however, the algorithm has not yet been applied. In this study, we proposed a new method of "ART+TV3D+MM," which applies (MM) algorithm to the images reconstructed by ART+TV3D for different imaging dose levels to investigate a possible reduction of radiation dose. METHODS: Projections of a real breast phantom (CD Pasmam 1054) were acquired with a Siemens MAMMOMAT DBT system. The proposed new method was repeated and tested with 3 different radiation dose levels. The quality of the images reconstructed using the proposed new method were compared with those generated by the commonly used FBP method using both qualitative and quantitative assessments. RESULTS: The new method showed superior results in terms of visual assessment, contrast to noise ratios (CNR), full width at half maximum (FWHM) values and 1D profiles compared with FBP of the Siemens MAMMOMAT. CNR values were evaluated for two different region of interests (ROIs). For instance, CNR values of ROI-2 of FBP and of new method were 1.670 and 1.978 at 100 mAs, respectively. Moreover, while CNR value of ROI-1 of FBP at 100 mAs was 0.955, CNR value of ROI 1 of using new method at 100 mAs was 48.163. FWHM values for FBP and the new method were 2.328 and 1.765 at 56 mAs, 2.032 and 1.661 at 100 mAs, and 2.111 and 1.736 at 199 mAs, respectively. CONCLUSIONS: The results support that using the new method of "ART+TV3D+MM" could help decrease the radiation dose level, which is one of the most critical limitations of DBT imaging. PMID- 29504550 TI - Optically active derivatives of terephthalic acid: four crystal structures from two powder patterns. AB - A novel important class of nanoporous crystalline solids, metal-organic frameworks (MOFs), composed of organic ligands (linkers) and metal ions, is now considered as a platform for the development of various functional hybrid materials. In order to design new MOF-based asymmetric catalysts, two terephthalic acid derivatives, namely 2-{[1-(1-tert-butoxycarbonyl)-L prolyl]amino}terephthalic acid, C18H22N2O7, (1), and 2-(L prolylamino)terephthalic acid, C13H14N2O5, (2), which could find potential applications as chiral linkers for the construction of enantioselective MOFs, were synthesized and their powder samples were measured at synchrotron station ID22 (ESRF). Each sample contained two unknown crystalline phases, so four new crystal structures were determined, namely, the 2.24-hydrate of (1), (1a) (space group C2221), and the 2.08-hydrate of (1), (1b) (P2221), which are crystallohydrates, and two polymorphs of (2), i.e. (2a) (C2221) and (2b) (P212121), and were validated with DFT-d (dispersion-corrected density functional theory) optimizations. PMID- 29504551 TI - Topological identification of the first uninodal 8-connected lsz MOF built from 2,2'-difluorobiphenyl-4,4'-dicarboxylate pillars and cadmium(II)-triazolate layers. AB - Using polynuclear metal clusters as nodes, many high-symmetry high-connectivity nets, like 8-connnected bcu and 12-connected fcu, have been attained in metal organic frameworks (MOFs). However, construction of low-symmetry high-connected MOFs with a novel topology still remains a big challenge. For example, a uninodal 8-connected lsz network, observed in inorganic ZrSiO4, has not been topologically identified in MOFs. Using 2,2'-difluorobiphenyl-4,4'-dicarboxylic acid (H2L) as a new linker and 1,2,4-triazole (Htrz) as a coligand, a novel three-dimensional CdII-MOF, namely poly[tetrakis(MU4-2,2'-difluorobiphenyl-4,4'-dicarboxylato kappa5O1,O1':O1':O4:O4')tetrakis(N,N-dimethylformamide-kappaO)tetrakis(MU3-1,2,4 triazolato-kappa3N1:N2:N4)hexacadmium(II)], [Cd6(C14H6F2O4)4(C2H2N3)4(C3H7NO)4]n, (I), has been prepared. Single-crystal structure analysis indicates that six different CdII ions co-exist in (I) and each CdII ion displays a distorted [CdO4N2] octahedral geometry with four equatorial O atoms and two axial N atoms. Three CdII ions are connected by four carboxylate groups and four trz- ligands to form a linear trinuclear [Cd3(COO)4(trz)4] cluster, as do the other three CdII ions. Two Cd3 clusters are linked by trz- ligands in a MU1,2,4-bridging mode to produce a two-dimensional CdII-triazolate layer with (6,3) topology in the ab plane. These two-dimensional layers are further pillared by the L2- ligands along the c axis to generate a complicated three-dimensional framework. Topologically, regarding the Cd3 cluster as an 8-connected node, the whole architecture of (I) is a uninodal 8-connected lsz framework with the Schlafli symbol (422.66). Complex (I) was further characterized by elemental analysis, IR spectroscopy, powder X-ray diffraction, thermogravimetric analysis and a photoluminescence study. MOF (I) has a high thermal and water stability. PMID- 29504552 TI - First-row transition metal-pyridine (py)-sulfate [(py)xM](SO4) complexes (M = Ni, Cu and Zn): crystal field theory in action. AB - The crystal structures of three first-row transition metal-pyridine-sulfate complexes, namely catena-poly[[tetrakis(pyridine-kappaN)nickel(II)]-MU-sulfato kappa2O:O'], [Ni(SO4)(C5H5N)4]n, (1), di-MU-sulfato-kappa4O:O-bis[tris(pyridine kappaN)copper(II)], [Cu2(SO4)2(C5H5N)6], (2), and catena-poly[[tetrakis(pyridine kappaN)zinc(II)]-MU-sulfato-kappa2O:O'-[bis(pyridine-kappaN)zinc(II)]-MU-sulfato kappa2O:O'], [Zn2(SO4)2(C5H5N)6]n, (3), are reported. Ni compound (1) displays a polymeric crystal structure, with infinite chains of NiII atoms adopting an octahedral N4O2 coordination environment that involves four pyridine ligands and two bridging sulfate ligands. Cu compound (2) features a dimeric molecular structure, with the CuII atoms possessing square-pyramidal N3O2 coordination environments that contain three pyridine ligands and two bridging sulfate ligands. Zn compound (3) exhibits a polymeric crystal structure of infinite chains, with two alternating zinc coordination environments, i.e. octahedral N4O2 coordination involving four pyridine ligands and two bridging sulfate ligands, and tetrahedral N2O2 coordination containing two pyridine ligands and two bridging sulfate ligands. The observed coordination environments are consistent with those predicted by crystal field theory. PMID- 29504553 TI - On the effect of Ga and In substitutions in the Ca11Bi10 and Yb11Bi10 bismuthides crystallizing in the tetragonal Ho11Ge10 structure type. AB - The Ga- and In-substituted bismuthides Ca11GaxBi10-x, Ca11InxBi10-x, Yb11GaxBi10 x, and Yb11InxBi10-x (x < 2) can be readily synthesized employing molten Ga or In metals as fluxes. They crystallize in the tetragonal space group I4/mmm and adopt the Ho11Ge10 structure type (Pearson code tI84; Wyckoff sequence n2 m j h2 e2 d). The structural response to the substitution of Bi with smaller and electron poorer In or Ga has been studied by single-crystal X-ray diffraction methods for the case of Ca11InxBi10-x [x = 1.73 (2); octabismuth undecacalcium diindium]. The refinements show that the In atoms substitute Bi only at the 8h site. The refined interatomic distances show an unconventional - for this structure type - bond length distribution within the anionic sublattice. The latter can be viewed as consisting of isolated Bi3- anions and [In4Bi820-] clusters for the idealized Ca11In2Bi8 model. Formal electron counting and first-principle calculations show that the peculiar bonding in this compound drives the system toward an electron precise state, thereby stabilizing the observed bond-length pattern. PMID- 29504554 TI - New solvates of the drug naltrexone: protonation, conformation and interplay of synthons. AB - Naltrexone [systematic name: (4R,4aS,7aR,12bS)-3-cyclopropylmethyl-4a,9-dihydroxy 2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one] is an important morphine-related drug used for combating alcoholism and opioid dependence. Of the eight crystal forms of naltrexone known thus far, only one exists in the neutral form and it crystallizes as a monohydrate. We have isolated the naltrexone free base as two new solvate forms, i.e. the ethyl acetate 0.33 solvate, C20H23NO4.0.33C4H8O2, (I), and the diethyl ether hemisolvate, C20H23NO4.0.5C4H10O, (II). While just one solvent molecule is present in the asymmetric unit of each solvate, there are three drug molecules (Z' = 3) in ethyl acetate solvate (I) and two (Z' = 2) in diethyl ether solvate (II). In (I), one of the three crystallographically independent drug molecules is present with its cyclopropyl group disordered over two sets of positions, as is the whole diethyl ether solvent molecule in (II). In all known forms, including the title forms, the naltrexone molecule exhibits the same conformation of the fused rings. The only conformational variability of naltrexone is in the cyclopropylmethyl group. Two conformations can be found around the bond connecting this group to the N heterocycle, which is directly related to drug protonation. We have calculated, at the B3LYP/6-31G** level of theory, the minimum energy conformations of protonated and neutral naltrexone molecules for a chosen torsion angle about this bond. The lowest energy conformers depend on the protonation state and are in agreement with those found in the solid state. Within the cyclopropylmethyl group, the bond joining the methylene C atom to the cyclopropyl fragment also evidences conformational variability. In the literature, there are two well defined conformations around this bond. A third cyclopropyl conformation around this second bond is observed in the title solvates. Concerning the supramolecular features of the previously reported crystal structures, only one classical hydrogen bond between naltrexone molecules and one C(8) homosynthon is known, pointing to the robustness of this synthon and the difficulty in disrupting it. New R22(7) and C22(10) homosynthons are found in both (I) and (II), suggesting that their occurrence derives from crystallization of the neutral drug from nonpolar solvents. PMID- 29504555 TI - Different supramolecular interactions mediated by Br atoms in the crystal structures of three anisole derivatives. AB - Three anisole building blocks featuring bis(hydroxymethyl) or bis(bromomethyl) pendants have been analyzed with regard to their molecular structures and packing behaviour. The compounds are ethyl 3,5-bis(hydroxymethyl)-4-methoxybenzoate, C12H16O5, (I), [5-bromo-3-(hydroxymethyl)-2-methoxyphenyl]methanol [or 4-bromo 2,6-bis(hydroxymethyl)anisole], C9H11BrO3, (II), and 5-bromo-1,3-bis(bromomethyl) 2-methoxybenzene [or 4-bromo-2,6-bis(bromomethyl)anisole], C9H9Br3O, (III). A typical supramolecular pattern involved C-H...pi interactions generating molecular stacks, while pi-pi interactions were only observed in the absence of bromine, indicating a striking influence on the distances between adjacent aromatic moieties. When comparing bis(hydroxymethyl) compound (II) with bis(bromomethyl) compound (III), we found that the strong O-H...O hydrogen bonds in a zigzag arrangement in the first are replaced by C-H...Br interactions in the second without a change in the general packing. PMID- 29504556 TI - 3,4-Lutidinium salts with the diiodidoaurate(I) anion: structure of [(3,4 lut)2H]+.[AuI2]- and of two polymorphs of [(3,4-lut)2H+]2.[AuI2]-.I. AB - Reactions between potassium tetraiodidoaurate(III) and pyridine (py, C5H5N) or 3,4-lutidine (3,4-dimethylpyridine, 3,4-lut, C7H9N) were tested as possible sources of azaaromatic complexes of gold(III) iodide, but all identifiable products contained gold(I). The previously known structure dipyridinegold(I) diiodidoaurate(I), [Au(py)2]+.[AuI2]-, (3) [Adams et al. (1982). Z. Anorg. Allg. Chem. 485, 81-91], was redetermined at 100 K. The reactions with 3,4-lutidine gave three different types of crystal in small quantities. 3,4-Dimethylpyridine 3,4-dimethylpyridinium diiodidoaurate(I), [(3,4-lut)2H]+.[AuI2]-, (1), consists of an [AuI2]- anion on a general position and two [(3,4-lut)2H]+ cations across twofold axes. Bis(3,4-dimethylpyridine-3,4-dimethylpyridinium) diiodidoaurate(I) iodide, [(3,4-lut)2H+]2.[AuI2]-.I-, (2), crystallizes as two polymorphs, each forming pseudosymmetric inversion twins, in the space groups P21 and Pc (but resembling P21/m and P2/c), respectively. These are essentially identical layer structures differing only in their stacking patterns and thus might be regarded as polytypes. PMID- 29504557 TI - Synthesis and crystal structure of a new Cu3Au-type ternary phase in the Au-In-Pd system: distribution of atoms over crystallographic positions. AB - A new Cu3Au-type ternary phase (tau phase) is found in the AuPd-rich part of the Au-In-Pd system. It has a broad homogeneity range based on extensive (Pd,Au) and (In,Au) replacement, with the composition varying between Au17.7In25.3Pd57.0 and Au50.8In16.2Pd33.0. The occupancies of the crystallographic positions were studied by single-crystal X-ray diffraction for three samples of different composition. The sites with m-3m symmetry are occupied by atoms with a smaller scattering power than the atoms located on 4/mmm sites. Two extreme structure models were refined. Within the first, the occupation type changes from (Au,In,Pd)3(Pd,In) to (Au,Pd)3(In,Pd,Au) with an increase in the Au gross content. For the second model, the occupation type (Au,In,Pd)3(Pd,Au) remains essentially unchanged for all Au concentrations. Although the diffraction data do not allow the choice of one of these models, the latter model, where Au substitutes In on 4/mmm sites, seems to be preferable, since it agrees with the fact that the homogeneity range of the tau phase is inclined to the Au corner and provides the same occupation type for all the studied samples of different compositions. PMID- 29504558 TI - Effect of pH on the charge-assisted hydrogen-bonded assembly of the anionic [Cu(oxalate)2]2- building unit and N,N'-ditopic cations. AB - By the solvothermal reaction under acidic conditions of Cu(NO3)2.3H2O, Na2C2O4 and the N,N'-ditopic organic coligands 1-(pyridin-4-yl)piperazine (ppz) and 1,2 bis(pyridin-4-yl)ethane (bpa), two novel anionic copper(II) coordination compounds were obtained, namely the one-dimensional coordination polymer catena poly[4-(pyridin-1-ium-4-yl)piperazin-1-ium [[(oxalato-kappa2O1,O2)copper(II)]-MU oxalato-kappa3O1,O2:O1']], {(C9H15N3)[Cu(C2O4)2)]}n or {(H2ppz)[Cu(C2O4)2]}n, (I), and the discrete ionic complex 4,4'-(ethane-1,2-diyl)dipyridinium bis(oxalato-kappa2O1,O2)copper(II), (C12H14N2)[Cu(C2O4)2] or (H2bpa)[Cu(C2O4)2], (II). The products were characterized by single-crystal X-ray diffraction, elemental analysis, powder X-ray diffraction, thermogravimetric analyses and UV and IR spectroscopic techniques. The [Cu(C2O4)2]2- units for (I) and (II) are stabilized by H2ppz2+ and H2bpa2+ cations, respectively, via charge-assisted hydrogen bonds. Also, a study of the pH-controlled synthesis of this system shows that (I) was obtained at pH values of 2-4. When using bpa, a two-dimensional square-grid network of [Cu(C2O4)(bpa)]n was obtained at a pH of 4. This indicates that the pH of the reaction also plays a key role in the structural assembly and coordination abilities of oxalate and N,N'-ditopic coligands. PMID- 29504559 TI - Zirconium tetrachloride revisited. AB - Zirconium tetrachloride, ZrCl4, is a strategic material with wide-ranging applications. Until now, only one crystallographic study on ZrCl4 has been reported [Krebs (1970). Z. Anorg. Allg. Chem. 378, 263-272] and that was more than 40 years ago. The compound used for the previous determination was prepared from ZrO2 and Cl2-CCl4, and single-crystal X-ray diffraction (SCXRD) studies on ZrCl4 obtained from Zr metal have not yet been reported. In this context, we prepared ZrCl4 from the reaction of Zr metal and Cl2 gas in a sealed tube and investigated its structure at 100, 150, 200, 250, and 300 K. At 300 K, the SCXRD analysis indicates that ZrCl4 crystallizes in the orthorhombic space group Pca21 [a = 6.262 (9), b = 7.402 (11), c = 12.039 (17) A, and V = 558.0 (14) A3] and consists of infinite zigzag chains of edge-sharing ZrCl6 octahedra. This chain motif is similar to that observed previously in ZrCl4, but the structural parameters and space group differ. In the temperature range 100-300 K, no phase transformation was identified, while elongation of intra-chain Zr...Zr [3.950 (1) A at 100 K and 3.968 (5) A at 300 K] and inter-chain Cl...Cl [3.630 (3) A at 100 K and 3.687 (9) A at 300 K] distances occurred. PMID- 29504560 TI - A concise, efficient and versatile synthesis of amino-substituted benzo[b]pyrimido[5,4-f]azepines: synthesis and spectroscopic characterization, together with the molecular and supramolecular structures of three products and one intermediate. AB - A concise, efficient and versatile synthesis of amino-substituted benzo[b]pyrimido[5,4-f]azepines is described: starting from a 5-allyl-4,6 dichloropyrimidine, the synthesis involves base-catalysed aminolysis followed by intramolecular Friedel-Crafts cyclization. Four new amino-substituted benzo[b]pyrimido[5,4-f]azepines are reported, and all the products and reaction intermediates have been fully characterized by IR, 1H and 13C NMR spectroscopy and mass spectrometry, and the molecular and supramolecular structures of three products and one intermediate have been determined. In each of N,2,6,11 tetramethyl-N-phenyl-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepin-4-amine, C22H24N5, (III), 4-(1H-benzo[d]imidazol-1-yl)-6,11-dimethyl-6,11-dihydro-5H benzo[b]pyrimido[5,4-f]azepine, which crystallizes as a 0.374-hydrate, C21H19N5.0.374H2O, (VIIIa), and 6,7,9,11-tetramethyl-4-(5-methyl-1H benzo[d]imidazol-1-yl)-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepine, C24H25N5, (VIIIc), the azepine ring adopts a boat conformation, but with a different configuration at the stereogenic centre in (VIIIc), as compared with (III) and (VIIIa). In the intermediate 5-allyl-6-(1H-benzo[d]imidazol-1-yl)-N-methyl-N-(4 methylphenyl)pyrimidin-4-amine, C22N21N5, (VIIb), the immediate precursor of 4 (1H-benzo[d]imidazol-1-yl)-6,8,11-trimethyl-6,11-dihydro-5H-benzo[b]pyrimido[5,4 f]azepine, (VIIIb), the allyl group is disordered over two sets of atomic sites having occupancies of 0.688 (5) and 0.312 (5). The molecules of (III) are linked into chains by a C-H...pi(pyrimidine) hydrogen bond, and those of (VIIb) are linked into complex sheets by three hydrogen bonds, one of the C-H...N type and two of C-H...pi(arene) type. The molecules of the organic component in (VIIIa) are linked into a chain of rings by two C-H...pi(arene) hydrogen bonds, and these chains are linked into sheets by the water components; a single weak C-H...N hydrogen bond links molecules of (VIIIc) into centrosymmetric R22(10) dimers. Comparisons are made with some related compounds. PMID- 29504561 TI - Structure determination of phase II of the antifungal drug griseofulvin by powder X-ray diffraction. AB - Two new crystalline polymorphs of the widely used antifungal drug griseofulvin (phases II and III), which originate from the crystallization of the melt, have been detected recently. The crystal structure of phase II of griseofulvin {systematic name: (2S,6'R)-7-chloro-2',4,6-trimethoxy-6'-methyl-3H,4'H-spiro[1 benzofuran-2,1'-cyclohex-2-ene]-3,4'-dione}, C17H17ClO6, has been solved by powder X-ray diffraction (PXRD). The PXRD pattern of this new phase was recorded at room temperature using synchrotron radiation. The starting structural model was generated by a Monte Carlo simulated annealing method. The final structure was obtained through Rietveld refinement with soft restraints for interatomic bond lengths and angles, except for the aromatic ring, where a rigid-body constraint was applied. The symmetry is orthorhombic (space group P212121) and the asymmetric unit contains two molecules. PMID- 29504562 TI - Supramolecular architectures in cytosinium 6-chloronicotinate monohydrate and 5 bromo-6-methylisocytosinium hydrogen sulfate. AB - Aminopyrimidine derivatives are biologically important as they are components of nucleic acids and drugs. The crystals of two new salts, namely cytosinium 6 chloronicotinate monohydrate, C4H6N3O+.C6H3ClNO2-.H2O, (I), and 5-bromo-6 methylisocytosinium hydrogen sulfate (or 2-amino-5-bromo-4-oxo-6 methylpyrimidinium hydrogen sulfate), C5H7BrN3O+.HSO4-, (II), have been prepared and characterized by single-crystal X-ray diffraction. The pyrimidine ring of both compounds is protonated at the imine N atom. In hydrated salt (I), the primary R22(8) ring motif (supramolecular heterosynthon) is formed via a pair of N-H...O(carboxylate) hydrogen bonds. The cations, anions and water molecule are hydrogen bonded through N-H...O, N-H...N, O-H...O and C-H...O hydrogen bonds, forming R22(8), R32(7) and R55(21) motifs, leading to a hydrogen-bonded supramolecular sheet structure. The supramolecular double sheet structure is formed via water-carboxylate O-H...O hydrogen bonds and pi-pi interactions between the anions and the cations. In salt (II), the hydrogen sulfate ions are linked via O-H...O hydrogen bonds to generate zigzag chains. The aminopyrimidinium cations are embedded between these zigzag chains. Each hydrogen sulfate ion bridges two cations via pairs of N-H...O hydrogen bonds and vice versa, generating two R22(8) ring motifs (supramolecular heterosynthon). The cations also interact with one another via halogen-halogen (Br...Br) and halogen oxygen (Br...O) interactions. PMID- 29504563 TI - A new copper(II) supramolecular coordination polymer and a dinuclear compound with multifunctional 2-amino-5-sulfobenzoic acid and flexible N-donor ligands: synthesis, structure and characterization. AB - Multifunctional 2-amino-5-sulfobenzoic acid (H2afsb) can exhibit a variety of roles during the construction of supramolecular coordination polymers. The pendant carboxylic acid, sulfonic acid and amino groups could not only play a role in directing bonding but could also have the potential to act as hydrogen bond donors and acceptors, resulting in extended high-dimensional supramolecular networks. Two new CuII coordination compounds, namely catena poly[[[diaquacopper(II)]-MU-1,6-bis(1H-1,2,4-triazol-1-yl)hexane-kappa2N4:N4'] bis(3-amino-4-carboxybenzenesulfonate) dihydrate], {[Cu(C10H16N6)2(H2O)2](C7H6NO5S)2.2H2O}n or {[Cu(bth)2(H2O)2](Hafsb)2.2H2O}n, (1), and bis(MU-2-amino-5-sulfonatobenzoato-kappa2O1:O1')bis{MU-1,2-bis[(1H imidazol-1-yl)methyl]benzene-kappa2N3:N3'}bis[aquacopper(II)] trihydrate, [Cu2(C7H5NO5S)2(C14H14N4)2(H2O)2].3H2O or [Cu2(afsb)2(obix)2(H2O)2].3H2O, (2), have been obtained through the assembly between H2afsb and the CuII ion in the presence of the flexible N-donor ligands 1,6-bis(1H-1,2,4-triazol-1-yl)hexane (bth) and 1,2-bis[(1H-1,2,4-triazol-1-yl)methyl]benzene (obix), respectively. Compound (1) consists of a cationic coordination polymeric chain and 3-amino-4 carboxybenzenesulfonate (Hafsb-) anions. Compound (2) exhibits an asymmetric dinuclear structure. There are hydrogen-bonded networks within the lattices of (1) and (2). Interestingly, both (1) and (2) exhibit reversible dehydration rehydration behaviour. PMID- 29504564 TI - Three zinc iodide complexes based on phosphane ligands: syntheses, structures, optical properties and TD-DFT calculations. AB - Three zinc iodide complexes based on phosphane ligands, namely diiodidobis(triphenylphosphane-kappaP)zinc(II), [ZnI2(C18H15P2)2], (1), diiodidobis[tris(4-methylphenyl)phosphane-kappaP]zinc(II), [ZnI2(C21H21P2)2], (2), and [bis(diphenylphosphoryl)methane-kappa2O,O']zinc(II) tetraiodidozinc(II), [Zn(C25H22O2P2)3][ZnI4], (3), have been synthesized and characterized. Single crystal X-ray diffraction revealed that the structures of (1) and (2) are both mononuclear four-coordinated ZnI2 complexes containing two monodentate phosphane ligands, respectively. Surprisingly, (2) spontaneously forms an acentric structure, suggesting it might be a potential second-order NLO material. The crystal structure of complex (3) is composed of two parts, namely a [Zn(dppmO2)3]2+ cation [dppmO2 is bis(diphenylphosphoryl)methane] and a [ZnI4]2- anion. The UV-Vis absorption spectra, thermal stabilities and photoluminescence spectra of the title complexes have also been studied. Time-dependent density functional theory (TD-DFT) calculations reveal that the low-energy UV absorption and the corresponding light emission both result from halide-ligand charge transfer (XLCT) excited states. PMID- 29504565 TI - Topological study of diverse hydrogen-bonded patterns found in a system of a nickel(II) complex and the sulfate anion. AB - A nickel(II) coordination complex, bis[2,6-bis(1H-benzimidazol-2-yl kappaN3)pyridine-kappaN]nickel(II) sulfate, [Ni(C19H13N5)2]SO4 or [Ni(H2L)2]SO4, having four peripheral tetrahedrally oriented N-H donor units, combines with sulfate bridges to create hydrogen-bonded structures of varied dimensionality. The three crystal structures reported herein in the space groups P212121, I-4 and Pccn are defined solely by strong charge-assisted N-H...O hydrogen bonds and contain disordered guests (water and dimethylformamide) that vary in size, shape and degree of hydrophilicity. Two of the compounds are channelled solids with three-dimensional structures, while the third is one-dimensional in nature. In spite of their differences, all three present a striking resemblance to the previously reported anhydrous relative [Guo et al. (2011). Chin. J. Inorg. Chem. 27, 1517-1520], which is considered as the reference framework from which all three title compounds are derived. The hydrogen-bonded frameworks are described and compared using crystallographic and topological approaches. PMID- 29504566 TI - New quaternary carbide Mg1.52Li0.24Al0.24C0.86 as a disorder derivative of the family of hexagonal close-packed (hcp) structures and the effect of structure modification on the electrochemical behaviour of the electrode. AB - Magnesium alloys are the basis for the creation of light and ultra-light alloys. They have attracted attention as potential materials for the accumulation and storage of hydrogen, as well as electrode materials in metal-hydride and magnesium-ion batteries. The search for new metal hydrides has involved magnesium alloys with rare-earth transition metals and doped by p- or s-elements. The synthesis and characterization of a new quaternary carbide, namely dimagnesium lithium aluminium carbide, Mg1.52Li0.24Al0.24C0.86, belonging to the family of hexagonal close-packed (hcp) structures, are reported. The title compound crystallizes with hexagonal symmetry (space group P-6m2), where two sites with 6m2 symmetry and one site with 3m. symmetry are occupied by an Mg/Li statistical mixture (in Wyckoff position 1a), an Mg/Al statistical mixture (in position 1d) and C atoms (2i). The cuboctahedral coordination is typical for Mg/Li and Mg/Al, and the C atom is enclosed in an octahedron. Electronic structure calculations were used for elucidation of the ability of lithium or aluminium to substitute magnesium, and evaluation of the nature of the bonding between atoms. The presence of carbon in the carbide phase improves the corrosion resistance of the Mg1.52Li0.24Al0.24C0.86 alloy compared to the ternary Mg1.52Li0.24Al0.24 alloy and Mg. PMID- 29504567 TI - Hydrothermal synthesis, crystal structure and properties of a two-dimensional uranyl coordination polymer based on a flexible zwitterionic ligand. AB - The interaction between the uranyl cation, (UO2)2+, and organic species is of interest due to the potential applications of the resulting compounds with regard to nuclear waste disposal and nuclear fuel reprocessing. The hydrothermal reaction of various uranyl compounds with flexible zwitterionic 1,1'-[1,4 phenylenebis(methylene)]bis(pyridin-1-ium-4-carboxylate) dihydrochloride (Bpmb.2HCl) in deionized water containing drops of H2SO4 resulted in the formation of a novel two-dimensional uranyl coordination polymer, namely poly[tetraoxido{MU2-1,1'-[1,4-phenylenebis(methylene)]bis(pyridin-1-ium-4 carboxylate)}di-MU3-sulfato-diuranium(VI)], [(UO2)2(SO4)2(C20H16N2O4)]n, (1). Single-crystal X-ray diffraction reveals that this coordination polymer exhibits a layered arrangement and the (UO2)2+ centre is coordinated by five equatorial O atoms. The structure was further characterized by FT-IR spectroscopy, powder X ray diffraction (PXRD) and thermogravimetric analysis (TGA). The polymer shows high thermal stability up to 696 K. Furthermore, the photoluminescence properties of (1) has also been studied, showing it to exhibit a typical uranyl fluorescence. PMID- 29504568 TI - The role of different nonspecific interactions and halogen contacts in the crystal structure organization of 5-chloroisatoic anhydride. AB - The crystal structure of 6-chloro-2,4-dihydro-1H-3,1-benzoxazine-2,4-dione (5 chloroisatoic anhydride), C8H4ClNO3, has been determined and analysed in terms of connectivity and packing patterns. The compound crystallizes in the noncentrosymmetric space group Pna21 with one molecule in the asymmetric unit. The role of different weak interactions is discussed with respect to three dimensional network organization. Molecules are extended into one-dimensional helical arrangements, making use of N-H...O hydrogen bonds and pi-pi interactions. The helices are further organized into monolayers via weak C-H...O and lone pair-pi interactions, and the monolayers are packed into a noncentrosymmetric three-dimensional architecture by C-Cl...pi interactions and C H...Cl and Cl...Cl contacts. A Hirshfeld surface (HS) analysis was carried out and two-dimensional (2D) fingerprint plots were generated to visualize the intermolecular interactions and to provide quantitative data for their relative contributions. In addition, tests of the antimicrobial activity and in vitro cytotoxity effects against fitoblast L929 were performed and are discussed. PMID- 29504569 TI - Crystal structure and Hirshfeld surface analysis of the anhydrous form of the nucleoside analogue entecavir. AB - The nucleoside analogue entecavir {systematic name: 2-amino-9-[(1S,3R,4S)-4 hydroxy-3-hydroxymethyl-2-methylenecyclopentyl]-1,9-dihydro-6H-purin-6-one}, C12H15N5O3, is an antihepatitis B virus drug that has been approved in the US, EU and several countries worldwide. We report here the single-crystal structure of the anhydrous form and compare it with that of the previously reported monohydrate form [Jiang & Liu (2009). Acta Cryst. E65, o2232]. Hirshfeld surface analysis has been employed to understand and visualize the subtle packing differences between the two crystalline forms. The results show that, compared to the previously reported hydrated form, the anhydrous crystal has significantly different intermolecular interactions and packing patterns. PMID- 29504570 TI - Two novel lanthanide(III) organic frameworks based on a biphenyltetracarboxylate ligand: synthesis, structure and magnetic and luminescence properties. AB - Two new two-dimensional lanthanide coordination polymers, namely poly[[tetra-MU2 acetato-tetraaquabis(MU4-biphenyl-3,3',5,5' tetracarboxylato)tetrakis(dimethylacetamide)tetraterbium(III)] pentahydrate], {[Tb4(C16H6O8)2(C2H3O2)4(C4H9NO)4(H2O)4].5H2O}n, (1), and poly[[tetra-MU2-acetato tetraaquabis(MU5-biphenyl-3,3',5,5' tetracarboxylato)tetrakis(dimethylacetamide)tetraeuropium(III)] tetrahydrate], {[Eu4(C16H6O8)2(C2H3O2)4(C4H9NO)4(H2O)4].4H2O}n, (2), have been synthesized from biphenyl-3,3',5,5'-tetracarboxylic acid (H4bpt) and Ln(NO3)3.6H2O (Ln = Tb and Eu) under solvothermal conditions. Single-crystal X-ray structure analysis shows that the two compounds are isostructural and crystallize in the monoclinic P21/n space group. The crystal structures are constructed from bpt4- ligands (as linkers) and {Ln2(MU2-CH3COO)2} building units (as nodes), which topological analysis shows to be a (4,6)-connected network with sql topology. Compounds (1) and (2) have been characterized by elemental analysis, IR spectroscopy, powder X ray diffraction (PXRD), thermogravimetric analysis (TGA) and fluorescence analysis in the solid state. In addition, a magnetic investigation shows the presence of antiferromagnetic interactions in compound (1). PMID- 29504571 TI - Reassessment of paracetamol orthorhombic Form III and determination of a novel low-temperature monoclinic Form III-m from powder diffraction data. AB - Paracetamol [N-(4-hydroxyphenyl)acetamide, C8H9NO2] has several polymorphs, just like many other drugs. The most stable polymorphs, denoted Forms I and II, can be obtained easily and their crystal structures are known. Crystals of the orthorhombic, less stable, room-temperature Form III are difficult to grow; they need a special recipe to crystallize and suffer from severe preferred orientation. A crystal structure model of Form III has been proposed and solved from a combination of structure prediction and powder X-ray diffraction (PXRD) [Perrin et al. (2009). Chem. Commun. 22, 3181-3183]. The final Rwp value of 0.138 and the corresponding considerable residual trace were reasons to check its validity. A new structure determination of Form III using new high-resolution PXRD data led to a final Rwp value of 0.042 and an improvement of the earlier proposed model. In addition, a reversible phase transition was found at 170-220 K between the orthorhombic Form III and a novel monoclinic Form III-m. The crystal structure of Form III-m has been determined and refined from PXRD data to a final Rwp value of 0.059. PMID- 29504572 TI - Planarity of heteroaryldithiocarbazic acid derivatives showing tuberculostatic activity: structure-activity relationships. AB - The search for new tuberculostatics is an important issue due to the increasing resistance of Mycobacterium tuberculosis to existing agents and the resulting spread of the pathogen. Heteroaryldithiocarbazic acid derivatives have shown potential tuberculostatic activity and investigations of the structural aspects of these compounds are thus of interest. Three new examples have been synthesized. The structure of methyl 2-[amino(pyridin-3 yl)methylidene]hydrazinecarbodithioate, C8H10N4S2, at 293 K has monoclinic (P21/n) symmetry. It is of interest with respect to antibacterial properties. The structure displays N-H...N and N-H...S hydrogen bonding. The structure of N' (pyrrolidine-1-carbonothioyl)picolinohydrazonamide, C11H15N5S, at 100 K has monoclinic (P21/n) symmetry and is also of interest with respect to antibacterial properties. The structure displays N-H...S hydrogen bonding. The structure of (Z) methyl 2-[amino(pyridin-2-yl)methylidene]-1-methylhydrazinecarbodithioate, C9H13N4S2, has triclinic (P-1) symmetry. The structure displays N-H...S hydrogen bonding. PMID- 29504573 TI - Performance control in one consecutive motor task sequence - Alphapproaching central neuronal motor behaviour preceding isometric contraction onsets and relaxation offsets at lower distinct torques. AB - OBJECTIVE: Motor-related cortical potentials (MRCP) often compared separated muscle activations; however, MRCP preceding combined contraction onsets and relaxation offsets of one consecutive motor task sequence remain to be elucidated. METHODS: Twelve healthy males (27.92+/-4.33 years, 181.83+/-7.15 cm, 84.58+/-7.15 kg) performed 40 submaximal isometric right-limb wrist flexions (i.e. motor task sequences). Each motor task sequence combined timed contractions to and relaxations from distinct torque levels, i.e. 20% and 40% of maximum voluntary contractions (MVC). Synchronized continuous EEG (32 Ag/AgCl-electrodes mounted over motor-related areas) and EMG (i.e. flexor carpi radialis, FCR) recordings served to detect torque level-on/offsets for MRCP analyses. RESULTS: Motor task sequences were accurately maintained with participants' mean values of FCR muscle activity revealing no signs of fatigue (p?0.05). Main findings (i.e. readiness potential) were larger amplitudes over frontal electrode sites (p?0.05) preceding contractions compared to relaxations, whereas amplitudes were larger (i.e. peak) over centro-parietal electrode sites (p?0.05) preceding 40% compared to 20% MVC. CONCLUSION: When performed in one consecutive motor task sequence, controlling the production as well as the releasing of force may require similar proprioceptive and visuo-motor processing preceding the same force level (i.e. 20% or 40%); however, this is irrespective of the muscle activation type (i.e. contraction or relaxation). PMID- 29504574 TI - Calf muscle density is independently associated with physical function in overweight and obese older adults. AB - OBJECTIVES: To determine whether associations of calf muscle density with physical function are independent of other determinants of functional decline in overweight and obese older adults. METHODS: This was a secondary analysis of a cross-sectional study of 85 community-dwelling overweight and obese adults (mean+/-SD age 62.8+/-7.9 years; BMI 32.3+/-6.1 kg/m2; 58% women). Peripheral quantitative computed tomography assessed mid-calf muscle density (66% tibial length) and dual-energy X-ray absorptiometry determined visceral fat area. Fasting glucose, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and C-reactive protein (CRP) were analysed. Physical function assessments included hand grip and knee extension strength, balance path length (computerised posturography), stair climb test, Short Physical Performance Battery (SPPB) and self-reported falls efficacy (Modified Falls Efficacy Scale; M-FES). RESULTS: Visceral fat area, not muscle density, was independently associated with CRP and fasting glucose (B=0.025; 95% CI 0.009-0.042 and B=0.009; 0.001-0.017, respectively). Nevertheless, higher muscle density was independently associated with lower path length and stair climb time, and higher SPPB and M-FES scores (all P?0.05). Visceral fat area, fasting glucose and CRP did not mediate these associations. CONCLUSIONS: Higher calf muscle density predicts better physical function in overweight and obese older adults independent of insulin resistance, visceral adiposity or inflammation. PMID- 29504576 TI - Leptin-deficiency eradicates the positive effect of traumatic brain injury on bone healing: histological analyses in a combined trauma mouse model. AB - INTRODUCTION: The combination of traumatic brain injury (TBI) and long-bone fracture leads to increased formation of callus and mineral density in wild-type (WT) mice. However, this effect was not detected radiologically in leptin deficient mice. Due to the complex interactions between hormonal and bone metabolism and the important role of leptin in this setting, our aim was to investigate morphologic properties and the tissue composition in the fracture callus comparing WT and leptin-deficient mice. METHODS: Female C57/Black6N mice (n=36) and leptin deficient ob/ob mice (n=36) each were assigned to two groups (fracture Fx/combined trauma Fx/TBI). Femoral osteotomy was stabilized with external fixator, TBI was induced with controlled cortical impact injury. After sacrifice of the animals, femora were harvested, cryofixated, and 7 um slices were prepared. Staining was performed adhering to Movat's Pentachrome protocol. Histomorphometric analysis, quantifying percentage of mineralized bone area, and a semi-quantitative evaluation of bone bridging were performed. RESULTS: Leptin deficient mice showed a higher rate of non-union after osteotomy, less callus formation in the osteotomy gap, and unexpected bone and cartilage formation independent of the osteotomy region. DISCUSSION: Leptin plays an important role in fracture healing and bone formation. Without Leptin, the positive effect of TBI on fracture healing ceases. The comprehension of the underlying pathophysiological process could sign important for novel strategies in stimulation of fracture healing. PMID- 29504575 TI - The "dark matter" of DNA and the regulation of bone metabolism: The role of non coding RNAs. AB - Epigenetics, present a new discipline that attempts to explain significant differences in phenotypes among patients with the same disease. In contrast to the other epigenetic mechanisms that modulate gene transcription, non-coding RNAs act at the post-transcriptional level. They directly modulate the gene expression of mRNA genes leading to mRNA target cleavage and degradation and translation repression. Bioinformatic predictions indicate that non coding RNAs may be involved in the regulation of 60% of the coding genes and each non-coding RNA can have multiple target genes, and each gene may be regulated by more than one non coding RNAs. In the last decade several studies have shown a significant role of non-coding RNAs in the regulation of bone metabolism and function of bone cells opening a new era in the understanding of bone biology in health and disease. PMID- 29504577 TI - Expression of BDNF in dorsal root ganglion of rats with bone cancer pain and its effect on pain behavior. AB - OBJECTIVE: To detect the expression of brain-derived neurotrophic factor (BDNF) in dorsal root ganglion (DRG) of rats with bone cancer pain, and to explore the effects of BDNF and anti-BDNF on pain behavior. METHODS: 40 SD rats were randomly divided into Sham group and Cancer group (n=20). Rats in Sham were injected with PBS into the tibia, while rats in Cancer group were injected with Walker 256 cells to construct rat tibial bone cancer pain model. Rats in Cancer group were further divided into physiological saline (NS) group and anti-BDNF group (n=10) to observe the effects of anti-BDNF on pain behavior in rats with bone cancer pain. RESULTS: Expression level of BDNF and its receptor in DRG of Cancer group was significantly higher than that of Sham group at 3 weeks after inoculation (p?0.05). The expression level of BDNF mRNA in the Cancer group was significantly higher than that in the Sham group at 5d, 10d and 20d (p?0.05). Hindpaw withdrawal latency was significantly shorter in Cancer group than in Sham group (p?0.05). Hindpaw withdrawal mechanical threshold was significantly lower in Cancer group than in Sham group (p?0.05). Hindpaw withdrawal latency was significantly longer and hindpaw withdrawal mechanical threshold was significantly higher in anti-BDNF group than in NS group after the use of anti BDNF (p?0.05). CONCLUSION: BDNF can aggravate bone pain in rats, and anti-BDNF has obvious antinociceptive function in bone cancer pain. PMID- 29504578 TI - Ultrasonography and clinical outcome comparison of extracorporeal shock wave therapy and corticosteroid injections for chronic plantar fasciitis: A randomized controlled trial. AB - OBJECTIVES: Extracorporeal shockwave therapy (ESWT) and corticosteroid injection (CSI) are treatment options for plantar fasciitis. Their clinical outcome comparison remains a debate. Also, the thickness changes of the plantar fascia on objective evaluation under the medium energy ESWT and CSI therapy are elusive. METHODS: A total of 97 patients with chronic plantar fasciitis were enrolled in the randomized prospective trial. Forty-seven patients received extracorporeal shock wave therapy (ESWT), and fifty patients received corticosteroid injection (CSI). The thickness of the plantar fascia was evaluated respectively before ESWT and CSI, and at the 4th and 12th week after ESWT and CSI by ultrasonography. Pain level and clinical outcomes were recorded using visual analogue scale (VAS) and 100-points scoring systems. Correlation analysis was performed between the thickness change and clinical outcome. RESULTS: Under ultrasonography, we observed more increase of plantar fascia thickness of ESWT group than CSI group at 4th week (p=0.048). VAS of plantar fasciitis patients receiving ESWT was lower than those who received corticosteroid injection (0.001 and p?0.001, at 4th and 12th week). On the assessment of 100-points scoring systems, the pain level of patients with ESWT was lower than those with CSI at the 12th week (p?0.001). On the other hand, the increase of plantar fascia thickness at 4th week was positively correlated with the decrease of VAS score at 12th week follow-up (R=0.302, P=0.039). CONCLUSIONS: At 4th week after treatment, the thickness of plantar fascia increased. Then it decreased gradually, but not to the baseline at 12th week. On the pain level outcome at 12th week, extracorporeal shockwave therapy (ESWT) was more efficient than corticosteroid injection (CSI) on chronic plantar fasciitis. The more change of plantar fascia after ESWT, the more efficient on clinical outcome. PMID- 29504579 TI - Efficacy of fibula fixation in the early treatment of Osteonecrosis of the femoral head and its effects on local microcirculation, articular surface collapse, joint pain and function. AB - OBJECTIVES: The aim of this study is to investigate the efficacy of fibula fixation in the early treatment of osteonecrosis of the femoral head (ONFH). METHODS: 130 patients with ONFH were selected and randomly divided into control group and observation group. Patients in the control group received core decompression treatment, while patients in the observation group received fibula fixation. The local microcirculation was observed by dynamic contrast-enhanced MRI, necrotic volume was measured using MRI, articular surface collapse by using X-ray, McGill pain questionnaire was used to understand and compared the joint pain condition. RESULTS: Tauhe total effective rate of the observation group was significantly higher than that of the control group (p?0.05). Necrosis volume of observation group was significantly smaller than that of control group (p?0.05). Degree of joint pain was significantly lower in observation group than in control (p?0.05). Harris scores were higher in observation group than in control group (p?0.05). All life scores of observation were significantly higher than those of control group (p?0.05). CONCLUSION: fibula fixation seems to be not superior to core decompression n preventing articular surface collapse, but it can effectively relieve the joint pain in patients with early ONFH. PMID- 29504581 TI - Effect of footwear on standing balance in healthy young adult males. AB - OBJECTIVE: The present study aimed to evaluate the effect of footwear on standing balance in healthy young adult males. METHODS: Thirty healthy male participants aged 20-30 years were tested for standing balance on the Balance Master on three occasions, including wearing a sandal, standard shoe, or no footwear (barefoot). The tests of postural stability include; "Modified Clinical Test of Sensory Interaction on Balance" (mCTSIB), "Unilateral Stance" (US), and the "Limits of Stability" (LOS). The balance scores (mCTSIB, US, and LOS) was analyzed. RESULTS: There was a significant effect between footwear conditions for mCTIB with eye closed on a firm surface (p=0.002). There was a significant effect between footwear conditions for the US with eye open and closed (p?0.05). There was a significant effect between footwear conditions for LOS reaction time during forward movement (p=0.02). Similarly, there was a significant effect between footwear conditions for LOS reaction time during left side movement (p=0.01). CONCLUSIONS: Wearing sandals compared to bare feet significantly increased postural sway and reduced stability in healthy young adult males. However, wearing a standard shoe compared to bare feet did not significantly affect balance scores in standing. PMID- 29504580 TI - Muscular changes after minimally invasive versus open spinal stabilization of thoracolumbar fractures: A literature review. AB - PURPOSE: This review addressed the question of whether minimally invasive surgery after traumatic thoracolumbar spine fractures can reduce paraspinal muscle injury, limit changes in muscular structure and function, and lead to better functional outcome. Special emphasis was given to studies using imaging techniques or electromyography to evaluate the lumbar multifidus muscle structure and function. METHODS: The authors searched the literature in the PubMed/Medline, EMBASE, by cross-referencing and additional hand search. Included were comparative studies between conventional open and minimally invasive or percutaneous surgical approaches. Twelve studies were included. RESULTS AND CONCLUSIONS: The literature review supports the assumption that minimally invasive surgery preserves muscles for the early post-operative period, even though the level of evidence is still low. The correlation of changes in muscular structure to pain, strength, disability, and quality of life remains ambiguous and should be addressed in further studies with a focus on the surgical approach. PMID- 29504582 TI - Hypercalcemia and hypercalciuria during denosumab treatment in children with osteogenesis imperfecta type VI. AB - Children with osteogenesis imperfecta (OI) type VI often have high fracture rates despite the current standard treatment with bisphosphonates. Subcutaneous injections of denosumab have been proposed as an alternative treatment approach, but safety data on denosumab in children are limited. Here we describe fluctuations in bone and mineral metabolism during denosumab treatment in four children with OI type VI who started denosumab (basic protocol: 1 mg per kg body mass every 3 months) between 1.9 and 9.0 years of age, after having received intravenous bisphosphonates previously. All four children developed hypercalciuria during active denosumab therapy. In two children aged 3.9 and 4.6 years, episodes of hypercalcemia were observed between 7 and 12 weeks after the preceding denosumab injection. During times when the interval between denosumab injections was increased to 6 months for clinical reasons, lumbar spine bone mineral density z-scores decreased rapidly. It appears that the duration of action of denosumab is short and variable in children with OI type VI. These observations call into question the concept that denosumab can be used as a stand alone alternative to bisphosphonates to treat children with OI. PMID- 29504583 TI - Changes in growth plate extracellular matrix composition and biomechanics following in vitro static versus dynamic mechanical modulation. AB - The objective of this study was to investigate the effects of mechanical modulation parameters on structural proteins biocomposition and mechanical properties of the growth plate. Establishing these parameters is a crucial step in the development of fusionless treatment of scoliosis. In this study, ulna explants from 4-weeks-old (pubertal) swines were used. The biocomposition was characterized using biochemical content evaluation and immunohistochemistry. Mechanical properties were characterized by fitting the data of the stress relaxation curves using a fibril reinforced biphasic model. For the mechanical loading, one static modulation condition and three different dynamic modulation conditions, with similar average stress but different amplitude and frequency values, were performed using a bioreactor. Results showed that static loading triggers a decrease in proteoglycan content and type X collagen in specific zones of the growth plate. These changes can be associated with the observed decrement of permeability in the static group. None of the three conditions evaluated for dynamic modulation affected the growth plate biocomposition and biomechanical responses. Results of this study provides an improved understanding of growth plate responses to mechanical environment, which will be useful in finding the optimal and non-damaging parameters for fusionless treatments based on the mechanical modulation of bone growth. PMID- 29504584 TI - Sex comparisons of non-local muscle fatigue in human elbow flexors and knee extensors. AB - OBJECTIVES: To examine non-local muscle fatigue (NLMF) in both contralateral homologous and non-related heterogonous muscles for both sexes. METHODS: Ten men and nine women participated in this study. After the familiarization visit, subjects completed four separate randomly sequenced experimental visits, during which the fatiguing interventions (six sets of 30-second maximal isometric contractions) were performed on either their right elbow flexors or knee extensors. Before (Pre-) and after (Post-) the fatiguing interventions, the isometric strength and the corresponding surface electromyographic (EMG) amplitude were measured for the non-exercised left elbow flexors or knee extensors. RESULTS: For the non-exercised elbow flexors, the isometric strength decreased for both sexes (sex combined mean+/-SE: Pre vs. Post=339.67+/-18.02 N vs. 314.41+/-16.37 N; p?0.001). For the non-exercised knee extensors, there is a time * sex interaction (p=0.025), showing a decreased isometric knee extension strength for men (Pre vs. Post =845.02+/-66.26 N vs. 817.39+/-67.64 N; p=0.019), but not for women. CONCLUSIONS: The presence of NMLF can be affected by factors such as sex and muscle being tested. Women are less likely to demonstrate NLMF in lower body muscle groups. PMID- 29504585 TI - High and odd impact exercise training improved physical function and fall risk factors in community-dwelling older men. AB - : High impact exercise programmes can improve bone strength, but little is known about whether this type of training further benefits fracture risk by improving physical function in older people. OBJECTIVES: This study investigated the influence of high impact exercise on balance, muscle function and morphology in older men. METHODS: Fifty, healthy men (65-80 years) were assigned to a 6-month multidirectional hopping programme (TG) and twenty age and physical activity matched volunteers served as controls (CG). Before and after training, muscle function (hop performance, leg press and plantar- and dorsiflexion strength) and physiological determinants (muscle thickness and architecture) as well as balance control (sway path, one leg stance duration) were measured. Resting gastrocnemius medialis (GM) muscle thickness and architecture were assessed using ultrasonography. RESULTS: Significant improvements in hop impulse (+12%), isometric leg-press strength (+4%) and ankle plantarflexion strength (+11%), dorsiflexor strength (+20%) were found in the TG compared to the CG (ANOVA interaction, P?0.05) and unilateral stance time improved over time for TG. GM muscle thickness indicated modest hypertrophy (+4%), but muscle architecture was unchanged. CONCLUSION: The positive changes in strength and balance after high impact and odd impact training would be expected to improve physical function in older adults. PMID- 29504587 TI - Global campaign against epilepsy : agenda for IEA/IES. PMID- 29504586 TI - Bone Research Society, Annual Meeting 2017 Proceedings. 25-27 June 2017, Bristol, UK. PMID- 29504588 TI - Hereditary ataxias : from phenotype to genotype. AB - Inherited ataxias constitute a large group of neurological diseases. Refinement in the classification and understanding of these diseases has been taking place in the recent years with advancement in molecular genetics. This review highlights the evolution and correlation of various classifications, phenotype and genotype correlation, mechanisms of phenotypic heterogeneity, and recent advances in the understanding of some of the commoner entities, in inherited ataxias. PMID- 29504589 TI - Antiepileptic pharmacotherapy : prevalence of polytherapy and its implications. PMID- 29504590 TI - Vasculitic neuropathy : clinical electrophysiological and histopathological characterstics. AB - The clinical, electrophysiological and pathological features of 16 patients with vasculitic neuropathy were evaluated. Vasculitic neuropathy accounted for 5.3 of biopsy proven cases of various neuropathies. They included 7 cases of systemic vasculitic neuropathy (SVN) and 9 cases of nonsystemic vasculitic neuropathy (NSVN). Mononeuritis multiplex, both clinically and electrophysiologically was seen in neoropathy in 11 (69.7) patients. Three patients had sensory neuropathy. All the patients had anecrotizing vasculitis on nerve biopsy. Axonal degeneration was seen in teased fibers in all the patients. Fifteen patients were treated with steroids and one patient with cyclophosphamide. Seven patients with NSVN recovered completely. Two patients withSVN were left with asymmetical foot drop and one patient with NSVN developed bilateral mild claw hands. There were no deaths. PMID- 29504591 TI - Nitric oxide synthase activity in human glioblastoma : a histochemical study. AB - Nitric oxide (NO), which is synthesised by the enzyme Nitric Oxide Synthase (NOS), mediates many physiological and pathological mechanisms in the brain. Experimental studies of rodent C6 glioma show that NO has a major role in regulation of tumour blood flow. To determine the relevance of these findings to human malignant glioma, NADPH diaphorase (NADPHd) histochemistry, which is a marker for NOS expression, was performed in 20 glioblastomas. Except for one tumour which was totally necrotic, all the 19 tumour specimens showed evidence of NADPHd expression. The neoplastic vascular endothelium, areas of endothelial proliferation and neoplastic astrocytes all consistently showed high levels of NADPHd positivity. Areas of necrotic tumour were always NADPHd negative. Both the extent and the intensity of cellular staining within the glioblastoma was considerably greater than NADPHd positivity in normal brain tissue. These results together with findings in experimental glioma strongly suggest that NOS has a definite role in the pathophysiology of glioblastoma and that it may be possible to pharmacologically manipulate them for therapeutic benefit. PMID- 29504592 TI - The Spectrum and clinical correlates of electrodiagnostic abnormalities in acute organophosphorus poisoning : a study of 55 patients. AB - Electrodiagnostic findings in 55 patients with acute organophosphorus intoxication have been correlated with clinical severity. Patients were assigned 3 grades of intoxication, depending upon the clinical severity of poisoning, muscarinic and nicotinic manifestations, ventilatory failure and altered sensorium. Repetitive responses upon single supramaximal stimulation of the median motor nerve were noted in all three grades of intoxication. In mild intoxication (grade I), low frequency repetitive nerve stimulation (< 3 Hz) produced no change in the amplitudes of the successive compound muscle action potentials. High frequency repetitive nerve stimulation (30 Hz and 50 Hz) resulted in either incremental responses (18 out of 29 cases), decremental responses (5 out of 29 cases) or decremental - incremental responses (6 out of 29 cases). Thirty five electrodiagnostic evaluations were performed in patients with overt neuromuscular weakness but not requiring mechanical ventilation (grade 2). Decremental responses were noted in only 3 instances at low frequency (< 3 Hz) repetitive nerve stimulation and in 34 out of 35 cases with high rates of stimulation. Patients who required mechanical ventilation had decremental responses at high (30 and 50 Hz) (12 out of 12 cases) as well as low rates (3 and 5 Hz) (7 out of 12 cases) of repetitive nerve stimulation. Serial electrodiagnostic evaluations, which were done in 12 patients, revealed that neuromuscular transmission abnormalities were either mild or absent within 24 hours in 9 patients. A deterioration in the neuromuscular transmission studies was noted during subsequent examinations performed, 1- 4 days later in these 9 patients. Electrodiagnostic testing is highly sensitive for establishing a diagnosisof organophosphorus poisoning and correlates well with clinical findings and the severity of poisoning. It may, however be normal in the early stages of intoxication. PMID- 29504593 TI - Prognostic value of facial nerve latency and blink reflex in Bell's palsy. AB - Twenty six patients of Bell's palsy, 16 men and 10 women, with the mean age of 27?0.2 years were enrolled for the study. An equal number of age and sex matched normal healthy individuals formed the control group. Clinical assessment and electrophysiological tests like facial nerve latency (FNL), blink reflex (BR), and peripheral nerve conduction studies were done to assess the prognostic value of these electrophysiological tests early in the disease. Clinical severity of weakness in the first week correlated positively with the outcome at 8 weeks. The mean FNL did not bear prognostic relation to the outcome, it being significantly prolonged in both partial and full recovery groups. BR proved to be of prognostic value. Though the amplitudes of various components of BR were low in all patients, significant prolongation of latencies was seen only among those with partial recovery. Nerve conduction studies of peripheral nerves were normal in all the patients. Clinical examination and early blink reflex abnormalities are of prognostic value in Bell's palsy patients. PMID- 29504594 TI - Microvascular anastomosis with clips. AB - A modified version of Payr's method for rapid vascular anastomosis was evaluated for high flow jugulo carotid anastomosis in rat. The end to end anastomosis is performed by mounting the artery on a cylinder by passing it through the lumen and cuffing the end back over the tube. The cylinder with the artery graft mounted on it is then telescoped into the vein and secured with an external circular clip. To allow easy introduction of the cylinder with the artery on it, into the vein, we used cylinderswith external diameter corresponding to the diameter of the carotid artery. The results suggest that the technique is simple and easy to execute requiring a short clamping time to complete the anastomosis using a prepared artery graft. Although the grafts remained patent, the histopathology studies done within one hour showed inflammation, platelet deposition and disruption of the venous endothelium. The arterial side of the anastomosis showed intact endothelium. The junctional area however, showed onlyminimal changes. Chronic specimens showed complete endothelisation over the junctional area. This nonsuture technique provides a rapid and a relatively atraumatic method of performing an anastomosis. PMID- 29504595 TI - Conventional and magnetic resonance angiographic evaluation of cirsoid aneurysm. AB - Cirsoid aneurysms are considered to be notoriously difficult lesions. A proper diagnostic evaluation is essential for the successful management of these lesions. The authors present here both conventional and magnetic resonance angiographic appearance of six cases of cirsoid aneurysms. Four of these had congenital and two had post traumatic cirsoid aneurysms. Only two out of the six patients were evaluated by magnetic resonance angiography, while all the six patients underwent conventional angiography. Though magnetic resonance angiography described the feeders of the malformation well, it could not define the draining veins satisfactorily. On the contrary, conventional angiography described both feeding arteries and the venous drainage. PMID- 29504596 TI - Tuberculous radiculomyelitis : a myelographic and cmputed tomographic study. AB - Tuberculous spinal arachnoditis is one of the commonest causes of paraplegia in India. Clinical and laboratory diagnosis is difficult and radiological evaluation often remains an important component of diagnosis and management The role of water soluble contrast medium myelography and CT features have been described. The most common features observed on myelography include long lengths of irregular contrast medium, nodular filling defects, thickened nerve roots and empty thecal sac. The CT features include irregular subarachnoid contrast medium, extradural and intradural filling defects with the spinal cord of variable dimension. Adherence of the nerve roots to one another and to the meninges was not an uncommon finding. Given the clinical setting,myelographic and CT myelographic features are reasonably characteristic to suggest a diagnosis of tuberculous spinal arachnoiditis. PMID- 29504597 TI - Video endoscopic neurosurgery (VENS) : a prospective study of 55 patients. AB - Neurosurgery has undergone dramatic innovations in the last few decades. It now allows the use of a microchip camera mounted on to an endoscope, introduced through a key hole in the brain. The image is projected onto a TV monitor located next to theoperating table. The minimally invasive technique is what we call Video Endoscopic Neurosurgery (VENS). Cab's universal rigid endoscope is used in all cases. VENS has a wide spectrum of diagnostic and therapeutic applications but cannot as yet replace open microscopic surgery. A prospective study of 55 patients from January, 1990 to February, 1995 is described. Hydrocephalus was a major indication, where VENS was useful for its diagnostic orientation especially when there were ambiguities on the CT/MRI.It also helped in the proper placement of the shunt, doing a III ventriculostomy and stenting of the aqueduct. VENS was utilised to diagnose, debulk and at times excise III ventricular and various other cystic lesions, visualize vascular loops in trigeminal neuralgia and hemifacial spasm. It is also useful in searching small CP angle lesions and residual tumour after intrassphenoidal excision of pituitary adenoma. Results were satisfactory in 94.5 of patients with an average follow up period of 26.4 months. Laser and CT-guided stereotactic VENS have already arrived which allows precise target localization and excellent visual control of any bleeding. PMID- 29504598 TI - Cerebello-pontine angle choroid plexus papilloma. AB - A 23 years male presented with clinical and rardiological features of right CP angle papillary tumour. Histopathology confirmed it to he choroid plexus papilloma, which is a rare CP angle tumour. PMID- 29504599 TI - Primary osteosarcoma of the anterior skull base. AB - Primary skull base osteosarcoma is extremely rare and has been reported mainly in the second decade of life. Two cases of primary osteosarcoma arising from the anterior cranial fossa have been described. Both these patients were in their fifth decades of life. PMID- 29504600 TI - Encysted haematoma in a cerebello-pontine angle. AB - A young primi-gravida with pre-eclamptic toxaemia underwent an elective caesarean at 38 weeks. On 10th day of delivery, she suddenly developed symptoms and signs of right cerebello-pontine angle lesion. On investigation a haematoma with a fluid level could be identified. Coagulation parameters were deranged and blood culture grew coagulase negative staphylococcus aureus. Possible causes of intracranial haematoma at such an unusual location are discussed. PMID- 29504601 TI - Multiphasic disseminated encephalomyelitis. AB - A forty five year old patient developed a chronic relapsing and remitting disease after receiving fourteen injections of beta propionalactone inactivated sheep brain vaccine. We offer evidence to support the view that this case is an illustration ofmultiphasic disseminated encephalomyelitis rather than multiple sclerosis. PMID- 29504602 TI - A Tribute to Prof. Macdonald Critchley (1900-1997). PMID- 29504603 TI - MRI in subacute combined degeneration of spinal cord. PMID- 29504605 TI - CNS tuberculosis. PMID- 29504604 TI - Radiculopathy : a complication in lumbo-peritoneal shunt. PMID- 29504606 TI - CTD-2020K17.1, a Novel Long Non-Coding RNA, Promotes Migration, Invasion, and Proliferation of Serous Ovarian Cancer Cells In Vitro. AB - BACKGROUND Ovarian cancer is the most lethal malignant tumor of the female reproductive system, and the metastasis is one of the major factors that contribute to the poor outcome of patients with OC. Accumulating evidence indicates that lncRNAs are expressed and play important regulatory roles in ovarian cancer. MATERIAL AND METHODS Aberrant lncRNAs in primary ovarian cancer tissues (POCTs) and paired omental metastasis tissues (OMTs) of patients with HGSOC were studied via lncRNA microarray. Real-time PCR was performed to examine CTD-2020K17.1 expression in HGSOC tissues from 38 patients, a normal ovarian surface epithelium cell line, and 4 ovarian cancer cell lines. Additionally, Transwell assays, wound healing assays, CCK-8 proliferation assays, and flow cytometry were used to explore the biological function of CTD-2020K17.1 in ovarian cancer cells. Finally, Western blot analysis was used to verify the potential target gene of CTD-2020K17.1. RESULTS A novel lncRNA named CTD 2020K17.1 was identified via microarray analysis. Expression of CTD-2020K17.1 was significantly increased in OMTs and in 4 ovarian cancer cell lines compared with POCTs (P<0.05) or normal ovarian surface epithelial cell line (P<0.05). Moreover, CTD-2020K17.1 overexpression promoted migration, invasion, and proliferation of ovarian cancer cells, and CTD-2020K17.1 regulated the expression of CARD11. CONCLUSIONS CTD-2020K17.1 is significantly upregulated in OMTs and ovarian cancer cell lines. It can promote the migration, invasion, and proliferation of ovarian cancer cells, and CARD11 is regulated by CTD-2020K17.1. PMID- 29504607 TI - The long non-coding RNA uc.4 influences cell differentiation through the TGF-beta signaling pathway. AB - In a previous study, we screened thousands of long non-coding RNAs (lncRNAs) to assess their potential relationship with congenital heart disease (CHD). In this study, uc.4 attracted our attention because of its high level of evolutionary conservation and its antisense orientation to the CASZ1 gene, which is vital for heart development. We explored the function of uc.4 in cells and in zebrafish, and describe a potential mechanism of action. P19 cells were used to investigate the function of uc.4. We studied the effect of uc.4 overexpression on heart development in zebrafish. The overexpression of uc.4 influenced cell differentiation by inhibiting the TGF-beta signaling pathway and suppressed heart development in zebrafish, resulting in cardiac malformation. Taken together, our findings show that uc.4 is involved in heart development, thus providing a potential therapeutic target for CHD. PMID- 29504608 TI - Nucleophosmin modulates the alleviation of atopic dermatitis caused by the marine derived compound dihydroaustrasulfone alcohol. AB - Atopic dermatitis (AD) is a chronic inflammatory skin disease, and its prevalence is increasing. AD usually elicits skin barrier dysfunction, dry skin and itching. As the mechanisms of AD remain unknown, there is an urgent need to find effective therapies. Because of the diversity and complexity of marine environments, the discovery of drugs from marine organisms as novel therapeutic agents for human diseases has seen renewed interest. Dihydroaustrasulfone alcohol (WA-25), the synthetic precursor of austrasulfone, which is a natural product isolated from a Formosan soft coral, has been shown to possess many therapeutic effects in our previous studies. However, the detailed mechanisms and therapeutic effects of WA 25 on AD are incompletely understood. We performed in vitro and in vivo studies to examine the effects of WA-25 on AD. We showed that WA-25 blocks inflammation and oxidative stress. Simultaneously, we also found that WA-25 reduces the AD scores and AD-induced transepidermal water loss (TEWL), scratching behavior, and alloknesis. WA-25 is more effective in cases of AD than are the drugs that are currently used clinically. Importantly, we also found that when nucleophosmin (NPM) was inhibited or when its expression was reduced, the anti-inflammatory and anti-AD effects of WA-25 were blocked. These data suggest that NPM plays dual roles in inflammation and AD. Overall, these results suggest that WA-25 is a potential anti-inflammatory and AD therapeutic agent that is modulated by NPM. PMID- 29504611 TI - Synthesis of three-dimensional mesoporous Cu-Al layered double hydroxide/g-C3N4 nanocomposites on Ni-foam for enhanced supercapacitors with excellent long-term cycling stability. AB - In this study, a novel composite of Cu-Al layered double hydroxide (LDH) nanosheets and g-C3N4-covered Ni-foam was fabricated via a simple and facile two step process. First, g-C3N4 sheets were deposited on Ni-foam by via electrodeposition method on a three-electrode system (Ni-foam@g-C3N4) and then, Cu-Al LDH nanosheets were grown on the Ni-foam via in situ redox reaction using a hydrothermal process (Ni-foam@Cu-Al LDH/g-C3N4). The FE-SEM image confirmed that the Cu-Al LDH nanosheets arose vertically and were anchored on the surface of electrodeposited g-C3N4 sheets, thus generating unique 3D porous interconnected networks. The electrochemical capacitive performances of the as-prepared samples were evaluated by cyclic volatammetry (CV), galvanostatic charge/discharge tests, and electrochemical impedance spectra (EIS) Nyquist plots. The specific capacitances of the Ni-foam@Cu-Al LDH/g-C3N4 nanocomposite measured from the CV curve (770.98 F g-1 at 50 mV s-1) and the galvanostatic charge/discharge curve (831.871 at 0.4 A g-1) were significantly higher than the others. Moreover, the Ni-foam@Cu-Al LDH/g-C3N4 nanocomposite revealed a remarkable high-current capacitive behavior and the capacitance retention could be maintained at 92.71% even after 5000 cycles of CV. Thus, the obtained results demonstrated that the as prepared nanocomposite has great potential to be used as a novel supercapacitor electrode. PMID- 29504609 TI - Macrophage migration inhibitory factor mediates peripheral nerve injury-induced hypersensitivity by curbing dopaminergic descending inhibition. AB - Our previous works disclosed the contributing role of macrophage migration inhibitory factor (MIF) and dopaminergic inhibition by lysine dimethyltransferase G9a/Glp complex in peripheral nerve injury-induced hypersensitivity. We herein propose that the proinflammatory cytokine MIF participates in the regulation of neuropathic hypersensitivity by interacting with and suppressing the descending dopaminergic system. The lumbar spinal cord (L-SC) and ventral tegmental area (VTA) are two major locations with significant upregulation of MIF after chronic constriction injury (CCI) of the sciatic nerve, and they display time-dependent changes, along with a behavioral trajectory. Correspondingly, dopamine (DA) content shows the reverse characteristic change to MIF with a time-dependent curve in post-surgical behavior. The levels of both MIF and DA are reversed by the MIF tautomerase inhibitor ISO-1, and a negative relationship exists between MIF and DA. The reversed role of ISO-1 also affects tyrosine hydroxylase expression. Furthermore, CCI induces Th promoter CpG site methylation in the L-SC and VTA areas, and this effect could be abated by ISO-1 administration. G9a/SUV39H1 and H3K9me2/H3K9me3 enrichment within the Th promoter region following CCI in the L-SC and VTA was also decreased by ISO-1. In cultured dopaminergic neurons, rMIF enhanced the recruitment of G9a and SUV39H1, followed by an increase in H3K9me2/H3K9me3. These molecular changes correspondingly exhibited alterations in Th promoter CpG site methylation and pain behaviors. In summary, MIF functions as a braking factor in curbing dopaminergic descending inhibition in peripheral nerve injury-induced hypersensitivity by mediating Th gene methylation through G9a/SUV39H1-associated H3K9 methylation. PMID- 29504612 TI - Multilamellar nanovesicles show distinct mechanical properties depending on their degree of lamellarity. AB - Small multilamellar vesicles may have benefits over unilamellar vesicles for drug delivery, such as an increased volume for hydrophobic drugs. In addition, their altered mechanical properties might be beneficial for cellular uptake. Here, we show how atomic force microscopy (AFM) can be used to detect and characterize multilamellar vesicles. We quantify the size of each break event occurring during AFM nanoindentations, which shows good agreement with the thickness of supported lipid bilayers. Analyzing the size and number of these events for individual vesicles allows us to distinguish between vesicles consisting of 1 up to 5 bilayers. We validate these results by comparison with correlative cryo-electron microscopy (cryo-EM) data at the vesicle population level. Finally, we quantify the vesicle geometry and mechanical properties, and show that with additional bilayers adherent vesicles are more spherical and stiffer. Surprisingly, at ~20% stiffening for each additional bilayer, the vesicle stiffness scales only weakly with lamellarity. Our results show the potential of AFM for studying liposomal nanoparticles and suggest that small multilamellar vesicles may have beneficial mechanical properties for cellular uptake. PMID- 29504610 TI - PI3Kdelta contributes to ER stress-associated asthma through ER-redox disturbances: the involvement of the RIDD-RIG-I-NF-kappaB axis. AB - Hyperactivation of phosphoinositol 3-kinase (PI3K) has been suggested to be a potential mechanism for endoplasmic reticulum (ER) stress-enhanced airway hyperresponsiveness, and PI3K inhibitors have been examined as asthma therapeutics. However, the regulatory mechanism linking PI3K to ER stress and related pathological signals in asthma have not been defined. To elucidate these pathogenic pathways, we investigated the influence of a selective PI3Kdelta inhibitor, IC87114, on airway inflammation in an ovalbumin/lipopolysaccharide (OVA/LPS)-induced asthma model. In OVA/LPS-induced asthmatic mice, the activity of PI3K, downstream phosphorylation of AKT and activation of nuclear factor kappaB (NF-kappaB) were all significantly elevated; these effects were reversed by IC87114. IC87114 treatment also reduced the OVA/LPS-induced ER stress response by enhancing the intra-ER oxidative folding status through suppression of protein disulfide isomerase activity, ER-associated reactive oxygen species (ROS) accumulation and NOX4 activity. Furthermore, inositol-requiring enzyme-1alpha (IRE1alpha)-dependent degradation (RIDD) of IRE1alpha was reduced by IC87114, resulting in a decreased release of proinflammatory cytokines from bronchial epithelial cells. These results suggest that PI3Kdelta may induce severe airway inflammation and hyperresponsiveness by activating NF-kappaB signaling through ER associated ROS and RIDD-RIG-I activation. The PI3Kdelta inhibitor IC87114 is a potential therapeutic agent against neutrophil-dominant asthma. PMID- 29504613 TI - Hydrogels: experimental characterization and mathematical modelling of their mechanical and diffusive behaviour. AB - Hydrogels are materials widely used in countless applications, particularly in the biomedical, pharmaceutical, and nutraceutical fields, because of their biocompatibility and their mechanical and transport properties. Several approaches are known to evaluate their properties, but only a few approaches are under development to mathematically describe their behaviour, in terms of how the materials answer to mechanical stimuli and how incorporated active substances are released. In this review, the main properties of hydrogels are summarized and the structure-property relationships are investigated (i.e. how the macromolecular structure influences the properties of macroscopic samples made of hydrogels). A selection criterion is proposed based on the comparison of three characteristic times: relaxation time, diffusion time, and process time. Then, the most common experimental methods to investigate the hydrogel properties are summarized, along with the state-of-the-art of mathematical modelling, with reference to the mechanical and transport properties of hydrogels, with particular attention to the viscoelastic and poroelastic behaviours. Last but not least, some case histories which can be classified as viscoelastic, poroelastic, or poroviscoelastic behaviours are presented. PMID- 29504614 TI - Microbial community structure with trends in methylation gene diversity and abundance in mercury-contaminated rice paddy soils in Guizhou, China. AB - Paddy soils from mercury (Hg)-contaminated rice fields in Guizhou, China were studied with respect to total mercury (THg) and methylmercury (MeHg) concentrations as well as Bacterial and Archaeal community composition. Total Hg (0.25-990 MUg g-1) and MeHg (1.3-30.5 ng g-1) varied between samples. Pyrosequencing (454 FLX) of the hypervariable v1-v3 regions of the 16S rRNA genes showed that Proteobacteria, Actinobacteria, Chloroflexi, Acidobacteria, Euryarchaeota, and Crenarchaeota were dominant in all samples. The Bacterial alpha-diversity was higher in samples with relatively Low THg and MeHg and decreased with increasing THg and MeHg concentrations. In contrast, Archaeal alpha-diversity increased with increasing of MeHg concentrations but did not correlate with changes in THg concentrations. Overall, the methylation gene hgcAB copy number increased with both increasing THg and MeHg concentrations. The microbial communities at High THg and High MeHg appear to be adapted by species that are both Hg resistant and carry hgcAB genes for MeHg production. The relatively high abundance of both sulfate-reducing delta-Proteobacteria and methanogenic Archaea, as well as their positive correlations with increasing THg and MeHg concentrations, suggests that these microorganisms are the primary Hg methylators in the rice paddy soils in Guizhou, China. PMID- 29504615 TI - Accessing highly functionalized cyclopentanoids via a cascade palladation approach: unprecedented benzylic C-H activation towards cyclopentenoindanes. AB - A Pd-catalyzed synthesis of 3,4,5-trisubstituted cyclopentenes from diazabicyclic olefins and o-iodobenzoates has been developed. The hitherto unknown cascade process involves three stages: carbopalladation, oxypalladation and a Tsuji-Trost reaction. We have also developed a facile route involving a novel benzylic C-H activation towards cyclopentenoindane moieties. PMID- 29504616 TI - A photo-responsive macroscopic switch constructed using a chiral azo calix[4]arene functionalized silicon surface. AB - A photo-responsive macroscopic switch was fabricated using a chiral azo calix[4]arene derivative (FC4AD) functionalized silicon surface and exhibited selective and reversible recognition of (1R,2S)-1-amino-2-indanol through the variation of wettability. This photo-responsive device may have wide applications in controlled release of chiral drugs and in biosensors. PMID- 29504617 TI - Optical sensing at the nanobiointerface of metal ion-optically-active nanocrystals. AB - Optically-active nanocrystals (such as quantum dots and plasmonic noble metal nanoparticles) have received great attention due to their size-tunable optical properties. The indicator displacement assay (IDA) with optically-active nanocrystals has become a common practice for optical sensor development, since no sophisticated surface functionalization of nanoparticles is required. Among the IDA-based optical sensors, the use of metal ions as receptors seems to be attractive. Therefore, in this review, the research progress of optical sensing at the nanobiointerface of metal ion-optically-active nanocrystals has been summarized. In particular, metal ion-mediated selective recognition has been summarized here based on the classical Hard-Soft-Acid-Base (HSAB) principle, which has been seldom mentioned before. Most of the references were therefore categorized according to their located place based on the HSAB theory. Besides, several metal ion modulation strategies that were not related to the HSAB theory (e.g., redox modulation) were also included. Finally, due to the cross-talk of metal ions in selective recognition, we have also summarized sensor array development based on multiple metal ion receptors in IDA sensing with optically active nanocrystals. Several interesting applications of the IDA sensing with metal ions as receptors and optically-active nanocrystals as indicators are presented, with specific emphasis on the design principles and photophysical mechanisms of these probes. PMID- 29504618 TI - Photoelectrochemical overall water splitting with textured CuBi2O4 as a photocathode. AB - Nanotextured CuBi2O4 photocathodes have been developed for applications toward solar water splitting. Tailoring the CuBi2O4 photocathodes to yield a high photocurrent and a positively large onset potential demonstrates their applicability in a photoelectrochemical tandem cell for entirely solar-driven overall water splitting. PMID- 29504619 TI - Electrocatalytic CO2 reduction with nickel complexes supported by tunable bipyridyl-N-heterocyclic carbene donors: understanding redox-active macrocycles. AB - A series of nickel complexes featuring redox-active macrocycles is reported for electrocatalytic CO2 reduction. A remarkable structure-activity relationship is elucidated from the series through electrochemical studies and DFT calculations, wherein a fine electronic balance between metal and ligand redox chemistry dictates selectivity for CO2 reduction versus the competing proton reduction reaction. PMID- 29504620 TI - Controlling anticancer drug mediated G-quadruplex formation and stabilization by a molecular container. AB - Controlling of ligand mediated G-quadruplex DNA (GQ-DNA) formation and stabilization is an important and challenging aspect due to its active involvement in many biologically important processes such as DNA replication, transcription, etc. Here, we have demonstrated that topotecan (TPT), a potential anticancer drug, can instigate the formation and stabilization of GQ-DNA (H24 -> GQ-DNA) in the absence of Na+/K+ ions via circular dichroism, fluorescence, NMR, UV melting and molecular dynamics (MD) simulation studies. The primary binding mode of TPT to GQ was found to be stacking at the terminal rather than binding to the groove. We have also reverted this conformational transition (GQ-DNA -> H24) using a molecular container, cucurbit[7]uril (CB7), by means of the translocation of the drug (TPT) from GQ-DNA to its nanocavity. Importantly, we have carried out the detection of these conformational transitions using the fluorescence color switch of the drug, which is more direct and simple than some of the other methods that involve sophisticated and complex detection techniques. PMID- 29504621 TI - Readily available titania nanostructuring routines based on mobility and polarity controlled phase separation of an amphiphilic diblock copolymer. AB - The amphiphilic diblock copolymer polystyrene-block-polyethylene oxide is combined with sol-gel chemistry to control the structure formation of blade coated foam-like titania thin films. The influence of evaporation time before immersion into a poor solvent bath and polarity of the poor solvent bath are studied. Resulting morphological changes are quantified by scanning electron microscopy (SEM) and grazing incidence small angle X-ray scattering (GISAXS) measurements. SEM images surface structures while GISAXS accesses inner film structures. Due to the correlation of evaporation time and mobility of the polymer template during the phase separation process, a decrease in the distances of neighboring titania nanostructures from 50 nm to 22 nm is achieved. Furthermore, through an increase of polarity of an immersion bath the energetic incompatibility of the hydrophobic block and the solvent can be enhanced, leading to an increase of titania nanostructure distances from 35 nm to 55 nm. Thus, a simple approach is presented to control titania nanostructure in foam-like films prepared via blade coating, which enables an easy upscaling of film preparation. PMID- 29504622 TI - Water soluble derivatives of platinum carbonyl Chini clusters: synthesis, molecular structures and cytotoxicity of [Pt12(CO)20(PTA)4]2- and [Pt15(CO)25(PTA)5]2- . AB - The reactions of [Pt3n(CO)6n]2- (n = 2-5) homoleptic Chini-type clusters with increasing amounts of 1,3,5-triaza-7-phosphaadamantane (PTA) result in the stepwise substitution of one terminal CO ligand per Pt3 triangular unit up to the formation of [Pt3n(CO)5n(PTA)n]2- (n = 2-5). Competition between the nonredox substitution with retention of the nuclearity and the redox fragmentation to afford lower nuclearity heteroleptic Chini-type clusters is observed as a function of the amount of PTA and the nuclearity of the starting cluster. Because of this, [Pt12(CO)20(PTA)4]2- and [Pt15(CO)25(PTA)5]2- are more conveniently obtained via the oxidation of [Pt9(CO)15(PTA)3]2-. All the new species were spectroscopically characterized, and the structures of [Pt12(CO)20(PTA)4]2- and [Pt15(CO)25(PTA)5]2- were determined by single-crystal X-ray diffraction. These clusters may be viewed as heteroleptic Chini-type clusters composed of stacks of four and five Pt3(MU-CO)3(CO)2(PTA) units, respectively. The solubility in water of [Pt12(CO)20(PTA)4]2- and [Pt15(CO)25(PTA)5]2- has been determined and their cytotoxicity towards human ovarian (A2780) cancer cells and their cisplatin resistant strain (A2780cisR) has been evaluated. PMID- 29504623 TI - Clinical applications of infrared and Raman spectroscopy: state of play and future challenges. AB - Vibrational spectroscopies, based on infrared absorption and/or Raman scattering provide a detailed fingerprint of a material, based on the chemical content. Diagnostic and prognostic tools based on these technologies have the potential to revolutionise our clinical systems leading to improved patient outcome, more efficient public services and significant economic savings. However, despite these strong drivers, there are many fundamental scientific and technological challenges which have limited the implementation of this technology in the clinical arena, although recent years have seen significant progress in addressing these challenges. This review examines (i) the state of the art of clinical applications of infrared absorption and Raman spectroscopy, and (ii) the outstanding challenges, and progress towards translation, highlighting specific examples in the areas of in vivo, ex vivo and in vitro applications. In addition, the requirements of instrumentation suitable for use in the clinic, strategies for pre-processing and statistical analysis in clinical spectroscopy and data sharing protocols, will be discussed. Emerging consensus recommendations are presented, and the future perspectives of the field are assessed, particularly in the context of national and international collaborative research initiatives, such as the UK EPSRC Clinical Infrared and Raman Spectroscopy Network, the EU COST Action Raman4Clinics, and the International Society for Clinical Spectroscopy. PMID- 29504625 TI - Fractionated dosage of radioiodine for the ablation of low-risk differentiated thyroid cancer has no impact on survival. AB - INTRODUCTION: Due to a limited number of hospital beds dedicated to radioiodine therapy (RIT) in some countries, a fractionated dose of radioiodine may be considered as the ablation therapy of differentiated thyroid cancer (DTC). The aim of the study was to compare the late effects of ablation therapy with single and fractionated dose of radioiodine in patients with DTC. PATIENTS AND METHODS: Patients with low-risk DTC referred to our institution 5-16 weeks after thyroidectomy, treated with 2.2 GBq of 131I, either in a single dose (2.2 GBq, group 1) or in two fractions (1.1 GBq+1.1 GBq administered with a 24 h interval, group 2) were retrospectively included. Clinical outcome of the treatment and overall survival (OS) was evaluated. RESULTS: 83 patients treated with single dose and 186 patients treated with fractionated dose of radioiodine were included. Mean duration of follow-up was 8.0 vs.7.8 years, respectively (p=ns). There were no significant differences between the groups in male to female ratio, age at the time of the first RIT, proportion of papillary thyroid cancers, volume of the thyroid tissue, thyroid-stimulating hormone and thyroglobulin levels before first RIT. RIT was repeated in 55.4% and 54.8% of patients from group 1 and 2 respectively (p=ns). There were no significant differences including the course and outcomes of the treatment between the groups, measured by: cumulative dose of 131I, mean number of 131I administrations and mean thyreoglobulin concentration at the follow-up. Also the overall survival did not differ significantly between the groups. Probability of 5-year OS was 98.6% for patients treated with single and 99.5% with fractionated dose of 131-I, 10 year OS - 98.6 and 97.1% respectively, 15 year OS - 95.5 and 92.9% respectively (p=ns). CONCLUSIONS: In the long-term follow-up, radioiodine ablation therapy with fractionated doses in low-risk DTC patients is equally effective as with single dose. < p > < /p >. PMID- 29504626 TI - Red cell distribution width - a new marker for exacerbation of heart failure in patients with hypothyroidism following radioiodine therapy. AB - INTRODUCTION: Cardiovascular diseases constitute a major cause of health problems and death in developed countries across the world. The increased value of the index of distribution of red blood cells volume (RDW) may be a prognostic marker in patients diagnosed with chronic heart failure (CHF). Hypothyroid patients present higher RDW values if compared to healthy controls. Taking into consideration that RDW might be both affected by thyroid status and CHF, we decided to determine the effect of concomitant hypothyroidism following radioiodine therapy (RIT) and CHF on hematological parameters. MATERIALS AND METHODS: Patients with toxic nodular goiter and heart failure with concomitant anemia were included. Patients underwent treatment with radioiodine before the planned heart transplant or pacemaker implantation (combined ICD/CRT-D). After RIT patients were divided into the three subgroups: with overt hypothyroidism (TSH >= 10uIU/mL, Group I), subclinically hypothyroid patients (TSH 4.3-9.0 uIU/mL, Group II) and with high-normal level of TSH (2.6-4.2 uIU/mL, Group III). RESULTS: Significant correlation between TSH and RDW was observed (r=0.46; P < 0.0001) after RIT, whereas no correlation between serum TSH levels and TIBC and Fe was observed. In Group I significant correlation between TSH and RDW (r= 0.48; P = 0.002) after RIT was observed, whereas in two other subgroups there were no significant correlation. CONCLUSIONS: Subclinical hypothyroidism or high-normal levels of TSH did not affect RDW in a significant manner in the studied population. Our results demonstrates that overt hypothyroidism may contribute to deterioration of CHF reflected in changes of RDW value. < p > < /p >. PMID- 29504627 TI - Nocturnal departure timing in songbirds facing distinct migratory challenges. AB - Most migratory songbirds travel between their breeding areas and wintering grounds through a series of nocturnal flights. The timing of their departures defines the potential flight duration and thus the distance covered during a migratory night. Yet, migratory songbirds show substantial variation in their nocturnal departure timing. With this study, we aim to assess whether the respective challenges of the migration route, namely its distance and nature, help to explain this variation. At a stopover site, we caught Northern Wheatears (Oenanthe oenanthe) of two subspecies that differ in distance and nature of their onward migration route in spring, but not in autumn. We determined the start of their nocturnal migratory restlessness during short-term captivity, and radiotracked their nocturnal departure timing after release in both migration seasons. Northern Wheatears started their nocturnal migratory restlessness earlier when facing a long remaining migration distance and an extended sea barrier in spring. Individual departure directions generally affected the nocturnal departure timing with early departures being directed towards the respective migratory destination. In spring, this pattern was predominantly found in birds carrying relatively large fuel stores, but was absent in lean birds. At the same time, birds facing a short remaining migration distance and no extended sea barrier strongly reacted to relatively large fuel stores by an early start of nocturnal migratory behaviour (migratory restlessness and departure timing), whereas this reaction was not found in birds facing a long remaining migration distance and sea barrier. These results suggest that the basic diel schedule of birds' migratory activity is adapted to the onward migration route. Further, they suggest that birds adjust their behavioural response, that is start of nocturnal migratory behaviour, to fuel stores in relation to their impending migratory challenges. This is a substantial step in understanding variation of nocturnal departure timing and its adjustments in migratory songbirds. Further, it emphasizes the importance of interpreting birds' nocturnal migratory behaviour in the respective ecological context. PMID- 29504628 TI - The level of collaboration amongst nurses in Turkey. AB - AIM: This study was conducted to determine the level of collaboration amongst nurses in Turkey. BACKGROUND: Collaboration amongst nurses is thought to increase nurse-physician collaboration and decrease medical mistakes. It has been connected with positive patient outcomes and increased job satisfaction for nurses. There are some studies on nurse-physician collaboration in Turkey, but nurse-nurse collaboration has not been measured before in this context. There are limited studies in the literature on nurse-nurse collaboration. METHODS: The sample of this study consisted of 859 nurses who work at one public hospital, one university hospital and four private hospitals in Turkey. The study was designed as descriptive and cross-sectional research. The data were collected using the nurse-nurse collaboration scale and a socio-demographic questionnaire. The nurse nurse collaboration scale comprises five subdimensions: problem-solving, shared process, communication, coordination and professionalism. The cut-off value of the scale for minimum expected collaboration degree was determined as 2.5. RESULTS: It was found that the total nurse-nurse collaboration level in the sample was 3.09, which is above minimum expected degree of collaboration (2.5). In regard to the subdimensions of the scale, the lowest mean score (2.97) was for problem-solving and the highest (3.20) was for professionalism. Graduate nurses' problem-solving, coordination, professionalism and cooperation skills were found to be higher than those of undergraduate nurses. Nurses employed under continuous employment contracts presented higher collaboration scores than those employed with annual, temporary contracts. CONCLUSIONS: Regarding the results obtained in the study, although the Turkish nurses were collaborating at the minimum expected level, they can collaborate more. Improved collaboration between nurses will increase patient satisfaction and thus will have a favourable impact on patient safety. IMPLICATIONS FOR NURSING POLICY AND HEALTH POLICY: Nurses who have a bachelor's or higher level degree should be hired, and nurses should be provided with job security in the form of a continuous employment contract to enhance nurse-nurse collaboration. PMID- 29504629 TI - Effects of chronic anthropogenic disturbance and rainfall on the specialization of ant-plant mutualistic networks in the Caatinga, a Brazilian dry forest. AB - Anthropogenic disturbance and climate change might negatively affect the ecosystem services provided by mutualistic networks. However, the effects of such forces remain poorly characterized. They may be especially important in dry forests, which (1) experience chronic anthropogenic disturbances (CADs) as human populations exploit forest resources, and (2) are predicted to face a 22% decline in rainfall under climate change. In this study, we investigated the separate and combined effects of CADs and rainfall levels on the specialization of mutualistic networks in the Caatinga, a seasonally dry tropical forest typical of north eastern Brazil. More specifically, we examined interactions between plants bearing extrafloral nectaries (EFNs) and ants. We analysed whether differences in network specialization could arise from environmentally mediated variation in the species composition, namely via the replacement of specialist by generalist species. We characterized these ant-plant networks in 15 plots (20 * 20 m) that varied in CAD intensity and mean annual rainfall. We quantified CAD intensity by calculating three indices related to the main sources of disturbance in the Caatinga: livestock grazing (LG), wood extraction (WE) and miscellaneous resource use (MU). We determined the degree of ant-plant network specialization using four metrics: generality, vulnerability, interaction evenness and H2 '. Our results indicate that CADs differentially influenced network specialization: we observed positive, negative, and neutral responses along LG, MU and WE gradients, respectively. The pattern was most pronounced with LG. Rainfall also shaped network specialization, markedly increasing it. While LG and rainfall were associated with changes in network species composition, this trend was not related to the degree of species specialization. This result suggests that shifts in network specialization might be related to changes in species behaviour, not species composition. Our study highlights the vulnerability of such dry forest ant-plant networks to climate change. Moreover, dry forests experience highly heterogeneous anthropogenic disturbances, creating a geographic mosaic of selective forces that may shape the co-evolution of interactions between ants and EFN-bearing plants. PMID- 29504630 TI - Effect of varying the dose of corn syrup on the insulin and glucose response to the oral sugar test. AB - BACKGROUND: The oral sugar test (OST) is used to identify equine insulin dysregulation (ID); however only a dose of 0.15 mL/kg bwt corn syrup has been evaluated. OBJECTIVES: To determine the effect of varying the dose of corn syrup on insulin and glucose response to the OST and the test's ability to distinguish between ponies with a history of laminitis (PL) and without laminitis (NL). STUDY DESIGN: Randomised crossover experiment. METHODS: After an overnight fast, in a three-way randomised crossover study with a 7-day washout, 0.15, 0.3 or 0.45 mL/kg bwt corn syrup was administered orally to eight ponies (5 PL and 3 NL) and blood obtained between 0 and 120 min. Serum [insulin] and [glucose] were measured using previously validated radioimmunoassay and colorimetric assays respectively. The repeatability of and the effect of continued pasture access on the dose that best distinguished PL and NL ponies were then assessed. The effect of dose, laminitis history and fasting on serum [insulin] and [glucose] responses were assessed using mixed-effects models. RESULTS: The serum [insulin] following 0.15 mL/kg bwt were not significantly different from 0.3 mL/kg bwt at any time point, while serum [insulin] following 0.45 mL/kg bwt significantly (P<0.01) differed from 0.15 and 0.3 mL/kg bwt at all time points apart from 0 min. The serum [insulin] concentration significantly (P<0.01) differed between NL (mean 86 [95% CI 59, 113] MUiu/mL) and PL (146 [95% CI 124, 167] MUiu/mL) only following 0.45 mL/kg bwt at 60 min. Repeatability of serum [insulin] at 60 min following 0.45 mL/kg bwt dose under fasted conditions was 0.51. Using AUC insulin improved repeatability to 0.83. There was no significant difference between the fasted and at pasture results. MAIN LIMITATIONS: The OST was performed in small numbers of ponies on limited occasions. CONCLUSIONS: A dose of 0.45 mL/kg bwt corn syrup may be preferable to differentiate PL and NL ponies. PMID- 29504632 TI - Videourodynamic characteristics of interstitial cystitis/bladder pain syndrome The role of bladder outlet dysfunction in the pathophysiology. AB - AIMS: To investigate the characteristics of videourodynamic study (VUDS) in females with interstitial cystitis/bladder pain syndrome (IC/BPS) focusing on the etiologies of bladder outlet dysfunction (BOD) and their associations with clinical and urodynamic parameters. METHODS: IC/BPS females with complete data on symptom assessment, VUDS, the potassium sensitivity test, and cystoscopic hydrodistention were reviewed retrospectively. Diagnoses of bladder dysfunction (hypersensitive bladder, HSB) and BOD including dysfunctional voiding (DV), poor relaxation of the external urethral sphincter (PRES), and bladder neck dysfunction (BND) were made by VUDS. The clinical and urodynamic parameters between patients with normal and abnormal VUDS diagnoses were analyzed. RESULTS: A total of 348 IC/BPS female patients (mean age 48.8 +/- 13.5) were enrolled. HSB was found in 307 (88.2%) patients and BOD in 209 (60.1%). The causes of BOD included DV in 40 (11.5%), PRES in 168 (48.3%), and BND in 1 (0.3%). Patients with DV and BND had higher, and those with PRES had lower detrusor pressures at maximum flow rate (Qmax ) than those with normal tracings. For all BOD patients, univariate logistic regression revealed a significant positive correlation of disease duration and negative correlations of urodynamic volume parameters with BOD in IC/BPS patients. Multivariate logistic regression found a cut-off value of Qmax ? 11 mL/s predicted BOD in IC/BPS with a receiver operating characteristic area of 0.81 (sensitivity = 82.0%, specificity = 68.5%). CONCLUSIONS: HSB and BOD are common findings on VUDS in IC/BPS females. BOD is associated with duration and hypersensitive bladder. A Qmax ? 11 mL/s predicts BOD in IC/BPS. PMID- 29504631 TI - WxcX is involved in bacterial attachment and virulence in Xanthomonas campestris pv. campestris. AB - Xanthomonas campestris pv. campestris (Xcc) is the causative agent of black rot in crucifers. Here, one EZ-Tn5 transposon mutant of Xcc, altered in bacterial attachment, was isolated. Further analysis revealed that the transposon was inserted in the wxcX gene (encodes a hypothetical protein) of the transposon mutant. Sequence analysis revealed that WxcX is highly conserved in Xanthomonas, but none has been characterized. In this study, it was indicated that mutation of wxcX resulted in enhanced bacterial attachment, reduced virulence on the host cabbage, and increased sensitivity to sodium dodecyl sulfate. The affected phenotypes of the wxcX mutant could be complemented to wild-type levels by the intact wxcX gene. Site-directed mutagenesis revealed that E408 and E411 are critical amino acid residues for WxcX function in bacterial attachment. Taken together, our results demonstrate the roles of wxcX in attachment, virulence, and tolerance to sodium dodecyl sulfate in Xanthomonas for the first time. PMID- 29504633 TI - Thyroid autoantibodies in pregnancy are associated with hypertensive disorders of pregnancy: Ma'anshan Birth Cohort Study. AB - OBJECTIVE: Hypertensive disorders of pregnancy (HDP) have been associated with adverse health outcomes for both mothers and children. Previous studies examining associations of maternal thyroid autoantibodies with HDP indicate conflicting results. The objective of this study was to examine associations of maternal thyroid autoantibody positivity in the first and the second trimesters with the risk of HDP. DESIGN, PARTICIPANTS AND MEASUREMENTS: In the Ma'anshan Birth Cohort study, a population-based prospective study in China, a total of 3474 pregnant women were enrolled between May 2013 and September 2014. Thyroid autoantibodies, including antithyroperoxidase autoantibody (TPOAb) and antithyroglobulin autoantibody (TgAb), as well as thyroid function tests, were measured in both the first and the second trimesters in 2893 pregnant women. Multivariate logistic regression analyses were conducted to calculate the odds ratio (OR) and 95% confidence interval (CI) for the associations between thyroid autoantibodies and HDP. RESULTS: Multivariate logistic regression analyses showed that TPOAb positivity in the first trimester was associated with a 1.80 (95% CI = 1.17-2.78) increased odds of HDP after adjustment for confounders, which was mainly due to an increased risk of gestational hypertension (OR = 1.93, 95% CI = 1.17-3.18). In addition, TgAb positivity in the first trimester was associated with a higher risk of HDP (OR = 1.78, 95% CI = 1.16-2.73) after adjustment for confounders, which was mainly due to an increased risk of gestational hypertension (OR = 1.89, 95% CI = 1.15-3.11). These associations were also seen among euthyroid women. Women with positive TPOAb in the second trimester seemed to have a higher risk of gestational hypertension (OR = 1.87, 95% CI = 1.02-3.43) after adjustment for confounders. However, among euthyroid women, TPOAb positivity in the second trimester was not associated with HDP. The TgAb status in the second trimester was not associated with HDP. CONCLUSIONS: Our results show that TPOAb positivity and TgAb positivity in the first trimester are associated with an increased risk of HDP. These data demonstrate that these associations are even seen among euthyroid women. PMID- 29504634 TI - Affective symptoms and quality of life in patients with voiding or storage dysfunction: Results before and after sacral neuromodulation: A prospective follow-up study. AB - AIMS: Sacral neuromodulation (SNM) is an effective treatment for patients with overactive bladder syndrome (OAB) or non-obstructive urinary retention (NOR). These lower urinary tract symptoms (LUTS) are the result of a functional urological cause but often coincide with psychological and/or psychiatric factors. It has been stated that there is an association between LUTS, depression and anxiety disorders. With this study we will investigate whether affective symptoms and quality of life (QoL) improve after successful SNM. METHODS: All patients eligible for SNM between March 2013 and March 2016, filled out the HADS (Hospital Anxiety and Depression Scale), SF-36 (Short Form-36) and either the International Consultation on Incontinence Modular Questionnaire (ICIQ) on Male/Female Lower Urinary Tract Symptoms (M/F-LUTS), or the OAB-q questionnaire, before and after the test procedure. Symptom improvement of >=50% was considered as success. Results were analyzed by paired T-tests and the Wilcoxon signed-rank test. RESULTS: In total 95 patients were included. Mean age was 52.1 (SD 13.9). Fifty-six patients (59%) were implanted. Successful OAB patients reported a significant improvement in all domains of OAB-q, health change and affective symptoms. Successful NOR patients showed a significant improvement in voiding symptoms (P = 0.04) and health change (P = 0.03). However, they did not report significant improvement in affective symptoms. CONCLUSION: QoL and affective symptoms can significantly improve in LUTS patients who are successfully treated with SNM. When divided per indication, a significant improvement in affective symptoms together with QoL was only reported in successful OAB patients and not in successfully treated NOR patients. PMID- 29504635 TI - Upregulation of nitric oxide in tumor cells as a negative adaptation to photodynamic therapy. AB - One of the advantages of PDT is that it can often circumvent tumor resistance to chemotherapeutic agents such as cisplatin and doxorubicin. However, pre-existing and acquired resistance to PDT has also been demonstrated. One type of resistance, which involves nitric oxide (NO) generated by inducible nitric oxide synthase (iNOS/NOS2) in tumor cells, was discovered in the author's laboratory. When subjected to a 5-aminolevulinic acid (ALA)-based photodynamic challenge, several cancer lines, including breast, prostate, and glioma, underwent intrinsic apoptosis that could be substantially enhanced by iNOS enzymatic inhibitors or a NO scavenger, implying iNOS/NO-mediated resistance. In most cases, iNOS was significantly upregulated by the challenge and this appeared to be more important in the hyper-resistance than pre-existing enzyme. Of added importance was our observation that cells surviving ALA/light treatment typically exhibited a more aggressive phenotype, proliferating and migrating/invading more rapidly than controls in iNOS/NO-dependent fashion. Most of these in vitro PDT findings have recently been confirmed at the in vivo level, using a human breast tumor xenograft model. We have also shown that upregulated iNOS in PDT-targeted cells can elicit a pro-growth/migration response in non-targeted bystander cells, NO again playing a key role. Post-PDT resistance and potentially dangerous hyper aggressiveness can be attenuated by inhibitors of iNOS enzymatic activity, some of which have seen pharmacologic use in non-cancer or PDT settings. These various aspects of PDT antagonism by tumor iNOS/NO and how they might be overcome will be discussed in this review. Lasers Surg. Med. 50:590-598, 2018.(c) 2018 Wiley Periodicals, Inc. PMID- 29504636 TI - Tuning the Mesomorphism and Redox Response of Anionic-Ligand-Based Mixed-Valent Nickel(II) Complexes by Alkyl-Substituted Quaternary Ammonium Cations. AB - The combination of the redox-active mesogenic anion [NiII (Bdt)(BdtSQ)]- (Bdt=1,2 benzenedithiolato; BdtSQ=1,2-dithia-semi-benzoquinonato) with alkyl-substituted ammonium cations afforded a series of redox-active ionic complexes of the type [NR4 ][NiII (Bdt)(BdtSQ)] [R=nC16 H33 (NC164 Ni) and C8,10 (NC8,104 Ni); C8,10=6 octylhexadecyl] or [NMe2 R2 ][NiII (Bdt)(BdtSQ)] [R=nC16 H33 (NMe2 C162 Ni) and C8,10 (NMe2 C8,102 Ni)]. X-ray crystallographic analyses of NMe2 C162 Ni and NC164 Ni revealed the formation of cation-dependent integrated ionic layers separated by interdigittated alkyl chains. Complexes NMe2 C162 Ni and NC164 Ni commonly form crystalline phases at room temperature, whereas complexes NMe2 C8,102 Ni and NC8,104 Ni, which contain branched alkyl chains, form a metastable mesophase and an amorphous phase at the same temperature, respectively. Furthermore, complexes NMe2 C162 Ni, NMe2 C8,102 Ni, and NC164 Ni commonly form a smectic A phase (SmA) at 375, 317, and 342 K, respectively. For the four complexes, well-defined cyclic voltammetry responses, derived from ligand-based oxidation and reduction, were observed in solution and the condensed phases, that is, upon casting these complexes on an indium-doped tin oxide working electrode. The present study demonstrates the tunability of the mesomorphism of ionic molecular assemblies composed of alkyl-substituted quaternary ammonium cations, while maintaining the well-defined redox responses of the anions even in the condensed phases. PMID- 29504638 TI - Substitution effects in the 15 N NMR chemical shifts of heterocyclic azines evaluated at the GIAO-DFT level. AB - A systematic study of the accuracy factors for the computation of 15 N NMR chemical shifts in comparison with available experiment in the series of 72 diverse heterocyclic azines substituted with a classical series of substituents (CH3 , F, Cl, Br, NH2 , OCH3 , SCH3 , COCH3 , CONH2 , COOH, and CN) providing marked electronic sigma- and pi-electronic effects and strongly affecting 15 N NMR chemical shifts is performed. The best computational scheme for heterocyclic azines at the DFT level was found to be KT3/pcS-3//pc-2 (IEF-PCM). A vast amount of unknown 15 N NMR chemical shifts was predicted using the best computational protocol for substituted heterocyclic azines, especially for trizine, tetrazine, and pentazine where experimental 15 N NMR chemical shifts are almost totally unknown throughout the series. It was found that substitution effects in the classical series of substituents providing typical sigma- and pi-electronic effects followed the expected trends, as derived from the correlations of experimental and calculated 15 N NMR chemical shifts with Swain-Lupton's F and R constants. PMID- 29504637 TI - Synthesis of l-[4-11 C]Asparagine by Ring-Opening Nucleophilic 11 C-Cyanation Reaction of a Chiral Cyclic Sulfamidate Precursor. AB - The development of a convenient and rapid method to synthesize radiolabeled, enantiomerically pure amino acids (AAs) as potential positron emission tomography (PET) imaging agents for mapping various biochemical transformations in living organisms remains a challenge. This is especially true for the synthesis of carbon-11-labeled AAs given the short half-life of carbon-11 (11 C, t1/2 =20.4 min). A facile synthetic pathway to prepare enantiomerically pure 11 C-labeled l asparagine was developed using a partially protected serine as a starting material with a four-step transformation providing a chiral five-membered cyclic sulfamidate as the radiolabeling precursor. Its structure and absolute configuration were confirmed by X-ray crystallography. Utilizing a [11 C]cyanide nucleophilic ring opening reaction followed by selective acidic hydrolysis and deprotection, enantiomerically pure l-[4-11 C]asparagine was synthesized. Further optimization of reaction parameters, including base, metal ion source, solvent, acid component, reaction temperature and reaction time, a reliable two-step method for synthesizing l-[4-11 C]asparagine was presented: within a 45+/-3 min (n=5, from end-of-bombardment), the desired enantiomerically pure product was synthesized with the initial nucleophilic cyanation yield of 69+/-4 % (n=5) and overall two-step radiochemical yield of 53+/-2 % (n=5) based on starting [11 C]HCN, and with radiochemical purity of 96+/-2 % (n=5). PMID- 29504639 TI - Efficient Detection of Structure and Dynamics in Unlabeled RNAs: The SELOPE Approach. AB - The knowledge of structure and dynamics is crucial to explain the function of RNAs. While nuclear magnetic resonance (NMR) is well suited to probe these for complex biomolecules, it requires expensive, isotopically labeled samples, and long measurement times. Here we present SELOPE, a new robust, proton-only NMR method that allows us to obtain site-specific overview of structure and dynamics in an entire RNA molecule using an unlabeled sample. SELOPE simplifies assignment and allows for cost-effective screening of the response of nucleic acids to physiological changes (e.g. ion concentration) or screening of drugs in a high throughput fashion. This single technique allows us to probe an unprecedented range of exchange time scales (the whole MUs to ms motion range) with increased sensitivity, surpassing all current experiments to detect chemical exchange. For the first time we could describe an RNA excited state using an unlabeled RNA. PMID- 29504640 TI - Development and validation of a liquid chromatography/tandem mass spectrometry method for determination of caspofungin in dried blood spots. AB - RATIONALE: A liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for quantification of caspofungin in dried blood spots (DBS) was developed and validated. METHODS: The DBS samples were prepared by spotting whole blood onto Whatman 903 filter paper, drying at room temperature and extracting with 50% methanol and further cleaned by protein precipitation with acetonitrile. Roxithromycin was selected as internal standard, and the separation of the analytes with endogenous ingredients was accomplished on a Hypersil GOLD aQ column with a mobile phase composed of 0.1% formic acid (v/v) and methanol in gradient mode. The detection of the analytes was performed on a triple quadrupole mass spectrometer in positive electrospray ionization mode, and the following selective reaction monitoring (SRM) transitions were monitored: m/z 547.6 -> 538.7 and 837.4-> 679.4 for quantification of caspofungin and the internal standard, respectively. RESULTS: The total analytical time was 8 min for each run. The calibration curve exhibited a good linearity over the range from 0.2 to 20 MUg/mL and the lower limit of quantification (LLOQ) was 0.2 MUg/mL for caspofungin in DBS. The recoveries of caspofungin ranged from 62.64% to 76.69%, and no obvious matrix effect was observed. The intra- and inter-day precision and accuracy were within acceptable limits, and caspofungin in DBS was stable after storage at room temperature for 24 h and at -80 degrees C for 30 days. There was no evident effect of the hematocrit value on the analysis of caspofungin. CONCLUSIONS: The proposed method presents an alternative to the conventional venous sampling method, and was successfully utilized for pharmacokinetics study of caspofungin in ICU patients. PMID- 29504641 TI - Spiro Bicyclic Guanidino Compounds from Pufferfish: Possible Biosynthetic Intermediates of Tetrodotoxin in Marine Environments. AB - Tetrodotoxin (TTX, 1) is a potent neurotoxin that is widely found in both terrestrial and marine animals; however, the biosynthetic pathway and genes for TTX have not yet been elucidated. Previously, we proposed that TTX originated from a monoterpene; this hypothesis was based on the structures of cyclic guanidino compounds that are commonly found in toxic newts. However, these compounds have not been detected in marine organisms. Instead, a series of deoxy analogues of TTX were found in toxic marine animals; thus, we further screened for TTX-related compounds in marine animals. Herein, we report seven novel spiro bicyclic guanidino compounds 2-8 that were isolated from the pufferfish Tetraodon biocellatus. In compounds 2-5 and 7-8, a six-membered cyclic guanidino amide is spiro-fused with 2,4-dimethyl cyclohexane, whereas in compound 6, the same cyclic guanidino amide is spiro-fused with 2,3,5-trimethylcyclopentane. Compounds 2-5 and 7-8 have the same carbon skeleton and relative configuration as TTX. Thus, we proposed that compounds 2-8 are biosynthetic intermediates of TTX in marine environments. TTX could be biosynthetically derived from compound 7 via intermediates 2-5 through several oxidations, amide hydrolysis, and formation of the hemiaminal and lactone found in 5,6,11-trideoxyTTX, the major TTX analogue, whereas compounds 6 and 8 might be shunt products. LC-MS analysis confirmed the wide distribution of compounds 2, 3, or both in TTX-containing marine animals, namely pufferfish, crab, octopus, and flatworm, but compounds 2-8 were not detected in newts. PMID- 29504642 TI - Partial correlation analysis of transcriptomes helps detangle the growth and defense network in spruce. AB - In plants, there can be a trade-off between resource allocations to growth vs defense. Here, we use partial correlation analysis of gene expression to make inferences about the nature of this interaction. We studied segregating progenies of Interior spruce subject to weevil attack. In a controlled experiment, we measured pre-attack plant growth and post-attack damage with several morphological measures, and profiled transcriptomes of 188 progeny. We used partial correlations of individual transcripts (expressed sequence tags, ESTs) with pairs of growth/defense traits to identify important nodes and edges in the inferred underlying gene network, for example, those pairs of growth/defense traits with high mutual correlation with a single EST transcript. We give a method to identify such ESTs. A terpenoid ABC transporter gene showed strongest correlations (P = 0.019); its transcript represented a hub within the compact 166 member gene-gene interaction network (P = 0.004) of the negative genetic correlations between growth and subsequent pest attack. A small 21-member interaction network (P = 0.004) represented the uncovered positive correlations. Our study demonstrates partial correlation analysis identifies important gene networks underlying growth and susceptibility to the weevil in spruce. In particular, we found transcripts that strongly modify the trade-off between growth and defense, and allow identification of networks more central to the trade-off. PMID- 29504644 TI - Catalytic [1,3] O-to-C Rearrangement: Rapid Access to Bridged Bicyclic Systems. AB - A catalytic [1,3] O-to-C rearrangement from enyne-ethers was developed for the rapid synthesis of diverse bridged bicyclic systems. In this reaction, a vinyl oxonium intermediate, generated in situ from enyne-ether, was the precursor for the [1,3] O-to-C rearrangement. This versatile protocol represents the first example of catalytic [1,3] O-to-C rearrangement based on ring-expansion strategy, enabling efficient access to bridged bicyclic scaffolds. PMID- 29504643 TI - Feasibility of an emotional health curriculum for elementary school students in an underserved Hispanic community. AB - PROBLEM: Hispanic children have greater mental health challenges but fewer received mental health services than other ethnic groups. A classroom-based Emotional Health Curriculum (EHC) was developed to address mental health disparities in an underserved Hispanic community. METHODS: A quasi-experimental design with one group pre- and post-intervention was used to test the feasibility of an 8-week EHC for one hundred 3rd and 4th grade children in a dual-immersion Spanish-English elementary school. Limited efficacy was measured by changes in depression and anxiety scores reported by children and teachers. Acceptance was evaluated by a child-reported satisfaction survey and a focus group in which the four teachers shared their experiences. Implementation was measured by participation, retention, and fidelity rates. FINDINGS: The child-reported depression and anxiety and teacher-reported depression were significantly decreased in at-risk children with the effect size ranging from 0.60 to 1.16 (ps < 0.05). The majority of children (89.7%) enjoyed the EHC and teachers observed that children had acquired skills to manage their emotional distress. The participation, retention, and fidelity rates were 98%, 94%, and 99.13%, respectively. CONCLUSIONS: The results provide promising evidence that the EHC has the potential to improve depression and anxiety symptoms in at-risk children. PMID- 29504645 TI - Methods in renal research: Measurement of autophagic flux in the renal cortex ex vivo. AB - The role of autophagy in the kidney and many nephrological diseases has gained prominence in recent years. Much of this research has been focused on markers of autophagy that are static and reveal little about the state of this dynamic pathway. Other mechanistic investigations are limited to in vitro studies, that often provide circumstantial evidence of autophagic flux. Here we describe a method for measuring autophagic flux ex vivo that allows more direct observations to be made in situ regarding the state of autophagic flux within the renal cortex of a single animal. PMID- 29504646 TI - Phyllosphere microbiology: at the interface between microbial individuals and the plant host. AB - Contents Summary 1327 I. Introduction 1327 II. Individuality and the relevance of scales for the investigation of bacteria 1328 III. Bacterial aggregation and community patterning at the single-cell resolution 1329 IV. What are the effects on the plant host? 1330 V. Future directions and current questions 1331 Acknowledgements 1332 ORCID 1332 References 1332 SUMMARY: Leaf surfaces are home to diverse bacterial communities. Within these communities, every individual cell perceives its unique environment and responds accordingly. In this insight article, the perspective of the bacterial individual is assumed in an attempt to describe how the spatially heterogeneous leaf surface determines the fate of bacteria. To investigate behaviour at scales relevant to bacteria, single-cell approaches are essential. Single-cell studies provide important lessons about how current 'omics' approaches fail to give an accurate picture of the behaviour of bacterial populations in heterogeneous environments. Upcoming techniques will soon allow us to combine the power of single-cell and omics approaches. PMID- 29504648 TI - Botulinum toxin: did the black box warning change how we treat children with cerebral palsy? PMID- 29504647 TI - Enhanced neuronal and blunted hemodynamic reactivity to cocaine in the prefrontal cortex following extended cocaine access: optical imaging study in anesthetized rats. AB - Cocaine addiction is associated with dysfunction of the prefrontal cortex (PFC), which facilitates relapse and compulsive drug taking. To assess if cocaine's effects on both neuronal and vascular activity contribute to PFC dysfunction, we used optical coherence tomography and multi-wavelength laser speckle to measure vascularization and hemodynamics and used GCaMP6f to monitor intracellular Ca2+ levels ([Ca2+ ]in ) as a marker of neuronal activity. Rats were given short (1 hour; ShA) or long (6 hours; LgA) access cocaine self-administration. As expected, LgA but not ShA rats escalated cocaine intake. In naive rats, acute cocaine decreased oxygenated hemoglobin, increased deoxygenated hemoglobin and reduced cerebral blood flow in PFC, likely due to cocaine-induced vasoconstriction. ShA rats showed enhanced hemodynamic response and slower recovery after cocaine, versus naive. LgA rats showed a blunted hemodynamic response, but an enhanced PFC neuronal [Ca2+ ]in increase after cocaine challenge associated with drug intake. Both ShA and LgA groups had higher vessel density, indicative of angiogenesis, presumably to compensate for cocaine's vasoconstricting effects. Cocaine self-administration modified the PFC cerebrovascular responses enhancing it in ShA and attenuating it in LgA animals. In contrast, LgA but not ShA animals showed sensitized neuronal reactivity to acute cocaine in the PFC. The opposite changes in hemodynamics (decreased) and neuronal responses (enhanced) in LgA rats indicate that these constitute distinct effects and suggest that the neuronal and not the vascular effects are associated with escalation of cocaine intake in addiction whereas its vascular effect in PFC might contribute to cognitive deficits that increase vulnerability to relapse. PMID- 29504649 TI - A General, Rhodium-Catalyzed, Synthesis of Deuterated Boranes and N-Methyl Polyaminoboranes. AB - The rhodium complex [Rh(Ph2 PCH2 CH2 CH2 PPh2 )(eta6 -FC6 H5 )][BArF4 ], 2, catalyzes BH/BD exchange between D2 and the boranes H3 B?NMe3 , H3 B?SMe2 and HBpin, facilitating the expedient isolation of a variety of deuterated analogues in high isotopic purities, and in particular the isotopologues of N-methylamine borane: R3 B?NMeR2 1-dx (R=H, D; x=0, 2, 3 or 5). It also acts to catalyze the dehydropolymerization of 1-dx to give deuterated polyaminoboranes. Mechanistic studies suggest a metal-based polymerization involving an unusual hybrid coordination insertion chain-growth/step-growth mechanism. PMID- 29504650 TI - The Child Adolescent Bullying Scale (CABS): Psychometric evaluation of a new measure. AB - While youth bullying is a significant public health problem, healthcare providers have been limited in their ability to identify bullied youths due to the lack of a reliable, and valid instrument appropriate for use in clinical settings. We conducted a multisite study to evaluate the psychometric properties of a new 22 item instrument for assessing youths' experiences of being bullied, the Child Adolescent Bullying Scale (CABS). The 20 items summed to produce the measure's score were evaluated here. Diagnostic performance was assessed through evaluation of sensitivity, specificity, predictive values, and area under receiver operating characteristic (AUROC) curve. A sample of 352 youths from diverse racial, ethnic, and geographic backgrounds (188 female, 159 male, 5 transgender, sample mean age 13.5 years) were recruited from two clinical sites. Participants completed the CABS and existing youth bullying measures. Analyses grounded in classical test theory, including assessments of reliability and validity, item analyses, and principal components analysis, were conducted. The diagnostic performance and test characteristics of the CABS were also evaluated. The CABS is comprised of one component, accounting for 67% of observed variance. Analyses established evidence of internal consistency reliability (Cronbach's alpha = 0.97), construct and convergent validity. Sensitivity was 84%, specificity was 65%, and the AUROC curve was 0.74 (95% CI: 0.69-0.80). Findings suggest that the CABS holds promise as a reliable, valid tool for healthcare provider use in screening for bullying exposure in the clinical setting. PMID- 29504652 TI - Method of self-harm in adolescents and young adults and risk of subsequent suicide. AB - BACKGROUND: Self-harm is common in youth and an important risk factor for suicide. Certain self-harm methods might indicate a higher risk of suicide. The main aim of this study was to determine whether some methods of self-harm in adolescents (10-17 years) and young adults (18-24 years) are associated with a particularly high risk of suicide. A secondary aim was to ascertain how different self-harm methods might affect the probability of psychiatric follow-up. METHOD: Five Swedish registers were linked in a national population-based cohort study. All nonfatal self-harm events recorded in specialist health care, excluding psychiatry and primary care services, among 10-24 year olds between 2000 and 2009 were included. Methods were classified as poisoning, cutting/piercing, violent method (gassing, hanging, strangulation/suffocation, drowning, jumping and firearms), other and multiple methods. Hazard Ratios (HR) for suicide were calculated in Cox regression models for each method with poisoning as the reference. Odds Ratios (OR) for psychiatric inpatient care were determined in logistic regression models. Analyses were adjusted for important covariates and stratified by age group and treatment setting (inpatient/outpatient). RESULTS: Among adolescents with initial medical hospitalisation, use of a violent method was associated with a near eightfold increase in HR for suicide compared to self poisoning in the adjusted analysis [HR 7.8; 95% confidence interval (CI) 3.2 19.0]. Among hospitalised young adult women, adjusted HRs were elevated fourfold for both cutting [4.0 (1.9-8.8)] and violent methods [3.9 (1.5-10.6)]. Method of self-harm did not affect suicide risk in young adult men. Adolescents using violent methods had an increased probability of psychiatric inpatient care following initial treatment for self-harm. CONCLUSIONS: Violent self-harm requiring medical hospitalisation may signal particularly high risk of future suicide in adolescents (both sexes) and in young adult women. For the latter group this is the case for cutting requiring hospitalisation as well. PMID- 29504651 TI - Early development of letter specialization in left fusiform is associated with better word reading and smaller fusiform face area. AB - A functional region of left fusiform gyrus termed "the visual word form area" (VWFA) develops during reading acquisition to respond more strongly to printed words than to other visual stimuli. Here, we examined responses to letters among 5- and 6-year-old early kindergarten children (N = 48) with little or no school based reading instruction who varied in their reading ability. We used functional magnetic resonance imaging (fMRI) to measure responses to individual letters, false fonts, and faces in left and right fusiform gyri. We then evaluated whether signal change and size (spatial extent) of letter-sensitive cortex (greater activation for letters versus faces) and letter-specific cortex (greater activation for letters versus false fonts) in these regions related to (a) standardized measures of word-reading ability and (b) signal change and size of face-sensitive cortex (fusiform face area or FFA; greater activation for faces versus letters). Greater letter specificity, but not letter sensitivity, in left fusiform gyrus correlated positively with word reading scores. Across children, in the left fusiform gyrus, greater size of letter-sensitive cortex correlated with lesser size of FFA. These findings are the first to suggest that in beginning readers, development of letter responsivity in left fusiform cortex is associated with both better reading ability and also a reduction of the size of left FFA that may result in right-hemisphere dominance for face perception. PMID- 29504653 TI - Two Aluminophosphate Molecular Sieves Built from Pairs of Enantiomeric Structural Building Units. AB - Herein we report the synthesis and structures of two new small-pore aluminophosphate molecular sieves PST-13 and PST-14 with mutually connected 8 ring channels. The structure of PST-13, synthesized using diethylamine as an organic structure-directing agent, contains penta-coordinated framework Al atoms bridged by hydroxy groups and thus edge-sharing 3- and 5-rings. Upon calcination, PST-13 undergoes a transformation to PST-14 with loss of bridging hydroxy groups and occluded organic species. The structures of both materials consist "nonjointly" of pairs of previously undiscovered 1,5- and 1,6-open double 4-rings (d4rs) which are mirror images of each other. We also present a series of novel chemically feasible hypothetical structures built from 1-open d4r (sti) or 1,3 open d4r (nsc) units, as well as from these two enantiomeric structural building units. PMID- 29504654 TI - De novo neurogenic bladder dysfunction after salvage lymph node dissection in patients with nodal recurrence of prostate cancer. AB - AIMS: To examine the impact of Salvage lymph node dissection (SLND) on bladder function and oncological outcome in hormone naive patients with nodal recurrence of prostate cancer (PCa) after radical prostatectomy (RP). METHODS: In a prospective study between October 2015 and November 2016, 20 patients underwent transperitoneal SLND for nodal recurrence of PCa after RP at our institution. Standardized urodynamics were performed pre- and postoperatively after 6 weeks, 3, and 6 to 12 months. Prostate-specific antigen (PSA) levels were used to monitor the oncological outcome. Perioperative outcomes encompassed, among others, type of complications after surgery classified to Clavien-Dindo. RESULTS: The proportion of patients with neurogenic bladder dysfunction was postoperative at 6 weeks, 3, and 6 to 12 months 78.5%, 70%, and 45.5%, respectively. Compared to preoperative urodynamics, follow-ups revealed a statistical significant cleavage of bladder wall compliance until six to twelve months after SLND (34.5 vs 22 mL/cmH2 O, P = 0.044). Referring to the oncological outcome all patients experienced a PSA progression, 10 patients (50%) within 11 weeks after surgery. Overall, four patients (20%) suffered from a postoperative complication after SLND, which comprises Clavien grade I-IIIa. CONCLUSIONS: Transperitoneal SLND, as a treatment option for patients with nodal recurrence of PCa after RP reveals additional potential pitfalls than previously reported. Urodynamics reveal a significant impact of SLND on postoperative functional bladder dysfunctions. Therefore, informed consent prior to SLND should include the risk of persistent low compliance bladder. PMID- 29504655 TI - Factors contributing to treatment outcomes of post-prostatectomy incontinence surgery for the selection of the proper surgical procedure for individual patients: A single-center experience. AB - OBJECTIVES: To investigate the clinical and urodynamic parameters affecting the treatment outcomes of post-prostatectomy incontinence (PPI) surgery. PATIENTS AND METHODS: We reviewed the patients with PPI who received an artificial urinary sphincter (AUS) or adjustable male sling (MS) from 2001 to 2016. RESULTS: A total of 103 patients (AUS, 53; adjustable MS, 50) with a mean age of 69.9 (+/-5.6, standard deviation) years were analyzed. The mean number of pads used daily was 4.8 (+/-3.4). The mean symptom duration and follow-up duration were 46.9 (+/ 31.1) and 31.0 (+/-21.4) months, respectively. The overall rate of treatment success (<=1 pad per day at last follow-up) at 12 months postoperatively was 81.6%. Based on univariate analysis, previous pelvic irradiation (P = 0.013), prior PPI surgery (P = 0.017), and degree of incontinence (P = 0.010) were inversely associated with the success of PPI surgery. In patients who received AUS, history of neurologic disease (P = 0.038) was inversely associated with treatment success. However, in patients with an adjustable MS, previous pelvic irradiation (P = 0.001), prior PPI surgery (P = 0.022), and degree of incontinence (P = 0.008) were inversely associated with treatment success. CONCLUSIONS: Adjustable MS should be avoided in patients with previous pelvic irradiation, prior PPI surgery, or severe symptoms. Physicians should be aware that the treatment outcome of AUS might be compromised in patients with neurologic disease. PMID- 29504656 TI - Carbo-biphenyls and Carbo-terphenyls: Oligo(phenylene ethynylene) Ring Carbo mers. AB - Ring carbo-mers of oligo(phenylene ethynylene)s (OPEn, n=0-2), made of C2 catenated C18 carbo-benzene rings, have been synthesized and characterized by NMR and UV-vis spectroscopy, crystallography and voltammetry. Analyses of crystal and DFT-optimized structures show that the C18 rings preserve their individual aromatic character according to structural and magnetic criteria (NICS indices). Carbo-terphenyls (n=2) are reversibly reduced at ca. -0.42 V/SCE, i.e. 0.41 V more readily than the corresponding carbo-benzene (-0.83 V/SCE), thus revealing efficient inter-ring pi-conjugation. An accurate linear fit of E1/2red1 vs. the DFT LUMO energy suggests a notably higher value (-0.30 V/SCE) for a carbo quaterphenyl congener (n=3). Increase with n of the effective pi-conjugation is also evidenced by a red shift of two of the three main visible light absorption bands, all being assigned to TDDFT-calculated excited states, one of them restricting to a HOMO->LUMO main one-electron transition. PMID- 29504657 TI - Differential surface phenotype and context-dependent reactivity of functionally diverse NKT cells. AB - Natural Killer T (NKT) cells are a functionally diverse population that recognizes lipid-based antigens in association with the antigen-presenting molecule CD1d. Here, we define a technique to separate the functionally distinct thymic NKT1, NKT2 and NKT17 cell subsets by their surface expression of CD278 (ICOS) and the activation-associated glycoform of CD43, enabling the investigation of subset-specific effector-functions. We report that all three subsets express the transcription factor GATA-3 and the potential to produce IL-4 and IL-10 following activation. This questions the notion that NKT2 cells are the predominant source of IL-4 within the NKT cell pool, and suggests that IL-10 production may be more indicative of NKT cell plasticity than the existence of a distinct regulatory lineage or subset. We also show that many NKT17 cells are CD4+ and are biased toward Vbeta8.3 TCR gene usage. Lastly, we demonstrate that the toll-like receptor (TLR) ligand lipopolysaccharide (LPS) can induce a NKT17 cell-biased response, even in the absence of exogenous antigen, and that combining LPS with alpha-GalCer resulted in enhanced IL-17A-production, and reduced levels of the immunosuppressive cytokine IL-10. This study provides a novel means to examine the context-dependent reactivity of the functionally heterogeneous NKT cell population and provides important new insight into the functional biology of these subsets. PMID- 29504658 TI - Can Remote N-Heterocyclic Carbenes Coordinate with Main Group Elements? Synthesis, Structure, and Quantum Chemical Analysis of N+ -Centered Complexes. AB - Remote N-heterocyclic carbenes (rNHCs), such as N-methyl-4-pyridylidene, are known to form coordination complexes with TMs. Herein, it is established that rNHCs can also coordinate to the N+ centre. Synthesis of some novel divalent NI complexes with the general formula (rNHC)->N+ <-(NHC) and (rNHC)->N+ <-(rNHC) was achieved, and X-ray diffraction studies supported the coordination bond character between the rNHCs and the N+ centre. Quantum chemical analysis established the presence of divalent NI character at the central nitrogen in these systems. PMID- 29504659 TI - Cu-Catalyzed Hydroxymethylation of Unactivated Alkyl Iodides with CO To Provide One-Carbon-Extended Alcohols. AB - We have developed a reductive carbonylation method by which unactivated alkyl iodides can be hydroxymethylated to provide one-carbon-extended alcohol products under Cu-catalyzed conditions. The method is tolerant of alkyl beta-hydrogen atoms, is robust towards a wide variety of functional groups, and was applied to primary, secondary, and tertiary alkyl iodide substrates. Mechanistic experiments indicate that the transformation proceeds by atom-transfer carbonylation (ATC) of the alkyl iodide followed in tandem by two CuH-mediated reductions in rapid succession. This radical mechanism renders the Cu-catalyzed system complementary to precious-metal-catalyzed reductive carbonylation reactions. PMID- 29504660 TI - What's Next for Acute Heart Failure Research: A Call for Multidisciplinary Collaborations. PMID- 29504661 TI - Sequence-Dependent Diastereospecific and Diastereodivergent Crosslinking of DNA by Decarbamoylmitomycin C. AB - Mitomycin C (MC), a potent antitumor drug, and decarbamoylmitomycin C (DMC), a derivative lacking the carbamoyl group, form highly cytotoxic DNA interstrand crosslinks. The major interstrand crosslink formed by DMC is the C1'' epimer of the major crosslink formed by MC. The molecular basis for the stereochemical configuration exhibited by DMC was investigated using biomimetic synthesis. The formation of DNA-DNA crosslinks by DMC is diastereospecific and diastereodivergent: Only the 1''S-diastereomer of the initially formed monoadduct can form crosslinks at GpC sequences, and only the 1''R-diastereomer of the monoadduct can form crosslinks at CpG sequences. We also show that CpG and GpC sequences react with divergent diastereoselectivity in the first alkylation step: 1"S stereochemistry is favored at GpC sequences and 1''R stereochemistry is favored at CpG sequences. Therefore, the first alkylation step results, at each sequence, in the selective formation of the diastereomer able to generate an interstrand DNA-DNA crosslink after the "second arm" alkylation. Examination of the known DNA adduct pattern obtained after treatment of cancer cell cultures with DMC indicates that the GpC sequence is the major target for the formation of DNA-DNA crosslinks in vivo by this drug. PMID- 29504663 TI - Salt-Free Strategy for the Insertion of CO2 into C-H Bonds: Catalytic Hydroxymethylation of Alkynes. AB - A copper(I) catalyst enables the insertion of carbon dioxide into alkyne C-H bonds by using a suitable organic base with which hydrogenation of the resulting carboxylate salt with regeneration of the base becomes thermodynamically feasible. In the presence of catalytic copper(I) chloride/4,7-diphenyl-1,10 phenanthroline, polymer-bound triphenylphosphine, and 2,2,6,6 tetramethylpiperidine as the base, terminal alkynes undergo carboxylation at 15 bar CO2 and room temperature. After filtration, the ammonium alkynecarboxylate can be hydrogenated to the primary alcohol and water at a rhodium/molybdenum catalyst, regenerating the amine base. This demonstrates the feasibility of a salt-free overall process, in which carbon dioxide serves as a C1 building block in a C-H functionalization. PMID- 29504662 TI - Prospective study evaluating the use of nasal glucagon for the treatment of moderate to severe hypoglycaemia in adults with type 1 diabetes in a real-world setting. AB - In the present multicentre, open-label, prospective, phase III study, we evaluated the real-world effectiveness and ease of use of nasal glucagon (NG) in the treatment of moderate/severe hypoglycaemic events (HEs) in adults with type 1 diabetes (T1D). Patients and caregivers were taught how to use NG (3 mg) to treat moderate/severe HEs, record the time taken to awaken or return to normal status, and measure blood glucose (BG) levels over time. Questionnaires were used to collect information about adverse events and ease of use of NG. In the efficacy analysis population, 69 patients experienced 157 HEs. In 95.7% patients, HEs resolved within 30 minutes of NG administration. In all the 12 severe HEs, patients awakened or returned to normal status within 15 minutes of NG administration without additional external medical help. Most caregivers reported that NG was easy to use. Most adverse events were local and of low to moderate severity. In this study, a single, 3-mg dose of NG demonstrated real-life effectiveness in treating moderate and severe HEs in adults with T1D. NG was well tolerated and easy to use. PMID- 29504664 TI - Perspectives, Commentaries, Consensus Reports, Grand Rounds, Meta-Analyses, Systematic Reviews, Narrative Reviews: Collecting useful information in one place. PMID- 29504665 TI - Structure of Nanoparticles Derived from Designer Surfactant TPGS-750-M in Water, As Used in Organic Synthesis. AB - Using density functional theory and the COSMO-RS implicit solvent model, we predict the structure and physical chemical properties of nanomicelles derived from the designer surfactant TPGS-750-M used in organic synthesis. We predict that the influence of chain length of the PEG region is low, while the termination of the PEG chain (-OH vs.-OCH3 ) plays a very large role. The interfacial tension is considerably lower between the micellar and water phases for the -OH than the -OCH3 terminated surfactant, and our calculations reproduce the large difference observed in average particle size as a function of PEG chain termination. We propose a structure for the nanoparticles formed by TPGS-750-M in water that is consistent with a ~50 nm average diameter, which is significantly larger than a single micelle. According to the calculations, each nanoparticle would consist of 30-40 aggregated TPGS-750-M micelles forming a compartmentalized nanoparticle, with considerable amounts of water in the PEG region. The whole particle is stabilized by vitamin E succinate at the nanoparticle-water interface. In the presence of Zn dust or powder, the surfactant collides with the Zn surface, and by interactions with the hydrophobic inner cores, form organozinc species that are protected from the surrounding water. This explains why highly moisture-sensitive Negishi-like couplings take place in surfactant-water systems. PMID- 29504667 TI - Long-term record of Argentine ant invasions reveals enduring ecological impacts. AB - The ecological effects of species introductions can change in magnitude over time, but an understanding of how and why they do so remains incompletely understood. Clarifying this issue requires consideration of how temporal variation in invader traits affects invasion impacts (e.g., through differential effects on the diversity and composition of native species assemblages). We examine the temporal dynamics of Argentine ant invasions in northern California by resurveying 202 sites first sampled 30-40 yr ago. To test how invasion impacts change over time, we estimated native ant richness and species composition at 20 riparian woodland sites that span a 30-yr invasion chronosequence. We then use these data to test how variation in two invader traits (aggression and relative abundance) is related to time since invasion and invasion impact. Native ant assemblages along the chronosequence exhibited reduced native ant richness and altered species composition (compared to uninvaded control sites), but the magnitude of these impacts was independent of time since invasion. These results are corroborated by additional temporal comparisons of native ant assemblages at riparian sites sampled 20-30 yr ago. Our findings together illustrate that the impacts of invasions can persist undiminished over at least a 30-yr time frame and remain evident at regional scales. Although neither invader trait varied with time since invasion, native ant richness declined as the relative abundance of the Argentine ant increased. This latter result supports the hypothesis that factors reducing invader abundance at particular sites can decrease invasion impacts, but also that such changes may be due to site-specific factors (e.g., abiotic conditions) that affect invader abundance rather than time since invasion per se. Future studies should attempt to differentiate factors that are intrinsic to the process of invasion (e.g., changes in invader populations) from long-term environmental changes (e.g., climate change) that represent extrinsic influences on the dynamics of invasion. PMID- 29504666 TI - A randomized trial using telehealth technology to link caregivers with dementia care experts for in-home caregiving support: FamTechCare protocol. AB - The number of persons with dementia (PWD) in the United States is expected to reach 16 million by 2050. Due to the behavioral and psychological symptoms of dementia, caregivers face challenging in-home care situations that lead to a range of negative health outcomes such as anxiety and depression for the caregivers and nursing home placement for PWD. Supporting Family Caregivers with Technology for Dementia Home Care (FamTechCare) is a multisite randomized controlled trial evaluating the effects of a telehealth intervention on caregiver well-being and PWD behavioral symptoms. The FamTechCare intervention provides individualized dementia-care strategies to in-home caregivers based on video recordings that the caregiver creates of challenging care situations. A team of dementia care experts review videos submitted by caregivers and provide interventions to improve care weekly for the experimental group. Caregivers in the control group receive feedback for improving care based on a weekly phone call with the interventionist and receive feedback on their videos at the end of the 3-month study. Using linear mixed modeling, we will compare experimental and control group outcomes (PWD behavioral symptoms and caregiver burden) after 1 and 3 months. An exploratory descriptive design will identify a typology of interventions for telehealth support for in-home dementia caregivers. Finally, the cost for FamTechCare will be determined and examined in relation to hypothesized effects on PWD behavioral symptoms, placement rates, and caregiver burden. This research will provide the foundation for future research for telehealth interventions with this population, especially for families in rural or remote locations. PMID- 29504668 TI - Treating the tear trough: A new classification system, a 6-step evaluation procedure, hyaluronic acid injection algorithm, and treatment sequences. AB - INTRODUCTION: The tear trough deformity is commonly requested for correction, most often by filler injections. However, the tear trough remains difficult to treat due to its complex anatomy, a variety of other concurrent deformities, and the high risk of complications. OBJECTIVES: To create a standardized categorization, evaluation, and treatment protocol for the management of tear troughs with fillers. METHODS: (1) Patient deformity profiles are determined using three categories of traits: A (Atrophy), B (Bulging), L (Laxity). (2) A 6 step evaluation process (Tilt, Snap, Smile, Squint, Pull, Push) aids in ABL determination. (3) Treatment is simplified into a comprehensive protocol for each category (with 6 major injection points and a variety of injection depths and volumes). RESULTS: The author has achieved satisfactory results using the presented protocols, with photographic examples. CONCLUSION: The author proposes a comprehensive categorization system that takes into account both the tear trough and other concurrent deformities. The author also presents 6 tests to aid in categorization, and simple protocols with injection sequences, amounts, and depth. PMID- 29504669 TI - Manipulating Clusters by Use of Competing N,O-Chelating Ligands: A Combined Crystallographic, Mass Spectrometric, and DFT Study. AB - Two heptanuclear discs, [Co7 (L1)6 (CH3 O)6 ]2+ (Co7 -L1) and [Co7 (L2)12 ](ClO4 )2 (Co7 -L2), have been prepared by the reaction of [Co(H2 O)6 ](ClO4 )2 with Schiff base HL1 (HL1=2-methoxy-6-[(methylimino)methyl]phenolate) or benzimidazole derivative HL2 (HL2=(1H-benzo[d]imidazol-2-yl)methanolate), respectively, at room temperature. In contrast, the reaction of [Co(H2 O)6 ](ClO4 )2 with a mixture of the two ligands, having similar coordination ability but different shapes, resulted in the butterfly-structured tetranuclear cobalt cluster [Co4 (L1)2 (L2)4 ](ClO4 )2 ?2H2 O (Co4 ). Electrospray ionization mass spectrometry (ESI-MS) analysis in real time revealed the {Co1 }->{Co2 }->{Co4 }->{Co7 } stepwise assembly when a single ligand was employed, but when both ligands were used only {Co4 } was obtained, an intermediate of the former reactions. Interestingly, ligand competition was evidenced in the assembly process of the reaction with two ligands; for example, [Co4 (L1)4 (L2)2 ]2+ and [Co4 (L1)3 (L2)3 ]2+ were the primary clusters observed at the beginning of the reaction, but [Co4 (L1)2 (L2)4 ]2+ was the final product. This observation suggests ligand exchange is taking place, and DFT calculations confirmed that these transformations were possible. By varying the ratio of ligands, the abundance of a certain species in the competitive reaction could be controlled. PMID- 29504670 TI - Alteration in intrinsic and extrinsic functional connectivity of resting state networks associated with subclinical hypothyroid. AB - Subclinical hypothyroidism (SCH) is characterized by mild elevation of thyroid stimulating hormone (TSH) (range 5-10 MUIU/ml) and normal free triiodothyronine (FT3) and free thyroxine (FT4). The cognitive function impairment is well known in thyroid disorders such as hypothyroidism and hyperthyroidism, but little is known about deficits in brain functions in SCH subjects. Also, whether hormone replacement treatment is necessary or not in SCH subjects is still debatable. In order to have an insight into the cognition of SCH subjects, intrinsic and extrinsic functional connectivity (FC) of the resting state networks (RSNs) was studied. For resting state data analysis we used an unbiased, data-driven approach based on Independent Component Analysis (ICA) and dual-regression that can emphasize widespread changes in FC without restricting to a set of predefined seeds. 28 SCH subjects and 28 matched healthy controls (HC) participated in the study. RSN analysis showed significantly decreased intrinsic FC in somato-motor network (SMN) and right fronto-parietal attention network (RAN) and increased intrinsic FC in default mode network (DMN) in SCH subjects as compared to control subjects. The reduced intrinsic FC in the SMN and RAN suggests neuro-cognitive alterations in SCH subjects in the corresponding functions which were also evident from the deficit in the neuropsychological performance of the SCH subjects on behavioural tests such as digit span, delayed recall, visual retention, recognition, Bender Gestalt and Mini-Mental State Examination (MMSE). We also found a significant reduction in extrinsic network FC between DMN and RAN; SMN and posterior default mode network (PDMN); and increased extrinsic FC between SMN and anterior default mode network (ADMN) in SCH subjects as compared to controls. An altered extrinsic FC in SCH suggests functional reorganization in response to neurological disruption. The partial correlation analysis between intrinsic and extrinsic RSNs FC and neuropsychological performances as well as clinical indices give interesting insights into brain-behavior relationship in SCH subjects. This article is protected by copyright. All rights reserved. PMID- 29504671 TI - A randomised cross-over study showed no difference in diaphragm activity during weaning from respiratory support. AB - AIM: We measured electrical activity of the diaphragm (Edi) to compare the breathing effort in preterm infants during weaning from respiratory support with high-flow nasal cannulae (HFNC) or nasal continuous positive airway pressure (nCPAP). METHODS: This randomised cross-over study was carried out at St Olav's University Hospital, Trondheim, Norway, from December 2013 to June 2015. We gave 21 preterm infants weighing at least 1000 g HFNC 6 L/minute for four hours and nCPAP 3 cmH2 O for four hours with a one-hour wash-out period. Measurements included diaphragmatic load, Edi, vital signs and a modified Silverman-Andersen Retraction Score. RESULTS: We found no differences in HFNC and nCPAP in the median Edi peak (8.0 MUV versus 7.8 MUV, p = 0.095), median Edi min (1.1 MUV versus 1.2 MUV in, p = 0.958) or mean heart rate (157 versus 159, p = 0.300) in the 21 infants who took part. The mean respiratory rate was significantly lower during HFNC than nCPAP (47 versus 52, p = 0.012). The modified Silverman-Andersen Retraction Score showed no significant differences. CONCLUSION: This study of preterm infants found no difference in the breathing effort measured by Edi between HFNC 6 L/minute and nCPAP 3 cmH2 O. HFNC could replace nCPAP when preterm infants are ready for weaning. PMID- 29504672 TI - Lack of interruption of the gene network underlying wing polyphenism in an early branching ant genus. AB - Ants evolved about 140 million years ago and have diversified into more than 15,000 species with tremendous ecological and morphological diversity, yet evolution of the gene regulatory networks (GRNs) underlying this diversification remains poorly understood. Wing polyphenism, the ability of a single genome to produce either winged or wingless castes during development in response to environmental cues, is a nearly universal feature of ants. The underlying wing GRN is evolutionarily labile in worker castes of phylogenetically derived species: it is conserved in winged castes but interrupted at different points in wingless castes of different species. However, it remains unknown whether the wing GRN is interrupted in wingless castes of species from early branching lineages, and if so, whether it is interrupted at similar locations in worker castes of derived species. We therefore used in situ hybridization to assay the expression of nine genes in the wing GRN in wing imaginal discs of larvae from two species from the early branching ('basal') genus Mystrium. These species possess two castes each: Mystrium rogeri has winged queens and wingless workers, and M. oberthueri has wingless queens and wingless workers. In contrast to derived species, we found no evidence of interruption points in the wing GRN kernel of wingless castes. Our finding supports: (1) a "phylogenetic ladder model" of wing GRN evolution, where interruption points move further upstream in the wing GRN as ant lineages become more derived; and (2) that evolutionary lability of the GRN underlying wing polyphenism originated later during ant evolution. PMID- 29504673 TI - Inhibition of In Vitro Metabolism of Opioids by Skeletal Muscle Relaxants. AB - The purpose of this study was to test the hypothesis that skeletal muscle relaxants could inhibit the in vitro metabolism of common comedications opioids buprenorphine, methadone and oxycodone. The compounds [solubility-limited concentration (MUM) studied] were as follows: baclofen (1000), carisoprodol (200), its metabolite meprobamate (1000), chlorzoxazone (200), cyclobenzaprine (1000), metaxalone (50), methocarbamol (1000), orphenadrine (1000) and tizanidine (1000). Compounds were first incubated with human liver microsomes +/- pre incubation, screened with pathway-specific cDNA-expressed cytochrome P450s (rCYP), and then IC50 values determined using either 8-concentration tests for those where the rCYP screen suggested an IC50 was achievable, or a 3 concentration test with downward extrapolation if screen suggested 50% inhibition was not achievable. These results were then extrapolated to determine an inhibitory potential. Six pathway inhibitor combinations were identified with a moderate inhibitory potential (>=2.0 < 5.0): five with chlorzoxazone, R-EDDP, S EDDP and noroxycodone production by CYP3A4, and R- and S-EDDP production by CYP2B6; and one for the meprobamate effect on noroxycodone production by CYP3A4. An additional eleven combinations were found with a weak inhibitory potential (>=1.25 < 2.0): five with carisoprodol, two each with methocarbamol and meprobamate, and one each with metaxalone and orphenadrine. This represents the first comprehensive study of the inhibitory effect of this class of drugs and suggests that some of them may produce significant drug-drug interactions with opioids that are frequent comedications with skeletal muscle relaxants. PMID- 29504675 TI - Oral health-related quality of life in young Cambodian children: a validation study with a focus on children with cleft lip and/or palate. AB - BACKGROUND: Oral Health-Related Quality-of-Life (OHRQoL) measures have been developed and cross-culturally validated for use in many populations in recent years. Their use in children with cleft lip and/or palate (CLP), however, is not as well established. AIM: This study aimed to validate two OHRQoL instruments for use with Cambodian children and to describe the OHRQoL of a sample of Cambodian children with CLP, compared with other children in the same cohort. METHODS: A convenience sample of 133 children aged 2-8 years and their families was recruited from two NGO health services in urban and rural areas of Cambodia. Children were assigned into clinical groups of cleft, malocclusion, severe caries (PUFA >= 1), and dentine caries. OHRQoL was measured using the Parental Caregivers Perception Questionnaire (P-CPQ-16) and Family Impact Scale (FIS-8). RESULTS: The validity of the instruments was acceptable with an expected gradient in both scale scores being evident across self-reported oral health ratings. Children with CLP and their families experienced significantly greater impacts on OHRQoL, and the pattern of these impacts differed among the clinical groups. CONCLUSIONS: This study has confirmed the validity of the P-CPQ-16 and FIS-8 for use with young Cambodian children. The results impart advocacy for needed improvements in the care of children with CLP and provide a foundation for future epidemiological research of oral health in Cambodia. PMID- 29504674 TI - Cat-scratch disease: ocular manifestations and treatment outcome. AB - PURPOSE: To characterize cat-scratch disease (CSD) ocular manifestations and visual outcome and evaluate the effect of systemic antibiotics and corticosteroids on final visual acuity (VA). METHODS: Multicentre retrospective cohort study. Medical records of 86 patients with ocular disease (107 eyes) of 3222 patients identified in a national CSD surveillance study were reviewed. RESULTS: Mean age was 35.1 +/- 14.2 years. Median follow-up was 20 weeks (range 1 806 weeks). Of 94/107 (88%) eyes with swollen disc, 60 (64%) had neuroretinitis at presentation, 14 (15%) developed neuroretinitis during follow-up, and 20 (21%) were diagnosed with inflammatory disc oedema. Optic nerve head lesion, uveitis, optic neuropathy and retinal vessel occlusion were found in 43 (40%), 38 (36%), 34 (33%) and 8 (7%) eyes, respectively. Good VA (better than 20/40), moderate vision loss (20/40-20/200) and severe vision loss (worse than 20/200) were found in 26/79 (33%), 35/79 (44%) and 18/79 (23%) eyes at baseline and in 63/79 (80%), 11/79 (14%) and 5/79 (6%) eyes at final follow-up, respectively (p < 0.001). Significant VA improvement (defined as improvement of >=3 Snellen lines at final follow-up compared to baseline) occurred in 12/24 (50%) eyes treated with antibiotics compared with 14/16 (88%) eyes treated with antibiotics and corticosteroids (p = 0.02). Multivariate logistic regression was suggestive of the same association (odds ratio 7.0; 95% CI 1.3-37.7; p = 0.024). CONCLUSION: Optic nerve head lesion is a common and unique manifestation of ocular CSD. Most patients improved and had final good VA. Combined antibiotics and corticosteroid treatment was associated with a better visual outcome. PMID- 29504676 TI - Effects of two different feeding positions on physiological characteristics and feeding performance of preterm infants: A randomized controlled trial. AB - PURPOSE: The aim of this randomized controlled study was to determine the effect of semielevated side-lying (ESL) and semielevated supine (ESU) positions, which are used to bottle-feed preterm infants, on their physiological characteristics and feeding performance. DESIGN AND METHODS: The sample consisted of preterm infants who were born in the 31st gestational week and below, and met the inclusion criteria. A randomization was provided in the sample group with a total of 80 infants including 38 infants in the ESL (experimental) group and 42 infants in the ESU (control) group. Both groups were compared in terms of their SpO2 values, heart rates, and feeding performances before, during, and after the feeding. The data were obtained by using a form for infant descriptive characteristics, feeding follow-up form, a Masimo Radical-7 pulse oximeter device, and a video camera. RESULTS: It was determined that the infants in the ESL group had statistically significantly higher SpO2 values (ESL: 96.77 +/- 2.51; ESU: 93.48 +/- 5.63) and lower heart rates (ESL: 155.87 +/- 11.18; ESU: 164.35 +/- 6.00) during the feeding compared to the infants in the ESU group (p < .05). Besides, oxygen saturation levels of the infants in the ESU group decreased more (p < .01) and their heart rates increased more (p < .05) during the feeding than those obtained before the feeding compared to the infants in the ESL group. PRACTICE IMPLICATIONS: The ESL position has a more positive effect on oxygen saturation and heart rate of infants and it is more effective in providing a physiological stabilization during the feeding, compared to the ESU position. According to these results, the ESL position can be recommended for preterm feeding. PMID- 29504677 TI - One-Pot Sequence-Controlled Synthesis of Oligosiloxanes. AB - Silicones (organopolysiloxanes) have found applications in a wide range of research areas, and their unique and valuable properties have rendered these materials virtually irreplaceable. Despite the fact that silicones have been employed industrially for more than 70 years, synthetic routes to generate silicones remain limited, and the sequence-controlled synthesis of oligo- and polysiloxanes still represents a major challenge in silicone chemistry. Described here is a highly selective sequence-controlled synthesis of linear, branched, and cyclic oligosiloxanes by simple iteration of two reactions, specifically, a B(C6 F5 )3 -catalyzed dehydrocarbonative cross-coupling of alkoxysilanes with hydrosilanes and a B(C6 F5 )3 -catalyzed hydrosilylation of carbonyl compounds, in a single flask. The sequence of the resulting oligosiloxanes can be controlled precisely by the order of addition of the hydrosilane monomers. PMID- 29504678 TI - Carbon Nanozymes: Enzymatic Properties, Catalytic Mechanism, and Applications. AB - Nanozymes have advantages over natural enzymes, such as facile production on large scale, long storage time, low costs, and high stability in harsh environments. Carbon nanomaterials (CNMs), including fullerenes, carbon nanotubes, graphene, carbon quantum dots, and graphene quantum dots, have become a star family in materials science. As a new class of nanozymes, the catalytic activity of CNMs and their hybrids has been extensively reported. In this Minireview, recent progress of CNMs based artificial enzymes, focusing on those with peroxidase-like activity, has been summarized. The enzymatic properties, catalytic mechanisms, and novel applications of CNM nanozymes in sensing, therapy, and environmental engineering are discussed in detail. Additionally, we also highlight the remaining challenges and unsolved problems. With the fast development of bionanotechnology, the unique enzymatic properties and advantages of CNM nanozymes have received much attention and will continue to be an active and challenging field for the years to come. PMID- 29504679 TI - On matters of mind and body: regarding Descartes. AB - In this paper the author considers Descartes' place in current thinking about the mind-body dilemma. The premise here is that in the history of ideas, the questions posed can be as significant as the answers acquired. Descartes' paramount question was 'How do we determine certainty?' and his pursuit of an answer led to cogito ergo sum. His discovery simultaneously raised the question whether mind is separate from or unified with the body. Some who currently hold that brain and subjectivity are unified contend that the philosopher 'split' mind from body and refer to 'Descartes' error'. This paper puts forward that Descartes' detractors fail to recognise Descartes' contribution to Western thought, which was to introduce the Enlightenment and to give a place to human subjectivity. Added to this, evidence from Descartes' correspondence with Princess Elisabeth of Bohemia supports the conclusion that Descartes did in fact believe in the unity of mind and body although he could not reconcile this rationally with the certainty from personal experience that they were separate substances. In this Descartes was engaged in just the same dilemma as that of current thinkers and researchers, a conflict which still is yet to be resolved. PMID- 29504680 TI - April editorial. PMID- 29504681 TI - Hiding in plain sight: Jung, astrology, and the psychology of the unconscious. AB - Astrology was a lifelong interest for C.G. Jung and an important aid in his formulation of psyche and psychic process. Archetypally configured, astrology provided Jung an objective means to a fuller understanding of the analysand's true nature and unique individuation journey. Jung credits astrology with helping to unlock the mystery of alchemy and in so doing providing the symbol language necessary for deciphering the historically remote cosmology of Gnosticism. Astrology also aided Jung's work on synchronicity. Despite astrology's worth to Jung's development of analytical psychology, its fundamental role in guiding his discoveries is all but absent from historical notice. The astrological natal chart seems rarely used clinically, and many clinicians seem unaware of its value as a dynamic diagram of the personality and the potentialities within which nature and nurture foster and/or discourage for individual growth and development over the lifespan. This paper charts Jung's interest in astrology and suggests why his great regard for it and other paranormal or occult practices remains largely neglected and unknown. PMID- 29504683 TI - Imaginal action: towards a Jungian conception of enactment, and an extraverted counterpart to active imagination. AB - This theoretical paper considers the fashion in which Jung's psychology radically challenges modern assumptions concerning the nature of subjectivity. With an eye for the clinical implications of Jung's late work, the author introduces the idea of imaginal action. In order to explain what is meant by this, the paper begins by exploring how Jung's thinking demonstrates an underlying bias towards introversion. It is argued that while Jung's interest in synchronicity ultimately resulted in his developing a worldview that might address the introverted biases of his psychology, the clinical implications of this shift have not been sufficiently clarified. With reference to some short examples from experience, the author outlines a conception of relational synchronicity wherein the intrapsychic emerges non-projectively within the interpersonal field itself. Comparing and contrasting these occurrences to the more introverted practice of active imagination, it is claimed that such a notion is implicit in Jung's work and is needed as a corrective to his emphasis on interiority. The author suggests that imaginal action might be conceived as a distinctly Jungian approach to the psychoanalytic notion of enactment. It is also shown how the idea outlined might find further support from recent developments in the field of transpersonal psychology. PMID- 29504685 TI - Imagining with the body in analytical psychology. Movement as active imagination: an interdisciplinary perspective from philosophy and neuroscience. AB - This article explores how the body and imagination operate as pathways of knowledge through the use of Movement as Active Imagination in clinical practice. This method activates the transcendent function, thus encouraging new therapeutic responses. A philosophical perspective (Spinoza, Nietzsche, Merleau-Ponty) and some concepts from neuroscience (embodied cognition, somatic markers, image schema, mirror neurons, neuronal plasticity) will accompany us throughout this work, illustrated with a clinical vignette. Three levels of integration: 1) body, 2) body-emotion, 3) body-emotion-imagination are proposed: these mark a progressive sense of articulation and complexity. Finally the relation between creativity and neuronal plasticity will be considered. PMID- 29504686 TI - The ethical dimension of analytical psychology. AB - The centrality of the ethical dimension in Carl Gustav Jung's analytical psychology is demonstrated through careful reference to fundamental moments in the Jungian text. Tracking Jung's statements about the primacy of the 'moral function' (or 'moral factor') in the cure of neurosis as well as in the process of individuation, the ethical nature of the psychotherapeutic praxis proposed by Jung is highlighted. This allows us to see the ethical aspect of psychological conflicts, and thus to understand better why individuation can be seen as a 'moral achievement'. Finally, the intelligible ethical structure of Jungian psychotherapeutic praxis is exposed. PMID- 29504687 TI - Traumatic dissociation of aspects of the feminine: an Asian cultural perspective. AB - The paper explores the impact of the dissociated feminine principle resulting from the trauma of cultural displacement in a young Chinese woman keen to embrace a modern Western identity. A case study illustrates the outcome of the client both consciously and unconsciously rejecting the traditional stereotypical Chinese feminine identity and instead embracing the distorted, yet seductive, image of the Western (Caucasian) woman as independent, intellectual and confident. Her defensive denial of the traditional feminine was dealt with by intellectualising both personal and professional relationships. Then, unconsciously, the dissociated traditional feminine was projected into a separate aspect of her identity that held the traumatised feelings. The intellectualisation was eventually understood as being a necessary defence to cope with the cultural as well as geographical dislocation trauma. And with this realisation a space was created to accept and integrate the denied feminine-in a literal as well as a symbolic manner. PMID- 29504688 TI - The Importance of Racial Socialization: School-Based Racial Discrimination and Racial Identity Among African American Adolescent Boys and Girls. AB - This study examined various parental racial socialization messages as mediators between school-based racial discrimination and racial identity formation over 4 years for African American boys (N = 639) and African American girls (N = 711). Findings indicated that school-based racial discrimination was associated with racial identity beliefs. For African American boys, behavioral racial socialization messages mediated the relation between school-based racial discrimination and racial centrality over time. Mediation also resulted for African American girls, but for a different set of race-related messages (negative messages and racial barriers) and racial identity beliefs. The developmental significance of the findings and implications for future research are discussed. PMID- 29504689 TI - Clinical aspects of the three major genetic forms of long QT syndrome (LQT1, LQT2, LQT3). AB - BACKGROUND: A comprehensive report on the clinical course of the three major genotypes of the long QT syndrome (LQTS) in a large U.S. patient cohort is lacking. METHODS: Our study consisted of 1,923 U.S. subjects from the Rochester based LQTS Registry with genotype-positive LQT1 (n = 879), LQT2 (n = 807), and LQT3 (n = 237). We evaluated the risk of a first cardiac event (syncope, aborted cardiac arrest, or sudden cardiac death, whichever occurred first) from birth through age 50 years. Cox proportional hazards regression models incorporating clinical covariates were used to assess genotype-specific risk of cardiac events. RESULTS: For all three genotypes, the cumulative probability of a first cardiac event increased most markedly during adolescence. Multivariate analysis identified proband status and QTc > 500 ms as predictors of cardiac events in all three genotypes, and males <14 years and females >14 years as predictors of cardiac events in LQT1 and LQT2 only. Beta-blockers significantly reduced the risk of cardiac events in LQT1 (HR: 0.49, p = .002) and LQT2 patients (HR: 0.48, p = .001). A trend toward beta-blocker benefit in reducing cardiac events was found in LQT3 females (HR: 0.32, p = .078), but not in LQT3 males (HR: 1.37, p = .611). CONCLUSION: Risk factors and outcomes in LQTS patients varied by genotype. In all three genotypes, proband status and prolonged QTc were risk factors for cardiac events. Younger males and older females experienced increased risk in LQT1 and LQT2 only. Beta-blockers were most effective in reducing cardiac events in LQT1 and LQT2, with a potential benefit in LQT3 females. PMID- 29504690 TI - A retrospective evaluation of patients with mechanical ocular trauma in a Danish emergency room without ophthalmic assistance. PMID- 29504691 TI - Axial vs. Equatorial Ligand Rivalry in Controlling the Reactivity of Iron(IV)-Oxo Species: Single-State vs. Two-State Reactivity. AB - High-valent iron-oxo species are known for their very high reactivity, and this aspect has been studied in detail over the years. The role of axial ligands in fine-tuning the reactivity of the iron(IV)-oxo species has been particularly well studied. The corresponding role of equatorial ligands, however, has rarely been explored, and is of prime importance in the development of non-heme chemistry. Here, we have undertaken detailed DFT calculations on [(LNHC )FeIV (O)(CH3 CN)]2+ (1; LNHC =3,9,14,20-tetraaza1,6,12,17-tetraazoniapenta-cyclohexacosane 1(23),4,6(26),10,12(25),15,17(24),21-octaene) in comparison to compound II of cytochrome P450 [(porphyrin)FeIV (O)(SH)]- (2) to probe this aspect. The electronic structures of 1 and 2 are found to vary significantly, implying a large variation in their reactivities. In particular, the strong equatorial ligand present in 1 significantly destabilizes the quintet states as compared to species 2. To fully understand the reactivity pattern of these species, we have modelled the hydroxylation of methane by both 1 and 2. Our calculations reveal that 1 reacts via a low-lying S=1 pi pathway, and that the generally available S=2 sigma pathway is not energetically accessible. In addition to having a significant barrier for C-H bond activation, the -OH rebound step is also computed to have a large barrier height, leading to a marked difference in reactivity between these two species. Of particular relevance here is the observation of pure triplet-state reactivity for 1. We have also attempted to test the role of axial ligands in fine-tuning the reactivity of 1, and our results demonstrate that, in contrast to heme systems, the axial ligands in 1 do not significantly influence the reactivity. This highlights the importance of designing equatorial ligands to fine-tune reactivity of high-valent iron(IV)-oxo species. PMID- 29504692 TI - Efficacy of ledipasvir/sofosbuvir with or without ribavirin for 12 weeks in genotype 1b HCV patients previously treated with a nonstructural protein 5A inhibitor-containing regimen. AB - AIM: The therapeutic benefit of adding ribavirin (RBV) to 12 weeks of ledipasvir/sofosbuvir (LDV/SOF) for patients who experienced failure of a previous nonstructural protein (NS) 5A inhibitor-containing regimen is unclear. METHODS: A total of 29 genotype 1b HCV patients who had failed prior daclatasvir (DCV) plus asunaprevir (ASV) treatment were retreated for 12 weeks of LDV/SOF, with or without RBV. Antiviral efficacy and predictive factors associating with a sustained virological response at 24 weeks (SVR24) were evaluated retrospectively. RESULTS: SVR24 was achieved in 67% (10/15) of patients who received LDV/SOF with, and 64% (9/14) without, RBV. The SVR24 rates were 80% in patients with, and 58% without, mild fibrosis (FIB-4 < 3.25). The SVR24 rate was lower with unfavorable IL28B rs8099917 SNP genotypes; specifically, the TT, TG and GG had SVR24 rates of 78%, 50% and 40%. The SVR24 rate was lower with a poor response to prior DCV plus ASV, where relapse, viral breakthrough and no response had SVR24 rates 71%, 58% and 0%. The SVR24 rate was lower with the number of NS5A resistance-associated substitutions (RAS), where 2, 3, 4 and 5 RAS had SVR24 rates of 78%, 67%, 50% and 0%. A patient with an NS5A-P32 deletion, which shows resistance to next-generation NS5A inhibitors, was retreated with LDV/SOF with RBV and achieved SVR24. CONCLUSIONS: The addition of RBV to 12 weeks of LDV/SOF has little therapeutic benefit when retreating patients in whom a prior NS5A inhibitor-containing regimen had failed. PMID- 29504693 TI - Effective Protection on Acute Liver Injury by Halo Tag-Flanked Recombinant Fibroblast Growth Factor 7. AB - The drug development of FGF7 has been restricted by its toxicity to the host, low expression, poor stability, and easy degradation. Recent studies have shown that Halo-tag-flanked recombinant human FGF7 can solve the problem of toxicity; however, its biological activity is unknown. This study aimed to explore the activity of Halo-rhFGF7 and rhFGF7 on acute liver injury in vitro and in vivo. The rhFGF7 is expressed with a N-terminal Halo-tag, followed by a tobacco etch virus (TEV) protease cleavage site, in Escherichia coli BL21 (DE3) pLysS in this study. The products could stimulate the proliferation of carbon tetrachloride damaged L-O2 cells (normal human liver cells); they also inhibited cell apoptosis. Due to the use of the Halo, the protein could be tracked using fluorescence localization. Recombinant protein exerted a protective effect on the acute liver injury model in vitro and in vivo. The MTT assay and Western blot analysis showed that this protective effect is realized through various paths, including promoting proliferation, inhibiting cell apoptosis and anti inflammatory. In conclusion, Halo-rhFGF7 and rhFGF7 displayed an excellent protective effect on acute liver injury. The present study provided an experimental basis and data support for further research on rhFGF7. PMID- 29504695 TI - Use of Dicloxacillin and Risk of Pregnancy among Users of Oral Contraceptives. AB - The antibiotic dicloxacillin has been shown to induce drug-metabolizing CYP enzymes to a clinically relevant extent. In this study, we investigated whether the use of dicloxacillin confers an increased risk of unwanted pregnancy among oral contraceptive users. The study population comprised Danish women falling pregnant (1997-2015) during oral contraceptive use, defined as having filled a prescription for an oral contraceptive within 120 days both before and after the estimated date of conception. Data were analysed using a case-crossover approach. For each woman, we assessed the use of dicloxacillin preceding the date of conception and during 10 previous control periods and estimated the odds ratio for such unintended pregnancies associated with the use of dicloxacillin. Among 364 women using dicloxacillin prior to conception, 40 (11%) were exposed to dicloxacillin at the time of conception, yielding an odds ratio (OR) associating use of dicloxacillin to unintended pregnancy of 1.18 (95% CI 0.84-1.65). Supplementary and sensitivity analyses generally returned similar estimates, except for a slightly increased risk among users of progestogen-only oral contraceptives (OR 1.83, 95% CI 0.63-5.34). Analysis of other antibiotics as negative controls yielded results close to unity (ORs ranging from 0.83 to 1.13). In conclusion, our study found no evidence for an increased risk of oral contraceptive failure when using dicloxacillin. However, acknowledging study limitations, we suggest the use of supplementary barrier methods during treatment with dicloxacillin, until our findings are confirmed in further studies. PMID- 29504696 TI - Clara Immerwahr Award: T. L. Lohr / Head of the Chemical Division, Hungarian Academy of Sciences: F. Fulop / JSPS 141st Committee on Microbeam Analysis Award: H.-J. Freund / Distinguished Scientist, Chinese Academy of Sciences: M. T. Reetz. PMID- 29504697 TI - Bacterial Vaginosis. PMID- 29504694 TI - Glyoxalase 1 sustains the metastatic phenotype of prostate cancer cells via EMT control. AB - Metastasis is the primary cause of death in prostate cancer (PCa) patients. Effective therapeutic intervention in metastatic PCa is undermined by our poor understanding of its molecular aetiology. Defining the mechanisms underlying PCa metastasis may lead to insights into how to decrease morbidity and mortality in this disease. Glyoxalase 1 (Glo1) is the detoxification enzyme of methylglyoxal (MG), a potent precursor of advanced glycation end products (AGEs). Hydroimidazolone (MG-H1) and argpyrimidine (AP) are AGEs originating from MG mediated post-translational modification of proteins at arginine residues. AP is involved in the control of epithelial to mesenchymal transition (EMT), a crucial determinant of cancer metastasis and invasion, whose regulation mechanisms in malignant cells are still emerging. Here, we uncover a novel mechanism linking Glo1 to the maintenance of the metastatic phenotype of PCa cells by controlling EMT by engaging the tumour suppressor miR-101, MG-H1-AP and TGF-beta1/Smad signalling. Moreover, circulating levels of Glo1, miR-101, MG-H1-AP and TGF-beta1 in patients with metastatic compared with non-metastatic PCa support our in vitro results, demonstrating their clinical relevance. We suggest that Glo1, together with miR-101, might be potential therapeutic targets for metastatic PCa, possibly by metformin administration. PMID- 29504698 TI - Highly Emissive Fused Heterocyclic Alkynylgold(III) Complexes for Multiple Color Emission Spanning from Green to Red for Solution-Processable Organic Light Emitting Devices. AB - A new class of fused heterocyclic tridentate ligand-containing alkynylgold(III) complexes with tunable emission color has been successfully designed and synthesized. Structural modification of the sigma-donating fused heterocyclic alkynyl ligands, including substituted fluorene, carbazole, and triphenylamine, enables a large spectral shift of about 110 nm (ca. 3310 cm-1 ) that covers the green to red region to be realized with the same tridentate ligand-containing alkynylgold(III) complexes in solid-state thin films. Interestingly, the energy of the excimeric emission can be controlled by the rational design of the fused heterocyclic alkynyl ligands. Superior solution-processable organic light emitting devices (OLEDs) with high external quantum efficiencies (EQEs) of 12.2, 13.5, 9.3, and 5.2 % were obtained with green, yellow, orange, and red emission. These high EQE values are comparable to those of the vacuum-deposited OLEDs based on structurally related alkynylgold(III) complexes. PMID- 29504699 TI - Frequency of Respiratory Nursing Diagnoses and Accuracy of Clinical Indicators in Preterm Infants. AB - PURPOSE: To identify the frequency of the nursing diagnoses, ineffective breathing pattern, impaired gas exchange and impaired spontaneous ventilation in newborns; and, to analyze the accuracy of diagnostic indicators identified for each of these diagnoses. METHODS: This was a cross-sectional study conducted with a nonprobability sample of 92 infants. Data collected were represented by demographic and clinical variables, clinical indicators of the three respiratory nursing diagnoses from NANDA International, and were analyzed according to frequency and agreement between pairs of expert nurses (Kappa). FINDINGS: Ineffective breathing pattern was identified in 74.5% of infants; impaired gas exchange was noted in 31.5%; impaired spontaneous ventilation was found in 16.8% of subjects. Use of accessory muscles to breathe showed the highest sensitivity for ineffective breathing pattern; abnormal blood gases had the best predictive value for impaired gas exchange. Use of accessory muscles to breathe had the highest sensitivity for impaired spontaneous ventilation. CONCLUSIONS: Ineffective breathing pattern was the most frequently identified; use of accessory muscles, alteration in depth of breathing, abnormal breathing, and dyspnea were the most representative signs/symptoms. IMPLICATION FOR NURSING PRACTICE: Early recognition of respiratory conditions can support safe interventions to ensure appropriate outcomes. PMID- 29504700 TI - Site-Directed Dimerization of Bowl-Shaped Radical Anions to Form a sigma-Bonded Dibenzocorannulene Dimer. AB - Designed site-directed dimerization of the monoanion radicals of a pi-bowl in the solid state is reported. Dibenzo[a,g]corannulene (C28 H14 ) was selected based on the asymmetry of the charge/spin localization in the C28 H14.- anion. Controlled one-electron reduction of C28 H14 with Cs metal in diglyme resulted in crystallization of a new dimer, [{Cs+ (diglyme)}2 (C28 H14 -C28 H14 )2- ] (1), as revealed by single crystal X-ray diffraction study performed in a broad range of temperatures. The C-C bond length between two C28 H14.- bowls (1.560(8) A) measured at -143 degrees C does not significantly change upon heating of the crystal to +67 degrees C. The single sigma-bond character of the C-C linker is confirmed by calculations. The trans-disposition of two bowls in 1 is observed with the torsion angles around the central C-C bond of 172.3(5) degrees and 173.5(5) degrees . A systematic theoretical evaluation of dimerization pathways of C28 H14.- radicals confirmed that the trans-isomer found in 1 is energetically favored. PMID- 29504702 TI - Wolf Prize in Chemistry: M. Fujita and O. M. Yaghi / Albrecht Kossel Prize: A. Beck-Sickinger. PMID- 29504703 TI - Fine versus coarse atrial fibrillation in rheumatic mitral stenosis: The impact of aging and the clinical significance. AB - BACKGROUND: Atrial fibrillation (AF) as the most rhythm disturbance in patients with rheumatic mitral stenosis (MS), is classified in to coarse and fine subtypes according to the height of fibrillatory wave amplitude. The aim of this study is to identify the factors associated with the presence of fine versus coarse morphology in patients with rheumatic MS. METHODS: In this cross-sectional study, patients with confirmed diagnosis of severe rheumatic MS admitted between March 2013 and March 2017 were screened. Patients were categorized to sinus rhythm (SR) and AF rhythm (coarse and fine subtypes) groups according to the admission electrocardiogram. The association between various clinical and echocardiographic factors and the development of fine versus coarse AF were examined. RESULTS: Among 754 patients with the diagnosis of rheumatic MS, 288 (198 female) were found to have AF (38%). Among them 206 (71.5%), and 82 (28.5%) patients had fine and coarse morphology respectively. Patient in these two groups were quite similar in terms of echocardiographic parameters and comorbidities. However, patients with fine morphology AF were significantly older. (p-Value=.007). CONCLUSION: Coarse morphology of AF is common in patients with rheumatic MS. While echocardiographic or most clinical parameters do not seem to associate with the occurrence of coarse or fine morphology, age seems to be the only independent factor correlated with the presence of fine subtype of AF in this population. PMID- 29504701 TI - Circulating long noncoding RNA act as potential novel biomarkers for diagnosis and prognosis of non-small cell lung cancer. AB - Lung cancer is the first leading cause of cancer deaths worldwide. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Increasing evidence shows that long noncoding RNA (lncRNA) are capable of modulating tumor initiation, proliferation and metastasis. In the present study, we aimed to evaluate whether circulating lncRNA could be used as biomarkers for diagnosis and prognosis of NSCLC. Expression profiles of 14 lncRNA selected from other studies were validated in 20 pairs of tissues by quantitative real-time PCR, and the dysregulated lncRNA thus identified were further validated in serum samples from two independent cohorts along with three tumor makers (CEA, CYFRA21-1, and SCCA). Receiver-operating characteristic analysis was utilized to estimate the diagnostic efficiency of the candidate lncRNA and tumor markers. Importantly, we observed an association between lncRNA expression and overall survival (OS) rate of NSCLC. The expressions of SOX2 overlapping transcript (SOX2OT) and ANRIL were obviously upregulated in NSCLC tissues and serum samples compared with normal controls (P < 0.01). Based on the data from the training set, we next used a logistic regression model to construct an NSCLC diagnostic panel consisting of two lncRNA and three tumor markers. The area under the curve of this panel was 0.853 (95% confidence interval = 0.804-0.894, sensitivity = 77.1%, specificity = 79.2%), and this was distinctly superior to any biomarker alone (all at P < 0.05). Similar results were observed in the validation set. Intriguingly, Kaplan Meier analysis demonstrated that low expressions of SOX2OT and ANRIL were both associated with higher OS rate (P = 0.008 and 0.017, respectively), and SOX2OT could be used as an independent prognostic factor (P = 0.036). Taken together, our study demonstrated that the newly developed diagnostic panel consisting of SOX2OT, ANRIL, CEA, CYFRA21-1, and SCCA could be valuable in NSCLC diagnosis. LncRNA SOX2OT and ANRIL might be ideal biomarkers for NSCLC prognosis. PMID- 29504704 TI - A Cross-Sectional Study to Assess the Modulation of Wnt Inhibitors following Anti Epileptic Drug Therapy and their Correlation with Vitamin D and Receptor Activator of Nuclear Factor kappa B Ligand in Indian Women with Epilepsy. AB - Long-term anti-epileptic drug (AED) therapy compromises bone health. Although vitamin D deficiency is proposed to be involved, it alone is not held responsible. This accounts for investigating other mechanisms in bone accrual. Recent studies have shown modulation of inhibitors of wnt pathway, sclerostin and dickkopf-1 (DKK-1), in glucocorticoids-induced osteoporosis. We investigated whether AED monotherapy modulates wnt inhibitors in Indian women with epilepsy. Women of age > 20-40 years with the diagnosis of epilepsy and receiving AEDs (carbamazepine, valproate and levetiracetam) for at least a year were enrolled. The results were compared with age-matched healthy controls with no evidence of metabolic bone disease. Women undergoing treatment with AEDs (mean duration: 50.59 +/- 37.929 months) exhibited higher serum sclerostin and receptor activator of nuclear factor kappa B ligand (RANKL) and lower vitamin D (25-hydroxy vitamin D) and DKK-1 levels when compared to age-matched healthy controls. Sclerostin showed a positive correlation with RANKL, while DKK-1 presented no such relationship. However, no association was evident after adjusting for age, duration of treatment and total daily dose. Although a correlation between wnt inhibitors and RANKL could not be obtained, AEDs displayed changes in serum levels of wnt inhibitors in persons with epilepsy and hence these drugs may compromise bone health through a disturbance in wnt signalling mechanisms. PMID- 29504705 TI - ABCB1 Variation Affects Myelosuppression, Progression-free Survival and Overall Survival in Paclitaxel/Carboplatin-treated Ovarian Cancer Patients. AB - The standard chemotherapy for ovarian cancer is paclitaxel/carboplatin. Patients often exhibit myelosuppressive toxicity, and the treatment response varies considerably. In this study, we investigated the previously reported SNPs 1199G>A (rs2229109), 1236C>T (rs1128503), 2677G>T/A (rs2032582), 3435C>T (rs1045642) in ABCB1, and 1196A>G (rs10509681) in CYP2C8 and their association with treatment induced myelosuppression, progression-free survival (PFS) and overall survival (OS). From the phase III study, OAS-07OVA, 525 patients (All) treated with carboplatin and paclitaxel administered as Paclical (Arm A, n = 260) or Taxol(r) (Arm B, n = 265) were included and genotyped using pyrosequencing. Genotype associations with myelosuppression, PFS and OS were investigated using anova, Kaplan-Meier analysis and Cox proportional hazard models. The most prominent finding was for the ABCB1 variant 3435TT, which was significantly associated with increased PFS in All (hazard ratio (HR) = 0.623), in Arm A (HR = 0.590) and in Arm B (HR = 0.627), as well as increased OS in All (HR = 0.443) and in Arm A (HR = 0.372) compared to the wild-type, 3435CC. For toxicity, the most interesting finding concerned the haplotype, including 1236TT, 2677TT and 3435TT, which was associated with higher neutrophil values in Arm B (p = 0.039) and less neutrophil decrease in All (p = 0.048) and in Arm B (p = 0.021). It is noteworthy that the results varied depending on the treatment arm which indicates that the effects of ABCB1 variants vary with the treatment regimen. Our results reflect the contradictory results of previous studies, confirming that small variations in the composition of treatment regimens and patient populations may influence the interpretation of SNPs effects on treatment outcome. PMID- 29504706 TI - EDITOR. PMID- 29504707 TI - EDITOR. PMID- 29504710 TI - Correction. PMID- 29504709 TI - Population collapse dynamics in Acropora downingi, an Arabian/Persian Gulf ecosystem-engineering coral, linked to rising temperature. AB - As in the tropical Atlantic, Acropora populations in the southern Persian/Arabian Gulf plummeted within two decades after having been ecosystem engineers on most wave-exposed reefs since the Pleistocene. Since 1996/1998 live coral cover in the Gulf declined by over 90% in many areas, primarily due to bleaching and diseases caused by rising temperatures. In the formerly dominant table-coral species A. downingi, population dynamics corresponding to disturbance regimes was quantified in three transition matrices (lower disturbance pre-1996; moderate disturbance from 1998 to 2010 and 2013 to 2017, disturbed in 1996/1998, 2010/11/12, 2017). Increased disturbance frequency and severity caused progressive reduction in coral size, cover, and population fecundity. Small size-classes were bolstered more by partial colony mortality than sexual recruitment. Some large corals had a size refuge and resisted die-back but were also lost with increasing disturbance. Matrix and biophysical larval flow models suggested one metapopulation. Southern, Arabian, populations could be connected to northern, Iranian, populations but this connectivity was lost under assumptions of pelagic larval duration at rising temperatures shortened to a third. Then, the metapopulation disintegrated into isolated populations. Connectivity required to avoid extinctions increased exponentially with disturbance frequency and correlation of disturbances across the metapopulation. Populations became unsustainable at eight disturbances in 15 years, when even highest theoretical recruitment no longer compensated mortality. This lethal disturbance frequency was 3-fold that of the moderately disturbed monitoring period and 4-fold of the preceding low-disturbance period-suggesting ongoing shortening of the disturbance-free period. Observed population collapse and environmental changes in the Gulf suggest that A. downingi is heading toward at least functional extinction mainly due to increasingly frequent temperature induced mortality events, clearly linked to climate change. PMID- 29504712 TI - The Curious Case of a Parasitic Twin of the Corroles. AB - An expanded porphyrinoid has been obtained by a simple ring expansion from a contracted porphyrinoid, namely corrole. Spectroscopic, structural, and computational investigations reveal peculiar pi-conjugation and geometry. The effect of extended pi-conjugation is evident from perturbed redox behavior and photophysical properties. Owing to the strong diatropic ring current of the corrole and cross-conjugation, the molecule exhibits a non-aromatic nature for the expanded pi-circuit, as evident from NMR studies. PMID- 29504713 TI - TAK1 mediates excessive autophagy via p38 and ERK in cisplatin-induced acute kidney injury. AB - The ability of cisplatin (cis-diamminedichloroplatinum II) toxicity to induce acute kidney injury (AKI) has attracted people's attention and concern for a long time, but its molecular mechanisms are still widely unknown. We found that the expression of transforming growth factor-beta (TGF-beta)-activated kinase 1 (TAK1) could be increased in kidneys of mice administrated with cisplatin. Autophagy is an evolutionarily conserved catabolic pathway and is involved in various acute and chronic injuries. Moreover, p38 MAPK (mitogen-activated protein kinase) and ERK regulate autophagy in response to various stimuli. Therefore, our hypothesis is that cisplatin activates TAK1, which phosphorylates p38 and ERK, leading to excessive autophagy of tubular epithelial cells and thus exacerbating kidney damage. Here, BALB/c mice were intraperitoneally injected with a TAK1 inhibitor and were then administrated with sham or cisplatin at 20 mg/kg by intraperitoneal injection. Compared with mice in the vehicle cisplatin group, mice intraperitoneally injected with a TAK1 inhibitor were found to have lower serum creatinine and less tubular damage following cisplatin-induced AKI. Furthermore, inhibition of TAK1 reduced p38 and Erk phosphorylation, decreased expression of LC3II and reversed the down-regulation of P62 expression induced by cisplatin. The hypothesis was verified with tubular epithelial cells administrated with cisplatin in vitro. Finally, p38 inhibitor or ERK inhibitor abated autophagy activation and cell viability reduction in tubular epithelial cells treated with cisplatin plus TAK1 overexpression vector. Taken together, our results show that cisplatin activates TAK1, which phosphorylates p38 and ERK, leading to excessive autophagy of tubular epithelial cells that exacerbates kidney damage. PMID- 29504714 TI - The Effect of Random and Block Copolymerization with Pendent Carbozole Donors and Naphthalimide Acceptors on Multilevel Memory Performance. AB - Polymeric materials have been widely used in the fabrication of data-storage devices, owing to their unique advantages and defined conduction mechanisms. To date, the most-functional polymers that have been reported for memory devices were synthesized through random copolymerization, whilst there have been no reports regarding the memory effect of block polymers. Herein, we synthesized a random copolymer (PMCz8 -co-PMBNa2 ) and its corresponding block copolymer (PMCz8 -b-PMBNa2 ) to study the effect of the method of polymerization on the memory properties of the corresponding devices. Interestingly, both devices (ITO/PMCz8 co-PMBNa2 /Al and ITO/PMCz8 -b-PMBNa2 /Al) exhibited ternary memory performance, with threshold voltages of -1.7 V/-3.3 V and -2.7 V/-3.8 V, respectively. However, based on comprehensive measurements, the memory properties of PMCz8 -co PMBNa2 and PMCz8 -b-PMBNa2 were found to be owing to the operation of different conduction mechanisms, which resulted from different molecular stacking in the film state. Therefore, we expect that this work will be helpful for improving our understanding of the conduction mechanisms in polymer-based data-storage devices. PMID- 29504715 TI - A practical introduction to Random Forest for genetic association studies in ecology and evolution. AB - Large genomic studies are becoming increasingly common with advances in sequencing technology, and our ability to understand how genomic variation influences phenotypic variation between individuals has never been greater. The exploration of such relationships first requires the identification of associations between molecular markers and phenotypes. Here, we explore the use of Random Forest (RF), a powerful machine-learning algorithm, in genomic studies to discern loci underlying both discrete and quantitative traits, particularly when studying wild or nonmodel organisms. RF is becoming increasingly used in ecological and population genetics because, unlike traditional methods, it can efficiently analyse thousands of loci simultaneously and account for nonadditive interactions. However, understanding both the power and limitations of Random Forest is important for its proper implementation and the interpretation of results. We therefore provide a practical introduction to the algorithm and its use for identifying associations between molecular markers and phenotypes, discussing such topics as data limitations, algorithm initiation and optimization, as well as interpretation. We also provide short R tutorials as examples, with the aim of providing a guide to the implementation of the algorithm. Topics discussed here are intended to serve as an entry point for molecular ecologists interested in employing Random Forest to identify trait associations in genomic data sets. PMID- 29504716 TI - Amyloid-Like Fibrillary Morphology Originated by Tyrosine-Containing Aromatic Hexapeptides. AB - Phenylalanine-based nanostructures have attracted the attention of the material science community for their functional properties. These properties strongly depend on the hierarchic organization of the nanostructure that in turn can be finely tuned by punctual chemical modifications of the building blocks. Herein, we investigate how the partial or the complete replacement of the Phe residues in PEG8 -(Phe)6 (PEG8 -F6) with tyrosines to generate PEG8 -(Phe-Tyr)3 (PEG8 -(FY)3) or PEG8 -(Tyr)6 (PEG8 -Y6) affects the structural/functional properties of the nanomaterial formed by the parental compound. Moreover, the effect of the PEG derivatization was evaluated through the characterization of the peptides without the PEG moiety (Tyr)6 (Y6) and (Phe-Tyr)3 ((FY)3). Both PEG8 -Y6 and PEG8 -(FY)3 can self-assemble in water at micromolar concentrations in beta-sheet-rich nanostructures. However, WAXS diffraction patterns of these compounds present significant differences. PEG8 -(FY)3 shows a 2D WAXS oriented fiber diffraction profile characterized by the concomitant presence of a 4.7 A meridional and a 12.5 A equatorial reflection that are generally associated with cross-beta structure. On the other hand, the pattern of PEG8 -Y6 is characterized by the presence of circles typically observed in the presence of PEG crystallization. Molecular modeling and dynamics provide an atomic structural model of the peptide spine of these compounds that is in good agreement with WAXS experimental data. Gelation phenomenon was only detected for PEG8 -(FY)3 above a concentration of 1.0 wt % as confirmed by storage (G'~100 Pa) and loss (G''~28 Pa) moduli in rheological studies. The cell viability on CHO cells of this soft hydrogel was certified to be 90 % after 24 hours of incubation. PMID- 29504717 TI - Controllably Confined ZnO on USY Zeolites (USY@ZnO/Al2 O3 ) as Efficient Lewis Acid Catalysts for Baeyer-Villiger Oxidation. AB - A ZnAl-LDHs (layered double hydroxides) phase was readily formed on the surface of a USY zeolite through a distinctive in situ growth method that benefitted from the interaction of the added Zn source and aluminum species extracted from the Al rich USY zeolite crystals. The migration of aluminum and simultaneous interaction with the external Zn source took place in one pot to form a ZnAl-LDHs phase coated on the surface of the USY crystals. Upon calcination, the ZnAl-LDHs phase was transformed into a ZnO/Al2 O3 composite that was still firmly anchored on the USY zeolite, without sacrificing the core-shell structure. The resultant USY@ZnO/Al2 O3 materials gave rise to unique Lewis acidity and hierarchical porosity, which endowed the catalyst with promising performance in the Baeyer Villiger oxidation of ketones with H2 O2 or bulky tert-butyl hydroxide as an oxidant. PMID- 29504718 TI - A Natural Glycyrrhizic Acid-Tailored Light-Responsive Gelator. AB - The construction of stimuli-responsive materials by using naturally occurring molecules as building blocks has received increasing attention owing to their bioavailability, biocompatibility, and biodegradability. Herein, a symmetrical azobenzene-functionalized natural glycyrrhizic acid (trans-GAG) was synthesized and could form stable supramolecular gels in DMSO/H2 O and MeOH/H2 O. Owing to trans-cis isomerization, this gel exhibited typical light-responsive behavior that led to a reversible gel-sol transition accompanied by a variation in morphology and rheology. Additionally, this trans-GAG gel displayed a distinct injectable self-healing property and outstanding biocompatibility. This work provides a simple yet rational strategy to fabricate stimuli-responsive materials from naturally occurring, eco-friendly molecules. PMID- 29504719 TI - The novel allele, HLA-A*11:264, was identified in a Chinese individual by sequence-based typing. AB - The novel allele, A*11:264, was identified in a Chinese individual by sequence based typing. PMID- 29504720 TI - Durvalumab in Stage III Non-Small-Cell Lung Cancer. PMID- 29504721 TI - Durvalumab in Stage III Non-Small-Cell Lung Cancer. PMID- 29504722 TI - Breast-Cancer Recurrence after Stopping Endocrine Therapy. PMID- 29504723 TI - Treating Onchocerciasis in Regions in Which Loa loa Is Endemic. PMID- 29504724 TI - [Teething: from symptomatology to practical approach]. AB - Scopo della presente trattazione e promuovere la consapevolezza del pediatra nei confronti della sintomatologia legata alla dentizione nei bambini con il supporto delle evidenze piu significative reperibili nella letteratura scientifica. Dopo la caratterizzazione dei disturbi piu comuni, con la relativa incidenza e durata nella popolazione pediatrica, e del ruolo dell'infiammazione saranno definiti i limiti delle terapie attualmente disponibili. Saranno quindi illustrate le prerogative di un medicinale omeopatico, Camilia(r) (Boiron, Francia), che interviene sull'infiammazione locale e sistemica e sulla composita fenomenologia correlata al processo di dentizione, con il vantaggio di un'azione multifunzionale ed efficace e l'assenza di effetti indesiderati o rischi di interazione con altri farmaci. PMID- 29504725 TI - More on an Unconscious Patient with a DNR Tattoo. PMID- 29504726 TI - More on an Unconscious Patient with a DNR Tattoo. PMID- 29504727 TI - More on an Unconscious Patient with a DNR Tattoo. PMID- 29504728 TI - The role of lifestyle changes in the treatment of polycystic ovary syndrome. AB - Polycystic ovary syndrome is one of the most common endocrinopathy of the reproductive age. Heterogenity of its clinical symptoms is related to the presence of a number of phenotypes of this disfunction, hence the necessity for individualized treatment is needed. A change of a lifestyle, well-balanced diet and physical activity are the most effective medical way contributing to the improvement of carbohydrate metabolism parameters and weight reduction which reactivates regular ovulation and facilitates getting pregnant. A change of diet should encompass determination for appropriate calorie requirements, content of particular macroelements as well as selection of the products with low glycemic index. Vitamin D supplemantation as well as inosital is of great importance as well. Both these ingredients are extremely effective in treating the disorders resulting from polycystic ovary syndrome. Adding them to a daily diet contributes to improving carbohydrate metabolism and reducing insulin resistance. Additionally, they accelerate weight loss, regulate menstrual cycles and enhance reinstating regular ovulation, hence facilitate to get pregnant. Together with introducing dietary changes, patients should be reminded about the crucial role of physical activity. A kind of exercises should be chosen according to a patient's preferences and be adjusted to her actual health condition. Only physical activity done with pleasure may become a healthy custom improving the effects of a proper diet. PMID- 29504729 TI - Possible etiology and treatment of amyotrophic lateral sclerosis. AB - Amyotrophic Lateral Sclerosis (ALS) is one of the most dangerous and least understood diseases with a pathophysiology that is still largely unknown. In this article we try to provide a pathophysiological explanation of the etiological, pathogenetic, and clinical aspects of ALS. After a description of the rather complicated classification of the disease, we continue with an evaluation of its clinical presentation. The bibliography reveals several suspect etiological factors including atherosclerosis, inflammation, tumors, cataracts, diabetes mellitus type 2, aging, and degeneration of the nervous system. One of the more intriguing factors involves changes associated with oxidative damage to both neurons and glial cells. It is known that astrocytes support the development of motor neurons. Oxidative damage is known to lead to the expression of stress sensitive genes, proteins, as well as inflammation of glial cells. Chronic inflammation could be a key factor in ALS since it has been linked to the death of motor neurons. Pathophysiological research has confirmed the influence of certains proteins on the prognosis of ALS. ALS is typically a proteinopathy in which proteins aggregate in motoneurons. Additionally, glutamate excitotoxicity has also been linked to ALS, with mutated superoxide dismutase (SOD1) having been shown to be responsible for familial ALS. As concerns the pathogenesis of ALS, we discussed several phenomenon such as increased levels of specific serum compounds, reduced concentrations of myelin, and changes in 5-hydroxytryptamine that could represent key indicators of the pathogenesis, prognosis, and therapy of ALS. Concerning ALS therapy; treatment with antioxidatives is potentially very important. Exposure to heavy metals is also thought to negatively influence ALS. Evidence also suggests that good nutrition is a very important factor in the treatment of ALS. From a pharmacological perspective, serotonin treatment appears to be a useful therapeutic agent. PMID- 29504730 TI - A pituitary abscess with one year follow-up after conservative treatment: A case report. AB - Pituitary abscess (PA) is a rare intrasellar infectious disease presented in less than one percent of all cases of pituitary disease.We reported a case of a 58 year-old woman with a history of type 2 diabetes (T2DM) exhibited with headaches, nasal discharge, anosmia, diabetes insipidus and hypopituitarism due to PA, she was diagnosed based on clinical presentations, endocrine examination and MRI image features. She was treated with nasal wash and antibiotic therapy without surgical intervention. She has received hormone replacement therapy for one year and her condition has gradually become stabilized. Meanwhile, the lesion of MRI image didn't become serious after one year. Conservative treatment might be an option for the patients with PA, those rejected operation or in a stable condition. PMID- 29504731 TI - Expression of matrix metalloproteinase enzymes in endometrium of women with abnormal uterine bleeding. AB - OBJECTIVES: Abnormal uterine bleeding (AUB) is caused by derangement of physiological processes of tissue growth, shedding and regeneration. It is known that interplay between metalloproteinases (MMP's) and tissue inhibitors of metalloproteinases (TIMP's) may play a crucial role in its occurrence. AIM: To define if expression of proMMP-2, MMP-2 and TIMP-1 in endometrium of women with AUB is dependent on steroid sex hormone concentration and histopathological picture. MATERIALS AND METHODS: Endometrial scraps were taken from 21 women with AUB and 19 controls. Samples were evaluated in light microscopy by a certified pathologist. Activity of proMMP-2 and MMP-2 proteins levels were evaluated by gelatin zymography and TIMP-1 by reversed zymography. The results has been correlated with serum estradiol and progesterone concentrations in linear regression model. RESULTS: Expression: of proMMP-2 in endometrium of women with AUB is correlated with estradiol concentration and inversely correlated with progesterone levels. It was significantly higher in women with dysfunctional endometrium (p<0.001). Expression of MMP-2 was highest in women with endometrial polyps and longer bleeding (p<0.01), while expression of TIMP-1 was independent from hormone concentration. CONCLUSION: Lack of correlation between proMMP-2 and MMP-2 levels suggest different pathway of their activation in AUB. ProMMP-2 is up regulated by estradiol and down regulated by progesterone while MMP-2 levels increase with the length of bleeding. PMID- 29504732 TI - Effect of the DASH-diet and salt Kardisal(r) on blood pressure in adolescents with prehypertension (Cooperative multicentre interventional study). AB - BACKGROUND: In a cooperative multi-center interventional study of 60 probands with prehypertension and normal BMIs were followed for 3 months. DESIGN: The intervention included the DASH diet for 3 months in 30 probands plus sodium limited intake using the low sodium salt Kardisal(r) (60% NaCl, 40% KCl) (group A) and the DASH diet for 3 months in 30 probands without Kardisal(r) (group B). RESULTS: In group A (n=26 probands evaluated) the systolic blood pressure (median) decreased significantly from 138 to 129 mmHg (p<0.001), while the diastolic blood pressure had a statistically non-significant decrease. In group B (n=25 probands evaluated) the SBP decreased significantly from 135 to 132 mmHg (p<0.001), and the DBP decreased significantly from 85 to 69 mmHg (p<0.001). CONCLUSION: Despite a relatively short period on the DASH diet, the intervention produced a significant decrease in the blood pressure of prehypertensive adolescents. The additional use of a low sodium salt for home cooking was not found to have any advantages over the DASH diet alone. PMID- 29504733 TI - QTc prolongation after ADHD medication. AB - OBJECTIVE: Multicenter studies have shown that cardiovascular risks of ADHD medication are extremely low. However, QTc length has been shown to be increased in smaller samples of patients or case reports after stimulant and atomoxetine medication. Based on recent studies of genetic polymorphisms associated with drug induced QTc prolongation and polymorphisms linkage to regional populations, we hypothesized that the drug-induced QTc prolongation could be a factor of particular polymorphisms linked to specific regional populations undistinguished in multicenter studies. METHODS: We included 69 patients from a region of central Slovakia, 36 patients were taking atomoxetine and 33 patients methylphenidate. QTc, heart rate, potassium levels and BMI were examined before and after 8 weeks of treatment. Therapeutic effect was measured by ADHD-RS-IV. RESULTS: We found QTc prolongation after 8 weeks of treatment both with atomoxetine and methylphenidate that was neither followed by the significant changes in BMI and potassium levels nor the significant increase of heart rate. CONCLUSION: This is the first study revealing QTc prolongation in the group of ADHD children from the same region after 8-week treatment with atomoxetine and methylphenidate, indicating the potential discrete abnormalities in cardiac functioning associated with polymorphisms in genes of dopaminergic and noradrenergic system. PMID- 29504734 TI - Estimation of vitamin D status in patients with secondary and primary hypothyroidism of different etiology. AB - BACKGROUND: Though vitamin D deficiency is a global problem with wide spectrum of severe public health consequences, inadequate vitamin D status still remains one of the most common and untreated medical conditions. Thyroid diseases, including hypothyroidism, also represent the most frequent endocrinopathies in general population. OBJECTIVES: To determine the vitamin D status in hypothyroid patients and to ascertain the status of thyroid hormone replacement. METHODS: The 25(OH)D concentrations (ECLIA) in 71 hypothyroid patients recruited in the Outpatient Clinic of Endocrinology or Department of Clinical Endocrinology were assessed. The examined group was composed of 59 subjects diagnosed with primary hypothyroidism of different etiology and 12 patients with secondary hypothyroidism. The control group included 16 healthy individuals. RESULTS: Mean serum 25(OH)D concentration in healthy volunteers was significantly lower than in hypothyroid subjects (13.09+/-1.63 vs. 19.92+/-1.37 ng/mL). Patients with a history of thyroidectomy presented with significantly higher mean 25(OH)D concentration than controls (23.25+/-2.75 vs. 13.09+/-1.63 ng/mL). Mean serum 25(OH)D concentration in effectively treated hypothyroidism was significantly higher than in controls (21.90+/-1.47 vs. 13.09+/-1.63 ng/mL) or undertreated hypothyroidism (21.90+/-1.47 vs. 13.52+/-3.39 ng/mL). Hypothyroid patients aged under 60 years presented with significantly lower mean 25(OH)D concentration than elders (16.46+/-1.54 vs. 24.39+/-1.18 ng/mL). The major 25(OH)D deficient (<=10 ng/mL) or deficient (<=20 ng/mL) hypothyroid patients were significantly younger than those with 25(OH)D concentrations exceeding 10 ng/mL or 20 ng/mL respectively. CONCLUSIONS: These findings confirm the necessity for vitamin D status improvement in the general population and more effective healthcare of hypothyroid patients. PMID- 29504735 TI - Does autoimmunity play a role in the risk of implantation failures? AB - 158 non-pregnant women with recurrent implantation failures after IVF/ET procedures were tested for peripheral blood autoimmune profile. The control group consisted of 76 patients after first successful IVF procedure and pregnancy outcome. The objective of this study was to investigate different autoantibodies peripheral blood profile after excluding anatomical, endocrinological, endometrial and genetic disorders and to estimate the risk of implantation failures. The study's including criteria were 1.indications for IVF/ET determined by male factor and unexplained infertility 2. absence of implantation after two consecutive cycles of IVF, ICSI or frozen embryo replacement cycles. The presence of ANA in the sera increased the risk of RIF after ET/IVF procedures, especially in older patients. Patients with RIF have a higher frequency of the presence of autoantibodies ACA IgG, IgM and anti-beta2GP I IgG in the sera than in patients with successful pregnancies after IVF/ET procedures. PMID- 29504736 TI - Anxiolytic effects of venlafaxine/olanzapine combination in treatment of anxious depression. AB - OBJECTIVE: Both venlafaxine and olanzapine have been previously found to have anxiolytic properties, however no study examined the effect of their combination on anxiety in anxious MDD. The aim of this study was to reveal if and when venlafaxine/olanzapine combination (VOC) can reduce the anxiety and depressive symptoms in patients with severe MDD at the level of patients with moderate severe depression treated with venlafaxine monotherapy. METHODS: Fifty seven patients were included into the study. Symptoms of depression were objectively assessed by Montgomery-Asberg Depression Rating Scale and subjectively scored by BECK Depression scale, symptoms of anxiety were objectively assessed by Hamilton Anxiety scale and subjectively evluated by ZUNG Self-Rating Anxiety scale before treatment and after each following week untill the fourth week of treatment. RESULTS: VOC eliminated the pre-treatment score differences in all the scales within the first week of treatment. At the third week, VOC group had significantly lower level of anxiety symptoms and the effect maintained through the fourth week of medication. CONCLUSION: Our results indicate that VOC could replace another anxiolytic medication in managing the symptoms of anxiety in patients with severe anxious MDD already within the first week of treatment. PMID- 29504737 TI - Anxiety disorders and marital satisfaction. AB - OBJECTIVES: Anxiety disorders can be a burden for the patient and his family. They affect the family everyday functioning, require greater demands on adaptation and re-evaluation of the existing habits of family members and consequently may result in family dysfunction due to anxiety disorders, especially in marital relationship or partnership. However, the knowledge about the impact of anxiety disorders on one or both partners in marital or partner life is still limited. METHOD: The relevant studies were identified through the Web of Science, PubMed, and Scopus databases, within the period 1990-2017. Additional references were found using reviews of relevant articles. The search terms included "anxiety disorders,""marital problems," "marital conflicts," "partnership," "family functioning," and "communication." RESULTS: Dissatisfaction in a relationship can act as a trigger for the development of anxiety disorders and could also be responsible for the modulation and maintenance of these disorders. However, this dissatisfaction may also be the consequence of manifestation of the anxiety disorders. The individuals with the anxiety may feel guilty about their partners because of the tolerance and help (does not matter what kind and quality of the help he/she provides), sometimes they are submissively grateful because of the support, they may feel inferior, tend to serve him /her. On the other hand, he/she begins to rebuke partner's supposed negative attitudes; the patient may start to use his psychological problems as an excuse and expects others to help him and solve the situation. Consequently, he /she starts to check and criticize the partner and this tense situation may lead to problems in marriage and disturbs family functioning. CONCLUSION: Distress elements that contribute to the development of anxiety disorders can be diverse and sometimes it is not easy to identify so-called precipitating factors. The link between anxiety disorders and family relationships is bi-directional: psychological problems adversely affect patient relationships and attitudes of the partner towards the patient significantly affect his/her anxiety. PMID- 29504738 TI - Insurer-Provider Networks in the Medical Care Market. AB - I use data on the hospital networks offered by managed care health insurers toestimate the expected division of profits between insurers and providers. I includea simple profit-maximization framework and an additional effect: hospitals thatcan secure demand without contracting with all insurers (e.g., those most attractiveto consumers and those that are capacity constrained) may demand highprices that some insurers refuse to pay. Hospital mergers may also affect pricebargaining. I estimate that all three types of hospitals capture higher markupsthan other providers. These results provide information on the hospital investmentincentives generated by bargaining. PMID- 29504739 TI - Controllable Carrier Type in Boron Phosphide Nanowires Toward Homostructural Optoelectronic Devices. AB - The p-n junction is one important and fundamental building block of the optoelectronic age. However, electrons and holes will be severely scattered in heterostructures led by the grain boundary at the alloy interface between two dissimilar semiconductors. In this work, we present boron phosphide (BP) nanowires with artificially controllable carrier type for the fabrication of homojunctions via adjusting borane/phosphine ratio during the deposition process, both prove high crystallization with fewer impurities. The homojunctions that consist of n-type and p-type BP nanowires show apparent photovoltaic effect [external quantum efficiency ~ 10% under a ~0.4 pW light @ 600 nm] and the quenched photoluminescence within the junction area, which indicates the effective separation and transfer of photogenerated charge carriers at the interface. The achievement of controllable carrier type implemented in the same material ushers in a frontier for the design of nanoscale homojunctions toward advanced optoelectronic devices. PMID- 29504740 TI - Soft Tendril-Inspired Grippers: Shape Morphing of Programmable Polymer-Paper Bilayer Composites. AB - Nastic movements in plants that occur in response to environmental stimuli have inspired many man-made shape-morphing systems. Tendril is an exemplification serving as a parasitic grasping component for the climbing plants by transforming from a straight shape into a coiled configuration via the asymmetric contraction of internal stratiform plant tissues. Inspired by tendrils, this study using a three-dimensional (3D) printing approach developed a class of soft grippers with preprogrammed deformations being capable of imitating the general motions of plant tendrils, including bending, spiral, and helical distortions for grasping. These grippers initially in flat configurations were tailored from a polymer paper bilayer composite sheet fabricated via 3D printing a polymer on the paper substrate with different patterns. The rough and porous paper surface provides a printed polymer that is well-adhered to the paper substrate which in turn serves as a passive strain-limiting layer. During printing, the melted polymer filament is stretched, enabling the internal strain to be stored in the printed polymer as memory, and then it can be thermally released, which will be concurrently resisted by the paper layer, resulting in various transformations based on the different printed geometries. These obtained transformations were then used for designing grippers to grasp objects with corresponding motions. Furthermore, a fully equipped robotic tendril with three segments was reproduced, where one segment was used for grasping the object and the other two segments were used for forming a tendril-like twistless spring-like structure. This study further helps in the development of soft robots using active polymer materials for engineered systems. PMID- 29504741 TI - Electric Field-Assisted Orientation of Short Phosphate Glass Fibers on Stainless Steel for Biomedical Applications. AB - Structural and compositional modifications of metallic implant surfaces are being actively investigated to achieve improved bone-to-implant bonding. In this study, a strategy to modify bulk metallic surfaces by electrophoretic deposition (EPD) of short phosphate glass fibers (sPGF) is presented. Random and aligned orientation of sPGF embedded in a poly(acrylic acid) matrix is achieved by vertical and horizontal EPD, respectively. The influence of EPD parameters on the degree of alignment is investigated to pave the way for the fabrication of highly aligned sPGF structures in large areas. Importantly, the oriented sPGF structure in the coating, owing to the synergistic effects of bioactive composition and fiber orientation, plays an important role in directional cell migration and enhanced proliferation. Moreover, gene expression of MC3T3-E1 cells cultured with different concentrations of sPGF is thoroughly assessed to elucidate the potential stimulating effect of sPGF on osteogenic differentiation. This study represents an innovative exploitation of EPD to develop textured surfaces by orientation of fibers in the macroscale, which shows great potential for directional functionalization of metallic implants. PMID- 29504742 TI - Achieving High-Performance Solution-Processed Orange OLEDs with the Phosphorescent Cyclometalated Trinuclear Pt(II) Complex. AB - Cyclometalated Pt(II) complexes can show intense phosphorescence at room temperature. Their emission properties are determined by both the organic ligand and the metal center. Whereas most of the related studies focus on tuning the properties by designing different types of organic ligands, only several reports investigate the key role played by the metal center. To address this issue, phosphorescent Pt(II) complexes with one, two, and three Pt(II) centers are designed and synthesized. With more Pt(II) centers, the cyclometalated multinuclear Pt(II) complexes display red-shifted emissions with increased photoluminescence quantum yields. Most importantly, solution-processed organic light-emitting diodes (OLEDs) with the conventional device structure using the multinuclear Pt(II) complexes as emitters show excellent performance. The controlled device based on the conventional mononuclear Pt(II) complex shows a peak external quantum efficiency, current efficiency, and power efficiency of 6.4%, 14.4 cd A-1, and 12.1 lm W-1, respectively. The efficiencies are dramatically improved to 10.5%, 21.4 cd A-1, and 12.9 lm W-1 for the OLED based on the dinuclear Pt(II) complex and to 17.0%, 35.4 cd A-1, and 27.2 lm W-1 for the OLED based on the trinuclear Pt(II) complex, respectively. To the best of our knowledge, these efficiencies are among the highest ever reported for the multinuclear Pt(II) complex-based OLEDs. PMID- 29504743 TI - Finely Tuned SnO2 Nanoparticles for Efficient Detection of Reducing and Oxidizing Gases: The Influence of Alkali Metal Cation on Gas-Sensing Properties. AB - Tin dioxide (SnO2) nanoparticles were straightforwardly synthesized using an easily scaled-up liquid route that involves the hydrothermal treatment, either under acidic or basic conditions, of a commercial tin dioxide particle suspension including potassium counterions. After further thermal post-treatment, the nanomaterials have been thoroughly characterized by Fourier transform infrared and Raman spectroscopy, powder X-ray diffraction, transmission electron microscopy, X-ray photoelectron spectroscopy, and nitrogen sorption porosimetry. Varying pH conditions and temperature of the thermal treatment provided cassiterite SnO2 nanoparticles with crystallite sizes ranging from 7.3 to 9.7 nm and Brunauer-Emmett-Teller surface areas ranging from 61 to 106 m2.g-1, acidic conditions favoring potassium cation removal. Upon exposure to a reducing gas (H2, CO, and volatile organic compounds such as ethanol and acetone) or oxidizing gas (NO2), layers of these SnO2 nanoparticles led to highly sensitive, reversible, and reproducible responses. The sensing results were discussed in regard to the crystallite size, specific area, valence band energy, Debye length, and chemical composition. Results highlight the impact of the counterion residuals, which affect the gas-sensing performance to an extent much higher than that of size and surface area effects. Tin dioxide nanoparticles prepared under acidic conditions and calcined in air showed the best sensing performances because of lower amount of potassium cations and higher crystallinity, despite the lower surface area. PMID- 29504744 TI - Printed Graphene Electrochemical Biosensors Fabricated by Inkjet Maskless Lithography for Rapid and Sensitive Detection of Organophosphates. AB - Solution phase printing of graphene-based electrodes has recently become an attractive low-cost, scalable manufacturing technique to create in-field electrochemical biosensors. Here, we report a graphene-based electrode developed via inkjet maskless lithography (IML) for the direct and rapid monitoring of triple-O linked phosphonate organophosphates (OPs); these constitute the active compounds found in chemical warfare agents and pesticides that exhibit acute toxicity as well as long-term pollution to soils and waterways. The IML-printed graphene electrode is nano/microstructured with a 1000 mW benchtop laser engraver and electrochemically deposited platinum nanoparticles (dia. ~25 nm) to improve its electrical conductivity (sheet resistance decreased from ~10 000 to 100 Omega/sq), surface area, and electroactive nature for subsequent enzyme functionalization and biosensing. The enzyme phosphotriesterase (PTE) was conjugated to the electrode surface via glutaraldehyde cross-linking. The resulting biosensor was able to rapidly measure (5 s response time) the insecticide paraoxon (a model OP) with a low detection limit (3 nM), and high sensitivity (370 nA/MUM) with negligible interference from similar nerve agents. Moreover, the biosensor exhibited high reusability (average of 0.3% decrease in sensitivity per sensing event), stability (90% anodic current signal retention over 1000 s), longevity (70% retained sensitivity after 8 weeks), and the ability to selectively sense OP in actual soil and water samples. Hence, this work presents a scalable printed graphene manufacturing technique that can be used to create OP biosensors that are suitable for in-field applications as well as, more generally, for low-cost biosensor test strips that could be incorporated into wearable or disposable sensing paradigms. PMID- 29504745 TI - Alkyne-DNA-Functionalized Alloyed Au/Ag Nanospheres for Ratiometric Surface Enhanced Raman Scattering Imaging Assay of Endonuclease Activity in Live Cells. AB - A novel ratiometric surface-enhanced Raman scattering (SERS) nanosensor has been developed to probe the activity of endonuclease under in vitro and in living cells conditions. The optimized alloyed Au/Ag nanoparticles (NPs) were synthesized as the SERS substrate, which combined the superior properties of both pure Au and pure Ag nanoparticles: they exhibit excellent plasmonic property with high chemical stability and low cytotoxicity. They were then employed for quantitative detection of endonuclease through functionalization with single stranded DNA (ssDNA) carrying 3-[4-(phenylethynyl)benzylthio]propanoic acid (PEB) as endonuclease-responsive SERS signaling molecule and 4-thiophenylacetylene (TPA) as the internal standard SERS signaling molecule. In the presence of endonuclease, the ssDNA was cleaved, releasing PEB molecules from the particle surface and decreasing the SERS signal at 2215 cm-1 from PEB. Since the SERS signal at 1983 cm-1 from alkynyl TPA remained the same, quantitative detection of endonuclease was achieved, based on the ratiometric peak intensity of I1983/ I2215, with a detection limit as low as 0.056 unit/mL. A highly biocompatible and antijamming ratiometric SERS sensor was established by combining the alloyed Au/AgNPs with two unique alkynes molecules with Raman signals in the cellular silent region. The ratiometric sensor was successfully employed to detect intracellular endonuclease activity as well as endonuclease in living cells for the first time. PMID- 29504746 TI - Glycosides of the Neurotoxin Tutin in Toxic Honeys Are from Coriaria arborea Phloem Sap, Not Insect Metabolism. AB - Some honeys contain the neurotoxin tutin (1) plus hyenanchin (2), 2-(beta-d glucopyranosyl)tutin (3), and 2-[6'-(alpha-d-glucopyranosyl)-beta-d glucopyranosyl]tutin (4). These honeys are made by bees collecting honeydew from passionvine hoppers feeding on the sap of tutu plants ( Coriaria spp.). We report a LC-MS study showing that all these picrotoxanes are of plant, not insect, origin. Hyenanchin was barely detectable and the diglucoside was not detectable in C. arborea leaves, but tutu phloem sap contained all four compounds at concentrations up to the highest found in honeydew. It is proposed that the diglucoside may function as a transport form of tutin, analogous to sucrose transport in phloem. PMID- 29504747 TI - Molecular Dynamics Study of Combustion Reactions in Supercritical Environment. Part 3: Boxed MD Study of CH3 + HO2 -> CH3O + OH Reaction Kinetics. AB - The kinetics of reaction CH3 + HO2 -> CH3O + OH in supercritical carbon dioxide media at pressures from 0.3 to 1000 atm in the temperature range (600-1600) K was studied using boxed molecular dynamics simulations at QM/MM theory level with periodical boundary conditions. The mechanism of this process includes two consecutive steps: formation and decomposition of CH3OOH intermediate. We calculated the activation free energies and rate constants of each step, then used Bodenstein's quasistationary concentrations approximation to estimate the rate constants of the reaction. On the basis of the temperature dependence of the rate constants, parameters in the extended Arrhenius equation were determined. We found that reaction rate of each step, as well as overall reaction, increases with increasing CO2 pressure in the system. The most effective zone for the process is T = 1000-1200 K, and the CO2 pressure is about 100 atm. PMID- 29504748 TI - Hydronium-Induced Switching between CO2 Electroreduction Pathways. AB - Over a broad range of operating conditions, many CO2 electroreduction catalysts can maintain selectivity toward certain reduction products, leading to materials and surfaces being categorized according to their products; here we ask, is product selectivity truly a property of the catalyst? Silver is among the best electrocatalysts for CO in aqueous electrolytes, where it reaches near-unity selectivity. We consider the hydrogenations of the oxygen and carbon atoms via the two proton-coupled-electron-transfer processes as chief determinants of product selectivity; and find using density functional theory (DFT) that the hydronium (H3O+) intermediate plays a key role in the first oxygen hydrogenation step and lowers the activation energy barrier for CO formation. When this hydronium influence is removed, the activation energy barrier for oxygen hydrogenation increases significantly, and the barrier for carbon hydrogenation is reduced. These effects make the formate reaction pathway more favorable than CO. Experimentally, we then carry out CO2 reduction in highly concentrated potassium hydroxide (KOH), limiting the hydronium concentration in the aqueous electrolyte. The product selectivity of a silver catalyst switches from entirely CO under neutral conditions to over 50% formate in the alkaline environment. The simulated and experimentally observed selectivity shift provides new insights into the role of hydronium on CO2 electroreduction processes and the ability for electrolyte manipulation to directly influence transition state (TS) kinetics, altering favored CO2 reaction pathways. We argue that selectivity should be considered less of an intrinsic catalyst property, and rather a combined product of the catalyst and reaction environment. PMID- 29504749 TI - Radium Sorption to Iron (Hydr)oxides, Pyrite, and Montmorillonite: Implications for Mobility. AB - Radium (Ra) is a radioactive element commonly found within soils, sediments, and natural waters. Elevated Ra activities arising through natural and anthropogenic processes pose a threat to groundwater resources and human health, and Ra isotope ratios are used to decipher groundwater movement, estimate submarine discharge flux, and fingerprint contamination associated with hydraulic fracturing operations. Although adsorption to metal (hydr)oxides and certain clay minerals is well established as a dominant mechanism controlling Ra transport and retention, the extent of Ra sorption to other minerals and under variable environmental conditions (e.g., pH and salinity) is limited. Accordingly, we present results of sorption studies and surface complexation modeling (SCM) of Ra to ferrihydrite, goethite, montmorillonite, and pyrite, for a range of pH values and common background cations. Ra sorption to all substrates is observed under geochemical conditions considered, but varies according to mineral, solution pH and specific competing cations. Literature derived SCMs for Ra sorption were fitted to match either sorption impacts due to pH or different background cations, but were not able to predict the impacts of different geochemical conditions. Despite this, the use of SCMs provided a more mechanistic understanding of Ra sorption as compared to commonly used distribution coefficients. PMID- 29504750 TI - FT-IR Spectroscopic Imaging of Endothelial Cells Response to Tumor Necrosis Factor-alpha: To Follow Markers of Inflammation Using Standard and High Magnification Resolution. AB - Two endothelial cell lines were selected as models to investigate an effect of incubation with cytokine tumor necrosis factor type alpha (TNF-alpha) using Fourier transform infrared (FT-IR) imaging spectroscopy. Both cell lines are often used in laboratories and are typical lung vascular endothelial cells (HMLVEC) derived from the fusion of umbilical vein endothelial cells with lung adenocarcinoma cells (EA.hy926). This study was focused on alteration of spectral changes accompanying inflammation at the cellular level by applying two resolution systems of FT-IR microscopy. The standard approach, with a pixel size of ca. 5.5 MUm2, determined the inflammatory state of the whole cell, while a high-magnification resolution (pixel size of ca. 1.1 MUm2) provided information at the subcellular level. Importantly, the analysis of IR spectra recorded with different modes produced similar results overall and yielded unambiguous classification of inflamed cells. Generally, the most significant changes in the cells under the influence of TNF-alpha are related with lipids-their composition and concentration; however, segregation of cells into subcellular compartments provided an additional insight into proteins and nucleic acids related events. The observed spectral alterations are specific for the type of endothelial cell line. PMID- 29504751 TI - On-Column Dimethylation with Capillary Liquid Chromatography-Tandem Mass Spectrometry for Online Determination of Neuropeptides in Rat Brain Microdialysate. AB - We have developed a method for online collection and quantitation of neuropeptides in rat brain microdialysates using on-column dimethylation with capillary liquid chromatography-tandem mass spectrometry (cLC-MS2). This method addresses a number of the challenges of quantifying neuropeptides with cLC-MS. It is also a completely automated and robust method for the preparation of stable isotope labeled-peptide internal standards to correct for matrix effects and thus ensure accurate quantitation. Originally developed for tissue-derived proteomics samples ( Raijmakers et al. Mol. Cell. Proteomics 2008 , 7 , 1755 - 1762 ), the efficacy of on-column dimethylation for native peptides in microdialysate has not been demonstrated until now. We have modified the process to make it more amenable to the time scale of microdialysis sampling and to reduce the accumulation of nonvolatile contaminants on the column and, thus, loss of sensitivity. By decreasing labeling time, we have a temporal resolution of 1 h from sample loading to elution and our peptide detection limits are in the low pM range for 5 MUL injections of microdialysate. We have demonstrated the effectiveness of this method by quantifying basal and potassium stimulated concentrations of the neuropeptides leu-enkephalin and met-enkephalin in the rat hippocampus. To our knowledge, this is the first report of quantitation of these peptides in the hippocampus using MS. PMID- 29504752 TI - Theoretical Study of the Oxidation of Methane to Methanol by the [CuIICuII(MU O)2CuIII(7- N-Etppz)]1+ Complex. AB - The reactivity patterns of a series of trivalent copper complexes have been studied to gain a better understanding of the chemical reactions occurring at the active site of particulate methane monooxygenase (pMMO). In this study, hybrid density functional theory is used to study the oxidation of methane to methanol mediated by the [CuIICuII(MU-O)2CuIII(7- N-Etppz)]1+ complex. Reaction mechanisms in different spin states were explored. Based on the calculated free-energy profile, a mechanism is suggested for the reaction of the oxidation of methane to methanol. The first step (1 -> 2) is a hydrogen transfer to the bridged oxygen in the Cu2O2 core from the methane to form a methyl radical. The second step (2 -> 3) is the radical recombination, in which the bridged hydroxyl rotates upward and exposes the oxygen moiety toward the methyl radical to form methanol. The radical recombination step is rate-limiting, with a calculated free-energy barrier of 19.6 kcal mol-1, which is in good agreement with the experimental value of 18.4 kcal mol-1. The mixed valent bis(MU-oxo)CuIICuIII species in the Cu3O4 core is directly responsible for the C-H activation of methane. PMID- 29504753 TI - Ratiometric Fluorescent Sensor Array as a Versatile Tool for Bacterial Pathogen Identification and Analysis. AB - Rapid and reliable identification of pathogenic microorganisms is of great importance for human and animal health. Most conventional approaches are time consuming and require expensive reagents, sophisticated equipment, trained personnel, and special storage and handling conditions. Sensor arrays based on small molecules offer a chemically stable and cost-effective alternative. Here we present a ratiometric fluorescent sensor array based on the derivatives of 2-(4'- N, N-dimethylamino)-3-hydroxyflavone and investigate its ability to provide a dual-channel ratiometric response. We demonstrate that, by using discriminant analysis of the sensor array responses, it is possible to effectively distinguish between eight bacterial species and recognize their Gram status. Thus, multiple parameters can be derived from the same data set. Moreover, the predictive potential of this sensor array is discussed, and its ability to analyze unknown samples beyond the list of species used for the training matrix is demonstrated. The proposed sensor array and analysis strategies open new avenues for the development of advanced ratiometric sensors for multiparametric analysis. PMID- 29504754 TI - Noninvasive Multimodal Imaging of Osteosarcoma and Lymph Nodes Using a 99mTc Labeled Biomineralization Nanoprobe. AB - The accurate imaging of the lymph nodes represents a critical indicator for tumor staging and surgical planning (e.g., osteosarcoma). Clinically, nodal tracing using a radio-nanocolloid is often limited by the inaccessibility of real-time images and inadequate anatomical information. Herein, we present a 99mTc-labeled biomineralization nanoprobe for the advanced detection of osteosarcoma and lymph nodes with multimodal imaging. Through the exploitation of the complementary strengths of MRI/SPECT/NIR fluorescence, the fabricated nanoprobe exhibited suitable stability and biocompatibility characteristics and was shown to be able to be located in osteosarcoma. The lymphatic drainage and network in healthy mice were imaged in real-time using NIR fluorescence and SPECT/CT. Furthermore, we demonstrated that our 99mTc-biomineralization nanoprobe could be used for the high-resolution and high-sensitivity imaging analysis of lymphatic drainage in an orthotopic osteosarcoma model. Overall, the 99mTc-labeled biomineralization nanoprobe features promising characteristics to be used as an intraoperative visualization tool to aid in precise tumor imaging and nodal resection. PMID- 29504756 TI - Semiconducting Organic-Inorganic Nanodots Heterojunctions: Platforms for General Photoelectrochemical Bioanalysis Application. AB - In this study, semiconducting organic polymer dots (Pdots) and inorganic quantum dots (Qdots) were first utilized to construct the organic-inorganic nanodots heterojunction for the photoelectrochemical (PEC) bioanalysis application. Specifically, n-type CdS Qdots, p-type CdTe Qdots, and tetraphenylporphyrin (TPP) doped poly[(9,9-dioctylfluorenyl-2,7-diyl)- co-(1,4-benzo-{2,1',3}-thiadazole)] (PFBT) Pdots were fabricated, and their energy levels, that is, their valence band (VB)/conduction band (CB) or lowest unoccupied molecular orbital (LUMO)/highest occupied molecular orbital (HOMO) values, were also determined. Then, these nanodots were integrated to construct four types of p-n and p-p organic-inorganic nanodots heterojunctions, that is, CdS Qdots/TPP-doped PFBT Pdots, TPP-doped PFBT Pdots/CdS Qdots, CdTe Qdots/TPP-doped PFBT Pdots, and TPP doped PFBT Pdots/CdTe Qdots, on the transparent glass electrode. Upon light irradiation, four heterojunctions exhibited different PEC behaviors with some having prominent photocurrent enhancement. With the model molecule l-cysteine (l cys) as target, the proposed PEC sensor exhibited good performances. In brief, this work presents the first semiconducting organic-inorganic nanodots heterojunction for PEC bioanalysis application, which could be easily used as a general platform for future PEC bioanalysis building. Besides, it is expected to inspire more interest in the design, development, and implementation of various organic-inorganic heterojunctions for advanced PEC bioanalysis in the future. PMID- 29504755 TI - Composition Dependence of Water Permeation Across Multicomponent Gel-Phase Bilayers. AB - The permeability of multicomponent phospholipid bilayers in the gel phase is investigated via molecular dynamics simulation. The physical role of the different molecules is probed by comparing multiple mixed-component bilayers containing distearylphosphatidylcholine (DSPC) with varying amounts of either the emollient isostearyl isostearate or long-chain alcohol (dodecanol, octadecanol, or tetracosanol) molecules. Permeability is found to depend on both the tail packing density and hydrogen bonding between lipid headgroups and water. Whereas the addition of emollient or alcohol molecules to a gel-phase DSPC bilayer can increase the tail packing density, it also disturbed the hydrogen-bonding network, which in turn can increase interfacial water dynamics. These phenomena have opposing effects on bilayer permeability, which is found to depend on the balance between enhanced tail packing and decreased hydrogen bonding. PMID- 29504757 TI - Single-Molecule Analysis of MicroRNA and Logic Operations Using a Smart Plasmonic Nanobiosensor. AB - Analysis of biomolecules at the single-molecule level is a great challenge in molecular diagnostics, gene profiling, and environmental monitoring. In this work, we design a smart plasmonic nanobiosensor based on individual Au@Ag core shell nanocube (Au@Ag NC) modified with tetrahedron-structured DNA (tsDNA) for detecting microRNA 21 (miR-21) at the single-molecule level. An average localized surface plasmon resonance (LSPR) scattering spectral wavelength shift of approximately 0.4 nm can be obtained for a single miR-21 hybridization event on the nanobiosensor. In addition, the sensing mechanism of the individual Au@Ag NC is further verified by the three-dimensional finite-difference time-domain (3D FDTD) simulations. Notably, this system not only allows the real-time detection of miR-21 with an aM level sensitivity over a large dynamic range from 1 aM to 1 nM, but also enables DNA-based logic operations as well as biomemory by exploiting miR-21, KpnI, and StuI-responsive assays. Our study opens a unique method for single-molecule detection of biomolecules and thus holds great promise in a variety of biological and biomedical applications. PMID- 29504758 TI - Crystallization Behavior of Poly(ethylene oxide) in Vertically Aligned Carbon Nanotube Array. AB - We investigate the effect of the presence of vertically aligned multiwalled carbon nanotubes (CNTs) on the orientation of poly(ethylene oxide) (PEO) lamellae and PEO crystallinity. The high alignment of carbon nanotubes acting as templates probably governs the orientation of PEO lamellae. This templating effect might result in the lamella planes of PEO crystals oriented along a direction parallel to the long axis of the nanotubes. The presence of aligned carbon nanotubes also gives rise to the decreases in PEO crystallinity, crystallization temperature, and melting temperature due to the perturbation of carbon nanotubes to the crystallization of PEO. These effects have significant implications for controlling the orientation of PEO lamellae and decreasing the crystallinity of PEO and thickness of PEO lamellae, which have significant impacts on ion transport in PEO/CNT composite and the capacitive performance of PEO/CNT composite. Both the decreased PEO crystallinity and the orientation of PEO lamellae along the long axes of vertically aligned CNTs give rise to the decrease in the charge transfer resistance, which is associated with the improvements in the ion transport and capacitive performance of PEO/CNT composite. PMID- 29504759 TI - Strongly Quantum Confined Colloidal Cesium Tin Iodide Perovskite Nanoplates: Lessons for Reducing Defect Density and Improving Stability. AB - Within the last several years, metal halide perovskites such as methylammonium lead iodide, CH3NH3PbI3, have come to the forefront of scientific investigation as defect-tolerant, solution-processable semiconductors that exhibit excellent optoelectronic properties. The vast majority of study has focused on Pb-based perovskites, which have limited applications because of their inherent toxicity. To enable the broad application of these materials, the properties of lead-free halide perovskites must be explored. Here, two-dimensional, lead-free cesium tin iodide, (CsSnI3), perovskite nanoplates have been synthesized and characterized for the first time. These CsSnI3 nanoplates exhibit thicknesses of less than 4 nm and exhibit significant quantum confinement with photoluminescence at 1.59 eV compared to 1.3 eV in the bulk. Ab initio calculations employing the generalized gradient approximation of Perdew-Burke-Ernzerhof elucidate that although the dominant intrinsic defects in CsSnI3 do not introduce deep levels inside the band gap, their concentration can be quite high. These simulations also highlight that synthesizing and processing CsSnI3 in Sn-rich conditions can reduce defect density and increase stability, which matches insights gained experimentally. This improvement in the understanding of CsSnI3 represents a step toward the broader challenge of building a deeper understanding of Sn-based halide perovskites and developing design principles that will lead to their successful application in optoelectronic devices. PMID- 29504760 TI - Plasmon-Induced Magnetic Resonance Enhanced Raman Spectroscopy. AB - Plasmon-induced magnetic resonance has shown great potentials in optical metamaterials, chemical (bio)-sensing, and surface-enhanced spectroscopies. Here, we have theoretically and experimentally revealed (1) a correspondence of the strongest near-field response to the far-field scattering valley and (2) a significant improvement in Raman signals of probing molecules by the plasmon induced magnetic resonance. These revelations are accomplished by designing a simple and practical metallic nanoparticle-film plasmonic system that generates magnetic resonances at visible-near-infrared frequencies. Our work may provide new insights for understanding the enhancement mechanism of various plasmon enhanced spectroscopies and also helps further explore light-matter interactions at the nanoscale. PMID- 29504761 TI - Intramolecular Schmidt Reaction of Vinyl Azides with Cyclic Ketones. AB - Cyclic ketones tethered with a vinyl azide group undergo a Schmidt-hydrolysis sequence to give secondary lactams bearing a ketone side chain. Secondary lactams are obtained in a regioselective manner that is not possible in a conventional Schimdt reaction. In addition to the well-documented C-2 nucleophilicity, the N nucleophilicity of vinyl azide disclosed in this work opens a new direction for reaction invention involving vinyl azides. PMID- 29504762 TI - Cu2+ Dual-Doped Layer-Tunnel Hybrid Na0.6Mn1- xCu xO2 as a Cathode of Sodium-Ion Battery with Enhanced Structure Stability, Electrochemical Property, and Air Stability. AB - Sodium-ion batteries (SIBs) have been regarded as a promising candidate for large scale renewable energy storage system. Layered manganese oxide cathode possesses the advantages of high energy density, low cost and natural abundance while suffering from limited cycling life and poor rate capacity. To overcome these weaknesses, layer-tunnel hybrid material was developed and served as the cathode of SIB, which integrated high capacity, superior cycle ability, and rate performance. In the current work, the doping of copper was adopted to suppress the Jahn-Teller effect of Mn3+ and to affect relevant structural parameters. Multifunctions of the Cu2+ doping were carefully investigated. It was found that the structure component ratio is varied with the Cu2+ doping amount. Results demonstrated that Na+/vacancy rearrangement and phase transitions were suppressed during cycling without sacrificing the reversible capacity and enhanced electrochemical performances evidenced with 96 mA h g-1 retained after 250 cycles at 4 C and 85 mA h g-1 at 8 C. Furthermore, ex situ X-ray diffraction has demonstrated high reversibility of the Na0.6Mn0.9Cu0.1O2 cathode during Na+ extraction/insertion processes and superior air stability that results in better storage properties. This study reveals that the Cu2+ doping could be an effective strategy to tune the properties and related performances of Mn-based layer-tunnel hybrid cathode. PMID- 29504763 TI - Disulfide-Bridged Peptides That Mediate Enantioselective Cycloadditions through Thiyl Radical Catalysis. AB - An enantioselective vinylcyclopropane ring-opening/cycloaddition cascade is described. The active thiyl radical catalysts are generated in situ via UV light promoted homolysis of cystine-based dimers. Amide-functionalization of the peptide at the 4-proline position is essential for effective asymmetric induction. Stereochemical communication is dependent on steric interactions with this substituent that are enforced by H-bonding to the peptide backbone. PMID- 29504764 TI - UV-Light-Induced Vibrational Coherences: The Key to Understand Kasha Rule Violation in trans-Azobenzene. AB - We combine sub-20 fs transient absorption spectroscopy with state-of-the-art computations to study the ultrafast photoinduced dynamics of trans-azobenzene (AB). We are able to resolve the lifetime of the pipi* state, whose decay within ca. 50 fs is correlated to the buildup of the npi* population and to the emergence of coherences in the dynamics, to date unobserved. Nonlinear spectroscopy simulations call for the CNN in-plane bendings as the active modes in the subps photoinduced coherent dynamics out of the pipi* state. Radiative to kinetic energy transfer into these modes drives the system to a high-energy planar npi*/ground state conical intersection, inaccessible upon direct excitation of the npi* state, that triggers an ultrafast (0.45 ps) nonproductive decay of the npi* state and is thus responsible for the observed Kasha rule violation in UV excited trans-AB. On the other hand, cis-AB is built only after intramolecular vibrational energy redistribution and population of the NN torsional mode. PMID- 29504765 TI - Phycocyanin: One Complex, Two States, Two Functions. AB - Solar energy captured by pigments embedded in light-harvesting complexes can be transferred to neighboring pigments, dissipated, or emitted as fluorescence. Only when it reaches a reaction center is the excitation energy stabilized in the form of a charge separation and converted into chemical energy. Well-directed and regulated energy transfer within the network of pigments is therefore of crucial importance for the success of the photosynthetic processes. Using single-molecule spectroscopy, we show that phycocyanin can dynamically switch between two spectrally distinct states originating from two different conformations. Unexpectedly, one of the two states has a red-shifted emission spectrum. This state is not involved in energy dissipation; instead, we propose that it is involved in direct energy transfer to photosystem I. Finally, our findings suggest that the function of linker proteins in phycobilisomes is to stabilize one state or the other, thus controlling the light-harvesting functions of phycocyanin. PMID- 29504766 TI - Synthesis, Characterization, and Solid State Dynamic Studies of a Hydrogen Bond Hindered Steroidal Molecular Rotor with a Flexible Axis. AB - A novel steroid molecular rotor was obtained in four steps from the naturally occurring spirostane sapogenin diosgenin. The structural and dynamic characterization was carried out by solution NMR, VT X-ray diffraction, solid state 13C CPMAS, and solid state 2H NMR experiments. They allowed the identification of a fast dynamic process with a frequency of 14 MHz at room temperature, featuring a barrier to rotation Ea = 7.87 kcal mol-1. The gathered experimental evidence indicated the presence of a hydrogen bond that becomes stronger as the temperature lowers. This interaction was characterized using theoretical calculations, based on topological analyses of the electronic density and energies. In addition, combining theoretical calculations with experimental measurements, it was possible to propose a partition to Ea (~8 kcal/mol) into three contributions, that are the cost of the intrinsic rotation (~2 kcal/mol), the hydrogen bond interaction (~2 kcal/mol), and the packing effects (~2-3 kcal/mol). The findings from the present work highlight the relevance of the individual components in the function of molecular machines in the solid state. PMID- 29504767 TI - Enhanced Selectivity by Passivation: Molecular Imprints for Viruses with Exceptional Binding Properties. AB - Inspired by the recognition processes found in biology such as enzyme-substrate and antibody-antigen interactions, synthetic systems with comparable molecular recognition properties have been investigated during recent years based on molecular imprinting strategies. While materials with recognition capabilities for small molecules (i.e., with low molecular weight) have achieved substantial advancements, the synthesis of molecularly imprinted materials with virus recognition properties remains challenging to date. Likewise, protein-surface and protein-protein interactions are essential for a wide variety of biological applications in biotechnology. In biological sensor technology the coating of surfaces to prevent nonspecific adsorption interactions plays an important role. Particularly, polyethylene glycol (PEG) stands out for its high performance in preventing proteins from nonspecifically interactions. However, blocking agents such as the protein bovine serum albumin (BSA) can also be useful as unspecific binding prevention agents for passivation, without modification of the surface. Herein the influence of blocking agents as unspecific reaction components is investigated on the enhancements of selectivity from adenovirus-imprinted particles, whereas adenovirus was used as target species in molecular imprinting. Furthermore, quantitative polymerase chain reaction (qPCR) was used for the first time as virus quantification approach in this context. PMID- 29504768 TI - Pulse Packet Stochastic Model for Gastric Emptying in the Fasted State: A Physiological Approach. AB - Fasted-state gastrointestinal (GI) fluid transit is typically represented as a first-order, deterministic process (averaged and viewed as a continuous approximation). It is, however, most likely a discrete process involving fluid packets interrupted by variable time periods of little to no fluid emptying. In this report we present a physiologically based pulsed-packet gastric fluid emptying model and evaluate it with respect to recent gastrointestinal fluid volume emptying results, published gastric emptying of various dosage forms, and gastric fluid emptying as a function of GI motility. We develop the mathematical model for gastric emptying of discrete volumes emptied during intermittent pulse times of variable lengths, defined as a function of gastric motility utilizing a Poisson point process with motility-dependent intensity. We compare the simulations with observed gastric emptying results. The discrete pulse packet gastric volumetric emptying model is a more physiologically realistic mathematical model for gastric emptying, and it accounts well for the average observed emptying rates and, importantly, encompasses the variability of of observed volume and dosage form emptying rates. PMID- 29504769 TI - Determining the Partial Pressure of Volatile Components via Substrate-Integrated Hollow Waveguide Infrared Spectroscopy with Integrated Microfluidics. AB - A microfluidic system combined with substrate-integrated hollow waveguide (iHWG) vapor phase infrared spectroscopy has been developed for evaluating the chemical activity of volatile compounds dissolved in complex fluids. Chemical activity is an important yet rarely exploited parameter in process analysis and control. Access to chemical activity parameters enables systematic studies on phase diagrams of complex fluids, the detection of aggregation processes, etc. The instrumental approach developed herein uniquely enables controlled evaporation/permeation from a sample solution into a hollow waveguide structure and the analysis of the partial pressures of volatile constituents. For the example of a binary system, it was shown that the chemical activity may be deduced from partial pressure measurements at thermodynamic equilibrium conditions. The combined microfluidic-iHWG midinfrared sensor system (MUFLUID-IR) allows the realization of such studies in the absence of any perturbations provoked by sampling operations, which is unavoidable using state-of-the-art analytical techniques such as headspace gas chromatography. For demonstration purposes, a water/ethanol mixture was investigated, and the derived data was cross-validated with established literature values at different mixture ratios. Next to perturbation-free measurements, a response time of the sensor <150 s ( t90) at a recovery time <300 s ( trecovery) has been achieved, which substantiates the utility of MUFLUID-IR for future process analysis-and-control applications. PMID- 29504770 TI - 3D Digital Pathology for a Chemical-Functional Analysis of Glomeruli in Health and Pathology. AB - Determining the filtration function and biochemical status of kidney at the single glomerulus level remains hardly accessible, even from biopsies. Here, we provide evidence that IR spectro-microscopy is a suitable method to account for the filtration capacity of individual glomeruli along with related physio pathological condition. A ~4 MUm voxel resolution 3D IR image reconstruction is built from consecutive tissue sections, thus, providing a 3D IR spectrum matrix of an individual glomerulus. The filtration capacity of glomeruli was quantitatively determined after BaSO4 perfusion, and additional chemical data could be used to determined oxidative stress effects and fibrosis, thus, combining functional and biochemical information from the same 3D IR spectrum matrix. This analytical approach was applied on mice with unilateral ureteral obstruction (UUO) inducing chronic kidney disease. Compared to the healthy condition, UUO induced a significant drop in glomeruli filtration capacity (-17 +/- 8% at day 4 and -48 +/- 14% at day 14) and volume (36 +/- 10% at day 4 and 67 +/- 13% at day 14), along a significant increase of oxidative stress (+61 +/- 19% at day 4 and +84 +/- 17% at day 14) and a change in the lipid-to-protein ratio ( 8.2 +/- 3.6% at day 4 and -18.1 +/- 5.9% at day 14). Therefore, IR spectro microscopy might be developed as a new 3D pathology resource for analyzing functional and biochemical parameters of glomeruli. PMID- 29504771 TI - Enthalpic Driving Force for the Selective Absorption of CO2 by an Ionic Liquid. AB - Molecular dynamics (MD) simulations validated against two-dimensional infrared (2D-IR) measurements of CO2 in an imidazolium-based ionic liquid have revealed new insights into the mechanism of CO2 solvation. The first solvation shell around CO2 has a distinctly quadrupolar structure, with strong negative charge density around the CO2 carbon atom and positive charge density near the CO2 oxygen atoms. When CO2 is modeled without atomic charges (thus removing its strong quadrupole moment), its solvation shell weakens and changes significantly into a structure that is similar to that of N2 in the same liquid. The solvation shell of CO2 evolves more quickly when its quadrupole is removed, and we find evidence that solvent cage dynamics is measured by 2D-IR spectroscopy. We also find that the solvent cage evolution of N2 is similar to that of CO2 with no atomic charges, implying that the weaker quadrupole of N2 is responsible for its higher diffusion and lower absorption in ionic liquids. PMID- 29504772 TI - A ball is not a Kong: Odor representation and search behavior in domestic dogs (Canis familiaris) of different education. AB - There has been a growing interest in the cognitive skills of domestic dogs, but most current knowledge about dogs' understanding of their environment is limited to the visual or auditory modality. Although it is well known that dogs have an excellent olfactory sense and that they rely on olfaction heavily when exploring the environment or recognizing individuals, it remains unclear whether dogs perceive odors as representing specific objects. In the current study, we examined this aspect of dogs' perception of the world. Dogs were presented with a violation-of-expectation paradigm in which they could track the odor trail of one target (Target A), but at the end of the trail, they found another target (Target B). We explored (a) what dogs expect when they smell the trail of an object, (b) how they search for an object, and (c) how their educational background influences their ability to find a hidden object, by comparing family dogs and working dogs that had passed exams for police or rescue dogs. We found that all subjects showed a flexible searching behavior, with the working dogs being more effective but the family dogs learning to be effective over trials. In the first trial, dogs showed measurable signs of "surprise" (i.e., further searching for Target A) when they found Target B, which did not correspond to the odor of Target A from the trail. We conclude that dogs represent what they smell and search flexibly, which is independent from their educational background. (PsycINFO Database Record PMID- 29504773 TI - Greater effort increases perceived value in an invertebrate. AB - Expending effort is generally considered to be undesirable. However, both humans and vertebrates will work for a reward they could also get for free. Moreover, cues associated with high-effort rewards are preferred to low-effort associated cues. Many explanations for these counterintuitive findings have been suggested, including cognitive dissonance (self-justification) or a greater contrast in state (e.g., energy or frustration level) before and after an effort-linked reward. Here, we test whether effort expenditure also increases perceived value in ants, using both classical cue-association methods and pheromone deposition, which correlates with perceived value. In 2 separate experimental setups, we show that pheromone deposition is higher toward the reward that requires more effort: 47% more pheromone deposition was performed for rewards reached via a vertical runway (high effort) compared with ones reached via a horizontal runway (low effort), and deposition rates were 28% higher on rough (high effort) versus smooth (low effort) runways. Using traditional cue-association methods, 63% of ants trained on different surface roughness, and 70% of ants trained on different runway elevations, preferred the high-effort related cues on a Y maze. Finally, pheromone deposition to feeders requiring memorization of one path bifurcation was up to 29% higher than to an identical feeder requiring no learning. Our results suggest that effort affects value perception in ants. This effect may stem from a cognitive process, which monitors the change in a generalized hedonic state before and after reward. (PsycINFO Database Record PMID- 29504774 TI - Social sensitivity and social, school, and psychological adjustment among children across contexts. AB - This study examined relations of social sensitivity to social, school, and psychological adjustment in rural Chinese, urban Chinese, and Canadian children. Participants were 4th to 6th grade students (Mage = 11 years) in China (n = 593 and 443 for the rural and urban samples) and Canada (n = 325). A self-report measure of social sensitivity was developed for the study. In addition to data on social sensitivity, information on adjustment was obtained from multiple sources. The analyses revealed that social sensitivity was associated with positive adjustment in rural Chinese children but with adjustment problems in Canadian children. The relations were largely mixed and nonsignificant in urban Chinese children. These results indicate the role of context in defining the functional meaning of children's social sensitivity. (PsycINFO Database Record PMID- 29504775 TI - The social values development of preschoolers: An investigation of the joint impact hypothesis. AB - We investigated the role of sociocultural (between-groups) and individual (within group) factors on the development of preschoolers' resource-allocation preferences. We tested claims of the joint impact hypothesis of social values development that social-emotional understanding skills would predict the transition from simpler (individualistic allocations) to more complex (cooperative, competitive allocations) social values and that cultural background would determine which values emerged. American children ages 37-67 months from Spanish-speaking Latino (n = 134), English-speaking Latino (n = 50), and English speaking Caucasian (n = 98) backgrounds twice completed a resource-allocation task and a social-emotional understanding assessment, separated by 6 months. Contrary to predictions, results revealed that for no group were complex choice allocations more common at Time 2 than at Time 1. Moreover, for the Caucasian group, social-emotional understanding did not predict time-dependent choice allocation behavior. For Latinos, however, results revealed differential social values development according to language background. For Spanish-speaking Latinos, higher social-emotional understanding scores predicted emergent cooperative choices, and for English-speaking Latinos, higher scores predicted emergent competitive choices. Findings are consistent with differential socialization wherein social-emotional understanding skills facilitate the development of culturally mainstream values for more acculturated Latinos and ethnic cultural values for less acculturated Latinos. (PsycINFO Database Record PMID- 29504776 TI - Cross-cultural differences in parental beliefs about infant motor development: A quantitative and qualitative report of middle-class Israeli and Dutch parents. AB - The present study explored cultural differences in parental beliefs about motor development across 2 Western cultures: Israel and the Netherlands. Can 2 cultural models be distinguished regarding infant motor development in Israel and the Netherlands or are parental beliefs about motor development similar across these cultures? Using a questionnaire containing closed and open questions, beliefs of 206 Israeli and 198 Dutch parents of first-born children between 2 and 7 months old were analyzed. Based on both quantitative and qualitative analyses, distinct cultural models were found showing that the Dutch attributed a bigger role to maturation and children's own pace than to stimulation. The Israeli parents found stimulation of motor development important and discussed active stimulation more elaborately. When discussing supportive activities, the Israeli parents mentioned specific activities, whereas the Dutch parents used more general, vague expressions about support. Moreover, the Israeli parents discussed the need for expert advice and advice from relatives and other parents more than the Dutch parents, who rely on their own observations, books, or websites more often. The cultural background was the strongest predictor of parental beliefs about motor development. Parental education, age, children's birth weight, gender, and having seen a physical therapist showed weaker relations with parental beliefs. Altogether, 2 distinguishing cultural models can be found, raising the question whether infant motor development can be approached similarly across Western cultures. Besides this implication for science, practitioners should also be aware of differences between cultures and between parents. (PsycINFO Database Record PMID- 29504777 TI - Pluralism and heterogeneity as criticism: Undergraduate history and systems of psychology courses in Argentinian psychology education (1983-2017). AB - Multiple studies have analyzed the aims, resources, and approaches to undergraduate and graduate history of psychology education in several countries. Argentina is one of the countries with the highest historiographical production in Latin America. However, to date, there are no published studies on the collective debates among professionals, institutions, and associations that were instrumental in the development of the historiography of science becoming a mandatory part of the curriculum in Argentinian psychology programs. This study describes and analyzes the role of undergraduate history of psychology courses in official debates that took place during the last 30 years regarding Argentinian psychologists' training and education, in the context of regional and international historiography. Data was retrieved from several primary sources, such as minutes and official dossiers, working documents on accreditation standards, and nationwide curricular diagnoses on undergraduate psychology education, as well as individual scholars' ideas. Our findings suggest that, in line with regional and international historiography, history of psychology courses in Argentina have repeatedly been considered as core content in debates and discussions about psychology education, from the restoration of democracy in 1983 to the present day, in which they are currently considered to be mandatory minimum curricular content. Although throughout its history Argentinian psychology has largely been reduced to the teaching of Freudian and Lacanian psychoanalysis, historical education has been perceived as a gateway toward a more plural and critical local psychology. We conclude by discussing some potential and actual concerns that pose a threat to Argentinian undergraduate history courses. (PsycINFO Database Record PMID- 29504778 TI - Organizational justice and health: Studying mental preoccupation with work and social support as mediators for lagged and reversed relationships. AB - Organizational justice perceptions are considered a predictor of health and well being. To date, empirical evidence about whether organizational justice perceptions predict health or health predicts organizational justice perceptions is mixed. Furthermore, the processes underlying these relationships are largely unknown. In this article, we study whether bidirectional relationships can be explained by 2 different mediation mechanisms. First, based on the allostatic load model, we suggest that the relationships between organizational justice perceptions and different health indicators are mediated through mental preoccupation with work. Second, based on the affective perception and affective reaction assumption, we investigate if the relationships between different health indicators and organizational justice perceptions are mediated by social support at work. Using a large-scale Swedish panel study (N = 3,236), we test the bidirectional mediating relationships between procedural justice perceptions and self-rated health, depressive symptoms, and sickness absence with a cross-lagged design with 3 waves of data. Significant lagged effects from procedural justice to health were found for models predicting depressive symptoms and sickness absence. Mental preoccupation with work was not found to mediate the longitudinal relationship between procedural justice perceptions and indicators of health. Significant lagged effects from health indicators to procedural justice were found for models involving self-rated health, depressive symptoms, and sickness absence. Social support mediated the longitudinal relationships between all 3 health indicators and procedural justice. Results are discussed in light of previous studies and implications for theory and practice are outlined. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29504779 TI - Effect of age and level of education on neurocognitive impairment in HIV positive Zambian adults. AB - OBJECTIVE: Older age and lower education levels are known to be associated with worse neurocognitive (NC) performance in healthy adults, and individuals with HIV infection may experience accelerated brain/cognition aging. However, higher education may possibly protect against HIV-associated neurocognitive disorders (HAND). The aim of the current cross-sectional study was to assess the effect of age and education in an HIV-1 clade C infected adult population in urban Zambia. METHOD: Demographically corrected Zambian norms on a neuropsychological (NP) test battery were used to correct for normal age and education effects. The study assessed 286 HIV positive (+) males (37.1%) and females (62.9%) with a mean age of 41.35 (SD = 8.56) and mean years of education = 10.16 (SD = 2.18). A comprehensive NP test battery was used to assess cognitive domains frequently affected by HIV: attention/working memory, learning/and delayed recall, executive function, verbal fluency, processing speed, verbal and visual episodic memory, and fine motor skills. RESULTS: In younger HIV+ Zambians, higher education evidenced protective effects against NC impairments overall, and for the specific domains of executive functions, learning and speed of information processing. Impairment scores did not support accelerated overall brain aging although the restricted age range and relative youth of our total sample may have precluded detection of such tendencies. CONCLUSIONS: The present study raises the need to investigate factors that could be implicated in the poor neurocognitive performance among the younger, less educated HIV+ individuals in Zambia. (PsycINFO Database Record PMID- 29504781 TI - A mediation analysis of treatment processes in the UK Alcohol Treatment Trial. AB - OBJECTIVE: To determine whether treatment outcomes are mediated by therapist behaviors consistent with the theoretical postulates on which two contrasting treatments are based. METHOD: We used data from the U.K. Alcohol Treatment Trial (UKATT), a pragmatic, multicenter, randomized controlled trial comparing the effectiveness of Motivational Enhancement Therapy (MET) and Social Behavior and Network Therapy (SBNT) in the treatment of alcohol problems. N = 376 clients (mean age 42.5, 74.5% male) had 12-month follow-up data and one treatment session recorded and coded using the UKATT Process Rating Scale, a reliable manual-based assessment of treatment fidelity including frequency and quality ratings of treatment-specific therapist tasks and therapist styles. Analyses were conducted using a mediation framework. RESULTS: Analysis of individual paths from treatment condition to treatment process indices (a path) and from treatment process indices to alcohol outcomes (b path) showed that (a) SBNT therapists more often used SBNT-specific behaviors, and did so with overall higher quality; (b) MET therapists more often used MET-specific behaviors, but there was no evidence that they performed these behaviors with higher quality than SBNT therapists; (c) only the quality of MET behaviors significantly predicted 12-month alcohol outcomes, irrespective of treatment condition. Consistently, there were no significant indirect effects. Multiple component analysis indicated that therapist quality of specific tasks influenced outcomes. CONCLUSIONS: The quality of delivery of the same treatment tasks in both treatments studied transcended the impact of delivering treatments according to different theoretical underpinnings in UKATT. (PsycINFO Database Record PMID- 29504780 TI - Effects of reduced nicotine content cigarettes on individual withdrawal symptoms over time and during abstinence. AB - In the United States, the Food and Drug Administration (FDA) has initiated a public dialogue about reducing the nicotine content of cigarettes. A reduced nicotine standard could increase withdrawal symptoms among current smokers. We examined the impact of switching smokers to cigarettes that varied in nicotine content on withdrawal symptoms over 6 weeks. A secondary analysis (N = 839) of a 10-site, double-blind clinical trial of nontreatment-seeking smokers was completed. Participants were instructed to smoke study cigarettes, containing 0.4 to 15.8 mg of nicotine/g of tobacco, for 6 weeks and were then abstinent overnight. Using latent growth curves, trajectories of individual withdrawal symptoms were compared between the reduced nicotine content (RNC) conditions and a normal nicotine content (NNC) condition. Path analyses compared symptoms after overnight abstinence. Relative to NNC cigarettes, participants smoking RNC cigarettes had increased anger/irritability/frustration and increased appetite/weight gain during the initial weeks, but the symptoms resolved by Week 6. Individuals who were biochemically verified as adherent with using only the 0.4 mg/g cigarettes had higher sadness levels (Cohen's d = .40) at Week 6 compared with the NNC condition, although symptoms were mild. After a post-Week 6 overnight abstinence challenge, some RNC conditions relative to NNC condition exhibited reduced withdrawal. Individuals who were biochemically confirmed as adherent to the lowest nicotine condition experienced only mild and transient symptom elevations. Thus, a reduced-nicotine standard for cigarettes produced a relatively mild and temporary increase in withdrawal among nontreatment-seeking smokers (ClinicalTrials.gov No. NCT01681875). (PsycINFO Database Record PMID- 29504782 TI - Immigration policy, practices, and procedures: The impact on the mental health of Mexican and Central American youth and families. AB - Currently, 15 million Mexican and Central American individuals live in the United States, with this number projected to rise in the next few decades (Lesser & Batalova, 2017; Zong & Batalova, 2017). Research has begun to investigate the impact of the nation's immigration practices and policies on immigrant Latino/a families and youth. Current immigration policies can create vulnerabilities, including fear and mistrust, discrimination, limited access to services, parent child separation, and poverty. These experiences increase risk for poor mental health outcomes and may exacerbate prior exposure to traumas in the home country (e.g., violence) and during migration (e.g., extortion). This paper reviews current immigration policies for arriving Mexican and Central American immigrants and links to mental health among documented and undocumented immigrant families and youth. A discussion of positive policies and resources that may mitigate the damaging impact of immigration-related stress is included. Finally, social justice implications for clinicians and researchers are discussed, with culturally sensitive interventions, advocacy, and dissemination of research and policy as primary recommendations. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29504783 TI - A swap methodology applied to implicit sequence learning. AB - Two experiments used a methodology in which elements in a serially presented sequence of 5 elements were randomly reinforced during training. To assess what was learned, elements were systematically swapped with each other during testing. The usual outcome measures in implicit sequence learning of this type are either a random test in which elements are disarrayed, or pairwise tests in which subjects choose between two elements. Each of these methods possesses shortcomings. The random test is a blunt measure, whereas pairwise tests disrupt the usual flow of elements in a serial sequence. Pairwise tests also present the problem of how to reinforce subjects during testing in a way that doesn't violate the delivery of reinforcement on a random basis. The swaps methodology is more targeted in that only two elements exchange ordinal positions. The procedure is at once more precise than the standard random test and is less disruptive to the flow of an implicit sequence than are pairwise tests. Results of both experiments indicated that the swaps manipulation was successful in disrupting latencies. Regression analyses indicated that subjects learned something about the ordinal position of elements. The separate analysis of symbolic distance versus spatial distance in Experiment 2 provided evidence, but only provisional evidence, of a symbolic distance effect in implicit learning. (PsycINFO Database Record PMID- 29504784 TI - The development of wrap-up processes in text reading: A study of children's eye movements. AB - Reading comprehension is the product of constructing a coherent mental model of a text. Although some of the processes that are necessary to construct such a mental model are executed incrementally, others are deferred to the end of the clause or sentence, where integration processing is wrapped up before the reader progresses further in the text. In this longitudinal study of 65 German-speaking children across Grades 2, 3, and 4, we investigated the development of wrap-up processes at clause and sentence boundaries by tracking the children's eye movements while they read age-appropriate texts. Our central finding was that children in Grade 2 showed strong wrap-up effects that then slowly decreased across school grades. Children in Grades 3 and 4 also increasingly used clause and sentence boundaries to initiate regressions and rereading. Finally, children in Grade 2 were shown to be significantly disrupted in their reading at line breaks, which are inherent in continuous text. This disruption decreased as the children progressed to Grades 3 and 4. Overall, our results show that children exhibit an adultlike pattern of wrap-up effects by the time they reach Grade 4. We discuss this developmental trajectory in relation to models of text processing and mechanisms of eye-movement control. (PsycINFO Database Record PMID- 29504785 TI - A memory advantage for past-oriented over future-oriented performance feedback. AB - People frequently receive performance feedback that describes how well they achieved in the past, and how they could improve in future. In educational contexts, future-oriented (directive) feedback is often argued to be more valuable to learners than past-oriented (evaluative) feedback; critically, prior research led us to predict that it should also be better remembered. We tested this prediction in six experiments. Subjects read written feedback containing evaluative and directive comments, which supposedly related to essays they had previously written (Experiments 1-2), or to essays another person had written (Experiments 3-6). Subjects then tried to reproduce the feedback from memory after a short delay. In all six experiments, the data strongly revealed the opposite effect to the one we predicted: despite only small differences in wording, evaluative feedback was in fact recalled consistently better than directive feedback. Furthermore, even when adult subjects did recall directive feedback, they frequently misremembered it in an evaluative style. These findings appear at odds with the position that being oriented toward the future is advantageous to memory. They also raise important questions about the possible behavioral effects and generalizability of such biases, in terms of students' academic performance. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29504786 TI - Justifying treatment bias: The legitimizing role of threat perception and immigrant-provider contact in healthcare. AB - OBJECTIVE: Immigrants tend to receive a lower quality of healthcare, which can be a sign of healthcare bias. We examined whether this bias in medical care is associated with a legitimizing process involving two psychosocial factors: threat perception and level of intergroup contact. METHOD: One hundred eighty six Portuguese health professionals (55.6% clinicians; 44.4% nurses; 78.5% female; Mage = 45.83, range = 23 and 71) completed a questionnaire on prejudiced attitudes toward immigrants, perceptions of health-specific threats, bias in medical practice and level of contact with immigrant patients. RESULTS: For healthcare providers who have more contact with immigrant patients, the perceived health threat mediated the relationship between prejudiced attitudes and treatment bias. In contrast, for healthcare providers with less contact with immigrant patients, the perceived threat was not associated with treatment bias. CONCLUSIONS: These findings help to understand the persistence of lower quality medical treatment among immigrants, providing guidelines for future research. In particular, they suggest that perceiving immigrants as a threat to public health is indicative of the providers' engagement in a legitimizing process of self reported biased treatment, making this engagement necessary only for providers with greater levels of contact with immigrant patients. (PsycINFO Database Record PMID- 29504787 TI - A novel examination of exposure patterns and posttraumatic stress after a university mass murder. AB - OBJECTIVE: Occurring at an alarming rate in the United States, mass violence has been linked to posttraumatic stress symptoms (PTSS) in both direct victims and community members who are indirectly exposed. Identifying what distinct exposure patterns exist and their relation to later PTSS has important clinical implications. The present study determined classes of exposure to an event of mass violence, and if PTSS differed across classes. METHOD: First- and second year college students (N = 1,189) participated in a confidential online survey following a mass murder at their university, which assessed event exposure and PTSS 3 months later. Latent class analysis (LCA) was used to empirically determine distinct classes of exposure patterns and links between class membership and PTSS. RESULTS: The final model yielded 4 classes: minimal exposure (55.5% of sample), auditory exposure (29.4% of sample), visual exposure (10% of sample), and interpersonal exposure (5% of sample). More severe direct exposure (i.e., the visual exposure class) was associated with significantly higher levels of PTSS than the auditory exposure or minimal exposure classes, as was the interpersonal exposure class. There were no significant differences in PTSS between the auditory exposure and minimal exposure classes or the visual exposure and interpersonal exposure classes. CONCLUSION: Results point to the differential impact of exposure categories, and provide empirical evidence for distinguishing among auditory, visual, and interpersonal exposures to events of mass violence on college campuses. Clinical implications suggest that visual and interpersonal exposure may warrant targeted efforts following mass violence. (PsycINFO Database Record PMID- 29504789 TI - Interaction between self-regulation, intentions and implicit attitudes in the prediction of physical activity among persons with obesity. AB - OBJECTIVE: Both explicit and implicit motivational processes predict physical activity (PA); however, their respective contributions may depend on interindividual differences. This study examined the moderating role of trait impulsivity and executive functions in the associations between PA intentions, implicit attitudes toward sedentary behavior, and PA measured with accelerometers in persons with obesity. METHODS: Participants (N = 76; Mage = 56 years, SD = 11.9; MBody Mass Index = 39.1, SD = 6.5) completed baseline questionnaires measuring their PA intentions and trait impulsivity. They also performed 2 computerized tests measuring implicit attitudes toward sedentary behavior and executive functions. PA was assessed 4 months later with an accelerometer. RESULTS: Implicit attitudes toward sedentary behavior and executive functions interacted to predict PA. Higher implicit attitudes were associated with significantly lower PA in participants with low and moderate executive functions but not high executive functions. CONCLUSIONS: These results support the role of implicit processes and cognitive factors in health-related behavior adoption through time. Practically, these variables may be useful to identify individuals at risk of abandoning PA after programs who thus may benefit from complementary interventions (e.g., provide feedback on implicit attitudes and develop self regulatory skills). (PsycINFO Database Record PMID- 29504788 TI - Psychological status and weight variability over eight years: Results from Look AHEAD. AB - OBJECTIVE: Cross-sectional studies suggest an association between weight cycling and psychological status. Although this is often interpreted as suggesting that weight cycles "cause" psychological distress, the relationship could be bidirectional. This study provides a prospective analysis of the bidirectional association between weight variability and psychological status over an 8-year period in overweight/obese adults with Type 2 diabetes. METHOD: Data were from the first 8 years of Look AHEAD, a randomized controlled trial comparing health outcomes in individuals with Type 2 diabetes assigned to an intensive lifestyle intervention designed to produce weight loss or a diabetes education and support control group. Psychological status (mental health, depressive symptoms, binge eating) was assessed via surveys and were examined in relation to weight variability at both baseline and year 8. Weight variability was derived from 8 possible annual measurements from participants who had a minimum of 3 consecutive body weight measurements (N = 4,774) and operationalized as the number of year-to year cycles and the coefficient of variation across all available weight measurements. RESULTS: Controlling for study group, higher baseline scores on mental health (Short Form-36 Mental Component Summary) and lower levels of depressive symptomatology (Beck Depression Inventory) and binge eating (Questionnaire on Eating and Weight Patterns) were associated with significantly less subsequent weight variability. The prospective association between weight variability and psychological status at year 8 was less robust. CONCLUSIONS: These results suggest that the cross-sectional relationship between weight variability and psychological status is due primarily to poorer psychological function preceding greater weight instability. (PsycINFO Database Record PMID- 29504792 TI - Satisfaction with life moderates the indirect effect of pain intensity on pain interference through pain catastrophizing. AB - OBJECTIVE: Satisfaction with life buffers the effect of stress on health, but its role in the mechanism through which pain may impact engagement in activities of daily living is not known. We tested whether satisfaction with life protects against engaging in pain catastrophizing and through this explains individual differences in the extent to which pain interferes with activities of daily living. METHOD: One-hundred and 42 patients with upper extremity musculoskeletal illness participated in this cross-sectional study and completed the PROMIS pain intensity, PROMIS pain interference, pain catastrophizing scale (PCS), satisfaction with life scale (SWLS), and demographic variables. RESULTS: A simple mediation model confirmed that the indirect effect of pain intensity on pain interference through PCS was 35.9% of the total effect. A moderated mediation analysis showed that the indirect effect of pain intensity on pain interference through PCS was differentially moderated by SWLS after controlling for relevant covariates. As satisfaction with life increased from low to moderate to high, a smaller proportion of the effect of pain intensity on pain interference (41.6%, 26.1%, and 10.5%) was carried through PCS, such that at the highest satisfaction with life, the indirect effect becomes completely nonsignificant. CONCLUSIONS: Satisfaction with life appears to buffer the effect of pain in individuals with upper extremity musculoskeletal illness. If replicated through longitudinal designs, results suggest that clinical interventions focused on increasing satisfaction with life, such as acceptance and commitment therapy, mindfulness training, gratitude, and other positive psychology skills, may improve outcomes in this population. (PsycINFO Database Record PMID- 29504790 TI - Training clinicians to deliver group CBT to manage anxiety in youth with ASD: Results of a multisite trial. AB - OBJECTIVE: Few guidelines are available regarding optimal training models for practitioners delivering cognitive-behavioral therapy (CBT) for anxiety in youth with autism spectrum disorder (ASD). The present study systematically compared 3 instructional conditions for delivering the Facing Your Fears program (FYF) to children with ASD and anxiety. METHOD: Thirty-four clinicians (Mage = 34 years; 94% women, 88% Caucasian) and an intent-to-treat sample of 91 children with ASD and anxiety (Mage = 11; 84% male 53% Caucasian) met eligibility criteria across 4 sites. A 3-group parallel design via a Latin square procedure was used to randomize 9 teams of clinicians to 1 of 3 training conditions: Manual, Workshop, Workshop-Plus. The effectiveness of instructional condition was assessed via implementation (CBT knowledge, treatment fidelity) and treatment outcomes (reductions in anxiety as measured by the Anxiety Disorders Interview Schedule Parent (ADIS-P). RESULTS: Clinicians in both Workshop conditions significantly increased CBT knowledge postworkshop, F(1, 18) = 19.8, p < .001. Excellent treatment fidelity was obtained across conditions (above 89%), although clinicians in the Workshop conditions obtained significantly higher fidelity ratings and delivered FYF with greater quality than the Manual condition. Children with ASD demonstrated significant reductions in anxiety symptoms for three of the four anxiety diagnoses, with no differences noted across instructional condition. Rates of improvement were lower than those obtained in a previous controlled trial. CONCLUSIONS: Results suggest that although there may be some advantage to participating in a Workshop, clinicians in all conditions could deliver FYF with excellent fidelity and yield positive treatment outcomes. Lack of a no-treatment comparison group limits interpretation of findings. (PsycINFO Database Record PMID- 29504791 TI - Maternal patterns of antenatal and postnatal depressed mood and the impact on child health at 3-years postpartum. AB - OBJECTIVE: The consequences of maternal depressed mood on children's growth, health, and cognitive and language development are examined over the first 3 years of life. METHOD: Pregnant women in 24 periurban township neighborhoods in Cape Town, South Africa (N = 1,238 mothers) were randomized by neighborhood to a home visiting intervention or a standard care condition. Reassessments were conducted for 93%-85% of mothers at 2-weeks, 6-, 18-, and 36-months postbirth. Regressions were conducted on measures of children's growth, behavior, language, and cognition to examine the impact of four patterns of depressed mood: antenatal only (n = 154, 13.8%), postnatal only (n = 272, 24.3%), antenatal and postnatal (n = 220, 19.7%), and no depressed mood on any assessment (n = 473, 42.3%). RESULTS: Patterns of depressed mood were similar across intervention conditions. Depressed mothers were significantly less educated, had lower incomes, were less likely to be employed or to have electricity; were more likely to report problematic drinking of alcohol, experience food insecurity, interpersonal partner violence, and to be HIV seropositive. At 36 months, the pattern of maternal depressed mood over time was significantly associated with children's compromised physical growth, both in weight and height, and more internalizing and externalizing symptoms of behavior problems. Measures of language and cognition were similar across maternal patterns of depressed mood. CONCLUSIONS: Mothers who report depressed mood face significantly more life challenges, both environmental stressors related to poverty and other problematic behaviors. More proximal, postnatal depressed mood appears to have a larger influence on their children, compared with antenatal depressed mood. (PsycINFO Database Record PMID- 29504793 TI - How does exposure therapy work? A comparison between generic and gastrointestinal anxiety-specific mediators in a dismantling study of exposure therapy for irritable bowel syndrome. AB - OBJECTIVE: Systematic exposure is potentially an effective treatment procedure for treating irritable bowel syndrome (IBS), but little is known about the processes by which it achieves its effect on outcome. The aim of this study was to identify mediators in a previously published randomized dismantling trial in which participants with IBS were randomized to Internet-delivered cognitive behavioral treatment (ICBT) that incorporated systematic exposure or to the same treatment protocol without exposure (ICBT-WE). METHOD: Weekly measurements of gastrointestinal anxiety-specific process variables (behavioral avoidance, gastrointestinal-specific anxiety) based on the gastrointestinal symptom-specific anxiety model, generic process variables (self-efficacy and mindful nonreactivity), and treatment outcome (IBS symptoms) were obtained from 309 participants with IBS. Growth models and cross-lagged panel models, estimated within structural equation modeling, were employed to evaluate mediators of outcome. RESULTS: Parallel process growth modeling showed that behavioral avoidance, gastrointestinal-specific anxiety, self-efficacy mediated the incremental effect of ICBT compared to ICBT-WE. The mediated effect of avoidance was stronger for individuals scoring high on the avoidance variable at 1st measurement point. Cross-lagged regression analyses with random effects revealed that behavioral avoidance and gastrointestinal-specific anxiety had a stronger effect on subsequent symptom change rather than vice versa, whereas mindful nonreactivity and self-efficacy displayed the opposite pattern. CONCLUSIONS: The evidence collectively provided support for the hypothesis that exposure for IBS achieves its positive results by virtue of changing gastrointestinal anxiety specific processes rather than generic processes. IBS-specific behavioral avoidance emerged as the most clear-cut mediator of the specific effect of exposure on outcome. (PsycINFO Database Record PMID- 29504794 TI - A randomized controlled trial of emotion regulation therapy for generalized anxiety disorder with and without co-occurring depression. AB - OBJECTIVE: Generalized anxiety disorder (GAD) and major depression (MDD), especially when they co-occur, are associated with suboptimal treatment response. One common feature of these disorders is negative self-referential processing (NSRP; i.e., worry, rumination), which worsens treatment outcome. Emotion Regulation Therapy (ERT) integrates principles from affect science with traditional and contemporary cognitive-behavioral treatments to identify and modify the functional nature of NSRP by targeting motivational and regulatory mechanisms, as well as behavioral consequences. METHOD: Building on encouraging open trial findings, 53 patients with a primary diagnosis of GAD (43% with comorbid MDD) were randomly assigned to immediate treatment with ERT (n = 28) or a modified attention control condition (MAC, n = 25). RESULTS: ERT patients, as compared with MAC patients, evidenced statistically and clinically meaningful improvement on clinical indicators of GAD and MDD, worry, rumination, comorbid disorder severity, functional impairment, quality of life, as well as hypothesized mechanisms reflecting mindful attentional, metacognitive, and overall emotion regulation, which all demonstrated mediation of primary outcomes. This superiority of ERT exceeded medium effect sizes with most outcomes surpassing conventions for a large effect. Treatment effects were maintained for nine months following the end of acute treatment. Overall, ERT resulted in high rates of high endstate functioning for both GAD and MDD that were maintained into the follow-up period. CONCLUSIONS: Findings provide encouraging support for the efficacy and hypothesized mechanisms underlying ERT and point to fruitful directions for improving our understanding and treatment of complex clinical conditions such as GAD with co-occurring MDD. (PsycINFO Database Record PMID- 29504796 TI - How you behave in school predicts life success above and beyond family background, broad traits, and cognitive ability. AB - In this study, we investigated the role of student characteristics and behaviors in a longitudinal study over a 50-year timespan (using a large U.S. representative sample of high school students). We addressed the question of whether behaviors in school have any long-lasting effects for one's later life. Specifically, we investigated the role of being a responsible student, interest in school, writing skills, and reading skills in predicting educational attainment, occupational prestige, and income 11 years (N = 81,912) and 50 years (N = 1,952) after high school. We controlled for parental socioeconomic status, IQ, and broad personality traits in all analyses. We found that student characteristics and behaviors in adolescence predicted later educational and occupational success above and beyond parental socioeconomic status, IQ, and broad personality traits. Having higher interest in school was related to higher educational attainment at years 11 and 50, higher occupational prestige at year 11, and higher income at year 50. Higher levels of being a responsible student were related to higher educational attainment and higher occupational prestige at years 11 and 50. This was the first longitudinal study to test the role of student characteristics and behaviors over and above broad personality traits. It highlights the potential importance of what students do in school and how they react to their experiences during that time. It also highlights the possibility that things that happen in specific periods of one's life may play out in ways far more significant than we expect. (PsycINFO Database Record PMID- 29504795 TI - Treating insomnia in depression: Insomnia related factors predict long-term depression trajectories. AB - OBJECTIVE: Insomnia and major depressive disorders (MDD) often co-occur, and such comorbidity has been associated with poorer outcomes for both conditions. However, individual differences in depressive symptom trajectories during and after treatment are poorly understood in comorbid insomnia and depression. This study explored the heterogeneity in long-term depression change trajectories, and examined their correlates, particularly insomnia-related characteristics. METHOD: Participants were 148 adults (age M +/- SD = 46.6 +/- 12.6, 73.0% female) with insomnia and MDD who received antidepressant pharmacotherapy, and were randomized to 7-session Cognitive Behavioral Therapy for Insomnia or control conditions over 16 weeks with 2-year follow-ups. Depression and insomnia severity were assessed at baseline, biweekly during treatment, and every 4 months thereafter. Sleep effort and beliefs about sleep were also assessed. RESULTS: Growth mixture modeling revealed three trajectories: (a) Partial-Responders (68.9%) had moderate symptom reduction during early treatment (p value < .001) and maintained mild depression during follow-ups. (b) Initial-Responders (17.6%) had marked symptom reduction during treatment (p values < .001) and low depression severity at posttreatment, but increased severity over follow-up (p value < .001). (c) Optimal-Responders (13.5%) achieved most gains during early treatment (p value < .001), continued to improve (p value < .01) and maintained minimal depression during follow-ups. The classes did not differ significantly on baseline measures or treatment received, but differed on insomnia-related measures after treatment began (p values < .05): Optimal-Responders consistently endorsed the lowest insomnia severity, sleep effort, and unhelpful beliefs about sleep. CONCLUSIONS: Three depression symptom trajectories were observed among patients with comorbid insomnia and MDD. These trajectories were associated with insomnia-related constructs after commencing treatment. Early changes in insomnia characteristics may predict long-term depression outcomes. (PsycINFO Database Record PMID- 29504797 TI - Depression, negative emotionality, and self-referential language: A multi-lab, multi-measure, and multi-language-task research synthesis. AB - Depressive symptomatology is manifested in greater first-person singular pronoun use (i.e., I-talk), but when and for whom this effect is most apparent, and the extent to which it is specific to depression or part of a broader association between negative emotionality and I-talk, remains unclear. Using pooled data from N = 4,754 participants from 6 labs across 2 countries, we examined, in a preregistered analysis, how the depression-I-talk effect varied by (a) first person singular pronoun type (i.e., subjective, objective, and possessive), (b) the communication context in which language was generated (i.e., personal, momentary thought, identity-related, and impersonal), and (c) gender. Overall, there was a small but reliable positive correlation between depression and I-talk (r = .10, 95% CI [.07, .13]). The effect was present for all first-person singular pronouns except the possessive type, in all communication contexts except the impersonal one, and for both females and males with little evidence of gender differences. Importantly, a similar pattern of results emerged for negative emotionality. Further, the depression-I-talk effect was substantially reduced when controlled for negative emotionality but this was not the case when the negative emotionality-I-talk effect was controlled for depression. These results suggest that the robust empirical link between depression and I-talk largely reflects a broader association between negative emotionality and I-talk. Self-referential language using first-person singular pronouns may therefore be better construed as a linguistic marker of general distress proneness or negative emotionality rather than as a specific marker of depression. (PsycINFO Database Record PMID- 29504798 TI - Environmental light and time of day modulate subjective liking and wanting. AB - Several studies demonstrated effects of light on affect via projections from the retina of the eye to the circadian clock or via projections to areas involved in mood and reward. Few field studies investigated how naturally fluctuating light levels affect positive and negative mood in everyday life, but none addressed two key components of the reward system: wanting and liking. To elucidate diurnal profiles and immediate effects of dynamically changing light intensity in everyday life, subjective wanting and liking were assessed using experience sampling, while continuously monitoring environmental illuminance. Using a smartphone and light sensors, healthy volunteers (n = 27, 14 females, 23.7 +/- 3.8 [M +/- SD] years of age) were probed for 1 week, 9 times a day, to rate positive and negative mood, and 6 novel dedicated questions each on subjective liking and wanting. The multiband light spectrum was continuously recorded from sensors worn on the chest and intensities were averaged over the intervals between subsequent probes. Mixed effect models were used to evaluate how time of day and light intensity modulated subjective ratings. A total of 1,102 valid observations indicated that liking and wanting peaked around 6 p.m. and increased, respectively, by 13 +/- 4% and 11 +/- 4% across an individual's range of experienced light intensities. More traditional mood questions were less sensitive to modulation by light intensity. Combined experience sampling and environmental monitoring opens up the possibility for field studies on light in disorders in which the reward system is highly relevant, like addiction, depression and insomnia. (PsycINFO Database Record PMID- 29504799 TI - Bending time: The role of affective appraisal in time perception. AB - Affective states are known to distort time perception, but it remains unclear why and how they do so. To test whether appraisal processes involved in affect may play a role in temporal distortions, we investigated bisection behavior during experimental events with varying appraisal values along three dimensions: goal relevance (high vs. low), goal type (approach vs. avoid), and goal congruence (conducive vs. obstructive). Forty female participants performed an incentive compatible gambling task attempting to accumulate wins and avoid losses of small amounts of chocolate. On each trial, a prechoice stimulus first announced whether a win, a loss, or no change was available. Participants then made a choice that ostensibly determined the outcome of the trial, which was communicated by a postchoice stimulus. Participants also made temporal bisection decisions indicating whether the presentation durations of pre- and postchoice stimuli (which varied between 200, 320, 440, 560, 680, and 800 ms) were closer to a previously learned short (200 ms) or long (800 ms) standard. We analyzed appraisal effects on psychometric bisection point, response speed, and drift diffusion parameter variance using custom regression contrasts. Subjective durations were found to be lengthened by high goal relevance, conducive goal congruence, and approach goal type. Analysis of diffusion parameters suggested that these results reflected appraisal-related shifts in duration perception rather than in subsequent decision-making. These findings encourage further research into the possibility that temporal distortions are among the cognitive changes triggered by appraisal processes during affective states. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29504800 TI - Auditory affective processing requires awareness. AB - Recent work has challenged the previously widely accepted belief that affective processing does not require awareness and can be carried out with more limited resources than semantic processing. This debate has focused exclusively on visual perception, even though evidence from both human and animal studies suggests that existence for nonconscious affective processing would be physiologically more feasible in the auditory system. Here we contrast affective and semantic processing of nonverbal emotional vocalizations under different levels of awareness in three experiments, using explicit (two-alternative forced choice masked affective and semantic categorization tasks, Experiments 1 and 2) and implicit (masked affective and semantic priming, Experiment 3) measures. Identical stimuli and design were used in the semantic and affective tasks. Awareness was manipulated by altering stimulus-mask signal-to-noise ratio during continuous auditory masking. Stimulus awareness was measured on each trial using a four-point perceptual awareness scale. In explicit tasks, neither affective nor semantic categorization could be performed in the complete absence of awareness, while both tasks could be performed above chance level when stimuli were consciously perceived. Semantic categorization was faster than affective evaluation. When the stimuli were partially perceived, semantic categorization accuracy exceeded affective evaluation accuracy. In implicit tasks neither affective nor semantic priming occurred in the complete absence of awareness, whereas both affective and semantic priming emerged when participants were aware of the primes. We conclude that auditory semantic processing is faster than affective processing, and that both affective and semantic auditory processing are dependent on awareness. (PsycINFO Database Record PMID- 29504801 TI - An appraisal profile of nostalgia. AB - The authors aimed to (a) identify the cognitive appraisals underlying nostalgia and (b) compare nostalgia with other emotions in terms of its appraisal profile. In Study 1, participants (N = 1,125) generated narratives. Next, they reported the level of nostalgia and 31 other emotions that these narratives elicited. Subsequently, participants evaluated the narrative events on several cognitive appraisals. Events that elicited nostalgia were pleasant, involved an irretrievable loss, felt psychologically distant, and were unique-an appraisal profile that differed from all other emotions. In Study 2 (N = 1,261), the authors experimentally varied these appraisals in a vignette paradigm and measured anticipated nostalgia and 10 other emotions. Participants anticipated most nostalgia when events were pleasant, involved irretrievable loss, were distant, and were unique-a profile shared only with longing. In Study 3 (N = 994), the authors used a guided autobiographical recall procedure in which they manipulated appraisals and measured the resultant emotions. Corroborating Studies 1-2, nostalgia was most intense for events that were pleasant, irretrievably lost, temporally distant, and unique. This appraisal profile was not shared by other emotions. The findings delineate the distinguishing cognitive appraisal profile of nostalgia. Nostalgia occupies a special place in the pantheon of emotions. (PsycINFO Database Record PMID- 29504803 TI - [Miscellaneous]. PMID- 29504802 TI - Review of Polymorphism of the Calcium-Sensing Receptor Gene and Breast Cancer Risk. AB - Polymorphism of the calcium-sensing receptor gene (CaSR or CaR) has been associated with an increased risk for breast cancer. This receptor plays an important role in calcium homeostasis, and has also been detected in several tissues that are unrelated to calcium metabolism, such as the skin, brain, and breast. The calcium-sensing receptor on cellular level, it regulates cell differentiation, proliferation, cell death, and gene expression. In breast cancer cells, CaSR seems to stimulate secretion of the parathyroid hormone-related protein (PTHrP), which stimulates cellular proliferation. Likewise, some studies have supported not only an association between calcium receptor gene polymorphism and breast cancer risk, but also a higher aggressiveness and unfavorable outcomes in breast cancer, which led us to make a survey in Pubmed on the subject in the last 10 years. Thus, in the literature there is a paucity of studies on the subject and the aim of this review was to show the role of calcium-sensing receptor and its association with breast cancer risk. PMID- 29504804 TI - How important is embeddedness in predicting Australian speech-language pathologists' intentions to leave their jobs and the profession? AB - PURPOSE: This study explored the predictors of the outcomes of turnover and occupation attrition intentions for speech-language pathologists. The researchers examined the mediating effects of job satisfaction and strain on the relationship between stress and the latter outcomes. Additionally, the researchers examined the importance of embeddedness in predicting turnover intentions after accounting for stress, strain and job satisfaction. METHOD: An online questionnaire was used to explore turnover and attrition intentions in 293 Australian speech-language pathologists. RESULT: Job satisfaction contributed to a significant indirect effect on the stress and turnover intention relationship, however strain did not. There was a significant direct effect between stress and turnover intention after accounting for covariates. Embeddedness and the perceived availability of alternative jobs were also found to be significant predictors of turnover intentions. The mediating model used to predict turnover intentions also predicted occupation attrition intentions. The effect of stress on occupation attrition intentions was indirect in nature, the direct effect negated by mediating variables. Qualitative data provided complementary evidence to the quantitative model. CONCLUSION: The findings indicate that the proposed parsimonious model adequately captures predictors of speech-language pathologists' turnover and occupation attrition intentions. Workplaces and the profession may wish to consider these retention factors. PMID- 29504805 TI - Vitamin D-binding protein and its polymorphisms as a predictor for metabolic syndrome. AB - AIM: To investigate the relationship of vitamin D-binding protein (GC) and genetic variation of GC (rs4588, rs7041 and rs2282679) with metabolic syndrome (MetS) in the Thai population. MATERIALS & METHODS: GC-globulin concentrations were measured by quantitative western blot analysis in 401 adults. All participants were genotyped using TaqMan allelic discrimination assays. RESULTS: GC-globulin levels were significatly lower in MetS subjects than in control subjects, in which significant negative correlations of GC-globulin levels with systolic blood pressure, glucose and age were found. Male participants who carried the GT genotype for rs4588 showed an increased risk of MetS compared with the GG wild-type (odds ratio: 3.25; p = 0.004). CONCLUSION: GC-globulin concentrations and variation in GC rs4588 were supported as a risk factor for MetS in Thais. PMID- 29504806 TI - Implicit attitudes and the improvement of exercise capacity during pulmonary rehabilitation. AB - The aim of this study was to examine the role of explicit and implicit attitudes in the improvement of exercise capacity during a 5-week pulmonary rehabilitation (PR). A total of 105 patients performed walking tests at baseline and at the end of PR. Change between performances was computed at the end of PR, and Minimal Clinically-Important-Difference (MCID) were used to categorize patients as responders (i.e. change above MCID, N = 54) or non-responders (i.e. change below MCID, N = 51). At baseline, implicit attitudes were measured through a physical activity versus sedentary behavior Implicit Association Test; explicit attitudes toward physical activity and sedentary behavior were measured by questionnaires. Only implicit attitudes significantly differed between the two groups (p = .015), responders displaying implicit attitudes significantly more in favor of physical activity (M = .91, SD = .54) than non-responders (M = .60, SD = .71) at baseline. Measuring implicit attitudes in PR could help to accurately estimate patients' motivation, and design more individualized rehabilitation programs. PMID- 29504808 TI - [Miscellaneous]. PMID- 29504807 TI - Association of pulse wave velocity with single nucleotide polymorphisms related to parathyroid hormone. AB - OBJECTIVE: Carotid-femoral pulse wave velocity (cfPWV) was associated with serum parathyroid hormone (PTH) in untreated Chinese. We investigated in the same cohort whether cfPWV, brachial-ankle (baPWV) and heart-brachial (hbPWV) pulse wave velocity (PWV) were associated with rs6127099 (CYP24A1) and rs4074995 (RGS14). A previously published genome-wide association study demonstrated that each additional copy of the T (rs6127099) or G (rs4074995) allele was associated with a 7% or 3% higher serum PTH, respectively. METHODS: In 1601 untreated Chinese patients (mean age, 51.0 years; 51.9% women), we measured cfPWV by tonometry (SphygmoCor) and baPWV and hbPWV by combined oscillometry and plethysmography (VP-2000 PWV/ABI analyser), serum PTH by an immunoassay, and genotypes by the SNapShot method. RESULTS: cfPWV, baPWV and hbPWV averaged 7.9, 14.6 and 5.5 m/s and serum PTH 65.7 pg/mL. Genotype frequencies were in Hardy Weinberg equilibrium, amounting to 41.7% (AA), 44.9% (AT) and 13.4% (TT) for rs6127099 and to 70.7% (GG), 26.9% (GA) and 2.3% (AA) for rs4074995. With adjustments applied for sex, age, body mass index, heart rate and season, hbPWV was 0.05 m/s (p = .042) lower with each additional copy of the minor allele (T) of rs6127099. In similarly adjusted analyses of 157 normotensive participants younger than 50 years, cfPWV was 0.32 m/s (p = .004) higher per additional copy of the T allele. Sensitivity analyses additionally accounting for the total-to HDL serum cholesterol ratio, plasma glucose, glomerular filtration rate and 24 h systolic blood pressure were consistent. No other association of PWV with the genetic variants reached significance. CONCLUSIONS: With an increasing number of rs6127099 T alleles, arterial stiffness, as exemplified by PWV, was lower in all participants in a muscular artery (hbPWV), but higher in young normotensive participants in an elastic artery (cfPWV). PMID- 29504809 TI - Effect of mobile technology featuring visual scene displays and just-in-time programming on communication turns by preadolescent and adolescent beginning communicators. AB - PURPOSE: Visual scene displays (VSDs) and just-in-time programming supports are augmentative and alternative communication (AAC) technology features with theoretical benefits for beginning communicators of all ages. The goal of the current study was to evaluate the effects of a communication application (app) on mobile technology that supported the just-in-time programming of VSDs on the communication of preadolescents and adolescents who were beginning communicators. METHOD: A single-subject multiple-baseline across participant design was employed to evaluate the effect of the AAC app with VSDs programmed just-in-time by the researcher on the communication turns expressed by five preadolescents and adolescents (9-18 years old) who were beginning communicators. RESULT: All five participants demonstrated marked increases in the frequency of their communication turns after the onset intervention. CONCLUSION: Just-in-time programming support and VSDs are two features that may positively impact communication for beginning communicators in preadolescence and adolescence. Apps with these features allow partners to quickly and easily capture photos of meaningful and motivating events and provide them immediately as VSDs with relevant vocabulary to support communication in response to beginning communicators' interests. PMID- 29504810 TI - Comparison of changes in irregularity and transverse width with nickel-titanium and niobium-titanium-tantalum-zirconium archwires during initial orthodontic alignment in adolescents: A double-blind randomized clinical trial. AB - OBJECTIVES: The purpose of this prospective, double-blind, randomized clinical trial was to compare the clinical efficiency of nickel-titanium (NiTi) and niobium-titanium-tantalum-zirconium (TiNbTaZr) archwires during initial orthodontic alignment. MATERIALS AND METHODS: All subjects (ages between 12 and 20 years) underwent nonextraction treatment using 0.022-inch brackets. All patients were randomized into two groups for initial alignment with 0.016-inch NiTi archwires (n = 14), or with 0.016-inch TiNbTaZr archwires (n = 14). Digital scans were taken during the course of treatment and were used to compare the improvement in Little's Irregularity Index and the changes in intercanine and intermolar widths. RESULTS: There was approximately a 27% reduction in crowding during the first month with the use of 0.016-inch TiNbTaZr (Gummetal) wire, and an additional 25% decrease in crowding was observed during the next month. There was no significant difference between the two treatment groups in the decrease in irregularity over time ( P = .29). There was no significant difference between the two groups in the changes in intercanine and intermolar width ( P = .80). CONCLUSIONS: It can be concluded that Gummetal wires and conventional NiTi wires possess a similar ability to align teeth, and Gummetal wires have additional advantages over conventional NiTi, such as formability and use in patients with nickel allergy. PMID- 29504811 TI - Membranous or Cytoplasmic HER2 Expression in Colorectal Carcinoma: Evaluation of Prognostic Value Using Both IHC & BDISH. AB - BACKGROUND: Human epidermal growth factor recptor-2 (HER2) was identified as a driver gene in several types of cancers with both prognostic and predictive value. However, the molecular association of HER2 gene mutation with HER2 gene amplification and/or protein expression in cancer tissues has not been clearly defined. Moreover, there is little information available on HER2 status role in tumor progression and metastasis in colorectal carcinoma (CRC) compared to other solid tumors. The aim of this study was to evaluate both HER2 amplification and protein expression profiles using immunohistochemistry (IHC) and bright-field dual in situ hybridization (BDISH) techniques, respectively. PATIENTS AND METHODS: Tissue microarray (TMA) was constructed to accommodate a total of 243 CRC formalin-fixed paraffin embedded (FFPE) samples of consent patients and stained by IHC and BDISH methods. The expression patterns of HER2 protein status were evaluated and correlated to HER2 gene amplification status and then assessed for its prognostic value. RESULTS: The expression profile of 58% samples showed cytoplasmic expression patterns of different categories. Interestingly, only 1% showed strong (+3) membranous expression pattern of HER2 with perfect match with their corresponding gene amplification status (>2). However, the cytoplasmic HER2 protein status did not show significant correlation with most clinicopathological features and survival outcomes except with age (p = 0.04) and tumor size (p = 0.03). CONCLUSION: We demonstrated that the membranous HER2 gene/protein status is infrequent, while the main fraction of HER2 overexpression was cytoplasmic and lacking prognostic value. This cytoplasmic HER2 overexpression was induced through a gene-amplification independent pathway, making the HER2 gene status evaluation approach in those cases not worthy. Further investigations about the molecular pathways of the cytoplasmic HER2 protein in CRC and its associations with survival outcomes are required to allow either a breakthrough in CRC management; or to confirm the hypothesis of a marginal role in CRC onset and progression. PMID- 29504813 TI - [Miscellaneous]. PMID- 29504812 TI - Comparative usability study of the dulaglutide single-use pen versus the insulin degludec FlexTouch(r) among self-injection-naive patients with type 2 diabetes mellitus in Japan. AB - OBJECTIVE: This study assessed training time with the dulaglutide single-use pen (SUP) and the insulin degludec disposable prefilled pen (FlexTouch(r)) in self injection-naive patients with type 2 diabetes mellitus (T2DM) in Japan. METHODS: This multi-center, open-label, comparative, crossover study measured training time with the dulaglutide SUP vs FlexTouch(r). Participants learned how to use both devices in a randomly assigned order. Healthcare providers (HCP) conducted the training. The primary end-point was the time required to train self-injection naive T2DM participants to self-inject correctly using each device. Secondary end points included performance measures, such as success and error rates, patient perceptions related to ease-of-use, and factors associated with training time and performance. RESULTS: Overall, 48 participants were randomized and completed the study. The mean training time to achieve correct administration was significantly shorter with the dulaglutide SUP vs FlexTouch(r) (7.4 min vs 19.7 min, p < .001). The proportions of participants who successfully completed the mock injection without error were similar for both devices. Ninety-two percent (44/48) of participants reported that the dulaglutide SUP was easier to use than FlexTouch(r). CONCLUSIONS: In this study, participants required a shorter training time to achieve correct administration with the dulaglutide SUP, and had a higher preference for the dulaglutide SUP, when compared to FlexTouch(r). These data suggest that the dulaglutide SUP is easy-to-use, which may decrease the burden on HCPs to train diabetic patients how to administer injection therapy and reduce patient injection hurdles, such as needle fear. PMID- 29504814 TI - Emotional responses to behavioral economic incentives for health behavior change. AB - Many people aim to change their lifestyle, but have trouble acting on their intentions. Behavioral economic incentives and related emotions can support commitment to personal health goals, but the related emotions remain unexplored. In a regret lottery, winners who do not attain their health goals do not get their prize but receive feedback on what their forgone earnings would have been. This counterfactual feedback should provoke anticipated regret and increase commitment to health goals. We explored which emotions were actually expected upon missing out on a prize due to unsuccessful weight loss and which incentive characteristics influence their likelihood and intensity. Participants reported their expected emotional response after missing out on a prize in one of 12 randomly presented incentive-scenarios, which varied in incentive type, incentive size and deadline distance. Participants primarily reported feeling disappointment, followed by regret. Regret was expected most when losing a lottery prize (vs. a fixed incentive) and intensified with prize size. Multiple features of the participant and the lottery incentive increase the occurrence and intensity of regret. As such, our findings can be helpful in designing behavioral economic incentives that leverage emotions to support health behavior change. PMID- 29504815 TI - Distortion product otoacoustic emission together with tympanometry for assessing otitis media with effusion in children. AB - OBJECTIVE: To investigate the diagnostic value of distortion product otoacoustic emission (DPOAE) together with tympanometry in assessing otitis media with effusion in children. METHODS: Three hundred and thirty-nine patients, who were diagnosed with obstructive sleep apnea-hypopnea syndrome (OSAHS) and prepared to undergo adenotonsillectomy and had a unilateral or bilateral type 'B' or 'C' tympanogram were enrolled in this study. Patients were divided into the following four groups: Group 1, type 'B' tympanogram with positive DPOAE; Group 2, type 'B' tympanogram with negative DPOAE; Group 3, type 'C' tympanogram with positive DPOAE and Group 4, type 'C' tympanogram with negative DPOAE. RESULTS: Tympanometry showed a type 'B' pattern in 467 ears and type 'C' pattern in 163 ears. Among 163 ears with type 'C' tympanogram, negative DPOAE results were seen in 96 ears. Group 4 (56/96) had a significant high rate of middle ear effusion than Group 3 (14/67) (p < .05). In patients with a type 'C' tympanogram, those with a low compliance value (~0.25 ml), concurrent chronic tonsillitis and large tonsils are likely to have middle ear effusion. CONCLUSIONS: DPOAE could be a great help in screening for middle ear effusion in patients with a type 'C' tympanogram. PMID- 29504816 TI - Guided Bone Regeneration of Femoral Segmental Defects using Equine Bone Graft: An In-Vivo Micro-Computed Tomographic Study in Rats. AB - BACKGROUND AND OBJECTIVES: Guided bone regeneration (GBR) is commonly used for osseous defect reconstruction. The objective of this study was to evaluate in real-time (in-vivo) the efficacy of equine bone graft for GBR in segmental critical-size defects (CSD) of the femur in a rat model. MATERIALS AND METHODS: Following ethical approval, 30 male Wistar-Albino rats (age 12-14 months/weight 450-500 grams) were included. Under general-anesthesia, a mid-diaphyseal segmental CSD (5 mm) was created in the femur and stabilized using titanium Miniplate(4 holes,1.0 mm thickness). Depending upon material used for GBR, animals were randomly divided into three groups(n = 10/per group). Negative control-Defect covered with resorbable collagen membrane(RCM); Positive control Defect filled with autologous bone and covered by RCM; Equine bone-Defect filled with equine bone and covered by RCM. Real-time in-vivo Micro-CT was performed at baseline, 2, 4, 6 and 8 weeks to determine volume and mineral density of newly formed bone (NFB) and remaining bone graft particles (BGP). RESULTS: In-vivo micro-CT revealed increase in volume and mineral density of NFB within defects from baseline to 8-weeks in all groups. At 8-weeks NFB-volume in the equine bone group(53.24 +/- 13.83 mm3; p < 0.01) was significantly higher than the negative control(5.6 +/- 1.06 mm3) and positive control(26.07 +/- 5.44 mm3) groups. Similarly, NFB-mineral density in the equine bone group(3.33 +/- 0.48 g/mm3; p < 0.01) was higher than the other (negative control-0.27 +/- 0.02 g/mm3; positive control-2.55 +/- 0.6 g/mm3). A gradual decrease in the BGP-volume and BGP-mineral density was observed. CONCLUSION: The use of equine bone for GBR in femoral segmental defects in rats, results in predictable new bone formation as early as 2-weeks after bone graft placement. PMID- 29504817 TI - Dysregulation of cell cycle in animal models and human neuroendocrine pituitary tumors (PitNET). PMID- 29504818 TI - Patient-reported symptoms and changes up to 1 year after meniscal surgery. AB - Background and purpose - Detailed information on the symptoms and limitations that patients with meniscal tears experience is lacking. This study was undertaken to map the most prevalent self-reported symptoms and functional limitations among patients undergoing arthroscopic meniscal surgery and investigate which symptoms and limitations had improved most at 1 year after surgery. Patients and methods - Patients aged 18-76 years from the Knee Arthroscopy Cohort Southern Denmark (KACS) undergoing arthroscopic meniscal surgery were included in this analysis of individual subscale items from the Knee Injury and Osteoarthritis Outcome Score and 1 question on knee stability. Severity of each item was scored as none, mild, moderate, severe, or extreme. Improvements were evaluated using Wilcoxon's signed-rank test and effect size (ES). Results - The most common symptoms were knee grinding and clicking, knee pain in general, pain when twisting and bending the knee and climbing stairs (88 98%), while the most common functional limitations were difficulty bending to the floor, squatting, twisting, kneeling, and knee awareness (97-99%). Knee pain in general and knee awareness improved most 1 year after meniscal surgery (ES -0.47 and -0.45; p < 0.001), while knee instability and general knee difficulties improved least (ES 0.10 and -0.08; p < 0.006). Interpretation - Adults undergoing surgery for a meniscal tear commonly report clinical symptoms and functional limitations related to their daily activities. Moderate improvements were observed in some symptoms and functional limitations and small to no improvement in others at 1 year after surgery. These findings can assist the clinical discussion of symptoms, treatments, and patients' expectations. PMID- 29504820 TI - Three-step Reduction Therapy of Integrated Chinese and Western Medicine for Thoracolumbar Burst Fracture. AB - OBJECTIVE: To investigate and compare the efficacy of three-step reduction (TSR) therapy of integrated Chinese and Western Medicine and posterior open (PO) surgery for thoracolumbar burst fracture. METHODS: We selected 60 patients diagnosed with thoracolumbar burst fracture and received treatment in our hospital from December 2014 to March 2017. According to randomized digital table, they were randomly divided into TSR and PO groups. VAS pain grade, Oswestry disability index, height of centrum front, Cobb's angle of spine, bleeding, and complication of internal fixation of the two groups were compared. RESULTS: Postoperative reduction of injured centrum, regained volume of canalis vertebralis, volume of bleeding, and early functional rehabilitation of TSR group were better than that of PO groups (P < 0.05). CONCLUSION: Through three-step reduction combined pedicle screw fixation surgery, we can achieve satisfied reduction of thoracolumbar burst fracture, rebuild the height of centrum, recover the biomechanics function of spine, and reduce bleeding. Three-step reduction therapy is an effective therapy for thoracolumbar burst fracture. PMID- 29504819 TI - Effects of miR-144 on the sensitivity of human anaplastic thyroid carcinoma cells to cisplatin by autophagy regulation. AB - BACKGROUND: We investigated the influence of miR-144 on the cisplatin-sensitivity of anaplastic thyroid carcinoma (ATC) cells and explored the internal molecular mechanism of miR-144. METHODS: Thyroid cancer cells ARO, TPC1 and normal thyroid cells HT-ori3 were used in this research. Expressions of miR-144 and TGF-alpha were uncovered by western blot and qRT-PCR. Expressions of autophagy-related protein LC3 II and apoptosis-related protein Caspase-3 and PARP were explored by western blot and immunofluorescence. Cell viability was detected by MTT assay and apoptosis condition was revealed by flow cytometric analysis and TUNEL staining. Dual-luciferase reporter assay was employed to verify the target relationship. Tissue sections were detected by IHC. Xenograft assay was conducted to further verify conclusions in vivo. RESULTS: MiR-144, which was low expressed in ATC cells and tissues, could inhibit autophagy activation induced by cisplatin, enhancing the sensitivity of ATC cells to cisplatin, and promoting cell apoptosis. TGF-alpha was the target of miR-144 and was negatively regulated by it. MiR-144 could improve the sensitivity of ATC cells to cisplatin and inhibit tumor growth by suppressing TGF-alpha both in vitro and in vivo. CONCLUSION: MiR 144 could inhibit autophagy of ATC cells by down-regulating TGF-alpha, enhancing the cisplatin-sensitivity of ATC cells. PMID- 29504821 TI - Users' intention to continue using social fitness-tracking apps: expectation confirmation theory and social comparison theory perspective. AB - INTRODUCTION: The key step in changing health behavior is understanding why users continue to use fitness apps. Therefore, we intend to investigate the users' intention to continue using social fitness-tracking apps. MATERIALS AND METHODS: We identify two major forces driving continuous behavior. Expectation confirmation is the internal driving force and social comparison is the external driving force. A survey was conducted to test this proposed research model. We obtained 211 valid questionnaires. RESULTS: Our results indicate that activity amount ranking (p < 0.001) and activity frequency ranking (p < 0.001) positively affect confirmation and that confirmation (p < 0.001) also positively affects the continuous intention of individuals using fitness-tracking apps. In addition, the impact of activity amount ranking and activity frequency ranking on continuous intention is moderated by expectation confirmation. Meanwhile, as the upward comparison tendency increases, the positive effect of confirmation on continuous intention decreases (p < 0.001). CONCLUSIONS: Social rank expectation and confirmation are the primary driving forces of continuous intention in individuals using fitness-tracking apps. Social rank is a meaningful and straightforward measurement individuals can use to evaluate their activity performance. An upward comparison tendency weakens the effect of confirmation on continuous intention. PMID- 29504822 TI - Family-centered services for children with complex communication needs: the practices and beliefs of school-based speech-language pathologists. AB - This study used an online focus group to examine the beliefs and practices of school-based speech-language pathologists (SLPs) who served children with complex communication needs regarding their provision of family-centered services. Participants revealed that despite their desire for family involvement and reported beliefs in the importance of family-centered services, there were barriers in place that often limited family-centered service provision. Across the SLPs, many were dissatisfied with their current provision of family-centered services. The SLPs varied in their reported practices, with some reporting family centered services and others, professional-centered services. Future research is recommended in order to investigate which factors contribute to the variation among SLPs and how the variation impacts children who require augmentative and alternative communication (AAC) and their families. Potential clinical implications for in-service and pre-service SLPs are discussed to improve future family-centered AAC services. PMID- 29504823 TI - A cohort study comparing 4 mg and 10 mg daily doses of postoperative oestradiol therapy to prevent adhesion reformation after hysteroscopic adhesiolysis. AB - This is a retrospective cohort study conducted in a national training centre for hysteroscopy between January 2012 and December 2014 to compare the clinical outcome of two doses of oestradiol valerate (4 mg and 10 mg daily) in the prevention of recurrence of adhesions after hysteroscopic adhesiolysis. A total of 176 women who suffered from Asherman syndrome with moderate to severe intrauterine adhesions were included: 91 subjects received a 10 mg daily dose of oestradiol and 85 subjects received a 4 mg daily dose of oestradiol in the postoperative period. Second look hysteroscopy was performed 4-6 weeks after the initial surgery. There was no difference in age and preoperative American Fertility Society (AFS) adhesion score between the two groups. The proportion of women in whom menstruation had returned to normal in the 10 mg group (49/91 = 53.8%) was significantly (p < 0.05) higher than that of subjects in the 4 mg group (35/85 = 41.2%). However, there was no difference in AFS scores at second look hysteroscopy between the two groups or in the conception rate and miscarriage rate between the two groups. The findings do not support the use of high-dose postoperative oestrogen therapy following hysteroscopic adhesiolysis. PMID- 29504824 TI - Projections of primary hip arthroplasty in Germany until 2040. AB - Background and purpose - The number of hip replacements in Germany has increased considerably during the last 2 decades but lately levelled off with no significant increase in operation rates. We analyzed the future trend of hip arthroplasty and projected the number of primary hip replacements that will be performed in Germany until 2040. Patients and methods - We used prevalence data of hip arthroplasty patients from 2010 to 2016 from the nationwide inpatient statistics and population forecasts from the German Federal Bureau of Statistics up to the year 2040. We used Poisson regression to estimate the expected annual number of arthroplasty surgeries with calendar year and patient age as covariates to account for differences among age groups and changes over time. Results - The number of primary hip replacements performed in Germany in 2040 was estimated to grow by 27% to 288 x 103 (95% CI 250 x 103-332 x 103) from 2010. Projected counts were highest for patients aged 60 to 70 years. The estimated incidence rate was projected to 360 (95% CI 312-414) per 100,000 residents. However, incidence rates for individual age classes were found to be constant with a slight decrease over time for individual age classes. Interpretation - Our findings suggest a growth in the total hip arthroplasty count whereas incidence rate remained constant over age classes. We consider the future demographic change to an older population as well as the increasing life expectancy to be the main reasons for the increasing patient numbers rather than a general increase in the operation frequency. PMID- 29504825 TI - Prevalence of microorganisms associated with feline gingivostomatitis. AB - Objectives Feline gingivostomatitis (FGS) is a painful chronic inflammatory disease of the oral cavity. The purpose of the study was to examine the frequency of detection of certain common feline bacteria and viruses to determine any potential associations with FGS. Methods A multicentre case-control study design was conducted. In total, 72 control cats and 32 cats with FGS were included in the study. Oral swabs were cultured for bacterial identification and a PCR assay was carried out to examine the infection of feline calicivirus (FCV), feline herpesvirus-1 (FHV-1), Chlamydia felis, Mycoplasma felis and Bordetella bronchiseptica. Results There was a significant difference in age distribution between the control and the FGS group. Based on a PCR assay, the positive rate of FCV was significantly higher in FGS cats than control animals. For other infectious pathogens, including FHV-1, C felis and M felis, there was no significant difference. Bacterial culture of oral swabs revealed that Pasteurella multocida was most frequently detected, but the detection rate was significantly lower in FGS cats. In FGS cats, the incidence of Enterococcus faecalis and anaerobic bacteria were more frequently isolated than in control cats. Conclusions and relevance This study indicates that the positive rate of FCV was significantly higher in cats with FGS, and the microflora of the oral cavity of cats with FGS might be disrupted, although additional studies are required to compare the oral microbiome in cats of a variety of ages. PMID- 29504826 TI - A response adaptive design for ordinal categorical responses. AB - A two treatment response adaptive design is developed for phase III clinical trials with ordinal categorical treatment outcome using Goodman-Kruskal measure of association. Properties of the proposed design are studied both empirically and theoretically and the acceptability is further illustrated using two real data-sets; one from a clinical trial with trauma patients and the other from a trial with patients having rheumatoid arthritis. PMID- 29504827 TI - Flavonoid metabolism: the interaction of metabolites and gut microbiota. AB - Several dietary flavonoids exhibit anti-oxidative, anti-inflammatory, and anti osteoporotic activities relevant to prevention of chronic diseases, including lifestyle-related diseases. Dietary flavonoids (glycoside forms) are enzymatically hydrolyzed and absorbed in the intestine, and are conjugated to their glucuronide/sulfate forms by phase II enzymes in epithelial cells and the liver. The intestinal microbiota plays an important role in the metabolism of flavonoids found in foods. Some specific products of bacterial transformation, such as ring-fission products and reduced metabolites, exhibit enhanced properties. Studies on the metabolism of flavonoids by the intestinal microbiota are crucial for understanding the role of these compounds and their impact on our health. This review focused on the metabolic pathways, bioavailability, and physiological role of flavonoids, especially metabolites of quercetin and isoflavone produced by the intestinal microbiota. PMID- 29504828 TI - Assessment of the efficacy of a local steroid rescue treatment administered 2 days after a moderate noise-induced trauma in guinea pig. AB - OBJECTIVES: Intratympanic injection of corticosteroids membrane after noise induced hearing loss is an accepted alternative to general administration. We investigated the effect on hearing of a hyaluronic acid gel with liposomes loaded with dexamethasone (DexP) administered into the middle ear. METHODS: An acute acoustic trauma was performed to 13 guinea pigs for a period of 1 h on Day -2. Two 2 days after the noise trauma, the animals were then assigned randomly to four experimental groups: control without gel, gel injection, gel-containing free DexP, gel-containing DexP loaded into liposomes. Auditory thresholds were measured with Auditory Brainstem Response before Day -2 and at Day 0, Day 7 and Day 30 after noise trauma. RESULTS: Seven days after, a complete hearing recovery was observed in the control group at all frequencies apart from 8 kHz, and no recovery was observed in the three groups receiving a gel injection. Thirty days after trauma, all of the animals had recovered normal hearing, apart from at the 8-kHz frequency, with similar auditory thresholds. CONCLUSIONS: Local DexP administration 48 h after a mild acoustic trauma did not improve hearing recovery, even with a sustained release in a specific gel formulation designed for inner ear therapy. PMID- 29504829 TI - Discovery of a new metal and NAD+-dependent formate dehydrogenase from Clostridium ljungdahlii. AB - Over the next decades, with the growing concern of rising atmospheric carbon dioxide (CO2) levels, the importance of investigating new approaches for its reduction becomes crucial. Reclamation of CO2 for conversion into biofuels represents an alternative and attractive production method that has been studied in recent years, now with enzymatic methods gaining more attention. Formate dehydrogenases (FDHs) are NAD(P)H-dependent oxidoreductases that catalyze the conversion of formate into CO2 and have been extensively used for cofactor recycling in chemoenzymatic processes. A new FDH from Clostridium ljungdahlii (ClFDH) has been recently shown to possess activity in the reverse reaction: the mineralization of CO2 into formate. In this study, we show the successful homologous expression of ClFDH in Escherichia coli. Biochemical and kinetic characterization of the enzyme revealed that this homologue also demonstrates activity toward CO2 reduction. Structural analysis of the enzyme through homology modeling is also presented. PMID- 29504830 TI - Preliminary Study: Impact of Strabismus and Surgery on Eye Movements When Children are Reading. AB - AIM: To evaluate differences in eye movements during reading in strabismic children and in non-strabismic age-matched children, and to evaluate the potential effect of strabismus surgery on eye movement performance. METHODS: The eye movements of nine strabismic children from 11 to 15 years old were recorded with an eye tracker as they were reading a text under three visual conditions before and six months after eye surgery. The results were compared with those obtained from control groups of non-strabismic age-matched children. Eye movements were recorded during reading a text with both eyes open and under monocular vision with the dominant and non-dominant eye alternately covered. RESULTS: The duration of fixation was longer in strabismic children than in age matched non-strabismic children. Children read faster under dominant eye open condition than under both eyes open condition. Surgery allowed an increase of reading speed and decrease of fixation duration. The number of backward saccades significantly decreased after surgery. CONCLUSION: In strabismic children, eye movements during reading are impaired. The reduction of the squint allowed a better word comprehension. PMID- 29504831 TI - Floristic surveys of hydrocarbon-polluted sites in some Cameroonian cities (Central Africa). AB - Soils pollution with hydrocarbons is on the increase, especially in developing countries like Cameroon. Identifying plant species capable of growing on hydrocarbon-polluted soils remains an essential step in phytoremediation, a low cost, solar energy driven clean up technique in which living green plants are used. Here, we report floristic surveys conducted in 4 cities of Cameroon to identify plants with phytoremediation capacities. A total of 13 hydrocarbon polluted sites were surveyed in each city using the quadrat method. Unpolluted sites served as the control. 106 species belonging to 76 genera and 30 families were identified on hydrocarbon-polluted sites. Plant diversity was shown to be higher (166 species contained in 125 genera and 50 families) in the control sites. Poaceae, Cyperaceae, Asteraceae and Amaranthaceae families have a higher taxonomic richness on polluted sites (16, 15, 10 and 8 taxa respectively). Shannon diversity index of the hydrocarbon-polluted sites (1.6 to 2.7 bits/ind.) were significantly lower than the control sites (2.7 to 3.2 bit/ind.). Based on a relative frequency > 10% and abundance > 7%, our results show that more than 15 plant species could be tested in preliminary trials to determine their phytoremediation/cleaning-up capacities on hydrocarbon-polluted soils in the tropics. PMID- 29504832 TI - Corrigendum. PMID- 29504833 TI - Erratum. PMID- 29504835 TI - The relationship of age-adjusted Charlson comorbidity index and diurnal variation of blood pressure. AB - BACKGROUNDS: Charlson Comorbidity index (CCI) is a scoring system to predict prognosis and mortality. It exhibits better utility when combined with age, age adjusted Charlson Comorbidity Index (ACCI). The aim of this study was to evaluate the relationship between ACCI and diurnal variation of blood pressure parameters in hypertensive patients and normotensive patients. METHODS: We enrolled 236 patients. All patients underwent a 24-h ambulatory blood pressure monitoring (ABPM) for evaluation of dipper or non-dipper pattern. We searched the correlation between ACCI and dipper or non-dipper pattern and other ABPM parameters. To further investigate the role of these parameters in predicting survival, a multivariate analysis using the Cox proportional hazard model was performed. RESULTS: 167 patients were in the hypertensive group (87 patients in non-dipper status) and 69 patients were in the normotensive group (41 patients in non-dipper status) of all study patients. We found a significant difference and negative correlation between AACI and 24-h diastolic blood pressure (DBP), awake DBP, awake mean blood pressure (MBP) and 24-h MBP and awake systolic blood pressure(SBP). Night decrease ratio of blood pressure had also a negative correlation with ACCI (p = 0.003, r = -0.233). However, we found a relationship with non-dipper pattern and ACCI in the hypertensive patients (p = 0.050). In multivariate Cox analysis sleep MBP was found related to mortality like ACCI (p = 0.023, HR = 1.086, %95 CI 1.012-1.165) Conclusion: ACCI was statistically significantly higher in non-dipper hypertensive patients than dipper hypertensive patients while ACCI had a negative correlation with blood pressure. Sleep MBP may predict mortality. PMID- 29504834 TI - Circulating Tumor DNA Analysis in Patients With Cancer: American Society of Clinical Oncology and College of American Pathologists Joint Review. AB - PURPOSE.-: Clinical use of analytical tests to assess genomic variants in circulating tumor DNA (ctDNA) is increasing. This joint review from the American Society of Clinical Oncology and the College of American Pathologists summarizes current information about clinical ctDNA assays and provides a framework for future research. METHODS.-: An Expert Panel conducted a literature review on the use of ctDNA assays for solid tumors, including preanalytical variables, analytical validity, interpretation and reporting, and clinical validity and utility. RESULTS.-: The literature search identified 1338 references. Of those, 390, plus 31 references supplied by the Expert Panel, were selected for full-text review. There were 77 articles selected for inclusion. CONCLUSIONS.-: The evidence indicates that testing for ctDNA is optimally performed on plasma collected in cell stabilization or EDTA tubes, with EDTA tubes processed within 6 hours of collection. Some ctDNA assays have demonstrated clinical validity and utility with certain types of advanced cancer; however, there is insufficient evidence of clinical validity and utility for the majority of ctDNA assays in advanced cancer. Evidence shows discordance between the results of ctDNA assays and genotyping tumor specimens, and supports tumor tissue genotyping to confirm undetected results from ctDNA tests. There is no evidence of clinical utility and little evidence of clinical validity of ctDNA assays in early-stage cancer, treatment monitoring, or residual disease detection. There is no evidence of clinical validity or clinical utility to suggest that ctDNA assays are useful for cancer screening, outside of a clinical trial. Given the rapid pace of research, reevaluation of the literature will shortly be required, along with the development of tools and guidance for clinical practice. PMID- 29504836 TI - Changes in physiological and performance variables in non-professional triathletes after taking part in an Olympic distance triathlon. AB - Given increasing popularity of triathlon, the objective of this study was to evaluate the acute effects upon the health of triathletes. To do so, with a sample of 23 male athletes (34.4 +/- 7.9 years old), an assessment was carried out both before and after an Olympic distance triathlon, of the bodily composition, the jumping ability and the BORG and VAS scales, as well as a blood analysis of the following: Lactate (mmol/L), Hematrocrit (%), Glucose (mg/dL), Total proteins (mg/dL), Triglycerides (mg/dL), Bilirubin (mg/dL), GOT (IU/L), GPT (IU/L), LDH (IU/L), CPK (IU/L). The results showed an increase (p < 0.001) in the different markers of metabolic stress and muscular damage following the triathlon, but always within a normal range considered to be healthy, with the exception of CPK (IU/L) (PRE 149.33 +/- 108.16 vs POST 290.10 +/- 102.48). Therefore, it would seem that competing in an Olympic-distance triathlon does not pose health risks for trained subjects. PMID- 29504838 TI - User-centered design of a mobile medication management. AB - BACKGROUND: The use of a nationwide medication plan has been promoted as an effective strategy to improve patient safety in Germany. However, the medication plan only exists as a paper-based version, which is related to several problems, that could be circumvented by an electronic alternative. OBJECTIVE: The main objective of this study was to report on the development of a mobile interface concept to support the management of medication information. METHODS: The human centered design (UCD) process was chosen. First the context of use was analyzed, and personas and an interaction concept were designed. Next, a paper prototype was developed and evaluated by experts. Based on those results, a medium-fidelity prototype was created and assessed by seven end-users who performed a thinking aloud test in combination with a questionnaire based on the System Usability Scale (SUS). RESULTS: Initially for one persona/user type, an interface design concept was developed, which received an average SUS-Score of 92.1 in the user test. Usability problems have been solved so that the design concept could be fixed for a future implementation. Contribution: The approach of the UCD process and the methods involved can be applied by other researchers as a framework for the development of similar applications. PMID- 29504837 TI - Information, communication, and online tool needs of Hispanic family caregivers of individuals with Alzheimer's disease and related dementias. AB - PURPOSE: To identify the information and communication needs of Hispanic family caregivers for individuals with Alzheimer's Disease and Related Dementias (ADRD) and the manner in which online tools may meet those needs. METHODS: We conducted 11 participatory design sessions with 10 English- and 14 Spanish-speaking urban dwelling Hispanic family caregivers and gathered data using a survey, collage assemblage, and audio and video recordings. Four investigators analyzed transcripts of audio recordings with a coding framework informed by several conceptual models. RESULTS: Participants had an average age of 59.7 years, were mostly female (79.2%), and had cared for a family member with ADRD for an average of 6.5 years. All participants accessed the Internet at least once a week with 75% >= daily. Most used the Internet to look up health information. All participants reported caregiver attributes including awareness of the disease symptoms or behaviors. The majority reported information needs/tasks (91.7%), communication needs/tasks (87.5%), and need for online tools (79.2%). CONCLUSION: Hispanic caregivers of individuals with ADRD reported key information and communication needs/tasks. Only Spanish-speaking participants reported Internet and technology use deficits suggesting the requirement for further technology support. Data show a need for online tools to meet the needs of caregivers. PMID- 29504839 TI - Participatory design of healthcare technology with children. AB - Purpose There are many frameworks and methods for involving children in design research. Human-Computer Interaction provides rich methods for involving children when designing technologies. The paper aims to discuss these issues. Design/methodology/approach This paper examines various approaches to involving children in design, considering whether users view children as study objects or active participants. Findings The BRIDGE method is a sociocultural approach to product design that views children as active participants, enabling them to contribute to the design process as competent and resourceful partners. An example is provided, in which BRIDGE was successfully applied to developing upper limb prostheses with children. Originality/value Approaching design in this way can provide children with opportunities to develop social, academic and design skills and to develop autonomy. PMID- 29504840 TI - Residents' educational attainment and preventive care utilization in China. AB - Purpose China launched a comprehensive health reform in 2009 to improve healthcare quality. Because preventive care utilization in China has not been frequently discussed, the purpose of this paper is to focus on the association between education level and preventive care before and after the initiation of the reform. Education has been referred to as the best health outcome indicator and China's educational reform has been progressive, such as the health reform. Design/methodology/approach The authors analyzed data from four China Health and Nutrition Surveys (CHNS): 2004 ( n=9,617); 2006 ( n=9,527); 2009 ( n=9,873); and 2011 ( n=9,430). Variables were selected based on Andersen's healthcare utilization model (predisposing, enabling and need factors). Multivariable logistic regression models, odds ratios (ORs) and 95 percent confidence intervals (95 percent CI) were conducted and reported. Findings In the adjusted multivariable logistic regression models, the authors found that general education was associated ( p<0.05) with access to preventive care in 2004, 2009 and 2011, but not in 2006. Individuals with higher education had higher ORs for utilizing preventive care, compared with lower education (primary school education or none). Practical implications Policy implications include providing educational protocols regarding preventive care's significance to residents educated at lower level schools, especially younger individuals. Originality/value To the authors' knowledge, this is the first comparative assessment on education level and preventive care utilization before and after the implementation of the Chinese health reform. PMID- 29504841 TI - Patient-perceived hospital service quality: an empirical assessment. AB - Purpose The purpose of this paper is to appraise Pai and Chary's (2016) conceptual framework for measuring patient-perceived hospital service quality (HSQ). Design/methodology/approach A structured questionnaire was used to obtain data from teaching, public and corporate hospital patients. Several tests were conducted to assess the instrument's reliability and validity. Pai and Chary's (2016) nine dimensions for measuring HSQ were examined in this paper. Findings The tests confirm that Pai and Chary's (2016) conceptual framework is reliable and valid. The study also establishes that the nine dimensions measure HSQ. Practical implications The framework empowers managers to assess service quality in any hospital settings, corporate, public and teaching, using an approach that is superior to the existing HSQ scales. Originality/value This paper helps researchers and practitioners to assess HSQ from patient perspectives in any hospital setting. PMID- 29504842 TI - Fall prevention strategy in an emergency department. AB - Purpose The purpose of this paper is to document the need for implementing a fall prevention strategy in an emergency department (ED). The paper also spells out the research process that led to approving an assessment tool for use in hospital outpatient services. Design/methodology/approach The fall risk assessment tool was based on the Morse Fall Scale. Gender mix and age above 65 and 80 years were assessed on six risk assessment variables using chi2 analyses. A logistic regression analysis and model were used to test predictor strength and relationships among variables. Findings In total, 5,371 (56.5 percent) geriatric outpatients were deemed to be at fall risk during the study. Women have a higher falls incidence in young and old age categories. Being on medications for patients above 80 years exposed both genders to equal fall risks. Regression analysis explained 73-98 percent of the variance in the six-variable tool. Originality/value Canadian quality and safe healthcare accreditation standards require that hospital staff develop and adhere to fall prevention policies. Anticipated physiological falls can be prevented by healthcare interventions, particularly with older people known to bear higher risk factors. An aging population is increasing healthcare volumes and medical challenges. Precautionary measures for patients with a vulnerable cognitive and physical status are essential for quality care. PMID- 29504843 TI - Factors influencing early stage healthcare-academia partnerships. AB - Purpose The purpose of this paper is to explore factors influencing early implementation and intermediate outcomes of a healthcare-academia partnership in a primary healthcare setting. Design/methodology/approach The Academic Primary Healthcare Network (APHN) initiative was launched in 2011 in Stockholm County, Sweden and included 201 primary healthcare centres. Semi-structured interviews were conducted in 2013-2014 with all coordinating managers ( n=8) and coordinators ( n=4). A strategic change model framework was used to collect and analyse data. Findings Several factors were identified to aid early implementation: assignment and guidelines that allowed flexibility; supportive management; dedicated staff; facilities that enabled APHN actions to be integrated into healthcare practice; and positive experiences from research and educational activities. Implementation was hindered by: discrepancies between objectives and resources; underspecified guidelines that trigger passivity; limited research and educational activities; a conflicting non-supportive reimbursement system; limited planning; and organisational fragmentation. Intermediate outcomes revealed that various actions, informed by the APHN assignment, were launched in all APHNs. Practical implications The findings can be rendered applicable by preparing stakeholders in healthcare services to optimise early implementation of healthcare-academia partnerships. Originality/value This study increases understanding of interactions between factors that influence early stage partnerships between healthcare services and academia in primary healthcare settings. PMID- 29504844 TI - Socio-economic inequalities in health services utilization: a cross-sectional study. AB - Purpose Developing country workers mainly face important challenges when examining equality in health services utilization among the population and identifying influential factors. The purpose of this paper us to: understand health service use among households with different socio-economic status in Isfahan province; and to investigate probable inequality determinants in service utilization. Design/methodology/approach Almost 1,040 households living in Isfahan province participated in this cross-sectional study in 2013. Data were collected by a questionnaire with three sections: demographic characteristics; socio-economic status; and health services utilization. The concentration index was applied to measure inequality. Analysts used STATA 11. Findings Economic status, educational level, insurance coverage and household gender were the most influential factors on health services utilization. Those with a high socio economic level were more likely to demand and use such services; although self medication patterns showed an opposite trend. Practical implications Female headed families face with more difficulties in access to basic human needs including health. Supportive policies are needed to meet their demands. Originality/value The authors used principle component analysis to assess households' economic situation, which reduced the variables into a single index. PMID- 29504845 TI - Context-based patient choice management in healthcare. AB - Purpose In healthcare, there is limited knowledge of and experience with patient choice management. The purpose of this paper is to focus on patient choice, apply and test demand-supply-based operating (DSO) logic integrated with clinical setting in clarifying choice contexts, investigate patient's choice-making at different contexts and suggest context-based choice architectures to manage and develop patient choice. Design/methodology/approach Prenatal screening and testing in the Helsinki and Uusimaa Hospital District (HUS), Finland, was taken as an example. Choice points were contextualized by using the DSO framework. Women's reflections, behaviors and experience at different choice contexts were studied by interviewing women participating in prenatal screening and testing. Semi-structured interview data were processed by thematic analysis. Findings By applying DSO logic, four choice contexts (prevention, cure, electives and continuous care) were relevant in the prenatal screening and testing episode. Women had different choice-making in prevention and cure mode contexts regarding choice activeness, information needs, social influence, preferences, emotion status and choice-making difficulty. Default choice was widely accepted by women in prevention mode and individual counseling can help women make informed choice in cure mode. Originality/value The authors apply the DSO model to contextualize the patient choice in one care episode and compare patient choice-making at different contexts. The authors also suggest the possible context-based choice architectures to manage and promote patient choice. PMID- 29504846 TI - Communicating medication risk to cardiovascular patients in Qatar. AB - Purpose Patient safety is gaining prominence in health professional curricula. Patient safety must be complemented by teaching and skill development in practice settings. The purpose of this paper is to explore how experienced pharmacists identify, prioritize and communicate adverse drug effects to patients. Design/methodology/approach A focus group discussion was conducted with cardiology pharmacy specialists working in a Doha hospital, Qatar. The topic guide sought to explore participants' views, experiences and approaches to educating patients regarding specific cardiovascular therapy safety and tolerability. Discussions were audio-recorded and transcribed verbatim. Data were coded and organized around identified themes and sub-themes. Working theories were developed by the three authors based on relevant topic characteristics associated with the means in which pharmacists prioritize and choose adverse effect information to communicate to patients. Findings Nine pharmacists participated in the discussion. The specific adverse effects prioritized were consistent with the reported highest prevalence. Concepts and connections to three main themes described how pharmacists further tailored patient counseling: potential adverse effects and their perceived importance; patient encounter; and cultural factors. Pharmacists relied on initial patient dialogue to judge an individual's needs and capabilities to digest safety information, and drew heavily upon experience with other counseling encounters to further prioritize this information, processes dependent upon development and accessing exemplar cases. Originality/value The findings underscore practical experience as a critical instructional element of undergraduate health professional patient safety curricula and for developing associated clinical reasoning. PMID- 29504847 TI - Circulating Tumor DNA Analysis in Patients With Cancer: American Society of Clinical Oncology and College of American Pathologists Joint Review. AB - Purpose Clinical use of analytical tests to assess genomic variants in circulating tumor DNA (ctDNA) is increasing. This joint review from ASCO and the College of American Pathologists summarizes current information about clinical ctDNA assays and provides a framework for future research. Methods An Expert Panel conducted a literature review on the use of ctDNA assays for solid tumors, including pre-analytical variables, analytical validity, interpretation and reporting, and clinical validity and utility. Results The literature search identified 1,338 references. Of those, 390, plus 31 references supplied by the Expert Panel, were selected for full-text review. There were 77 articles selected for inclusion. Conclusion The evidence indicates that testing for ctDNA is optimally performed on plasma collected in cell stabilization or EDTA tubes, with EDTA tubes processed within 6 hours of collection. Some ctDNA assays have demonstrated clinical validity and utility with certain types of advanced cancer; however, there is insufficient evidence of clinical validity and utility for the majority of ctDNA assays in advanced cancer. Evidence shows discordance between the results of ctDNA assays and genotyping tumor specimens and supports tumor tissue genotyping to confirm undetected results from ctDNA tests. There is no evidence of clinical utility and little evidence of clinical validity of ctDNA assays in early-stage cancer, treatment monitoring, or residual disease detection. There is no evidence of clinical validity and clinical utility to suggest that ctDNA assays are useful for cancer screening, outside of a clinical trial. Given the rapid pace of research, re-evaluation of the literature will shortly be required, along with the development of tools and guidance for clinical practice.